PMID- 10634380
TI  - Cardiac function, physical exercise capacity, and quality of life during long
      term thyrotropin-suppressive therapy with levothyroxine: effect of individual
      dose tailoring.
AB  - As recently claimed, TSH-suppressive therapy with L-T4 may have adverse effects
      on the heart, but these results have not been consistently confirmed. We assessed
      cardiac function by clinical, echocardiographic, and ergometabolic criteria in 19
      patients (16 women and 3 men) receiving long term L-T4 at a fixed daily dose
      ranging from 1.8-4.0 microg/kg. The results showed significant alterations in
      several cardiac parameters suggestive of subclinical hyperthyroidism. In
      particular, intraventricular septum thickness (10.0+/-1.4 vs. 8.1+/-1.1 mm), left
      ventricular posterior wall thickness (9.4 1.5 vs. 8.1+/-1.1 mm), end-diastolic
      dimension (47+/-4 vs. 44+/-3 mm), and left ventricular mass index (102+/-15 vs.
      75+/-15 g/m2) were significantly increased compared to values in age- and sex
      matched euthyroid controls. Exercise tolerance (expressed as maximal tolerated
      workload; 102+/-14 vs. 117+/-12 watts), maximal VO2 achieved at peak exercise
      (maximum VO2, 17.3+/-3.3 vs. 21.9+/-2.5 mL/min x kg), and anaerobic threshold
      (expressed as a percentage of VO2max, 46.5+/-8.4 vs. 56.2+/-6.6) were
      significantly reduced in L-T4-treated patients. The L-T4 dose was then reduced to
      the minimal amount able to keep the serum TSH concentration at 0.1 mU/L or less
      in 7 patients who were reevaluated 6 months after the initial study. This
      individual tailoring of the TSH-suppressive L-T4 dose was in all cases associated
      with normalization of all echocardiographic and ergometabolic parameters. In
      conclusion, our findings show that abnormalities of heart morphology associated
      with impaired exercise performance occur as a consequence of long term therapy
      with fixed TSH-suppressive doses of L-T4, but that these abnormalities improve or
      disappear after careful tailoring of TSH-suppressive therapy.

PMID- 10634381
TI  - Familial isolated hyperparathyroidism as a variant of multiple endocrine
      neoplasia type 1 in a large Danish pedigree.
AB  - We report here our genetic findings of a family in which 14 members were affected
      with isolated primary hyperparathyroidism. Hyperparathyroidism is the main
      feature of multiple endocrine neoplasia type 1 (MEN1), making the recently cloned
      MEN1 gene a prime candidate gene in this family. Significantly positive lod
      scores were achieved with D11S4946 (3.36) and D11S4940 (3.53), and by combining
      the results from these two markers, a maximum positive lod score of 4.12 at
      recombination fraction 0.00 was obtained. Mutation analysis of MEN1 performed by
      full sequencing identified a missense mutation in exon 4, causing an amino acid
      change from glutamine to proline at codon 260. This mutation (Q260P) was present
      in all affected family members, and the inheritance of the mutation was in
      complete agreement with the disease-associated haplotype. In comparison with the
      recent functional studies of the menin protein interactions, this mutation is
      located in a region with little or no binding activity to JunD and activating
      protein-1 transcription factor. We conclude that some of the familial isolated
      primary hyperparathyroidism families constitute a milder variant of MEN 1, which
      is associated with a functionally milder missense mutation.

PMID- 10634382
TI  - Pituitary tumor registry: a novel clinical resource.
AB  - Pituitary adenomas result in clinical sequelae and accelerated mortality due to
      central mass effects or pituitary hormone hypersecretion and/or insufficiency.
      The low annual incidence and prolonged natural history of these rare tumors has
      hindered efforts to evaluate long-term clinical outcomes. Care of these patients
      is often provided by larger tertiary specialist referral centers. A novel
      evidence-based computerized pituitary tumor registry was developed to
      systematically evaluate epidemiological, biochemical, and clinical outcome data.
      Retrospective registration of 371 patients [99 clinically nonfunctioning tumors
      (CNFTs), 176 acromegalics, and 96 prolactinomas] with radiological, biochemical,
      and clinical evidence of pituitary tumors was performed. Analysis of this
      primarily specialist-referred population revealed a female predominance among
      CNFT (60%) and prolactinoma (69%) patients. Males had a significantly greater
      frequency of macroadenomas than females for CNFTs (92% vs. (68%) and for
      prolactinomas (74% vs. 40%). Males with prolactinomas also had higher mean
      pretreatment serum PRL levels (1206 vs. 219 ng/mL). Concurrent hyperprolactinemia
      was present in CNFT (47%) and acromegaly (33%) patients. Radiographic cure,
      defined as absence of visualized tumor, was achieved in 21% of CNFTs, 34% of
      acromegalies, and 21% of prolactinomas. Biochemical remission, defined by
      normalization of hormonal tumor markers, was observed in 35% of acromegaly and
      39% of prolactinoma patients in the registry, thus reflecting the tertiary
      referral patterns. Nine premature deaths (patients aged < or =65 yr) occurred in
      the acromegaly subpopulation, whereas no premature deaths were encountered in
      nonacromegalic patients. In conclusion, this unique and comprehensive pituitary
      tumor registry enables identification of diagnostic and prognostic markers and
      evaluation of long-term clinical outcomes. Prospectively, this registry will
      improve therapeutic guidelines and cost-effective pituitary tumor management.

PMID- 10634383
TI  - Is diagnostic iodine-131 scanning useful after total thyroid ablation for
      differentiated thyroid cancer?
AB  - A diagnostic iodine-131 (131I) total body scan (TBS) is usually recommended 6 to
      12 months after thyroid ablation for differentiated thyroid carcinoma. Its
      usefulness was evaluated in 256 consecutive patients treated and followed up at
      the Institut Gustave Roussy for papillary (n = 200), well differentiated (n =
      27), or poorly differentiated (n = 29) follicular thyroid carcinomas. All
      patients underwent a near-total or total thyroidectomy and 131I ablation with 3.7
      GBq (100 mCi). No TBS was performed before 131I ablation. The TBS performed after
      the administration of 131I to destroy the thyroid remnants showed uptake (<2%)
      limited to the thyroid bed. A diagnostic 131I-TBS was obtained after withdrawal
      of T4 treatment, with either 74 MBq (2 mCi; n = 82) or 185 MBq (5 mCi; n = 174),
      6 to 12 months after initial treatment, with serum thyroglobulin (Tg)
      determination. No interference in the Tg assay was found in these 256 patients.
      Uptake in the thyroid bed was not detected (total ablation) in 236 patients, was
      visible but too low to be measured in 19 patients, and attained 1% in only 1
      patient. No uptake was found outside the thyroid bed. The serum Tg level, once
      thyroid hormone treatment had been withdrawn, was below 1 ng/mL in 210 patients,
      ranged from 1-10 ng/mL in 31 patients, and was above 10 ng/mL in 15 patients. A
      131I-TBS performed with 3.7 GBq in nine patients with a Tg level above 10 ng/mL,
      showed foci of uptake outside the thyroid bed in three patients; lung metastases
      were demonstrated by a CT scan in another patient, and palpable lymph node
      metastases were found in one patient. In conclusion, a diagnostic 131I-TBS with
      74-185 MBq performed 1 yr after thyroid ablation demonstrated no abnormal uptake;
      it did not correlate with results of Tg determination and only confirmed the
      completeness of thyroid ablation. The serum Tg level obtained after withdrawal of
      T4 treatment permits the selection of patients with a Tg level exceeding 10
      ng/mL, for scanning with 3.7 GBq (100 mCi).

PMID- 10634384
TI  - Cardiovascular effects of short-term growth hormone hypersecretion.
AB  - Many studies have shown that acromegaly has relevant effects on cardiovascular
      system, but few data are available regarding the effects of short-term acromegaly
      on heart morphology and function. These data would help to clarify the natural
      history of acromegalic disease and could provide new insight into the mechanisms
      of GH action on the human heart. Therefore, we studied by Doppler
      echocardiography a group of 10 young subjects strictly selected as having short
      term (<5 yr) uncomplicated acromegaly. The results of this study have shown that
      shortterm acromegaly is characterized by significantly increased left ventricular
      mass (P<0.005), with normal relative wall thickness, associated with Doppler
      indices of diastolic function in the normal range. Furthermore, stroke index and
      cardiac index were significantly enhanced in the patient group (P<0.01 and
      P<0.001, respectively), whereas systemic vascular resistance was significantly
      reduced (P<0.001). In conclusion, our study shows that short-term acromegaly
      significantly affects the heart, but, at variance with long-term disease, it is
      characterized by increased left ventricular mass, with eccentric remodeling and
      normal diastolic function. Moreover, short-term acromegaly induces a high cardiac
      output state with reduction of systemic vascular resistance.

PMID- 10634385
TI  - A paradoxical gender dissociation within the growth hormone/insulin-like growth
      factor I axis during protracted critical illness.
AB  - Female gender appears to protect against adverse outcome from prolonged critical
      illness, a condition characterized by blunted and disorderly GH secretion and
      impaired anabolism. As a sexual dimorphism in the GH secretory pattern of healthy
      humans and rodents determines gender differences in metabolism, we here compared
      GH secretion and responsiveness to GH secretagogues in male and female protracted
      critically ill patients. GH secretion was quantified by deconvolution analysis
      and approximate entropy estimates of 9-h nocturnal time series in 9 male and 9
      female patients matched for age (mean +/- SD, 67+/-11 and 67+/-15 yr), body mass
      index, severity and duration of illness, feeding, and medication. Serum
      concentrations of PRL, TSH, cortisol, and sex steroids were measured
      concomitantly. Serum levels of GH-binding protein, insulin-like growth factor I
      (IGF-I), IGF-binding proteins (IGFBPs), and PRL were compared with those of 50
      male and 50 female community-living control subjects matched for age and body
      mass index. In a second study, GH responses to GHRH (1 microg/kg), GH-releasing
      peptide-2 (GHRP-2; 1 microg/ kg) and GHRH plus GHRP-2 (1 and 1 microg/kg) were
      examined in comparable, carefully matched male (n = 15) and female (n = 15)
      patients. Despite identical mean serum GH concentrations, total GH output, GH
      half-life, and number of GH pulses, critically ill men paradoxically presented
      with less pulsatile (mean +/- SD pulsatile GH fraction, 39+/-14% vs. 67+/-20%; P
      = 0.002) and more disorderly (approximate entropy, 0.946+/-0.113 vs. 0.805+/
      0.147; P = 0.02) GH secretion than women. Serum IGF-I, IGFBP-3, and acid-labile
      subunit (ALS) levels were low in patients compared with controls, with male
      patients revealing lower IGF-I (P = 0.01) and ALS (P = 0.005) concentrations than
      female patients. Correspondingly, circulating IGF-I and ALS levels correlated
      positively with pulsatile (but not with nonpulsatile) GH secretion. Circulating
      levels of GH-binding protein and IGFBP-1, -2, and -6 were higher in patients than
      controls, without a detectable gender difference. In female patients, PRL levels
      were 3-fold higher, and TSH and cortisol tended to be higher than levels in
      males. In both genders, estrogen levels were more than 3-fold higher than normal,
      and testosterone (2.25+/-1.94 vs. 0.97+/-0.39 nmol/L; P = 0.03) and
      dehydroepiandrosterone sulfate concentrations were low. In male patients, low
      testosterone levels were related to reduced GH pulse amplitude (r = 0.91; P =
      0.0008). GH responses to GHRH were relatively low and equal in critically ill men
      and women (7.3+/-9.4 vs. 7.8+/-4.1 microg/L; P = 0.99). GH responses to GHRP-2 in
      women (93+/-38 microg/L) were supranormal and higher (P<0.0001) than those in men
      (28+/-16 microg/L). Combining GHRH with GHRP-2 nullified this gender difference
      (77+/-58 in men vs. 120+/-69 microg/L in women; P = 0.4). In conclusion, a
      paradoxical gender dissociation within the GH/ IGF-I axis is evident in
      protracted critical illness, with men showing greater loss of pulsatility and
      regularity within the GH secretory pattern than women (despite indistinguishable
      total GH output) and concomitantly lower IGF-I and ALS levels. Less endogenous
      GHRH action in severely ill men compared with women, possibly due to profound
      hypoandrogenism, accompanying loss of the putative endogenous GHRP-like ligand
      action with prolonged stress in both genders may explain these novel findings.

PMID- 10634386
TI  - Systemic hypertension and impaired glucose tolerance are independently correlated
      to the severity of the acromegalic cardiomyopathy.
AB  - Increased mortality from cardiovascular diseases has been reported in acromegaly.
      Our objective was to evaluate the impact of glucose tolerance abnormalities
      and/or systemic hypertension in further worsening the acromegalic cardiomyopathy.
      The study design was open transversal. The subjects studied were 130 consecutive
      naive acromegalic patients (74 women and 56 men; age, 17-80 yr). Interventricular
      septum (IST) and left ventricular (LV) posterior wall thickness (PWT), LV mass
      index (LVMi), maximal early to late diastolic flow velocity ratio (E/A),
      isovolumic relaxation time (IRT), and LV ejection fraction (EF) were measured by
      echocardiography. The results were analyzed in line with the presence of glucose
      tolerance abnormalities (normal in 60, impaired in 38, diabetes mellitus in 32)
      and the presence (in 46) or absence (in 84) of hypertension. Patients with
      impaired glucose tolerance and diabetes mellitus had significantly higher age (P
      = 0.01), and systolic (P = 0.01) and diastolic (P = 0.01) blood pressures and
      lower E/A (P = 0.01) and EF (P = 0.01) than those with normal glucose tolerance.
      Disease duration, circulating GH and insulin-like growth factor I (IGF-I) levels,
      IST, LVPWT, LVMi, and IRT were similar in the 3 groups. Normotensive patients had
      significantly lower age (P<0.001), LVPWT (P<0.001), IST (P = 0.003), LVMi
      (P<0.001), and IRT (P = 0.02) and significantly higher E/A (P<0.001) and EF
      (P<0.001) than hypertensive subjects. Disease duration, circulating GH, and IGF-I
      levels were similar in the 2 groups. Multiple regression analysis showed that
      systolic blood pressure was the strongest predictor of LVMi (P = 0.0004),
      followed by GH levels (P = 0.02), whereas diastolic blood pressure was the
      strongest predictor of LVEF reduction (P<0.0001), followed by glucose tolerance
      status (P = 0.02). Age was the strongest predictor of both E/A impairment
      (P<0.0001) and IRT (P = 0.01), followed by IGF-I levels (P = 0.02). Compared to
      patients with uncomplicated acromegaly, those with hypertension but without
      abnormalities of glucose tolerance had an increased prevalence of LV hypertrophy
      (75% vs. 37.2%) as well as of impaired diastolic (50% vs. 7.8%) and systolic
      function (18.7% vs. 3.9%), whereas patients with glucose tolerance abnormalities
      but without hypertension had only an increased prevalence of impaired diastolic
      (39.7%) and systolic function (31.7%). The subgroup of acromegalic patients
      suffering from hypertension and diabetes mellitus had the highest prevalence of
      LV hypertrophy (84.6%), diastolic filling abnormalities (69.2%), and impaired
      systolic function at rest (53.9%). A careful cardiac investigation should thus be
      performed in all acromegalic patients showing these complications.

PMID- 10634387
TI  - The relationship between bone turnover and body weight, serum insulin-like growth
      factor (IGF) I, and serum IGF-binding protein levels in patients with anorexia
      nervosa.
AB  - Malnutrition is one of the risk factors for bone loss in patients with anorexia
      nervosa (AN). To clarify the effects of nutritional status on bone metabolism, we
      examined the relationship between serum levels of nutritional indicators [insulin
      like growth factor I (IGF-I), IGF-binding protein-2 (IGFBP-2), and IGFBP-3] and
      markers for bone metabolism [serum osteocalcin and urinary excretion of C
      terminal telopeptide of collagen type I (CrossLaps)] in 45 AN out-patients,
      including 8 severely malnourished patients who required hospitalization and iv
      hyperalimentation (IVH). Compared to healthy subjects, serum IGF-I and IGFBP-3
      were lower, whereas IGFBP-2 was higher in out-patients who had a body mass index
      (BMI) less than 16.5 kg/m2. In these patients, urinary excretion of CrossLaps, a
      marker of bone resorption, was higher, whereas serum osteocalcin, a marker of
      bone formation, was lower than those in control subjects. All of these parameters
      were normal in patients whose BMI ranged from 16.5-18.5 kg/m2. Serum levels of
      osteocalcin correlated positively with BMI (r = 0.512; P<0.0001), IGF-I (r =
      0.558; P<0.0001), and IGFBP-3 (r = 0.369; P<0.001) in AN out-patients. In the 8
      severely malnourished AN patients, serum levels of IGF-I and osteocalcin
      significantly increased 3 and 7 days, respectively, after the start of a 5-week
      IVH therapy regimen and reached normal levels within 5 weeks, accompanied by
      still elevated urinary excretion of CrossLaps. The present study demonstrates
      that an improvement in nutritional status in AN patients during IVH therapy
      rapidly increases the serum IGF-I levels, followed by a progressive increase in
      osteocalcin, suggesting immediate start of bone formation. However, increased
      bone resorption appears to continue for at least 5 weeks.

PMID- 10634388
TI  - Short-term fasting selectively suppresses leptin pulse mass and 24-hour rhythmic
      leptin release in healthy midluteal phase women without disturbing leptin pulse
      frequency or its entropy control (pattern orderliness).
AB  - Nutritional signals strongly regulate neuroendocrine axes, such as those
      subserving release of LH, GH, and TSH, presumptively in part via the adipocyte
      derived neuroactive peptide leptin. In turn, leptin release is controlled by both
      acute (fasting) and long-term (adipose store) nutrient status. Here, we
      investigate the neuroendocrine impact of short-term (2.5-day) fasting on leptin
      release in healthy young women studied in the steroid-replete midluteal phase of
      the normal menstrual cycle. Eight women each underwent 24-h blood sampling at 10
      min intervals during a randomly ordered 2.5-day fasting vs. fed session in
      separate menstrual cycles. Pulsatile leptin release was quantified by model-free
      Cluster analysis, the orderliness of leptin patterns by the approximate entropy
      statistic, and nyctohemeral leptin rhythmicity by cosinor analysis. Mean (24-h)
      serum leptin concentrations fell by 4.6-fold during fasting; namely, from 15.2+/
      2.3 to 3.4+/-0.6 microg/L (P = 0.0007). Cluster analysis identified 13.9+/-1.1
      and 14.3+/-1.1 leptin peaks per 24 h in the fed and fasting states (P = NS), and
      unchanging leptin interpeak intervals (89+/-5.4 vs. 92+/-5.3 min). Leptin peak
      area declined by 4.2-fold (155+/-21 vs. 37+/-7 area units, P = 0.004), due to a
      reduction in incremental leptin pulse amplitude (4.4+/-0.7 vs. 1.0+/-0.13
      microg/L, P = 0.0011). The cosine amplitude and mesor (mean) of the 24-h leptin
      rhythm decreased by 4-fold, whereas the acrophase (timing of the nyctohemeral
      leptin peak) remained fixed. The approximate entropy of leptin release was
      stable, thus indicating preserved orderliness of leptin release patterns in
      fasting. Cross-correlation analysis revealed both positive (fed) and negative
      (fasting) leptin-GH relationships, but no leptin-LH correlations. In summary,
      short-term (2.5-day) fasting profoundly suppresses 24-h serum leptin
      concentrations and pulsatile leptin release in the sex steroid-sufficient
      midluteal phase of healthy women via mechanisms that selectively attenuate leptin
      pulse area and incremental amplitude. In contrast, the pulse-generating,
      nyctohemeral phase-determining, and entropy-control mechanisms that govern 24-h
      leptin release are not altered by acute nutrient restriction at this menstrual
      phase. Leptin-GH (but not leptin-LH) showed nutrient-dependent positive (fed) and
      negative (fasting) cross-correlations. Whether similar neuroendocrine mechanisms
      supervise altered leptin signaling during short-term nutrient restriction in men,
      children, or postmenopausal women is not known.

PMID- 10634389
TI  - The effects of hormone replacement therapy and raloxifene on C-reactive protein
      and homocysteine in healthy postmenopausal women: a randomized, controlled trial.
AB  - C-Reactive protein and homocysteine are independent risk factors for the
      development of cardiovascular disease. This study compared the effects of hormone
      replacement therapy (HRT) and raloxifene on serum C-reactive protein and
      homocysteine levels as markers of cardiovascular risk in healthy postmenopausal
      women. Healthy postmenopausal women (n = 390) were enrolled in a double blind,
      randomized, placebo-controlled, 6-month trial at eight out-patient sites in the
      United States. Women were randomly assigned to receive continuous combined HRT
      (0.625 mg/day conjugated equine estrogen and 2.5 mg/day medroxyprogesterone
      acetate), raloxifene (60 or 120 mg/day), or placebo for 6 months. C-Reactive
      protein and homocysteine were measured in baseline and 6-month serum samples. HRT
      increased C-reactive protein levels by 84% (P<0.001), whereas raloxifene (60 and
      120 mg/day) had no significant effect (-6% and -4%;, respectively; P>0.2).
      Raloxifene (60 and 120 mg/day) significantly lowered serum levels ofhomocysteine
      by 8% (P = 0.014) and 6% (P = 0.024), respectively, similar to the 7% (P = 0.014)
      reduction obtained with HRT. We conclude that HRT and raloxifene lower serum
      homocysteine levels to a comparable extent in postmenopausal women. Whereas
      cardiovascular risk predicted by C-reactive protein in healthy postmenopausal
      women is not influenced by raloxifene, the relationship between elevated C
      reactive protein levels with HRT and cardiovascular disease events requires
      further study.

PMID- 10634390
TI  - Low levels of estradiol are associated with vertebral fractures in older men, but
      not women: the Rancho Bernardo Study.
AB  - This longitudinal study included 288 postmenopausal women without estrogen use
      (median age, 72 yr) and 352 men (median age, 66 yr). All were community-dwelling,
      ambulatory, and Caucasian. Blood for hormone assays (total and bioavailable
      estradiol and testosterone, estrone, androstenedione, dihydrotestosterone,
      dehydroepiandrosterone, and dehydroepiandrosterone sulfate) was obtained in 1984
      1987, and vertebral fractures were diagnosed from lateral spine radiographs
      obtained in 1992-1996. At least one vertebral fracture was found in 21% of women
      and 8% of men. Among men, age-adjusted hormone levels differed by fracture status
      only for total (64.1 vs. 75.4 pmol/L, P = 0.012) and bioavailable (43.0 vs. 51.4
      pmol/L, P = 0.008) estradiol. There was a graded association between higher
      concentrations of total and bioavailable estradiol and lower fracture prevalence
      (trend P<0.01 for both hormones). Men with total testosterone levels compatible
      with hypogonadism (<7 nmol/L) were not more likely to have vertebral fractures.
      In women, none of the measured sex hormones was associated with vertebral
      fractures. There was also no increased prevalence of fractures in women with
      estradiol levels below the assay sensitivity (<11 pmol/L). These data suggest
      that estrogen plays a critical role in the skeletal health of older men and
      confirm other studies showing no association of postmenopausal endogenous
      estrogen levels with vertebral fractures in older women.

PMID- 10634391
TI  - Effects of gender on neuroendocrine and metabolic counterregulatory responses to
      exercise in normal man.
AB  - Significant, sexual dimorphisms exist in counterregulatory responses to commonly
      occurring stresses, such as hypoglycemia, fasting, and cognitive testing. The
      question of whether counterregulatory responses differ during exercise in healthy
      men and women remains controversial. The aim of this study was to determine
      whether a sexual dimorphism exists in neuroendocrine, metabolic, or
      cardiovascular responses to prolonged moderate exercise. Sixteen healthy (eight
      men and eight women) subjects matched for age (28+/-2 yr), body mass index (22+/
      1 kg/m2), nutrient intake, and spectrum of physical fitness were studied in a
      randomized fashion during 90 min of exercise on a cycle ergometer at 80% of their
      anaerobic threshold (approximately 50% VO2 max). Respiratory quotient and oxygen
      consumption relative to body weight were identical in men and women. Glycemia was
      equated (5.3+/-0.2 mmol/L) during exercise via an exogenous glucose infusion.
      Gender had significant effects on counterregulatory responses during exercise.
      Arterialized epinephrine (1.05+/-0.2 vs. 0.45+/-0.04 nmol/L), norepinephrine
      (9.2+/-1.1 vs. 5.8+/-1.1 nmol/L), and pancreatic polypeptide (52+/-6 vs. 37+/-6
      pmol/L) were significantly (P<0.01) increased in men compared to women,
      respectively. Plasma glucagon, cortisol, and GH levels responded similarly in men
      and women. Insulin values were higher at baseline in men and fell by a greater
      amount to reach similar levels during exercise compared to those in women.
      Endogenous glucose production, measured with [3-3H]glucose was similar in men and
      women. Carbohydrate oxidation was significantly increased in men relative to
      women (21.2+/-2 vs. 15.6+/-2 mg/kg fat free mass x min; P<0.05). Despite reduced
      sympathetic nervous system (SNS) drive, lipolytic responses were increased in
      women. Arterialized blood glycerol (215+/-30 vs. 140+/-20 micromol/L), beta
      hydroxybutyrate (54+/-9 vs. 25+/-10 micromol/L), and plasma nonesterified fatty
      acids (720+/-56 vs. 469+/-103 micromol/L) were significantly (P<0.01) increased
      in women. In keeping with increased SNS activity, systolic blood pressure and
      mean arterial pressure were significantly increased (P<0.01) in men. In summary,
      this study demonstrates that a significant sexual dimorphism exists in
      neuroendocrine, metabolic, and cardiovascular counterregulatory responses to
      prolonged moderate exercise in man. We conclude that during exercise, men have
      increased autonomic nervous system (epinephrine, norepinephrine, pancreatic
      polypeptide), cardiovascular (systolic, mean arterial pressure) and certain
      metabolic (carbohydrate oxidation) counterregulatory responses, but that women
      have increased lipolytic (glycerol, nonesterified fatty acids) and ketogenic
      (beta-hydroxybutyrate) responses. Women may compensate for diminished SNS
      activity during exercise by increased lipolytic responses.

PMID- 10634392
TI  - Antifracture efficacy of antiresorptive agents are related to changes in bone
      density.
AB  - There is a current debate about the extent to which antifracture efficacy of
      antiresorptive drugs are related to changes in bone mineral density (BMD). In
      vitro studies show that most of the variability in bone strength is related to
      BMD, and prospective studies have shown that low BMD is an important predictor of
      fracture risk. It seems that higher levels of bone turnover are also associated
      with increased fracture risk. Over the short term, a reduction in activation
      frequency or resorption depth would lead to fewer (and/or shallower) resorption
      sites and refilling of existing sites initially. There is also evidence that
      inhibiting resorption allows bone to respond to mechanical demands,
      preferentially thickening critical trabeculae, and this may help compensate for
      reduced connectivity. Each of these mechanisms would increase BMD and would
      disproportionately improve bone strength. Over the long term, maintaining bone
      mass and preventing loss of structural elements would result in progressively
      greater differences in BMD and fracture risk over time, relative to untreated
      women. The conceptual model predicts that both the short- and long-term
      antifracture efficacy of antiresorptive drugs will depend on the extent to which
      treatment can increase and maintain BMD. To examine this issue, we compiled data
      from clinical trials of antiresorptive agents and plotted the relative risk of
      vertebral fractures against the average change in BMD for each trial. The
      confidence intervals are large for individual trials, and there was substantial
      variability in antifracture efficacy at any given level of change in BMD.
      Overall, however, trials that reported larger increases in BMD tended to observe
      greater reductions in vertebral fracture risk. Poisson regression was used to
      quantify this relationship. The model predicts that treatments that increase
      spine BMD by 8% would reduce risk by 54%; most of the total effect of treatment
      was explained by the 8% increase in BMD (41% risk reduction). These findings are
      consistent with the short-term predictions of the conceptual model and with
      reports from randomized trials. The small but significant reductions in risk that
      were not explained by measurable changes in BMD might be related to publication
      bias, measurement errors, or limitations of current BMD technology.

PMID- 10634393
TI  - Recombinant human thyrotropin for the diagnosis and treatment of a highly
      functional metastatic struma ovarii.
AB  - The optimal treatment of metastatic thyroid cancer that produces high amounts of
      thyroid hormone has not been well defined. A 46-yr-old woman presented with a
      follicular thyroid carcinoma arising from a struma ovarii with hepatic
      metastases. After the removal of both the struma and the thyroid gland, the liver
      metastases showed evidence of a high degree of hormonogenesis. Brain, chest,
      abdomen, and bone imaging was negative for additional metastases. Because iodine
      uptake by most thyroid carcinomas is quite low in the absence of high levels of
      ambient TSH, we used recombinant human TSH (rhTSH) (Thyrogen) to achieve a
      concentration of 131I activity in the tumor high enough for a significant
      cytotoxic effect. After rhTSH administration (0.9 mg im daily for 2 consecutive
      days), a 131I diagnostic whole body scan confirmed the existence of 17 discrete
      hepatic foci of 131I uptake. To calculate the amount of 131I that would deliver
      an absorbed radiation dose that would be optimally cytotoxic to the metastases
      (>8000 rad/lesion) and not to the normal liver, we performed lesion dosimetry.
      Analysis of dosimetric data showed that 15 of 17 lesions would receive an
      adequate radiation dose following the administration of 65 mCi of 131I.
      Additionally, we performed whole body dosimetry to assure that this dose would
      not cause bone marrow toxicity. The patient was reevaluated 6 months after
      therapy; the liver metastases showed significant, but partial, response. In
      conclusion, we used the combination of rhTSH with lesional and whole body
      dosimetry for the treatment of highly functional metastases from follicular
      thyroid carcinoma arising within a struma ovarii. This strategy can be applied to
      determine a safe and effective dose of 131I for the treatment of any thyroid
      cancer metastases that produce enough TH to preclude stimulation of endogenous
      pituitary TSH secretion.

PMID- 10634394
TI  - Identification of short stature caused by SHOX defects and therapeutic effect of
      recombinant human growth hormone.
AB  - Point mutations or complete deletions of SHOX, the short-stature homeobox
      containing gene on the pseudoautosomal region of the sex chromosomes (Xp22 and
      Yp11.3), were recently reported in one family with idiopathic short stature and
      in several families with Leri-Weill syndrome (dyschondrosteosis). The missing
      SHOX is also thought to attribute to the growth failure in Turner syndrome. For
      testing the frequency of defects of SHOX in unexplained growth failure and
      recombinant human GH (rhGH) as a possible growth-promoting agent, we selected 68
      children with idiopathic short stature. These probands had heights below -2.0 SD
      score for age, normal target heights, no significant bone age retardations, no
      endocrine abnormalities, no skeletal diseases, and no other organic diseases. No
      mutations were detected by single-strand conformational polymorphism analysis of
      the PCR-amplified SHOX. The analysis of three microsatellite DNA markers of the
      pseudoautosomal region, including one located on the 5' untranslated region of
      SHOX-exon 1, identified a 15-yr-old girl who carried a mutation in the form of a
      complete SHOX deletion. This girl who had a normal karyotype presented with mild
      mesomelic shortening of the forearms and lower legs. We treated two children with
      short stature on the basis of a SHOX point mutation (C674T) with rhGH at a dose
      of 1.0 IU/kg body weight-week in accordance with the regimen used in Turner
      syndrome. During the first 12 months of treatment, these two children (5.9- and
      8.4-yr-old) showed an excellent growth spurt with a growth rate of 9.5 and 9.4
      cm/yr, respectively. Growth of the lower extremities was weaker than in the trunk
      and arms. Our data suggest that short stature due to SHOX deletions is not a rare
      entity. Growth-promoting therapy with rhGH was effective with regard to height
      gain, but a tendency to disproportionate growth was apparent. In cases of
      unexplained growth failure, especially if associated with any mild skeletal
      disproportions, genetic analysis of SHOX should be considered.

PMID- 10634395
TI  - Microsatellite instability in sporadic parathyroid adenoma.
AB  - Parathyroid adenomas are usually benign uniglandular tumors, and inactivation of
      several tumor suppressor genes, notably the MEN 1 gene, or activation of
      oncogenes have been implicated in the tumorigenesis. Genomic instability,
      indicative of the involvement of DNA mismatch repair genes, has not been
      previously described in parathyroid adenomas. A single large parathyroid adenoma
      was resected from an 8.5-yr-old Brazilian patient with no personal or family
      history of other endocrinopathies. Analysis of paired tumor-nontumor DNA using 23
      microsatellite markers, located on chromosomes 1, 10, and 11 was carried out.
      Microsatellite instability was detected in nine markers (D1S191, D1S212, D1S413,
      D1S2848, RET, D11S901, D11S903, INSR, and INT2), whereas no allelic loss was
      detected with any of the analyzed markers. Immunohistochemical analysis of
      retinoblastoma protein expression revealed low levels of expression, but no
      histopathological signs of malignancy. We conclude that in this single,
      apparently sporadic parathyroid adenoma, DNA mismatch repair genes might be
      involved in parathyroid tumorigenesis.

PMID- 10634396
TI  - Construction of gene therapy vectors targeting adrenocortical cells: enhancement
      of activity and specificity with agents modulating the cyclic adenosine 3',5'
      monophosphate pathway.
AB  - In preliminary studies we demonstrated that the CYP11B1 (11beta-hydroxylase)
      promoter could direct specific expression of a suicide gene in adrenocortical
      cancer cells, providing a potentially specific therapeutic option for
      adrenocortical cancer. In this present study we describe our attempts to enhance
      the activity of the CYP11B1 promoter while maintaining its specificity for
      adrenal cells. Using a putative enhancer element from the cholesterol side-chain
      cleavage (P450scc) gene, the activity of the CYP11B1 promoter in and its
      specificity for adrenocortical cells were enhanced. Treatment with 8-bromo-cAMP
      or forskolin resulted in further enhancement. In stably transfected Y-1 cells, in
      which the herpes simplex virus thymidine kinase (HSV-TK) gene was driven by the
      CYP11B1 promoter with the P450scc enhancer element, HSV-TK expression and
      ganciclovir sensitivity were augmented by treatment with 8-bromo-cAMP, forskolin,
      and ACTH. In summary, we report the construction of a suicide HSV-TK vector with
      preferential toxicity to adrenocortical cells. We propose that a similar strategy
      using differentiating agents may be useful in the gene therapy of tumors with
      unique differentiated properties, including those arising from other endocrine
      organs.

PMID- 10634397
TI  - High levels of matrix metalloproteinases regulate proliferation and hormone
      secretion in pituitary cells.
AB  - Beside the digestion of the extracellular matrix during tumor invasion and
      metastasis, more recently, new functions for matrix metalloproteinases (MMPs)
      have been proposed. We studied the expression and function of these enzymes in
      pituitary cells. We observed the activities of MMP-2 and MMP-9 together with
      expression of membrane-type MMP and tissue inhibitor of metalloproteinase-1 in
      all types of human pituitary adenomas. We found surprisingly high levels of MMP
      activity and low levels of tissue inhibitor of metalloproteinases, indicating a
      high level of extracellular matrix-degrading activity in pituitary adenomas. To
      examine the function of metalloproteinase activity in pituitary cells we used the
      synthetic MMP inhibitor batimastat. These studies demonstrate that MMPs secreted
      by pituitary cells can release growth factors anchored to the extracellular
      matrix that, in turn, control pituitary cell proliferation and hormone secretion.
      These results define a new additional mechanism for the control of pituitary
      hormone secretion and indicate new potential therapeutic targets for pituitary
      adenomas.

PMID- 10634398
TI  - Gonadotropins, prolactin, inhibin A, inhibin B, and activin A in human fetal
      serum from midpregnancy and term pregnancy.
AB  - Using specific enzyme-linked immunosorbent assays we measured inhibin A, inhibin
      B, and activin A in relation to LH, FSH, and PRL in normal human fetal
      midpregnancy serum obtained by in utero cord venipuncture (n = 25) and compared
      these results to those in fetal serum from term pregnancies (n = 23). We also
      tested serum from fetuses with intrauterine growth retardation (n = 6) or trisomy
      21 (n = 6). We found no measurable inhibin A, except in three midpregnancy males
      (3 of 14). Inhibin B, however, was detected in midpregnancy male fetuses (167+/
      67 pg/mL) and was higher than that in females (16+/-12 pg/mL). It was present in
      male term fetuses (125+/-32 pg/mL), but not in females. The activin A levels did
      not significantly differ between term and midpregnancy males and females. LH and
      FSH were detected in midpregnancy male fetuses (4.4+/-3.3 and 0.77+/-0.49 mIU/mL,
      respectively), with higher levels in females (33.0+/-23.2 and 54.4+/-27.7 mIU/mL,
      respectively), and were suppressed at term. PRL did not exhibit sexual
      difference, but showed a higher level at term (322.4+/-113.8 ng/mL) than at
      midpregnancy (33.0+/-26.1 ng/mL). Comparison of inhibin B with FSH levels showed
      correlation coefficients of -0.565 at midpregnancy vs. +0.445 at term. Serum from
      fetuses with intrauterine growth retardation or trisomy 21 did not show any
      different hormonal profiles. These data suggest that inhibin B is probably an
      additional factor in FSH inhibition at midpregnancy, whereas activin A is not
      associated with any change in the different studied populations. We speculate
      that inhibin A could be a method to detect maternal blood contamination in cord
      venipuncture.

PMID- 10634399
TI  - Effects of keratinocyte growth factor in the endometrium of rhesus macaques
      during the luteal-follicular transition.
AB  - We previously reported that keratinocyte growth factor (KGF) is up-regulated by
      the action of progesterone (P) in the primate endometrium, and we suggested that
      this protein is a likely mediator of P-dependent stromal-epithelial paracrine
      interactions in this tissue. At the end of the menstrual cycle, P levels fall,
      and the abundance of endometrial KGF transcripts decreases approximately 9-fold.
      In macaques, withdrawal of P induces the luteal-follicular transition (LFT),
      marked by menstrual sloughing of the functionalis zone and apoptotic regression
      of the basalis zone. Because KGF levels fall so dramatically during the LFT, we
      hypothesized that replacement with exogenous KGF during the LFT would prevent
      some of the endometrial changes seen after P withdrawal. Here we describe two
      studies of the effects of exogenously administered KGF during the LFT in rhesus
      macaques. In one experiment we administered KGF systemically to ovariectomized,
      juvenile rhesus macaques during an LFT induced by hormonal manipulations. KGF had
      dramatic proliferative effects on the bladder and salivary glands, known targets
      of KGF, but did not affect cell proliferation in the endometrium or block
      menstrual sloughing and bleeding. However, KGF strongly inhibited apoptosis in
      the basalis zone, increased glandular sacculation and folding in this zone, and
      had a marked trophic effect on the spiral arteries. In the second experiment we
      installed oviductal catheters in ovariectomized adult rhesus macaques and infused
      KGF directly into the uterine lumen during a hormonally induced LFT. Again,
      arteriotrophic, antiapoptotic, and basalis gland sacculation effects were
      observed in the absence of any effect on cell proliferation. We concluded that
      although KGF is mitogenic for many epithelial cell types, it does not play this
      role in the primate endometrium. Its most important roles may be to stimulate
      spiral artery growth and inhibit glandular apoptosis during the nonfertile
      menstrual cycle. Because its expression rises coincident with the time of
      implantation and because spiral arteries are essential to successful
      establishment of pregnancy, the role of KGF in the fertile menstrual cycle
      deserves further study.

PMID- 10634400
TI  - Germline mutations of the APC gene in patients with familial adenomatous
      polyposis-associated thyroid carcinoma: results from a European cooperative
      study.
AB  - Papillary thyroid carcinoma (PTC) is one extracolonic manifestation affecting
      about 1-2% of patients with familial adenomatous polyposis (FAP). Ninety-seven
      patients with FAP-associated PTC have previously been reported, including 6 pairs
      of siblings. During a European collaborative study, 15 patients with FAP
      associated PTC were collected. All 15 patients were females. The mean age at
      thyroidectomy was 24.9 yr (range, 19-39 yr). In 13 subjects, APC germline
      mutations had been detected; they were at codons 140, 593, 778, 976, 993, 1061 (n
      = 5), 1105 (n = 1), and 1309 (n = 2), respectively. A review of the literature
      added 11 other patients with FAP-associated PTC and detection of germline APC
      mutations; they were at codons 313 (n = 2), 698 (n = 3), 848 (n = 2), 1209 (n =
      2), 1061 (n = 1), and 1105 (n = 1), respectively. The latter led to formation of
      the same stop codon (TAA) at 1125-1126 as the mutation at codon 1061. Therefore,
      21 of 24 mutations were in exon 15 in the genomic area usually associated with
      congenital hypertrophy of the retinal pigment epithelium (CHRPE), i.e. codons 463
      1387. Typical CHRPE was found in 17 of 18 affected patients who had specific
      screening. Interestingly, 22 of the 24 patients had their mutation out of the
      mutation cluster region (codons 1286-1513), which is currently considered the hot
      spot mutation area, in particular for extracolonic manifestations of FAP. The
      difference in the incidence of germline mutations before and after codon 1220
      between PTC and non-PTC FAP patients was statistically significant (P<0.05) for
      both patients and kindreds (P = 0.005 and P = 0.049, respectively). Even if most
      mutations were scattered throughout the entire 5'-portion of exon 15, 8 of 23
      patients (6 with mutation at 1061 and 2 with mutation at 1105; i.e. more than one
      third) had the same truncated protein product. The awareness that patients with
      PTC usually have APC mutations that cluster in a well defined genomic area, in
      addition to giving a deeper insight into gene function, could facilitate both
      earlier diagnosis and better treatment. In particular, intensive screening for
      thyroid nodules after age 15 yr is recommended when a single patient or an entire
      kindred have CHRPE and/or mutations in the 5'-portion of exon 15.

PMID- 10634401
TI  - Diet and sex hormone-binding globulin.
AB  - The serum concentration of sex hormone-binding globulin (SHBG) is inversely
      related to weight and in animal studies is inversely related to protein intake.
      As SHBG can affect the biological activity of testosterone and estradiol, we
      wished to determine the role of protein intake on SHBG levels in men. Using data
      from the Massachusetts Male Aging Study we examined cross-sectional relationships
      between dietary components and SHBG levels in 1552 men (aged 40-70 yr) for whom
      these factors were known. Analyzed by multiple regression, controlling for
      testosterone and estradiol levels, age (P<0.001) and fiber intake (P = 0.02) were
      positively correlated to SHBG concentration, whereas body mass index (P<0.001)
      and protein intake (P<0.03) were negatively correlated to SHBG concentration. The
      intakes of calories, fat (animal or vegetable), and carbohydrate were not related
      to SHBG concentration. We conclude that age and body mass index are major
      determinants of SHBG concentrations in older men, and fiber and protein intake
      are also significant contributors to SHBG levels, but total caloric intake and
      the intake of carbohydrate or fat are not significant. Thus, diets low in protein
      in elderly men may lead to elevated SHBG levels and decreased testosterone
      bioactivity. The decrease in bioavailable testosterone can then result in
      declines in sexual function and muscle and red cell mass, and contribute to the
      loss of bone density.

PMID- 10634402
TI  - Progestin-epidermal growth factor regulation of tissue factor expression during
      decidualization of human endometrial stromal cells.
AB  - Perivascular decidualized human endometrial stromal cells (HESCs) are ideally
      positioned to prevent peri-implantational hemorrhage during endovascular
      trophoblast invasion by expressing tissue factor (TF), the primary cellular
      mediator of hemostasis. Earlier in vivo and in vitro studies have demonstrated
      enhanced TF expression in estradiol (E2)-primed HESCs during progestin-induced
      decidualization. However, the absence of estrogen or progesterone response
      elements from the TF gene promoter suggests that paracrine factor(s) may mediate
      these effects. We now demonstrate that significant elevation of TF messenger RNA
      and protein levels in the cultured HESCs require incubation with both epidermal
      growth factor (EGF) and the progestin medroxyprogesterone acetate (MPA) added,
      with or without E2. By contrast, no effects were elicited by adding EGF with E2,
      or by the separate additions of EGF, MPA, or E2 plus MPA. Our finding, that
      transforming growth factor-alpha, but not transforming growth factor-beta or
      interleukin 1-beta mimics these EGF effects, indicates that progestin-enhanced TF
      expression in cultured HESCs requires activation of the EGF receptor (EGFR).
      Western blot analysis indicated that MPA increased EGFR levels 2-to 3-fold in
      cultured HESCs. The current results suggest that the progestin up-regulation of
      TF levels in decidualized HESCs is mediated by enhanced EGFR expression.

PMID- 10634403
TI  - Effects of exogenous p53 transduction in thyroid tumor cells with different p53
      status.
AB  - Recovery of p53 function in undifferentiated thyroid carcinoma cells carrying an
      altered p53 gene is able to modify cell tumorigenic properties. It is not known
      whether such an effect may also be achieved in thyroid cancer cells expressing
      wild-type p53, as in the majority of differentiated thyroid carcinomas. Effects
      of p53 transduction in a thyroid carcinoma cell line (FRO) exhibiting a wild-type
      endogenous p53 gene, in comparison to a cell line (WRO) exhibiting mutant p53,
      were investigated by using an inducible chimeric construct containing human p53
      complementary DNA fused to the ligand binding domain of the estrogen receptor
      (p53ER). FRO cells were unaffected by exogenous p53 expression in terms of both
      proliferation and viability. On the contrary, p53 reexpression in WRO cells
      containing hemizygous mutated p53 allele caused a strong growth inhibition due to
      cell accumulation in the G1 phase of the cell cycle. In addition, exogenous p53
      did not influence FRO cell behavior in response to TSH treatment or modify cell
      resistance to the chemotherapeutic agent, doxorubicin. Our results indicate that
      exogenous expression of wild-type p53 affects thyroid tumorigenic properties only
      in cells carrying an altered p53, whereas it is ineffective in cells expressing
      wild-type p53 activity. Therefore, the endogenous p53 status seems to be a major
      determinant for the effectiveness of a p53-based gene therapy for thyroid cancer.

PMID- 10634404
TI  - Autoantibody recognition of COOH-terminal epitopes of GAD65 marks the risk for
      insulin requirement in adult-onset diabetes mellitus.
AB  - Some type 2 diabetic subjects develop secondary failure to sulphonylurea
      treatment and require insulin therapy. To test the diagnostic sensitivity and
      specificity of epitopes of GAD65 autoantibodies (GAD65Ab) for insulin
      requirement, in patients with latent autoimmune diabetes of the adult, we studied
      569 adult subjects with a clinical diagnosis of type 2 diabetes mellitus. All the
      patients had been initially treated with hypoglycemic agents and/or diet for at
      least 1 yr. The presence of GAD65Ab (61/569, 10.7%) depended on insulin therapy
      (P<0.0001), low BMI (P<0.0001), and low basal C-peptide (P = 0.01). The majority
      of GAD65Ab-positive subjects (47/61, 77%) had antibodies directed to both middle
      (GAD65-MAb) and COOH-terminal (GAD65-CAb) epitopes. However, GAD65-CAb were more
      frequent in insulin-treated subjects (92% of GAD65Ab+ individuals) than in
      subjects treated with hypoglycemic agents and/or diet (18.2% of GAD65Ab+
      individuals), while the exclusive presence of GAD65-MAb was more frequent in
      subjects treated with hypoglycemic agents and/or diet (81.8% vs. 8%) (P<0.0001).
      The presence of GAD65-CAb had a diagnostic specificity for insulin requirement as
      high as 99.4% (compared with 96.9% of GAD65Ab as measured in the traditional
      radiobinding assay) and identified a subgroup of patients with low BMI, low basal
      C-peptide values, and a need for insulin therapy. Subjects carrying only GAD65
      MAb were phenotypically indistinguishable from GAD65Ab-negative patients.
      Patients positive for GAD65-M+CAb, but not those positive for GAD65-MAb only,
      showed an increased risk for thyroid autoimmunity, as revealed by the presence of
      thyroid peroxidase autoantibodies. Our study demonstrates that the use of epitope
      specific antibody assays improves the diagnostic specificity of GAD65Ab, and that
      the presence of GAD65Ab binding to COOH-terminal epitopes is strongly associated
      with a need for insulin requirement.

PMID- 10634405
TI  - Prostate-specific antigen synthesis and secretion by human placenta: a
      physiological kallikrein source during pregnancy.
AB  - Prostate-specific antigen (PSA), a kallikrein-like serine protease until recently
      thought to be prostate specific, has been demonstrated in various nonprostatic
      tissues and body fluids. PSA has been also found in human endometrium and
      amniotic fluids, even if the significance of this novel expression is unclear. In
      this study, we have demonstrated by multiple techniques that human placental
      tissue, obtained at delivery from normal full-term pregnancies, synthesizes and
      secretes PSA. RT-PCR showed the presence of PSA messenger ribonucleic acid;
      biochemical, chromatographic, and immunological studies revealed the expression
      of both free and complexed PSA forms; immunoelectron microscopy indicated the
      syncytiotrophoblast as the site of PSA synthesis and secretion. Moreover, in
      vitro experiments demonstrated that PSA production and secretion are up-regulated
      by 17beta-estradiol, a pregnancy-related steroid hormone. These results suggest
      that human placenta is a source of the PSA present in amniotic fluid and maternal
      serum during pregnancy.

PMID- 10634406
TI  - High expression of cyclin E and G1 CDK and loss of function of p57KIP2 are
      involved in proliferation of malignant sporadic adrenocortical tumors.
AB  - Maternal loss of heterozygosity (LOH) of the 11p15 region and overexpression of
      the insulin-like growth factor (IGF)-II gene are associated with the malignant
      phenotype in sporadic adrenocortical tumors. In the imprinted 11p15 region, the
      p57KIP2 gene is maternally expressed and encodes a cyclin-dependent kinase (CDK)
      inhibitor involved in G1/S phase of the cell cycle. We hypothesized that maternal
      LOH in malignant adrenocortical tumors could be responsible for loss of p57KIP2
      gene expression and, thus, could favor progression through the cell cycle. We
      investigated 3 normal adrenals, 31 adrenocortical tumors [11 tumors with normal
      expression of the IGF-II gene (mainly benign) and 20 with IGF-II gene
      overexpression (mainly malignant)], and the human adrenocortical tumor cell line
      NCI H295R for expression of the p57KIP2 gene, G1 cyclins (cyclin D2 and E) and G1
      CDK (CDK2, CDK3 and CDK4) protein contents and for kinase activity of G1 cyclin
      CDK complexes. The expression of p57KIP2, G1 cyclins, and G1 CDKs in benign
      tumors was similar to that in normal adrenal tissues, as were kinase activities
      of G1 cyclin-CDK complexes. By contrast, abrogation of the p57KIP2 gene
      expression and increased expression of G1 cyclins (cyclin E) and G1 CDKs (CDK2
      and CDK4) were associated with high activity of G1 cyclin-CDK complexes in
      malignant tumors and in the H295R cell line. These data suggest that the p57KIP2
      gene might act as a tumor suppressor gene in adrenocortical tumors. Maternal LOH
      with duplication of the paternal allele or pathological functional imprinting of
      the 11p15 region are responsible for loss of expression of the p57KIP2 gene and
      increased expression of the IGF-II gene. Consequently, both events favor cell
      proliferation in malignant adrenocortical tumors.

PMID- 10634407
TI  - Identification and functional analysis of mutations in the hepatocyte nuclear
      factor-1alpha gene in anti-islet autoantibody-negative Japanese patients with
      type 1 diabetes.
AB  - Mutations in the hepatocyte nuclear factor-1alpha (HNF-1alpha) gene are the cause
      of maturity-onset diabetes of the young type 3 (MODY 3), which is characterized
      by a severe impairment of insulin secretion and early onset of the disease.
      Although the majority of patients with type 1 diabetes have type 1A, immune
      mediated diabetes, there is a significant percentage of the patients who have no
      evidence of an autoimmune disorder at the onset of disease. The aim of this study
      was to estimate the prevalence of MODY 3 in antiislet autoantibody negative
      patients with type 1 diabetes. From a large population-based sample of unrelated
      Japanese patients with type 1 diabetes, 28 patients who lacked autoantibodies to
      glutamic acid decarboxylase, islet cell antigen 512/insulinoma-associated antigen
      2, phogrin (phosphate homolog of granules of insulinoma)/insulinoma-associated
      antigen-2beta, and insulin at the onset of type 1 diabetes were examined by PCR
      based direct sequencing of the 10 exons, flanking introns, and the promoter
      region of the HNF-1alpha gene. Two (7.1%) of 28 autoantibody-negative patients
      with type 1 diabetes were identified as carrying mutations in the HNF-1alpha
      gene. One patient carried a frameshift mutation (Pro379fsdelCT) in exon 6, and
      another patient carried a novel 2-bp substitution at nucleotides +45 (G to A) and
      +46 (C to A) from the transcriptional site of the promoter region. These
      mutations were identified in heterozygous form and were not identified in 64
      unrelated healthy control subjects or 54 unrelated islet autoantibody-positive
      patients with type 1 diabetes. Functional analysis of the mutant HNF-1alpha gene
      indicated that the Pro379fsdelCT mutation had no transcriptional trans-activation
      activity and acted in a dominant negative manner. The +45/46 GC to AA mutation in
      the promoter region showed reduced promoter activity by 10-20% compared to the
      wild-type sequence. In conclusion, about 7% of Japanese diabetic patients lacking
      antiislet autoantibodies initially classified as having type 1 diabetes could
      have diabetes caused by mutations in the HNF-1alpha gene.

PMID- 10634408
TI  - Synergistic effect of adrenal steroids and angiotensin II on plasminogen
      activator inhibitor-1 production.
AB  - Recent data suggest an interaction between the renin-angiotensin-aldosterone
      system and fibrinolysis. Although previous work has focused on the effect of
      angiotensin II (Ang II) on plasminogen activator inhibitor (PAI-1) expression,
      the present study tests the hypothesis that aldosterone contributes to the
      regulation of PAI-1 expression. To test this hypothesis in vitro, luciferase
      reporter constructs containing the human PAI-1 promoter were transfected into rat
      aortic smooth muscle cells. Exposure of the cells to 100 nmol/L Ang II resulted
      in a 3-fold increase in luciferase activity. Neither 1 micromol/L dexamethasone
      nor 1 micromol/L aldosterone alone increased PAI-1 expression. However, both
      dexamethasone and aldosterone enhanced the effect of Ang II in a dose-dependent
      manner. This effect was abolished by mutation in the region of a putative
      glucocorticoid-responsive element. A similar interactive effect of Ang II and
      aldosterone was observed in cultured human umbilical vein endothelial cells. The
      time course of the effect of aldosterone on Ang II-induced PAI-1 expression was
      consistent with a classical mineralocorticoid receptor mechanism, and the effect
      of aldosterone on PAI-1 synthesis was attenuated by spironolactone. To determine
      whether aldosterone affected PAI-1 expression in vivo, we measured local venous
      PAI-1 antigen concentrations in six patients with primary hyperaldosteronism
      undergoing selective adrenal vein sampling. PAI-1 antigen, but not tissue
      plasminogen activator antigen, concentrations were significantly higher in
      adrenal venous blood than in peripheral venous blood. Taken together, these data
      support the hypothesis that aldosterone modulates the effect of Ang II on PAI-1
      expression in vitro and in vivo in humans.

PMID- 10634409
TI  - Loss of expression of the ubiquitous transcription factor cAMP response element
      binding protein (CREB) and compensatory overexpression of the activator CREMtau
      in the human adrenocortical cancer cell line H295R.
AB  - The pituitary hormone ACTH, acting through the cAMP pathway, plays a key role in
      proliferation and differentiation of the adrenal cortex. CAMP response element
      (CRE)-binding protein (CREB) is an ubiquitous transcription factor that binds to
      the CRE present in the promoter of numerous genes and mediates transcription
      stimulation by cAMP. Characterization of CRE-binding proteins was performed in
      the H295R cell line, which is considered a model for human adrenocortical tumor
      studies. Western blot and RT-PCR studies demonstrated that CREB is not expressed
      in the human adrenocortical cancer cell line H295R, whereas it is expressed in
      normal adrenal. During transient transfection experiments, cAMP stimulation of
      two reporter genes containing canonical CRE was maintained. Cotransfection of the
      dominant negative inhibitor A-CREB, which prevents transcription factors
      containing a CREB-like leucine zipper domain to bind DNA, completely inhibited
      cAMP-induced stimulation of CRE activity. Western blot and RT-PCR studies showed
      that activating transcription factor-1 (ATF-1), CRE modulator-alpha/gamma
      (CREMalpha/gamma), and CREMtau2alpha are expressed in H295R cells. High amounts
      of CREM proteins were present in H295R, demonstrating an overexpression of this
      transcription factor in the absence of CREB. Furthermore, expression of the
      activator isoform CREMtau was very high in H295R compared to normal adrenal
      cortex. Transfection assays demonstrated that CREMtau2alpha is a potent
      stimulator of CRE activity in H295R. Finally, gel retardation assays showed that
      CREM and ATF-1 are the nuclear proteins that specifically bind the CRE in H295R
      cells, whereas CREM binding to CRE is not observed in a CREB-expressing cell
      line. H295R cells are the first established nontransgenic cell line that does not
      express the ubiquitous transcription factor CREB. H295R demonstrates that CREMtau
      up-regulation can compensate for CREB deficiency to maintain CRE regulation by
      cAMP and is a model of compensation mechanisms between the members of the CREB/
      CREM/ATF-1 family of transcription factors. This loss of CREB expression and the
      overexpression of CREM could be linked to cellular transformation, as the normal
      adrenal cortex express high levels of CREB and no or low levels of CREMtau.

PMID- 10634410
TI  - Levels and molecular properties of secretoneurin-immunoreactivity in the serum
      and urine of control and neuroendocrine tumor patients.
AB  - We have determined the levels of secretoneurin (SN), a novel 33-amino acid
      neuropeptide belonging to the class of chromogranins, in the serum and urine of
      healthy subjects and patients suffering from various tumors. SN serum levels
      averaged 22.1+/-1.1 fmol/mL. They were 5-fold higher in younger children and then
      declined continuously. SN levels were positively correlated with serum
      creatinine, suggesting an influence of renal function on the clearance of SN from
      the serum. In the urine 80.0 fmol/mL SN was present. In patients with endocrine
      tumors like gut carcinoids, endocrine pancreatic tumors, oat cell lung
      carcinomas, and pheochromocytomas, SN serum levels were elevated up to 45-fold.
      Patients suffering from neuroblastomas, insulinomas, pituitary adenomas including
      acromegaly, and solid nonendocrine tumors had concentrations in the normal range.
      In human serum, SN-immunoreactivity was confined to the free peptide SN; neither
      larger intermediate-sized forms nor the precursor secretogranin II were detected.
      An efficient removal of the small molecule SN from the serum by the kidney
      explains why SN serum levels are lower when compared to chromogranin A, which is
      present as large molecule in serum.

PMID- 10634411
TI  - Novel human corticosteroid-binding globulin variant with low cortisol-binding
      affinity.
AB  - Corticosteroid-binding globulin (CBG) is the plasma transport protein that
      regulates the access of glucocorticoid hormones to target cells. Genetic
      deficiencies of CBG are rare, and only a single human CBG variant (Trancortin
      Leuven) has been related so far to decreased cortisol-binding affinity. We report
      here on a 43-yr-old woman, referred for chronic asthenia and hypotension, with
      repeatedly low morning serum cortisol levels (22-61 nmol/L; normal range, 204-546
      nmol/L), normal plasma ACTH levels (38-49 pg/mL; normal, <50 pg/mL), and normal
      urinary cortisol (10-76 nmol/24 h; normal range, 10-105 nmol/24 h). An increased
      percent-free (dialysable fraction) serum cortisol (8.7-9.7%, normal range, 2.9
      3.9%) suggested abnormal CBG binding activity. Indeed, she had a low serum CBG
      concentration (24 mg/L vs. 44+/-6 mg/L in normal women), and the affinity of her
      CBG for cortisol was decreased (association constant, Ka = 0.12 L/nmol vs. 0.82+/
      0.29 L/nmol). In her immediate family members, the serum CBG concentration and
      cortisol-binding activity were normal in her husband, but the four living
      children had slightly lower serum CBG concentrations than the reference ranges
      for their pre- and postpubertal status. Measurements of cortisol distribution in
      undiluted serum indicated that an increase in the percentage of nonprotein-bound
      cortisol offsets the low cortisol levels to give approximately normal
      concentrations of free cortisol in serum. Direct sequencing of PCR-amplified
      exons encoding CBG revealed that the proband was homozygous for a polymorphism
      (GAC-AAC) in the codon for residue 367, which results in a Asp367-->Asn
      substitution. Her children were heterozygous for this polymorphism. When this
      nucleotide change was introduced into a normal human CBG complementary DNA, for
      expression in Chinese hamster ovary cells, Scatchard analysis demonstrated that
      the Asn367 substitution reduced the affinity of human CBG for cortisol by
      approximately 4-fold (Ka = 0.15 L/nmol), as compared to normal recombinant CBG
      (Ka = 0.66 L/nmol). These results suggest that Asp367 is an important determinant
      of CBG steroid-binding activity and that normal negative regulation of the
      hypothalamic-pituitary-adrenal axis is maintained by relatively normal serum-free
      cortisol concentrations, despite a marked reduction in the steroid-binding
      affinity of this novel human CBG variant, which we have designated as CBG-Lyon.

PMID- 10634412
TI  - Identification of thyroxine-binding globulin-San Diego in a family from Houston
      and its characterization by in vitro expression using Xenopus oocytes.
AB  - T4-binding globulin (TBG) is a liver glycoprotein that transports iodothyronines
      in serum. Several TBG variants with reduced T4 binding affinity have been
      described, all of which are also characterized by reduced serum TBG
      concentrations and reduced heat stability. Their loss of binding thus appears to
      be due to a general defect of the molecule. We now report the occurrence of a
      variant TBG, detected in a family from Houston, TX, with half the normal T4
      binding affinity and heat stability but normal serum concentration and
      isoelectric focussing pattern. The propositus was identified by reduced total T4
      and T3 serum levels. All family members were euthyroid, and inheritance followed
      an X-linked pattern. Sequence analysis of the TBG gene of the propositus and his
      heterozygous mother revealed two amino acid substitutions: serine 23 with
      threonine (S23T), and the known polymorphism leucine 283 with phenylalanine
      (L283F). These substitutions are identical to those of TBG-San Diego (TBG-SD), a
      variant with similar properties except for a reduced serum concentration.
      Expression of recombinant TBG-SD/H with the S23T substitution in Xenopus oocytes
      reproduced the binding defect and heat lability. The amount of TBG-SD/H
      synthesized and secreted by the oocytes was not different from that of normal
      TBG. The difference in serum TBG concentrations in affected members of the San
      Diego and Houston families thus does not appear to be due to an error in the
      measurement of TBG, but may be related to differences in the rates of
      degradation.

PMID- 10634413
TI  - Studies on human pregnancy-induced insulin-like growth factor (IGF)-binding
      protein-4 proteases in serum: determination of IGF-II dependency and localization
      of cleavage site.
AB  - Insulin-like growth factor (IGF)-binding protein-4 (IGFBP-4), a consistent
      inhibitor of IGF action, is subject to proteolytic cleavage by the IGF-II
      dependent IGFBP-4 protease. However, regulation of the IGF-II-dependent IGFBP-4
      protease in vivo is not known. As IGFBP proteases are known to be triggered
      during pregnancy, we systematically evaluated the changes in IGFBP-4 proteolysis
      by serum collected throughout human pregnancy. Results from in vitro protease
      assays using recombinant IGFBP-4 revealed that IGFBP-4 proteolysis determined in
      both the presence and absence of exogenous IGF-II significantly increased during
      the first and second trimesters and reached a plateau by the third trimester.
      However, in the absence of IGF-II, IGFBP-4 proteolysis by pregnancy serum was
      only observed after prolonged incubation. IGF-II dose dependently increased IGFBP
      4 proteolysis by pregnancy serum, with maximal stimulation observed at a
      concentration of 0.7 mol/L relative to IGFBP-4. In contrast, IGF-II at an
      equimolar dose had little effect on proteolysis of recombinant human IGFBP-3,
      whereas excess IGF-II reproducibly inhibited recombinant human IGFBP-3
      proteolysis by pregnancy serum. Although IGF-II enhanced IGFBP-4 proteolysis,
      results from N-terminal sequence and mass spectrometric analyses of IGFBP-4
      proteolytic fragments demonstrate that the cleavage site (Met135-Lys136) in human
      IGFBP-4 was not altered by IGF-II. Deletion of the residues 121-141 containing
      this cleavage site blocked IGFBP-4 proteolysis. These findings demonstrate that
      the increase in IGFBP-4 proteolysis during pregnancy was accounted for mainly by
      the IGF-II-dependent IGFBP-4 proteolysis. Because IGFBP-4 is a potent inhibitor
      of IGF actions, it can be speculated that the pregnancy-induced IGFBP-4 proteases
      may play an important role in regulating fetal growth.

PMID- 10634414
TI  - Thyrocyte proliferation by cellular adhesion to infiltrating lymphocytes through
      the intercellular adhesion molecule-1/lymphocyte function-associated antigen-1
      pathway in Graves' disease.
AB  - Graves' disease (GD) is an autoimmune thyroid disease characterized by
      infiltration of lymphocytes into the thyroid, and intrathyroid lymphocytes are
      known to play an important role in the pathogenesis of GD. However, it remains to
      be understood how lymphocytes adhere to thyrocytes and regulate the thyrocyte
      function through cellular adhesion. We studied the mechanisms of T cell adhesion
      to thyrocytes using intrathyroid mononuclear cells (ITMC) and thyrocytes purified
      from the thyroids of patients with GD. The following novel features of cellular
      adhesion of ITMC to thyrocytes in the regulation of the thyrocyte function in GD
      were observed: 1) GD-ITMC expressed lymphocyte function-associated antigen (LFA)
      1, which became an active adhesive configuration much higher than peripheral
      blood mononuclear cells (PBMC) from normal volunteers and GD patients; 2) GD
      thyrocytes expressed a high quantity of intercellular adhesion molecule (ICAM)-1;
      3) GD-ITMC adhered to GD-thyrocytes, whereas normal PBMC required activation
      stimuli by phorbol myriacetate, a pharmacological integrin-trigger, to adhere to
      GD- thyrocytes; 4) monoclonal antibody-blocking studies showed that the adhesion
      of the activated PBMC and ITMC to thyrocytes was mainly mediated by the LFA
      1/ICAM-1 pathway; 5) the adhesion of GD-thyrocytes to the activated-PBMC or ITMC
      induced the proliferation of the thyrocytes, which was blocked by the addition of
      ICAM-1 and/or LFA-1 monoclonal antibodies; and 6) in GD thyrocytes of early
      cultures, ICAM-1 expression on GD-thyrocytes and its adhesion to LFA-1 on phorbol
      myriacetate-activated PBMC or ITMC were not modulated by the addition of
      interleukin-1beta or interferon-gamma, and proliferation of thyrocytes by the
      cellular adhesion via the ICAM-1/LFA-1 pathway was independent of the
      proliferative response of these cytokines. Taken together, these results suggest
      that lymphocytes infiltrating GD thyroid induce proliferation of GD-thyrocyte by
      the cellular adhesion to thyrocytes via ICAM-1/LFA-1, which may lead to the
      development of a goiter.

PMID- 10634415
TI  - Impaired adrenocorticotropin-adrenal axis in combined pituitary hormone
      deficiency caused by a two-base pair deletion (301-302delAG) in the prophet of
      Pit-1 gene.
AB  - The Prophet of Pit-1 gene (PROP1) encodes a paired-like homeodomain protein,
      which is expressed early in pituitary gland development. When mutated, it is
      responsible for combined pituitary hormone deficiency (CPHD) in humans, as well
      as in Ames dwarf mice (df/df). Several independent mutations in the homeodomain
      of PROP1 have been identified as causative for the human CPHD phenotype, which
      has been characterized, thus far, as absence or low levels of GH, PRL, TSH, LH,
      and FSH. Here, we report 10 CPHD cases, 9 of which were born to consanguineous
      marriages occurring in a large family living in an isolated area in the Southeast
      of Brazil. All affected patients present complete absence of puberty and low GH,
      PRL, TSH, LH, and FSH associated with severe hypoplasia of the pituitary gland,
      as seen by MRI. All 3 exons of the PROP1 genes of these patients were sequenced.
      The 301-302delAG frameshift mutation was found in both alleles of each affected
      case. Surprisingly, we observed ACTH/cortisol insufficiency associated with the
      PROP1 phenotype. The patients' ages varied between 8 and 67 yr, and cortisol
      response impairment was identified in 5 of 6 of the older patients and in an 11
      yr-old patient. Previous studies have not fully characterized patients at
      advanced ages, leading us to conclude that the phenotype of this PROP1 mutation
      includes late-onset adrenal insufficiency. We present an extensive clinical
      analysis of all of these patients. The presence of ACTH/cortisol deficiency in
      this family bearing the PROP1 301-302delAG mutation indicates the importance of a
      complete endocrine characterization and of life-long monitoring of PROP1
      patients.

PMID- 10634416
TI  - Malignant prolactinoma discovered by D2 receptor imaging.

PMID- 10634417
TI  - Vascular endothelial growth factor expression in human endometrium is regulated
      by hypoxia.
AB  - Endometrial growth and repair after menstruation are associated with profound
      angiogenesis. Abnormalities in these processes result in excessive or
      unpredictable bleeding patterns and are common in many women. It is therefore
      important to understand which factors regulate normal endometrial angiogenesis.
      Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen
      that plays an important role in normal and pathological angiogenesis. In this
      study we show that expression of VEGF is regulated by hypoxia in human
      endometrium. Culture in vitro for 24 h under hypoxic conditions resulted in a 2-
      to 6-fold increase in VEGF secretion by both stromal and epithelial cells
      isolated from human endometrium. Quantitative RT-PCR was used to measure VEGF
      messenger ribonucleic acid (mRNA) levels in these cells. After hypoxia, VEGF mRNA
      levels increased 1.8-fold in stromal cells and 3.4-fold in glandular epithelial
      cells. The mRNA for each VEGF splice variant increased to an equal extent. The
      increase in VEGF secretion by stromal and epithelial cells in response to hypoxia
      was not altered by treatment at the same time with estradiol or progesterone. In
      situ hybridization of human endometrium during menstruation, when steroid levels
      are low but the tissue is subject to ischemia, showed strong hybridization to
      VEGF mRNA in both stromal and glandular cells. These results show that local
      factors, such as hypoxia, can regulate VEGF expression in the endometrium. This
      may play an important part in normal endometrial repair after menstruation. The
      secretion of VEGF by endometrial cells under hypoxic conditions may also be
      important in the pathogenesis of endometriosis, because it would be predicted to
      assist revascularization of desquamated endometrial explants when they attach at
      ectopic sites.

PMID- 10634418
TI  - 17beta-hydroxysteroid dehydrogenase type 1 and 2 expression in the human fetus.
AB  - The present study investigates the expression patterns of 17beta-hydroxysteroid
      dehydrogenase (17betaHSD) isozymes in human fetal tissues to understand how
      estrogenic activity is regulated in the human fetus. Using enzyme assay, high
      17betaHSD activity was detected in the placenta and liver, and low levels of
      17betaHSD activity were also present in the gastrointestinal tract and kidney.
      After Northern blot analysis, we detected the messenger ribonucleic acid for
      17betaHSD type 1 (17betaHSD1) only in the placenta, whereas that for 17betaHSD
      type 2 (17betaHSD2) was detected in the placenta, liver, gastrointestinal tract,
      and urinary tract at 20 gestational weeks. In RT-PCR analysis of the messenger
      ribonucleic acid transcripts, 17betaHSD 1 was predominantly expressed in the
      placenta, brain, heart, lung, and adrenal, whereas 17betaHSD2 expression was
      predominantly detected in the liver, gastrointestinal tract, and kidney. In
      addition, we detected 17betaHSD2 immunoreactive protein in surface epithelial
      cells of the stomach, absorptive epithelial cells of the small intestine and
      colon, hepatocytes of the liver, and interstitial cells surrounding the urinary
      tubules of the renal medulla. 17betaHSD2 in these tissues may be functioning in
      the prevention of in utero exposure of the fetus to excessive estradiol from the
      maternal circulation and amniotic fluids.

PMID- 10634419
TI  - Regulated on activation normal T expressed and secreted chemokine is induced by
      tumor necrosis factor-alpha in granulosa cells from human preovulatory follicle.
AB  - We examined the production of regulated on activation normal T expressed and
      secreted (RANTES) chemokine, which may contribute to the recruitment and local
      accumulation of leukocytes in human preovulatory follicles. Cells were obtained
      from follicular aspirates collected from in vitro fertilization patients, then
      cultured. RANTES production in culture was measured by immunoenzymatic assay,
      RANTES-producing cells were measured by flow cytometry, and messenger ribonucleic
      acid as measured by RT-PCR and in situ hybridization. RANTES was detected in
      follicular fluids and culture supernatants; RANTES protein and messenger
      ribonucleic acid were expressed in granulosa cells. RANTES production was
      stimulated by tumor necrosis factor-alpha (TNFalpha) and was inhibited in
      cultures containing a neutralizing anti-TNFa antibody. p55 TNF receptors were
      detected by RT-PCR and visualized on granulosa cells by flow cytometry. RANTES
      production was increased by phorbol 12-myristate 13-acetate, but not by 8-bromo
      cAMP. RANTES was produced by granulosa cells from human preovulatory follicles.
      This production was activated by TNFalpha, probably through TNF receptor p55.
      This suggests that RANTES may play an active role in ovarian processes involving
      the local accumulation of immune cells.

PMID- 10634420
TI  - Novel mutations of the cathepsin K gene in patients with pycnodysostosis and
      their characterization.
AB  - Pycnodysostosis is a rare autosomal recessive skeletal dysplasia characterized by
      short stature, osteosclerosis, acroosteolysis, bone fragility, and skull
      deformities. Recently, mutations in the gene encoding cathepsin K (CK), a
      lysosomal cysteine protease localized exclusively in osteoclasts, were found to
      be responsible for this disease. We analyzed genomic DNA from four unrelated
      Japanese patients with this disorder and identified three different mutations of
      their CK genes: a previously reported missense mutation (A277 V), a novel single
      base deletion mutation (531 del T) causing a frame shift from codon 142 that
      results in a premature termination codon, and a novel missense mutation (L9P) in
      the signal peptide region. To investigate whether the L9P mutation disrupts
      signal peptide function and decreases protein synthesis, mutant and wild-type CK
      complementary DNAs driven by the cytomegalovirus promoter were transfected into
      COS-7 cells, and their gene products were detected by immunohistochemistry and
      Western blotting. Expression of the mutant protein was markedly reduced,
      suggesting decreased mature CK production in this patient, which may have been
      due to dysfunction of the signal peptide. These results provide evidence that a
      structural change in the signal peptide of the CK protein was involved in the
      pathogenesis of pycnodysostosis.

PMID- 10634421
TI  - Mechanisms of coxsackievirus-induced damage to human pancreatic beta-cells.
AB  - Enteroviruses may be involved in the pathogenesis of insulin-dependent diabetes
      mellitus, either through direct beta-cell infection or as triggers of
      autoimmunity. In the present study we investigated the patterns of infection in
      adult human islet cell preparations (consisting of 56+/-14% beta-cells) by
      several coxsackieviruses. The cells were infected with prototype strains of
      coxsackievirus B (CBV) 3, 4, and 5 as well as coxsackievirus A9 (CAV-9). The
      previously characterized diabetogenic strain of coxsackievirus B4 (CBV-4-E2) was
      used as a reference. All viruses replicated well in beta-cells, but only CBVs
      caused cell death. One week after infection, the insulin response of the beta
      cells to glucose or glucose plus theophylline was most severely impaired by CBV-3
      and CBV-5 infections. CBV-4 also caused significant functional impairment,
      whereas CAV-9-infected cells responded like uninfected controls. After 2 days of
      infection, about 40% of CBV-5-infected cells had undergone morphological changes
      characteristic of pyknosis, i.e. highly distorted nuclei with condensed but
      intact chromatin. Both mitochondria and plasma membrane were intact in these
      cells. DNA fragmentation was found in 5.9+/-1.1% of CBV-5-infected beta-cell
      nuclei (2.1+/-0.3% in controls; P<0.01). CAV-9 infection did not induce DNA
      fragmentation. One week after infection the majority of infected cells showed
      characteristics of secondary necrosis. Medium nitrite and inducible nitric oxide
      synthase messenger ribonucleic acid levels were not significantly up-regulated by
      CBV infection. These results suggest that several enteroviruses may infect human
      beta-cells. The infection may result in functional impairment or death of the
      beta-cell or may have no apparent immediate adverse effects, as shown here for
      CAV-9. Coxsackie B viruses cause functional impairment and beta-cell death
      characterized by nuclear pyknosis. Apoptosis appears to play a minor role during
      a productive CBV infection in beta-cells.

PMID- 10634422
TI  - Complete sequencing and messenger ribonucleic acid expression analysis of the MEN
      I gene in adrenal cancer.
AB  - Adrenal cancer is a rare sporadic disease that has also been observed in the
      context of multiple endocrine neoplasia type I (MEN I). Adrenal lesions occur in
      up to 40% of MEN I patients. Loss of heterozygosity of the 11q13 band harboring
      the menin gene has been reported in more than 50% of patients with adrenal
      cancer. Despite this high index of suspicion, former screening studies did not
      reveal mutations of the MEN I gene in 28 patients. We identified loss of
      heterozygosity of 11q13 microsatellites in five of five patients (100%). In 40%,
      heterozygosity was retained in codon 418 of the MEN I gene. Complete direct DNA
      sequencing data of the entire coding region and adjacent splice sites of the MEN
      I gene were obtained in 14 patients with sporadic adrenal cancer. In only one of
      them a heterozygous missense mutation, R176Q (exon 3), was identified. Due to the
      heterozygous pattern and unknown biological effect of this mutation, it is not
      clear whether there is a causal relationship with adrenal cancer. The total
      mutation frequency in sporadic adrenal cancer is 1 of 14 (7%). Menin messenger
      RNA expression was identified in 14 of 14 patients (100%). Transcriptional
      inactivation of the menin gene is, hence, unlikely to cause loss of its tumor
      suppressor function in adrenal cancer. Furthermore, we examined three patients
      who presented adrenal cancer in the context of sporadic multiglandular endocrine
      tumor disease previously diagnosed on clinical grounds to be MEN I syndrome. An
      opal stop codon mutation was identified in codon 126 (exon 2) in the adrenal
      cancer of one of these patients. Formation of the adrenal cancer in this patient
      may be rather coincidental because the mutation was present in a heterozygous
      pattern. There was no mutation of the menin gene in the two other patients. This
      may mean that formation of adrenal cancer in the context of multiglandular
      endocrine disease denotes an entity different from MEN I in some patients.

PMID- 10634423
TI  - Regulated expression and potential roles of p53 and Wilms' tumor suppressor gene
      (WT1) during follicular development in the human ovary.
AB  - It has been previously demonstrated that the gonadotropin-mediated inhibition
      ofapoptosis in rat ovarian granulosa cells is associated with changes in the
      expression of several cell death-regulatory genes, including p53. In addition, it
      has been shown that the actions of p53 may be amplified through a cooperative
      interaction with the Wilms' tumor suppressor gene product (WT1). Based on these
      findings, the present studies were conducted to determine whether p53 and WT1 are
      expressed and gonadotropin regulated in the human ovary and to study the
      relationship between tumor suppressor gene expression and apoptosis in human
      granulosa/lutein cells (GCs). Analysis of total RNA prepared from human GCs using
      the RT-PCR demonstrated the presence of p53 messenger RNA (mRNA) and four WT1
      mRNA splice variants. These observations were supported by Northern blot analysis
      of total RNA prepared from human GCs, which revealed the presence of a single
      (approximately 2.8 kb) p53 mRNA transcript and two primary (approximately 1.8 and
      approximately 3.5 kb) WT1 mRNA transcripts. Western blot analysis of nuclear
      protein extracts from human GCs yielded one immunoreactive protein of the
      expected size (approximately 53 kDa) recognized by a p53 antibody and one
      immunoreactive protein of the expected size (approximately 52-54 kDa) recognized
      by the WT1 antibody. Immunohistochemical staining showed that both molecules were
      localized to nuclei of human GCs and were coordinately regulated during
      follicular development. Immunofluorescence analysis showed that p53 protein was
      localized exclusively to nuclei of GCs undergoing apoptosis during in vitro
      culture and was similarly localized to nuclei and cytoplasm of apoptotic
      granulosa cells in atretic follicles in vivo. To further evaluate whether human
      GC apoptosis is linked to increased expression of tumor suppressor genes, we
      analyzed levels of p53 and WT1 mRNA and protein in GCs induced to undergo
      apoptosis in vitro. Healthy (nonapoptotic) GCs snap-frozen immediately after
      isolation from patients undergoing in vitro fertilization-embryo transfer
      possessed relatively low, but detectable, levels of p53 and WT1 mRNA and protein.
      However, following serum-free culture to induce apoptosis, p53 mRNA and protein
      levels increased significantly after 24 h, paralleling the increase in the number
      of apoptotic GCs. The induction of both p53 mRNA and protein in GCs was inhibited
      by the addition of human CG to the culture medium. In contrast, WT1 mRNA and
      protein levels remained constitutive in GCs incubated for 24 h compared with GCs
      snap-frozen immediately after isolation. We conclude that the p53 and WT1 genes
      are expressed at the mRNA and protein levels in human GCs and that expression of
      p53 is regulated during follicular maturation. Nuclear accumulation of p53
      protein occurs in human GCs during apoptosis in vitro and in vivo, and p53 mRNA
      and protein are up-regulated in GCs starved of hormonal support but down
      regulated by the presence of human CG. We propose that the products of these two
      principal tumor suppressor genes serve as important regulators of human
      follicular development and corpus luteum function.

PMID- 10634424
TI  - Autoantibodies against aromatic L-amino acid decarboxylase identifies a subgroup
      of patients with Addison's disease.
AB  - Autoantibodies against aromatic L-amino acid decarboxylase (AADC) are present in
      about 50 percent of sera from patients with autoimmune polyendocrine syndrome
      type I (APS I) but absent in sera from patients with different organ-specific
      autoimmune diseases, such as insulin-dependent diabetes mellitus, Hashimoto's
      thyroiditis, and Graves' disease. AADC is expressed in the pancreatic beta-cells,
      the liver, and the nervous system; and the presence of AADC antibodies has been
      shown to correlate to hepatitis and vitiligo in APS I patients. Among 101
      investigated patients with autoimmune Addison's disease, 15 had high titers of
      AADC antibodies. According to the clinical characteristics of these patients,
      only 3 had APS I. The remaining 12 had either isolated Addison's disease or
      associated diabetes mellitus, hypothyroidism, vitiligo, alopecia, gonadal
      failure, and pernicious anemia. Autoantibodies against 21-hydroxylase were
      present in 9 of 12, whereas autoantibodies against side-chain cleavage enzyme and
      17alpha-hydroxylase were present in 3 of 12. Two patients had only autoantibodies
      against AADC. DNA was available from 3 of these 12 patients. One of the patients,
      a woman with Addison's disease, autoimmune thyroiditis, and premature menopause
      was heterozygous for a point mutation (G1021A, Val301Met) in the first plant
      homeodomain zinc finger domain of the autoimmune regulator (AIRE) gene. The
      presence of AADC autoantibodies identifies patients with APS I and a subgroup of
      Addison patients who may have a milder atypical form of APS I or represent a
      distinct entity. Measurement of autoantibodies against AADC should be included in
      the evaluation of Addison's disease.

PMID- 10634425
TI  - A switch from oral (2 mg/day) to transdermal (50 microg/day) 17beta-estradiol
      therapy increases serum insulin-like growth factor-I levels in recombinant human
      growth hormone (GH)-substituted women with GH deficiency.
AB  - The response to GH therapy in adults with GH deficiency (GHD) is considerably
      variable. Generally, the response with regard to serum insulin-like growth factor
      (IGF)-I concentrations is significantly lower in females compared with males with
      GHD, which could at least partly be explained by the use of oral estrogen
      replacement therapy. In the present study, we investigated whether a switch from
      oral to transdermal estrogen therapy alters serum IGF-I concentrations in women
      with GHD on stable GH therapy. Six females with GHD and LH deficiency were
      investigated. During cycles 1 and 2, an oral dose of estradiol was given (2
      mg/day), whereas during cycles 3, 4, and 5 estradiol was administered via the
      transdermal route at a dose of 50 microg/day. Serum estrone levels significantly
      decreased (2470+/-475 to 110+/-26 pmol/L, P = 0.005), serum sex hormone-binding
      globulin levels significantly decreased (102+/-13 to 63+/-7 nmol/L, P = 0.004),
      and serum estradiol levels also decreased albeit nonsignificantly with
      transdermal therapy (273+/-81 to 114+/-18, P = 0.083). Serum IGF-I levels
      significantly increased after the switch from oral to transdermal estrogen
      therapy (18.7+/-1.6 and 23.4+/-2.5 nmol/L, respectively, P = 0.008). Two of the
      six patients experienced fluid retention-related side effects, which disappeared
      after a reduction in dose at the end of the study. The results of the present
      study suggest that the potency of GH is altered in patients on transdermal
      compared to oral estradiol therapy. Further investigation should be undertaken to
      answer the question whether the increase in serum IGF-I levels is due to lower
      serum levels of estradiol or to differences in the mode of administration of
      estradiol.

PMID- 10634426
TI  - Telomerase activity is significantly enhanced in malignant adrenocortical tumors
      in comparison to benign adrenocortical adenomas.
AB  - Telomerase is an enzyme that causes short repeated sequence addition to the ends
      of chromosomes, thereby preventing their shortening during cell division and
      counteracting cell senescence. Telomerase activity is generally absent in adult
      differentiated cells, whereas it has been demonstrated in tumor cells, suggesting
      that its presence might be considered an index of malignancy. To evaluate whether
      telomerase might be considered a good predictive index of malignancy in
      adrenocortical tumors, we measured telomerase activity in 11 adrenal adenomas and
      7 carcinomas obtained at surgery, using an original quantitative method.
      Telomerase activity was significantly higher (P<0.001) in carcinomas than in
      adenomas (median, 15.2 ng DNA/microg protein; range, 9.0-27.6 vs. 2.0; range, 0
      8.3), and no overlap was observed between the 2 groups. In carcinomas, telomerase
      activity was significantly correlated with tumor diameter (r = 0.939; P<0.0001),
      whereas in adenomas it was not. The results of this study suggest that
      quantitative telomerase measurement may represent a useful tool to differentiate
      malignant from benign adrenocortical tumors.

PMID- 10634427
TI  - A novel method for assessing assisted female fertility: bioelectric impedance.
AB  - Early detection of declining female fertility is important for effective
      prevention and treatment of infertility. Age, serum concentration of FSH in the
      early follicular phase (basal FSH), and the clomiphene citrate (CC) challenge
      test correlate only with large declines in fertility. We serendipitously
      discovered that by a novel mechanism bioelectric impedance (BEI) sensitively
      reflects early fertility decrements. BEI was measured between the right and left
      arms by the tetrapolar method before and during ovarian stimulation for in vitro
      fertilization (IVF). In a stepwise multiple logistic regression analysis of five
      factors (BEI on luteal day 4 prior to the IVF cycle [BEI-L4], age, basal FSH,
      body height, and body mass index), BEI-L4 alone was a significant predictor
      (P<0.05) of achievement of pregnancy by IVF in 148 women (74 pregnant and 74
      nonpregnant). BEI showed a nadir on the day of administration of hCG in the
      pregnant but not the nonpregnant group. Serum concentrations of VEGF during
      ovarian stimulation were significantly higher in the pregnant group, but not
      those of 17beta-estradiol and progesterone. The CC challenge test revealed no
      significant difference between 11 pregnant and 15 nonpregnant women. The clinical
      usefulness of BEI was evaluated in 272 consecutive IVF cycles. Rate of pregnancy
      was significantly higher (P<0.01) in IVF cycles with BEI-L4 > or =600 Ohms than
      <600 Ohms (44% and 26% in 149 and 123 cycles, respectively). When BEI-L4 was > or
      =600 Ohms, pregnancy rates were constantly high irrespective of age and basal
      FSH. In prediction of nonpregnancy, sensitivity of BEI-L4 (0.52) was
      significantly (P<0.05) higher than those of age and basal FSH (0.39 and 0.046,
      respectively). BEI, which is easy, noninvasive, and inexpensive, predicts female
      fertility more sensitively than age and basal FSH, probably reflecting angiogenic
      capacity of reproductive organs.

PMID- 10634428
TI  - Multiple sclerosis as a neuronal disease.

PMID- 10634429
TI  - Familial risk for Alzheimer disease in ethnic minorities: nondiscriminating
      genes.

PMID- 10634430
TI  - Amyotrophy in prion diseases.
AB  - Amyotrophic lateral sclerosis was once thought to be caused by persistent viral
      infection, partly because some patients with transmissible Creutzfeldt-Jakob
      disease showed prominent amyotrophy. However, in the past 15 years there has been
      little interest in the amyotrophy in prion diseases, and the possible link to
      amyotrophic lateral sclerosis has been eschewed. We analyzed case reports of
      prion disease published after 1968 for evidence of amyotrophy. We defined
      amyotrophy as clinically evident fasciculation buttressed by electromyographic
      results in some cases. We sought evidence of motor neuron degeneration at
      autopsy. Prion disease was proved by transmissibility, immunohistochemistry
      demonstration of protease-resistant prion protein, or finding a mutation in the
      prion protein gene. Amyotrophy was noted in 27 patients: 13 with sporadic
      Creutzfeldt-Jakob disease, 2 with familial Creutzfeldt-Jakob disease, and 12 with
      Gerstmann-Straussler-Scheinker disease. Of the 27, 23 showed clinical
      fasciculation and 10 had electromyographic evidence of denervation. The spinal
      cord was examined in 8 patients: 6 showed loss of motor neurons, 1 showed
      vacuolation of motor neurons, and 1 reported no abnormalities. Another 23
      patients had typical histopathological characteristics but lacked molecular or
      biochemical proof of prion disease. The total number of patients with amyotrophy
      and proven prion disease that we identified was 50. This case review supports the
      belief that amyotrophy is occasionally a prominent feature of Creutzfeldt-Jakob
      disease and underscores the importance of documenting lower motor neuron function
      and the crucial role of examining the spinal cord at autopsy in cases of prion
      disease.

PMID- 10634431
TI  - Carotid endarterectomy: a neurotherapeutic advance.

PMID- 10634432
TI  - The brain code in health and disease.

PMID- 10634433
TI  - The initial strategy for assembly of part of the central nervous system.

PMID- 10634434
TI  - A century and a half of modern neurology, a decade of the brain, and the
      millennium.

PMID- 10634435
TI  - Clinical neurology: 20th-century achievements.

PMID- 10634436
TI  - Genomic neurology.

PMID- 10634437
TI  - Neurogene therapy for the 21st century.

PMID- 10634438
TI  - Stroke research and the 21st century.

PMID- 10634439
TI  - Hey Mrs Robinson, it's therapeutics!

PMID- 10634440
TI  - Will neurological practice be different during the 21st century.

PMID- 10634441
TI  - Neurobiological understanding of myelination in the 21st century.

PMID- 10634442
TI  - Neurology: from nihilism to therapy.

PMID- 10634443
TI  - A century of imaging.

PMID- 10634445
TI  - Neurology at the millennium.

PMID- 10634444
TI  - Neurogenetics: three wishes to Santa Claus.

PMID- 10634446
TI  - Advances in neurology in the 20th century.

PMID- 10634447
TI  - Achievements of the last century in neurosurgery and a view to the 21st century.

PMID- 10634448
TI  - Medical and neurologic education at the millennium.

PMID- 10634449
TI  - Fiction, reality, and molecular neurology.

PMID- 10634450
TI  - Axonal injury or loss in the internal capsule and motor impairment in multiple
      sclerosis.
AB  - OBJECTIVE: To test the hypothesis that axonal damage extending into primarily
      normal-appearing white matter is clinically important by comparing the
      concentrations of N-acetylaspartate (NAA) bilaterally within the internal capsule
      with lateralization of motor impairment in patients with multiple sclerosis (MS)
      and persistent asymmetrical motor deficit. DESIGN: We performed magnetic
      resonance spectroscopy and T2-weighted imaging of the internal capsule,
      calculated central motor conduction times, and related these results to measures
      of motor function asymmetry in 12 patients with MS. RESULTS: Levels of NAA from
      normal-appearing white matter of the internal capsule in patients with MS were
      significantly lower than those in control subjects (P = .05). Side-to-side
      differences in NAA levels were also significantly greater in patients with MS
      than in controls (P = .01). There was a correlation between asymmetry in motor
      function for the left and right limbs and asymmetry of internal capsule NAA
      concentrations (r = 0.60; P = .04). This correlation seemed slightly stronger
      when tests specifically of arm and hand motor asymmetry were considered alone.
      Central motor conduction times were abnormal in most patients with MS and showed
      a side-to-side difference that also correlated with asymmetry in motor function.
      CONCLUSION: Our demonstration of a graded association between NAA concentrations
      within primarily normal-appearing white matter of a specific tract and functional
      impairments referable to that tract suggests that axonal pathology distant from
      macroscopic lesions might be an important determinant of disability in MS.

PMID- 10634451
TI  - Familial aggregation of Alzheimer disease among whites, African Americans, and
      Caribbean Hispanics in northern Manhattan.
AB  - BACKGROUND: Alzheimer disease (AD) aggregates in families. OBJECTIVE: To compare
      the familial aggregation and lifetime risk of AD to the age of 90 years in the
      first-degree relatives of patients with AD and unrelated controls among Caribbean
      Hispanics, African Americans, and whites in Washington Heights, Manhattan, New
      York, NY. METHODS: Family history of AD and demographic information were obtained
      from informants of 435 patients with probable or possible AD concerning 1577
      siblings and parents and from 1094 controls without dementia concerning 3952
      siblings and parents. RESULTS: Lifetime risk of AD to the age of 90 years was
      25.9% in relatives of patients and 19.1% in relatives of controls. Rate ratio
      (RR) for AD in relatives of patients compared with relatives of controls was 1.5
      overall (95% confidence interval [CI], 1.2-1.9), and was greater for siblings
      (RR, 1.8; 95% CI, 1.2-2.5) than for parents (RR, 1.2; 95% CI, 0.9-1.8). Within
      ethnic groups, RR for AD among relatives was significantly elevated in whites
      (RR, 2.0; 95% CI, 1.2-3.3) and Hispanics (RR, 1.5; 95% CI, 1.1-2.1), but the
      difference did not reach statistical significance in African Americans (RR, 1.4;
      95% CI, 0.7-2.7). Risk of AD was greater among relatives who were women compared
      with men (RR, 1.5; 95% CI, 1.2-1.9). CONCLUSIONS: Familial aggregation of AD was
      increased among families of patients compared with those of controls in all 3
      ethnic groups. Risk of AD was highest among siblings and women relatives.

PMID- 10634452
TI  - Plaque morphology correlates with cerebrovascular symptoms in patients with
      complex aortic arch plaque.
AB  - BACKGROUND: Studies of aortic arch plaques with transesophageal echocardiography
      have demonstrated that complex aortic arch plaques (CAPs) greater than or equal
      to 4 mm in thickness are associated with ischemic stroke. Recent studies have
      demonstrated that the morphological features of plaques may aid in the
      identification of aortic plaques that are more likely to be associated with
      embolic stroke. OBJECTIVE: To identify aortic plaques that are more likely to be
      associated with embolic stroke by means of their morphological features. METHODS:
      Transcutaneous B-mode ultrasonography was used to image aortic arch plaques in
      500 consecutive patients. The criteria used to identify the morphological
      features of carotid artery plaques that are more likely to be associated with
      ischemic stroke (heterogeneous rather than homogeneous) were applied to aortic
      arch plaques. Statistical comparisons were made using the Fisher exact test.
      RESULTS: Ischemic symptoms (eg, stroke, transient ischemic attack, and amaurosis
      fugax) were present in 38% of 104 patients with CAP and in 34% of 391 patients
      without CAP. Nineteen (51%) of 37 patients with heterogeneous CAP were
      symptomatic. Twenty-one (31%) of 67 patients with homogeneous CAP were
      symptomatic (P = .04). CONCLUSION: Transcutaneous B-mode ultrasonography of the
      aortic arch can help to identify heterogeneous plaques that are more likely to be
      associated with ischemic stroke using morphological criteria derived from studies
      of carotid artery plaque.

PMID- 10634453
TI  - Educational attainment and socioeconomic status of patients with autopsy
      confirmed Alzheimer disease.
AB  - OBJECTIVE: To determine whether patients with autopsy-confirmed Alzheimer disease
      (AD) have different educational attainment and socioeconomic status than subjects
      without neurodegenerative disease. DESIGN: Comparison of 2 groups of autopsied
      patients. Information on education and occupation was obtained by telephone
      interview of relatives conducted post mortem. PATIENTS: One hundred fifteen
      patients enrolled in the University of Western Ontario Dementia Study with
      dementia and fulfilling diagnostic criteria of AD at autopsy were compared with
      142 patients 65 years or older without dementia who died in the hospital and in
      whom autopsy did not show neurodegenerative disease. MAIN OUTCOME MEASURES:
      Highest education level attained, years of education, occupation, and
      socioeconomic and income levels. All results were adjusted for sex, age at time
      of death, and year of birth. RESULTS: There were no statistically significant
      differences in education, occupation, or socioeconomic and income levels between
      the groups. CONCLUSIONS: There is no evidence that educational attainment is
      different in patients with AD than in subjects who die in the hospital from other
      diseases. These results indicate that education does not protect against advanced
      AD.

PMID- 10634454
TI  - Donepezil therapy in clinical practice: a randomized crossover study.
AB  - OBJECTIVE: To determine the efficacy of donepezil hydrochloride for the treatment
      of Alzheimer disease in patients drawn from clinical practice. DESIGN: Two
      center, randomized, placebo-controlled, double-masked crossover study. SETTING:
      Memory disorders units at Massachusetts General and Brigham and Women's
      hospitals, Boston. PATIENTS: Sixty individuals (30 men and 30 women; mean +/- SD
      age, 75.0+/-9.5 years) with probable Alzheimer disease and scores of 20 or less
      on the information-memory-concentration subscale of the Blessed Dementia Scale.
      INTERVENTIONS: Placebo wash-in, followed in randomized sequence by (1) donepezil
      hydrochloride therapy, 5 mg/d, for 6 weeks, followed by placebo washout for 6
      weeks and (2) placebo treatment for 6 weeks. PRIMARY OUTCOME MEASURE: Change in
      Alzheimer's Disease Assessment Scale cognitive subscale scores from the beginning
      to the end of the two 6-week treatment periods. RESULTS: Among patients
      completing treatment and testing for both periods (n = 48), subscale scores
      improved (mean +/- SEM) 2.17+/-0.98 points (95% confidence interval, 0.20-4.10
      points) during donepezil therapy relative to placebo therapy (P = .04). Scores
      returned toward baseline within 3 weeks of drug washout. There was no associated
      change in caregiver-rated global impression (donepezil vs placebo: proportion
      improved, 0.24 vs 0.22; proportion worsened, 0.27 vs 0.35; P = .34) or on
      specific tests of explicit memory or verbal fluency. Contrary to studies with
      tacrine, the presence of the apolipoprotein E epsilon4 allele did not predict
      donepezil treatment failure. Most common adverse events related to donepezil
      therapy were nausea (5 patients), diarrhea (3 patients), and agitation (3
      patients). Serious events possibly related to drug use were seizure,
      pancreatitis, and syncope (1 patient each). CONCLUSION: This independent
      confirmation of data from phase 3 trials suggests that donepezil therapy modestly
      improves cognition in patients with Alzheimer disease who are encountered in
      clinical practice.

PMID- 10634455
TI  - Plasma and cerebrospinal fluid levels of amyloid beta proteins 1-40 and 1-42 in
      Alzheimer disease.
AB  - BACKGROUND: In brains with AD, Abeta is a major component of diffuse plaques.
      Previous reports showed that CSF Abeta42 levels were lower in patients with AD
      than in controls. Although studies showed higher plasma Abeta42 levels in
      familial AD, a recent report has indicated that plasma Abeta42 levels were
      similar in a sporadic AD group and controls. However, no information is published
      on plasma Abeta40 and Abeta42 levels in relation to Apo E genotype or severity of
      dementia in sporadic AD. OBJECTIVE: To examine plasma and cerebrospinal fluid
      (CSF) levels of amyloid beta protein 1-40 (Abeta40) and 1-42 (Abeta42) levels in
      patients with probable Alzheimer disease (AD) and elderly nondemented control
      subjects in relation to the apolipoprotein E (Apo E) genotype and dementia
      severity. SETTING: Two university medical centers. PATIENTS AND METHODS: Levels
      of Abeta40 and Abeta42 were measured in plasma from 78 patients with AD and 61
      controls and in CSF from 36 patients with AD and 29 controls by means of a
      sandwich enzyme-linked immunosorbent assay. RESULTS: Mean plasma Abeta40 levels
      were higher in the AD group than in controls (P = .005), but there was
      substantial overlap; Abeta42 levels were similar between the groups. Levels of
      Abeta40 and Abeta42 showed no association with sex or Mini-Mental State
      Examination scores. There was a significant relationship between age and Abeta40
      level in controls but not in the AD group. Levels of Abeta40 were higher in
      patients with AD with the Apo E epsilon4 allele than in controls (P<.01).
      Cerebrospinal fluid Abeta40 levels were similar in the AD group and controls.
      However, Abeta42 levels were lower in the AD group than in controls (P<.001). The
      levels showed no association with severity of dementia. CONCLUSIONS: Although
      mean plasma Abeta40 levels are elevated in sporadic AD and influenced by Apo E
      genotype, measurement of plasma Abeta40 levels is not useful to support the
      clinical diagnosis of AD. Lower levels of CSF Abeta42 in the AD group are
      consistent with previous studies.

PMID- 10634456
TI  - Amyotrophic lateral sclerosis mimic syndromes: a population-based study.
AB  - BACKGROUND: The Irish ALS Register is a population-based register of the
      epidemiological characteristics of amyotrophic lateral sclerosis (ALS) in the
      republic of Ireland. OBJECTIVE: To describe the clinical and demographic details
      of those patients included in the Irish ALS Register who were incorrectly
      diagnosed as having ALS (patients who were ultimately rediagnosed as having an
      "ALS mimic syndrome"). METHODS: The medical records of each patient referred to
      the register are routinely reviewed and, where possible, patients are examined by
      our group during their illness. RESULTS: Between January 1, 1993, and December
      31, 1997, 32 patients (representing 7.3% of 437 referrals) were rediagnosed as
      having a condition other than ALS. The median age at onset for these 32 patients
      was 56.0 years (range, 19.5-85.8 years) for men and 53.5 years (range, 39.5-70.4
      years) for women. Twenty-nine patients (91%) presented with symptoms referable to
      the limbs, and the remainder presented with symptoms involving the bulbar
      musculature. Multifocal motor neuropathy was the most common condition mistaken
      for ALS, accounting for 7 cases (22%), followed closely by Kennedy disease (4
      cases [13%]). Factors leading to diagnostic revision included evolution of
      atypical symptoms, results of specific investigations, and failure of symptoms to
      progress. Twenty-seven (84%) of the patients with an ALS mimic syndrome fulfilled
      the El Escorial criteria for either "suspected" or "possible" ALS, 4 (13%) met
      the criteria for probable ALS, and 1 (3%) had definite ALS. CONCLUSIONS: The
      application of the El Escorial diagnostic criteria may facilitate early
      recognition of non-ALS cases. Misdiagnosis of ALS remains a common clinical
      problem despite the increased availability of investigations and a greater
      awareness among neurologists of potential diagnostic pitfalls.

PMID- 10634457
TI  - St Louis encephalitis: a review of 11 cases in a 1995 Dallas, Tex, epidemic.
AB  - OBJECTIVE: To update some of the clinical features of St Louis encephalitis
      (SLE), a common arboviral infection that occurs in epidemic patterns in the south
      central and midwestern United States. METHODS: Eleven patients with SLE from a
      1995 epidemic in Dallas, Tex, were studied clinically, radiologically,
      neurophysiologically, and neuropathologically (in 1 case). RESULTS: The
      electroencephalograms and magnetic resonance imaging (MRI) scans of our patients
      revealed features that have received little attention in previous studies. Of the
      9 patients who were examined with electroencephalography, all 9 had seizures or
      other abnormalities, and 1 had nonconvulsive status epilepticus. Two of 6
      patients who had MRIs showed substantia nigra edema. Finally, 2 (18%) of our
      patients had coinfection with the human immunodeficiency virus. CONCLUSIONS: The
      MRI findings of substantia nigra edema in patients with SLE have not been
      previously reported. Nonconvulsive status epilepticus can occur in patients with
      SLE and should be considered in patients with prolonged encephalopathy. Finally,
      human immunodeficiency virus coinfection may be a risk factor for symptomatic SLE
      infection.

PMID- 10634458
TI  - Multifocal dural enhancement associated with temporal arteritis.
AB  - OBJECTIVE: To report the association of temporal arteritis and enhancement of the
      dura mater and temporalis muscle. DESIGN AND METHODS: A single patient with a
      complaint of headache and diplopia was studied. SETTING: Academic medical center.
      PATIENT: A 69-year-old man presented with lateral rectus weakness, temporal
      artery tenderness, and an erythrocyte sedimentation rate of 65 mm/h.
      INTERVENTION: Biopsy of temporal artery and dura mater. MAIN OUTCOME MEASURES:
      Brain magnetic resonance imaging and pathological findings. RESULTS: Magnetic
      resonance imaging of the brain showed multifocal dural enhancement and
      enhancement of the temporalis muscles. The temporal artery showed a necrotizing
      vasculitis and the dura showed perivascular inflammatory cells. CONCLUSION: It is
      proposed that the temporal arteritis caused the multifocal dural enhancement and
      temporalis muscle enhancement on magnetic resonance imaging.

PMID- 10634459
TI  - Bilateral focal polymicrogyria in Ehlers-Danlos syndrome.
AB  - BACKGROUND: Ehlers-Danlos syndrome (EDS) is a heterogeneous group of generalized
      connective tissue disorders that has been described in association with epilepsy
      and cerebral cortical dysplasia, mostly gray matter heterotopias, in 3 reports.
      However, to our knowledge, association of EDS with another type of cortical
      cerebral dysplasia, bilateral focal polymicrogyria, has never previously been
      described. SETTING: Two research-oriented hospitals. PATIENTS: We describe 2
      patients with EDS and bilateral polymicrogyria. The first, a 29-year-old black
      man, presented with EDS of unspecified type, seizures, and bilateral
      frontocentral and frontoposterior polymicrogyria with hypoplasia of the inferior
      part of the cerebellar vermis. The second, a 20-year-old woman, had type III EDS,
      seizures and congenital bilateral perisylvian syndrome with polymicrogyria.
      CONCLUSIONS: The association of bilateral focal polymicrogyria and EDS in these 2
      patients suggests that extracellular matrix proteins implicated in the
      pathogenesis of EDS, such as collagen and tenascin, may play an important role in
      cerebral cortical formation and organization. In a clinical setting, the
      association of EDS with these cortical structural lesions has implications for
      diagnosis and management.

PMID- 10634460
TI  - Craniospinal intradural arachnoid cyst.

PMID- 10634461
TI  - Medical record documentation in 1999: let's cooperate.

PMID- 10634462
TI  - Medical record documentation in 1999: let's not cooperate.

PMID- 10634463
TI  - Medical record documentation: 1999.

PMID- 10634464
TI  - Pompe's disease.

PMID- 10634465
TI  - Complementary and complimentary neurology.

PMID- 10634466
TI  - Microelectrophoresis and auxilary micromethods.
AB  - In this retrospect of approximately 30 years of work with micromethods, some of
      them developed in our own laboratory, their principles and application to
      different separation problems are described, such as one- and two-dimensional
      microelectrophoresis in capillaries and microslab gels, isoelectric focusing in
      capillaries or microslab gels, microchromatography, microphotometry, and
      microfluorometry for qualitative and quantitative evaluation of separation
      patterns. In addition, some useful auxiliary methods are also described, e.g., a
      method for quantitative protein determination in a microliter volume when neither
      the volume nor the protein content in that volume are known, and methods for the
      determination of glycoproteins, amino acids, and sugars in the picomole range.

PMID- 10634467
TI  - Polymer microfabrication methods for microfluidic analytical applications.
AB  - A growing number of microsystem technology (MST) applications, particularly in
      the field of microfluidics with its applications in the life sciences, have a
      need for novel fabrication methods which account for substrates other than
      silicon or glass. We present in this paper an overview of existing polymer
      microfabrication technologies for microfluidic applications, namely replication
      methods such as hot embossing, injection molding and casting, and the
      technologies necessary to fabricate the molding masters. In addition, techniques
      such as laser ablation and layering techniques are examined. Methods for bonding
      and dicing of polymer materials, which are necessary for complete systems, are
      evaluated.

PMID- 10634468
TI  - Fabrication of microfluidic systems in poly(dimethylsiloxane).
AB  - Microfluidic devices are finding increasing application as analytical systems,
      biomedical devices, tools for chemistry and biochemistry, and systems for
      fundamental research. Conventional methods of fabricating microfluidic devices
      have centered on etching in glass and silicon. Fabrication of microfluidic
      devices in poly(dimethylsiloxane) (PDMS) by soft lithography provides faster,
      less expensive routes than these conventional methods to devices that handle
      aqueous solutions. These soft-lithographic methods are based on rapid prototyping
      and replica molding and are more accessible to chemists and biologists working
      under benchtop conditions than are the microelectronics-derived methods because,
      in soft lithography, devices do not need to be fabricated in a cleanroom. This
      paper describes devices fabricated in PDMS for separations, patterning of
      biological and nonbiological material, and components for integrated systems.

PMID- 10634469
TI  - Capillary electrophoresis on microchip.
AB  - Capillary electrophoresis and related techniques on microchips have made great
      strides in recent years. This review concentrates on progress in capillary zone
      electrophoresis, but also covers other capillary techniques such as isoelectric
      focusing, isotachophoresis, free flow electrophoresis, and micellar
      electrokinetic chromatography. The material and technologies used to prepare
      microchips, microchip designs, channel geometries, sample manipulation and
      derivatization, detection, and applications of capillary electrophoresis to
      microchips are discussed. The progress in separation of nucleic acids and
      proteins is particularly emphasized.

PMID- 10634470
TI  - DNA sequencing by capillary array electrophoresis and microfabricated array
      systems.
AB  - To comply with the current needs for high-speed DNA sequencing analysis, several
      instruments and innovative technologies have been introduced by several groups in
      recent years. This review article discusses and compares the issues regarding
      high-throughput DNA sequencing by electrophoretic methods in miniaturized
      systems, such as capillaries, capillary arrays, and microchannels. Initially,
      general features of several capillary array designs (including commercial ones)
      will be considered, followed by similar analyses with microfabricated array
      electrophoretic devices and how they can contribute to the success of large
      sequencing projects.

PMID- 10634471
TI  - Dielectrophoretic manipulation of suspended submicron particles.
AB  - Planar and three-dimensional multi-electrode systems with dimensions of 2 - 40
      microm were fabricated by IC technology and used for trapping and aggregation of
      microparticles. To achieve negative dielectrophoresis (repelling forces) in
      aqueous solution, radiofrequency (RF) electric fields were used. Experimentally,
      particles down to 100 nm in diameter were enriched and trapped as aggregates in
      field cages and dielectrophoretic microfilters and observed using confocal
      fluorimetry. Theoretically, single particles with an effective diameter down to
      about 35 nm should be trappable in micron field cages. Due to the unavoidable
      Ohmic heating, RF electric fields can induce liquid streaming in extremely small
      channels (12 microm in height). This can be used for pumping and particle
      enrichment but it enhances Brownian motion and counteracts dielectrophoretic
      trapping. Combining Brownian motion with ratchet-like dielectrophoretic forces
      enables the creation of Brownian pumps that could be used as sensitive separation
      devices for submicron particles if liquid pumping is avoided in smaller
      structures.

PMID- 10634472
TI  - Differential transport of DNA by a rectified Brownian motion device.
AB  - An interdigitated electrode array (IDEA) device has been designed and used to
      transport DNA based on a Brownian ratchet mechanism. This migration is produced
      by the periodic formation of an asymmetric sawtooth electric field in the device.
      Oligonucleotides of 25, 50, and 100 bases in length were tested using two
      different array geometries. DNA transport as a function of DNA size, electric
      field frequency, and array geometry is shown to be in qualitative agreement with
      theory. Such a device could provide for DNA separations over a broad size range,
      and can be readily scaled as a component in a microfabricated DNA analysis
      system.

PMID- 10634473
TI  - Sorting biomolecules with microdevices.
AB  - Micro- and nanofabrication techniques have provided an unprecedented opportunity
      to create a designed world in which separation and fractionation technologies
      which normally occur on the macroscopic scale can be optimized by designing
      structures which utilize the basic physics of the process, or new processes can
      be realized by building structures which normally do not exist without external
      design. Since microfabrication is exceedingly sophisticated in its development,
      it is possible to design and construct highly creative microdevices which allow
      one to probe specific aspects of biological objects. We give examples of uses of
      micro- and nanofabrication which, as opposed to simply shrinking the size of the
      vessels or tubes used in macroscopic lab environments, utilize our understanding
      of the physics of the process to take advantage of fabrication technologies.

PMID- 10634474
TI  - Parallel reactions in open chip-based nanovials with continuous compensation for
      solvent evaporation.
AB  - In an earlier report (Litborn, E., Emmer, A., Roeraade, J., Anal. Chim. Acta
      1999, 401, 11-19, we described a technique for performing chemistry in chip-based
      vials. A major problem, solvent evaporation, was partially remedied by using a
      closed humidity chamber. In this paper we report an improved technique for
      performing parallel reactions in open, 15 nL volume, chip-based vials. The
      evaporation of solvent from the reaction fluid was continuously compensated by
      addition of solvent via an array of microcapillaries. The suitability of the
      method was demonstrated by performing eight separate peptide maps of myoglobin in
      parallel, using the three enzymes trypsin, alpha-chymotrypsin and endoproteinase
      Glu-C. The total amount of myoglobin utilized to perform the eight digests was
      less than 100 pmol. The corresponding amount of enzymes was ca. 0.1 pmol per
      reaction. In order to evaluate the operating limits of the technique, a study of
      the evaporation of solvents from a series of vials with proportionally smaller
      volumes operated at different temperatures was performed. The results showed that
      the concept for continuous compensation of solvent evaporation should be
      applicable to reaction volumes down to 30 pL.

PMID- 10634475
TI  - Effects of the electric field distribution on microchip valving performance.
AB  - Valving characteristics on microfluidic devices were controlled through
      manipulation of the electric field strengths during both the sample loading and
      dispensing steps. Three sample loading profiles for the constant volume valve
      (pinched injection) in conjunction with four dispensing schemes were investigated
      to study valving performance. The sample confinement profiles for the sample
      loading step consisted of a weakly pinched sample, a medium pinched sample, and a
      strongly pinched sample. Four dispensing schemes varied the electric field
      strengths in the sample and sample waste channels relative to the analysis
      channel to control the volume of the sample dispensed from the valve. The axial
      extent of the sample plug decreased as the electric field strengths in the sample
      and sample waste channels were raised relative to the analysis channel. In
      addition, a trade-off existed between sample plug length and sensitivity.

PMID- 10634476
TI  - Electrokinetic control of fluid flow in native poly(dimethylsiloxane) capillary
      electrophoresis devices.
AB  - Capillary zone electrophoresis (CZE) devices fabricated in poly(dimethylsiloxane)
      (PDMS) require continuous voltage control of all intersecting channels in the
      fluidic network in order to avoid catastrophic leakage at the intersections. This
      contrasts with the behavior of similar flow channel designs fabricated in glass
      substrates. When the injection plugs are shaped by voltage control and leakage
      from side channels is controlled by the application of pushback voltages during
      separation, fluorescein samples give 64 200 theoretical plates (7000 V separation
      voltage, E = 1340 V/cm). Native PDMS devices exhibit stable retention times (+/-
      8.6% RSD) over a period of five days when filled with water. Contact angles were
      unchanged (+/- 1.9% RSD) over a period of 16 weeks of dry storage, in contrast to
      the known behavior of plasma-oxidized PDMS surfaces. Electroosmotic flow (EOF)
      was observed in the direction of the cathode for the buffer systems studied
      (phosphate, pH 3-10.5), in the presence or absence of hydrophobic ions such as
      tetrabutylammonium or dodecyl sulfate. Electroosmotic mobilities of 1.49 x 10(-5)
      and 5.84 x 10(-4) cm2/Vs were observed on average at pH 3 and 10.5, respectively,
      the variation strongly suggesting that silica fillers in the polymer dominate the
      zeta potential of the material. Hydrophobic compounds such as dodecyl sulfate and
      BODIPY 493/503 adsorbed strongly to the PDMS, indicating the hydrophobicity of
      the channel walls is clearly problematic for CZE analysis of hydrophobic
      analytes. A method to stack multiple channel layers in PDMS is also described.

PMID- 10634477
TI  - Active micromixer for microfluidic systems using lead-zirconate-titanate (PZT)
      generated ultrasonic vibration.
AB  - A micromixer using direct ultrasonic vibration is first reported in this paper.
      The ultrasonic vibration was induced by a bulk lead-zirconate-titanate (PZT; 5 x
      4 x 0.2 mm), which was excited by a 48 kHz square wave at 150 V (peak-to-peak).
      Liquids were mixed in a chamber (6 x 6 x 0.06 mm) with an oscillating diaphragm
      driven by the PZT. The oscillating diaphragm was in the size of 6 x 6 x 0.15 mm.
      Ethanol and water were used to test the mixing effectiveness. The laminar flows
      of ethanol (115 microL/min) and water (100 microL/min) were mixed effectively
      when the PZT was excited. The entire process was recorded using a video camera.

PMID- 10634478
TI  - Towards stationary phases for chromatography on a microchip: molded porous
      polymer monoliths prepared in capillaries by photoinitiated in situ
      polymerization as separation media for electrochromatography.
AB  - Photoinitiated free radical polymerization has been used for the preparation of
      porous polymer monoliths within UV transparent fused silica capillaries and
      quartz tubes. These formats were used as models for the preparation of the
      separation media within channels of microfabricated devices. A mixture of
      ethylene dimethacrylate, butyl methacrylate, and 2-acrylamido-2-methyl-1
      propanesulfonic acid was polymerized in the presence of a porogenic solvent
      consisting of 1-propanol, 1,4-butanediol, and water at room temperature under UV
      irradiation. Modification of the porogen composition enables the tailoring of
      pore size within the broad range from ca. 100 to 4000 nm. Scanning electron
      micrographs confirmed the homogeneity of the porous structure of the materials
      prepared, even in a quartz tube with a diameter as large as 4 mm. Separation
      properties of the resulting capillary columns were tested in capillary
      electrochromatography (CEC) mode using a mixture of thiourea and eight aromatic
      compounds. Plate number as high as 210 000 plates/m were found for a capillary
      column with optimized porous properties. The monolithic columns were also able to
      separate mixtures of peptides.

PMID- 10634479
TI  - A microfluidic system for high-speed reproducible DNA sizing and quantitation.
AB  - Microfabrication technology was used to develop a system consisting of disposable
      glass chips containing etched channels, reagents including polymer matrix and
      size standards, computer-controlled instrumentation for performing
      electrophoretic separations and fluorescence detection of double-stranded DNA,
      and software for automated data analysis. System performance was validated for
      separation and quantitation reproducibility using samples varying in amount and
      size of DNA fragments, buffer composition, and salt concentrations. Several
      applications of the microfluidic system for DNA analysis have been demonstrated,
      such as of polymerase chain reaction (PCR) products, sizing of plasmid digests,
      and detection of point mutations by restriction fragment length polymorphism
      (RFLP) mapping.

PMID- 10634480
TI  - A transmission imaging spectrograph and microfabricated channel system for DNA
      analysis.
AB  - In this paper we present the development of a DNA analysis system using a
      microfabricated channel device and a novel transmission imaging spectrograph
      which can be efficiently incorporated into a high throughput genomics facility
      for both sizing and sequencing of DNA fragments. The device contains 48 channels
      etched on a glass substrate. The channels are sealed with a flat glass plate
      which also provides a series of apertures for sample loading and contact with
      buffer reservoirs. Samples can be easily loaded in volumes up to 640 nL without
      band broadening because of an efficient electrokinetic stacking at the
      electrophoresis channel entrance. The system uses a dual laser excitation source
      and a highly sensitive charge-coupled device (CCD) detector allowing for
      simultaneous detection of many fluorescent dyes. The sieving matrices for the
      separation of single-stranded DNA fragments are polymerized in situ in denaturing
      buffer systems. Examples of separation of single-stranded DNA fragments up to 500
      bases in length are shown, including accurate sizing of GeneCalling fragments,
      and sequencing samples prepared with a reduced amount of dye terminators. An
      increase in sample throughput has been achieved by color multiplexing.

PMID- 10634481
TI  - DNA sequencing in a monolithic microchannel device.
AB  - We present 50 cm long microchannels in a monolithic device for high resolution,
      long read-length DNA sequencing. These devices were fabricated and bonded in
      borofloat glass using unconventional photolithography techniques with 48-188
      independent, straight microchannels. The microchannel DNA separation was tested
      with POP-6 polymer and a DNA sequencing ladder separated at room temperature and
      200 V/cm. Single-base resolution greater than 600 bases was achieved and the
      sequence base called to 640 bases with 98% accuracy. Under the same experimental
      conditions, the performance of the microchip was identical to a fused-silica
      capillary with similar cross-sectional area.

PMID- 10634482
TI  - Active microeletronic chip devices which utilize controlled electrophoretic
      fields for multiplex DNA hybridization and other genomic applications.
AB  - Microelectronic DNA chip devices that contain planar arrays of microelectrodes
      have been developed for multiplex DNA hybridization and a variety of genomic
      research and DNA diagnostic applications. These devices are able to produce
      almost any desired electric field configuration on their surface. This ability to
      produce well-defined electric fields allows charged molecules (DNA, RNA,
      proteins, enzymes, antibodies, nanobeads, and even micron scale semiconductor
      devices) to be electrophoretically transported to or from any microlocation on
      the planar surface of the device. Of key importance to the device function is the
      permeation layer which overcoats the microelectrodes. The permeation layer is
      generally a porous hydrogel material that allows water molecules and small ions
      (Na+, CI-, etc.) to freely contact the microelectrode surface, but impedes the
      transport of the larger analytes (oligonucleotides, DNA, RNA, proteins, etc.).
      The permeation layer prevents the destruction of DNA at the active microelectrode
      surface, ameliorates the adverse effects of electrolysis products on the
      sensitive hybridization reactions, and serves as a porous support structure for
      attaching DNA probes and other molecules to the array. In order to maintain rapid
      transport of DNA molecules, facilitate hybridization, and work within constrained
      current and voltage ranges, low conductance buffers and various electronic
      pulsing scenarios have also been developed. These active microelectronic array
      devices allow electrophoretic fields to be used to carry out accelerated DNA
      hybridization reactions and to improve selectivity for single nucleotide
      polymorphism (SNP), short tandem repeat (STR), and point mutation analysis.

PMID- 10634483
TI  - Analysis of DNA fragments by microchip electrophoresis fabricated on poly(methyl
      methacrylate) substrates using a wire-imprinting method.
AB  - Microfluidic devices were fabricated on poly(methyl methacrylate) (PMMA)
      substrate using two small-diameter (79 microm) wires to create a cross impression
      in plastics softened by low-temperature heating. The resulting channels had a
      rounded shape and 75 microm in depth. The variability of the channel dimensions
      was found to be less than 6% from different locations of the same channel and
      less than 10% between chips. Moreover, the fabricated PMMA chip appeared to
      sustain an electric field strength up to 300 V/cm without significant Joule
      heating. The function of resulting devices for electrophoretic injection and
      separation of a DNA size marker, HaeIII digest of (phiX174, was also
      characterized. Results indicated that all of the 11 DNA fragments of the size
      marker could be identified in less than 3 min with relative standard deviations
      less than 0.4% and 8% for migration time and peak area, respectively. Moreover,
      with the use of near infrared (IR) dye, fluorescence signals of the higher
      molecular weight fragments (> 603 bp in length) could be detected at total DNA
      concentrations as low as 0.1 microg/mL (S/N = 4.2). In conclusion, the
      performance of wire-imprinted devices on PMMA substrate were comparable to those
      fabricated by other professional means.

PMID- 10634484
TI  - Manipulation of globular DNA molecules for sizing and separation.
AB  - Handling large DNA molecules, such as chromosomal DNA, has become necessary due
      to recent developments in genome science. However, large DNA molecules are
      fragile and easily broken by shear stress accompanying flow in solution. This
      fragility causes difficulties in the preparation and handling of large DNA
      molecules. This study demonstrates the transition of DNA from a coiled to a
      globular form, which is highly condensed. This state suppresses DNA fragmentation
      due to shear stress in solution. The transition enables large DNA molecules to
      undergo mechanical manipulation. We confirmed that the fluorescence intensity of
      stained globular DNA increases with increasing length, suggesting that the
      resistance of globular DNA to shear stress is the factor that allows analysis of
      large DNA by flow cytometry.

PMID- 10634485
TI  - Fast separation of oligonucleotide and triplet repeat DNA on a microfabricated
      capillary electrophoresis device and capillary electrophoresis.
AB  - A laser-induced fluorescence detection system coupled with a highly sensitive
      silicon-intensified target (SIT) camera is successfully applied to the imaging of
      a band for DNA fragment labeling by fluorescence dye in a microchannel, and to
      the visualizing of the separation process on a microfabricated chip. We
      demonstrated that an only 6 mm separation channel is sufficient for the
      separation of triplet repeat DNA fragment and DNA molecular marker within only 12
      s. The separation using the microfabricated capillary electrophoresis device is
      confirmed to be at least 18 times faster than the same separation carried out by
      conventional capillary electrophoresis with 24.5 cm effective length. The use of
      a short capillary with 8.5 cm effective length is also efficient for fast
      separation of DNA; however, the microchip technology is even faster than
      capillary electrophoresis using a short capillary.

PMID- 10634486
TI  - An enhanced microfluidic chip coupled to an electrospray Qstar mass spectrometer
      for protein identification.
AB  - The combination of microfabricated fluidic systems (muFAB) and electrospray mass
      spectrometers (ESI-MS) will provide multiplexed and integrated analytical systems
      for proteins and other biomolecules. Implementation of this novel approach
      requires the development of robust and user-friendly muFAB devices. Here, we
      present new approaches that improve the robustness, user friendliness and
      performance of muFAB devices coupled to MS. First, we present the development of
      a convenient mount to connect a muFAB device to the ESI-MS and the incorporation
      of filters in the reservoirs and exit of the muFAB. This mount facilitates
      interfacing and significantly reduces the chemical noise observed by the MS.
      Furthermore, we demonstrate improvements in sample handling and delivery by using
      either a nonaqueous electrolyte or a cationic coating on the surfaces in the
      muFAB device and transfer capillary. These improvements are applied to protein
      analysis by continuous infusion of proteolytic digests.

PMID- 10634487
TI  - Microfabricated isoelectric focusing device for direct electrospray ionization
      mass spectrometry.
AB  - A novel microfabricated device for isoelectric focusing (IEF) incorporating an
      optimized electrospray ionization (ESI) tip was constructed on polycarbonate
      plates using laser micromachining. The IEF microchip incorporated a separation
      channel (50 micro x 30 micro x 16 cm), three fluid connectors, and two buffer
      reservoirs. Electrical potentials used for IEF focusing and electrospray were
      applied through platinum electrodes placed in the buffer reservoirs, which were
      isolated from the separation channel by porous membranes. Direct ESI-mass
      spectrometry (MS) using electrosprays produced directly from a sharp emitter
      "tip" on the microchip was evaluated. The results indicated that this design can
      produce a stable electrospray and that performance was further improved and made
      more flexible with the assistance of a sheath gas and sheath liquid. Error
      analysis of the spectral data showed that the standard deviation in signal
      intensity for an analyte peak was less than approximately 5% over 3 h. The
      production of stable electrosprays directly from microchip IEF device represents
      a step towards easily fabricated microanalytical devices. Microchannel IEF
      separations of protein mixtures were demonstrated for uncoated polycarbonate
      microchips. Direct microchannel IEF-ESI-MS was demonstrated using the
      microfabricated chip with an ion-trap mass spectrometer for characterization of
      protein mixtures.

PMID- 10634488
TI  - Rapid and sensitive separation of trace level protein digests using
      microfabricated devices coupled to a quadrupole--time-of-flight mass
      spectrometer.
AB  - The application of microfabricated devices coupled to a quadrupole time-of-flight
      mass spectrometer (Qq-TOF-MS) is presented for the analysis of trace level
      digests of gel-isolated proteins. In order to enhance the sample loading for
      proteomics analyses, two different on-chip sample preconcentration techniques
      were evaluated. First, a sample stacking procedure that used polarity switching
      to remove the sample buffer prior to zone electrophoresis was easily integrated
      on the microfabricated devices. With the present chip design, this
      preconcentration technique provided up to 70 nL sample injection with sub-nM
      detection limits for most peptide standards. For applications requiring larger
      sample loading, a disposable adsorption preconcentrator using a C18 membrane is
      incorporated outside the chip. This preconcentration method yielded lower peptide
      recoveries than that obtainable with sample stacking, and provided a convenient
      means of injecting several microL of sample with detection limits of typically
      2.5 nM for hydrophobic peptides. The analytical merits of both sample enrichment
      approaches are described for the identification of bands isolated from two
      dimensional (2-D) gel separation of protein extracts from Haemophilus influenzae.
      Accurate molecular mass measurements (< 5 ppm) in peptide mapping experiments is
      obtained by introducing an internal standard via a post-separation channel. Rapid
      identification of trace level peptides is also demonstrated using on-line tandem
      mass spectrometry and database searching with peptide sequence tags.

PMID- 10634489
TI  - High-speed chiral separations on microchip electrophoresis devices.
AB  - High-speed electrophoretic chiral separations have been successfully performed in
      a microfabricated device by employing cyclodextrin-modified micellar
      electrokinetic chromatography (CD-MEKC). Utilizing short separation channels and
      relatively high field strengths in combination with small volume-defined
      injection plugs, and operating in counter-electroosmotic flow conditions, fast
      and efficient separations of fluorescein insothiocyanate (FITC)-labeled amino
      acid enantiomers were obtained. Analysis time ranged from 75 s for the most basic
      amino acids to 160 s for the most acidic ones with associated efficiencies from
      7000 up to 28 000 effective plates (100 000 to 395 000 plates/m). Buffer
      parameters were varied in order to study the effect on chiral resolution. A
      buffer system consisting of 100 mM borate (pH 9.4), 30 mM of SDS, and 10 mM gamma
      CD as chiral selector provided adequate resolution of the majority of FITC-amino
      acid enantiomers tested.

PMID- 10634490
TI  - Ultratrace analysis of drugs in biological fluids using affinity probe capillary
      electrophoresis: analysis of dorzolamide with fluorescently labeled carbonic
      anhydrase.
AB  - This work demonstrates the use of affinity probe capillary electrophoresis (APCE)
      in the quantitative analysis of drugs in biological fluids at the low pM level.
      The interaction of human carbonic anhydrase II (HCAII) with the glaucoma drug
      dorzolamide (Dz) was chosen as a model system. HCAII was labeled at its single
      cysteine residue using a thiol-specific fluorescein reagent. The peak area of
      HCAII complexed with the tight-binding drug Dz provided a direct assay of the
      drug concentration in solution. A charged competitive ligand added to the running
      buffer was employed in APCE to distinguish Dz-bound from free forms of the HCAII.
      Using laser-induced fluorescence (LIF), the Dz detection limit was 16.5 pM in
      aqueous solution and 62.5 pM in both urine and plasma. Normalized peak area
      reproducibility of the drug was within 3.4% RSD. Each analysis was completed
      within 10 min, including incubation, and consumed only 0.3 pmol of labeled
      protein. The APCE approach provides an effective method for trace level detection
      of drugs in biological matrices.

PMID- 10634491
TI  - On-line coupling of high performance gel filtration chromatography with imaged
      capillary isoelectric focusing using a membrane interface.
AB  - A high performance liquid chromatography system, a sample preparation device, and
      an imaged capillary IEF (CIEF) instrument are integrated and multiplexed on-line.
      The system is equivalent to two-dimensional polyacrylamide gel electrophoresis (2
      D PAGE), by transferring the principle of 2-D separation to the capillary format.
      High performance liquid chromatography (HPLC) provides protein separation based
      on size using a gel filtration chromatography (GFC) column. Each eluted protein
      is sampled and directed to a novel microdialysis hollow fiber membrane device,
      where simultaneous desalting and carrier ampholyte mixing occurs. The sample is
      then driven to the separation column in an on-line fashion, where CIEF takes
      place. The fluidic technology used by our 2-D system leads to natural automation.
      The coupling of the two techniques is simple. This is attributed to high speed
      and efficiency of the sample preparation device that acts as an interface between
      the two systems, as well as the speed and simplicity of our whole column
      absorption imaged CIEF instrument. To demonstrate the feasibility of this
      approach, the separation of a mixture of two model proteins is studied. Sample
      preparation and CIEF were complete in just 4-5 min, for each of the eluted
      proteins. Total analysis time is about 24 min. Three-dimensional data
      representations are constructed. Challenges and methods to further improve our
      instrument are discussed, and the design of an improved horseshoe-shaped sample
      preparation sample loop membrane interface is presented and characterized.

PMID- 10634492
TI  - Ultrafast detection of microsatellite repeat polymorphism in endothelin 1 gene by
      electrophoresis in short capillaries.
AB  - The methodology and instrumentation for fast denaturing electrophoresis in short
      capillaries was developed and exemplified by detection of short tandem repeat
      polymorphism in the endothelin 1 gene. The resolution of two nucleotides, which
      is required for the detection of a dinucleotide repeat polymorphism, was achieved
      in a capillary of an effective length of 2.5 cm at a temperature of 600C and an
      electric field strength of 600 V/cm in 42 s. Thus, the use of denaturing
      electrophoresis in short capillaries with laser-induced fluorescence detection
      resulted in a reduction of analysis time by a factor of 200 when compared to the
      conventional slab gel electrophoresis. The developed methodology and
      instrumentation is advantageous for an implementation in clinical diagnostics and
      genetic population screening where fast analytical instrumentation amenable to
      automation is of paramount importance.

PMID- 10634493
TI  - Fraction collection in micropreparative capillary zone electrophoresis and
      capillary isoelectric focusing.
AB  - A new fraction collection system for capillary zone electrophoresis (CZE) and
      capillary isolelectric focusing (CIEF) is described. Exact timing of the
      collector steps was based on determining the velocity of each individual zone
      measured between two detection points close to the end of the capillary.
      Determination of the zone velocity shortly before collection overcame the need
      for constant analyte velocity throughout the column. Consequently, sample
      stacking in CZE with large injection volumes as well as zone focusing in CIEF
      could be utilized with high collection accuracy. Capillaries of 200 microm inner
      diameter (ID) were employed in CZE and 100 microm ID in CIEF for the
      micropreparative mode. A sheath flow fraction collector was used to maintain
      permanent electric current during the collection. The bulk liquid flow due to
      siphoning, as well as the backflow arising from the sheath flow droplet pressure,
      were suppressed by closing the separation system at the inlet with a
      semipermeable membrane. In the CZE mode, the performance of the fraction
      collector is demonstrated by isolation of individual peaks from a fluorescently
      derivatized oligosaccharide ladder. In the CIEF mode, collection of several
      proteins from a mixture of standards is shown, followed by subsequent analysis of
      each protein fraction by matrix-assisted laser desorption/ionization time-of
      flight mass spectrometry (MALDI-TOF-MS).

PMID- 10634494
TI  - A developmental time line in a retinal slice from rainbow trout.
AB  - The retina in teleost fish continues to grow throughout much of the life of the
      animal, in part by the continuing differentiation of new tissue at the retinal
      margin, an area termed the peripheral growth zone (PGZ) (Lyall, Q J Micros Sci,
      1957:98:101-110). We have developed a retinal slice preparation--including the
      PGZ--from juvenile rainbow trout (Onchorynchus mykiss), a species in which
      retinal growth is rapid and the PGZ is correspondingly pronounced. The PGZ slice
      preparation contains a time line of retinal development, with cells at different
      stages of maturation present side by side. We present evidence that the birth
      sequence of the various retinal cell types in the PGZ recapitulates the sequence
      during embryonic development. We also report data on the rate of growth of the
      PGZ in juvenile trout in vivo. Finally, we have used the PGZ slice preparation to
      make whole-cell voltage clamp recordings from individual retinal GCs at both
      early and late stages of maturation. We report that the amplitude of delayed
      rectifier and A-type potassium currents increases during GC maturation.

PMID- 10634495
TI  - Algorithmic complexity as an index of cortical function in awake and
      pentobarbital-anesthetized rats.
AB  - This study introduces algorithmic complexity to measure characteristics of brain
      functions. The EEG of the rat was recorded with implanted electrodes. The
      normalized complexity value was relatively independent of data length, and it
      showed a simpler and easier calculation characteristic than other non-linear
      indexes. The complexity index revealed significant differences among awake,
      asleep, and anesthetized states. It may be useful in tracking short-term and long
      term changes in brain functions, such as anesthetized depth, drug effects, or
      sleep-wakefulness.

PMID- 10634496
TI  - Histochemical mapping of the substrate for brain-stimulation reward with glycogen
      phosphorylase.
AB  - Glycogen phosphorylase is the enzyme that regulates glycogenolysis and it appears
      that there is a relationship between central levels of glycogen and neuronal
      activity, which is influenced by a variety of neurotransmitters. In the present
      study, glycogen phosphorylase histochemistry was used to correlate changes in
      metabolic activity in response to rewarding lateral hypothalamic stimulation.
      Rats were allowed to self-stimulate for 1 h per day for ten consecutive days
      following which postmortem phosphorylase a activity was examined. Significant
      differences in optical density between the stimulated and contralateral
      hemispheres were found in three of the eight analyzed structures, two of which,
      the diagonal band of Broca and the caudate nucleus, showed a greater density of
      glycogen phosphorylase a on the stimulated side and the third, the habenula, had
      greater contralateral activity. In conclusion, our data suggest that glycogen
      phosphorylase activity is a viable but not weighty marker of energy alterations
      induced by chronic exposure to intracranial self-stimulation, and that it is
      generally consistent with the patterns revealed by other metabolic indices such
      as cytochrome oxidase and 2-deoxyglucose autoradiography.

PMID- 10634497
TI  - Computer-vision-based extraction of neural dendrograms.
AB  - This work introduces a new approach to the characterization of neural cells by
      means of semi-automated generation of dendrograms; data structures which describe
      the inherently hierarchical nature of neuronal arborizations. Dendrograms
      describe the branched structure of neurons in terms of the length, average
      thickness and bending energy of each of the dendritic segments and allow in a
      straightforward manner, the inclusion of additional measures. The bending energy
      quantifies the complexity of the shape and can be used to characterize the
      spatial coverage of the arborizations (the bending energy is an alternative for
      other complexity measures such as the fractal dimension). The new approach is
      based on the partitioning of the cell's outer contour as a function of the high
      curvature points followed by a syntactical analysis of the segmented contours.
      The semi-automated method is robust and is an improvement on the time consuming
      manual generation of the dendrograms. Several experimental results are included
      in this paper which illustrate and corroborate the effectiveness of the approach.
      The technique presented in this paper is limited to planar neurons but could be
      extended to a 3D approach.

PMID- 10634498
TI  - Methods to uncover an antibody epitope in the KPI domain of Alzheimer's amyloid
      precursor protein for immunohistochemistry in human brain.
AB  - A novel polyclonal antibody (Ab993), specific for a KPI domain epitope of APP,
      was characterised for use in immunoprecipitation, Western blotting and
      immunohistochemistry. Conditioned medium from NTera2/D1 cells was used for
      immunoprecipitation and Western blots. Paraffin-embedded human brain sections
      were used for immunohistochemistry. The antibody recognised KPI-containing APP on
      Western blots after standard solubilisation but immunoprecipitation of soluble
      APP required reduction with 2-mercaptoethanol followed by alkylation of reduced
      sulphydryl bonds with sodium iodoacetate. Immunohistochemical staining of human
      brain sections was significantly enhanced by this pre-treatment. Microwaving of
      sections also increased immunolabelling, by a mechanism that was additive to
      reduction and alkylation. Incubation in 80% formic acid did not confer any
      enhancement of immunoreactivity. Ab993, applied with the methods reported here,
      is expected to be valuable in investigations of the pathogenesis of Alzheimer's
      disease to determine the source of the beta-amyloid peptide.

PMID- 10634499
TI  - Wheat germ agglutinin conjugated to TRITC: a novel approach for labeling primary
      projection neurons of peripheral afferent nerves.
AB  - Wheat germ agglutinin conjugated to tetramethylrhodamine isothiocyanate-dextran
      (WGA-TRITC) was studied as a novel tracer of primary projection neurons of
      pharyngeal (PhN) and superior laryngeal (SLN) branches of the vagus nerve. The
      SLN and PhN were dissected from rat cervical tissues and the proximal end of the
      nerves were bathed in tracer for 60-90 min. The animals were sacrificed 42-72 h
      later. The tissue was fixed, sliced, mounted on slides and viewed under
      epifluorescence. The clarity of the fluorescent label in projection neurons was
      confounded in some regions of the brainstem by autofluorescence. A computer image
      analysis method was developed to quantify fluorescence intensity for definitive
      identification of labeled neurons. Brainstem neurons labeled by afferent
      projections of the SLN and PhN were localized to the nucleus tractus solitarius.
      Efferents were identified in the nucleus ambiguus. WGA-TRITC labeled cells were
      observed in the ipsilateral brainstem at intensities significantly different from
      the fluorescence observed in controls (P<0.01). The distribution and density of
      labeling is in agreement with results of previous investigations, suggesting that
      WGA-TRITC is a useful alternative for tracing SLN and PhN projections to
      brainstem nuclei.

PMID- 10634500
TI  - A simple and sensitive antigen retrieval method for free-floating and slide
      mounted tissue sections.
AB  - The masking of antigens by aldehyde-containing fixatives or by paraffin embedding
      procedures is a problem for immunohistochemical studies. Enzymatic digestion,
      formic acid treatment, microwave heating and autoclave heating have been used to
      deal with this problem, with microwave heating-based antigen retrieval having
      become widely used as the method of choice. Microwave heating, however, has the
      shortcoming that it is difficult to precisely control the heating temperature and
      it is difficult to apply this method of heating to free-floating sections without
      damaging the sections. We describe here a simple, reliable and sensitive antigen
      retrieval method that uses water-bath heating. By this method, the temperature
      can be precisely controlled to yield effective antigen retrieval with minimal
      tissue damage in free-floating or paraffin-embedded slide-mounted sections. We
      found that the best results were obtained with a 30 min incubation in a 10-50 mM
      sodium citrate solution (pH 8.5-9.0) preheated to and maintained at 80 degrees C
      in a water-bath, followed by 30 min incubation in 0.3-3% nonfat dry milk to
      reduce nonspecfic staining. This method is highly effective for both 40 microm
      free floating sections, slide-mounted cryostat sections and paraffin-embedded
      slide-mounted sections, and it works well for tissue from diverse species (human,
      rat, mouse, pigeon, and zebra finch) and for diverse antigens (e.g. enkephalin,
      substance P, huntingtin, GluR1, GFAP, and ubiquitin). This method was also found
      to enhance immunolabeling in glutaraldehyde-fixed tissue that had been prepared
      for ultrastructural examination, without having a deleterious effect on the
      ultrastructure.

PMID- 10634501
TI  - Two-dimensional photon counting imaging and spatiotemporal characterization of
      ultraweak photon emission from a rat's brain in vivo.
AB  - The process of metabolic reactions within living cells leads to spontaneous
      ultraweak light emission. The development of a system for highly sensitive
      imaging and spatiotemporal analysis of ultraweak photon emission from a rat's
      brain is reported in this paper. The equipment used in this experiment consists
      of a two-dimensional photon-counting tube with a photocathode measuring 40 mm in
      diameter, a highly efficient lens system, and an electronic device to record time
      series of a photoelectron train with spatial information. The sensitivity and
      ability to extract spatiotemporal information from sequential data of a single
      photoelectron train were examined. The minimum detectable radiant flux density of
      the system was experimentally estimated to be 9.9 x 10(-17) W/cm2 with a 1-s
      observation time. Spontaneous photon emission was demonstrated from an exposed
      rat's cortex in vivo without adding any chemical agent or employing external
      excitation. An image of ultraweak photon emission was compared with one obtained
      after cardiac arrest. The intensity after cardiac arrest was depressed to
      approximately 60% of before that. The regional properties of time courses of
      emission intensity were also demonstrated, indicating the potential usefulness
      for spatiotemporal characterization of photon emission with mapping of
      physiological information such as oxidative stress. This technology constitutes a
      novel method, with the potential to extract pathophysiological information from
      the central nervous system.

PMID- 10634502
TI  - An eyecup preparation for the rat and mouse.
AB  - The eyecup preparation has traditionally been used to study retinal physiology in
      lower vertebrates and in some mammals. The procedures for preparing eyecups of
      the rat and mouse have not been described, however. We now describe methods for
      preparing and maintaining viable eyecups for these two species. Eyecups were
      everted over a plastic dome and held in place between the two halves of a
      superfusion chamber. Fluid exchange in the chamber was rapid, with near total
      exchange occurring in 9 s. Eyecup viability was tested by monitoring light-evoked
      retinal responses as the preparation aged. In both rat and mouse, the amplitude
      of the electroretinogram (ERG) b-wave decreased slowly, declining to 1/2 maximal
      amplitude in approximately 70 min. Light-evoked spike activity of neurons in the
      ganglion cell layer remained stable for approximately 3 h and attenuated
      responses were recorded for an additional 1-2 h. Eyecups were able to dark adapt.
      Retinal sensitivity, tested by monitoring b-wave amplitude, recovered following
      exposure to an adapting light.

PMID- 10634503
TI  - Comparison of tRNA activity under homologous and heterologous conditions during
      the reproductive cycle of Heteropneustes fossilis.
AB  - Rate of protein synthesis in ovary is analyzed throughout the annual reproductive
      cycle of H. fossilis. It is highest during previtellogenic phase and lowest
      during post spawning phase. The variation pattern matches with aminoacylation
      capacity of tRNA. The aminoacylation capacity of tRNA is compared in the two
      phases under homologous and heterologous conditions. Both tRNA and aRS are
      obtained from the same phase under homologous conditions and from different
      phases under heterologous conditions. Aminoacylation capacity is also compared in
      ovary and liver under homologous and heterologous conditions. Both tRNA and aRS
      show higher activity in previtellogenic phase. However, tRNA contributes more for
      higher aminoacylation activity. Transfer RNA fractionates into similar
      isoacceptors during the two phases. This indicates that the primary structure of
      tRNA may not change during the reproductive cycle. Therefore, it is suggested
      that the difference in aminoacylation activity may be due to post-transcriptional
      modifications of tRNA leading to conformational changes. Gm modification and 2-O'
      methylation of tRNA are reported earlier to vary during the reproductive cycle
      [2]. The results support the earlier suggestion of conformational changes in tRNA
      in 'active' and 'inactive' forms in previtellogenic and post spawning phases
      respectively. Aminoacylation capacity of tRNA shows organ specificity. It is high
      in ovary than in liver. Poor aminoacylation capacity is shown under heterologous
      conditions. This may be due to incompatible aRS related to specific amino acid
      pool in the tissue, or post transcriptional changes in tRNA, which may not allow
      cross acylation with full efficiency.

PMID- 10634504
TI  - Differential binding of NF1 transcription factor to P53 gene promoter and its
      depletion in human breast tumours.
AB  - Different transcription factors activate and repress the p53 gene expression.
      Recently, a tissue specific binding of NF1/YY1 to p53 promoter has been reported
      and further, it has been demonstrated that NF1/YY1 activates p53 promoter
      activity. The deregulated expression of p53 appears to be a central feature of
      malignant transformation and the basis of this deregulation is not well defined.
      Hence, an attempt has been made to know the binding of NF1/YY1 to p53 promoter
      taking breast tumour as a model system. Results have indicated a differential
      binding of NF1 to p53 promoter and a depletion or low level of NF1 in majority of
      breast tumour samples. Further, a correlation between NF1 and p53 has indicated
      the presence of p53 RNA even without NF1. Hence it is assumed that p53 expression
      is not NF1-dependent in breast tumours. However, the results clearly demonstrate
      a deregulation of NF1 transcription factor in breast tumours.

PMID- 10634505
TI  - Some unusual nucleic acid bases are products of hydroxyl radical oxidation of DNA
      and RNA.
AB  - There are over 100 modified bases and their derivatives found in RNA and DNA. For
      some of them, data concerning their properties, synthesis and roles in cellular
      metabolism are available, but for others the knowledge of their functions and
      biosynthetic pathways is rather limited. We have analysed the chemical structure
      of modified nucleosides of DNA and RNA considering mainly their putative
      synthetic routes. On this basis we suggest, that in addition to enzymatic
      biosynthetic pathways well established for some odd bases, many rare nucleosides
      can be recognised as products of random chemical reactions. We identify them as
      primary or secondary products of the reaction of nucleic acids with hydroxyl
      radicals, the most active oxidising agent in the cell.

PMID- 10634506
TI  - Sex-specific alterations in chromatin conformation of the brain of aging mouse.
AB  - Chromatin conformation has been analysed in the brain cortex of adult (24+/-2
      weeks) and old (65+/-4 weeks) male and female mice. Nuclei purified from
      different groups of mice were digested with MNase and DNase I for varying time
      periods (0-90 min), and with endogenous endonucleases for 1 h. MNase and DNase I
      digestion kinetics showed that the percentage of acid solubility of chromatin was
      relatively lower in old than adult and in female than male. This was further
      supported by electrophoretic analysis of nuclease digested DNA fragments. When
      the nuclei were incubated with only Ca2+ or Mg2+, no endonuclease digestion was
      observed. However, under similar conditions, the liver DNA was cleaved
      substantially. When divalent cations were added together, they activated
      endogenous endonucleases and digested the brain chromatin. The activity of
      Ca2+/Mg2+-dependent endogenous endonucleases was higher in male than female. Thus
      the accessibility of chromatin to MNase, DNase I and endogenous endonucleases was
      higher in male than female, and MNase as well as DNase I were more active in
      adult than old. Such sex- and age-dependent conformation of chromatin may
      attribute to differential expression of genes in the mouse brain.

PMID- 10634507
TI  - Binding of small phosphorylated chromatin peptides to DNA.
AB  - Low-molecular-weight peptides involved in gene expression and cell growth have
      been isolated from DNA preparation from eukaryotic cells. After phosphorylation
      with protein kinase CKII (pCKII) these peptides are able to bind to DNA in
      presence of divalent cations and salt/ethanol. This finding may explain the
      mechanism by which the peptides exert their activity.

PMID- 10634508
TI  - Phosphorylation of the synthetic octapeptide pyroGlu-ASP-ASP-SER-ASP-GLU-GLU-ASN
      and binding to DNA in presence of divalent cations.
AB  - Small acidic peptides involved in gene expression have been isolated from
      prokaryotic and eukaryotic cells. Synthetic peptides, designed on the basis of
      native peptides characteristics, show a biological activity similar to that of
      native peptides in in vitro reconstituted systems. These synthetic peptides are
      able to bind to DNA in presence of divalent cations (Cu2+, Fe2+, Mg2+) and
      salt/ethanol.

PMID- 10634509
TI  - Efficiency of expression of transfected genes depends on the cell cycle.
AB  - Lipofection, a lipid-mediated DNA transfection procedure, was used to transfect
      synchronized L929 mouse fibroblast cells with a reporter plasmid containing the
      bacterial chloramphenicol acetyltransferase gene. The efficiency of gene
      expression was investigated on transfection of cells at different stages of the
      cell cycle. Our data show that expression of the reporter gene was minimal when
      transfection was performed in G0-phase and parallel experimental data disproved
      the possibility that the reduced expression observed was due to differential
      uptake at different times in the cell cycle. Investigation into the condensation
      state of the plasmid has shown that the low chloramphenicol acetyltransferase
      gene expression could be a direct consequence of the packaging of the plasmid
      into condensed chromatin when transfection occurs in G0-phase. The inactivation
      of the reporter gene is not reversed by growth of the cells in high serum or by
      treatment with Trichostatin A, a specific inhibitor of histone deacetylase,
      suggesting that the inactive chromatin formed in G0-phase cells lacks associated
      histone acetylase activity. In contrast, the high activity seen when cells in S
      phase are transfected is enhanced even further by treatment with Trichostatin A.

PMID- 10634510
TI  - Influence of highly curved DNA segments on in vivo topology of plasmids.
AB  - Recombinant plasmids carrying a highly curved DNA structure are sometimes
      unstable in Escherichia coli. In order to know the underlying mechanism, several
      plasmids carrying one or two highly bent DNA segment(s) from the human adenovirus
      type 2 (Ad2) enhancer and/or origin region of phage lambda replication were
      systematically constructed and propagated in E. coli. The highly bent DNA
      segments disturbed the action of DNA topoisomerases: i.e. they were shown to be
      able to produce an anomalously wide spectrum of linking number topoisomers that
      tails toward lower supercoiling with a little of the DNA actually positively
      supercoiled. Furthermore, bent DNA caused multimeric plasmid formation. The
      linking number topoisomers and multimers seemed to be intermediate topological
      states of the bent DNA-containing plasmids that would lead to the deletion
      occurring in them. The nucleotide sequence of a deletion product of a bent DNA
      containing plasmid showed that the putative source of the severe topological
      constraint was entirely eliminated from the plasmid.

PMID- 10634511
TI  - Gender related and dexamethasone induced differences in the mRNA levels of the
      MRF genes in rat anterior tibial skeletal muscle.
AB  - Muscle formation and postnatal growth is under the control of the muscle
      regulatory factors (MRF) gene family, consisting of four genes: MyoD1, myogenin,
      myf-5, and myf-6. Muscle mass is also known to be affected by specific drugs,
      like glucocorticoids. Glucocorticoids have also been characterized as muscle
      atrophying agents. However, glucocorticoids are also the only drugs reported to
      have a beneficial effect on the treatment of muscle degenerative disorders. Since
      muscle mass relates to gender, this may be partially caused by gender. The aim of
      this study is to investigate gender-related basal and dexamethasone-induced
      expression of the MRF genes. Gender-specific MRF mRNA levels were investigated in
      anterior tibial muscles of the rat. Myogenin, myf-5, and myf-6 mRNA level was
      significantly higher in female rats than in male rats. Since muscle mass is
      usually higher in males, we conclude that the development of gender-related
      differences in muscle mass is not primarily under the control of the mRNA levels
      of the MRF genes. Male rats treated with dexamethasone for 14 days (1 mg per kg
      body weight) showed increased levels of MyoD1, myogenin and myf-5 compared to
      control male rats. Female rats treated with dexamethasone showed decreased
      expression of myf-6 compared to control female rats. These results suggest that
      dexamethasone increase satellite cell-specific MRF activity in male muscle
      tissue, which is suggested to be associated with muscle hypertrophy, while
      maintenance of muscle tissue is affected in female muscle tissue. Therefore, we
      conclude that both basal and dexamethasone-induced MRF gene mRNA levels are
      regulated gender-specific.

PMID- 10634512
TI  - Coexpression of c-kit and stem cell factor in breast cancer results in enhanced
      sensitivity to members of the EGF family of growth factors.
AB  - Kit, a tyrosine kinase growth factor receptor, and its ligand, stem cell factor
      (SCF), are commonly coexpressed in breast cancer. We have previously shown that
      MCF7 cells (that naturally express SCF) transfected with a c-kit expression
      vector exhibit enhanced growth in serum-free medium supplemented with IGF-1.
      Consequently, we wished to examine the interaction of Kit/SCF with additional
      growth factors important in the biology of breast cancer. MCF7 transfectants
      expressing Kit, cultured in serum-free medium supplemented with EGF, displayed
      more than twice the growth of controls at identical EGF concentrations. Similar
      responses were seen in the presence of heregulin alpha. The specificity of the
      Kit-mediated response was illustrated by a reduction in heregulin-stimulated
      growth in the presence of a monoclonal antibody directed against the Kit
      receptor. In addition, EGF- and heregulin-stimulated growth of the ZR75-1 cell
      line that naturally coexpresses Kit and SCF was also inhibited by the Kit
      blocking antibody. Preliminary investigations into the signal transduction
      pathways activated by these growth factors revealed that SCF activated both the
      Ras-MAP kinase and phosphatidyl-inositol-3-kinase (PI3 kinase) pathway. Both EGF
      and heregulin activated MAPK but to a lesser degree than SCF, and combination of
      SCF with these growth factors resulted in enhanced MAPK activation. Assessment of
      PI3K pathway activation using antiphospho-Akt antibodies revealed that EGF was a
      poor activator of Akt; activation of this pathway was markedly enhanced by the
      addition of SCF. Heregulin activated Akt and addition of SCF provided no further
      activation. Taken together these results suggest that coexpression of SCF and Kit
      may enhance responsiveness to erbB ligands by enhancing activation of the MAPK
      and PI3K pathways.

PMID- 10634513
TI  - BRCA1 mutation testing for Japanese patients with ovarian cancer in breast cancer
      screening.
AB  - From February 1996 to April 1998, 2967 women received screening for breast cancer
      in the gynecologic ambulatory practice of the Hokkaido University Hospital. In
      116 Japanese women with epithelial ovarian cancer, mutation analysis of BRCA1
      exon 11 in genomic DNA was performed by the stop codon (SC) assay and DNA
      sequence analysis. Clinicopathological factors were also investigated in these
      patients. The aim of this study was to examine the advantages of performing BRCA1
      mutation testing for ovarian cancer patients during breast cancer screening. We
      achieved a high detection rate (6.0%) of patients with germline mutations in
      BRCA1. The high frequencies of breast ovarian cancer syndrome, serous
      adenocarcinoma, high histological grades, advanced FIGO stages, and breast cancer
      as double cancer were found to be characteristic of ovarian cancer with germline
      mutations in BRCA1. These characteristics may assist physicians in selecting
      BRCA1 mutation testing for ovarian cancer patients. The mean age at diagnosis of
      ovarian cancer was 51.0 and 51.2 years in the groups with and without mutation,
      respectively, and no difference was found in age at diagnosis. All of the nine
      living female mutation carriers were offered the options of increased
      surveillance or prophylactic surgery, and all chose the former. We have performed
      breast cancer screening and/or ovarian cancer screening every 6 months for these
      carriers. This may allow another advantage in establishing a relationship of
      mutual trust with a patient from a series of responsible follow-ups.

PMID- 10634514
TI  - Differential levels of soluble intercellular adhesion molecule-1 (sICAM-1) in
      early breast cancer and benign breast lesions.
AB  - To date, no soluble markers can discriminate benign from malignant breast
      lesions; therefore, to assess the diagnostic potential of circulating
      intercellular adhesion molecule-1 (sICAM-1), serum concentrations of sICAM-1 were
      quantitated in 230 consecutive patients that underwent surgery for breast
      neoplasias, utilizing an enzyme-linked immunosorbent assay. Histological
      diagnosis revealed that 177 patients had breast cancer and 53 had a benign breast
      disease. In the cancer patient group, 90 subjects had pT1 tumors without
      (pT1N0M0, n = 46) or with (pT1N1M0, n = 41; pT1N2M0, n = 3) regional lymph node
      metastases. Mean levels of serum sICAM-1 of patients with pT1 breast cancer,
      without or with regional lymph node involvement, were significantly (P < 0.05)
      higher than those of patients with benign breast lesions and of 49 age-matched
      control subjects. Elevated levels of serum sICAM-1 were detected in 27/90 (30%)
      pT1 breast tumors and in 1/53 (2%) benign breast lesions; thus, among subjects
      with high levels of sICAM-1, 96% had breast cancer. No significant correlation
      was found between levels of serum sICAM-1 and breast cancer progression. These
      observations, altogether, suggest that in the presence of a suspicious breast
      neoplasm the quantitative analysis of serum sICAM-1 can orient clinical diagnosis
      towards malignancy.

PMID- 10634515
TI  - p73 mutations are not detected in sporadic and hereditary breast cancer.
AB  - Recently, a novel tumor suppressor gene, p73, was isolated and mapped to
      chromosome 1p36, a region commonly associated with loss of heterozygosity in
      neuroblastoma and other human malignancies, including breast cancer. The p73 gene
      shares considerable homology with the common tumor suppressor gene p53, both in
      composition and function. This study examines the potential participation of p73
      in the pathogenesis of sporadic and hereditary breast cancers. Mutation analysis
      of 29 hereditary breast cancer cases revealed five independent silent mutations
      in the hereditary cases that are unlikely to play a role in tumor development.
      Mutation analysis of 48 sporadic breast tumors did not identify any unique
      variants. Eleven common polymorphisms scattered throughout the gene were also
      detected. Thus, mutations in the p73 gene appear to play little if any role in
      hereditary or sporadic breast cancer.

PMID- 10634516
TI  - Policy guidelines for the utilization of formalin-fixed, paraffin-embedded tissue
      sections: the UNC SPORE experience. University of North Carolina Specialized
      Program of Research Excellence.
AB  - Paraffin blocks represent a valuable resource that has allowed investigators to
      apply today's technology to address scientific questions in a shorter period of
      time and in more diverse populations than would have been possible with fresh or
      frozen tissue. However, in addition to being an exhaustible resource, there is
      concern regarding the appropriate use of these tissues, both with respect to
      medical or legal considerations and quality control and quality assurance
      practices. We describe policy guidelines to address these concerns, including:
      safeguards to address medical/legal and patient confidentiality issues, quality
      control and quality assurance for tissue sectioning, processing and storage,
      database management for sample tracking, and scientific review for utilization of
      specimens. These policies and procedures have been developed and implemented by
      the University of North Carolina (UNC) Specialized Program of Research Excellence
      (SPORE) in the Breast Cancer Immunohistochemistry (IHC) Core laboratory, in
      collaboration with our study pathologists, participants, and research
      investigators. It is our hope that the information and experience described here
      may stimulate discussion that can ultimately lead to a uniform policy for
      handling formalin-fixed paraffin-embedded tissues in research.

PMID- 10634517
TI  - Acquired antiestrogen resistance in MCF-7 human breast cancer sublines is not
      accomplished by altered expression of receptors in the ErbB-family.
AB  - Development of acquired resistance against antiestrogen treatment is a serious
      problem in human breast cancer, and knowledge of alterations resulting in
      resistance is important for selection of further treatment. To mimic the clinical
      situation we have established a series of MCF-7 human breast cancer cell lines by
      long term treatment with the antiestrogens tamoxifen, ICI 164,384, and ICI
      182,780. Common for these cell lines is a decreased expression of the estrogen
      receptor alpha (ER alpha). In human breast cancer, lack of response to endocrine
      therapy is often associated with decreased expression of the estrogen receptor
      and increased expression of epidermal growth factor receptor (EGFR) and/or HER
      2/neu (ErbB-2). Our antiestrogen resistant cell lines did not express altered
      levels of EGFR, HER-2/neu, ErbB-3, or ErbB-4. Estrogen and antiestrogen
      regulation of HER-2/neu expression was essentially similar in parent and
      resistant MCF-7 cells. Treatment with antibodies to HER-2/neu (Herceptin) did not
      affect growth of MCF-7 cells or resistant cells, indicating that in this in vitro
      model system, acquired antiestrogen resistance does not emerge from activation of
      the HER-2/neu signaling pathway. In MCF-7 cells transfected with HER-2/neu and/or
      ErbB-3, overexpression alone did not result in resistance. However, addition of
      heregulinl-beta1 abolished the inhibitory activity of ICI 182,780 on both vector
      and HER-2/neu/ErbB-3 transfected MCF-7 cells, demonstrating that activation of
      the HER-2/neu receptor signaling pathway can override the growth inhibitory
      effect of ICI 182,780.

PMID- 10634518
TI  - Local signals induce CCAAT/enhancer binding protein-delta (C/EBP-delta) and C/EBP
      beta mRNA expression in the involuting mouse mammary gland.
AB  - The repeated lactation cycles in the mammary gland offer a unique environment for
      the study of cell growth, differentiation, and death. The CCAAT/enhancer binding
      proteins (C/EBPs) are a family of transcription factors important in growth
      control and differentiation in many tissues. Our laboratory and others have shown
      that C/EBP-delta and C/EBP-beta mRNA expression is closely associated with normal
      mouse mammary gland involution. To examine the relative influence of local versus
      systemic factors in C/EBP expression and tissue remodeling, a gland sealing mouse
      model was used. Mice with unilateral sealing continue to lactate and nurse pups
      via nonsealed glands, while sealed glands initiate involution. The expression of
      C/EBP-alpha, beta and delta mRNA was investigated in sealed and nonsealed nursing
      glands. In situ apoptosis was documented and glandular morphology was also
      examined. C/EBP-delta mRNA levels are low in nonsealed glands, but are rapidly
      and transiently induced in sealed glands by 24 h. C/EBP-beta mRNA expression is
      also relatively low in nonsealed glands, but is induced in sealed glands within
      72 h. Expression of the apoptosis-associated mRNAs encoding bax and TRPM-2 is
      also induced in sealed glands by 24-48 h. Apoptosis and a moderate degree of
      tissue remodeling occur within the sealed glands in spite of systemic hormone
      levels capable of sustaining lactation. These data demonstrate that local factors
      are sufficient to induce C/EBP-beta and C/EBP-delta in the mouse mammary gland.
      In addition, mammary epithelial apoptosis and glandular remodeling occur in
      sealed glands, confirming a critical role for local factors in mammary
      involution.

PMID- 10634519
TI  - Telomerase activity in ductal carcinoma in situ of the breast.
AB  - Telomerase plays an important role in maintaining the stability of the
      chromosomes. Activity of telomerase has been detected in proliferating and
      immortalized cell lines and in a number of malignant tumors including invasive
      breast cancer. The aim of the study was to examine telomerase activity in ductal
      carcinoma in situ (DCIS), which is considered to be a precursor lesion of
      infiltrating breast carcinoma, using a PCR-based telomerase activity protocol
      (TRAP). We examined 35 samples obtained from histologically confirmed breast
      biopsies, including 13 normal breast tissues, 11 infiltrating ductal carcinoma
      (IDC), nine DCIS, and two DCIS with microinvasion. Telomerase activity was
      demonstrated in 8/9 samples of DCIS, both samples of DCIS with microinvasion, and
      all but one sample of IDC. Normal breast tissue had no demonstrable telomerase
      activity. Our results indicate that telomerase is activated frequently in early
      breast carcinogenesis, although its utilization as a biomarker in DCIS is
      questionable.

PMID- 10634520
TI  - Pharmacokinetics of sterically stabilized hexadecylphosphocholine liposomes
      versus conventional liposomes and free hexadecylphosphocholine in tumor-free and
      human breast carcinoma bearing mice.
AB  - The pharmacokinetics of free and different liposomal formulations of
      hexadecylphosphocholine (HPC) was investigated in tumor-bearing (human mammary
      tumor MaTu) and tumor-free mice after intravenous and intraperitoneal
      administration. The levels of HPC were evaluated at different times in serum,
      normal tissues, and tumor. The purpose was to test the hypothesis that the
      enhanced therapeutic efficacy of sterically stabilized HPC liposomes in
      comparison to conventional vesicles and free HPC is due to its pharmacokinetics.
      Conventional non-compartmental pharmacokinetic analysis and an elaborate three-
      and four-compartmental model were used for explaining the experimental data. The
      serum levels of HPC obtained with sterically stabilized liposomes were only
      consistently higher in comparison to conventional vesicles and free HPC in the
      first 4 h. In the xenografted MaTu carcinoma, the differences of the HPC content
      between the different groups are unexpectedly low and do not reflect the high
      therapeutic activity [5] of sterically stabilized HPC liposomes. Detailed
      analysis shows that the liposomally encapsulated drug displays a modified
      pharmacokinetic behavior, which may also involve lymphatic absorption of the
      liposomal drug.

PMID- 10634521
TI  - Gallbladder ejection fraction: correlation of scintigraphic and ultrasonographic
      techniques.
AB  - PURPOSE: The assessment of gallbladder function and ejection fraction using
      sincalide-enhanced biliary scintigraphy is a useful way to evaluate patients with
      recurrent right upper quadrant pain but no gallstones. MATERIALS AND METHODS: We
      wanted to determine whether gallbladder contraction measured by ultrasonography
      could be used in place of biliary scintigraphy. Biliary scans with an infusion of
      sincalide and concurrent ultrasonography were performed in 17 patients with
      histories of recurrent abdominal pain and no evidence of gallstones by
      ultrasound. RESULTS: Gallbladder ejection fractions calculated by ultrasound and
      scintigraphy using standard techniques showed only a weak correlation. The poor
      performance of ultrasound appears to arise because the variable shape of the
      gallbladder invalidates the calculation of its volume by the formula for a
      prolate spheroid. When gallbladders that were ellipsoidal were subselected,
      correlation was improved. The level of training of the sonologist did not have a
      significant effect on the results. CONCLUSION: Gallbladder ejection fraction
      calculated by ultrasonography cannot be used routinely as a substitute for
      biliary scintigraphy.

PMID- 10634522
TI  - Tc-99m hexamethylpropylene amine oxime scintigraphy in the diagnosis of brain
      death and its implications for the harvesting of organs used for transplantation.
AB  - PURPOSE: Diagnosing brain death is important in managing the comatose patient for
      whom the continuation of life support is being questioned and when organ
      harvesting is being considered. The virtual immediate localization of Tc-99m
      HMPAO to cerebral and cerebellar tissue provides an index of blood perfusion, and
      its absence denotes brain death. Other methods for assessing brain death include
      cerebral angiography, MRI, CT imaging after inhalation of stable xenon,
      electroencephalography, and clinical examination. The contrast material used for
      angiography may damage harvested organs, and the other studies have significant
      errors. MRI, CT imaging, and angiography are unsuitable for bedside use. METHODS:
      Twenty-three patients, who presented with head trauma, prolonged anoxia or
      intrinsic brain disease (e.g., glioblastoma multiforme) and who were brain-dead
      by clinical examination criteria, were referred to the nuclear medicine division
      for verification of brain death. For adults, approximately 25 mCi Tc-99m
      hexamethylpropylene amineoxime (HMPAO) was administered intravenously. All
      patients but one were imaged using a mobile scintillation camera at the bedside.
      RESULTS: We demonstrated (1) both cerebral and cerebellar perfusion, (2) neither
      cerebral nor cerebellar perfusion, (3) cerebral without cerebellar perfusion, and
      (4) cerebellar without cerebral perfusion. Patients without cerebral perfusion
      were diagnosed as brain-dead. The significance of a viable cerebellum in the
      absence of cerebral viability was not fully appreciated, although organs were
      harvested from such patients. We determined how well the clinical examination
      criteria held up in the diagnosis of brain death against the new gold standard of
      Tc-99m HMPAO scintigraphy: Clinical examination criteria correctly predicted
      brain death only 83% of the time compared with HMPAO scintigraphy. CONCLUSIONS:
      Brain death assessment by Tc-99m HM-PAO scintigraphy has proved to be a reliable,
      safe, and cost-effective bedside method and may have practical application in the
      assessment of brain death in potential cadaveric donors.

PMID- 10634523
TI  - Evaluation of standardized uptake value to assess cerebral glucose metabolism.
AB  - PURPOSE: When the cerebral metabolic rate of glucose (CMRglc) is to be measured,
      arterial blood sampling is usually required for fluorine-18 fluorodeoxyglucose
      (FDG) and positron emission tomography (PET) studies. However, blood sampling is
      inconvenient because it requires several staff members and is invasive for
      patients. METHODS: To assess cerebral glucose metabolism by a noninvasive and
      simplified method, the authors used the standardized uptake value (SUV), which
      requires no input function or blood sampling. The study participants included 18
      healthy volunteers (4 men and 14 women; mean +/- SD age, 68.2+/-6.3 years), 18
      patients with mild Alzheimer's disease (AD) (4 men and 14 women; mean +/- SD age,
      68.8+/-7.3 years), and 18 patients with moderate AD (5 men and 13 women, mean +/-
      SD age, 69.5+/-8.5 years). Regional CMRglc and regional cerebral SUV were
      measured in the three groups using FDG PET, and the correlation between global
      CMRglc and global SUV was estimated. RESULTS: The correlation coefficients of
      global CMRglc and global SUV in the healthy volunteers, mild AD patients, and
      moderate AD patients were 0.82, 0.67, and 0.62, respectively. Compared with the
      healthy persons, the patients with mild AD showed significantly decreased CMRglc
      in the temporal, frontal, and parietal cortices, but they did not show
      significantly decreased SUV in any region. Patients with moderate AD had
      significantly decreased CMRglc in the temporal, frontal, occipital, parietal, and
      sensorimotor cortices and significantly decreased SUV in the temporal, frontal,
      occipital, and parietal cortices. CONCLUSION: The SUV would be useful as a
      semiquantitative index of cerebral glucose metabolism only in healthy persons or
      those with mild AD.

PMID- 10634524
TI  - Scintigraphic findings in peroneal tendonitis: a case report.
AB  - A case report of radionuclide bone scan findings in a patient with peroneus
      brevis tendonitis is presented. Peroneal tendonopathy is a common cause of
      lateral ankle pain. Although magnetic resonance imaging (MRI) findings have been
      described in the literature, we know of no other detailed report of three-phase
      bone scan findings, which we believe can provide an alternate means to diagnose
      this condition. The positive findings consist of a curvilinear band of increased
      activity that corresponded to the anatomic position of the peroneus brevis tendon
      and was detected only on the first two phases of the study.

PMID- 10634525
TI  - The effect of P-glycoprotein function inhibition with cyclosporine A on the
      biodistribution of Tc-99m sestamibi.
AB  - PURPOSE: The failure to cure persons with cancer is caused primarily by the
      development of drug resistance by overexpression of p-glycoprotein. Diverse
      groups of drugs have been identified, including cyclosporine A, which can reverse
      drug resistance by inhibiting P-glycoprotein transport. Tc-99m sestamibi is a
      substrate for P-glycoprotein. P-glycoprotein is normally expressed in biliary
      canalicular surfaces of hepatocytes and is responsible for the excretion of
      cationic metabolites from the liver. The aim of the current study was to evaluate
      the effect of cyclosporine A on the biological distribution of Tc-99m sestamibi
      in vivo. METHODS: Five patients with alopecia and two renal transplant patients
      who were treated with cyclosporine A were selected for the study. All patients
      were examined before and at least 2 weeks after administration of cyclosporine A.
      Tc-99m sestamibi scintigraphy was performed by obtaining planar abdominal images
      at 5, 30, 60, 120, and 180 minutes after injection, and the liver-heart ratios
      were calculated. RESULTS: Plasma cyclosporine A, bilirubin levels, liver enzymes,
      and creatinine clearance values were obtained from all patients. In three, the
      plasma cyclosporine A level was increased to more than 400 pg/dl. The liver-heart
      ratio was increased significantly after cyclosporine A administration (P < 0.01).
      After cyclosporine A administration Tc-99m sestamibi excretion was delayed and
      the uptake in the liver was increased. The difference was 17% at 5 minutes and
      38% at 180 minutes. Liver retention was greatest in patients with cyclosporine A
      toxicity. CONCLUSIONS: With a limited number of patients, this study suggests
      that Tc-99m sestamibi excretion from the liver is mediated by P-glycoprotein, and
      inhibition of P-glycoprotein transport not only delays liver excretion but also
      increases the liver uptake of Tc-99m sestamibi. Because this observation deserves
      further investigation, the inhibition of P-glycoprotein function with nontoxic
      multidrug-resistance reversing agents may be used as an intervention to increase
      the tumor uptake of Tc-99m sestamibi and to increase the sensitivity of Tc-99m
      sestamibi tumor imaging.

PMID- 10634526
TI  - Imaging of non-small-cell lung cancer with indium-111 pentetreotide.
AB  - PURPOSE: Lung cancer is the leading cause of cancer deaths in the United States.
      Non-small-cell lung cancer (NSCLC) accounts for 75% to 85% of lung cancers. CT
      has been the standard anatomic study for localizing and staging NSCLC, although
      it is associated only with moderate accuracy. In-111 pentetreotide, a
      radiolabeled somatostatin analog largely used in the scintigraphic localization
      of neuroendocrine tumors, has been shown incidentally to identify NSCLC lesions.
      This observation is important in the workup for metastatic disease for
      neuroendocrine tumors, because presumed metastatic lesions may actually be second
      primary tumors of NSCLC. In-111 may also serve as a potentially useful adjunct to
      CT in the anatomic evaluation of NSCLC. The purpose of this study was to
      determine the likelihood of detecting and localizing NSCLC using In-111
      pentetreotide scintigraphy. MATERIALS AND METHODS: Ten patients with known or
      possible NSCLC were examined using In-111 pentetreotide. Scans were compared with
      the patients' previously performed chest radiographs and CT scans. RESULTS: In
      111 pentetreotide imaging correctly identified sites of tumor involvement as
      detected by chest CT and surgery in all 10 patients with NSCLC. CONCLUSION: This
      study demonstrates the uptake of In-111 pentetreotide by NSCLC. This important
      observation should be considered in the workup for metastatic disease of
      neuroendocrine tumors with In-111 pentetreotide, because NSCLC can be a source of
      false-positive findings. In-111 pentetreotide imaging may also serve as a
      potentially useful adjunct to CT for identifying obscured or equivocal lesions
      and as an aid in localizing tissue for biopsy.

PMID- 10634527
TI  - Comparative evaluation of Tc-99m MIBI and Tl-201 chloride SPECT in non-small-cell
      lung cancer mediastinal lymph node metastases.
AB  - PURPOSE: To compare the utility of Tc-99m MIBI SPECT and Tl-201 chloride SPECT
      for presurgical assessment of lung cancer mediastinal lymph node metastases.
      METHODS: Forty-one patients with non-small-cell lung cancer underwent dual
      isotope imaging with Tl-201 chloride and Tc-99m MIBI and were evaluated for
      mediastinal lymph node involvement. RESULTS: The sensitivity rates of early and
      delayed Tc-99m MIBI SPECT and of early and delayed Tl-201 chloride SPECT for
      detecting mediastinal nodal metastases were 69%, 69%, 92%, and 92%, respectively.
      The corresponding specificity rates were 96%, 96%, 93%, and 96%. CONCLUSION: Tl
      201 chloride SPECT is superior to Tc-99m MIBI SPECT when used to detect
      mediastinal lymph node metastases in patients with non-small-cell lung cancer.

PMID- 10634528
TI  - The dual-isotope ProstaScint imaging procedure: clinical experience and staging
      results in 145 patients.
AB  - PURPOSE: Whole-body, regional planar, and SPECT imaging using the In-111-labeled
      monoclonal antibody capromab pendetide (In-111 MAb; ProstaScint) has been shown
      to increase the detection of early disease spread in patients with prostate
      cancer. However, recognition of metastatic tumor sites can be difficult,
      especially if the involved nodes are near blood vessels. We have developed an
      alternate approach to the identification of metastatic sites that is based on a
      single simultaneous In-111 MAb and Tc-99m RBC SPECT acquisition of the pelvis and
      abdomen on day 5 after injection. We have also developed software that
      dynamically subtracts the Tc-99m RBC data set (vascular component) from the In
      111 MAb data set (prostate and lymph node component), which allows for easier
      identification of metastatic sites. METHODS: We evaluated the effectiveness of
      ProstaScint for staging 145 patients with prostate cancer, 19 newly diagnosed and
      126 with recurrence, using these two modifications. RESULTS: With clinical follow
      up in 13 of 19 (68%) patients with primary disease, 10 of 13 (78%) had organ
      confined disease. With follow-up in 64 of 126 (51%) patients with possible
      recurrent disease, 49 of 64 (77%) were found to have prostatic fossa activity
      only. Disease stage was deemed more advanced in 3 of 13 (22%) patients with
      primary cancer and in 13 of 64 (20%) of those with recurrent disease based on
      ProstaScint findings when all other imaging tests were inconclusive. Six patients
      with recurrent disease had negative results of their scans. In the 16 patients
      with more advanced disease, 3 of 59 lesions (5%) were documented as false
      positive, and there were no reported cases of false-negative findings.
      CONCLUSIONS: Using both the dual-isotope procedure and the subtraction analysis
      software with the ProstaScint examination provides additional information for
      staging primary and possibly recurrent prostate cancer compared with standard
      imaging techniques.

PMID- 10634529
TI  - Pediatric duodenal perforation demonstrated by hepatobiliary imaging.
AB  - The diagnosis of intestinal perforation in children is difficult. Computed
      tomography has been a useful investigative modality. A case of duodenal
      perforation is presented in which radionuclide hepatobiliary imaging was useful.

PMID- 10634530
TI  - Brown tumor of the sternum: a potential source of false-positive Tl-201 and Tc
      99m subtraction imaging in the mediastinum.
AB  - Tl-201 and Tc-99m subtraction imaging is a well-established technique for
      detecting parathyroid adenomas. We report a case of a brown tumor of the upper
      sternum mimicking an ectopic mediastinal parathyroid adenoma on Tl-201 and Tc-99m
      subtraction imaging in a patient with hyperparathyroidism. This brown tumor
      showed Tl-201 uptake but not Tc-99m uptake and thus did not subtract out in this
      scan.

PMID- 10634531
TI  - The effect of fluorine-18 fluorodeoxyglucose positron emission tomography on the
      management of cutaneous malignant melanoma.
AB  - PURPOSE: To assess the effect of positron emission tomography (PET) with fluorine
      18 fluorodeoxyglucose (FDG) on the treatment of patients with cutaneous malignant
      melanoma. MATERIALS AND METHODS: We retrospectively reviewed the medical records
      of 38 patients with newly diagnosed (n = 25) and recurrent (n = 13) cutaneous
      melanoma who were referred for evaluation with FDG PET imaging at our
      institution. We compared the PET findings with computed tomography (CT), which
      was available in 21 (55%) patients, and tabulated the changes in the diagnostic
      evaluation and therapeutic management that were prompted by PET during a follow
      up period of 10 to 36 months. RESULTS: Compared with PET, the extent of disease
      was underestimated by CT in 5 (13%) patients. Planned surgical resection of
      metastases was canceled in two of these patients. In another patient,
      surveillance PET detected an unsuspected hypermetabolic abdominal mass that was
      noted on a subsequent CT to arise from the small bowel. The mass was found to be
      jejunal metastatic melanoma at the time of resection. Overall, PET influenced
      surgical management in 3 (8%) patients, but it did not affect the wait-and-watch
      strategy or decision to initiate immunotherapy in the others. CONCLUSIONS: FDG
      PET contributes important information not provided by CT and has a substantial
      effect on the clinical management of patients with malignant melanoma.

PMID- 10634532
TI  - Reverse discordant Tc-99m and I-131 imaging in a patient with a toxic thyroid
      adenoma.

PMID- 10634533
TI  - Tc-99m nofetumomab merpentan complements an equivocal bone scan for detecting
      skeletal metastatic disease from lung cancer.

PMID- 10634534
TI  - Bilateral increased Tl-201 uptake of lacrimal glands caused by crying of a child
      during injection.

PMID- 10634535
TI  - Retrodisplaced gallbladder detected on hepatobiliary scintigraphy.

PMID- 10634536
TI  - Intrathymic parathyroid adenoma: planar and SPECT Tc-99m sestamibi scintigraphy.

PMID- 10634537
TI  - Congenital septal aneurysm: a rare cause of fixed defect on myocardial perfusion
      SPECT.

PMID- 10634538
TI  - Massive pleural effusion secondary to continuous ambulatory peritoneal dialysis,
      confirmed by Tc-99m sulfur colloid peritoneoscintigraphy.

PMID- 10634539
TI  - Gallium scan without hepatic or renal activity.

PMID- 10634540
TI  - Tc-99m tetrofosmin imaging in chondrosarcoma.

PMID- 10634541
TI  - Extraosseous uptake of Tc-99m methylene diphosphonate in the pectoralis muscles 8
      days after exercise.

PMID- 10634542
TI  - Ga-67 uptake in a patient with Takayasu's arteritis.

PMID- 10634543
TI  - Incidental detection of a pheochromocytoma on fluorine-18 fluorodeoxyglucose
      coincidence imaging.

PMID- 10634544
TI  - Paraspinal abscess complicating facet joint injection.

PMID- 10634545
TI  - Diffuse abdominal uptake of Ga-67 citrate in two cases.

PMID- 10634546
TI  - Detection of Coxsackie B2 virus myocarditis in a neonate using Tl-201 and I-123
      BMIPP myocardial imaging.

PMID- 10634547
TI  - The utility of furosemide in complex bone scintigraphy.

PMID- 10634548
TI  - Current readings in nuclear medicine.

PMID- 10634549
TI  - Thrombophilia: a feature of importance in retinal vein thrombosis?

PMID- 10634550
TI  - Factor V Leiden and prothrombin 20210 A mutations in patients with central and
      branch retinal vein occlusion.
AB  - PURPOSE: The role of factor V Leiden and prothrombin 20210 A mutations has been
      investigated in patients with central retinal vein occlusion (CRVO), hemispheric
      retinal vein occlusion (HRVO), and branch retinal vein occlusion (BRVO). METHODS:
      Factor V Leiden and prothrombin 20210 A were investigated in DNA obtained from
      the peripheral blood of 52 patients with retinal vein occlusion. Twenty-five of
      the patients had either CRVO or HRVO, and 27 patients had BRVO. The control
      groups for factor V Leiden and prothrombin 20210 A were comprised of two separate
      groups of 81 and 87 healthy individuals, respectively, who had been previously
      investigated for the mutations at Hacettepe University Department of Hematology.
      The frequencies of factor V Leiden and prothrombin 20210 A mutations were
      compared between the patients and the controls using Fisher's exact test.
      RESULTS: Factor V Leiden mutation was found in 8% of all patients, 4% of the CRVO
      HRVO group and 11% of the BRVO patients. Prothrombin 20210 A mutation was not
      found in any of the patients. Factor V Leiden and prothrombin 20210 A mutations
      have been previously found in 7% and 2% of the healthy controls, respectively.
      The differences of frequencies between the patients and the controls were not
      statistically significant. CONCLUSION: Factor V Leiden and prothrombin 20210 A
      mutations have not been found to be risk factors in either type of retinal vein
      occlusion.

PMID- 10634551
TI  - Recurrent optic nerve head infarctions associated with combined factor V Leiden-
      and factor II:G20210A-mutation.
AB  - PURPOSE: To demonstrate the association of bilateral recurrent optic nerve head
      infarctions with thrombophilia due to combined factor V:R506Q- and factor
      II:G20210A-mutation. METHODS: Case report. We examined a 55-year-old man with a
      two-year history of three segmental optic nerve head infarctions. Visual acuity
      was 20/80 on the left and 20/25 on the right eye. RESULTS: Ophthalmologic,
      cardiologic, radiologic, neurologic and hematologic-immunologic examinations were
      unremarkable except for increased APC-resistance (APC ratio: 1.4; normal value
      >2) due to heterozygous factor V:R506Q-mutation and high factor II-levels due to
      factor II:G20210A-mutation. Therapy with coumarin was instituted at INR 2.0-3.0
      and no relapse has occurred over the past 1-year period. CONCLUSION: Combined
      occurrence of thrombogenic factor II:G20210A-mutation and factor V:R506Q-mutation
      may be causally linked to recurrent optic nerve head infarctions.

PMID- 10634552
TI  - Protein C, protein S and antithrombin III deficiencies in retinal vein occlusion.
AB  - PURPOSE: The role of decreased levels of protein C, protein S and antithrombin
      III were investigated in patients with branch and central retinal vein occlusion.
      METHODS: Forty-five patients with retinal vein occlusion and 20 healthy subjects
      as a control group was studied. Fourteen patients (31%) had central retinal vein
      occlusion and 31 (69%) had branch retinal vein occlusion. The concentrations of
      protein C, protein S and antithrombin III were measured. RESULTS: Plasma levels
      of protein C, protein S and antithrombin III were not reduced in the control
      group. Six of the 14 central retinal vein occlusion cases and 3 of the 31 retinal
      branch vein occlusion cases had decreased levels of protein C. One of the 14
      central retinal vein occlusion cases and 1 of the 31 retinal branch vein
      occlusion cases had decreased levels of protein S. Antithrombin III was reduced
      in 1 patient of the 31 retinal branch vein occlusions. We found statistically
      significant differences for number of cases with protein C deficiency between the
      central retinal vein occlusion cases and the branch retinal vein occlusion cases
      (p<0.05). CONCLUSION: Deficiency of anticoagulant proteins, especially protein C,
      may play a role in the etiology of retinal vein occlusion. Measurement of these
      parameters may be useful in preventing venous thrombosis elsewhere in the body.

PMID- 10634553
TI  - Prevalence of factor V Leiden in patients with retinal vein occlusion.
AB  - PURPOSE: Factor V Leiden mutation is a common genetic defect associated with a
      tendency to venous thrombosis. The aim of this study was to evaluate the
      prevalence of factor V Leiden in patients with retinal vein occlusion (RVO).
      METHODS: Blood samples were obtained from fifty RVO patients and were tested for
      factor V Leiden using DNA analysis. Twenty-three patients had central RVO (CRVO),
      twenty-five had branch RVO (BRVO) and two had CRVO in one eye and BRVO in the
      other eye. RESULTS: DNA analysis showed that only 4 patients (8%) were
      heterozygous carriers of factor V Leiden. None of the patients were found to be
      homozygous. In the control group 11 (9.2%) were heterozygous carriers of factor V
      Leiden. The difference between the patients and the controls was not
      statistically significant. CONCLUSION: There was no clear association between RVO
      and factor V Leiden in this pool of patients. Factor V Leiden does not seem to
      play an important role in the development of RVO.

PMID- 10634554
TI  - Activated protein C resistance and anticoagulant proteins in young adults with
      central retinal vein occlusion.
AB  - BACKGROUND: Central retinal vein occlusion is a disease that is most common in
      old people, and often associated with atherosclerosis, hypertension, diabetes or
      glaucoma. Since these diseases are much less evident in young people, we wanted
      to investigate the prevalence of disorders in the most common anticoagulant
      proteins in a group of young patients with central retinal vein occlusion.
      METHODS: 37 consecutive patients younger than 50 years and with a history of
      central retinal vein occlusion, were analysed for deficiencies of natural
      inhibitors of coagulation (protein C, S, and antithrombin III), plasminogen,
      resistance to activated protein C, and the presence of anticardiolipin or lupus
      anticoagulants. RESULTS: Anticoagulant protein deficiencies were found in 4
      patients (11%) and activated protein C resistance in 7 patients (19%).
      Anticardiolipin or lupus anticoagulants were not found in the patients.
      CONCLUSION: Activated protein C resistance and anticoagulant protein deficiencies
      seem to be important factors to the etiology to central retinal vein occlusion in
      young patients.

PMID- 10634555
TI  - Assessment of diabetic retinopathy using two-field 60 degrees fundus photography.
      A comparison between red-free, black-and-white prints and colour transparencies.
AB  - PURPOSE: To assess the severity of diabetic retinopathy and maculopathy by
      comparing two different photographic methods; two-field 60 degrees photography
      using red-free, black-and-white prints and colour transparencies. METHODS: Two
      ophthalmologists independently graded the photographs of 74 patients using
      grading scales for retinopathy and maculopathy designed for 60 degrees
      photography. A set of nine 60 degrees red-free, black-and-white standard
      photographs were chosen to represent the severity of principal diabetic
      retinopathy and maculopathy abnormalities. RESULTS: The inter-observer agreement
      for five pooled retinopathy severity levels was 88% (kappa 0.83, weighted kappa
      0.96) and 81% (kappa 0.73, weighted kappa 0.89) using red-free, black-and-white
      prints and colour transparencies respectively. The corresponding figures for six
      pooled maculopathy levels were 96% (kappa 0.84, weighted kappa 0.97) and 93%
      (kappa 0.67, weighted kappa 0.86). The analyses revealed that red-free, black-and
      white prints disclosed a higher severity level of retinopathy in 83% (Grader 1)
      and 76% (Grader 2) in those eyes for which the grading was discordant.
      CONCLUSION: High-quality monochrome, red-free, wide-angle fundus photographs may
      be useful for the detection of early and advanced diabetic retinopathy.

PMID- 10634556
TI  - Biometric changes in the eyes of Norwegian university students--a three-year
      longitudinal study.
AB  - PURPOSE: The aim of this study was to investigate the changes in biometric
      measurements and corresponding refractive errors during a three-year period among
      university students exposed to high educational demands. METHODS: A three-year
      longitudinal cohort study was performed among 149 Norwegian engineering students
      (79 females and 70 males, mean age 20.6+/-1.2 years) measuring their refraction
      and ocular dimensions at the beginning and at the end of the period. The
      examinations included refraction, keratometry, and A-scan ultrasonographic
      measurements of the ocular components, all made in cycloplegia. RESULTS: After
      three years the mean refractive change was -0.52+/-0.45 D (p<0.05), which was
      accompanied by a change in lens thickness of 0.07+/-0.10 mm (p<0.05), and a
      vitreous chamber elongation of 0.27+/-0.30 mm (p<0.05). The results refer to the
      right eye. Stratification of the sample based on their initial refraction
      (myopes, emmetropes, and hyperopes) showed refractive change towards myopia for
      all subgroups as well as a significant increase in lens thickness and vitreous
      chamber depth. No significant three-year change in anterior chamber depth or
      corneal curvature was found in any of the groups. For all groups, vitreous
      chamber elongation gave a notable dioptric change in myopic direction.
      CONCLUSIONS: A shift in refraction towards myopia after puberty is accompanied by
      vitreous chamber elongation which can explain the dioptric change in myopic
      direction.

PMID- 10634557
TI  - Inheritance of strabismus and the gain of using heredity to determine populations
      at risk of developing strabismus.
AB  - PURPOSE: In the Nordic countries 2 to 4% of the population squint or have been
      squinting. Since strabismus is one of the major causes of amblyopia early
      detection and treatment is important for preventing this development. For
      centuries it has been recognized that strabismus is hereditary. Identifying
      individuals with a family history of squinting could give access to a risk
      population for a selective screening. METHODS AND RESULTS: 1,571 children were
      selected for this study. All children that took part in a voluntary eye
      examination at one year of age (born 1978-1983) in the city of Vasteras, Sweden
      and that had a family history of strabismus were selected together with controls.
      The study was a 6-year follow-up from 1 to 7 years of age. Parental knowledge of
      squint among relatives and measured high hyperopia (>3.0 D) present at 1 year of
      age were each and in combination evaluated as a risk indicator for development of
      strabismus between 1 to 7 years of age. CONCLUSION: The study indicates that a
      family history of squint in combination with measured high hyperopia can be used
      in a selective screening to identify a population with an increased risk of 4 to
      6 times for developing strabismus. Among the children with parental knowledge of
      squint among several relatives of both the parents, those with high hyperopia
      developed strabismus in almost every second case while this was the case in only
      approximately 10% of those with low hyperopia. Finally, heredity is an important
      risk indicator that can be used for selective screening purpose. Its potential as
      a risk indicator is substantially increased when combined with a high hyperopia.

PMID- 10634558
TI  - Variations in ocular hemodynamics in patients with early and late glaucoma.
AB  - PURPOSE: To determine the retrobulbar hemodynamics in glaucoma patients with
      different degrees of optic nerve damage. METHODS: Color Doppler imaging was
      performed in 52 patients with controlled primary open angle glaucoma (POAG) and
      in 25 control subjects. Glaucomatous eyes were divided into early and late groups
      based on the perimetry findings. Peak systolic velocity (PSV), end diastolic
      velocity (EDV), and resistive index of the central retinal artery (CRA) and
      posterior ciliary arteries (PCA) were evaluated. RESULTS: Early glaucoma showed
      significantly decreased PSV in nasal PCA when compared with the normal. Late
      glaucoma showed significantly decreased PSV and EDV in the CRA and nasal PCA, and
      significantly decreased PSV in temporal PCA as compared with the control and
      early glaucoma. The resistive index of the CRA also increased significantly in
      late glaucoma. CONCLUSION: Eyes with advanced glaucomatous optic neuropathy were
      associated with more marked alterations in retrobulbar circulation than eyes with
      less nerve damage.

PMID- 10634559
TI  - Homologous penetrating central limbo-keratoplasty (HPCLK) in bilateral limbal
      stem cell insufficiency.
AB  - PURPOSE: Bilateral stem cell deficiency can be overcome only by keratoplasty plus
      additional homologous limbal transplantation. We have four years' experience with
      a new surgical one-stage procedure, homologous penetrating central limbo
      keratoplasty (HPCLK). METHODS: A clinical trial was performed in order to
      evaluate the effectiveness of this new method. The first 25 eyes after HPCLK for
      limbal stem cell deficiency have been followed for more than 12 months. The
      eccentrically trephined unmatched grafts contained 40% limbus and were
      transplanted centrally in the host. Systemic cyclosporin A (CSA) was administered
      for at least one year. Central clear graft survival was the main outcome
      criterion. RESULTS: 18 grafts failed, mostly because of postoperative surface
      disorders. Seven grafts have remained centrally clear 12-41 months after HPCLK.
      CONCLUSIONS: In the majority of the grafts the transplanted limbal stem cells
      underwent immune destruction. The survival of seven grafts, however, shows that
      HPCLK is principally a promising new procedure. Further progress can be expected
      from the use of well HLA-matched grafts instead of unmatched grafts and from
      further improved systemic immune modulation.

PMID- 10634560
TI  - Latanoprost 0.005% and anterior segment uveitis.
AB  - PURPOSE: To evaluate the association of latanoprost with anterior chamber uveitis
      in glaucoma patients. METHODS: We retrospectively reviewed 527 charts in
      latanoprost treated patients with: no prior uveitis (Group 1); prior uveitis but
      were inactive at the time of the study (Group 2); and active uveitis (Group 3).
      RESULTS: In Group 1 five (1.0%) of 505 patients developed uveitis after beginning
      latanoprost. The uveitis was trace to 1+ cell in severity and delayed in onset
      99.8+/-73.9 days In Group 2 three of 13 (23.1%) patients developed delayed
      uveitis (trace to 1+ cell). In Group 3 zero of nine (0%) patients had worsened
      inflammation and the intraocular pressure remained unchanged (22.8+/-7.8 mmHg to
      22.0+/-7.3 mmHg) after beginning latanoprost (p=0.38). CONCLUSION: In patients
      without a prior history a mild delayed uveitis with latanoprost treatment may
      develop rarely. In patients with a uveitis history, a mild delayed exacerbation
      potentially may occur and the intraocular pressure may not be decreased in active
      uveitis.

PMID- 10634561
TI  - Variability of measurements of visual acuity in a large eye clinic.
AB  - PURPOSE: The aim of this study was to determine the variability of visual acuity
      in a large eye clinic. METHODS: A cross-sectional study using 50, consecutively
      presenting adult patients with visual acuity of at least 6/60 and aged between 18
      and 75 years was performed. Measurements of visual acuity obtained under normal
      clinical conditions were compared to measurements obtained using standard
      clinical research protocols. The variability of visual acuity was assessed by
      determining the 95% limits of agreement between test and retest measures.
      RESULTS: There were no significant differences between test-retest measurements
      of visual acuity, either aided or unaided. Pearson r correlation coefficients
      between test and retest measurements were high for both aided and unaided visual
      acuity. The 95% limits of agreement revealed repeatability of about +/-1.5 logMAR
      or 1.5 lines on a standard logMAR chart. CONCLUSION: In large eye clinics, in
      order to be confident that a real change in visual acuity has occurred between
      measurements, a difference of at least 0.15 logMAR (8 letters on a standard
      logMAR visual acuity chart) is required.

PMID- 10634562
TI  - Complications after early surgery for congenital cataracts.
AB  - PURPOSE: To study the type and frequency of complications requiring additional
      surgery in infants operated on for congenital cataract before 12 months of age.
      METHODS: The medical records of 57 infants who underwent surgery for unilateral
      and bilateral congenital cataracts during a five-year-period were reviewed
      retrospectively. The follow-up period ranged from 9 to 70 months with a mean of
      37 months. Cataract extraction was performed on 83 eyes. RESULTS: Thirty-eight
      operations for after-cataracts were performed on 32 out of 83 eyes. Fourteen
      vitrectomies were made on 11 eyes because of pupillary block glaucoma. Glaucoma
      requiring trabeculectomy developed in eight eyes 2 to 14 months after cataract
      extraction. This type of glaucoma occurred almost exclusively in eyes operated on
      during the first two months of life. CONCLUSION: Complications requiring
      additional surgery are very common in infants operated on for congenital
      cataracts during the first year of life. Glaucoma requiring trabeculectomy
      developed particularly in infants who had their cataract extraction very early.
      Glaucoma development was not more common in infants operated on for after
      cataract.

PMID- 10634563
TI  - The decrease of visual acuity in cataract patients waiting for surgery.
AB  - PURPOSE: To investigate the rapidity of vision loss in eyes waiting for cataract
      surgery and to estimate what proportion of life expectancy the extended wait for
      surgery comprised. METHODS: The visual acuities at the time of referral and on
      the day before surgery were compared in 124 patients operated on for cataract in
      the Vaasa Central Hospital, Finland. The expected survival of the patients after
      surgery was calculated individually using the Finnish life statistics. RESULTS:
      During the waiting time of 13 months on the average, the visual acuity in the
      study eye decreased from 0.68 logMAR (0.2 in decimal values) to 0.96 logMAR
      (0.1). The average decrease in vision was 0.27 logMAR per year varying from none
      to 2.07 logMAR units. 30% of the eyes experienced worsening of vision by 60% or
      more while 48% had no or minimal worsening (<0.2 logMAR). The rapidity of change
      in visual acuity was somewhat less in older patients (75 years or older), but the
      difference was not statistically significant. The percentage of persons with
      visual acuity of 0.5 or better in the better eye decreased from 66% to 41% and
      those with low vision (<0.3 in the better eye) increased from 8% to 21%. The mean
      waiting time in relation to the expected survival for all patients was 13%
      varying from less than 5% in 10 patients to more than 25% in 8 patients.
      CONCLUSION: Progression of vision loss in eyes waiting for cataract surgery
      varies significantly. For many patients the extended delay caused remarkable
      disability for a considerable part of their remaining lifetime.

PMID- 10634564
TI  - Current trends in cataract surgery in Denmark--1998 survey.
AB  - A survey of the preferred techniques and choices in cataract surgery of the
      members of the Danish Ophthalmological Society with address in Denmark was
      performed in January 1999. Only ophthalmologists performing cataract surgery were
      asked to return the questionnaire. Ninety-three responses were received by the
      cut-off day, representing 32,832 cataract operations per year. The data were
      compared to data from previous surveys in Denmark, and similar data from the US
      and Japan.

PMID- 10634565
TI  - Lens opacities after repeated exposure to ultraviolet radiation.
AB  - PURPOSE: To investigate the effect of the interval between two, near-threshold
      exposures to ultraviolet radiation (UVR) on cataract development. METHODS: One
      eye of Sprague-Dawley rats was exposed twice to 4 kJ/m2 narrow band UVR
      (lambdaMAX=300 nm) for 15 min each. The interval between exposures was 0, 6, 24
      or 48 h. One week after the first exposure both lenses were removed for
      photography and measurement of the intensity of forward light scattering to
      quantify lens opacities. RESULTS: All exposed lenses developed cataract. Forward
      light scattering was the same after double exposure with no interval or a 6 h
      interval. Forward light scattering after a 24 or 48 h interval was nearly twofold
      greater than that following no interval or a 6 h interval. The exposed lenses in
      all groups had mild anterior surface opacities and intense equatorial opacities
      as judged with a stereomicroscope. CONCLUSION: Two, near-threshold UVR exposures
      at 0 or a 6 h interval produce the same degree of lens opacification. When the
      second exposure follows 24 or 48 h after the first, lenticular damage increases.
      Repair processes between 24 and 48 h after exposure appear to be sensitive to
      UVR, and an additional exposure during this time may aggravate cataract
      development.

PMID- 10634566
TI  - Ocular pulse amplitude in patients with Graves' disease: a preliminary study.
AB  - PURPOSE: The purpose of this study was to evaluate the ocular pulse amplitude
      changes in patients with Graves' disease. METHODS: The pulse amplitudes of 31
      patients with Graves' disease were measured with the OBF-Tonograph (OBF Labs UK).
      All patients were in the euthyroid phase of the disease. 17 patients (Group I)
      had no ocular involvement or only mild lid retraction. 14 patients (Group II) had
      either proptosis and/or extraocular muscle involvement. Only the worst involved
      eye of each patient was included into the study. RESULTS: There was no
      statistically significant difference between the two groups among the parameters
      which might influence the pulse amplitude measurement. The pulse amplitude was
      statistically significantly lower in Group II than in Group I (2.34+/-0.79 and
      3.22+/-0.94 mmHg respectively, p<0.013). CONCLUSION: Pulse amplitude measurements
      may be an important discrimination and classification parameter for patients with
      ophthalmic Graves' disease.

PMID- 10634567
TI  - Loss of visual acuity due to eye injuries among 6292 school children in the
      Sultanate of Oman.
AB  - PURPOSE: In 1992-94 a nation-wide survey in primary schools in the Sultanate of
      Oman for ocular disorders was conducted. This report focuses on the prevalence of
      visual acuity loss after injury. METHODS AND MATERIAL: A random selection of
      6,292 children from Grades 1 and 6 from all primary schools in the country
      provided the research sample. Children who failed the visual acuity screening
      test received a complete "on the spot" eye examination by the pediatric
      ophthalmologist. RESULTS: 12 children were found to have monocular low vision (VA
      <0.3 to amaurosis) caused by injury. Total prevalence for loss of vision in one
      eye was 0.19%, with 0.15% in 6-year-olds and 0.25% in 12-year-olds Traumatic
      cataracts were noted in 4 children, 3 of these were in need of surgery. One child
      had aphakia after trauma surgery and needed a secondary lens implant. CONCLUSION:
      Altogether the prevalence of traumatic monocular visual damage in our study was
      0.19%. Next to amblyopia, injury is the main reason for monocular loss of vision
      in childhood, however, both are preventable. Information about trauma prevention
      and the need for adequate ophthalmic care should be emphasized. Regular and
      repeated screening of visual acuity in children is essential.

PMID- 10634568
TI  - A new sponge profile for retinal detachment surgery: design and in vitro
      effectiveness.
AB  - PURPOSE: To develop a new, calculated design for episcleral sponges to achieve
      sufficient indentation under avoidance of form related side effects. DESIGN AND
      METHODS: The new sponge profile consists of two convex halves with different
      radii, with a calculated optimum relation between inner and outer radius. It was
      tested on pig eyes and compared with round and half cut sponges. The height of
      the intraocular buckle was determined by ultrasound (A-Scan, Biovision V Plus),
      the extraocular height using ultrasound biomicroscopy (Humphrey Biomicroscope
      System Model 840). RESULTS: The buckle height achieved with the new design showed
      no significant difference to round sponges, whereas the extrascleral height was
      significantly lower compared to round sponges (p<0.001). Half cut sponges showed
      significantly less buckle height compared to round sponges (p<0.001) and to the
      new design (p<0.02). CONCLUSION: The new design produces sufficient indentation
      combined with minor change of the outer globe contour. It has the potential to be
      as efficient as conventional round sponges, but more tolerable for the patient by
      reduction of form related side effects.

PMID- 10634569
TI  - Solitary fibrous tumor of the orbit: a poorly-recognized orbital lesion.
AB  - PURPOSE: The authors report three cases with solitary fibrous tumor (SFT) of the
      orbit with variable clinical presentation. METHODS: The authors identified three
      patients with a diagnosis of SFT, and clinical histories, radiographs and
      pathologic specimens were reviewed. RESULTS: Two SFTs are reported arising in the
      lacrimal gland fossa of a 24-year-old male and a 26-year-old female and a
      retrobulbar SFT is reported occurring in a 40-year-old female. While two patients
      had slow growth histories, one patient had a history of rapid progression.
      Immunohistochemically, the tumor cells were strongly positive for CD34 in all
      three cases. CONCLUSION: The clinical presentation of the orbital SFT may be
      varied. Immunohistochemical analysis may help in the diagnosis of solitary
      fibrous tumor and the treatment is en bloc excision. A careful follow-up is
      necessary because it may recur years after excision of the primary tumor.

PMID- 10634570
TI  - Leiomyoma of the ciliary body. Report of 2 cases.
AB  - PURPOSE AND METHODS: The files of the Eye Pathology Institute contain only two
      cases of leiomyoma of the ciliary body. The diagnoses were re-evaluated, applying
      modern immunostainings. RESULTS: The tumors were composed of interlacing
      fascicles of spindle-shaped cells with bright eosinophilic cytoplasm and cigar
      shaped nuclei. Both tumors were well-vascularized, mostly by thin, branching
      capillaries. Larger vessels were also seen. In one case the tumor perforated the
      sclera. The tumor cells reacted with the reticulum stain and the Masson trichrome
      and were positive for antibodies against: smooth muscle actin (SMA), muscle
      specific actin (MSA), laminin and vimentin (one case). CONCLUSION: Leiomyoma of
      the ciliary body is a rare smooth muscle cell tumor that may arise from either
      pericytes, ciliary - or intrascleral heterotopic muscle.

PMID- 10634571
TI  - Carcinoma of the ovary with primary presentation in the choroid.
AB  - PURPOSE: An unusual case of choroidal metastases from an ovarian adenocarcinoma
      is described, and a brief review of the literature is presented. METHODS:
      Clinical and autopsy findings are presented. RESULTS: After having diagnosed
      bilateral choroidal metastatic lesions, a clinical investigation and a subsequent
      laparotomy disclosed bilateral ovarian tumors with histopathological features of
      mucinous adenocarcinoma. At autopsy the tumor was confirmed to be a primary
      ovarian mucinous adenocarcinoma with choroidal metastases. CONCLUSION: This
      article describes what is believed to be the first case report of a primary
      epithelial carcinoma of the ovary with histopathologically documented metastases
      to the choroid. Metastatic disease must be considered in the evaluation of
      patients with choroidal lesions of unknown etiology.

PMID- 10634572
TI  - Cilioretinal artery occlusion during coronary catheterization.
AB  - PURPOSE: To report on a patient with cilioretinal artery occlusion during cardiac
      catheterization. METHODS: A 51-year-old man complained of blurred vision in the
      left eye immediately following cardiac catheterization. Visual acuity was 6/12
      and the eye had a dense central scotoma. RESULTS: Mild retinal whitening of the
      posterior pole and segmented filling of the cilio-retinal artery established the
      diagnosis of cilioretinal artery occlusion. Immediate paracentesis was performed.
      Two weeks later, a tiny central scotoma could be observed and visual acuity was
      6/6. CONCLUSIONS: Cardiac catheterization may result in retinal infarction.
      Awareness to any visual symptoms, immediate diagnosis and prompt intervention may
      prevent permanent visual impairment.

PMID- 10634573
TI  - Irreversible blindness after amyl nitrite inhalation.
AB  - PURPOSE: To present a case of blinding bilateral acute optic nerve disease in a
      15-year-old male apparently induced by inhalation of amyl nitrite. METHODS:
      Sequentially over four days he lost his four altitudinal visual hemifields,
      leaving atrophic discs and only 2/60 and a small field in the better eye.
      Scannings by CT and MRI and a full laboratory research gave no specific clue to
      the pathogenesis. CONCLUSIONS: No similar cases have been described in the more
      than 100-year history of pharmacological use of amyl nitrite for angina pectoris,
      and pharmacologically it is hard to point out a rationale behind the sequential
      visual loss As an alternative to frank toxicity, therefore, we have considered a
      parainfectious mechanism as related to an influenza-like disease immediately
      prior to the abuse episode.

PMID- 10634574
TI  - Unilateral papilloedema after hepatitis B vaccination in a migraine patient. A
      case report including forensic aspects.
AB  - PURPOSE: To report on a unilateral optic nerve reaction appearing 9-10 hours
      after vaccination against hepatitis B. METHODS: To describe the case and discuss
      the underlying mechanisms. There was a scintillating scotoma leaving a permanent
      inferior notch in the visual field, but central vision was left normal and with
      only a slight affection of colour perception. Shortly the optic nervehead
      appeared engorged, then slightly ischaemic, but was hardly left with evidence of
      atrophy. RESULTS: Immune-based reactions could hardly be held responsible,
      multiple sclerosis was unlikely, and ultrasonography excluded optic nervehead
      drusen. An optic nerve migraine mechanism is probable, possibly with the
      vaccination having acted as the trigger.

PMID- 10634575
TI  - Trabeculectomy. Analysis of intraocular pressure regulation, visual field
      survival, and occurrence of complications

PMID- 10634576
TI  - Aspects on prostanoid and cholinergic effects on aqueous humour dynamics in human
      eyes

PMID- 10634577
TI  - Cataract surgery in patients with diabetes mellitus

PMID- 10634579
TI  - Eyelid basal cell carcinoma

PMID- 10634578
TI  - Surgical management of refractory glaucoma with Molteno implant

PMID- 10634580
TI  - Impact of cataract surgery. A population based approach

PMID- 10634581
TI  - Proteinases in developing dental enamel.
AB  - For almost three decades, proteinases have been known to reside within developing
      dental enamel. However, identification and characterization of these proteinases
      have been slow and difficult, because they are present in very small quantities
      and they are difficult to purify directly from the mineralizing enamel. Enamel
      matrix proteins such as amelogenin, ameloblastin, and enamelin are cleaved by
      proteinases soon after they are secreted, and their cleavage products accumulate
      in the deeper, more mature enamel layers, while the full-length proteins are
      observed only at the surface. These results suggest that proteinases are
      necessary for "activating" enamel proteins so the parent proteins and their
      cleavage products may perform different functions. A novel matrix
      metalloproteinase named enamelysin (MMP-20) was recently cloned from tooth
      tissues and was later shown to localize primarily within the most recently formed
      enamel. Furthermore, recombinant porcine enamelysin was demonstrated to cleave
      recombinant porcine amelogenin at virtually all of the sites that have previously
      been described in vivo. Therefore, enamelysin is at least one enzyme that may be
      important during early enamel development. As enamel development progresses to
      the later stages, a profound decrease in the enamel protein content is observed.
      Proteinases have traditionally been assumed to degrade the organic matrix prior
      to its removal from the enamel. Recently, a novel serine proteinase named enamel
      matrix serine proteinase-1 (EMSP1) was cloned from enamel organ epithelia. EMSP1
      localizes primarily to the early maturation stage enamel and may, therefore, be
      involved in the degradation of proteins prior to their removal from the maturing
      enamel. Other, as yet unidentified, proteinases and proteinase inhibitors are
      almost certainly present within the forming enamel and await discovery.

PMID- 10634582
TI  - Signal transduction pathways controlling the switch between keratinocyte growth
      and differentiation.
AB  - Self-renewing epithelia are characterized by a high turnover rate and a fine
      balance between growth and differentiation. Such a balance is influenced by many
      exogenous factors, including gradients of diffusible molecules, cell/substrate
      adhesion contacts, and direct cell-cell communication. The inter-connection
      between these various extracellular signals and underlying intracellular pathways
      is clearly of great interest. Primary keratinocytes of either human or murine
      origin provide an ideal experimental system to elucidate early signaling events
      involved in the control of epithelial differentiation. Relative to established
      cell lines, use of a primary system eliminates the possibility of alterations in
      critical regulatory events which may occur during prolonged propagation in
      culture. Primary keratinocytes are easily grown in large numbers, and their
      differentiation can be induced under well-defined culture conditions. The ensuing
      rapid and homogeneous response is amenable to careful biochemical analysis. Gene
      transfer technology (transient transfections, adenoviral and retroviral vectors),
      together with the use of keratinocytes derived from gene knockout and transgenic
      mice, makes it possible to assess the specific contribution of individual genes
      to the control of the differentiation process. This review focuses on the
      significant progress that has been made over the last few years in our
      understanding of the specific signals that trigger keratinocyte differentiation,
      the underlying signaling pathways, and how they impinge on specific transcription
      and cell-cycle control mechanisms associated with the onset of keratinocyte
      differentiation. Recent developments and future directions in this important area
      of research will be highlighted.

PMID- 10634583
TI  - Oxidative injury and inflammatory periodontal diseases: the challenge of anti
      oxidants to free radicals and reactive oxygen species.
AB  - In recent years, there has been a tremendous expansion in medical and dental
      research concerned with free radicals, reactive oxygen species, and anti-oxidant
      defense mechanisms. This review is intended to provide a critical, up-to-date
      summary of the field, with particular emphasis on its implications for the
      application of "anti-oxidant therapy" in periodontal disease. We have reviewed
      the nomenclature, mechanisms of actions, features, and sources of most common
      free radicals and reactive oxygen species, as well as analyzed the typical
      biological targets for oxidative damage. Based on a review of direct and indirect
      anti-oxidant host defenses, particularly in relation to the key role of
      polymorphonuclear neutrophils in periodontitis, we review current evidence for
      oxidative damage in chronic inflammatory periodontal disease, and the possible
      therapeutic effects of anti-oxidants in treating and/or preventing such
      pathology, with special attention to vitamin E and Co-enzyme Q.

PMID- 10634584
TI  - Actions of hedgehog proteins on skeletal cells.
AB  - Recent advances in developmental and molecular biology during embryogenesis and
      organogenesis have provided new insights into the mechanism of bone formation.
      Members of the hedgehog gene family were initially characterized as patterning
      factors in embryonic development, but recently they have been shown to regulate
      skeletal formation in vertebrates. The amino terminal fragment of Sonic hedgehog
      (Shh-N), which is an active domain of Shh, has the ability to induce ectopic
      cartilage and bone formation in vivo. Shh-N stimulates chondrogenic
      differentiation in cultures of chondrogenic cell line cells in vitro and inhibits
      chondrogenesis in primary limb bud cells. These findings suggest that the
      regulation of chondrogenesis by hedgehog proteins depends on the cell populations
      being studied. Indian hedgehog (Ihh) is prominently expressed in developing
      cartilage. Ectopic expression of Ihh decreases type X collagen expression and
      induces the up-regulation of parathyroid hormone-related peptide (PTHrp) gene
      expression in perichondrium cells. A negative feedback loop consisting of Ihh and
      PTHrp, induced by Ihh, appears to regulate the rate of chondrocyte maturation.
      The direct actions of Shh and Ihh on stimulation of osteoblast differentiation
      are evidenced by the findings that these factors stimulate alkaline phosphatase
      activity in cultures of pluripotent mesenchymal cell line cells and osteoblastic
      cells and that these cells express putative receptors of hedgehog proteins. In
      conclusion, hedgehog proteins seem to be significantly involved in skeletal
      formation through multiple actions on chondrogenic mesenchymal cells,
      chondrocytes, and osteogenic cells.

PMID- 10634585
TI  - Glucose and lactate metabolism by Actinomyces naeslundii.
AB  - Actinomyces are among the predominant bacteria in the oral microflora. This
      review discusses the glucose and lactate metabolism of Actinomyces naeslundii and
      its ecological significance in dental plaque. This bacterium has the Embden
      Meyerhof-Parnas (EMP) pathway as the main route to degrade glucose. The EMP
      pathway-derived metabolic intermediates, phosphoenolpyruvate (PEP) and pyruvate,
      are further converted into different end-products, depending on the environment.
      Under anaerobic conditions in the absence of bicarbonate, the pyruvate is
      converted into lactate by a lactate dehydrogenase. In the presence of
      bicarbonate, the PEP is combined with bicarbonate and then converted into
      succinate through the succinate pathway, while the pyruvate is converted into
      formate and acetate through the pyruvate formate-lyase pathway. Under aerobic
      conditions, the pyruvate liberates acetate and CO2 through a pathway initiated by
      a pyruvate dehydrogenase. A. naeslundii strains also degrade lactate,
      aerobically, to acetate and CO2 through the conversion of lactate into pyruvate
      by a NAD-independent lactate dehydrogenase. These strains also synthesize
      glycogen from a glycolytic intermediate, glucose 6-phosphate. Besides atmospheric
      conditions and bicarbonate, the intracellular reduction-oxidation potential,
      carbohydrate concentration, and environmental pH also modulate the metabolism of
      A. naeslundii. Some of the phosphorylating enzymes involved in A. naeslundii
      metabolism--e.g., GTP/polyphosphate (PPn)-dependent glucokinase, pyrophosphate
      (PPi)-dependent phosphofructokinase, UDP-glucose pyrophosphorylase, and GDP/IDP
      dependent PEP carboxykinase--are unique to A. naeslundii and have not been found
      in other oral bacteria. The utilization of PPn and PPi as phosphoryl donors,
      together with glycogen synthesis and lactate utilization, could contribute to the
      efficient energy metabolism found in A. naeslundii. Through this flexible and
      efficient metabolic capacity, A. naeslundii can adapt to fluctuating environments
      and compete with other bacteria in dental plaque. Further, this bacterium may
      modify the dental plaque environment and promote the microbial population shifts
      in dental plaque.

PMID- 10634586
TI  - Craniofacial pain and motor function: pathogenesis, clinical correlates, and
      implications.
AB  - Many structural, behavioral, and pharmacological interventions imply that
      favorable treatment effects in musculoskeletal pain states are mediated through
      the correction of muscle function. The common theme of these interventions is
      captured in the popular idea that structural or psychological factors cause
      muscle hyperactivity, muscle overwork, muscle fatigue, and ultimately pain.
      Although symptoms and signs of motor dysfunction can sometimes be explained by
      changes in structure, there is strong evidence that they can also be caused by
      pain. This new understanding has resulted in a better appreciation of the
      pathogenesis of symptoms and signs of the musculoskeletal pain conditions,
      including the sequence of events that leads to the development of motor
      dysfunction. With the improved understanding of the relationship between pain and
      motor function, including the inappropriateness of many clinical assumptions, a
      new literature emerges that opens the door to exciting therapeutic opportunities.
      Novel treatments are expected to have a profound impact on the care of
      musculoskeletal pain and its effect on motor function in the not-too-distant
      future.

PMID- 10634587
TI  - Radiologic anatomy of the paranasal air sinuses.
AB  - Over the last decade, significant strides have been made in the imaging-guided
      management of sinonasal inflammation. We are now able to achieve an enhanced
      level of understanding of the complex functional and surgical anatomy of this
      region. This facilitates meaningful communication with the surgeons who consult
      with us. Sectional imaging using both CT and MR is applied well to sinonasal
      imaging, but anatomic CT landmarks are emphasized in this article with its
      connection to minimally invasive sinus surgery. Our ongoing research efforts
      target dynamic functional anatomy with advanced postprocessing techniques.

PMID- 10634588
TI  - Sinonasal inflammatory disease: pathophysiology, imaging, and surgery.
AB  - The body of literature regarding imaging inflammatory diseases of the sinonasal
      cavity is extensive. This article will not recapitulate standard imaging
      protocols, osteomeatal complex (OMC) anatomy, or drainage pathways to any
      significant extent. Clinical and radiographic topics that create confusion for
      radiologists will be covered in some depth to include the pathophysiology of
      rhinosinusitis and bone response to inflammation. Fungal sinusitis is covered
      elsewhere in this issue. Clinical imaging issues will be followed by a discussion
      of common surgical procedures, their complications, and postoperative recurrent
      disease. The role of MRI as a problem-solving modality will be emphasized.

PMID- 10634589
TI  - Fungal diseases of the paranasal sinuses.
AB  - Fungal diseases of the paranasal sinuses can be categorized into the invasive and
      noninvasive varieties. The invasive form has been classified as acute fulminant
      fungal sinusitis, granulomatous invasive fungal sinusitis, and chronic invasive
      fungal sinusitis. The noninvasive form can be classified as the fungus ball and
      the allergic fungal sinusitis. The following review discusses the various types
      of fungal sinusitis with a special emphasis on the CT and MR imaging features.

PMID- 10634590
TI  - Sinonasal imaging: malignant disease.
AB  - The clinical presentation of sinonasal malignancy overlaps that of more common
      benign inflammatory disease. For this reason, unsuspected malignant lesions are
      often first recognized on the screening CT exam. We will focus on the initial CT
      appearance of various malignancies and discuss the goals of imaging including the
      use of MR.

PMID- 10634591
TI  - Vascular lesions of the paranasal sinuses and nasal cavity.
AB  - The vascular supply to the face and paranasal sinuses is predominantly derived
      from branches of the external carotid artery. An extensive collateral arterial
      network exists between branches of the external carotid artery and the internal
      carotid artery that is important in the assessment of head and neck vascular
      disease. We illustrate the normal vascular anatomy and correlate cross-sectional
      and angiographic images of head and neck vascular disease, with a focus on
      lesions affecting the paranasal sinuses and nasal cavity.

PMID- 10634592
TI  - Albinism: its implications for refractive development.
AB  - PURPOSE: Albinism involves the mutation of one or more of the genes associated
      with melanin synthesis and has many ramifications for vision. This study focuses
      on the refractive implications of albinism in the context of emmetropization.
      METHODS: Refractive, biometric, and visual acuity data were collected for a group
      of 25 albino individuals that included the following: 18 oculocutaneous (13
      tyrosine positive, 5 tyrosine negative); 7 ocular (2 autosomal recessive, 5 sex
      linked recessive). Their age range was 3 to 51 years. All exhibited horizontal
      pendular nystagmus. RESULTS: There were no statistically significant differences
      relating to albino subtype for any of the measured parameters. All the subjects
      had reduced visual acuity (mean: 0.90, logMAR) and overall, there was a bias
      toward hyperopia in their refractive errors (mean: + 1.07 D). However the
      refractive errors of the group covered a broad range (SD: 4.67 D) and included
      both high myopia and high hyperopia. An axial origin to the refractive errors is
      implied by the high correlation between refractive errors and axial lengths.
      Refractive astigmatism averaged 2.37 D and was consistently with-the-rule and
      highly correlated with corneal astigmatism, which was also with-the-rule.
      Meridional analysis of the refractive data indicated that the vertical meridian
      for hyperopic subjects was consistently nearer emmetropia compared to their
      horizontal meridian. Myopic subjects showed the opposite trend. CONCLUSIONS: The
      overall refractive profile of the subjects is consistent with emmetropization
      being impaired in albinism. However, the refractive errors of hyperopic subjects
      also can be explained in terms of "meridional emmetropization." The contrasting
      refractive profiles of myopic subjects may reflect operational constraints of the
      emmetropization process.

PMID- 10634593
TI  - Expression of a single pair of desmosomal glycoproteins renders the corneal
      epithelium unique amongst stratified epithelia.
AB  - PURPOSE: To determine desmosomal glycoprotein isoform expression in bovine
      corneal, limbal, and conjunctival epithelium and desmosomal profile and
      distribution during corneal re-epithelialization. METHODS: Immunofluorescence
      (IF) for desmosomal components on cryostat sections of fresh epithelia was
      supported by immunoblot analysis of tissue lysates. Wounded corneas maintained in
      organ culture were examined by IF at times up to full re-epithelialization (96
      hours). RESULT: Immunofluorescence for desmoplakin confirmed desmosome presence
      throughout all three epithelia. Plakoglobin was also ubiquitous. Of the
      desmosomal glycoproteins, desmocollin 2 (Dsc2) and desmoglein 2 (Dsg2) were
      expressed throughout, but Dsc3 and Dsg3 were confined to the limbus and
      conjunctiva, and Dscl and Dsgl were absent. Dsc2 and Dsg2 IFs were stronger in
      superficial layers, but Dsc3 and Dsg3 were stronger basally, fading suprabasally.
      Glycoprotein expression in cornea and conjunctiva was confirmed by immunoblot
      analysis. No change in glycoprotein expression occurred during re
      epithelialization. CONCLUSIONS: Uniquely among stratified epithelia, cornea
      expresses only a single pair of desmosomal glycoproteins, Dsc2 and Dsg2.
      Expression of Dsc3 and Dsg3 in limbus and conjunctiva coincides with their
      association with cell proliferation in other epithelia, but corneal epithelial
      cells did not express Dsc3 or Dsg3 during re-epithelialization. Absence of Dscl
      and Dsgl correlates with lack of keratinization in ocular epithelia. These
      expression patterns may have significance for the specific properties and
      differentiation patterns of the epithelia. Presence of desmosomes throughout re
      epithelialization raises the question of how migrating cells mutually re
      position.

PMID- 10634594
TI  - An analysis of ABCR mutations in British patients with recessive retinal
      dystrophies.
AB  - PURPOSE: Several reports have shown that mutations in the ABCR gene can lead to
      Stargardt disease (STGD)/fundus flavimaculatus (FFM), autosomal recessive
      retinitis pigmentosa (arRP), and autosomal recessive cone-rod dystrophy (arCRD).
      To assess the involvement of ABCR in these retinal dystrophies, the gene was
      screened in a panel of 70 patients of British origin. METHODS: Fifty-six patients
      exhibiting the STGD/FFM phenotype, 6 with arRP, and 8 with arCRD, were screened
      for mutations in the 50 exons of the ABCR gene by heteroduplex analysis and
      direct sequencing. Microsatellite marker haplotyping was used to determine
      ancestry. RESULTS: In the 70 patients analyzed, 31 sequence changes were
      identified, of which 20 were considered to be novel mutations, in a variety of
      phenotypes. An identical haplotype was associated with the same pair of in-cis
      alterations in 5 seemingly unrelated patients and their affected siblings with
      STGD/FFM. Four of the aforementioned patients were found to carry three
      alterations in the coding sequence of the ABCR gene, with two of them being in
      cis. CONCLUSIONS: These results suggest that ABCR is a relatively polymorphic
      gene. Because putative mutations have been identified thus far only in 25 of 70
      patients, of whom only 8 are compound heterozygotes, a large number of mutations
      have yet to be ascertained. The disease haplotype seen in the 5 patients carrying
      the same "complex" allele is consistent with the presence of a common ancestor.

PMID- 10634595
TI  - Distribution of ascorbate in the anterior bovine eye.
AB  - PURPOSE: To analyze the ascorbate distribution in the anterior eye wall to better
      understand the functional significance of this compound in the eye. METHOD:
      Ascorbic acid was determined by high-performance liquid chromatography using an
      LC-10 system (Shimadzu, Kyoto, Japan). Bovine eye samples were used. RESULTS: The
      highest ascorbate concentration was observed in the corneal epithelium, with
      significantly higher values in the central (1.56 mg/g) than in the peripheral
      (1.39 mg/g) area. The ascorbate content was similar in the corneal stroma (0.22
      mg/g), the Descemet's membrane (DM)/endothelium (0.22 mg/g), and the aqueous
      humor (0.21 mg/ml). By comparison, the sclera (0.15 mg/g) and the conjunctiva
      (0.11 mg/g) showed lower values, as did the lacrimal gland (0.09 mg/g) and the
      serum (0.0008 mg/ml). CONCLUSIONS: (1) Peak ascorbate concentration was observed
      in the central corneal epithelium covering the pupillary area. This is compatible
      with the idea that the ascorbate may act as an UV filter shielding internal eye
      structures from radiation damage. (2) The ascorbate concentration in the corneal
      stroma and DM/endothelium was as high as in the aqueous humor, and it is
      suggested that the aqueous humor plays a key role in the distribution of
      ascorbate to the anterior eye wall.

PMID- 10634596
TI  - Expression profile and chromosomal location of cDNA clones, identified from an
      enriched adult retina library.
AB  - PURPOSE: To delineate the profile of genes expressed in the adult human retina
      and assign chromosomal location of cDNA clones. METHODS: The end-sequence of
      random clones from an enriched human retinal cDNA library was analyzed by NCBI
      database search. Expression profile was established by northern blot analysis,
      database search, or both. Selected cDNA clones were localized to human
      chromosomes by somatic cell hybrid analysis, in situ hybridization to metaphase
      chromosomes, or both. Chromosomal location was also obtained by searching the
      databases. RESULT: One hundred and thirty-seven clones were isolated from the
      subtracted retinal library. Fifty-one clones were identical with 35 known human
      genes in GenBank, and 24 clones corresponded to 23 uncharacterized human
      expressed sequenced tags (ESTs), novel genes, or both. The remaining 59 clones
      were not pursued further because they contained bacterial sequences or repetitive
      elements. Several clones indicated a restricted pattern of expression with high
      levels of transcripts in the retina. Chromosomal location of novel retinal ESTs
      is also reported. CONCLUSIONS: This study provides a profile of genes expressed
      in the adult human retina. One round of subtraction eliminated most
      constitutively expressed genes and permitted partial normalization of the retinal
      library. Twenty-three novel genes were identified. The combined information
      obtained from expression analysis and chromosomal localization of retinal cDNAs
      should be valuable in identifying candidate genes for diseases involving retinal
      dysfunction.

PMID- 10634597
TI  - Induction of a 55-kDa PKN cleavage product by ischemia/reperfusion model in the
      rat retina.
AB  - PURPOSE: To investigate the physiological role of a protein kinase, PKN, and its
      relation to apoptosis in vivo. METHODS: An ischemia/reperfusion model of the rat
      retina was created by elevating the intraocular pressure. Retinal samples were
      obtained after ischemic insult (15-45 minutes) followed by reperfusion (1-7
      days). The effect of ischemia on the fragmentation of PKN was examined by
      immunoblotting and immunocytochemical procedures using the antibody against PKN.
      N-methyl-D-aspartate (NMDA) or a caspase-3 inhibitor (DEVD-CHO) was administered
      intravitreally to investigate its effect on the induction of PKN fragmentation.
      The retinal cell loss in each sample was evaluated by toluidine blue staining.
      RESULTS: Ischemia induced a 55-kDa PKN cleavage fragment corresponding to the
      molecular size of the constitutively active fragment of PKN. The appearance of
      the cleavage fragment depended on the duration of reperfusion and correlated with
      the occurrence of retinal cell loss. Immunocytochemical analysis revealed that
      ischemia increased PKN immunoreactivity in the inner layers of the retina. DEVD
      CHO significantly inhibited the appearance of the 55-kDa fragment and protected
      against retinal cell loss. The administration of NMDA also induced cleavage of
      PKN. CONCLUSIONS: PKN is specifically cleaved by caspase-3 or a related protease
      during apoptosis in vivo, and PKN cleavage is at least partially initiated by
      activation of the NMDA receptor.

PMID- 10634598
TI  - A new locus for autosomal dominant congenital cataracts maps to chromosome 3.
AB  - PURPOSE: To map a gene for cataracts in a family with congenital nuclear and
      sutural cataracts and to examine candidate genes in the linked region. METHODS: A
      large family with autosomal dominant congenital nuclear and sutural cataracts was
      identified and characterized. A genome-wide screen was conducted with a set of
      markers spaced at 10- to 15-cM intervals, and linkage was assessed using standard
      LOD score analysis. RESULT: Fifteen (15) affected individuals were identified.
      This form of congenital cataracts maps to a 12-cM region on chromosome 3q21.2
      q22.3 between markers D3S3674 and D3S3612, with a maximum multipoint LOD score of
      6.94 at D3S1273. The crystallin gene, CRYGS, was excluded as a candidate gene for
      this locus. CONCLUSIONS: There are now more than 12 different genetic loci that
      cause congenital cataracts. The most recent locus to be identified is on
      chromosome 3q21.2-q22.3, in a family with congenital nuclear and sutural
      cataracts.

PMID- 10634599
TI  - Prevalence of glaucoma in a rural East African population.
AB  - PURPOSE: To determine the prevalence of glaucoma in an adult population in rural
      central Tanzania. METHODS: Six villages were randomly selected from eligible
      villages in the Kongwa district, and all residents more than 40 years of age were
      enumerated and invited to a comprehensive eye examination including presenting
      visual acuity, refraction, automated 40-point Dicon (San Diego, CA)
      suprathreshold screening field test, Tono-Pen (Bio-Rad, Inc., Boston, MA)
      intraocular pressure (IOP) measurement, and standardized examination by an
      ophthalmologist of anterior segment, optic nerve head, and retina after pupil
      dilation. Gonioscopy and Glaucoma-Scope (Ophthalmic Imaging Systems, Sacramento,
      CA) optic disc imaging were performed on those with IOP higher than 23 mm Hg and
      cup-to-disc ratio (c/d) more than 0.6 and on a 20% random sample of participants.
      RESULTS: Of 3641 eligible persons, 3268 (90%) underwent ophthalmic examination.
      The prevalence of glaucoma of all types was 4.16% (95% confidence interval [CI] =
      3.5, 4.9%). Primary open-angle glaucoma (OAG) was diagnosed in 3.1% (95% CI =
      2.5, 3.8%), primary angle-closure glaucoma (ACG) in 0.59% (95% CI = 0.35, 0.91%),
      and other forms of glaucoma in 0.49%. The prevalence of glaucoma was found to be
      sensitive to changes in the diagnostic criteria. CONCLUSIONS: The high prevalence
      of OAG in this group was similar to that of African-derived persons in the United
      States but less than in African-Caribbean populations. ACG was more prevalent in
      east Africans than suggested by anecdotal reports.

PMID- 10634600
TI  - Vision and low self-rated health: the Blue Mountains Eye Study.
AB  - PURPOSE: To assess the relationship between reduced vision and low self-rating of
      global health, after taking into account many other related factors. METHODS: The
      Blue Mountains Eye Study examined 3654 residents aged > or =49 years (82.4%
      response) in an area west of Sydney, Australia. Presenting and best-corrected
      visual acuity (VA) were measured before and after refraction using a LogMAR
      chart. During a face-to-face interview, self-rated health was assessed by asking:
      "For someone of your age, how would you rate your overall health?: excellent,
      good, fair, or poor." Information about demography, socioeconomic status, need
      for assistance in daily living activities, medical history, and health risk
      behaviors was also collected. Logistic regression analyses were performed after
      dichotomizing self-rated health as poor or fair (low) versus good or excellent.
      RESULTS: Among persons without visual impairment (defined from best-corrected VA
      in the better eye), 24.5% rated their health as either poor or fair, compared
      with 35.5% and 48.8% of persons with mild or moderate-to-severe visual
      impairment, respectively. In multivariate logistic regression models that
      included 17 other related factors, reduced vision was statistically significantly
      associated with lower self-rated health in persons aged <80 years. For each one
      line (5 letter) reduction in best-corrected VA, there was 20% increased
      likelihood of low self-rated health, after adjustment for other factors found
      associated with self-rated health (multivariate-adjusted odds ratio 1.2, 95%
      confidence interval 1.1-1.3). In persons aged 80 years or older, reduced vision
      had no impact on global health rating. CONCLUSIONS: Decreased vision was found to
      have an independent impact on global health ranking by persons younger than age
      80 years, but not by older persons in this population. Taking into account many
      other factors affecting perceived health, people younger than age 80 years who
      see well are also more likely to say that they feel well!

PMID- 10634601
TI  - Developmentally regulated appearance of spliced variants of type XII collagen in
      the cornea.
AB  - PURPOSE: To determine whether temporal and spatial changes in the distribution of
      the long and short alternatively spliced variants of type XII collagen are
      associated with any specific morphogenetic events in pre- and postnatal
      development of the cornea and surrounding tissues. METHODS: The distribution of
      alternatively spliced variants of type XII collagen in fetal and newborn rabbit
      tissues was analyzed immunohistochemically using monoclonal antibodies that
      recognize either only the long form or both the short and the long forms of type
      XII collagen. RESULTS: During early fetal development of the cornea in rabbit
      (days 14 -17), the short form of type XII collagen was detected in the corneal
      stroma, the sclera, and the stroma in the rudimentary eyelid folds, whereas the
      long form was present only in the sclera. The long form was first evident in the
      cornea at day 24 but only in the posterior stroma. At later stages of prenatal
      development, the distribution of the long variant gradually extended toward the
      anterior stroma and in the newborn rabbit, the long variant was distributed
      throughout the entire stroma. However, in the eyelid, although the short form was
      present along the entire subepidermal regions both during fetal and neonatal
      development, the long form was transiently expressed between days 21 and 24 and
      was restricted to the subepidermal regions at the junction of the opposing
      eyelids. The long form of type XII collagen was first detectable in the basal
      epithelial cells and in its basement membrane (BM) at day 12 after birth, just
      before the opening of the eyelids. It continued to be present in the corneal BM
      zone in the adult rabbit but was not present in the limbal or conjunctival BM
      zone. CONCLUSIONS: The expression and distribution of the alternatively spliced
      forms of type XII collagen are developmentally and differentially regulated in
      the cornea, the sclera, and the eyelid. Although the short form is expressed in
      the stromal matrices of the cornea and surrounding tissues from early stages of
      corneal development, the appearance and distribution of the long variant form of
      type XII collagen coincide with the pattern of stromal condensation. Its first
      appearance in the corneal epithelial BM precedes the eyelid opening by 1 to 2
      days, possibly suggesting that it may be involved in the tighter anchoring of the
      corneal epithelium to the underlying tissue or in promoting stromal condensation
      to assist in the separation of the corneal epithelium from the juxtaposed
      palpebral conjunctival epithelium of the eyelid.

PMID- 10634602
TI  - Expression of androgen receptor in mouse eye tissues.
AB  - PURPOSE: To test the possibility that androgen directly affects the corneal
      cells, the possible occurrence of androgen receptor (AR) in the cornea and other
      eye tissues of mice was examined. METHODS: To examine the occurrence of AR
      protein in the mouse eye tissues, an immunocytochemical method was used. To
      examine the occurrence of AR mRNA in the cornea and lens, reverse transcription
      polymerase chain reaction (RT-PCR) was used. RESULTS: Immunocytochemical
      examination revealed that antigenicity for AR antibody exists in cell nuclei of
      cornea, lens, iris, and ciliary body of both male and female mice. RT-PCR
      revealed that mRNA of AR occurs in the cornea and lens of both male and female
      mice. CONCLUSIONS: It is concluded that AR occurs in cells of cornea, lens, iris,
      and ciliary body of the mouse eye. Androgen may affect cells in these tissues
      directly through interaction with AR.

PMID- 10634603
TI  - Persistent corneal haze after excimer laser photokeratectomy in plasminogen
      deficient mice.
AB  - PURPOSE: Excimer laser photorefractive keratectomy creates a nonvascular wound of
      the cornea. Fibrin deposition and resolution after excimer laser photokeratectomy
      were investigated in relation to corneal repair and restoration of clarity in
      mice with a genetic deficiency of plasminogen. METHODS: A Summit Apex Laser
      (Summit, Waltham, MA) was used to perform 2-mm, 175-pulse, transepithelial
      photoablations that resulted in deep stromal keratectomies. Photokeratectomy was
      performed on the corneas of plasminogen-deficient (Plg-/-) mice and littermate
      control animals. Eyes were examined for re-epithelialization and clarity
      throughout the 21-day observational period. Histologic sections were taken during
      the observational period and fibrin(ogen) was detected immunohistochemically.
      RESULTS: Re-epithelialization was rapid and complete within 3 days in both
      control and Plg-/- animals. Exuberant corneal fibrin(ogen) deposition was noted
      in Plg-/- mice and sparse fibrin(ogen) deposition in control mice on days 1 and 3
      after injury. Fibrin(ogen) deposits resolved in control mice but persisted in Plg
      /- mice (74% of eyes at 21 days; P < 0.004). Corneal opacification, scarring, and
      the presence of anterior chamber fibrin(ogen) occurred in plasminogen-deficient
      mice but not in control mice. CONCLUSIONS: Fibrin(ogen) deposition occurs during
      corneal wound repair after photokeratectomy. Impaired fibrinolysis in Plg-/- mice
      caused persistent stromal fibrin deposits that correlated with the development of
      corneal opacity.

PMID- 10634604
TI  - Reepithelialization of the human cornea is regulated by endogenous opioids.
AB  - PURPOSE: To determine the influence of endogenous opioid modulation on
      reepithelialization of the human cornea. METHODS: Eight-millimeter-diameter
      epithelial defects were created with a trephine and mechanical scraping in the
      center of human corneas. Resurfacing was studied in organ culture. The size of
      the defect, the number of specimens with complete reepithelialization, and rate
      of closure were evaluated using topical fluorescein and morphometric analysis.
      The influence of opioid receptor blockade was studied using the potent and long
      acting opioid antagonist, naltrexone (NTX; 10(-6) M), and the effects of excess
      (10(-6) M) opioid growth factor (OGF), [Met5]enkephalin, also were determined.
      The modulatory activity of NTX and OGF on DNA synthesis was evaluated by
      monitoring the labeling index (LI) using radioactive thymidine. The presence and
      location of OGF and its receptor (OGFr) were ascertained by immunocytochemistry 1
      hour and 24 hours after abrasion. RESULTS: NTX accelerated the wound-healing
      process, with 21% to 89% less defect than controls observed from 24 to 96 hours.
      At 72 hours, 62% of the subjects in the NTX group had complete closure of the
      corneal defects, in contrast to only 19% of the control specimens. All epithelial
      abrasions were resurfaced in the NTX group between 96 and 120 hours, whereas all
      controls were not closed until 168 hours. The rate of healing in the NTX group
      was 1.06 mm2/h compared to a rate of 0.68 mm2/h in the control group. OGF delayed
      corneal wound healing, with 24% to 260% more defect recorded than in control
      specimens at day 7. The healing rate of the OGF group was 0.42 mm2/h compared to
      0.82 mm2/h for control subjects. The corneal epithelium adjacent to the wound had
      an LI that was 152% greater than control specimens, whereas OGF decreased the LI
      of this region by 75%. OGF and OGFr were detected in the epithelium bordering the
      damaged region at 1 hour, and both peptide and receptor were noted in the
      regenerating epithelium at 24 hours. CONCLUSIONS: These results indicate that an
      endogenous opioid is present and functions as a tonically active, receptor
      mediated, negative growth factor during reepithelialization of the abraded human
      cornea.

PMID- 10634605
TI  - Vitamin A deficiency alters the expression of mucin genes by the rat ocular
      surface epithelium.
AB  - PURPOSE: To study effects of depletion of retinoic acid on expression of the
      mucins ASGP (rMuc4), rMuc5AC, and rMuc1, by the corneal and conjunctival
      epithelia of the rat. METHODS: Nineteen-day-old Sprague-Dawley male rats were fed
      a casein-based vitamin A- deficient diet or casein-based diet with vitamin A as
      control. Rats from both groups were killed at 1, 3, 5, 13, 15, 18, and 20 weeks
      after initiation of feeding. Expression of the three mucin genes by the ocular
      surface epithelium was assayed by reverse transcription-polymerase chain reaction
      (RT-PCR) and in situ hybridization. RESULTS: In vitamin A-deficient rats, ASGP
      mRNA was not detected by RT-PCR after 15 weeks of feeding. rMuc5AC mRNA was
      detected by RT-PCR at 15 weeks, but by 18 and 20 weeks was no longer detectable.
      By in situ hybridization, ASGP mRNA was localized in the entire ocular surface
      epithelium after 1 week of feeding, was diminished but detectable above
      background by 13 weeks, and was not detectable at 20 weeks. rMuc5AC mRNA was
      detected in the goblet cells of vitamin A- deficient rats by in situ
      hybridization at 13 weeks, but was lost by 20 weeks, as were identifiable goblet
      cells. rMuc1 mRNA were detected by RT-PCR through all time points of 1 to 20
      weeks in both vitamin A-deficient and control rats, indicating no significant
      change in rMuc1 mRNA expression with vitamin A deficiency. CONCLUSIONS: Both the
      membrane-spanning mucin ASGP (rMuc4) and the secretory mucin rMuc5AC are directly
      or indirectly regulated by vitamin A in the ocular surface epithelium, whereas
      the membrane-spanning mucin rMuc1 is not.

PMID- 10634606
TI  - TGF-beta receptor expression and smad2 localization are cell density dependent in
      fibroblasts.
AB  - PURPOSE: In nonconfluent cultures, TGF-beta induces differentiation of corneal
      fibroblasts to myofibroblasts. However, in confluent cultures, few fibroblasts
      differentiate to myofibroblasts after TGF-beta1 addition. This study investigated
      the hypothesis that functional TGF-beta receptor expression is greater in low
      density cultures and is decreased in confluent cultures. METHODS: Northern and
      western blot analyses were used to detect smooth muscle (SM) a-actin message and
      protein. 125I-labeled TGF-beta1 was used in a radioreceptor-binding assay as an
      index of functional receptors on the cell surface of rabbit corneal fibroblast
      cultures prepared either at high density (cell-cell contact) or low density
      (absence of contact). Cell lysates were analyzed by SDS-PAGE and autoradiography.
      Total TGF-beta receptor expression was evaluated in western blot analysis. Smad2,
      a downstream effector of TGF-beta receptor activation, was immunodetected.
      RESULTS: Low-density cultures expressed more SM alpha-actin mRNA and protein than
      high-density cultures, indicating that the low-density cells were differentiating
      into myofibroblasts. When 125I-TGF-beta1 was added to low- and high-density
      fibroblasts, fibroblasts plated at low density bound more than fibroblasts in
      high density, confluent cultures. Furthermore, after the cells differentiated
      into myofibroblasts, they continued to bind 125I-TGF-beta1. Specificity of 125I
      TGF-beta1 binding was demonstrated by complete inhibition by excess
      nonradioactive TGF-beta1. Localization of Smad2 was correlated with SM alpha
      actin induction: Smad was nuclear in low-density cells and cytoplasmic in high
      density cells. After TGF-beta1 treatment, Smad2 remained cytoplasmic in high
      density cells but was localized to nuclei in cells that were nonconfluent.
      CONCLUSIONS: Low cell density is correlated with increased functional expression
      of TGF-beta receptors and promotion of signal transmission from these receptors.
      Thus, conditions that decrease cell density such as wounding favor myofibroblast
      differentiation in response to TGF-beta.

PMID- 10634607
TI  - IL-1 and TNF-alpha are important factors in the pathogenesis of murine recurrent
      herpetic stromal keratitis.
AB  - PURPOSE: To better understand the role of interleukin (IL)-1 and tumor necrosis
      factor (NF)alpha in recurrent herpetic stromal keratitis (HSK), the cytokine
      content and the effects of anti-cytokine antibodies on mouse corneas with the
      disease were examined. METHODS: Competitive reverse transcription-polymerase
      chain reaction and enzyme-linked immunosorbent analyses of IL-1alpha and TNF
      alpha content were performed on corneas removed 3, 5, 7, 10, 14, and 21 days
      after latently infected NIH mice were irradiated with UV-B light to reactivate
      herpes simplex virus (HSV). In separate experiments, mice were injected with anti
      IL-1 or anti-TNF-a antibodies 1 day before and 7 days after reactivation.
      RESULTS: UV-B irradiation stimulated an increase in corneal IL-la mRNA in
      reactivated (virus shedding) mice. This increase persisted longer and was higher
      than in UV-B irradiated uninfected control animals. IL-1alpha and TNF-alpha
      protein in corneas of reactivated mice was significantly elevated on days 3 to 10
      compared with day 0 levels, and exceeded levels in control corneas on the same
      days. Anti-IL-1 and anti-TNF-alpha antibody administration both resulted in
      significantly decreased virus-induced corneal opacity between 7 and 21 days after
      UV-B exposure. CONCLUSIONS: IL-1alpha and TNF-alpha are upregulated in corneas in
      mice experiencing recurrent HSK. Abrogation of virus-induced corneal disease by
      anti-cytokine antibodies suggests that these cytokines play important roles in
      the pathogenesis of recurrent disease. Therefore, neutralization of specific
      proinflammatory cytokines may have potential therapeutic value.

PMID- 10634608
TI  - Vitronectin or fibronectin is required for corneal fibroblast-seeded collagen gel
      contraction.
AB  - PURPOSE: The wound healing process in the corneal stroma involves the activation
      of corneal keratocytes and the expression of associated phenotypes (fibroblasts
      and myofibroblasts). One of these phenotypes, the myofibroblasts, synthesizes
      alpha-smooth muscle actin in order to affect wound closure by contracting the
      surrounding matrix. Excessive contraction results in the formation of
      unresolvable scars that are undesirable in the corneal stroma. The authors tested
      the effect of vitronectin and fibronectin on the contraction process associated
      with corneal wound healing. METHODS: Collagen gels were prepared and were exposed
      to different treatments of fetal calf serum (FCS). The FCS used was either
      depleted of fibronectin and vitronectin or contained a known concentration of
      fibronectin, vitronectin, or both at 50 microg/ml. Contraction was measured using
      image analysis and cross sections of contracted gels were examined for alpha
      smooth muscle actin expression using laser confocal microscopy. RESULTS:
      Fibroblasts seeded in collagen gels paralleled the morphologic characteristics
      and cell distribution of keratocytes in unwounded cornea. Matrix contraction was
      dependent on the presence of fibronectin and/or vitronectin where myofibroblasts
      were present. The cell-mediated contraction process was maximal at 0.5 x 10(5)
      fibroblasts/ml. CONCLUSIONS: These studies showed that vitronectin or fibronectin
      is required for the myofibroblast-associated contraction to occur in this in
      vitro model of stromal wound healing. This model system shows a distinct
      potential for further studies relating to the corneal wound healing process.

PMID- 10634609
TI  - Visual outcome after contact lens and intraocular lens correction of neonatal
      monocular aphakia in monkeys.
AB  - PURPOSE: A monkey model was used to evaluate intraocular lenses (IOLs) and
      extended-wear contact lenses (EWCLs) for the optical treatment of infantile
      aphakia in humans. Specifically, the relative effectiveness of EWCLs used alone
      and IOLs used in combination with EWCLs in preventing amblyopia was assessed.
      METHODS: A total of 33 rhesus monkeys was studied in this project, 24 assigned to
      experimental treatment groups and 9 to normal controls. Contact lenses made from
      a diffusing material or dyed opaque were placed on one eye at birth to simulate
      an infantile cataract. A unilateral lensectomy was then performed on the same eye
      within 2.5 weeks after birth. In 15 monkeys this was combined with implantation
      of an IOL. The eyes were left aphakic in the remaining 9 animals. EWCLs were used
      to adjust the optical correction of both aphakic and pseudophakic eyes to a near
      point (3-5 D). Opaque lenses were used to maintain daily part-time (approximately
      70%) occlusion of the fellow eye. The primary outcome measure was grating acuity
      assessed with behavioral methods. Some animals were also assessed for acuity with
      sweep visually evoked potentials (VEPs) and for optotype acuity (Landolt C) with
      behavioral methods. RESULTS: Two of the animals with IOLs developed complications
      in the eye that precluded completion of the behavioral assessment protocol. Only
      behavioral outcomes obtained before or in the absence of surgical complications
      are presented. There was a developmental delay in the maturation of grating
      acuity in both eyes of both treatment groups. Normal adult levels of grating
      acuity were eventually achieved in the group treated with IOLs combined with
      EWCLs. Grating acuity was significantly poorer than normal in aphakic eyes
      treated only with EWCLs. Comparison of the two treatment groups revealed that
      pseudophakic eyes treated with multifocal IOLs had significantly better gating
      acuity than aphakic eyes. Assessments of optotype acuity and sweep VEP acuity
      revealed amblyopic deficits in both pseudophakic and aphakic eyes. CONCLUSIONS:
      Given an absence of serious postoperative complications, neonatal correction of
      aphakia with IOLs combined with EWCLs can lead to normal grating acuity in a
      primate model. Correction with EWCLs alone was not sufficient to produce normal
      grating acuity. Multifocal IOL treatments combined with EWCL provided a
      significantly better outcome than EWCL methods alone. However, neither IOL nor
      EWCL methods were able to prevent amblyopia as evaluated using behavioral testing
      with optotypes or with sweep VEPs.

PMID- 10634610
TI  - Expression of CD40 and CD40 ligand in the human conjunctival epithelium.
AB  - PURPOSE: CD40 antigen is a membrane receptor that plays a role in the regulation
      of immune reactions. The expressions of CD40 and CD40 ligand (CD40L) were
      investigated ex vivo and in vitro in conjunctival epithelial cells, in
      correlation with HLA DR class H antigen, previously shown to be upregulated in
      conjunctival inflammatory conditions. METHODS: Impression cytology specimens were
      collected in 186 patients: 52 normal ones, 65 with keratoconjunctivitis sicca,
      and 69 with chronic conjunctivitis. Cells were processed for flow cytometry, by
      using monoclonal antibodies to CD40, CD40L, and HLA DR antigens. Chang
      conjunctival cells were also used and treated with human recombinant interferon
      (IFN)-gamma or tumor necrosis factor (TNF)-alpha. CD40, CD40L, and HLA DR
      expressions were studied by flow cytometry after 24 and 48 hours of treatment.
      RESULTS: CD40 was found in both normal and pathologic eyes. Quantitation of
      levels of fluorescence showed a significantly higher expression in pathologic
      eyes than in normal ones (P < 0.0001). CD40L was variably and inconstantly
      expressed by conjunctival cells. A strong expression of HLA DR was observed in
      pathologic eyes, whereas normal eyes showed very low levels (P < 0.0001).
      Significantly positive correlations were found among CD40, CD40L, and HLA DR
      levels. Chang conjunctival cells expressed CD40 in basal conditions, whereas
      CD40L and HLA DR were negative. CD40 expression significantly increased after 24
      hours of IFNgamma treatment and after 48 hours' exposure to TNFalpha. These
      cytokines had no effect on CD40L expression. HLA DR was upregulated after 24
      hours of treatment with IFNgamma but remained negative after exposure to
      TNFalpha. CONCLUSIONS: Human conjunctival epithelial cells normally express CD40
      antigen, and, more inconsistently, CD40L. Flow cytometry showed higher expression
      of these molecules in inflammatory eyes than in normal ones in correlation with
      class II antigen expression, as well as CD40 and HLA DR upregulation after
      treatment with proinflammatory cytokines in vitro.

PMID- 10634611
TI  - Identification of a new epitope of human IRBP that induces autoimmune
      uveoretinitis in mice of the H-2b haplotype.
AB  - PURPOSE: Experimental autoimmune uveoretinitis (EAU) is a T-cell-mediated disease
      induced by immunization with interphotoreceptor retinoid binding protein (IRBP).
      Major uveitogenic sites have been identified for mice of the H-2r and H-2k
      haplotypes but not for the H-2b haplotype. The present communication describes
      the characterization of an epitope contained in residues 1 to 20 of human IRBP
      that induces EAU in H-2b mice. METHODS: H-2b (C57BL/6, 129/J) and H-2r (BIO.RIII)
      mice were immunized with peptide 1-20 or with whole (bovine) IRBP. EAU
      (histopathology) and immunologic responses (delayed-type hypersensitivity [DTH],
      lymphocyte proliferation, and cytokine production) were assessed after 21 days.
      RESULTS: C57BL/6 mice, 129/J and (129/JxC57BL/6)F1 mice, immunized with 200 to
      300 microg of peptide, developed DTH and EAU with scores comparable to those
      induced by 100 microg IRBP. Their lymphocytes proliferated to the peptide and
      produced interferon-gamma (but not interleukin-4) and transferred EAU to
      syngeneic recipients. Lymphocytes of IRBP-immunized mice also responded to the
      peptide. Peptide 1-20-immunized B1O.RIII mice failed to develop either disease or
      immunologic responses. CONCLUSIONS. Human IRBP peptide 1-20 contains a major
      epitope for the H-2b haplotype, which is apparently not presented by the H-2r
      haplotype.

PMID- 10634612
TI  - Natural killer cells prevent direct anterior-to-posterior spread of herpes
      simplex virus type 1 in the eye.
AB  - PURPOSE: Anterior chamber (AC) inoculation of the KOS strain of herpes simplex
      virus type 1 (HSV-1) results in morphologic sparing of the ipsilateral retina,
      whereas the retina of the uninoculated contralateral eye becomes infected and
      undergoes acute retinal necrosis. Natural killer (NK) cells are an important
      component of the primary immune response to most virus infections. The purpose of
      this study was to determine whether NK cells are involved in preventing early
      direct anterior-to-posterior spread of HSV-1 after AC inoculation. METHODS:
      Normal BALB/c mice were inoculated with 4 X 10(4) plaque-forming units (PFU) of
      the KOS strain of HSV-1 using the AC route. NK activity was measured in the
      spleen, the superficial cervical and submandibular lymph nodes, and the
      inoculated eye by lysis of chromium-labeled, NK-sensitive YAC-1 target cells.
      Histopathologic scoring and immunohistochemical staining for HSV-1 were performed
      in NK-depleted (injected intravenously with anti-asialo GM1) or mock-depleted
      (injected intravenously with normal rabbit serum) mice. RESULTS: In mock-depleted
      mice, NK activity in the spleens, superficial cervical and submandibular lymph
      nodes, and inoculated eyes peaked at postinoculation (pi) day 5 and declined by
      pi day 7. Treatment with anti-asialo GM1 eliminated NK activity in the eye and at
      nonocular sites. The histopathologic scores at pi day 5 indicated more damage to
      the retinas of NK-depleted mice than to those of mock-depleted mice, and
      immunohistochemical staining for HSV-1 showed spread of the virus to the sensory
      retina only in NK-depleted mice. CONCLUSIONS: NK cells were activated within 5
      days after AC inoculation of the KOS strain of HSV-1. Activation of NK cells
      appears to play a role in preventing direct anterior-to-posterior spread of the
      virus in the inoculated eye which, in turn, protects the retina of this eye and
      helps to explain why the architecture of the retina of this eye is spared.

PMID- 10634613
TI  - Unique characteristics of lacrimal glands as a part of mucosal immune network:
      high frequency of IgA-committed B-1 cells and NK1.1+ alphabeta T cells.
AB  - PURPOSE: Immunologic characterization of IgA-committed B-1 and B-2 cells, and
      unique subsets of T cells isolated from the murine lacrimal gland (LG), the
      primary exocrine tissue for the ocular surface, which is considered to be a part
      of the mucosal immune system. METHODS: Single cells were obtained from LGs of
      C57BL/6 mice by the enzyme dissociation method using collagenase type IV. Samples
      underwent flow cytometric analysis to characterize the unique subsets of T and B
      cells. To test the effectiveness of ocular vaccination, mice were immunized
      ocularly or nasally with cholera toxin (CT; 10 microg/mouse) suspended in
      phosphate-buffered saline. Antigen-specific immune responses were determined by
      isotype and CT-specific enzyme-linked immunosorbent assay (ELISA) and enzyme
      linked immunospot (ELISPOT) assay. RESULTS: When mononuclear cells (MC) isolated
      from LG samples were examined by flow cytometry, approximately 28% of cells were
      characterized as B220+ B cells. Because surface IgA+ (sIgA+) B cells develop from
      B-1 and B-2 lineages, it was important to examine which subset of B cells gives
      rise to LG sIgA+ B cells. Examination of the MC isolated from LG samples showed
      that approximately 4% of cells were sIgA+ B cells. Furthermore, nearly all these
      sIgA+ B cells (97.5%) belonged to the B-1 lineage, especially the B-1a cell line
      (B220low, CD5+). Of the isolated CD3+ T cells, 75% were alpha(beta) and 25% were
      gamma(delta)T-cell receptor positive. The proportion of NK1.1+ alpha(beta) T
      cells was higher (3%) in LG samples than in submandibular gland samples (0.5%).
      Ocular immunization with CT-induced antigen-specific mucosal (e.g., found in tear
      wash and saliva samples) and systemic (e.g., serum) immune responses. The
      magnitude of antigen-specific antibody responses was comparable to those induced
      by nasal immunization. CONCLUSIONS: These results show that LG contains unique
      subsets of B (e.g., sIgA+ B-1 cells) and T (e.g., NK1.1+ alpha(beta)T cells)
      cells. Furthermore, as a part of the mucosal immune barrier, the LG is an
      important immunologic tissue for the ocular surface.

PMID- 10634614
TI  - Adhesion molecule expression in a rat model of Staphylococcus aureus
      endophthalmitis.
AB  - PURPOSE: To determine whether Staphylococcus aureus and its components induce
      expression of E-selectin and intercellular adhesion molecule (ICAM)-1 in rat
      ocular tissues and on human endothelial cells in culture. METHODS: Experimental
      and control rat eyes were injected with 80 colony-forming units of viable S.
      aureus and lipopolysaccharide-free sterile saline (NS), respectively. Eyes were
      enucleated and immediately frozen. E-selectin and ICAM-1 expression were
      evaluated on frozen sections by using standard immunohistochemical techniques.
      Using an enzyme-linked immunoassay, in vitro expression of E-selectin and ICAM-1
      was evaluated on macrovascular endothelial cells after stimulation with S. aureus
      and selected purified components. RESULTS: In S. aureus-injected eyes, E-selectin
      and ICAM-1 expression peaked at six to 24 hours, decreased slightly at 24 and 48
      hours, and further declined by 72 hours. However, in NS-injected eyes, peak
      levels of E-selectin and ICAM-1 were seen at 6 hours, after which expression
      declined in the areas in which an increase was previously observed. In in vitro
      assays, peptidoglycan (0.01 microg/ml) induced a fourfold increase in E-selectin
      (P < 0.0001) and a twofold increase in ICAM-1 (P < 0.002) expression. Ribitol
      teichoic acid (RTA) (1 microg/ml) induced a twofold increase in E-selectin (P <
      0.0001) and a threefold increase in ICAM-1 (P < 0.0001) expression. CONCLUSIONS:
      Eyes injected with S. aureus demonstrated a more intense and prolonged expression
      of both E-selectin and ICAM-1 than did eyes injected with NS. In addition, S.
      aureus components induced the in vitro expression of these adhesion molecules on
      macrovascular endothelial cells. The relevance of these findings to microvascular
      endothelial cells is yet to be determined.

PMID- 10634615
TI  - Effects of 1alpha,25-dihydroxyvitamin D3 on Langerhans cell migration and corneal
      neovascularization in mice.
AB  - PURPOSE: To examine the effects of 1alpha,25-dihydroxyvitamin D3
      (1alpha,25[OH]2D3), a hormone that has immunosuppressive properties, on
      Langerhans cell (LC) migration and corneal neovascularization in mouse corneas.
      METHODS: Two 10-0 nylon interrupted sutures were placed in the center of 50
      BALB/c mouse corneas to induce LC migration and corneal neovascularization. The
      mice were then randomly assigned to one of five groups. Three groups (n = 11, n =
      11, n = 6) received topical 1alpha,25(OH)2D3 (at concentrations of 10(-7) M, 10(
      )8 M, 10(-9) M), one group (n = 11) received vehicle only, and one group (n = 11)
      received no eye drops. Instillation (three times a day) began on the first day
      after suturing. Corneal neovascularization was assessed by slit lamp microscopy
      and scored according to the length of newly formed corneal vessels. Fourteen days
      after suturing, the number of LCs that had migrated into the central corneal
      epithelium was counted by an immunofluorescence assay using an anti-Ia antibody.
      RESULTS: The number of LCs in the central cornea was 21.9 +/- 2.8 cells/mm2 in
      the nontreated group and 17.8 +/- 3.9 cells/mm2 in the vehicle-only group.
      Significantly fewer LCs were detected in all groups that had received
      1alpha,25(OH)2D3 compared with the vehicle only and nontreated groups (10(-7) M:
      7.4 +/- 1.2 cells/mm2, 10(-8) M: 7.2 +/- 2.0 cells/mm2, 10(-9) M: 6.2 +/- 0.7
      cells/mm2). Moderate inhibition of corneal vascularization was observed in the
      10(-7) M 1alpha,25(OH)2D3 group, but not the other groups. CONCLUSIONS: Topical
      administration of 1alpha,25(OH)2D3 can be effective in suppressing ocular surface
      inflammation by inhibiting LC migration into mouse corneas.

PMID- 10634616
TI  - Genetic heterogeneity of the Coppock-like cataract: a mutation in CRYBB2 on
      chromosome 22q11.2.
AB  - PURPOSE: To identify the genetic defect for the Coppock-like cataract (CCL)
      affecting a Swiss family, which defect was unlinked to the chromosome 2q33-35 CCL
      locus. METHODS: A large family was characterized for linkage analysis by slit
      lamp examination or by the review of drawings made before cataract extraction.
      The affection status was attributed before genotyping, and the genotyping was
      masked to the affection status. Two-point and multipoint linkage analyses were
      performed using the MLINK and the LINKMAP components of the LINKAGE program
      package (ver. 5.1), respectively. Mutational analysis of candidate genes was
      performed by a combination of direct cycle sequencing and an amplification
      refractory mutation system assay. RESULTS: Ten individuals were affected with the
      CCL phenotype. The disease was autosomal dominant and appeared to be fully
      penetrant. A new CCL locus was identified on chromosome 22q11.2 within a 11.67-cM
      interval (maximum lod score [Zmax] = 4.14; theta = 0). Mutational analysis of the
      CRYBB2 candidate gene identified a disease-causing mutation in exon 6. This
      sequence change was identical with that previously described to be associated
      with the cerulean cataract, a clinically distinct entity. CONCLUSIONS: The CCL
      phenotype is genetically heterogeneous with a second gene on chromosome 22q11.2,
      CRYBB2. The CCL and the cerulean cataract are two distinct clinical entities
      associated with the same genetic defect. This work provides evidence for a
      modifier factor that influences cataract formation and that remains to be
      identified.

PMID- 10634617
TI  - Tropomodulin and tropomyosin mediate lens cell actin cytoskeleton reorganization
      in vitro.
AB  - PURPOSE: To determine the role of the actin cytoskeleton regulatory proteins
      tropomyosin and tropomodulin (Tmod) in the reorganization of the actin
      cytoskeleton during lens epithelial cell differentiation. METHODS: Primary
      cultures of chick lens epithelial cells were allowed to differentiate in vitro to
      form lentoid bodies. Localization of F-actin, Tmod, and tropomyosin were
      determined by immunofluorescent staining followed by confocal microscopy.
      Tropomyosin and Tmod isoform expression was determined by immunoprecipitation and
      western blot analysis. RESULTS: In undifferentiated epithelial cells F-actin was
      organized in polygonal arrays of stress fibers and was also associated with the
      adherens belt. In contrast, F-actin in differentiated cells was predominantly
      associated with membranes in a reticular or fibrillar pattern and was organized
      in curvilinear fibrils in the cytoplasm. Tmod was not detected in the
      undifferentiated epithelial cells but was expressed upon cell differentiation and
      assembled into F-actin and non-F-actin structures. Tmod isoforms expressed in the
      lens cell cultures were identical with those expressed in the embryonic chick
      lens fiber cells. Tropomyosin was associated with the polygonal arrays of stress
      fibers in the undifferentiated epithelial cells and was recruited to cortical F
      actin at the cell periphery during differentiation. This occurred coincident with
      a shift in tropomyosin isoform expression. CONCLUSIONS: Expression and sequential
      assembly of low-molecular-weight tropomyosin and Tmod into the cortical actin
      cytoskeleton of differentiated lens cells may help to reorganize the actin
      cytoskeleton during morphogenetic differentiation. Moreover, lens epithelial cell
      differentiation may include the generation of novel Tmod-containing, non-F-actin
      cytoskeletal structures.

PMID- 10634618
TI  - Characterization of human lens major intrinsic protein structure.
AB  - PURPOSE: To determine the primary covalent structure of human lens major
      intrinsic protein (MIP) in lenses of varying age. METHODS: MIP was isolated from
      single human lenses of various ages (7- 86 years) by homogenization of the
      lenses, followed by centrifugation and urea washes of the membranes. Proteins
      present in the membrane preparation were reduced, alkylated, and cleaved by CNBr.
      Peptide fragments were fractionated by reverse-phase high-performance liquid
      chromatography, and the primary structures of the peptides were determined by
      tandem mass spectrometry and Edman sequencing. RESULTS: Complete coverage of the
      human MIP sequence was observed in the form of CNBr fragments. In addition,
      peptide structures resulting from in vivo heterogeneous N- and C-terminal
      cleavage were characterized. The amount of intact MIP decreased with lens age;
      however, the pattern of truncation did not change from 7 to 86 years. The major
      site of phosphorylation was identified as serine 235. Asparagine residues 246 and
      259 were completely deamidated by age 7 years. CONCLUSIONS: The major structural
      modifications of human lens MIP have been determined. Human MIP is
      heterogeneously modified in lenses ranging in age from 7 to 86 years of age by N-
      and C-terminal truncation, phosphorylation, and deamidation, resulting in
      decreased levels of native intact MIP with age.

PMID- 10634619
TI  - Differentiation of chick lens epithelial cells: involvement of the epidermal
      growth factor receptor and endogenous ligand.
AB  - PURPOSE: To characterize the constitutively activated epidermal growth factor
      receptor in a lens epithelial cell population experiencing initial stages of lens
      fiber formation, the chick lens annular pad. METHODS: Phosphotyrosine levels of
      the receptor were examined with western blot analysis and immunoprecipitation
      after ligand stimulation. Endogenous receptor ligands were immunologically
      identified in whole cell lysates of freshly isolated cells. The expression of
      lens fiber-specific differentiation marker proteins was examined with western
      blot analysis and enzyme-linked immunosorbent assay (ELISA) in short-term primary
      cultures of annular pad cells exposed to ligand. RESULTS: The major
      phosphotyrosine-containing protein in annular pad cells comigrated with the
      epidermal growth factor receptor and increased its phosphotyrosine content after
      epidermal growth factor treatment. Both time- and dose-dependent responses were
      noted. The constitutive activation of the receptor was determined in the presence
      of phosphatase inhibitors. Endogenous transforming growth factor-alpha, but not
      epidermal growth factor, was detected in freshly isolated cells. Transforming
      growth factor-alpha (TGF-alpha) treatment produced greater increases in receptor
      phosphotyrosine levels than equimolar levels of epidermal growth factor. Finally,
      TGF-alpha treatment induced increased expression of the beaded filament protein
      filensin when compared with control cells. Filensin expression was increased
      further when cells were costimulated with TGF-alpha and cAMP analogs.
      CONCLUSIONS: At least in the postnatal lens, endogenous TGF-alpha may affect
      overall growth patterns by modulating differentiation-specific protein
      expression. Furthermore, signaling pathways elicited by TGF-alpha and cAMP
      analogs converge to cooperatively enhance lens fiber differentiation.

PMID- 10634620
TI  - Effect of UV-A light on the chaperone-like properties of young and old lens alpha
      crystallin.
AB  - PURPOSE: To study the damaging effect of UV-A irradiation on the chaperone-like
      properties of alpha-crystallin and the subsequent recovery process of young and
      old bovine lenses. METHODS: Young and old bovine lenses were kept in organ
      culture. After 24 hours of incubation they were irradiated with UV-A at 365 nm,
      and optical quality measurements were performed during the experiments (192
      hours). alpha-Crystallin and alpha1-, alphaA2-, alphaB1-, and alphaB2-crystallin
      subunits were analyzed, separated by gel filtration and cation exchange
      chromatography, respectively, after different culture times. Protein patterns
      were obtained after two-dimensional (2-D) gel electrophoresis. Chaperone-like
      activity was determined on the basis of insulin B-chain and betaL-crystallin
      aggregation assays. Aggregation of alpha-crystallin was analyzed, tryptophan
      fluorescence measurements were performed, and alpha-crystallin mRNA levels were
      determined. RESULTS: The water-soluble alpha-crystallin obtained from old lenses
      compared with young lenses after UV irradiation had decreased chaperone activity,
      a higher molecular weight, and increased loss of tryptophan fluorescence.
      Moreover, alpha-crystallin mRNA virtually disappeared, whereas extra spots on the
      2-D protein pattern appeared, possibly because of deamidation. CONCLUSIONS: alpha
      Crystallin obtained from old lenses is more affected by irradiation than alpha
      crystallin derived from young lenses. Moreover, it appeared that alphaB
      crystallin from UV-treated old lenses compared with control lenses was less
      susceptible to UV-A than alphaA-crystallin. It may well be that alphaB-crystallin
      protects alphaA-crystallin in vivo.

PMID- 10634621
TI  - Galectin-3 is associated with the plasma membrane of lens fiber cells.
AB  - PURPOSE: To discover proteins that have the potential to contribute to the tight
      packing of fiber cells in the lens. METHODS: Crude fiber cell membranes were
      isolated from ovine lens cortex. Proteins were separated by two-dimensional gel
      electrophoresis, and selected protein spots identified by micro-sequencing. The
      identification of galectin-3 was confirmed by immunoblotting with a specific
      antibody. The association of galectin-3 with the fiber cell plasma membrane was
      investigated using immunofluorescence microscopy, solubilization trials with
      selected reagents, and immunoprecipitation to identify candidate ligands.
      RESULTS: A cluster of three protein spots with an apparent molecular weight of
      31,000 and isoelectric points ranging between 7 and 8.5 were resolved and
      identified as galectin-3. This protein was associated peripherally with the fiber
      cell plasma membrane and interacted with MP20, an abundant intrinsic membrane
      protein that had been identified previously as a component of membrane junctions
      between fiber cells. CONCLUSIONS: The detection of galectin-3 in the lens is a
      novel result and adds to the growing list of lens proteins with adhesive
      properties. Its location at the fiber cell membrane and its association with the
      junction-forming MP20 is consistent with a potential role in the development or
      maintenance of the tightly packed lens tissue architecture.

PMID- 10634622
TI  - Repair in the rat lens after threshold ultraviolet radiation injury.
AB  - PURPOSE: To investigate the development and recovery of lens damage after in vivo
      close-to-threshold exposure to ultraviolet B radiation. METHODS: One eye of
      young, female Sprague-Dawley rats was exposed to 5 kJ/m2 narrowband ultraviolet
      radiation (UVR) (lambda(max) = 302 nm) for 15 minutes. Groups of rats were killed
      1, 7, and 56 days after exposure. The structure of the exposed and nonexposed
      lenses was examined with light microscopy, scanning electron microscopy,
      transmission electron microscopy, freeze-fracture, fluorescent membrane staining,
      and Fourier transform analysis. RESULTS: One day after UVR exposure the lens
      surface had flakelike opacities. Seven days after exposure, the lens surface
      appeared opaque and corrugated, and the equatorial cortex had small opacities. At
      56 days postexposure, the surface and equator appeared clear, but the cortex had
      a subtle shell-shaped opacity. At 1 day postexposure, apoptotic cell death
      occurred in the lens epithelium, but the cortical fibers were normal. At 7 days
      postexposure, the epithelium and the fibers between the 10th and 40th growth
      shell below the capsule contained extracellular spaces of different sizes. After
      56 days, the epithelial layer appeared normal, and the extracellular spaces had
      disappeared; but abnormal fibers were found between the 60th and 100th growth
      shell below the capsule. Fibers above and below the damaged growth shells
      appeared fully normal. CONCLUSIONS: A close-to-threshold dose of UVR causes
      cataract, which is largely reversible. The UVR exposure leads to apoptosis in the
      lens epithelium, and after a latency period of several days, lens fibers are
      abnormal. Extracellular spaces develop in the epithelium and fibers. Within
      several weeks after exposure, the epithelium fully recovers and new fibers
      develop normally. The originally affected fibers are repaired. However, this
      repair is incomplete, leaving a small zone of enhanced light scattering in the
      equatorial cortex.

PMID- 10634623
TI  - L-Arginine-nitric oxide pathway-related metabolites in the aqueous humor of
      diabetic patients.
AB  - PURPOSE: Nitric oxide (NO) is an important signal-transduction molecule that
      plays a significant role in the regulation of cardiovascular functions. In the L
      arginine-NO pathway, NO synthase (NOS) converts L-arginine (L-Arg), the only
      known biologic substrate for NO formation, to NO and L-citrulline (L-Cit).
      Excessive NO production mediated by the inducible isoform of NOS has been
      implicated in the pathogenesis of various diseases. In the present study it was
      hypothesized that in vitreoretinal disorders such as diabetic retinopathy the
      production of L-Arg-NO pathway-related metabolites may be upregulated as a result
      of increased NO generation. METHODS: From 20 eyes of nondiabetic subjects and 22
      eyes of diabetic patients with (n = 14) and without (n = 8) diabetic retinopathy,
      undiluted samples of aqueous humor were drawn before cataract surgery. Levels of
      L-Arg, L-Cit, and the specific NOS by-product N(G)-hydroxy-L-arginine (HOArg)
      were measured by high-performance liquid chromatography. RESULTS: L-Arg, L-Cit,
      and HOArg were detected in all aqueous humor samples from diabetic and
      nondiabetic patients (n = 42). Comparison of HOArg levels in nondiabetic and
      diabetic subjects showed significantly higher levels in diabetic patients (P =
      0.002). Concentrations of HOArg were higher in samples from patients with (P =
      0.005) and without diabetic retinopathy (P = 0.033) than in control subjects. No
      statistically significant differences were observed in L-Arg or L-Cit levels.
      CONCLUSIONS: Elevated levels of HOArg in the aqueous humor of diabetic patients
      reflect the possible role of NO as a significant factor in the regulation of
      retinal vascular functions and intraocular proliferative changes in diabetes
      mellitus in vivo. The control of intraocular NO production may constitute a
      potential therapeutic approach in diabetic retinopathy.

PMID- 10634624
TI  - 5' nucleotidase and adenosine during retinal vasculogenesis and oxygen-induced
      retinopathy.
AB  - PURPOSE: 5' nucleotidase (5'N) is a major source of the vasogenic substance
      adenosine in most tissues. The distribution and relative levels of 5'N and
      adenosine were examined in neonatal dog inner retina during normal vasculogenesis
      and oxygen-induced retinopathy (OIR). METHODS: Animals ranging in age from 1 to
      22 days of age were used in this study. Adenosine immunolocalization was
      performed on frozen sections with an antibody against adenosine conjugated to
      laevulinic acid using a streptavidin peroxidase technique. Triplicate room air
      control animals at different postnatal ages and triplicate oxygen-treated animals
      at different time points during or after hyperoxic insult were analyzed.
      Adenosine immunoreactivity (AI) and 5'N enzyme histochemical reaction product
      were quantified using microdensitometry. Adjacent sections were incubated for von
      Willebrand factor to label blood vessels. RESULTS: During normal vasculogenesis,
      AI was most prominent within the inner retina. The peak of immunoreactivity was
      located at the border of vascularized retina throughout the period of primary
      retinal vasculogenesis (1-15 days of age). At 22 days when vasculogenesis was
      complete, AI decreased within the inner retina. The highest 5'N activity was
      localized to inner Muller cell processes in inner retina and decreased after
      vasculogenesis was complete. In animals killed after 4 days of oxygen breathing,
      the vasoobliterative stage of OIR, AI and 5'N activity were reduced throughout
      the retina. During the vasoproliferative stage, AI was markedly elevated at the
      edge of reforming vasculature as well as throughout the more posterior inner
      retina where 5'N activity also was elevated. AI was also in intravitreal
      neovascularization. CONCLUSIONS: Peak adenosine levels in the inner retina
      correlated temporally with active vasculogenesis. Adenosine and 5'N levels were
      reduced in hyperoxia and then returned to above normal levels during the
      vasoproliferative stage of OIR.

PMID- 10634625
TI  - Localization of adenosine A2a receptor in retinal development and oxygen-induced
      retinopathy.
AB  - PURPOSE: To investigate the association of adenosine A2a receptors (A2aR) with
      retinal vasculogenesis and angiogenesis that occurs in the canine model of oxygen
      induced retinopathy (OIR). METHODS: One-day-old dogs were exposed to 100/o oxygen
      for 4 days and killed in oxygen (5 days old) and at 3, 10, 17, and 23 days after
      exposure to hyperoxia. Room air control animals were killed at 1, 5, 8, 15, 22,
      and 28 days of age. Immunolocalization of A2aR was performed on frozen sections,
      and reaction product density was quantified using microdensitometry. Cell types
      were identified in serial sections using antibodies against von Willebrand factor
      (endothelial cells) and GFAP (astrocytes), and enzyme histochemistry for
      menadione-dependent a-glycerophosphate dehydrogenase (M-a-GPDH) (to label
      angioblasts and developing blood vessels). RESULTS: A2aR immunoreactivity was
      associated with forming blood vessels and angioblasts in the nerve fiber layer
      (NFL) of peripheral retina. As development progressed, vascular labeling
      decreased, whereas labeling of neuronal elements increased. In OIR, A2aR
      immunoreactivity in the NFL was reduced after exposure to hyperoxia and
      significantly elevated in the inner retina throughout vascularized retina and in
      advance of forming vasculature in all oxygen-treated animals returned to room
      air. A2aR immunoreactivity was also prominent in fronds of intravitreal
      neovascularization. CONCLUSIONS: A2aR immunoreactivity was associated with
      developing retinal vessels. As development progressed, vascular-associated A2aR
      labeling decreased and, concomitantly, labeling of neuronal elements increased.
      A2aR immunoreactivity was significantly elevated at the edge of forming
      vasculature in all animals returned to room air after hyperoxia and in
      intravitreal neovas cular formations. These results provide additional evidence
      for the importance of A2aR and its ligand adenosine in retinal vascular
      development and in the vasoproliferative stage of canine OIR.

PMID- 10634626
TI  - ABCR gene analysis in familial exudative age-related macular degeneration.
AB  - PURPOSE: Identification of genetic factors in the pathogenesis of age-related
      macular degeneration (AMD) is of crucial importance in this common cause of
      blindness. Mutations in the Stargardt disease gene (ABCR) were previously
      reported in patients with atrophic forms of AMD. The purpose of this study was to
      analyze familial segregation of ABCR gene mutations in 52 unrelated multiplex
      cases of exudative AMD. METHODS: A complete ophthalmological examination
      including visual acuity measurement, fundus examination, and fluorescein
      angiography (FA) was performed on each exudative AMD patient. The entire coding
      sequence of the ABCR gene was analyzed using a combination of single-strand
      conformation polymorphism and confirmatory sequencing of the exons showing an
      abnormal pattern of migration. RESULTS: Six heterozygous missense changes were
      identified. A lack of familial segregation was observed in 4 of 6 codon changes
      (Arg943Gln, Val1433Ile, Pro1948Leu, and Ser2255Ile). Conversely, 2 codon changes
      cosegregated with the disease in 2 small families: Pro940Arg and Leu1970Phe.
      CONCLUSIONS: The authors believe that segregation of the ABCR gene mutations with
      familial cases of AMD has not yet been shown. The analysis of familial
      segregation allowed the authors to exclude 4 of 6 codon changes as disease
      causing mutations. Furthermore, it was shown here that the ABCR gene may be
      rarely involved in exudative AMD, with at best 2 of 52 familial cases (4%)
      related to this susceptibility factor.

PMID- 10634627
TI  - Autosomal dominant macular atrophy at 6q14 excludes CORD7 and MCDR1/PBCRA loci.
AB  - PURPOSE: Localization of the gene responsible for autosomal dominant atrophic
      macular degeneration (adMD) in a large pedigree UM:H785. METHODS: Standard
      ophthalmologic examinations were performed. Microsatellite markers were used to
      map the disease gene by linkage and haplotype analyses. RESULTS: The macular
      degeneration in this family is characterized by progressive retinal pigment
      epithelial atrophy in the macula without apparent peripheral involvement by
      ophthalmoscopy or functional studies. Acuity loss progressed with age and
      generally was worse in the older affected individuals. The rod and cone function
      remained normal or nearly normal in all tested affected members up to 61 years of
      age. The phenotype in our family has characteristics similar to Stargardt-like
      macular degeneration with some differences. Haplotype analysis localized the
      disease gene in our adMD family to an 8-cM region at 6q14, which is within the 18
      cM interval of STGD3 but excludes cone-rod dystrophy 7 (CORD7; centromeric) and
      North Carolina macular degeneration and progressive bifocal chorioretinal atrophy
      (MCDR1/PBCRA; telomeric). The mapping interval overlaps with that of recessive
      retinitis pigmentosa (RP25). CONCLUSIONS: These results implicate at least three
      genetically distinct loci for forms of macular degeneration that lie within a 30
      cM interval on chromosome 6p11-6q16: CORD7, adMD, and MCDR1/PBCRA. Because the
      critical interval for the adMD family studied overlaps with STGD3 and RP25, these
      loci could be allelic.

PMID- 10634628
TI  - Failure of potassium siphoning by Muller cells: a new hypothesis of
      perfluorocarbon liquid-induced retinopathy.
AB  - PURPOSE: To determine the effect of perfluorocarbon liquid (PFCL)-induced
      abolition of potassium siphoning by the vitreal end feet of Miller cells.
      METHODS: Porcine eyecups were filled with stained balanced salt solution and
      PFCLs (perfluorodecalin, perfluorooctane, perfluoroperhydrophenanthrene or the
      semifluorocarbon perfluorohexylhexane). With optical coherence tomography, the
      distance between PFCL and retina was determined, and the size of the aqueous
      space covering the retinal surface was estimated. The data were used to calculate
      the retinal potassium siphoning into small aqueous volumes. RESULTS: The distance
      between PFCL and retinal surface was found to be less than 5 to 10 microm with
      any PFCL tested. The resultant volume of the aqueous space was too small to act
      as a sufficient sink for K+ ion siphoning. CONCLUSIONS: A certain threshold
      volume of vitreal fluid seems to be necessary for efficient buffering of
      intraretinal increases of K+ and perhaps other (e.g., H+) ions through the Muller
      cells. When the aqueous fluid is replaced by a PFCL (or by silicone oil) for
      longer periods, the outer retina becomes subject to long-lasting K+ accumulation,
      and consequent neurodegeneration and reactive gliosis occurs. The authors propose
      to search for new vitreous-substituting fluids with the capability to dissolve
      ions.

PMID- 10634629
TI  - Human melanoma-associated retinopathy (MAR) antibodies alter the retinal ON
      response of the monkey ERG in vivo.
AB  - PURPOSE: Melanoma-associated retinopathy (MAR) is a paraneoplastic condition that
      causes visual symptoms of night-blindness and photopsias. The electroretinogram
      (ERG) of MAR patients is characteristically abnormal in a way that implicates
      retinal depolarizing bipolar cell (DBC) dysfunction. Whether an injection of IgG
      from MAR patients into the vitreous of monkeys would alter the ERG acutely as a
      demonstration of a functional basis for patients' visual symptoms was explored.
      METHODS: MAR IgG was isolated from three visually symptomatic melanoma patients.
      Control IgG was from melanoma patients with no vision problems. The ERG was
      monitored after intravitreal injections into monkey eyes. One eye was injected
      with 2-amino-4-phosphonobutyric acid (APB), which is known to block DBC ON
      pathway responses. Retinal immunocytochemistry was performed using fluorescein
      isothiocyanate-labeled goat anti-human IgG. RESULTS: Within 1 to 3 hours after
      MAR IgG injection, the ERG photopic b-wave was diminished, with far less effect
      on the a- and d-waves. These changes are characteristic of DBC dysfunction and
      were similar to the effects of APB. The scotopic ERG b-wave, which reflects
      activity of rod-driven DBCs, showed a loss of amplitude and threshold sensitivity
      after MAR IgG. Retinal immunocytochemistry with anti-IgG antibody showed IgG
      penetration throughout the retinal layers, but staining was not specific for a
      single type of retinal neuron. CONCLUSIONS: Intravitreal injection of human MAR
      IgG altered the monkey ERG acutely in ways that implicate functional disruption
      of retinal DBC signaling. These results support the hypothesis that MAR IgG
      circulating antibodies are responsible for the reported visual symptoms. Bipolar
      cells in the ON-pathway appear to be affected more than OFF-pathway bipolar cells
      of the cone pathway in this acute preparation.

PMID- 10634630
TI  - Psychophysical evidence for rod vulnerability in age-related macular
      degeneration.
AB  - PURPOSE: To determine whether there is rod system dysfunction in the central
      retina of patients with age-related macular degeneration (AMD). METHODS: Dark
      adapted sensitivity (500-nm stimulus) and light-adapted sensitivity (600 nm) were
      measured psychophysically at 52 loci in the central 38 degrees (diameter) of
      retina in 80 patients with AMD, and results were compared with those from older
      adult normal controls. All dark-adapted data were corrected for preretinal
      absorption. RESULTS: Mean field dark-adapted sensitivity was significantly lower
      in AMD patients as a group than in normal subjects. Within the AMD group were
      subsets of patients with normal mean dark- and light-adapted sensitivities;
      reduced dark-adapted sensitivities without detectable light-adapted losses; both
      types of losses; and, least commonly, only light-adapted losses. Regional retinal
      analyses of the dark-adapted deficit indicated the greatest severity was 2
      degrees to 4 degrees or approximately 1 mm from the fovea, and the deficit
      decreased with increasing eccentricity. CONCLUSIONS: These psychophysical results
      are consistent with histopathologic findings of a selective vulnerability for
      parafoveal rod photoreceptors in AMD. The different patterns of rod and cone
      system losses among patients at similar clinical stages reinforces the notion
      that AMD is a group of disorders with underlying heterogeneity of mechanism of
      visual loss. Dark-adapted macula-wide testing may be a useful complement to the
      more traditional outcome measures of fundus pathology and foveal cone-based
      psychophysics in future AMD trials.

PMID- 10634631
TI  - Short-wavelength automated perimetry and capillary density in early diabetic
      maculopathy.
AB  - PURPOSE: To correlate short-wavelength cone-mediated sensitivity (SWS) assessed
      by blue-on-yellow perimetry with alterations of the perifoveal vascular bed in
      early diabetic maculopathy. METHODS: Thirty-one patients (21 M, 10 F; mean age,
      35 +/- 12 years; no lens opacities) with no clinically significant macular edema
      were included in this study. All patients underwent short-wavelength automated
      perimetry (SWAP) and conventional white-on-white perimetry (Humphrey, 10-2). In
      digitized video fluorescein angiograms (Scanning Laser Ophthalmoscope), the size
      of the foveal avascular zone (FAZ) and the mean perifoveal intercapillary area
      (PIA) as a measure of capillary density were quantified interactively. RESULTS:
      Mean thresholds of SWAP were significantly correlated with increasing size of FAZ
      (r = -0.51, P = 0.003) and PIA (r = -0.47, P = 0.01), whereas visual acuity
      expressed by log MAR (FAZ: r = 0.15, P = 0.41; PIA: r = 0.06, P = 0.76) and mean
      thresholds assessed with white-on-white perimetry (FAZ: r = -0.25, P = 0.20; PIA:
      r = -0.31, P = 0.14) were unrelated to diabetic changes of the perifoveal
      capillary network. CONCLUSIONS: The alterations of the perifoveal network are
      related to selective disturbances of visual function as measured by blue-on
      yellow-perimetry. SWAP may act as an early detector of visual function loss in
      early diabetic maculopathy and serve as a helpful technique to predict early
      ischemic damage of the macula and to monitor therapy.

PMID- 10634632
TI  - Slow optical changes in human photoreceptors induced by light.
AB  - PURPOSE: The basic assumption of fundus reflection densitometry is that changes
      in reflectance are solely determined by photolysis and regenerating visual
      pigments. This study was undertaken to investigate small but systematic
      deviations from this rule. METHODS: Spectral reflectance changes (450-740 nm) of
      the fovea were measured during light and dark adaptation over a period of 66
      minutes in five healthy subjects. The directional properties of the fundus
      reflection were examined with a custom-built scanning laser ophthalmoscope (SLO)
      at 514, 633, and 790 nm. The same instrument was also used to find the spatial
      distribution of the reflectance changes. RESULTS: In addition to fast changes
      consistent with visual pigment, slower reflectance changes (lasting 10-20
      minutes) were observed at all wavelengths including 740 nm. Because visual
      pigment does not absorb at 740 nm, a second mechanism must be involved. Factor
      analysis generated two factors (i.e., spectral curves) that explained more than
      97% of the variations in the time course of the spectral reflectance. Total
      reflectance was modeled by means of an existing model for fundus reflection, and
      it was found that the first factor strongly resembled the rapid changes in
      absorption of the cone pigments. The second factor seems linked to slow changes
      in cone reflectance. Measurements with the SLO showed a clear increase in
      directionally dependent reflectance from 6 to 30 minutes in the dark. This was
      observed only in the central 6 degrees of the retina. CONCLUSIONS: The
      characteristics of the slow reflectance changes all point to the cone
      photoreceptors as the origin. Most likely, alterations in the index of refraction
      between the interphotoreceptor matrix and photoreceptors lie at the base of this
      hitherto unknown phenomenon.

PMID- 10634633
TI  - A new Leu253Arg mutation in the RP2 gene in a Japanese family with X-linked
      retinitis pigmentosa.
AB  - PURPOSE: To identify the clinical findings in a Japanese family with X-linked
      retinitis pigmentosa associated with mutation in codon 253 (Leu253Arg) in the RP2
      gene. METHODS: Case reports included clinical features and results of fluorescein
      angiography, electroretinogram, kinetic visual field testing, and DNA analysis.
      Two affected hemizygotes with retinitis pigmentosa associated with transversion
      mutations in codon 253 (Leu253Arg) of the RP2 gene and the obligate carriers were
      examined. RESULTS: A novel Leu253Arg mutation of the RP2 gene was found to
      cosegregate with retinal degeneration in two affected males and two carriers in
      female heterozygote in a Japanese family. The ophthalmic findings in hemizygote
      showed severe retinal degeneration. In the obligate carrier, mild chorioretinal
      degeneration was observed in both eyes but a tapetal-like reflex of the fundus
      was not apparent. CONCLUSIONS: The mutation at codon 253 of the RP2 gene is the
      first mutation reported in a Japanese family. It is concluded that the mutation
      of the RP2 gene also causes the X-linked retinitis pigmentosa in Japanese
      patients.

PMID- 10634634
TI  - Expression of Dp71 in Muller glial cells: a comparison with utrophin- and
      dystrophin-associated proteins.
AB  - PURPOSE: The abnormal retinal electrophysiology observed in patients with
      Duchenne muscular dystrophy (DMD) has been attributed to an altered expression of
      C-terminal products of the dystrophin gene. It has been shown that Dp260 is
      expressed by photoreceptor cells, whereas Dp71 is present in glial cells. The
      present study was intended to identify all known members of the dystrophin
      superfamily and their associated proteins expressed in Muller glial cells (MGC).
      METHODS: The expression of the proteins and of their messengers was studied in
      MGC cultures from 2-week-old rats, by polymerase chain reaction amplification,
      Western blot analysis, and immunocytochemistry. An immunocytochemical
      localization of the proteins was also performed on enzymatically dissociated
      Muller cells from adult rat retinas. RESULTS: MGCs expressed a spliced isoform of
      Dp71 called Dp71f, as well as utrophin, beta-dystroglycan, delta and gamma
      sarcoglycans, and alpha1-syntrophin. In morphologically preserved differentiated
      Muller cells, Dp71f was localized in clusters, utrophin was diffusely distributed
      in the cytoplasm, and dystrophin-associated proteins (DAPs) were membrane-bound.
      Most of these proteins were preferentially expressed in the vitread portion of
      the cells. Dp71f and utrophin expression was restricted to MGCs, whereas all DAPs
      were also present in other retinal cell types. CONCLUSIONS: The exclusive
      localization of Dp71f and utrophin in MGCs suggests that these proteins, together
      with DAPs, play a specific role in these cells. Further knowledge of possible
      interactions of these proteins within a functional complex may provide new
      insights into the molecular basis of the electroretinogram phenotype in DMD.

PMID- 10634635
TI  - Immunohistochemical analysis of the developing inner plexiform layer in postnatal
      rat retina.
AB  - PURPOSE: To investigate the development from early postnatal life to adulthood of
      neural cell processes that establish the circuitry of the inner plexiform layer
      (IPL). Emphasis was focused on the ontogeny of subsets of cGMP- and protein
      kinase C (PKC)immunoreactive amacrine and bipolar cells. METHODS:
      Paraformaldehyde-fixed postnatal and adult retinas were used for light
      microscopic analysis of immunohistochemical labeling of cryo-sections. Synthesis
      of cGMP in neural structures was achieved by means of an in vitro stimulation
      with a well-established nitric oxide donor. RESULTS: In vitro stimulation of
      postnatal and mature retina with the nitric oxide donor results in NO-activated
      cGMP synthesis in subsets of bipolar and amacrine cells. NO-activated cGMP
      immunoreactivity is expressed in specific cell populations during the first
      postnatal week. Other cell subsets, consisting of amacrine cells and rod bipolar
      cells, express PKC immunoreactivity during postnatal development. An increasing
      number of rod bipolar cells start to exhibit cGMP labeling after eye opening, and
      a colocalization with PKC is established in adult retinas. Processes from these
      cell populations terminate in several sublaminas in the developing IPL, but cGMP-
      and PKC-labeled terminals appear to be confined to ON-lamina as the retina
      matures. CONCLUSIONS: The development of cGMP- and PKC-labeled fibers within the
      IPL appears to be in concert with events of neural differentiation and
      synaptogenesis. These results suggest that the nitric oxide/cGMP signaling
      pathway and PKC may participate in activity-dependent processes during
      development that establish the mature circuitry of synaptic contacts within the
      IPL. The presence of cGMP in mature rod bipolar cells suggests a role in the
      signal transduction of rod bipolar cell-AII amacrine cell pathway.

PMID- 10634636
TI  - Coexpression patterns of mGLuR mRNAs in rat retinal ganglion cells: a single-cell
      RT-PCR study.
AB  - PURPOSE: Eight different subunits of metabotropic glutamate receptors (mGluRs)
      are known to date. mGluRs have been linked to an extensive list of
      neuromodulatory effects, depending on which intracellular or membrane-bound
      effector system is activated. Activation of mGluRs can influence neuronal
      activity and can result in changes of intracellular Ca2+ homeostasis-that is,
      changes in factors that are known to be crucial for cellular differentiation and
      cell death. Because mGluRs are known in modulating both intracellular and
      intercellular activities, this study was designed to determine which types of
      mGluRs are coexpressed in a neuron and whether distinct coexpression patterns can
      be found that reflect the different physiological requirements of a neuron at
      different stages of development and to learn whether neuronal injury results in
      adaptive changes of mGluR expression. METHODS: Juvenile and adult rat retinal
      ganglion cells (RGCs) and adult RGCs after axotomy were analyzed for their gene
      expression pattern of mGluRs by single-cell reverse transcription-polymerase
      chain reaction (RT-PCR). RESULTS: Adult RGCs predominantly expressed one or two
      different mGluR mRNAs, whereas juvenile RGCs coexpressed two and more. mGluR3, 
      5, and -7 mRNAs were found more frequently in juvenile than in adult RGCs. mGluR6
      was detected in juvenile RGCs in low abundance but never in adult RGCs. However,
      mGluR6 was expressed in adult RGCs after axotomy. mGluR1 and -7 were also found
      more frequently in axotomized RGCs than in the adult control group. CONCLUSIONS:
      All types of mGluR mRNAs are expressed in RGCs. This is in contrast with previous
      in situ hybridization and immunohistochemical studies in which expression of
      mGluR3, -5, and -6 was not reported. The expression of some mGluR mRNAs seems to
      be developmental, although no distinct copatterns were found.

PMID- 10634637
TI  - Background adaptation in children with a history of mild retinopathy of
      prematurity.
AB  - PURPOSE: In children with a history of mild retinopathy of prematurity (ROP),
      test the hypothesis that elevation of the parafoveal over peripheral dark-adapted
      threshold is due to photoreceptor rather than postreceptor dysfunction. METHODS:
      A forced choice procedure was used to measure thresholds, for detection of 2
      degrees diameter, 50 msec, blue stimuli presented 10 degrees (parafoveal) or 30
      degrees (peripheral) eccentric in the dark and in the presence of steady red
      backgrounds (-4 to +2 log scot td). Four ROP and four control subjects were
      tested at both eccentricities. A model of the increment threshold function was
      fit to the data to calculate the eigengrau and dark-adapted threshold. RESULTS:
      Both ROP subjects with elevated parafoveal thresholds also have elevated
      parafoveal eigengraus. On the other hand, parafoveal and peripheral eigengraus
      are equal in ROP subjects without parafoveal threshold elevation. Nevertheless,
      the dark-adapted thresholds of all ROP subjects are higher than those of any
      control subject at both sites. CONCLUSIONS: The parafoveal threshold elevation is
      due to rod dysfunction. There is also evidence of peripheral rod photoreceptor
      involvement in the subjects with ROP.

PMID- 10634638
TI  - Effects of glaucoma and aging on photopic and scotopic motion perception.
AB  - PURPOSE: To examine the effects of primary open-angle glaucoma and normal aging
      on visual sensitivity for targets known to bias responses from the magnocellular
      visual processing stream. METHODS: Contrast sensitivity was measured for the
      detection and direction discrimination of low-spatial-frequency (0.5 cyc/deg),
      drifting (4-24 Hz) sinusoidal gratings in 15 patients with glaucoma (mean age,
      58.7 years), 14 age-matched control subjects (mean age 55.8 years), and 10 young
      control subjects (mean age, 24.4 years). As a control, sensitivity was measured
      for the detection of stationary stimuli. Stimuli of 4.7 degrees square were
      presented at either 0 degrees eccentricity or at 20 degrees along the nasal
      horizontal meridian, under both photopic and scotopic levels of lighting.
      RESULTS: Across a wide range of conditions, the ability to detect and
      discriminate visual motion declined significantly (P < 0.05) with increasing age,
      whereas the ability to detect stationary patterns was generally unaffected. The
      rate of decline was adequately described by a simple linear function. Control
      studies showed that the age-related motion sensitivity losses could not be
      attributed solely to decreases in retinal illuminance associated with increasing
      age. Of note, however, there were no significant differences in mean sensitivity
      between glaucoma and age-matched control groups for any of the conditions used.
      CONCLUSIONS: Even under conditions believed to bias the response of the visual
      system to the magnocellular pathway, glaucoma subjects could not be reliably
      differentiated from control subjects on the basis of mean sensitivity to motion
      stimuli. The findings have two broad implications: first, that substantial neural
      loss specific for motion perception occurs during the processes of normal aging,
      and second, that sensitivity to motion targets per se may not be a useful
      indicator of neural integrity in the early stages of glaucoma.

PMID- 10634639
TI  - Myeloid and monocytoid leukemia cells have different sensitivity to
      differentiation-inducing activity of deoxyadenosine analogs.
AB  - The differentiation-inducing effect of clinically applicable analogs of
      deoxyadenosine on myelomonocytic leukemia cells was examined. Monocytoid leukemia
      cells were more sensitive to the analogs than were erythroid or myeloid leukemia
      cells based on the inhibition of cell growth and induction of cell
      differentiation. Monocytoid leukemia cells were highly sensitive to combined
      treatment with 2'-deoxycoformycin (dCF) and 9-beta-D-arabinofuranosyladenine (Ara
      A) for inducing cell differentiation. Ara A induced the differentiation of
      monocytoid leukemia U937 and THP-1 cells at concentrations which were 1/1000
      10000 of that at which it induced the differentiation of other cell lines in the
      presence of dCF. In combination with a low concentration of 1alpha,25
      dihydroxyvitamin D3 (VD3), the induction of the monocytic differentiation was
      greater in monoblastic U937 cells. Adenosine deaminase-resistant analogs such as
      fludarabine (FLU) and cladribine (CdA) also induced the differentiation of human
      myelomonocytic leukemia cells, and these analogs synergistically enhanced the
      differentiation induced by all-trans retinoic acid (ATRA) or VD3. CdA was the
      most potent analog for inducing the differentiation of myeloid leukemia NB4 and
      HL-60 cells in the presence or absence of ATRA. These findings indicate that dCF
      + Ara A and CdA may be effective for the therapy of acute monocytoid and myeloid
      leukemia, respectively.

PMID- 10634640
TI  - Lineage specificity of CBFA2 fusion transcripts.
AB  - The CBFA2 gene on chromosome band 21q22 is one of the most commonly translocated
      genes in leukemia. As with other translocations, those involving CBFA2 are
      associated with specific disease phenotypes. Only one of the different
      translocations involving CBFA2, the t(12;21), has been associated with a non
      myeloid lineage. Several different CBFA2 fusion transcripts were expressed in the
      myeloid 32Dcl3 cell line, and show that unlike the myeloid specific fusion
      transcripts, the lymphoid specific ETV6/CBFA2 transcript is not compatible with
      myeloid cell differentiation. It is shown that myeloid cells expressing the
      ETV6/CBFA2 transcript undergo apoptosis in response to a G-CSF differentiation
      signal. The molecular differences in the cells we studied are characterized using
      Western blot analysis to show that t(12;21) expressing cells fail to express the
      G-CSF receptor.

PMID- 10634641
TI  - Effects of retinoids on cell toxicity and apoptosis in leukemic blast cells from
      patients with non-M3 AML.
AB  - All-trans retinoic acid (ATRA) induces complete remission in acute promyelocytic
      leukemia (APL or M3). In this study we measured the effect of retinoids alone and
      in combination with daunorubicin (DNR) on cell growth and apoptosis in blast
      cells from patients with non-M3 AML. Cells from 21 patients were incubated in 0.2
      microM daunorubicin for 1 h or in 1 microM ATRA or 9-cis-RA continuously and in
      the combinations of DNR with both retinoids. Cell toxicity and apoptosis were
      analyzed after 96 h. Both ATRA and 9-cis-RA reduced the viability significantly
      to 86 and 84%, respectively (P = 0.003 for ATRA and 0.02 for 9-cis-RA). The
      expression of CD34 correlated to a higher sensitivity to ATRA (P = 0.003). When
      retinoids were added to DNR the mean decrease in viability was 11 percentage
      points with ATRA (P = 0.003) and nine percentage points with 9-cis-RA (P = 0.02).
      Apoptosis was induced by both retinoids and the percentage of apoptotic cells was
      increased from 16% in the controls to 24% with ATRA (P = 0.03) and to 26% with 9
      cis-RA (P = 0.04). When the retinoids were added to DNR the apoptotic rate
      increased from 41% with DNR alone to 51% with ATRA (P = 0.01) and to 49% with 9
      cis-RA (P = 0.03). We conclude that ATRA and RA exert a slight but clear
      cytotoxic and apoptotic effect on AML blast cells after 96 h incubation and that
      retinoids can have an additive or synergistic effects on cell toxicity when added
      to daunorubicin.

PMID- 10634642
TI  - Immunoglobulin V(H) gene mutational analysis suggests that blastic variant of
      mantle cell lymphoma derives from different stages of B-cell maturation.
AB  - To characterise the nature of the cellular origin of the blastic variant of
      mantle cell lymphoma (MCL-BV), we analysed the immunoglobulin (Ig) heavy chain
      variable region (V(H)) genes in four cases of MCL-BV. The rearranged V(H)-D J(H)
      genes were PCR-amplified, cloned and sequenced. In one case, the comparison of
      the rearranged V(H) gene sequence to known germline V(H) gene templates showed no
      somatic mutations suggesting a pre-germinal centre B-cell origin for tumour
      cells. In the other three cases, the V(H) gene sequences showed varied number of
      point mutations relative to the putative germline V(H) gene sequences but the
      point mutations were not associated with intraclonal diversification. In one of
      the mutated cases, the distribution and type of the mutations indicated that
      tumour cells had been selected by an antigen. Since somatically mutated Ig genes
      are expressed by B-cells that have reached a germinal centre/post-germinal centre
      stage of development, these findings suggest that the MCL-BV cell of origin may
      also be a germinal centre or a post-germinal centre B-cell. Taken together, our
      findings suggest that the development of MCL-BC may not be restricted to one
      stage of B-cell differentiation and that they may represent transformants of B
      cells at different stages of ontogeny.

PMID- 10634643
TI  - Overexpression of Ras, Raf and L-myc but not Bcl-2 family proteins is linked with
      resistance to TCR-mediated apoptosis and tumorigenesis in thymic lymphomas from
      TCR transgenic mice.
AB  - Mice with transgenic TCR anti H-Y/Db develop spontaneous thymic tumors with a
      high frequency (up to 50%). Oncogenicity of TCR transgenes could depend on the
      deregulated expression of oncoproteins engaged in transduction pathways leading
      to proliferation or apoptosis. In agreement with this possibility we have found
      that cells of thymic lymphomas from TCR transgenic mice were largely resistant to
      TCR-dependent Ca++-mediated apoptosis but not to TCR-independent, p53-mediated
      (etoposide) apoptosis. Here we show raised expression of Bcl-2 protein in some
      but not in all thymic lymphoma cell lines. It suggests that the antiapoptotic
      function of Bcl-2 is not necessary for the process of tumorigenesis and the
      resistance of these lymphomas to Ca++-mediated apoptosis. On the other hand we
      show that all thymic lymphomas overexpressed Ras/Raf and L-myc proteins.
      Stimulation of the Ras/Raf pathway was reported to be required to maintain cell
      viability by preventing programmed cell death in thymic tumors derived from lck
      transgenic mice. Similarly, in TCR transgenic lymphomas overexpression of Ras,
      Raf and L-myc but not Bcl-2 family proteins may be responsible for the resistance
      of these lymphomas to TCR-mediated apoptosis but not affect p53-mediated
      apoptosis.

PMID- 10634644
TI  - Hypermethylation of p16 and p15 genes and RB protein expression in acute
      leukemia.
AB  - Both p16 and p15, encoded by genes located on chromosome 9p21, are inhibitors of
      cyclin-dependent kinases 4/6 (CDK4/6) and upstream regulators of RB function, and
      set up the RB/p16 tumor suppressive pathway, which is abrogated frequently in
      human neoplasms, either through inactivation of the RB or p16 tumor-suppressor
      protein, or alteration of the cyclin D1 or CDK4 oncoproteins. In hematological
      malignancies, deletion of p16/p15 locus has been shown to be highly specific to
      lymphoid malignancies, and more particularly to T-cell acute lymphoblastic
      leukemia (T-ALL). However, in the other subsets of ALL, deletions of p16 and p15
      are relatively rare events. To investigate whether these genes are inactivated by
      methylation of the 5' CpG islands, we examined 35 leukemia cell lines and 29
      childhood acute myeloid leukemia (AML) patients by Southern blot, polymerase
      chain reaction (PCR) and Western blot analyses. We found methylation of p16 in 12
      (50%) of 24 ALL cell lines, 5 (50%) of 10 AML cell lines without homozygous
      deletion of p16, and 11 (38%) of 29 AML patients. Those leukemia cell lines
      subjected to p16 methylation were found to have lost p16 protein expression. The
      p15 gene was methylated in 10 (34%) of 29 ALL cell lines, 6 (60%) of 10 AML cell
      lines without homozygous deletion of p15, and 15 (52%) of 29 AML patients. These
      results revealed the frequent methylation of p16 and p15 genes in B-ALL and AML
      despite a low frequency of p16 and p15 deletions and mutations in these
      leukemias. In the study for expression of RB protein, we found no expression of
      RB in 4 of 16 leukemia cell lines. Inactivation of the p16 gene was found in all
      the cell lines with expression of RB. Neither amplification nor rearrangement of
      cyclin D1 gene was found in any cell lines. These results suggest that
      inactivation of p16 and p15 genes is one of the most common genetic events in
      acute leukemia, and plays an important role for the RB/p16 pathway in the
      pathogenesis of acute leukemia.

PMID- 10634645
TI  - Alternative effects of RAS and RAF oncogenes on the proliferation and apoptosis
      of factor-dependent FDC-P1 cells.
AB  - Despite the fact that RAF-1 lies immediately downstream of p21RAS in the MAP
      kinase-signalling cascade, recent evidence in non-haematopoietic environments
      suggest that RAS and RAF can transduce signals through alternative pathways
      specific to a particular cell type. Since mutational activation of RAS occurs at
      high frequency in human leukaemia, we have investigated the contribution of
      signalling from mutant RAF in mediating the transforming effects of the N-RAS
      oncogene in the growth factor-dependent cell line, FDC-P1. Independent activation
      of N-RAS extended the period of exponential growth leading to an increased
      saturating density under optimal growth conditions. Under conditions of growth
      factor withdrawal, cells expressing mutant RAS, but not control cells,
      demonstrated protection against apoptotic death. Although RAF promoted cell
      proliferation in a similar manner to that observed in FDCP-RAS cells, expression
      of mutant RAF was not as effective at protecting these cells against apoptotic
      death following growth factor withdrawal. The results suggest that RAS utilises
      RAF-dependent signals in promoting the proliferation of FDC-P1 cells but the anti
      apoptotic effects of this oncogene are mediated through a RAF- and BCL-2
      independent pathway.

PMID- 10634646
TI  - Effects of G-CSF and high-dose methylprednisolone on peripheral stem cells, serum
      IL-3 levels and hematological parameters in acute lymphoblastic leukemia patients
      with neutropenia: a pilot study.
AB  - Several agents, used either alone or in combination, have been shown to boost
      absolute numbers of PMLs and CD34+ stem cells in PB. In this study, we compared
      the effects of three different treatments, G-CSF, HDMP, and G-CSF + HDMP, for
      neutropenic patients (absolute PML count < 0.5 x 10(9)/l) who were on maintenance
      therapy for ALL with a control group who received no treatment. Hematological
      parameters, PB-CD34+33- and -CD34+ HLA-DR- stem cell numbers, and serum IL-3
      levels were measured prior to, and a week after, the first day of treatment. WBC
      and absolute PML counts were significantly increased compared to pretreatment
      values in all treatment groups. However, peripheral CD34+ 33- and CD34+ HLA-DR
      stem cell numbers and serum IL-3 levels were increased significantly only in the
      G-CSF group. There was also a significant increase in serun IL-3 levels in the G
      CSF + HDMP group. This study suggests that G-CSF may induce an increase in
      peripheral stem cell numbers, and that it supports hemopoietic recovery by
      increasing IL-3 in patients with chemotherapy-induced neutropenia.

PMID- 10634647
TI  - Co-infection of HHV-6 and HHV-8 is rare in primary effusion lymphoma.
AB  - The presence and distribution of Epstein-Barr virus (EBV), as well as human
      herpesvirus-6 and-8 (HHV-6 and HHV-8) was investigated by polymerase chain
      reaction in 191 samples from a variety of lymphoproliferative disorders. HHV-6
      DNA was detected in 18% (30 of 169) of non-HHV-8 related lymphoproliferative
      disorders, with the highest frequency in AIDS-related lymphomas (8 of 25, 32%).
      In contrast, HHV-6 DNA was present in less than 5% (1 of 22) of HHV-8 related
      lymphoproliferative disorders [21 primary effusion lymphomas (PEL), and 1 cases
      of Castleman disease]. As compared to HHV-6, EBV DNA was frequently detected in
      PEL (11 of 19 samples, 58%). This study suggests that transformation to PEL is
      not enhanced by HHV-6, furthermore HHV-6 and -8 may interfere with each other.

PMID- 10634648
TI  - Consilience across evolving dysplasias affecting myeloid, cervical, esophageal,
      gastric and liver cells: common themes and emerging patterns.
AB  - In the present paper, an attempt is made to identify common biologic themes
      across dysplastic states affecting the marrow, gastro intestinal tissue, the
      cervix and liver as well as unifying patterns during disease evolution. The
      following algorithm appears generally applicable, although individual variations
      must necessarily be anticipated. It appears that there is an initial transforming
      event which in all dysplasias except that affecting the marrow has been found to
      be infectious. Increased cellular proliferation-increased apoptosis, telomere
      shortening, appearance of telomerase expression and clonal expansion follow the
      initial insult. Abnormalities in the cytokine environment are universally
      described and it is likely that the quintessential monoclonality aspect of
      dysplasia predisposes to accumulation of genetic mutations, and microsatellite
      instability leading to the appearance of evolved sub-clones. The conversion of a
      dysplastic phenotype to a malignant one reflects the success of one such sub
      clone in developing a survival advantage over a large population of prematurely
      apoptotic neighbors. This state is usually acquired by silencing tumor suppressor
      genes through hypermethylation or actual loss or dysfunction. Thus, excessive
      apoptosis of cells resulting from a persistent infectious process predisposes the
      organ towards developing a cancerous phenotype. Evidence for the shared pathology
      is presented at length with the hope that these parallels between dysplastic
      states will be helpful in both biologic and therapeutic research.

PMID- 10634649
TI  - Acute myeloid leukemia possessing jumping translocation is related to highly
      elevated levels of EAT/mcl-1, a Bcl-2 related gene with anti-apoptotic functions.
AB  - Jumping translocations (JTs) are unbalanced chromosomal translocations in which
      an identical chromosomal region is translocated to the telomeric region of
      different chromosomes. JTs are rare in hematological malignancies where they are
      second translocations and may be an indicator of poor prognosis. We report a case
      of acute myeloid leukemia with t(16;21) and a JT in which the long arm of
      chromosome 1 distal to q21 is translocated to the terminal region of chromosome
      10. The leukemic cells exhibit high expression of EAT/mcl1, an anti-apoptotic Bcl
      2 related gene. Since EAT/mcl1 is mapped to 1q21 near the breakpoint in the JTs,
      high level expression of EAT/mcl1 may be associated with the poor prognosis of
      leukemia with JTs.

PMID- 10634650
TI  - Acute promyelocytic leukemia with del(6)(p23).
AB  - We report a unique case of de novo acute promyelocytic leukemia (APL) with
      cryptic 15;17 rearrangements. Cytogenetically, structural rearrangements of the
      6p23 region has been reported mainly in secondary leukemia. This patient had a
      karyotype of 46, XY, del(6)(p23) and no additional chromosomal abnormalities.
      Molecular analyses revealed the presence of PML-RAR alpha fusion genes. Deletion
      of the 6p23 region is extremely rare in APL.

PMID- 10634651
TI  - Sweet's syndrome accompanying leukaemia: seven cases and review of the
      literature.
AB  - Seven patients with Sweet's Syndrome (SS) accompanying leukaemia are presented.
      Six had acute myeloid leukaemia and one chronic myeloid leukaemia. SS developed
      during G-CSF therapy in two patients and following long periods of chemotherapy
      associated neutropenia in two. This finding may suggest a possible role of G-CSF
      in the pathogenesis of SS. SS was diagnosed during the first presentation of
      three patients with leukaemia. Skin lesions on the lower extremities in two
      patients, widespread distribution in one, a local infiltration at the inguinal
      region and pleural effusion in one were interesting findings in our patients
      which are not usual for classical SS.

PMID- 10634652
TI  - Minimally differentiated acute myeloid leukemia (AML-M0) with extensive
      erythrophagocytosis and del(20)(q11) chromosome abnormality.
AB  - We describe an 84-year-old woman who presented severe pancytopenia and 36.6% of
      blasts accompanied with erythrophagocytosis in the bone marrow. According to
      cytochemical and immunological findings, a diagnosis of minimally differentiated
      acute myeloid leukemia (AML-M0) was established. Cytogenetic analysis revealed
      del(20)(q11) which were previously reported for one case each of ALL and MDS
      associated with cytophagocytosis by blasts, leading us to speculate a disease
      entity. Interestingly, a high expression of mRNA of TNF-alpha was detected by RT
      PCR on the bone marrow mononuclear cells.

PMID- 10634653
TI  - Relapsing polychondritis, smouldering non-secretory myeloma and early
      myelodysplastic syndrome in the same patient: three difficult diagnoses produce a
      life threatening illness.
AB  - Multiple myeloma, relapsing polychondritis and myelodysplastic syndrome are all
      serious diseases in which making a clear diagnosis can be difficult. This case of
      a 72-year-old man found after extensive investigation to have all three of the
      above, demonstrates how difficult diagnosis and treatment can be, producing in
      this case a life threatening clinical syndrome. We also postulate that the
      association of these three diseases may be an immune-derived complication of
      myelodysplastic syndrome.

PMID- 10634654
TI  - Hand-mirror blasts, AML-M1, and der(1)t(1;19)-(p13;p13.1)

PMID- 10634655
TI  - Telomeric associations and karyotypic evolution in myelodysplastic syndrome.

PMID- 10634656
TI  - Pathology of lung cancer.
AB  - Microscopic examination of stained smears and tissue sections remains the
      standard method for definitive diagnosis and classification of lung cancer.
      However, the morphology of lung cancer is complex, and consensus classifications
      such as those prepared by a panel World Health Organization (WHO) are required
      for the sake of consistency and clinical relevance. In the most recent (1999) WHO
      classification, the diagnostic categories of greatest clinical importance, small
      cell lung carcinoma and non-small cell lung carcinoma, remain fundamentally
      unchanged. However, application of immunohistochemistry and electron microscopy
      has revealed expression of neuroendocrine markers in a wide variety of tumors.
      Expression of these markers is not taken into account in current treatment
      protocols, and additional correlative studies will be required to determine the
      clinical relevance of neuroendocrine differentiation in lung carcinoma. In
      addition to histological classification, microscopic analysis can provide in situ
      evidence of response to chemotherapy, as well as information on precursor lesions
      and multistep carcinogenesis in the airways. Finally, it is likely that
      morphological assessment of lung carcinoma and preneoplastic lesions will
      continue to be refined as new diagnostic modalities such as spiral computed
      tomography and fluorescence bronchoscopy provide previously inaccessible
      specimens for morphological and correlative molecular studies.

PMID- 10634657
TI  - Potential biomarkers for the early detection of lung cancer.
AB  - Lung cancer remains the leading cause of cancer death among men and women in the
      United States. Early detection of premalignant lesions provides the possibility
      of treatment at earlier stages. Because malignancy develops from genetic
      alterations, the early detection of these genetic changes should be associated
      with the earliest clues to transformation. This article presents an overview of
      detection of molecular markers and their relevance to lung cancer. In the future,
      such molecular markers may play a role in guiding therapy for lung cancer.

PMID- 10634658
TI  - Screening for lung cancer.
AB  - Screening for lung cancer has remained controversial since the completion, more
      than two decades ago, of the three large randomized controlled trials, sponsored
      by the National Cancer Institute, which led to the recommendation against
      screening by major medical organizations. Details of the controversy are given,
      which include concerns about the study design, implementation, and analysis. New
      evidence about the potential benefit of screening with chest radiography that has
      emerged since the completion of those trials is reviewed, as well as the results
      of studies of CT screening for lung cancer.

PMID- 10634659
TI  - Thoracicrad.org.

PMID- 10634660
TI  - Notes from the 1999 annual meeting of the Korean Society of Thoracic Radiology.

PMID- 10634661
TI  - Primary bronchogenic carcinoma after heart or lung transplantation: radiologic
      and clinical findings.
AB  - Chronic immunosuppression in organ transplant recipients predisposes to the
      development of malignant disease. The authors describe their 29-year
      institutional experience of bronchogenic carcinoma developing after heart and
      lung transplantation. Seven cases of bronchogenic carcinoma were diagnosed in
      1,119 heart and lung transplant recipients. Computed tomography scans and
      radiographs at time of diagnosis, as well as prior radiographs available in six
      patients were retrospectively analyzed by two radiologists in consensus. The
      seven cases involved six heart and one lung transplant recipients. Six patients
      were smokers with a mean smoking history of 66 pack-years. Mean time interval
      from transplantation to cancer detection was 25 months. Radiologic findings
      consisted of a solitary pulmonary nodule (n = 3), mass with satellite nodules (n
      = 1), and obstructive pneumonitis (n = 1). In the sixth patient, the cancer was
      not radiographically visible because of obscuration by adjacent fibrosis. On
      review, radiographic abnormalities were present a mean of 12 months prior to
      diagnosis in 66% of patients. In the heart or lung transplant population,
      bronchogenic carcinoma develops in recipients with extensive smoking histories.
      It presents radiographically as a nodule, mass, or obstructive pneumonitis, and
      is usually visible on radiographs before the time of diagnosis.

PMID- 10634662
TI  - Magnetic resonance imaging of bronchioloalveolar carcinoma.
AB  - The purpose of this study is to describe the magnetic resonance (MR) features of
      bronchioloalveolar carcinoma. MR examinations of 18 patients with proven
      bronchioloalveolar carcinoma were reviewed. Detection at computed tomography (CT)
      and pathologic confirmation were the entry criteria. Nine patients had a solitary
      nodule, three patients a lobar consolidation, and six patients had diffuse
      disease. For each patient, both breath-hold T2-weighted fast spin-echo, and
      breath-hold T1-weighted gradient-echo images, before and after injection of
      gadolinium, were available. Nine patients with pulmonary consolidation or diffuse
      disease had also heavily T2-weighted MR imaging (Haste or TSE 240; Siemens,
      Erlangen, Germany). MR imaging showed pulmonary abnormalities in 17 of 18
      patients. Unenhanced T1-weighted and T2-weighted images depicted tumor in 16 of
      18 patients. Contrast-enhanced T1-weighted images showed tumor in 17 of 18
      patients. In no case did MR imaging depict abnormalities corresponding to the
      ground-glass opacities seen on CT scans. In three patients with mucinous
      bronchioloalveolar carcinoma, heavily T2-weighted images showed lesions
      isointense with respect to static fluid of the human body. In conclusion, the
      ability of MR imaging in detecting small nodules and ground-glass opacities is
      limited. However, heavily T2-weighted sequences are able to show the presence of
      mucin. This is useful information because mucinous bronchioloalveolar carcinoma
      carries a poor prognosis.

PMID- 10634663
TI  - Comparison between computer-aided diagnosis and radiologists: assessment of
      pulmonary blood flow on chest radiographs.
AB  - To evaluate the performance of a computer-aided diagnosis (CAD) scheme for
      estimating increased pulmonary blood flow on chest radiographs, we compared
      computerized assessment with findings by radiologists. Our CAD scheme extracts
      selectively linear opacities corresponding to vessels in regions of interest
      (ROIs) in the right upper and lower lung zones on digitized chest radiographs,
      and then calculates a radiographic index as a physical measure that reflects the
      area of the extracted opacities in selected ROIs. As a measure of increased
      pulmonary blood flow, the upper/lower radiographic index ratio was calculated for
      each patient. Seven radiologists estimated the degree of increased pulmonary
      blood flow for the same images of ROI sets presented on a cathode-ray tube
      monitor in a randomized order. Between the normal-pulmonary capillary wedge
      pressure (PCWP) group and increased-PCWP groups, there was no significant
      difference in performance between CAD and radiologists (p = 0.105). However, when
      the normal and mild PCWP groups were compared, the performance of CAD was
      superior to that of radiologists (p = 0.001). This study indicates that our CAD
      scheme is promising for quantitative estimation of increased pulmonary blood
      flow, especially in mild cases.

PMID- 10634664
TI  - Chest radiographic features of engraftment syndrome.
AB  - About the time of hematopoietic engraftment, patients undergoing autologous
      hematopoietic stem cell transplantation in the form of peripheral blood stem cell
      transplantation (PSCT) may develop an "engraftment syndrome" that includes fever,
      skin rash, and capillary leak. This condition is usually self-limited, as opposed
      to other early complications of bone marrow transplantation such as infection and
      drug reactions. This article describes the chest radiographic manifestations of
      engraftment syndrome. The medical records and chest radiographs of 50 consecutive
      breast cancer patients who underwent PSCT were retrospectively reviewed.
      Engraftment syndrome was diagnosed if the expected clinical findings occurred at
      the time of engraftment of neutrophils and no other cause was identified. The
      chest radiographs were correlated with the clinical course. Sixteen patients were
      found to have engraftment syndrome (32%). Of these, eight had abnormal
      radiographs. Radiographic findings consisted of pleural effusions and
      interstitial pulmonary edema. No patient progressed to adult respiratory distress
      syndrome. Interstitial pulmonary edema and pleural effusions were observed in
      association with engraftment syndrome from PSCT. Correlation of these findings
      with clinical history and neutrophil count is important so that engraftment
      syndrome can be distinguished from other causes of fever.

PMID- 10634665
TI  - Retained intrathoracic surgical swab: CT appearances.
AB  - A retained surgical swab (gossypiboma) is a rare but important complication of
      intrathoracic surgery. The radiographic and computed tomography (CT) appearances
      are variable and depend on the chronicity and site of the swab within the chest.
      Two cases of retained swabs within the chest are reported. In both cases, the
      swab had become surrounded by lung. The swab within the pleural space acted as a
      nidus and resulted in infolding of the lung, superficially resembling an
      intrapulmonary abscess on CT.

PMID- 10634666
TI  - Short air bubble in the gastric fundus during fasting: radiographic sign of
      gastroparesis after lung transplantation.
AB  - This study was undertaken to assess whether gastroparesis, as a chronic
      complication of lung transplantation, correlates with height of the gastric air
      bubble on chest radiographs of erect fasting subjects. Height of the gastric air
      bubble and presence or absence of a gastric air-fluid level were assessed on
      chest radiographic examinations (posteroanterior, lateral, upright position,
      during fasting, immediately after bronchoscopy, median 148 days after
      transplantation) obtained on 3 separate days for each of 19 recipients of lung
      transplantation. Seven of the subjects (five women, two men) had chronic upper
      gastrointestinal symptoms after transplantation and a confirmed diagnosis of
      gastroparesis. The gastroparesis was idiopathic in six of the subjects and
      associated with cytomegalovirus gastritis in one subject. The other 12 subjects,
      each without upper gastrointestinal symptoms, served as controls. Median height
      of the gastric air bubble was significantly less in the gastroparetic (2.8 cm;
      range, 1.0-4.6 cm) than in the control (4.7 cm; range, 1.0-12.4 cm) group
      (p<0.05). Height of the gastric air bubble was at most 4.6 cm among the seven
      gastroparetic subjects, whereas it exceeded 5.0 cm on at least one occasion in 8
      (67%) of the 12 control subjects (p<0.005). The likelihood of a gastric air-fluid
      level was 86% for symptomatic subjects and 25% for the control group (p<0.01).
      When lung transplantation is complicated by chronic gastroparesis,
      postbronchoscopic chest radiographic examinations of fasting subjects are
      associated with a gastric air bubble limited to high in the fundus, usually
      including a fluid level.

PMID- 10634667
TI  - Pulmonary nodules in early fat embolism syndrome: a case report.
AB  - The radiologic abnormalities in a patient with mild clinical manifestations of
      fat embolism are reported. The findings consisted of small nodular opacities,
      which were shown on computed tomography (CT) scans to be located predominantly in
      the centrilobular and subpleural regions. The nodules presumably represented
      alveolar edema or hemorrhage secondary to the fat embolism syndrome.

PMID- 10634668
TI  - Heart failure awareness.

PMID- 10634669
TI  - HOPE for an ACE inhibitor.

PMID- 10634670
TI  - Beneficial effects of long-term treatment with enalapril on cardiac function and
      heart rate variability in patients with old myocardial infarction.
AB  - BACKGROUND: The beneficial effects of the early use of angiotensin-converting
      enzyme inhibitors (ACEis) in patients with acute myocardial infarction (MI) are
      well documented. However, the effects of ACEis in patients with an old MI and
      preserved cardiac function have not yet been studied. We examined the effects of
      12 months of enalapril treatment in patients with previous MI. METHODS AND
      RESULTS: Thirteen patients with an old MI and no overt congestive heart failure
      (CHF), aged 70 +/- 2 years, were treated with enalapril for 12 months. We also
      included 13 age- and sex-matched control patients who had a similar clinical
      background but were not treated with enalapril. Holter electrocardiography and
      echocardiography were performed at entry and after 12 months of treatment. Heart
      rate variability, low- and high-frequency powers (LF and HF), and the ratio
      between LF and HF (LF/HF) were analyzed. Changes from baseline to 12 months in
      HF, LF/HF, left ventricular end-diastolic dimension (LVEDD), and end-systolic
      dimension (LVESD) were significantly different in the enalapril group (HF, 8.1 +/
      0.9 to 9.3 +/- 0.9 milliseconds: LF/HF, 1.65 +/- 0.11 to 1.53 +/- 0.16; LVEDD,
      57.2 +/- 1.6 to 54.7 +/- 1.6 mm; LVESD, 40.0 +/- 2.4 to 36.3 +/- 1.9 mm) compared
      with the control group (HF, 8.9 +/- 0.9 to 8.5 +/- 0.7 milliseconds; LF/HF, 1.78
      +/- 0.18 to 1.88 +/- 0.15; LVEDD, 52.3 +/- 2.5 to 55.9 +/- 2.2 mm; LVESD, 32.5 +/
      2.6 to 36.1 +/- 2.6 mm; P < .05). The delta change (delta) in LVESD between the
      end and the start of study correlated inversely with deltaHF (r = -0.56; P < .05)
      and positively with deltaLF/HF (r = 0.65; P < .01). CONCLUSION: Our results
      suggest possible ongoing structural changes in patients with old MI even in the
      absence of overt CHF. Enalapril seemed to prevent such changes and to restore
      cardiac autonomic tone toward normal. Further prospective studies using a larger
      sample size are warranted to confirm potential beneficial effects of ACEis in
      patients with previous MI and preserved left ventricular function.

PMID- 10634671
TI  - Aerobic training involving a minor muscle mass shows greater efficiency than
      training involving a major muscle mass in chronic heart failure patients.
AB  - BACKGROUND: Beneficial training outcomes have been reported in sedentary patients
      with chronic heart failure (CHF) after exercise training. However, data on
      training effects in previously trained patients, as well as comparisons of
      different exercise modes, are lacking. The aim of this study is to compare
      exercise training on a cycle ergometer (major muscle mass) and aerobic knee
      extensor training (minor muscle mass) in previously trained patients with CHF.
      METHODS AND RESULTS: Twenty-four men and women (age, 63 +/- 10 years [mean +/-
      SD]) with stable, moderate CHF (left ventricular ejection fraction, 30% +/- 11%)
      who had completed their first exercise training period more than 1 year ago were
      allocated to either the exercise or control group. After stratification for sex,
      age, ejection fraction, and cardiac output response, the training group was
      further randomized to either cycle ergometer or knee-extensor training for 8
      weeks. The control and training patients did not differ at baseline, and the
      measured variables did not change in the control group during the 8 weeks.
      Citrate synthase activity in skeletal muscle increased after cycle training (23%;
      P < .02) and knee-extensor training (45%; P < .008), and blood lactate
      concentration at submaximal intensities decreased (P < .04) in both groups.
      However, only after knee-extensor training did the peak oxygen uptake increase
      (19%; P < .01) and sympathetic nervous system activity, measured as plasma
      norepinephrine concentration at rest (P < .05) and during exercise (P < .008),
      decrease. Minnesota Living with Heart Failure questionnaire scores also showed
      improvement in the health-related quality of life (P < .05) only after knee
      extensor training. CONCLUSION: Physical training is beneficial in previously
      trained patients with CHF. Aerobic training involving a minor muscle mass shows
      greater efficiency than training involving a major muscle mass.

PMID- 10634672
TI  - Apoptosis, Bcl-2, and proliferating cell nuclear antigen in the failing human
      heart: observations made after implantation of left ventricular assist device.
AB  - BACKGROUND: Heart failure is characterized by progressive left ventricular
      remodeling, a complex process that results from cell growth and cell death. The
      quantitative contribution of apoptotic cells toward left ventricular remodeling
      has varied widely in tissue removed from cardiomyopathic hearts. Apoptosis has
      been responsive to angiotensin-converting enzyme inhibition in experimental heart
      failure, but the dynamics and responsiveness to chronic left ventricular
      unloading have not been studied. METHODS AND RESULTS: We studied 8 patients with
      severe heart failure before and after chronic left ventricular unloading with a
      left ventricular assist device (LVAD). Tissue from the left ventricular apex
      removed at the time of LVAD implantation was examined for apoptosis using the
      technique of terminal deoxynucleotidyl transferase deoxyuridine triphosphate
      biotin nick end-labeling (TUNEL) in 10 patients. These same hearts explanted at
      the time of cardiac transplantation were then examined for apoptosis after
      patients had been on the LVAD for 99 +/- 20 (SEM) days. An additional 10 patients
      with equally severe heart failure who underwent heart transplantation without the
      use of an LVAD served as controls. Eight hearts obtained at autopsy approximately
      6 hours after death from patients who died of non-cardiovascular disease causes
      served as non-heart failure controls. Additionally, 6 hearts were examined by
      immunohistochemistry for the antiapoptotic protein, Bcl-2, and for the repair
      and/or proliferation marker, proliferating cell nuclear antigen (PCNA), before
      and after LVAD. Apoptosis was not detected in the tissue sections from the hearts
      of 8 patients at the time of LVAD implantation. Only 1 of these patients had
      limited apoptosis (< 1 apoptotic cell/1,000 myocytes) after LVAD insertion. Three
      of 10 patients with severe heart failure who did not receive an LVAD but
      underwent transplantation showed limited apoptosis (< 1 apoptotic cell/1,000
      myocytes). Likewise, none of the control hearts from patients who died of
      noncardiovascular disease manifested apoptosis. Six of 6 patients overexpressed
      Bcl-2 at the time of LVAD insertion. In all these patients, Bcl-2 returned to
      negligible levels after chronic unloading of the heart. Likewise, PCNA was
      abundantly expressed in 5 of 6 failing hearts at the time of LVAD implantation
      and was reduced in 4 of 5 hearts after chronic unloading by LVAD. CONCLUSION:
      Apoptosis is a rare or inconsistent finding in the failing human heart.
      Overexpression of such indicators of cellular stress and DNA replication and/or
      repair as Bcl-2 and PNCA in heart failure may be altered by optimizing left
      ventricular loading conditions by such mechanical devices as the LVAD.

PMID- 10634673
TI  - Sympathoinhibitory effects of atrial natriuretic peptide in rats with heart
      failure.
AB  - BACKGROUND: It has been suggested that a blunted sympathoinhibitory response to
      atrial natriuretic peptide (ANP) may contribute to the elevation of sympathetic
      activity seen in heart failure. METHODS AND RESULTS: Experiments were performed
      in anesthetized rats 6 to 9 weeks after coronary ligation to induce heart
      failure. Responses to intravenous injections of ANP (4 microg/kg) did not differ
      between the sham-operated (n = 11) and heart-failure (n = 7) rats. Before
      sinoaortic denervation, ANP decreased mean arterial pressure (MAP) by 8 mm Hg in
      both the heart-failure and sham rats, renal sympathetic nerve activity (RSNA) by
      9% to 10% in both groups, and heart rate (HR) by 12 to 13 beats/min in both
      groups. After baroreceptor denervation, ANP decreased MAP by approximately 22 mm
      Hg, RSNA by 14%, and HR by 16 beats/min in both the heart-failure and sham rats.
      After vagotomy, there was no longer a significant decrease in RSNA or HR in
      response to ANP. CONCLUSION: The sympathoinhibitory effects of ANP are maintained
      in heart failure. This suggests that the elevated sympathetic activity observed
      in heart failure cannot be attributed to a blunting of the response to ANP.

PMID- 10634674
TI  - Noninvasive evaluation of cardiac dysfunction by echocardiography in
      streptozotocin-induced diabetic rats.
AB  - BACKGROUND: There has not been a noninvasive in vivo longitudinal evaluation of
      cardiac function in diabetic rats. The objective of this study is to examine the
      time course of development of cardiac dysfunction in streptozotocin (STZ)-induced
      diabetic rats. METHODS AND RESULTS: Cardiac function was evaluated by M-mode and
      Doppler echocardiography in anesthetized Wistar rats at 2, 4, 5, 6, and 8 weeks
      after injection with 65 mg of STZ/kg and in age-matched control rats before and
      after the administration of isoproterenol. Body weight (BW) was significantly
      less and blood glucose level significantly greater in diabetic rats compared with
      controls at 2 weeks and remained at these levels at all time points. The
      calculated left ventricular (LV) mass appeared slightly decreased in diabetic
      rats. However, LV mass-BW ratios were similar in controls and diabetic rats at 2,
      4, and 5 weeks, but were significantly greater in diabetic rats at 6 and 8 weeks.
      Basal heart rate (HR) was significantly lower in diabetic rats at all time points
      studied. Basal LV systolic and diastolic dimensions, fractional shortening (FS),
      velocity of circumferential shortening (Vcf), peak emptying rate (PER), peak
      filling rate (PFR), and aortic peak velocity (APV) were not significantly
      different between controls and diabetic rats at 2 and 4 weeks. PER and PFR were
      significantly less in 5-week diabetic rats. However, Vcf, PER, and PFR were
      significantly less and FS and APV were similar at 6 and 8 weeks. Administration
      of isoproterenol increased HR, Vcf, FS, PFR, and PER in controls at all time
      points, but the increases in diabetic rats at 5, 6, and 8 weeks were less
      compared with those in controls. The increase in APV was significantly less in
      diabetic rats at all time points studied. CONCLUSION: STZ-induced diabetic rats
      showed bradycardia before contractile dysfunction. Overt and covert contractile
      dysfunction unmasked by isoproterenol begins at 5 weeks of diabetes. The overt LV
      systolic and diastolic dysfunction are fully manifested after 6 weeks of
      diabetes.

PMID- 10634675
TI  - Use of standard imaging techniques for prediction of postrevascularization
      functional recovery in patients with heart failure.

PMID- 10634676
TI  - Vasopressin: a therapeutic target in congestive heart failure?

PMID- 10634677
TI  - Heart Failure Society of America (HFSA) practice guidelines. HFSA guidelines for
      management of patients with heart failure caused by left ventricular systolic
      dysfunction--pharmacological approaches.

PMID- 10634678
TI  - Analysis strategies for longitudinal attachment loss data.
AB  - The purpose of this invited review is to describe and discuss methods currently
      in use to quantify the progression of attachment loss in epidemiological studies
      of periodontal disease, and to make recommendations for specific analytic methods
      based upon the particular design of the study and structure of the data. The
      review concentrates on the definition of incident attachment loss (ALOSS) and its
      component parts; measurement issues including thresholds and regression to the
      mean; methods of accounting for longitudinal change, including changes in means,
      changes in proportions of affected sites, incidence density, the effect of tooth
      loss and reversals, and repeated events; statistical models of longitudinal
      change, including the incorporation of the time element, use of linear, logistic
      or Poisson regression or survival analysis, and statistical tests; site vs person
      level of analysis, including statistical adjustment for correlated data; the
      strengths and limitations of ALOSS data. Examples from the Piedmont 65+ Dental
      Study are used to illustrate specific concepts. We conclude that incidence
      density is the preferred methodology to use for periodontal studies with more
      than one period of follow-up and that the use of studies not employing methods
      for dealing with complex samples, correlated data, and repeated measures does not
      take advantage of our current understanding of the site- and person-level
      variables important in periodontal disease and may generate biased results.

PMID- 10634679
TI  - A study of dental staining among competitive swimmers.
AB  - OBJECTIVE: To estimate the prevalence of dental stains (DS) in competitive
      swimmers and quantify the risk of these stains compared with sportsmen in a non
      swimmers group in Castellon, Spain. METHODS: Cross-sectional and case-control
      designs. Between July 1996 and March 1997, 404 subjects, (171 enrolled in two
      clubs of competitive swimming and 233 sportsmen from two schools), were examined
      in order to detect and classify yellowish-brown or dark-brown stains on the
      facial surface of the eight incisors. Participation rates were 88.6% for
      swimmers, and 95.7% for sportsmen. Mean of participants' age was 12 years, range
      7-22 years. Castellon has three public competition swimming pools, two of which
      are indoors. Two of the pools used chloride products, and the third bromine for
      the disinfection of water. The recommended hygiene regulations were adhered to.
      RESULTS: Prevalence of DS was 60.2% in swimmers and 12.9% in sportsmen (P=
      0.0001). Risk factors for DS included: use of competition swimming pools, age,
      gender, years of competition, daily consumption of coffee, red wine, and iron
      supplement during the last year. Professional dental cleanliness was a protective
      factor. In a logistic regression analysis, the use of competition swimming pools
      maintained a high risk of DS, odds ratio (OR)=9.28; 95% confidence interval (CI)
      5.21-16.5, adjusted by the other variables. Amongst swimmers, more than 6 h of
      training a week increased the risk of these stains (OR=3.51; 95% CI 1.35-9.10).
      CONCLUSION: The study indicated a high risk of DS in competitive swimmers.

PMID- 10634680
TI  - Using partial recording to assess tooth wear in older adults.
AB  - OBJECTIVES: To establish whether partial recording can be used for the
      measurement and reporting of tooth wear data in samples of adult populations,
      whilst maintaining the usefulness of the index. METHODS: Using whole mouth
      coronal tooth wear data from a large random population sample of 1200 dentate
      older adults in England, several different partial recording systems were
      investigated to establish which teeth would maintain a high level of sensitivity
      for the most economic use of codes and index teeth. Tooth wear data were recorded
      on a surface-by-surface basis on all teeth in the sample using the tooth wear
      index. RESULTS: Five different partial mouth recording systems were assessed,
      including half-mouth scoring, assessment of just upper or just lower anterior
      teeth, assessment of all anterior teeth and use of six index teeth. The 12
      anterior teeth were the ones most often affected by moderate or severe wear, and
      when all 12 teeth were used as the index teeth few wear cases were missed, and
      all the most extensive and severe cases of coronal wear were classified as having
      some wear. A limited index of only six anterior teeth (three uppers and three
      lowers) was almost as sensitive, but allowed less flexibility when reporting the
      extent of coronal wear. Other systems for partial recording were less sensitive.
      CONCLUSIONS: Partial recording using six or 12 anterior teeth is appropriate for
      measuring and reporting tooth wear data in large population surveys.

PMID- 10634681
TI  - Application of the high-risk strategy to control dental caries.
AB  - OBJECTIVE: The aim of this prospective study was to determine whether a child
      population with low overall caries frequency benefits when prevention is targeted
      to high-risk individuals. METHODS: Data from clinical examinations and salivary
      tests were used to assess caries risk in 12-year-olds (n=1465). Children who were
      regarded as being at high risk of developing caries were randomized into two
      groups. Half (HRI group) were offered intensive prevention (counseling, F-varnish
      applications, F-lozenges, sealants, chlorhexidine), and the other half (HRB
      group) were provided the same basic prevention given to low-risk children
      (counseling, one F-varnish application/year). A random sample of the low-risk
      children (LRB) was followed up for the same 3-year period as the high-risk
      children. The number of children completing the study was 216 in the LRB group,
      199 in the HRI group and 174 in the HRB group. RESULTS: The mean (SD) 3-year DMFS
      increment was 2.0 (2.4), 4.4 (4.7) and 5.1 (5.0) in the LRB, HRI and HRB groups,
      respectively. Comparison between the LRB and HRB groups revealed that risk
      assessment was fairly successful in terms of mean DMFS increment. However, 63% of
      the children in the LRB group developed at least one new lesion (max. 12).
      CONCLUSIONS: The negligible difference between the HRI and HRB groups implies
      that intensifying prevention produced practically no additional benefit. By
      offering all children only basic prevention, virtually the same preventive effect
      could have been obtained with substantially less effort and lower costs.

PMID- 10634682
TI  - Outlining the morphological characteristics of acceptable occlusion.
AB  - OBJECTIVES: The aim of this study was to outline the definitions of a
      morphologically acceptable occlusion in young adults that could be applied to
      assess the outcome and effectiveness of orthodontic treatment. The opinions of
      Finnish orthodontists and general practitioners were investigated for this
      purpose. METHODS: A semi-structured questionnaire was sent to all health centres
      where at least one orthodontist was employed (n=37), to health centres without
      any orthodontist (n=31), to private orthodontists working as consultants (n=12)
      and to orthodontists working at university dental clinics (n = 13). The criteria
      for moderate and little orthodontic treatment need in the Need of Orthodontic
      Treatment Index (NOTI) and the Index of Orthodontic Treatment Need (IOTN) were
      chosen to describe the basic characteristics of occlusal acceptability. RESULTS:
      The questionnaire was returned by 76 subjects (82%). The respondents' views on an
      acceptable occlusion in young adults were not totally in line with the chosen
      definitions. Only 16% of the respondents accepted the definitions of both indices
      as such; the criteria in NOTI were accepted by 25% and those in IOTN by 21% of
      the respondents. Functional considerations of the occlusion were the main reasons
      for the desire for further details in the description of an acceptable occlusion.
      Crossbites with a discrepancy between retruded contact position and intercuspal
      position were the least accepted anomalies. The opinions were statistically
      significantly associated with the level of the respondents' orthodontic education
      and their type of employment. CONCLUSIONS: We conclude that the selected
      definitions of NOTI and IOTN can serve as a basis for the characteristics of a
      morphologically acceptable occlusion in young Finnish adults, but measures of the
      functional aspects of occlusion must be added for studies on the outcome of
      orthodontic services.

PMID- 10634683
TI  - Effect of diagnostic threshold on the validity and reliability of epidemiological
      caries diagnosis using the Dundee Selectable Threshold Method for caries
      diagnosis (DSTM).
AB  - OBJECTIVES: To develop a method for recording dental caries at the D1 (enamel and
      dentine) diagnostic threshold (without loss of D3 information) and assess its
      reliability, 'benchmark' validity and potential effects on reported caries
      prevalence and needs assessment. METHODS: Multi-examiner training, calibration
      and validation trial. Two groups of 10 dental examiners were trained to diagnose
      dental caries at the D1 (enamel and dentine) diagnostic threshold under the
      conditions of a caries prevalence survey, prior to a calibration trial being
      undertaken. RESULTS: Where 'experienced examiners' were trained to examine at the
      D1 (enamel and dentine) diagnostic threshold, under the conditions of a cross
      sectional epidemiological survey, there was no significant deterioration in inter
      examiner agreement on the assessment of teeth and a significant difference in one
      of two comparisons on the assessment of surfaces using the kappa statistic.
      Assessed against a benchmark examiner, there was no significant loss of
      sensitivity at the D1 diagnostic threshold compared with the D3 threshold and,
      although there was a significant loss of specificity at the D1 threshold, all
      specificity values could be considered to be high. CONCLUSIONS: Modifying the
      diagnostic criteria typically used in surveys of caries prevalence (to allow
      assessment of the levels of enamel caries which could benefit from preventive
      care as well as dentinal caries requiring restorative care) in adolescents does
      not adversely affect the reliability or benchmark validity of experienced
      examiners to a significant degree.

PMID- 10634684
TI  - In vitro validity of the Dundee Selectable Threshold Method for caries diagnosis
      (DSTM).
AB  - OBJECTIVES: It is not generally possible to assess diagnostic accuracy in dental
      surveys as no histological 'gold standards' are available, therefore examiner
      agreement tends to be used as a proxy for accuracy. The aim of this study was to
      investigate, using extracted teeth in arch models, the in vitro validity of a
      diagnostic system to assess caries at the D1 (enamel and dentine) and D3
      (dentine) diagnostic thresholds, for epidemiological purposes. METHOD: Two groups
      of 10 dental examiners trained in the use of the Dundee Selectable Threshold
      Method for caries diagnosis (DSTM) each examined (on two occasions) 160 extracted
      permanent molar and premolar teeth set in arch models in phantom heads according
      to the codes and criteria of the DSTM. The teeth were subsequently radiographed
      and sectioned to provide validation of the diagnoses. RESULTS: Intra-examiner
      agreement according to the kappa statistic was substantial. In general terms the
      results of the in vitro validation exercise demonstrated significantly higher
      sensitivity values at the D1 diagnostic threshold than were found at the D3
      diagnostic threshold with a consequent loss of specificity. CONCLUSIONS: The
      results of this in vitro validation exercise demonstrate that at the D1
      diagnostic threshold the sensitivity of the DSTM was greater than at the D3
      threshold indicating no loss of diagnostic accuracy at the D1 threshold.

PMID- 10634685
TI  - Salivary flow and oral complaints in adult dental patients.
AB  - Saliva plays an important role in maintaining oral health and functions. In the
      present study, unstimulated and stimulated whole salivary flow and various oral
      complaints were surveyed in 1427 individuals, 669 men (47%) and 758 women (53%).
      These individuals, aged 20 to 69 years and from different socioeconomic
      backgrounds, were recruited from 2000 randomly selected men and women in the
      register of the public dental health service in northern Sweden. The unstimulated
      salivary flow rate ranged from 0 to 2.07 mL/min (mean 0.33+/-SD 0.26) for men,
      and from 0 to 1.35 mL/min (mean 0.26+/-SD 0.21) for women. The stimulated
      salivary flow rate ranged from 0.17 to 7.3 mL/min (mean 2.50+/-SD 1.06) for men,
      and from 0 to 6.40 mL/min (mean 2.02+/-SD 0.93) for women. Women over 55 years of
      age had a reduced unstimulated salivary flow (P<0.05). Individuals with many
      teeth had a higher stimulated salivary flow than those with fewer teeth
      (P<0.001). Male smokers had a lower unstimulated salivary flow than male non
      smokers (P<0.05). Women with oral lesion complaints had a lower unstimulated
      salivary flow (P<0.05), and women with burning mouth had a lower stimulated
      salivary flow (P<0.01). Individuals with subjective oral dryness had reduced
      salivary flow, both unstimulated (men P<0.01, women P<0.001) and stimulated
      (P<0.001). Subjective oral dryness was associated with complaints of burning
      mouth (P<0.001), muscle pain (P<0.01), taste disturbances (P<0.01), and dry eyes
      (P<0.05). Individuals with subjective oral dryness had fewer teeth than
      individuals with no such complaints (P<0.001). Information regarding salivary
      flow rate in adults is important in understanding and evaluating the relationship
      between salivary flow and various types of oral complaints in patients.

PMID- 10634686
TI  - Risk indicators associated with tooth loss in Jordanian adults.
AB  - OBJECTIVES: The purpose of this study was to evaluate the risk indicators of
      tooth loss in Jordanian adults. METHODS: A sample of 509 Jordanian adults was
      randomly selected. The subjects were interviewed regarding demographics, social
      economic status, smoking habits, and oral hygiene practices and then clinically
      examined by a single examiner. Multiple regression analysis was performed to
      estimate the simultaneous impact of risk indicators on tooth loss. RESULTS: The
      subjects' mean age was 42.6 years with an average of 20.9 teeth remaining per
      person. The overall educational level of the subjects was low. More than 40%
      reported not brushing their teeth regularly and 56% had had no professional teeth
      cleaning during the last year. Monthly family income averaged JOD 231, and about
      a third of the subjects were smokers. The mean number of remaining teeth
      decreased significantly with age. Smokers, those who brushed irregularly, and
      those who had not had professional teeth cleaning in the last year had
      significantly fewer remaining teeth. Men also had significantly fewer remaining
      teeth. Education and income were also significantly associated with the number of
      remaining teeth. Age, income, brushing, prophylaxis, and gender collectively
      explain 75.1% of the variance in the number of remaining teeth. CONCLUSION:
      Modification of non-disease independent factors could reduce tooth loss and
      improve oral health in Jordanians.

PMID- 10634687
TI  - Oral hygiene in 12-year-old disabled children in Flanders, Belgium, related to
      manual dexterity.
AB  - As part of a larger epidemiological survey of a stratified sample of 12-year-old
      handicapped children in Flanders, Belgium, the present study describes gingival
      health, gingival hypertrophy, oral cleanliness and the presence of calculus.
      Statistical analysis was performed with motor skills, brushing help, the use of
      chemical agents, the use of anti-epileptic drugs, the knowledge of parents and
      educators (or caregivers) and their opinion of the oral hygiene of their
      children/ pupils as response variables. From this study, it became clear that
      mildly mentally retarded and learning-impaired children had significantly better
      manual dexterity skills than moderately and severely mentally retarded and
      physically impaired children. However, this was not reflected in improved oral
      hygiene. The use of chemical plaque controlling agents was found to be extremely
      low and, with the exception of children with gingival hyperplasia, the users of
      these agents did not have better oral hygiene. No difference was found between
      subtypes in the opinion of parents and educators on oral status. There was,
      however, a difference between their assessment and the clinical picture. It was
      concluded that there was a need for in-service training programmes in oral health
      care for educators as well as for parents.

PMID- 10634688
TI  - Colocalisation of neuropeptides, nitric oxide synthase and immunomarkers for
      catecholamines in nerve fibres of the adult human vas deferens.
AB  - Single and double-label immunofluorescence methods were used to determine the
      distribution and patterns of colocalisation of various neuropeptides and nitric
      oxide synthase (NOS) with the catecholamine synthesising enzymes tyrosine
      hydroxylase (TH) and dopamine-beta-hydroxylase (DbetaH) in nerve fibres within
      specimens of adult human vas deferens obtained at vasectomy (age range 28 to 83
      y). Cholinergic nerve fibres were immunolabelled with an antiserum to vesicular
      acetylcholine transporter (VAChT). Using the general nerve marker protein gene
      product 9.5 (PGP) the density of intramural nerve fibres was found to be similar
      irrespective of age. Many of these axons, especially in the outer 2 muscle layers
      were TH and DbetaH-immunoreactive (IR) and were thus confirmed as noradrenergic.
      Fewer such axons were seen in the inner longitudinal muscle layer. All the
      noradrenergic nerve fibres also displayed NPY-immunoreactivity with minor
      populations containing galanin (GAL) or somatostatin (SOM). Nerve fibres lacking
      TH and DbetaH-IR were immunoreactive for VAChT and were sparsely distributed
      throughout the 2 outer muscle layers but more numerous in the inner muscle layer.
      Nerves lacking TH and DbetaH were immunoreactive for NPY and some also contained
      NOS, VIP or CGRP. These results have been compared with those obtained previously
      from specimens of human neonatal and infant vas deferens where, in contrast to
      the present results, NOS and VIP were shown to be colocalised with TH in many of
      the intramuscular nerve fibres. It thus appears that NOS and VIP cease their
      coexistence with TH in intramuscular nerve fibres of the human vas deferens
      between the pre- and postpubertal states. In addition to the intramuscular nerve
      fibres a VAChT-IR subepithelial nerve plexus occurs in the vas deferens and may
      control the secretory activity of the lining epithelium. Most of these
      subepithelial nerve fibres were immunoreactive for NPY and many also contained
      VIP while minor populations were immunoreactive for NOS, GAL, SOM or SP although
      fibres containing CGRP were not observed. The neuropeptide content of the
      subepithelial nerve plexus was similar to that observed in the infant, except for
      an increased density of VIP-IR nerves, which may reflect greater activity of the
      lining epithelial cells in the adult vas deferens.

PMID- 10634689
TI  - Morphological variation in great ape and modern human mandibles.
AB  - Adult mandibles of 317 modern humans and 91 great apes were selected that showed
      no pathology. Adult mandibles of Pan troglodytes troglodytes, Pongo pygmaeus
      pygmaeus and Gorilla gorilla gorilla and from 2 modern human populations (Zulu
      and Europeans from Spitalfields) were reliably sexed. Thirteen measurements were
      defined and included mandibular height, length and breadth in representative
      positions. Univariate statistical techniques and multivariate (principal
      component analysis and discriminant analysis) statistical techniques were used to
      investigate interspecific variability and sexual dimorphism in human and great
      ape mandibles, and intraspecific variability among the modern human mandibles.
      Analysis of interspecific differences revealed some pairs of variables with a
      tight linear relationship and others where Homo and the great apes pulled apart
      from one another due to shape differences. Homo and Pan are least sexually
      dimorphic in the mandible, Pan less so than Homo sapiens, but both the magnitude
      of sexual dimorphism and the distribution of sexually dimorphic measurements
      varied both among and between modern humans and great apes. Intraspecific
      variation among the 10 populations of modern humans was less than that generally
      reported in studies of crania (74.3% of mandibles were correctly classified into
      1 of 10 populations using discriminant functions based on 13 variables as
      compared with 93% of crania from 17 populations based on 70 variables in one
      extensive study of crania). A subrecent European population (Poundbury) emerged
      as more different from a recent European population (Spitalfields) than other
      more diverse modern populations were from each other, suggesting considerable
      morphological plasticity in the mandible through time. This study forms a sound
      basis on which to explore mandibular variation in Neanderthals, early Homo
      sapiens and other more ancient fossil hominids.

PMID- 10634690
TI  - Ultrastructural features of goat oviductal secretory cells at follicular and
      luteal phases of the oestrous cycle.
AB  - The aim of the present study was to investigate the ultrastructure of secretory
      cells in the various regions of the goat oviduct during the follicular and luteal
      phases of the oestrous cycle. During the follicular phase in the fimbriae, the
      secretory cells contained small secretory granules with electron-dense matrices.
      In the luteal phase, the secretory granules disappeared and cytoplasmic
      protrusions, extending beyond the luminal border of the ciliated cells and often
      containing the nucleus, were predominant. During the follicular phase in
      ampullary secretory cells, numerous secretory granules with moderately electron
      dense matrices were present in the supranuclear cytoplasm and exocytosis of
      secretory granules was observed. The number of secretory granules was
      dramatically reduced in the ampullary secretory cells at the luteal phase.
      Conspicuous cytoplasmic protrusions of secretory cells were observed similar to
      those of the fimbrial epithelium. Isthmic cells were almost free of secretory
      granules and lysosome-like bodies were found both at the follicular and luteal
      phases. In conclusion, our ultrastructural observations of goat oviduct revealed
      marked cyclic changes in the ultrastructural features of secretory cells and the
      ultrastructural features and the numbers of secretory granules were distinctive
      for each particular segment.

PMID- 10634691
TI  - Immunohistochemical characterisation of epithelial cells of rodent harderian
      glands in primary culture.
AB  - The aims of the current investigation were (1) to establish an efficient
      procedure for the isolation of rodent harderian gland cells and to define
      conditions for maintenance of viable differentiated cells; (2) to compare the in
      vitro growth pattern of cultured epithelial cells; and (3) to characterise the
      cultured epithelial cells from 3 rodent species: Wistar rats, Syrian hamsters and
      Djungarian hamsters. We have established primary culture conditions that permit
      the maintenance of viable and differentiated secretory cells from adult rodent
      harderian gland. This study demonstrates that the cell growth pattern is faster
      in hamsters than in rats and despite morphological changes, epithelial cells
      reestablish their distinctive (biochemical/metabolic) phenotype as indicated by
      lipid-containing vacuoles, porphyrin pigment and serotonin and tryptophan
      hydroxylase labelling.

PMID- 10634693
TI  - Scoring of nonmetric cranial traits: a methodological approach.
AB  - The purpose of the present study was to analyse the replicability of the scoring
      of discontinuous traits. This was assessed on a sample of 100 skulls from the
      Frassetto collection (Dipartimento di Biologia Evoluzionistica Sperimentale of
      Bologna University) analysed through intraobserver comparisons: the discontinuous
      traits were determined on the same skulls and by the same observer on 3 separate
      occasions. The scoring was also assessed through interobserver comparisons: 3
      different observers performed an independent survey on the same skulls. The
      results show that there were no significant differences in the discontinuous
      trait frequencies between the 3 different scorings by the same observer, but
      there were sometimes significant differences between different observers. Caution
      should thus be taken in applying the frequencies of these traits to population
      research. After an indispensable control of material conditions (subject age
      included), consideration must be given to standardisation procedures between
      observers, otherwise this may be an additional source of variability in cranial
      discontinuous trait scoring.

PMID- 10634692
TI  - Immuno-inflammatory cell dynamics during cutaneous wound healing.
AB  - The process of wound healing begins with an inflammatory reaction that is
      principally dependent on cellular immune elements. Although the involvement in
      wound healing of leucocytes that mediate nonspecific immunity (e.g. neutrophils
      and macrophages) is well known, the participation of cells which prime the immune
      reaction, i.e. the lymphocytes, requires further investigation. This study was
      performed to examine the temporal sequence and kinetics of these cells during
      cutaneous wound repair. The model selected was a full-thickness skin excisional
      wound made on the flanks of female Wistar rats. At time points ranging from 3 h
      to 2 wk wound samples were processed for polyester wax-embedding. Target antigens
      were identified and monitored quantitatively in sections stained
      immunohistochemically. Monoclonal antibodies against neutrophils, macrophages,
      pan T cells and cytotoxic populations of lymphocytes were used. The results
      showed that these cells are involved in the process of wound healing in a
      distinctive dynamic pattern. The accumulation of CD3+ T lymphocytes in the wound
      bed was mainly associated with the phase of granulation tissue formation.
      Intraepithelial CD3+ T lymphocytes were detected in considerable numbers within
      the regenerating epidermis. The cytotoxic cell populations (OX8+) were classified
      morphologically into the cytotoxic/suppressor subset of T cells and NK cells. The
      OX8+ T cells were shown to have a kinetic pattern similar to CD3+ T lymphocytes
      but of a lower magnitude. The accumulation of OX8+ NK cells was confined to the
      early inflammatory phase of repair. It is concluded that CD3+ T lymphocytes as
      well as OX8+ cytotoxic populations of the immune system are involved in the
      process of cutaneous wound healing in temporal sequences which suggest that they
      may be involved in its modulation.

PMID- 10634694
TI  - Scoring of nonmetric cranial traits: a population study.
AB  - The aims of the present study were: (1) to supply further knowledge about
      variations in nonmetric cranial traits in relation to sex, age and laterality and
      (2) to evaluate biological distance between samples from a recent population. The
      incidence of 18 nonmetric variants of the cranium were determined in 3 adult
      samples of 394 skulls of known sex from North Sardinia (Sassari, Alghero and
      Ozieri); for the Sassari sample (n = 200) age at death was also known. Some
      significant sex differences were observed. Age did not appear to influence the
      frequency of the discontinuous traits but did for legibility. Side differences
      may provide important information about environmental influences. The
      interpopulation analysis indicates a stronger relationship between samples that
      are geographically closer (Sassari and Alghero), in accordance with other
      studies, strengthening the hypothesis of the validity of the use of nonmetric
      traits in the study of the peopling of a territory.

PMID- 10634695
TI  - Morphometric and ultrastructural changes with ageing in mouse peripheral nerve.
AB  - Qualitative and quantitative information is reported on the morphological changes
      that occur in nerve fibres and nonneuronal cells of peripheral nerve during the
      lifetime of the mouse. Tibial nerves of mice aged 6-33 mo were studied. With
      ageing, collagen accumulates in the perineurium and lipid droplets in the
      perineurial cells. Macrophages and mast cells increase in number, and onion bulbs
      and collagen pockets are frequently present. Schwann cells associated with
      myelinated fibres (MF) slightly decrease in number in parallel with an increase
      of the internodal length from 6 to 12 mo, but increase in older nerves when
      demyelination and remyelination are common. The unmyelinated axon to myelinated
      fibre (UA/MF) ratio was about 2 until 12 mo, decreasing to 1.6 by 27 mo. In older
      mice, the loss of nerve fibres involves UA (50% loss of 27-33 mo cf. 6 mo) more
      markedly than MF (35%). In aged nerves wide incisures and infolded or outfolded
      myelin loops are frequent, resulting in an increased irregularity in the
      morphology of fibres along the internodes. In the mouse there is an adult time
      period, 12-20 mo, during which several features of degeneration progressively
      appear, and an ageing period from 20 mo upwards when the nerve suffers a general
      disorganisation and marked fibre loss.

PMID- 10634697
TI  - The vomeronasal organ of the South American armadillo Chaetophractus villosus
      (Xenarthra, Mammalia): anatomy, histology and ultrastructure.
AB  - The vomeronasal organ (VNO) is a chemoreceptive structure that has not been
      extensively studied in the Xenarthran order. Tissue samples from the VNO of the
      armadillo Chaetophractus villosus were prepared for light and electron
      microscopy. The VNO is located in the anterior part of the base of the nasal
      septum. It is tubular in shape, approximately 18 mm in length and opens in the
      rostral region of the nasal cavity and with a blind caudal end. Its lumen is
      lined by sensory (SE) and nonsensory (NSE) epithelium. The SE shows sensory,
      supporting and basal cells whereas the NSE contains ciliated and nonciliated
      secretory cells and basal cells. At the ultrastructural level, the sensory cells
      appear as bipolar neurons with conspicuous microvilli on their free surface. The
      supporting cells of the SE contain numerous membrane-bound vesicles in their
      apical regions. A peculiar feature not found in other mammals, is the presence of
      concentric whorls of RER cisterns frequently observed in their basal expansions.
      Infiltrating plasma cells can be detected in the SE basal region close to the
      dorsal junctional area. This region also exhibits an unusual type of basal cell,
      probably responsible for the generation of new vomeronasal receptor neurons. The
      ciliated NSE cells exhibit numerous ovoids or irregularly shaped membranous
      protrusions projecting from the plasma membrane of the cilia. As far as we know,
      this is the first study reporting the presence of this feature in ciliated NSE
      cells. The nonciliated cells are characterised by scarce large secretory granules
      and apical microvilli. The vomeronasal glands are compound-branched tubuloacinar
      glands with serous acinar cells. Four types of secretory granules are present.
      The ducts of these glands reach the lumen in the dorsolateral region between the
      NSE and SE. Hypolemmal nerve terminals were observed contacting secretory cells.
      Fenestrated and nonfenestrated capillaries constitute the vascular supply to
      these glands. Plasma cells, intimately associated with acinar cells, were
      frequently observed.

PMID- 10634696
TI  - Mast cells in the sheep, hedgehog and rat forebrain.
AB  - The study was designed to reveal the distribution of various mast cell types in
      the forebrain of the adult sheep, hedgehog and rat. Based on their histochemical
      and immunocytochemical characteristics, mast cells were categorised as (1)
      connective tissue-type mast cells, staining metachromatically purple with the
      toluidine blue method, or pale red with the Alcian blue/safranin method, (2)
      mucosal-type or immature mast cells staining blue with the Alcian blue/safranin
      method and (3) serotonin immunopositive mast cells. All 3 types of brain mast
      cells in all species studied were located in both white and grey matter, often
      associated with intraparenchymal blood vessels. Their distribution pattern
      exhibited interspecies differences, while their number varied considerably not
      only between species but also between individuals of each species. A
      distributional left-right asymmetry, with more cells present on the left side,
      was observed in all species studied but it was most prominent in the sheep brain.
      In the sheep, mast cells were abundantly distributed in forebrain areas, while in
      the hedgehog and the rat forebrain, mast cells were less widely distributed and
      were relatively or substantially fewer in number respectively. A limited number
      of brain mast cells, in all 3 species, but primarily in the rat, were found to
      react both immunocytochemically to 5-HT antibody and histochemically with Alcian
      blue/safranin staining.

PMID- 10634698
TI  - Supra and infralevator neurovascular pathways to the penile corpora cavernosa.
AB  - The aim of this study was to provide a comprehensive description of both penile
      innervation and vascularisation. Eighty-five male cadavers were examined through
      gross and microscopic anatomical analysis. The pelvic nerve plexus had both
      parasympathetic and sympathetic roots. It was distributed to the external
      urethral sphincter giving rise to cavernous nerves which anastomosed in 70% of
      the cases with the pudendal nerve in the penile root. Accessory pudendal arteries
      were present in the pelvis in 70% of the cases, anastomosing in 70% of the cases
      with the cavernous arteries that originated from the pudendal arteries.
      Transalbugineal anastomoses were always seen between the cavernous artery and the
      spongiosal arterial network. There were 2 venous pathways, 1 in the pelvis and 1
      in the perineum with a common origin from the deep dorsal penile vein. It is
      concluded that there are 2 neurovascular pathways destined for the penis that are
      topographically distinct. One is located in the pelvis and the other in the
      perineum. We were unable to determine the functional balance between these 2
      anastomosing pathways but experimental data have shown that they are both
      involved in penile erection. These 2 neurovascular pathways, above and below the
      levator ani, together with their anastomoses, form a neurovascular loop around
      the levator ani.

PMID- 10634699
TI  - Location of the phrenic nucleus in the human spinal cord.
AB  - Eight normal human spinal cords were studied. Spinal segments were identified and
      embedded in paraffin wax. Serial cross sections were cut at 25 microm and stained
      by cresyl violet. Motor columns were reconstructed adapting Elliott's (1942)
      methods. Motor columns were classified into the medial and lateral divisions and
      were numbered sequentially from medial to lateral at the level of C1. In the
      cervical cord, 8 motor columns were traced. Column 1, corresponding to the medial
      column, presented 3 subdivisions designated as 1a, 1b and 1c with ventral, dorsal
      and lateral positions respectively. Columns 1a and 1b extended throughout the
      cervical region while 1c was confined to 3rd, 4th and 5th cervical segments. At
      the level of C3, 1c was a discrete column situated lateral to 1a and 1b but at C4
      and C5 it became displaced medially close to the medial margin of the ventral
      horn. In cross section, it presented smaller medial and large lateral part. With
      the help of clinical and developmental evidence an attempt was made to correlate
      column 1c with the phrenic nucleus.

PMID- 10634700
TI  - The taxonomy, ecology and cultivation of bacterial genera belonging to the family
      Flavobacteriaceae.
AB  - The group known as the 'flavobacteria' has previously been regarded as synonymous
      with the genus Flavobacterium. Today, however, flavobacteria refers to the family
      Flavobacteriaceae comprising 10 genera. This review deals with the rapid changes
      in the taxonomy of these bacteria, especially over the last decade. It also
      briefly reviews the ecology of the genera in this family and describes the media
      that have been utilized in the general and selective cultivation of these
      organisms.

PMID- 10634701
TI  - Helicobacter pylori: characteristics, pathogenicity, detection methods and mode
      of transmission implicating foods and water.
AB  - Helicobacter pylori is an organism involved in the pathogenesis of human active
      chronic gastritis, peptic and duodenal ulcer diseases and gastric cancer. This
      review article covers this emerging human pathogen in terms of its phenotypic and
      genotypic characteristics, methods for culturing, its role in gastric
      pathogenicity, evidence involving its mode of transmission, difficulty in its
      isolation and detection methodology. In terms of transmission, both foodborne and
      waterborne pathways have been speculated as the mode of transmission for H.
      pylori as the patterns of the infection are consistent with those from fecal-oral
      and oral-oral transmission. Therefore, it is important to also evaluate methods
      for the detection of H. pylori from specifically food products and water. The
      detection of this pathogen has proved difficult since changes in cell morphology,
      metabolism and growth patterns occur when H. pylori is exposed to different
      environmental stimuli. The development of a viable but non-culturable coccoid
      (VNC) form is observed. These VNC forms do not undergo cellular division and
      cannot be cultured by traditional methods, increasing the difficulty in their
      detection. Since both viability and virulence in the VNC form of H. pylori are
      retained, the examination of food products and water for these forms is critical.
      Current methods include filtration, immuno-separation (IMS), polymerase chain
      reaction (PCR), probe hybridization, immuno-staining, autoradiography and ATP
      bioluminescence.

PMID- 10634702
TI  - Effect of chelators and nisin produced in situ on inhibition and inactivation of
      gram negatives.
AB  - The ability of chelators and nisin generated in situ to inhibit and inactivate E.
      coli and other gram negatives in a model substrate was investigated. The effect
      of various chelators and different concentrations of exogenous nisin on
      inhibition of E. coli in broth medium showed that only EDTA and pyrophosphates
      were able to cause appreciable inhibition of E. coli by nisin. In a broth where
      L. lactis NCFB 497 produced nisin in a concentration of 250-300 IU/ml,
      pyrophosphates were unable to inactivate E. coli. Under the same conditions,
      addition of EDTA led to inactivation of E. coli at neutral and slightly acidic pH
      only. A cocktail of strains of E. coli was less sensitive than E. coli ATCC 25922
      alone. Pseudomonas aeruginosa was more sensitive and salmonellae more resistant.
      EDTA also caused a slight reduction in the L. lactis population and its
      biochemical activity as regards pH drop and acid production. Some of the
      inhibition of E. coli could be ascribed to the physical presence of Lactococcus
      cells rather than their metabolites excreted into the medium. Failure to observe
      any inhibition in fermented broths at their natural pH (4.0) was ascribed to the
      poor chelating power of EDTA under acid conditions.

PMID- 10634703
TI  - Hydrolysis of muscle myofibrillar proteins by Lactobacillus curvatus and
      Lactobacillus sake.
AB  - Proteolytic enzyme activities of whole cells and cell free extracts (CFE) of
      Lactobacillus curvatus CECT 904 and Lactobacillus sake CECT 4808 were
      characterised using synthetic chromogenic compounds and myofibrillar proteins as
      substrates. The hydrolytic action was monitored by SDS-PAGE and reverse phase
      HPLC analyses. The CFE of L. sake partially contributed, together with muscle
      enzymes, to the initial hydrolysis of myofibrillar proteins. Whole-cells of both
      L. curvatus and L. sake generated peptides considered important for cured-meat
      taste. The peptide mapping, resulting from the action on the substrates assayed,
      revealed a profile of extra and intracellular enzymes. Both strains expressed
      strong amino acid metabolism.

PMID- 10634704
TI  - Listeria monocytogenes in pork slaughtering and cutting plants. Use of RAPD, PFGE
      and PCR-REA for tracing and molecular epidemiology.
AB  - In order to determine the origin of pork cuts contamination by Listeria
      monocytogenes, 287 isolates, collected from five French pork slaughtering and
      cutting plants, from live pigs to pork cuts, were characterised using three
      molecular typing methods: random amplification of polymorphic DNA (RAPD) carried
      out with five different primers, genomic macrorestriction using ApaI with pulsed
      field gel electrophoresis (PFGE) and a PCR-restriction enzyme analysis (PCR-REA)
      based on the polymorphism existing within the inlA and inlB genes. Results
      obtained from RAPD and PFGE were closely related and distinguished respectively
      17 RAPD types (r1-r17) and 17 PFGE types (a1-a17) among the 287 isolates, whereas
      the PCR-REA analysis only yielded two profiles (p1 and p2). Considering the
      combined results obtained with the three molecular typing methods, 19 Listeria
      monocytogenes genotypes (1-19) were distinguished. Serotyping led at least four
      serotypes being distinguished: 1/2a, 3a, 1/2c and 3c. The application of
      genotyping identified the predominance of a Listeria monocytogenes strain of type
      (1) and other very closely related ones (5, 9, 10, 12, 13, 14, 16 and 19) which
      were present on pork as well as in the environment within the five investigated
      plants. This study also pointed out the presence of these closely related
      Listeria monocytogenes strains over a 1-year period in the environments of two
      plants, even after cleaning and disinfection procedures. This highlights the
      possibility for some Listeria monocytogenes strains to persist in pork processing
      environments and raises the problem of the efficiency of cleaning and
      disinfection procedures used in pork slaughterhouses, chilling and cutting rooms.

PMID- 10634705
TI  - Occurrence of nisin Z production in Lactococcus lactis BFE 1500 isolated from
      wara, a traditional Nigerian cheese product.
AB  - Screening for bacteriocin production of 500 strains of lactic acid bacteria (LAB)
      from various African fermented foods resulted in the detection of a bacteriocin
      producing Lactococcus lactis (BFE 1500) isolated from a dairy product called
      wara. The bacteriocin inhibited not only the closely related LAB, but also
      strains of Listeria monocytogenes, Listeria innocua, Clostridium butyricum,
      Clostridium perfringens, Bacillis cereus and Staphylococcus aureus. It was heat
      stable even at autoclaving temperature (121 degrees C for 15 min) and was active
      over a wide pH range (2-10), but highest activity was observed in the lower pH
      range. The bacteriocin was inactivated by alpha-chymotrypsin and proteinase K,
      but not by other proteases. Growth kinetic assay indicated stronger growth
      inhibition by the bacteriocin produced by Lc. lactis BFE 1500 on L. monocytogenes
      WS 2250 and B. cereus DSM 2301 than with the nisin A producing strain DSM 20729.
      Polymerase chain reaction indicated the presence of the nisin operon in strain
      BFE 1500 and sequencing of its structural gene showed that Lc. lactis BFE 1500
      produced the natural nisin variant, nisin Z, as indicated by the substitution of
      asparagine residue instead of histidine at position 27. The genetic determinants
      for bacteriocin production in strain BFE 1500 are located on a conjugative
      transposon. The ability of the bacteriocin produced by Lc. lactis BFE 1500 to
      inhibit a wide range of food-borne pathogens is of special interest for food
      safety, especially in the African environment with perennial problems of poor
      food hygiene.

PMID- 10634706
TI  - Survival and growth of Pseudomonas aeruginosa in natural mineral water: a 5-year
      study.
AB  - A 5-year study was carried out on the growth curve of two strains of P.
      aeruginosa inoculated at a density of 10(2) cfu/ml into samples of natural
      mineral water with different levels of dissolved solids (TDS at 180 degrees C:
      72.5 and 382 mg/l) and low organic content (TOC: 0.17 and 0.35 mg/l). The
      resulting growth curves were similar for both strains, with only slight
      differences depending on the different amounts of dissolved solids in the water.
      After 4-5 days counts were increased by 3 log units. This level was maintained
      until 70-100 days from inoculation, after which a slow decrease began,
      culminating in the death of one of the strains after 5 years. No difference in
      recovery was observed between the method using direct inoculation on Cetrimide
      Agar and the resuscitation technique (preincubation in Tryptone Soya Agar
      followed by inoculation on Cetrimide Agar) in the exponential phase of the growth
      curve. During the stationary and death phases, however, the enrichment technique
      gave statistically slightly higher counts than the selective technique,
      indicating the presence of damaged P. aeruginosa cells. The use of a
      resuscitation step when using Cetrimide Agar to assess bottled water quality is
      recommended.

PMID- 10634707
TI  - Heterogeneity observed in the components of hemolysin BL, an enterotoxin produced
      by Bacillus cereus.
AB  - Hemolysin BL (HBL), a diarrheal enterotoxin originally isolated from Bacillus
      cereus strain F837/76, is composed of three antigenically distinct proteins
      designated B, L1, and L2. All three components are required for biological
      activity. Here, we report antigenic and physical variations in HBL components
      produced by other B. cereus isolates. Reactions of partial identity were observed
      in double gel immunodiffusion assays using antibodies to highly purified B, L1,
      and L2 components of F837/76 and culture supernatants of strains F837/76 and S1C.
      Western blot analysis showed that F837/76 produced one 38-kDa B protein, one 38
      kDa L1, and one 43-kDa L1 protein. In strain S1C, two B (38 and 42 kDa), two L1
      (38 and 41 kDa), and one L1 (43 kDa) proteins were detected. Further Western blot
      analysis of 127 B. cereus isolates showed that 90 produced one or more of the
      three HBL components. Approximately half of these 90 isolates (43/90; 48%)
      produced protein profiles which differed from that of F837/76. A total of four B,
      two L1, and three L2 component profiles with proteins of different sizes were
      observed. Individual strains produced various combinations of single or multiple
      bands of each component. In addition, some strains produced only one or two of
      the three HBL components. The public health significance of these strains is
      unknown, as all three components are required for biological activity. The data
      presented here demonstrates a high degree of heterogeneity in HBL and provide the
      basis for further studies to characterize the variations in HBL and to determine
      the role of the variant components in pathogenicity.

PMID- 10634708
TI  - Degradation of cyanogenic glycosides by Lactobacillus plantarum strains from
      spontaneous cassava fermentation and other microorganisms.
AB  - Strains of Lactobacillus plantarum, Leuconostoc mesenteroides, Candida tropicalis
      and Penicillium sclerotiorum were screened for 19 enzymatic activities using the
      commercial kit API zym (Bio Merieux). This activity was compared to the ability
      of degrading the toxic cyanogenic glycosides amygdalin, linamarin, and linseed
      cyanogens (a mixture of linustatin and neolinustatin). Good correlation between
      the beta-glucosidase activity found in the API zym screening and the ability to
      degrade the cyanogenic glycosides was found for the first three species
      mentioned. P. sclerotiorum strains exhibited very high activity in the API zym
      test (substrate: 6-Br-2-naphthyl-beta-D-glucopyranoside), but proved unable to
      degrade any of the cyanogenic substrates. Among the seven strains of L. plantarum
      tested, a great variation was seen in the beta-glucosidase activity as well as in
      the ability to degrade the cyanogens. This was also the case for the strains of
      C. tropicalis. However, all the glucosidase positive strains of these species
      were also able to degrade all of the cyanogens tested and at approximately the
      same rate. A co-culture of the most active strain of L. plantarum and C.
      tropicalis seemed to degrade linamarin faster than the mono cultures. L.
      plantarum LPI (originally isolated from fermented cassava) was investigated in
      further detail. The hydrolytic activity of this strain was intracellular or cell
      bound, and beta-bis-glycosides such as amygdalin were hydrolysed by a two-stage
      sequential mechanism as follows: (1) amygdalin to prunasin and (2) prunasin to
      cyanohydrin. Finally, inoculation of extracted linseed meal (containing
      linustatin and neolinustatin) with L. plantarum LPI resulted in hydrolysis of the
      glycosides.

PMID- 10634709
TI  - The effects of the surface charge and hydrophobicity of Escherichia coli on its
      adhesion to beef muscle.
AB  - The surface characteristics of Escherichia coli strains were studied to evaluate
      the effect upon bacterial adhesion to beef muscle. The influence of suspension
      conditions upon the surface charge of a pathogenic strain, E. coli O157:H7
      (EC01), and a saprophytic laboratory strain, E. coli JM109 (EC22) were
      investigated and compared. The cellular surface charge of most E. coli O157:H7
      strains were much less affected by changes in the pH, ionic strength or
      concentration of surfactants in the suspending medium than was the surface charge
      of E. coli JM109 cells. Strong adhesion to beef muscle was found in suspending
      conditions of pH 4 or 10, and with a lowered ionic strength. All E. coli strains
      tested were negatively charged in 150 mM PBS buffer (pH 7.4) as measured by zeta
      potentials, ranging from -4.9 to -33.9 mV. Based on the results of adhesion to
      hexadecane, nine out of 22 strains tested were moderately hydrophobic with about
      50% of the cells bound to the solvent. Cellular adhesion of 16 E. coli strains to
      beef muscle was examined in 150 mM PBS buffer. Generally, O157:H7 strains had
      lower adhesive properties (Sr value less than 0.10) to beef muscle than other
      serotypes (up to 0.39). No correlation was found between E. coli cell surface
      charge, hydrophobicity and adhesion to beef muscle.

PMID- 10634710
TI  - Incidence and control of Listeria monocytogenes in foods in Denmark.
AB  - The Danish regulatory policy on Listeria monocytogenes in foods is based on the
      principles of HACCP and was developed using a health risk assessment approach.
      The Danish policy focuses examinations and criteria for L. monocytogenes in ready
      to-eat foods and is based on a combination of inspection and product-testing.
      Based on current epidemiological information from several countries, a
      concentration of L. monocytogenes not exceeding 100 cfu/g of food at the time of
      consumption, seems to be of low risk to the consumers. In Denmark, ready-to-eat
      foods have been placed into six categories where absence of L. monocytogenes in
      25 g is required in foods heat treated in the final package and in heat-treated
      as well as preserved, non heat-treated foods which can support growth within the
      shelf life. This level is necessary in foods capable of supporting growth, in
      order not to exceed 100 L. monocytogenes per g at the point of consumption. In
      heat-treated and preserved foods, which are not supportive of growth within the
      shelf-life and for raw, ready to eat foods, a level below 10 L. monocytogenes per
      g is regarded acceptable. A level between 10 and 100 L. monocytogenes per g is
      not satisfactory and a level above 100/g is not acceptable. Data on the
      qualitative and quantitative occurrence of L. monocytogenes in foods in Denmark
      are presented and discussed. In 1997 and 1998, greater than 15,000 samples from
      different categories of food were examined (semi-quantitatively) for the presence
      of L. monocytogenes. A significant difference could be seen in the number of
      samples containing more than 100 L. monocytogenes per g, between different
      categories of foods (1997, P = 0.001; 1998, P = 0.016). In 1997, preserved meat
      products and preserved fish products and to a lesser extent vegetables and meat
      or vegetable mayonnaise were more likely to contain high numbers (i.e. above 100
      cfu/g) of L. monocytogenes than other food categories. In 1998, preserved meat
      products, but also heat-treated meat products, vegetables and meat or vegetable
      mayonnaise had the highest frequency of samples with > 100 L. monocytogenes per
      g. In a survey performed in 1994 and 1995, 1.3% of ready-to-eat food samples
      (heat-treated meat products, preserved meat and fish products) were found to be
      contaminated with L. monocytogenes at a level above 100 cfu/g. The samples
      included in this survey were primarily products produced by authorized companies
      and were comprised mainly of vacuum packed products or products packed in
      modified atmosphere and with long shelf lives, typically above several weeks. The
      corresponding percentages of positive samples primarily processed in the retail
      outlets (heat-treated meat products, preserved meat and fish products) in 1997
      and 1998 were 0.3% and 0.6%, respectively. The results suggest that ready-to-eat
      meat and fish products with extended shelf-lives produced by authorized companies
      are more likely to contain high numbers (> 100 cfu/g) of L. monocytogenes than
      products processed in the retail sector which often have a shorter shelf life.

PMID- 10634711
TI  - A good death. An important aim for health services and for us all.

PMID- 10634712
TI  - Sore throats and antibiotics. Applying evidence on small effects is hard;
      variations are probably inevitable.

PMID- 10634713
TI  - Generic prescribing: time to regulate the market? Price rises are a blow to
      nascent primary care groups.

PMID- 10634714
TI  - Gout. Easy to misdiagnose.

PMID- 10634715
TI  - Future directions for geriatric medicine. Geriatricians must move with their
      patients into the community.

PMID- 10634716
TI  - Disseminating good practice in clinical information. New format will harness
      paper and web.

PMID- 10634717
TI  - Leading health maintenance organisation near bankruptcy.

PMID- 10634718
TI  - GP reprimanded for testing patients for HIV without consent.

PMID- 10634719
TI  - Cloned calves are grown from cultured cells

PMID- 10634720
TI  - UK GPs will have to show they are fit to practise

PMID- 10634722
TI  - Procedures on dying patients are wrong, study concludes

PMID- 10634721
TI  - In brief

PMID- 10634723
TI  - Belgium considers legalising euthanasia.

PMID- 10634724
TI  - Doctors and politicians clash over size of flu problem.

PMID- 10634725
TI  - Flu rates in Wales highest for a decade.

PMID- 10634726
TI  - Scotland facing worst flu outbreak for six years.

PMID- 10634728
TI  - Pain relief in US emergency rooms is related to patients' race

PMID- 10634727
TI  - Breast cancer screening may not save lives, study finds

PMID- 10634729
TI  - Psychologists question "debriefing" for traumatised employees.

PMID- 10634730
TI  - Scientists identify gene to prevent atherosclerosis.

PMID- 10634732
TI  - Extent of misclassification of death from Creutzfeldt-Jakob disease in England
      1979-96: retrospective examination of clinical records.
AB  - OBJECTIVE: To investigate the extent to which deaths from Creutzfeldt-Jakob
      disease were misclassified during 1979-96. DESIGN: Structured review of clinical
      records based on predetermined criteria to determine whether death could have
      been due to sporadic or variant Creutzfeldt-Jakob disease. SETTING: 100 health
      authorities and 275 NHS trusts in England. SUBJECTS: 1485 people who died aged 15
      44 years from selected neurological disorders in England during 1979-96. MAIN
      OUTCOME MEASURE: Cause of death. RESULTS: The clinical records of 705 (48%)
      subjects were successfully traced. Tracing of clinical records was highest in
      subjects who died during 1990-6. There was sufficient information in the records
      of 640 (91%) of the 705 subjects to exclude Creutzfeldt-Jakob disease as a cause
      of death. In 61 (9%) subjects, there was insufficient information to reach any
      conclusion about the validity of the cause of death recorded on the death
      certificate. The clinical records of four subjects were examined further by the
      National Creutzfeldt-Jakob Disease Surveillance Unit; none was thought to have
      died from Creutzfeldt-Jakob disease. CONCLUSIONS: No new cases of sporadic or
      variant Creutzfeldt-Jakob disease were detected in a sample of deaths most likely
      to have included misclassified cases. This suggests that the surveillance system
      is unlikely to have missed a significant number of cases among people aged 15-44
      years. Hence, any rapid increase in the number of cases of variant Creutzfeldt
      Jakob disease in this age group is likely to be real not artefactual.

PMID- 10634731
TI  - Risk of subarachnoid haemorrhage in first degree relatives of patients with
      subarachnoid haemorrhage: follow up study based on national registries in
      Denmark.
AB  - OBJECTIVE: To estimate the risk of occurrence of subarachnoid haemorrhage in
      first degree relatives (parents, siblings, children) of patients with
      subarachnoid haemorrhage. DESIGN: Population based cohort study using data from
      the Danish National Discharge Registry and the Central Person Registry. SUBJECTS:
      Incident cases of subarachnoid haemorrhage admitted to hospital from 1977 to 1995
      (9367 patients) and their first degree relatives (14 781). MAIN OUTCOME MEASURES:
      The incidence rate of subarachnoid haemorrhage was determined for the relatives
      and compared with that of the entire population, standardised for age, sex, and
      calendar period. This process was repeated for patients discharged from
      neurosurgery units, as diagnoses from these wards had high validity (93%).
      RESULTS: 18 patients had a total of 19 first degree relatives with subarachnoid
      haemorrhage during the study period, corresponding to a standardised incidence
      ratio of 2.9 (95% confidence interval 1.9 to 4.6). Patients discharged from
      neurosurgery wards had a higher standardised incidence ratio (4.5, 2.7 to 7.3).
      CONCLUSIONS: First degree relatives of patients with subarachnoid haemorrhage
      have a threefold to fivefold increased risk of subarachnoid haemorrhage compared
      with the general population.

PMID- 10634733
TI  - Comparison of new faecal antigen test with (13)C-urea breath test for detecting
      Helicobacter pylori infection and monitoring eradication treatment: prospective
      clinical evaluation.

PMID- 10634734
TI  - Incidence of childhood fractures in affluent and deprived areas: population based
      study.

PMID- 10634735
TI  - Penicillin for acute sore throat: randomised double blind trial of seven days
      versus three days treatment or placebo in adults.
AB  - OBJECTIVE: To assess whether treatment with penicillin for three days and the
      traditional treatment for seven days were equally as effective at accelerating
      resolution of symptoms in patients with sore throat compared with placebo.
      DESIGN: Randomised double blind placebo controlled trial. SETTING: 43 family
      practices in the Netherlands. PARTICIPANTS: 561 patients, aged 15-60 years, with
      sore throat for less than seven days and at least three of the four Centor
      criteria-that is, history of fever, absence of cough, swollen tender anterior
      cervical lymph nodes, and tonsillar exudate. 142 patients were excluded for
      medical reasons and 73 needed penicillin. INTERVENTIONS: Patients were randomly
      assigned to penicillin V for seven days, penicillin V for three days followed by
      placebo for four days, or placebo for seven days. MAIN OUTCOME MEASURES:
      Resolution of symptoms in the first week, eradication of bacteria after two
      weeks, and recurrences of sore throat after two, four, and six months. RESULTS:
      Symptoms resolved 1.9 and 1.7 days earlier in patients taking penicillin for
      seven days than in those taking penicillin for three days or placebo
      respectively. Symptoms resolved 2.5 days earlier in patients with group A
      streptococci and 1.3 days earlier in patients with high colony counts of non
      group A streptococci. 23 (13%) of the placebo group had to be given antibiotics
      later in the week because of clinical deterioration; three developed a
      peritonsillar abscess. The eradication rate for group A streptococci was 72% in
      the seven day penicillin group, 41% in the three day penicillin group, and 7% in
      the placebo group. Sore throat recurred more often in the three day penicillin
      group than in the seven day penicillin or placebo groups. CONCLUSION: Penicillin
      treatment for seven days was superior to treatment for three days or placebo in
      resolving symptoms of sore throat in patients with group A streptococcal
      pharyngitis and, possibly, in those with non-group A streptococcal pharyngitis.

PMID- 10634736
TI  - Randomised controlled trial comparing effectiveness of touch screen system with
      leaflet for providing women with information on prenatal tests.
AB  - OBJECTIVE: To compare the effectiveness of touch screen system with information
      leaflet for providing women with information on prenatal tests. DESIGN:
      Randomised controlled trial; participants allocated to intervention group (given
      access to touch screen and leaflet information) or control group (leaflet
      information only). SETTING: Antenatal clinic in university teaching hospital.
      SUBJECTS: 875 women booking antenatal care. INTERVENTIONS: All participants
      received a leaflet providing information on prenatal tests. Women in the
      intervention arm also had access to touch screen information system in antenatal
      clinic. MAIN OUTCOME MEASURES: Women's informed decision making on prenatal
      testing as measured by their uptake of and understanding of the purpose of
      specific tests; their satisfaction with information provided; and their levels of
      anxiety. RESULTS: All women in the trial had a good baseline knowledge of
      prenatal tests. Women in the intervention group did not show any greater
      understanding of the purpose of the tests than control women. However, uptake of
      detailed anomaly scans was significantly higher in intervention group than the
      control group (94% (351/375) v 87% (310/358), P=0.0014). Levels of anxiety among
      nulliparous women in intervention group declined significantly over time
      (P<0.001). CONCLUSIONS: The touch screen seemed to convey no benefit over well
      prepared leaflets in improving understanding of prenatal tests among the pregnant
      women. It did, however, seem to reduce levels of anxiety and may be most
      effective for providing information to selected women who have a relevant adverse
      history or abnormal results from tests in their current pregnancy.

PMID- 10634737
TI  - Managing information overload: developing an electronic directory.

PMID- 10634739
TI  - Evidence based case report. Asymptomatic haematuria ... in the doctor.

PMID- 10634738
TI  - Uses of botulinum toxin injection in medicine today.

PMID- 10634740
TI  - ABC of heart failure. Pathophysiology.

PMID- 10634741
TI  - New surgical procedures: can we minimise the learning curve?

PMID- 10634742
TI  - Lurigancho prison: Lima's "high school" for criminality.

PMID- 10634743
TI  - Has the sun protection factor had its day?

PMID- 10634745
TI  - Unqualified practice

PMID- 10634744
TI  - Qualitative research in health care. Using qualitative methods in health related
      action research.

PMID- 10634746
TI  - Feeding the fish

PMID- 10634747
TI  - Acute otitis media. Norwegian consensus is that only children with recurrent
      episodes of otitis media need antibiotics.

PMID- 10634748
TI  - Screening for hereditary haemochromatosis should be implemented now.

PMID- 10634749
TI  - Social and productive activities in elderly people. Activities have been
      confused.

PMID- 10634750
TI  - Health promotion activity should be retargeted at secondary prevention.

PMID- 10634751
TI  - Randomised controlled trials in psychiatry. Trials show that psychotherapy is
      effective for wide range of psychological conditions.

PMID- 10634752
TI  - Evaluation of questionnaire on cancer family history in general practice.
      Principal role of primary care is not to seek out those at increased genetic
      risk.

PMID- 10634753
TI  - Magnetic resonance imaging is preferred in diagnosing suspected cerebral
      infections.

PMID- 10634754
TI  - All journals from the BMJ publishing group should be free online.

PMID- 10634755
TI  - Complementary medicine must be research led and evidence based.

PMID- 10634756
TI  - Obituaries

PMID- 10634757
TI  - GPs' questions on supporting doctors, protecting patients

PMID- 10634758
TI  - Curbing the epidemic: governments and the economics of tobacco control

PMID- 10634760
TI  - Evidence-based health care: the open learning resource

PMID- 10634759
TI  - Textbook of prostate cancer: pathology, diagnosis and treatment

PMID- 10634761
TI  - Health and disease among women: biological and environmental influences

PMID- 10634762
TI  - Future medicine

PMID- 10634763
TI  - Death and dying

PMID- 10634764
TI  - Far, far away

PMID- 10634765
TI  - What was it like for you?

PMID- 10634766
TI  - Using evidence on yourself

PMID- 10634767
TI  - Risk of subarachnoid haemorrhage is raised in families of patients with the
      condition

PMID- 10634769
TI  - Faecal antigen test for H pylori may be useful alternative to (13)C urea breath
      test

PMID- 10634768
TI  - Increase in cases of CJD is likely to be real

PMID- 10634770
TI  - Childhood fracture rates are similar in poor and rich areas

PMID- 10634771
TI  - Penicillin for seven days can effectively treat sore throat

PMID- 10634772
TI  - Touch screen system and leaflet equally effective at informing women about
      prenatal tests

PMID- 10634773
TI  - Memory--a century of consolidation.
AB  - The memory consolidation hypothesis proposed 100 years ago by Muller and
      Pilzecker continues to guide memory research. The hypothesis that new memories
      consolidate slowly over time has stimulated studies revealing the hormonal and
      neural influences regulating memory consolidation, as well as molecular and
      cellular mechanisms. This review examines the progress made over the century in
      understanding the time-dependent processes that create our lasting memories.

PMID- 10634774
TI  - Cenozoic deep-Sea temperatures and global ice volumes from Mg/Ca in benthic
      foraminiferal calcite
AB  - A deep-sea temperature record for the past 50 million years has been produced
      from the magnesium/calcium ratio (Mg/Ca) in benthic foraminiferal calcite. The
      record is strikingly similar in form to the corresponding benthic oxygen isotope
      (delta(18)O) record and defines an overall cooling of about 12 degrees C in the
      deep oceans with four main cooling periods. Used in conjunction with the benthic
      delta(18)O record, the magnesium temperature record indicates that the first
      major accumulation of Antarctic ice occurred rapidly in the earliest Oligocene
      (34 million years ago) and was not accompanied by a decrease in deep-sea
      temperatures.

PMID- 10634775
TI  - Organizing principles for a diversity of GABAergic interneurons and synapses in
      the neocortex.
AB  - A puzzling feature of the neocortex is the rich array of inhibitory interneurons.
      Multiple neuron recordings revealed numerous electrophysiological-anatomical
      subclasses of neocortical gamma-aminobutyric acid-ergic (GABAergic) interneurons
      and three types of GABAergic synapses. The type of synapse used by each
      interneuron to influence its neighbors follows three functional organizing
      principles. These principles suggest that inhibitory synapses could shape the
      impact of different interneurons according to their specific spatiotemporal
      patterns of activity and that GABAergic interneuron and synapse diversity may
      enable combinatorial inhibitory effects in the neocortex.

PMID- 10634776
TI  - Rutile-bearing refractory eclogites: missing link between continents and depleted
      mantle
AB  - A mass imbalance exists in Earth for Nb, Ta, and possibly Ti: continental crust
      and depleted mantle both have subchondritic Nb/Ta, Nb/La, and Ti/Zr, which
      requires the existence of an additional reservoir with superchondritic ratios,
      such as refractory eclogite produced by slab melting. Trace element compositions
      of minerals in xenolithic eclogites derived from cratonic lithospheric mantle
      show that rutile dominates the budget of Nb and Ta in the eclogites and imparts a
      superchondritic Nb/Ta, Nb/La, and Ti/Zr to the whole rocks. About 1 to 6 percent
      by weight of eclogite is required to solve the mass imbalance in the silicate
      Earth, and this reservoir must have an Nb concentration >/= 2 parts per million,
      Nb/La >/= 1.2, and Nb/Ta between 19 and 37-values that overlap those of the
      xenolithic eclogites. As the mass of eclogite in the continental lithosphere is
      significantly lower than this, much of this material may reside in the lower
      mantle, perhaps as deep as the core-mantle boundary.

PMID- 10634777
TI  - Influences of dietary uptake and reactive sulfides on metal bioavailability from
      aquatic sediments.
AB  - Understanding how animals are exposed to the large repository of metal pollutants
      in aquatic sediments is complicated and is important in regulatory decisions.
      Experiments with four types of invertebrates showed that feeding behavior and
      dietary uptake control bioaccumulation of cadmium, silver, nickel, and zinc.
      Metal concentrations in animal tissue correlated with metal concentrations
      extracted from sediments, but not with metal in porewater, across a range of
      reactive sulfide concentrations, from 0.5 to 30 micromoles per gram. These
      results contradict the notion that metal bioavailability in sediments is
      controlled by geochemical equilibration of metals between porewater and reactive
      sulfides, a proposed basis for regulatory criteria for metals.

PMID- 10634778
TI  - Reaction of plutonium dioxide with water: formation and properties of PuO(2+x)
AB  - Results show that PuO(2+x), a high-composition (x </= 0.27) phase containing
      Pu(VI), is the stable binary oxide in air. This nonstoichiometric oxide forms by
      reaction of dioxide with water and by water-catalyzed reaction of dioxide with
      oxygen. The PuO(2) + H(2)O reaction rate is 0.27 nanomoles per meter squared per
      hour at 25 degrees C; the activation energy at 25 degrees to 350 degrees C is 39
      kilojoules per mole. Slow kinetics and a low lattice parameter-composition
      dependence for fluorite-related PuO(2+x) are consistent with a failure to observe
      the phase in earlier studies. Perplexing aspects of plutonium oxide chemistry can
      now be explained.

PMID- 10634779
TI  - Communication through a diffusive medium: coherence and capacity
AB  - Coherent wave propagation in disordered media gives rise to many fascinating
      phenomena as diverse as universal conductance fluctuations in mesoscopic metals
      and speckle patterns in light scattering. Here, the theory of electromagnetic
      wave propagation in diffusive media is combined with information theory to show
      how interference affects the information transmission rate between antenna
      arrays. Nontrivial dependencies of the information capacity on the nature of the
      antenna arrays are found, such as the dimensionality of the arrays and their
      direction with respect to the local scattering medium. This approach provides a
      physical picture for understanding the importance of scattering in the transfer
      of information through wireless communications.

PMID- 10634780
TI  - Direct observation of dynamical heterogeneities in colloidal hard-sphere
      suspensions
AB  - The real-space dynamics in a model system of colloidal hard spheres was studied
      by means of time-resolved fluorescence confocal scanning microscopy. Direct
      experimental evidence for the presence of dynamical heterogeneities in a dense
      liquid was obtained from an analysis of particle trajectories in two-dimensional
      slices of the bulk sample. These heterogeneities manifest themselves as a non
      Gaussian probability distribution of particle displacements and also affect the
      onset of long-time diffusive behavior.

PMID- 10634781
TI  - Formation of cyclic water hexamer in liquid helium: the smallest piece of Ice
AB  - The cyclic water hexamer, a higher energy isomer than the cage structure
      previously characterized in the gas phase, was formed in liquid helium droplets
      and studied with infrared spectroscopy. This isomer is formed selectively as a
      result of unique cluster growth processes in liquid helium. The experimental
      results indicate that the cyclic hexamer is formed by insertion of water
      molecules into smaller preformed cyclic complexes and that the rapid quenching
      provided by the liquid helium inhibits its rearrangement to the more stable cage
      structure.

PMID- 10634782
TI  - Distal initiation and active propagation of action potentials in interneuron
      dendrites.
AB  - Fast and reliable activation of inhibitory interneurons is critical for the
      stability of cortical neuronal networks. Active conductances in dendrites may
      facilitate interneuron activation, but direct experimental evidence was
      unavailable. Patch-clamp recordings from dendrites of hippocampal oriens-alveus
      interneurons revealed high densities of voltage-gated sodium and potassium ion
      channels. Simultaneous recordings from dendrites and somata suggested that action
      potential initiation occurs preferentially in the axon with long threshold
      stimuli, but can be shifted to somatodendritic sites when brief stimuli are
      applied. After initiation, action potentials propagate over the somatodendritic
      domain with constant amplitude, high velocity, and reliability, even during high
      frequency trains.

PMID- 10634783
TI  - Regulation of abscisic acid-induced stomatal closure and anion channels by guard
      cell AAPK kinase.
AB  - Abscisic acid (ABA) stimulates stomatal closure and thus supports water
      conservation by plants during drought. Mass spectrometry-generated peptide
      sequence information was used to clone a Vicia faba complementary DNA, AAPK,
      encoding a guard cell-specific ABA-activated serine-threonine protein kinase
      (AAPK). Expression in transformed guard cells of AAPK altered by one amino acid
      (lysine 43 to alanine 43) renders stomata insensitive to ABA-induced closure by
      eliminating ABA activation of plasma membrane anion channels. This information
      should allow cell-specific, targeted biotechnological manipulation of crop water
      status.

PMID- 10634784
TI  - Engineering the provitamin A (beta-carotene) biosynthetic pathway into
      (carotenoid-free) rice endosperm.
AB  - Rice (Oryza sativa), a major staple food, is usually milled to remove the oil
      rich aleurone layer that turns rancid upon storage, especially in tropical areas.
      The remaining edible part of rice grains, the endosperm, lacks several essential
      nutrients, such as provitamin A. Thus, predominant rice consumption promotes
      vitamin A deficiency, a serious public health problem in at least 26 countries,
      including highly populated areas of Asia, Africa, and Latin America. Recombinant
      DNA technology was used to improve its nutritional value in this respect. A
      combination of transgenes enabled biosynthesis of provitamin A in the endosperm.

PMID- 10634785
TI  - Natural selection and parallel speciation in sympatric sticklebacks.
AB  - Natural selection plays a fundamental role in most theories of speciation, but
      empirical evidence from the wild has been lacking. Here the post-Pleistocene
      radiation of threespine sticklebacks was used to infer natural selection in the
      origin of species. Populations of sticklebacks that evolved under different
      ecological conditions show strong reproductive isolation, whereas populations
      that evolved independently under similar ecological conditions lack isolation.
      Speciation has proceeded in this adaptive radiation in a repeatable fashion,
      ultimately as a consequence of adaptation to alternative environments.

PMID- 10634786
TI  - Rapid evolution of a geographic cline in size in an introduced fly.
AB  - The introduction and rapid spread of Drosophila subobscura in the New World two
      decades ago provide an opportunity to determine the predictability and rate of
      evolution of a geographic cline. In ancestral Old World populations, wing length
      increases clinally with latitude. In North American populations, no wing length
      cline was detected one decade after the introduction. After two decades, however,
      a cline has evolved and largely converged on the ancestral cline. The rate of
      morphological evolution on a continental scale is very fast, relative even to
      rates measured within local populations. Nevertheless, different wing sections
      dominate the New versus Old World clines. Thus, the evolution of geographic
      variation in wing length has been predictable, but the means by which the cline
      is achieved is contingent.

PMID- 10634787
TI  - Crystal structure of a gammadelta T cell receptor ligand T22: a truncated MHC
      like fold.
AB  - Murine T10 and T22 are highly related nonclassical major histocompatibility
      complex (MHC) class Ib proteins that bind to certain gammadelta T cell receptors
      (TCRs) in the absence of other components. The crystal structure of T22b at 3.1
      angstroms reveals similarities to MHC class I molecules, but one side of the
      normal peptide-binding groove is severely truncated, which allows direct access
      to the beta-sheet floor. Potential gammadelta TCR-binding sites can be inferred
      from functional mapping of T10 and T22 point mutants and allelic variants. Thus,
      T22 represents an unusual variant of the MHC-like fold and indicates that
      gammadelta and alphabeta TCRs interact differently with their respective MHC
      ligands.

PMID- 10634788
TI  - A population of murine gammadelta T cells that recognize an inducible MHC class
      Ib molecule.
AB  - Although gammadelta T cells are implicated in regulating immune responses,
      gammadelta T cell-ligand pairs that could mediate such regulatory functions have
      not been identified. Here, the expression of the major histocompatibility complex
      (MHC) class Ib T22 and the closely related T10 molecules is shown to be
      activation-induced, and they confer specificity to about 0.4% of the gammadelta T
      cells in normal mice. Thus, the increased expression of T22 and/or T10 might
      trigger immunoregulatory gammadelta T cells during immune responses. Furthermore,
      the fast on-rates and slow off-rates that characterize this receptor/ligand
      interaction would compensate for the low ligand stability and suggest a high
      threshold for gammadelta T cell activation.

PMID- 10634789
TI  - Clonal propagation of primate offspring by embryo splitting.
AB  - Primates that are identical in both nuclear and cytoplasmic components have not
      been produced by current cloning strategies, yet such identicals represent the
      ideal model for investigations of human diseases. Here, genetically identical
      nonhuman embryos were produced as twin and larger sets by separation and
      reaggregation of blastomeres of cleavage-stage embryos. A total of 368 multiples
      were created by the splitting of 107 rhesus embryos with four pregnancies
      established after 13 embryo transfers (31% versus 53% in vitro fertilization
      controls). The birth of Tetra, a healthy female cloned from a quarter of an
      embryo, proves that this approach can result in live offspring.

PMID- 10634790
TI  - Severely reduced female fertility in CD9-deficient mice.
AB  - CD9 is a widely expressed cell surface molecule that belongs to the tetraspanin
      superfamily of proteins. The tetraspanins CD9, KAI-1/CD82, and CD63 are involved
      in metastasis suppression, an effect that may be related to their association
      with beta1 integrins. Knockout mice lacking CD9 were created to evaluate the
      physiological importance of CD9. CD9-/- females displayed a severe reduction of
      fertility. Oocytes were ovulated but were not successfully fertilized because
      sperm did not fuse with the oocytes from CD9-/- females. Thus, CD9 appears to be
      essential for sperm-egg fusion, a process involving the CD9-associated integrin
      alpha6beta1.

PMID- 10634791
TI  - Requirement of CD9 on the egg plasma membrane for fertilization.
AB  - CD9 is an integral membrane protein associated with integrins and other membrane
      proteins. Mice lacking CD9 were produced by homologous recombination. Both male
      and female CD9-/- mice were born healthy and grew normally. However, the litter
      size from CD9-/- females was less than 2% of that of the wild type. In vitro
      fertilization experiments indicated that the cause of this infertility was due to
      the failure of sperm-egg fusion. When sperm were injected into oocytes with
      assisted microfertilization techniques, however, the fertilized eggs developed to
      term. These results indicate that CD9 has a crucial role in sperm-egg fusion.

PMID- 10634793
TI  - A progress report

PMID- 10634792
TI  - Regulation of JNK by Src during Drosophila development.
AB  - In Drosophila, the Jun amino-terminal kinase (JNK) homolog Basket (Bsk) is
      required for epidermal closure. Mutants for Src42A, a Drosophila c-src
      protooncogene homolog, are described. Src42A functions in epidermal closure
      during both embryogenesis and metamorphosis. The severity of the epidermal
      closure defect in the Src42A mutant depended on the amount of Bsk activity, and
      the amount of Bsk activity depended on the amount of Src42A. Thus, activation of
      the Bsk pathway is required downstream of Src42A in epidermal closure. This work
      confirms mammalian studies that demonstrated a physiological link between Src and
      JNK.

PMID- 10634794
TI  - Sol Sherry Lecture in Thrombosis : research on clot stabilization provides clues
      for improving thrombolytic therapies.

PMID- 10634795
TI  - Oligoclonal T cell expansions in atherosclerotic lesions of apolipoprotein E
      deficient mice.
AB  - T cells are present in atherosclerotic lesions at all stages of development. They
      exhibit activation markers and are particularly prominent at sites of plaque
      rupture. This suggests that T-cell-mediated immune responses are involved in the
      pathogenesis of atherosclerosis. Antigen-specific T cells reactive with oxidized
      lipoproteins and heat shock proteins have been isolated from plaques, indicating
      that local activation and clonal expansion might occur. To analyze different
      stages of atherosclerosis, we have used a murine model. Targeted deletion of the
      apolipoprotein E gene results in severe hypercholesterolemia and spontaneous
      atherosclerosis, with lesions containing large numbers of T cells and
      macrophages. We have analyzed mRNA for T-cell antigen receptors (TCRs) from
      aortic fatty streaks, early fibrofatty plaques, and advanced fibrofatty plaques
      of such mice. Polymerase chain reaction amplification of complementarity
      determining region 3 (CDR3 region) of TCRs was followed by spectratyping of
      fragment lengths. This analysis detected all types of variable (V) segments with
      a gaussian distribution of CDR3 in lymph nodes. In contrast, a restricted
      heterogeneity was found in atherosclerotic lesions, with expansion of a limited
      set of Vbeta and Valpha segments and a monotypic or oligotypic CDR3 spectrum in
      each lesion. Vbeta6 was expressed in all lesions; Vbeta5.2, Vbeta16, Valpha34s,
      and Valpha9, in the majority of lesions; and Vbeta6, Vbeta5.2, and Valpha34S, in
      lesions at all 3 stages of development. The strongly skewed pattern of the CDR3
      region in the TCR is indicative of oligoclonal expansions of T cells and suggests
      the occurrence of antigen-driven T-cell proliferation in atherosclerosis.

PMID- 10634796
TI  - Hyperexpression and activation of extracellular signal-regulated kinases (ERK1/2)
      in atherosclerotic lesions of cholesterol-fed rabbits.
AB  - A hallmark of hyperlipidemia-induced atherosclerosis is altered gene expression
      that initiates cell proliferation and (de)differentiation in the intima of the
      arterial wall. The molecular signaling that mediates this process in vivo has yet
      to be identified. Extracellular signal-regulated kinases (ERKs) are thought to
      play a pivotal role in transmitting transmembrane signals required for cell
      proliferation in vitro. The present studies were designed to investigate the
      activity, abundance, and localization of ERK1/2 in atherosclerotic lesions of
      cholesterol-fed rabbits. Immunofluorescence analysis revealed abundant and
      heterogeneous distribution of ERK1/2, mainly localized in the cap and basal
      regions of atheromas. A population of ERK-enriched cells was identified as alpha
      actin-positive smooth muscle cells (SMCs). ERK1 and 2 were heavily phosphorylated
      on tyrosyl residues and coexpressed with proliferating cell nuclear antigen in
      atherosclerotic lesions. ERK1/2 protein levels in protein extracts from
      atherosclerotic lesions were 2- to 3-fold higher than the vessels of chow-fed
      rabbits, and their activities were elevated 3- to 5-fold over those of the normal
      vessel. SMCs derived from atherosclerotic lesions had increased
      migratory/proliferative ability and higher ERK activity in response to LDL
      stimulation compared with cells from the normal vessel. Inhibition of ERK
      activation by PD98059, a specific inhibitor of mitogen-activated protein kinase
      kinases (MEK1/2), abrogated LDL-induced SMC proliferation in vitro. Taken
      together, our findings support the proposition that persistent activation and
      hyperexpression of ERK1/2 may be a critical element to initiate and perpetuate
      cell proliferation during the development of atherosclerosis.

PMID- 10634797
TI  - Nitric oxide-induced increase in p21(Sdi1/Cip1/Waf1) expression during the cell
      cycle in aortic adventitial fibroblasts.
AB  - This study was performed to investigate whether the expression of
      p21(Sdi1/Cip1/Waf1), one of the cyclin-dependent kinase inhibitor proteins, could
      be regulated by nitric oxide (NO) and might account for the antiproliferative
      effect of NO. Quiescent adventitial fibroblasts were stimulated to proliferate by
      serum addition and by NO donors added during different phases of the cell cycle.
      [(3)H]Thymidine incorporation was markedly reduced by S-nitroso-N-acetyl
      penicillamine (SNAP) added either with serum at quiescence or at later time point
      in the cell cycle. Northern and Western blot analyses showed that addition of
      SNAP either at quiescence or 15 hours after serum addition induced a rapid
      induction of p21 mRNA and protein. Immunoprecipitation studies and
      electrophoretic mobility shift analysis indicate that the treatment of cells with
      SNAP induced the phosphorylation of p53 (a tumor suppressor protein) and enhanced
      the ability of p53 to bind DNA when SNAP was added during the cell cycle. The
      increased expression of p21 mRNA or p53 activation during late G(1) or S phase
      was also caused by addition of 8-bromo-cGMP and effectively blocked by a specific
      inhibitor of the soluble guanylate cyclase. Furthermore, this response to SNAP
      was blocked by an inhibitor of protein kinase G. These studies implicate NO as a
      potential regulator of the cell cycle in aortic adventitial fibroblasts through a
      cGMP-mediated transcriptional mechanism involving the induction of p21.

PMID- 10634798
TI  - Shear-induced increase in hydraulic conductivity in endothelial cells is mediated
      by a nitric oxide-dependent mechanism.
AB  - This study addresses the role of nitric oxide (NO) and its downstream mechanism
      in mediating the shear-induced increase in hydraulic conductivity (L(p)) of
      bovine aortic endothelial cell monolayers grown on porous polycarbonate filters.
      Direct exposure of endothelial monolayers to 20-dyne/cm(2) shear stress induced a
      4. 70+/-0.20-fold increase in L(p) at the end of 3 hours. Shear stress (20
      dyne/cm(2)) also elicited a multiphasic NO production pattern in which a rapid
      initial production was followed by a less rapid, sustained production. In the
      absence of shear stress, an exogenous NO donor, S-nitroso-N-acetylpenicillamine,
      increased endothelial L(p) 2.23+/-0.14-fold (100 micromol/L) and 4.8+/-0.66-fold
      (500 micromol/L) at the end of 3 hours. In separate experiments, bovine aortic
      endothelial cells exposed to NO synthase inhibitors, N(G)-monomethyl-L-arginine
      and N(G)-nitro-L-arginine methyl ester, exhibited significant attenuation of
      shear-induced increase in L(p) in a dose-dependent manner. Inhibition of
      guanylate cyclase (GC) with LY-83,583 (1 micromol/L) or protein kinase G (PKG)
      with KT5823 (1 micromol/L) failed to attenuate the shear-induced increase in
      L(p). Furthermore, direct addition of a stable cGMP analogue, 8-bromo-cGMP, had
      no effect in altering baseline L(p), indicating that the GC/cGMP/PKG pathway is
      not involved in shear stress-NO-L(p) response. Incubation with iodoacetate (IAA),
      a putative inhibitor of glycolysis, dose-dependently increased L(p). Addition of
      IAA at levels that did not affect baseline L(p) greatly potentiated the response
      of L(p) to 20-dyne/cm(2) shear stress. Finally, both shear stress-induced and IAA
      induced increases in L(p) could be reversed with the addition of dibutyryl cAMP.
      However, additional metabolic inhibitors, 2 deoxyglucose (10 mmol/L) and
      oligomycin (1 micromol/L), or reactive oxygen species scavengers, deferoxamine (1
      mmol/L) and ascorbate (10 mmol/L), failed to alter shear-induced increases in
      L(p). Our results show that neither the NO/cGMP/PKG pathway nor a metabolic
      pathway mediates the shear stress-L(p) response. An alternate mechanism
      downstream from NO that is sensitive to IAA must mediate this response.

PMID- 10634799
TI  - Differential expression of rat frizzled-related frzb-1 and frizzled receptor fz1
      and fz2 genes in the rat aorta after balloon injury.
AB  - Frzb-1 is a secreted protein, presenting similarity with the Wnt-binding domain
      of the frizzled family of receptors, which acts as an antagonist of Wnt
      signaling. Using mRNA differential display in the rat aorta balloon injury model,
      we identified overexpression of Frzb-1 mRNA and determined its cDNA sequence. By
      quantitative reverse transcription-polymerase chain reaction and RNase protection
      assay, a biphasic upregulation of rFrzb-1 expression was observed, with
      significant peaks of a 1.7-fold increase at 4 days and a 1. 5-fold increase at 3
      weeks after aortic injury in vivo. In contrast, expression of the rat frizzled
      receptor genes rfz1 and rfz2 were transiently downregulated at 1 and 4 hours
      after balloon injury. rFrzb-1 was expressed predominantly in rat aortic smooth
      muscle cells (RASMCs) and barely in aortic fibroblasts and endothelial cells
      (RAECs), whereas rfz1 and rfz2 were expressed in all of these cells when
      stimulated with serum. Transient downregulation of rfz1 and rfz2 expression was
      reproduced by stimulation of quiescent RASMCs with serum, platelet-derived growth
      factor-BB, or fibroblast growth factor-2. In contrast, rFrzb-1 expression
      diminished slowly, to reach a 2-fold decrease 24 hours after growth factor
      stimulation, implying that quiescent RASMCs expressed higher levels of rFrzb-1
      mRNA than did proliferative ones. Overexpression of rFrzb-1 in the aorta seemed
      to coincide with the arrest of RASMC proliferation occurring in the media 4 days
      and in the neointima 3 weeks after balloon injury. Our results demonstrate that
      rfrzb-1, rfz1, and rfz2 are differentially regulated in response to arterial
      injury and that this modulation seems to follow the proliferative state of
      RASMCs, suggesting that these Wnt-signaling components may be involved in intimal
      vascular disease.

PMID- 10634800
TI  - Retrovirus-mediated, stable scavenger-receptor gene transfer leads to functional
      endocytotic receptor expression, foam cell formation, and increased
      susceptibility to apoptosis in rabbit aortic smooth muscle cells.
AB  - The type II, class A macrophage scavenger receptor (SR-A) plays an important role
      in the pathogenesis of atherosclerosis and foam cell formation. However, its role
      in nonmacrophage cell lines remains unknown. To test the hypothesis that SR-A
      activity leads to proatherogenic changes in nonmacrophage cell lines, we
      generated Moloney murine leukemia virus- and vesicular stomatitis virus G protein
      pseudotyped retroviruses containing SR-A type II cDNA, which were used for stable
      transfection of SR-A activity into mouse fibroblasts and rabbit aortic smooth
      muscle cells (SMCs). beta-Galactosidase-transfected cell lines were used as
      controls. Transfected cell lines expressed functional SR-A mRNA and protein.
      Expression of SR-A activity was stable for at least 9 months. By electron
      microscopy, transfected receptors were located in coated pits and in
      intracellular structures resembling endocytotic vesicles. Expression of SR-A on
      the cell surface was verified by flow cytometry and by uptake and degradation of
      (125)I-labeled acetylated low density lipoprotein (LDL). Increases of 5- to 25
      fold and of 6- to 8-fold in the rate of acetylated LDL degradation were observed
      in transfected fibroblasts and SMCs, respectively, compared with beta
      galactosidase-transfected control cell lines. Incubation of the transfected SMCs
      and fibroblasts with acetylated or oxidized LDL led to foam cell formation.
      Incubation with oxidized LDL also led to increased apoptosis and cell death. An
      altered morphology with increased cell size and granularity was observed in the
      most active SR-A SMC clones. It is concluded that stable overexpression of SR-A
      leads to foam cell formation and other proatherogenic changes in nonmacrophage
      cell lines. Stable SMC and fibroblast cell lines can be used as models for foam
      cell formation. The results also suggest that increased SR activity may play an
      important role in SMC-related pathology in atherosclerotic arteries.

PMID- 10634801
TI  - Improvement of nitric oxide-dependent vasodilatation by HMG-CoA reductase
      inhibitors through attenuation of endothelial superoxide anion formation.
AB  - Three 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors
      (HCRIs), atorvastatin, pravastatin, and cerivastatin, inhibited phorbol ester
      stimulated superoxide anion (O(2)(-)) formation in endothelium-intact segments of
      the rat aorta in a time- and concentration-dependent manner (maximum inhibition
      of 70% after 18 hours at 1 to 10 micromol/L). The HMG-CoA reductase product
      mevalonic acid (400 micromol/L) reversed the inhibitory effect of the HCRIs,
      which, conversely, was mimicked by inactivation of p21 Rac with Clostridium
      sordellii lethal toxin but not by inactivation of p21 Rho with Clostridium
      botulinum exoenzyme (C3). A mevalonate-sensitive inhibition of phorbol ester
      stimulated O(2)(-) formation by atorvastatin was also observed in porcine
      cultured endothelial cells and in a murine macrophage cell line. In the rat
      aorta, no effect of the HCRIs on protein kinase C, NADPH oxidase, or superoxide
      dismutase (SOD) activity and expression was detected, whereas that of endothelial
      nitric oxide (NO) synthase was enhanced approximately 2-fold. Moreover, exposure
      of the segments to atorvastatin resulted in a significant improvement of
      endothelium-dependent NO-mediated relaxation, and this effect was abolished in
      the presence of SOD. Taken together, these findings suggest that in addition to
      augmenting endothelial NO synthesis, HCRIs inhibit endothelial O(2)(-) formation
      by preventing the isoprenylation of p21 Rac, which is critical for the assembly
      of NADPH oxidase after activation of protein kinase C. The resulting shift in the
      balance between NO and O(2)(-) in the endothelium improves endothelial function
      even in healthy blood vessels and therefore may provide a reasonable explanation
      for the beneficial effects of HCRIs in patients with coronary heart disease in
      addition to or as an alternative to the reduction in serum LDL cholesterol.

PMID- 10634802
TI  - The ACAT inhibitor avasimibe reduces macrophages and matrix metalloproteinase
      expression in atherosclerotic lesions of hypercholesterolemic rabbits.
AB  - Given the significance of cholesteryl ester (CE) accumulation in macrophage foam
      cell formation, we hypothesized that inhibitors of acyl-CoA:cholesterol O
      acyltransferase (ACAT) would produce a histologically stable lesion by limiting
      macrophage enrichment and thereby a source of matrix metalloproteinases (MMPs).
      Male New Zealand White rabbits were sequentially fed a cholesterol/fat diet for 9
      weeks, a fat-only diet for 6 weeks, and 25 mg/kg avasimibe for 7 to 8 weeks.
      Avasimibe had no effect on plasma total cholesterol exposure. Plasma avasimibe
      maximal concentration and 24-hour area-under-the-curve levels were 178 ng/mL and
      2525 ng. h/mL, respectively, after 7 weeks of treatment with 25 mg/kg avasimibe.
      The median inhibitory concentration against human monocyte-macrophage ACAT was 12
      ng/mL when determined in the absence of albumin, and aortic arch avasimibe levels
      were 25 ng/g of tissue wet weight. Avasimibe reduced thoracic aortic and iliac
      femoral CE content by 39%, the extent of thoracic aortic lesions by 41%, aortic
      arch cross-sectional lesions area by 35%, and monocyte-macrophage area by 27%.
      The reduction in monocyte-macrophage area reflected a change in cell number and
      not cell size. In the iliac-femoral artery, avasimibe decreased monocyte
      macrophage content by 77% and reduced the macrophage-to-lesion ratio from 0.16 to
      0.05. Within the aortic arch, the catalytic activity of latent and active MMP-9
      was reduced by 65% and 33%, respectively; latent and active MMP-1 and MMP-3
      activity measured collectively was decreased by 52% and 60%, respectively, and
      MMP-2 was unchanged. Aortic arch MMP-9, tissue inhibitor of matrix
      metalloproteinase (TIMP)-1, and TIMP-2 mRNA levels were reduced 29% to 39%, and
      MMP-2 mRNA levels increased. We conclude that the bioavailable ACAT inhibitor
      avasimibe can directly limit macrophage accumulation, resulting in the
      histological appearance of mainly fibromuscular lesions, and can potentially
      stabilize preestablished atherosclerotic lesions by reducing MMP expression
      within the lesion.

PMID- 10634804
TI  - All-trans-retinoic acid limits restenosis after balloon angioplasty in the
      focally atherosclerotic rabbit : a favorable effect on vessel remodeling.
AB  - All-trans-retinoic acid (atRA) has potent in vitro effects on a number of
      processes involved in vascular injury and repair, such as modulating smooth
      muscle cell (SMC) proliferation and inducing SMC differentiation, and may play an
      important role in the in vivo response to vascular injury. We hypothesized that
      atRA would limit restenosis after balloon angioplasty through SMC-modulated
      changes in plaque size and vessel geometry. Balloon angioplasty was performed on
      rabbits with focal femoral atherosclerosis randomized to treatment with atRA or
      saline. At 28 days after balloon angioplasty, minimal luminal diameter was
      significantly larger in the atRA group (1.24+/-0.17 versus 1.12+/-0.22 mm,
      P=0.02). Histomorphometry confirmed a larger lumen area (0.51+/-0.20 versus 0.
      34+/-0.13 mm(2), P=0.004) in the atRA group, with no difference in absolute
      plaque area. Internal elastic lamina and external elastic lamina areas were
      significantly larger in the atRA group (0.89+/-0. 27 versus 0.66+/-0.24 mm(2),
      P=0.001, and 1.29+/-0.38 versus 0. 98+/-0.32 mm(2), P=0.001, respectively).
      Vessel sections exhibited significantly more alpha-actin and desmin
      immunostaining (P=0.01) in the atRA-treated group. No differences in early
      cellular proliferation and collagen content were detected with the use of
      bromodeoxyuridine. In this atherosclerotic model of vascular injury, atRA limits
      restenosis after balloon angioplasty by effects secondary to overall vessel
      segment enlargement at the angioplasty site rather than by effects on plaque size
      or cellular proliferation. Increased alpha-actin and desmin immunostaining
      suggest a possible role for phenotypic modulation of SMCs in this favorable
      remodeling effect.

PMID- 10634803
TI  - Platelet-activating factor enhances vascular endothelial growth factor-induced
      endothelial cell motility and neoangiogenesis in a murine matrigel model.
AB  - We previously reported that platelet-activating factor (PAF) enhances the
      angiogenic activity of certain polypeptide mediators such as tumor necrosis
      factor and hepatocyte growth factor by promoting endothelial cell motility. The
      purpose of the present study was to evaluate whether the synthesis of PAF induced
      by vascular endothelial growth factor (VEGF) might affect endothelial cell
      motility, microvascular permeability, and angiogenesis. The neoangiogenesis and
      synthesis of PAF induced by VEGF were studied in vivo in a murine Matrigel model.
      Dermal permeability was studied in mice by injection of (125)I-albumin. The
      synthesis of PAF, cell motility, and the increased (125)I-albumin transfer across
      endothelial monolayers were studied in vitro by using cultures of human umbilical
      cord vein-derived endothelial cells (HUVECs). The results obtained demonstrate
      that the neoangiogenesis induced by VEGF in vivo was associated with a local
      synthesis of PAF and was inhibited by WEB2170 and CV3988, 2 chemically unrelated,
      specific PAF-receptor antagonists. In contrast, WEB2170 did not inhibit VEGF
      enhanced dermal permeability, suggesting that the latter was independent of the
      synthesis of PAF. In vitro, it was found that VEGF induced the synthesis of PAF
      by HUVECs in a dose- and time-dependent manner. The cell motility induced by VEGF
      was inhibited by PAF-receptor antagonists. In contrast, VEGF-induced
      proliferation of HUVECs and albumin transfer through HUVEC monolayer were
      unaffected by PAF-receptor antagonists. These results suggest that the synthesis
      of PAF induced by VEGF enhances endothelial cell migration and contributes to the
      angiogenic effect of VEGF in the in vivo Matrigel model.

PMID- 10634805
TI  - Pressure-induced upregulation of preproendothelin-1 and endothelin B receptor
      expression in rabbit jugular vein in situ : implications for vein graft failure?
AB  - Upregulation of endothelin-1 (ET-1) synthesis in venous bypass grafts in response
      to arterial levels of blood pressure may play a major role in graft failure. To
      investigate this hypothesis, isolated segments of the rabbit jugular vein were
      perfused at physiological (0 to 5 mm Hg) and nonphysiological (20 mm Hg) levels
      of intraluminal pressure. As judged by reverse transcription-polymerase chain
      reaction analysis (mRNA level), neither endothelin-converting enzyme nor
      endothelin A receptor expression appeared to be pressure sensitive. In contrast,
      there was a profound and time-dependent increase in endothelial prepro-ET-1 mRNA
      and intravascular ET-1 abundance (by ELISA) as well as in smooth muscle
      endothelin B receptor mRNA and functional protein (by superfusion bioassay) on
      raising the perfusion pressure from 5 to 20 mm Hg, but not from 0 to 5 mm Hg, for
      up to 12 hours. Video microscopy analysis revealed that the segments were
      distended by 75% at 5 mm Hg and near maximally at 20 mm Hg compared with the
      resting diameter at 0 to 1 mm Hg. Treatment of the segments with actinomycin D (1
      micromol/L), the specific protein kinase C inhibitor, Ro 31-8220 (0.1
      micromol/L), or the c-Src family-specific tyrosine kinase inhibitor, herbimycin A
      (0.1 micromol/L), demonstrated that the pressure-induced expression of these gene
      products occurs at the level of transcription and requires activation of protein
      kinase C, but not c-Src. In venous bypass grafts such deformation-induced changes
      in gene expression may contribute not only to acute graft failure through ET-1
      induced vasospasm but also to endothelin A receptor- and/or endothelin B receptor
      mediated smooth muscle cell hyperplasia and graft occlusion.

PMID- 10634806
TI  - Differential regulation of macrophage peroxisome proliferator-activated receptor
      expression by glucose : role of peroxisome proliferator-activated receptors in
      lipoprotein lipase gene expression.
AB  - Peroxisome proliferator-activated receptors (PPARs) are implicated in several
      metabolic disorders with altered glucose and lipid metabolism, including
      atherosclerosis and diabetes. In the present study, we evaluated the in vitro and
      ex vivo effects of high glucose concentrations on macrophage PPAR mRNA
      expression. Exposition of monocyte-derived macrophages isolated from healthy
      donors to a high glucose environment led to an increase in PPARalpha and PPARbeta
      mRNA expression. In contrast, this treatment significantly decreased human
      macrophage PPARgamma mRNA expression. Overexpression of PPARalpha and PPARbeta
      mRNA and inhibition of PPARgamma mRNA expression were also observed in monocyte
      derived macrophages isolated from patients with type 2 diabetes. Because high
      glucose and PPARalpha agonists increase lipoprotein lipase (LPL) gene expression,
      the role of PPARalpha in the glucose-mediated upregulation of macrophage LPL gene
      expression was next evaluated. Incubation of murine J774 macrophages with high
      glucose concentrations increased the expression of PPARalpha at the mRNA and
      protein levels and enhanced nuclear protein binding to the peroxisome
      proliferator responsive element of the LPL promoter. Incubation of nuclear
      extracts in the presence of anti-PPARalpha and anti-PPARbeta antibodies decreased
      glucose-stimulated nuclear protein binding to the peroxisome proliferator
      responsive element. These results demonstrate that glucose is an important
      regulator of macrophage PPAR expression and suggest a role of PPARalpha and
      PPARbeta in the upregulation of macrophage LPL by glucose. Dysregulation of
      macrophage PPAR expression in type 2 diabetes may contribute, by altering
      arterial lipid metabolism and inflammatory response, to the accelerated
      atherosclerosis associated with diabetes.

PMID- 10634807
TI  - The heparin-binding proteins apolipoprotein E and lipoprotein lipase enhance
      cellular proteoglycan production.
AB  - Apolipoprotein E (apoE) and lipoprotein lipase (LPL), key proteins in the
      regulation of lipoprotein metabolism, bind with high affinity to heparin and cell
      surface heparan sulfate proteoglycan (HSPG). In the present study, we tested
      whether the expression of apoE or LPL would modulate proteoglycan (PG) metabolism
      in cells. Two apoE-expressing cells, macrophages and fibroblasts, and LPL
      expressing Chinese hamster ovary (CHO) cells were used to study the effect of
      apoE and LPL on PG production. Cellular PGs were metabolically labeled with
      (35)[S]sulfate for 20 hours, and medium, pericellular PGs, and intracellular PGs
      were assessed. In all transfected cells, PG levels in the 3 pools increased 1.6-
      to 3-fold when compared with control cells. Initial PG production was assessed
      from the time of addition of radiolabeled sulfate; at 1 hour, there was no
      difference in PG synthesis by apoE-expressing cells when compared with control
      cells. After 1 hour, apoE-expressing cells had significantly greater production
      of PGs. Total production assessed with [(3)H]glucosamine was also increased. This
      was due to an increase in the length of the glycosaminoglycan chains. To assess
      whether the increase in PGs was due to a decrease in PG degradation, a pulse
      chase experiment was performed. Loss of sulfate-labeled pericellular PGs was
      similar in apoE and control cells, but more labeled PGs appeared in the medium of
      the apoE-expressing cells. Addition of exogenous apoE and anti-human apoE
      antibody to both non-apoE-expressing and apoE-expressing cells did not alter PG
      production. Moreover, LPL addition did not alter cell-surface PG metabolism.
      These results show that enhanced gene expression of apoE and LPL increases
      cellular PG production. We postulate that such changes in vascular PGs can affect
      the atherogenic potential of arteries.

PMID- 10634808
TI  - Effect of macrophage-derived mouse ApoE, human ApoE3-Leiden, and human ApoE2
      (Arg158-->Cys) on cholesterol levels and atherosclerosis in ApoE-deficient mice.
AB  - The effect of monocyte/macrophage-derived wild-type mouse apolipoprotein E
      (apoE), human apoE3-Leiden, and human apoE2 on serum cholesterol levels and the
      development of atherosclerosis in apoE-deficient (apoe-/-) mice was investigated
      by using bone marrow transplantation (BMT). At 4 weeks after BMT, murine apoe+/+
      bone marrow reduced serum cholesterol levels by 87% in apoe-/- mice, whereas
      macrophage-derived human apoE3-Leiden and human apoE2 induced a maximal,
      transient reduction of 35% and 48%, respectively. At 4 months after BMT,
      atherosclerosis was 23-fold (P<0.001) reduced in apoe+/+-->apoe-/- mice, whereas
      no significant reduction in apoE3-Leiden.apoe-/--->apoe-/- and apoE2.apoe-/--
      >apoe-/- mice could be demonstrated. A highly significant decrease in serum
      cholesterol levels (78% reduction) and atherosclerosis (21-fold, P<0. 001) was
      found in apoE3-Leiden.apoe-/- animals expressing high levels of apoE in multiple
      tissues, whereas apoE2 was ineffective even at high concentrations. Furthermore,
      in contrast to apoE-deficient macrophages, cholesterol efflux from apoE2 or apoE3
      Leiden macrophages was not impaired. In conclusion, apoE3-Leiden as well as apoE2
      are less effective in reducing cholesterol levels and atherosclerosis in apoe-/-
      animals, compared with apoe+/+, with apoE2<apoE3-Leiden<apoe+/+, irrespective of
      the observed adequate efflux of cholesterol from macrophages expressing apoE2 and
      apoE3-Leiden, indicating that normalization of cholesterol efflux by macrophages
      is not accompanied by measurable effects on lesion growth.

PMID- 10634809
TI  - Induction of ubiquitin-conjugating enzyme by aggregated low density lipoprotein
      in human macrophages and its implications for atherosclerosis.
AB  - Recently, we have found that aggregated low density lipoprotein (agLDL) inhibits
      apoptosis of lipid-bearing macrophages, thereby facilitating foam cell formation
      and atherosclerosis. To clarify the mechanisms by which agLDL inhibits apoptosis
      of macrophages, we isolated the genes specifically induced by agLDL by using a
      subtraction-based cloning strategy. One of the cloned genes, termed low density
      lipoprotein (LDL)-inducible gene (LIG), encodes a human homologue of bovine
      ubiquitin-conjugating enzyme E2-25K. Although LIG mRNA was ubiquitously expressed
      among human tissues, including hematopoietic cells, the abundance of transcripts
      was markedly increased by agLDL treatment in activated monocytes. LIG mRNA
      expression was not enhanced by nonatherogenic lipoproteins such as native LDL and
      high density lipoprotein, suggesting a role in atherosclerosis.
      Polyubiquitination of intracellular proteins was observed in monocytes cultured
      with agLDL, which coincided with upregulation of LIG. Furthermore, ubiquitin
      dependent degradation of p53, an inducer of apoptosis, was accompanied by LIG
      induction in agLDL-treated monocytes. The antiapoptotic effect of agLDL was
      abrogated by a specific proteasome inhibitor, which also increased the half-life
      of p53 in monocytes. These results suggest that LIG contributes to foam cell
      formation by the suppression of apoptosis of lipid-bearing macrophages through
      ubiquitination and subsequent degradation of p53.

PMID- 10634810
TI  - Stimulation of phospholipase D activity by oxidized LDL in mouse peritoneal
      macrophages.
AB  - Oxidation of LDL is an important factor in the development of atherosclerosis.
      However, the mechanisms by which oxidized LDL exerts its atherogenic actions are
      poorly understood. In the present work, we show that oxidized LDL stimulates
      phospholipase D (PLD) activity in mouse peritoneal macrophages and that this
      effect increases with the degree of LDL oxidation. Oxidative modification of LDL
      results in the production of lipid peroxides and the conversion of
      phosphatidylcholine to lysophosphatidylcholine. Although we found that
      lysophosphatidylcholine alone activates PLD, the stimulation of this enzyme
      activity by oxidized LDL is independent of lysophosphatidylcholine formation.
      Also, 7-ketocholesterol, the major oxysterol in oxidized LDL, failed to stimulate
      PLD activity. To determine the mechanism(s) whereby oxidized LDL activates PLD,
      the possible involvements of protein kinase C and tyrosine phosphorylation were
      investigated. Pretreatment of macrophages with the protein kinase C inhibitor Ro
      32-0432 or downregulation of protein kinase C activity by prolonged incubation
      with 100 nmol/L 4beta-phorbol 12-myristate 13-acetate did not alter the
      stimulatory effect of oxidized LDL on PLD activation. However, oxidized LDL
      stimulated tyrosine phosphorylation of several macrophage proteins, and
      preincubation of the macrophages with genistein, a tyrosine kinase inhibitor,
      blocked the activation of PLD by oxidized LDL. In addition, pretreatment with
      orthovanadate, which inhibits tyrosine phosphatases, enhanced basal and oxidized
      LDL-stimulated PLD activity. Pretreatment of macrophages with pertussis toxin
      decreased the stimulatory effect of oxidized LDL, indicating that GTP-binding
      proteins may also be involved in the activation of PLD by oxidized LDL. We also
      found that the platelet-activating factor receptor antagonists WEB 2086 and L
      659,989 inhibit the oxidized LDL stimulation of PLD, suggesting a role for
      platelet-activating factor receptor in this process. The stimulation of the PLD
      pathway by oxidized LDL may be of importance in atherogenesis, because PLD
      activation leads to generation of important second messengers such as
      phosphatidate, lysophosphatidate, and diacylglycerol, which are known to regulate
      many cellular functions.

PMID- 10634811
TI  - Oxidized VLDL induces less triglyceride accumulation in J774 macrophages than
      native VLDL due to an impaired extracellular lipolysis.
AB  - The present study examined the relative contributions of the different pathways
      by which oxidatively modified VLDL (oxVLDL) promotes the uptake and intracellular
      accumulation of lipids in J774 macrophages. VLDL was oxidized for a maximum of 4
      hours, resulting in an increase in thiobarbituric acid-reactive substances and an
      increased electrophoretic mobility on agarose gel. The lipid composition of the
      relatively moderately oxidized VLDL samples did not differ significantly from
      that of nonoxidized VLDL samples. The uptake of (125)I-labeled VLDL by the J774
      cells increased with oxidation time and was completely blocked on coincubation
      with polyinosinic acid (PolyI), indicating that oxVLDL is taken up by the cells
      via the scavenger receptor only. Despite the 2-fold increased uptake of oxVLDL
      protein, the cell association of triglyceride (TG)-derived fatty acids by the
      J774 macrophages after incubation with oxVLDL was only 50% of that with native
      VLDL. In line with these observations, the induction of de novo synthesis of TG
      by J774 cells was approximately 3-fold less efficient after incubation with
      oxVLDL than after incubation with native VLDL. The induction of de novo synthesis
      of TG with oxVLDL was even further decreased on simultaneous incubation with
      PolyI, whereas PolyI did not affect the native VLDL-induced TG synthesis. These
      results indicate that oxVLDL induces endogenous TG synthesis predominantly
      through particle uptake via the scavenger receptor and much less via the
      extracellular lipoprotein lipase (LPL)-mediated hydrolysis of TG, as is the case
      for native VLDL. In line with these observations, we showed that the suitability
      of VLDL as a substrate for LPL decreases with oxidation time. Addition of oxVLDL
      to the LPL assay did not interfere with the lipolysis of native VLDL. However,
      enrichment of the oxidized lipoprotein particle with native apoC2 was able to
      fully restore the impaired lipolysis. Thus, from these studies it can be
      concluded that on oxidation, VLDL becomes less efficient in inducing TG
      accumulation in J774 cells as a consequence of a defect in apoC2 as an activator
      for the LPL-mediated extracellular lipolysis.

PMID- 10634812
TI  - Fish oil supplementation prevents neointima formation in nonhypercholesterolemic
      balloon-injured rabbit carotid artery by reducing medial and adventitial cell
      activation.
AB  - We asked whether balloon-injured neointima formation in the presence of high/low
      serum cholesterol (CT) levels might be affected by dietary supplementation with
      fish oil (FO). To test this hypothesis, we examined the differentiation,
      proliferation, or apoptosis profile of smooth muscle cell (SMC) and adventitial
      cell response to a mild injury induced via a Fogarty catheter in the carotid
      artery of adult rabbits that had been fed a standard chow or 0.5% CT-enriched
      diet starting 4 weeks before the lesion. One week before surgery, animals
      received FO supplementation. This regimen was continued for the following 3
      weeks. The effect of FO on the early proliferative/migratory response of carotid
      SMCs was also examined in 2- and 7-day-injured normocholesterolemic rabbits. As
      controls, animals subjected to 3-week endothelial injury and animals kept on a 7
      week CT diet were used. Carotid cryosections from the various animal groups were
      evaluated for morphometry (image analysis), differentiation (immunofluorescence
      with monoclonal antibodies specific for smooth muscle markers, ie, myosin
      isoforms, SM22, and fibronectin), proliferation (bromodeoxyuridine
      incorporation), and apoptosis (terminal deoxynucleotidyl transferase-mediated
      dUTP nick end-labeling). FO treatment significantly reduced the development of
      intimal thickening in normocholesterolemic rabbits but had no efficacy in the
      presence of relatively higher serum CT levels. At day 2 (adventitia) and day 7
      (neointima, media, and adventitia), the proliferation index of SMCs in FO-treated
      injured rabbits was markedly lower than in untreated injured controls.
      Concomitantly with the antiproliferative effect, FO was able to decrease the size
      of 2 cell types involved in the cell growth response to endothelial injury,
      namely, the "fetal-type" medial SMC subpopulation and the fibroblast-derived
      adventitial myofibroblasts. Thus, in our experimental conditions, a low CT level
      is a permissive condition for FO to prevent neointima formation to a considerable
      extent. This event is attributable to the early postinjury effect of FO on
      SMC/adventitial cell proliferation/differentiation patterns.

PMID- 10634813
TI  - Impaired free fatty acid suppression during hyperinsulinemia is a characteristic
      finding in familial combined hyperlipidemia, but insulin resistance is observed
      only in hypertriglyceridemic patients.
AB  - Insulin resistance has been associated with hypertriglyceridemia, combined
      hyperlipidemia, and familial combined hyperlipidemia (FCHL). Whether all FCHL
      patients with different types of dyslipidemia have low insulin sensitivity has
      not been evaluated. We measured insulin sensitivity by the hyperinsulinemic
      euglycemic clamp with indirect calorimetry in 110 healthy controls and in 105
      nondiabetic, FCHL family members: in 50 without dyslipidemia, in 19 with
      hypercholesterolemia (total cholesterol >/=7.7 mmol/L), in 22 with
      hypertriglyceridemia (total triglycerides >/=2.4 mmol/L in men 2.4 mmol/L in
      women), and in 14 with combined hyperlipidemia. During the hyperinsulinemic
      clamp, FCHL family members had higher free fatty acid levels than did controls
      (0.06+/-0.06 [mean+/-SD] in controls versus 0.16+/-0.11 in relatives without
      dyslipidemia versus 0.15+/-0. 07 in hypercholesterolemic patients versus 0.29+/
      0.14 in hypertriglyceridemic patients versus 0.27+/-0.17 mmol/L in patients with
      combined hyperlipidemia; P<0.001 after adjustment for age, sex, and body mass
      index). Relatives without dyslipidemia (16.4+/-4.4 micromol. kg(-1). min(-1),
      P=0.001) and patients with hypertriglyceridemia (12.8+/-3.8 micromol. kg(-1).
      min(-1), P<0.001) and with combined hyperlipidemia (13.7+/-3.1 micromol. kg(-1).
      min(-1), P<0.001) had lower rates of insulin-stimulated glucose oxidation than
      did controls (19.4+/-4.7 micromol. kg(-1). min(-1)). Also, the rates of
      nonoxidative glucose disposal were lower in patients with hypertriglyceridemia
      (P=0.001) and combined hyperlipidemia (P=0.011) than in controls. In contrast,
      subjects with hypercholesterolemia and control subjects had similar rates of
      insulin-stimulated glucose uptake. We conclude that a defect in free fatty acid
      suppression during hyperinsulinemia, probably located in adipose tissue, is
      characteristic for all FCHL patients with varying types of dyslipidemia, whereas
      insulin resistance in skeletal muscle is observed only in FCHL patients with
      elevated triglyceride levels.

PMID- 10634814
TI  - Postprandial hyperlipidemia in streptozotocin-induced diabetic rats is due to
      abnormal increase in intestinal acyl coenzyme A:cholesterol acyltransferase
      activity.
AB  - Postprandial hyperlipidemia (PH) is recognized as a significant risk factor for
      cardiovascular disease. The present study, involving rats with streptozotocin
      (STZ)-induced diabetes, was performed to establish a PH model and to examine the
      relation between small intestinal acyl-coenzyme A:cholesterol acyltransferase
      (ACAT) activity and serum lipid levels in the postprandial state. The small
      intestinal ACAT activities in normal rats during the experimental period were 4
      to 5 pmol/mg protein per minute. In contrast, in the diabetic rats, the ACAT
      activities were 2 to 3 times higher than activities seen in normal rats from 7 to
      21 days after the STZ injection in the absence of a high fat diet and hyperplasia
      in the gut. In an oral fat-loading test that used diabetic rats that had been
      injected with STZ (60 mg/kg) intravenously 14 days previously, the postloading
      changes in the serum concentrations of total cholesterol (TC) and triglyceride
      (TG) were significantly greater in the diabetic rats than in normal rats. Single
      oral administration of (1s,2s)-2-[3-(2,2-dimethylpropyl)-3
      nonylureido]cyclohexane- 1-yl 3-[(4R)-N-(2,2,5,5-tetramethyl-1, 3-dioxane-4
      carbonyl)amino]propionate (F-1394, 3 to 30 mg/kg), a potent ACAT inhibitor,
      suppressed the post-fat-loading elevation of serum TC levels in the diabetic rats
      in a dose-dependent manner without affecting serum glucose levels. Furthermore,
      the small intestinal ACAT activity, serum TG levels, and lymphatic absorption of
      TC and TG in the rats that were administered F-1394 (30 mg/kg) were reduced by
      approximately 90%, 70%, 30%, and 15%, respectively. This is the first evidence
      that elevated ACAT activity in the gut, unlike hyperplasia and hyperphagia,
      induces PH in rats. Our results strongly suggest that F-1394 may be a potential
      treatment for PH in humans.

PMID- 10634815
TI  - Clearance of cationized LDL cholesterol from a muscle depot is not enhanced in
      human apolipoprotein A-IV transgenic mice.
AB  - Human apolipoprotein A-IV (apoA-IV) transgenic mice fed an atherogenic diet were
      shown previously to develop less atherosclerosis than control mice. The question
      arose whether the antiatherogenic effect of human apoA-IV is due to enhancement
      of reverse cholesterol transport despite no increase in plasma high-density
      lipoprotein (HDL) cholesterol. We studied male and female mice overexpressing
      human apoA-IV and their wild-type (WT) controls, all of which were fed a chow
      diet. Plasma total and HDL cholesterol and total phospholipids were not increased
      in the transgenic mice, and regression analysis showed no correlation between
      plasma levels of cholesterol or phospholipids and plasma human apoA-IV. To study
      reverse cholesterol transport in vivo, the disappearance of cholesterol from a
      depot of [(3)H]cholesterol-labeled cationized low-density lipoprotein injected
      into the rectus femoris muscle was compared in high expressers of human apoA-IV
      and WT controls. The loss of radioactivity and the diminution of the exogenous
      cholesterol mass were determined on days 8 and 12 after injection. No enhanced
      loss of radioactivity or cholesterol mass was seen in the transgenic mice even at
      levels of 2500 mg/dL of human apoA-IV. In some instances, there was even slower
      loss of exogenous cholesterol (radioactivity and mass) in the transgenic mice.
      Although [(3)H]cholesterol efflux from cultured human skin fibroblasts and mouse
      peritoneal macrophages was only approximately 30% higher in the presence of sera
      from high expressers of human apoA-IV, addition of phosphatidylcholine liposomes
      enhanced the efflux in both groups to the same extent. Another paradoxical
      finding was that the cholesterol esterification rate in plasma was 34% to 36%
      lower in human apoA-IV mice than in WT controls. In conclusion, even though apoA
      IV was found previously to be atheroprotective under hypercholesterolemic
      conditions, high plasma levels of human apoA-IV did not enhance cholesterol
      mobilization in vivo in normocholesterolemic mice.

PMID- 10634816
TI  - Influence of folic acid on postprandial endothelial dysfunction.
AB  - Triglyceride-rich lipoproteins that circulate postprandially are increasingly
      being recognized as potentially atherogenic. These particles also have been shown
      to cause endothelial dysfunction. We recently demonstrated that acute parenteral
      administration of folic acid restores endothelial function in vivo in patients
      with increased LDL cholesterol levels. In vitro data suggested that this effect
      could be mediated by a reduction of radical stress. In the present study,
      therefore, we evaluated the effect of an acute oral fat load on both endothelial
      function and oxygen radical production. Next, we studied whether 2 weeks of
      pretreatment with 10 mg folic acid PO could prevent these fat-induced changes. We
      conducted a prospective, randomized, placebo-controlled study to evaluate the
      effect of oral folic acid administration (10 mg/d for 2 weeks) on basal
      endothelial function as well as endothelial function on an acute fat load in 20
      healthy volunteers 18 to 33 years old. Endothelial function was assessed as flow
      mediated dilatation (FMD). Endothelium-independent dilatation was measured after
      sublingual nitroglycerin spray. Oxygen radical stress was assessed by measurement
      of the urinary excretion of the stable radical-damage end product
      malondialdehyde. During administration of placebo, FMD decreased significantly
      after an acute oral fat load, with a median from 10.6% (8.3% to 12.2%) to 5.8%
      (3.0% to 10.2%), P<0.05. During folic acid administration, FMD was unaffected by
      a fat load, with a median from 9.6% (7.1% to 12.8%) to 9.9% (7.5% to 14.1%),
      P=NS. The increase in malondialdehyde excretion in the urine after fat loading
      was also prevented during folic acid administration (absolute increase after an
      acute fat load during placebo, 0.11+/-0.1 micromol/L versus folic acid, 0.02+/
      0.1 micromol/L, P<0.05). The response to the endothelium-independent vasodilator
      nitroglycerin remained unaltered throughout the study. Pretreatment with oral
      folic acid prevents the lipid-induced decrease in FMD as well as the lipid
      induced increase in urinary radical-damage end products. Because these
      observations were made in healthy volunteers with normal folate and homocysteine
      levels, it is suggested that a higher folate intake in the general population may
      have vasculoprotective effects.

PMID- 10634817
TI  - Action of atorvastatin in combined hyperlipidemia : preferential reduction of
      cholesteryl ester transfer from HDL to VLDL1 particles.
AB  - Combined hyperlipidemia (CHL) is characterized by a concomitant elevation of
      plasma levels of triglyceride-rich, very low density lipoproteins (VLDLs) and
      cholesterol-rich, low density lipoproteins (LDLs). The predominance of small,
      dense LDLs contributes significantly to the premature development of coronary
      artery disease in patients with this atherogenic dyslipoproteinemia. In the
      present study, we evaluated the impact of atorvastatin, a newly developed
      inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase, on the
      cholesteryl ester transfer protein (CETP)-mediated remodeling of apolipoprotein
      (apo) B-containing lipoprotein subspecies, and more specifically, the particle
      subpopulations of VLDL and LDL in CHL. In parallel, we evaluated the atorvastatin
      induced modulation of the quantitative and qualitative features of atherogenic
      apo B-containing and cardioprotective apo AI-containing lipoprotein subspecies.
      Atorvastatin therapy (10 mg/d for a 6-week period) in patients with a lipid
      phenotype typical of CHL (n=18) induced reductions of 31% (P<0.0001) and 36%
      (P<0.0001) in plasma total cholesterol and LDL cholesterol, respectively. In
      addition, atorvastatin significantly reduced VLDL cholesterol, triglycerides, and
      apo B levels by 43% (P<0.0001), 27% (P=0.0006), and 31% (P<0.0001), respectively.
      The plasma concentrations of triglyceride-rich lipoproteins (VLDL1, Sf 60 to 400;
      VLDL2, Sf 20 to 60; and intermediate density lipoproteins, Sf 12 to 20) and of
      LDL, as determined by chemical analysis, were markedly diminished after drug
      therapy (-30% and -28%, respectively; P<0.0007). Atorvastatin significantly
      reduced circulating levels of all major LDL subspecies, ie, light (-28%,
      P<0.0008), intermediate (-27%, P<0.0008), and dense (-32%, P<0.0008) LDL;
      moreover, in terms of absolute lipoprotein mass, the reduction in dense LDL
      levels (mean -62 mg/dL) was preponderant. In addition, the reduction in plasma
      dense LDL concentration after therapy was significantly correlated with a
      reduction in plasma VLDL1 levels (r=0.429, P=0.0218). Atorvastatin induced a
      significant reduction (-7%, P=0.0039) in total CETP-dependent CET activity, which
      accurately reflects a reduction in plasma CETP mass concentration. Total CETP
      mediated CET from high density lipoproteins to apo B-containing lipoproteins was
      significantly reduced (-26%, P<0.0001) with drug therapy. Furthermore, CETP
      activity was significantly correlated with the atorvastatin-induced reduction in
      plasma VLDL1 levels (r=0.456, P=0. 0138). Indeed, atorvastatin significantly and
      preferentially decreased CET from HDL to the VLDL1 subfraction (-37%, P=0.0064),
      thereby reducing both the levels (-37%, P=0.0001) and the CE content (-20%,
      P<0.005) of VLDL1. We interpret our data to indicate that 2 independent but
      complementary mechanisms may be operative in the atorvastatin-induced reduction
      of atherogenic LDL levels in CHL: first, a significant degree of normalization of
      both the circulating levels and the quality of their key precursors, ie, VLDL1,
      and second, enhanced catabolism of the major LDL particle subclasses (ie, light,
      intermediate, and dense LDL) due to upregulation of hepatic LDL receptors.

PMID- 10634818
TI  - C-reactive protein in offspring is associated with the occurrence of myocardial
      infarction in first-degree relatives.
AB  - The relevance of elevated levels of C-reactive protein (CRP) in cardiovascular
      disease is gaining increasing recognition. A family history of coronary artery
      disease is a major determinant of coronary artery disease in the offspring. In a
      cohort of 1048 individuals without clinical evidence of atherosclerosis, we
      investigated the relationships between CRP levels and a family history of
      myocardial infarction. We measured CRP, fibrinogen, plasminogen activator
      inhibitor-1, total cholesterol, triglycerides, and some genetic polymorphisms:
      plasminogen activator inhibitor-1 (4G/5G), fibrinogen (Bbeta-chain G-->A(-455)),
      and angiotensin-converting enzyme insertion/deletion (I/D). Clinical data were
      collected by a World Health Organization-modified questionnaire for
      cardiovascular disease. When compared with subjects without first-degree
      relatives who had suffered a myocardial infarction (n=867), subjects with such
      first-degree relatives (n=181) were older (P=0.001), more often hypertensive
      (P<0. 001), and homozygous for the 4G allele (4G/4G) of the plasminogen activator
      inhibitor-1 gene (P=0.003). In addition, they had a higher body mass index
      (P=0.036), raised plasma fibrinogen (P<0.007) and total cholesterol (P<0.001)
      concentrations, and CRP levels >0.33 mg/L (P=0.005). In a multiple logistic
      regression analysis, age (odds ratio [OR] 1.03, 95% confidence interval [95% CI]
      1.01 to 1. 05), total cholesterol (OR 1.35, 95% CI 1.11 to 1.65), plasminogen
      activator inhibitor-1 4G/4G (OR 1.72, 95% CI 1.20 to 2.45), and CRP levels >0.33
      mg/L (OR 1.75, 95% CI 1.05 to 2.91) were all independently associated with a
      positive family history of myocardial infarction. We therefore conclude that
      raised levels of CRP independently identify the offspring of patients with a
      myocardial infarction.

PMID- 10634819
TI  - Autoantibodies against oxidized low-density lipoprotein and cardiolipin in
      patients with coronary heart disease.
AB  - Autoantibodies against oxidized low density lipoprotein (oxLDL) have been
      proposed to be independent predictors of atherosclerotic vascular disease.
      Because the levels of autoantibodies against oxLDL and cardiolipin might be
      modified by the presentation and severity of coronary heart disease (CHD), we
      measured their levels in patients with different manifestations of CHD (n=415,
      mean age 61 years, range 33 to 74 years) in a subset of the European Action on
      Secondary Prevention through Intervention to Reduce Events (EUROASPIRE) study.
      There were 109 patients with coronary artery bypass surgery, 106 patients with
      balloon angioplasty, 101 patients with acute myocardial infarction, and 99
      patients with acute myocardial ischemia. Autoantibodies were measured by ELISA.
      Food records and fatty acid profiles of serum cholesteryl esters were used to
      evaluate dietary intake. Anti-oxLDL antibodies were significantly higher in the
      group with acute myocardial infarction than in other groups in men (coronary
      artery bypass surgery 1.91+/-1. 41, balloon angioplasty 2.11+/-2.19, acute
      myocardial infarction 2. 52+/-2.05, and acute myocardial ischemia 1.96+/-1.78;
      P=0.022, mean+/-SD) but not in women. The titers of anti-cardiolipin antibodies
      did not differ among the patient groups. Neither of the autoantibodies was
      associated with recurrent coronary events. Anti-oxLDL and anti-cardiolipin
      autoantibodies were not correlated with serum total cholesterol, high density
      lipoprotein cholesterol, or triglycerides, except that in women anti-oxLDL
      antibodies and triglycerides were positively correlated (r=0.225, P=0.011). In
      men, anti-cardiolipin antibodies were higher in the lowest quartiles of dietary
      intakes of vitamin E and polyunsaturated fat. Dietary intakes of vitamin E and
      polyunsaturated fat were correlated (r=0. 588, P<0.001). In conclusion,
      autoantibodies against oxLDL were associated with myocardial infarction in men.
      Anti-cardiolipin autoantibodies were inversely correlated with dietary intakes of
      vitamin E and polyunsaturated fat in men with CHD.

PMID- 10634820
TI  - A single amino acid deletion in the carboxy terminal of apolipoprotein A-I
      impairs lipid binding and cellular interaction.
AB  - The carboxy-terminal region of apolipoprotein (apo) A-I has been shown by
      mutagenesis or synthetic peptides to play an important role in lipid binding.
      However, the precise functional domain of the C-terminal remains to be defined.
      In this study, apoA-I Nichinan, a naturally occurring human apoA-I variant with a
      deletion of glutamic acid 235, was expressed in Escherichia coli to examine the
      effect of this mutation on the functional domain of apoA-I for lipid binding and
      related consequences. A dimyristoyl phosphatidylcholine binding study with
      recombinant (r-) proapoA-I Nichinan showed a significantly slow initial rate of
      lipid binding. On preincubation with human plasma lipoprotein fractions (d<1.225
      g/mL) at 37 degrees C for 1 hour, (125)I-labeled normal r-proapoA-I was
      chromatographed as a single peak at the high density lipoprotein (HDL) fraction,
      whereas (125)I-labeled r-proapoA-I Nichinan was chromatographed into the HDL
      fraction as well as the free r-proapoA-I fraction (23% of radioactivity).
      Circular dichroism measurements showed that the alpha-helix content of lipid
      bound r-proapoA-I Nichinan was reduced, being 62% (versus 73%) of normal r
      proapoA-I. Nondenaturing gradient gel electrophoresis of reconstituted HDL
      particles assembled with r-proapoA-I Nichinan and normal r-proapoA-I showed
      similar particle size. To study cholesterol efflux, human skin fibroblasts were
      labeled with [(3)H]cholesterol, followed by incubation with either lipid-free r
      proapoA-I or DMPC/r-proapoA-I complex. Fractional cholesterol efflux from
      [(3)H]cholesterol-labeled fibroblasts to lipid-free r-proapoA-I Nichinan or
      DMPC/r-proapoA-I Nichinan complexes was significantly reduced relative to that of
      normal r-proapoA-I or DMPC/r-proapoA-I during the 6-hour incubation. Binding
      assays of human skin fibroblasts by lipid-free r-proapoA-I showed that r-proapoA
      I Nichinan was 32% less bound to fibroblasts than was normal r-proapoA-I. Our
      data demonstrate that the deletion of glutamic acid 235 at the C-terminus
      substantially reduces the lipid-binding properties of r-proapoA-I Nichinan, which
      may cause a reduction in its capacity to interact with plasma membranes as well
      as to promote cholesterol efflux from cultured fibroblasts.

PMID- 10634821
TI  - The private hepatocyte nuclear factor-1alpha G319S variant is associated with
      plasma lipoprotein variation in Canadian Oji-Cree.
AB  - We previously showed an extremely strong association between type 2 diabetes and
      a private polymorphism, namely G319S, in the hepatocyte nuclear transcription
      factor (HNF)-1alpha. Because HNF-1alpha is involved in the transcription of
      several apolipoprotein genes, we tested for an association between the private
      HNF1A G319S variant and plasma lipoproteins in a sample of 55 unrelated Oji-Cree
      subjects with type 2 diabetes and 175 unrelated Oji-Cree subjects without type 2
      diabetes. In Oji-Cree subjects with type 2 diabetes, we found that the HNF1A
      G319S genotype was significantly associated with lower plasma concentrations of
      total cholesterol, low density lipoprotein cholesterol, and apolipoprotein (apo)
      B. In Oji-Cree subjects without type 2 diabetes, we found that the HNF1A G319S
      genotype was significantly associated with higher plasma concentrations of high
      density lipoprotein cholesterol and apo AI. There were no associations with
      plasma triglycerides or lipoprotein(a). Regression analysis indicated that the
      HNF1A genotype accounted for approximately 10% of the variation in the apo B
      related traits in the diabetic subjects and for approximately 5% of the variation
      in the apo AI-related traits in the nondiabetic subjects. Furthermore, the
      regression model indicated that the HNF1A S319 allele affected these traits in a
      dominant manner in subjects with and without type 2 diabetes. These findings
      provide the first evidence that a rare variant in a nuclear transcription factor
      is associated with variation in plasma lipoprotein traits.

PMID- 10634822
TI  - Identification of quantitative trait loci for serum cholesterol levels in stroke
      prone spontaneously hypertensive rats.
AB  - The stroke-prone spontaneously hypertensive rat (SHRSP) has been reported to show
      significantly lower levels of serum total cholesterol than the normotensive
      control strain Wistar-Kyoto rat (WKY). Because selective inbreeding was conducted
      for stroke proneness, this concomitantly inherited characteristic of SHRSP may
      play some pathophysiological role in stroke. We evaluated the genetic
      determinants of the cholesterol trait by estimating heritability and subsequently
      by undertaking a genome-wide screen with 161 genetic markers in F(2) progeny
      involving SHRSP and WKY (104 male and 106 female rats). Three quantitative trait
      loci (QTLs) were detected on rat chromosomes 5, 7, and 15. Markers from the
      linked region on chromosome 15 indicated significant evidence of linkage with a
      maximal log of the odds (LOD) score of 7.7, whereas those on chromosomes 5 and 7
      cosegregated with the trait in a sex-specific manner (the QTL close to genetic
      marker D5 Mit5 reached an LOD score of 7.3 in males, and that close to D7 Mit10
      reached an LOD score of 3.2 in females). The male-specific QTL on chromosome 5
      appeared to overlap with previously reported QTLs for stroke-associated
      phenotypes, but an identical gene (or genes) appeared unlikely to control these
      and the cholesterol traits simultaneously. In the present study, serum
      cholesterol levels were shown to be highly genetically determined in SHRSP (the
      heritability estimates are 76% in males and 83% in females), and 3 QTLs with
      substantial effects were identified. Further work, however, is required to
      clarify whether the cholesterol trait is related to the etiology of stroke or has
      been retained by chance through the inbreeding process in SHRSP.

PMID- 10634823
TI  - Controlled trial of alpha-tocopherol and beta-carotene supplements on stroke
      incidence and mortality in male smokers.
AB  - Observational data suggest that diets rich in fruits and vegetables and with high
      serum levels of antioxidants are associated with decreased incidence and
      mortality of stroke. We studied the effects of alpha-tocopherol and beta-carotene
      supplementation. The incidence and mortality of stroke were examined in 28 519
      male cigarette smokers aged 50 to 69 years without history of stroke who
      participated in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC
      Study). The daily supplementation was 50 mg alpha-tocopherol, 20 mg beta
      carotene, both, or placebo. The median follow-up was 6.0 years. A total of 1057
      men suffered from incident stroke: 85 men had subarachnoid hemorrhage; 112,
      intracerebral hemorrhage; 807, cerebral infarction; and 53, unspecified stroke.
      Deaths due to stroke within 3 months numbered 38, 50, 65, and 7, respectively
      (total 160). alpha-Tocopherol supplementation increased the risk of subarachnoid
      hemorrhage 50% (95% CI -3% to 132%, P=0.07) but decreased that of cerebral
      infarction 14% (95% CI -25% to -1%, P=0.03), whereas beta-carotene
      supplementation increased the risk of intracerebral hemorrhage 62% (95% CI 10% to
      136%, P=0.01). alpha-Tocopherol supplementation also increased the risk of fatal
      subarachnoid hemorrhage 181% (95% CI 37% to 479%, P=0.01). The overall net
      effects of either supplementation on the incidence and mortality from total
      stroke were nonsignificant. alpha-Tocopherol supplementation increases the risk
      of fatal hemorrhagic strokes but prevents cerebral infarction. The effects may be
      due to the antiplatelet actions of alpha-tocopherol. beta-Carotene
      supplementation increases the risk of intracerebral hemorrhage, but no obvious
      mechanism is available.

PMID- 10634824
TI  - Influence of beta(0)-thalassemia on the phenotypic expression of heterozygous
      familial hypercholesterolemia : a study of patients with familial
      hypercholesterolemia from Sardinia.
AB  - One of the genetic features of the Sardinian population is the high prevalence of
      hemoglobin disorders. It has been estimated that 13% to 33% of Sardinians carry a
      mutant allele of the alpha-globin gene (alpha-thalassemia trait) and that 6% to
      17% are beta-thalassemia carriers. In this population, a single mutation of beta
      globin gene (Q39X, beta(0) 39) accounts for >95% of beta-thalassemia cases.
      Because previous studies have shown that Sardinian beta-thalassemia carriers have
      lower total and low density lipoprotein (LDL) cholesterol than noncarriers, we
      wondered whether this LDL-lowering effect of the beta-thalassemia trait was also
      present in subjects with familial hypercholesterolemia (FH). In a group of 63
      Sardinian patients with the clinical diagnosis of FH, we identified 21 unrelated
      probands carrying 7 different mutations of the LDL receptor gene, 2 already known
      (313+1 g>a and C95R) and 5 not previously reported (D118N, C255W, A378T, T413R,
      and Fs572). The 313+1 g>a and Fs572 mutations were found in several families. In
      cluster Fs572, the plasma LDL cholesterol level was 5.76+/-1.08 mmol/L in
      subjects with beta(0)-thalassemia trait and 8.25+/-1.66 mmol/L in subjects
      without this trait (P<0.001). This LDL-lowering effect was confirmed in an FH
      heterozygote of the same cluster who had beta(0)-thalassemia major and whose LDL
      cholesterol level was below the 50th percentile of the distribution in the normal
      Sardinian population. The hypocholesterolemic effect of beta(0)-thalassemia trait
      emerged also when we pooled the data from all FH subjects with and without
      beta(0)-thalassemia trait, regardless of the type of mutation in the LDL receptor
      gene. The LDL-lowering effect of beta(0)-thalassemia may be related to (1) the
      mild erythroid hyperplasia, which would increase the LDL removal by the bone
      marrow, and (2) the chronic activation of the monocyte-macrophage system, causing
      an increased secretion of some cytokines (interleukin-1, interleukin-6, and tumor
      necrosis factor-alpha) known to affect the hepatic secretion and the receptor
      mediated removal of apolipoprotein B-containing lipoproteins. The observation
      that our FH subjects with beta(0)-thalassemia trait (compared with noncarriers)
      have an increase of blood reticulocytes (40%) and plasma levels of interleukin-6
      (+60%) supports these hypotheses. The lifelong LDL-lowering effect of beta(0)
      thalassemia trait might slow the development and progression of coronary
      atherosclerosis in FH.

PMID- 10634825
TI  - Lysophosphatidylcholine induces urokinase-type plasminogen activator and its
      receptor in human macrophages partly through redox-sensitive pathway.
AB  - Urokinase-type plasminogen activator (uPA) and its cell surface receptor (uPAR)
      have been shown to be expressed in macrophages in atherosclerotic arterial walls,
      but the regulatory mechanisms of their expression remain unclear. The present
      study was performed to examine the effects of lysophosphatidylcholine (lysoPC),
      an important atherogenic lipid, on the expression of uPA and uPAR in human
      monocyte-derived macrophages. LysoPC upregulated the mRNA expression of uPA and
      uPAR, and it increased the protein expression of uPA in the culture medium and
      bound to the cell surface and of uPAR in the particulate fraction of the cells.
      LysoPC significantly increased the binding of the amino-terminal fragment of uPA
      to the treated cells and the cell-associated plasminogen activator activity.
      LysoPC stimulated superoxide anion production and increased intracellular oxidant
      levels in the cells. The combined incubation with reduced glutathione diethyl
      ester or N-acetylcysteine, antioxidants, suppressed the upregulation of uPA and
      uPAR mRNA and the increase in plasminogen activator activity by lysoPC. uPA and
      uPAR mRNA expression was also induced by the incubation with xanthine and
      xanthine oxidase, a superoxide anion-generating system. The results suggest that
      lysoPC increased the expression of uPA and uPAR and their functional activities
      in human monocyte-derived macrophages, at least in part through a redox-sensitive
      mechanism. This coordinate increase in the expression of uPA and uPAR in human
      macrophages by lysoPC could play an important role in plaque formation and
      disruption, arterial remodeling, and angiogenesis in atherosclerotic arterial
      walls.

PMID- 10634826
TI  - Intravascular free tissue factor pathway inhibitor is inversely correlated with
      HDL cholesterol and postheparin lipoprotein lipase but proportional to
      apolipoprotein A-II.
AB  - To elucidate the distribution and clinical implications of tissue factor pathway
      inhibitor (TFPI) concentrations, we measured TFPI levels consisting of preheparin
      free, lipoprotein-bound (Lp-bound), and endothelial cell-anchor pools in 156
      patients with coronary artery disease (average age, 61.2+/-9.1 years; range, 32
      to 78 years) by heparin infusion (50 IU/kg) and compared them with the preheparin
      TFPI levels of 229 healthy subjects (average age, 59. 6+/-9.4 years; range, 41 to
      80 years). The patients had lower preheparin free TFPI and lower HDL cholesterol
      (HDL-C) levels than the healthy subjects with equivalent Lp-bound forms (free
      TFPI, 15. 9+/-6.5 versus 19.2+/-8.1 ng/mL). In a partial correlation analysis,
      the preheparin free TFPI levels were shown to be inversely correlated with the
      HDL-C concentrations in both the patients (r=-0. 454, P<0.001) and the healthy
      subjects (r=-0.136, P<0.05). As determined by comparison of preheparin and
      postheparin plasma, the patients generally showed preheparin free TFPI <10%, Lp
      bound TFPI at 30%, and endothelial cell-anchor TFPI at 60%. When the patients
      were divided into 4 categories by their LDL cholesterol (LDL-C, 130 mg/dL) and
      HDL-C (40 mg/dL) levels to specify their coronary risks, the low-HDL-C groups had
      significantly increased preheparin and postheparin free TFPI levels and decreased
      postheparin LPL levels, whereas the high-LDL-C groups showed increased levels of
      Lp-bound TFPI. In a partial correlation analysis, we found a proportional
      relation between postheparin free TFPI and apolipoprotein A-II (r=0. 5327) and
      between HDL-C and LPL (r=0.4906), whereas postheparin free TFPI was inversely
      correlated with HDL-C (r=-0.4280) and postheparin LPL (r=-0.4791). The inverse
      relationship between TFPI and LPL suggests that increased free TFPI
      concentrations as a compensatory response of the endothelium to prevent
      atherothrombotic processes compete with and displace LPL on endothelial surface,
      resulting in reduced LPL and low HDL-C.

PMID- 10634827
TI  - Effect of omega-3 fatty acids and simvastatin on hemostatic risk factors and
      postprandial hyperlipemia in patients with combined hyperlipemia.
AB  - Patients with combined hyperlipemia have lipid abnormalities associated with an
      increased tendency to develop atherosclerosis and thrombosis. This tendency may
      be accelerated during postprandial hyperlipemia. In the present double-blind
      parallel study, 41 patients with combined hyperlipemia and serum triacylglycerols
      between 2.0 and 15.0 mmol/L and serum total cholesterol >5.3 mmol/L at the end of
      a 3-month dietary run-in period were treated with simvastatin at 20 mg/d for at
      least 10 weeks; patients were then randomized into 2 groups receiving
      simvastatin+omega-3 fatty acids at 3.36 g/d or placebo (corn oil) for an
      additional 5 weeks. Hemostatic variables that have been associated with increased
      thrombotic tendency were evaluated with subjects in the fasting state and during
      postprandial hyperlipemia before and after combined treatment. Supplementation of
      omega-3 fatty acid reduced tissue factor pathway inhibitor antigen (P<0.05) in
      the fasting state, reduced the degree of postprandial hyperlipemia (P<0.005), and
      reduced activated factor VII concentration appearing during postprandial
      hyperlipemia. In conclusion, omega-3 fatty acids given in addition to simvastatin
      to patients with combined hyperlipemia reduced the free tissue factor pathway
      inhibitor fraction in the fasting state and inhibited the activation of factor
      VII occurring during postprandial lipemia, thus representing a potential
      beneficial effect on the hemostatic risk profile in this patient group.

PMID- 10634828
TI  - Prospective evaluation of the risk conferred by factor V Leiden and thermolabile
      methylenetetrahydrofolate reductase polymorphisms in pregnancy.
AB  - Factor V (FV) Leiden and thermolabile methylenetetrahydrofolate reductase (MTHFR)
      are 2 common polymorphisms that have been implicated in vascular thrombosis. We
      determined whether these mutations predicted an adverse outcome in pregnancy.
      Second, we looked for an interaction between these 2 mutations in patients with
      recurrent fetal loss or thrombosis in pregnancy. Primigravid subjects at their
      booking visit to the National Maternity Hospital (Holles Street, Dublin, Ireland)
      were screened for the polymorphisms. Thermolabile MTHFR and FV Leiden genotypes
      were detected by either restriction fragment length polymorphism or heteroduplex
      capillary chromatography. The carrier frequency of FV Leiden in the screened
      primigravid population was 2.7% (allele frequency 1.36%), all being heterozygous
      for the mutation. This value was lower than expected from previous studies in
      European populations. Forty-nine percent of the screened population (289 of 584)
      were heterozygous for thermolabile MTHFR, and 10.6% were homozygous (62 of 584).
      The frequency of the 2 polymorphisms was no higher in those who subsequently
      developed preeclampsia (n=12) or intrauterine growth retardation (n=9), and none
      of the screened population developed thrombosis. However, the frequency of FV
      Leiden was higher in patients who subsequently miscarried after the first
      trimester of pregnancy (allele frequency of 5.5%, P=0.0356). Among those positive
      for FV Leiden, 3 of 27 miscarried, compared with 24 of 572 of FV Leiden-negative
      patients (11% versus 4.2%). No interaction was found between the 2 mutations in
      the control or patient populations. In patients with a prior history of venous
      thrombosis, the carrier rate of FV Leiden was increased (4 of 33, allele
      frequency of 7.6%, P=0. 0115). In contrast, the carrier frequency for
      thermolabile MTHFR was no higher, and there was no interaction between the 2
      mutations. Neither mutation occurred at a significantly higher frequency in
      patients with a prior history of recurrent fetal loss. In conclusion, FV Leiden
      is a risk factor for thrombosis in pregnancy and possibly for second-trimester
      miscarriage independent of thermolabile MTHFR. However, prospective analysis
      suggests that the risk conferred by FV Leiden is low in a primigravid population.
      The thermolabile MTHFR genotype was not implicated in any adverse outcome.

PMID- 10634829
TI  - Lifestyle and hemostatic risk factors for ischemic heart disease : the Caerphilly
      Study.
AB  - We have recently shown that fibrin D-dimer, tissue plasminogen activator (tPA)
      antigen, von Willebrand factor antigen, fibrinogen, plasma viscosity, and white
      cell count are associated with subsequent ischemic heart disease (IHD) in men
      aged 49 to 65 years in the Caerphilly Study from South Wales. We now report the
      contribution of major lifestyle factors to plasma levels of these new risk
      predictors for IHD. Results were available for up to 2188 men. The contribution
      of factors associated with lifestyle (smoking, alcohol, body mass index, leisure
      and work activity, social class, and use of prescribed medicines) to variation in
      plasma levels of 8 hemostatic variables was examined. All results were adjusted
      for other lifestyle variables, age, and time of day. Most hemostatic variables
      increased with age and smoking habit. Increasing levels of alcohol consumption
      were associated with increases in tPA and plasminogen activator inhibitor (PAI-1)
      activity and with decreases in fibrinogen and white cell count. tPA, PAI-1,
      fibrinogen (nephelometric), and viscosity were positively associated with body
      mass index. Increasing levels of leisure activity were inversely associated with
      D-dimer, von Willebrand factor, nephelometric fibrinogen, and viscosity. Use of
      prescribed medicines (a marker for chronic illness) was associated with adverse
      levels of D-dimer, fibrinogen, plasma viscosity, and white cell count. tPA, PAI
      1, and plasma viscosity were associated with blood pressure, cholesterol, and
      triglycerides but not with lipoprotein(a) or homocysteine. We conclude that
      several lifestyle factors are associated with hemostatic risk predictors for IHD.
      Lifestyle modifications may reduce IHD risk partly by altering hemostatic
      function; large intervention studies are required to test this hypothesis.

PMID- 10634830
TI  - Rationing antibiotic use in neonatal units.

PMID- 10634831
TI  - Should cisapride have been "blacklisted"?

PMID- 10634832
TI  - International randomised controlled trial of patient triggered ventilation in
      neonatal respiratory distress syndrome.
AB  - AIM: To compare the effects of patient triggered ventilation (PTV) with
      conventional ventilation (IMV) in preterm infants ventilated for respiratory
      distress syndrome (RDS). METHODS: Nine hundred and twenty four babies from 22
      neonatal intensive care units were assessed. They were under 32 weeks of
      gestation and had been ventilated for respiratory distress syndrome (RDS) for
      less than 6 hours within 72 hours of birth. The infants were randomly allocated
      to receive either PTV or IMV. Analysis was on an "intention to treat" basis.
      Death before discharge home or oxygen therapy at 36 weeks of gestation;
      pneumothorax while ventilated; cerebral ultrasound abnormality nearest to 6
      weeks; and duration of ventilation in survivors were the main outcome measures.
      RESULTS: There was no significant difference in outcome between the two groups.
      Unadjusted rates for death or oxygen dependency at 36 weeks of gestation were
      47.4% and 48.7%, for PTV and IMV, respectively; for pneumothorax these were 13.4%
      and 10.3%; and for cerebral ultrasound abnormality nearest to 6 weeks these were
      35.4% and 36.9%. Median duration of ventilation for survivors in both groups was
      6 days. Overall, 79% of babies received only their assigned ventilation. PTV
      babies were more likely to depart from their intended ventilation (27% vs 15%).
      The trend towards higher pneumothorax rates with PTV occurred only in infants
      below 28 weeks of gestation (18.8% vs 11.8%). CONCLUSIONS: There was no observed
      benefit from the use of PTV, with a trend towards a higher rate of pneumothorax
      under 28 weeks of gestation. Although PTV has a similar outcome to IMV for
      treatment of RDS in infants of 28 weeks or more gestation, within 72 hours of
      birth, it was abandoned more often. It cannot be recommended for infants of less
      than 28 weeks' gestation with the ventilators used in this study.

PMID- 10634833
TI  - Fetal acalvaria with amniotic band syndrome.
AB  - A case of amniotic band syndrome (ABS) presenting with acalvaria is reported. ABS
      includes a spectrum of non-genetic anomalies, varying from simple digital band
      constriction to major craniofacial and visceral defects, and even fetal death.
      Acalvaria is a rare congenital malformation characterised by the absence of the
      dome-like superior portion of the cranium comprising the frontal, parietal, and
      occipital bones and dura mater, in the presence of a normal skull base and facial
      bones with complete cranial contents. No two cases are the same. Acrania or
      absence of the flat skull bones with disorganised cerebral hemispheres have been
      reported in the presence of amniotic bands. ABS is an aetiological factor in
      acalvaria. Appropriate counselling for affected families needs to be given after
      prenatal diagnosis.

PMID- 10634834
TI  - Stamps in neonatology. The patient's tale.

PMID- 10634835
TI  - Randomised controlled trial of patient triggered and conventional fast rate
      ventilation in neonatal respiratory distress syndrome.
AB  - AIM: To compare patient triggered, with conventional fast rate, ventilation in a
      randomised controlled trial using the incidence of chronic lung disease as the
      primary outcome measure. METHODS: Three hundred and eighty six preterm infants
      with birthweights from 1000 to 2000 g, and requiring ventilation for respiratory
      distress syndrome within 24 hours of birth, were randomised to receive either
      conventional or trigger ventilation with the SLE 2000 ventilator. RESULTS: There
      were no significant differences in the incidence of chronic lung disease (28 day
      and 36 week definitions), death, pneumothorax, intraventricular haemorrhage,
      number of ventilator days, or length of oxygen dependency between groups.
      CONCLUSIONS: Patient triggered ventilation in preterm infants with respiratory
      distress syndrome is feasible. No significant differences, when compared with
      conventional fast rate ventilation in important medium and longer term outcome
      measures, were evident.

PMID- 10634836
TI  - Randomised controlled trial of postnatal sodium supplementation on oxygen
      dependency and body weight in 25-30 week gestational age infants.
AB  - AIM: To compare the effects of early against delayed sodium supplementation on
      oxygen dependency and body weight, in preterm infants of 25-30 weeks of
      gestational age. METHODS: Infants were stratified by gender and gestation and
      randomly assigned to receive a sodium intake of 4 mmol/kg/day starting on either
      the second day after birth or when weight loss of 6% of birthweight was achieved.
      Daily sodium intake, serum sodium concentration, total fluid intake, energy
      intake, clinical risk index for babies (CRIB) score and duration of ventilatory
      support and additional oxygen therapy were recorded. Infants were weighed daily.
      Weights at 36 weeks and six months of postmenstrual age were also recorded.
      RESULTS: Twenty four infants received early, and 22 delayed, sodium
      supplementation. There were no significant differences in total fluid and energy
      intake between the two groups. There was a significant difference in oxygen
      requirement at the end of the first week, with 9% of the early group in air in
      contrast to 35% of the delayed group (difference 26%, 95% confidence interval 2,
      50). At 28 days after birth the proportions were 18% of the early group and 40%
      of the delayed group (difference 22%, 95% CI -5, 49). Proportional hazards
      modelling showed early sodium supplementation and lower birthweight to be
      significantly associated with increased risk of continuing oxygen requirement.
      The delayed sodium group had a greater maximum weight loss (delayed 16.1%; early
      11.4%, p=0.02), but there were no significant differences in time to maximum
      weight loss, time to regain birthweight, and weight at 36 weeks and 6 months of
      postmenstrual age. CONCLUSION: In infants below 30 weeks of gestation, delaying
      sodium supplementation until at least 6% of birthweight is lost has a beneficial
      effect on the risk of continuing oxygen requirement and does not compromise
      growth.

PMID- 10634837
TI  - Randomised controlled trial of postnatal sodium supplementation on body
      composition in 25 to 30 week gestational age infants.
AB  - AIMS: To compare the effects of early and delayed sodium supplementation on body
      composition and body water compartments during the first two weeks of postnatal
      life. METHODS: Preterm infants of 25-30 weeks' gestation were stratified and
      randomly assigned according to gender and gestational age, to receive a sodium
      intake of 4 mmol/kg/day beginning either on the second day after birth or when
      weight loss of 6% of birthweight had been achieved. Daily sodium intake, total
      fluid intake, energy intake, urine volume, and urinary sodium excretion were
      recorded. Total body water was measured by H(2)(18)O dilution on days 1, 7, and
      14, and extracellular fluid volume by sodium bromide dilution on days 1 and 14.
      RESULTS: Twenty four infants received early, and 22 delayed, sodium
      supplementation. There were no significant differences between the groups in body
      water compartments on day 1. In the delayed group, but not the early group, there
      was a significant loss of total body water during the first week (delayed -44
      ml/kg, p=0. 048; early 6 ml/kg, p=0.970). By day 14 the delayed, but not the
      early group, also had a significant reduction in extracellular fluid volume
      (delayed -53 ml/kg, p=0.01; early -37 ml/kg, p=0.2). These changes resulted in a
      significant alteration in body composition at the end of the first week (total
      body weight: delayed 791 ml/kg; early 849 ml/kg, p=0.013). By day 14 there were
      once again no significant differences in body composition between the two groups.
      CONCLUSIONS: Body composition after preterm birth is influenced by the timing of
      introduction of routine sodium supplements. Early sodium supplementation can
      delay the physiological loss of body water that is part of normal postnatal
      adaptation. This is likely to be of particular relevance to babies with
      respiratory distress syndrome. A tailored approach to clinical management,
      delaying the introduction of routine sodium supplements until there has been
      postnatal loss of body water, is recommended.

PMID- 10634838
TI  - Randomised controlled study of clinical outcome following trophic feeding.
AB  - AIMS: To determine the effect of trophic feeding on clinical outcome in ill
      preterm infants. METHODS: A randomised, controlled, prospective study of 100
      preterm infants, weighing less than 1750 g at birth and requiring ventilatory
      support and parenteral nutrition, was performed. Group TF (48 infants) received
      trophic feeding from day 3 (0.5-1 ml/h) along with parenteral nutrition until
      ventilatory support finished. Group C (52 infants) received parenteral nutrition
      alone. "Nutritive" milk feeding was then introduced to both groups. Clinical
      outcomes measured included total energy intake and growth over the first six
      postnatal weeks, sepsis incidence, liver function, milk tolerance, duration of
      respiratory support, duration of hospital stay and complication incidence.
      RESULTS: Groups were well matched for birthweight, gestation and CRIB scores.
      Infants in group TF had significantly greater energy intake, mean difference 41.4
      (95% confidence interval 9, 73.7) kcal/kg p=0.02; weight gain, 130 (CI 1, 250) g
      p = 0.02; head circumference gain, mean difference 0.7 (CI 0.1, 1.3) cm, p =
      0.04; fewer episodes of culture confirmed sepsis, mean difference -0.7 (-1.3, 
      0.2) episodes, p = 0.04; less parenteral nutrition, mean difference -11.5 (CI 
      20, -3) days, p = 0. 03; tolerated full milk feeds (165 ml/kg/day) earlier, mean
      difference -11.2 (CI -19, -3) days, p = 0.03; reduced requirement for
      supplemental oxygen, mean difference -22.4 (CI-41.5, -3.3) days, p = 0.02; and
      were discharged home earlier, mean difference -22.1 (CI -42.1, -2.2) days, p =
      0.04. There was no significant difference in the relative risk of any
      complication. CONCLUSIONS: Trophic feeding improves clinical outcome in ill
      preterm infants requiring parenteral nutrition.

PMID- 10634839
TI  - Randomised controlled trial of thiopental for intubation in neonates.
AB  - AIMS: To determine the effects of premedication with thiopental on heart rate,
      blood pressure, and oxygen saturation during semi-elective nasotracheal
      intubation in neonates. METHODS: A randomised, placebo controlled, non-blinded
      study design was used to study 30 neonates (mean birthweight 3.27 kg) requiring
      semi-elective nasotracheal intubation. The babies were randomly allocated to
      receive either 6 mg/kg of thiopental (study group) or an equivalent volume of
      physiological saline (control group) one minute before the start of the
      procedure. Six infants were intubated primarily and 24 were changed from
      orotracheal to a nasotracheal tube. The electrocardiogram, arterial pressure
      wave, and transcutaneous oxygen saturation were recorded continuously 10 minutes
      before, during, and 20 minutes after intubation. Minute by minute measurements of
      heart rate, heart rate variability, mean blood pressure (MBP) and transcutaneous
      oxygen saturation (SpO(2)) were computed. The differences for all of these
      between the baseline measurements and those made during and after intubation were
      determined. Differences in the measurements made in the study and the control
      groups were compared using Student's t test. RESULTS: During intubation, heart
      rate increased to a greater degree (12.0 vs -0.5 beats per minute, p < 0.03) and
      MBP increased to a lesser degree (-2.9 vs 4.4 mm Hg; p < 0.002) in the infants
      who were premedicated with thiopental. After intubation only the changes in MBP
      differed significantly between the two groups (-3.8 vs 4.6 mm Hg; p < 0.001).
      There were no significant changes in the oxygen saturation between the two groups
      during or after intubation. The time taken for intubation was significantly
      shorter in the study group (p < 0.04). CONCLUSIONS: The heart rate and blood
      pressure of infants who are premedicated with thiopental are maintained nearer to
      baseline values than those of similar infants who receive no premedication.
      Whether this lessening of the acute drop in the heart rate and increase in blood
      pressure typically seen during intubation of unmedicated infants is associated
      with long term advantages to the infants remains to be determined.

PMID- 10634840
TI  - Premedication before intubation in UK neonatal units.
AB  - AIMS: To establish the extent and type of premedication used before intubation in
      neonatal units in the United Kingdom. METHODS: A structured telephone survey was
      conducted of 241 eligible units. Units were subdivided into those that routinely
      intubated and ventilated babies (routine group) and those that transferred
      intubated and ventilated babies (transfer group). RESULTS: Of the units
      contacted, 239 (99%) participated. Only 88/239 (37%) gave any sedation before
      intubating on the unit and only 34/239 (14%) had a written policy covering this.
      Morphine was used most commonly (66%), with other opioids and benzodiazepines
      used less frequently. Of the 88 units using sedation, 19 (22%) also used
      paralysis. Suxamethonium was given by 10/19 (53%) but only half of these combined
      it with atropine. Drug doses varied by factors of up to 200, even for commonly
      used drugs. CONCLUSION: Most UK neonatal units do not sedate babies before
      intubating, despite evidence of physiological and practical benefits. Only a
      minority have written guidelines, which prohibits auditing of practice.

PMID- 10634841
TI  - Local anaesthetic effect of topical amethocaine gel in neonates: randomised
      controlled trial.
AB  - AIM: To assess the efficacy of amethocaine as a topical local anaesthetic in
      neonates. METHODS: A randomised, double blind controlled trial compared 4%
      amethocaine gel (Ametop) with placebo in 60 healthy neonates (29 to 42 weeks of
      gestation) in the first week after birth. Either 1.5 g 4% w/w amethocaine (gel)
      or 1.5 g placebo gel were applied to the dorsum of one foot. No gel was applied
      to the other foot. Each foot was occluded and left for one hour. Local
      anaesthesia was then assessed by eliciting the cutaneous withdrawal reflex in
      response to stimulation with a series of graded nylon filaments (von Frey hairs).
      The reflex was first elicited from the control and then the treated foot. The
      difference in filament thickness and deforming weight required to elicit the
      reflex was recorded. RESULTS: In infants treated with amethocaine, 17 of 31 (54.
      8%) showed evidence of local anaesthetic action compared with five of 29 (17.2%)
      in the placebo group (p=0.003). The mean difference in deforming weight required
      to elicit the reflex was 18.8 g in the amethocaine group compared with 3.9 g in
      the placebo group (p=0.02). The apparent local anaesthetic action of the placebo
      can be explained by habituation to repeated stimulation. CONCLUSIONS: It is
      concluded that topical amethocaine gel has a local anaesthetic action on neonatal
      skin which merits further investigation. An effective and safe surface local
      anaesthetic would be valuable for the relief of procedure related pain in
      neonates.

PMID- 10634842
TI  - Neonatal hypoglycaemia in Nepal 1. Prevalence and risk factors.
AB  - AIMS: To measure the prevalence of hypoglycaemia among newborn infants in Nepal,
      where classic risk factors prevail, and to evaluate their importance. METHODS: A
      cross sectional study was done of 578 term newborn infants aged 0 to 48 hours on
      the postnatal wards of a government maternity hospital in Kathmandu, with
      unmatched case-control analysis of risk factors for moderate hypoglycaemia (less
      than 2.0 mmol /l). RESULTS: Two hundred and thirty eight (41%) newborn infants
      had mild (less than 2.6 mmol/l) and 66 (11%) moderate hypoglycaemia. Significant
      independent risk factors for moderate hypoglycaemia included postmaturity (OR
      2.62), birthweight under 2.5 kg (OR 2.11), small head size (OR 0.59), infant
      haemoglobin >210 g/l (OR 2.77), and raised maternal thyroid stimulating hormone
      (TSH) (OR 3.08). Feeding delay increased the risk of hypoglycaemia at age 12-24
      hours (OR 4.09). Disproportionality affected the risk of moderate hypoglycaemia:
      lower with increasing ponderal index (OR 0.29), higher as the head circumference
      to birthweight ratio increased (OR 1.41). Regression expressing blood glucose
      concentration as a continuous variable revealed associations with infant
      haemoglobin (negative) and maternal haemoglobin (positive), but no other textbook
      risk factors. CONCLUSIONS: Neonatal hypoglycaemia is more common in a developing
      country, but may not be a clinical problem unless all fuel availability is
      reduced. Some textbook risk factors, such as hypothermia, disappear after
      controlling for confounding variables. Early feeding could reduce moderate
      hypoglycaemia in the second 12 hours of life. The clinical significance of raised
      maternal TSH and maternal anaemia as prenatal risk factors requires further
      research.

PMID- 10634843
TI  - Neonatal hypoglycaemia in Nepal 2. Availability of alternative fuels.
AB  - AIMS: To study early neonatal metabolic adaptation in a hospital population of
      neonates in Nepal. METHODS: A cross sectional study was made of 578 neonates, 0
      to 48 hours after birth, in the main maternity hospital in Kathmandu. The
      following clinical and nutritional variables were assessed: concentrations and
      age profiles of blood glucose, hydroxybutyrate, lactate, pyruvate, free fatty
      acids (FFA) and glycerol; associations between alternative fuel levels and
      hypoglycaemia; and regression of possible risk factors for ketone availability.
      RESULTS: Risk factors for impaired metabolic adaptation were common, especially
      low birthweight (32%), feeding delays, and cold stress. Blood glucose and ketones
      rose with age, but important age effects were also found for risk factors like
      hypothermia, thyroid hormone activities, and feeding practices. Alternative fuel
      concentrations, except FFA, were significantly reduced in infants with moderate
      hypoglycaemia during the first 48 hours after birth. Unlike earlier studies,
      small for gestational age (SGA) infants had significantly higher
      hydroxybutyrate:glucose ratios which suggested counter regulatory ketogenesis.
      Hypoglycaemic infants were not hyperinsulinaemic. Regression analysis showed risk
      factors for impaired counter regulation which included male and large infants,
      hypothermia, and poorer infant thyroid function. SGA infants and those whose
      mothers had received no antenatal care had increased counter regulation.
      CONCLUSIONS: Alternative fuels are important in the metabolic assessment of
      neonates, and they might provide effective cerebral metabolism even during
      moderate hypoglycaemia. Hypoglycaemic infants generally had lower concentrations
      of alternative fuels through either reduced availability or increased
      consumption. SGA and post term infants increased counter regulatory ketogenesis
      with early neonatal hypoglycaemia, but hypothermia, male gender, and low infant
      T4 were associated with impaired counter regulation after birth.

PMID- 10634844
TI  - Perinatal cortical infarction within middle cerebral artery trunks.
AB  - AIM: To define neonatal pial middle cerebral artery infarction. METHODS: A
      retrospective study was made of neonates in whom focal arterial infarction had
      been detected ultrasonographically. A detailed study was made of cortical middle
      cerebral artery infarction subtypes. RESULTS: Forty infarctions, with the
      exception of those in a posterior cerebral artery, were detected
      ultrasonographically over a period of 10 years. Most were confirmed by computed
      tomography or magnetic resonance imaging. Factor V Leiden heterozygosity was
      documented in three. The onset was probably antepartum in three, and associated
      with fetal distress before labour in one. There were 19 cases of cortical middle
      cerebral artery stroke. The truncal type (n=13) was more common than complete (n
      = 5) middle cerebral artery infarction. Of six infarcts in the anterior trunk,
      four were in term infants and five affected the right hemisphere. Clinical
      seizures were part of the anterior truncal presentation in three. One of these
      infants, with involvement of the primary motor area, developed a severe motor
      hemisyndrome. The Bayley Mental Developmental Index was above 80 in all of three
      infants tested with anterior truncal infarction. Of seven patients with posterior
      truncal infarction, six were at or near term. Six of these lesions were left
      sided. Clinical seizures were observed in three. A mild motor hemisyndrome
      developed in at least three of these infants due to involvement of parieto
      temporal non-primary cortex. CONCLUSIONS: Inability to differentiate between
      truncal and complete middle cerebral artery stroke is one of the explanations for
      the reported different outcomes. Severe motor hemisyndrome can be predicted from
      neonatal ultrasonography on the basis of primary motor cortex involvement.
      Clinical seizures were recognised in less than half of the patients with truncal
      infarction; left sided presentation was present in the posterior, but not the
      anterior truncal type of infarction. Asphyxia is a rare cause of focal arterial
      infarction.

PMID- 10634845
TI  - Six years' experience of prophylactic oral vitamin K.
AB  - AIMS: The ability of oral vitamin K to eliminate all risk of vitamin K deficiency
      bleeding during the first three months of life was studied. METHODS: Babies
      (n=182,000) in the north of England judged well enough to be offered milk within
      12 hours of birth were given 1 mg of phytomenadione (vitamin K(1)) suspended in a
      medium chain triglyceride oil by mouth at delivery between 1993 and 1998. The
      parents of those who were breastfed were given a further three doses to give to
      the baby once every two weeks after discharge. RESULTS: Four breastfed babies
      developed late vitamin K deficiency bleeding. In two, staff failed to follow
      policy guidelines, and in two there was undiagnosed alpha(1) antitrypsin
      deficiency. Audit suggested that 93% of breastfed babies had all four doses, as
      advised. CONCLUSIONS: An oral product that parents can administer themselves
      would be popular if licensed, but the total dose offered may need to be more than
      in this study if babies with undiagnosed liver disease are to be protected.

PMID- 10634846
TI  - Lung growth: implications for the newborn infant.

PMID- 10634847
TI  - Sir Joseph Barcroft of Cambridge (1872-1947) and prenatal research.

PMID- 10634848
TI  - Control strategies for the transition from multijoint to single-joint arm
      movements studied using a simple mechanical constraint.
AB  - Changes were studied in neuromotor control that were evoked by constraining the
      motion of the elbow joint during planar, supported movements of the dominant arm
      in eight normal human subjects. Electromyograph (EMG) recordings from shoulder
      and arm muscles were used to determine whether the normal multijoint muscle
      activity patterns associated with reaching to a visual target were modified when
      the movement was reduced to a single-joint task, by pinning the elbow to a
      particular location in the planar work space. Three blocks of 150 movements each
      were used in the experiments. Subjects were presented with the unconstrained task
      in the first and third blocks with an intervening block of constrained trials.
      Kinematic, dynamic, and EMG measures of performance were compared across blocks.
      The imposition of the pin constraint caused predictable changes in kinematic
      performance, in that near-linear motions of the hand became curved. This was
      followed by changes in limb dynamic performance at the elbow. However, changes in
      EMG activity at the shoulder lagged the kinematic changes substantially (by about
      15 trials). The gradual character of the changes in EMG timing does not support a
      primary role for segmental reflex action in mediating the transition between
      multijoint and single-joint control strategies. Furthermore, the scope and
      magnitude of these changes argues against the notion that human motor performance
      is driven by the optimization of muscle- or joint-related criteria alone. The
      findings are best described as reflecting the actions of a feedforward adaptive
      controller that has properties that are modified progressively according to the
      environmental state.

PMID- 10634849
TI  - Cerebellar flocculus and paraflocculus Purkinje cell activity during circular
      pursuit in monkey.
AB  - Responses from 69 Purkinje cells in the flocculus and paraflocculus of two rhesus
      monkeys were studied during smooth pursuit of targets moving along circular
      trajectories and compared with responses during sinusoidal pursuit and fixation.
      A variety of interesting responses was observed during circular pursuit. Although
      some neurons fired most strongly in a single preferred direction during clockwise
      (CW) and counterclockwise (CCW) pursuit, others had directional preferences that
      changed with rotation direction. Some of these neurons showed similar modulation
      amplitudes during CW and CCW pursuit, whereas other neurons showed a preference
      for a particular rotation direction. Response specificity also was observed
      during sinusoidal pursuit. Some neurons showed responses that were much stronger
      during centrifugal pursuit, others showed a preference for centripetal pursuit,
      and still others showed responses during both centripetal and centrifugal motion.
      Differences in preferred response direction were sometimes observed for
      centripetal versus centrifugal pursuit. CW/CCW and centrifugal/centripetal
      preferences were not explained by a breakdown in component additivity. That is,
      modulations in firing rate during pursuit along a circular trajectory equaled the
      sum of modulations during horizontal and vertical sinusoidal components as well
      as for diagonal components. Instead all responses were well fit by a model that
      expressed the instantaneous firing rate of each neuron as a multilinear function
      of the two-dimensional position and velocity of the eye. This model generalized
      well to performance at different sinusoidal frequencies. It did somewhat less
      well for responses during fixation, suggesting some separation in the neural
      mechanisms of dynamic and static positioning. The model indicates that position
      sensitivity accounted for approximately 36% of the modulation during circular
      pursuit, and velocity sensitivity accounted for approximately 64%. When position
      and velocity sensitivity vectors were aligned, responses were simpler and
      modulations were similar during CW versus CCW pursuit. In contrast, when these
      vectors pointed in different directions, response complexity increased.
      Nonaligned position and velocity influences tended to reinforce during circular
      pursuit in one direction and to cancel each other during pursuit in the opposite
      direction. They also tended to produce response differences during centripetal
      versus centrifugal sinusoidal pursuit. The distinct roles played by position and
      velocity in shaping Purkinje cell responses are compatible with the control
      signals required to generate smooth pursuit along circular and other two
      dimensional trajectories.

PMID- 10634850
TI  - Glutamate and GABA activate different receptors and Cl(-) conductances in crab
      peptide-secretory neurons.
AB  - Responses to rapid application of glutamic acid (Glu) and gamma-aminobutyric acid
      (GABA), 0.01-3 mM, were recorded by whole-cell patch clamp of cultured crab
      (Cardisoma carnifex) X-organ neurons. Responses peaked within 200 ms. Both Glu
      and GABA currents had reversal potentials that followed the Nernst Cl(-)
      potential when [Cl(-)](i) was varied. A Boltzmann fit to the normalized, averaged
      dose-response curve for Glu indicated an EC(50) of 0.15 mM and a Hill coefficient
      of 1.05. Rapid (t(1/2) approximately 1 s) desensitization occurred during Glu but
      not GABA application that required >2 min for recovery. Desensitization was
      unaffected by concanavalin A or cyclothiazide. N-methyl-D-aspartate, alpha-amino
      3-hydroxy-5-methyl-4-isoxazolepropionic acid, quisqualate, and kainate (to 1 mM)
      were ineffective, nor were Glu responses influenced by glycine (1 microM) or
      Mg(2+) (0-26 mM). Glu effects were imitated by ibotenic acid (0.1 mM). The
      following support the conclusion that Glu and GABA act on different receptors: 1)
      responses sum; 2) desensitization to Glu or ibotenic acid did not diminish GABA
      responses; 3) the Cl(-)-channel blockers picrotoxin and niflumic acid (0.5 mM)
      inhibited Glu responses by approximately 90 and 80% but GABA responses by
      approximately 50 and 20%; and 4) polyvinylpyrrolydone-25 (2 mM in normal crab
      saline) eliminated Glu responses but left GABA responses unaltered. Thus crab
      secretory neurons have separate receptors responsive to Glu and to GABA, both
      probably ionotropic, and mediating Cl(-) conductance increases. In its responses
      and pharmacology, this crustacean Glu receptor resembles Cl(-)-permeable Glu
      receptors previously described in invertebrates and differs from cation-permeable
      Glu receptors of vertebrates and invertebrates.

PMID- 10634851
TI  - Effect of adaptation to telescopic spectacles on the initial human horizontal
      vestibuloocular reflex.
AB  - Gain of the vestibuloocular reflex (VOR) not only varies with target distance and
      rotational axis, but can be chronically modified in response to prolonged wearing
      of head-mounted magnifiers. This study examined the effect of adaptation to
      telescopic spectacles on the variation of the VOR with changes in target distance
      and yaw rotational axis for head velocity transients having peak accelerations of
      2,800 and 1,000 degrees /s(2). Eye and head movements were recorded with search
      coils in 10 subjects who underwent whole body rotations around vertical axes that
      were 10 cm anterior to the eyes, centered between the eyes, between the otoliths,
      or 20 cm posterior to the eyes. Immediately before each rotation, subjects viewed
      a target 15 or 500 cm distant. Lighting was extinguished immediately before and
      was restored after completion of each rotation. After initial rotations, subjects
      wore 1.9x magnification binocular telescopic spectacles during their daily
      activities for at least 6 h. Test spectacles were removed and measurement
      rotations were repeated. Of the eight subjects tolerant of adaptation to the
      telescopes, six demonstrated VOR gain enhancement after adaptation, while gain in
      two subjects was not increased. For all subjects, the earliest VOR began 7-10 ms
      after onset of head rotation regardless of axis eccentricity or target distance.
      Regardless of adaptation, VOR gain for the proximate target exceeded that for the
      distant target beginning at 20 ms after onset of head rotation. Adaptation
      increased VOR gain as measured 90-100 ms after head rotation onset by an average
      of 0.12 +/- 0.02 (SE) for the higher head acceleration and 0.19 +/- 0.02 for the
      lower head acceleration. After adaptation, four subjects exhibited significant
      increases in the canal VOR gain only, whereas two subjects exhibited significant
      increases in both angular and linear VOR gains. The latencies of linear and early
      angular target distance effects on VOR gain were unaffected by adaptation. The
      earliest significant change in angular VOR gain in response to adaptation
      occurred 50 and 68 ms after onset of the 2,800 and 1,000 degrees /s(2) peak head
      accelerations, respectively. The latency of the adaptive increase in linear VOR
      gain was approximately 50 ms for the peak head acceleration of 2,800 degrees
      /s(2), and 100 ms for the peak head acceleration of 1,000 degrees /s(2). Thus VOR
      gain changes and latency were consistent with modification in the angular VOR in
      most subjects, and additionally in the linear VOR in a minority of subjects.

PMID- 10634852
TI  - Contribution of Ca(2+)-permeable AMPA/KA receptors to glutamate-induced Ca(2+)
      rise in embryonic lumbar motoneurons in situ.
AB  - Intracellular Ca(2+) ([Ca(2+)](i)) was fluorometrically measured with fura-2 in
      lumbar motoneurons of acutely isolated spinal cord slices from embryonic rats. In
      ester-loaded cells, bath-applied glutamate (3 microM to 1 mM) evoked a
      [Ca(2+)](i) increase by up to 250 nM that was abolished by 6-cyano-7
      nitroquinoxaline-2,3-dione (CNQX) plus 2-amino-5-phosphonovalerate (APV). CNQX or
      APV alone reduced the response by 82 and 25%, respectively. The glutamatergic
      agonists kainate (KA), quisqualate (QUI), and S-alpha-amino-3-hydroxy-5-methyl-4
      isoxalone (S-AMPA) evoked a similar [Ca(2+)](i) transient as glutamate. N-methyl
      D-aspartate (NMDA) was only effective to increase [Ca(2+)](i) in Mg(2+)-free
      saline, whereas [1S,3R]-1-aminocyclopentane-1,3-dicarboxylic acid ([1S,3R]-ACPD)
      had no effect. The glutamate-induced [Ca(2+)](i) rise was suppressed in Ca(2+)
      free superfusate. Depletion of Ca(2+) stores with cyclopiazonic acid (CPA) did
      not affect the response. Thirty-six percent of the [Ca(2+)](i) increase in
      response to membrane depolarization induced by a 50 mM K(+) solution persisted on
      combined application of the voltage-gated Ca(2+) channel blockers nifedipine,
      omega-conotoxin-GVIA and omega-agatoxin-IVA. In fura-2 dialyzed motoneurons, the
      glutamate-induced [Ca(2+)](i) increase was attenuated by approximately 70% after
      changing from current to voltage clamp. Forty percent of the remaining
      [Ca(2+)](i) transient and 20% of the concomitant inward current of 0.3 nA were
      blocked by Joro spider toxin-3 (JSTX). The results show that voltage-gated Ca(2+)
      channels, including a major portion of R-type channels, constitute the
      predominant component of glutamate-induced [Ca(2+)](i) rises. NMDA and Ca(2+)
      permeable KA/AMPA receptors contribute about equally to the remaining component
      of the Ca(2+) rise. The results substantiate previous assumptions that Ca(2+)
      influx through JSTX-sensitive KA/AMPA receptors is involved in (trophic)
      signaling in developing motoneurons.

PMID- 10634853
TI  - Role of pertussis toxin-sensitive G-proteins in synaptic transmission and
      plasticity at corticostriatal synapses.
AB  - The role of pertussis toxin (PTX)-sensitive G-proteins in corticostriatal
      synaptic transmission and long-term synaptic depression (LTD) was examined using
      extracellular field potential and whole cell voltage-clamp recordings in striatal
      slices. High-frequency stimulation (HFS) produced LTD, defined as long-lasting
      decreases both in synaptically driven population spikes (PSs) measured with field
      potential recording and in excitatory postsynaptic currents (EPSCs) measured with
      whole cell recording. Striatal LTD could not be induced in slices obtained from
      rats that had received a unilateral intrastriatal injection of PTX. However, LTD
      could be induced in slices obtained from paired control slices. Furthermore,
      striatal LTD was prevented by pretreatment with N-ethylmaleimide (NEM), another
      compound that disrupts the function of PTX-sensitive G-proteins. NEM, itself,
      also potentiated PS and EPSC amplitudes. In addition, NEM increased the frequency
      and amplitude of both spontaneous and miniature EPSCs and decreased the paired
      pulse facilitation ratio, suggesting that it may act on both pre- and
      postsynaptic sites. The findings suggest that PTX-sensitive G-proteins have
      multiple roles at corticostriatal synapses, including regulation of synaptic
      transmission at both pre- and postsynaptic sites, and a key role in striatal LTD.

PMID- 10634854
TI  - Voltage-gated potassium channels activated during action potentials in layer V
      neocortical pyramidal neurons.
AB  - To investigate voltage-gated potassium channels underlying action potentials
      (APs), we simultaneously recorded neuronal APs and single K(+) channel
      activities, using dual patch-clamp recordings (1 whole cell and 1 cell-attached
      patch) in single-layer V neocortical pyramidal neurons of rat brain slices. A
      fast voltage-gated K(+) channel with a conductance of 37 pS (K(f)) opened briefly
      during AP repolarization. Activation of K(f) channels also was triggered by patch
      depolarization and did not require Ca(2+) influx. Activation threshold was about 
      20 mV and inactivation was voltage dependent. Mean duration of channel activities
      after single APs was 6.1 +/- 0.6 ms (mean +/- SD) at resting membrane potential (
      64 mV), 6.7 +/- 0.7 ms at -54 mV, and 62 +/- 15 ms at -24 mV. The activation and
      inactivation properties suggest that K(f) channels function mainly in AP
      repolarization but not in regulation of firing. K(f) channels were sensitive to a
      low concentration of tetraethylammonium (TEA, 1 mM) but not to charybdotoxin
      (ChTX, 100 nM). Activities of A-type channels (K(A)) also were observed during AP
      repolarization. K(A) channels were activated by depolarization with a threshold
      near -45 mV, suggesting that K(A) channels function in both repolarization and
      timing of APs. Inactivation was voltage dependent with decay time constants of 32
      +/- 6 ms at -64 mV (rest), 112 +/- 28 ms at -54 mV, and 367 +/- 34 ms at -24 mV.
      K(A) channels were localized in clusters and were characterized by steady-state
      inactivation, multiple subconductance states (36 and 19 pS), and inhibition by 5
      mM 4-aminopyridine (4-AP) but not by 1 mM TEA. A delayed rectifier K(+) channel
      (K(dr)) with a unique conductance of 17 pS was recorded from cell-attached
      patches with TEA/4-AP-filled pipettes. K(dr) channels were activated by
      depolarization with a threshold near -25 mV and showed delayed long-lasting
      activation. K(dr) channels were not activated by single action potentials. Large
      conductance Ca(2+)-activated K(+) (BK) channels were not triggered by neuronal
      action potentials in normal slices and only opened as neuronal responses
      deteriorated (e.g., smaller or absent spikes) and in a spike-independent manner.
      This study provides direct evidence for different roles of various K(+) channels
      during action potentials in layer V neocortical pyramidal neurons. K(f) and K(A)
      channels contribute to AP repolarization, while K(A) channels also regulate
      repetitive firing. K(dr) channels also may function in regulating repetitive
      firing, whereas BK channels appear to be activated only in pathological
      conditions.

PMID- 10634855
TI  - Two mechanisms that raise free intracellular calcium in rat hippocampal neurons
      during hypoosmotic and low NaCl treatment.
AB  - Previous studies have shown that exposing hippocampal slices to low osmolarity
      (pi(o)) or to low extracellular NaCl concentration ([NaCl](o)) enhances synaptic
      transmission and also causes interstitial calcium ([Ca(2+)](o)) to decrease.
      Reduction of [Ca(2+)](o) suggests cellular uptake and could explain the
      potentiation of synaptic transmission. We measured intracellular calcium activity
      ([Ca(2+)](i)) using fluorescent indicator dyes. In CA1 hippocampal pyramidal
      neurons in tissue slices, lowering pi(o) by approximately 70 mOsm caused
      "resting" [Ca(2+)](i) as well as synaptically or directly stimulated transient
      increases of calcium activity (Delta[Ca(2+)](i)) to transiently decrease and then
      to increase. In dissociated cells, lowering pi(o) by approximately 70 mOsm caused
      [Ca(2+)](i) to almost double on average from 83 to 155 nM. The increase of
      [Ca(2+)](i) was not significantly correlated with hypotonic cell swelling.
      Isoosmotic (mannitol- or sucrose-substituted) lowering of [NaCl](o), which did
      not cause cell swelling, also raised [Ca(2+)](i). Substituting NaCl with choline
      Cl or Na-methyl-sulfate did not affect [Ca(2+)](i). In neurons bathed in calcium
      free medium, lowering pi(o) caused a milder increase of [Ca(2+)](i), which was
      correlated with cell swelling, but in the absence of external Ca(2+), isotonic
      lowering of [NaCl](o) triggered only a brief, transient response. We conclude
      that decrease of extracellular ionic strength (i.e., in both low pi(o) and low
      [NaCl](o)) causes a net influx of Ca(2+) from the extracellular medium whereas
      cell swelling, or the increase in membrane tension, is a signal for the release
      of Ca(2+) from intracellular stores.

PMID- 10634856
TI  - Cumulative effects of glutamate microstimulation on Ca(2+) responses of CA1
      hippocampal pyramidal neurons in slice.
AB  - Glutamate stimulation of hippocampal CA1 neurons in slice was delivered via
      iontophoresis from a microelectrode. Five pulses (approximately 5 muA, 10 s
      duration, repeated at 1 min intervals) were applied with the electrode tip
      positioned in the stratum radiatum near the dendrites of a neuron filled with the
      Ca(2+) indicator fura-2. A single stimulus set produced Ca(2+) elevations that
      ranged from several hundred nM to several microM and that, in all but a few
      neurons, recovered within 1 min of stimulus termination. Subsequent identical
      stimulation produced Ca(2+) elevations that outlasted the local glutamate
      elevations by several minutes as judged by response recoveries in neighboring
      cells or in other parts of the same neuron. These long responses ultimately
      recovered but persisted for up to 10 min and were most prominent in the mid and
      distal dendrites. Recovery was not observed for responses that spread to the
      soma. The elevated Ca(2+) levels were accompanied by membrane depolarization but
      did not appear to depend on the depolarization. High-resolution images
      demonstrated responsive areas that involved only a few mu(m) of dendrite. Our
      results confirm the previous general findings from isolated and cell culture
      neurons that glutamate stimulation, if carried beyond a certain range, results in
      long-lasting Ca(2+) elevation. The response characterized here in mature in situ
      neurons was significantly different in terms of time course and reversibility. We
      suggest that the extended Ca(2+) elevations might serve not only as a trigger for
      delayed neuron death but, where more spatially restricted, as a signal for local
      remodeling in dendrites.

PMID- 10634857
TI  - Correlations between corticomotoneuronal (CM) cell postspike effects and cell
      target muscle covariation.
AB  - The presence of postspike facilitation (PSpF) in spike-triggered averages of
      electromyographic (EMG) activity provides a useful means of identifying cortical
      neurons with excitatory synaptic linkages to motoneurons. Similarly the presence
      of postspike suppression (PSpS) suggests the presence of underlying inhibitory
      synaptic linkages. The question we have addressed in this study concerns the
      extent to which the presence and strength of PSpF and PSpS from
      corticomotoneuronal (CM) cells correlates with the magnitude of covariation in
      activity of the CM cell and its target muscles. For this purpose, we have
      isolated cells during a reach and prehension task during which the activity of 24
      individual proximal and distal forelimb muscles was recorded. These muscles show
      broad coactivation but with a highly fractionated and muscle specific fine
      structure of peaks and valleys. Covariation was assessed by computing long-term
      (2 s) cross-correlations between CM cells and forelimb muscles. The magnitude of
      cross-correlations was greater for muscles with facilitation effects than muscles
      lacking effects in spike-triggered averages. The results also demonstrate a
      significant relationship between the sign of the postspike effect (facilitation
      or suppression) and the presence of a peak or trough in the cross-correlation. Of
      all the target muscles with facilitation effects in spike-triggered averages
      (PSpF, PSpF with synchrony, or synchrony facilitation alone), 89.5% were
      associated with significant cross-correlation peaks, indicating positively
      covarying muscle and CM cell activity. Seven percent of facilitation effects were
      not associated with a significant effect in the cross-correlation, whereas only
      3.4% of effects were associated with correlation troughs. In contrast, of all the
      muscles with suppression effects in spike-triggered averages, 38.9% were
      associated with significant troughs in the cross-correlation, indicating an
      inverse relation between CM cell and muscle activity consistent with the presence
      of suppression. Fifty-five percent of suppression effects was associated with
      correlation peaks, whereas 5.6% was not associated with a significant effect in
      the cross-correlation. Limiting the analysis to moderate and strong facilitation
      effects, the magnitude of PSpF was correlated weakly with the magnitude of the
      cell-muscle cross-correlation peak. Nevertheless, the results show that although
      many CM cell-target muscle pairs covary during the reach and prehension task in a
      way consistent with the sign and strength of the CM cell's synaptic effects on
      target motoneurons, many exceptions exist. The results are compatible with a
      model in which control of particular motoneuron pools reflects not only the
      summation of signals from many CM cells but also signals from additional
      descending, sensory afferent, and intrinsic spinal cord neurons. Any one neuron
      will make only a small contribution to the overall activity of the motoneuron
      pool. In view of this, it is not surprising that relationships between postspike
      effects and CM cell-target muscle covariation are relatively weak with many
      apparent incongruities.

PMID- 10634858
TI  - Nitric oxide and carbon monoxide modulate oscillations of olfactory interneurons
      in a terrestrial mollusk.
AB  - Spontaneous or odor-induced oscillations in local field potential are a general
      feature of olfactory processing centers in a large number of vertebrate and
      invertebrate species. The ubiquity of such oscillations in the olfactory bulb of
      vertebrates and analogous structures in arthropods and mollusks suggests that
      oscillations are fundamental to the computations performed during processing of
      odor stimuli. Diffusible intercellular messengers such as nitric oxide (NO) and
      carbon monoxide (CO) also are associated with central olfactory structures in a
      wide array of species. We use the procerebral (PC) lobe of the terrestrial
      mollusk Limax maximus to demonstrate a role for NO and CO in the oscillatory
      dynamics of the PC lobe: synthesizing enzymes for NO and CO are associated with
      the PC lobes of Limax, application of NO to the Limax PC lobe increases the local
      field potential oscillation frequency, whereas block of NO synthesis slows or
      stops the oscillation, the bursting cells of the PC lobe that drive the field
      potential oscillation are driven to higher burst frequency by application of NO,
      the nonbursting cells of the PC lobe receive trains of inhibitory postsynaptic
      potentials, presumably from bursting cells, due to application of NO, and
      application of CO to the PC lobe by photolysis of caged CO results in an increase
      in oscillation frequency proportional to CO dosage.

PMID- 10634859
TI  - Temporal dynamics of acoustic stimuli enhance amplitude tuning of inferior
      colliculus neurons.
AB  - Sounds in real-world situations seldom occur in isolation. In spite of this, most
      studies in the auditory system have employed sounds that serve to isolate
      physiological responses, namely, at low rates of stimulation. It is unclear,
      however, whether the basic response properties of a neuron derived thereof, such
      as its amplitude and frequency selectivities, are applicable to real-world
      situations where sounds occur in rapid succession. In the present study, we
      investigated one of the basic response properties of neurons in the bat inferior
      colliculus (IC), i.e., the rate-level function, to tone pulses in three different
      configurations: individual tone pulses of constant amplitude at different rates
      of stimulation, random-amplitude pulse trains, and dynamic-amplitude-modulated
      pulse trains the temporal pattern of which was similar to what bats encounter in
      a behavioral context. We reported that for the majority of IC neurons, amplitude
      selectivity to tone pulses was dependent on the rate of stimulation. In general,
      the selectivity was greater at high rates or in a behavioral context than at low
      rates. For a small population of IC neurons, however, the rate of stimulation had
      little or no effect on their rate-level functions. Thus for IC neurons, responses
      to sounds presented at low rates may or may not be used to predict the responses
      to the same stimuli presented at high rates or in a behavioral context. The
      possible neural mechanisms underlying the rate-dependent effects are discussed.

PMID- 10634860
TI  - Odor specificity of habituation in the rat anterior piriform cortex.
AB  - Exposure to odorants results in a rapid (<10 s) reduction in odor-evoked activity
      in the rat piriform cortex despite relatively maintained afferent input from
      olfactory bulb mitral cells. To further understand this form of cortical
      plasticity, a detailed analysis of its odor specificity was performed.
      Habituation of odor responses in anterior piriform cortex single units was
      examined in anesthetized, freely breathing rats. The magnitude of single-unit
      responses of layer II/III neurons to 2-s odor pulses were examined before and
      after a 50-s habituating stimulus of either the same or different odor. The
      results demonstrated that odor habituation was odor specific, with no significant
      cross-habituation between either markedly different single odors or between odors
      within a series of straight chain alkanes. Furthermore, habituation to binary 1:1
      mixtures produced minimal cross-habituation to the components of that mixture.
      These latter results may suggest synthetic odor processing in the olfactory
      system, with novel odor mixtures processed as unique stimuli. Potential
      mechanisms of odor habituation in the piriform cortex must be able to account for
      the high degree of specificity of this effect.

PMID- 10634861
TI  - Electrically evoked fictive swimming in the low-spinal immobilized turtle.
AB  - Fictive swimming was elicited in low-spinal immobilized turtles by electrically
      stimulating the contralateral dorsolateral funiculus (cDLF) at the level of the
      third postcervical segment (D(3)). Fictive hindlimb motor output was recorded as
      electroneurograms (ENGs) from up to five peripheral nerves on the right side,
      including three knee extensors (KE; iliotibialis [IT]-KE, ambiens [AM]-KE, and
      femorotibialis [FT]-KE), a hip flexor (HF), and a hip extensor (HE). Quantitative
      analyses of burst amplitude, duty cycle and phase were used to demonstrate the
      close similarity of these cDLF-evoked fictive motor patterns with previous
      myographic recordings obtained from the corresponding hindlimb muscles during
      actual swimming. Fictive rostral scratching was elicited in the same animals by
      cutaneous stimulation of the shell bridge, anterior to the hindlimb. Fictive swim
      and rostral scratch motor patterns displayed similar phasing in hip and knee
      motor pools but differed in the relative amplitudes and durations of ENG bursts.
      Both motor patterns exhibited alternating HF and HE discharge, with monoarticular
      knee extensor (FT-KE) discharge during the late HF phase. The two motor patterns
      differed principally in the relative amplitudes and durations of HF and HE
      bursts. Swim cycles were dominated by large-amplitude, long-duration HE bursts,
      whereas rostral scratch cycles were dominated by large-amplitude, long-duration
      HF discharge. Small but significant differences were also observed during the two
      behaviors in the onset phase of biarticular knee extensor bursts (IT-KE and AM
      KE) within each hip cycle. Finally, interactions between swim and scratch motor
      networks were investigated. Brief activation of the rostral scratch during an
      ongoing fictive swim episode could insert one or more scratch cycles into the
      swim motor pattern and permanently reset the burst rhythm. Similarly, brief swim
      stimulation could interrupt and reset an ongoing fictive rostral scratch. This
      shows that there are strong central interactions between swim and scratch neural
      networks and suggests that they may share key neural elements.

PMID- 10634862
TI  - Scratch-swim hybrids in the spinal turtle: blending of rostral scratch and
      forward swim.
AB  - Turtles with a complete transection of the spinal cord just posterior to the
      forelimb enlargement at the D2-D3 segmental border produced coordinated rhythmic
      hindlimb movements. Ipsilateral stimulation of cutaneous afferents in the midbody
      shell bridge evoked a rostral scratch. Electrical stimulation of the
      contralateral dorsolateral funiculus (DLF) at the anterior cut face of the D3
      segment activated a forward swim. Simultaneous stimulation of the ipsilateral
      shell bridge and the contralateral DLF elicited a scratch-swim hybrid: a behavior
      that blended features of both rostral scratch and forward swim into each cycle of
      rhythmic movement. This is the first demonstration of a scratch-locomotion hybrid
      in a spinal vertebrate. The rostral scratch and the forward swim shared some
      characteristics: alternating hip flexion and extension, similar timing of knee
      extensor activity within the hip cycle, and a behavioral event during which force
      was exerted against a substrate. During each cycle, each behavior exhibited three
      sequential stages, preevent, event, and postevent. The rostral scratch event was
      a rub of the foot against the stimulated shell site. The forward swim event was a
      powerstroke, a hip extension movement with the foot held in a vertical position
      with toes and webbing spread. The two behaviors differed with respect to several
      features: amount of hip flexion and extension, electromyogram (EMG) amplitudes,
      and EMG duty cycles. Scratch-swim hybrids displayed two events, the scratch rub
      and the swim powerstroke, within each cycle. Hybrid hip flexion excursion, knee
      extensor EMGs, and hip flexor EMGs were similar to those of the scratch; hybrid
      hip extension excursion and hip extensor EMGs were similar to those of the swim.
      The hybrid also had three sequential stages during each cycle: 1) a combined
      scratch prerub and swim postpowerstroke, 2) a scratch rub that also served as a
      swim prepowerstroke, and 3) a swim powerstroke that also served as a scratch
      postrub. Merging of the rostral scratch with the forward swim was possible
      because of similarities between the sequential stages of the two forms, making
      them biomechanically compatible for hybrid formation. Kinematic and myographic
      similarities between the rostral scratch and the forward swim support the
      hypothesis that the two behaviors share common neural circuitry. The common
      features of the sequential stages of each behavior and the production of scratch
      swim hybrids provide additional support for the hypothesis of a shared core of
      spinal cord neurons common to both rostral scratch and forward swim.

PMID- 10634863
TI  - Neurophysiological aspects of eye and eyelid movements during blinking in humans.
AB  - The neural relationships between eyelid movements and eye movements during
      spontaneous, voluntary, and reflex blinking in a group of healthy subjects were
      examined. Electromyographic (EMG) recording of the orbicularis oculi (OO) muscles
      was performed using surface electrodes. Concurrently, horizontal and vertical eye
      positions were recorded by means of the double magnetic induction (DMI) ring
      method. In addition, movement of the upper eyelid was measured by a specially
      designed search coil, placed on the upper eyelid. The reflex blink was elicited
      electrically by supraorbital nerve stimulation either on the right or the left
      side. It is found that disconjugate oblique eye movements accompany spontaneous,
      voluntary as well as reflex blinking. Depending on the gaze position before
      blinking, the amplitude of horizontal and vertical components of the eye movement
      during blinking varies in a systematic way. With adduction and downward gaze the
      amplitude is minimal. With abduction the horizontal amplitude increases, whereas
      with upward gaze the vertical amplitude increases. Unilateral electrical
      supraorbital nerve stimulation at low currents elicits eye movements with a
      bilateral late component. At stimulus intensities approximately two to three
      times above the threshold, the early ipsilateral blink reflex response (R(1)) in
      the OO muscle can be observed together with an early ipsilateral eye movement
      component at a latency of approximately 15 ms. In addition, during the electrical
      blink reflex, early ipsilateral and late bilateral components can also be
      identified in the upper eyelid movement. In contrast to the late bilateral
      component of upper eyelid movement, the early ipsilateral component of upper
      eyelid movement appears to open the eye to a greater degree. This early
      ipsilateral component of upper eyelid movement occurs more or less simultaneously
      with the early eye movement component. It is suggested that both early
      ipsilateral movements following electrical stimulation do not have a central
      neural origin. Late components of the eye movements slightly precede the late
      components of the eyelid movement. Synchrony between late components of eyelid
      movements and eye movements as well as similarity of oblique eye movement
      components in different types of blinking suggest the existence of a premotor
      neural structure acting as a generator that coordinates impulses to different
      subnuclei of the oculomotor nucleus as well as the facial nerve nucleus during
      blinking independent from the ocular saccadic and/or vergence system. The profile
      and direction of the eye movement rotation during blinking gives support to the
      idea that it may be secondary to eyeball retraction; an extra cocontraction of
      the inferior and superior rectus muscle would be sufficient to explain both eye
      retraction and rotation in the horizontal vertical and torsional planes.

PMID- 10634864
TI  - 2-Deoxyglucose-induced long-term potentiation in CA1 is not prevented by
      intraneuronal chelator.
AB  - In hippocampal slices, temporary (10-20 min) replacement of glucose with 10 mM 2
      deoxyglucose is followed by marked and very sustained potentiation of EPSPs (2-DG
      LTP). To investigate its mechanism, we examined 2-DG's effect in CA1 neurons
      recorded with sharp 3 M KCl electrodes containing a strong chelator, 50 or 100 mM
      ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA). In
      most cases, field EPSPs were simultaneously recorded and conventional LTP was
      also elicited in some cells by tetanic stimulation of stratum radiatum. 2-DG
      potentiated intracellular EPSP slopes by 48 +/- 5.1% (SE) in nine cells recorded
      with plain KCl electrodes and by 52 +/- 6.2% in seven cells recorded with EGTA
      containing electrodes. In four of the latter cells, tetanic stimulation (twice
      100 Hz for 1 s) failed to evoke LTP (2 +/- 1.1%), although field EPSPs were
      clearly potentiated (by 28 +/- 6.9%). Thus unlike tetanic LTP, 2-DG LTP is not
      readily prevented by postsynaptic intraneuronal injection of EGTA. These findings
      agree with other evidence that the rise in postsynaptic (somatic) [Ca(2+)](i)
      caused by 2-DG is not the principal trigger for the subsequent 2-DG LTP and that
      it may be a purely presynaptic phenomenon.

PMID- 10634865
TI  - Properties of miniature glutamatergic EPSCs in neurons of the locomotor regions
      of the developing zebrafish.
AB  - As a first step in understanding the development of synaptic activation in the
      locomotor network of the zebrafish, we examined the properties of spontaneous,
      glutamatergic miniature excitatory postsynaptic currents (mEPSCs). Whole cell
      patch-clamp recordings were obtained from visually identified hindbrain
      reticulospinal neurons and spinal motoneurons of curarized zebrafish 1-5 days
      postfertilization (larvae hatch after the 2nd day of embryogenesis). In the
      presence of tetrodotoxin (TTX) and blockers of inhibitory receptors (strychnine
      and picrotoxin), we detected fast glutamatergic mEPSCs that were blocked by the
      AMPA/kainate receptor-selective antagonist 6-cyano-7-nitroquinoxaline-2,3-dione
      (CNQX). At positive voltages or in the absence of Mg(2+), a second, slower
      component of the mEPSCs was revealed that the N-methyl-D-aspartate (NMDA)
      receptor-selective antagonist DL-2-amino-5-phosphonovalerate (AP-5) abolished. In
      the presence of both CNQX and AP-5, all mEPSCs were eliminated. The NMDA
      component of reticulospinal mEPSCs had a large single-channel conductance
      estimated to be 48 pS. Larval AMPA/kainate and NMDA components of the mEPSCs
      decayed with biexponential time courses that changed little during development.
      At all stages examined, approximately one-half of synapses had only NMDA
      responses (lacking AMPA/kainate receptors), whereas the remainder of the synapses
      were composed of a mixture of AMPA/kainate and NMDA receptors. There was an
      overall increase in the frequency and amplitude of mEPSCs with an NMDA component
      in reticulospinal (but not motoneurons) during development. These results
      indicate that glutamate is a prominent excitatory transmitter in the locomotor
      regions of the developing zebrafish and that it activates either NMDA receptors
      alone at functionally silent synapses or together with AMPA/kainate receptors.

PMID- 10634866
TI  - Calcium release from internal stores is required for the generation of
      spontaneous hyperpolarizations in dopaminergic neurons of neonatal rats.
AB  - We recently have demonstrated the existence of spontaneous hyperpolarizations in
      midbrain dopaminergic neurons of neonatal but not adult rats. These events are
      mediated by the opening of apamin-sensitive K(+) channels after a rise in the
      intracellular concentration of Ca(2+). They are resistant to tetrodotoxin in most
      cases and are probably endogenous (i.e., not synaptically activated). Here their
      mechanism was investigated. Cyclopiazonic acid (10 microM), a specific inhibitor
      of endoplasmic reticulum Ca(2+) ATPases, reversibly abolished the events.
      Caffeine, which promotes Ca(2+) release from intracellular stores, had
      concentration-dependent effects. At 1 mM, it markedly and steadily increased the
      frequency and the amplitude of the hyperpolarizations. At 10 mM, it induced a
      transient increase in their frequency followed by their cessation. All these
      effects were quickly reversible. Ryanodine (10 microM), which decreases the
      conductance of Ca(2+) release channels, irreversibly blocked the spontaneous
      hyperpolarizations. Dantrolene (100 microM), a blocker of Ca(2+) release from
      sarcoplasmic reticulum of striated muscle, did not affect the events. On the
      other hand, Cd(2+) (100-300 microM), a broad antagonist of membrane voltage-gated
      Ca(2+) channels, significantly reduced the amplitude and the frequency of the
      hyperpolarizations. However, when the frequency of the events was increased by 1
      mM caffeine, Cd(2+) affected them to a smaller extent, whereas cyclopiazonic acid
      still abolished them. We conclude that internal stores are the major source of
      Ca(2+) ions that induce the K(+) channel openings underlying the spontaneous
      hyperpolarizations of these neurons.

PMID- 10634867
TI  - Calcium channel activation facilitated by nitric oxide in retinal ganglion cells.
AB  - We investigated the modulation of voltage-gated Ca channels by nitric oxide (NO)
      in isolated salamander retinal ganglion cells with the goals of determining the
      type of Ca channel affected and the signaling pathway by which modulation might
      occur. The NO donors, S-nitroso-N-acetyl-penicillamine (SNAP, 1 mM) and S-nitroso
      cysteine (1 mM) induced modest increases in the amplitude of Ca channel currents
      recorded with ruptured- and permeabilized-patch techniques by causing a
      subpopulation of the Ca channels to activate at more negative potentials. The Ca
      channel antagonists omega-conotoxin GVIA and nisoldipine each reduced the Ca
      channel current partially, but only omega-conotoxin GVIA blocked the enhancement
      by SNAP. The SNAP-induced increase was blocked by oxadiazolo-quinoxaline (50
      microM), suggesting that the NO generated by SNAP acts via a soluble guanylyl
      cyclase to raise levels of cGMP. The membrane-permeant cGMP analog 8-(4
      chlorophenylthio) guanosine cyclic monophosphate also enhanced Ca channel
      currents and 8-bromo guanosine cyclic monophosphate (1 mM) occluded enhancement
      by SNAP. Consistent with these results, isobutyl-methyl-xanthine (IBMX, 10
      microM), which can raise cGMP levels by inhibiting phosphodiesterase activity,
      increased Ca channel current by the same amount as SNAP and occluded subsequent
      enhancement by SNAP. Neither IBMX, the cGMP analogs, nor SNAP itself, led to
      activation of cGMP-gated channels. N-[2-(methylamino)ethyl]-5-isoquinoline
      sulfonamide (2 microM), a broad spectrum inhibitor of protein kinase activity,
      KT5823 (1 microM), a specific protein kinase G (PKG) inhibitor, and a peptide
      inhibitor of PKG (200 microM) blocked SNAP enhancement, as did 5'
      adenylylimidophosphate (1.5 mM), a nonhydrolyzable ATP analog that prevents
      protein phosphorylation. A peptide inhibitor of protein kinase A (10 nM) did not
      block the facilitory effects of SNAP. Okadaic acid (1 microM), a phosphatase
      inhibitor, had no effect by itself but increased the enhancement of Ca channel
      current by SNAP. These results suggest that NO modulates retinal ganglion cell N
      type Ca channels by facilitating their voltage-dependent activation via a
      mechanism involving guanylyl cyclase/PKG-dependent phosphorylation. This effect
      could fine-tune neural integration in ganglion cells or play a role in ganglion
      cell disease by modulating intracellular calcium signaling.

PMID- 10634868
TI  - The neuromuscular transform: the dynamic, nonlinear link between motor neuron
      firing patterns and muscle contraction in rhythmic behaviors.
AB  - The nervous system issues motor commands to muscles to generate behavior. All
      such commands must, however, pass through a filter that we call here the
      neuromuscular transform (NMT). The NMT transforms patterns of motor neuron firing
      to muscle contractions. This work is motivated by the fact that the NMT is far
      from being a straightforward, transparent link between motor neuron and muscle.
      The NMT is a dynamic, nonlinear, and modifiable filter. Consequently motor neuron
      firing translates to muscle contraction in a complex way. This complexity must be
      taken into account by the nervous system when issuing its motor commands, as well
      as by us when assessing their significance. This is the first of three papers in
      which we consider the properties and the functional role of the NMT.
      Physiologically, the motor neuron-muscle link comprises multiple steps of
      presynaptic and postsynaptic Ca(2+) elevation, transmitter release, and
      activation of the contractile machinery. The NMT formalizes all these into an
      overall input-output relation between patterns of motor neuron firing and shapes
      of muscle contractions. We develop here an analytic framework, essentially an
      elementary dynamical systems approach, with which we can study the global
      properties of the transformation. We analyze the principles that determine how
      different firing patterns are transformed to contractions, and different
      parameters of the former to parameters of the latter. The key properties of the
      NMT are its nonlinearity and its time dependence, relative to the time scale of
      the firing pattern. We then discuss issues of neuromuscular prediction, control,
      and coding. Does the firing pattern contain a code by means of which particular
      parameters of motor neuron firing control particular parameters of muscle
      contraction? What information must the motor neuron, and the nervous system
      generally, have about the periphery to be able to control it effectively? We
      focus here particularly on cyclical, rhythmic contractions which reveal the
      principles particularly clearly. Where possible, we illustrate the principles in
      an experimentally advantageous model system, the accessory radula closer (ARC)
      opener neuromuscular system of Aplysia. In the following papers, we use the
      framework developed here to examine how the properties of the NMT govern
      functional performance in different rhythmic behaviors that the nervous system
      may command.

PMID- 10634869
TI  - The neuromuscular transform constrains the production of functional rhythmic
      behaviors.
AB  - We continue our study of the properties and the functional role of the
      neuromuscular transform (NMT). The NMT is an input-output relation that
      formalizes the processes by which patterns of motor neuron firing are transformed
      to muscle contractions. Because the NMT acts as a dynamic, nonlinear, and
      modifiable filter, the transformation is complex. In the preceding paper we
      developed a framework for analysis of the NMT and identified with it principles
      by which the NMT transforms different firing patterns to contractions. The
      ultimate question is functional, however. In sending different firing patterns
      through the NMT, the nervous system is seeking to command different functional
      behaviors, with specific contraction requirements. To what extent do the
      contractions that emerge from the NMT actually satisfy those requirements? In
      this paper we extend our analysis to address this issue. We define representative
      behavioral tasks and corresponding measures of performance, for a single
      neuromuscular unit, for two antagonistic units, and, in a real illustration, for
      the accessory radula closer (ARC)-opener neuromuscular system of Aplysia. We
      focus on cyclical, rhythmic behaviors which reveal the underlying principles
      particularly clearly. We find that, although every pattern of motor neuron firing
      produces some state of muscle contraction, only a few patterns produce functional
      behavior, and even fewer produce efficient functional behavior. The functional
      requirements thus dictate certain patterns to the nervous system. But many
      desirable functional behaviors are not possible with any pattern. We examine, in
      particular, how rhythmic behaviors degrade and disintegrate as the nervous system
      attempts to speed up their cycle frequency. This happens because, with fixed
      properties, the NMT produces only a limited range of contraction shapes that are
      kinetically well matched to the firing pattern only on certain time scales. Thus
      the properties of the NMT constrain and restrict the production of functional
      behaviors. In the following paper, we see how the constraint may be alleviated
      and the range of functional behaviors expanded by appropriately tuning the
      properties of the NMT through neuromuscular plasticity and modulation.

PMID- 10634870
TI  - Optimization of rhythmic behaviors by modulation of the neuromuscular transform.
AB  - We conclude our study of the properties and the functional role of the
      neuromuscular transform (NMT). The NMT is an input-output relation that
      formalizes the processes by which patterns of motor neuron firing are transformed
      to muscle contractions. Because the NMT acts as a dynamic, nonlinear, and
      modifiable filter, the transformation is complex. In the two preceding papers we
      developed a framework for analysis of the NMT and identified with it principles
      by which the NMT transforms different firing patterns to contractions. We then
      saw that, with fixed properties, the NMT significantly constrains the production
      of functional behavior. Many desirable behaviors are not possible with any firing
      pattern. Here we examine, theoretically as well as experimentally in the
      accessory radula closer (ARC) neuromuscular system of Aplysia, how this
      constraint is alleviated by making the properties of the NMT variable by
      neuromuscular plasticity and modulation. These processes dynamically tune the
      properties of the NMT to match the desired behavior, expanding the range of
      behaviors that can be produced. For specific illustration, we continue to focus
      on the relation between the speed of the NMT and the speed of cyclical, rhythmic
      behavior. Our analytic framework emphasizes the functional distinction between
      intrinsic plasticity or modulation of the NMT, dependent, like the contraction
      itself, on the motor neuron firing pattern, and extrinsic modulation, independent
      of it. The former is well suited to automatically optimizing the performance of a
      single behavior; the latter, to multiplying contraction shapes for multiple
      behaviors. In any case, to alleviate the constraint of the NMT, the plasticity
      and modulation must be peripheral. Such processes are likely to play a critical
      role wherever the nervous system must command, through the constraint of the NMT,
      a broad range of functional behaviors.

PMID- 10634871
TI  - Evidence for paracrine signaling between macrophages and bovine adrenal
      chromaffin cell Ca(2+) channels.
AB  - The adrenal gland contains resident macrophages, some of which lie adjacent to
      the catecholamine producing chromaffin cells. Because macrophages release a
      variety of secretory products, it is possible that paracrine signaling between
      these two cell types exists. Of particular interest is the potential paracrine
      modulation of voltage-gated calcium channels (I(Ca)), which are the main calcium
      influx pathway triggering catecholamine release from chromaffin cells. We report
      that prostaglandin E(2) (PGE(2)), one of the main signals produced by
      macrophages, inhibited I(Ca) in cultured bovine adrenal chromaffin cells. The
      inhibition is rapid, robust, and voltage dependent; the activation kinetics are
      slowed and inhibition is largely reversed by a large depolarizing prepulse,
      suggesting that the inhibition is mediated by a direct G-protein betagamma
      subunit interaction with the calcium channels. About half of the response to
      PGE(2) was sensitive to pertussis toxin (PTX) incubation, suggesting both PTX
      sensitive and -insensitive G proteins were involved. We show that activation of
      macrophages by endotoxin rapidly (within minutes) releases a signal that inhibits
      I(Ca) in chromaffin cells. The inhibition is voltage dependent and partially PTX
      sensitive. PGE(2) is not responsible for this inhibition as blocking
      cyclooxygenase with ibuprofen did not prevent the production of the inhibitory
      signal by the macrophages. Nor did blocking the lipoxygenase pathway with
      nordihydroguaiaretic acid alter production of the inhibitory signal. Our results
      suggest that macrophages may modulate I(Ca) and catecholamine secretion by
      releasing PGE(2) and other chemical signal(s).

PMID- 10634872
TI  - Interactions between posture and locomotion: motor patterns in humans walking
      with bent posture versus erect posture.
AB  - Human erect locomotion is unique among living primates. Evolution selected
      specific biomechanical features that make human locomotion mechanically
      efficient. These features are matched by the motor patterns generated in the CNS.
      What happens when humans walk with bent postures? Are normal motor patterns of
      erect locomotion maintained or completely reorganized? Five healthy volunteers
      walked straight and forward at different speeds in three different postures
      (regular, knee-flexed, and knee- and trunk-flexed) while their motion, ground
      reaction forces, and electromyographic (EMG) activity were recorded. The three
      postures imply large differences in the position of the center of body mass
      relative to the body segments. The elevation angles of the trunk, pelvis, and
      lower limb segments relative to the vertical in the sagittal plane, the ground
      reaction forces and the rectified EMGs were analyzed over the gait cycle. The
      waveforms of the elevation angles along the gait cycle remained essentially
      unchanged irrespective of the adopted postures. The first two harmonics of these
      kinematic waveforms explain >95% of their variance. The phase shift but not the
      amplitude ratio between the first harmonic of the elevation angle waveforms of
      adjacent pairs was affected systematically by changes in posture. Thigh, shank,
      and foot angles covaried close to a plane in all conditions, but the plane
      orientation was systematically different in bent versus erect locomotion. This
      was explained by the changes in the temporal coupling among the three segments.
      For walking speeds >1 m s(-1), the plane orientation of bent locomotion indicates
      a much lower mechanical efficiency relative to erect locomotion. Ground reaction
      forces differed prominently in bent versus erect posture displaying
      characteristics intermediate between those typical of walking and those of
      running. Mean EMG activity was greater in bent postures for all recorded muscles
      independent of the functional role. The waveforms of the muscle activities and
      muscle synergies also were affected by the adopted posture. We conclude that
      maintaining bent postures does not interfere either with the generation of
      segmental kinematic waveforms or with the planar constraint of intersegmental
      covariation. These characteristics are maintained at the expense of adjustments
      in kinetic parameters, muscle synergies and the temporal coupling among the
      oscillating body segments. We argue that an integrated control of gait and
      posture is made possible because these two motor functions share some common
      principles of spatial organization.

PMID- 10634873
TI  - Contributions of ion conductances to the onset responses of octopus cells in the
      ventral cochlear nucleus: simulation results.
AB  - The onset response pattern displayed by octopus cells has been attributed to
      intrinsic membrane properties, low membrane impedance, and/or synaptic inputs.
      Although the importance of a low membrane impedance generally is acknowledged as
      an essential component, views differ on the role that ion channels play in
      producing the onset response. In this study, we use a computer model to
      investigate the contributions of ion channels to the responses of octopus cells.
      Simulations using current ramps indicate that, during the "ramp-up" stage, the
      membrane depolarizes, activating a low-threshold K(+) channel, K(LT), which
      increases membrane conductance and dynamically increases the current required to
      evoke an action potential. As a result, the model is sensitive to the rate that
      membrane potential changes when initiating an action potential. Results obtained
      when experimentally recorded spike trains of auditory-nerve fibers served as
      model inputs (simulating acoustic stimulation) demonstrate that a model with
      K(LT) conductance as the dominant conductance produces realistic onset response
      patterns. Systematically replacing the K(LT) conductance by a h-type conductance
      (which corresponds to a hyperpolarization-activated inward rectifier current,
      I(h)) or by a leakage conductance reduces the model's sensitivity to rate of
      change in membrane potential, and the model's response to "acoustic stimulation"
      becomes more chopper-like. Increasing the h-type conductance while maintaining a
      large K(LT) conductance causes an increase in threshold to both current steps and
      acoustic stimulation but does not significantly affect the model's sensitivity to
      rate of change in membrane potential and the onset response pattern under
      acoustic stimulation. These findings support the idea that K(LT), which is
      activated during depolarization, is the primary membrane conductance determining
      the response properties of octopus cells, and its dynamic role cannot be provided
      by a static membrane conductance. On the other hand, I(h), which is activated
      during hyperpolarization, does not play a large role in the basic onset response
      pattern but may regulate response threshold through its contribution to the
      membrane conductance.

PMID- 10634874
TI  - Alterations in NMDA receptors in a rat model of cortical dysplasia.
AB  - Recent studies have demonstrated an important role for the N-methyl-D-aspartate
      receptor (NMDAR) in epilepsy. NMDARs have also been shown to play a critical role
      in hyperexcitability associated with several animal models of human epilepsy.
      Using whole-cell voltage clamp recordings in brain slices, we studied evoked
      paroxysmal discharges in the freeze-lesion model of neocortical microgyria. The
      voltage dependence of epileptiform discharges indicated that these paroxysmal
      events were produced by a complex pattern of excitatory and inhibitory inputs. We
      examined the effect of the NMDAR antagonist D-2-amino-5-phosphopentanoic acid
      (APV) and the NMDA receptor subunit type 2B (NR2B)-selective antagonist
      ifenprodil on the threshold, peak amplitude, and area of evoked epileptiform
      discharges in brain slices from lesioned animals. Both compounds consistently
      raised the threshold for evoking the discharge but had modest effects on the
      discharge peak and amplitude. For comparison with nonlesioned cortex, we examined
      the effects of ifenprodil on the epileptiform discharge evoked in the presence of
      2 microM bicuculline (partial disinhibition). In slices from nonlesioned cortex,
      10 microM ifenprodil had little effect on the threshold whereas 71% of the
      recordings in bicuculline-treated lesioned cortex showed a >25% increase in
      threshold. These results suggest that NR2B-containing receptors are functionally
      enhanced in freeze-lesioned cortex and may contribute to the abnormal
      hyperexcitability observed in this model of neocortical microgyria.

PMID- 10634875
TI  - Adenosine receptor expression and modulation of Ca(2+) channels in rat striatal
      cholinergic interneurons.
AB  - Adenosine is a potent regulator of acetylcholine release in the striatum, yet the
      mechanisms mediating this regulation are largely undefined. To begin to fill this
      gap, adenosine receptor expression and coupling to voltage-dependent Ca(2+)
      channels were studied in cholinergic interneurons by combined whole cell voltage
      clamp recording and single-cell reverse transcription-polymerase chain reaction.
      Cholinergic interneurons were identified by the presence of choline
      acetyltransferase mRNA. Nearly all of these interneurons (90%, n = 28) expressed
      detectable levels of A(1) adenosine receptor mRNA. A(2a) and A(2b) receptor mRNAs
      were less frequently detected. A(3) receptor mRNA was undetectable. Adenosine
      rapidly and reversibly reduced N-type Ca(2+) currents in cholinergic
      interneurons. The A(1) receptor antagonist 8-cyclopentyl-1, 3-dimethylxanthine
      completely blocked the effect of adenosine. The IC(50) of the A(1) receptor
      selective agonist 2-chloro-N6-cyclopentyladenosine was 45 nM, whereas it was near
      30 microM for the A(2a) receptor agonist CGS-21680. Dialysis with GDPbetaS or
      brief exposure to the G protein (G(i/o)) alkylating agent N-ethylmaleimide also
      blocked the adenosine modulation. The reduction in N-type currents was partially
      reversed by depolarizing prepulses. A membrane-delimited pathway mediated the
      modulation, because it was not seen in cell-attached patches when agonist was
      applied to the bath. Activation of protein kinase C attenuated the adenosine
      modulation. Taken together, our results argue that activation of A(1) adenosine
      receptors in cholinergic interneurons reduces N-type Ca(2+) currents via a
      membrane-delimited, G(i/o) class G-protein pathway that is regulated by protein
      kinase C. These observations establish a cellular mechanism by which adenosine
      may serve to reduce acetylcholine release.

PMID- 10634876
TI  - Effect of ethanol upon respiratory-related hypoglossal nerve output of neonatal
      rat brain stem slices.
AB  - The actions of ethanol (EtOH) on the respiratory output of the neonatal rat brain
      stem slice preparation in vitro are described. Ethanol inhibited respiratory
      related hypoglossal nerve activity in a dose-dependent manner. The effect of EtOH
      was evident within 5 min and was reversible on EtOH washout. The actions of EtOH
      were qualitatively similar to those of two other alcohols, methanol and octanol.
      We investigated the dose-response relationship for each alcohol and determined
      that the order of potency was methanol < EtOH << octanol, with EC(50) values of
      291 mM, 39.7 mM, and 49.2 microM respectively. Application of either strychnine
      (5 microM) or bicuculline (5 microM) alone, partially but not significantly,
      reversed the inhibition of respiratory-related hypoglossal nerve activity
      produced by 50 mM EtOH. Preincubation of rhythmic slices with a combination of
      both strychnine and bicuculline (both 5 microM) partially, but significantly,
      blocked the inhibitory actions of EtOH, suggesting that other mechanisms also
      play a role in the action of EtOH. Preincubation of the slices with 25 microM APV
      reduced the relative degree of inhibition caused by EtOH suggesting that N-methyl
      D-aspartate (NMDA)-receptor-mediated events can be affected by EtOH. Furthermore
      inhibition of protein kinase C by incubation with 100 nM staurosporine also
      reduced the efficacy of EtOH. These results suggest that the actions of EtOH may
      be mediated via glycine, GABA(A), and NMDA receptors and that activation of
      protein kinase C is involved in the EtOH-induced inhibition of respiratory
      related hypoglossal nerve activity.

PMID- 10634877
TI  - Corticotropin-releasing factor produces a protein synthesis--dependent long
      lasting potentiation in dentate gyrus neurons.
AB  - Corticotropin-releasing factor (CRF) was shown to produce a long-lasting
      potentiation of synaptic efficacy in dentate gyrus neurons of the rat hippocampus
      in vivo. This potentiation was shown to share some similarities with tetanization
      induced long-term potentiation (LTP). In the present study, we further examined
      the mechanism underlying CRF-induced long-lasting potentiation in rat hippocampus
      in vivo. Results indicated that the RNA synthesis inhibitor actinomycin-D, at a
      concentration that did not change basal synaptic transmission alone (5
      microgram), significantly decreased CRF-induced potentiation. Similarly, the
      protein synthesis inhibitor emetine, at a concentration that did not affect
      hippocampal synaptic transmission alone (5 microgram), also markedly inhibited
      CRF-induced potentiation. These results suggest that like the late phase of LTP,
      CRF-induced long-lasting potentiation also critically depend on protein
      synthesis. Further, prior maximum excitation of dentate gyrus neurons with
      tetanization occluded further potentiation of these neurons produced by CRF and
      vise versa. Moreover, quantitative reverse transcription-polymerase chain
      reaction analysis revealed that CRF mRNA level in the dentate gyrus was
      significantly increased 1 h after LTP recording. Together with our previous
      findings that CRF antagonist dose-dependently diminishes tetanization-induced
      LTP, these results suggest that both CRF-induced long-lasting potentiation and
      tetanization-induced LTP require protein synthesis and that CRF neurons are
      possibly involved in the neural circuits underlying LTP.

PMID- 10634878
TI  - Nucleus-specific differences in GABA(A)-receptor-mediated inhibition are enhanced
      during thalamic development.
AB  - Inhibitory postsynaptic currents (IPSCs) mediated by GABA(A) receptors are much
      slower in neurons of the thalamic reticular nucleus (RTN) versus those in the
      ventrobasal complex (VB) of young rats. Here we confirm and extend those findings
      regarding GABA(A) response heterogeneity especially in relation to development.
      Whole cell patch-clamp recordings were used to investigate GABA(A) spontaneous
      and electrically evoked IPSCs (sIPSCs/eIPSCs) in RTN and VB cells of different
      aged rats. Consistent with earlier findings, sIPSC duration at P8-12 was
      considerably longer in RTN (weighted decay time constant: tau(D,W) = 56.2 +/- 4.9
      ms; mean +/- SE) than in VB (tau(D,W) = 15.8 +/- 1.0 ms) neurons. Decay kinetics
      in RTN neurons did not differ at P21-30 (45.5 +/- 4.7 ms) or P42-60 (51.6 +/-
      10.6 ms). In contrast, VB sIPSCs were significantly faster at both P21-30
      (tau(D,W) = 10.8 +/- 0.9 ms) and P42-60 (tau(D,W) = 9.2 +/- 0.4 ms) compared with
      P8-12 animals. IPSCs displayed differential outward rectification and temperature
      dependence, providing further support for nucleus-specific responses. tau(D,W)
      increased with membrane depolarization but with a net larger effect in VB. By
      contrast, tau(D,W) was always smaller at higher temperatures but with relatively
      greater difference observed in RTN. Thus nuclear differences in GABA(A) IPSCs are
      not only maintained, but enhanced in the mature rodent under physiological
      conditions. These findings support our hypothesis that unique GABA(A) receptors
      mediate slowly decaying RTN IPSCs that are a critical and enduring feature of the
      thalamic circuit. This promotes powerful intranuclear inhibition and likely
      prevents epileptiform thalamocortical hypersynchrony.

PMID- 10634879
TI  - Synaptic GABA(A) activation inhibits AMPA-kainate receptor-mediated bursting in
      the newborn (P0-P2) rat hippocampus.
AB  - The mechanisms of synaptic transmission in the rat hippocampus at birth are
      assumed to be fundamentally different from those found in the adult. It has been
      reported that in the CA3-CA1 pyramidal cells a conversion of "silent"
      glutamatergic synapses to conductive alpha-amino-3-hydroxy-5-methyl-4
      isoxazolepropionic acid (AMPA) synapses starts gradually after P2. Further, GABA
      via its depolarizing action seems to give rise to grossly synchronous yet slow
      calcium oscillations. Therefore, GABA is generally thought to have a purely
      excitatory rather than an inhibitory role during the first postnatal week. In the
      present study field potential recordings and gramicidin perforated and whole cell
      clamp techniques as well as K(+)-selective microelectrodes were used to examine
      the relative contributions of AMPA and GABA(A) receptors to network activity of
      CA3-CA1 pyramidal cells in the newborn rat hippocampus. As early as postnatal day
      (P0-P2), highly coherent spontaneous firing of CA3 pyramidal cells was seen in
      vitro. Negative-going extracellular spikes confined to periodic bursts (interval
      16 +/- 3 s) consisting of 2.9 +/- 0.1 spikes were observed in stratum pyramidale.
      The spikes were accompanied by AMPA-R-mediated postsynaptic currents (PSCs) in
      simultaneously recorded pyramidal neurons (7.6 +/- 3.0 unitary currents per
      burst). In CA1 pyramidal cells synchronous discharging of CA3 circuitry produced
      a barrage of AMPA currents at >20 Hz frequencies, thus demonstrating a transfer
      of the fast CA3 network activity to CA1 area. Despite its depolarizing action,
      GABA(A)-R-mediated transmission appeared to exert inhibition in the CA3 pyramidal
      cell population. The GABA(A)-R antagonist bicuculline hypersynchronized the
      output of glutamatergic CA3 circuitry and increased the network-driven excitatory
      input to the pyramidal neurons, whereas the GABA(A)-R agonist muscimol (100 nM)
      did the opposite. However, the occurrence of unitary GABA(A)-R currents was
      increased after muscimol application from 0.66 +/- 0.16 s(-1) to 1.43 +/- 0.29 s(
      1). It was concluded that AMPA synapses are critical in the generation of
      spontaneous high-frequency bursts in CA3 as well as in CA3-CA1 transmission as
      early as P0-P2 in rat hippocampus. Concurrently, although GABA(A)-R-mediated
      depolarization may excite hippocampal interneurons, in CA3 pyramidal neurons it
      can restrain excitatory inputs and limit the size of the activated neuronal
      population.

PMID- 10634880
TI  - Neuronal mechanisms for the control of body orientation in clione II.
      Modifications in the activity of postural control system.
AB  - The marine mollusk Clione limacina, when swimming, can stabilize different body
      orientations in the gravitational field. The stabilization is based on the
      reflexes initiated by activation of the statocyst receptor cells and mediated by
      the cerebro-pedal interneurons that produce excitation of the motoneurons of the
      effector organs; tail and wings. Here we describe changes in the reflex pathways
      underlying different modes of postural activity; the maintenance of the head-up
      orientation at low temperature, the maintenance of the head-down orientation at
      higher temperature, and a complete inactivation of the postural mechanisms during
      defense reaction. Experiments were performed on the CNS-statocyst preparation.
      Spike discharges in the axons of different types of neurons were recorded
      extracellularly while the preparation was rotated in space through 360 degrees in
      different planes. We characterized the spatial zones of activity of the tail and
      wing motoneurons and the CPB3 interneurons mediating the effects of statocyst
      receptor cells on the tail motoneurons. This was done at different temperatures
      (10 and 20 degrees C). The "fictive" defense reaction was evoked by electrical
      stimulation of the head nerve. At 10 degrees C, a tilt of the preparation evoked
      activation in the tail motoneurons and wing retractor motoneurons contralateral
      to the tilt and in the wing locomotor motoneurons ipsilateral to the tilt. At 20
      degrees C, the responses in the tail motoneurons and in the wing retractor
      motoneurons occurred reversed; these neurons were now activated with the
      ipsilateral tilt. In the wing locomotor motoneurons the responses at 20 degrees C
      were suppressed. During the defense reaction, gravitational responses in all
      neuron types were suppressed. Changes in the chains of tail reflexes most likely
      occurred at the level of connections from the statocyst receptor cells to the
      CPB3 interneurons. The changes in gravitational reflexes revealed in the present
      study are sufficient to explain the corresponding modifications of the postural
      behavior in Clione.

PMID- 10634881
TI  - Modulation of fictive feeding by dopamine and serotonin in aplysia.
AB  - The buccal ganglia of Aplysia contain a central pattern generator (CPG) that
      mediates rhythmic movements of the buccal apparatus during feeding. Activity in
      this CPG is believed to be regulated, in part, by extrinsic serotonergic inputs
      and by an intrinsic and extrinsic system of putative dopaminergic cells. The
      present study investigated the roles of dopamine (DA) and serotonin (5-HT) in
      regulating feeding movements of the buccal apparatus and properties of the
      underlying neural circuitry. Perfusing a semi-intact head preparation with DA (50
      microM) or the metabolic precursor of catecholamines (L-3-4
      dihydroxyphenylalanine, DOPA, 250 microM) induced feeding-like movements of the
      jaws and radula/odontophore. These DA-induced movements were similar to bites in
      intact animals. Perfusing with 5-HT (5 microM) also induced feeding-like
      movements, but the 5-HT-induced movements were similar to swallows. In
      preparations of isolated buccal ganglia, buccal motor programs (BMPs) that
      represented at least two different aspects of fictive feeding (i.e., ingestion
      and rejection) could be recorded. Bath application of DA (50 microM) increased
      the frequency of BMPs, in part, by increasing the number of ingestion-like BMPs.
      Bath application of 5-HT (5 microM) did not significantly increase the frequency
      of BMPs nor did it significantly increase the proportion of ingestion-like BMPs
      being expressed. Many of the cells and synaptic connections within the CPG
      appeared to be modulated by DA or 5-HT. For example, bath application of DA
      decreased the excitability of cells B4/5 and B34, which in turn may have
      contributed to the DA-induced increase in ingestion-like BMPs. In summary, bite
      like movements were induced by DA in the semi-intact preparation, and neural
      correlates of these DA-induced effects were manifest as an increase in ingestion
      like BMPs in the isolated ganglia. Swallow-like movements were induced by 5-HT in
      the semi-intact preparation. Neural correlates of these 5-HT-induced effects were
      not evident in isolated buccal ganglia, however.

PMID- 10634882
TI  - Maintenance of rat head direction cell firing during locomotion in the vertical
      plane.
AB  - Previous studies have identified a subset of neurons in the rat anterodorsal
      thalamus (ADN) that encode head direction (HD) in absolute space and may be
      involved in navigation. These HD cells discharge selectively when the rat points
      its head in a specific direction (the preferred firing direction) in the
      horizontal plane. HD cells are typically recorded during free movement about a
      single horizontal surface. The current experiment examined how HD cell firing was
      influenced by 1) locomotion in the vertical plane and 2) locomotion on two
      different horizontal surfaces separated in height. Rats were trained in a
      cylindrical enclosure containing a single polarizing cue card attached to the
      cylinder wall, covering approximately 100 degrees of arc. The enclosure contained
      two horizontal surfaces: the cylinder floor and an annulus around the cylinder
      top 76 cm above the floor. A 90 degrees vertical mesh ladder that could be
      affixed at any angular position on the cylinder wall allowed the rats to locomote
      back and forth between the two horizontal surfaces. Rats were trained to retrieve
      food pellets on the cylinder floor as well as climb the mesh ladder to retrieve
      food pellets on the annulus. HD cell activity was monitored as the rat traversed
      the horizontal and vertical surfaces of the apparatus. When the angular position
      of the mesh corresponded to the cell's preferred firing direction, the HD cells
      maintained their peak discharge rate as the rat climbed up the mesh, but did not
      fire when the rat climbed down the mesh. In contrast, when the mesh was
      positioned 180 degrees opposite the preferred firing direction, HD cells did not
      fire when the rat climbed up the mesh, but exhibited maximal firing when the rat
      climbed down the mesh. When the mesh was placed 90 or 270 degrees from the
      preferred firing direction, HD cells exhibited background firing rates during
      climbing up or down the mesh. While preferred firing directions were maintained
      between the two horizontal surfaces, peak firing rate increased significantly
      (approximately 30%) on the annulus as compared with the cylinder floor. These
      data demonstrate that HD cells continue to discharge in the vertical plane if the
      vertical locomotion began with the rat's orientation corresponding to the
      preferred firing direction. One model consistent with these data are that HD
      cells define the horizontal reference frame as the animal's plane of locomotion.
      Further, we propose that HD cell firing, as viewed within a three-dimensional
      coordinate system, can be characterized as the surface of a hemitorus.

PMID- 10634883
TI  - Chloride-cotransport blockade desynchronizes neuronal discharge in the
      "epileptic" hippocampal slice.
AB  - Antagonism of the chloride-cotransport system in hippocampal slices has been
      shown to block spontaneous epileptiform (i.e., hypersynchronized) discharges
      without diminishing excitatory synaptic transmission. Here we test the hypotheses
      that chloride-cotransport blockade, with furosemide or low-chloride (low-[Cl(
      )](o)) medium, desynchronizes the firing activity of neuronal populations and
      that this desynchronization is mediated through nonsynaptic mechanisms.
      Spontaneous epileptiform discharges were recorded from the CA1 and CA3 cell body
      layers of hippocampal slices. Treatment with low-[Cl(-)](o) medium led to
      cessation of spontaneous synchronized bursting in CA1 >/=5-10 min before its
      disappearance from CA3. During the time that CA3 continued to burst spontaneously
      but CA1 was silent, electrical stimulation of the Schaffer collaterals showed
      that hyperexcited CA1 synaptic responses were maintained. Paired intracellular
      recordings from CA1 pyramidal cells showed that during low-[Cl(-)](o) treatment,
      the timing of action potential discharges became desynchronized;
      desynchronization was identified with phase lags in firing times of action
      potentials between pairs of neurons as well as a with a broadening and diminution
      of the CA1 field amplitude. Continued exposure to low-[Cl(-)](o) medium increased
      the degree of the firing-time phase shifts between pairs of CA1 pyramidal cells
      until the epileptiform CA1 field potential was abolished completely.
      Intracellular recordings during 4-aminopyridine (4-AP) treatment showed that
      prolonged low-[Cl(-)](o) exposure did not diminish the frequency or amplitude of
      spontaneous postsynaptic potentials. CA3 antidromic responses to Schaffer
      collateral stimulation were not significantly affected by prolonged low-[Cl(
      )](o) exposure. In contrast to CA1, paired intracellular recordings from CA3
      pyramidal cells showed that chloride-cotransport blockade did not cause a
      significant desynchronization of action potential firing times in the CA3
      subregion at the time that CA1 synchronous discharge was blocked but did reduce
      the number of action potentials associated with CA3 burst discharges. These data
      support our hypothesis that the anti-epileptic effects of chloride-cotransport
      antagonism in CA1 are mediated through the desynchronization of population
      activity. We hypothesize that interference with Na(+),K(+),2Cl(-) cotransport
      results in an increase in extracellular potassium ([K(+)](o)) that reduces the
      number of action potentials that are able to invade axonal arborizations and
      varicosities in all hippocampal subregions. This reduced efficacy of presynaptic
      action potential propagation ultimately leads to a reduction of synaptic drive
      and a desynchronization of the firing of CA1 pyramidal cells.

PMID- 10634884
TI  - Characterization with barium of potassium currents in turtle retinal Muller
      cells.
AB  - Muller cells are highly permeable to potassium ions and play a crucial role in
      maintaining potassium homeostasis in the vertebrate retina. The potassium current
      found in turtle Muller cells consists of two components: an inwardly rectifying
      component and a linear, passive component. These currents are insensitive to
      broadband potassium channel blockers, tetraethylammonium (TEA) and 4
      aminopyridine (4-AP) and well blocked by barium. Differential block by the
      polyamine spermine suggests that these currents flow through different channels.
      In this study, we used barium ions as a probe to investigate the properties of
      these currents by whole cell, voltage-clamp recordings from isolated cells.
      Current-voltage (I-V) relationships generated from current responses to short (35
      ms) and long (3.5 s) voltage pulses were fit with the Hill equation. With
      extracellular barium, the time course of block and unblock was voltage and
      concentration dependent and could be fit with single exponential functions and
      time constants larger than 100 ms. Blocking effects by extracellular barium on
      the two types of currents were indistinguishable. The decrease of the outward
      current originates in part due to charge effects. We also found that
      intracellular barium was an effective blocker of the potassium currents. The
      relative block of the inward rectifier by intracellular barium suggests the
      existence of two "apparent" binding sites available for barium within the
      channel. Under depolarizing conditions favoring the block by internal polyamines,
      the Hill coefficient for barium binding was 1, indicating a single apparent
      binding site for barium within the pore of the passive linear conductance. The
      difference in the steepness of the blocking functions suggests that the potassium
      currents flow through two different types of channels, an inward rectifier and a
      linear passive conductance. Last, we consider the use of barium as an
      intracellular K(+) channel blocker for voltage-clamp experiments.

PMID- 10634885
TI  - Ankle restraint modifies motility at E12 in chick embryos.
AB  - The chick's relationship to its environment changes dramatically over 21 days of
      embryonic development. At early ages embryos are buoyant; their posture and
      movements are relatively unconstrained. As embryos grow and fluid level in ovo
      decreases, movements are increasingly constrained by gravitational forces and
      reactive forces due to body contact with the shell wall. The issue of how age
      related changes in the constraints on movement in ovo may affect embryonic
      motility is addressed in this paper. Our long-term goal is to determine whether
      experience imposed by these conditions contributes to development of posthatching
      motor behaviors. Because previous work indicated that parameters of motility can
      be modified by a reduction in buoyancy at embryonic day (E) 9, we sought to
      determine whether a restraint localized to a single joint could also alter either
      the episodic distribution of activity or the spatiotemporal patterns of limb
      movement at either E9 or E12. Thus a restraint was applied to the right ankle of
      embryos prepared for kinematic recordings. Video and kinematic analyses indicated
      that the restraint had minimal effect at E9, but significantly modified several
      motility parameters in both the wing and leg at E12. Ankle restraint decreased
      episode duration. Restraint also decreased most joint excursion parameters,
      including excursion range, cycles per sequence, and excursion velocity. Restraint
      increased cycle period duration and signal frequency content under 1.0 Hz.
      Parameters of intralimb and interlimb coordination exhibited small mixed effects.
      Results provide support for the hypothesis that environmental conditions
      contribute to features of embryonic motility. Further, significant modifications
      of wing excursions in ankle restrained embryos suggest that sensory feedback
      arising from mechanical perturbations of leg movements may entrain rostral spinal
      circuits for preservation of interlimb coordination at E12. Potential mechanisms
      and implications are discussed.

PMID- 10634886
TI  - Motor-unit synchronization increases EMG amplitude and decreases force steadiness
      of simulated contractions.
AB  - The purpose of the study was to determine the effect of motor-unit
      synchronization on the surface electromyogram (EMG) and isometric force using a
      computer model of muscle contraction. The EMG and force were simulated by
      generating muscle fiber action potentials, defining motor-unit mechanical
      characteristics and territories, estimating motor-unit action potentials,
      specifying motor-unit discharge times, and imposing various levels of motor-unit
      synchronization. The output (EMG and force) was simulated at 11 levels of
      excitation, ranging from 5 to 100% of maximum. To synchronize motor-unit
      activity, selected motor-unit discharge times were adjusted; however, the number
      of motor units recruited and the average discharge rate of each unit was constant
      across synchronization conditions for a given level of excitation. Two levels of
      synchronization were imposed on the discharge times: a moderate and a high level,
      which approximated the experimentally observed range of motor-unit
      synchronization. The moderate level of synchrony caused the average EMG to
      increase by approximately 65%, whereas the high level caused a 130% increase in
      the EMG with respect to the no-synchrony condition. Neither synchrony condition
      influenced the magnitude of the average force. However, motor-unit
      synchronization did increase the amplitude of the fluctuations in the simulated
      force, especially at intermediate levels of excitation. In conclusion, motor-unit
      synchronization increased the amplitude of the average rectified EMG and
      decreased the steadiness of the force exerted by the muscle in simulated
      contractions.

PMID- 10634887
TI  - Kinematic synergy adaptation to microgravity during forward trunk movement.
AB  - The aim of the present investigation was to see whether the kinematic synergy
      responsible for equilibrium control during upper trunk movement was preserved in
      absence of gravity constraints. In this context, forward trunk movements were
      studied during both straight-and-level flights (earth-normal gravity condition:
      normogravity) and periods of weightlessness in parabolic flights (microgravity).
      Five standing adult subjects had their feet attached to a platform, their eyes
      were open, and their hands were clasped behind their back. They were instructed
      to bend the trunk (the head and the trunk together) forward by approximately 35
      degrees with respect to the vertical in the sagittal plane as fast as possible in
      response to a tone, and then to hold the final position for 3 s. The initial and
      final anteroposterior center of mass (CM) positions (i.e., 200 ms before the
      onset of the movement and 400 ms after the offset of the movement, respectively),
      the time course of the anteroposterior CM shift during the movement, and the
      electromyographic (EMG) pattern of the main muscles involved in the movement were
      studied under both normo- and microgravity. The kinematic synergy was quantified
      by performing a principal components analysis on the hip, knee, and ankle angle
      changes occurring during the movement. The results indicate that 1) the
      anteroposterior position of the CM remains minimized during performance of
      forward trunk movement in microgravity, in spite of the absence of equilibrium
      constraints; 2) the strong joint coupling between hip, knee, and ankle, which
      characterizes the kinematic synergy in normogravity and which is responsible for
      the minimization of the CM shift during movement, is preserved in microgravity.
      It represents an invariant parameter controlled by the CNS. 3) The EMG pattern
      underlying the kinematic synergy is deeply reorganized. This is in contrast with
      the invariance of the kinematic synergy. It is concluded that during short-term
      microgravity episodes, the kinematic synergy that minimizes the anteroposterior
      CM shift is surprisingly preserved due to fast adaptation of the muscle forces to
      the new constraint.

PMID- 10634888
TI  - Extent and role of multisegmental coupling in the Lamprey spinal locomotor
      pattern generator.
AB  - Timing of oscillatory activity along the longitudinal body axis is critical for
      locomotion in the lamprey and other elongated animals. In the lamprey spinal
      locomotor central pattern generator (CPG), intersegmental coordination is thought
      to arise from the pattern of extensive connections made by propriospinal
      interneurons. However, the mechanisms responsible for intersegmental coordination
      remain unknown, in large part because of the difficulty in obtaining quantitative
      information on these multisegmental fibers. System-level experiments were
      performed on isolated 50-segment preparations of spinal cord of adult silver
      lampreys, Ichthyomyzon unicuspis, to determine the dependence of CPG performance
      on multisegmental coupling. Coupling was manipulated through use of an experiment
      chamber with movable partitions, which allowed separate application of solution
      to rostral, middle, and caudal regions of the spinal cord preparation. During
      control trials, fictive locomotion, induced by bath application of D-glutamate in
      all three regions, was recorded extracellularly from ventral roots. Local
      synaptic activity in a variable number of middle segments was subsequently
      blocked with a low-Ca(2+), high-Mn(2+) saline solution in the middle compartment,
      whereas conduction in axons spanning the middle segments was unaffected. Spectral
      analysis was used to assess the effects of blocking propriospinal coupling on
      intersegmental phase lag, rhythm frequency, correlation, and variability.
      Significant correlation and a stable phase lag between the rostral and caudal
      regions of the spinal cord preparation were maintained during block of as many as
      16 and sometimes 20 intervening segments. However, the mean value of this
      rostrocaudal phase decreased with increasing number of blocked segments from the
      control value of approximately 1% per segment. By contrast, phase lags within the
      rostral and caudal end regions remained unaffected. The cycle frequency in the
      rostral and caudal regions decreased with the number of blocked middle segments
      and tended to diverge when a large number of middle segments was blocked. The
      variability in cycle frequency and intersegmental phase both increased with
      increasing number of blocked segments. In addition, a number of differences were
      noted in the properties of the motor output of the rostral and caudal regions of
      the spinal cord. The results indicate that the maximal functional length of
      propriospinal coupling fibers is at least 16-20 segments in I. unicuspis, whereas
      intersegmental phase lags are controlled at a local level and are not dependent
      on extended multisegmental coupling. Other possible roles for multisegmental
      coupling are discussed.

PMID- 10634889
TI  - Presynaptic calcium channels and the depletion of synaptic cleft calcium ions.
AB  - The entry of calcium ions (Ca(2+)) through voltage-gated calcium channels is an
      essential step in the release of neurotransmitter at the presynaptic nerve
      terminal. Because the calcium channels are clustered at the release sites, the
      flux of Ca(2+) into the terminal inevitably removes the ion from the adjacent
      extracellular space, the synaptic cleft. We have used the large calyx-type
      synapse of the chick ciliary ganglion to test for synaptic cleft Ca(2+)
      depletion. The terminal was voltage clamped at a holding potential (V(H)) of -80
      mV and a depolarizing pulse was applied to a range of potentials (-60 to +60 mV).
      The voltage pulse activated a sustained inward calcium current and was followed,
      on return of the membrane potential to V(H), by an inward calcium tail current.
      The amplitude of the tail current reflects both the number of open calcium
      channels at the end of the voltage pulse and the Ca(2+) electrochemical gradient.
      External barium was substituted for calcium as the charge-carrying ion because
      initial experiments demonstrated calcium-dependent inactivation of the
      presynaptic calcium channels. Tail current recruitment was compared in calyx
      nerve terminals that remained attached to the postsynaptic neuron and therefore
      retained a synaptic cleft, with terminals that had been fully isolated. In
      isolated terminals, the tail currents exhibited recruitment curves that could be
      fit by a Boltzmann distribution with a mean V(1/2) of 0.4 mV and a slope factor
      of 5.4. However, in attached calyces tail current recruitment was skewed to
      depolarized potentials with a mean V(1/2) of 11.9 mV and a slope factor of 12.0.
      The degree of skew of the recruitment curve in the attached calyces correlated
      with the amplitude of the inward current evoked by the step depolarization. The
      simplest interpretation of these findings is that during the depolarizing pulse
      Ba(2+) is removed from the synaptic cleft faster than it is replenished, thus
      reducing the tail current by reducing the driving force for ion entry. Ca(2+)
      depletion during presynaptic calcium channel activation is likely to be a general
      property of chemical transmission at fast synapses that sets a functional limit
      to the duration of sustained secretion. The synapse may have evolved to minimized
      cleft depletion by developing a calcium-efficient mechanism to gate transmitter
      release that requires the concurrent opening of only a few low conductance
      calcium channels.

PMID- 10634890
TI  - Summation of effective synaptic currents and firing rate modulation in cat spinal
      motoneurons.
AB  - The aim of this study was to examine how cat spinal motoneurons integrate the
      synaptic currents generated by the concurrent activation of large groups of
      presynaptic neurons. We obtained intracellular recordings from cat triceps surae
      motoneurons and measured the effects of repetitive activity in different sets of
      presynaptic neurons produced by electrical stimulation of descending fibers or
      peripheral nerves and by longitudinal vibration of the triceps surae muscles (to
      activate primary muscle spindle Ia afferent fibers). We combined synaptic
      activation with subthreshold injected currents to obtain estimates of effective
      synaptic currents at the resting potential (I(Nrest)) and at the threshold for
      repetitive discharge (I(Nthresh)). We then superimposed synaptic activation on
      suprathreshold injected current steps to measure the synaptically evoked change
      in firing rate. We studied eight different pairs of synaptic inputs. When any two
      synaptic inputs were activated concurrently, both the effective synaptic currents
      (I(Nrest)) and the synaptically evoked changes in firing rate generally were
      equal to or slightly less than the linear sum of the effects produced by
      activating each input alone. However, there were several instances in which the
      summation was substantially less than linear. In some motoneurons, we induced a
      partial blockade of potassium channels by adding tetraethylammonium (TEA) or
      cesium to the electrolyte solution in the intracellular pipette. In these cells,
      persistent inward currents were evoked by depolarization that led to instances of
      substantially greater-than linear summation of injected and synaptic currents.
      Overall our results indicate that the spatial distribution of synaptic boutons on
      motoneurons acts to minimize electrical interactions between synaptic sites
      permitting near linear summation of synaptic currents. However, modulation of
      voltage-gated conductances on the soma and dendrites of the motoneuron can lead
      to marked nonlinearities in synaptic integration.

PMID- 10634891
TI  - Amplification of odor-induced Ca(2+) transients by store-operated Ca(2+) release
      and its role in olfactory signal transduction.
AB  - A critical role of Ca(2+) in vertebrate olfactory receptor neurons (ORNs) is to
      couple odor-induced excitation to intracellular feedback pathways that are
      responsible for the regulation of the sensitivity of the sense of smell, but the
      role of intracellular Ca(2+) stores in this process remains unclear. Using
      confocal Ca(2+) imaging and perforated patch recording, we show that salamander
      ORNs contain a releasable pool of Ca(2+) that can be discharged at rest by the
      SERCA inhibitor thapsigargin and the ryanodine receptor agonist caffeine. The
      Ca(2+) stores are spatially restricted; emptying produces compartmentalized
      Ca(2+) release and capacitative-like Ca(2+) entry in the dendrite and soma but
      not in the cilia, the site of odor transduction. We deplete the stores to show
      that odor stimulation causes store-dependent Ca(2+) mobilization. This odor
      induced Ca(2+) release does not seem to be necessary for generation of an
      immediate electrophysiological response, nor does it contribute significantly to
      the Ca(2+) transients in the olfactory cilia. Rather, it is important for
      amplifying the magnitude and duration of Ca(2+) transients in the dendrite and
      soma and is thus necessary for the spread of an odor-induced Ca(2+) wave from the
      cilia to the soma. We show that this amplification process depends on Ca(2+)
      induced Ca(2+) release. The results indicate that stimulation of ORNs with
      odorants can produce Ca(2+) mobilization from intracellular stores without an
      immediate effect on the receptor potential. Odor-induced, store-dependent Ca(2+)
      mobilization may be part of a feedback pathway by which information is
      transferred from the distal dendrite of an ORN to its soma.

PMID- 10634892
TI  - Differential expression of high- and two types of low-voltage-activated calcium
      currents in rod and cone bipolar cells of the rat retina.
AB  - Whole cell voltage-clamp recordings were performed to investigate voltage
      activated Ca(2+) currents in acutely isolated retinal bipolar cells of rats. Two
      groups of morphologically different bipolar cells were observed. Bipolar cells of
      the first group, which represent the majority of isolated bipolar cells, were
      immunoreactive to protein kinase C (PKC) and, therefore likely to be rod bipolar
      cells. Bipolar cells of the second group, which represent only a small population
      of isolated bipolar cells, did not show PKC immunoreactivity and were likely to
      be cone bipolar cells. The validity of morphological identification of bipolar
      cells was further confirmed by the presence of GABA(C) responses in these cells.
      Bipolar cells of both groups displayed low-voltage-activated (LVA) Ca(2+)
      currents with similar voltage dependence of activation and steady-state
      inactivation. However, the activation, inactivation, and deactivation kinetics of
      the LVA Ca(2+) currents between rod and cone bipolar cells differed.
      Particularly, the LVA Ca(2+) currents of rod bipolar cells displayed both
      transient and sustained components. In contrast, the LVA Ca(2+) currents of cone
      bipolar cells were mainly transient. In addition, the LVA Ca(2+) channels of rod
      bipolar cells were more permeable to Ba(2+) than to Ca(2+), whereas those of cone
      bipolar cells were equally or less permeable to Ba(2+) than to Ca(2+). The LVA
      Ca(2+) currents of both rod and cone bipolar cells were antagonized by high
      concentrations of nimodipine with IC(50) of 17 and 23 microM, respectively, but
      largely resistant to Cd(2+) and Ni(2+). Bipolar cells of both groups also
      displayed high-voltage-activated (HVA) Ca(2+) currents. The HVA Ca(2+) currents
      were, at least in part, to be L-type that were potentiated by BayK-8644 (1
      microM) and largely antagonized by low concentrations of nimodipine (5 microM).
      The L-type Ca(2+) channels were almost exclusively located at the axon terminals
      of rod bipolar cells but expressed at least in the cell soma of cone bipolar
      cells. Results of this study indicate that rod and cone bipolar cells of the
      mammalian retina differentially express at least two types of LVA Ca(2+)
      channels. Rod and cone bipolar cells also show different spatial distribution of
      L-type Ca(2+) channels.

PMID- 10634893
TI  - Cortical activity in precision- versus power-grip tasks: an fMRI study.
AB  - Most manual grips can be divided in precision and power grips on the basis of
      phylogenetic and functional considerations. We used functional magnetic resonance
      imaging to compare human brain activity during force production by the right hand
      when subjects used a precision grip and a power grip. During the precision-grip
      task, subjects applied fine grip forces between the tips of the index finger and
      the thumb. During the power-grip task, subjects squeezed a cylindrical object
      using all digits in a palmar opposition grasp. The activity recorded in the
      primary sensory and motor cortex contralateral to the operating hand was higher
      when the power grip was applied than when subjects applied force with a precision
      grip. In contrast, the activity in the ipsilateral ventral premotor area, the
      rostral cingulate motor area, and at several locations in the posterior parietal
      and prefrontal cortices was stronger while making the precision grip than during
      the power grip. The power grip was associated predominately with contralateral
      left-sided activity, whereas the precision-grip task involved extensive
      activations in both hemispheres. Thus our findings indicate that in addition to
      the primary motor cortex, premotor and parietal areas are important for control
      of fingertip forces during precision grip. Moreover, the ipsilateral hemisphere
      appears to be strongly engaged in the control of precision-grip tasks performed
      with the right hand.

PMID- 10634894
TI  - Time course of odorant-induced activation in the human primary olfactory cortex.
AB  - Paradoxically, attempts to visualize odorant-induced functional magnetic
      resonance imaging (fMRI) activation in the human have yielded activations in
      secondary olfactory regions but not in the primary olfactory cortex-piriform
      cortex. We show that odorant-induced activation in primary olfactory cortex was
      not previously made evident with fMRI because of the unique time course of
      activity in this region: in primary olfactory cortex, odorants induced a strong
      early transient increase in signal amplitude that then habituated within 30-40 s
      of odorant presence. This time course of activation seen here in the primary
      olfactory cortex of the human is almost identical to that recorded
      electrophysiologically in the piriform cortex of the rat. Mapping activation with
      analyses that are sensitive to both this transient increase in signal amplitude,
      and temporal-variance, enabled us to use fMRI to consistently visualize odorant
      induced activation in the human primary olfactory cortex. The combination of
      continued accurate odorant detection at the behavioral level despite primary
      olfactory cortex habituation at the physiological level suggests that the
      functional neuroanatomy of the olfactory response may change throughout prolonged
      olfactory stimulation.

PMID- 10634895
TI  - Presynaptic Ca(2+) influx at the inhibitor of the crayfish neuromuscular
      junction: a photometric study at a high time resolution.
AB  - Presynaptic calcium influx at the inhibitor of the crayfish neuromuscular
      junction was investigated by measuring fluorescence transients generated by
      calcium-sensitive dyes. This approach allowed us to correlate presynaptic calcium
      influx with transmitter release at a high time resolution. Systematic testing of
      the calcium indicators showed that only low-affinity dyes, with affinities in the
      range of micromolar, should be used to avoid saturation of dye binding and
      interference with transmitter release. Presynaptic calcium influx was regulated
      by slowly increasing the duration of the action potential through progressive
      block of potassium channels. The amplitude of the calcium transient, measured
      from a cluster of varicosities, was linearly related to the duration of the
      action potential with a slope of 1.2. Gradual changes in potassium channel block
      allowed us to estimate the calcium cooperativity of transmitter release over a 10
      fold range in presynaptic calcium influx. Calcium cooperativity measured here
      exhibited one component with an average value of 3.1. Inspection of
      simultaneously recorded presynaptic calcium transients and inhibitory
      postsynaptic currents (IPSCs) showed that prolonged action potentials were
      associated with a slow rising phase of presynaptic calcium transients, which were
      matched by a slow rate of rise of IPSCs. The close correlation suggests that
      fluorescence transients provide information on the rate of calcium influx.
      Because there is an anatomic mismatch between the presynaptic calcium transient,
      measured from a cluster of varicosities, and IPSC, measured with two-electrode
      voltage clamp, macropatch recording was used to monitor inhibitory postsynaptic
      responses from the same cluster of varicosities from which the calcium transient
      was measured. Inhibitory postsynaptic responses recorded with the macropatch
      method exhibited a faster rising phase than that recorded with two-electrode
      voltage clamp. This difference could be attributed to slight asynchrony of
      transmitter release due to action potential conduction along fine branches. In
      conclusion, this report shows that fluorescence transients generated by calcium
      sensitive dyes can provide insights to the properties of presynaptic calcium
      influx, and its correlation with transmitter release, at a high time resolution.

PMID- 10634896
TI  - Activity of smooth pursuit-related neurons in the monkey periarcuate cortex
      during pursuit and passive whole-body rotation.
AB  - Smooth pursuit and vestibularly induced eye movements interact to maintain the
      accuracy of eye movements in space (i.e., gaze). To understand the role played by
      the frontal eye fields in pursuit-vestibular interactions, we examined activity
      of 110 neurons in the periarcuate areas of head-stabilized Japanese monkeys
      during pursuit eye movements and passive whole-body rotation. The majority (92%)
      responded with the peak of their modulation near peak stimulus velocity during
      suppression of the vestibuloocular reflex (VOR) when the monkeys tracked a target
      that moved with the same amplitude and phase and in the same plane as the chair.
      We classified pursuit-related neurons (n = 100) as gaze- velocity if their peak
      modulation occurred for eye (pursuit) and head (VOR suppression) movements in the
      same direction; the amplitude of modulation during one less than twice that of
      the other; and modulation was lower during target-stationary-in-space condition
      (VOR x1) than during VOR suppression. In addition, we examined responses during
      VOR enhancement (x2) in which the target moved with equal amplitude as, but
      opposite direction to, the chair. Gaze-velocity neurons responded maximally for
      opposite directions during VOR x2 and suppression. Based on these criteria, the
      majority of pursuit-related neurons (66%) were classified as gaze-velocity with
      preferred directions uniformly distributed. Because the majority of the remaining
      cells (32/34) also responded during VOR suppression, they were classified as
      eye/head-velocity neurons. Thirteen preferred pursuit and VOR suppression in the
      same direction; 13 in the opposite direction, and 6 showed biphasic modulation
      during VOR suppression. Eye- and gaze-velocity sensitivity of the two groups of
      cells were similar; mean (+/- SD) was 0.53 +/- 0.30 and 0.50 +/- 0.44 spikes/s
      per degrees /s, respectively. Gaze-velocity (but not eye/head-velocity) neurons
      showed significant correlation between eye- and gaze-velocity sensitivity, and
      both groups maintained their responses when the tracking target was extinguished
      briefly. The majority of pursuit-related neurons (28/43 = about 65%) responded to
      chair rotation in complete darkness. When the monkeys fixated a stationary
      target, more than half of cells tested (21/40) discharged in proportion to the
      velocity of retinal motion of a second laser spot (mean velocity sensitivity =
      0.20 +/- 0.16 spikes/s per degrees /s). Preferred directions of individual cells
      to the second spot were similar to those during pursuit. Visual responses to the
      second spot movement were maintained even when it was extinguished briefly. These
      results indicate that both retinal image- and gaze-velocity signals are carried
      by single periarcuate pursuit-related neurons, suggesting that these signals can
      provide target-velocity-in-space and gaze-velocity commands during pursuit
      vestibular interactions.

PMID- 10634897
TI  - Fourier analysis of sinusoidally driven thalamocortical relay neurons and a
      minimal integrate-and-fire-or-burst model.
AB  - We performed intracellular recordings of relay neurons from the lateral
      geniculate nucleus of a cat thalamic slice preparation. We measured responses
      during both tonic and burst firing modes to sinusoidal current injection and
      performed Fourier analysis on these responses. For comparison, we constructed a
      minimal "integrate-and-fire-or-burst" (IFB) neuron model that reproduces salient
      features of the relay cell responses. The IFB model is constrained to
      quantitatively fit our Fourier analysis of experimental relay neuron responses,
      including: the temporal tuning of the response in both tonic and burst modes,
      including a finding of low-pass and sometimes broadband behavior of tonic firing
      and band-pass characteristics during bursting, and the generally greater
      linearity of tonic compared with burst responses at low frequencies. In tonic
      mode, both experimental and theoretical responses display a frequency-dependent
      transition from massively superharmonic spiking to phase-locked superharmonic
      spiking near 3 Hz, followed by phase-locked subharmonic spiking at higher
      frequencies. Subharmonic and superharmonic burst responses also were observed
      experimentally. Characterizing the response properties of the "tuned" IFB model
      leads to insights regarding the observed stimulus dependence of burst versus
      tonic response mode in relay neurons. Furthermore the simplicity of the IFB model
      makes it a candidate for large scale network simulations of thalamic functioning.

PMID- 10634898
TI  - Chronic recording of regenerating VIIIth nerve axons with a sieve electrode.
AB  - A micromachined silicon substrate sieve electrode was implanted within transected
      toadfish (Opsanus tau) otolith nerves. High fidelity, single unit neural activity
      was recorded from seven alert and unrestrained fish 30 to 60 days after
      implantation. Fibrous coatings of genetically engineered bioactive protein
      polymers and nerve guide tubes increased the number of axons regenerating through
      the electrode pores when compared with controls. Sieve electrodes have potential
      as permanent interfaces to the nervous system and to bridge missing connections
      between severed or damaged nerves and muscles. Recorded impulses might also be
      amplified and used to control prosthetic devices.

PMID- 10634899
TI  - Fast NMDA receptor-mediated synaptic currents in neurons from mice lacking the
      epsilon2 (NR2B) subunit.
AB  - The N-methyl-D-aspartate (NMDA) receptor has been implicated in the formation of
      synaptic connections. To investigate the role of the epsilon2 (NR2B) NMDA
      receptor subunit, which is prominently expressed during early development, we
      used neurons from mice lacking this subunit. Although epsilon2(-/-) mice die soon
      after birth, we examined whether NMDA receptor targeting to the postsynaptic
      membrane was dependent on the epsilon2 subunit by rescuing hippocampal neurons
      from these mice and studying them in autaptic cultures. In voltage-clamp
      recordings, excitatory postsynaptic currents (EPSCs) from epsilon2(-/-) neurons
      expressed an NMDA receptor-mediated EPSC that was apparent as soon as synaptic
      activity developed. However, compared with wild-type neurons, NMDA receptor
      mediated EPSC deactivation kinetics were much faster and were less sensitive to
      glycine, but were blocked by Mg(2+) or AP5. Whole cell currents from epsilon2(-/
      ) neurons were also more sensitive to block by low concentrations of Zn(2+) and
      much less sensitive to the epsilon2-specific antagonist ifenprodil than wild-type
      currents. The rapid NMDA receptor-mediated EPSC deactivation kinetics and the
      pharmacological profile from epsilon2(-/-) neurons are consistent with the
      expression of zeta1/epsilon1 diheteromeric receptors in excitatory hippocampal
      neurons from mice lacking the epsilon2 subunit. Thus epsilon1 can substitute for
      the epsilon2 subunit at synapses and epsilon2 is not required for targeting of
      NMDA receptors to the postsynaptic membrane.

PMID- 10634900
TI  - Burst firing induces a rebound of synaptic strength at unitary neocortical
      synapses.
AB  - High-frequency activity produces transient depression at many synapses but also,
      as recently demonstrated, may accelerate the recovery from use-dependent
      depression. We have examined the possible consequences of this synaptic mechanism
      in neocortical excitatory synapses by recording simultaneously from presynaptic
      pyramidal neurons and their postsynaptic targets. Brief bursts of high-frequency
      spikes produced a strong depression of the amplitude of unitary excitatory
      postsynaptic currents (uEPSCs). However, when burst firing was combined with low
      frequency ongoing activity, we found that the strong synaptic depression was
      followed by a transient rebound of synaptic strength. This rebound overshot the
      low-frequency baseline values and lasted 1-2 s. These results suggest that in the
      presence of ongoing activity, neocortical synapses may functionally facilitate
      following burst firing.

PMID- 10634901
TI  - Disparity sensitivity of frontal eye field neurons.
AB  - Information about depth is necessary to generate saccades to visual stimuli
      located in three-dimensional space. To determine whether monkey frontal eye field
      (FEF) neurons play a role in the visuo-motor processes underlying this behavior,
      we studied their visual responses to stimuli at different disparities. Disparity
      sensitivity was tested from 3 degrees of crossed disparity (near) to 3 degrees
      degrees of uncrossed disparity (far). The responses of about two thirds of FEF
      visual and visuo-movement neurons were sensitive to disparity and showed a broad
      tuning in depth for near or far disparities. Early phasic and late tonic visual
      responses often displayed different disparity sensitivity. These findings provide
      evidence of depth-related signals in FEF and suggest a role for FEF in the
      control of disconjugate as well as conjugate eye movements.

PMID- 10634902
TI  - Comparing extraocular motoneuron discharges during head-restrained saccades and
      head-unrestrained gaze shifts.
AB  - Burst neurons (BNs) in the paramedian pontine reticular formation provide the
      primary input to the extraocular motoneurons (MNs) during head-restrained
      saccades and combined eye-head gaze shifts. Prior studies have shown that BNs
      carry eye movement-related signals during saccades and carry head as well as eye
      movement-related signals during gaze shifts. Therefore MNs receive signals
      related to head motion during gaze shifts, yet they solely drive eye motion. Here
      we addressed whether the relationship between MN firing rates and eye movements
      is influenced by the additional premotor signals present during gaze shifts.
      Neurons in the abducens nucleus of monkeys were first studied during saccades
      made with the head stationary. We then recorded from the same neurons during
      voluntary combined eye-head gaze shifts. We conclude that the activity of MNs, in
      contrast to that of BNs, is related to eye motion by the same dynamic
      relationship during head-restrained saccades and head-unrestrained gaze shifts.
      In addition, we show that a standard metric-based analysis [i.e., counting the
      number of spikes (NOS) in a burst] yields misleading results when applied to the
      same data set. We argue that this latter approach fails because it does not
      properly consider the system's dynamics or the strong interactions between eye
      and head motion.

PMID- 10634903
TI  - Photoreceptors in signal transduction. Pathways of enlightenment.

PMID- 10634905
TI  - Determining the physical limits of the Brassica S locus by recombinational
      analysis.
AB  - A genetic analysis was performed to study the frequency of recombination for
      intervals across the Brassica S locus region. No recombination was observed
      between the S locus glycoprotein gene and the S receptor kinase gene in the
      segregating populations that we analyzed. However, a number of recombination
      breakpoints in regions flanking these genes were identified, allowing the
      construction of an integrated genetic and physical map of the genomic region
      encompassing one S haplotype. We identified, based on the pollination phenotype
      of plants homozygous for recombinant S haplotypes, a 50-kb region that
      encompasses all specificity functions in the S haplotype that we analyzed.
      Mechanisms that might operate to preserve the tight linkage of self
      incompatibility specificity genes within the S locus complex are discussed in
      light of the relatively uniform recombination frequencies that we observed across
      the S locus region and of the structural heteromorphisms that characterize
      different S haplotypes.

PMID- 10634904
TI  - The late developmental pattern of Mu transposon excision is conferred by a
      cauliflower mosaic virus 35S -driven MURA cDNA in transgenic maize.
AB  - The MuDR element responsible for Mutator activities in maize encodes two genes,
      mudrA and mudrB. Each encodes multiple transcripts hypothesized to regulate,
      directly or indirectly, the unique late timing and switch in transposition
      mechanism during maize development. mudrA, which encodes the MURA transposase, is
      unstable in bacterial plasmids, a technical problem solved by using phage M13 as
      a vector to prepare DNA for biolistic transformation. In transgenic maize, a
      single 2.7-kb mudrA cDNA predicted to encode an 823-amino acid protein is
      sufficient to catalyze late somatic excisions, despite removal of the native
      promoter, alternative transcription start sites, known introns, polymorphic 5'
      and 3' untranslated sequences, and the mudrB gene. These results suggest that
      post-translational regulation confers Mu excision timing. The transgene is active
      in lines containing silencing MuDR elements. This suggests that endogenous MuDR
      transposons do not measurably immunize the host against expression of a
      homologous transgene.

PMID- 10634906
TI  - ABI3 affects plastid differentiation in dark-grown Arabidopsis seedlings.
AB  - The Arabidopsis ABSCISIC ACID-INSENSITIVE3 (ABI3) protein has been identified
      previously as a crucial regulator of late seed development. Here, we show that
      dark-grown abi3 plants, or abi3 plants returned to the dark after germination in
      the light, developed and maintained an etioplast with a prominent prolamellar
      body at developmental stages in which the wild type did not. Overexpression of
      ABI3 led to the preservation of the plastid ultrastructure that was present at
      the onset of darkness. These observations suggest that ABI3 plays a role in
      plastid differentiation pathways in vegetative tissues. Furthermore, the analysis
      of deetiolated (det1) abi3 double mutants revealed that DET1 and ABI3 impinge on
      a multitude of common processes. During seed maturation, ABI3 required DET1 to
      achieve its full expression. Mature det1 abi3 seeds were found to be in a highly
      germinative state, indicating that germination is controlled by both DET1 and
      ABI3. During plastid differentiation in leaves of dark-grown plants, DET1 is
      required for the action of ABI3 as it is during seed development. Together, the
      results suggest that ABI3 is at least partly regulated by light.

PMID- 10634907
TI  - 14-3-3 proteins form a guidance complex with chloroplast precursor proteins in
      plants.
AB  - Transit sequences of chloroplast-destined precursor proteins are phosphorylated
      on a serine or threonine residue. The amino acid motif around the phosphorylation
      site is related to the phosphopeptide binding motif for 14-3-3 proteins. Plant 14
      3-3 proteins interact specifically with wheat germ lysate-synthesized chloroplast
      precursor proteins and require an intact phosphorylation motif within the transit
      sequence. Chloroplast precursor proteins do not interact with 14-3-3 when
      synthesized in the heterologous reticulocyte lysate. In contrast, a precursor
      protein destined for plant mitochondria was found to be associated with 14-3-3
      proteins present in the reticulocyte lysate but not with 14-3-3 from wheat germ
      lysate. This indicates an unrecognized selectivity of 14-3-3 proteins for
      precursors from mitochondria and plastids in plants in comparison to fungi and
      animals. The heterooligomeric complex has an apparent size of 200 kD. In addition
      to the precursor protein, it contains 14-3-3 (probably as a dimer) and a heat
      shock protein Hsp70 isoform. Dissociation of the precursor complex requires ATP.
      Protein import experiments of precursor from the oligomeric complex into intact
      pea chloroplasts reveal three- to fourfold higher translocation rates compared
      with the free precursor, which is not complexed. We conclude that the 14-3-3
      Hsp70-precursor protein complex is a bona fide intermediate in the in vivo
      protein import pathway in plants.

PMID- 10634908
TI  - Expression profiling of the maize flavonoid pathway genes controlled by estradiol
      inducible transcription factors CRC and P.
AB  - To determine the scope of gene expression controlled by the maize transcription
      factors C1/R and P, which are responsible for activating flavonoid synthesis, we
      used GeneCalling, an open-ended, gel-based, mRNA-profiling technology, to analyze
      cell suspension lines of the maize inbred Black Mexican Sweet (BMS) that harbored
      estradiol-inducible versions of these factors. BMS cells were transformed with a
      continually expressed estrogen receptor/maize C1 activator domain fusion gene (ER
      C1) and either a fusion of C1 and R (CRC), P, or luciferase genes regulated by a
      promoter containing four repeats of an estrogen receptor binding site. Increasing
      amounts of luciferase activity, anthocyanins, and flavan-4-ols were detected in
      the respective cell lines after the addition of estradiol. The expression of both
      known and novel genes was detected simultaneously in these BMS lines by profiling
      the mRNA isolated from replicate samples at 0, 6, and 24 hr after estradiol
      treatment. Numerous cDNA fragments were identified that showed a twofold or
      greater difference in abundance at 6 and 24 hr than at 0 hr. The cDNA fragments
      from the known flavonoid genes, except chalcone isomerase (chi1), were induced in
      the CRC-expressing line after hormone induction, whereas only the chalcone
      synthase (c2) and flavanone/dihydroflavonol reductase (a1) genes were induced in
      the P-expressing line, as was expected. Many novel cDNA fragments were also
      induced or repressed by lines expressing CRC alone, P alone, or both
      transcription factors in unique temporal patterns. The temporal differences and
      the evidence of repression indicate a more diverse set of regulatory controls by
      CRC or P than originally expected. GeneCalling analysis was successful in
      detecting members of complex metabolic pathways and uncovering novel genes that
      were either coincidentally regulated or directly involved in such pathways.

PMID- 10634909
TI  - Cryptochrome nucleocytoplasmic distribution and gene expression are regulated by
      light quality in the fern Adiantum capillus-veneris.
AB  - Numerous cellular responses are reportedly regulated by blue light in
      gametophytes of lower plants; however, the molecular mechanisms of these
      responses are not known. Here, we report the isolation of two blue light
      photoreceptor genes, designated cryptochrome genes 4 and 5 (CRY4 and CRY5), from
      the fern Adiantum capillus-veneris. Because previously we identified three
      cryptochrome genes, this fern cryptochrome gene family of five members is the
      largest identified to date in plants. The deduced amino acid sequences of the
      five genes show remarkable similarities with previously identified cryptochromes
      as well as class I photolyases. Like the other plant cryptochromes, none of the
      cryptochromes of this fern possesses photolyase activity. RNA gel blot analysis
      and competitive polymerase chain reaction analysis indicate that the expression
      of the newly identified CRY4 and CRY5 genes is regulated by light and is under
      phytochrome control. The intracellular distribution of reporter beta
      glucuronidase (GUS)-CRY fusion proteins indicates that GUS-CRY3 and GUS-CRY4
      localize in fern gametophyte nuclei. The nuclear localization of GUS-CRY3 is
      regulated in a light-dependent manner. Together with our physiological knowledge,
      these results suggest that CRY3, CRY4, or both might be the photoreceptor that
      mediates inhibition of spore germination by blue light.

PMID- 10634910
TI  - The ROOT MERISTEMLESS1/CADMIUM SENSITIVE2 gene defines a glutathione-dependent
      pathway involved in initiation and maintenance of cell division during
      postembryonic root development.
AB  - Activation of cell division in the root apical meristem after germination is
      essential for postembryonic root development. Arabidopsis plants homozygous for a
      mutation in the ROOT MERISTEMLESS1 (RML1) gene are unable to establish an active
      postembryonic meristem in the root apex. This mutation abolishes cell division in
      the root but not in the shoot. We report the molecular cloning of the RML1 gene,
      which encodes the first enzyme of glutathione (GSH) biosynthesis, gamma
      glutamylcysteine synthetase, and which is allelic to CADMIUM SENSITIVE2. The
      phenotype of the rml1 mutant, which was also evident in the roots of wild-type
      Arabidopsis and tobacco treated with an inhibitor of GSH biosynthesis, could be
      relieved by applying GSH to rml1 seedlings. By using a synchronized tobacco cell
      suspension culture, we showed that the G(1)-to-S phase transition requires an
      adequate level of GSH. These observations suggest the existence of a GSH
      dependent developmental pathway essential for initiation and maintenance of cell
      division during postembryonic root development.

PMID- 10634911
TI  - Water deficit triggers phospholipase D activity in the resurrection plant
      Craterostigma plantagineum.
AB  - Phospholipids play an important role in many signaling pathways in animal cells.
      Signaling cascades are triggered by the activation of phospholipid cleaving
      enzymes such as phospholipases C, D (PLD), and A(2). Their activities result in
      the formation of second messengers and amplification of the initial signal. In
      this study, we provide experimental evidence that PLD is involved in the early
      events of dehydration in the resurrection plant Craterostigma plantagineum. The
      enzymatic activity of the PLD protein was activated within minutes after the
      onset of dehydration, and although it was not inducible by abscisic acid, PLD
      activity did increase in response to mastoparan, which suggests a role for
      heterotrimeric G proteins in PLD regulation. Two cDNA clones encoding PLDs, CpPLD
      1 and CpPLD-2, were isolated. The CpPLD-1 transcript was constitutively
      expressed, whereas CpPLD-2 was induced by dehydration and abscisic acid.
      Immunological studies revealed changes in the subcellular localization of the PLD
      protein in response to dehydration. Taken together, the data on enzymatic
      activity as well as transcript and protein distributions allowed us to propose a
      role for PLD in the events leading to desiccation tolerance in C. plantagineum.

PMID- 10634912
TI  - Role of the TATA binding protein-transcription factor IIB interaction in
      supporting basal and activated transcription in plant cells.
AB  - The TATA binding protein (TBP) and transcription factor IIB (TFIIB) play crucial
      roles in transcription of class II genes. The requirement for TBP-TFIIB
      interactions was evaluated in maize cells by introducing mutations into the
      Arabidopsis TBP (AtTBP2) within the C-terminal stirrup. Protein binding
      experiments indicated that amino acid residues E-144 and E-146 of AtTBP2 are both
      essential for TFIIB binding in vitro. Activation domains derived from herpes
      simplex viral protein VP16, the Drosophila fushi tarazu glutamine-rich domain
      (ftzQ), and yeast Gal4 were tested in transient assays. TBP-TFIIB interactions
      were dispensable for basal transcription but were required for activated
      transcription. In general, activated transcription was more severely inhibited by
      TBP mutation E-146R than by mutation E-144R. However, these TBP mutations had
      little effect on activity of the full-length cauliflower mosaic virus 35S and
      maize ubiquitin promoters, thus demonstrating that strong TBP-TFIIB contacts are
      not always required for transcription driven by complex promoters.

PMID- 10634913
TI  - Evidence for a role of ClpP in the degradation of the chloroplast cytochrome
      b(6)f complex.
AB  - In the green alga Chlamydomonas reinhardtii, the ClpP protease is encoded by an
      essential chloroplast gene. Mutating its AUG translation initiation codon to AUU
      reduced ClpP accumulation to 25 to 45% of that of the wild type. Both the mature
      protein and the putative precursor containing its insertion sequence were present
      in reduced amounts. Attenuation of ClpP did not affect growth rates under normal
      conditions but restricted the ability of the cells to adapt to elevated CO(2)
      levels. It also affected the rate of degradation of the cytochrome b(6)f complex
      of the thylakoid membrane in two experimental situations: (1) during nitrogen
      starvation, and (2) in mutants deficient in the Rieske iron-sulfur protein. The
      ClpP level also controls the steady state accumulation of a mutated version of
      the Rieske protein. In contrast, attenuation of ClpP did not rescue the fully
      unassembled subunits in other cytochrome b(6)f mutants. We conclude that
      proteolytic disposal of fully or partially assembled cytochrome b(6)f is
      controlled by the Clp protease.

PMID- 10634914
TI  - A lipid transfer-like protein is necessary for lily pollen tube adhesion to an in
      vitro stylar matrix.
AB  - Flowering plants possess specialized extracellular matrices in the female organs
      of the flower that support pollen tube growth and sperm cell transfer along the
      transmitting tract of the gynoecium. Transport of the pollen tube cell and the
      sperm cells involves a cell adhesion and migration event in species such as lily
      that possess a transmitting tract epidermis in the stigma, style, and ovary. A
      bioassay for adhesion was used to isolate from the lily stigma/stylar exudate the
      components that are responsible for in vivo pollen tube adhesion. At least two
      stylar components are necessary for adhesion: a large molecule and a small (9 kD)
      protein. In combination, the two molecules induced adhesion of pollen tubes to an
      artificial stylar matrix in vitro. The 9-kD protein was purified, and its
      corresponding cDNA was cloned. This molecule shares some similarity with plant
      lipid transfer proteins. Immunolocalization data support its role in facilitating
      adhesion of pollen tubes to the stylar transmitting tract epidermis.

PMID- 10634916
TI  - Physiological and psychosocial contributors to malnutrition in children with
      cystic fibrosis: review.
AB  - Malnutrition was once thought to be an inevitable consequence of cystic fibrosis
      (CF). It is now considered preventable but still contributes considerable
      morbidity in children. Malnutrition is linked to poorer pulmonary function,
      reduced survival and quality of life. As the anticipated lifespan of children
      with CF continues to lengthen, the prevention of malnutrition attains greater
      importance. This review explores the complex organic and psychosocial factors
      implicated in the aetiology of malnutrition associated with CF.

PMID- 10634917
TI  - Nutrition and intestinal mucosal immunity.

PMID- 10634915
TI  - Osmotic stress induces rapid activation of a salicylic acid-induced protein
      kinase and a homolog of protein kinase ASK1 in tobacco cells.
AB  - In tobacco cells, osmotic stress induced the rapid activation of two protein
      kinases that phosphorylate myelin basic protein. Immunological studies
      demonstrated that the 48-kD kinase is the salicylic acid-induced protein kinase
      (SIPK), a member of the mitogen-activated protein kinase family. SIPK was
      activated 5 to 10 min after the cells were exposed to osmotic stresses, and its
      activity persisted for approximately 30 min. In contrast, the 42-kD kinase was
      activated within 1 min after osmotic stress, and its activity was maintained for
      approximately 2 hr. Moreover, in addition to myelin basic protein, the 42-kD
      kinase phosphorylated casein and two transcription factors, c-Jun and ATF-2. This
      latter enzyme was inactivated by a serine/threonine-specific phosphatase but,
      unlike SIPK, was not affected by a tyrosine-specific phosphatase. After the 42-kD
      kinase was purified to apparent homogeneity, tryptic peptide analysis indicated
      that it is a homolog of Arabidopsis serine/threonine kinase1 (ASK1).

PMID- 10634918
TI  - Preoperative nutritional evaluation of elderly patients: the Mini Nutritional
      Assessment as a practical tool.
AB  - BACKGROUND AND GOAL: Age and malnutrition are each surgical risk factors. Because
      the Mini Nutritional Assessment (MNA) has been specifically designed for
      assessing the nutritional status of elderly patients, it can be used for
      preoperative nutritional evaluation. Therefore, the MNA was included in the
      preoperative clinical evaluation of patients over 60 years of age to describe
      their nutritional status. METHODS: Every patient over 60 years of age, scheduled
      for elective surgery, was seen in anaesthesiology consultation and was submitted
      to the MNA. The MNA is a clinical score consisting of four additive items:
      'Anthropometric assessment' based on BMI, mid-arm and calf circumferences, weight
      loss; global evaluation; dietetic assessment, and subjective assessment - these
      last three items being obtained through a specific questionnaire. It requires no
      biological marker. Awarding to the obtained score, the MNA stratifies patients in
      the following categories: well-nourished (24 </= MNA </= 30), at risk of
      malnutrition (17 </= MNA < 23.5), and undernutrition (MNA < 17). Also recorded
      were: age, gender, type of scheduled operation, and the American Society of
      Anesthesiologists (ASA) physical status score. Results are given as median
      (extremes). RESULTS: Four hundred and nineteen patients (50.4% women) were seen
      between January and October 1996. The mean age was 72 years (range, 60-98 years);
      BMI: 25.2 (12.8-40.4) kg m(-2). The MNA score was recorded in 408 patients,
      ranging from 1.5 to 30 (median: 26). According to the score, the patients were
      stratified in: well-nourished, 276 patients (67.6%), at risk, 104 patients (25.
      5%) and suffering from overt malnutrition, 28 patients (6.9%). According to the
      ASA score, 290 patients were found to be at low or mild risk for anaesthesia and
      surgery (ASA 1 and 2), and 72 patients (24.8%) were stratified as being at least
      at risk of malnutrition. One hundred and eighteen other patients were found to be
      at a higher risk (ASA 3 and 4), and 58 (49.2%) were not well-nourished (MNA <
      24). CONCLUSION: The MNA was found to be well-suited for the preoperative
      assessment during anaesthesia consultation because it required no biological
      marker. It showed that approximately one-third of all the examined patients, and
      half of the ASA 3-4 patients, were not well-nourished. The ASA score could not
      predict poor nutritional status. The results suggested that nutritional
      assessment should be routinely performed in ASA 3-4 patients over 60 years of
      age.

PMID- 10634919
TI  - A comparison of skinfold anthropometry and dual-energy X-ray absorptiometry for
      the evaluation of body fat in cirrhotic patients.
AB  - BACKGROUND AND AIMS: Skinfold anthropometry has been used to evaluate the
      nutritional status in cirrhosis. Such estimates are based on the calculations
      which derive from healthy subjects and may not apply to cirrhotic patients. We
      aimed to calculate the limits of agreement between Skinfold anthropometry (SA)
      and dual-energy X-ray absorptiometry (DXA) in estimating body fat in cirrhotics.
      METHODS: Forty cirrhotic patients were studied by both methods. The limits of
      agreement were estimated by the Bland and Altman method. RESULTS: Percentage body
      fat was similar when measured by DXA and SA (29.6 +/- 9.2 vs 28.9 +/- 7.5 %).
      Body fat mass was also similar (20.3 +/- 8.4 vs 20.3 +/- 7.7 kg). The limits of
      agreement between DXA and SA measurements were -7.04 (95%CI: -9.55 to -5.2) +8.56
      (95%CI: +10.7 to +6.4.) in the assessment of percentage body fat and -5.32
      (95%CI: -6.77 to -3.87) +5.24 (95%CI: +3.79 to +6.69) in the assessment of fat
      mass. CONCLUSION: Percentage body fat can be evaluated by SA or DXA with a
      difference of less then 5% in the majority of cirrhotic patients without overt
      fluid retention. This result is important when considering the large
      applicability of SA.

PMID- 10634920
TI  - Non-alcoholic fatty liver: another feature of the metabolic syndrome?
AB  - BACKGROUND AND AIMS: Hepatic steatosis and nonalcoholic steatohepatitis (NASH)
      have been associated with obesity, non insulin-dependent diabetes mellitus and
      hyperlipidemia. The present study was designed in order to evaluate whether
      patients with steatosis/NASH presented common features with the metabolic
      syndrome. METHODS: In 30 patients with nonalcoholic fatty liver the prevalence of
      hypertension and diabetes; the glucose/insulin profile, lipid profile, and serum
      leptin were evaluated and correlated with body composition and energy
      expenditure, assessed by bioimpedance spectroscopy and indirect calorimetry,
      respectively. Results were compared with a group of eight controls. RESULTS:
      Obesity was present in 80% of patients, hypertension in 50% and non insulin
      dependent diabetes in 33%. Glucose metabolism was altered in 69%, with elevated
      insulin in 14 patients. Serum leptin, higher in women, was increased in patients:
      33.9 +/- 38.9 vs 9.6 +/- 6.9 ng/ml, P< 0.05. There was a correlation between
      insulin and leptin, both of which correlated with body mass index, fat mass and
      percentage of body fat. Dyslipidaemia was found in 80% of patients: 45% presented
      low high density lipoproteins cholesterol, 58% high low density lipoproteins and
      38% elevated very low density lipoproteins. CONCLUSIONS: There is a strong
      association between nonalcoholic fatty liver and features of the metabolic
      syndrome, suggesting a simultaneous insulin resistance and decreased sensitivity
      to leptin.

PMID- 10634921
TI  - Medium chain triglycerides activate distal but not proximal gut hormones.
AB  - BACKGROUND AND AIMS: Compared to long chain triglycerides (LCT), medium chain
      triglycerides (MCT) are considered an attractive caloric source in malabsorptive
      diseases because of their favorable physico-chemical characteristics. The use of
      MCTis, however, limited by the occurrence of gastrointestinal symptoms such as
      diarrhoea. We have, therefore, investigated the effects of MCT and LCT on
      proximal (cholecystokinin; CCK) and distal (peptide YY; PYY) gut hormone
      secretion. METHODS: Eight healthy volunteers participated in four experiments
      performed in random order during continuous intraduodenal administration for 360
      min of a) saline (control); b) LCT15 mmol/h; c) MCT15mmol/h (equimolar); d) MCT
      30 mmol/h (equicaloric). Plasma CCK and PYY were determined at regular intervals
      (radioimmunoassay). Duodenocecal transit (DCTT) was measured by lactulose
      H(2)breath test. RESULTS: DCTT during LCT (105 +/- 11 min) was not significantly
      different from saline (111 +/- 10 min). Both low dose MCT (54 +/- 5 min) and high
      dose MCT (61 +/- 6 min) significantly accelerated DCTT (P< 0.05). Plasma CCK
      increased significantly (P< 0.05) during LCT but not during MCT or saline. PYY
      increased significantly (P< 0.05) not only during LCT, but also during low and
      high dose MCT but not during saline. CONCLUSIONS: Intraduodenal MCTs a)
      accelerate intestinal transit; b) do not stimulate CCK release; c) but stimulate
      release of the distal gut hormone PYY. These results suggest that MCTs are not
      rapidly absorbed in the proximal gut but probably reach the ileocolonic region
      and stimulate PYY release.

PMID- 10634922
TI  - Is glutamine a 'conditionally essential' amino acid in Duchenne muscular
      dystrophy?
AB  - To determine whether whole body protein kinetics are altered in Duchenne muscular
      dystrophy (DMD), six 9 +/- 1-year-old children with DMD and five weight and
      height matched controls, received intravenous infusion of L-[1-(13)C]leucine and
      L-[2-(15)N]glutamine in the post-absorptive state. Glutamine rate of appearance
      was approximatly 24% lower in DMD boys than in controls (321 +/- 22 vs 425 +/- 37
      micromol kg(-1)h(-1), P< 0.05) resulting from a 32% decrease in glutamine de novo
      synthesis (230 +/- 21 vs 340 +/- 34 micromol kg(-1)h(-1), P< 0.05). Whereas there
      was no difference between groups in estimates of protein degradation and
      synthesis, leucine oxidation rate was 44% higher in DMD boys than in controls (23
      +/- 2 vs 16 +/- 2 micromol kg(-1)h(-1), P< 0.05). The data suggest that the
      dramatic mucle mass loss observed in DMD boys is associated with a) significant
      protein wasting, since increased leucine oxidation reflects a more negative whole
      body leucine balance, and b) a significant decrease in glutamine availability in
      the postabsorptive state. Glutamine might therefore be a 'conditionally
      essential' amino-acid in DMD.

PMID- 10634923
TI  - Oral supplements as adjunctive treatment to nutritional counseling in
      malnourished HIV-infected patients: randomized controlled trial.
AB  - AIMS: To compare nutritional counseling with and without oral supplements in HIV
      infected patients with recent weight loss. DESIGN: Randomized non-blinded
      controlled trial, stratified for change in antiretroviral treatment at baseline.
      PATIENTS: HIV-infected patients with recent weight loss (> 5% of total, and >3%
      in the last month). INTERVENTION: Nutritional counseling to increase dietary
      intake by 600 kcal/day over 8 weeks; in group A (n=24) by normal food, and in
      group B (n=26) by a range of fortified drink supplements with a calorific value
      of 0.6 to 1.5 kcal/ml. METHODS: Body composition by bioelectrical impedance
      analysis, dietary intake by 24 h recall. RESULTS: Fat free mass increased from
      baseline to week 8 (P<0.05) with no difference between groups A and B (P=0.97).
      Body cell mass and weight gain were not significant and equal between groups.
      Assessed at weeks 2 and 4, group B patients consumed 11 +/- 6 kcal/kg as
      supplements, and their total energy intake was 6 kcal/kg higher than in group A
      (P<0.01). Total energy intake was not different between groups at weeks 6 and 8.
      DISCUSSION: Nutritional counseling and oral supplements are both feasible methods
      to restore food energy intake in malnourished HIV-infected patients. Although
      normal food intake is partially replaced, oral supplements may improve the
      adherence to a weight gain regimen.

PMID- 10634924
TI  - Thiamin deficiency in HIV-positive patients: evaluation by erythrocyte
      transketolase activity and thiamin pyrophosphate effect.
AB  - BACKGROUND AND AIMS: The aim of the study was to determine the thiamin status in
      HIV-positive patients. METHODS: Measurement of erythrocyte transketolase activity
      (ETK) and thiaminpyrophosphate (TPP) effect in 55 consecutive HIV-positive
      patients of a specialized outpatient clinic were grouped into five groups
      according to their CD4 counts. Comparison of results of HIV-positive patients
      with age-matched control group of 22 healthy subjects. RESULTS: Of the patients,
      27% had a pathologically-increased TPP effect, 18% of the patients had
      pathologically-low ETK. The percentage of pathological values of TPP effect in
      the patients was significantly higher compared with the control group. There was
      no statistically significant correlation between pathological thiamin status and
      stage of the disease, zidovudine therapy or nutritional status of the patients.
      CONCLUSIONS: Thiamin deficiency in HIV-positive patients was found in a higher
      percentage than previously reported. Thiamine deficiency is not only present in
      advanced stages of HIV-infection, but also in clinically asymptomatic patients.

PMID- 10634925
TI  - The role of the nutritional support dietitian in Europe.
AB  - The European Community now supports the potential for professionals to practice
      in any of the member states subject to recognized local standards of education
      and practice being achieved. However, there is no agreed role for the nutritional
      support dietitian. This leads to an inconsistent and, sometimes, fragmented
      approach to the nutritional management of patients throughout Europe. There is a
      need to develop a common dietetic approach to nutritional support in order to
      raise awareness and rationalize standards. This will help to optimize care to
      individual patients by fostering good practice, developing effective
      communication and encouraging research. BACKGROUND: The role of the clinical
      dietitian varies widely throughout Europe - it tends to be more highly developed
      in some countries than in others, which is a cause for concern among dietitians
      in ESPEN. This appears to be caused by several factors including education,
      clinical awareness of the benefits of dietetic support and access to adequate
      financial resources. The intention of this paper is to focus on the key aspects
      of the role of the dietitian working in nutritional support. The educational
      requirements of such a dietitian are outlined and these could be used as a
      preliminary guide for institutions responsible for delivering undergraduate
      dietetic programmes. The overall intention is to identify minimum educational
      standards for practice in this field throughout Europe. However, these should be
      viewed as a baseline from which to proceed. They should also be perceived as a
      quality standard for facilitating professional development, sharing clinical
      practice and enhancing patient outcomes. This paper does not address issues of
      resource allocation. RECOMMENDATIONS: a) There should be agreement about the key
      functions of the dietitian working in nutritional support; b) There should be a
      common standard at first degree level for all dietitians; c) There should be an
      identified programme of post-graduate study (both clinical and academic) leading
      to specialization in nutritional support; d) There should be an innovative
      approach to providing clinical support for emerging specialists; e) ESPEN should
      investigate the potential for developing an accredited and integrated European
      dietetic standard in nutritional support.

PMID- 10634926
TI  - Camptothecin enhances random integration of transfected DNA into the genome of
      mammalian cells.
AB  - In order to study the involvement of DNA topoisomerase I (top1) in recombination,
      we examined the effect of the anti-neoplastic drug camptothecin, which
      selectively poisons top1 by trapping top1-cleavable complexes on integration of
      exogenic vector into the genome of mammalian cells. We transfected mouse F9
      teratocarcinoma cells as well as Chinese hamster V79 cells with a plasmid
      carrying a selectable neo gene treated with camptothecin, and determined the
      frequency of neo+ (G418(R)) colonies. We found that treatment with camptothecin
      for as short a time as 4 h after electroporation resulted in a 4- to 33-fold
      stimulation of plasmid integration into the recipient genome via non-homologous
      recombination. These results imply that top1-cleavable complexes trapped by
      camptothecin could be potentially recombinogenic structures and could stimulate
      non-homologous recombination in vivo, promoting the integration of transfected
      plasmids into mammalian genome.

PMID- 10634927
TI  - Implication of free radicals and glutathione in the mechanism of cadmium-induced
      expression of stress proteins in the A549 human lung cell-line.
AB  - Cellular mechanisms underlying the expression of stress proteins (HSP) were
      studied in the human cell-line A549 submitted to a pollutant, cadmium, in the
      presence of several agents which modulate the glutathione level and, supposedly,
      the effects of this metal in the cell. It was observed that HSP 90, HSP 72 and
      HSP 27 are significantly over-expressed after exposure to cadmium chloride for 24
      h. Low cadmium concentrations (i.e. from 1 to 10 microM) also triggered a slight
      accumulation of glutathione, whereas this compound was depleted after exposure to
      higher cadmium concentrations (25-100 microM). When 50 microM diethyl-maleate,
      which traps glutathione, was added together with cadmium, the over-expression of
      HSP 72 and HSP 90 was much stronger. Treatment of cells with 20 or 40 mM N-acetyl
      L-cysteine, which traps free radicals, was found to increase by 30% the
      glutathione level and to suppress the HSP over-expression. From our results, it
      is suggested that HSP induction by cadmium in A549 cells is due, at least in
      part, to the oxidative stress consisting in formation of reactive oxygen species
      and inhibition of peroxides detoxification. Due to this oxidative status within
      the cell, more proteins would be damaged inducing the HSP over-expression.

PMID- 10634928
TI  - Insulin-induced Ca(2+) entry in hepatocytes is important for PI 3-kinase
      activation, but not for insulin receptor and IRS-1 tyrosine phosphorylation.
AB  - Insulin produces an influx of Ca(2+) into isolated rat hepatocyte couplets that
      is important to couple its tyrosine kinase receptor to MAPK activity (Benzeroual
      et al., Am. J. Physiol. 272, (1997) G1425-G1432. In the present study, we have
      examined the implication of Ca(2+) in the phosphorylation state of the insulin
      receptor (IR) beta-subunit and of insulin receptor substrate-1 (IRS-1), as well
      as in the stimulation of PI 3-kinase activity in cultured hepatocytes. External
      Ca(2+) chelation (EGTA 4 mM) or administration of Ca(2+) channel inhibitors
      gadolinium 50 microM or nickel 500 microM inhibited insulin-induced PI 3-kinase
      activation by 85, 50 and 50%, respectively, whereas 200 microM verapamil was
      without effect. In contrast, the insulin-induced tyrosine phosphorylation of IR
      beta-subunit and of IRS-1 was not affected by any of the experimental conditions.
      Our data demonstrate that the stimulation of PI 3-kinase activity by the
      activated insulin receptor, but not the phosphorylation of IR beta-subunit and
      IRS-1, requires an influx of Ca(2+). Ca(2+) thus appears to play an important
      role as a second messenger in insulin signaling in liver cells.

PMID- 10634930
TI  - Simultaneous measurements of ionic currents and leucine uptake at the amino acid
      cotransporter KAAT1 expressed in Xenopus laevis oocytes.
AB  - The transport properties of the intestinal amino acid cotransporter KAAT1,
      heterologously expressed in Xenopus oocytes, were studied using simultaneous
      voltage-clamp and tritiated leucine uptake measurements. While addition of 1 mM
      leucine to oocytes kept at -80 mV in presence of Na(+) or K(+) caused an increase
      in holding current, in presence of Li(+) the current was reduced. Uptake
      measurements in voltage-clamp conditions showed that a comparable accumulation of
      amino acid occurred in all three ionic conditions and irrespective of the
      direction and amount of the current change. The ratio of moles of transferred
      charge to moles of transported amino acid ranges from 1.45 for K(+) to 3.52 for
      Li(+). A hypothetical interpretation involving the coexistence of two populations
      of transporters, one operating in the uncoupled mode and the other in the
      substrate transport mode is discussed.

PMID- 10634929
TI  - PKC signaling in CF/T43 cell line: regulation of NKCC1 by PKC-delta isotype.
AB  - Cystic fibrosis (CF) airway epithelial cells have a reduced mass of ether-linked
      diacylglycerols which might alter protein kinase C (PKC)-regulated Cl secretion.
      PKC regulation of basolateral Na-K-2Cl cotransport (NKCC1) was investigated in CF
      nasal polyp epithelial cells and a CF/T43 cell line to ascertain whether PKC
      signaling was altered in CF. NKCC1 was detected as bumetanide-sensitive (86)Rb
      influx. Methoxamine, a alpha(1)-adrenergic agonist, increased PKC activity in
      cytosol and a particulate fraction for a prolonged time period, as predicted from
      previous studies on the generation of diglycerides induced with methoxamine.
      Short-term stimulation of CF/T43 cells for 40 s promoted a shift in PKC-delta and
      -zeta to a particulate fraction, increased activity of immune complexes of
      cytosolic PKC-delta and of particulate PKC-zeta and increased activity of NKCC1.
      Pretreatment with antisense oligonucleotide to PKC-delta blocked methoxamine
      stimulated PKC-delta activity, reduced PKC-delta mass by 61.4%, and prevented
      methoxamine-stimulated activity of NKCC1. Sense and missense oligonucleotide to
      PKC-delta and antisense oligonucleotide to PKC-zeta did not alter expression of
      PKC-delta or the effects of methoxamine. These results demonstrate that PKC-delta
      dependent activation of NKCC1 is preserved in CF cells and suggest that
      regulation of NKCC1 is independent of low ether-linked diglyceride mass.

PMID- 10634931
TI  - Cooperation of fibronectin with lysophosphatidic acid induces motility and
      transcellular migration of rat ascites hepatoma cells.
AB  - We have previously shown that the transcellular migration of rat ascites hepatoma
      (AH130-MM1) cells through a cultured mesothelial cell monolayer (MCL) is
      triggered with lysophosphatidic acid (LPA) that stimulates actin polymerization
      and myosin light chain phosphorylation through the activation of Rho-ROCK (Rho
      kinase) cascade. When, however, the motility of MM1 cells on a glass surface was
      tested by phagokinetic track motility assay, LPA failed to induce the motility.
      Nevertheless, when the glass had been coated with fibronectin (FN), LPA could
      induce phagokinetic motility which was accompanied by transformation of MM1 cells
      to fusiform-shape and assembly of focal adhesion. beta1 integrin, the counter
      receptor of FN, was expressed on MM1 cells. Anti-FN antibody, anti-beta1 integrin
      antibody and cyclo-GRGDSPA remarkably suppressed LPA-induced phagokinetic
      motility. These antibodies suppressed LPA-induced transcellular migration through
      MCL, as well. These results indicate that actin polymerization and
      phosphorylation of myosin light chain through Rho activation are insufficient for
      inducing motility but the cooperative FN/beta1 integrin-mediated adhesion is
      necessary for both the phagokinetic motility and transcellular migration of MM1
      cells.

PMID- 10634932
TI  - Transcriptional regulation of E2F-1 and eIF-2 genes by alpha-pal: a potential
      mechanism for coordinated regulation of protein synthesis, growth, and the cell
      cycle.
AB  - alpha-Pal regulates the basal transcription of the alpha and beta subunits of
      eukaryotic initiation factor two (eIF-2), a rate-limiting enzyme for the
      initiation of protein biosynthesis. We recently showed that its global function
      may be to modulate the expression of key metabolic genes in response to cellular
      proliferation. In this paper, we examined a potential molecular mechanism by
      which alpha-Pal may achieve this function. When overexpressed, alpha-Pal
      upregulated protein synthesis and growth, but downregulated the cell cycle. The
      mechanism for the increased protein synthesis and growth appeared to be a
      transcriptional upregulation of the eIF-2alpha and eIF-2beta genes. The mechanism
      for the cell cycle downregulation appeared to be a transcriptional downregulation
      of E2F-1, a transcription factor that regulates genes required for cell cycle
      progression beyond the G1/S interphase. Specifically, an apparently modified
      species of alpha-Pal bound to the eIF-2 promoters and induced transcriptional
      upregulation, whereas, an apparently unmodified species of the alpha-Pal bound to
      the E2F-1 promoter and induced transcriptional downregulation. By this mechanism,
      alpha-Pal may participate in coordinating the regulation of global protein
      synthesis, growth and the cell cycle; a regulation that is essential to cellular
      differentiation.

PMID- 10634933
TI  - Expression of kininogen, kallikrein and kinin receptor genes by rat
      cardiomyocytes.
AB  - To ascertain the existence of the kallikrein-kinin system in the heart, we have
      studied in vivo and in vitro whether rat cardiac tissue expresses kininogen,
      kallikrein and kinin receptor mRNAs. The reverse transcription-polymerase chain
      reaction demonstrated that the ventricular myocardium of adult male rats
      expressed mRNAs for T- and low-molecular-weight (L-) kininogens, tissue
      kallikreins such as true kallikrein and T-kininogenase, and bradykinin B2
      receptor, but not those for high-molecular-weight kininogen and B1 receptor.
      Lipopolysaccharide (LPS; 0.5 mg/kg, i.v.) increased the levels of mRNA for T
      kininogen at 12 h and the bradykinin B1 receptor at 24 h without affecting that
      for other components. All of these mRNAs for the kallikrein-kinin system were
      also detected in cultured cardiomyocytes derived from neonatal rat ventricles;
      dibutyryl cyclic AMP, LPS or inflammatory cytokines such as interleukin-1 and
      tumor necrosis factor, up-regulated mRNA expression of T-kininogen, T
      kininogenase, or B1 receptor in these cells in vitro. These results suggest that
      there are two kinin-generating systems in rat myocardium comprising T-kininogen/T
      kininogenase and L-kininogen/true kallikrein respectively, and that the former
      may be relatively important in inflammatory diseases or conditions in which cAMP
      levels increase in cardiomyocytes.

PMID- 10634934
TI  - Cyclic AMP mediates the elevation of proline by AKH peptides in the cetoniid
      beetle, Pachnoda sinuata.
AB  - The role of cyclic nucleotides in the transduction of the hyperprolinaemic and
      hypertrehalosaemic signal of the endogenous neuropeptide Mem-CC was investigated
      in the cetoniid beetle Pachnoda sinuata. Flight and injection of Mem-CC into the
      haemocoel of the beetle induce an increase of cAMP levels in the fat body of the
      beetle. This increase is tissue-specific and does not occur in brain and flight
      muscles. An elevation of cAMP levels was also found when in vitro preparations of
      fat body tissue were subjected to Mem-CC. Elevation of the cAMP concentration
      after injection of Mem-CC is time- and dose-dependent: the maximum response is
      measured after 1 min, and a dose of 25 pmol Mem-CC is needed. Injection of cpt
      cAMP, a cAMP analogue which penetrates the cell membrane, causes a stimulation of
      proline synthesis but no mobilisation of carbohydrate reserves. The same is
      measured when IBMX, an inhibitor of phosphodiesterase, is injected. cGMP seems
      not to be involved in synthesis of proline nor carbohydrate release, because
      injection of cpt-cGMP has no influence on the levels of proline, alanine and
      carbohydrates in the haemolymph. Although glycogen phosphorylase of the fat body
      is activated by Mem-CC in a time- and dose-dependent manner, it cannot be
      stimulated by cpt-cAMP. The combined data suggest that cAMP is involved in
      regulation of proline levels by Mem-CC but not in regulation of carbohydrates.
      Octopamine has no effect on metabolites in the haemolymph and is not capable of
      activating glycogen phosphorylase, indicating that it is not involved in the
      regulation of substrates in this beetle. Furthermore, the requirements of the
      receptor of Mem-CC are different for eliciting a hypertrehalosaemic and a
      hyperprolinaemic effect, respectively, suggesting that differentiation in signal
      transduction begins at the receptor level.

PMID- 10634935
TI  - Extremely low frequency pulsed DC electric fields promote neutrophil extension,
      metabolic resonance and DNA damage when phase-matched with metabolic oscillators.
AB  - Application of extremely low frequency pulsed DC electric fields that are
      frequency- and phase-matched with endogenous metabolic oscillations leads to
      greatly exaggerated neutrophil extension and metabolic resonance wherein
      oscillatory NAD(P)H amplitudes are increased. In the presence of a resonant
      field, migrating cell length grows from 10 to approximately 40 microm, as does
      the overall length of microfilament assemblies. In contrast, cells stop
      locomotion and become spherical when exposed to phase-mismatched fields. Although
      cellular effects were not found to be dependent on electrode type and buffer,
      they were sensitive to temporal constraints (phase and pulse length) and cell
      surface charge. We suggest an electromechanical coupling hypothesis wherein
      applied electric fields and cytoskeletal polymerization forces act together to
      overcome the surface/cortical tension of neutrophils, thus promoting net
      cytoskeletal assembly and heightened metabolic amplitudes. Metabolic resonance
      enhances reactive oxygen metabolic production by neutrophils. Furthermore,
      cellular DNA damage was observed after prolonged metabolic resonance using both
      single cell gel electrophoresis ('comet' assay) and 3'-OH DNA labeling using
      terminal deoxynucleotidyl transferase. These results provide insights into
      transmembrane signal processing and cell interactions with weak electric fields.

PMID- 10634936
TI  - Regulated von Willebrand factor (vWf) secretion is restored by pro-vWf expression
      in a transfectable endothelial cell line.
AB  - Von Willebrand factor (vWf) is a glycoprotein involved in primary hemostasis and
      synthesized in endothelial cells (EC). vWf is stored in secretory granules
      specific for EC called Weibel-Palade bodies (WPb). Studies on the molecular
      mechanisms of vWf storage and acute release are hampered by the limitations of
      the available endothelial cell culture models. We created a suitable model by
      stable transfection of the vWf-negative ECV304 endothelial cell line with pro-vWf
      cDNA. Pro-vWf was normally cleaved to mature vWf and stored in WPb. Acute vWf
      release occurred in response to the calcium ionophore A23187. Thus, vWf
      expression is sufficient to restore functional secretory granules in ECV304
      cells. We used this model to study the role of WPb in the storage of tissue-type
      plasminogen activator (t-PA), a key fibrinolytic enzyme that is acutely released
      by EC, but whose intracellular storage compartment is still a matter of debate.
      We observed that restoration of WPb in ECV304 cells results in the targeting of t
      PA to these storage granules.

PMID- 10634937
TI  - Anionic phospholipids, interfacial binding and the regulation of cell functions.

PMID- 10634938
TI  - High density lipoprotein oxidation: in vitro susceptibility and potential in vivo
      consequences.
AB  - Elevated levels of plasma high density lipoprotein (HDL) are strongly predictive
      of protection against atherosclerotic vascular disease. HDL particles likely have
      several beneficial actions in vivo, including the initiation of reverse
      cholesterol transport. The apparent importance of oxidative modification of low
      density lipoprotein in atherogenesis raises the question of how oxidative
      modification of HDL might affect its cardioprotective actions. HDL is readily
      oxidized using numerous models of lipoprotein oxidation. In vitro evidence
      suggests oxidation might impair some protective actions, but actually enhance
      other mechanisms induced by HDL that prevent the accumulation of cholesterol in
      the artery wall. This article reviews the current literature concerning the
      relative oxidizability of HDL, the structural changes induced in HDL by oxidation
      in vitro, and the potential consequences of oxidative modification on the
      protective actions of HDL in vivo.

PMID- 10634939
TI  - Unusually high reactivity of apolipoprotein B-100 among proteins to radical
      reactions induced in human plasma.
AB  - Relative reactivities of proteins to radical reactions caused in human plasma
      were studied for the first time utilizing an immunoblotting assay. When radical
      reactions were caused by Cu(2+), apolipoprotein B-100 (apoB) underwent extensive
      fragmentation concurrently with the decrease in alpha-tocopherol, while human
      serum albumin (HSA) and transferrin (TF) were not decreased at all. When radical
      reactions were initiated by Cu(2+) with hydrogen peroxide or 2,2'-azobis(2
      amidinopropane)dihydrochloride (AAPH), alpha-tocopherol and apoB were also
      decreased steadily but HSA and TF were not decreased. These observations indicate
      that apoB is extremely reactive, even comparable to alpha-tocopherol, towards
      radical reactions. These results also suggest that the radical reaction of apoB
      is a possible process in vivo and it is involved in atherogenesis along with low
      density lipoprotein lipid peroxidation, which has been studied extensively.

PMID- 10634940
TI  - Higher cardol homologs (5-alkylresorcinols) in rye seedlings.
AB  - The occurrence of alkylresorcinols, polyketide compounds that in the same
      homologous series as cardol isolated from Anacardium occidentale (cashew) or
      bilobol from Ginkgo biloba which are derivatives of 1,3-dihydroxy-5
      alk(en)ylbenzene, have been demonstrated in developing rye (Secale cereale L.)
      kernels. The 3-day-old seedlings grown in sterile conditions already contain
      detectable amounts of phenolic compounds that were identified as
      alkylresorcinols. This fraction is the mixture of saturated and enoic homologs of
      various lengths of the aliphatic side chain. The composition of homologs is
      similar to that determined in mature grains. The relatively high level of
      alkylresorcinols in mitochondria and plastids (enhanced approximately twice in
      the absence of light) suggests that their synthetic pathway and/or biological
      function may be related to these cellular compartments. Resorcinolic lipids, when
      present in the external medium, are taken up by seedlings in the energy-dependent
      manner.

PMID- 10634941
TI  - The lipolytic stimulation of 3T3-L1 adipocytes promotes the translocation of
      hormone-sensitive lipase to the surfaces of lipid storage droplets.
AB  - Hormone-sensitive lipase catalyzes the rate-limiting step in the release of fatty
      acids from triacylglycerol-rich lipid storage droplets of adipocytes, which
      contain the body's major energy reserves. Hormonal stimulation of cAMP formation
      and the activation of cAMP-dependent protein kinase leads to the phosphorylation
      of hormone-sensitive lipase and a large increase in lipolysis in adipocytes. By
      contrast, phosphorylation of hormone-sensitive lipase by the kinase in vitro
      results in a comparatively minor increase in catalytic activity. In this study,
      we investigate the basis for this discrepancy by using immunofluorescence
      microscopy to locate hormone-sensitive lipase in lipolytically stimulated and
      unstimulated 3T3-L1 adipocytes. In unstimulated cells, hormone-sensitive lipase
      is diffusely distributed throughout the cytosol. Upon stimulation of cells with
      the beta-adrenergic receptor agonist, isoproterenol, hormone-sensitive lipase
      translocates from the cytosol to the surfaces of intracellular lipid droplets
      concomitant with the onset of lipolysis, as measured by the release of glycerol
      to the culture medium. Both hormone-sensitive lipase translocation and lipolysis
      are reversed by the incubation of cells with the beta-adrenergic receptor
      antagonist, propranolol. The treatment of cells with cycloheximide fails to
      inhibit lipase translocation or lipolysis, indicating that the synthesis of
      nascent proteins is not required. Cytochalasin D and nocodazole used singly and
      in combination also failed to have a major effect, thus suggesting that the
      polymerization of microfilaments and microtubules and the formation of
      intermediate filament networks is unnecessary. Hormone-sensitive lipase
      translocation and lipolysis were inhibited by N-ethylmaleimide and a combination
      of deoxyglucose and sodium azide. We propose that the major consequence of the
      phosphorylation of hormone-sensitive lipase following the lipolytic stimulation
      of adipocytes is the translocation of the lipase from the cytosol to the surfaces
      of lipid storage droplets.

PMID- 10634942
TI  - A second Escherichia coli protein with CL synthase activity.
AB  - The Escherichia coli open reading frame f413, which has the potential to code for
      a polypeptide homologous to cardiolipin (CL) synthase, has been cloned. Its
      polypeptide product has a molecular mass of 48 kDa, is membrane-bound, and
      catalyzes CL formation but does not hydrolyze CL. A comparison of the sequences
      predicted for the polypeptides encoded by f413 and cls indicates that the N
      terminal residues specified by cls may be unnecessary for CL synthase activity.
      Construction of a truncated cls gene and characterization of its polypeptide
      product have confirmed this conclusion.

PMID- 10634943
TI  - Expression of a lipid transfer protein gene family during cotton fibre
      development.
AB  - There are six to eight lipid transfer protein-related genes in the allotetraploid
      Gossypium hirsutum genome, three of which, FSltp1, FSltp2 and FSltp3, were
      isolated in two genomic clones. All three genes potentially encode full-length
      lipid transfer proteins (LTPs), but sequence differences between these and the
      cotton fibre-specific cDNA previously reported, pFS6, suggest that none is likely
      to encode the fibre transcripts. Gene-specific RT-PCR experiments showed that
      expression patterns of the three new LTP genes are similar to each other, with
      transcripts present in all aerial cotton tissues tested, and only pFS6
      transcripts are present in fibre cells at elevated levels. PCR analysis of cotton
      genomic DNA suggested that FSltp1 and FSltp3 are alloalleles, with FSltp3 being
      derived from the ancestral A genome, and FSltp1 from the D genome. The fibre
      specific gene, yet to be isolated, and FSltp2 are also derived from the ancestral
      D genome of G. hirsutum.

PMID- 10634944
TI  - The utilization of recombinant prostanoid receptors to determine the affinities
      and selectivities of prostaglandins and related analogs.
AB  - Stable cell lines that individually express the eight known human prostanoid
      receptors (EP(1), EP(2), EP(3), EP(4), DP, FP, IP and TP) have been established
      using human embryonic kidney (HEK) 293(EBNA) cells. These recombinant cell lines
      have been employed in radioligand binding assays to determine the equilibrium
      inhibitor constants of known prostanoid receptor ligands at these eight
      receptors. This has allowed, for the first time, an assessment of the affinity
      and selectivity of several novel compounds at the individual human prostanoid
      receptors. This information should facilitate interpretation of pharmacological
      studies that employ these ligands as tools to study human tissues and cell lines
      and should, therefore, result in a greater understanding of prostanoid receptor
      biology.

PMID- 10634945
TI  - Differential formation of octadecadienoic acid and octadecatrienoic acid products
      in control and injured/infected potato tubers.
AB  - Lipoxygenases in plants have been implicated in the activation of defense
      responses against injury/infection. Pathogen-derived polyunsaturated fatty acids,
      such as arachidonic acid, eicosapentaenoic acid and their metabolites have been
      shown to elicit defense responses against pathogen infection in plants. However,
      not much is known about the role of host-derived fatty acids and their
      metabolites in plant defense responses. In this study, isolation and
      characterisation of endogenous lipoxygenase metabolites formed in potato tubers
      in response to injury/infection was undertaken. While 9
      hydroperoxyoctadecadienoic acid (9-HPODE), derived from octadecdienoic acid
      (linoleic acid) is the major lipoxygenase product formed in control potato
      tubers, 9-hydroperoxyoctadecatrienoic acid (9-HPOTrE), derived from
      octadecatrienoic acid (alpha-linolenic acid) is the major lipoxygenase product
      formed in potato tubers in response to injury or infection with Rhizoctonia
      bataticola. As a result, the relative ratio of 9-HPODE to 9-HPOTrE showed a shift
      from 4:1 in control to 1:2 and 1:4.5 in injured and infected potato tubers
      respectively. From this study, it is proposed that lipoxygenase metabolites of
      octadecadienoic acid may be involved in physiological responses under control
      conditions, while octadecatrienoic acid metabolites are mediating the defense
      responses. This forms the first report on the differential formation of
      endogenous lipoxygenase products in potato tubers under control and stress
      conditions.

PMID- 10634946
TI  - A novel fabrication method of macroporous biodegradable polymer scaffolds using
      gas foaming salt as a porogen additive.
AB  - Highly open porous biodegradable poly(L-lactic acid) ?PLLA scaffolds for tissue
      regeneration were fabricated by using ammonium bicarbonate as an efficient gas
      foaming agent as well as a particulate porogen salt. A binary mixture of PLLA
      solvent gel containing dispersed ammonium bicarbonate salt particles, which
      became a paste state, was cast in a mold and subsequently immersed in a hot water
      solution to permit the evolution of ammonia and carbon dioxide within the
      solidifying polymer matrix. This resulted in the expansion of pores within the
      polymer matrix to a great extent, leading to well interconnected macroporous
      scaffolds having mean pore diameters of around 300-400 microm, ideal for high
      density cell seeding. Rat hepatocytes seeded into the scaffolds exhibited about
      95% seeding efficiency and up to 40% viability at 1 day after the seeding. The
      novelty of this new method is that the PLLA paste containing ammonium bicarbonate
      salt particles can be easily handled and molded into any shape, allowing for
      fabricating a wide range of temporal tissue scaffolds requiring a specific shape
      and geometry.

PMID- 10634947
TI  - Wound dressing with sustained anti-microbial capability.
AB  - To overcome current limitations in wound dressings for treating mustard-burn
      induced septic wound injuries, a nonadherent wound dressing with sustained anti
      microbial capability has been developed. The wound dressing consists of two
      layers: the upper layer is a carboxymethyl-chitin hydrogel material, while the
      lower layer is an anti-microbial impregnated biomaterial. The hydrogel layer acts
      as a mechanical and microbial barrier, and is capable of absorbing wound exudate.
      In physiological fluid, the carboxymethylated-chitin hydrogel swells
      considerably, imbibing up to 4 times its own weight of water and is also highly
      porous to water vapor. The moisture permeability of the dressing prevents the
      accumulation of fluid in heavily exudating wounds seen in second-degree burns.
      The lower layer, fabricated from chitosan acetate foam, is impregnated with
      chlorhexidine gluconate. From the in vitro release studies, the loading
      concentration was optimized to deliver sufficient anti-microbial drug into the
      wound area to sustain the anti-microbial activity for 24 h. The anti-microbial
      activity of the dressing against Pseudomonas aeruginosa and Staphylococcus aureus
      was tested using the Bauer-Kirby Disk Diffusion Test.

PMID- 10634948
TI  - In vivo behavior of epoxy-crosslinked porcine heart valve cusps and walls.
AB  - Calcification limits the long-term durability of xenograft glutaraldehyde
      crosslinked heart valves. In this study, epoxy-crosslinked porcine aortic valve
      tissue was evaluated after subcutaneous implantation in weanling rats. Non
      crosslinked valves and valves crosslinked with glutaraldehyde or carbodiimide
      functioned as control. Epoxy-crosslinked valves had somewhat lower shrinkage
      temperatures than the crosslinked controls, and within the series also some
      macroscopic and microscopic differences were obvious. After 8 weeks implantation,
      cusps from non-crosslinked valves were not retrieved. The matching walls were
      more degraded than the epoxy- and control-crosslinked walls. This was observed
      from the higher cellular ingrowth with fibroblasts, macrophages, and giant cells.
      Furthermore, non-crosslinked walls showed highest numbers of lymphocytes, which
      were most obvious in the capsules. Epoxy- and control-crosslinked cusps and walls
      induced lower reactions. Calcification, measured by von Kossa-staining and by Ca
      analysis, was always observed. Crosslinked cusps calcified more than walls. Of
      all wall samples, the non-crosslinked walls showed the highest calcification. It
      is concluded that epoxy-crosslinked valve tissue induced a foreign body and
      calcification reaction similar to the two crosslinked controls. Therefore, epoxy
      crosslinking does not represent a solution for the calcification problem of heart
      valve bioprostheses.

PMID- 10634949
TI  - Bonding of alkali- and heat-treated tantalum implants to bone.
AB  - Alkali- and heat-treated tantalum (Ta) has been shown to bond to bone. The
      purpose of this study was to investigate the effects of chemical treatments on
      the bone-bonding ability of tantalum implants in rabbit tibiae. Miyazaki et al.
      reported in vitro that alkali- and heat-treated tantalum had an apatite forming
      ability in an acellular simulated body fluid (SBF). In this study, smooth
      surfaced rectangular plates (15 x 10 x 2 mm) of pure tantalum and treated
      tantalum were prepared. The plates were implanted transcortically into the
      proximal metaphyses of bilateral rabbit tibiae, alkali- and heat-treated plates
      for one limb and untreated plates for the contralateral limb, which served as a
      paired control. Bone bonding at the bone/implant interface was evaluated by
      tensile testing and undecalcified histological examination, at 8 and 16 weeks
      after implantation. The treated implants showed weak bonding to bone at 8 weeks,
      and exhibited significantly higher tensile failure loads compared with untreated
      tantalum implants at 16 weeks. The untreated implants showed almost no bonding,
      even at 16 weeks. Histological examination by Giemsa surface staining, contact
      microradiography (CMR), and scanning electron microscopy (SEM) revealed that
      treated tantalum implants bonded directly to bone tissue. In contrast, the
      untreated tantalum implants had a intervening fibrous tissue layer between the
      bone and the plate and did not bond to bone at 8 and 16 weeks. It is clear from
      these results that alkali and heat treatment induce the bone-bonding ability of
      tantalum. This new bioactive tantalum should be an effective material for weight
      bearing and bone-bonding orthopedic devices.

PMID- 10634950
TI  - Preliminary in vivo studies on the osteogenic potential of bone morphogenetic
      proteins delivered from an absorbable puttylike polymer matrix.
AB  - This article describes preliminary in vivo studies evaluating the osteogeneic
      potential of bone morphogenetic proteins (BMPs) delivered from an absorbable
      puttylike polymer matrix. In the first study, bovine-derived bone morphogenetic
      proteins were incorporated in an polymer matrix consisting of 50:50 poly(DL
      lactide-co-glycolide) dissolved in N-methyl-2-pyrrolidone. The matrix was
      implanted in an 8 mm critical-size calvarial defect created in the skull of adult
      Sprague-Dawley rats (n = 5 per treatment group). After 28 days, the implant sites
      were removed and examined for new bone formation, polymer degradation, and tissue
      reaction. Gamma-irradiated polymer matrices appeared to give more bone formation
      than nonirradiated samples (histological analysis; 2. 76 + 1.34 mm(2) of bone
      versus 1.30 + 0.90 mm(2) of bone, respectively and x-ray analysis; 27.2 + 15.9
      mm(2) of bone versus 20. 7 + 16.7 mm(2) of bone, respectively) and less residual
      polymer (0.0 + 0.0 versus 0.2 + 0.4, respectively). The polymer implants with
      bone morphogenetic protein also gave less inflammatory response than the polymer
      controls (gamma irradiated polymer/BMP = 1.8 + 0.4 and nonirradiated polymer/BMP
      = 1.2 + 0.4 versus polymer only = 3.0 + 1. 2, respectively). However, despite
      trends in both the x-ray and histological data there was no statistical
      difference in the amount of new bone formed among the four treatment groups (P >
      0.05). This was most likely due to the large variance in the data scatter and the
      small number of animals per group. In the second animal study, bovine-derived
      BMPs and the polymeric carrier were gamma irradiated separately, at doses of 1.5
      or 2.5 Mrad, and their ability to form bone in a rat skull onlay model was
      evaluated using Sprague-Dawley rats (n = 5 per treatment group). Histomorphometry
      of skull caps harvested 28 days after implantation showed no significant
      differences as compared to non-irradiated samples, in implant area, new bone
      area, and percent new bone (P > 0.05). These results suggest gamma irradiation
      may be useful in sterilization of the bovine-derived BMPs and the polymeric
      carrier for potential bone repair and/or regeneration applications.

PMID- 10634951
TI  - Apatite growth on calcium adsorbed surface of wet flocculated silica particles
      immersed in a modified simulated body fluid.
AB  - An alternative method for the calcium phosphate apatite formation onto the
      surface of flocculated pure silica particles is reported, in an attempt to
      understand the possible mechanism for the apatite formation. A stable silica sol
      was flocculated by adding calcium ions in aqueous solution. The wet flocks were
      resuspended in a basic aqueous solution containing a calcium salt, trying to
      allow the absorption of calcium ions onto the silica surface through a hydrogen
      ion exchange. The as-prepared materials were immersed in a modified simulated
      body fluid at different temperatures (37 and 90 degrees C) and silica
      concentrations. It was found that these factors have a strong influence on the
      apatite formation. The apatite formation was confirmed by (31)P MAS-NMR, FT
      Raman, XRD, and TEM.

PMID- 10634952
TI  - Bioactive bone cement: effect of surface curing properties on bone-bonding
      strength.
AB  - The fact that bisphenol-a-glycidyl methacrylate (bis-GMA)-based cements contain
      an uncured surface is believed to play an important role when determining the
      surface curing properties of the cements. Therefore, in the present study, the
      bone-bonding strength of cement plates having an uncured surface on one side and
      a cured surface on the other side has been evaluated. These cement plates were
      composites of a bis-GMA-based resin with either an apatite- and wollastonite
      containing glass-ceramic (AW-GC) powder or a hydroxyapatite (HA) powder,
      respectively designated AWC and HAC. The amount of each of these powders in a
      composite cement was 70 wt %. We formulate the hypothesis that the uncured
      surface of a cement plate is bioactive having bone-bonding properties. The goal
      of the present study was to indicate the bone-bonding strength of the uncured
      surfaces of AWC and HAC and compare the strength with the respective cured
      surfaces by a detaching in vivo test, as well as to histologically examine the
      bone-cement interface. Each plate has been implanted into the tibiae of male
      Japanese white rabbits, taking care to retain the surface properties, and the so
      called "failure load has been measured using a detaching test followed 8 weeks
      after implantation. The failure load for AWC-plates at the uncured surface (2.05
      +/- 1.11 kgf, n = 8) was significantly higher than AWC at its cured surface side
      (0.28 +/- 0.64 kgf, n = 8). The failure load for HAC-plates at the uncured
      surfaces (1.40 +/- 0.68 kgf, n = 8) was significantly higher than HAC at its
      cured surface (0.00 +/- 0.00 kgf, n = 8). Failure loads for AWC at its uncured
      and cured surfaces were both higher than for HAC, although not significantly.
      Direct bone formation has been observed histologically for both AWC and HAC on
      the uncured surfaces, and a Ca-P-rich layer was observed only at the uncured
      surface of AWC. These findings strongly suggest that uncured surfaces are useful
      for exposing a bioactive filler on a surface of composites, being very effective
      in inducing bone bonding.

PMID- 10634953
TI  - Cranial defect repair using e-PTFE: part I. Evaluation of bone stiffness.
AB  - Autologous bone grafts are the preferred material for craniofacial
      reconstruction, but such procedures lead to increased operative time and
      bleeding, donor site morbidity, and graft resorption. The efficacy of expanded
      polytetrafluoroethylene (e-PTFE) sheets to increase bone regeneration and
      remodeling in cranial defects using a rabbit model was evaluated by mechanical
      testing. New Zealand white rabbits were divided into 3 groups and sacrificed 6
      months after surgery. In the Split Table group, (n = 16), a bilateral bone defect
      was created on the outer table of the parietal bones. In the Full Table group, (n
      = 16), a bilateral defect was created through both the inner and outer table of
      the cranium. The control group, (n = 10) was subjected to a sham operation.
      Indentation testing was performed to determine the stiffness of newly formed bone
      in and around the defect. Near the center of the defect, Split Table defects
      repaired with e-PTFE resulted in significantly stiffer bone than regenerated
      control bone. The Full Table defects repaired with e-PTFE also resulted in bone
      significantly stiffer than control regenerated bone around the central region of
      the defect. The data supports the hypothesis that e-PTFE improves the repair of
      cranial defects in a rabbit model. It is surmised that the porosity of the e-PTFE
      provides a stable scaffold for migration of tissue regenerating cells, which may
      be preferentially localized near the cranial suture lines. This porosity may also
      provide a barrier to fibrous tissue regenerating cells.

PMID- 10634954
TI  - Mechanical environment affects allograft incorporation.
AB  - In a bilateral canine tibial model, the mechanical, radiologic, and histologic
      characteristics of intercalary allografts stabilized with locked intramedullary
      nails were compared with those of allografts fixed with compression plates. Both
      methods of fixation achieved healing to host bone. Tibiae that were plated had
      more callus with statistically greater mean torsional rigidity and strength than
      those treated with nails (paired t-test, p </= 0.05). On average, tibiae which
      had been plated had much higher bending rigidity than those fixed with locked
      nails; however, the difference in means was not statistically significant.
      Histomorphometric analysis showed an overall greater total bone formation in
      those limbs treated with plates compared to nails (paired t-test, p </= 0.04).
      The mechanical environment created by the different fixation methods are thought
      to be responsible for the observed differences in healing pattern. The
      traditional concept of fixation for allografts to achieve maximum rigidity of the
      construct may not necessarily promote the most appropriate host healing response
      in all situations. A less rigid fixation method (plates) produced more callus
      resulting in superior torsional and bending properties. These data show that in
      this canine intercalary allograft model, limbs fixed with plates produced more
      external callus resulting in stronger, more rigid healing.

PMID- 10634955
TI  - Fluid sorption of orthopedic grade ultrahigh molecular weight polyethylene in a
      serum environment is affected by the surface area and sterilization method.
AB  - It is shown in this work that lubricant sorption in ultrahigh molecular weight
      polyethylene (UHMWPE) increases with available surface area of the component.
      This has clinical relevance, because sliding and articulation experienced in
      simulator studies can result in changes in surface roughness and the creation of
      new surfaces. This study compares the fluid sorption of orthopedic grade UHMWPE
      with different surface areas (but equivalent volume) for different sterilization
      methods. For both the gamma radiation and nonsterile control samples, the gain in
      total fluid absorbed scaled proportionately with surface area. For the EtO
      sterilization treatment, the fluid gain was nonlinear and substantially less than
      the radiated and control groups. The findings from this study clearly indicate
      that the sterilization and surface area affect the fluid uptake and weight gain
      of UHMWPE.

PMID- 10634956
TI  - Long-term changes of hydroxyapatite-coated dental implants.
AB  - There are many controversies about the long-term prognosis of hydroxyapatite (HA)
      coated implants. Failure may be related to compositional and structural changes
      of the coating occurring during implantation. Two retrieved and two unused HA
      coated blade-type implants were examined by stereomicroscopy, secondary electron
      microscopy, Fourier transform infrared spectroscopy, X-ray diffraction, and
      electron probe microanalysis. The objective was to investigate the HA morphology,
      composition, and structure, and to characterize the changes that occurred in the
      retrieved implant coatings. Retrieved implants presented partial loss of the
      coating, especially at the apical and mesiodistal edges. Remaining HA was thick
      and flattened in the cervical and central areas and gradually thinner and rougher
      towards the apical and mesiodistal edges. Increase of Cl and Mg, decrease of OH,
      and X-ray diffraction peak broadening were found in the retrieved implant
      coatings, in comparison with the unused implants. Morphological changes of the
      retrieved implants seem to depend on stress values in the surrounding bone and on
      implant mobility. Compositional changes and increased amount of lattice
      imperfections appeared in the retrieved implant coatings, as a result of ion
      substitutions in the apatite lattice. However, the present study could not
      confirm the influence of these changes on implant failure.

PMID- 10634957
TI  - Interaction patterns between dentin and adhesive on prepared class V cavities in
      vitro and in vivo.
AB  - The interface between dentin and an acetone-based single-component adhesive
      system (Prime&Bond 2.1, DeTrey Dentsply, Germany) was morphologically
      investigated by scanning electron microscopy (SEM). Interaction patterns of human
      teeth were correlated in vivo and in vitro. The SEM examination proved that the
      formation of a hybrid and an adhesive layer, the peri- and intratubular adhesive
      penetration, as well as hiatus and nanoleakage formation were no different on
      vital and nonvital dentin within the limitation of the experimental arrangement
      of this study.

PMID- 10634958
TI  - Two-year clinical performance of two primer adhesives on class V restorations.
AB  - The prime purpose of this clinical trial was to examine the clinical quality and
      retention rate of resin composite in connection with two recently developed
      acetone-based primer adhesives in Class V lesions according to ADA Clinical
      Protocol Guidelines for Dentin and Enamel Adhesive Materials. All cavities were
      nonretentive and predominantly in dentin (mixed Class V lesions). Total bonding
      was not limited either by sub-base or by base materials. All the trial
      restorations were placed under rubber dam. Group 1 (Version 16-135-1) and group 2
      (Version 17-17-1) consisted of 42 patients with 46 trials and 38 patients with 43
      fillings, respectively. The mean follow-up period and the recall response at the
      end of the study of group 1 were 22.8 months and 92.9% and of group 2 were 22.4
      months and 94.7%. The trial restorations of both groups maintained their
      predominantly rated USPHS-Code Alpha level within the follow-up period. The
      cumulative failure rate of two trials in group 1 and four in group 2 determined a
      failure percentage of 4.4% and 9.3%, respectively, which is within the ADA-18
      month limit of <10% Charlie. The Version KL 16-135-1 came into the market as
      Prime & Bond(R) 2.1, and the other one turned out to be Dyract Adhesive(R) PSA,
      which was primarily introduced as a single-component adhesive for compomer
      restorative Dyract(R) (Dentsply DeTrey, Germany).

PMID- 10634959
TI  - Quantitative analysis of ultrahigh molecular weight polyethylene (UHMWPE) wear
      debris associated with total knee replacements.
AB  - The size and morphology of particulate wear debris retrieved from tissues around
      18 failed total knee replacements (TKR) were characterized. Interfacial membranes
      from nine cemented and nine uncemented TKR were harvested from below the tibial
      components during revision surgery. Wear debris were extracted using papain and
      potassium hydroxide digestion. Ultrahigh molecular weight polyethylene (UHMWPE)
      particles from around cemented or uncemented TKR were similar in size and
      morphology. The mean size was 1.7 +/- 0. 7 microm with a range of 0.1-18 microm.
      Thirty-six percent of the particles were less than 1 microm and 90% were less
      than 3 microm. Morphologically the particles were predominantly spherical with
      occasional fibrillar attachments and flakes. Particles from TKR were greater than
      threefold larger than previously characterized particles from total hip
      replacements, which were 0.5 microm in mean size. Differences in joint conformity
      and wear patterns between the hip and knee articulations may explain the
      disparity in size of the wear debris. Since particle size represents an important
      variable influencing the magnitude of the biological response, it is possible
      that in vivo the larger TKR debris results in a diminished mediator release,
      which in turn may account for the lower incidence of osteolysis and aseptic
      loosening in some designs of TKR.

PMID- 10634960
TI  - Surface roughness of retrieved CoCrMo alloy femoral components from PCA
      artificial total knee joints.
AB  - In this study, we analyzed the surface roughness of retrieved cobalt-chromium
      molybdenum (CoCrMo) femoral components of porous coated anatomic (PCA) artificial
      total knee joints, using a white light interference surface profilometer (WLISP).
      Thirty-eight PCA retrieved specimens obtained from the Anderson Clinic
      (Arlington, VA) were used. The artificial knees were originally implanted between
      1982-1993, and the specimens were retrieved during revision surgeries between
      1988-1996. We examined specimens damaged by three wear modes: femoral component
      against the ultra high molecular weight polyethylene (UHMWPE) articular surface
      (mode I), femoral component against the metal tibial tray (because of UHMWPE
      tibial component wear-through) (mode II), and femoral component against metal
      debris-embedded-UHMWPE (with metal debris from the porous coating) (mode III).
      The mean surface roughness of each femoral component was the average of 80
      surface roughness measurements. The in vivo alloy femoral component surfaces were
      rougher by an order of magnitude over controls, and the alloy surfaces were
      predominantly worn by the formation of parallel scratches in the direction of
      articulation. There was no correlation between the surface roughness of the
      femoral components and patient age, sex, weight, and total time of implantation.
      Significant surface roughness increases accompanied mode II and mode III wear.
      Different carbide morphologies were found on different femoral component
      surfaces, indicating that a variety of sintering processes, with different times
      and temperatures, may have been applied to the alloy femoral components during
      manufacture. Metal component roughness may be important to the wear of UHMWPE
      components and the success of total artificial knee joint.

PMID- 10634961
TI  - Relative roles of cement molecular weight and mixing method on the fatigue
      performance of acrylic bone cement: Simplex P versus Osteopal.
AB  - The weight-average molecular weight (MW(w)) of a cement and the method used to
      mix its powder and liquid monomer constituents have been identified in the
      literature as key variables that affect mechanical properties of the fully
      polymerized cement that are relevant to its performance as a grouting agent in
      cemented arthroplasties. The goal of the present work was to identify which of
      these two variables exerts the greater effect in the case of fully reversed
      tension-compression fatigue performance. A judicious choice of cement brands,
      Surgical Simplex P and Osteopal, and the use of hand versus vacuum mixing,
      permitted this identification to be achieved. Three key observations were made in
      this work. First, for a given cement, the fatigue performance of vacuum-mixed
      specimens is far superior to that of hand-mixed ones, which may be a consequence
      of the substantially lower percentage areal porosity of the former specimens.
      Second, regardless of the mixing method, the fatigue performance of Osteopal
      outstrips that of Simplex P, a result that is attributed to the much higher MW(w)
      of the former cement. Third, hand-mixed Osteopal outperforms vacuum-mixed Simplex
      P (especially at low alternating stress levels), indicating that MW(w) of a bone
      cement is more influential than mixing method on its fatigue performance.

PMID- 10634962
TI  - In this issue

PMID- 10634963
TI  - Effect of glucagon on carbohydrate-mediated secretion of glucose-dependent
      insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (7-36 amide) (GLP
      1).
AB  - BACKGROUND: The insulinotropic hormones, glucose-dependent insulinotropic
      polypeptide (GIP) and glucagon-like peptide-1 (7-36 amide) (GLP-1), regulate
      insulin secretion to nutrient intake and constitute the endocrine arm of the
      entero-insular axis. Glucagon has been implicated in the pathophysiology of
      conditions characterised by abnormal glucose tolerance such as obesity and
      diabetes mellitus although its effect on the entero-insular axis is not fully
      understood. Materials and methods We investigated the effect of exogenous
      glucagon on the entero-insular axis and its relation to gastric emptying in six
      healthy men aged [mean (+/-S.E.M. )] 23.6 (0.9) years with a body mass index of
      24.0 (1.5) kg/m(2). Plasma glucose, GIP, GLP-1, insulin and paracetamol
      concentrations were measured before and after a 100 g oral carhohydrate load
      containing 1.5 g of paracetamol for 6 h during intravenous infusion of either
      glucagon or saline. RESULTS: When compared to the saline infusion, peak and
      integrated insulin and glucose concentrations were higher (p<0.05) following
      glucagon infusion. After 60 min paracetamol concentrations were lower (p<0.05)
      following glucagon infusion. Integrated responses for GIP and GLP-1 were markedly
      reduced following glucagon infusion. CONCLUSIONS: Exogenous glucagon in addition
      to its well-documented action of increasing glucose and insulin concentrations
      and delaying gastric emptying also markedly reduces GIP and GLP-1 secretion. The
      inhibition of GLP-1 soon after commencement of glucagon infusion supports a
      direct effect of glucagon on intestinal L-cells. We speculate that the marked
      inhibition of postprandial GLP-1 secretion by glucagon may be of importance in
      the pathogenesis of relative insulinopenia in Type 2 diabetes and in the
      development of reduced satiety in obesity and diabetes.

PMID- 10634964
TI  - Atherogenic lipoprotein phenotype in type 2 diabetes: reversal with micronised
      fenofibrate.
AB  - BACKGROUND: To assess the short-term effects of a micronised formulation of
      fenofibrate on lipids, lipoproteins and their composition, reflecting an
      atherogenic lipoprotein phenotype (ALP), in patients with stable Type 2 diabetes.
      METHODS: Thirty-two (18 male, 14 female) patients with Type 2 diabetes were
      randomised to a double-blind, placebo-controlled parallel group study after a 4
      week diet run-in phase to a 12-week treatment period with either daily micronised
      fenofibrate 200 mg (Lipantil Micro((R))) or placebo. RESULTS: Baseline mean lipid
      and lipoproteins were similar in both groups: total cholesterol (TC) 7.5 mmol/l,
      serum triglyceride (TG) 3. 1 mmol/l, HDL-cholesterol (HDL-c) 1.2 mmol/l, LDL
      cholesterol (LDL-c) 4.7 mmol/l, and a predominance (52%) of small dense LDL-III
      at concentration of 192 mg lipoprotein/100 ml, reflecting an ALP. Treatment with
      micronised fenofibrate resulted in significant changes in TC (-17%, p<0.001),
      serum TG (-44%, p<0.05), HDL-c (+20%, p<0.01), LDL-c (-22%, p<0.001), apo-B (
      18%, p<0.05) and alterations in LDL subfraction masses (LDL-I +64%, p<0.05; LDL
      II +53%, p<0.05; LDL-III -51%, p<0.001) resulting in LDL-III comprising 28% of
      total LDL (p<0.001). In the placebo group the only significant changes were in TG
      (+21%, p<0.05) and apo-B (+9%, p<0.05). CONCLUSIONS: Micronised fenofibrate
      therapy in patients with Type 2 diabetes improved an establisheded ALP resulting
      in a more favourable lipid and LDL subfraction profile. The long-term clinical
      implications of these changes await the results of the major intervention trials
      of lipid modification in Type 2 diabetes.

PMID- 10634965
TI  - Reversal of increased lymphocyte PC-1 activity in patients with type 2 diabetes
      treated with metformin.
AB  - BACKGROUND: The plasma cell differentiation antigen (PC-1) is an inhibitor of
      insulin receptor tyrosine kinase activity, and has been implicated in the
      pathogenesis of insulin resistance in Type 2 diabetes. Metformin increases
      peripheral insulin sensitivity and, therefore, we have studied the effect of
      metformin treatment on lymphocyte PC-1 (ecto-alkaline phosphodiesterase I, APD)
      in patients with Type 2 diabetes. METHODS: Basal, concanavalin A (Con A)-, and
      phorbol-12-myristate-13-acetate (PMA)-stimulated lymphocyte PC-1, aminopeptidase
      N (APN), and dipeptidylpeptidase IV (DPP IV) activities were determined in 16
      patients with Type 2 diabetes before and after 3 months of metformin treatment.
      RESULTS: Lymphocyte PC-1 in patients with Type 2 diabetes was increased
      significantly (p<0.001) over control; however, metformin treatment brought its
      activity in unstimulated and Con A-stimulated lymphocytes to the control level.
      PMA-stimulated PC-1 in patients with Type 2 diabetes was 17-times higher than in
      controls, and was reduced to near the control level by 3-month metformin
      treatment. In Type 2 diabetes, PMA-stimulated ecto-DPP IV was significantly (p<0.
      005) increased over control, but was reduced after metformin treatment.
      CONCLUSION: This study has shown an increased activity of lymphocyte PC-1 in Type
      2 diabetes and its reversal by 3-month metformin treatment, corresponding to the
      improvement of insulin sensitivity. Data obtained are consistent with a role of
      PC-1 in insulin resistance and suggest a new mechanism of action for metformin
      via PC-1 inhibition.

PMID- 10634966
TI  - Abnormal markers of endothelial cell activation and oxidative stress in children,
      adolescents and young adults with type 1 diabetes with no clinical vascular
      disease.
AB  - BACKGROUND: Endothelial cell dysfunction is an early feature of vascular disease
      and oxidative stress may be involved in its pathogenesis. METHODS: Fifty-one
      children, adolescents and young people with Type 1 diabetes with no clinical
      diabetic angiopathy, mean age+/-SD of 16+/-4 years, diabetes duration of 8+/-5
      years, and HbA(1c) of 8.5+/-1.6%, and 29 age, sex matched normal controls had
      blood samples assayed for E-selectin, intercellular cell adhesion molecule-1, von
      Willebrand Factor, red cell superoxide dismutase, plasma thiol and red cell
      glutathione. RESULTS: E-selectin and ICAM-1 levels were significantly higher in
      the diabetic patients at 72+/-24 ng/ml and 287+/-57 ng/ml, respectively vs 43+/
      16 ng/ml and 248+/-71 ng/ml in the normal controls (p<0.0002 and p<0.013). Von
      Willebrand Factor levels were not different between the two groups. Superoxide
      dismutase activity was significantly higher in the diabetic group at 220+/-58
      micro/ml vs 175+/-24 micro/ml in the normal controls p<0.001, and those of plasma
      thiol and red cell glutathione were significantly lower in the diabetic group, at
      1267+/-202 micromol/l and 458+/-38 micromol/l, respectively vs 1403+/-278
      micromol/l and 487+/-70 micromol/l in the controls p<0.02 and p<0.03. Levels of
      superoxide dismutase correlated negatively with plasma thiol, age and diabetes
      duration r=-0.318, p<0.02; r=-0. 328, p<0.02; and r=-0.286, p<0.05, respectively.
      CONCLUSION: These results confirm evidence of endothelial perturbation in young
      people with diabetes mellitus, and they also suggest that free radical generation
      may contribute to this dysfunction. This supports the hypothesis that vascular
      disease starts early in the course of childhood diabetes, akin to the situation
      in adults with diabetes.

PMID- 10634967
TI  - Ketone bodies: a review of physiology, pathophysiology and application of
      monitoring to diabetes.
AB  - Ketone bodies are produced by the liver and used peripherally as an energy source
      when glucose is not readily available. The two main ketone bodies are
      acetoacetate (AcAc) and 3-beta-hydroxybutyrate (3HB), while acetone is the third,
      and least abundant, ketone body. Ketones are always present in the blood and
      their levels increase during fasting and prolonged exercise. They are also found
      in the blood of neonates and pregnant women. Diabetes is the most common
      pathological cause of elevated blood ketones. In diabetic ketoacidosis (DKA),
      high levels of ketones are produced in response to low insulin levels and high
      levels of counterregulatory hormones. In acute DKA, the ketone body ratio
      (3HB:AcAc) rises from normal (1:1) to as high as 10:1. In response to insulin
      therapy, 3HB levels commonly decrease long before AcAc levels. The frequently
      employed nitroprusside test only detects AcAc in blood and urine. This test is
      inconvenient, does not assess the best indicator of ketone body levels (3HB),
      provides only a semiquantitative assessment of ketone levels and is associated
      with false-positive results. Recently, inexpensive quantitative tests of 3HB
      levels have become available for use with small blood samples (5-25 microl).
      These tests offer new options for monitoring and treating diabetes and other
      states characterized by the abnormal metabolism of ketone bodies.

PMID- 10634968
TI  - Neuroendocrine perturbations as a cause of insulin resistance.
AB  - Insulin resistance is followed by several prevalent diseases. The most common
      condition with insulin resistance is obesity, particularly when localized to
      abdominal, visceral regions. A summary of recent reviews on the pathogenesis of
      systemic insulin resistance indicates that major factors are decreased insulin
      effects on muscular glycogen synthase or preceding steps in the insulin
      signalling cascade, on endogenous glucose production and on circulating free
      fatty acids (FFA) from adipose tissue lipolysis. Contributions of morphologic
      changes in muscle and other factors are considered more uncertain. Newly
      developed methodology has made it possible to determine more precisely the
      neuroendocrine abnormalities in abdominal obesity including increased cortisol
      and adrenal androgen secretions. This is probably due to a hyperactivity of the
      hypothalamic-pituitary-adrenal (HPA) axis, amplified by inefficient feedback
      inhibition by central glucocorticoid receptors, associated with molecular genetic
      defects. Secondly, secretion of gender-specific sex steroid hormones becomes
      inhibited and the sympathetic nervous system activated. At this stage the HPA
      axis shows signs of a 'burned-out' condition, and cortisol secretion is no longer
      elevated. Cortisol counteracts the insulin activation of glycogen synthase in
      muscle, the insulin inhibition of hepatic glucose production and the insulin
      inhibition of lipolysis in adipose tissue, leading to the well-established
      systemic insulin resistance caused by excess cortisol. This is exaggerated by
      increased free fatty acid mobilization, particularly with a concomitant elevation
      of the activity of the sympathetic nervous system. Furthermore, capillarization
      and fiber composition in muscle are changed. These are the identical
      perturbations responsible for insulin resistance in recent reviews. The
      diminished sex steroid secretion in abdominal obesity has the same consequences.
      It is thus clear that insulin resistance may be induced by neuroendocrine
      abnormalities, such as those seen in abdominal obesity. These endocrine
      perturbations also direct excess fat to visceral fat depots via mechanisms that
      are largely known, indicating why abdominal obesity is commonly associated with
      insulin resistance. This possible background to the most prevalent condition of
      insulin resistance has been revealed by development of methodology that allows
      sufficiently sensitive measurements of HPA axis activity. These findings
      demonstrate the power of neuroendocrine regulations for somatic health.

PMID- 10634969
TI  - Intragenomic heterogeneity of a ribosomal DNA spacer (ITS2) varies regionally in
      the neotropical malaria vector Anopheles nuneztovari (Diptera:Culicidae).
AB  - We investigated intragenomic heterogeneity of ITS2 within twenty individual
      Anopheles nuneztovari (subgenus Nyssorhynchus) from five geographical localities
      in the neotropics (three from Brazil and one each from Colombia and Venezuela) by
      cloning and sequencing PCR-amplified copies of this spacer. Intragenomic
      heterogeneity was observed in thirteen of twenty mosquitoes of both sexes from
      all localities. As estimated by uncorrected P, however, mean sequence divergence
      was greater in mosquitoes from Brazil (PR = 0.0100, BL = 0.0196, AB = 0.0182)
      than in those from Venezuela (SO = 0.0026) or Colombia (SI = 0.0078). Sequence
      divergence per genome was significantly higher in mosquitoes from Brazil than in
      those from SO and SI. In fact, divergence among ITS2 variants within single
      mosquitoes from the Brazilian localities was often as great as that between
      localities. Similarly, the number of variants per mosquito was significantly
      greater in Brazil (maximum of six variants) than in both SO and SI (maximum of
      two variants). These results indicate that homogenization of ITS2 has proceeded
      to a greater extent in SO and SI than in the localities in Brazil. The
      differences in intragenomic heterogeneity between both SO and SI versus the
      Brazilian localities probably reflect either differences in population-level
      processes such as gene flow and genetic drift, or the fact that these localities
      may represent two or more cryptic species, as suggested by other studies.

PMID- 10634970
TI  - Germline transformation of Drosophila melanogaster with the piggyBac transposon
      vector.
AB  - Germline transformation of Drosophila melanogaster was attempted with the
      piggyBac gene-transfer system from the cabbage looper moth, Trichoplusia ni.
      Using a self-regulated transposase helper and a white marked vector, a
      transformation frequency of 1-3% per fertile G0 was obtained, similar to that
      previously achieved in the medfly. Use of an hsp70-regulated helper increased
      this frequency more than eight-fold. Transformation with a vector marked with
      white and green fluorescent protein (GFP) under polyubiquitin-nuclear localizing
      sequence regulation yielded seventy G1 transformants which all expressed GFP, but
      only twenty-seven of these expressed eye pigmentation that would have allowed
      their selection based on white+ expression. PiggyBac transformation in two
      distantly related dipteran species and efficient expression of the gfp marker
      supports the potential use of this system in other dipterans, and perhaps insects
      in general.

PMID- 10634971
TI  - Phylogenetic relationships of seven palearctic members of the maculipennis
      complex inferred from ITS2 sequence analysis.
AB  - The sequences of the second internal transcribed spacer (ITS2) of ribosomal DNA
      (rDNA) were determined from seven palearctic mosquitoes species belonging to the
      Anopheles maculipennis species complex, namely An. atroparvus, An. labranchiae,
      An. maculipennis, An. messeae, An. melanoon, An. sacharovi and An. martinius. The
      length of the ITS2 ranged from 280 to 300 bp, with a GC content of 49.4-54.1%.
      With the exception of An. messeae, negligible levels of intraspecific
      polymorphism and no intrapopulation variation were observed. The phylogenetic
      relationships among the members of the maculipennis complex were inferred by
      maximum-parsimony analysis of the PAUP program and the neighbour-joining and
      maximum-likelihood analysis of the PHYLIP program. All of the trees obtained were
      almost identical in topology, although the relationships among three species,
      i.e. An. maculipennis, An. messeae and An. melanoon, remained unresolved. The
      phylogenies were in good agreement with the previous gene-enzyme and polytene
      chromosome banding pattern studies.

PMID- 10634972
TI  - FST, a female-specific transcript from the medfly Ceratitis capitata (Diptera:
      Tephritidae).
AB  - We report here the sequence of a novel cDNA clone (FST, female-specific
      transcript), isolated by differential screening during a search for sexually
      mature accessory gland-specific transcripts from the medfly Ceratitis capitata.
      It contains an open reading frame (ORF) with a potential translational start site
      encoding a putative precursor peptide of 100 amino acids. The FST gene is
      expressed only in the female reproductive accessory glands. Like the accessory
      gland-specific antibacterial peptides ceratotoxins, its expression reaches the
      maximum level when sexual maturity is achieved. However, in contrast to
      ceratotoxins, it is expressed at a basal level in newly emerged females, and its
      expression does not increase after mating.

PMID- 10634973
TI  - Molecular identification of a male-killing agent in the ladybird Harmonia
      axyridis (Pallas) (Coleoptera: Coccinellidae).

PMID- 10634974
TI  - Satellite DNA variation in parental and derived unisexual hybrids of Bacillus
      stick insects (Phasmatodea).
AB  - The Bag320 sequence family of satellite DNA (satDNA) has been found in some stick
      insect taxa: the bisexual Bacillus grandii, the related parthenogen B. atticus
      and their hybrids with B. rossius. However, under the same experimental
      conditions, the Bag320 sequences were not found in B. rossius. Bag320 sequences
      of the clonal hybrid B. whitei (= B. rossius/grandii grandii) intermingled with
      those of B. grandii in all plotted dendrograms. On the whole, satDNA features
      (restriction pattern, sequence variation, fluorescent in situ hybridization
      (FISH)), allozymes and karyology support a relatively recent origin of B. whitei.
      Our investigations on unisexual hybrids of Bacillus also suggested that their
      origin and clonal reproduction allow the occurrence of different sequence subsets
      of limited variability in isolated populations stemming from the hybridization
      focus.

PMID- 10634975
TI  - Lung function outcome in children of premature birth.
AB  - Since the 1960s there has been a continual improvement in the survival of
      premature infants of birthweight less than 1500 g. This has resulted in an
      increase in the prevalence of bronchopulmonary dysplasia (BPD), or its milder
      form, chronic lung disease (CLD) of prematurity. In children with BPD; the
      initial air trapping improves in the first 3-4 years of life, but small airway
      obstruction is often slow to improve, suggesting dysanaptic lung growth. Despite
      this, the majority of older children and adolescents with BPD/CLD do not have
      significant respiratory symptoms. Children born prematurely with or without
      hyaline membrane disease may also have a reduction in expiratory flows during
      childhood, albeit less severe. The clinical significance of this in the longer
      term is unclear. Although significant associations between decrements in
      expiratory flows, neonatal oxygen therapy and assisted ventilation have been
      demonstrated. Airway function has also been reported to be largely unrelated with
      perinatal events but strongly associated with birthweight. The latter suggests
      that intra-uterine factors such as under-nutrition may be more important than
      hitherto recognized. Because of a lack of longitudinal studies, it is unclear how
      lung function will track during adolescence and adult life. Bronchial hyper
      responsiveness is significantly increased in children with BPD and to a lesser
      extent in those born prematurely with or without hyaline membrane disease. It is
      unclear whether this is due to a genetic predisposition, neonatal lung injury or
      anatomically smaller airways. Given the morbidity and fiscal cost of a premature
      birth, effective strategies to reduce the premature birth rate are needed.

PMID- 10634976
TI  - A child and adolescent psychiatric outreach service for rural New South Wales: a
      telemedicine pilot study.
AB  - OBJECTIVE: To examine the feasibility of a tertiary outreach service in child and
      adolescent psychiatry to two rural health centres in New South Wales, Australia.
      METHODS: Following a site visit to Dubbo Hospital and Bourke Hospital,
      telemedical videoconferencing was provided for 2 h/week for 32 weeks. Details of
      referrers, patients' diagnosis and outcome, and satisfaction with the service
      were obtained. RESULTS: Cases were triaged by a nominated rural adolescent mental
      health worker. The service provided detailed assessment and management of
      servere, complex, mental and neuropsychiatric disorders. Fifty-four young people
      were assessed and 72 joint consultative videoconferencing interviews were
      undertaken, including 26 initial consultations. Twenty-three initial
      consultations were undertaken on the visit to the rural centres. Clinical
      descriptions illustrate the flexibility and sensitivity of the service.
      CONCLUSION: Telepsychiatry provides access to a flexible, effective tertiary
      service for those with special, complex needs, including the disadvantaged or
      isolated. It makes a valuable economic contribution to supporting and educating
      rural health professionals, thereby enriching rural mental health services.

PMID- 10634977
TI  - Safety of synthetic surfactant use before preterm newborn transport.
AB  - OBJECTIVE: The benefit of surfactant administration in preterm newborns is well
      described. The increase in lung compliance and other effects that it produces
      might however be dangerous in a transportation situation. This study examined the
      safety of surfactant (primarily Exosurf; Burroughs-Wellcome Research, Triangle
      Park, NC, USA) administration in preterm babies prior to their transportation
      from a peripheral hospital to a tertiary Neonatal Intensive Care Unit.
      METHODOLOGY: Two groups of babies were examined retrospectively over a 4-year
      period. One group, designated C (n = 46), received surfactant prior to transport
      and the other, designated Z (n = 85), did not. RESULTS: There was no significant
      difference in morbidity or mortality between the groups. The benefits of early
      surfactant were reinforced in Group C with fewer days ventilated while having no
      significant change in days on continuous positive airways pressure, in oxygen or
      days before discharge. During transport, mean airway pressure was unchanged but
      group C had a significantly greater drop in oxygen requirement. In those less
      than 30 weeks gestation, increased respiratory benefit was apparent in those who
      received pretransport surfactant. CONCLUSION: Administration of synthetic
      surfactant prior to preterm newborn transportation is safe with no intra
      transport complications.

PMID- 10634978
TI  - Surveillance of acute flaccid paralysis in Australia, 1995-97. Australian
      Paediatric Surveillance Unit.
AB  - OBJECTIVE: Acute flaccid paralysis (AFP) surveillance in Australia as part of the
      World Health Organization (WHO) certification process for polio eradication in
      the Western Pacific region. METHODS: Active monthly AFP surveillance through the
      Australian Paediatric Surveillance Unit, from March 1995 to December 1997.
      RESULTS: Based on 80 cases, the reported overall rate of AFP was 0.73 per 10(5)
      children < 15 years (below the expected 1 per 10(5)). The major causes of AFP
      were Guillain-Barre syndrome (51%) and transverse myelitis (19%). According to
      the WHO virological classification, there was no case of poliomyelitis, 37.5%
      were 'non-polio' and 62.5% cases were 'polio compatible' due to inadequate stool
      testing and follow-up. However, case review by an expert panel enabled 95% to be
      classified as 'non-polio'. CONCLUSION: Australia must improve AFP surveillance to
      confirm absence of wild poliovirus. Paediatricians can help Australia meet its
      certification requirements and contribute to the global eradication effort by
      reporting and investigating all cases of AFP.

PMID- 10634979
TI  - Infant care practices in a metropolitan aboriginal population Bibbulung Gnarneep
      Team.
AB  - OBJECTIVE: To describe sleeping position, room and bed-sharing, tobacco smoke
      exposure and infant feeding for a sample of Australian Aboriginal infants from a
      metropolitan area. METHODS: Interviews with Aboriginal mothers who resided in the
      Perth metropolitan area and had given birth during a continuous 15-month study
      period. The interviews took place when the infants were approximately 6-12 weeks
      old and efforts were made to contact all eligible mothers. Results are presented
      as proportions with 95% confidence intervals. RESULTS: Of all the eligible
      mothers (n = 515), 87% were contacted and 53% (n = 273) completed the interview.
      Of all the infants, 11% slept prone, 96% shared a room and 68% shared a bed; 65%
      of mothers smoked during pregnancy and 65% were smokers at the time of interview;
      66% of the partners were smokers and 80% of the infants were regularly exposed to
      tobacco smoke; 89% of mothers initiated breast-feeding and 70% were breast
      feeding at time of interview. CONCLUSION: Prevalences of non-prone sleeping and
      breast-feeding are similar to the overall Western Australian population, whilst
      tobacco smoke exposure of the infants is markedly higher. Programs of community
      and family education and support are required urgently to decrease this exposure.

PMID- 10634980
TI  - Bacterial endocarditis in neonatal intensive care.
AB  - OBJECTIVES: To ascertain the incidence of bacterial endocarditis in a level III
      neonatal nursery. To document the clinical features, assess survival, and
      evaluate the role of central venous catheters in neonates with bacterial
      endocarditis. METHODOLOGY: Index cases were identified by retrospective review of
      the echocardiographic records of infants admitted to the neonatal nursery from
      1983 to 1995. Data obtained by review of the clinical records of these infants,
      and case-matched controls. RESULTS: From January 1983 to December 1995, 12,249
      infants were admitted to the Special Care Nursery. Eight infants with
      endocarditis were identified, an incidence of 0.07%. Presenting symptoms and
      signs were often vague and nonspecific. Gestation less than 32 weeks, birthweight
      less than 1500 g, thrombocytopenia and neutropenia or neutrophilia were common
      features. Infants with endocarditis had a significantly higher Clinical Risk
      Index for Babies score than those without endocarditis. The tricuspid valve was
      involved in seven infants, six of whom had a percutaneous central venous catheter
      in situ before diagnosis. Mitral valve involvement occurred in two infants,
      neither of whom had central lines inserted. However, compared to infants without
      endocarditis, the placement of a central venous line was not of statistical
      significance. Seven of the eight infants survived following prolonged antibiotic
      therapy. CONCLUSIONS: Bacterial endocarditis is a rare but serious condition
      which is usually not fatal. In the premature newborn infant, presenting signs and
      symptoms are often nonspecific. Endocarditis should therefore be considered in
      the unwell very low birthweight infant.

PMID- 10634981
TI  - Vaccination of children following a previous hypotonic-hyporesponsive episode.
AB  - BACKGROUND: Hypotonic-hyporesponsive episodes (HHE) were once considered a
      contraindication to pertussis vaccination. METHODOLOGY: To evaluate the safety of
      further vaccination, chart review was conducted of 66 children who had
      experienced an HHE, and who were assessed in one of three special clinics in
      three capital city tertiary paediatric hospitals. Immediately prior to the HHE,
      63 children had received whole-cell pertussis vaccine, three had received
      acellular pertussis vaccine. RESULTS: Sixty-four of the 66 children were
      vaccinated in the special clinic, 59 with pertussis-containing vaccines (55
      acellular, four whole-cell), without serious adverse events. There were no HHE
      after these further vaccinations. CONCLUSIONS: Previously healthy children who
      experience HHE reactions can safely continue standard vaccination schedules.

PMID- 10634982
TI  - Awake daytime oximetry measurements in the management of infants with chronic
      lung disease.
AB  - OBJECTIVE: To assess the value of 1-h daytime awake oximetry as a means of
      weaning oxygen flows in infants with oxygen dependent chronic lung disease.
      METHODS: A cohort study of oxygen dependent infants enrolled in a 3-month period.
      One hour of awake oximetry data were compared with equal time periods defined
      within a polysomnographic study and at the same oxygen flow rate. Sensitivity
      results were derived from the decision to wean oxygen to a lower flow or air.
      RESULTS: Twenty-two infants were enrolled and 27 studies were performed. The
      infants that could be weaned had an awake median of mean oxygen saturations of
      97% and spent 14% of the time < or = 95% but only 2% < or = 92%, while for those
      not weaned, the awake median of mean oxygen saturations was 94% with 43% of their
      time < or = 95% and 26.8% < or = 92% saturation. CONCLUSIONS: Daytime oximetry
      can predict the outcome of polysomnography with a sensitivity of 100% and a
      specificity of 65%, and could be used to wean oxygen or as a screening tool for
      polysomnographic studies in infants with chronic lung disease provided there are
      reasonably long periods of monitoring and mean oxygen saturations above 95%.

PMID- 10634983
TI  - Antibiotic resistance in Streptococcus pneumoniae isolated from children.
AB  - OBJECTIVE: To determine the level of antibiotic resistance in pneumoniae (S.
      pneumoniae) isolated from nasal swabs of healthy children. METHOD: Cross
      sectional community survey. SETTING: Survey was undertaken in general practice
      settings in Canberra during March and April 1998. SUBJECTS: Four hundred and
      sixty-one children under 3 years of age enrolled in general practice trial of
      clinical practice guidelines for antibiotic use. OUTCOME MEASURES: Resistance to
      penicillin, erythromycin, co-trimoxazole, tetracycline, chloramphenicol and
      cefotaxime among the isolates of S. pneumoniae. RESULTS: A total of 461 nasal
      swabs were collected and S. pneumoniae was isolated from 171 (37.1%). Penicillin
      resistance was found in 12.3% of these isolates, with high level resistance in
      0.6%. Resistance rates were higher for cotrimoxazole (44.4%) and erythromycin
      (18.1%) than for penicillin. Multidrug resistance was found in 19% of these
      isolates. There was a significant association between the attendance at a day
      care centre and carriage of pneumococcus (53% vs 32%, odds ratio (OR) 2.4, 95%
      confidence interval (CI) 1.5-3.7, P < 0.001). Children who attended day care
      centers and had received antibiotics during the 4 months prior to swab collection
      were three times more likely to carry an antibiotic-resistant isolate than
      children who had neither attended a day care centre nor received antibiotics (68%
      vs 40%, OR 3.1, 95% CI 1.2-8.4, P = 0.02). CONCLUSION: The level of antibiotic
      resistance in pneumococci from healthy children was of concern. Carriage of
      pneumococcus was significantly higher in children who attended a day care centre.
      Resistance was significantly correlated with antibiotic use in combination with
      day-care attendance. These findings warrant more judicious use of antibiotics in
      children.

PMID- 10634984
TI  - Behavioural and cognitive associations of short stature at 5 years.
AB  - OBJECTIVES: To determine the extent to which childhood short stature is
      associated with cognitive, behavioural and chronic health problems, and whether
      these problems could be attributed to recognized adverse biological, psychosocial
      or psychological factors. METHODOLOGY: At their first antenatal session, 8556
      women were enrolled in a prospective study of pregnancy. When their children were
      4 and 6 years of age, mothers completed a detailed questionnaire concerning their
      child's health and behaviour. A Peabody Picture Vocabulary Test-Revised (PPVT-R)
      was completed by the child at 5 years of age. Z scores were used to categorize
      height measurements in 3986 children. The relationship of these height categories
      with the child's health, and behavioural and cognitive problems was then
      examined. RESULTS: No association was found between height and symptoms of
      chronic disease or behaviour problems in boys or girls. On the unadjusted
      analysis, mean PPVT-R scores were significantly lower in boys with heights < 3
      percentile and 3-< 10 percentile compared with study children between 10 to 90
      percentile (P < 0.01). Scores were similarly significantly lower in girls with
      heights < 3 percentile and 3-10 percentile (P = 0.01). Even after adjusting for
      psychosocial and biological confounders, short stature remained a significant
      predictor for lower PPVT-R scores in both boys and girls, although height only
      accounted for 1.1% of the variance in scores in boys and 0.5% of the variance in
      PPVT-R scores in girls. Psychosocial factors had a greater role than height in
      determining PPVT-R scores at 5 years of age. CONCLUSIONS: These findings suggest
      a significant, though small, association between height and PPVT-R scores at 5
      years of age, independent of psychosocial disadvantage and known biological risk
      factors.

PMID- 10634985
TI  - Gastro-oesophageal reflux: clinical profiles and outcome.
AB  - OBJECTIVES: To assess the clinical features, investigations and outcome of 69
      children (40 males, 29 females) with gastro-oesophageal reflux (GOER) referred to
      a tertiary referral centre in paediatric gastroenterology. METHODS: A study of
      all patients with significant GOER seen at the Paediatric Gastroenterology Unit,
      Queen Elizabeth Hospital for Children, Hackney Road, London, between December
      1994 and August 1995. RESULTS: The median age at referral was 16 months.
      Presenting symptoms were recurrent vomiting (72%), epigastric and abdominal pain
      (36%), feeding difficulties (29%), failure to thrive (28%) and irritability
      (19%). Continuous 24-h lower oesophageal pH studies performed in 57 children
      showed 20 (35%) had a reflux index of between 10% to 20%, 14 (25%) had a index >
      20%, and six (11%) had a postprandial reflux index > 10%. Reflux was shown in 38
      (62%) of 62 children who underwent barium studies. None had significant
      anatomical abnormalities, but in the 22 children who had a negative barium
      studies, six had severe reflux (reflux index > 20%). Upper gastrointestinal
      endoscopy performed in 47 children showed reflux oesophagitis in 29 (62%),
      oesophageal ulceration in three, and Barrett's oesophagus in one. All of the
      children were treated with standard medical therapy. Sixty-six per cent were able
      to discontinue medication within 12 months and remained well. Four children (6%)
      required Nissen's fundoplication for failure to respond to medical therapy.
      CONCLUSIONS: Most infants with GOER have an uncomplicated course. False negative
      results were noted in both pH monitoring and barium meal. Up to 80% of children,
      with therapy, will improve within 12 months.

PMID- 10634986
TI  - Children at play: the death and injury pattern in New South Wales, Australia,
      July 1990-June 1994.
AB  - OBJECTIVES: To describe and to understand the pattern of play-related deaths and
      injury (excluding organized sports) among children in New South Wales (NSW),
      Australia. METHODOLOGY: This study utilized a state-wide prospective surveillance
      data collection of paediatric traumatic deaths and injuries at the Royal
      Alexandra Hospital for Children. Deaths and injury cases were selected from the
      NSW Trauma Death Registry and Childsafe NSW database. Information including basic
      demographics, the surrounding circumstances of death and injury incidents, and
      the required treatment was collected. RESULTS: There were 30 play-related deaths
      and 92 drownings over the 4-year period. The male to female ratio was about 2:1.
      Excluding drowning, which has been reported elsewhere, and sports, the leading
      causes of play-related deaths were burns (eight) and asphyxiation (eight). An
      average of 6444 presentations to the emergency departments per year were recorded
      with sex ratio and age distribution pattern similar to the deaths. The home was
      the most common place (55.5%) of play-related injury, specifically the living and
      sleeping area. Falls, both under and above 1 metre, were the most common causes
      of injury (50.9%). The leading mechanism was cuts and lacerations (21.2%). Nearly
      one-third (32.7%) of all injuries were to the head, with face, cheek, forehead
      and scalp as the most common injured body part. Significant associations between
      place of injury, injured body parts and age were observed. CONCLUSIONS: Play
      related injury is common among children, and in some cases causes severe injury
      and death. To tackle the problem of play-related deaths and injuries, a holistic
      approach is suggested. This includes the provision of a safe environment,
      supervision by parents, education of children and detailed data collection.

PMID- 10634987
TI  - Clinical significance of quantitative blood cultures in newborn infants.
AB  - AIM: To evaluate quantitative blood culture as a secondary test on a positive
      blood culture for the diagnosis of sepsis in newborn infants. METHOD: A 15-month
      prospective study of colony forming units (CFU) on positive blood cultures from
      newborn infants clinically suspected of having bacterial sepsis. Growth of
      bacteria in peripheral blood cultures was quantified using the isolater 1.5
      microbial tube lysis direct plating culture system. Colony forming units were
      evaluated against a clinical assessment of infection. RESULTS: Of 137 positive
      blood cultures, 71 (51.8%) were taken from neonates with clinically defined
      infection and 66 (48.2%) were from non-infected infants. The clinical and
      biographical data in these two groups were similar. Coagulase negative
      staphylococci were the most commonly isolated organisms in each group (60.6% vs
      93.9%). Eight deaths from sepsis occurred in the clinically infected group.
      Eighty-five per cent of sepsis was late onset. Although a CFU count > or = 30/mL
      predicted sepsis (sensitivity 83%, specificity 60%, positive predictive value
      69%, negative predictive value 76%), a CFU count < 30/mL did not rule out serious
      sepsis. The higher the CFU count the greater the likelihood of sepsis.
      CONCLUSION: Quantitative blood culture was not shown to be a sensitive secondary
      test on a positive blood culture to distinguish clinical sepsis from culture
      contamination. Although a positive threshold of > or = 30 CFU/mL proved to be
      optimal, improvement in test performance would be expected with a lower incidence
      of culture contamination.

PMID- 10634988
TI  - Early onset of hypernatraemic dehydration and fever in exclusively breast-fed
      infants.
AB  - Five cases of moderately severe hypernatraemic dehydration were identified within
      a 5-month period between two regional hospitals in Hong Kong. Unlike previous
      reported cases, these exclusively breast-fed infants presented with the unusual
      triad of fever, absence of overt signs of dehydration and within the first week
      of life. Three of the cases also had high serum bilirubin concentrations at
      presentation. The fever subsided quickly and the serum bilirubin concentration
      fell rapidly within a few hours of rehydration. All infants made an uneventful
      recovery without permanent neurological sequelae. Fever, presumably secondary to
      dehydration, is an useful early warning sign. These cases emphasize the
      importance of early and regular measurement of bodyweight in exclusively breast
      fed infants so that prompt identification of affected cases may prevent
      potentially detrimental complications.

PMID- 10634989
TI  - Group A streptococcal myositis.
AB  - Myositis is a relatively uncommon presentation of group A streptococcal
      infection. We present a case of a 3-year-old girl with group A streptococcal
      myositis primarily involving the soleus muscle. Magnetic resonance imaging was
      valuable in localizing the affected muscle and avoiding surgical exploration.

PMID- 10634990
TI  - Herb Hultgren in Peru: what causes high altitude pulmonary edema?
AB  - Herbert Hultgren, a cardiologist who kept a careful diary all his career, arrived
      in Peru at the beginning of 1959 to study the occurrence of pulmonary
      hypertension in children at high altitude with patent ductus arteriosus. There,
      he was told about a strange condition, high altitude pulmonary edema (HAPE), and
      found that to Peruvian physicians looking after mine employees and their
      families, its occurrence was almost routine. With his Peruvian colleagues, Herb
      immediately began a systematic study of the condition, including catheter
      studies. Though the absence of left ventricular enlargement suggested a non
      cardiac form of pulmonary edema, and though this is what he suggested in his
      first publication, in two subsequent papers, one written with Charles Houston,
      who contributed cases occurring in mountaineers, Herb wrote that the most
      probable cause was left ventricular failure. What is extraordinary is that before
      he finally submitted the two papers, he had certain knowledge that in one case of
      HAPE at least, left atrial pressure had been shown to be normal. Herb's
      contributions, then and later, to the elucidation of HAPE were enormous.

PMID- 10634991
TI  - High altitude cerebral edema and acute mountain sickness. A pathophysiology
      update.
AB  - The diagnosis, treatment and prevention of high altitude cerebral edema (HACE)
      are fairly well established. The major unresolved issues are 1) the
      pathophysiology, 2) the individual susceptibility, and 3) the relationship of
      HACE to acute mountain sickness (AMS) and to high altitude pulmonary edema
      (HAPE). In the context of the two types of cerebral edema, cytotoxic
      (intracellular) and vasogenic, a leaking of proteins and water through the blood
      brain barrier (BBB), a recent MRI study in persons ill with HACE (16) suggested a
      predominantly vasogenic mechanism. Causes of increased BBB permeability might
      include mechanical factors (loss of autoregulation and increased capillary
      pressure), ischemia, neurogenic influences (adrenergic and cholinergic
      activation), and a host of permeability mediators. Once vasogenic edema develops,
      cytotoxic edema generally follows, and although likely in HACE, this is still
      unproven. Symptoms of HACE are related to increased intracranial pressure (ICP),
      and death is from brain herniation. Treatment is directed both to lowering ICP by
      reducing the volume of intracranial contents, and to stopping the vasogenic leak.
      Evidence is accumulating that established moderate to severe AMS is due to
      cerebral edema, but whether this is true for early AMS (headache) is unclear. New
      work suggests that the brain swells on ascent to altitude, but that this is
      unrelated to AMS. Preliminary data showing that those with less cerebrospinal
      fluid volume (a tighter fit of the brain in the cranium) were more likely to
      develop AMS supports the hypothesis of Ross that those with less ability to
      accommodate the increased brain volume are the ones that suffer AMS. The blood
      brain barrier and intracranial hemodynamics are the two key elements in the
      pathophysiology of HACE and AMS.

PMID- 10634992
TI  - Lung disease at high altitude.
AB  - The lungs are a delicate interface between the atmosphere and our bodies across
      which oxygen diffuses from the air we breathe to the blood which carries oxygen
      to the cells and mitochondria. In healthy lungs at sea level where there is a
      surfeit of oxygen, this process occurs easily, whereas, in lungs with disease it
      becomes a task which may not be fully successful and hypoxemia may ensue or
      worsen. At high altitude where the barometric pressure (Pb) and thus the supply
      of oxygen is lower, the job of getting oxygen to the blood, even in the healthy
      lung is more difficult, and in the diseased lung it may be impossible. This
      presentation will review the lungs' responses to high altitude, with emphasis on
      the abnormal. Both acute and chronic responses of patients with pre-existing lung
      disease will be reviewed. Pulmonary diseases encountered at high altitude in
      previously healthy people, such as high altitude pulmonary edema and chronic
      mountain sickness will be touched on only as they pertain to other patients. Pre
      existing lung disease (with and without hypoxemia at sea level) such as
      obstructive lung diseases (asthma, COPD, emphysema), and restrictive lung
      diseases (sarcoid, asbestosis, interstitial pulmonary fibrosis) will be discussed
      in terms of gas exchange, lung mechanics, and treatment at high altitude.
      Disorders of ventilatory control; e.g., obesity-hypoventilation syndrome and
      sleep apnea, may present formidable problems, and guidelines for their treatment
      will be discussed. Infectious lung diseases; e.g., pneumonia, cystic fibrosis,
      and pulmonary vascular disorders such as chronic mountain sickness, primary
      pulmonary hypertension, and congenital absence of the pulmonary artery are
      important disorders that require special attention because of the accentuated
      hypoxic pulmonary vascular response encountered at high altitude. The purpose
      therefore, is to provide the medical practitioner with the insight into
      prevention, recognition, and treatment of pulmonary problems encountered
      specifically at high altitude, as well as guidance on how best to advise patients
      with lung disease who want to fly in airplanes and/or ascend to high altitude for
      work or pleasure.

PMID- 10634993
TI  - Commuting to high altitude. Recent studies of oxygen enrichment.
AB  - Further studies have been carried out on the potential value of oxygen enrichment
      of room air for commuters to high altitude. Novel ways of providing oxygen
      enriched spaces for working and sleeping are being tested at the California
      Institute of Technology where a radiotelescope is being designed for an altitude
      of 5,000 m in north Chile. The modules are containers such as those used on
      container ships, and they are fitted out in California and then sealed and
      transported to the telescope site in Chile. The result is a turnkey facility
      which shows promise for field studies. The oxygen is provided by oxygen
      concentrators, and different modules are used for sleeping, living, and
      laboratory quarters. Two extensive experiments on oxygen enrichment were carried
      out at the University of California White Mountain Research Station, altitude
      3,800 m, in the summer of 1998. The first study was devoted to the mechanism for
      the increase in arterial oxygen saturation on the day after sleeping in an oxygen
      enriched atmosphere compared with sleeping in ambient air (5). Possible
      mechanisms include less fluid accumulation in the lung associated with acute
      mountain sickness, or a change in the control of ventilation. A double blind
      study was therefore carried out of the effects of sleeping in oxygen enrichment
      on both the ventilatory response to hypoxia and to carbon dioxide. In a related
      study, subjects who had been at an altitude of 3,800 m for two days, and were
      therefore partially acclimatized, were studied at a simulated altitude of 5,000
      both breathing ambient air and 27% oxygen. The studies were done at 3800 m
      altitude by enriching the atmosphere of the test room with appropriate amounts of
      nitrogen or oxygen. An extensive series of neuropsychological tests were carried
      out with the objective of determining which features of CNS function were
      improved by oxygen enrichment at an altitude of 5,000 m.

PMID- 10634994
TI  - The pregnant altitude visitor.
AB  - The human fetus develops normally under low-oxygen conditions. Exposure of a
      pregnant woman to the hypoxia of high altitude results in acclimatization
      responses which act to preserve the fetal oxygen supply. The fetus also utilizes
      several compensatory mechanisms to survive brief periods of hypoxia. While fetal
      heart rate monitoring data during air travel suggest no compromise of fetal
      oxygenation, exercise at high altitude may place further stress on oxygen
      delivery to the fetus. The limited data on maternal exercise at high altitude
      suggest good tolerance in most pregnancies; however, short-term abnormalities in
      fetal heart rate and subsequent pregnancy complications have been observed, as
      well. A survey of Colorado obstetrical care providers yielded consensus that
      preterm labor and bleeding complications of pregnancy are the most commonly
      encountered pregnancy complications among high-altitude pregnant visitors.
      Dehydration, engaging in strenuous exercise before acclimatization, and
      participation in activities with high risk of trauma are behaviors that may
      increase the risk of pregnancy complications. Medical and obstetrical conditions
      which impair oxygen transfer at any step between the environment and fetal tissue
      may compromise fetal oxygenation. Knowledge of the medical, obstetrical, and
      behavioral risk factors during pregnancy at high altitude can help the pregnant
      visitor to high altitude avoid such complications.

PMID- 10634995
TI  - Pulmonary hemodynamics: implications for high altitude pulmonary edema (HAPE). A
      review.
AB  - The role of pulmonary hemodynamics is central to the pathogenesis of high
      altitude pulmonary edema (HAPE). High pulmonary artery pressure is a marker of
      HAPE susceptibility in hypoxia and to a lesser extent in normoxia. Compared to
      non-susceptible subjects high pulmonary artery pressure is present not only at
      rest, but also during exercise and sleep. The reasons for elevated pulmonary
      artery pressure in HAPE susceptible subjects include increased vasomotor tone,
      severe hypoxic vasoconstriction and diminished capacity of the pulmonary
      circulation. Overperfusion of some parts of the capillary bed and wave
      reflections in the pulmonary circulation may result in pressure transients in the
      peripheral circulation which are considerably greater than the pressure in the
      main arteries. The mechanism by which pulmonary hypertension causes the pulmonary
      circulation to leak involves hydraulic stress. Patchy vasoconstriction may expose
      parts of the capillary bed to high pressure resulting in stress failure of the
      capillary wall. The development of an inflammatory process may then occur after
      the initiation of the leak.

PMID- 10634996
TI  - High-altitude pulmonary edema: from exaggerated pulmonary hypertension to a
      defect in transepithelial sodium transport.
AB  - High-altitude pulmonary edema (HAPE) is a form of lung edema which occurs in
      otherwise healthy subjects, thereby allowing the study of underlying mechanisms
      of pulmonary edema in the absence of confounding factors. Exaggerated pulmonary
      hypertension is a hallmark of HAPE and is thought to play an important part in
      its pathogenesis. Pulmonary vascular endothelial dysfunction and augmented
      hypoxia-induced sympathetic activation may be underlying mechanisms contributing
      to exaggerated pulmonary vasoconstriction in HAPE. Recent observations by our
      group suggest, however, that pulmonary hypertension itself may not be sufficient
      to trigger HAPE. Based on studies in rats, indicating that perinatal exposure to
      hypoxia predisposes to exaggerated hypoxic pulmonary vasoconstriction in
      adulthood, we examined effects of high-altitude exposure on pulmonary-artery
      pressure in a group of young adults who had suffered from transient perinatal
      pulmonary hypertension. We found that these young adults had exaggerated
      pulmonary vasoconstriction of similar magnitude to that observed in HAPE
      susceptible subjects. Surprisingly, however, none of the subjects developed lung
      edema. These findings strongly suggest that additional mechanisms are needed to
      trigger pulmonary edema at high-altitude. Observations in vitro, and in vivo
      suggest that a defect of the alveolar transepithelial sodium transport could act
      as a sensitizer to pulmonary edema. The aim of this article is to review very
      recent experimental evidence consistent with this concept. We will discuss data
      gathered in mice with targeted disruption of the gene of the alpha subunit of the
      amiloride-sensitive epithelial sodium channel (alpha ENaC), and present
      preliminary data on measurements of transepithelial sodium transport in vivo in
      HAPE-susceptible and HAPE-resistant mountaineers.

PMID- 10634997
TI  - What is the blood-brain barrier? A molecular perspective. Cerebral vascular
      biology.
AB  - The term "blood-brain barrier" was coined over one hundred years ago as a result
      of the observation that vital dyes introduced into the circulation quickly
      penetrated and stained nearly all organs and tissues of the mammalian body except
      the brain which retained its pale creamy appearance. Advances in microscopy
      revealed that, in contrast to other vascular beds, the brain endothelial cells
      lining the vascular wall are tightly linked with junctional complexes that
      eliminate gaps or spaces between cells and prevent any free diffusion of blood
      borne substances into the brain parenchymal space. The endothelial cells,
      situated at the interface between blood and brain, therefore, play a critical
      role in performing essential biological functions including transport of micro-
      and macronutrients, receptor-mediated signaling, leukocyte trafficking, and
      osmoregulation. A number of molecular components responsible for some of these
      unique properties have now been identified and are being characterized under
      physiological and disease conditions. These include the proteins involved in
      formation and assembly of tight junctions; the plasma membrane-embedded proteins
      that are responsible for transport of brain energy substrates and nutrients
      (glucose, monocarboxylic acids, nucleosides, amino acids, others); the multi-drug
      transporter protein, p-glycoprotein, and other drug-rejecting proteins that
      protect the brain from foreign, potentially disruptive chemicals. These and other
      recent findings, taken as a whole, reveal the brain endothelium as a complex and
      dynamic biological system, in contrast to the simple, inert and rigid barrier
      initially perceived.

PMID- 10634998
TI  - Mediators of cerebral edema.
AB  - The blood-brain barrier (BBB) which is located in the continuous endothelial
      lining of cerebral blood vessels rigidly controls exchange of water soluble
      compounds under physiological conditions. Under pathological conditions such as
      trauma or ischemia, BBB permeability may increase thus allowing plasma
      constituents to escape into brain tissue. This "opening" of the BBB may, at least
      in part, be mediated by massive release of autacoids resulting in vasogenic brain
      edema. Five criteria have to be fulfilled by an individual autacoid to be
      considered a mediator candidate of cerebral edema: i) a permeability-enhancing
      action under physiological conditions, ii) a vasodilatory action, iii) the
      ability to induce vasogenic brain edema, iv) an increase of concentration in the
      tissue or interstitial fluid under pathological conditions, and v) a decrease of
      brain edema by specific interference with the release or action of a given
      autacoid. Among the mediator candidates considered, bradykinin is the only one to
      meet all criteria. Histamine, arachidonic acid and free radicals including nitric
      oxide may also be considered mediators of brain edema, but for each of these
      compounds evidence is less clear than for bradykinin. Although the concept of
      mediators inducing brain edema is well established by experimental studies, only
      a bradykinin receptor antagonist has so far gained entrance into clinical
      evaluation.

PMID- 10634999
TI  - High altitude headache. Lessons from headaches at sea level.
AB  - There is little known about high altitude headache, except that it is an
      important and serious problem that often heralds the onset of acute mountain
      sickness. We do know that the brain itself is an insensate organ except for its
      meninges which contain sensory axons projecting from the trigeminal nerve. These
      nerve fibers travel in proximity to meningeal blood vessels and constitute an
      important component of the trigeminovascular system. Signals generated at high
      altitude which may activate the trigeminovascular system can arise from brain,
      blood or the blood vessel wall, include protons, neurotransmitters and other
      potential noxious agents which can discharge or sensitize small unmyelinated
      fibers. Brain edema and raised intracranial pressure may cause headache by
      compressing brain structures leading to displacement and stretching of the pain
      sensitive intracranial structures. Small hemorrhage may irritate and discharge
      these fibers chemically. Furthermore, high altitude seems capable of decreasing
      the threshold of response to sensory stimulation. Therefore, headache can be
      attributed to activation of a common pathway, the trigeminovascular system by
      both chemical or mechanical stimulation.

PMID- 10635000
TI  - The hypoxic brain. Insights from ischemia research.
AB  - The high energy requirements compared to the low energy reserves render the brain
      particularly vulnerable to hypoxic conditions. To protect the brain against
      hypoxia, powerful cerebrovascular regulatory systems assure an increase of blood
      flow to compensate for the reduced arterial oxygen content. This system is so
      efficient that during respiratory hypoxia brain metabolism is little disturbed as
      long as cardiac function does not fail. Only with declining blood pressure
      cerebral blood flow also declines, and brain energy metabolism rapidly collapses.
      Under experimental conditions, oxygen delivery to the brain is therefore more
      readily impaired by reducing blood flow in the first place, e.g. by occluding a
      supplying brain artery. With declining flow values metabolic and
      electrophysiological functions stepwise disappear according to the threshold
      concept of brain ischemia: first the most complex functions such as protein
      synthesis or the spontaneous electrical activity are suppressed, followed at much
      lower flow values by the breakdown of energy state and the depolarisation of cell
      membranes. The tissue supplied at a flow range between functional impairment and
      the suppression of vital functions has been called penumbra to characterize its
      potential revivability, provided oxygen supply is resumed. Besides its immediate
      effects, hypoxia causes delayed functional and metabolic disturbances which may
      even progress to cell death. The brain regions most sensitive to this type of
      injury are parts of the hippocampus, the dorsolateral caudate nucleus and the
      reticular nucleus of thalamus. Mechanisms contributing to delayed injury include
      coupling disturbances between brain function and blood flow, glutamate-propagated
      functional disturbances such as spreading depression, free radical mediated
      changes, disturbances of signal transduction pathways and complex abnormalities
      in the genomic expression patterns leading, in the worst case, to programmed cell
      death. A key mechanism in this complex stress response is the disturbed calcium
      homoeostasis of the endoplasmic reticulum which, among others, leads to the
      inhibition of protein synthesis at the translational level. Modulations of these
      pathological interactions are a major area of current ischemia research.

PMID- 10635001
TI  - Food for thought: altitude versus normal brain function.
AB  - This paper presents a general overview of the implementation of cognitive skills
      in the normal human brain as viewed from a modern functional brain imaging
      perspective. It is hoped that information of this type will assist eventually in
      developing a more informed neurobiological basis for the understanding of the
      cognitive impairments that occur all too frequently during sojourns to extreme
      altitude.

PMID- 10635002
TI  - Are arterial, muscle and working limb lactate exchange data obtained on men at
      altitude consistent with the hypothesis of an intracellular lactate shuttle?
AB  - The "Lactate Shuttle" Hypothesis posits that lactate removal requires exchange
      among producing and consuming cells. The "Intra-cellular Lactate Shuttle"
      hypothesis posits that lactate exchange occurs among compartments within cells,
      and that mitochondria are the major sites of cellular lactate disposal. Thus,
      cells with high mitochondrial densities (cardiocytes, myocytes, hepatocytes) are
      those which participate in lactate clearance. The model of an Intracellular
      Lactate Shuttle recognizes that the Keq for LDH is 3.6 x 10(4) M-1; thus,
      glycolysis results in cytosolic lactate production regardless of the
      intracellular PO2. The model also requires presence of a mitochondrial
      monocarboxylate transporter (MCT) that allows uptake of lactate as well as
      pyruvate, and intra-mitochondrial LDH whose function is linked to the ETC, and
      which permits lactate-->pyruvate conversion and oxidation. Recently, we have
      shown that liver, heart and muscle mitochondria readily oxidize lactate and
      contain LDH and MCT1. Accordingly, we have concluded that lactate is the
      predominant monocarboxylate oxidized by mitochondria in vivo. The model of an
      "Intra-cellular Lactate Shuttle" is consistent with many of the observations on
      men at sea level and altitude. The observations include: oxidation is the primary
      fate of lactate disposal during rest and exercise; lactate production and
      oxidation occur simultaneously within resting and working muscle; increasing
      [lactate]a increases muscle lactate extraction, and that by increasing SaO2
      acclimatization reduces blood [lactate].

PMID- 10635003
TI  - Role of pyruvate dehydrogenase in lactate production in exercising human skeletal
      muscle.
AB  - The mechanisms responsible for lactate production with increased intensity of
      muscle contraction are controversial. Some investigators suggest that the
      mitochondria are O2-limited, whereas others suggest that lactate production
      occurs when O2 to the mitochondria is adequate and that the increased lactate
      production is due to a "mass-action effect" when pyruvate production exceeds the
      rate of pyruvate oxidation. Pyruvate dehydrogenase is a rate-limiting enzyme for
      pyruvate entry into the tricarboxylic acid cycle; its catalytic activity
      influences both pyruvate oxidation and lactate production. Since lactate
      dehydrogenase is an equilibrium enzyme, increased lactate production will be due
      to a mass-action effect exerted by increases in pyruvate concentrations. Because
      the equilibrium constant of the lactate dehydrogenase reaction markedly favors
      lactate over pyruvate, small increases in pyruvate concentration will result in
      large increases in lactate concentration. At higher exercise intensities, which
      are more reliant on glycogen as substrate, the rate of pyruvate production
      exceeds the catalytic activity of pyruvate dehydrogenase, and lactate production
      occurs. Studies using dichloroacetate, induced acid-base changes, diet and short
      term endurance training, indicate that lactate production is related to complex
      interactions of metabolic pathways and not related to inadequate O2 supply. As
      pyruvate dehydrogenase plays a central role in the integration of carbohydrate
      and fat metabolism, and in the entry of pyruvate into the tricarboxylic acid
      cycle, this enzyme plays a key role in lactate production.

PMID- 10635004
TI  - Cross-species studies of glycolytic function.
AB  - Researchers probing the functional properties of glycogen (glucose) fermentation
      to lactate typically work within either one of two theoretical frameworks or
      models. The first assumes that the cell is analogous to a watery bag of enzymes,
      while the second assumes that three dimensional order and structure constrain the
      behaviors of glycolytic intermediates, of glycolytic enzymes, and of integrated
      glycolytic pathway functions per se. The former approach has been quite
      successful in accounting for many glycolytic functions but has not been able to
      satisfactorily explain a hallmark property of the pathway: namely, that large
      scale change in pathway flux is reflected in only modest changes in
      concentrations of pathway intermediates. Despite being composed of very different
      kinds of enzymes, the pathway is remarkably homeostatic by criterion of stability
      of concentrations of its intermediates in different metabolic states. The view of
      the cell as a system in which enzyme, substrate, and modulator mobilities are
      constrained by intracellular structures, the second framework above, posits
      intracellular perfusion or convection as a means for increasing rates of enzyme
      substrate encounter and as an explanation for how high glycolytic pathway fluxes
      and homeostasis of pathway intermediates can be sustained simultaneously.

PMID- 10635005
TI  - Hypoxia induces cell-specific changes in gene expression in vascular wall cells:
      implications for pulmonary hypertension.
AB  - Mammals respond to reduced oxygen concentrations (hypoxia) in many different ways
      at the systemic, local, cellular and molecular levels. Within the pulmonary
      circulation, exposure to chronic hypoxia has been demonstrated to illicit
      increases in pulmonary artery pressure as well as dramatic structural changes in
      both large and small vessels. It has become increasingly clear that the response
      to hypoxia in vivo is differentially regulated at the level of specific cell
      types within the vessel wall. For instance, in large pulmonary blood vessels
      there is now convincing evidence to suggest that the medial layer is made up of
      many different subpopulations of smooth muscle cells. In response to hypoxia
      there are remarkable differences in the proliferative and matrix producing
      responses of these cells to the hypoxic environment. Some cell populations
      proliferate and increase matrix protein synthesis, while in other cell
      populations no apparent change in the proliferative or differentiation state of
      the cell takes place. In more peripheral vessels, the predominant proliferative
      changes in response to hypoxia in the pulmonary circulation occur in the
      adventitial layer rather than in the medial layer. Here again, specific increases
      in proliferation and matrix protein synthesis take place. Accumulating evidence
      suggests that the unique responses exhibited by specific cell types of hypoxia in
      vivo can be modeled in vitro. We have isolated, in culture, specific medial cell
      populations which demonstrate significant increases in proliferation in response
      to hypoxia, and others which exhibit no change or, in fact, a decrease in
      proliferation under hypoxic conditions. We have also isolated and cloned several
      unique populations of adventitial fibroblasts. There is good evidence that only
      certain fibroblast populations are capable of responding to hypoxia with an
      increase in proliferation. We have begun to elucidate the signaling pathways
      which are activated in those cell populations that exhibit proliferative
      responses to hypoxia. We show that hypoxia, in the absence of serum or mitogens,
      specifically activates select members of the protein kinase C isozyme family, as
      well as members of the mitogen-activated protein kinase (MAPK) family of
      proteins. This selective activation appears to take place in response to hypoxia
      only in those cells exhibiting a proliferative response, and antagonists of this
      pathway inhibit the response. Thus, there appear to be cells within each organ
      that demonstrate unique responses to hypoxia. A better understanding of why these
      cells exist and how they specifically transduce hypoxia-mediated signals will
      lead to a better understanding of how the changes in the pulmonary circulation
      take place under conditions of chronic hypoxia.

PMID- 10635006
TI  - Oxygen and placental vascular development.
AB  - Human embryogenesis takes place in a hypoxic environment because the trophoblast
      shell excludes entry of maternal blood. The first fetal-placental villi develop
      as trophoblast sprouts. These are invaded by allantoic mesoderm to form secondary
      villi and are transformed, by vasculogenesis, into tertiary villi. The placental
      barrier to maternal blood is gradually breached between 8-12 weeks of gestation,
      due to invasion of placental-bed uteroplacental spiral arteries by the
      extravillous trophoblast (EVT). Placental oxygen tension thus rises and a phase
      of branching angiogenesis continues until 24 weeks. Thereafter a gradual shift
      takes place favoring non-branching angiogenesis. Gas-exchanging terminal villi
      thus form which are essential for rapid fetal growth and development of a high
      flow, low-resistance fetal-placental circulation. Inadequate invasion of the
      uteroplacental spiral arteries by EVT results in placental ischemia and the
      development of obstetrical complications--preeclampsia and/or intrauterine growth
      restriction (IUGR). Placental villi often show evidence of continued branching
      angiogenesis, as is the case with anemic pregnancy, and pregnancy at high
      altitude. These structural alterations may reflect continued hypoxia-driven
      activity of vascular endothelial growth factor (VEGF). By contrast, a minority of
      severe early-onset IUGR pregnancies exhibit reduced fetal-placental blood flow
      with elongated maldeveloped villous capillaries. Placenta-like growth factor
      (PIGF) expression is increased while trophoblast proliferation is reduced,
      suggesting "hyperoxia" in the placental villous tree. IUGR may thus have two
      phenotypes--a more common hypoxic and a rarer hyperoxic type. While this concept
      is gaining acceptance, we have no insight as to the initiating mechanism(s).

PMID- 10635007
TI  - Vascular growth in hypoxic skeletal muscle.
AB  - The critical role of skeletal muscle capillaries is the supply of oxygen to
      skeletal muscle fibers during conditions of maximal aerobic work. The supply of
      substrates under these conditions is not limited by the vascular bed but rather
      by the capacity of the sarcolemmal transporter systems. Because of this dominant
      role of oxygen supply in muscle tissue, hypoxia has generally been considered to
      be an important stimulus for capillary neo-formation in skeletal muscle. Early
      morphometric work seemed to indicate that animals exposed to permanent hypoxia
      had in fact a significantly improved vascular supply in muscle tissue. Later work
      questioned these early findings and it was concluded that hypoxia per se was not
      a sufficient stimulus for capillary neo-formation but that additional stimuli
      such as cold-exposure needed to be present. In humans exposed to severe hypoxia
      during simulated or real ascents to Mt. Everest an increase in capillary density
      was in fact found. However, this increase could be shown to result from a
      reduction of muscle fiber volume and not from capillary growth. Broadly
      compatible results were obtained in animal experiments in which changes in
      capillarity were assessed in muscles with limited blood supply which were exposed
      to chronic electrical stimulation. Recently we have shown that endurance exercise
      training in humans results in a rise in mRNA of vascular endothelial growth
      factor (VEGF) only when carried out vigorously and in hypoxia. These results
      indicate that molecular techniques will allow in the near future to delineate the
      role played by hypoxia in capillary neo-formation.

PMID- 10635008
TI  - Recent advances in human physiology at extreme altitude.
AB  - There have been recent advances in the physiology of extreme altitude, especially
      on the barometric pressure-altitude relationship, and pulmonary gas exchange.
      Until recently, the only direct measurement of barometric pressure on the summit
      of Mt. Everest was the value of 253 Torr obtained in October 1981. During the
      1997 NOVA Everest expedition, another measurement was made with a hand-held
      barometer and, after calibration, the value was within approximately 1 Torr of
      the previous measurement. In addition, weather balloons released at approximately
      the same time in the vicinity of Mt. Everest gave values that agreed closely. In
      1998, a large series of measurements of barometric pressure were made using a
      weather probe placed on the South Col of Everest (altitude 7,986 m). The mean
      pressure in May was 283.7 Torr which agrees well with the measurements made just
      above the South Col in October 1981. The new data fit closely with the Model
      Atmosphere Equation PB = exp (6.63268-0.1112 h-0.00149 h2) where h is in km. The
      conclusion is that on days when the mountain is usually climbed during May and
      October, the summit pressure is 251-253 Torr. The inspired PO2 is therefore 43
      Torr and these data clarify expected pulmonary gas exchange on the summit. Sixty
      three measurements of alveolar PO2 for barometric pressures of 300 to 253 Torr
      from the Silver Hut and AMREE field expeditions gave a mean value for PO2 of 35
      Torr. Therefore for this value the alveolar PCO2 cannot be greater than 8 Torr
      under steady-state, conditions when the respiratory exchange ratio (R) is 1. When
      R is less than 1, the alveolar PCO2 must be even lower.

PMID- 10635009
TI  - Operation Everest III (COMEX '97). Effects of prolonged and progressive hypoxia
      on humans during a simulated ascent to 8,848 M in a hypobaric chamber.
AB  - Exposure to high altitude induces physiological or pathological modifications
      that are not always clearly attributable to a specific environmental factor:
      hypoxia, cold, stress, inadequate food. The principal goal of hypobaric chamber
      studies is to determine the specific effect of hypoxia. Eight male volunteers
      ("altinauts"), aged 23 to 37 were selected. They were first preacclimatized in
      the Observatoire Vallot (4,350 m) before entering the chamber. The chamber was
      progressively decompressed down to 253 mmHg barometric pressure, with a recovery
      period of 3 days at 5,000 m in the middle of the decompression period. They spent
      a total of 31 days in the chamber. Eighteen protocols were organized by 14
      European teams, exploring the limiting factors of physical and psychological
      performance, and the pathophysiology of acute mountain sickness (AMS). All
      subjects reached 8,000 m and 7 of them reached the simulated altitude of 8,848 m.
      Three altinauts complained of transient neurological symptoms which resolved
      rapidly with reoxygenation. Body weight decreased by 5.4 kg through a negative
      caloric balance. Only four days after the return to sea-level, subjects had
      recovered 3.4 kg, i.e. 63% of the total loss. At 8,848 m (n = 5), PaO2 was 30.6
      +/- 1.4 mmHg, PCO2 11.9 +/- 1.4 mmHg, pH 7.58 +/- 0.02 (arterialized capillary
      blood). Hemoglobin concentration increased from 14.8 +/- 1.4 to 18.4 +/- 1.5 g/dl
      at 8,000 m and recovered within 4 days at sea-level. AMS score increased rapidly
      at 6,000 m and was maximal at 7,000 m, especially for sleep. AMS was related to
      alteration in color vision and elevation of body temperature. VO2MAX decreased by
      59% at 7,000 m. The purpose of this paper is to give a general description of the
      study and the time course of the main clinical and physiological parameters. The
      altinauts reached the "summit" (for some of them three consecutive times) in
      better physiological conditions than it would have been possible in the
      mountains, probably because acclimatization and other environmental factors such
      as cold and nutrition were controlled.

PMID- 10635011
TI  - Kangchenjunga 1998. A venture undertaken with "medical expeditions".
AB  - The article describes the research carried out on the recent Kanchenjunga Medical
      Expedition to Eastern Nepal during the post-monsoon season of 1998. Twenty-two
      projects are described, under the general functional headings of respiratory,
      cardiovascular, hormonal, sensory and neurological and infection and immunity.

PMID- 10635010
TI  - Dynamic cerebral autoregulation at high altitude.

PMID- 10635012
TI  - Why does the exercise cardiac output fall during altitude residence and is it
      important?

PMID- 10635013
TI  - International consensus group on chronic mountain sickness.

PMID- 10635014
TI  - A tribute to Niels Lassen. December 7th, 1926--April 30th, 1997.

PMID- 10635015
TI  - Developmental regulation in the Schwann cell lineage.

PMID- 10635016
TI  - Transcriptional regulation of the POU gene Oct-6 in Schwann cells.
AB  - Genetic evidence suggests that the POU transcription factor Oct-6 plays a pivotal
      role as an intracellular regulator of Schwann cell differentiation. In the
      absence of Oct-6 function Schwann cells are generated in appropriate numbers and
      these cells differentiate normally up to the promyelin stage at which they
      transiently arrest. During peripheral nerve development Oct-6 expression is
      initiated in Schwann cell precursors and is strongly upregulated in promyelin
      cells. Oct-6 expression is subsequently extinguished in terminally
      differentiating Schwann cells. Thus, identification and characterisation of the
      DNA elements involved in this stage specific regulation may lead us to the
      signaling cascade and the axon-derived signals that drive Schwann cell
      differentiation and initiate myelination. Here we present experiments that aim at
      identifying such regulatory sequences.

PMID- 10635017
TI  - Glia development in the embryonic CNS of Drosophila.
AB  - The major axon tracts in the embryonic CNS of Drosophila are organized in a
      simple, ladder like pattern. Each neuromere contains two commissures which
      connect the contra-lateral hemi-neuromeres and two longitudinal connectives which
      connect the different neuromeres along the anterior-posterior axis. The formation
      of these axon tracts occurs in close association with different glial cells. Loss
      of specific glial cells within the CNS leads to predictable defects in the
      organization of the CNS axon pattern. To unravel the genes underlying CNS glia
      development, we have conducted a saturating F2 EMS mutagenesis, screening for
      mutations, which disrupt axon pattern in the embryonic nervous system. We found a
      large number of mutations that lead to phenotypes indicative for glia defects.
      The analysis of the genes identified, show that glial cell differentiation
      requires the function of two independent regulatory pathways.

PMID- 10635018
TI  - Role and mechanism of action of glial cell deficient/glial cell missing
      (glide/gcm), the fly glial promoting factor.

PMID- 10635019
TI  - Expression and functional analysis of glutamate receptors in glial cells.

PMID- 10635020
TI  - Astrocytes as active participants of glutamatergic function and regulators of its
      homeostasis.

PMID- 10635021
TI  - Glia-neuron interaction by high-affinity glutamate transporters in
      neurotransmission.

PMID- 10635022
TI  - On how altered glutamate homeostasis may contribute to demyelinating diseases of
      the CNS.
AB  - Glial cells communicate reciprocally with neurons in multiple ways, both in
      synaptic and non-synaptic regions of the central nervous system. In the latter,
      neuron to glial and glial to glial signals can be mediated by neurotransmitters.
      Here, we review the presence and some of the functional properties of glutamate
      transporters and receptors in oligodendrocytes. In addition, we present data
      illustrating that alterations in glutamate homeostasis can be excitotoxic to
      oligodendroglia and that the tissue lesions caused by overactivation of glutamate
      receptors resemble those observed in demyelinating diseases such as multiple
      sclerosis. Overall, this information indicates that aberrant glutamate signaling
      may contribute to the development of some white matter pathologies.

PMID- 10635023
TI  - Possible role of microglial prostanoids and free radicals in neuroprotection and
      neurodegeneration.

PMID- 10635024
TI  - The role of microglia and astrocytes in CNS immune surveillance and
      immunopathology.

PMID- 10635025
TI  - The role of chemokines in the pathogenesis of multiple sclerosis.

PMID- 10635026
TI  - Humoral and cellular immune functions of cytokine-treated Schwann cells.

PMID- 10635027
TI  - Axotomy-induced glial reactions in normal and cytokine transgenic mice.

PMID- 10635028
TI  - Contribution of astrocytes to activity-dependent structural plasticity in the
      adult brain.
AB  - A striking example of the capacity of adult astrocytes to undergo reversible
      morphological changes in response to stimuli which enhance neuronal activity is
      offered by astrocytes of the adult hypothalamo-neurohypophysial system (HNS). The
      HNS is composed of magnocellular neurons secreting the neurohormones oxytocin and
      vasopressin from axon terminals in the neurohypophysis. Upon activation of HNS
      secretion, glial coverage of oxytocin neurons significantly diminishes and their
      surfaces become extensively juxtaposed. These glial changes are invariably
      accompanied by structural synaptic remodelling resulting in increased numbers of
      GABAergic, glutamatergic, and noradrenergic afferents. In the neurohypophysis,
      they result in an enhanced neurohemal contact area. HNS glia in the adult
      continue to display "embryonic" features that may allow such activity-dependent
      structural plasticity. For example, supraoptic astrocytes display a radial glia
      like morphology and continue to express vimentin, together with GFAP. All HNS
      astrocytes secrete extracellular matrix glycoproteins, like tenascin-C; they also
      express high levels of polysialylated NCAM or PSA-NCAM and the glycoprotein F3,
      molecules considered essential for neuronal-glial interactions in the developing
      and lesioned CNS. HNS expression of most of these proteins does not visibly vary
      under different conditions of neurohormone secretion. We consider them as
      permissive factors, therefore, allowing HNS cells to undergo remodeling whenever
      the proper stimuli intervene. In the hypothalamic nuclei, one such stimulus is
      oxytocin itself which, in synergy with steroids, can induce neuronal-glial
      remodelling; adrenaline does so in the neurohypophysis.

PMID- 10635029
TI  - The role of oligodendrocytes and oligodendrocyte progenitors in CNS
      remyelination.
AB  - Remyelination enables restoration of saltatory conduction and a return of normal
      function lost during demyelination. Unfortunately, remyelination is often
      incomplete in the adult human central nervous system (CNS) and this failure of
      remyelination is one of the main reasons for clinical deficits in demyelinating
      disease. An understanding of the failure of remyelination in demyelinating
      diseases such as Multiple Sclerosis depends upon the elucidation of cellular
      events underlying successful remyelination. Although the potential for
      remyelination of the adult CNS has been well established, there is still some
      dispute regarding the origin of the remyelinating cell population. The literature
      variously reports that remyelinating oligodendrocytes arise from
      dedifferentiation and/or proliferation of mature oligodendrocytes, or are
      generated solely from proliferation and differentiation of glial progenitor
      cells. This review focuses on studies carried out on remyelinating lesions in the
      adult rat spinal cord produced by injection of antibodies to galactocerebroside
      plus serum complement that demonstrate: 1) oligodendrocytes which survive within
      an area of demyelination do not contribute to remyelination, 2) remyelination is
      carried out by oligodendrocyte progenitor cells, 3) recruitment of
      oligodendrocyte progenitors to an area of demyelination is a local response, and
      4) division of oligodendrocyte progenitors is symmetrical and results in chronic
      depletion of the oligodendrocyte progenitor population in the normal white matter
      around an area of remyelination. These results suggest that failure of
      remyelination may be contributed to by a depletion of oligodendrocyte progenitors
      especially following repeated episodes of demyelination. Remyelination allows the
      return of saltatory conduction (Smith et al., 1979) and the functional recovery
      of demyelination-induced deficits (Jeffery et al., 1997). Findings such as these
      have encouraged research aimed at enhancing the limited remyelination found in
      Multiple Sclerosis (MS) lesions, evidenced by a rim of thin myelin sheaths around
      the edges of a lesion, or, in a minority of acute foci, throughout the entire
      lesion (Prineas et al., 1989; Raine et al., 1981). It must be said, however, that
      although remyelination is clearly a prerequisite to sustained functional
      recovery, other factors such as the state of the inflammatory response and degree
      of axonal survival within the demyelinated region contribute to the extent of
      functional recovery that may be possible following therapeutic intervention aimed
      at halting disease progression. It is not yet clear whether the progression of
      functional deficits in MS is primarily the result of an increasing load of
      demyelination, or axon loss, or a combination of the two processes. However,
      given the increasing recognition that myelin sheaths play a role in protecting
      axons from degeneration, the success or failure of remyelination has functional
      consequences for the patient. To understand why remyelination should fail in
      demyelinating disease and develop strategies to enhance remyelination requires an
      understanding of the biology of successful remyelination. Firstly, what is the
      origin of the remyelinating cell population in the adult CNS? Secondly, what are
      the dynamics of the cellular response of this population during demyelination and
      remyelination? And thirdly, what are the consequences to the tissue of an episode
      of demyelination? This review will focus on studies that address these issues,
      and discuss the implications of the results of these experiments for our
      understanding of MS and the development of therapeutic interventions aimed at
      enhancing remyelination.

PMID- 10635030
TI  - Growth promoting and inhibitory effects of glial cells in the mammalian nervous
      system.
AB  - In the central nervous system (CNS) of mammals axonal regeneration is limited by
      two main factors: first, the low intrinsic regenerative potential of adult CNS
      neurons and second, inhibitory influences of the glial and extracellular
      environment. Myelin-associated inhibitors of neurite growth as well as some
      properties of so called "reactive astrocytes" contribute to the non-permissive of
      CNS tissue for axonal growth. In contrast, the peripheral nervous system (PNS)
      environment is supportive of regeneration because Schwann cells provide suitable
      substrates for regrowing axons. Purified PNS myelin, however, inhibits growth of
      PNS and CNS axons to a similar extent as does CNS myelin. The molecular basis of
      glial substrate properties has been studied intensively in the recent years and a
      large number of molecules have been recognized which might play a role in the
      regulation of axonal growth. Although the exact mechanisms are still not fully
      understood, accumulating data shed light on the complex interactions between
      neurons and glia that are required to establish, maintain, and regenerate axonal
      connections in the nervous system. In the following chapter we review the role of
      glial cells in the CNS and PNS during processes of de- and regeneration with
      respect to our own work.

PMID- 10635031
TI  - Neurite outgrowth inhibitors in gliotic tissue.
AB  - Gliotic tissue is the major obstacle to axon regeneration after CNS injury. We
      designed tissue culture assays to search for molecules responsible for neurite
      outgrowth inhibition in gliotic tissue. All the inhibitory activity in injured
      brain tissue was located in a plasma membrane heparan-sulphate and condroitin
      sulphate type-proteoglycan of apparent molecular weight 200 kDalton. The
      proteoglycan core protein (apparent MW 48,000 kD) was biologically inactive,
      whereas the glycosamine-glycan (GAG) chains accounted for the inhibitory
      activity. Because of its cell location and mode of induction, the inhibitor was
      called injured membrane proteoglycan, IMP. IMP prevented neurite outgrowth
      initiation when attached to the culture substrate and caused growth cone collapse
      when added in solution to neurons with already growing neurites. We concluded
      that IMP was responsible for preventing injured CNS fibre regeneration. Double
      staining immunohistochemistry of normal and gliotic tissue with anti-IMP
      monoclonal antibodies together with glial and neuronal markers, permitted the
      unequivocal definition of inhibitor presenting cells by confocal microscopy. IMP
      immunostaining in normal CNS was observed exclusively on neurons. However, after
      a lesion, immunostaining occurred primarily on intensely GFAP-positive reactive
      astrocytes, but not on OX-42 positive microglia. The availability of antibodies
      permitted rapid affinity-purification of the neurite inhibitor and comparison
      with similar molecules possibly expressed during development. IMP itself or a
      highly related form, was expressed in embryonic brain, reaching maximal
      expression around postnatal day 3 and decreasing strongly in normal adult tissue.
      Perinatal rat brain proteoglycans inhibited neurite outgrowth similarly, though
      not identically, to IMP. Our data suggest that perinatal membrane and injured
      membrane proteoglycans may differ in GAG composition. IMP-like immunoreactivity
      was also found in developing brain, predominantly in neurons in normal brain,
      associating after a lesion with reactive astrocytes. Thes results suggest that
      injury evokes re-expression of IMP previously expressed during CNS development.
      One of the monoclonal antibodies to IMP blocked inhibitory activity, restoring
      neurite outgrowth in vitro. We are currently preparing Fab fragments to test the
      possibility that the antibody may block inhibition of central sprout growth in
      vivo. The combined use of blocking antibody fragments to neurite outgrowth
      inhibitors and transplants of growth-promoting glia, may help in the repair brain
      and spinal cord lesions.

PMID- 10635032
TI  - Connexin32 in hereditary neuropathies.

PMID- 10635033
TI  - Genetic analysis of myelin galactolipid function.
AB  - The CGT enzyme is responsible for catalyzing the final step in GalC synthesis.
      The isolation of the CGT cDNA has allowed for the genetic analysis of
      galactolipid function by providing the opportunity to generate null mutants
      deficient in CGT enzymatic activity. The detailed analyses of CGT mutant mice
      demonstrate that the galactolipids are essential for the formation and
      maintenance of normal CNS myelin, but neither GalC or sulfatide appear to be
      required for the development of structurally normal PNS myelin. These studies
      also show that the differentiation of myelinating cells is not dependent on
      galactolipid function, in contrast to the conclusions drawn from prior antibody
      perturbation studies. The abnormal node of Ranvier formations present in the CNS
      likely explain the disrupted electrophysiological properties displayed by mutant
      spinal cord axons and the tremoring phenotype of these mice. The abnormal myelin
      structures present in the mutant animals are consistent with the possibility that
      the galactolipids play a role in regulating or mediating proper axo-glial
      interactions. The further detailed analysis of these animals should help refine
      our understanding of galactolipid function in the myelination process.

PMID- 10635034
TI  - Transgenic models of TNF induced demyelination.

PMID- 10635035
TI  - Dysmyelination in mice and the proteolipid protein gene family.

PMID- 10635036
TI  - Neurotrophins in cell survival/death decisions.
AB  - Neurotrophins are target-derived soluble factors required for neuronal survival.
      Nerve growth factor (NGF) the founding member of the neurotrophin family, binds
      to two types of receptors: Trk tyrosine kinase and the p75 neurotrophin receptor,
      which belongs to the Fas-tumor necrosis factor (TNF) receptor superfamily.
      Binding of neurotrophins to Trk receptor tyrosine kinases initiate signaling
      cascades that promote cell survival sand differentiation. In contrast, p75 NGFR
      has been shown to modulate the susceptibility to death of selective cellular
      populations--including differentiated rat oligodendrocytes--in specific
      conditions. Notably, NGF effect on viability was only observed in fully
      differentiated oligodendrocytes and not in oligodendrocyte progenitor cells. The
      effect of p75 activation on oligodendrocyte survival correlates with increased
      activity of the stress related kinase JNK-1 and cleavage of specific caspases.
      Indeed, activation of additional stress pathways or impairment of survival
      signals may be required for p75 mediated activation of cell death execution
      programs. Interestingly, co-expression of the TrkA receptor in the same cell type
      abolishes the JNK-1 mediated death signal and induces MAP kinase activity,
      resulting in cell survival. This suggests that glial cell survival results from a
      balance between positive and negative regulators modulated by selective
      signalling pathways by tyrosine kinases and cytokine receptors.

PMID- 10635037
TI  - Neuregulin in neuron/glial interactions in the central nervous system. GGF2
      diminishes autoimmune demyelination, promotes oligodendrocyte progenitor
      expansion, and enhances remyelination.
AB  - Glial growth factor 2 (GGF2) is a neuronal signal that promotes the proliferation
      and survival of the oligodendrocyte, the myelinating cell of the central nervous
      system (CNS). This study has focused on recombinant human GGF2 (rhGGF2) and it's
      potential to affect clinical recovery and repair to damaged myelin in chronic
      relapsing experimental autoimmune encephalomyelitis (EAE) in the mouse, a major
      animal model for the human demyelinating disease, multiple sclerosis (MS). Mice
      with EAE were treated with rhGGF2 during both the acute and relapsing phases, and
      GGF2 treatment led to delayed signs, decreased severity and resulted in
      statistically significant reductions in relapse rate. Further, rhGGF2-treated
      groups displayed CNS lesions with more remyelination than in controls. This
      correlated with increased expression of myelin basic protein exon 2, a marker for
      remyelination, and with an increase of the regulatory cytokine, IL-10. Thus, a
      beneficial effect of a neurotrophic growth factor has been demonstrated upon the
      clinical, pathologic and molecular manifestations of autoimmune demyelination, an
      effect that was associated with increased expression of a Th2 cytokine. rhGGF2
      treatment may represent a novel approach to the treatment of MS (Cannella et al.,
      1998).

PMID- 10635038
TI  - Adhesion molecule expression and phenotype of glial cells in the olfactory tract.
AB  - These data illustrate that OBECs have a highly plastic nature in keeping with
      their need to respond rapidly to changing environmental cues. This relates to
      their required function in supporting axonal extension throughout life. Future
      studies using antibodies to PSA-NCAM and L-NGFr together with FACS sorting to
      purify the two types of OBEC should give us a clearer understanding of the
      lineage relationship of the two phenotypes. With purified populations of the
      astrocyte-like and Schwann cell-like OBEC we should be able to determine if these
      cells have different functions in vivo, using several approaches namely: i)
      identifying the growth factors that regulate their growth and differentiation,
      ii) measuring the ability of the purified cells to remyelinate the experimentally
      created CNS lesions and iii) carry out more detailed cellular and molecular
      comparisons of the two phenotypes.

PMID- 10635039
TI  - Bidirectional signaling between neurons and glial cells via the F3 neuronal
      adhesion molecule.
AB  - F3, a glycosyl-phosphatidylinositol anchored molecule of the immunoglobulin
      superfamily, is known to influence axonal growth and fasciculation via multiple
      interactions of its modular immunoglobulin-like domains. We prepared a Fc
      chimeric molecule (F3IgFc) to identify a) the phenotype of cells bearing F3Ig
      receptors, b) the glial-expressed molecules interacting with these domains and,
      c) to characterize in in vitro models the functional impact of the interactions.
      We observed a strong binding of F3IgFc coated fluorospheres to astrocytes in
      neural primary cultures and to C6 astrocytoma cells. In agreement, in extracts of
      developing mouse brain F3IgFc is able to bind tenascin-R, tenascin-C, and
      isoforms of the proteoglycan-type protein tyrosine phosphatases z/beta. All these
      molecules are synthetized by glial cells as an indication that F3 participates in
      neuron-glia interactions. We showed that C6 glia-expressed PTPz/RPTP beta
      stimulated neurite outgrowth by cortical and cerebellar neurons whereas
      preclustered F3IgFc specifically modified the distribution and intensity of
      phosphotyrosine labeling in these glial cells. We also showed that inhibition of
      tenascin-R interaction with F3 prevented defasciculation of cerebellar explants
      which normally display a defasciculated outgrowth of neurites on a growth
      permissive substrate. These results identify F3, RTPz/RPTP beta, and tenascin-R
      as potential mediators of a reciprocal exchange of information between glia and
      neurons.

PMID- 10635040
TI  - Connexins and information transfer through glia.

PMID- 10635042
TI  - Metabolic coupling and the role played by astrocytes in energy distribution and
      homeostasis.

PMID- 10635041
TI  - Gap junctions in glia. Types, roles, and plasticity.

PMID- 10635043
TI  - Consequences of impaired gap junctional communication in glial cells.
AB  - Astrocytes are characterized by extensive gap junctional intercellular
      communication (GJIC) mediated by channels composed primarily of connexin43. To
      examine some of the functions of this intercellular communication in glial cells,
      we have used three approaches. The first involves transfection of glioma cells,
      which are deficient in connexin expression and gap junctional communication, with
      connexin cDNAs to examine changes in cellular phenotype following increased gap
      junctional communication. Using differential display, we have identified several
      genes which appear to be regulated by GJIC. The second is to study astrocytes
      cultured from embryonic mice with a null mutation in the connexin43 gene. These
      homozygous null astrocytes are devoid of connexin43 and also deficient in
      intercellular dye transfer. Markers of glial differentiation appear similar in
      all genotypes. Measurement of intercellular calcium concentration following
      mechanical stimulation of confluent astrocytes revealed that the number of cells
      affected by a rise in intracellular calcium was reduced in homozygous cultures
      compared to wild type. The growth rate of astrocytes lacking connexin43 was
      reduced compared to wild-type astrocytes. The third approach employs the use of
      gap junction blockers in a model of neuronal and glial differentiation, namely
      P19 mouse embryonal carcinoma cells treated with retinoic acid. In this case,
      blocking GJIC during the differentiation protocol prevents the appearance of
      neuronal and astrocytic phenotypes. Taken together, these data suggest an
      important role for GJIC in glial function and differentiation.

PMID- 10635044
TI  - Advances in HIV/AIDS therapy.
AB  - Advances in HIV/AIDS therapy have been rapid and profound. An improved
      understanding of HIV pathogenesis has demonstrated the need for aggressive
      antiretroviral therapy in most persons with HIV infection. Combinations of at
      least three drugs are necessary to fully suppress viral replication. Suppression
      of viral replication prevents the development of drug resistance and allows
      immune reconstitution to occur. Current therapies do have limitations including
      side effects, cross-resistance, adherence challenges, and drug interactions.
      However, most patients have derived great benefit from these therapies. The
      consequences of immune reconstitution have included resolution of existing
      opportunistic infections and a markedly reduced risk of new infections. In
      certain settings, immune reconstitution may allow the discontinuation of
      opportunistic infection prophylaxis or treatments. The net result has been a
      substantial improvement in the quality and quantity of life for HIV-infected
      patients.

PMID- 10635045
TI  - Early prostate cancer diagnosis and therapy.

PMID- 10635046
TI  - Advances in the treatment of hepatitis C.
AB  - The health care burden caused by hepatitis C is projected to increase
      significantly in the next 20 years, on the basis of modeling estimates of
      cirrhosis, hepatic decompensation, and HCC likely to be seen in this population
      in the future. The number of cases of HCV-induced liver decompensation and
      mortality in the United States is projected to be approximately 4 times higher by
      the year 2018 than is currently seen, because of the aging of those presently
      infected. HCV also poses a significant quality-of-life decrement in the majority
      of individuals with chronic infection. Quality-of-life assessment in these
      patients has shown substantial reductions in both somatic and physical
      functioning compared with the general population, regardless of disease severity.
      The impact of chronic HCV on quality-of-life issues has been equated to that of
      non-insulin-dependent diabetes. Thus, HCV imparts a considerable toll on
      individual level of functioning and on overall health care resources. Hepatitis C
      evolves into a chronic infection in approximately 85% of individuals exposed to
      the virus, and progression to cirrhosis occurs in 20% to 30% of patients, with a
      disease duration up to 20 years. Hepatic decompensation will occur in
      approximately 20% and HCC in about 10% of those with HCV-related cirrhosis within
      5 years of the determination of cirrhosis. End-stage liver disease caused by HCV
      is now the most common indication for liver transplantation in this country.
      Patients in whom liver decompensation develops should be considered for liver
      transplant evaluation, with referral to appropriate centers if these
      complications arise. Individuals with decompensated disease should not be treated
      with any of the current regimens available for HCV eradication, because these
      agents can accelerate hepatic dysfunction and will not mitigate the clinical
      outcome after the onset of decompensation. Available treatment options for HCV
      are rapidly changing, with INF as the standard and combination therapy with INF
      plus ribavirin rising to prominence as the optimal option. The need for
      abstinence from alcohol cannot be underestimated, given its documented
      synergistic effects on hepatotoxicity when combined with chronic HCV. Patients
      must be counseled in this regard and provided with the rationale for this
      recommendation. The benefits of therapy from a medical resource standpoint have
      recently been defined through analyses of cost-effectiveness. Bennett et al. used
      a mathematical model to estimate the cost-effectiveness of INF in the treatment
      of mild chronic HCV (no bridging fibrosis or cirrhosis). Therapy was found to be
      cost-saving for patients aged 20 to 35 years and was found to increase life
      expectancy by 3 and 1.5 years, respectively, at the spectrums of this age range.
      Kim et al. found the cost-effectiveness of a 12-month course of INF to compare
      favorably to other accepted medical interventions in the United States in
      patients younger than 60 years. Similar data for combination therapy has not yet
      been reported but would be expected to be comparable. Interferon monotherapy for
      12 months is the current standard treatment recommendation for individuals with
      chronic HCV and elevated ALT levels. The explosive expansion of information now
      available to, and frequently quoted by, HCV patients seeking treatment will
      increasingly make this option less acceptable to a great many of this group.
      Combination therapy has emerged as the most efficacious option to date, both as
      initial treatment and for patients who relapse after standard INF. Unless data
      appear to the contrary, combination therapy should be considered first-line
      treatment in these groups. A suggested treatment algorithm for chronic HCV is
      outlined in Figure 2. Patients intolerant to ribavirin should be considered for
      continuation of INF to complete a 12-month course, dependent upon the assessment
      of HCV PCR status at week 12 of therapy. (ABSTRACT TRUNCATED)

PMID- 10635047
TI  - The systemic amyloidoses: an overview.

PMID- 10635048
TI  - The role of Chlamydia pneumoniae in cardiovascular disease.

PMID- 10635049
TI  - Herpes simplex type 2 infections--an update.

PMID- 10635050
TI  - Sarcoidosis: developments in etiology, immunology, and therapeutics.

PMID- 10635051
TI  - Selective estrogen receptor modulators and postmenopausal health.
AB  - SERMs are a class of drugs with mixed estrogen agonist/antagonist effects that
      have great potential at targeting changes seen in the postmenopausal period.
      Raloxifene is effective in preventing bone loss and may prevent fractures in
      postmenopausal osteoporosis. It induces changes in lipoprotein concentrations
      that should be cardioprotective. It has no stimulatory effect on the uterus and
      is well tolerated. Raloxifene is an attractive alternative to HRT in preventing
      postmenopausal bone loss, especially for women that are more concerned about the
      risk of breast cancer or vaginal bleeding. Unanswered questions include
      raloxifene's effect on fracture incidence, cardiac events, and dementia; long
      term safety data are also needed. Its potential role in the primary prevention of
      breast cancer also needs large, long-term studies. Tamoxifen has been used
      traditionally as adjuvant therapy for breast cancer, but new data indicate that
      it is effective in the primary prevention of breast cancer in women at increased
      risk. Its effects on bone and lipoproteins are attractive complementary effects
      when used in the subset of women at increased risk for breast cancer. New
      generations of SERMs are being developed that may have more potent estrogen
      agonist effects on bone and cardiovascular disease, or more potent antiestrogen
      effects, especially at the breast. There will likely be a selection of SERMs
      available, and the choice of SERM for a woman will be tailored to her specific
      issues and risk profile.

PMID- 10635052
TI  - Classification of diabetes mellitus.

PMID- 10635053
TI  - The adult growth hormone deficiency syndrome.
AB  - The diagnosis of the adult GH deficiency syndrome from a clinical and laboratory
      standpoint has been reviewed. Therapy guidelines and monitoring should focus on
      the patient's symptoms and IGF-1 concentrations from a laboratory standpoint.
      Successful patient/physician interaction depends on physician awareness of the
      symptoms of the deficiency syndrome and symptoms associated with therapy.
      Successful therapy with GH almost always results in an extremely satisfied
      patient, family, and physician.

PMID- 10635054
TI  - Advances in glucocorticoid therapy.

PMID- 10635055
TI  - Obstructive sleep apnea.

PMID- 10635056
TI  - Novel risk factors and markers for coronary disease.

PMID- 10635057
TI  - Prothrombotic effects of angiotensin.
AB  - In vitro and in vivo data provide compelling evidence for an interaction between
      the RAS and thrombosis. Furthermore, angiotensin and AT1 receptor blockers may
      influence platelet function. ACE is strategically poised to regulate these
      interactions. ACE catalyzes the conversion of Ang I to Ang II, which in turn
      stimulates the production of PAI-1, sensitizes platelets, promotes the production
      of superoxide radicals that scavenge free NO, and induces the expression of
      tissue factor. Conversely, ACE catalyzes the breakdown of bradykinin, a potent
      stimulus to t-PA secretion. These data suggest that clinical, genetic, or
      environmental factors (such as salt intake and medications) that alter ACE
      activity and Ang II production would be expected to impact on clotting and
      fibrinolytic mechanisms.

PMID- 10635058
TI  - Cytokine therapy of mycobacterial infections.
AB  - More than a century after the discovery of tuberculosis, mycobacterial infections
      are resurgent. The recent identification of mutations affecting the control of
      mycobacteria offer critical insights into the pathways necessary for the control
      of intracellular pathogens and bring us several steps closer to understanding the
      basic mechanisms involved. Therapy, which until recently seemed simple and
      straightforward, is now complicated by the emergence of drug-resistant organisms
      and immunocompromised hosts. Despite these problems, multidrug therapy remains
      the mainstay of successful treatment. Adjuvant cytokines such as IL-2, IFN-gamma,
      IL-12, and GM-CSF hold great promise for shortening the duration of treatment and
      overcoming drug resistance. Control of cytokine production by agents such as
      thalidomide opens the door to selective control of deleterious parts of the
      inflammatory response while effective drug treatment is instituted. Modulation of
      the host response in the fight against mycobacteria will be the focus of the next
      decades, and it promises to be at the forefront of immunotherapeutics.

PMID- 10635059
TI  - Cloning and functional characterization of a Caenorhabditis elegans muscarinic
      acetylcholine receptor.
AB  - A cDNA clone encoding a muscarinic acetylcholine receptor (mAChR) has been
      isolated from the nematode Caenorhabditis elegans. The nematode mAChR, consisted
      of 585 amino acids, displays a high degree of amino acid sequence homology to
      other invertebrate and vertebrate mAChRs. Excluding a highly variable middle
      portion of the third intracellular loop, the C. elegans mAChR shares about 51%
      amino acid sequence identity with a Drosophila mAChR and 42-44% identity with
      human m1-m5 mAChR subtypes. Comparison of the cDNA sequence with the
      corresponding genomic sequence reveals that the C. elegans mAChR gene contains
      ten introns, eight of them in the coding region. Pharmacological profiles of the
      C. elegans mAChR expressed in Chinese hamster ovary (CHO) cells were shown to be
      similar to those of mammalian counterparts, indicating that ligand binding
      domains of the receptor have been conserved during evolution. When this cloned
      receptor was expressed in Xenopus oocytes, acetylcholine evoked a transient Cl-
      current. Furthermore, activation of the receptor with oxotremorine, acetylcholine
      or carbachol resulted in the stimulation of phosphatidylinositol metabolism in
      CHO cells, suggesting that the receptor is coupled to phospholipase C activation.

PMID- 10635060
TI  - The bradykinin B2 receptor couples less efficiently than the angiotensin AT1
      receptor to the G protein Gq in transiently transfected COS-7 cells.
AB  - The purpose of this study was to compare the efficiency of two different Gq
      protein-coupled receptors (AT1 receptor for angiotensin II and B2 receptor for
      bradykinin) to activate phospholipase C (PLC). When the receptors were expressed
      at a similar level of 0.5 pmol/mg of protein, inositol trisphosphate (IP)
      accumulation elicited by AT1 receptor was four times higher than that elicited by
      B2 receptor. Genistein and pertussis toxin did not modify AT1 receptor- or B2
      receptor-induced IP accumulation. These results indicate that in COS-7 cells, the
      two receptors activate PLC beta through G proteins of the Gq family. AT1 or B2
      receptors were co-expressed with the alpha subunit of either Gq or G11. Both
      alpha subunits potentiated to the same extent AT1 receptor-induced IP
      accumulation. alpha 11 was also as efficient as alpha q to potentiate B2 receptor
      induced response. Interestingly, however, the potentiating effect of alpha q and
      alpha 11 was more important (by 5-fold) on AT1 receptor-mediated response than on
      B2 receptor-mediated response. These results demonstrate that the extent of
      activation of PLC beta by different Gq-coupled receptors depends on the level of
      expression of these receptors and on their coupling efficiency. These are
      important parameters that determine the relative contribution of specific
      hormones to different biological processes.

PMID- 10635061
TI  - Ion currents through mutant phospholemman channel molecules.
AB  - Phospholemman (PLM), a small membrane protein with a single transmembrane domain,
      is a major substrate for protein kinases in muscle. In lipid bilayers, PLM forms
      ion channels with two unusual features--selectivity for the zwitterion taurine,
      and switching among cation- and anion-selective conformations. To investigate the
      molecular determinants of channel behavior, we measured ion currents through (1)
      PLM channels with point mutations in the extracellular and cytoplasmic domains,
      (2) chimeric PLM channels with the transmembrane domain of IsK, a K channel
      subunit, and (3) truncated PLM channels lacking the cytoplasmic domain. Truncated
      channels and those with a mutation at the cytoplasmic face had altered
      selectivity. Channels with a point mutation near the extracellular face were non
      selective. Switching among channel conformations was less frequent in truncated
      channels and in channels with point mutations in either the extracellular or
      cytoplasmic domain. Chimeric channels with a different transmembrane domain had
      only a small reduction in conductance. We conclude that both the extracellular
      and cytoplasmic domains play roles in channel selectivity and conformational
      changes. Cation-binding sites appear to lie in the cytoplasmic domain, and an
      anion-binding site may reside in the extracellular domain. The cytoplasmic domain
      may function as a "ball and chain" to regulate channel selectivity.

PMID- 10635062
TI  - Studies of chromaffin granule functioning by flow cytometry: transport of
      fluorescent epsilon-ATP and granular size increase induced by ATP.
AB  - Flow cytometry techniques, usually employed to characterize cellular populations,
      are reported here to be a valuable tool to approach the study of subcellular
      organelle functioning. Chromaffin granules rendered fluorescent by using an
      antibody against their membrane protein, synaptophysin, are detectable by flow
      cytometry. Moreover, these storage granules are able to transport the fluorescent
      ATP analogue, epsilon-ATP (1,N6-ethenoadenosine 5'-triphosphate), and the
      resulting granular fluorescence increase can also be followed by this technique.
      The saturation studies show a non-hyperbolic kinetic behaviour, with a two step
      curve. The K0.5 values were 0.26 and 2.5 mM and Hill numbers 1 and 6
      respectively. In addition, an unexpected granular size increase, which was
      dependent on the epsilon-ATP concentration, occurred together with the
      fluorescence increase. Other nucleotide triphosphate substrates of V-ATPase, such
      as ATP or GTP, but not the non-hydrolyzable analogue ATP gamma S (adenosine 5'-O
      (3-thiotriphosphate), mimic this effect, which exhibited sigmoidal saturation
      curves with K0.5 values of 1.8 and 3.1 mM for ATP and epsilon-ATP respectively.
      The V-ATPase inhibitors, suramin, EGTA or EDTA significantly reduced the granular
      size increase in the presence of ATP. Extragranular addition of noradrenaline has
      no effect by itself on the granular size, but significantly reduced the granular
      size increase induced by ATP. This effect was reversed by the amine transport
      inhibitor reserpine. The granular size increase induced by ATP was more effective
      in the presence of Cl- than Br- or I-. Moreover, no increase occurred in the
      presence of F- or acetate. The Cl- channel blockers were poorly effective, and
      only 2-(phenylamino)-benzoic acid (DPC) exhibited an effect on the ATP-induced
      granular size increase.

PMID- 10635063
TI  - Localization of GABA receptor rho 2 and rho 3 subunits in rat brain and
      functional expression of homooligomeric rho 3 receptors and heterooligomeric rho
      2 rho 3 receptors.
AB  - Ionotropic GABA receptors that are composed of rho subunits act to gate
      bicuculline-insensitive Cl- currents. Reverse transcription-polymerase chain
      reaction analysis revealed that the expression of rho 2 mRNA in adult rat brain
      was approximately eight times higher than mRNA in the rat brain at embryonic day
      16, while that of rho 3 in the embryonic brain was approximately six times higher
      than in the adult brain. In the adult rat brain the rho 3 mRNA was present in the
      mesencephalon, hippocampus, cerebellum, thalamus and basal ganglia. In situ
      hybridization has been used to demonstrate the presence of rho 2 mRNA in the
      hippocampal CA1 region of the 8-day-old rat, and in the CAl region of the
      hippocampus, lateral geniculate nucleus, superficial gray layer of the superior
      colliculus and the pars compacta of the substantia nigra of the adult rat. When
      the homooligomeric rho 3 receptors were expressed in Xenopus oocytes,
      applications of agonists induced ionic currents. The order of potency of the
      agonists was muscimol > GABA = trans-4-amino-crotonic acid > cis-4-aminocrotonic
      acid. The ionic currents induced by GABA were blocked by picrotoxinin and Zn2+ in
      dose-dependent manner. In heterooligomeric rho 2 rho 3 receptors, picrotoxinin
      sensitivity was significantly reduced.

PMID- 10635064
TI  - Bacillus stearothermophilus lctB gene gives rise to functional K+ channels in
      Escherichia coli and in Xenopus oocytes.
AB  - We have cloned a small K+ channel subunit (LctB) of the gram-positive bacterium
      Bacillus stearothermophilus (B. stearo.). The B. stearo. LctB protein is only 134
      amino acids long. The sequence contains a typical K+ channel P-domain with a K+
      channel GYGD signature sequence and two hydrophobic, possibly membrane-spanning
      segments M1 and M2. Unexpectedly, LctB K+ channels exhibited properties which
      differed markedly from the ones reported for KcsA channels of the gram-positive
      bacterium Streptomyces lividans. LctB channels, when expressed in E. coli, were
      targeted to the outer membrane and not like KcsA channels to the inner membrane.
      After reconstitution in black lipid membrane, LctB channels mediated K+ currents
      at neutral pH. They were apparently not gated by pH like KcsA channels. Also,
      LctB cRNA produced functional LctB channels in the Xenopus oocyte expression
      system in marked contrast to KcsA. The results demonstrated that heterologous
      expression produced functional LctB channels both in E. coli and in Xenopus
      oocytes. It is proposed that bacterial LctB subunits can be properly handled by
      the Xenopus oocyte leading to the occurrence of functional LctB K+ channels in
      the oocyte plasma membrane.

PMID- 10635065
TI  - Genomic organization of a voltage-gated Na+ channel in a hydrozoan jellyfish:
      insights into the evolution of voltage-gated Na+ channel genes.
AB  - Voltage-gated Na+ channels are responsible for fast propagating action
      potentials. The structurally simplest animals known to contain rapid, transient,
      voltage-gated currents carried exclusively by Na+ ions are the Cnidaria. The
      Cnidaria are thought to be close to the origin of the metazoan radiation and thus
      are pivotal organisms for studying the evolution of the Na+ channel gene. Here we
      describe the genomic organization of the Na+ channel alpha subunit, PpSCN1, from
      the hydrozoan jellyfish, Polyorchis penicillatus. We show that most of the 20
      intron sites in this diploblast are conserved in mammalian Na+ channel genes,
      with some even shared by Ca2+ channels. One of these conserved introns is spliced
      by a rare U 12-type spliceosome. Such conservation places the origin of the
      primary exon arrangement of Na+ channels and different intron splicing mechanisms
      to at least the common ancestors of diploblasts and triploblasts, approximately
      600 million-1 billion years ago.

PMID- 10635066
TI  - [Internal Medicine in Toulouse and Mid-Pyrenees].

PMID- 10635067
TI  - [Philosophia medicatrix].

PMID- 10635068
TI  - [D-penicillamine: an outdated cure for systemic scleroderma?].

PMID- 10635069
TI  - [1977 mortality rate in HIV-infected patients presenting with hepatitis C
      cirrhosis. Results of the GERMIVC multicenter survey conducted in French
      departments of internal medicine or infectious disease].
AB  - PURPOSE: Hepatitis C (HCV) has a high prevalence (10-30%) among human
      immunodeficiency virus (HIV)-infected patients. However, little information is
      available regarding the impact of hepatitis C on survival. The objective of our
      study was to determine the incidence of hepatitis C-related deaths in HIV-HCV co
      infected patients. METHODS: The study was a retrospective (1-year), multicenter
      cohort survey conducted in 63 departments of either internal medicine or
      infectious diseases in France. It included 26,497 HIV-infected patients, of whom
      4,465 (16.8%) presented coinfection due to the hepatitis C virus. The following
      parameters were studied for the year 1997: total number of deaths, number of
      deaths related to either AIDS, cirrhosis, hepatocellular carcinoma, or other
      causes. RESULTS: Among the 26,497 patients, 543 deaths (incidence: 2%) were
      observed in 1997; 543 deaths were due to AIDS (incidence: 1.7%), 36 to cirrhosis
      and/or hepatocellular carcinoma (incidence: 0.13%), and 48 (incidence: 0.18%) to
      another cause. In the subgroup including 4,465 HIV-HCV-coinfected patients, 29
      deaths (incidence: 0.64%) were due to either HCV-related cirrhosis or
      hepatocellular carcinoma. These results were compared with those of a previous
      similar survey conducted in 1995, before the era of highly active antiretroviral
      therapy. The only significant difference is the dramatic regression of deaths due
      to AIDS. CONCLUSION: The impact of hepatitis C virus on the mortality among HIV
      infected patients whose follow-up took place in departments of either internal
      medicine or infectious diseases in France was very low in 1997. The expected
      increase in the life span in these patients could modify these results in the
      future, due to recent improvements in the HIV infection treatment.

PMID- 10635070
TI  - [Influence of age on the clinical and biological characteristics of systemic
      scleroderma].
AB  - PURPOSE: The present study was aimed at assessing the influence of age on
      clinical and biological features of systemic sclerosis. METHODS: This
      retrospective study included 151 consecutive patients with systemic sclerosis.
      The median age at diagnosis was 50.0 years (range: 10-84 years). Patients were
      divided into two groups according to their age (lower than 50.0 years of age: 73
      patients, equal to or above 50 years of age: 78 patients). The following features
      were compared between the two groups: gender, disease duration, extent of skin
      sclerosis, Crest syndrome, lung fibrosis, secondary Sjogren's syndrome,
      antinuclear, anticentromere, and anti-Scl70 antibodies. RESULTS: The disease
      duration was significantly higher in patients over 50 years of age (7.1 +/- 6.8
      years vs 5.5 +/- 5.0 years, P < 0.05). Crest syndrome, secondary Sjogren's
      syndrome and anticentromere antibodies were significantly more common in patients
      over 50 years of age (17/73 vs 30/78, P < 10(-2); 9/73 vs 20/78, P < 10(-2), and
      19/73 vs 31/78, P < 0.05; respectively). Anti-Scl70 antibodies were significantly
      more common in patients under 50 years of age (17/73 vs 10/78, P < 10(-2)). No
      significant difference was found in regard to the other features. CONCLUSION: The
      clinical and biological patterns of systemic sclerosis are different according to
      the age at disease onset. Crest syndrome including anticentromere antibodies and
      Sjogren's syndrome is more common in elderly patients, while anti- Scl-70
      antibodies are more common in younger patients. This suggests the involvement of
      various mechanisms in the pathogenesis of systemic sclerosis, and that these
      mechanisms may depend on the age.

PMID- 10635071
TI  - [Role of video-thoracoscopy in the pretreatment evaluation of lung carcinoma].
AB  - INTRODUCTION: Lung cancer is the first cause of cancer mortality in male patients
      in France. Treatment varies depending on the histological type and the disease
      extent at diagnosis. CURRENT KNOWLEDGE AND KEY POINTS: Videothoracoscopic staging
      appears to be an accurate method to assess the stage of lung cancer to guide
      rational management as it allows for 1) an accurate tissue diagnosis when
      standard methods failed, 2) the identification of a parietal or mediastinal
      invasion when suspected by CT-scan findings, 3) lymph node sampling of sites that
      are poorly or not reachable with mediastinoscopy, 4) the diagnosis of pleural or
      pericardial metastases in patients with effusion or indeterminate nodules, and
      finally 5) the conclusive answer to the diagnostic dilemma caused by the presence
      of a contralateral pulmonary nodule in patients with a potentially curable tumor.
      FUTURE PROSPECTS AND PROJECTS: Video-assisted thoracoscopy thus appears to have a
      complementary role in intrathoracic lung cancer staging when conventional methods
      are equivocal. Its main side-advantage is the opportunity to proceed without
      delay to the surgical treatment, when appropriate, in the same operative
      settings, or to perform in the same session various procedures, i.e., talc
      poudrage and pericardial window, to palliate adverse symptoms occurring in some
      of those patients. Obviously, equally efficient and less invasive approaches
      should have been considered previously. To date, however, videothoracoscopic
      evaluation of tumor resectability is not achievable. Finally, one may suppose
      that positron emission tomography will probably reduce the role of those invasive
      surgical procedures in a near future.

PMID- 10635072
TI  - [Adhesion molecules and cancer].
AB  - INTRODUCTION: This review was aimed at summarizing recent advances in the
      understanding of cell adhesion in order to discuss the possible relevance of new
      knowledge to the exploration of cancer patients and elaboration of therapeutic
      strategies. CURRENT KNOWLEDGE AND KEY POINTS: During the last 10 years, many
      adhesion molecules were identified, thus allowing to determine their tissue
      distribution and functional regulation. The concept of adhesiveness was refined.
      It is now well known that adhesive rate (i.e., the minimal contact time required
      for bond formation) and binding strength (i.e., the minimal force required to
      detach bound cells) are distinct parameters. They may be regulated independently,
      and influence the cell behavior in different ways. It is now possible to achieve
      accurate control of tumor cell adhesiveness, either by inhibiting an adhesive
      mechanism (through monoclonal antibodies, competitive ligands, or inhibition of
      receptor expression with antisense strategy or gene knock-out) or by promoting a
      binding mechanism (with receptor transfection or pro-inflammatory stimulation).
      FUTURE PROSPECTS AND PROJECTS: Recent progress opens new possibilities for
      diagnosis and treatment. First, the interpretation of experimental data may be
      improved. Cell adhesive behavior is not entirely accounted for by the density of
      membrane adhesion receptors. Indeed, adhesion is influenced by receptor
      connection to the cytoskeleton and structure of the cell coat. An adhesion
      receptor may be anti-metastatic through an increase in tumor cohesion and cell
      differentiation, or pro-metastatic, through facilitation of cell migration
      towards a target tissue. New therapeutic strategies may include anti-adhesive
      procedure aimed at preventing metastasis formation. The potential importance of a
      better control of inflammatory processes is also emphasized in view of the
      influence of these processes on the expression of adhesion molecules.

PMID- 10635073
TI  - [Thyroid hormone resistance syndromes: clinical aspects].
AB  - INTRODUCTION: Syndromes of resistance to thyroid hormone correspond to variable
      clinical states which are usually transmitted as autosomal dominant traits and
      characterized by the lack of sensitivity of target tissues to triiodothyronine
      (T3). The diagnosis has to be performed in order to offer an appropriate therapy.
      CURRENT KNOWLEDGE AND KEY POINTS: Clinical states range between two extremes: the
      generalized form, with global euthyroidism, and the predominantly pituitary form,
      with thyrotoxicosis. Surprisingly, these various clinical situations are usually
      determined by the same genetic defect, i.e., an anomaly of one of the two alleles
      of the gene encoding the thyroid hormone receptor TR beta. High levels of
      circulating thyroid hormones in the presence of detectable thyroid stimulating
      hormone (TSH) levels is the characteristic biological feature. Pituitary
      thyreotropic adenoma, another etiology of inappropriate secretion of TSH, needs
      thus to be ruled out. No treatment is required in case of generalized resistance
      to thyroid hormone, whereas two specific drugs (TRIAC and D-T4) appear to be
      useful in the predominantly pituitary form. FUTURE PROSPECTS AND PROJECTS:
      Mechanisms of resistance have been well documented, therefore allowing better
      understanding of T3 action on its nuclear receptor. Several transcriptional
      cofactors or corepressors have been identified and have to be investigated to
      explain the intriguing inter- and intra-familial, and even intra-individual,
      phenotypic variability. New insights should, furthermore, be gained from these
      studies to precisely determine how therapeutic agents work in resistance to
      thyroid hormone.

PMID- 10635074
TI  - [Mediastinoscopy in the case of recurrent uveitis].
AB  - INTRODUCTION: The authors report the case of a patient who presented for 4 years
      recurrent anterior uveitis accompanied by asymptomatic tuberculous mediastinal
      lymphadenitis. EXEGESIS: CT scan of the chest showed the existence of mediastinal
      lymphadenopathy (< 1 cm). Mediastinoscopy with biopsy of the right laterotracheal
      lymph node was performed. The culture was positive for Mycobacterium
      tuberculosis, thus permitting the diagnosis of tuberculosis. CONCLUSION: This
      case report stresses the advantage of extensive etiological assessment when faced
      with unexplained uveitis; particularly it emphasizes the importance of
      investigating potential tuberculosis. The existence of granulomatous uveitis, a
      positive skin test, the ethnic origin, and mostly results of chest CT scan, were
      the rationale for the use of mediastinoscopy with lymph node biopsy to help guide
      diagnosis.

PMID- 10635075
TI  - [Acrodystrophic neuropathy of Bureau and Barriere].
AB  - INTRODUCTION: The acrodystrophic neuropathy described by Bureau and Barriere in
      the 1950s is a rare trophic complication of chronic, analgesic neuropathy due to
      alcohol abuse, which is at the origin of perforating ulcers of the foot,
      vasomotor disorders with dysautonomia, and leads to mutilating arthropathy of the
      lower limb. This neuroacropathy, also termed vagabonds' or vagrants' disease,
      usually occurs in subjects with a debilitated condition, chronic alcoholism, and
      unfavourable socioeconomic conditions. EXEGESIS: We report four cases of Bureau
      Barriere disease which occurred in male subjects who were on average 55 years of
      age. The clinical presentation was close to that reported in the literature.
      Indeed, all four patients were alcoholic, nondiabetic and lived under conditions
      of precarious hygiene. Therapeutic management of the patients was difficult due
      to bad compliance with the treatment and persistence of alcohol abuse.
      Immobilization of the foot is considered to be the primary treatment. Local care
      including baths and bandages with hydrocolloids must be continued during several
      months, and associated with antibiotic therapy, administered by infusion when
      necessary. The outcome is often chronic, with poor prognosis. Given the limited
      therapeutic possibilities, acrodystrophic neuropathy is an invalidating disease
      with high morbidity. CONCLUSION: Bureau-Barriere disease is a rare, serious
      invalidating disease. The clinical symptomatology is usually based on the
      diagnostic triad: analgesia of the foot, perforating ulcers of the foot, and
      deforming and mutilating arthropathy of the lower limb. Treatment is often
      hampered due to poor compliance with local care and persistence of alcohol abuse.

PMID- 10635076
TI  - [Localized periarteritis nodosa with periostal new bone formation].
AB  - INTRODUCTION: Polyarteritis nodosa is a disease process with a wide clinical
      spectrum, ranging from a severe generalized multisystem disorder to a more benign
      condition which may remain limited to the skin, muscles and peripheral nerves,
      and is termed cutaneous polyarteritis nodosa. Periosteal bone formation is
      uncommon in this condition. EXEGESIS: We report two cases (two female patients of
      80 and 55 years of age, respectively) who complained of red, tender nodules of
      legs and bone pain. Histological changes were those of necrotizing arteritis of
      the small and medium arteries in the panniculus and dermis. Bone X-ray showed
      periosteal bone formation. CONCLUSION: In patients with pain, skin changes and
      swelling of the lower limbs, the diagnosis of periarteritis nodosa with
      periostitis has to be considered.

PMID- 10635077
TI  - [Philosophy and medicine].

PMID- 10635078
TI  - [WBC count-formula in a blood disorder].

PMID- 10635079
TI  - [Chronic inflammatory polyradiculoneuropathy and hepatitis C virus].

PMID- 10635080
TI  - [Lupus and macrocreatine phosphokinase induced by mesalazine: a case report].

PMID- 10635081
TI  - [Retroperitoneal fibrosis in an HLA-B27-positive patient].

PMID- 10635082
TI  - ["Hypereosinophilia pseudo-syndrome" presenting as an intestinal T-cell lymphoma,
      associated with an atrophic villosity].

PMID- 10635083
TI  - Using information systems to improve practice.
AB  - Information systems are becoming a key tool for improving and measuring practice.
      They can improve care by providing decision support during routine care, by
      making important information more readily accessible, by pointing out
      redundancies, by suggesting alternatives, and by making guidelines accessible.
      Key domains, which are particularly amenable to such decision support, include
      drug prescribing, test ordering and implementation of critical pathways. In
      addition to their role in quality improvement, information systems can accomplish
      most quality measurement if key data are captured in coded form during the
      provision of routine care. These changes can help close the gap between knowledge
      and practice and promise to make the practice of evidence-based medicine a
      reality.

PMID- 10635084
TI  - [Estrogens and Alzheimer disease].
AB  - Several factors lead to a higher number of female patients with Alzheimer's
      disease, and thus prevention and treatment are of particular concern to women.
      Given the slow development of histopathological alterations in Alzheimer's
      disease, prevention should start early in life. Several lines of evidence
      document in vitro and in vivo a protective effect of oestrogen on neurons. Women
      substitute oestrogen during the immediate postmenopausal years, and this offers a
      natural experiment for testing the preventive action of oestrogen against
      Alzheimer's disease. Case control studies and cohort studies support a general
      protective effect of hormone (i.e. oestrogen) replacement therapy (HRT). Short
      term and small-scale intervention trials in patients with Alzheimer's disease
      show positive results. However, it is not clear to what extent cognition is
      improved by the known effects of oestrogen on mood and behavioural symptoms. More
      studies are needed to establish the value of oestrogen replacement therapy in
      primary and secondary prevention of Alzheimer's disease. At present, oestrogen
      can be recommended in women at risk for familial Alzheimer's disease and as
      adjuvant therapy in mild early Alzheimer's disease.

PMID- 10635085
TI  - [Selective estrogen receptor modulators (SERM): new substances for hormone
      replacement therapy].
AB  - The term "SERM" stands for "Selective Estrogen Receptor Modulators", substances
      which act on certain organs as oestrogen agonists and on other organs as
      oestrogen antagonists. They can exert the known oestrogen-like effects on bone
      and lipids without exerting any action on the endometrium and the breast, a
      potentially ideal profile for postmenopausal hormone replacement treatment. Long
      known are clomifen, an ovulation stimulator, and tamoxifen, used for secondary
      prevention in breast cancer. Tamoxifen prevents postmenopausal bone loss as
      efficiently as hormone replacement treatment, and lowers blood lipids and the
      coronary risk, but increases the risk of endometrial cancer; for this reason it
      cannot be used in the prevention of postmenopausal osteoporosis. Raloxifen
      stimulates neither the endometrium nor the mammary gland, and probably even
      lowers the risk of breast cancer. Its relatively mild but significant effect on
      BMD (+ 2-3%/2 years) is sufficient for prevention, and in osteoporotics goes
      along with a substantial decrease in vertebral fracture incidence (by about 50%)
      comparable to the effect of other treatments. As in hormone replacement
      treatment, thromboembolism and leg cramps occur more frequently. Therefore,
      raloxifen can be used in women free of climacteric symptoms for the prevention
      and treatment of postmenopausal osteoporosis with no increased risk of phlebitis,
      alone or in combination with calcium, vitamin D, bisphosphonates and calcitonin;
      in future it may also be useful in male osteoporosis.

PMID- 10635086
TI  - [C-reactive protein and relative lymphocytopenia: early markers of acute
      myocardial infarction?].
AB  - OBJECTIVE: Recent data suggest that relative lymphocytopenia and elevated C
      reactive protein (CRP) are early markers of myocardial infarction. We tested
      these two parameters to predict myocardial infarction before elevation of
      creatine kinase. METHODS: Over a two-year period, 260 patients presented at the
      emergency room of Mannedorf Hospital with suspicion of unstable angina or
      myocardial infarction. 197 patients were excluded because of intercurrent
      conditions associated with an acute-phase response or changes in leukocyte
      counts, as well as patients with established myocardial infarction (creatine
      kinase elevation at entry). The remaining 63 patients were reviewed for relative
      lymphocytopenia (< 20.3%) and C-reactive protein levels > 5 mg/l at admission.
      RESULTS: Elevated levels of C-reactive protein were found in 8 of 20 patients
      (40%) with unstable angina and in 29 of 43 patients (67%) with myocardial
      infarction. A value for C-reactive protein > 5 mg/l on admission had a
      sensitivity of 67% and a predictive value of 78% for subsequent myocardial
      infarction. Relative lymphocytopenia was found in 2 patients (10%) with unstable
      angina and in 19 patients (44%) with myocardial infarction. The positive
      predictive value of both markers diagnosing myocardial infarction was 93%
      compared to 78% of elevated CRP or 90% of relative lymphocytopenia. In contrast,
      the sensitivity of both markers combined was 33%. CONCLUSIONS: At present,
      elevation of C-reactive protein and relative lymphocytopenia allow early
      diagnosis of myocardial infarction. However, the markers' sensitivity is
      relatively low.

PMID- 10635087
TI  - [Evaluation of drug prescription in the primary care clinic in Geneva in 1997].
AB  - INTRODUCTION: The analysis of drug prescription in a primary care clinic is a
      useful tool to evaluate the quality of medical care provided to outpatients.
      METHODOLOGY: We analysed drug prescriptions of the first consultations with 701
      patients attending between May 14 and June 6 1997, and compared this data to
      previous surveys conducted in 1988, 1991 and 1993. RESULTS AND DISCUSSION: The
      three most common diagnoses were hypertension, lumbar pain and diabetes. The
      prescription of non steroidal antiinflammatory drugs (NSAID) increased from 7.1%
      in 1988 to 20% in 1997. For acute lumbar pain physicians prescribed NSAID to 58%
      of patients and paracetamol only to 33%. Further, doctors often prescribed muscle
      relaxants although an additional antalgic effect has not been proven. The
      prescription of psychotropic drugs decreased from 22.5% in 1988 to 12.7% in 1997.
      ACE inhibitors and calcium antagonists were the most frequently prescribed
      antihypertensive drugs. Therefore physicians do not follow the American (JNC VI)
      and our institutional guidelines, which recommend beta-blockers and diuretics as
      first line agents.

PMID- 10635088
TI  - [Toxoplasmosis IgG avidity: what importance does it have in pregnancy?].
AB  - Avidity describes the binding strength of specific antibody to antigen. It was
      found to be low in the first phase after primary infection but then to increase
      over time. In addition to classic serodiagnosis of toxoplasmosis, measurement of
      avidity provides information making it possible to distinguish between acute and
      chronic infection and is of particular interest in pregnant women. In 229 women
      we found IgG and IgM antibodies suggestive of acute infection. A total of 188
      (82%) had an avidity index > 0.3, indicating that the infection had occurred at
      least four months earlier. Based on this additional information, repeated testing
      and unnecessary anxiety can be avoided.

PMID- 10635089
TI  - Medical-ethical guidelines on borderline questions in intensive-care medicine.
      Swiss Academy of Medical Sciences (SAMS).

PMID- 10635090
TI  - [Treatment of tuberculosis: scalpel or chemistry?].

PMID- 10635091
TI  - The medial malleolar network: a constant vascular base of the distally based
      saphenous neurocutaneous island flap.
AB  - Based on 30 fresh cadaver dissections a detailed anatomic study of the medial
      malleolar network is presented with particular attention to the anastomoses
      between the latter and the vascular axis that follows the saphenous nerve. The
      medial malleolar network is formed by the anterior medial malleolar artery,
      branches from the medial tarsal arteries, the posterior medial malleolar artery
      and branches from the medial plantar artery. A distinct anterior medial malleolar
      artery and posterior medial malleolar artery could be identified in 80 and 20%,
      respectively, as well as constant additional small branches arising from the
      anterior tibial or posterior tibial artery. A constant anastomosis was found
      between the arcade formed by the medial tarsal arteries and the medial plantar a.
      in 60%, and the medial branch of the medial plantar artery in 40%, respectively.
      This anastomosis always gave rise to branches to the medial malleolar network. In
      the perimalleolar area and with regard to the great saphenous v. a larger
      anterior and a smaller posterior branch of the saphenous nerve was found in 100
      and 90%, respectively. In all dissections, for both branches of the saphenous
      nerve two to four small, but distinct anastomoses between the medial malleolar
      network and the perineural vascular axis were identified. These constant
      anastomoses represent a new and reliable vascular base for the distally-based
      saphenous neurocutaneous island flap. Thus, the pivotal point of the flap can be
      chosen in the area of the medial malleolus without respecting the most distal
      septocutaneous anastomosis between the perineural vascular axis and the posterior
      tibial artery. Additionally, an illustrative clinical case is presented.

PMID- 10635092
TI  - A posterior approach for inspection of reduction of sacroiliac joint disruption.
AB  - This anatomic study was undertaken to describe a new posterior approach enabling
      direct inspection of reduction of sacroiliac joint disruption (SIJD), and
      guidance of iliosacral screw placement. The reduction of SIJD is usually
      monitored by inspection of the opposing sacrum and ilium at the posterior margin
      of the greater sciatic notch and there is a relative lack of information
      concerning inspection of reduction of SIJD from the posterosuperior aspect of the
      sacroiliac joint surface. Ten cadavers were dissected to determine the
      possibility of inspecting reduction of SIJD from the posterosuperior aspect of
      the sacroiliac joint by means of a posterior approach which passed immediately
      lateral to the deep back muscles and the fifth lumbar transverse process. The
      results indicated that the posterosuperior aspect of the sacroiliac joint surface
      and sacral ala can be directly palpated or visualised. This approach facilitates
      improved access for inspection of reduction of SIJD and guidance of iliosacral
      screw placement.

PMID- 10635093
TI  - Anatomic bases for compression of the superior gluteal artery at the level of the
      gluteal canal.
AB  - Based on dissections, angiograms, frozen sections, anatomopathologic examination,
      and CT reconstructions, this anatomic study demonstrates the potential causes of
      compression of the superior gluteal artery (SGA) at the level of the gluteal
      canal. Findings suggest the existence of an osseofibromuscular trap responsible
      for stenosis of the SGA.

PMID- 10635094
TI  - Study of the variations in length of the anterior cruciate ligament during
      flexion of the knee: use of a 3D model reconstructed from MRI sections.
AB  - The aim of this study is to suggest an anatomic study of the modifications of the
      length of the anterior cruciate ligament (ACL) and its bundles during flexion
      with the aid of a 3D computerized model of the knee in a living subject. The
      method of evaluation suggested is a 3D computerized reconstruction based on MRI
      sections, reproducing the movement of flexion of the knee from 0 to 75 degrees.
      Twenty-one sections were made for each of the 13 positions of flexion. The
      reconstruction of Delaunay and the realignment of each position provided a 3D
      model which allowed monitoring of a bony point during the movement. By knowing
      the relative displacement of the ligamentous attachments it was possible to
      define the biometry of the ligament by calculating the length of the bundles of
      the ACL in each position and to demonstrate the variations in length during the
      movement. The mean length of the ligament was 3.4 mm. The anteromedial bundle was
      longer by 30% compared with the other two bundles. During flexion the
      anteromedial bundle was not much modified (this feature seems to provide a
      reference position for a ligamentoplasty), the posterolateral bundle became taut
      after 30 degrees, and the intermediate bundle relaxed from the beginning of
      movement. Based on the data from the literature, this method allows an anatomic
      approach to the ACL, bundle by bundle, during flexion movement.

PMID- 10635095
TI  - The surgical anatomy of the fasciae and the fascial spaces related to the rectum.
AB  - The perirectal fasciae and their vascular and neural relationships were studied
      based on the dissection of 46 fresh cadavers. The rectal fascia is a tubular
      sleeve, areolar in nature, which houses the superior rectal vessels and
      lymphatics. The nerves which supply fibres to the pelvic plexus run close to the
      rectum, contained in the urogenital and presacral fasciae. The rectum is attached
      to these two fasciae by the rectal stalks, which take a spiral course round the
      rectum, being posterolateral in the upper rectum, lateral in the mid-rectum and
      anterolateral in the lower rectum. During rectal resection the pelvic nn. may be
      preserved if the rectal dissection proceeds close to the rectal fascia. After
      cutting the rectal insertion of the presacral fascia, the lower rectal stalks
      (paraproctium) come into direct view and can be divided close to the rectal wall
      with no risk of damage to the pelvic plexus.

PMID- 10635096
TI  - Congenital anatomical abnormalities of the extrahepatic biliary duct: a personal
      audit.
AB  - Awareness of variations in the anatomy of extrahepatic bile ducts may be
      important in preventing iatrogenic injury to the duct system during
      cholecystectomy. Their delineation, before or during surgery is therefore
      considered mandatory in this surgical unit, and a policy of always performing a
      per-operative cholangiogram has allowed us to evaluate the duct system in a
      retrospective review of 2080 cases. Twelve surgically significant anatomical
      variations were found, consisting of absent cystic duct (three cases), abnormal
      termination of cystic duct (two into the right hepatic duct, and one into the
      left hepatic duct), one case of double cystic duct, and five cases of significant
      accessory bile ducts.

PMID- 10635097
TI  - Neuro-arterial relations in the region of the optic canal.
AB  - In this paper, we present the results of our investigations on the neuro-arterial
      relations in the region of the optic canal. A thorough knowledge of the
      microanatomic features of the ophthalmic artery, optic canal and optic nerve is
      very important for surgeons approaching lesions of this area. We aimed to extend
      our present knowledge of the origin of the ophthalmic artery and microsurgical
      anatomy of the optic canal with exposure of the optic nerve. The optic canal
      walls and width and height of the orbital and cranial apertures, and thickness of
      the bony roof of the optic canal were measured on the right and left sides of 57
      sphenoid bones, 102 skull bases and 58 fixed adult cadaver heads. The ophthalmic
      artery originated from the rostromedial circumference of the internal carotid
      artery in 51.8%, from the medial circumference in 26.2% and the laterobasal
      circumference in 22% of the specimens. The outer diameter of the ophthalmic
      artery at its origin was 1.81 +/- 0.36 mm on the right and 1.75 +/- 0.37 mm on
      the left side.

PMID- 10635098
TI  - Familial congenital bilateral agenesis of the acromion: a radiologically
      illustrated case report.
AB  - Familial congenital bilateral acromion absence was found in four members of one
      family. Only one of them presented with gradually increasing pain in his left
      shoulder, resembling a shoulder impingement syndrome. The other members did not
      have any symptoms. This is the first report of familial occurrence of this
      extremely rare congenital anomaly.

PMID- 10635099
TI  - Correlation between computed tomography and gross anatomy of the suspensory
      ligament of the ovary.
AB  - To assess the morphology of the suspensory ligament of the ovary on CT scan
      examination, an anatomic study of the suspensory ligament of the ovary was
      performed to demonstrate its morphology on CT and to facilitate the visualization
      of the ovaries. Twelve female cadavers were studied after intravascular injection
      of latex (venous: 2, arterial: 6, arterio-venous: 4). We first observed all the
      pelvises after their transection. Six dissections were then made to obtain
      optimal anatomic correlations on the content and relations of the infundibulo
      pelvic ligament. The arterial opacifications were poor compared with to the good
      quality of the venous or arteriovenous opacifications. An upright correlation
      between CT slices and the anatomic study was made. This radio-anatomic study
      emphazises the importance of the veins, which really support the suspensory
      ligament of the ovary, as opposed to the involution of the arteries. This study
      points out the link between the infundibulo-pelvic ligament above and the utero
      ovarian below, then with the superficial uterine vv. All these structures were
      well analyzed on CT and during the anatomic studies. A very well developed
      periovarian venous plexus which frequently concealed the ovaries was
      demonstrated. Some anatomic variations which were invisible on the CT scan
      examinations were displayed. The visualization of the suspensory ligament of the
      ovary should facilitate the visualization of the ovaries and could optimize the
      search for lymphadenopathies originating from ovarian cancers.

PMID- 10635100
TI  - The Graz learning and training model for arthroscopic surgery.
AB  - Up to 30% of all operative procedures in orthopaedic surgery are performed
      arthroscopically. Because of the steadily increasing number of residents, it
      seems to be difficult both to maintain high standards and to guarantee an
      adequate training in arthroscopic surgery. However, in contrast to many other
      surgical techniques it is possible to learn and practice arthroscopy using
      artificial models and cadaver joints, provided that experienced surgeons and
      anatomists act as supervisors and instructors. The aim of this paper is to assess
      practice models and training programs which should guarantee sufficient practical
      experience during the training period.

PMID- 10635101
TI  - Origin and incidence of xiphoid branch of the internal thoracic artery.
AB  - The study presents the incidence of a variant terminal branch of the internal
      thoracic artery (ITA). The ITA's were cannulated in situ, injected with coloured
      latex and dissected together with its branches in 62 cadavers. Unlike the usual
      termination of the ITA bifurcating into the musculophrenic and superior
      epigastric arteries, this third branch arose from the medial border of the ITA at
      the level of the 6th costal cartilage. As it descends it inclines medially
      towards the angle between the xiphoid process and the 7th costal cartilage,
      giving off 2 or 3 fine branches to the lower sternum. It then passes deep to this
      angle and can be observed on the anterior surface of the xiphoid process,
      terminating in fine branches distributed to the inferior aspect of the xiphoid
      cartilage. It is proposed that this branch at the "trifurcation" of the ITA be
      termed the xiphoid branch. This branch was noted in 61.3%. An incidence of 30.7%
      was seen on the right and 21% on the left with bilateral presence in 9.7%. The
      xiphoid branch contributes to the supply to the lower sternal region and may be
      of special importance when the collateral supply to the region is compromised in
      the event of the internal thoracic or superior epigastric artery damage or when
      used as a conduit in coronary artery by-pass grafts.

PMID- 10635102
TI  - Prosthodontics and the general dentist. A study of practice profiles and
      prosthodontic decision making in Sweden.

PMID- 10635103
TI  - Conventional spiral and low-dose computed mandibular tomography for dental
      implant planning.
AB  - Absorbed doses to radiosensitive organs in the head and neck from pre-implant
      conventional hypocycloidal, conventional spiral and computed tomography (CT) were
      measured with thermoluminescent dosimeters in an anthropomorphic phantom head.
      From conventional tomography organ doses, except to the major salivary glands,
      were below 0.2 mGy. They were considerably higher with CT than conventional
      tomography. Tomographic images of posterior lower jaw regions were evaluated
      regarding measurement reliability in conventional spiral tomograms. Observers
      measured the distance marginal crest-mandibular canal, marked their measuring
      points and estimated the length of an intended Branemark implant. The variability
      between observers, mainly due to the intra-observer variation, decreased with
      multiple readings and optimized image quality. The suggested implant length was
      the same as the one inserted in 70% of the cases. Tomographic images from
      mandibular body segments were used to test the influence of radiation exposure
      and scanning mode on image quality in CT and compare the quality of the CT images
      with that in conventional spiral tomograms. Mandibular canal and marginal bone
      crest visibility was unaffected by radiation dose in CT examinations. Differences
      among CT scanning modes and between CT and conventional spiral tomography were
      highly significant. Frontal CT scans or conventional spiral tomograms were
      preferred. In cross-sectional images of the posterior lower jaw image quality in
      conventional spiral and reformatted CT at 40 mAs and 80 mAs was compared.
      Observers graded the acceptability of images for implant planning and traced the
      contours of the mandibular body and canal. Conventional, spiral tomograms were
      subjectively preferred over reformatted CT images. Differences between CT images
      at different mAs settings were not statistically significant. The mandibular
      canal was more frequently untraceable in high-dose CT. The use of tomography for
      dental implant planning was studied by means of a survey among oral radiology
      clinics in Sweden and implantology clinics in other countries. It was used by
      93.4% but varied markedly between and within anatomic regions. CT was used by
      73%. Radiation doses varied considerably within and between different CT brands.
      The availability rather than the clinical need strongly influenced the choice of
      technique. From the point of view of radiation dose and information necessary for
      implant planning conventional spiral tomography is to be preferred over
      reformatted CT. However, when CT is the only technique at hand, it can be
      performed with a lower than standard mA-setting.

PMID- 10635104
TI  - Some characteristics of solid-state and photo-stimulable phosphor detectors for
      intra-oral radiography.
AB  - The general aim of the study was to evaluate and compare different solid-state
      and photo-stimulable phosphor systems for digital intra-oral radiography and to
      compare different generations of some of the systems. The evaluations concerned
      physical and psychophysical performance, subjective image quality and the
      influence of image processing. Physical performance was tested by means of large
      area transfer characteristics, noise, contrast, and modulation transfer function.
      For the physical performance it was found that grey level values in images from
      solid-state systems decreased faster with increasing exposure than in images from
      photo-stimulable phosphor systems. Noise increased with increased exposure for
      both solid-state and photo-stimulable phosphor systems. Solid-state systems
      reached their highest contrast index at lower doses than the photo-stimulable
      phosphor systems. Solid-state systems had better resolving power due to higher
      contrast and smaller pixel sizes than the PSP systems. The resolving power of the
      photo-stimulable phosphor systems improved when the images were enhanced.
      Psychophysical tests were performed by determining the sensitivity of the systems
      for detecting small mass differences in test objects. It was found that when
      contrast enhancement were applied lower exposures could be used to detect low
      contrast objects in images from both solid-state and photo-stimulable phosphor
      systems. Blooming effects deteriorated images from solid-state systems at lower
      doses than burn-out effects deteriorated conventional radiographs or images from
      a photo-stimulable phosphor system. Some improvement in physical and
      psychophysical performance could be seen in the new generation of solid-state
      systems. Subjective image quality was tested by visual grading analysis in which
      observers graded the visibility of structures important for the diagnosis of
      common dental diseases. All systems produced diagnostically acceptable image
      quality but the photo-stimulable phosphor systems over a much wider exposure
      range than the solid-state systems. Histogram equalization did not improve image
      quality. A common diagnostic task; measurement of marginal bone level around
      implants, was used to study the influence of image processing. Radiographic
      measurements of bone height around implants in images from a photo-stimulable
      phosphor system was as accurate and precise as film images. Image processing was
      found to be task dependent. For a specific task, related to marginal bone height
      measurements around implants, a strong edge enhancement algorithm was found to be
      best.

PMID- 10635105
TI  - [Veterinary assistance to dairy farms in the Netherlands: an assessment of the
      situation by dairy farmers].
AB  - A questionnaire-based study was conducted among 466 dairy farmers in the
      Netherlands. The study investigated the experiences and opinions of dairy farmers
      about veterinary herd health and production management programmes. The dairy
      farmers were selected at random, and thus some took part in such programmes
      whereas others did not. The questionnaire comprised general questions about the
      farm operation and specific questions about the herd health programme and the
      practice conducting it, as well as perceived advantages and disadvantages of the
      veterinary programme. Farmers who did not participate in such programmes were
      questioned about their reasons for not participating. Both groups were questioned
      about future perspectives and opportunities. The costs of the programme appeared
      to be a drawback for participation but not as much as perceived by the practices.
      According to farmers, programmes focus too much on curative aspects and too
      little on analysis or prevention, where the needs are. Farm areas not included in
      the programme are so far not yet covered by other institutions, contrary to the
      expectations of the veterinarians. In the future, the farmers would be willing to
      take part in similar or expanded programmes, provided that certain conditions,
      such as product definition, structure, planning, costs, are properly met.

PMID- 10635106
TI  - [The importance of a correct diagnosis for bovine tuberculosis].

PMID- 10635107
TI  - [Separation of care, residence and health costs in the future at AWBZ].

PMID- 10635108
TI  - [Powerful knowledge about brittle bones].

PMID- 10635110
TI  - [Ethical code. Opposition by mentally incompetent (psycho) geriatric patients
      within the framework of the Law concerning Medical-Scientific Research with
      Humans. Dutch Society of Nursing Home Physicians, Dutch Society of Clinical
      Geriatrics, Dutch Society of Social Geriatrics].

PMID- 10635109
TI  - [Ethical code for evaluation of unwillingness in scientific research legally
      incompetent (psycho) geriatric patients. Background].

PMID- 10635111
TI  - [Normal values for a short form of the Raven Colored Progressive Matrices].
AB  - Psychometric data are presented for the Raven Coloured Progressive Matrices
      (RCPM), shortened to series A and B. The data were derived from a sample of 2791
      persons aged 55 to 85 years. Six 5-year age strata were equally represented, as
      well as both sexes. The distribution of educational attainment was representative
      for the elderly population. Norms were stratified for age and education; gender
      differences were too small to necessitate separate norms. Analysis of reliability
      according to Mokken's IRT-model indicated modest scalability, but high internal
      consistency. A loss of 2 to 4 points at retest (depending on personal
      characteristics) is interpretable as a loss of capacity. Ample attention is paid
      to qualitative aspects of test performance, but it is concluded that error
      analysis is mainly useful to def1p4 positional preferences.

PMID- 10635112
TI  - [Sleep disorders in elderly, the sleep apnea syndrome in particular: are they a
      cause of insomnia? A review of literature].
AB  - In this publication a review is presented based on the findings resulting from
      sleep-wake investigations searching for sleep disorders associated with insomnia
      in relatively healthy elderly. 44 Relevant journal articles published between
      1980-1998 were found. The four most important sleep disorders which can be
      accompanied by sleeplessness in relatively healthy elderly people are periodic
      leg movements disorder (PLM), restless legs syndrome (RLS), REM sleep behaviour
      disorder (RBD) and sleep apnea syndrome (SAS). Of these disorders, sleep apnea
      and periodic leg movements occur most frequently, in a quarter of the elderly.
      The latter, however, seldom complain about sleeplessness. Within the category of
      older people disorders characterized by movements during sleep increase
      significantly with age, nightly respiration disorders do not. SAS, PLM and RBD
      appear most frequently in men and RLS in women. The disorders characterized by
      movements during sleep (especially RLS and RBD) are often accompanied by
      sleeplessness. SAS, however, is more closely associated with day-time sleepiness
      than with sleeplessness. No combination of demographic variables and symptoms
      allows a reliable prediction of these sleep disorders. Fortunately, these
      disorders are not a major threat to the health of older people.

PMID- 10635113
TI  - [Resident Assessment Instrument (RAI): a review of international research on the
      psychometric qualities and effects of implementation in nursing homes].
AB  - This article is a review of the available literature on psychometric qualities
      and effects of implementation of the Resident Assessment Instrument (RAI) on
      quality of care and health of nursing homes residents. The RAI was developed in
      the USA to assess the needs of nursing home residents. It consists of a
      comprehensive assessment of the resident (the Minimum Data Set) and 18 protocols
      (Resident Assessment Protocols) for further analysis of major problem areas. RAI
      is implemented in nursing homes in the United States, Canada, Japan and several
      European countries. The interrater reliability was adequate for clinical use in
      several studies. The validity is good for the appraisal of ADL- and cognitive
      functions, but moderate for mood and behaviour. In Japan and the United States
      positive effects were found after implementation of the RAI, especially on the
      care process. Implementation of RAI has shown to have positive effects on the
      physical and cognitive function of the resident, but there were negative effects
      on a number of psychosocial domains. Fourteen Dutch nursing homes have recently
      implemented the RAI. Studies concerning reliability, validity and effects on
      quality of care and quality of life are underway.

PMID- 10635114
TI  - Two tropinone reductases, that catalyze opposite stereospecific reductions in
      tropane alkaloid biosynthesis, are localized in plant root with different cell
      specific patterns.
AB  - In the plant species that produce tropane alkaloids, two tropinone reductases
      (TRs) catalyze the stereospecific reductions of the 3-carbonyl group of
      tropinone. This reduction is a key branch point that determines the metabolite
      flow into the separate alkaloid groups, each with different stereospecific
      configurations. In this study, a specific antibody was prepared for each of the
      TRs by immunizing mice with recombinant TR protein and subsequent immuno-affinity
      purification of the antiserum. Immunoblot analyses revealed that accumulation of
      both TRs was highest in the lateral roots of Hyoscyamus niger throughout its
      development. In cultured roots, TR proteins were accumulated in a basal region
      but not in root apex. These patterns were similar to that of hyoscyamine 6 beta
      hydroxylase (H6H), an enzyme that catalyzes a downstream step in the same
      biosynthetic pathway. However, an immunohistochemical analysis revealed that the
      two TRs and H6H were accumulated with different cell-specific patterns in the
      cultured root, suggesting transportation of the alkaloid intermediate(s) across
      the different cell layers.

PMID- 10635115
TI  - Characterization of violaxanthin de-epoxidase purified in the presence of Tween
      20: effects of dithiothreitol and pepstatin A.
AB  - Violaxanthin de-epoxidase (VDE) was purified from thylakoid membranes of spinach
      by conventional column chromatography in the presence of Tween 20. The neutral
      detergent was necessary to prevent non-specific interaction of VDE with column
      resins. In anion-exchange chromatography on Mono Q, VDE appeared in two peaks.
      Both peaks exhibited a polypeptide of 41 kDa when fully reduced with 5 mM
      dithiothreitol. Re-chromatography of either peak gave rise to both peaks,
      suggesting that the two forms of VDE are interconvertible. VDE characteristically
      changed its electrophoretic mobility depending on the concentration of
      dithiothreitol with which the protein was treated. When non-reduced, it showed
      two polypeptides of 43 and 42 kDa. These polypeptides moved down to the position
      of 40 kDa, and then up to the position of 41 kDa, along with the increase in the
      dithiothreitol concentration from 0 to 2 mM. These findings suggest that VDE has
      more than one disulfide bond and takes multiple forms depending on the extent of
      the reduction. Studies with various types of protein-modifying reagent revealed
      that VDE is sensitive to pepstatin A, a specific inhibitor of aspartic protease.
      This finding suggests that the reaction center of VDE contains a reactive
      aspartic acid residue(s).

PMID- 10635116
TI  - Identification and characterization of Arabidopsis mutants with reduced quenching
      of chlorophyll fluorescence.
AB  - Regulation of nonradiative dissipation of absorbed light energy in PSII is an
      indispensable process to avoid photoinhibition in plants. To dissect molecular
      mechanisms of the regulation, we identified Arabidopsis mutants with reduced
      quenching of Chl fluorescence using a fluorescence imaging system. By analyses of
      Chl fluorescence induction pattern in the light and quantum yield of both
      photosystems, 37 mutants were classified into three groups. The first group was
      characterized by an extremely high level of minimum Chl fluorescence at the open
      PSII center possibly due to a defect in PSII. Mutants with significant reduction
      in the nonphotochemical quenching formation but not in quantum yield of both
      photosystems were classified into the second group. Mutants in the third group
      showed reduction in quantum yield of both photosystems possibly due to a defect
      in the electron transport activity. Mutants in the second and third groups were
      further characterized by light intensity dependence of Chl fluorescence
      parameters and steady state redox level of P700.

PMID- 10635117
TI  - The N-terminal propeptide and the C terminus of the precursor to 20-kilo-dalton
      potato tuber protein can function as different types of vacuolar sorting signals.
AB  - Two types of vacuolar sorting signals (VSSs), an asparagine-proline-isoleucine
      arginine-leucine (NPIRL)-related VSS in the N-terminal propeptides (NTPPs) and a
      C-terminal VSS in the C-terminal propeptides (CTPPs), function differently in
      plant cells. A precursor to a 20-kDa protein of potato tuber (PT20) contains two
      NPIRL-related sequences, NPINL in a short NTPP and NPLDV close to the C terminus
      of the precursor. We made mutant forms of sweet potato sporamin (SPO), nPT20-SPO,
      in which the N-terminal pre-pro part was exchanged with that of the precursor to
      PT20, and SPO-PT20c, in which the C-terminal 13 amino acids of the precursor to
      PT20 was attached to the C terminus of delta pro-SPO which lacked NTPP. Both
      nPT20-SPO and SPO-PT20c were efficiently transported to the vacuoles in tobacco
      cells. Unlike nPT20-SPO, the vacuolar transport of SPO-PT20c was inhibited by
      wortmannin and by the C-terminal addition of Gly or Gly-Gly suggesting its
      similarity to the vacuolar transport of sporamin mediated by CTPP of barley
      lectin. Further analysis of the C-terminal sequence of PT20 indicated that the
      most C-terminal SFKQVQ sequence functions as the C-terminal VSS. These results
      suggest that the precursor to PT20 contains both NPIRL-like VSS in its NTPP and C
      terminal VSS at the C terminus.

PMID- 10635118
TI  - AtUCP2: a novel isoform of the mitochondrial uncoupling protein of Arabidopsis
      thaliana.
AB  - Mitochondrial uncoupling proteins (UCPs) play a central role in adaptive
      thermogenesis in mammals. The UCPs dissipate the proton gradient formed through
      respiration without ATP synthesis, and the freed energy is readily converted to
      heat, helping the animals to maintain their body temperature in cold
      environments. Recently, it was found that UCPs also function in plant
      mitochondria. Subsequently, a cDNA clone encoding a UCP in potato was isolated.
      Whereas the UCP gene constitutes a multigene family in mammals, only a single
      cDNA sequence has been reported so far for the potato UCP. Moreover, it has been
      recently suggested that Arabidopsis has only a single nuclear gene for UCP. Here
      we report the existence of another UCP gene in the Arabidopsis genome, showing
      for the first time the occurrence of a multigene family for the protein in higher
      plants. A cDNA analysis of this gene showed that the novel isoform possesses all
      typical features reported for known UCPs. However, the new gene, unlike the other
      gene in Arabidopsis and the gene in potato, did not appear to respond to low
      temperature.

PMID- 10635119
TI  - cDNA cloning of a novel lectin-like xylem sap protein and its root-specific
      expression in cucumber.
AB  - A novel cDNA encoding a major 30-kDa protein in xylem sap of cucumber Cucumis
      sativus (XSP30) was homologous to the B chains of galactose-binding lectins such
      as ricin and abrin. XSP30 gene was specifically expressed in roots, and XSP30 was
      immunologically detected only in the xylem sap, but not in any organs.

PMID- 10635120
TI  - Molecular cloning and biochemical characterization of a novel cytochrome P450,
      flavone synthase II, that catalyzes direct conversion of flavanones to flavones.
AB  - Cytochrome P450 cDNAs, AFNS2 and TFNS5, were isolated from snapdragon and torenia
      petal cDNA libraries, respectively, based on the sequence homology with licorice
      CYP93B1 cDNA encoding (2S)-flavanone 2-hydroxylase. They were expressed in yeast
      and identified to encode flavone synthase II catalyzing direct conversion of
      flavanones to flavones probably via 2-hydroxyflavanones.

PMID- 10635121
TI  - The role of diet, fluoride and saliva in caries prevention.
AB  - Saliva is rich in calcium and phosphates, facilitating remineralization of early
      carious lesions. There is evidence that remineralization is associated with an
      increase in the size of enamel crystals and a consequent increase in resistance
      to caries. The contribution of sucrose to the implantation, colonization and
      metabolic activities of cariogenic bacteria has been clearly established, and has
      led to the search for sucrose substitutes. Recent report from Australia and the
      United States of America have reconfirmed the safety and efficacy of fluoride in
      preventing dental caries. The use of fluoride in various forms thus remains the
      cornerstone of most caries prevention programme.

PMID- 10635122
TI  - Prevalence of malocclusion and periodontal status in Tibetan school children of
      Kushalnagar, Mysore district.
AB  - A representative sample of 817 Tibetan school children aged 7 to 17 years of
      Mysore district were examined for malocclusion, gingival bleeding and calculus,
      using plane mouth mirror, sickle explorer and periodontal probes, under natural
      light. A very slight increase in malocclusion was noted in school girls, in
      addition to the statistically significant increase in gingival bleeding among 8
      13 years and 17 year old girls and 7-10 years and 15-16 year old boys. Moreover,
      a highly statistically significant increase in calculus was perceived amongst
      girls. The present study thus showed an increasing demand for preventive and
      therapeutic dental treatment in these children and early identification of such
      individuals at risk, can lead to better disease management.

PMID- 10635123
TI  - Non-familial cherubism--a case report.
AB  - A case of cherubism in a 9 year old boy with no familial history is presented.
      Clinical features, histologic appearance, radiographic findings, differential
      diagnosis and rationale for treatment is discussed.

PMID- 10635124
TI  - Chemical analysis of sound and carious enamel of permanent tooth.
AB  - Enamel consists mainly of inorganic material (96%) and only a small amount of
      organic substance and water (4%). The inorganic material is similar to apatite.
      The originally found apatite mineral remains basically unchanged except at the
      surface in contact with the oral tissues, where diffusion processes operate.
      Enamel reflects the trace element environment present in the tissue fluids at the
      time of tissue development. These are variations of types and concentration of
      inorganic elements found in permanent and deciduous enamel. Variations are also
      seen in sound and carious enamel.

PMID- 10635125
TI  - Knowledge, attitude and practice of dental caries and periodontal disease
      prevention among primary school teachers in Udupi municipality.
AB  - Primary school teachers of Udupi municipal corporation were surveyed to determine
      their knowledge, attitude and practice toward dental caries and periodontal
      disease prevention. Fourteen schools were selected by cluster sampling and the
      teachers working in these schools were included in the sample. The questionnaires
      were completed by one hundred teachers. The results showed that school dental
      health services must compulsorily hold demonstrations or lectures on prevention
      of oral diseases during school feasts and parent teacher meetings, in order to
      involve the teachers and parents in oral health promotion of the child.

PMID- 10635126
TI  - Peripheral fibroma with calcification--a case report.
AB  - A female patient aged 10 years reported with an intra oral swelling on the labial
      aspect of 32 & 33, appearing to originate from the marginal gingiva & interdental
      papilla. The swelling was pedunculated, mobile, non-tender, firm in consistency
      with an irregular surface. The colour of the gingiva was normal with slight
      ulceration. The swelling was excised & diagnosed histopathologically as
      peripheral cementifying/ossifying fibroma.

PMID- 10635127
TI  - Evaluation of antimicrobial efficacy of various root canal filling materials for
      primary teeth.
AB  - Four materials viz. zinc oxide-eugenol, iodoform paste, Kri paste, Maisto's paste
      and Vitapex (Calcium hydroxide + iodoform) were tested for their antibacterial
      effect against the aerobic and anerobic bacteria, viz. Staphylococcus aureus,
      Streptococcus viridans, Streptococcus faecalis, Bacteroides melaninogenicus and
      mixed bacterial culture; obtained from infected non-vital deciduous anterior
      teeth. The antimicrobial sensitivity was checked on BHI-agar plates using well
      method. The results showed that all the 4 materials were distinctly different
      from each other in their antimicrobial activity. Maisto's paste was invariably
      the superior most in its antibacterial efficacy (in comparison to all the 5 micro
      organism strains). Iodoformized zincoxide eugenol appeared to be the second best
      followed by Kri paste. Vitapex showed the least antibacterial activity.

PMID- 10635128
TI  - Remineralizing efficacy of a mineral enriched mouth rinse and fluoridated
      dentifrice on artificial carious lesions: an in vivo scanning electron
      microscopic study.
AB  - This comparative investigation was carried out to evaluate the remineralization
      potential on early artificial carious lesions under Scanning Electron Microscope
      (SEM) of a Mineral enriched mouthrinse and a fluoridated dentifrice using an in
      vivo intra-oral removable appliance model. This findings revealed that the
      remineralization was found to have occurred in almost all the samples (in
      children) using non-fluoridated, fluoridated dentifrices as well as those using
      mineral enriched mouthrinse. However the qualitative analysis of the
      remineralization revealed that in case of non-fluoridated dentifrice group, the
      prismatic holes showed deposition of granular, variable sized particles with
      uneven distribution, while in fluoridated dentifrice group, deposits were found
      to have partially but more densely filled up the prism cores. In case of mineral
      enriched mouthrinse group these deposits were found to be in the form of
      amorphous globular precipitate.

PMID- 10635129
TI  - A comparative study of effects of mouth breathing and normal breathing on
      gingival health in children.
AB  - The present study was conducted to assess the effects of mouth breathing, lip
      seal and upper lip coverage on gingival health of children. 240 school children
      aged 10-14 years were selected irrespective of sex race and socioeconomic status.
      They were divided into two major groups i.e. mouth breathers and normal
      breathers. These groups were further subdivided into six sub-groups or categories
      on the basis of lip seal and upper incisor coverage. Gingival index was found to
      be higher in the mouth breathers than in the normal breathers in the subjects
      with incompetent lip seal. Increased lip separation and decreased upper lip
      coverage were all associated with higher levels of Plaque index and Gingival
      index. No statistical difference existed between mouth breathers and normal
      breathers with respect to Plaque index.

PMID- 10635130
TI  - An epidemiological study on the prevalence of dental caries and treatment need in
      12-15 year old children in Bhiwandi (Maharashtra).
AB  - An epidemiological survey of the prevalence of dental caries and treatment need
      in the powerloom township of Bhiwandi revealed a prevalence level of 56.93%. The
      overall mean DMFT score was 1.25 +/- 1.34. Decayed teeth accounted for the
      largest component of the reported DMF teeth followed by an almost equal
      proportion of missing and filled teeth. Single surface restorations were the most
      frequent type of treatment required, followed by the two or more surface
      restorations, extractions and pulp therapy.

PMID- 10635131
TI  - Calcium hydroxide as a root canal filling material in primary teeth--a pilot
      study.
AB  - A pilot study was carried out in five mandibular primary molars using calcium
      hydroxide (Ca(OH)2) Paste as root canal filling material to find out an
      alternative to the routinely used zinc oxide eugenol (ZnOE), which is non
      resorbable and causes deflection of succedaneous teeth. The six month clinical
      and radiographic follow-up carried out at 2 months interval, revealed that the
      treated teeth with Ca(OH)2 as root canal filling material were successful,
      showing no pain and tenderness to percussion. A tendency for decrease in size of
      radiolucency was seen. Two teeth showed complete healing of the periradicular
      radiolucency. Depletion of Ca(OH)2 paste was seen from the root canals even prior
      to physiological resorption of roots in 2 out of 5 treated teeth.

PMID- 10635132
TI  - Mesiodens in the primary dentition--a case report.
AB  - Supernumerary teeth are among the most significant dental anomalies affecting the
      primary and the permanent dentitions. Mesiodens is a supernumerary tooth with a
      cone shaped crown and a short root. Though it occurs frequently in the permanent
      dentition, it is extremely rare in the primary dentition. The exact etiology is
      still obscure and not well understood. Supernumerary teeth occur as isolated
      dental findings or as part of a syndrome. The frequency with which supernumerary
      teeth occur and the effects they have on development of normal occlusion justify
      the radiographic examination of preschool children. Early removal of such teeth
      is recommended if they impede the eruption of adjacent permanent teeth, appear
      inverted or rudimentary, associated with certain pathologic conditions or are
      symptomatic.

PMID- 10635133
TI  - Bite mark analysis in child abuse.
AB  - The science of bite mark analysis is relatively new and potentially valuable.
      This science has been greatly used in identifying the suspects involved in crimes
      related to sex, child abuse, and altercations of various types. Child abuse is
      presenting a serious social problem with global dimensions, which is increasing
      at an alarming rate in all socioeconomic strata and all ethnic or racial
      communities. The aim of the present study was to assess these bite marks and
      analyze the effectiveness of a simple technique used in the department of
      pedodontics and preventive dentistry, College of Dental Surgery, Manipal.

PMID- 10635134
TI  - Root development in relation to impacted mesiodens.
AB  - Presented here is a case of 7 years 6 month old child with an apically impacted
      mesiodens in relation to the developing root of right upper central incisor. The
      removal of mesiodens was deferred in order to avoid disturbance in the natural
      development of the upper central incisor. Serial X-rays are presented and case is
      discussed.

PMID- 10635135
TI  - The role of the fissure morphology in caries prevalence of the first permanent
      molar in Libyan children.
AB  - Dental caries is one of the commonest of all dental diseases and is the main
      cause of loss of teeth in young people. It is a common belief that the high
      caries susceptibility of occlusal surfaces of posterior teeth is directly related
      to the morphology of the pits and fissures. Occlusal fissures are deep
      invaginations of enamel, they can be classified into V-type: Wide at the top and
      gradually narrowing towards the bottom U-type almost the same width from top to
      bottom. I-type an extremely narrow slit IK-type extremely narrow slit associated
      with large space at the bottom Y-type wide at the top and suddenly narrowing
      towards the bottom.

PMID- 10635136
TI  - Compound composite odontoma in primary dentition--a case report.
AB  - Compound composite odontoma, is a tumor formed by the overgrowth of transitory or
      complete dental tissue, made up of one or more rudimentary teeth. Although
      odontomes are considered to be quite common of odontogenic tumors, these rarely
      occur solely in primary dentition. This paper is a report of case of a compound
      composite odontoma, five year old child who presented to the Department of
      Pedodontics and preventive Dentistry, College of Dental Surgery, Manipal.

PMID- 10635137
TI  - Comparison of sealing efficacy of materials placed in lateral root perforations-
      an in vitro study.
AB  - An endodontic perforation interferes with the principal goal of sealing the root
      canal system. An in vitro study was conducted on comparative efficacy of three
      materials-Dispersalloy, Cavit and Prisma VLC Dycal when placed in lateral root
      perforations in cervical third areas. Root canals were prepared and irrigated
      thoroughly. Perforations were made with No. 2 round bur and sealed with
      Dispersalloy, Cavit and Prisma VLC Dycal. Dispersalloy Group I showed best
      sealing ability. Prisma VLC Dycal Group I too was comparable to Dispersalloy
      Group I in its sealing ability, followed by Cavit Group II, Prisma VLC Dycal
      Group II, Dispersalloy Group II in that order. Cavit Group I was least effective
      in sealing perforations.

PMID- 10635138
TI  - Foreign body in a mandibular permanent molar--a case report.
AB  - A thirteen-year-old boy was examined in the Department of Pedodontics during a
      school-screening programme. On examination the left mandibular first permanent
      molar was found to be grossly destroyed. On radiographic evaluation a radio
      opaque screw shaped foreign object was seen in the pulp chamber of the said
      tooth. Retrieval of the foreign object was tried but the attempt was unsuccessful
      and an extraction was planned. A case of a unique foreign object in the pulp
      chamber of the tooth is reported.

PMID- 10635139
TI  - Comparison of sealing ability of three different root canal sealers--an in vitro
      study.
AB  - The main objective of endodontic therapy is complete obturation of the root canal
      system after it has been adequately prepared and sterilised. A wide variety of
      root canal sealers are available for obturation of the root canal system. A
      number of different invitro methods have been used to evaluate the sealing
      ability of endodontic filling materials. By combining one or two tests it may be
      possible to obtain information about sealing ability of the test material.
      Therefore, the present invitro study compared the sealing ability of three
      different root canal sealers, namely Sealapex, AH-26 and ZnOE by two different
      methods, bacterial leakage and dye penetration. The results showed that AH-26 has
      the maximum sealing ability followed by Sealapex and ZnOE.

PMID- 10635140
TI  - Congenital gingival granular cell tumor--a case report.
AB  - Presented here is a case report of a congenital granular cell tumor commonly
      known as congenital epulis. It has been found to be ten time more common in
      females as compared to males. The most common presenting problem is that of
      difficulties in feeding and respiration. Surgical excision is indicated in case
      the above problems are present. In the absence of any respiratory or feeding
      difficulties it is advisable to wait for spontaneous regression.

PMID- 10635141
TI  - Shear bond strength of resin-modified restorative glass-ionomer cements to dentin
      -an in vitro study.
AB  - An in vitro study was carried out on 40 periodontally involved, caries free human
      maxillary and mandibular molars to evaluate shear bond strength of resin-
      modified restorative glass-ionomer cements to dentin. Teeth were divided into
      four groups, Group I--Fuji II (Conventional glass ionomer) Group II (Fuji II LC),
      Group III (Vitremer), Group IV (Geristore). Shear bond strength was tested using
      a transaxial testing machine. Results showed that shear bond strength of all
      resin-modified restorative glass-ionomer cements was higher than conventional
      glass ionomer (Fuji II) tested. No statistical difference was found between Fuji
      II LC and Geristore. However, bond strength of Vitremer was lower than Fuji II LC
      and Geristore but higher than Fuji II.

PMID- 10635142
TI  - Crouzon disease--a case report.
AB  - The present case of a ten year old boy with craniofacial dysostosis with the
      features of midfacial hypoplasia is a disease known as Crouzon disease. This
      disease is characterised by cranial deformities, facial malformation, eye changes
      and occasional other associated abnormalities. The aim of this case is to discuss
      the clinical, radiographic features and management of the problems.

PMID- 10635143
TI  - With all of life's ups and downs. What about recovery?

PMID- 10635144
TI  - Interproximal finishing of esthetic restorations.

PMID- 10635145
TI  - Clinical pathology case conference: Stevens-Johnson Syndrome.

PMID- 10635146
TI  - Endodontics in the '90s: old dogma and new tricks ... can we be re-taught?
AB  - Endodontics has gone through many changes in the past several years. Electronic
      apex locators and surgical microscopes have taken a lot of the guess work out of
      doing root canal. Digital radiograpy has expanded our diagnostic abilities.
      Ultrasonic intrumentation and the advent of new filing systems have increased the
      efficacy of canal cleaning. There have also been some major refinements in how we
      can now obturate canals. Apicoectomies can now be performed with refined
      ultrasonic root end preparations, and we have increased our ability to better
      seal root ends with new filling materials. The result is that endodontic
      procedures can now be performed more expediently and with a more predictable
      outcome. This article is written from the perspective of a full-time practicing
      endodontist, and describes the various changes occurring within the specialty of
      endodontics.

PMID- 10635147
TI  - Accepting change in a year of challenges.

PMID- 10635148
TI  - Determinants of correct clinical reporting.

PMID- 10635149
TI  - Staff issues when buying or selling a practice.

PMID- 10635150
TI  - Riding change along an open road. An interview with 1999/2000 ODA President Dr.
      Don Friedlander. Interview by Mark Levine.

PMID- 10635151
TI  - Human resource issues: a comparison by region.

PMID- 10635152
TI  - Being a witness: testifying in court.

PMID- 10635153
TI  - New experimental model to study the bone interface of endosseous implants: an in
      vitro three-dimensional model of cell culture.
AB  - To set up a three-dimensional culture model of endosseous implant material
      osteoblast, titanium (Ti) discs were placed onto confluent cellular layers of
      human fetal osteoblasts that were cultured in calcifying conditions. Follow-up
      observations of living cells with phase-contrast microscopy and histological
      observations of the cell-Ti disc interface with ordinary microscopy and
      transmission electron microscopy were used to monitor and verify the formation of
      three-dimensional cellular structures at the osteoblast-Ti disc interface. These
      methods were further used to study osteoblast cell behavior during the early
      stage of bone healing in this three-dimensional cellular model. The follow-up
      observation showed that, upon the placement of the Ti disc, cells migrated from
      the cellular layer and attached to the rim of the disc, forming cell bridges.
      Cells continued to attach and orient throughout the culture time. A cellular
      multilayer at the osteoblast-Ti interface was formed, which resulted in the three
      dimensional model. Furthermore, transmission electron microscopy observation
      showed that there was a mineralizing process at the osteoblast-Ti disc interface
      just like bone, which confirms the reality of this model. Histological
      observations with conventional microscopy demonstrated the interfacial relation
      between biomaterial and cells. If osteoblasts were replaced by other types of
      cells, this model could be used to study the other kinds of interfaces.

PMID- 10635154
TI  - Protein adsorption and osteoblast responses to heat-treated titanium surfaces.
AB  - The clinical success of dental implants is governed in part by surface properties
      of implants and their interactions with the surrounding tissues. The objective of
      this study was to investigate the effect of heat-treated titanium (Ti) surfaces
      on protein adsorption and osteoblast responses in vitro. The passivated Ti
      samples used in this study were either nonheat-treated or heat-treated at 750
      degrees C for 90 minutes. Using x-ray diffraction analyses, no oxide peaks were
      observed on the nonheat-treated surfaces, suggesting an amorphous oxide.
      Crystalline rutile TiO2 peaks were observed on the heat-treated Ti surfaces. The
      contact angles of water on heat-treated Ti surfaces (32.0 +/- 2.5 degrees) were
      statistically lower compared with the nonheat-treated Ti surfaces (47.7 +/- 2.3
      degrees). In addition, the mean albumin concentration on the nonheat-treated Ti
      surfaces (3.57 +/- 0.33 micrograms/mL) was observed to be significantly different
      from the mean albumin concentration on heat-treated Ti surfaces (2.25 +/- 0.26
      micrograms/mL). In the presence of an osteoblast precursor cell line,
      significantly different hexosaminidase activity, protein production, and alkaline
      phosphatase activity were observed for cells grown on heat-treated Ti surfaces
      compared with nonheat-treated Ti surfaces.

PMID- 10635155
TI  - Evaluation of the implant master cast by means of the Periotest method.
AB  - Accurate master casts are essential for the construction of implant-supported
      prostheses with a precision of fit. The stability of the abutment replicas in the
      master cast is critical in the accurate reproduction of the patient's oral
      presentation. The Periotest method is an objective method of quantifying mobility
      in a tooth and implant. Eighteen gypsum implant master casts containing two brass
      abutment replicas per cast were evaluated. The abutment replicas were measured
      three times each for a total of 108 measurements. The mean periotest values and
      standard deviations were calculated for the master casts and the abutment
      replicas. The abutment replicas displayed mean periotest values that ranged from
      +1.3 to -8.0. The study shows that there are significant differences between
      stable and unstable implant master casts (P = 0.0001, ANOVA-Fisher's protected
      least significant difference) and abutment replicas (P = 0.0001, Contrast test).
      The Periotest method will quantify differences in gypsum stone implant master
      casts as well as the prosthesis supporting brass abutment replicas that are an
      integral part of the master cast.

PMID- 10635156
TI  - In vitro stress analyses of dental implants supporting screw-retained and cement
      retained prostheses.
AB  - A photoelastic and strain gauge analysis was performed to evaluate the stress
      transferred to implants through the provisional-cement-retained, the permanent
      cement-retained, and the screw-retained prostheses. The deflections of the
      prostheses at the time of the loading were also measured. In the single crown
      test, the provisional-cement-retained crowns transferred less stress. In the two
      unit fixed partial denture test, there were no differences between the three
      different prostheses. In the two-implant supported distal cantilevered
      prostheses, the screw-type and the permanent-cement-retained prostheses developed
      more stress around the apex of both implants. The permanent-cement-retained
      prostheses acted almost the same as the screw-type.

PMID- 10635158
TI  - Punch technique for preservation of interdental papillae at nonsubmerged implant
      placement.
AB  - Surgical flap procedures currently used for the placement of endosseous implants
      often can result in damage to the interdental papilla with subsequent poor
      esthetics. A simple technique is presented whereby the implants are placed by
      using a tissue punch and without raising a full thickness flap. At no time is the
      subperiosteal soft tissue flap raised, and the integrity of the interdental
      papilla is never disrupted. There is no discontinuation of the alveolar blood
      supply of the surrounding osseous tissue. In the authors' experience, there has
      been a significant reduction in postoperative discomfort. It is proposed that
      this technique warrants further evaluation, especially to compare the rate of
      bone resorption, because it is hypothesized that because of lack of
      discontinuation of the blood supply, there might be reduced bone resorption
      compared with conventional flap procedures.

PMID- 10635157
TI  - Study of the effect of using mini-transitional implants as temporary abutments in
      implant overdenture cases.
AB  - In an attempt to improve patient satisfaction during the healing period after
      placement of implants, mini-transitional implants (MTIs) have been advocated to
      allow immediate use of temporary dentures and to prevent transmucosal loads over
      the definitive implants. Twelve edentulous patients received two screw implants
      each in the predetermined mandibular canine region. At the time of surgery, six
      patients had two MTIs placed medially to the permanent ones. The flap was
      repositioned allowing transmucosal penetration of MTIs. Patients left the
      operating room wearing their relined lower dentures. The results indicated that
      MTIs integrated sufficiently in bone, giving successful immediate support for the
      transitional prosthesis and allowing proper mucosal healing. Two of these
      transitional implants showed mobility three months after phase I surgery. After
      loading the final implants, patients who had MTI-supported dentures showed bone
      loss that was not significantly different from the control group.

PMID- 10635159
TI  - Localized ridge maintenance using bone membrane.
AB  - The immediate placement of a dental implant into a fresh extraction socket has
      been limited in many instances by the quantity of bone that remains after the
      extraction. This article presents two clinical cases that demonstrate successful
      regeneration of alveolar ridges in which there was extensive loss of the buccal
      plate of bone. This lack of alveolar process impeded the immediate placement of
      dental implants into fresh extraction sockets. The surgical technique performed
      in these cases was based on the principles of guided bone regeneration using a
      demineralized freeze-dried bone membrane. The bone membrane acted as an efficient
      barrier that excluded the nonosteogenic tissues. Bone formation took place for
      the placement of endosseous dental implants 8 months after the procedures were
      initiated. These human clinical cases confirm positive results of previous animal
      findings.

PMID- 10635160
TI  - Why do dental implants fail? Part I.
AB  - Many factors are attributed to failure of the dental implant, either directly or
      indirectly. The focus of this article is to define the causation of dental
      implant failure, as well as to present an evaluation of the implant literature
      regarding etiology, classification, management, and treatment of implant
      failures. This article will highlight the initial signs of implant failure with a
      view of some clinical cases in terms of classification and degrees of implant
      failure. Finally, a dental implant failure checklist is formulated to guide the
      practitioner in defining the cause of implant failure, be it infective or
      noninfective, and to establish percentages and frequency of occurrence. The
      checklist applies to all implant systems and will help to determine the factors
      responsible for causation and the repair procedures, whether they are at the
      surgical or restorative phases. The definition of implant failure is set forth in
      terms of ailing, failing, failed, and surviving implants, and the appropriate
      treatments and dispositions are outlined.

PMID- 10635161
TI  - Fixed implant rehabilitation of the edentulous maxilla: clinical guidelines and
      case reports. Part I.
AB  - Fixed implant reconstruction is one of the most challenging prosthetic treatment
      alternatives for the edentulous maxilla. Accurate diagnosis and treatment
      planning are essential to successful, predictable clinical results. Decisions
      concerning the placement of implants may have a lasting impact on the quality and
      prognosis of the final restoration. A series of clinical guidelines and
      considerations is presented with illustrative clinical treatment protocols of
      edentulous maxillae that vary in degrees of anatomical and prosthetic difficulty.
      This article addresses the fixed implant rehabilitation of edentulous maxillas
      with favorable anatomy and favorable arch position, favorable anatomy, and
      unfavorable arch position, and unfavorable anatomy and favorable arch position.

PMID- 10635162
TI  - The less than 7-mm edentulous mandible: the implant/overdenture reconstructive
      option.
AB  - The edentulous patient with a severely atrophic mandible (less than 7 mm in
      height) can be successfully restored with two endosseous implants and a clip-bar
      overdenture, with minimal morbidity. Two of the three cases reported illustrate
      the long-term potential of this treatment modality.

PMID- 10635163
TI  - The prevalence of orofacial myofunctional disorders among children identified
      with speech and language disorders in grades kindergarten through six.

PMID- 10635164
TI  - Relationship between malocclusion and fonoarticulatory disorders.

PMID- 10635165
TI  - Feeding impairments in children: diagnosis and effective intervention.
AB  - The four main requirements for oral-motor development are stability and mobility
      of the ingestive system, rhythmicity, sensation, oral-motor efficiency and
      economy. Ingestion can be divided into oral, pharyngeal and esophageal stages.
      The main categories of pathology encountered in our swallowing and dysphagia
      clinic are encephalopathies (including cerebral palsy), genetic disorders
      (including chromosomal aberrations), syndromes associated with swallowing
      difficulty (e.g. Rett, Dandy-Walker, DiGeorge), head injuries, brain tumors,
      developmental delay and the oral deprivation syndrome (e.g. due to prolonged tube
      feeding on a preterm infant). The behavioral expression of the many different
      pathologies falls into three categories: (1) resistance to accepting food orally;
      (2) lack of energy and endurance to do the 'work' of eating; and (3) oral-motor
      disabilities resulting in an inability to produce the necessary motor skills for
      ingestion. Expect expression and exacerbation of feeding problems during periods
      of most active growth, i.e. from birth to 2 years and during the adolescent
      growth spurt. Identify the source of the feeding problem. Establish its pathology
      and note the clinical manifestations. Determine if the problem has a strictly
      physiologic origin or whether it may be exacerbated by the feeding interaction
      between child and feeder. Determine what diagnostic tests are needed and refer
      child for testing Formulate the treatment approach based on clinical observations
      and results of diagnostic tests. Teach and monitor treatment which can be given
      by caregivers. Set time limits for treatment and clearly state expected results.
      Evaluate progress by comparing outcome to stated treatment objectives. Refer
      children with more severe problems to a multidisciplinary treatment team.

PMID- 10635166
TI  - A descriptive study of the thumb/finger-sucking behavior of female and male
      subjects three years and older.

PMID- 10635167
TI  - Preliminary observation of rest posture habituation time.

PMID- 10635168
TI  - Treatment of furcation defects with DFDBA combined with GTR: human histologic
      evaluation of a case.
AB  - The purpose of this study was to evaluate whether regeneration is possible in
      human furcation defects. Three molars with Class II furcation involvement were
      included in this study. A notch was placed in calculus in the furcation to serve
      as a reference point for histologic evaluation. The defects were treated with a
      demineralized freeze-dried bone allograft combined with a bioabsorbable membrane.
      At 6 months postoperative, the teeth were extracted with a small piece of tissue
      from the furcation area. The samples were then processed for histologic
      evaluation. Regeneration was found in 2 of the 3 samples. This study demonstrated
      that regeneration is possible in human furcation defects.

PMID- 10635169
TI  - Abutment selection in implant-supported fixed prosthodontics.
AB  - Selecting the appropriate abutment can be both complex and confusing with the
      ever-increasing number of implant choices and transepithelial abutments
      available. Many restorative dentists resort to fabricating costly custom
      abutments to avoid the selection process. Although custom abutments are at times
      necessary, prefabricated abutments are usually more desirable. This article will
      describe the various abutments available and how to select the correct abutment
      for a given clinical situation in an organized, systematic fashion. Criteria
      discussed include implant position, angulation, soft tissue height, and
      interocclusal space. The latest modifications and developments in implant
      abutments are reviewed along with an indirect method of selecting abutments in a
      laboratory setting.

PMID- 10635170
TI  - Treatment of a large periapical lesion with loss of labial cortical plate using
      GTR: a case report.
AB  - Following endodontic treatment, a large periapical lesion (9.0 mm x 9.0 mm) at a
      maxillary central incisor was treated with demineralized freeze-dried bone
      allograft (DFDBA) using the principles of guided tissue regeneration. The
      physical barrier was removed 6 months postsurgical. The cortical alveolar plate
      was observed to be completely reconstructed. Histologic evaluation demonstrated
      lamellar bone surrounding DFDBA particles. Radiographic follow-up 1 year
      posttreatment demonstrated complete resolution of the periapical radiolucency.

PMID- 10635171
TI  - Furcation depth and interroot separation dimensions for 5 different tooth types.
AB  - The purpose of this study was to document mean, standard deviation, and range of
      furcation depth and Interroot separation dimensions of 5 multirooted tooth types.
      A total of 412 extracted teeth were examined and classified as: maxillary first
      molar, maxillary second molar, maxillary first premolar, mandibular first molar,
      and mandibular second molar. The furcation depth was measured at the level of the
      furcation dome and 3 and 5 mm apical to the dome. Interroot separation was
      measured 3 and 5 mm apical to the furcation dome. Mean furcation depth at the
      dome was 7.48 mm buccally and 6.67 mm mesiodistally for maxillary first molars;
      6.69 mm buccally and 5.94 mm mesiodistally for maxillary second molars; 3.54 mm
      mesiodistally for maxillary first premolars; 7.96 mm buccolingually for
      mandibular first molars; and 7.46 mm buccolingually for mandibular second molars.
      Interroot separation dimensions 3 mm apical to the dome were: 2.58 mm buccally,
      4.17 mm mesially, and 4.48 mm distally for maxillary first molars; 1.92 mm
      buccally, 3.89 mm mesially, and 4.04 mm distally for maxillary second molars;
      2.47 mm mesially and 2.58 mm distally for maxillary first premolars; 3.15 mm
      buccally and 2.95 mm lingually for mandibular first molars; and 2.54 mm buccally
      and 2.75 mm lingually for mandibular second molars.

PMID- 10635172
TI  - GBR in human extraction sockets and ridge defects prior to implant placement:
      clinical results and histologic evidence of osteoblastic and osteoclastic
      activities in DFDBA.
AB  - This study evaluated new bone formation in 3 types of osseous defects following
      treatment with demineralized freeze-dried bone allografts (DFDBA) and cell
      occlusive membranes. For 8 patients electing to receive implant treatment, a
      distinction was made among 3 clinical situations: (1) existing alveolar ridge
      defects; (2) extraction sockets with lost buccal plate; and (3) extraction
      sockets with an intact alveolus. Implants were placed a mean of 6 months after
      the regenerative procedure. Clinical examination of bone width and height at the
      time of implant placement showed sufficient augmentation or preservation, and
      implants were inserted without incident. Histologic examination of hard tissue
      biopsies obtained from the implant sites revealed no discernible differences
      among the 3 types of defects. Specifically, all sites demonstrated DFDBA
      particles surrounded by woven or lamellar bone. No fibrous encapsulation of DFDBA
      or inflammatory reaction was observed. Osteoblasts were found lining marrow
      spaces. Howeship's lacunae, with and without resident osteoclasts, were clearly
      seen in several DFDBA particles; this finding supports the belief that DFDBA
      undergoes osteoclasis in vivo. These results demonstrate that commercially
      available DFDBA has osteoconductive properties that lead to appositional new bone
      growth in both self-contained and non-self contained osseous defects.

PMID- 10635173
TI  - Bone regeneration in the edentulous ridge expansion technique: histologic and
      ultrastructural study of 20 clinical cases.
AB  - The edentulous ridge expansion (ERE) technique is a partial-thickness flap
      procedure for implant surgery that was developed in 1986. The ERE technique
      permits the use of osseointegrated implants at sites whose minimal orofacial
      dimensions are insufficient for traditional implant surgery. The present work is
      a histologic and ultrastructural study of hard tissue repair modalities at
      edentulous sites that were treated with the ERE technique in 20 humans. Biopsies
      were obtained from the tissue regenerating within the surgically created bone gap
      between the mobile buccal and nonmobile lingual or palatal bone-periosteum plates
      ("bone flaps") on days 40, 90, 120, 150, and 480 (day 0 = day of implant
      insertion). The results suggest that osteoblasts differentiate from preexisting
      mesenchymal cells located on the original fissure walls, with consequent
      deposition of new bone in the surgically created intrabony defect.

PMID- 10635174
TI  - A single-incision technique to harvest subepithelial connective tissue grafts
      from the palate.
AB  - This article describes a new and simplified surgical approach to harvest
      subepithelial connective tissue grafts from the palate. For this procedure, only
      a single incision parallel to the gingival margin is used to access the donor
      site for graft preparation and harvesting. Grafts of variable size and thickness
      can be obtained. Since no band of epithelium is removed with the connective
      tissue graft the palatal donor site can heal with primary intention. No stents or
      hemostatic agents are necessary to cover the donor area postoperatively, and
      suturing can be reduced to a minimum. The harvesting technique is illustrated
      step by step, and the clinical application of connective tissue grafts harvested
      with the proposed method is demonstrated with the coverage of a gingival
      recession.

PMID- 10635175
TI  - Controlled subperiosteal tissue expansion to facilitate GBR for the placement of
      endosseous dental implants.
AB  - The success of endosseous dental implants is enhanced when sufficient bone is
      present to stabilize the implant. If adequate bone for full coverage of the
      implant is not possible, then the use of guided bone regeneration to regenerate
      the missing bone has been shown to be a predictable solution. Defect size can
      often limit the amount of soft tissue available for coverage of the membrane,
      which is essential in obtaining an optimal result when using regenerative and
      osseointegrative principles. The treatment philosophy demonstrated in this case
      report uses controlled subperiosteal tissue expansion to facilitate the
      incorporation of guided bone regeneration with the subsequent placement of
      endosseous dental implants. This treatment modality provided a successful
      treatment for an otherwise compromised case.

PMID- 10635176
TI  - Lateral periodontal cyst: report of a case with 1-year reentry.
AB  - The lateral periodontal cyst is a relatively rare cyst of the jaw (0.8%) of
      unproven origin. It is most commonly found in the mandible between the roots of
      canines and premolars. This article reports a case of a lateral periodontal cyst
      in a 73-year-old woman, documents its diagnosis and treatment, and also presents
      a 1-year reentry. No grafting or barrier techniques were used. The result was
      complete bony regeneration of the defect after 1 year.

PMID- 10635177
TI  - A human histologic analysis of osseotite and machined surfaces using implants
      with 2 opposing surfaces.
AB  - A human histologic study was conducted to compare the percentage of bone-to
      implant contact (BIC) at 6 months for Osseotite and machined, commercially pure
      titanium implant surfaces. To eliminate potential influences caused by
      differences in bone density at different intraoral locations, 2 mm x 5 mm,
      threaded, 2-surfaced titanium implants were manufactured; 1 side received the
      Osseotite surface modification and the opposite side maintained a machined
      surface. In each of 11 patients, 1 test implant was placed in the posterior
      maxilla (Types III and IV bone) during conventional dental implant surgery.
      Following 6 months of unloaded healing, the conventional implants were uncovered,
      and the test implants and surrounding hard tissue were removed. Histologic
      analysis indicated that at 6 months of unloaded healing, the mean BIC value for
      the Osseotite surfaces (72.96% +/- 25.13%) was statistically significantly higher
      (P < 0.05) than the mean BIC value for the machined surfaces (33.98% +/- 31.04%).
      When the BIC values for the machined and Osseotite surface pairs were ranked from
      high to low based on the machined BIC value range of 93% to 0%, the upper 50th
      percentile (20 surface pairs) mean BIC value was 86.1% +/- 16.7% for the
      Osseotite surfaces and 60.1% +/- 18.3% for the machined surfaces. The lower 50th
      percentile (19 surface pairs) mean BIC value was 59.1% +/- 25.3% for the
      Osseotite surfaces and 6.5% +/- 10.8% for the machined surfaces. Differences
      between mean BIC values for the 2 surfaces in both the upper and lower 50th
      percentiles were statistically significant (P < 0.05). The results of this study
      indicate that in the poorer quality bone typically found in the posterior
      maxilla, a statistically significantly higher percentage of bone contacts
      Osseotite surfaces when compared to opposing machined surfaces on the same
      implant.

PMID- 10635178
TI  - Supracrestal bone regeneration: a pilot study.
AB  - The purpose of this study was to determine the feasibility of regenerating bone
      in patients with advanced horizontal bone loss. Demineralized freeze-dried bone
      allografts (DFDBA) in particle, strut, and laminar forms were used in combination
      with guided tissue regeneration. The cortical struts and strips were processed
      from long bones and were supplied in different widths and lengths. The strips
      were prepared in various thicknesses ranging from 100 to 500 microns; the struts
      ranged from 1 to 3 mm thick. These 2 materials provided structural support for
      the retention of DFDBA particles supracrestally, and they supported the gingival
      flap as a space maintainer, preventing the collapse of the tissue onto the roots
      and existing bone. The results indicated successful supracrestal regeneration of
      horizontal defects when combining existing techniques and materials. The mean
      attachment gain for the 7 patients studied ranged from 2.6 to 3.0 mm.

PMID- 10635179
TI  - Localized soft tissue ridge augmentation at phase 2 implant surgery: a case
      report.
AB  - A case of congenitally missing maxillary lateral incisors is presented to
      illustrate a modification of Abrams's roll technique. Buccal releasing incisions
      are avoided by using an intrasulcular incision on the adjacent teeth. The tissue
      overlying the cover screw is transferred between the buccal cortical bone and the
      buccal masticatory mucosa, thus correcting the localized buccal ridge atrophy.

PMID- 10635180
TI  - Treatment sequencing for implant restoration of partially edentulous patients.
AB  - Over the years implant companies have provided more and more components to
      address the varied clinical situations that occur. While these new components
      have allowed for improved restorative designs, it can now be somewhat confusing
      to determine the most appropriate components, especially abutments. This article
      describes restorative steps for both single-implant and multiple-implant
      restorations; these steps help guide restorative dentists through the treatment
      process, enabling them to follow standard protocols for single- and multiple
      implant restorations. With these protocols it is possible to select the most
      appropriate components and proceed with treatment in a time-efficient and cost
      effective manner.

PMID- 10635181
TI  - Treatment of intrabony periodontal defects with an enamel matrix protein
      derivative (Emdogain): a report of 32 cases.
AB  - Enamel matrix proteins, including Emdogain, have been proposed as a new modality
      for regenerative periodontal treatment. However, limited information is available
      concerning the clinical applicability and therapeutic results with Emdogain. The
      aim of the present study was therefore to evaluate the clinical outcome following
      the application of Emdogain in the treatment of intrabony periodontal defects.
      Twenty-eight patients with marginal periodontitis (thirty-two 2- and 3-walled
      intrabony defects) were included in this study. The following parameters were
      evaluated prior to treatment and 8 months after treatment: probing pocket depth,
      recession of the gingival margin, and clinical attachment level. The
      postoperative healing phase was uneventful in all cases. There were no
      complications such as allergic reactions, abscess formation, or infections
      throughout the entire study period. The mean probing pocket depth was reduced
      from 8.7 +/- 1.5 mm at baseline to 4.3 +/- 1.6 mm after 8 months (P < 0.001), the
      mean gingival recession increased from 1.8 +/- 1.2 mm to 3.3 +/- 0.9 mm, and the
      mean clinical attachment level changed from 10.6 +/- 1.9 mm to 7.6 +/- 1.8 mm (P
      < 0.001). New hard tissue formation was radiographically observed in 26 of the 32
      defects. The present results suggest that the treatment of intrabony periodontal
      defects with Emdogain may lead to significant improvements of all of the
      investigated clinical parameters. However, controlled histologic and clinical
      trials are needed to compare this treatment modality with other conventional and
      regenerative periodontal surgical methods.

PMID- 10635182
TI  - Autogenous bone harvesting: a chin graft technique for particulate and
      monocortical bone blocks.
AB  - The use of the mandibular symphysis for harvesting intraoral autografts in
      implant reconstruction cases is based on the ample supply of donor material, the
      proximity to the recipient site, and the ease of access to the tissue. This
      article discusses the technique of successful bone harvesting from the mandibular
      symphysis. As with other harvesting techniques, morbidity can occur. This report
      demonstrates a low morbidity rate and presents guidelines to help accomplish
      this.

PMID- 10635183
TI  - Split palatal flap. I. A surgical approach for primary soft tissue healing in
      ridge augmentation procedures: technique and clinical results.
AB  - This article describes a surgical procedure to predictably obtain primary closure
      over extraction sockets in the maxilla. The technique offers a valuable treatment
      approach for the achievement of primary soft tissue closure over bone grafts
      and/or occlusive osteopromotive membranes, although the use of an osteopromotive
      membrane may not always be necessary in cases of single-tooth extraction. The
      surgical technique is based on a split-thickness palatal flap in which the
      pediculated deep portion is rotated to cover the grafted alveolus or membrane.
      This procedure was used in a total of 40 sites in 32 consecutive patients; a
      barrier membrane was used in 20 sites. All treated sites allowed proper implant
      placement after healing. Two membranes became prematurely exposed and one was
      removed before implant surgery. Proper soft and hard tissue anatomy was
      predictably obtained prior to implant placement. This surgical procedure is
      useful in preserving and/or augmenting the alveolar ridge prior to or during
      implant placement in cases of advanced alveolar bone loss.

PMID- 10635184
TI  - A technique for compensating for the loose CeraOne screw.
AB  - Clinical experience indicates that implant-supported crowns for the replacement
      of individual molars using the original, regular platform CeraOne protocol (Nobel
      Biocare) infrequently result in gold screws loosening. This article offers a
      technique that may prevent the CeraOne gold screw from working loose. It is
      intended to be a correction for a problem, not a first-time treatment. Also, this
      is a treatment that should be offered only after the prescribed Branemark
      protocol for screw tightening and elimination of excursive contacts has proven
      ineffective.

PMID- 10635185
TI  - The nonresilient hybrid removable prosthesis: treatment of choice for the
      atrophic maxilla.
AB  - This article presents the ments of the nonresilient hybrid removable prosthesis,
      which is the treatment of choice for the atrophic maxilla. The technique
      described may be adapted to yield a predictable outcome that provides functional
      and biomechanical stability that are superior to a resilient over-denture, along
      with a cosmetic and phonetic result that often proves superior to that of the
      fixed prosthesis.

PMID- 10635186
TI  - Treatment of multiple adjacent gingival recessions with the tunnel subepithelial
      connective tissue graft: a clinical report.
AB  - This article describes a surgical periodontal plastic procedure for the coverage
      of multiple adjacent gingival recessions. This surgical technique is based on the
      construction of a tunnel under the gingival tissue by means of a sulcular
      incision beyond the mucogingival line without raising the papillae. A large
      connective tissue graft obtained from the palatal mucosa is introduced through
      this tunnel, covering the adjacent gingival recessions. A suturing technique to
      allow this graft to slip through the tunnel under the gingival tissues and to
      secure and stabilize the graft covering the recessions is described. Twelve-month
      postoperative results are presented from 21 teeth that were treated with this
      technique: 100% root coverage was achieved in 66.7% of the recessions treated,
      with a mean root surface coverage of 91.6%. This study suggests that the use of
      this surgical procedure allows the treatment of multiple adjacent recessions in a
      single procedure with adequate early healing and highly predictable root coverage
      results.

PMID- 10635187
TI  - Precision of CNC-milled titanium frameworks for implant treatment in the
      edentulous jaw.
AB  - PURPOSE: The purpose of this report was to describe a new technique to fabricate
      one-piece, implant-supported titanium frameworks by means of a computer numeric
      controlled (CNC) milling technique, and to compare the fit of these frameworks
      with conventional cast prostheses. MATERIALS AND METHODS: The study comprised 20
      patients who were provided with 5 standard Branemark implants each in the
      edentulous mandible. The fit of the first 10 prostheses with CNC-milled
      frameworks was measured by means of a 3-dimensional photogrammetric technique.
      The distortion of the center point of the framework cylinders was measured in
      relation to the master cast replicas. These measurements were compared with 10
      randomly selected routine prostheses with cast frameworks. RESULTS: No
      significant differences were found between the 2 groups. The 3-dimensional
      distortion of the cylinders in the completed prostheses ranged from 3 to 80
      microns; no passive framework was observed. More distortion was observed in the
      horizontal plane (x and y axes) as compared to the distortion in the vertical
      direction (z axis). CONCLUSION: The precision of fit of the first CNC-milled
      prostheses presented a comparable fit to the conventional cast frameworks.
      Consequently, this new technique could be a valid option for the routine
      fabrication of frameworks for implant prostheses.

PMID- 10635188
TI  - Tooth-implant and implant supported fixed partial dentures: a 10-year report.
AB  - PURPOSE: The use of implants for prosthetic rehabilitation of partially
      edentulous patients is increasing. However, the possibilities of placing implants
      in the posterior part of the mandible are often limited. The purpose of this
      longitudinal study with 10 years of follow-up was to evaluate the use of short
      implants supporting fixed partial dentures (FPD) in the posterior part of the
      mandible, and to compare implant supported FPDs to tooth-implant supported FPDs.
      MATERIALS AND METHODS: The patient material comprised 23 patients with residual
      mandibular anterior teeth, and each patient received FPDs unilaterally. On one
      side the FPD was supported by two implants, and on the other side by one implant
      and one tooth, thus permitting intraindividual comparison. The distribution of
      the two types of FPDs in each jaw was randomized. Implant success rates, marginal
      bone changes, and mechanical complications were studied. RESULTS: The tooth
      implant connection did not demonstrate any negative influences on the overall
      success rates for the 10-year period, nor were the shorter implants found to be
      less favorable. CONCLUSION: It is suggested that a prosthetic construction
      supported by both a tooth and an implant may be recommended as a predictable and
      reliable treatment alternative in the posterior mandible.

PMID- 10635189
TI  - Mandibular overdentures stabilized by Astra Tech implants with either ball
      attachments or magnets: 5-year results.
AB  - PURPOSE: The purpose of this work was to report on the use of implant-stabilized
      overdentures in the mandible using the Astra Tech implant system with either ball
      attachments or magnets as the retentive mechanism. MATERIALS AND METHODS:
      Mandibular overdentures that used ball attachments on 2 implants were provided
      for 13 edentulous patients; 12 edentulous patients were provided with mandibular
      overdentures with magnet retention, using 2 implants in 10 patients and 3
      implants in 2 patients. Once they were comfortable, the participants were placed
      on annual recall. Any other visits were initiated by the patients. Detailed
      records were kept for all visits. At the annual recall the following parameters
      were monitored: plaque levels, mucosal health, marginal bone levels, and the
      patients' assessment of the treatment. The patients were followed for 5 years.
      RESULTS: There was no statistical difference between the 2 groups for mucosal
      health and postinsertion maintenance. The magnet group had more abutment surfaces
      covered with plaque. Statistical analysis of the patients' subjective assessment
      of their treatment showed that the magnet group was less comfortable and chewing
      was less effective. CONCLUSION: The results indicate that both ball attachments
      and magnets used on isolated Astra Tech implants in the mandible are viable
      treatment options. Both attachment mechanisms provided patient satisfaction,
      although the ball attachments were better in this respect than the magnets.

PMID- 10635190
TI  - Effects of thermocycling on the tensile bond strength between resin cement and
      dentin surfaces after temporary cement application.
AB  - PURPOSE: In a previous study the authors found that 2 of 3 tooth conditioners
      examined were able to reduce the negative effect of temporary cement on the bond
      strength between resin cement and teeth. The aim of this study was to evaluate
      the bond durability with the conditioners, as well as their capability for
      temporary cement dissolution. MATERIALS AND METHODS: After eliminating the
      temporary cement with a curette from the bovine dentin surface, a conditioner
      (ethyl dihydrogen phosphate, EP; or methacryloxyethyl dihydrogen phosphate, MEP)
      was applied to the surface and a resin cement was adhered. Tensile bond strength
      measurement, scanning electron microscopic observation, and energy-dispersive
      analysis were carried out without thermocycling and after thermocycling. RESULTS:
      The tensile bond strength gradually decreased with an increase in the number of
      thermocycles. However, specimens treated with EP or MEP showed significantly
      higher tensile bond strength values compared to those that did not receive
      conditioner application (P < 0.0001); EP showed significantly higher tensile bond
      strength values compared to the specimens that did not receive both temporary
      cement and conditioner application (P < 0.0001). The scanning electron
      microscopic, energy-dispersive, and solubility analyses suggest that both
      conditioners have the capability of dissolving temporary cement remnants.
      CONCLUSION: Both EP and MEP have potential value as conditioners to reduce the
      negative effect of temporary cement on the bond strength between resin cement and
      dentin and to improve the bond durability.

PMID- 10635191
TI  - Assessing the quality of clinical procedures and technical standards of dental
      laboratories in fixed partial denture therapy.
AB  - PURPOSE: This study was conducted to assess the quality of impressions and tooth
      preparations sent to dental laboratories in Jordan and to determine the technical
      capabilities of these laboratories to construct fixed partial dentures. MATERIALS
      AND METHODS: A sample of 136 impressions and stone casts were examined for
      clinical errors in 35 laboratories that construct fixed partial dentures. They
      were sorted into unusable, unsatisfactory, acceptable, or satisfactory
      categories. The type of impression material and tray, opposing arch impressions,
      and occlusal records were noted. Instructions to technicians were assessed for
      completeness and clarity. Information regarding laboratory staff and equipment
      were collected. RESULTS: Half of the specimens inspected were categorized as
      unusable or unsatisfactory; these were found in commercial laboratories. They
      showed at least one clinical error such as drags or indefinite finishing lines in
      impressions and inadequate reduction, undercuts, or obvious taper on stone casts.
      Alginate impression material was used for 65% of the cases. Only 27% of specimens
      were accompanied with instructions; of these 22% were graded poor. No occlusal
      records were available with 54% of the specimens and no articulators were used
      except in dental school laboratories. The dental schools and some commercial
      laboratories had the best staff and equipment and were more capable of
      fabricating fixed partial dentures than those of the Ministry of Health and the
      Royal Med cal Services. CONCLUSION: The quality of abutment preparation and
      impressions were unsatisfactory or unusable in 50% of cases. Of the 37 available
      instructions 8 were not clear. The dental schools and some commercial
      laboratories were technically capable of producing good quality fixed partial
      dentures.

PMID- 10635192
TI  - Long-term cytotoxicity of dental casting alloys.
AB  - PURPOSE: Current in vitro cytotoxicity tests for dental casting alloys may be
      inadequate because they use a short-term test (generally < 168 h) for a material
      that is present in the mouth for years. A modified in vitro test was used to test
      the cytotoxicity of 8 dental casting alloys and 3 pure metals. This modified test
      attempted to simulate the long-term effects of dental casting alloys in the
      mouth. MATERIALS AND METHODS: Alloys were tested in cell culture either
      immediately after polishing (initial) or after 10 months of conditioning in a
      biologic medium containing serum proteins. The cytotoxicities of the 2 conditions
      were then compared. Alloys were repolished to assess the reversibility of the 10
      month conditioning. RESULTS: Alloys with little initial cytotoxicity showed no 10
      month cytotoxicity. Alloys with significant initial toxicity showed significantly
      less toxicity at 10 months. No alloy increased in toxicity after conditioning.
      Repolishing multiple times did not necessarily reestablish the initial
      cytotoxicity response. CONCLUSION: The results indicate that short-term
      cytotoxicity tests may not accurately measure the long-term cytotoxicity of these
      types of alloys.

PMID- 10635193
TI  - Investigations into the failure of dental magnets.
AB  - PURPOSE: The aim of this study was to determine the mechanisms of failure of
      magnets used for denture retention. MATERIALS AND METHODS: Magnets were retrieved
      from dentures that had failed after 4 to 18 months of clinical use. The magnets
      were sectioned and the failure modes were evaluated using optical or scanning
      electron microscopy. RESULTS: The magnetic retention system investigated consists
      of a neodymium-iron-boron magnet sandwiched in a stainless steel keeper, capped
      with a titanium dome, and sealed with epoxy resin. The diffusion of moisture
      through the epoxy seal and the breakdown of the encapsulating material led to
      corrosion of the magnet. In both cases, a loss in retention occurred as the
      corrosion products weakened the overall magnetic attraction. CONCLUSION: The
      failure of magnets may occur by either breakdown of the epoxy seal or breakdown
      of the encapsulating material. Both problems need to be addressed to prolong the
      life span of these magnets.

PMID- 10635194
TI  - The effect of film thickness and surface texture on the resistance of cemented
      extracoronal restorations to lateral fatigue loading.
AB  - PURPOSE: The aim of the present study was to assess the effect of cement-film
      thickness and surface texture (roughness) on the resistance of cemented crowns to
      dynamic lateral loading. MATERIALS AND METHODS: Crown and abutment analogues were
      cemented using zinc-oxide-eugenol, zinc-phosphate, glass-ionomer, and composite
      cements. The space left for the cement lute was 0.02, 0.05, 0.1, 0.2, and 0.5 mm.
      The 3 degrees of surface texture subjected to investigation were (1) polished
      with up to 4,000-grit paper, (2) sanded using a 1,000-grit paper, and (3)
      sandblasted with 50-micron aluminum oxide. Testing was conducted according to the
      staircase procedure. The specimens were subjected to rotational fatigue loading
      until the cement bond failed or the components reached 1,000,000 stress cycles.
      RESULTS: The results showed that the relation between cement thickness and
      resistance to dynamic lateral loading is hyperbolic. For the zinc-oxide-eugenol,
      the zinc-phosphate, and the glass-ionomer cements increasing surface texture had
      a moderate effect. For composite cement, sandblasting doubled the resistance to
      dynamic lateral loading. For both parameters tested (cement thickness and surface
      texture), the ascending order of resistance was: zinc-oxide-eugenol, zinc
      phosphate, and glass-ionomer cements. Crowns cemented with composite cement
      presented the highest resistance to dynamic lateral loading. CONCLUSION: Within
      the confines of the present experimental design, it is concluded that (1)
      decreasing the width of the cement layer increases the resistance to dynamic
      lateral loading, and (2) texturing the surface of the abutment and the
      restorations as after sandblasting increases the resistance to dynamic lateral
      loading.

PMID- 10635195
TI  - Mandibular incisor position for English consonant sounds.
AB  - PURPOSE: The purpose of this study was to describe the mandibular incisor
      positions for the 24 consonant sounds of the English language. Further aims were
      to determine if the incisor format for each sound is affected by its position in
      a word, or by combination with an open or closed vowel. MATERIALS AND METHODS: A
      total of 30 young adult subjects had their incisal positions determined using an
      electrognathographic technique during performance of a number of speech tests.
      RESULTS: The mean values of the 24 consonants, in the vertical direction, showed
      a range from the intercuspal position of 2.5 mm for a sibilant sound to 11.7 mm
      for the /H/ sound, and an anteroposterior range of 1.4 mm anterior for a sibilant
      sound to 1.8 mm posterior for the /M/ sound. The range in the mean lateral
      dimension was always less than 1 mm on either side of the midline. The placement
      of a sound in the initial or final position in a word had no effect on the
      incisal position. The degree of vertical opening was significantly greater for 8
      of the consonant sounds when in combination with an open vowel sound. The
      anteroposterior and lateral positions were unaffected by vowel association.
      CONCLUSION: The incisor position for consonant sounds is unaffected by initial or
      final word placement. Some consonant sound positions are affected by combination
      with an open or closed vowel sound. Sibilant sounds produced a clinically
      acceptable measure of the most superior and anterior speaking positions in all
      subjects.

PMID- 10635196
TI  - Patient evaluation of treatment success as related to denture tooth type.
AB  - PURPOSE: Tooth selection is considered an important factor in the construction of
      complete dentures that function harmoniously and comfortably and preserve the
      denture-supporting tissues. To bring a scientific background to clinical
      impressions, the hypothesis that different cusp angles bring different levels of
      patient satisfaction was tested. MATERIALS AND METHODS: Four different occlusal
      schemes were compared. The dependent variables (3 groups of visual analogue
      scores of patient satisfaction) were analyzed by means of multivariate analysis
      of variance (MANOVA) for repeated measures. RESULTS: All MANOVAs showed
      nonsignificant results for the effect of tooth type on the 3 groups of variables
      (P values between 0.1 and 0.8). CONCLUSION: The results did not show
      statistically significant differences in patient satisfaction among the different
      occlusal schemes. It is recommended that future research use more sensitive
      instruments to evaluate this specific aspect of treatment success.

PMID- 10635197
TI  - From bite to mind: TMD--a personal and literature review.
AB  - PURPOSE: The purpose of this study was to present a personal view of the
      development of prevailing opinions about temporomandibular disorders (TMD) during
      the last half century from a mechanistic to a psychosomatic concept. It also
      presents some hypotheses concerning: (1) the role of stress in the etiology of
      human oral parafunctions and its relationship to oral stereotypies in domestic
      animals; and (2) the pathogenetic mechanisms of masticatory muscle pain.
      MATERIALS AND METHODS: The basis for this article was a review of personal
      experiences derived from clinical and research work with TMD patients. Studies of
      both older and more recent literature on TMD and related disorders--especially in
      the fields of stress research, psychosocial medicine, occupational medicine, and
      etiology--were also used. RESULTS: A clear line is found in the development of
      the ideas on etiology, pathogenesis, and therapy of TMD, from the mechanistic
      attitude of Costen syndrome through the introduction of psychologic and
      psychophysical theories by the Columbia and Chicago schools to the now
      increasingly accepted biopsychosocial concept and the view of refractory TMD as a
      chronic pain condition. CONCLUSION: The formerly dominant bite-centered therapies
      -including intraoral appliances, the effects of which still are unexplained-
      appear to be increasingly banished to the domain of placebo Hence, to an ever
      increasing extent occlusal treatments are replaced by physiotherapy and cognitive
      behavior therapy. The presented hypotheses may have implications for the
      understanding of the origin of oral parafunction and masticatory muscle pain.

PMID- 10635198
TI  - Clinical and technical aspects of implant-supported restorations in the
      edentulous maxilla: the fixed partial denture design.
AB  - PURPOSE: The aim of the present article was to describe the treatment planning
      for an implant-supported maxillary fixed prosthesis and the clinical procedure
      involved, including the laboratory fabrication sequence. MATERIALS AND METHODS:
      If patients request a fixed prosthesis to restore the edentulous maxilla, it is
      essential to decide as soon as possible whether this prosthesis design can
      satisfy the requirements of esthetics, phonetics, comfort, and function. Thus,
      the crucial clinical factors need to be checked during examination. Furthermore,
      the relationships between ideal implant angulation, available bone, and intended
      crown should be assessed using reformatted computed tomography. RESULTS: In
      patients with minimal bone resorption and limited intermaxillary space, implants
      can usually be placed in the prosthetically driven implant position for a fixed
      prosthesis. To evaluate and optimize esthetics, biology, and function, a fixed
      provisional restoration should be inserted for a 6-month diagnostic period. The
      ideal provisional then serves as a guide for the final restoration. CONCLUSION:
      If clinical and radiologic diagnostics indicate that an implant-supported fixed
      complete denture is feasible, meticulous presurgical planning, precise execution
      of implant positioning, and a progressive prosthetic treatment sequence are
      required. The ceramometal fixed implant-supported restoration can then be
      established in an ideally prepared and matured oral environment.

PMID- 10635199
TI  - A preliminary report on continuous recording of salivary pH using telemetry in an
      edentulous patient.
AB  - PURPOSE: This study reports on the development and evaluation of a telemetry
      system for recording salivary pH. MATERIALS AND METHODS: The system used an
      iridium-oxide pH sensor (Metoxy sensor) and was housed inside a mandibular
      complete denture. It transmitted the data using the AM band (radio frequency of
      12.3 MHz) and had a maximum power output of approximately 1 mW with a 3-V lithium
      battery (capacity 190 mAh). For the clinical evaluation, a 69-year-old woman who
      was edentulous and had no systemic disease was the subject. RESULTS: Under the
      conditions of the study, the system was able to operate for 19 hours. The maximum
      error of transmitted pH data values was pH 0.15 within the range from pH 5.0 to
      9.0. The evaluation of the test subject showed that this system operated without
      problems, and that the pH levels responded appropriately. CONCLUSION: The
      developed system was shown to successfully record salivary pH, and it functioned
      as expected in a single test subject.

PMID- 10635200
TI  - Ceramic implant abutments used for short-span fixed partial dentures: a
      prospective 2-year multicenter study.
AB  - PURPOSE: This is a 2-year report from an ongoing prospective 5-year multicenter
      study. The aim of the study was to evaluate the short- and long-term clinical
      function of CerAdapt ceramic abutments supporting short-span fixed partial
      dentures (FPD). MATERIALS AND METHODS: Initially, 105 Branemark System implants
      were placed in a total of 32 patients at 3 different clinics. After initial
      healing 103 implants remained. For the support of 36 FPDs, 53 ceramic and 50
      titanium abutments were connected, 19 on ceramic and 17 on titanium abutments.
      RESULTS: All patients remained in the study after 2 years. There was a cumulative
      survival rate of 97.1% for implants and a cumulative success rate of 97.2% for
      FPDs (94.7% for ceramic and 100% for titanium abutment-supported FPDs). One of 53
      ceramic but none of 50 titanium abutments failed, giving a cumulative success
      rate of 98.1% and 100%, respectively, for the abutments. Soft tissue around
      abutments and adjacent teeth appeared healthy. More crown margins were placed
      submucosally at titanium (31%) than at ceramic (14%) abutments, and the level of
      the periimplant mucosa was relatively stable in relation to the abutment/crown.
      No differences were seen between ceramic and titanium abutments regarding
      bleeding of the periimplant mucosa. There was a minimal marginal bone loss
      recorded after 1 year, which was slightly more at titanium (0.4 mm) than at
      ceramic (0.2 mm) abutments. All patients and dentists were satisfied with the
      achieved esthetic result and no FPD was remade because of compromised esthetics.
      CONCLUSION: So far the ceramic abutments have worked very well and the 2-year
      results have been very encouraging for CerAdapt abutments supporting short-span
      FPDs. However, ceramic materials tend to undergo static fatigue, and it is
      therefore important to wait for the 5-year results before making any more
      definite statement about the long-term prognosis for CerAdapt abutments.

PMID- 10635201
TI  - Resin pattern material with low polymerization shrinkage.
AB  - PURPOSE: The purpose of this study was to develop a material with low
      polymerization shrinkage for resin patterns to improve the fit of a long
      superstructure to implants. MATERIALS AND METHODS: Three different chemical
      substances were added at 1, 2, 3, 5, 10, and 20 wt% to the liquid component of a
      self-curing acrylic resin. Specimens for measuring shrinkage during self curing
      were prepared in a metal mold that took the form of a conical cavity with
      slightly tapered walls. The specimens were prepared using three different
      methods: (1) a brush-on technique, (2) an injection method, and (3) an injection
      press method. The percentage of linear shrinkage was calculated from the
      protrusion of the specimen from the bottom of the cavity. RESULTS: The injection
      press method and the brush-on method gave the lowest polymerization shrinkage
      results (P < 0.05). The standard deviation of the former method was smaller than
      that of the latter. The linear shrinkage in the injection-press method decreased
      with the increase of the powder-to-liquid ratio (P < 0.05). All three additives
      reduced shrinkage to about 1/3 of the shrinkage of the basic resin using the
      injection-press method and a 2.00:1.00 powder-to-liquid ratio. CONCLUSION: The
      addition of three different chemical substances to liquid reduces linear
      shrinkage to about 1/3 of the shrinkage of the original self-curing acrylic
      resin.

PMID- 10635202
TI  - The effect of surface treatments on the bond strength of a nonprecious alloy
      ceramic interface.
AB  - PURPOSE: The purpose of this study was to compare the effect of seven different
      alloy surface treatments on the bond strength of the porcelain-metal interface.
      MATERIALS AND METHODS: Three layers of opaque porcelain and a measured thickness
      of dentin porcelain were applied to nickel-chromium alloy. A tensile bond
      strength test was used. RESULTS: The alloy surface treatment that exhibited the
      highest bond strength was sandblast + surface grinding + sandblast + de-gas,
      whereas the alloy surface treatment that exhibited the lowest bond strength was
      sandblast + surface grinding + sandblast + steam cleaning + de-gas. There was a
      significant difference between the two methods (P < 0.05). CONCLUSION: It was
      concluded that de-gassing the alloy prior to porcelain application increased the
      bond strength and excess surface grinding of the alloy reduced bond strength;
      steam cleaning the alloy surface prior to de-gassing and porcelain application
      also significantly reduced the bond strength.

PMID- 10635203
TI  - Esthetic outcome of implant-supported single-tooth replacements assessed by the
      patient and by prosthodontists.
AB  - PURPOSE: The objective of this study was to assess and compare patients' and
      clinicians' judgments of the esthetic outcome of implant-supported single-tooth
      replacements. MATERIALS AND METHODS: In all, 29 patients with 41 single implant
      supported crowns in the maxillary anterior region participated in the study. The
      esthetic outcome of the implant-supported crowns was assessed by the patients and
      by 5 prosthodontists by means of a questionnaire in which various esthetics
      related variables were addressed and responded to using visual analogue scales.
      Multiple regression analyses were used to evaluate the influence of the variables
      on the "overall satisfaction" with the implant-supported crown. RESULTS: Most
      variables in the patients' assessments revealed mean values above 90% and median
      values close to 100%. No single factor used in the multiple regression analysis
      was found to influence a patient's satisfaction with appearance of the crown at a
      statistically significant level. The clinicians' degree of satisfaction was for
      all variables lower than that of the patients. In 89% of the cases the clinicians
      could correctly locate the single implant-supported crown. Among the variables
      assessed, surrounding soft tissue appearance and form of the crown had the
      strongest influence on the clinician's overall satisfaction with the appearance
      of the crown. CONCLUSION: Appreciation of the esthetic outcome of the single
      implant-supported crowns was rated higher by the patients than by the
      prosthodontists. Furthermore, factors considered by professionals to be of
      significance for the esthetic result of the restorative treatment may not be of
      decisive importance for the patient's satisfaction.

PMID- 10635204
TI  - In vitro evaluation of fit of adhesively luted ceramic inlays.
AB  - PURPOSE: The purpose of this study was to evaluate both marginal and overall
      adaptation of 4 adhesively luted ceramic inlay systems. MATERIALS AND METHODS: A
      total of 40 extracted teeth were restored with mesio-occlusodistal ceramic inlays
      using 4 different techniques: Colorlogic, IPS Empress, Celay direct, and Celay
      indirect. After cementation with a resin luting agent, the samples were sectioned
      along a mesiodistal line passing through the center of the restoration. The
      thickness of the cement was measured at the margins and at several points along
      the inside of the restorations by means of a stereomicroscope fitted with a
      measuring grid. RESULTS: The results were analyzed by one-way analysis of
      variance. The marginal precision of IPS Empress and Colorlogic inlays averaged
      below 50 microns. Marginal precision of Celay inlays averaged between 110 and 130
      microns. IPS Empress and Celay inlays showed a uniform distribution of the cement
      along the entire prepared surface. Colorlogic inlays showed an uneven
      distribution of the cement film. CONCLUSION: IPS Empress inlays showed the best
      clinical features compared to Colorlogic and Celay inlays.

PMID- 10635205
TI  - Equilibrium strengths of denture polymers subjected to long-term water immersion.
AB  - PURPOSE: This study characterized the effect of water immersion on the strength
      of denture polymers. MATERIALS AND METHODS: Four denture-base polymers and four
      denture-reline polymers were tested for flexural strength at proportional limits
      (FSpl) at 24 hours and at monthly intervals. The equilibrium strength of each
      polymer was estimated. RESULTS: The denture polymers took from 24 hours to 4
      months to reach their equilibrium strength. The equilibrium strengths of the
      denture polymers were significantly different. CONCLUSION: Water immersion
      affected the strength of most denture polymers. Different denture polymers
      behaved differently in response to water immersion.

PMID- 10635206
TI  - Influence of occlusal scheme on the pressure distribution under a complete
      denture.
AB  - PURPOSE: The purpose of this study was to estimate which occlusion offers the
      best conditions of pressure distribution on the supporting structure under a
      complete denture when crushing food. MATERIALS AND METHODS: Simulated maxillary
      and mandibular complete dentures with three different posterior occlusal schemes-
      fully balanced occlusion, lingualized occlusion, and monoplane occlusion--were
      fabricated. Eight pressure transducers were placed in the basal surface of a
      mandibular denture. The pressure distribution on the mandibular edentulous mouth
      model with 1.5-mm-thick artificial tissue under a complete denture was recorded
      when crushing three different foods: soft food (kamaboko), peanuts, and carrot.
      The mean pressure values at each measurement point and the force required for
      each test were compared using one-way analysis of variance with P < or = 0.05
      representing statistical significance. RESULTS: The required force for crushing a
      soft food or carrot in the left molar region in monoplane occlusion was
      significantly larger than that required in fully balanced occlusion or
      lingualized occlusion. In crushing soft food, fully balanced occlusion showed
      significantly higher pressure values on the working side than in monoplane
      occlusion or lingualized occlusion. In crushing the carrot, the pressure values
      in fully balanced occlusion and in lingualized occlusion were significantly lower
      than those in monoplane occlusion. CONCLUSION: These results demonstrate that
      with fully balanced occlusion and lingualized occlusion a large occlusal force is
      not needed for crushing hard food, and the stress to the supporting tissues is
      smaller than with monoplane occlusion.

PMID- 10635207
TI  - Mechanical properties of 2 new addition-vulcanizing silicone prosthetic
      elastomers.
AB  - PURPOSE: This study evaluated some mechanical properties of 2 newly introduced,
      addition-type silicone prosthetic elastomers (Cosmesil and Episil). MATERIALS AND
      METHODS: The properties evaluated were tensile strength, modulus at 100%
      elongation, elongation at break, tear strength, and hardness. The properties
      tested were selected because of their clinical significance for fabricating
      facial prostheses. RESULTS: Episil showed greater tensile strength (P = 0.0002),
      elastic modulus (P = 0.0001), hardness (P = 0.0002), and tear strength (P =
      0.0004) than Cosmesil material. Cosmesil exhibited a higher elongation at break
      (P = 0.0002) than Episil. CONCLUSION: Cosmesil and Episil showed reasonable
      properties as facial prosthetic elastomers and neither was superior for all
      properties tested. Both materials showed favorable combinations of elongation at
      break and tear strength.

PMID- 10635208
TI  - Photogrammetry--an alternative to conventional impressions in implant dentistry?
      A clinical pilot study.
AB  - PURPOSE: The purpose of this clinical pilot study was to describe a
      photogrammetric technique to determine implant positions in the oral cavity, and
      to test and compare this technique to conventional impression/master cast
      procedures for fabrication of titanium frameworks with a computer numeric
      controlled (CNC) milling technique. MATERIALS AND METHODS: Implant positions were
      recorded by means of conventional impressions/master casts as well as intraoral 3
      dimensional photogrammetric measurements in 2 patients who were provided with 5
      Branemark implants each in the edentulous mandible. For each patient 2 titanium
      frameworks were made by means of a CNC milling technique (All-in-One). Both
      frameworks had an identical design, but the orientations of the framework
      cylinder fit surfaces were machined either from measurements from the master
      casts or from the intraoral photogrammetric measurements. The frameworks were
      tried for fit in the oral cavity and on the master casts. RESULTS: Both cases
      showed different precision of fit when comparing the 2 frameworks on the master
      casts. One of the 2 photogrammetric frameworks was not considered acceptable when
      tried on the models. In the oral cavity, however, all 4 frameworks presented
      comparable fit, and all were accepted for clinical use. CONCLUSION: The clinical
      experiences with try-in of the 4 different frameworks indicated that the
      photogrammetric technique could be a valid option for conventional impressions
      when using CNC milling fabrication in implant dentistry. The different results
      from the model and oral examinations also imply the difficulties of assessing
      clinical fit when testing fit at the master cast level only.

PMID- 10635216
TI  - A new method to assess the results of instrumentation techniques in the root
      canal.
AB  - In the present study, the shape of the root canal was assessed with pre- and
      postinstrumentation silicone impressions. Curved root canals of 30 extracted
      molars were instrumented with the Canal Leader (CL), the ProFile System (PF), and
      hand instrumentation (HI). Photographs from each impression were digitized, and
      the enlargement of the canals was computed by substracting the preinstrumentation
      from the postinstrumentation images. Technical errors of preparation were also
      recorded. There was no significant difference in total dentin removal between the
      systems. However, CL removed significantly more dentin from the convex side of
      the root canal than PF. Instrument separation occurred in five cases, only with
      PF. Roughness of canal walls was recorded significantly more often with the use
      of CL than with PF or HI. CL also produced a significantly higher incidence of
      elbow formation, compared with PF or HI. With this method of assessment, it was
      possible to record details and differences between the tested instrumentation
      techniques.

PMID- 10635217
TI  - Formation of crystals on the surface of calcium hydroxide-containing materials in
      vitro.
AB  - The purpose of the present study was to examine the surface of calcium hydroxide
      containing materials when treated in different in vitro conditions. Five calcium
      hydroxide-containing materials (Dycal, Nu-Cap, Life, Sealapex, and Apexit) and
      two control calcium hydroxide-free materials (Roth 811 and AH26) were tested. The
      materials were placed onto Teflon discs or root dentin samples; maintained in
      distilled water or phosphate-buffered saline, or culture medium supplemented or
      not supplemented with fetal calf serum; incubated at 37 degrees C in humidified
      atmosphere containing or not containing 5% CO2; and examined by scanning electron
      microscope. The results demonstrated precipitation of simple crystal units or
      organized crystalline structures in the calcium hydroxide-containing specimens
      treated in all experimental conditions, except those maintained in distilled
      water without 5% CO2. X-ray elemental microanalysis of the different crystalline
      structures showed one or two peaks corresponding to calcium or calcium and
      phosphorus. These data indicate that the crystals formed by reactions of calcium
      ions released from the calcium hydroxide-containing materials with the
      environmental ions might modify the material surface, especially in the presence
      of substrate adhesion molecules, such as fibronectin. This modification might
      play an important role in the regulation of cell adhesion and the initiation of
      new matrix synthesis.

PMID- 10635218
TI  - Scanning electron microscopic analysis of diseased and healthy dental hard
      tissues after Er:YAG laser irradiation: in vitro study.
AB  - The aim of this study was to treat carious lesions, sound dentin, and enamel
      either with conventional methods or with an Er:YAG laser and to compare the
      results. Thirty freshly extracted carious human teeth were divided into two
      groups. In the first group, lesions were treated with burs in a dental handpiece;
      in the second group, we used the Er:YAG laser with parameters recommended by the
      manufacturer (Kavo). After treatment, the teeth were prepared for scanning
      electron microscopic observation. On laser-treated teeth, scaly, flaky, rough
      surfaces were seen: surfaces were clean with several morphological reliefs that
      may enhance bonding resin restoration. The Er:YAG laser beam can ablate carious
      dentin with an energy level of 250 mJ at 2 Hz. Sound dentin can be cut at 300 mJ
      and 2 Hz; for enamel, 350 mJ and 3 Hz are required. The Er:YAG laser seems to be
      effective in the treatment of carious lesions and in cavity preparation in vitro.

PMID- 10635219
TI  - Antimicrobial effect of camphorated chloroxylenol (ED 84) in the treatment of
      infected root canals.
AB  - During and after chemomechanical preparation, particularly before the definitive
      filling of an infected root canal, a temporary intracanal dressing with an
      antimicrobial activity is generally indicated. Therefore, the aim of this study
      was to investigate the antimicrobial effect of ED 84, a liquid root canal
      disinfectant containing chloroxylenol (10%) and camphor (15%), against selected
      test organisms (Staphylococcus aureus, Streptococcus faecalis, Escherichia coli,
      and Candida albicans) both in vitro and under clinical conditions, using
      extracted teeth. With a contact time of 180 min between undiluted ED 84 and the
      four bacterial suspensions in the canal, there was a 2 to 3 log reduction in the
      number of organisms. Under in vitro conditions, the reduction was even greater
      than 3 logs. When using a liquid medication as a temporary root canal dressing
      for a duration of approximately 2 days, ED 84 can definitely be used.

PMID- 10635220
TI  - Longitudinal microleakage evaluation of Super-EBA as a root-end sealing material.
AB  - This study evaluated the sealing ability of fast and regular set Super-EBA with
      different powder-to-liquid ratios as a root-end filling material. Fifty extracted
      maxillary central incisors were uniformly cleaned and shaped using a crown-down
      technique with Gates-Glidden drills and Profile series 29.04 taper rotary
      instruments. After root-end resection and ultrasonic preparation, 48 root
      sections were randomly assigned to 4 groups of 12 teeth each and filled with a
      thick or thin mix of fast or regular set Super-EBA. Fast and regular set Super
      EBA were mixed to a thick (1 scoop powder:1 drop liquid) or a thin (1 scoop
      powder:2 drops liquid) consistency. Positive and negative controls were used.
      Microleakage was assessed at 24 h, 72 h, 1 wk, 2 wk, 4 wk, 6 wk, and 8 wk using a
      fluid filtration system. There were no significant differences in the
      microleakage measured for any group at any of the time points evaluated. These
      results suggest that either fast or regular set Super-EBA mixed to various
      consistencies may be acceptable for root-end filling.

PMID- 10635221
TI  - Survey for collagenase gene prtC in Porphyromonas gingivalis and Porphyromonas
      endodontalis isolated from endodontic infections.
AB  - Collagenase is a potential virulence factor shown to be expressed by
      Porphyromonas gingivalis associated with periodontal disease. The purpose of this
      study was to use the polymerase chain reaction (PCR) to detect the presence of
      the collagenase gene (prtC) in 21 strains of Porphyromonas species isolated from
      endodontic infections. Type strains for P. gingivalis (ATCC 33277), P.
      endodontalis (ATCC 35406), Prevotella intermedia (ATCC 25611), and Prevotella
      nigrescens (ATCC 33563) were used as controls. When PCR primers specific for the
      16S ribosomal RNA gene of P. gingivalis or P. endodontalis were used, 16 of the
      strains were identified as P. gingivalis, and five strains were identified as P.
      endodontalis. The presence of the prtC gene for collagenase was detected using
      PCR. Amplicons were analyzed by agarose gel electrophoresis, with an 815 bp
      amplicon representing the presence of the collagenase gene. Type strain ATCC
      33277 and all 16 clinical isolates of P. gingivalis produced the collagenase gene
      amplicon. Neither type strain ATCC 35406 nor the five strains from clinical
      isolates of P. endodontalis produced the collagenase gene amplicon. These results
      indicate that P. gingivalis from endodontic infections possesses the prtC gene.
      P. endodontalis does not seem to exhibit prtC. The virulence of P. gingivalis may
      be related to its production of collagenase.

PMID- 10635222
TI  - Super-EBA as an endodontic apical plug.
AB  - Forty extracted human single-rooted teeth were sequentially instrumented with
      nickel-titanium rotary files to a size 0.36 mm at the working length. Ten teeth
      were randomly assigned to the two control groups. The other 30 teeth were
      randomly divided into three groups and were obturated by a 5-mm apical plug of
      either Super-EBA, IRM, or laterally condensed gutta-percha and Roth's sealer.
      After 2 days, and at 1 month, the samples were tested for microleakage by the
      fluid filtration system under 15 psi. The negative controls were used to consider
      the time that it took the fluid filtration system to stabilize. A one-way
      analysis of variance showed that, at 1 month post obturation, there was no
      statistical difference in the ability of the three materials to seal the apex
      from coronal microleakage. However, at 2 days, Super-EBA gave a significantly
      better seal than IRM or laterally condensed gutta-percha and sealer.

PMID- 10635223
TI  - Corrosion and cytotoxicity evaluation of thermafil endodontic obturator carriers.
AB  - The purpose of this study was to evaluate the in vitro cytotoxicity of two
      metallic and two plastic Thermafil carrier materials, and to separately evaluate
      the in vitro corrosion behavior of the two metallic carriers. Stainless-steel, Ti
      6AI-4V, Polysulfone, and Vectra carriers were evaluated for cytotoxicity using
      the ISO-recommended agar overlay test. The two metallic carriers were
      additionally corrosion tested in 0.9% NaCl solution for 174 wk, at 37 degrees C.
      Elemental analyses of the corrosion solutions were periodically conducted using
      inductively coupled plasma-mass spectroscopy. Agar overlay results showed that
      the four carrier materials were not cytotoxic to L929 fibroblasts. Inductively
      coupled plasma-mass spectroscopy results showed that the metallic materials had
      small mass loss rates. Scanning electron microscopy showed no evidence of pitting
      or crevice corrosion.

PMID- 10635224
TI  - A scanning electron microscopic study of in vivo ultrasonic root-end
      preparations.
AB  - The purpose of this in vivo study was to evaluate root-ends for cracks after root
      resection and again after ultrasonic root-end preparation in patients undergoing
      endodontic surgery. Endodontic surgery was performed on 25 roots from 20
      patients. In vivo vinyl polysiloxane impressions were made after root resection
      and again after ultrasonic root-end preparations. Epoxy resin casts were made
      from the impressions and scanning electron micrographic examination of the root
      end replicas was performed. There was no evidence of cracks after root resection.
      One incomplete canal crack was evident after ultrasonic root-end preparation.

PMID- 10635225
TI  - Maxillary second molar with two palatal roots.
AB  - A case report is presented describing the endodontic treatment of a maxillary
      second molar with two palatal roots.

PMID- 10635226
TI  - Zebra XVII. Part 1: The case of the elusive gutta-percha.

PMID- 10635227
TI  - Restoration of partially edentulous patients using customized implant abutments.
AB  - The ideal placement of implants is not always possible in partially edentulous
      patients. The diverse and unique implant positions that occur in clinical
      practice may be difficult or impossible to restore through the use of
      conventional abutments. Customized abutments permit the fabrication of aesthetic
      restorations that correct deficiencies in implant angulation, alignment, and
      position. These abutments also enhance the soft tissue emergence profile of the
      restorations and allow the prosthetic margins to be properly positioned in all
      dimensions. Additional benefits include ease of treatment delivery and
      comparative expense.

PMID- 10635228
TI  - Utilization of ceramic optimized polymer restorations in the anterior region.

PMID- 10635229
TI  - Implant anchorage for the occlusal management of developmental defects in
      children: a preliminary report.
AB  - Congenital anomalies and developmental defects of the face and jaws often present
      orthodontic anchorage challenges in which the residual dentition cannot be
      adequately positioned for restorative objectives. This article presents a method
      of classification for the formulation of implant-based treatment protocols in
      children, reviews the application of implants in the developing dentition, and
      provides guidelines for occlusal treatment. Procedures performed according to the
      protocols outlined in this article will facilitate orthodontics and orthopedic
      movement and accelerate three-dimensional jaw movement by sutural distraction of
      basal bone.

PMID- 10635230
TI  - Craniofacial prostheses retained with osseointegrated implants.

PMID- 10635231
TI  - Multidisciplinary full-mouth restoration with porcelain veneers and laboratory
      fabricated resin inlays.
AB  - Recent advances in dental materials, laboratory technology, and adhesive
      protocols have significantly expanded the contemporary restorative armamentarium.
      Utilized in combination with comprehensive treatment planning, these innovations
      enable clinicians to provide enhanced aesthetic care that achieves the increasing
      expectations of their patients. Using a detailed case presentation, this article
      highlights the harmonious integration of modern smile design, material selection,
      and interdisciplinary communication that must be addressed in order to deliver
      optimal treatment with porcelain laminate veneer and laboratory-fabricated resin
      inlay restorations.

PMID- 10635232
TI  - Treatment options for the exposed vital pulp.
AB  - The exposure of dental pulp generally occurs as the result of accidental trauma
      or preparation techniques utilized during the restoration of carious lesions.
      While frank carious exposures are optimally treated with pulpectomy and root
      canal therapy, the ideal treatment of mechanically exposed pulps has remained
      controversial. This article describes the indications, clinical techniques, and
      prognosis for direct pulp capping and partial pulpotomy.

PMID- 10635233
TI  - Considerations in the use of polymer and fiber-based indirect restorative
      materials.
AB  - Restorative materials and techniques are constantly refined in order to address
      the aesthetic expectations of patients. Second-generation laboratory-fabricated
      composite materials have recently been developed to combine the advantages of
      porcelain with composite resin. This class of biomaterial can be utilized in a
      variety of direct and indirect clinical applications than include inlay/onlay
      restorations, full-coverage crowns, fixed partial dentures, and implant-supported
      prostheses. This article reviews considerations for the use of these materials
      from clinical indications through cementation.

PMID- 10635234
TI  - Restoration of maxillary anterior teeth with porcelain laminate veneers.

PMID- 10635235
TI  - Shade matching and communication in conjunction with segmental porcelain buildup.
AB  - To the majority of patients, the aesthetic appearance of a restoration is often
      as important as its biological compatibility and function. While technological
      advancements have significantly improved the procedures and biomaterials utilized
      to fabricate ceramic restorations, the definitive result must address these
      increasing aesthetic expectations. A means of properly matching a crown
      restoration with the surrounding natural dentition is therefore critical. This
      article discusses shade communication between the members of the restorative team
      as well as ceramic layering techniques that can be utilized to achieve enhanced
      aesthetic results.

PMID- 10635236
TI  - Bonding agent as an instrument lubricant: potential effect on marginal integrity.

PMID- 10635237
TI  - Etiology and identification of oral cancer.

PMID- 10635239
TI  - A metal-free fiber-reinforced replacement of a fractured tooth--a case report.

PMID- 10635238
TI  - Predictable elastomeric impressions in advanced fixed prosthodontics: a
      comprehensive review.
AB  - Despite advances in dental material technology, the predictable procurement of
      accurate impressions for the fabrication of complex fixed prosthodontic
      restorations remains an elusive objective. The technical challenges and potential
      negative sequelae are exponentially magnified in advanced applications that
      involve multiple abutments and preparatory phases. A protocol for consistently
      achieving accurate impressions with the use of polyether impression materials and
      automatic instrumentation is presented and illustrated with multiple clinical
      examples. The technique is capable of yielding reliable results in extensive
      cases and requires minimal support from auxiliary personnel.

PMID- 10635240
TI  - Immediate core buildup of endodontically treated teeth: the rest of the seal.
AB  - One primary objective of endodontic therapy is to establish an adequate seal with
      the root canal filling material. The placement of an immediate amalgam buildup at
      obturation, in conjunction with rubber dam isolation, allows an endodontic seal
      to be extended from the foramen to the cavosurface margin. As a result of this
      immediate buildup, the length of the seal and the longevity of the endodontic
      treatment are presumably extended. This article describes an effective means of
      performing the immediate core buildup of endodontically treated teeth.

PMID- 10635241
TI  - Anterior implant-supported reconstructions: a surgical challenge.
AB  - Reconstructive procedures are able to provide improved aesthetics for implant
      patients who present with anatomical limitations (e.g., vertical or horizontal
      tissue loss) in the anterior maxilla. Aesthetic results, however, are directly
      related to the ability of the treatment team to reconstruct the lost bone and
      soft tissue, place the implant into its proper tridimensional position in the
      patient's arch, and use precise restorative techniques. This article presents
      comprehensive treatment steps for the utilization of single-unit and multiple
      unit implant-supported restorations in the anterior maxilla.

PMID- 10635242
TI  - Single-unit implant-supported restoration in the vertically deficient anterior
      maxilla.

PMID- 10635243
TI  - The importance of direct resins in dental practice.

PMID- 10635244
TI  - Anterior implant-supported reconstructions: a prosthetic challenge.
AB  - Recent investigations have demonstrated that the successful utilization of
      anterior implant-supported restorations in the maxilla is dependent upon the
      satisfaction of numerous surgical and prosthodontic criteria. Conservative
      treatment alternatives that use a provisionalization phase can provide clinical
      benefits for patients with partial edentulism by guiding tissue maturation
      following completion of a meticulous surgical procedure. This article
      demonstrates a series of prosthetic considerations that guide contemporary
      aesthetic restorations, and highlights the underlying surgical factors related to
      this treatment.

PMID- 10635245
TI  - Aesthetic management of extractions for implant site development: delayed versus
      staged implant placement.
AB  - Resorption of the dentoalveolar bone and collapse of the gingival ridge following
      tooth loss often results in aesthetic compromise and inadequate bone for
      "prosthetically driven" implant placement. Preventing alveolar bone resorption
      with a conservative procedure at the time of extraction can enhance aesthetics
      and reduce the duration and extent of treatment required for implant placement.
      This article describes the aesthetic management of extraction sites using a
      conservative bone grafting procedure at the time of extraction for implant site
      development. The case presented demonstrates staged and delayed implant placement
      techniques.

PMID- 10635246
TI  - Enamel matrix derivative in treatment of infrabony defects.

PMID- 10635247
TI  - Integration of technology in the dental practice.

PMID- 10635248
TI  - Surgical crown lengthening of the maxillary anterior dentition: aesthetic
      considerations.
AB  - Recent patient interest in aesthetic treatment has resulted in the development of
      advanced surgical and restorative procedures that are capable of conservatively
      addressing such objectives. While numerous materials and techniques have been
      developed accordingly, each must respect specific biological criteria in order to
      be successful. This article demonstrates the implementation of surgical
      periodontal plastic and restorative procedures that facilitate the full-mouth
      rehabilitation of a patient who presented with excessive wear of the natural
      dentition. The procedure described is specific for the maxillary anterior.

PMID- 10635249
TI  - Cosmetic or esthetic dentistry?
AB  - This article, through presentation of case studies, defines differences and
      suggests separate definitions for the terms cosmetic dentistry and esthetic
      dentistry. Dentistry strives to emulate harmonious form and function for therapy,
      and modification of appearance is an integral part of dental treatment. Cosmetic
      dentistry suggests a certain accommodation and is a compromise of current
      technology. Cosmetic dentistry is commonly selected as an interim procedure that
      does not necessarily function ideally and does not always emulate the pristine
      state of a natural dentition. Esthetic dentistry requires less accommodation,
      incorporates acceptable biologic technology for long-term survival, functions
      suitably, and mimics the pristine state of the natural dentition. Cosmetic and
      esthetic dentistry are different in definition, concept, and execution.

PMID- 10635250
TI  - Restoration longevity and analysis of reasons for the placement and replacement
      of restorations provided by vocational dental practitioners and their trainers in
      the United Kingdom.
AB  - OBJECTIVE: This study examined the reasons given by vocational dental
      practitioners and their trainers for placement and replacement of restorations.
      METHOD AND MATERIALS: Each participant was asked to record the reason for
      placement or replacement of restorations. The age and class of the restoration
      being replaced were also recorded, as was the material being used and the
      material being replaced (if known). RESULTS: Details of the reason for placement
      or replacement was received on 9,031 restorations. Of the restorations placed,
      53.9% were amalgam, 29.8% were resin composite, and 16.3% were glass-ionomer
      cement. The reasons for placement or replacement of the restorations were
      principally primary caries (41.3%), secondary caries (21.9%), tooth fracture
      (6.4%), marginal fracture or degradation (6.1%), and noncarious defects (5.8%).
      Of the amalgam restorations, most were placed to restore Class II and Class I
      preparations (65.8% and 29.9%, respectively). Of the composite restorations, most
      were placed in Class III and Class V cavities (35.5% and 26.3%, respectively).
      Glass-ionomer cement was used predominantly to restore Class V cavities (63.5%).
      CONCLUSION: Secondary caries was the most prevalent reason for replacement of
      restorations, regardless of material. Statistical analysis indicated that amalgam
      provided significantly greater longevity than composite or glass-ionomer
      materials.

PMID- 10635251
TI  - Mechanical stabilization in the mandibular anterior segment.
AB  - Teeth in the mandibular anterior region of the mouth, affected by years of
      periodontal disease and resultant bone loss, frequently require treatment for the
      patient to be able to chew comfortably and effectively. Often patients choose to
      keep compromised teeth, despite being presented with treatment options involving
      a fixed or removable prosthesis. In these situations, mechanical stabilization
      becomes necessary. Current treatment possibilities include bonding with resin
      composite or placement of a bonded metal mesh splint, a cast metal resin-bonded
      retainer, or a fiber-reinforced resin composite splint. Coupled with good oral
      hygiene practices, these mechanical stabilization techniques can provide
      increased oral comfort and improved function, especially for geriatric dental
      patients.

PMID- 10635253
TI  - Ankyloglossia (tongue-tie): a diagnostic and treatment quandary.
AB  - The tongue is an important oral structure that affects speech, the position of
      teeth, periodontal tissue, nutrition, swallowing, nursing, and certain social
      activities. Ankyloglossia (tongue-tie) limits the range of motion of the tongue,
      impairing its ability to fulfill its functions. In this article, diagnostic
      criteria needed to evaluate and treat ankyloglossia are suggested, and a method
      for classifying ankyloglossia is proposed.

PMID- 10635252
TI  - Flowable resin composites as "filled adhesives": literature review and clinical
      recommendations.
AB  - There is increasing reliance on laboratory testing of new products. The clinical
      significance of many such studies can be questioned. To function clinically, bond
      strength must develop more quickly than the shrinkage stress. Oxygen inhibition
      of extremely thin resin layers prohibits establishment of the bond, perhaps
      particularly relevant for single-component dentin bonding agents. Use of thicker
      layers of radiolucent hydrophilic bonding materials can lead to difficulties
      during subsequent radiographic diagnosis and may contribute to degradation at
      enamel margins. Shrinkage stress is influenced significantly by many factors. The
      cavity geometry probably plays the most important role but cannot be controlled
      to any major extent by the operator. Shrinkage and modulus kinetics are also
      critical, involving variables such as content and type of monomers, the catalyst
      system, and the light intensity. In general, a high modulus of elasticity or more
      rapid polymerization leads to increased shrinkage stress. Combining a single
      component adhesive as a dentin primer with a highly radiopaque flowable resin
      composite as a filled adhesive may help overcome these difficulties.

PMID- 10635254
TI  - Cat-scratch disease: a case report.
AB  - Cat-scratch disease is the most common cause of benign lymphadenopathy in
      children and young adults. A 21-year-old patient presented with a 14-day history
      of asymptomatic left submental swelling. Clinical and radiographic examination
      revealed no dental cause. An enlarged, firm nodule was excised. The
      histopathologic appearance was consistent with cat-scratch disease. This article
      summarizes the relevant literature and discusses diagnosis and treatment of cat
      scratch disease.

PMID- 10635255
TI  - Demineralizing effect of dental cements on human dentin.
AB  - OBJECTIVE: This study was undertaken to verify the hypothesis that dentin
      surfaces are demineralized during placement of four kinds of chemically setting
      cements (zinc phosphate cement, luting glass-ionomer cement, restorative glass
      ionomer cement, and zinc polycarboxylate cement). METHOD AND MATERIALS: Sixty
      cemented dentin disks were observed under scanning electron microscopy and with
      confocal laser scanning microscopy after use of an argon-ion etching technique.
      To determine the surface effects of the cements, 30 dentin surfaces were treated
      with 1 of 6 freshly mixed cements (5 per group) for 60 seconds. The disks were
      subjected to rinsing with a water spray and ultrasonic washing prior to scanning
      electron microscopic observation. RESULTS: Observation of cemented dentin
      specimens revealed that the dentin was not completely demineralized at the
      interface formed by the cement and dentin and that the extent and depth of
      demineralization along the interface tended to be nonuniform. Zinc phosphate
      cement caused the greatest demineralization of dentin, followed by luting glass
      ionomer cement. The extent of demineralization with restorative glass-ionomer
      cement or zinc polycarboxylate cement was less discernible. Confocal laser
      scanning microscopy generally confirmed scanning electron microscopic
      observations and revealed that most of the specimens showed close adaptation of
      the cements to the dentin surfaces. CONCLUSION: Acid-containing cements have self
      etching properties that are effective, to various degrees, in removing the smear
      layer and promoting close adaptation to dentin surfaces.

PMID- 10635256
TI  - "Wrecking ball" dental fractures: report of 2 cases.

PMID- 10635257
TI  - Computer-based oral health records on the World Wide Web.
AB  - Recently, the World Wide Web has emerged as a platform for computer-based oral
      health records. Web-based patient records can make teledentistry an instant
      reality. Because an increasing number of dental care providers can access Web
      pages, traditional barriers to exchanging information are dropping. Web-based
      records also make cumulative, longitudinal patient records possible.
      Sophisticated security mechanisms can ensure the integrity and confidentiality of
      patient information. Because Web-based systems are simpler to install and
      configure, the cost of operating them may be reduced. However, their development
      is complex, difficult, and expensive because the Web was not developed as a
      programming environment. Furthermore, the technologies underlying the Web are
      constantly evolving, forcing developers to continuously reengineer their systems.
      In addition, several policy questions, such as storage of and access to computer
      based patient records, have to be answered. This article describes CMSWeb, a Web
      based clinical information system implemented at Temple University School of
      Dentistry.

PMID- 10635258
TI  - Broken anesthetic injection needles: report of 5 cases.
AB  - A broken anesthetic needle is a rare complication in clinical practice. This
      article reports on 5 patients referred for removal of broken needles. The needles
      were located in the pterygomandibular space or near the maxillary tuberosity.
      These complications were the result of an unexpected movement by the patient or
      an incorrect anesthetic technique. The article also describes the case of a
      patient in whom an image observed in a routine panoramic radiograph could have
      been caused by a broken needle.

PMID- 10635259
TI  - New clinical index for drug-induced gingival overgrowth.
AB  - The numbers of patients using medications that induce gingival overgrowth are
      expanding rapidly. The tremendous increase in the number of organ transplants
      being performed, each requiring treatment with the immunosuppressive drug of
      choice, cyclosporine, has created a new dilemma in management of the gingival
      tissues. Additionally, cyclosporine-induced hypertension is frequently treated
      with calcium channel blockers, such as nifedipine, both drugs acting
      synergistically to induce gingival overgrowth. At present, the profession lacks a
      well-defined and easy-to-use clinical index for classifying overgrown gingival
      tissue. This article describes a comprehensive, yet simple, scoring system for
      enlarged tissues that may provide direction to the clinician and standardize
      evaluation. This system may also give guidance for the most appropriate time for
      surgical treatment of drug-induced gingival overgrowth.

PMID- 10635260
TI  - Mucogingival surgical procedures: a review of the literature.
AB  - This article provides an in-depth review of the literature on mucogingival
      surgical techniques. Indications and contraindications of various surgical
      procedures are discussed with reference to the literature. Surgical techniques
      and indications for increasing the zone of keratinized tissue, such as free
      autogenous grafts, applications of freeze-dried skin, and dermal matrix
      allografts, are described. Procedures to attain root coverage, such as various
      autogenous grafts and guided tissue regeneration techniques, along with
      application of chemicals such as citric acid to improve their success, are also
      described.

PMID- 10635261
TI  - Incidence and severity of postoperative pain following routine placement of
      amalgam restorations.
AB  - OBJECTIVE: This study investigated the incidence and severity of postoperative
      sensitivity, examining several potential sources of pain. METHOD AND MATERIALS:
      One hundred eighteen subjects were asked about pain that they experienced
      following an appointment for restoration of a moderate Class I or II carious
      lesion. The survey required subjects to complete 3 questionnaires, 1, 4, and 7
      days posttreatment. Questions covered 9 different potential sources of
      postoperative pain and the use of pain medication following the dental
      appointment. RESULTS: A great majority of subjects experienced postoperative pain
      from at least 1 source, and approximately half of those who reported pain
      following the appointment found it necessary to take medication for relief. For
      almost all categories, the level of pain reported at 4 and 7 days was
      substantially less than that reported after 24 hours. CONCLUSION: Patients
      commonly experience pain in the first 24 hours after operative treatment.
      Dentists should consider recommending that patients who are likely to experience
      postoperative pain take a nonprescription analgesic around the time of the
      treatment and for 24 hours afterward to prevent discomfort.

PMID- 10635262
TI  - Resin composite polishing--filling the gaps.
AB  - OBJECTIVE: The search for the ideal polishing agent for resin composite materials
      is still ongoing. A new polishing brush with abrasive bristles for polishing
      resin-based restorations was tested to determine if it polishes restorations,
      including those with concave surfaces, macrostructured occlusal surfaces, and
      textured surfaces, without destroying their delicate texture or microstructure.
      METHOD AND MATERIALS: The polishing effectiveness and the ultimate destructive
      potential of these brushes were assessed quantitatively and subjectively in
      vitro. In addition, the durability of the brushes after repeated use and
      autoclaving was also evaluated. RESULTS: The brushes were nondestructive to resin
      based restorative, enamel, dentin, and the restoration interface. They produced a
      shiny surface on resin-based restorative materials without destroying the surface
      texture. The abrasive brushes were autoclavable and demonstrated satisfactory
      durability, despite multiple heat sterilization cycles. CONCLUSION: These brushes
      can be considered to be key products to polish concave surfaces, anatomically
      shaped occlusal surfaces, and textured surfaces without damaging the surface
      characteristics.

PMID- 10635263
TI  - A comparative study of fluoride uptake from dentin bonding agents and glass
      ionomer cements in permanent and primary tooth enamel.
AB  - OBJECTIVE: Many fluoride-releasing dental materials are being sold on the basis
      of their cariostatic properties. However, the amount of fluoride release of these
      materials is still uncertain. The aim of this study was to determine the amount
      of fluoride uptake in primary and permanent tooth enamel from 1 conventional
      glass-ionomer cement (Fuji II), 1 resin-modified glass-ionomer cement (Fuji II
      LC), and 2 fluoride-releasing dentin bonding agents (Liner Bond 2 and Optibond)
      in vitro. METHOD AND MATERIALS: One hundred sixty caries-free primary and
      permanent molar teeth were assigned to the study. Materials were applied
      according to the manufacturer's instructions to standard windows created on the
      enamel surfaces. The amount of fluoride uptake by enamel was investigated by
      using a specific fluoride electrode and acid-etching biopsy technique. RESULTS:
      The amount of fluoride taken up from Fuji II and Fuji II LC by permanent and
      primary tooth enamel was found to be statistically significant. However, no
      significant fluoride uptake from Optibond and Liner Bond 2 was found. CONCLUSION:
      Fuji II and Fuji II LC glass-ionomer materials seemed to provide more effective
      fluoride release than did Optibond and Liner Bond 2 in permanent and primary
      enamel.

PMID- 10635264
TI  - Unprotected protein at the dentin-adhesive interface.
AB  - OBJECTIVE: With dental bonding systems that require acid etching of dentin,
      inadequate adhesive penetration can leave exposed collagen at the dentin-adhesive
      interface. The exposed collagen could be degraded by bacterial proteases,
      compromising the integrity of the dentin-adhesive bond and, ultimately, the
      restoration. The purpose of this study was to develop a nondestructive staining
      technique to identify exposed collagenous protein at the dentin-adhesive
      interface. METHOD AND MATERIALS: The following adhesives were placed, according
      to manufacturer's instructions, on dentin cut from 15 human third molars:
      Scotchbond Multi-Purpose, Scotchbond Multi-Purpose Plus, and 3M Single Bond.
      Light microscopic sections of native dentin-adhesive interfaces of each tooth
      were cut and stained with Goldner's trichrome. This reagent stained exposed
      protein in the sections a distinct red-orange. RESULTS: Exposed protein was
      identified at the dentin-adhesive interface with each of the adhesives. Corollary
      scanning electron microscopic examination confirmed the presence of exposed
      protein, i.e., protein that was removed by sodium hypochlorite, at the interface.
      Sites of exposed protein that were clearly identified in the light microscopic
      sections were obscured in the transmission electron microscopic sections.
      CONCLUSION: In vitro identification of inadequacies in the dentin-adhesive bond
      is the first step in determining sites that may be vulnerable to premature
      breakdown under clinical conditions.

PMID- 10635265
TI  - Resin-bonded prostheses: the current state of development.
AB  - In the 25 years since the first resin-bonded prosthesis was described, this
      adhesive technique for splinting mobile teeth has developed into a conservative
      method for replacing missing teeth. There was a high debond rate associated with
      the early resin-bonded prostheses, which led many clinicians to question their
      clinical appropriateness for long-term use. These early failures were attributed
      to the limited bond strength between the metalwork and etched enamel. Despite
      improvements in the adhesive bond strengths, there was still an unacceptable
      number of clinical debonds. The biomechanical design of resin-bonded prostheses
      did not develop with the same rapidity or with the same predictability as did the
      advancements with the associated adhesive technology. Through ongoing
      development, studies have shown various biomechanical designs that may improve
      clinical retention. The purpose of this article is to examine the biomechanical
      principles for current resin-bonded prosthesis design, including aspects of tooth
      preparation and framework design that will improve clinical retention.

PMID- 10635266
TI  - Comparison between manual and mechanical methods of interproximal hygiene.
AB  - OBJECTIVE: The aim of this study was to compare the effectiveness of the
      automated Interclean Interdental Plaque Remover with that of interdental brushes
      and Ultrafloss. METHOD AND MATERIALS: The interdental hygiene effectiveness of 35
      healthy patients suffering from gingivitis was studied by an examiner daily over
      a period of 1 week. The sizes of the interdental spaces were classified and
      corresponding-sized interdental brushes or floss was selected. In a random, split
      mouth design both interdental cleaning methods, mechanical and manual, were
      applied while the patients continued to use standard brushing techniques.
      Disclosed proximal plaque, the papillary bleeding index, and interdental bleeding
      tendency on stimulation were evaluated. RESULTS: The papillary bleeding index was
      reduced from an average value of 40% to 25%. Only 5% of interproximal plaque
      remained after manual interdental cleaning, whereas 40% of plaque was still
      present after use of the Interclean device. Cleaning efficiency of manual and
      mechanical methods was comparable in only 1 interproximal space size. At the end
      of the study, the interdental bleeding on stimulation was significantly higher in
      the automatically cleaned interspaces than in the manually cleaned spaces.
      CONCLUSION: Manual interproximal cleaning was more effective than the automated
      device.

PMID- 10635267
TI  - New radiographic programs for transverse conventional tomograms in the
      dentomaxillofacial region.
AB  - Using only 7 programs, Orthophos Plus permits transverse conventional tomograms
      of all maxillomandibular regions. The precision of the magnification factors of
      these programs is very high. Factors influencing the image quality of the 7
      programs were assessed. Image quality depends on technical precision and on
      correct patient positioning, i.e., jaw axis alignment to the direction of
      projection. This procedure with 7 programs is more demanding than the procedure
      for x-ray units that use many programs for the different projections. Especially
      for implantology, it is important that the patient's jaw be positioned in
      accordance with the projection to avoid oblique cuts and incorrect information
      about the jaw dimensions. The correct region is best selected by positioning a
      cast in the positioning aids prior to exposure and using the same setting for the
      patient's exposures. For correct implant planning, it is helpful to digitize the
      tomograms with Friacom so that, despite different magnification factors of the
      programs, the correct implant dimensions are determined. If these suggestions are
      followed, use of these programs in dental practice can be recommended.

PMID- 10635268
TI  - Modern alternatives to amalgam: cementable restorations and inlays.
AB  - There are still no replacement materials on the market that are equal to amalgam.
      However, alternatives of differing qualities are available and, for the most
      part, clinically proven. This article attempts to make a scientific and clinical
      comparison of these alternatives with respect to esthetics, biocompatibility,
      chemical durability, and treatment cost. The evaluation suggests that cementable
      restorations, in particular electroformed inlays and onlays, are superior to
      bonded ceramic inlays.

PMID- 10635269
TI  - Gold-acrylic resin facing replaced by intraoral bonding of a polyglass: a case
      report.
AB  - A gold-acrylic resin abutment for a removable partial denture was esthetically
      and functionally restored with a bonded Artglass facing. Surface preparations
      utilized were intraoral sandblasting and tin plating. An adhesive resin
      composite, Panavia 21, bonded the new Artglass facing to the prepared gold
      surface of the abutment.

PMID- 10635270
TI  - Apical bridging in association with regular root formation following single-visit
      apexification: a case report.
AB  - A case report is presented in which continuing root formation occurred in a
      carious nonvital and immature mandibular second premolar after single-visit
      calcium hydroxide apexification treatment. An apical hard tissue barrier was
      formed, accompanied by a separate, mesioapically growing root, 7 months
      posttreatment. Treatment was concluded with gutta-percha root canal restoration.
      The success of this single-visit apexification treatment supports the contention
      that frequent changing of the calcium hydroxide dressing is not always required
      to induce apical closure.

PMID- 10635271
TI  - Dental education for women dentists in the United States: the beginnings.
AB  - During the 19th century, dentistry was changing from a craft that was usually
      transmitted by a preceptor to a science that was taught in established schools.
      The first dental school, established in 1827 in Bainbridge, Ohio, was soon
      followed by a large number of proprietary and freestanding schools of dentistry.
      However, no matter what the status of the dental school, none would admit women.
      In contrast, the first woman to be admitted to a medical college graduated in
      1849. The Ohio College of Dental Surgery was the first dental school to open its
      doors to a woman and granted a degree to Lucy Beaman Hobbs Taylor in 1866.
      Although the number of women to graduate from dental school increased, the number
      was small compared to the increase in male graduates. By 1893, about 200 women
      had graduated with degrees in dentistry, including a number who came from outside
      the United States.

PMID- 10635272
TI  - In vitro shear bond strength of adhesive to normal and fluoridated enamel under
      various contaminated conditions.
AB  - OBJECTIVE: This study examined the shear bond strength of bonding agents to
      normal or fluoridated enamel following use of weak or strong acids to prepare
      enamel surfaces and after contamination with a measured amount of saliva at
      various stages of the bonding procedure. METHOD AND MATERIALS: One hundred
      extracted human third molar teeth were randomly separated into 2 basic groups
      (normal or fluoridated teeth), then divided into 5 subgroups. Group A specimens
      were not contaminated. After etching, enamel surfaces were dry and clean. Group B
      was left with wet surfaces after etching. Group C specimens were contaminated
      with artificial saliva and then dried. Group D specimens were contaminated with
      artificial saliva, rinsed, and then dried. In group E, all enamel surfaces were
      left contaminated with saliva after the etching procedures (with maleic acid or
      phosphoric acids). Adhesive resins were applied to all enamel surfaces according
      to the manufacturer's instructions. The specimens were then mounted and tested to
      determine shear bond strength. RESULTS: If normal enamel surfaces were rinsed and
      dried immediately after contamination, there was no significant reduction of
      shear bond strength of adhesive to enamel. Specimens in group E and group C had
      significantly lower bond strengths than did control specimens (group A). In the
      fluoridated groups etched with the phosphoric acid, statistically significant
      reductions in bond strengths were obtained in all contamination groups and in the
      control group. In the fluoridated specimens, there were no statistically
      significant differences between any of the contamination groups and the control
      group when maleic acid was used. CONCLUSION: Saliva contamination may not be a
      risk factor for successful bonding between bonding agent and dental tissues for
      normal or fluoridated enamel surfaces if they are rinsed and dried immediately
      after contamination. Etching of normal enamel surfaces with phosphoric acid in
      the presence of contamination may provide higher shear bond strength than etching
      with maleic acid.

PMID- 10635273
TI  - All-ceramic posts and cores: the state of the art.
AB  - Metal posts used to restore endodontically treated teeth may shine through all
      ceramic crowns and thin gingival tissue. When nonprecious alloys are used,
      corrosion products may lead to discoloration. All-ceramic posts and cores can be
      used in combination with all-ceramic crowns to prevent these problems. All
      ceramic posts and cores are highly biocompatible and will almost always increase
      the translucency of an all-ceramic restoration. The purpose of this article is to
      describe the fabrication of all-ceramic posts and cores, using high-toughness
      ceramic materials such as alumina or zirconia ceramics, through 4 different
      techniques: the slip-casting technique; the copy-milling technique; the 2-piece
      technique, which involves a prefabricated zirconia ceramic post and a copy-milled
      alumina or zirconia ceramic core; and the heat-press technique, which involves a
      prefabricated zirconia ceramic post and a heat-pressed glass-ceramic core.
      Indications, contraindications, advantages, and disadvantages of the different
      techniques are compared.

PMID- 10635274
TI  - Presentation of quantitative tooth wear data to clinicians.
AB  - OBJECTIVE: The purpose of this study was to ascertain the ease of interpretation
      and usefulness of different modes of presenting quantitative tooth wear data to
      clinicians. METHOD AND MATERIALS: A questionnaire that sought to ascertain both
      the ease of interpretation and usefulness of different modes of presentation for
      monitoring tooth wear was distributed to 67 clinicians. These modes (contour
      maps, surface topography and difference plots, and color-coded surface difference
      plots) were a product of ongoing development that used a mathematic algorithm to
      detect and quantify wear of teeth with time. A follow-up questionnaire, based on
      a fusion of the desirable features of surface topography and color-coded surface
      difference plots, was distributed to 40 of the original respondents to ascertain
      any improvement in clarity. RESULTS: In all respects, contour maps were rated
      significantly more difficult to interpret and less useful than the other
      techniques evaluated. No significant difference was detected between the other
      modalities. The follow-up questionnaire demonstrated a significantly enhanced
      utility of the revised plot in informing the clinician as to the worn sites and
      quantity of wear. CONCLUSION: The combined mode of presentation seems an
      excellent way of presenting wear results to clinicians for clinical application.

PMID- 10635275
TI  - Marshall H. Webb and extension for prevention: a literature review.
AB  - Dr Marshall Webb (1844-1883), author, lecturer, debater, clinician, inventor, and
      dentist extraordinaire, was a decade ahead of others in putting forth a concept
      of "extension for prevention." One hundred twenty years ago, he was one of the
      best known, most advanced, and highly regarded dentists in the world. His
      pioneering work in cardiology, preventive dentistry, ethics, and prevention of
      recurrent decay raised the standards of what we call operative or conservative
      dentistry, but he is almost unknown now. However, his concept of conservative
      tooth preparation could be applied today.

PMID- 10635276
TI  - A short-term clinical evaluation of a tricure glass-ionomer system as a
      transitional restoration and core buildup material.
AB  - OBJECTIVE: A general dental practice study investigated the use of a resin
      modified glass ionomer material as a transitional restoration and as a core
      buildup material. The study also assessed a resin-modified glass-ionomer luting
      system. METHOD AND MATERIALS: Fifty-one badly broken-down vital permanent molar
      teeth in 44 patients were restored. No dentin pins were placed; however,
      preexisting pins were retained in 7 teeth. Following baseline and 3-month
      assessments, complete veneer gold crowns were placed on the selected teeth. The
      preparations involved ferruling in sound tooth tissue. The completed crowns were
      reviewed 3 and 12 months after placement. Modified US Public Health Service
      criteria were used for assessment throughout. Clinical assessment was
      complemented by examination of photographic records and replicas obtained from
      silicone impressions. RESULTS: All 51 transitional restorations were found to be
      clinically satisfactory at the 3-month review. Nineteen (37%) transitional
      restorations had limited defects that were eliminated in crown preparation. Of
      the 51 permanent crowns, 46 (90%) were reviewed at 3 months and 44 (86%) at 1
      year. All the crowns reviewed at 3 and 12 months were clinically satisfactory.
      The luting system investigated showed favorable handling characteristics and
      excellent short-term performance. CONCLUSION: The materials investigated are,
      over a period of at least 12 months, effective in the restoration of broken-down
      molar teeth destined to be crowned. With the use of these materials and
      ferruling, the use of dentin pins may be unnecessary in selected cases.

PMID- 10635277
TI  - The effect of finishing and polishing on the decision to replace existing amalgam
      restorations.
AB  - OBJECTIVE: The purpose of this investigation was to evaluate the influence of
      finishing and polishing procedures on the decision to replace existing amalgam
      restorations. METHOD AND MATERIALS: Twenty Class I and Class II amalgam
      restorations, free from obvious defects, were selected in 6 patients. The
      restorations were photographed before and after being submitted to a standard
      finishing and polishing procedure. In the first phase, the preoperative slides
      were examined by 27 clinicians and senior dental students, who were instructed to
      inspect each restoration and answer a questionnaire indicating if and why the
      restoration needed to be replaced. Two weeks later, the postoperative slides were
      presented to the same examiners, who were asked to answer the same questionnaire
      as before. RESULTS: At the first phase, there were 236 decisions (44%) to replace
      existing amalgam restorations. Following the finishing and polishing procedures,
      114 decisions (21%) were made to replace existing amalgam restorations. This
      difference was statistically significant. Secondary caries was the most common
      reason for replacement. CONCLUSION: The finishing and polishing procedure
      reversed the decision to replace old amalgam restorations.

PMID- 10635278
TI  - Bite-formed posterior resin composite restorations, placed with a self-etching
      primer and a novel matrix.
AB  - Problems encountered in placement of posterior resin composite restorations have
      limited their clinical application. This article identifies and solves 4 of the
      frequently encountered problems: establishment of tight and anatomically correct
      contacts, refinement of occlusion, postoperative sensitivity, and time required
      for the procedure. A posterior resin composite is placed using a self-etching
      primer. A novel matrix, flowable composite, and bite-formed occlusion facilitate
      the clinical procedure.

PMID- 10635279
TI  - Apert syndrome: a case report with discussion of craniofacial features.
AB  - Apert syndrome is a rare congenital anomaly characterized by acrocephaly,
      syndactyly, and abnormalities of other organs. It has characteristic features in
      the orofacial region, affecting the eyes, palate, middle third of face, and
      uvula. In this case report, the features of Apert syndrome, particularly in
      relation to the orofacial region, are discussed.

PMID- 10635281
TI  - Primary anterior tooth restoration using posts with macroretentive elements.

PMID- 10635280
TI  - Effectiveness of surface protection for resin-modified glass-ionomer materials.
AB  - OBJECTIVE: The purpose of this study was to evaluate the effectiveness of various
      surface treatments for resin-modified glass-ionomer restorative materials by
      determining dye uptake spectrophotometrically. METHOD AND MATERIALS: Two hundred
      twenty-four specimens, 4.1 mm in diameter and 2.0 mm thick, were made of 3
      materials: Vitremer, Fuji II LC, and Photac-Fil Aplicap. Specimens were divided
      into 15 groups. The positive and negative control specimens remained unprotected,
      while the experimental specimens were protected with Heliobond light-activated
      bonding resin, Colorama nail varnish, or surface coatings indicated by the
      manufacturers of the glass-ionomer materials: Finishing Gloss for Vitremer, Fuji
      Varnish for Fuji II LC, and Ketac Glaze for Photac-Fil. The disks were immersed
      in 0.05% methylene blue for 24 hours except for the negative control group, which
      was immersed in deionized water. After 24 hours, the disks were removed, washed,
      and individually placed in 1 mL of 65% nitric acid for 24 hours. The solutions
      were centrifuged and the spectrophotometric absorbance was determined at 606 nm.
      The dye uptake was expressed in micrograms of dye per milliliter, and the results
      were analyzed with the Kruskal-Wallis test. RESULTS: There were no differences in
      dye uptake among the 3 resin-modified glass-ionomer restorative materials;
      however, all of them required surface protection. CONCLUSION: The best surface
      protection for the 3 evaluated materials was obtained with Heliobond light
      activated bonding resin.

PMID- 10635282
TI  - Operation of bad breath clinics.
AB  - The diagnosis and management of bad breath can be easily incorporated in routine
      dental care by attending dentists. This article outlines the information
      necessary to establish a differential diagnosis of oral malodor. This includes
      evaluation of medical, dental, and halitosis history. It also includes the
      examination of extraoral and intraoral tissues and a thorough periodontal
      examination. The presence of bad breath is established with organoleptic and
      hydrogen sulfide-monitor (Halimeter) measurements. The treatment of malodor
      resulting from oral overgrowth of anaerobic organisms in the oral cavity consists
      of mechanical and chemical reduction of the microbial flora by methods that are
      supported by scientific evidence.

PMID- 10635283
TI  - Clinical application of a questionnaire for diagnosis and treatment of halitosis.
AB  - To treat halitosis, clinicians must examine the psychologic condition of a
      patient as well as the disease history and plausible causes of oral malodor, such
      as periodontal disease. However, it is not easy for a practitioner to carry out a
      psychologic examination other than the normal inquiry concerning oral malodor
      itself. Hence, a questionnaire that appears to be a normal inquiry, rather than
      one containing psychologic questions, was composed to survey the causes of
      halitosis and psychosomatic tendencies.

PMID- 10635284
TI  - An inventory of patients' response to treatment at a multidisciplinary breath
      odor clinic.
AB  - OBJECTIVE: This study was undertaken to assess patients' response to their
      treatment at a multidisciplinary oral malodor clinic. METHOD AND MATERIALS: In 4
      years, a multidisciplinary breath odor clinic in Belgium examined 406 patients.
      The team consisted of an ear, nose, and throat specialist, a periodontologist,
      occasionally a specialist in internal medicine, and, more recently, a
      psychiatrist. After the initial visit, each patient was scheduled for a follow-up
      appointment 2 to 6 months later; however, only 143 patients (35%) showed up for
      this control visit. The remaining 65% of the patients answered a mailed
      questionnaire. RESULTS: About half of the patients who returned no longer had
      complaints, while 17% reported no improvement. This group was characterized by
      imaginary bad breath and manifest psychologic problems. There was also disbelief
      of their cure, although clinical examination (organoleptic evaluation and
      volatile sulfide measurement by means of a portable monitor) did not reveal any
      oral malodor. Some also insufficiently performed the recommended oral hygiene
      measures (tongue brushing and interdental cleaning). Most of the patients who
      returned the questionnaire were disappointed by the suggestion that their
      halitosis was the result of insufficient oral hygiene. CONCLUSION: Better
      education of both the public and dental professionals as to the most frequent
      cause of halitosis, insufficient oral hygiene, might elevate the level of
      compliance by patients.

PMID- 10635285
TI  - The effects of antimicrobial mouthrinses on oral malodor and their status
      relative to US Food and Drug Administration regulations.
AB  - This study was undertaken to review the rationale behind the usage of
      antibacterial mouthrinses to control oral malodor and to evaluate the claims made
      for antibacterial mouthrinses against the statements of US Food and Drug
      Administration regulations. The literature from 1960 to August 1997, found in a
      MEDLINE search on oral malodor, halitosis, and tongue microbiology, was examined.
      Clinical trials that were double blind and had selected subjects who exhibited a
      detectable level of oral malodor were evaluated. Individuals who experience oral
      malodor resulting from the overgrowth of proteolytic, anaerobic bacteria on their
      tongue surfaces can be successfully treated by a regimen that includes tongue
      brushing and toothbrushing, often in combination with use of a mouthrinse
      containing an antibacterial agent. Several candidate mouthrinses containing
      essential oils, zinc chloride, or an oil-water-cetylpyridinium chloride
      mouthrinse have reduced the organoleptic scores of individuals with moderate
      levels of oral malodor in the absence of tongue brushing. Very little long-term
      data beyond 6 weeks of usage are available. These mouthrinses should be marketed
      as oral deodorants that are analogous in purpose to the usage of deodorant soaps
      to control and/or eliminate body malodors.

PMID- 10635286
TI  - Mechanical effects and volatile sulfur compound-reducing effects of chewing gums:
      comparison between test and base gums and a control group.
AB  - OBJECTIVE: Chewing gum may act as a masking or a therapeutic agent against the
      different chemical compounds that are responsible for oral malodor. An open-label
      exploratory study investigated the effect of mastication and aromatic components
      of chewing gum on reducing oral volatile sulfur compounds. METHOD AND MATERIALS:
      Twelve dental students (5 males and 7 females) acted as their own controls.
      Toothbrushing stopped 12 hours before observations. Measurements included
      organoleptic and volatile sulfur compound scores and the pH of the anterior and
      posterior zones of the dorsal tongue. Measurements were made at 9 AM and 12 PM on
      1 day for 3 successive weeks; week 1, no gum (control); week 2, test gum; week 3,
      unsweetened gum base. This open-label study was then completed by an observer
      blind study, according to the same schedule; the recorded measurement was the
      plaque index. RESULTS: The pH, volatile sulfur compounds, and organoleptic scores
      were similar for all groups. The pH was more basic in the posterior part than in
      the anterior zone of the dorsal tongue, irrespective of time and presence or
      absence of chewing gum. In addition, the volatile sulfur compound score rose
      transiently immediately after the test gum, and the organoleptic score fell in
      the first hour only after the test gum. The two chewing gum groups seemed to have
      a greater reduction in plaque index than did the control (no gum) group.
      CONCLUSION: Chewing gum may have a valuable mechanical role in cleaning dental
      surfaces, and the test gum may temporarily control bad breath. After 3 hours,
      similar volatile sulfur compound scores were observed for subjects who chewed
      either test or unsweetened gum base and control subjects.

PMID- 10635287
TI  - Self-assessment of oral malodor 1 year following initial consultation.
AB  - OBJECTIVE: In an initial study, subjects complaining of bad breath were generally
      unable to score the level of their own oral malodor in an objective fashion.
      Subjects were taught several techniques for self-measurement of bad breath. One
      year following the initial consultation, subjects were recalled to determine
      whether their ability to assess their own oral malodor had improved. METHOD AND
      MATERIALS: In the study, subjects were blinded to their own scores 1 year
      earlier, to the odor-judge scores, and to the results of the clinical laboratory
      tests. Thirty-two of 43 subjects in the original study who presented with a
      complaint of oral malodor agreed to participate in the follow-up study. Odor
      judge scores and self-assessments of oral malodor (whole-mouth odor, tongue odor,
      and saliva odor) were compared with one another as well as with clinical
      parameters. RESULTS: Objective improvements were noted in both oral health
      parameters and malodor levels of subjects. Despite this, self-assessments
      generally remained unrelated to objective parameters (odor-judge scores, clinical
      indices, and laboratory tests). Self-assessments were all significantly
      correlated with one another, and also were significantly associated with
      corresponding self-estimates made 1 year earlier. CONCLUSION: Subjects with a
      complaint of oral malodor remain largely unable to score their own bad breath in
      an objective fashion. In addition, they are not capable of sensing reductions in
      oral malodor 1 year following the original assessment, even though, from a
      clinical standpoint, improvements have taken place.

PMID- 10635288
TI  - Clinical dilemmas posed by patients with psychosomatic halitosis.
AB  - Patients affected by psychosomatic halitosis never wish to visit a psychologic
      specialist, because they cannot recognize their own psychosomatic condition. They
      also never doubt that they have offensive oral malodor. Other people's behavior,
      such as covering the nose or averting the face, is interpreted by these patients
      as an indication that their breath is offensive, and these behaviors or attitudes
      reinforce their belief that they have a strong oral malodor. To clarify whether
      the patient's perception of another individual's attitude is affected by his or
      her delusion, this article is focused on the relationship between the behavior
      toward oral malodor and the psychologic profiles of patients with psychosomatic
      halitosis. If a patient expects simple avoidance behavior from other individuals,
      the development of psychosomatic halitosis may be accelerated, as it becomes a
      self-fulfilling prophecy. Individuals who are concerned with their own oral
      malodor but exhibit no oral malodor may have latent psychosomatic tendencies and
      may be mentally immature. A protocol for referring a patient to a psychologic
      specialist is presented.

PMID- 10635289
TI  - Cell and molecular biology of olfaction.
AB  - Genetics, experience, environment, and health can all affect the anatomic and
      physiologic components of the olfactory system and thereby influence olfactory
      performance. Large individual differences exist among subjects with respect to
      olfactory sensitivity and identification ability, which may result in both
      qualitative and quantitative differences in perceptual ability.

PMID- 10635290
TI  - Function of gingival fibroblasts and periodontal ligament cells in the presence
      of methyl mercaptan.
AB  - OBJECTIVE: This study examined the effects of methyl mercaptan, a product of the
      bacterial putrefaction of protein in periodontal pockets, on the function of
      cells in culture. METHOD AND MATERIALS: Human gingival fibroblasts and
      periodontal ligament cells were exposed to a constant, continuous flow of methyl
      mercaptan in vitro. Control and test cultures were then examined for changes in
      intracellular pH, an event often associated with alterations in cellular
      function. Intracellular pH was determined by single-cell image analysis of cells
      loaded with a fluorescent, pH-sensitive dye. Periodontal ligament cells were also
      tested for changes in synthesis of total protein and fibronectin. RESULTS: Test
      cells exhibited a consistent decrease in intracellular pH following exposure to
      methyl mercaptan. Measurements of total protein production showed that test
      periodontal ligament cell cultures produced approximately 30% less protein than
      control cultures (P < 0.05). Western-blot analysis of fibronectin in medium
      demonstrated that abnormal monomeric fibronectins were a major protein in test,
      but not in control, cell cultures. CONCLUSION: Exposure to methyl mercaptan
      induced alterations in intracellular events that paralleled changes in
      extracellular matrix proteins. The observed changes in extracellular matrix
      proteins support the hypothesis that methyl mercaptan contributes to the
      progression of periodontal disease.

PMID- 10635291
TI  - In vitro volatile sulfur compound production of oral bacteria in different
      culture media.
AB  - OBJECTIVE: The purpose of this study was to detect the relative contribution of
      Porphyromonas gingivalis, Fusobacterium nucleatum, and Prevotella intermedia in
      the production of oral malodor. METHOD AND MATERIALS: The volatile sulfur
      compounds produced by these bacteria in vitro were measured semiquantitatively by
      a portable sulfide monitor. RESULTS: Samples from the tongue, tonsils, and
      pharynx showed a significantly higher production (550 ppb) of volatile sulfur
      compounds during the first 6 hours after anaerobic incubation in broths (brain
      heart infusion, Columbia, and Trypticase Soy) than after incubation in agar media
      (300 ppb) (P < 0.001). After 24 hours, values in broths and agars leveled off at
      350 ppb (P = 0.3) and remained constant during the next 6 days. Measurement of
      separate pure cultures showed that maximal volatile sulfur compound production
      was reached 6 hours after incubation (450 ppb for the 3 bacteria). Higher
      volatile sulfur compound values were measured in brain-heart infusion. When
      measurements of mixed cultures of the 3 pathogens were performed every 15
      minutes, the maximal value was reached after only 30 minutes of incubation
      (nearly 500 ppb). CONCLUSION: The in vitro volatile sulfur compound production of
      oral samples is preferably measured in broths. Maximal sulfur production from
      mixed cultures is reached after 30 minutes of incubation. Samples should always
      be inoculated at the same dilution.

PMID- 10635292
TI  - Modeling of the oral malodor system and methods of analysis.
AB  - Bacterial putrefaction is the central metabolic process involved in oral malodor
      and can easily be modeled in the salivary sediment system developed from
      centrifuged whole saliva. Methods used in this system for examining malodor have
      included measurement of (1) head space (gaseous-phase) and liquid-phase odors,
      organoleptically; (2) volatile sulfur compounds, by means of an electrochemical
      sensory instrument; (3) pH, Po2, and oxidation-reduction potential with
      appropriate respective electrodes; (4) the malodorous compounds indole and
      skatole, colorimetrically; (5) substrate levels and their effects; and (6)
      bacterial numbers and types. The simplicity of the system permits other analyses
      to be easily added, if needed, and the influence of factors and agents that
      affect oral malodor to be assessed. Addition of odorigenic or non-odorigenic pure
      cultures to the mixed bacterial flora of the system enables modification of the
      microflora composition and high- and low-odor-production microflora to be
      simulated and compared. Modeling validity has been enhanced by the use of
      complementary in vivo methods, such as a method used to measure the ability or
      potential of an oral microbial flora to produce malodor. The method involves in
      vivo challenge testing with cysteine, an amino acid, and measuring the hydrogen
      sulfide produced. Oral malodor is a multifactorial condition and models enable
      its systematic study and the quantitative testing of antimalodor agents.

PMID- 10635293
TI  - [Dendritic cells and tumor specific immunity].
AB  - Dendritic cells (DCs) are the most efficient antigen presenting cells (APCs) that
      initiate and modulate our internal immune responses in stimulating both B cells
      to produce various antibodies and T cells to control cell-mediated immunity. Such
      DCs can be classified into three groups based on their origin. One is the myeloid
      DCs originating from CD34+ stem cells that are further differentiated into CD14+
      CD1a- phagocytotic, glass-adherent macrophages with the help of M-CSF, or into
      CD14- CD1a+, Birbeck granule containing LAG-1+ Langerhans cells by GM-CSF, TNF
      alpha and TGF-beta 1 stimulation. The latter Langerhans cells appear to
      differentiate into DC1 as strong stimulators of T cells displaying large amounts
      of MHC-peptide complexes and co-stimulatory molecules, such as B7-1 and B7-2,
      after capturing antigens and migrating to a regional lymphoid organ. The second
      group is the lymphoid DCs originating from CD4+CD11c- cells, which differentiate
      into DC2 when cultured with IL-3. Third is the follicular dendritic cells (FDC)
      observed in lymphofollicules that capture foreign antigens with their Fc-receptor
      or complement-receptors and keep the antigens inside the follicules. DC1s secrete
      IL-12, which turns CD4 T cells into Th1 cells to induce cellular immunity,
      whereas DC2s favor production of Th2 cells to organize humoral immunity.
      Therefore, DCs appear to control our internal self-defense system. These unique
      features of DCs enable us to manipulate Th1 and Th2 activation selectively, and
      thus antigen-pulsed DCs are currently thought of as excellent tools to induce
      specific T cell immunity towards virus-infected cells or tumor cells.

PMID- 10635294
TI  - [Detection of numerical aberrations in chromosomes by fluorescence in situ
      hybridization in fine needle aspirates in the preoperative diagnosis of cancer].
AB  - Fine needle aspiration (FNA) samples were obtained from 176 breast tumors
      suspected of malignancy, which were then subjected to conventional cytological
      and fluorescence in situ hybridization (FISH) analyses using the centromeric
      probes for chromosomes 1, 11, and 17. Histological examination revealed 157
      breast cancers and 19 benign diseases (ten fibroadenomas, six intraductal
      papillomas, one intracystic papilloma, and two ADH). Sensitivity, specificity,
      and diagnostic accuracy were 85.4% 94.7%, and 86.4%, respectively, for cytology
      and 90.4%, 100%, and 91.5%, respectively, for FISH. These results demonstrate
      that FISH diagnosis of FNA samples has a diagnostic accuracy comparable to that
      of conventional cytology.

PMID- 10635295
TI  - [Role of angiogenesis in lung cancer and its metastases].
AB  - Although the modalities for the diagnosis and treatment of lung cancer patients
      have been improved, the prognosis of the patients is still poor. However, new
      technology and advances in the fields of molecular and cell biology have allowed
      investigators to explore the mechanisms of growth, invasion, and metastasis of
      lung cancer. In fact, it has been reported that angiogenesis is necessary for the
      growth and metastasis of lung cancer, thus indicating the therapeutic target.
      Moreover, VEGF has been shown to be essential not only for angiogenesis but also
      for the formation of pleural effusions produced by lung cancer via induction of
      vascular hyperpermeability. Here, we review recent findings on angiogenesis in
      lung cancer, and the possibility of the clinical use of antiangiogenic agents for
      lung cancer patients.

PMID- 10635296
TI  - [Molecular biology in gastric cancer].
AB  - In gastric cancer, the process of carcinogenesis is thought to occur as a
      stepwise accumulation of genetic abnormalities. However, the mechanisms of the
      process of multistage carcinogenesis is still unknown for gastric cancer. Gene
      abnormalities seen in gastric cancer, including ras, myc, c-erbB-2, met, K-sam
      and cript are summarized herein. Abnormalities of cancer suppressor genes,
      including p53, RB and APC are also described. In our studies, the biological
      malignancy of patients with c-erbB-2 amplification was higher than that of
      patients without amplification. Moreover, the cases with amplification of c-erbB
      2 were found to be highly correlated with distant organ metastasis. However, very
      little is currently known of the molecular abnormalities leading to gastric
      cancer. In order to clarify the multiple gene abnormalities in gastric cancer, we
      used the method of restriction landmark genomic scanning (RLGS). RLGS provides a
      useful method for genomic analysis of gastric cancer. In the future, new
      analytical methods that will permit screening of all gene abnormalities at once
      promise to improve our understanding of the mechanisms of gastric cancer.

PMID- 10635297
TI  - [Molecular biology in the development of colorectal cancer].
AB  - In 1988, Vogelstein and colleagues published a paper entitled "Genetic
      alterations during colorectal-tumor development." This marked the beginning of a
      series of advances in our understanding of how colorectal cancer develops. This
      paper also provided evidence for the adenoma-carcinoma sequence. Furthermore, the
      importance of DNA mismatch repair genes in hereditary nonpolyposis colorectal
      cancer has been recognized. We herein discuss the development of colorectal
      cancer on the basis of molecular biology, including specific abnormalities of
      related genes.

PMID- 10635298
TI  - [Molecular mechanism of hepatocarcinogenesis].
AB  - Hepatocellular carcinoma (HCC) in Japan is closely associated with the chronic
      liver diseases of infection with the hepatitis B or C viruses. Analysis of HCC
      tissues frequently detects loss of heterozygosity at chromosomes 1p, 4, 6q, 8p,
      10q, 13q, 16q, 17p, and many genomic and epigenomic abnormalities have been found
      in p53, beta-catenin, p16CDKI, DNA mismatch repair genes, and others. However, no
      specific abnormal genetic or epigenetic changes for HCC have been found so far.
      The development of HCC has been reported in mice transgenic for the hepatitis B
      virus X gene or the hepatitis C virus core gene, and these viral proteins might
      play essential roles in hepatocarcinogenesis. Chronic hepatitis and fibrosis due
      to persistent viral infection might also influence the genomic instability of
      hepatocytes, leading to accumulation of genomic changes.

PMID- 10635299
TI  - [Molecular biology of ovarian cancer].
AB  - It has been suggested that the accumulation in multiple steps of gene abnormality
      is related to the malignant transformation of the normal cell. Understanding such
      abnormalities would be useful in the establishment of effective measures for the
      early detection and treatment of cancers with poor prognoses. In gynecological
      malignancies, the prognosis for epithelial ovarian cancer is poor even though
      great numbers of patients are treated with multimodal therapy. Uncovering the
      genes associated with the epithelial ovarian cancer crisis could lead to the
      identification of high risk cases, and accurate screening could open the way to
      early detection. Among the genes searched to date for abnormalities related to
      ovarian cancer, BRCA1 is thought to be the most likely candidate for having a
      causal relation with the familial ovarian cancer syndrome.

PMID- 10635300
TI  - [5-FU sensitivity and thymidylate synthase in gastric cancer].
AB  - The relationship of 5-FU-sensitivity to thymidylate synthase (TS) was
      investigated in a total of 82 gastric cancers of stage III or IV. The sensitivity
      test was done by Histoculture Drug Response Assay and TS expression was stained
      immunohistochemically using anti-TS antibody. Sensitivity to 5-FU of more than
      50% of the inhibitory index (high sensitivity) was observed in 28.1% of the
      materials, less than 50% (low sensitivity) in 71.9% and less than 20% in 50.0%.
      The expression of TS was found in 25.6% of the patients. The incidence of
      positive TS expression was 34.5% in the high sensitivity group, against 22.0% in
      the low sensitivity group, with no statistical difference between them. No
      particular relationship was found between 5-FU-sensitivity group and TS
      expression rate when the tumor-histology was divided into high and low
      differentiation. In the present study, the ratio of patients negative for TS
      among the high 5-FU-sensitivity group both was 65.2%, both of which have been
      reported as producing high survival rates. In contrast, the ratio of patients
      positive for TS in the low 5-FU-sensitivity group was 22.0%. From these results,
      TS is considered to be responsible for approximately 40-50% of either high or low
      5-FU-sensitivity, respectively, when the lower TS expression in the present study
      was taken into consideration and corrected.

PMID- 10635301
TI  - [PMC (pharmacokinetic modulating chemotherapy) for advanced gastric cancer].
AB  - We performed pharmacokinetic modulating chemotherapy (PMC) postoperatively in
      patients with advanced gastric cancer and examined its antitumor and the side
      effects. Nineteen patients with advanced gastric cancer (all were above Stage II)
      were treated: 10 had undergone total gastrectomy and 9 distal gastrectomy. UFT
      (400 mg/day) was orally administered daily and a continuous infusion of 5-FU (600
      mg/m2/24 hr) was given once a week. The average observation period was 14.26
      months (4-30 months). All patients with Stage II or III disease have survived,
      but two patients with Stage IV disease died. One patient received insufficient
      PMC and the other had a liver metastasis. Two patients experienced Grade 3
      inappetence, but all other side effects were Grade 2 or lower and the incidence
      was less than 25%. In conclusion. PMC has tolerable side effects and may be
      effective in postoperative chemotherapy for advanced gastric cancer.

PMID- 10635302
TI  - [Usefulness of pharmacokinetic modulating chemotherapy (PMC) for the
      postoperative adjuvant therapy of colorectal carcinoma: a preliminary report].
AB  - Pharmacokinetic modulating chemotherapy (PMC) using oral UFT and continuous
      venous 5-FU infusion was administered to 22 resectable patients with Dukes' B2-D
      colorectal carcinomas. The regimen was arranged as follows: Group A (n = 12) UFT
      300-450 mg/day, 5 days a week and 5-FU 440-600 mg/m2/24 hr (750-1,000 mg/body/24
      hr) once a week, Group B (n = 10), UFT less than 300 mg/day, 5 days a week, and/
      or 5-FU less than 440 mg/m2/24 hr (750 mg/body/ 24 hr) once a week. The control
      group (Group C, n = 26) was selected at random from among non-PMC cases matched
      for other background factors and in which surgery had been performed during the
      past 4 years. Fifteen out of 26 patients in Group C were treated with 5-FU masked
      compounds orally. The cumulative 2 year recurrent rates of Groups A, B and C were
      8.3%, 52.0% and 50.0%, respectively; the rate of Group A was significantly lower
      than that of Group B (p < 0.05). Four patients who suffered from PMC-related side
      effects of grade 1-2 wanted to decrease their dosage of UFT and/or 5-FU. They
      were registered in Group B. These results suggest that the regimen of Group A was
      advantageous in improving the prognosis after resection of Dukes' B2-D colorectal
      carcinoma.

PMID- 10635303
TI  - [Detection of serum p53 antibodies in colorectal cancer patients and the clinical
      significance of postoperative monitoring].
AB  - p53 protein overexpression was found to induce the production of antibodies in
      patient serum and, recently, the easy detection of serum antibodies has been made
      possible. The aim of this study is to determine the significance of serum p53
      antibodies in patients with primary colorectal adenocarcinoma in comparison with
      their clinicopathological features, and the tumor marker sensitivities of
      carcinoembryonic antigen (CEA), carcinoma antigen 19-9 (CA19-9) and alpha
      fetoprotein (AFP). Thirty-nine of 86 patients (45.3%) were positive for serum p53
      antibodies. However, there was no relation with the cancer progression or
      clinicopathological findings. The sensitivities of CEA, CA19-9 and AFP were
      36.0%, 38.4%, and 8.1% respectively, but there was no relation between serum p53
      antibodies and these three markers. When the sensitivity of serum p53 antibodies
      and CEA was evaluated according to clinical stage, the presence of serum p53
      antibodies was more significantly associated with stage 0, I and II colorectal
      cancer than was CEA. Thirty-three patients who showed preoperative positivity for
      serum p53 antibodies were followed by serial evaluation of circulating antibodies
      after resection. Negative conversions after resection were significantly higher
      in the "Cur A" group than in the "Cur B" or "Cur C" groups. Serum p53 antibodies
      appear to be a useful tumor marker independent of the other markers, especially
      in the early stage, and are expected to be useful in the development of a method
      of early diagnosis for mass screening, and as a postoperative monitoring marker
      for colorectal cancer.

PMID- 10635304
TI  - [Merocyanine 540-mediated photodynamic therapy inhibits P-glycoprotein (P-gp)
      activity in adriamycin-resistant K562 cells].
AB  - The photosensitizing dye merocyanine 540 (MC540) has been used in preclinical
      models and in a phase I clinical trial in the U.S.A. for the extracorporeal
      purging of autologous bone marrow grafts contaminated with leukemia or lymphoma.
      In this communication, we report MC540-mediated photodynamic therapy (PDT) was
      effective in purging leukemic cells expressing P-gp. When K562 and K562/ADM were
      exposed to MC540 (15 micrograms/ml) and white light (145.8 kJ/m2), the
      concentration of K562 and K 562/ADR was reduced by 1.8 and 3.0 log, respectively.
      Using flow cytometry and confocal laser scan microscopy, MC540 and calcein-AM
      were bound intracellularly and effluxed by P-gp in K562/ADM. In K562/ADM, calcein
      AM efflux was inhibited by P-gp modulator, cyclosporin A (5 microM) and verapamil
      (15 micrograms/ml). In contrast, MC540 efflux was inhibited by cyclosporin A but
      not verapamil. Furthermore, MC540-mediated PDT inhibited efflux of calcein-AM and
      MC540, and induced the accumulation of dyes in K562/ADM. We conclude that MC540
      is a substrate of P-gp and that MC540-mediated PDT is useful for purging MDR
      cells through inhibition of P-gp activity.

PMID- 10635305
TI  - [Sequential changes in hormone levels in postmenopausal breast cancer patients
      under long-term treatment with an aromatase inhibitor. Kanagawa AI Study Group].
AB  - Sequential changes in hormone levels were assessed for one year in postmenopausal
      breast cancer patients administered the aromatase inhibitor fodrozole
      hydrochloride hydrate (Afema) in order to evaluate its efficacy and safety in
      long-term treatment. Forty patients received Afema alone as postoperative
      adjuvant therapy, while 30 received it with 5-FU. Plasma estrone and estradiol
      levels decreased significantly in both groups (p < 0.001) and were not affected
      by body mass index (BMI). Plasma androstenedione and testosterone levels
      increased within the normal range. Aldosterone levels hit bottom 3 months after
      treatment was started, and tended to return to the pre-treatment baseline
      thereafter. Plasma cortisol levels increased significantly within the normal
      range. FDP and alpha 2-PIPC, parameters related to blood coagulation and
      fibrinolysis, showed no significant change. Adverse reactions, mainly nausea and
      elevation of LDH levels, were all slight. Thus, long-term administration of Afema
      resulted in significant decreases in estrogen levels with few adverse reactions
      regardless of the BMI, suggesting that it can be safely used as effective
      postoperative adjuvant therapy.

PMID- 10635306
TI  - [Phase I study of a combination chemotherapy of nedaplatin and cisplatin].
AB  - A new platinum complex, nedaplatin, has been reported to be effective for both
      ovarian and cervical cancers. We designated a phase I dose-escalation study of a
      combination chemotherapy of nedaplatin and cisplatin to investigate the dose
      limiting toxicity (DLT) and the maximum tolerated dose (MTD). Six patients,
      including two with advanced cervical cancer, three with ovarian clear cell
      adenocarcinoma and one with endometrial clear cell adenocarcinoma, were enrolled
      in this study. The doses of the two agents were escalated alternatively, i.e., a
      tandem method, from 40 to 80 mg/m2 by 20 mg/m2. Nedaplatin and cisplatin were
      administrated by intravenous drip infusion and repeated after an interval of at
      least 4 weeks, as a rule. The major toxicity observed was hematotoxicity. One of
      the 6 patients dropped out of this study because of severe hematotoxicity after
      80 mg/m2 of nedaplatin and 60 mg/m2 of cisplatin were administered. With a dose
      of 80 mg/m2 nedaplatin and 80 mg/m2 cisplatin, severe neutropenia was found in
      all 6 patients, and thrombocytopenia and anemia were found in 1 patient,
      respectively. A slight hearing loss was detected by audiometry in 5 patients, but
      no one was inconvenienced in daily life. Mild nausea and vomiting were also
      observed in all 6 patients. In conclusion, the DLT of this combination therapy
      was hematotoxicity and the MTD was 80 mg/m2 for nedaplatin and 60 mg/m2 for
      cisplatin, respectively. Thus, 60 mg/m2 of nedaplatin and 60 mg/m2 of cisplatin
      may be recommended for combined administration.

PMID- 10635308
TI  - [A case of synchronous bilateral double primary lung cancer successfully treated
      by Nd-YAG laser therapy and chemotherapy].
AB  - A 61-year-old man was admitted to our hospital with the chief complaint of
      hemosputum. He was a heavy smoker. A chest radiograph revealed a tumor shadow in
      right S3 which invaded the pulmonary artery. There was also an associated patchy
      shadow in the periphery as well as ipsilateral pleural effusion. Bronchoscopy
      revealed a near occlusion with superficial infiltration at the right B3 bronchus
      and a nodular tumor at the bifurcation between the left upper and lingual
      division bronchi, which was consistent with endoscopic early lung cancer.
      Although both tumors were histologically diagnosed as squamous cell carcinoma,
      this was considered to be a case of synchronous double primary lung cancer due to
      their mutual isolation. The left tumor was subsequently diagnosed as carcinoma in
      situ. Following Nd-YAG laser therapy for carcinoma in situ and 4 courses of
      systemic chemotherapy using TXT and CDDP, bronchoscopy revealed no residual
      cancerous tissue and no tumor apart from the nodular shadow in right S3 was seen
      on a radiograph. Subsequent right upper and middle lobectomy and lymph node (R2a)
      dissection revealed no residual tumors.

PMID- 10635307
TI  - [Optimal timing of granisetron administration for the prevention of carboplatin
      induced acute emesis].
AB  - This prospective pilot study was undertaken to determine whether delayed
      administration of one of the serotonin-receptor antagonists (granisetron) reduced
      carboplatin--induced emesis. The subjects were patients who were scheduled to
      undergo at least three courses of carboplatin based chemotherapy, in whom acute
      emesis occurred at the first course. Granisetron was administered therapeutically
      for the first course. Conventional prophylactic granisetron was given 30 min
      before carboplatin administration for the second course. For the third course,
      granisetron was administered 5 hr after completion of carboplatin administration.
      The degrees of appetite loss, nausea and frequency of vomiting on the Day 1 were
      compared between the three courses. Thirteen patients were evaluated. Acute
      emesis occurred 8 +/- hr after completion of carboplatin administration in the
      first courses of these patients. The degree of nausea and frequency of vomiting
      were reduced by administrating the granisetron five hours after carboplatin when
      compared with therapeutic granisetron administration or administration 30 min
      before carboplatin. The degree of appetite loss was significantly lowered by
      administering the granisetron 5 hr after carboplatin administration.
      Administration of granisetron 5 hr after carboplatin may thus lessen carboplatin
      induced emesis more than conventional granisetron administration. A large-scale
      comparative study is warranted.

PMID- 10635309
TI  - [Effective and low toxicity chemoradiotherapy for distant metastatic esophageal
      cancer].
AB  - A sixty-seven-year-old male who had T4N4M1 (stage IV) advanced esophageal cancer
      with bilateral pulmonary and multiple lymph-node metastases received 1-hr drip
      intravenous infusions of low-dose cisplatin (CDDP) at 7 mg/m2 on Days 1-5, 8-12,
      15-19, and 22-26, protracted intravenous infusions of 5-fluorouracil at 200 mg/m2
      on Days 1-28, and X-ray therapy of 2 gray/fraction x 5 fractions/week (total 40
      Gy; LDFPX therapy). XRT was also administered alone (total 60 Gy). After 1 course
      of LDFPX therapy, the primary and multiple lymph node metastases responded
      completely. The bilateral pulmonary metastases were remarkably reduced in size
      and performance status improved. After that we tried low dose CDDP 10 mg/body
      twice a week and UFT 600 mg/body (LDP + UFT therapy) on an outpatient basis.
      Especially, bilateral pulmonary metastases were more reducing tumor size by LDP +
      UFT therapy. These treatments had a therapeutic effect and very low toxicity.
      This chemotherapy is thought to be effective against advanced esophageal cancer.

PMID- 10635310
TI  - [A case of stage IV esophageal cancer successfully treated by chemoradiation].
AB  - A 63-year-old man was admitted to our institution with a hard tumor on the left
      side of the neck. He was diagnosed as having advanced esophageal cancer (Stage
      IV) with a massive supraclavicular lymph node metastasis, and the lesion was
      thought to be unresectable. He was treated with chemotherapy (CDDP-VDS-5-FU) and
      radiation therapy, and all the tumors completely disappeared on endoscopic and CT
      examination. A stricture with scarring was detected in the esophagus at 6 months
      after treatment. No neoplastic tissue was detected in the lesion, and his
      dysphagia was relieved by dilation of the stricture. Recurrence on the left side
      of the neck was detected by CT at 2.5 years after chemoradiation therapy.
      However, the tumor has not grown over the 2-year interval since then, so it seems
      to be dormant. He has now survived with a good QOL for 5 years since the first
      hospital admission. We conclude that advanced esophageal cancer can be treated
      with chemoradiation therapy if the patient is in sufficiently good overall
      condition.

PMID- 10635311
TI  - [A case of stage IV (A3) cervical and upper thoracic esophageal adenocarcinoma
      successfully treated with concurrent chemoradiotherapy].
AB  - We report a case of cervical and upper thoracic esophageal adenocarcinoma with
      tracheal stenosis and bilateral recurrent nerve palsy. A 64-year-old man with
      unresectable esophageal cancer (A3, N1, M0) was treated with concurrent
      chemoradiotherapy. A dose of 67.4 Gy was irradiated to the cervical and upper
      thoracic area where the primary tumor and lymph node metastases were located, and
      six courses of 5-FU (250 mg/24 h/day 1-5) and CDDP (5 mg/1 h, just before
      radiation/day 1-5) were delivered concurrently. The esophageal tumor showed a
      complete response (CR), and the paratracheal lymph node metastases showed partial
      responses (PR). The reason these therapies were more effective against the tumor
      than the lymph node metastases is uncertain. The patient is no longer required to
      stay in the hospital, and his QOL has been improving. His condition has been
      maintained for 4 months, so this type of concurrent chemoradiotherapy may be
      recommended for cervical and upper thoracic esophageal adenocarcinoma.

PMID- 10635312
TI  - [Hemodynamics at hepatoarterial infusion of 5-FU in a chronic renal failure
      patient maintained by hemodialysis].
AB  - The authors studied the hemodynamics of 5-FU hepatoarterial infusion in a
      colorectal cancer patient with multiple liver metastases, who had chronic renal
      failure maintained by hemodialysis. Under weekly high dose 5-FU hepatoarterial
      infusion (1,000 mg/m2, 5 hours), on a non-dialysis day, serum 5-FU concentration
      was 1,090 ng/ml just after the 5 h infusion, 391 ng/ml at 15 min, 217 ng/ml at 30
      min, 47 ng/ml at 60 min, and < 4 ng/ml at 120 min after infusion. On a dialysis
      day it was 1,500 ng/ml just after infusion, 41 ng/ml at 15 min, 5 ng/ml at 30
      min, and < 4 ng/ml at 60 and 120 min after infusion. A control group (n = 4), who
      had liver metastases from colorectal cancers and normal renal functions, showed 5
      FU serum concentration of 987 +/- 384 ng/ml just after infusion, 226 +/- 117
      ng/ml at 15 min, 18.5 +/- 5.8 ng/ml at 30 min, < 4 ng/ml at 60 and 120 min after
      infusion. The serum 5-FU concentration of the patient was maintained higher on
      non-dialysis days, while it decreased more rapidly on dialysis days than that of
      the control group. There were no clinical complications due to the weekly high
      dose 5-FU hepatoarterial infusion. Under the treatment of continuous 5-FU
      hepatoarterial infusion (500 mg/day), the serum 5-FU concentration of this
      patient was kept under 115 ng/ml. After hemodialysis, the concentration
      decreased. The serum 5-FU concentration of the control group (n = 4) was under 66
      ng/ml. There were no side effects under the protocol of continuous 5-FU
      hepatoarterial infusion. 5-FU hepatoarterial infusion for liver metastasis was a
      safe treatment for a renal failure patient with hemodialysis.

PMID- 10635313
TI  - [Roles of matrix metalloproteinases and tissue inhibitor of metalloproteinase
      (TIMP) in cancer invasion and metastasis].
AB  - During the progression of cancer invasion and metastasis, remodeling such as
      degradation of extracellular matrices (ECM) in cancer tissues and surrounding
      tissues is the most important event. Degradation of ECM modulates cell-cell and
      cell-matrix interactions, and this changes cell behavior and the cell
      microenvironment. This review considers the cellular and organismal function of
      matrix metalloproteinases, especially of membrane-type matrix metalloproteinases,
      and their inhibitor, tissue inhibitor of metalloproteinase (TIMP).

PMID- 10635314
TI  - Modes of protein movement that lead to the asymmetric localization of partner of
      Numb during Drosophila neuroblast division.
AB  - Partner of Numb (Pon) colocalizes with the determinant Numb and is required for
      its proper asymmetric localization in Drosophila. How the asymmetric localization
      of Pon is accomplished is not well understood. Here, we show that Pon
      localization takes place at the protein level and that its C-terminal region is
      necessary and sufficient for asymmetric localization. Fusion of the Pon
      localization domain with green fluorescent protein (GFP) allowed monitoring of
      the localization process in living embryos. Upon a neuroblast's entry into
      mitosis, Pon is recruited from the cytoplasm to the cortex. Cortically recruited
      Pon can move apically or basally within the two-dimensional confines of the
      cortex. This movement can occur when myosin motor activity is inhibited. However,
      the restriction of Pon to the basal cortex requires both actomyosin and
      Inscuteable.

PMID- 10635315
TI  - Presenilin-1 forms complexes with the cadherin/catenin cell-cell adhesion system
      and is recruited to intercellular and synaptic contacts.
AB  - In MDCK cells, presenilin-1 (PS1) accumulates at intercellular contacts where it
      colocalizes with components of the cadherin-based adherens junctions. PS1
      fragments form complexes with E-cadherin, beta-catenin, and alpha-catenin, all
      components of adherens junctions. In confluent MDCK cells, PS1 forms complexes
      with cell surface E-cadherin; disruption of Ca(2+)-dependent cell-cell contacts
      reduces surface PS1 and the levels of PS1-E-cadherin complexes. PS1
      overexpression in human kidney cells enhances cell-cell adhesion. Together, these
      data show that PS1 incorporates into the cadherin/catenin adhesion system and
      regulates cell-cell adhesion. PS1 concentrates at intercellular contacts in
      epithelial tissue; in brain, it forms complexes with both E- and N-cadherin and
      concentrates at synaptic adhesions. That PS1 is a constituent of the
      cadherin/catenin complex makes that complex a potential target for PS1 FAD
      mutations.

PMID- 10635316
TI  - Multiple ephrins control cell organization in C. elegans using kinase-dependent
      and -independent functions of the VAB-1 Eph receptor.
AB  - Eph receptor (EphR) tyrosine kinases and their ephrin ligands mediate direct cell
      to-cell signaling. The C. elegans genome encodes four potential GPI-modified
      ephrins (EFN-1 to -4) and one EphR (VAB-1). Single and multiple ephrin mutants
      reveal functions for EFN-1, EFN-2, and EFN-3 in epidermal cell organization that,
      in aggregate, mirror those of VAB-1. Ephrin mutants have defects in head
      morphology and enclosure of the embryo by the epidermis and identify ephrin-EphR
      signaling functions involved in aligning and fusing tail and head epidermal
      cells, respectively. Biochemical analyses indicate that EFN-1, EFN-2, and EFN-3
      jointly activate the VAB-1 tyrosine kinase in vivo. Mutant phenotypes and
      expression pattern analysis suggest that multiple ephrins are involved in
      distinct aspects of kinase-dependent and kinase-independent VAB-1 signaling
      required for proper cell organization during development in C. elegans.

PMID- 10635318
TI  - The engagement of Sec61p in the ER dislocation process.
AB  - Sec61p comprises the endoplasmic reticulum (ER) channel through which nascent
      polypeptides are imported and from which malfolded proteins have been suggested
      to be exported, or dislocated, back to the cytoplasm. We have devised a genetic
      screen for dislocation-specific mutant alleles of SEC61 from S. cerevisiae by
      employing the unfolded protein response to report on the accumulation of
      misfolded proteins in the ER. Three of the isolated sec61 alleles are fully
      proficient in protein translocation into the ER, but defective in the elimination
      of a misfolded ER luminal substrate and a short-lived ER membrane-spanning model
      protein, which are otherwise rapidly degraded by cytoplasmic proteolysis in wild
      type cells. Our results point to the fourth luminal loop and third transmembrane
      domain of Sec61p that markedly influence dislocation. We suggest that distinct
      features of the Sec61-translocon direct the two-way translocation processes.

PMID- 10635317
TI  - Selective requirement for Src kinases during VEGF-induced angiogenesis and
      vascular permeability.
AB  - Src kinase activity was found to protect endothelial cells from apoptosis during
      vascular endothelial growth factor (VEGF)-, but not basic fibroblast growth
      factor (bFGF)-, mediated angiogenesis in chick embryos and mice. In fact,
      retroviral targeting of kinase-deleted Src to tumor-associated blood vessels
      suppressed angiogenesis and the growth of a VEGF-producing tumor. Although mice
      lacking individual Src family kinases (SFKs) showed normal angiogenesis, mice
      deficient in pp60c-src or pp62c-yes showed no VEGF-induced vascular permeability
      (VP), yet fyn-/- mice displayed normal VP. In contrast, inflammation-mediated VP
      appeared normal in Src-deficient mice. Therefore, VEGF-, but not bFGF-, mediated
      angiogenesis requires SFK activity in general, whereas the VP activity of VEGF
      specifically depends on the SFKs, Src, or Yes.

PMID- 10635319
TI  - The RAG1/RAG2 complex constitutes a 3' flap endonuclease: implications for
      junctional diversity in V(D)J and transpositional recombination.
AB  - During V(D)J recombination, processing of branched coding end intermediates is
      essential for generating junctional diversity. Here, we report that the RAG1/
      RAG2 recombinase is a 3' flap endonuclease. Substrates of this nuclease activity
      include various coding end intermediates, suggesting a direct role for RAG1/ RAG2
      in generating junctional diversity during V(D)J recombination. Evidence is also
      provided indicating that site-specific RSS nicking involves RAG1/RAG2-mediated
      processing of a localized flap-like structure, implying 3' flap nicking in
      multiple DNA processing reactions. We have also demonstrated that the bacterial
      transposase Tn10 contains a 3' flap endonuclease activity, suggesting a
      mechanistic parallel between RAG1/RAG2 and other transposases. Based on these
      data, we propose that numerous transposases may facilitate genomic evolution by
      removing single-stranded extensions during the processing of excision site
      junctions.

PMID- 10635320
TI  - Reciprocal control of catalysis by the tyrosine recombinases XerC and XerD: an
      enzymatic switch in site-specific recombination.
AB  - In Xer site-specific recombination, sequential DNA strand exchange reactions are
      catalyzed by a heterotetrameric complex composed of two recombinases, XerC and
      XerD. It is demonstrated that XerC and XerD catalytic activity is controlled by
      an interaction involving the C-terminal end of each protein (the donor region)
      and an internal region close to the active site (the acceptor region). Mutations
      in these regions reciprocally alter the relative activity of XerC and XerD, with
      their combination producing synergistic effects on catalysis. The data support a
      model in which C-terminal intersubunit interactions contribute to coupled protein
      DNA conformational changes that lead to sequential activation and reciprocal
      inhibition of pairs of active sites in the recombinase tetramer during
      recombination.

PMID- 10635321
TI  - An early developmental transcription factor complex that is more stable on
      nucleosome core particles than on free DNA.
AB  - In vivo footprinting studies have shown that transcription factor binding sites
      for HNF3 and GATA-4 are occupied on the albumin gene enhancer in embryonic
      endoderm, prior to the developmental activation of liver gene transcription. We
      have investigated how these factors can stably occupy silent chromatin.
      Remarkably, we find that HNF3, but not GATA-4 or a GAL4 control protein, binds
      far more stably to nucleosome core particles than to free DNA. In the presence of
      HNF3, GATA-4 binds stably to an HNF3-positioned nucleosome. Histone acetylation
      does not affect HNF3 binding. This is evidence for stable nucleosome binding by a
      transcription factor and shows that a winged helix protein is sufficient to
      initiate the assembly of an enhancer complex on nonacetylated nucleosomes.

PMID- 10635322
TI  - Transcriptional regulation of an archaeal operon in vivo and in vitro.
AB  - The basal transcription apparatus of Archaea corresponds to the core machinery of
      the eucaryal RNA polymerase II system. However, it is not yet known how
      regulation of archaeal transcription is achieved. Examination of complete
      archaeal genome sequences reveals homologs of bacterial transcriptional
      regulators. We have studied one such molecule, MDR1, an A. fulgidus homolog of
      the bacterial metal-dependent transcriptional repressor, DtxR. We find that in
      vivo expression of the MDR1-containing operon is regulated by metal ion
      availability. In vitro analyses show that MDR1 recognizes three operator elements
      in its own promoter in a metal-dependent manner. MDR1 negatively regulates
      transcription of its own gene in a reconstituted in vitro system, not by
      abrogating the binding of TBP or TFB to the promoter but by preventing RNA
      polymerase recruitment.

PMID- 10635323
TI  - The spatial position and replication timing of chromosomal domains are both
      established in early G1 phase.
AB  - Mammalian chromosomal domains replicate at defined, developmentally regulated
      times during S phase. The positions of these domains in Chinese hamster nuclei
      were established within 1 hr after nuclear envelope formation and maintained
      thereafter. When G1 phase nuclei were incubated in Xenopus egg extracts, domains
      were replicated in the proper temporal order with nuclei isolated after spatial
      repositioning, but not with nuclei isolated prior to repositioning. Mcm2 was
      bound both to early- and late-replicating chromatin domains prior to this
      transition whereas specification of the dihydrofolate reductase replication
      origin took place several hours thereafter. These results identify an early G1
      phase point at which replication timing is determined and demonstrate a
      provocative temporal coincidence between the establishment of nuclear position
      and replication timing.

PMID- 10635324
TI  - A distal heterochromatic block displays centromeric activity when detached from a
      natural centromere.
AB  - We repeatedly released a distal block of heterochromatin lacking a natural
      centromere in mitotic cells and assayed its segregation. At anaphase, control
      acentric fragments typically remained unoriented between daughter nuclei and were
      subsequently lost. Fragments containing the brownDominant (bWD) heterochromatic
      element displayed regular anaphase movement upon release. These fragments were
      found to segregate and function based on both cytological and phenotypic
      criteria. We also found that intact bWD-containing chromosomes normally display
      occasional dicentric behavior, suggesting that bWD has centromeric activity on
      the intact chromosome as well. Our findings suggest that centromere competence is
      innate to satellite-containing blocks of heterochromatin, challenging models for
      centromere identity in which competence is an acquired characteristic.

PMID- 10635325
TI  - Near-cognate peptidyl-tRNAs promote +1 programmed translational frameshifting in
      yeast.
AB  - Translational frameshifting is a ubiquitous, if rare, form of alternative
      decoding in which ribosomes spontaneously shift reading frames during translation
      elongation. In studying +1 frameshifting in Ty retrotransposons of the yeast S.
      cerevisiae, we previously showed that unusual P site tRNAs induce frameshifting.
      The frameshift-inducing tRNAs we show here are near-cognates for the P site
      codon. Their abnormal decoding induces frameshifting in either of two ways: weak
      codon-anticodon pairing allows the tRNA to disengage from the mRNA and slip +1,
      or an unusual codon-anticodon structure interferes with cognate in-frame decoding
      allowing out-of-frame decoding in the A site. We draw parallels between this
      mechanism and a proposed mechanism of frameshift suppression by mutant tRNAs.

PMID- 10635326
TI  - Maskin is a CPEB-associated factor that transiently interacts with elF-4E.
AB  - In Xenopus, the CPE is a bifunctional 3' UTR sequence that maintains maternal
      mRNA in a dormant state in oocytes and activates polyadenylation-induced
      translation during oocyte maturation. Here, we report that CPEB, which binds the
      CPE and stimulates polyadenylation, interacts with a new factor we term maskin.
      Maskin contains a peptide sequence that is conserved among elF-4E-binding
      proteins. Affinity chromatography demonstrates that CPEB, maskin, and elF-4E
      reside in a complex in oocytes, and yeast two-hybrid analyses indicate that CPEB
      and maskin bind directly, as do maskin and elF-4E. While CPEB and maskin remain
      together during oocyte maturation, the maskin-elF-4E interaction is substantially
      reduced. The dissolution of this complex may result in the binding of elF-4E to
      elF-4G and the translational activation of CPE-containing mRNAs.

PMID- 10635327
TI  - Ubiquitin ligase activity and tyrosine phosphorylation underlie suppression of
      growth factor signaling by c-Cbl/Sli-1.
AB  - Receptor desensitization is accomplished by accelerated endocytosis and
      degradation of ligand-receptor complexes. An in vitro reconstituted system
      indicates that Cbl adaptor proteins directly control downregulation of the
      receptor for the epidermal growth factor (EGFR) by recruiting ubiquitin
      activating and -conjugating enzymes. We infer a sequential process initiated by
      autophosphorylation of EGFR at a previously identified lysosome-targeting motif
      that subsequently recruits Cbl. This is followed by tyrosine phosphorylation of c
      Cbl at a site flanking its RING finger, which enables receptor ubiquitination and
      degradation. Whereas all three members of the Cbl family can enhance
      ubiquitination, two oncogenic Cbl variants, whose RING fingers are defective and
      phosphorylation sites are missing, are unable to desensitize EGFR. Our study
      identifies Cbl proteins as components of the ubiquitin ligation machinery and
      implies that they similarly suppress many other signaling pathways.

PMID- 10635328
TI  - TRANCE, a TNF family member, activates Akt/PKB through a signaling complex
      involving TRAF6 and c-Src.
AB  - TRANCE, a TNF family member, and its receptor, TRANCE-R, are critical regulators
      of dendritic cell and osteoclast function. Here, we demonstrate that TRANCE
      activates the antiapoptotic serine/threonine kinase Akt/PKB through a signaling
      complex involving c-Src and TRAF6. A deficiency in c-Src or addition of Src
      family kinase inhibitors blocks TRANCE-mediated PKB activation in osteoclasts. c
      Src and TRAF6 interact with each other and with TRANCE-R upon receptor
      engagement. TRAF6, in turn, enhances the kinase activity of c-Src leading to
      tyrosine phosphorylation of downstream signaling molecules such as c-Cbl. These
      results define a mechanism by which TRANCE activates Src family kinases and PKB
      and provide evidence of cross-talk between TRAF proteins and Src family kinases.

PMID- 10635329
TI  - Formation of the VHL-elongin BC tumor suppressor complex is mediated by the
      chaperonin TRiC.
AB  - von Hippel-Lindau (VHL) disease is caused by loss of function of the VHL tumor
      suppressor protein. Here, we demonstrate that the folding and assembly of VHL
      into a complex with its partner proteins, elongin B and elongin C (herein,
      elongin BC), is directly mediated by the chaperonin TRiC/CCT. Association of VHL
      with TRiC is required for formation of the VHL-elongin BC complex. A 55-amino
      acid domain of VHL is both necessary and sufficient for binding to TRiC.
      Importantly, mutation or deletion of this domain is associated with VHL disease.
      We identified two mutations that disrupt the normal interaction with TRiC and
      impair VHL folding. Our results define a novel role for TRiC in mediating
      oligomerization and suggest that inactivating mutations can impair polypeptide
      function by interfering with chaperone-mediated folding.

PMID- 10635330
TI  - Structure of the lnlB leucine-rich repeats, a domain that triggers host cell
      invasion by the bacterial pathogen L. monocytogenes.
AB  - The L. monocytogenes protein lnlB activates phosphoinositide 3-kinase and induces
      phagocytosis in several mammalian cell types. The 1.86 A resolution X-ray crystal
      structure of the leucine-rich repeat domain of lnlB that is both necessary and
      sufficient to induce phagocytosis is presented here. The structure supports a
      crucial role for calcium in host cell invasion by L. monocytogenes and supplies a
      rationale for its function. Calciums are bound to the protein in an unusually
      exposed manner that suggests that the metals may act as a bridge between lnlB and
      mammalian cell surface receptors. The structure also identifies surfaces on the
      curved and elongated molecule that may constitute additional interaction sites in
      forming a bacterial-mammalian signaling complex.

PMID- 10635331
TI  - Notch signaling is not sufficient to define the affinity boundary between dorsal
      and ventral compartments.
AB  - The developing limbs of Drosophila are subdivided into distinct cells populations
      known as compartments. Short-range interaction between cells in adjacent
      compartments induces expression of signaling molecules at the compartment
      boundaries. In addition to serving as the sources of long-range signals,
      compartment boundaries prevent mixing of the adjacent cell populations. One model
      for boundary formation proposes that affinity differences between compartments
      are defined autonomously as one aspect of compartment-specific cell identity. An
      alternative is that the affinity boundary depends on signaling between
      compartments. Here, we present evidence that the dorsal selector gene apterous
      plays a role in establishing the dorsoventral affinity boundary that is
      independent of Notch-mediated signaling between dorsal and ventral cells.

PMID- 10635332
TI  - Inhibition of FEN-1 processing by DNA secondary structure at trinucleotide
      repeats.
AB  - The mechanism by which trinucleotide expansion occurs in human genes is not
      understood. However, it has been hypothesized that DNA secondary structure may
      actively participate by preventing FEN-1 cleavage of displaced Okazaki fragments.
      We show here that secondary structure can, indeed, play a role in expansion by a
      FEN-1-dependent mechanism. Secondary structure inhibits flap processing at CAG,
      CGG, or CTG repeats in a length-dependent manner by concealing the 5' end of the
      flap that is necessary for both binding and cleavage by FEN-1. Thus, secondary
      structure can defeat the protective function of FEN-1, leading to site-specific
      expansions. However, when FEN-1 is absent from the cell, alternative pathways to
      simple inhibition of flap processing contribute to expansion.

PMID- 10635333
TI  - Phosphorylation of rat serine 105 or mouse threonine 217 in C/EBP beta is
      required for hepatocyte proliferation induced by TGF alpha.
AB  - We report that TGF alpha induces activation of the p90 ribosomal S kinase (RSK),
      which results in the phosphorylation of rat C/EBP beta on Ser-105 and of mouse
      C/EBP beta on Thr-217 and concomitantly stimulates proliferation in
      differentiated hepatocytes. Moreover, C/EBP beta-/- mouse hepatocytes respond to
      TGF alpha when wild-type C/EBP beta is reexpressed, whereas they remain
      refractory to the growth effect of TGF alpha when expressing phosphoacceptor
      mutants rat C/EBP beta Ala-105 or mouse C/EBP beta Ala-217. In contrast, C/EBP
      beta-/- hepatocytes expressing the phosphorylation mimic mutants, rat C/EBP beta
      Asp-105 or mouse C/EBP beta Glu-217, exhibited marked proliferation in the
      absence of TGF alpha. Thus, a site-specific phosphorylation of the transcription
      factor C/EBP beta is critical for hepatocyte proliferation induced by TGF alpha
      and other stimuli that activate RSK.

PMID- 10635334
TI  - Genetic analysis of BRCA1 function in a defined tumor cell line.
AB  - Retrovirally expressed, wild-type BRCA1 decreased the gamma radiation (IR)
      sensitivity and increased the efficiency of double-strand DNA break repair (DSBR)
      of the BRCA1-/- human breast cancer line, HCC1937. It also reduced its
      susceptibility to DSB generation by IR. By contrast, multiple, clinically
      validated, missense mutant BRCA1 products were nonfunctional in these assays.
      These data constitute the basis for a BRCA1 functional assay and suggest that
      efficient repair of double-strand DNA breaks is linked to BRCA1 tumor suppression
      function.

PMID- 10635335
TI  - Inhibition of L-tyrosine-induced micronuclei production by phenylthiourea in
      human melanoma cells.
AB  - It was previously found that L-tyrosine oxidation product(s) are cytotoxic,
      genotoxic and increase the sister chromatid exchange (SCE) levels in human
      melanoma cells. In this work, the micronucleus assay has been performed on human
      melanotic and amelanotic melanoma cell lines (Carl-1 MEL and AMEL) in the
      presence of 1.0, 0.5 and 0.1 mM L-tyrosine concentrations to investigate if
      melanin synthesis intermediate(s) increase micronuclei production. L-Tyrosine
      oxidation product(s) increased the frequency of micronuclei in melanoma cells;
      0.1 mM phenylthiourea (PTU), an inhibitor of L-tyrosine oxidation by tyrosinase,
      lowered the micronucleus production to the control levels. The culture of
      melanoma cells with high L-tyrosine in the culture medium resulted in a positive
      response to an ELISA-based apoptotic test. For comparison the effect of L
      tyrosine on micronuclei production in human amelanotic melanoma cells was also
      investigated; the micronucleus production in the presence of 1 mM L-tyrosine in
      the culture medium was lower than that found with melanotic melanoma cells of the
      same cell line. The data suggest that melanin synthesis intermediates arising
      from L-tyrosine oxidation may cause micronuclei production in Carl-1 human
      melanoma cells; the addition of PTU in the presence of L-tyrosine decreased the
      frequency of micronuclei to about the control values thus the inhibition of
      melanogenesis may have some clinical implication in melanotic melanoma.

PMID- 10635336
TI  - The effect of hyperthermia on micronucleus induction by mutagens in mice.
AB  - We administered mitomycin C (0.5 mg/kg) intraperitoneally to hyperthermic-treated
      mice and examined the effect of hyperthermia on micronucleus induction.
      Hyperthermia enhanced micronucleus induction. The timing of chemical
      administration relative to the start of hyperthermic treatment (37 degrees C
      ambient temperature) influenced micronucleus frequency, and the effect was
      greatest 2 h after the start of hyperthermic treatment. But the hyperthermic
      treatment did not change the time course of micronucleus induction. In addition,
      we investigated the effect of hyperthermia on micronucleus induction by chemicals
      with different modes of action, i.e., alkylating agents (mitomycin C at 0.1-0.5
      mg/kg, cyclophosphamide at 1.25-10 mg/kg), a spindle poison (colchicine at 0.05
      1.0 mg/kg), and an antimetabolite (5-fluorouracil at 2.5-50 mg/kg). Hyperthermia
      enhanced only the clastogenicity of alkylating agents.

PMID- 10635338
TI  - Reduction in Ames Salmonella mutagenicity of mainstream cigarette smoke
      condensate by tobacco protein removal.
AB  - The mutagenic activity of cigarette smoke condensates (CSC) made from tobacco
      before and after removal of protein was assessed by the Ames Salmonella assay in
      bacterial strains TA98 and TA100. Removal of protein and peptides from flue-cured
      tobacco via water extraction followed by protease digestion reduced the
      mutagenicity of the resultant CSC by 80% in the TA98 strain and 50% in the TA100
      strain. Similarly, reductions of 81% in TA98 and 54% in TA100 were seen following
      water extraction and protease digestion of burley tobacco. The significant
      reductions in Ames mutagenicity following protein removal suggest that protein
      pyrolysis products are a principal contributor to the genotoxicity of CSC as
      measured in this assay.

PMID- 10635337
TI  - Effect of various concentrations of acyclovir on cell survival and micronuclei
      induction on cultured HeLa cells.
AB  - The HeLa cells were treated with 0, 0.01, 0.1, 1, 10 and 100 microM acyclovir
      (ACV) for 8 h duration and the growth kinetics, cell survival and micronuclei
      induction were determined. Treatment of HeLa cells with various concentrations of
      ACV resulted in a concentration-dependent decline in growth kinetics, cell
      proliferation indices and cell survival. ACV, 100 microM, completely inhibited
      cell division, where no appreciable changes in cell number were observed from 1
      to 5 days post-treatment. This is reflected in cell survival, where the surviving
      fraction of cells was reduced to 1/2 at 100 microM ACV. Conversely, the frequency
      of micronuclei showed a concentration-dependent elevation at 20, 30 and 40 h post
      treatment. ACV not only induced one micronuclei-bearing binucleate cell but also
      binucleate cells bearing two and multiple micronuclei in a concentration
      dependent manner. The micronuclei frequency increased with time up to 30 h post
      treatment and declined thereafter. The relationship between micronuclei induction
      and cell survival was determined by plotting the former on Y- and the latter on X
      axes, respectively. The surviving fraction of cells declined with the elevation
      in micronuclei frequency and a best fit was observed for linear quadratic
      formalism.

PMID- 10635339
TI  - Micronuclei in peripheral lymphocytes and exfoliated urothelial cells of workers
      exposed to 4,4'-methylenebis-(2-chloroaniline) (MOCA).
AB  - 4,4'-Methylenebis-(2-chloroaniline) (MOCA) is used in the manufacture of
      polyurethane. The IARC classifies MOCA as a probable human carcinogen. Suggested
      changes to guidelines for health surveillance of MOCA-exposed workers in
      Australia include a reduction in acceptable levels of urinary MOCA to below 15
      mumol/mol creatinine. Twelve male workers aged 24 and 42 years were recruited
      into this study from four work locations where MOCA is used. Exfoliated
      urothelial cells from prework urine samples on a midweek work day were assessed
      for micronucleus (MN) frequencies. Postwork urine samples were analysed for total
      MOCA. Blood samples collected on the same day were cultured for 96 h and
      cytochalasin-B-blocked cells were scored for MN. Eighteen male control subjects
      (23-59 years) provided corresponding urine and blood samples. Median urinary MOCA
      concentrations were 6.5 mumol/mol creatinine (range 0.4-48.6 mumol/mol
      creatinine) in postwork samples of MOCA-exposed workers. MOCA was not detected in
      urine of control workers. Mean MN frequencies were higher in urothelial cells and
      lymphocytes of MOCA workers (14.27 +/- 0.56 and 13.25 +/- 0.48 MN/1000 cells)
      than in controls (6.90 +/- 0.18 and 9.24 +/- 0.29 MN/1000 cells). The mean number
      of micronucleate cells was also higher in both tissues of exposed workers (9.69
      +/- 0.32 and 8.54 +/- 0.14 MN cells/1000 cells) than in controls (5.18 +/- 0.11
      and 5.93 +/- 0.13 MN cells/1000). There was no correlation between postwork
      urinary MOCA concentrations and MN frequencies in either tissue. This study
      suggests that exposures to MOCA in South Australia are similar to those of a
      decade ago and are at levels similar to those currently acceptable in Australia.
      These are associated with genotoxic effects in urothelial cells and peripheral
      blood lymphocytes. It may be prudent to reduce MOCA exposures in line with
      proposed guidance values.

PMID- 10635340
TI  - A comparative evaluation of aflatoxin B1 genotoxicity in fish models using the
      Comet assay.
AB  - Aflatoxin B1 (AFB1) is classified as a Group I hepatocarcinogen in humans by the
      International Agency for Research on Cancer (IARC). The alkaline Comet assay is a
      simple and rapid method by which DNA damage can be demonstrated as a function of
      tail moment. The present work is the first to evaluate the genotoxicity of AFB1
      in fish using the Comet assay. Two different species of fish were selected as
      models due to previously established sensitivity to AFB1: rainbow trout
      (sensitive) and channel catfish (resistant). Fish were i.p. injected with 0.5 mg
      AFB1/1 ml DMSO/1 kg body weight. The Comet assay was performed after 4 and 24 h
      on whole blood, liver, and kidney cells of both species. Trout blood and kidney
      tissue tested displayed significant (p < 0.05) and extensive DNA damage (shown by
      increased tail moment) after 4 h which then decreased by 24 h. In liver cells,
      damage progressively increased over time. Conversely, similarly treated catfish
      showed no elevation in DNA damage over controls at the same doses. These results
      suggest that the Comet assay is a useful tool for monitoring the genotoxicity of
      mycotoxins such as AFB1 and for evaluating organ specific effects of these agents
      in different species.

PMID- 10635341
TI  - On the persistence of the radioprotective effect of chlorophyllin (CHLN) in
      somatic cells of Drosophila.
AB  - By delaying the time of gamma irradiation of 72 h larvae, pretreated at 48 h with
      5% chlorophyllin (CHLN), it was established that the overall inhibiting effect of
      CHLN in somatic cells of Drosophila, as measured in the wing spot test, persists
      for about 4 days or until the time of cessation of the proliferation of wing
      anlagen. In the same population of cells, some spot classes gave evidence of an
      inhibitory effect whereas others did not arguing against the suggestion that the
      radioprotective effect of CHLN is a consequence of an induced delay in
      development, shrinking of the potential radiation target and lowering the
      probability of induced events. Other observations of interest are described.

PMID- 10635342
TI  - Persistence of chromosomal alterations affecting the 1cen-q12 region in a human
      lymphoblastoid cell line exposed to diepoxybutane and mitomycin C.
AB  - Multicolor fluorescence in situ hybridization (FISH) with tandem-labeling probes
      for the 1cen-q12 region is a potential biomarker for the detection of structural
      chromosomal aberrations (CAs) in human cells. To determine the suitability of
      this technique for biomonitoring humans exposed to 1,3-butadiene (BD) and to
      characterize the alterations induced as well as their stability over time, the
      human lymphoblastoid cell line AZH-1 was treated with 5 microM diepoxybutane
      (DEB) or the positive control mitomycin C (MMC; 0.1 microM) for 24 h. Following
      the removal of the test chemicals, cell cultures were grown for an additional 19
      days in the absence of the test compound. Using the tandem FISH technique,
      aliquots from the main cultures were examined for the induction of CAs affecting
      the 1cen-q12 region at various intervals. A significant increase in chromosomal
      breakage/exchanges affecting the 1cen-q12 region was seen in both the DEB- and
      MMC-treated interphase and metaphase cells. The damage peaked at approximately 48
      h following the addition of the test compound and declined with time. However, at
      day 20, the frequency of aberrant cells was still significantly higher than the
      control levels. For comparison, the frequency of micronuclei (MN) formed and
      their origin was determined using the cytochalasin B-modified MN assay and FISH
      with a pancentromeric probe. Showing a similar pattern, the frequency of
      centronere-negative MN peaked at 48 h, but however was not significantly elevated
      above control levels at 20 days. At early time points, aberrations detected using
      the FISH assay consisted of nearly equal proportions of unstable- and stable-type
      aberrations, while at the later time points, translocations were the predominant
      aberration type. In addition, the use of tandem-label FISH in combination with
      BrdU-immunfluorescence staining, showed that almost identical frequencies of
      structural aberrations could be seen in actively replicating and non-replicating
      cell populations. These studies indicate that a small but significant proportion
      of the alterations detected using this FISH technique persists over time and that
      this technique may be valuable for biomonitoring chromosomal alterations in BD
      exposed populations.

PMID- 10635343
TI  - Mutagenicity of thiol compounds in Escherichia coli WP2 tester strain IC203,
      deficient in OxyR: effects of S9 fractions from rat liver and kidney.
AB  - Low doses of L-cysteine (CYS), cysteinyl-glycine (CYSGLY) and reduced glutathione
      (GSH) activated by gamma-glutamyl transpeptidase (GGT) were mutagenic in strain
      IC203 (oxyR), whereas higher doses were required to observe a weak mutagenicity
      in the oxyR+ strain WP2 uvrA/pKM101 (denoted IC188). This indicates that thiol
      mutagenesis is suppressed by OxyR-regulated antioxidant defenses and confirms its
      oxidative character. The mutagenesis by low doses of CYS, CYSGLY and GSH + GGT
      detected in IC203 was abolished by rat liver S9, through the activity of
      catalase, as well as by the metal chelator diethyldithiocarbamate (DETC),
      supporting the dependence of this mutagenesis on H2O2 production, probably in
      thiol autoxidation reactions in which transition metals are involved.
      Surprisingly, low DETC concentrations greatly potentiate the mutagenicity of low
      CYS doses. Mutagenesis by high doses of CYS and CYSGLY occurred in both IC203 and
      IC188 in the presence of liver S9, and was resistant to inhibition by catalase,
      although it was prevented by DETC. Mutagenesis by GSH activated by rat kidney S9,
      rich in GGT, was detected in IC203 and IC188 only at high doses since catalase
      and glutathione peroxidase, both present in kidney S9, might inhibit its
      induction by low GSH doses. In the presence of liver S9, almost deficient in GGT,
      GSH was not mutagenic. The mutagenicity of a high GSH dose occurring in the
      presence either of GGT plus liver S9 or of kidney S9 was weakly prevented by
      DETC.

PMID- 10635344
TI  - Age-related increases of 8-hydroxy-2'-deoxyguanosine and DNA-protein crosslinks
      in mouse organs.
AB  - Experimental data suggest a possible role of DNA damage in aging, mainly related
      to oxidative lesions. With the objective of evaluating DNA lesions as molecular
      biomarkers of aging, we measured 8-hydroxy-2'-deoxyguanosine (8-OH-dG) and DNA
      protein crosslinks (DPXL) levels in different organs of mice aged 12 and 24
      months. 8-OH-dG was detected by 32P postlabelling after removing unmodified dG by
      trifluoracetic acid, which prevented the artificial formation of 8-OH-dG during
      32P labelling procedures. Appreciable 8-OH-dG amounts were detected in 12-month
      old mice in liver (1.8 +/- 0.7 8-OH-dG/10(5) normal nucleotides), brain (1.6 +/-
      0.5) and heart (2.3 +/- 0.5). In 24-month-old mice these values were higher in
      all examined organs (liver, 2.7 +/- 0.4; brain, 3.6 +/- 1.1; heart, 6.8 +/- 2.2 8
      OH-dG/10(5) normal nucleotides). This accounted for a 1.5-fold increase in liver
      (not significant), 2.3-fold increase in brain (P < 0.01), and 3.0-fold increase
      in heart (P < 0.001). A similar trend was observed for DPXL levels, which were
      the 1.8 +/- 0.3%, 1.2 +/- 0.2%, and 2.2 +/- 0.3% of total DNA in liver, brain,
      and heart of 12-month-old mice and 1.9 +/- 0.4%, 2.0 +/- 0.4%, and 3.4 +/- 0.5%
      in 24-month-old mice, with ratios of 1.0, 1.7 (P < 0.01), and 1.5 (P < 0.001),
      respectively. Highly significant correlations between 8-OH-dG and DPXL levels
      were recorded in brain (r = 0.619, P < 0.001) and heart (r = 0.800, P < 0.0001),
      but not in liver (r = 0.201, not significant). These data suggest that brain and
      heart are more severely affected by the monitored age-related DNA lesions than
      liver, which can be ascribed to certain characteristics of these postmitotic
      organs, including the low detoxifying capacities, the high oxygen consumption,
      and the impossibility to replace damaged cells by mitosis. The strong correlation
      between 8-OH-dG and DPXL supports a possible contribution of oxidative mechanisms
      to formation of DPXL in those organs, such as brain and heart, which play a
      primary role in the aging of the whole organism.

PMID- 10635345
TI  - Antimutagenicity of a suberin extract from Quercus suber cork.
AB  - The possible protective effect of a suberin extract from Quercus suber cork on
      acridine orange (AO)-, ofloxacin- and UV radiation-induced mutagenicity
      (bleaching activity) in Euglena gracilis was examined. To our knowledge, the
      present results are the first attempt to analyse suberin in relation to
      mutagenicity of some chemicals. Suberin exhibits a significant dose-dependent
      protective effect against AO-induced mutagenicity and the concentration of 500
      micrograms/ml completely eliminates the Euglena-bleaching activity of AO. The
      mutagenicity of ofloxacin is also significantly reduced in the presence of
      suberin (125, 250 and 500 micrograms/ml). However, the moderate protective effect
      of suberin on UV radiation-induced mutagenicity was observed only at
      concentrations 500 and 1000 micrograms/ml. Our data shows that suberin extract
      from Q. suber cork possess antimutagenic properties and can be included in the
      group of natural antimutagens acting in a desmutagenic manner.

PMID- 10635346
TI  - Chromosomal aberrations in peripheral lymphocytes from healthy subjects as
      detected in first cell division.
AB  - Baseline frequencies of chromosomal aberrations were analysed in human peripheral
      lymphocytes and the influence of age, sex and smoking habits was considered. From
      53 healthy subjects (29 males, 24 females) 54,689 exclusively first division
      cells (M1) were scored. The frequencies of chromosome aberrations per 1000 cells
      were 1.15 +/- 0.15 dicentrics (dic), 2.6 +/- 0.3 excess acentric fragments (ace)
      and 7.0 +/- 0.6 chromatid breaks (crb). An age dependency could only be
      established for ace. Between males and females no differences in any of the
      aberration types were observed. For heavy smokers (> 30 cigarettes per day) a
      significant increase was only found for dic (2.5 +/- 0.6 per 1000 cells).
      Dicentric frequency was compared with background levels of other studies in which
      results were reported also from exclusively M1 cells. Despite cell cycle control,
      differences between laboratories can be observed which may be partly influenced
      by environmental conditions. But on the other hand the mean frequency of dic
      (excluding heavy smokers) of 0.95 per 1000 cells reported here is consistent for
      more than one decade. Since such a consistency of the mean frequency of dic is
      reported also from another laboratory, the conclusion is drawn that especially
      for the detection of low-level exposures, each laboratory should establish its
      own base line data, otherwise, the interpretation of the findings is dependent on
      the selected background level from the literature.

PMID- 10635347
TI  - Induction of micronuclei by CsCl in vivo and in vitro.
AB  - In the present study, we report the results of an investigation of the potential
      of nonradioactive CsCl for the induction of micronuclei in polychromatic
      erythrocytes of mouse bone marrow and in human lymphocytes cultured and blocked
      with cytochalasin-B. No significant increase in micronucleus frequency was
      observed in the polychromatic erythrocytes of mice which received 500 mg/kg of
      CsCl. In vitro experiments with human lymphocytes cultured in medium containing
      250 and 500 micrograms/ml CsCl also showed no increase in micronucleus frequency
      compared to untreated controls. These same experiments, however, demonstrated a
      reduction in mitotic activity with increasing CsCl concentration in the culture
      medium. This report is the first to describe studies on the possible induction of
      micronuclei in vitro and in vivo by nonradioactive CsCl.

PMID- 10635348
TI  - Chromosome aberrations in lymphocytes and clastogenic factors in plasma detected
      in Belarus children 10 years after Chernobyl accident.
AB  - In 1996, 10 years after Chernobyl accident, a cytogenetic analysis was carried
      out to assess whether chromosome aberrant cells (CA) were still detectable in the
      lymphocytes and clastogenic factors (CFs) were present in the plasma of children
      coming from Gomel (Belarus), one of the most heavily contaminated regions.
      Furthermore, the possible contribution of plasmatic CFs to the amount of CA was
      investigated. The presence of CA was examined in the lymphocytes from 29 thyroid
      tumour-affected children and 41 healthy children (local controls). Thirty healthy
      children living in Pisa (Italy) were enrolled in the study as additional controls
      from an uncontaminated area. No significant difference was observed between the
      two control groups, whereas a significantly increased frequency of CA was found
      in the tumour-affected children, as compared with Gomel and Pisa controls (chi 2
      test, p < 0.001). However, when soil contamination level was taken into account,
      the chromosome type CA frequency observed in tumour-affected children coming from
      the more contaminated areas (> 4 Ci/km2) resulted significantly higher than that
      in other children, either affected or not (p = 0.003). The presence of CFs was
      analyzed on the plasma ultrafiltrate from 41 children. 7/10 (70%) plasma samples
      from tumour-affected children and 17/23 (74%) Gomel controls resulted to possess
      clastogenic activity irrespective of soil contamination levels. No activity was
      detected in the plasma of eight Pisa controls (0%). The difference between both
      Gomel groups and Pisa controls was highly significant (p = 0.002). A borderline,
      but not statistically significant correlation (p = 0.08) was observed between
      basal CA frequency and CF potency, which became significant (p = 0.03) when only
      chromosome type of aberrations was considered. We conclude that, although the
      presence of CFs in the plasma of these children might be partly responsible of
      the cytogenetic effects observed, the main source of damage has considered to be
      do to the previous and/or continuous exposure to environmental radiocontaminants.
      Tumour-affected children may represent a subset of the population either more
      sensitive to clastogenic damage or exposed to higher levels of contaminants.

PMID- 10635349
TI  - GC-MS analysis of fatty acids in phospholipids from Chlorella vulgaris cultivated
      synchronously in the presence of propranolol.
AB  - Changes in the content and composition of fatty acids in phospholipids were
      determined to estimate the effect of propranolol on the growth of unicellular
      green algae Chlorella vulgaris cultivated synchronously. The general biological
      activity of the cells and the division coefficient (DC) as well as the cell
      synchronisation were disturbed by propranolol in a concentration dependent
      manner. Also, the effect of propranolol on the fatty acids content of Chlorella
      vulgaris phospholipids was proportional to its concentration.

PMID- 10635350
TI  - Effect of the components extracted from the needles of Taxus baccata on protein
      biosynthesis in a cell-free rat liver system.
AB  - Various species of Taxus contain taxanes that promote polymerization and
      stabilization of microtubules. They have been reported as antineoplastic
      compounds with highly effective chemiotherapeutic application. A decrease in
      incorporation of the radiolabelled precursors into DNA, RNA and proteins in vivo
      has been reported too. The preliminary results have shown that also the other
      compounds present in the aqueous extract from Taxus baccata needles, participate
      in the inhibition of the protein biosynthesis. The binding site of eEF-2 on the
      ribosome seems to be the target of this inhibition process.

PMID- 10635351
TI  - Genotoxicity of adriamycin in human cell lines differing in antioxidant enzymes
      activity.
AB  - Genotoxicity of adriamycin in human cell lines was investigated by using a
      micronucleus assay. The result obtained was negative: the cells treated showed no
      increase in micronuclei. The chromosome aberration study with adriamycin
      indicated that the number of aberrant cells, high immediately after treatment,
      decreased to nearly the control level in 24 h of postincubation, probably as a
      result of the DNA repair process. Experiments with caffeine--a DNA repair
      inhibitor--indicated an increase micronuclei in the cells treated with adriamycin
      and caffeine together. The results obtained suggest that, in a human cells,
      adriamycin--induced DNA damages are quickly repaired to prevent micronuclei
      formation.

PMID- 10635352
TI  - Synthesis of 5-imino-5H-dipyrido[1,2-a; 2',3'-d]pyrimidines as potential
      antiallergy agents (1).
AB  - A novel route to 5-imino-5H-dipyrido[1,2-a; 2',3'-d]pyrimidines is described. The
      method is based on the Ullmann condensation of 2-chloro-3-cyano-5-nitropyridine
      with 2-amino-pyridine 1-oxides, followed by intramolecular cyclization of the
      resulting 2-(3-cyano-5-nitro-2-pyridylamino)pyridine 1-oxides with phosphorous
      trichloride.

PMID- 10635353
TI  - Chiral 2-amino-1-butanol xanthone derivatives as potential antiarrhythmic and
      hypotensive agents.

PMID- 10635354
TI  - Anorectic activity of 2H-4,6-dimethyl-2-[(4-phenylpiperazin-1- yl)methyl]-3-oxo
      2,3-dihydroisothiazolo[5,4-b]pyridine.
AB  - The effect of 2H-4,5-dimethyl-2-[(4-phenylpiperazin-1-yl)methyl]-3- oxo-2,3
      dihydroisothiazolo[5,4-b]pyridine on feeding in rats was investigated. The tested
      compound decreased food intake in food-deprived rats and in rats receiving
      palatable-diet.

PMID- 10635355
TI  - Identification and assay of lamotrigine in human milk with gas chromatography and
      densitometry.
AB  - Conditions necessary for isolation and assay of lamotrigine in the human milk
      with gas chromatography in the range of concentrations 2-20 micrograms/ml, and
      densitometry in the range of 2-10 micrograms/ml are discussed. Lamotrigine was
      extracted with methylene chloride from the alkaline solution. In gas
      chromatography capillary column DB-17, flame-ionizing detector, and octacozanole
      as the internal standard have been used. Densitometric measurements have been
      performed at 217 nm.

PMID- 10635356
TI  - Studies on pyrazine derivatives. XXXIII. Synthesis and tuberculostatic activity
      of 1-[1-(2-pyrazinyl)-ethyl]-4-N-substituted thiosemicarbazide derivatives.
AB  - Hydrogenation of 4-N-substituted thiosemicarbazonic acid acetylpyrazine
      derivatives with NaBH4 in dry ethanol led to seventeen new compounds. The in
      vitro tuberculostatic activity investigations of the 15 synthesized compound were
      carried out. MIC few of i.v. compounds were lower than 32 micrograms/cm3.

PMID- 10635357
TI  - Synthesis of some 2-hydroxy-1-[(4-chloro-2-mercaptophenyl)sulfonyl]imidazole
      derivatives with potential anticancer activity.
AB  - Several 2-(hydroxy or alkoxy)-1-[(4-chloro-5-R1-2
      mercaptophenyl)sulfonyl]limidazoles [II-VI, IX-XI] and bis ?5-chloro-4-methyl-2
      [(2-aryloxyimidazol-1-yl)sulfonyl]phenyl disulfides [XII-XV] were obtained by
      either the selective hydrolysis or alcoholysis of the appropriate 7-R1-8
      chloroimidazo[1,2-b] [1,4,2]benzodithiazine 5,5-dioxides [Ia-d]. The structures
      of the products and their S-substituted derivatives [VII, VIII] were established
      on the basis of elemental analysis and spectral data (IR, 1H and 13C NMR).
      Preliminary screening data indicated that the investigated compounds [III, X, XII
      and XIII] exhibited weak [III, X], moderate [XII] or fairly high [XIII] activity
      against some human tumor cell lines (Table 1).

PMID- 10635358
TI  - Synthesis of 1-amino-2-(4-chloro-2-mercaptobenzenesulfonyl)guanidine derivatives
      with potential pharmacological activity.
AB  - Syntheses of 1-amino-3-R2-2-(4-chloro-2- mercaptobenzenesulfonyl)guanidines [Va
      o], 1-benzylidencimino-3-R2-2-(4-chloro-2- mercaptobenzenesulfonyl)guanidines [X,
      XII-XIX] and N-(4-chlorobenzylidene)-N'-(6-chloro-7-methyl-l, 1-dioxo- 1,4,2
      benzodithiazin-3-yl)hydrazine [XX] have been described. The moderate anticancer
      and weak anti-HIV activities were observed in vitro for compounds [Va, e.g]. The
      obtained compounds were evaluated for their in vitro antimycobacterial activity
      towards a strain of Mycobacterium tuberculosis H 37 Rv.

PMID- 10635359
TI  - Studies on quinoxaline derivatives. Synthesis of quinoxalylamino-1,3
      diazacycloalkanes with potential hypotensive activity.
AB  - A series of quinoxalylamino-1,3-diazacycloalkanes was obtained by the reaction of
      the corresponding substituted aminoquinoxalines with alcohols and amines. The
      effect of selected compounds on the blood pressure of anaesthesized normotensive
      rats was studied.

PMID- 10635360
TI  - Synthesis and antimicrobial activity of bis[6-phenyl-4-methyl-3-substituted
      pyrazo[4,5-d] pyrazol-1-yl]thioketones.
AB  - New bis[6-phenyl-4-methyl-3-substituted-pyrazo[4,5-d] pyrazol-1-yl]thioketones
      have been obtained in good yield by the reaction of thiocarbohydrazine with 1
      phenyl-3-methyl-4-acetyl/benzoyl-pyrazol-5-one, followed by cyclization of the
      intermediate. The new compounds exhibit excellent antimicrobial activity.

PMID- 10635361
TI  - Synthesis of new derivatives of 1-alkyl-2-aryl-1H-2,3-dihydroimidazo[1,2
      a]pyrimidin-5-one active in CNS. Part 2. Synthesis and results of preliminary
      pharmacological screening of 7-(substituted)amino-1-alkyl-2-aryl-1H-2,3
      dihydroimidazo[1,2-a]pyrimid in-5- ones.
AB  - Synthesis of new 7-(substituted)amino-1-alkyl-2-aryl-1H-2,3-dihydroimidazo[1,2
      a]py rimidin-5- ones bearing the 4-arylpiperazin-1-yl moiety connected by ethyl
      or acetoyl two-carbonyl chain extension was described. The arylpiperazinyl moiety
      was introduced by alkylation or acylation with corresponding halogeno
      derivatives. Preliminary pharmacological screening showed the 7-(substituted)
      amino derivatives of the system investigated to exhibit the CNS activity lesser
      than that of the 7-amino derivatives and to have no effect on the serotonin
      neurotransmission pathway.

PMID- 10635362
TI  - Blood pressure and hypothalamic NA-GABA interaction in spontaneously hypertensive
      rats (SHR): effect of administration DSP-4.
AB  - The effect of DSP-4 [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine] on the content
      of catecholamines (NA and DA) and gamma-aminobutyric acid (GABA) in the
      hypothalamus and on the blood pressure were studied in rats. Wistar-Kyoto (WKY)
      and spontaneously hypertensive rats (SHR) were injected with DSP-4 (50 mg/kg i.p.
      twice) and tested for 15 days thereafter. Fifteen days after DSP-4 lesioning, a
      significant reduction of NA levels without changes in DA and GABA concentration
      in the hypothalamus of both strains was found. However the blood pressure
      appeared unaffected by the DSP-4 pretreatment in WKY and SHR rats. In line with
      previous data the amounts of catecholamines and GABA in the hypothalamus were
      significantly lower in SHR control animals than in WKY control rats. The results
      suggest that NA/GABA interaction in the hypothalamus do not play an important
      role in blood pressure regulation. It may be further supposed that the local NA
      transmission does not play an important role in the phenomenon discussed.
      Moreover, a contribution of hypothalamic GABA and DA to the control of blood
      pressure is confirmed.

PMID- 10635363
TI  - Synthesis and antibacterial activities of some 1,2,4-triazole derivatives.
AB  - Reactions of 3-amino-1,2,4-triazole with some dicarboxylic acid anhydrides and
      diketones were studied. The structural assignments of the compounds obtained from
      the reactions are based on elemental analyses and spectral data. The compounds
      were screened for their in vitro antibacterial activities.

PMID- 10635364
TI  - The activity of rat brain nitric oxide synthase following chronic antidepressant
      treatment.
AB  - Nitric oxide synthase (NOS) is an enzyme involved in the activation of the
      glutamate/NMDA receptor-induced cascade of events. In this study we investigated
      the NOS activity in different rat brain regions after chronic electroconvulsive,
      imipramine and citalopram treatments. Chronic electroconvulsive treatment
      significantly increased the NOS activity (by 49%) in the cerebral cortex.
      However, chronic treatment with imipramine or citalopram did not alter the
      activity of NOS in all examined brain regions (cortex, hippocampus or
      cerebellum). The increased NOS activity after electroconvulsive but not
      pharmacologic (imipramine or citalopram) treatment may well reflect the
      differences between the adaptive changes of the NMDA receptor complex induced by
      these treatments.

PMID- 10635365
TI  - Pharmacological properties of some xanthone derivatives.
AB  - A series of aminoalkanolic derivatives of xanthone were examined in some
      experimental models of epilepsia, i.e., pilocarpine, aminophylline and
      pentetrazole-induced seizures. A final objective of this research was to examine
      the action of these compounds on the central nervous system, namely on
      spontaneous locomotor activity, amphetamine-induced hyperactivity and narcotic
      sleep induced by hexobarbital, as well as their influence on the gamma
      aminobutyric acid (GABA) level and glutamic acid decarboxylase (GAD) activity in
      mice brain. The most interesting were the pharmacological results of (R)-2-N
      methylamino-1-butanol derivative of 7-chloro-2-methylxanthone [Id], which
      displayed protective activity against the seizures induced by maximum
      electroshock and pentetrazole induced seizures; moreover, this compound had a
      relatively low toxicity and did not exhibit a neurotoxic effect. The influence on
      the locomotor activity as well as on the amphetamine-induced locomotor
      hyperactivity in mice was also seen for Id. Compound Id did not decrease the GABA
      level in mice brain.

PMID- 10635366
TI  - Antiplatelets activity of some xanthone derivatives.
AB  - The effects of twelve aminoalkanolic derivatives of xanthone on platelet
      aggregation have been evaluated. Five from them inhibited thrombin-induced
      platelet aggregation. The most active compound was R-(+)-2-N-(7-chloro-2
      xanthonemethyl)-2-N-methylamino-1-butanol [IV] which, at a concentration of 40
      micrograms/ml, nearly completely inhibited the aggregation concentration (TAC) of
      thrombin.

PMID- 10635367
TI  - Theory and practice of microdialysis--prospect for future clinical use.
AB  - The application of microdialysis for neurochemical monitoring in neurosurgery and
      neurointensive care is rapidly expanding in a number of clinical centers around
      the world. In order for microdialysis to become a future routine method in these
      clinical settings a number of problems, outlined in this communication, must be
      solved by the clinical researchers and the commercial companies. Regardless of
      the future success as a routine method, it is already obvious that microdialysis
      will be an important clinical research tool for years to come, providing new
      important insights into the pathophysiology of acute human brain injury.

PMID- 10635368
TI  - Unbound plasma concentrations may predict neuroprotective brain concentrations: a
      brain microdialysis and pharmacokinetic study of enadoline in rats.
AB  - A rat brain microdialysis study of enadoline (CI-977), a k-opioid agonist, was
      conducted in nonanesthetized healthy rats to determine brain extracellular fluid
      (ECF) concentrations of CI-977 associated with neuroprotective subcutaneous
      (s.c.) doses. Three groups of 3 to 4 nonanesthetized yet restrained Sprague
      Dawley rats with jugular cannulas and implanted brain (striatum) microdialysis
      probes received single s.c. doses of 0.3, 1.0, or 3.0 mg/kg CI-977. Blood and
      microdialysate samples were collected over a 12-hour period. Extent of rat plasma
      protein binding was 77.5%. Unbound plasma concentrations associated with
      neuroprotection were 10-50 ng eq/mL. At each dose, brain ECF concentration-time
      profiles (corrected for probe recovery) were nearly coincident with enadoline
      plasma unbound concentration-time profiles. Consequently, at each dose the ratio
      of AUCecf/AUCffplasma, (AUC = Area Under the concentration-time Curve; ffplasma =
      free fraction in plasma = unbound plasma) which represents the distribution of
      drug between plasma and brain, was determined to be unity within experimental
      error. These results suggest that unbound plasma concentrations may predict brain
      ECF concentrations of CI-977. Further, our findings allow us to postulate
      enadoline unbound brain ECF concentrations necessary for neuroprotection.

PMID- 10635369
TI  - Intraoperative enzyme-amperometric monitoring of extracellular glutamate
      concentration with a dialysis electrode in ischemic human brain.
AB  - Changes in the extracellular concentration of glutamate in the brain ([Glu]e)
      were monitored continuously by an enzyme-amperometric technique employing a
      dialysis electrode during ischemia caused by isolation of the brain tissue in
      rats and human patients. In the rat (n = 10), the dialysis electrode was placed
      in the frontal cortex and the frontal lobe was transected. A transient sharp
      increase in [Glu]e was frequently observed during the transection. A biphasic
      elevation (a rapid increase followed by a slowly continuing increase)
      subsequently occurred with a latent period of 1-3 min after the transection of
      the rat frontal lobe. In patients (n = 7), the dialysis electrode was placed in
      tumor-free cortical areas which were planned to be resected together with
      gliomas. Progressive increases in [Glu]e were observed in all of the patients as
      the isolation of the brain tissue progressed. A biphasic increase, similar to
      that seen in the rat, was identified in 2 patients in whom the cortical area
      surrounding the dialysis electrode was rapidly isolated. The present enzyme
      amperometric technique employing a dialysis electrode appears to be useful for
      detecting the occurrence of potentially harmful ischemia and for securing minimal
      metabolic stress caused during various surgical manipulations.

PMID- 10635370
TI  - CSF and ECF glutamate concentrations in head injured patients.
AB  - Excitatory Amino Acids (EAAs) release has been considered to be neurotoxic in
      traumatic brain injury patients. Microdialysis samples of extracellular space
      (ECS) and high glutamate concentrations in cerebrospinal fluid (CSF) following
      Traumatic Brain Injury (TBI) have been documented. The objective of this study
      was to determine the correlation between EAA release in ECS and CSF in focal and
      diffuse injury. Head injury patients (GCS < or = 8, n = 16) admitted to Medical
      College of Virginia Hospital were instrumented for microdialysis collection of
      ECS samples. CSF samples were collected through the external ventricular drainage
      catheter at four hour intervals for the first four days following injury. As a
      control group, CSF was collected from normal pressure hydrocephalus patients (n =
      6). Elevated glutamate levels were observed in both CSF and ECS following head
      injury. The average glutamate concentration in CSF (3.20 +/- 3.62 mumol/l) was
      significantly increased from control levels (1.13 +/- 0.49 mumol/l, p < 0.05).
      Comparison of CSF and extracellular fluid (ECF) samples showed that the glutamate
      concentrations were maximal on the first and second days and gradually decreased
      on days 3 and 4. On days 4, the level of the glutamate had remained elevated
      above the normal level.

PMID- 10635371
TI  - Glucose and lactate metabolism after severe human head injury: influence of
      excitatory neurotransmitters and injury type.
AB  - The survival of traumatized brain tissue depends on energy substrate delivery and
      consumption. Excitatory amino acids produce a disturbance of ion homeostasis and
      thus, increase energy demand. In head-injured patients, massive release of
      glutamate has been reported, especially in patients with focal contusions.
      Therefore, we studied the interrelationship between glutamate, glucose and
      lactate in relation to the type of injury. We investigated 37 severely head
      injured patients in which a microdialysis probe was placed next to a focal
      contusion (n = 14) or together with a ventricular catheter in diffusely injured
      tissue (n = 23). Within-subject Spearman-rank correlation revealed an overall
      strong relationship between glutamate and lactate (p < 0.001) and glutamate and
      glucose (p < 0.01), but not between glucose and lactate (n.s.). The
      interrelationship was more pronounced in diffusely injured brain (normal CT
      appearance) compared to the contused tissue. The results demonstrate that
      glutamate clearly influences the release of lactate following injury, supporting
      the hypothesis that glutamate "drives" glycolysis in astrocytes. The strong
      positive correlation between glutamate and glucose might indicate an effect of
      glutamate upon glucose uptake by cells which differs according to the type of
      injury.

PMID- 10635372
TI  - Evidence for time-dependent glutamate-mediated glycolysis in head-injured
      patients: a microdialysis study.
AB  - In the brain, lactate is not only a marker of anaerobic glycolysis due to
      hypoxia/ischemia, but also a neuronal energy source which is provided by
      glutamate-induced astrocytic glycolysis. In the present study we wanted to
      investigate the relationship between glutamate release and lactate production
      during the entire time-course and during three time periods of microdialytic
      monitoring in 54 severely head injured patients. Within-subject Spearman rank
      correlations were calculated in each period for glutamate and lactate, for each
      patient and the mean of all correlation coefficients were analyzed for difference
      from zero by a one-sample t-test. The results show a strong overall positive
      relationship between glutamate and lactate. However, during the first 12 hours
      after injury, there was no significant correlation. Thereafter, good correlation
      was seen. The splitting of patients into groups with good (Glasgow Outcome Scale;
      GOS 0-2) and poor outcome (GOS 3-4) showed a similar strong correlation for
      patients with good outcome, but this was lost for patients with poor outcome. The
      results clearly indicate that glutamate "drives" astrocytic lactate production in
      head-injured patients. The contribution of glutamate to overall lactate release
      is thus time-dependent. During the first 12 hours after injury, factors such as
      hypoxia, ischemia or edema overshadowed glutamate-induced glycolysis in
      astrocytes. In addition, the effect of glutamate is more pronounced in patients
      with good outcome.

PMID- 10635373
TI  - Determinants of cerebral extracellular potassium after severe human head injury.
AB  - The key role players of brain swelling seen after severe human head injury have
      only been partly determined. We used our human head injury data base to determine
      relationships between potassium, glutamate, lactate and cerebral blood flow
      (CBF). A total of 70 severely head injured patients (GCS < or = 8) were studied
      using intracerebral microdialysis to measure extracellular glutamate, potassium
      and lactate. Xenon CT was used to determine regional cerebral blood flow (rCBF).
      The mean +/- SEM of the r value of all patients, between potassium and glutamate,
      and potassium and lactate was 0.25 +/- 0.04 (p < 0.0001) and 0.17 +/- 0.06 (p =
      0.006), respectively, demonstrating in both cases a positive relationship. rCBF
      was negatively correlated with potassium with marginal significance (r = -0.35, p
      = 0.08). When separated into two groups, patients with contusion had higher
      potassium levels than patients without contusion (1.55 +/- 0.03 mmol/l versus
      1.26 +/- 0.02 mmol/l, respectively). These results in severely head injured
      patients confirm previous in vitro and animal studies in which relationships
      between potassium, glutamate, lactate and CBF were found. Potassium efflux is a
      major determinant of cell swelling leading to clinically significant cytotoxic
      edema due to increased glutamate release during reduced cerebral blood flow.

PMID- 10635374
TI  - Simultaneous measurement of cortical potassium, calcium, and magnesium levels
      measured in head injured patients using microdialysis with ion chromatography.
AB  - Potassium, calcium and magnesium were measured in 3717 microdialysate samples in
      43 patients with head injury experiencing refractory increased ICP, episodes of
      jugular venous oxygen desaturation and brain death. Cation analysis was performed
      with 'ion chromatography'. Potassium levels remained stable until severe
      physiological deterioration occurred, whereupon they increased 100-400%, usually
      associated with release of amino-acids including glutamate, aspartate, and
      taurine into the extracellular space. The magnesium and calcium levels remained
      unchanged, regardless of the severity of physiological deterioration.

PMID- 10635375
TI  - What does measurement of brain tissue pO2, pCO2 & pH add to neuromonitoring?
AB  - In this paper the rationale behind utilizing the brain tissue measurements of
      oxygen, carbon dioxide, pH and temperature is evaluated in the context of
      ischemia. These parameters were measured using an intraparenchymal multi
      parametric brain tissue monitor (Paratrend 7). The need to establish the
      relevance of this type of monitoring becomes acute as further experience is
      gained using this kind of technology. Our experience with such a device is
      presented and is illustrated with two clinical cases. The potential caveats and
      areas of possible future work are also delineated.

PMID- 10635376
TI  - Effect of hypocapnea on CBF and extracellular intermediates of secondary brain
      injury.
AB  - We examined the metabolic response of the brain underlying subdural hematomas or
      surrounding contusions to hyperventilation and looked for evidence of ischemia.
      Twelve consecutive patients with severe traumatic brain injury (TBI) (GCS < 8)
      who required surgery for evacuation of subdural hematoma or hemorrhagic contusion
      were studied. At surgery, a microdialysis catheter was placed into the cortex in
      a gyrus adjacent to the contusion or underlying the subdural hematoma. A thermal
      diffusion flow probe was placed on the cortex directly above the dialysis
      catheter. On days 1 and 3 post injury, two trials of hyperventilation were
      performed which dropped the patients' pCO2 10 mm Hg for 30 minutes. Monitoring of
      CBF and collection of dialysis fluid continued throughout each hyperventilation
      trial. Data was analyzed for a three hour window surrounding each
      hyperventilation. Brief periods of hyperventilation did not cause a significant
      elevation of the extracellular lactate/pyruvate ratio or glutamate level in areas
      of the brain likely to be the most vulnerable to secondary injury. In spite of
      hyperventilation leading to a significant decline in local CBF in 20% of the
      trials, there was no evidence of ischemia or excitatory amino acid release
      associated with hyperventilation.

PMID- 10635377
TI  - Continuous monitoring of cerebrospinal fluid acid-base balance and oxygen
      metabolism in patients with severe head injury: pathophysiology and treatments
      for cerebral acidosis and ischemia.
AB  - INTRODUCTION: Continuous monitoring of cerebral acid-base balance and oxygen
      metabolism has been introduced in neurointensive care settings. The hypothesis of
      this study utilizing multimodal neuromonitoring modalities is that
      hyperventilation and hypothermia improve cerebral acidosis through prevention of
      cerebral ischemia aggravation in patients with severe head injury. PATIENTS AND
      METHODS: Continuous monitoring of cerebrospinal fluid (CSF) pH, PCO2, HCO3-, base
      excess (BE), PO2, SO2, temperature, lactate and pyruvate (La and Py) measurements
      were conducted in 8 patients with severe head injury. Temperature-corrected CSF
      parameters were correlated with those in the jugular blood including oxygen
      saturation (SjO2), regional oxygen saturation (rSO2), intracranial pressure (ICP)
      and cerebral perfusion pressure (CPP), jugular blood temperature (Tjb), and
      endtidal PCO2 (PetCO2). Therapeutic significance of hyperventilation and
      hypothermia was evaluated. RESULTS: 1) CSF acidosis was observed in all cases
      (minimum pH 6.59-7.17) due to increased CSF PCO2 and/or decreased CSF HCO3- and
      tended to associate with abnormal ICP and/or CPP or ischemic episodes indicated
      by CSF PO2 and SO2, rSO2, and/or SjO2 during monitoring. 2) It was more obvious
      in CSF than in jugular blood that increased PCO2, La and Py, and/or decreased
      HCO3- resulted in decreased BE and pH. 3) Decreased CSF PO2 and SO2 only
      correlated with severe CSF acidosis. 4) Hyperventilation: Decreased PetCO2 did
      not always closely correlate with CSF PCO2 decrease and CSFpH increase. 5)
      Hypothermia: There were negative correlations of Tjb with CSF pH and SO2 in all
      cases, though correlation coefficients were not always high. CONCLUSIONS: CSF
      acidosis caused by increased CSF PCO2, La and Py, and/or decreased HCO3- tended
      to associate with abnormal ICP and CPP, and desaturation indicated by CSF SO2,
      rSO2, and/or SjO2. Hypothermia rather than hyperventilation tends to improve
      cerebral acidosis and ischemia.

PMID- 10635378
TI  - Monitoring by subcutaneous microdialysis in neurosurgical intensive care.
AB  - Microdialysis is an in vivo sampling technique which provides a powerful approach
      to monitoring metabolic events. We have performed a study to determine the
      feasibility and effectiveness of subcutaneous microdialysis in monitoring
      patients on the Neurosurgical Intensive Care Unit (NICU). A microdialysis probe
      was placed in the subcutaneous fat of the anterior abdominal wall and perfused
      with Ringer's solution. Collecting vials were changed every 30 minutes and
      monitoring continued for 2-6 days. Biochemical analysis of glucose, lactate, and
      glutamate was correlated with clinical events. The normal ranges of glucose,
      lactate and glutamate were 3-6 mM. 1-2.5 mM and 5-20 microM, respectively.
      Periods of low tissue glucose were detected by microdialysis which were not
      detected by routine plasma sampling. In one patient, following an apparently
      brief period of hypoxia, there was a prolonged disturbance of tissue chemistry.
      Another patient with obesity had significantly higher concentrations of dialysate
      glucose, lactate and glutamate. Monitoring by subcutaneous microdialysis on
      intensive care units is feasible, reveals unexpected changes in tissue metabolism
      and might be an important adjunct for the interpretation of intracerebral data.

PMID- 10635379
TI  - Brain viability and function analyzer: multiparametric real-time monitoring in
      neurosurgical patients.
AB  - We have developed the Brain Viability (BVA) and Brain Function (BFA) Analyzers
      for monitoring the following parameters from the human cerebral cortex cerebral
      blood flow: (CBF), NADH redox state, Electro corticography (ECoG), brain
      temperature, extracellular K+, DC potential and intracranial pressure (ICP). The
      BVA monitors the first 4 parameters only. The Brain viability probe (BVP) and
      Brain function multiprobe (BFM) were used during 11 operations and in 18 ICU
      patients, respectively. Preliminary results from the OR showed that 5 patients
      exhibited a typical increase in CBF in response to changes in end-tidal CO2
      without a significant change in the NADH redox state. In 4 other patients no
      changes in CBF and NADH were observed. Two patients exhibited a "steeling
      response", i.e., a decrease in CBF and an increase in NADH. In 18 comatose
      patients monitored in the ICU, the ICP, CBF and ECoG were measured correctly in
      most patients, whereas NADH and K+ were more problematic. One patient exhibited a
      typical response, may be due to repeated cortical spreading depression cycles and
      an ischemic depolarization event. Continuous realtime multiparametric monitoring
      in neurosurgical patients is feasible and practical in the OR and the ICU. The
      information provided could be used as a diagnostic tool to guide the procedures
      or treatment given to the patients.

PMID- 10635381
TI  - Diagnostic procedures in head and neck cancer.
AB  - Accurate, methodical diagnostic work up and staging are of the most importance in
      the treatment of Head and Neck tumours. It allows an initial multidisciplinary
      decision making, giving the patient the best chance of curation, with the least
      morbidity. In this paper the authors try to give a generally accepted work-up and
      try to get in to some of the newer techniques.

PMID- 10635380
TI  - Importance of metabolic monitoring systems as an early prognostic indicator in
      severe head injured patients.
AB  - We have analyzed and evaluated what is the best metabolic monitoring system to
      determine the prognosis for maintenance of neurological function in severe head
      injured patients. Acute subdural hematoma (ASDH) was recognized in fifteen of 22
      patients and cerebral contusion in seven in this series. Intracranial pressure
      (ICP), jugular venous pH and jugular bulb venous oxygen saturation (SjO2) were
      continuously monitored as soon as possible following stabilization. The
      measurement of cerebral blood flow (CBF) was carried out using a stable Xenon
      computerized tomography (Xe-CT). After measuring CBF, 3% carbon dioxide (CO2)
      loading was conducted to determine CO2 responses (delta CBF/delta CO2). In
      patients who died (D), jugular venous pH showed evidence of acidosis (6.3-7.2)
      with delta CBF/delta CO2 < 1 and cerebral metabolic rate of oxygen (CMRO2) < 1.21
      within several hours of the trauma. On the other hand, arterial pH was shown to
      be within the normal range. In vegetative state (VS) and severe disability (SD)
      patients, jugular venous pH was shown to be within normal range, with delta
      CBF/delta CO2 < 1 and 1.44 < CMRO2 < 1.79. In all of moderate disability (MD) and
      good recovery (GR) patients, jugular venous pH was shown to be within the normal
      range, with delta CBF/delta CO2 > 1 and 1.65 < CMRO2 < 1.85. These results
      suggest that jugular venous pH, CO2 response and CMRO2, were useful as early
      prognostic indicators in the maintenance of neurological function.

PMID- 10635382
TI  - The TNM classification revisited: role of anatomic and functional imaging in head
      and neck cancer.
AB  - Several imaging-derived parameters are powerful predictors of local and
      locoregional control in irradiated head and neck cancer, offering additional
      information to the TN-classification. Most information is available on the use of
      CT-determined parameters as predictor of local outcome of laryngeal cancer after
      curative radiation therapy. There is evidence that also functional imaging will
      provide complementary information on the prognosis of head and neck tumours. Such
      prognostic information is helpful in determining the relative value of surgery
      and radiation therapy, the selection of patients likely to benefit from
      neoadjuvant treatment, and identifying patients at high risk for recurrence to be
      followed more closely.

PMID- 10635383
TI  - Prognostic factors in squamous cell carcinomas of the head and neck.
AB  - This review will focus on prognostic factors that can be disclosed by the
      pathological and molecular analysis of squamous cell carcinomas of the head and
      neck. The following pathological prognostic factors are considered and discussed:
      location, histopathology, lymph node metastasis. In addition, a number of
      molecular genetic markers have been identified such as: DNA content, chromosomal
      abnormalities, cell proliferation, RAS gene family, epidermal growth factor and
      its receptor, tumor-suppressor genes, cell adhesion molecules and proteinases.

PMID- 10635384
TI  - Total thyroidectomy is the recommended treatment for all Papillary Thyroid
      Carcinoma (PTC).
AB  - Surgical treatment of well differentiated carcinomas of the thyroid gland remains
      a discussed topic and there is still no evidence of global and total harmony in
      the appropriate surgical procedure to be applied in the approach of these tumors.
      The major unresolved debate concerning the ideal surgical management of PTC
      focuses on the extent of thyroidectomy. The most common recommended options range
      from thyroid lobectomy to a total extracapsular thyroidectomy. Controversy
      concern not only the extent of thyroidectomy but also the indications for, and
      the extent of cervical lymph node dissection. To date, there are no controlled
      prospective trials comparing the results of different surgical treatments of PTC.
      There are, however, several large retrospective reports that have addressed the
      extent of thyroidectomy in the management of patients with PCT1. The purpose of
      this review article is to demonstrate that total thyroidectomy seems to be the
      optimal treatment for most patients with clinically significant PTC. We also
      emphasize that the ability to perform thyroid surgery safely is of paramount
      importance with an excellent long-term prognosis. To determine the ideal
      treatment surgeons must weigh the risk-complications of a more aggressive
      surgical resection (total thyroidectomy) versus the risk of morbidity, mortality,
      recurrence rates and difficulty in following patients who undergo less gland
      resection (lobectomy). It is mandatory to expand efforts to identify high-risk
      patients more accurately, thereby facilating more rational approaches to
      treatment.

PMID- 10635385
TI  - Surgical treatment of thyroid papillary carcinoma: current controversies.
AB  - Papillary cancer is the most frequent thyroid cancer occurring in all age groups
      with a good prognosis. Surgery is commonly recognized as the primary treatment of
      PC, but controversy concerning the type of resection continues. We are still
      waiting for the best predictors of tumor aggressiveness which would help us to
      select patients for the type of surgery according to the tumor prognosis. We
      currently recommend total thyroidectomy in all cases leading to eradicate all
      tumoral tissue specially in multicentric disease, to optimize the effect of
      postoperative Iodine-131 therapy and to allow thyroglobulin levels to be reliably
      used as a marker of recurrence. We advocate lymphnode dissection only if chain
      nodes are palpable. Total thyroidectomy should be made by experienced surgeon in
      order to minimize post-operative morbidity.

PMID- 10635386
TI  - Unilateral thyroid lobectomy for differentiated thyroid carcinoma: long-term
      results.

PMID- 10635387
TI  - Transoral laser microsurgery is the recommended treatment for early glottic
      cancers.
AB  - Medical terminology frequently mistakes the instrument for the surgical
      procedure: endoscopic excision of laryngeal cancers existed long before laser
      came into use. Lasing obeys the same rules as those of suspension laryngoscopy:
      if adequate laryngeal exposure is not attained, then the procedure is at risk of
      being incomplete and of providing few satisfactory results. Because a certain
      degree of literary anarchy exists in terms of definitions for the different
      cordectomy types, the Nomenclature Committee of the European Laryngological
      Society has proposed a classification. This categorization is a synthesis and a
      compromise between members of the Society who had developed and used, for several
      years, a personal classification. The proposed classification has two aims: to
      better understand each surgeon's technique in function of the tumoral extent; and
      to compare more rigorously the postoperative results. This classification
      includes the following procedures: Subepithelial cordectomy or decortication
      (Type I); Subligamentous cordectomy (Type II); Transmuscular cordectomy (Type
      III); Total or complete cordectomy (Type IV); Extended cordectomy encompassing
      the contralateral vocal fold (Type Va); encompassing the arytenoid (Type Vb);
      encompassing the ventricular fold (Type Vc); encompassing the subglottis (1 cm)
      (Type Vd).

PMID- 10635388
TI  - Surgical treatment of T1-T2 glottic carcinomas.
AB  - Transoral laser surgery (TLS) is a safe, time and cost-effective method of
      treatment for early stage glottic squamous cell carcinoma. This technique is more
      controversial in case of local extension to other subsite or in case of limited
      mobility.

PMID- 10635389
TI  - From concept to clinical reality: implementing tracheal autotransplantation in
      conservation laryngectomy.
AB  - The implementation of tracheal autotransplantation in conservation laryngectomy
      is an illustration of how surgical research on laryngotracheal reconstruction was
      taken from the bedside to the laboratory and back. The study started in 1989 in
      an effort to improve laryngeal reconstructive methods because a total
      laryngectomy seemed unnecessary radical for unilateral fixed-cord glottic
      lesions. The clinical problem we chose for investigation was taken to the
      laboratory and a rabbit model allowing tracheal revascularization and
      transplantation was developed. Different steps in surgical research resulted in a
      reconstructive method for hemicricolaryngectomy defects. The reconstruction
      consist of revascularized pathes of cervical trachea which may be
      autotransplanted to the larynx. After experimental evaluation, tracheal
      autotransplantation was applied clinically in the functional treatment of
      laryngeal cancer necessitating a resection of the cricoid cartilage. The first
      patient was treated in 1996 and 25 patients were treated in a 3 years period. It
      is estimated that 25% of the currently performed total laryngectomies may be
      considered for organ saving through tracheal autotransplantation.

PMID- 10635390
TI  - Developing gene therapy for head and neck cancer communicating bench to bedside.

PMID- 10635391
TI  - Surgery of the anterior skull base for malignant tumors.
AB  - Craniofacial resection is one of the surgical approaches for treatment of
      malignant tumours near or involving the anterior skull base. The indications,
      preoperative evaluation, surgical procedure, reconstruction, complications and
      prognostic factors are discussed.

PMID- 10635392
TI  - Invasive surgery for paranasal sinus cancer: is there still any indication for
      lateral rhinotomy and non endoscopic approaches?
AB  - A combined intracranial and transfacial approach for often very malignant lesions
      of the sino-nasal complex yields the best chance of curation. The operative risk
      diminishes in a centre with a large turnover after an initial learning curve and
      it is the only possibility to try to cure the patient from his or her disease.
      The removal of a rather small malignant lesion in the anterior part of the middle
      meatus can be safely done through the nostril with correct oncologic margins. In
      case of inoperability because of local destructions or because of the
      histological type (malignant melanoma e.g.) freeing up the nasal airway
      endoscopically can help patients symptomatically and repeatedly.

PMID- 10635393
TI  - Possibilities and limitations of endoscopic management of nasal and paranasal
      sinus malignancies.
AB  - Over the last decade, the use of rigid endoscopes in surgery of tumorous lesions
      of the nose, paranasal sinuses, nasopharynx and anterior skull base has extended
      and diversified. Endoscopic surgical approaches for malignant lesions are very
      controversially discussed as of today, yet. From 1989-1999 we have treated 43
      patients with invasive/destructive tumors of the paranasal sinuses and the
      anterior skull base strictly endoscopically, transnasally. These included 5
      patients with juvenile angiofibromas and 36 patients with various malignant
      tumors, one with a large invasive macroadenoma of the pituitary and one case of a
      craniopharyngeoma. The age range was 3 months to 82 years. Whereas the very first
      patients were approached endoscopically in a palliative intention, we have
      started endoscopic surgery for selected malignancies with curative intention in
      the last years. Histologically, patients with various carcinoma differentiation
      were operated (n = 18), as well as patients with malignant melanoma (n = 5),
      esthesioneuroblastoma (n = 8), clivus chordoma (n = 3), immature teratoma (n = 1)
      and leiomyosarcoma (n = 1). Our first results appear to indicate, that outcome is
      at least equal to standard external approaches, however with excellent functional
      terms and significantly better overall quality of life. The limitations result
      from the anatomical spread of the tumor, when extensive infiltration of orbit,
      dura/brain and other vital structures exist. However, in experienced hands,
      endoscopic surgery in this region can be rather radical, bone and even dura of
      the anterior skull base can be resected as can the periorbit, and all structures
      reconstructed in the same session. Endoscopic techniques lend themselves very
      well to cooperation with neighbouring specialities like neurosurgery. In
      individual cases, gamma-knife therapy has proven an extremely helpful adjunctive.
      With this combined approach, all 8 patients with esthesioneuroblastoma are alive
      and free of disease with a mean observation time of 37.2 months. We will
      therefore continue to use this procedure in selected cases as a reliable
      alternative to external approaches in the future. However we recommend, that
      these techniques are only applied at centers, where all other surgical approaches
      can be performed, should need for this arise.

PMID- 10635395
TI  - New challenges in head and neck bone and soft tissue reconstruction.
AB  - Emphasizing the major impact of reconstructive microsurgery on the treatment of
      head and neck tumors, the present paper makes a synthesis of the ideal
      transplants now commonly used to repair specific cephalic bone and soft tissue
      defects. It also explores and discusses the new perspectives actually developed
      to improve their present anatomical, functional and aesthetic results. By
      extending the use of chimaeric or prefabricated flaps, neurovascular allografts
      or dynamic transfers, all these new challenges combine the progresses made in
      surgical skill, conceptual inventivity and basic molecular biology.

PMID- 10635394
TI  - Conservation surgery for laryngeal and hypopharyngeal cancer.
AB  - The charts of 173 patients treated by conservation laryngectomy and
      pharyngolaryngectomy were retrospectively reviewed. The patients treated by
      endoscopic laser resection were excluded of this study. Glottic carcinoma was
      diagnosed in 101 patients, supraglottic carcinoma in 44 patients, hypopharyngeal
      carcinoma in 24 patients and oropharyngeal carcinoma in 4 patients. The median
      follow-up period was 44 months, 84/101 glottic cancer, 34/44 supraglottic cancer,
      23/24 hypopharyngeal cancer and 2/4 oropharyngeal cancer were staged as T1 and
      T2. A voice-sparing external approach was carried on in 20 patients with locally
      advanced tumor (T3-T4). At time of the last follow-up, 132 patients (77%) were
      alive when 41 patients (23%) died. Overall survival rates for patients treated
      for T1-T2 glottic cancer at 3, 5 and 10 years were 90, 90 and 78% respectively.
      Overall survival rates for patients treated for T1-T2 supralottic cancer at 3, 5
      and 10 years were 73, 68 and 48% respectively. Overall survival rates for
      patients treated for T1-T2 hypopharyngeal cancer at 3 and 5 years were 74 and 37%
      respectively. The site of the primary tumor (glottic versus supraglottic or
      hypopharynx) showed significant impact on survival (P = 0.0025)). Regarding
      survival, T stage and N stage were not found statistically significant.

PMID- 10635396
TI  - Management of the N0 neck.

PMID- 10635397
TI  - Organ preservation ... where do we stand?
AB  - Organ preservation in advanced larynx and hypopharynx cancers can be achieved
      using irradiation, subtotal larynx surgery and induction chemotherapy, but larynx
      preservation remains investigational.

PMID- 10635398
TI  - Fractionation modification: a way to increase the biological dose?
AB  - This review addresses the possibilities and limitations of fractionation
      modification such as: hyperfractionation, pure accelerated fractionation and
      hybrid accelerated fractionation.

PMID- 10635399
TI  - Conformal radiotherapy in head and neck tumors: increased tumor control and
      decreased morbidity?
AB  - Conformal radiotherapy in head and neck tumors is only at its premise. Its offers
      attractive prospect to decrease late morbidity and increase loco-regional control
      probability not only in patients with primary treatment but also in patients with
      recurrent disease previously fully irradiated. Such modality however, requires
      complex infrastructure and qualified staff. Comprehensive evaluation are thus
      needed to determine the patient population that will benefit the most from this
      new promising technique before its use can be generalized.

PMID- 10635400
TI  - Pharyngeal flora in patients undergoing head and neck oncologic surgery.
AB  - In order to specify the correlation between pharyngeal flora and the onset of
      surgical wound infection, we conducted two prospective studies on patients
      undergoing oncologic surgical procedures with expected contamination by
      pharyngeal secretions. In the first study, an oropharyngeal swab and a specific
      swab of the tumour were collected the day before, or on the day of surgery. As
      potential pathogens were always isolated in the oropharyngeal swab, it was
      considered that the tumour is not infected but is colonised by the oropharyngeal
      flora. A second pharyngeal swab was collected at day 5-7 in the second study.
      Preliminary results in the second study showed that 50% (11/22) of patients were
      orpharyngeal carriers of pathogens before surgery. This rate is 70% (15/22) in
      the post-operative period with a higher rate of gram negative rods. WSI occurred
      in 7/22 patients (32%), mainly with isolated rods similar to those observed in
      the oropharyngeal post-operative flora and potential pathogens in 5/7 patients.
      More patients are necessary to establish a link between pre-operative
      ropharyngeal pathogens and the occurrence of SWI.

PMID- 10635401
TI  - Risk factors for surgical wound infections in patients undergoing head and neck
      oncologic surgery.
AB  - Risk factors for surgical wound infection are difficult to establish in head and
      neck surgery. Flap reconstruction, which correlates with tumour size and surgical
      procedure, appears to be the main risk factor. Attempts should be made by the
      surgical staff to improve surgical procedures in terms of duration of surgery and
      choice of the procedure. The intraoperative choice between primary closure and
      flap reconstruction should be studied further. More subtle risk factors may
      appear in studies of large groups of patients and/or if a distinction is drawn
      between early and late SWI.

PMID- 10635402
TI  - Postoperative wound infection in head and neck oncologic procedures.

PMID- 10635403
TI  - The chemotherapy of head and neck cancer.
AB  - Chemotherapy in head and neck cancer can be given in metastatic disease at
      presentation, in locally far advanced disease not amendable for curative
      treatment with surgery and/or radiotherapy, in the neo-adjuvant setting, in
      recurrent disease after previous surgery and radiotherapy and either concurrent
      or alternating with radiotherapy. Most data are gathered in the recurrent and
      locally far advanced disease setting. Combination therapy (with agents such as
      cisplatinum, 5-FU and methotrexate) have shown some improvements in response
      rate, however no obvious survival advantage over monotherapy in the treatment of
      patients with metastatic or advanced locoregional cancer of the head and neck has
      been observed. In the neo-adjuvant setting, chemotherapy is helpful in preserving
      the larynx and hypopharynx but has no proven impact (positive or negative) on
      survival. New compounds and approaches are needed to improve survival in head and
      neck cancer. Among the new options for chemotherapy in metastatic/recurrent
      disease are the taxanes. With monotherapy docetaxel, response rates of 23%-42%
      are seen, and, when used in combination with cisplatinum and 5-FU, response rates
      of 52-100% have been reported in phase I/II trials. A phase III trial of the
      addition of docetaxel to standard neo-adjuvant therapy with cisplatinum and 5-FU
      is now underway.

PMID- 10635404
TI  - Taxoids in head and neck cancer: the American approach.
AB  - The taxoids docetaxel and paclitaxel entered into clinical trials in the 1980s.
      Paclitaxel has dominated clinical investigations in the United States while
      docetaxel gained a foothold early in Europe. Now both agents are under intensive
      study in both countries. The Eastern Cooperative Oncology Group (ECOG) conducted
      a series of paclitaxel trials in patients with recurrent or metastatic squamous
      cell head and neck. The current study directly compares paclitaxel + cisplatin to
      cisplatin + 5-FU. Similarly, an international trial is in progress directly
      comparing docetaxel-based chemotherapy to cisplatin + 5-FU. For patients with
      locally advanced disease, phase I-II trials evaluating various doses and
      schedules of paclitaxel or docetaxel administered concurrently with radiotherapy
      are in progress or recently reported in preliminary form. No one regimen is
      clearly preferred. The results of selected studies and trials in progress in the
      United States are reviewed.

PMID- 10635405
TI  - Other new drugs in head and neck cancer.
AB  - Chemotherapy plays a definite role in the management of head and neck cancer.
      Several new agents have been introduced recently. The following are reviewed
      briefly: gemcitabine, edatexate, MTA, vinorelbine and topoisomerase I inhibitors.

PMID- 10635406
TI  - Postoperative radiotherapy of paranasal sinus tumours: a challenge for intensity
      modulated radiotherapy.
AB  - BACKGROUND AND PURPOSE: Intensity modulated radiotherapy (IMRT) is used in our
      department for treatment of paranasal sinuses. We describe the methodology that
      was developed together with the clinical implementation, illustrated by a case
      report. MATERIAL AND METHODS: Patient history, treatment and short follow-up are
      described. An IMRT, obtained by superposition of static beam segments was
      implemented. Electronic portal images, compared to digitally reconstructed
      radiographs (DRR) were used to evaluate and adjust patient positioning. RESULTS,
      DISCUSSION AND CONCLUSION: IMRT is an appropriate and feasible treatment
      technique for head and neck cancer in anatomical regions that are difficult to
      treat. A high tumour dose can be combined with a good sparing of the surrounding
      organs at risk (OAR's).

PMID- 10635407
TI  - Conformal and intensity modulated irradiation of head and neck cancer: the
      potential for improved target irradiation, salivary gland function, and quality
      of life.
AB  - PURPOSE: To develop techniques which facilitate sparing of the major salivary
      glands while adequately treating the targets in patients requiring comprehensive
      bilateral neck irradiation (RT). PATIENTS AND METHODS: Conformal and static,
      multisegmental intensity modulated (IMRT) techniques have been developed. The
      salivary flow rates before and periodically after RT have been measured
      selectively from each major salivary gland and the residual flows correlated with
      glands' dose volume histograms. Subjective xerostomia questionnaires have been
      developed and validated. The pattern of local-regional recurrences has been
      examined using CT scans at the time of recurrence, transferring the recurrence
      volumes to the planning CT scans and regenerating the dose distributions at the
      recurrence sites. RESULTS: Target coverage and dose homogeneity in IMRT treatment
      plans were found to be significantly better than standard RT plans. Significant
      parotid gland sparing was achieved. The relationships among dose, irradiated
      volume and saliva flow rates from the parotid glands were characterized by dose
      and volume thresholds. A mean dose of 26 Gy was found to be the threshold for
      stimulated saliva. Subjective xerostomia was significantly reduced in patients
      irradiated with parotid sparing techniques, compared to patients with similar
      tumors treated with standard RT. The large majority of recurrences occurred
      inside high-risk targets. CONCLUSIONS: Tangible gains in salivary gland sparing
      and target coverage are being achieved and an improvement in some measures of
      quality of life is suggested by our findings. A mean parotid gland dose of < or =
      26 Gy should be a planning objective if significant parotid function preservation
      is desired. The pattern of recurrence suggests that careful escalation of the
      dose to targets judged to be at highest risk may improve tumor control.

PMID- 10635408
TI  - Induction and adjuvant chemotherapy for head and neck cancer: future
      perspectives.
AB  - Induction and adjuvant chemotherapy have been studied in combined modality trials
      over the last two decades. Induction chemotherapy as a strategy has failed to
      improve survival or local-regional control although some studies have reported a
      decrease in the rate of development of distant metastases. The role of induction
      chemotherapy is limited to preserving the larynx for patients with larynx or
      hypopharynx primaries. Trials of adjuvant chemotherapy or chemoradiation in
      resected patients suggest benefit for those with high risk features (multiple
      involved nodes, extracapsular extension, positive surgical margin). Definitive
      randomized studies are in progress in the United States and Europe. New targeted
      therapies will be investigated in future trials to improve survival.

PMID- 10635409
TI  - On the road towards better health gain through co-operation in the European
      Union?
AB  - Explained are some 4 paradoxes, amongst many others, in healthcare and hospital
      policy and the turbulent "changes" and so-called changes they are going through
      all over Europe:--change vs being changed?--cost vs investment?--compete vs co
      operate?--patients vs healthcare workers? There is certainly not yet a
      politically explicit option for a comprehensive European (Union) healthcare
      system. The national governments explicitly want to keep their part of the social
      organisation of society in their own hands. But at the same time the EU is active
      in the healthcare field when exercising its (reduced) competencies in public
      health and in data comparison as well as when acting in its very broad domains of
      the internal market. The informative and benchmarking role of the EU is immense
      and it has huge means to stimulate European networks and scientific research even
      in healthcare systems and policymaking. A strong message here is certainly to
      correctly invest in real health gain for patients and society through co
      operation and networking among the many stakeholders in health and healthcare.
      The challenge for the future, for the numerous actors on the very slippery slope
      of health is to keep upright as moderate consumers, producers and rulers. This
      appeal to moderation, i.e. to prevention of exaggeration, which comes down to an
      attitude of subsidiarity, is a general conclusion, which may seem idealistic.
      However, one can qualify it also as "2000 realism" which our western social
      healthcare systems need for surviving, as they will have to see to a more
      solidarity-based coverage of health risks instead of reserving healthcare to the
      rich, and as they will have to open their social quality systems even more
      throughout the world.

PMID- 10635410
TI  - How should treatment costs impact on physician's decisions?
AB  - This article first discusses at what level of clinical decision making cost
      considerations may be most pertinent and important. It is argued that cost
      assessments will be of most relevance and value at an intermediate level of
      clinical decision making i.e. at a level where so-called policy decisions are
      made. These are decisions such as which drugs to include in a hospital formulary
      or which standard treatment 'protocols' to choose for particular types of
      patients. The personal encounter between individual patients and physicians will
      take place within the framework of available treatment options determined by
      these policy decisions, which must necessarily be based on a prior assessment of
      the expected costs and benefits of treatments. The article goes on to give a
      brief introduction to the various methods of economic evaluation that have been
      developed in order to provide the decision makers with the means to make policy
      decisions on the basis of the most reliable and pertinent information possible.

PMID- 10635411
TI  - [Risk reduction in major elective surgical procedures through improved
      preoperative oxygen administration by means of Dopexamine].

PMID- 10635412
TI  - [Symposium: "Balanced Anesthesia", within the framework of the German Anesthesia
      Congress, Wiesbaden, 7 Mai 1999].

PMID- 10635413
TI  - [The future of clinical microbiology as a laboratory service].

PMID- 10635414
TI  - [The capacity of the mycelia of Streptomyces chrysomallus variants to bind
      exogenous actinomycin D and the synthesis by these variants of macrotetralides].
AB  - Streptomyces chrysomallus is known as an organism producing macrotetrolides (MTL)
      and actinomycin C. The dynamics of the MTL biosynthesis by some variants of S.
      chrysomallus in the process of their growth in liquid media was studied. In
      parallel the ability of the culture mycelium (washed or suspended in
      physiological solution) to bind exogenous actinomycin D (AMD) was estimated. An
      inverse correlation between the dynamics of MTL biosynthesis and the rate of the
      AMD binding by the washed mycelium during the whole period of the culture
      development was observed: a decrease in the culture ability to bind AMD
      corresponded to active biosynthesis of MTL and an increase in the culture ability
      to bind AMD corresponded to lower biosynthesis of MTL. It was suggested that the
      active biosynthesis of MTL correlated not only with a decrease in the ability of
      the suspended mycelium to bind AMD but also with a decrease in binding of
      actinomycin synthesized and excreted to the medium by the culture. A decrease in
      the reflux of the synthesized antibiotic to the cells was likely one of the
      components of the system of the S. chrysomallus insensitivity to its own
      antibiotic.

PMID- 10635415
TI  - [The immunotropic properties of the deoxyribonucleic acid from Salmonidae milt].
AB  - The study of the immunotropic action of DNA from salmon milt showed that it
      increased the antiinfectious resistance of mice to Escherichia coli and
      Salmonella enteritidis, stimulated the antibody response to the thymus-dependent
      corpuscular antigen (sheep erythrocytes), increased the production of the
      antibody forming cells (AFC) in the murine spleen and intensified the absorptive
      and digestive activities of the cells of the mononuclear phagocytes. The
      immunotropic properties of the DNA permitted to broaden the DNA application
      spectrum with its supplementing by immunodeficiency of various genesis and
      diseases with phagocytic protection mechanisms. It is quite possible that the
      salmon milt DNA be used as a food additive.

PMID- 10635416
TI  - [The microbiological aspects of infectious complications in the oncology clinic].
AB  - At present 10 to 30 per cent of the microbial strains from cancer patients are
      problem ones: oxacillin resistant strains of Staphylococcus aureus, coagulase
      negative strains of Staphylococcus spp., aminoglycoside resistant strains of
      Escherichia coli, 3rd generation cephalosporin resistant strains of Klebsiella
      spp. and fungi of Candida which requires development of more rational approaches
      to antibacterial chemotherapy and prophylaxis of infectious complications. The
      infectious processes in the cancer patients proved to be highly polyetiological.
      Therefore, the study is significant for epidemiologic and therapeutic measures.
      Such an analysis in oncological clinic should be regular.

PMID- 10635417
TI  - [The safety of ofloxacin].
AB  - The data on a comparative study of ofloxacin arthrotoxicity in pediatric and
      adult patients are presented. The tolerability of ofloxacin used in various doses
      and treatment terms (acute and cumulative effects) was investigated in children.
      The impact of the patient pubertal age, sex, ofloxacin concentrations (Cmax above
      4 micrograms/ml) and arthrological diseases (in adult patients) on the risk of
      the quinolone arthropathy was evaluated. Good tolerability of the various
      ofloxacin dosing regimens in both the adult and pediatric patients was shown.

PMID- 10635418
TI  - [New semisynthetic macrolides. Clarithromycin--its importance in the current
      therapy of bacterial infections].

PMID- 10635420
TI  - [Prions--a new class of infectious disease causative agents].

PMID- 10635419
TI  - [The clinical and economic efficacies of short courses of azithromycin in acute
      sinusitis].
AB  - A randomized study of a 3-day course of azithromycin therapy (500 mg once daily)
      vs. a 10-day course of co-amoxiclav therapy (625 mg thrice daily) in patients
      with acute sinusitis was performed with an account of the GCP criteria. One
      hundred patients in 2 groups each of 50 persons were enrolled. The estimates of
      the patient body temperature, headache, pain on palpation in the area of the
      accessory nasal sinuses, nasal cavity stuffing, nasal discharge nature and the
      nose mucous membrane appearance were recorded prior to the treatment, in 72 hours
      and on the 10th-12th and 26th-30th days of the treatment. The microbiological
      analysis of the punctate from the accessory nasal sinuses was undertaken before
      the antibiotic therapy and 72 hours after its start. The economic analysis
      included the cost of the antibiotic therapy course, hospitalization term, medical
      manipulations and laboratory tests as well as the cost/efficacy index. The
      frequency of the relapses within 6 months after the cure was estimated in the two
      groups compared. In 72 hours and on the 10th-12th days after the treatment start
      the efficacy of azithromycin was significantly higher than that of co-amoxiclav.
      The cure was stated in 41 (82 per cent) and 26 (52 per cent) patients on the 10th
      12th days, in 6 (12 per cent) and 21 (42 per cent) patients the improvement was
      stated and the fail was stated in 3 (6 per cent) and 2 (4 per cent) patients
      respectively. The efficacy of the drugs on the 26th-30th days after the treatment
      start did not differ. The isolates of Staphylococcus aureus and Streptococcus
      pyogenes were the main pathogens. The bacteriologic eradication was recorded in
      29 (90.6 per cent) patients treated with azithromycin and only in 18 (69.2 per
      cent) patients treated with co-amoxiclav. Adverse reactions and relapses of the
      disease within 6 months after the cure were more frequent in the patients treated
      with co-amoxiclav. The cost of the azithromycin therapy was significantly lower.
      It was shown that the shortened course of the azithromycin therapy provided
      earlier cure of the patients with acute sinusitis, better tolerance of the drug,
      less frequent adverse reactions, lower cost as compared to the use of co
      amoxiclav and no relapses.

PMID- 10635421
TI  - [The status of and outlook for the creation of new preparations for the therapy
      and prevention of HIV infection and AIDS].

PMID- 10635422
TI  - The gifts we bring.

PMID- 10635423
TI  - Trends and values in our business of the future.

PMID- 10635424
TI  - Pediatric septic arthritis.
AB  - Acute septic arthritis, or septic joint, results from bacterial invasion of the
      joint space. Infecting organisms can invade any joint through the blood-stream,
      from adjacent osteomyelltis, or through direct inoculation of the wound. Although
      this can occur at any age, children are particularly susceptible and must be
      treated rapidly by joint aspiration, arthrotomy, or by a combination of
      procedures.

PMID- 10635425
TI  - Perioperative care of the older adult with auditory and visual changes.
AB  - Perioperative nurses can initiate measures during the perioperative period when
      working with older adults who have hearing and visual deficits. There are methods
      of assessing perioperative patients by interview and observation to provide
      indicators for nursing intervention. Caring and advocacy interventions include
      environmental modifications to enhance the patient's ability to hear, see, and
      understand what is happening during this anxiety-promoting time.

PMID- 10635426
TI  - Evaluating and selecting video equipment for the OR.
AB  - Purchasing video equipment for minimally invasive procedures can present a huge
      challenge. Standardization offers obvious advantages; however, it often is
      dismissed as an unattainable goal when dealing with physicians of multiple
      specialties. Standardization of video equipment throughout all specialties,
      however, is attainable. The keys to evaluating and selecting one product or
      vendor are clearly defined goals, the proper tools, and education. Although it
      might seem like an overwhelming task, it is possible to stay in control
      throughout this process and achieve the facility's goals.

PMID- 10635427
TI  - Strategic problem solving in the new millennium.
AB  - Diagnosing problems, such as those related to failing equipment, lack of
      supplies, or scheduling disputes, and finding immediate and effective solutions
      can pose a challenge to perioperative nurses. Solving these problems can be
      accomplished, however, without excessive paperwork and cumbersome protocols. The
      problem tracking system is a standardized problem-solving method that creates a
      continuous cycle of documentation, feedback, action, and assessment, thus
      establishing an interdependence between problem identification, solution, and
      evaluation. In this system, all participants have a vested interest in ensuring
      successful outcomes, valuable internal resources are optimized, and measurable
      results are demonstrated.

PMID- 10635428
TI  - Using adult learning principles for perioperative orientation programs.
AB  - New graduates and experienced nurses who choose perioperative nursing need
      comprehensive training because of the specialized nature of the OR. A
      comprehensive orientation program results in quality care for patients. This
      article presents four adult learning principles and strategies for orienting new
      nurses to the OR. The strategies suggest a framework for developing, organizing,
      or revising a perioperative nursing orientation program. The program gives nurses
      who are interested in perioperative nursing the opportunity to enter this
      specialty.

PMID- 10635430
TI  - Automated endoscope reprocessing; sterile setup monitoring; air exchange rates;
      cleaning ice machines

PMID- 10635429
TI  - Pain management after total joint replacement and its impact on patient outcomes.

PMID- 10635431
TI  - Consumers are using the Internet to revolutionize health care.

PMID- 10635432
TI  - Recommended practices for sponge, sharp, and instrument counts. AORN Recommended
      Practices Committee. Association of periOperative Registered Nurses.

PMID- 10635433
TI  - Neurobehavioral effects of acute exposure to inorganic mercury vapor.
AB  - Mercury has well-established toxic effects on the central nervous system. This
      article describes comprehensive neuropsychological and emotional functioning of a
      group of 13 workers exposed to inorganic mercury vapor compared to that of a
      normal control group. The exposed group was exposed over a 2- to 4-week period
      and had elevated blood mercury levels. The evaluations were conducted between 10
      and 15 months after exposure was terminated. Observed cognitive deficits included
      impairment in the following domains: motor coordination, speeded processing with
      and without a motor component, cognitive flexibility, verbal fluency, verbal
      memory, and visual problem solving and conceptualization. Emotional problems
      included increased focus on physical functioning, depression, anxiety, and social
      withdrawal. Cognitive deficits were, for the most part, not significantly
      associated with the degree of depression present.

PMID- 10635434
TI  - Detection of malingerers using the Rey Complex Figure and Recognition Trial.
AB  - The detection of malingered performance on neuropsychological tests is important
      for the clinical practitioner. However, malingering is often impossible to detect
      based on individual test scores. This article suggests that the relation of
      scores to one another (profile pattern) adds a dimension to identifying
      malingered performance not available through examination of individual test
      scores. This article examines Memory Error Patterns (MEPs) of the Rey Complex
      Figure Test and Recognition Trial (RCFT; Meyers & Meyers, 1995). The patterns
      were found to be good predictors of malingering. Malingering participants and
      simulators produce storage and attention MEPs whereas these 2 patterns do not
      appear in mild brain injury participants who have adequate motivation. Therefore,
      MEPs on the RCFT appear to be a method that can be used to detect malingered
      performance. It is important that the validity of the individual
      neuropsychological test performance used in an assessment be evaluated as part of
      the interpretation process.

PMID- 10635435
TI  - Malingering and mild brain injury: how low is too low.
AB  - The purpose of this study was to investigate potential validity markers for 4
      commonly used neuropsychological tests. Participants were divided into 5 groups:
      moderate/severe brain injury (n = 27), mild brain injury--nonlitigating (n = 35),
      normal controls (n = 30), mild brain injury--litigating (n = 49), and malingering
      "actors" (n = 20). Participants completed a flexible neuropsychological battery
      that included the 4 tests of interest (Judgment of Line Orientation, Token Test,
      Dichotic Listening, and 20-item forced choice). Results demonstrated cutoff
      levels on all 4 tests below which people with mild brain injury would not be
      expected to fall. The fact that some litigants, but no nonlitigants, fell below
      these cutoff levels suggests these tests and their cutoff levels may be used
      appropriately as internal validity markers. There was 100% specificity and 95%
      sensitivity found when all 4 tests were used together (1-test criteria) to
      separate litigants, nonlitigants, and actors. It is suggested that further
      examination of these tests and other neuropsychological tests, be completed so
      that, eventually, all neuropsychological tests will have internal validity
      markers.

PMID- 10635436
TI  - Head trauma and intellectual status: relation to quantitative magnetic resonance
      imaging findings.
AB  - This article contrasts 2 groups that sustained somewhat similar moderate to
      severe closed-head traumatic brain injury (TBI), but were deliberately selected
      to be different with regard to postinjury intellectual status--one group average
      or above, the other below. The purpose of this comparison was to describe any
      morphological characteristics of the 2 groups ascertained from quantitative
      magnetic resonance (QMR) imaging. Thirty-five TBI participants with Full Scale IQ
      (FSIQ) less than or equal to 90 were compared to 33 TBI participants whose FSIQ
      was above 90. A group of normal volunteer participants, age and gender matched,
      constituted a third magnetic resonance comparison group. All participants
      received uniform MRI from which QMR analysis was performed, including total
      cranial volume, subarachnoid cerebral spinal fluid ventricular volume, and
      hippocampal volume. Both TBI groups received neuropsychological testing in the
      course of clinical follow-up. Morphological comparisons between groups were made
      using multivariate analysis of variance. The TBI group with an IQ less than or
      equal to 90 had significantly enlarged third and temporal horn compartments.
      Total intracranial volume was smaller in this group as well. Lower psychometric
      intelligence postinjury may be associated with more temporal lobe atrophy and
      subcortical pathology. Smaller premorbid brain size may be another risk factor.

PMID- 10635437
TI  - The effects of age and gender on the perception of lexical emotion.
AB  - The primary purpose of this study was to examine the perception of lexical/verbal
      emotion across the adult life span. Secondary goals were to examine the
      contribution of gender and valence (i.e., pleasantness/unpleasantness) to the
      processing of lexical emotional stimuli. Participants were 28 young (ages 20-39),
      28 middle-aged (ages 40-59), and 28 older (ages 60-85) right-handed adults; there
      were 14 men and 14 women in each age group. Age groups were comparable on
      demographic and cognitive variables. Participants made accuracy judgments and
      intensity ratings of emotional (both positive and negative) and nonemotional
      stimuli from lexical perception tasks from the New York Emotion Battery (Borod,
      Welkowitz, & Obler, 1992). Accuracy and intensity measures were not significantly
      correlated. When age was examined, older participants perceived emotional and
      nonemotional lexical stimuli with significantly less accuracy than did younger
      and middle-aged participants. On the other hand, older participants evaluated the
      nonemotional lexical stimuli as significantly more intense than younger
      participants. When gender was examined, lexical stimuli were processed more
      accurately by female than male participants. Further, emotional stimuli were
      rated more intense by female participants. Clinical implications of these
      findings are discussed.

PMID- 10635438
TI  - External validation of the equivalence of two computational formulas for a WAIS-R
      seven-subtest short form.
AB  - The usefulness of an abbreviated form of the Wechsler Adult Intelligence Scale-R
      (WAIS-R) has been noted by several researchers. A 7-subtest short form yielding
      estimates of Verbal, Performance, and Full Scale IQs (FSIQs) has shown good
      reliability and validity. Both weighted and prorated formulas have been used
      interchangeably to compute estimated IQs derived from this short form. The
      purpose of this study was to compare the equivalence of these formulas with the
      full WAIS-R in a mixed clinical sample. Results show that both formulas produce
      nearly identical results, with neither formula emerging as clearly superior over
      the other; validity coefficients for WAIS-R IQs ranged from .95 to .97. A very
      slight absolute advantage was noted for the prorated over the weighted formula in
      that it resulted in fewer IQ differences greater than 2 standard errors of
      measurement, fewer misclassifications of FSIQ, and stronger correlations with
      WAIS-R Verbal, Performance, and FSIQs.

PMID- 10635439
TI  - Validity of the Ward seven-subtest WAIS-III short form in a neuropsychological
      population.
AB  - An investigation of the Ward 7-subtest short form of the Wechsler Adult
      Intelligence Scale-III (WAIS-III) in a neuropsychological clinic sample finds
      that the short form retains equivalent psychometric properties to those
      previously reported for the same short form of the Wechsler Adult Intelligence
      Scale-Revised (WAIS-R). The correlations found for the 7-subtest form of the WAIS
      III were .95 for Performance IQ, .97 for Verbal IQ, and .98 for Full Scale IQ.
      The 7-subtest short form of the WAIS-III was also found to perform similarly to
      its WAIS-R counterpart on other markers of test accuracy. These results support
      the continued use of the Ward 7-subtest short form of the WAIS-III in a
      neuropsychological population.

PMID- 10635440
TI  - Cross-validation of the two- and three-subtest short forms of the Wechsler Memory
      Scale-Revised.
AB  - Researchers have noted the usefulness of an abbreviated form of the Wechsler
      Memory Scale-Revised. A number of studies have suggested that estimating General
      Memory and Delayed Recall scores using 3-subtest or 2-subtest equations decreases
      testing time without sacrificing reliability or clinical accuracy. The purpose of
      this study was to cross-validate previous results in a mixed clinical sample, as
      well as to examine the validity of the 2-subtest equations. Results of this study
      provide support for the use of the 3-subtest short form to estimate memory
      ability in normal and cognitively impaired patients. However, using only 2
      subtests to estimate index scores resulted in a decline in predictive accuracy.

PMID- 10635441
TI  - Pharmacokinetics of NS-105, a novel cognition enhancer. 2nd communication:
      distribution and transfer into fetus and milk after single administration, and
      effects of repeated administration on pharmacokinetics and hepatic drug
      metabolizing enzyme activities in rats.
AB  - The tissue distribution and transfer into the fetus and milk of NS-105 ((+)-5-oxo
      D-prolinepiperidinamide monohydrate, CAS 110958-19-5), a novel cognition
      enhancer, were investigated in rats after single oral administration of 14C-NS
      105. The effects of repeated oral administration on the pharmacokinetics of NS
      105 and hepatic drug-metabolizing enzyme activities also were investigated in
      rats. The radioactivity concentration in most tissues of male rats reached a
      maximum of 0.5 h after the single oral administration of 14C-NS-105, indicating
      rapid absorption and distribution, 0.5 h after the administration, the highest
      concentrations were present in the kidney and stomach, and the lowest in the
      white fat. The concentrations in the remaining tissues were moderately lower than
      the plasma value. The radioactivity concentrations in all the tissues tested
      decreased along with the plasma concentration, and were below or near the
      detection limit 24 h after the administration. Most of the radioactivity in the
      plasma, liver, kidney and cerebrum was due to unchanged NS-105. The tissue
      distribution patterns of radioactivity in female (non-pregnant) and pregnant rats
      after the oral administration of 14C-NS-105 did not differ from the pattern in
      male rats, revealing neither sex- nor pregnancy-related differences in NS-105
      distribution. In pregnant rats, the maximum concentration in the fetus was 66% of
      that in the maternal plasma. In lactating rats, the radioactivity concentration
      in the milk was similar to that in the plasma. During and after the repeated oral
      administration of 14C-NS-105, the plasma concentrations and cumulative urinary
      and fecal excretions of radioactivity did not change with the number of
      administrations and were similar to the corresponding values after the single
      administration. The radioactivity concentrations in most tissues 8 h after the
      7th, 14th and 21st administrations were about twice the corresponding values
      after the single administration, indicating that there is no marked accumulation
      of radioactivity in the tissues and that a steady state level was reached within
      1 week. Repeated oral administration of NS-105 (10 mg/kg) to male rats did not
      affect hepatic drug-metabolizing enzyme activities.

PMID- 10635442
TI  - Study of the antidepressant activity of 4-phenyl-2-thioxo-benzo[4,5]thieno[2,3
      d]pyrimidine derivatives.
AB  - A series of 23 4-phenyl-2-thioxo-benzo[4,5]thieno[2,3-d]pyrimidine derivatives
      were tested for acute toxicity and antidepressant activity in mice. Eight of the
      23 compounds tested clearly antagonised the tetrabenazine effects and four of
      them (5, 7, 19, 23) showed activity values ranging from 40 to 75%, close to those
      shown by imipramine and viloxazine, the drugs chosen as reference standards.
      Compounds 7, 19 and 23 were also notably effective in the Porsolt test,
      shortening the immobility period of mice by more than 20%. The values obtained
      were very close to those elicited by imipramine and viloxazine. The most
      effective compounds in these tests were found among those bearing a primary amine
      or a benzoylamino group at the position 3 of the thieno[2,3-d]pyrimidine general
      structure (7, 19 and 23). The substitution of the thioxocarbonyl group at
      position 2 by a methylmercapto substituent maintained the activity (23).
      Compounds 7, 19 and 23 were chosen as prototypes for the design of new molecules
      with better antidepressant activity. These compounds did not present the adverse
      anticholinergic effects found in most tricyclic antidepressant drugs.

PMID- 10635443
TI  - Pharmacokinetics and pharmacodynamics of zofenopril in healthy volunteers.
AB  - This study was carried out to investigate the pharmacokinetics of zofenopril (CAS
      81938-43-4) and zofenoprilat, the behaviour of the angiotensin converting enzyme
      (ACE) (pharmacodynamics) following the administration of zofenopril calcium at
      the single oral dose of 60 mg in eighteen healthy volunteers. This open label,
      one-way study was carried out in a single centre on 18 healthy volunteers. The
      volunteers received an oral single 60 mg dose of zofenopril calcium following an
      overnight fast. The tablet was swallowed with 250 ml of water. Fasting continued
      for additional 4 h after dosing and no other liquid intake was allowed from 1 h
      before to 2 h after administration. Plasma concentrations of zofenopril and its
      active metabolite zofenoprilat as well as serum ACE activity were measured before
      drug intake (baseline) and on timed samples over a 36 h period after dosing by LC
      MS-MS, a highly sensitive, validated method for active moiety concentrations.
      Peak plasma concentration was reached on average at 1.19 h with zofenopril and at
      1.36 h with zofenoprilat. Concentrations then decreased reaching values under or
      close to the limit of quantitation (1 ng.ml-1 for zofenopril, 2 ng.ml-1 for
      zofenoprilat) from 8 to 16 h after dosing. Complete inhibition of ACE was seen at
      the first blood sampling time (1 h) and lasted on average up to 9.44 h. ACE
      activity then slowly reactivated, but enzyme inhibition continued and was
      estimated to be 74% and 56% at 24 and 36 h following drug administration,
      respectively. From these data a complete or almost complete enzyme inhibition is
      expected with zofenopril given in repeated dose regimen.

PMID- 10635444
TI  - 1H-pyrazolo[2,3-d][1,2,4]triazine-3,7-diones as a new class of human leukocyte
      elastase inhibitors.
AB  - A novel series of 1H-2-phenyl-substituted-pyrazolo[2,3-d][1,2,4]triazine-3,7
      diones (3a-g) as potential inhibitors of Human Leukocyte Elastase (HLE) are
      reported, the acyl-pyrazole being probably involved in the inhibition mechanism
      of the serino-protease enzymes. The most potent inhibitor both in vivo and in
      vitro was 2-o-methoxyphenyl-5-methyl-6-nitro-pyrazolo[2,3-d][1,2,4]triazine-3,7
      di one (3e), which significantly suppressed the HLE-induced pulmonary injury in
      rats when administered orally (100 mg/kg, 3 h prior to HLE administration.

PMID- 10635445
TI  - Synthesis, conformational analysis and antinociceptive activity of 1-[N-methyl-(2
      phenylethyl)amino]methyl-1,2,3,4-tetrahydroisoquinoline derivatives.
AB  - New derivatives of 1-[N-methyl-(2-phenylethyl)amino]methyl-1,2,3,4
      tetrahydroisoquinoline were synthesized. The antinociceptive activity of the
      compounds, determined by the mouse tail-flick test, showed that the introduction
      of a hydroxy substituent in position 5 of the isoquinoline nucleus generated
      compounds 4c and 5c, which were as potent as codeine. Conformational analysis and
      superimposition of energy minima conformers of the compounds on phenazocine
      revealed that the main proposed opioid pharmacophores were well matched.

PMID- 10635446
TI  - Synthesis and evaluation of anti-inflammatory activity of some thiazolo[3,2-b]
      1,2,4-triazole-5(6H)-ones and their Michael addition products.
AB  - Thiazolo[3,2-b]-1,2,4-triazole-5(6H)-ones (4-10) were obtained in a one step
      synthesis by heating 3-aryl-5-mercapto-1,2,4-triazoles (3a-d) with chloroacetic
      acid and appropriate aromatic aldehyde in acetic acid and acetic anhydride in the
      presence of anhydrous NaOAc. Michael type addition of cyclic secondary amines (N
      methylpiperazine, piperidine) to 4-10 gave 2-phenyl-6-(alpha
      aminoarylmethyl)thiazolo[3,2-b]-1,2,4-triazole-5 -ols (4a-10b). The structures of
      the compounds were confirmed by spectral and elementary analysis. The compounds
      synthesized in previous and present studies were investigated for their anti
      inflammatory activities.

PMID- 10635447
TI  - Influence of the formulation on the in vitro transdermal penetration of sodium
      diclofenac. Evaluation of the topical and systemic anti-inflammatory activity in
      the rat.
AB  - A study on the transdermal permeation through human skin was performed with a
      series of 6 semisolid formulations (A-F) containing 1% sodium diclofenac (CAS
      15307-79-6) (w/w). A commercially available drug preparation was tested as a
      reference. Based on permeation characteristics, a study on the topical and
      systemic anti-inflammatory activities of three formulations (A, F and the
      reference formulation) was conducted using the model of erythema induced by UV
      radiation in hairless rats. This is expected, together with the index of topical
      anti-inflammatory activity to allow the selection of the most suitable
      formulation for dermal application. The following representative parameters were
      measured in the permeation study: amount of diclofenac permeated at 24 h, flow,
      lag time and amount of drug retained in skin at 24 h. Of the formulations tested,
      diclofenac formulated in the reference formulation showed the highest values of
      amount of diclofenac permeated at 24 h, amount of drug retained in skin at 24 and
      flow. As regards the skin inflammation test, no significant differences (p <
      0.05) are seen between the topical and systemic anti-inflammatory activities of
      the three formulations tested. However, in absolute value, formulation F shows a
      lower systemic activity, which would prevent potential side effects of
      diclofenac. Since the topical anti-inflammatory index obtained for this
      formulation was > 1, it is concluded that a good therapeutic performance could be
      obtained in the treatment of local inflammation with diclofenac by using
      formulation F.

PMID- 10635448
TI  - General pharmacological properties of YJA 20379-1, a novel proton pump inhibitor
      with antiulcer activities.
AB  - The general pharmacological properties of YJA 20379-1 (2-amino-4,5-dihydro-8
      phenylimidazo[2,1-b]thiazolo[4,5-g]benzo thi azole), a novel proton pump
      inhibitor with antiulcer activities, were investigated in mice, rats, guinea pig
      and rabbits. YJA 20379-1 at oral doses of 50, 100 and 200 mg/kg did not affect
      the general behaviour, hexobarbital hypnosis, motor coordination and body
      temperature in mice. The drug does not have analgesic and anticonvulsant action
      at 200 mg/kg p.o. The locomotor activity was not affected at 100 mg/kg p.o., but
      at 200 mg/kg, the activity was suppressed. YJA 20379-1 (at 2 x 10(-4) g/ml) did
      neither produce any contraction nor relaxation of isolated organs such as rat
      fundus, rat uterus, guinea pig ileum and guinea pig vas deferens, and the drug
      did not antagonize the contractile response to several spasmogens, such as
      histamine, acetylcholine, serotonin and oxytocin, and the drug up to 200 mg/kg
      p.o. did not affect pupil size of mice. The intestinal propulsion in mice was not
      affected up to 200 mg/kg p.o. The gastric emptying in rats was not affected at
      100 mg/kg p.o., even if retardation in gastric emptying occurred at 200 mg/kg.
      YJA 20379-1 did not show anti-inflammatory action nor did it affect urinary
      excretion up to 200 mg/kg p.o. From these results, it is suggested that YJA 20379
      1 at the high dose of 100 mg/kg p.o. may not exert any adverse effects.

PMID- 10635449
TI  - Structure-activity relationship analysis of 4'-bromo-[1,1'-biphenyl]-4-yl 4-X
      phenyl methanone derivatives and activity against Mycobacterium tuberculosis.
AB  - Principal Component Analysis (PCA) and Artificial Neural Network (ANN) were used
      to analyze the relationship between the structure and the activities of a series
      of nine biphenyl-phenyl methanone derivatives against Mycobacterium tuberculosis
      in vitro. Both PCA and ANN were able to classify these derivatives in two
      categories: low active and highly active compounds. Empirical and theoretical
      descriptors were used in the classification process. The descriptors selected by
      PCA indicated that the reactivity plays an important role in the determination of
      antimycobacterial activity of biphenylphenyl methanone derivatives (BPM). The BPM
      showed a moderate activity against the M. tuberculosis strain tested with the
      exception of chloride-, bromide- and nitroderivatives (when X = Cl, Br, NO2)
      which were the most actives against M. tuberculosis in vitro among all the
      methanones studied.

PMID- 10635451
TI  - Synthesis and in vitro antifungal activity of 2-aryl-5-phenylsulfonyl-1,3,4
      thiadiazole derivatives.
AB  - The synthesis and antifungal activity of a series of 2-nitroaryl-5-phenylsulfonyl
      1,3,4-thiadiazoles (5a-e) are described. The in vitro antifungal activity of the
      compounds was determined against a variety of fungal strains in comparison to
      miconazole (CAS 22916-47-8) and fluconazole (CAS 86386-73-4). Two derivatives
      (5d, 5e) showed high activity against Candida albicans and Candida spp. having
      MIC values ranging from 0.048-3.12 micrograms/ml, providing higher potencies than
      the reference drug fluconazole. Compound 5a also showed high activity against
      Cryptococcus neoformans (MIC < 0.048 microgram/ml). The activity of this compound
      against Aspergillus niger and Aspergillus fumigatus was moderate (MIC = 1.56-6.25
      micrograms/ml), while fluconazole was inactive. Moreover, the nitroimidazole
      derivative 5d possessed good activity against most fungal strains in comparison
      to fluconazole.

PMID- 10635450
TI  - Phase II study with 5-fluorouracil and ginkgo biloba extract (GBE 761 ONC) in
      patients with pancreatic cancer.
AB  - The aim of the study was to evaluate the efficacy and tolerability of as well as
      the quality of life under treatment with 5-fluorouracil (CAS 51-21-8, 5-FU)
      combined with parenteral GBE 761 ONC (i.e. the ginkgo biloba special extract EGb
      761) in patients with pancreatic cancer. Forty-eight patients with locally or
      metastatic advanced pancreatic cancer were treated within a phase II study. The
      treatment was repeated every three weeks until progression. Response to therapy
      was evaluated after 2 and 4 treatment courses. Thirty-two patients were evaluable
      for response. Progressive disease was observed in 22 (68.8%) patients, no change
      in 7 (21.9%) patients and partial response in 3 (9.4%) patients (overall response
      = 9.4%). GBE 761 ONC was well tolerated. Adverse events which occurred during the
      study consisted mainly of myelosuppression and gastrointestinal symptoms and were
      judged as 5-FU-related or consisted of liver toxicity, respectively, and were
      judged as tumour-related. These results suggest a good benefit-risk ratio of the
      combination of 5-FU and GBE 761 ONC in the treatment of pancreatic cancer. In
      comparison with the results of studies with either 5-FU or gemcitabine as single
      agents the combination of 5-FU/GBE 761 ONC shows comparable response rates. The
      toxicity of the 5-FU/GBE 761 ONC combination was low. This combination therapy
      therefore warrants further clinical investigation, such as a controlled clinical
      trial against 5-FU or gemcitabine monotherapy.

PMID- 10635452
TI  - In vitro antifungal evaluation and studies on the mode of action of xanthoxyline
      derivatives.
AB  - This study describes the fungistatic effect of xanthoxyline (CAS 90-24-4) and its
      derivatives against a panel of yeasts, filamentous fungi and dermatophytes, by
      using the agar dilution method. Results indicated that simple structural
      modifications led to more potent derivatives, especially in relation with
      dermatophytes. The most active compound tested (10), which is a benzenesulphonyl
      derivative, was 12-fold more potent than xanthoxyline itself against Trichophyton
      rubrum. The evaluation of the mode of action with the whole cell Neurospora
      crassa assay, suggested that some selected compounds may be acting by the
      inhibition of fungal cell-wall polymers synthesis or assembly.

PMID- 10635454
TI  - Dental drug-delivery devices: local and sustained-release applications.
AB  - Dental diseases are among the most prevalent illnesses in humans. Many
      pharmaceutical dosage forms are used to prevent and treat these diseases.
      Toothpastes and mouthwashes are two of the most popular dental medicaments. A
      local delivery application that prolongs the release of the drug in the mouth
      offers great advantages in preventing and treating caries and periodontal
      diseases. Sustained-release devices are a relatively new concept in dentistry.
      This paper describes several types of sustained-release devices that are
      available commercially or are in the premarketing stage.

PMID- 10635453
TI  - Use of acetylcysteine as the life-saving antidote in Amanita phalloides (death
      cap) poisoning. Case report on 11 patients.
AB  - alpha-Amanitin is an amatoxin known to produce deleterious effects on the liver
      and the kidneys, when circulating in the blood. It is produced by a particular
      kind of mushroom called amanita phalloides. Therapeutic options employed to treat
      mushroom intoxication, such as haemodiaperfusion on activated charcoal, high
      dosages of penicillin G, oral charcoal, etc., very often failed to act properly
      and liver transplantation (when a graft is available) appeared to be the only
      solution. In recent years, as suggest by some authors, it has been postulated
      that the oxidant effects of alpha-amanitin could be counteracted by the use of
      antioxidants such as silibinin. High dosages of N-acetyl-cysteine (CAS 616-91-1,
      NAC), already used as antioxidant in paracetamol poisoning, were successfully
      used in our Intensive Care Unit (ICU) in the treatment of Amanita phalloides
      poisoning. In the last two years, 11 patients (mean age of 5-72 = 38.5) were
      treated for Amanita phalloides poisoning of various degrees, with a protocol
      (haemodiaperfusion on activated charcoal, high dosages of penicillin G, etc.)
      further comprehending NAC (fluimucil). All the patients recovered successfully
      but one (bearing precedent liver disease) needed liver transplantation. Daily
      monitoring of liver enzymes, creatinine, coagulation, LDH, blood and urinary
      alpha-amanitin were used to screen the progresses of the patients.

PMID- 10635455
TI  - Microemulsions: an overview and pharmaceutical applications.
AB  - Microemulsions are potential drug carrier systems for oral, topical, and
      parenteral administration. They offer the advantage of spontaneous formation,
      ease of manufacturing and scale-up, thermodynamic stability, and improved drug
      solubilization and bioavailability. Preparing a pharmaceutically acceptable
      dosage form demands a clear understanding of the microemulsion structure, phase
      behavior, factors leading to its thermodynamic stability, factors influencing
      drug release from the formulation, requirements of ideal microemulsion
      excipients, and the potential uses and limitations of the microemulsion system.
      Knowledge of the various methods available to thoroughly characterize a
      microemulsion system is essential. An overview of these factors is presented in
      this review. While microemulsion is used in several fields, in this review the
      pharmaceutical applications are emphasized. Several references are cited, but the
      list is by no means exhaustive. The review is written so that a newcomer to the
      field can easily grasp the important facts pertaining to this novel delivery
      system.

PMID- 10635456
TI  - Evolution and development of distinct cell lineages derived from somites.
AB  - In the vertebrate embryo, the somites arise from the paraxial mesoderm as paired
      mesodermal units in a craniocaudal sequence. Segmentation is also the underlying
      principle of the body plan in annelids and arthropods. Genes controlling
      segmentation have been identified that are highly conserved in organisms
      belonging to different phyla. Segmentation facilitates movement and
      regionalization of the vertebrate body. Its traces in humans are, for example,
      vertebral bodies, intervertebral disks, ribs, and spinal nerves. Somite research
      has a history of at least three centuries. Detailed morphological data have
      accumulated on the development of the avian somite. Especially in connection with
      the quailchick interspecific marker system, progress was made toward an
      understanding of underlying mechanisms. At first each somite consists of an outer
      epithelium and a mesenchymal core. Later, the ventral portion of the somite
      undergoes de-epithelialization and gives rise to the sclerotome, whereas the
      dorsal portion forms the dermomyotome. The dermomyotome is the source of myotomal
      muscle cells and the dermis of the back. It also yields the hypaxial muscle buds
      at flank level and the myogenic cells invading the limb buds. The dorsal and
      ventral somitic domains express different sets of developmental control genes,
      for example, those of the Pax family. During later stages of development, the
      sclerotomes undergo a new arrangement called "resegmentation" leading to the
      fusion of the caudal half of one sclerotome with the cranial half of the
      following sclerotome. Further somitic derivatives include fibroblasts, smooth
      muscle, and endothelial cells. While sclerotome formation is controlled by the
      notochord, signals from the dorsal neural tube and ectoderm support the
      development of the dermomyotome. Myogenic precursor cells for the limb bud are
      recruited from the dermomyotome by the interaction of c-met with its ligand
      scatter factor (SF/HGF). In the evolution of metamerism in vertebrates, the first
      skeletal elements were primitive parts of neural arches, while axial elements
      developed only later in teleosts as pleurocentra and hypocentra.

PMID- 10635457
TI  - Duality of molecular signaling involved in vertebral chondrogenesis.

PMID- 10635458
TI  - Sclerotome induction and differentiation.
AB  - Inductive events in the development of the sclerotome and their possible
      underlying mechanisms were reviewed from the primary literature. A brief review
      of morphological and anatomical aspects of sclerotome development was given. The
      importance of the notochord and neural tube in sclerotome induction and somite
      chondrogenesis in vivo and in vitro was established. The functions and patterns
      of expression of different sclerotome markers were discussed. Shh and Noggin were
      discussed as two molecules produced by the neural tube and notochord that appear
      to maintain and initiate the sclerotome, respectively. While the abilities of the
      axial organs and Shh and Noggin to induce sclerotome marker expression in the
      somite was not disputed, the exact nature of these inductions was discussed with
      regard to possible effects on gene expression, effects on cell survival, and
      physical effects on the cells and it was argued that the fundamental nature of
      inductive events in the sclerotome is still unknown.

PMID- 10635459
TI  - Genetics of muscle determination and development.
AB  - Skeletal muscles in vertebrates develop from somites as the result of patterning
      and cell type specification events. Here, we review the current knowledge of
      genes and signals implicated in these processes. We discuss in particular the
      role of the myogenic determination genes as deduced from targeted gene
      disruptions in mice and how their expression may be controlled. We also refer to
      other transcription factors which collaborate with the myogenic regulators in
      positive or negative ways to control myogenesis. Moreover, we review experiments
      that demonstrate the influence of tissues surrounding the somites on the process
      of muscle formation and provide model views on the underlying mechanisms.
      Finally, we present recent evidence on genes that play a role in regeneration of
      muscle in adult organisms.

PMID- 10635460
TI  - Multiple tissue interactions and signal transduction pathways control somite
      myogenesis.

PMID- 10635461
TI  - The birth of muscle progenitor cells in the mouse: spatiotemporal considerations.

PMID- 10635462
TI  - Mouse-chick chimera: an experimental system for study of somite development.
AB  - As the mammalian embryo is implanted in the uterus and not readily accessible to
      direct observation or manipulation, much of our understanding of mammalian somite
      development is based on findings in lower vertebrates. One means of overcoming
      the difficulties raised by intrauterine development is to engraft mouse tissue in
      ovo. The experiments described in this chapter relate to the unilateral
      replacement of somites in chick embryo with those from mouse fetus. Mouse somites
      differentiate in ovo in dermis, cartilage, and skeletal muscle and are able to
      migrate into chick host limb. A LacZ transgenic mouse strain was used to
      ascertain the role of the implanted somites in forming epaxial and hypaxial
      muscle in the chick embryo. Myogenesis occurred normally in in ovo developing
      mouse somites, and muscle cells from mouse myotome formed neuromuscular contacts
      with chick motor axons. After fragments of fetal mouse neural primordium were
      transplanted into chick embryo, mouse neural tube contributed to the mechanism
      maintaining myogenesis in the somites of the host embryo. A recently developed
      double-grafting procedure involving neural tube and somites from knockout mouse
      strains should elucidate the molecular events involved in early somitogenesis.

PMID- 10635463
TI  - Transcriptional regulation during somitogenesis.

PMID- 10635464
TI  - Determination and morphogenesis in myogenic progenitor cells: an experimental
      embryological approach.

PMID- 10635465
TI  - Epidemiology of orofacial sports-related injuries.
AB  - Orofacial sports-related injuries occur across a wide range of both organized and
      unorganized sports. Different types of injuries are associated with each sport.
      The current database for incidence, prevalence, severity, and causality is found
      only in published reports and scientific articles. Careful analysis and use of
      recent data are necessary because rule changes in sports have made the
      application of outdated information to current sports issues obsolete.

PMID- 10635466
TI  - Prediction of sports-related dental traumatic injuries.
AB  - Predicting sports-related traumatic injuries is an important concern for dental
      health professionals. A predictive index has been developed that determines the
      likelihood of a sports-related traumatic dental injury in children and
      adolescents. This index can be used to aid in the prevention of injury by
      understanding who is most likely to be injured and what factors influence the
      chance of injury. The index has been designed for ease of use by dental health
      professionals, and has incorporated data collection and tracking features.

PMID- 10635467
TI  - Prevention of sports-related traumatic dental injuries.
AB  - Many sports-related traumatic dental injuries are preventable with the use of
      appropriate, properly fitted athletic equipment such as helmets, facemasks, and
      mouthguards. This article presents information regarding the current generation
      of athletic mouthguards, and issues a challenge for the development of future
      independent scientific research that will transform current clinical empiricism
      into evidence based knowledge in sports dentistry.

PMID- 10635468
TI  - Attitudinal factors influencing mouthguard utilization.
AB  - From the introduction of a protective mouthpiece in the sport of boxing, the
      evidence for the importance of this piece of athletic equipment in injury
      prevention has grown. Yet, despite this knowledge, only five amateur sports and
      one professional sport have regulations requiring the use of mouthguards. Even in
      the sports that require their use, compliance is not universal. Attitudes of
      coaches, officials, parents, and players about wearing mouthguards all influence
      their usage. Studies of the attitudes of these groups reveal that coaches are
      perceived as the individuals with the most impact on whether or not players wear
      mouthguards. There is reluctance among college football officials to enforce
      mouthguard violations that they believe are inappropriate. Parents see themselves
      as having responsibility in determining mouthguard use; however, their views
      about when and for whom mouthguards are necessary reveal a lack of complete
      understanding of the benefits. Resistance on the part of players stems from the
      physical characteristics of the mouthguard, interference with breathing and
      speech, and the effect on the players' image. Education on the effectiveness of
      properly fitted mouthguards for injury prevention, information on the risk for
      injury, availability of more comfortable and appealing mouthguards, and
      development of an approach for expanding regulations are all tools that can lead
      to the development of more positive attitudes and increased usage.

PMID- 10635469
TI  - Management of sports-related concussions.
AB  - Mild head injury is a frequent occurrence in a multitude of athletic endeavors
      across all levels of play. Clinicians should carefully consider all interventions
      at their disposal to reduce the prevalence and severity of injury to protect
      those involved. The exploration and evaluation of using properly fitted
      mouthguards to provide effective, albeit limited, defense against brain injury
      merits attention. The minimal costs of such an intervention when properly applied
      would no doubt reap numerous benefits in terms of reducing the medical,
      financial, cognitive, psychological, and social consequences of mild head injury.
      The cosmetic salvation would be no small side effect to efficacious, properly
      fitted mouthguard use.

PMID- 10635470
TI  - Management of sports-related crown fractures.
AB  - Uncomplicated tooth crown fractures are the most common sports-related mouth
      injury and can have an excellent outcome if treated appropriately. Many times,
      however, crown fractures occur at the same time as concussion, luxation,
      displacement, or even avulsion injuries. This article discusses the treatment for
      and management of tooth crown fractures from sports-related injuries.

PMID- 10635471
TI  - Management of sports-related root fractures.
AB  - Fractures that occur midroot are most frequently missed in radiographs unless
      multiple exposures at different angles are used for diagnosis. Immediate
      treatment consists of reduction of the fracture with close apposition of segments
      and rigid splinting for 3 months. Because of the good potential for healing, root
      canal therapy is delayed until evidence of pulpal necrosis is confirmed. Healing
      is by hard tissue, connective tissue, bone, or a combination of these accompanied
      by obliteration of the root canal.

PMID- 10635472
TI  - Management of sports-related tooth displacements and avulsions.
AB  - Between 500,000 and 750,000 dental injuries occur each year during sports
      activities in the United States. Twenty percent of these are tooth displacements:
      extrusive or lateral luxations, intrusions, or exarticulations. Such injuries
      pose serious problems and the manner in which they are treated can affect the
      prognosis. This article discusses displacement injuries and recommends optimal
      treatment for each type of displacement.

PMID- 10635473
TI  - Surgical management of sports-related traumatic injuries.
AB  - The increasing popularity of all sporting events results in increased potential
      for injury. Despite helmet, facemask, and mouthguard use, the face often remains
      an exposed area at risk in many sports. Dentists rehabilitating patients after
      facial injuries should understand their patients' previous injuries and
      treatment.

PMID- 10635474
TI  - Dental implications of nutritional factors in young athletes.
AB  - A balanced and healthful diet is important for young athletes participating in
      sports. Additionally, nutritional recommendations for athletes must take into
      consideration the effects diet has on the developing dentition. The integration
      of oral and nutritional health guidelines will allow the dentist and the
      dietician to function as partners in providing counseling to young athletes. This
      article reviews caloric and nutritional requirements along with dental
      implications that may affect young athletes.

PMID- 10635475
TI  - Tobacco and athletics. Update and current status.
AB  - The 1990's marked the beginning of a new era in the war against tobacco. This
      time, however, the major initiatives to exert control of and reduce tobacco use
      were directed at the tobacco industry. To succeed, these efforts had first to
      overcome intense political, economic, and other obstacles that are inexorably
      intertwined with the influential power base of tobacco interests that are, in
      turn, supported by the vast wealth of the tobacco industry. There were also
      disturbing revelations of an increase in new tobacco users among American youth.
      Furthermore, the intimate associations between athletics and the use of smokeless
      tobacco appear not to have abated. Another generation of tobacco users must now
      be provided with all the available science, techniques, and support systems to
      reduce or eliminate use of tobacco. Members of the dental profession must
      continue to monitor the use of all forms of tobacco by their patients; provide
      counseling; initiate intervention and cessation programs; and, particularly,
      discourage teenagers from initiating use. Similar efforts are required from
      physicians.

PMID- 10635476
TI  - Legal considerations in sports dentistry.
AB  - This article discusses legal issues relevant to a dentist who provides services
      to individuals who participate in sports. It addresses the potential liability of
      both volunteer and paid team dentists as well as spectators at events. It also
      discusses private practice dentists providing fee-for-service care to athletes.
      This article is intended to stimulate dentists to consider the potential
      liabilities that may arise from the seemingly innocent act of helping others.

PMID- 10635477
TI  - Private practice and community activities in sports dentistry.
AB  - For dentists interested in sports dentistry, there are a wide variety of private
      practice and community activities available for involvement. These activities
      include, among others, volunteering for mouth guard programs, participating as a
      sports team dentist, and becoming an active member in the Academy for Sports
      Dentistry.

PMID- 10635478
TI  - Helping special olympics athletes sport good smiles. An effort to reach out to
      people with special needs.
AB  - For the millions of people in the world with special needs, dental care is
      usually not a priority, often taking a back seat to more pressing and complicated
      medical issues. This article offers a brief overview of the integration of a
      dental program into the Special Olympics organization. This overview is followed
      by a discussion on dental education with regard to people with special needs, and
      then reviews measures for the prevention of injuries.

PMID- 10635479
TI  - [Successful and effective: Montelukast in clinical practice].

PMID- 10635480
TI  - [Acute coronary syndrome, stent and cardiac insufficiency. Advances in thrombosis
      prevention].

PMID- 10635481
TI  - [Raloxifene: a selective modulator of estrogen receptors].
AB  - It has been demonstrated that postmenopausal hypoestrogenia induces numerous
      complications including osteoporosis and increased risk of cardiovascular
      disease. Oral or transdermal administration of estrogens can reduce these risks,
      but induces adverse effects. Recently, raloxifene, a new molecule from the
      benzothiophene family, has been demonstrated to prevent postmenopausal bone loss.
      It does not induce endometrial stimulation, and recent studies show that it could
      reduce breast cancer incidence. Its mode of action, consisting of mixed agonist
      and antagonistic estrogenic actions on different organs and systems, allows to
      classify it into the selective estrogen receptor modulator (SERM) family. In this
      review article, we will describe the characteristics of the molecule, its mode of
      action and the potential indications of its clinical use.

PMID- 10635482
TI  - [Idiopathic granulomatous mastitis. Review of the literature illustrated by 4
      cases].
AB  - INTRODUCTION: Idiopathic granulomatous mastitis (IGM) was described as a specific
      entity in 1972 by Kessler and Wolloch. Despite the 120 cases reported in the
      international literature, this pathology remains quite unknown. MATERIAL AND
      METHODS: Four cases of idiopathic granulomatous mastitis are reported in this
      article in order to outline the main clinical features of this affection. Data in
      the literature were used to discuss diagnostic and therapeutic particularities.
      DISCUSSION: The histologic findings of a non-caseating granulomatous
      inflammation, centered on breast lobules, composed of epithelioid cells and
      multinucleated giant cells, allow establishing the diagnosis of granulomatous
      mastitis (GM). The main presenting symptom of GM is a single inflammatory mass of
      the breast; the diagnosis is thus often mistaken for breast carcinoma (more than
      50% of the reported cases). Radiologic and cytologic findings alone do not enable
      reaching certain diagnosis because they cannot resolve the differential diagnosis
      of inflammatory process and malignancy. The diagnosis of IGM can be established
      after the etiological work up remains negative. A course of oral corticosteroid
      therapy, non-steroidian anti-inflammatory drugs, or colchicine can be used in
      order to shrink the breast mass, allowing more conservative surgery. Local
      excision is of limited benefit as there is a strong tendency for recurrence.
      CONCLUSION: Different therapeutic options of IGM are explained by its clinical
      variability. A more pragmatic therapeutic approach would be enabled by a new
      classification based on course and severity.

PMID- 10635483
TI  - [Prescription of hormone replacement therapy. Review on the management with
      abnormal mammography].
AB  - Mammography must be performed before restauring RHT. We discuss the radiological
      contrindications before RHT, and the predictive positive value of malignancy for
      stellate lesions, round opacities, diffuse microcalcifications, cluster of
      microcalcifications. Ultrasonography is essential for differentiating benign from
      malignant lesions. Diagnosis strategy (clinical follow-up, fine needle
      aspiration, biopsy, surgery) depends also on personal and familial history.

PMID- 10635484
TI  - [Value of histologic examination of the interamniotic membrane in the twin
      placenta for confirmation of chorionicity diagnosis].
AB  - The interest of twin chorionocity and zygosity diagnosis is unquestioned. Indeed,
      in many medical situations, the knowledge of zygosity is an important fact for
      management of twins. Prenatal echographia is not a perfect tool to characterize
      chorionicity, and so postnatal examination of the placenta is always necessary.
      But macroscopic examination is also not relevant, and competent midwives can make
      many mistakes. Considering that biological postnatal diagnosis of twin zygosity
      is difficult and costly, we believe that microscopic chorionicity confirmation is
      required for identical twins.

PMID- 10635485
TI  - [Twin delivery after cesarean section: is a trial of labor warranted?].
AB  - OBJECTIVE: To determine whether a trial of labor in twin pregnancy is a valuable
      alternative to routine repeat cesarean section. MATERIAL AND METHODS: Based on
      retrospective analysis of 31 cases of twin gestation with previous cesarean
      section, we tried to assess the outcomes of 25 cases of trial of labor. The
      outcomes of trial of labor in twin pregnancy were compared to those of trial of
      labor in singleton pregnancy. RESULTS: The trial of labor was successful in 21
      cases (84%). There was one case of scar dehiscence among the women who underwent
      a trial of labor, that occurred in the parturient with two previous cesarean
      sections after complete breech extraction. There were no significant differences
      in perinatal outcomes in any comparison of trial of labor versus no trial of
      labor. The outcomes of trial of labor in the twin pregnancy were similar to
      singleton pregnancy. CONCLUSIONS: Routine repeat cesarean section in the twin
      pregnancy is not necessarily warranted; a controlled trial of labor in selected
      cases would be a valuable alternative.

PMID- 10635486
TI  - [Interposition of a synthetic mesh by vaginal approach in the cure of genital
      prolapse].
AB  - There are two goals for treatment if vaginal prolapse, restauration of normal
      function and anatomy and prevention of recurrence. Most operations described for
      replacement and maintenance of prolapsed organs in the pelvic cavity do not treat
      the cause of the prolapse which is diastasis of levator muscles and, in most
      cases, failure of the pelvic fascia. By analogy with the treatment of parietal
      hernias, the concept of a synthetic graft to reinforce failing fascias and
      restauration of normal anatomy has been proposed. From June 1994 through March
      1999, 46 patients were treated for genital prolapse by a vaginal approach with
      positioning of a polyester mesh sutured to the vaginal angles. No major
      complication was observed. One mesh exposure occurred 4 months after treatment of
      a cystocele with vaginal hysterectomy and was treated by partial resection with
      good outcome. With a 5-year follow-up (median 26 months), all patients are
      totally satisfied. No recurrence of prolapse was observed. Sexual function was
      preserved without dyspareunia. This study demonstrates the feasability and
      efficacy of using a synthetic graft in the cure via a vaginal approach of genital
      prolapse. Complementary studies are necessary to evaluate the indications for
      which the procedure can be proposed and how it should be integrated in to schemes
      with other procedures.

PMID- 10635487
TI  - [Multiple vulvar cystic and papillary fibroadenomas].
AB  - We report a new case of multiple vulvar fibroadenoma arising in a 47-year-old
      woman. This papillary and cystic lesion shares similarities with papilliferum
      hidradenoma and mammary fibroadenomas. After describing clinical and pathological
      characteristics, we try to detail its origin according to the literature and
      particularly its relationship with anogenital sweat glands and ectopic mammary
      glands.

PMID- 10635488
TI  - [Blepharophimosis-ptosis-epicanthus inversus associated with infertility].
AB  - Blepharophimosis-ptosis-epicanthus syndrome (BPES) is a rare genetic condition
      occurring sporadically and transmitted by autosomal dominant inheritance. Type I
      BPES is associated with a high incidence of menstrual irregularities and
      infertility. Its clinical presentation is attributed to either an ovarian
      resistance to gonadotropins or to a true premature menopause. Two
      pathophysiological underlying mechanisms have been proposed: one suggests that
      one or more mechanisms lead to inhibition of early follicular development or
      follicule atresia. The other raises the possibility that BPES results from
      microdeletion of genetic material containing at least 2 independent genes. We
      report a familial case of BPES identified at birth and who required several
      surgical procedures. Several members of the patient's family are also affected.
      Early recognition of this condition may allow appropriate counselling and/or
      treatments including egg donation in case of hypergonadotropic hypogonadism.

PMID- 10635489
TI  - [Varicella pneumonia during pregnancy after double exposure in the 2nd trimester.
      Value of seroprophylaxis].
AB  - We report on a case of varicella pneumonia at 29 weeks of gestation after double
      contact during the second trimester of pregnancy although passive immunotherapy
      by polyvalent immunoglobulins was used. Our case report highlights the
      difficulties of varicella pneumonia diagnosis that was here confirmed by
      seroconversion and the presence of pathognomonic microcalcifications, on a
      pulmonary X-ray, realized two years after pregnancy. Although the absence of
      publications asserting the efficacy of immunotherapy by polyvalent
      immunoglobulins to prevent maternal complications of varicella during pregnancy,
      they remain widely employed in such cases. Our point of view is that this
      indication must be revisited.

PMID- 10635490
TI  - [Inherited factor VII deficiency and pregnancy. Apropos of 1 case].
AB  - Hereditary factor VII deficiency is a rare autosomal recessive condition. Factor
      VII's level elevates during pregnancy in normal patients, as well in deficient
      individuals for some authors. Various treatments (fresh frozen plasma,
      prothrombin complex or factor VII concentrate) have been used to lessen the peri
      partum hemorrhage in those factor VII-deficient pregnant women. We report the
      case of a pregnant woman presenting a factor VII deficiency (level 4%), without
      variation of level during her pregnancy. The single infusion of factor VII
      concentrate, prior to delivery, has elevated factor VII's level at 17% and has
      likely permitted minimal post-partum bleeding. The peripartum management of
      factor VII deficiency is discussed.

PMID- 10635491
TI  - [Hysterectomies and PMSI].

PMID- 10635492
TI  - [Perineology...reaching equilibrium and preserving it?].

PMID- 10635493
TI  - End-of-life decisions.

PMID- 10635494
TI  - The medical ethics of physician-assisted suicide.

PMID- 10635495
TI  - Withholding/withdrawing treatment from neonates: legislation and official
      guidelines across Europe.
AB  - Representatives from eight European countries compared the legal, ethical and
      professional settings within which decision making for neonates takes place. When
      it comes to limiting treatment there is general agreement across all countries
      that overly aggressive treatment is to be discouraged. Nevertheless, strong
      emphasis has been placed on the need for compassionate care even where cure is
      not possible. Where a child will die irrespective of medical intervention, there
      is widespread acceptance of the practice of limiting aggressive treatment or
      alleviating suffering even if death may be hastened as a result. Where the infant
      could be saved but the future outlook is bleak there is more debate, but only two
      countries have tested the courts with such cases. When it comes to the active
      intentional ending of life, the legal position is standard across Europe; it is
      prohibited. However, recognising those intractable situations where death may be
      lingering and unpleasant, Dutch paediatricians have reported that they do
      sometimes assist babies to die with parental consent. Two cases have been tried
      through the courts and recent official recommendations have set out standards by
      which such actions may be assessed.

PMID- 10635496
TI  - The milk and the honey: ethics of artificial nutrition and hydration of the
      elderly on the other side of Europe.
AB  - Many health problems that elderly people face today relate not only to the nature
      of their affliction but also to the kind of treatment required. Such treatment
      often includes artificial nutrition and hydration, (ANH) a procedure which,
      despite its technical and invasive character, is still considered to be vested
      with symbolic meanings. It is precisely during the efforts to reach a legal
      consensus that the discrepancies between various cultural contexts become
      obvious. The following case explores the Greek clinical territory in comparison
      with the international situation, and the reasons why, in Greece, the right to
      refuse treatment is not necessarily interpreted as including the right to refuse
      artificial nutrition and hydration as well.

PMID- 10635497
TI  - Food refusal in prisoners: a communication or a method of self-killing? The role
      of the psychiatrist and resulting ethical challenges.
AB  - Food refusal occurs for a variety of reasons. It may be used as a political tool,
      as a method of exercising control over others, at either the individual, family
      or societal level, or as a method of self-harm, and occasionally it indicates
      possible mental illness. This article examines the motivation behind hunger
      strikes in prisoners. It describes the psychiatrist's role in assessment and
      management of prisoners by referring to case examples. The paper discusses the
      assessment of an individual's competence to commit suicide by starvation, legal
      restraints to intervention, practical difficulties and associated ethical
      dilemmas. Anecdotal evidence suggests that most prisoners who refuse food are
      motivated by the desire to achieve an end rather than killing themselves, and
      that hunger-strike secondary to mental illness is uncommon. Although rarely
      required, the psychiatrist may have an important contribution to make in the
      management of practical and ethical difficulties.

PMID- 10635498
TI  - Autonomy, rationality and the wish to die.
AB  - Although suicide has traditionally carried a negative sanction in Western
      societies, this is now being challenged, and while there remains substantial
      public concern surrounding youth and elder suicide, there is a paradoxical push
      to relax the prohibition under certain circumstances. Central to the arguments
      behind this are the principles of respect for autonomy and the importance of
      rationality. It is argued here that the concepts of rationality and autonomy,
      while valuable, are not strong enough to substantiate a categorical "right to
      suicide" and that the concepts of "understandability" and "respect" are more
      useful and able to provide the foundation for responding to a person expressing a
      wish to die. Roman suicide, sometimes held as an example of "rational suicide",
      illustrates the effects of culture, tradition and values on the attitudes to, and
      the practice of, suicide.

PMID- 10635499
TI  - Bioethics of the refusal of blood by Jehovah's Witnesses: Part 3. A proposal for
      a don't-ask-don't-tell policy.
AB  - Of growing concern over Jehovah's Witnesses' (JWs) refusal of blood is the
      intrusion of the religious organisation into its members' personal decision
      making about medical care. The organisation currently may apply severe religious
      sanctions to JWs who opt for certain forms of blood-based treatment. While the
      doctrine may be maintained as the unchangeable "law of God", the autonomy of
      individual JW patients could still be protected by the organisation modifying its
      current policy so that it strictly adheres to the right of privacy regarding
      personal medical information. The author proposes that the controlling religious
      organisation adopt a "don't-ask-don't-tell" policy, which assures JWs that they
      would neither be asked nor compelled to reveal personal medical information,
      either to one another or to the church organisation. This would relieve patients
      of the fear of breach of medical confidentiality and ensure a truly autonomous
      decision on blood-based treatments without fear of organisational control or
      sanction.

PMID- 10635500
TI  - Jehovah's Witnesses' refusal of blood: obedience to scripture and religious
      conscience.
AB  - Jehovah's Witnesses are students of the Bible. They refuse transfusions out of
      obedience to the scriptural directive to abstain and keep from blood. Dr Muramoto
      disagrees with the Witnesses' religious beliefs in this regard. Despite this
      basic disagreement over the meaning of Biblical texts, Muramoto flouts the
      religious basis for the Witnesses' position. His proposed policy change about
      accepting transfusions in private not only conflicts with the Witnesses'
      fundamental beliefs but it promotes hypocrisy. In addition, Muramoto's arguments
      about pressure to conform and coerced disclosure of private information
      misrepresent the beliefs and practices of Jehovah's Witnesses and ignore the
      element of individual conscience. In short, Muramoto resorts to distortion and
      uncorroborated assertions in his effort to portray a matter of religious faith as
      a matter of medical ethical debate.

PMID- 10635501
TI  - Re-examining death: against a higher brain criterion.
AB  - While there is increasing pressure on scarce health care resources, advances in
      medical science have blurred the boundary between life and death. Individuals can
      survive for decades without consciousness and individuals whose whole brains are
      dead can be supported for extended periods. One suggested response is to redefine
      death, justifying a higher brain criterion for death. This argument fails because
      it conflates two distinct notions about the demise of human beings--the one,
      biological and the other, ontological. Death is a biological phenomenon. This
      view entails the rejection of a higher brain criterion of death. Moreover, I
      claim that the justification of the whole brain (or brain stem) criterion of
      death is also cast into doubt by these advances in medical science. I proceed to
      argue that there is no need to redefine death in order to identify which
      treatments ought to be provided for the permanently and irreversibly unconscious.
      There are already clear treatment guidelines.

PMID- 10635502
TI  - The virtue of nursing: the covenant of care.
AB  - It is argued that the current confusion about the role and purpose of the British
      nurse is a consequence of the modern rejection and consequent fragmentation of
      the inherited nursing tradition. The nature of this tradition, in which nurses
      were inducted into the moral virtues of care, is examined and its relevance to
      patient welfare is demonstrated. Practical suggestions are made as to how this
      moral tradition might be reappropriated and reinvigorated for modern nursing.

PMID- 10635503
TI  - Arguments for zero tolerance of sexual contact between doctors and patients.
AB  - Some doctors do enter into sexual relationships with patients. These
      relationships can be damaging to the patient involved. One response available to
      both individual doctors and to disciplinary bodies is to prohibit sexual contact
      between doctors and patients ("zero tolerance"). This paper considers five ways
      of arguing for a zero tolerance policy. The first rests on an empirical claim
      that such contact is almost always harmful to the patient involved. The second is
      based on a "principles" approach while the third originates in "virtues" ethics.
      The fourth argues that zero tolerance is an "a priori" truth. These four attempt
      to establish that the behaviour is always wrong and ought, therefore, to be
      prohibited. The fifth argument is counterfactual. It claims a policy that allowed
      sexual contact would have unacceptable consequences. Given the responsibility of
      regulatory bodies to protect the public, zero tolerance is a natural policy to
      develop.

PMID- 10635504
TI  - On becoming non-judgmental: some difficulties for an ethics of counselling.
AB  - The growth in the availability of counselling services has been accompanied by
      growing concern about the conduct of counsellors, which in turn has led to the
      expressed need for an ethics of counselling. This paper will argue that there is
      an inherent tension between this need and the central tenets of one variety of
      counselling, client-centred counselling. The tension is identifiable on the basis
      of an inquiry into the nature of moral judgment which results in the recognition
      of the implicit value base in client-centred counselling. It is only when this
      value base is made explicit that any adequate ethics of counselling becomes a
      viable possibility.

PMID- 10635506
TI  - Fraud, misconduct or normal science in medical research--an empirical study of
      demarcation.
AB  - OBJECTIVES: To study and describe how a group of senior researchers and a group
      of postgraduate students perceived the so-called "grey zone" between normal
      scientific practice and obvious misconduct. DESIGN: A questionnaire concerning
      various practices including dishonesty and obvious misconduct. The answers were
      obtained by means of a visual analogue scale (VAS). The central (two quarters) of
      the VAS were designated as a grey zone. SETTING: A Swedish medical faculty.
      SURVEY SAMPLE: 30 senior researchers and 30 postgraduate students. RESULTS:
      Twenty of the senior researchers and 25 of the postgraduate students answered the
      questionnaire. In five cases out of 14 the senior researchers' median was found
      to be clearly within the interval of the grey zone, compared with three cases for
      the postgraduate students. Three examples of experienced misconduct were
      provided. Compared with postgraduate students, established researchers do not
      call for more research ethical guidelines and restrictions. CONCLUSION: Although
      the results indicate that consensus exists regarding certain obvious types of
      misconduct the response pattern also indicates that there is no general consensus
      on several procedures.

PMID- 10635505
TI  - The family rule: a framework for obtaining ethical consent for medical
      interventions from children.
AB  - Children's consent to treatment remains a contentious topic, with confusing legal
      precepts and advice. This paper proposes that informed consent in children should
      be regarded as shared between children and their families, the balance being
      determined by implicit, developmentally based negotiations between child and
      parent--a "family rule" for consent. Consistent, operationalized procedures for
      ethically obtaining consent can be derived from its application to both routine
      and contentious situations. Therefore, use of the "family Rule" concept can
      consistently define negligent procedure in obtaining consent from children, and
      could be used as a unifying framework in the development of new professional
      guidelines. A "guideline"-based approach to children's consent to treatment may
      offer greater individuality than a "rights"-based approach, though careful
      training and oversight will be needed for it to be effective.

PMID- 10635508
TI  - An international survey of medical ethics curricula in Asia.
AB  - SETTING: Medical ethics education has become common, and the integrated ethics
      curriculum has been recommended in Western countries. It should be questioned
      whether there is one, universal method of teaching ethics applicable worldwide to
      medical schools, especially those in non-Western developing countries. OBJECTIVE:
      To characterise the medical ethics curricula at Asian medical schools. DESIGN:
      Mailed survey of 206 medical schools in China, Hong Kong, Taiwan, Korea,
      Mongolia, Philippines, Thailand, Malaysia, Singapore, Indonesia, Sri Lanka,
      Australia and New Zealand. PARTICIPANTS: A total of 100 medical schools
      responded, a response rate of 49%, ranging from 23%-100% by country. MAIN OUTCOME
      MEASURES: The degree of integration of the ethics programme into the formal
      medical curriculum was measured by lecture time; whether compulsory or elective;
      whether separate courses or unit of other courses; number of courses; schedule;
      total length, and diversity of teachers' specialties. RESULTS: A total of 89
      medical schools (89%) reported offering some courses in which ethical topics were
      taught. Separate medical ethics courses were mostly offered in all countries, and
      the structure of vertical integration was divided into four patterns. Most deans
      reported that physicians' obligations and patients' rights were the most
      important topics for their students. However, the evaluation was diverse for more
      concrete topics. CONCLUSION: Offering formal medical ethics education is a
      widespread feature of medical curricula throughout the study area. However, the
      kinds of programmes, especially with regard to integration into clinical
      teaching, were greatly diverse.

PMID- 10635507
TI  - Power and the teaching of medical ethics.
AB  - This paper argues that ethics education needs to become more reflective about its
      social and political ethic as it participates in the construction and
      transmission of medical ethics. It argues for a critical approach to medical
      ethics and explores the political context in medical schools and some of the
      peculiar problems in medical ethics education.

PMID- 10635509
TI  - Autonomy, liberalism and advance care planning.
AB  - The justification for advance directives is grounded in the notion that they
      extend patient autonomy into future states of incompetency through patient
      participation in decision making about end-of-life care. Four objections
      challenge the necessity and sufficiency of individual autonomy, perceived to be a
      defining feature of liberal philosophical theory, as a basis of advance care
      planning. These objections are that the liberal concept of autonomy (i) implies a
      misconception of the individual self, (ii) entails the denial of values of social
      justice, (iii) does not account for justifiable acts of paternalism, and (iv)
      does not account for the importance of personal relationships in the advance care
      planning process. The last objection is especially pertinent in light of recent
      empirical research highlighting the importance of personal relationships in
      advance care planning. This article examines these four objections to autonomy,
      and the liberal theoretical framework with which it is associated, in order to re
      evaluate the philosophical basis of advance care planning. We argue that liberal
      autonomy (i) is not a misconceived concept as critics assume, (ii) does not
      entail the denial of values of social justice, (iii) can account for justifiable
      acts of paternalism, though it (iv) is not the best account of the value of
      personal relationships that arise in advance care planning. In conclusion, we
      suggest that liberalism is a necessary component of a theoretical framework for
      advance care planning but that it needs to be supplemented with theories that
      focus explicitly on the significance of personal relationships.

PMID- 10635510
TI  - Altruism, blood donation and public policy: a reply to Keown.
AB  - This is a continuation of and a development of a debate between John Keown and
      me. The issue discussed is whether, in Britain, an unpaid system of blood
      donation promotes and is justified by its promotion of altruism. Doubt is cast on
      the notions that public policies can, and, if they can, that they should, be
      aimed at the promotion and expression of altruism rather than of self-interest,
      especially that of a mercenary sort. Reflections upon President Kennedy's
      proposition, introduced into the debate by Keown, that we should ask not what our
      country can do for us but what we can do for our country is pivotal to this
      casting of doubt. A case is made for suggesting that advocacy along the lines
      which Keown presents of an exclusive reliance on a voluntary, unpaid system of
      blood donation encourages inappropriate attitudes towards the provision of health
      care. Perhaps, it is suggested, and the suggestion represents, on my part, a
      change of mind as a consequence of the debate, a dual system of blood provision
      might be preferable.

PMID- 10635511
TI  - Pregnancy, autonomy and paternalism.
AB  - Modern medicine is increasingly aware of the significance of patient autonomy in
      making treatment choices. This would seem to be particularly important where the
      therapy requested was "voluntary" as in fertility treatment or cosmetic surgery.
      However, the Hippocratic doctrine "Primum non nocere", seems especially relevant
      where the treatment sought may have a low chance of a successful outcome or even
      be life-threatening. Mrs A's case demonstrates the difficulty faced by the
      physician who wants to maximise her patient's autonomy, but "Above all, do no
      harm".

PMID- 10635512
TI  - At the coalface, but on the receiving end.
AB  - In dealing with patients the doctor is very often paternalistic. No more so than
      when the patient is unable to help him--or herself. Modern technology allows
      people to be kept alive in "intensive care" where they often become an "object"
      at the centre of proceedings. Fortunately for them, most patients who survive
      intensive care cannot remember the experience though this does not mean that they
      were not suffering at the time. There is a strong case for explaining things as
      much as possible and for making practical procedures as tolerable as possible.
      The relatives and families of the seriously ill often have great difficulty in
      understanding what is happening to their loved ones and, in these situations,
      suffer a great deal of stress and foreboding regarding the ultimate outcome of
      their illness. The stress on the staff who may become "attached" to their
      patients often shows through as an indifferent attitude. Peter remembers three
      out of fourteen days in intensive care and Jane, his wife, remembers the whole
      experience. Here we tell our stories in the hope that they may help our medical
      and nursing colleagues to manage better the patients under their care in this
      situation.

PMID- 10635513
TI  - (In)valid consent of advance directives.

PMID- 10635514
TI  - [8th Annual Session of the Society for Ophthalmology of Sachsen-Anhalt and
      Thurigia (SATh8), Magdeburg, 16 October 1999. Refractive surgery and free
      subjects].

PMID- 10635515
TI  - [Sachson++ Society of Ophthalmology in Torgau. 9-10 October 1999].

PMID- 10635516
TI  - An update on primary care management of type 2 diabetes.
AB  - Diabetes is one of the deadliest and costliest chronic diseases in the United
      States. New criteria indicate a diabetes diagnosis if the fasting plasma glucose
      is greater than or equal to 126 mg/dl or if random plasma glucose is greater than
      or equal to 200 mg/dl. Use of these criteria enables early detection and
      treatment of the one-third of Americans with type 2 diabetes who are undiagnosed
      and at high risk for complications. Treatment incorporating nutrition, exercise,
      pharmacologic therapy, and insulin can effectively control blood glucose,
      hypertension, and lipids. In the managed-care environment, primary care providers
      will be increasingly accountable for the delivery of care based on national
      quality indicators. The treatment strategies discussed in this article can help
      clinicians meet this responsibility.

PMID- 10635517
TI  - Over-the-counter medications and self-care.
AB  - More than 100,000 over-the-counter (OTC) products are now sold in drugstores,
      convenience stores, gas stations, and supermarkets. In 1997, the OTC retail
      market was responsible for an estimated $20.6 billion in health care savings.
      This article discusses the methods by which drugs are approved for OTC use by the
      Food and Drug Administration. The article also reviews trends and issues related
      to self-care with OTC medications, including cost-effectiveness, managed care,
      advertising, and safety. The clinician should assume that OTC use is a common
      patient self-care behavior; therefore, information regarding the patient's OTC
      use should be collected during the history taking. Other implications of OTC use
      for primary care providers are proposed.

PMID- 10635518
TI  - NP ownership of home care, long-term care, assisted living, and community care.

PMID- 10635519
TI  - Treatment of scoliosis. An historical perspective.

PMID- 10635520
TI  - Cause of idiopathic scoliosis.

PMID- 10635521
TI  - School screening for scoliosis.

PMID- 10635522
TI  - Natural history.

PMID- 10635523
TI  - Spinal deformity--adolescent idiopathic scoliosis. Nonoperative treatment.

PMID- 10635524
TI  - Surgical treatment of idiopathic adolescent scoliosis.

PMID- 10635525
TI  - Adult scoliosis: surgical indications, operative management, complications, and
      outcomes.

PMID- 10635526
TI  - Scheuermann kyphosis.

PMID- 10635527
TI  - Spondylolisthesis in children. Cause, natural history, and management.

PMID- 10635528
TI  - The application of intraoperative monitoring during surgery for spinal deformity.

PMID- 10635529
TI  - [Metabolic disorders in drug addictions].
AB  - The metabolic disturbances caused by compulsory drug intake into animals and men
      were characterized. The probable mechanisms of these disturbances are discussed.

PMID- 10635530
TI  - [Functional state of glutamate receptors during treatment with ethanol].
AB  - A growing bulk of experimental data indicates that change of certain
      neurotransmitter receptors and voltage-dependent ion cannels are characteristic
      manifestations accompanying ethanol consumption. A likely target for ethanol
      effects is the glutamate receptors. Glutamate is one of major excitatory
      neurotransmitter in the mammalian brain. While the acute application of ethanol
      inhibits glutamate-induced cationic currents, chronic treatment with ethanol
      leads to an up-regulation of glutamate receptors.

PMID- 10635531
TI  - [Inhibitory activity of monomeric and polymeric selectin ligands].
AB  - The ability of tetrasaccharides (SiaLex, SiaLea, HSO3Lex), their conjugates with
      polyacrylamide (40 kDa), and several other monomeric and polymeric substances to
      block selectins has been compared with that of polysaccaride fucoidan. Two assay
      systems were used: one was constructed on the base of recombinant E-, P-, and L
      selectins; the other was a rat model of peritoneal inflammation. IC50 values for
      the neoglycoconjugate SiaLea-PAA were 6, 40, and 85 microM with the recombinant E
      , P-, and L-selectins, respectively; all monomeric inhibitors were about two
      orders of magnitude weaker. PAA-conjugates, containing as a ligand tyrosine-o
      sulfate in addition to one of the above mentioned oligosaccharides, were the most
      potent synthetic blockers. Compared with the most potent of the known inhibitors,
      fucoidan, bi-ligand glycoconjugate HSO3Lea-PAA-sTyr, displayed in vitro similar
      activity in blocking L-selectin, while its activity towards P-selectin was ten
      times lower. All the synthetic polymers tested were able to inhibit neutrophil
      extravasation to inflammation site, acting in concentration about 10 mg/kg. Thus,
      the effect of SiaLex is considerably more effective in vivo than in vitro,
      whereas heavily charged fucoidan and bi-ligand neoglycoconjugate acted in
      converse manner.

PMID- 10635532
TI  - [Cytoprotective effect of antihypoxic and antioxidant preparations on cultured
      human cells in a model of toxic response].
AB  - An oxidative stress is considered to be one of the major mechanisms of
      cytotoxicity. The purpose of present work was to study effects of some drugs with
      antihypoxic/antioxidant activity in cultured human lung embryonic fibroblasts
      under conditions of cytotoxic response, provoked by cationic or anionic
      antiseptics. The following preparations were under study: Mafusol (Na-fumarate),
      superoxide dismutase from human erythrocytes (SOD), cytochrome c, alpha
      tocopherol and Thioctacid T (lipoate) which were applied at concentrations
      comparable with those, employed in clinical application. The combinations of the
      used drugs were also under study. The cytotoxic response was induced by an
      application of antiseptics into the cell incubation medium in 2-5 fold dilutions
      up to minimum toxic doses for 2-24 h. The drugs under study were introduced
      simultaneously with antiseptics. The maximum cytoprotective effect was revealed
      in the case of combination fumarate-alpha-tocopherol; the combination fumarate
      plus SOD being the second in effectiveness. When the drugs were introduced
      separately, the most effective proved to be fumarate, followed by vitamin E and
      cytochrome c. SOD and lipoate did not reveal any cytoprotective activity in our
      experimental conditions. The designed model of cytotoxicity in vitro can be
      considered as a prospective test-system for the screening of cytoprotective drugs
      and their combinations.

PMID- 10635533
TI  - Protective effect of various forms of superoxide dismutase on phospholipid
      composition of hepatocyte and adipocyte plasma membranes and blood lipoprotein
      spectrum during hemorrhagic shock on cats.
AB  - Using a model of hemorrhagic shock, the possibility of protection by Cu,Zn
      superoxide dismutase (SOD) of the phospholipid bilayer of plasma membranes of
      hepatocytes and adipocytes as well as of the blood lipoproteins was studied. SOD
      (5 mg/kg), injected 30 min after the onset of bleeding, efficiently prevented
      changes in the phospholipid bilayer of hepatocytic plasma membranes in cats.
      Simultaneous injection of SOD partly restored the concentration of different
      classes of phospholipids in plasma membranes of mesenterial fatty tissue
      adipocytes altered by shock. When incorporated into liposomes, SOD exerted a
      weaker corrective effect on the phospholipid composition of hepatocytic plasma
      membranes in animals with hemorrhagic shock and simultaneously produced a
      membrane-stabilizing effect on adipocytes. In contrast to pure SOD (which had no
      effect on the lipoprotein composition of the blood in animals with hemorrhagic
      shock), SOD-containing liposomes decreased the amount of chylomicrons and very
      low density lipoproteins in the venous blood of central vessels.

PMID- 10635535
TI  - [Concentration and properties of albumin in the serum and peritoneal exudate in
      patients with peritonitis].
AB  - A new fluorescent method was used to study albumin concentration and properties
      in blood serum and peritoneal exudate of patients with peritonitis of different
      origin excluding pancreatogenic one. Total albumin concentration (TA), effective
      albumin concentration (EA) dependent on both TA and properties of binding sites
      in albumin molecules, and their ratio EA/TA dependent only on the site properties
      were measured. Peritonitis led to significant decrease of TA, EA and their ratio
      EA/TA. Thus, leak of blood albumin was accompanied by some change of albumin
      binding site structure. As a rule, albumin of peritoneal exudate was changed in
      the same extent of blood albumin, i.e. the albumin transfer from blood to exudate
      keeps it's changed structure because the ratio EA/TA correlated well in serum and
      exudate (r = 0.75) while the ratio was very mach variable both in serum and
      exudate. The gradient TA exudate/TA serum was found as a linear function of the
      serum TA with personal correlation coefficients from 0.8 up to 1.0 in 12 of 16
      patients studied. The linear equation coefficients reflected character of the
      peritonitis development in these patients.

PMID- 10635534
TI  - [Dynamics of malonic aldehyde, transferrin levels and blood antioxidant activity
      in women with normal pregnancy and pregnancy complicated by toxicosis: effect of
      eiconol].
AB  - Malonic dyaldehyde (MDA) and transferrin (TF) content and total antioxidant
      activity (AOA) were measured in blood of pregnant women with normal pregnancy (27
      women) and preeclamptic pregnancy (46 women) at different pregnancy stages (17
      28, 29-34 and 35-40 weeks of pregnancy). It was shown that in normal pregnancy
      AOA increased from 24 weeks of pregnancy with a maximum at 30 weeks, while MDA
      level did not change significantly through all time of pregnancy. On the
      contrary, in preeclamptic pregnancy blood AOA did not change significantly, while
      MDA content increased at the 26-34 weeks of pregnancy with a maximum at 30-34
      weeks of pregnancy. Blood TF content in normal pregnancy increased during
      pregnancy development with a maximum at 30-34 weeks, while in preeclamptic
      pregnancy TF changed only a little. These data show the important role of TF in
      the AOA blood status formation in normal pregnancy, and great pathogenetic role
      of the absence of such an increase of TF at preeclamptic pregnancy in AOA
      impairment at this condition. Eiconol (omega-3 polyunsaturated fatty acid
      concentrate from north fish oil) intake by preeclamptic pregnant women
      drastically decreased blood MDA level (1,5-2 times compared to the women that did
      not receive eiconol), especially at 29-34 week of gestation. Blood AOA, that was
      decreased at preeclampsia increased under influence of eiconol intake at all
      pregnancy stages studied. Eiconol intake greatly increased also the TF blood
      content that was decreased at preeclampsia. It is supposed that eiconol ability
      to increase AOA may be explained by its capacity to increase the level of TF--one
      of the most important compounds of serum blood antioxidant system.

PMID- 10635536
TI  - [Expression constructs of inducible isoform of nitric oxide synthase in
      Escherichia coli cells].
AB  - In the present work we describe the construction of expression system for
      inducible murine macrophage nitric oxide synthase (iNOS) in E.coli. For this
      purpose a framework of translation iNOS was cloned in the expression vector
      pCWori +. As biosynthesis of active iNOS requires coexpression of calmodulin
      (CaM), for obtaining functional expression of this protein we conducted
      amplification of an appropriate site of the library total cDNA a frog Xenopus
      laevis, then plasmids for coexpression of calmodulin were constructed under a
      control tac and T7 promotors. Recombinant iNOS was functionally active as
      revealed by the analysis of CO-reduced spectrums, detection of derivation NO with
      the help of reaction conversion HbO2 in metHb, and also identification of a
      molecule NO by EPR method. The output of recombinant iNOS at usage of different
      constructions varied from 10 up to 22 mg/l culture, and specific activity was
      from 0.42 up to 0.64 U/mg of protein. These data coincide with the earlier
      published results of other investigators. It was established, that the expressed
      iNOS is associated to a membrane fraction of cells, thus in the 105,000 g
      supernatant the activity of an enzyme is not detected. The data on membrane
      localization iNOS are inconsistent with general notion this enzyme is soluble.

PMID- 10635537
TI  - Within-day variability of magnetic fields among electric utility workers:
      consequences for measurement strategies.
AB  - Occupational exposure to 50-Hz magnetic fields was surveyed among electric
      utility workers to investigate (1) components of exposure variability, (2)
      patterns of autocorrelation between short-term measurements, and (3) imprecision
      and misclassification due to short-term measurements. Spot measurements every 10
      seconds during 81 working days were analyzed for 42 electric utility workers from
      10 occupational subgroups and during 8 working days for 4 office workers from the
      same company. For the 8-hour time-weighted average (TWA) magnetic fields, the
      variability was partitioned into its components: within workers, between workers,
      and between groups. For spot measurements of magnetic fields, the within-day
      variance component also was examined. Autocorrelation functions were determined
      and numbers of short-term measurements necessary for reliable estimates of 8-hour
      TWA magnetic fields were assessed. Spot measurements of magnetic fields, as well
      as 8-hour TWA magnetic fields, were approximately log normally distributed among
      workers. The mean exposure to magnetic fields was 0.47 microT (n = 81 days) in
      electric utility workers and 0.12 microT (n = 8 days) in office workers. A large
      fraction, 76% of the spot measurements total variance, could be attributed to
      variability within days. For the 8-hour TWA magnetic fields, between-group
      variability was small and of the same magnitude as between-worker variability.
      Significant autocorrelations between short-term averages of 7.5, 15, and 30
      minutes were present, when taken within periods of 30 minutes. One-hour averages
      showed no autocorrelation. Simulations showed that, due to high within-day
      variability and autocorrelation, a limited number of short-term measurements of
      magnetic fields in electric utility workers are likely to result in imprecise
      estimates of 8-hour TWA magnetic fields. Measurement strategies relying on short
      term (spot) measurements are therefore likely to result in misclassification of
      exposure and consequently absent or spurious exposure-response relations.

PMID- 10635538
TI  - Effect of relative humidity on the adsorption of selected water-miscible organic
      vapors by activated carbon.
AB  - The adsorptive capacity of activated charcoal was determined experimentally for
      the vapors of 2-ethoxyethanol, pyridine, acetic acid, and piperidine from dry air
      and from air saturated with water vapor. Vapor concentrations ranged from 100
      mg/m3 to at least 1000 mg/m3; the temperature was kept constant at 25 degrees C.
      The reduction in the adsorptive capacity of the activated charcoal by the
      relative humidity over the entire range of experimental conditions was accounted
      for by the Hansen-Fackler modification of the Dubinin-Radushkevich equation. This
      procedure allows the use of the activity coefficients, which are basic
      thermodynamic factors often available in the literature, to estimate the effect
      of adsorbed moisture on the adsorption of these organic compounds from a
      humidified atmosphere.

PMID- 10635540
TI  - Fluid replacement preferences in heat-exposed workers.
AB  - This study examined fluid intake, weight changes, and palatability of water and a
      carbohydrate-electrolyte (ECHO) beverage in two groups of eight subjects
      performing 4 hours of simulated industrial work while wearing impermeable
      protective clothing. Subjects also rated the palatability of a flavorless orange
      colored water and four commercially available orange-flavored fluid-replacement
      drinks. Subjects worked 30 min at 300 Kcal/hour (moderate work rate), followed by
      30 min of rest for a total of 4 hours in each of three environments: 18, 23, 27
      degrees C wet bulb globe temperature (WBGT). Eight subjects drank water and eight
      drank an ECHO beverage (Drink 1). Mean sweat production was similar between
      groups at each WBGT, (p > 0.05). Mean weight changes expressed as percentage of
      total body weight for the water-drinking group were -0.25 (+/- 0.16) kg in 18
      degrees C, -0.55 (+/- 0.09) kg in 23 degrees C, and -0.93 (+/- 0.13) kg in 27
      degrees C. Mean weight changes for the ECHO-drinking group were 0.49 (+/- 0.12)
      kg in 18 degrees C, 0.13 (+/- 0.12) kg in 23 degrees C, and -0.02 (+/- 0.14) kg
      in 27 degrees C. Each change was significantly different from that of the water
      drinking group at the same temperatures (p < 0.05). Mean pre- to post-trial
      palatability rating results for all temperatures revealed differences in taste
      perception with strong preferences for Drinks 1 and 2 (pre to post): Drink 1, 3.8
      to 3.6; Drink 2, 3.8 to 3.7; Drink 3, 3.0 to 2.7, Drink 4 (water), 3.2 to 3.0,
      and Drink 5, 2.1 to 1.6. Drinks 1 and 2 were rated significantly more palatable
      (p < 0.05) than Drink 3. All drinks had a reduced flavor appeal from 3.18 (+0.96)
      preratings to 2.92 (+1.01) postratings (p < 0.05). Mean voluntary consumption
      during work across the three temperatures was 1561.5 mL (+/- 720.1) for ECHO
      versus 1062.7 mL (+/- 666.4) for water (p = 0.054). The water group experienced
      greater weight loss than the ECHO group, suggesting a greater rate of dehydration
      when water was used for fluid replacement.

PMID- 10635539
TI  - Development and application of a dichotomous vapor/aerosol sampler for HDI
      derived total reactive isocyanate group.
AB  - A dichotomous vapor/aerosol sampler was developed for measurement of HDI (1,6
      hexamethylene diisocyanate)-derived total reactive isocyanate group (TRIG). The
      sampler consisted of an impactor or cyclone inlet, followed by an annular
      diffusional denuder, and a glass-fiber filter backup. The denuder walls and
      backup filter were each coated with 20 mg tributylphosphate and 1 mg MAMA reagent
      (9-N-methylamino-methylanthracene). After collection, MAMA-derivatized
      isocyanates were desorbed from the sampler and determined by high-performance
      liquid chromatography with dual-wavelength ultraviolet absorbance and
      fluorescence detection. Test atmospheres of HDI vapor and of HDI/HDI-biuret
      aerosols were generated in the laboratory and sampled with the optimized
      dichotomous sampler. Vapor phase HDI was completely collected by the diffusional
      denuder. When a mixture of HDI-biuret and HDI (approximately 30 ppb) was
      nebulized and collected with the dichotomous sampler, approximately 78% of the
      HDI was in the vapor phase, whereas about 22% was associated with the aerosol
      fraction. The dichotomous sampler was then used to measure vapor and condensed
      phase TRIG in a paint spray booth during application of a polyurethane paint.
      Measured levels of TRIG during the spraying operation averaged 391 +/- 154
      micrograms/m3. Concentrations of HDI monomer averaged only 14 +/- 6.5
      micrograms/m3. HDI-biuret was the largest component of TRIG found in these
      samples and was completely in the condensed aerosol phase. In contrast, the
      majority of the HDI was in the vapor phase, but significant (15-26%) amounts were
      measured in the aerosol fraction of the paint overspray. Thus, significant
      partitioning of HDI between vapor and condensed phases was demonstrated in both
      the laboratory and field, even when its concentration was well below the vapor
      saturation point.

PMID- 10635542
TI  - The effects of keyswitch stiffness on typing force, finger electromyography, and
      subjective discomfort.
AB  - The effects of keyswitch stiffness and key action on typing force,
      electromyography (EMG), and subjective preference were examined. Each subject's
      own keyboard (with an audible key click and key activation force of 0.72 N) and
      three keyboards with no key click that were identical in design but had different
      key activation forces (0.28 N, 0.56 N, and 0.83 N) were used. Subjects (24 female
      transcriptionists) typed on each keyboard for 15 min while typing force and left
      hand surface EMG of the finger flexor and extensor muscles were monitored.
      Subjects then used one of the keyboards at their workstations for 7 workdays and
      were monitored again. This procedure was repeated for all four keyboards. Typing
      force and finger flexor and extensor EMG activity were highest for the 0.83 N
      keyboard. Lowest EMG values were for the 0.28 N and the 0.72 N audible key click
      keyboards. Baseline (10th percentile) and median (50th percentile) extensor EMG
      values were significantly higher than flexor EMG values. Peak (90th percentile)
      EMG values were comparable for flexors and extensors. Mean subjective discomfort
      was significantly higher for the 0.83 N keyboard at the fingers (36% higher),
      lower arm (40% higher), and overall (39% higher). Seventeen of 24 subjects
      preferred the 0.72 N keyboard, 4 the 0.28 N keyboard, and 3 preferred the 0.56 N
      keyboard. Results suggest that increasing make force causes typing force and EMG
      to increase but that the ratio of 90th centile typing force to make force
      decreases as make force increases. Subjective discomfort was significantly higher
      for the keyboard with 0.83 N make force. Buckling spring keyboards have better
      feedback characteristics, which may be responsible for a decrease in the amount
      of typing force and EMG produced.

PMID- 10635543
TI  - Four assessment tools of ergonomics interventions: case study at an electric
      utility's warehouse system.
AB  - An ergonomics program was developed in a Midwestern electric utility warehouse
      system. Tasks problematic with respect to work-related musculoskeletal disorders
      (WMSDs) affecting both the back and upper extremities were identified and
      engineering controls were implemented. Quantitative analysis was performed on
      each task before and after ergonomics intervention to evaluate exposure to the
      risk of WMSDs. Four methods were used to evaluate the risk of exposure to injury
      before and after ergonomics intervention: the 1991 National Institute for
      Occupational Safety and Health (NIOSH) lifting equation, the Static Strength
      Prediction Program, the Lumbar Motion Monitor, and the Borg psychophysical
      assessment of effort. Results from applying these four methods to the
      reengineered tasks showed that the probability of low-back disorder risk factors
      was reduced by as much as 29%, the percentage of people capable of performing
      tasks was increased by as much as 90%, the NIOSH Lifting Index was reduced from
      above 2.0 to less than 2.0, and the psychophysical assessment of effort was
      consistently reduced from the "heavy or strong" range to the "light or moderate"
      range.

PMID- 10635541
TI  - Farmworker exposure to organophosphorus pesticide residues during apple thinning
      in central Washington State.
AB  - The purpose of this study was to characterize worker exposure to azinphos-methyl
      (Guthion) over an entire 4-6 week apple-thinning season. Twenty workers from
      three work sites in the Chelan-Douglas County region of Washington state were
      recruited for the study. Exposure potential was estimated by dislodgeable foliar
      residue measurements, and individual exposures were estimated by biological
      monitoring through urinary metabolites. Measureable azinphos-methyl residues were
      found on apple foliage at all sites throughout the six-week sampling period,
      indicating continuous exposure potential (median residue level of 0.5
      microgram/cm2). Measurable levels of the urinary dialkylphosphate metabolite,
      DMTP, were found in virtually all urine samples (limit of detection = 0.04
      microgram/mL). Mean DMTP concentrations differed significantly across sites
      (0.53, 0.29, and 0.90 microgram/mL for Sites 1-3, respectively; analysis of
      variance, p < .002), and intraindividual variability was much greater than
      interindividual differences. Group mean DMTP concentrations at each site
      fluctuated according to foliar residue levels. Measurable DMTP concentrations
      were found in 9% of reference workers, ranging from 0.04-0.18 microgram/mL.
      Cholinesterase activity levels monitored with a field test kit were not
      considered reliable due to temperature changes of the instrument.

PMID- 10635544
TI  - Evaluation of leakage from a metal machining center using tracer gas methods: a
      case study.
AB  - To evaluate the efficacy of engineering controls in reducing worker exposure to
      metalworking fluids, an evaluation of an enclosure for a machining center during
      face milling was performed. The enclosure was built around a vertical metal
      machining center with an attached ventilation system consisting of a 25-cm
      diameter duct, a fan, and an air-cleaning filter. The evaluation method included
      using sulfur hexafluoride (SF6) tracer gas to determine the ventilation system's
      flow rate and capture efficiency, a respirable aerosol monitor (RAM) to identify
      aerosol leak locations around the enclosure, and smoke tubes and a velometer to
      evaluate air movement around the outside of the enclosure. Results of the tracer
      gas evaluation indicated that the control system was approximately 98% efficient
      at capturing tracer gas released near the spindle of the machining center. This
      result was not significantly different from 100% efficiency (p = 0.2). The
      measured SF6 concentration when released directly into the duct had a relative
      standard deviation of 2.2%; whereas, when releasing SF6 at the spindle, the
      concentration had a significantly higher relative standard deviation of 7.8% (p =
      0.016). This increased variability could be due to a cyclic leakage at a small
      gap between the upper and lower portion of the enclosure or due to cyclic
      stagnation. Leakage also was observed with smoke tubes, a velometer, and an
      aerosol photometer. The tool and fluid motion combined to induce a periodic
      airflow in and out of the enclosure. These results suggest that tracer gas
      methods could be used to evaluate enclosure efficiency. However, smoke tubes and
      aerosol instrumentation such as optical particle counters or aerosol photometers
      also need to be used to locate leakage from enclosures.

PMID- 10635545
TI  - Exposure to fungicides in fruit growing: re-entry time as a predictor for dermal
      exposure.
AB  - As part of a European Concerted Action on Male Reproduction Capability an
      exposure assessment survey was conducted among seasonal workers in the fruit
      growing sector in the Netherlands. Dermal exposure to the fungicides captan and
      tolylfluanid was measured using cotton gloves (12 persons) and skin pads on
      several body parts (12 persons). In addition, a set of exposure data was used
      from a study conducted recently among Dutch fruit growers. For harvesting
      activities, re-entry time appeared to be an important determinant of dermal
      exposure to captan and tolyfluanid. Explained variance of regression models was
      moderate to high (range 0.30-0.87). For captan, calculated half-life times from
      the most recent exposure survey were lower (glove data: 5 days; pad data: 6 days)
      compared with half-life times based on the previously conducted study (11 days).
      Possible explanations for the discrepancy are discussed. For tolylfluanid,
      estimated half-life times during harvesting were 2 and 3 days, based on pad and
      glove data, respectively. Prediction of captan exposure during other crop
      activities appeared to be far more difficult (explained variance equal to 0.06),
      although the estimated half-life time was comparable with that for harvesting.
      The data suggest that re-entry time gives useful information to group workers in
      broad exposure categories. Nonetheless, it was concluded that large studies are
      needed to evaluate the importance of re-entry time in more detail.

PMID- 10635546
TI  - Indoor airborne fiber levels of MMVF in residential and commercial buildings.
AB  - Man-made vitreous fibers (MMVF) have been used widely in commercial and
      residential buildings for over 50 years. Concerns have been expressed since the
      late 1960s that MMVF products may erode and contribute to fiber levels in the
      indoor environment. This cooperative investigation was undertaken to quantify
      indoor respirable fiber levels by phase contrast optical microscopy (PCOM) and to
      differentiate between fiber types using scanning electron microscopy with energy
      dispersive X-ray microanalysis (SEM-EDX). A total of 205 stationary samples were
      collected using standard industrial hygiene methods in 51 residential and
      commercial buildings. Twenty-one simultaneous outdoor samples were collected at
      19 buildings. All samples were analyzed by PCOM following the NIOSH 7400 Fiber
      method, "B" counting rules, and 50 randomly selected samples were analyzed by SEM
      EDX. The PCOM mean value for all respirable fiber levels was 0.008 f/cc with a
      median value of 0.007 f/cc and a maximum value of 0.029 f/cc. Ninety-seven
      percent of the respirable fibers identified by SEM-EDX were determined to be
      organic. MMVF were detected on only two samples. Airborne fiber levels were very
      low and the respirable fibers present were primarily organic. The inorganic fiber
      levels determined by SEM-EDX which included MMVF were less than 0.0001 f/cc.

PMID- 10635547
TI  - Prediction of rectal temperature by the Questemp II personal heat strain monitor
      under low and moderate heat stress.
AB  - This study assessed the use of aural canal temperature measured with the Questemp
      II personal heat strain monitor (Tq) relative to rectal temperature (Tre) during
      simulated industrial work in three different wet bulb globe temperatures (WBGT).
      Sixteen subjects performed walking and arm curl exercise at a rate of 300
      kcal/hour for 4 hours while wearing Saranex protective coveralls in 18, 23, and
      27 degrees C WBGT environments and wearing the Questemp II. Correlations were
      determined between Tre and Tq for the three conditions and for all conditions
      combined. Pearson r values were 0.48 (18 degrees C WBGT), 0.42 (23 degrees C
      WBGT), 0.38 (27 degrees WBGT), and 0.50 (all trials). Because a major concern is
      safe maximum core body temperature, means and standard deviations for differences
      between Tre and Tq were assessed at peak temperatures to determine the
      predictability of Tre from Tq solely at these points. Large standard deviations
      in delta values relative to a small overall tolerable temperature range ruled out
      the use of Tq in this manner. Based on the current data, aural canal temperature
      as measured with the Questemp II did not provide an accurate reflection of Tre
      across time nor at peak core temperatures during low to moderate heat strain.

PMID- 10635548
TI  - An assessment of occupational noise exposures in four construction trades.
AB  - Three hundred thirty-eight noise exposure samples were collected from 133
      construction workers employed in 4 construction trades: carpenters, laborers,
      ironworkers, and operating engineers. Four sites using a variety of construction
      techniques were sampled at least 12 times on a randomly chosen date over a 22
      week period. Up to 10 volunteer workers were sampled for an entire work shift on
      each sampling day using datalogging noise dosimeters, which recorded both daily
      time-weighted averages (TWAs) and 1-min averages. Workers also completed a
      questionnaire throughout the workday detailing the tasks performed and tools used
      throughout the day. Regression models identified work characteristics associated
      with elevated exposure levels. Comparisons were made between exposures measured
      using the Occupational Safety and Health Administration (OSHA) exposure metric
      and the 1996 draft National Institute for Occupational Safety and
      Health/International Organization for Standardization (NIOSH/ISO) metric to
      examine the effects of differing exchange rates and instrument response times on
      construction noise exposures. The mean OSHA TWA for 338 samples was 82.8 dBA +/-
      6.8 dBA, whereas the mean NIOSH/ISO TWA for 174 samples was 89.7 dBA +/- 6.0 dBA.
      Forty percent of OSHA TWAs exceeded 85 dBA, and 13% exceeded 90 dBA, the OSHA
      permissible exposure limit. The tasks and tools associated with the highest
      exposure levels were those involving pneumatically operated tools and heavy
      equipment. Trade was a poor predictor of noise exposure; construction method,
      stage of construction, and work tasks and tools used were found to be better
      exposure predictors. An internal validation substudy indicated excellent
      agreement between worker self-reporting and researcher observation. These data
      provide substantial documentation that construction workers in several key trades
      are frequently exposed to noise levels that have been associated with hearing
      loss, and demonstrate the need for targeted noise reduction efforts and
      comprehensive hearing conservation programs in the industry.

PMID- 10635549
TI  - Assessment of magnetic field exposures for a mortality study at a uranium
      enrichment plant.
AB  - A survey of workplace exposures to 60-Hz magnetic fields was carried out at a
      large uranium enrichment facility to assign exposures for an updated mortality
      study. Stratified random selection was used to choose workers for measurement in
      all jobs and areas, to determine whether consistent distinctions could be made
      between job groups based on average magnetic field exposures. A total of 252
      workdays was measured with a personal monitor, and individual average magnetic
      field exposures ranged from 0.20 to 82.6 mG. A priori job groups showed
      significant differences between geometric mean exposures, which ranged from 0.80
      to 3.51 mG. Most of these groups showed widely ranging exposures, so they were
      subdivided based on location and job title to improve the precision of the
      exposure assignments for the mortality study. These final assignments were made
      up of 26 groups having arithmetic means ranging from 0.43 to 24.9 mG, with most
      groups defined by location in addition to job title. In general, electrical
      maintenance workers did not have elevated magnetic field exposures (> 3 mG), but
      the exposures of the electricians in switchyard (substation) jobs were elevated.
      Available employment records did not allow most electricians to be distinguished
      based on location, so they were assigned exposures based on their plantwide
      average (above 7 mG). An estimated 9% of the work time of this cohort was spent
      at daily average exposures above 3 mG, despite the very large electric power
      consumption at this plant.

PMID- 10635551
TI  - Characterization of a thermostable esterase activity from the moderate
      thermophile Bacillus licheniformis.
AB  - A new esterase activity from Bacillus licheniformis was characterized from an
      Escherichia coli recombinant strain. The protein was a single polypeptide chain
      with a molecular mass of 81 kDa. The optimum pH for esterase activity was 8-8.5
      and it was stable in the range 7-8.5. The optimum temperature for activity was 45
      degrees C and the half-life was 1 h at 64 degrees C. Maximum activity was
      observed on p-nitrophenyl caproate with little activity toward long-chain fatty
      acid esters. The enzyme had a KM of 0.52 mM for p-nitrophenyl caproate hydrolysis
      at pH 8 and 37 degrees C. The enzyme activity was not affected by either metal
      ions or sulfydryl reagents. Surprisingly, the enzyme was only slightly inhibited
      by PMSF. These characteristics classified the new enzyme as a thermostable
      esterase that shared similarities with lipases. The esterase might be useful for
      biotechnological applications such as ester synthesis.

PMID- 10635550
TI  - Molecular cloning and characterization of a cysteine-rich 16.6-kDa prolamin in
      rice seeds.
AB  - An alcohol-soluble storage protein, a 16.6-kDa prolamin found in rice seeds, was
      purified from both the total protein body and purified type I protein body
      fractions. The partial amino acid sequences of three tryptic peptides generated
      from the purified polypeptide were analyzed. A part of the 16.6-kDa prolamin cDNA
      was amplified from developing seed mRNA by the reverse transcribed polymerase
      chain reaction using an oligo (dT) primer and a primer which was synthesized
      based on the partial amino acid sequence. The amplified product was used to
      isolate the full-length cDNA clone (lambda RP16) from a developing seed cDNA
      library. The cDNA has an open reading frame encoding a hydrophobic polypeptide of
      149 amino acids. The polypeptide was rich in glutamine (20.0%), cysteine (10.0%),
      and methionine (6.9%). The cysteine content was higher than those of most other
      rice storage proteins. Messenger RNA of the 16.6-kDa prolamin was detected in
      seeds, but not in other aerial tissues.

PMID- 10635552
TI  - Involvement of thioredoxin peroxidase type II (Ahp1p) of Saccharomyces cerevisiae
      in Mn2+ homeostasis.
AB  - To identify new proteins involved in Mn2+ homeostasis, we isolated Mn(2+)
      resistant mutants of Saccharomyces cerevisiae starting from a calcineurin
      deficient, Mn2+ hypersensitive strain (delta cmp1 delta cmp2). The mutations were
      found to lie in the PMR1 gene, known to encode a "P-type" Ca(2+)-ATPase that
      transports Ca2+ and Mn2+ from the cytosol to the Golgi apparatus. A second gene,
      AHP1, was cloned as a suppressor of the Mn2+ tolerance of a delta cmp1 delta cmp2
      pmr1 mutant. Ahp1p was recently described as a thioredoxin peroxidase type II, an
      antioxidant protein with alkyl hydroperoxide defense properties in yeast. AHP1
      disruption in strain W303 decreased tolerance to Mn2+ and H2O2. We found that a
      GFP-Ahp1p fusion construct was in the cytosol when cells were grown in glucose,
      and in the mitochondria when cells were grown in oleate. Based on Mn2+ transport
      data, we concluded that Ahp1p is involved in cellular Mn2+ homeostasis in
      trafficking of Mn2+ from cytosol to mitochondria and from cytosol for export
      across the plasma membrane.

PMID- 10635553
TI  - Relationship between polyploidy and pollen self-incompatibility phenotype in
      Petunia hybrida Vilm.
AB  - Self-incompatibility in Solanaceae is controlled by a single multiallelic locus,
      the S-locus. The S-allele associated ribonucleases (S-RNases) in the pistil are
      involved in pollen rejection. In this work, we analyzed two newly isolated lines
      of Petunia hybrida, termed PB and PF. They both had the same set of S-RNases (SB1
      and SB2-RNases), however the PB was a self-incompatible diploid while PF was a
      self-compatible tetraploid. Cross pollination tests between PB and PF indicated
      diploid pollen from PF lost the incompatibility phenotype. In order to clarify
      the effects of polyploidy on pollen phenotypic change, we artificially induced
      tetraploid plants from a diploid SB1SB2 heterozygote (= PB) and a diploid SB1SB1
      homozygote. The obtained SB1 SB1SB1SB1 homoallelic tetraploid remained self
      incompatible, whereas the SB1SB1SB2SB2 heteroallelic tetraploid became self
      compatible. These data suggested that the diploid heteroallelic pollen lost the
      incompatibility phenotype and had the characteristics of self-compatibility with
      SB1SB2 style.

PMID- 10635554
TI  - Structure and regulatory expression of a single copy alternative oxidase gene
      from the yeast Pichia anomala.
AB  - To investigate the regulatory mechanism of alternative oxidase gene expression,
      genomic DNA was cloned from the yeast Pichia anomala. Genomic Southern blot
      analysis suggested that a single copy nuclear gene encoded an alternative oxidase
      in the yeast. The nucleotide sequence showed an uninterrupted coding region for
      the alternative oxidase protein. In the upstream region from the transcription
      initiation site found by primer extension analysis, CCAAT, TATAA, and UAS2-like
      elements were detected. The UAS2 is the element involved in transcriptional
      regulation by carbon source and the target site for the factor, HAP2/3/4/5
      protein complex, in Saccharomyces cerevisiae. By a gel mobility shift assay, a
      specific retardation band was detected when a protein extract from cells grown on
      an inducing carbon source was incubated with a UAS2-containing probe. These
      results suggest that carbon source regulation of alternative oxidase gene
      expression is mediated by the UAS2-like element and a HAP-like factor in P.
      anomala.

PMID- 10635555
TI  - Transcriptional regulation of the Bacillus ohbensis cyclodextrin
      glucanotransferase gene in B. subtilis.
AB  - The expression of the cyclodextrin glucanotransferase (CGTase) gene (cgt) of
      Bacillus ohbensis, when introduced into an alpha-amylase-defective strain of B.
      subtilis on a multicopy plasmid, pHY300PLK, was induced in the presence of starch
      and was subject to catabolite repression by glucose as well as in the original
      strain, B. ohbensis. We constructed a cgt'::'lacZ translational fusion to study
      the expression in B. subtilis, and this construct was confirmed to be subject to
      both starch induction and catabolite repression. In order to define the region
      involved in the regulation of the cgt gene, a series of cgt'::'lacZ gene with
      various lengths of deletion in the promoter region was constructed on pHY300PLK.
      DNA regions responsible for starch induction and catabolite repression by glucose
      could be separated in the deletion experiment. Primer extension analysis showed
      that the catabolite repression was controlled at the initiation of transcription,
      while the starch induction is likely to be controlled by a transcriptional
      termination-antitermination mechanism.

PMID- 10635556
TI  - Polypeptide compositions and NH2-terminal amino acid sequences of proteins in
      foxtail and proso millets.
AB  - Seed protein of foxtail and proso millets were fractionated into polypeptides
      that were analyzed for their major protein, prolamin, and the NH2-terminal amino
      acid sequences of the proteins were determined. The proteins extracted from
      foxtail and proso millets were 64.1% and 80.0% prolamin, respectively. The
      polypeptides of the prolamins were classified into two groups. The major
      polypeptides of 27-19 kDa were rich in leucine and alanine, whereas the 17-14 kDa
      polypeptides were rich in methionine and cysteine. Glutelin-like proteins that
      were extracted with a reducing reagent were high in proline content, the major
      polypeptides being 17 and 20 kDa. The NH2-terminal amino acid sequence showed
      that the major polypeptides of prolamin were homologous to alpha-zein and a
      glutelin-like protein containing the Pro-Pro-Pro sequence, like the repetitive
      sequence of gamma-zein. Although the prolamin consisted of a similar subunit to
      that of zein, polypeptides with various pI values were found among them.

PMID- 10635557
TI  - Purification and properties of extracellular carboxyl proteases of acid-tolerant
      bacteria, isolated from compost.
AB  - Four strains of acid-tolerant and protein-using bacteria were isolated from
      compost. Two of them, Gram-negative strains MB8 and MB11, were identified as a
      new genus close to Stenotrophomonas species MB8 and Burkholderia species MB11,
      respectively. Both bacteria produced extracellular carboxyl proteases (CP) in
      acid-casein-starch medium. The enzymes, termed CP MB8 and CP MB11, purified
      through ion exchange and gel filtration chromatographies had molecular weights of
      61,000 (CP MB8) and 36,000 (CP MB11) as estimated by SDS-PAGE, and showed optimum
      activities with hemoglobin as a substrate at pH 3.5 (CP MB8) and pH 3.7 (CP MB11)
      at 55 degrees C. Both of the enzymes were not inhibited by pepstatin, DAN, or
      EPNP. These results suggest that both enzymes are members of the pepstatin
      insensitive carboxyl proteinase family (EC 3.4.23.33), except for a larger
      molecular weight of the CP MB8 enzyme.

PMID- 10635558
TI  - Safety assessment of transgenic potatoes with soybean glycinin by feeding studies
      in rats.
AB  - Feeding studies of transgenic potatoes with native and designed soybean glycinins
      in rats were done for four weeks. The designed glycinin has four additional
      methioninyl residues in the middle of the glycinin molecule. Rats were divided
      into four groups fed (I) only a commercial diet, (II) the diet plus non
      transgenic potatoes, (III) the diet plus transgenic potatoes with native
      glycinin, and (IV) the diet plus transgenic potatoes with designed glycinin. Rats
      were fed 2,000 mg/kg-weight potatoes every day by oral administration. During the
      period tested, rats in each group (groups II, III, and IV) grew well without
      marked differences in appearance, food intake, body weight, or in cumulative body
      weight gain. No significant differences were also found in blood count, blood
      composition, and in internal organ weights among the rats after feeding potatoes
      (groups II, III, and IV) for four weeks. Necropsy at the end of experiment
      indicated neither pathologic symptoms in all rats tested nor histopathological
      abnormalities in liver and kidney. Judging from these results, the transgenic
      potatoes with glycinins are confirmed to have nearly the same nutritional and
      biochemical characteristics as non-transgenic one.

PMID- 10635559
TI  - Purification and characterization of a novel extracellular lipase catalyzing
      hydrolysis of oleyl benzoate from Acinetobacter nov. sp. strain KM109.
AB  - A new lipase (OBase) which efficiently hydrolyzes oleyl benzoate (OB) was found
      in the culture supernatant of Acinetobacter nov. sp. strain KM109, a new isolate
      growing in a minimum medium containing OB as the sole carbon source. OBase was
      purified to homogeneity with 213-fold purification and 0.8% yield. The molecular
      weight was estimated to be 62,000 +/- 1,000 by SDS-PAGE under denatured-reduced
      conditions and to be 50,000 +/- 1,000 by gel-filtration HPLC under native
      conditions; these findings indicate that OBase is a monomeric enzyme. The optimum
      temperature and pH of OBase were about 45 degrees C and pH 8. Temperature and pH
      stabilities were at or lower than 35 degrees C and in a range of pH 6-8,
      respectively. Purified OBase preferentially hydrolyzed p-nitrophenyl benzoate
      (pNPB) over p-nitrophenyl acetate (pNPA) or p-nitrophenyl caproate (pNPC)
      [pNPB/pNPA = 20 and pNPB/pNPC = 5.4], indicating that OBase has a high affinity
      for benzoyl esters. Partial amino-acid sequences of OBase fragments obtained
      after lysyl endopeptidase treatment showed no similarity with known proteins.

PMID- 10635560
TI  - Structural conversion from non-native to native form of recombinant human
      epidermal growth factor by Brevibacillus choshinensis.
AB  - Brevibacillus choshinensis (Bacillus brevis) HPD31 is a very efficient producer
      of recombinant human epidermal growth factor (EGF). The produced EGF is secreted
      into the medium with high efficiency. However part of the EGF that accumulates in
      the medium, exists as multimeric forms which are biologically inactive. We found
      the bacterium has the activity to structurally convert multimeric forms to the
      monomeric, native ones. Optimal temperature and pH for the conversion were 40
      degrees C and pH 9, respectively. The reaction was promoted in the presence of
      reduced glutathione or cysteine. But the cells which had been sonicated or
      exposed to moderate heat treatment completely lost the activity. Thus, it was
      presumed that the activity might be due to the enzyme(s) that catalyze the
      protein disulfide exchanging reaction, and that they resides on the surface of
      viable cells.

PMID- 10635561
TI  - Interaction among the subunits of Golgi membrane mannosyltransferase complexes of
      the yeast Saccharomyces cerevisiae.
AB  - Saccharomyces cerevisiae Mnn9 protein is a type II Golgi membrane protein which
      concerns in protein mannosylation. When solubilized by Triton X-100, it was
      recovered in two distinct complexes both having mannosyltransferase activity; one
      with Van1 protein (V-complex) and the other with Anp1, Hoc1, Mnn10, and Mnn11
      proteins (A-complex). Characterization of the null mutants suggested that A
      complex is also concerned in protein O-glycosylation. A-complex was more
      resistant than V-complex to dissociating conditions. Interaction between the
      lumenal domains of Van1 and Mnn9 was detected by a two-hybrid experiment. The
      anchor domain of Mnn9 protein could be replaced with other membrane anchors
      without losing the ability to form complexes similar to V- and A-complexes. Thus
      the lumenal domains are important to assemble these distinct complexes.

PMID- 10635562
TI  - Human lysozyme secretion increased by alpha-factor pro-sequence in Pichia
      pastoris.
AB  - To get high level secretion of human lysozyme in Pichia pastoris, the following
      three signal sequences and one prepro sequence were evaluated: chicken lysozyme
      signal peptide, leucine-rich artificial signal peptide, Saccharomyces invertase
      signal peptide, and Saccharomyces prepro sequence of alpha factor (MF-alpha
      Prepro). Transformants harboring a lysozyme gene with MF-alpha Prepro secreted 20
      fold more lysozyme than those harboring the lysozyme gene with any one of the
      other three signal sequences. Three mutant leader sequences derived from MF-alpha
      Prepro were constructed to discover the function of the pro region. The secretion
      was dramatically decreased by eliminating the pro region of MF-alpha Prepro. In
      contrast, MF-alpha Prepro with the EAEAEA sequence directed the secretion of an
      equivalent level of lysozyme having the extra amino acids (EAEAEA) in its N
      terminus. For the effective secretion of native human lysozyme, MF-alpha Prepro
      without any spacer sequences was most suitable. The secreted protein by MF-alpha
      Prepro construct was identical with the authentic human lysozyme, judging from N
      terminal amino acid sequencing and molecular mass spectrometric and
      crystallographic analysis.

PMID- 10635563
TI  - Improving effect of dietary taurine on marked hypercholesterolemia induced by a
      high-cholesterol diet in streptozotocin-induced diabetic rats.
AB  - The effect of dietary taurine on hypercholesterolemia induced by a high
      cholesterol diet in streptozotocin (STZ)-induced diabetic rats was investigated.
      The concentrations of serum and liver cholesterol were markedly elevated in STZ
      diabetic rats fed on the cholesterol-containing diet, and dietary taurine
      significantly reduced this elevated level of cholesterol in the serum and liver.
      The gene expression of cholesterol 7 alpha-hydroxylase (CYP7A1), which is the
      rate-limiting enzyme for cholesterol degradation, was induced by the
      supplementation of taurine to the high-cholesterol diet. It is suggested that one
      of the reasons for this hypocholesterolemic action by taurine might have been the
      enhancement of cholesterol degradation.

PMID- 10635564
TI  - Effects of methanol and temperature on enzyme immunoassay with monoclonal
      antibodies specific to the insecticide etofenprox.
AB  - We examined the effects of methanol and temperature on the reactivity of
      monoclonal antibodies specific to the insecticide etofenprox. When the antigen
      antibody reaction was done at 4 degrees C in 10% methanol, the sensitivity in the
      enzyme immunoassay with each antibody was more than 10-fold higher than that
      measured at 37 degrees C. Although in 10% methanol one of the antibodies reacted
      equally with both etofenprox and the carbonate-derivative of etofenprox, in 50%
      methanol the antibody reacted with etofenprox, but not with the derivative.

PMID- 10635565
TI  - Resolution and synthesis of (S)-1-(2-naphthyl)ethanol with immobilized pea
      protein: as a new biocatalyst.
AB  - (S)-1-(2-Naphthyl)ethanol was yielded by immobilized pea (Pisum sativum L.)
      protein (IPP) from (R, S) 2-naphthyl ethanol (> 99% ee, yield; about 50%), in
      which the (R)-enantiomer was selectively oxidized to 2-acetonaphthone. IPP could
      be reused consecutively at least three times without any decrease of yield and
      optical purity.

PMID- 10635566
TI  - The trichothecene biosynthesis regulatory gene from the type B producer Fusarium
      strains: sequence of Tri6 and its expression in Escherichia coli.
AB  - A genomic DNA fragment containing Tri6, a transcription activator gene of
      trichothecene biosynthesis, was cloned by vectorette PCR from Fusarium
      graminearum F15, which produces type B trichothecene, deoxynivalenol. The
      nucleotide sequence of the gene showed 84% of identity to that of the type A
      trichothecene producer Fusarium sporotrichioides NRRL 3299, but the sequence
      around the initiation codon was not highly conserved between these producers.
      Based on the upstream and downstream sequences of the coding region of F.
      graminearum, Tri6 could be amplified by PCR from other type B trichothecene
      producers. Tri6 appeared to be expressed for only a limited period prior to the
      toxin production.

PMID- 10635568
TI  - Induction of GM-CSF production of macrophages by advanced glycation end products
      of the Maillard reaction.
AB  - We previously reported that AGEs can induce macrophage growth. In this paper, we
      examined whether advanced glycation end products (AGE) of protein induced GM-CSF
      production of macrophages. AGE of bovine serum albumin markedly stimulated not
      only the expression of GM-CSF mRNA, but also GM-CSF secretion in macrophage
      supernatant. Thus GM-CSF is suggested to be an endogenous signal for macrophage
      growth induction by AGEs.

PMID- 10635567
TI  - Effects of dietary protein type on the response of lipid metabolism to orotic
      acid in rats.
AB  - The effects of orotic acid supplementation to casein, egg protein, soy protein
      and wheat gluten diets on the lipids of liver and serum were compared. When
      orotic acid was added, the contents of total lipids and triacylglycerol in the
      liver of the casein group were significantly higher or tended to be higher than
      those of the other three dietary groups. Dietary orotic acid had no effect on the
      food intake. The liver weight, and liver total lipids, triacylglycerol,
      cholesterol and phospholipids were increased or tended to be increased by the
      addition of orotic acid. The serum triacylglycerol level was decreased by the
      addition of orotic acid to either the casein or soy protein diet. Thus, the
      response to liver lipid accumulation induced by orotic acid feeding depended on
      the dietary protein type.

PMID- 10635569
TI  - Purification and characterization of beta-1,3-xylanase from a marine bacterium,
      Vibrio sp. XY-214.
AB  - beta-1,3-Xylanase was purified to gel electrophoretic homogeneity and 83-fold
      from a cell-free culture fluid of Vibrio sp. XY-214 by ammonium sulfate
      precipitation and successive chromatographies. The enzyme had a pl of 3.6 and a
      molecular mass of 52 kDa. The enzyme had the highest level of activity at pH 7.0
      and 37 degrees C. The enzyme activity was completely inhibited by Cu2+, Hg2+, and
      N-bromosuccinimide. The enzyme hydrolyzed beta-1,3-xylan to produce mainly
      xylotriose and xylobiose but did not act on xylobiose, p-nitrophenyl-beta-D
      xyloside, beta-1,4-xylan, beta-1,3-glucan, or carboxymethyl cellulose.

PMID- 10635571
TI  - Effects of a feedback-resistant aspartokinase III gene on L-isoleucine production
      in Escherichia coli K-12.
AB  - An L-isoleucine-overproducing recombinant strain of E. coli, TVD5, was also found
      to overproduce L-valine. The L-isoleucine productivity of TVD5 was markedly
      decreased by addition of L-lysine to the medium. Introduction of a gene encoding
      feedback-resistant aspartokinase III increased L-isoleucine productivity and
      decreased L-valine by-production. The resulting strain accumulated 12 g/l L
      isoleucine from 40 g/l glucose, and suppression of L-isoleucine productivity by L
      lysine was relieved.

PMID- 10635570
TI  - The subunit structure of nitrite reductase purified from the denitrifier
      Achromobacter cycloclastes.
AB  - The copper-containing nitrite reductase of Achromobacter cycloclastes has been
      considered to be a homotrimer with three identical subunits both in the crystal
      and in solution. In this study, however, the enzyme was found to be a
      heterotrimer consisting of two subunits with molecular masses of 37 kDa and 36.2
      kDa, and the 37 kDa subunit was 6 amino acid residues longer than the smaller
      subunit. Signal-peptide cleavage sites in its N-terminal region are discussed.

PMID- 10635572
TI  - Further characterization of earthworm serine proteases: cleavage specificity
      against peptide substrates and on autolysis.
AB  - Cleavage specificity of two fibrinolytic enzymes from Lumbricus rubellus
      [Nakajima, N., et al., Biosci. Biotechnol. Biochem., 57, 1726-1730 (1993) and 60,
      293-300 (1996)] was investigated using beta-amyloid 1-40 and oxidized insulin B
      chain as peptide substrates. The serine protease, F-III-2, cleaved the former
      substrate at six sites, and the latter at five sites. F-II digested them at six
      and ten, respectively. The cleavage specificity of F-III-2 resembled those of
      both trypsin and chymotrypsin. F-II had a broader specificity than F-III-2 and
      preferred also the bonds consisting neutral or hydrophobic amino acids.
      Furthermore, F-III-2 itself was digested initially on the site of Arg(144)
      Tyr(145) to produce two peptide fragments, when it was autolyzed regularly by
      heating.

PMID- 10635573
TI  - New cyclization mechanism for squalene: a ring-expansion step for the five
      membered C-ring intermediate in hopene biosynthesis.
AB  - Three triterpenes having the 6/6/5-fused tri- and 6/6/6/5-fused tetracyclic
      skeletons were isolated from an incubation mixture of the mutated F601A enzyme,
      these products being in accordance with a Markovnikov closure. Successful
      trapping of the tricyclic cationic intermediate by using the squalene analog
      having a highly nucleophilic hydroxyl group leads us to propose that the ring
      expansion process of the 5-membered C-ring is involved in the squalene
      cyclization cascade.

PMID- 10635574
TI  - Cloning and characterization of a Drosophila melanogaster cDNA encoding a
      glutamate transporter.
AB  - A Drosophila cDNA encoding a glutamate transporter was cloned and examined. The
      predicted protein (479 amino acid residues) shows significant sequence identity
      with mammalian counterparts. The protein expressed in Xenopus oocytes had a
      glutamate transport activity. Northern blot analysis showed that the transcript
      increased in amount developmentally. This expression pattern is different from
      those of Drosophila glutamate receptors.

PMID- 10635575
TI  - The mine tailing accident in Aznalcollar.
AB  - Massive amounts of acidic waters and mud (pH approximately 3) containing toxic
      metals such as zinc, lead, arsenic, copper, antimony, cobalt, thallium, bismuth,
      cadmium, silver, mercury and selenium were released in the surroundings of Donana
      Park as a consequence of the mine tailings spill accident in Aznalcollar (SW
      Spain). This introductory paper describes the main characteristics of Donana
      Park, the mine activities developed in Aznalcollar and their related
      environmental risks. The tailing spill accident and the first package of urgent
      actions undertaken for preventive and mitigation purposes are also summarized.

PMID- 10635576
TI  - The extent of the Aznalcollar pyritic sludge spill and its effects on soils.
AB  - This paper presents some initial results from the Instituto Tecnologico Geominero
      de Espana's (ITGE) study of the Aznalcollar mine spill. The spatial distribution
      of the pyritic sludge released was surveyed by using remote sensing data, aerial
      photography, and more than 700 field measurements on the sludge thickness.
      Initial estimation of the extent of the sludge was provided by radar data. Maps
      at 1:10,000 scale, drawn on the basis of field data and interpretation of aerial
      photos, show the distribution of the sludge, divided into 168 subsections on the
      basis of average thickness. GIS analysis provided estimates of the area and
      volume of the sludge. Three approaches were followed in order to survey the
      effects of the spill on the Guadiamar river alluvial soils: (1) Mineralogical and
      chemical characterization of the sludge and its evolution until its removal.
      Alteration products of the pyritic sludge were also analyzed. (2) Determination
      of geochemical background of soils in the Guadiamar river basin, in order to
      establish the content of heavy metals and other elements in the soil before the
      spill. (3) Assessment of the sludge effect on soils caused by the acid water and
      the deposited sludge, by comparison of the heavy metal content of soil under the
      sludge layer with that of background soil. Finally, an airborne multispectral
      survey was carried out over the Aznalcollar-Donana area to evaluate its
      efficiency for monitoring soil condition during and after sludge removal.

PMID- 10635577
TI  - Physico-chemical characterization of atmospheric aerosols in a rural area
      affected by the Aznalcollar toxic spill, south-west Spain during the soil
      reclamation activities.
AB  - High levels of atmospheric contamination due to the re-suspension of pyrite
      particles from the mining waste slurry were recorded in the Guadiamar valley (the
      Guadiamar is a tributary of the Guadalquivir river) after the toxic spill of
      Aznalcollar, north of the Donana Natural Park (SW Spain). Major high-particulate
      events occurred during the extraction of the pyrite-rich mud layer, which covered
      an extensive area of the valley downstream of the confluence of the Agrio and
      Guadiamar rivers. This study deals with the monitoring of the ambient air quality
      at two stations near the village of Aznalcazar in the central part of the flooded
      area. Although the Spanish legal limit for atmospheric particles and lead in
      environmental air were not exceeded, high daily levels of total suspended
      particles (TSP) and of some elements with an environmental significance (As, Cd,
      Cu, Mn, Ni, Pb, Sn, Tl and Zn) were recorded at Aznalcazar and in the Guadiamar
      valley during soil reclamation (July-August 1998). Despite a progressive decrease
      in TSP levels through September-October 1998, background was higher than the
      levels for the May-June period. Evolution of levels for most of the elements
      studied showed a similar trend. The exceptions were copper, which was partially
      increased by other emission sources such as fumigation activities, and sodium,
      which remained at relatively constant levels during the study period because of
      its marine origin. The physico-chemical characterisation of the atmospheric
      particulates allowed us to determine the major grain size modes of the pyrite
      related elements and the solubility of the potentially toxic elements, and to
      identify the major particulate types present in the atmosphere in the area.
      Secondary and tertiary aromatic amines (i.e. alkyldiphenylamines and
      phenylcarbazoles, respectively) were identified in the suspended particles and in
      the vapour phase collected at the same station as the TSP samples. As some of
      these aromatic amines had been previously identified in the pyrite sludge, it is
      assumed that fine sludge particles containing aromatic amines were re-suspended
      in the atmosphere. The highest concentrations of aromatic amines in the
      particulate phase were recorded in August 1998 during the pyrite slurry
      extraction in the proximity of the Aznalcazar sampling site. Despite a sharp drop
      in the suspended particles of the aromatic amine concentrations, a significant
      concentration was detected in the vapour phase (< 1.2 mm) during autumn, probably
      because of longer residence time in the atmosphere. Although health hazards
      associated with the presence of these aromatic amines are unknown, their acute
      toxicity exceeded that of urban aerosols.

PMID- 10635578
TI  - Pollution of soils by the toxic spill of a pyrite mine (Aznalcollar, Spain).
AB  - On 25 April 1998 the retention walls broke open in a pond containing the residues
      from a pyrite mine of Aznalcollar (southern Spain), spilling some 45 x 10(5) m3
      of polluted water and toxic tailings into the Agrio and Guadiamar River basin,
      affecting some 55 km2. On 5 May, seven sectors in the affected area were studied,
      analysing tailings, polluted water, and contaminated as well as uncontaminated
      soils. The principal pollutants were: Zn, Pb, Cu, As, Sb, Bi, Cd and Tl. The
      range of total contamination of each element was extremely broad, as penetration
      of the tailings depended on the soil characteristics. Most of the Cu, Zn and Cd
      penetrated the soil in the solution phase of the spill, while the other elements
      penetrated mostly as part of the solid phase. Zn exceeded the maximum
      concentrations permitted by the international community in four of the seven
      sectors studied, As in three, and the other elements only in one sector. Drying
      and consequent aeration of the tailings rapidly oxidized sulphides to sulphates,
      lowered the pH and solubilized the pollutants. Therefore, future rains could
      aggravate the pollution problem, if the tailings are not quickly removed.

PMID- 10635579
TI  - Heavy metal pollution of soils affected by the Guadiamar toxic flood.
AB  - Total heavy metal concentrations were determined in soil samples of seven
      selected areas along the Guadiamar river valley affected by the toxic flood,
      after removal of the deposited sludge. Mean total concentrations of nine elements
      (As, Au, Bi, Cd, Cu, Pb, Sb, Tl and Zn) out of the 23 (As, Au, Ba, Be, Bi, Cd,
      Co, Cr, Cu, In, Mn, Mo, Ni, Pb, Sb, Sc, Sn, Th, Tl, U, V, Y and Zn) analysed were
      higher in sludge-covered soils than in unaffected soils. Mean values of total As,
      Au, Pb, Sb, Tl and Zn in sludge-affected soils were higher than the upper limits
      for normal soils world-wide. Mean concentrations of Bi, Cd and Cu were within
      these ranges, although some individual values exceeded the upper limits. In all
      sampling areas, severe heavy metal pollution was observed in the superficial
      layers (0-20 cm) of most of the affected soils, which decreased downward in the
      soil profile. Generally, in soils with more than 25% of clay, concentration of
      heavy metals below the 20-cm depth decreased to values close to those of the
      background level of the Guadiamar valley soils, while in coarser soils, heavy
      metal pollution penetrated below this depth, being noticeable down to a depth of
      at least 50-80 cm.

PMID- 10635580
TI  - Prediction of the impact of the Aznalcollar toxic spill on the trace element
      contamination of agricultural soils.
AB  - The interaction of several trace elements (Cd, Zn, Cu, Pb, As, Bi, and Tl) was
      studied by leaching experiments in agricultural soils affected by the Aznalcollar
      toxic spill. The spill led to contamination by acid waste waters and sludge
      deposition. The levels of contamination recorded after the sludge was removed
      from soils showed that highly contaminated areas remained. A comparison of soils
      directly affected by sludge deposition and acid waste waters with soils
      contaminated only by acid waste waters demonstrated that Zn/As and Cd/As ratios
      were good indicators of the two contributions to the contamination. Soil samples
      were characterised and grouped according to their texture and carbonate content.
      The response of elements to single extractions with CaCl2 0.01 mol l-1, CaCl2 1
      mol l-1, CH3COOH 0.43 mol l-1, and EDTA 0.05 mol l-1 enabled us to estimate their
      mobility in the soils. Cd and Zn were found to be the most mobile elements. Cu
      showed an intermediate mobility, especially in an acidic medium. Pb, As, Bi and
      Tl were found to be non-mobile elements. A comparison of referent, low and highly
      contaminated samples showed that the presence of sludge had an effect on
      desorption yields, in part due to the short-term after the contamination.
      Calculations of a relative scale of long-term mobility, between soils and trace
      elements, provided further conclusions derived from the use of single
      extractions.

PMID- 10635581
TI  - The impact of the Aznalcollar mine tailing spill on groundwater.
AB  - As a consequence of a mine tailing dam collapse on the 25th April 1998, more than
      4000 ha of the Guadiamar riverflat and farmlands were flooded by 4 hm3 of
      sulphide slurry. A number of open wells (12 of the 47 analyzed) were also flooded
      and the water was contaminated. Before the spill, the groundwater in the aquifers
      was of calcium-carbonate and calcium-sulphate type, with moderate mineralisation
      and near neutral pH. With the exception of some of the wells close to the mine,
      this groundwater had a low concentration of the metals associated with the
      Aznalcollar mine. After the flood the following metals had anomalous
      concentrations in well water: Zn, Mn, Pb, Co, Cd and Tl. Of these, Zn seems to be
      the best tracer of the contamination, owing to its high concentrations. During
      the 5 months following the spill, water from the unflooded wells did not show an
      increase in metal concentration. Apart from some exceptions in August, the metal
      concentration in the affected wells showed a progressive decrease reaching levels
      closer to those in the wells free from contamination. Nevertheless, in the
      following dry seasons the draw-down of the water level may lead to exposure and
      weathering of sulphides in the wells, which could cause an increase in pollution.
      Therefore, thorough cleaning of all highly contaminated wells is strongly
      recommended.

PMID- 10635582
TI  - Effect of dumping and cleaning activities on the aquatic ecosystems of the
      Guadiamar River following a toxic flood.
AB  - The main aim of the study was to document the recovery of the aquatic ecosystem
      after the release of toxic mining waste in the Guadiamar River Basin (Sevilla, SW
      Spain) in April 1998. Samples of water, plankton, periphyton and
      macroinvertebrates were taken once a month at nine sampling stations (six
      affected by the toxic release and three for control). Water hardness and pH
      recovered in a few weeks and did not change significantly thereafter in the river
      or in the marsh stations. Only the Agrio River (the tributary that received the
      initial waste dump) had a low pH (3-5) throughout the study period. High ammonia
      contents (up to 300 microM) were measured at two sampling stations due to sewage
      and oil mill pollution. Eutrophication was also common at most of the stations,
      including one reference site. The planktonic community did not differ
      substantially between reference and affected stations. On all occasions the small
      phytoplankton and zooplankton (rotifers) were dominant. Compared with the
      reference station, chlorophyll a in the riverine area increased, especially in
      the sewage-affected stations, while in the marsh area, no significant differences
      were found between affected and reference stations. After 6 months of cleaning
      operations, in November 1998 the macroinvertebrate community of the river was
      composed mainly of species of short life cycles typical of ponds (Heteroptera,
      Coleoptera and Odonata), while typical riverine species found at the upstream
      control station had not recolonized the river due to the transformation of the
      river into a series of artificial ponds constructed as sediment traps. An
      analysis of variance showed significantly higher values (P < 0.05) for all heavy
      metals analysed (Zn, Cu, Pb, As, Cd, Sb, Tl) in plankton and macroinvertebrate
      communities from impacted sites. Values found in invertebrates were highly
      variable, with a mean concentration of the most abundant metals, Zn and Cu,
      between two and three times those found in unpolluted areas. Values for As were
      up to five times higher while Pb, Sb and Tl showed up to 10-fold increases. At
      the affected stations, the metal concentrations found in biofilms, plankton and
      particulate material were more than five times greater than those in
      invertebrates. The slow recovery of the aquatic ecosystem clearly reflected the
      impact of the metal discharge and the subsequent cleaning activities following
      the mine spill, as well as the sewage inputs at two of the stations studied.

PMID- 10635583
TI  - Heavy metals in organisms of the River Guadalquivir estuary: possible incidence
      of the Aznalcollar disaster.
AB  - On the 25 April 1998, the giant holding pool of the Aznalcollar mine, owned by
      the Canadian-Swedish Company Boliden Ltd burst its banks; 5 million cubic meters
      (6.7 million cubic yards) of sludge poured into the nearby River Guadiamar, which
      is a tributary of the River Guadalquivir (the main river of the south Iberian
      Peninsula). Within hours of the accident, approximately 2.5 Hm3 of acidic water
      with high concentrations of metals, especially Zn, had entered the River
      Guadalquivir. A biomonitoring program has been carried out to evaluate the
      incidence of this spill on the fauna of the River Guadalquivir. Six sampling
      stations within the estuary of were established and six species of molluscs
      (Crassostrea angulata, Scrobicularia plana), crustaceans (Palameon longirostris,
      Uca tangeri, Melicertus kerathurus) and fish (Liza ramada) were chosen for
      analysis. In the Portuguese oyster, Crassostrea angulata, Cd and Cu
      concentrations were above the maximum allowed by the Spanish legislation for
      bivalves for human consumption (60 micrograms.g-1 wet wt. for Cu and 1.0
      microgram.g-1 wet wt. for Cd). The crustaceans Palaemon longirostris and Uca
      tangeri, also showed values above the legal limits for Cu (20 micrograms.g-1 wet
      wt.). An increase of the Zn levels was observed, as Zn concentrations in C.
      angulata were higher than those reported 30 years ago. The heavy metal
      concentrations in some of the organisms collected in the River Guadalquivir were
      higher than in the Bay of Cadiz or the Mediterranean Sea (clean sites), showing
      that this estuary was subjected to a heavy metal load. One month after the
      accident, concentrations of Zn were higher in C. angulata and in Palaemon
      longirostris compared with levels recorded on the 25 April. Nevertheless, some
      organisms did not show a clear tendency during the sampling period, probably due
      to the fluctuations of environmental (salinity, temperature) and physiological
      variables that affect bioaccumulation.

PMID- 10635584
TI  - Total and inorganic arsenic in the fauna of the Guadalquivir estuary:
      environmental and human health implications.
AB  - To evaluate the impact on fauna of the release of toxic waste from the tailings
      dam operated by the Boliden Apirsa S.L company at Aznalcollar, Seville (Spain) a
      study was carried out of total and inorganic arsenic contents in 164 samples from
      six different estuary species, including molluscs, crustaceans and fish,
      collected at six sampling stations distributed along the estuary and mouth of the
      River Guadalquivir. The contents found, expressed in micrograms per gram wet
      weight, were as follows. Total arsenic: Crassostrea angulata--giant cupped oyster
      (2.44 +/- 0.45); Scrobicularia plana--peppery furrow (2.50 +/- 0.73); Palaemon
      longirostris--delta prawn (1.33 +/- 0.54); Uca tangeri--AfroEuropean fiddler crab
      (1.76 +/- 0.08); Melicertus kerathurus--shrimp (3.60 +/- 1.92); and Liza ramada-
      mullet (0.65 +/- 0.38). Inorganic arsenic: C. angulata (0.09 +/- 0.02); S. plana
      (0.38 +/- 0.23); P. longirostris (0.04 +/- 0.01); U. tangeri (0.22 +/- 0.03); M.
      kerathurus (0.03 +/- 0.01); and L. ramada (0.03 +/- 0.03). The levels of total As
      are comparable to those obtained by other authors. With respect to inorganic
      arsenic, only S. plana and U. tangeri present high levels of inorganic arsenic.
      This may be due to the fact that these organisms live in estuary sediments,
      reservoirs of inorganic arsenic, and ingest particles of sediments during
      feeding. Because of the lack of information for this area concerning previous
      levels of total and inorganic arsenic in the species analysed, it was not
      possible to establish the impact on the fauna of the River Guadalquivir estuary
      of the toxic spill resulting from the failure of the mine tailings dam at
      Aznalcollar. With respect to the implications to human health as a result of
      consumption of species from the Guadalquivir estuary, only with the species
      Scrobicularia plana, as a high consumption of this mollusc might, in some cases,
      exceed the maximum tolerable intake for inorganic arsenic indicated by the
      FAO/WHO. Consumption of the liver of L. ramada does not appear to present
      problems to human health.

PMID- 10635585
TI  - Initial effects of the toxic waste spill (Aznalcollar mine accident) on the
      aquatic macrofauna of the Guadalquivir Estuary.
AB  - The initial effects of the toxic waste spill in April 1998 at the Aznalcollar
      mine (SW Spain) on the nektonic community of the Guadalquivir Estuary were
      examined at three sampling sites using univariate and multivariate techniques.
      Since studied communities showed a considerable seasonal trend, only seasonally
      homogenous periods were compared to analyse effects of the spill: May-August 1997
      (before spill) and May-August 1998 (after spill). Results of both techniques (two
      way nested ANOVA and ANOSIM tests, P > 0.05) indicated that there was no
      significant difference between the nektonic community of the estuary before and
      after the spill (monthly number of species, abundance, biomass and similarity
      among samples). Conversely, an unusually high density was observed at the outer
      sampling site immediately after the spill for species typical of more stagnant
      estuarine habitats. This feature seems to indicate that the fauna in the
      estuarine area through which the untreated water penetrated into the main course
      may have been disturbed. Results also suggest that this initial sudden input of
      fresh water to the estuary could have enhanced the effects of an increased river
      flow (a drop in the salinity). Nevertheless, longer temporal series of data,
      especially for permanent estuarine inhabitants, are recommended before
      conclusions can be drawn on the effects of the toxic waste spill on estuarine
      communities.

PMID- 10635586
TI  - Accumulation of heavy metals in sunflower and sorghum plants affected by the
      Guadiamar spill.
AB  - The collapse of a pyrite-mining, tailing dam on 25 April 1998 contaminated
      approximately 2000 ha of croplands along the Agrio and Guadiamar river valleys in
      southern Spain. This paper reports the accumulation of chemical elements in soil
      and in two crops--sunflower and sorghum--affected by the spill. Total
      concentrations of As, Bi, Cd, Cu, Mn, Pb, Sb, Tl and Zn in spill-affected soils
      were greater than in adjacent, unaffected soils. Leaves of spill-affected crop
      plants had higher nutrient (K, Ca and Mg for sunflower and N and K for sorghum)
      concentrations than controls, indicating a 'fertilising' effect caused by the
      sludge. Seeds of spill-affected sunflower plants did accumulate more As, Cd, Cu
      and Zn than controls, but values were below toxic levels. Leaves of sorghum
      plants accumulated more As, Bi, Cd, Mn, Pb, Tl and Zn than controls, but these
      values were also below toxic levels for livestock consumption. In general, none
      of the heavy metals studied in both crops reached either phytotoxic or toxic
      levels for humans or livestock. Nevertheless, a continuous monitoring of heavy
      metal accumulation in soil and plants must be established in the spill-affected
      area.

PMID- 10635587
TI  - Interactive effects of selenium and mercury on the restoration potential of
      leaves of the medicinal plant, Portulaca oleracea Linn.
AB  - Leaves of Portulaca oleracea have the potential of regeneration, when grown in a
      distilled water medium. The two heavy metals, Se and Hg individually and in
      combination affected both shoot and root development. They completely arrested
      shoot development at all concentrations. However, they produced concentration
      dependent changes in the development of roots, which ranged from their complete
      inhibition to variation in their initiation time, number and length. Leaf decay
      was initiated on day 46 in control leaves. Concentration-dependent changes were
      also observed in the time of initiation and magnitude of decay of leaves. The
      data indicates that Hg was more toxic than Se. The protective effect of Se
      against Hg toxicity was evident only at very low concentrations. With further
      increases in the concentration of both Se and Hg, the protective effect decreased
      and simultaneously the toxicity increased. Following the decay of leaves, a pink
      colour development was observed only on leaves exposed to Se. Microbial analysis
      of leaves showed the presence of Acinetobacter only in Se-exposed leaves.
      Acinetobacter was therefore considered as probably involved in the formation of
      elemental Se, which produced a pink colour.

PMID- 10635588
TI  - Variation of 66 elements in European bottled mineral waters.
AB  - Fifty-six bottled mineral waters bought at random all over Europe were analysed
      for 66 chemical elements by ICP-AES, ICP-MS and IC-techniques. Results show that
      there is a wide spread in the chemical composition of mineral waters. The EEC
      drinking water safeguard values for chemical constituents do not apply to mineral
      water, although mineral water is increasingly used for general drinking water
      purposes. Only 15 of the randomly selected 56 mineral waters would fulfil the
      drinking water regulations for all parameters where action levels are defined.
      Differences in chemical composition observed between countries or regions are due
      to geological environment and to different taste or local regulations of what is
      mineral water. There are indications that element concentrations for some
      unwanted constituents (e.g. Pb) are higher in waters sold in glass bottles than
      in those in plastic bottles. Some elements show a clear regional dependency.
      Studying the large natural variation in concentration for many of the 66 studied
      elements it becomes clear that we know little about the natural variation of
      element concentration in water and the health effects of most elements in
      drinking water.

PMID- 10635589
TI  - Estimates of early-industrial inputs of nutrients to river systems: implication
      for coastal eutrophication.
AB  - Although coastal eutrophication is generally recognised as a recent phenomenon
      related to the well-documented increase in riverine nutrient delivery during the
      last 30 or 40 years, a few historical records paradoxically show that, in some
      places like the Southern Bight of the North Sea, or the Northern Adriatic, algal
      proliferation as intense as presently observed was already regularly occurring at
      the end of the 19th century. Estimated riverine nutrient loads from diffuse
      sources or from domestic point sources of waste water at that time are too low to
      account for these observations. We attempted a retrospective evaluation of the
      possible contribution of industrial activity to nutrient river loading. The
      figures indicate that, by the end of the last century, large scale use of
      traditional processes in textile and paper industries, in tanneries, candles
      factories and others was responsible for a dominant part of the nutrient load
      carried by rivers in Western Europe and could have caused nutrient inputs to
      coastal zones similar to the present ones.

PMID- 10635590
TI  - Emission testing and inhalational exposure-based risk assessment for candles
      having Pb metal wick cores.
AB  - Segments of seven candles with wicks having a Pb metal core have been tested in a
      purpose-built combustion chamber to assess air Pb emissions. Emissions were
      collected on glass fibre filters that have been digested in concentrated HNO3 and
      analysed by flame atomic absorption spectroscopy (FAAS). Despite an indication of
      a bimodal distribution in Pb emission rates, and a range from 450 to 1130
      micrograms Pb/h, the mean rate from the seven candles was 770 micrograms Pb/h.
      The 38-cm long candles are, on average, capable of emitting 104,000 micrograms of
      Pb into the air over approximately 127 h. A mean value of 20% of the Pb metal in
      the wick consumed by the candle is emitted into the air, the remainder appears to
      accumulate at the base of a molten wax-pool adjacent to the wick. Individual Pb
      bearing particles from the combustion of candles were observed in a field
      emission scanning electron microscope (FESEM) to have a diameter of 1 micron or
      less. The emission from the candles has been analysed by X-ray diffraction (XRD)
      and identified as Sodium Lead Carbonate Hydroxide [NaPb2(CO3)2OH]. This compound,
      being a Pb carbonate, is likely to be easily absorbed in the lungs and
      gastrointestinal tract. Risks associated with inhalational exposure have been
      assessed after determining indoor lead in air (PbA) concentrations. Given a lack
      of information on the duration of use of candles, a range of scenarios from worst
      possible case to daily and weekly burning regimes are evaluated. Detailed
      evaluations of PbA are based on the emission from a single candle at rates of 500
      and 1000 micrograms Pb/h, room volumes of 25 and 50 m3, durations of emission of
      1.5, 3 and 6 h and air infiltration rates of 0, 0.25, 0.5, 0.75 and 1.0 air
      volume changes per hour (ACH). A candle burnt for 3 h at 1000 micrograms/h in a
      50 m3 room having poor ventilation at 0.25 ACH is estimated to yield a 24-h
      average lead in air concentration of 9.9 micrograms/m3 with a peak PbA value of
      42.1 micrograms/m3. Daily exposure to such candle burning where children spend
      80% of their time indoors is likely to elevate PbB in children by a minimum of 24
      to 40 micrograms/dl, according to the PbB:PbA relationship of Brunekreef, 1984
      (The relationship between air lead and blood lead in children: a critical
      review). Estimating child Pb uptake from first principles using a range of
      exposure factors, a child would obtain some 85 to 127% of the provisional
      tolerable weekly Pb intake (PTWI) from such daily exposure. Child blood lead
      levels could readily exceed levels of 10 micrograms/dl, largely due to exposure
      to emissions from burning Pb wick core candles for several hours once per week.
      The regular burning of multiple candles in small, poorly ventilated spaces could
      readily be associated with clinical Pb poisonings and death. High levels of
      exposure could occur with Pb metal core wick candles in less developed countries
      where candles are used on a daily basis for indoor lighting purposes in small
      dwellings. Prolonged burning of candles may occur in religious and in ceremonial
      circumstances or restaurants where they may be of particular concern. On the
      basis of the limited investigation carried out, candles having a wick with a Pb
      metal core have the potential to present highly unacceptable and avoidable risks
      to human health.

PMID- 10635591
TI  - Inorganic deterioration affecting the Altamira Cave, N Spain: quantitative
      approach to wall-corrosion (solutional etching) processes induced by visitors.
AB  - In order to study the wall corrosion processes induced by visitors in the
      Altamira Cave (northern Spain), a multidisciplinary study was conducted in the
      cave. For a period of 1 year, a microclimate monitoring system, measuring the
      temperature, relative humidity, CO2 and 222Rn concentrations was operated. Host
      rock samples were collected as well as indoor and outdoor atmospheric particulate
      matter. These data are used for a quantitative assessment of the wall corrosion
      processes. The presence of visitors was found to enhance the corrosion processes
      up to 78 times in comparison with the natural processes. Outdoor air pollution
      did not have a significant affect.

PMID- 10635592
TI  - Relationship between foliar chemical parameters measured in Melia azedarach L.
      and environmental conditions in urban areas.
AB  - A diagnostic study was done on Melia azedarach L. in relation to atmospheric
      pollutants in Cordoba city, Argentina. The study area receives regional
      pollutants, and it was categorized taking into account traffic level, industrial
      level, location of the sample point in relation to the corner, treeless
      condition, building type, topographic level and distance to the river. Water
      content and Specific Leaf Area (SLA) were calculated; and concentrations of
      soluble proteins, sulphur, hydroperoxy conjugated dienes (HPCD), chlorophylls
      (Total Chl) and pheophytins (Total Paeoph) were determined in leaf samples. HPCD
      correlated positively with industry, topographic level and distance to the river,
      and with a combination of the environmental variables (ECI); pigments correlated
      negatively with traffic level and with ECI; Total Phaeoph/Total Chl ratio
      correlated positively with traffic, building and ECI. On the basis of our
      results, traffic level, industrial level, building type, topographic level and
      distance to the river are the environmental variables to bear in mind when
      selecting analogous sampling points in a passive monitoring program. An
      approximation to predict tree injury may be obtained by measuring water content,
      soluble proteins, sulphur, HPCD and pigments as they are responsible for the
      major variability of data. This study revealed that M. azedarach was sensitive to
      air pollutants from traffic and industry. Thus, in those sampling sites with the
      maximum score for traffic level, industrial level and ECI, the highest values of
      the parameters that indicate foliar damage together with the least pigment
      concentration were observed.

PMID- 10635593
TI  - Assessment of toxicity hazards of dredged lake sediment contaminated by creosote.
AB  - In order to predict the potential toxicity hazards of sediment remediation by
      dredging, an experimental laboratory simulation was made by investigating seven
      ratios of creosote-contaminated sediment (Lake Jamsanvesi, central Finland) and
      artificial lake water mixtures. Sediment was suspended in water at the ratios of
      1:1, 1:2, 1:4, 1:8, 1:16, 1:32, 1:64, 1:128 v/v. The elutriates were analysed for
      the acute toxicity by photoluminescence bacterial and waterflea (Daphnia magna
      Straus) tests. The concentrations of polycyclic aromatic hydrocarbons (PAHs) are
      determined by gas chromatography (GC/FID). The elutriate of ratio 1:2 was most
      toxic to bacteria (EC50 = 4.5%), whereas the ratio 1:4 was most toxic to
      waterfleas (EC50 = 21%). The elutriate of 1:1 contained the highest total PAH
      concentration (1.67 mg/l) and total organic carbon (TOC) content (39.4 mg/l).
      When compared to the 1:1 ratio, taken as unity, the relative toxic emission yield
      (RTE) for bacteria was 307 for the ratio 1:128, so the high mixing ratio may
      cause a considerable ecotoxicological hazard. The highest amounts of PAHs were
      desorbed from sediment to water layer when the sediment was mixed with water at
      the ratios 1:1, 1:2 and 1:4 (v/v). It is assumed that dredging of creosote
      contaminated sediment can potentially cause an ecotoxicological risk for a lake
      system at wide range of suspension ratios. We recommended that basic knowledge
      for these risks can be produced by simple laboratory simulation.

PMID- 10635594
TI  - Sediment content of metals before and after lake water liming.
AB  - Long-term liming (1980-1991) of an acidified lake (Lake Terjevann) in the
      southernmost part of Norway, show an increased accumulation of Al, Fe, Mn, Cd,
      Cu, Ni, Zn in the sediments which clearly corresponds with the liming history.
      The increased precipitation of Al, Fe and Mn are ascribed to extended formation
      of oxyhydroxides due to increased pH after introduction of the lime.
      Statistically significant correlations indicate that Cu, Ni and Zn are
      coprecipitated with both Al and Fe oxyhydroxides while Cd is coprecipitated
      primarily with Fe oxyhydroxides both previous to and after lake water liming.

PMID- 10635595
TI  - Acute toxicity assessment of Polish (waste) water with a microplate-based Hydra
      attenuata assay: a comparison with the Microtox test.
AB  - The use of Hydra attenuata in acute toxicity assessment is a potentially useful
      tool in (waste) water biomonitoring. The purpose of this study was to compare the
      sensitivity of H. attenuata with the extensively used Microtox test on 14 (waste)
      water samples from the Krakow region (South Poland). To this end, specific
      morphological changes displayed by the freshwater cnidarian Hydra attenuata
      (lethal LC50s and sublethal EC50s effects) and bioluminescence of the marine
      bacteria Vibrio fisheri (Microtox) were compared. Clearly, the Hydra assay was
      the more sensitive indicator of toxicity. No relationship was found among Hydra
      toxicological responses and water levels of As, Cd, Co, Cu, Pb and Zn. However,
      it appeared that toxicity to Hydra might be due to ammonia levels. Additional
      studies to better circumscribe the tolerance of H. attenuata to 'natural' water
      characteristics are needed.

PMID- 10635596
TI  - Essential elements and priority contaminants in liver, kidney, muscle and blubber
      of harp seal beaters.
AB  - Concentrations of 22 elements were determined in blubber, liver, kidney and
      muscle of five male and five female, 8-month-old harp seals (Phoca groenlandica)
      by ICP-MS. Young harp seals are hunted during the spring and fall and represent
      an important traditional dietary item for some northern fishing communities.
      Interest in the commercial use of seal meat products and the limited data on the
      level of contaminants in tissues of harp seal beaters motivated our
      investigation. For most elements, concentrations in liver or kidney were greater
      than those in muscle. Blubber concentrations were generally lowest, but
      concentrations of Li, As, Sr, Ba and Pb were highest in blubber. Largest
      concentration factors [(tissue)/(water) > 10,000] were seen for P, Fe, Zn, Cu,
      Cd, Se, Mn, Ag, Pb and Co, a list that includes essential elements such as Fe and
      Zn, as well as several important contaminants such as Cd and Pb. Differences in
      concentration between male and female seals were only seen in eight of 88
      element/tissue comparisons. Any effects of environmental exposure due to location
      or dietary intake are difficult to detect. Principle component analysis shows an
      association of Ca with Sr and P with S; and also a distinct grouping of the
      elements V, Mo, Cu and Ag.

PMID- 10635597
TI  - Levels and patterns of PCBs and OC pesticides in harbour and grey seals from the
      St Lawrence Estuary, Canada.
AB  - Blubber samples from harbour (Phoca vitulina) and grey seals (Halichoerus grypus)
      captured in the St Lawrence Estuary were analysed for PCBs and OC pesticides.
      Concentrations of sigma PCB, sigma DDT, sigma CHLOR and mirex were higher in
      harbour than in grey seals, while sigma HCH and HCB were similar in the two
      species. Age vs. concentration plots showed that sigma PCB, sigma DDT and sigma
      CHLOR concentrations increased with age in males, but plateaued at sexual
      maturity in females. Concentrations of sigma HCH decreased and mirex increased
      with age for post-weaning animals, regardless of gender. HCB did not show age
      related trends. PCB congener and OC pesticide patterns varied within harbour
      seals (based on gender and maturity) and between harbour and grey seals. PCB and
      OC concentrations in harbour seals were lower than those seen in a sample of
      significantly older beluga whales. Both species remain in the Estuary year-round.
      PCB and OC pesticide concentrations were higher in resident harbour seals than in
      either grey or harp seals that visit the Estuary seasonally. PCB and OC pesticide
      concentrations in harbour seals from the Estuary were generally higher than in
      harbour seals from other regions of North America. They were comparable to, or
      higher than those from the NE Atlantic Ocean and the North Sea, and lower than
      those from the Wadden and Baltic Seas.

PMID- 10635598
TI  - Concentration and mobilization of Cd, Cu, Pb and Zn by meiofauna populations
      living in harbour sediment: their role in the heavy metal flux from sediment to
      food web.
AB  - The bioavailability of Cd, Cu, Pb and Zn was assessed in different harbours of
      the Atlantic coast (France). The responses of the two dominant meiobenthic groups
      (nematodes and copepods) to a heavy metal contamination gradient measured in
      similar subtidal sediments were observed in field surveys. Heavy metal
      concentrations were measured in nematodes and copepods. Nematodes have higher Cd,
      Cu, Pb and Zn transfer factors than copepods or other benthic species. The flux
      of heavy metal through nematodes was estimated and appears to be important
      compared to plankton in the process of heavy metal transfer to benthic or pelagic
      food webs.

PMID- 10635599
TI  - The estimation of the bioaccessibility of heavy metals in soils using artificial
      biofluids by two novel methods: mass-balance and soil recapture.
AB  - The possible human health effects resulting from the ingestion of soil bound
      heavy metals can be poorly estimated if concentration of total metals in soil,
      rather than bioavailable fraction of metals, are incorporated into dose
      calculations. Information regarding bioavailability often is obtained from animal
      studies, which are not easily conducted and still may not represent human
      conditions. A rapid simulation of the bioaccessible fraction of contaminant in a
      soil, in which that fraction is mass soluble in gastrointestinal tract fluids,
      has been employed in an in vitro sequential extraction technique. Using a mass
      balance analytical approach to measure bioaccessibility in four soils, the
      results indicated that each metal had a bioaccessible fraction less than its
      total metal content. Lead (Pb) in Standard Reference Material, Montana SRM 2710,
      was found to be 62 +/- 1% bioaccessible; Pb in contaminated soil collected from
      Bunker Hill, ID, USA was 70 +/- 11%. Lead in Jersey City, NJ, USA slag material
      was only 39 +/- 14% bioaccessible while Pb in a residential soil was 69%. Arsenic
      (As) and chromium (Cr) data from select soils also have bioaccessibility less
      than the corresponding total metal in soil, with 41 +/- 2% As in a residential
      soil, 66 +/- 8% As in SRM 2710, and 34 +/- 14% Cr in Jersey City slag material.
      Recovering the soil at the end of the in vitro extraction allowed for the
      determination of the insoluble fraction of total metal in soil. This recaptured
      soil metal mass was a valuable measurement since it greatly reduced analysis and
      therefore labor and time, yet also provided a reasonable estimate of
      bioaccessibility. It also allowed for calculation of a bioaccessibility value in
      a soil containing very low metal mass, which would otherwise have resulted in a
      non-detectable concentration at the dilutions required in the synthetic human
      biofluid system.

PMID- 10635600
TI  - Simple method of detecting enteroviruses in contaminated molluscs and sewage by
      using polymerase chain reaction coupled with a colorimetric microwell detection
      assay.
AB  - The methods normally used for the detection of enteroviruses in environmental
      samples involve the use of cell cultures, which are expensive and time consuming.
      The Polymerase Chain Reaction (PCR) is a useful tool for the detection of
      enteroviruses in several matrixes because primary cell culture is not needed and
      the increased sensitivity of PCR allows detection of the low numbers of target
      nucleic acids usually found in environmental samples. A 5-h, user-friendly PCR
      assay was used to detect enteroviruses in bivalves molluscs (clams) and sewage.
      Reverse transcription and amplification were performed in a one-step reaction
      using rTth polymerase. Carryover contamination was prevented with dUTP and uracil
      N-glycosylase. Detection was performed colorimetrically in a microwell titer
      plate. This method has greater advantages over conventional methodologies for
      routinely screening a large number of samples, namely, the rapid acquisition of
      results and cost effectiveness.

PMID- 10635601
TI  - Trace elements in children's hair, as related exposure in wastewater spreading
      field of Marrakesh (Morocco).
AB  - Lead and cadmium concentration was determined in the hair of 327 school children
      living in a wastewater spreading field of Marrakesh (Morocco). The influence of
      age, sex, food habits and family occupation on the children's hair Pb and Cd
      concentration was also evaluated. Girls had more metal in their hair than boys
      (16.5 +/- 5.4 micrograms/g and 12.5 +/- 3.5 micrograms/g, respectively). However,
      for Cd the boys had more metal (2.9 +/- 0.6 and 2.2 +/- 0.4, respectively) but
      the difference was not statistically significant and metal levels decreased with
      age. Family occupation, direct contact with wastewater, customs and food habits
      were the most significant factors influencing the metal content of children's
      hair. The average Pb and Cd content were higher in the exposed children (14.8 +/-
      4.5 micrograms/g and 2.5 +/- 0.5 micrograms/g, respectively) than in the non
      exposed children (4.6 +/- 2.2 micrograms/g and 0.6 +/- 0.2, respectively), but
      the difference was not statistically significant. This study shows that in this
      area all the population (especially children) was extremely exposed to the danger
      caused by potentially toxic metals.

PMID- 10635602
TI  - Contaminant residue levels in arctic wolves (Canis lupus) from the Yukon
      Territory, Canada.
AB  - Kidney, liver and bone samples were taken from 19 wolves (Canis lupus) collected
      from two locations in the Yukon Territory. Liver samples pooled by age and sex
      were analyzed for 22 organochlorine pesticides and 101 PCB congeners. Individual
      kidney and liver samples were analyzed for arsenic, cadmium, copper, lead, total
      mercury, selenium and zinc. Thirteen individual bone samples were analyzed for
      lead. While most organochlorines were not present at detectable levels in wolf
      liver, some chlorobenzenes, dieldrin and sigma PCB were present at low levels.
      PCB congeners 149, 153, 170/190, 180 and 187/182 made up 86% of the total PCBs
      measured in wolf liver. The hexa- and heptachlorobiphenyls dominated the pattern
      in wolf liver, while congeners containing less than five chlorine atoms were not
      detected. The pattern of chlorobenzene and PCB homologues found in wolf liver are
      more similar to those found in marten (Martes americana) and other carnivores
      than caribou (Rangifer tarandus), perhaps reflecting similarities in food habits
      and metabolic capacities. With the exception of cadmium, average element
      concentrations in all wolf tissues are similar to those found in other arctic
      carnivores. Cadmium concentrations in wolf liver and kidney were somewhat higher
      in Yukon wolves than other arctic wolves. This may reflect high cadmium
      concentrations found in livers and kidneys of moose and some caribou herds in the
      Yukon. Renal arsenic and bone lead decreased significantly with age in wolves,
      while renal mercury increased with age. Because the ranges seen are relatively
      small, and all values are within the range normally seen in wildlife, it is
      difficult to determine the biological significance of these relationships.
      Contaminant levels in Yukon wolves are generally low and are similar to those
      found in other arctic terrestrial carnivores. They do not approach levels that
      are known to potentially cause adverse effects in animals. Contaminant
      concentrations found in this study should be considered baseline levels.

PMID- 10635603
TI  - Investigating potential associations between chronic exposure to polychlorinated
      biphenyls and infectious disease mortality in harbour porpoises from England and
      Wales.
AB  - Bioaccumulation of immunosuppressive organochlorines like polychlorinated
      biphenyls (PCBs) may pose a threat to the health and viability of cetacean
      populations. To investigate possible associations between chronic exposure to
      PCBs and infectious disease mortality in harbour porpoises Phocoena phocoena in
      UK waters, blubber concentrations of 25 individual chlorobiphenyl (CB) congeners
      in 34 healthy harbour porpoises that died due to physical trauma (mainly by
      catch) were compared with CB concentrations in 33 animals that died due to
      infectious disease. The infectious disease group had significantly greater total
      25 CBs (sigma 25CBs) concentrations than the physical trauma group (P < 0.001).
      The mean sigma 25CBs concentration in animals that died due to physical trauma
      was 13.6 mg kg-1 extractable lipid whereas the mean concentration in the
      infectious disease group was 31.1 mg kg-1 extractable lipid. The relationship
      between higher sigma 25CBs and the infectious disease group was not confounded by
      age, sex, nutritional status, season, location or year of stranding. In addition,
      adult females had significantly lower sigma 25CBs levels than adult males (P <
      0.05) due to maternal transfer of CBs to offspring. These findings are consistent
      with the hypothesis that chronic PCB exposure predisposes harbour porpoises in UK
      waters to infectious disease mortality, although further research is required to
      test these associations more robustly.

PMID- 10635604
TI  - Methanol reference values in urine from inhabitants of Brazil.
AB  - In order to properly evaluate the results of the occupational biomonitoring of
      chemicals it is necessary to establish reference values for the biomarkers of
      exposure. The aim of this study was to determine the reference values for
      methanol in urine of the general population non-occupationally exposed to the
      xenobiotic under study. Thus, urinary methanol was measured in 84 occupationally
      non-exposed subjects from the city of Sao Paulo, Brazil, by means of headspace
      gas chromatography with a flame ionization detector. The results revealed a mean
      of 2.26 +/- 1.26 mg methanol/l urine and a geometric mean of 2.10 mg/l for the
      studied population. The reference values varied within the range of 0.50-4.78
      mg/l (mean +/- 2 S.D.). Methanol levels in urine did not differ statistically
      between male and female subjects. Urinary methanol in the total population was
      less than 4.80 mg/l in 95% of cases.

PMID- 10635605
TI  - New cases seen at genitourinary medicine clinics: England 1998.

PMID- 10635607
TI  - Hepatitis A and drug misuse in the West Midlands.

PMID- 10635606
TI  - Fatal hand, foot, and mouth disease in the Far East--vigilance needed in the UK.

PMID- 10635608
TI  - AIDS and HIV infection worldwide.

PMID- 10635609
TI  - Dohi Memorial Lecture. Exploding myths about melanoma!

PMID- 10635610
TI  - Medical education and dermatology.

PMID- 10635611
TI  - The American Academy of Dermatology: challenges and opportunities as we approach
      the new century.

PMID- 10635612
TI  - The significance and measurement of scaling.

PMID- 10635613
TI  - Treatment of severe drug eruptions.
AB  - Severe drug eruptions are rare, life-threatening events. The management begins
      with the withdrawal of the suspect drug(s). We recently confirmed that an earlier
      withdrawal of drugs with short elimination half-life was associated with a better
      survival of patients with Stevens-Johnson syndrome (SJS) or toxic epidermal
      necrolysis (TEN). In cases of "acute skin failure" (exfoliative dermatitis,
      extensive SJS or TEN), management of patients must be undertaken in specialized
      intensive care units or in burn units. The main principles of symptomatic therapy
      are the same as for major burns: warming of the environment, correction of
      electrolyte disturbances, high caloric intake, and prevention of sepsis. The
      suspected immunologic orgin of drug eruptions prompted the use of
      corticosteroids, immunosuppressive drugs, and anti-cytokines. Systemic
      corticosteroids are useful in "hypersensitivity syndrome" when visceral lesions
      depend on infiltration by activated cosinophils. Systemic corticosteroids were
      shown to be deleterious in cases of advanced TEN. Their potential usefulness at
      earlier stages of SJS or TEN remains controversial. High intravenous doses of
      cyclophosphamide or oral cyclosporin have been administered to a few patients
      with TEN, most often following ineffective treatment with corticosteroids for 1
      to 5 days. It remains doubtful that the progression of the lesions was shortened.
      A few patients appeared to benefit from treatment with pentoxifyllin, a drug
      suppressing the production of TNF. Thalidomide, another suppressor of TNF
      production, significantly increased the death rate when tested in a double-blind
      placebo controlled trial in patients with early TEN. High dose intravenous
      immunoglobulins were used in 10 patients with TEN on the basis of their ability
      to inhibit fas-fas ligand mediated apoptosis. The potential benefit of this
      treatment needs confirmation by further studies. Patients and their first degree
      relatives should be advised to avoid the responsible drug and chemically related
      compounds. Regulatory agencies should be notified of such cases.

PMID- 10635614
TI  - Current consensus and update on psoriasis therapy: a perspective from the U.S.
AB  - Psoriasis is one of the more common forms of chronic dermatitis in the world. The
      latest U.S.-wide epidemiological study conducted by the author revealed a
      prevalence rate of 2.6% of the population, which translates to over 6 million
      Americans (1). Psoriasis comes in many different degrees of severity and
      responsiveness to treatment modalities. Some cases are very mild and quite
      responsive to treatment, while others are so severe, chronic and recalcitrant
      that they test the skill and ingenuity of the best clinicians. Fortunately, there
      are also many different treatment options. Topical therapies include crude coal
      tar, anthralin, corticosteroids, calcipotriol, and tazarotene. Phototherapy may
      be a better choice in patients with more extensive psoriasis; UVB or psoralen
      plus subsequest UVA (PUVA) can be used. There are also a host of systemic
      therapies (cyclosporine, methotrexate, acitretin), which can be chosen in
      recalcitrant cases, or when topical or phototherapy is impractical. Importantly,
      significant increases in efficacy can be obtained by combining multiple therapies
      (Re-PUVA, topical calcipotriol plus topical halobetasol) and significant
      decreases in side effects can be obtained by transitioning through or rotating
      between therapies (cyclosporine transitioning into acitretin).

PMID- 10635615
TI  - Biological role of tyrosinase-related protein and its relevance to pigmentary
      disorders (vitiligo vulgaris).

PMID- 10635616
TI  - The pink-eyed dilution gene and the molecular pathogenesis of tyrosinase-positive
      albinism (OCA2).

PMID- 10635617
TI  - Analysis of the T cells that are potentially involved in autoantibody production
      in pemphigus vulgaris.
AB  - Pemphigus vulgaris (PV) is a classical example of an antibody-mediated autoimmune
      disease of the skin. Direct evidence exists that autoantibodies against the
      desmosomal adhesion molecule, desmoglein 3 (Dsg3), are critical in the
      pathogenesis of this disease. The transfer of serum IgG antibodies reactive with
      Dsg3 into newborn mice induces a bullous skin disease resembling PV. Autoreactive
      T cell responses to Dsg3 may be critical in the pathogenesis of PV because 1)
      antibody production generally requires T cell help, 2) the involvement of CD4+ T
      lymphocytes in PV has been suggested by the strong association with distinct HLA
      class II alleles, and 3) T cell recognition of epitopes of Dsg3 may be crucial
      for the initiation and perpetuation of the production of Dsg3-specific
      autoantibodies by B cells. We and others have identified autoreactive T cells
      recognizing distinct epitopes of the extracellular portion of Dsg3 in PV
      patients. These autoreactive CD4+ T cells preferentially produced TH2 cytokines
      such as IL-4, and IL-10. Autoantibodies of the TH2-dependent IgG4 subtype are
      preferentially seen in active stages of PV disease, while autoantibodies of the
      TH1-dependent IgG1 subclass are predominant upon remission of PV. Healthy
      individuals who carried HLA class II alleles similar or identical to those found
      to be highly prevalent in PV also developed autoreactive T cell responses to
      Dsg3. Autoreactive T cells from PV patients produced both TH1 and TH2 cytokines;
      autoreactive T cells from normals produced TH0 cytokines. These observations
      suggest that Dsg3-specific T cells may provide targets to eventually modulate the
      T cell-dependent production of pathogenic autoantibodies in PV.

PMID- 10635618
TI  - How to survive and thrive under managed care: lessons from U.S. dermatologists.
AB  - Dermatologists in the US have had many years experience in dealing with managed
      care and some lessons for survival and even thriving have become clear. First is
      to try to prevent managed care. By pointing out its history of failure in many
      countries it is still possible to prevent the catastrophe, to patient, physician
      and final payer, that managed care does represent. If prevention is not possible,
      minimizing its impact by promoting direct access, unbundling, and wider coverage
      is important. In addition, dermatologists will need to maximize reasonable
      sources of direct pay alternatives.

PMID- 10635619
TI  - New technologies toward dendritic cell-based cancer immunotherapies.
AB  - Immunologically naive T cells are activated most efficiently or even exclusively
      by special subsets of antigen presenting cells, termed dendritic cells (DC).
      Members of the DC family have been identified in virtually all epithelial tissues
      that are constantly exposed to environmental antigens or infectious microbes. For
      example, skin is equipped with at least two members of this family, epidermal
      Langerhans cells (LC) and dermal DC. DC have been shown to play pathogenic roles
      in several different inflammatory/immunological disorders and protective roles
      against infectious pathogenes and cancer development. In this review article, we
      will overview the recent progress in the development of DC-based immunotherapies
      for the prevention and treatment of cancers.

PMID- 10635620
TI  - A novel genodermatosis caused by mutations in plakophilin 1, a structural
      component of desmosomes.
AB  - Desmosomes are adhesive intercellular junctions that link adjacent cells and
      provide anchoring points for the keratin filament cytoskeleton. The mechanical
      integrity of desmosomes depends on a complex network of transmembranous and
      cytoplasmic proteins and glycoproteins each encoded by distinct genes. Recently,
      naturally occurring human mutations in one of these desmosomal structural
      components, plakophilin 1, have been described. The clinical features of the
      affected individuals, who have total ablation of plakophilin 1, comprise a
      combination of skin fragility and ectodermal dysplasia with loss of hair, reduced
      sweating and nail dystrophy. Desmosomes in the skin are small and poorly formed
      and there is widening of intercellular spaces between keratinocytes as well as
      detachment of the keratin filament network from the cell membrane. These
      clinicopathological observations demonstrate the relevance of plakophilin 1 to
      keratinocyte adhesion and epidermal morphogenesis. This new form of
      genodermatosis represents the first example of human desmosome gene mutations and
      its clinical and ultrastructural characteristics are highlighted in this article.

PMID- 10635621
TI  - Itch and atopic dermatitis: an overview.
AB  - Itching is the hallmark of atopic dermatitis, and a vicious itch-scratch circle
      is easily established. Itching and scratching are important factors in the
      maintenance of symptoms and can have a significant impact on the sufferer's
      quality of life. The pathophysiology of itch in atopic dermatitis is still not
      understood. Unlike in urticaria, histamine is not considered to be a major
      pruritogen in atopic dermatitis. In fact, the peripheral pruritogens and their
      cellular origin(s) still remain to be identified in this disease. Various
      treatments are used to relieve the skin inflammation, itching, and scratching in
      patients with atopic dermatitis, but no specific antipruritic therapy is
      available. However, several nonspecific therapies can effectively break the
      vicious itch-scratch circle. The use of topical corticosteroids and emollients
      and the elimination of individual trigger factors are still first-line measures.

PMID- 10635622
TI  - [Molecular genetic tumor markers and their analysis for diagnosis and therapy of
      cancer patients].

PMID- 10635623
TI  - [Current aspects of using beta-blockers in patients with congestive heart
      failure].

PMID- 10635624
TI  - [Compliance - a decisive factor in physician-patient relations and treatment
      effectiveness].

PMID- 10635625
TI  - [Myocardial infarction and sudden cardiac death in seamen of the north ship
      line].
AB  - Ischemic heart disease (IHD) is the leading cause of mortality, disability and
      posting from a ship among seamen. As shown by analysis of case records of 124
      seamen who died suddenly of myocardial infarction, IHD lethality on board the
      ship is much higher than on land. The greatest number of myocardial infarctions
      and IHD deaths occur on sailing month 3 and 4, within month 1 after returning
      home. Specific features of myocardial infarction in seamen are the following:
      absence of typical history, high incidence of painless forms and postmortem
      diagnosis, rare hospitalization, relationship with low exercise tolerance and
      inability to reach submaximal heart rate at bicycle exercise. Coronaroangiography
      performed after myocardial infarction detected stenosing atherosclerosis of the
      coronary arteries in 95% of cases.

PMID- 10635626
TI  - [Changes in bioelectric activity of myocardium in Chernobyl wreckers few years
      after the accident].

PMID- 10635627
TI  - [Dynamics of inflammatory cytokines levels in patients with different forms of
      ischemic heart disease].

PMID- 10635628
TI  - [Concentrations of phosphatidylinositols in patients different variants of
      neurocirculatory asthenia].
AB  - Levels of phosphatidylinosites (PI) in blood lymphocytes were measured in 59
      children and adolescents (mean age 11 +/- 3.8 years) with neurocirculatory
      dystonia (NCD). Sex-specific minimal PI differences were determined. Contrary to
      childhood, in adolescence PI levels are elevated both in healthy and NCD subjects
      (p < 0.01). PI in controls and NCD patients differed more in arrhythmogenic,
      cardialgic and hypotonic NCD, less--in hypertensive variant. PI values closely
      correlated both with clinical course of NCD and type of neurodynamic regulation
      of autonomic nervous system.

PMID- 10635629
TI  - [Permeability of intestinal barrier fo macromolecules in patients with Crohn's
      disease and ulcerative colitis].
AB  - Ovalbumin loading enzyme immunoassay was made in 44 patients with ulcerative
      colitis (UC) and 8 patients with Crohn's disease (CD). Enhanced intestinal
      permeability for macromolecules was found in 87.5 and 65.9% of patients with CD
      and UC, respectively. Blood serum of UC patients suffering from combination of
      food intolerance with dysbacteriosis contained ovalbumin in amounts exceeding
      those in patients without the above disorders 3.4 times (p < 0.05). No
      significant relationship existed between UC patients' high intestinal
      permeability and such indices as age, duration of the disease, intestinal lesion
      extension, administration of corticosteroids. It was found desirable to include
      ovalbumin intestinal permeability test in examination of UC and CD patients to
      differentiate treatment policy.

PMID- 10635630
TI  - [Use of biologically active food additive cardiohels in the treatment of patients
      with ischemic heart disease].
AB  - Biologically active food additive (Inrich production) cardiohels was added to the
      diet of ischemic heart disease patients with hypertension and chronic heart
      failure stage IIB receiving basic medication with hypotensive, coronarolytic
      drugs and cardiac glycosides. As shown by control 24-h blood pressure and ECG
      monitoring, echocardiography, cardiohels has a mild hypotensive effect, improves
      coronary circulation and microcirculation, myocardial contractility. Mechanism of
      these positive effects are discussed. Cardiohels is recommended for patients with
      ischemic heart disease as it allows to reduce the dose of hypotensive and
      coronarolytic drugs by 35% and cardiac glycosides by 25%, thus lowering the risk
      of relevand side effects.

PMID- 10635631
TI  - [Effects of theopek and saltos on cardiorespiratory system in bronchial asthma].
AB  - The study of cardiorespiratory system function in 244 BA patients showed how to
      prognosticate unfavorable effects of different course programs including long
      acting broncholytics (teopek and saltos) on cardiovascular system and how to
      optimize therapeutic policy.

PMID- 10635632
TI  - [Ophthalmological applications of hydrocortisone ointment].
AB  - In spite of 40 years of active clinical use, hydrocortisone remains a potent
      therapeutic tool. Hydrocortisone ointment in ophthalmological practice relieves
      allergic symptoms in the eyes, inflammatory reaction in traumas and operative
      interventions. If the instructions for use are not violated, the ointment is
      quite safe.

PMID- 10635633
TI  - [Pumpan treatment of ischemic heart disease with heart failure in elderly].

PMID- 10635634
TI  - [Losek therapy of duodenal ulcer in contamination with different strains of
      Helicobacter pylori].

PMID- 10635635
TI  - [Diagnostic algorithms of heart electric axis and myocardial infarction
      location].

PMID- 10635636
TI  - [Chronic duodenitis associating with Helicobacter pylori].

PMID- 10635637
TI  - [Heart changes as long-term aftereffects of radiotherapy].

PMID- 10635638
TI  - [Case of congenital Marfan's syndrome].

PMID- 10635639
TI  - [Possible explanations of molecular mechanisms underlying etiology and
      pathogenesis of periodic disease].

PMID- 10635640
TI  - [Role of inflammatory and infection factors in development of atherosclerosis
      (review of XX congress of European Cardiology Society, August 1998, Vein)].

PMID- 10635641
TI  - [M.G. Kurlov - an outstanding Russian physician (the 140 anniversary of birth)].

PMID- 10635642
TI  - [Ischemic heart disease in poems by A.S.Pushkin].

PMID- 10635643
TI  - [The studying of Chlamydia pneumoniae in atherosclerosis].

PMID- 10635644
TI  - [Contemporary trends in pharmacotherapy of intestinal tract diseases].

PMID- 10635645
TI  - [The relationship between the 24 hour arterial pressure profile with heart
      changes in patients with essential hypertension].
AB  - A 24-h profile of arterial pressure (AP), structural-geometrical changes of the
      left ventricle (LV) and severity of hypertensive heart were compared in 47
      patients with essential hypertension. Absolute AP and LV geometric models were
      not related. In patients with concentric LV hypertrophy, the time index (TI) of
      night systolic hypertension was significantly higher than TI in excentric LV
      hypertrophy. A relationship was found between mean day systolic pressure, a
      morning rise in AP and form of LV hypertrophy. The severity of hypertensive heart
      correlated with TI of 24-h systolic arterial pressure (SAP), TI of 24-h diastolic
      arterial pressure (DAP), mean 24-h SAP, mean daytime SAP, mean night SAP, mean 24
      h DAP, mean daytime DAP, a morning rise in DAP. Thus, a 24-h AP profile, a
      morning rise in DAP, 24-h hypertension time correlate with LV structural
      geometric changes and severity of hypertensive heart.

PMID- 10635646
TI  - [Spectrum of apolipoproteins of blood serum in patients with non- insulin
      dependent diabetes mellitus on acarbose treatment].

PMID- 10635647
TI  - [Effectiveness of various hepatoprotective agents in liver encephalopathy].

PMID- 10635648
TI  - [Functional renal status in patients with hypothyroidism].
AB  - Examination of 29 patients with decompensated hypothyroidism has detected in them
      abnormal renal concentration, reduction of the glomerular filtration rate,
      elevation of the intraglomerular pressure. The detected albuminuria, decreased
      renal functional reserve and hyperlipidemia suggest initiation of hypothyroidism
      related glomerulopathy resultant from physicochemical processes in glomerular
      endothelium.

PMID- 10635649
TI  - [On prospective applications of veloergometry in patients with myocardial
      ischemia].
AB  - Standardization of veloergometry for functional assessment of oxygen transport in
      patients with ischemic heart disease (IHD) was studied using cardiopulmonary
      complex Siregnost FD 88S (Siemens, Germany) and spiroveloergometry. Standard
      veloergometry protocol was applied for 30 healthy and 55 IHD males. The
      methodological approach and validity of application of standard veloergometry
      protocol in IHD patients are discussed. The regression equations for indirect
      estimation of maximal oxygen consumption by the time of action of the standard
      veloergometry protocol in healthy subjects and IHD males have been devised on the
      basis of the data obtained at linear regression analysis. The method provides an
      approximate indirect estimate of maximal oxygen consumption in the absence of
      gasoanalytical equipment.

PMID- 10635650
TI  - [Thermal skin reaction to food intake and its changes in certain forms of
      obesity].
AB  - The authors review data on recently discovered temperature response of deep skin
      layers to the meal. The reaction is of a reflex nature and is one of the
      mechanisms regulating heat exchange in the body. In healthy people this reaction
      is weak. In alimentary obesity, it becomes much stronger, probably due to
      impaired heat exchange because of accumulated fat. In obesity related to
      diencephalic syndrome skin reaction is similar to control. In this obesity,
      pituitory seems to lose ability to regulate circulation in the blood. The above
      reaction can be used as a test differentiating the two forms of obesity.

PMID- 10635651
TI  - [Thrombo ASS in the prophylaxis of vascular disorders in antiphospholipid
      syndrome].
AB  - The aim of the study was to try thrombo ASS in combined therapy of patients with
      antiphospholipid syndrome (APS), to evaluate its efficacy in prevention of
      recurrent vascular defects. Thrombo ASS tablets (50-100 mg) were included in
      combined treatment of 45 patients with APS (6 males and 39 females, mean age 36.1
      +/- 11.7 years, mean APS duration 10.2 +/- 9.0 years) and 8 patients with SLE (1
      male and 7 females) matched for age. Antiphospholipin antibodies and clinical
      status were assessed before treatment and after the treatment within 9 months. It
      was found that addition of thrombo ASS to combined treatment of APS improves
      coagulation and microcirculation due to effective muscular blood flow, increases
      number of platelets in peripheral blood. Tablets covered with coating resistant
      to gastric juice reduce frequency of gastric side effects.

PMID- 10635652
TI  - [The application of fozinopril in the treatment of refractory angina pectoris in
      elderly patients].

PMID- 10635653
TI  - [The influence of magnesium-containing agents on blood rheology and
      hemocoagulation in patients with heart ischemia].

PMID- 10635654
TI  - [Time-dependent effects of ramipril in patients with hypertension of 2 stage].
AB  - Time-related effects of ramipril were studied in 30 patients with essential
      hypertension stage II. Central hemodynamics, chronostructure of circadian rhythms
      of systolic, diastolic and mean arterial pressure, heart rate, double product
      were assessed before and after ramipril intake throughout 24 hours. The patients
      were randomized into 3 equal groups by time of ramipril administration: morning,
      afternoon and evening. Ramipril was given in dose 5 mg at 8 a.m., 14.00 or 17.00
      and 20.00 p.m. Some hemodynamic parameters were measured each 4 hours. The data
      were analyzed using variation statistics and cosinor-analysis. Hypotensive effect
      of ramipril appeared approximately the same. Hemodynamics responded better after
      the evening intake of the drug.

PMID- 10635655
TI  - [Effectiveness of enalapril in chronic cor pulmonale].
AB  - The aim of our investigation was assessment of enalapril effects in cor
      pulmonale. 20 patients with chronic obstructive pulmonary diseases complicate
      with cor pulmonale received combined treatment including enalapril. The course of
      such treatment led to a significant lowering of systolic and diastolic pressure
      in the pulmonary artery, systemic arterial pressure, specific peripheral
      resistance and minute volume in patients with hyperkinetic and mixed types of
      hemodynamics. Parameters of ECG and exercise tolerance improved. Enalapril is
      effective in correction of pulmonary and central hemocirculation in chronic cor
      pulmonale.

PMID- 10635656
TI  - [Comparative assessment of antacid agents with intragastric ph-metry].
AB  - Alkalizing effects of maalox, renni and tams were compared in 63 patients (27
      males and 36 females) aged 19-56 with endoscopically confirmed superficial
      gastroduodenitis using intragastric pH-metry. Liquid antacids (maalox) began
      their action quicker (1.3-1.7 times) than tablets (renni and tams) but the
      tablets had longer alkalizing effects. Maximal and minimal alkalizing effects
      were achieved with maalox and renni, respectively. It is inferred that rapid
      intragastric pH-metry can be used for comparative assessment of different antacid
      drugs. Of the drugs studied the highest antiacid effect was exhibited by maalox.

PMID- 10635657
TI  - [Causes of delayed detection of pulmonary tuberculosis].
AB  - As shown by analysis of 335 case histories, low alertness for tuberculosis among
      the population and doctors, underestimation of the clinical and anamnestic data,
      late and inadequate x-ray and bacteriological investigations are responsible for
      late diagnosis of pulmonary tuberculosis in primary care institutions. Measures
      to correct the situation are proposed.

PMID- 10635658
TI  - [Pulmonary arterial hypertension as an indirect cause of status asthmaticus].

PMID- 10635659
TI  - [A case of Pfeifer-Weber-Christian syndrome].

PMID- 10635660
TI  - [Liver abscess manifesting as Crohn's disease].

PMID- 10635661
TI  - [On the article "On discussion of the role of Helicobacter pylori in the
      pathogenesis of peptic ulcers" by Prof. A.A. Krylov].

PMID- 10635662
TI  - [Informed consent of patients in experimental studies and medical practice].

PMID- 10635663
TI  - [I.P. Pavlov and clinical medicine].

PMID- 10635664
TI  - Effects of a peer-mediated aerobic conditioning program on fitness levels of
      youth with mental retardation: two systematic replications.
AB  - The generality of a peer-mediated exercise program designed to enhance aerobic
      fitness of 17 children with moderate and severe cognitive disabilities was
      evaluated. Two systematic replications of the program were conducted.
      Participants' ages, disability levels, and school settings varied. Target
      participants were paired with peers without disabilities. These students
      encouraged their peers to maintain requisite levels of exercise intensity and
      monitored their heart rates. A between-group multiple-baseline design was used to
      evaluate program effects. Results replicated earlier findings. Aerobic fitness of
      participants, measured by exercise heart-rates, improved when the exercise
      program was introduced. Results for individual participants reflected more
      variability than combined group data. Implications for overcoming motivational
      barriers and obtaining valued outcomes correlated with the program are discussed.

PMID- 10635665
TI  - Autonomy in residential facilities and community functioning of adults with
      mental retardation.
AB  - Over a 3-year period, we examined whether the autonomy of 58 adults living in
      residences for people with developmental disabilities was associated with their
      adaptive behavior and community integration. Degree of resident autonomy included
      measures of opportunities for choice-making and level of involvement in
      policymaking. All of the participants lived in nursing homes at baseline and in
      residential settings for people with developmental disabilities at follow-up.
      Results indicated that opportunities for autonomy in residential settings were
      related to residents' adaptive behavior and community integration. More
      opportunities for choice-making in residences was associated with greater
      adaptive behavior, whereas smaller residence size and more resident involvement
      in decision-making were associated with greater community integration.

PMID- 10635666
TI  - According to their peers: inclusion as high school students see it.
AB  - Inclusive education has been studied from a number of perspectives, including
      those of general and special education teachers, administrators, and parents. The
      perspectives of 257 high school students about inclusive education were examined.
      Results indicate that these students were supportive of inclusive education and
      recommended the practice. Students also indicated that their peers with
      disabilities added a dimension of diversity to the school, had become part of the
      learning community, and needed to be prepared for the future.

PMID- 10635667
TI  - Autonomy, solidarity, and self-realization: policy views of Dutch service
      providers.
AB  - The popularity of autonomy and self-determination in thinking and talking about
      quality of life of individuals with mental retardation suggests a dominance of
      these concepts in the field today. Here we offer an analysis and evaluation of
      this view and compare it with two alternative and complementary views--solidarity
      and self-realization. Recent policy documents of central government and parents'
      organizations and recent policy documents of 22 agencies for people with mental
      retardation in the Netherlands are the basis of this analysis. Results suggest
      that proponents of these alternative views offer valuable criticisms of the
      dominant view. We appeal for an open discussion of various concepts and their
      respective strengths and weaknesses in relation to different clients and
      institutional contexts.

PMID- 10635668
TI  - Burnout among direct-care staff members of facilities for persons with mental
      retardation in Japan.
AB  - Using the Pines' Burnout Scale, we conducted the first nationwide survey in Japan
      to study burnout among 3,774 staff members in 216 social welfare facilities for
      persons with mental retardation. Mean burnout scores were significantly higher
      among direct-care staff members than among facility directors, middle managers,
      and other types of staff personnel. Burnout scores were significantly lower for
      staff members who reported having supervisors whom they could consult about work
      or personal problems than those who reported they could not. Findings suggest
      that supervisor support can reduce burnout among direct-care staff members at
      social welfare facilities for persons with mental retardation.

PMID- 10635669
TI  - Effectiveness of challenging behavior IHP objectives in residential settings: a
      longitudinal study.
AB  - Effectiveness of challenging behavior Individualized Habilitation Plan (IHP)
      objectives in residential settings was examined. We evaluated three indicators of
      successful intervention: discontinuation of challenging behavior IHP objectives,
      change in challenging behavior over time, and frequency of one-to-one crisis
      intervention and found little evidence of effective intervention. Less than a
      fourth of participants had a challenging behavior objective discontinued within a
      year. There was no significant change in challenging behavior from one annual
      assessment to the next, although the decrease in asocial challenging behavior
      approached significance. Frequency of crisis intervention also did not change
      significantly over time. These findings suggest that most challenging behavior
      IHP objectives are ineffective in reducing challenging behavior.

PMID- 10635670
TI  - Thinking outside the box: use of invitational counseling to promote self
      determination for people with disabilities.

PMID- 10635672
TI  - Intellectual disabilities: have we lost our senses?

PMID- 10635671
TI  - Level of need and behavioral needs of persons admitted to institutions in Texas,
      1994 to 1998.

PMID- 10635673
TI  - Darwin's last child: mental retardation and the need for a romantic science.

PMID- 10635674
TI  - Doctors of the new millennium.

PMID- 10635675
TI  - Back to medicine's future.

PMID- 10635676
TI  - Minnesota's top 10 contributions to medicine.

PMID- 10635677
TI  - Our ancient-modern art.

PMID- 10635678
TI  - Advocacy leads to Medicare progress.

PMID- 10635679
TI  - The portrait of a doctor.

PMID- 10635680
TI  - A century of neonatal medicine.

PMID- 10635681
TI  - Healthy Minnesotans. A goal we all share.

PMID- 10635682
TI  - Highlights of trends in pregnancies and pregnancy rates by outcome: estimates for
      the United States, 1976-96.
AB  - OBJECTIVES: This report presents key findings from a comprehensive report on
      pregnancies and pregnancy rates for U.S. women. The study incorporates birth,
      abortion, and fetal loss data to compile national estimates of pregnancy rates
      according to a variety of characteristics including age, race, Hispanic origin,
      and marital status. Summary data are presented for 1976-96. Data from the
      National Survey of Family Growth (NSFG) are used to show information on sexual
      activity and contraceptive practices, as well as women's reports of pregnancy
      intentions. METHODS: Tabular and graphic data on pregnancy rates by demographic
      characteristics are presented and interpreted. Birth data are from the birth
      registration system for all births registered in the United States and reported
      by State health departments to NCHS; abortion data are from The Alan Guttmacher
      Institute (AGI) and the National Center for Chronic Disease Prevention and Health
      Promotion, Centers for Disease Control and Prevention (CDC); and fetal loss data
      are from pregnancy history information collected in the NSFG. RESULTS: In 1996 an
      estimated 6.24 million pregnancies resulted in 3.89 million live births, 1.37
      million induced abortions, and 0.98 million fetal losses. The pregnancy rate in
      1996 was 104.7 pregnancies per 1,000 women aged 15-44 years, 9 percent lower than
      in 1990 (115.6), and the lowest recorded since 1976 (102.7). Since 1990 rates
      have dropped 8 percent for live births, 16 percent for induced abortions, and 4
      percent for fetal losses. The teenage pregnancy rate has declined considerably in
      the 1990's, falling 15 percent from its 1991 high of 116.5 per 1,000 women aged
      15-19 to 98.7 in 1996. Among the factors accounting for this decline are
      decreased sexual activity, increases in condom use, and the adoption of the
      injectable and implant contraceptives.

PMID- 10635683
TI  - United States life tables, 1997.
AB  - The life tables in this report are current life tables for the United States
      based on age-specific death rates in 1997. Beginning with 1997 mortality data,
      complete U.S. life tables were constructed using a new methodology that replaces
      the abridged life table methodology used previously. The methodology is similar
      to that used in the decennial life tables. Also, life expectancy and other life
      table values are shown for ages 85 to 100 years for the first time as part of the
      annual U.S. life tables. Data used to prepare these life tables are 1997 final
      mortality statistics; July 1, 1997, population estimates; and data from the
      Medicare program. Presented are complete life tables by age, race, and sex. In
      1997 the overall expectation of life at birth was 76.5 years, an increase of 0.4
      years compared with life expectancy in 1996. Life expectancy increased from 1996
      to 1997 for each of the four race-sex groups for which life expectancy is
      reported. Life expectancy increased for black males by 1.1 year (from 66.1 to
      67.2), for black females by 0.5 year (from 74.2 to 74.7), for white males by 0.4
      year (from 73.9 to 74.3), and for white females by 0.2 year (from 79.7 to 79.9).

PMID- 10635684
TI  - The physician's eyes. American nursing and the diagnostic revolution in medicine.

PMID- 10635685
TI  - Eleanor Clarke Slagle and Susan E. Tracy: personal and professional identity and
      the development of occupational therapy in Progressive Era America.

PMID- 10635686
TI  - Nursing reorganization in occupied Japan, 1945-1951.

PMID- 10635687
TI  - Medical service to settlers. The gestation and establishment of a nursing service
      in Quebec, 1932-1943.

PMID- 10635688
TI  - To cultivate a feeling of confidence. The nursing of obstetric patients, 1890
      1940.

PMID- 10635689
TI  - We must have nurses. Spanish influenza in America 1918-1919.

PMID- 10635690
TI  - The miners' hospitals of West Virginia. Nurses and healthcare come to the coal
      fields, 1900-1920.

PMID- 10635691
TI  - A hard day's work. Institutional nursing in the post-World War II era.

PMID- 10635692
TI  - A review of studies on seated whole body vibration and low back pain.
AB  - The paper reviews the epidemiologic evidence linking low back pain (LBP) and
      exposure to whole body vibration (WBV). Particular emphasis is placed on studies
      where the exposure is quantified. Biomechanical studies show a resonance at 4-5
      Hz. At the resonance the transmissibility exceeds 1.0, and is dependent on seat
      attenuation, posture and seat back inclination. Increased spinal loading is
      evidenced by increased muscle activity, muscle fatigue, and disc pressure, and by
      decreased stature. Physiologic changes also occur with WBV. The risk of LBP can
      be reduced by vibration damping, good ergonomic design, reducing exposure, and
      reducing other risks such as lifting.

PMID- 10635693
TI  - Discriminant analysis of human kinematic data: application to human lumbar spinal
      motion.
AB  - A study was undertaken to determine the applicability of a multivariate
      discriminant technique in order to analyse human kinematic data, specifically
      lumbar motion during forward flexion. This method was used in an attempt to allow
      comparison of time-series data (three joint angles and three linear
      displacements) between groups of subjects. Results obtained from ten healthy
      subjects performing simulated abnormal styles of forward flexion indicate the
      feasibility and potential utility of this method in a clinical environment.
      Further investigations will be undertaken on clinical subjects to discriminate
      more effectively between healthy and pathological movements.

PMID- 10635694
TI  - A hip joint simulator study using simplified loading and motion cycles generating
      physiological wear paths and rates.
AB  - In some designs of hip joint simulator the cost of building a highly complex
      machine has been offset with the requirement for a large number of test stations.
      The application of the wear results generated by these machines depends on their
      ability to reproduce physiological wear rates and processes. In this study a hip
      joint simulator has been shown to reproduce physiological wear using only one
      load vector and two degrees of motion with simplified input cycles. The actual
      path of points on the femoral head relative to the acetabular cup were calculated
      and compared for physiological and simplified input cycles. The in vitro wear
      rates were found to be highly dependent on the shape of these paths and
      similarities could be drawn between the shape of the physiological paths and the
      simplified elliptical paths.

PMID- 10635695
TI  - Evaluation of a hip joint simulator.
AB  - To evaluate the functioning of the Durham hip joint wear simulator, the wear
      rates of ultra high molecular weight polyethylene (UHMWPE) and
      polytetrafluoroethylene (PTFE) acetabular cups articulating against 22 mm
      diameter cobalt-chromium-molybdenum (CoCrMo) femoral heads were studied. A wear
      test was conducted in a lubricant of distilled water at 37 degrees C for a
      duration of 4.8 million cycles. The average penetration rate for the CoCrMo
      femoral heads against UHMWPE acetabular cups was 0.03 mm/10(6) cycles, while
      penetration rate for PTFE cups was some twenty times greater. These results are
      of a similar order of magnitude to other simulator studies in distilled water and
      are in a similar ratio to clinical data.

PMID- 10635696
TI  - A comparison between gravimetric and volumetric techniques of wear measurement of
      UHMWPE acetabular cups against zirconia and cobalt-chromium-molybdenum femoral
      heads in a hip simulator.
AB  - Five cobalt-chromium-molybdenum (CoCrMo) and five zirconia femoral head
      components have been wear tested against 28 mm diameter ultra high molecular
      weight polyethylene (UHMWPE) acetabular cups for 5 million cycles in the Durham
      hip joint wear simulator using bovine serum as a lubricant. Wear measurements
      used gravimetric and volumetric techniques and no statistically significant
      difference was found between the measurement methods. The wear rates of the
      acetabular cups against both femoral heads are presented for both measurement
      methods. The UHMWPE acetabular cups showed a statistically significant higher
      linear wear rate for the first 2 million cycles than the lower linear wear rate
      from 2 million cycles to the end of the test, against both femoral head
      materials. Over the full duration of the wear test, the wear rates of acetabular
      cups articulating against zirconia femoral heads were lower than against CoCrMo
      femoral heads. The wear rates up to 2 million cycles and from 2 to 5 million
      cycles for both femoral head materials were consistent with other studies.

PMID- 10635697
TI  - Optimizing the configuration of cement keyholes for acetabular fixation in total
      hip replacement using Taguchi experimental design.
AB  - Cement fixation of the acetabular component is increasingly recognized as a
      common site of loosening when hip replacements fail. Cement keyholes drilled into
      the acetabulum have been recommended to improve this fixation but little is known
      of the optimum positions or sizes of these holes. This study investigates the
      diameter, depth and number of keyholes to be drilled to maximize the failure
      torque in a model system. A Taguchi experimental design was used to identify the
      most significant factors and to predict the best configuration of keyholes within
      the constraints of the experimental test rig. One hole at each of the pubic,
      iliac and ischial sites, of 12 mm diameter and 6 mm depth, was found to be the
      optimum configuration. The failure torque was most strongly dependent on the hole
      diameter in the pubic region, decreased with increasing hole depth and was not
      sensitive to the number of holes.

PMID- 10635698
TI  - Puncture resistance and tensile strength of skin simulants.
AB  - This study aims ultimately to quantify the force needed to penetrate human
      tissue. The results will reduce the subjectivity of expert opinion in stabbing
      incidents. They will also aid clinicians in assessing the severity of injury and
      help prevent the unnecessary deaths which can occur when this is not fully
      appreciated. Tensile tests were performed to identify suitable skin simulants
      with synthetic chamois and pigskin as candidate materials. Quasi-static
      penetration experiments were also performed in which a knife blade penetrated a
      skin simulant target. Pigskin was found to be much stronger than chamois under
      tensile load yet the puncture resistance was almost identical for the two
      materials.

PMID- 10635699
TI  - Analysis of debris from brushing the femoral canal with a plastic brush--a
      potential cause of loosening in total hip replacement.
AB  - The generation of submicrometre sized polyethylene particles has been shown to be
      one of the major causes of osteolysis, loosening and failure of total replacement
      joints. It has been reported that intramedullary brushing of the femoral canal
      with polymer brushes prior to total hip arthroplasty results in the release of
      polymer particles into the femoral canal. The aim of this study was to isolate
      and characterize these particles on the basis of morphology and size and to
      determine whether these particles may play a role in osteolysis and loosening of
      the total hip prostheses. It was found that the majority of the particles shed by
      the polymer brushes were submicrometre in size and were similar in morphology to
      UHMWPE wear particles isolated from periprosthetic tissues. In addition, the
      majority of the particles released by the brushes were in the biologically active
      size range (0.1-10 microns), and may contribute to osteolysis and loosening of
      hip prostheses.

PMID- 10635700
TI  - The segmental motor system--advances, issues, and possibilities.

PMID- 10635701
TI  - Repetitive impulse firing in motoneurons: facts and perspectives.

PMID- 10635702
TI  - Plateau potentials and their role in regulating motoneuronal firing.

PMID- 10635703
TI  - Synaptic integration in bistable motoneurons.

PMID- 10635704
TI  - Adapting motoneurons for motor behavior.

PMID- 10635705
TI  - Assessing the strengths of motoneuron inputs: different anatomical and
      physiological approaches compared.

PMID- 10635706
TI  - Models of spike encoding and their use in the interpretation of motor unit
      recordings in man.

PMID- 10635707
TI  - Non-linear summation of synaptic currents on spinal motoneurons: lessons from
      simulations of the behaviour of anatomically realistic models.

PMID- 10635708
TI  - Selectivity of presynaptic inhibition: a mechanism for independent control of
      information flow through individual collaterals of single muscle spindle
      afferents.

PMID- 10635709
TI  - Why are there three types of intrafusal muscle fibers?

PMID- 10635710
TI  - Quantifying proprioception.

PMID- 10635711
TI  - Movement detection thresholds at the human elbow joint.

PMID- 10635712
TI  - A positive feedback circuit involving muscle spindle secondaries and gamma
      motoneurons in the cat.

PMID- 10635714
TI  - Revisiting the notion of 'motor unit types'.
AB  - Like many areas of biology, the study of motor units and their types has
      progressed from apparent simplicity to intimations of deep complexities as
      information has accumulated from different muscles, species, and methodolgical
      approaches. In my own (not unbiassed) view, the general notion of motor units
      'types' has been amply validated by over two decades of work from many
      laboratories. From the standpoint of function, it still seems valid to think of
      three basic types in mammalian limb muscles. However, it is clear that the
      details of how these types are best recognized, and how their mechanical
      properties are mapped onto muscle fiber biochemistry, are still open questions.
      The organization of motor units clearly remains an exciting and interesting
      field.

PMID- 10635713
TI  - Neurotrophin-3 and maintenance of muscle afferent function.

PMID- 10635715
TI  - Orderly recruitment tested across muscle boundaries.

PMID- 10635716
TI  - Limited plasticity of adult motor units conserves recruitment order and rate
      coding.

PMID- 10635717
TI  - Motor cortical control of human masticatory muscles.
AB  - The corticotrigeminal projections to masseter and anterior digastric motoneuron
      pools that are activated by TMS are bilateral, but not symmetrical. This
      conclusion is supported by whole-muscle data showing larger MEPs in the
      contralateral muscle with unilateral focal TMS, as well as evidence that TMS
      stimulation of one hemisphere may produce excitation in a masseter or digastric
      single motor unit while stimulation of the opposite hemisphere produced
      inhibition of the same motor unit. The asymmetry is particularly marked for
      masseter, in which the low-threshold motor units were most commonly excited with
      contralateral TMS and inhibited with ipsilateral TMS. Spike-triggered averaging
      of digastric motor unit activity revealed cross-talk in surface EMG recordings
      from digastric muscles, and no evidence that muscle fibres in both digastric
      muscles were innervated by a common motor axon. Narrow excitatory peaks in the
      PSTH of motor unit discharge elicited by TMS in masseter (either hemisphere) and
      digastric motor units (ipsilateral hemisphere) suggest a direct
      corticomotoneuronal projection. The contralateral projection to digastric
      motoneurons may include additional oligosynaptic connections, as judged by the
      broader peaks in the PSTH with contralateral TMS. The organisation of bilateral
      corticotrigeminal inputs revealed with TMS suggests that: (a) the contralateral
      hemisphere provides relatively more of the excitatory input delivered via the
      fast corticotrigeminal pathway for both masseter and digastric motoneuron pools,
      and (b) corticotrigeminal projections from either hemisphere are capable of
      contributing to the voluntary command mediating activation of masseter, and (to a
      lesser extent) anterior digastric muscles on one side, that is independent of the
      homologous muscles on the other side.

PMID- 10635718
TI  - Do lengthening contractions represent a case of reversal in recruitment order?

PMID- 10635719
TI  - Motor units of extraocular muscles: recent findings.

PMID- 10635720
TI  - Neuromuscular strategies underlying ballistic movements.

PMID- 10635721
TI  - General principles of rhythmic motor pattern generation derived from invertebrate
      CPGs.

PMID- 10635722
TI  - Central pattern generators and interphyletic awareness.
AB  - Our understandings of how neuronal networks organized as central pattern
      generators generate motor behavior have greatly increased in the last 40 years.
      In the 60s, many investigators studying invertebrate motor behaviors were not
      aware of the work of those studying vertebrate motor behaviors, and vice versa.
      In the 70s, key conferences provided venues for important interactions among
      investigators working on preparations in different species. These interactions,
      termed interphyletic awareness, continued in the 80s and 90s at major conferences
      and played important roles in the development of our understandings of central
      pattern generators for motor behavior in these decades.

PMID- 10635723
TI  - A brain region in insects that supervises walking.

PMID- 10635724
TI  - Behavior of hindbrain neurons during the transition from rest to evoked
      locomotion in a newt.
AB  - Trains of electrical stimuli were delivered to the mesencephalic 'locomotor
      region' in the rough skin newt. The current (3-12 mcA) and the interstimulus
      interval (100 to 200 ms) were adjusted so that locomotion arose in approximately
      10 s, or so that the train remained subthreshold for initiation of locomotion.
      Impulses of single neurons in the hindbrain were recorded during the transition
      period from rest to locomotion. Time-locked synaptic responses were bi- or
      unimodal with typical latencies close to 18, 23 or 28 ms, and weak irregular mode
      near 13 ms. Impulses that were not locked to the stimuli arose in some silent
      neurons, and the rate of firing of neurons with background discharge was
      sometimes enhanced. Composite responses consisted of both time-locked component
      and impulses distributed throughout the interstimulus interval. The data suggest
      that short-lived, wave-like propagation of the input volley ceases or is
      transformed into asynchronous activity after three or four translations. The
      latter variant could occur if the train reached the threshold for initiation of
      locomotion. The asynchronous activity persisted throughout interstimulus interval
      and could coexist with time-locked impulses. Some neurons generated only a few
      impulses, while others remained active from beginning to end of the train. These
      active neurons could either spike at a steady rate, or decrement or augment their
      rate of firing during the train. The time course of their activity was related to
      the initial rate of firing. The augmenting type of firing in a subset of neurons
      may arise due to the interaction of neurons with unstable, steady state and
      decrementing activity.

PMID- 10635725
TI  - On the cellular bases of vertebrate locomotion.

PMID- 10635726
TI  - The roles of spinal interneurons and motoneurons in the lamprey locomotor
      network.
AB  - The isolated lamprey spinal cord offers a relatively simple and convenient adult
      preparation in which to investigate how nerve cells generate behavior and in
      particular the rhythmic motor patterns of locomotion. Nerve cell classes can be
      identified and their cellular and synaptic properties characterized, and a simple
      model based on demonstrated synaptic connectivity can account for major aspects
      of fictive swimming. Clearly, however, much remains to be learned. In particular,
      the properties of the spinal neurons have been shown to change during swimming
      activity but relatively little is known about how these changes occur or the
      effects that these changes have upon the activities of the network. In addition,
      much remains to be learned about the cell types and their synaptic interactions
      as demonstrated here with the newly discovered feedback connections from
      motoneurons, which have not been previously taken into account in modeling of the
      lamprey locomotor network.

PMID- 10635727
TI  - Primate spinal interneurons: muscle fields and response properties during
      voluntary movement.

PMID- 10635728
TI  - Correlations between neurograms and locomotor drive potentials in motoneurons
      during fictive locomotion: implications for the organization of locomotor
      commands.
AB  - The patterns of correlation found between motoneuron pools during fictive
      locomotion are the same whether the coherence functions used to detect the
      correlations are determined using pairs of rectified ENGs or motoneuron LDPs and
      rectified ENGs. This finding suggests that the higher frequencies in rectified
      ENGs (and, perhaps, EMGs) contain information about the synaptic input to
      motoneurons. Nevertheless, differences between the coherence functions of
      rectified ENG pairs and those of LDPs and rectified ENGs suggests that this
      information is distorted by harmonics introduced by rectification. The activities
      of many motoneuron pools are correlated during the flexor or extensor phase of
      fictive locomotion, indicating that they receive common synaptic input from
      branched presynaptic axons or from pools of interneurons whose activities are
      synchronized. Similar findings were reported by Bayev (1978), based on temporal
      correlations. Our results indicate that the investigated motor nuclei, which
      innervate muscles with actions at the hip, knee and ankle, are subject to a set
      of common locomotor commands. These commands are also received by inhibitory
      interneurons that project to the motor nuclei of antagonists, as indicated by the
      correlations between the hyperpolarizing phase of LDPs and activity in the
      rectified ENGs of antagonists. This last result is consistent with a modular
      organization for the spinal locomotor generator, in which one set of interneurons
      drives a motor pool and the inhibitory interneurons that project to the motor
      pool's antagonist (Jordan, 1991). However, these results also suggest that the
      spinal modules for locomotion may not be separable into independent unit-burst
      generators that produce commands for control of each joint as Grillner (1981) has
      suggested. Our results are more consistent with a model in which a generator
      distributes flexor and extensor commands to many motor pools (like the half
      center model) with as yet unidentified spinal mechanisms that determine
      differences in the initiation and termination of activity of individual motor
      nuclei. Alternatively, the correlations between motor pools that we have observed
      could be explained by spinal mechanisms that synchronize the activity of unit
      burst type generators. Despite the distribution of common locomotor commands to
      many functionally diverse motor nuclei, the spinal locomotor pattern generator is
      differentiated to the extent that some motor nuclei, like EDL and FDL, receive
      separate locomotor commands. This conclusion is consistent with other
      observations. EDL and FDL display distinctive, individualized patterns of
      locomotor activity that may vary in a facultative manner or in different forms of
      locomotion (O'Donovan et al., 1980; Trank et al., 1996). A recent study has shown
      that during fictive locomotion EDL and FDL motoneurons receive input from
      different sets of last-order interneurons than those which project to other motor
      pools (Degtyarenko et al., 1998). These results suggest that spinal locomotor
      generators are differentiated for the individualized control of some digit
      muscles, like FDL and EDL.

PMID- 10635729
TI  - Failure analysis of stepping in adult spinal cats.

PMID- 10635730
TI  - Locomotor performance and adaptation after partial or complete spinal cord
      lesions in the cat.

PMID- 10635731
TI  - The role of musculoskeletal mechanics in motor coordination.

PMID- 10635732
TI  - Kinematic redundancy.

PMID- 10635733
TI  - Task- and age-dependent variations in steadiness.

PMID- 10635734
TI  - Mechanical actions of compartments of the cat hamstring muscle, biceps femoris.

PMID- 10635735
TI  - What might the brain know about muscles, limbs and spinal circuits?

PMID- 10635736
TI  - Animal models of motor systems: cautionary tales from studies of head movement.

PMID- 10635737
TI  - The sharing principle.

PMID- 10635738
TI  - Properties of human peripheral nerves: implications for studies of human motor
      control.

PMID- 10635739
TI  - Rhythmic cortical activity and its relation to the neurogenic components of
      normal and pathological tremors.

PMID- 10635740
TI  - Stopping and turning during human walking.

PMID- 10635741
TI  - Disturbances of voluntary movement coordination in stroke: problems of planning
      or execution?

PMID- 10635742
TI  - Group II spindle afferent fibers in humans: their possible role in the reflex
      control of stance.

PMID- 10635743
TI  - Indices of cortical motor function following severe brain injury in man.

PMID- 10635744
TI  - [I.P. Pavlov and genetics].
AB  - Genetic aspects in I. P. Pavlov's studies were assessed. Evidence is provided for
      that he was the first to raise a question as to experimental studies of the
      genetics of the higher nervous system and in the late 1920s to the early 1930s he
      laid its foundation in Koltushi. I. P. Pavlov recognized his first
      misinterpretation of inheritance of conditioned reflexes and decisively refused
      to recognized the inheritance of acquired behavioral traits. His interest in
      genetics gave impetus to the formation of medical genetics as a science in our
      country in the 1930s.

PMID- 10635745
TI  - [Epidemiology of hereditary diseases in Russian population].
AB  - The results of genetic epidemiological investigations performed in different
      regions of Russia are presented. The size of the population surveyed is over 1.5
      million persons. The prevalence rates of autosomal dominant, autosomal recessive,
      and X-linked recessive disorders in Russia were first assessed. It has been shown
      that there is a clear genetic differentiation in the prevalence rates of
      autosomal recessive disorders for some of the populations studied. A correlation
      between random inbreeding and the prevalence of recessive and dominant disorders
      is not only significant, but very high and the differences in random inbreeding
      values are a main reason of this genetic differentiation in Russia's populations.
      A wide spectrum of hereditary diseases is found. This includes 115 autosomal
      dominant, 125 autosomal recessive, and above 30 X-linked recessive hereditary
      disorders. Only a small part of this spectrum occurs at a rate of 1:50,000 or
      greater; however, it is these disorders that determine a considerable proportion
      (more than 50%) of all forms of hereditary disorders. A small share of the
      hereditary diseases revealed shows a local accumulation, which can be also
      explained by a gene drift. The influence of the revealed regularities in the
      distribution of hereditary disorders in the populations of Russia on the
      organization of genetic service in the country is considered.

PMID- 10635746
TI  - [Molecular cytogenetic pre- and postnatal diagnosis of chromosomal
      abnormalities].
AB  - Molecular cytogenetic studies in the prenatal and postnatal identification of
      chromosomal anomalies in children with mental retardation and congenital
      developmental malformations are discussed. Molecular cytogenetic techniques, such
      as fluorescence in situ hybridization (FISH) are employed after the use of
      classic cytogenetic studies. FISH diagnosis is recommended to apply in the cases
      when classic cytogenetic methods are not beneficial: post- and prenatal autosomal
      trisomies; gonosomal aneuploidies, including mosaic forms; marker chromosomes;
      structural chromosomal anomalies, including fragile X syndrome. The authors'
      experience showed that (1) FISH should be utilized only as an adjunctive test for
      classical cytogenetic studies when banding techniques are ineffective; (2) FISH
      confirms a cytogenetic diagnosis; (3) multicolored probe detection gives an
      additional possibility in the FISH analysis. The findings demonstrate that
      molecular cytogenetic methods provide a rapid accurate approach to investigating
      and diagnosing chromosomal anomalies. Molecular cytogenetic diagnosis allows a
      more correct correlation of chromosomal abnormalities to be shown with a clinical
      picture and assists in identifying new chromosomal syndromes in children with
      undifferentiated forms of mental retardation and congenital malformations.

PMID- 10635747
TI  - [Program for diagnosis and prevention of inherited metabolic diseases of cellular
      organelles].
AB  - A programme for diagnosis and prevention of lysosomal, peroxisomal, and
      mitochondrial [respiratory chain diseases (RCD)] diseases was developed on
      clinical, biochemical, and molecular approaches. The authors made postnatal
      diagnosis was made in 674 patients from 516 families and prenatal diagnosis in
      124 fetuses in 94 families at risk. DNA analysis of mutant alleles in the
      mucopolysaccharidoses (MPS) I, II, and VI revealed 14, 13, and 4 new mutant
      alleles in IDS, ASB, IDUA genes, respectively. The pressure of a mutation process
      played a major role in the distribution of mutant alleles leading to MPS I and
      VI, but along with this factor genetic drift and migration undoubtedly influenced
      the observed spectrum of IDUA alleles in Russia. A clinical phenotype of patients
      with different MPS was analyzed on the basis of uniform registration of 167
      symptoms and signs in 249 patients. Special statistical approaches were developed
      to characterize early manifestations of different MPS and "unique" signs and
      symptoms for many of them and "phenotypic distances" between them. The similar
      problems were solved for RCD through uniform registration of 110 symptoms and
      signs in 54 patients with different syndromes: pathognomonic symptoms for the
      whole RCD and "unique" symptoms for syndromes were defined.

PMID- 10635748
TI  - [Regulation of child development: genetic aspects].
AB  - Since antiquity numerous attempts have been made to evaluate a relative role of
      heredity and the environment in human development. In the last quarter of the
      19th century Francis Galton formulated this problem as a dilemma of "Nature or
      Nurture"? Actually, human development is the fulfillment of a genetic programme
      inherited by an individual from his/her parents under quite definite
      environmental conditions. So, Galton's query is rather to be reformulated into a
      statement--"Nature or Nurture". The genetic programme of an individual is
      established during fertilization when the haploid nuclei of an egg-cell and sperm
      are united to form a diploid nucleus of the zygote. During subsequent
      proliferation and differentiation, the zygote progressively develops into an
      embryo, fetus, neonate and so on. Little known about genetic factors regulating
      human embryogenesis and fetogenesis. Some important inferences were made when it
      was found that many regulatory genes and gene families comprehensively
      investigated in Drosophila are close homologues to respective human genes. Among
      such genes are those coding for transcription factors presumably taking part in
      cascade regulation of embryogenesis. Some mutations of these genes were found to
      be involved in the origin of certain malformations in humans (Sonic Hedgehog,
      HOXD13 etc.). Within a wide spectrum of human malformation syndromes, a
      considerable part is comprised by chromosomal disorders, especially those related
      to partial aneusomies (some 2,000 forms). Clinical manifestations of such
      chromosomal syndromes are highly variable, which calls for application of
      computer-assisted devices for their classification and diagnosis. In addition to
      a number of well elaborated English- and French-language databases, Russian
      language computer banks of cytogenetic and clinical data aimed at practical use
      in genetic health care, teaching, and research are already available; among them
      there are "SYNGEN", "CHRODYS", "CHRODYS-PHOTO" elaborated in the Research Center
      for Medical Genetics of the Russian Academy of Medical Sciences, Moscow.

PMID- 10635749
TI  - [Current problems in diagnosis and treatment of hereditary disturbances of growth
      and development in children].
AB  - The authors' long-term experience in diagnosing and treating childhood hereditary
      growth and developmental disturbances, such as genetic diseases of connective
      tissue, amino acid metabolic disturbances, rickets-like diseases, mitochondrial
      abnormalities, Rett syndrome, and fragile X syndrome is presented. The findings
      suggest that multimodality treatment is highly effective in treating children
      with hereditary growth and developmental disturbances in genetic care.

PMID- 10635750
TI  - [Monitoring of congenital developmental anomalies].

PMID- 10635751
TI  - [Medical and prophylactic aids to children with hereditary diseases in Russia].
AB  - The state-of-the-art of medical and prophylactic aids to children with hereditary
      diseases in the Russian Federation and the main ways of its further development
      are analyzed.

PMID- 10635752
TI  - [Current ideas of hereditary nephropathies].
AB  - The paper describes a number of hereditary nephropathies, including hereditary
      nephritis (Alport's syndrome), the most common genetically determined renal
      disease, in the context of recent genetic studies. The specific features of
      tuberous sclerosis, a systemic disease inherited in a monogenic manner are
      outlined. Dysmetabolic nephropathy with oxalate-calcium crystalluria is presented
      as an example of multifactorial pathology.

PMID- 10635753
TI  - [Current aspects of epilepsies and epileptic syndromes genetics].
AB  - The paper gives current data on the genetic aspects of different epileptic
      syndromes. The data available in the world literature on clinicogenealogic, twin,
      and molecular genetic studies is summarized. New prospects in studying the
      genetics of epilepsies and epileptic syndromes are defined.

PMID- 10635754
TI  - [Computer systems in supporting the operation of medico-genetic establishments].
AB  - Nowadays there is a transition from the automation of some tasks to a complex
      computerization of medicogenetic service in Russia on the basis of the Federal
      genetic register. The system is multifunctional and ensures the keeping all
      medical records. It is realized through the corporate global network. The
      operations performed will also provide an intellectual support of medical
      geneticists' decisions.

PMID- 10635755
TI  - [Perception of remote warm and cold point stimulation of different areas in human
      skin].
AB  - The study was made in 57 female students to investigate the verbal and
      temperature characteristics of the perception of remote thermo- and
      cryostimulation in 3 skin points, 3 mm in diameter, having different innervation,
      such as the back, forearm, concha auriculae. No information on the site and
      modality of a stimulus was given to the examinees. The mean time of thermo- and
      cryostimulation applied to each skin point was 40 to 300 sec. The students were
      found to have a right perception of the site and modality of a stimulus in the
      ear skin most commonly, they perceived those in the back less commonly, and in
      the forearm least commonly. Control studies measuring the temperature of a
      microarea in the forearm skin indicated that remote thermo- and cryo-stimulation
      caused exponential temperature changes: a sharper rise on heating and a "gently
      sloping" decrease on cooling.

PMID- 10635756
TI  - [Impact of stressors on serogroup B neisseria meningitidis outer membrane
      proteins during cultivation in bioreactor].
AB  - The authors examined the antigenic complexes obtained from serogroup B Neisseria
      meningitidis strain 125 cells grown in the bioreactor to different phases of
      growth in the reaction of gel precipitation and counter immunophoresis in a
      periodical fashion. A set of serotypic antigens was shown to increase from 3 to 9
      with cultural growth. Their largest quantities were seen in the cells grown till
      the end of the stationary growth phase, the concentration of high-molecular
      weight peptides rising from 19% (in the exponential growth phase cells) to 54%
      (in the stationary growth phase ones). The revealed regularities were evidenced
      by gel precipitation examinations of the sera from rabbits immunized with
      meningococci grown till different growth phases. At the same time, there were the
      largest quantities of serotypic antigenic precipitation bands when the sera
      obtained in the culture grown till the end of the stationary growth phase were
      used. It cannot be excluded that the results depend on the combined effects of
      several stressors on Neisseria meningitidis in the transition from the
      exponential to stationary growth phase, as resulted from the increased synthesis
      of high-molecular weight proteins that seem to act as protectors.

PMID- 10635757
TI  - [Synthetic media for cultivation of lipophilic yeast malassezia spp].
AB  - The capacity of the lipophilic yeast Malassezia spp. (Pityrosporum spp.) to grown
      in a synthetic nutritional media has been studied. The modified Dixon's medium
      was taken as a prototype for preparing the medium containing amino acid, Tween,
      and an emulsifier as carbon and energy sources. The isolates of M. sympodialis
      have demonstrated to relatively more rapidly grow in the medium than those of M.
      globosa.

PMID- 10635758
TI  - [Priorities in research of hemoblastosis].
AB  - Evidence is provided for that it is urgent to elaborate a problem of
      hemoblastosis and hemopoietic depressions within the framework of a special
      federal research and technological programme. Priorities of research lines in
      this areas, trends of their development till 2005 are presented.

PMID- 10635759
TI  - Plague manual--epidemiology, distribution, surveillance and control.

PMID- 10635760
TI  - [Immunoglobulin G (IgG) and IgG subclass].

PMID- 10635761
TI  - [Immunoglobulin A].

PMID- 10635762
TI  - [Immunoglobulin M].

PMID- 10635763
TI  - [Immunoglobulin D].

PMID- 10635764
TI  - [Pyroglobulin, cryoglobulin].

PMID- 10635765
TI  - [Anti IgA antibody].

PMID- 10635766
TI  - [Activation pathways and function of their products in complement system].

PMID- 10635767
TI  - [Hemolytic complement activity via classical pathway].

PMID- 10635768
TI  - [C1q].

PMID- 10635769
TI  - [C1-inhibitor].

PMID- 10635770
TI  - [The second component of complement, C2].

PMID- 10635771
TI  - [The third component of complement, C3].

PMID- 10635772
TI  - [C3 receptor (CR1, 2, 3, 4)].

PMID- 10635773
TI  - [Factor B (C3 proactivator), factor H, factor I].

PMID- 10635774
TI  - [Anaphylatoxins C3a, C4a, C5a].

PMID- 10635775
TI  - [The fourth component of complement, C4].

PMID- 10635776
TI  - [C4BP (C4b-binding protein)].

PMID- 10635777
TI  - [The fifth component of complement, C5].

PMID- 10635778
TI  - [C6, C7, C8 and C9].

PMID- 10635779
TI  - [Membrane cofactor protein (MCP, CD46)].

PMID- 10635781
TI  - [Opsonin].

PMID- 10635780
TI  - [Decay-accelerating factor (DAF; CD55)].

PMID- 10635782
TI  - [Assay for detecting immune complex].

PMID- 10635783
TI  - [C1q-bound immune complex].

PMID- 10635784
TI  - [Autoantibody to the collagen-like region of C1q].

PMID- 10635785
TI  - [C3d-bound immune complex].

PMID- 10635786
TI  - [Conglutinin binding test].

PMID- 10635787
TI  - [Polyethylene glycol complement consumption test (PEG-CC)].

PMID- 10635788
TI  - [Monoclonal RF immune complex].

PMID- 10635789
TI  - [Serological diagnosis of streptococcal infection (anti-streptolysin O; ASO, anti
      streptokinase; ASK, anti-deoxyribonuclease B; ADNB, anti-hyaluronidase; AHD, anti
      streptococcal polysaccharide; ASP)].

PMID- 10635790
TI  - [Cold agglutinin titration].

PMID- 10635791
TI  - [Serological tests for syphilis].

PMID- 10635792
TI  - [Widal test].

PMID- 10635793
TI  - [Weil-Felix test].

PMID- 10635794
TI  - [Immunodiagnosis of mycobacterial infection].

PMID- 10635795
TI  - [Mycobacterium leprae].

PMID- 10635796
TI  - [Streptococcus pneumoniae].

PMID- 10635797
TI  - [Neisseria gonorrhoeae].

PMID- 10635798
TI  - [Corynebacterium diphtheriae].

PMID- 10635799
TI  - [Campylobacter (detection and identification of Campylobacter species)].

PMID- 10635800
TI  - [Helicobacter pylori, serum IgG antibody, urea breath test].

PMID- 10635801
TI  - [Bordetella pertussis].

PMID- 10635802
TI  - [Legionella pneumophila].

PMID- 10635803
TI  - [Diagnosis of typhoid fever and paratyphoid fever].

PMID- 10635804
TI  - [Antibodies to Escherichia coli O157].

PMID- 10635805
TI  - [Escherichia coli verotoxin (relationship between verotoxin produced by E. coli
      O157: H7 and HUS)].

PMID- 10635806
TI  - [Endotoxin (lipopolysaccharide; LPS)].

PMID- 10635807
TI  - [Bacterial protein toxins].

PMID- 10635808
TI  - [Clostridium tetani].

PMID- 10635809
TI  - [Clostridium difficile].

PMID- 10635810
TI  - [Leptospirosis].

PMID- 10635811
TI  - [Lyme borreliosis].

PMID- 10635812
TI  - [Diagnosis of chlamydial infection].

PMID- 10635813
TI  - [Mycoplasma].

PMID- 10635814
TI  - [Orientia tsutsugamushi].

PMID- 10635815
TI  - [Rickettsiae].

PMID- 10635816
TI  - [Cat scratch disease].

PMID- 10635817
TI  - [Candida].

PMID- 10635818
TI  - [beta-D-glucan].

PMID- 10635819
TI  - [Cryptococcus].

PMID- 10635820
TI  - [Immunoserodiagnosis of histoplasmosis].

PMID- 10635821
TI  - [Blastomyces and Coccidioides].

PMID- 10635822
TI  - [Aspergillus].

PMID- 10635823
TI  - [Toxoplasma].

PMID- 10635824
TI  - [Entamoeba histolytica].

PMID- 10635825
TI  - [Echinococcus].

PMID- 10635827
TI  - [Serum immunological diagnosis of Anisakis infection].

PMID- 10635826
TI  - [Filaria].

PMID- 10635828
TI  - [Laboratory diagnosis of HSV infection].

PMID- 10635830
TI  - [Laboratory diagnosis of CMV infection].

PMID- 10635829
TI  - [Varicella-zoster virus].

PMID- 10635831
TI  - [Epstein-Barr virus].

PMID- 10635832
TI  - [Paul-Bunnell reaction test].

PMID- 10635833
TI  - [Human herpesvirus-6 (HHV-6) and human herpesvirus-7 (HHV-7)].

PMID- 10635834
TI  - [Adenovirus].

PMID- 10635835
TI  - [Antibody toward human papillomavirus type 16 (HPV16) L1-capsids].

PMID- 10635836
TI  - [Diagnosis of human parvovirus B19].

PMID- 10635837
TI  - [Rotavirus and other gastroenteritis viruses].

PMID- 10635838
TI  - [Japanese encephalitis virus and other flavivirus].

PMID- 10635839
TI  - [Coronavirus].

PMID- 10635840
TI  - [Influenza A, B and C viruses].

PMID- 10635841
TI  - [Laboratory diagnosis of parainfluenza virus].

PMID- 10635842
TI  - [Mumps virus].

PMID- 10635843
TI  - [Rubella virus].

PMID- 10635844
TI  - [Measles virus].

PMID- 10635845
TI  - [Respiratory syncytial virus].

PMID- 10635846
TI  - [Rhinovirus].

PMID- 10635847
TI  - [Echo viruses].

PMID- 10635849
TI  - [Laboratory diagnosis of poliomyelitis].

PMID- 10635848
TI  - [Coxsackie virus].

PMID- 10635850
TI  - [Laboratory diagnosis of human non-polio enteroviruses].

PMID- 10635851
TI  - [Diagnosis of hepatitis A virus infection].

PMID- 10635852
TI  - [Serological markers of hepatitis B virus].

PMID- 10635853
TI  - [HBV-DNA].

PMID- 10635854
TI  - [Hepatitis C virus-related antibody].

PMID- 10635855
TI  - [Hepatitis C virus RNA].

PMID- 10635856
TI  - [Delta hepatitis virus (HDV) marker].

PMID- 10635857
TI  - [Hepatitis E virus].

PMID- 10635858
TI  - [HGV RNA].

PMID- 10635859
TI  - [TT virus].

PMID- 10635860
TI  - [Human T lymphotropic virus type I].

PMID- 10635861
TI  - [Human immunodeficiency virus type 1, type 2].

PMID- 10635862
TI  - [Progress in detection of autoantibodies and analysis of autoantigens].

PMID- 10635863
TI  - [Rheumatoid factor].

PMID- 10635864
TI  - [LE cell phenomenon].

PMID- 10635865
TI  - [Antinuclear antibodies].

PMID- 10635866
TI  - [Anticentromere antibody (ACA)].

PMID- 10635867
TI  - [Anti-histone antibodies].

PMID- 10635868
TI  - [Anti-DNA (dsDNA, ssDNA) antibodies].

PMID- 10635869
TI  - [Anti-Sm antibody].

PMID- 10635870
TI  - [Anti ribosome antibody].

PMID- 10635871
TI  - [Anti RNA polymerase antibody].

PMID- 10635873
TI  - [Anti-Scl-70 antibody (anti-topoisomerase I antibody)].

PMID- 10635872
TI  - [Anti SS-A/Ro antibodies, anti SS-B/La antibodies].

PMID- 10635874
TI  - [Anti-PM-Scl antibody].

PMID- 10635875
TI  - [Anti-Jo-1 autoantibodies (anti-histidyl tRNA synthetase autoantibodies)].

PMID- 10635876
TI  - [Anti-PL-7 autoantibodies and anti-PL-12 autoantibodies (anti-aminoacyl-tRNA
      'other than histidyl' synthetase autoantibodies)].

PMID- 10635877
TI  - [Anti-U1-RNP antibody and anti-U2-RNP antibody].

PMID- 10635878
TI  - [Anti-U3RNP (fibrillarin) and anti-7-2RNP (Th/To) antibodies].

PMID- 10635879
TI  - [Anti Ki antibodies].

PMID- 10635880
TI  - [Anti-Ku antibodies].

PMID- 10635881
TI  - [Anti poly ADP-ribose antibody].

PMID- 10635882
TI  - [Anti-PCNA antibody].

PMID- 10635883
TI  - [Anti-tropomyosin antibody].

PMID- 10635884
TI  - [Anti-mitochondrial antibody].

PMID- 10635885
TI  - [Antipituitary antibodies].

PMID- 10635886
TI  - [Anti-liver kidney microsome antibodies].

PMID- 10635887
TI  - [Anti-smooth muscle antibody].

PMID- 10635888
TI  - [Anti-parietal cell antibody].

PMID- 10635889
TI  - [Anti-intrinsic factor antibody].

PMID- 10635890
TI  - [Anti-colon antibody].

PMID- 10635891
TI  - [Anti skeletal muscle antibody].

PMID- 10635892
TI  - [Antimyocardial antibody].

PMID- 10635893
TI  - [Anti-desmoglein antibody].

PMID- 10635895
TI  - [Antigonad antibodies].

PMID- 10635894
TI  - [Adrenal-cortex autoantibodies].

PMID- 10635896
TI  - [Antisperm antibodies].

PMID- 10635897
TI  - [Anti-acetylcholine receptor antibody].

PMID- 10635898
TI  - [Myelin basic protein (MBP) and anti-MBP antibody].

PMID- 10635899
TI  - [Anti glomerular basement membrane antibody].

PMID- 10635900
TI  - [Anti-reticulin antibody].

PMID- 10635901
TI  - [Anti-brush border antibody].

PMID- 10635902
TI  - [Anti-mitotic spindle associated antibody].

PMID- 10635903
TI  - [Anti-neutrophil antibody].

PMID- 10635904
TI  - [Anti lymphocyte antibody].

PMID- 10635905
TI  - [Red cell autoantibodies].

PMID- 10635906
TI  - [Antiplatelet antibody].

PMID- 10635907
TI  - [Anti-neutrophil cytoplasmic antibody].

PMID- 10635908
TI  - [Anti-calmodulin antibody].

PMID- 10635909
TI  - [Anti-type II collagen autoantibody].

PMID- 10635910
TI  - [Anti-vimentin antibody].

PMID- 10635911
TI  - [Anti-sulfatide antibody].

PMID- 10635912
TI  - [Antibodies to GM1 and GQ1b gangliosides].

PMID- 10635913
TI  - [Immunoglobulin E].

PMID- 10635914
TI  - [Allergen-specific IgE].

PMID- 10635915
TI  - [Antibody-dependent cell-mediated cytotoxicity (ADCC)].

PMID- 10635916
TI  - [Histamine release test].

PMID- 10635917
TI  - [On basic blood phenotype of Japanese].

PMID- 10635918
TI  - [Clinical significance of screening test for irregular antibodies].

PMID- 10635920
TI  - [Rh blood group system and Rh antibodies].

PMID- 10635919
TI  - [ABO blood group and subtype].

PMID- 10635921
TI  - [Lewis blood group system and their antibodies (anti-Le(a), anti-Le(b))].

PMID- 10635922
TI  - [MNSs blood group system and antibodies (anti-M, -N, -S and -s antibodies)].

PMID- 10635923
TI  - [P blood group system and P antibodies].

PMID- 10635924
TI  - [Kell blood group system].

PMID- 10635925
TI  - [Duffy blood groups and their antibodies (anti Fya antibody, anti FyB antibody)].

PMID- 10635926
TI  - [Diego blood group system].

PMID- 10635927
TI  - [Ii blood group system].

PMID- 10635928
TI  - [Kidd blood group system and antibodies (anti-Jka, anti-Jkb)].

PMID- 10635929
TI  - [Lutheran blood group system].

PMID- 10635930
TI  - [Xg blood group system and anti-Xga antibody].

PMID- 10635931
TI  - [The Oka antigen and anti-Oka].

PMID- 10635932
TI  - [Cross matching test].

PMID- 10635933
TI  - [Galactosaminyltransferase].

PMID- 10635934
TI  - [Direct and indirect anti-globulin test].

PMID- 10635935
TI  - [Anti-D human immunoglobulin test].

PMID- 10635936
TI  - [Antibody elution from red blood cells].

PMID- 10635937
TI  - [Donath-Landsteiner test].

PMID- 10635938
TI  - [Blood group incompatible pregnancy].

PMID- 10635939
TI  - [Flow cytometric cell analysis according to CD grouping].

PMID- 10635940
TI  - [Blast gating method for flow cytometric analysis of leukemia cells].

PMID- 10635941
TI  - [Percentages of human T-, B-cells].

PMID- 10635942
TI  - [Percentage of T cells bearing receptors for IgG or IgM Fc portion].

PMID- 10635943
TI  - [Natural killer cell activity, activity of lymphokine activated killer cells (LAK
      activity), killer helper factor (KHF)].

PMID- 10635944
TI  - [Macrophage migration inhibition test: MIT, leukocyte migration inhibition test:
      LMT].

PMID- 10635945
TI  - [Lymphocyte blastogenesis].

PMID- 10635946
TI  - [Interleukin-2 production test].

PMID- 10635947
TI  - [Introduction for HLA typing; variety of antigens, condition of sample
      collection, applications of testing, and clinical significance].

PMID- 10635948
TI  - [Serological typing of HLA].

PMID- 10635949
TI  - [Mixed lymphocyte culture].

PMID- 10635950
TI  - [DNA typing of HLA alleles].

PMID- 10635951
TI  - [Analysis of HLA chimerism].

PMID- 10635952
TI  - [Cytokines and their receptors].

PMID- 10635953
TI  - [Prostaglandin F2 alpha].

PMID- 10635954
TI  - [Prostaglandin E1, E2 and their metabolites].

PMID- 10635956
TI  - [Prostacyclin and its metabolites].

PMID- 10635955
TI  - [Prostaglandin D2].

PMID- 10635957
TI  - [Thromboxane B2 (TXB2)].

PMID- 10635958
TI  - [Leukotriene (B4, C4, D4, E4)].

PMID- 10635959
TI  - [MCP-1].

PMID- 10635960
TI  - [MIP-1].

PMID- 10635961
TI  - [Macrophage chemotactic factor and macrophage migration inhibitory factor].

PMID- 10635962
TI  - [Macrophage-activating factor (MAF)].

PMID- 10635963
TI  - [Granulocyte colony-stimulating factor (G-CSF)].

PMID- 10635964
TI  - [Granulocyte-macrophage colony-stimulating factor (GM-CSF)].

PMID- 10635965
TI  - [Macrophage colony-stimulating factor].

PMID- 10635966
TI  - [Interleukin-1 (IL-1), IL-1 receptor, IL-1 receptor antagonist (IL-1ra)].

PMID- 10635967
TI  - [Interleukin-2 (IL-2) and IL-2 receptor].

PMID- 10635968
TI  - [Interleukin-3 (IL-3), IL-4, IL-5].

PMID- 10635969
TI  - [Interleukin-6/soluble interleukin-6 receptor].

PMID- 10635970
TI  - [Interleukin-7, 8, 9, 10].

PMID- 10635971
TI  - [Interleukin-11, 12, 13, 14, 15, 16, 17, 18 (IL-11, 12, 13, 14, 15, 16, 17, 18)].

PMID- 10635972
TI  - [Tumor necrosis factor alpha (TNF alpha)].

PMID- 10635973
TI  - [Interferon].

PMID- 10635974
TI  - [Transforming growth factor].

PMID- 10635975
TI  - [VEGF (vascular endothelial growth factor)].

PMID- 10635976
TI  - [PDGF (platelet-derived growth factor)].

PMID- 10635977
TI  - [Epidermal growth factor (EGF)].

PMID- 10635978
TI  - [Heparin-binding EGF-like growth factor (HB-EGF)].

PMID- 10635979
TI  - [Basic fibroblast growth factor].

PMID- 10635980
TI  - [Hepatocyte growth factor (HGF) levels and diseases].

PMID- 10635981
TI  - [LIF (leukemia inhibitory factor)].

PMID- 10635982
TI  - [Stem cell factor].

PMID- 10635983
TI  - Research dealing with mutations in the X-chromosomal housekeeping hypoxanthine
      guanine phosphoribosyltransferase (HPRT).

PMID- 10635984
TI  - Assessing the replicative history of human T cells.
AB  - Upon encountering antigen, T cells clonally expand and differentiate into
      effector cells that directly or indirectly eliminate antigen-bearing pathogens.
      When renewed contact with the same pathogen occurs the immune response is mounted
      in a faster and more accurate way, a process that is referred to as immunological
      memory. The basis for T-cell memory is at least partially provided by an enhanced
      precursor frequency of antigen-specific T cells, and an increased responsiveness
      of primed T cells to activation signals. In contrast to B cells, which acquire
      mutations in the immunoglobulin genes after antigenic challenge, somatic markers
      are lacking that distinguish unprimed (or naive) from primed (encompassing memory
      and effector) T cells. Instead, differential expression of cell surface molecules
      on subsets of T cells and measures for replicative history can be used to obtain
      insight into the antigen-driven development of the T-cell compartment. Apart from
      fundamental issues addressing lineage relationships between naive, memory and
      effector T cells and the cellular basis for long-term T-cell memory, these types
      of studies have proved to be valuable in understanding T-cell reconstitution in
      situations of severe T-cell depletion, i.e., after chemotherapy, treatment with
      depleting CD4 monoclonal antibodies or during HIV infection.

PMID- 10635985
TI  - T lymphocyte dynamics and the ecology of mutations.

PMID- 10635986
TI  - HPRT mutations in vivo in human CD 34+ hematopoietic stem cells.
AB  - The HPRT mutations in T lymphocytes are widely utilized as biomarkers of
      environmental exposure and effect. The HPRT gene detects a wide variety of
      mutation types, many of which are similar at the molecular level to those found
      in oncogenes in cancers. However, it remains to be determined whether the assay
      for mutations in T lymphocytes is reflective of mutagenic events in tissues or
      cells which have high frequencies of malignancy in humans. We now demonstrate
      that the HPRT gene can be utilized to detect mutations in myeloid stem cells,
      which are frequent progenitor cells of leukemias. This myeloid stem cell assay
      shows an age related increase in mutation at HPRT and also detects increases in
      mutant frequency (M-MF) in patients who have undergone chemotherapy. The myeloid
      mutants are confirmed to have mutations in the HPRT gene by DNA sequence
      analysis. Increases in M-MF are seen as expected in the clonally unstable myeloid
      stem cells of patients with myelodysplastic syndromes; however, unexpectedly
      these patients also have elevated T-lymphocyte mutant frequencies (T-MF). A good
      correlation is shown between M-MFs and T-MFs in the same patients. Thus, it
      appears that the T-lymphocyte assay, which is technically much less demanding
      than the myeloid assay, appears to faithfully represent the frequency of
      mutagenic events in the myeloid lineage.

PMID- 10635987
TI  - New approaches to understanding p53 gene tumor mutation spectra.
AB  - The first p53 gene mutation arising in a human tumor was described a decade ago
      by Baker et al. [S.J. Baker, E.R. Fearon, J.M. Nigro, S.R. Hamilton, A.C.
      Preisinger, J.M. Jessup, P. van Tuinen, D.H. Ledbetter, D.F. Barker, Y. Nakamura,
      R. White, B. Vogelstein, Chromosome 17 deletions and p53 gene mutations in
      colorectal carcinomas, Science 244 (1989) 217-221]. There are now over 10,000
      mutations extracted from the published literature in the IARC database of human
      p53 tumor mutations [P. Hainaut, T. Hernandez, A. Robinson, P. Rodriguez-Tome, T.
      Flores, M. Hollstein, C.C. Harris, R. Montesano, IARC database of p53 gene
      mutations in human tumors and cell lines: updated compilation, revised formats
      and new visualization tools, Nucleic Acids Res. 26 (1998) 205-213; Version R3,
      January 1999]. A large and diverse collection of tumor mutations in cancer
      patients provides important information on the nature of environmental factors or
      biological processes that are important causes of human gene mutation, since
      xenobiotic mutagens as well as endogenous mechanisms of genetic change produce
      characteristic types of patterns in target DNA [J.H. Miller, Mutational
      specificity in bacteria, Annu. Rev. Genet. 17 (1983) 215-238; T. Lindahl,
      Instability and decay of the primary structure of DNA, Nature 362 (1993) 709-715;
      S.P. Hussain, C.C. Harris, Molecular epidemiology of human cancer: contribution
      of mutation spectra studies of tumor suppressor genes, Cancer Res. 58 (1998) 4023
      4037; P. Hainaut, M. Hollstein, p53 and human cancer: the first ten thousand
      mutations, Adv. Cancer Res. 2000]. P53 gene mutations in cancers can be compared
      to point mutation spectra at the HPRT locus of human lymphocytes from patients or
      healthy individuals with known exposure histories, and accumulated data indicate
      that mutation patterns at the two loci share certain general features. Hypotheses
      regarding specific cancer risk factors can be tested by comparing p53 tumor
      mutations typical of a defined patient group against mutations generated
      experimentally in rodents or in prokaryotic and eukaryotic cells in vitro.
      Refinements of this approach to hypothesis testing are being explored that employ
      human p53 sequences introduced artificially into experimental organisms used in
      laboratory mutagenesis assays. P53-specific laboratory models, combined with DNA
      microchips designed for high through-put mutation screening promise to unmask
      information currently hidden in the compilation of human tumor p53 mutations.

PMID- 10635988
TI  - Validation of the human T-lymphocyte cloning assay--ring test report from the EU
      concerted action on HPRT mutation (EUCAHM).
AB  - The T-cell cloning assay, which enables the enumeration and molecular analysis of
      6-thioguanine resistant (HPRT-negative) mutant T-cells, has been extensively used
      for studying human somatic gene mutation in vivo. However, large inter-laboratory
      variations in the HPRT mutant frequency (MF) call for further investigation of
      inter-laboratory differences in the experimental methodology, and development of
      an optimal but easy uniform cloning protocol. As part of the EU Concerted Action
      on HPRT Mutation (EUCAHM), we have carried out two Ring tests for the T-cell
      cloning assay. For each test, duplicate and coded samples from three buffy coats
      were distributed to five laboratories for determination of MF using six different
      protocols. The results indicated a good agreement between split samples within
      each laboratory. However, both the cloning efficiencies (CEs) and MFs measured
      for the same blood donors showed substantial inter-laboratory variations. Also,
      different medium compositions used in one and the same laboratory resulted in a
      remarkable difference in the level of MF. A uniform operating protocol (UOP) was
      proposed and compared with the traditional protocols in the second Ring test. The
      UOP (preincubation) increased the CE in laboratories traditionally using
      preincubation, but decreased the CE in laboratories traditionally using priming.
      Adjusted for donor, use of different protocols contributed significantly to the
      overall variation in lnCE (P = 0.0004) and lnMF (P = 0.03), but there was no
      significant laboratory effect on the lnCE (P = 0.38) or lnMF (P = 0.14) produced
      by the UOP alone. Finally, a simplified version of the UOP using the serum-free
      medium X-Vivo 10 and PMA was tested in one laboratory, and found to produce a
      considerable increase in CE. This modified UOP needs to be further evaluated in
      order to be used for future databases on HPRT MFs in various populations.

PMID- 10635989
TI  - Bromodeoxyuridine labelling as an alternative method to identify 6-thioguanine
      resistant mutant lymphocytes in humans.
AB  - 6-Thioguanine-resistant (TGR) mutant lymphocytes in human blood are usually
      enumerated by the cloning assay which allows the molecular characterisation of
      the HPRT mutations to be detected. A "short-term" alternative approach is
      provided by the anti-bromodeoxyuridine (anti-BrdU) technique in which TGR
      lymphocytes are identified immunocytochemically by their ability to synthesise
      DNA in the presence of 6-thioguanine (TG). We have evaluated the influence of
      various experimental factors that could affect the frequency of TGR lymphocytes.
      A standard protocol is proposed, based on 24-h cold storage of isolated
      lymphocytes at 4 degrees C and 40-h culture with and without TG, the last 16 h
      with BrdU. The harvested cells are treated with hypotonic (0.075 M) KCl, fixed
      with methanol:acetic acid (3:1) and put on microscopic slides. For the TG
      cultures, all cells are prepared on the slides, while slides from the control
      cultures are made by a 1/50 dilution. DNA is denatured by formamide, and the BrdU
      label is identified by anti-BrdU antibody detected by immunoperoxidase staining
      using a peroxidase-conjugated secondary antibody with diaminobenzidine as
      substrate. In 10 donors, the frequency of TGR lymphocytes (variant frequency, Vf)
      detected by this protocol ranged from 69.65 x 10(-6) to 83.45 x 10(-6), and split
      measurements showed a relatively small intra-assay variation in Vf values of each
      donor. BrdU in DNA was also detected by immunofluorescence using a fluorescein
      conjugated anti-BrdU monoclonal antibody. This method, facilitating easy
      identification of positive cells and rapid microscopic scoring, may serve as a
      basis for an automated analysis of TGR lymphocytes. Vf values detected by the
      anti-BrdU assay are higher than mutant frequencies obtained by the cloning assay,
      which has been assigned to the presence of non-mutant phenocopies considered to
      represent spontaneously cycling lymphocytes. Although the anti-BrdU assay is
      rapid and easy and has been shown to respond to genotoxic exposures, its true
      value could be evaluated only when it can be ascertained that phenocopies do not
      significantly contribute to the Vf values obtained.

PMID- 10635990
TI  - Total gene deletions and mutant frequency of the HPRT gene as indicators of
      radiation exposure in Chernobyl liquidators.
AB  - This study was conducted to determine the utility of deletion spectrum and mutant
      frequency (MF) of the hypoxanthine phosphoribosyl transferase gene (HPRT) as
      indicators of radiation exposure in Russian Liquidators who served in 1986 or
      1987 in the clean up effort following the nuclear power plant accident at
      Chernobyl. HPRT MF was determined using the cloning assay for 117 Russian
      Controls and 122 Liquidators whose blood samples were obtained between 1991 and
      1998. Only subjects from whom mutants were obtained for deletion analysis are
      included. Multiplex PCR analysis was performed on cell extracts of 1080
      thioguanine resistant clones from Controls and 944 clones from Liquidators.
      Although the deletion spectra of Liquidators and Controls were similar overall,
      the Liquidator deletion spectrum was heterogeneous over time. Most notable, the
      proportion of total gene deletions was higher in 1991-1992 Liquidators than in
      Russian Controls (chi 2 = 10.5, p = 0.001) and in 1993-1994 Liquidators (chi 2 =
      8.3, p = 0.004), and was marginally elevated relative to 1995-1996 Liquidators
      (chi 2 = 3.3, p = 0.07). This type of mutations has been highly associated with
      radiation exposure. Total gene deletions were not increased after 1992. Band
      shift mutations were also increased in the 1991-1992 Liquidators but were
      associated with increased MF of both Liquidators and Controls (p = 0.009), not
      with increased MF in 1991-1992 Liquidators (p = 0.7), and hence are not believed
      to be associated with radiation exposure. Regression analysis demonstrated that
      relative to Russian Controls HPRT MF was elevated in Liquidators overall when
      adjusted for age and smoking status (37%, p = 0.0001), and also was elevated in
      Liquidators sampled in 1991-1992 (72%, p = 0.0076), 1993-1994 (22%, p = 0.037),
      and 1995-1996 (62%, p = 0.0001). In summary, HPRT MF was found to be the more
      sensitive and persistent indicator of radiation exposure, but the specificity of
      total gene deletions led to detection of probable heterogeneity of radiation
      exposure within the exposed population.

PMID- 10635991
TI  - Effects of arsenic exposure on the frequency of HPRT-mutant lymphocytes in a
      population of copper roasters in Antofagasta, Chile: a pilot study.
AB  - A pilot biomarker study was conducted to investigate the feasibility of using the
      hypoxanthine guanine phosphoribosyltransferase (HPRT) gene in peripheral blood
      lymphocytes as a biomarker for detecting genetic effects of arsenic exposure.
      Blood and urine samples were obtained from workers highly exposed to arsenic in a
      copper roasting plant in Antofagasta, Chile. Individuals were classified
      according to their job titles into three potential exposure groups: high, medium,
      and low. To confirm exposure, arsenic concentration was determined in urine
      samples. The HPRT mutant frequencies were measured in lymphocytes from 15
      individuals ranging in age from 24 to 66 years. The mean mutant frequencies for
      the three exposure groups were: low (9 x 10(-6)), medium (11 x 10(-6)), and high
      (24 x 10(-6)). An increased mutant frequency was observed in the highly exposed
      group, but the response was so slight that it is not likely that this assay will
      be capable of providing dose-response information across a range of lower, more
      typical environmental arsenic levels.

PMID- 10635992
TI  - Influence of GSTM1, GSTT1, GSTP1, and EPHX gene polymorphisms on DNA adduct level
      and HPRT mutant frequency in coke-oven workers.
AB  - To evaluate the influence of individual susceptibility factors on the level of
      polyaromatic (PAH) hydrocarbon DNA adducts and hypoxanthine guanine
      phosphoribosyl transferase (HPRT) mutants in peripheral lymphocytes, 70 coke-oven
      workers exposed to PAH were genotyped for four metabolic enzyme polymorphisms of
      potential importance in PAH metabolism. The examined genetic polymorphisms
      concerned glutathione S-transferases M1 (GSTM1; gene deletion; 96 workers), T1
      (GSTT1; gene deletion), P1 (GSTP1; Ile-->Val substitution at codon 104 or Ile-
      >Val at codon 104 and Val-->Ala at codon 113), and microsomal epoxide hydrolase
      (EPHX; Tyr-->His substitution at codon 113 and His-->Arg at codon 139). The
      workers were classified in a high- and low-exposure group on the basis of urinary
      concentration of 1-pyrenol. The GSTM1 null genotype increased the number of DNA
      adducts in smoking coke-oven workers with high PAH exposure. DNA adducts were
      affected by PAH-exposure in non-smokers and in GSTM1 null smokers and by smoking
      in GSTM1 null individuals. In a multiple linear regression analysis, the
      interaction of the GSTM1 genotype was statistically significant (p = 0.04) with
      smoking (yes/no) and of borderline significance (p = 0.06) with PAH-exposure
      (high/low). As smoking also increased urinary 1-pyrenol, the genotype
      modification seemed to concern DNA adducts due to smoking rather than
      occupational exposure. GSTT1 positive individuals showed an elevated level of DNA
      adducts in comparison with GSTT1 null subjects (p = 0.04), and EPHX genotypes
      associated with slow hydroxylation reaction yielded a higher (p = 0.05) HPRT
      mutant frequency than fast EPHX genotypes; these findings were, however, based on
      small numbers of subjects and need to be clarified in further studies. In
      conclusion, our findings indicate that homozygous deletion of GSTM1 results in an
      increased sensitivity to genotoxic PAHs in tobacco smoke, which is seen as an
      increase in aromatic DNA adducts in blood mononuclear cells.

PMID- 10635993
TI  - Analysis of point mutations in HPRT mutant T-lymphocytes derived from coke-oven
      workers.
AB  - We studied mutations in exon 3 of the hypoxanthine-guanine
      phosphoribosyltransferase (HPRT) locus in 113 6-thioguanine-resistant T-cell
      clones derived from coke-oven workers and control subjects in order to analyse
      possible changes in the mutational spectrum associated with the exposure to
      polycyclic aromatic hydrocarbons (PAHs). In 99 mutants, HPRT exon 3 was analysed
      by means of genomic polymerase chain reaction (PCR) and single-strand
      conformation polymorphism (SSCP). Products for which SSCP indicated the presence
      of a mutation were further analysed by DNA sequencing. In addition, HPRT cDNA
      from 14 clones was analysed by reverse transcription (RT) PCR and DNA sequencing.
      In total, 18/113 mutants (16%) had a mutation in exon 3. This frequency was
      similar in PAH-exposed (9/57) and non-exposed (9/56) subjects. Base substitutions
      caused 14 mutations at 13 different sites. Three +/- 1 bp frameshifts and one 6
      bp deletion were identified. No significant differences between PAH-exposed and
      non-exposed workers were observed in this limited mutational spectrum. These
      results indicate that deletions/insertions at the HPRT exon 3 account for 22% of
      the mutations, and base substitutions for 78%.

PMID- 10635994
TI  - Impact of maternal lifestyle factors on newborn HPRT mutant frequencies and
      molecular spectrum--initial results from the Prenatal Exposures and Preeclampsia
      Prevention (PEPP) Study.
AB  - Epidemiological studies have demonstrated associations between maternal tobacco
      smoke exposure and consumption of alcohol during pregnancy and increased risk of
      pediatric malignancies, particularly infant leukemias. Molecular evidence also
      suggests that somatic mutational events occurring during fetal hematopoiesis in
      utero can contribute to this process. As part of an ongoing multi-endpoint
      biomarker study of 2000 mothers and newborns, the HPRT T-lymphocyte cloning assay
      was used to determine mutant frequencies (Mf) in umbilical cord blood samples
      from an initial group of 60 neonates born to a sociodemographically diverse
      cohort of mothers characterized with respect to age, ethnicity, socioeconomic
      status, and cigarette smoke and alcohol exposure. Non-zero Mf (N = 47) ranged
      from 0.19 to 5.62 x 10(-6), median 0.70 x 10(-6), mean +/- SD 0.98 +/- 0.95 x 10(
      6). No significant difference in Mf was observed between female and male
      newborns. Multivariable Poisson regression analysis revealed that increased HPRT
      Mf were significantly associated with maternal consumption of alcohol at the
      beginning [Relative Rate (RR) = 1.84, 95% CI = 0.99-3.40, P = 0.052) and during
      pregnancy (RR = 2.99, 95% CI = 1.14-7.84, P = 0.026). No independent effect of
      self-reported active maternal cigarette smoking, either at the beginning or
      throughout pregnancy, nor maternal passive exposure to cigarette smoke was
      observed. Although based on limited initial data, this is the first report of a
      positive association between maternal alcohol consumption during pregnancy and
      HPRT Mf in human newborns. In addition, the spectrum of mutations at the HPRT
      locus was determined in 33 mutant clones derived from 19 newborns of mothers with
      no self-reported exposure to tobacco smoke and 14 newborns of mothers exposed
      passively or actively to cigarette smoke. In the unexposed group, alterations
      leading to specific exon 2-3 deletions, presumably as a result of illegitimate
      V(D)J recombinase activity, were found in five of the 19 mutants (26.3%); in the
      passively exposed group, two exon 2-3 deletions were present among the seven
      mutants (28.6%); and in the actively exposed group, six of the seven mutants
      (85.7%) were exon 2-3 deletions. Although no overall increase in HPRT Mf was
      observed and the number of mutant clones examined was small, these initial
      results point to an increase in V(D)J recombinase-associated HPRT gene exon 2-3
      deletions in cord blood T-lymphocytes in newborns of actively smoking mothers
      relative to unexposed mothers (P = 0.011). Together, these results add to growing
      molecular evidence that in utero exposures to genotoxicants result in detectable
      transplacental mutagenic effects in human newborns.

PMID- 10635995
TI  - Quantification of illegitimate V(D)J recombinase-mediated mutations in
      lymphocytes of newborns and adults.
AB  - We used a direct polymerase chain reaction (PCR) method for quantification of
      HPRT exons 2 + 3 deletions and t(14;18) translocations as a measure of
      illegitimate V(D)J recombination. We determined the baseline frequencies of these
      two mutations in mononuclear leukocyte DNA from the umbilical cord blood of
      newborns and from the peripheral blood of adults. In an initial group of 21
      newborns, no t(14;18) translocations were detected (< 0.049 x 10(-7)). The
      frequency of HPRT exons 2 + 3 deletions was 0.10 x 10(-7) per mononuclear
      leukocyte, lower than expected based on the T-cell proportion of this cell
      fraction (55%-70%) and previous results using the T-cell cloning assay
      (approximately 2-3 x 10(-7) per clonable T-cell). Phytohemagglutinin (PHA), as
      used in the T-cell cloning assay, was examined for its effect on the frequencies
      of these mutation events in mononuclear leukocytes from an additional 11 newborns
      and from 12 adults. There was no significant effect of PHA on t(14;18)
      translocations which were rare among the newborns (1 detected among 2.7 x 10(8)
      leukocytes analyzed), and which occurred at frequencies from < 1 x 10(-7)
      (undetected) to 1.6 x 10(-4) among the adults. The extremely high frequencies of
      t(14;18)-bearing cells in three adults were due mainly to in vivo expansion of
      two to six clones. However, PHA appeared to stimulate a modest (although not
      significant) increase in the frequency of HPRT exons 2 + 3 deletions in the
      leukocytes of the newborns, from 0.07 x 10(-7) to 0.23 x 10(-7). We show that
      both the direct PCR assay and the T-cell cloning assay detect similar frequencies
      of HPRT exons 2 + 3 deletions when calculations are normalized to blood volume,
      indicating that the apparent discrepancy is probably due to the different
      population of cells used in the assays. This direct PCR assay may have utility in
      characterizing the effects of environmental genotoxic agents on this clinically
      important recombination mechanism.

PMID- 10635996
TI  - Effect of dietary intake and lifestyle factors on in vivo mutant frequency at the
      HPRT gene locus in healthy human subjects.
AB  - This paper describes the results of a study designed to assess the effects of a
      variety of dietary and lifestyle factors on background levels of mutant frequency
      (MF) at the hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene locus in
      humans. Eighty-three healthy and free-living subjects (aged 20-80 yr; 61 males
      and 22 females; mean age of 63.07 +/- 14.71 yr) were recruited. Background levels
      of MF were determined for each subject using a cloning assay. The mean MF/10(6)
      clonable cells (MF) for the study subjects was 4.63 +/- 2.20. An interview
      administered questionnaire was completed by each study subject in order to assess
      details of dietary history, physical activity, health and potential genotoxin
      exposure history. A 7-day estimated dietary record method with a food frequency
      questionnaire was used to determine average intakes of energy and macronutrients
      (including alcohol), and a range of micronutrients (including vitamin and mineral
      supplement usage). The relationships between individual dietary and lifestyle
      factors and HPRT MF were investigated by univariate and multivariate analysis
      (data was adjusted for age, lymphocyte plating efficiency [PE] and energy intake
      [EI]). Univariate analysis revealed a significant positive correlation between EI
      and MF and multivariate analysis revealed significant positive correlations
      between, body mass index (BMI), % energy intake from total carbohydrate, starch,
      fat and MF. These findings suggest that a reduction in EI may be a useful
      preventative measure against the onset of carcinogenesis in humans. No
      correlations were found between alcohol intake and MF or between estimated
      antioxidant intake and MF. Thus, estimated intakes of antioxidants may not
      reflect their bioavailability and functional capacity in vivo and it may be more
      useful to examine actual plasma/cell levels vs. MF to establish if any
      significant relationship exists.

PMID- 10635997
TI  - Investigation of mutant frequency at the HPRT locus and changes in microsatellite
      sequences in healthy young adults.
AB  - In an attempt to understand the inter-individual variation that occurs in in vivo
      mutant frequency at the HPRT locus, we have examined the effect of polymorphisms
      in genes for metabolic enzymes on the mutation rate. In the same population of
      human volunteers, the background variant frequency in a number of microsatellite
      sequences was studied to determine individual variation in the capacity to repair
      mismatches in these sequences. The HPRT mutant frequency of T-cells isolated from
      a group of 49 healthy, non-smoking adults varied from 0.25 to 9.64 x 10(-6). The
      frequency of polymorphisms in CYP1A1, GSTM1 and NAT2 among these individuals was
      similar to those published, and when subjected to univariate analysis these
      polymorphisms showed no influence on the HPRT mutant frequency. However, there
      was a significant interaction between the GSTM1 null genotype and the slow
      acetylator status in NAT2 (P < 0.05) which was associated with higher mutant
      frequency. Analysis of 30 microsatellite sequences in 20 HPRT proficient clones
      per individual showed only six alterations in total, giving an overall mutation
      rate per allele of 0.01%, whilst three alterations were found in five HPRT
      deficient clones per individual examined for changes in 10 microsatellites,
      giving an overall mutation rate per allele of 0.3%. Thus, the alterations
      detected are probably due to background mutations and not to differences in
      mismatch repair capacity.

PMID- 10635998
TI  - Influence of smoking and donor age on the spectrum of in vivo mutation at the
      HPRT-locus in T lymphocytes of healthy adults.
AB  - Types and frequencies of in vivo mutation in the hypoxanthine-guanine
      phosphoribosyl-transferase (HPRT) gene was studied in 142 T cell mutants from 78
      healthy nonsmoking and smoking adults with a mean of 65 years. The HPRT mutant
      frequency in the nonsmokers was 18.7 +/- 12.0 x 10(-6), and in the smokers 26.6
      +/- 18.5 x 10(-6) (mean +/- S.D., P < 0.01). Among 107 single base pair
      substitutions (SBS) in the coding region of the HPRT gene, one new mutable site,
      one novel nonsense mutation and three not previously reported SBS were
      identified. Transitions accounted for 59% of the SBS and transversions for 41%.
      GC > AT transitions were the predominant type of mutation, with 50% of all SBS.
      The mutations showed a nonrandom distribution along the coding sequence, with
      three significant hotspots at positions 143, 197 and 617 (13, 14 and 7 mutations,
      respectively). There was no difference between smokers and nonsmokers with regard
      to the distribution of mutations at these hotspot positions. However, 85% of the
      mutations at GC base pairs and 88% of the mutations at AT base pairs in smokers
      occurred at sites with guanine or thymine, respectively, in the nontranscribed
      DNA strand. Moreover, smokers had a higher frequency of transversions and lower
      frequency of transitions than nonsmokers did. Particularly, GC > TA transversions
      were increased in smokers (11%) compared to nonsmokers (2%), which suggests that
      tobacco-smoke induced adducts at guanine bases in the nontranscribed DNA strand
      contributes to the increase of HPRT mutation in smokers. Overall, these results
      were very similar to the mutational spectra in two younger study populations
      reported previously [K.J. Burkhart-Schultz, C.L. Thompson, I.M. Jones, Spectrum
      of somatic mutation at the hypoxanthine phosphoribosyltransferase (HPRT) gene of
      healthy people, Carcinogenesis 17 (1996) 1871-1883; A. Podlutsky, A.-M.
      Osterholm, S.-M. Hou, A. Hofmaier, B. Lambert, Spectrum of point mutations in the
      coding region of the hypoxanthine-guanine phosphoribosyltransferase,
      Carcinogenesis 19 (1998) 557-566]. With the possible exception of an increase of
      mutations at hotspot position 143, and a decrease of 5-methylcytosine deamination
      mediated transitions at CpG-sites in the older individuals, there were no
      differences between the mutational spectra of old and young adults. In
      conclusion, both smoking and ageing seem to have minor influences on the spectrum
      of HPRT mutation in T cells.

PMID- 10635999
TI  - Molecular spectra of HPRT deletion mutations in circulating T-lymphocytes in
      Fanconi anemia patients.
AB  - The principal cellular feature of Fanconi anemia (FA), an inherited cancer prone
      disorder, is a high level of chromosomal breakage, amplified after treatment with
      crosslinking agents. Three of the eight genes involved in FA have been cloned:
      FANCA, FANCC and FANCG. However, their biological functions remain unknown. We
      previously observed an excessive production of deletions at the HPRT locus in FA
      lymphoblasts belonging to the relatively rare complementation group D(1) and an
      increased frequency of glycophorin A (GPA) variants in erythrocytes derived from
      FA patients (2). In thi study, we examined the molecular nature of 31 HPRT
      mutations formed in vivo in circulating T-lymphocytes isolated from 9 FA male
      patients. The results show that in all FA patients investigated the deletions are
      by far the most prevalent mutational event in contrast to age matched healthy
      donors, in which point mutations predominate. The complementation group in the FA
      patients examined in the present study has not yet been defined. However, knowing
      that mutations in the FANCA and FANCC gene are found to be involved in at least
      70% of the FA patients, it can be expected that the excessive production of
      deletions is a general feature of the FA phenotype. In addition, the spectrum of
      HPRT deletions observed in FA patients differs from that of healthy children:
      there is a high frequency of 3'-terminal deletions and a strikingly low
      proportion of V(D)J mediated events. Based on previous findings, a decreased
      fidelity of coding V(D)J joint formation (3) and an inaccurate repair of specific
      DNA double strand breaks via Non-Homologous End Joining (4), we propose that FA
      genes play a role in the control of the fidelity of rejoining of specific DNA
      ends. Such a defect may explain several basic features of FA, such as chromosomal
      instability and deletion pronenness.

PMID- 10636000
TI  - Analysis of oxidative DNA damage and HPRT mutations in humans after hyperbaric
      oxygen treatment.
AB  - DNA damage induced by reactive oxygen species (ROS) seems to play an important
      role in the induction of mutations and cancer. We have recently shown that
      hyperbaric oxygen (HBO) treatment of volunteers (i.e., exposure to 100% oxygen at
      a pressure of 2.5 ATA) induces DNA damage detected in leukocytes with the comet
      assay. Using formamidopyrimidine-DNA glycosylase (FPG protein) we provided
      indirect evidence for the induction of oxidative DNA base damage. We now
      comparatively evaluated FPG-sensitive sites with the comet assay and 7,8-dihydro
      8-oxo-deoxyguanosine (8-OHdG) with HPLC analysis after a single HBO. As 8
      OHguanine (8-OHgua) is one of the major DNA modifications induced by ROS and a
      pre-mutagenic lesion, we looked for HBO-induced mutations at the HPRT locus with
      the T cell cloning test. We also determined the genotypes for glutathione
      transferases (GST) and tested a possible influence of the GSTM1 and GSTT1
      genotypes on the sensitivity of subjects against HBO-induced genotoxicity. Our
      results indicate that despite a clear induction of FPG-sensitive sites no
      increased levels of 8-OHdG and no induction of HPRT mutations was detected in
      lymphocytes after HBO. Furthermore, the DNA effects in the comet assay and the
      mutant frequencies in the HPRT test seem to be unrelated to the GST genotypes of
      the test subjects.

PMID- 10636001
TI  - Analysis of oxidative DNA damage and HPRT mutant frequencies in cancer patients
      before and after radiotherapy.
AB  - Various markers of radiation-induced DNA damage including DNA oxidation were
      investigated in peripheral lymphocytes of 23 cancer patients prior to and one
      week after receiving radiotherapy with a cumulative dose of 54-70 Gy. Exposure to
      ionizing radiation nonsignificantly increased the ratio 2'deoxy-7-dihydro-8
      oxoguanosine/2'deoxyguanosine (8-oxodG/dG) from 1.73 x 10(-5) to 3.33 x 10(-5).
      Frequencies of micronuclei significantly (p = 0.0003) increased from 6.4 to 38.9
      per 1000 cells. The frequency of hypoxanthine-guanine-phosphoribosyltransferase
      (HPRT) mutant lymphocytes measured as 6-thioguanine resistant variant cells by 5
      bromodeoxyuridine labeling, was elevated eight-fold, from 4.7 x 10(-6) to 36.2 x
      10(-6) (p = 0.008) after termination of the radiotherapy, thus showing a clear
      response to the radiation treatment. No correlation between levels of oxidative
      DNA damage and frequencies of HPRT mutant lymphocytes or micronuclei could be
      established.

PMID- 10636003
TI  - Hprt mutant frequency and molecular analysis of Hprt mutations in rats treated
      with mutagenic carcinogens.
AB  - Much of the progress in the field of cancer research has come from the increased
      understanding of the molecular events associated with the initiation and
      accumulation of mutational events associated with carcinogenesis. Genetic
      toxicologists have developed a number of in vitro and in vivo non-mammalian and
      mammalian systems to predict those genetic events required to induce the cancer
      process. Several model rodent systems have been proposed that have the ability to
      detect and quantify in vivo somatic mutation in endogenous genes and transgenes
      and relate the nature of the mutation to the specific type of chemical damage.
      One such system, the rat lymphocyte hypoxanthine guanine phosphoribosyl
      transferase (Hprt) assay is described in this review. Data are presented that
      describe mutant induction and mutational spectra in N-ethyl-N-nitrosourea (ENU),
      7,12-dimethylbenzo[a]anthracene (DMBA) and thiotepa (TEPA) treated rats.

PMID- 10636002
TI  - Relationships between exposure, cell loss and proliferation, and manifestation of
      Hprt mutant T cells following treatment of preweanling, weanling, and adult male
      mice with N-ethyl-N-nitrosourea.
AB  - Experiments were performed to characterize the age-related patterns of appearance
      and frequency of hypoxanthine-guanine phosphoribosyl transferase (Hprt) mutant T
      lymphocytes in thymus and spleen following exposure of preweanling (12-day-old),
      weanling (22-day-old), and young adult (8-week-old) male B6C3F1 mice to
      ethylnitrosourea (ENU). Mice were given single i.p. injections of 0 or 40 mg
      ENU/kg and then groups of animals were necropsied from 2 h to 116 days after
      treatment to examine the relationships between exposure, cell loss and
      proliferation, and the frequency of Hprt mutant T cells in thymus and spleen.
      Hprt mutant frequency (Mf) data for thymus of ENU-exposed (0, 11.7, 35, 58, or 72
      mg/kg, or five weekly doses of 1.7 mg/kg i.p.) male C57BL/6 mice (12- or 62-week
      old), obtained during an earlier study of spleen cells [I.M. Jones, K. Burkhart
      Schultz, C.L. Strout, T.L. Crippen, Factors that affect the frequency of
      thioguanine-resistant lymphocytes in mice following exposure to ethylnitrosourea,
      Environ. Mutagen, 9 (1987) 317-329.], were compared to results in B6C3F1 mice.
      Isolated T cells were cultured in the presence of mitogen, growth factor, and 6
      thioguanine to detect Hprt mutants. The time required to achieve maximum Mfs in
      thymus was uniformly found at 2 weeks after ENU treatment, while the times needed
      to reach peak values in spleen were proportional to animal age at treatment.
      These data indicate that age-related differences in the appearance of Hprt mutant
      cells in spleen are largely defined by the physiologically based, age-dependent
      trafficking of mutant cells from or through the thymus. Three modes of handling
      the resulting Hprt Mf data were evaluated: (i) comparing the Mfs at a single time
      point, (ii) comparing the maximum Mfs observed, and (iii) comparing the change in
      Mfs over time (or the mutant T cell 'manifestation' curves in treated vs. control
      mice) in each age group post-exposure. Measuring the Mfs in spleen at multiple
      time points after cessation of exposure and integrating the frequency of mutants
      as a function of time appeared to be the superior method for comparing mutagenic
      responses in different age groups. Some of the underlying assumptions of this
      approach, as well as its strengths and weaknesses, are discussed.

PMID- 10636004
TI  - Measurement of HPRT mutations in splenic lymphocytes and haemoglobin adducts in
      erythrocytes of Lewis rats exposed to ethylene oxide.
AB  - Young adult male Lewis rats were exposed to ethylene oxide (EO) via single
      intraperitoneal (i.p.) injections (10-80 mg kg-1) or drinking water (4 weeks at
      concentrations of 2, 5, and 10 mM) or inhalation (50, 100 or 200 ppm for 4 weeks,
      5 days week-1, 6 h day-1) to measure induction of HPRT mutations in lymphocytes
      from spleen by means of a cloning assay. N-ethyl-N-nitrosourea (ENU) and N-(2
      hydroxyethyl)-N-nitrosourea (HOENU) were used as positive controls. Levels of N
      (2-hydroxyethyl)valine (HOEtVal) adducts in haemoglobin (expressed in nmol g-1
      globin) were measured to determine blood doses of EO (mmol kg-1 h, mM h). Blood
      doses were used as a common denominator for comparison of mutagenic effects of EO
      administered via the three routes. The mean HPRT mutant frequency (MF) of the
      historical control was 4.3 x 10(-6). Maximal mean MFs for ENU (100 mg kg-1) and
      HOENU (75 mg kg-1) were 243 x 10(-6) and 93 x 10(-6), respectively. In two
      independent experiments, EO injections led to a statistically significant dose
      dependent induction of mutations, with a maximal increase in MF by 2.3-fold over
      the background. Administration of EO via drinking water gave statistically
      significant increases of MFs in two independent experiments. Effects were, at
      most, 2.5-fold above the concurrent control. Finally, inhalation exposure also
      caused a statistically significant maximal increase in MF by 1.4-fold over the
      background. Plotting of mutagenicity data (i.e., selected data pertaining to
      expression times where maximal mutagenic effects were found) for the three
      exposure routes against blood dose as common denominator indicated that, at equal
      blood doses, acute i.p. exposure led to higher observed MFs than drinking water
      treatment, which was more mutagenic than exposure via inhalation. In the
      injection experiments, there was evidence for a saturation of detoxification
      processes at the highest doses. This was not seen after subchronic administration
      of EO. The resulting HPRT mutagenicity data suggest that EO is a relatively weak
      mutagen in T-lymphocytes of rats following exposure(s) by i.p. injection, in
      drinking water or by inhalation.

PMID- 10636005
TI  - Spontaneous and chemically induced point mutations in HPRT cDNA of the
      metabolically competent human lymphoblastoid cell line, MCL-5.
AB  - Thioguanine-resistant clones of the human lymphoblastoid cell, MCL-5, which
      carries two recombinant plasmids expressing xenobiotic metabolizing enzymes, were
      obtained spontaneously and after treatment with 0.1 microgram/ml benzo[a]pyrene
      (BaP), 1.0 microgram/ml 4-(N-nitrosomethylamino)-1-(3-pyridyl)-1-butanone (NNK),
      and 10 micrograms/ml cigarette smoke condensate (CSC). Treatment with the
      chemicals reduced the cloning efficiency (CE) of MCL-5 cells from about 30% in
      untreated cultures to about 10% after treatment with NNK and to about 1% or to
      less than 1% after treatment with CSC or BaP, respectively. At the same time, the
      mutant frequencies were increased about sevenfold above those of untreated
      cultures. Among a total of 138 independent mutant clones that had resulted from
      55 separate cultures, 60 point mutations were identified within the hypoxanthine
      guanine phosphoribosyltransferase (HPRT) reading frame by sequencing full-size
      reverse transcription polymerase chain reaction (RT-PCR) products from
      thioguanine-resistant clones. The identified 53 coding errors were distributed
      among 33 locations and types. Among the 30 types of single basepair substitutions
      leading to coding errors, 12 had not been described before. In the present set of
      point mutations, the distribution of base substitution types as well as of
      mutated sites appeared to be influenced by the treatment with the chemicals.
      Thus, the ratio of G to T transversions increased from 3 among 19 spontaneous
      point mutations in the HPRT coding region to 9 among 21 BaP-induced point
      mutations. The G119T and G208T transversions were found three times each,
      exclusively after treatment with BaP, while the accumulation of two to eight
      incidences of the G97T, CG142/3TA, C508T, T583A and G599A mutations was split
      among different treatments. All eight identified point mutations identified after
      NNK treatment were at G or T residues on either strand that were followed by
      additional G or T residues.

PMID- 10636006
TI  - Mutation induction by different types of radiation at the Hprt locus.
AB  - Mutation induction at the Hprt locus in Chinese hamster cells was studied after
      exposure to ultraviolet light, X-rays and alpha particles. While mutant frequency
      as a function of dose or fluence followed a linear-quadratic relationship with UV
      and X-rays, it showed a linear dependence for alpha particles. If mutant
      frequency is plotted vs. the logarithm of surviving fraction, a linear
      relationship is found in all cases although with different slopes. These are
      about equal with the two types of ionising radiations but about 10 times larger
      for UV. They can be used as a measure of mutagenic potential and are termed
      mutagenicity. It is shown that this parameter is correlated with the maximum of
      mutant yield, i.e., the number of mutants per cell at risk. It is concluded from
      this analysis that the maximum mutant yield is always found at doses or fluences
      which lead to 37% survival irrespective of the kind of radiation. If mutation
      induction is measured in X-irradiated cells after pre-exposure to UV, mutant
      frequency is higher than expected on the basis of independent action of the two
      radiations. Deletion spectra were determined by using multiplex polymerase chain
      reaction. It was found that the background of spontaneous mutants varied
      considerably and showed frequently repetitive patterns, presumably because of
      clonal expansion of pre-formed mutants. UV-induced mutants did not contain any
      deletions, while those with both X-rays and alpha particles the majority
      displayed partial and total deletions. Based on a total number of 134 X-ray- and
      192 alpha-induced mutants, it is concluded that the total fraction of mutant
      clones without deletions (partial or total) is about 40% for X-rays and only
      about 20% for alpha-particles.

PMID- 10636007
TI  - [Combined transplantation of liver and small intestine in an adult. First case in
      France. Surgical aspects].
AB  - BACKGROUND: We report hare the first adult case of combined liver-small bowel
      transplantation performed in France. CASE REPORT: A double liver + small bowel
      graft was transplanted in a 21-year-old patient hospitalized for 4 years for a
      short bowel syndrome requiring total parenteral nutrition. The patient also had
      severe hepatic fibrosis. The immediate post-operative period was uneventful. Two
      and one-half years after the double graft, the patient is on strictly oral
      nutrition, no longer has a stomy and lives a normal life in his home. DISCUSSION:
      The advent of tacrolimus has led to long-term success of bowel grafts, developed
      earlier in children and now possible in adults. Combined liver-small bowel
      transplantation is formally indicated in patients with cirrhogenic liver disease
      associated with ineversible small bowel failure.

PMID- 10636008
TI  - [Combined liver and small intestine transplantation in an adult. First case in
      France. Medical aspects: digestive and nutritional].
AB  - OBJECTIVE: We report the digestive, hepatic, intestinal and nutritional history
      of the first combined liver-small bowel transplantation performed in France in an
      adult recipient. Currently, the clinical course has been favorable at 30 months.
      METHODS: In May 1997, a 21-year-old man underwent a double liver-small bowel
      transplantation for irreversible chronic bowel failure with severe chronic liver
      disease subsequent to post-surgical short-bowel syndrome. After 28 laparotomies,
      there were 15 cm of small bowel left for the gastric anastomosis. The patient had
      a terminal jejunostomy and a left colostomy, excluding a short segment of the
      transverse colon and the rectum. Total parenteral nutrition including lipids and
      been initiated in December 1992 (3500 kcal/d) and had led to severe
      complications. Intestinal absorption before and after the graft were studied with
      the balance method (input-output) and used bomb calorimetry and measurements of
      the steatorhhea and creatorrhea. Functional enterocyte mass was assessed from
      serum citrullin. RESULTS: The postoperative period after the liver-bowel graft
      (220 cm small bowel with terminal ileostomy and jejunostomy) was uneventful. The
      immunosuppression protocol included tacrolimus, corticosteroids and azathioprin.
      One mild episode of acute rejection occurred at day 26 and was controlled with a
      corticosteroid bolus. No episode of liver rejection occurred. Moderate renal
      failure regressed partially after reestablishing the fluid-electrolyte balance
      and adapting tacrolimus dosage. Total parenteral nutrition which had sustained
      the patient for 4 and a half years was definitely discontinued three months after
      transplantation. Oral nutrition was initially associated with enteral nutrition
      (from day 20 to day 90) and became exclusive three months after the
      transplantation. Intestinal absorption coefficients measured before
      tranplantation, at 3 months (2200 kcal/d, ileostomy flow 1600 g/d), and at 18
      months (2400 kcal/d, ileostomy flow 1300 g/d) post transplantation were,
      respectively, 22%, 90% and 88% for overall calorie absorption, 25%, 65% and 73%
      for fat absorption, and 47%, 83% and 67% for nitrogen absorption. At 18 months
      post-graft, there was a spectacular improvement in the patient's neurological
      status and his liver function was normal. Endoscopy, radiography, histology, and
      immunohistochemistry explorations were normal. Ileo-rectal anastomosis was re
      established at 23 months post-transplantation. At 30 months the patient is living
      in his home and on 100% oral nutrition. CONCLUSION: Clinical, nutritional and
      functional outcome at 30 months in this first French case of liver-small bowel
      transplantation in an adult recipient has been excellent.

PMID- 10636009
TI  - [An unusual cause of long-term fever: Behcet disease].
AB  - BACKGROUND: Behcet's disease is an uncommon cause of prolonged fever. This
      misleading presentation is illustrated by a new case where fever occurred after
      polyvalent vaccination. CASE REPORT: A 39-year-old female patient was seen for
      prolonged fever after returning from a trip to Africa. She had received
      polyvalent vaccinations prior to leaving France. At admission fever had persisted
      for 2 months. The diagnosis of Behcet's disease was finally established on the
      basis of clinical signs, buccogenital aphtosis and pathergy. Colchicine was
      partially effective against although low-grade persisted in the evening.
      DISCUSSION: Clinicians should be aware that Behcet's disease can provoke long
      term fever which can sometimes be an inaugural sign. Sensitivity tests may be
      useful to identify the trigger, for example polyvalent vaccination.

PMID- 10636010
TI  - [Myiasis caused by Dermatoba hominis after an organized tours in Amazonia].
AB  - BACKGROUND: Human cutaneous myiasis is a common disease in endemic tropical
      zones. The incidence of imported cases follows the development of organized tours
      in the tropics. CASE REPORTS: We report 2 cases of Dermatobia hominis furonculoid
      myiasis in patients who took 2 different organized tours which both visited the
      same Amazonian site in Peru (Puerto Maldonado). DISCUSSION: In Latin American
      countries, D. hominis myiasis is transmitted by Diptera (generally mosquitos,
      rarely flies) who carry eggs laid by an adult fly to man. This phenomena is
      called "phoresia" and explains the preferential localization of lesions in
      exposed areas unlike African myiasis caused by Cordylobia anthropophaga which
      contaminates clothing soiled when drying.

PMID- 10636011
TI  - [Eosinophilic folliculitis associated with AIDS after antiretroviral tri
      therapy].

PMID- 10636012
TI  - [Psoriatic rheumatism in a patient taking interferon alpha, reversible with
      treatment cessation].

PMID- 10636013
TI  - [Pre-hospitalization underestimation of the potential severity of generalized
      seizures].

PMID- 10636014
TI  - [Rheumatoid purpura in a patient with pulmonary tuberculosis].

PMID- 10636015
TI  - [Pseudohypoparathyroidism due to magnesium deficiency].

PMID- 10636016
TI  - [Do we have to "declare war" on obesity?].

PMID- 10636017
TI  - [Small bowel graft in adults: a real breakthrough].

PMID- 10636019
TI  - [In Process Citation]

PMID- 10636018
TI  - [Standards, options and recommendations for the management of adult patients with
      Hodgkin disease. Standards, Options and Recommendations (SOR) in Cancerology.
      Groupe d'Etude des Lymphomes de l'Adulte]].

PMID- 10636020
TI  - [Subcutaneous perfusion of hypodermoclysis: a useful rehydration method in
      geriatrics].
AB  - A USEFUL TECHNIQUE IN GERIATRICS: Older people are at high risk of dehydration.
      In common practice, oral intakes are often inadequate. Intravenous infusion may
      be difficult and may generate complications. Hypodermoclysis or subcutaneous
      infusion is a useful technique for the prevention or cure of moderate dehydration
      in the older subjects. MANY ADVANTAGES AND FEW RISKS: When it is used correctly
      (i.e. volume and type of solutions, aseptic conditions) and when its
      contraindications are respected (i.e. emergency situations), hypodermoclysis is a
      simple technique that is safe, effective and comfortable. It does not need
      intensive surveillance and can be used both at home or in an institution, thus
      avoiding hospitalization of older subjects. A TECHNIQUE THAT SHOULD BE DEVELOPED:
      The numerous advantages of hypodermoclysis in older patients should encourage its
      wider use in geriatrics.

PMID- 10636021
TI  - [Molecular pathways of T lymphocyte activation].
AB  - TRIGGERING T CELL ACTIVATION: A quiescent T cell must encounter an antigen
      presenting cell to become activated. The T receptor for the antigen delivers a
      first specific signal which alone is insufficient to trigger total T cell
      activation. A second signal independent of antigen recognition is furnished by
      the antigen presenting cell, leading to total activation. PATHWAYS CAPABLE OF
      DELIVERING THE SECOND SIGNAL: CD28 and CTLA-4 are two molecules capable of
      playing a powerful role in regulating immune response. The fate of B cells
      depends on the CD40 molecule they carry on their surface as well as on T cells
      which express its ligand. Adherence molecules CD11a/CD18 induce tight adherence
      between T cells and antigen presenting cells by binding their CD50 ligand (ICAM
      3); this bond activates the T cell, completing the first signal. The CD2 pathway
      and its ligands, a constitutional expression on two partner cells, is a strong
      adherence pathway which also transmits two powerful activation signals for T
      cells. SEVERAL FUNCTIONAL STATES: These different activation pathways illustrate
      the subtle interaction between surface molecules, capable of inducing different
      functional states depending on the environment.

PMID- 10636022
TI  - [Lactic acidosis and multi-organ failure secondary to anti-retroviral therapy in
      HIV-infected patients].
AB  - A SERIOUS COMPLICATION: Antiretroviral therapy may induce severe lactic acidosis
      with multiorgan failure in HIV-infected patients. CLINICAL DESCRIPTION: Patients
      are admitted for onset of dyspnea, abdominal pain, nausea, vomiting or diarrhea,
      with weight loss and general fatigue over the past few days. Physical findings
      are usually not contributive except for constant presence of hepatomegaly.
      Laboratory examinations reveal severe metabolic acidosis with increased anion gap
      and serum lactate elevation. Perturbations of hepatic and pancreatic enzyme
      values may exist. Echotomography and CT scan demonstrate fatty liver, confirmed
      by histological examination of the biopsy. Outcome in the intensive care unit is
      generally multiorgan failure and death. Symptomatic treatments, mechanical
      ventilation, bicarbonate infusion or hemodialysis appear to be ineffective in
      most severe cases. PATHOPHYSIOLOGY: Antiretroviral nuceloside analogs are
      inhibitors of mitochondrial DNA polymerase gamma. This explains the dysfunction
      of the mitochondrial respiratory chain, leading to inhibition of lactate
      metabolism in the liver and enhancement of serum lactate and acetone body levels.
      Elevation of lactate/pyruvate and beta-hydroxybutyrate/acetoacetate ratios
      suggest mitochondrial dysfunction. Many other co-factors may be associated.
      THERAPEUTIC APPROACH: Several therapeutic strategies (thiamine, coenzyme <Aucun>
      Q, carnitine and riboflavin) have been tried. They rely on the pathophysiological
      hypothesis that sustained cellular dysfunctions cause this clinical syndrome.

PMID- 10636023
TI  - [Diffusion in bone tissue of antibiotics].
AB  - DIFFICULT ASSESSMENT: Bone and joint infections are difficult to treat.
      Therapeutic success depends greatly on the diffusion of antibiotics into bone
      tissue. Few studies have been devoted to this subject and the variable nature of
      those reported hinders interpretation. Bone biopsies are generally obtained
      during orthopedic procedures. Antibiotic administration routes vary although
      intravenous infusion predominates. Agar gel diffusion is generally used for
      antibiotic assays but methodology varies depending of the study. The most recent
      reports use high-performance liquid chromatography. DIFFUSION STUDIES: The
      different studies examining antibiotic diffusion in bone tissue describe three
      classes: good diffusion (greater than 30%), moderate diffusion (between 15% and
      30%), and low diffusion (less than 15%). Antibiotics in the good diffusion class
      include fluoroquinolones, teicoplanin, macrolides, rifampicin and trimethoprime.
      Antibiotics with moderate bone diffusion are ureidopenicillins, second and third
      generation cephalosporins, aminoglycosides, clindamycin, fosfomycin and
      vancomycin. Those with low bone diffusion are aminopenicillins, penicillin M and
      first generation cephalosporins. No data is available on the bone diffusion of
      pristinamycin. DATA INTERPRETATION: The clinical impact of these classifications
      must be interpreted with precaution when considering bone and joint infections as
      they were established on the basis of pharmacokinetic studies and not clinical
      trials. They would however appear to be useful in guiding antibiotic prophylaxis
      for orthopedic surgery in protocols with administration conditions and
      concentration goals similar to the experimental conditions. PRACTICAL ATTITUDES:
      These laboratory results could be used in clinical practice by comparing the
      MIC50 of the germs regularly encountered in bone infections (staphylococci,
      streptococci including enterococci, Gram negative bacilli including P. aeruginosa
      and H. influenzae) with concentrations obtained in the different studies, i.e. by
      calculating the inhibitor coefficient (IQ) of each antibiotic for each
      susceptible germ. This gives a classification by efficacy (excellent IQ > 10,
      good 1 < IQ < 10, poor IQ < 1) useful for guiding antibiotic choice in the
      difficult situation of bone and joint infection.

PMID- 10636024
TI  - [Images in medicine. Foreign bodies in in the colon extracted by endoscopy].

PMID- 10636025
TI  - The evolution of cellular computing: nature's solution to a computational
      problem.
AB  - How do cells and nature 'compute'? They read and 'rewrite' DNA all the time, by
      processes that modify sequences at the DNA or RNA level. In 1994, Adleman's
      elegant solution to a seven-city directed Hamiltonian path problem using DNA
      launched the new field of DNA computing, which in a few years has grown to
      international scope. However, unknown to this field, two ciliated protozoans of
      the genus Oxytricha had solved a potentially harder problem using DNA several
      million years earlier. The solution to this problem, which occurs during the
      process of gene unscrambling, represents one of nature's ingenious solutions to
      the problem of the creation of genes. RNA editing, which can also be viewed as a
      computational process, offers a second algorithm for the construction of
      functional genes from encrypted pieces of the genome.

PMID- 10636026
TI  - A biomolecular implementation of logically reversible computation with minimal
      energy dissipation.
AB  - Energy dissipation associated with logic operations imposes a fundamental
      physical limit on computation and is generated by the entropic cost of
      information erasure, which is a consequence of irreversible logic elements. We
      show how to encode information in DNA and use DNA amplification to implement a
      logically reversible gate that comprises a complete set of operators capable of
      universal computation. We also propose a method using this design to connect, or
      'wire', these gates together in a biochemical fashion to create a logic network,
      allowing complex parallel computations to be executed. The architecture of the
      system permits highly parallel operations and has properties that resemble well
      known genetic regulatory systems.

PMID- 10636027
TI  - Progress toward demonstration of a surface based DNA computation: a one word
      approach to solve a model satisfiability problem.
AB  - A multi-base encoding strategy is used in a one word approach to surface-based
      DNA computation. In this designed DNA model system, a set of 16 oligonucleotides,
      each a 16mer, is used with the format 5'-FFFFvvvvvvvvFFFF-3' in which 4-8 bits of
      data are stored in eight central variable ('v') base locations, and the remaining
      fixed ('F') base locations are used as a word label. The detailed implementations
      are reported here. In order to achieve perfect discrimination between each
      oligonucleotide, the efficiency and specificity of hybridization discrimination
      of the set of 16 oligonucleotides were examined by carrying out the hybridization
      of each individual fluorescently tagged complement to an array of 16 addressed
      immobilized oligonucleotides. A series of preliminary hybridization experiments
      are presented and further studies about hybridization, enzymatic destruction,
      read out and demonstrations of a SAT problem are forthcoming.

PMID- 10636028
TI  - Chess games: a model for RNA based computation.
AB  - Here we develop the theory of RNA computing and a method for solving the 'knight
      problem' as an instance of a satisfiability (SAT) problem. Using only biological
      molecules and enzymes as tools, we developed an algorithm for solving the knight
      problem (3 x 3 chess board) using a 10-bit combinatorial pool and sequential
      RNase H digestions. The results of preliminary experiments presented here reveal
      that the protocol recovers far more correct solutions than expected at random,
      but the persistence of errors still presents the greatest challenge.

PMID- 10636029
TI  - New computing paradigms suggested by DNA computing: computing by carving.
AB  - Inspired by the experiments in the emerging area of DNA computing, a somewhat
      unusual type of computation strategy was recently proposed by one of us: to
      generate a (large) set of candidate solutions of a problem, then remove the non
      solutions such that what remains is the set of solutions. This has been called a
      computation by carving. This idea leads both to a speculation with possible
      important consequences--computing non-recursively enumerable languages--and to
      interesting theoretical computer science (formal language) questions.

PMID- 10636030
TI  - Algebraic properties of DNA operations.
AB  - Any DNA strand can be identified with a word in the language X* where X=?A, C, G,
      T?. By encoding A as 000, C as 010, G as 101, and T as 111, we treat the DNA
      operations concatenation, union, reverse, complement, annealing and melting, from
      the algebraic point of view. The concatenation and union play the roles of
      multiplication and addition over some algebraic structures, respectively. Then
      the rest of the operations turn out to be the homomorphisms or anti-homomorphisms
      of these algebraic structures. Using this technique, we find the relationship
      among these DNA operations.

PMID- 10636031
TI  - The bounded complexity of DNA computing.
AB  - This paper proposes a new approach to analyzing DNA-based algorithms in molecular
      computation. Such protocols are characterized abstractly by: encoding, tube
      operations and extraction. Implementation of these approaches involves encoding
      in a multiset of molecules that are assembled in a tube having a number of
      physical attributes. The physico-chemical state of a tube can be changed by a
      prescribed number of elementary operations. Based on realistic definitions of
      these elementary operations, we define complexity of a DNA-based algorithm using
      the physico-chemical property of each operation. We show that new algorithms for
      Hamiltonian path are about twice as efficient as Adleman's original one and that
      a recent algorithm for Max-Clique provides a similar increase in efficiency.
      Consequences of this approach to tube complexity and DNA computing are discussed.

PMID- 10636032
TI  - A universal time-varying distributed H-system of degree 2.
AB  - A time-varying distributed H system is a splicing system which has the following
      feature: at different moments one uses different sets of splicing rules. The
      number of these sets is called the degree of the system. The passing from a set
      of rules to another one is specified in a cycle. It is a well known fact that any
      formal language can be generated by a time-varying distributed H-system of degree
      at least 7. Here we prove that there are universal time-varying distributed H
      systems of degree 2. The question of whether or not there are universal time
      varying distributed H-systems of degree 1 remains open.

PMID- 10636034
TI  - Design and implementation of computational systems based on programmed
      mutagenesis.
AB  - In a new system for DNA computation called programmed mutagenesis, DNA strands
      are rewritten according to 'rules' that are sequence specific. In a programmed
      mutagenesis reaction DNA sequences undergo programmed changes, and these changes
      are implemented by an in-vitro mutagenesis system that is based on thermal
      cycling the rewriting reaction. We describe experimental results that demonstrate
      the key aspects of programmed mutagenesis. These results include the creation of
      full-length product DNA molecules that have embedded rewriting, the ability for
      later sequence changes to depend on earlier sequence changes, and the ability for
      multiple oligonucleotides to be active in close proximity on a template sequence.
      We also discuss the application of programmed mutagenesis to computational
      problems.

PMID- 10636033
TI  - State transitions by molecules.
AB  - In our previous paper, we described a method by which a state machine is
      implemented by a single-stranded DNA molecule whose 3'-end sequence encodes the
      current state of the machine. Successive state transitions are performed in such
      a way that the current state is annealed onto an appropriate portion of DNA
      encoding the transition table of the state machine and the next state is copied
      to the 3'-end by extension with polymerase. In this paper, we first show that
      combined with parallel overlap assembly, a single series of successive
      transitions can solve NP-complete problems. This means that the number of
      necessary laboratory steps is independent from the problem size. We then report
      the results of two experiments concerning the implementation of our method. One
      is on isothermal reactions which greatly increase the efficiency of state
      transitions compared with reactions controlled by thermal cycles. The other is on
      the use of unnatural bases for avoiding out-of-frame annealing. The latter result
      can also be applied to many DNA-based computing paradigms.

PMID- 10636035
TI  - Molecular and evolutionary computation: the tug of war between context freedom
      and context sensitivity.
AB  - Proteins and nucleic acids constitute a vast potential reservoir of pattern
      recognizers that operate on the basis of shape complementarity. It is possible to
      construct models of computing in which these shape-based interactions contribute
      directly to recognition of signal patterns at the device (or cell) level. The
      input-output transform is molded by variation-selection evolution. Such models
      provide clues as to the organizational features that enable biomolecular matter
      to acquire nonevolutionary modes of problem solving through the evolutionary
      process. The requisite organizations are characterized by a high dimensionality
      that allows them to simultaneously exhibit aspects of context-sensitivity and
      context-independence.

PMID- 10636036
TI  - Elements of a more comprehensive theory of computing.
AB  - Problems implementing DNA computers stem from the physical nature of molecules
      and their reactions. The present theory of computation requires assumptions that,
      at best, are extremely crude approximations of the physical chemistry. Here, I
      consider the hypothesis that discarding those assumptions in favor of more
      physically realistic descriptions would produce a more comprehensive theory of
      computing, yielding both theoretical insights and help in designing better
      molecular computers. I describe the discordances between the theories of physical
      biochemistry and computation, indicate some elements of a more comprehensive
      theory, and discuss some of the challenges the construction of a unified theory
      faces.

PMID- 10636037
TI  - The cell as the smallest DNA-based molecular computer.
AB  - The pioneering work of Adleman (1994) demonstrated that DNA molecules in test
      tubes can be manipulated to perform a certain type of mathematical computation.
      This has stimulated a theoretical interest in the possibility of constructing DNA
      based molecular computers. To gauge the practicality of realizing such
      microscopic computers, it was thought necessary to learn as much as possible from
      the biology of the living cell--presently the only known DNA-based molecular
      computer in existence. Here the recently developed theoretical model of the
      living cell (the Bhopalator) and its associated theories (e.g. cell language),
      principles, laws and concepts (e.g. conformons, IDS's) are briefly reviewed and
      summarized in the form of a set of five laws of 'molecular semiotics' (synonyms
      include 'microsemiotics', 'cellular semiotics', or 'cytosemiotics') the study of
      signs mediating measurement, computation, and communication on the cellular and
      molecular levels. Hopefully, these laws will find practical applications in
      designing DNA-based computing systems.

PMID- 10636038
TI  - On solving 3CNF-satisfiability with an in vivo algorithm.
AB  - Several in vitro DNA algorithms have been proposed in the literature for solving
      various combinatorial search problems. The next logical step is the critical
      examination of whether or not such computation can be performed within the
      cellular environment. We consider the possibility of solving 3-conjunctive-normal
      form Satisfiability with one possible in vivo algorithm. The exact biological
      details still remain to be defined and seem beyond the capabilities of current
      technologies, but perhaps, this will serve as a springboard for further
      theoretical inquiry into in vivo approaches.

PMID- 10636039
TI  - Three dimensional DNA structures in computing.
AB  - We show that 3-dimensional graph structures can be used for solving computational
      problems with DNA molecules. Vertex building blocks consisting of k-armed (k = 3
      or 4) branched junction molecules are used to form graphs. We present procedures
      for the 3-SAT and 3-vertex-colorability problems. Construction of one graph
      structure (in many copies) is sufficient to determine the solution to the
      problem. In our proposed procedure for 3-SAT, the number of steps required is
      equal to the number of variables in the formula. For the 3-vertex-colorability
      problem, the procedure requires a constant number of steps regardless of the size
      of the graph.

PMID- 10636040
TI  - Length bounded molecular computing.
AB  - The length of DNA strands is an important resource in DNA computing. We show how
      to decrease strand lengths in known molecular algorithms for some NP-complete
      problems, such as like 3-SAT and Independent Set, without substantially
      increasing their running time or volume.

PMID- 10636041
TI  - DNA implementation of addition in which the input strands are separate from the
      operator strands.
AB  - A DNA representation of Boolean logic for which the input strands are separate
      from the operator strands is described and used to construct a two-bit DNA adder.
      The successful operation of the adder for several test inputs demonstrates that
      digital molecular computation with a complexity of order 30 gates is feasible.

PMID- 10636042
TI  - Article for analog vector algebra computation.
AB  - We introduce the concept of an analog neural network represented by chemical
      operations performed on strands of DNA. This new type of DNA computing has the
      advantage that it should be fault tolerant and thus more immune to DNA
      hybridization errors than a Boolean DNA computer. We describe a particular set of
      DNA operations to effect the interconversion of electrical and DNA data and to
      represent the Hopfield associative memory and the feed-forward neural network of
      Rumelhart et al. We speculate that networks containing as many as 10(9) neurons
      might be feasible.

PMID- 10636043
TI  - Ligation errors in DNA computing.
AB  - DNA computing is a novel method of computing proposed by Adleman (1994), in which
      the data is encoded in the sequences of oligonucleotides. Massively parallel
      reactions between oligonucleotides are expected to make it possible to solve huge
      problems. In this study, reliability of the ligation process employed in the DNA
      computing is tested by estimating the error rate at which wrong oligonucleotides
      are ligated. Ligation of wrong oligonucleotides would result in a wrong answer in
      the DNA computing. The dependence of the error rate on the number of mismatches
      between oligonucleotides and on the combination of bases is investigated.

PMID- 10636044
TI  - Surface-based DNA computing operations: DESTROY and READOUT.
AB  - DNA computing on surfaces is where complex combinatorial mixtures of DNA
      molecules are immobilized on a substrate and subsets are tagged and enzymatically
      modified (DESTROY) in repeated cycles of the DNA computation. A restriction
      enzyme has been chosen for the surface DESTROY operation. For the READOUT
      operation, both cycle sequencing and PCR amplification followed by addressed
      array hybridization were studied to determine the DNA sequences after the
      computations.

PMID- 10636045
TI  - Counting DNA: estimating the complexity of a test tube of DNA.
AB  - We consider the problem of estimation of the 'complexity' of a test tube of DNA.
      The complexity of a test tube is the number of different kinds of strands of DNA
      in the test tube. It is quite easy to estimate the number of total strands in a
      test tube, especially if the strands are all the same length. Estimation of the
      complexity is much less clear. We propose a simple kind of DNA computation that
      can estimate the complexity.

PMID- 10636046
TI  - Micro flow bio-molecular computation.
AB  - In this paper we provide a model for micro-flow based bio-molecular computation
      (MF-BMC). It provides an abstraction for the design of algorithms which account
      for the constraints of the model. Our MF-BMC model uses abstractions of both the
      recombinant DNA (RDNA) technology as well as of the micro-flow technology and
      takes into account both of their limitations. For example, when considering the
      efficiency of the recombinant DNA operation of annealing, we take into account
      the limitation imposed by the concentration of the reactants. The fabrication
      technology used to construct MEMS is limited to constructing relatively thin 3D
      structures. We abstract this by limiting the model to a small constant number of
      layers (as is done with VLSI models). Besides our contribution of the MF-BMC
      model, the paper contains two other classes of results. The main result is the
      volume and time efficient algorithm for message routing in the MF-BMC model,
      specifically useful for PA-Match. We will show that routing of strands between
      chambers will occur in time O(N x D/ m x n), where N is the number of strands in
      the MF-BMC, n is the number of chambers where RDNA operations are occurring, D is
      the diameter of the topology of the layout of the chambers, and m is proportional
      to the channel width. Operations that need annealing, such as PA-Match, are shown
      feasible in O(N2logN/n/n) volume instead of the previous use of omega(N2) volume,
      with reasonable time constraints. Applications of the volume efficient algorithm
      include the use of the Join operation for databases, logarithmic depth solutions
      to SAT (Boolean formula satisfiability) problems and parallel algorithms that
      execute on a PRAM. Existent algorithms can be mapped to ones that work
      efficiently in the MF-BMC model, whereas previous methods for applications such
      as PRAM simulation in BMC were not both time and volume efficient. Our other
      class of results are theoretical lower bounds on the quantities of DNA and the
      time needed to solve a problem in the MF-BMC model, analogous to lower bounds in
      VLSI. We bound the product BT from below, and further show that BT2 has a
      stronger lower bound of I2. Here B is the maximum amount of information encoded
      in the MF-BMC system at a time. T is the time for an algorithm to complete, and I
      is the information content of a problem.

PMID- 10636047
TI  - An O(2n) volume molecular algorithm for Hamiltonian path.
AB  - We design volume-efficient molecular algorithms for all problems in #P, using
      only reasonable biological operations. In particular, we give a polynomial-time
      0(2(n)n2log2n)-volume algorithm to compute the number of Hamiltonian paths in an
      n-node graph. This improves Adleman's celebrated n!-volume algorithm for finding
      a single Hamiltonian path.

PMID- 10636048
TI  - Automated constraint-based nucleotide sequence selection for DNA computation.
AB  - We present techniques for automating the design of computational systems built
      using DNA, given a set of high-level constraints on the desired behavior and
      performance of the system. We have developed a program called SCAN that exploits
      a previously implemented computational melting temperature primitive to search a
      'nucleotide space' for sequences satisfying a pre-specified set of constraints,
      including hybridization discrimination, primer 5' end and 3' end stability,
      secondary structure reduction, and prevention of oligonucleotide dimer formation.
      The first version of SCAN utilized 24 h of computer time to search a space of
      over 7.5 billion unary counter designs and found only nine designs satisfying all
      of the pre-specified constraints. One of SCAN's designs has been implemented in
      the laboratory and has shown a marked improvement in performance over the
      products of previous attempts at manual design. We conclude with some novel ideas
      for improving the overall speed of the program that offer the promise of an
      efficient method for selecting optimal nucleotide sequences in an automated
      fashion.

PMID- 10636049
TI  - A simple estimated fetal weight equation for fetuses between 24 and 34 weeks of
      gestation.
AB  - OBJECTIVE: To develop a mathematical equation that is simple, accurate and easy
      to use when applied to low-birth weight or preterm fetuses (< 35 weeks) and to
      assess previous normal ultrasonic fetal weight curves and make a comparison with
      normal fetal delivery weight curves. METHOD: In a large teaching hospital, 269
      pregnant mothers were identified by the criteria of normalities, such as: well
      known LMP, regular menstrual cycles, no use of OCP for the last 3 months, no
      smoking and no history of diabetes. Birth-weight measurements (adjusted for
      maternal age, baby's sex, parity and week of gestation) were taken immediately
      after birth. RESULTS: Mean gestational age and mean birth' weight + S.D. were
      29.5 + 3.02 weeks and 1530.238 237.856 g, respectively. With the aid of a
      scientific calculator the data were analyzed and a simple regression equation has
      been derived: EFW (kg) = 0.17 (G.A. - 20), S.D. - 235 g (Honarvar's Formula 1).
      CONCLUSION: For estimating weights of preterm or low-birth weight fetuses of less
      than 2500 g, this simple equation appears to be clinically reliable and easy to
      use and suggests that previous normal ultrasonic fetal weight curves may
      underestimate or overestimate normal fetal delivery weight between the 24th and
      34th week of gestation. Our formula approximates actual birth weight better and
      recommends Ott's ultrasonic weight curve for Iranian population.

PMID- 10636050
TI  - Predictive score for the systemic treatment of unruptured ectopic pregnancy with
      a single dose of methotrexate.
AB  - OBJECTIVE: To evaluate the efficacy of a predictive score for the systemic
      treatment of unruptured ectopic pregnancy with a single dose of methotrexate in
      order to select the best cases for the medical treatment. METHOD: Our study
      included 40 patients. The inclusion criteria were: hemodynamic stability; adnexal
      mass < or = 3.5 cm; desire of future pregnancy; and a written permission to
      participate in the study. All patients were treated with a single dose of
      methotrexate (50 mg/m2 i.m.). A predictive score was elaborated based on four
      parameters: initial levels of beta-hCG, aspects of the image at ultrasound
      (hematosalpinx, tubal ring or live embryo), size of the mass, vascular flow of
      the color Doppler. Each parameter received a grade from 0 to 2. Grade 0
      represented an unfavorable situation, grade 1 a borderline situation and grade 2
      a favorable situation. RESULTS: The success rate with a single dose of
      methotrexate was 75% (30/40). In the present study the cut off grade was 5,
      because the majority of patients with grade > or = 5 were treated successfully
      (29/30 - 97%), while those with grade < 5 failed. CONCLUSION: The predictive
      score helps us to indicate the best cases for the medical treatment. Therefore,
      we do not advise it when the grade is < 5. However, we can predict a good
      evolution of the treatment when the grade is > or = 5. Federation of Gynecology
      and Obstetrics.

PMID- 10636051
TI  - Saline sonohysterography for monitoring asymptomatic postmenopausal breast cancer
      patients taking tamoxifen.
AB  - OBJECTIVES: To evaluate the effectiveness of sonohysterography for monitoring
      asymptomatic postmenopausal breast cancer patients on long-term tamoxifen
      therapy. METHODS: Thirty-eight asymptomatic postmenopausal patients receiving
      tamoxifen for breast cancer were enrolled into the study. The endometrium of
      study subjects was measured by transvaginal ultrasound. If a distinct echo
      measured < or = 5 mm, no further procedure was performed. For thickened or
      inadequately visualized endometrium by transvaginal ultrasound (TVS),
      sonohysterography was performed. Endometrial biopsies were performed for patients
      with generalized symmetrical changes on sonohysterography. In cases with focal
      changes, or inadequate SHG, hysteroscopy/dilatation and curettage (D&C) were
      performed. RESULTS: Transvaginal ultrasound examination showed 12 (31.6%)
      patients with thin endometrium < or = 5 mm, 18 (47.4%) cases with thickened
      endometrium while eight (21%) cases were not adequately visualized by TVS.
      Sonohysterography was satisfactorily performed in 22 of 26 (84.6%) cases. Of
      these, three cases showed thin endometrium, 10 patients had endometrial polyps
      (45.5%) and nine patients showed abnormal endometrial-myometrial junction.
      Histology revealed hyperplasia in three cases and well differentiated
      adenocarcinoma associated with one polyp. Endometrial curettage for cases with
      abnormal endometrial-myometrial junction showed endometrial hyperplasia in two
      cases. Hysteroscopy and D&C were performed for four (15.4%) patients where SHG
      was unsuccessful, histopathology revealed inactive endometrium in three cases and
      one was hyperplastic. CONCLUSIONS: Sonohysterography is superior to unenhanced
      transvaginal sonography in specifying the abnormal ultrasonographic appearance
      induced by prolonged tamoxifen therapy, it is easily performed, cost-effective
      and very well tolerated by the patients with no complications. Sonohysterography
      is recommended as a minimally invasive diagnostic tool for the assessment of
      endometrial changes in asymptomatic postmenopausal breast cancer patients on long
      term tamoxifen therapy with thickened endometrium or inadequately visualized
      endometrial echo on transvaginal sonography.

PMID- 10636052
TI  - Risk factors for cervical squamous intraepithelial lesions among HIV-1
      seropositive women in Dar es Salaam, Tanzania.
AB  - OBJECTIVES: To determine the prevalence and risk factors for cervical squamous
      intraepithelial lesions (SIL) among HIV-infected women in Dar es Salaam,
      Tanzania. METHODS: Between July 1996 and December 1997 we interviewed 691 HIV
      infected women to obtain information about risk factors for SIL. Cervical smears
      and samples for lymphocyte subsets and sexually transmitted diseases (STD)
      diagnosis were collected. RESULTS: The prevalence of SIL was 2.9% (20/686) (95%
      CI = 1.7-4.2%). Eleven women had low-grade SIL while nine women had high-grade
      SIL. The number of lifetime sexual partners and live births was associated with a
      marginally non-significant increased risk of SIL. The risk of SIL was
      significantly increased among women with CD4+ cell count < 200/mm3 (multivariate
      odds ratio (OR) = 6.15, 95% CI = 1.19-41.37) and decreased by 68% for each 5-cm
      increase in mid-upper arm circumference (multivariate OR = 0.32, 95% CI = 0.10
      0.93). CONCLUSIONS: HIV-related immunosuppression and wasting and long-term
      sexual behavior were the major determinants of SIL in this population. Federation
      of Gynecology and Obstetrics.

PMID- 10636053
TI  - Prenatal sonographic features of sacrococcygeal teratoma.
AB  - OBJECTIVE: To describe the potential role of ultrasound in prenatal diagnosis of
      fetal sacrococcygeal teratoma (SCT). SUBJECTS: A total of four fetuses with
      prenatal diagnosis of SCT were sonographically evaluated and followed-up.
      RESULTS: Fetal SCT was diagnosed at 13, 17, 26 and 27 weeks of gestation. Three
      of them had predominantly solid tumors with scattered cystic areas, whereas the
      other one had an entirely cystic tumor. One had a rapid growth tumor and finally
      developed early hydrops. Three had polyhydramnios and delivered prematurely. The
      diagnosis was posnatally confirmed in all cases. In the case with the large
      tumor, a cesarean section was done to avoid traumatic delivery. Two cases
      survived and the tumors were successfully resected, whereas the others died due
      to heart failure secondary to hydrops in one case and prematurity in the other
      one. CONCLUSION: This small series suggests that SCT be readily diagnosed in
      utero, possibly as early as first trimester. The important clue was an abnormal
      mass in the sacrococcygeal area. The prenatal diagnosis can contribute to changes
      in clinical decision.

PMID- 10636054
TI  - Maternal mortality from obstructed labor in south-eastern Nigeria: the role of
      spiritual churches.

PMID- 10636055
TI  - Hemoperitoneum secondary to pelvic endometriosis in pregnancy.

PMID- 10636056
TI  - Laparoscopic approach and color Doppler findings of borderline ovarian tumors.

PMID- 10636057
TI  - Trochar site metastasis after laparoscopic pelvic lymphadenectomy for cervical
      squamous cell carcinoma.

PMID- 10636058
TI  - Infertility in Kuwait.

PMID- 10636059
TI  - Suction curettage in early pregnancy utilizing transrectal sonography and a
      curved metal cannula.

PMID- 10636060
TI  - ACOG practice bulletin: Thrombocytopenia in pregnancy. Number 6, September 1999.
      Clinical management guidelines for obstetrician-gynecologists. American College
      of Obstetricians and Gynecologists.
AB  - Thrombocytopenia in pregnant women is diagnosed frequently by obstetricians
      because platelet counts are now included with automated complete blood cell
      counts (CBCs) obtained during routine prenatal screening (1). The condition is
      common, occurring in 7-8% of pregnancies (2). Thrombocytopenia can result from a
      variety of physiologic or pathologic conditions, several of which are unique to
      pregnancy. Some causes of thrombocytopenia are serious medical disorders that
      have the potential for profound maternal and fetal morbidity. In contrast, other
      conditions, such as gestational thrombocytopenia, are benign and pose no maternal
      or fetal risks. Because of the increased recognition of maternal and fetal
      thrombocytopenia, there are numerous controversies regarding obstetric
      management. Clinicians must weigh the risks of maternal and fetal bleeding
      complications against the costs and morbidity of diagnostic tests and invasive
      interventions.

PMID- 10636061
TI  - Managing the uninvestigated dyspeptic patient.

PMID- 10636062
TI  - Splenic-vein thrombosis complicating chronic pancreatitis.

PMID- 10636063
TI  - Endoscopic ultrasonography in the preoperative staging of adenocarcinoma of the
      distal oesophagus and oesophagogastric junction.
AB  - BACKGROUND: Endoscopic ultrasonography is considered to be the most accurate
      procedure in the preoperative staging of oesophageal carcinoma. Its accuracy was
      evaluated in the preoperative staging of adenocarcinoma of the distal oesophagus
      and oesophagogastric junction. METHODS: Thirty-two consecutive patients with
      adenocarcinoma of the distal oesophagus and oesophagogastric junction were
      preoperatively examined and staged by means of endoscopic ultrasonography. All
      patients underwent radical en bloc resection of the oesophagus and proximal
      stomach (or total gastrectomy) with standard lymphadenectomy including thoracic
      duct and mediastinal fat tissue. The postoperative histopathologic TNM stage was
      taken as reference. RESULTS: An endoscopic ultrasonography examination could be
      completed in 26 of the patients; the other 6 had obstructive tumour. In two
      patients infiltration of the tumour into the vital organs (in one patient aortic
      infiltration and in a second patient pericardial infiltration) was incorrectly
      suspected. The ability to predict T stage was 65.6%. T stage was overstaged in
      31.2% and understaged in 3.1% of the cases. The ability to predict N stage was
      71.9%. N stage was overstaged in 25.0% and understaged 3.1% of the cases.
      CONCLUSIONS: In adenocarcinoma of the oesophagus and oesophagogastric junction
      endoscopic ultrasonography helps in predicting resectability, but the exact TN
      staging is not accurate. Since early detection of tumour and aggressive surgical
      intervention constitute the only curative treatment, caution must be exercised
      when judging a patient to be inoperable solely on the basis of endoscopic
      ultrasonography findings without proven distant metastases.

PMID- 10636064
TI  - Helicobacter pylori extracts reduce gastric mucosal blood flow by a nitric oxide
      independent but mast cell- and platelet-activating factor receptor-dependent
      pathway in rats.
AB  - BACKGROUND: We have previously shown that water extracts from Helicobacter pylori
      reduce gastric mucosal blood flow by approximately 15%. It has also been
      suggested that H. pylori can inhibit endogenous nitric oxide (NO) biosynthesis.
      Our aim was to examine whether the reduction in blood flow induced by H. pylori
      is the direct consequence of an NO synthase inhibition and the possible
      involvement of mast cell degranulation. METHODS: A water extract was produced
      from wildtype strain 88-23. The extract was applied on the exteriorized gastric
      corporal mucosa in inactin-anesthetized rats, after removing as much as possible
      of the mucus layer, during intravital microscopy. Blood flow was measured with
      laser-Doppler flowmetry. RESULTS: In rats pretreated with the NO synthase
      inhibitor N-nitro-L-arginine there was a 19% +/- 6% reduction in blood flow 40
      min after application of the extract, and a 27% +/- 9% reduction after another 20
      min with saline. The reduction was abolished by concomitant pretreatment with the
      mast cell stabilizer ketotifen or the platelet-activating factor (PAF) receptor
      antagonist WEB2086. CONCLUSION: The reduction in mucosal blood flow induced by
      the extract was probably mediated through an acute inflammatory response
      involving mast cell degranulation with consequent PAF secretion. The effect on
      blood flow was not the result of a decrease in vascular tone due to an inhibition
      of endogenous NO biosynthesis.

PMID- 10636065
TI  - Gastrointestinal motility in patients with irritable bowel syndrome studied by
      using radiopaque markers.
AB  - BACKGROUND: Irritable bowel syndrome (IBS) has been identified as a physiologic
      abnormality, but no test has been established as a diagnostic standard for
      gastrointestinal dyskinesia in IBS patients. The aim of this study was to
      investigate gastrointestinal motility in patients with IBS by using radiopaque
      markers. METHODS: Gastrointestinal motility was studied in IBS patients (n = 72),
      constipation patients (n = 19), diarrhoea patients (n = 9), and healthy controls
      (n = 23). Using three types of radiopaque markers, analysis was performed to
      establish the transit time and a new indicator, the 'scattering index'. RESULTS:
      Transit times were not characteristic in IBS. The patients with IBS had
      significantly higher scattering indexes in the colon and total gut than the
      healthy controls and the patients with constipation and diarrhoea. The transit
      time and scattering index of the colon were linearly correlated in the healthy
      controls and the constipation and diarrhoea patients but were not correlated in
      the IBS patients. Using transit time and scattering index was a reliable means of
      evaluating gastrointestinal motility in IBS patients, with a sensitivity of 65%
      and a specificity of 96%. CONCLUSION: Three days' use of the radiopaque marker
      method was useful for providing an objective means of detecting gastrointestinal
      dysmotility in IBS patients.

PMID- 10636066
TI  - Prevalence of gastrointestinal symptoms in young and middle-aged diabetic
      patients.
AB  - BACKGROUND: Gastrointestinal disorders have been reported in patients with
      diabetes mellitus. The present investigation was carried out to evaluate the
      frequency of gastrointestinal symptoms in out-clinic diabetic patients in the
      county of Umea, Sweden. METHODS: Diabetic patients aged 24-59 years residing in
      Umea County (population, 136,000) were included in the study (n = 489), as were
      200 sex- and age-matched healthy controls. A questionnaire was mailed to the
      patients and controls, and a reminder was sent 5 months later. The questionnaire
      contained 28 questions concerning gastrointestinal symptoms, bowel habits, and
      medication during the preceding year. RESULTS: Fifty-nine per cent of the
      patients and 53% of the controls responded. The total number of reported
      gastrointestinal symptoms was significantly greater in patients (1.25 +/- 0.10;
      mean +/- standard deviation) than in control subjects (0.50 +/- 0.08). This
      increase was seen in both type-1 (1.12 +/- 0.11) and type-2 (1.52 +/- 0.25)
      diabetic patients. Female diabetic patients reported significantly more symptoms
      than did male patients (1.59 +/- 0.17 and 0.81 +/- 0.12, respectively). Patients
      with neuropathy had significantly more symptoms than the other patients. Symptom
      frequency was not correlated with nephropathy or retinopathy or with the duration
      of diabetes, body mass index, glycosylated haemoglobin, or insulin dose.
      Heartburn, constipation, and nocturnal urge to defecate were significantly more
      frequent in patients than in controls. Furthermore, a feeling of incomplete
      defecation, a need to strain at defecation, and urgency were significantly more
      common in patients. CONCLUSION: Diabetic patients had more gastrointestinal
      symptoms than non-diabetic population. These symptoms did not correlate with
      duration of the disease, metabolic control, or any other complication except
      neuropathy. Heartburn and constipation were among the symptoms that occurred more
      frequently in diabetic patients than in the non-diabetic population.

PMID- 10636067
TI  - Substance P causes a chloride-dependent short-circuit current response in rabbit
      colonic mucosa in vitro.
AB  - BACKGROUND: The neuropeptide substance P (SP) induces secretion in animals. The
      effect of SP on rabbit colon is not known. We therefore investigated the effect
      of SP on rabbit colonic mucosa mounted in Ussing chambers. METHODS: Colonic
      mucosae were incubated with SP in Cl -containing or Cl -free buffer. Drugs for
      pharmacologic characterization of SP-induced electrophysiologic changes were
      applied to the serosal bath 30 min before SP administration. RESULTS: Serosal,
      but not luminal, administration of SP (10(-8)-10(-6) M) induced a rapid,
      transient, bumetanide-sensitive, dose- and chloride-dependent short-circuit
      current (Isc) increase (P < 0.001), which was inhibited by 85%, 80%, 82%, 90%,
      and 70% after serosal preincubation with the neurokinin-1 (NK-1) receptor
      antagonist CP-96,345, the neuronal blocker tetrodotoxin (10(-6)M), the mast cell
      stabilizer lodoxamide (10(-6) M), the H1-receptor antagonist pyrilamine (10(-6)
      M), or the prostaglandin synthesis inhibitor indomethacin (10(-6) M),
      respectively (P < 0.001). CONCLUSIONS: SP stimulates a chloride-dependent Isc
      increase in the rabbit colon which is mediated by nerves and mast cells and the
      mast cell product histamine.

PMID- 10636068
TI  - Proctocolectomy is associated with a higher complication rate but carries a lower
      recurrence rate than total colectomy and ileorectal anastomosis in Crohn colitis.
AB  - BACKGROUND: Most patients with extensive colonic Crohn disease are treated with
      total colectomy and ileorectal anastomosis or, when there is severe anorectal
      disease, with proctocolectomy. This study was undertaken to compare postoperative
      complications and recurrence rates for these two operations. METHODS: Eighty-six
      patients who underwent a single-stage proctocolectomy and 65 who underwent total
      colectomy and ileorectal anastomosis for colonic Crohn disease were
      retrospectively reviewed. RESULTS: Anorectal disease (severe proctitis, perianal
      sepsis, complex fistula) was seen in 77 patients (90%) at proctocolectomy,
      compared with 7 patients (11%) at colectomy and ileorectal anastomosis (P <
      0.0001). After proctocolectomy the commonest complication was perineal wound
      sepsis (36%). After colectomy and ileorectal anastomosis only three patients (5%)
      developed anastomotic leak. The overall complication rate was 53% after
      proctocolectomy compared with 32% after colectomy and ileorectal anastomosis (P =
      0.02). Twenty-four patients (29%) after proctocolectomy and 43 patients (68%)
      after colectomy and ileorectal anastomosis developed symptomatic recurrence (P <
      0.0001). After proctocolectomy the 5-, 10-, and 15-year cumulative reoperation
      rate for recurrence were 13%, 16%, and 26%, which were significantly lower than
      the 29%, 46%, and 48% after colectomy and ileorectal anastomosis (P = 0.002).
      CONCLUSIONS: The overall complication rate was lower after colectomy and
      ileorectal anastomosis than after proctocolectomy. However, proctocolectomy was
      associated with a lower incidence of reoperation for recurrence than colectomy
      and ileorectal anastomosis.

PMID- 10636069
TI  - Granulocyte marker protein is increased in stools from rats with azoxymethane
      induced colon cancer.
AB  - BACKGROUND: We wanted to investigate the relationship between the fecal levels of
      granulocyte marker protein (GMP) and the presence of aberrant crypt foci (ACF)
      and colorectal cancer in rats given injections of azoxymethane (AOM) and fed
      either of two different diets, a basal diet plus 20% corn oil or 20% beef suet,
      respectively. METHODS: The rats received intraperitoneal injections of AOM, 15
      mg/kg, once weekly for 6 weeks and were killed after 22 weeks. RESULTS: In the
      group fed beef suet 17 of 19 rats developed colon cancer, whereas in the group
      fed corn oil 4 of 14 rats developed cancer. None of the 20 control rats fed
      either the beef suet or corn oil diets developed cancer or aberrant crypts, and
      GMP remained unchanged. Surprisingly, the numbers of ACF were significantly
      higher (467 versus 295; P = 0.004) in the group fed corn oil than in the group
      fed beef suet. On the other hand, the size (crypts/focus) of the ACF was
      significantly higher (P = 0.03) in the beef suet group. Furthermore, fecal GMP
      was significantly higher in the beef suet group than in the corn oil group after
      18 weeks, and this difference increased further toward the end of the study. GMP
      was greatly increased in all rats with colorectal cancer. CONCLUSIONS: Fecal GMP
      may have provided us with a valuable tool for further studies of the induction
      and progression of neoplasia in rats and, possibly, in mice, since the anti-GMP
      antibody cross-reacts with feces extracts from mice.

PMID- 10636070
TI  - The effect of bombesin, cholecystokinin, gastrin, and their antagonists on
      proliferation of pancreatic cancer cell lines.
AB  - BACKGROUND: The role of cholecystokinin (CCK) and gastrin in the development and
      growth of pancreatic cancer cells is controversial. The aim of this study was to
      evaluate the role of CCK-8S, gastrin-17, bombesin, and their antagonists on cell
      lines from patients with pancreatic cancer. METHODS: Cell lines were established
      from pancreatic cancers operated on at our department. The cells were grown in
      10% fetal calf serum (FCS). The effects of CCK-8S, gastrin-17, bombesin, and
      their antagonists in different concentrations and for different time intervals
      were studied. The cell number was evaluated with the XTT method. RESULTS: The
      cell line LN 36 responded with increased cell number to stimulation by gastrin-17
      and decreased cell number to inhibition by the CCK-B receptor antagonist L
      365,260. In contrast, LPC 1 responded with increased cell number to CCK-8S and
      decreased cell number to the CCK-A receptor antagonist devazepide. LPC 2, 6, and
      7 were stimulated by CCK-8S, gastrin-17, and their antagonists. LPC 3 showed
      decreased cell number after inhibition by the antagonists, and LPC 5 and 10
      showed increased cell number after stimulation by CCK-8S and gastrin-17. LPC 4
      was stimulated by CCK-8S, and LPC 8 was stimulated by all substances except
      gastrin-17. Intermittent administration of the substances to LN 36 led to a
      greater effect on the cell number than administration every day, which was not
      the case with LPC 1 and LPC 3. Bombesin led to an increased growth in LPC 5 but
      not in LPC 3. CONCLUSION: CCK-8S and gastrin-17 led to an increased cell number
      in some cell lines. A blockade of the CCK-A and CCK-B receptors by their
      antagonists led to an increased, an unaffected, or a decreased cell number of the
      cell lines. The effect of bombesin on different cell lines also varied. This
      shows a great heterogenicity among pancreatic cancer cells from different
      patients.

PMID- 10636071
TI  - Epidemiology of familial adenomatous polyposis in Sweden: changes over time and
      differences in phenotype between males and females.
AB  - BACKGROUND: The Swedish Polyposis Registry was set up in Sweden in the late 1950s
      to promote screening of familial adenomatous polyposis (FAP). The aim of this
      study was to examine the epidemiology of FAP in Sweden, including the influence
      of screening on morbidity and mortality in colorectal cancer (CRC). METHODS: Four
      hundred and thirty-one patients (213 males and 218 females) with FAP from 145
      families recorded by the Swedish Polyposis Registry were investigated. The effect
      of screening on morbidity and mortality in CRC was evaluated by comparing the 216
      probands with the 215 call-up patients. Three different periods were studied: the
      pre-screening period (1912-1956), the first screening period (1957-1976), and the
      second screening period (1977-1996). RESULTS: The mean annual incidence rates
      during the three periods were 0.2, 1.38, and 0.86 per million, respectively. The
      birth frequency was calculated to be 1 in 18,000 between 1947 and 1966, and the
      prevalence was 32 per million at the end of 1996. The proportion of new mutants
      among the FAP patients born between 1927 and 1966 was estimated to be 11%. The
      median age at diagnosis of probands was 39 (range, 11-71) years and did not
      change over time, although an increase was seen in the subgroup with CRC at
      diagnosis (P = 0.02). In the call-up group the median age at diagnosis was 22
      (range, 3-65) years. Sixty-seven per cent of the probands and 3.3% of the call-up
      patients had CRC at diagnosis, and the corresponding mortality figures were 44%
      and 1.9%. The risk among probands of having CRC at diagnosis decreased from 81%
      to 49% (P = 0.0006). Female probands were diagnosed with symptoms (P = 0.03) and
      CRC (P = 0.04) earlier than male probands. CONCLUSIONS: A nationwide screening
      program facilitates detection and early diagnosis of FAP. A decrease in CRC
      morbidity among probands contributed to the improved prognosis. An earlier onset
      of symptoms and CRC in females indicate that the course of FAP is influenced by
      sex.

PMID- 10636072
TI  - Two-dose combined vaccination against hepatitis A and B in healthy subjects aged
      11-18 years.
AB  - BACKGROUND: In this open, randomized trial the safety, reactogenicity, and
      immunogenicity profile of a high-dose combined hepatitis A and B candidate
      vaccine was compared with that of Twinrix Paediatric in healthy volunteers aged
      11-18 years. METHODS: One hundred subjects were randomly allocated to either of
      two groups. One group received the high-dose vaccine (720 E1.U HAV antigen; 20
      microg hepatitis B surface antigen (HBsAg) at months 0 and 6; the second group
      received Twinrix Paediatric (360 E1.U HAV antigen; 10 microg HBsAg), following a
      0-1-6-month schedule. RESULTS: Injection site soreness and fatigue were the most
      frequently reported solicited symptoms. For hepatitis A all subjects had
      seroconverted at month 7, and geometric mean titres (GMT) were 8,151 mIU/ml in
      the high-dose group and 6,394 mIU/ml in the Twinrix Paediatric group. For
      hepatitis B the GMT for the Twinrix Paediatric group was significantly higher at
      month 2 and month 6. However, no difference in GMT between groups could be
      established at month 7. The seroprotection rate attained 100% in both groups, and
      GMT were 4,212 mIU/ml (high-dose group) and 6,330 mIU/ml (Twinrix Paediatric).
      CONCLUSIONS: The two vaccines showed similar safety and reactogenicity profiles.
      After completion of the vaccination schedule, no difference in immunogenicity was
      shown. This high-dose vaccine, administered following a two-dose schedule, can be
      considered an alternative regimen for the immunization of healthy adolescents
      against hepatitis A and hepatitis B infections, in a setting where vaccinees are
      not immediately at risk of exposure to hepatitis B.

PMID- 10636073
TI  - The liver in hereditary hemorrhagic telangiectasia (Weber-Rendu-Osler disease).
AB  - BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT, Osler disease) is an
      inborn error in the structure of different vessels. This leads to vascular
      malformations in multiple organ systems. In the liver vascular abnormalities are
      associated with a marked fibrosis and/or cirrhosis. METHODS AND RESULTS: We found
      hepatic manifestation of Osler disease in four women and one man (51-63 years
      old) presenting initially with slight disturbances of liver function. In three
      patients progressive liver insufficiency developed. The characteristic histologic
      and sonographic findings are described and discussed. CONCLUSION: Ultrasonography
      with color and Doppler analysis is diagnostic, replacing more extensive
      procedures like angiography, computer tomography, or magnetic resonance
      tomography.

PMID- 10636074
TI  - Hydrosonography of the small intestine: comparison with radiologic barium study.
AB  - BACKGROUND: Transabdominal ultrasonography of the small intestine is hampered by
      luminal gas. We have developed a new sonographic method (hydrosonography) that
      largely eliminates the gas problem and have compared this method with radiologic
      barium study. METHODS: Fifty-six patients admitted for X-ray examination of the
      small bowel because of abdominal pain, diarrhoea, weight loss and/or known
      inflammatory bowel disease were examined. To remove luminal gas before performing
      transabdominal ultrasonography, 21 of polyethylene glycol solution was inserted
      through a nasojejunal tube by means of a peristaltic pump. Wall thickness,
      peristalsis, luminal narrowing, prestenotic dilatation, and extraintestinal
      complications were recorded. RESULTS: On ultrasonography we were able to
      visualize the terminal part of the ileum in 98% of the patients. Perfect
      agreement between hydrosonography and barium studies was seen in 50 of 55
      patients. However, 44 patients had normal findings on both examinations. The
      sensitivity and specificity of hydrosonography were 64% and 100%, respectively.
      The positive predictive value was 100%. For X-ray examination sensitivity and
      specificity were 91% and 100%, respectively. Four patients with minor mucosal
      abnormalities or pathologic findings in the upper part of the small intestine
      accounted for the relatively low overall sensitivity found for hydrosonography
      compared with roentgenography. However, important extraintestinal complications
      were disclosed by ultrasound. CONCLUSIONS: Hydrosonography of the small bowel is
      a new, convenient, and reliable method for examining the lower part of the small
      intestine. However, it cannot replace barium studies in patients with mucosal
      abnormalities. especially in the upper part of the small bowel.

PMID- 10636075
TI  - Fistula in ano: evaluation with low-field magnetic resonance imaging (0.1 T).
AB  - BACKGROUND: Patients suspected of having perianal suppurative disease often
      undergo a combination of several potentially painful, invasive procedures to
      establish or rule out the diagnosis. To evaluate the accuracy of low-field
      magnetic resonance imaging (MRI) in distinguishing patients with active anal
      fistulae and patients with no active fistulation we performed a retrospective
      study. METHODS: Fifty-six patients suspected of having anal fistulation were
      evaluated in the surgical outpatient clinic. Patients were examined with low
      field MRI (0.1 T; gradient echo technique, TR/TE 1,500/40 and TR/TE 115/25, +/-
      gadodiamide (0.1 mM/kg intravenously)) in both coronal and axial planes, using a
      body quadrature coil. Altogether 71 MRIs were performed. In selected patients
      evaluation included endoanal ultrasonography, fistulography, and/or surgery. On
      the basis of the combined results of all available follow-up data for 6 months
      after the MRI, patients were placed in groups either having active fistulation or
      not. RESULTS: MRI findings agreed with the combined findings of other
      examinations in 54 patients. Active or possibly active fistulae were found in 36
      cases, whereas 33 patients showed no active fistulae. The kappa value is 0.944
      (95% confidence limits, 0.866-1.021). In two patients the MRI findings disagreed
      with the combined findings of the other modalities. CONCLUSION: The use of low
      field MRI of the pelvic region in the investigation of suspected perianal
      fistulae is a feasible, reliable, and painless examination. MRI should be
      considered in patients with suspected complex anal fistulae. Future prospective
      studies are warranted.

PMID- 10636076
TI  - Mesenteric lymph node cavitation: a rare hallmark of celiac disease.
AB  - The cavitation of mesenteric lymph nodes represents a rare complication of celiac
      disease (only 30 reported cases) whose pathogenesis remains to be clarified. We
      here report the case of a 67-year-old woman referred to us because of a
      malabsorption syndrome lasting for 2 years; massive lymph node enlargement and
      cavitation were detected by means of ultrasonography and a computed tomography
      scan. Celiac disease was definitely diagnosed by means of duodenal histology, and
      a laparotomy was performed to exclude an underlying T-cell lymphoma. The adoption
      of a gluten-free diet led to a rapid and dramatic improvement in the clinical and
      histologic picture and normalization of the size of the lymph nodes. Celiac
      disease should be considered in the differential diagnosis of all patients with
      mesenteric lymph node cavitation.

PMID- 10636077
TI  - Increased sweat chloride concentrations in adult patients with pancreatic
      insufficiency: cystic fibrosis phenotype or lack of specificity of sweat test?

PMID- 10636078
TI  - Folding of oligoglutamines: a theoretical approach based upon thermodynamics and
      molecular mechanics.
AB  - Folding of oligoglutamine chains of different lengths is of crucial interest for
      exploring the molecular mechanisms of Huntington's disease. A simple
      oligoglutamine model based upon the Flory-Huggins theory of polymer solutions
      demonstrates a random coil instability in chains containing more than 40
      glutamine residues with respect to beta-sheet formation. This is in striking
      quantitative agreement with biochemical results on the chain length dependence of
      polyglutamine aggregation in vivo and in vitro, as well as with clinical data on
      the polyglutamine chain length dependence of the onset of Huntington's disease.
      Furthermore, a detailed molecular-mechanical investigation of a polypeptide chain
      carrying 40 glutamine residues was performed. Two possible folding modes of such
      an oligoglutamine chain were revealed: a) a beta-hairpin and b) a highly compact
      random coil entity stabilized by a wealth of H-bonds among the glutamine side
      chains. A possible role of these folding modes in polyglutamine aggregation, as
      well as in the onset of Huntington's disease, is discussed.

PMID- 10636079
TI  - Comparison of the solution conformations of a cell-adhesive peptide LBE and its
      reverse sequence EBL.
AB  - T-cell adhesion is mediated by an ICAM-1/LFA-1 interaction; this interaction
      plays a crucial role in T-cell activation during immune response. LBE peptide,
      which is derived from the beta-subunit of LFA-1, has been shown to inhibit ICAM
      1/LFA-1-mediated T-cell adhesion. In this work, we studied the solution
      conformations of LBE peptide and its reverse sequence (EBL) by NMR, CD and
      molecular dynamics simulations. Reverse peptides have been used as controls in
      biological studies. The effect of reversing the sequence of LBE to EBL peptides
      on their respective conformations is important in understanding their biological
      properties in vitro or in vivo. The NMR studies for these peptides were carried
      out in water and in TFE/water solvent systems. In 40% TFE/water, both peptides
      exhibited helical conformation. CD studies suggested that the LBE exhibits 30%
      helical conformation, while the EBL exhibits 20% helical conformation. From the
      NMR and MD simulation studies, it was evident that the peptides exhibited a
      stable helical conformation; a stable helical structure was found at Leu6 to
      Leu15 for LBE and at Gly9 to Leu17 for EBL. The helical conformations of LBE and
      EBL may be in equilibrium with other possible conformers; the other conformers
      contain loop and turn structures. Both peptides bind to divalent cations because
      the LBE is derived from the cation-binding region of the LFA-1. This study shows
      that reversing the peptide sequence did not alter the secondary structure of the
      corresponding sequence. Hence, caution must be exercised when using reverse
      peptides as controls in biological studies. This report will improve our ability
      to design a better inhibitor of ICAM-1/LFA-1 interaction.

PMID- 10636080
TI  - The delta-selective opioid peptide dermenkephalin and the mu-selective hybrid
      peptide dermenkephalin-[1-4]-dermophin-[5-7] display strikingly different
      conformations despite identical tetrapeptide N-termini. A quantitative 2-D NMR
      and molecular modeling analysis.
AB  - The selective recognition of the aminoterminal binding pharmacophore Tyr-D-Xaa
      Phe of the opioid heptapeptide dermorphin, Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2
      (DRM)1, and of dermenkephalin, Tyr-D-Met-Phe-His-Leu-Met-Asp-NH2 (DREK), by the
      mu-opioid receptor and delta-opioid receptor, respectively, depends upon the
      constitution / conformation of the C-terminal tripeptide. The hybrid peptide DREK
      [1-4]-DRM-[5-7] is very potent at, and exquisitely selective for the mu-opioid
      receptor, and differs only from dermenkephalin by its C-terminal tripeptide.
      Comparison of the structural features of DREK-[1-4]-DRM-[5-7] and dermenkephalin
      by nmr analysis and molecular modeling revealed striking differences, as well in
      the trans (Tyr5 - Pro6) isomer (population 75%) than in the cis isomer.. Whereas
      the folded C-terminal tail of dermenkephalin influenced the tertiary structure of
      the N-terminal tetrapeptide and placed the Tyr1 and Phe3 aromatic rings in
      definite orientations that are best suited for the delta-receptor, there were
      only weak contacts, as shown by NOE data, between the aminoterminal and
      carboxyterminal parts of the hybrid peptide. This promoted increased flexibility
      of the whole backbone and relaxed orientations for the side-chains of Tyr1 and
      Phe3 that are compatible with the mu-receptor but unsuitable for the delta
      receptor. The steric hindrance introduced by Pro6 in DREK-[1-4]-DRM-[5-7], plus
      the absence of large hydrophobic side-chains in positions 5 and 6 may prevent
      close contacts between the N-terminal and C-terminal domains and reorientation of
      the main pharmacophoric elements Tyr1 and Phe3.

PMID- 10636081
TI  - Osmotic pressure effects on EcoRV cleavage and binding.
AB  - Investigations of DNA binding proteins frequently measure pH and salt dependence,
      but relatively few studies measure protein binding in high concentrations of
      small molecules often found in vivo. We have measured kinetics of the restriction
      enzyme EcoRV in concentrated solutions of three small cosolvents that produce
      osmotic pressures from 0.25 to 2.5 mol/kg (6 to 62 atm or water activity of 0.995
      to 0.956). We have correlated DNA cleavage and binding parameters with four
      solution parameters (dielectric constant, viscosity, water concentration, and
      water activity). We found that the responses of maximum velocity (Vmax) and the
      dissociation constant for nonspecific binding (Kd,ns) best correlate with water
      activity. The Michaelis constant (Km) correlates with both water activity and
      solution viscosity, the latter due to the highly dilute reactant concentrations,
      which make enzyme-substrate combination diffusion limited. Dielectric constant
      does not influence any of the kinetic parameters, which is consistent with a view
      that protein and DNA are preferentially hydrated, and excluded solutes cannot
      affect the local dielectric constant.

PMID- 10636082
TI  - Interaction of RNase A with VO3- and VO2+ ions. Metal ion binding mode and
      protein secondary structure.
AB  - Some of vanadyl complexes have shown potential to inhibit RNase activity by
      acting as transition state analogue, while at the same time not inhibiting DNase.
      To gain an insight into the interaction of protein with vanadate (VO3-) and
      vanadyl (VO2+) ions, the present study was designed to examine the binding of
      ribonuclase A (RNase A) with NaVO3 and VOSO4 in aqueous solution at physiological
      pH with metal ion concentrations of 0.001 mM to 1 mM, and protein concentration
      of 2% w/v. Absorption spectra and Fourier transform infrared (FTIR) spectroscopy
      with self-deconvolution and second derivative resolution enhancement were used to
      determine the cation binding mode, association constant and the protein secondary
      structure in the presence of vanadate and vanadyl ions in aqueous solution.
      Spectroscopic results show that an indirect metal ion interaction occurs with the
      polypeptide C = O, C-N (via H2O) with overall binding constants of K(VO3-) =
      3.93x10(2) M(-1) and K(VO2+) = 4.20x10(3) M(-1). At high metal ion
      concentrations, major protein secondary structural changes occur from that of the
      alpha-helix 29% (free enzyme) to 23-24%; beta-sheet (pleated and anti) 50% (free
      enzyme) to 64-66% and turn 21% (free enzyme) to 10-12% in the metal-RNase
      complexes. The observed structural changes indicate a partial protein unfolding
      in the presence of high metal ion concentration.

PMID- 10636083
TI  - Differential stability of the triple helix of (Pro-Pro-Gly)10 in H2O and D2O:
      thermodynamic and structural explanations.
AB  - (Pro-Pro-Gly)10 [(PPG10)], a collagen-like polypeptide, forms a triple-helical,
      polyproline-II structure in aqueous solution at temperatures somewhat lower than
      physiological, with a melting temperature of 24.5 degrees C. In this article, we
      present circular dichroism spectra that demonstrate an increase of the melting
      temperature with the addition of increasing amounts of D2O to an H2O solution of
      (PPG)10, with the melting temperature reaching 40 degrees C in pure D2O. A
      thermodynamic analysis of the data demonstrates that this result is due to an
      increasing enthalpy of unfolding in D2O vs. H2O. To provide a theoretical
      explanation for this result, we have used a model for hydration of (PPG)10 that
      we developed previously, in which inter-chain water bridges are formed between
      sterically crowded waters and peptide bond carbonyls. Energy minimizations were
      performed upon this model using hydrogen bond parameters for water, and altered
      hydrogen bond parameters that reproduced the differences in carbonyl oxygen-water
      oxygen distances found in small-molecule crystal structures containing oxygen
      oxygen hydrogen bonds between organic molecules and H2O or D2O. It was found that
      using hydrogen bond parameters that reproduced the distance typical of hydrogen
      bonds to D2O resulted in a significant lowering of the potential energy of
      hydrated (PPG)10. This lowering of the energy involved energetic terms that were
      only indirectly related to the altered hydrogen bond parameters, and were
      therefore not artifactual; the intra-(PPG10) energy, plus the water-(PPG10) van
      der Waals energy (not including hydrogen bond interactions), were lowered enough
      to qualitatively account for the lower enthalpy of the triple-helical
      conformation, relative to the unfolded state, in D2O vs. H2O. This result
      indicates that the geometry of the carbonyl-D2O hydrogen bonds allows formation
      of good hydrogen bonds without making as much of an energetic sacrifice from
      other factors as in the case of hydration by H2O.

PMID- 10636084
TI  - Comparative molecular dynamics of mesophilic and psychrophilic protein homologues
      studied by 1.2 ns simulations.
AB  - It is well established that the dynamic motion of proteins plays an important
      functional role, and that the adaptation of a protein molecule to its environment
      requires optimization of internal non-covalent interactions and protein-solvent
      interactions. Serine proteinases in general, and trypsin in particular has been
      used as a model system in exploring possible structural features for cold
      adaptation. In this study, a 500 p.s. and a 1200 p.s. molecular dynamics (MD)
      simulation at 300 K of both anionic salmon trypsin and cationic bovine trypsin
      are analyzed in terms of molecular flexibility, internal non-covalent
      interactions and protein-solvent interactions. The present MD simulations do not
      indicate any increased flexibility of the cold adapted enzyme on an overall
      basis. However, the apparent higher flexibility and deformability of the active
      site of anionic salmon trypsin may lower the activation energy for ligand binding
      and for catalysis, and might be a reason for the increased binding affinity and
      catalytic efficiency compared to cationic bovine trypsin.

PMID- 10636085
TI  - Shape-selective recognition of a model Okazaki fragment by geometrically
      constrained bis-distamycins.
AB  - Okazaki fragments represent interesting targets for the design of anticancer
      drugs because of their selective occurrence during DNA replication, a process
      often elevated in aggressive malignancies. Structural studies have indicated a
      bend occurs in the helical axis at the junction region (JR) that joins the DNA
      duplex region (DDR) and the RNA-DNA hybrid duplex region (HDR) of model Okazaki
      fragments. To identify a structural motif that provides a shape complementary to
      the Okazaki fragment minor groove, we have investigated the binding of
      geometrically-constrained bis-distamycins to a model Okazaki fragment, [OKA],
      with a sequence derived from the genome of simian virus 40 (SV40). Both the JR
      and the DDR of [OKA] contain consecutive A/T base pairs that could accommodate
      distamycin binding. Of the six bis-distamycins selected for analysis, the two
      with a para configuration of the distamycins on the benzene or pyridine scaffold
      bound [OKA] tightly (Kd approximately 10(-6) M from gel-shift assays; Kd
      approximately 10(-8) M from deltaT(M)) while the four with a meta orientation did
      not bind. The two mono-distamycins studied also did not bind [OKA]. Molecular
      modeling of the complex between the para bis-distamycin MT-9 and [OKA] revealed
      MT-9 adopted an S- shape complementary to the minor groove of the model Okazaki
      fragment.

PMID- 10636086
TI  - DNA binding of lambda- and delta-cis-beta-[Ru(RR-picchxn)(phen)](2)+ studied by
      NMR and flow linear dichroism spectroscopy.
AB  - Two novel substitutionally-inert diastereomeric ruthenium(II) cations of the form
      lambda- and delta-cis-beta-[Ru(RR-picchxn)(phen)]2+, where RR-picchxn is N,N'
      dimethyl-N,N'-di(2-picolyl)-1R,2R-diaminocyclohexane and phen is 1,10
      phenanthroline, have been studied with respect to their interactions with duplex
      DNA. NMR investigations show that both diastereomers bind to the oligonucleotide
      [d(CGCGATCGCG)]2 in the fast exchange regime and that binding predominantly takes
      place in the minor groove of the oligonucleotide, but that the governing
      interactions are significantly different for the two delta and lambda forms.
      Linear dichroism data support the latter interpretation, in that the relative
      orientations of cis-beta-[Ru(RR-picchxn)(phen)]2+ to calf thymus DNA also are
      observed to differ for the delta and lambda diastereomers. Interpretation of
      these data indicates the lambda form to be bound with the planar phen ligand
      closely parallel to the DNA base-pairs, but the average orientation of the phen
      ligand in the delta form deviates significantly from a parallel alignment.

PMID- 10636087
TI  - Evaluation of single-stranded nucleic acids as carriers in the DNA-directed
      assembly of macromolecules.
AB  - Current developments in nanosciences indicate that the self-assembly of
      macromolecules, such as proteins or metallic nanoclusters, can be conveniently
      achieved by means of nucleic acid hybridization. Within this context, we here
      report on the evaluation of single-stranded nucleic acids to be utilized as
      carrier backbones in DNA-directed self-assembly. A microplate solid-phase
      hybridization assay is described which allows rapid experimental determination of
      the hybridization efficiencies of various sequence stretches within a given
      nucleic acid carrier strand. As demonstrated for two DNA fragments of different
      sequence, the binding efficiencies of several oligonucleotides depend on the
      formation of specific secondary structure elements within the carrier molecule. A
      correlation of sequence-specific hybridization capability with modeled secondary
      structure is also obvious from experiments using the fluorescence gel-shift
      analysis. Electrophoretic studies on the employment of helper oligonucleotides in
      the formation of supramolecular conjugates of several oligonucleotide-tagged
      proteins indicate, that structural constraints can be minimized by disruption of
      intramolecular secondary structures of the carrier molecule. To estimate the
      influences of the chemical nature of the carrier, gel-shift experiments are
      carried out to compare a 170mer RNA molecule with its DNA analogue. Ternary
      aggregates, containing two protein components bound to the carrier, are formed
      with a greater efficiency on the DNA instead of the RNA carrier backbone.

PMID- 10636088
TI  - Hybridization kinetics of oligodeoxyribonucleotides with a d(GCGAAGC) hairpin at
      the 3'-end.
AB  - In order to protect them against enzymatic attack of serum in the antisense
      strategy, oligodeoxyribonucleotides can be protected on their 3'-side by the
      sequence d(GCGAAGC) which spontaneously forms a hairpin which is known for its
      extraordinary stability with regard to thermal denaturation or nuclease
      degradation (I. Hirao, G. Kawai, S. Yoshizawa, Y. Nishimura, Y. Ishido, K.
      Watanabe and K. Miura, Nucleic Acids Res. 22, 576-582 (1994)). By contrast, the
      hairpin does not prevent hybridization of the 5'-stem part of the oligonucleotide
      to a target DNA strand. As soon as this pairing occurs, the stability of the
      hairpin is disrupted. Its opening rate, followed by its pairing if possible, is
      of the same order than that of hybridization of the stem part.

PMID- 10636089
TI  - Complexes of (dG-dC)20 with Mn2+ ions: a study by vibrational circular dichroism
      and infrared absorption spectroscopy.
AB  - The B-Z transition of the synthetic oligonucleotide, (dG-dC)20, induced by Mn2+
      ions at room temperature, was investigated by absorption and Vibrational Circular
      Dichroism (VCD) spectroscopy in the range of 1800-800 cm(-1). Metal ion
      concentration was varied from 0 to 0.73 M Mn2+ (0 to 8.5 moles of Mn2+ per mole
      of oligonucleotide phosphate, [Mn]/[P]). While both types of spectra showed
      considerable changes as the Mn2+ concentrations were raised, differences between
      the two were often complementary in their expression and extent, those displayed
      by VCD being more clearly evident due to the inversion of the opposite helical
      sense from the right-handed to the left-handed conformation. The main phase of
      the transition occurred in the metal ion concentration between 0.8-1.1 [Mn]/[P].
      Gradual changes that took place in the spectra were interpreted in terms of
      simultaneous processes that depended on metal ion concentration, namely B-Z
      transformation, binding of Mn2+ to phosphates and to nitrogen bases, and partial
      denaturation. Below approximately 0.6 [Mn]/[P], only a small portion of the
      oligonucleotide adopted the Z conformation within a 3 hour period, whereas
      conversion was completed in the same time interval for concentrations between 0.9
      1.2 [Mn]/[P]. At [Mn]/[P] >1.7, complete transition to the Z-form took place
      immediately on adding Mn2+. Applying VCD spectroscopy in combination with
      conventional infrared absorption proved most useful for corroborating changes in
      the absorption spectra, and for detecting in an unique manner, not attainable by
      absorption methods, conformational changes that lead to the inversion of the
      helical sense of the oligonucleotide.

PMID- 10636090
TI  - The terminal phosphate in d(pGpG) reduces self-association.
AB  - An investigation of the self-association behavior of 2'-deoxy[5'-phosphate
      guanylyl-(3'-5')-guanosine] (d(pGpG)) in the presence of Na+ and K+ ions has been
      carried out by 1H and 31P NMR and FTIR spectroscopy. A comparison has been made
      of the self- association behavior of d(pGpG) with that of the related
      dinucleotide d(GpG), which has been shown to form extended structures based on
      stacked G-tetrads. Chemically, d(pGpG) monomer differs from d(GpG) only by the
      addition of a phosphate at the 5'-OH of the sugar residue. It was found that the
      addition of the second phosphate interferes with self-association. A suitable
      counterion is all that is required by d(GpG) to induce the formation of large
      super structures, but for d(pGpG) a large excess of salt is needed to produce the
      same effect. However, once self-association occurs, d(pGpG) forms similar
      structures to d(GpG) and has nearly the same properties. For both compounds, the
      K+ ion induces a more stable structure than the Na+ ion. The 31P NMR chemical
      shift ranges of d(pGpG) were consistent with the reported data for a
      phosphodiester and terminal phosphate. The small change in the chemical shift of
      the terminal phosphate with increasing temperature suggests that no major change
      in the terminal phosphate conformation occurred upon self-association. It was
      concluded that the terminal phosphate did not result in steric hindrance to self
      association, but that interference to self-association was due to electrostatic
      repulsion effects.

PMID- 10636092
TI  - A Boltzmann filter improves the prediction of RNA folding pathways in a massively
      parallel genetic algorithm.
AB  - RNA folding using the massively parallel genetic algorithm (GA) has been enhanced
      by the addition of a Boltzmann filter. The filter uses the Boltzmann probability
      distribution in conjunction with Metropolis' relaxation algorithm. The
      combination of these two concepts within the GA's massively parallel
      computational environment helps guide the genetic algorithm to more accurately
      reflect RNA folding pathways and thus final solution structures. Helical regions
      (base-paired stems) now form in the structures based upon the stochastic
      properties of the thermodynamic parameters that have been determined from
      experiments. Thus, structural changes occur based upon the relative energetic
      impact that the change causes rather than just geometric conflicts alone. As a
      result, when comparing the predictions to phylogenetically determined structures,
      over multiple runs, fewer false-positive stems (predicted incorrectly) and more
      true-positive stems (predicted correctly) are generated, and the total number of
      predicted stems representing a solution is diminished. In addition, the
      significance (rate of occurrence) of the true-positive stems is increased. Thus,
      the predicted results more accurately reflect phylogenetically determined
      structures.

PMID- 10636091
TI  - Higher-order structure of mammalian chromatin deduced from viscoelastometry data.
AB  - The results of viscoelastometry (VE) for mammalian DNA have been puzzling because
      they have two orders of magnitude smaller measured viscoelastic relaxation times
      for mammalian chromosomes than that expected for DNA linear coils of chromosomal
      size. In an attempt to resolve this discrepancy, we have applied a recent model
      of G1 chromosome structure (J.Y. Ostashevsky, Mol Biol. Cell 9, 3031-3040, 1998)
      in which the 30 nm chromatin fiber of each chromosome forms a string of loop
      clusters (micelles). This model has two parameters: the number of loops per
      micelle (f) and the average loop size (Mf), which can be estimated independently
      from VE data. Using our VE data for plateau phase V79 Chinese hamster cells
      (unirradiated and X-irradiated with doses up to 40 Gy) we show that f
      approximately 13 , which is close to other estimates made using the model (f
      ranges from 10-20), and Mf approximately 2 Mbp, which is similar to estimates
      made from our nucleoid data (1.3 Mbp) and to estimates made in the literature
      using a variety of techniques (1-3 Mbp).

PMID- 10636093
TI  - Stochastic properties of one-parameter discrete model of genetic diversity in the
      unique random parameter case.
AB  - Stochastic properties of previously introduced one parameter discrete model of
      genetic diversity (M. Yu. Shchelkanov et al, J. Biomol. Struct. Dyn. 15, 887-894
      (1998)) are investigated. Two approaches are compared: (A) when the on-step
      substitution number and/or the number of substitution steps are random variables;
      (B) referred parameters are replaced by mathematical expectations of the
      respective variables. It has been demonstrated, that estimations of sequence
      measure based on the number of replication steps are more under the assumption of
      case (A) as compared with (B). Thus, real biological situation relating to the
      case (A) could additionally promote the increasing of distinctions between
      different taxons (e.g. HIV, etc.). Peculiarities of one-parameter discrete model
      of genetic diversity during calculation of the distinctions between symbol (e.g.
      nucleotide) sequence sets are also discussed.

PMID- 10636094
TI  - Mediation of a phase transition in hyaluronate films by the counterions Li, Cs,
      Mg and Ca as observed by infrared spectroscopy, optical microscopy and optical
      birefringence.
AB  - Infrared (IR) spectroscopy and optical microscopy have been performed as a
      function of relative humidity (rh) on wet-spun oriented films of hyaluronate (HA)
      prepared with various counterions. Complete swelling measurements have been
      obtained through optical microscopy for films of Cs-, Mg-, and CaHA. IR
      spectroscopy of Cs-, Mg-, Ca-, and LiHA films was performed for skeletal
      vibrations (800-1000 cm(-1)) and for vibrational modes (1150-1300 cm(-1))
      attributed to C-C and C-O stretching modes and C-C-H and C-O-H bending modes.
      These techniques reveal evidence of a counterion-dependent phase transition
      occuring at high relative humidities. Optical birefringence measurements on the
      polycrystalline samples showed order before and disorder after the transition
      from lower to higher humidity.

PMID- 10636096
TI  - Common mucosal immunity: a novel hypothesis.

PMID- 10636095
TI  - Bombesin recovers gut-associated lymphoid tissue and preserves immunity to
      bacterial pneumonia in mice receiving total parenteral nutrition.
AB  - OBJECTIVE: To study the ability of bombesin (BBS) to recover gut-associated
      lymphoid tissue (GALT) and preserve immunity in a lethal model of Pseudomonas
      aeruginosa (Ps) pneumonia in mice receiving total parenteral nutrition (TPN).
      SUMMARY BACKGROUND DATA: TPN causes depression of mucosal immunity compared with
      enterally fed animals, which may explain the increased incidence of pneumonia in
      parenterally fed trauma patients. BBS prevents this TPN-induced GALT atrophy,
      depressed gastrointestinal and respiratory tract IgA levels, and impaired
      antiviral IgA-mediated mucosal immunity. The authors examined whether some
      supplement could be added to TPN to avoid this GALT atrophy and lower the
      incidence of infectious complications in the parenterally fed animal. METHODS:
      Male mice were randomized to chow or intravenous (IV) TPN. After 5 days of IV
      TPN, mice received 0, 1, 2, or 3 days of BBS IV three times a day and then were
      killed to harvest Peyer's patch, intraepithelium, and lamina propria for cell
      yields. Gastrointestinal and respiratory tract IgA levels were analyzed by enzyme
      linked immunosorbent assay. Next, mice underwent intranasal inoculation with
      liposomes alone (nonimmune) or liposome-containing Ps polysaccharide. Ps immune
      mice were catheterized and randomized to chow, IV TPN, or IV TPN + BBS. The
      liposome group received chow but no IV catheter. These mice were given an LD90
      dose of intratracheal Ps, and death rates were recorded. RESULTS: GALT and
      gastrointestinal and respiratory tract IgA levels improved to those in chow-fed
      mice after 3 days of BBS. Immunization reduced the death rate from 92% in chow
      fed liposome-only animals to 20% in immunized animals. TPN-fed animals lost their
      mucosal immunity, with a death rate of 86% compared with 21% in the TPN + BBS
      group. CONCLUSION: The results demonstrate that BBS reverses TPN-induced changes
      in GALT and preserves mucosal immunity. Ps immunization reduces the death rate in
      a gram-negative pneumonia model and maintains gastrointestinal and respiratory
      immunity in Ps immune mice receiving IV TPN.

PMID- 10636098
TI  - Bilateral oblique approach to parathyroid glands.
AB  - OBJECTIVE: To propose a simple and minimally invasive approach for parathyroid
      surgery. SUMMARY BACKGROUND DATA: Minimally invasive approaches to the
      parathyroid glands may involve preoperative morphologic explorations,
      perioperative biologic controls, or videocervicoscopy, a new method. METHODS: The
      authors describe 597 patients who underwent parathyroidectomy through an original
      bilateral oblique approach between 1976 and 1997. None underwent morphologic
      exploration or biologic perioperative monitoring. In primary hyperparathyroidism,
      the four glands are controlled and it is possible to check their abnormalities of
      location or number. In secondary hyperparathyroidism and multiple endocrine
      neoplasia (MEN), a total or subtotal parathyroidectomy is performed. RESULTS: The
      results and vocal morbidity are the same as that from authors using transverse
      cervicotomy, but this approach is more comfortable for the patient and allows
      total exploration of the location through short incisions without bleeding,
      visceral contusions, or muscle lesion. CONCLUSIONS: This cervicotomy is easy and
      secure even if the surgeon is not trained in this approach because it uses and
      respects the anatomy of the cervical fasciae. It can be used without preoperative
      localization, intraoperative monitoring, or specialized material. But this
      approach could be also proposed for unilateral exploration guided by these
      methods and for surgical treatment of recurrent hyperparathyroidism after a
      transverse cervicotomy.

PMID- 10636097
TI  - Cell surface molecules and their prognostic values in assessing colorectal
      carcinomas.
AB  - OBJECTIVE: Carcinomas of the colon and rectum are the third leading cause of
      cancer-related deaths. Although advances in the surgical treatment of primary
      colorectal cancers have lead to improvements in patient survival at early tumor
      stages, treatment of more progressive cancers has not resulted in dramatic
      improvements in patient survival. However, the selection of patient subgroups
      based on their prognosis and other characteristics could result in improved
      outcomes from adjuvant therapies in patients with Dukes B and C carcinomas.
      METHODS: The authors reviewed the available data on the value of cell surface
      molecules in assessing the prognosis of colorectal carcinomas, paying specific
      attention to the evaluation of statistical analysis and multivariate procedures.
      RESULTS: Cell surface molecules have been identified on colorectal carcinoma
      cells whose expression appears to be related to malignant transformation, tumor
      progression, or patient prognosis. Among these cell surface molecules, various
      cell adhesion molecules, growth factor receptors, proteinases, and their
      receptors and inhibitors have been identified as potentially useful prognostic
      markers. CONCLUSIONS: Although data exist on the prognostic values of certain
      cell surface markers, the use of multivariate analysis for the identification of
      valuable prognostic factors remains uncommon. Using reproducible and standardized
      multivariate analysis procedures, new tumor markers should be carefully examined
      for their biologic and prognostic relevance before being considered as
      potentially useful in the management of colorectal cancers.

PMID- 10636099
TI  - The false-positive parathyroid sestamibi: a real or perceived problem and a case
      for radioguided parathyroidectomy.
AB  - OBJECTIVE: To demonstrate that the positive parathyroid sestamibi scan, if
      correctly interpreted and applied, truly represents a parathyroid adenoma, never
      a "false-positive" scan. SUMMARY BACKGROUND DATA: Although the sestamibi scan is
      widely ordered preoperatively to locate parathyroid adenomas, concern about a
      false-positive scan often causes surgeons to distrust the results. Tissues such
      as thyroid adenomas and lymph nodes have been blamed for false-positive studies,
      but the radioactivity of these presumed false-positive tissues has never been
      measured. METHODS: Over an 1 8-month period, 17 patients were referred for
      persistent primary hyperparathyroidism after undergoing at least one neck
      exploration. All patients had a sestamibi scan prior to their initial operation
      that was interpreted as clearly positive and then, during or after an
      unsuccessful operation, deemed false-positive by the surgeon. At the authors'
      institution, all patients underwent repeat sestamibi scintigraphy and were taken
      to the operating room while radioactive for a minimally invasive radioguided
      parathyroidectomy (MIRP). RESULTS: The authors' sestamibi scans demonstrated the
      same single focus of radioactivity displayed on the outside scans, clearly
      positive. During MIRP, an adenoma was successfully located and removed in all
      patients, with confirmation of the diagnosis by quantitative differential
      radioactivity and subsequent histologic examination. Removal of the radioactive
      tissue cured all patients. CONCLUSION: Intraoperative nuclear mapping permitted
      identification and removal of parathyroid adenomas in all patients with positive
      sestamibi scans that had previously been labelled false-positive, indicating that
      each patient would have been cured during their previous operation if radioguided
      techniques were used. Surgeons should be extremely cautious in deciding
      intraoperatively that a positive sestamibi scan is a false-positive scan.

PMID- 10636100
TI  - Risk factors for surgery and postoperative recurrence in Crohn's disease.
AB  - OBJECTIVE: To assess the impact of possible risk factors on intestinal resection
      and postoperative recurrence in Crohn's disease (CD) and to evaluate the disease
      course. SUMMARY BACKGROUND DATA: The results of previous studies on possible risk
      factors for surgery and recurrence in Crohn's disease have been inconsistent.
      Varying findings may be explained by referral biases and small numbers of
      patients in some studies. METHODS: Data on initial intestinal resection and
      postoperative recurrence were evaluated retrospectively in a population-based
      cohort of 1,936 patients. The influence of concomitant risk factors was assessed
      using uni- and multivariate analyses. RESULTS: The cumulative rate of intestinal
      resection was 44%, 61%, and 71% at 1, 5, and 10 years after diagnosis.
      Postoperative recurrences occurred in 33% and 44% at 5 and 10 years after
      resection. The relative risk of surgery was increased in patients with CD
      involving any part of the small bowel, in those having perianal fistulas, and in
      those who were 45 to 59 years of age at diagnosis. Female gender and perianal
      fistulas, as well as small bowel and continuous ileocolonic disease, increase the
      relative risk of recurrence. CONCLUSIONS: Three of four patients with CD will
      undergo an intestinal resection; half of them will ultimately relapse. The extent
      of disease at diagnosis and the presence of perianal fistulas have an impact on
      the risk of surgery and the risk of postoperative recurrence. Women run a higher
      risk of postoperative recurrence than men. The frequency of surgery has decreased
      over time, but the postoperative relapse rate remains unchanged.

PMID- 10636101
TI  - Stricture formation in Crohn's disease: the role of intestinal fibroblasts.
AB  - OBJECTIVE: To determine whether intestinal fibroblasts in patients with Crohn's
      disease (CD) have an enhanced capacity to reorganize collagen and thus cause
      stricture formation. SUMMARY BACKGROUND DATA: Stricture formation is a
      characteristic feature of CD that may distinguish it from other forms of
      inflammatory bowel disease. Methods Fibroblasts were obtained at surgery from the
      colon and ileum of patients with CD and ulcerative colitis (UC) and control
      patients. Primary fibroblast cultures were obtained by explant technique.
      Fibroblast contractile activity was measured using fibroblast-populated collagen
      lattices (FPCLs), in which the cultured fibroblasts were seeded in free-floating
      collagen gel matrices that they reorganize and contract. Fibroblast contractile
      activity was measured as the reduction of surface area (mm2) of collagen gel
      matrix at 24-hour intervals for 1 week. RESULTS: Fibroblasts from patients with
      CD displayed enhanced capacity to contract FPCL when compared to UC and control
      fibroblasts. This activity was maximal in fibroblasts recovered from strictured
      regions in CD. Fibroblasts from patients with UC had a contractile capacity
      similar to that of controls. Hydrocortisone inhibited this in vitro contractile
      activity in a dose-dependent manner. CONCLUSIONS: Intestinal fibroblasts in CD
      possess enhanced capacity for collagen reorganization and contractile activity in
      vitro. This activity may be responsible for stricture formation in CD.

PMID- 10636102
TI  - Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic
      factors for survival.
AB  - OBJECTIVE: To analyze the outcome of 200 patients with gastrointestinal stromal
      tumor (GIST) who were treated at a single institution and followed up
      prospectively. SUMMARY BACKGROUND DATA: A GIST is a visceral sarcoma that arises
      from the gastrointestinal tract. Surgical resection is the mainstay of treatment
      because adjuvant therapy is unproven. METHODS: Two hundred patients with
      malignant GIST were admitted and treated at Memorial Hospital during the past 16
      years. Patient, tumor, and treatment variables were analyzed to identify patterns
      of tumor recurrence and factors that predict survival. RESULTS: Of the 200
      patients, 46% had primary disease without metastasis, 47% had metastasis, and 7%
      had isolated local recurrence. In patients with primary disease who underwent
      complete resection of gross disease (n = 80), the 5-year actuarial survival rate
      was 54%, and survival was predicted by tumor size but not microscopic margins of
      resection. Recurrence of disease after resection was predominantly intraabdominal
      and involved the original tumor site, peritoneum, and liver. CONCLUSIONS: GISTs
      are uncommon sarcomas. Tumor size predicts disease-specific survival in patients
      with primary disease who undergo complete gross resection. Tumor recurrence tends
      to be intraabdominal. Investigational protocols are indicated to reduce the rate
      of recurrence after resection and to improve the outcome for patients with GIST.

PMID- 10636103
TI  - Indicators for treatment strategies of colorectal liver metastases.
AB  - OBJECTIVE: To analyze the survival predictors of patients undergoing hepatectomy
      for colorectal liver metastasis to determine useful indicators for therapy
      selection. SUMMARY BACKGROUND DATA: Although recurrence develops in more than two
      thirds of patients undergoing hepatectomy for colorectal liver metastasis,
      preoperative characteristics that might predict such recurrence have yet to be
      clearly identified. METHODS: Clinicopathologic data of 85 consecutive patients
      with colorectal cancer who underwent a curative resection of primary lesions and
      metastatic liver diseases at one institute were analyzed using the multivariate
      method with respect to both the metastatic state and the primary lesion. RESULTS:
      Multivariate analysis indicated that the aggressiveness of the primary tumor,
      early liver metastasis, and a large number of liver metastases were the
      characteristics that could be detected before hepatectomy and that independently
      indicated a worse survival. A three-ranked classification based on these
      coefficients (H-staging) was significantly related to both the recurrence rate
      within 6 months (7% in H-stage A, 30% in B, and 44% in C) and the 5-year survival
      rates (55%, 14%, and 0% respectively). An additional scoring system (H'-staging)
      based on the aggressiveness of the primary tumor and the level of
      carcinoembryonic antigen 1 to 3 months after hepatectomy was found to be related
      to the mode of subsequent recurrence and surgical resectability of the recurrent
      foci. CONCLUSIONS: H-staging can provide useful prognostic information for the
      treatment of liver metastasis. H-staging could also help in predicting the
      possible mode of recurrence after hepatectomy and in determining the most
      suitable mode of additional therapy. Further multiinstitutional studies based on
      a large collective database will confirm the utility of these two staging
      systems.

PMID- 10636104
TI  - Implications of human macrophage metalloelastase and vascular endothelial growth
      factor gene expression in angiogenesis of hepatocellular carcinoma.
AB  - OBJECTIVE: To determine molecular mechanisms involved in angiogenesis of
      hepatocellular carcinoma (HCC). SUMMARY BACKGROUND DATA: Tumor angiogenesis is
      believed to derive from the balance between angiogenic stimulators and
      inhibitors. It has been suggested that the switch to the angiogenic phenotype
      requires both upregulation of the first and downregulation of the second.
      However, its molecular basis in vivo remains obscure. In this study the authors
      analyze the participation of two factors in angiogenesis of HCC- human macrophage
      metalloelastase (HME), a matrix metalloproteinase responsible for the generation
      of angiostatin, a potent angiogenesis inhibitor, and vascular endothelial growth
      factor (VEGF), the most potent endogenous angiogenic factor. METHODS: Tumorous
      and contiguous nontumorous tissues from 25 patients with HCC who underwent
      curative partial hepatectomy were subjected to Northern blot analysis to detect
      HME and VEGF messenger RNA (mRNA) expression. Western blot analysis was used to
      detected angiostatin. Tumor vascularity was evaluated using hepatic angiography.
      RESULTS: Eleven of the 15 cases expressing the HME gene showed hypovascular
      tumors, whereas hypervascular tumors were seen in 9 of the 10 HME-negative cases.
      The median of HME mRNA expression (tumorous/nontumorous ratio) was 6.5 (range 0
      264.5) in the hypovascular group and 0 (range 0-3.2) in the hypervascular group.
      A stepwise logistic analysis revealed that HME and VEGF mRNA expression were two
      independent variables significantly affecting the vascularity of HCC tumors.
      CONCLUSION: HME gene expression is significantly associated with hypovascular
      tumors; moreover, angiogenesis in HCC is not determined by a single factor, but
      depends on the net balance between HME and VEGF gene expressions.

PMID- 10636105
TI  - Liver adenomatosis: reappraisal, diagnosis, and surgical management: eight new
      cases and review of the literature.
AB  - OBJECTIVE: Liver adenomatosis (LA) is a rare disease originally defined by Flejou
      et al in 1985 from a series of 13 cases. In 1998, 38 cases were available for
      analysis, including eight personal cases. The aim of this study was to review and
      reappraise the characteristics of this rare liver disease and to discuss
      diagnosis and therapeutic options. BACKGROUND: LA was defined as the presence of
      >10 adenomas in an otherwise normal parenchyma. Neither female predominance nor a
      relation with estrogen/progesterone intake has been noted. Natural progression is
      poorly known. METHODS: The clinical presentation, evolution, histologic
      characteristics, and therapeutic options and results were analyzed based on a
      personal series of eight new cases and an updated review of the literature.
      RESULTS: From a diagnostic standpoint, two forms of liver adenomatosis with
      different presentations and evolution can be defined: a massive form and a
      multifocal form. The role of estrogen and progesterone is reevaluated. The risks
      of hemorrhage and malignant transformation are of major concern. In the authors'
      series, liver transplantation was indicated in two young women with the massive,
      aggressive form, and good results were obtained. CONCLUSION: Liver adenomatosis
      is a rare disease, more common in women, where outcome and evolution vary and are
      exacerbated by estrogen intake. Most often, conservative surgery is indicated.
      Liver transplantation is indicated only in highly symptomatic and aggressive
      forms of the disease.

PMID- 10636106
TI  - Preoperative versus postoperative endoscopic retrograde cholangiopancreatography
      in mild to moderate gallstone pancreatitis: a prospective randomized trial.
AB  - OBJECTIVE: To determine whether endoscopic retrograde cholangiopancreatography
      (ERCP) and common bile duct (CBD) stone extraction should be performed routinely
      before surgery or'selectively after surgery in patients with mild to moderate
      gallstone pancreatitis. SUMMARY BACKGROUND DATA: The role and timing of ERCP in
      mild to moderate gallstone pancreatitis remains controversial. Routine
      preoperative ERCP identifies persisting CBD stones but carries risks of
      complications and may delay definitive care. Selective postoperative ERCP,
      performed only if a CBD stone is seen on intraoperative cholangiography (IOC),
      avoids unnecessary ERCP but risks unsuccessful stone extraction. METHODS: A
      prospective, randomized study of consecutive patients with gallstone pancreatitis
      was conducted. Using previously determined criteria, patients with acute
      cholangitis or necrotizing pancreatitis were excluded. Patients considered at
      high risk for persisting CBD stones (CBD size > or =8 mm on admission ultrasound,
      serum total bilirubin > or = 1.7 mg/dL, or serum amylase > or = 150 U/L on
      hospital day 4) were randomly assigned to routine preoperative ERCP followed by
      laparoscopic cholecystectomy, or laparoscopic cholecystectomy with selective
      postoperative ERCP and endoscopic sphincterotomy only if a CBD stone was present
      on IOC. Primary end points were costs, length of hospital stay, and the combined
      treatment failure rates (failure of diagnostic ERCP and IOC, complications of
      ERCP and endoscopic sphincterotomy, and complications of surgery). RESULTS: One
      hundred fifty-four consecutive patients with gallstone pancreatitis were
      evaluated prospectively for study eligibility. Sixty patients met the
      randomization criteria. Thirty patients were randomized to routine preoperative
      ERCP and 29 patients to selective postoperative ERCP (1 patient refused). Age,
      admission laboratory values, and APACHE II and Imrie scores were similar in both
      groups. By protocol, ERCP was performed in all patients in the preoperative ERCP
      group. In the postoperative ERCP group, ERCP was necessary in only 7 of 29
      patients (24%). Mean hospital stay was significantly longer in the routine
      preoperative ERCP group (11.7 days) than in the selective postoperative ERCP
      group (9.0 days). Mean total cost was higher in the preoperative ERCP group
      ($9,426) than in the postoperative ERCP group ($7,798). The combined treatment
      failure rate was 10% in both groups. CONCLUSIONS: In patients with mild to
      moderate gallstone pancreatitis without cholangitis, selective postoperative ERCP
      and CBD stone extraction is associated with a shorter hospital stay, less cost,
      no increase in combined treatment failure rate, and significant reduction in ERCP
      use compared with routine preoperative ERCP.

PMID- 10636107
TI  - Lack of correlation between failure of gut barrier function and septic
      complications after major upper gastrointestinal surgery.
AB  - OBJECTIVE: To determine the influence of abnormal gut barrier function on the
      risk of septic complications in patients undergoing major resectional surgery for
      upper gastrointestinal cancer. SUMMARY BACKGROUND DATA: A failure of the gut
      mucosal barrier to exclude bacteria and endotoxin from the portal and systemic
      circulation is incriminated in the development of sepsis and multiple organ
      failure. Although the experimental data is compelling, corroborative evidence
      from studies in humans is sparse. This study attempted to correlate both
      preoperative gut barrier dysfunction and the pattern of change after surgery with
      septic outcome. METHODS: Sixty-eight patients undergoing curative resectional
      surgery for upper gastrointestinal cancer were monitored for 30-day septic
      morbidity (intraabdominal abscesses/empyema and pneumonia). Intestinal
      permeability, serum IgM and IgG anti-endotoxin antibodies (EndoCAb), and serum C
      reactive protein were measured before surgery and on postoperative days 1 and 7.
      RESULTS: Increased intestinal permeability before surgery did not predict septic
      outcome. Major surgery was associated with increased intestinal permeability and
      evidence of endotoxin exposure. Comparing sepsis and nonsepsis groups, however,
      there was no significant difference in intestinal permeability, endotoxin
      exposure, and the acute phase response after surgery. CONCLUSIONS: This study
      demonstrates that gut barrier dysfunction occurs after surgery, but the magnitude
      of change does not differentiate patients in whom sepsis develops and those in
      whom it does not. Preoperative increased intestinal permeability had no
      predictive value for sepsis. This study failed to support the thesis that gut
      barrier dysfunction is directly linked to sepsis.

PMID- 10636108
TI  - Total warm ischemia and reperfusion impairs flow in all rat gut layers but
      increases leukocyte-vessel wall interactions in the submucosa only.
AB  - OBJECTIVE: To study the effect of warm ischemia and reperfusion (I/R) on local
      perfusion and leukocyte-vessel wall interactions in vivo in all small bowel
      layers, and to quantify small bowel tissue injury histologically and by measuring
      intestinal fatty acid binding protein (I-FABP) release from the enterocytes.
      SUMMARY BACKGROUND DATA: Gut injury as a result of I/R plays a pivotal role in a
      variety of clinical conditions, such as small bowel transplantation, heart or
      aortic surgery, and (septic) shock. The precise mechanism behind I/R injury and
      the role of microvascular changes remain unclear. The influence of warm I/R of
      the gut on microvascular parameters in the different gut layers has not been
      studied before. METHODS: Anesthetized Lewis rats were either subjected to 30
      minutes of ischemia and 1 hour of reperfusion or sham-treated as controls. After
      ligating the inferior mesenteric artery, total warm ischemia was induced by
      clamping the superior mesenteric artery. Intravital video microscopic
      measurements were obtained at intervals. Tissue injury of the small bowel and
      other organs was histologically evaluated afterward. In addition, plasma levels
      of I-FABP were determined to measure enterocyte damage. RESULTS: After ischemia,
      mean red blood cell velocity decreased significantly in all layers of the small
      bowel, but no diameter changes were observed. Leukocyte-vessel wall interactions
      increased in the submucosa but not in the muscle layers. Plasma levels of I-FABP
      significantly increased from 30 minutes of reperfusion onward. The intestinal
      mucosa was severely injured; no histologic damage was detected in other tissues.
      CONCLUSIONS: This is the first in vivo study showing that total warm ischemia of
      the rat gut impairs perfusion in the whole small bowel, whereas leukocyte-vessel
      wall interactions increase in the submucosal layer only. Therefore, the early
      inflammatory response to I/R seems to be limited to the submucosa. Both
      microvascular effects may have contributed to the severe morphologic and
      functional mucosal injury observed after I/R.

PMID- 10636109
TI  - Intestinal ischemia and reperfusion impairs vasomotor functions of pulmonary
      vascular bed.
AB  - OBJECTIVE: To investigate the effects of intestinal ischemia and reperfusion
      (I/R) on the pulmonary vascular endothelium and smooth muscle. SUMMARY BACKGROUND
      DATA: Respiratory failure is an important cause of death and complications after
      intestinal I/R. Although the mechanism of respiratory failure in this setting is
      complex and poorly understood, recent studies of lung injury suggest that
      endothelial dysfunction may play a significant role. METHODS: A rat model of
      acute lung injury was studied after 60 minutes of superior mesenteric arterial
      occlusion followed by either 120 or 240 minutes of reperfusion. The pulmonary
      vasomotor function was examined in isolated lungs perfused at a constant flow
      rate. RESULTS: Sixty minutes of intestinal ischemia followed by 120 or 240
      minutes of reperfusion led to a significant reduction in the ability of the
      pulmonary vasculature to respond to angiotensin II, acetylcholine, and calcium
      ionophore but not to nitroglycerin. The vasoconstriction response to N(G)-nitro-L
      arginine methyl ester, which is a measure of basal nitric oxide release, was
      diminished in the 240-minute reperfusion group. Intestinal I/R was also
      associated with pulmonary leukosequestration and increased pulmonary
      microvascular leakage. CONCLUSIONS: Basal and agonist-stimulated release of
      nitric oxide from the pulmonary vascular endothelium and the ability of pulmonary
      smooth muscle to contract in response to angiotensin II were impaired by
      intestinal I/R. Such functional impairment in both pulmonary vascular endothelium
      and smooth muscle may contribute to the alveolocapillary dysfunction and
      pulmonary hypertension found in acute lung injury after intestinal I/R.

PMID- 10636110
TI  - Small amount of low-residue diet with parenteral nutrition can prevent decreases
      in intestinal mucosal integrity.
AB  - OBJECTIVE: To investigate the suitable combination ratio of low-residue diet
      (LRD) and parenteral nutrition (PN) for nutritional support of surgical patients.
      SUMMARY BACKGROUND DATA: Bacterial translocation (BT) is a severe complication of
      total parenteral nutrition (TPN). However, it is sometimes impossible to supply
      sufficient amounts of nutrients to surgical patients by the enteral route. The
      authors reported previously that concomitant use of LRD with PN provided
      preferable nutritional support for patients undergoing surgery for colorectal
      cancer. METHODS: Ninety male Donryu rats were used for three experiments. In
      experiment 1, rats were divided into two groups to receive TPN or total enteral
      nutrition with LRD. In experiment 2, rats were divided into six groups, receiving
      variable amounts of LRD. In experiment 3, rats were divided into five groups to
      receive isocaloric nutritional support with variable proportions of PN and LRD.
      Intestinal permeability was assessed by monitoring urinary excretion of
      phenolsulfonphthalein. BT was assessed in tissue cultures of mesenteric lymph
      nodes and spleen. RESULTS: In experiment 1, increases in intestinal permeability
      and BT were observed in rats maintained on 7-day TPN, but not in those maintained
      on total enteral nutrition for up to 14 days. In experiment 2, the changes in
      body weight of rats were correlated with the dose of LRD. However, the intestinal
      permeability was increased only in rats receiving LRD at 15 kcal/kg per day. In
      experiment 3, additive LRD corresponding to 15% of total caloric intake prevented
      increases in intestinal permeability and BT. CONCLUSION: Combined nutritional
      therapy consisting of PN and small amounts of LRD can provide better nutritional
      support than TPN for surgical patients.

PMID- 10636111
TI  - Different effects of lung volume reduction surgery and lobectomy on pulmonary
      circulation.
AB  - OBJECTIVE: To clarify the effects of lung volume reduction surgery (LVRS) on
      cardiopulmonary circulation during exercise in comparison with pulmonary
      lobectomy for lung cancer. SUMMARY BACKGROUND DATA: LVRS improves pulmonary
      function and dyspnea symptoms acutely in selected patients with heterogeneous
      emphysema. However, there are few data concerning the effects of LVRS on the
      cardiopulmonary circulation, especially during exercise. METHODS: Pulmonary
      function tests and pulmonary hemodynamic study at rest and during exercise were
      performed before and 6 months after LVRS (seven patients) or pulmonary lobectomy
      (eight patients). In the workload test, an electrically braked bicycle ergometer
      (25 w) was used in the supine position for at least 2 minutes or until exhaustion
      or breathlessness developed. RESULTS: After lung lobectomy, the values of vital
      capacity, percentage of predicted vital capacity, forced expiratory volume in 1
      second, percentage of predicted forced expiratory volume in 1 second, residual
      volume/total lung capacity, and maximal voluntary ventilation deteriorated
      significantly. Six months after LVRS, however, vital capacity, percentage vital
      capacity showed no significant change, and forced expiratory volume in 1 second,
      percentage of forced expiratory volume in 1 second, diffusing capacity for carbon
      monoxide, and maximal voluntary ventilation showed marked improvement. Cardiac
      index was changed neither at rest nor during exercise in either group by the
      operation. Although postoperative pulmonary arterial pressure in the lobectomy
      group was significantly increased by the exercise, LVRS did not affect
      postoperative pulmonary arterial pressure at rest or during exercise. Pulmonary
      capillary wedge pressure in the lobectomy group showed no significant change
      after the operation, whereas LVRS ameliorated the marked elevation of pulmonary
      capillary wedge pressure observed during exercise. After lobectomy, significant
      increases in the pulmonary vascular resistance index were observed at rest and
      during exercise. LVRS markedly increased the pulmonary vascular resistance index
      at rest but not during exercise. In the lobectomy group, the postoperative flow
      pressure curve moved upward, and its gradient became steeper than the
      preoperative one. In the LVRS group, the curve moved upward in a parallel
      fashion. These results show that much more right-sided heart work is needed to
      achieve the same cardiac output against higher pulmonary arterial pressure, not
      only after lobectomy but also LVRS. CONCLUSION: The current study demonstrated
      that the effects of LVRS on the cardiopulmonary circulation were not negligible,
      especially during exercise, and successful LVRS may depend on improved
      respiratory function and also preserved cardiac function that can tolerate the
      damage to the pulmonary vascular bed induced by this operation.

PMID- 10636112
TI  - Technical refinement in adult-to-adult living donor liver transplantation using
      right lobe graft.
AB  - OBJECTIVE: To report the authors' experience with living donor liver
      transplantation in adults using right lobe liver grafts, performed by a modified
      technique. SUMMARY BACKGROUND DATA: The initial results of seven living donor
      liver transplants in adults using extended right lobe grafts were satisfactory,
      but serious complications occurred in two donors, and six recipients required
      repeat laparotomy. Another 11 similar operations were performed. Further
      evaluation was made with the aim of improving the postoperative outcome. METHODS:
      From December 1996 to August 1998, 11 patients underwent living donor liver
      transplantation using right lobe grafts. The first four patients underwent
      surgery using methods previously designed and the next seven underwent a
      modification designed to minimize devitalized tissues on the liver transection
      surface, improve hepatic venous drainage, and reduce the number of hepatic duct
      orifices. RESULTS: There were no donor deaths. Donor complications included
      cholestasis (n = 1) and minor wound infection (n = 1). All the first four
      recipients required a repeat laparotomy for infected necrotic liver transection
      surface (n = 1), acute pancreatitis (n = 1), hepatic vein thrombosis (n = 1), and
      leakage from one of the two bilioenteric anastomoses (n = 1). The patient with
      hepatic vein thrombosis died. In the last seven recipients, all of whom survived
      the operation, one required a repeat laparotomy with the discovery of a
      methicillin-resistant Staphylococcus aureus culture of fibrinous exudate at the
      left subphrenic peritoneum, and another had right hepatic duct stump necrosis.
      The latter was likely related to hypovolemic shock secondary to bleeding from the
      right saphenous vein on removal of a hemofiltration catheter. Comparison of the
      incidence of repeat laparotomy between the first four and the remaining seven
      recipients showed a significant trend of improvement. Combining the result of the
      seven patients reported previously, the improvement in terms of relaparotomy rate
      is significant. CONCLUSION: With modification of surgical technique, living donor
      liver transplantation in adults using right lobe liver grafts can become a
      relatively safe procedure.

PMID- 10636113
TI  - Anterior tension-free repair of recurrent inguinal hernia under local anesthesia:
      a 7-year experience in a teaching hospital.
AB  - OBJECTIVE: To describe a 7-year experience with recurrent inguinal hernia repair
      performed mainly with tension-free mesh or plug technique under local anesthesia
      through the anterior approach, and to evaluate the safety and effectiveness of
      this method of treatment. METHODS: One hundred forty-five elective and 1
      emergency herniorrhaphies for recurrent groin hernia were performed in 141
      subjects (134 men and 7 women) with a mean age of 65 years (range 30-89).
      Concomitant medical and surgical problems were present in 73% and 8% of subjects,
      respectively. In 28 instances, the relapsed hernia had already been operated on
      once or twice for recurrence. A traditional hernioplasty had been previously
      performed in the vast majority of cases (136). Tension-free mesh or plug
      techniques through an anterior approach under local anesthesia were performed in
      144 reoperations. Preperitoneal mesh repair and general or spinal anesthesia were
      used in all but one case when herniorrhaphy was performed during simultaneous
      operations. RESULTS: Mean hospital stay after surgery was 1.5 days (range 3 hours
      14 days). No perioperative deaths occurred in this series. General complications
      were one case of acute intestinal bleeding and two cases of urinary retention.
      Local complications consisted of eight (5.5%) minor complications and one case of
      orchitis (0.7%) followed by testicular atrophy. In no instance was postoperative
      neuralgia or chronic pain reported. Two re-recurrences occurred. CONCLUSIONS:
      Given the low complication rate in this and other reported series and the absence
      of surgical or general complications described after preperitoneal open or
      laparoscopic repair and after general and spinal anesthesia, anterior mesh repair
      under local anesthesia seems to be a low-cost surgical technique that can be
      safely and effectively used even in a teaching hospital for the treatment of the
      majority of patients with recurrent groin hernias.

PMID- 10636115
TI  - Sentinel node biopsy in breast cancer.

PMID- 10636114
TI  - Early wound healing exhibits cytokine surge without evidence of hypoxia.
AB  - OBJECTIVE: To ascertain the spatial and temporal relation of wound hypoxia to the
      cell types involved, expression of selected angiogenic cytokines, the
      proliferative status of cells in the wound site, and angiogenesis. SUMMARY
      BACKGROUND DATA: Hypoxia is considered to drive the angiogenic response by
      upregulating angiogenic cytokines observed during wound healing. But this
      correlation has not been shown on a cell-to-cell basis in vivo because of
      limitations in measuring tissue PO2 at the cellular level. METHODS: Using punch
      biopsy wounds in rats as a wound healing model, the distributions of vascular
      endothelial growth factor, transforming growth factor-beta, tumor necrosis factor
      alpha, and pimonidazole adducts (as a hypoxia marker) were followed
      immunohistochemically during the healing process. RESULTS: Hypoxia was absent on
      day 1 after wounding, even though angiogenesis and maximal expression of
      cytokines were observed in the wounds. Hypoxia peaked in the granulation tissue
      stage at day 4 and correlated with increased cellularity and cellular
      proliferation. Hypoxia started to decrease after day 4 and was limited to the
      remnant blood vessels and epithelial layer in the scar tissue. CONCLUSIONS:
      Induction of angiogenic cytokines early during wound healing may be due to
      triggering mechanisms other than hypoxia. Alternatively, the unique pattern of
      development and decline of cellular hypoxia as wound cellularity and
      proliferation regress suggest its involvement in initiating vascular regression
      during the later stages of healing.

PMID- 10636116
TI  - The question of familial meningiomas and schwannomas: NF2B or not to be?

PMID- 10636117
TI  - Viral hide-and-seek in sporadic ALS: a new challenge.

PMID- 10636118
TI  - Neurology and psychiatry: closing the great divide.

PMID- 10636119
TI  - Total brain N-acetylaspartate: a new measure of disease load in MS.
AB  - OBJECTIVE: To quantitate the extent of neuronal cell loss in MS via the whole
      brain's N-acetylaspartate (NAA) concentration (WBNAA). METHODS: Because NAA is
      assumed to be present only in neuronal cell bodies and their axons, we measured
      WBNAA as a marker for viable neurons in 12 patients (9 women and 3 men, 26 to 53
      years of age) suffering from relapsing-remitting (RR) MS for at least 5 years and
      compared them with 13 age- and sex-matched normal controls. Total brain NAA was
      determined with proton MR spectroscopy, and WBNAA was obtained by dividing it by
      the total brain volume, calculated from high resolution MRI. RESULTS: The WBNAA
      of the RR MS patients was lower than their matched controls (p<0.005). This
      difference was greater among older than younger subjects. The linear prediction
      equations of WBNAA with age indicate a faster, x10, decline in the patients,
      approximately 0.8% per year of age (p = 0.022). CONCLUSION: The age-dependent
      decrease of whole brain N-acetylaspartate (WBNAA) in the patients suggests that
      progressive neuronal cell loss is a cardinal feature of this disease. WBNAA
      offers a quick, highly reproducible measure of disease progression and may be an
      important marker of treatment efficacy in MS as well as other neurodegenerative
      diseases.

PMID- 10636120
TI  - Detection and cellular localization of enterovirus RNA sequences in spinal cord
      of patients with ALS.
AB  - OBJECTIVE: To investigate the possible association of persistent enterovirus (EV)
      infection with the development of ALS. BACKGROUND: Although ALS is a clinically
      well-defined motor neuron disease, little is known about the etiology and
      pathogenesis of the sporadic cases. Among the different causes that have been
      hypothesized, conflicting results have been reported about the possible role of
      persistent enteroviral infection. METHODS: Reverse transcriptase-PCR (RT-PCR) and
      direct RT in situ PCR (RT-IS-PCR) were performed in formaldehyde-fixed spinal
      cord samples of 17 patients with confirmed ALS and 29 control subjects with no
      history of motor neuron disease. When obtained, PCR products were sequenced
      subsequently. RESULTS: Using direct RT-IS-PCR, EV nucleic acid sequences were
      detected in 15 (88.3%) of 17 patients with ALS compared to 1 (3.4%) of 29 control
      subjects. PCR products were located in neuronal cell bodies of the anterior horns
      of the spinal cord. The RT-PCR products obtained in 13 of the 17 patients with
      ALS showed between 94% and 86% homology with echovirus 7 sequences. CONCLUSION:
      The 88.3% rate of detection of enterovirus (EV) nucleic acids in the neuronal
      cell bodies within the gray matter of the spinal cord of patients with ALS
      strongly suggests association between persistent EV RNA and ALS. Further work is
      required to confirm that the persisting EV sequences we detected are somehow
      involved in the development of ALS.

PMID- 10636121
TI  - Multifocal inflammatory demyelinating neuropathy: a distinct clinical entity?
AB  - BACKGROUND: Several patients have been reported with an asymmetric sensory or
      sensorimotor demyelinating neuropathy not fulfilling the diagnostic criteria for
      chronic inflammatory demyelinating polyneuropathy or multifocal motor neuropathy.
      OBJECTIVE: To present the clinical, electrophysiologic, radiologic, and
      pathologic features of six patients with an asymmetric sensory or sensorimotor
      demyelinating neuropathy. RESULTS: All six patients were initially affected in
      only one limb; in four patients the neuropathy progressed to other limbs in an
      asymmetric fashion during several years. On electrophysiologic examination,
      evidence of multifocal demyelination and conduction block in motor and sensory
      nerves was found in all patients. MRI of the brachial plexus revealed swollen
      nerves and an increased signal intensity on T2-weighted imaging in four patients.
      A biopsy sample taken from the brachial plexus of one patient revealed evidence
      of inflammation. All patients showed a beneficial response to IV immunoglobulin
      treatment. Thirty-four similar patients have been reported previously, many of
      whom were initially diagnosed as having various other (nontreatable) diseases.
      CONCLUSIONS: The authors propose calling this neuropathy "multifocal inflammatory
      demyelinating neuropathy" and considering it as a distinct clinical entity to
      facilitate early diagnosis of this treatable disorder.

PMID- 10636122
TI  - Physiologic-pathologic correlation in Guillain-Barre syndrome in children.
AB  - OBJECTIVE: To correlate electrophysiologic patterns with sural nerve pathology in
      children with Guillain-Barre syndrome (GBS). BACKGROUND: Based on
      electrophysiologic and pathologic observations, GBS has been divided into
      demyelinating and axonal subtypes. The acute motor axonal neuropathy (AMAN)
      involves predominantly motor nerve fibers with a physiologic pattern suggesting
      axonal damage, whereas the acute inflammatory demyelinating polyneuropathy (AIDP)
      involves both motor and sensory nerve fibers with a physiologic pattern
      suggesting demyelination. In this study, we sought to confirm these observations
      by correlating sural nerve pathology with electrophysiologic findings in GBS
      patients. METHODS: Biopsies of sural nerve from 29 of 50 prospectively studied
      GBS patients were obtained. Nerves were examined by light and electron
      microscopy, and with immunocytochemistry for macrophages, lymphocytes, and
      complement activation products. RESULTS: Sural nerves from AMAN patients were
      normal or had only a few (0.1% to 0.7%) degenerating fibers without lymphocytic
      infiltration or complement activation. One patient with reduced sural sensory
      nerve action potential classified as acute motor sensory axonal neuropathy
      (AMSAN) had many degenerating fibers (2.3%) in the sural nerve. All three AIDP
      patients displayed active demyelination, and in two patients, lymphocytic
      infiltration and complement activation products were observed on the abaxonal
      Schwann cell surface. CONCLUSION: Classification of Guillain-Barre syndrome
      subtypes based on motor conduction studies correlates closely with pathologic
      changes seen in sural nerve. In acute motor axonal neuropathy cases, the sural
      nerve is almost completely spared pathologically. In acute inflammatory
      demyelinating polyneuropathy cases, macrophage-mediated demyelination and
      lymphocytic infiltration are common in the biopsies of sural nerves.

PMID- 10636123
TI  - Electrodiagnostic features of hereditary neuropathy with liability to pressure
      palsies.
AB  - OBJECTIVE: Because diagnosis of hereditary neuropathy with liability to pressure
      palsies (HNPP) frequently is missed or delayed, we looked for electrodiagnostic
      features that raise suspicion of the disorder by making comparisons with two more
      common diseases that mimic it electrophysiologically: chronic inflammatory
      demyelinating polyneuropathy (CIDP) and diabetic polyneuropathy. METHODS: A
      retrospective review of the neuromuscular laboratory database was performed.
      RESULTS: Nine HNPP subjects, 22 with CIDP and 49 with diabetic polyneuropathy. Of
      all the HNPP nerves studied, abnormally slow sensory nerve conduction velocity
      (SNCV) was found in 93%, prolonged distal motor latencies (DML) in 78%, slow
      motor nerve conduction velocity in 31%, and prolonged F-wave latencies in 90%.
      Mean SNCV for HNPP was 85.6%+/-10.6% of the lower limit of normal and
      significantly slower than for CIDP (114.3%+/-20.1%; p<0.0001) or diabetes
      (108.1%+/-14.8%; p<0.0001). Excluding the carpal tunnel site from the analysis
      did not alter this observation: Mean DML were more prolonged in HNPP, even
      without median nerve data in the analysis (118.5%+/-31.0% of the upper limit of
      normal), than in CIDP (103.2%+/-31.6%; p<0.05) or diabetes (86.3%+/-18.3%;
      p<0.0001). Mean HNPP motor nerve conduction velocity was within normal limits.
      CONCLUSIONS: According to findings, hereditary neuropathy with liability to
      pressure palsies (HNPP) has a distinctive background polyneuropathy independent
      of superimposed entrapment neuropathy. It is characterized by diffuse sensory
      nerve conduction velocity (SNCV) slowing and prolongation of distal motor
      latencies with relatively infrequent and minor reduction of motor nerve
      conduction velocities. This indicates disproportionate distal conduction slowing
      in the disorder.

PMID- 10636124
TI  - Ulcero-mutilating neuropathy in an Austrian kinship without linkage to hereditary
      motor and sensory neuropathy IIB and hereditary sensory neuropathy I loci.
AB  - OBJECTIVE: To elucidate genetic heterogeneity in ulcero-mutilating neuropathy.
      BACKGROUND: Ulcero-mutilating features and sensory loss have been observed in
      hereditary sensory neuropathy (HSN) and hereditary motor and sensory neuropathy
      (HMSN). HSN is characterized by marked distal sensory loss, frequent toe and foot
      ulcerations, osteomyelitis, and necrosis, which may be complicated by toe or limb
      amputations. Motor and autonomic nerve involvement can also occur to a variable
      degree. Recently, autosomal-dominant HSN type I was mapped to chromosome 9q22 in
      four families. In two other families with ulcero-mutilating neuropathy, a gene
      locus was assigned to chromosome 3q13-q22. Because motor symptoms were prominent
      in these latter two kinships, the disease was designated HMSN type IIB or Charcot
      Marie-Tooth type 2B (CMT2B) neuropathy. METHODS: We report detailed clinical,
      electrophysiologic, and genetic data on a large Austrian family with ulcero
      mutilating neuropathy, sensory loss, and amputations. RESULTS: Linkage analysis
      with chromosomal markers representing the HSN I and HMSN IIB loci excluded these
      gene loci in our family. CONCLUSIONS: These findings therefore indicate the
      existence of a third gene locus in autosomal-dominant inherited ulcero-mutilating
      neuropathies, showing that these neuropathies are genetically highly
      heterogeneous.

PMID- 10636125
TI  - The ALS patient care database: goals, design, and early results. ALS C.A.R.E.
      Study Group.
AB  - OBJECTIVE: The ALS Patient Care Database was created to improve the quality of
      care for patients with ALS by 1) providing neurologists with data to evaluate and
      improve their practices, 2) publishing data on temporal trends in the care of
      patients with ALS, and 3) developing hypotheses to be tested during formal
      clinical trials. BACKGROUND: Substantial variations exist in managing ALS, but
      there has been no North American database to measure outcomes in ALS until now.
      METHODS: This observational database is open to all neurologists practicing in
      North America, who are encouraged to enroll both incident and prevalent ALS
      patients. Longitudinal data are collected at intervals of 3 to 6 months by using
      standard data collection instruments. Forms are submitted to a central data
      coordinating center, which mails quarterly reports to participating neurologists.
      RESULTS: Beginning in September 1996 through November 30, 1998, 1,857 patients
      were enrolled at 83 clinical sites. On enrollment, patients had a mean age of
      58.6 years +/-12.9 (SD) years (range, 20.1 to 95.1 years), 92% were white, and
      61% were men. The mean interval between onset of symptoms and diagnosis was 1.2+/
      1.6 years (range, 0 to 31.9 years). Riluzole was the most frequently used disease
      specific therapy (48%). Physical therapy was the most common nonpharmacologic
      intervention (45%). The primary caregiver was generally the spouse (77%). Advance
      directives were in place at the time of death for 70% of 213 enrolled patients
      who were reported to have died. CONCLUSIONS: The ALS Patient Care Database
      appears to provide valuable data on physician practices and patient-focused
      outcomes in ALS.

PMID- 10636126
TI  - Pharmacologic reversal of cortical hyperexcitability in patients with ALS.
AB  - OBJECTIVE: To reverse the profile of abnormal intracortical excitability in
      patients with ALS by administering drugs that promote GABAergic transmission.
      BACKGROUND: Transcranial magnetic stimulation (TMS) has revealed abnormalities of
      cortical inhibition in ALS, a reduction of the silent period, and the absence of
      intracortical inhibition normally occurring in response to paired TMS. Impaired
      inhibitory transmission could play a role in the physiopathology of this illness.
      METHODS: Using paired TMS with conditioning stimuli from 1-to-6-msec
      interstimulus intervals, we investigated 16 patients with ALS. The protocol
      included: (1) the "drug-free" profile of paired TMS; (2) paired TMS 30 minutes
      after the intake of diazepam (3.5 mg); (3) paired TMS after 3 weeks' treatment
      with gabapentin (GBP) (600 mg/day) or riluzole (50 mg/twice a day). RESULTS:
      Intracortical inhibition is lost in patients with ALS, and this abnormal profile
      is reversed by diazepam or sustained treatment with GBP. We also noted that motor
      evoked potential amplitudes to single stimuli increased (p<0.01) after diazepam
      and GBP. CONCLUSIONS: The demonstration of pharmacologic reversal of
      hyperexcitability in patients with ALS makes a potentially significant
      contribution toward understanding the pathophysiology of a disease that has so
      far eluded an effective cure.

PMID- 10636127
TI  - Expression of matrix metalloproteinases in the muscle of patients with
      inflammatory myopathies.
AB  - OBJECTIVE: To investigate the role of matrix metalloproteinases (MMPs) in the
      pathogenesis of inflammatory myopathies and the amyloid formation in sporadic
      inclusion body myositis (s-IBM). BACKGROUND: MMPs comprise a family of calcium
      dependent zinc endoproteinases induced by cytokines and secreted by inflammatory
      cells. They enhance T-cell migration or adhesion and degrade components of the
      extracellular matrix proteins. Some MMPs also have been implicated in the
      formation of beta-amyloid. METHODS: We examined the expression of MMPs with
      single and double immunocytochemistry using antibodies against MMP-2, MMP-3, MMP
      7, MMP-9, major histocompatibility complex (MHC) class I, CD8+ cells, macrophage,
      and beta-amyloid precursor protein (beta-APP) on serial muscle biopsy sections
      from patients with s-IBM, polymyositis (PM), dermatomyositis (DM), and disease
      control specimens. The enzyme activity of MMPs was measured by gelatin substrate
      zymography. RESULTS: Only the gelatinases, MMP-9 and MMP-2, were expressed in the
      muscle. In s-IBM and PM, but not the control specimens, MMP-9 and MMP-2
      immunostained the non-necrotic and MHC class-I-expressing muscle fibers, and MMP
      9, but not MMP-2, immunostained the autoinvasive CD8+ cytotoxic T cells.
      Zymography in muscle homogenates confirmed the increased MMP-2 and MMP-9
      enzymatic activity. MMP-2, but not MMP-9, immunostained the rimmed vacuoles in s
      IBM and colocalized with beta-APP, suggesting a possible involvement with the
      amyloid deposits. CONCLUSIONS: Because collagen IV is prominent on the muscle
      membrane, the overexpression of matrix metalloproteinases (MMPs) 2 and 9 on the
      non-necrotic muscle fibers in polymyositis (PM) and sporadic inclusion body
      myositis (s-IBM) may facilitate lymphocyte adhesion and enhance T-cell-mediated
      cytotoxicity by degrading extracellular matrix proteins. The findings may have
      practical implications in considering therapeutic trials with MMP inhibitors in
      patients with PM and s-IBM.

PMID- 10636128
TI  - Population-based analysis of sporadic and type 2 neurofibromatosis-associated
      meningiomas and schwannomas.
AB  - OBJECTIVE: To estimate the incidence of meningiomatosis and schwannomatosis, and
      their familial occurrences and relation to type 2 neurofibromatosis (NF2) in a
      well-defined population. METHODS: Patients with histologically verified
      intracranial, spinal, or peripheral schwannomas or meningiomas, who were
      residents of the Helsinki University Hospital catchment area (population,
      1,713,000) from January 1, 1985, to December 31, 1995, were included in the
      study. The Population Register Center was used to identify relatives of all the
      patients, and their data were linked further to the Finnish Cancer Registry to
      find NF2-related tumors. Detailed pedigrees were constructed for the patients
      with NF2, schwannomatosis, meningiomatosis, patients with relatives with
      histologically verified schwannomas or meningiomas, and patients younger than 25
      years of age at the time of diagnosis. RESULTS: Approximately 3% (12 of 455) of
      the schwannoma patients had multiple schwannomas in association with NF2, and 2%
      (11 of 455) had schwannomatosis without NF2. Two of the patients with
      schwannomatosis (2 of 11) had familial schwannomatosis. Approximately 1% (7 of
      823) of the patients with meningioma had multiple meningiomas in association with
      NF2, and 4% (29 of 823) had meningiomatosis without NF2. No families with
      meningiomatosis were found among the 823 patients with meningioma studied. The
      birth occurrence of NF2 was 1 in 87,410. CONCLUSIONS: The current diagnostic
      criteria of type 2 neurofibromatosis (NF2) seem valid because NF2 patients were
      differentiated rather easily from patients with sporadic schwannomatosis and
      meningiomatosis. Familial meningiomatosis, if it truly exists, is very rare, and
      familial schwannomatosis is uncommon.

PMID- 10636129
TI  - Antifibrinolytic treatment in subarachnoid hemorrhage: a randomized placebo
      controlled trial. STAR Study Group.
AB  - OBJECTIVE: To investigate whether antifibrinolytics in combination with treatment
      to prevent cerebral ischemia improve outcome in patients with subarachnoid
      hemorrhage (SAH) in whom occlusion of the aneurysm is delayed. BACKGROUND:
      Antifibrinolytic treatment reduces rebleeding, but outcome does not improve
      because of a concurrent increase in the occurrence of cerebral ischemia. Because
      treatment of ischemia has improved, antifibrinolytics might now have a beneficial
      effect. METHODS: A prospective, double-blind, placebo-controlled multicenter
      clinical trial was performed. Randomized were 462 patients (229 received
      tranexamic acid, 233 placebo) admitted within 96 hours after onset of SAH, in
      whom treatment of the aneurysm was delayed beyond 48 hours after SAH. All
      patients were treated with calcium antagonists and hypervolemia. At 3 months,
      outcome was assessed with the Glasgow Outcome Scale. The occurrence of cerebral
      ischemia and other complications were recorded, and the effects of treatment were
      related to the clinical condition on admission. RESULTS: Antifibrinolytic
      treatment had no beneficial effect on outcome (relative risk [RR], 1.10; 95%
      confidence limits [CL], 0.91-1.34). Antifibrinolytics significantly reduced the
      occurrence of rebleeding (RR, 0.58; 95% CL, 0.42-0.80); the occurrence of
      ischemic and other complications was the same in the two groups. CONCLUSION:
      Antifibrinolytic treatment combined with treatment to prevent cerebral ischemia
      does not improve outcome.

PMID- 10636130
TI  - Diffusion-weighted MRI in vascular dementia.
AB  - OBJECTIVE: To examine the ability of diffusion-weighted MRI (DWI) to detect
      ongoing cerebral ischemia in patients with vascular dementia (VaD). BACKGROUND:
      VaD due to small-vessel disease results from the cumulative impact of recurrent
      cerebral ischemia. Cerebral ischemia may produce clinical manifestations,
      producing the "stepwise" decline characteristic of VaD. Conventional MRI can
      detect small regions of ischemic damage but cannot determine when injury
      developed. In contrast, DWI shows sensitivity in detecting ischemia of recent
      onset. DESIGN/METHODS: Patients with VaD (n = 30) underwent DWI in addition to
      standard MRI sequences. Patients were divided into two groups according to the
      presence of new focal deficits or mental change within 10 days before MRI. In 10
      patients of positive group, symptomatic neurologic decline occurred an average of
      4.2 days before the imaging procedure. RESULTS: Seven (70%) of 10 patients with a
      recent neurologic event showed 15 new regions of signal abnormality on DWI. The
      anatomic distribution of signal change could account for the patients' new
      symptoms or signs in all but one patient. Similar signal abnormality was detected
      in 4 (20%) of 20 patients without a recent neurologic event. New foci of altered
      signal intensity were distinguishable from prior injuries only with DWI. No
      significant difference was found between patients with and without DWI
      abnormalities in gender, age, Mini-Mental State Examination score, Hachinski
      Ischemic Score, vascular risk factors, or severity of increased signal on T2
      weighted MRI scans. CONCLUSION: Small foci of abnormal signal on diffusion
      weighted MRI (DWI), presumably representing recent small infarcts, occur often in
      vascular dementia (VaD) from small-vessel disease, even in patients without a
      recent "stepwise decline." The results suggest that DWI might be used to monitor
      VaD progression in future observational and interventional studies of this
      disorder.

PMID- 10636131
TI  - Does leukoaraiosis predict morbidity and mortality?
AB  - OBJECTIVE: To determine whether leukoaraiosis predicts morbidity and mortality.
      BACKGROUND: Gait disturbance and leukoaraiosis both are common in the elderly.
      Gait disturbance predicts mortality. Leukoaraiosis may be a unifying factor to
      both gait disturbance and mortality. METHODS: We followed 221 patients
      prospectively evaluated for severity of neurologic deficits by the National
      Institutes of Health (NIH) stroke scale and for leukoaraiosis in seven brain
      regions by CT, graded as absent (n = 119, 54%), mild (in at least one of seven
      brain regions; n = 54, 24%), or severe (present in all seven brain regions; n =
      48, 22%). Pneumonia (n = 27, 12%), falls resulting in fracture requiring
      hospitalization (n = 7, 3%), and death (n = 38, 17%) were end points. RESULTS:
      Severe leukoaraiosis predicted death (Cox hazard ratio [HR] = 2.91; 95% CI = 1.5 
      5.6), pneumonia (HR = 5.1; 95% CI = 2.4 - 10.9), death from pneumonia (HR = 8.3;
      95% CI = 1.5 - 46), and falls (HR = 6.8; 95% CI = 1.5 - 30). Severe leukoaraiosis
      predicted a combined end point of death, pneumonia, and falls (HR = 3.5; 95% CI =
      2 - 6). Other predictors were NIH stroke scale score, age, smoking, diabetes,
      gait score, and referral diagnosis of either dementia or Parkinsonism. Severe
      leukoaraiosis remained a predictor after adjustment for these other factors (HR =
      2.2; 95% CI = 1.2 - 3.9), but was borderline after adjusting for gait (HR = 1.96;
      95% CI = 0.97 - 3.94; p = 0.061). The combination of severe leukoaraiosis and
      gait disturbance had the highest risk (HR = 4.4; 95% CI = 2.4 - 7.9). CONCLUSION:
      Severe leukoaraiosis predicts morbidity and mortality independently of
      preexisting neurologic deficits. The combination of leukoaraiosis and gait
      disturbance carries a poor prognosis.

PMID- 10636132
TI  - Low education and childhood rural residence: risk for Alzheimer's disease in
      African Americans.
AB  - OBJECTIVE: To examine the relationship between level of education and childhood
      rural residence as possible risk factors for AD in African Americans in
      Indianapolis. BACKGROUND: Low level of education has been a risk factor for AD in
      some studies, but childhood rural residence has not been addressed in most of
      these studies. METHODS: A two-stage community-based prevalence study of AD was
      conducted in a random sample of 2,212 African Americans > or =65 years of age. A
      subsample of clinically assessed normal individuals (180) and individuals
      diagnosed with AD (43) were compared on the variables of rural/urban residence in
      childhood and low (< or =6 years) or high (> or =7 years) education. A logistic
      regression model was used with interaction between rural residence and low
      education to estimate odds ratios for the two risk factors combined, adjusting
      for age and gender. RESULTS: Odds ratios for AD: 6.5 (95% CI: 2.6 to 16.7) low
      education/rural residence; 0.5 (95% CI: 0.1 to 2.9) low education/urban
      residence; 1.5 (95% CI: 0.4 to 5.2) high education/rural residence, comparing
      with the group of high education/urban residence. CONCLUSION: Childhood rural
      residence, combined with < or =6 years of school, was associated with an
      increased risk of AD in this sample. It is possible that low education by itself
      is not a major risk factor for AD, but, rather, is a marker for other
      accompanying deleterious socioeconomic or environmental influences in childhood.

PMID- 10636134
TI  - The Oregon brain aging study: neuropathology accompanying healthy aging in the
      oldest old.
AB  - OBJECTIVE: To describe the relationship between neuropathologic aging and
      longitudinal measures of cognitive function in healthy oldest old individuals.
      METHODS: Nondemented individuals without cardiovascular or other age-associated
      diseases of age > or =85 years were followed until death. Regional postmortem
      measures of senile plaque (SP) and neurofibrillary tangle (NFT) severity were
      examined in relationship to clinical status, cognitive measures, and rate of
      cognitive change. RESULTS: Among 19 healthy individuals, 10 became demented or
      had incipient dementia develop. Clinical status and rate of change in cognitive
      scores correlated with increasing brain lesion burden, particularly in
      neocortical regions. Compared to demented individuals, nondemented individuals
      had few or no neocortical NFT (p = 0.009) or SP (p = 0.001). There was a strong
      correlation between rate of cognitive change on Mini-Mental State Examination
      (MMSE) and neocortical NFT (r = 0.859, p = 0.001). The few NFT and SP in
      nondemented patients had a predilection for limbic areas. CONCLUSIONS: These
      results support a continuum in which AD is infrequent in the healthy, cognitively
      stable, oldest old. The minimal abnormalities in cognitively stable individuals
      are consistent with the notion that preclinical pathologic AD precedes obvious
      cognitive impairment. Longitudinal cognitive testing shows an increased burden of
      neuropathologic changes in those who have cognitive decline but are not
      functionally impaired and do not meet criteria for the diagnosis of dementia. The
      strong relationship between cumulative pathologic changes and rate of cognitive
      decline suggests that these lesions may have clinical consequences at any age and
      are not likely to be benign senescent changes.

PMID- 10636133
TI  - AMY plaques in familial AD: comparison with sporadic Alzheimer's disease.
AB  - OBJECTIVE: To assess AMY expression in familial AD (FAD). BACKGROUND: The
      discovery of nonbeta-amyloid (Abeta), plaque-like deposits composed of a 100-kd
      protein (AMY) in sporadic AD (SAD) brains prompted us to determine whether these
      plaques (AMY plaques) also occur in AD due to mutations of the presenilin-1 (PS
      1), presenilin-2 (PS-2), or the amyloid precursor protein (APP) genes. METHODS:
      We used immunohistochemistry and confocal laser scanning microscopy to probe the
      brains of 22 patients with FAD (13 with PS-1, 5 with PS-2, and 4 with APP
      mutations) and 14 patients with SAD. RESULTS: AMY plaques were present in all SAD
      and FAD brains, including an FAD/PS-1 brain from an individual with preclinical
      disease. The morphology of AMY plaques in SAD and FAD brains was
      indistinguishable, but they differed from Abeta deposits because AMY plaques
      lacked an immunoreactive core. AMY plaques sometimes colocalized with Abeta(x-42)
      deposits, but they did not colocalize with Abeta(x-40) plaque cores in either SAD
      or FAD brains. The percent of cortical area occupied by AMY was greater in FAD
      than in SAD brains (mean percent area = 9.8% and 5.9%, t = 2.487, p = 0.018). In
      particular, APP and PS-1 cases had more AMY deposition than PS-2 or SAD cases
      (12.9%, 10.5%, 6.2% in APP, PS-1, and PS-2 AD). CONCLUSIONS: AMY plaques are
      consistently present in familial AD due to presenilin-1 (PS-1), PS-2, and amyloid
      precursor protein mutations, and they can begin to accumulate before the
      emergence of dementia.

PMID- 10636135
TI  - Smoking habits in multiple system atrophy and progressive supranuclear palsy.
      European Study Group on Atypical Parkinsonisms.
AB  - OBJECTIVE: To evaluate smoking habits in patients with multiple system atrophy
      (MSA) and progressive supranuclear palsy (PSP) in a multicenter case-control
      study to determine whether these two forms of atypical parkinsonism share the
      inverse association with smoking previously found in PD. BACKGROUND: No
      epidemiologic studies have been performed on smoking habits in MSA. A previous
      investigation in PSP revealed no differences in smoking habits between patients
      and hospital control subjects. METHODS: Seventy-six MSA patients, 55 PSP
      patients, 140 PD patients, and 134 healthy control subjects were enrolled
      consecutively at seven neurologic clinics from January 1, 1994, to July 31, 1998.
      Detailed information on smoking habits was obtained using a structured
      questionnaire. RESULTS: The comparison between frequencies of never-smokers
      versus ever-smokers (ex-smokers/current smokers; adjusted odds ratio [ORadj],
      0.56; 95% CI, 0.29 to 1.06) and a dose-response analysis for never-smokers,
      moderate smokers (ORadj, 0.64; 95% CI, 0.31 to 1.32), and heavy smokers (ORadj,
      0.47; 95% CI, 0.21 to 1.05) suggest that MSA patients smoke less than population
      control subjects. By contrast, the comparison of frequencies of never-smokers
      versus ever-smokers (ORadj, 0.91; 95% CI, 0.42 to 1.98) and a dose-response
      analysis for never-smokers, moderate smokers (ORadj, 0.68; 95% CI, 0.27 to 1.69),
      and heavy smokers (ORadj, 1.24; CI 95%, 0.51 to 3.06) revealed no differences in
      smoking habits between PSP patients and population control subjects. CONCLUSIONS:
      The fact that the inverse association with smoking found previously in PD is
      shared by multiple system atrophy but not by progressive supranuclear palsy lends
      epidemiologic support to the notion that different smoking habits are associated
      with different groups of neurodegenerative disease.

PMID- 10636136
TI  - Bradykinesia in early Huntington's disease.
AB  - BACKGROUND: Huntington's disease (HD) is generally considered a hyperkinetic
      disorder, although hypokinetic features are part of the motor syndrome. Moreover,
      the striatum is considered to play a key role in initiating and executing motor
      programs and achieving optimal scheduling in response generation. Controversial
      results regarding the association between clinical features and markers of
      progression of the disease might be the result of inadequate restriction of
      clinical signs to the choreatic syndrome. OBJECTIVE: To determine the
      relationship of neurologic motor and cognitive indices in patients with HD with
      intrinsic neuronal loss in the striatum, as measured using raclopride C11 and
      PET. PATIENTS AND METHODS: A cross-sectional study was performed on 11 patients
      with mild HD (stages 0-2). Motor (Unified Huntington's Disease Rating Scale
      [UHDRS], saccadic and tapping speed) and cognitive (verbal fluency, Trail Making
      Test, Stroop Test, Symbol Digit Modalities Test, Conditioned Associative Learning
      Test, and silhouette identification and object decision of the Visual Object and
      Space Perception battery) scores were correlated with raclopride C11 binding.
      RESULTS: Bradykinesia (a summation of five items of the UHDRS motor scale) was
      the best predictor for stage, that is, functional capacity, and showed a highly
      significant relationship with putaminous D2 binding (r = -0.94) and with CAG
      expansion length x years of age (r = 0.96). The exclusion of two patients with a
      rigid-akinetic HD variant did not alter these coefficients. Chorea was less well
      correlated than bradykinesia with D2 binding in all striatal regions. Performance
      on different cognitive tests, especially in timed tasks, was highly correlated
      with raclopride C11 binding in caudate nucleus and ventral striatum. CONCLUSION:
      Loss of D2 binding in the striatum is highly correlated with the deficit in fast
      motor and cognitive processing in patients with early Huntington's Disease. Thus,
      impairment of rapid execution of adequate responses to environmental changes
      seems to be a common manifestation of striatal disorders.

PMID- 10636137
TI  - A locus for paroxysmal kinesigenic dyskinesia maps to human chromosome 16.
AB  - OBJECTIVE: To use genetic linkage analysis to localize a gene for paroxysmal
      kinesigenic dyskinesia (PKD) in a three generation African-American kindred.
      BACKGROUND: PKD is a rare autosomal dominant disorder characterized by episodic
      choreiform or dystonic movements that are brought on or exacerbated by voluntary
      movement. There are individuals with the clinical features of PKD but with no
      family history of the disease, but whether these sporadic cases represent
      spontaneous mutations of PKD or have a distinct condition is unknown. METHODS: A
      genome-wide linkage scan of polymorphic microsatellites at 25 cM resolution was
      performed to localize a gene for PKD in one African-American kindred. Pairwise
      multipoint linkage analyses were performed at different penetrance estimates.
      RESULTS: Evidence for linkage of the kinesigenic form of paroxysmal dyskinesia to
      chromosome 16 was obtained. A maximum lod score of 4.40 at theta = 0 was obtained
      with D16S419. Critical recombinants place the PKD gene between D16S3100 and
      D16S771. CONCLUSIONS: A paroxysmal kinesigenic dyskinesia (PKD) locus lies within
      an 18 cM interval on 16p11.2-q11.2, between D16S3100 and D16S771. A gene for
      infantile convulsions with paroxysmal choreoathetosis has also been mapped to
      this region. These two regions overlap by approximately 6 cM. These two diseases
      could be caused by different mutations in the same gene or two distinct genes may
      lie within this region.

PMID- 10636138
TI  - Shortened cortical silent period in facial muscles of patients with cranial
      dystonia.
AB  - OBJECTIVE: To study the cortical silent period (SP) in the orbicularis oculi and
      perioral muscles in 23 patients with cranial dystonia and 10 age-matched control
      subjects. METHODS: High-intensity magnetic stimuli were delivered with a round
      coil centered at the vertex during a maximal muscle contraction.
      Electromyographic (EMG) responses were recorded from surface electrodes placed
      over the orbicularis oculi and perioral muscles. RESULTS: SPs elicited in upper
      and lower facial muscles had a similar duration. Facial muscle SPs were
      significantly shorter in patients than in control subjects. Patients with
      blepharospasm plus oromandibular dystonia had shorter SPs than patients with
      blepharospasm alone. Although patients' recordings showed reduced voluntary and
      evoked EMG activity, neither activities correlated with the duration of the SP.
      CONCLUSIONS: Silent period (SP) shortening depends neither on the level of
      electromyographic activity nor on segmentary mechanisms. The shortened SP in
      facial muscles reflects hypoexcitability of cortical inhibitory neurons in
      cranial dystonia.

PMID- 10636139
TI  - Functional MRI cerebral activation and deactivation during finger movement.
AB  - OBJECTIVE: To examine interhemispheric interactions of motor processes by using
      functional MRI (fMRI). BACKGROUND: Despite evidence of interhemispheric
      inhibition from animal, clinical, and transcranial magnetic stimulation (TMS)
      studies, fMRI has not been used to explore activation and deactivation during
      unilateral motor tasks. fMRI changes associated with motor activity have
      traditionally been described by comparing cerebral activation during motor tasks
      relative to a "resting state." In addition to this standard comparison, we
      examined fMRI changes in the resting state relative to a motor task. METHODS:
      Thirteen healthy volunteers performed self-paced sequential finger/thumb tapping
      for each hand. During fMRI data acquisition, four epochs were obtained; each
      comprised of 30 seconds of rest, 30 seconds of right hand activity, and 30
      seconds of left hand activity. Resultant echoplanar images were spatially
      normalized and spatially and temporally smoothed. RESULTS: As expected, hand
      movements produced activation in the contralateral sensorimotor cortex and
      adjacent subcortical regions and, when present, the ipsilateral cerebellum.
      However, hand movement also produced a significant deactivation (i.e., decreased
      blood flow) in the ipsilateral sensorimotor cortex and subcortical regions, and
      when present, the contralateral cerebellum. Conjunction analysis demonstrated
      regions that are activated by one hand and deactivated by the contralateral hand.
      CONCLUSION: Unilateral hand movements are associated with contralateral cerebral
      activation and ipsilateral cerebral deactivation, which we hypothesize result
      from transcallosal inhibition.

PMID- 10636140
TI  - Altered cortical excitability in obsessive-compulsive disorder.
AB  - OBJECTIVE: To assess cortical inhibitory and excitatory mechanisms in obsessive
      compulsive disorder (OCD). BACKGROUND: Transcranial magnetic stimulation (TMS)
      studies have found decreased neuronal inhibition and a reduced cortical silent
      period in the primary motor area in Tourette's syndrome, focal dystonia, and
      other disorders believed to involve dysfunction of subcortical structures,
      including the basal ganglia. Dysfunction of the basal ganglia and linked regions
      also has been implicated in OCD, which has significant clinical and familial
      overlap with tic disorders. METHODS: We applied the TMS techniques previously
      used in Tourette's syndrome to a group of 16 OCD patients (seven unmedicated) and
      11 age-matched healthy volunteers extensively screened for psychopathology.
      Measures of motor cortex excitability included resting and active motor
      threshold, cortical silent period duration, and intracortical inhibition and
      facilitation using a paired-pulse TMS technique with a subthreshold conditioning
      stimulus. RESULTS: Similar to recent findings in Tourette's syndrome and focal
      dystonia, this study reports significantly decreased intracortical inhibition
      (ICI) relative to the volunteers at interstimulus intervals from 2 to 5 msec. We
      also found decreased active and resting motor evoked potential threshold in the
      OCD patients, another indication of increased cortical excitability. Neither
      abnormality appeared medication related. The decreases in ICI and motor threshold
      were greatest in OCD patients with comorbid tics, but remained significant in
      patients without tics. CONCLUSIONS: The data suggest abnormal cortical
      excitability in obsessive-compulsive disorder. These findings are congruent with
      the hypothesis that Tourette's syndrome and obsessive-compulsive disorder (OCD)
      are analogous disorders with overlapping dysfunction in corticobasal circuits.
      Patients with tic-related OCD may have more abnormal motor cortex excitability
      than OCD patients without tics.

PMID- 10636141
TI  - Cerebellar activation during optokinetic stimulation and saccades.
AB  - OBJECTIVE: To investigate the activation pattern of cerebellar structures during
      small-field optokinetic stimulation (OKN) by functional MRI (fMRI) and compare it
      with that obtained during voluntary saccades and fixation suppression of OKN.
      METHODS: Functional images were acquired from oblique transverse slices of eight
      healthy, right-handed volunteers using a radio frequency-spoiled, single-slice,
      fast low-angle shot (FLASH) pulse sequence with high-spatial resolution. RESULTS:
      Horizontal OKN and saccades were associated with bilateral activity in the
      cerebellar hemispheres (superior semilunar lobule, simple lobule, quadrangular
      lobule, inferior semilunar lobule), the middle cerebellar peduncle, the dentate
      nucleus, and medially in the culmen and uvula of cerebellar nuclei. The pattern
      and extent of activation were independent of the stimulus direction for OKN and
      saccades. During fixation suppression, the extent of activation was significantly
      diminished (hemispheres) or even absent (uvula, culmen). CONCLUSION: The
      differential effects of fixation suppression on this complex pattern of
      cerebellar activation in part allow us to separate visual and attentional from
      ocular motor processing. Our data agree with behavioral and physiologic animal
      data about ocular motor processes and motor learning in the vestibulospinal and
      optokinetic reflex. This suggests that hemispheric cerebellar activity may be
      mainly associated with changes in attention, whereas vermal activity seems to be
      associated with ocular motor control, and activity of the dentate nuclei and the
      cerebellar peduncles seems to be associated with both.

PMID- 10636142
TI  - Eletriptan in acute migraine: a double-blind, placebo-controlled comparison to
      sumatriptan. Eletriptan Steering Committee.
AB  - OBJECTIVE: To compare the efficacy, safety, and tolerability of oral eletriptan
      (20 mg, 40 mg, and 80 mg) with that of oral sumatriptan (100 mg) and placebo for
      the acute treatment of migraine. BACKGROUND: Eletriptan is a potent and selective
      agonist at human recombinant 5HT1B/1D receptors, with efficacy in animal models
      that predict antimigraine activity. In healthy volunteers, the pharmacokinetics
      of eletriptan are characterized by linear and rapid oral absorption. METHODS:
      Randomized, double-blind, parallel-group study conducted in 857 outpatients with
      a diagnosis of migraine according to the International Headache Society (IHS)
      criteria. Of these, 692 took study medication for one acute migraine attack and
      provided on-drug efficacy data. Subjects received either placebo, 100 mg of
      sumatriptan or 20 mg, 40 mg, or 80 mg of eletriptan for the treatment of an acute
      migraine attack. The primary endpoint was the percentage of patients with a
      headache response (improvement in pain intensity from moderate or severe to mild
      or none) at 2 hours after treatment. RESULTS: At the primary endpoint (2 hours
      after dosing), headache response rates were 24% (30/126) for placebo; 55%
      (63/115) for sumatriptan, 100 mg; 54% (70/129) for eletriptan, 20 mg; 65%
      (76/117) for eletriptan, 40 mg; and 77% (91/118) for eletriptan, 80 mg. There was
      a difference compared with placebo (p<0.001) for all doses of eletriptan, and at
      2 hours there was a difference between sumatriptan, 100 mg, and eletriptan, 80 mg
      (p<0.001). Headache-free rates at 2 hours were superior to placebo (6%; p<0.001)
      for both the 80-mg dose of eletriptan (37%) and the 40-mg dose (29%), with the 80
      mg dose also being superior to 100 mg of sumatriptan (23%; p<0.05). Eletriptan
      and sumatriptan were well tolerated, and the majority of adverse events were mild
      or moderate in intensity and transient. CONCLUSION: In this placebo-controlled
      trial, eletriptan, at selected doses, demonstrated superior efficacy, onset of
      action and patient acceptability in the acute treatment of migraine when compared
      with oral sumatriptan and placebo.

PMID- 10636143
TI  - Use of estrogen in young girls with Turner syndrome: effects on memory.
AB  - BACKGROUND: The Turner syndrome (TS) phenotype is characterized by a specific
      neurocognitive profile of normal verbal skills, impaired visual-spatial and
      visual-perceptual abilities, and impaired nonverbal more than verbal memory. We
      compared verbal and nonverbal memory in estrogen- and placebo-treated girls with
      TS (ages 7 to 9 years) and age-matched female controls. METHODS: Children
      received either estrogen (ethinyl estradiol, 25 ng/kg/d) or placebo for 1 to 3
      years (mean, 2.1+/-0.9 years) in a randomized, double-blind study. Memory and
      language tasks administered included the Wechsler Intelligence Scale for Children
      Revised, Digit Span (forward and backward), the Children's Word List, the Denman
      Paragraph, the Peabody Picture Vocabulary Test, Boston Naming, immediate and
      delayed Recall of the Rey Complex Figure, Nonword Reading, Wide Range Achievement
      Test-Revised reading subtest, Verbal fluency, and the Token Test. RESULTS: The
      estrogen-treated TS group performed better than the placebo-treated TS group for
      the Children's Word List immediate and delayed recall and the Digit Span
      backwards test (p<0.01 to 0.04), although the results were not significant after
      adjusting for multiple comparisons. The placebo-treated TS group performed less
      well than the controls for recall of Digit Span backward (p<0.0001; placebo
      treated, 2.8+/-1.3; estrogen-treated, 3.4+/-1.2; and controls, 4.2+/-1.3) and
      immediate and delayed recall of the Children's Word List (delayed recall,
      p<0.0001; placebo-treated, 6.2+/-3.1; estrogen-treated, 8.0+/-2.9; and controls,
      9.0+/-2.9). Performance for these measures was similar for the estrogen-treated
      TS group and the control group. CONCLUSIONS: Estrogen replacement therapy in
      young girls with Turner Syndrome is associated with improved verbal and nonverbal
      memory. The optimal patient age, dose, and duration of estrogen replacement
      require further study.

PMID- 10636144
TI  - Intracranial EEG versus flumazenil and glucose PET in children with extratemporal
      lobe epilepsy.
AB  - OBJECTIVE: To compare abnormalities determined in 2-deoxy-2-[18F]fluoro-D-glucose
      (FDG) and [11C]flumazenil (FMZ) PET images with intracranial EEG data in patients
      with extratemporal lobe epilepsy. BACKGROUND: Although PET studies with FDG and
      FMZ are being used clinically to localize epileptogenic regions in patients with
      refractory epilepsy, the electrophysiologic significance of the identified PET
      abnormalities remains poorly understood. METHODS: We studied 10 patients, mostly
      children (4 boys, 6 girls, aged 2 to 19 years; mean age, 11 years), who underwent
      FDG and FMZ PET scans, intracranial EEG monitoring, and cortical resection for
      intractable epilepsy. EEG electrode positions relative to the brain surface were
      determined from MRI image volumes. Cortical areas of abnormal glucose metabolism
      or FMZ binding were determined objectively based on asymmetry measures derived
      from homotopic cortical areas at three asymmetry thresholds. PET data were then
      coregistered with the MRI and overlaid on the MRI surface. A receiver operating
      characteristics (ROC) analysis was performed to determine the specificity and
      sensitivity of PET-defined abnormalities against the gold standard of
      intracranial EEG data. RESULTS: FMZ PET detected at least part of the seizure
      onset zone in all subjects, whereas FDG PET failed to detect the seizure onset
      region in two of 10 patients. The area under the ROC curves was higher for FMZ
      than FDG PET for both seizure onset (p = 0.01) and frequent interictal spiking (p
      = 0.04). Both FMZ and FDG PET showed poor performance for detection of rapid
      seizure spread (area under the ROC curve not significantly different from 0.5).
      CONCLUSIONS: [11C]flumazenil (FMZ) PET is significantly more sensitive than 2
      deoxy-2-[18F]fluoro-D-glucose (FDG) PET for the detection of cortical regions of
      seizure onset and frequent spiking in patients with extratemporal lobe epilepsy,
      whereas both FDG and FMZ PET show low sensitivity in the detection of cortical
      areas of rapid seizure spread. The application of PET, in particular FMZ PET, in
      guiding subdural electrode placement in refractory extratemporal lobe epilepsy
      will enhance coverage of the epileptogenic zone.

PMID- 10636145
TI  - Functional anatomy of cognitive development: fMRI of verbal fluency in children
      and adults.
AB  - OBJECTIVE: To identify age-dependent activation patterns of verbal fluency with
      functional MRI (fMRI). BACKGROUND: Few fMRI language studies have been performed
      in children, and none provide comparison data to adult studies. Normative data
      are important for interpretation of similar studies in patients with epilepsy.
      METHODS: A total of 10 normal children (5 boys, 5 girls; mean age, 10.7 years;
      range, 8.1 to 13.1 years) and 10 normal adults (5 men, 5 women; mean age, 28.7
      years; range, 19.3 to 48 years) were studied on a 1.5-T Signa MRI scanner using
      BOLD echo planar imaging of the frontal lobes with a verbal fluency paradigm,
      covert word generation to letters. Studies were analyzed with a cross-correlation
      algorithm (r = 0.7). A region-of-interest analysis was used to determine the
      extent, magnitude, and laterality of brain activation. RESULTS: Children and
      adults activated similar regions, predominantly in left inferior frontal cortex
      (Broca's area) and left middle frontal gyrus (dorsolateral prefrontal cortex).
      Children had, on average, 60% greater extent of activation than adults, with a
      trend for greater magnitude of activation. Children also had significantly more
      right hemisphere and inferior frontal gyrus activation than adults. CONCLUSIONS:
      In a test of verbal fluency, children tended to activate cortex more widely than
      adults, but activation patterns for fluency appear to be established by middle
      childhood. Thus, functional MRI using verbal fluency paradigms may be applied to
      pediatric patient populations for determining language dominance in anterior
      brain regions. The greater activation found in children, including the right
      inferior frontal gyrus, may reflect developmental plasticity for the ongoing
      organization of neural networks, which underlie language capacity.

PMID- 10636146
TI  - A magnetization transfer histogram study of normal-appearing brain tissue in MS.
AB  - OBJECTIVE: To evaluate 1) the ability of magnetization transfer ratio (MTR)
      histogram analysis to detect the extent of changes occurring outside MS lesions
      seen on conventional scans, 2) whether such changes vary in the different MS
      clinical phenotypes, 3) whether the changes are associated with the extent and
      severity of the macroscopic lesion load, and 4) the contribution to brain
      atrophy. METHODS: Dual-echo, T1-weighted, and MT scans of the brain were obtained
      from 77 patients with varying MS courses and 20 age- and sex-matched control
      subjects. To create MT histograms of the normal-appearing cerebral tissue, MS
      lesions were segmented from dual-echo scans, superimposed automatically, and
      nulled out from the coregistered and scalp-stripped MTR maps. Average MTR, peak
      height, and peak position were considered. T2 and T1 lesion loads, average lesion
      MTR, and brain volume were also measured. RESULTS: Average histogram MTR
      (p<0.0001) and peak position (p<0.0001) from patients with relapsing-remitting MS
      (RMMS) were lower than those from control subjects. Patients with primary
      progressive MS (PPMS) had lower average histogram MTR (p = 0.002) and histogram
      peak height (p = 0.01) than control subjects. Patients with secondary progressive
      MS (SPMS) had a lower peak height (p = 0.05) than those with RRMS. Average lesion
      MTR (p<0.0001) correlated highly with the histogram MTR. Average histogram MTR
      (p<0.0001) and T2 lesion load (p = 0.001) correlated highly with brain volume.
      CONCLUSIONS: The amount of microscopic changes account for an important fraction
      of the lesion load in MS. They may contribute to the development of brain atrophy
      and tend to be more evident in patients with secondary progressive MS.

PMID- 10636147
TI  - Mx proteins in blood leukocytes for monitoring interferon beta-1b therapy in
      patients with MS.
AB  - OBJECTIVE: To correlate Mx protein (Mx) levels in lysed blood leukocytes with the
      clinical response to interferon (IFN) beta-1b (IFNbeta-1b) in relapsing-remitting
      MS (RR-MS) patients for monitoring treatment. BACKGROUND: Intracellular Mx
      expression is exclusively induced by the type I IFNs (IFN-alpha, -beta, and 
      omega) or by viruses and is strongly increased under IFN treatment. Quantitative
      determination of Mx allows objective assessment of biological effects of IFN.
      METHODS: Mx protein levels were measured in blood leukocyte lysates from IFNbeta
      1b-treated RR-MS patients by ELISA and correlated to clinical parameters,
      including relapse rate and clinical deterioration. RESULTS: In stable IFNbeta-1b
      treated MS patients, Mx levels were significantly increased compared to patients
      with or without immunosuppressive treatment. In IFN-1b-treated MS patients during
      relapse, Mx levels were significantly lower than during stable phases of the
      disease. Mean values of Mx (MVMx) over time of treatment in patients with a
      reduction of relapse rate were significantly higher than in patients without
      response. CONCLUSION: Mx levels in lysed blood cells may represent a useful
      surrogate marker for IFNbeta-1b activity corresponding to the clinical response
      during treatment of MS.

PMID- 10636148
TI  - Effect of interferon beta-1b in MS: assessment of annual accumulation of PD/T2
      activity on MRI. UBC MS/MRI Analysis Group and the MS Study Group.
AB  - OBJECTIVE: To determine whether the efficacy of interferon beta-1b (IFNbeta-1b)
      on lesion activity could be shown with annual analysis of MRI. BACKGROUND:
      Clinical outcomes and MRI burden of disease changes in MS patients in a
      multicenter double-blind placebo-controlled 5-year trial of IFNbeta-1b have been
      reported, together with an analysis of 6-weekly MRI activity in a small subgroup
      during 2 years. MRI activity measurements based on annual scans have not been
      documented. METHODS: Patients were randomized into three treatment arms: placebo,
      1.6 mIU, and 8 mIU IFNbeta-1b self-administered subcutaneously every other day.
      Active lesions were identified as new, enlarging, or recurrent on proton density
      and T2-weighted MRI scans. Gadolinium was not used. An annual accumulation
      activity index was developed as an additional analysis of lesion activity.
      RESULTS: During the 5 years, both high- and low-dose IFNbeta-1b groups showed a
      striking reduction in lesion annual accumulation activity on the activity index
      versus placebo (p = 0.001). Thirty-five percent of the high-dose patients and 29%
      of the low-dose patients were MRI inactive by this method of analysis, whereas
      only 16% of placebo patients were inactive (p = 0.001, placebo versus 8 mIU).
      CONCLUSIONS: This analysis of the annual accumulation of lesion activity shows
      that the previously reported treatment effect seen on MRI scanning once every 6
      weeks in a subcohort of the patients can also be seen on yearly scans. This
      annual accumulation activity analysis provides an independent MRI confirmation of
      a treatment and dose effect for IFNbeta-1b.

PMID- 10636150
TI  - Acute cerebellitis: MRI findings.

PMID- 10636149
TI  - A conventional and magnetization transfer MRI study of the cervical cord in
      patients with MS.
AB  - OBJECTIVE: To evaluate the contribution made by cervical cord damage, assessed
      using a fast short-tau inversion recovery (fast-STIR) sequence and magnetization
      transfer ratio (MTR) histogram analysis to the clinical manifestations of MS.
      BACKGROUND: Previous studies have failed to show significant correlations between
      the number and extent of T2 spinal cord lesions and the clinical status of
      patients with MS. Fast-STIR is more sensitive than T2-weighted imaging for
      detecting cervical cord MS lesions. MTR histogram analysis provides estimates of
      the overall disease burden in the cervical cord with higher pathologic
      specificity to the more destructive aspects of MS than T2-weighted scans.
      METHODS: We obtained fast-STIR and magnetization transfer (MT) scans from 96
      patients with MS (52 with relapsing-remitting [RRMS], 33 with secondary
      progressive [SPMS], and 11 with primary progressive [PPMS] MS) and 21 control
      subjects. Dual-echo scans of the brain were also obtained and lesion load
      measured. RESULTS: Eighty-one of the patients with MS had an abnormal cervical
      cord scan. Patients with SPMS had more cervical cord lesions and more images with
      visible cervical cord damage than did patients with RRMS or PPMS (p = 0.04). The
      entire cohort of patients with MS had lower average MTR of the cervical cord (p =
      0.006) than control subjects. Compared to control subjects, patients with RRMS
      had similar cervical cord MTR histogram-derived measures, whereas those with PPMS
      had lower average MTR (p = 0.01) and peak height (p = 0.02). Patients with SPMS
      had lower histogram peak height than did those with RRMS (p = 0.03). The peak
      position and height of the cervical cord MTR histogram were independent
      predictors of the probability of having locomotor disability. We found no
      correlation between brain T2 lesion load and any of the cervical cord MTR
      histogram metrics. CONCLUSIONS: This study shows that the amount and severity of
      MS pathology in the cervical cord are greater in the progressive forms of the
      disease. An accurate assessment of cervical cord damage in MS gives information
      that can be used in part to explain the clinical manifestations of the disease.

PMID- 10636151
TI  - Employment-seeking experiences of residents in 1996: a window into the neurology
      marketplace.
AB  - OBJECTIVE: To assess career choice and employment-seeking experience of senior
      neurology residents in 1996. METHODS: Graduating residents in adult and pediatric
      neurology (n = 573) were surveyed to obtain career plans, initial job selection,
      health care attitudes, and demographic information. Results were compared with
      1996 data on all United States neurologists and data from an American Medical
      Association (AMA) resident survey regarding the employment status of new
      physicians. RESULTS: Survey response rate was 71%. There was a significant
      increase in international medical graduates and women entering neurology compared
      with the current workforce. Seventy-four percent of graduates planned to enter a
      fellowship position; 19%, private practice; 5%, an academic position; and 2%, a
      career outside of clinical medicine. Neurology residents differ from aggregate
      national data because only 28% of residents responding to an AMA survey across
      all specialties applied to fellowships in 1996. Overall, 44% of neurology
      graduates planned an academic career. CONCLUSIONS: Changing demographics and
      career choice of recent graduates may require continued monitoring and could be
      important in neurology workforce planning. The high rate of fellowship training
      and plans for academic careers in 1996 is of interest and may reflect both
      resident response to new demands in the changing health care market and a need to
      modify residency programs to enhance academic training and competitiveness of
      neurology graduates.

PMID- 10636152
TI  - Cluster headache with aura.
AB  - Cluster headache with aura is rare. The authors retrospectively reviewed 101
      cluster headache patient charts at the Jefferson Headache Center. Six patients
      had an associated aura, five visual and one olfactory, lasting 5 to 120 minutes.
      Only one had migraine (without aura). Auras always occurred with or were followed
      by a severe cluster headache. Two patients were related.

PMID- 10636153
TI  - Spontaneous and reflex movements in brain death.
AB  - Spontaneous and reflex movements may be found in patients with brain death (BD).
      The authors prospectively evaluated their frequency using a standardized
      protocol. Among 38 patients who fulfilled criteria for BD, the authors found 15
      (39%) with spontaneous or reflex movements. The most common movement was finger
      jerks. Undulating toe flexion sign, triple flexion response, Lazarus sign,
      pronation-extension reflex, and facial myokymia also were seen. These movements
      may be more common than reported and do not preclude the diagnosis of BD.

PMID- 10636154
TI  - Decerebrate-like posturing with mechanical ventilation in brain death.
AB  - Complex spinal cord, spontaneous, or upper limb reflexes are rarely observed in
      brain death. The authors describe two brain-dead heart-beating cadavers (out of
      400 consecutive cases in their hospital in the past 9 years) that, immediately
      after brain-death diagnosis, exhibited symmetric upper limb movements resembling
      decerebrate posture that were triggered by each mechanical pulmonary
      insufflation, and also by superficial pressure and noxious stimuli applied to the
      arms, thorax, or abdomen. These movements persisted until disconnection from
      mechanical ventilation.

PMID- 10636155
TI  - The value of pelvic thrusting in the diagnosis of seizures and pseudoseizures.
AB  - We evaluated pelvic thrusting as a potential diagnostic sign and localizing
      indicator of ictal onset. By reviewing the video-EEG results of patients with
      temporal lobe epilepsy, frontal lobe epilepsy, generalized epilepsy, and
      pseudoseizures. Pelvic thrusting occurred in 4% of right and 2% of left temporal
      lobe epilepsy patients, in 24% of frontal lobe epilepsy patients, and in 17% of
      patients with pseudoseizures. Pelvic thrusting is relatively common in frontal
      lobe epilepsy and in pseudoseizures, but also occurs in temporal lobe epilepsy.

PMID- 10636156
TI  - Valproate-induced hyperammonemic encephalopathy in the presence of topiramate.
AB  - Two adult patients with focal epilepsy who tolerated valproate (VPA) well in
      different combinations of anticonvulsants developed hyperammonemic encephalopathy
      when treated with VPA in combination with topiramate (TPM). Topiramate may
      contribute to the increased ammonia level by its inhibition of carbonic anhydrase
      and cerebral glutamine synthetase, thereby facilitating VPA/TPM hyperammonemic
      encephalopathy. Recovery occurred after withdrawal of VPA or TPM.

PMID- 10636157
TI  - Transdermal selegiline in HIV-associated cognitive impairment: pilot, placebo
      controlled study.
AB  - The authors conducted a pilot randomized, double-blind, placebo-controlled
      clinical trial of the transdermal administration of selegiline in HIV+ patients
      to obtain preliminary data to assess its safety, tolerability, and impact on HIV
      associated cognitive impairment. Both selegiline and placebo were well tolerated
      with few adverse events. Improvements favoring the selegiline group were
      suggested on single tests of verbal memory and motor/psychomotor performance,
      warranting a larger study.

PMID- 10636158
TI  - Relating axonal injury to functional recovery in MS.
AB  - A patient was followed after the new onset of hemiparesis from relapse of MS with
      serial MR spectroscopy and functional MRI. The association of clinical
      improvement with recovery of N-acetylaspartate, a marker of neuronal integrity,
      and progressive reduction of abnormally large functional MRI cortical activation
      with movement demonstrates that dynamic reorganization of the motor cortex
      accompanies remission of MS.

PMID- 10636160
TI  - Absence of cystatin C mutation in sporadic cerebral amyloid angiopathy-related
      hemorrhage.
AB  - In Icelandic pedigrees a cystatin C mutation, glutamine 68 (L68Q), causes
      autosomal dominant cerebral amyloid angiopathy-related hemorrhage (CAAH). We
      examined 33 patients with sporadic CAAH for this mutation. None carried L68Q and,
      including this report, only one of 52 published cases of sporadic CAAH has had
      the cystatin C mutation. Despite vascular colocalization of cystatin C with
      amyloid beta-protein, cystatin C L68Q is rare in sporadic CAAH.

PMID- 10636159
TI  - Serum cholesterol, APOE genotype, and the risk of Alzheimer's disease: a
      population-based study of African Americans.
AB  - A significant interaction among total serum cholesterol (TC), APOE genotype, and
      AD risk was found in a population-based study of elderly African Americans.
      Increasing TC was associated with increased AD risk in the group with no epsilon4
      alleles, whereas TC was not associated with increased AD risk in the group with
      one or more epsilon4 alleles. Further study of the relationship between
      cholesterol and APOE genotype is needed to confirm this association, but the
      results suggest that cholesterol may be a potentially modifiable environmental
      risk factor for AD.

PMID- 10636161
TI  - Botulinum toxin A as treatment for drooling saliva in PD.
AB  - The authors evaluated intraparotid injections of botulinum toxin A in reducing
      salivary secretions and drooling in nine patients with PD. There was a marked
      objective reduction in secretion, and two thirds of the patients had subjective
      improvement in drooling. No side effects were observed. The authors conclude that
      botulinum toxin A promises to be a simple and effective treatment for the common
      problem of drooling saliva in chronic neurologic disease.

PMID- 10636162
TI  - Apomorphine can sustain the long-duration response to L-DOPA in fluctuating PD.
AB  - The authors investigated the ability of daytime infusions of apomorphine, a D-1
      and D-2 dopamine agonist, to sustain the long-duration response (LDR) in seven
      subjects with fluctuating PD in whom L-DOPA was discontinued for 3 days.
      Apomorphine maintained the LDR to the extent that it kept the subjects "on"
      during the day. This observation suggests that the LDR can be a postsynaptic
      effect, independent of dopamine storage.

PMID- 10636163
TI  - Posttraumatic delayed sleep phase syndrome.
AB  - Circadian rhythm sleep disorders may occur after traumatic brain injury. We
      describe a 48-year-old man who presented with sleep onset insomnia and cognitive
      dysfunction after a car accident. A diagnosis of delayed sleep phase syndrome
      (DSPS) was confirmed by sleep logs and actigraphy, which revealed sleep onset in
      the early morning hours and awakening around noon.

PMID- 10636164
TI  - Resistance of extraocular motoneuron terminals to effects of amyotrophic lateral
      sclerosis sera.
AB  - In sporadic ALS (s-ALS), axon terminals contain increased intracellular calcium.
      Passively transferred sera from patients with s-ALS increase intracellular
      calcium in spinal motoneuron terminals in vivo and enhance spontaneous
      transmitter release, a calcium-dependent process. In this study, passive transfer
      of s-ALS sera increased spontaneous release from spinal but not extraocular
      motoneuron terminals, suggesting that the resistance to physiologic abnormalities
      induced by s-ALS sera in mice parallels the resistance of extraocular motoneurons
      to dysfunction and degeneration in ALS.

PMID- 10636165
TI  - MRI study of human brain exposed to high-dose repetitive magnetic stimulation of
      visual cortex.
AB  - T1-, T2-, and diffusion-weighted MRI was used to determine whether repetitive
      transcranial magnetic stimulation (rTMS) affects the blood-brain barrier or
      induces localized brain edema. In 11 healthy individuals, 1,200 to 3,800 stimuli
      were applied over the visual cortex of one hemisphere in series of 5-, 10-, or 20
      Hz stimulus trains. MRI performed 6 minutes to 6 hours after rTMS did not show
      pathologic changes in conventional MRI sequences, after application of gadolinium
      diethylenetriamine pentaacetic acid (Gd-DTPA), or by determining apparent
      diffusion coefficients.

PMID- 10636166
TI  - Glioblastoma causing granulocytosis by secretion of granulocyte-colony
      stimulating factor.
AB  - We describe a patient with a glioblastoma multiforme with excessive
      granulocytosis in the peripheral blood. Shown at both protein and mRNA levels,
      the tumor produced very high levels of granulocyte-colony-stimulating factor (G
      CSF). G-CSF is a growth factor that induces the recruitment of granulocytes. The
      paraneoplastic phenomenon described here partly mimicked a brain abscess.
      Production of G-CSF by (brain) tumor cells might be related to the granulocytosis
      common in malignant disease.

PMID- 10636167
TI  - Gaucher disease with oculomotor apraxia and cardiovascular calcification (Gaucher
      type IIIC).
AB  - The authors describe four siblings from consanguineous parents who presented with
      oculomotor deficit in early childhood characterized by impaired volitional
      horizontal saccades, compensatory lateral head thrust, and preservation of
      vertical movement. When about 10 years of age, heavily calcified aortic and
      mitral valves required surgery. Fibroblast beta-glucocerebrosidase activity was
      markedly reduced. Genotype analysis indicated that the two patients who were
      tested were homozygous for the D409H (1342G-->C) mutation. Relating this rare
      phenotype of Gaucher disease to D409H mutation will facilitate management of the
      disease and counseling of families.

PMID- 10636168
TI  - Roller coaster headache and subdural hematoma.

PMID- 10636169
TI  - Failure to detect Chlamydia pneumoniae in the central nervous system of patients
      with MS.

PMID- 10636170
TI  - Coexistence of expanded CAG repeats in the MJD1a and DRPLA genes.

PMID- 10636171
TI  - Chronic diarrhea associated with the A3243G mtDNA mutation.

PMID- 10636172
TI  - Remission of HIV myelopathy after highly active antiretroviral therapy.

PMID- 10636173
TI  - Autism's home in the brain.

PMID- 10636174
TI  - Cognitive effects of topiramate, gabapentin, and lamotrigine in healthy young
      adults.

PMID- 10636175
TI  - Cognitive effects of topiramate, gabapentin, and lamotrigine in healthy young
      adults.

PMID- 10636176
TI  - The cerebellar seizures of Hughlings Jackson.

PMID- 10636177
TI  - Simultaneous repetitive transcranial magnetic stimulation does not speed fine
      movement in PD.

PMID- 10636178
TI  - Phenotypic variability in rippling muscle disease.

PMID- 10636179
TI  - Falling asleep at the wheel: motor vehicle mishaps in people taking pramipexole
      and ropinirole.

PMID- 10636180
TI  - Falling asleep at the wheel: motor vehicle mishaps in people taking pramipexole
      and ropinirole.

PMID- 10636181
TI  - Falling asleep at the wheel: motor vehicle mishaps in people taking pramipexole
      and ropinirole.

PMID- 10636182
TI  - Falling asleep at the wheel: motor vehicle mishaps in people taking pramipexole
      and ropinirole.

PMID- 10636183
TI  - Falling asleep at the wheel: motor vehicle mishaps in people taking pramipexole
      and ropinirole.

PMID- 10636184
TI  - Falling asleep at the wheel: motor vehicle mishaps in people taking pramipexole
      and ropinirole.

PMID- 10636185
TI  - Falling asleep at the wheel: motor vehicle mishaps in people taking pramipexole
      and ropinirole.

PMID- 10636186
TI  - Electrophysiologic effects of selective right versus left atrial linear lesions
      in a canine model of chronic atrial fibrillation.
AB  - INTRODUCTION: Long linear lesions have been shown to eliminate atrial
      fibrillation in animal models, but little is known about the electrophysiologic
      response in one atrium to lesions in the contralateral atrium. METHODS AND
      RESULTS: Twelve dogs with chronic atrial fibrillation were randomized to either
      right atrial ablation (n = 4), left atrial ablation first (n = 4), or a sham
      procedure (n = 4). Simultaneous biatrial endocardial mapping was performed before
      and after three linear lesions were applied at specific points in either atrium,
      using an expandable ablation catheter. Atrial fibrillation was reinducible after
      single atrial ablation in each dog and no longer inducible after biatrial
      ablation in five dogs. At baseline, the mean atrial fibrillation cycle length was
      longer on the trabeculated (117+/-15 msec) compared with the smooth right (101+/
      16 msec) or left atrium (88+/-10 msec; P < 0.01). Single right and left atrial
      ablation caused a significant cycle length increase in the ablated atrium. Left
      atrial ablation increased the cycle length on both the trabeculated (121+/-18
      msec vs 137+/-11 msec; P < 0.05) and smooth right atrium (108+/-12 msec vs 124+/
      9 msec; P < 0.05). Right atrial ablation, however, had no significant effect on
      left atrial fibrillation cycle length (82+/-8 msec vs 86+/-7 msec). CONCLUSION:
      Left atrial linear lesions affect right atrial endocardial activation, whereas
      right atrial lesions do not affect left atrial activation in a canine model of
      atrial fibrillation. These findings suggest that the left atrium is the driver
      during chronic atrial fibrillation in this animal model and may explain the
      limited success of right atrial ablation alone in human atrial fibrillation.

PMID- 10636187
TI  - Finding our way through the maze.

PMID- 10636188
TI  - Inducibility of atrial fibrillation during atrioventricular pacing with varying
      intervals: role of atrial electrophysiology and the autonomic nervous system.
AB  - INTRODUCTION: Patients receiving VVI pacemakers have a higher incidence of
      paroxysmal atrial fibrillation (AF) than those receiving DDD pacemakers. However,
      the mechanism behind the difference is not clear. The purpose of this study was
      to investigate whether atrial electrophysiology and the autonomic nervous system
      play a role in the occurrence of AF during AV pacing. METHODS AND RESULTS: The
      study population consisted of 28 patients who had (group I, n = 15) or did not
      have (group II, n = 13) AF induced by a single extrastimulus during pacing with
      different AV intervals. Atrial pressure, atrial size, atrial effective refractory
      periods, and atrial dispersion were evaluated during pacing with different AV
      intervals. Twenty-four-hour heart rate variability and baroreflex sensitivity
      also were examined. Atrial pressure, atrial size, effective refractory periods in
      the right posterolateral atrium and distal coronary sinus, and atrial dispersion
      increased as the AV interval shortened from 160 to 0 msec. During AV pacing,
      group I patients had greater minimal (52+/-17 vs 25+/-7 msec; P < 0.005) and
      maximal (76+/-16 vs 36+/-9 msec; P < 0.005) atrial dispersion than group II
      patients. The differences in atrial size and atrial dispersion among different AV
      intervals were greater in patients with AF than in those without AF. Baroreflex
      sensitivity (6.6+/-1.7 vs 3.9+/-1.0; P < 0.00005), but not heart rate
      variability, was higher in patients with AF than in those without AF. CONCLUSION:
      Abnormal atrial electrophysiology and higher vagal reflex activity can play
      important roles in the genesis of AF in patients receiving pacemakers.

PMID- 10636189
TI  - Variation of spectral power immediately prior to spontaneous onset of ventricular
      tachycardia/ventricular fibrillation in implantable cardioverter defibrillator
      patients.
AB  - INTRODUCTION: Short-term heart rate variability (HRV) may change immediately
      before onset of a ventricular arrhythmia (ONSET). METHODS AND RESULTS: Power
      spectrum analysis was performed on instantaneous heart rate (IHR; including all
      beats) and normal heart rate (NHR; excluding ectopics) curves obtained at equally
      spaced 0.5-second intervals using a cubic spline. The database consisted of 135
      sets of 1,024 RR intervals leading to ventricular arrhythmia (VA) and controls
      from 78 patients. Total periodogram and time course of spectral power were
      obtained. Ten spectral bands of 0.1-Hz bandwidth (0 to 1 Hz) were analyzed. A
      simple threshold technique was retrospectively used to predict the onset of a VA.
      RR intervals that led to VA ONSET had significantly higher total spectral power
      than controls (P < 0.001 for both NHR and IHR for every band). Spectral power
      remained constant until 100 seconds before ONSET and then increased significantly
      in the time window immediately preceding ONSET (P < 0.02 compared with others).
      Using a simple threshold method, a predictive accuracy of 68%+/-1.4% was obtained
      with different window sizes. Using specific spectral bands, the predictive
      accuracy of VA ONSET could be improved to 76% for IHR and 71% for NHR (0.8- to
      0.9-Hz band). CONCLUSION: Our results suggest that a sustained higher power
      increase in NHR and IHR occurs during the course of 12.11+/-.57 minutes, followed
      by a sudden elevation in spectral power within 100 seconds of ONSET, and may be a
      precursor to ventricular tachycardia/ventricular fibrillation episodes.

PMID- 10636190
TI  - Droperidol lengthens cardiac repolarization due to block of the rapid component
      of the delayed rectifier potassium current.
AB  - INTRODUCTION: Torsades de pointes have been observed during treatment with
      droperidol, a butyrophenone neuroleptic agent. Our objectives were (1) to
      characterize the effects of droperidol on cardiac repolarization and (2) to
      evaluate effects of droperidol on a major time-dependent outward potassium
      current involved in cardiac repolarization (I(K)r). METHODS AND RESULTS:
      Isolated, buffer-perfused guinea pig hearts (n = 32) were stimulated at different
      pacing cycle lengths (150 to 250 msec) and exposed to droperidol in
      concentrations ranging from 10 to 300 nmol/L. Droperidol increased monophasic
      action potential duration measured at 90% repolarization (MAPD90) in a
      concentration-dependent manner by 9.8+/-2.3 msec (7.3%+/-0.7%) at 10 nmol/L but
      by 32.7+/-3.6 msec (25.7%+/-2.2%) at 300 nmol/L (250-msec cycle length). Increase
      in MAPD90 also was reverse frequency dependent. As noted previously, droperidol
      300 nmol/L increased MAPD90 by 32.7+/-3.6 msec (25.7%+/-2.2%) at a pacing cycle
      length of 250 msec but by only 14.1+/-1.3 msec (13.6%+/-2.3%) at a pacing cycle
      length of 150 msec. Patch clamp experiments performed in isolated guinea pig
      ventricular myocytes demonstrated that droperidol decreases the time-dependent
      outward K+ current elicited by short depolarizations (250 msec; I(K)250) in a
      concentration-dependent manner. Estimated IC50 for I(K)250, which mostly
      underlies I(K)r, was 28 nmol/L. Finally, HERG K+ current elicited in HEK293 cells
      expressing high levels of HERG protein was decreased 50% by droperidol 32.2
      nmol/L. CONCLUSION: Potent block of I(K)r by droperidol is likely to underlie QT
      prolongation observed in patients treated at therapeutic plasma concentrations
      (10 to 400 nmol/L) of the drug.

PMID- 10636191
TI  - Mechanisms of the spatial distribution of QT intervals on the epicardial and body
      surfaces.
AB  - INTRODUCTION: The role of QT dispersion as a predictor of arrhythmia
      vulnerability has not been consistently confirmed in the literature. Therefore,
      it is important to identify the electrophysiologic mechanisms that affect QT
      duration and distribution. We compared the spatial distributions of QT intervals
      (QTI) with potential distributions on cardiac and body surfaces and with recovery
      times on the cardiac surface. We hypothesized that the measure of QTI is affected
      by the presence of the zero potential line in the potential distribution, as well
      as the sequence of recovery. We also investigated use of the STT area as a
      possible indicator of recovery times on the cardiac surface. METHODS AND RESULTS:
      High-resolution spatial distributions of QTI and potentials were determined on
      the body surface of human subjects and on the surface of a torso-shaped tank
      containing an isolated canine heart. Additionally, spatial distributions of QTI,
      recovery times, and STT areas were determined on the surface of exposed canine
      hearts. Unipolar electrograms were recorded during atrial and ventricular pacing
      for normal hearts and cases of myocardial infarction. Regions of shortest QTI
      always coincided with the location of the zero potential line on the cardiac and
      body surfaces. On the cardiac surface, in regions away from the zero line,
      similarities were observed between the patterns of QTI and the sequence of
      recovery. STT areas and recovery times were highly correlated on the cardiac
      surface. CONCLUSION: QTI is not a robust index of local recovery time on the
      cardiac surface. QTI distributions were affected by the position of the zero
      potential line, which is unrelated to local recovery times. However, similarities
      in the patterns of QTI and recovery times in some regions may help explain the
      frequently reported predictive value of QT dispersion. Preliminary results
      indicate STT area may be a better index of recovery time and recovery time
      dispersion on the epicardium than QTI.

PMID- 10636192
TI  - Sinusoidal stimulation of myocardial tissue: effects on single cells.
AB  - INTRODUCTION: Cardiac tissue subjected to sinusoidal stimulus is characterized by
      action potentials (APs) that have extended plateau phases, sustained for the
      duration of the stimulus. Extended action potential durations (APDs) are
      beneficial because they disrupt wandering wavelets in the fibrillating heart. To
      investigate the mechanisms by which periodic stimulus affects cardiac tissue,
      particularly the development of sustained depolarization, computer simulations of
      single cardiac cells exposed to alternating current (AC) are performed. METHODS
      AND RESULTS: Two modes of stimulation of the cell are examined: external field
      stimulation and transmembrane current injection. Several membrane models,
      including Luo-Rudy I and II, are used in the simulations. External AC field
      stimuli increase the APD of the single cell. The extended plateau of the cellular
      AP is characterized by periodic oscillations that are 1:2 phase locked with the
      applied stimulus. This specific behavior is due to the variations in stimulus
      magnitude and polarity along the cell border, which elicit opposite electrical
      responses from the cell sides. These pointwise responses are averaged in the
      macroscopic cellular response and result in sustained oscillatory depolarization
      that lasts for the duration of the stimulus. In contrast, the cell undergoing
      current injection does not develop an extended APD. CONCLUSION: The simulations
      demonstrate that variation of membrane potential within a cell is of paramount
      importance to the formation of an extended AP plateau in response to AC
      stimulation.

PMID- 10636193
TI  - Transient QT prolongation with torsades de pointes tachycardia after ablation of
      permanent junctional reciprocating tachycardia.
AB  - INTRODUCTION: Catheter ablation with radiofrequency energy is a curative therapy
      in patients with permanent junctional reciprocating tachycardia (PJRT). METHODS
      AND RESULTS: For the first time, we report a case of transient QT prolongation
      with torsades de pointes tachycardia 18 hours after successful radiofrequency
      energy ablation of PJRT in a 25-year-old woman with tachycardia-induced
      cardiomyopathy. Of note, the torsades de pointes occurred in the absence of
      bradycardia, electrolyte disturbances, or QT-prolonging drugs. This patient
      initially was thought to have a hereditary long QT syndrome that was unmasked by
      PJRT ablation. Therefore, the patient received an implantable defibrillator in
      addition to beta-blocker therapy, which was discontinued 6 months later.
      Surprisingly, the QT interval completely normalized within 1 week after PJRT
      ablation, and the patient remained free of arrhythmias during a follow-up period
      of 4.5 years. CONCLUSION: Patients with incessant tachyarrhythmias should undergo
      ECG monitoring for at least 24 hours following successful radiofrequency catheter
      ablation because transient QT prolongation with torsades de pointes may occur
      even in the absence of bradycardia, QT-prolonging drugs, or electrolyte
      disturbances.

PMID- 10636194
TI  - Incessant nonreentrant atrioventricular nodal tachycardia due to multiple nodal
      pathways treated by radiofrequency ablation of the slow pathways.
AB  - In patients with dual AV nodal physiology, simultaneous anterograde fast and slow
      pathway conduction resulting in an unusual form of nonreentrant AV nodal
      tachycardia has been observed. We describe the case of a young patient with an
      incessant form of complex supraventricular tachycardia who underwent
      electrophysiologic evaluation, which showed simultaneous conduction via multiple
      AV nodal pathways that caused a unique form of incessant nonreentrant AV nodal
      tachycardia. Radiofrequency ablation of the spatially closed intermediate and
      slow pathways effectively treated the tachycardia. The electrophysiologic
      determinants of simultaneous conduction through the multiple nodal pathways and
      the apparently different behavior of the fast pathway before and after ablation
      are discussed.

PMID- 10636195
TI  - Epicardial mapping and radiofrequency catheter ablation of ischemic ventricular
      tachycardia using a three-dimensional nonfluoroscopic mapping system.
AB  - Endocardial radiofrequency catheter ablation of ischemic left ventricular
      tachycardia has been of variable success due to multiple factors. Two such
      factors include the location of the reentrant circuit in the deep myocardium or
      on the epicardial surface and the inherent limitations of fluoroscopy as a guide
      for target localization. We report a patient in whom successful epicardial
      mapping and radiofrequency catheter ablation of an ischemic left ventricular
      tachycardia was performed using pericardial access and the CARTO electroanatomic
      mapping system.

PMID- 10636196
TI  - Connexins and impulse propagation in the mouse heart.
AB  - Gap junction channels are essential for normal cardiac impulse propagation. Three
      gap junction proteins, known as connexins, are expressed in the heart: Cx40,
      Cx43, and Cx45. Each of these proteins forms channels with unique biophysical and
      electrophysiologic properties, as well as spatial distribution of expression
      throughout the heart. However, the specific functional role of the individual
      connexins in normal and abnormal propagation is unknown. The availability of
      genetically engineered mouse models, together with new developments in optical
      mapping technology, makes it possible to integrate knowledge about molecular
      mechanisms of intercellular communication and its regulation with our growing
      understanding of the microscopic and global dynamics of electrical impulse
      propagation during normal and abnormal cardiac rhythms. This article reviews
      knowledge on the mechanisms of cardiac impulse propagation, with particular focus
      on the role of cardiac connexins in electrical communication between cells. It
      summarizes results of recent studies on the electrophysiologic consequences of
      defects in the functional expression of specific gap junction channels in mice
      lacking either the Cx43 or Cx40 gene. It also reviews data obtained in a
      transgenic mouse model in which cell loss and remodeling of gap junction
      distribution leads to increased susceptibility to arrhythmias and sudden cardiac
      death. Overall, the results demonstrate that these are potentially powerful
      strategies for studying fundamental mechanisms of cardiac electrical activity and
      for testing the hypothesis that certain cardiac arrhythmias involve gap junction
      or other membrane channel dysfunction. These new approaches, which permit one to
      manipulate electrical wave propagation at the molecular level, should provide new
      insight into the detailed mechanisms of initiation, maintenance, and termination
      of cardiac arrhythmias, and may lead to more effective means to treat arrhythmias
      and prevent sudden cardiac death.

PMID- 10636197
TI  - Inherited long QT syndromes: a paradigm for understanding arrhythmogenesis.
AB  - The inherited long QT syndrome (LQTS) is a familial disease characterized by QT
      interval changes that often are labile, syncope, and sudden death due to
      arrhythmias, predominantly in young people. Multiple mutations in five genes
      encoding structural subunits of cardiac ion channels now have been identified in
      families with LQTS. Correlations are being described between genotype and
      specific clinical features in LQTS. However, increasing screening of affected
      families and sporadic cases has identified incomplete penetrance with highly
      variable clinical manifestations, even among individuals carrying the same
      mutations. The identification of LQTS disease genes represents a crucial first
      step in developing an understanding of the molecular basis for normal cardiac
      repolarization. This information will be important not only for identifying new
      therapies in LQTS, but also in further understanding arrhythmias, and their
      potential therapies, in situations such as heart failure, cardiac hypertrophy,
      myocardial infarction, or sudden infant death syndrome, where abnormal
      repolarization has been linked to sudden death. LQTS thus presents a new paradigm
      to cardiac electrophysiology, in which new molecular information is being brought
      to bear both on clinical management of patients and on development of a new
      framework to study the fundamental causes of arrhythmias and new approaches to
      therapy.

PMID- 10636198
TI  - Electrophysiologic remodeling: what happens to gap junctions?

PMID- 10636199
TI  - Adenosine-Responsive wide QRS complex tachycardia: what is the mechanism?

PMID- 10636200
TI  - External migration of an infected subcutaneous ICD patch through mammary tissue.

PMID- 10636201
TI  - The existence of a lower common pathway in AV nodal reentrant tachycardia: a
      controversy reluctant to die.

PMID- 10636202
TI  - Patients with implantable cardioverter defibrillators (ICDs)

PMID- 10636203
TI  - Gastroesophageal reflux and abnormal esophageal pressures: cause or effect?

PMID- 10636204
TI  - Cobalamin (Vitamin B12) deficiency: is it a problem for our aging population and
      is the problem compounded by drugs that inhibit gastric acid secretion?

PMID- 10636205
TI  - The efficacy of proton-pump inhibitors in acute ulcer bleeding: a qualitative
      review.
AB  - Despite remarkable progress in the treatment of chronic peptic ulcer disease,
      acute gastroduodenal ulcer hemorrhage remains a therapeutic challenge. Numerous
      trials of H-2 receptor antagonists have not consistently shown a significant
      benefit in such patients. Proton-pump inhibitors, which more profoundly suppress
      gastric acid, are being increasingly evaluated. We have performed a qualitative
      systematic review to analyze the results of these trials to determine if a
      reasonable consensus can be reached. We searched for all published, randomized,
      controlled studies that evaluated proton-pump inhibitors in patients with acute
      peptic ulcer hemorrhage. The primary outcomes evaluated were: (A) persistent or
      recurrent bleeding; (B) need for surgery; and (C) mortality. Sixteen trials were
      evaluated, enrolling 3154 patients. Four of the sixteen studies showed a
      statistically significant decrease in overall rebleeding rate, and two described
      specific benefit in patients with Type IIa and IIb endoscopic stigmata. Four
      studies also showed a significantly decreased surgery rate, but none demonstrated
      a significant mortality reduction. Proton-pump inhibitors may improve outcome in
      acute peptic ulcer bleeding, but the available clinical data remain inconsistent.
      Further study is necessary to define the optimal dosage, route of administration,
      duration of therapy, and subsets of patients most likely to benefit.

PMID- 10636206
TI  - Transjugular intrahepatic portosystemic shunts (TIPS): a decade later.
AB  - Since the introduction of transjugular intrahepatic portosystemic shunt (TIPS) 10
      years ago, it has been used increasingly in the management of portal hypertension
      and its complications. TIPS is now considered the procedure of choice for
      management of refractory variceal bleeding. Its role in the management of
      refractory ascites, hepatic hydrothorax, hepatorenal syndrome, and
      hepatopulmonary syndrome still awaits further prospective studies. The two main
      complications of TIPS are hepatic encephalopathy and shunt malfunction.
      Generally, TIPS stenosis or occlusion is a major drawback requiring routine
      surveillance of TIPS with doppler ultrasound. Venography with balloon dilation of
      the stent or placement of serial or parallel stents may be required in some
      cases. Promising modalities of preventing TIPS malfunction (e.g., brachy-therapy,
      covered stents, or anti-platelet derived growth factor) are currently being
      investigated.

PMID- 10636207
TI  - Vitamin B12 levels during prolonged treatment with proton pump inhibitors.
AB  - Reduced serum vitamin B12 (cobalamin) levels have been documented occasionally
      during long-term treatment with a proton pump inhibitor (PPI) in selected groups
      of patients. This has largely been confined to patients being treated for
      Zollinger-Ellison syndrome who have sustained drug-induced achlorhydria, which
      does not ordinarily occur during treatment with a PPI. An appreciation of normal
      cobalamin metabolism and the pharmacological action of the PPIs adequately
      explain the mechanism for this reduction. PPIs do not promote the development of
      pernicious anemia.

PMID- 10636208
TI  - Pediatric feeding disorders.
AB  - Pediatric feeding disorders are common: 25% of children are reported to present
      with some form of feeding disorder. This number increases to 80% in
      developmentally delayed children. Consequences of feeding disorders can be
      severe, including growth failure, susceptibility to chronic illness, and even
      death. Feeding disorders occur in children who are healthy, who have
      gastrointestinal disorders, and in those with special needs. Most feeding
      disorders have underlying organic causes. However, overwhelming evidence
      indicates that abnormal feeding patterns are not solely due to organic
      impairment. As such, feeding disorders should be conceptualized on a continuum
      between psycho-social and organic factors. Disordered feeding in a child is
      seldom limited to the child alone; it also is a family problem. Assessment and
      treatment are best conducted by an interdisciplinary team of professionals. At
      minimum, the team should include a gastroenterologist, nutritionist, behavioral
      psychologist, and occupational and/or speech therapist. Intervention should be
      comprehensive and include treatment of the medical condition, behavioral
      modification to alter the child's inappropriate learned feeding patterns, and
      parent education and training in appropriate parenting and feeding skills. A
      majority of feeding problems can be resolved or greatly improved through medical,
      oromotor, and behavioral therapy. Behavioral feeding strategies have been applied
      successfully even in organically mediated feeding disorders. To avoid iatrogenic
      feeding problems, initial attempts to achieve nutritional goals in malnourished
      children should be via the oral route. The need for exclusive tube feedings
      should be minimized.

PMID- 10636209
TI  - Evidence of in vivo peroxynitrite formation in patients with colorectal
      carcinoma, higher plasma nitrate/nitrite levels, and lower protection against
      oxygen free radicals.
AB  - Endogenously formed nitrogen and oxygen free radicals are believed to be involved
      in human cancer etiology. Plasma nitrate/nitrite originates from endogenous
      nitric oxide production in fasting humans, decrease in superoxide scavenger
      activity (SSA), and free sulfhydryl groups (SH) reflects the amount of superoxide
      anion generated, and nitrotyrosine is believed to be formed by the interaction of
      tyrosine and peroxynitrite in vivo. The aim of the current study was to measure
      plasma nitrate/ nitrite, SSA, and SH in 69 patients (mean age +/- standard
      deviation, 66 +/- 11 years) with colorectal carcinoma. Nitrotyrosine was measured
      from both the plasma and tumor tissues in 32 patients. All patients had
      adenocarcinoma of the colon or rectum. Twenty-five patients were classified as
      stage B according to Dukes classification as modified by Astler-Coller, 13 were
      classified as stage C, and 31 patients were classified as stage D. To determine
      whether the changes are specific for colorectal cancer, 20 patients with active
      inflammatory bowel disease (IBD; mean age, 52 +/- 18 years) and 30 healthy
      volunteers, who served as control subjects (mean age, 48 +/- 11 years), were
      studied. Plasma nitrate/nitrite was measured by the modified Griess method, SSA
      was measured by an electron/spin resonance spin trapping method, free SH was
      measured by Ellman's method, and the presence of nitrotyrosine in the plasma and
      tumor tissue was detected by high performance liquid chromatography (HPLC) using
      C- 18-derivatized silica (5 microm) column (C18S, Crestpaque, New York, NY, USA)
      and at a wavelength of 274 nm. Patients with colorectal carcinoma and with active
      IBD had a significantly higher plasma nitrate/ nitrite level (51.2 +/- 26.2
      microm and 56.0 +/- 14.6 microm versus. 29.6 +/- 6.3 microm; p < 0.01), and a
      lower SSA level (39 +/- 11.5 U/g protein and 52.0 +/- 18.9 U/g protein versus. 88
      +/- 25.1 U/g protein; p < 0.05) and SH level (7.7 +/- 3.89 microm protein and 6.4

PMID- 10636211
TI  - Does the duration of gastroesophageal reflux disease and degree of acid reflux
      correlate with esophageal function? A retrospective analysis of 768 patients.
AB  - To reconfirm that the duration of symptoms is not associated with esophageal
      motility in patients with gastroesophageal reflux disease (GERD), esophageal
      manometric data from 768 patients with GERD were retrospectively analyzed with
      relation to the duration of symptoms. GERD was defined by positive acid reflux
      test results monitored by ambulatory 24-hour pH monitoring. Correlation of the
      duration of symptoms with esophageal body pressures, the presence of dysmotility
      determined by simultaneous waves, average resting pressure of the lower
      esophageal sphincter (LES), and abdominal and overall lengths of the LES were
      statistically analyzed. The median duration of the symptoms was 60 months (range,
      1-600). Duration of symptoms was not associated with contraction pressures of the
      esophageal body at 3 and 8 cm above the LES (r = -0.070 and -0.063,
      respectively). There was no correlation between LES pressures, LES lengths, or
      the percentage of simultaneous waves and duration of symptoms. Stricture
      formation is related to decreased distal esophageal function in GERD patients. In
      conclusion, the duration of GERD has little influence on esophageal body and LES
      function.

PMID- 10636210
TI  - Humoral intestinal immunity in systemic lupus erythematosus.
AB  - Forty-five patients with systemic lupus erythematosus (SLE) underwent a cross
      sectional study to evaluate intestinal secretory immunity. Peroral jejunal biopsy
      with histologic and immunohistochemical assessment of the mucosa were carried out
      in the patients and in 12 healthy volunteers. It was observed that an altered
      pattern of immunoglobulin-bearing plasma cells distributed in the lamina propria
      and complementary components were invariably present, mainly in the patients with
      active disease. The basement membrane of the intestinal crypt epithelium
      exhibited immunoglobulin and complementary deposits, similar to the lupus band
      test. None of the immunologic findings correlated with the medical treatment and
      with the peripheral blood analysis. The local changes in humoral immunity in
      patients with SLE did not correlate with gastrointestinal symptoms and may
      reflect the systemic effects of the disease.

PMID- 10636212
TI  - Clinical significance of telomerase activity in biopsy specimens of gastric
      cancer.
AB  - Telomerase has been reported to be activated in most immortal cells and human
      cancers. The purpose of this study was to assess the clinical significance of
      telomerase activity in biopsy specimens of gastric cancer. Telomerase activity in
      endoscopic biopsy specimens obtained preoperatively from 31 patients with gastric
      cancer was determined semiquantitatively using the telomeric repeat amplification
      protocol assay, a polymerase chain reaction-based assay. Cancer tissues had
      significantly higher telomerase activity than adjacent normal tissues (13.9 +/
      2.0% vs. 7.0 +/- 0.8%; p < 0.05). The ratio of the telomerase activity in cancer
      tissues to that in normal tissues (telomerase index) was significantly higher in
      tumors invading the proper muscle layer or deeper or in tumors with moderate or
      marked lymphatic invasion than in tumors without these invasive factors (4.7 +/-
      1.4 vs. 1.1 +/- 0.1 for depth of invasion and 4.4 +/- 1.3 vs. 1.2 +/- 0.2 for
      lymphatic invasion; p < 0.05 for both). These results suggest that the analysis
      of telomerase activity in biopsy specimens might contribute to preoperative
      assessment of the invasive activity or stage of gastric cancer.

PMID- 10636213
TI  - Admixture with whole blood does not explain false-negative urease tests.
AB  - Rapid urease test sensitivity for Helicobacter pylori is reduced in the presence
      of active upper gastrointestinal bleeding. The aim of this study was to evaluate
      the in vitro effect of whole blood on rapid urease testing. Urease solution was
      added to normal saline, and heparinized whole blood both positive and negative
      for H. pylori antibody. The mixtures were then serially diluted in saline, and/or
      whole blood and added to three different rapid urease kits. The admixture of
      urease in H. pylori-seropositive whole blood diluted in either saline or whole
      blood enhanced performance in both kits fourfold compared with saline alone. No
      false-negative results were observed in either kit. Seronegative whole blood
      produced similar results. Undiluted saline or whole blood produced no positive
      rapid urease tests. Whole blood accelerates the urease reaction in vitro. Neither
      H. pylori antibody-positive nor -negative whole blood adversely impacted the
      rapid urease test. False-negative rapid urease test results in upper
      gastrointestinal bleeding cannot be explained by admixture with whole blood.

PMID- 10636214
TI  - The role of natural anticoagulant deficiencies and factor V Leiden in the
      development of idiopathic portal vein thrombosis.
AB  - One of the causes of portal hypertension is portal vein thrombosis (PVT). The aim
      of this study was to determine whether natural anticoagulant deficiencies,
      activated protein C resistance (APCR), and factor V Leiden play a role in the
      development of PVT, leading to cavernous transformation of the portal vein
      (CTPV). Twenty-three patients with idiopathic CTPV (group 1) seen at Hacettepe
      University Hospital during the past 12 years were identified and prospectively
      studied. These 23 patients underwent a detailed hematological evaluation
      including measurement of protein S, protein C, antithrombin III, activated
      protein C resistance (APCR), and factor V Leiden gene mutation. Additionally, all
      patients were tested for anticardiolipin antibodies (ACA), IgG, IgM, and lupus
      anticoagulant (LA). Natural anticoagulants and APCR were measured using available
      commercial kits, and factor V Leiden mutation (R506Q) was detected by Mnl I
      digestion of an amplified factor V DNA fragment. All parameters were measured at
      least 6 months after the diagnosis of CTPV was established. No patient was on
      anticoagulant or antiaggregant treatment while tested. The findings in these 23
      patients were compared with those in 20 healthy control subjects (group 2), in
      whom all tests mentioned above were also performed. In 23 patients (group 1), who
      had no recognizable factor for portal vein thrombosis, considerably natural
      anticoagulant deficiencies and factor V Leiden mutation positivity were found
      when we compare them to those healthy controls (group 2). The protein C levels of
      six patients (26%), the protein S levels of 10 patients (43.5%), and the
      antithrombin III levels of five patients (26%) were lower than in control
      subjects. Two patients were found to have combined protein S and antithrombin III
      deficiency, and one had combined protein S and C deficiency and APCR. APCR was
      detected in seven of the 23 patients, and six of these seven patients were found
      to have R506Q factor V Leiden mutations. In group 1, ACA IgG levels were higher
      in four patients (17%) and ACA IgM level was higher in one (4%) compared with the
      control group. LA was positive in only one patient in group 1. Natural
      anticoagulant deficiencies and factor V Leiden mutation are strongly associated
      with PVT. The natural anticoagulant deficiencies and APCR (almost totally caused
      by R506Q mutation) produce a favorable medium for thrombus generation. PVT seems
      to be related to the natural anticoagulant deficiencies and factor V Leiden R506Q
      mutation. A combination of these defects increases the incidence of PVT and these
      factors should be evaluated carefully in patients with idiopathic CTPV.

PMID- 10636215
TI  - Gallstone ileus: diagnostic pitfalls and therapeutic successes.
AB  - Gallstone ileus is a surgical emergency that occurs almost exclusively in the
      elderly. It is of increasing significance with current demographic changes.
      Clinical records and diagnostic imaging of 15 consecutive patients treated for
      gallstone ileus at one hospital over a 6-year period were reviewed. The median
      patient age was 80 years. Six plain-film diagnoses were made correctly. Contrast
      studies provided a diagnosis of intestinal obstruction in four patients.
      Abdominal X-ray findings were assessed incorrectly in two patients, with one
      false-positive and one false-negative result. The median preoperative hospital
      stay was 2 days. Three patients had Bouveret's syndrome, two of whom required a
      gastrostomy and enterolithotomy, and one of whom required a gastroenterostomy.
      The remaining 12 patients underwent enterolithotomies. Only one patient underwent
      a cholecystectomy. There was one postoperative death. No patient had biliary
      symptoms on follow-up. Gallstone ileus is a difficult clinical and radiologic
      diagnosis. Enterolithotomy alone is adequate treatment in the elderly, and
      subsequent cholecystectomy is not mandatory.

PMID- 10636216
TI  - Effects of oral nutritional supplementation on the intestinal mucosa of patients
      with AIDS.
AB  - Weight loss is a major component of the clinical syndrome in patients with
      acquired immunodeficiency syndrome (AIDS). The impact of malnutrition on the
      outcome of the disease has been unappreciated in many investigations. The authors
      evaluated the effects of oral nutritional supplementation on the morphology and
      immunology of the intestinal mucosa of patients with AIDS. Twelve patients with
      AIDS without diarrhea or opportunistic infections, with at least 10% of body
      weight loss over 1 year, were submitted to anthropometric measures, peripheral
      blood T-lymphocyte counts, and peroral jejunal biopsy before and after oral
      nutritional supplementation. An industrialized peptide-based formula containing
      omega-3 fatty acids was given for 6 weeks. Jejunal samples were analyzed by
      histomorphometry, including villous-to-crypt ratio, lamina propria, and
      intraepithelial lymphocyte count. Immunologic assessment of the intestinal mucosa
      was made by indirect immunoperoxidase using monoclonal antibodies against CD3,
      CD4, and CD8. Seven patients with irritable bowel syndrome and two healthy
      volunteers were selected as a control group for histologic and
      immunohistochemical comparisons. After 6 weeks the patient group maintained their
      body weight and increased their tricipital fold. The number of peripheral blood T
      cells, albumin, transferrin, and the number of CD3+, CD4+, and CD8+ cells in
      jejunal mucosa as well as the intestinal morphometry remained stable. Oral
      supplementation contributed to maintaining body weight and may constitute a
      reasonable adjuvant therapeutic tool against AIDS progression.

PMID- 10636218
TI  - Intestinal motility in small bowel diverticulosis: a case report and review of
      the literature.
AB  - Small bowel diverticulosis is a rare disease that is usually associated with
      recurrent pseudo-obstruction, bacterial overgrowth, and malabsorption. The more
      severe complications include hemorrhage and perforation. There is evidence to
      suggest that this entity is a result of small bowel motor dysfunction. For this
      reason, it has been associated with disorders in which a myopathic or neuropathic
      process is involved, such as scleroderma. The majority of patients with jejunal
      diverticulosis do not require surgery and can be managed medically. We report a
      case of jejunal diverticulosis in a 63-year-old gentleman who presented with
      symptoms of pseudo-obstruction. Ambulatory duodenojejunal manometry revealed
      several abnormalities suggestive of small bowel motor dysfunction. Enteroclysis,
      however, did not find evidence of mechanical obstruction, and the patient had
      marked improvement with cisapride and antibiotics.

PMID- 10636217
TI  - Pancreatic pseudocyst located in the liver: a case report and literature review.
AB  - Pancreatic pseudocyst in the liver is a rare complication of acute or chronic
      pancreatitis. However, its frequency seems to be increasing with modem imaging
      procedures. The authors report a case of pancreatic pseudocyst involving the left
      lobe of the liver that occurred in a patient who never showed clinical evidence
      of pancreatitis or pancreatic injury. Complete screening led to the discovery of
      alcoholic chronic pancreatitis. The pseudocyst was treated successfully by
      radiologic drainage. The pancreatic pseudocyst location and therapeutic
      approaches are discussed. A literature review uncovered 26 cases of hepatic
      pancreatic pseudocysts. Clinical presentation, imaging characteristics, and
      treatment of these cases are analyzed.

PMID- 10636219
TI  - Meckel's diverticulitis in an elderly man diagnosed by computed tomography.
AB  - Meckel's diverticulum is the most common congenital abnormality of the
      gastrointestinal tract. Complications most frequently arise in children younger
      than 2 years who present with gastrointestinal bleeding. The diagnosis is usually
      made via radionuclide scintigraphy or intraoperatively. The authors report a 71
      year-old man who developed a sudden onset of right lower quadrant abdominal pain,
      without bleeding, and was diagnosed as having Meckel's diverticulitis via
      computed tomography. The presence of Meckel' s diverticulitis was confirmed at
      surgery. Complications of a Meckel's diverticulum must be considered at any age.
      Computed tomography is another modality that may be helpful in the preoperative
      diagnosis.

PMID- 10636220
TI  - Sturge-Weber syndrome: a rare cause of gastrointestinal hemorrhage.
AB  - A case of Sturge-Weber syndrome (SWS) with gastrointestinal hemorrhage is
      presented. SWS is a neurocutaneous disorder characterized by cutaneous facial
      angioma leptomeningeal angioma with seizures and other neurologic complications.
      Associated anomalies beyond the encephalofacial territory are very rare. The
      patient presented repeated bleeds from extensive gastric varices of the fundus
      secondary to a splenic venous malformation. This is the first report on this
      association to our knowledge.

PMID- 10636221
TI  - Successful treatment of percutaneous transhepatic papillary dilation in patients
      with obstructive jaundice due to common bile duct stones after Billroth II
      gastrectomy: report of two emergent cases.
AB  - Successful treatment of two patients with obstructive jaundice due to
      choledocholithiasis after Billroth II gastrectomy was performed by elimination of
      stones by percutaneous transhepatic balloon dilatation of the sphincter of Oddi.
      Patient 1 was an 82-year-old man and Patient 2 was a 73-year-old man. Both
      patients presented with obstructive jaundice. The papilla was not observed in
      either patient because of previous Billroth II gastrectomy. Because an endoscopic
      approach was impossible, percutaneous transhepatic cholangiodrainage (PTCD) was
      performed to alleviate jaundice. Choledocholithiasis was treated as follows: The
      sphincter of Oddi was dilated by percutaneous transhepatic balloon, and stone
      particles were removed from the papilla with a stone-eliminating balloon catheter
      via the same route of PTCD. This method is less invasive than the percutaneous
      transhepatic cholangioscopic method, and the use of existing appliances such as a
      balloon for papillary dilation is possible. Hence, this method appears to be an
      effective and simple method for the treatment of choledocholithiasis after
      gastrectomy that is difficult to treat endoscopically.

PMID- 10636222
TI  - Protein-losing enteropathy caused by mesenteric venous thrombosis with protein C
      deficiency.
AB  - A 64-year-old man presented with leg edema and hypoproteinemia. His alpha-1
      antitrypsin clearance rate of 174 mL/day indicated the presence of protein-losing
      enteropathy (PLE). Computed tomographic scans demonstrated thickened ileal wall
      and mesenteric edema. Angiography revealed occlusion in a peripheral branch of
      the superior mesenteric vein. Furthermore, both the patient and his son had low
      protein C levels. The patient was treated successfully with partial resection of
      the ileum. Histologic examination of the resected ileum revealed multiple
      erosions and submucosal fibrosis with organized venous thrombi in the mesenteric
      veins. This is the first case report of PLE caused by mesenteric venous
      thrombosis, and our findings suggest that serum protein was lost through erosion
      of the ileum caused by ischemia due to mesenteric venous thrombosis.

PMID- 10636223
TI  - The coexistance of familial Mediterranean fever and Addison disease.

PMID- 10636224
TI  - A mesalazine tablet in the distal ileum of a patient with Crohn's disease.

PMID- 10636225
TI  - Treatment of phlegmonous gastritis.

PMID- 10636226
TI  - Resolution of peptic stenosis after cure of Helicobacter pylori infection: how
      should we evaluate the therapeutic success?

PMID- 10636227
TI  - Food intolerance not related to gallstones.

PMID- 10636228
TI  - Food intolerance and gallstones

PMID- 10636229
TI  - Amidinohydrazones as guanidine bioisosteres: application to a new class of
      potent, selective and orally bioavailable, non-amide-based small-molecule
      thrombin inhibitors.
AB  - We describe a new class of potent, non-amide-based small molecule thrombin
      inhibitors in which an amidinohydrazone is used as a guanidine bioisostere on a
      non-peptide scaffold. Compound 4 exhibits nM inhibition of thrombin, is selective
      for thrombin, and shows 60 and 23% bioavailability in rabbits and dogs,
      respectively. Crystallographic analysis of 4 bound to thrombin confirmed the
      amindinohydrazone binding mode.

PMID- 10636230
TI  - Modeling directed design and biological evaluation of quinazolinones as non
      peptidic growth hormone secretagogues.
AB  - Quinazolinone derivatives were synthesized and evaluated as non-peptidic growth
      hormone secretagogues. Modeling guided design of quinazolinone compound 21 led to
      a potency enhancement of greater than 200-fold compared to human growth hormone
      secretagogue affinity of a screening lead 4.

PMID- 10636231
TI  - Phenanthrenequinone antiretroviral agents.
AB  - Compounds 3 and 5 are the first phenanthrenequinones to exhibit significant
      virucidal activity against the retrovirus equine infectious anemia virus. They
      differ from hypericin in that their virucidal activity is not light dependent.

PMID- 10636232
TI  - Design, synthesis and structure-activity relationship of a series of arginine
      aldehyde factor Xa inhibitors. Part 1: structures based on the (D)-Arg-Gly-Arg
      tripeptide sequence.
AB  - A series of arginine aldehyde inhibitors was designed as transition state (TS)
      analogues based on the known factor Xa specific substrate Cbz-D-Arg-Gly-Arg-pNA.
      BnSO2-(D)Arg-Gly-Arg-H (20) was found to be the most potent and selective
      inhibitor of factor Xa and prothrombinase activity in this series.

PMID- 10636233
TI  - A sigma-1 receptor selective analogue of BD1008. A potential substitute for (+)
      opioids in sigma receptor binding assays.
AB  - A simple, achiral monoamine sigma-1 (sigma1) receptor selective ligand
      (sigma2Ki/sigma1Ki>2000) is described, which could replace the chiral (+)
      pentazocine or dextrallorphan as a sigma1 masking agent in sigma2 binding assays.

PMID- 10636235
TI  - Binding dynamics of two water molecules constrained within the scytalone
      dehydratase binding pocket.
AB  - Two water molecules reside between inhibitors and active site residues of
      scytalone dehydratase. A molecular dynamics study is consistent with one water
      molecule binding less tightly than the other. Inhibitor binding studies with site
      directed mutants indicate that the hydrogen bonding network around the less
      mobile water molecule contributes much greater binding energy than that around
      the more mobile one.

PMID- 10636234
TI  - Synthesis of the repeating unit of the O-specific polysaccharide of Shigella
      sonnei and quantitation of its serologic activity.
AB  - The chemical synthesis of the zwitterionic disaccharide 2 is described that
      corresponds to the repeating unit of the O-specific polysaccharide (1) of the
      gram-negative human pathogen Shigella sonnei. Passive hemolysis inhibition tests
      using a hyperimmune rabbit serum raised against S. sonnei showed that the
      serologic activity of the disaccharide 2 is nearly 2- to 3-fold higher than those
      of its component monosaccharides. NMR data of 2 are in support of the proposed
      structure of the O-specific polysaccharide.

PMID- 10636236
TI  - 6-Acylamino-2-[(alkylsulfonyl)oxy]-1H-isoindole-1,3-dione mechanism-based
      inhibitors of human leukocyte elastase.
AB  - A study of various 2-[(alkylsulfonyl)oxy]-6-substituted-1H-isoindole-1,3-diones'
      inhibition of chymotrypsin compared to inhibition of HLE reveals that acylamino
      substitution in the 6-position increases selectivity and potency of these
      inhibitors for HLE. The best HLE inhibitor in this series was 6
      (methylglutaryl)amino-2-[(ethylsulfonyl)oxy]-1H-isoindole-1,3-di one with a
      kobs/[I] = 220,000 M(-1) s(-1).

PMID- 10636237
TI  - The utilization of a unified pharmacophore query in the discovery of new
      antagonists of the adenosine receptor family.
AB  - Pharmacophore queries from previously known potent selective A3 antagonists were
      generated by Chem-X. These queries were used to search a pharmacophore database
      of diverse compounds (CNS-Set). In vitro assays of 186 'hits' yielded over 30
      active compounds, for four adenosine receptor subtypes. This search strategy may
      also be applicable to the discovery of new ligands via receptor homology data.

PMID- 10636238
TI  - Synthesis and structure-activity relationships of 4-oxo-1-phenyl-3,4,6,7
      tetrahydro-[1,4]diazepino[6,7,1-hi]indoles: novel PDE4 inhibitors.
AB  - A novel series of benzodiazepine derivatives have been discovered as inhibitors
      of PDE4 enzymes. We have found that our compounds are selective versus other PDE
      enzymes, and that the activity can be modulated by specific structural
      modifications. One compound exhibited a strong eosinophilic infiltration
      inhibiting action on sensitized Brown-Norway rats (compound 9, 5.1 mg/kg p.o.),
      moreover this compound is not emetic at 3 mg/kg i.v.

PMID- 10636239
TI  - Design and synthesis of highly potent fumagillin analogues from homology modeling
      for a human MetAP-2.
AB  - New fumagillin analogues were designed through structure-based molecular modeling
      with a human methionine aminopeptidase-2. Among the fumagillin analogues,
      cinnamic acid ester derivative CKD-731 showed 1000-fold more potent proliferation
      inhibitory activity on endothelial cell than TNP-470.

PMID- 10636241
TI  - Highly versatile solid phase synthesis of biofunctional 4-aryl-3,4
      dihydropyrimidines using resin-bound isothiourea building blocks and
      multidirectional resin cleavage.
AB  - A series of pharmacologically active, functionalized 4-aryl-3,4-dihydropyrimidine
      5-carboxylates (DHPMs) are prepared by a versatile novel solid phase approach. In
      the key step, a polymer-bound thiouronium salt is condensed with unsaturated 1
      ketoesters. The resulting polymer bound 1,4-dihydropyrimidines are cleaved from
      the resin employing multidirectional resin cleavage strategies.

PMID- 10636240
TI  - Structure-based design of ketone-containing, tripeptidyl human rhinovirus 3C
      protease inhibitors.
AB  - Tripeptide-derived molecules incorporating C-terminal ketone electrophiles were
      evaluated as reversible inhibitors of the cysteine-containing human rhinovirus 3C
      protease (3CP). An optimized example of such compounds displayed potent 3CP
      inhibition activity (K = 0.0045 microM) and in vitro antiviral properties
      (EC50=0.34 microM) when tested against HRV serotype-14.

PMID- 10636242
TI  - Antitumour activity of sphingoid base adducts of phenethyl isothiocyanate.
AB  - N-(N'-Phenethylthiocarbamoyl) derivatives of sphingosine and sphinganine were
      prepared. They had antitumour activity: GC50 values of 0.64+/-0.02 microM (N =
      18) and 1.6+/-0.01 microM (N = 18). respectively, with human leukaemia 60 cells
      in vitro. This antitumour effect may contribute to the suppression of
      carcinogenesis associated with dietary phenethyl isothiocyanate and sphingolipid
      bases.

PMID- 10636243
TI  - Synthesis and binding studies of some epibatidine analogues.
AB  - A series of epibatidine analogues and their positional isomers bearing an 8
      azabicyclo[3.2.1]octane moiety is described. Some of the compounds, especially
      those containing 8-azabicyclo[3.2.1]oct-2-ene moiety show high affinity for the
      nicotinic cholinergic receptor.

PMID- 10636244
TI  - 1,1-Dimethylallylcoumarins potently suppress both lipopolysaccharide- and
      interferon-gamma-induced nitric oxide generation in mouse macrophage RAW 264.7
      cells.
AB  - We investigated the suppressive effects of 16 coumarin-related compounds on both
      lipopolysaccharide (LPS)- and interferon (IFN)-gamma-induced nitric oxide (NO)
      generation in a mouse macrophage cell line, RAW 264.7. Notably, coumarins
      possessing prenyl unit(s) were found to be highly active, a tendency consistent
      with our previous study. Among the coumarins tested, 1,1-dimethylallylcoumarins
      showed the highest inhibitory activity. Western blotting analysis revealed that
      they inhibited NO generation by suppressing inducible NO synthase (iNOS) protein
      expression. Our ongoing studies suggest that coumarins are prominent natural
      compounds that attenuate excessive and prolonged NO generation at inflammatory
      sites.

PMID- 10636245
TI  - Role of the hydrophobic moiety of tumor promoters. Synthesis and activity of 2
      alkylated benzolactams.
AB  - The size and position of a hydrophobic moiety on a benzolactam skeleton, which
      reproduces the active conformation and biological activity of teleocidins, play
      an important role in the appearance of the activity. Compounds with alkyl groups
      of various sizes and shapes at the 2-position of benzolactam were synthesized.
      Structure-activity results indicate that a hydrophobic substituent at the C-2
      position plays a critical role in the appearance of biological activities, as in
      the case of substitution at C-9.

PMID- 10636246
TI  - Traceless synthesis of benzimidazoles on solid support.
AB  - Traceless solid-phase syntheses of benzimidazoles and 5-(benzimidazol-2
      yl)benzimidazoles on 2-(4-formyl-3-methoxyphenoxy)ethyl polystyrene are
      described. No auxiliary functional groups are left in the products after ultimate
      cleavage and cyclization.

PMID- 10636247
TI  - New 2-substituted 1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridine having highly active
      and potent central alpha 2-antagonistic activity as potential antidepressants.
AB  - The synthesis and biological activity of a series of benzofuro[3,2-c]pyridines
      and a benzothieno[3,2-c]pyridine are described. These compounds exhibit high
      affinity for the alpha 2-adrenoceptor, with high selectivity versus the alpha 1
      receptor. Compound 1 also shows potent in vivo central activity and has been
      selected for further biological and clinical evaluation.

PMID- 10636248
TI  - Synthesis, radiolabelling and biological characterization of (D)-7-iodo-N-(1
      phosphonoethyl)-5-aminomethylquinoxaline-2,3-dione, a glycine-binding site
      antagonist of NMDA receptors.
AB  - (D)-7-Iodo-N-(1-phosphonoethyl)-5-aminomethylquinoxaline-2,3 -dione (I-PAMQX), is
      a potent, in vivo active antagonist acting at the glycine binding site of the
      NMDA receptor complex. Radioiodinated [131I]I-PAMQX was prepared with good yields
      and high specific activity from its 7-bromo analogue. Biodistribution studies of
      [131I]I-PAMQX in mice showed a relatively slow clearance from the blood. The
      uptake of radioactivity was highest in the kidneys, moderate in the heart, lung,
      liver and bones, and low in the brain.

PMID- 10636249
TI  - Structure-activity and crystallographic analysis of a new class of non-amide
      based thrombin inhibitor.
AB  - The structure activity relationships of a novel series of non-amide-based
      thrombin inhibitors are described. Exploration of the P2 and the aryl binding
      region for this series has identified optimal groups for achieving nanomolar
      potency. The binding modes of these optimal groups have been confirmed by X-ray
      structural analysis.

PMID- 10636250
TI  - Non-peptidic phenyl-based thrombin inhibitors: exploring structural requirements
      of the S1 specificity pocket with amidines.
AB  - We expand the structural requirements and structure-activity relationship of a
      novel class of non-peptidic aryl-based thrombin inhibitors through exploration of
      the S1 specificity pocket of thrombin using flexible and constrained amidines.
      The most active compound of this class is 11 with Ki = 69 nM, which is ca. 15
      fold less potent than constrained guanidine 5.

PMID- 10636251
TI  - Antioxidant function of phenethyl-5-bromo-pyridyl thiourea compounds with potent
      anti-HIV activity.
AB  - In a systematic search for novel dual function antioxidants with potent anti-HIV
      activity, we evaluated 9 rationally designed non-nucleoside inhibitors (NNI) of
      HIV-1 RT for antioxidant and anti-HIV activities. Our lead phenethyl-5
      bromopyridyl thiourea (PEPT) compounds, N-[2-(2-methoxyphenylethyl)]-N'-[2-(5
      bromopyridyl)]-thioure a (2) and N-[2-(2-chlorophenylethyl)]-N'-[2-(5
      bromopyridyl)]-thiourea (9), inhibited the oxidation of ABTS to ABTS*+ by
      metmyoglobin in the presence of hydrogen peroxide with EC50 values of 79 and 75
      microM, respectively. Both compounds effectively inhibited the oxidation-induced
      green fluorescence emission from the free radical-sensitive indicator dye 2',7'
      dichlorodihydrofluorescein diacetate in CEM human T-cells and Nalm-6 human B
      cells exposed to hydrogen peroxide. To our knowledge, compounds 2 and 9 are the
      first NNI of HIV-1 RT with potent anti-oxidant activity. Furthermore, the
      activity center was defined as the sulfhydryl group since alkylated PEPT
      derivatives were inactive. The presence of a free thiourea group was also
      essential for the anti-HIV activity of the PEPT compounds.

PMID- 10636252
TI  - The evolving role of statins in the management of atherosclerosis.
AB  - Significant advances in the management of cardiovascular disease have been made
      possible by the development of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA)
      reductase inhibitors--"statins." Initial studies explored the impact of statin
      therapy on coronary artery disease (CAD) progression and regression. Although the
      angiographic changes were small, associated clinical responses appeared
      significant. Subsequent large prospective placebo-controlled clinical trials with
      statins demonstrated benefit in the secondary and primary prevention of CAD in
      subjects with elevated cholesterol levels. More recently, the efficacy of statins
      has been extended to the primary prevention of CAD in subjects with average
      cholesterol levels. Recent studies also suggest that statins have benefits beyond
      the coronary vascular bed and are capable of reducing ischemic stroke risk by
      approximately one-third in patients with evidence of vascular disease. In
      addition to lowering low-density lipoprotein (LDL) cholesterol, statin therapy
      appears to exhibit pleiotropic effects on many components of atherosclerosis
      including plaque thrombogenicity, cellular migration, endothelial function and
      thrombotic tendency. Growing clinical and experimental evidence indicates that
      the beneficial actions of statins occur rapidly and yield potentially clinically
      important anti-ischemic effects as early as one month after commencement of
      therapy. Future investigations are warranted to determine threshold LDL values in
      primary prevention studies, and to elucidate effects of statins other than LDL
      lowering. Finally, given the rapid and protean effects of statins on determinants
      of platelet reactivity, coagulation, and endothelial function, further research
      may establish a role for statin therapy in acute coronary syndromes.

PMID- 10636253
TI  - Antimyosin autoantibodies are associated with deterioration of systolic and
      diastolic left ventricular function in patients with chronic myocarditis.
AB  - OBJECTIVES: The study evaluates the clinical course and the development of
      systolic and diastolic left ventricular function in patients with chronic
      myocarditis with or without autoantibodies against cardiac myosin. BACKGROUND:
      Patients with myocarditis often show autoantibodies against cardiac myosin. The
      clinical and pathophysiologic significance of these antimyosin autoantibodies
      (AMAAB) is yet unknown. The results from studies comparing the clinical course
      and the development of left ventricular function in patients with chronic
      myocarditis with or without AMAAB are not yet available. METHODS: Thirty-three
      patients with biopsy proven chronic myocarditis underwent analysis of AMAAB,
      right and left heart catheterization and left ventriculography at baseline and
      after six months. Left ventricular volumes and ejection fraction as well as the
      time constant of left ventricular relaxation "tau" and the constant of myocardial
      stiffness "b" were determined at baseline and at follow-up. RESULTS: In 17 (52%)
      patients, AMAAB could be detected at baseline. After six months, AMAAB were still
      found in 13 (76%) initially antibody-positive patients. No initially antibody
      negative (n = 16) patient developed AMAAB during follow-up. Clinical symptoms
      improved slightly in antibody-negative patients and remained stable in antibody
      positive patients. Left ventricular ejection fraction developed significantly
      better in antibody-negative patients (+8.9 +/- 10.1%) compared with antibody
      positive patients (-0.1 +/- 9.4%) (p < 0.012). Stroke volume (SV) and stroke
      volume index (SVI) also improved in antibody-negative patients (SV: +20 +/- 31
      ml; SVI: +10 +/- 17 ml) compared with antibody-positive patients (SV: -14 +/- 43
      ml; SVI: -8 +/- 22 ml) (SV: p < 0.015; SVI: p < 0.016). Left ventricular end
      diastolic and end-systolic volumes and the time constant of left ventricular
      relaxation "tau" did not change significantly different in antibody-positive and
      antibody-negative patients. The constant of myocardial stiffness "b" improved
      significantly in antibody-negative patients (-6.1 +/- 10.8) compared with
      antibody-positive patients (+7.3 +/- 22.6) (p < 0.040). Analyzing only the
      persistently antibody-positive patients yielded essentially the same results.
      CONCLUSIONS: Antimyosin autoantibodies are associated with worse development of
      left ventricular systolic function and diastolic stiffness in patients with
      chronic myocarditis.

PMID- 10636254
TI  - Regional myocardial blood flow reserve impairment and metabolic changes
      suggesting myocardial ischemia in patients with idiopathic dilated
      cardiomyopathy.
AB  - OBJECTIVES: We performed positron emission tomography (PET) to evaluate
      myocardial ischemia in patients with idiopathic dilated cardiomyopathy (IDC).
      BACKGROUND: Patients with IDC have anatomically normal coronary arteries, and it
      has been assumed that myocardial ischemia does not occur. METHODS: We studied 22
      patients with IDC and 22 control subjects using PET with nitrogen-13 ammonia to
      measure myocardial blood flow (MBF) at rest and during dipyridamole-induced
      hyperemia. To investigate glucose metabolism, fluorine-18 deoxyglucose (18FDG)
      was used. For imaging of oxygen consumption, carbon-11 acetate clearance rate
      constants (k(mono)) were assessed at rest and during submaximal dobutamine
      infusion (20 microg/kg body weight per min). RESULTS: Global MBF reserve
      (dipyridamole-induced) was impaired in patients with IDC versus control subjects
      (1.7 +/- 0.21 vs. 2.7 +/- 0.10, p < 0.05). In patients with IDC, MBF reserve
      correlated with left ventricular (LV) systolic wall stress (r = -0.61, p = 0.01).
      Furthermore, in 16 of 22 patients with IDC (derived by dipyridamole perfusion)
      mismatch (decreased flow/increased 18FDG uptake) was observed in 17 +/- 8% of the
      myocardium. The extent of mismatch correlated with LV systolic wall stress (r =
      0.64, p = 0.02). The MBF reserve was lower in the mismatch regions than in the
      normal regions (1.58 +/- 0.13 vs. 1.90 +/- 0.18, p < 0.05). During dobutamine
      infusion k(mono) was higher in the mismatch regions than in the normal regions
      (0.104 +/- 0.017 vs. 0.087 +/- 0.016 min(-1), p < 0.05). In the mismatch regions
      18FDG uptake correlated negatively with rest k(mono) (r = -0.65, p < 0.05),
      suggesting a switch from aerobic to anaerobic metabolism. CONCLUSIONS: Patients
      with IDC have a decreased MBF reserve. In addition, low MBF reserve was
      paralleled by high LV systolic wall stress. These global observations were
      associated with substantial myocardial mismatch areas showing the lowest MBF
      reserves. In geographically identical regions an abnormal oxygen consumption
      pattern was seen together with a switch from aerobic to anaerobic metabolism.
      These data support the notion that regional myocardial ischemia plays a role in
      IDC.

PMID- 10636255
TI  - Lack of association between polymorphisms of eight candidate genes and idiopathic
      dilated cardiomyopathy: the CARDIGENE study.
AB  - OBJECTIVES: The study investigated the potential role of eight candidate genes in
      the susceptibility to idiopathic dilated cardiomyopathy (IDC). BACKGROUND:
      Idiopathic dilated cardiomyopathy has a familial origin in 20% to 25% of cases,
      and several genetic loci have been identified in rare monogenic forms of the
      disease. These findings led to the hypothesis that genetic factors might also be
      involved in sporadic forms of the disease. In complex diseases that do not
      exhibit a clear pattern of familial aggregation, the candidate gene approach is a
      strategy widely used to identify susceptibility genes. All genes coding for
      proteins involved in biochemical or physiological abnormalities of cardiac
      function are potential candidates for IDC. METHODS: We studied 433 patients with
      IDC and 401 gender- and age-matched controls. Polymorphisms investigated were the
      I/D polymorphism of the angiotensin I-converting enzyme (ACE) gene, the T174M and
      M235T polymorphisms of the angiotensinogen (AGT) gene, the A-153G and A+39C
      polymorphisms of the angiotensin-II type 1 receptor (AGTR1) gene, the T-344C
      polymorphism of the aldosterone synthase (CYP11B2) gene, the G-308A polymorphism
      of the tumor necrosis factor-alpha (TNF) gene, the R25P polymorphism of the
      transforming growth factor beta1 (TGFB1) gene, the G+11/in23T polymorphism of the
      endothelial nitric oxide synthase (NOS3) gene and the C-1563T polymorphism of the
      brain natriuretic peptide (BNP) gene. RESULTS: None of the polymorphisms were
      significantly associated with the risk or the severity of the disease.
      CONCLUSIONS: We did not find evidence for an involvement of any of the 10
      investigated polymorphisms in the susceptibility to IDC.

PMID- 10636256
TI  - Morphology and significance of the left ventricular collagen network in young
      patients with hypertrophic cardiomyopathy and sudden cardiac death.
AB  - BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a primary cardiac disease with a
      diverse clinical spectrum, in which many of the abnormal structural and
      pathophysiologic features are consequences of inappropriate left ventricular
      hypertrophy. METHODS: We analyzed the amount, distribution and structure of the
      cardiac collagen network in transmural sections of the ventricular septum
      (thickness 17 to 40 mm, mean 25 mm) in 16 previously asymptomatic children and
      young adults with HCM (11 to 31 years of age, mean 20 years) who died suddenly.
      The morphologic appearance and volume fractions of interstitial (matrix) and
      perivascular (adventitial) collagen were analyzed with polarization microscopy
      and computerized videodensitometry in picrosirius red-stained sections. Findings
      were compared with 16 structurally normal hearts, 5 with systemic hypertension
      and 6 infants who died of HCM. RESULTS: Adults and young children with HCM had an
      eightfold greater amount of matrix collagen compared with normal controls (14.1
      +/- 8.8% vs. 1.8 +/- 1% of the tissue section; p < 0.0001), and a threefold
      increase compared with patients with systemic hypertension (4.5 +/- 1.3%; p <
      0.001) and infants with HCM (4.0 +/- 2.4%; p < 0.001). Compared with normal
      controls and hypertensives, adults and young children (and infants) with HCM
      showed increased numbers and thickness of each collagen fiber component of the
      matrix (perimysial coils, pericellular weaves and struts), which were often
      arranged in disorganized patterns. In HCM patients, the amount of collagen was
      not a consequence of other clinical, demographic and morphologic disease
      variables. CONCLUSIONS: Left ventricular collagen matrix in young, previously
      asymptomatic patients with HCM who died suddenly is morphologically abnormal and
      substantially increased in size. The enlarged matrix collagen compartment is
      present in HCM at an early age, further expands during growth, is partially
      responsible for increased ventricular septal thickness and likely represents a
      primary morphologic abnormality in this disease. These findings support the view
      that the complex HCM disease process is not confined to sarcomere protein
      abnormalities, but also involves connective tissue elements.

PMID- 10636257
TI  - Hemodynamic comparison of twice daily metoprolol tartrate with once daily
      metoprolol succinate in congestive heart failure.
AB  - OBJECTIVES: To compare the hemodynamic effects of twice daily metoprolol tartrate
      (MT) and once daily metoprolol succinate (MS) in congestive heart failure
      patients. BACKGROUND: Adverse hemodynamic effects with MT demonstrated during
      initiation persist with drug readministration during chronic therapy. METHODS:
      Patients were randomly assigned to 6.25 mg MT or 25 mg MS orally and the dose was
      gradually increased to a target of 50 mg twice a day or 100 mg once a day,
      respectively. Hemodynamic measurements were obtained at baseline and after three
      months of therapy--both before and after drug readministration. RESULTS: Long
      term metoprolol therapy produced significant functional, exercise and hemodynamic
      benefits with no difference in response between either metoprolol preparation in
      the 27 patients (MT [14], MS [13]). When full dose metoprolol was readministered
      during chronic therapy, there were parallel adverse hemodynamic effects in both
      drug groups. Cardiac index decreased by 0.6 liters/min/m2 (p < 0.0001) with MT
      and by 0.5 liters/min/m2 (p < 0.0001) with MS. Systematic vascular resistance
      increased by 253 dyne-sec-cm(-5) (p < 0.001) with MT and by 267 dyne-sec-cm(-5)
      (p < 0.0005) with MS. Stroke volume index decreased by 7.0 ml/m2 (p < 0.0005)
      with MT and by 6.5 ml/m2 (p < 0.0001) with MS, while SWI decreased by 6.2 g-m/m2
      (p < 0.0005) with MT and by 6.0 g-m/m2 (p < 0.001) with MS. CONCLUSION:
      Metoprolol tartrate and MS produce similar hemodynamic and clinical effects
      acutely and chronically despite the fourfold greater starting dose of MS used in
      this study. A more rapid initiation with readily available starting doses of MS
      may offer distinct advantages compared with MT in treating chronic heart failure
      patients with beta-adrenergic blocking agents.

PMID- 10636258
TI  - Contracted plasma and blood volume in chronic heart failure.
AB  - OBJECTIVES: The purpose of this study was to determine if long-term
      pharmacotherapy mediated changes in intravascular plasma and blood volumes in
      patients with chronic heart failure (CHF). BACKGROUND: Intravascular fluid volume
      expansion is an acute compensatory adaptation to ventricular dysfunction in
      patients with CHF. To our knowledge there are no reports on plasma and blood
      volume measures in clinically stable patients with CHF receiving standard
      pharmacotherapy. Such information may provide a better understanding of the
      clinical hallmarks of heart failure. METHODS: Plasma volume (PV) and blood volume
      (BV) were measured in 12 patients (62.8 +/- 8.2 years old, 175.2 +/- 6.8 cm, 96.2
      +/- 18.2 kg, peak oxygen consumption (VO2max) 15.2 +/- 3.3 ml/kg per min) with
      CHF secondary to coronary artery disease (left ventricular ejection fraction 31.2
      +/- 9.7, New York Heart Association functional class 2.5 +/- 0.5) and seven
      healthy subjects (71.7 +/- 5.3 years old, 177.1 +/- 10.8 cm, 84.4 +/- 11.7 kg,
      VO2max 26.0 +/- 6.5 ml/kg per min) 3 to 4 h after eating and after supine rest
      using the Evan's blue dye dilution technique. Venous blood samples were collected
      before blue dye infusion and analyzed for hematocrit (corrected 4% for trapped
      plasma and venous to whole body hematocrit ratio) and hemoglobin. RESULTS:
      Hematocrit was 36.6 +/- 3.5% and 37.4 +/- 1.1%, and hemoglobin was 15.4 +/- 1.9
      and 16.2 +/- 1.4 g/dl for patients with CHF and control subjects, respectively.
      Absolute PV was 3489.3 +/- 655.0 and 3728.7 +/- 813.2 ml, and absolute BV was
      5,496.8 +/- 1,025.4 and 5,942.4 +/- 1,182.2 ml in patients with CHF and control
      subjects, respectively. Relative PV was 34.1 +/- 12.9 versus 44.5 +/- 9.0 ml/kg
      (p < or = 0.05), and relative BV was 58.5 +/- 12.3 versus 70.8 +/- 12.6 ml/kg (p
      < or = 0.05) in patients with CHF and control subjects, respectively.
      CONCLUSIONS: Our data indicate significantly lower intravascular volumes in
      patients with CHF than in control subjects, indicating a deconditioned state or
      excessive diuresis, or both. The contracted PV and BV may contribute to exercise
      intolerance, shortness of breath and chronic fatigue, secondary to reduced
      cardiac output or regional blood flow, or both.

PMID- 10636259
TI  - Effects of BG9719 (CVT-124), an A1-adenosine receptor antagonist, and furosemide
      on glomerular filtration rate and natriuresis in patients with congestive heart
      failure.
AB  - OBJECTIVES: To determine the effects of furosemide and the selective A1 adenosine
      receptor BG9719 on renal function in patients with congestive heart failure
      (CHF). BACKGROUND: Studies suggest that adenosine may affect renal function by
      various mechanisms, but the effects of blockade of this system in humans is
      unknown. In addition, the effects of a therapeutic dose of furosemide on
      glomerular filtration rate (GFR) and renal plasma flow (RPF) in heart failure
      patients are controversial. METHODS: On different days, 12 patients received
      placebo, BG9719 and furosemide. Glomerular filtration rate, RPF and sodium and
      water excretion were assessed immediately following drug administration. RESULTS:
      Glomerular filtration rate was 84 +/- 23 ml/min/1.73m2 after receiving placebo,
      82 +/- 24 following BG9719 administration and a decreased (p < 0.005) 63 +/- 18
      following furosemide. Renal plasma flow was unchanged at 293 +/- 124
      ml/min/1.73m2 on placebo, 334 +/- 155 after receiving BG9719 and 374 +/- 231
      after receiving furosemide. Sodium excretion increased from 8 +/- 8 mEq following
      placebo administration to 37 +/- 26 mEq following BG9719 administration. In the
      six patients in whom it was measured, sodium excretion was 104 +/- 78 mEq
      following furosemide administration. CONCLUSIONS: Natriuresis is effectively
      induced by both furosemide and the adenosine A1 antagonist BG9719 in patients
      with CHF. Doses of the two drugs used in this study did not cause equivalent
      sodium and water excretion but only furosemide decreased GFR. These data suggest
      that adenosine is an important determinant of renal function in patients with
      heart failure.

PMID- 10636260
TI  - Comparative study of ACE-inhibition, angiotensin II antagonism, and calcium
      channel blockade on flow-mediated vasodilation in patients with coronary disease
      (BANFF study)
AB  - OBJECTIVES: To determine the effect of angiotensin-converting enzyme (ACE)
      inhibition on brachial flow-mediated vasodilation. BACKGROUND: Quinapril, an ACE
      inhibitor with high affinity, has been shown to improve coronary endothelial
      dysfunction in patients with coronary artery disease. The effectiveness of
      different vasoactive agents to improve human endothelial function is unknown.
      METHODS: High resolution ultrasound was used to assess endothelium-dependent
      brachial artery flow-mediated vasodilation (FMD) in patients with coronary
      disease. We studied 80 patients (mean age 58 +/- 0.9 years) in a partial-block,
      cross-over design trial. Patients were randomized to one of four different drug
      sequences to receive quinapril 20 mg, enalapril 10 mg, losartan 50 mg or
      amlodipine 5 mg daily. Each patient received three drugs with a two-week washout
      period between treatments. The primary end point was the absolute difference in
      FMD after eight weeks of each study drug compared with their respective baselines
      analyzed in a blinded fashion. RESULTS: There was mild impairment of FMD at
      baseline (7.3 +/- 0.6%). The change in FMD from baseline was significant only for
      quinapril (1.8 +/- 1%, p < 0.02). No change was seen with losartan (0.8 +/- 1.1%,
      p = 0.57), amlodipine (0.3 +/- 0.9%, p = 0.97) or enalapril (-0.2 +/- 0.8%, p =
      0.84). No significant change in nitroglycerin-induced dilation occurred with drug
      therapy. The improvement in quinapril response was not seen in those with the DD
      ACE genotype (0.5 +/- 2.1%) but was seen in those with the ID and II genotype
      (3.3 +/- 1.2 and 3.2 +/- 1.9%, respectively, p = 0.03). CONCLUSION: Only
      quinapril was associated with significant improvement in FMD, and this response
      is related to the presence of the insertion allele of the ACE genotype.

PMID- 10636261
TI  - Endothelium: a new target for cardiovascular therapeutics.

PMID- 10636262
TI  - Tetrahydrobiopterin restores endothelial function in long-term smokers.
AB  - OBJECTIVES: We sought to test whether tetrahydrobiopterin (BH4) supplementation
      improves nitric oxide (NO) bioactivity in smokers. BACKGROUND: In smokers,
      endothelium-derived NO bioactivity is impaired. BH4 is an essential cofactor of
      NO synthase, and its deficiency decreases NO bioactivity. METHODS: Sapropterin
      hydrochloride, an active analogue of BH4 (2 mg/kg body weight), was administered
      orally to healthy male smokers and age-matched nonsmokers. Before and 3 and 24 h
      after sapropterin, we measured plasma levels of BH4 and examined flow-mediated
      vasodilation (FMV) of the brachial artery by high resolution ultrasonography, a
      noninvasive test of endothelial function. RESULTS: Basal plasma levels of BH4
      were not different between smokers and nonsmokers. Sapropterin administration
      increased plasma levels of BH4 by threefold at 3 h, which returned to the
      baseline at 24 h. Before sapropterin, FMV was significantly smaller in smokers (p
      = 0.0002). Sapropterin significantly augmented endothelium-dependent vasodilation
      in smokers, but did not affect it in nonsmokers (p = 0.001 by analysis of
      variance [ANOVA]). Coadministration of N(G)-monomethyl-L-arginine (L-NMMA), an NO
      synthase inhibitor (20 micromol), into the brachial artery completely abolished
      the vasodilatory effects of sapropterin (p = 0.002 by ANOVA). Endothelium
      independent vasodilation by glyceryl trinitrate was not different between smokers
      and nonsmokers and was not altered by BH4. CONCLUSIONS: We demonstrated that BH4
      supplementation improved bioactivity of endothelium-derived NO in smokers. These
      observations strongly suggest that decreased NO-dependent vasodilation in smokers
      could be related to reduced bioactivity of BH4.

PMID- 10636263
TI  - Cholesterol reduction improves myocardial perfusion abnormalities in patients
      with coronary artery disease and average cholesterol levels.
AB  - OBJECTIVES: We sought to evaluate whether pravastatin treatment increases
      myocardial perfusion, as assessed by thallium-201 single-photon emission computed
      tomographic (SPECT) dipyridamole testing, in patients with coronary artery
      disease (CAD) and average cholesterol levels. BACKGROUND: Previous studies in
      hypercholesterolemic patients have demonstrated that cholesterol reduction
      restores peripheral and coronary endothelium-dependent vasodilation and increases
      myocardial perfusion. METHODS: This was a randomized, placebo-controlled study
      with a cross-over design. Twenty patients with CAD were randomly assigned to
      receive 20 mg of pravastatin or placebo for 16 weeks and then were crossed over
      to the opposite medication for a further 16 weeks. Lipid and lipoprotein analysis
      and dipyridamole thallium-201 SPECT were performed at the end of each period. The
      SPECT images were visually analyzed in eight myocardial segments using a 4-point
      scoring system by two independent observers. A summed stress score and a summed
      rest score were obtained for each patient. Quantitative evaluation was performed
      by the Cedars-Sinai method. The magnitude of the defect was expressed as a
      percentage of global myocardial perfusion. RESULTS: Total and low density
      lipoprotein cholesterol levels during placebo were 214 +/- 29 mg/dl and 148 +/-
      25 mg/dl, respectively. These levels with pravastatin were 170 +/- 23 mg/dl and
      103 +/- 23 mg/dl, respectively. The summed stress score and summed rest score
      were lower with pravastatin than with placebo (7.2 +/- 2.3 vs. 5.9 +/- 2.3, p =
      0.012 and 3.2 +/- 1.6 vs. 2.4 +/- 2.2, p = 0.043, respectively). Quantitative
      analysis showed a smaller perfusion defect with pravastatin (29.2%) as compared
      with placebo (33.8%) (p = 0.021) during dipyridamole stress. No differences were
      found at rest. CONCLUSIONS: Reducing cholesterol levels with pravastatin in
      patients with CAD improves myocardial perfusion during dipyridamole stress
      thallium-201 SPECT.

PMID- 10636264
TI  - Low-dose dipyridamole infusion acutely increases exercise capacity in angina
      pectoris: a double-blind, placebo controlled crossover stress echocardiographic
      study.
AB  - OBJECTIVES: The aim of this study was to assess whether endogenous accumulation
      of adenosine, induced by low-dose dipyridamole infusion, protects from exercise
      induced ischemia. BACKGROUND: Adenosine is a recognized mediator of ischemic
      preconditioning in experimental settings. METHODS: Ten patients (all men: mean
      age 63.4 +/- 7.3 years) with chronic stable angina, angiographically assessed
      coronary artery disease (n = 7) or previous myocardial infarction (n = 3) and
      exercise-induced ischemia underwent on different days two exercise-stress echo
      tests after premedication with placebo or dipyridamole (15 mg in 30 min, stopped
      5 min before testing) in a double-blind, placebo controlled, randomized crossover
      design. RESULTS: In comparison with placebo, dipyridamole less frequently induced
      chest pain (20% vs. 100%, p = 0.001) and >0.1 mV ST segment depression (50% vs.
      100%, p < 0.05). Wall motion abnormalities during exercise-stress test were less
      frequent (placebo = 100% vs. dipyridamole = 70%, p = ns) and significantly less
      severe (wall motion score index at peak stress: placebo = 1.55 +/- 0.17 vs.
      dipyridamole = 1.27 +/- 0.2, p < 0.01) following dipyridamole, which also
      determined an increase in exercise time up to echocardiographic positivity
      (placebo = 385.9 +/- 51.4 vs. dipyridamole = 594.4 +/- 156.9 s, p < 0.01).
      CONCLUSIONS: Low-dose dipyridamole infusion increases exercise tolerance in
      chronic stable angina, possibly by endogenous adenosine accumulation acting on
      high affinity A1 myocardial receptors involved in preconditioning or positively
      modulating coronary flow through collaterals.

PMID- 10636265
TI  - Interactions between angiotensin-I converting enzyme insertion/deletion
      polymorphism and response of plasma lipids and coronary atherosclerosis to
      treatment with fluvastatin: the lipoprotein and coronary atherosclerosis study.
AB  - OBJECTIVES: Our objectives were to determine whether angiotensin-1 converting
      enzyme (ACE) insertion/deletion (I/D) polymorphism was associated with the
      severity of coronary artery disease (CAD) and its progression/regression in
      response to fluvastatin therapy in the Lipoprotein and Coronary Atherosclerosis
      Study (LCAS) population. BACKGROUND: Genetic factors are involved in
      susceptibility to CAD. Angiotensin-1 converting enzyme I/D polymorphism, which
      accounts for half of the variance of plasma and tissue levels of ACE, has been
      implicated in susceptibility to CAD and myocardial infarction (MI). METHODS:
      Angiotensin-1 converting enzyme genotypes were determined by polymerase chain
      reaction (PCR). Fasting plasma lipids were measured and quantitative coronary
      angiograms were obtained at baseline and 2.5 years following randomization to
      fluvastatin or placebo. RESULTS: Ninety-one subjects had DD, 198 ID and 75 II
      genotypes. The mean blood pressure, minimum lumen diameter (MLD), number of
      coronary lesions and total occlusions were not significantly different at
      baseline or follow-up among the genotypes. There was a significant genotype-by
      treatment interaction for total cholesterol (p = 0.018), low-density lipoprotein
      cholesterol (LDL-C) (p = 0.005) and apolipoprotein (apo) B (p = 0.045). In
      response to fluvastatin therapy, subjects with DD, compared with those with ID
      and II genotypes, had a greater reduction in total cholesterol (19% vs. 15% vs.
      13%), LDL-C (31% vs. 25% vs. 21%) and apo B (23% vs. 15% vs. 12%). Definite
      progression was less (14%) and regression was more common (24%) in DD as compared
      with those with ID (32% and 17%) and II (33% and 3%) genotypes (p = 0.023).
      Changes in the mean MLD and lesion-specific MLD also followed the same trend.
      CONCLUSIONS: Angiotensin-1 converting enzyme I/D polymorphism is associated with
      the response of plasma lipids and coronary atherosclerosis to treatment with
      fluvastatin. Subjects with DD genotype had a greater reduction in LDL-C, a higher
      rate of regression and a lower rate of progression of CAD.

PMID- 10636266
TI  - Light-to-moderate alcohol consumption and mortality in the Physicians' Health
      Study enrollment cohort.
AB  - OBJECTIVES: This study examined the relationship between light-to-moderate
      alcohol consumption and cause-specific mortality. BACKGROUND: Previous studies
      suggest a J-shaped relation between alcohol and total mortality in men. A
      decrease in cardiovascular disease (CVD) mortality without a significant increase
      in other causes of mortality may explain the overall risk reduction at light-to
      moderate levels. METHODS: We conducted a prospective cohort study of 89,299 U.S.
      men from the Physicians' Health Study enrollment cohort who were 40 to 84 years
      old in 1982 and free of known myocardial infarction, stroke, cancer or liver
      disease at baseline. Usual alcohol consumption was estimated by a limited food
      frequency questionnaire. RESULTS: There were 3,216 deaths over 5.5 years of
      follow-up. We observed a U-shaped relationship between alcohol consumption and
      total mortality. Compared with rarely/never drinkers, consumers of 1, 2 to 4 and
      5 to 6 drinks per week and 1 drink per day had significant reductions in risk of
      death (multivariate relative risks [RRs] of 0.74, 0.77, 0.78 and 0.82,
      respectively) with no overall benefit or harm detected at the > or =2 drinks per
      day level (RR = 0.95; 95% confidence interval (CI), 0.79 to 1.14). The
      relationship with CVD mortality was inverse or L-shaped with apparent risk
      reductions even in the highest category of > or =2 drinks per day (RR = 0.76; 95%
      CI, 0.57 to 1.01). We found no clear harm or benefit for total or common site
      specific cancers. For remaining other cancers, there was a nonsignificant 28%
      increased risk for those consuming > or =2 drinks per day. CONCLUSIONS: These
      data support a U-shaped relation between alcohol and total mortality among light
      to-moderate drinking men. The U-shaped curve may reflect an inverse association
      for CVD mortality, no association for common site-specific cancers and a possible
      positive association for less common cancers.

PMID- 10636267
TI  - Morphology of vulnerable coronary plaque: insights from follow-up of patients
      examined by intravascular ultrasound before an acute coronary syndrome.
AB  - OBJECTIVES: To determine the morphologic features of coronary plaques associated
      with acute coronary syndrome, we prospectively followed patients with
      atherosclerotic disease identified by intravascular ultrasound (IVUS).
      BACKGROUND: Although clinical evaluation of the vulnerable atherosclerotic plaque
      is important, few data exist regarding the morphology of the vulnerable plaque in
      clinical settings. METHODS: We examined 114 coronary sites without significant
      stenosis by angiography (<50% diameter stenosis) in 106 patients. All the sites
      exhibited atherosclerotic lesions by IVUS. These lesions consisted of 22
      concentric and 92 eccentric plaques with a percent plaque area averaging 59 +/-
      12%. RESULTS: During the follow-up period of 21.8 +/- 6.4 months (range 1 to 24),
      12 patients had an acute coronary event at a previously examined coronary site at
      an average of 4.0 +/- 3.4 months after the initial IVUS study. All the
      preexisting plaques related to the acute events exhibited an eccentric pattern
      and the mean percent plaque area was 67 +/- 9%, which was greater than plaque
      area in the other 90 patients without acute events (57 +/- 12%, p < 0.05). There
      was no statistically significant difference in lumen area between two patient
      groups (6.7 +/- 3.0 vs. 7.5 +/- 3.7 mm2). Among 12 coronary sites with an acute
      occlusion, 10 sites contained the echolucent zones, eight of these shallow and
      two deep, likely representing a lipid-rich core. In 90 sites without acute
      events, an echolucent zone in the shallow portion was seen at only four sites (p
      < 0.05). CONCLUSIONS: Large eccentric plaque containing an echolucent zone by
      IVUS can be at increased risk for instability even though the lumen area is
      preserved at the time of initial study. Compensatory enlargement of vessel wall
      due to remodeling may contribute to the relatively small degree of stenosis by
      angiography.

PMID- 10636268
TI  - Seropositivity to chlamydial lipopolysaccharide and Chlamydia pneumoniae,
      systemic inflammation and stable coronary artery disease: negative results of a
      case-control study.
AB  - OBJECTIVES: We investigated the association between seropositivity to chlamydial
      lipopolysaccharide (cLPS) or Chlamydia pneumoniae (CP) and angiographically
      documented coronary artery disease (CAD), and we examined the relationship
      between serostatus and markers of systemic inflammation. BACKGROUND: The
      potential contribution of CP to atherogenesis is still a matter of debate, and
      inflammation has been suggested to represent the link between infection and
      atherosclerotic disease. METHODS: Subjects age 40 to 68 years were recruited for
      this case-control study between October 1996 and November 1997: 312 patients with
      at least one coronary stenosis >50% and 479 age- and sex-matched blood donors
      without manifest CAD or history of angina. Antibodies against cLPS and CP, C
      reactive protein (CRP), fibrinogen, plasma viscosity, leukocytes and neutrophils
      were determined. The study had a power of >80% to detect an odds ratio (OR) of
      1.55 or above for the prevalence of immunoglobulin (IgG) antibodies against cLPS
      at a significance level of alpha = 0.05. RESULTS: Prevalence of IgG antibodies
      against cLPS was not different between cases and controls (61% vs. 62%; p = 0.7).
      The adjusted OR for the presence of CAD given positive IgG serostatus against
      cLPS was 0.9 (95% CI; 0.6 to 1.3). Similarly, no difference in the prevalence of
      IgG antibodies against CP was seen (88% vs. 87%; p = 0.6); the adjusted OR was
      1.0 (95% CI; 0.6 to 1.6). Markers of inflammation did not show any statistically
      significant difference between cLPS seropositives and seronegatives. CONCLUSIONS:
      Our results indicate no strong association between CP and CAD, and increased
      systemic inflammation in patients with CAD does not seem to be due to
      seropositivity to cLPS or CP.

PMID- 10636269
TI  - Prevalence, predisposing factors, and prognosis of clinically unrecognized
      myocardial infarction in the elderly.
AB  - OBJECTIVES: This study was designed to determine the prevalence of unrecognized
      myocardial infarction (UMI), as well as risk factors, and to compare prognosis
      after detection of previously UMI to that after recognized myocardial infarction
      (RMI). BACKGROUND: Past studies revealed that a significant proportion of MIs
      escape recognition, and that prognosis after such events is poor, but the
      epidemiology of UMI has not been reassessed in the contemporary era. METHODS: The
      Cardiovascular Health Study (CHS) database, composed of individuals > or =65, was
      queried for participants who, at entry, demonstrated electrocardiographic
      evidence of a prior Q-wave MI, but who lacked a history of this diagnosis. The
      features and outcomes of this group were compared to those of individuals with
      prevalent RMI. RESULTS: Of 5,888 participants, 901 evidenced a past MI, and 201
      (22.3%) were previously unrecognized. The independent predictors of UMI were the
      absence of angina and the absence of congestive heart failure (CHF). Six-year
      mortality did not significantly differ between the two groups. CONCLUSIONS: 1) In
      the elderly, UMI continues to represent a significant proportion of all MIs; 2)
      associations with angina and CHF may reflect complex neurological issues, but
      they also may represent diagnosis bias; 3) these individuals can otherwise not be
      distinguished from those with recognized infarctions; and 4) mortality rates
      after UMI and RMI are similar. Future studies should address screening for UMI,
      risk stratification after detection of previously UMI, and the role of standard
      post-MI therapies.

PMID- 10636270
TI  - Electrocardiographic evolutionary changes and left ventricular remodeling after
      acute myocardial infarction: results of the GISSI-3 Echo substudy.
AB  - OBJECTIVES: The aim of this study was to describe the electrocardiographic (ECG)
      evolutionary changes after an acute myocardial infarction (AMI) and to evaluate
      their correlation with left ventricular function and remodeling. BACKGROUND: The
      QRS complex changes after AMI have been correlated with infarct size and left
      ventricular function. By contrast, the significance of T wave changes is
      controversial. METHODS: We studied 536 patients enrolled in the GISSI-3-Echo
      substudy who underwent ECG and echocardiographic studies at 24 to 48 h (S1), at
      hospital discharge (S2), at six weeks (S3) and six months (S4) after AMI.
      RESULTS: The number of Qwaves (nQ) and QRS quantitative score (QRSs) did not
      change over time. From S2 to S4, the number of negative T waves (nT NEG)
      decreased (p < 0.0001), wall motion abnormalities (%WMA) improved (p < 0.001),
      ventricular volumes increased (p < 0.0001) while ejection fraction remained
      stable. According to the T wave changes after hospital discharge, patients were
      divided into four groups: stable positive T waves (group 1, n = 35), patients who
      showed a decrease > or =1 in nT NEG (group 2, n = 361), patients with no change
      in nT NEG (group 3, n = 64) and those with an increase > or =1 in nT NEG (group
      4, n = 76). The QRSs and nQ remained stable in all groups. Groups 3 and 4 showed
      less recovery in %WMA, more pronounced ventricular enlargement and progressive
      decline in ejection fraction than groups 1 and 2 (interaction time x groups p <
      0.0001). CONCLUSIONS: The analysis of serial ECG can predict postinfarct left
      ventricular remodeling. Normalization of negative T waves during the follow-up
      appears more strictly related to recovery of regional dysfunction than QRS
      changes. Lack of resolution and late appearance of new negative T predict
      unfavorable remodeling with progressive deterioration of ventricular function.

PMID- 10636271
TI  - Predictors of cardiogenic shock after thrombolytic therapy for acute myocardial
      infarction.
AB  - OBJECTIVES: This study characterized clinical factors predictive of cardiogenic
      shock developing after thrombolytic therapy for acute myocardial infarction
      (AMI). BACKGROUND: Cardiogenic shock remains a common and ominous complication of
      AMI. By identifying patients at risk of developing shock, preventive measures may
      be implemented to avert its development. METHODS: We analyzed baseline variables
      associated with the development of shock after thrombolytic therapy in the Global
      Utilization of Streptikonase and Tissue-Plasminogen Activator for Occluded
      Coronary Arteries (GUSTO-I) trial. Using a Cox proportional hazards model, we
      devised a scoring system predicting the risk of shock. This model was then
      validated in the Global Use of Strategies to Open Occluded Coronary Arteries
      (GUSTO-III) cohort. RESULTS: Shock developed in 1,889 patients a median of 11.6 h
      after enrollment. The major factors associated with increased adjusted risk of
      shock were age (chi2 = 285, hazard ratio [95% confidence interval] 1.47 [1.40,
      1.53]), systolic blood pressure (chi2 = 280), heart rate (chi2 = 225) and Killip
      class (chi2 = 161, hazard ratio 1.70 [1.52, 1.90] and 2.95 [2.39, 3.63] for
      Killip II versus I and Killip III versus I, respectively) upon presentation.
      Together, these four variables accounted for >85% of the predictive information.
      These findings were transformed into an algorithm with a validated concordance
      index of 0.758. Applied to the GUSTO-III cohort, the four variables accounted for
      > 95% of the predictive information, and the validated concordance index was
      0.796. CONCLUSIONS: A scoring system accurately predicts the risk of shock after
      thrombolytic therapy for AMI based primarily on the patient's age and physical
      examination on presentation.

PMID- 10636272
TI  - Out-of-hospital ventricular fibrillation in patients with acute myocardial
      infarction: coronary angiographic determinants.
AB  - OBJECTIVES: The study intended to compare the acute coronary anatomy of patients
      with acute myocardial infarction (AMI) complicated by out-of-hospital ventricular
      fibrillation (VF) versus patients with AMI without this complication. BACKGROUND:
      More than half of the deaths associated with AMI occur out of the hospital and
      within 1 h of symptom onset. The angiographic determinants of out-of-hospital VF
      in patients with AMI have not been investigated in detail. METHODS: Acute
      coronary angiographic findings of 72 consecutive patients with AMI complicated by
      out-of-hospital VF were compared with findings from 144 matched patients with AMI
      without this complication. RESULTS: Patients with an acute occlusion of the left
      anterior descending coronary artery (LAD) or left circumflex coronary artery
      (LCx) had a higher risk for out-of-hospital VF compared with patients with an
      acute occlusion of the right coronary artery (RCA) (odds ratio and 95% confidence
      interval, respectively, 4.82 [2.35 to 9.92] and 4.92 [2.34 to 10.39]). With
      regard to extent of coronary artery disease (CAD), the location of the culprit
      lesion in the coronary arteries (proximal vs. mid or distal), the flow in the
      infarct related artery (IRA), the presence or absence of collaterals to the IRA
      and chronic occlusions, there were no differences between the two groups.
      CONCLUSIONS: Acute myocardial infarction due to occlusion in the left coronary
      artery (LCA) is associated with greater risk for out-of-hospital VF compared to
      the RCA. The location of occlusion within LCA (LAD, LCx, proximal or distal),
      amount of myocardium at risk for necrosis and extent of CAD are not related to
      out-of-hospital VF.

PMID- 10636273
TI  - Effect of plaque debulking and stenting on short- and long-term outcomes after
      revascularization of chronic total occlusions.
AB  - OBJECTIVES: We evaluated the effect of plaque burden modification (debulking) on
      the short- and long-term clinical outcomes of patients with a totally occluded
      native coronary artery undergoing successful stent deployment. BACKGROUND:
      Although the primary success rate of crossing a chronic totally occluded coronary
      artery has improved with the development of new interventional devices and
      guidewires, the rate of acute reocclusion and restenosis remains high. METHODS:
      The in-hospital and late clinical outcomes of 150 patients who had undergone
      successful stenting of 176 chronic total occlusions were analyzed. After
      successful crossing of the lesion, 44 patients with 50 lesions underwent
      debulking by laser angioplasty, rotational or directional atherectomy followed by
      stenting, whereas 106 patients with 126 lesions underwent stent implantation
      without prior debulking. RESULTS: Baseline clinical and angiographic
      characteristics were similar for the two groups, except for a higher incidence of
      left anterior descending coronary artery location and longer lesions in the group
      of patients who underwent debulking prior to stenting. In-hospital mortality,
      myocardial infarction and repeat angioplasty rates were similar for the two
      groups. At a mean 14 +/- 8 months follow-up time, there were no deaths in either
      group, and target lesion revascularization rates were the same (16.3% in the
      debulking plus stent group vs. 14.4% in the stent alone group, p = NS).
      CONCLUSIONS: Treatment of chronic total native coronary artery occlusions with
      stent deployment with and without lesion modification (debulking) results in a
      favorable in-hospital outcome, with relatively low long-term target lesion
      revascularization rates.

PMID- 10636274
TI  - Acute and chronic tissue response to coronary stent implantation: pathologic
      findings in human specimen.
AB  - OBJECTIVES: The aim of our study was to analyze the cellular components of
      neointimal tissue regeneration after coronary stenting. BACKGROUND: High
      restenosis rates are a major limiting factor of coronary stenting. To reduce the
      occurrence of restenoses, more insights into the mechanisms leading to
      proliferation and expression of extracellular matrix are necessary. METHODS:
      Twenty-one autopsy cases with coronary stents implanted 25 h to 340 days before
      death were studied. The stented vessel segments were analyzed postmortem by light
      microscopy and immunohistochemical staining. RESULTS: In the initial phase stents
      are covered by a thin multilayered thrombus. Alpha-actin-positive smooth muscle
      cells (SMCs) are found as the main cellular component of the neointimal tissue.
      Later (>6 weeks) extracellular matrix increases and fewer SMCs can be found. In
      every phase the SMC layers are loosely infiltrated by inflammatory cells (T
      lymphocytes). In the early postinterventional phase all endothelial cells are
      destroyed. The borderline between the vessel lumen and the vascular wall is
      constituted by a thin, membranous thrombus. Six weeks after stenting, SMCs form
      the vessel surface. Complete reendothelialization is first found 12 weeks after
      stenting. CONCLUSIONS: Stent integration is a multifactorally triggered process
      with proliferating SMCs generating regenerative tissue. In the early phase
      predominantly thrombotic material can be observed at the site of stenting,
      followed by the invasion of SMCs, T lymphocytes and macrophages. The incidence of
      delayed reendothelializations and the occurrence of deep dissections may be
      associated with excessive SMC hyperplasia.

PMID- 10636275
TI  - Value of acceleration flow and the prestenotic to stenotic coronary flow velocity
      ratio by transthoracic color Doppler echocardiography in noninvasive diagnosis of
      restenosis after percutaneous transluminal coronary angioplasty.
AB  - OBJECTIVES: The study evaluated the value of coronary flow velocity measurement
      by transthoracic color Doppler echocardiography (TTCDE) for the noninvasive
      diagnosis of restenosis after percutaneous transluminal coronary angioplasty
      (PTCA) for left anterior descending coronary artery (LAD) lesions. BACKGROUND:
      Recent advances in TTCDE provide coronary flow velocity measurements in the LAD
      under the guidance of color flow mapping. METHODS: We studied 53 patients who
      underwent successful PTCA for LAD lesions and follow-up coronary angiography (18
      patients with restenosis [Group-R], 35 patients without restenosis [Group-N]). We
      searched localized color aliasing corresponding to local flow acceleration to
      obtain coronary flow velocity at PTCA sites in the LAD. When localized aliasing
      was detected, we measured coronary flow velocity at the aliasing (stenotic site)
      and the prestenotic site. RESULTS: Using TTCDE, it was possible to measure mean
      diastolic velocity (MDV) in the LAD in 41 (77%) of 53 patients (14 of 18 patients
      in Group-R; 27 of 35 patients in Group-N). Localized aliasing was displayed by
      color flow mapping in 14 (100%) of 14 patients in Group-R, and 15 (56%) of 27
      patients in Group-N. Stenotic MDV in Group-R was significantly higher than that
      in Group-N (60.3 +/- 21.1 vs. 35.1 +/- 7.6 cm/s, p < 0.01), although prestenotic
      MDV did not differ between Group-R and Group-N (20.2 +/- 3.0 vs. 19.6 +/- 2.3
      cm/s). There were significant differences in the prestenotic to stenotic MDV
      ratio between Group-R and Group-N (0.36 +/- 0.10 vs. 0.57 +/- 0.09, p < 0.001).
      Localized aliasing with the prestenotic to stenotic MDV ratio <0.45 as the
      optimal cutoff value had a sensitivity of 86% and a specificity of 93% for the
      presence of restenosis in LAD lesions. CONCLUSIONS: Detection of localized color
      aliasing and measurement of the prestenotic to stenotic MDV ratio in the LAD by
      TTCDE are useful in the noninvasive diagnosis of restenosis after PTCA for LAD
      lesions.

PMID- 10636276
TI  - Long-term clinical and echocardiographic outcome of percutaneous mitral
      valvuloplasty: randomized comparison of Inoue and double-balloon techniques.
AB  - OBJECTIVES: The purpose of the present study was to compare the long-term
      clinical and echocardiographic results of the Inoue and the double-balloon
      techniques. BACKGROUND: The large randomized trial comparing the extent of
      commissurotomy and the long-term results between the double-balloon and Inoue
      balloon techniques has not been reported. METHODS: We conducted a prospective,
      randomized trial comparing two procedures in 302 consecutive patients who
      underwent percutaneous mitral valvuloplasty (PMV) using Inoue (n = 152; group I)
      or double-balloon technique (n = 150, group D) between 1989 and 1995. The sample
      size was planned to provide the study with approximately 80% power for the
      detection of a 10% difference between the two groups. RESULTS: There were no
      significant differences in baseline characteristics between the two groups.
      Immediately after PMV, mitral valve area (MVA) increased from 0.9 +/- 0.2 to 1.8
      +/- 0.3 cm2 in group I and from 0.9 +/- 0.2 to 1.9 +/- 0.3 cm2 in group D. No
      significant differences existed between the two groups in terms of development of
      commissural splitting, commissural mitral regurgitation (CMR), moderate to severe
      mitral regurgitation (MR) and MVA after PMV. The successful immediate results
      (MVA > or =1.5 cm2 and MR < or =2) were achieved in 127 (84%) patients of group I
      and 122 (81%) patients of group D (p = NS). Annual clinical and echocardiographic
      evaluation was completed for 290 (96%) patients with mean follow-up of 51 +/- 27
      months. Adverse events occurred in 19 (13%) patients of group I (3 deaths, 7
      mitral valve replacements, 5 repeat PMV, 2 NYHA class > or =3, 2 technical
      failures) and 16 (11%) patients of group D (2 deaths, 10 mitral valve
      replacements, 3 repeat PMV, 1 NYHA class > or =3). Estimated actuarial seven-year
      event-free survival was 75 +/- 7% in group I and 82 +/- 6% in group D (p = NS).
      Estimated actuarial seven-year restenosis-free survival was 67 +/- 7% in group I
      and 76 +/- 6% in group D (p = NS). On multivariate analysis, unsuccessful
      immediate result (p < 0.001) and absence of CMR (p < 0.01) were independently
      related with events. Absence of CMR and smaller mitral valve area after PMV were
      independently related with restenosis (p < 0.001). CONCLUSIONS: The Inoue and
      double-balloon techniques were equally effective in commissurotomy and produced
      similar, excellent long-term results. The achievement of complete commissurotomy
      with development of CMR or larger post-PMV mitral valve area is important to
      optimize the long-term results of PMV.

PMID- 10636277
TI  - A comparison of the acute hemodynamic effects of inhaled nitric oxide and
      aerosolized iloprost in primary pulmonary hypertension. German PPH study group.
AB  - OBJECTIVE: We sought to compare the acute hemodynamic effects of inhaled nitric
      oxide (NO) and aerosolized iloprost in primary pulmonary hypertension (PPH).
      BACKGROUND: Inhalation of the stable prostacyclin analogue iloprost has recently
      been described as a novel therapeutic strategy for PPH and may offer an
      alternative to continuous intravenous infusion of prostacyclin or inhalation of
      NO. METHODS: During right heart catheterization, 35 patients with PPH
      sequentially inhaled 40 ppm of NO and 14 to 17 microg of iloprost, and the
      effects on hemodynamics and blood gases were monitored. RESULTS: Both NO and
      iloprost caused significant increases in cardiac output, mixed-venous oxygen
      saturation and stroke volume as well as significant decreases in pulmonary artery
      pressure and pulmonary vascular resistance, whereas only inhaled iloprost
      significantly increased the arterial PO2 (p = 0.01). Compared with inhaled NO,
      aerosolized iloprost was more effective in reducing pulmonary artery pressure (
      8.3 +/- 7.5 mm Hg vs. -4.3 +/- 8.8 mm Hg; p = 0.0001) and the pulmonary vascular
      resistance (-447 +/- 340 dynes x s x cm(-5) vs. -183 +/- 305 dyne x s x cm(-5); p
      < 0.0001). Furthermore, aerosolized iloprost caused a significantly greater
      increase of the cardiac output compared with NO (+0.7 +/- 0.6 liter/min vs. +0.3
      +/- 0.4 liter/min; p = 0.0002) and had a more pronounced effect on the mixed
      venous oxygen saturation (p = 0.003). CONCLUSIONS: During acute drug testing,
      aerosolized iloprost was more potent than inhaled NO as a pulmonary vasodilator
      in PPH at the doses used in this study.

PMID- 10636278
TI  - Stroke with intermittent atrial fibrillation: incidence and predictors during
      aspirin therapy. Stroke Prevention in Atrial Fibrillation Investigators.
AB  - OBJECTIVE: This study was performed to characterize the risk of stroke in elderly
      patients with recurrent intermittent atrial fibrillation (AF). BACKGROUND:
      Although intermittent AF is common, relatively little is known about the
      attendant risk of stroke. METHODS: A longitudinal cohort study was performed
      comparing 460 participants with intermittent AF with 1,552 with sustained AF
      treated with aspirin in the Stroke Prevention in Atrial Fibrillation studies and
      followed for a mean of two years. Independent risk factors for ischemic stroke
      were identified by multivariate analysis. RESULTS: Patients with intermittent AF
      were, on average, younger (66 vs. 70 years, p < 0.001), were more often women
      (37% vs. 26% p < 0.001) and less often had heart failure (11% vs. 21%, p < 0.001)
      than those with sustained AF. The annualized rate of ischemic stroke was similar
      for those with intermittent (3.2%) and sustained AF (3.3%). In patients with
      intermittent AF, independent predictors of ischemic stroke were advancing age
      (relative risk [RR] = 2.1 per decade, p < 0.001), hypertension (RR = 3.4, p =
      0.003) and prior stroke (RR = 4.1, p = 0.01). Of those with intermittent AF
      predicted to be high risk (24%), the observed stroke rate was 7.8% per year (95%
      confidence interval 4.5 to 14). CONCLUSIONS: In this large cohort of AF patients
      given aspirin, those with intermittent AF had stroke rates similar to patients
      with sustained AF and similar stroke risk factors. Many elderly patients with
      recurrent intermittent AF have substantial rates of stroke and likely benefit
      from anticoagulation. High-risk patients with intermittent AF can be identified
      using the same clinical criteria that apply to patients with sustained AF.

PMID- 10636279
TI  - False positive head-up tilt: hemodynamic and neurohumoral profile.
AB  - OBJECTIVES: This study examined differences in mechanisms of head-up tilt (HUT)
      induced syncope between normal controls and patients with neurocardiogenic
      syncope. BACKGROUND: A variable proportion of normal individuals experience
      syncope during HUT. Differences in the mechanisms of HUT-mediated syncope between
      this group and patients with neurocardiogenic syncope have not been elucidated.
      METHODS: A 30-min 80 degrees HUT was performed in eight HUT-negative volunteers
      (Group I), eight HUT-positive volunteers (Group II) and 15 patients with
      neurocardiogenic syncope. Heart rate and blood pressure (BP) were monitored
      continuously. Epinephrine and norepinephrine plasma levels, as well as left
      ventricular dimensions and contractility determined by echocardiography, were
      measured at baseline and at regular intervals during the test. RESULTS: The main
      findings of this study were the following: 1) All parameters were similar at
      baseline in the three groups; and 2) During tilt: a) the time to syncope was
      shorter in Group III than in group II (9.5 +/- 3 vs. 17 +/- 3 min p < 0.05); b)
      there was an immediate, persisting drop in mean BP in Group III; c) the decrease
      rate of left ventricular end-diastolic dimensions was greater in Group III than
      in Group II or Group I (-1.76 +/- 0.42 vs. -0.87 +/- 0.35 and -0.67 +/- 0.29
      mm/min, respectively, p < 0.05); d) the leftventricular shortening fraction was
      greater in Group III than in the other two groups (39 +/- 1 vs. 34 +/- 1 and 32
      +/- 1%, respectively, p < 0.05); and e) although the norepinephrine level
      remained comparable among the groups, there was a significantly higher peak
      epinephrine level in Group III than in Group II and Group I (112.3 +/- 34 vs.
      77.6 +/- 10 and 65 +/- 12 pg/ml, p < 0.05). CONCLUSIONS: Mechanisms of syncope
      during HUT appeared to be different in normal volunteers and patients with
      neurocardiogenic syncope. In the latter, there was evidence of an impaired
      vascular resistance response from the beginning of the orthostatic challenge.
      Furthermore, in the patients there was more rapid peripheral blood pooling, as
      indicated by the echocardiographic measurements of left ventricular end-diastolic
      changes, leading to more precocious symptoms. In syncopal patients, the higher
      level of plasma epinephrine probably mediated the increased cardiac contractility
      and possibly contributed to the impaired vasoconstrictive response.

PMID- 10636280
TI  - Baroreflex sensitivity and variants of the renin angiotensin system genes.
AB  - OBJECTIVES: Because the renin-angiotensin-aldosterone system (RAS) modifies
      cardiovascular autonomic regulation, we studied the possible associations between
      baroreflex sensitivity (BRS) and polymorphism in the RAS genes. BACKGROUND: Wide
      intersubject variability in BRS is not well explained by cardiovascular risk
      factors or life style, suggesting a genetic component responsible for the
      variation of BRS. METHODS: Baroreflex sensitivity as measured from the overshoot
      phase of the Valsalva maneuver and genetic polymorphisms were examined in a
      random sample of 161 women and 154 men aged 41 to 61 years and then in an
      independent random cohort of 29 men and 37 women aged 36 to 37 years. An
      insertion/deletion (I/D) polymorphism of angiotensin-converting enzyme (ACE),
      M235T variants of angiotensinogen (AGT) and two diallelic polymorphisms in the
      gene encoding aldosterone synthase (CYP11B2), one in the promoter (-344C/T) and
      the other in the second intron, were identified by polymerase chain reaction.
      RESULTS: In the older population, BRS differed significantly across CYP11B2
      genotype groups in women (10.1 +/- 4.5, 8.7 +/- 3.8 and 7.1 +/- 3.2 ms x mm Hg(
      1) in genotypes -344TT, CT and CC, respectively, p = 0.003 and 11.1 +/- 4.4, 8.9
      +/- 4.1 and 7.5 +/- 3.4 ms x mm Hg(-1) in intron 2 genotypes 1/1, 1/2 and 2/2,
      respectively, p = 0.002), but not in men. No comparable associations were found
      for BRS with the I/D polymorphism of ACE or the M235T variant of AGT. In the
      younger population, BRS was even more strongly related to the CYP11B2 promoter
      genotype (p = 0.0003). The association was statistically significant both in men
      (p = 0.015) and in women (p = 0.03). CONCLUSIONS: Common genetic polymorphisms in
      the aldosterone synthase (CYP11B2) gene is associated with interindividual
      variation in BRS.

PMID- 10636281
TI  - Color M-mode Doppler flow propagation velocity is a preload insensitive index of
      left ventricular relaxation: animal and human validation.
AB  - OBJECTIVES: To determine the effect of preload in color M-mode Doppler flow
      propagation velocity (v(p)). BACKGROUND: The interpretation of Doppler filling
      patterns is limited by confounding effects of left ventricular (LV) relaxation
      and preload. Color M-mode v(p) has been proposed as a new index of LV relaxation.
      METHODS: We studied four dogs before and during inferior caval (IVC) occlusion at
      five different inotropic stages and 14 patients before and during partial
      cardiopulmonary bypass. Left ventricular (LV) end-diastolic volumes (LV-EDV), the
      time constant of isovolumic relaxation (tau), left atrial (LA) pre-A and LV end
      diastolic pressures (LV-EDP) were measured. Peak velocity during early filling
      (E) and v(p) were extracted by digital analysis of color M-mode Doppler images.
      RESULTS: In both animals and humans, LV-EDV and LV-EDP decreased significantly
      from baseline to IVC occlusion (both p < 0.001). Peak early filling (E) velocity
      decreased in animals from 56 +/- 21 to 42 +/- 17 cm/s (p < 0.001) without change
      in v(p) (from 35 +/- 15 to 35 +/- 16, p = 0.99). Results were similar in humans
      (from 69 +/- 15 to 53 +/- 22 cm/s, p < 0.001, and 37 +/- 12 to 34 +/- 16, p =
      0.30). In both species, there was a strong correlation between LV relaxation
      (tau) and v(p) (r = 0.78, p < 0.001, r = 0.86, p < 0.001). CONCLUSIONS: Our
      results indicate that color M-mode Doppler v(p) is not affected by preload
      alterations and confirms that LV relaxation is its main physiologic determinant
      in both animals during varying lusitropic conditions and in humans with heart
      disease.

PMID- 10636282
TI  - Balloon angioplasty of postsurgical recoarctation in infants: the risk of
      restenosis and long-term follow-up.
AB  - OBJECTIVES: This study was undertaken to evaluate the long-term results of
      balloon angioplasty (BA) for postsurgical recoarctation in infants. BACKGROUND:
      Balloon angioplasty is a well-accepted modality for the treatment of
      recoarctation. However, infants remain a group of concern because of their size,
      risk for complications and the potential for restenosis with growth. Age <12
      months has been determined to be a risk factor for the development of
      recoarctation after angioplasty for native coarctation. Although studies on
      postsurgical coarctation have found no relationship between age at angioplasty
      and the development of recoarctation, few studies specifically addressing infants
      have been performed. METHODS: Clinical, echocardiographic, hemodynamic and
      angiographic data on 22 consecutive children <1 year of age who underwent BA
      between 1986 and 1996 were reviewed. RESULTS: A successful result, defined as a
      postprocedure gradient of < or =20 mm Hg, was achieved in 20 of 22 (91%) infants
      with a reduction in the systolic peak pressure gradient from 48 +/- 27 to 9 +/-
      10 mm Hg (p < 0.001) and an increase in coarctation diameter from 2.7 +/- 1.1 to
      5.2 +/- 1.5 mm (p < 0.001). At long-term follow-up of a median of 56 months (0.6
      to 12 years), the restenosis rate after an initial optimal result was 16% (3 of
      19). Five (24%) infants required reintervention (2 initially unsuccessful; 3
      recoarctation), with a success rate of 95% after two procedures. Suboptimal long
      term outcome correlated with a lower infant weight. CONCLUSIONS: Balloon
      angioplasty can be safely performed in infants, with good long-term results. The
      risk of restenosis is low and can be successfully managed with repeat
      angioplasty.

PMID- 10636283
TI  - Effects of hydroxymethylglutaryl coenzyme A reductase inhibitor simvastatin on
      smooth muscle cell proliferation in vitro and neointimal formation in vivo after
      vascular injury.
AB  - OBJECTIVES: We sought to evaluate the effects of hydroxymethylglutaryl coenzyme A
      (HMG-CoA) reductase inhibitors on vascular smooth muscle cell (VSMC)
      proliferation in vitro and neointimal formation in vivo after vascular injury.
      BACKGROUND: Neointimal hyperplasia after vascular injury is responsible for
      restenosis after arterial stenting, whereas arterial remodeling and neointimal
      formation are the causes of restenosis after percutaneous transluminal coronary
      angioplasty. METHODS: We assessed the effect of simvastatin on in vitro VSMC
      proliferation. To study the effects of simvastatin in vivo, balloon injury and
      stent deployment were performed in the common carotid artery of rats. Neointimal
      area was measured two weeks later in the balloon injury model and three weeks
      after stent deployment. RESULTS: Simvastatin markedly inhibits VSMC proliferation
      in vitro. In vivo, simvastatin reduced, in a dose-dependent manner, the
      neointimal area and the neointima-media ratio after balloon injury from 0.266 +/-
      0.015 mm2 to 0.080 +/- 0.026 mm2 and from 1.271 +/- 0.074 to 0.436 +/- 0.158 (p <
      0.001 vs. control rats) at the highest dose. Simvastatin also significantly
      reduced the neointimal formation and the neointima-media ratio after stenting
      from 0.508 +/- 0.035 mm2 to 0.362 +/- 0.047 mm2 (p < 0.05 vs. control rats) and
      from 2.000 +/- 0.136 to 1.374 +/- 0.180 (p < 0.05 vs. control rats). The vessel
      thrombosis rate after stent deployment was 30% in the control group and 11.1% in
      the treated group (p = NS). Moreover, the systemic administration of simvastatin
      did not affect hepatic and renal functions, blood pressure or heart rate.
      CONCLUSIONS: Simvastatin potently inhibits VSMC proliferation in vitro and
      reduces neointimal formation in a rat model of vascular injury.

PMID- 10636284
TI  - Effects of long-term therapy with bosentan on the progression of left ventricular
      dysfunction and remodeling in dogs with heart failure.
AB  - OBJECTIVES: In this study, we examined the effects of long-term therapy with
      bosentan on the progression of LV dysfunction and remodeling in dogs with
      moderate HF. BACKGROUND: Acute intravenous administration of bosentan, a mixed
      endothelin-1 type A and type B receptor antagonist, was shown to improve left
      ventricular (LV) function in patients and dogs with heart failure (HF). METHODS:
      Left ventricular dysfunction was induced by multiple, sequential intracoronary
      microembolizations in 14 dogs. Embolizations were discontinued when LV ejection
      fraction (EF) was between 30% and 40%. Dogs were randomized to three months of
      therapy with bosentan (30 mg/kg twice daily, n = 7) or no therapy at all
      (control, n = 7). RESULTS: In untreated dogs, EF decreased from 35 +/- 1% before
      initiating therapy to 29 +/- 1% at the end of three months of therapy (p =
      0.001), and LV end-diastolic volume (EDV) and end-systolic volume (ESV) increased
      (EDV: 71 +/- 3 vs. 84 +/- 8 ml, p = 0.08; ESV: 46 +/- 2 vs. 60 +/- 6 ml, p =
      0.03). By contrast, in dogs treated with bosentan, EF tended to increase from 34
      +/- 2% before initiating therapy to 39 +/- 1% at the end of three months of
      therapy (p = 0.06), and EDV and ESV decreased (EDV: 75 +/- 3 vs. 71 +/- 4 ml, p =
      0.05; ESV: 48 +/- 2 vs. 43 +/- 3 ml, p = 0.01). Furthermore, compared with
      untreated dogs, dogs treated with bosentan showed significantly less LV
      cardiomyocyte hypertrophy and LV volume fraction of interstitial fibrosis.
      CONCLUSIONS: In dogs with moderate HF, long-term therapy with bosentan prevents
      the progression of LV dysfunction and attenuates LV chamber remodeling. The
      findings support the use of mixed endothelin-1 receptor antagonists as adjuncts
      to the long-term treatment of HF.

PMID- 10636285
TI  - Stereolithographic biomodeling to create tangible hard copies of cardiac
      structures from echocardiographic data: in vitro and in vivo validation.
AB  - OBJECTIVES: This study investigated the feasibility, accuracy and clinical
      potential of creating polymer hard copies of echocardiographic data using
      stereolithography. BACKGROUND: Three-dimensional (3D) echocardiography has so far
      been limited by the need to display reconstructed 3D objects on a two-dimensional
      screen. Thus, tangible stereolithographic polymer models created from
      echocardiographic data could enhance our spatial perception of cardiac anatomy
      and pathology. METHODS: Hard-copy replicas of water-filled latex balloon phantoms
      (n = 7) and porcine liver specimens (n = 12) were generated from
      echocardiographic images using stereolithography (computerized laser
      polymerization). In addition, we created 24 models of the mitral valve from 12
      transesophageal studies (normal = 6, mitral stenosis n = 4, prolapse/flail
      leaflet n = 8, annular dilation n = 2, leaflet restriction n = 2 and following
      mitral valve repair n = 2). RESULTS: Excellent agreement was found for comparison
      of volumes (r = 0.98, SEE = 3.46 mm3, mean difference = 0.25 +/- 3.33 mm3) and
      maximal dimensions (r = 0.99, SEE = 0.16 cm, mean difference = 0.03 +/- 0.16 cm)
      between phantoms and their corresponding replicas. Visual and tactile examination
      of mitral valve models by two blinded observers allowed correct depiction of
      mitral valve anatomy and pathology in all cases. CONCLUSIONS: Stereolithographic
      modeling of echocardiographic images is feasible and provides tangible
      polyacrylic models that are true to scale, shape and volume. Such models offer
      accurate depiction of mitral valve anatomy and pathology in patients studied with
      transesophageal echocardiography. This technique could have substantial impact on
      diagnosis, management and preoperative planning in complex cardiovascular
      disorders.

PMID- 10636286
TI  - Roles of mitochondrial ATP-sensitive K channels and PKC in anti-infarct tolerance
      afforded by adenosine A1 receptor activation.
AB  - OBJECTIVES: This study intended to assess the role of mitochondrial ATP-sensitive
      potassium (mitoK ATP) channels and the sequence of signal transduction with
      protein kinase C (PKC) and adenosine A1 receptors in rabbits. BACKGROUND: To our
      knowledge, the link between trigger receptors of preconditioning, PKC and mitoK
      ATP channels has not been examined in a whole heart model of infarction. METHODS:
      In the first series of experiments, myocardial infarction was induced in isolated
      buffer-perfused rabbit hearts by 30-min global ischemia and 2-h reperfusion.
      Infarct size in the left ventricle was determined by tetrazolium staining and
      expressed as a percentage of area at risk (i.e., the whole left ventricle)
      (%IS/AR). In the second series of experiments, mitochondria were isolated from
      the heart, and their respiratory function was examined using glutamate as a
      substrate. RESULTS: Pretreatment with R-phenylisopropyladenosine (R-PIA, 1
      micromol/liter), an A1-receptor agonist, reduced %IS/AR from 49.8 +/- 6.5% to
      13.4 +/- 2.9%. This protection was abolished by calphostin C, a PKC inhibitor,
      and by 5-hydroxydecanoate (5-HD), a selective inhibitor of mitoK ATP channels. A
      selective mitoK ATP channel opener, diazoxide (100 micromol/liter), mimicked the
      effect of R-PIA on infarct size (%IS/AR = 11.6 +/- 4.0%), and this protective
      effect was also abolished by 5-HD. However, calphostin C failed to block the
      infarct size-limiting effect of diazoxide. Neither calphostin C nor 5-HD alone
      modified %IS/AR. State III respiration (QO2) and respiratory control index (RCI)
      were reduced after 30 min of ischemia (QO2 = 147.3 +/- 5.3 vs. 108.5 +/- 12.3,
      RCI = 22.3 +/- 1.1 vs. 12.1 +/- 1.8, p < 0.05). This mitochondrial dysfunction
      was persistent after 10 min of reperfusion (QO2 = 96.1 +/- 15.5, RCI = 9.5 +/-
      1.9). Diazoxide significantly attenuated the respiratory dysfunction after 30 min
      of ischemia (QO2 = 142.8 +/- 9.7, RCI = 16.2 +/- 0.8) and subsequent 10-min
      reperfusion (QO2 = 135.3 +/- 7.2, RCI = 19.1 +/- 0.8). CONCLUSIONS: These results
      suggest that mitoK ATP channels are downstream of PKC in the mechanism of infarct
      size limitation by A1-receptor activation and that the anti-infarct tolerance
      afforded by opening of mitoK ATP channels is associated with preservation of
      mitochondrial function during ischemia/reperfusion.

PMID- 10636287
TI  - Determination of refractory periods and conduction velocity during atrial
      fibrillation using atrial capture in dogs: direct assessment of the wavelength
      and its modulation by a sodium channel blocker, pilsicainide.
AB  - OBJECTIVES: The purposes of this study were to measure the atrial refractory
      period and the conduction velocity (CV) during atrial fibrillation (AF) and to
      explore the antiarrhythmic mechanism of a sodium channel blocker, pilsicainide,
      during AF. BACKGROUND: Sodium channel blockers not only decrease the CV, but also
      prolong the atrial refractory period, particularly during rapid excitation.
      Because these effects on the wavelength are counteractive and rate dependent, it
      is critical to measure these parameters during AF. METHODS: In eight dogs, after
      AF was induced under vagal stimulation, a single extra-stimulus was repeatedly
      introduced from the left atrium and its capture was statistically determined for
      each coupling interval. The local CV was also measured during constant capture of
      the fibrillating atrium by rapid pacing. The same procedure was repeated after
      pilsicainide administration. RESULTS: Pilsicainide significantly increased the
      mode of AF intervals from 81 +/- 10 to 107 +/- 16 ms (p < 0.01). While the CV was
      decreased from 0.9 +/- 0.1 to 0.7 +/- 0.1 m/s (p < 0.02), the effective
      refractory period during AF was increased from 69 +/- 11 ms to 99 +/- 17 ms (p <
      0.01). As a result, the wavelength was significantly increased by pilsicainide
      from 6.6 +/- 0.9 to 7.6 +/- 1.2 cm (p < 0.05). CONCLUSIONS: During AF, whereas
      the sodium channel blocker pilsicainide decreases CV, it lengthens the wavelength
      by increasing the refractory period, an action that is likely to contribute to
      the drug's ability to terminate the arrhythmia. The direct measurement of
      refractoriness and CV during AF may provide new insights into the determinations
      of the arrhythmia and antiarrhythmic drug action.

PMID- 10636288
TI  - Electrocardiogram in myocardial infarction: what is most relevant?

PMID- 10636289
TI  - Does flow reserve match contractility?

PMID- 10636290
TI  - Preconditioning, collateral recruitment and adenosine.

PMID- 10636291
TI  - Pressure recovery and aortic stenosis.

PMID- 10636292
TI  - Can angiography predict the vulnerable lesion that progresses to myocardial
      infarction?

PMID- 10636293
TI  - Place navigation in rats guided by a vestibular and kinesthetic orienting
      gradient.
AB  - The role of the slope of terrain in orientation was examined in rats trained to
      find, among 4 equidistant feeders, the 1 located in the upper left quadrant of a
      10% tilted arena (1-m radius). Rats started from the center in light and with
      randomly changing slope direction reached the correct goal in 90% of 1st choices
      after 29 sessions. The same rats maintained 83% correct choices when the
      experiment was conducted in darkness. On a horizontal arena, their performance
      became random. After training, successful navigation was also observed (71%
      correct 1st choices) when the rats were started from different points at about 30
      cm from the wall. This finding suggests that the slope of terrain may be used to
      establish a cognitive map based primarily on kinesthetic and vestibular signals.
      The flexibility of such a map seems to be rather limited, however, because
      changing the goal position with respect to inclination requires prolonged
      retraining.

PMID- 10636294
TI  - Long-term effects of neonatal damage to the hippocampal formation and amygdaloid
      complex on object discrimination and object recognition in rhesus monkeys (Macaca
      mulatta).
AB  - Rhesus monkeys with neonatal aspiration lesions of the hippocampal formation or
      the amygdaloid complex were tested on concurrent discrimination learning (24-hr
      intertrial interval [ITI]) at 3 months, on object recognition memory (delayed
      nonmatching-to-sample [DNMS]) at 10 months, and retested on both tasks at 6-7
      years of age. Neonatal amygdaloid damage mildly impaired acquisition at the 24-hr
      ITI and the performance test of DNMS at both ages. In contrast, early hippocampal
      lesions impaired performance only on the longest lists of 10 items in DNMS in
      adult monkeys. Thus, early amygdala lesions appeared to have resulted in a
      greater object memory loss than early hippocampal lesions. However, in light of
      recent findings from lesion studies in adult monkeys, the object memory
      impairment after early amygdaloid lesions is better accounted for by damage to
      the entorhinal and perirhinal cortex than by damage to the amygdaloid nuclei.

PMID- 10636295
TI  - Muscimol in the deep layers of the superior colliculus/mesencephalic reticular
      formation blocks expression but not acquisition of fear-potentiated startle in
      rats.
AB  - Deposits of the retrograde tracer Fluoro-Gold into the ventrolateral nucleus
      reticularis pontis caudalis labeled neurons in the deep layers of the superior
      colliculus/mesencephalic reticular formation (deep SC/Me). To test the
      involvement of this area in the fear-potentiated startle effect, rats were
      implanted with cannulas into the deep SC/Me and trained for fear-potentiated
      startle after infusion of the GABA(A) agonist muscimol (0.1 microg/0.5 microl).
      Two days later, they were tested for fear-potentiated startle. Rats then received
      a 2nd training session without any infusions, and 2 days later they were
      reinfused with muscimol (0.1 microg/0.5 microl) and tested for fear-potentiated
      startle. Local infusion of muscimol into the deep SC/Me completely blocked the
      expression but not the acquisition of fear-potentiated startle. These results
      indicate that a synapse in the midbrain is critical for the expression of fear
      potentiated startle.

PMID- 10636296
TI  - A peculiar pattern of temporal involvement of rat perirhinal cortex in memory
      processing.
AB  - By means of the fully reversible tetrodotoxin inactivation technique, perirhinal
      cortex (PC) mnemonic function was investigated in rats trained to a passive
      avoidance response (PAR). It was shown that PC functional integrity is necessary
      during PAR acquisition, during late and very late consolidation (from 24 hr up to
      192 hr after the training session), and during retrieval. An unexpected finding
      was that the PC was not involved in the early consolidation period. Thus the PC
      may play a relatively simple relay or connective role during acquisition, but its
      very late and very long consolidative involvement may indicate a peculiar
      function in consolidation and possibly in the storage of the PAR engram. The
      results are discussed in terms of the mnemonic characteristics of other neural
      sites (amygdala, hippocampus, and entorhinal cortex) involved in the same
      learning process.

PMID- 10636297
TI  - Double dissociation of function within the hippocampus: a comparison of dorsal,
      ventral, and complete hippocampal cytotoxic lesions.
AB  - Rats with complete cytotoxic hippocampal lesions exhibited spatial memory
      impairments in both the water maze and elevated T maze. They were hyperactive in
      photocell cages; swam faster in the water maze; and were less efficient on a
      nonspatial, differential reinforcement of low rates (DRL) task. Performance on
      both spatial tasks was also impaired by selective dorsal but not ventral lesions;
      swim speed was increased by ventral but not dorsal lesions. Both partial lesions
      caused a comparable reduction in DRL efficiency, although these effects were
      smaller than those of complete lesions. Neither partial lesion induced
      hyperactivity when rats were tested in photocell cages, although both complete
      and ventral lesion groups showed increased activity after footshock in other
      studies (Richmond et al., 1999). These results demonstrate possible functional
      dissociations along the septotemporal axis of the hippocampus.

PMID- 10636298
TI  - Dissociating context and space within the hippocampus: effects of complete,
      dorsal, and ventral excitotoxic hippocampal lesions on conditioned freezing and
      spatial learning.
AB  - Rats with complete excitotoxic hippocampal lesions or selective damage to the
      dorsal or ventral hippocampus were compared with controls on measures of
      contextually conditioned freezing in a signaled shock procedure and on a spatial
      water-maze task. Complete and ventral lesions produced equivalent, significant
      anterograde deficits in conditioned freezing relative to both dorsal lesions and
      controls. Complete hippocampal lesions impaired water-maze performance; in
      contrast, ventral lesions improved performance relative to the dorsal group,
      which was itself unexpectedly unimpaired relative to controls. Thus, the partial
      lesion effects seen in the 2 tasks never resembled each other. Anterograde
      impairments in contextual freezing and spatial learning do not share a common
      underlying neural basis; complete and ventral lesions may induce anterograde
      contextual freezing impairments by enhancing locomotor activity under conditions
      of mild stress.

PMID- 10636299
TI  - Neonatal 192 IgG-saporin lesions of basal forebrain cholinergic neurons
      selectively impair response to spatial novelty in adult rats.
AB  - The role of the developing cholinergic basal forebrain system on cognitive
      behaviors was examined in 7 day-old rats by giving lesions with intraventricular
      injections of 192 IgG-saporin or saline. Rats were subjected to passive avoidance
      on postnatal days (PND) 22-23, water maze testing on PND 50-60, and a open-field
      test (in which reactions to spatial and object novelty were measured) on PND 54.
      Behavioral effects of the lesions were evident only in the open-field test with 5
      objects. Unlike controls, the lesioned rats did not detect a spatial change after
      a displacement of 2 of the 5 objects. Control and lesioned rats, however, showed
      comparable novelty responses to an unfamiliar object. Lesion effectiveness was
      confirmed by 75% and 84% decreases in choline acetyltransferase activity in
      cortex and hippocampus. These results suggest that the developing cholinergic
      system may be involved in spatial information processing or attention to spatial
      modifications.

PMID- 10636300
TI  - Effects of ovariectomy, 192 IgG-saporin-induced cortical cholinergic
      deafferentation, and administration of estradiol on sustained attention
      performance in rats.
AB  - Female ovariectomized (OVX) and sham-OVX rats were trained in a task designed to
      assess sustained attention. After achieving asymptotic performance, OVX rats did
      not exhibit the impairment in performance over blocks of trials (i.e., the
      vigilance decrement) observed in sham-OVX rats. Furthermore, OVX rats'
      performance over blocks of trials was unaffected by the normally detrimental
      effects of a visual distractor. 192 IgG-saporin-induced lesions of basal
      forebrain cholinergic neurons resulted in similar impairments in the performance
      of OVX and sham-OVX rats. The acute, but not chronic, administration of 17beta
      estradiol attenuated the lesion-induced decrease in the relative number of hits
      to longest signals exclusively in rats with intact ovaries. These findings
      indicate that the variables contributing to the potential therapeutic effects of
      estradiol remain poorly understood.

PMID- 10636301
TI  - Lesions of the amygdala central nucleus abolish lipoprivic-enhanced responding
      during oil-predicting conditioned stimuli.
AB  - T. L. Davidson, A. M. Altizer, S. C. Benoit, E. K. Walls, and T. L. Powley (1997)
      reported that rats show facilitated responding to conditioned stimuli (CSs) that
      predict oil, after administration of the lipoprivic agent, Na-2-mercaptoacetate
      (MA). This facilitation was blocked by vagal deafferentation. The present article
      extends that investigation to another structure, the amygdala central nucleus
      (CN). The CN receives inputs from dorsal vagal nuclei, and neurotoxic lesions of
      this nucleus are reported to abolish feeding in response to lipoprivic
      challenges. In Experiment 1, rats with ibotenic acid (IBO) lesions of the CN
      failed to show enhanced appetitive responding during oil-predicting CSs after
      administration of MA. Experiment 2 used a conditioned taste-aversion procedure to
      establish that rats with IBO lesions of the CN were able to discriminate the
      tastes of sucrose and peanut oil and had intact CS-US representations. It is
      concluded that the amygdala CN is a necessary structure for the detection of
      lipoprivic challenges.

PMID- 10636302
TI  - Gustatory thalamus lesions eliminate successive negative contrast in rats.
AB  - Neurologically intact rats expecting to receive a high-value reward (1.0 M
      sucrose), licked less for an unexpected low-value reward (0.15% saccharin) than
      did control subjects that only received the saccharin solution. This reward
      comparison effect, termed successive negative contrast, was eliminated after
      bilateral electrolytic lesions of the gustatory thalamus. The results are
      discussed in terms of disrupted memory processes that may have rendered the
      lesioned rats incapable of computing the relative reward value of the available
      solution (0.15% saccharin) with respect to the memory of the preferred solution
      (1.0 M sucrose).

PMID- 10636303
TI  - The role of cognitive and affective processing in a transgenic mouse model of
      cortical-limbic neuropotentiated compulsive behavior.
AB  - Obsessive compulsive disorder (OCD) may involve abnormal cortical-limbic
      processing or responsiveness. Mice with behaviors resembling the symptoms of OCD
      and related disorders were made by expression of a neuropotentiating cholera
      toxin (CT) transgene in cortical-limbic D1 receptor-expressing neurons. Because
      these D1CT mice express CT in the piriform cortex and amygdala (major cognitive
      and affective olfactory processing areas) it was tested whether abnormal odor
      perception, discrimination, or responsiveness facilitates their compulsion-like
      behavior. The mice exhibited normal olfactory discriminative capability. An
      anxiogenic odor potentiated their abnormal repetitive leaping, but novel or
      familiar nonthreatening odors did not. These data suggest that compulsions can be
      triggered not by impaired cortical-limbic processing but by increased cortical
      limbic responsiveness, particularly to sensory or cognitive stimuli with
      affective properties.

PMID- 10636304
TI  - Monocular deprivation alters the direction of functional and morphological
      asymmetries in the pigeon's (Columba livia) visual system.
AB  - One-day-old pigeons (Columba livia) were monocularly deprived by occluding the
      left or the right eye for 10 days. Up to 3 years later, degree and direction of
      functional and morphological asymmetries of deprived and control pigeons were
      analyzed. In control pigeons, the usual right-eye superiority was obtained in a
      visual discrimination task. In left-eye deprived pigeons, this behavioral
      asymmetry was strengthened, whereas the direction of lateralization was reversed
      in right-eye deprived birds. A morphological tectum analysis revealed that
      control and left-eye deprived pigeons displayed similar asymmetries, with the
      left-monocular deprived pigeons exhibiting more pronounced left-right
      differences. Tectal morphometry of right-eye deprived pigeons displayed a
      reversed pattern. Overall, the present study shows that a short period of
      posthatch monocular deprivation is sufficient to alter behavioral and
      morphological visual asymmetry for several years.

PMID- 10636305
TI  - Light exposure of chick embryo influences lateralized recall of imprinting
      memory.
AB  - Environmental cues, such as light during the later part of incubation, are known
      to establish lateralization of some forms of visually guided behaviors in birds.
      The authors investigated the effect of light on lateralized recall of imprinting
      memory in chicks. On Day E19 of incubation, one eye was occluded for 24 hr. The
      other eye received stimulation by light. Chicks were imprinted and then tested
      for their imprinting preferences after administration of a low dose (500 ng) of
      glutamate into either hemisphere. Chicks that had the right eye exposed to light
      during incubation showed recall of the imprinting stimulus after injection of the
      left hemisphere but not after injection into the right hemisphere. The reverse
      was found for chicks that had the left eye exposed to light. Hence, the
      hemisphere ipsilateral to the eye exposed to light before hatching became
      essential for recall of imprinting memory. The hemisphere used in recall of
      imprinting memory received indirect visual inputs and was determined by
      environmental stimulation (asymmetrical light input).

PMID- 10636306
TI  - Cardiovascular concomitants of ultrasound production during cold exposure in
      infant rats.
AB  - Two experiments explored the cardiovascular consequences of extreme cold exposure
      and their relationship with ultrasound production in infant rats. Experiment 1
      addressed the thermoregulatory and cardiovascular concomitants of ultrasound
      production during cold exposure in rats pretreated with saline or the ganglionic
      blocker chlorisondamine (5 mg/kg). For both groups, emission of ultrasound was
      associated with hypothermia and bradycardia. Experiment 2 explored whether the
      hypothermia experienced by pups in Experiment 1 is associated with increased
      blood viscosity, which is an important factor affecting venous return to the
      heart. Blood viscosity increased significantly as temperature decreased from 38
      degrees C to 22 degrees C. These experiments suggest that, during extreme cold
      exposure, decreased cardiac output and increased blood viscosity combine to
      diminish venous return. The authors have hypothesized that pups respond to
      decreased return by recruiting the abdominal compression reaction, a
      physiological maneuver that propels blood back to the heart, resulting in
      emission of ultrasound as an acoustic by-product.

PMID- 10636307
TI  - Long-lasting consequences of a social conflict in rats: behavior during the
      interaction predicts subsequent changes in daily rhythms of heart rate,
      temperature, and activity.
AB  - This study shows that the long-term consequences of a social conflict in rats do
      not depend on the physical intensity of the fight in terms of aggression received
      but, especially, on how the subjects deal with it. Experimental rats were
      introduced into the cage of an aggressive conspecific for 1 hr, and the effects
      on daily rhythms of heart rate, body temperature, and activity thereafter were
      measured by means of telemetry. In some rats, the confrontation caused a strong
      decrease in the daily rhythm amplitude that lasted up to 3 weeks, whereas other
      subjects showed only minor changes. The changes in rhythm amplitude did not
      correlate with the number of attacks received from the territory owner. Contrary
      to this, the changes showed a clear negative correlation with the aggression of
      the experimental rats themselves. Subjects fighting back and counterattacking the
      cage owner subsequently had a smaller reduction in rhythm amplitude.

PMID- 10636308
TI  - Genetic influences on latent inhibition.
AB  - The present study examined the development of latent inhibition in a number of
      inbred strains of mice. C57BL/6J, DBA/2J, C3H/Ibg, BALB/cByJ, A/J, CBA/J,
      129/SvevTac, 129/SvJ, and AKR/J mice were screened for the development of latent
      inhibition. The latent inhibition paradigm involved 1 day of either 40
      preexposures to the conditioned stimulus (CS) or no preexposure. On the following
      training day, the CS was twice paired with a shock unconditioned stimulus (US).
      On a subsequent test day, the strength of the CS-US association was measured.
      Mice preexposed to the CS should show a weaker CS-US association, which would
      reflect development of latent inhibition. Significant between-strain differences
      existed. The 129/Svev, C57BL/6, BALB/cByJ, AKR, and DBA/2 mice developed latent
      inhibition, but 129/SvJ, CBA, A, and C3H mice did not. Thus, genetic variance
      contributes to variability in the development of latent inhibition.

PMID- 10636309
TI  - Conditioned stimulus control in the rat circadian system depends on clock
      resetting during conditioning.
AB  - The authors examined the ability of a conditioned stimulus (CS; mild air
      disturbance) previously paired with an entraining light pulse to reset the
      circadian pacemaker in rats. Rats were entrained to a single 30-min light
      stimulus delivered every 25 hr or 24 hr (T cycle). Each daily light presentation
      was paired with the CS. After at least 20 days of stable entrainment to each of
      the T cycles, the rats were allowed to free run and were then presented with the
      CS at circadian time 15. CS-induced phase shifts in wheel-running activity
      rhythms were taken as evidence for conditioning. For the most part, conditioning
      occurred after CS-light pairings on the 25-hr but not 24-hr T cycle. The results
      suggest that CS control of the circadian clock phase depends on the effect that
      the entraining light pulse has on the clock during conditioning.

PMID- 10636310
TI  - Interventions on the recently dead.

PMID- 10636311
TI  - Other people's ethics.

PMID- 10636312
TI  - Chest injuries after active compression-decompression cardiopulmonary
      resuscitation (ACD-CPR) in cadavers.
AB  - In a prospective study of 38 cadavers of patients older than 18 without previous
      chest injury or cardiopulmonary resuscitation (CPR), active compression
      decompression (ACD) resuscitation manoeuvres were performed to determine possible
      factors influencing sternal and/or rib fractures. ACD was performed for 60 s,
      with compression and decompression forces being continuously recorded. A stepwise
      logistic regression analysis was applied. Factors analyzed were age, gender, use
      of a compression cushion beneath the piston of the ACD device (Ambu CardioPump),
      and maximal compression and decompression forces. After ACD, the cadavers were
      autopsied and thoracic injuries were assessed. There was a significant
      correlation between sternal fractures and gender (P = 0.008), and between rib
      fractures and age (P = 0.008). Women were found to have a higher risk for sternal
      fractures, whereas older patients had a higher risk for rib fractures. Maximal
      compression force was another factor in sternal and/or rib fracture (P = 0.048).
      Even though a significantly higher incidence of sternal fractures was observed
      when the compression cushion was used (P = 0.045), inclusion of this variable in
      the regression analysis only marginally improved the prediction for correct
      classification of sternal fractures. In conclusion, when well controlled ACD-CPR
      is performed in cadavers, age is the most important factor determining the
      incidence of rib fracture. Sternal fractures were more common in female cadavers.

PMID- 10636313
TI  - Measuring forces and frequency during active compression decompression
      cardiopulmonary resuscitation: a device for training, research and real CPR.
AB  - Active compression decompression (ACD) cardiopulmonary resuscitation (CPR) is
      possibly a superior alternative to standard (STD) CPR, but an optimal compression
      and decompression pattern has to be ensured. ACD-CPR can be evaluated during CPR
      training sessions using commercially available manikins; however devices for
      recording compression and decompression forces or frequency during real CPR are
      lacking. Using the Ambu CardioPump without changing its mechanical
      characteristics, two force transducers were integrated into the ACD device. Using
      specially designed electronics and a portable computer, compression and
      decompression forces were measured and displayed continuously and compression
      frequency and the compression decompression phase are calculated on-line during
      real CPR action. All measured parameters were stored on a hard disk for later
      retrieval and analysis. Linearity of force measurement was better than 6% within
      a -250- +500 N range. The error in repeatability was below 5% thus outperforming
      the original mechanical force measurement system of the Ambu CardioPump.
      Compression frequency was calculated very accurately (error < 1%). The system has
      been successfully used during CPR training, during ACD-CPR in 37 corpses under
      research conditions and in five out-of-hospital CPR casualties. Simple and safe
      in use, our modified CardioPump with integrated electronics provides an
      important, technically advanced solution for monitoring ACD-CPR on-line. It
      warrants quality assurance during ACD-CPR training and in real CPR scenarios and
      guarantees accurate recording of compression and decompression forces and
      compression frequency.

PMID- 10636314
TI  - Effects of smaller tidal volumes during basic life support ventilation in
      patients with respiratory arrest: good ventilation, less risk?
AB  - OBJECTIVE: When ventilating an unintubated patient in cardiac or respiratory
      arrest, smaller tidal volumes of 500 ml instead of 800-1200 ml may be beneficial
      to decrease peak airway pressure, and to minimise stomach inflation. The purpose
      was to determine the effects of small (approximately 500 ml) versus large
      (approximately 1000 ml) tidal volumes given with paediatric versus adult self
      inflatable bags and approximately 50% oxygen on respiratory parameters in
      patients during simulated basic life support ventilation. METHODS: While
      undergoing induction of anaesthesia, patients were randomised to three minutes of
      ventilation with either an adult (n = 40) or paediatric (n = 40) self-inflatable
      bag. RESULTS: When compared with an adult self-inflatable bag, the paediatric bag
      resulted in significantly lower mean (+/- standard deviation) exhaled tidal
      volume (365 +/- 55 versus 779 +/- 122 ml; P < 0.0001), peak airway pressure (20
      +/- 2 versus 25 +/- 5 cm H2O; P < 0.0001), but comparable oxygen saturation (97
      +/- 1% versus 98 +/- 1%; NS (nonsignificant)). Stomach inflation occurred in five
      of 40 patients ventilated with an adult self-inflatable bag, but in no patients
      who were ventilated with a paediatric self-inflatable bag (P = 0.054).
      CONCLUSION: Administering smaller tidal volumes with a paediatric instead of an
      adult self-inflatable bag in unintubated adult patients with respiratory arrest
      maintains good oxygenation and carbon dioxide elimination while decreasing peak
      airway pressure, which makes stomach inflation less likely.

PMID- 10636315
TI  - Smaller tidal volumes during cardiopulmonary resuscitation: comparison of adult
      and paediatric self-inflatable bags with three different ventilatory devices.
AB  - Gastric inflation and subsequent regurgitation of stomach contents is a major
      hazard of bag-valve-face mask ventilation during the basic life support phase of
      cardiopulmonary resuscitation (CPR). Recent investigations suggested that use of
      a paediatric self-inflating bag may reduce stomach inflation while ensuring
      sufficient lung ventilation. The purpose of our study was to examine whether use
      of a paediatric self-inflating bag in association with laryngeal mask airway,
      combitube, and bag-valve-face mask may provide adequate lung ventilation, while
      reducing the risk of gastric inflation in a bench model simulating the initial
      phase of CPR. Sixteen intensive care unit registered nurses volunteered for our
      study. Use of a paediatric versus adult self-inflating bag resulted in a
      significantly (P < 0.01) lower mean (+/- S.D.) tidal lung volume with both the
      laryngeal mask airway and combitube (laryngeal mask airway 349 +/- 149 ml versus
      725 +/- 266 ml, combitube 389 +/- 113 ml versus 1061 +/- 451 ml). Lung tidal
      volumes were below the European Resuscitation Council recommendation with both
      self-inflatable bags in the bag-valve-face mask group (paediatric versus adult
      self-inflatable bag 256 +/- 77 ml versus 334 +/- 125 ml). Esophageal tidal
      volumes were significantly (P < 0.05) lower using the paediatric self-inflatable
      bag in the bag-valve-face mask group; almost no gastric inflation occurred with
      the laryngeal mask airway, and none with the combitube. In conclusion, use of the
      paediatric self-inflating bag may reduce gastric inflation, but measured lung
      tidal volumes are below the European Resuscitation Council recommendation when
      used with either, the laryngeal mask airway, combitube, or bag-valve-face mask.

PMID- 10636316
TI  - Effects of traditional versus delayed resuscitation on serum lactate and base
      deficit.
AB  - OBJECTIVE: To test the hypothesis that delayed resuscitation of hemorrhagic shock
      produces a less severe shock insult than traditional resuscitation, characterized
      by repeated episodes of alternating hypotension and normotension. METHODS: Female
      pigs were divided into three groups. Sham operated controls (C) (n = 4),
      sustained hypotension (SS) (n = 6), and hypotension with multiple cycles of shock
      and resuscitation (SR) (n = 6). SS and SR animals were bled to a mean arterial
      pressure (MAP) of 50 mmHg. SS animals were maintained at an MAP of 50 mmHg for 65
      min and then resuscitated to baseline blood pressure with normal saline and shed
      blood. SR animals were initially bled and maintained at an MAP of 50 mmHg for 35
      min, resuscitated to baseline BP, and subsequently bled and resuscitated twice
      more. The total period of shock was the same in both SS and SR. RESULTS:
      Following hemorrhage, there was a significant increase in lactate and base
      deficit in SS as compared to C and SR. CONCLUSION: Delayed resuscitation produces
      a more profound shock insult than traditional resuscitation.

PMID- 10636317
TI  - Adrenaline upregulates monocyte L-selectin in vitro.
AB  - OBJECTIVE: Although surface adhesion molecules mediate leucocyte-endothelial
      interactions at sites of inflammation, relatively little is known of the factors
      which increase the expression of L-selectin in circulating leucocytes. The
      expression of leucocyte L-selectin increases during acute stress events such as
      injury and is temporally related to an early neuroendocrine response. This study
      investigates whether adrenaline increases the expression of L-selectin on
      monocytes, neutrophils and lymphocytes in vitro and whether these effects are
      mediated via beta-adrenoceptors. METHODS: A total of 20 ml of blood was withdrawn
      from 28 healthy volunteers (21 males) with a mean age of 29 years (range 23-67
      years). Adrenaline at physiological doses mimicking trauma (0-200 nmol/l) was
      added to whole blood prior to immunofluorescent staining and analysis by flow
      cytometry. Propranolol (50 microl of 2 x 10(-5) M) was also added to separate
      tubes prior to incubation with adrenaline. Saline (40 microl 0.9% solution) was
      used as a control. Expression is described firstly as percentage of cells
      expressing L-selectin and secondly as average intensity (mean channel
      fluorescence, mcf) per cell expressing CD62L. Summary measures were used to
      analyse the data. RESULTS: A significant increase in both the percentage of
      monocytes expressing L-selectin and mean channel fluorescence of L-selectin was
      evident with adrenaline in vitro (P < 0.0001). Maximal increases occurred at 100
      nmol/l adrenaline when a 9% increase in the percentage of monocytes expressing L
      selectin and a 23% increase in mean channel fluorescence were observed. These
      effects were both blocked by propranolol (P < 0.0001). No significant differences
      were observed for neutrophils or lymphocytes except for a slight increase in the
      percent neutrophils expressing L-selectin, and a small decreasing trend in
      percent lymphocytes expressing L-selectin. CONCLUSIONS: Adrenaline upregulates
      the surface expression of L-selectin on monocytes in vitro, an effect which is
      partially mediated by beta-adrenoceptors. As monocytes initiate early aspects of
      the inflammatory response, these findings suggest that beta-blockade may have an
      inhibitory role for certain aspects of leucocyte trafficking.

PMID- 10636318
TI  - The place of general practitioners in the management of out-of-hospital
      cardiopulmonary resuscitation.
AB  - BACKGROUND: The involvement of general practitioners in community based
      resuscitation of out-of-hospital cardiac arrest has been found to be effective in
      improving survival rates. The aim of the study was to assess the potential for
      including general practitioners in Nottinghamshire in the resuscitation of out-of
      hospital cardiac arrest victims by first determining whether they had the skill,
      experience and equipment to provide cardio-pulmonary resuscitation in the
      community; and second to ascertain what proportion of them would be prepared to
      establish a 'rapid response' scheme for patients requiring resuscitation.
      METHODS: A postal questionnaire survey, between March and April 1997, of all 738
      general practitioners in Nottinghamshire who serve, in total, a population of 1
      million. RESULTS: A total of 592 general practitioners (80%) responded to our
      survey. The majority worked in a predominantly urban environment and carried out
      their own out-of-hours on-call duties. Of them 93% had previous experience in
      cardiopulmonary resuscitation (median of 3 years), while 72.1% had experience of
      advanced life support, including use of a defibrillator but not recently (median
      of 8 years). General practitioners in rural practices were more likely to be
      trained in advanced life support (ALS), had more recent experience in
      cardiopulmonary resuscitation (including defibrillation) and were more willing to
      be involved in any proposed local resuscitation scheme. Only 9% of general
      practitioners carried a defibrillator when on-call and only 13% had access to a
      defibrillator within their practice premises. Of the general practitioners
      surveyed 349 (59%) reported a willingness to participate in a 'rapid response
      cardiac arrest' scheme and general practitioners who had no formal advanced life
      support training were as willing to become involved in such a scheme as those who
      were trained in ALS. CONCLUSIONS: General practitioners may have an important
      role to play in improving the survival outcome of out-of-hospital cardiac arrest
      as many are ALS trained and have recent experience in resuscitation. However, few
      have access to a defibrillator and many do not have recent experience of
      defibrillation. Any proposed local resuscitation scheme would be particularly
      applicable to rural general practitioners as many have recent training in ALS,
      recent experience in advanced life support and most of all, are more willing to
      participate in such a scheme.

PMID- 10636319
TI  - Pulse oximetry with the laryngeal mask airway.
AB  - This study evaluated the accuracy of pulse oximetry measured by a modified
      laryngeal mask airway (LMA). Ten anaesthetized patients (ASA I-II, aged 18-45)
      undergoing elective knee arthroscopies (mean-duration 40 min) were studied. A
      transmission pulse oximeter probe/sound OHMEDA was attached on the back of LMA
      (sizes 4 and 5) in an area in contact with the floor of the laryngeal part of the
      pharynx. Pharyngeal pulse oximetry as well as LMA cuff pressure were monitored
      and recorded every 5 min from the time of insertion (T0) to removal (T8) and were
      compared to simultaneous finger pulse oximeter readings. At T2 the cuff was over
      inflated to obtain a 100 cm H2O intracuff pressure. At T3 the cuff pressure was
      decreased at 60 cm H2O. Pharyngeal pulse oximetry correlated with finger pulse
      oximetry throughout the study and was not effected by over-inflation of the LMA.
      This modification of the LMA provides an accurate method of measuring pulse
      oximetry which may be of use in a variety of circumstances.

PMID- 10636320
TI  - Electricity-associated injuries I: outdoor management of current-induced
      casualties.

PMID- 10636321
TI  - A proposal for adaptation of the Berden Scoring System according to the 1998 ERC
      guidelines.

PMID- 10636322
TI  - Airway management during cardiopulmonary resuscitation--a comparative study of
      bag-valve-mask, laryngeal mask airway and Combitube in a bench model.

PMID- 10636323
TI  - The psychological pain assessment scale.

PMID- 10636324
TI  - Sex differences in adolescent suicides in Norway, 1990-1992.
AB  - All suicides in persons under 20 years in Norway in the time period 1990-1992 (99
      males, 30 females) were included in a postmortem case-control study with seven
      controls for each suicide, focusing on gender differences. Few sex differences
      between the suicide completers were evident, in spite of the difference in
      suicide rates (M/F rate ratio = 3.0). Females more often attempted suicide (p =
      .05), more often wrote farewell notes (p = .03), and used less violent suicide
      methods (ns). The adjusted risk for suicide related to affective disorders
      (Female OR = 22,1; Male OR = 24.0, both p = .000) and disruptive disorders
      (female OR = 14,7, ns; male OR = 5.0, p = .002) differed little, as did the
      effect of frequent use of alcohol or substances (female OR = 0.4, ns; male OR =
      0.4, ns).

PMID- 10636325
TI  - Depression, hopelessness, and self-esteem: accounting for suicidality in
      adolescent psychiatric inpatients.
AB  - The present study was designed to examine depression, hopelessness, and self
      esteem as related to suicidal behavior in three groups of depressed adolescent
      psychiatric inpatients. Depressed adolescents who had never attempted suicide
      were compared to depressed adolescents who had attempted suicide once and to
      depressed adolescents who had attempted suicide on several different occasions.
      Results showed that suicidal adolescents experienced significantly greater
      depression and hopelessness than did the nonsuicidal adolescents. However, all
      three groups of depressed adolescents reported similar low levels of self-esteem.
      Measures of depression and hopelessness were useful in classifying the
      adolescents based on their suicidal behavior. Results suggest that the treatment
      of suicidal adolescents could benefit from strategies that focus on reducing
      feelings of depression and hopelessness.

PMID- 10636326
TI  - Treatment adherence among Latina female adolescent suicide attempters.
AB  - Clinicians must identify factors among suicide-attempting adolescents and their
      families that increase treatment adherence. Researchers assessed a consecutive
      series of 140 disenfranchised Latina adolescents (ages 12-18 years) and their
      mothers presenting at a large urban emergency room after a suicide attempt by the
      adolescent. Adherence was examined as it related to service delivery, individual
      background characteristics, and psychosocial factors (current symptomatology,
      treatment attitudes). Each factor was found to predict adolescent treatment
      adherence. Adolescents receiving a specialized emergency room program, those with
      a diagnosis of disruptive behavior disorder, and those from single-parent
      households attended significantly more therapy sessions compared to their suicide
      attempting peers receiving standard emergency room care. Adolescents with a
      diagnosis of anxiety disorders and those whose mothers reported more
      psychopathology and perceived more cohesive family relationships tended to attend
      significantly fewer treatment sessions. The implications for the delivery of
      emergency room interventions are discussed.

PMID- 10636327
TI  - Factors associated with suicide ideation among American Indian adolescents: does
      culture matter?
AB  - Data from self-report surveys of 1,353 high school students representing three
      culturally distinct American Indian tribes were analyzed for tribal differences
      in factors associated with suicidal ideation. In the multivariate analysis, no
      single correlate of suicide ideation was common to all three tribes. The
      correlates of suicide ideation were consistent with each tribe's social
      structure, conceptualization of individual and gender roles, support systems, and
      conceptualization of death. These results underscore the heterogeneity of suicide
      ideation across three distinct American Indian tribes consistent with their
      cultural heterogeneity. Suicide prevention and screening programs may be
      difficult to adapt from one tribe to another.

PMID- 10636328
TI  - Toward a standard of care for treating suicidal outpatients: a survey of social
      workers' beliefs about appropriate treatment behaviors.
AB  - This study attempts to establish what reasonable, prudent professionals, named in
      the standard of care, believe is appropriate treatment for suicidal outpatients.
      We hope to move toward establishing a standard of care based on actuarial data,
      rather than after the fact evaluation by experts, judges, and lawyers.
      Previously, Greaney (1995, doctoral dissertation, Pacific Graduate School, Palo
      Alto, CA) empirically examined the beliefs of psychologists in appropriately
      treating suicidal outpatients. Our goal is to broaden the perspective of existing
      empirical data by examining the beliefs of clinical social workers in treating
      suicidal outpatients.

PMID- 10636329
TI  - The suicide survivor's grief and recovery.
AB  - While official estimates report approximately 30,000 completed suicides each
      year, some researchers claim the numbers range much higher. Each suicide has
      severe and prolonged effects on the family members and friends left behind. Those
      left behind, the survivors of the suicide, tend to experience a very complicated
      form of bereavement. This is due to the combination of the sudden shock, the
      unanswered question of "why," and possibly the trauma of discovering or
      witnessing the suicide. Survivors' grief reactions can become even more
      exacerbated by inappropriate responses from the community to the suicide. A
      mental health professional can help the survivor through this difficult grieving
      process by direct and indirect means.

PMID- 10636330
TI  - A demographic analysis of suicide among U.S. Navy personnel.
AB  - Age-, sex-, race-, and employment-adjusted standardized mortality ratios (SMRs)
      were calculated for sailors committing suicide between 1990 and 1996 and compared
      with adjusted SMRs for civilians. Cluster analyses were conducted on annual rates
      from 1983 through 1995 to examine differences between comparison groups across
      time and location. Results showed fewer than expected suicides for Caucasian and
      African American males and a somewhat higher than expected suicide rate among
      other ethnic group males and among Caucasian women. The suicide rate showed an
      increase during the study period, with some evidence toward a clustering effect
      in time and space.

PMID- 10636332
TI  - On the need for a new term for suicide.

PMID- 10636331
TI  - Suicide ideation among recent immigrants to Israel from the former Soviet Union:
      an epidemiological survey of prevalence and risk factors.
AB  - This paper reports results of a national community survey of self-reported
      suicide ideation and attempts and their relation to psychological distress,
      depression, social support, and adjustment difficulties in a sample of recent
      immigrants from the former Soviet Union (FSU) to Israel. Using a door-to-door
      sampling procedure, a sample of 788 Russian-born Jewish immigrants, ages 18-74
      years, was selected to match the age and sex structure of the total immigrant
      population. An indigenous sample of Jews in Russia (n = 411) was matched with the
      immigrants for comparison. Parameters of interest were measured with the
      Demographic Inventory, Talbieh Brief Distress Inventory, Beck Depression
      Inventory, and Multidimensional Scale of Perceived Social Support. The 1-month
      prevalence rate of suicide ideation in the immigrant sample (15.1%) was found to
      be significantly higher than that in Russian controls (6.6%). A total of 5.5% of
      immigrants but only 0.5% of controls had made a suicide attempt at some time in
      their lives. Risk factors for suicide ideation included younger age, living
      without a spouse, low level of social support, being a physician or teacher, a
      history of immigration from the Baltic countries or Moscow, or duration of stay
      in Israel from 2 to 3 years. The strongest risk factors were higher level of
      psychological distress and symptoms such as depression, hostility, and paranoid
      ideation. These findings can be used as a point of departure for the development
      of community-based suicide prevention programs for recent immigrants.

PMID- 10636333
TI  - Pharmacokinetic and pharmacodynamic modelling in drug development.

PMID- 10636334
TI  - Population modelling in drug development.
AB  - In this paper we discuss the vital role that population (hierarchical) modelling
      can play within the drug development process. Specifically, population
      pharmacokinetic/pharmacodynamic models can provide reliable predictions of an
      individualized dose-exposure-response relationship. A predictive model of this
      kind can be used to simulate and hence design clinical trials, find initial
      dosage regimens satisfying an optimality criterion on the population distribution
      of responses, and individualized regimens satisfying such a criterion conditional
      on individual features, such as sex, age, etc. Throughout we emphasize prediction
      and advocate mechanistic as opposed to empirical modelling, and argue that the
      Bayesian approach is particularly natural in this setting.

PMID- 10636335
TI  - The Bayesian analysis of a pivotal pharmacokinetic study.
AB  - The aim of this paper is to carry out a detailed Bayesian population
      pharmacokinetic analysis of a three-period cross-over study of the drug
      fluticasone propionate carried out in 12 healthy male volunteers. The study was
      carried out to characterize the pharmacokinetics of the drug, in particular to
      investigate dose proportionality. We examine the appropriateness of modelling
      assumptions via a variety of diagnostic techniques. We also examine the effect of
      deleting time points at which the concentration was recorded as below the limit
      of quantification, as opposed to including these points as censored observations.
      We assess dose proportionality before carrying out a final combined analysis of
      data from all three doses.

PMID- 10636336
TI  - A regulatory perspective on pharmacokinetic/pharmacodynamic modelling.
AB  - We present an integrated summary from statistical and pharmacological
      perspectives of pharmacokinetic/pharmacodynamic (PK/PD) modelling and its use in
      drug development and regulation for guiding appropriate dosing. An overview of
      the technical aspects of PK/PD modelling describes how structural models are
      constructed and refined using pharmacokinetic and pharmacodynamic principles and
      how random effects models are used to account for individual differences in
      desired (and undesired) responses due to patient characteristics. Lastly, we
      describe applications of PK/PD modelling for the purposes of drug labelling, for
      resolving a safety concern, and for improving therapeutic monitoring of
      anaesthetic depth during surgery.

PMID- 10636337
TI  - The impact of compliance in pharmacokinetic studies.
AB  - In population pharmacokinetic (PK) studies, one observes just a few concentration
      measures spread out in time, on a sizable sample of the target population. Common
      sense dictates that for estimation of a drug exposure-plasma concentration
      relationship, one needs accurate information on drug intake history besides the
      concentration measures. The population PK literature is well aware of this.
      Studies of simulated compliance behaviour have helped quantify the problem with
      naive compliance estimators and pointed towards a solution. In this paper we look
      at actually observed compliance patterns recorded via electronic monitoring. We
      simulate a documented pharmacokinetic model from the hypertensive literature on
      top of these and come to some interesting findings. In this clinical trial the
      problem of noncompliance is much more dramatic than simulated compliance patterns
      suggested so far. The systematic errors made by compliance naive estimators can
      be corrected when using timing explicit hierarchical nonlinear models and
      accurate information on a number of previous dose timings. When it is possible to
      observe irregular drug intake times in a well-controlled study, a substantial
      amount of precision is retrieved from the same number of data points. In general,
      the estimators of PK parameters benefit greatly from information that enters
      through greater variation in the drug-exposure process. Here we find support for
      the claim that noncompliance as a rich natural experiment of dosing variation can
      be a blessing rather than a curse from the information/learning point of view.

PMID- 10636338
TI  - Clinical cross-over trials in phase I.
AB  - We review the role of cross-over trials in pharmacokinetic and pharmacodynamic
      studies, in particular as applied in phase I. Design and analysis considerations
      are covered. We also consider the use of pharmacokinetic and pharmacodynamic
      theories in planning cross-over trials. Finally some practical considerations are
      covered.

PMID- 10636339
TI  - Ethics in surgery: historical perspective.
AB  - Ethics codes and guidelines date back to the origins of medicine in virtually all
      civilizations. Developed by the medical practitioners of each era and culture,
      oaths, prayers, and codes bound new physicians to the profession through
      agreement with the principles of conduct toward patients, colleagues, and
      society. Although less famous than the Hippocratic oath, the medical fraternities
      of ancient India, seventh-century China, and early Hebrew society each had
      medical oaths or codes that medical apprentices swore to on professional
      initiation. The Hippocratic oath, which graduating medical students swear to at
      more than 60% of US medical schools, is perhaps the most enduring medical oath of
      Western civilization. Other oaths commonly sworn to by new physicians include the
      Declaration of Geneva (a secular, updated form of the Hippocratic oath formulated
      by the World Medical Association, Ferney-Voltaire, France) and the Prayer of
      Moses Maimondes, developed by the 18th-century Jewish physician Marcus Herz.

PMID- 10636340
TI  - Ethical problems special to surgery: surgical teaching, surgical innovation, and
      the surgeon in managed care.
AB  - This article will concern itself with 3 ethical challenges that are special to
      the role of the surgeon in our society. First is the teaching of surgery. This
      might be called "performing an operation for the first time (for the individual
      surgeon)." Second is surgical innovation. This might be termed "performing a new
      operation for the first time ever." The third ethical challenge is the role of
      the surgeon in managed care. This might be stated as "Can we trust corporations
      to provide all-risk coverage and freedom in clinical decisions?"

PMID- 10636341
TI  - Ethonomics: the ethics of the unaffordable.
AB  - The most familiar basis for medical ethics since the 1950s has been principle
      based ethics. The 4 basic principles are known as the "Georgetown mantra" of
      beneficence, nonmaleficence, respect for autonomy, and justice. These principles
      have served us well since their enunciation in the wake of the activities of the
      Nazi doctors in the concentration and extermination camps of World War II. In the
      past 15 years, however, they have begun to serve less well. In the era of
      resource constraints, however, the clinical relationship has become more complex.
      It now involves many more stakeholders, who control funds, make policy, and
      effectively ration services. Lawyers are also involved in important ways. All
      these people take part with varying directness in the processes of consultation
      and treatment. The consulting room has become a crowded office. For these
      reasons, the old ethics will no longer serve us. We need a new ethics that
      recognizes the involvement of the new stakeholders, and recognizes that resource
      constraints influence clinical practice.

PMID- 10636342
TI  - Ethical aspects of clinical practice.
AB  - HYPOTHESIS: Clinical ethics is grounded in the belief that medicine is an
      inherently moral enterprise. Sick persons ask physicians to help them get better
      and physicians profess to be morally committed and technically competent to help
      the sick. DATA SOURCES: MEDLINE literature search and review of published works
      on medical ethics, and the references cited therein. STUDY SELECTION: Critical
      studies containing supporting evidence were selected. DATA SYNTHESIS: The central
      ethical aspects of modern medical practice are clinical competence, respect for
      patients and their health care decisions, and maintaining the primacy of
      patient's need in the face of external pressure in a changing social, economic,
      and political climate. There is a need to teach both the cognitive and behavioral
      aspects of ethics. Development of these skills, in turn, depends on the character
      of the physician who will be applying these skills. CONCLUSIONS: The outcome of
      patient care can be improved by efforts made to secure informed consent of the
      patient. This also helps avoid ethical conflicts, confusion, and misunderstanding
      between patients and physicians. Clinical ethics should be an integral part of
      medical education at all levels in medical school, in the residency, and in
      continuing education.

PMID- 10636343
TI  - Hospital informed consent for procedure forms: facilitating quality patient
      physician interaction.
AB  - BACKGROUND: Informed consent forms should document and reflect the goals of
      informed consent and shared decision making. We conducted this study to examine
      the extent to which informed consent for procedure forms meet accepted informed
      consent standards, how well state informed consent statutes correlate with these
      standards, and whether existing forms can enhance the interactions between
      patients and physicians or other health care providers. HYPOTHESIS: Informed
      consent forms do not meet accepted standards. A different format may be more
      useful for patient-physician interactions. DESIGN: A content analysis was
      conducted of hospital informed consent for procedure forms from a random
      selection of hospitals in the 1994 American Hospital Association membership
      directory. Forms were examined for evidence of the basic elements of informed
      consent (nature of the procedure, risks, benefits, and alternatives) and items
      that might enhance patient-physician interactions and encourage shared decision
      making. UNIT OF ANALYSIS: From 157 hospitals nationwide, 540 hospital informed
      consent for procedure forms were examined. MEASUREMENTS AND MAIN RESULTS: Ninety
      six percent of forms indicated the nature of the procedure, but risks, benefits,
      and alternatives were found less often. Only 26% of forms included all 4 basic
      elements, 35% included 3 of 4 elements, 23% had 2 of 4 elements, 14% had only 1
      element, and 2% had none of the elements. Forms appear to authorize treatment
      (75%) or protect hospitals and caregivers from liability (59%) rather than
      clarify information about procedures (40%) or aid patients in decision making
      (14%). Forms from states with statutes that require that all 4 elements be
      provided were no more likely than other states to include them (Fisher exact test
      = 1.000). Fewer than 40% of forms supported models of shared decision making.
      CONCLUSIONS: The content of most forms did not meet accepted standards of
      informed consent or patient-physician interactions. We propose a form that more
      fully supports the models of ideal informed consent and shared decision making to
      enhance the applicability of informed consent in the clinical setting.

PMID- 10636344
TI  - Management of the geriatric trauma patient at risk of death: therapy withdrawal
      decision making.
AB  - HYPOTHESIS: The management of geriatric injured patients admitted to a trauma
      center includes the selective decision to provide comfort care only, including
      withdrawal of therapy, and a choice to not use full application of standard
      therapies. The decision makers in this process include multiple individuals in
      addition to the patient. DESIGN: Retrospective review of documentation by 2
      blinded reviewers of the cohort of patients over a recent 5-year period (1993
      1997). SETTING: Trauma service of a level I trauma center. PATIENTS: A
      convenience sample of patients aged 65 years and older who died, and whose
      medical record was available for review. MAIN OUTCOME MEASURES: Patients were
      categorized as having withdrawal of therapy, and documentation in the medical
      record of who made the assessment decisions and recommendations, and to what
      extent the processes of care were documented. RESULTS: Among 87 geriatric trauma
      patients who died, 47 had documentation interpreted as indicating a decision was
      made to withdraw therapy. In only a few circumstances was the patient capable of
      actively participating in these decisions. The other individuals involved in
      recommendations for withdrawal of therapy were, in order of prevalence, the
      treating trauma surgeon, family members (as proxy reporting the patient's
      preferences), or a second physician. Documentation regarding the end-of-life
      decisions was often fragmentary, and in some cases ambiguous. Copies of legal
      advance directives were rarely available in the medical record, and ethics
      committee participation was used only once. CONCLUSIONS: Withdrawal of therapy is
      a common event in the terminal care of geriatric injured patients. The process
      for reaching a decision regarding withdrawal of therapy is complex because in
      most circumstances patients' injuries preclude their full participation.
      Standards for documentation of essential information, including patients'
      preferences and decision-making ability, should be developed to improve the
      process and assist with recording these complicated decisions that often occur
      over several days of discussion.

PMID- 10636345
TI  - Translational ethics: a perspective for the new millennium.
AB  - Modern medical care is increasingly dependent on the application of science to
      clinical practice, which occurs through clinical or translational research. We
      propose the concept of translational ethics, which incorporates the contributions
      of research codes of ethics that involve the protection of human subjects into
      the ethics of clinical practice. The modern research environment, which has
      contributed the scientific tools of modern medicine, has also framed the ethical
      environment in which medicine is practiced. The single most important
      contribution of research codes for protection of human research subjects to
      clinical practice is the doctrine of informed consent. Translational ethics,
      based on autonomy and informed consent, progresses beyond the narrow
      interpretation of those 2 concepts. It requires consensual understanding of a
      spectrum of clinical interventions that are increasingly complicated.
      Translational ethics helps navigate the ethical ramifications of technological
      and scientific advances that will increasingly challenge the corporate-oriented
      health system in the new millennium.

PMID- 10636346
TI  - Human values in the care of the surgical patient.
AB  - Viewing ethics in surgical practice as applying critical thinking to issues of
      human values leads to 4 levels of consideration: the individual patient, the
      surgeon, surgical research and education, and surgical organizations. This
      perspective starts with quantitative and qualitative feedback from patients,
      studies of the process of surgical decision making, and understanding how
      surgeons matter in preoperative counseling and postoperative recovery. Surgeons
      should become as active in research on the psychosocial aspects of surgical care
      as they are in research on the biological. Based on this information, surgical
      training should become explicit in preparing surgeons for patient-centered
      management of surgical care. Finally, surgical organizations can help by
      recognizing research in the human values domain, setting standards that recognize
      feedback from patients, and addressing more formally the needs of underserved
      populations. This approach fails to give the basis for clear answers but gives
      priority to more understanding of the moral dilemmas faced by patients and their
      surgeons.

PMID- 10636347
TI  - AIDS, surgery, and the Americans With Disabilities Act.
AB  - The acquired immunodeficiency syndrome and human immunodeficiency virus have had
      a major impact on the practice of medicine in the past 2 decades. Medical
      professionals are once again faced with a lethal contagious disease that has been
      transmitted in the health care setting to both patients and providers. Because of
      the stigma and fear associated with the infection, civil rights legislation, such
      as the Americans With Disabilities Act, has been used to protect infected
      individuals from inappropriate discrimination based on unwarranted fears and
      public hysteria. Various courts, with the backing of organized medicine and the
      public health authorities, have made it clear that it is illegal for a physician
      to refuse to treat a patient based on the patient's seropositivity.
      Unfortunately, various courts, with the backing of the American Medical
      Association and the Centers for Disease Control and Prevention, have made it
      clear that infected physicians are not necessarily afforded equal protection
      under the civil rights statutes.

PMID- 10636348
TI  - Maintaining trust in the surgeon-patient relationship: challenges for the new
      millennium.
AB  - Changes in the structure of the health care system have placed unprecedented
      stress on the surgeon-patient relationship. The essential trust placed in the
      surgeon by her patients has been weakened by changes in the structure and
      financing of the health care system. This article considers the historical and
      ethical foundation of the surgeon-patient relationship and proposes that the
      primary moral obligation of surgeons is to strengthen and earn patient trust. By
      improving communication skills, enhancing ethical education, serving as
      consistent advocates for patients, and conducting patient-focused outcome
      research, the surgical community can meet its moral obligation by increasing
      trust in the surgeon-patient relationship.

PMID- 10636349
TI  - Effect of intracorporeal-extracorporeal instrument length ratio on endoscopic
      task performance and surgeon movements.
AB  - HYPOTHESIS: Better endoscopic task performance and more ergonomic movements of a
      surgeon's dominant upper limb can be achieved within a certain range of
      intracorporeal-extracorporeal instrument length ratio. DESIGN: Investigating the
      effect of 3 intracorporeal-extracorporeal instrument length ratios (240:120 mm,
      level 1; 180:180 mm, level 2; and 120:240 mm, level 3) on efficiency and quality
      of a standardized endoscopic task (intracorporeal surgeon's knot). Ten surgeons
      tied 360 knots inside a trainer in a random sequence. Task efficiency was
      measured by the execution time, which was recorded for each knot. Task quality
      was measured by the knot quality score, derived from the force-extension curves
      obtained by distraction of each knot in a tensiometer. Motion analysis parameters
      were obtained at the elbow and shoulder joints using a 3-dimensional motion
      analysis system (Kinemetrix Model 5.0-3D/3MBM; Medical Research Ltd, Leeds,
      England). The Kruskal-Wallis and Mann-Whitney tests were used for analysis.
      RESULTS: The level 3 ratio had the lowest knot quality score (P = .07) and
      longest execution time (P<.05). The range of movement at the elbow was
      significantly greater with the level 3 ratio than with the level 1 ratio (P<.05).
      The level 3 ratio also resulted in the widest range of movement at the shoulder
      (P<.05 for level 2 vs 3; P = .06 for level 1 vs 3). The median angular velocity
      was 329.5 degrees/s, 360 degrees/s, and 530 degrees/s for levels 1, 2, and 3,
      respectively (P = .10). CONCLUSIONS: Intracorporeal-extracorporeal instrument
      length ratio below 1.0 degrades task performance and is associated with a wider
      range of movement at the elbow and shoulder and a higher angular velocity at the
      shoulder.

PMID- 10636350
TI  - The need for antibiotic prophylaxis in elective laparoscopic cholecystectomy: a
      prospective randomized study.
AB  - HYPOTHESIS: The need for antibiotic treatment when performing elective
      laparoscopic cholecystectomy may not be as important as it is thought. This study
      assesses the real efficacy of antibiotic prophylaxis in elective laparoscopic
      cholecystectomy with respect to the postoperative infection rate. DESIGN: A
      prospective randomized study on the routine use of antibiotic prophylaxis in
      laparoscopic cholecystectomy. SETTING: University teaching hospital, La Sapienza,
      Italy. PATIENTS: Eighty-four patients randomly placed into 2 groups (A [n = 44]
      and B [n = 40]) immediately before undergoing laparoscopic cholecystectomy.
      METHODS: Before anesthesia was administered, group A received intravenously 2 g
      of cefotaxime sodium diluted in 100 mL of isotonic sodium chloride solution;
      group B, 10 mL of isotonic sodium chloride solution in 100 mL of saline. A
      gallbladder bile sample for culture was withdrawn intraoperatively from all
      patients. In both groups, age, sex, weight, duration of surgery, presence of
      diabetes, American Society of Anesthesiologists patient classification score,
      preoperative autologous blood donation, antibiotic administration, intraoperative
      gallbladder rupture, findings from bile culture positive for bacteria, episodes
      of colic within 30 days before surgery, length of postoperative hospital stay,
      and number of septic complications were recorded. All data were correlated by
      univariate and multivariate analyses with the onset of septic phenomena. RESULTS:
      In group A, 3 cases of wound infection, 1 case of subhepatic abscess from bile
      leakage, and 1 case of urinary tract infection were observed; group B, 4 cases of
      wound infection, 1 case of bronchopneumonia, and 2 cases of urinary tract
      infection. Comparison of data showed no statistically significant difference
      between the groups. Findings from bile examination in patients with sepsis
      complications were positive in 5 patients in group A and in 6 in group B (P =
      .91). Multivariate analysis showed diabetes mellitus and colic episodes within 30
      days before surgery as independent factors significantly associated to the onset
      of infectious complications. CONCLUSIONS: In elective laparoscopic
      cholecystectomy, antibiotic treatment did not seem to affect the incidence and
      severity of infections or the degree of bile contamination.

PMID- 10636351
TI  - Perioperative collagen deposition in elderly and young men and women.
AB  - HYPOTHESIS: Women deposit more collagen after major abdominal surgery than men.
      DESIGN: A post hoc analysis of data obtained from 2 prospective, randomized,
      double-blind clinical trials. SETTING: University hospital general surgical
      service. PATIENTS: One hundred sixteen patients undergoing colon resection. MAIN
      OUTCOME MEASURES: Protein and hydroxyproline (collagen) deposition during the
      first 7 postoperative days in expanded polytetrafluoroethylene implants
      positioned subcutaneously. RESULTS: On univariate analysis, men and women
      deposited comparable amounts of collagen (257 +/- 120 vs 281 +/- 117 ng/mm,
      respectively). When potential confounding factors were entered into a generalized
      mixed-effects model, only the interaction between age and sex was a significant
      factor (P = .047). Collagen deposition decreased with age in men, being 317 +/-
      133 ng/mm in men younger than 45 years, but only 238 +/- 113 ng/mm in those older
      than 45 years (P = .03). In contrast, collagen deposition was virtually identical
      in women younger than 45 years (280 +/- 133 ng/mm) and in those older than 45
      years (281 +/- 110 ng/mm). Only 3 of these women were receiving hormone
      replacement therapy. CONCLUSIONS: Collagen deposition after surgery decreased
      significantly with age in men, while remaining unchanged in women. Younger men
      and women deposited similar amounts of collagen. Therefore, older men made less
      collagen after surgery than older women, perhaps explaining the consistent
      observation that wound dehiscence is twice as common in men than in women. Our
      results differ from previous studies conducted in healthy, nonsurgical
      volunteers, which showed that (1) young women made significantly more collagen
      than young men and (2) collagen deposition was reduced in postmenopausal women,
      but deposition returned to premenopausal values with hormone replacement therapy.
      Differences between our results and those reported previously likely stem from
      the populations studied. In particular, multiple perioperative factors decrease
      collagen deposition, which apparently obscures the differences observed
      previously in healthy, unstressed volunteers.

PMID- 10636352
TI  - Peripheral bypass surgery and amputation: northern Illinois demographics, 1993 to
      1997.
AB  - HYPOTHESIS: This study tests whether age, sex, income, and racial differences
      predict rates of aortoiliac and femorodistal bypass surgery and above- and below
      knee amputation for residents of northern Illinois from 1993 to 1997. DESIGN: A
      hospital discharge survey study describing standardized procedure rates and the
      odds of undergoing amputation vs bypass procedures for specified sociodemographic
      populations. Multiple logistic regression was used to compare the odds of
      undergoing major amputation vs bypass surgery controlling for the prevalence of
      diabetes, gangrene, high-risk comorbid conditions, and treatment at major area
      teaching hospitals. RESULTS: Between 1993 and 1997, 19,250 study procedures were
      performed during 18,603 admissions at 105 Illinois hospitals. The mean annual
      major amputation rate per 100,000 was 20.77; femorodistal and aortoiliac bypass
      rates were 24.26 and 4.70, respectively. Significantly higher odds (between 1.14
      and 1.36) of undergoing amputation were found for low-income areas and ZIP codes
      with large and medium African American populations. Severe comorbidity, diabetes,
      and especially gangrene (odds ratio, 12.9) predicted amputation, while treatment
      at a major teaching hospital and male sex predicted a higher odds of undergoing
      bypass procedures. CONCLUSIONS: Results are consistent with unmeasured racial and
      income differences in the severity of atherosclerosis (or related risk factors
      such as smoking, diet, and exercise), barriers to timely primary care, or
      selective referral of lower-income and African American patients to hospitals
      with less vascular surgery capacity. These findings imply a particular need to
      identify and review the quality of care for patients undergoing primary lower
      extremity amputations.

PMID- 10636353
TI  - Preoperative chemotherapy, radiotherapy, and surgical resection of locally
      advanced pancreatic cancer.
AB  - HYPOTHESIS: Neoadjuvant therapy has the potential to induce regression of high
      risk, locally advanced cancers and render them resectable. Preoperative
      chemoradiotherapy is proposed as a testable treatment concept for locally
      advanced pancreatic cancer. DESIGN: Fourteen patients (8 men, 6 women) with
      locally advanced pancreatic cancer were surgically explored to exclude distant
      spread of disease, to perform bypass of biliary and/or gastric obstruction, and
      to provide a jejunostomy feeding tube for long-term nutritional support. A course
      of chemotherapy with fluorouracil and cisplatin plus radiotherapy was then
      initiated. Reexploration and resection were planned subsequent to neoadjuvant
      therapy. MAIN OUTCOME MEASURES: Tumor regression and survival. INTERVENTIONS:
      Surgically staged patients with locally advanced pancreatic cancer were treated
      by preoperative chemotherapy with bolus fluorouracil, 400 mg/m2, on days 1
      through 3 and 28 through 30 accompanied by a 3-day infusion of cisplatin, 25 mg
      m2, on days 1 through 3 and 28 through 30 and concurrent radiotherapy, 45 Gy.
      Enteral nutritional support was maintained via jejunostomy tube. RESULTS: Of 14
      patients who enrolled in the protocol and were initially surgically explored, 3
      refused the second operation and 11 were reexplored; 2 showed progressive disease
      and were unresectable and 9 (81%) had definitive resection. Surgical pathologic
      stages of the resected patients were: Ib (2 patients), II (2 patients), and III
      (5 patients). Pancreatic resection included standard Whipple resection in 1
      patient, resection of body and neck in 1 patient, and extended resection in 6
      patients (portal vein resection in 6, arterial resection in 4). One patient who
      was considered too frail for resection had core biopsies of the pancreatic head,
      node dissection, and an interstitial implant of the tumorous head. Pathologic
      response: 2 patients had apparent complete pathologic response; 1 patient had no
      residual cancer in the pancreatectomy specimen, the other patient who had an
      iridium 192 interstitial implant had normal core biopsies of the pancreatic head.
      Five patients had minimal residual cancer in the resected pancreas or microscopic
      foci only with extensive fibrosis, and 2 patients had fully viable residual
      cancer. Lymph node downstaging occurred in 2 of 4 patients who had positive
      peripancreatic nodes at the initial surgical staging. There was 1 postoperative
      death at 10 days. Sepsis, prolonged ileus, and failure to thrive were major
      complications. In the definitive surgery group the median survival was 19 months
      after beginning chemoradiotherapy and 16 months after definitive surgery. The
      absolute 5-year survival was 11% of 9 patients, 1 is surviving 96 months (with no
      evidence of disease) after chemoradiotherapy and extended pancreatic resection
      including resection of the superior mesenteric artery and the portal vein for
      stage III cancer. In the nonresected group the mean survival was 9 months
      (survival range, 7-12 months) after initiation of chemoradiotherapy. CONCLUSION:
      A pilot study of preoperative chemoradiotherapy with infusional cisplatin and
      radiation induced a high rate of clinical pathologic response in patients with
      locally advanced pancreatic cancer and merits further study in these high-risk
      patients.

PMID- 10636354
TI  - Pancreas-preserving total gastrectomy for gastric cancer.
AB  - BACKGROUND: Pancreas-preserving total gastrectomy for gastric cancer has been
      proposed to remove lymph nodes along the upper border of the pancreas without
      performing a distal pancreatic resection. However, the original technique
      includes the ligation of the splenic artery at its origin and thus carries the
      risk of pancreatic necrosis. HYPOTHESIS: A technique of pancreas-preserving total
      gastrectomy that includes ligation of the splenic artery approximately 5 cm
      distally from the root may reduce the risk of postoperative pancreatic necrosis.
      DESIGN: Case series. SETTING: Both primary and referral hospital care. PATIENTS:
      Hospital records of 228 consecutive patients who, according to a personal
      technique, underwent D3 pancreas-preserving total gastrectomy for gastric cancer
      from 1981 to 1997 were reviewed. MAIN OUTCOME MEASURES: Surgical complications,
      postoperative deaths, and survival. RESULTS: Hospital morbidity and mortality
      were 33.3% and 3.9%, respectively. No patients experienced pancreatic necrosis.
      The 5-year survival rate after curative resection was 53.6%: 96.9% for stage IA,
      76.3% for stage IB, 63.0% for stage II, 35.6% for stage IIIA, 27.0% for stage
      IIIB, and 20.3% for stage IV (N3-positive patients) disease. CONCLUSION: Results
      of the present study show the efficacy of this method of radical resection for
      gastric cancer as demonstrated by the low incidence of postoperative
      complications and high survival rates.

PMID- 10636355
TI  - Hypoalbuminemia, surgical leak, and clinical capillary leak syndrome.

PMID- 10636356
TI  - The big cut.

PMID- 10636357
TI  - Colorectal surgery.

PMID- 10636358
TI  - An undervalued vaccine for adults.

PMID- 10636359
TI  - Quinupristin/dalfopristin, a new addition to the antimicrobial arsenal.

PMID- 10636360
TI  - Vulvar melanoma, biologically different from other cutaneous melanomas.

PMID- 10636361
TI  - Second thoughts about safety of St John's wort.

PMID- 10636362
TI  - Rehabilitation still the only way to improve function in multiple sclerosis.

PMID- 10636363
TI  - Is there a pharmacological basis for therapy with rapid opioid detoxification?

PMID- 10636364
TI  - Breaking the silence surrounding rape.

PMID- 10636365
TI  - Outcomes at 1 year and economic implications of platelet glycoprotein IIb/IIIa
      blockade in patients undergoing coronary stenting: results from a multicentre
      randomised trial. EPISTENT Investigators. Evaluation of Platelet IIb/IIIa
      Inhibitor for Stenting.
AB  - BACKGROUND: We assessed in a randomised trial the long-term outcomes for potent
      adjunctive antiplatelet therapy given at the time of coronary stenting. METHODS:
      In 63 hospitals in the USA and Canada, 2399 patients were randomly assigned
      stenting with abciximab, stenting with placebo, or balloon angioplasty with
      abciximab. Standard adjunctive therapy with aspirin, ticlopidine, and heparin was
      used. The major outcomes of death and myocardial infarction were assessed at 1
      year follow-up by intention to treat. We also investigated the 1-year cost
      effectiveness of combined stenting and abciximab therapy. FINDINGS: At 1-year
      follow-up, eight (1.0%) of 794 patients in the stent plus abciximab group had
      died, compared with 19 (2.4%) of 809 in the stent plus placebo group (hazard
      ratio 0.43 [95% CI 0.19-0.97], p=0.037). The combined endpoint of death or large
      myocardial infarction occurred in 42 (5.3%) and 89 (11.0%), respectively (0.46
      [0.32-0.67], p<0.001). By multivariate modelling, the factors independently
      associated with improved survival were assignment to stenting with abciximab
      (p=0.027) and greater preprocedural stenosis (p=0.002); those associated with
      worse survival were age greater than 70 years (p<0.001), previous heart failure
      (p=0.001), diabetes treated with insulin (p=0.02), and postprocedural occlusion
      (p<0.001). Relative to stenting plus placebo and balloon angioplasty plus
      abciximab, the incremental 1-year costs of stenting plus abciximab were US$581
      and $932. The corresponding cost-effectiveness ratios were US$5291 and $6213 per
      added life-year. INTERPRETATION: Coronary stenting with abciximab, compared with
      stenting alone or balloon angioplasty with abciximab, is associated with improved
      survival and is an economically attractive therapy by conventional standards.

PMID- 10636366
TI  - Effect of vitamin C on frequency of reflex sympathetic dystrophy in wrist
      fractures: a randomised trial.
AB  - BACKGROUND: The pathogenesis of reflex sympathetic dystrophy (RSD) is not clear,
      nor is there a definitive treatment for this syndrome. The morbidity, costs in
      health care, and loss of work time justify the search for a means to prevent post
      traumatic dystrophy. Although the role of toxic oxygen radicals has not yet been
      clarified, we investigated vitamin C (ascorbic acid) as a prophylactic
      antioxidant drug. METHODS: 123 adults with 127 conservatively treated wrist
      fractures were randomly allocated in a double-blind trial to take a capsule of
      500 mg vitamin C or placebo daily for 50 days. Each participant's sex, age, side
      of fracture, dominance, fracture type, dislocation, reduction, and complaints
      with the plaster cast were recorded, and they were clinically scored for RSD. The
      follow-up lasted 1 year. FINDINGS: Eight patients were withdrawn after
      randomisation. 52 patients with 54 fractures (male 22%, female 78%; mean age 57
      years) received vitamin C and 63 patients with 65 fractures (male 20%, female
      80%; mean age 60 years) received placebo. RSD occurred in four (7%) wrists in the
      vitamin C group and 14 (22%) in the placebo group 15% (95% CI for differences 2
      26). Other significant prognostic variables for the occurrence of RSD were
      complaints while wearing the cast (relative risk 0.17 [0.07-0.41]) and fracture
      type (0.37 [0.16-0.89]). INTERPRETATION: This prospective, double-blind study
      shows that vitamin C was associated with a lower risk of RSD after wrist
      fractures. Our hypothesis is that this beneficial effect of prophylaxis would be
      useful in other forms of trauma.

PMID- 10636367
TI  - Radiation-induced acute myeloid leukaemia and other cancers in commercial jet
      cockpit crew: a population-based cohort study.
AB  - BACKGROUND: Cockpit crews receive cosmic radiation during flight operations. The
      increasing total accumulated dose over the years might be expected to cause
      increased frequency of radiation-induced cancer. The rate should increase with
      number of flight hours per year, number of years of flying, and higher flight
      altitude. If the cumulative radiation exposure during flights is of concern, we
      would expect an increased cancer risk to be present among those crew members
      flying jets. METHODS: Cockpit-crew medical records (pilots and flight engineers)
      from 1946 onwards, holding information on the individual, flight hours, aircraft
      type, and date of commercial certification and decertification, were linked to
      the population-based Danish Cancer Registry, the central population registry, and
      the National Death Index. FINDINGS: Altogether 3877 cockpit crew members could be
      traced for follow-up, accruing 61095 person-years at risk in 3790 men and 661 in
      87 women. The total number of cancers observed was 169 whereas 153.1 were
      expected (standardised incidence ratio 1.1 [95% CI 0.94-1.28]). Significantly
      increased risks of acute myeloid leukaemia (5.1 [1.03-14.91]), skin cancer,
      excluding melanoma (3.0 [2.12-4.23]), and total cancer (1.2 [1.00-1.53]) were
      observed among Danish male jet cockpit crew members flying more than 5000 h.
      Increased risk of malignant melanoma irrespective of aircraft type was also found
      among those flying more than 5000 h. INTERPRETATION: Both malignant melanoma and
      skin cancer were found in excess in cockpit crew members with a long flying
      history, probably attributable to sun exposure during leisure time at holiday
      destinations. We cannot confirm previously reported increased risk of brain and
      rectal cancers in pilots. The study shows that male cockpit crew members in jets
      flying more than 5000 h have significantly increased frequency of acute myeloid
      leukaemia.

PMID- 10636368
TI  - Effects of video information on precolonoscopy anxiety and knowledge: a
      randomised trial.
AB  - BACKGROUND: The provision of information before medical or surgical procedures
      should improve knowledge and allay anxiety about the pending procedure. This
      trial aimed to assess the value of an information video in this process. METHODS:
      Patients scheduled to undergo colonoscopy were approached about 1 week before the
      procedure. All patients were given an information leaflet about colonoscopy, and
      completed a Spielberger state anxiety inventory (STAI) questionnaire to assess
      baseline anxiety. The patients were then randomly assigned to watch or not watch
      the information video. Immediately before colonoscopy, all patients completed a
      second anxiety questionnaire and a knowledge questionnaire. FINDINGS: 198
      patients were screened. 31 declined to participate and 17 were unable to complete
      the forms. Of the remaining 150 patients, 72 were assigned the video, and 78 no
      video. The groups were similar with regard to age, sex, educational attainment,
      and initial anxiety score. Female patients had higher baseline anxiety than male
      patients (mean STAI 46.3 [95% CI 44.9-47.7] vs 36.9 [35.5-38.3]; difference 9.4
      [7.8-12.2], p=0.0008). Patients who had not had a previous colonoscopy had higher
      baseline anxiety scores than those who had prior experience of the procedure
      (46.9 [45.4-48.5] vs 36.3 [34.7-37.9]; difference 10.6 [7.5-13.8], p=0.0008).
      Patients who watched the video were significantly less anxious before colonoscopy
      than those who did not. The former also scored more highly in the knowledge
      questionnaire than the latter with regard to the purpose of the procedure,
      procedural details, and potential complications of colonoscopy. INTERPRETATION:
      An information video increases knowledge and decreases anxiety in patients
      preparing for colonoscopy.

PMID- 10636369
TI  - Low-dose oral contraceptives and acquired resistance to activated protein C: a
      randomised cross-over study.
AB  - BACKGROUND: We have reported previously that, compared with use of second
      generation oral contraceptives, the use of third-generation oral contraceptives
      is associated with increased resistance to the anticoagulant action of activated
      protein C (APC). Owing to the cross-sectional design of that study, these
      observations may have been subject to unknown bias or uncontrolled effects of the
      menstrual cycle. We aimed to overcome these sources of bias by doing a cycle
      controlled randomised cross-over trial. METHODS: The response to APC in plasma
      was assessed in 33 women who received two consecutive cycles of a second
      generation oral contraceptive (150 microg levonorgestrel and 30 microg
      ethinyloestradiol) or a third-generation oral contraceptive (150 microg
      desogestrel and 30 microg ethinyloestradiol), and who switched preparations after
      two pill-free cycles. Normalised APC sensitivity ratios were calculated by
      measurement of the effect of APC on thrombin generation in the plasma of these
      women and in pooled plasma from 90 controls. FINDINGS: Of the 33 women, five were
      excluded because not all required plasma samples were available. In the remaining
      28 women, the normalised APC sensitivity ratio increased during treatment with
      both preparations. Compared with levonorgestrel, desogestrel-containing oral
      contraceptive treatment caused a highly significant (p<0.0001) additional
      increase in normalised APC sensitivity ratio (0.51 [95% CI 0.37-0.66]).
      Normalised APC sensitivity ratios during oral-contraceptive treatment correlated
      with the values before oral-contraceptive use. INTERPRETATION: Oral-contraceptive
      treatment diminishes the efficacy with which APC down-regulates in-vitro thrombin
      formation. This phenomenon, designated as acquired APC resistance, is more
      pronounced in women using desogestrel-containing oral contraceptives than in
      women using levonorgestrel-containing preparations. Whether acquired APC
      resistance induced by oral contraceptives explains the increased risk of venous
      thromboembolism in oral-contraceptive users remains to be established.

PMID- 10636370
TI  - Continued breastfeeding and child growth in the second year of life: a
      prospective cohort study in western Kenya.
AB  - BACKGROUND: The value of postinfancy breastfeeding for growth and nutritional
      status is debated. We have investigated this issue in a longitudinal study.
      METHODS: We prospectively followed up a cohort of 264 children in western Kenya
      for 6 months (mean age 14 months [range 9-18] at baseline) to investigate the
      nature of the association between breastfeeding and growth. Only 14 (5.3%)
      children had been weaned at baseline, and 173 (65.5%) were still breastfed at
      follow-up. For analysis, children were classified into three groups of
      breastfeeding duration as a proportion of the total follow-up period (0-49%,
      n=42; 50-99%, n=49; and 100%, n=173). FINDINGS: In general linear models
      multivariate analysis, children in the longest-duration breastfeeding group
      gained 3.4 cm (p=0.0001) and 370 g (p=0.005) more than those in the shortest
      duration group, and 0.6 cm (p=0.0015) and 230 g (p=0.038) more than children in
      the intermediate group. The strongest association between breastfeeding and
      linear growth was observed in households that had no latrine and daily water use
      of less than 10 L per person. INTERPRETATION: Our findings support WHO's
      recommendation to continue breastfeeding for at least 2 years, especially in
      settings with poor sanitation and inadequate water supply.

PMID- 10636371
TI  - A child with cardiac arrhythmia and convulsions.

PMID- 10636372
TI  - National infant mortality rates in relation to gross national product and
      distribution of income.
AB  - We examined the relation between infant mortality rates, gross national product,
      and income distribution. Our findings support the hypothesis that average
      measures of population health are influenced by the distribution of income within
      societies.

PMID- 10636373
TI  - Treatment of hypertension with ascorbic acid.
AB  - In a randomised, double-blind, placebo-controlled study we showed that treatment
      of hypertensive patients with ascorbic acid lowers blood pressure. Further
      studies of ascorbic acid to treat hypertension, with clinical endpoints, are
      warranted.

PMID- 10636374
TI  - Magnetic-resonance-guided percutaneous laser ablation of uterine fibroids.
AB  - Percutaneous laser ablation of uterine fibroids with magnetic resonance thermal
      monitoring causes shrinkage of treated areas by 37.5% 3 months later. This
      technique may provide an alternative to open surgery.

PMID- 10636375
TI  - 15-month efficacy of maternal oral zidovudine to decrease vertical transmission
      of HIV-1 in breastfed African children. DITRAME ANRS 049 Study Group.
AB  - In a randomised, double-blind comparison of a maternal short regimen of oral
      zidovudine with placebo in West Africa the 15-month efficacy of zidovudine in
      preventing mother-to-child transmission of HIV-1 infection was estimated at 30%
      (95% CI -2 to 52).

PMID- 10636376
TI  - Postcoital injuries treated at the Addis Ababa Fistula Hospital, 1991-97.
AB  - 91 young Ethiopian women who had developed total faecal incontinence from
      injuries sustained from sexual intercourse within marriage or rape were
      successfully treated at this hospital.

PMID- 10636377
TI  - Effects of bypass on ocular ischaemic syndrome caused by reversed flow in the
      ophthalmic artery.
AB  - Superficial temporal to middle cerebral artery bypass was useful for ocular
      ischaemic syndrome caused by reversed flow in the ophthalmic artery as shown by
      ophthalmic-artery colour doppler flow imaging.

PMID- 10636378
TI  - Sickness in pregnancy and sex of child.
AB  - We report a female predominance among the offspring of mothers with hyperemesis
      gravidarum.

PMID- 10636379
TI  - Inverse relation between prostate-specific antigen and insulin-like growth factor
      binding protein 3 in bone metastases and serum of patients with prostate cancer.
AB  - The usual osteoblastic phenotype of metastatic prostate cancer is unexplained.
      Here we show that tissue and serum concentrations of prostate-specific antigen
      (PSA)-vary inversely with a substrate protein that binds a growth factor known to
      activate osteoblasts. These findings suggest that PSA may contribute to the
      osteoblastic phenotype, and could thus represent a new drug target devoid of
      antiandrogenic toxicity.

PMID- 10636381
TI  - Septic shock: finding the way through the maze.

PMID- 10636380
TI  - Consent requirements for necropsy may change in UK.

PMID- 10636382
TI  - Japanese face reality about sexually transmitted diseases.

PMID- 10636383
TI  - International health regulations: putting public health on the centre stage.

PMID- 10636385
TI  - Ernest Duchesne and the concept of fungal antibiotic therapy.

PMID- 10636384
TI  - Combined vaccination of Haemophilus influenzae type b conjugate and diphtheria
      tetanus-pertussis containing acellular pertussis.
AB  - After the introduction of effective Haemophilus influenzae type b (Hib) conjugate
      vaccines, clinical practice has driven the development of combination vaccines
      comprising Hib conjugates with the infant diphtheria-tetanus-pertussis (DTP)
      vaccines. However, when such combinations contain an acellular pertussis
      component (Pa), the antibody response to Hib is lower than that with separate
      injections and doubts have been raised about their efficacy. We believe that such
      concerns are unwarranted, since the serological correlates of efficacy previously
      applied for Hib polysaccharide vaccines seem inappropriate for Hib conjugates.
      Furthermore, our own studies have shown that the lower antibody responses are not
      associated with impaired function of the antibodies induced, nor, and possibly
      more importantly, with the induction of immune memory against Hib. Therefore,
      with the proviso that careful clinical surveillance of Hib disease is maintained,
      we encourage the introduction of DTPa-Hib combinations to facilitate the
      inclusion of Hib into the already crowded childhood immunisation schedule.

PMID- 10636386
TI  - An alternative view of homocysteine.

PMID- 10636387
TI  - East Timor: extreme deprivation of health and human rights.

PMID- 10636388
TI  - WHO recommendations put women first.

PMID- 10636389
TI  - Assessment of international medical evacuations in Macedonia.

PMID- 10636390
TI  - Functional somatic syndromes.

PMID- 10636391
TI  - Functional somatic syndromes.

PMID- 10636392
TI  - Functional somatic syndromes.

PMID- 10636393
TI  - Functional somatic syndromes.

PMID- 10636394
TI  - Functional somatic syndromes.

PMID- 10636395
TI  - Sublingual cobalamin for pernicious anaemia.

PMID- 10636396
TI  - Sublingual cobalamin for pernicious anaemia.

PMID- 10636397
TI  - HIV-1 therapy and fetal mitochondrial dysfunction.

PMID- 10636398
TI  - Hypothermia for hypertension.

PMID- 10636399
TI  - Neonatal seizures after pyridoxine use.

PMID- 10636400
TI  - Will to live in the terminally ill.

PMID- 10636401
TI  - Will to live in the terminally ill.

PMID- 10636402
TI  - Will to live in the terminally ill.

PMID- 10636403
TI  - Safe motherhood.

PMID- 10636404
TI  - Safe motherhood.

PMID- 10636405
TI  - Safe motherhood.

PMID- 10636406
TI  - No laughing matter.

PMID- 10636407
TI  - The spectrum of ocular inflammation caused by euphorbia plant sap.
AB  - OBJECTIVE: To report the spectrum of clinical findings in patients with ocular
      inflammation caused by plant sap from Euphorbia species. DESIGN: Clinical case
      series. SETTING: Ophthalmology emergency referrals in the United Kingdom.
      PATIENTS: We examined 7 patients, all of whom gave a history of recent ocular
      exposure to the sap of Euphorbia species. INTERVENTIONS: All patients were
      treated with antibiotic drops or ointment (chloramphenicol). Cycloplegic and
      steroid drops were also used for some patients. Patients were observed until all
      signs and symptoms had resolved. MAIN OUTCOME MEASURES: Symptoms, visual acuity,
      and clinical signs of inflammation. All patients provided a specimen of the plant
      for formal identification. RESULTS: Initial symptoms were generally burning or
      stinging pain with blurred vision. In most cases, visual acuity was reduced
      between 1 and 2 Snellen lines. In 1 patient with age-related maculopathy, acuity
      dropped from 20/80 to hand motions before recovering. Clinical findings varied
      from a mild epithelial keratoconjunctivitis to a severe keratitis with stromal
      edema, epithelial sloughing, and anterior uveitis. All signs and symptoms had
      resolved by 1 to 2 weeks. CONCLUSIONS: These cases illustrate the range of
      severity of Euphorbia sap keratouveitis. The condition seems to be self-limiting
      when managed supportively. People who work with Euphorbia plant species should
      wear eye protection. Clinicians managing keratopathy caused by Euphorbia species
      should be aware of the danger of sight-threatening infection and uveitis,
      particularly during the first few days.

PMID- 10636408
TI  - Ocular optical aberrations after photorefractive keratectomy for myopia and
      myopic astigmatism.
AB  - OBJECTIVES: To study the effects of photorefractive keratectomy on ocular optical
      aberrations and to establish correlations with glare vision and low-contrast
      vision. METHODS: Preoperative ocular aberroscopy of 15 eyes undergoing
      photorefractive keratectomy was compared with aberroscopy at 3 months
      postoperatively by means of a newly developed automated aberroscope of the
      Tscherning type. The correlation of the wavefront errors with best spectacle
      corrected visual acuity, low-contrast visual acuity, and visual acuity under
      glare conditions was analyzed. RESULTS: In any individual treated, the total
      wavefront error increased. On average, the total wavefront error increased by a
      factor of 17.65; this increase was highly statistically significant (P = .001).
      Also, the correlation with best-corrected visual acuity, low-contrast visual
      acuity, and glare visual acuity was statistically significant (P = .02, P = .001,
      and P = .03, respectively). The increase in ocular aberrations was significantly
      related with the virtual pupil size. CONCLUSIONS: Photorefractive keratectomy
      increases the ocular aberrations, impairing the visual performance of the eyes
      treated. In detail, scotopic visual measures such as low-contrast visual acuity
      and glare visual acuity suffer most from the myopia correction. Aberroscopy
      guided photorefractive keratectomy may avoid such effects.

PMID- 10636409
TI  - The retinal nerve fiber layer thickness in ocular hypertensive, normal, and
      glaucomatous eyes with optical coherence tomography.
AB  - OBJECTIVE: To quantitatively assess and compare the thickness of the retinal
      nerve fiber layer (RNFL) in ocular hypertensive eyes with normal and glaucomatous
      eyes using the Optical Coherence Tomograph (OCT 2000, software version A4X1;
      Humphrey Instruments, San Leandro, Calif). METHODS: The mean RNFL thickness of
      ocular hypertensive (n = 28) eyes was compared with age-matched normal (n = 30)
      and glaucomatous (n = 29) eyes. Subject eyes were classified into diagnostic
      groups based on intraocular pressure, stereoscopic disc photographs, and standard
      automated perimetry. Three circular scans were obtained for each eye at a
      diameter of 3.4 mm around the optic disc. In each eye, average RNFL thickness
      measurements were obtained in temporal, superior, nasal, and inferior quadrants.
      A single index of average RNFL thickness throughout 360 degrees also was
      obtained. RESULTS: Mean (95% confidence interval) RNFL was significantly thinner
      in ocular hypertensive eyes than in normal eyes, 72.8 microm (66.4-78.1 microm)
      and 85.8 microm (80.2-91.7 microm), respectively. More specifically, RNFL was
      significantly thinner in ocular hypertensive eyes than in normal eyes in the
      inferior quadrant, 84.8 microm (75.6-94.0 microm) vs 107.6 microm (99.3-115.9
      microm); and in the nasal quadrant, 44.1 microm (37.5-51.7 microm) vs 61.8 microm
      (53.0-65.6 microm). Retinal nerve fiber layer was significantly thinner in
      glaucomatous eyes than in ocular hypertensive and normal eyes throughout 360
      degrees and in all quadrants. CONCLUSION: These findings suggest that
      quantitative differences in RNFL thickness exist between age-matched ocular
      hypertensive, normal, and glaucomatous eyes.

PMID- 10636410
TI  - Relative contributions of the neurosensory retina and retinal pigment epithelium
      to macular hypofluorescence.
AB  - OBJECTIVE: To determine quantitatively the relative contributions of the
      neurosensory retina (NR) and retinal pigment epithelium (RPE) to the macular
      hypofluorescence observed during routine fundus fluorescein angiography. METHODS:
      Macular and peripheral buttons of neurosensory retina and retinal pigment
      epithelium were obtained from 10 postmortem human eyes. A well was created to
      simulate a fluorescein-filled choroid. The fluorescence of each tissue and
      combinations of tissue atop the well was determined using a fluorescence
      microscope. The percent reduction in the fluorescence of each, relative to the
      baseline fluorescence of the well alone, was calculated. RESULTS: Macular RPE
      demonstrated substantially lower fluorescence than peripheral RPE in all
      subjects. Macular NR demonstrated lower fluorescence than peripheral NR in all
      but one subject. The addition of macular NR to macular RPE caused significantly
      less fluorescence in all cases. Macular RPE caused a much greater percent
      reduction in fluorescence than macular NR in all subjects. CONCLUSIONS:
      Hypofluorescence of the macula relative to the peripheral retina is a well-known
      feature of fluorescein angiography. This phenomenon is predominantly owing to the
      RPE and minimally to the NR, which cause 90.6 and 13.6 mean percent reductions in
      fluorescence, respectively.

PMID- 10636411
TI  - Papillofoveal traction in macular hole formation: the role of optical coherence
      tomography.
AB  - OBJECTIVES: To determine the validity of the assumption that optical coherence
      tomographic scans of macular holes have a discrete linear signal (DLS) that
      represents a detached posterior vitreous face, and to analyze the DLS in macular
      hole pathogenesis. METHODS: Optical coherence tomographic scans were taken of 3
      situations in which the vitreous conditions were known: (1) dissected intact
      vitreous, (2) clinically evident Weiss rings, and (3) maculae before and after
      saccades in eyes without a biomicroscopic posterior vitreous detachment. In
      addition, 70 eyes of 35 patients with macular holes underwent clinical
      examination and optical coherence tomographic scanning that passed through the
      optic disc and the fovea or macular hole. RESULTS: Spatial properties of the DLS
      matched those of the posterior vitreous face in the situations examined. Of the
      70 eyes, 16 (23%) had a biomicroscopic posterior vitreous detachment, whereas a
      DLS was demonstrated in 40 (57%). Of the 54 eyes without a biomicroscopic
      posterior vitreous detachment, 18 (33%) had a DLS attached focally to the optic
      disc margin and the fovea or macular hole. All 7 of the "can opener" holes
      examined had a nasally "hinged" central flap, 6 with a focally attached DLS.
      CONCLUSIONS: The DLS corresponds to the posterior vitreous face. Anteronasal
      papillofoveal traction may generate some macular holes.

PMID- 10636412
TI  - The visual performance and metamorphopsia of patients with macular holes.
AB  - BACKGROUND: Most patients attain better visual acuity with the elimination of
      metamorphopsia after successful closure of a macular hole (MH) by vitrectomy.
      OBJECTIVE: To determine the presurgical visual function of eyes with an MH.
      METHODS: We examined 54 eyes of 51 patients with an idiopathic MH using the
      Amsler chart. We evaluated the types of subjective metamorphopsia and compared
      them with the clinical factors associated with MHs. In a prospective study, we
      performed a montage test on a separate group of 16 patients with unilateral
      idiopathic MHs. The patients were asked to choose, while viewing with their
      better eye, the computer-modified picture that best matched the unmodified image
      seen by the eye with the MH. RESULTS: From the results of the Amsler chart test,
      we divided the subjective changes into 2 types of metamorphopsia; of the 54 eyes,
      pincushion distortion (bowed toward the center) was found in 33 (61%), and
      unpatterned distortion (no specific pattern) was found in 21 (39%). Pincushion
      distortion was significantly associated with an MH of shorter duration (< or =6
      months) (P = .03) and an early stage (stage 2) of MH formation (P = .02). A
      scotoma was hard to detect, and patients had difficulty describing their
      scotomata and distortions. In the montage test, patients with early MHs chose
      portraits modified with a pincushion type of distortion. CONCLUSIONS: We found
      concentric pincushion metamorphopsia without subjective scotomata, which we
      suggest arises from an eccentric displacement of the photoreceptors. This
      accounts for the main characteristic of the visual performance of patients with
      idiopathic MHs.

PMID- 10636413
TI  - Utility values and age-related macular degeneration.
AB  - OBJECTIVE: To ascertain the utility values associated with age-related macular
      degeneration and varying degrees of visual loss. DESIGN: A cross-sectional study.
      PARTICIPANTS: Eighty white patients with unilateral or bilateral age-related
      macular degeneration in 1 or both eyes, and visual loss to a minimum of the 20/40
      level in at least 1 eye. MAIN OUTCOME MEASURES: Utility values were measured in 5
      groups according to the visual acuity in the better-seeing eye, 1 (20/20 to
      20/25), 2 (20/30 to 20/ 50), 3 (20/60 to 20/100), 4 (20/200 to 20/400), and 5
      (counting fingers to light perception), using the time trade-off and the standard
      gamble methods. Conventionally assigned anchor utility values were 1.0 for
      perfect health and 0.0 for death. RESULTS: The mean utility value for the total
      group with age-related macular degeneration was 0.72 (95% confidence interval
      [CI], 0.66-0.78) using the time trade-off method and 0.81 (95% CI, 0.76-0.86)
      using the standard gamble method. Using the time trade-off method correlated with
      the visual acuity in the better-seeing eye, the results were as follow: group 1,
      0.89 (95% CI, 0.82-0.96), group 2, 0.81 (95% CI, 0.73-0.89), group 3, 0.57 (95%
      CI, 0.47-0.67), group 4, 0.52 (95% CI, 0.38-0.66), and group 5, 0.40 (95% CI,
      0.29-0.50). Thus, those patients in group 1 were willing to trade 11% of their
      remaining lifetime in return for perfect vision in each eye, whereas those in
      group 5 were willing to trade 60% of their remaining lifetime in return for
      perfect vision in each eye. CONCLUSION: Age-related macular degeneration causes a
      substantial decrease in patient utility values and is highly dependent on the
      degree of visual loss in the better-seeing eye.

PMID- 10636414
TI  - Effects of insulin on retinal and pulsatile choroidal blood flow in humans.
AB  - BACKGROUND: Insulin induces vasodilation in several tissues, including skeletal
      muscle and kidneys. OBJECTIVE: To investigate whether insulin may contribute to
      ocular blood flow regulation. METHODS: The study was performed in a balanced,
      randomized, placebo-controlled, single-masked, 3-way, crossover design in 9
      healthy male subjects. Each subject received 2 doses of insulin (1.5 or 3 mU/kg
      per minute) or placebo on 3 different study days. Measurements of fundus
      pulsation amplitude with laser interferometry to assess pulsatile choroidal blood
      flow, of retinal blood flow with the blue-field entoptic technique, and of mean
      blood flow velocity in the ophthalmic artery with Doppler sonography were
      performed under euglycemic clamp conditions over 120 minutes. RESULTS:
      Hyperinsulinemia significantly increased fundus pulsation amplitude (1.5 mU/kg
      per minute: 8.7% +/- 1.1% vs baseline; 3 mU/kg per minute: 13.2% +/- 2.3% vs
      baseline; P<.001 vs placebo [analysis of variance]) and mean blood flow velocity
      (1.5 mU/kg per minute: 10.0% +/- 4.3% vs baseline; 3 mU/kg per minute: 6.6% +/-
      3.5% vs baseline; P = .03 vs placebo). Retinal blood flow did not increase during
      administration of insulin (1.5 mU/kg per minute: 6.4% +/- 8.0% vs baseline; 3
      mU/kg per minute: 8.0% +/- 5.1% vs baseline; P = .99 vs placebo). Neither the
      effect in the choroid nor that in the ophthalmic artery was dose-dependent.
      CONCLUSION: Hyperinsulinemia significantly increases choroidal blood flow and
      mean blood flow velocity in the ophthalmic artery. By contrast, retinal blood
      flow was not influenced by hyperinsulinemia. The maximum effective dose of
      insulin for ocular hemodynamics is likely to be within the physiological range.

PMID- 10636415
TI  - Changing trends in paintball sport-related ocular injuries.
AB  - OBJECTIVES: To describe the type and severity of ocular injuries caused by
      paintballs, to summarize the outcomes, to determine if the injury occurred in a
      commercial or noncommercial setting, to compare the number of injuries in each
      setting as a function of time, and to ascertain whether eye-protective devices
      were worn and why they were removed. DESIGN: Retrospective analysis of 35
      patients who sustained ocular injuries caused by paintballs and underwent
      evaluation and treatment at an eye hospital from January 1, 1985, to September
      30, 1998. Thirty-five eyes of 35 patients underwent a complete ocular
      examination, diagnostic testing, and surgical intervention when indicated.
      RESULTS: All patients were male (average age, 22 years). Twenty-six patients
      (74%) had an initial visual acuity of 20/200 or worse, and visual acuity in 16
      (46%) remained 20/200 or worse on follow-up (range, 2 weeks to 22 months).
      Traumatic hyphema was seen in 21 patients (60%). Twenty-two patients (63%) had
      access to goggles, 7 (33%) of whom removed them due to fogging before the injury.
      Injuries sustained after 1995 were 5.8 times (relative risk, 5.8; 95% confidence
      interval, 1.5-22.4) more likely to occur during a noncommercial war game than
      those occurring in 1995 or before. CONCLUSIONS: As the popularity of war games
      increases, so does the potential for serious ocular injury caused by paint pellet
      guns. Most injuries seen after 1995 occurred in noncommercial war game settings,
      where the use of eye-protective devices is not required. Industry standards for
      eye protection have been developed recently and should be implemented.

PMID- 10636416
TI  - A comparison of manual kinetic and automated static perimetry in obtaining ptosis
      fields.
AB  - OBJECTIVE: To compare examination time and visual field loss for ptosis fields
      obtained with manual kinetic (Goldmann) perimetry and automated static (Humphrey)
      perimetry. METHODS: Both eyes of 12 patients with bilateral aponeurogenic ptosis
      were prospectively examined using Goldmann and Humphrey (ptosis protocol)
      perimetry with the eyelids ptotic and taped into a normal position. RESULTS:
      Bilateral examination time for Goldmann fields was 10 +/- 2 minutes and for
      Humphrey fields was 50 +/- 10 minutes (P<.001, n = 12). Superior fields at the
      12:00 meridian were 46 degrees +/- 6 degrees taped, and 28 degrees +/- 12 degrees
      untaped for Goldmann perimetry (P<.001), and 38 degrees +/- 8 degrees taped, and
      24 degrees +/- 12 degrees untaped for Humphrey perimetry P<.001). Goldmann field
      loss was 18 degrees +/- 9 degrees (taped minus untaped). Humphrey field loss was
      14 degrees +/- 13 degrees (P<.04, n = 24). Mean Goldmann radial fields were 56
      degrees +/- 6 degrees taped and 39 degrees +/- 13 degrees untaped (P<.001).
      Goldmann superior hemifield areas were 5,167 +/- 964 degrees2 taped and 2,830 +/-
      1,466 degrees2 untaped (P<.001). Humphrey mean vertical superior hemifield was 37
      degrees +/- 9 degrees taped and 21 degrees +/- 11 degrees untaped (P<.001). Mean
      sensitivity of Humphrey fields was 15 +/- 3 dB taped and 9 +/- 5 dB untaped
      (P<.001). Mean vertical center of gravity was 23 degrees +/- 3 degrees taped and
      16 degrees +/- 5 degrees untaped (P <.001). CONCLUSION: Goldmann manual kinetic
      and Humphrey automated static visual field testing are both effective in
      documenting ptosis associated visual field loss. Humphrey automated ptosis
      fields, as performed in this study, require longer examination times than
      Goldmann manual fields and may be a less sensitive indicator of field loss.

PMID- 10636417
TI  - Obtaining maximal optic nerve length during enucleation procedures.
AB  - OBJECTIVE: To determine optimal scissor blade design and surgical approach to
      facilitate obtaining a long optic nerve segment during enucleation procedures.
      METHODS: Two hundred mock enucleations were performed with the use of a human
      child skull model and a silicone sphere to simulate an eye. Temporal and nasal
      approaches with scissor blades with noncurved, mildly curved, or strongly curved
      blades were tested. RESULTS: Longer optic nerve segments were obtained with
      mildly curved scissor blades from both temporal and nasal surgical approaches.
      Strongly curved scissor blades uniformly produced smaller specimens. CONCLUSIONS:
      Mildly curved scissors should be used for enucleation when a long optic nerve
      specimen is desired. Strongly curved scissors should be avoided.

PMID- 10636418
TI  - Effect of latanoprost or 8-iso prostaglandin E2 alone and in combination on
      intraocular pressure in glaucomatous monkey eyes.
AB  - OBJECTIVE: To evaluate the possible additivity of the effects of latanoprost and
      8-iso prostaglandin E2 (8-iso PGE2) on intraocular pressure (IOP) in monkey eyes
      with laser-induced glaucoma. METHODS: The IOP was measured hourly for 6 hours
      beginning at 9:30 AM on day 1 (baseline day), days 6 and 7 (single-agent
      therapy), and days 13 and 14 (combination therapy with both agents). Following 1
      day of baseline measurement, 4 monkeys with unilateral glaucoma received
      monotherapy) twice daily with either 1 drop of 0.005% latanoprost, or 0.1% 8-iso
      PGE2, 25 microL, at 9:30 AM and 3:30 PM from days 2 through 7. From days 8
      through 14, both agents were applied twice daily 5 minutes apart. RESULTS: The
      maximum reduction of IOP (mean +/- SEM) was 8.8 +/- 1.9 mmHg (26%) (P<.05) with
      latanoprost alone and 6.5 +/- 1.0 mmHg (21%) (P<.0l) with 8-iso PGE2 alone, 2
      hours after the morning dosing on day 7. A further reduction of IOP of 4.0 +/-
      0.6 mm Hg was produced when 8-iso PGE2 was added to latanoprost and of 3.0 +/-
      0.7 mm Hg was produced when latanoprost was added to 8-iso PGE2 on day 13 before
      the morning dosing. Combination therapy with both agents caused maximum IOP
      reductions from baseline of 11.3 +/- 3.0 mm Hg (33%) (P<.05) (latanoprost with 8
      iso PGE2 added) and of 9.8 +/- 1.3 mm Hg (31%) (P<.01) (8-iso PGE2 with
      latanoprost added) on day 14. CONCLUSION: Latanoprost and 8-iso PGE2 have an
      additive effect on IOP in glaucomatous monkey eyes. CLINICAL RELEVANCE: At least
      50% of patients are treated with more than 1 ocular hypotensive medication. Thus,
      the determination of the additive effects on IOP of glaucoma medications will
      help to define optimum treatment regimens.

PMID- 10636419
TI  - Angiography of fluoresceinated anti-vascular endothelial growth factor antibody
      and dextrans in experimental choroidal neovascularization.
AB  - OBJECTIVE: To determine if anti-vascular endothelial growth factor antibody and a
      range of dextrans with varying diffusion radii and molecular weights are
      permeable through experimental choroidal neovascularization (CNV). METHODS:
      Choroidal neovascularization was induced in 10 cynomolgus monkey retinas by means
      of argon laser injury. Digital fundus fluorescein angiograms were performed with
      fluorescein sodium, fluoresceinated IgG antibodies (anti-vascular endothelial
      growth factor and a control antibody), and fluoresceinated dextrans with
      molecular weights of 4, 20, 40, 70 and 150 kd. The 40- and 70-kd dextrans
      straddle the effective diffusion radius of IgG. For each reagent, early and late
      angiograms were performed in a standardized fashion, with follow-up images
      obtained to monitor residual fluorescence. RESULTS: Perfusion of retinal vessels
      and choroidal vasculature was seen with all reagents. Fluorescein and 4- and 20
      kd dextran leaked rapidly from the CNV within the first minute. Angiography with
      the use of 40-kd dextran and fluoresceinated antibody, either anti-vascular
      endothelial growth factor or control IgG, showed fluorescence within the CNV that
      increased during the first 1 to 5 hours, with mild leakage from the CNV. By 24
      hours, fluorescence in the CNV was minimal, although in some cases persistent
      fluorescence in the surrounding tissue was evident up to 2 weeks. The 70-kd
      dextran showed fluorescence within the CNV and leakage in 1 of 3 eyes. The 150-kd
      dextran showed fluorescence within the CNV but did not demonstrate leakage.
      CONCLUSIONS: Fluoresceinated antibodies and dextran with smaller effective
      diffusion radii showed CNV perfusion and leakage. Dextrans with larger effective
      diffusion radii (70 kd and 150 kd) perfused into CNV but did not show leakage
      consistently. CLINICAL RELEVANCE: Determining the permeablity of antibodies and
      molecules of similar size through CNV can help ascertain the feasibility of using
      intravenously administered antibodies against angiogenic growth factors as a
      future treatment for choroidal neovascularization.

PMID- 10636420
TI  - Autosomal dominant hemorrhagic macular dystrophy not associated with the TIMP3
      gene.
AB  - OBJECTIVE: To describe the ophthalmic and genetic findings of a large kindred
      (UM:H389) with autosomal dominant hemorrhagic macular dystrophy. METHODS: The
      disease state of family members was documented by dilated fundus examination,
      electroretinography, color vision tests, fluorescein angiography, measurement of
      visual fields, biomicroscopy, gonioscopy, and intraocular pressure measurement.
      Linkage and haplo-type analyses were carried out with markers flanking the Sorsby
      fundus dystrophy TIMP3 (tissue inhibitor of metalloproteinase 3) gene locus, and
      mutation analysis was carried out by screening exon 5 of the TIMP3 gene. RESULTS:
      This 4-generation pedigree with autosomal dominant hemorrhagic macular
      degeneration has visual symptoms beginning in the sixth decade of life. Several
      family members developed choroidal neovascular membrane formation in the macula
      of both eyes. The phenotype overlaps that of Sorsby fundus dystrophy. Some of the
      affected members have unusual zonularlike radial striations on the anterior lens
      capsule surface, and glaucoma or ocular hypertension has developed in 2 of them.
      Involvement of the TIMP3 gene was excluded by linkage, haplotype, and mutation
      analyses. CONCLUSIONS: The phenotype of this family with autosomal dominant
      macular dystrophy overlaps that of Sorsby fundus dystrophy. Exclusion of the
      TIMP3 gene in this family indicates genetic heterogeneity for hemorrhagic macular
      dystrophy. Anterior segment anomalies may occur with this condition, but
      cosegregation has not yet been established. CLINICAL RELEVANCE: This study
      broadens the spectrum of hemorrhagic macular dystrophy by identifying a family in
      which the TIMP3 gene is not involved. Once the gene is cloned, we are eager to
      learn whether this gene may be involved in age-related macular degeneration.

PMID- 10636421
TI  - X-linked retinoschisis with point mutations in the XLRS1 gene.
AB  - BACKGROUND: X-linked retinoschisis (XLRS) is a relatively rare vitreoretinal
      dystrophy that causes visual loss in young men. Recently, a gene responsible for
      this disease, designated XLRS1, was identified, and several deleterious gene
      mutations were reported. OBJECTIVE: To analyze Japanese patients clinically
      diagnosed as having XLRS formutational changes in the XLRS1 gene. METHODS: Ten
      patients with XLRS underwent full ophthalmologic examination, including slitlamp
      biomicroscopy and dilated funduscopy. Genomic DNA was isolated from leukocytes,
      and all exons of the XLRS1 gene were amplified by polymerase chain reaction and
      analyzed using a direct sequencing method. RESULTS: Point mutations in the XLRS1
      gene were identified in all 10 patients. The mutations were identical in each of
      2 pairs of brothers. Six of the point mutations represented missense mutations, 1
      was a nonsense mutation, and 1 was a frameshift mutation. Five of the mutations
      are newly reported herein. CONCLUSIONS: The discovery of new point mutations in
      this study increases the available information regarding the spectrum of genetic
      abnormalities and clinical manifestations of XLRS. However, the limited data
      failed to reveal a correlation between mutation and disease phenotype. CLINICAL
      RELEVANCE: Identification of mutations in the XLRS1 gene and expanded information
      on clinical manifestations will facilitate early diagnosis, appropriate early
      therapy, and genetic counseling regarding the prognosis of XLRS.

PMID- 10636422
TI  - Diabetic retinopathy in African Americans with type 1 diabetes: The New Jersey
      725: I. Methodology, population, frequency of retinopathy, and visual impairment.
AB  - OBJECTIVE: To determine the frequency and severity of diabetic retinopathy, as
      well as associated visual impairment, among African Americans with type 1
      diabetes. METHODS: A total of 725 African Americans with type 1 diabetes were
      enrolled in the study (The New Jersey 725). Clinical evaluations included
      structured clinical interview, ocular examination, stereoscopic fundus
      photography, and blood pressure measurements. Severity of retinopathy was
      determined via masked grading of fundus photographs. Biological evaluations
      included blood and urine assays. RESULTS: Of the 725 patients, 463 (63.9%)
      presented with any diabetic retinopathy and 137 (18.9%) with proliferative
      diabetic retinopathy. The frequency and severity of retinopathy were both
      significantly associated with older age at examination. Visual impairment (visual
      acuity in the better eye < or =20/40) was present in 79 (11.0%) and legal
      blindness in 22 (3.1%) of the patients. Diabetic retinopathy was responsible for
      90.9% of the blindness. Frequency of visual impairment was significantly
      associated with older age and female sex, and only weakly with lower education.
      CONCLUSIONS: Diabetic retinopathy in African Americans with type 1 diabetes is
      common, being found in almost two thirds of the patients studied. Its frequency
      and severity increase with age. Visual impairment is common, increasing with age
      and duration of diabetes and is more frequent in women than in men.

PMID- 10636424
TI  - Ocular inflammatory disease in the new millennium.

PMID- 10636423
TI  - Diabetic retinopathy in African Americans with type 1 diabetes: The New Jersey
      725: II. Risk factors.
AB  - OBJECTIVE: To determine whether diabetic retinopathy in African Americans with
      type 1 diabetes is associated with the following 6 putative risk factors:
      duration of diabetes, glycemic control, systemic hypertension, renal disease,
      socioeconomic status, and male sex. METHODS: Patients in The New Jersey 725 study
      underwent detailed ocular evaluation, a structured clinical interview, blood
      pressure measurements, and assays of blood and urine samples. RESULTS: Glycemic
      control was poor; 89.8% of the patients had glycosylated hemoglobin values of
      more than 0.08. Renal disease and systemic hypertension were present in 49.8% and
      34.3% of patients, respectively. Frequency and severity of retinopathy were
      significantly associated with longer duration of diabetes (P<.001). After
      adjusting for duration of diabetes and other confounding variables, on average,
      patients with total glycosylated hemoglobin values in the highest quartile were 3
      times more likely to have any retinopathy than those in the lowest quartile;
      patients with renal disease, 3 times more likely to have any retinopathy and 10
      times more likely to have proliferative retinopathy than patients without renal
      disease; and patients in the highest quartile of systolic sitting blood pressure,
      3 times more likely to have proliferative retinopathy than patients in the lowest
      quartile. CONCLUSIONS: Risk factors for diabetic retinopathy in African Americans
      with type 1 diabetes include presence of renal disease, poor glycemic control,
      high systolic blood pressure, and long duration of diabetes.

PMID- 10636425
TI  - Iridology: not useful and potentially harmful.
AB  - More than 1,000 licensed naturopathic physicians practice in the United States,
      and iridology is being described as "the most valuable diagnostic tool of the
      naturopath." Some therapists are using iridology as a basis for recommending
      dietary supplements and/or herbs. Several US iridologist organizations exist: the
      National Iridology Research Association is an iridologists' service organization,
      the International Association of Iridologists is the leading organization for
      European-style iridology and runs training programs (minimum of 72 hours in
      class), and the Bastyr Naturopathic College in Seattle, Wash, has an elective
      course on iridology (J. Colton, e-mail communication, December 2, 1998). In the
      United States, insurance programs do not normally cover iridology, but in some
      European countries, they do. In Germany, for instance, 80% of the Heilpraktiker
      (nonmedically qualified health practitioners) practice iridology.
      Ophthalmologists may therefore ask what is iridology and how valuable is it?

PMID- 10636426
TI  - Clinical standards for alternative medicine.

PMID- 10636427
TI  - Treatment of severe ocular-surface disorders with corneal epithelial stem cell
      transplantation.

PMID- 10636428
TI  - Acute unilateral corneal immunoprotein deposition in IgM monoclonal gammopathy.
AB  - A healthy 43-year-old officer of a merchant ship at sea developed pain, redness,
      and photophobia in his right eye. During the next 2 weeks, he noted the presence
      of a band of opacity spreading from his temporal limbus toward his central
      cornea. His episcleral vessels were engorged in a distribution contiguous with
      the peripheral, sectorial, fleck-like corneal opacities. The opacity had
      progressed during topical and systemic antibiotic therapy, but halted with use of
      topical corticosteroids. Systemic evaluation showed mild IgM monoclonal
      gammopathy. Transmission electron microscopy of a corneal biopsy specimen
      revealed electron-dense fibrils identified as immunoprotein. To our knowledge,
      this is the first report of a case of acute unilateral deposition of corneal
      immunoprotein in a patient with monoclonal gammopathy. Clinicians should begin
      with a broad differential diagnosis when evaluating patients with corneal
      opacity.

PMID- 10636429
TI  - Clinical phenotype associated with the arg141 his mutation in the X-linked
      retinoschisis gene.

PMID- 10636430
TI  - Bietti crystalline retinopathy affecting all 3 male siblings in a family.

PMID- 10636431
TI  - Macular hole surgery in the presence of prominent macular drusen.

PMID- 10636432
TI  - Synkinesis following diabetic third nerve palsy.

PMID- 10636433
TI  - Oral ivermectin therapy for phthiriasis palpebrum.

PMID- 10636434
TI  - Full-thickness skin grafting of eyelids in a patient with generalized morphea
      taking thalidomide.

PMID- 10636435
TI  - A study of surgical approaches to retinal vascular occlusions.
AB  - OBJECTIVE: To develop a surgical approach to retinal vascular occlusive diseases.
      METHODS: Surgical manipulations were performed on the retinal vasculature to
      explore the feasibility of retinal vascular surgery. In a human cadaver eye model
      (25 procedures, 21 eyes), we performed (1) cannulations of retinal blood vessels
      with a flexible stylet and (2) arteriovenous sheathotomies. Histological findings
      were correlated with surgical outcomes. In an in vivo model (6 eyes, 5 animals),
      we examined the technical feasibility and anatomical outcome of surgical
      penetration of retinal blood vessels. RESULTS: Cannulations of branch retinal
      arterioles were successful in 7 of 9 procedures, cannulations of branch retinal
      venules were successful in 1 of 3 procedures, cannulations of central retinal
      arteries were successful in 0 of 2 procedures, and cannulations of central
      retinal veins were successful in 2 of 4 procedures. Arteriovenous sheathotomies
      were successful in 4 of 7 procedures. In the in vivo model, surgical penetration
      of retinal blood vessels was accomplished in 5 of 6 eyes. Immediately
      postoperatively, thrombus formation with obstruction of the retinal vasculature
      was observed. At 2 weeks postoperatively, the retinal vasculature was completely
      patent. CONCLUSIONS: Multiple surgical techniques aimed at assisting
      recanalization of occluded retinal vasculature have been evaluated. Retinal
      vascular surgery has become more feasible and deserves further investigation.

PMID- 10636436
TI  - Spontaneous rupture of a macroaneurysm documented in real time during fluorescein
      angiography.

PMID- 10636437
TI  - Valsalva retinopathy associated with a congenital retinal macrovessel.

PMID- 10636438
TI  - Ethical conflicts in university-based research.

PMID- 10636439
TI  - The hook is not the most dangerous.

PMID- 10636440
TI  - Pharmacogenetics and pharmacogenomics: why is this relevant to the clinical
      geneticist?
AB  - Adverse drug reactions, due at least in part to interindividual variability in
      drug response, rank between the 4th and 6th leading causes of death in the USA.
      The field of 'pharmacogenetics', which is 'the study of variability in drug
      response due to heredity', should help in reducing drug-caused morbidity and
      mortality. The recently coined term 'pharmacogenomics' usually refers to 'the
      field of new drug development based on our rapidly increasing knowledge of all
      genes in the human genome'. However, the two terms - pharmacogenetics and
      pharmacogenomics - are often used interchangeably. A classification of more than
      five dozen pharmacogenetic differences is presented here. Most of these
      variations occur in drug-metabolizing enzyme (DME) genes, with some presumed to
      exist in the DME receptor and drug transporter genes, and others have not yet
      been explained on a molecular basis. A method for unequivocally defining a
      quantitative phenotype (drug efficacy, toxicity, etc.) is proposed; this is where
      help from the clinical geneticist can be especially important. Our current
      appreciation of the degree of variability (including single-nucleotide
      polymorphisms, SNPs) in the human genome is described, with emphasis on the need
      to prove that a particular genotype is indeed the cause of a specific phenotype;
      this topic has been termed 'functional genomics'. Furthermore, the current amount
      of admixture amongst almost all ethnic groups will obviously make studies of gene
      drug interactions more complicated, as will the withholding of ethnic information
      about DNA samples during any molecular epidemiologic study. DME genes and DME
      receptor and drug transporter genes can be regarded as 'modifier genes', because
      they influence disorders as diverse as risk of cancer, bone marrow toxicity
      resulting from occupational exposure, and Parkinson's disease; for this reason,
      the clinical geneticist, as well as the medical genetics counselor, should be
      knowledgeable in the rapidly expanding fields of pharmacogenetics and
      pharmacogenomics.

PMID- 10636441
TI  - The ups and downs of parting COMPany. Poly-aspartic acid tract instability: a
      novel expansion-contraction mutation.

PMID- 10636442
TI  - Growing up without sulfate.

PMID- 10636443
TI  - A SHOXing new kind of inheritance.

PMID- 10636444
TI  - Neural stem cells -- a versatile tool for cell replacement and gene therapy in
      the central nervous system.
AB  - In recent years, it has become evident that the developing and even the adult
      mammalian central nervous system contains a population of undifferentiated,
      multipotent cell precursors, neural stem cells, the plastic properties of which
      might be of advantage for the design of more effective therapies for many
      neurological diseases. This article reviews the recent progress in establishing
      rodent and human clonal neural stem cell lines, their biological properties, and
      how these cells can be utilized to a correct variety of defects, with prospects
      for the near future to harness their behaviour for neural stem cell-based
      treatment of diseases in humans.

PMID- 10636445
TI  - Genetic landmarks through philately-hemophilia.

PMID- 10636446
TI  - FISH analysis of terminal deletions in patients diagnosed with cri-du-chat
      syndrome.
AB  - Most patients with cri-du-chat syndrome have a de novo deletion of the short arm
      of chromosome 5 (5p). In order to perform extensive phenotype-genotype
      correlation studies, a relatively easy method for the precise determination of
      the extent of a patient's deletion is essential. Towards this purpose, a set of
      minimally overlapping YAC clones that span 5p was identified. A BAC that maps at
      or near the 5p telomere was also used. A total of 110 patients with previously
      determined de novo terminal deletions by standard cytogenetic approaches were
      reanalyzed using the YAC clones and fluorescent in situ hybridization (FISH). Of
      the 110 samples, 4 patients were determined to have interstitial deletions, 1
      patient had an unbalanced translocation, and no deletion could be detected in 2
      patients. The FISH results in the 7 patients affect the clinical prognosis for
      some of these patients. These results demonstrate the need for supplementing
      standard cytogenetics with FISH analysis when an abnormal karyotype is detected.

PMID- 10636447
TI  - Association of pre-eclampsia with common coding sequence variations in the
      lipoprotein lipase gene.
AB  - Marked dyslipidemia may contribute to endothelial cell dysfunction in pre
      eclampsia. Carriers of N291S or D9N missense mutations in the lipoprotein lipase
      (LPL) gene exhibit reductions in LPL activity and are predisposed to dyslipidemia
      and cardiovascular disease. In Caucasians, the D9N variant is in strong linkage
      disequilibrium with the - 93T --> G promoter variant. A fourth LPL variant,
      S447X, is often associated with a beneficial lipid profile. We asked if the N291S
      and the combination D9N/- 93T --> G variants are more prevalent, and if the S447X
      variant is less prevalent, in Caucasian women with pre-eclampsia as compared with
      normal pregnancies. DNA amplification was followed by an allele-specific
      oligonucleotide ligation assay. Allele frequencies were analyzed with a chi2
      table and Yates' correction. The N291S variant was identified in 11.1% of pre
      eclamptics as compared with 2.9% of pregnancy controls (p = 0.008). All carriers
      of D9N were also carriers of - 93T --> G. The D9N/ - 93T --> G combined variant
      was found in 7.1% of pre-eclamptics as compared with 1.4% of pregnancy controls
      (p = 0.02). No individuals were carriers of both N291S and D9N/ - 93T --> G.
      Thus, 18.2% of pre-eclamptics had either of these LPL mutations compared with
      4.3% of pregnancy controls (and 4.4% of population controls). The frequency of
      the S447X variant did not differ among groups. We conclude that carriers of N291S
      or combined D9N/ - 93T --> G mutations in the LPL gene are at substantially
      increased risk of pre-eclampsia.

PMID- 10636449
TI  - New' manifestations of BOR syndrome.
AB  - Defined in 1975, branchio-oto-renal (BOR) syndrome is an autosomal dominant
      disorder consisting of branchial arch anomalies, hearing loss, and urinary tract
      malformations. It is the prototype of the non-chromosomal syndromes that have
      branchial arch anomalies as major clinical manifestations: BOR, branchio-otic
      (BO), branchio-otic-facial (BOF), and Townes-Brock syndromes. Subsequently,
      several clinical manifestations have expanded its phenotype. Retrospective
      analysis of 31020 families evaluated between January 2, 1982 and December 31,
      1996 at the genetic clinics of the University of South Florida, showed seven
      probands with BOR/?BOR syndrome. Four of the probands and affected relatives had
      manifestations that further expanded the phenotype: gustatory lacrimation,
      hypospadias, imperforate anus, osteosclerosis, microcephaly, hypodontia,
      congenital vocal cord paresis, and congenital incomplete fixation of the
      transverse colon. Thus, BOR/ ?BOR syndrome appears to be a clinically and
      genetically heterogeneous multiorgan/system entity that manifests itself
      predominantly during organogenesis. Clinicians and researchers alike should be
      cognizant of the expanded phenotype and heterogeneity, while in the DNA
      laboratories the latter will be sorted out.

PMID- 10636448
TI  - Two common mutations (D9N, N291S) in lipoprotein lipase: a cumulative analysis of
      their influence on plasma lipids and lipoproteins in men and women.
AB  - We assessed the effect of two common mutations in the lipoprotein lipase gene
      (LPL), D9N and N291S, which have been shown to modulate plasma lipids in a wide
      spectrum of patients. A total of 1114 men and 1 144 women from the Framingham
      Offspring Study (FOS) were analyzed for these two LPL variants. Subsequently, the
      association with fasting plasma lipids and risk of coronary artery disease (CHD)
      was determined. We extended our study by calculating weighed means of lipids and
      lipoproteins in carriers and non-carriers for these LPL mutations in patients
      with genetic dyslipidemias, CHD patients and healthy controls. In the FOS sample,
      the D9N and N291S alleles were associated with lower high-density lipoprotein
      cholesterol (HDL-C) (delta = - 0.07 mmol/ 1, p = 0.03) and a trend towards
      increased triglycerides (delta = 0.25 mmol/ 1, p = 0.07). In women, a trend
      towards the high triglyceride, low HDL-C phenotype was evident (delta = - 0.02
      mmol/1 for HDL-C and delta = 0.14 mmol/l for triglycerides, respectively).
      Cumulative analysis of other studies of male carriers of the D9N and N291S
      revealed higher levels of triglycerides (D291N; 2.60(1.85) mmol/l vs. 1.62(1.18)
      mmol/l: p < 0.0001) (D9N; 1.94 (1.19) mmol/l vs. 1.74(1.17) mmol/l: p < 0.001)
      and lower HDL-C (N291S; 1.04(0.32) mmol/l vs. 1.15(0.28) mmol/l: p < 0.0001)
      (D9N; 1.08(0.24) mmol/l vs. 1.16(0.28) mmol/l: p < 0.0001). In females, results
      differed with higher TG levels (N291S; 1.70(0.99) mmol/l vs. 1.10(0.63) mmol/l: p
      < 0.001) (D9N; 1.08(0.76) mmol/l vs. 0.96(0.51) mmol/l: p < 0.01) and lower HDL-C
      levels (N291S; 1.27(0.33) mmol/l vs. 1.51(0.32) mmol/l: p < 0.0001); however, the
      HDL-C levels for D9N carriers were similar to non-carriers (D9N; 1.52(0.29)
      mmol/l vs. 1.53(0.35) mmol/l: p = 0.83). Our data provide evidence that common
      variants of the LPL gene are significant modulators of lipid and lipoprotein
      levels in both men and women.

PMID- 10636450
TI  - Perinatal hypophosphatasia: diagnosis and detection of heterozygote carriers
      within the family.
AB  - We report on two families in which one or two children had a severe disorder of
      skeletal development detected by prenatal ultrasonography. The children died
      postnatally and showed typical radiological and biochemical findings of perinatal
      hypophosphatasia. Biochemical analysis revealed a low activity of alkaline
      phosphatase (AP) and a high value of pyridoxal-5-phosphate (PLP), one of its
      natural substrates. The screening for mutations of the tissue nonspecific
      alkaline phosphatase (TNSALP) gene showed homozygosity for a point mutation (G
      317 --> D) in the two affected children of the first family. The affected child
      of the second family was homozygous for a nonsense mutation (R 411 --> X). Family
      screening revealed that the determination of AP and PLP is helpful for detection
      of heterozygotes. However, heterozygote children had values of AP in the lower
      normal range during phases of rapid growth. The determination of PLP proved to be
      more sensitive in these cases. It should be kept in mind that during the last
      trimester of gestation there is an increase in maternal AP activity and a
      normalization of PLP due to placental AP, which is not affected. Therefore, in
      the course of a prenatal diagnosis in an index case, paternal blood should be
      analyzed in parallel. For detailed genetic counseling and early prenatal
      diagnosis in following pregnancies, the possibility of mutation analysis should
      be used.

PMID- 10636452
TI  - Mexican geneticists' views of ethical issues in genetics testing and screening.
      Are eugenic principles involved?
AB  - Herein we discuss Mexican geneticists' views of ethical issues in genetic testing
      and screening, analyzing whether eugenic principles are involved in this
      activity. The information was obtained from a comprehensive survey on genetics,
      ethics, and society organized by Wertz and Fletcher in 1993, in which 37 nations
      participated. The responses to 21 questions from 64 out of 89 (72%) geneticists
      invited to participate are analyzed in this paper. The questions were practically
      the same as those answered recently by a group of Chinese geneticists (Mao X.
      Chinese geneticists' views of ethical issues in genetic testing and screening:
      evidence for eugenics in China. Am J Hum Genet 1998: 63: 688-695), who work in a
      country where the furtherance of eugenic principles is considered to be the goal
      of human genetics. We concluded that although there are many similarities in the
      answers from both countries, this is not indicative of Mexican geneticists
      pursuing eugenic goals because: a) there is no coercion involved; and b) there is
      no intention of improving the gene pool.

PMID- 10636451
TI  - Three common CFTR mutations should be included in a neonatal screening programme
      for cystic fibrosis in Sweden.
AB  - Children with cystic fibrosis (CF) diagnosed by neonatal screening have a better
      nutritional development and other advantages compared with those in a nonscreened
      group. The two-tier immunoreactive trypsinogen (IRT)/DNA screening protocol has
      been found superior to the single-tier IRT approach, improving the positive
      predictive value and thus reducing the false-positive rate. However, variations
      of the DNA test are required for different populations. In this study we examined
      CFTR (cystic fibrosis transmembrane conductance regulator) mutations in 331 CF
      patients attending the centres in Stockholm, Lund and Uppsala, comprising about
      75% of the CF population in Sweden. The frequency of deltaF508 among CF alleles
      was 68.3%. There were two other mutations, 394delTT and 3659delC, found to be
      fairly frequent, amounting to 8.5 and 7.9%, respectively. Other mutations were
      comparatively rare. A simple and effective method of analysing the three
      mutations from Guthrie cards has been developed. Assuming Hardy-Weinberg
      equilibrium, 90% of our CF patients will be expected to carry at least one
      deltaF508 allele and 97.6% to carry at least one deltaF508, 394delTT or 3659delC
      copy. Including the latter two in a screening programme would thus substantially
      reduce the risk of a false-negative outcome.

PMID- 10636453
TI  - A half cryptic derivative der(18)t(5;18)pat identified by M-FISH and subtelomere
      probes: clinical findings and review of subtelomeric rearrangements.

PMID- 10636454
TI  - Interleukin-4 receptor variant Q576R: ethnic differences and association with
      atopy.

PMID- 10636455
TI  - Venous thromboses of upper limbs are more frequently associated with occult
      cancer as compared with those of lower limbs.
AB  - Three hundred and forty-three consecutive patients with deep vein thrombosis
      (DVT) were investigated for the possible presence of occult or undiagnosed
      cancer, of whom 305 patients had DVT of the lower limbs whereas 38 had DVT of the
      upper limbs. Cancer was diagnosed during a 12-month follow-up in nine patients
      with DVT of the upper limbs (23.7%) and in 34 patients with DVT of the lower
      limbs (11.1%). The difference was statistically significant. Furthermore, it was
      shown that the majority of cancers (seven of nine) in the case of DVT of the
      upper limbs were discovered during the first week of hospital admission. In
      contrast, in the case of DVT of lower limbs, only eight of 34 cancers were
      discovered during the initial investigation. Lung cancer and lymphomas
      represented the majority of cancers associated with upper limb venous thrombosis
      (seven of nine). In the case of DVT of the lower limbs, cancers were
      heterogeneous; however, 12 of 34 were cancers of the colon or prostate.

PMID- 10636456
TI  - Pre-operative plasma levels of soluble fibrin polymers correlate with the
      development of deep vein thrombosis after elective neurosurgery.
AB  - The role of blood tests in identifying patients at high risk for post-operative
      venous thromboembolism is undefined. The aim of this study was to evaluate the
      correlation between pre-operative plasma levels of soluble fibrin polymers (SFP),
      as determined by a recently developed enzyme-linked immunosorbent assay (ELISA)
      assay (TpP), and the incidence of deep vein thrombosis (DVT) after elective
      neurosurgery. Blood samples for SFP assay were withdrawn on the day before
      surgery from 157 consecutive patients undergoing elective neurosurgery for brain
      or spinal tumour. Patients were randomized to subcutaneous enoxaparin (40 mg once
      daily) or placebo given for at least 7 days. All patients wore compression
      stockings. DVT was assessed by bilateral venography, performed on day 8 +/- 1.
      Thirty-four patients (21.7%) were found to have a DVT, proximal in 11 (7%) and
      isolated distal in 23. Patients with and without DVT had a plasma pre-operative
      SFP levels of 6.2 +/- 4.6 and 1.9 +/- 1.5 mg/ml respectively (mean +/- SD) (P <
      0.001). SFP levels in patients with proximal and isolated distal DVT were 7.6 +/-
      5.1 and 5.5 +/- 4.4 microg/ml, respectively (P = 0.22). SFP cut-off levels
      categorized patients into three classes of DVT incidence. The incidence of DVT
      was 7.4% (6 of 81) for SFP levels < 2 microg/ml, 20.4% (11 of 54) for levels
      between 2 and 4.5 microg/ml, and 77.3% (17 of 22) for levels > 4.5 microg/ml (P=
      0.001, Cochran-Mantel-Haenszel test). We conclude that pre-operative SFP levels
      correlate with post-operative DVT in elective neurosurgery patients. Further
      studies are required to define whether pre-operative SFP measurement could be
      useful in patient management.

PMID- 10636457
TI  - Haemostatic parameters related to lipids and adhesion molecules.
AB  - Several components of blood, e.g. lipids, coagulation and fibrinolytic factors,
      are thought to be important risk factors in cardiovascular diseases. The aim of
      this study was to correlate these risk factors and the soluble adhesion proteins,
      soluble P-selection (sP-selectin) and soluble vascular cell adhesion molecule
      (sVCAM-1), in healthy men and women as well as to unravel any effects of smoking.
      One hundred and forty-two fasting men (median age 36 years) including 39 smokers,
      and 124 women (median age 34 years) including 35 smokers, were tested between
      0800 h and 1000 h. Fibrinogen correlated positively with white blood cells (WBC)
      (r = 0.25), prothrombin fragment 1.2 (F1.2) (r = 0.21), cholesterol (r = 0.27),
      beta-thromboglobulin (r = 0.29), Factor VII clotting activity (FVIIc) (r = 0.27)
      (all P < 0.0001), tissue plasminogen activator antigen (t-PAag) (r = 0.22, P <
      0.0005), plasminogen activator inhibitor-1 antigen (PAI-1ag) (r= 0.20) and VCAM-1
      (r= 0.19) (both P< 0.002). Cholesterol and triacylglycerol (TG) correlated
      positively with t-PA antigen (t-PAag) (r = 0.36 and r = 0.38), PAI-1 antigen (PAI
      1ag) (r = 0.35 and r = 0.50), P-selectin (r = 0.26 and r = 0.27) (all P < 0.0001)
      and WBC (r = 0.17, P < 0.007 and r = 0.18, P < 0.004). Cholesterol correlated
      also with F1.2 (r = 0.29) and TG (r= 0.44) (P< 0.0001). In addition to
      cholesterol and TG, sP-selectin correlated postively with PAI-1ag (r= 0.39), t
      PAag (r= 0.27) and WBC (r = 0.25) (all P < 0.0001). Comparing the various test
      parameters in men and women, it was found that women had significantly higher
      levels of F 1.2 and high-density lipoprotein-cholesterol than men, whereas men
      had higher levels of t-PAag, PAI-lag and P-selectin than women. Smoking was
      associated with a rise in several of the test parameters. It can be concluded
      that there are correlations between several risk factors. Of particular interest
      is the positive correlation between sP-selectin and a number of established risk
      factors of cardiovascular diseases.

PMID- 10636458
TI  - A protease isolated from human plasma activating factor VII independent of tissue
      factor.
AB  - An activity detected in a prothrombin complex concentrate, termed 'thrombin-like'
      due to its amidolytic properties, was recently reported by another working group.
      This serine-protease revealed partial structural homology with a 'hepatocyte
      growth factor activator'. An impact of this protease on coagulation has not yet
      been described. The protease was isolated from plasma fractions by ion exchange
      chromatography and adsorption to immobilized heparin and/or aprotinin. Clotting
      tests including the FVIIa-rTF assay were performed employing coagulometry. A
      monoclonal antibody-derived F(ab')2 to FVIII was used to investigate the FVIII
      bypassing activity (FEIBA). The identity of the-protease with the so-called
      'thrombin-like' protease was supported by sequencing of the amino-termini. Its
      amidolytic activity was significantly enhanced in the presence of calcium and/or
      heparin. Incubation with purified FVII revealed the generation of FVIIa, but was
      prevented by pre-incubation of the protease with aprotinin. In contrast, purified
      FV and FVIII were inactivated. Studying coagulation parameters, clotting times
      like plasma recalcification times and the prothrombin times were found to be
      shortened by addition of the protease. Employing a FVIII-inhibitory F(ab')2 and
      enhancing clotting times significantly, FEIBA of the protease was found. We
      demonstrated that the isolated protease activates FVII independent of tissue
      factor. Net acceleration of coagulation was found in several global clotting
      assays resulting in an in vitro FEIBA. The physiological relevance of these
      findings deserves further investigation.

PMID- 10636459
TI  - Relationship between thyroid hormones and fibrinogen levels.
AB  - Hypothyroid patients may have several haemostatic abnormalities such as
      modification of the coagulation proteins and a bleeding tendency. However,
      conflicting data have been reported, although in some reports, the groups of
      patients studied were small. We previously reported in a large population that
      plasma D-dimers and free thyroxine (FT4) levels were inversely correlated. Since
      D-dimers are also associated with fibrinogen levels, we analysed the relationship
      between fibrinogen and FT4 levels. The population consisted of 959 patients (61%
      men and 39% women), 28% of whom were current smokers. We showed that fibrinogen
      and FT4 levels were inversely correlated (r = -0.12, P = 0.0001) in the overall
      population, in the non-smoker subgroup (r = -0.13, P = 0.0007) and in the
      subgroup of patients with strictly normal FT4 levels (r = -0.11, P = 0.0006). The
      relationship between FT4 and fibrinogen levels was independent of age, sex and
      smoking habits. Furthermore, there was a significant difference between the mean
      fibrinogen levels in the patients in the lowest FT4 subgroup and those in the
      highest FT4 subgroup, which was similar to the difference previously observed in
      patients with or without evidence of atherosclerotic disease in epidemiological
      studies. In conclusion, we found a negative and independent relationship between
      fibrinogen and FT4. These results are consistent with our previous findings of a
      tendency to a more coagulable state in patients with normal-low FT4 levels
      compared with those with normal-high FT4 levels.

PMID- 10636460
TI  - Specific determination of plasmin inhibitor activity in plasma: documentation of
      specificity of manual and automated procedures.
AB  - Recently, a chromogenic kit for determination of plasmin inhibitor activity,
      Coamatic Plasmin Inhibitor, has been developed with the aim to increase
      specificity and to allow application to a wide range of automates. The highly
      sensitive plasmin substrate S-2403 is used and, to further improve specificity, a
      low level of plasmin and a short incubation time is utilized as well as the
      incorporation of methylamine to quench alpha2-macroglobulin activity. The
      Coamatic Plasmin Inhibitor kit has been evaluated regarding specificity and
      compared with six commercially available plasmin inhibitor (also denoted alpha2
      antiplasmin) kits and with the manual Immediate Plasmin Inhibition Test (IPIT)
      method, the reference method within the framework of the European Concerted
      Action against Thrombosis and Disabilities. Analysis of plasmin inhibitor
      deficient plasma with Coamatic Plasmin Inhibitor resulted in activities below 5%
      for all instrument applications, whereas all other commercial kits displayed
      unexpectedly higher values for this plasma (16-35%). There was a good agreement
      between the Coamatic Plasmin Inhibitor method and the IPIT method for all tested
      instrument applications; slope =0.80-1.02 and r = 0.92-0.97. No interference was
      detected from alpha2-macroglobulin, lysine, unfractionated and low-molecular
      weight heparin, and epsilon-amino caproic acid or from the non-plasminogen
      binding form of plasmin inhibitor.

PMID- 10636461
TI  - Inactivation of factor Xa by the synthetic inhibitor DX-9065a causes strong
      anticoagulant and antiplatelet actions in human blood.
AB  - In an in vitro study, anticoagulant and antiplatelet effects of the synthetic,
      direct factor Xa inhibitor DX-9065a, (+)-2S-2-[4-[[(3S)-1-acetimidoyl-3
      pyrrolidinyl]oxy]phenyl]-3-[7-a midino-2-naphthyl]propanoic acid hydrochloride
      pentahydrate, which shows a high affinity and selectivity towards the enzyme,
      were investigated. Anticoagulant actions of DX-9065a were studied in human plasma
      using global clotting assays [prothrombin time (PT), activated partial
      thromboplastin time (APTT), thrombin time (TT) and Heptest]. The effect on
      thrombin generation was measured in whole blood by determining the plasma
      concentration of prothrombin fragment F1.2. The influence on agonist-induced
      platelet activation in whole blood was studied using flow cytometric analysis. DX
      9065a caused a concentration-dependent prolongation of clotting times in the PT
      and APTT assay, whereas Heptest was less affected and TT was not influenced.
      Furthermore, DX-9065a strongly inhibited the generation of thrombin without and
      after coagulation activation. The factor Xa inhibitor did not affect platelet
      activation mediated by either thrombin receptor activating peptide, arachidonic
      acid or y-thrombin, but prevented tissue factor- and factor Xa-induced activation
      of platelets in a concentration-dependent manner. Inactivation of factor Xa by a
      highly effective and selective inhibitor, and the resulting inhibition of
      thrombin generation leads to strong anticoagulant and antiplatelet actions. The
      interference with the coagulation system at the early level of factor Xa is
      expected to be an effective approach for a successful
      anticoagulant/antithrombotic therapy.

PMID- 10636462
TI  - ATIII-independence of anticoagulant effect of human urinary soluble
      thrombomodulin.
AB  - We investigated antithrombin III (ATIII)-dependency of the anticoagulant effects
      of human urinary soluble thrombomodulin (UTM) both in vivo and in vitro, in
      comparison with those of heparins. For neutralization of rat plasma ATIII
      activity, we used F(ab')2 fragment of anti-rat ATIII antibody and could establish
      an appropriate in vivo model to evaluate the ATIII-dependency of antithrombotic
      agents. The efficacy of UTM on thromboplastin-induced disseminated intravascular
      coagulation produced in ATIII-decreased rats was almost the same as that in
      normal rats, whereas unfractionated (UF)-heparin remarkably diminished its effect
      in ATIII-decreased rats. The prolongation effect of UTM on activated partial
      thromboplastin time or prothrombin time in plasma in vitro was unchanged in both
      normal and ATIII-decreased rats, but the effect of UF-heparin remarkably
      diminished in ATIII-decreased rat plasma. Such ATIII-independence in the
      anticoagulant effect of UTM was also observed in human plasma. Thus, differing
      from heparins, since the anticoagulant effect of UTM does not depend on plasma
      ATIII activity, UTM is expected to be a useful antithrombotic agent for the
      treatment of thromboembolic diseases, even in the case with low plasma ATIII
      activity.

PMID- 10636463
TI  - Effects of sarpogrelate hydrochloride on platelet aggregation, and its relation
      to the release of serotonin and P-selectin.
AB  - Inhibitory effects of sarpogrelate hydrochloride (sarpogrelate), a 5-HT2 receptor
      antagonist, on platelet aggregation was examined as well as the relationship to
      serotonin and P-selectin, a platelet alpha-granule membrane glycoprotein.
      Platelet aggregation was induced by simultaneous addition of collagen (0.06-0.12
      microg/ml), which did not induce aggregation alone, and serotonin (0.88
      micromol/1) to platelet-rich plasma (PRP). The PRP was obtained from healthy
      volunteers and percentage maximum aggregation (MA) was measured. Serotonin levels
      and P-selectin levels in the supernatant of PRP after aggregation were
      determined. When vehicle-treated PRP was stimulated in the aforementioned manner,
      platelet aggregation dependent on collagen concentration was induced. Serotonin
      levels and P-selectin levels were also dependent on collagen concentration.
      Sarpogrelate (10(-6) to 10(-4) mol/l) inhibited such aggregation dose
      dependently, and decreased serotonin levels and P-selectin levels in a dose
      dependent manner. There were close correlations between MA and serotonin levels,
      MA and P-selectin levels, as well as serotonin and P-selectin levels. These
      results suggest that extracellular release of serotonin and P-selectin from
      platelets was caused by induction of aggregation, and these responses were
      suppressed by sarpogrelate.

PMID- 10636464
TI  - Small doses of recombinant factor VIIa in acquired deficiencies of vitamin K
      dependent factors.

PMID- 10636465
TI  - Prothrombin 20210A and familial thrombophilia.

PMID- 10636466
TI  - Expression of superoxide dismutase messenger RNA in adult rat brain cholinergic
      neurons.
AB  - Superoxide dismutase (SOD) protects cells exposed to an excess of the free
      radical nitric oxide, by preventing the formation of peroxynitrite. Certain
      central cholinergic neurons express constitutive nitric oxide synthase (nNOS),
      and presumably they are at risk from peroxynitrite intoxication.
      Immunocytochemistry for choline acetyltransferase (ChAT) was combined with in
      situ hybridization histochemistry (ISHH) to examine whether brain cholinergic
      populations differ with respect to their expression of the messenger RNA
      molecules (mRNAs) for the manganese-dependent (Mn-SOD) and copper/zinc-dependent
      superoxide dismutases (Cu /Zn-SOD). The cholinergic neurons located in the
      reticular formation of the upper brainstem (the laterodorsal tegmental nucleus
      [LDTN] and the pedunculopontine nucleus [PPN]) were found to express relatively
      high levels of Mn-SOD mRNA, whereas cholinergic neurons located in the basal
      forebrain (substantia innominata [SI], diagonal band [DB], medial septum [MS],
      and the nucleus basalis magnocellularis [nBM]), and the striatal cholinergic
      interneurons expressed low to intermediate levels of Mn-SOD mRNA. The rank order
      of median Mn-SOD mRNA density per cholinergic cell was LDTN > PPN > SI > striatum
      = nBM = DB > MS. This is similar to the rank order of nNOS mRNA densities in the
      cholinergic cells in these regions (R = 0.9, p < 0.02). The rank order of Cu/Zn
      SOD mRNA levels in cholinergic populations (DB > LDTN = PPN =MS > SI = nBM =
      striatum) was not correlated with nNOS mRNA (R = 0.29, P > 0.05). Thus, for
      cholinergic neurons, Mn-SOD may be important for protection from NO-related
      oxidative stress.

PMID- 10636467
TI  - Characterization of the chicken transitin gene reveals a strong relationship to
      the nestin intermediate filament class.
AB  - Our laboratory previously reported that transitin is a radial glial intermediate
      filament protein sharing the basic structural features common to all intermediate
      filament (IF) proteins. It contains an alpha-helical core domain flanked by a
      short nonhelical head and a long COOH-terminal tail. The core sequence of
      transitin shows the greatest similarity to Xenopus tanabin and to rat and human
      nestin. We also reported that transitin has multiple splice variants derived from
      the deletion or inclusion of a leucine-zipper heptad repeat domain in the COOH
      terminal tail. In the present study, we provide new evidence to support the
      classification of nestin and transitin in the same group of IF proteins based on
      the number and position of its introns. In addition, we suggest that the
      different isoforms of transitin are produced by a splicing mechanism that
      recognizes consensus 5' and 3' splice sites contained within the coding sequence
      of the leucine-zipper heptad repeat domain.

PMID- 10636468
TI  - Identification of amino-terminal sequences contributing to tryptophan hydroxylase
      tetramer formation.
AB  - Tryptophan hydroxylase (TPH) catalyzes the rate-limiting step in the biosynthesis
      of serotonin. In the rabbit, TPH exists as a tetramer of four identical 51-kDa
      subunits comprised of 444 amino acids each. The enzyme consists of an amino
      terminal regulatory domain and a carboxyl-terminal catalytic domain. Previous
      studies demonstrated that within the carboxyl-terminus of TPH, there resides an
      intersubunit binding domain (a leucine zipper) that is essential for tetramer
      formation. However, it is hypothesized that a 4,3-hydrophobic repeat identified
      within the regulatory domain of TPH (residues 21-41) may also be involved in
      macromolecular assembly. To test this hypothesis, a series of amino-terminal
      deletions (Ndelta15, 30, 41, and 90) were created and assessed for macromolecular
      structure using size-exclusion chromatography. The amino-terminal deletion
      Ndelta15, upstream from the 4,3-hydrophobic repeat, was capable of forming
      tetramers. However, when a portion of the 4,3-hydrophobic repeat was deleted
      (Ndelta30), a heterogeneous elution pattern of tetramers, dimers, and monomers
      was observed. Complete removal of the 4,3-hydrophobic repeat (Ndelta41) rendered
      the enzyme incapable of forming tetramers; a monomeric form predominated. In
      addition, a double-point mutation (V28R-L31R) was created in the hydrophobic
      region of the enzyme. The introduction of two arginines (R) at positions 28 and
      31 respectively, in the helix disrupted the native tetrameric state of TPH.
      According to size-exclusion chromatography analysis, the double-point mutant
      (V28R-L31R) formed dimers of 127 kDa. Thus, it is concluded that there is
      information within the amino-terminus that is necessary for tetramer formation of
      TPH. This additional intersubunit binding domain in the amino-terminus is similar
      to that found in the carboxyl-terminus.

PMID- 10636469
TI  - PhosphoCREB and CREM/ICER: positive and negative regulation of proenkephalin gene
      expression in the paraventricular nucleus of the hypothalamus.
AB  - In the hypothalamic paraventricular nucleus (PVN), the proenkephalin gene may be
      upregulated by lipopolysaccharide (LPS) and downregulated by the GABA-A agonist
      muscimol. Candidate transcription factors regulating the proenkephalin gene in
      opposite directions are cAMP-response-element-binding protein (CREB) (when
      phosphorylated, a positive regulator) and cAMP-responsive modulatory inducible
      cAMP early repressor (CREM/ICER) (a negative regulator). Our results demonstrate
      that CREM alpha,beta,gamma transcripts and ICER are induced in the PVN by LPS and
      remain elevated for periods of up to 12 h. PhosphoCREB is elevated after LPS
      administration, peaking at 8 h, but remaining elevated over control levels at 12
      h. Phospho-CREB induction by LPS is also seen in primary hypothalamic cultures.
      Cotransfection of ICER with ENK-CAT12 into primary hypothalamic cultures produced
      a decrease in chloramphenicol acetyl transferase (CAT) levels following cAMP or
      LPS stimulation. PhosphoCREB is downregulated and CREM/ICER is upregulated in the
      PVN by muscimol, suggesting that the regulation of these transcription factors
      may underlie the inhibitory effect of muscimol on target genes in the PVN.

PMID- 10636470
TI  - Neural regulation of phenylethanolamine N-methyltransferase (PNMT) gene
      expression in bovine chromaffin cells differs from other catecholamine enzyme
      genes.
AB  - Expression of the gene encoding the epinephrine-synthesizing enzyme
      phenylethanolamine N-methyltransferase (PNMT) is regulated by hormonal and neural
      stimuli. Because the 5'-upstream regions of the PNMT do not contain sequences
      analogous to those demonstrated to convey neural regulation to the tyrosine
      hydroxylase (TH) and dopamine beta-hydroxylase (DBH) catecholamine-synthesizing
      enzyme genes, functional and biochemical analyses have been utilized to
      characterize PNMT promoter responses to cholinergic and depolarizing agents. In
      primary cultures of bovine adrenal medullary chromaffin cells, reporter gene
      expression from transiently transfected 3- and 0.9-kb-containing PNMT promoter
      constructs is stimulated approximately twofold by nicotine and muscarine.
      Depolarizing concentrations of K+ produce fourfold increases in expression. These
      responses are not detected with constructs containing the proximal 0.3-kb
      promoter, indicating that the regions between -273 and -877 bp convey neural
      responsiveness for the PNMT gene in bovine chromaffin cells. Electrophoretic
      mobility shift assays (EMSAs) with oligonucleotides encoding these regions of the
      PNMT promoter revealed distinctions in migration of nuclear protein complexes
      formed following treatment of chromaffin cells with nicotine, muscarine, or 50 mM
      K+. Thus, the PNMT promoter between 0.3 and 0.9 kb contains sequences capable of
      responding to cholinergic and depolarization stimuli. Moreover, these treatments
      influence the interactions of specific nuclear proteins with this region of the
      PNMT promoter.

PMID- 10636472
TI  - Melatonin administered in the afternoon decreases next-day luteinizing hormone
      levels in men: lack of antagonism by flumazenil.
AB  - The role of melatonin in the regulation of human reproduction remains unclear. In
      the present study, we examined the influence of exogenous melatonin on pulsatile
      luteinizing hormone (LH), diurnal rhythm of testosterone, and endogenous
      melatonin profile in six healthy young adult males. To test the hypothesis that
      the effect of melatonin on LH or testosterone secretory patterns may be mediated
      through the benzodiazepine-(BNZ) gamma-amino-butyric acid (GABA) receptor
      complex, a benzodiazepine receptor antagonist (Flumazenil) was administered. The
      study design comprised four 10-h (4:00 PM-2:00 AM) testing periods. During each
      experimental period, subjects were given an oral dose of placebo, or 3 mg
      melatonin or 10 mg flumazenil, at 5:00 PM, in a randomized, double-blind,
      partially repeated Latin square design in the following combinations: placebo
      placebo, placebo-melatonin, flumazenil-placebo, and flumazenil-melatonin. The
      following day, serum samples were obtained every 20 min between 4:00 PM and 2:00
      AM in a controlled light-dark environment for the determination of LH and
      melatonin levels. Serum testosterone concentrations were determined every 20 min
      between 7:00 and 8:00 AM and 7:00 and 8:00 PM. A significant decrease in mean
      serum LH levels (p < 0.02) was observed in the melatonin-treated groups as
      compared with placebo-flumazenil groups. There was no change in LH pulse
      frequency, testosterone levels, or in melatonin onset time and amplitude. No
      additional effect of flumazenil on LH or testosterone levels was observed. These
      data indicate that an evening melatonin administration decreases the next-day LH
      secretion in normal adult males without altering testosterone levels or the
      endogenous nocturnal melatonin secretory pattern. This effect of melatonin is not
      mediated through the benzodiazepine-GABA receptor complex.

PMID- 10636471
TI  - Inhibition of the NGF and IL-1beta-induced expression of Alzheimer's amyloid
      precursor protein by antisense oligonucleotides.
AB  - Alzheimer's disease (AD) is a neurodegenerative disorder of the brain
      characterized by the extracellular deposition of amyloid in senile plaques and
      along the walls of the cerebral vasculature. The principal constituent of amyloid
      deposit is amyloid beta peptide (Abeta) derived from its larger precursor
      protein, amyloid precursor protein (APP). The overexpression of APP is known to
      be a risk factor for Abeta deposit in AD and in Down syndrome (DS). The
      inhibition of APP expression has been thought to be beneficial to patients with
      AD and DS. In this study, we investigated the effects of antisense
      oligonucleotide (AO) on the overexpression of APP induced by IL-1beta and NGF.
      Using phosphorothioate-oligonucleotides against initiation codon significantly
      reduced the protein levels of APP induced by NGF and IL-1beta to basal level in
      PC12 cell culture systems. These results showed that these antisense
      oligonucleotides may have a potential to be a therapeutic agent for some patients
      with AD and DS.

PMID- 10636473
TI  - Identification of thymus specific and developmentally regulated genes by an
      improved version of the mRNA differential display technique.
AB  - During embryogenesis in mouse, the thymus is seeded by waves of hematopoietic
      stem cells that provide the first peripheral T lymphocytes after birth. It is
      known that embryo thymocytes and adult thymocytes have different phenotypic and
      functional features. The identification of genes expressed in the thymus only
      during embryogenesis would help to understand the molecular basis underlying
      these characteristics. We used the mRNA differential display technique to compare
      gene expression between thymus and kidney from embryo (171/2 days) and adult
      mice. This technique is the method of choice for comparing gene expression
      because it is able to display rapidly and simultaneously the mRNA complement from
      several different types of cells. The major drawback of the method is that it
      leads to the cloning of many false positives and therefore needs a high
      throughput method to screen for the truly differentially expressed cDNAs. We
      combined advantages from previously described methods in order to develop a new
      version of the mRNA differential display technique that is fast, cheap, and
      reliable. Instead of oligo dT priming, we used random hexameres for the reverse
      transcription of total RNA and 10-mer primers for the amplification of internal
      parts of the cDNAs. We obtained reproducible and clean patterns of discrete
      bands. We were able to easily identify DNAs differentially amplified between
      embryo and adult tissues (embryo specific; E 58.73), between thymus and kidney
      (thymus specific; Thy 52.54), or between embryo and adult thymus (embryo thymus
      specific; E Thy 58.73) cDNA fragments. After reamplification, cloning, and
      sequencing of these DNA fragments, it appeared that in most cases, one band
      corresponded to a single DNA sequence. On a northern blot, each of these
      candidate genes recognized a transcript that is differentially expressed as
      expected. Thus, we report an optimized, reproducible, and fast mRNA differential
      display method that overcomes the usual problems met with the originally
      described technique or its reported modifications.

PMID- 10636474
TI  - A developmental bias in reading frame usage by human fetal thymic TCRBDJ
      transcripts is not present in genomic TCRBDJ rearrangements.
AB  - We have previously reported that reading-frame usage and functional
      diversification is developmentally regulated, with virtually all TCRB DJ mRNA
      transcripts using a single reading frame at 8 weeks of gestational age, tapering
      to 50% by adult life. We used the polymerase chain reaction to create genomic
      libraries of DJ rearrangements in the TCRB locus from thymuses at 7.7, 10, and 16
      weeks of gestational age, and from adult thymuses. Clones were randomly picked
      and sequenced to determine junctional sequences and reading-frame utilization.
      The resulting data address the hypothesis that cells bearing genomic joints in
      reading frame one are preferentially selected during fetal life. This hypothesis
      predicts that reading-frame bias would also be observed among genomic DJ joints.
      Instead, we observed random utilization of the three possible D-region reading
      frames among genomic D1s1 ==> J1s1 joints during fetal life. Similar results were
      obtained at 7.7 weeks of gestational age in a second thymus in which both RNA and
      DNA were simultaneously isolated and used to create libraries of TCRBDJ
      transcripts or rearrangements. We conclude that reading-frame utilization is
      random among genomic D1s1-JB1s1 rearrangements and that the preferential usage of
      a single reading frame among mRNA transcripts of TCRB DJ transcripts is the
      result of preferential transcription of genomic TCRB DJ joints in a single
      reading frame, or that TCRB DJ transcripts have a longer half-life than
      transcripts in reading frames two or three.

PMID- 10636475
TI  - Effects of the Japanese herbal medicine "Sho-saiko-to" (TJ-9) on interleukin-12
      production in patients with HCV-positive liver cirrhosis.
AB  - Interleukin-12 (IL-12) is an important cytokine for maintenance of normal
      systemic defense and bioregulation. The Japanese herbal medicine Sho-saiko-to (TJ
      9) has been administered to 1.5 million Japanese patients with chronic liver
      diseases. TJ-9 is known to significantly suppress cancer development in the liver
      and has macrobiotic effects. In the present study, we examined the in vitro
      production of IL-12 by circulating mononuclear cells from liver cirrhosis
      patients and the effects of TJ-9 on IL-12 production. The monocyte/macrophage
      fraction and the lymphocyte fraction of peripheral blood were obtained from 11
      HCV-positive liver cirrhosis patients and 12 healthy subjects. Interleukin-12
      levels in the supernatants were measured using ELISA kits. The levels of IL-12
      produced by the patients' fractions were significantly lower than those produced
      by healthy subjects (p < 0.01, p < 0.05). However, when TJ-9 was added to the
      cultures, the IL-12 production levels in both cell fractions increased
      approximately three fold, and the levels from the monocyte/macrophage fraction
      were almost the same as those from healthy subjects. This effect of TJ-9 was
      attributable to two of its seven herb components, that is, scutellaria root and
      glycyrrhiza root. One possible mechanism for the macrobiotic effects of TJ-9 on
      liver cirrhosis patients may be the improvement in IL-12 production.

PMID- 10636476
TI  - Immune response to "self" lens in Xenopus laevis enucleated during larval life.
AB  - We have reinvestigated an important issue in the amphibian immunology that has
      not been settled for years since the pioneer work of Triplett, concerning the
      necessity of being exposed to organ-specific antigens early in development. It
      was found that syngeneic Lenses were rejected by frogs, Xenopus laevis, that had
      been enucleated (eye removed) during early larval life. This rejection did not
      occur in intact frogs or in those enucleated in later larval or adult life.
      Whereas the splenocytes from intact frogs did not proliferate in response to a co
      cultured syngeneic lens, those from frogs that had been enucleated at any of the
      larval stages, or even after metamorphosis, proliferated intensely. Both of these
      responses were shown to be thymus-dependent. In conclusion, it was demonstrated
      that the frog immune system rejected even syngeneic lenses by enucleation in
      early larval life and that it began to recognize the syngeneic lenses by lymphoid
      proliferation after enucleation, even in later life.

PMID- 10636477
TI  - Uterine cytokine production during the menstrual cycle and preimplantation stages
      in mice.
AB  - Female reproduction is the only system subjected to well defined periodic
      changes. The final stage of the menstrual cycle in mammals is the maturation of
      the ovum and the preparation of the female organism to support fetal development
      fertilization. Once pregnancy occurs, both maternal and fetal sites emit
      regulatory signals to ensure embryo development and maternal protection against a
      graft versus host (GvH) reaction initiated by the semi-allogeneic fetus. We and
      others have previously shown that each day of fetal development in mice is
      characterized by different cytokine production, detected not only at the
      proximity of the feto-placental unit (decidua, uterus), but also in maternal
      lymphoid organs (spleen), as well as in the serum. In the present study, we
      concentrated on the menstrual cycle and the preimplantation stages of pregnancy
      and defined the levels of GM-CSF, IL-10, IL-6, and IL-3 in the murine uterus
      during anoestrus, proestrus, oestrus, and second and third day of gestation. We
      show by immunofluorescence and ELISA techniques that GM-CSF is maintained at high
      levels during anoestrus, proestus, oestrus, and the second day of pregnancy while
      dropping on the third day. IL-3 levels are found elevated during proestrus,
      second and third day of gestation, IL-6 increases essentially during proestrus,
      whereas the production of IL-10 was detected during oestrus and the early stages
      of pregnancy. Immunoperoxidase staining on frozen sections of uteri during the
      early gestational period localize GM-CSF and IL-3 production in the endometrium,
      IL-10 in the endometrium on the second day of pregnancy, and
      endometrium/myometrium on the third day. Low levels of IL-6 could be detected in
      the endometrium/epithelium on the second day and endometrium/myometrium on the
      third day of gestation. The role of IL-3, IL-10, and, to a lesser degree, IL-6 is
      fortified by the embryo itself, since these cytokines were found to be produced
      by blastocysts as well. These results demonstrate the existence of a specific
      distribution of lymphokines within the uterine tissue, the role of which is being
      discussed.

PMID- 10636478
TI  - A mouse with a monoclonal primary immunoglobulin repertoire not further
      diversified by V-gene replacement.
AB  - We have generated a monoclonal B-cell mouse by introducing homozygous,
      nonfunctional RAG-2 alleles and a lambda1 light-chain transgene into the quasi
      monoclonal (QM) mouse, which contains a "knocked-in" V(H)DJ(H) rearrangement.
      Thus, this mouse, which we call MonoB, is devoid of T cells and contains
      preformed heavy- and light-chain genes encoding immunoglobulin with an anti-NP
      specificity. The MonoB mouse allows us to examine immunoglobulin diversity in the
      absence of processes mediated by V(D)J recombination and T cells. Here we report
      that not only is the MonoB's primary immunoglobulin repertoire monoclonal, but
      also that its secondary repertoire is not further diversified by V-gene
      replacement or gene conversion. Among 99 heavy-chain and 41 lambda light-chain
      genes from peripheral B cells of the MonoB mouse, there were no V-gene
      replacements. When compared to the QM mouse, which has RAG activity, and for
      which V-gene replacement is the major diversifying mechanism, these data suggest
      that V-gene replacement is mediated by V(D)J recombination and not by other
      recombination systems.

PMID- 10636479
TI  - Dopamine, a neurotransmitter, influences the immune system.
AB  - Dopamine (DA) is a monoamine neurotransmitter of both central and peripheral
      nervous system. Its role in the neural-immune communication has been discussed in
      the present review. Results reveal that in vivo damage or stimulation of specific
      central dopaminergic system suppresses or enhances functional activities of the
      immune effector cells. The possible influences of other immunomodulators of the
      brain by altering brain DA may be the underlying mechanism. Direct effects of DA
      on the immune effector cells are also contradictory, it is suppressive in vitro,
      while in pharmacological doses, it is mostly stimulatory in vivo. The possible
      mechanisms have been discussed. Lastly, future areas of relevance on DA and
      immunity have been highlighted to advance our knowledge regarding DA as an immune
      regulator.

PMID- 10636480
TI  - Human immunodeficiency virus type-1 Nef protein induces blood-brain barrier
      disruption in the rat: role of matrix metalloproteinase-9.
AB  - We recently showed that MMP-9 activity was detectable in the cerebrospinal fluid
      (CSF) of about half of neurologically symptomatic HIV-infected patients. Using an
      experimental animal model, we detected MMP-9 activity in CSF samples from rats
      that had been injected intracisternally with recombinant HIV-1 Nef protein, but
      not after injection of heat-treated Nef, gp120, gp160 or PBS. Nef also induced a
      breaching of the blood-brain barrier (BBB), which could be inhibited by
      pretreatment with the matrix metalloproteinase (MMP) inhibitor batimastat. In
      vitro Nef only slightly induced MMP-9 activity in freshly isolated human
      peripheral blood mononuclear cells and in the murine macrophage cell line RAW
      264.7, but not in endothelial, neuronal or astroglial cell lines. Taken together,
      our findings indicate that HIV-1 Nef protein can induce BBB disruption in the rat
      - presumably via MMP induction.

PMID- 10636481
TI  - Superantigen presenting capacity of human astrocytes.
AB  - We found that human fetal astrocytes (HFA) are able to support superantigen (SAG)
      staphylococcal enterotoxin B (SEB) and toxic shock syndrome toxin-1 (TSST-1)
      induced activation of immediately ex vivo allogenic human CD4 T cells. Using
      radiolabelled toxins, we demonstrate that both SEB and TSST-1 bind with high
      affinity to MHC class II antigen expressing astrocytes; binding is displaceable
      with excess cold toxin. Competition experiments further indicate that TSST-1 and
      SEB at least partially compete with each other for binding to astrocytes
      suggesting they bind to the same HLA-DR region on these cells. Our study supports
      the hypothesis that SAG would be capable of stimulating immune responses within
      the human CNS and contribute to persistence or recurrence of inflammatory
      responses within this compartment.

PMID- 10636483
TI  - Immune deviation following stress odor exposure: role of endogenous opioids.
AB  - Olfactory cues can alter immune function. BALB/c mice exposed to odors produced
      by footshock stressed donor mice have increased antibody responses and increased
      splenic interleukin (IL)-4 production following immunization relative to
      recipients of odors from unstressed animals. Here we document that exposure to
      stress odors results in analgesia that is blocked by the non-selective opioid
      receptor antagonist naltrexone. The stress odor-induced increase in antigen
      driven IL-4 and antibody is also blocked by oral administration of naltrexone.
      Thus, we provide evidence that immune deviation can occur following a
      psychosocial stressor, and that the deviation appears to be mediated by
      endogenous opioid production.

PMID- 10636482
TI  - Leukocyte adhesion molecule expression and T cell naive/memory status following
      isoproterenol infusion.
AB  - This study examined adhesion molecules on peripheral leukocytes following a 30
      min infusion of the beta-adrenergic agonist isoproterenol in 23 healthy subjects.
      In response to isoproterenol, the number of CD8 +CD62L- T cells and both CD62L+
      and CD62L-natural killer (NK) (CD3 CD16+ 56+) cells increased markedly in
      circulation (p < 0.001). In addition, the surface density of CD62L was
      significantly lower on both CD8+ and CD4+ T cells (p < 0.001). Plasma levels of
      soluble CD62L remained unchanged, arguing against an isoproterenol-induced
      shedding of L-selectin. In contrast to CD62L, the surface density of the beta2
      integrin LFA-1 (CD11a) was higher on circulating lymphocytes (p < 0.001) (but not
      monocytes or lymphocytes) post-infusion. Isoproterenol also led to a mobilization
      of memory/activated CD8+CD29high T cells (p < 0.01), but had no significant
      effect on the number of circulating CD8+ CD45RA+ CD62L+ naive T cells. beta
      blockade with the non-specific antagonist propranolol eliminated these
      isoproterenol-induced effects.

PMID- 10636484
TI  - Astrocytes modulate macrophage phagocytosis of myelin in vitro.
AB  - Previous work from this laboratory has shown that both macrophages and microglia
      phagocytize relatively little myelin in vitro under basal conditions. In an
      effort to better simulate the conditions within the central nervous system (CNS),
      we have co-cultured these cells with astrocytes, the most numerous of the neural
      cells in the CNS, and have compared myelin phagocytosis in the co-cultures with
      that in cells cultured alone. Both macrophages and microglia in company with
      astrocytes phagocytized about three times as much myelin as controls, as measured
      by the formation of cholesterol ester, while astrocytes alone showed little
      evidence of myelin phagocytosis. Astrocyte-conditioned medium increased
      phagocytic activity in macrophages by 2.3-fold, and by 3.5-fold in microglia. A
      number of adhesion molecules and extracellular matrices were tested for their
      effects on myelin phagocytosis. Matrigel was most effective in activating the
      macrophages, and in the presence of conditioned medium, stimulated these cells to
      phagocytize as much myelin as when co-cultured with astrocytes. On the other
      hand, Matrigel inhibited myelin phagocytosis in microglia. These results indicate
      that activation of macrophages by astrocytes may be due to an adhesion component,
      as well as to soluble factors secreted by the astrocytes. While microglia were
      also stimulated by conditioned medium, adhesion to astrocytes or Matrigel induced
      a downregulation in phagocytic activity.

PMID- 10636485
TI  - Substance P activates NF-kappaB independent of elevations in intracellular
      calcium in murine macrophages and dendritic cells.
AB  - Professional antigen presenting cells, such as macrophages, can be activated by
      intracellular calcium-dependent as well as calcium-independent mechanisms,
      depending upon the stimulus used. In this report, we addressed the mechanism of
      substance P-induced intracellular signalling in murine macrophages and dendritic
      cells. While no increases in intracellular calcium concentration were detected in
      macrophages or dendritic cells using sensitive fluorimetric techniques, substance
      P did induce rapid enhanced activation of NF-kappaB, a transcriptional activator
      known to regulate pro-inflammatory cytokines. These data provide an important
      mechanism by which substance P may augment the production of pro-inflammatory
      molecules.

PMID- 10636486
TI  - Induction of inflammatory cytokines in the brain following respiratory infection
      with Bordetella pertussis.
AB  - Parenteral injection of endotoxin has been used as a model to examine the role of
      pro-inflammatory cytokines in the centrally controlled responses to Gram-negative
      bacterial infection. However, the events that occur following mucosal exposure to
      live bacteria have received little attention. In this study, we have used a
      murine model to demonstrate that respiratory infection with Bordetella pertussis,
      which is associated with a number of systemic complications including fever,
      seizure and encephalopathy in children, resulted in persistent expression of mRNA
      transcripts for IL-1beta and TNFalpha and transient expression of IL-6 in the
      hippocampus and hypothalamus. These changes correlated with elevated levels of
      cytokine protein in the same brain areas. The results demonstrate that infection
      at a mucosal surface can result in the induction of pro-inflammatory cytokine
      production in the brain and suggest that these locally synthesized mediators may
      contribute to the centrally controlled clinical manifestations of B. pertussis
      infection.

PMID- 10636487
TI  - The effect of cytokines on the replication of T. gondii within rat retinal
      vascular endothelial cells.
AB  - Toxoplasma gondii infection of the eye can result in a recurrent necrotising
      retinochoroiditis (TR) which may lead to a permanent loss of visual acuity. The
      mechanisms responsible for the control of TR within the retina are unknown. The
      aim of this study was to examine the effects of cytokines on the replication of
      T. gondii RH strain tachyzoites within rat retinal vascular endothelial (rRVE)
      cells. Pretreatment of rRVE with IFNgamma, TNF or IL-1beta resulted in a
      significant decrease in T. gondii replication from day 2 onwards. There was no
      significant difference in nitric oxide (NO) production by IFNgamma, TNF or IL
      1beta treated rRVE as compared to controls at any time point. By comparison, the
      addition of L-tryptophan to IFNgamma treated cultures significantly restored T.
      gondii replication from 48 h post inoculation. Thus, IFNgamma, TNF and IL-1beta
      can significantly inhibit the replication of T. gondii within rRVE. However, this
      inhibition appears to be independent of NO production. L-tryptophan catabolism
      may have a role in IFNgamma mediated inhibition of T. gondii replication in rRVE
      cells.

PMID- 10636488
TI  - The central nervous system-specific myelin oligodendrocytic basic protein (MOBP)
      is encephalitogenic and a potential target antigen in multiple sclerosis (MS).
AB  - Uncovering primary target antigens in multiple sclerosis (MS) is of major
      significance for understanding the etiology and pathophysiology of the disease,
      and for designing immunospecific therapy. In this study, a synthetic peptide
      representing a predicted T cell epitope on myelin oligodendrocytic basic protein
      (MOBP) was found to be encephalitogenic in C3H.SW mice, inducing experimental
      autoimmune encephalomyelitis with an abrupt onset. Two separate preliminary
      studies with MOBP peptides indicated that autoreactivity to MOBP occurs in MS.
      These data strongly suggest that MOBP is a highly relevant target in MS and
      further point to the complexity of antigen specificities in MS.

PMID- 10636489
TI  - Phenotypic and functional properties of gamma delta T cells from patients with
      Guillain Barre syndrome.
AB  - In this study we have examined the phenotypic and functional properties of
      circulating gamma delta T cells in patients with Guillain Barre syndrome (GBS),
      in normal healthy controls, and in patients with active multiple sclerosis (MS).
      Cells expressing the Vdelta2 T cell receptor showed elevated expression of the C
      lectin receptor NKRP1A in both GBS and MS, suggestive of an activated state.
      However, in patients with GBS these cells failed to respond to pyrenil
      pyrophosphate derivatives and Vdelta2 + T cell clones derived from these patients
      released lower levels of IFNgamma than Vdelta2 + clones derived from controls and
      MS patients. In contrast, in patients with GBS the Vdelta1 + subset was expanded,
      showed elevated expression of NKRPIA and Vdelta1 + clones derived from these
      patients secreted high levels of IL-4. Our findings of expanded NKRP-1A +, IL-4
      producing Vdelta1 T cells in the GBS patients suggests the possibility that these
      cells are activated by the recognition of non-protein antigens in an MHC
      unrestricted manner and contribute to the humoral response to glycolipids that is
      a hallmark of this disease.

PMID- 10636490
TI  - HTLV-I specific IFN-gamma+ CD8+ lymphocytes correlate with the proviral load in
      peripheral blood of infected individuals.
AB  - Human T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic
      paraparesis (HAM/TSP) is an inflammatory neurological disease caused by HTLV-I
      infection. It has been shown that HAM/TSP patients have high proviral loads and
      an extraordinarily high frequency of circulating CD8 + cytotoxic T lymphocytes
      specific for HTLV-I in their peripheral blood when compared to asymptomatic HTLV
      I carriers (AC). We have previously described an intracellular cytokine detection
      assay, in which interferon-gamma (IFN-gamma) + CD8 + lymphocytes are specific for
      HTLV-I in infected individuals. Here, we have established a competitive
      polymerase chain reaction assay to measure the proviral load of patients and
      investigate a potential relationship between proviral load and virus-specific CD8
      + lymphocytes. Genomic DNA was extracted from peripheral blood lymphocytes (PBL)
      from eight HAM/TSP patients and seven AC for the measurement of HTLV-I measuring
      proviral loads. The same PBL were analyzed for intracellular IFN-gamma expression
      by flow cytometry. In the HAM/TSP patients and AC, the average proviral loads
      were 34,482 and 9784 copy/microg DNA (P = 0.021), and the average of IFN-gamma +
      CD8 + lymphocytes in total PBL were 1.47 and 0.08% (P = 0.001), respectively. It
      was confirmed that HAM/TSP patients have both high proviral loads and increased
      HTLV-I-specific CD8 + lymphocytes. Furthermore, we found a positive correlation
      between both factors in the patients with HAM/TSP (P = 0.044) but not in the AC
      (P = 0.508). These findings suggest that the high number of HTLV-I-specific
      lymphocytes may result from the increased proviral load in HAM/TSP patients.

PMID- 10636491
TI  - Cerebrospinal fluid beta2-microglobulin, monocyte chemotactic protein-1, and
      soluble tumour necrosis factor alpha receptors before and after treatment with
      lamivudine plus zidovudine or stavudine.
AB  - CSF levels of beta2-microglobulin (b2m), monocyte chemotactic protein-1 (MCP-1),
      soluble tumor necrosis factor receptors (sTNFRs), and HIV-1 RNA were determined
      in 16 neurologically asymptomatic HIV-1 infected patients before and 12 weeks
      after treatment with lamivudine plus zidovudine or stavudine. b2m levels were
      significantly higher in patients (1.7 mg/l) compared with controls (0.8 mg/l) (P
      < 0.001), and decreased to 1.1 mg/l during treatment (P = 0.001). MCP-1 levels
      were low, and did not change during treatment. Levels of sTNFR type I were
      elevated in patients (0.92 ng/ml) compared to controls (0.30 ng/ml) (P = 0.03),
      but did not change during treatment. Levels of sTNFR type II were below the limit
      of detection in most patients and controls. In conclusion, CSF levels of b2m and
      HIV-I RNA, but not sTNFRs or MCP-1, are candidate surrogate markers of treatment
      efficacy in early CNS infection.

PMID- 10636492
TI  - Ten goals for the American College of Obstetricians and Gynecologists for the
      first decade of the next millennium.

PMID- 10636493
TI  - Effect of Medicaid managed care on pregnancy complications.
AB  - OBJECTIVE: This study examined the impact of managed care on hospital obstetric
      outcomes in Medicaid-sponsored women. METHODS: The study sample consisted of a
      total of 525,517 maternal deliveries for singleton births from three payer
      groups, Medicaid managed care, Medicaid fee-for-service, and private managed care
      in 439 short-term-stay nonfederal hospitals in California and Florida. Quality of
      care comparisons were made using six indicators. Data were derived from linked
      computer files of birth certificates, hospital discharge abstracts, Medicaid
      eligibility records, Medicaid health care claims, and surveys of hospital
      characteristics. RESULTS: The overall multivariate likelihood of an adverse
      maternal outcome during hospitalization for a delivery was not significantly
      different between Medicaid managed care and Medicaid fee-for-service groups in
      California and Florida. However, mothers in the Medicaid managed care group
      compared with mothers in the private managed care group experienced a higher
      likelihood of eclampsia (California) (adjusted odds ratio = 1.26; 95% confidence
      interval 1.05, 1.57; P = .04). CONCLUSION: Overall, managed care has not
      adversely affected pregnancy outcomes in Medicaid-sponsored women. Yet, payer
      system changes may be insufficient to achieve complete parity of outcomes
      relative to private managed care patients.

PMID- 10636494
TI  - Parity and sleep patterns during and after pregnancy.
AB  - OBJECTIVE: To describe changes in women's sleep patterns from prepregnancy to
      postpartum. METHODS: Polysomnography was done in women's homes for 2 consecutive
      nights. Forty-five women were studied during the follicular and luteal phases of
      their menstrual cycles, and 33 conceived and were studied during each trimester
      of pregnancy. Twenty-nine were studied at 1 and 3 months postpartum. RESULTS:
      Compared with prepregnant sleep characteristics, significant changes in sleep
      patterns were evident by 11-12 weeks' gestation, with a significant increase in
      total sleep time but less deep sleep and more awakening during sleep. By the
      third month postpartum, there was improvement in sleep characteristics; however,
      sleep efficiency remained significantly lower than baseline prepregnancy values.
      CONCLUSION: Sleep disturbance was greatest during the first postpartum month,
      particularly for first-time mothers.

PMID- 10636495
TI  - Complementary and alternative medicine in pregnancy: a survey of North Carolina
      certified nurse-midwives.
AB  - OBJECTIVE: To determine the prevalence and types of complementary and alternative
      medicine therapies used by certified nurse-midwives in North Carolina. METHODS:
      Surveys were sent to all 120 licensed certified nurse-midwives in North Carolina
      requesting information concerning their recommendations for use of complementary
      and alternative medicine for their pregnant or postpartum patients. RESULTS:
      Eighty-two responses were received (68.3%). Seventy-seven (93.9%) reported
      recommending complementary and alternative medicine to their pregnant patients in
      the past year. Forty-seven (57.3%) reported recommending complementary and
      alternative medicine to more than 10% of patients. The percentage of nurse
      midwives who recommended each type of complementary and alternative medicine was
      as follows: herbal therapy (73.2%), massage therapy (67.1%), chiropractic
      (57.3%), acupressure (52.4%), mind-body interventions (48.8%), aromatherapy
      (32.9%), homeopathy (30.5%), spiritual healing (23.2%), acupuncture (19.5%), and
      bioelectric or magnetic applications (14.6%). The 60 respondents who reported
      prescribing herbal therapies gave them for the following indications: nausea and
      vomiting, labor stimulation, perineal discomfort, lactation disorders, postpartum
      depression, preterm labor, postpartum hemorrhage, labor analgesia, and
      malpresentation. CONCLUSION: Complementary and alternative medicine, especially
      herbal therapy, is commonly prescribed to pregnant women by nurse-midwives in
      North Carolina.

PMID- 10636496
TI  - Pregnancy outcomes in healthy nulliparas who developed hypertension. Calcium for
      Preeclampsia Prevention Study Group.
AB  - OBJECTIVE: To determine maternal and perinatal outcomes in nulliparas with
      pregnancy-associated hypertension or preeclampsia. METHODS: We conducted (and
      reported elsewhere) a randomized, double-masked, placebo-controlled trial calcium
      supplementation of 4589 healthy nulliparas assigned at 13-21 weeks' gestation.
      This well-defined and characterized data set provided an opportunity to detail
      more precisely adverse maternal, fetal, and newborn outcomes in women who
      developed hypertension among a prospective series of healthy nulliparas. RESULTS:
      Of 4302 women observed to or beyond 20 weeks' gestation, 1073 (24.9%) developed
      mild or severe pregnancy-associated hypertension or preeclampsia. One hundred
      sixteen women of the 1073 with hypertension (10.8%) and 336 of the 3229 without
      hypertension (10.4%) were delivered before 37 weeks' gestation. Fetal and
      neonatal mortality were similar in those groups; however, selected maternal and
      newborn morbidities were significantly greater in women with hypertension.
      Significantly increased maternal morbidities included increased cesarean
      deliveries, abruptio placentae, and acute renal dysfunction; and significantly
      increased perinatal morbidities included respiratory distress syndrome,
      ventilatory support, and fetal growth restriction. Adverse outcomes were highest
      in women with severe pregnancy-associated hypertension or preeclampsia.
      CONCLUSION: Hypertension, especially severe hypertension, was associated with an
      appreciable increase in important maternal and perinatal morbidity but not
      perinatal mortality.

PMID- 10636497
TI  - Platelet count at term pregnancy: a reappraisal of the threshold.
AB  - OBJECTIVE: To assess the safety of a new platelet count threshold for the
      definition of maternal thrombocytopenia late in pregnancy. METHODS: A platelet
      count was performed in 6770 pregnant women late in pregnancy and in 6103 of their
      newborns as well as in a control group of 287 age-matched nonpregnant healthy
      women. RESULTS: The prevalence of maternal thrombocytopenia (platelet count less
      than 150 x 10(9)/L) was 11.6%. The mean platelet counts (248 compared with 213 x
      10(9)/L) and 2.5th percentile (164 compared with 116 x 10(9)/L) were
      significantly higher in healthy nonpregnant women than in pregnant women. Among
      thrombocytopenic pregnant women, 621 (79%) had platelet counts between 116 and
      149 x 10(9)/L; none (0%; 95% confidence interval 0, 0.6) had complications
      related to thrombocytopenia, and none of their newborns had severe
      thrombocytopenia (platelet count less than 20 x 10(9)/L). CONCLUSION: In healthy
      pregnant women, a platelet count over 115 x 10(9)/L late in pregnancy does not
      require further investigation during pregnancy and may be considered a safe
      threshold.

PMID- 10636498
TI  - Effectiveness of multidose antenatal steroids.
AB  - OBJECTIVE: To compare effectiveness between single and multiple courses of
      antenatal steroids in preterm births and determine adverse effects attributable
      to multiple courses. METHODS: We studied retrospectively the neonatal outcomes of
      infants who weighed 1750 g or less at birth between January 1990 and December
      1997. Infants exposed to a single course were compared with those exposed to two
      or more courses of antenatal steroids, with respect to various perinatal outcome
      variables. RESULTS: Ninety-three neonates were exposed to two or more courses of
      antenatal steroids and 261 neonates had been given single courses. The mean (+/-
      standard deviation) gestational age (29.6 +/- 2.8 weeks compared with 28.7 +/-
      2.7 weeks; P = .007) and birth weight (1252 +/- 321 g compared with 1159 +/- 339
      g; P = .013) were significantly higher among neonates exposed to multiple
      courses. There were no significant differences between groups in perinatal
      outcomes; however, those exposed to multiple courses had a significantly lower
      rate of respiratory distress syndrome (RDS) (17 [18%] compared with 107 [41%]; P
      < or = .001) and surfactant use (40 [43%] compared with 149 [57%]; P = .02).
      Adjusting for confounding variables, multiple courses of steroids were
      significantly associated with a 65% reduction in the incidence of RDS (odds ratio
      0.35; 95% confidence interval = 0.18, 0.70; P = .003). CONCLUSION: Compared with
      single courses, multiple courses of antenatal steroids reduced significantly the
      incidence of RDS with no apparent increase in neonatal sepsis or disturbances in
      fetal growth.

PMID- 10636499
TI  - Delivery of breech first twins: a multicenter retrospective study.
AB  - OBJECTIVE: To assess the risk of vaginal birth of breech first twins by Apgar
      scores and mortality. METHODS: We did a retrospective case-control analysis of
      data from 13 centers that allow vaginal birth for breech first twins. We used
      depressed 5-minute Apgar scores and neonatal mortality as main outcome measures
      between vaginal (n = 239) and cesarean (n = 374) deliveries of pairs with breech
      first twins, stratified by parity, birth weights of first twins, and types of
      cesarean. The 95% power of our sample size (alpha = .05) was sensitive enough to
      detect differences of 5% of the overall sample and 25-30% of subgroups. RESULTS:
      Vaginal birth was attempted in 61% of 613 pairs. There were significantly more
      depressed Apgar scores (P = .008, odds ratio [OR] 2.4, 95% confidence interval
      [CI] 1.2, 4.7) and neonatal deaths (P < .001, OR 9.5, 95% CI 4.0, 23.4) among
      vaginal births of pairs in whom first twins weighed less than 1500 g but not
      among the higher-birth-weight cohort (for depressed Apgar scores: P = .76, OR
      1.1, 95% CI 0.6, 2.1). Multiparity and elective cesarean seemed to have little
      influence on outcome measures. Neonatal mortality was associated with extremely
      preterm twins. CONCLUSION: There was no evidence that vaginal birth is unsafe, in
      terms of depressed Apgar scores and neonatal mortality, for breech first twins
      that weighed at least 1500 g.

PMID- 10636500
TI  - Analysis of McRoberts' maneuver by x-ray pelvimetry.
AB  - OBJECTIVE: To document radiographically the changes in pelvic dimensions created
      by McRoberts' maneuver. METHODS: Women at least 37 weeks' pregnant who presented
      to labor and delivery were eligible for study entry. Anterior-posterior and
      lateral x-rays were taken with women in the dorsal lithotomy position and after
      application of McRoberts' maneuver, in which the maternal legs were hyperflexed
      45 degrees onto the maternal abdomen. A two-tailed paired t test was used to
      assess the changes in the pelvic diameters, with P < .05 considered statistically
      significant. RESULTS: Thirty-six subjects were enrolled in the study and 34 x
      rays were suitable for analysis. McRoberts' maneuver was associated with an
      increase in the mean angle of inclination between the symphysis pubis and the
      sacral promontory (51.53 +/- 2.03 versus 38.07 +/- 1.96 degrees, P < .001). There
      was a 24% decrease in the angle created by drawing a line bisecting the symphysis
      pubis relative to the horizontal (P < .001). With McRoberts' maneuver the angle
      created by a line bisecting the longitudinal axis of the fifth lumbar vertebra
      and the longitudinal axis of the upper sacrum also increased (133.75 +/- 2.25 to
      140.14 +/- 2.12 degrees, P = .04). CONCLUSION: Ours are the first systematic
      observations of pelvic changes associated with McRoberts' maneuver, confirming
      the traditional thinking that the maneuver causes a significant cephalad rotation
      of the symphysis pubis and subsequent flattening of the sacrum.

PMID- 10636501
TI  - Need for urgent delivery after third-trimester amniocentesis.
AB  - OBJECTIVE: To estimate the risk of need for urgent delivery after third-trimester
      amniocentesis as currently done using ultrasound guidance to assess fetal lung
      maturity. METHODS: Ultrasound records of women scheduled for third-trimester
      amniocenteses to assess fetal lung maturity from February 1990 through October
      1997 were reviewed for possible complications during or immediately after
      procedures. Collected data included gestational age, indication for the
      procedure, number of needle passes, transplacental passage, needle gauge, and
      fluid color. The primary outcome examined was procedure-related complications
      that required emergency delivery or the decision to deliver before completion of
      maturity studies. Infants who developed hyaline membrane disease leading to
      neonatal intensive care admission were also identified. RESULTS: During the 7 1/2
      year study period, 962 amniocenteses were done to assess lung maturity. Complete
      data were not available for 49 cases. Of the remaining 913 procedures, 15 (1.6%)
      were unsuccessful (needle pass without collecting fluid). Forty-one infants were
      delivered spontaneously or by cesarean on the same day as the procedure. However,
      complications that required delivery were identified in only six cases, an
      incidence of 0.7% (95% confidence interval = 0.16, 1.24). Complications included
      fetal heart rate abnormalities (n = 3), placental bleeding (n = 1), abruptio
      placentae (n = 1), and uterine rupture (n = 1). Only one of six complications had
      a single needle pass with clear fluid collected. Hyaline membrane disease
      occurred in 14 neonates, including two with mature indices. CONCLUSION: Although
      complications that required urgent delivery after third-trimester amniocentesis
      are rare, the risks of the procedure should be carefully weighed against the
      benefits.

PMID- 10636502
TI  - Ultrasound findings and multiple marker screening in trisomy 18.
AB  - OBJECTIVE: To compare detection of trisomy 18 in the second trimester by
      ultrasound and multiple-marker testing. METHODS: A computerized genetics database
      was used to identify fetuses of 14-22 weeks' gestation who had comprehensive
      ultrasound examinations, multiple-marker screening tests (alpha-fetoprotein
      [AFP]), hCG, unconjugated estriol [E3], and trisomy 18 karyotype. A positive
      trisomy 18 screen was defined as AFP up to 0.75 multiples of the median (MoM),
      hCG up to 0.55 MoM, and unconjugated E3 up to 0.60 MoM. A risk of at least 1:190
      defined a positive Down syndrome screen. Ultrasound abnormalities were diagnosed
      prospectively and were confirmed later by retrospective review of sonographic
      images. RESULTS: From 1988-1997, 30 trisomy 18 fetuses who had comprehensive
      ultrasounds and multiple-marker testing were identified. Twenty-one (70%) had
      abnormalities detected by ultrasound, of which the most common isolated finding
      was choroid plexus cyst. Eleven fetuses (37%) had positive trisomy 18 screens,
      and two had positive Down syndrome screens, for a total of 13 of 30 (43%) fetuses
      with positive multiple-marker screening tests. CONCLUSION: We found that
      ultrasound was more likely to be abnormal than multiple-marker screening tests in
      fetuses with trisomy 18 (70%) (95% confidence interval [CI] 54, 86 versus 43% CI
      25, 61). However, combining the two testing methods yielded the highest detection
      rate (80% [CI 66%, 94%]).

PMID- 10636503
TI  - Ethnic differences in depressive symptomatology among young women.
AB  - OBJECTIVE: To examine racial and ethnic differences in moderate to severe
      depressive symptoms among young women seeking reproductive health care. METHODS:
      Nine hundred four white, black, or Hispanic women between 14 and 26 years of age
      completed an anonymous questionnaire that assessed demographic and reproductive
      characteristics; recent substance use, including binge drinking; sexual
      behaviors; occurrence of assault; and depressive symptoms. Logistic regression
      analysis was used to develop adjusted odds ratios (OR) and 95% confidence
      intervals for correlates of depressive symptomatology for each racial or ethnic
      group. RESULTS: Twenty-one percent (68 of 321) of whites, 28% (88 of 316) of
      blacks, and 29% (77 of 267) of Hispanics reported moderate to severe depressive
      symptoms. White females with moderate to severe depressive symptoms were more
      likely to report sexual assault (OR = 3.1); being a high school dropout (OR =
      2.6); unemployment (OR = 2.4); two or more episodes of binge drinking (OR = 2.1);
      and having a mother with less than a high school education (OR = 2.4). Black
      females with depressive symptoms were more likely to report smoking one to nine
      cigarettes per day (OR = 3.5); sexual assault (OR = 3.2); and unemployment (OR =
      2.1). Hispanic females with depressive symptoms were more likely to report
      adolescent age (OR = 3.5); physical assault (OR = 3.2); and smoking one or more
      cigarettes per day (OR = 2.4). CONCLUSION: Twenty to 25% of young women,
      regardless of race or ethnicity, have moderate to severe depressive symptoms, and
      behavioral markers vary according to ethnicity.

PMID- 10636505
TI  - Scrape cytology for intraoperative evaluation of lymph nodes in gynecologic
      cancer.
AB  - OBJECTIVE: To compare scrape cytology with frozen section in accuracy and time
      required for preparation and interpretation and assess accuracy and surgical
      effect of scrape cytology as the only method of intraoperative evaluation of
      lymph nodes from women with gynecologic cancers. METHODS: Between February 1998
      and March 1999, 242 lymph nodes removed from 60 women with gynecologic cancers
      were submitted for scrape cytology alone (34 women, 177 lymph nodes) or with
      frozen section (26 women, 65 lymph nodes). Results of scrape cytology and time
      required for preparation and interpretation were compared with those from frozen
      section. Accuracy and proportion of incorrect surgical decisions based on
      combined evaluation by scrape cytology and frozen section were compared with
      those from scrape cytology alone. For statistical analysis, we used Student t
      test, chi2, and Cohen's kappa statistics. Two-tailed P < .05 was considered
      significant. RESULTS: There was excellent agreement between scrape cytology and
      frozen section (kappa = .78 with 95% confidence interval .495, 1.065). Scrape
      cytology had a higher accuracy than frozen section and required significantly
      less time (95.8% versus 87.5% and 14 +/- 3.2 versus 25 +/- 5.1 minutes, P <
      .005). The accuracy and proportion of incorrect surgical decisions based on
      combined evaluation were similar to those based on cytology alone (91.7% for both
      and 7.7% versus 8.8%, respectively). CONCLUSION: Scrape cytology is as accurate
      and faster than frozen section in intraoperative evaluation of lymph nodes from
      women with gynecologic cancers. Adding frozen section to scrape cytology did not
      seem to improve accuracy or reduce incorrect surgical decisions.

PMID- 10636504
TI  - Recent trends in assisted reproductive techniques and associated outcomes.
AB  - OBJECTIVE: We examined recent trends in success rates for assisted reproduction
      and determined the influence of changes in patient selection and treatment
      characteristics on these trends. METHODS: We collected baseline information and
      abstracted treatment-related details and outcomes on 1244 couples accepted for in
      vitro fertilization (IVF) or gamete intrafallopian transfer (GIFT) at three
      clinics in greater Boston from 1994-1998. RESULTS: Delivery rates per initiated
      cycle improved significantly from 14.9% for IVF and 20.6% for GIFT in 1994-1995
      to 22.5% for IVF and 28.0% for GIFT in 1997-1998 (P < or = .001). After adjusting
      for female age, the two treatment-related variables that appeared most likely to
      explain this trend were decreased use of GnRH agonists in short course (flare)
      regimens and increased use of highly purified forms of urinary gonadotropins.
      CONCLUSION: There were significant improvements in the success rates for IVF and
      GIFT from 1994-1998 that correlated with changes in ovulation induction regimens.

PMID- 10636506
TI  - Human leukocyte antigen class II DQ alleles associated with Chlamydia trachomatis
      tubal infertility.
AB  - OBJECTIVE: To investigate epidemiologic tubal infertility risk factors and the
      relationship between HLA class II alleles and Chlamydia trachomatis tubal
      infertility. METHODS: Forty-seven women with tubal infertility and 46 fertile
      controls were studied in Nairobi, Kenya. A questionnaire was administered and
      serum collected for measurement of C trachomatis antibodies. HLA class II
      molecular typing was done with DNA extracted from peripheral blood lymphocytes.
      The prevalence of C trachomatis microimmunofluorescence antibody, chlamydia heat
      shock protein 60 antibody, and HLA class II alleles was compared among cases of
      tubal infertility and fertile controls. RESULTS: Women with tubal infertility
      more often had histories of pelvic inflammatory disease (15% versus 0%; odds
      ratio [OR] 16; 95% confidence interval [CI] 5.5, 47) histories of spontaneous
      abortion (34% versus 7%; OR 6.7; 95% CI 2.8, 16), and antibodies to C trachomatis
      (53% versus 26%; OR 3.2; 95% CI 1.3, 7.7) than controls. Among infertile women,
      DQA*0101 and DQB*0501 alleles were positively associated with C trachomatis tubal
      infertility (OR 4.9; 95% CI 1.3, 18.6, and OR 6.8; 95% CI 1.6, 29.2,
      respectively). DQA*0102 was negatively associated with C trachomatis tubal
      infertility (OR 0.2; 95% CI 0.005, 0.6). CONCLUSION: Chlamydia trachomatis
      infection is an important cause of tubal infertility in Nairobi. The association
      of specific HLA class II alleles with C trachomatis microimmunofluorescence
      seropositivity among women with tubal infertility suggests that the DQ locus
      might modify susceptibility to and pathogenicity of C trachomatis infection.

PMID- 10636507
TI  - Smoking, oral contraceptives, and cardiovascular reactivity to stress.
AB  - OBJECTIVE: To investigate the effects of smoking and oral contraceptive (OC)
      formulation on hemodynamic responses to stress in women. METHODS: Twenty-three
      smokers and 23 nonsmokers taking different OC formulations (ie, containing higher
      or lower androgenic progesterones) were tested for cardiovascular reactivity
      during mathematic, speech preparation, speech, and cold pressor stress. RESULTS:
      During mental stress, smokers, regardless of OC formulation, had lower systolic
      blood pressure (BP) (eg, 10.2 versus 15.1 mmHg, P < .05), heart rate (eg, 7.5
      versus 15.0 beats per minute, P < .01), and cardiac index reactivity (eg, 0.08
      versus 0.48 L/minute/M2, P < .01) but greater vascular resistance index responses
      (eg, 115.6 versus -51.9 dyne-sec x cm(-5) x M2, P < .05). Women who took higher
      androgen OCs, regardless of smoking status, showed greater vascular resistance
      index increases during speech stress than those who took lower androgen OCs
      (215.8 versus 9.4 dyne-sec x cm(-5) x M2, P < .05). Smokers who took more
      androgenic OCs had greater systolic BP responses to speech preparation compared
      with nonsmokers who took the same OCs (12.1 versus 6.1 mmHg, P < .05), and
      smokers who took lower androgen OCs (12.1 versus 4.4 mmHg, P < .05). Least
      squares means examination found that smokers who took higher androgen OCs had
      greater vascular resistance index increases to all mental stressors than
      nonsmokers who took lower androgen OCs. CONCLUSION: Higher androgen OCs might be
      linked to greater vascular and BP increases during stress, especially in smokers.
      Given that increased vascular resistance and BP contribute to cardiovascular
      mortality, those results suggest that androgenic profiles of synthetic
      progesterones might be an important consideration in OC choice.

PMID- 10636508
TI  - Nucleated red blood cells in healthy infants of women with gestational diabetes.
AB  - OBJECTIVE: To evaluate whether absolute nucleated red blood cell (RBC) counts are
      elevated in large-for-gestational-age (LGA) infants of women with gestational
      diabetes compared with appropriate-for-gestational-age (AGA) infants of women
      with or without gestational diabetes. METHODS: We compared absolute nucleated RBC
      counts during the first 12 hours of life in three groups of term, vaginally
      delivered infants, LGA infants of women with gestational diabetes (n = 20), AGA
      infants of women with gestational diabetes (n = 20), and AGA infants of
      nondiabetic women (n = 30). We excluded infants of women with hypertension,
      smoking, alcohol or drug abuse, and those with fetal heart rate abnormalities in
      labor, low Apgar scores, hemolysis, blood loss, or chromosomal anomalies.
      RESULTS: There were no significant differences among groups in gestational age,
      gravidity, parity, maternal analgesia, 1- and 5-minute Apgar scores, and
      lymphocyte counts. Corrected white blood cell counts and hematocrit were
      significantly higher in LGA infants of women with gestational diabetes than in
      the other groups. The median nucleated RBC count was significantly higher in LGA
      infants of women with gestational diabetes (0.56 x 10(9)/L, range 0-1.8 x
      10(9)/L) than AGA infants of women with gestational diabetes (0.13 x 10(9)/L,
      range 0-0.65 x 10(9)/L) and controls (0.0005 x 10(9)/L, range 0-0.6 x 10(9)/L) (P
      < .001). Multiple regression analysis showed that absolute nucleated RBC count
      was significantly correlated with birth weight (or macrosomia) and maternal
      diabetic status (r2 = .25, P < .001 for the multiple regression, contribution of
      birth weight r2 = .19, and diabetes r2 = .06). CONCLUSION: At birth, term LGA
      infants born to women with gestational diabetes had higher absolute nucleated RBC
      counts compared with AGA infants born to women with gestational diabetes and
      controls.

PMID- 10636509
TI  - A randomized trial of oral contraceptive and hormone replacement therapy on bone
      mineral density and coronary heart disease risk factors in postmenopausal women.
AB  - OBJECTIVE: To identify the effects of oral contraceptive (OC) and hormone
      replacement therapy (HRT) on bone mineral density and coronary heart disease risk
      factors in postmenopausal women. METHODS: Eighty healthy postmenopausal women
      were randomly assigned to a cyclic regimen of OC containing 30 microg of ethinyl
      estradiol and 150 microg of desogestrel or HRT containing 0.625 mg of conjugated
      equine estrogens 21 days per cycle and 5 mg of medrogestone 10 days per cycle for
      12 months. Bone mineral density of lumbar spine and hip, biochemical markers of
      bone turnover, lipid-lipoprotein profiles, coagulation profiles, fasting plasma
      glucose, and blood pressure were evaluated. RESULTS: Both regimens caused
      significant increase in bone mineral density of lumbar spine, trochanter,
      intertrochanteric region, total hip, and Ward triangle. Only OC therapy was
      associated with a significant increase in femoral neck bone mineral density (mean
      score +/- standard error 2.5% +/- 0.7%, P < .01). Biochemical markers of bone
      turnover, total cholesterol, and low-density lipoprotein cholesterol decreased
      significantly in both groups. Posttreatment levels of those bone markers and
      lipid-lipoprotein were significantly lower after OC therapy than HRT. Fasting
      plasma glucose and systolic blood pressure decreased significantly in both
      groups; however, only the OC group showed a significant decrease in diastolic
      blood pressure. CONCLUSION: Both OC and HRT increased bone mineral density of
      lumbar spine and hip, but OC suppressed bone turnover more than HRT. Both methods
      favorably affected lipid-lipoprotein metabolism, fasting plasma glucose, and
      blood pressure during the 12 months of treatment.

PMID- 10636510
TI  - A 12-month comparative study of raloxifene, estrogen, and placebo on the
      postmenopausal endometrium.
AB  - OBJECTIVE: To determine the effects of a selective estrogen receptor modulator,
      raloxifene, on postmenopausal endometrium. METHODS: Healthy postmenopausal women
      (n = 415) were randomly assigned to one of the following four groups: 60 or 150
      mg/day raloxifene hydrochloride, 0.625 mg/day conjugated equine estrogens, or
      placebo, and treated for 1 year. Endometrial biopsies were obtained in a blinded
      fashion at baseline and every 6 months after the ultrasound studies. Transvaginal
      ultrasound, with uterine size measurements, was done at baseline and at 3-month
      intervals. Saline-infusion sonohysterography was done at baseline and every 6
      months. RESULTS: There were no statistically significant differences in baseline
      characteristics. Mean endometrial thickness, measured by transvaginal ultrasound,
      was unchanged from baseline to end point in the placebo and raloxifene groups,
      whereas in the estrogen group it was significantly thicker by 5.5 mm (P < .001).
      Mean uterine volume, calculated from transvaginal ultrasound measurements, was
      higher in the estrogen group only (22 cm3, P < .001). Of the 358 women with
      paired biopsies, endometrial hyperplasia was present in 2.1%, 0%, and 26.1% of
      the end-point biopsies in the placebo, raloxifene, and estrogen groups,
      respectively (P < .001). Proliferative endometrium was present in 2.1% of the end
      point biopsies in the placebo group, 1.7% in the combined raloxifene groups, and
      39.8% in the estrogen group (P < .001). CONCLUSION: Raloxifene, at 60 or 150
      mg/day for 1 year, did not stimulate the postmenopausal endometrium. End-point
      endometrial thickness, morphology, and uterine volume in the raloxifene groups
      were similar to those observed at baseline and in the placebo group.

PMID- 10636511
TI  - Uterine effects of 3-year raloxifene therapy in postmenopausal women younger than
      age 60.
AB  - OBJECTIVE: To assess the uterine effects of 3 years of therapy with raloxifene in
      healthy, postmenopausal women under age 60. METHODS: Integrated data from two
      identically designed, randomized, double-masked, placebo-controlled clinical
      trials were analyzed. Nine hundred sixty-nine healthy women with uteri (ages 45
      through 60, 2 to 8 years postmenopausal) were assigned randomly to raloxifene 30,
      60, or 150 mg per day, or an identical placebo for 3 years. Endometrial thickness
      was evaluated with transvaginal ultrasonography every 6 months for 2 years and
      again after 3 years. Further uterine evaluation, including endometrial sampling
      if necessary, was initiated for vaginal bleeding or findings of endometrial
      thickness greater than 5 mm. RESULTS: Endometrial thickness was unchanged by
      raloxifene and not significantly different from placebo at any time. One hundred
      seventy-two women had at least one episode of endometrial thickness greater than
      5 mm or vaginal bleeding distributed equally among all groups. A total of 102
      (10.5%) women underwent endometrial sampling at least once: 15 (1.5%) for vaginal
      bleeding, 78 (8.0%) for endometrial thickness greater than 5 mm, and nine (0.9%)
      for other reasons. There were no significant treatment differences in the
      proportion of women sampled, in the clinical findings, or in the histologic
      diagnoses. CONCLUSION: Raloxifene given to healthy postmenopausal women at doses
      from 30 to 150 mg per day does not stimulate uterine growth and does not cause
      vaginal bleeding, spotting, or discharge through 3 years of therapy. Thus, any
      bleeding during therapy should be deemed unexpected and prompt a clinical
      evaluation.

PMID- 10636512
TI  - Lipid effects of hormone replacement therapy with sequential transdermal 17-beta
      estradiol and oral dydrogesterone.
AB  - OBJECTIVE: To assess the effects on lipid and lipoprotein levels of a combination
      therapy of matrix patch and oral sequential dydrogesterone. METHODS: The lipid
      effects of transdermal estradiol (E2) (80 microg/day continuously) and oral
      dydrogesterone (10 mg from days 15-28 of each cycle) were assessed in a
      multicenter, prospective, open, baseline-controlled study. Subjects were 42
      healthy, postmenopausal women who had not had hysterectomies. Fasting blood
      samples were taken at baseline, day 14 of cycle 3 (estrogen alone), and day 25 of
      cycle 6 (estrogen and progestogen). The main outcome measures were changes from
      baseline in total cholesterol, high-density lipoprotein (HDL) cholesterol, low
      density lipoprotein (LDL) cholesterol, and triglycerides after six cycles.
      RESULTS: Thirty-six subjects completed six cycles and in the 28 with complete
      data, HDL cholesterol increased by 10.6% from 65.25 to 72.2 mg/dL (95% confidence
      interval [CI] 2.32, 11.58, P = .005) and LDL cholesterol fell by 5.1% from 130.9
      to 124.3 mg/dL (95% CI 13.9, 1.16, P = .07). There was a nonsignificant decrease
      in LDL cholesterol from 130.9 at baseline to 124.3 mg/dL at 6 months and in
      triglycerides from 110.6 to 107.1 mg/dL. CONCLUSION: Sequential treatment with
      transdermal E2 and oral dydrogesterone increased HDL cholesterol, without the
      accompanying increase in triglycerides that occurs with oral estrogen replacement
      therapy.

PMID- 10636513
TI  - Endometrial release of soluble intercellular adhesion molecule 1 and
      endometriosis: relationship to the extent of the disease.
AB  - OBJECTIVE: To relate endometrial release of the soluble form of intercellular
      adhesion molecule 1 with extent of endometriosis. METHODS: Samples of endometrium
      were collected from 23 women with endometriosis. Soluble intercellular adhesion
      molecule 1 was quantified in conditioned medium from 48-hour endometrial stromal
      cell cultures with use of a specific enzyme-linked immunosorbent assay. Levels
      were correlated with revised American Society for Reproductive Medicine
      classification score for adhesions, implants, and cysts and total score; number
      of endometriotic implants; cyst diameter; and presence or absence of pelvic pain
      symptoms and previous surgical procedures for endometriosis. RESULTS: Endometrial
      release of soluble intercellular adhesion molecule 1 directly correlated with
      number of implants (r = .64, P < .005) and score for implants (r = .61, P <
      .005). There was no significant correlation between levels of the soluble
      molecule and score for adhesions or total score. Soluble intercellular adhesion
      molecule 1 shed by endometrium did not correlate with the score for ovarian
      cysts, although an inverse relationship was found with ovarian cyst diameter (r =
      -0.52, P < .05). No differences were detected between women who had pelvic pain
      and those who did not and between those who had previous surgery for
      endometriosis and those who had not. CONCLUSION: The association between
      endometrial release of soluble intercellular adhesion molecule 1 and the number
      and score of endometriotic implants suggests that the molecule might be of value
      in evaluating spread potential of refluxed endometrium.

PMID- 10636514
TI  - Prognostic factors in early-onset epithelial ovarian cancer: a population-based
      study.
AB  - OBJECTIVE: To investigate the clinical prognostic factors that influence ovarian
      cancer survival in women with early-onset epithelial ovarian cancer using
      population-based data. METHODS: Subjects in the current study were from a
      population-based series of 197 patients with invasive ovarian cancer and 60
      patients with ovarian cancer of low malignant potential who were identified from
      the Cancer and Steroid Hormone study. All subjects were between 20 and 54 years
      of age at diagnosis for ovarian cancer. Epidemiologic data were obtained from
      each participant. Immunohistochemical staining was performed to assess p53
      expression in paraffin-embedded ovarian cancers. Univariate and multivariate
      analyses for survival were conducted using the proportional hazards model to test
      the prognostic significance of several clinicopathologic factors among subjects.
      RESULTS: Among women with invasive tumors, the proportional hazards model
      revealed that advanced stage at diagnosis [hazard ratio = 4.1, 95% confidence
      interval (CI) = 2.5, 6.6], age at diagnosis 46-54 (hazard ratio = 2.0, 95% CI =
      1.3, 3.0), and overexpression of p53 (hazard ratio = 1.5, 95% CI = 1.1, 2.3) were
      significantly associated with decreased survival. CONCLUSION: These results
      provide evidence that stage, age, and p53 overexpression are independent
      predictors of decreased survival in women with invasive ovarian cancer diagnosed
      younger than age 55. Further investigation of the effect of age at diagnosis on
      the relationship between p53 overexpression and ovarian cancer survival is
      warranted.

PMID- 10636515
TI  - Malignant germ cell tumors of the ovary.
AB  - OBJECTIVE: To evaluate the efficacy of adjuvant therapy for ovarian germ cell
      tumors. METHODS: We reviewed records of women who had malignant germ cell tumors
      of the ovary from 1977-1997. RESULTS: Seventy-two women had surgical resections
      of malignant ovarian germ cell tumors and most received adjuvant therapy. Fifty
      six women (78%) presented with stage I disease, and 16 (22%) had more advanced
      disease. Tumor subtypes included dysgerminoma (n = 20), yolk sac tumor (n = 8),
      immature teratoma (n = 29) and mixed germ cell tumor (n = 15). Surgical
      management of the 56 with stage I disease consisted of total abdominal
      hysterectomy, bilateral salpingo-oophorectomy, and extensive surgical staging in
      ten women, whereas a conservative surgical approach, consisting of unilateral
      adnexectomy with or without comprehensive surgical staging, was adopted in later
      years (n = 46). Fifty-six women were treated with postoperative chemotherapy,
      predominantly platinum-based regimens. The 5-year actuarial survival rate was
      93%. None of the 36 women who presented after 1984 have died of disease.
      CONCLUSION: These data confirmed that platinum-based adjuvant treatments allow
      most women with ovarian germ cell malignancies to have conservative surgery
      without compromising survival.

PMID- 10636516
TI  - Association between DQB1 and cervical cancer in patients with human
      papillomavirus and family controls.
AB  - OBJECTIVE: The role of human leukocyte antigen (HLA) DQB1 alleles and human
      papillomavirus (HPV) as contributing factors to invasive cervical cancer was
      investigated. To overcome problems of misleading causal inferences common in
      traditional case-control studies, a family-based test, the
      transmission/disequilibrium test, was used. METHODS: Ninety-six patients with
      pathologically confirmed invasive cervical cancer were ascertained. Human
      papillomavirus types were determined in 80 patients, of whom 81.25% were HPV
      positive, and 18.75% were HPV-negative. Deoxyribonucleic acid was extracted from
      samples, taken from patients and their parents, and sequenced to determine DQB1
      genotypes. Nuclear family data were used to test whether the DQB1 locus is
      associated with invasive cervical cancer while controlling for high-risk HPV
      positive patients. The transmission/disequilibrium test evaluates whether the
      frequency of transmission of parental marker alleles to their affected offspring
      deviates from the expected Mendelian frequency of 50%. RESULTS: The HLA DQB1
      locus showed evidence for allelic association with invasive cervical cancer in
      high-risk HPV-positive patients (P = .006). The transmission/disequilibrium test
      showed that the DQB1*0303 allele was transmitted to high-risk HPV patients more
      often than expected by chance, chi2(1) = 8.0, P = .005 (P = .035 when correcting
      for multiple tests). Tests of association were negative when applied to all 96
      patients, irrespective of HPV status. No significant differences were found in
      the distribution of the DQB1 alleles among HPV-positive patients compared with
      those who were HPV-negative, indicating that HLA alleles are not associated with
      susceptibility to HPV infection. CONCLUSION: These results suggest that the
      DQB1*0303 allele increases the risk for invasive cervical cancer in women who are
      HPV-positive.

PMID- 10636517
TI  - Induction of cell-cycle arrest in cervical cancer cells by the human
      immunodeficiency virus type 1 viral protein R.
AB  - OBJECTIVE: To determine the ability of the human immunodeficiency virus type 1
      (HIV-1) gene vpr to induce cell-cycle arrest in cervical cancer cells with or
      without human papillomavirus (HPV) type 16 E6 or E7 expression. METHODS: High-
      and low-level expression vectors for vpr (designated pVPR(HIGH) and pVPR(LOW),
      respectively) were used in conjunction with HPV-16 E6 or E7 vectors to transfect
      HPV-negative C33A cervical cancer cells. Vpr expression vectors encode a cell
      surface marker gene, murine Thy-1, for specific detection of transfected cells.
      Dual staining for the surface molecule Thy-1 and DNA content was used to
      determine cell-cycle profile and G2-phase arrest. RESULTS: C33A cells not
      expressing HPV-16 E6 showed some but not maximal G2-phase arrest when transfected
      with pVPR(HIGH) alone (43.2% of cells in the G2 phase). Addition of HPV-16 E6 or
      E6 plus E7 to pVPR(HIGH) substantially increased the percentages of cells in the
      G2 phase (51.3% and 53.0%, respectively). Cotransfection with pVPR(HIGH) and HPV
      16 E7 did not increase significantly the percentage of cells in the G2 phase
      compared with pVPR(HIGH) alone (40.6% versus 43.2%). In transfections involving
      pVPR(LOW), a slight degree of G2-phase arrest was observed when Vpr was expressed
      alone (29.0% of cells in the G2 phase) or in cotransfection with HPV-16 E7 (33.2%
      of cells), and G2-phase arrest was augmented with the addition of HPV-16 E6
      (41.7%) or E6 plus E7 (45.7%). CONCLUSION: Cervical cancer cells are susceptible
      to cell-cycle arrest induced by HIV-1 vpr. This effect is exacerbated by
      coexpression of HPV-16 E6, although E6 alone is incapable of inducing any
      detectable G2-phase arrest, suggesting that E6 and VPR share links in cell-cycle
      signaling pathways.

PMID- 10636518
TI  - Vulvar lichen sclerosus: an immunologic study.
AB  - OBJECTIVE: To investigate the seroimmunologic (CD3, CD4, CD8 lymphocytes, C3c and
      C4 complement fractions, and several autoantibodies) and immunohistochemical (T
      lymphocyte subpopulations, B lymphocytes, natural killer cells, macrophages,
      immunoglobulin [Ig] G, Ig M, and C3c complement fraction) characteristics of
      vulvar lichen sclerosus. METHODS: Serum samples from 68 women with histologically
      proven lichen sclerosus were compared with those from 53 healthy controls, and
      tissue samples from 14 of 68 women chosen at random were compared with those from
      14 of 53 healthy controls. A scoring system was constructed to compare the number
      of cells in the tissue. RESULTS: Patients had significantly lower counts of
      circulating lymphocytes CD3 and CD4 than controls (P < .05) and a higher number
      of autoantibodies (P < .01). Analysis of the tissue samples confirmed a lower
      number of CD2 cells (two-tailed P = .002 in epidermis, .005 in dermis), CD3 cells
      (two-tailed P = .001 in epidermis and in dermis), CD4 cells (two-tailed P = .002
      in epidermis, .011 in dermis), and CD8 cells (two-tailed P = .002 in epidermis,
      .051 in dermis) in subjects than in controls. Numbers of monocyte-macrophage
      cells were similar in the epidermis but different in the dermis (two-tailed P =
      .003). No natural killer CD56 cells or B lymphocytes (CD19-CD21) were detected in
      the affected areas. Deposits of IgG, IgM, and C3 were no greater in biopsy
      specimens of patients than in those of controls. CONCLUSION: Vulvar lichen
      sclerosus is not caused by a T cell-mediated response, and a viral origin is
      unlikely. The absence of CD19 and CD21 cells excludes local production of
      autoantibodies. Our data do not confirm an autoimmune pathogenesis for vulvar
      lichen sclerosus but help explain why systemic cortisone is of no benefit and
      justify the use of petroleum jelly to relieve pruritus.

PMID- 10636519
TI  - Laparoscopic Burch colposuspension for stress urinary incontinence: a randomized
      comparison of one or two sutures on each side of the urethra.
AB  - OBJECTIVE: To compare 1-year cure rates after laparoscopic Burch colposuspension
      using one double-bite or two single-bite sutures on each side of the urethra.
      METHODS: Consecutive women with primary stress urinary incontinence at one
      university hospital were included. Preoperative clinical and urodynamic
      evaluation included cystoscopy, cystouretrometry at rest and stress, and a
      standardized pad test. Immediately before surgery, the patients were randomized
      to have one or two polytetrafluoroethylene (GoreTex CV 2; W. L. Gore Inc.,
      Flagstaff, AZ) sutures placed on each side of the urethra. During surgery, access
      to the space of Retzius was achieved by transperitoneal videolaparoscopic
      technique. Women were scheduled for postoperative interview and pad test 1 year
      after surgery. RESULTS: We included 161 women in the study; 78 were randomized to
      one suture (group A) and 83 to two sutures (group B). Median time for surgery was
      significantly shorter for group A than for group B (60 compared with 77 minutes;
      P < .001). We examined 158 women 1 year after surgery, at which time 148
      performed a pad test. Objective cure rate was significantly higher in group B
      than in group A (83% compared with 58%; P = .001). CONCLUSION: Two single-bite
      sutures resulted in a significantly higher objective short-term cure rate than
      one double-bite suture on each side of the urethra.

PMID- 10636520
TI  - Correlation of intraurethral ultrasonography and needle electromyography of the
      urethra.
AB  - OBJECTIVE: To correlate structural intraurethral ultrasound findings with needle
      electromyography of striated urethral sphincters in young continent nulliparas.
      METHODS: Twenty-three nulliparas, each less than 35 years old and without pelvic
      floor disorders, were recruited at Methodist Hospital in Indianapolis, Indiana,
      and the University of Louisville in Louisville, Kentucky. Each had concentric
      needle electromyography of their urethra to localize their striated urethral
      sphincter. Intraurethral ultrasound was used to identify the needle tip and layer
      in which it was found, examine the sonographic appearance of periurethral
      anatomy, and measure the thickness of hypoechoic and outer hyperechoic layers.
      RESULTS: Three layers were seen on intraurethral ultrasound: a mildly hyperechoic
      inner layer, a hypoechoic middle layer, and a hyperechoic outer layer. The
      concentric needle tip was seen in all subjects and showed motor unit action
      potentials when located in the outer hyperechoic layer. The mean thickness of the
      hypoechoic layer was 2.5 mm, and the mean thickness of the outer hyperechoic
      layer was 2.6 mm. CONCLUSION: Motor unit action potentials showed that striated
      muscle was present in the outer hyperechoic layer on intraurethral ultrasound,
      implying that it contains the striated urethral sphincter.

PMID- 10636521
TI  - Effect of obstetrics-gynecology clerkship duration on medical student examination
      performance.
AB  - OBJECTIVE: To compare medical student performance on the obstetrics and
      gynecology national board subject examination during two different clerkship
      rotation formats. METHODS: We compared medical student performance on the
      National Board of Medical Examiners (NBME) subject examination in obstetrics and
      gynecology for 2 years before and 2 years after the length of the clerkship at
      the University of Florida was decreased from 8 to 6 weeks. Medical College
      Admission Test (MCAT) and United States Medical Licensing Examination (USMLE)
      step 1 and step 2 scores were used to assess comparability between groups.
      Student t test and chi2 analysis were used as appropriate. RESULTS: Medical
      school classes were similar with respect to MCAT and USMLE step 1 and step 2
      scores. Collectively, 231 students who completed the 8-week clerkship scored
      significantly higher on the subject examination than 239 who completed the 6-week
      clerkship (618.6 versus 593.5, P = .001). When analyzed by semester, students who
      completed the clerkship in the second half of the academic year scored similarly
      regardless of clerkship length (630.6 versus 616.7, P = .11); however, students
      who completed the clerkship during the first half of the academic year scored
      significantly higher with the 8-week than the 6-week clerkship (607.3 versus
      569.7, P < .001). Students who took the clerkship in the last half of the
      academic year scored higher than students who took the clerkship in the first
      half for both the 8-week (630.6 versus 607.3; P = .02) and 6-week (616.7 versus
      569.7; P < .001) formats. Those differences persisted on examination letter grade
      assignment. CONCLUSION: Decreasing the duration of the obstetrics-gynecology
      medical student clerkship resulted in lower subject examination scores,
      especially for students who matriculated in the first half of the academic year.

PMID- 10636522
TI  - Laparoscopic vaginal delivery: report of a case, literature review, and
      discussion.
AB  - I review the literature on laparoscopically assisted vaginal delivery, present
      and discuss a case, and describe the technique. Laparoscopically assisted vaginal
      delivery will emerge as a triumphant obstetric innovation that will radically
      transform operative obstetrics in the 21st century.

PMID- 10636523
TI  - Ross procedure: the treatment of choice for aortic valve disease?

PMID- 10636524
TI  - Left ventricular remodelling: the chicken and egg story of structure and
      function.

PMID- 10636525
TI  - Protective effect of intravenous magnesium in acute myocardial infarction
      following thrombolytic therapy.
AB  - The role of intravenous magnesium therapy in patients with acute myocardial
      infarction (AMI) who received thrombolytic therapy is controversial. The results
      from previous clinical trials were not in consonance. We therefore conducted a
      prospective, randomized, double-blind, placebo controlled study in 350 patients
      with confirmed AMI during the period January 1994 to December 1996. The role of
      intravenous magnesium sulphate therapy (2 g over 5 min followed by 16 g over 24
      h) was evaluated in patients with AMI who received thrombolytic therapy. Study
      group consisted of 169 patients who were administered magnesium sulphate. Control
      group comprised of 181 patients who were given isotonic saline. Among those in
      the magnesium group, 70% received magnesium within 6 h after the onset of
      symptoms. All patients received magnesium immediately after the completion of
      thrombolytic therapy. Patients were followed up for 30 days after AMI. The number
      of deaths in the study group was 6 (3.5%) compared with control arm in which 18
      patients (9.9%) died (P value <0.01 95% Confidence intervals [CI] 1.2 to 11.6).
      Ventricular arrhythmias were also less in the magnesium arm; 27 patients (13%)
      compared with 83 patients (48.6%) in the control arm (P value 0.00001 95% Cl 26.7
      to 44.5). In the magnesium group 15 patients (8.8%) had re-infarction compared
      with 23 patients (12.7%) in the placebo arm (P value not significant). Post
      myocardial infarction angina was observed in 47 patients (27.8%) in the magnesium
      arm compared with 60 patients (33.1%) in the placebo arm (P value not
      significant). The main side effect of intravenous magnesium was transient
      flushing observed in 152 (90%) patients. Intravenous magnesium sulphate in
      patients with AMI is a safe and useful adjunct to thrombolytic therapy in
      reducing the short-term mortality and ventricular arrhythmias after AMI.

PMID- 10636526
TI  - Magnesium in the management of acute myocardial infarction--has it proved
      beneficial?

PMID- 10636528
TI  - Tissue Doppler imaging in the normal fetus.
AB  - Tissue Doppler imaging is a new non-invasive method that derives measurements of
      relaxation velocities directly from the myocardium. This approach to studying
      myocardial velocities offers the potential for quantitative assessment of
      diastolic ventricular function. Data on myocardial tissue velocities in normal
      fetuses have not been established. We measured motion velocities of the left
      ventricular posterior wall, right ventricular anterior wall, interventricular
      septum along the long axis in 30 normal fetuses aged 19-38 weeks gestation (mean,
      26.3+/-6.0 weeks). In all fetuses, peak myocardial velocities during early
      diastole (EW) and atrial contraction (AW) waves were recorded. The mean values
      for EW, AW, and E/AW of left ventricle were 5.4+/-1.7, 7.0+/-1.4 cm/s, and 0.77+/
      0.19, respectively, and those of right ventricle were 5.5+/-1.5, 7.8+/-1.5 cm/s,
      and 0.70+/-0.14, respectively. The EW(4.1+/-1.0 cm/s) and the AW (5.3+/-0.8 cm/s)
      of the interventricular septum were significantly lower than those of the left
      and right ventricular walls (P<0.01). The EW and E/AW of the left ventricular
      wall increased significantly with increasing gestational age (r=0.81 and 0.85,
      respectively, P<0.01). Similar changes were observed in the myocardial velocities
      of the right ventricular wall. The EW and E/AW of the interventricular septum
      also increased significantly with age (r=0.63 and 0.78, respectively, P<0.01).
      However, AW of the interventricular septum showed little changes. In both
      ventricles, there were significant correlations between tissue Doppler E/AW and
      pulsed Doppler E/A (LV, r=0.56; and RV, r=0.60, P<0.01). Assessment of myocardial
      tissue velocities in fetuses is feasible with tissue Doppler imaging. Age-related
      alterations in tissue Doppler velocities may suggest age-related maturational
      changes in diastolic function.

PMID- 10636527
TI  - The prognostic implications of outpatient diuretic dose in heart failure.
AB  - In 111 patients with left ventricular ejection fraction < or =30% who required
      hospitalization for heart failure, we examined the association between outpatient
      dose of diuretic agents and all-cause mortality. In comparison to patients who
      were not on treatment with diuretics prior to hospitalization, patients being
      treated with 'low' doses of diuretics (<80 mg/day of furosemide) and those being
      treated with 'high' doses of diuretics (> or =80 mg/day of furosemide) were more
      likely to die during follow-up after adjustment for other clinical parameters
      (adjusted relative risks, RR, 3.1 and 4.6).

PMID- 10636529
TI  - Increased QT dispersion in patients with insulin-dependent diabetes mellitus.
AB  - AIM: To compare the QT dispersion in unselected patients with insulin-dependent
      diabetes mellitus to non-diabetic control subjects and to assess the association
      between the QT dispersion and cardiac autonomic neuropathy, ischaemic heart
      disease, blood pressure level and nephropathy. METHODS: 42 patients with insulin
      dependent diabetes mellitus and 80 control subjects aged 40-57 years
      participated. The QT interval was measured in a resting 12-lead electrocardiogram
      (ECG) and the QT dispersion defined as the difference between the maximum and
      minimum QT interval. Bazett's formula was used to correct for heart rate (QTc).
      The degree of cardiac autonomic neuropathy was assessed by five function tests
      and ischaemic heart disease was defined by a previous myocardial infarction, ECG
      abnormalities or a positive exercise test. RESULTS: Compared to control subjects,
      diabetic patients had a longer QTc interval (433 vs. 416 ms; P=0.002) and a
      higher QT dispersion (36 vs. 30 ms; P=0.02). In the diabetic group, the QTc
      interval was prolonged in patients with autonomic neuropathy (449 vs. 420 ms;
      P=0.007) and the QT dispersion was increased in patients with ischaemic heart
      disease (51 vs. 33 ms; P=0.004). No association was found to urinary albumin
      excretion rate or blood pressure. CONCLUSION: The QT dispersion as well as the
      QTc interval is increased in patients with insulin-dependent diabetes mellitus.
      The association between QT dispersion and ischaemic heart disease indicates that
      abnormalities in cardiac repolarisation may be caused by complications to
      diabetes rather than diabetes in itself.

PMID- 10636530
TI  - Risk stratification of sudden cardiac death and malignant ventricular arrhythmias
      in right ventricular dysplasia-cardiomyopathy.
AB  - Arrhythmogenic right ventricular dysplasia-cardiomyopathy is in most cases a
      benign cause of ventricular arrhythmias in young patients. The major reason of
      mortality is sudden arrhythmic death with an annual rate of 2-3% as the first
      manifestation of the disease in most cases. Little is known about risk factors of
      sudden arrhythmic death so far. The purpose of the retrospective study was to
      classify risk factors from invasive and non-invasive examinations. METHODS: In a
      cohort of 121 consecutive patients sampled from 1986 to 1998 the value of right
      ventricular dilatation, left ventricular involvement analysed by
      angiocardiography or echocardiography and standard ECG parameters such as
      precordial T wave inversions, right precordial ST elevation, precordial QRS
      dispersion, left precordial JT interval prolongation and complete right bundle
      branch block were determined. The whole cohort of patients were divided into two
      groups with high arrhythmic risk (aborted or non-aborted sudden death, recurrent
      ventricular tachycardia despite medical treatment, recurrent syncopes) and low
      risk (frequent ventricular premature beats, non sustained ventricular
      tachycardia, uneventful course under medical therapy). RESULTS: From
      angiocardiography or echocardiography in a quantitative approach right
      ventricular dilatation (p<0.0001) and additional left ventricular abnormalities
      (p<0.0001) could be identified as major risk factors. From an ECG point of view
      increased precordial QRS dispersion > or =50 ms (p<0.01) with complete right
      bundle branch block and right ventricular dilatation in most cases and precordial
      T wave inversions beyond V3 (p<0.0001) and the phenomenon of left precordial JT
      interval prolongation (JT dispersion > or =30 ms) in cases of additional left
      ventricular abnormalities represented non-invasive predictors of recurrent
      arrhythmic events. Right precordial ST segment elevation could be excluded as
      risk factor of sudden arrhythmic death. CONCLUSIONS: Right ventricular dilatation
      with ECG depolarisation abnormalities and additional left ventricular involvement
      with striking ECG repolarisation abnormalities could be identified as strong risk
      factors of recurrent arrhythmic events in ARVD with unfavorable prognosis.

PMID- 10636531
TI  - Heart failure in arrhythmogenic right ventricular dysplasia-cardiomyopathy.
AB  - Sudden arrhythmic death and heart failure are essential factors influencing the
      prognosis of arrhythmogenic right ventricular dysplasia-cardiomyopathy. Heart
      failure is a rare, but often lethargic event although little is known about
      morphology, time course and non-invasive predictors. METHOD: In a retrospective
      study of a consecutive cohort of 121 patients with ARVD over a follow-up period
      of up to 12 years morphological features of heart failure, time course from the
      initial diagnosis and standard 12-lead ECG as a non-invasive predictor of
      developing heart failure were analysed. RESULTS: Heart failure occurred in 13
      patients (11%) with isolated right ventricular dilatation and loss of function in
      10 cases (77%) and biventricular failure in three cases (23%). Patients developed
      NYHA class IV in four cases, class III-IV in two cases and class II in seven
      cases in 4-8 years. In standard ECG of 12 patients (92%) complete right bundle
      branch block was present at the time of initial diagnosis (n=6) or in a time
      interval of 4 years (n=6). Morphological distinction of isolated right and
      biventricular heart failure could be achieved not only by imaging techniques such
      as echocardiography or cardioangiography, but also by standard ECG with right
      atrial hypertrophy and an increased mean precordial QRS dispersion of 47.1+/-18.9
      ms in cases of right heart failure and biatrial hypertrophy and a reduced
      precordial QRS dispersion of 33.0+/-23.1 ms in cases of biventricular heart
      failure. CONCLUSIONS: Heart failure in ARVD consists of isolated right
      ventricular and biventricular dilatation and pump failure in a time course of 4-8
      years after developing complete right bundle branch block as a strong non
      invasive predictor from standard 12-lead ECG.

PMID- 10636532
TI  - Elevated tumor necrosis factor alpha of blood mononuclear cells in patients with
      congestive heart failure.
AB  - To study the changes of tumor necrosis factor-alpha (TNF-alpha) produced by
      peripheral blood mononuclear cells (PBMC) of patients with congestive heart
      failure (CHF), we determined the TNF-alpha concentrations of plasma and culture
      supernatant of PBMCs in 113 patients with various heart diseases. The results
      showed that plasma levels of TNF-alpha were significantly higher in CHF patients
      (n=50, 13.36+/-6.09 pg/ml) and in cachetic CHF patients (n=26, 19.20+/-10.42
      pg/ml) than in the controls (n=37, 6.73+/-3.91 ng/ml). The supernatant levels of
      TNF-alpha in cultured PBMC (PBMC-TNF-alpha) were also significantly elevated in
      CHF patients (5.77+/-2.11 ng/ml), and even higher in cachetic CHF patients
      (7.01+/-5.11 ng/ml), as compared with the controls (2.27+/-2.24 ng/ml). There was
      a significant correlation between levels of PBMC-TNF-alpha and severity of heart
      failure (r=0.48, P<0.01). But no correlation between PBMC-TNF-alpha and plasma
      TNF-alpha was observed. These results demonstrate that the expression of TNF
      alpha in PBMC is increased in patients with CHF, especially in patients with CHF
      accompanied by cachexia, suggesting that PBMC-TNF-alpha may be a potential
      biochemical indicator to evaluate the patients with CHF.

PMID- 10636533
TI  - Elevated serum and monocyte tumour necrosis factor alpha in patients with
      congestive heart failure.

PMID- 10636534
TI  - Do the presence and amount of dysfunctional but viable myocardium affect the
      perioperative outcome of coronary artery bypass graft surgery?
AB  - The aim of our study was to assess the influence of the presence and amount of
      dysfunctional but viable myocardium on the perioperative outcomes in patients
      with coronary artery disease and moderate-to-severe left ventricular systolic
      dysfunction, who underwent coronary artery bypass graft surgery. Viability
      evaluation with low-dose dobutamine echocardiography was performed in 302
      consecutive patients with coronary artery disease and left ventricular ejection
      fraction < or =40%, who were referred for coronary angiography and potential
      coronary revascularization. To quantify the amount of dysfunctional but viable
      myocardium, wall motion was scored using a 16-segment model. The dysfunctional
      segments were defined as viable if they exhibited improvement in their thickening
      by at least one grade. One hundred and twenty-seven patients underwent coronary
      artery bypass graft surgery. The perioperative outcomes were evaluated in 122 of
      them. Five patients were excluded because of inability to revascularize all
      vessels supplying dysfunctional but viable myocardial segments. Twenty-five
      patients exhibited a large amount of dysfunctional but viable myocardium (> or =6
      segments, group A), 59 patients had a small amount of such myocardium (2-5
      segments, group B), and 38 patients were found to have their dysfunctional
      myocardium irreversibly damaged (group C). The perioperative mortality in groups
      A, B, and C was 4, 10, and 11% (all P = NS), respectively. The rate of
      perioperative Q-wave myocardial infarction was 8, 10, and 3% (all P = NS),
      respectively. Similarly, there were no significant differences among the groups
      with respect to perioperative outcome variables including ventricular
      arrhythmias, duration and magnitude of catecholamine support, renal failure,
      pulmonary edema, and need for mechanical ventricular support or artificial
      ventilation. In patients with coronary artery disease and moderate-to-severe left
      ventricular dysfunction who underwent coronary artery bypass graft surgery, the
      presence and amount of dysfunctional but viable myocardium did not influence the
      perioperative outcome.

PMID- 10636536
TI  - Recurrent symptomatic bilateral bundle branch block in a 74-year-old patient with
      a prosthetic aortic valve: a description of a case and review of the literature.
AB  - This report concerns a 74-year-old patient who had undergone aortic valve
      replacement 11 years earlier. On admission, the patient complained of shortness
      of breath when climbing two flights of stairs; there was no history of dizziness,
      fainting or sensations of arrhythmias. An ECG at rest showed first-degree
      atrioventricular (A-V) block together with left bundle branch block (LBBB). On
      bicycle ergometry, there was a fall in blood pressure and in heart rate due to a
      second-degree (2:1) A-V block along with the LBBB. After termination of exercise,
      the PR interval increased further from 0.24 s to >0.3 s, together with right
      bundle branch block (RBBB) and 1:1 A-V conduction instead of LBBB. Finally, at a
      constant atrial rate of 98/min, the RBBB disappeared, LBBB recurred, again with
      2:1 A-V conduction. The diagnosis was bilateral BBB together with first degree A
      V block at rest and higher-degree A-V block on effort. The patient underwent
      pacemaker implantation and was discharged shortly thereafter free of symptoms.

PMID- 10636535
TI  - Combination therapy with tirofiban and enoxaparin in acute coronary syndromes.
AB  - BACKGROUND: Tirofiban, an intravenous glycoprotein IIb/IIIa antagonist, and
      enoxaparin, a low molecular weight heparin, have each been shown to be effective
      at reducing cardiac ischemic events compared to unfractionated heparin alone in
      separate trials of patients with unstable angina and non-Q-wave myocardial
      infarction. The combination of these agents may offer further therapeutic
      benefit. MATERIALS AND METHODS: Fifty-five patients with non-Q-wave myocardial
      infarction were randomized to receive double-blind treatment with tirofiban (0.1
      microgram/kg/min i.v.) for 48-108 h coadministered with either enoxaparin (1
      mg/kg sc q 12 h) (n=26) or unfractionated heparin (i.v. adjusted to activated
      partial-thromboplastin time) (n=27) to evaluate pharmacokinetics,
      pharmacodynamics, and safety. The primary objective of the study was to
      investigate the effect of unfractionated heparin versus enoxaparin on the plasma
      clearance of tirofiban. RESULTS: Coadministration of tirofiban and enoxaparin was
      generally well tolerated. Plasma clearance of tirofiban was 176.7+/-59.8 and
      187.5+/-81.8 ml/min, respectively, for enoxaparin and unfractionated heparin
      treated patients (P=NS). The mean difference was well within the prespecified
      criterion for comparability. Administration of tirofiban with enoxaparin vs.
      unfractionated heparin resulted in lesser variability and a trend towards greater
      inhibition of platelet aggregation using 5 microM adenosine phosphate agonist.
      More patients achieved target inhibition of platelet aggregation >70% in the
      tirofiban and enoxaparin group (84% vs. 65%, P=0.19). Median bleeding time was 21
      min for tirofiban and enoxaparin vs. > or =30 min for tirofiban and
      unfractionated heparin (P=NS). For a given level of inhibition of platelet
      aggregation, bleeding time was less prolonged with tirofiban and enoxaparin than
      tirofiban and unfractionated heparin (adjusted mean bleeding time 19.6 vs. 24.9
      min, P=0.02). Tirofiban plasma concentration and clearance were comparable
      whether coadministered with enoxaparin or unfractionated heparin. There were no
      major or minor bleeding events in either group by the TIMI criteria.
      INTERPRETATION: The more consistent inhibition of platelet aggregation and lower
      adjusted bleeding time of tirofiban and enoxaparin vs. tirofiban and
      unfractionated heparin support the therapeutic potential of combining these two
      agents. These data from the first clinical report of coadministration of a
      glycoprotein IIb/IIIa receptor antagonist and a low molecular weight heparin are
      consistent with prior data which show differential pharmacodynamic effects of
      enoxaparin and unfractionated heparin on platelet aggregation.

PMID- 10636537
TI  - Atrial septal aneurysm--is it a benign finding?

PMID- 10636538
TI  - Device therapy for malignant neonatal long QT syndrome.

PMID- 10636539
TI  - Statin + fibrate combination therapy--fluvastatin with bezafibrate or
      ciprofibrate in high risk patients with vascular disease.

PMID- 10636540
TI  - Blunt injury of the thoracic aorta.

PMID- 10636541
TI  - Long term results after multiple injuries including severe head injury.
AB  - OBJECTIVE: To describe the long term results in patients with multiple injuries
      including severe head injury. DESIGN: Retrospective and prospective clinical
      study. SETTING: Level I trauma centre, Germany. PATIENTS: Patients aged 16-60
      years who had been injured more than 2 years before, whose Injury Severity Score
      was over 20 and whose cranial Abbreviated Injury Score (AIS) was over 3. MAIN
      OUTCOME MEASURES: Glasgow Outcome Scale (GOS), functional, neuropsychological,
      vocational and social outcomes. RESULTS: 58 patients, median age 24 (range 16-53,
      interquartile range (IQR) 21-32) years were investigated 5 (3-9; IQR 4-7) years
      after their injury. Median ISS was 34 (21-57; IQR 26-41) and GCS 6 (3-8; IQR 4
      7). Duration of coma was 10 (2-51; IQR 7-22) days and neurological rehabilitation
      lasted 169 (10-830; IQR 80-300) days. Movements of the elbow and ankle was most
      impaired by injury. All psychometric tests showed deficits, particularly in speed
      of processing, concentration, recent memory, and learning performance. The social
      environment had been changed in half and vocational rehabilitation was dependent
      on age. 24 (42%) returned to their former profession, 18 (31%) were retrained to
      another profession, 16 (27%) were unemployed or retired on a pension. 31 (53%)
      made a good recovery with moderate disability, 19 (33%) had severe disability,
      and 8 (14%) remained in a persistent vegetative state assessed by the GOS.
      CONCLUSION: Early and concentrated rehabilitation facilitates functional, social,
      and neuropsychological reintegration.

PMID- 10636542
TI  - Lessons from analysis of World Wide Web server activity data:
      http://www.swsahs.nsw.gov.au/livtrauma.
AB  - OBJECTIVE: To establish visiting patterns and use of resources within an
      educational world wide web site, to develop strategies for its more effective use
      as a teaching medium. DESIGN: Prospective descriptive study. SETTING: A web site
      maintained by a major Australian metropolitan trauma service. SUBJECTS: All
      visitors to the web site over a 40 day period. MAIN OUTCOME MEASURES: Number of
      visitors, requests for pages, and transfer of files; timing and duration of
      visits; first and last pages viewed during visits; pages viewed most often;
      source of referral and country of origin of visitors. RESULTS: There were 2237
      visits, and a mean of 5.8 pages/visit were viewed. Mean duration of each visit
      was 4 minutes 35 seconds, and only half the visitors entered through the home
      page. The collection of radiographs was most commonly consulted. Visitors came
      from 26 different countries, 42% from Australia. CONCLUSIONS: Factors that
      influenced the use of the site were identified and have altered our plans for
      development.

PMID- 10636543
TI  - Education of the trauma team: video evaluation of the compliance with universal
      barrier precautions in resuscitation.
AB  - OBJECTIVE: To assess the effectiveness of an educational symposium designed to
      improve compliance with universal barrier precautions by the use of video
      analysis of resuscitations. DESIGN: Prospective single blind analysis of data.
      SETTING: Hospital Trauma Unit, Johannesburg, South Africa. SUBJECTS: 100 severely
      injured patients who presented to the emergency room, divided into two study
      periods. INTERVENTIONS: An educational symposium held between the study periods,
      which focused on universal barrier precautions and the risk of occupational
      transmission of HIV. MAIN OUTCOME MEASURES: Compliance with items of universal
      precautions; mechanism; Injury Severity Score and Revised Trauma Score. RESULTS:
      There was a significant improvement in compliance from 48% to 74% after the
      symposium (p = 0.007), with specific improvement in the wearing of masks and
      visors. Initially there was poor compliance with universal precautions in
      severely injured patients, which significantly improved to 83% compliance (p =
      0.0004). CONCLUSION: Video analysis of resuscitations is an effective audit and
      educational tool that allows analysis of compliance with protocol. The education
      symposium was effective in altering attitudes and behaviour towards universal
      barrier precautions.

PMID- 10636544
TI  - Reduced B cell HLA-DR expression and natural killer cell counts in patients prone
      to sepsis after injury.
AB  - OBJECTIVE: To examine the influence of natural killer (NK) cells and HLA-DR
      molecules on B cells in the development of severe sepsis after injury. DESIGN:
      Prospective study. SETTING: Medical school, Germany. SUBJECTS: 46 severely
      injured (Injury Severity Score >16) patients. INTERVENTIONS: Blood samples were
      taken immediately after admission and subsequently for 14 days. MAIN OUTCOME
      MEASURES: HLA-DR expression on B cells and counts of B and NK cells measured by
      flow cytometry, and morphological estimation of large granular lymphocytes by
      microscopy. RESULTS: HLA-DR expression on circulating B cells was significantly
      reduced from days 6-14 after admission in 13 patients with subsequent severe
      sepsis compared with 33 patients who did not develop sepsis. In septic patients
      NK cell counts were significantly decreased from day 4 onwards (p < 0.05).
      CD16+/CD56+ cells correlated with the morphology of large granular lymphocytes.
      CONCLUSION: In severely injured patients reduced counts of NK cells and HLA-DR
      molecules on B lymphocytes seem to be part of an immune deviation that is
      associated with the development of severe sepsis.

PMID- 10636545
TI  - Risk factors of delayed diagnosis of pancreatic trauma.
AB  - OBJECTIVE: To identify risk factors associated with delayed diagnosis of
      pancreatic injuries. DESIGN: Retrospective study. SETTING: University hospital,
      Finland. PATIENTS: 31 patients treated for pancreatic injuries from January 1986
      to April 1998. INTERVENTIONS: Clinical, laboratory, and radiological assessment.
      Initial management operative (n = 22) and non-operative (n = 9). MAIN OUTCOME
      MEASURES: Timely or delayed (>12 hours after injury) recognition of pancreatic
      trauma. RESULTS: Blunt trauma (7/17 timely and 12/14 delayed diagnosis, p =
      0.03), intoxication on admission (4/10 compared with 5/5 patients studied, p <
      0.05), low New Injury Severity Score (median, interquartile 34, 11.5-41 compared
      with 14.5, 10-25, p = 0.02), low Abdominal Trauma Index (38, 20-54 compared with
      16.5 15-24, p = 0.01), absence of associated abdominal organ injuries (1/17
      compared with 8/14, p = 0.004), and initial nonoperative management (2/17
      compared with 7/14, p = 0.04) were significant risk factors of delayed diagnosis
      of pancreatic trauma. The main reasons for the delay in diagnosis were missed
      pancreatic injury at initial operation (n = 4, 2 penetrating), failure to exclude
      blunt pancreatic injury before non-operative management (n = 4), delay in
      presentation (n = 3), underestimation of the severity of pancreatic injury on
      initial computed tomogram (n = 2), and missed diagnosis of blunt duodenal rupture
      with mild pancreatic injury (n = 1). CONCLUSIONS: In patients with blunt
      abdominal trauma and altered consciousness with few clinical signs, and no or
      mild associated abdominal injuries, we recommend additional diagnostic studies to
      exclude pancreatic rupture before starting non-operative management. Exposure and
      evaluation of the pancreas during laparotomy for trauma is essential.

PMID- 10636546
TI  - Harris or axis ring: an aid in diagnosing low (type 3) odontoid fractures.
AB  - OBJECTIVE: To present our experience of diagnosing fractures of the odontoid
      process on lateral radiographs of the cervical spine that show the Harris (axis)
      ring. DESIGN: Retrospective study. SETTING: Teaching hospital, Belgium. SUBJECTS:
      12 patients with multiple injuries, including cervical spine, 8 of them
      unconscious or uncooperative. INTERVENTIONS: Cross table lateral view of the
      cervical spine. MAIN OUTCOME MEASURE: Identification of otherwise hidden type 3
      axial fractures. RESULTS: Diagnosis of low odontoid fractures in all cases.
      CONCLUSION: The Harris ring is disrupted in low odontoid fractures and intact in
      fractures of the odontoid process. Awareness of this sign will allow diagnosis of
      otherwise hidden axial fractures.

PMID- 10636547
TI  - One-stage lengthening and derotational osteotomy of the femur stabilised with a
      gamma nail.
AB  - OBJECTIVES: To study the results of a one-stage lengthening and derotational
      osteotomy stabilised with a Gamma nail. DESIGN: Retrospective study. SETTING: 2
      hospitals, The Netherlands. PATIENTS: 5 patients after failed osteosynthesis of
      femoral fractures. INTERVENTIONS: Mean lengthening of 3 cm and derotation of 30
      degrees. MAIN OUTCOME MEASURES: Complications and functional results, after a
      mean follow-up of 43 months (range 30-57). RESULTS: Two patients required
      dynamisation and a cancellous bone graft to achieve union, which resulted in 1
      and 1.5 cm loss of length. One patient had a temporary peroneal neurapraxy. No
      infections were observed. CONCLUSIONS: Our method is not an ultimate solution,
      but is suitable for one-stage lengthening and derotation osteotomies.

PMID- 10636548
TI  - Role of technetium tetrofosmin scintimammography in the diagnosis of malignant
      breast masses and axillary lymph node involvement: a comparative study with
      mammography and histopathology.
AB  - OBJECTIVE: To assess the role of Technetium-99m (99mTc) tetrofosmin
      scintimammography in the detection of breast cancer and involvement of axillary
      nodes. DESIGN: Open study. SETTING: General hospital, Turkey. SUBJECTS: 128 women
      who presented with masses in the breast. INTERVENTIONS: Scintimammography,
      standard mammography, and either excision or fine-needle aspiration biopsy to
      confirm the diagnosis. MAIN OUTCOME MEASURES: Sensitivity, specificity, and
      positive and negative predictive value of scintimammography compared with
      mammography. RESULTS: Sensitivity, specificity, and positive and negative
      predictive value (%) of 99mTc scintimammography were 95, 96, 97 and 92,
      respectively. The corresponding figures for standard mammography were 87, 26, 68
      and 52. Scintimammography changed the 34 false positive mammograms into true
      negatives, at the expense of four false negatives. The sensitivity of
      scintimammography in detecting axillary lymph node metastases was 72% and
      specificity 100%. CONCLUSION: Scintimammography with 99mTc tetrofosmin seems to
      be of value in the detection of breast malignancy and axillary metastases. It may
      help to avoid unnecessary operations in patients whose mammograms do not give a
      definite diagnosis.

PMID- 10636549
TI  - Surgical treatment of non-parasitic hepatic cysts: report of 12 cases.
AB  - OBJECTIVE: To present our experience of non-parasitic hepatic cysts. DESIGN:
      Retrospective study. SETTING: University Hospital, Greece. SUBJECTS: 12
      consecutive patients with symptomatic non-parasitic hepatic cysts operated on
      during the 7-year period 1990-97 inclusive. INTERVENTIONS: Wide unroofing of the
      hepatic cysts. MAIN OUTCOME MEASURES: Persistence or recurrence of symptoms and
      recurrence of cysts. RESULTS: Symptoms persisted or recurred in 2/12 patients and
      cysts recurred in 2/9 who had ultrasound scans. CONCLUSION: Surgical treatment of
      non-parasitic hepatic cysts was effective and safe.

PMID- 10636550
TI  - Choledochal cysts in children: a review of 28 years of treatment in a Dutch
      children's hospital.
AB  - OBJECTIVE: To analyse the results of surgical treatment of choledochal cysts.
      DESIGN: Retrospective study. SETTING: Children's hospital, The Netherlands.
      PATIENTS: 14 children presenting with choledochal cysts. INTERVENTIONS:
      Choledochoduodenostomy, Roux-en-Y choledochojejunostomy or Roux-en-Y
      hepaticojejunostomy. MAIN OUTCOME MEASURES: Morbidity and mortality RESULTS: The
      mean age of the patients was 20 months (2 weeks to 7 years). 10 patients had a
      type I choledochal cyst; three a type IV, and one a type V. Mean follow-up period
      was 6 years (18 months to 16 years). One patient with a type I cyst died of
      Klebsiella pneumoniae that was resistant to treatment. One patient with a type I
      cyst treated by choledochojejunostomy had two episodes of cholangitis. Another
      patient with a type I cyst, treated by choledochoduodenostomy, had one episode of
      cholangitis. Both could be treated with antibiotics. The other patients had had
      no complications up to 1997. CONCLUSION: This rare anomaly may lead to severe
      complications when left untreated or after late treatment. It is easy to manage
      with low associated morbidity.

PMID- 10636551
TI  - Laparoscopic myotomy without fundoplication in patients with achalasia.
AB  - OBJECTIVE: Analysis of outcome after laparoscopic myotomy for achalasia. DESIGN:
      Prospective audit. SETTING: Teaching hospital, Sweden. SUBJECTS: All patients
      with achalasia who had a laparoscopic myotomy without a simultaneous
      fundoplication. INTERVENTIONS: Questionnaire, pH-measurements, radiography and
      manometry. MAIN OUTCOME MEASURES: Operative and postoperative complications and
      reoperations. RESULTS: Twenty-one patients were scheduled for laparoscopic
      myotomy. Three were converted to open operations, and four were reoperated on
      transabdominally for persistent or recurrent symptoms. All patients were
      satisfied afterwards. Follow-up in 14 patients, after a median of 22 months
      (range, 6-40), included manometry, questionnaire, and 24-hour pH measurements,
      and showed significant reduction in the lower oesophageal sphincter pressure
      together with relief of symptoms. Three patients had reflux symptoms and abnormal
      pH readings. An additional five patients had abnormal pH measurements but no
      symptoms of reflux. CONCLUSIONS: Heller myotomy can safely be done
      laparoscopically. Whether a simultaneous antireflux procedure is needed remains
      to be seen.

PMID- 10636552
TI  - Selective inhibition of inducible nitric oxide synthase maintains haemodynamic
      stability without untoward consequences for hepatic function or morphology.
AB  - OBJECTIVE: To examine the effects of the inducible nitric oxide synthase
      inhibitor aminoethyl-isothiourea (AE-ITU) on haemodynamic measurements, and
      correlate these with hepatic morphology and function in a porcine model of
      endotoxaemia. DESIGN: Experimental study. ANIMALS: 15 juvenile pigs.
      INTERVENTIONS: Flow probes were placed around the hepatic artery and portal vein.
      Catheters were introduced into the portal and hepatic veins, pulmonary artery,
      and aorta. Infusion of AE-ITU was started one hour before that of endotoxin
      (study group n = 6); thereafter both substances were infused simultaneously until
      the end of the study (6 hours). The controls (n = 9) had endotoxin alone. MAIN
      OUTCOME MEASURES: Hepatic morphology assessed by light and electron microscopy;
      and hepatic integrity and function by transaminase activities and oxygen
      consumption. Systemic, pulmonary, and hepatic blood flow and pressure. RESULTS:
      AE-ITU maintained systemic blood pressure (p < 0.05 compared with controls)
      without causing pulmonary hypertension. Neither hepatic morphology nor function
      were adversely influenced. CONCLUSION: In endotoxaemia AE-ITU has a favourable
      haemodynamic profile which is achieved without impairment of hepatic function or
      morphology.

PMID- 10636553
TI  - Replacement of a tracheal segment by a mixed graft (aorta and prosthesis): an
      experimental study in rabbits.
AB  - OBJECTIVE: To develop a new graft and to verify its technical feasibility,
      viability, and ability to reduce the risk of infection by interposition of an
      aortic segment between the airway and the prosthetic component of the graft.
      DESIGN: Experimental study. SETTING: Multicentre study, France. ANIMALS: 38 New
      Zealand rabbits. INTRODUCTION: A 1 cm aortic segment was obtained from the
      thoracic aorta of a rabbit and cryopreserved or stored at +4 degrees C. The
      aortic segment, surrounded by a ringed expanded polytetrafluoroethylene (ePTFE)
      prosthesis was used to replace 1 cm of cervical trachea in two groups of rabbits,
      either with cryopreserved or fresh aorta. MAIN OUTCOME MEASURES: Macroscopic,
      microbiological, and histological studies four months later. RESULTS: 12/20
      animals in the cryopreserved group survived and 13/18 in those had had fresh
      aorta inserted. Partial or total necrosis of the aortic muscular layer was
      replaced by connective tissue, which was a guide for epithelialisation from the
      anastomoses. CONCLUSION: This new graft is worthy of further investigation, as it
      is technically feasible and easy to insert.

PMID- 10636555
TI  - Treatment of lateral incisional hernias.

PMID- 10636556
TI  - Supernumerary mediastinal parathyroid adenoma: role of 99mTc sestamibi scanning.

PMID- 10636554
TI  - Myoelectric assessment of large bowel viability: an experiment in dogs.
AB  - OBJECTIVE: To design a device for myoelectric assessment of intestinal ischaemia
      and compare it with every day surgical experience and Doppler signals recorded on
      the bowel wall. DESIGN: Experimental study. SETTING: Thessaloniki university
      hospital, Greece. MATERIAL: 12 adult mongrel dogs. INTERVENTIONS: On the first
      day the large intestine was devascularised for a length of 20 cm, 5 cm away from
      the ileocaecal valve, and the threshold of the electric stimulus (mA) required to
      produce a contraction of the normal large bowel was recorded. On the second day,
      measurements were made on the ischaemic segment of the large bowel at 0.5 cm
      intervals. Bowel resection and anastomoses were done at the stimulus level of 40
      mA. RESULTS: The mean (SD) stimulus threshold of the normal large intestine was
      12.2 mA. The necrotic intestine demanded current stimulus of 100 mA or failed to
      contract. On the eighth postoperative day the animals were killed to assess
      anastomotic healing. Of the 12 anastomoses made at the 40 mA stimulus point, only
      one ruptured. The 40 mA limit of the stimulus level seems to be of value in
      assessments of bowel viability in vivo. CONCLUSION: The use of a personal
      computer as a read out device makes myoelectric analysis easier and more reliable
      in the assessment of intestinal viability. This method may have a clinical
      application.

PMID- 10636557
TI  - Malignant gastric carcinoid and paraneoplastic cerebellar degeneration.

PMID- 10636558
TI  - Right retroperitoneal splenosis presenting as an adrenal mass.

PMID- 10636559
TI  - Laparoscopic removal of accessory spleens after splenectomy for relapsing
      autoimmune thrombocytopenic purpura.

PMID- 10636560
TI  - Aortoenteric fistula with aortic graft infection--reconstruction of the abdominal
      aorta without a graft: a possible approach in selected cases.

PMID- 10636561
TI  - Laparoscopic intragastric resection of gastric leiomyoma close to the cardia
      using a flexible endocutter intraluminally.

PMID- 10636562
TI  - Evaluating lower urinary tract symptoms suggestive of benign prostatic
      obstruction.

PMID- 10636563
TI  - Treatment of benign prostatic enlargement with alpha-blockers: an updated review.

PMID- 10636564
TI  - Finasteride in the treatment of benign prostatic hypertrophy: an update. New
      indications for finasteride therapy.
AB  - A phenomenon of the prostate gland, which is also shared by hair follicles, is
      that it is little influenced by testosterone (T) for androgenic stimulation, but
      instead by its metabolite 5alpha-dihydrotestosterone (DHT). By blocking the
      conversion of T to DHT, the circulating level of DHT is reduced by 80%, the size
      of the prostate gland is reduced by about 20% and the level of prostate-specific
      antigen (PSA) by about 50%. Treatment of patients with obstructive benign
      prostatic hypertrophy (BPH) with the drug Finasteride leads to a moderately
      improved urinary flow, symptomatic improvement and halts the natural progress of
      the disease. Since DHT potentiates the effect of testosterone on erectile
      function, the side-effects are impotence in 3% of patients, decreased ejaculatory
      volume, and gynaecomastia in 0.4% of patients. The drug could be regarded as a
      safe way to treat moderately symptomatic BPH. The efficacy of the drug is long
      lasting (more than 7 years). It has also been tried in prostate cancer, but is
      less effective. It reduces PSA levels by 50% and, in combination therapy,
      therefore, PSA levels remain low for longer when Finasteride is added. An
      important finding is the efficacy of Finasteride treatment in haematuria from
      BPH. The drug interacts with vascular endothelium growth factor and efficiently
      prevents new bleeding. It could be regarded as a first-line therapy for this type
      of haematuria. Finasteride can also be used to stop male baldness. It seems
      particularly effective in men aged 20-40 years; 85% of patients stopped losing
      hair when given Finasteride. When the treatment was stopped hair loss continued,
      thus therapy may have to be "lifelong".

PMID- 10636565
TI  - Interstitial laser coagulation and transurethral needle ablation in the
      management of lower urinary tract symptoms due to benign prostatic obstruction.
AB  - Interstitial laser coagulation and transurethral needle ablation, two different
      techniques for heat-treatment of symptomatic benign prostatic hyperplasia, are
      outlined. Both treatments have been performed in sedoanalgesia. The results of
      this research and data from the literature show that both treatment modalities
      have a marked effect on symptoms. Objective parameters, such as uroflow, are
      moderately changed postoperatively. The side-effect profiles appear favourable,
      especially with respect to bleeding per- and post-operatively. However, further
      long-term data is required.

PMID- 10636566
TI  - Hereditary prostate cancer.
AB  - Recent research makes it probable that there is a hereditary form of prostate
      cancer. By identifying prostate cancer cases in the Swedish twin registry it was
      possible to show a pronounced difference in proband concordance rates and
      correlation of liability between monozygotic and dizygotic twin pairs, which
      indicates strongly that genetic factors are important for prostate cancer. In a
      nation-wide register cohort study it was found that the risk for prostate cancer
      was approximately two times higher among sons to prostate cancer patients when
      compared to Swedish men in general. By linkage analyses at least two loci for
      putative prostate cancer genes have been identified, one on chromosome 1 (1q24
      25) and one on the X-chromosome (Xq27-28). Before genetic testing becomes
      available it was suggested that men with the familiar aggregation of prostate
      cancer should be evaluated with a PSA test on a regular basis.

PMID- 10636567
TI  - Prostate cancer in Denmark. Incidence, morbidity and mortality.
AB  - Prostate cancer incidence and mortality rates in Denmark are reviewed for a 50
      year period from 1943 to 1992. The prostate cancer incidence rate nearly tripled
      and prostate cancer mortality rate increased during this period. Until recently
      in Denmark the routine management of prostate cancer has been by deferred
      hormonal therapy. Morbidity and mortality associated with prostate cancer are
      analysed in a group of 1459 patients aged 55-74 years, who were diagnosed as
      having clinically localized prostate cancer in the 5-year period 1983 to 1987. In
      this group of patients prostate cancer is demonstrated to cause significant
      morbidity. Furthermore, the patients suffered significant excess mortality and
      loss of life expectancy.

PMID- 10636568
TI  - Treatment of clinically organ confined prostate cancer.

PMID- 10636569
TI  - Treatment of advanced prostate cancer: the vaccine approach.

PMID- 10636570
TI  - Intermittent androgen suppression. Too good to be true?
AB  - The progression of metastatic prostate cancers to an androgen-independent state
      removes the possibility of further androgen therapy. In response to this, new
      treatments that do not cause the loss of androgen sensitivity have been sought.
      Intermittent androgen suppression therapy, an adaptation of the previously used
      androgen ablation techniques, has shown great promise, comparing favourably with
      continuous androgen deprivation in pilot studies. It may, therefore, prove to be
      an excellent treatment, both individually and in combination, although further
      studies are required.

PMID- 10636571
TI  - Good quality of life in prostate cancer patients: how can it be obtained?

PMID- 10636572
TI  - The Scandinavian Prostatic Cancer Group. A short review of its history and work.
AB  - The Scandinavian Prostatic Cancer Group (SPCG) was founded in 1981 as one of
      eight collaborative groups instituted by the Scandinavian Association of Urology
      within different fields of urology. The purpose of these groups was to promote
      research, education and information provision within their different fields and
      to stimulate collaboration between the Nordic countries. The main purpose of the
      SPCG gradually evolved into conducting clinical trials. This paper presents a
      summary of the different clinical trials carried out by the group and reviews
      some of its history and other activities.

PMID- 10636573
TI  - Injectable dextranomer-based implant: histopathology, volume changes and DNA
      analysis.
AB  - OBJECTIVE: To study the tissue reaction in and around the implant, the changes in
      implant volume and the DNA profile of the invading cells when a new substance,
      dextranomers in sodium hyaluronan solution (DiHA), was injected into experimental
      animals. MATERIALS AND METHODS: Nine pigs were followed up from 2 weeks to 3.5
      months and 34 rats were followed up from 3 weeks to 16 months after injection of
      DiHA into the bladder in pigs and into the subcutaneous tissue in rats.
      Histopathological analysis was performed in 16 pig and 63 rat implants. In 31 of
      the rat implants the DNA profile was analysed. Changes in implant volume over
      time were estimated in 51 rat implants during the period up to 12 months after
      implantation. RESULTS: Histologically, in the early phases the area within and
      around the implant was fairly rich in cells, predominantly fibroblasts,
      inflammatory cells and giant cells of the foreign body type. Later in the process
      an increase in extracellular matrix around the microspheres and ingrowth of blood
      vessels was seen. No tissue necrosis or significant eosinophilia was observed
      around the implants. DNA measurements by flow cytometry revealed no aneuploid
      cells. There was a decrease in implant volume by 23% over a period of 12 months.
      CONCLUSIONS: DiHA does not induce any major tissue changes in and around the
      implants. No DNA changes were observed during the study period of 16 months. DiHA
      seem to be a safe and suitable injectable substance with good tissue-augmenting
      properties.

PMID- 10636574
TI  - Presence of arteriovenous shunting in transplanted but not in native single
      kidney in the rat.
AB  - OBJECTIVE: We previously reported the presence of renal arteriovenous (A-V)
      shunting in rats subjected to renal transplant rejection, hydronephrosis and
      severe hypotension caused by bleeding. The question as to whether blood partially
      by-passes the renal cortex under certain conditions is still controversial and an
      alternative explanation for the findings has been vasodilatation. The aim of this
      investigation was to determine whether A-V shunting is part of the haemodynamic
      changes taking place after unilateral nephrectomy and if the sympathetic nervous
      system is involved. MATERIAL AND METHODS: Unilateral nephrectomy was performed
      and radioactive microspheres (15.5 microm) were injected into the right remaining
      renal artery 30 min (n = 10), 24 h (n = 13) and 3 weeks (n = 14) later. The
      proportion of radioactivity in the lungs was considered to reflect A-V shunting
      in the kidney. Sham-operated animals (n = 30) and animals (n = 10) without
      previous sham operation, all with two kidneys, were used as controls. Isogenic
      renal transplantation (n = 10) was performed after bilateral nephrectomy to
      represent a denervated single kidney status. RESULTS: Renal A-V shunting was
      significantly (p < 0.001) reduced 30 min and 3 weeks after unilateral nephrectomy
      compared with controls. In isogenically transplanted rats, A-V shunting was not
      reduced compared with sham-operated animals, and significantly (p < 0.001)
      greater compared with the reduced levels of shunting at all times after
      unilateral nephrectomy. CONCLUSIONS: Reduced renal shunting of microspheres was
      observed after uninephrectomy and seems to require an intact renal innervation.
      It is likely that vasodilatation after unilateral nephrectomy and A-V shunting
      are two separate phenomena.

PMID- 10636575
TI  - Hyperoxaluria in idiopathic calcium nephrolithiasis--what are the limits?
AB  - OBJECTIVE: The object of this study was to investigate the role for measurement
      of 24-h renal oxalate excretion in the evaluation of idiopathic calcium stone
      formers. MATERIALS AND METHODS: Renal excretion rates of oxalate and creatinine
      were measured in 24-h urines in 46 consecutive male recurrent idiopathic calcium
      stone formers and 61 healthy males. Furthermore, day-to-day variation in renal
      oxalate excretion in 10 male recurrent stone formers and 10 healthy males were
      evaluated by measuring 24-h oxalate excretion on 5 different days in each
      individual. Concentrations of oxalate in urine were measured using an enzymatic
      method without ascorbate interference. RESULTS: The cumulative frequency
      distribution curves of 24-h renal oxalate excretion rates of stone formers and
      controls were congruent, and there were no statistically significant differences
      in oxalate excretion rates between stone formers and controls. Mean 24-h oxalate
      excretion (95%-confidence intervals) was 0.22 (0.18-0.25) mmol and 0.21 (0.18
      0.24) mmol in stone formers and controls, respectively (p = 0.9). The day-to-day
      variation study did not reveal any differences in renal oxalate excretion pattern
      between stone formers and controls, and the presence of intermittent
      hyperoxaluria could not be confirmed. The oxalate excretion rates were generally
      low. CONCLUSION: In our region, there appear to be no differences in 24-h renal
      excretion rates of oxalate between male recurrent idiopathic calcium stone
      formers and healthy males, and the syndrome of mild hyperoxaluric calcium
      nephrolithiasis could not be identified in our population of idiopathic stone
      formers. Hence, a limit of abnormal oxalate excretion that distinguishes an
      idiopathic stone former from a non-stone former could not be defined in our
      population. Therefore, the value of routine measurement of urinary oxalate in
      idiopathic urolithiasis is difficult to accept, and cannot be recommended.

PMID- 10636576
TI  - Metabolic evaluation and medical management of upper urinary tract stone disease.
      Guidelines from the Scandinavian Cooperative Group for Urinary Stones.
AB  - A set of simple guidelines for metabolic evaluation and medical/dietary
      management of patients with urolithiasis is presented. The evaluation scheme is
      based on the documented risk factors in the Nordic area and the results of
      controlled clinical trials, and takes its basis in the severity of the stone
      disease in the individual stone patient. The initial evaluation in all patients
      aims at diagnosing conditions with a definitive metabolic, infectious or
      anatomical/functional cause of stone formation (MIAF urolithiasis). Patients with
      MIAF urolithiasis are treated according to the nature of the underlying disease.
      Having excluded/diagnosed MIAF urolithiasis, patients with idiopathic calcium
      nephrolithiasis remain, and in this group, which comprises approximately 85% of
      the total stone population in the Scandinavian region, only those with a
      complicated stone disease are subjected to additional evaluation, which aims at
      identifying underlying pathophysiological derangements for which medical therapy
      has been proven to be effective in controlled clinical trials.

PMID- 10636577
TI  - The place of diuretic enhanced Doppler sonography in distinguishing between
      obstructive and non-obstructive hydronephrosis in children.
AB  - OBJECTIVE: In an attempt to differentiate obstructive from non-obstructive
      dilation of the renal collecting system in children, a prospective clinical study
      was carried out. MATERIAL AND METHODS: During duplex Doppler sonography
      examination in 23 children resistive index (RI) and pulsatility index (PI) and RI
      ratio values before and after intraverous furasemide administration were compared
      with the findings obtained with diuretic renogram examination (t(1/2)). RESULTS:
      Evaluation of the results demonstrated that diuresis RI and PI determination may
      aid differentiation of severely obstructed renal units from those with slight
      (equivocal) or no obstruction. CONCLUSION: Kidneys with severe UPJ obstruction
      tended to have more elevated RI and PI values than the non-obstructed or
      equivocally obstructed ones. Again, determination of RIR values for each kidney
      showed the same elevation in severely obstructed kidneys, while non-obstructive
      or indeterminately obstructed ones demonstrated statistically insignificant
      changes.

PMID- 10636578
TI  - Effect of a full bladder on urine production in humans.
AB  - OBJECTIVE: To demonstrate the reduction in urine production in healthy humans
      upon bladder distension and to identify the factors responsible for this
      reduction. MATERIALS AND METHODS: Twelve healthy females were investigated twice
      in a cross-over designed experiment: once with the urinary bladder empty at the
      start and once pre-filled to 60% of the maximum bladder capacity. Glomerular
      filtration rate, effective renal plasma flow, urine content of catecholamines,
      blood pressure, pulse rate, plasma arginine vasopressin (AVP) and plasma
      concentration of renine and electrolytes were analysed together with serum
      osmolality. RESULTS: Three subjects failed to reach maximum bladder capacity
      during the "full bladder" test and were excluded. The urine production in the
      "full-bladder" test was significantly lower than the "empty-bladder" test (p =
      0.024). In the "full-bladder" test a significant increase in mean blood pressure
      was found (p=0.01). No further significant changes were demonstrated.
      CONCLUSIONS: Acute bladder distension causes a reduction in urine production or a
      "pooling of urine" in the upper urinary tract in healthy humans. The mechanism is
      unknown.

PMID- 10636579
TI  - Effect of insulin therapy for diabetic cystopathy--urodynamic and histological
      findings in a rabbit model.
AB  - OBJECTIVE: To investigate the efficacy of insulin therapy in preventing
      cystopathic changes in diabetes using a rabbit model. MATERIALS AND METHODS:
      Twenty-four New Zealand white rabbits were studied in three groups: eight in
      group 1 as control, eight in group 2 with diabetes by administration
      intravenously alloxan hydrochloride and eight in group 3 administered insulin
      therapy after induction of diabetes. Urodynamic investigations were carried out
      in three groups at the end of 8 weeks. Tissue sections prepared from all groups
      were studied histologically. RESULTS: Bladder capacity and compliance increased
      in diabetic non-treated group. There was no significant difference between the
      control group and the diabetic group treated with insulin. The neuropathic
      changes were observed in the diabetic group, whereas the findings of the
      histological study were similar in the control and in the insulin treatment
      group. CONCLUSIONS: This animal model indicates that insulin therapy can prevent
      or delay urodynamic and histopathological changes in diabetes mellitus. These
      results must be supported by in vitro pharmacological studies.

PMID- 10636580
TI  - Eosinophilic cystitis--not that uncommon!
AB  - The clinical presentation, radiological manifestations and response to therapy of
      seven cases of biopsy-proven eosinophilic cystitis seen over an 8-year period
      were evaluated retrospectively. All of the five men and two women had symptoms of
      dysuria and frequency, with haematuria in two cases. One developed acute painful
      retention. The urine was sterile in all. Radiological findings included bladder
      mass lesions and upper tract dilatation. Cystoscopy showed papillary,
      erythematous and ulcerative mucosal lesions, and in one instance a large mass
      lesion. The various procedures carried out were cold cup biopsies, transurethral
      resections, or fulgration of lesions and partial cystectomy. Medical therapy
      included non-steroidal anti-inflammatory drugs and prophylactic antibiotics to
      cover the procedures carried out. There was excellent symptomatic improvement in
      all patients. This is the largest single-centre experience reported, and is
      unusual as the majority of the patients in this series were men.

PMID- 10636581
TI  - Renovascular disease and renal insufficiency--diagnosis and treatment.
AB  - Renovascular disease as cause of end-stage renal disease has become more frequent
      during the last decade. In order to minimize the need for dialysis treatment non
      invasive screening for the disease is needed. However, both ultrasonic duplex
      scanning and renal scintigraphy are not sufficient for detection of all stenosis.
      Furthermore, there is little data on non-invasive tests in patients with renal
      insufficiency. Renal arteriography is the gold standard for detection of
      renovascular disease. One disadvantage is the risk of contrast-agent induced
      acute renal insufficiency. This problem can be avoided using carbon dioxide
      angiography. In the near future spiral computed tomography and magnetic resonance
      angiography may be alternatives for identifying patients with renovascular
      disease. Ischaemic nephropathy is potentially curable. Percutaneous transluminal
      renal angioplasty is first line treatment in most cases. Intervention often
      results in improvement or preservation of renal function which is very important
      in order to avoid chronic dialysis.

PMID- 10636582
TI  - Primary malignant melanoma of the urinary bladder associated with widespread
      metastases.
AB  - Malignant melanoma in the urinary tract is very rare. Tumours found in the
      urinary bladder are usually metastatic. Some ten cases of primary malignant
      melanoma have been described in the literature, and in only a few of those has a
      primary bladder melanoma with many distant metastases and rapid fatal outcome
      been reported. For the first time in Finland, we present a case of primary
      malignant bladder melanoma associated with widespread metastases.

PMID- 10636583
TI  - Tiaprofenic acid-induced cystitis--three cases and a literature review.
AB  - Tiaprofenic acid is a non-steroidal anti-inflammatory drug that may cause severe
      non-bacterial cystitis. Three cases are described and the literature is reviewed.

PMID- 10636584
TI  - Interstitial cystitis provoked by tiaprofenic acid.
AB  - A patient developed clinical and histological interstitial cystitis as an adverse
      effect of treatment with tiaprofenic acid for rheumatism. After cessation of the
      drug, full symptomatic recovery was obtained. Bladder biopsies 6 months later
      demonstrated normalization of detrusor muscle histology.

PMID- 10636585
TI  - Primary synovial sarcoma of the penis--case report and literature review.
AB  - Urogenital synovial sarcoma is an exceedingly rare lesion that can be clinically
      confused with chronic inflammatory masses and granulomas, squamous cell
      carcinoma, malignant melanoma or metastatic tumours. We present a case of primary
      synovial sarcoma of the penis in a 29-year-old Egyptian male. This case report
      is, to the best of our knowledge, the first report in the medical literature. A
      review of other penile sarcomas is included with a description and discussion of
      their pathological and clinical manifestations.

PMID- 10636586
TI  - Tumor metastasis to an oncocytoma.
AB  - A case of squamous carcinoma of the lung metastatic to a renal oncocytoma is
      described. The terms "tumor-to-tumor metastasis" and "collision tumor" for
      describing the existence of two neoplasms in the same location are discussed.

PMID- 10636587
TI  - Penile necrosis: an unexpected complication following transurethral resection of
      the prostate.
AB  - A 69-year-old man who had undergone a transurethral resection of the prostate for
      benign prostatic hyperplasia developed necrosis of the glans penis following
      traction of the urethral catheter

PMID- 10636588
TI  - Double cancers of the kidney and ureter complicated with emphysematous
      pyelonephritis within the parenchyma of the renal tumour.
AB  - Emphysematous pyelonephritis and double cancers of the kidney and urinary tract
      are rare. We describe here a case of a diabetic man who had simultaneous renal
      cell carcinoma of the right kidney and transitional cell carcinoma of the right
      ureter complicated with emphysematous pyelonephritis within the tumour parenchyma
      of renal cell carcinoma. Imaging and pathology are demonstrated.

PMID- 10636589
TI  - Adult medullary cystic disease of the kidney and pancreatic cystic disease: a new
      association.
AB  - A rare case of a woman with the adult form of medullary cystic disease associated
      with pancreatic cysts in pancreas divisum is described, which suggests that
      specific attention should be paid to computed tomography findings in the presence
      of pancreatic and renal cysts.

PMID- 10636590
TI  - Enteral feeding in the preterm infant.
AB  - In planning enteral feeding in the preterm infant, decisions need to be made
      regarding the feeding schedule, choice of milk, and the route of administration.
      Feeds should be commenced within a week after birth beginning with subnutritional
      quantities. Preterm human milk from the infant's own mother is the milk of
      choice. When full enteral feeding is established, supplementation with human milk
      fortifier is recommended. Donor human milk and preterm formula are alternatives.
      Early establishment of enteral nutrition and maintenance of optimal nutrition
      during infancy are important as dietary manipulations in preterm infants have
      potential long-term influences on their health, growth and neurodevelopment.

PMID- 10636591
TI  - A comparison of three ultrasound estimates of intrapartum oligohydramnios for
      prediction of fetal hypoxia-reperfusion injury.
AB  - A prospective observational study assessed the predictive value of three
      techniques for amniotic fluid volume assessment on umbilical cord arterial lipid
      peroxide levels and acid-base balance. Women with singleton, term, cephalic
      presentation, and an initially normal fetal heart rate tracing were recruited.
      All pregnancies had the largest vertical pocket (LVP), two diameter pocket
      (2phi), and amniotic fluid index (AFI) assessments before and after amniotomy and
      cord arterial acid-base and lipid peroxide determinations at delivery. In 171
      cases with confirmed cord arterial samples, malondialdehyde (MDA), organic
      hydroperoxide (OHP), pH and base excess (BE) were examined in relationship to
      intrapartum LVP, 2phi and AFI before and after amniotomy. Improvements in
      correlation between the estimates of amniotic fluid volume and outcome measures
      were observed 30 min after amniotomy, particularly with lipid peroxide
      measurements. Examination of scatter-plots using Lowess regression suggested that
      the correlation was only valid in cases of oligohydramnios but that the cutoff
      values recommended in the literature for defining oligohydramnios were not
      appropriate in our population sample. We suggest that oligohydramnios should be
      defined as an AFI < 8 cm or LVP < 4 cm. We concur with the recommendation of < 15
      cm2 for the 2phi measurement.

PMID- 10636592
TI  - Bone metabolism and circulating IGF-I and IGFBPs in dexamethasone-treated preterm
      infants.
AB  - AIM: To characterize the ontogeny of circulating IGF-I, the IGF binding proteins
      (IGFBPs) and biochemical markers of bone turnover in dexamethasone (DEX)-treated
      preterm infants with chronic lung disease. METHODS: Plasma and urine samples from
      17 infants were obtained prior to DEX, after 9-12 days of DEX and 10 days after
      the completion of DEX to assess plasma IGF-I, IGFBPs, osteocalcin and urinary N
      telopeptide. Nutrient intakes and growth were monitored from birth until term
      corrected age at which time body composition was evaluated by dual energy X-ray
      absorptiometry. RESULTS: Although nutrient intakes did not differ during or after
      DEX, weight gain (115 vs. 174 g/week) and length gain (0.7 vs. 1.0 cm/week) were
      higher after DEX treatment. Plasma IGF-I, IGFBP-3 and osteocalcin increased over
      time. N-telopeptide was the only biochemical parameter which appeared to be
      suppressed during DEX (1342 nM bone collagen equivalents/mM creatinine vs. 2486
      (pre-DEX) and 2292 (post-DEX)). At term corrected age, bone mineral content was
      lower in dexamethasone-treated infants compared to preterm and term reference
      infants. CONCLUSION: Changes in circulating IGFBP-2 and IGFBP-3 paralleled the
      changes reported in non-steroid-treated infants; however, it remains uncertain
      whether the natural rise in IGF-I was suppressed by DEX treatment. Assessment of
      these circulating components provided limited insight into the mechanisms by
      which DEX alters growth and bone turnover.

PMID- 10636593
TI  - Epidermal growth factor in maternal urine--a predictor of intrauterine growth
      restriction?
AB  - Epidermal growth factor (EGF), an angiogenic and mitogenic peptide, is known to
      be essential for normal fetal development in mice. Hypothetically, low maternal
      urine EGF levels might be associated with intrauterine growth restriction (IUGR)
      or pre-eclampsia (PE). We carried out a prospective study of 1009 consecutive
      women whose urine was sampled in early pregnancy (at a median of 13 weeks of
      gestation) between January and November 1993. Thirty women gave birth to IUGR
      babies and 24 developed PE. The study was designed as a nested case-control study
      with two matched controls for each case. EGF and human chorionic gonadotrophin
      (HCG) levels were measured and expressed in ng EGF/mg creatinine and IU HCG/mg
      creatinine. Logistic regression analysis was made with EGF or HCG levels as
      explanatory variables. Urinary EGF levels were significantly lower in the IUGR
      subgroup than in their controls, but no such difference was found between the PE
      subgroup and their controls. In the series as a whole, smokers were found to have
      lower EGF and HCG levels than non-smokers. In addition, correlation was found to
      exist between EGF and HCG levels (Spearman's rho 0.35; P<0.001). We conclude that
      a relative deficiency of EGF in early pregnancy might be one of the
      pathophysiological mechanisms of IUGR. However, the EGF level was an
      insufficiently discriminative variable to be of use for screening purposes.

PMID- 10636594
TI  - Intra-arterial blood pressure reference ranges, death and morbidity in very low
      birthweight infants during the first seven days of life.
AB  - OBJECTIVES: We aimed to: (1) assess the association of average, low, high and
      variable mean blood pressure (mbp) on death and the common morbidities of very
      low birthweight infants, and in doing so, (2) to derive representative reference
      ranges for mbp in very low birthweight infants. STUDY DESIGN: This five year
      retrospective study assessed 1 min computer recordings of intra-arterial mbp in
      232 very low birthweight infants over the first 7 days of life in a tertiary
      NICU. Four measures of mbp were assessed: average, variability, maximum (per time
      period), and percentage of time with a mean blood pressure less than the infant's
      gestation. Correlation was made with death and the development of
      intraventricular haemorrhage (IVH), periventricular leukomalacia (PVL) and
      retinopathy of prematurity (ROP). RESULTS: The mbp increased with increasing
      birthweight and postnatal age (though with a slight decrease on days 6 and 7).
      Birthweight, gestation and colloid support (adjusted for birthweight and
      gestation) were the only factors significantly associated with mbp. IVH was
      predominantly associated with a low and variable mbp on the day IVH was noted or
      the day before. PVL and ROP were not associated with blood pressure. CONCLUSIONS:
      These reference ranges include more infants and data than previously published
      and relate mbp in this cohort to morbidity and mortality. They could assist
      clinicians in judging appropriate mbp for birthweight.

PMID- 10636595
TI  - Comparing the effects of nasal synchronized intermittent positive pressure
      ventilation (nSIPPV) and nasal continuous positive airway pressure (nCPAP) after
      extubation in very low birth weight infants.
AB  - In this study we hypothesized that nasal synchronized intermittent positive
      pressure ventilation (nSIPPV) would provide more ventilatory support than nasal
      continuous positive airway pressure (nCPAP) in the immediate post-extubation
      period in very low birth weight (VLBW) infants. We tested this hypothesis by
      comparing the effects of these two ventilatory techniques on ventilation, gas
      exchange, and patient inspiratory effort in 11 preterm infants immediately after
      extubation. All neonates studied (BW: 1141+/-(SEM) 53 g; GA: 28.1+/-(SEM) 0.5
      wks) had received mechanical ventilation because of respiratory distress at birth
      and were extubated by day 14 of life. Nasal SIPPV and nCPAP were applied in
      random order to each infant after extubation so that each was his/her own
      control. Both nCPAP and nSIPPV were delivered at end-expiratory pressures (PEEP)
      of 3 cm H2O. Inspiratory times (Ti) and peak inspiratory pressures set during
      nSIPPV were the same as those used at the time of extubation. Recordings lasted
      45 min in each mode of ventilation. Tidal volume (Vt), minute volume (Ve),
      respiratory rate (RR), airway pressure (Paw), transcutaneous PO2 (TcPO2) and PCO2
      (TcPCO2) as well as phasic esophageal pressure deflections (Pe), as an estimate
      of inspiratory effort, were measured. The measurements obtained during both modes
      of ventilation indicated significant differences between the two techniques.
      Indeed, application of nSIPPV was associated with a statistically significant
      increase in Vt and Ve. In addition, Pe decreased by 30% during nSIPPV (P<0.01).
      TcPCO2 was statistically significantly lower during nSIPPV than nCPAP, and RR as
      well. These data therefore suggest that nSIPPV may provide more ventilatory
      support than nCPAP in the post-extubation period with less patient inspiratory
      effort.

PMID- 10636596
TI  - Limb anomalies among offspring of women with a septate uterus: a report of three
      cases.
AB  - A retrospective analysis of 467 births among 255 women with uterine malformations
      revealed that three (0.64%) newborns had limb reduction defects. Two women had a
      subseptate uterus and one a complete septate uterus with a longitudinal vaginal
      septum. One newborn had a bilateral split hand and split foot, one had absence of
      left hand and wrist. One infant born without left hand, wrist and one
      antebrachial bone associated with omphalocele and diaphragmatic hernia died
      during the neonatal period. An association between severe limb reduction defects
      and septate uterus is possible, although the mechanism is unclear. The findings
      indicate a need to evaluate the uterine cavity if a newborn has this invalid
      defect, and a detailed ultrasound examination of fetal limbs is warranted in a
      case of a pregnant septate uterus.

PMID- 10636597
TI  - Night-time non-nutritive sucking in infants aged 1 to 5 months: relationship with
      infant state, breastfeeding, and bed-sharing versus room-sharing.
AB  - AIM: Epidemiological studies suggest that pacifier use may be protective against
      SIDS but little is known of the relationship between pacifier use and other forms
      of non-nutritive sucking (NNS) in infancy, or of patterns of NNS during the
      night, when most SIDS deaths occur. We report the first longitudinal study of NNS
      by direct overnight observations in healthy infants in a sleep laboratory.
      METHODS: Healthy, breast fed term infants (n = 10) were enrolled at birth, and
      sequential overnight polygraphic and infrared video recordings of infants with
      their mothers performed at monthly intervals from 1 to 5 months. Each month,
      mother baby pairs were randomized to 1 night bed-sharing (BN) then 1 room-sharing
      (RN), or vice versa. 'Episodes' of pacifier, own digit and mother's digit sucking
      (> 1 min) were identified and compared with state-matched control periods without
      sucking or feeding before and after each such episode. RESULTS: 329 episodes of
      NNS were identified in 749 h of video recording. The prevalence of pacifier
      sucking decreased with age, whilst digit sucking increased. Routine pacifier
      users rarely sucked their digits. There were temporal differences throughout the
      night in the distribution of different types of sucking and in infant state
      during and around sucking episodes. Sleeping in the 'non-routine' location was
      associated with a larger percentage of nights with sucking episodes and increased
      sleep latency. Bed sharing (routinely or on a given night) was associated with
      less sucking behavior and more breastfeeding. Non-nutritive sucking was not,
      however, associated with decreased total time breastfeeding per night or number
      of feeds per night. CONCLUSION: Patterns of NNS during the night change with age
      and are affected by maternal proximity. Digit sucking has state modulating
      effects, and may be suppressed by pacifier use. Thus any benefits of pacifier use
      must be set against the potential loss of a self-directed ability to modulate
      state during the night, and possible shortening of breastfeeding duration.

PMID- 10636598
TI  - Perinatal predictors of growth at six months in small for gestational age babies.
AB  - Poor growth in childhood is associated with a number of later complications and
      early recognition may enable early intervention to improve outcomes.
      Approximately 20% of small for gestational age (SGA) babies remain small at two
      years. Most catch up growth occurs in the first 6 months and smallness at 6
      months predicts later small size in the majority of cases. There are no previous
      reports of perinatal predictors of size at 6 months in SGA babies. The aim of
      this study was to identify the perinatal factors associated with small size at 6
      months in infants who were SGA at birth (birthweight < 10th%). SGA infants had
      assessments of length, weight, and head circumference performed at three monthly
      intervals by the same researcher. Detailed perinatal data was collected in all
      cases. Abnormal size was defined as a length, weight or head circumference
      measurement < 10th% for 6 months corrected age. Infants were considered to show
      failure of catch-up growth if measurements at 6 months were further below the
      population mean than birth measurements. Two hundred and forty eight babies were
      recruited of whom 203 (82%) completed followup at 6 months. Forty (20%) babies
      were short, and in logistic regression shortness at 6 months was predicted by
      shortness at birth and male sex. Thirty one (16%) had weight < 10th% and low
      weight was predicted in logistic regression by early gestation at diagnosis of
      SGA (median 30.8 weeks in those who were under weight and 33.9 weeks in those of
      normal weight p < 0.0001). Thirty seven (18%) had a low head circumference which
      was predicted by small head size at birth. Three quarters of the babies who were
      short, underweight, or had low head circumference at 6 months also showed failure
      of catch-up growth. Shortness and small head circumference at 6 months were
      predicted by shortness and small head circumference at birth, especially in boys.
      Underweight was predicted by early detection of SGA antenatally. Most SGA babies
      who remained small at 6 months failed to show catch up growth after birth.

PMID- 10636599
TI  - Development of oxygen sensitivity in infants of smoking and non-smoking mothers.
AB  - AIMS: To assess the effect of prenatal cigarette smoke exposure on the postnatal
      resetting of oxygen sensitivity in term infants. METHODS: 15 healthy term infants
      of smoking mothers (median 10 cigarettes/day) and 16 controls were studied during
      quiet sleep 1, 3, and 10 days and 10 weeks postnatally. Strain-gauge respiratory
      trace was continuously recorded. Repeated 15-s challenges with 100% O2 and 15% O2
      were presented in randomised order through a face mask. A median of six hyperoxic
      and six hypoxic challenges per recording were obtained. Breath-by-breath
      ventilation in a time-window from 20 s before onset of stimulus to 60 s after was
      extracted. For each infant at each age, the normalised coherently averaged
      response to hyperoxia and hypoxia was calculated. Mean ventilation at end of the
      15-s stimulus was analysed with ANOVA, as were parameters describing a function
      fitted to each averaged response. RESULTS: During air breathing, smoke-exposed
      infants had higher respiratory rates and lower tidal volumes than controls.
      Nicotine concentration in infant hair, measured by gas chromatography, was
      positively correlated with maternal level of smoking. A long-term development in
      oxygen sensitivity was demonstrated in both groups. However, neither the time
      course nor the magnitude of O2 responses was affected by maternal smoking.
      Overall, hyperoxia reduced ventilation by 6.3% at day 1, 13.2% at day 3, 29.6% at
      day 10, and 40.0% at week 10. Transient hypoxia increased ventilation by 3.5%,
      3.2%, 6.4%, and 8.8%, respectively, at the four ages studied.

PMID- 10636600
TI  - Using ethnographic methodology in substance abuse treatment outcome research.
AB  - The purpose of this article is to argue for a greater inclusion of ethnography as
      an adjunctive methodology within the context of traditional substance abuse
      treatment outcome studies. First we describe what is meant by "ethnographic
      methodology," then discuss the various methodological elements of ethnographic
      research that are relevant to substance abuse research. A number of suggested
      applications of ethnographic research pertaining to a substance abuse treatment
      outcome context are then presented. The article concludes with a discussion about
      how ethnographic methods can enhance and broaden our understanding of important
      questions relating to substance abuse treatment processes and outcomes.

PMID- 10636601
TI  - Effectiveness of coerced addiction treatment (alternative consequences): a review
      of the clinical research.
AB  - Of central importance is that our clinical experience and treatment outcome
      studies to date strongly suggest that coercion is fundamental to addiction
      treatment and favorable outcomes from therapeutic interventions. Often the
      alcoholic/drug abuser must be given an opportunity to feel, face, or experience
      the "consequences" of their alcohol and drug addiction before the denial of their
      illness can be penetrated and motivation for treatment to recover from addictive
      illness can be developed. Continued use of alcohol and drugs is an unhealthy and
      dangerous state for those who are addicted and for others who are affected by
      their addictive illnesses. Effective therapeutic interventions and long-term
      recovery are more likely to succeed if avoiding "alternative consequences" are
      contingent on continued compliance with addiction treatment by those who suffer
      from addictive illnesses.

PMID- 10636602
TI  - HIV post-exposure therapy for drug users in treatment.
AB  - The purpose of this study was to evaluate the attitudes of drug treatment program
      providers concerning human immunodeficiency virus (HIV) post-exposure therapy
      (PET) for drug users enrolled in drug treatment. This was a cross-sectional
      evaluation of drug treatment program providers in four methadone maintenance
      programs (MMPs) in New Haven, Connecticut. Thirty-five MMP providers including:
      29 MMP treatment staff (physicians, nurses, counselors) and 6 primary care
      provider staff (physicians, nurse practitioners, and nurses) participated in the
      study. The providers were presented with four case vignettes of individuals
      exposed to HIV through a needle stick ("stick"): a phlebotomist with occupational
      exposure (Case A) and three drug users with nonoccupational exposure to HIV
      (Cases B, C, and D). Case B had the same estimated future risk as Case A (three
      sticks/4 years) and the other cases had increased risk: Case C (four to six
      sticks/year) and Case D (monthly "sticks"). For each vignette, providers were
      asked whether they would offer HIV PET ("yes" or "no"). In addition, focus groups
      were held within each group of providers who were asked: "What role should drug
      treatment programs play in the implementation of PET?" All MMP staff (29/29) and
      primary care providers (6/6) felt that the phlebotomist with occupational
      exposure should be offered PET. The percent of MMP and Primary care provider
      staff recommending PET for the other cases were: Case B (MMP staff: 86% [25/29],
      PCPs: 100% [6/6]), Case C (MMP staff: 69% [20/29], PCPs: 33% [2/6]), and Case D
      (MMP staff: 59% [17/29], PCPs: 17% [1/6]). The "common themes" that were
      identified in the focus groups included: concern that MMPs lack resources to
      provide PET, the ethics of withholding PET, the "limit" on the number of times
      PET should be offered, and the role of PET in the overall HIV prevention message.
      Both MMP staff and PCPs felt that MMPs should have an "indirect" role in
      providing HIV PET by providing education and referral only. MMP staff and PCPs
      differed in their likelihood of offering HIV PET to drug users enrolled in MMPs.
      The possibility of HIV PET for drug users in treatment raises significant
      implementation issues for MMPs that will require further study if HIV PET becomes
      widely used in drug users.

PMID- 10636603
TI  - Prevalence of family violence in clients entering substance abuse treatment.
AB  - The present study evaluated 105 clients who were assessed for substance-related
      problems and a history of domestic violence. A brief survey on family violence
      examined whether clients were adult victims, childhood victims, and/or
      perpetrators of physical violence. Results indicated that 37% of the sample
      reported that they experienced a family history of physical violence. A total of
      22% reported being an adult victim of physical violence, 14% reported being a
      victim of childhood abuse, and 18% reported being a perpetrator of physical
      violence. There was a significant positive correlation between subtypes of family
      violence. Substance-using clients who were older reported more incidences of
      family violence. Results showed that substance-using clients with a history of
      family violence (SAFV+) tended to have more individual therapy sessions attended
      than substance-using clients without a history of family violence (SAFV-). The
      SAFV+ group was different from the SAFV- group in that they had significantly
      higher scores on the Michigan Alcoholism Screening Test and the Beck Depression
      Inventory (BDI) scores. The SAFV+ group also had significantly more self-reported
      and positive urine screens for cocaine use within the 2-month monitoring period.
      Additionally, substance-using clients with a history of childhood trauma had
      significantly more individual therapy sessions attended than clients without a
      history of childhood trauma. The group with a history of childhood trauma had
      significantly higher scores on the BDI. Findings indicate the importance of
      assessing family history of violence in substance abusers entering treatment, as
      this may have significant implications for treatment outcome.

PMID- 10636604
TI  - Perceptions of the importance of physical setting in substance abuse treatment.
AB  - Research indicates that architectural design can provide therapeutic effects. Six
      setting characteristics are considered of primary importance in health-care
      facilities: comforts and conveniences, safety, attractiveness, size, privacy, and
      arrangement/location. This study presents the perceptions regarding these and
      other setting features held by female clients and staff from a substance abuse
      treatment facility. Results support the importance of these six setting
      characteristics in influencing clients' treatment goals. Four other setting
      variables emerged as important to women's recovery: participation in a
      residential, drug-free, gender-specific program that provides on-site child care.
      Attention to these variables may provide facilities with an advantage in today's
      competitive market for clients.

PMID- 10636605
TI  - Psychosocially enhanced treatment for cocaine-dependent mothers: evidence of
      efficacy.
AB  - Eighty-four cocaine-dependent mothers were randomly assigned either to a case
      management-oriented outpatient treatment program (CM), or to a psychosocially
      enhanced treatment program (PET). Both programs included onsite child care and
      both offered daily group therapy sessions. Subjects randomized to the PET
      condition were offered a variety of additional onsite services designed to meet
      their special psychosocial needs including parenting skills class, access to a
      psychiatrist, individual therapy sessions, and GED class. Patients in the CM
      program could gain access to these services only through referrals to community
      resources. Program retention was significantly better for patients in the PET
      condition. In addition, while the mean number of days of cocaine use decreased
      from baseline in both groups, the PET group had significantly fewer days of
      cocaine use at 12-month follow-up than the CM group. These results show that
      providing psychosocial enhancement services onsite can improve treatment outcome
      for cocaine-dependent mothers.

PMID- 10636606
TI  - Behavioral couples therapy for alcoholism and drug abuse.
AB  - Behavioral couples therapy (BCT) sees the substance-abusing patient with the
      spouse to arrange a daily "sobriety contract" in which the patient states his or
      her intent not to drink or use drugs and the spouse expresses support for the
      patient's efforts to stay abstinent. BCT also teaches communication and increases
      positive activities. Research supports three conclusions. First, BCT for both
      alcoholism and drug abuse produces more abstinence and fewer substance-related
      problems, happier relationships, fewer couple separations and lower risk of
      divorce than does individual-based treatment. Second, domestic violence is
      substantially reduced after BCT for both alcoholism and drug abuse. Third, cost
      outcomes after BCT are very favorable for both alcoholism and drug abuse, and are
      superior to individual-based treatment for drug abuse. The Institute of Medicine
      (1998) documented a large gap between research and practice in substance abuse
      treatment. BCT is one example of this gap. BCT has relatively strong research
      support, but it has not yet become widely used.

PMID- 10636607
TI  - The triad of substance abuse, violence, and depression are interrelated in
      pregnancy.
AB  - A study group of 271 registrants had their medical and social history taken by a
      nurse-interviewer and were requested to take the Substance Abuse Subtle Screening
      Inventory. If the nurse interviewer felt that the patient needed social service
      assessment, referral was made, and a social worker completed the the Social
      Service Review Questionnaire. The patients who were reported as positive for
      substance abuse did not respond differently from their negative counterparts for
      issues of demographics, pregnancy, social support, and career. They were highly
      likely to have had a history of severe depression and/or have been a victim of
      physical and/or sexual abuse. On the basis of these data we recommend that the
      prenatal patient who responds positively in her personal history regarding any of
      these three experiences should be carefully evaluated for problems related to the
      other two.

PMID- 10636608
TI  - Female substance abuse: characteristics and correlates in a sample of inpatient
      clients.
AB  - This article reports on a study of 64 female substance abusers in residential
      treatment for chemical dependency. This study was conducted with the purpose of
      describing the associations between: (a) demographic characteristics, (b)
      presence and severity of addiction, (c) depression, and (d) self-esteem. All
      participants were drawn from inpatient females, and were administered
      questionnaires that included the following instruments: (a) Screening/Intake
      Assessment, (b) the Michigan Alcohol Screening Test, (c) the Addiction Presence
      and Severity Index, (d) the Provision of Social Relations Scale, (e) the
      Rosenberg Self-Esteem Scale, and (f) the Costello-Comrey Depression Scale.
      Multivariate analyses revealed that levels of self-esteem were related to
      detoxification status and social support. Depression levels were associated with
      social support, and severity of addiction was more pronounced for White clients
      than Black clients in this study. Implications for program development are
      discussed.

PMID- 10636609
TI  - Drug treatment and 12-step program participation: the additive effects of
      integrated recovery activities.
AB  - The dramatic rise in the number of 12-step programs and participants raises
      questions concerning client participation in drug treatment and 12-step programs,
      and their separate and combined effects on recovery. The results of a treatment
      outcomes study indicate that rather than recovery alternatives, drug treatment
      and 12-step programs are utilized by the client as integrated recovery
      activities. Treatment participants with pretreatment 12-step involvement stayed
      in treatment longer, and were more likely to complete the 24-week program. Both
      pretreatment 12-step involvement and duration of participation in drug treatment
      are associated with subsequent 12-step involvement. Most importantly, there is an
      additive effect of these recovery activities in that those who participated
      concurrently in both drug treatment and 12-step programs had higher rates of
      abstinence than those who participated only in treatment or in 12-step programs.

PMID- 10636610
TI  - Treating the substance-abusing patient in the public sector: "medical necessity"
      versus "social necessity and social responsibility" in the philadelphia target
      cities demonstration project.

PMID- 10636611
TI  - Sexual abuse, depression, and eating disorders in African American women who
      smoke cocaine.

PMID- 10636612
TI  - A rehabilitation model for drug-addicted individuals in two Polish centers.
AB  - A new rehabilitation model for drug-addicted individuals developed by
      psychologist and director, Jaroslaw Straszny, and his colleagues and patients is
      currently being implemented in two rehabilitation centers in Czechowice-Dziedzice
      and Bielsko-Biala, Poland. The model approaches drug addiction treatment from the
      human psychology perspective and underscores the significance of individual
      responsibility, initiative, and ability for self-direction in the treatment
      process. The purpose of the article is to describe where the model fits in the
      context of past and current rehabilitation efforts, show how the model is applied
      in the centers, and to provide a theoretical framework for the model. Updated
      statistics at the end of the article show that at the longest-operating center,
      80% of the intravenous opiate users who completed the program have maintained
      abstinence and are, in general, coping well with life.

PMID- 10636613
TI  - Cerebrovenous blood temperature-influence of cerebral perfusion pressure changes
      and hyperventilation: evaluation in a porcine study and in man.
AB  - The objective of the first part of this study was to use an animal model to
      investigate the relationship between temperature in the cerebrovenous compartment
      and cerebral perfusion pressure. In the second part of the study, the objective
      was to examine the influence of hyperventilation and hypothermia on jugular bulb
      temperature and body temperature in patients undergoing elective neurosurgery.
      Intracranial pressure was increased artificially by inflating an infratentorial
      supracerebellar placed balloon catheter in nine pigs under general anesthesia.
      Temperature was monitored by thermocouples inserted in the sagittal sinus, white
      matter of the left lobe and abdominal aorta during the ensuing decrease in
      cerebral profusion pressure (CPP). Cerebrovenous blood temperature (jugular bulb)
      and body temperature (urinary bladder) were simultaneously monitored in 24
      patients undergoing craniotomy. Moderate hyperventilation was performed in all
      patients. Cerebrovenous blood and core body temperature were recorded and
      differences between these two temperatures calculated at the beginning and the
      end of hyperventilation. At the beginning of the intracranial pressure (ICP),
      increase mean temperatures of cerebrovenous blood and cerebral tissue (left lobe)
      were lower than core body temperature. During CPP reduction the difference
      between core body temperature and cerebrovenous blood temperature increased
      significantly from 0.86+/-0.44 degrees C prior to ICP rise to 1.19+/-0.58 degrees
      C at maximum ICP. Before hyperventilation, cerebrovenous blood temperature was
      higher in 19 patients (+/- difference: 0.34 degrees C +/- 0.27) and equal or
      lower in five patients (difference: -0.08 degrees C +/- 0.11), than core body
      temperature. At the end of hyperventilation, the difference between cerebrovenous
      blood temperature and core body temperature increased (+0.42 degrees C +/- 0.24)
      in those 19 patients who had started with a higher cerebrovenous blood
      temperature and decreased (-0.10 degrees C +/- 0. 18) in the other five patients.
      Both studies demonstrated that the temperature of cerebrovenous blood is
      influenced by maneuvers which are supposed to decrease cerebral blood flow.

PMID- 10636614
TI  - Effects of neck position and head elevation on intracranial pressure in
      anaesthetized neurosurgical patients: preliminary results.
AB  - This study reports the collective effect of the positions of the operating table,
      head, and neck on intracranial pressure (ICP) of 15 adult patients scheduled for
      elective intracerebral surgery. Patients were anesthetized with propofol,
      fentanyl, and maintained with a propofol infusion and fentanyl. Intracranial
      pressure was recorded following 20 minutes of stabilization after induction at
      different table positions (neutral, 30 degrees head up, 30 degrees head down)
      with the patient's neck either 1) straight in the axis of the body, 2) flexed, or
      3) extended, and in the five following head positions: a) head straight, b) head
      angled at 45 degrees to the right, c) head angled at 45 degrees to the left, d)
      head rotated to the right, or e) head rotated the left. For ethical reasons, only
      patients with ICP < or = 20 mm Hg were included. Intracranial pressure increased
      every time the head was in a nonneutral position. The most important and
      statistically significant increases in ICP were recorded when the table was in a
      30 degree Trendelenburg position with the head straight or rotated to the right
      or left, or every time the head was flexed and rotated to the right or left
      whatever the position of the table was. These observations suggest that patients
      with known compromised cerebral compliance would benefit from monitoring ICP
      during positioning, if the use of a lumbar drainage is planed to improve venous
      return, cerebral blood volume, ICP, and overall operating conditions.

PMID- 10636616
TI  - Anesthetic management of surgical neuroendoscopies: usefulness of monitoring the
      pressure inside the neuroendoscope.
AB  - Neuroendoscopic procedures are increasing in frequency in neurosurgical practice.
      We describe the anesthetic technique and the perioperative complications found in
      100 neuroendoscopic interventions performed at our institution. Cranial tumor
      biopsy or retrieval (62%) and cisternostomy for hydrocephalus (33%) were the most
      frequent indications for neuroendoscopy. The mortality rate was low (1%).
      Intraoperative complications occurred in 36 patients, with arterial hypertension
      being the most frequent (53%). Postoperative complications occurred in 52
      patients; anisocoria (31%) and delayed arousal (29%) were the most frequent. The
      pressure inside the endoscope was monitored intraoperatively in the last 47
      patients. A saline-filled catheter from a pressure transducer connected to the
      neuroendoscopy system was used for pressure monitoring. We recorded the highest
      peak of pressure values measured during each procedure. Twenty-three patients
      (49%) had peak pressure values >30 mm Hg, 12 patients (25%) >50 mm Hg, and 3
      patients >100 mm Hg. Only one patient had hemodynamic changes occurring
      simultaneously with the pressure changes. We found an association between
      pressure inside the endoscope >30 mm Hg and postoperative (P = .003) but not
      intraoperative complications. A relationship was found between surgical duration
      and postoperative complications (P = .002). Neither the pressure inside the
      endoscope or the intraoperative morbidity were related to surgical duration. We
      conclude that there may be a high rate of postoperative complications after
      neuroendoscopies, namely, new neurologic deficits. High pressure levels inside
      the endoscope during neuroendoscopic procedures can occur without hemodynamic
      warning signs. Pressure values >30 mm Hg are associated with postoperative
      morbidity, especially unexpected delayed recovery. Measuring the pressure inside
      the endoscope is technically easy and might be beneficial if performed in all
      neuroendoscopic procedures. Reducing the incidence of episodes of high peak
      pressure values might decrease the rate of postoperative complications.

PMID- 10636615
TI  - Propofol anesthesia for craniotomy: a double-blind comparison of remifentanil,
      alfentanil, and fentanyl.
AB  - For patients undergoing craniotomy, it is desirable to have stable and easily
      controllable hemodynamics during intense surgical stimulation. However, rapid
      postoperative recovery is essential to assess neurologic function. Remifentanil,
      an ultra-short-acting mu-opioid receptor agonist, may be the ideal agent to
      confer the above characteristics. In this prospective randomized study, we
      compared the hemodynamic stability, recovery characteristics, and the dose of
      propofol required for maintaining anesthesia supplemented with an infusion of
      remifentanil, alfentanil, or fentanyl in 34 patients scheduled for supratentorial
      craniotomy. With routine monitors in place, anesthesia was induced with propofol
      (2-3 mg/kg), atracurium (0.5 mg/kg), and either remifentanil (1 microg/kg),
      alfentanil (10 microg/kg), or fentanyl (2 micro/kg). The lungs were ventilated
      with O2/air to mild hypocapnia. Anesthesia was maintained with infusions of
      propofol (50-100 microg/kg/min) and either remifentanil (0.2 microg/kg/min),
      alfentanil (20 microg/kg/h), or fentanyl (2 microg/kg/h). There were no
      significant differences among the groups in the dose of propofol maintenance
      required, heart rate, or mean arterial pressure. However, the time to eye opening
      (minutes) was significantly shorter in the remifentanil compared to the
      alfentanil group (6+/-3; 21+/-14; P = 0.0027) but not the fentanyl group (15+/
      9). We conclude that remifentanil is an appropriate opioid to use in combination
      with propofol during anesthesia for supratentorial craniotomy.

PMID- 10636617
TI  - Detectable concentrations of urinary trypsin inhibitor in cerebrospinal fluid.
AB  - Urinary trypsin inhibitor (UTI) is a physiological protease inhibitor produced in
      the liver and excreted into urine. Urinary trypsin inhibitor-like antigen has
      been demonstrated on glial cells in the brain. This study measured cerebrospinal
      UTI levels in various conditions. Seven subjects in each of the following groups
      were studied: patients undergoing spinal anesthesia for minor surgery, spinal
      anesthesia for cesarean section, removal of meningioma, or at postoperative day 3
      after ruptured intracranial aneurysm clipping. Cerebrospinal fluid was collected
      from a spinal needle, a needle puncturing the sylvian fissure, or a drainage tube
      from the optical carotid cistern. Urine was collected from a urinary catheter.
      Cerebrospinal and urinary UTI concentrations were measured by radioimmunoassay,
      and the urinary UTI concentration was divided by urinary creatinine concentration
      to give the systemic UTI concentration. The cerebrospinal UTI concentration in
      the brain tumor and postoperative state groups was significantly higher than in
      the spinal anesthesia and cesarean section groups. The systemic UTI concentration
      in the cesarean section and postoperative state groups was significantly higher
      than in the spinal anesthesia and brain tumor groups. The present results
      demonstrate that UTI can be detected in the cerebrospinal fluid, and suggest that
      cerebrospinal UTI increases in patients with a brain tumor or inflammation and is
      not affected by systemic UTI.

PMID- 10636618
TI  - Evaluation of acute normovolemic hemodilution for surgical repair of
      craniosynostosis.
AB  - This clinical report investigated the potential benefit of acute normovolemic
      hemodilution (ANH) as a blood-saving technique in the surgical repair of
      craniosynostosis. Over a 4-year period, 34 healthy children undergoing surgical
      repair of scaphocephaly or pachycephaly were randomly assigned to two groups of
      17 patients each. Patients of the first group (ANH group) were submitted to ANH
      (target Ht: 25%) immediately before surgery and patients of the second group
      (Control group) were not. During surgery, estimated blood loss was compensated
      with a 5% albumin solution and no autologous or homologous blood was transfused.
      At the end of surgery, intraoperative blood loss (mean +/- SD) calculated on the
      basis of the Ht value and the children weight was 21.3+/-8% of the estimated
      blood volume (EBV) in the ANH group and 24+/-6.6% in the Control group. Children
      of the ANH group received their autologous blood (18.9+/-3.3% of EBV)
      systematically at the end of surgery. In the postoperative period, homologous
      blood was transfused when the Ht value was equal or less than 21%. Both groups
      were comparable regarding age, weight, type of craniosynostosis, duration of
      surgery, EBV, and preoperative Ht value. No difference was observed between ANH
      and Control groups in the number of patients who received homologous blood (15/17
      and 14/17, respectively), in the amount of homologous blood transfused (17+/-4.7%
      and 19.6+/-6.3% of the EBV, respectively), and in the Ht value before hospital
      discharge (29.4+/-5.0% and 30.7+/-4.9%, respectively). In conclusion, this report
      suggests that ANH reduces neither the incidence of homologous transfusion nor the
      amount of homologous blood transfused in this series of children undergoing
      surgical repair of craniosynostosis.

PMID- 10636619
TI  - Rate of CSF formation and resistance to reabsorption of CSF during sevoflurane or
      remifentanil in rabbits.
AB  - Information on the effects of sevoflurane on the rate of cerebrospinal fluid
      (CSF) formation (Vf) and resistance to reabsorption of CSF (Ra) is incomplete,
      and no such information is available for remifentanil. The present study examined
      the dose-related effects of sevoflurane and remifentanil on Vf and Ra in rabbits.
      Eight rabbits were studied during isoflurane 1.4% (baseline) and sevoflurane
      1.4%, 2.5%, and 3.7%, and eight were studied during isoflurane 1.4% (baseline)
      and remifentanil 0.30, 0.67, and 1.00 microg x kg(-1) x min(-1) in randomized
      order. Ventriculocisternal perfusion at two CSF pressure states for each
      experimental condition was used to determine Vf and Ra. There was no dose
      response relation for Vf (10.4+/-2.5, 9.0+/-2.0, and 10.0+/-3.0 microl x min(-1))
      or Ra (0.81+/-0.33, 1.35+/-0.54, and 0.84+/-0.27 cm H2O x microl(-1) x min)
      between the three sevoflurane concentrations. There also was no dose-response
      relation for Vf (7.8+/-1.2, 8.8+/-3.0, and 6.5+/-2.3 microl x min(-1)) or Ra
      (1.07+/-0.54, 1.23+/-0.50, and 1.13+/-0.51 cm H2O x microl(-1) x min) between the
      three remifentanil doses. Vf and Ra during either sevoflurane or remifentanil
      were not significantly different from Vf and Ra during the two isoflurane
      baseline conditions (Vf = 8.5+/-2.5 and 9.8+/-1.3 microl x min(-1), and Ra =
      0.97+/-0.36 and 1.38+/-0.55 cm H2O x microl(-1) x min, mean +/- SD). Vf and Ra
      are of interest because they influence CSF volume, intracranial pressure, and/or
      intracranial elastance. In our model, sevoflurane or remifentanil did not
      significantly alter Vf or Ra.

PMID- 10636620
TI  - Inhibition of cyclooxygenase 2 by nimesulide decreases prostaglandin E2 formation
      but does not alter brain edema or clinical recovery after closed head injury in
      rats.
AB  - Recently, the enzyme cyclooxygenase (COX) has been recognized to exist as
      constitutive (COX-1) and inducible isoforms (COX-2). In previous studies, drugs
      that were inhibitors of both COX-1 and COX-2 failed to decrease brain edema
      formation or improve Neurological Severity Score (NSS) after closed head trauma
      (CHT), although some did decrease prostaglandin-E2 (PGE2) formation. The present
      study examined whether or not a specific inhibitor of COX-2 (nimesulide) exerts a
      beneficial effect after CHT in rats. Halothane-anesthetized rats (n = 8 in each
      group) were randomly assigned to one of four groups: surgery, no CHT, no drug
      (group 1); surgery, no CHT, nimesulide 30 mg/kg intraperitoneally (IP) (group 2);
      surgery, CHT, no drug (group 3); and surgery, CHT, nimesulide 30 mg/kg IP (group
      4). NSS was determined at 1 and 24 h, and brain tissue PGE2 concentration and
      water content were determined after killing at 24 h. Treatment with nimesulide
      did not improve NSS (NSS at 24 h = 11+/-6 [median +/- range] in group 3 and 12+/
      4 in group 4) or edema formation (brain water content at 24 h = 84.3+/-1.8% [mean
      +/- SD] in group 3 and 83.8+/-1.9% in group 4). However, nimesulide did decrease
      cortical and hypothalamic PGE2 formation by 41% and 47%, respectively during the
      first hour of incubation after brain tissue sampling. The authors conclude that
      although nimesulide does reduce tissue PGE2 formation, it does not exert a
      beneficial effect on brain tissue edema or functional activity after CHT in rats.

PMID- 10636622
TI  - Venous oxygen embolism due to hydrogen peroxide irrigation during posterior fossa
      surgery.
AB  - Hazards of application of hydrogen peroxide to semiclosed space are well known.
      We present a case of suspected gas embolism following hydrogen peroxide
      irrigation of the surgical field during posterior fossa surgery in the prone
      position. Severe cardiovascular collapse occurred when the wound was irrigated
      with hydrogen peroxide solution. Generation of pressure gradient leads to
      absorption of a considerable amount of oxygen giving rise to features of venous
      gas embolism. Although the case was associated with an uneventful recovery, use
      of hydrogen peroxide for securing hemostasis should be avoided.

PMID- 10636621
TI  - Intermittent propofol sedation during embolization of cerebral arteriovenous
      malformations.
AB  - Embolization procedure was performed for a 12-year-old boy with a left parietal
      arteriovenous malformation. Although provocative tests for the feeders to be
      occluded were considered very informative, the patient had to be sedated during
      microcatheter insertion. We used intermittent sedation with propofol during the
      interventional procedure, and obtained successful embolization.

PMID- 10636623
TI  - Intraoperative cardiac arrest in a neurosurgical patient: what are the options?
AB  - Intraoperative cardiac arrest is uncommon. We describe a case of intraoperative
      cardiac arrest in a patient undergoing anesthesia for surgical repair of an
      intracranial arteriovenous malformation (AVM).

PMID- 10636624
TI  - Blood loss after endoscopic strip craniectomy for craniosynostosis.

PMID- 10636625
TI  - Cytoprotection in acute myocardial infarction.

PMID- 10636626
TI  - Pyrexia, procalcitonin, immune activation and survival in cardiogenic shock: the
      potential importance of bacterial translocation.
AB  - AIMS: Exposure to bacterial endotoxin, perhaps due to bowel congestion or
      ischaemia and altered gut permeability, may result in immune activation that is
      characteristic for patients with severe heart failure. It is known that blood
      procalcitonin rises in response to bacterial endotoxin exposure. METHODS: We
      measured procalcitonin in a group of 29 patients with acute cardiogenic shock and
      no sign of infection (all without bacteraemia) and 26 with septic shock. Blood
      was analysed for procalcitonin, interleukin-6, tumour necrosis factor-alpha (TNF
      alpha), c-reactive protein (CRP) and neopterin. Patients were managed
      conventionally in an intensive care unit with no further experimental procedures.
      RESULTS: Three cardiogenic (10%) and seven septic shock patients (27%) survived.
      Most patients with acute heart failure surviving 12 h or more (18 of 20)
      developed a pyrexia (738.0 degrees C) of unknown origin in the absence of
      positive cultures, with a rise in procalcitonin (1.4+/-0.8 to 48.0+/-16.2 ng/ml,
      P<0.001), CRP (76.5+/-16.4 to 154.7+/-22.9 mg/l, P<0.001) and neopterin (20.7+/
      3.5 to 41.2+/-6.7 nmol/l, P<0.001). Patients with septic shock had higher initial
      levels of cytokines, and higher peak levels. Those with heart failure surviving
      (n=3) and those dying in the first 12 h (n=9) had no rise in cytokine levels. The
      patients with high procalcitonin had a higher temperature (38.9+/-0.3 vs. 37.3+/
      0.23 degrees C, P<0.05), TNF-alpha (43.95+/-9.64 vs. 16.43+/-4.33 pg/ml; P<0.005)
      and CRP (146.1+/-18.4 vs. 68.2+/-39.6 mg/ml, P<0.005). Peak procalcitonin levels
      correlated with peak temperature (r=0.74, P<0.001). CONCLUSION: Cardiogenic shock
      causes a pyrexia of unknown origin in patients surviving for 12 h and that is
      associated with a rise in procalcitonin levels. This lends support to the
      hypothesis that patients with cardiogenic shock may be being exposed to bacterial
      endotoxin at a time when bowel wall congestion and or ischaemia is likely to be
      present.

PMID- 10636627
TI  - Bacterial translocation in cardiopenic shock: the gastrointestinal tract as the
      motor of sepsis?

PMID- 10636628
TI  - Value of QT dispersion in diagnosis of restenosis after intracoronary stent
      implantation.
AB  - We studied the ECGs of patients with single vessel disease before and after (long
      term) coronary stent implantation. The interlead variability of the QT interval,
      known as QT dispersion (QTd), is believed to reflect the regional variations in
      ventricular repolarization and, thus, may provide an indirect marker of
      arrhythmogenicity. There are no reliable noninvasive markers of significant
      restenosis after stent implantation. The effect of coronary revascularization on
      QTd in patients who underwent coronary stenting has not been investigated
      extensively. The aim of this study was to evaluate the value of QTd in predicting
      restenosis after intracoronary stent implantation. QTd with 12 lead surface ECG
      was measured in 48 patients (21 with restenosis and 27 without restenosis; 33
      male; mean age, 58+/-10.8 years) before the procedure and after long-term follow
      up (mean, 6.8+/-3.2 months). All patients had coronary angiographic control at
      the end of the follow-up period. QTd (as the difference between the maximum and
      minimum QT interval measured from 12 lead ECG) and rate-corrected QT (QTcd) were
      evaluated at rest. In 27 patients without restenosis, QTd and QTcd decreased from
      58+/-14.4 and 62.8+/-20.4 ms to 26.3+/-9.2 and 29.6+/-10.6 ms in the long term
      follow-up, respectively (P<0.001). However, in 21 patients with restenosis, there
      was no significant change in QTd and QTcd intervals and they were still increased
      at the end of the long-term follow-up (P>0.05). In conclusion, increased QT
      interval dispersion may be an inexpensive and simple marker of restenosis after
      intracoronary stent implantation.

PMID- 10636629
TI  - Echocardiographic determination of left atrial function and its application for
      assessment of mitral flow velocity pattern.
AB  - We determined left atrial (LA) volume changes to evaluate LA function, and to
      correlate the Doppler-determined mitral flow velocity (MFV) pattern. Twenty-four
      patients with ischemic heart disease who showed 'normal' MFV pattern by pulsed
      Doppler echocardiography were studied. The patients were divided into 14 patients
      with left ventricular end diastolic pressure < 18 mmHg (true normals) and 10
      patients with > or = 18 mmHg (pseudo normals). The changes in LA volume were
      determined by echocardiography from apical two- and four-chamber views with
      modified Simpson's method. The volume measurements were done at the time of
      mitral valve opening (Vmax), at onset of atrial systole (Va) and at mitral valve
      closure (Vmin). Then the passive LA emptying volume was calculated by subtracting
      Va from Vmax, and the active LA emptying volume by subtracting Vmin from Va. The
      LA ejection fraction was calculated by the formula: [(Va-Vmin)Va] x 100. There
      was no significant difference in LA ejection fraction in pseudo normal (39+/-6%)
      and in true normal (41+/-13%) patients. Although the passive LA emptying volume
      was 16+/-4 ml/beat in true normal and was 11+/-3 ml/beat in pseudo normal (NS),
      the active LA emptying volume was significantly greater in pseudo normals (22+/-4
      m/beat) than in true normals (12+/-2 ml/beat, P<0.001). Thus, the ratio of
      passive and active LA emptying volume was markedly greater in true normals
      (1.28+/-0.35) than in pseudo normals (0.52+/-0.19, P<0.001), facilitating the
      differentiation of these two groups. These results indicate that two-dimensional
      echocardiographic measurement of LA volume can be valuable in assessing the LA
      function, providing an alternative method for differentiating pseudo normal from
      true normal MFV pattern in clinical settings, although several technological
      shortcomings should be resolved.

PMID- 10636630
TI  - Resting heart rate and cardiac function in dilated cardiomyopathy.
AB  - We hypothesized that, within the normal range of resting heart rate, heart rate
      and left ventricular ejection fraction would be inversely correlated and heart
      rate and left ventricular filling would be correlated in patients with dilated
      cardiomyopathy and not correlated in patients with normal cardiac function. At
      rest, heart rate, left ventricular ejection fraction, and three measures of
      diastolic filling (time to peak filling rate, peak filling rate, and first half
      filling fraction) were recorded using radionuclide ventriculography in subjects
      with no cardiac disease, patients with idiopathic dilated cardiomyopathy, and
      patients with dilated cardiomyopathy associated with ischemic heart disease.
      Heart rate had significant inverse correlations with left ventricular ejection
      fraction (r=-0.55, P=0.0007) and time to peak filling rate (r=-0.47, P=0.005) and
      a positive correlation with peak filling rate (r=0.73, P<0.0001) in patients with
      idiopathic dilated cardiomyopathy; heart rate was correlated only weakly with
      these measures in the absence of cardiac disease and essentially was not
      correlated in dilated cardiomyopathy due to ischemic heart disease. The change in
      resting heart rate with left ventricular ejection fraction and time to peak
      filling rate were significantly (P<0.05) different between patients with no
      cardiac disease and those with idiopathic dilated cardiomyopathy. Thus, resting
      heart rate correlated significantly with left ventricular ejection fraction and
      diastolic filling in patients with idiopathic dilated cardiomyopathy.

PMID- 10636631
TI  - Psychosocial and clinical factors predicting resumption of work following acute
      myocardial infarction in Japanese men.
AB  - We investigated psychosocial and clinical factors related to work resumption,
      delay in returning to work and level of work activity after an acute myocardial
      infarction in Japanese male patients. A total of 111 married male patients
      experiencing a first acute myocardial infarction, aged less than 66 years and in
      full-time employment participated. Interviews and questionnaires were
      administered during hospitalization to assess potential predictors of work
      related outcomes, with follow-up (81.6%) after an average of 8 months. We found
      that failure to return to work was predicated independently by older age
      (P=0.019), an introverted personality (P=0.011) and the presence of depressive
      symptoms during hospitalization (P=0.031). Delay in returning to work was
      predicted by greater concerns about health (P=0.011), low social support
      (P=0.021), and a failure to recognise a link between stress, coping style and
      illness (P=0.001). Resuming work at a lower activity level than before infarction
      was associated with older age (P=0.008), higher health concerns (P=0.012), and
      patients' predictions of their lower work activity (P=0.001). Clinical indices of
      infarction size and disease severity did not predict work-related outcomes. We
      conclude that psychosocial factors are associated with work resumption in
      Japanese men characterised by a job-centred lifestyle, with different factors
      being important for different work outcomes. The psychosocial factors found to be
      important are similar to those identified in Western societies.

PMID- 10636632
TI  - Return to work after MI, the roles of depression, health beliefs and
      rehabilitation.

PMID- 10636633
TI  - Glimepiride (Hoe490) inhibits the rilmakalim induced decrease in intracellular
      free calcium and contraction of isolated heart muscle cells from guinea pigs to a
      lesser extent than glibenclamide.
AB  - Glibenclamide is a potent inhibitor of the ATP-dependent potassium channel.
      Opening of the ATP-dependent potassium channel is regarded as a mechanism of
      ischemic preconditioning. This in vitro study examines the influence of
      glibenclamide and glimepiride, a new sulfonylurea, on the negative inotropic
      action of the potassium channel opener rilmakalim in isolated ventricular
      myocytes. Cardiac myocytes were isolated from adult guinea pig hearts by
      collagenase perfusion and incubated with rilmakalim (concentration range 0.1-12.0
      microM), glibenclamide (concentration range 0.03-3.0 microM) plus rilmakalim (3.0
      or 7.5 microM), and glimepiride (0.03-9.0 microM) plus rilmakalim (3.0 or 7.5
      microM) and paced by electrical field stimulation. Contractility of the myocytes
      was evaluated by digital image analysis, intracellular free calcium was
      determined by means of fura-2 fluorescence measurements, and cell viability was
      assessed morphologically as well as by measurement of lactate dehydrogenase
      activity. Rilmakalim reduced the systolic intracellular free calcium and
      contractility of ventricular myocytes in a concentration dependent manner. This
      effect was antagonized by glibenclamide at lower concentrations (0.3 microM) than
      glimepiride (3.0 microM). The smaller antagonistic action of glimepiride on the
      negative inotropic effect of rilmakalim as compared with glibenclamide most
      likely reflects a less potent inhibition of ATP-dependent potassium channels by
      glimepiride.

PMID- 10636634
TI  - Serial changes in negative T wave on electrocardiogram in acute pulmonary
      thromboembolism.
AB  - A negative T wave is frequently observed in precordial ECG leads in patients with
      acute pulmonary thromboembolism. We investigated the clinical significance of
      negative T wave in 15 patients with acute pulmonary thromboembolism who were
      treated with thrombolytic agents by measuring the mean pulmonary artery pressure
      and ratio of right to left ventricular end-diastolic diameter using
      echocardiography and ECG. The study included only patients with massive acute
      pulmonary thromboembolism of a mean age of 65+/-9.7 years (+/-SD). A negative T
      wave was observed on admission in 10 patients but was later detected in 14 of the
      15 patients. The mean amplitude of the negative T wave increased within 1 week
      then decreased after thrombolytic treatment. The peak negative amplitude of the T
      wave was observed from 1 to 7 days (mean, 2.6+/-1.8 days) and disappeared
      afterwards. During this period, improvements in both the mean pulmonary artery
      pressure (37.8+/-11.2 to 19.1+/-6.7 mmHg) and the ratio of right to left
      ventricular end-diastolic diameter (0.97+/-0.16 to 0.51+/-0.13) were noted in all
      patients. Our results suggest that an increase in the amplitude of negative T
      wave in precordial leads after thrombolytic therapy in patients with massive
      acute pulmonary thromboembolism reflects improvement in cardiopulmonary
      hemodynamics.

PMID- 10636635
TI  - Arrhythmogenic substrate in young patients with repaired tetralogy of Fallot:
      role of an abnormal ventricular repolarization.
AB  - Ventricular repolarization analysis has been shown to be effective in the
      identification of electrical myocardial instability leading to ventricular
      arrhythmias. The aim of the present study was to examine ventricular
      repolarization time indexes, in terms of both absolute measures and dispersion
      across the myocardium, in young patients with repaired tetralogy of Fallot (41
      pts; 28M/13F, age 11.7+/-3.6 years), assessing, furthermore, the possible
      influence of known negative prognostic factors relative to the surgical operation
      and residual haemodynamic abnormalities. The data of the study group were
      compared with those of 33 aged-matched asymptomatic control subjects (22M/11F,
      age 11.7+/-2.3 years). Ventricular depolarisation, as expressed by QRS duration,
      resulted significantly longer in total Fallot group than in the Control group
      (P<0.0001). Particularly, patients operated through a right ventricular approach
      showed higher values of QRS interval (P<0.0001) than those operated through a
      combined transatrial-transpulmonary approach. All the patients operated on for
      tetralogy of Fallot exhibit, with respect to control subjects, an inhomogeneous
      prolongation of ventricular repolarization across the myocardium, as showed by
      the significant increase in the absolute indexes of ventricular repolarization,
      JTc (P<0.001), QT (P<0.0001) and QTc (P<0.0001) with a concomitant prolongation
      of the indexes of dispersion of ventricular recovery time, QTcD (P<0.0001), JTcD
      (P<0.0001), 'adjusted' QTcD (P<0.001) and Tp-Te interval (P<0.0001). A temporal
      and regional variation in the ventricular repolarization across the myocardium in
      patients with repaired tetralogy of Fallot, could create the pathophysiological
      substrate for an increased cardiac electrical instability. The presence of
      negative prognostic factors, relative to the surgical intervention or residual
      haemodynamic abnormalities, even if not influencing the arrhythmic substrate,
      invariably present, could determine 'trigger' conditions essential for the
      development of ventricular arrhythmias.

PMID- 10636636
TI  - Juvenile tricuspid stenosis and rheumatic tricuspid valve disease: an
      echocardiographic study.
AB  - Tricuspid valve involvement is not uncommon in patients with rheumatic heart
      disease and is frequently missed on routine clinical examination. We
      prospectively studied the echocardiographic profile of tricuspid valve disease in
      788 consecutive patients with rheumatic heart disease. Out of these patients 9%
      (70) had tricuspid valve disease and 55.7% (39) of these were of < or = 20 years
      of age. Of these 60% were females and 40% were males. Their ages ranged from 9 to
      64 years (mean 24.2+/-13.6 years). Of these patients, 50% had tricuspid stenosis
      with or without tricuspid regurgitation whereas 50% had isolated tricuspid
      regurgitation. Isolated tricuspid stenosis was present in 7.4% of these cases.
      All patients had associated mitral stenosis. Severe mitral stenosis was present
      more commonly in patients with juvenile tricuspid stenosis compared to older
      patients (94.1% vs. 55.6%, P<0.005). Mitral regurgitation was present more
      commonly in juvenile age group patients compared to older patients (53.8% vs.
      25.8%, P<0.01). A combination of mitral, aortic and tricuspid stenosis was
      present in five cases and four of these were in the juvenile age group. Left
      ventricular enlargement and dysfunction were present in 28.6 and 14.3% patients,
      respectively, and the majority of these patients were in the juvenile age group
      (P<0.05). We conclude that rheumatic tricuspid valve disease occurs early in the
      course of the disease and progresses faster in India and is always associated
      with mitral stenosis. Juvenile tricuspid stenosis is more commonly associated
      with severe mitral stenosis, mitral regurgitation, left ventricular enlargement
      and dysfunction as compared with older patients.

PMID- 10636637
TI  - Prognostic significance of diabetes in acute myocardial infarction. Are the
      differences linked to female gender?

PMID- 10636638
TI  - Multiple cerebral infarcts from dislodgement of mobile apical left ventricular
      thrombus: therapeutic implications.

PMID- 10636639
TI  - Repetitive loss of consciousness during echocardiography.

PMID- 10636640
TI  - QT dispersion in hypothyroidism.

PMID- 10636642
TI  - [Molecular biology meeting of the SItI Study Group. Roma, Italy, 4 June 1999.
      Proceedings].

PMID- 10636641
TI  - Novel trends in neutrophil structure, function and development.

PMID- 10636643
TI  - Diastolic Heart Failure: A Challenge in Clinical Cardiology. Proceedings of a
      meeting. Lisbon, Portugal, January 23-24, 1998.

PMID- 10636644
TI  - Anaesthetic Research Society meeting. Aberdeen. March 25-26, 1999. Abstracts.

PMID- 10636645
TI  - Laceration of the eye with a fishing hook.

PMID- 10636646
TI  - Intraocular infestation with the worm, Thelazia callipaeda.

PMID- 10636647
TI  - Macular dystrophy of malattia leventinese. A 25 year follow up.

PMID- 10636648
TI  - Acute central retinal vein occlusion successfully treated with intravenous
      thrombolysis.

PMID- 10636649
TI  - Retinitis pigmentosa with visual fluctuation and arrestin gene mutation.

PMID- 10636650
TI  - Orbital Kimura's disease in a white child.

PMID- 10636651
TI  - Amikacin retinal toxicity.

PMID- 10636652
TI  - Simultaneous administration of hepatitis B and polio vaccines associated with
      bilateral optic neuritis.

PMID- 10636653
TI  - Retinopathy after long term, standard doses of hydroxychloroquine.

PMID- 10636654
TI  - Visual loss after primary trabeculotomy with mitomycin C in Ehlers-Danlos
      syndrome.

PMID- 10636655
TI  - Fluctuating oculomotor hyperfunction and hypofunction caused by aneurysmal
      compression of the third cranial nerve.

PMID- 10636657
TI  - Acute onset comitant esotropia as presenting sign of demyelinating disease.

PMID- 10636656
TI  - Late onset of Leber's hereditary optic neuropathy in HIV infection.

PMID- 10636658
TI  - Indocyanine green angiography in choroidal tuberculomas.

PMID- 10636659
TI  - Diagnosis of an atypical case of ocular toxoplasmosis using the demonstration of
      intraocular antibody production and the polymerase chain reaction.

PMID- 10636660
TI  - Protein C and protein S deficiency associated with retinal, optic nerve, and
      cerebral ischaemia.

PMID- 10636661
TI  - Macular hole following YAG capsulotomy.

PMID- 10636662
TI  - Magnetic resonance imaging of colobomatous optic hypoplasia.

PMID- 10636663
TI  - Orbital haemangiopericytoma simulating an intraocular mass.

PMID- 10636664
TI  - Delayed suprachoroidal haemorrhage following trabeculectomy bleb needling.

PMID- 10636665
TI  - Spontaneous intracorneal haemorrhage.

PMID- 10636666
TI  - Central serous papillopathy.

PMID- 10636667
TI  - Immunohistological findings in a patient with unusual late onset manifestations
      of ligneous conjunctivitis.

PMID- 10636668
TI  - Multifocal electroretinography in patients with occult macular dystrophy.

PMID- 10636669
TI  - Kimura's disease: no evidence of clonality.

PMID- 10636670
TI  - Correction of the inadequate lower fornix in the anophthalmic socket.

PMID- 10636671
TI  - Lymphocytoma cutis with conjunctival lesions.

PMID- 10636672
TI  - Acute myelogenous leukaemia in an adult presenting with uveitis.

PMID- 10636673
TI  - Subretinal haemorrhage in idiopathic intracranial hypertension.

PMID- 10636674
TI  - Accidental instillation of N-butyl cyanoacrylate into the anterior chamber.

PMID- 10636675
TI  - Late dehiscence of healed corneal scars.

PMID- 10636676
TI  - Transpupillary thermotherapy of choroidal melanoma with or without brachytherapy:
      a dilemma.

PMID- 10636677
TI  - Asymmetric diabetic retinopathy associated with Fuch's heterochromic cyclitis.

PMID- 10636678
TI  - Anterior capsular phimosis following Acrysof lens insertion.

PMID- 10636679
TI  - Central serous retinopathy complicated by massive bilateral subretinal
      haemorrhage.

PMID- 10636680
TI  - Various phenotypic expressions of familial aniridia with a PAX6 mutation.

PMID- 10636681
TI  - Iopidine allergy causing lower eyelid ectropion progressing to cicatricial
      entropion.

PMID- 10636682
TI  - Surgically removed submacular nematode.

PMID- 10636683
TI  - Acanthamoeba keratitis occurring with daily disposable contact lens wear.

PMID- 10636684
TI  - Clinical course of acute retinal zonal occult outer retinopathy in visual field
      and multifocal electroretinogram.

PMID- 10636685
TI  - Hypotonic maculopathy following pneumatic retinopathy: a UBM study.

PMID- 10636686
TI  - Bilateral electrical cataract.

PMID- 10636687
TI  - Monckeberg's sclerosis in temporal artery biopsy specimens.

PMID- 10636688
TI  - Retinal vascular abnormality in Poland's syndrome.

PMID- 10636689
TI  - Bilateral optic disc oedema associated with latanoprost.

PMID- 10636690
TI  - Somatostatin scan positive gastrinoma ocular metastasis.

PMID- 10636691
TI  - Retinal neovascularisation in Goltz syndrome (focal dermal hypoplasia)

PMID- 10636692
TI  - Retinitis sclopeteria associated with airbag inflation.

PMID- 10636693
TI  - Specular microscopic findings of corneal deposits in patients with Bietti's
      crystalline corneal retinal dystrophy.

PMID- 10636694
TI  - Structure and biosynthesis of glycoproteins. Preface.

PMID- 10636695
TI  - Induction of minor histocompatiblity antigen HA-1-specific cytotoxic T cells for
      the treatment of leukemia after allogeneic stem cell transplantation.

PMID- 10636696
TI  - Interleukin 12 and psoriasis.

PMID- 10636697
TI  - Genomes and evolution. Web alert.

PMID- 10636698
TI  - Motor systems.

PMID- 10636700
TI  - Analytical study of penicillamine in pharmaceuticals by capillary zone
      electrophoresis.
AB  - The ability of capillary zone electrophoresis in the development of analytical
      methods devoted to the quality control of the thiol drug penicillamine is shown.
      Using 50 mM phosphate running buffer (pH 2.5), good quantitations of
      underivatized penicillamine and its disulfide were achieved; detection at 200 nm
      allowed checking the presence of the disulfide impurity in pharmaceuticals. The
      use of 1,1-[ethenylidenebis(sulfonyl)]bis-benzene as a thiol specific reagent
      resulted in an increased sensitivity for the quantitation of D-penicillamine
      (limit of detection at 200 nm wavelength was 1.5 microM). Introducing beta
      cyclodextrin as chiral selector in the running buffer, enantioseparation of D-L
      penicillamine was obtained; for this purpose (+)-camphor-10-sulfonic acid, a
      chiral ion-pairing reagent, was found to be an essential additive in obtaining a
      baseline separation. The resulting enantioseparative system was validated in
      order to evaluate the presence of the toxic L-penicillamine enantiomer in
      pharmaceutical samples.

PMID- 10636699
TI  - Neurobiology of behaviour.

PMID- 10636701
TI  - Application of microemulsion electrokinetic chromatography to the analysis of a
      wide range of pharmaceuticals and excipients.
AB  - Microemulsion electrokinetic chromatography (MEEKC) is a capillary
      electrophoresis (CE) technique in which solutes partition with moving oil
      droplets present in a microemulsion buffer. Ionised species will also separate by
      electrophoresis. In this paper MEEKC is shown to give highly efficient and
      relatively rapid separations for a wide range of pharmaceuticals, vitamins and
      excipients. A single set of operating conditions was used to resolve both water
      soluble and insoluble compounds. The method was also used to separate both ionic
      and neutral compounds. The method was especially useful in the analysis of water
      insoluble neutral compounds such as steroids and lecithin, which are difficult to
      analyse by CE. The method was found to be both quantitative and highly
      repeatable. The quality of the separation was found to be dependent upon the
      sample diluent used if large injection volumes are employed. The use of MEEKC for
      the determination of complex mixtures such as multi-ingredient formulations and
      drug-related impurities was successfully demonstrated. MEEKC offers significant
      advantages over many forms of CE and capillary electrochromatography (CEC) and
      should be considered as an extremely useful option in pharmaceutical analysis.

PMID- 10636702
TI  - Poor reproducibility of in-source collisional atmospheric pressure ionization
      mass spectra of toxicologically relevant drugs.
AB  - The purpose of the study was to examine the intra- and interlaboratory
      reproducibility of mass spectra obtained with liquid chromatography-atmospheric
      pressure ionization mass spectrometry (LC--API-MS) both in electrospray (ESI) and
      atmospheric pressure chemical ionization (APCI) modes. Toxicologically relevant
      drugs of different polarity were selected as test substances: morphine-6
      glucuronide, 6-monoacetylmorphine, codeine, lysergic acid diethylamide,
      methylenedioxymethamphetamine. The study was performed in two laboratories using
      identical instruments and in one using a slightly different instrument. Basic
      instrument settings and mobile phase were identical in all laboratories. Mass
      spectra of drugs were taken at four collision energy voltages and using mobile
      phase of different composition (four concentration levels of acetonitrile and of
      ammonium formate buffer). The experiments demonstrated that mass spectra of given
      drugs, obtained in identical conditions with identical instruments, may show very
      different degrees of fragmentation. Mass spectra obtained with different
      instruments differed profoundly not only in the degree of fragmentation, but also
      different fragments and adducts were observed. Short-term intralaboratory
      reproducibility of mass spectra was satisfactory. On the other hand, the long
      term experiments showed different degrees of fragmentation of APCI-generated mass
      spectra at nominally identical fragmentation energy. The changes in the
      composition of the mobile phase (concentration of organic modifier or buffer
      molarity) did not affect the reproducibility of fragmentation to any relevant
      degree. The study showed that the interlaboratory exchange and use of mass
      spectrum library, generated by single-quadrupole (LC--API-MS instruments, is
      hardly feasible at the moment, even under very carefully standardized conditions.

PMID- 10636703
TI  - Live kidney donor assessment in the UK and Ireland.

PMID- 10636704
TI  - Live kidney donor assessment in the UK and Ireland.

PMID- 10636705
TI  - Saphenoperitoneal shunts for patients with intractable ascites associated with
      chronic liver disease.

PMID- 10636706
TI  - Surgical implications of underestimation of adrenal tumour size by computed
      tomography.

PMID- 10636707
TI  - Transhiatal approach to total gastrectomy for adenocarcinoma of the gastric
      cardia.

PMID- 10636708
TI  - Modern management of pulmonary embolism.

PMID- 10636709
TI  - Lower back pain management in injured workers.

PMID- 10636710
TI  - Catalysis and regulation. There is always another way.

PMID- 10636711
TI  - ECT and manic switching: bipolar IV disorder.

PMID- 10636712
TI  - Quality assurance of fixed-dose combinations of anti-tuberculosis medications.
      Proceedings of an IUATLD/WHO workshop, 29th IUATLD World Conference. Bangkok,
      Thailand, November 1998.

PMID- 10636713
TI  - Awareness intervention: who needs it?

PMID- 10636714
TI  - Precipitation of trace elements in parenteral nutrition mixtures.

PMID- 10636715
TI  - Special issue--pharmaceutical applications of modulated temperature calorimetric
      techniques.

PMID- 10636716
TI  - Oxidative damage to the lipids and proteins pf the lungs, testis and kidney of
      rats during carbon tetrachloride intoxication.

PMID- 10636717
TI  - 16th SMYTE (Small Meeting on Yeast Transport and Energetics). Casta-Papiernicka,
      Slovakia, September 23-27, 1998. Abstracts.

PMID- 10636718
TI  - Clonal origin, virulence factors, and virulence.

PMID- 10636719
TI  - [Emporiatrics].

PMID- 10636720
TI  - [Planned cholecystectomy: preoperative endoscopy of the upper gastrointestinal
      tract].

PMID- 10636721
TI  - [Diagnosis of acute pulmonary embolism].

PMID- 10636723
TI  - Collective bargaining is AMA's answer to managed care woes.

PMID- 10636722
TI  - [Individual therapeutic experiments. Ethical problems exemplified in oncology].

PMID- 10636724
TI  - Solving state's health problems is possible. New director pushes for creative
      solutions.

PMID- 10636725
TI  - Mentoring--a security blanket or a cover-up?

PMID- 10636726
TI  - Field evaluation of rapid tests for tuberculosis diagnosis.

PMID- 10636727
TI  - Dilemma of the virulence of Strptococcus suis strains.

PMID- 10636728
TI  - Proficiency of Spanish laboratories in detecting vancomycin-resistant
      enterococci.

PMID- 10636729
TI  - Third World debt puts AIDS drugs beyond reach.

PMID- 10636730
TI  - Compound heterozygosity for novel splice site mutations in the BPAG2/COL17A1 gene
      underlies generalized atrophic benign epidermolysis bullosa.
AB  - Generalized atrophic benign epidermolysis bullosa, GABEB (OMIM# 226650), is a
      nonlethal variant of epidermolysis bullosa with autosomal recessive inheritance
      pattern. The pathogenesis of this disorder can be caused by mutations affecting
      two different gene/protein systems. Most of the mutations have been identified in
      the BPAG2/COL17A1 gene encoding a hemidesmosomal transmembrane protein, the 180
      kDa bullous pemphigoid antigen (BP180), also known as type XVII collagen. The
      minority of the mutations are localized in the LAMB3 gene encoding the beta3
      polypeptide of laminin 5. In In this study we describe a GABEB patient who showed
      absent expression of BP180 in the cultured keratinocytes as well as in the skin.
      The patient was a compound heterozygote for two different splice site mutations,
      3053-1G-->C and 3871+1G-->C, affecting the extra-cellular domain of the protein.
      These mutations resulted in multiple aberrant splice variants, three of them
      causing premature termination codons for translation. This case, dealing with out
      of-frame splice site mutations in BPAG2/COL17A1, attests to the molecular
      heterogeneity of GABEB.

PMID- 10636731
TI  - Ulcerative colitis is not associated with differences in MUC2 mucin allele
      length.

PMID- 10636732
TI  - Mutation analysis of the DKC1 gene in incontinentia pigmenti.

PMID- 10636734
TI  - Skewed X chromosome inactivation in a female with haemophilia B and in her non
      carrier daughter: a genetic influence on X chromosome inactivation?

PMID- 10636733
TI  - A nonsense mutation in the retinal specific guanylate cyclase gene is the cause
      of Leber congenital amaurosis in a large inbred kindred from Jordan.

PMID- 10636735
TI  - 46,XX/46,XY at amniocentesis in a fetus with true hermaphroditism.

PMID- 10636736
TI  - A dominant relationship between the ACE D allele and serum ACE levels in a
      Ghanaian population.

PMID- 10636737
TI  - Coexistence of Gaucher disease type 1 and Joubert syndrome.

PMID- 10636738
TI  - Leigh syndrome transmitted by uniparental disomy of chromosome 9.

PMID- 10636739
TI  - A case of Williams syndrome with a large, visible cytogenetic deletion.

PMID- 10636740
TI  - First molecular evidence for a de novo mutation in RS1 (XLRS1) associated with X
      linked juvenile retinoschisis.

PMID- 10636741
TI  - Pathogenicity of homoplasmic mitochondrial DNA mutation and nuclear gene
      involvement.

PMID- 10636742
TI  - Identification and clinical presentation of beta thalassaemia mutations in the
      eastern region of Saudi Arabia.

PMID- 10636743
TI  - Rapid screening for the most common beta thalassaemia mutations in south east
      Asia by PCR based restriction fragment length polymorphism analysis (PCR-RFLP)

PMID- 10636744
TI  - Clinical and molecular findings in a patient with a deletion on the long arm of
      chromosome 12.

PMID- 10636745
TI  - Amelogenesis imperfecta, sensorineural hearing loss, and Beau's lines, a second
      case report of Heimler's syndrome.

PMID- 10636746
TI  - PTEN and LKB1 genes in laryngeal tumours.

PMID- 10636747
TI  - Movers and Shakers in the Vascular Tree--Hemodynamic and Biomechanical Factors in
      Blood Vessel Pathology. Research Initiatives in Vascular Disease Conference.
      Bethesda, Maryland, USA. March 11-12, 1999. Abstracts.

PMID- 10636748
TI  - [More stringent requirements for thermo-therapeutic equipment used in prostatic
      hypertrophy].

PMID- 10636749
TI  - William Osler of Bond Head, Canada.

PMID- 10636750
TI  - Spironolactone in patients with heart failure.

PMID- 10636751
TI  - Spironolactone in patients with heart failure.

PMID- 10636752
TI  - Spironolactone in patients with heart failure.

PMID- 10636753
TI  - Spironolactone in patients with heart failure.

PMID- 10636754
TI  - Increased mortality associated with growth hormone treatment in critically ill
      adults.

PMID- 10636755
TI  - Increased mortality associated with growth hormone treatment in critically ill
      adults.

PMID- 10636756
TI  - Enoxaparin for the prevention of venous thromboembolism.

PMID- 10636757
TI  - Enoxaparin for the prevention of venous thromboembolism.

PMID- 10636758
TI  - Enoxaparin for the prevention of venous thromboembolism.

PMID- 10636759
TI  - Genetic and phenotypic correlates of colorectal cancer in young patients.

PMID- 10636760
TI  - Clinician-educators in academic medical centers.

PMID- 10636761
TI  - Clinician-educators in academic medical centers.

PMID- 10636762
TI  - Clinician-educators in academic medical centers.

PMID- 10636763
TI  - Clinician-educators in academic medical centers.

PMID- 10636764
TI  - [The positive action of refracterin on the reserve potentials and metabolism of
      the myocardium during its overload in toxic-allergic myocarditis].
AB  - Heart overloading due to pressure as a result of 8 periodic full aortic
      constriction in heart failure (HF) caused by 10-day toxic-allergic myocarditis
      (TAM) leads to deterioration of heart contractility (pump function). This is
      explained by additional decline in functional activity of all three systems of
      cardiomyocyte responsible for contraction-relaxation. In particular, by a sharp
      fall of ATP and CP content in the myocardium, a 400% decrease in myofibril power,
      200% reduction in efficiency of contraction and marked deterioration of calcium
      transport. The resultant exhaustion of myocardial reserve brought 70% lethality
      among the animals. Under the above conditions coordination between the systolic
      and diastolic cardiac functions, correlation between myocardial functional
      activity and subcellular systems of cardiomyocyte are impaired. In pressure heart
      overloading refracterin initiates profound metabolic rearrangements improving
      metabolism, remodelling of the system of energy supply, reestablishment of
      systemic homeostasis, normalization of cardiomyocyte and cardiac reserves.

PMID- 10636765
TI  - [The protective effect of preliminary adaptation to the stress from disorders of
      the gas-transport function of the blood in hemorrhagic shock].
AB  - To prevent disturbances of blood gas-transport function in hemorrhagic shock, we
      used cross-over protective effect of adaptation to short-term immobilization
      stress. Adaptation of rats to stress was associated with a rise in baseline
      arterial blood, pH in venous blood; fall in PO2, PCO2,P50. Stress-adapted rats
      appeared more resistant to blood loss. Gas transport 1 hour after hemorrhage was
      better than in non-adapted animals demonstrated more active compensatory
      reactions in l low hypoxic damage to the tissues. 2.5-h survival after start of
      bleeding in control animals made up 35%, in the group of adapted animals--67%.
      Thus, adaptation to short-term immobilization stress is a non-pharmacological
      method to prevent hemorrhagic shock.

PMID- 10636766
TI  - [The energy-informational role of the right ventricle in the informational
      thermodynamic system of the heart].
AB  - Criteria for estimation of the energy-informational requirements of the right and
      left ventricles have been obtained using morphological data of the
      chronobiological experiment performed at Pathophysiology Chair of the RPFU in
      1984. The estimates, due to greater energy-informational support of the right
      ventricle, demonstrate the leading role of the right ventricle, in regulation of
      the heart's informational-thermodynamic system (ITDS). The role of the left
      ventricle consists in maintenance of the heart contractility. Therefore, the left
      ventricle can function at lower energo-informational potential. These findings
      provide new evidence on internal mechanisms of the right and left ventricle
      dysfunction which could necessitate corrections of relevant diagnostic and
      therapeutic approaches.

PMID- 10636767
TI  - (The internist is also a decision-maker)

PMID- 10636768
TI  - Leishmania donovani parasites interact with gamma/delta+ human peripheral blood T
      cells and induce susceptibility to NK cell-mediated lysis.
AB  - We recently reported that Leishmania donovani infect the human T-cell line in
      vitro. To examine whether primary human T cells could be infected by this
      parasite, a direct interaction of the peripheral blood T cells with L. donovani
      was examined. The percentage of gamma/delta+ T cells was markedly increased when
      in vitro generated normal human T-cell blasts were cultured with L. donovani
      amastigotes. About 30% of the gamma/delta+ T cells in the parasite exposed T-cell
      blasts expressed parasite antigens intracellularly without detectable
      intracellular parasites. Parasite exposed T-cell blasts had a reduced surface
      expression of HLA-DR and were lysed by the sorted CD56+ cells. In contrast,
      neither L. donovani amastigotes nor T-cell blasts exposed to heat killed
      amastigotes and/or were sensitive to the NK cell-mediated lysis. Of interest is
      that about 10% CD3+ peripheral blood T cells in two out of three Indian Kala-azar
      patients tested expressed intracellular L. donovani antigens.

PMID- 10636769
TI  - Use of alpha-, beta- and gamma-hexachlorocyclohexane in Europe, 1970-1996.
AB  - Data on current and historical usage of alpha, beta, and gamma
      hexachlorocyclohexane (HCH) in Europe are presented. The data were collected and
      estimated as a part of a project studying the regional cycling of persistent
      organic pollutants (POPs) in the Baltic environment (Popcycling-Baltic). Better
      data on sources, environmental discharges and atmospheric emissions of HCH and
      other POPs are needed to study, and hopefully reduce, the impact of these
      pollutants on the environment. Substantial uncertainties are assigned to the
      estimated data for individual countries and years, but it seems likely that the
      general trend of usage in Europe is captured. The quality of the estimates is
      thought to improve in general throughout the period, thus, reflecting the
      availability of reliable data. The results suggest that 382,000 t of technical
      HCH and 81,000 t of lindane were used in Europe from 1970 to 1996. This is
      equivalent to an estimated cumulative usage of 259,000 t alpha-HCH, 235,000 t
      gamma-HCH and 20,000 t beta-HCH. The usage of technical HCH was the major source
      of gamma-HCH until the late 1970s, and thereafter lindane became the dominating
      source of this isomer. The use of gamma-HCH in 1996 was estimated to still be
      nearly one-third of the European usage in 1970. The pattern of decreasing
      concentrations in biota follows the pattern of reductions in usage for the
      studied period within the Baltic area.

PMID- 10636770
TI  - Research on the variability of physico-chemical parameters characterising acid
      precipitation at the Jeziory Ecological Station in the Wielkopolski National Park
      (Poland).
AB  - Here the water quality of precipitation at the Adam Mickiewicz University
      Ecological station is presented for the period 1992-1997 to examine one of the
      main factors causing the degradation of the natural environment of the
      Weilkopolski National Park. In the course of daily observations the amount of
      rainfall, its electrical conductivity and pH were measured. As much as 61% of the
      tested precipitation had a pH < 4.6, and 92% had a pH < 5.6; some very low pH
      values, even below 3.0, were occasionally observed. The annual volume-weighted
      average pH during the full period was 4.28 and the lowest yearly average was 3.92
      (1994). The chemical composition of precipitation showed the dominance of
      sulphate and calcium ions. Fluoride ions also contributed significantly to the
      anion charge. There were also small amounts of heavy metals and polycyclic
      aromatic hydrocarbons. A chemical analysis of throughfall showed a considerably
      increased concentration of some ions, in particular potassium.

PMID- 10636771
TI  - Bacterial bioluminescence: isolation and expression of the luciferase genes from
      Vibrio harveyi.
AB  - Genes for the luciferase enzyme of Vibrio harveyi were isolated in Escherichia
      coli by a general method in which nonluminous, transposon insertion mutants were
      used. Conditions necessary for light production in E. coli were examined.
      Stimulation of transcription of the genes for luciferase (lux A and lux B) was
      required for efficient synethesis of luciferase. To enhance transcription
      bacteriophage promoter elements were coupled to the cloned lux gene fragments.

PMID- 10636772
TI  - Breakthrough of the year. Capturing the promise of youth.

PMID- 10636773
TI  - Breakthrough of the year. The runners-up.

PMID- 10636774
TI  - Gene therapy death prompts review of adenovirus vector.

PMID- 10636775
TI  - Promising antibiotic candidate identified.

PMID- 10636776
TI  - NIMH. Mental health agency shrugs off critics.

PMID- 10636778
TI  - Computer science. Big Blue aims to crack protein riddle.

PMID- 10636777
TI  - Scientific misconduct. Researcher rebuked for 20-year-old misdeed.

PMID- 10636779
TI  - PCR. Taq polymerase patent ruled invalid.

PMID- 10636780
TI  - Lab safety. Licenses suspended at 3 Toronto hospitals.

PMID- 10636781
TI  - Does cancer therapy trigger cell suicide?

PMID- 10636782
TI  - Scientific misconduct. Europe stresses prevention rather than cure.

PMID- 10636783
TI  - Biological imaging. Scanners get a fix on lab animals.

PMID- 10636784
TI  - Breakthroughs 1999.

PMID- 10636785
TI  - Dietary supplements: what is in the public's best interest?

PMID- 10636786
TI  - Dietary supplements: what is in the public's best interest?

PMID- 10636787
TI  - Policy forum: food safety. Food irradiation--the neglected solution to food-borne
      illness.

PMID- 10636788
TI  - Policy forum: genetic technologies. Commercialization of genetic research and
      public policy.

PMID- 10636789
TI  - Perspectives: cognition. An innate basis for language?

PMID- 10636790
TI  - Mutant dyskerin ends relationship with telomerase.

PMID- 10636791
TI  - DNA methylation de novo.

PMID- 10636792
TI  - Techsighting. Cell biology. Sorting on silicon.

PMID- 10636793
TI  - New NIH rules promote greater sharing of tools and materials.

PMID- 10636794
TI  - Bracing p53 for the war on cancer.

PMID- 10636795
TI  - Checkpoint gene linked to human cancer.

PMID- 10636796
TI  - Deformed frogs. Link to parasites grows stronger.

PMID- 10636797
TI  - Circadian rhythms. Possible clock messenger identified.

PMID- 10636798
TI  - Human genetics. mtDNA shows signs of paternal influence.

PMID- 10636799
TI  - Mice cloned from cultured stem cells.

PMID- 10636800
TI  - DNA cuts its teeth--as an enzyme.

PMID- 10636801
TI  - UCSF on the move to new Mission Bay campus.

PMID- 10636802
TI  - Life sciences' stewardship of science.

PMID- 10636803
TI  - The Bayesian way.

PMID- 10636804
TI  - The Bayesian way.

PMID- 10636805
TI  - U.S. and Cuban scientific exchange.

PMID- 10636806
TI  - Responding to The River.

PMID- 10636807
TI  - Funding for the unexpected.

PMID- 10636808
TI  - Policy forum: public health. Reducing liver cancer--global control of aflatoxin.

PMID- 10636809
TI  - Perspectives: evolutionary biology. Sex and death.

PMID- 10636810
TI  - Perspectives: neurobiology. The CRYs fo flies and mice.

PMID- 10636811
TI  - Surgery and respiratory muscles.

PMID- 10636812
TI  - Postoperative air leaks.

PMID- 10636813
TI  - Rare diseases.

PMID- 10636814
TI  - Aspergillus fumigatus: re-invention of the wheel.

PMID- 10636815
TI  - [Incidence of cancer after primary deep venous thrombosis or pulmonary embolism].

PMID- 10636816
TI  - [The riddles of the first article by Ivan Petrovich Pavlov].

PMID- 10636817
TI  - Bovine viral diarrhea disease associated with a contaminated vaccine.

PMID- 10636818
TI  - [120 years since the birth of Prof. B. S. Doinikov].

PMID- 10636819
TI  - Postinfectious glomerulonephritis.

PMID- 10636820
TI  - Vaporisers.

PMID- 10636821
TI  - The use of mini-dose suxamethonium to facilitate the insertion of a laryngeal
      mask airway.

PMID- 10636822
TI  - Hazard notices. MDA HN1999(05) August 1999. Tracheostomy tubes--Shiley Adult Dual
      Cannula/ manufacturers' recall.

PMID- 10636823
TI  - Augmented destruction test with an electromechanical pulsatile total artificial
      heart.
AB  - The total artificial heart (TAH) being developed by these authors successfully
      completed hydrodynamic and hemolysis studies followed by two acute implantations.
      Before commencing preclinical studies on any device, documentation of the
      reliability and durability of each component has to be done. This TAH was
      submitted to a 4 month destruction test under the most severe driving conditions
      to detect any weak mechanical components of the system. The maximum dP-dt in the
      left pumping chamber was chosen of more than 15,000 mm Hg/s, which is almost 6
      times higher than that of the normal driving condition. The pump was submersed
      into a water bath that was maintained at 37 degrees C. The TAH was driven in a
      left master alternative (LMA) variable rate mode at 8 L/min output flow, 15 mm Hg
      reload, 100 mm Hg left afterload, and 25 mm Hg right afterload. The outflow,
      pressures, and temperature inside the TAH were monitored. Several stress
      concentration areas were detected. The connection between the roller nut and
      support plate proved to be one of the most stressed regions, and a more reliable
      fixing procedure was required. This portion was redesigned to offer a durable
      connection. No malfunctions of the actuator or controller were detected
      throughout the testing duration. No temperature elevation more than 1 degree C on
      the center piece of the TAH was demonstrated.

PMID- 10636824
TI  - The cytoskeleton and polarization during pollen development in Carex blanda
      (Cyperaceae).
AB  - Patterns of cytoskeletal organization during distinct polarizations that
      characterize pollen development in the sedge Carex blanda (Cyperaceae) were
      studied by correlated methods of immunohistochemistry and confocal and
      transmission electron microscopy. As is typical of the family Cyperaceae, Carex
      produces a unique pollen type known as a pseudomonad in which all four
      microspores of the tetrad are enclosed within the wall of a single pollen grain.
      Only one member of the tetrad is functional and the other three abort. The
      pseudomonads are precisely oriented in the locule with the functional microspore
      in the wide abaxial portion of the wedge-shaped cytoplasm adjacent to the
      tapetum, and the degenerative microspores are packed tightly in the pointed
      adaxial portion. A unique sequence of post-meiotic developmental events reflects
      both intracellular and intercellular polarity. Development includes: (1) random
      placement of tetrad nuclei in the coenocytic sporocyte after meiosis, (2)
      interrupted cytokinesis resulting in a tetrad of nuclei that migrates as a unit
      into the narrow adaxial tip, (3) completion of unequal cytokinesis and centering
      of the functional nucleus in the wide abaxial portion of the microsporocyte via a
      radial array of microtubules and microfilaments, (4) unequal mitosis resulting in
      a small generative cell at the proximal surface of the functional microspore
      (adjacent to the abortive microspores), and (5) recentering of the vegetative
      nucleus in the abaxial cytoplasm via a radial cytoskeletal array.

PMID- 10636825
TI  - Changes in cell structure during the formation of root aerenchyma inSAGITTARIA
      LANCIFOLIA (Alismataceae).
AB  - In many wetland species, root aerenchyma is produced by the predictable collapse
      of root cortex cells, indicating a programmed cell death (PCD). The objective of
      this study was to characterize the cellular changes that accompany this PCD in
      the marsh species Sagittaria lancifolia. Structural changes in membranes and
      organelles were examined during development of root cortex cells to compare with
      previous examples of PCD. The organization of cortical microtubule (CMT) arrays
      in root cells from S. lancifolia was also evaluated as a possible predictor of
      cell lysis. Nuclear fragmentation and condensation were the earliest changes
      observed in cells undergoing lysis. Breakdown of the tonoplast and other
      organelles and disruption of the plasma membrane followed. After loss of
      cytoplasm, cells collapsed to form gas spaces. These results were compared to
      collapse of root cortical cells of Zea mays and Oryza sativa during aerenchyma
      development. Changes in the appearance of the cytoplasm of all three species were
      similar at later stages of aerenchyma development. The relative timing of
      disintegration of the tonoplast and middle lamella appeared to differ among the
      three species. Changes in the organization of CMT arrays did not appear to be a
      predictor of PCD in S. lancifolia. Aerenchyma production in plants involves a
      type of PCD that is morphologically distinct from PCD described from many
      animals.

PMID- 10636826
TI  - Wood anatomy of Elaeagnaceae, with comments on vestured pits, helical
      thickenings, and systematic relationships.
AB  - The secondary xylem of Elaeagnus, Hippophae, and Shepherdia is described and
      illustrated in detail. Shrubs and small trees of Elaeagnaceae have ring-porous or
      semi-ring-porous wood with simple perforation plates, vascular tracheids, fiber
      tracheids, diffuse or rarely paratracheal axial parenchyma, and uni- or biseriate
      rays in Hippophae and Shepherdia, but wider rays in Elaeagnus. Walls of vessel
      elements, especially narrow ones, tracheids, or fiber-tracheids sometimes show
      helical thickenings; in a few instances these intergrade with small bud-like
      protrusions associated with pits. Scanning electron microscopy illustrates that
      small to vestigial vestures are present in all species studied, although
      nonvestured pits are also common. The analogous nature of vestures and helical
      thickenings is considered. Comparative wood anatomy suggests a rather isolated
      position of the family Elaeagnaceae; affinities with Rhamnaceae, Proteaceae, and
      Thymelaeaceae are discussed.

PMID- 10636827
TI  - Reorientation of daffodil(Narcissus: Amaryllidaceae) flowers inwind: drag
      reduction andtorsional flexibility.
AB  - Daffodil flowers extend laterally from the long axes of their stems; as a result,
      wind on a flower exerts torsional as well as flexural stress on the stem. Stems
      respond by twisting, and thus flowers reorient to face downwind in moderate
      winds, in the process reducing their drag by ~30%. This repositioning is
      facilitated by the stems' relatively low torsional stiffness. Daffodil stems have
      a ratio of flexural to torsional stiffness of 13.27 +/- 0.96 (SD), compared with
      8.33 +/- 3.20 (SD) for tulip stems, which bear flowers as symmetrical extensions
      of their long axes, and compared with 1.5 for isotropic, incompressible, circular
      cylinders.

PMID- 10636828
TI  - Meristem growth dynamics and branching patterns in the Cladoniaceae.
AB  - Branching patterns in the lichen family Cladoniaceae are varied and taxonomically
      important. Branching occurs on the podetium, the erect secondary thallus that
      characterizes most species in the Cladoniaceae, and is influenced by growth
      dynamics of the fungal meristem tissue at the apex of the podetium. Branching is
      primarily the result of meristem divisions, and branching patterns are modified
      by meristem enlargement, deformation, and torsion. Branching processes are
      conserved, and early branch ontogeny provides information from which to determine
      relationships in the Cladoniaceae. Branching is characterized by two major
      patterns. In one pattern, branches arise from the relatively late divisions of a
      large meristem (>=100 MUm in diameter), whose shape changes during ontogeny. In a
      second pattern, branches arise from small meristems (<100 MUm in diameter), which
      split early in ontogeny but whose shape does not change. The trend toward reduced
      meristems that split early in ontogeny is seen as an evolutionary advance in the
      Cladoniaceae. Some "small meristem" species retain aspects of the "large
      meristem" habit in early ontogeny, and this provides a clue to their
      relationships. Patterns of meristem growth dynamics provide a basis for
      interpreting phylogeny in mycobionts of the Cladoniaceae. Meristem activities in
      four genera of the Cladoniaceae were compared in order to determine trends in
      growth dynamics within the family.

PMID- 10636829
TI  - Pollinator-mediated interactions between a pathogenic fungus, Uromyces pisi
      (Pucciniaceae), and its host plant,Euphorbia cyparissias (Euphorbiaceae).
AB  - The plant Euphorbia cyparissias is commonly infected by rust fungi of the species
      complex Uromyces pisi. When infected, E. cyparissias is unable to flower, but
      instead is induced by the fungus to form pseudoflowers. Pseudoflowers are
      rosettes of yellow leaves upon which the fungus presents its gametes in a sweet
      smelling fungal nectar. We hypothesized that the fungi, as they are
      heterothallic, are dependent on insect visitation to cross-fertilize their mating
      types. We confirmed that insects are required with an insect exclusion
      experiment. We further hypothesized that pseudoflowers of U. pisi interact with
      uninfected true host flowers through insects during their period of co
      "flowering" in early spring. We conducted artificial array experiments in the
      field to test whether the two species share insects and whether they influenced
      each other's insect visitation. Insects moved between true flowers and
      pseudoflowers, but true flowers received more visits over all. Pseudoflowers and
      true flowers did not influence each other's visitation rates in mixtures.
      However, shorter visits were observed on pseudoflowers in mixtures than
      monocultures, suggesting that true flowers might be competitors for
      pseudoflowers. Further experiments are needed to determine whether the similarity
      of pseudoflowers to true flowers is adaptive.

PMID- 10636830
TI  - Patterns of seed mass variation and their effects on seedling traits inAlliaria
      petiolata (Brassicaceae).
AB  - Seed mass is considered to be the least plastic component of reproductive yield.
      Yet, in invasive populations of garlic mustard, Alliaria petiolata, seed mass was
      highly variable (eightfold among populations, 2.5-7.5 fold within populations,
      two-threefold within individuals, and 1.4-1.8 fold within fruits). Variation in
      seed mass among populations explained nearly half of the total variance.
      Variation among seeds within fruits accounted for a further 25% of variance.
      Individual seed mass within a plant decreased with increased distance from the
      main stem, suggesting that access to parental resources limits seed size in a
      predictable manner. MANOVAs and Roy-Bargmann stepdown analyses revealed
      significant effects of seed mass, but not seed position (within a fruit or within
      an infructescence), on an array of subsequent seedling traits. Smaller seeds
      germinated significantly earlier, and seedlings from small seeds produced their
      first primary leaves significantly later and grew significantly taller. After
      accounting for seed mass as a covariate, only one seedling trait, date of first
      leaf emergence, was affected by seed position in a fruit. Differences in seed
      mass may therefore affect seedling recruitment via effects on early seedling
      growth in this weedy species.

PMID- 10636831
TI  - Phylogenetic relationships of Salix (Salicaceae) based on rbcL sequence data.
AB  - Nucleotide sequences of the chloroplast-encoded rbcL gene were used to examine
      phylogenetic relationships of the genus Salix together with other allied genera
      of the family Salicaceae. Phylogenetic analyses of rbcL sequences strongly
      suggest the monophyly of three commonly recognized genera (Chosenia, Salix, and
      Toisusu). Two monophyletic groups are recognized within the larger monophyletic
      group. They do not correspond with any infrageneric taxa proposed so far. With
      regard to character evolution, it is thought that the reduction of stamen number
      from more than two stamens to two might occur in at least three lineages and that
      fused bud scales evolved several times and/or the reverse evolution occurred from
      fused to free. Some types of pollen surfaces are considered to have evolved
      independently.

PMID- 10636832
TI  - A phylogeny of Apiaceae tribe Scandiceae: evidence from nuclear ribosomal DNA
      internal transcribed spacer sequences.
AB  - The evolutionary relationships among members of Apiaceae (Umbelliferae) tribe
      Scandiceae and representatives of all major lineages of Apioideae (including
      putatively allied Caucalideae) identified in earlier molecular studies were
      inferred from nucleotide sequence variation in the internal transcribed spacer
      regions (ITS1 and ITS2) of nuclear ribosomal DNA. In all, 134 accessions
      representing 18 genera commonly treated in Scandiceae were analyzed. Phylogenies
      estimated using maximum parsimony and distance methods were generally similar and
      suggest that: (1) Scandiceae form a well-supported clade, consisting of the
      genera Anthriscus, Athamanta (in part), Balansaea, Chaerophyllum, Conopodium,
      Geocaryum, Kozlovia, Krasnovia, Myrrhis, Myrrhoides, Neoconopodium, Osmorhiza,
      Scandix, Sphallerocarpus, and Tinguarra; (2) Athamanta is polyphyletic, with A.
      della-cellae allied with Daucus and A. macedonica placed close to Pimpinella; and
      (3) Rhabdosciadium and Grammosciadium find affinity with the Aegopodium group of
      umbellifers, whereas the placement of the monotypic Molopospermum cannot be
      inferred because of its high sequence divergence. The genus Bubon has been
      restored with two new combinations, B. macedonicum subsp. albanicum and B.
      macedonicum subsp. arachnoideum. Scandiceae arise within paraphyletic
      Caucalideae, the latter comprising two major lineages whose relationships to
      Scandiceae are not clear. Therefore, a broad treatment of Scandiceae is proposed,
      with subtribes Scandicinae, Daucinae, and Torilidinae (the latter two
      representing the Daucus and Torilis subgroups, respectively, of recent molecular
      systematic investigations).

PMID- 10636833
TI  - Phylogenetic structure in the grass family (Poaceae): evidence from the nuclear
      gene phytochrome B.
AB  - Phylogenetic analyses of partial phytochrome B (PHYB) nuclear DNA sequences
      provide unambiguous resolution of evolutionary relationships within Poaceae.
      Analysis of PHYB nucleotides from 51 taxa representing seven traditionally
      recognized subfamilies clearly distinguishes three early-diverging herbaceous
      "bambusoid" lineages. First and most basal are Anomochloa and Streptochaeta,
      second is Pharus, and third is Puelia. The remaining grasses occur in two
      principal, highly supported clades. The first comprises bambusoid, oryzoid, and
      pooid genera (the BOP clade); the second comprises panicoid, arundinoid,
      chloridoid, and centothecoid genera (the PACC clade). The PHYB phylogeny is the
      first nuclear gene tree to address comprehensively phylogenetic relationships
      among grasses. It corroborates several inferences made from chloroplast gene
      trees, including the PACC clade, and the basal position of the herbaceous bamboos
      Anomochloa, Streptochaeta, and Pharus. However, the clear resolution of the
      sister group relationship among bambusoids, oryzoids, and pooids in the PHYB tree
      is novel; the relationship is only weakly supported in ndhF trees and is
      nonexistent in rbcL and plastid restriction site trees. Nuclear PHYB data support
      Anomochlooideae, Pharoideae, Pooideae sensu lato, Oryzoideae, Panicoideae, and
      Chloridoideae, and concur in the polyphyly of both Arundinoideae and
      Bambusoideae.

PMID- 10636834
TI  - Diversification of the North American shrub genus Ceanothus (Rhamnaceae):
      conflicting phylogenies from nuclear ribosomal DNA and chloroplast DNA.
AB  - Ceanothus comprises ~55 morphologically and ecologically diverse species of woody
      perennials endemic to North America. Interpretations of the natural history of
      Ceanothus have served as a general model of evolution for woody perennials with
      simple entomophilous pollination systems, but these interpretations lacked
      explicit phylogenetic context. We used cladistic analysis of sequences of the
      chloroplast-encoded matK and the internal transcribed spacers (ITS) and 5.8S
      coding region of nuclear ribosomal DNA (nrDNA) to reconstruct the phylogeny of
      Ceanothus. The nuclear and organellar phylogenies exhibited very low levels of
      both topological and character congruence. Subgenera Ceanothus and Cerastes are
      monophyletic sister taxa in both phylogenies, but both data sets suffer from a
      lack of resolution below the level of subgenus. Lack of taxonomic congruence
      between the two data sets may be a result of introgression and/or lineage
      sorting. The ITS tree was accepted as the better estimate of a species phylogeny
      for Ceanothus, on the assumption that nuclear markers are less prone to
      introgression. Three of five polytypic species in the ITS data set were
      paraphyletic, and four of six polytypic species in the matK data set were
      paraphyletic. This study demonstrates the degree to which matched independent
      data sets can produce conflicting summaries of evolutionary history.

PMID- 10636835
TI  - Variation in seed traits of Lobelia inflata (Campanulaceae): sources and fitness
      consequences.
AB  - Seed germination constitutes an important event in the life cycle of plants. Two
      related seed traits affect fitness: seed size and the timing of seed germination.
      In three sets of experiments, we (1) partition the sources of seed-size variance
      in Lobelia inflata into components attributable to fruit size, relative fruit
      position, and parental identity; (2) examine the influence of pregermination
      conditions and seed size on time to germination; and (3) assess the fitness
      consequences of seed size and germination timing under seminatural, harsh
      conditions. Seed-size variance is attributable to both parental identity and
      fruit position within an individual. Distal fruits produce larger but fewer
      seeds. No significant correlation exists between fruit size and seed size, but a
      trade-off is found between the number and size of seeds contained in a fruit
      after correcting for fruit size. The timing of germination is influenced by seed
      size, light conditions before winter, and winter duration. Germination timing
      influences survival, and despite small seed size in this species (2 * 10 g/seed),
      seed size has a persistent and significant association with both final plant size
      and the probability of survival to autumn.

PMID- 10636836
TI  - Seasonal patterns of terpene content and emission from seven Mediterranean woody
      species in field conditions.
AB  - The seasonal pattern of terpene content and emission by seven Mediterranean woody
      species was studied under field conditions. Emission rates were normalized at 30
      degrees C and 1000 MUmol.m.s PFD (photosynthetic photon flux density). Bupleurum
      fruticosum, Pinus halepensis, and Cistus albidus stored large amounts of terpenes
      (0.01-1.77% [dry matter]) with maximum values in autumn and minimum values in
      spring. They emitted large amounts of terpenes (2-40 MUg.g DM.h), but with no
      clear seasonal trend except for Cistus albidus, which had maximum values in
      spring and minimum values in autumn. The nonstoring species Arbutus unedo, Erica
      arborea, Quercus coccifera and Quercus ilex also emitted large amounts of
      terpenes (0-40 MUg.g DM.h) and also tended to present maximum emission rates in
      spring, although this trend was significant only for A. unedo. At the seasonal
      scale, emission rates did not follow changes in photosynthetic rates; instead,
      they mostly followed changes in temperature. From autumn to spring, the least
      volatile monoterpenes such as limonene were emitted at highest rates, whereas the
      most volatile monoterpenes such as alpha-pinene and beta-pinene were the most
      emitted in summer. The monoterpene emission rates represented a greater
      percentage of the photosynthetic carbon fixation in summer (from 0.51% in Arbutus
      unedo to 5.64% in Quercus coccifera) than in the rest of the seasons. All these
      seasonality trends must be considered when inventorying and modeling annual
      emission rates in Mediterranean ecosystems.

PMID- 10636837
TI  - Exploiting wild population diversity and somaclonal variation in the salt marsh
      grass Distichlis spicata (Poaceae) for marsh creation and restoration.
AB  - The salt marsh grass Distichlis spicata was regenerated from tissue culture and
      propagated in a greenhouse. Selected regenerants, along with selections from six
      wild populations, were grown for two years in a common garden flood-irrigated
      thrice weekly with tidal creek water. Selected wild and regenerated plants were
      also planted in a created salt marsh. Significant differences among regenerant
      and wild population selections were found in several functionally important salt
      marsh plant characteristics, including potential detritus production, belowground
      organic matter production, canopy structure, and decomposition rate. A
      combination of characteristics not found in the wild populations was evident in a
      regenerated line that exhibited both a high detritus production potential and a
      high decomposition rate. The amount of variation that occurred among regenerants
      from one parental line via somaclonal variation was similar to that which
      occurred among the wild population selections. Results of this study suggest that
      tissue culture may provide a means of producing marsh grasses with specific
      characteristics for directing the functional development of newly created salt
      marshes.

PMID- 10636838
TI  - The hemostatic system as a regulator of angiogenesis.

PMID- 10636839
TI  - The role of presenilin-1 in the gamma-secretase cleavage of the amyloid precursor
      protein of Alzheimer's disease.
AB  - Presenilin-1 (PS1) is required for the release of the intracellular domain of
      Notch from the plasma membrane as well as for the cleavage of the amyloid
      precursor protein (APP) at the gamma-secretase cleavage site. It remains to be
      demonstrated whether PS1 acts by facilitating the activity of the protease
      concerned or is the protease itself. PS1 could have a gamma-secretase activity by
      itself or could traffic APP and Notch to the appropriate cellular compartment for
      processing. Human APP 695 and PS1 were coexpressed in Sf9 insect cells, in which
      endogenous gamma-secretase activity is not detected. In baculovirus-infected Sf9
      cells, PS1 undergoes endoproteolysis and interacts with APP. However, PS1 does
      not cleave APP in Sf9 cells. In CHO cells, endocytosis of APP is required for
      Abeta secretion. Deletion of the cytoplasmic sequence of APP (APPDeltaC) inhibits
      both APP endocytosis and Abeta production. When APPDeltaC and PS1 are coexpressed
      in CHO cells, Abeta is secreted without endocytosis of APP. Taken together, these
      results conclusively show that, although PS1 does not cleave APP in Sf9 cells,
      PS1 allows the secretion of Abeta without endocytosis of APP by CHO cells.

PMID- 10636840
TI  - Chloroplast Oxa1p homolog albino3 is required for post-translational integration
      of the light harvesting chlorophyll-binding protein into thylakoid membranes.
AB  - Multiple sorting pathways operate in chloroplasts to localize proteins to the
      thylakoid membrane. The signal recognition particle (SRP) pathway in chloroplasts
      employs the function of a signal recognition particle (cpSRP) to target light
      harvesting chlorophyll-binding protein (LHCP) to the thylakoid membrane. In
      assays that reconstitute stroma-dependent LHCP integration in vitro, the stroma
      is replaceable by the addition of GTP, cpSRP, and an SRP receptor homolog,
      cpFtsY. Still lacking is an understanding of events that take place at the
      thylakoid membrane including the identification of membrane proteins that may
      function at the level of cpFtsY binding or LHCP integration. The identification
      of Oxa1p in mitochondria, an inner membrane translocase component homologous to
      predicted proteins in bacteria and to the albino3 (ALB3) protein in thylakoids,
      led us to investigate the potential role of ALB3 in LHCP integration. Antibody
      raised against a 50-amino acid region of ALB3 (ALB3-50aa) identified a single 45
      kDa thylakoid protein. Treatment of thylakoids with antibody to ALB3-50aa
      inhibited LHCP integration, whereas the same antibody treatment performed in the
      presence of antigen reversed the inhibition. In contrast, transport by the
      thylakoid Sec or Delta pH pathways was unaffected. These data support a model
      whereby a distinct translocase containing ALB3 is used to integrate LHCP into
      thylakoid membranes.

PMID- 10636841
TI  - Cloning and characterization of Drosophila topoisomerase IIIbeta. Relaxation of
      hypernegatively supercoiled DNA.
AB  - We cloned cDNA encoding Drosophila DNA topoisomerase III. The top3 cDNA encodes
      an 875-amino acid protein, which is nearly 60% identical to mammalian
      topoisomerase IIIbeta enzymes. Similarity between the Drosophila protein and the
      topoisomerase IIIbetas is particularly striking in the carboxyl-terminal region,
      where all contain eight highly conserved CXXC motifs not found in other
      topoisomerase III enzymes. We therefore propose the Drosophila protein is a
      member of the beta-subfamily of topoisomerase III enzymes. The top3beta gene is a
      single-copy gene located at 5 E-F on the X chromosome. P-element insertion into
      the 5'-untranslated region of this gene affects topoisomerase IIIbeta protein
      levels, but not the overall fertility and viability of the fly. We purified
      topoisomerase IIIbeta to near homogeneity and observed relaxation activity only
      with a hypernegatively supercoiled substrate, but not with plasmid DNA directly
      isolated from bacterial cells. Despite this difference in substrate preference,
      the degree of relaxation of the hypernegatively supercoiled substrate is
      comparable to relaxation of plasmid DNA by other type I enzymes. Drosophila
      topoisomerase IIIbeta forms a covalent linkage to 5' DNA phosphoryl groups, and
      the DNA cleavage reaction prefers single-stranded substrate over double-stranded,
      suggesting an affinity of this enzyme for DNA with non-double-helical structure.

PMID- 10636842
TI  - Activation of DNA-dependent protein kinase by single-stranded DNA ends.
AB  - DNA-dependent protein kinase (DNA-PK) is involved in joining DNA double-strand
      breaks induced by ionizing radiation or V(D)J recombination. The kinase is
      activated by DNA ends and composed of a DNA binding subunit, Ku, and a catalytic
      subunit, DNA-PK(CS). To define the DNA structure required for kinase activation,
      we synthesized a series of DNA molecules and tested their interactions with
      purified DNA-PK(CS). The addition of unpaired single strands to blunt DNA ends
      increased binding and activation of the kinase. When single-stranded loops were
      added to the DNA ends, binding was preserved, but kinase activation was severely
      reduced. Obstruction of DNA ends by streptavidin reduced both binding and
      activation of the kinase. Significantly, short single-stranded oligonucleotides
      of 3-10 bases were capable of activating DNA-PK(CS). Taken together, these data
      indicate that kinase activation involves a specific interaction with free single
      stranded DNA ends. The structure of DNA-PK(CS) contains an open channel large
      enough for double-stranded DNA and an adjacent enclosed cavity with the
      dimensions of single-stranded DNA. The data presented here support a model in
      which duplex DNA binds to the open channel, and a single-stranded DNA end is
      inserted into the enclosed cavity to activate the kinase.

PMID- 10636843
TI  - Nitric oxide-forming reaction between the iron-N-methyl-D-glucamine
      dithiocarbamate complex and nitrite.
AB  - The objective of this study was to elucidate the origin of the nitric oxide
      forming reactions from nitrite in the presence of the iron-N-methyl-D-glucamine
      dithiocarbamate complex ((MGD)(2)Fe(2+)). The (MGD)(2)Fe(2+) complex is commonly
      used in electron paramagnetic resonance (EPR) spectroscopic detection of NO both
      in vivo and in vitro. Although it is widely believed that only NO can react with
      (MGD)(2)Fe(2+) complex to form the (MGD)(2)Fe(2+).NO complex, a recent article
      reported that the (MGD)(2)Fe(2+) complex can react not only with NO, but also
      with nitrite to produce the characteristic triplet EPR signal of
      (MGD)(2)Fe(2+).NO (Hiramoto, K., Tomiyama, S., and Kikugawa, K. (1997) Free
      Radical Res. 27, 505-509). However, no detailed reaction mechanisms were given.
      Alternatively, nitrite is considered to be a spontaneous NO donor, especially at
      acidic pH values (Samouilov, A., Kuppusamy, P., and Zweier, J. L. (1998) Arch
      Biochem. Biophys. 357, 1-7). However, its production of nitric oxide at
      physiological pH is unclear. In this report, we demonstrate that the
      (MGD)(2)Fe(2+) complex and nitrite reacted to form NO as follows: 1)
      (MGD)(2)Fe(2).NO complex was produced at pH 7.4; 2) concomitantly, the
      (MGD)(3)Fe(3+) complex, which is the oxidized form of (MGD)(2)Fe(2+), was formed;
      3) the rate of formation of the (MGD)(2)Fe(2+).NO complex was a function of the
      concentration of [Fe(2+)](2), [MGD], [H(+)] and [nitrite].

PMID- 10636844
TI  - The second messenger binding site of inositol 1,4,5-trisphosphate 3-kinase is
      centered in the catalytic domain and related to the inositol trisphosphate
      receptor site.
AB  - A segment of inositol 1,4,5-trisphosphate 3-kinase responsible for inositol 1,4,5
      trisphosphate (InsP(3)) binding was characterized and confirmed by three
      different approaches employing the fully active expressed catalytic domain of the
      enzyme. Part of this moiety was protected from limited tryptic proteolysis by
      InsP(3). Sequencing of two fragments of 16 and 21 kDa, generated in the absence
      or presence of InsP(3), respectively, identified segment Glu-271 to Arg-305 as
      being protected. 15 monoclonal antibodies, all binding to epitopes within this
      region, inhibited enzyme activity and interfered with inositol phosphate binding.
      Detailed enzyme kinetic parameters of 32 site-directed mutants revealed residues
      Arg-276 and Lys-303 in this segment and Arg-322, located nearby, as directly
      involved in and five other closely neighbored residues, all located within a
      segment of 73 amino acids, as also influencing InsP(3) binding. Part of this
      region is similar in sequence to an InsP(3) binding segment in InsP(3) receptors.
      Combined with the finding that mutants influencing only ATP binding all lie
      outside this region, these data indicate that an InsP(3) binding core domain is
      inserted between two segments acting together in ATP binding and phosphate
      transfer.

PMID- 10636845
TI  - Degradation of heterotrimeric Galpha(o) subunits via the proteosome pathway is
      induced by the hsp90-specific compound geldanamycin.
AB  - One mechanism utilized by cells to maintain signaling pathways is to regulate the
      levels of specific signal transduction proteins. The compound geldanamycin (GA)
      specifically interacts with heat shock protein 90 (hsp90) complexes and has been
      widely utilized to study the role of hsp90 in modulating the function of
      signaling proteins. In this study, we used GA to demonstrate that levels of
      heterotrimeric Galpha subunits can be regulated through interactions with hsp90.
      In a dose-dependent manner, GA significantly reduced the steady state levels of
      endogenous Galpha(o) expression in two cell lines (PC12 and GH3) and had a
      similar effect on Galpha(o) transiently expressed in COS cells. Galpha(o)
      synthesis and degradation was studied in PC12 cells and in transiently
      transfected COS cells. (35)S labeling followed by immunoprecipitation
      demonstrated no effect of GA on the rate of Galpha(o) synthesis, but GA
      accelerated degradation of Galpha(o) in both PC12 cells and COS cells. The use of
      inhibitors, including lactacystin (a proteosome-specific inhibitor), suggests
      that Galpha(o) is predominantly degraded through the proteosome pathway. In vitro
      translated (35)S-labeled Galpha(o) could be detected in hsp90 immunoprecipitates,
      and this interaction did not require N-terminal myristoylation. Taken together,
      these results suggest that heterotrimeric Galpha(o) subunits are protected from
      degradation by interaction with hsp90 and that the interaction of Galpha subunits
      with heat shock proteins may be a general mechanism for regulating Galpha levels
      in the cell.

PMID- 10636846
TI  - Thermodynamic modulation of light chain amyloid fibril formation.
AB  - To obtain further insight into the pathogenesis of amyloidosis and develop
      therapeutic strategies to inhibit fibril formation we investigated: 1) the
      relationship between intrinsic physical properties (thermodynamic stability and
      hydrogen-deuterium (H-D) exchange rates) and the propensity of human
      immunoglobulin light chains to form amyloid fibrils in vitro; and 2) the effects
      of extrinsically modulating these properties on fibril formation. An amyloid
      associated protein readily formed amyloid fibrils in vitro and had a lower free
      energy of unfolding than a homologous nonpathological protein, which did not form
      fibrils in vitro. H-D exchange was much faster for the pathological protein,
      suggesting it had a greater fraction of partially folded molecules. The
      thermodynamic stabilizer sucrose completely inhibited fibril formation by the
      pathological protein and shifted the values for its physical parameters to those
      measured for the nonpathological protein in buffer alone. Conversely, urea
      sufficiently destabilized the nonpathological protein such that its measured
      physical properties were equivalent to those of the pathological protein in
      buffer, and it formed fibrils. Thus, fibril formation by light chains is
      predominantly controlled by thermodynamic stability; and a rational strategy to
      inhibit amyloidosis is to design high affinity ligands that specifically increase
      the stability of the native protein.

PMID- 10636847
TI  - Endocytosis and degradation of the growth hormone receptor are proteasome
      dependent.
AB  - The ubiquitin conjugation system is involved in ligand-induced endocytosis of the
      growth hormone receptor (GHR) via a cytosolic 10-amino acid ubiquitin-dependent
      endocytosis motif. Herein, we demonstrate that the proteasome is also involved in
      growth hormone receptor down-regulation. Ligand-induced degradation was blocked
      in the presence of specific proteasomal inhibitors. In addition, growth hormone
      (GH) internalization was inhibited, whereas the transferrin receptor cycle
      remained unaffected. A truncated GHR entered the cells independent of proteasome
      action. In addition, we show that GH internalization is independent of the
      presence of lysine residues in the cytosolic domain of the receptor, whereas its
      internalization can still be inhibited by proteasomal inhibitors. Thus, GHR
      internalization requires proteasome action in addition to an active ubiquitin
      conjugation system, but ubiquitination of the GHR itself seems not to be
      required.

PMID- 10636848
TI  - Tapasin is required for efficient peptide binding to transporter associated with
      antigen processing.
AB  - The transporter associated with antigen processing (TAP) binds peptides in its
      cytosolic part and subsequently translocates the peptides into the lumen of the
      endoplasmic reticulum (ER), where assembly of major histocompatibility complex
      (MHC) class I and peptide takes place. Tapasin is a subunit of the TAP complex
      and binds both to TAP1 and MHC class I. In the absence of tapasin, the assembly
      of MHC class I in the ER is impaired, and the surface expression is reduced. To
      clarify the function of tapasin in the processing of antigenic peptides, we
      studied the interaction of peptide and TAP, peptide transport across the membrane
      of the ER, and association of peptides with MHC class I molecules in the
      microsomes derived from tapasin mutant cell line 721.220, its sister cell line
      721.221 expressing tapasin, and their HLA-A2 transfectants. The binding of
      peptides to TAP in tapasin mutant 721.220 cells was significantly diminished in
      comparison with 721.221 cells. Impaired peptide-TAP interaction resulted in a
      defective peptide transport in tapasin mutant 721.220 cells. Interestingly,
      despite the diminished peptide binding to TAP, the transport rate of TAP
      associated peptides was not significantly altered in 721.220 cells. After
      transfection of tapasin cDNA into 721.220 cells, efficient peptide-TAP
      interaction was restored. Thus, we conclude that tapasin is required for
      efficient peptide-TAP interaction.

PMID- 10636849
TI  - The oscillatory behavior of pancreatic islets from mice with mitochondrial
      glycerol-3-phosphate dehydrogenase knockout.
AB  - Glucose stimulation of pancreatic beta cells induces oscillations of the membrane
      potential, cytosolic Ca(2+) ([Ca(2+)](i)), and insulin secretion. Each of these
      events depends on glucose metabolism. Both intrinsic oscillations of metabolism
      and repetitive activation of mitochondrial dehydrogenases by Ca(2+) have been
      suggested to be decisive for this oscillatory behavior. Among these
      dehydrogenases, mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH), the key
      enzyme of the glycerol phosphate NADH shuttle, is activated by cytosolic
      [Ca(2+)](i). In the present study, we compared different types of oscillations in
      beta cells from wild-type and mGPDH(-/-) mice. In clusters of 5-30 islet cells
      and in intact islets, 15 mM glucose induced an initial drop of [Ca(2+)](i),
      followed by an increase in three phases: a marked initial rise, a partial
      decrease with rapid oscillations and eventually large and slow oscillations.
      These changes, in particular the frequency of the oscillations and the magnitude
      of the [Ca(2+)] rise, were similar in wild-type and mGPDH(-/-) mice. Glucose
      induced electrical activity (oscillations of the membrane potential with bursts
      of action potentials) was not altered in mGPDH(-/-) beta cells. In single islets
      from either type of mouse, insulin secretion strictly followed the changes in
      [Ca(2+)](i) during imposed oscillations induced by pulses of high K(+) or glucose
      and during the biphasic elevation induced by sustained stimulation with glucose.
      An imposed and controlled rise of [Ca(2+)](i) in beta cells similarly increased
      NAD(P)H fluorescence in control and mGDPH(-/-) islets. Inhibition of the malate
      aspartate NADH shuttle with aminooxyacetate only had minor effects in control
      islets but abolished the electrical, [Ca(2+)](i) and secretory responses in
      mGPDH(-/-) islets. The results show that the two distinct NADH shuttles play an
      important but at least partially redundant role in glucose-induced insulin
      secretion. The oscillatory behavior of beta cells does not depend on the
      functioning of mGPDH and on metabolic oscillations that would be generated by
      cyclic activation of this enzyme by Ca(2+).

PMID- 10636850
TI  - Refolded outer membrane protein A of Escherichia coli forms ion channels with two
      conductance states in planar lipid bilayers.
AB  - Outer membrane protein A (OmpA), a major structural protein of the outer membrane
      of Escherichia coli, consists of an N-terminal 8-stranded beta-barrel
      transmembrane domain and a C-terminal periplasmic domain. OmpA has served as an
      excellent model for studying the mechanism of insertion, folding, and assembly of
      constitutive integral membrane proteins in vivo and in vitro. The function of
      OmpA is currently not well understood. Particularly, the question whether or not
      OmpA forms an ion channel and/or nonspecific pore for uncharged larger solutes,
      as some other porins do, has been controversial. We have incorporated detergent
      purified OmpA into planar lipid bilayers and studied its permeability to ions by
      single channel conductance measurements. In 1 M KCl, OmpA formed small (50-80 pS)
      and large (260-320 pS) channels. These two conductance states were
      interconvertible, presumably corresponding to two different conformations of OmpA
      in the membrane. The smaller channels are associated with the N-terminal
      transmembrane domain, whereas both domains are required to form the larger
      channels. The two channel activities provide a new functional assay for the
      refolding in vitro of the two respective domains of OmpA. Wild-type and five
      single tryptophan mutants of urea-denatured OmpA are shown to refold into
      functional channels in lipid bilayers.

PMID- 10636851
TI  - Regulation of human involucrin promoter activity by novel protein kinase C
      isoforms.
AB  - Human involucrin (hINV) mRNA level and promoter activity increase when
      keratinocytes are treated with the differentiating agent, 12-O
      tetradecanoylphorbol-13-acetate (TPA). This response is mediated via a p38
      mitogen-activated protein kinase-dependent pathway that targets activator protein
      1 (Efimova, T., LaCelle, P. T. , Welter, J. F., and Eckert, R. L. (1998) J. Biol.
      Chem. 273, 24387-24395). In the present study we examine the role of various PKC
      isoforms in this regulation. Transfection of expression plasmids encoding the
      novel PKC isoforms delta, epsilon, and eta increase hINV promoter activity. In
      contrast, neither conventional PKC isoforms (alpha, beta, and gamma) nor the
      atypical isoform (zeta) regulate promoter activity. Consistent with these
      observations, promoter activity is inhibited by the PKCdelta-selective inhibitor,
      rottlerin, but not by Go-6976, an inhibitor of conventional PKC isoforms, and
      novel PKC isoform-dependent promoter activation is inhibited by dominant-negative
      PKCdelta. This regulation appears to be physiologically important, as
      transfection of keratinocytes with PKCdelta, -epsilon, or -eta increases
      expression of the endogenous hINV gene. Synergistic promoter activation (>/=100
      fold) is observed when PKCepsilon- or -eta-transfected cells are treated with
      TPA. In contrast, the PKCdelta-dependent response is more complex as either
      activation or inhibition is observed, depending upon PKCdelta concentration.

PMID- 10636852
TI  - Transport-dependent accessibility of a cytoplasmic loop cysteine in the human
      dopamine transporter.
AB  - The effect of covalent sulfhydryl modification on dopamine uptake by the human
      dopamine transporter was determined by rotating disc electrode voltammetry. A
      transporter construct, X5C, with five mutated cysteines (C90A, C135A, C306A,
      C319F, and C342A) and the constructs into which the wild-type cysteines were
      substituted back into X5C, one at a time, all showed nearly normal binding
      affinity for [(3)H]CFT and for cocaine, but they displayed significant reductions
      in K(m) and V(max) for DA uptake. Reaction of Cys-90 or Cys-306 with impermeant
      methanethiosulfonate derivatives enhanced dopamine uptake to a similar extent as
      the previously observed enhancement of [(3)H]CFT binding caused by the same
      reaction, suggesting that cocaine may bind preferentially to a conformation in
      the transport cycle. m-Tyramine increased the rate of reaction of (2
      aminoethyl)methanethiosulfonate (MTSEA) with X-A342C, the construct with a
      cytoplasmic loop residue Cys-342 restored. This m-tyramine-induced increase in
      reactivity appeared to require the inward transport rather than the outward
      transport or external binding of m-tyramine, and it was prevented by cocaine.
      Thus, inward translocation of substrates may involve structural rearrangement of
      hDAT, which likely exposes Cys-342 to reaction with MTSEA, and Cys-342 may be
      located on a part of the transporter associated with cytoplasmic gating.

PMID- 10636853
TI  - Identification of the Xenopus laevis homolog of Saccharomyces cerevisiae DNA2 and
      its role in DNA replication.
AB  - The DNA2 gene of Saccharomyces cerevisiae is essential for growth and appears to
      be required for a late stage of chromosomal DNA replication. S. cerevisiae Dna2p
      (ScDna2p) is a DNA helicase and also a nuclease. We have cloned and sequenced the
      homologous gene from Xenopus (Xenopus Dna2). Xenopus Dna2p (XDna2p) is 32%
      identical to ScDna2p, and the similarity extends over the entire length,
      including but not limited to the five conserved helicase motifs. XDna2p is even
      more closely related (60% identical) to a partial human cDNA. The Xenopus Dna2
      (XDna2) gene was able to complement an S. cerevisiae dna2-1 mutant strain for
      growth at the nonpermissive temperature, suggesting that XDna2p is a functional
      as well as a structural homolog of the yeast protein. Recombinant XDna2p was
      expressed in insect cells and purified. Like the ScDna2p purified from yeast, it
      is a single-stranded DNA endonuclease and a DNA-dependent ATPase, suggesting that
      both of these activities are part of the essential function of Dna2p. However,
      unlike ScDna2p from yeast, recombinant XDna2p showed no DNA helicase activity.
      When XDna2 was immunodepleted from interphase egg extracts, chromosomal DNA
      replication was almost completely inhibited. From the size of the residually
      synthesized DNA from the XDna2-depleted egg extracts, it seems that initiation of
      DNA replication may be impaired. This interpretation is also supported by the
      normal DNA replication of M13 single-stranded DNA in the XDna2-depleted egg
      extracts.

PMID- 10636854
TI  - Size-dependent DNA mobility in cytoplasm and nucleus.
AB  - The diffusion of DNA in cytoplasm is thought to be an important determinant of
      the efficacy of gene delivery and antisense therapy. We have measured the
      translational diffusion of fluorescein-labeled double-stranded DNA fragments (in
      base pairs (bp): 21, 100, 250, 500, 1000, 2000, 3000, 6000) after microinjection
      into cytoplasm and nucleus of HeLa cells. Diffusion was measured by spot
      photobleaching using a focused argon laser spot (488 nm). In aqueous solutions,
      diffusion coefficients of the DNA fragments in water (D(w)) decreased from 53 x
      10(-8) to 0.81 x 10(-8) cm(2)/s for sizes of 21-6000 bp; D(w) was related
      empirically to DNA size: D(w) = 4.9 x 10(-6) cm(2)/s.[bp size](-0.72). DNA
      diffusion coefficients in cytoplasm (D(cyto)) were lower than D(w) and depended
      strongly on DNA size. D(cyto)/D(w) decreased from 0.19 for a 100-bp DNA fragment
      to 0.06 for a 250-bp DNA fragment and was <0.01 for >2000 bp. Diffusion of
      microinjected fluorescein isothiocyanate (FITC) dextrans was faster than that of
      comparably sized DNA fragments of 250 bp and greater. In nucleus, all DNA
      fragments were nearly immobile, whereas FITC dextrans of molecular size up to 580
      kDa were fully mobile. These results suggest that the highly restricted diffusion
      of DNA fragments in nucleoplasm results from extensive binding to immobile
      obstacles and that the decreased lateral mobility of DNAs >250 bp in cytoplasm is
      because of molecular crowding. The diffusion of DNA in cytoplasm may thus be an
      important rate-limiting barrier in gene delivery utilizing non-viral vectors.

PMID- 10636855
TI  - Isolation and characterization of proteins that bind to galactose,
      lipopolysaccharide of Escherichia coli, and protein A of Staphylococcus aureus
      from the hemolymph of Tachypleus tridentatus.
AB  - In this study, we report the isolation and characterization of three novel
      hemolymph proteins that are believed to be involved in the innate immune response
      of horseshoe crabs, Tachypleus tridentatus. They include two closely related
      proteins, one that binds to the protein A of Staphylococcus aureus (PAP) and
      another that binds to the lipopolysaccharide of Escherichia coli (LBP). PAP binds
      specifically to staphylococcal protein A (SpA) with a K(D) of 3.86 x 10(-5) M,
      whereas LBP binds to lipopolysaccharide (LPS) with a K(D) of 1.03 x 10(-6) M.
      Both PAP and LBP are glycoproteins with an apparent molecular mass of about 40
      kDa. N-terminal sequences of PAP and LBP showed 61.9 and 72.2% identity,
      respectively, to tachylectin-3, a lectin isolated from the amebocyte of T.
      tridentatus, previously characterized by its affinity to the O-antigen of LPS and
      blood group A antigen (Muta, T., and Iwanaga, S. (1996) Curr. Opin. Immunol. 8,
      41-47). The third protein, a galactose-binding protein (GBP), was found to bind
      tightly to Sepharose CL-4B and could only be eluted from the column matrix with
      chaotropic agents, such as 4 M urea or 2 M guanidine hydrochloride. Further
      analysis indicated that GBP binds to D(+)-galactose with a K(D) of 2.47 x 10(-7)
      M. N-terminal sequence analysis showed that GBP shared a 50% identity with lectin
      L-6, identified in the granules of amebocyte of T. tridentatus. (Gokudan, S.,
      Muta, T., Tsuda, R., Koori, K., Kawahara, T., Seki, N., Mizunoe, Y., Wai, S. N. ,
      Iwanaga, S., and Kawabata, S. (1999) Proc. Natl. Acad. Sci. U. S. A. 96, 10086
      10091). Lectin-L6 and tachylectin-3 are nonglycosylated intracellular proteins
      with about half the molecular mass of PAP, LBP, and GBP. GBP also binds to PAP
      and LBP with K(D) values of 1.25 x 10(-7) and 1.43 x 10(-8) M, respectively, and
      this binding is enhanced about 10-fold upon the addition of SpA and LPS to form
      the GBP.PAP.SpA and GBP.LBP.LPS complexes, respectively.

PMID- 10636856
TI  - Macrophages can decrease the level of cholesteryl ester hydroperoxides in low
      density lipoprotein.
AB  - Murine and human macrophages rapidly decreased the level of cholesteryl ester
      hydroperoxides in low density lipoprotein (LDL) when cultured in media non
      permissive for LDL oxidation. This process was proportional to cell number but
      could not be attributed to the net lipoprotein uptake. Macrophage-mediated loss
      of lipid hydroperoxides in LDL appears to be metal ion-independent. Degradation
      of cholesteryl linoleate hydroperoxides was accompanied by accumulation of the
      corresponding hydroxide as the major product and cholesteryl keto
      octadecadienoate as a minor product, although taken together these products could
      not completely account for the hydroperoxide consumption. Cell-conditioned medium
      possessed a similar capacity to remove lipid hydroperoxides as seen with cellular
      monolayers, suggesting that the activity is not an integral component of the cell
      but is secreted from it. The activity of cell-conditioned medium to lower the
      level of LDL lipid hydroperoxides is associated with its high molecular weight
      fraction and is modulated by the availability of free thiol groups. Cell-mediated
      loss of LDL cholesteryl ester hydroperoxides is facilitated by the presence of
      alpha-tocopherol in the lipoprotein. Together with our earlier reports on the
      ability of macrophages to remove peroxides rapidly from oxidized amino acids,
      peptides, and proteins as well as to clear selectively cholesterol 7-beta
      hydroperoxide, results presented in this paper provide evidence of a potential
      protective activity of the cell against further LDL oxidation by removing
      reactive peroxide groups in the lipoprotein.

PMID- 10636857
TI  - The histone-interacting domain of nuclear factor I activates simian virus 40 DNA
      replication in vivo.
AB  - Efficient initiation of SV40 DNA replication requires transcription factors that
      bind auxiliary sequences flanking the minimally required origin. To evaluate the
      possibility that transcription factors may activate SV40 replication by acting on
      the chromatin structure of the origin, we used an in vivo replication system in
      which we targeted GAL4 fusion proteins to the minimally required origin. We found
      that the proline-rich transcriptional activation domain of nuclear factor I (NF
      I), which has been previously shown to interact with histone H3, specifically
      activates replication. Evaluation of a series of deletion and point mutants of NF
      I indicates that the H3-binding domain and the replication activity coincide
      perfectly. Assays with other transcription factors, such as Sp1, confirmed the
      correlation between the interaction with H3 and the activation of replication.
      These findings imply that transcription factors such as NF-I can activate SV40
      replication via direct interaction with chromatin components, thereby
      contributing to the relief of nucleosomal repression at the SV40 origin.

PMID- 10636858
TI  - Overexpression of the ferritin iron-responsive element decreases the labile iron
      pool and abolishes the regulation of iron absorption by intestinal epithelial
      (Caco-2) cells.
AB  - Mammalian cells regulate iron levels tightly through the activity of iron
      regulatory proteins (IRPs) that bind to RNA motifs called iron-responsive
      elements (IREs). When cells become iron-depleted, IRPs bind to IREs present in
      the mRNAs of ferritin and the transferrin receptor, resulting in diminished
      translation of the ferritin mRNA and increased translation of the transferrin
      receptor mRNA. Likewise, intestinal epithelial cells regulate iron absorption by
      a process that also depends on the intracellular levels of iron. Although
      intestinal epithelial cells have an active IRE/IRP system, it has not been proven
      that this system is involved in the regulation of iron absorption in these cells.
      In this study, we characterized the effect of overexpression of the ferritin IRE
      on iron absorption by Caco-2 cells, a model of intestinal epithelial cells. Cells
      overexpressing ferritin IRE had increased levels of ferritin, whereas the levels
      of the transferrin receptor were decreased. Iron absorption in IRE-transfected
      cells was deregulated: iron uptake from the apical medium was increased, but the
      capacity to retain this newly incorporated iron diminished. Cells overexpressing
      IRE were not able to control iron absorption as a function of intracellular iron,
      because both iron-deficient cells as well as iron-loaded cells absorbed similarly
      high levels of iron. The labile iron pool of IRE-transfected cell was extremely
      low. Likewise, the reduction of the labile iron pool in control cells resulted in
      cells having increased iron absorption. These results indicate that cells
      overexpressing IRE do not regulate iron absorption, an effect associated with
      decreased levels of the regulatory iron pool.

PMID- 10636859
TI  - Human complement 5a (C5a) anaphylatoxin receptor (CD88) phosphorylation sites and
      their specific role in receptor phosphorylation and attenuation of G protein
      mediated responses. Desensitization of C5a receptor controls superoxide
      production but not receptor sequestration in HL-60 cells.
AB  - Upon agonist binding, the anaphylatoxin human complement 5a receptor (C5aR) has
      previously been found to be phosphorylated on the six serine residues of its
      carboxyl-terminal tail (Giannini, E., Brouchon, L., and Boulay, F. (1995) J.
      Biol. Chem. 270, 19166-19172). To evaluate the precise roles that specific
      phosphorylation sites may play in receptor signaling, a series of mutants were
      expressed transiently in COS-7 cells and stably in the physiologically relevant
      myeloid HL-60 cells. Ser(334) was found to be a key residue that controls
      receptor phosphorylation. Phosphorylation of either of two serine pairs, namely
      Ser(332) and Ser(334) or Ser(334) and Ser(338), was critical for the
      phosphorylation of C5aR and its subsequent desensitization. Full phosphorylation
      and desensitization of C5aR were obtained when these serines were replaced by
      aspartic acid residues. The mutation S338A had no marked effect on the agonist
      mediated phosphorylation of C5aR, but it allowed a sustained C5a-evoked calcium
      mobilization in HL-60 cells. These findings and the ability of the
      S314A/S317A/S327A/S332A mutant receptor to undergo desensitization indicate that
      the phosphorylation of Ser(334) and Ser(338) is critical and sufficient for C5aR
      desensitization. The lack of phosphorylation was found to result not only in a
      sustained calcium mobilization and extracellular signal-regulated kinase 2
      activity but also in the enhancement of the C5a-mediated respiratory burst in
      neutrophil-like HL-60 cells. For instance, the nonphosphorylatable S332A/S334A
      mutant receptor triggered a 1.8-2-fold higher production of superoxide as
      compared with the wild-type receptor. Interestingly, although the desensitization
      of this mutant was defective, it was sequestered with the same time course and
      the same efficiency as the wild-type receptor. Thus, in myeloid HL-60 cells,
      desensitization and sequestration of C5aR appear to occur through divergent
      molecular mechanisms.

PMID- 10636860
TI  - The spectral and thermodynamic properties of staphylococcal enterotoxin A, E, and
      variants suggest that structural modifications are important to control their
      function.
AB  - The superantigens staphylococcal enterotoxin A and E (SEA and SEE) can activate a
      large number of T-cells. SEA and SEE have approximately 80% sequence identity but
      show some differences in their biological function. Here, the two superantigens
      and analogues were characterized biophysically. SEE was shown to have a
      substantially higher thermal stability than SEA. Both SEA and SEE were thermally
      stabilized by 0.1 mM Zn(2+) compared with Zn(2+)-reduced conditions achieved
      using 1 mM EDTA or specific replacements that affect Zn(2+) coordination. The
      higher stability of SEE was only partly caused by the T-cell receptor (TCR)
      binding regions, whereas regions in the vicinity of the major histocompatibility
      complex class II binding sites affected the stability to a greater extent. SEE
      exhibited a biphasic denaturation between pH 5.0-6.5, influenced by residues in
      the TCR binding regions. Interestingly, enzyme-linked immunosorbent assay,
      isoelectric focusing, and circular dichroism analysis indicated that
      conformational changes had occurred in the SEA/E chimerical constructs relative
      to SEA and SEE. Thus, it is proposed that the Zn(2+) binding site is very
      important for the stability and potency of SEA and SEE, whereas residues in the
      TCR binding site have a substantial influence on the molecular conformation to
      control specificity and function.

PMID- 10636861
TI  - Controlling polymerization of beta-amyloid and prion-derived peptides with
      synthetic small molecule ligands.
AB  - The Alzheimer beta-amyloid peptide (Abeta) and a fragment of the prion protein
      have the capacity of forming amyloid-like fibrils when incubated under
      physiological conditions in vitro. Here we show that a small amyloid ligand, RO
      47-1816/001, enhances this process severalfold by binding to amyloid molecules
      and apparently promote formation of the peptide-to-peptide bonds that join the
      monomers of the amyloid fibrils. This effect could be antagonized by other
      ligands, including analogues of RO-47-1816/001, as well as the structurally
      unrelated ligand Congo red. Analogues of RO-47-1816/001 with low affinity for
      amyloid did not display any antagonistic effect. In conclusion, these data
      suggest that synthetic molecules, and possibly also small natural substances
      present in the brain, may act in a chaperone-like fashion, promoting Abeta
      polymerization and growth of amyloid fibrils in vitro and possibly also in vivo.
      Furthermore, we demonstrate that small organic molecules can be used to inhibit
      the action of amyloid-enhancing compounds.

PMID- 10636862
TI  - A cooperative oxygen binding hemoglobin from Mycobacterium tuberculosis.
      Stabilization of heme ligands by a distal tyrosine residue.
AB  - The homodimeric hemoglobin (HbN) from Mycobacterium tuberculosis displays an
      extremely high oxygen binding affinity and cooperativity. Sequence alignment with
      other hemoglobins suggests that the proximal F8 ligand is histidine, the distal
      E7 residue is leucine, and the B10 position is occupied by tyrosine. To determine
      how these heme pocket residues regulate the ligand binding affinities and
      physiological functions of HbN, we have measured the resonance Raman spectra of
      the O(2), CO, and OH(-) derivatives of the wild type protein and the B10 Tyr -->
      Leu and Phe mutants. Taken together these data demonstrate a unique distal
      environment in which the heme bound ligands strongly interact with the B10
      tyrosine residue. The implications of these data on the physiological functions
      of HbN and another heme-containing protein, cytochrome c oxidase, are considered.

PMID- 10636863
TI  - Direct interaction of the CD38 cytoplasmic tail and the Lck SH2 domain. Cd38
      transduces T cell activation signals through associated Lck.
AB  - CD38 ligation has been shown to induce activation of intracellular signaling
      cascade in T lymphocytes through a Lck-dependent pathway. However, it is not
      clear how Lck initiates the CD38-mediated signaling process. In the present
      study, we showed that CD38 and Lck were physically associated through the
      cytoplasmic tail and the Src homology 2 domain, respectively. This was evidenced
      by coimmunoprecipitation of Lck with CD38 and Lck with isolated CD38 cytoplasmic
      domain from T cell lysate, cell lysate of COS-7 cells cotransfected with cDNAs of
      Lck and CD38, or a mixture of in vitro translated CD38 and Lck. Because the CD38
      cytoplasmic domain does not contain any tyrosine residue, the interaction should
      be independent of phosphotyrosine. The interaction was further confirmed by in
      vitro interaction between a purified Lck Src homology 2 domain and a
      nonphosphosynthetic peptide corresponding to the membrane proximal region of the
      CD38 cytoplasmic domain. In addition, CD38 ligation resulted in an elevated
      tyrosine kinase activity of the CD38-associated Lck and ultimate activation of
      interleukin-2 gene transcription. Furthermore, expression of a kinase-deficient
      Lck mutant suppressed interleukin-2 gene activation in a dose-dependent manner.
      These results strongly suggested that CD38 ligation indeed tranduced signals for
      T cell activation using its associated Lck.

PMID- 10636864
TI  - "ADP sulfurylase" from Thiobacillus denitrificans is an adenylylsulfate:phosphate
      adenylyltransferase and belongs to a new family of nucleotidyltransferases.
AB  - During AMP-dependent sulfite oxidation by some sulfur bacteria, the liberation of
      sulfate from adenosine-5'-phosphosulfate (APS) is catalyzed by APS:phosphate
      adenylyltransferase (APAT). Here we report the first biochemical and genetic
      characterization of APAT. We isolated this enzyme from the chemolithoautotroph
      Thiobacillus denitrificans and cloned the corresponding gene. The enzyme is
      homodimeric with 41,387-Da subunits and exhibits a specific activity of 2100
      micromol min(-1) mg(-1). The K(m) values are K(m(APS)) = 300 microM and
      K(m(P(i))) = 12 mM. Catalysis occurs by a ping-pong mechanism with a covalently
      bound AMP as reaction intermediate. The arsenolysis of APS, but not of ADP, CDP,
      GDP, UDP, or IDP, is also catalyzed, indicating a specific and unidirectional
      function. The former enzyme name ADP-sulfurylase implies that the reverse
      reaction is catalyzed; therefore, this name should not be used any longer.
      Histidine modification of APAT results in complete inactivation that can be
      suppressed by substrate addition. APAT is highly similar to galactose-1-phosphate
      uridylyltransferase and also related to Ap(4)A phosphorylase. Active site
      residues of galactose-1-phosphate uridylyltransferase are conserved in APAT and
      Ap(4)A phosphorylase, suggesting a histidine as the nucleotide-binding residue in
      all three enzymes, which together form a new family of nucleotidyltransferases.

PMID- 10636865
TI  - beta-lactam antibiotics as substrates for OCTN2, an organic cation/carnitine
      transporter.
AB  - Therapeutic use of cephaloridine, a beta-lactam antibiotic, in humans is
      associated with carnitine deficiency. A potential mechanism for the development
      of carnitine deficiency is competition between cephaloridine and carnitine for
      the renal reabsorptive process. OCTN2 is an organic cation/carnitine transporter
      that is responsible for Na(+)-coupled transport of carnitine in the kidney and
      other tissues. We investigated the interaction of several beta-lactam antibiotics
      with OCTN2 using human cell lines that express the transporter constitutively as
      well as using cloned human and rat OCTN2s expressed heterologously in human cell
      lines. The beta-lactam antibiotics cephaloridine, cefoselis, cefepime, and
      cefluprenam were found to inhibit OCTN2-mediated carnitine transport. These
      antibiotics possess a quaternary nitrogen as does carnitine. Several other beta
      lactam antibiotics that do not possess this structural feature did not interact
      with OCTN2. The interaction of cephaloridine with OCTN2 is competitive with
      respect to carnitine. Interestingly, many of the beta-lactam antibiotics that
      were not recognized by OCTN2 were good substrates for the H(+)-coupled peptide
      transporters PEPT1 and PEPT2. In contrast, cephaloridine, cefoselis, cefepime,
      and cefluprenam, which were recognized by OCTN2, did not interact with PEPT1 and
      PEPT2. The interaction of cephaloridine with OCTN2 was Na(+)-dependent, whereas
      the interaction of cefoselis and cefepime with OCTN2 was largely Na(+)
      independent. Furthermore, the Na(+)-dependent, OCTN2-mediated cellular uptake of
      cephaloridine could be demonstrated by direct uptake measurements. These studies
      show that OCTN2 plays a crucial role in the pharmacokinetics and therapeutic
      efficacy of certain beta-lactam antibiotics such as cephaloridine and that
      cephaloridine-induced carnitine deficiency is likely to be due to inhibition of
      carnitine reabsorption in the kidney.

PMID- 10636866
TI  - Sp1 binding is critical for promoter assembly and activation of the MCP-1 gene by
      tumor necrosis factor.
AB  - The monocyte chemoattractant protein-1 gene (MCP-1) is induced by the
      inflammatory cytokine tumor necrosis factor through the coordinate assembly of an
      NF-kappaB-dependent distal regulatory region and a proximal region that has been
      suggested to bind Sp1 as well as other factors. To provide a genetic correlation
      for Sp1 activity in this system, a cell line homozygous for a targeted truncation
      of the Sp1 gene was derived and examined. We found that the lack of Sp1 binding
      activity resulted in the inability of both the distal and proximal regions to
      assemble in vivo even though the binding of NF-kappaB to distal region DNA was
      unaffected in vitro. We also found that Sp1 and NF-kappaB were the minimal
      mammalian transcription factors required for efficient activity when transfected
      into Drosophila Schneider cells. Additionally, Sp3 was able to compensate for Sp1
      in the Drosophila tissue cell system but not in the Sp1(-/-) cell line suggesting
      that Sp1 usage is site-specific and is likely to depend on the context of the
      binding site. Together, these data provide genetic and biochemical proof for Sp1
      in regulating the MCP-1 gene.

PMID- 10636867
TI  - A novel DNA damage checkpoint involving post-transcriptional regulation of cyclin
      A expression.
AB  - The intracellular metabolism of many carcinogenic polycyclic aryl hydrocarbons
      (PAHs, typified by the ubiquitous pollutant benzo[a]pyrene or B[a]P) generates
      electrophilic products that react covalently with genomic DNA. Cells that acquire
      PAH-induced DNA damage undergo growth arrest in a p53-independent manner (Vaziri,
      C., and Faller, D. V. (1997) J. Biol. Chem. 272, 2762-2769). In this report we
      have investigated the molecular basis of PAH-induced cell cycle arrest. Mitogenic
      signaling events involving cyclins D and E, Rb phosphorylation, and
      transcriptional activation of E2F-responsive genes (including cyclin E and cyclin
      A) were unaffected in cells containing PAH-damaged DNA. However, PAH-induced
      growth arrest was associated with post-transcriptional decreases in cyclin A
      expression. Mitogen-induced expression of cyclin B, an event that is temporally
      distal to cyclin A expression, was also inhibited in PAH-treated cells. The PAH
      induced cell cycle block was transient, and arrested cells resumed DNA synthesis
      after a prolonged ( approximately 20 h) delay. Resumption of DNA synthesis in PAH
      treated cells occurred concomitant with elevated expression of cyclins A and B.
      PAH-induced cell cycle arrest was overcome by ectopically expressed cyclin A
      (encoded by a recombinant adenovirus in transiently infected cells). Overall, our
      results suggest the existence of a DNA damage checkpoint pathway that arrests
      cell cycle progression via post-transcriptional control of cyclin A expression.

PMID- 10636868
TI  - ABFs, a family of ABA-responsive element binding factors.
AB  - Abscisic acid (ABA) plays an important role in environmental stress responses of
      higher plants during vegetative growth. One of the ABA-mediated responses is the
      induced expression of a large number of genes, which is mediated by cis
      regulatory elements known as abscisic acid-responsive elements (ABREs). Although
      a number of ABRE binding transcription factors have been known, they are not
      specifically from vegetative tissues under induced conditions. Considering the
      tissue specificity of ABA signaling pathways, factors mediating ABA-dependent
      stress responses during vegetative growth phase may thus have been unidentified
      so far. Here, we report a family of ABRE binding factors isolated from young
      Arabidopsis plants under stress conditions. The factors, isolated by a yeast one
      hybrid system using a prototypical ABRE and named as ABFs (ABRE binding factors)
      belong to a distinct subfamily of bZIP proteins. Binding site selection assay
      performed with one ABF showed that its preferred binding site is the strong ABRE,
      CACGTGGC. ABFs can transactivate an ABRE-containing reporter gene in yeast.
      Expression of ABFs is induced by ABA and various stress treatments, whereas their
      induction patterns are different from one another. Thus, a new family of ABRE
      binding factors indeed exists that have the potential to activate a large number
      of ABA/stress-responsive genes in Arabidopsis.

PMID- 10636869
TI  - Ordered and cooperative binding of opposing globular domains of calmodulin to the
      plasma membrane Ca-ATPase.
AB  - We have investigated the mechanisms of activation of the plasma membrane (PM) Ca
      ATPase by calmodulin (CaM), which result in enhanced calcium transport rates and
      the maintenance of low intracellular calcium levels. We have isolated the amino-
      or carboxyl-terminal domains of CaM (i.e. CaMN or CaMC), permitting an
      identification of their relative specificity for binding to sites on either the
      PM Ca-ATPase or a peptide (C28W) corresponding to the CaM-binding sequence. We
      find that either CaMN or CaMC alone is capable of productive interactions with
      the PM Ca-ATPase that induces enzyme activation. There are, however, large
      differences in the affinity and specificity of binding between CaMN and CaMC and
      either C28W or the PM Ca-ATPase. The initial binding interaction between CaMC and
      the PM Ca-ATPase is highly specific, having approximately 10,000-fold greater
      affinity in comparison with CaMN. However, following the initial association of
      either CaMC or CaMN, there is a 300-fold enhancement in the affinity of CaMN for
      the secondary binding site. Thus, while CaMC binds with a high affinity to the
      two CaM-binding sites within the PM Ca-ATPase in a sequential manner, CaMN binds
      cooperatively with a lower affinity to both binding sites. These large
      differences in the binding affinities and specificities of the amino- and
      carboxyl-terminal domains ensure that CaM binding to the PM Ca-ATPase normally
      involves the formation of a specific complex in which the initial high affinity
      association of the carboxyl-terminal domain promotes the association of the amino
      terminal domain necessary for enzyme activation.

PMID- 10636870
TI  - Reactive oxygen species activate p90 ribosomal S6 kinase via Fyn and Ras.
AB  - Reactive oxygen species and growth factors stimulate similar intracellular signal
      transduction events including activation of Src kinase family members and
      extracellular signal-regulated kinases (ERK1/2). A potentially important
      downstream effector of Src and ERK1/2 is p90 ribosomal S6 kinase (p90RSK), which
      plays an important role in cell growth by activating several transcription
      factors as well as the Na(+)/H(+) exchanger. In the present study, we determined
      whether H(2)O(2) activates p90RSK to gain insight into signal transduction
      mechanisms activated by reactive oxygen species. H(2)O(2) (200 microM) stimulated
      ERK1/2 and p90RSK activity in lymphocytes, endothelial cells, and fibroblasts.
      The MEK-1 inhibitor, PD98059 (30 microM), inhibited H(2)O(2)-mediated activation
      of ERK1/2 but not of p90RSK. An essential role for Fyn and Ras in p90RSK
      activation was suggested by five findings. 1) The tyrosine kinase inhibitor,
      herbimycin A, and the specific Src kinase family inhibitor, PP1, blocked p90RSK
      activation by H(2)O(2) in a concentration-dependent manner. 2) p90RSK activation
      by H(2)O(2) was significantly reduced in fibroblasts derived from transgenic mice
      deficient in Fyn, but not c-Src. 3) H(2)O(2) rapidly activated Ras (peak at 2-5
      min), which preceded p90RSK activation (peak at 20 min). 4) Dominant negative Ras
      completely blocked H(2)O(2)-induced activation of p90RSK. 5) In Fyn-/-
      fibroblasts, activation of Ras by H(2)O(2) was significantly attenuated. These
      results show essential roles for Fyn and Ras in H(2)O(2)-mediated activation of
      p90RSK and establish redox-sensitive regulation of Ras and p90RSK as a new
      function for Fyn.

PMID- 10636872
TI  - Dimer formation by ternary complex factor ELK-1.
AB  - Ternary complex factors (TCFs), a subgroup of the ets protein family, bind with a
      dimer of serum response factor to the c-fos serum response element. Both DNA
      binding and transcriptional activation by TCFs are regulated by mitogen-activated
      protein kinases. When activated, mitogen-activated protein kinases form
      homodimers that translocate to the nucleus, where they interact with TCFs via
      specific docking sites. Here we show by three different criteria that Elk-1 is
      capable of forming dimers in eukaryotic cells through two distinct interaction
      domains. These observations are consistent with a dynamic model of TCF-promoter
      interactions.

PMID- 10636871
TI  - Residues of the fourth transmembrane segments of the Na,K-ATPase and the gastric
      H,K-ATPase contribute to cation selectivity.
AB  - We have generated protein chimeras to investigate the role of the fourth
      transmembrane segments (TM4) of the Na,K- and gastric H, K-ATPases in determining
      the distinct cation selectivities of these two pumps. Based on a helical wheel
      analysis, three residues of TM4 of the Na,K-ATPase were changed to their H,K
      counterparts. A construct carrying three mutations in TM4 (L319F, N326Y, and
      T340S) and two control constructs were heterologously expressed in Xenopus laevis
      oocytes and in the pig kidney epithelial cell line LLC-PK(1). Biochemical ATPase
      assays demonstrated a large sodium-independent ATPase activity at pH 6.0 for the
      pump carrying the TM4 substitutions, whereas the control constructs exhibited
      little or no activity in the absence of sodium. Furthermore, at pH 6.0 the
      K(1/2)(Na(+)) shifted to 1.5 mM for the TM4 construct compared with 9.4 and 5.9
      mM for the controls. In contrast, at pH 7.5 all three constructs had
      characteristics similar to wild type Na,K-ATPase. Large increases in K(1/2)(K(+))
      were observed for the TM4 construct compared with the control constructs both in
      two-electrode voltage clamp experiments in Xenopus oocytes and in ATPase assays.
      ATPase assays also revealed a 10-fold shift in vanadate sensitivity for the TM4
      construct. Based on these findings, it appears that the three identified TM4
      residues play an important role in determining both the specific cation
      selectivities and the E(1)/E(2) conformational equilibria of the Na,K- and H,K
      ATPase.

PMID- 10636873
TI  - alpha(2A)-adrenergic receptor stimulation potentiates calcium release in
      platelets by modulating cAMP levels.
AB  - alpha(2A)-Adrenergic receptor-mediated Ca(2+) signaling and integrin
      alpha(IIb)beta(3) exposure were investigated in human platelets under conditions
      where indirect, thromboxane- or ADP-mediated effects were absent. The alpha(2)
      adrenergic receptor agonists, UK14304 and epinephrine (EPI), were unable to raise
      cytosolic levels of inositol 1,4,5-trisphosphate (InsP(3)) or Ca(2+) but
      potentiated the [Ca(2+)](i) rises evoked by other agonists that act through
      stimulation of phospholipase C (thrombin or platelet-activating factor) or
      stimulation of Ca(2+)-induced Ca(2+) release (CICR) in the absence of InsP(3)
      generation (thimerosal or thapsigargin). In addition, alpha(2)-adrenergic
      stimulation resulted in a 20% lowering in the cytosolic cAMP level. In platelets
      treated with G(salpha)-stimulating prostaglandin E(1), EPI increased the Ca(2+)
      signal evoked by either phospholipase C- or CICR-stimulating agonists mainly
      through modulation of the cAMP level. The stimulating effects of UK14304 and EPI
      on platelet Ca(2+) responses, and also on integrin alpha(IIb)beta(3) exposure and
      platelet aggregation, were abolished by pharmacological stimulation of cAMP
      dependent protein kinase, and these effects were mimicked by inhibition of this
      activity. In permeabilized platelets, UK14304 and EPI potentiated InsP(3)
      induced, CICR-mediated mobilization of Ca(2+) from internal stores in a similar
      way as did inhibition of cAMP-dependent protein kinase. In summary, a G(ialpha)
      mediated decrease in cAMP level appears to play a major role in the platelet
      activating effects of alpha(2A)-adrenergic receptor stimulation. Thus, in
      platelets, unlike other cell types, occupation of the G(ialpha)-coupled alpha(2A)
      adrenergic receptors does not result in phospholipase C activation but rather in
      modulation of the Ca(2+) response by relieving cAMP-mediated suppression of
      InsP(3)-dependent CICR.

PMID- 10636874
TI  - The HPr kinase from Bacillus subtilis is a homo-oligomeric enzyme which exhibits
      strong positive cooperativity for nucleotide and fructose 1,6-bisphosphate
      binding.
AB  - Carbon catabolite repression allows bacteria to rapidly alter the expression of
      catabolic genes in response to the availability of metabolizable carbon sources.
      In Bacillus subtilis, this phenomenon is controlled by the HPr kinase (HprK) that
      catalyzes ATP-dependent phosphorylation of either HPr (histidine containing
      protein) or Crh (catabolite repression HPr) on residue Ser-46. We report here
      that B. subtilis HprK forms homo-oligomers constituted most likely of eight
      subunits. Related to this complex structure, the enzyme displays strong positive
      cooperativity for the binding of its allosteric activator, fructose 1,6
      bisphosphate, as evidenced by either kinetics of its phosphorylation activity or
      the intrinsic fluorescence properties of its unique tryptophan residue, Trp-235.
      It is further shown that activation of HPr phosphorylation by fructose 1,6
      bisphosphate essentially occurs at low ATP and enzyme concentrations. A positive
      cooperativity was also detected for the binding of natural nucleotides or their
      2'(3')-N-methylanthraniloyl derivatives, in either phosphorylation or
      fluorescence experiments. Most interestingly, quenching of the HprK tryptophan
      fluorescence by using either iodide or acrylamide revealed a heterogeneity of
      tryptophan residues within the population of oligomers, suggesting that the
      enzyme exists in two different conformations. This result suggests a concerted
      symmetry model for the catalytic mechanism of positive cooperativity displayed by
      HprK.

PMID- 10636875
TI  - Fluorophores at the N terminus of nascent chloramphenicol acetyltransferase
      peptides affect translation and movement through the ribosome.
AB  - Structurally different fluorescent probes were covalently attached to methionyl
      tRNA(f) and tested for their incorporation into nascent peptides and full-length
      protein using an Escherichia coli cell-free coupled transcription/translation
      system. Bovine rhodanese and bacterial chloramphenicol acetyltransferase (CAT)
      were synthesized using derivatives of cascade yellow, eosin, pyrene, or coumarin
      attached to [(35)S]Met-tRNA(f). All of the probes tested were incorporated into
      polypeptides, although less efficiently when compared with formyl-methionine.
      Eosin, the largest of the fluorophores used with estimated dimensions of 20 x 11
      A, caused the largest reduction in product formed. The rate of initiation was
      reduced with the fluorophore-Met-tRNA(f) compared with fMet-tRNA(f) with pyrene
      having the least and eosin the biggest effect. Analysis of the nascent
      polypeptides showed that the modifications at the N terminus affected the rate at
      which nascent CAT peptides were elongated causing accumulation of peptides of
      about 4 kDa, possibly by steric hindrance inside the tunnel within the 50 S
      ribosomal subunit. Fluorescence measurements indicate that the probe at the N
      terminus of nascent pyrene-CAT peptides is in a relatively hydrophilic
      environment. This finding is in agreement with recent data showing cross-linking
      of the N terminus of nascent peptides to nucleotides of the 23 S ribosomal RNA.

PMID- 10636876
TI  - Thyroid hormone-independent interaction between the thyroid hormone receptor
      beta2 amino terminus and coactivators.
AB  - Thyroid hormone receptors (TRs) mediate hormone action by binding to DNA response
      elements (TREs) and either activating or repressing gene expression in the
      presence of ligand, T(3). Coactivator recruitment to the AF-2 region of TR in the
      presence of T(3) is central to this process. The different TR isoforms, TR-beta1,
      TR-beta2, and TR-alpha1, share strong homology in their DNA- and ligand-binding
      domains but differ in their amino-terminal domains. Because TR-beta2 exhibits
      greater T(3)-independent activation on TREs than other TR isoforms, we wanted to
      determine whether coactivators bound to TR-beta2 in the absence of ligand. Our
      results show that TR-beta2, unlike TR-beta1 or TR-alpha1, is able to bind certain
      coactivators (CBP, SRC-1, and pCIP) in the absence of T(3) through a domain which
      maps to the amino-terminal half of its A/B domain. This interaction is specific
      for certain coactivators, as TR-beta2 does not interact with other co-factors
      (p120 or the CBP-associated factor (pCAF)) in the absence of T(3). The minimal TR
      beta2 domain for coactivator binding is aa 21-50, although aa 1-50 are required
      for the full functional response. Thus, isoform-specific regulation by TRs may
      involve T(3)-independent coactivator recruitment to the transcription complex via
      the AF-1 domain.

PMID- 10636877
TI  - Architecture of high mobility group protein I-C.DNA complex and its perturbation
      upon phosphorylation by Cdc2 kinase.
AB  - The high mobility group I-C (HMGI-C) protein is an abundant component of rapidly
      proliferating undifferentiated cells. High level expression of this protein is
      characteristic for early embryonic tissue and diverse tumors. HMGI-C can function
      as an architectural factor enhancing the activity of transcription factor NF
      kappaB on the beta-interferon promoter. The protein has three minor groove DNA
      binding domains (AT-hooks). Here, we describe the complex of HMGI-C with a
      fragment of the beta-interferon promoter. We show that the protein binds to NRDI
      and PRDII elements of the promoter with its first and second AT-hook,
      respectively. Phosphorylation by Cdc2 kinase leads to a partial derailing of the
      AT-hooks from the minor groove, affecting mainly the second binding domain. In
      contrast, binding to long AT stretches of DNA involves contacts with all three AT
      hooks and is marginally sensitive to phosphorylation. Our data stress the
      importance of conformation of the DNA binding site and protein phosphorylation
      for its function.

PMID- 10636878
TI  - A novel protein that binds juvenile hormone esterase in fat body tissue and
      pericardial cells of the tobacco hornworm Manduca sexta L.
AB  - Juvenile hormone esterase degrades juvenile hormone, which acts in conjunction
      with ecdysteroids to control gene expression in insects. Circulating juvenile
      hormone esterase is removed from insect blood by pericardial cells and degraded
      in lysosomes. In experiments designed to characterize proteins involved in the
      degradation of juvenile hormone esterase, a pericardial cell cDNA phage display
      library derived from the tobacco hornworm moth Manduca sexta L. was constructed
      and screened for proteins that bind juvenile hormone esterase. A 732-base pair
      cDNA encoding a novel 29-kDa protein (P29) was isolated. Western and Northern
      analyses indicated that P29 is present in both pericardial cell and fat body
      tissues and is expressed in each larval instar. In immunoprecipitation
      experiments, P29 bound injected recombinant juvenile hormone esterase taken up by
      pericardial cells and native M. sexta juvenile hormone esterase in fat body
      tissue, where the enzyme is synthesized. Binding assays showed that P29 bound
      juvenile hormone esterase more strongly than it did a mutant form of the enzyme
      with mutations that perturb lysosomal targeting. Based on these data, we propose
      that P29 functions in pericardial cells to facilitate lysosomal degradation of
      juvenile hormone esterase.

PMID- 10636879
TI  - Parathyroid hormone controls the size of the intracellular Ca(2+) stores
      available to receptors linked to inositol trisphosphate formation.
AB  - In HEK 293 cells stably expressing type 1 parathyroid (PTH) receptors, PTH
      stimulated release of intracellular Ca(2+) stores in only 27% of cells, whereas
      96% of cells responded to carbachol. However, in almost all cells PTH potentiated
      the response to carbachol by about 3-fold. Responses to carbachol did not
      desensitize, but only the first challenge in Ca(2+)-free medium caused an
      increase in [Ca(2+)](i), indicating that the carbachol-sensitive Ca(2+) stores
      had been emptied. Subsequent addition of PTH also failed to increase [Ca(2+)](i),
      but when it was followed by carbachol there was a substantial increase in
      [Ca(2+)](i). A similar potentiation was observed between ATP and PTH but not
      between carbachol and ATP. Intracellular heparin inhibited responses to carbachol
      and PTH, and pretreatment with ATP and carbachol abolished responses to PTH,
      suggesting that the effects of PTH involve inositol trisphosphate (IP(3))
      receptors. PTH neither stimulated detectable IP(3) formation nor affected the
      amount formed in response to ATP or carbachol. PTH stimulated cyclic AMP
      formation, but this was not the means whereby PTH potentiated Ca(2+) signals. We
      suggest that PTH may regulate Ca(2+) mobilization by facilitating translocation
      of Ca(2+) between discrete intracellular stores and that it thereby regulates the
      size of the Ca(2+) pool available to receptors linked to IP(3) formation.

PMID- 10636880
TI  - Crystal structure of the gephyrin-related molybdenum cofactor biosynthesis
      protein MogA from Escherichia coli.
AB  - Molybdenum cofactor (Moco) biosynthesis is an evolutionarily conserved pathway in
      archaea, eubacteria, and eukaryotes, including humans. Genetic deficiencies of
      enzymes involved in this biosynthetic pathway trigger an autosomal recessive
      disease with severe neurological symptoms, which usually leads to death in early
      childhood. The MogA protein exhibits affinity for molybdopterin, the organic
      component of Moco, and has been proposed to act as a molybdochelatase
      incorporating molybdenum into Moco. MogA is related to the protein gephyrin,
      which, in addition to its role in Moco biosynthesis, is also responsible for
      anchoring glycinergic receptors to the cytoskeleton at inhibitory synapses. The
      high resolution crystal structure of the Escherichia coli MogA protein has been
      determined, and it reveals a trimeric arrangement in which each monomer contains
      a central, mostly parallel beta-sheet surrounded by alpha-helices on either side.
      Based on structural and biochemical data, a putative active site was identified,
      including two residues that are essential for the catalytic mechanism.

PMID- 10636881
TI  - The contribution of residues 192 and 193 to the specificity of snake venom serine
      proteinases.
AB  - Snake venom serine proteinases, which belong to the subfamily of trypsin-like
      serine proteinases, exhibit a high degree of sequence identity (60-66%). Their
      stringent macromolecular substrate specificity contrasts with that of the less
      specific enzyme trypsin. One of them, the plasminogen activator from Trimeresurus
      stejnegeri venom (TSV-PA), which shares 63% sequence identity with batroxobin, a
      fibrinogen clotting enzyme from Bothrops atrox venom, specifically activates
      plasminogen to plasmin like tissue-type plasminogen activator (t-PA), even though
      it exhibits only 23% sequence identity with t-PA. This study shows that TSV-PA, t
      PA, and batroxobin are quite different in their specificity toward small
      chromogenic substrates, TSV-PA being less selective than t-PA, and batroxobin not
      being efficient at all. The specificity of TSV-PA, with respect to t-PA and
      batroxobin, was investigated further by site-directed mutagenesis in the 189-195
      segment, which forms the basement of the S(1) pocket of TSV-PA and presents a His
      at position 192 and a unique Phe at position 193. This study demonstrates that
      Phe(193) plays a more significant role than His(192) in determining substrate
      specificity and inhibition resistance. Interestingly, the TSV-PA variant F193G
      possesses a 8-9-fold increased activity for plasminogen and becomes sensitive to
      bovine pancreatic trypsin inhibitor.

PMID- 10636882
TI  - CD44 interaction with tiam1 promotes Rac1 signaling and hyaluronic acid-mediated
      breast tumor cell migration.
AB  - In this study we have explored the interaction between CD44 (the hyaluronic acid
      (HA)-binding receptor) and Tiam1 (a guanine nucleotide exchange factor) in
      metastatic breast tumor cells (SP1 cell line). Immunoprecipitation and immunoblot
      analyses indicate that both the CD44v3 isoform and the Tiam1 protein are
      expressed in SP1 cells and that these two proteins are physically associated as a
      complex in vivo. Using an Escherichia coli-derived calmodulin-binding peptide
      tagged Tiam1 fragment (i.e. the NH(2)-terminal pleckstrin homology (PHn) domain
      and an adjacent protein interaction domain designated as PHn-CC-Ex, amino acids
      393-738 of Tiam1) and an in vitro binding assay, we have detected a specific
      binding interaction between the Tiam1 PHn-CC-Ex domain and CD44. Scatchard plot
      analysis indicates that there is a single high affinity CD44 binding site in the
      PHn-CC-Ex domain of Tiam1 with an apparent dissociation constant (K(d)) of 0.2
      nM, which is comparable with CD44 binding (K(d) = approximately 0.13 nM) to
      intact Tiam1. These findings suggest that the PHn-CC-Ex domain is the primary
      Tiam1-binding region for CD44. Most importantly, the binding of HA to CD44v3 of
      SP1 cells stimulates Tiam1-catalyzed Rac1 signaling and cytoskeleton-mediated
      tumor cell migration. Transfection of SP1 cells with Tiam1cDNA promotes Tiam1
      association with CD44v3 and up-regulates Rac1 signaling as well as HA/CD44v3
      mediated breast tumor cell migration. Co-transfection of SP1 cells with PHn-CC-Ex
      cDNA and Tiam1 cDNA effectively inhibits Tiam1 association with CD44 and
      efficiently blocks tumor behaviors. Taken together, we believe that the linkage
      between CD44v3 isoform and the PHn-CC-EX domain of Tiam1 is required for HA
      stimulated Rac1 signaling and cytoskeleton-mediated tumor cell migration during
      breast cancer progression.

PMID- 10636883
TI  - Interactions between HIV-1 gp41 core and detergents and their implications for
      membrane fusion.
AB  - The gp41 envelope protein mediates entry of human immunodeficiency virus type 1
      (HIV-1) into the cell by promoting membrane fusion. The crystal structure of a
      gp41 ectodomain core in its fusion-active state is a six-helix bundle in which a
      N-terminal trimeric coiled coil is surrounded by three C-terminal outer helices
      in an antiparallel orientation. Here we demonstrate that the N34(L6)C28 model of
      the gp41 core is stabilized by interaction with the ionic detergent sodium
      dodecyl sulfate (SDS) or the nonionic detergent n-octyl-beta-D-glucopyranoside
      (betaOG). The high resolution x-ray structures of N34(L6)C28 crystallized from
      two different detergent micellar media reveal a six-helix bundle conformation
      very similar to that of the molecule in water. Moreover, N34(L6)C28 adopts a
      highly alpha-helical conformation in lipid vesicles. Taken together, these
      results suggest that the six-helix bundle of the gp41 core displays substantial
      affinity for lipid bilayers rather than unfolding in the membrane environment.
      This characteristic may be important for formation of the fusion-active gp41 core
      structure and close apposition of the viral and cellular membranes for fusion.

PMID- 10636884
TI  - Serine/threonine protein phosphatase type 1gamma1 is required for the completion
      of cytokinesis in human A549 lung carcinoma cells.
AB  - In lower eukaryotic organisms, the loss of serine/threonine protein phosphatase
      type 1 (PP1) results in growth arrest after the onset of mitosis. In humans, four
      highly homologous isoforms of PP1 (PP1alpha, PP1delta, PP1gamma1, and PP1gamma2)
      have been identified. Determining the roles of these phosphatases, however, has
      proven difficult due to the lack of subtype-specific inhibitors. In this study,
      we developed chimeric antisense 2'-O-(2-methoxy)ethylphosphothioate
      oligonucleotides targeting human PP1gamma1 that specifically inhibit PP1gamma1
      gene expression. Two potent antisense oligonucleotides (ISIS 14435 and 14439;
      IC(50) approximately 50 nM) were then employed to elucidate the cellular
      functions of PP1gamma1 during cell cycle progression. In A549 cells, the
      inhibition of PP1gamma1 expression resulted in a dose-dependent inhibition of
      cellular proliferation, with growth arrest occurring after approximately 36-48 h,
      when PP1gamma1 mRNA expression was inhibited by >85%. Fluorescence-activated cell
      sorter analysis revealed that ISIS 14435/14439-induced growth arrest was
      associated with an increase in the number of cells containing 4N DNA.
      Immunostaining of treated cells revealed that the inhibition of PP1gamma1
      expression had no apparent effect on the formation of mitotic spindles. However,
      decreased expression was associated with the failure of cell division in a late
      stage of cytokinesis and the formation of dikaryons.

PMID- 10636885
TI  - Electrical stimulation of neonatal cardiac myocytes activates the NFAT3 and GATA4
      pathways and up-regulates the adenylosuccinate synthetase 1 gene.
AB  - Electrically stimulated pacing of cultured cardiomyocytes serves as an
      experimentally convenient and physiologically relevant in vitro model of cardiac
      hypertrophy. Electrical pacing triggers a signaling cascade that results in the
      activation of the muscle-specific Adss1 gene and the repression of the nonmuscle
      Adss2 isoform. Activation of the Adss1 gene involves the calcineurin-mediated
      dephosphorylation of NFAT3, allowing its translocation to the nucleus, where it
      can directly participate in Adss1 gene activation. Mutational studies show that
      an NFAT binding site located in the Adss1 5'-flanking region is essential for
      this activation. Electrical pacing also results in the increased synthesis of
      GATA4, another critical cardiac transcription factor required for Adss1 gene
      expression. MEF2C also produces transactivation of the Adss1 gene reporter in
      control and paced cardiac myocytes. Using the Adss1 gene as a model, these
      studies are the first to demonstrate that electrical pacing activates the
      calcineurin/NFAT3 and GATA4 pathways as a means of regulating cardiac gene
      expression.

PMID- 10636886
TI  - Binding of flavin adenine dinucleotide to molybdenum-containing carbon monoxide
      dehydrogenase from Oligotropha carboxidovorans. Structural and functional
      analysis of a carbon monoxide dehydrogenase species in which the native
      flavoprotein has been replaced by its recombinant counterpart produced in
      Escherichia coli.
AB  - The carbon monoxide (CO) dehydrogenase of Oligotropha carboxidovorans is composed
      of an S-selanylcysteine-containing 88. 7-kDa molybdoprotein (L), a 17.8-kDa iron
      sulfur protein (S), and a 30.2-kDa flavoprotein (M) in a (LMS)(2) subunit
      structure. The flavoprotein could be removed from CO dehydrogenase by
      dissociation with sodium dodecylsulfate. The resulting M(LS)(2)- or (LS)(2)
      structured CO dehydrogenase species could be reconstituted with the recombinant
      apoflavoprotein produced in Escherichia coli. The formation of the heterotrimeric
      complex composed of the apoflavoprotein, the molybdoprotein, and the iron-sulfur
      protein involves structural changes that translate into the conversion of the
      apoflavoprotein from non-FAD binding to FAD binding. Binding of FAD to the
      reconstituted deflavo (LMS)(2) species occurred with second-order kinetics (k(+1)
      = 1350 M(-1) s(-1)) and high affinity (K(d) = 1.0 x 10(-9) M). The structure of
      the resulting flavo (LMS)(2) species at a 2.8-A resolution established the same
      fold and binding of the flavoprotein as in wild-type CO dehydrogenase, whereas
      the S-selanylcysteine 388 in the active-site loop on the molybdoprotein was
      disordered. In addition, the structural changes related to heterotrimeric complex
      formation or FAD binding were transmitted to the iron-sulfur protein and could be
      monitored by EPR. The type II 2Fe:2S center was identified in the N-terminal
      domain and the type I center in the C-terminal domain of the iron-sulfur protein.

PMID- 10636887
TI  - A synthetic antagonist for the peroxisome proliferator-activated receptor gamma
      inhibits adipocyte differentiation.
AB  - While searching for natural ligands for the peroxisome proliferator-activated
      receptor (PPAR) gamma, we identified a synthetic compound that binds to this
      receptor. Bisphenol A diglycidyl ether (BADGE) is a ligand for PPARgamma with a
      K(d(app)) of 100 microM. This compound has no apparent ability to activate the
      transcriptional activity of PPARgamma; however, BADGE can antagonize the ability
      of agonist ligands such as rosiglitazone to activate the transcriptional and
      adipogenic action of this receptor. BADGE also specifically blocks the ability of
      natural adipogenic cell lines such as 3T3-L1 and 3T3-F442A cells to undergo
      hormone-mediated cell differentiation. These results provide the first
      pharmacological evidence that PPARgamma activity is required for the hormonally
      induced differentiation of adipogenic cells.

PMID- 10636888
TI  - A leptomycin B-sensitive homologue of human CRM1 promotes nuclear export of
      nuclear export sequence-containing proteins in Drosophila cells.
AB  - The Rev protein of human immunodeficiency virus is a nuclear shuttling protein
      that promotes nuclear export of mRNAs that encode the viral structural proteins
      Gag, Pol, and Env. Rev binds to a highly structured RNA motif, the Rev-responsive
      element (RRE), that is present in all Rev-responsive viral transcripts and
      facilitates their entry into a nuclear export pathway by recruiting cellular
      export factors. In mammalian and yeast cells, the principal export receptor
      engaged by Rev has been identified as the importin/transportin family member
      CRM1/exportin 1. CRM1 binds directly to a leucine-rich nuclear export sequence
      (NES) present in Rev, and similar motifs have been identified in a variety of
      cellular nuclear shuttling proteins. We and our colleagues previously
      demonstrated that, in transfected Drosophila cells, HIV-1 Rev is fully functional
      and promotes expression of the viral envelope glycoprotein. We now demonstrate
      that the fundamental mechanism of Rev action in insect cells is identical to that
      observed in the mammalian systems. In particular, we show that Drosophila cells
      express a leptomycin B-sensitive homologue of human CRM1 that supports Rev
      dependent gene expression and is required for nuclear export of NES-containing
      proteins in insect cells.

PMID- 10636889
TI  - Up-regulation of multidrug resistance P-glycoprotein via nuclear factor-kappaB
      activation protects kidney proximal tubule cells from cadmium- and reactive
      oxygen species-induced apoptosis.
AB  - Cadmium-mediated toxicity of cultured proximal tubule (PT) cells is associated
      with increased production of reactive oxygen species (ROS) and apoptosis. We
      found that cadmium-dependent apoptosis (Hoechst 33342 and annexin V assays)
      decreased with prolonged CdCl(2) (10 microM) application (controls: 2.4 +/- 1.6%;
      5 h: +5.1 +/- 2.3%, 20 h: +5.7 +/- 2.5%, 48 h: +3.3 +/- 1.0% and 72 h: +2.1 +/-
      0.4% above controls), while cell proliferation was not affected. Reduction of
      apoptosis correlated with a time-dependent up-regulation of the drug efflux pump
      multidrug resistance P-glycoprotein (mdr1) in cadmium-treated cells (
      approximately 4-fold after 72 h), as determined by immunoblotting with the
      monoclonal antibody C219 and measurement of intracellular accumulation of the
      fluorescent probe calcein +/- the mdr1 inhibitor PSC833 (0.5 microM). When mdr1
      inhibitors (PSC833, cyclosporine A, verapamil) were transiently added to cells
      with mdr1 up-regulation by pretreatment for 72 h with cadmium, cadmium-induced
      apoptosis increased significantly and to a percentage similar to that obtained in
      cells with no mdr1 up-regulation (72-h cadmium: 5.2 +/- 0.9% versus 72-h cadmium
      + 1-h PSC833: 7.2 +/- 1.4%; p < or = 0.001). Cadmium-induced apoptosis and mdr1
      up-regulation depended on ROS, since co-incubation with the ROS scavengers N
      acetylcysteine (15 mM) or pyrrolidine dithiocarbamate (0.1 mM) abolished both
      responses. Moreover, cadmium- and ROS-associated mdr1 up-regulation was linked to
      activation of the transcription factor NF-kappaB; N-acetylcysteine, pyrrolidine
      dithiocarbamate, and the IkappaB-alpha kinase inhibitor Bay 11-7082 (20 microM)
      prevented both, mdr1 overexpression and degradation of the inhibitory NF-kappaB
      subunit, IkappaB-alpha, induced by cadmium. The data show that 1) cadmium
      mediated apoptosis in PT cells is associated with ROS production, 2) ROS increase
      mdr1 expression by a process involving NF-kappaB activation, and 3) mdr1
      overexpression protects PT cells against cadmium-mediated apoptosis. These data
      suggest that mdr1 up-regulation, at least in part, provides anti-apoptotic
      protection for PT cells against cadmium-mediated stress.

PMID- 10636890
TI  - Primary structure and function analysis of the Abrus precatorius agglutinin A
      chain by site-directed mutagenesis. Pro(199) Of amphiphilic alpha-helix H impairs
      protein synthesis inhibitory activity.
AB  - Abrus agglutinin (AAG), a low-toxicity protein from the plant Abrus precatorius,
      is less lethal than abrina (ABRa) in mice (LD(50) = 5 mg/kg versus 20 microg/kg
      of body weight). Nucleotide sequence analysis of a cDNA clone encoding full
      length AAG showed an open reading frame with 1641 base pairs, corresponding to a
      547-amino acid residue preproprotein containing a signal peptide and a linker
      region (two amino acid residues) between the AAG-A and AAG-B subunits. AAG had
      high homology to ABRa (77.8%). The 13 amino acid residues involved in catalytic
      function, which are highly conserved among abrins and ricins, were also conserved
      within AAG-A. The protein synthesis inhibitory activity of AAG-A (IC(50) = 3.5
      nM) was weaker than that of ABRa-A (0.05 nM). Molecular modeling followed by site
      directed mutagenesis showed that Pro(199) of AAG-A, located in amphiphilic helix
      H and corresponding to Asn(200) of ABRa-A, can induce bending of helix H. This
      bending would presumably affect the binding of AAG-A to its target sequence,
      GpApGpAp, in the tetraloop structure of the 28 S rRNA subunit and could be one of
      the major factors contributing to the relatively weak protein synthesis
      inhibitory activity and toxicity of AAG.

PMID- 10636891
TI  - Inhibition of the c-Jun N-terminal kinase/AP-1 and NF-kappaB pathways by PICOT, a
      novel protein kinase C-interacting protein with a thioredoxin homology domain.
AB  - Protein kinase C-theta (PKCtheta) is a Ca(2+)-independent PKC isoform that is
      selectively expressed in T lymphocytes (and muscle), and is thought to play an
      important role in T cell receptor-induced activation. To gain a better
      understanding of the function and regulation of PKCtheta, we have employed the
      yeast two-hybrid system to identify PKCtheta-interacting proteins. We report the
      isolation and characterization of a cDNA encoding a novel 335-amino acid (37. 5
      kDa) PKCtheta-interacting protein termed PICOT (for PKC-interacting cousin of
      thioredoxin). PICOT is expressed in various tissues, including in T cells, where
      it colocalizes with PKCtheta. PICOT displays an N-terminal thioredoxin homology
      domain, which is required for the interaction with PKC. Comparison of the unique
      C-terminal region of PICOT with expressed sequence tag data bases revealed two
      tandem repeats of a novel domain that is highly conserved from plants to mammals.
      Transient overexpression of full-length PICOT (but not its N- or C-terminal
      fragments) in T cells inhibited the activation of c-Jun N-terminal kinase (but
      not extracellular signal-regulated kinase), and the transcription factors AP-1 or
      NF-kappaB. These findings suggest that PICOT and its evolutionary conserved
      homologues may interact with PKC-related kinases in multiple organisms and,
      second, that it plays a role in regulating the function of the thioredoxin
      system.

PMID- 10636892
TI  - Time dependence of the catalytic intermediates in cytochrome c oxidase.
AB  - Cytochrome c oxidase, the terminal enzyme in the electron transfer chain,
      catalyzes the reduction of oxygen to water in a multiple step process by
      utilizing four electrons from cytochrome c. To study the reaction mechanism, the
      resonance Raman spectra of the intermediate states were measured during single
      turnover of the enzyme after catalytic initiation by photolysis of CO from the
      fully reduced CO-bound enzyme. By measuring the change in intensity of lines
      associated with heme a, the electron transfer steps were determined and found to
      be biphasic with apparent rate constants of approximately 40 x 10(3) s(-1) and
      approximately 1 x 10(3) s(-1). The time dependence for the oxidation of heme a
      and for the measured formation and decay of the oxy, the ferryl ("F"), and the
      hydroxy intermediates could be simulated by a simple reaction scheme. In this
      scheme, the presence of the "peroxy" ("P") intermediate does not build up a
      sufficient population to be detected because its decay rate is too fast in
      buffered H(2)O at neutral pH. A comparison of the change in the spin equilibrium
      with the formation of the hydroxy intermediate demonstrates that this
      intermediate is high spin. We also confirm the presence of an oxygen isotope
      sensitive line at 355 cm(-1), detectable in the spectrum from 130 to 980 micros,
      coincident with the presence of the F intermediate.

PMID- 10636893
TI  - Protein-disulfide isomerase (PDI) in FRTL5 cells. pH-dependent thyroglobulin/PDI
      interactions determine a novel PDI function in the post-endoplasmic reticulum of
      thyrocytes.
AB  - Thyroglobulin (TG) is secreted by the thyrocytes into the follicular lumen of the
      thyroid. After maturation and hormone formation, TG is endocytosed and delivered
      to lysosomes. Quality control mechanisms may occur during this bidirectional
      traffic since 1) several molecular chaperones are cosecreted with TG in vivo, and
      2) lysosomal targeting of immature TG is thought to be prevented via the
      interaction, in acidic conditions, between the Ser(789)-Met(1172) TG hormonogenic
      domain (BD) and an unidentified membrane receptor. We investigated the secretion
      and cell surface expression of PDI and other chaperones in the FRTL5 thyroid cell
      line, and then studied the characteristics of the interaction between TG and PDI.
      We demonstrated that PDI, but also other chaperones such as calnexin and KDEL
      containing proteins are exposed at the cell surface. We observed on living cells
      or membrane preparations that PDI specifically binds TG in acidic conditions, and
      that only BD is involved in binding. Surface plasmon resonance analysis of TG/PDI
      interactions indicated: 1) that PDI bound TG but only in acidic conditions, and
      that it preferentially recognized immature molecules, and 2) BD is involved in
      binding even if cysteine-rich modules are deleted. The notion that PDI acts as an
      "escort" for immature TG in acidic post-endoplasmic reticulum compartments is
      discussed.

PMID- 10636894
TI  - The amino terminus of the fourth cytoplasmic loop of rhodopsin modulates
      rhodopsin-transducin interaction.
AB  - Rhodopsin is a seven-transmembrane helix receptor that binds and catalytically
      activates the heterotrimeric G protein transducin (G(t)). This interaction
      involves the cytoplasmic surface of rhodopsin, which comprises four putative
      loops and the carboxyl-terminal tail. The fourth loop connects the carboxyl end
      of transmembrane helix 7 with Cys(322) and Cys(323), which are both modified by
      membrane-inserted palmitoyl groups. Published data on the roles of the fourth
      loop in the binding and activation of G(t) are contradictory. Here, we attempt to
      reconcile these conflicts and define a role for the fourth loop in rhodopsin-G(t)
      interactions. Fluorescence experiments demonstrated that a synthetic peptide
      corresponding to the fourth loop of rhodopsin inhibited the activation of G(t) by
      rhodopsin and interacted directly with the alpha subunit of G(t). A series of
      rhodopsin mutants was prepared in which portions of the fourth loop were replaced
      with analogous sequences from the beta(2)-adrenergic receptor or the m1
      muscarinic receptor. Chimeric receptors in which residues 310-312 were replaced
      could not efficiently activate G(t). The defect in G(t) interaction in the fourth
      loop mutants was not affected by preventing palmitoylation of Cys(322) and
      Cys(323). We suggest that the amino terminus of the fourth loop interacts
      directly with G(t), particularly with Galpha(t), and with other regions of the
      intracellular surface of rhodopsin to support G(t) binding.

PMID- 10636896
TI  - Identification and genomic cloning of CMHC1. A unique myosin heavy chain
      expressed exclusively in the developing chicken heart.
AB  - We report the identification and cloning of a unique chick myosin heavy chain
      (CMHC1) that is expressed exclusively in the heart during embryogenesis. Using
      primers specific to myosin heavy chains, we used reverse transcriptase-polymerase
      chain reaction to clone and isolate CMHC1 from embryonic day 10 chicken heart
      RNA. Sequence analysis indicated that CMHC1 was a novel member of the myosin
      heavy chain family. Expression of the CMHC1 transcripts was detected in Hamburger
      Hamilton stage 10 chick embryos in the fusing myocardium. Expression of CMHC1 was
      maintained at high levels throughout the tubular heart of later stage embryos.
      Reverse transcriptase-polymerase chain reaction and in situ hybridizations failed
      to detect CMHC1 transcripts in the developing somites, limb buds, or skeletal
      musculature at any stage of chick development. Genomic CMHC1 clones have been
      isolated that contain sequences approximately 5.2 kilobase upstream of the
      presumptive CMHC1 transcription start site. Portions of the upstream regulatory
      region induced a 21-fold increase in reporter gene expression in primary
      cardiomyocytes. Because of its unique cardiac-restricted expression, CMHC1 will
      provide an excellent model system to study the molecular mechanisms required for
      the early developmental regulation of heart-specific genes.

PMID- 10636895
TI  - Mutation of the fourth cytoplasmic loop of rhodopsin affects binding of
      transducin and peptides derived from the carboxyl-terminal sequences of
      transducin alpha and gamma subunits.
AB  - The role of the putative fourth cytoplasmic loop of rhodopsin in the binding and
      catalytic activation of the heterotrimeric G protein, transducin (G(t)), is not
      well defined. We developed a novel assay to measure the ability of G(t), or G(t)
      derived peptides, to inhibit the photoregeneration of rhodopsin from its active
      metarhodopsin II state. We show that a peptide corresponding to residues 340-350
      of the alpha subunit of G(t), or a cysteinyl-thioetherfarnesyl peptide
      corresponding to residues 50-71 of the gamma subunit of G(t), are able to
      interact with metarhodopsin II and inhibit its photoconversion to rhodopsin.
      Alteration of the amino acid sequence of either peptide, or removal of the
      farnesyl group from the gamma-derived peptide, prevents inhibition. Mutation of
      the amino-terminal region of the fourth cytoplasmic loop of rhodopsin affects
      interaction with G(t) (Marin, E. P., Krishna, A. G., Zvyaga T. A., Isele, J.,
      Siebert, F., and Sakmar, T. P. (2000) J. Biol. Chem. 275, 1930-1936). Here, we
      provide evidence that this segment of rhodopsin interacts with the carboxyl
      terminal peptide of the alpha subunit of G(t). We propose that the amino-terminal
      region of the fourth cytoplasmic loop of rhodopsin is part of the binding site
      for the carboxyl terminus of the alpha subunit of G(t) and plays a role in the
      regulation of betagamma subunit binding.

PMID- 10636897
TI  - Control of organ-specific demethylation by an element of the T-cell receptor
      alpha locus control region.
AB  - DNA methylation is important for mammalian development and the control of gene
      expression. Recent data suggest that DNA methylation causes chromatin closure and
      gene silencing. During development, tissue specifically expressed gene loci
      become selectively demethylated in the appropriate cell types by poorly
      understood processes. Locus control regions (LCRs), which are cis-acting elements
      providing stable, tissue-specific expression to linked transgenes in chromatin,
      may play a role in tissue-specific DNA demethylation. We studied the methylation
      status of the LCR for the mouse T-cell receptor alpha/delta locus using a novel
      assay for scanning large distances of DNA for methylation sites. Tissue-specific
      functions of this LCR depend largely on two DNase I-hypersensitive site clusters
      (HS), HS1 (T-cell receptor alpha enhancer) and HS1'. We report that these HS
      induce lymphoid organ-specific DNA demethylation in a region located 3.8
      kilobases away with little effect on intervening, methylated DNA. This
      demethylation is impaired in mice with a germline deletion of the HS1/HS1'
      clusters. Using 5'-deletion mutants of a transgenic LCR reporter gene construct,
      we show that HS1' can act in the absence of HS1 to direct this tissue-specific
      DNA demethylation event. Thus, elements of an LCR can control tissue-specific DNA
      methylation patterns both in transgenes and inside its native locus.

PMID- 10636898
TI  - Phosphorylation of caldesmon by p21-activated kinase. Implications for the Ca(2+)
      sensitivity of smooth muscle contraction.
AB  - We have previously shown that p21-activated kinase, PAK, induces Ca(2+)
      independent contraction of Triton-skinned smooth muscle with concomitant increase
      in phosphorylation of caldesmon and desmin but not myosin-regulatory light chain
      (Van Eyk, J. E., Arrell, D. K., Foster, D. B., Strauss, J. D., Heinonen, T. Y.,
      Furmaniak-Kazmierczak, E., Cote, G. P., and Mak, A. S. (1998) J. Biol. Chem. 273,
      23433-23439). In this study, we provide biochemical evidence implicating a role
      for PAK in Ca(2+)-independent contraction of smooth muscle via phosphorylation of
      caldesmon. Mass spectroscopy data show that stoichiometric phosphorylation occurs
      at Ser(657) and Ser(687) abutting the calmodulin-binding sites A and B of chicken
      gizzard caldesmon, respectively. Phosphorylation of Ser(657) and Ser(687) has an
      important functional impact on caldesmon. PAK-phosphorylation reduces binding of
      caldesmon to calmodulin by about 10-fold whereas binding of calmodulin to
      caldesmon partially inhibits PAK phosphorylation. Phosphorylated caldesmon
      displays a modest reduction in affinity for actin-tropomyosin but is
      significantly less effective in inhibiting actin-activated S1 ATPase activity in
      the presence of tropomyosin. We conclude that PAK-phosphorylation of caldesmon at
      the calmodulin-binding sites modulates caldesmon inhibition of actin-myosin
      ATPase activity and may, in concert with the actions of Rho-kinase, contribute to
      the regulation of Ca(2+) sensitivity of smooth muscle contraction.

PMID- 10636899
TI  - Cytochromes P-450 from cassava (Manihot esculenta Crantz) catalyzing the first
      steps in the biosynthesis of the cyanogenic glucosides linamarin and
      lotaustralin. Cloning, functional expression in Pichia pastoris, and substrate
      specificity of the isolated recombinant enzymes.
AB  - The first committed steps in the biosynthesis of the two cyanogenic glucosides
      linamarin and lotaustralin in cassava are the conversion of L-valine and L
      isoleucine, respectively, to the corresponding oximes. Two full-length cDNA
      clones that encode cytochromes P-450 catalyzing these reactions have been
      isolated. The two cassava cytochromes P-450 are 85% identical, share 54% sequence
      identity to CYP79A1 from sorghum, and have been assigned CYP79D1 and CYP79D2.
      Functional expression has been achieved using the methylotrophic yeast, Pichia
      pastoris. The amount of CYP79D1 isolated from 1 liter of P. pastoris culture
      exceeds the amounts that putatively could be isolated from 22,000 grown-up
      cassava plants. Each cytochrome P-450 metabolizes L-valine as well as L
      isoleucine consistent with the co-occurrence of linamarin and lotaustralin in
      cassava. CYP79D1 was isolated from P. pastoris. Reconstitution in lipid micelles
      showed that CYP79D1 has a higher k(c) value with L-valine as substrate than with
      L-isoleucine, which is consistent with linamarin being the major cyanogenic
      glucoside in cassava. Both CYP79D1 and CYP79D2 are present in the genome of
      cassava cultivar MCol22 in agreement with cassava being allotetraploid. CYP79D1
      and CYP79D2 are actively transcribed, and production of acyanogenic cassava
      plants would therefore require down-regulation of both genes.

PMID- 10636900
TI  - Transport and pharmacological properties of nine different human Na, K-ATPase
      isozymes.
AB  - Na,K-ATPase plays a crucial role in cellular ion homeostasis and is the
      pharmacological receptor for digitalis in man. Nine different human Na,K-ATPase
      isozymes, composed of 3 alpha and beta isoforms, were expressed in Xenopus
      oocytes and were analyzed for their transport and pharmacological properties.
      According to ouabain binding and K(+)-activated pump current measurements, all
      human isozymes are functional but differ in their turnover rates depending on the
      alpha isoform. On the other hand, variations in external K(+) activation are
      determined by a cooperative interaction mechanism between alpha and beta isoforms
      with alpha2-beta2 complexes having the lowest apparent K(+) affinity. alpha
      Isoforms influence the apparent internal Na(+) affinity in the order alpha1 >
      alpha2 > alpha3 and the voltage dependence in the order alpha2 > alpha1 > alpha3.
      All human Na,K-ATPase isozymes have a similar, high affinity for ouabain.
      However, alpha2-beta isozymes exhibit more rapid ouabain association as well as
      dissociation rate constants than alpha1-beta and alpha3-beta isozymes. Finally,
      isoform-specific differences exist in the K(+)/ouabain antagonism which may
      protect alpha1 but not alpha2 or alpha3 from digitalis inhibition at
      physiological K(+) levels. In conclusion, our study reveals several new
      functional characteristics of human Na,K-ATPase isozymes which help to better
      understand their role in ion homeostasis in different tissues and in digitalis
      action and toxicity.

PMID- 10636901
TI  - Glucosidase and mannosidase inhibitors mediate increased secretion of mutant
      alpha1 antitrypsin Z.
AB  - It is now well known that the addition and trimming of oligosaccharide side
      chains during post-translational modification play an important role in
      determining the fate of secretory, membrane, and lysosomal glycoproteins. Recent
      studies have suggested that trimming of oligosaccharide side chains also plays a
      role in the degradation of misfolded glycoproteins as a part of the quality
      control mechanism of the endoplasmic reticulum (ER). In this study, we examined
      the effect of several inhibitors of carbohydrate processing on the fate of the
      misfolded secretory protein alpha1 antitrypsin Z. Retention of this misfolded
      glycoprotein in the ER of liver cells in the classical form of alpha1 antitrypsin
      (alpha1-AT) deficiency is associated with severe liver injury and hepatocellular
      carcinoma and lack of its secretion is associated with destructive lung
      disease/emphysema. The results show marked alterations in the fate of alpha1
      antitrypsin Z (alpha1-ATZ). Indeed, one glucosidase inhibitor, castanospermine
      (CST), and two mannosidase inhibitors, kifunensine (KIF) and deoxymannojirimycin
      (DMJ), mediate marked increases in secretion of alpha1-ATZ by distinct
      mechanisms. The effects of these inhibitors on secretion have interesting
      implications for our understanding of the quality control apparatus of the ER.
      These inhibitors may also constitute models for development of additional drugs
      for chemoprophylaxis of liver injury and emphysema in patients with alpha1-AT
      deficiency.

PMID- 10636902
TI  - A urokinase receptor-associated protein with specific collagen binding
      properties.
AB  - The plasminogen activation cascade system, directed by urokinase and the
      urokinase receptor, plays a key role in extracellular proteolysis during tissue
      remodeling. To identify molecular interaction partners of these trigger proteins
      on the cell, we combined covalent protein cross-linking with mass spectrometry
      based methods for peptide mapping and primary structure analysis of
      electrophoretically isolated protein conjugates. A specific tri-molecular complex
      was observed upon addition of pro-urokinase to human U937 cells. This complex
      included the urokinase receptor, pro-urokinase, and an unknown, high molecular
      weight urokinase receptor-associated protein. The tryptic peptide mixture derived
      from a cross-linked complex of pro-urokinase and the latter protein was analyzed
      by nanoelectrospray tandem mass spectrometric sequencing. This analysis
      identified the novel protein as the human homologue of a murine membrane-bound
      lectin with hitherto unknown function. The human cDNA was cloned and sequenced.
      The protein, designated uPARAP, is a member of the macrophage mannose receptor
      protein family and contains a putative collagen-binding (fibronectin type II)
      domain in addition to 8 C-type carbohydrate recognition domains. It proved
      capable of binding strongly to a single type of collagen, collagen V. This
      collagen binding reaction at the exact site of plasminogen activation on the cell
      may lead to adhesive functions as well as a contribution to cellular degradation
      of collagen matrices.

PMID- 10636903
TI  - Oxidative DNA damage by vitamin A and its derivative via superoxide generation.
AB  - Recent intervention studies revealed that beta-carotene supplement to smokers
      resulted in a higher incidence of lung cancer. However, the causal mechanisms
      remain to be clarified. We reported here that vitamin A (retinol) and its
      derivative (retinal) caused cellular DNA cleavage detected by pulsed field gel
      electrophoresis. Retinol and retinal significantly induced 8-oxo-7,8-dihydro-2'
      deoxyguanosine formation in HL-60 cells but not in H(2)O(2)-resistant HP100
      cells, suggesting the involvement of H(2)O(2) in cellular DNA damage. Experiments
      using (32)P-labeled isolated DNA demonstrated that retinol and retinal caused
      Cu(II)-mediated DNA damage, which was inhibited by catalase. UV-visible
      spectroscopic and electron spin resonance-trapping studies revealed the
      generation of superoxide and carbon-centered radicals, respectively. The
      superoxide generation during autoxidation of retinoids was significantly
      correlated with the formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine, although
      the yield of carbon-centered radicals was not necessarily related to the
      intensity of DNA damage. These findings suggest that superoxide generated by
      autoxidation of retinoids was dismutated to H(2)O(2), which was responsible for
      DNA damage in the presence of endogenous metals. Retinol and retinal have
      prooxidant abilities, which might lead to carcinogenesis of the supplements of
      beta-carotene.

PMID- 10636904
TI  - Biochemical analysis of recombinant fungal mutanases. A new family of alpha1,3
      glucanases with novel carbohydrate-binding domains.
AB  - Nucleotide sequence analysis shows that Trichoderma harzianum and Penicillium
      purpurogenum alpha1,3-glucanases (mutanases) have homologous primary structures
      (53% amino acid sequence identity), and are composed of two distinct domains: a
      NH(2)-terminal catalytic domain and a putative COOH-terminal polysaccharide
      binding domain separated by a O-glycosylated Pro-Ser-Thr-rich linker peptide.
      Each mutanase was expressed in Aspergillus oryzae host under the transcriptional
      control of a strong alpha-amylase gene promoter. The purified recombinant
      mutanases show a pH optimum in the range from pH 3.5 to 4.5 and a temperature
      optimum around 50-55 degrees C at pH 5.5. Also, they exhibit strong binding to
      insoluble mutan with K(D) around 0.11 and 0.13 microM at pH 7 for the P.
      purpurogenum and T. harzianum mutanases, respectively. Partial hydrolysis showed
      that the COOH-terminal domain of the T. harzianum mutanase binds to mutan. The
      catalytic domains and the binding domains were assigned to a new family of
      glycoside hydrolases and to a new family of carbohydrate-binding domains,
      respectively.

PMID- 10636905
TI  - Entrance port for Na(+) and K(+) ions on Na(+),K(+)-ATPase in the cytoplasmic
      loop between trans-membrane segments M6 and M7 of the alpha subunit. Proximity Of
      the cytoplasmic segment of the beta subunit.
AB  - Based on the following observations we propose that the cytoplasmic loop between
      trans-membrane segments M6 and M7 (L6/7) of the alpha subunit of Na(+),K(+)
      ATPase acts as an entrance port for Na(+) and K(+) ions. 1) In defined conditions
      chymotrypsin specifically cleaves L6/7 in the M5/M6 fragment of 19-kDa membranes,
      produced by extensive proteolysis of Na(+),K(+)-ATPase, and in parallel
      inactivates Rb(+) occlusion. 2) Dissociation of the M5/M6 fragment from 19-kDa
      membranes is prevented either by occluded cations or by competitive antagonists
      such as Ca(2+), Mg(2+), La(3+), p-xylylene bisguanidinium and m-xylylene
      bisguanidinium, or 1-bromo-2,4, 6-tris(methylisothiouronium)benzene and 1,3
      dibromo-2,4,6-tris (methylisothiouronium)benzene (Br(2)-TITU(3+)). 3) Ca(2+) ions
      raise electrophoretic mobility of the M5/M6 fragment but not that of the other
      fragments of the alpha subunit. It appears that negatively charged residues in
      L6/7 recognize either Na(+) or K(+) ions or the competitive cation antagonists.
      Na(+) and K(+) ions are then occluded within trans-membrane segments and can be
      transported, whereas the cation antagonists are not occluded and block transport
      at the entrance port. The cytoplasmic segment of the beta subunit appears to be
      close to or contributes to the entrance port, as inferred from the following
      observations. 1) Specific chymotryptic cleavage of the 16-kDa fragment of the
      beta subunit to 15-kDa at 20 degrees C (Shainskaya, A., and Karlish, S. J. D.
      (1996) J. Biol. Chem. 271, 10309-10316) markedly reduces affinity for Br(2)
      TITU(3+) and for Na(+) ions, detected by Na(+) occlusion assays or electrogenic
      Na(+) binding, whereas Rb(+) occlusion is unchanged. 2) Na(+) ions specifically
      protect the 16-kDa fragment against this chymotryptic cleavage.

PMID- 10636907
TI  - Ribosome-independent regulation of translocon composition and Sec61alpha
      conformation.
AB  - In this study, the contributions of membrane-bound ribosomes to the regulation of
      endoplasmic reticulum translocon composition and Sec61alpha conformation were
      examined. Following solubilization of rough microsomes (RM) with digitonin,
      ribosomes co-sedimented in complexes containing the translocon proteins
      Sec61alpha, ribophorin I, and TRAPalpha, and endoplasmic reticulum phospholipids.
      Complexes of similar composition were identified in digitonin extracts of
      ribosome-free membranes, indicating that the ribosome does not define the
      composition of the digitonin-soluble translocon. Whereas in digitonin solution a
      highly electrostatic ribosome-translocon junction is observed, no stable
      interactions between ribosomes and Sec61alpha, ribophorin I, or TRAPalpha were
      observed following solubilization of RM with lipid-derived detergents at
      physiological salt concentrations. Sec61alpha was found to exist in at least two
      conformational states, as defined by mild proteolysis. A protease-resistant form
      was observed in RM and detergent-solubilized RM. Removal of peripheral proteins
      and ribosomes markedly enhanced the sensitivity of Sec61alpha to proteolysis, yet
      the readdition of inactive ribosomes to salt-washed membranes yielded only modest
      reductions in protease sensitivity. Addition of sublytic concentrations of
      detergents to salt-washed RM markedly decreased the protease sensitivity of
      Sec61alpha, indicating that a protease-resistant conformation of Sec61alpha can
      be conferred in a ribosome-independent manner.

PMID- 10636906
TI  - Pantophysin is a phosphoprotein component of adipocyte transport vesicles and
      associates with GLUT4-containing vesicles.
AB  - Pantophysin, a protein related to the neuroendocrine-specific synaptophysin,
      recently has been identified in non-neuronal tissues. In the present study,
      Northern blots showed that pantophysin mRNA was abundant in adipose tissue and
      increased during adipogenesis of 3T3-L1 cells. Immunoblot analysis of subcellular
      fractions showed pantophysin present exclusively in membrane fractions and
      relatively evenly distributed in the plasma membrane and internal membrane
      fractions. Sucrose gradient ultracentrifugation demonstrated that pantophysin and
      GLUT4 exhibited overlapping distribution profiles. Furthermore, immunopurified
      GLUT4 vesicles contained pantophysin, and both GLUT4 and pantophysin were
      depleted from this vesicle population following treatment with insulin.
      Additionally, a subpopulation of immunopurified pantophysin vesicles contained
      insulin-responsive GLUT4. Consistent with the interaction of synaptophysin with
      vesicle-associated membrane protein 2 in neuroendocrine tissues, pantophysin
      associated with vesicle-associated membrane protein 2 in adipocytes. Furthermore,
      in [(32)P]orthophosphate-labeled cells, pantophysin was phosphorylated in the
      basal state. This phosphorylation was unchanged in response to insulin; however,
      insulin stimulated the phosphorylation of a 77-kDa protein associated with alpha
      pantophysin immunoprecipitates. Although the functional role of pantophysin in
      vesicle trafficking is unclear, its presence on GLUT4 vesicles is consistent with
      the emerging role of soluble N-ethylmaleimide-sensitive protein receptor (SNARE)
      factor complex and related proteins in regulated vesicle transport in adipocytes.
      In addition, pantophysin may provide a marker for the analysis of other vesicles
      in adipocytes.

PMID- 10636908
TI  - Identification of cis-elements regulating exon 15 splicing of the amyloid
      precursor protein pre-mRNA.
AB  - Alternative splicing of exon 15 of the amyloid precursor protein (APP) pre-mRNA
      generates two APP isoform groups APP(ex15) (containing exon 15) and L-APP
      (without exon 15), which show a cell-specific distribution in non-neuronal cells
      and neurons of rat. Both APP isoforms differ in regard to functional properties
      like post-translational modification, APP secretion, and proteolytic production
      of Abeta peptide from APP molecules. Since Abeta generation is an important
      factor in the development of Alzheimer's disease, one could anticipate that these
      major APP isoforms might contribute differentially to the mechanisms underlying
      neurodegeneration in Alzheimer's disease. In this study, we established an APP
      minigene system in a murine cell system to identify cis-acting elements
      controlling exon 15 recognition. A 12. 5-kilobase pair genomic fragment of the
      murine APP gene contained all cis-regulatory elements to reproduce the splicing
      pattern of the endogenous APP transcripts. By using this approach, two intronic
      cis-elements flanking exon 15 were identified that block the inclusion of exon 15
      in APP transcripts of non-neuronal cells. Point mutation analysis of these
      intronic regions indicated that pyrimidine-rich sequences are involved in the
      splice repressor function. Finally, grafting experiments demonstrated that these
      regulatory regions cell-specifically enhance the blockage of a chimeric exon in
      the non-neuronal splicing system.

PMID- 10636909
TI  - Palmitoylation targets CD39/endothelial ATP diphosphohydrolase to caveolae.
AB  - Ectonucleotidases influence purinergic receptor function by the hydrolysis of
      extracellular nucleotides. CD39 is an integral membrane protein that is a
      prototype member of the nucleoside 5'-triphosphate diphosphohydrolase family. The
      native CD39 protein has two intracytoplasmic and two transmembrane domains. There
      is a large extracellular domain that undergoes extensive glycosylation and can be
      post-translationally modified by limited proteolysis. We have identified a
      potential thioester linkage site for S-acylation within the N-terminal region of
      CD39 and demonstrate that this region undergoes palmitoylation in a constitutive
      manner. The covalent lipid modification of this region of the protein appears to
      be important both in plasma membrane association and in targeting CD39 to
      caveolae. These specialized plasmalemmal domains are enriched in G protein
      coupled receptors and appear to integrate cellular activation events. We suggest
      that palmitoylation could modulate the function of CD39 in regulating cellular
      signal transduction pathways.

PMID- 10636910
TI  - Targeted disruption in murine cells reveals variable requirement for Smad4 in
      transforming growth factor beta-related signaling.
AB  - The tumor suppressor gene Smad4 has been proposed to be a common mediator of
      transforming growth factor beta (TGFbeta)-related signaling pathways. We
      investigated the role of Smad4 in TGFbeta-related pathways by targeted disruption
      of its locus in murine cell lines. TGFbeta responses, including growth arrest,
      induction of the endogenous PAI-1 gene, and other extracellular matrix
      components, were normal in Smad4-deficient fibroblasts. Assembly of a TGFbeta
      induced DNA-binding complex on one of two regulatory regions in the human
      plasminogen activator inhibitor (PAI)-1 promoter did not require Smad4 but was,
      instead, dependent on a TFE-3 binding site. In contrast, Smad4 was required for
      activation of the Xenopus Mix.2 promoter in response to TGFbeta/activin. Smad4
      was also involved in the regulation of the Msx homeobox protein family members in
      response to bone morphogenetic protein (BMP). Interestingly, the expression of
      the endogenous Msx-2 was reduced, whereas that of Msx-3 was activated in
      differentiating Smad4(-/-) ES cells relative to wild-type cells. Moreover,
      reporter assays of the Msx-2 promoter revealed an absolute requirement for Smad4
      in fibroblasts and ES cells for activation. Our results indicate that Smad4 is
      dispensable for critical TGFbeta-induced responses but is required for others in
      murine fibroblasts. We have identified transcriptional targets for Smad4 in the
      BMP signaling pathway, which may contribute to the genetic defect observed in the
      Smad4-deficient embryos.

PMID- 10636911
TI  - Lipopolysaccharide-activated kinase, an essential component for the induction of
      the antimicrobial peptide genes in Drosophila melanogaster cells.
AB  - Eukaryotic organisms use a similar Rel/NF-kappaB signaling cascade for the
      induction of innate immune genes. In Drosophila, lipopolysaccharide (LPS) signal
      induced activation of the Rel/NF-kappaB family transcription factors is an
      essential step in the transcriptional activation of inducible antimicrobial
      peptide genes. However, the mechanism by which the LPS-induced signaling pathway
      proceeds remains largely unknown. Here we have cloned a novel Drosophila LPS
      activated kinase (DLAK) that is structurally related to mammalian IkappaB
      kinases. DLAK is expressed and transiently activated in LPS-responsive Drosophila
      cells following LPS stimulation. Furthermore, DLAK can interact with Cactus, a
      Drosophila IkappaB and phosphorylate recombinant Cactus, in vitro. Overexpression
      of dominant-negative mutant DLAK (DLAK(K50A)) blocks LPS-induced Cactus
      degradation. DLAK-bound Cactus can be degraded in a LPS signal-dependent fashion,
      whereas the DLAK(K50A) mutant-bound Cactus is completely resistant to degradation
      in the presence of LPS. The DLAK(K50A) mutant also inhibits nuclear kappaB
      binding activity and kappaB-dependent diptericin reporter gene activity in a dose
      dependent manner, but the kappaB-dependent diptericin reporter gene activity can
      be rescued by overexpression of wild type DLAK. Moreover, mRNA analysis of
      various kappaB-dependent antimicrobial peptide genes shows that LPS inducibility
      of these genes is greatly impaired in cells overexpressing DLAK(K50A). These
      results establish that DLAK is a novel LPS-activated kinase, which is an
      essential signaling component for the induction of antimicrobial peptide genes
      following LPS treatment in Drosophila cells.

PMID- 10636912
TI  - Mutation in the magnesium binding site of hMSH6 disables the hMutSalpha sliding
      clamp from translocating along DNA.
AB  - In human cells, binding of base/base mismatches and small insertion/deletion
      loops is mediated by hMutSalpha, a heterodimer of hMSH2 and hMSH6. In the
      presence of ATP and magnesium, hMutSalpha dissociates from the mismatch by
      following the DNA contour in the form of a sliding clamp. This process is enabled
      by a conformational change of the heterodimer, which is driven by the binding of
      ATP and magnesium in the Walker type A and B motifs of the polypeptides,
      respectively. We show that a purified recombinant hMutSalpha variant, hMutSalpha
      6DV, which contains an aspartate to valine substitution in the Walker type B
      motif of the hMSH6 subunit, fails to undergo the conformational change compatible
      with translocation. Instead, its direct dissociation from the mismatch-containing
      DNA substrate in the presence of ATP and magnesium precludes the assembly of a
      functional mismatch repair complex. The "translocation-prone" conformation of
      wild type hMutSalpha could be observed solely under conditions that favor
      hydrolysis of the nucleotide and mismatch repair in vitro. Thus, whereas
      magnesium could be substituted with manganese, ATP could not be replaced with its
      slowly or nonhydrolyzable homologues ATP-gammaS or AMPPNP, respectively. The
      finding that ATP induces different conformational changes in hMutSalpha in the
      presence and in the absence of magnesium helps explain the functional differences
      between hMutSalpha variants incapable of binding ATP as compared with those
      unable to bind the metal ion.

PMID- 10636913
TI  - Constitutively active mutants of the alpha(1a)- and the alpha(1b)-adrenergic
      receptor subtypes reveal coupling to different signaling pathways and
      physiological responses in rat cardiac myocytes.
AB  - Activation of alpha(1)-adrenergic receptors influences both the contractile
      activity and the growth potential of cardiac myocytes. However, the signaling
      pathways linking activation of specific alpha(1)-adrenergic receptor (AR)
      subtypes to these physiological responses remain controversial. In the present
      study, a molecular approach was used to identify conclusively the signaling
      pathways activated in response to the individual alpha(1A)- and alpha(1B)-AR
      subtypes in cardiac myocytes. For this purpose, a mutant alpha(1a)-AR subtype
      (alpha(1a)-S(290/293)-AR) was constructed based on analogy to the previously
      described constitutively active mutant alpha(1b)-AR subtype (alpha(1b)-S(288-294)
      AR). The mutant alpha(1a)-S(290/293)-AR subtype displayed constitutive activity
      based on four criteria. To introduce the constitutively active alpha(1)-AR
      subtypes into cardiac myocytes, recombinant Sindbis viruses encoding either the
      alpha(1a)-S(290/293)-AR or alpha(1b)-S(288-294)-AR subtype were used to infect
      the whole cell population with >90% efficiency, thereby allowing the biochemical
      activities of the various signaling pathways to be measured. When expressed at
      comparable levels, the alpha(1a)-S(290/293)-AR subtype exhibited a significantly
      elevated basal level as well as agonist-stimulated level of inositol phosphate
      accumulation, coincident with activation of atrial natriuretic factor-luciferase
      gene expression. By contrast, the alpha(1b)-S(288-294)-AR subtype displayed a
      markedly increased serum response element-luciferase gene expression but no
      activation of atrial natriuretic factor-luciferase gene expression. Taken
      together, this study provides the first molecular evidence for coupling of the
      alpha(1a)-AR and the alpha(1b)-AR subtypes to different signaling pathways in
      cardiac myocytes.

PMID- 10636914
TI  - G protein betagamma subunits induce stress fiber formation and focal adhesion
      assembly in a Rho-dependent manner in HeLa cells.
AB  - In fibroblasts, the G protein alpha subunits Galpha(12) and Galpha(13) stimulate
      Rho-dependent stress fiber formation and focal adhesion assembly, whereas G
      protein betagamma subunits instead exert a disruptive influence. We show here
      that the latter can, however, stimulate the formation of stress fibers and focal
      adhesions in epithelial-like HeLa cells. Transient expression of beta(1) with
      gamma(2), gamma(5), gamma(7), and gamma(12) in quiescent HeLa cells induced
      stress fiber formation and focal adhesion assembly as did expression of the
      constitutively active Galpha(12). Co-expression of betagamma with Galpha(i2) and
      the C-terminal fragment of the beta-adrenergic receptor kinase, both of which are
      known to bind and sequester free betagamma, blocked betagamma-induced stress
      fiber and focal adhesion formation. Inhibition was also noted with co-expression
      of a dominant negative mutant of Rho. Botulinum C3 exoenzyme, which ADP
      ribosylates and inactivates Rho, and a Rho-associated protein kinase inhibitor, Y
      27632, similarly inhibited betagamma-induced stress fiber and focal adhesion
      assembly. These results indicate that G protein betagamma subunits regulate Rho
      dependent actin polymerization in HeLa cells.

PMID- 10636915
TI  - Janus kinase 2-dependent activation of p38 mitogen-activated protein kinase by
      growth hormone. Resultant transcriptional activation of ATF-2 and CHOP,
      cytoskeletal re-organization and mitogenesis.
AB  - We demonstrate here that p38 mitogen-activated protein (MAP) kinase is activated
      in response to cellular stimulation by human GH (hGH) in Chinese hamster ovary
      cells stably transfected with GH receptor cDNA. This activation requires the
      proline-rich box 1 region of the GH receptor required for JAK2 association and is
      prevented by pretreatment of cells with the JAK2-specific inhibitor AG490. ATF-2
      is both phosphorylated and transcriptionally activated by hGH, and its
      transcriptional activation also requires the proline-rich box 1 region of the GH
      receptor. Expression of wild type JAK2 can further enhance hGH-induced ATF-2-,
      CHOP-, and Elk-1-mediated transcriptional activation, whereas pretreatment with
      AG490 is inhibitory. Use of either specific pharmacological inhibitors or
      transient transfection of cells with p38alpha MAP kinase cDNA or a dominant
      negative variant demonstrated that hGH-stimulated transcriptional activation of
      ATF-2 and CHOP, but not Elk-1, is regulated by p38 MAP kinase. Both the p38 MAP
      kinase and p44/42 MAP kinase are critical for hGH-stimulated mitogenesis, whereas
      only p38 MAP kinase is required for hGH-induced actin cytoskeletal re
      organization. p38 MAP kinase is therefore an important regulator in coordinating
      the pleiotropic effects of GH.

PMID- 10636916
TI  - The Smad4 activation domain (SAD) is a proline-rich, p300-dependent
      transcriptional activation domain.
AB  - Transforming growth factor-beta (TGF-beta) family members signal through a unique
      set of intracellular proteins called Smads. Smad4, previously identified as the
      tumor suppressor DPC4, is functionally distinct among the Smad family, and is
      required for the assembly and transcriptional activation of diverse, Smad-DNA
      complexes. We previously identified a 48-amino acid proline-rich regulatory
      element within the middle linker domain of this molecule, the Smad4 activation
      domain (SAD), which is essential for mediating these signaling activities. We now
      characterize the functional activity of the SAD. Mutants lacking the SAD are
      still able to form complexes with other Smad family members and associated
      transcription factors, but cannot activate transcription in these complexes.
      Furthermore, the SAD itself is able to activate transcription in heterologous
      reporter assays, identifying it as a proline-rich transcriptional activation
      domain, and indicating that the SAD is both necessary and sufficient to activate
      Smad-dependent transcriptional responses. We show that transcriptional activation
      by the SAD is p300-dependent, and demonstrate that this activity is associated
      with a physical interaction of the SAD with the amino terminus of p300. These
      data identify a novel function of the middle linker region of Smad4, and define
      the role of the SAD as an important locus determining the transcriptional
      activation of the Smad complex.

PMID- 10636917
TI  - Identification in vitreous and molecular cloning of opticin, a novel member of
      the family of leucine-rich repeat proteins of the extracellular matrix.
AB  - A prominent 45-kDa component was identified by protein staining following SDS
      polyacrylamide gel electrophoresis of a 4 M guanidine hydrochloride extract from
      bovine vitreous collagen fibrils. Peptide sequences obtained from this component
      were used as a basis for the cloning (from human retinal cDNA) and sequencing of
      a novel member of the leucine-rich repeat extracellular matrix protein family
      that we have named opticin. Opticin mRNA was found by reverse transcription
      polymerase chain reaction in ligament and skin as well as in retina. An open
      reading frame containing 332 amino acids was identified, the first 19 amino acids
      representing a signal peptide. The deduced amino acid sequence of the mature
      protein encodes a 35-kDa protein with a calculated isoelectric point of 5.4. The
      central domain of this protein consists of six B-type leucine-rich repeats. This
      domain is flanked by cysteine clusters including a C-terminal two-cysteine
      cluster containing an additional leucine-rich repeat. The N-terminal region
      contains a cluster of potential O-glycosylation sites, and analysis of bovine
      vitreous opticin demonstrated the presence of sialylated O-linked
      oligosaccharides substituting the core protein. Opticin shows highest protein
      sequence identity to epiphycan (42%) and osteoglycin (35%) and belongs to Class
      III of the leucine-rich repeat extracellular matrix protein family.

PMID- 10636918
TI  - The RNA interacting domain but not the protein interacting domain is highly
      conserved in ribosomal protein P0.
AB  - Protein P0 interacts with proteins P1alpha, P1beta, P2alpha, and P2beta, and
      forms the Saccharomyces cerevisiae ribosomal stalk. The capacity of RPP0 genes
      from Aspergillus fumigatus, Dictyostelium discoideum, Rattus norvegicus, Homo
      sapiens, and Leishmania infantum to complement the absence of the homologous gene
      has been tested. In S. cerevisiae W303dGP0, a strain containing standard amounts
      of the four P1/P2 protein types, all heterologous genes were functional except
      the one from L. infantum, some of them inducing an osmosensitive phenotype at 37
      degrees C. The polymerizing activity and the elongation factor-dependent
      functions but not the peptide bond formation capacity is affected in the
      heterologous P0 containing ribosomes. The heterologous P0 proteins bind to the
      yeast ribosomes but the composition of the ribosomal stalk is altered. Only
      proteins P1alpha and P2beta are found in ribosomes carrying the A. fumigatus, R.
      norvegicus, and H. sapiens proteins. When the heterologous genes are expressed in
      a conditional null-P0 mutant whose ribosomes are totally deprived of P1/P2
      proteins, none of the heterologous P0 proteins complemented the conditional
      phenotype. In contrast, chimeric P0 proteins made of different amino-terminal
      fragments from mammalian origin and the complementary carboxyl-terminal fragments
      from yeast allow W303dGP0 and D67dGP0 growth at restrictive conditions. These
      results indicate that while the P0 protein RNA-binding domain is functionally
      conserved in eukaryotes, the regions involved in protein-protein interactions
      with either the other stalk proteins or the elongation factors have notably
      evolved.

PMID- 10636919
TI  - A novel mechanism of cell killing by anti-topoisomerase II bisdioxopiperazines.
AB  - Bisdioxopiperazines are a unique class of topoisomerase II inhibitors that lock
      topoisomerase II at a point in the enzyme reaction cycle where the enzyme forms a
      closed clamp around DNA. We examined cell killing by ICRF-187 and ICRF-193 in
      yeast cells expressing human topoisomerase II alpha (htop-IIalpha). Expression of
      htop-IIalpha in yeast cells sensitizes them to both ICRF-187 and ICRF-193,
      compared with cells expressing yeast topoisomerase II. ICRF-193 is still able to
      exert growth inhibition in the presence of genes encoding both ICRF-193-resistant
      and ICRF-193-sensitive htop-IIalpha enzymes, indicating that sensitivity to
      bisdioxopiperazines is dominant. Killing by ICRF-193 occurs more rapidly, than
      the killing in yeast cells due to a temperature-sensitive yeast topoisomerase II
      incubated at the non-permissive temperature. These results are reminiscent of a
      top-II poison such as etoposide. However, the killing caused by ICRF-193 and ICRF
      187 is not enhanced by mutations in the RAD52 pathway. The levels of drug-induced
      DNA cleavage observed with htop-IIalpha in vitro is insufficient to explain the
      sensitivity induced by this enzyme in yeast cells. Finally, arrest of cells in
      G(1) does not protect cells from ICRF-193 lethality, a result inconsistent with
      killing mechanisms due to catalytic inhibition of top-II or stabilization of a
      cleavable complex. We suggest that the observed pattern of cell killing is most
      consistent with a poisoning of htop-II by ICRF-193 by a novel mechanism. The
      accumulation of closed clamp conformations of htop-II induced by ICRF-193 that
      are trapped on DNA might interfere with transcription, or other DNA metabolic
      processes, resulting in cell death.

PMID- 10636920
TI  - Activation of the Stat3 signaling pathway is required for differentiation by
      interleukin-6 in PC12-E2 cells.
AB  - The role of signal transducer and activator of transcription (STAT) signaling
      pathways in the interleukin-6 (IL-6)-induced morphological differentiation of
      PC12-E2 cells was assessed using wild type and dominant negative mutants of Stat1
      and Stat3, containing Tyr --> Phe (YF), Ser --> Ala (SA), and the double
      mutations (DM), respectively. FS3-YF or FS3-DM markedly inhibited the IL-6
      induced response, but overexpression of FS3-SA caused only a modest inhibition.
      Expression of all Stat3 mutants had no effect on NGF-induced neurite outgrowth.
      Overexpression of wild type Stat1 protein inhibited IL-6 activated DNA binding
      complexes containing Stat3 homodimers, which may explain the partial negative
      effect of Stat1 on IL-6-induced neurite outgrowth. Specificity of these STAT
      constructs was confirmed using luciferase reporter gene assays, which showed that
      IL-6-activated transcription was blocked by expression of FS3-YF and FS3-DM and
      that FS1 enhanced the interferon gamma-activated transcription. Thus, in PC12-E2
      cells, Stat3 homodimers are preferentially activated by IL-6, indicating a role
      for Stat3 in the regulation of cellular differentiation. Furthermore, IL-6
      induced robust neurite outgrowth in PC12-E2 cells expressing dominant negative
      forms of RAS or SHC or in cells pretreated with the mitogen-activated protein
      kinase mitogen-activated protein kinase kinase inhibitor, PD98059. Thus,
      activation of the Stat3 signaling pathway, but not RAS/ERK dependent pathways, is
      essential for differentiation of PC12-E2 cells by IL-6.

PMID- 10636921
TI  - Activation of protein kinase D by signaling through the alpha subunit of the
      heterotrimeric G protein G(q).
AB  - Protein kinase D (PKD/PKCmu) immunoprecipitated from COS-7 cells transiently
      transfected with a constitutively active alpha subunit of G(q) (Galpha(q)Q209L)
      exhibited a marked increase in basal activity, which was not further enhanced by
      treatment of the cells with phorbol 12,13-dibutyrate. In contrast, transient
      transfection of COS-7 cells with activated Galpha(12)Q229L or Galpha(13)Q226L
      neither promoted PKD activation nor interfered with the increase of PKD activity
      induced by phorbol 12,13-dibutyrate. The addition of aluminum fluoride to cells
      co-transfected with PKD and wild type Galpha(q) induced a marked increase in PKD
      activity, which was comparable with that induced by expression of Galpha(q)Q209L.
      Treatment with the protein kinase C inhibitor GF I or Ro 31-8220 prevented the
      increase in PKD activity induced by aluminum fluoride. Expression of a COOH
      terminal fragment of Galpha(q) that acts in a dominant negative fashion
      attenuated PKD activation in response to agonist stimulation of bombesin
      receptor. PKD activation in response to either Galpha(q) or bombesin was
      completely prevented by mutation of Ser(744) and Ser(748) to Ala in the kinase
      activation loop of PKD. Our results show that Galpha(q) activation is sufficient
      to stimulate sustained PKD activation via protein kinase C and indicate that the
      endogenous Galpha(q) mediates PKD activation in response to acute bombesin
      receptor stimulation.

PMID- 10636922
TI  - Determinants of the peptide-induced conformational change in the human class II
      major histocompatibility complex protein HLA-DR1.
AB  - The human class II major histocompatibility complex protein HLA-DR1 has been
      shown previously to undergo a distinct conformational change from an open to a
      compact form upon binding peptide. To investigate the role of peptide in
      triggering the conformational change, the minimal requirements for inducing the
      compact conformation were determined. Peptides as short as two and four residues,
      which occupy only a small fraction of the peptide-binding cleft, were able to
      induce the conformational change. A mutant HLA-DR1 protein with a substitution in
      the beta subunit designed to fill the P1 pocket from within the protein (Gly(86)
      to Tyr) adopted to a large extent the compact, peptide-bound conformation.
      Interactions important in stabilizing the compact conformation are shown to be
      distinct from those responsible for high affinity binding or for stabilization of
      the complex against thermal denaturation. The results suggest that occupancy of
      the P1 pocket is responsible for partial conversion to the compact form but that
      both side chain and main chain interactions contribute to the full conformational
      change. The implications of the conformational change to intracellular antigen
      loading and presentation are discussed.

PMID- 10636923
TI  - DNA polymerase III proofreading mutants enhance the expansion and deletion of
      triplet repeat sequences in Escherichia coli.
AB  - The influence of mutations in the 3' to 5' exonucleolytic proofreading epsilon
      subunit of Escherichia coli DNA polymerase III on the genetic instabilities of
      the CGG.CCG and the CTG.CAG repeats that cause human hereditary neurological
      diseases was investigated. The dnaQ49(ts) and the mutD5 mutations destabilize the
      CGG.CCG repeats. The distributions of the deletion products indicate that slipped
      structures containing a small number of repeats in the loop mediate the deletion
      process. The CTG.CAG repeats were destabilized by the dnaQ49(ts) mutation by a
      process mediated by long hairpin loop structures (>/=5 repeats). The mutD5
      mutator strain stabilized the (CTG.CAG)(175) tract, which contained two
      interruptions. Since the mutD5 mutator strain has a saturated mismatch repair
      system, the stabilization is probably an indirect effect of the nonfunctional
      mismatch repair system in these strains. Shorter uninterrupted tracts expand
      readily in the mutD5 strain, presumably due to the greater stability of long
      CTG.CAG tracts (>100 repeats) in this strain. When parallel studies were
      conducted in minimal medium, where the mutD5 strain is defective in
      exonucleolytic proofreading but has a functional MMR system, both CTG.CAG and
      CGG.CCG repeats were destabilized, showing that the proofreading activity is
      essential for maintaining the integrity of TRS tracts. Thus, we conclude that the
      expansion and deletion of triplet repeats are enhanced by mutations that reduce
      the fidelity of replication.

PMID- 10636924
TI  - A guanine nucleotide exchange factor-independent function of Vav1 in
      transcriptional activation.
AB  - T cell antigen receptor (TCR) stimulation induces the tyrosine phosphorylation of
      several intracellular proteins including the protooncogene Vav1. Vav1 expression
      is necessary for normal T cell development and activation. We previously showed
      that overexpression of Vav1 in Jurkat T cells potentiates the activity of the
      transcription factor nuclear factor of activated T cells (NF-AT). The mechanism
      by which Vav1 participates in TCR signaling events is not clear. Vav1 contains a
      guanine nucleotide exchange factor (GEF) domain that has specificity for Rac and
      other Rho GTPases that have been recently implicated in T cell activation events.
      Significantly, in vitro tyrosine phosphoryation of Vav1 by Lck activates its
      exchange activity. This Lck-mediated phosphorylation of Vav1 has been reported to
      depend upon Tyr-174 in Vav1, a site implicated in Vav1 function by other studies
      as well. In this report, we demonstrated that Tyr-174 is not required for the TCR
      induced phosphorylation of Vav1 in vivo. Moreover, mutation of Tyr-174 augmented
      the ability of Vav1 to up-regulate NF-AT activation as well as the Vav1 GEF
      function leading to Rac activation. However, we also showed that the GEF activity
      of Vav1 was neither sufficient nor necessary for potentiation of NF-AT, and
      thereby we identify a GEF-independent role of Vav1 in potentiating NF-AT-driven
      transcription. Oncogenic Vav1 in which the amino-terminal 67 amino acids were
      deleted had elevated GEF activity but did not potentiate NF-AT when overexpressed
      in Jurkat cells. We also showed that a GEF mutant form of Vav1 that had impaired
      GEF function could still potentiate NF-AT. These studies reveal a previously
      unrecognized negative regulatory function of Tyr-174 in Vav1 and suggest that
      domains other than the Vav1 GEF domain contribute to TCR signals leading to NF-AT
      activation.

PMID- 10636925
TI  - Lipid-dependent targeting of G proteins into rafts.
AB  - Domains rich in sphingolipids and cholesterol, or rafts, may organize signal
      transduction complexes at the plasma membrane. Raft lipids are believed to exist
      in a state similar to the liquid-ordered phase. It has been proposed that
      proteins with a high affinity for an ordered lipid environment will
      preferentially partition into rafts (Melkonian, K. A., Ostermeyer, A. G., Chen,
      J. Z., Roth, M. G., and Brown, D. A. (1999) J. Biol. Chem. 274, 3910-3917). We
      investigated the possibility that lipid-lipid interactions between lipid-modified
      proteins and raft lipids mediate targeting of proteins to these domains. G
      protein monomers or trimers were reconstituted in liposomes, engineered to mimic
      raft domains. Assay for partitioning of G proteins into rafts was based on Triton
      X-100 insolubility. Myristoylation and palmitoylation of Galpha(i) were necessary
      and sufficient for association with liposomes and partitioning into rafts.
      Strikingly, the amount of fatty-acylated Galpha(i) in rafts was significantly
      reduced when myristoylated Galpha(i) was thioacylated with cis-unsaturated fatty
      acids instead of saturated fatty acids such as palmitate. Prenylated betagamma
      subunits were excluded from rafts, whether reconstituted alone or with fatty
      acylated alpha subunits. These results suggest that the structural difference
      between lipids that modify proteins is one basis for the selectivity of protein
      targeting to rafts.

PMID- 10636926
TI  - Transcription factor BETA2 acts cooperatively with E2A and PDX1 to activate the
      insulin gene promoter.
AB  - The insulin gene is efficiently expressed only in pancreatic beta cells. Using
      reverse transcriptase-polymerase chain reaction analysis, we show that insulin
      mRNA levels are at least 10(5)-fold higher in beta cells than non-beta cells. To
      examine the underlying mechanisms, we expressed beta cell transcription factors
      by transfection of non-beta cells. Separate expression of BETA2, E2A, or PDX1 led
      to modest (<10-fold) activation of the insulin promoter, whereas co-expression of
      the three proteins produced synergistic, high level activation (160-fold). This
      level of activity is approximately 25% that observed in transfected beta cell
      lines. Of the three factors studied, BETA2 appears to play a dominant role.
      Efficient transcription required a C-terminal activation domain of BETA2 and an N
      terminal region, which does not function as an independent activation domain. The
      myogenic basic helix-loop-helix (bHLH) protein MyoD was unable to bind and
      activate the promoter, even when its DNA binding region was replaced with that of
      BETA2. Our results demonstrate the central importance of BETA2 in insulin gene
      transcription and the importance of sequences outside the canonical DNA binding
      domain in permitting efficient DNA binding and cell-specific activity of the
      insulin gene promoter.

PMID- 10636927
TI  - Initial steps in assembly of microfibrils. Formation of disulfide-cross-linked
      multimers containing fibrillin-1.
AB  - Fibrillins are the major constituents of extracellular microfibrils. How
      fibrillin molecules assemble into microfibrils is not known. Sequential
      extractions and pulse-chase labeling of organ cultures of embryonic chick aortae
      revealed rapid formation of disulfide-cross-linked aggregates containing
      fibrillin-1. These results demonstrated that intermolecular disulfide bond
      formation is an initial step in the assembly process. To identify free cysteine
      residues available for intermolecular cross-linking, small recombinant peptides
      of fibrillin-1 harboring candidate cysteine residues were analyzed. Results
      revealed that the first four cysteine residues in the unique N terminus form
      intramolecular disulfide bonds. One cysteine residue (Cys(204)) in the first
      hybrid domain of fibrillin-1 was found to occur as a free thiol and is therefore
      a good candidate for intermolecular disulfide bonding in initial steps of the
      assembly process. Furthermore, evidence indicated that the comparable cysteine
      residue in fibrillin-2 (Cys(233)) also occurs as a free thiol. These free
      cysteine residues in fibrillins are readily available for intermolecular
      disulfide bond formation, as determined by reaction with Ellman's reagent. In
      addition to these major results, the cleavage site of the fibrillin-1 signal
      peptide and the N-terminal sequence of monomeric authentic fibrillin-1 from
      conditioned fibroblast medium were determined.

PMID- 10636928
TI  - Protection against methylation-induced cytotoxicity by DNA polymerase beta
      dependent long patch base excision repair.
AB  - Using a plasmid-based uracil-containing DNA substrate, we found that the long
      patch base excision repair (BER) activity of a wild-type mouse fibroblast extract
      was partially inhibited by an antibody to DNA polymerase beta (beta-pol). This
      suggests that beta-pol participates in long patch BER, in addition to single
      nucleotide BER. In single-nucleotide BER, the deoxyribose phosphate (dRP) in the
      abasic site is removed by the lyase activity of beta-pol. Methoxyamine (MX) can
      react with the aldehyde of an abasic site, making it refractory to the beta
      elimination step of the dRP lyase mechanism, thus blocking single-nucleotide BER.
      MX exposure sensitizes wild-type, but not beta-pol null mouse embryonic
      fibroblasts, to the cytotoxic effects of methyl methanesulfonate (MMS) and
      methylnitrosourea. Expression of beta-pol in the null cells restores the ability
      of MX to modulate sensitivity to MMS. The beta-pol null cells are known to be
      hypersensitive to MMS and methylnitrosourea, and in the presence of MX (i.e.
      under conditions where single-nucleotide BER is blocked) the null cells are still
      considerably more sensitive than wild-type. The data are consistent with a role
      of beta-pol in long patch BER, which helps protect cells against methylation
      damage-induced cytotoxicity.

PMID- 10636929
TI  - Biochemical interactions integrating Itk with the T cell receptor-initiated
      signaling cascade.
AB  - Itk, a Tec family tyrosine kinase, acts downstream of Lck and
      phosphatidylinositol 3'-kinase to facilitate T cell receptor (TCR)-dependent
      calcium influxes and increases in extracellular-regulated kinase activity. Here
      we demonstrate interactions between Itk and crucial components of TCR-dependent
      signaling pathways. First, the inositide-binding pocket of the Itk pleckstrin
      homology domain directs the constitutive association of Itk with buoyant
      membranes that are the primary site of TCR activation and are enriched in both
      Lck and LAT. This association is required for the transphosphorylation of Itk.
      Second, the Itk proline-rich region binds to Grb2 and LAT. Third, the Itk Src
      homology (SH3) 3 and SH2 domains interact cooperatively with Syk-phosphorylated
      SLP-76. Notably, SLP-76 contains a predicted binding motif for the Itk SH2 domain
      and binds to full-length Itk in vitro. Finally, we show that kinase-inactive Itk
      can antagonize the SLP-76-dependent activation of NF-AT. The inhibition of NF-AT
      activation depends on the Itk pleckstrin homology domain, proline-rich region,
      and SH2 domain. Together, these observations suggest that multivalent
      interactions recruit Itk to LAT-nucleated signaling complexes and facilitate the
      activation of LAT-associated phospholipase Cgamma1 by Itk.

PMID- 10636930
TI  - Tetrahelical forms of the fragile X syndrome expanded sequence d(CGG)(n) are
      destabilized by two heterogeneous nuclear ribonucleoprotein-related telomeric DNA
      binding proteins.
AB  - Formations of hairpin and tetrahelical structures by the trinucleotide repeat
      sequence d(CGG)(n) might contribute to its expansion in fragile X syndrome. Here
      we show that tetraplex structures of d(CGG)(n) are destabilized by two mammalian
      heterogeneous nuclear ribonucleoprotein-related tetraplex telomeric DNA-binding
      and -stabilizing proteins, quadruplex telomeric DNA-binding protein 42 (qTBP42)
      (Sarig, G., Weisman-Shomer, P., Erlitzki, R., and Fry, M. (1997) J. Biol. Chem.
      272, 4474-4482) and unimolecular quadruplex telomeric DNA-binding protein 25
      (uqTBP25) (Erlitzki, R., and Fry, M. (1997) J. Biol. Chem. 272, 15881-15890).
      Blunt-ended and 3'-tailed or 3'- and 5'-tailed bimolecular tetraplex structures
      of d(CGG)(n) and guanine-sparse 20-/46-mer partial DNA duplex were progressively
      destabilized by increasing amounts of qTBP42 or uqTBP25 in time-dependent and ATP
      or Mg(2+)-independent reactions. By contrast, tetraplex structures of telomeric
      and IgG sequences or guanine-rich double-stranded DNA resisted destabilization by
      qTBP42 or uqTBP25. Increased stability of tetraplex d(CGG)(n) in the presence of
      K(+) or Na(+) ions or at lowered reaction temperature diminished the
      destabilizing activity of uqTBP25. The contrasting stabilization of tetraplex
      telomeric DNA and destabilization of tetraplex d(CGG)(n) by qTBP42 and uqTBP25
      suggested that sequence or structural differences between these tetraplexes might
      serve as cues for the differential stabilizing/destabilizing activities.

PMID- 10636931
TI  - Pasteurella multocida toxin stimulates mitogen-activated protein kinase via
      G(q/11)-dependent transactivation of the epidermal growth factor receptor.
AB  - The dermatonecrotic toxin produced by Pasteurella multocida is one of the most
      potent mitogenic substances known for fibroblasts in vitro. Exposure to
      recombinant P. multocida toxin (rPMT) causes phospholipase C-mediated hydrolysis
      of inositol phospholipids, calcium mobilization, and activation of protein kinase
      C via a poorly characterized mechanism involving G(q/11) family heterotrimeric G
      proteins. To determine whether the regulation of G protein pathways contributes
      to the mitogenic effects of rPMT, we have examined the mechanism whereby rPMT
      stimulates the Erk mitogen-activated protein kinase cascade in cultured HEK-293
      cells. Treatment with rPMT resulted in a dose and time-dependent increase in Erk
      1/2 phosphorylation that paralleled its stimulation of inositol phospholipid
      hydrolysis. Both rPMT- and alpha-thrombin receptor- stimulated Erk
      phosphorylation were selectively blocked by cellular expression of two peptide
      inhibitors of G(q/11) signaling, the dominant negative mutant G protein-coupled
      receptor kinase, GRK2(K220R), and the Galpha(q) carboxyl-terminal peptide,
      Galpha(q)-(305-359). Like alpha-thrombin receptor-mediated Erk activation, the
      effect of rPMT was insensitive to the protein kinase C inhibitor GF109203X, but
      was blocked by the epidermal growth factor receptor-specific tyrphostin, AG1478
      and by dominant negative mutants of mSos1 and Ha-Ras. These data indicate that
      rPMT employs G(q/11) family heterotrimeric G proteins to induce Ras-dependent Erk
      activation via protein kinase C-independent "transactivation" of the epidermal
      growth factor receptor.

PMID- 10636932
TI  - Correctness of local probability in graphical models with loops.
AB  - Graphical models, such as Bayesian networks and Markov networks, represent joint
      distributions over a set of variables by means of a graph. When the graph is
      singly connected, local propagation rules of the sort proposed by Pearl (1988)
      are guaranteed to converge to the correct posterior probabilities. Recently a
      number of researchers have empirically demonstrated good performance of these
      same local propagation schemes on graphs with loops, but a theoretical
      understanding of this performance has yet to be achieved. For graphical models
      with a single loop, we derive an analytical relationship between the
      probabilities computed using local propagation and the correct marginals. Using
      this relationship we show a category of graphical models with loops for which
      local propagation gives rise to provably optimal maximum a posteriori assignments
      (although the computed marginals will be incorrect). We also show how nodes can
      use local information in the messages they receive in order to correct their
      computed marginals. We discuss how these results can be extended to graphical
      models with multiple loops and show simulation results suggesting that some
      properties of propagation on single-loop graphs may hold for a larger class of
      graphs. Specifically we discuss the implication of our results for understanding
      a class of recently proposed error-correcting codes known as turbo codes.

PMID- 10636933
TI  - Population dynamics of spiking neurons: fast transients, asynchronous states, and
      locking.
AB  - An integral equation describing the time evolution of the population activity in
      a homogeneous pool of spiking neurons of the integrate-and-fire type is
      discussed. It is analytically shown that transients from a state of incoherent
      firing can be immediate. The stability of incoherent firing is analyzed in terms
      of the noise level and transmission delay, and a bifurcation diagram is derived.
      The response of a population of noisy integrate-and-fire neurons to an input
      current of small amplitude is calculated and characterized by a linear filter L.
      The stability of perfectly synchronized"locked"solutions is analyzed.

PMID- 10636934
TI  - Dynamics of strongly-coupled spiking neurons.
AB  - We present a dynamical theory of integrate-and-fire neurons with strong synaptic
      coupling. We show how phase-locked states that are stable in the weak coupling
      regime can destabilize as the coupling is increased, leading to states
      characterized by spatiotemporal variations in the interspike intervals (ISIs).
      The dynamics is compared with that of a corresponding network of analog neurons
      in which the outputs of the neurons are taken to be mean firing rates. A
      fundamental result is that for slow interactions, there is good agreement between
      the two models (on an appropriately defined timescale). Various examples of
      desynchronization in the strong coupling regime are presented. First, a globally
      coupled network of identical neurons with strong inhibitory coupling is shown to
      exhibit oscillator death in which some of the neurons suppress the activity of
      others. However, the stability of the synchronous state persists for very large
      networks and fast synapses. Second, an asymmetric network with a mixture of
      excitation and inhibition is shown to exhibit periodic bursting patterns.
      Finally, a one-dimensional network of neurons with long-range interactions is
      shown to desynchronize to a state with a spatially periodic pattern of mean
      firing rates across the network. This is modulated by deterministic fluctuations
      of the instantaneous firing rate whose size is an increasing function of the
      speed of synaptic response.

PMID- 10636935
TI  - On connectedness: a solution based on oscillatory correlation.
AB  - A long-standing problem in Neural Comp has been the problem of connectedness,
      first identified by Minsky and Papert (1969). This problem served as the
      cornerstone for them to establish analytically that perceptrons are fundamentally
      limited in computing geometrical (topological) properties. A solution to this
      problem is offered by a different class of neural networks: oscillator networks.
      To solve the problem, the representation of oscillatory correlation is employed,
      whereby one pattern is represented as a synchronized block of oscillators and
      different patterns are represented by distinct blocks that desynchronize from
      each other. Oscillatory correlation emerges from LEGION (locally excitatory
      globally inhibitory oscillator network), whose architecture consists of local
      excitation and global inhibition among neural oscillators. It is further shown
      that these oscillator networks exhibit sensitivity to topological structure,
      which may lay a neurocomputational foundation for explaining the psychophysical
      phenomenon of topological perception.

PMID- 10636936
TI  - Practical identifiability of finite mixtures of multivariate bernoulli
      distributions.
AB  - The class of finite mixtures of multivariate Bernoulli distributions is known to
      be nonidentifiable; that is, different values of the mixture parameters can
      correspond to exactly the same probability distribution. In principle, this would
      mean that sample estimates using this model would give rise to different
      interpretations. We give empirical support to the fact that estimation of this
      class of mixtures can still produce meaningful results in practice, thus
      lessening the importance of the identifiability problem. We also show that the
      expectation-maximization algorithm is guaranteed to converge to a proper maximum
      likelihood estimate, owing to a property of the log-likelihood surface.
      Experiments with synthetic data sets show that an original generating
      distribution can be estimated from a sample. Experiments with an
      electropalatography data set show important structure in the data.

PMID- 10636937
TI  - The effects of pair-wise and higher order correlations on the firing rate of a
      post-synaptic neuron.
AB  - Coincident firing of neurons projecting to a common target cell is likely to
      raise the probability of firing of this postsynaptic cell. Therefore,
      synchronized firing constitutes a significant event for postsynaptic neurons and
      is likely to play a role in neuronal information processing. Physiological data
      on synchronized firing in cortical networks are based primarily on paired
      recordings and cross-correlation analysis. However, pair-wise correlations among
      all inputs onto a postsynaptic neuron do not uniquely determine the distribution
      of simultaneous postsynaptic events. We develop a framework in order to calculate
      the amount of synchronous firing that, based on maximum entropy, should exist in
      a homogeneous neural network in which the neurons have known pair-wise
      correlations and higher-order structure is absent. According to the distribution
      of maximal entropy, synchronous events in which a large proportion of the neurons
      participates should exist even in the case of weak pair-wise correlations.
      Network simulations also exhibit these highly synchronous events in the case of
      weak pair-wise correlations. If such a group of neurons provides input to a
      common postsynaptic target, these network bursts may enhance the impact of this
      input, especially in the case of a high postsynaptic threshold. The proportion of
      neurons participating in synchronous bursts can be approximated by our method
      under restricted conditions. When these conditions are not fulfilled, the spike
      trains have less than maximal entropy, which is indicative of the presence of
      higher-order structure. In this situation, the degree of synchronicity cannot be
      derived from the pair-wise correlations.

PMID- 10636938
TI  - Effects of spike timing on winner-take-all competition in model cortical
      circuits.
AB  - Synaptic interactions in cortical circuits involve strong recurrent excitation
      between nearby neurons and lateral inhibition that is more widely spread. This
      architecture is commonly thought to promote a winner-take-all competition, in
      which a small fraction of neuronal responses is selected for further processing.
      Here I report that such a competition is remarkably sensitive to the timing of
      neuronal action potentials. This is shown using simulations of model neurons and
      synaptic connections representing a patch of cortical tissue. In the simulations,
      uncorrelated discharge among neuronal units results in patterns of response
      dominance and suppression, that is, in a winner-take-all competition.
      Synchronization of firing, however, prevents such competition. These results
      demonstrate a novel property of recurrent cortical-like circuits, suggesting that
      the temporal patterning of cortical activity may play an important part in
      selection among stimuli competing for the control of attention and motor action.

PMID- 10636939
TI  - Model dependence in quantification of spike interdependence by joint peri
      stimulus time histogram.
AB  - Multineuronal recordings have enabled us to examine context-dependent changes in
      the relationship between the activities of multiple cells. The joint peri
      stimulus time histogram (JPSTH) is a much-used method for investigating the
      dynamics of the interdependence of spike events between pairs of cells. Its
      results are often taken as an estimate of interaction strength between cells,
      independent of modulations in the cells' firing rates. We evaluate the adequacy
      of this estimate by examining the mathematical structure of how the JPSTH
      quantifies an interaction strength after excluding the contribution of firing
      rates. We introduce a simple probabilistic model of interacting point processes
      to generate simulated spike data and show that the normalized JPSTH incorrectly
      infers the temporal structure of variations in the interaction parameter
      strength. This occurs because, in our model, the correct normalization of firing
      rate contributions is different than that used in Aertsen, Gerstein, Habib, and
      Palm's (1989) effective connectivity model. This demonstrates that firing-rate
      modulations cannot be corrected for in a model-independent manner, and therefore
      the effective connectivity does not represent a universal characteristic that is
      independent of modulation of the firing rates. Aertsen et al.'s (1989) effective
      connectivity may still be used in the analysis of experimental data, provided we
      are aware that this is simply one of many ways of describing the structure of
      interdependence. We also discuss some measure-independent characteristics of the
      structure of interdependence.

PMID- 10636940
TI  - Reinforcement learning in continuous time and space.
AB  - This article presents a reinforcement learning framework for continuous-time
      dynamical systems without a priori discretization of time, state, and action.
      Based on the Hamilton-Jacobi-Bellman (HJB) equation for infinite-horizon,
      discounted reward problems, we derive algorithms for estimating value functions
      and improving policies with the use of function approximators. The process of
      value function estimation is formulated as the minimization of a continuous-time
      form of the temporal difference (TD) error. Update methods based on backward
      Euler approximation and exponential eligibility traces are derived, and their
      correspondences with the conventional residual gradient, TD(0), and TD(lambda)
      algorithms are shown. For policy improvement, two methods-a continuous actor
      critic method and a value-gradient-based greedy policy-are formulated. As a
      special case of the latter, a nonlinear feedback control law using the value
      gradient and the model of the input gain is derived. The advantage updating, a
      model-free algorithm derived previously, is also formulated in the HJB-based
      framework. The performance of the proposed algorithms is first tested in a
      nonlinear control task of swinging a pendulum up with limited torque. It is shown
      in the simulations that (1) the task is accomplished by the continuous actor
      critic method in a number of trials several times fewer than by the conventional
      discrete actor-critic method; (2) among the continuous policy update methods, the
      value-gradient-based policy with a known or learned dynamic model performs
      several times better than the actor-critic method; and (3) a value function
      update using exponential eligibility traces is more efficient and stable than
      that based on Euler approximation. The algorithms are then tested in a higher
      dimensional task: cart-pole swing-up. This task is accomplished in several
      hundred trials using the value-gradient-based policy with a learned dynamic
      model.

PMID- 10636941
TI  - Minimizing binding errors using learned conjunctive features.
AB  - We have studied some of the design trade-offs governing visual representations
      based on spatially invariant conjunctive feature detectors, with an emphasis on
      the susceptibility of such systems to false-positive recognition errors
      Malsburg's classical binding problem. We begin by deriving an analytical model
      that makes explicit how recognition performance is affected by the number of
      objects that must be distinguished, the number of features included in the
      representation, the complexity of individual objects, and the clutter load, that
      is, the amount of visual material in the field of view in which multiple objects
      must be simultaneously recognized, independent of pose, and without explicit
      segmentation. Using the domain of text to model object recognition in cluttered
      scenes, we show that with corrections for the nonuniform probability and
      nonindependence of text features, the analytical model achieves good fits to
      measured recognition rates in simulations involving a wide range of clutter
      loads, word size, and feature counts. We then introduce a greedy algorithm for
      feature learning, derived from the analytical model, which grows a representation
      by choosing those conjunctive features that are most likely to distinguish
      objects from the cluttered backgrounds in which they are embedded. We show that
      the representations produced by this algorithm are compact, decorrelated, and
      heavily weighted toward features of low conjunctive order. Our results provide a
      more quantitative basis for understanding when spatially invariant conjunctive
      features can support unambiguous perception in multiobject scenes, and lead to
      several insights regarding the properties of visual representations optimized for
      specific recognition tasks.

PMID- 10636942
TI  - Relationship between phase and energy methods for disparity computation.
AB  - The phase and energy methods for computing binocular disparity maps from
      stereograms are motivated differently, have different physiological relevances,
      and involve different computational steps. Nevertheless, we demonstrate that at
      the final stages where disparity values are made explicit, the simplest versions
      of the two methods are exactly equivalent. The equivalence also holds when the
      quadrature-pair construction in the energy method is replaced with a more
      physiologically plausible phase-averaging step. The equivalence fails, however,
      when the phase-difference receptive field model is replaced by the position-shift
      model. Additionally, intermediate results from the two methods are always quite
      distinct. In particular, the energy method generates a distributed disparity
      representation similar to that found in the visual cortex, while the phase method
      does not. Finally, more elaborate versions of the two methods are in general not
      equivalent. We also briefly compare these two methods with some other stereo
      models in the literature.

PMID- 10636943
TI  - N-tuple network, CART and bagging.
AB  - Similarities between bootstrap aggregation (bagging) and N-tuple sampling are
      explored to propose a retina-free data-driven version of the N-tuple network,
      whose close analogies to aggregated regression trees, such as classification and
      regression trees (CART), lead to further architectural enhancements. Performance
      of the proposed algorithms is compared with the traditional versions of the N
      tuple and CART networks on a number of regression problems. The architecture
      significantly outperforms conventional N-tuple networks while leading to more
      compact solutions and avoiding certain implementational pitfalls of the latter.

PMID- 10636944
TI  - Improving the practice of classifier performance assessment.
AB  - In this note we use examples from the literature to illustrate some poor
      practices in assessing the performance of supervised classification rules, and we
      suggest guidelines for better methodology. We also describe a new assessment
      criterion that is suitable for the needs of many practical problems.

PMID- 10636945
TI  - Do simple cells in primary visual cortex form a tight frame?
AB  - Sets of neuronal tuning curves, which describe the responses of neurons as
      functions of a stimulus, can serve as a basis for approximating other functions
      of stimulus parameters. In a function-approximating network, synaptic weights
      determined by a correlation-based Hebbian rule are closely related to the
      coefficients that result when a function is expanded in an orthogonal basis.
      Although neuronal tuning curves typically are not orthogonal functions, the
      relationship between function approximation and correlation-based synaptic
      weights can be retained if the tuning curves satisfy the conditions of a tight
      frame. We examine whether the spatial receptive fields of simple cells in cat and
      monkey primary visual cortex (V1) form a tight frame, allowing them to serve as a
      basis for constructing more complicated extrastriate receptive fields using
      correlation-based synaptic weights. Our calculations show that the set of V1
      simple cell receptive fields is not tight enough to account for the acuity
      observed psychophysically.

PMID- 10636946
TI  - Learning overcomplete representations.
AB  - In an overcomplete basis, the number of basis vectors is greater than the
      dimensionality of the input, and the representation of an input is not a unique
      combination of basis vectors. Overcomplete representations have been advocated
      because they have greater robustness in the presence of noise, can be sparser,
      and can have greater flexibility in matching structure in the data. Overcomplete
      codes have also been proposed as a model of some of the response properties of
      neurons in primary visual cortex. Previous work has focused on finding the best
      representation of a signal using a fixed overcomplete basis (or dictionary). We
      present an algorithm for learning an overcomplete basis by viewing it as
      probabilistic model of the observed data. We show that overcomplete bases can
      yield a better approximation of the underlying statistical distribution of the
      data and can thus lead to greater coding efficiency. This can be viewed as a
      generalization of the technique of independent component analysis and provides a
      method for Bayesian reconstruction of signals in the presence of noise and for
      blind source separation when there are more sources than mixtures.

PMID- 10636947
TI  - Noise in integrate-and-fire neurons: from stochastic input to escape rates.
AB  - We analyze the effect of noise in integrate-and-fire neurons driven by time
      dependent input and compare the diffusion approximation for the membrane
      potential to escape noise. It is shown that for time-dependent subthreshold
      input, diffusive noise can be replaced by escape noise with a hazard function
      that has a gaussian dependence on the distance between the (noise-free) membrane
      voltage and threshold. The approximation is improved if we add to the hazard
      function a probability current proportional to the derivative of the voltage.
      Stochastic resonance in response to periodic input occurs in both noise models
      and exhibits similar characteristics.

PMID- 10636948
TI  - Modeling synaptic plasticity in conjuction with the timing of pre- and
      postsynaptic action potentials.
AB  - We present a spiking neuron model that allows for an analytic calculation of the
      correlations between pre- and postsynaptic spikes. The neuron model is a
      generalization of the integrate-and-fire model and equipped with a probabilistic
      spike-triggering mechanism. We show that under certain biologically plausible
      conditions, pre- and postsynaptic spike trains can be described simultaneously as
      an inhomogeneous Poisson process. Inspired by experimental findings, we develop a
      model for synaptic long-term plasticity that relies on the relative timing of pre
      and post-synaptic action potentials. Being given an input statistics, we compute
      the stationary synaptic weights that result from the temporal correlations
      between the pre- and postsynaptic spikes. By means of both analytic calculations
      and computer simulations, we show that such a mechanism of synaptic plasticity is
      able to strengthen those input synapses that convey precisely timed spikes at the
      expense of synapses that deliver spikes with a broad temporal distribution. This
      may be of vital importance for any kind of information processing based on
      spiking neurons and temporal coding.

PMID- 10636949
TI  - On-line EM algorithm for the normalized gaussian network.
AB  - A normalized gaussian network (NGnet) (Moody & Darken, 1989) is a network of
      local linear regression units. The model softly partitions the input space by
      normalized gaussian functions, and each local unit linearly approximates the
      output within the partition. In this article, we propose a new on-line
      EMalgorithm for the NGnet, which is derived from the batch EMalgorithm (Xu,
      Jordan, &Hinton 1995), by introducing a discount factor. We show that the on-line
      EM algorithm is equivalent to the batch EM algorithm if a specific scheduling of
      the discount factor is employed. In addition, we show that the on-line EM
      algorithm can be considered as a stochastic approximation method to find the
      maximum likelihood estimator. A new regularization method is proposed in order to
      deal with a singular input distribution. In order to manage dynamic environments,
      where the input-output distribution of data changes over time, unit manipulation
      mechanisms such as unit production, unit deletion, and unit division are also
      introduced based on probabilistic interpretation. Experimental results show that
      our approach is suitable for function approximation problems in dynamic
      environments. We also apply our on-line EM algorithm to robot dynamics problems
      and compare our algorithm with the mixtures-of-experts family.

PMID- 10636950
TI  - A general probability estimation approach for neural comp.
AB  - We describe an analytical framework for the adaptations of neural systems that
      adapt its internal structure on the basis of subjective probabilities constructed
      by computation of randomly received input signals. A principled approach is
      provided with the key property that it defines a probability density model that
      allows studying the convergence of the adaptation process. In particular, the
      derived algorithm can be applied for approximation problems such as the
      estimation of probability densities or the recognition of regression functions.
      These approximation algorithms can be easily extended to higher-dimensional
      cases. Certain neural network models can be derived from our approach (e.g.,
      topological feature maps and associative networks).

PMID- 10636952
TI  - In memoriam

PMID- 10636951
TI  - On the synthesis of brain-state-in-a-box neural models with application to
      associative memory.
AB  - In this article we present techniques for designing associative memories to be
      implemented by a class of synchronous discrete-time neural networks based on a
      generalization of the brain-state-in-a-box neural model. First, we address the
      local qualitative properties and global qualitative aspects of the class of
      neural networks considered. Our approach to the stability analysis of the
      equilibrium points of the network gives insight into the extent of the domain of
      attraction for the patterns to be stored as asymptotically stable equilibrium
      points and is useful in the analysis of the retrieval performance of the network
      and also for design purposes. By making use of the analysis results as
      constraints, the design for associative memory is performed by solving a
      constraint optimization problem whereby each of the stored patterns is guaranteed
      a substantial domain of attraction. The performance of the designed network is
      illustrated by means of three specific examples.

PMID- 10636953
TI  - Development and testing of a clinical tool measuring self-management of heart
      failure.
AB  - BACKGROUND: Self-management is a primary goal of treatment for heart failure. Yet
      no measure of self-management in this patient group currently exists. OBJECTIVES:
      To develop a clinically useful measure of the abilities of patients with heart
      failure to manage their disease. Self-management in this context was defined as a
      cognitive decision-making process undertaken in response to signs and symptoms of
      heart failure. A panel of experts agreed that the process involved 4 distinct
      stages: recognizing a change, evaluating the change, implementing a treatment
      strategy, and evaluating the treatment. The tool was developed to reflect this
      process. METHODS: Face validity of the process model was assessed in a sample of
      25 patients with heart failure and used to develop a 65-item tool with 6
      subscales. The subscales measure the 4 stages as well as the patients' ease in
      evaluating the signs and symptoms and their self-efficacy. The tool was pilot
      tested with 2 samples of patients with heart failure (N = 17; N = 129).
      Psychometrics of the final tool were then tested in a sample of 127 patients with
      heart failure. RESULTS: Face and content validity of the tool were demonstrated
      adequately through this study. Internal consistency scores of the 6 subscales of
      the Self-Management of Heart Failure instrument ranged from 0.79 (ease of
      evaluating treatment) to 0.92 (evaluating the change). Reliability could not be
      calculated for 1 subscale (evaluating the treatment) because of missing data that
      resulted from patients skipping sections because they had not experienced a
      symptom. CONCLUSION: Clinicians interested in evaluating the self-management
      abilities of their patients with heart failure are encouraged to use this tool
      and to contribute to additional testing.

PMID- 10636955
TI  - Functional status outcomes of patients with a coronary artery bypass graft over
      time.
AB  - OBJECTIVE: To examine functional status outcomes among patients with a coronary
      artery bypass graft (CABG) over time (ie, at baseline; 3 months, 6 months, and 12
      months after surgery) and the impact of selected patient characteristics (ie,
      age, sex, comorbidities, and cardiac rehabilitation participation) on functional
      outcomes. DESIGN: A prospective, repeated-measures design was used to examine
      functional status in patients with a CABG over time. SETTING: A midwestern
      community hospital and regional cardiac referral center was the setting for
      enrolling patients with a CABG. OUTCOME MEASURES: Functional status outcomes were
      measured by using the Medical Outcomes Study (MOS) Short Form 36 (SF-36) and
      Modified 7-Day Activity instruments. METHODS: Baseline data were obtained by
      patient interview in the hospital setting after CABG surgery. At 3 months, 6
      months, and 12 months after surgery, telephone interviews were conducted to
      administer research instruments. RESULTS: Baseline scores on 7 of the 8 subscales
      of the MOS SF-36 were significantly lower than at 3 months, 6 months, or 12
      months after surgery. Role-emotional functioning baseline scores were not
      significantly lower than 3-month scores; however, baseline scores were
      significantly lower than 6-month and 12-month scores. Three-month subscale scores
      were also significantly lower than 6-month or 12-month scores except for the
      subscales measuring social and general health functioning. Functional status as
      measured by the Modified 7-Day Activity tool did not demonstrate any significant
      differences between 3-month, 6-month, or 12-month activity levels. There were no
      significant differences by age group on any of the 8 subscales of the MOS SF-36
      instrument. Women and subjects with more than 1 comorbidity had a significantly
      lower preoperative level of physical functioning. Cardiac rehabilitation
      participants had lower preoperative scores on role-emotional functioning than
      subjects who were not in rehabilitation. CONCLUSION: Findings from this study can
      assist nurses and other health care workers to gain a perspective of the recovery
      and rehabilitation trajectory of patients with a CABG. The results of the study
      provide a basis for determining areas of functional limitations during recovery
      from CABG surgery. Study results can also be the foundation for evaluating
      outcomes of patients with a CABG when specific interventions (eg, pain
      management, psychosocial support, physical strengthening, fatigue management) are
      implemented during hospitalization, home recovery, and rehabilitation to target
      optimal psychosocial and physiologic functioning of patients with a CABG.

PMID- 10636954
TI  - Current medical therapy for advanced heart failure.

PMID- 10636957
TI  - Dyspnea self-management in African Americans with chronic lung disease.
AB  - PURPOSE: To explore dyspnea self-management in African Americans with chronic
      obstructive pulmonary disease (COPD) or chronic restrictive pulmonary disease
      resulting from sarcoidosis. DESIGN: Descriptive. SAMPLE: Convenience sample of 29
      African Americans, 15 with COPD (forced expiratory volume in 1 second/forced
      vital capacity = 53%), and 14 with sarcoidosis (forced expiratory volume in 1
      second/forced vital capacity = 88%; total lung capacity 62.4% of predicted).
      METHODS: Semistructured interviews. FINDINGS: Content analysis revealed 4 dyspnea
      self-management themes: (1) traditional medical care, (2) self-care wisdom, (3)
      self-care action, and (4) self-care resources. Breathing strategies (a subtheme
      for self-care action) for patients with COPD focused on both inhalation and
      exhalation, whereas patients with sarcoidosis described inhalation breathing
      strategies only. CONCLUSION: African Americans with chronic lung disease
      described use of different breathing strategies for COPD and sarcoidosis
      disorders. Both groups actively engaged in health-promoting activities for
      dyspnea management.

PMID- 10636956
TI  - Atrial fibrillation and tumor emboli as manifestations of metastatic
      leiomyosarcoma to the heart and lung.
AB  - Leiomyosarcoma is a malignant tumor of the smooth muscle that rarely occurs in
      the gastrointestinal tract. High-grade leiomyosarcomas of the rectosigmoid
      usually metastasize to the liver and lungs. Although it is unusual, metastases to
      the heart have been reported. When this occurs, the metastatic tumor usually
      seeds in the right atrium and pulmonary artery. We report on and discuss a
      patient who had atrial fibrillation, peripheral emboli, and thrombocytopenia
      resulting from a low-grade rectosigmoid leiomyosarcoma metastatic to the
      pulmonary vein and left atrium. Atrial fibrillation is not a common manifestation
      of malignant neoplasms that have spread to the heart. Surgical removal of the
      tumor terminated the arrhythmia and thrombocytopenia.

PMID- 10636958
TI  - Humidification method that decreases condensate contamination in ventilator
      tubing.
AB  - OBJECTIVE: To demonstrate combining unheated bubble-through humidifier with a
      heat-moisture exchanger filter for the purpose of decreasing condensate
      contamination in mechanical ventilator tubing. DESIGN: Single-case, pretest and
      posttest. SETTING: University-affiliated and nonprofit hospital. PATIENT: A 32
      year-old man with Pickwickian syndrome and pneumonia caused by Pseudomonas
      aeruginosa received mechanical ventilation for 14 days. METHODS: Ventilator
      tubing was cultured in two 24-hour trials, using a pretest and posttest design,
      to assess tubing bacterial contamination during use of 2 humidification methods.
      In the first trial, a traditional heated bubble-through humidifier (HBH) was used
      for 24 hours. Before the start of the second trial, the "wet" tubing and the
      heated bubble-through humidifier were removed and replaced with clean equipment
      through the use of aseptic technique. The bubble-through humidifier was placed on
      the "cold," or unheated mode, and a heat-moisture exchanger filter was attached
      to the Y-connector of the ventilator tubing. RESULTS: The heated bubble-through
      humidifier method revealed contamination of the ventilator tubing in 3 places
      with the patient's strain of P aeruginosa in addition to copious water
      condensate. The unheated bubble-through humidifier/heat moisture exchanger filter
      method demonstrated no bacterial contamination or condensate in the tubing.
      CONCLUSION: It can be inferred that the humidification method using the
      combination of an unheated bubble-through humidifier and a heat moisture
      exchanger filter has the potential benefit of preventing "reseeding" of the
      patient's airway with contaminated condensate.

PMID- 10636959
TI  - Preventing treatment interference: the nurse's role in maintaining technologic
      devices.
AB  - BACKGROUND: Treatment interference, the disruption or self-removal of technologic
      devices, is a primary reason for application of physical restraints in acute and
      critical care settings. The processes of care surrounding treatment interference
      and the prevention of device disruption have not been comprehensively analyzed.
      OBJECTIVES: To describe the processes used by critical care nurses to prevent
      treatment interference in critically ill older adults. METHODS: Participant
      observation field research was conducted in medical and intermediate medical
      intensive care units. Data were analyzed by using the constant comparative method
      and event analysis. RESULTS: Maintaining technologic devices is almost
      exclusively a nursing responsibility and involves the skillful assessment of
      patient awareness and trustworthiness and interpretation of behaviors. Critical
      care nurses are most protective of those devices for which accidental removal is
      perceived as life threatening: endotracheal tubes, arterial catheters, and
      central venous catheters. Nurses assess patients' cognitive status, mobility,
      strength, and trustworthiness, as well as device considerations such as
      replacement difficulty and device necessity. In addition to verbal strategies,
      such as explaining, nurses use distraction, deception, comfort measures, watchful
      family members, physical restraints, and sedation to prevent treatment
      interference. CONCLUSION: This analysis considers the social context of the
      intensive care unit, including roles and the human-technology interaction. It
      illustrates the tremendous responsibility that nurses assume in maintaining
      technologic devices. Next steps in research and policy development are also
      considered.

PMID- 10636961
TI  - Join us in DC!

PMID- 10636960
TI  - Effects of changing needles prior to administering heparin subcutaneously.
AB  - OBJECTIVES: To determine if changing needles before administering subcutaneous
      heparin would cause less ecchymosis at the injection site. DESIGN: A quantitative
      study. SETTING: A large northeastern, urban, nonprofit, tertiary medical center.
      OUTCOME MEASURES: A measurement of ecchymosis was obtained 48 hours after
      injection of heparin on the right side of the abdomen, where the needle was
      changed before injection. A second measurement was obtained 48 hours after
      injection on the left side of the abdomen, where the needle was not changed
      before injection. A comparison was then made of the two measurements. RESULTS:
      The Student t test for related samples was used, and the significance was set at
      P <.05. The mean size of the ecchymoses for the sites where the needle was
      changed was 5.16 mm, and the mean size of the ecchymoses for the sites where the
      needle was not changed was 5.44 mm (P =.87). CONCLUSION: Changing the needle
      before the administration of subcutaneous heparin did not decrease the size of
      ecchymoses as compared with the size to the size of ecchymoses when the
      investigator did not change the needle.

PMID- 10636962
TI  - Infant dialysis: the future is now.

PMID- 10636963
TI  - Acquired versus congenital renal scarring after childhood urinary tract
      infection.

PMID- 10636964
TI  - Childhood constipation: finally some hard data about hard stools!

PMID- 10636965
TI  - Fat intake in children: is there a need for revised recommendations?

PMID- 10636966
TI  - Congenital hypothyroidism: expanding the spectrum.

PMID- 10636967
TI  - When is careless conception a form of child abuse? Lessons from maternal
      phenylketonuria.

PMID- 10636968
TI  - Culture and the patient-physician relationship: achieving cultural competency in
      health care.

PMID- 10636969
TI  - Long-term outcome of peritoneal dialysis in infants.
AB  - Debate continues concerning the treatment of infants with end-stage renal
      disease. We evaluated progress and outcome of 20 infants with a mean age of 0.34
      year (range, 0.02-1 year) in a long-term peritoneal dialysis program at a single
      center. Mean weight at the start of dialysis was 4.8 kg (range, 1.7-11.4 kg), and
      the duration of dialysis was 17.3 months (range, 1-59 months). Eleven infants
      received renal transplants, 4 were switched to hemodialysis and then received
      transplants, 4 died, and 1 continues to receive peritoneal dialysis. There was
      significant co-morbidity in 6 infants who died or required hemodialysis. Catheter
      interventions were frequent, with 12 infants requiring at least one replacement.
      There were 1.1 episodes of peritonitis per patient-year; 70% of infants had 0 to
      1 episode. Mean weight standard deviation score (SDS) was -1.6 at the start, -0.3
      at 1 year (P =.0008), and 0.3 at 2 years (P =.0008). Height SDSs were -1.8 at the
      start, -1.1 at 1 year (P =.046), and -0. 8 at 2 years (P =.06). Head
      circumference SDSs were -1.9 at the start, -1.3 at 6 months (P =.003), and -0.9
      at 1 year (P =.015). Fourteen of 16 survivors are achieving normal developmental
      milestones or attend mainstream school. Peritoneal dialysis in infancy is a
      demanding treatment, but outcome for growth, development, and transplantation
      justifies this intensive approach. When parents are counseled, the importance of
      non-renal co-morbidity must be emphasized.

PMID- 10636970
TI  - Primary and acquired renal scarring in boys and girls with urinary tract
      infection.
AB  - OBJECTIVES: To determine when pyelonephritic renal scarring was detected in
      children with urinary tract infection (UTI) and characterize those with primary
      and acquired scarring, respectively. STUDY DESIGN: A population-based cohort of
      1221 children (989 girls and 232 boys) with first recognized symptomatic UTI,
      aged 0 to 15 years, were diagnosed and followed up prospectively at a single
      children's hospital; 652 had febrile UTI. Seven hundred fifty-three were
      evaluated by urography. Renal scarring was classified as primary or acquired, the
      latter without signs of scarring at the first investigation. To evaluate the
      frequency of recurrent UTI in those with acquired scarring, a comparison with
      group-matched children without scarring was performed. RESULTS: A total of 74
      children without obstruction had renal scarring (acquired in 40). Primary
      scarring was found in 18 of 21 (86%) of the boys and 16 of 53 (30%) of the girls
      (P <.001). The majority of boys with scarring had dilated reflux (67%) in
      contrast to girls (23%). Recurrent UTI was rare in boys, whereas girls with
      acquired scarring had significantly more febrile recurrences than girls without
      scarring. CONCLUSIONS: Most boys had primary, probably congenital, reflux
      associated renal damage, whereas most girls had acquired scarring related to
      recurrences of febrile UTI.

PMID- 10636971
TI  - Cisapride for the treatment of constipation in children: A double-blind study.
AB  - OBJECTIVE: To determine whether cisapride is effective in the treatment of
      children with constipation. STUDY DESIGN: Double-blind, placebo-controlled study
      in which children with chronic constipation were randomly assigned to treatment
      with cisapride or placebo for 12 weeks. RESULTS: Forty children were enrolled,
      and 36 completed the therapy. Treatment successes occurred in 13 of 17 (76%)
      subjects in the cisapride group and 8 of 19 (37%) subjects in the placebo group
      (P <.03). The odds ratio for response after cisapride administration was 8.2
      times higher (95% CI 1.3 to 49.4). During cisapride therapy, there was a
      significant improvement in number of spontaneous bowel movements per week (from
      0.9 +/- 0.1 to 4.1 +/- 1.1), and there was a significant decrease in number of
      fecal soiling episodes per day (1.8 +/- 0.5 to 0.08 +/- 0.4), percent with
      encopresis (82% vs 23%), number of laxative doses per week (from 10.3 +/- 2.6 to
      0.8 +/- 0.6), percent using laxatives (77% to 24%), and total gastrointestinal
      transit time (from 115.0 +/- 3.7 hours to 77.0 +/- 11.1 hours). With placebo,
      there were no significant changes in the number of spontaneous bowel movements
      (from 1.0 +/- 0.8 to 2.2 +/- 0.6), percent with encopresis (74% vs 47%), or total
      gastrointestinal transit time (from 112.5 +/- 4.9 hours to 95.4 +/- 9.8 hours);
      but there was a significant decrease in number of fecal soiling episodes per day
      (from 1.3 +/- 0.4 to 0.4 +/- 0.2) and number of laxative doses used per week
      (from 11.5 +/- 2.9 to 2.05 +/- 0.7). The final number of spontaneous bowel
      movements, fecal soiling episodes, laxatives used, or percent patients with
      encopresis was not different when patients receiving cisapride were compared with
      those receiving placebo. CONCLUSION: Cisapride was effective in the treatment of
      children with constipation.

PMID- 10636972
TI  - Effect of the dietary fiber glucomannan on chronic constipation in neurologically
      impaired children.
AB  - OBJECTIVE: Inadequate dietary fiber intake is a widely accepted explanation for
      chronic constipation in children with severe brain damage. The aim of our study
      was to evaluate the efficacy of glucomannan, a soluble fiber, as a treatment for
      chronic constipation in these children. STUDY DESIGN: Twenty children with severe
      brain damage and chronic constipation were randomly assigned to double-blind
      treatment with either glucomannan (n = 10) or placebo (n = 10) for 12 weeks.
      Stool habits, total and segmental gastrointestinal transit times, and anorectal
      motility were evaluated in all children before and after the treatment period.
      RESULTS: Glucomannan significantly increased (P <.01) stool frequency, whereas
      the effect of placebo was not significant. Laxative or suppository use was
      significantly reduced (P <.01) by glucomannan but was not affected by placebo.
      Clinical scores of stool consistency were significantly improved and episodes of
      painful defecation per week were significantly reduced by glucomannan (P <.01)
      but not by placebo. However, neither glucomannan nor placebo had a measurable
      effect on total and segmental transit times. CONCLUSIONS: In neurologically
      impaired children, glucomannan improves stool frequency but has no effect on
      colonic motility.

PMID- 10636973
TI  - Low-saturated fat, low-cholesterol diet in 3-year-old children: effect on intake
      and composition of trans fatty acids and other fatty acids in serum phospholipid
      fraction-The STRIP study. Special Turku coronary Risk factor Intervention Project
      for children.
AB  - OBJECTIVE: We evaluated whether replacing a proportion of saturated fat with
      vegetable oils in the diet of young children increases trans fatty acid intake.
      STUDY DESIGN: Dietary counseling aimed to reach a dietary fat ratio of
      unsaturated to saturated fat of 2:1 within a total fat intake of 30% to 35% of
      energy (E%). Four-day food records of 813 3-year-old children were analyzed, and
      serum phospholipid fatty acid compositions of 25 randomly selected intervention
      children and 17 control children were analyzed. RESULTS: trans fatty acid intake
      of the intervention and control children was small (0.8 E% and 0.6 E%,
      respectively; P <.001). The relative content of serum phospholipid trans 18:1 was
      closely similar in intervention and control children (1.0% and 0.9% of all fatty
      acids, respectively). Trans fatty acid intake and serum trans 18:1 correlated
      poorly with children's serum cholesterol and HDL cholesterol concentrations and
      inversely with serum phospholipid arachidonic to linoleic acid ratio (r = 
      0.373). CONCLUSIONS: Trans fatty acid intake of children in Finland is minimal.
      Dietary intervention replacing saturated with unsaturated fatty acids is safe
      because it does not increase trans fatty acid intake or the relative content of
      trans fatty acids in the serum phospholipid fraction.

PMID- 10636974
TI  - Three-year follow-up of borderline congenital hypothyroidism.
AB  - The purpose of this study was to determine whether children with borderline
      hypothyroidism in the neonatal period had persistent hypothyroidism after 3 years
      of levothyroxine replacement therapy. Fourteen term infants with slightly
      abnormal newborn screening results (thyroxine <10th percentile, thyroid
      stimulating hormone ?TSH <40 microU/mL) were identified. The subsequent serum
      confirmatory TSH results of 12 subjects were modestly elevated (5.3 to 18.8
      microU/mL, normal 0.6 to 4.6), whereas 2 subjects who had borderline confirmatory
      TSH (4.6 and 4.7 microU/mL) had abnormal TSH responses to thyrotropin releasing
      hormone testing. After 3 years of therapy, levothyroxine was discontinued in 13
      patients, and repeat thyroid function tests were obtained 1 month later.
      Levothyroxine was not discontinued in one patient because he had an elevated
      random TSH (10 microU/mL) while receiving therapy. At 3 years of age, 13 patients
      had persistently abnormal thyroid function tests (TSH >4.6 microU/mL or a thyroid
      releasing hormone test result consistent with primary hypothyroidism), and
      levothyroxine was reinitiated. Only one patient had normal thyroid function
      studies. Although prospective studies are still lacking, we recommend
      levothyroxine replacement in newborns with borderline hypothyroidism.

PMID- 10636975
TI  - Maternal phenylketonuria syndrome: congenital heart defects, microcephaly, and
      developmental outcomes.
AB  - OBJECTIVE: A cohort of women with phenylketonuria (PKU) were selected to explore
      the impact of phenylalanine (Phe) levels and other factors on congenital heart
      defects (CHDs), microcephaly, and development of their offspring. STUDY DESIGN:
      Three hundred fifty-four women with PKU were followed up weekly with diet
      records, blood Phe levels, and sonograms obtained at 18 to 20 and 32 weeks'
      gestation. At birth, 413 offspring were examined and followed up at 6 months and
      annually by means of Bayley Mental Developmental Index and Psychomotor
      Developmental Index tests at 1 and 2 years. The women had Wechsler Adult
      Intelligence Scales and DNA testing. RESULTS: Thirty-one offspring had CHDs; of
      these, 17 also had microcephaly. Mean Phe levels at 4 to 8 weeks' gestation
      predicted CHDs (P <.0001). An infant with a CHD had a 3-fold risk of having
      microcephaly when the mother had higher Phe levels (P =.02). The Bayley Mental
      Developmental Index and Psychomotor Developmental Index scores correlated with
      both CHDs (P =.037 and.0015, respectively) and microcephaly (P =.0001 for both).
      No direct relationship to the PKU mutation was found. CONCLUSION: None of the
      women whose offspring had CHDs had blood Phe levels in control during the first 8
      weeks of gestation. Women with PKU need to be well controlled on a low
      phenylalanine diet before conception and throughout pregnancy.

PMID- 10636976
TI  - A new disorder of hyaluronan metabolism associated with generalized folding and
      thickening of the skin.
AB  - OBJECTIVE: To describe and characterize a new disorder of hyaluronan metabolism
      associated with marked abnormalities of cutaneous tissue and to determine whether
      a relationship with a phenotypically similar disorder in the shar-pei dog exists.
      METHODS: Biopsy specimens of the skin of a child with extreme cutaneous
      thickening and folding were examined by light and electron microscopy. The
      concentration of hyaluronan and the activity of hyaluronidase were measured in
      the patient's serum and plasma, respectively, and the activity of hyaluronan
      synthase was examined in cultured dermal fibroblasts. Hyaluronan concentration
      was also measured in the plasma of 23 shar-pei and 34 control dogs. RESULTS: The
      patient's skin displayed gross accumulation of hyaluronan, and the serum
      concentration of hyaluronan was markedly elevated (up to 3100 microg/L) during
      infancy. Hyaluronan synthase activity of cultured dermal fibroblasts was
      increased, whereas hyaluronidase activity in plasma was normal (5.5 +/- 0.08
      IU/L). Plasma hyaluronan concentration was higher in the shar-pei dogs than in
      control dogs (median, 378 microg/L vs 73 microg/L, respectively). CONCLUSION: The
      child we describe has a novel disorder of hyaluronan metabolism, which appears to
      result from abnormal control of hyaluronan synthesis. An analogous disorder may
      be present in the shar-pei dog.

PMID- 10636977
TI  - Novel missense mutations in the glutamate dehydrogenase gene in the congenital
      hyperinsulinism-hyperammonemia syndrome.
AB  - OBJECTIVES: The objectives of this study were to clarify the involvement of the
      glutamate dehydrogenase gene in congenital hyperinsulinemia-hyperammonemia
      syndrome (CHHS) and the relationships between the mutation of the gene and
      clinical severity. STUDY DESIGN: Five unrelated Japanese patients (3 girls and 2
      boys) with CHHS were investigated. All patients had convulsions or loss of
      consciousness resulting from hypoglycemia at less than 1 year of age. We examined
      mutations of the glutamate dehydrogenase gene using genomic or reverse
      transcriptase polymerase chain reactions, followed by direct sequencing. RESULTS:
      We identified heterozygous missense mutations in all patients. Three patients had
      a previously identified mutation (C-->T at nt 1506) at codon 445 in the
      allosteric domain. Two novel missense mutations were identified in the other
      patients. These mutations included a change of A-->C at nt 1059 and a change of G
      ->A at nt 966, within the catalytic domain of the glutamate dehydrogenase gene.
      The locus of the mutations was not associated with the severity of hypoglycemia.
      CONCLUSIONS: Our results suggest that structural aberrations of not only the
      allosteric domain but also the catalytic domain of the glutamate dehydrogenase
      protein, caused by missense mutations, can result in the development of CHHS.

PMID- 10636978
TI  - Total and resting energy expenditure in children with sickle cell disease.
AB  - OBJECTIVE: To investigate energy balance in children with sickle cell disease
      (SCD) as the possible cause of impaired growth and undernutrition. STUDY DESIGN:
      Growth, resting (REE), total (TEE), and activity-related (AEE) energy expenditure
      and dietary intake were examined in 36 African American children with SCD (20
      girls and 16 boys) and 30 control subjects (15 girls and 15 boys) of similar age
      (mean, 11.2 years) and ethnicity. TEE was measured by means of the doubly labeled
      water technique and REE by indirect calorimetry. AEE was calculated as TEE minus
      REE. Fat free mass (FFM) was calculated from skinfold prediction equations.
      RESULTS: REE was significantly increased (131 kcal/d) in children with SCD (P
      =.001), after adjusting for sex and FFM. Children with SCD tended to have lower
      TEE (214 kcal/d) than control subjects, but there was no difference after
      adjusting for FFM and sex (P =.57). Children with SCD had significantly (P =.025)
      lower AEE (268 kcal/d) but only marginally (P =.08) lower AEE after adjusting for
      FFM and sex. CONCLUSIONS: The elevated REE and lower AEE, in combination with
      poor growth status, indicate chronic energy deficiency in children with SCD.
      Further studies are needed to determine the best approaches to the treatment and
      prevention of undernutrition in children with SCD.

PMID- 10636979
TI  - Gallstones in sickle cell disease: observations from The Jamaican Cohort study.
AB  - The prevalence, incidence, risk factors, clinical associations, and morbidity of
      gallstones were studied in 311 patients with homozygous sickle cell disease and
      167 patients with sickle cell-hemoglobin C disease in a cohort study from birth.
      Gallstones developed in 96 patients with homozygous sickle cell disease and 18
      patients with sickle cell-hemoglobin C disease; specific symptoms necessitating
      cholecystectomy occurred in only 7 patients with homozygous sickle cell disease.

PMID- 10636980
TI  - The prevalence of celiac disease in at-risk groups of children in the United
      States.
AB  - OBJECTIVE: In contrast to its prevalence in Europe, celiac disease (CD) is
      considered rare in the United States. We aimed to determine the prevalence of CD
      in children presenting with symptoms or conditions associated with CD. STUDY
      DESIGN: Individuals aged 6 months to 20 years were screened for IgG and IgA
      antigliadin (AGA-IgG and AGA-IgA) and antiendomysium (EMA) antibodies. Those with
      only elevated AGA-IgG were screened for selective IgA deficiency. Patients with
      elevated EMA, or AGA-IgG elevation and selective IgA deficiency, were advised to
      undergo small intestinal biopsy. RESULTS: A total of 1200 individuals were
      studied; 34 were EMA positive-26 (19 EMA positive) consented to biopsy and 21 had
      CD, giving a prevalence of 1 in 57 (21/1200). Including the 15 EMA positive
      patients who refused a biopsy, the prevalence of CD in this study could be as
      high as 1 in 33 (36/1200). CONCLUSIONS: CD is not rare in the United States and
      may be as common as in Europe. AGA and EMA are useful for identifying patients
      who should undergo a small intestinal biopsy.

PMID- 10636981
TI  - Methotrexate and corticosteroid therapy for pediatric localized scleroderma.
AB  - INTRODUCTION: Localized scleroderma (LS) can cause permanent disability, and
      there is no universally accepted effective treatment. Methotrexate (MTX) has been
      shown to be effective in the treatment of systemic sclerosis. OBJECTIVES: To
      determine the efficacy and tolerability of MTX and corticosteroid therapy in
      patients with LS. METHODS: MTX, 0.3 to 0.6 mg/kg per week, was given to 10
      patients (6 girls, 4 boys; mean age, 6.8 years; mean disease duration before
      starting treatment, 4 years) with active LS. In addition, pulse intravenous
      methylprednisolone, 30 mg/kg for 3 days monthly for 3 months, was given to 9
      patients at the initiation of therapy. RESULTS: One patient discontinued taking
      MTX after a month; the remaining 9 patients responded. The median time to
      response was 3 months (95% CI, 1.15-4.85). One responder discontinued taking MTX
      after a year because of leukopenia; the LS worsened within 2 months. In another
      patient LS flared up after 10 months and responded to an increased dose of MTX
      and intravenous methylprednisolone. At the last follow-up visit, all patients who
      continued to receive MTX therapy had inactive skin lesions. CONCLUSION: Treatment
      with MTX and corticosteroids appears to be effective in the treatment of LS and
      is generally well tolerated. A placebo-controlled study is necessary to confirm
      the efficacy of MTX therapy in LS.

PMID- 10636982
TI  - Is short stature a handicap? A comparison of the psychosocial functioning of
      referred and nonreferred children with normal short stature and children with
      normal stature.
AB  - OBJECTIVES: Normal short stature (NSS), defined as height below the 5th
      percentile for age and sex norms that is not due to illness, hormonal deficiency,
      or part of a dysmorphic syndrome, has been thought to have a deleterious effect
      on psychosocial functioning based on observations of referred populations. Recent
      studies of nonreferred children with NSS, however, have demonstrated normal
      function. This study directly compared the psychosocial functioning of referred
      children with NSS, nonreferred children with NSS, and children with normal
      stature. STUDY DESIGN: Participants, 90 children (46 boys, 44 girls) between 6
      and 12 years of age (mean, 9. 6 years), were administered intelligence and
      achievement tests. Parents and teachers assessed adaptive and problem behaviors.
      Family adaptability and cohesiveness were measured. RESULTS: Intelligence and
      achievement for referred and nonreferred children with NSS were average. Referred
      children with NSS were reported to have more externalizing behavior problems and
      poorer social skills than nonreferred children with NSS and children in the
      control group. Family adaptability and cohesiveness were comparable across
      groups. CONCLUSIONS: Children with NSS have normal psychosocial function, and
      results suggest that externalizing behavior problems, attention problems, and
      poor social skills in children referred to clinics for NSS are inappropriately
      attributed to short stature.

PMID- 10636983
TI  - Growth hormone therapy for the short normal child: who needs it and who wants it?
      The case against growth hormone therapy.

PMID- 10636984
TI  - Acquired hypothyroidism in a very young infant with Omenn's syndrome.
AB  - A very young male infant with Omenn's syndrome had acquired hypothyroidism that
      was most likely caused by autoimmune thyroiditis. The hypothyroidism appeared at
      3 months of age. These 2 rare conditions have not previously been reported
      occurring together. This case suggests that autoimmune thyroiditis may be another
      abnormal finding in Omenn's syndrome.

PMID- 10636985
TI  - Basilar invagination as a sequela of multisystem Langerhans' cell histiocytosis.
AB  - We report the presence of basilar invagination, an unexpected and previously
      undescribed abnormality of the skull base, in 7 of 38 long-term survivors of
      multisystem Langerhans' cell histiocytosis. The abnormality is acquired, but its
      pathogenesis is uncertain.

PMID- 10636986
TI  - Time course of allergy to extensively hydrolyzed cow's milk proteins in infants.
AB  - We report on the follow-up of 22 infants allergic to cow's milk proteins who did
      not tolerate extensively hydrolyzed protein formulas. After successful use of an
      amino acid-based diet for a duration of 11.8 +/- 8.7 months, evolution differed
      according to the presence or absence of associated allergy to other foods. Cow's
      milk protein tolerance occurred earlier in the patients (n = 9) whose allergy was
      limited to cow's milk proteins and to extensively hydrolyzed protein formulas.

PMID- 10636987
TI  - Rapidly progressive cholestasis: An unusual reaction to amoxicillin/clavulanic
      acid therapy in a child.
AB  - Hepatotoxity associated with amoxicillin/clavulanic acid is usually a self
      limited disease with complete recovery. We report a rapidly progressing liver
      disease with ductopenia and portal fibrosis in a 3-year-old boy treated with
      Augmentin.

PMID- 10636988
TI  - Twentieth century's Nobel Prizes in physiology or medicine with a note on
      pediatric laureates.

PMID- 10636989
TI  - Insights: If the eye drops down.

PMID- 10636990
TI  - Possible decrease in prevalence of cerebral palsy in premature infants.

PMID- 10636991
TI  - Treatment of hemophagocytic lymphohistiocytosis with cyclosporin A and steroids
      in a boy with lysinuric protein intolerance.

PMID- 10636992
TI  - Reply

PMID- 10636993
TI  - Small hand joint involvement in juvenile rheumatoid arthritis.

PMID- 10636994
TI  - Reply

PMID- 10636996
TI  - Tetsuzo inouye, M.D

PMID- 10636995
TI  - Diagnostic dilemma caused by overlapping features of Prader-Willi syndrome and
      trisomy 18 during infancy.

PMID- 10636997
TI  - Safety of cryogen spray cooling during pulsed laser treatment of selected
      dermatoses.

PMID- 10636998
TI  - Temperature controlled CO(2) laser welding of soft tissues: urinary bladder
      welding in different animal models (rats, rabbits, and cats).
AB  - BACKGROUND AND OBJECTIVE: Laser welding of tissues is a method of closure of
      surgical incisions that, in principle, may have advantages over conventional
      closure methods. It is a noncontact technique that introduces no foreign body,
      the closure is continuous and watertight, and the procedure is faster and
      requires less skill to master. However, in practice, there have been difficulties
      in obtaining strong and reliable welding. We assumed that the quality of the weld
      depends on the ability to monitor and control the surface temperature of the
      welded zone during the procedure. Our objective was to develop a "smart"
      fiberoptic laser system for controlled temperature welding. STUDY
      DESIGN/MATERIALS AND METHODS: We have developed a welding system based on a CO(2)
      laser and on infrared transmitting AgClBr fibers. This fiberoptic system plays a
      double role: transmitting laser power for tissue heating and noncontact
      (radiometric) temperature monitoring and control. The "true" temperature of the
      heated tissue was determined by using an improved calibration method. We carried
      out long-studies of CO(2) laser welding of urinary bladders in various animal
      models. Cystotomies were performed on the animals, and complete closure of the
      bladder was obtained with a surface temperature of 55 +/- 5 degrees C at the
      welding site. RESULTS: In early experiments on 31 rats, the success rate was 73%.
      In later experiments with 10 rabbits and 3 cats, there was an 80% and a 100%
      success rate, respectively. CONCLUSION: The success rate in these preliminary
      experiments and the quality of the weld, as determined histologically,
      demonstrate that temperature controlled CO(2) laser welding can produce effective
      welding of tissues. The fiberoptic system can be adapted for endoscopic laser
      welding.

PMID- 10636999
TI  - Q-switch laser and tattoo pigments: first results of the chemical and
      photophysical analysis of 41 compounds.
AB  - BACKGROUND AND OBJECTIVE: In the Western world, there are at least 20-30 million
      people with tattoos. Improved self-image and social stigmatization are the main
      reasons for removing tattoos from skin. Q-switched lasers are applied to destroy
      the tattoo compounds in the skin. The treatment of tattoos containing ink often
      gives excellent results, whereas the results of treatments for coloured tattoos
      are not predictable and usually are worse. The chemical structure and the
      absorption spectra of the tattoo pigments are usually unknown. However, the
      efficacy of the treatment by using light of different Q-switched lasers
      (wavelengths 510, 532, 694, 755, 1064 nm) is correlated to both the chemical
      structure of the tattooed compounds yielding specific absorption spectra and the
      laser wavelength used. STUDY DESIGN/MATERIALS AND METHODS: A structural and
      spectroscopic analysis of 41 coloured pigments was performed. RESULTS: The 41
      substances were identified, and they consist of 16 individual chemicals of
      different structured well-known industrial organic pigments. The absorption
      spectra of the 16 pigments were measured quantitatively. CONCLUSION: The results
      of the present analysis explain to some extent the outcome of clinical studies
      regarding laser therapy of coloured tattoos. Because the laser energy used
      produces a high temperature in the azo or polycyclic pigments, it is necessary to
      investigate whether that change causes possibly toxic or cancerogenic compounds.

PMID- 10637001
TI  - Influence of the anagen:telogen ratio on Q-switched Nd:YAG laser hair removal
      efficacy.
AB  - BACKGROUND AND OBJECTIVE: Laser hair removal is believed to affect only anagen
      hairs. However, proof of this belief in humans is lacking. The objective of this
      study was to determine the influence of the anagen: telogen ratio on the results
      of Q-switched Nd:YAG laser hair removal. STUDY DESIGN/MATERIALS AND METHODS:
      Fifteen subjects had four test sites delineated in one body area. The test sites
      were chosen by trimming the hair and evaluating the area in 2 weeks. At that
      time, the anagen hairs were at least twice as long as the nongrowing telogen
      hairs and, therefore, could be differentiated and counted. Two sites with a low
      anagen number and two with a high number were chosen for comparison. All sites
      were then treated with a Q-switched Nd:YAG laser. Follow-up examination was in 1
      month. RESULTS: Test sites with a low anagen number demonstrated a low level of
      hair loss compared with those sites with a high anagen number. A significantly
      higher percentage of hair loss was noted when comparing the anagen-only with
      total hair loss. In addition, lasing plus shaving demonstrated more hair loss
      than lasing alone. These findings indicated that anagen hairs were clearly
      affected, but the immediate clinical effect on telogen hairs was minimal.
      CONCLUSION: Q-switched Nd:YAG laser treatment of anagen hairs results in a rapid
      switch to telogen and a subsequent clinically obvious shedding of the hair shaft.
      This process causes a greater percentage hair loss at sites with high anagen
      number. Telogen hairs demonstrate no such effect and remain in their pretreatment
      phase after lasing.

PMID- 10637000
TI  - Wound healing and collagen thermal damage in 7.5-microsec pulsed CO(2) laser skin
      incisions.
AB  - BACKGROUND AND OBJECTIVE: Wound-healing delays caused by lateral thermal damage
      to tissue remain a drawback of CO(2) surgical lasers. This study compares the
      thermal damage and wound-healing properties of a 7.5-micros pulsed CO(2) laser
      with scalpel and continuous wave (CW) CO(2) laser incisions. STUDY
      DESIGN/MATERIALS AND METHODS: We created incisions on the dorsal pelts of rats
      with a 7.5-micros pulsed CO(2) laser at 5-, 10-, or 15-Hz repetition rate, a
      conventional CW laser, or scalpel. Animals were euthanized at postoperative days
      3, 7, 14, 21, and 80. Tissue was harvested and analyzed histologically and for
      wound tensile strength. In addition, tissue was harvested acutely and analyzed
      for acute thermal injury lateral to the incisions. RESULTS: Incisions made with
      the pulsed laser had significantly higher tensile strength and histologic
      rankings than did CW laser incisions at days 3-21, producing 118 microm of
      thermal damage to tissue as compared with 333 microm for CW laser. Pulsed laser
      incisions were not statistically different than scalpel incisions at days 3-14 of
      healing. Mathematical modeling showed the pulsed laser to produce a wound healing
      delay of 1.0 day by tensiometry and 1.9 days by histology, compared with 3.2 days
      by tensiometry and 6.0 days by histology for CW laser. There were no significant
      differences in wound healing when the pulsed laser was used at repetition rates
      of 5-15 Hz. CONCLUSIONS: Using a 7.5-micros pulse duration, CO(2) laser incisions
      healed at a rate similar to scalpel incisions and reduced the wound-healing delay
      seen with typical surgical CO(2) lasers.

PMID- 10637002
TI  - Effect of low-intensity laser irradiation (660 nm) on a radiation-impaired wound
      healing model in murine skin.
AB  - BACKGROUND AND OBJECTIVE: The use of low-intensity laser therapy (LILT) as a
      therapeutic modality has become popular in a variety of clinical applications
      including the promotion of wound repair. Although the clinical evidence base for
      such application remains sparse, recent studies have demonstrated a number of
      quantifiable photobiological effects associated with such therapy. In the present
      study, the effect of laser irradiation at various radiant exposures on a
      radiation-impaired wound-healing model in murine skin was investigated. STUDY
      DESIGN/MATERIALS AND METHODS: The study included two phases; in phase one, male
      Balb/c mice (n = 36; age-matched at 10 weeks) were randomly allocated to three
      experimental groups (n = 12, each group). In all groups, a well-defined area on
      the dorsum was exposed to 20 Gy x-rays. Seventy-two hours postirradiation, all
      mice were anaesthetised and a 7 x 7 mm area wound was made on the dorsum. All
      wounds were videotaped alongside a marker scale (three times weekly) until
      closure was complete. In groups 2 and 3, mice were treated with laser irradiation
      (0.5 and 1.5 J/cm(2), respectively) three times weekly by using a 660-nm GaAlAs
      laser unit (5 kHz; 15 mW; Omega Laser Systems, London, UK). Wound areas were then
      calculated by using an image analysis system (Fenestra 2.1), and results were
      analyzed by using repeated measures and one-factor analysis of variance
      statistical tests. In phase two, two experimental groups were included (n = 12
      each group); the protocol was identical to that described for phase 1; however,
      mice in group 2 were treated with a radiant exposure of 4 J/cm(2). RESULTS:
      Results from this investigation demonstrated that treatment with 0.5, 1.5. and 4
      J/cm(2) had no beneficial effect on the rate of wound closure (P > 0.05).
      CONCLUSION: These findings provide little evidence of the putative stimulatory
      effects of LILT in vivo at the parameters investigated.

PMID- 10637003
TI  - Long-term effectiveness of photodynamic therapy by using a hydrophilic
      photosensitizer ATX-S10(Na) against experimental choroidal neovascularization in
      rats.
AB  - BACKGROUND AND OBJECTIVE: We previously demonstrated that a hydrophilic
      photosensitizer ATX-S10 had a potent photodynamic effect. This study was designed
      to reveal the long-term effectiveness of photodynamic therapy (PDT) with this
      agent in occluding choroidal neovascularization (CNV) and its selectivity in the
      neovascular tissue. STUDY DESIGN/MATERIALS AND METHODS: Experimental CNV was
      induced by intense photocoagulation in rat eyes. Immediately or 2 hours after
      intravenous injection of 8 mg/kg body weight of ATX-S10(Na), a cis isomer of ATX
      S10, eyes were irradiated by a diode laser at the radiance of 3.25-65.3 J/cm(2)
      Vascular occlusion was identified by fundus photography, fluorescein angiography,
      and histology at 1, 3, 7, 14, and 28 days after PDT. As controls, non-neovascular
      eyes were subjected to PDT and similarly analyzed. RESULTS: By using the
      following treatment parameters, PDT with ATX-S10(Na) successfully occluded CNV
      without causing occlusion of retinal capillaries for 28 days; 7.4 and 19.6
      J/cm(2) immediately after dye injection and 36.7 and 65.3 J/cm(2) 2 hours after
      injection. Although these conditions also caused occlusion of normal
      choriocapillaries and mild injuries of retinal vessels, retinal pigment
      epithelium, and photoreceptors at 1 day, retinal vessels and pigment epithelial
      cells recovered from damages by 28 days. No injuries were found in the inner
      retina. CONCLUSION: In optimal treatment conditions, PDT with ATX-S10(Na) can
      induce long-term, selective occlusion of CNV without causing irreversible damages
      in the inner retina.

PMID- 10637004
TI  - Optical integrating balloon device for photodynamic therapy.
AB  - BACKGROUND AND OBJECTIVES: It is difficult to deliver light uniformly and
      efficiently over the complex shapes presented by various organs for photodynamic
      therapy (PDT). A balloon delivery device for photodynamic therapy was designed
      and tested for treatment of various anatomic tissues. The device uses the
      principle of optical integration by multiple internal diffuse reflections to
      achieve uniform output illumination. STUDY DESIGN/MATERIALS AND METHODS: Soft,
      white, medical-grade silicone balloons were made in various shapes and tested for
      optical output, uniformity, efficiency, and power capabilities. Balloons were
      cast to be approximately the shape of the target tissue surface, organ, or
      cavity. Laser power was introduced into the saline-filled balloon by one or more
      fiber optics. Devices were constructed and used to illuminate oral mucosa and
      uterine endometrium for PDT. RESULTS: The balloon walls had low optical
      absorption, high diffuse reflectivity (80-95%), and low diffuse transmittance (5
      20%) in the 500- to 900-nm wavelength region. Optical efficiencies of 65% were
      typical with emitted light over complex, nonspherical surfaces. Efficiency
      increased with inflation of the device, such that irradiance (power/area) at the
      balloon surface was nearly constant with inflation. CONCLUSION: Optically
      integrating balloons can provide highly uniform, efficient light exposure over
      complex tissue surfaces. Uniformity and irradiance were not strongly affected by
      balloon inflation, and these robust devices are easy to produce in essentially
      any shape.

PMID- 10637005
TI  - Development of stereotactically guided laser interstitial thermotherapy of breast
      cancer: in situ measurement and analysis of the temperature field in ex vivo and
      in vivo adipose tissue.
AB  - BACKGROUND AND OBJECTIVE: The size (0.5-1.0 cm) of early nonpalpable breast
      tumors currently detected by mammography and confirmed by stereotactic core
      biopsy is of the order of the penetration depth of near infrared photons in
      breast tissue. In principle, stereotactically biopsied tumors, therefore, could
      be safely and efficiently treated with laser thermotherapy. The aim of the
      current study is to confirm the controlled heating produced by clinically
      relevant power levels delivered with an interstitial laser fiber optic probe
      adapted for use with stereotactic mammography and biopsy procedures. STUDY
      DESIGN/MATERIALS AND METHODS: Temperature increases and the resultant thermal
      field produced by the irradiation of ex vivo (porcine and human) and in vivo
      (porcine) tissue models appropriate to the treatment of human breast tissue by
      using cw Nd:YAG laser radiation delivered with a interstitial fiber optic probe
      with a quartz diffusing tip, were recorded with an array of fifteen 23-gauge
      needle thermocouple probes connected to a laboratory computer-based data
      acquisition system. RESULTS: By using a stepwise decreasing power cycle to avoid
      tissue charring, acceptably symmetric thermal fields of repeatable volumetric
      dimensions were obtained. Reproducible thermal gradients and predictable tissue
      necrosis without carbonization could be induced in a 3-cm-diameter region around
      the fiber probe during a single treatment lasting only 3 minutes. The time
      dependences of the temperature rise of the thermocouples surrounding the LITT
      probe were quantitatively modeled with simple linear functions during the applied
      laser heating cycles. CONCLUSION: Analysis of our experimental results show that
      reproducible, symmetric and predictable volumetric temperature increases in time
      can be reliably produced by interstitial laser thermotherapy.

PMID- 10637006
TI  - Preliminary evaluation of two fluorescence imaging methods for the detection and
      the delineation of basal cell carcinomas of the skin.
AB  - BACKGROUND AND OBJECTIVE: Fluorescence techniques can provide powerful
      noninvasive means for medical diagnosis, based on the detection of either
      endogenous or exogenous fluorophores. The fluorescence of delta-aminolevulinic
      acid (ALA)-induced protoporphyrin IX (PpIX) has already shown promise for the
      diagnosis of tumors. The aim of the study was to investigate the localization of
      skin tumors after the topical application of ALA, by detecting the PpIX
      fluorescence either in the spectral or in the time domain. STUDY DESIGN/MATERIALS
      N AND METHODS: Two fluorescence imaging systems were used to identify basal cell
      carcinomas of the skin in humans, after topical application of 20% ALA ointment.
      Both systems rely on the comparison between the exogenous and the endogenous
      fluorescence, performed either in the spectral domain or in the time domain. The
      first system works by using three images acquired through different spectral
      filters, whereas the second one measures the spatial map of the average
      fluorescence lifetime of the sample. RESULTS: A clear demarcation of skin
      malignancies was successfully performed in vivo noninvasively with both
      fluorescence imaging systems. CONCLUSION: The two complementary approaches
      considered in the present study show promise for skin tumor detection and
      delineation based on specific fluorescence features.

PMID- 10637007
TI  - Localization of experimental submucosal esophageal tumor in rabbits by using mono
      L-aspartyl chlorin e6 and long-wavelength photodynamic excitation.
AB  - BACKGROUND AND OBJECTIVE: To increase the applicability of photodynamic diagnosis
      with regard to deep-seated tumor, we illuminated tumors with a long-wavelength
      laser beam after photosensitization with mono-L-aspartyl chlorin e6 (NPe6). STUDY
      DESIGN/MATERIALS AND METHODS: Rabbits with VX2 esophageal tumors were divided
      into four groups. The control group was not treated, and the other three groups
      were injected with 1, 2.5, and 5 mg/kg mono-L-aspartyl chlorin e6 (NPe6),
      respectively. After excitation with a 664-nm laser beam (10 mW, 10 seconds), the
      fluorescence image and the relative fluorescence intensity (tumor/normal tissue)
      were recorded every 2 hours up to 8 hours by a newly developed diode laser
      endoscopic fluorescence imaging system. The tissue concentration of NPe6 was
      examined by high performance liquid chromatography at 2, 4, and 6 hours after
      injection with 1 and 5 mg/kg NPe6. RESULTS: The diode laser endoscopic
      fluorescence imaging system was able to selectively detect fluorescence from
      submucosal tumor by comparison with the surrounding normal mucosa after NPe6
      injection. The fluorescence intensity correlated with NPe6 dose, selectively
      accumulated in the tumor tissue and relative intensity peaked at 6 hours after
      injection. No fluorescent images were detected in controls. CONCLUSION: Given
      intravenously, NPe6 at a dose of 5 mg/kg and excited with a 664-nm wavelength
      laser beam 6 hours later can define experimentally induced deep-seated esophageal
      carcinoma in rabbits, by using an endoscopic fluorescence imaging system.

PMID- 10637014
TI  - Medical errors. Patient, protect thyself.

PMID- 10637013
TI  - Medical economics. Seven ways to cut your pill bill.

PMID- 10637015
TI  - COX-2 inhibitors. Magic bullets or merely mortal?

PMID- 10637016
TI  - Love and health. Cupid's arrows.

PMID- 10637017
TI  - Diabetes. Policing your blood sugar.

PMID- 10637018
TI  - Insulin. A memory hormone?

PMID- 10637019
TI  - By the way, doctor... I am 87 and have been taking blood pressure medications for
      years. In the past, side effects were a problem, but for about the last year I've
      done very well taking valsartan (Diovan) and hydrochlorothiazide (Esidrex). Now
      My blood pressure is about 165/72 mm hg. The top number seems high. One doctor
      told me that as long as the bottom number is low, I shouldn't be concerned. But I
      am. My father died from a stroke many years ago, and I'm pretty sure he had high
      blood pressure.

PMID- 10637020
TI  - Violence and mental health - part II.

PMID- 10637022
TI  - Negotiating the alliance.

PMID- 10637021
TI  - Temperament and mood disorders.

PMID- 10637023
TI  - Forum. What are the mental health complications of steroid therapy?

PMID- 10637024
TI  - Supplements: a scorecard.

PMID- 10637025
TI  - Nocturnal erections.

PMID- 10637026
TI  - Coronary artery disease: a lifelong process.

PMID- 10637027
TI  - Ask the doctor: I just got a new pair of soft contact lenses. They are very
      comfortable, and my ophthalmologist told me I can keep them in for a week. I'd
      like to wear them all the time, but I'm not sure it's safe. What do you think?

PMID- 10637028
TI  - Echinacea vs. the common cold.

PMID- 10637029
TI  - Respiratory illnesses. Asthma in women.

PMID- 10637031
TI  - Exercise. Pilates incorporates mind and body.

PMID- 10637030
TI  - Mental health. Relieving depression.

PMID- 10637032
TI  - By the way, doctor. I've been trying to get enough fiber in my diet without
      adding too many calories. Are fiber supplements like Metamucil just as good as
      the fiber found naturally in food? They are certainly a lot easier to track and
      have less calories than food.

PMID- 10637033
TI  - By the way, doctor. I'm 53 and have been taking HRT with Estradiol and Prometrium
      daily for about a year. Should I also take a soy vitamin supplement? I took one
      before starting HRT because I thought it was supposed to prevent breast cancer.
      But I want to be on as little estrogen as possible. Will soy along with estrogen
      increase my risk of breast tumors?

PMID- 10637035
TI  - Feed a cold, starve a fever, poison a headache.

PMID- 10637036
TI  - By the way, doctor... After I get a cold, I get a dry cough that lasts for
      months. Eventually It goes away, but not before I drive myself and everyone
      around me crazy. Any suggestions?

PMID- 10637037
TI  - PTSD: the long view.

PMID- 10637038
TI  - By the way, doctor. I am 68 years old and healthy. For the past two years, I've
      gotten a flu shot in October. Nonetheless, both winters I experienced what felt
      like influenza. I was thrilled to read about a new flu treatment. If I get the
      flu again this year, should I try the drug?

PMID- 10637040
TI  - Journal of agricultural and food chemistry-2000

PMID- 10637039
TI  - By the way, doctor. Although I've always been prone to cold hands and feet, this
      winter my hands began to turn blue and really ache in the cold. My doctor
      suspects Raynaud's phenomenon. Is this a common condition? Should I do anything
      more for this than wear warm gloves?

PMID- 10637041
TI  - Synthesis of structured triacylglycerols by lipase-catalyzed acidolysis in a
      packed bed bioreactor.
AB  - Structured triacylglycerols (ST) from canola oil were produced by enzymatic
      acidolysis in a packed bed bioreactor. A commercially immobilized 1,3-specific
      lipase, Lipozyme IM, from Rhizomucormiehei, was the biocatalyst and caprylic acid
      the acyl donor. Parameters such as substrate flow rate, substrate molar ratio,
      reaction temperature, and substrate water content were examined. High-performance
      liquid chromatography was used to monitor the reaction and product yields. The
      study showed that all of the parameters had effects on the yields of the expected
      di-incorporated (dicaprylic) ST products. Flow rates below 1 mL/min led to
      reaction equilibrium, and lower flow rates did not raise the incorporation of
      caprylic acid and the product yield. Incorporation of caprylic acid and the
      targeted di-incorporated ST was increased by approximately 20% with temperature
      increase from 40 to 70 degrees C. Increasing the substrate molar ratio from 1:1
      to 7:1 increased the incorporation of caprylic acid and the product yield
      slightly. Water content in the substrate also had a mild influence on the
      reaction. Water content at 0.08% added to the substrate gave the lowest
      incorporation and product yield. The use of solvent in the medium was also
      studied, and results demonstrated that it did not increase the reaction rate at
      55 degrees C when 33% hexane (v/v) was added. The main fatty acids at the sn-2
      position of the ST were C(18:1), 54. 7 mol %; C(18:2), 30.7 mol %; and C(18:3),
      11.0 mol %.

PMID- 10637042
TI  - Influence of the physical state of water on the barrier properties of hydrophilic
      and hydrophobic films.
AB  - Water transfer through different films, as a function of the physical state of
      water in contact with the film, the relative humidity difference, and the water
      vapor pressure difference, was investigated. The films were two synthetic
      packagings (hydrophobic polyethylene and hydrophilic cellophane) and an edible
      film. The physical state of water affects water sensitive films, such as
      cellophane, inducing a higher liquid water transfer due to interactions with the
      polymer. For hydrophobic polymers, such as polyethylene, neither the physical
      state of water nor the relative humidity has an influence on the water
      permeability. In complex system, such as an edible film composed of hydrophilic
      particles dispersed in a lipid phase, barrier efficiency is influenced by the
      continuous hydrophobic phase but could also be affected by the physical state of
      water due to the presence of hydrophilic compounds.

PMID- 10637044
TI  - Editor's change of address

PMID- 10637043
TI  - Preparation of neoglycoprotein from carp myofibrillar protein and alginate
      oligosaccharide: improved solubility in low ionic strength medium.
AB  - Alginate oligosaccharide (AO) was conjugated with carp myofibrillar protein (Mf)
      by using the controlled Maillard reaction, and the change in the solubility of Mf
      in low ionic strength media as affected by the glycosylation was investigated. AO
      was prepared by degrading sodium alginate using alginate lyase, which was
      purified from the culture supernatant of Pseudoalteromonas elyakovii. When a
      lyophilized Mf and AO mixture was incubated at 40 degrees C and 65% relative
      humidity, the conjugation of AO was confirmed at myosin heavy chain, actin, and
      tropomyosin. When >30 microg/mg of AO was conjugated to Mf, the protein
      solubility in a low ionic strength medium was greatly improved without
      significant loss of available lysine. These results indicate that the conjugation
      with AO is a superior manner for improving the water solubility of Mf in view of
      its nutritional aspect.

PMID- 10637045
TI  - "Cyclamen Red" colors based on a macrocyclic anthocyanin in carnation flowers.
AB  - The "cyclamen" red (or pink) colors in carnation flowers-cultivars Red Rox and
      eight others-are based on the presence of a new macrocyclic anthocyanin,
      pelargonidin 3,5-di-O-beta-glucoside(6' ', 6' "-malyl diester) identified by
      spectroscopic methods. The instability of the bridging malyl group with sugars in
      acidic medium readily causes the formation of the opened ring form, 3-O-(6' '-O
      malylglucoside)-5-O-glucoside. The issue of cyclamen colors based in carnations
      on this original acylated pelargonidin derivative simulating those based on
      simpler cyanidin glycosides in Rosa cultivars is discussed using CIELAB
      colorimetric coordinates.

PMID- 10637046
TI  - Development of immunoassays for tyramine and tryptamine toxins of Phalaris
      aquatica L.
AB  - The leaves of the perennial pasture grass Phalaris aquatica L. (phalaris) contain
      two groups of known toxins, indole alkaloids, primarily dimethyltryptamines and N
      methyltyramines, which cause illnesses in grazing animals, especially sheep.
      Using amino-reactive and phenolic hydroxyl-reactive homobifunctional reagents,
      simple methods were devised for coupling toxins representative of those in
      phalaris to carrier proteins and enzymes for ELISA development. ELISAs were
      produced for both groups of toxins. Dimethyltryptamines were most sensitively
      detected [lower limit of detection (LLD) of 1 microg/L for bufotenine] using
      rabbit anti-bufotenine antibodies, coupled to ovalbumin using divinyl sulfone,
      with detection using a peroxidase conjugate prepared using the same hapten
      coupled with 1, 4-butanediol diglycidyl ether. The assay cross-reacted with other
      toxins of the same class (N,N-dimethyltryptamine and N, N-dimethyl-5
      methoxytryptamine) but not with the structurally related amino acids histidine
      and tryptophan. The most sensitive N-methyltyramine assay (LLD of 1 microg/mL for
      N-methyltyramine) utilized antisera to tyramine with N-methyltyramine coupled to
      peroxidase. Significant cross-reaction was seen with the low-grade toxin
      hordenine, but detection of tyramine was poorer, whereas the amino acid tyrosine
      was not detected. These assays could be applied to the analysis of simple
      extracts of Phalaris leaves with minimal interference. A good correspondence was
      observed between toxin levels by ELISA and estimates from a more tedious thin
      layer chromatography method. The method has now been incorporated in a Phalaris
      breeding program.

PMID- 10637047
TI  - Application of an ELISA to the determination of benalaxyl in red wines.
AB  - The applicability of an ELISA for detection and quantification of benalaxyl in
      red wine samples is described. The study of the influence of this matrix on the
      reliability of the assay indicates that red wine samples require a rapid and
      simple cleanup step before ELISA assay. Recovery and precision of the method were
      evaluated by spiking red wine samples with benalaxyl in the 0.5-24 ng/mL range.
      Benalaxyl can be determined with good accuracy and precision up to 0. 5 ng/mL in
      starting red wine samples (detection limit of 0.13 ng/mL). No false negative or
      positive results were obtained. Authentic red wine samples were analyzed by ELISA
      and by RP-HPLC. The amounts of benalaxyl found by ELISA were in good agreement
      with RP-HPLC analysis.

PMID- 10637048
TI  - Epimeric separation of L-ascorbic acid and D-isoascorbic acid by capillary zone
      electrophoresis.
AB  - Capillary zone electrophoresis (CZE) was used for separation of L-ascorbic acid
      (L-AA) and D-isoascorbic acid (D-IAA) in a model system. The effects of borate
      buffer concentration (0.05-0.25 M) and pH (pH 7.5-9.0) on migration time,
      resolution (Rs), and theoretical plates (N) were investigated. The migration
      times of L-AA and D-IAA increased with the increasing pH of carrier electrolyte
      (0.2 borate buffer), and the resolutions (Rs) of L-AA and D-IAA were calculated
      to be 12.98 at pH 9.0. Concentrations of borate buffer (pH 9.0) increased the Rs
      values of L-AA and D-IAA, and buffer concentrations >0.1 M were found to be
      effective for separation of L-AA and D-IAA. Methanol in the carrier electrolyte
      was also influential in improving the separation of L-AA and D-IAA, which
      increased with the increasing concentrations (0-10%) of methanol. The optimal
      separation conditions for L-AA and D-IAA were as follows: carrier electrolyte,
      0.2 M borate buffer (pH 9.0); applied voltage, 25 kV, with an uncoated fused
      silica capillary, 75 microm (i.d.) x 57 cm.

PMID- 10637049
TI  - Application of directly coupled HPLC-NMR-MS/MS to the identification of
      metabolites of 5-trifluoromethylpyridone (2-hydroxy-5-trifluoromethylpyridine) in
      hydroponically grown plants.
AB  - Directly coupled HPLC-NMR-MS was used to characterize two major metabolites of 5
      trifluoromethylpyridone (2-hydroxy-5-trifluoromethylpyridine), a model compound
      for herbicides, after it had been dosed into hydroponically grown maize plants.
      The combination of NMR and MS data allowed the identification of both of these
      metabolites, namely, the N-glucoside and O-malonylglucoside conjugates of the
      parent pyridone. This work demonstrates the efficiency and the potential
      application of HPLC-NMR-MS to the investigation of the metabolism of
      agrochemicals. The work also indicates that combination of the use of
      hydroponically grown plants and directly coupled HPLC-NMR-MS allows rapid
      identification of metabolites with little sample preparation.

PMID- 10637050
TI  - Use of microcalorimetry in monitoring stability studies. Example: vitamin A
      esters.
AB  - Vitamin A is very sensitive to chemical degradation caused by oxygen, light,
      heat, and other stress factors. If light and oxygen are excluded, the dominant
      degradation reaction for vitamin A derivatives is heat-induced formation of
      kitols, that is, dimers or higher oligomers. In this study vitamin A esters were
      used as model systems to evaluate microcalorimetry as a tool for monitoring the
      stability of heat sensitive substances. To obtain more knowledge about the model
      reaction, analytical investigations (supercritical fluid chromatography) were
      also performed. Because analytical and microcalorimetry data were consistent, a
      quantitative description of the kinetics and thermodynamics of the kitol
      formation reaction could be obtained. Aside from the academic motivation, this is
      important for practical purposes such as shelf life stability of vitamin A in
      feed, food, and pharmaceutical products. The vitamin A stability of a given
      sample can easily be predicted from the initial heat flow in a simple
      microcalorimetry experiment. Compared to conventional stability tests, this
      offers savings of money and time.

PMID- 10637051
TI  - Mass spectrometric identification and high-performance liquid chromatographic
      determination of a flavonoid glycoside naringin in human urine.
AB  - The aim of this study was to evaluate the absorption of a citrus flavonoid,
      naringin, as its glycosylated form. Six healthy volunteers (three males and three
      females) were studied. After a single oral administeration of 500 mg of naringin,
      intact naringin was isolated from 2-4 h urine. Isolated naringin was identified
      by the LC/electrospray ionization mass spectrometry (ESI-MS), MS/MS, and MS/MS/MS
      techniques. The cumulative urinary excretion of naringin and its metabolites
      (naringenin and naringenin glucuronides) was determined by HPLC for 0-24 h.
      Approximately 0.02% of the administered dose was recovered in urine as unchanged
      naringin, whereas urinary recoveries of naringenin and naringenin glucuronides
      were approximately 0.4 and 3.6% of the administered dose, respectively. It was
      concluded that trace amounts of orally administered naringin can be absorbed as
      the glycoside. However, it is not clear whether the glycoside is cleaved before
      or after absorption to generate naringenin.

PMID- 10637052
TI  - Multiresidue screen for cardiotoxins by two-dimensional thin-layer
      chromatography.
AB  - A two-dimensional thin-layer chromatographic method was developed for the
      qualitative determination of the cardiotoxins oleandrin, gitoxin, digitoxin,
      gitoxigenin, and grayanotoxins I, II, and III in gastrointestinal contents
      (stomach, rumen, colon, and cecum contents), feces, and plant material. The
      cardiotoxins were extracted with dichloromethane. The extract was cleaned up by
      charcoal and reverse phase solid-phase extraction columns. Analysis was performed
      by two-dimensional thin-layer chromatography on silica gel plates and visualized
      by aluminum chloride followed by chloramine T spray. The method detection limits
      were 0.05 microg/g for oleandrin, 0.1 microg/g for gitoxin, and 0.2 microg/g for
      the other toxicants in gastrointestinal contents and feces and were 5 times
      higher in plant material. Four replicate fortifications of bovine rumen contents,
      bovine feces, and alfalfa at these levels were all well recovered. The diagnostic
      utility of the method was tested by analyzing samples submitted to the veterinary
      toxicology laboratory.

PMID- 10637053
TI  - Comparison of extraction buffers for the detection of fumonisin B(1) in corn by
      immunoassay and high-performance liquid chromatography.
AB  - The Associatian of Official Analytical Chemists approved method for
      quantification of fumonisin B(1) (FB(1)) in corn meal or corn-based food products
      includes extraction into methanol (MeOH)/water (3:1, v/v). Disposal of the
      extraction medium can pose safety and environmental problems. To secure a rapid
      and inexpensive screen for FB(1) contamination, a sensitive competitive ELISA
      using a rabbit polyclonal antibody was developed. This assay was used in a
      comparative study measuring the extraction efficiency of FB(1) in aqueous or
      organic solvent buffers using 16 field corn samples. An aqueous phosphate buffer
      was found to be suitable for extracting FB(1), thus eliminating the need for
      organic solvents. HPLC and ELISA determinations compared well in fortified
      samples at known concentrations between 1 and 50 microg/mL of extract.
      Overestimation at levels >50 microg/mL were common. The characteristics and
      application of the ELISA for screening purposes are discussed.

PMID- 10637054
TI  - Potent aroma compounds of two red wine vinegars.
AB  - Gas chromatography olfactometry (GCO) was used to determine key aroma compounds
      of two red wine vinegars. Sensory analysis was performed to choose the best
      neutralization agent of acetic acid (NaOH or MgO) and to test representativeness
      of four extracts obtained by different methods (dichloromethane extraction, XAD
      2, mixture of XAD-2 and XAD-7, and Extrelut resins extraction). Neutralization
      with NaOH followed by dichloromethane extraction was selected to extract volatile
      compounds of vinegars. Key odorant compounds were determined by GCO based on
      detection frequency with 13 people. In the two red wine vinegars, 13 odors were
      perceived by at least 70% of the panelists, and 8 compounds among the 13 were
      identified: acetic acid, 3-methylbutyric acid, 2-phenyl-1-ethanol, 2, 3
      butanedione, butyric acid, 2-methylbutyric acid, mixture of 2- and 3-methyl-1
      butanol, and two newly identified compounds in vinegar, 3-hydroxy-2-pentanone and
      3-(methylthio)-1-propanal. Quantification of all the volatile compounds was
      performed by GC-FID, and 10 other compounds were identified for the first time in
      wine vinegar.

PMID- 10637055
TI  - Hydroxymethylfurfural and furosine reaction kinetics in tomato products.
AB  - The reaction kinetics of two heat damage indices, HMF and furosine, were examined
      in four tomato products with different dry matter contents (10.2, 25.5, 28.6, and
      34.5%) over a temperature-time range of 80-120 degrees C and 0-255 min. The
      reactions followed pseudo-zero order kinetics. E(a) and z-value were,
      respectively, 139. 9 kJ/mol and 19.2 degrees C for HMF, and 93.9 kJ/mol and 28.4
      degrees C for furosine. The analyses of both indices in several samples of
      commercial and industrial tomato products showed very low levels of HMF (from 1
      to 42 ppm) and a lack of correlation between HMF and furosine mainly because of
      the different evolution of the two indices during storage. The HMF level of a
      tomato paste sample stored at 25 degrees C decreased from 609 to 17 ppm after 98
      days, while furosine increased from 458 to 550 mg/100 g of protein.

PMID- 10637056
TI  - Synthesis of phenoxyphenyl pyridine and pyrazine carboxamides. Activity against
      Cydia pomonella (L.) eggs.
AB  - Several N-(4-phenoxyphenyl)pyridinecarboxamides and N-(4
      phenoxyphenyl)pyrazinecarboxamides were synthesized from commercially available
      material, and their ovicidal activities against Cydia pomonella (L.) were tested.
      Some of the tested products showed a moderate activity when <24-h-old eggs were
      sprayed using a Potter tower. A significant increase in the length of the
      development period of the eggs was also observed in many cases. A clear
      correlation between both effects was noticed: the products that produced higher
      mortality also produced higher increase of the length of the development. These
      results seem to confirm our hypothesis that these compounds could be defined as a
      juvenile hormone analogues.

PMID- 10637057
TI  - Insecticidal activity of Maytenus species (Celastraceae) nortriterpene quinone
      methides against codling moth, Cydia pomonella (L.) (Lepidoptera: tortricidae).
AB  - The insecticidal effects of nortriterpene quinone methides (pristimerin,
      tingenonee, and 20-alpha-hydroxytingenone) are reported for the first time. The
      natural products were isolated from Maytenus sp. (Celastraceae) and their effects
      tested on larvae of codling moth (Cydia pomonella, Lepidoptera: Tortricidae). The
      three metabolites produce the same effects on codling moth larvae that
      azadirachtin does, although at higher concentrations. 20-alpha-Hydroxytingenone
      was the most active compound, showing lethal, antifeedant, and insect growth
      regulation activities. Pristimerin showed also a high antifeedant activity
      together with its molt effect suppression. Tingenone showed the lowest activity.
      The differences in the activity of the three products are related to the
      structure of the E ring.

PMID- 10637058
TI  - Natural soil colloids To retard simazine and 2,4-D leaching in soil.
AB  - Natural or synthetic sorbents for pesticides can be used to reduce contamination
      of soils and natural waters. The sorption of simazine and 2,4-D on
      montmorillonite minerals has been studied and their potential use to retard
      pesticide leaching in soil evaluated. Simazine and 2,4-D did not sorb on high
      layer charge montmorillonite, whereas sorption on the lower layer charge
      montmorillonite SWy varied depending on the saturating cation. Simazine sorption
      increased in the order Ca(2+)SWy << K(+)SWy < Fe(3+)SWy. Simazine molecules sorb
      on hydrophobic microsites of the montmorillonite. Once protonated, further
      sorption through cation exchange takes place in the interlamellar space of the
      montmorillonite, as corroborated by X-ray diffraction and FT-IR studies. 2,4-D
      does not sorb on K(+)SWy or Ca(2+)SWy, but does sorb on Fe(3+)SWy, because the
      acidic character of this sorbent allows the molecular form of 2, 4-D to sorb by
      hydrogen bonding and/or by hydrophobic interactions. Leaching experiments in hand
      packed soil columns indicate that simazine and 2,4-D application as a complex
      with FeSWy renders later breakthrough and lower maximum concentration peaks, and
      the total herbicide leached is lower than when applied as the pure analytical
      grade compound. These results suggest the possible use of natural soil colloids
      as sorbents for herbicides such as simazine and 2,4-D to retard pesticide
      leaching in soil, thus reducing their ground water contamination potential.

PMID- 10637059
TI  - Inositol hexaphosphate hydrolysis by Baker's yeast. Capacity, kinetics, and
      degradation products.
AB  - Phytases hydrolyze myo-inositol 1,2,3,4,5,6-hexaphosphate (IP(6)), yielding lower
      inositol phosphates and inorganic orthophosphate. Two commercial strains of
      baker's yeast (Saccharomyces cerevisiae), Y(1) and Y(2), were able to express
      phytase activity. This was determined by the capacity to grow in a synthetic
      medium with IP(6) as the sole phosphorus source. IP(6) hydrolysis was rapid for
      both strains, and after 24 h, all IP(6) was degraded. Control cultures contained
      inorganic orthophosphate (P(i)) and no IP(6). Growth rate in IP(6) medium was for
      both strains essentially identical to growth in P(i) medium, indicating a well
      adapted metabolism for utilization of phosphorus from IP(6). There was some
      difference in growth yield (milligrams of biomass per milligram of glucose)
      between the two strains: 0.95 (Y(1)) and 1.35 (Y(2)) in IP(6) medium and 1.03 and
      1. 35, respectively, in P(i) medium. The phytases were of the 3-phytase type,
      forming mainly DL-Ins(1,2,4,5,6)P(5), DL-Ins(1,2,5,6)P(4), and DL-Ins(1,2,6)P(3).

PMID- 10637060
TI  - Isolation, purification, and characterization of a cold-active lipase from
      Aspergillus nidulans.
AB  - Aspergillus nidulans WG312 strain secreted lipase activity when cultured in
      liquid media with olive oil as carbon source. Highest lipase productivity was
      found when the mycelium was grown at 30 degrees C in a rich medium. The new
      enzyme was purified to homogeneity from the extracellular culture of A. nidulans
      by phenyl-Sepharose chromatography and affinity binding on linolenic acid
      agarose. The lipase was monomeric with an apparent M(r) of 29 kDa and a pI of
      4.85 and showed no glycosylation. Kinetic of enzyme activity versus substrate
      concentration showed a typical lipase behavior, with K(M) and K(cat) values of
      0.28 mM and 494 s(-)(1) and 0.30 mM and 320 s(-)(1) for the isotropic solution
      and for the turbid emulsion, respectively. All glycerides assayed were hydrolyzed
      efficiently by the enzyme, but this showed preference toward esters of short- and
      middle-chain fatty acids. The optimum temperature and pH for the lipolytic
      activity were 40 degrees C and 6.5, with high activity in the range 0-20 degrees
      C and reduced thermal stability.

PMID- 10637061
TI  - Effects of hen egg yolk immunoglobulin in passive protection of rainbow trout
      against Yersinia ruckeri.
AB  - Anti-Yersinia ruckeri egg yolk immunoglobulin (IgY) was transferred to egg yolk
      after immunization of White Leghorn hens with formalin-killed whole cells of
      serovar 1 (RS1154) and serovar 2 (RS1153)Y. ruckeri and its lipopolysaccharide
      (LPS). The IgY was specific for its homologous LPS in western immunoblot, whereas
      some protein bands were commonly recognized, even by IgY from eggs of unimmunized
      hens. Purified LPS from both Y. ruckeri serovar types 1 and 2 had a very poor
      immunogenicity. The IgY activity was stable when processed into pellet form by a
      microbial transglutaminase treatment and showed a considerable resistance against
      acid pepsin for at least 2 h. Feeding specific anti-serovar 1 Y. ruckeri IgY to
      fish either before or after immersion infection produced marginal reductions in
      mortalities and in intestine infection. The same IgY did passively protect
      rainbow trout against infection when administered by intraperitoneal injection 4
      h before an immersion challenge.

PMID- 10637062
TI  - Release of lipids during yeast autolysis in a model wine system.
AB  - The release of lipids during the aging of sparkling wines in contact with yeast
      can influence wine sensory attributes and, especially, foam characteristics.
      Model systems allow study of the autolysis process in a reasonable period of time
      compared to natural conditions, at which it can last several months. In this
      paper, the release of the different classes of lipids during the autolysis of
      three commercial yeast strains in a model wine medium has been monitored. Due to
      the absence of accurate quantitative methods, an HPLC method for separating and
      quantifying the different neutral and polar yeast lipid classes was developed.
      Lipids were eluted through a YMC PVA-Sil column with a complex solvent mixture.
      Detection was carried out with a light-scattering detector. The yeasts were
      suspended in the model wine buffer and incubated at 30 degrees C for up to 12
      days. A release of triacylglycerols, 1,3-diacylglycerols, 2-monoacylglycerols,
      free fatty acids, sterol esters, and sterols was observed over the first 2 days,
      a period that corresponded to the maximum loss of yeast viability. A decrease in
      most of these lipids was observed from day 2, possibly indicative of the release
      of yeast hydrolytic enzymes due to the breakdown of the cell wall. Phospholipids
      were not detected in any of the autolysates. The mean lipid content in the
      autolysates as a percentage of the total lipid content in the yeasts was 8.6% for
      sterol esters, 3.8% for sterols, 2% for triacylglycerols, and <2% for 1,3
      diacylglycerols and free fatty acids.

PMID- 10637063
TI  - Behavior of estrogen-associated female genital tract cancer and its relation to
      neoplasia following intrauterine exposure to diethylstilbestrol (DES).

PMID- 10637064
TI  - Intraperitoneal versus intravenous cisplatin in combination with intravenous
      cyclophosphamide and epidoxorubicin in optimally cytoreduced advanced epithelial
      ovarian cancer: a randomized trial of the Gruppo Oncologico Nord-Ovest.
AB  - Intraperitoneal chemotherapy has a strong biological and pharmacological
      rationale in the treatment of ovarian cancer. From 1989 to 1996 the present study
      included 113 patients with FIGO stage II-IV ovarian cancer with residual disease
      less than 2 cm who were randomly allocated to receive 50 mg/m(2) intraperitoneal
      cisplatin (CDDP) plus 60 mg/m(2) intravenous epidoxorubicin (EPIDOX) and 600
      mg/m(2) intravenous cyclophosphamide (CTX) (ipPEC arm) or 50 mg/m(2) intravenous
      CDDP plus 60 mg/m(2) intravenous EPIDOX and 600 mg/m(2) intravenous CTX (ivPEC
      arm). Chemotherapy was repeated every 4 weeks for six cycles. Treatment protocol
      was changed in 22 patients, 2 from the iv arm (who received single-agent
      carboplatin) and 20 from the ip arm (who were crossed to systemic chemotherapy,
      ivPEC, or single-agent carboplatin). At the end of chemotherapy, a second-look
      was performed in 33 of the 54 patients from the ip arm and in 34 of the 57
      patients from the systemic arm. The pathologic complete response rate was 41% of
      all entered patients and 69% of patients submitted to second-look. No significant
      difference in pathologic response rate as well as in hematologic and
      nonhematologic toxicities was seen between the two arms. Up to September 1998, 72
      patients showed a disease recurrence (33 treated with ipPEC and 39 treated with
      ivPEC), 55 died (22 ipPEC and 30 ivPEC), and 10 were lost to follow-up (6 ipPEC
      and 4 ivPEC). Median progression-free survival was 42 and 25 months for ipPEC and
      ivPEC, respectively (p = 0.13). Median overall survival was 67 and 51 months for
      ipPEC and ivPEC, respectively (p = 0.14). In conclusion, besides confirming that
      intraperitoneal chemotherapy is feasible with acceptable toxicity but with poor
      compliance in community hospitals, this trial showed that intraperitoneal CDDP
      compared with intravenous CDDP in combination with EPIDOX and CTX obtained a
      slight (not significant) improvement in progression-free survival and overall
      survival of optimally cytoreduced advanced ovarian cancer patients.

PMID- 10637065
TI  - Job satisfaction among gynecologic oncologists practicing in the United States.
AB  - OBJECTIVE: We sought to determine whether there have been any significant changes
      in professional satisfaction among gynecologic oncologists over the past 30
      years. METHODS: We mailed surveys to all U.S. gynecologic oncologists belonging
      to the Society of Gynecologic Oncologists to compile data on demographics,
      training, motivating factors, overall professional satisfaction, and the effect
      of managed care. We compared these factors among oncologists who completed
      training in different years and among different demographic groups. We used
      calculated confidence intervals to determine statistical significance. RESULTS:
      We surveyed 767 gynecologic oncologists and received 344 evaluable responses,
      representing 47% of the total eligible. Results show that neither the factor
      rated most important in looking for a first job nor the factor rated most
      important in giving job satisfaction once in a job has changed significantly
      among gynecologic oncologists over time. In addition, the importance placed on
      salary has not varied across the fellowship graduate classes, although within
      each class salary increased in importance from the first job to the current job.
      Our analysis shows that while male and female gynecologic oncologists are similar
      in their job satisfaction and practice patterns, men report being sued twice as
      often as women, and men tend to stay in their first jobs significantly longer
      than women. We also compare the surveyed academic gynecologic oncologists to the
      private gynecologic oncologists and show that while overall job satisfaction is
      similar, their ratings of the factors that provide job satisfaction do differ
      significantly. Our data show that managed care penetration has increased over
      time among gynecologic oncology practices and that gynecologic oncologists' job
      satisfaction ratings tend to decrease with the increase in managed care
      penetration, although not reaching statistical significance. CONCLUSIONS: Our
      results show that changes in practice styles since the 1960s have not affected
      overall job satisfaction among gynecologic oncologists. However, several trends
      in practice styles can be noted, including differences between sexes, academic
      versus private physicians, and attitudes about managed care. The survey also
      suggests that there is interest among gynecologic oncologists in continuing to
      monitor changes in patterns of practice and satisfaction.

PMID- 10637066
TI  - Induction of apoptosis and growth inhibition of cultured human endometrial
      adenocarcinoma cells (Sawano) by an antitumor lipoprotein fraction of rice bran.
AB  - OBJECTIVE: A lipoprotein fraction extracted from rice bran (RBF) has been proved
      to be nontoxic to normal cells and to possess the ability to derange energy
      metabolism and induce apoptosis in Ehrlich ascites tumor cells. This study is
      designed to investigate the therapeutic effects of RBF as an antitumor substance
      on endometrial adenocarcinoma cells (Sawano). METHODS: Cultured human endometrial
      adenocarcinoma cells were treated with medium only (untreated), DMSO, or RBF at
      100, 200, and 300 microg/ml. Mitotic indexes were counted by Giemsa stain and
      apoptotic index by fluorescent TUNEL stain for confocal laser scanning
      microscopy. DNA fragments were examined by agarose gel electrophoresis. RESULTS:
      Characteristic apoptotic morphology was observed in Giemsa-stained cells and
      further confirmed by confocal laser scanning microscopy in RBF-treated cells.
      Growth of Sawano cells was inhibited by RBF in a dose- and time-dependent manner.
      Apoptotic indexes (AI) showed an increasing tendency, and mitotic indexes (MI)
      showed a downward tendency. In 300 microg/ml RBF-treated Sawano cells, AI even
      reached 41.62 +/- 2. 23% and MI decreased to 0.79 +/- 0.08% at 96 h. Both showed
      significant differences from to controls and other RBF-treated groups. DNA
      agarose electrophoresis revealed DNA fragmentation in a ladder pattern.
      CONCLUSIONS: RBF can induce apoptosis of cultured human endometrial
      adenocarcinoma cells (Sawano) and inhibit its cell proliferation as an antitumor
      substance.

PMID- 10637067
TI  - Expression of complement regulatory proteins-CD 35, CD 46, CD 55, and CD 59-in
      benign and malignant endometrial tissue.
AB  - OBJECTIVE: Complement system plays an important role in host defense mechanisms
      against microorganisms and tumor cells. To protect themselves from autologous
      complement-mediated damage, normal host tissues express cell membrane-associated
      complement regulatory proteins (CRPs). To investigate whether neoplastic
      endometrial tissues overexpress these proteins to escape complement damage, we
      examined the distribution of complement receptor type 1 (CR1, CD35), membrane
      cofactor protein (MCP, CD46), decay-accelerating factor (DAF, CD55), and
      protectin (MACIF, CD59) on frozen endometrial tissue samples. METHODS: A total of
      54 endometrial tissue samples were collected. Cryosections were obtained of 31
      benign and 23 malignant tissue specimens. Tissue sections were stained by
      immunohistochemical staining procedure using specific antibodies and employing
      the avidin-biotin technique. Quantitation of the protein content of these CRPs
      was determined using the Samba 4000 image analysis system. RESULTS: For all four
      of the CRPs studied, a statistically significant difference in protein expression
      between the benign and malignant endometrial tissue specimens (P < 0.0001) was
      observed. CONCLUSIONS: Overexpression of all the CRPs studied (CD35, CD46, CD55,
      CD59) was observed in the malignant as compared with the benign endometrial
      tissues. The upregulation of these CRPs may promote resistance of the endometrial
      malignant tissue to complement-mediated damage, thereby allowing the tumor cells
      to escape from cytolysis and thus promoting carcinogenesis.

PMID- 10637068
TI  - 2-5A antisense directed against telomerase RNA produces apoptosis in ovarian
      cancer cells.
AB  - OBJECTIVE: RNase L is converted to an active form upon binding short 2',5'
      oligoadenylates (2-5A). To direct RNase L to an RNA target, 2-5A is attached to
      an antisense oligonucleotide (2-5A antisense). This chimera can be directed
      against telomerase-an RNA-protein complex that elongates telomeric DNA and is
      involved in cellular immortalization. Our objective is to investigate the effect
      of 2-5A antisense by targeting telomerase RNA (hTR) in the ovarian cancer cell
      line, HEY-1B. METHODS: Baseline RNase L levels and telomerase activities were
      measured in both HEY-1B and normal ovarian epithelial cells (NOE). Cells were
      treated daily with chimeric oligonuclotides (ODN) directed against four different
      hTR sites, or control ODNs including nonchimeric antisense, 2-5A fused to a
      mismatched sequence, or inactive 2-5A fused to antisense. At 48 h, apoptosis was
      evaluated using the TUNEL assay. After six daily ODN administrations, telomerase
      activity was redetermined, and at 7 days viability counts were obtained. RESULTS:
      Both cell lines expressed similar levels of RNase L. Hey-1B displayed telomerase
      activity while NOE did not. After 7 days of transfection, 2-5A antisense ODNs
      caused profound cell death in the HEY-1B cells, but not in the NOE cells. This
      effect was seen regardless of hTR target site, and ODN controls showed no
      significant decrease in cell viability in either cell line. HEY1B cells treated
      with 2-5A antisense against hTR showed a decrease in telomerase activity and a
      profound induction of programmed cell death. CONCLUSIONS: The results suggest
      that 2-5A antisense directed against telomerase RNA results in apoptotic cell
      death in ovarian cancer cells, but not normal ovarian epithelial cells. The 2-5A
      antisense strategy may hold a considerable advantage over the conventional
      antisense approach in targeting cancer-causing genes.

PMID- 10637069
TI  - Mutation analysis of the putative tumor suppressor gene PTEN/MMAC1 in cervical
      cancer.
AB  - OBJECTIVE: PTEN/MMAC1, a candidate tumor suppressor gene located at chromosome
      10q23.3, was recently identified and found to be homozygously deleted or mutated
      in several different types of human tumors. The aim of this study is to determine
      whether PTEN/MMAC1 is a target for 10q loss of heterozygosity in cervical cancer.
      METHOD: We examined 50 primary cervical carcinoma specimens using a PCR-based
      assay followed by SSCP and direct sequencing. The genomic DNA was also confirmed
      by Southern blot analysis. RESULTS: All specimens except one, which has a 7-base
      deletion, showed a negative result. Among them, 30 randomly selected cases and
      their paired noncancerous tissue were further screened using nested RT-PCR. Six
      of 30 cervical cancerous tissues had aberrant transcripts. However, 4 of the
      matched noncancerous tissues also had aberrant transcripts. Southern blot
      analysis of the entire genomic DNA did not reveal any evidence of gene
      alteration. CONCLUSIONS: Sequence abnormalities in the PTEN/MMAC1 gene were only
      detected in 1 of 50 cervical cancers analyzed indicating that aberrant PTEN/MMAC1
      function is an uncommon event in the development of cervix cancers. However,
      similar to studies with the TSG101 gene, screening for aberrant transcripts of
      PTEN/MMAC1 with nested RT-PCR may detect transcripts, which, although they vary
      from the normal size, may not be related to oncogenesis as they are also
      frequently found in normal tissues of the same patient.

PMID- 10637070
TI  - The usefulness of cystoscopy in the staging of cervical cancer.
AB  - OBJECTIVE: The aim of this study was to clarify the usefulness of cystoscopy in
      the staging of cervical cancer and to evaluate the clinical indications for
      performing ureteric catheterization to rule out ureteral obstruction in cervical
      cancer. METHODS: Both rigid cystoscopy and CT were performed before treatment in
      patients with cervical cancer of FIGO stage IB or greater. Cystoscopically
      directed biopsy specimens were taken from all areas in the bladder which were
      suspected of cancerous development. If a jet of urine spurting from each ureteral
      orifice was not found, a ureteric catheter was inserted into the orifice to rule
      out ureteral obstruction. The cystoscopic findings were compared with a CT
      examination. RESULTS: A total of 100 patients were included in the study (mean
      age 59 years). There were 30 stage IB cancers, 20 stage IIA, 17 stage IIB, 5
      stage IIIA, 18 stage IIIB, and 10 stage IV. A total of 90 patients had squamous
      cell carcinomas and 10 had adenocarcinomas. Cystoscopy identified 8 patients with
      bladder invasion including 1 stage IIIA, 2 stage IIIB, and 5 stage IV. All of
      these patients had CT indication of possible invasion. CT indication of possible
      invasion was proved to be false by cystoscopy in 2 patients. Both the sensitivity
      and the negative predictive value of CT for bladder invasion were 100%. Of the 14
      patients in whom ureteral obstruction was diagnosed by ureteric catheterization,
      11 cases were indicated by CT scan, but for the other 3 patients CT found no
      significant ureteral obstruction. CONCLUSIONS: The results of this study suggest
      that cystoscopy is indicated only in cervical cancer patients for whom CT
      examination indicates possible bladder invasion. In addition, the results suggest
      that placement of ureteric catheterization using cystoscopy to rule out ureteral
      obstruction is not indicated in the staging of cervical cancer.

PMID- 10637071
TI  - Evaluation of gemcitabine in patients with squamous cell carcinoma of the cervix:
      a Phase II study of the gynecologic oncology group.
AB  - PURPOSE: A multicenter Phase II trial was conducted to evaluate the activity and
      toxicity of gemcitabine in patients with previously treated squamous cell
      carcinoma of the uterine cervix. PATIENTS AND METHODS: Patients were required to
      have measurable disease with adequate performance status, bone marrow, hepatic,
      and renal function. Histologic confirmation of the primary diagnosis as squamous
      cell cancer of the uterine cervix was mandatory. Patients were allowed one prior
      chemotherapy regimen, usually cisplatin-based. The initial dose of gemcitabine
      was 800 mg/m(2) weekly times three with 1 week off until progressive disease or
      adverse effects prohibited further therapy. Doses were escalated or reduced based
      on previous cycle toxicity. RESULTS: Twenty-seven patients were entered into the
      trial. One patient never received the drug and 1 patient was inevaluable for
      response. A median of two cycles were administered to each patient (range: 1-7
      cycles). The overall response rate (two partial responses) was 8% with 21% of
      patients having stable disease. The median progression-free interval was 1.9
      months (range: 0.5-9.0) and overall survival was 4.9 months (range: 1.5-16.3).
      Two patients had grade 4 neutropenia; 1 patient had grade 4 anemia. The median
      WBC nadir in the 13 patients experiencing any leukopenia was 2300/microl (range:
      400-3800). There was only one episode of grade 4 gastrointestinal toxicity.
      CONCLUSIONS: Gemcitabine as a single agent demonstrated minimal antitumor
      activity in previously treated patients with squamous cell cancer of the uterine
      cervix. Since gemcitabine in the dose and schedule employed is known to
      potentiate the cytotoxicity of cisplatin and radiotherapy (the current standard
      therapies for this disease), further development of gemcitabine would only be
      indicated in combination with these treatment modalities.

PMID- 10637072
TI  - Cardiac metastasis of cloacagenic carcinoma of the vagina: a case and review of
      gynecologic malignancies with cardiac metastasis.
AB  - We report of a case of a 44-year-old woman with a vaginal cloacagenic carcinoma
      who initially presented with a hymenal lesion that metastasized first to the
      perihilar lymph nodes and then consequently to the right ventricle. The
      embryological tumor is rare with only a few cases of vaginal or vulvar
      involvement. We present the first case of cloacagenic cancer of the vagina with
      metastasis to the heart. The lesion was surgically resected after completion of
      neoadjuvant therapy. Herein we present this unique case and the clinical
      manifestations of intracardiac and pericardial lesions from gynecologic
      malignancies.

PMID- 10637073
TI  - Primary vaginal squamous cell carcinoma presenting as a cystic pelvic mass.
AB  - A 57-year-old woman presented with urinary retention, diarrhea, rectal bleeding,
      a cystic pelvic mass with thick irregular borders posterior to the vagina
      displacing the cervix and the bladder, and an intact vaginal mucosa. The patient
      underwent exploratory laparotomy on the assumption that she had an ovarian
      neoplasm. The mass originated from the posterior vaginal wall and was consistent
      with primary squamous cell carcinoma. The patient was treated with surgical
      cytoreduction followed by external radiation therapy and weekly cisplatin with
      good response. One year following treatment the patient remains without evidence
      of disease. Primary vaginal squamous cell carcinoma arising from the posterior
      vaginal wall can present as a cystic pelvic mass resembling an ovarian neoplasm.
      Cytoreductive surgery followed by chemoradiation might be of value in some
      patients with primary vaginal carcinoma.

PMID- 10637074
TI  - Hypercalcemia due to parathyroid hormone-related protein produced by primary
      ovarian clear cell adenocarcinoma: case report.
AB  - OBJECTIVE: Amongovarian carcinomas, clear cell adenocarcinoma is one of the most
      common histologic subtypes associated with hypercalcemia. However, the mechanisms
      of hypercalcemia in clear cell adenocarcinoma are still unclear. In the following
      case report, we tried to determine the etiology of hypercalcemia and also to
      demonstrate the management of hypercalcemia diagnosed preoperatively. CASE: A 49
      year-old woman was diagnosed as having a malignant ovarian tumor with
      hypercalcemia caused by elevated serum parathyroid hormone-related protein
      (PTHrP) prior to her primary surgery. Treatment with disodium incadronate
      promptly normalized the serum calcium level. An immunohistochemical study
      demonstrated PTHrP expression in the primary ovarian lesion, but not in the
      metastatic lesion. A Northern blot analysis of the cancer cells from the ovarian
      tumor confirmed the presence of PTHrP mRNA. CONCLUSION: Humoral hypercalcemia of
      malignancy in this case has been conclusively shown to be due to the production
      of PTHrP at the primary ovarian tumor, based on both immunohistochemical and
      molecular analyses.

PMID- 10637075
TI  - Hemorrhagic pyelitis, ureteritis, and cystitis secondary to cyclophosphamide:
      case report and review of the literature.
AB  - OBJECTIVE: Hemorrhagic cystitis is a well-known complication of cyclophosphamide
      therapy but extensive involvement of the entire urinary tract is far less common.
      We report here a patient who developed severe hemorrhagic pyelitis, ureteritis,
      and cystitis after one cycle of cyclophosphamide-containing combination
      chemotherapy. METHOD: A patient with synchronous carcinoma of the ovary and the
      uterus developed severe hemorrhagic pyelitis, ureteritis, and cystitis leading to
      bilateral hydronephroses and acute renal failure after one cycle of combination
      chemotherapy containing cyclophosphamide. The blood clots in the upper urinary
      tract were aspirated endoscopically and bilateral internal ureteric stents were
      inserted. RESULT: She underwent a prolonged diuretic phase with several episodes
      of hypokalemia, hypomagnesemia, and hypocalcemia and required intensive fluid and
      electrolytes replacement. Subsequently, she recovered fully with the ureteric
      stents removed 26 days later. CONCLUSION: In contrast to previous reports, where
      2.8 g of cyclophosphamide was estimated to be the minimum cumulative dose
      required to cause hemorrhagic cystitis, this case illustrates that severe
      hemorrhagic complication can occur even after a low dose of cyclophosphamide (600
      mg/m(2), total dose of 846 mg). Prompt diagnosis and intervention may be life
      saving.

PMID- 10637076
TI  - Carcinosarcoma of the ovary in a patient with a germline BRCA2 mutation: evidence
      for monoclonal origin.
AB  - BACKGROUND: Themajority of hereditary breast and ovarian cancers are associated
      with germline mutations in BRCA1 or BRCA2. While the occurrence of breast
      carcinoma and epithelial ovarian carcinoma in association with BRCA mutations is
      firmly established, the etiologic role of these genes in the development of other
      tumor types is less well documented. Carcinosarcoma of the ovary is an uncommon
      tumor consisting of both malignant epithelial and malignant mesenchymal
      components. OBJECTIVE: Here we report a patient with an ovarian carcinosarcoma
      who was found to harbor a germline mutation in BRCA2. We sought to link the BRCA2
      mutation to the pathogenesis of this tumor as well as to determine whether both
      histologic components arose from the same progenitor cell. METHODS:
      Microdissection and molecular genetic analyses of the carcinomatous and
      sarcomatous components of this tumor were performed. RESULTS: Clonal loss of the
      wild-type BRCA2 allele as well as the same somatic mutation of the TP53 gene was
      evident in both histologic components. CONCLUSIONS: These data indicate that
      hereditary ovarian carcinosarcoma may result from a mutation in BRCA2 and that
      both histologic elements of this tumor arose from the same progenitor cell.

PMID- 10637077
TI  - Electron beam computed tomography: on its way into mainstrem cardiology?

PMID- 10637078
TI  - Intravascular ultrasound guided PTCA: a way to escape stent mania?

PMID- 10637079
TI  - Diagnosing primary diastolic heart failure.

PMID- 10637080
TI  - On checking the pulse.

PMID- 10637081
TI  - Prognosis in heart failure: the value of parameter-changes over time.

PMID- 10637082
TI  - Routine tests should be challenged in cardiology.

PMID- 10637083
TI  - Patients with ischaemic heart disease and severe left ventricular dysfunction -
      who should not be revascularized?

PMID- 10637084
TI  - Pulmonary vascular disease and pregnancy: current controversies, management
      strategies, and perspectives.

PMID- 10637085
TI  - The association of resting heart rate with cardiovascular, cancer and all-cause
      mortality. Eight year follow-up of 3527 male Israeli employees (the CORDIS Study)
AB  - BACKGROUND: Resting heart rate has frequently been shown to be a predictor of
      coronary heart disease mortality. Elevated heart rate could also be a marker for
      the presence of other risk factors, which have not been taken into consideration
      in previous studies. OBJECTIVE: To evaluate the effect of resting heart rate on
      the risk of all-cause cardiovascular and cancer mortality, taking into
      consideration haematological variables. METHOD: The association between resting
      heart rate and mortality was assessed applying Cox's proportional hazard models
      to data obtained in an 8 year follow-up of 3527 Israeli male industrial
      employees. During this period 135 deaths were recorded, 57 from cardiovascular
      disease and 45 from cancer. Resting heart rate was assessed at entry; potential
      confounding demographic, anthropometric and socioeconomic variables,
      haematological data, serum lipid levels and health-related habits were accounted
      for. RESULTS: We found that the relative risk of all-cause mortality increased
      with increasing resting heart rate, workers with resting heart rate >90 beats.
      min(-1)had an adjusted relative risk of 2.23 (95% CI 1.4-3.6) compared with those
      with a heart rate <70 beats. min(-1). A similar result was achieved for
      cardiovascular disease mortality (adjusted relative risk 2.02, 95% CI 1.1-4.0).
      Cancer mortality was not associated with resting heart rate. CONCLUSION: This
      study found that resting heart rate is associated with all-cause and
      cardiovascular disease mortality after controlling (in various statistical
      models) for platelet counts, haemoglobin concentration, white blood cell counts,
      total protein, and other recognized risk factors.

PMID- 10637086
TI  - Prediction of global left ventricular function after bypass surgery in patients
      with severe left ventricular dysfunction. Impact of pre-operative myocardial
      function, perfusion, and metabolism.
AB  - AIMS: Previous studies have compared the accuracy of various tests of viability
      for the prediction of recovery of regional left ventricular function; global left
      ventricular recovery has been less well studied, although it has important
      prognostic and functional ramifications. We sought to identify the relative
      contribution of ischaemia, regional and global contractile reserve, perfusion and
      metabolic function to changes in left ventricular volumes and global function
      after coronary artery bypass surgery in patients with severe left ventricular
      dysfunction. METHODS AND RESULTS: Dipyridamole stress Rb-82, fluorodeoxyglucose
      positron emission tomography and low and high-dose dobutamine-atropine stress
      echocardiography were obtained in 66 patients with left ventricular impairment.
      Myocardial segments were considered viable if ischaemia or either metabolic or
      contractile reserve were present, on positron emission tomography or dobutamine
      echocardiography. Resting left ventricular function was reassessed after surgery
      (mean 10+/-3 weeks) in the 59 patients who had not suffered a major peri
      operative event; functional improvement was defined by a 5% increment of ejection
      fraction. Myocardial viability was found in 37 (63%) patients using positron
      emission tomography and in 42 (71%) patients using dobutamine echocardiography;
      post-operative functional improvement was noted in 28 (47%) patients. In
      univariate analyses, predictors of global post-operative functional recovery
      included: the extent of viability according to positron emission tomography [OR
      (odds ratio): 2.08 for each additional viable segment, 95% CI (confidence
      interval): 1.33-3. 25, P=0.001] or dobutamine echocardiography (OR: 2.06 for each
      additional viable segment, 95% CI: 1.28-3.30, P=0.003) and the increase in
      ejection fraction with low-dose dobutamine (OR: 1.9 for each 1% increase in
      ejection fraction with low dose dobutamine, 95% CI 1.39-2.61, P<0.0001). In a
      multivariate model which included evidence of viability by either technique, and
      change in ejection fraction with low-dose dobutamine echocardiography, only
      change in ejection fraction with low-dose dobutamine echocardiography was
      predictive of post-operative left ventricular functional recovery (adjusted OR:
      1.81, 95% CI: 1.30-2.52, P=0.0005). CONCLUSION: Among patients with severe left
      ventricular dysfunction who are referred for surgical revascularization, the
      overall accuracies of positron emission tomography and dobutamine
      echocardiography for the prediction of post-operative myocardial recovery are
      comparable. However, the strongest predictor of overall improvement of post
      operative left ventricular function is an increase of ejection fraction with a
      low-dose dobutamine infusion.

PMID- 10637087
TI  - The impact of untreated coronary dissections on acute and long-term outcome after
      intravascular ultrasound guided PTCA.
AB  - AIM: Vessel size adapted PTCA results in the use of larger balloons with an
      increased incidence of severe vascular dissections. The aim of our trial was (a)
      to evaluate the effect of severe dissections on the acute outcome and (b) to
      study the natural history of dissections after 1 year. METHODS AND RESULTS: One
      hundred and seventy-eight patients with 195 lesions underwent vessel size adapted
      PTCA using intravascular ultrasound. Clinical and angiographic 1 year follow-up
      was obtained for all patients. Intravascular ultrasound was performed before PTCA
      to measure the external elastic membrane diameter at the lesion site so that the
      balloon size could be adopted (external elastic membrane-10%) and post
      interventionally to determine the procedural success and the incidence of
      intracoronary dissections. Stent implantation was reduced to persistently flow
      limiting dissections (TIMI I, II). Dissections were detected by intravascular
      ultrasound in 128/195 (66%) lesions (by angiography in 111/195 [58%] lesions) and
      classified by intravascular ultrasound criteria into four groups: group I: no
      dissection (67 lesions [34%]), group II: mild dissections (21 lesions [11%]),
      group III: medium dissections (19 lesions [10%]) and group IV: severe dissections
      (88 lesions [45%]). Because of threatened vessel closure, GPIIb/IIIa antagonists
      were used in eight (4.5%) patients and a stent was implanted in two (1. 1%)
      patients. The cumulative event rate after 1 year was 12% and the global
      angiographic restenosis rate was 19%. The post-interventional evidence of severe
      dissections was associated with a decrease in clinical events during long-term
      follow up (group I: 13 events [19%] vs group IV: seven events [7%];P=0.03). This
      was also true for the occurrence of restenosis which was significantly lower in
      patients with severe dissections (group I: 19 [28%] lesions vs group IV:10 [11%]
      lesions;P=0.01). CONCLUSIONS: According to the theory of 'therapeutic
      dissections', our data suggest that substantial dissections following PTCA, which
      do not diminish antegrade blood flow, do not lead to an increase in acute or long
      term events. The natural history of vessel injury seems to provide favourable
      wound healing without increase of restenosis. Thus, stenting for treatment of
      large dissections without flow limitation does not seem to be mandatory.

PMID- 10637088
TI  - Prognostic value of changes over time in exercise capacity and echocardiographic
      measurements in patients with chronic heart failure.
AB  - AIMS: This study sought to examine the predictive values of changes over time in
      exercise capacity and echocardiographic measurements of ventricular dimensions or
      function in predicting mortality in patients with chronic heart failure. METHODS
      AND RESULTS: Sixty-two patients with chronic heart failure (58 men, mean [+/-SD]
      age 60+/-10 years, mean peak oxygen consumption (VO(2)) 18.2+/- 5.9 ml. kg(-1).
      min(-1), mean left ventricular ejection fraction 38.9+/-15. 8%) who underwent
      both treadmill exercise testing and echocardiographic examination on two
      occasions, separated by 19+/-15 months were followed-up for a mean of 17 months
      (interquartile range 9-30 months). During the follow-up period, 19 patients (30%)
      died and three (4.8%) underwent heart transplantation. Of measurements taken at a
      single time-point (visit 2) exercise duration, peak VO(2), ventilatory response
      to exercise (VE/VCO(2)), left atrial diameter and left ventricular ejection
      fraction were found, by Cox proportional-hazard analysis, to predict the outcome
      in these patients (all P<0.05). Of the changes in parameters between visit 1 to
      visit 2, only changes in peak VO(2)per year (P=0.026) predicted non-transplanted
      survival (independent of changes in left ventricular ejection fraction and
      VE/VCO(2)). In Kaplan-Meier survival analysis patients with increased peak
      VO(2)over time (n=28) showed a better prognosis at 2 years (cumulative survival
      75% [95% confidence interval: 56-95%] than those with a decrease in peak
      VO(2)(n=34, cumulative survival 50% [95% confidence interval: 31-68%]).
      CONCLUSIONS: Although single estimates of peak VO(2), VE/VCO(2)and left
      ventricular ejection fraction have significant prognostic importance in patients
      with chronic heart failure, when monitoring changes over time only peak
      VO(2)remains a significant predictor of outcome.

PMID- 10637089
TI  - Cardiopulmonary exercise testing for prognosis in chronic heart failure:
      continuous and independent prognostic value from VE/VCO(2)slope and peak VO(2).
AB  - BACKGROUND: Chronic heart failure carries a poor prognosis. Cardiopulmonary
      exercise testing is useful in predicting survival. We set out to establish the
      prognostic value of peak VO(2)and VE/VCO(2)slope across a range of threshold
      values. METHOD AND RESULTS: Three hundred and three consecutive patients with
      stable chronic heart failure underwent cardiopulmonary exercise testing between
      1992 and 1996. Their age was 59+/-11 years (mean+/-SD), peak VO(2)17. 8+/- 6.6
      ml. kg(-1)min(-1), VE/VCO(2)slope 37+/-12. At the end of follow-up in January
      1999, 91 patients had died (after a median of 7 months, interquartile range 3-16
      months). The median follow-up for the survivors was 47 months (interquartile
      range 37-57 months). The areas under the receiver-operating characteristic curves
      for predicting mortality at 2 years were 0.77 for both peak VO(2)and
      VE/VCO(2)slope. With peak VO(2)and VE/VCO(2)slope viewed as continuous variables
      in the Cox proportional-hazards model, they were both highly significant
      prognostic indicators, both in univariate analysis and bivariate analysis
      (P<0.001 for VE/VCO(2)slope, P<0.003 for peak VO(2)). CONCLUSIONS: Lower peak
      VO(2)implies poorer prognosis across a range of values from 10 to 20 ml. kg(
      1)min(-1), without a unique threshold. Gradations of elevation of the
      VE/VCO(2)slope also carry prognostic information over a wide range (30-55). The
      two parameters are comparable in terms of prognostic power, and contribute
      complementary prognostic information.

PMID- 10637090
TI  - Is there a need for routine testing of ICD defibrillation capacity? Results from
      more than 1000 studies.
AB  - AIMS: Benefits and complications of postoperative implantable cardioverter
      defibrillator tests are controversial matters. This study sought to assess the
      necessity of defibrillation function tests after implantation. METHODS AND
      RESULTS: We retrospectively analysed 1007 implantable cardioverter-defibrillator
      tests in 587 systems and 556 patients. Nine hundred and thirty implantable
      cardioverter-defibrillator tests (89.4%) were routinely performed. Seventy-one
      tests (7%) were performed after a change in the antiarrhythmic drug regimen and
      six tests (0.60%) because of a suspected dysfunction of the implantable
      cardioverter-defibrillator. During routine tests, four systems (0.4%) failed to
      defibrillate the patient. However, in all but one test, abnormalities of the
      system had been observed before the test. After the addition of antiarrhythmic
      drugs, two of 71 implantable cardioverter-defibrillator systems (2.8%) failed to
      defibrillate the patient. One of six systems tested due to a suspected
      dysfunction failed to defibrillate the patient. During 16 tests (1.6%),
      complications occurred. CONCLUSIONS: Our experience demonstrates that
      postoperative tests of the defibrillation function of implantable cardioverter
      defibrillators rarely reveal dysfunctions. As testing is unpleasant for the
      patient and not free of complications, tests might be restricted to those
      patients in whom a dysfunction is suspected and to those patients in whom class I
      or class III antiarrhythmic drugs have been added to the antiarrhythmic drug
      regimen.

PMID- 10637091
TI  - Shifting the balance: direct stenting a novel approach to improve the cost
      effectiveness of intra-coronary stenting.

PMID- 10637092
TI  - Animal models of myasthenia gravis.
AB  - Myasthenia gravis (MG) is an antibody-mediated, autoimmune neuromuscular disease.
      Animal models of experimental autoimmune myasthenia gravis (EAMG) can be induced
      in vertebrates by immunization with Torpedo californica acetylcholine receptors
      (AChR) in complete Freund's adjuvant. The MHC class II genes influence the
      cellular and humoral immune response to AChR and are involved in the development
      of clinical EAMG in mice. A dominant epitope within the AChR alpha146-162 region
      activates MHC class II-restricted CD4 cells and is involved in the production of
      pathogenic anti-AChR antibodies by B cells. Neonatal or adult tolerance to this T
      cell epitope could prevent EAMG. During an immune response to AChR in vivo,
      multiple TCR genes are used. The CD28-B7 and CD40L-CD40 interaction is required
      during the primary immune response to AChR. However, CTLA-4 blockade augmented T-
      and B-cell immune response to AChR and disease. Cytokines IFN-gamma and IL-12
      upregulate, while IFN-alpha downregulates, EAMG pathogenesis. However, the Th2
      cytokine IL-4 fails to play a significant role in the development of antibody
      mediated EAMG. Systemic or mucosal tolerance to AChR or its dominant peptide(s)
      has prevented EAMG in an antigen-specific manner. Antigen-specific tolerance and
      downregulation of pathogenic cytokines could achieve effective therapy of EAMG
      and probably MG.

PMID- 10637093
TI  - Stimulatory and inhibitory differentiation of human myeloid dendritic cells.
AB  - Dendritic cells (DCs) play a critical obligate role in presenting antigens to T
      cells for activation. In the process, upon antigen capture, DCs undergo
      maturation and become more stimulatory. Human myeloid DCs can be generated from
      various sources, including blood, bone marrow, and CD34(+) stem cells. As such,
      plastic-adherent monocytes from circulation have served as a ready source for
      generating myeloid DCs in culture in granulocyte-macrophage colony-stimulating
      factor (GM-CSF) and interleukin-4 (IL-4) for translational research in active
      specific immunotherapy, especially in cancer, with the belief that they are
      essentially stimulatory or "immunogenic." Here we show that in vitro cultures of
      plastic-adherent circulating monocytes in GM-CSF and IL-4 followed by further
      maturation in interferon-gamma plus bacterial superantigens (DC maturing agents)
      can give rise to two diametrically opposite types of DCs-one stimulatory and
      another inhibitory. The stimulatory DCs express higher amounts of costimulatory
      molecules, synthesize IL-12, and efficiently stimulate naive allogeneic T cells
      in mixed lymphocyte reaction (MLR). The inhibitory DCs, in contrast, express
      lower concentrations of the critical costimulatory molecules, synthesize large
      amounts of IL-10, and are nonstimulatory in allogeneic primary MLR. Moreover,
      while the stimulatory DCs further amplify proliferation of T cells in lectin
      driven proliferation assays, the inhibitory DCs totally block T cell
      proliferation in similar assays, in vitro. Most interestingly, neutralization of
      the endogenously derived IL-10 with anti-IL-10 antibody in DC cultures
      repolarizes the inhibitory DCs toward stimulatory phenotype. Accordingly, these
      observations have important implications in translational research involving
      myeloid DCs.

PMID- 10637094
TI  - Downregulation of TGF-beta1 mRNA and protein in the muscles of patients with
      inflammatory myopathies after treatment with high-dose intravenous
      immunoglobulin.
AB  - We used reverse transcription-polymerase chain reaction to study the level of TGF
      beta1 mRNA expression and immunocytochemistry to examine the immunoreactive TGF
      beta1 in muscle biopsy specimens from five patients with dermatomyositis (DM) and
      five patients with inclusion body myositis (IBM) obtained before and after 3
      months treatment with intravenous immunoglobulin (IVIg). At baseline, the mRNA
      expression of TGF-beta1 was increased up to fivefold in the muscles of DM
      patients compared to that of IBM patients. After IVIg, TGF-beta1 was
      downregulated and the TGF-beta1 mRNA decreased twofold in the muscles of patients
      with DM who had successfully responded to therapy, but remained unchanged in the
      muscles of patients with IBM who did not respond. The downregulation of TGF-beta1
      in DM was associated with improvement of the muscle cytoarchitecture and
      reduction of the endomysial inflammation and connective tissue, suggesting that
      in DM the excess of TGF-beta1 may be involved in the pathogenesis of chronic
      inflammation, fibrosis, and accumulation of extracellular matrix proteins.

PMID- 10637095
TI  - Chemokine production by rat myocytes exposed to interferon-gamma.
AB  - Messenger RNA that encodes for monocyte chemotactic protein-1 (MCP-1), as well as
      its protein product, was observed to be constitutively expressed at low levels in
      a monoclonal Lewis rat skeletal muscle cell line (LE1). Immunohistochemical
      analyses of sections of skeletal muscle yielded similar results. Since interferon
      gamma (IFN-gamma) has been reported to have a likely role in determining the
      severity of symptoms in the neuromuscular autoimmune disease experimental
      myasthenia gravis (EAMG), the hypothesis tested and proven true in these studies
      was that IFN-gamma would up-regulate the production of MCP-1 in LE1 cells. It was
      also observed that muscle-derived MCP-1 could be up-regulated in vivo in rats
      receiving a monoclonal anti-acetylcholine receptor antibody (mAb35), a potent
      inducer of symptoms of EAMG. Therefore, it is concluded that muscle may
      contribute to disease progression by producing factors that influence activities
      of the immune system.

PMID- 10637096
TI  - Differential cytokine and chemokine production characterizes experimental
      autoimmune meningitis and experimental autoimmune encephalomyelitis.
AB  - After primary immunization with myelin/oligodendrocyte glycoprotein, CD28(-/-)
      mice developed experimental autoimmune meningitis (EAM) rather than experimental
      autoimmune encephalomyelitis (EAE). Cytokine and chemokine production in EAE and
      EAM were compared to understand the differences in disease phenotype. T cells
      from the central nervous system lesions of mice with either EAE or EAM expressed
      intracellular TNF-alpha. Splenic T cells from mice with EAM produced TNF-alpha
      and IL-6 but no IL-2. Conversely, EAE-derived splenic T cells produced TNF-alpha
      and IL-2 but no IL-6. Altered T cell differentiation in EAM was not due to a Th1
      to Th2 shift, because equivalent amounts of T cell IFN-gamma mRNA were produced
      in both diseases. Neutrophils also produced inflammatory mediators such as TNF
      alpha and IL-6 in EAM. Autocrine production of MIP-2 mRNA was observed in
      neutrophils from mice with EAM but not EAE. Therefore, distinct patterns of
      cytokines and chemokines distinguish EAE and EAM.

PMID- 10637098
TI  - Myocytes respond to both interleukin-4 and interferon-gamma: cytokine
      responsiveness with the potential to influence the severity and course of
      experimental myasthenia gravis.
AB  - Messenger RNA that encodes for interleukin-15 (IL-15) has been reported to be
      constitutively expressed in skeletal muscle, although the protein product is not
      generally observed. Furthermore, interferon-gamma (IFN-gamma) has been reported
      to exacerbate symptoms of experimental myasthenia gravis (EAMG). Therefore, since
      IL-15 is an activator of IFN-gamma-producing cells, the hypothesis that drove the
      study reported below proposes that muscle is not a passive participant in the
      development of disease symptoms in EAMG and, in fact, plays a very important
      active role by producing immunomodulating factors that can influence the eventual
      immunopathological impact of the immune system on muscle. Tests of this
      hypothesis, made using a monoclonal skeletal myocyte line from the Lewis rat,
      have indicated that myocytes produce IL-15 protein following exposure to
      interleukin-4 (IL-4), an interesting paradox in light of the usual anti
      inflammatory role played by IL-4. Furthermore, the level of IL-15 also can be
      regulated by IFN-gamma itself. Although yet to be confirmed in vivo, IFN-gamma
      has been shown to be capable of activating cultured myocytes in a variety of ways
      that could influence the ongoing autoimmune response associated with EAMG.

PMID- 10637097
TI  - A monoclonal lewis rat myocyte line that responds to interferon-gamma:
      responsiveness with the potential to influence subsequent interactions with the
      immune system.
AB  - In order to begin asking questions about immunopathology associated with the
      model of the neuromuscular disease experimental autoimmune myasthenia gravis, a
      monoclonal myocyte line, LE1, has been prepared from the Lewis rat. The LE1
      myocyte clone was selected from among several clones produced based on its ease
      of maintenance in culture and for the stability of its phenotype, which is very
      similar to that reported for in vivo muscle and other cultured myocyte lines.
      Thus, LE1 cells were observed to produce, constitutively, the myocyte-associated
      neural cell adhesion molecule (CD56), the intracellular adhesion molecule (ICAM
      1), and the acetylcholine receptor. LE1 cells were also observed to
      constitutively secrete relatively low levels of IL-6 and TGF-beta. Moreover, the
      LE1 cell line may be of use for predicting muscle responses to various immune
      mediators. For example, the inflammatory cytokine interferon-gamma (IFN-gamma)
      has been recently reported by others to play a role in experimental myasthenia
      gravis. Thus, it was of interest that LE1 cells could be activated by IFN-gamma
      to express increased levels of immunopathologically relevant membrane molecules
      such as ICAM-1 and Class II major histocompatibility molecules (i.e., RT-1B).

PMID- 10637099
TI  - Cell-free recombination of immunoglobulin switch-region DNA with nuclear
      extracts.
AB  - We have developed an in vitro recombination system employing cell-free nuclear
      extracts from human B lymphocytes capable of detecting the recombination between
      human mu switch (Smu) and Sepsilon sequences in a model plasmid. Nuclear extracts
      from CD40-stimulated B lymphocytes gave a higher frequency of recombination in
      the assay than the unstimulated B cells. Recombination between Smu and Sepsilon
      was mediated by the nuclear extracts as the recombinational products could be
      amplified prior to bacterial transformation. Characterization of the
      recombination products demonstrated that the recombination process had the
      characteristics of immunoglobulin (Ig) isotype switching, as it was (i) switch
      region-sequence specific, (ii) nonhomologous recombination, and (iii) enhanced by
      CD40 stimulation. Transcription through the S region DNA was not required for
      recombination in the system. These results demonstrate that Ig switch-region DNA
      recombination can be accomplished in vitro by cell-free nuclear extracts. This in
      vitro system for Ig switch-region DNA recombination using cell-free nuclear
      extracts will permit the dissection of the events involved in IgE class switch
      recombination, a critical event in the development of allergic diseases.

PMID- 10637100
TI  - Experimental Characterization of the Higher Vibrationally Excited States of
      HCO(+): Determination of omega(2), x(22), g(22), and B(030).
AB  - Analyses of high Rydberg series of HCO converging to the (030) vibrational state
      of the cation establish rovibrational state-detailed thresholds for HCO(+). UV
      visible laser double resonance isolates series for assignment. Strongly vertical
      Rydberg-Rydberg transitions from photoselected N' = 0 and N' = 2 rotational
      levels of the Sigma(-) Renner-Teller vibronic component of the 3ppi (2)Pi (030)
      complex define individual series converging to rotational levels, N(+) = 1
      through 5 and 3 through 5 of the HCO(+) vibrational states (03(1)0) and (03(3)0),
      respectively. Extrapolation of autoionizing series locates the positions of these
      rovibrational states to within +/-0.01 cm(-1). The use of this information
      combined with precise ionization limits for lower vibrational states determined
      from earlier Rydberg extrapolations and spectroscopic information available from
      infrared absorption measurements enables an estimate of the force-field
      parameters for HCO(+) bending. These parameters include the harmonic bending
      frequency, omega(2) = 842.57 cm(-1), the vibrational angular momentum splitting
      constant, g(22) = 3.26 cm(-1), and the diagonal bending anharmonicity, x(22) = 
      2.53 cm(-1), separated from the off-diagonal contribution, x(12), by reference to
      ab initio calculations. Results of experiment on the higher vibrationally excited
      states of HCO(+) are compared with recent theoretical predictions. Copyright 2000
      Academic Press.

PMID- 10637101
TI  - The 3nu(2) Band of D(2)(16)O.
AB  - The 3nu(2) overtone band of deuterium oxide, D(2)O, centered at 3474.3193 cm(-1),
      has been measured with high resolution in a 4-m base-length White cell attached
      to a Fourier transform spectrometer. The analysis of the spectrum led to the
      assignment of 347 transitions in this band, defining rovibrational energy levels
      in the (030) state up to K(a) = 7 for J as high as 9, and lower K(a) levels for J
      as high as 16. The (030) state was treated as an isolated state, following a Pade
      Borel approximation in the effective Hamiltonian. Of the 115 energy levels
      included in the analysis, 80% were reproduced by the 21 adjusted parameters to
      within 0.0008 cm(-1), and the largest error was 0.0017 cm(-1). Copyright 2000
      Academic Press.

PMID- 10637102
TI  - Experimental Line Parameters of the Oxygen A Band at 760 nm.
AB  - To support atmospheric remote sensing applications, line positions, intensities,
      self- and nitrogen-broadened linewidths and their temperature dependences and
      pressure-induced shifts in line positions at room temperature were measured up to
      J' and N' = 22 for the oxygen A band at 13 122 cm(-1). Line intensities were
      obtained with 1% precisions and 2% absolute accuracies using absorption spectra
      recorded at Doppler-limited (0.02 cm(-1)) resolution with the McMath Fourier
      transform spectrometer (FTS) located at Kitt Peak National Observatory/National
      Solar Observatory in Arizona. The oxygen line positions were calibrated using
      near-infrared transitions of the 2-0 and 3-0 bands of CO as secondary standards.
      The intensities and positions of seven H(2)O lines near 13 900 cm(-1) were also
      remeasured to validate the FTS performance. The O(2) intensities fell within 1%
      of the values currently assumed for the molecular databases, but it was found
      that broadening coefficients and line positions should be revised for the A band
      of molecular oxygen. Copyright 2000 Academic Press.

PMID- 10637103
TI  - The Comet-Tail (A(2)Pi(i)-X(2)Sigma(+)) System of (12)C(16)O(+): A
      Reinvestigation.
AB  - The emission spectrum of the comet-tail (A(2)Pi(i)-X(2)Sigma(+)) system of
      (12)C(16)O(+) produced in the cathode glow of a hollow-cathode discharge tube and
      photographed in the spectral region 3345-8500 A at high resolution was
      reinvestigated. Detailed rotational analysis of 10 bands involving 5 vibrational
      levels v = 0 to 4 of each of the A and X states was carried out. Spin-splitting
      of the rotational levels was observed for the analyzed bands. The observed
      intensity distribution of the branches is found to be in good agreement with
      theoretical calculations. Molecular constants for both the A and X states were
      obtained from a global fit of the present data of the A-X system and the infrared
      and microwave data available from the literature for v = 0, 1, 2, 3, and 4 of
      state X, using effective Hamiltonian for the A(2)Pi state and matrix elements for
      both A and X states. The present work suggests that the A(2)Pi(i) state changes
      from Hund's case (a) at low J values to Hund's case (b) at high J values.
      Copyright 2000 Academic Press.

PMID- 10637104
TI  - New Accurate Fit of an Extended Set of Saturation Data for the nu(3) Band of
      SF(6): Comparison of Hamiltonians in the Spherical and Cubic Tensor Formalisms.
AB  - An extended set of 321 frequencies of vibration-rotation lines of the nu(3) band
      of SF(6) has been measured by saturation spectroscopy using various isotopic
      species of CO(2). A least-squares fit of these data has been performed using an
      effective Hamiltonian written either with a spherical tensor or with a cubic
      tensor formalism. We have derived correspondence formulas between the parameters
      in the two approaches and checked that both formalisms give the same results up
      to the seventh order. Corrected parameters are given for the fit with a fifth
      order Hamiltonian. An accurate representation of the band is obtained at the
      tenth order (standard deviation approximately 12 kHz) with a remarkable
      predictive power (better than 40 kHz) for J values </= 100. The convergence
      properties of the Hamiltonian power expansion are discussed. Copyright 2000
      Academic Press.

PMID- 10637105
TI  - The Dynamics of N(2)-O(3) and N(2)-SO(2) Probed by Microwave Spectroscopy.
AB  - The microwave spectra of N(2)-O(3) and N(2)-SO(2) have been recorded in the 6-18
      GHz range using a pulsed-nozzle, Fourier transform microwave spectrometer. C-type
      transitions have been observed for both complexes which are slightly shifted by
      internal tunneling motions of the O(3) or SO(2) moieties. In addition, unshifted
      a-type transitions have been observed for N(2)-O(3). The nuclear hyperfine
      pattern is typical of equivalent nitrogen nuclei. Two sets of rotational and
      hyperfine constants are required to fit the symmetric and antisymmetric nuclear
      spin states, indicating that the equivalence arises from tunneling rotation of
      the nitrogen molecule. Internal tunneling motions along three tunneling pathways
      have been identified, although no information on the N(2) tunneling frequency is
      available from the spectra. From the N(2)-O(3) data the tunneling frequencies
      cannot be decorrelated from the rotational parameters; however, the O(3)
      tunneling frequency upper limit is estimated to be 2.0 MHz and the frequency of
      the concerted tunneling motion of both moieties is estimated to be about 8.9 MHz.
      For N(2)-SO(2), the SO(2) tunneling frequency is 11.5 kHz and the concerted
      frequency 173.9 kHz. Both complexes are roughly T shaped with the N(2) axis
      approximately perpendicular to the O(3) or SO(2) plane. In the equilibrium
      structures of both complexes, the a-c inertial plane is a plane of symmetry. The
      centers of mass separations are estimated from the rotational parameters to be
      3.582 A for N(2)-O(3) and 3.875 A for N(2)-SO(2). The angle between the symmetry
      axes of the O(3) or SO(2) and the line joining their centers of mass have been
      calculated as 130.84 degrees (or 49.16 degrees ) and 119.71 degrees (or 60.29
      degrees ), respectively. From the quadrupole analysis, the average angle between
      the N(2) axis and the a-inertial axis is 32.12 degrees for N(2)-O(3) and 27.81
      degrees for N(2)-SO(2). Model electrostatic and ab initio calculations confirm
      these structures. Differences between the experimental and calculated structural
      parameters highlight the role of tunneling dynamics in these complexes. Copyright
      2000 Academic Press.

PMID- 10637106
TI  - Quantum Number Dependence of Lineshift Coefficients Induced by Collisions with
      Noble Gas Perturbers in the nu(3) Band of NO(2).
AB  - To complete our study concerning lineshift in the rovibrational spectrum of
      (14)N(16)O(2), a pulse-driven three-channel lead salt diode laser spectrometer
      was applied to record high-resolution spectra at room temperature in the 6.2-um
      region corresponding to the nu(3) band at low NO(2) concentrations. The shift was
      studied for collisions with the noble gases He, Ne, Ar, Kr, and Xe. This paper
      extends our recently published data in order to analyze the quantum number
      dependence of the shift effect more precisely. Therefore, in this paper,
      additionally eight unresolved NO(2) doublets covering an enlarged quantum number
      range (10 </= N(") </= 34, 2 </= K(")(a) </= 6) were studied. For all doublets,
      shift coefficients delta(NO(2)-noble gas) and additionally broadening
      coefficients gamma(NO(2)-noble gas) were determined. Hereby, the experimental
      data confirm general trends published recently. In this study, in the case of
      broadening for the lighter rare gases helium, neon, and argon, only a slight
      decrease of gamma(NO(2)-noble gas) was observed, whereas for the rare gases with
      a higher atomic weight, i.e., krypton and xenon, a pronounced decrease of
      gamma(NO(2)-noble gas) with increasing rotational quantum number N(") occurred.
      All measured lineshift coefficients were negative. The absolute value of the
      determined lineshift coefficient ||delta(NO(2)-noble gas) || increases with the
      mass of the noble gas perturber, i.e., ||delta(NO(2)-He) || < ||delta(NO(2)-Ne)
      || < ||delta(NO(2)-Ar) || < ||delta(NO(2)-Kr) || < ||delta(NO(2)-Xe) ||. Within
      the studied quantum number range, an increase ||delta(NO(2)-noble gas) || with
      increase of N(") was observed. A typical trend of the shift and broadening data
      on the quantum number K(")(a) was not observed. Copyright 2000 Academic Press.

PMID- 10637107
TI  - Laser-Induced Irradiance Fluorescence of Molecular Sodium Excited by the 4765 A
      Ar(+) Laser Line.
AB  - A study of irradiance fluorescence spectrum induced by 476-nm laser line of an
      Ar(+) laser is presented for the B(1)Pi(u)-X(1)Sigma(+)(g) system of Na(2)
      molecule. A calibrated halogen lamp was used to calibrate a diode array
      spectrograph. Measured intensities are in agreement with calculated intensities.
      RKR potentials and theoretical transition dipole moment are utilized for
      intensity calculations. Copyright 2000 Academic Press.

PMID- 10637108
TI  - Rovibrational Intensities of the (00(0)3) <-- (10(0)0) Dyad Absorption Bands of
      (12)C(16)O(2).
AB  - Absolute line intensities of (12)C(16)O(2) are experimentally measured for the
      first time for the (00(0)3)(I) <-- (10(0)0)(II) band at 5687.17 cm(-1) and the
      (00(0)3)(I) <-- (10(0)0)(I) band at 5584.39 cm(-1). The spectra were obtained
      using a Bomem DA8 Fourier transform spectrometer and a 25-m base-path White cell
      at NASA-Ames Research Center. The rotationless bandstrengths at a temperature of
      296 K and the Herman-Wallis parameters are S(0)(vib) = 6.68(30) x 10(-25) cm(
      1)/(molecule/cm(2)); A(1) = 1.4(9) x 10(-4), and A(2) = -1.1(5) x 10(-5) for the
      (00(0)3)(I) <-- (10(0)0)(II) band and S(0)(vib) = 6.07(22) x 10(-25) cm(
      1)/(molecule/cm(2)); A(1) = 5.2(1.5) x 10(-4) and A(2) = -4.0(7) x 10(-5) for the
      (00(0)3)(I) <-- (10(0)0)(I) band.

PMID- 10637109
TI  - Rovibrational Energies of Triatomic Molecules by Means of the Rayleigh
      Schrodinger Perturbation Theory.
AB  - A Rayleigh-Schrodinger perturbation theory approach based on the adiabatic (Born
      Oppenheimer) separation of vibrational motions was previously developed and used
      to evaluate for a system of coupled oscillators the adiabatic energy levels and
      their nonadiabatic corrections. This method is applied here to calculate rotation
      vibration energies of the triatomic molecular ions HeH(+)(2) and ArNO(+)
      consisting of a strongly bound diatomic fragment and a relatively loosely bound
      rare gas atom. In these systems the high-frequency stretching motion of the
      diatomic fragment can be separated from the other two low-frequency motions
      without substantial loss of accuracy. Treating the diatomic fragment as a rigid
      rotor, the low-frequency stretching motion is decoupled from the bending motion
      in analogy to the concept of the adiabatic (Born-Oppenheimer) separation of
      motions and the strong nonadiabatic couplings between these two motions are
      accounted for perturbationally. Although the resulting perturbation series may
      show poor convergence, they turn out to be accurately summable by applying
      standard techniques for the summation of divergent series. Comparison with the
      results obtained from full-dimensional calculations for the two ions shows that
      the approach is capable of providing accurate energies for quite a few of the
      bound rotation-vibration states and that in the case of the HeH(+)(2) ion it is
      even able to predict the positions and widths of some low-lying resonance states
      with good accuracy. The perturbation approach yields zeroth-order energies and
      corrections in terms of the relevant quantum numbers. It thus allows a direct
      assignment of the energy levels without any reference to the corresponding
      eigenfunctions. The weak couplings between the high- and low-frequency motions
      can easily be treated by the same perturbative approach and numerically exact
      energies can finally be obtained. Copyright 2000 Academic Press.

PMID- 10637110
TI  - The Mystery of a Band Vanishing upon Isotopic Substitution: The Case of the v(3)
      = 1 State of FClO(3).
AB  - F. Meguellati, G. Graner, K. Burczyk, and H. Burger [J. Mol. Spectrosc. 185, 392
      402 (1997)] reported in their paper on nu(3)(A(1)) bands of the (35,37)Cl and
      (16,18)O isotopomers of FClO(3) that the nu(3) bands, which, although weak, could
      be well observed for the (16)O isotopomers, disappear almost completely in the
      spectra of the (18)O isotopomers. Because the A and B values for the (18)O
      isotopomers are so similar that these molecules are very close to spherical tops,
      much closer than the values for the (16)O species, disappearance of the band was
      ascribed to selection rules for tetrahedral molecules, the A(1) vibrations of
      which are inactive. Alternative explanations are proposed in this paper and
      analyzed. The most likely explanation is that a coincidence among the intensity
      parameters is responsible for a very low value of the dipole moment derivative; a
      weak Fermi resonance with the (v(6) = 2, l = 0) state may also participate in the
      final total wipeout of the band. It is believed that the last mechanism may be of
      more general interest. Copyright 2000 Academic Press.

PMID- 10637111
TI  - Dynamical Stark Effect in the nu(2)/nu(4) Vibrational Polyad of SiH(4): Theory
      and Observation.
AB  - We report a theoretical and experimental investigation of the dynamical Stark
      effect in a tetrahedral molecule, silane (SiH(4)). We use a tetrahedral formalism
      and Floquet theory to calculate the absorption spectra for the molecule dressed
      by an intense nonresonant pulsed laser. Experimentally, the dynamical Stark
      effect is observed for transitions of the nu(2)/nu(4) vibrational polyad of
      SiH(4) by means of nanosecond diode laser absorption spectroscopy and a Nd:YAG
      laser excitation. Copyright 2000 Academic Press.

PMID- 10637112
TI  - The Rotational Spectrum of Tricarbonyl(trans,trans-2,4-hexadiene) Iron.
AB  - The microwave spectrum of tricarbonyl(trans,trans-2,4-hexadiene) iron has been
      recorded in the range from 3 to 22 GHz using a Balle-Flygare type Fourier
      transform microwave spectrometer. The b- and c-type spectrum for the (56)Fe and
      the (54)Fe isotopomer could be assigned. The internal rotation of the two
      equivalent methyl groups results in a fine structure of the rotational
      transitions which is analogous to that of 2,2-dimethyloxirane [H. Hartwig and H.
      Dreizler, Z. Naturforsch., A: Phys. Sci. 47, 1063-1066 (1992)] and cis-2,3
      dimethyloxirane [H. Hartwig and H. Dreizler, Z. Naturforsch., A: Phys. Sci. 47,
      1051-1057 (1992)]. Analyzing this fine structure yields the internal rotation
      barrier in addition to the rotational constants and the quartic centrifugal
      distortion constants. Copyright 2000 Academic Press.

PMID- 10637113
TI  - Observation of Coriolis Coupling between nu(2) + 4nu(4) and 7nu(4) in Acetylene
      &Xtilde;(1)Sigma(+)(g) by Stimulated Emission Pumping Spectroscopy.
AB  - Stimulated emission pumping (SEP) spectroscopy has been used to examine a low
      energy region (E(vib) approximately 4400 cm(-1)) of &Xtilde;(1)Sigma(+)(g)
      acetylene at higher resolution than was possible in previous dispersed
      fluorescence studies. The expected bright state, nu(2) + 4nu(4), is observed to
      be coupled to the nearly degenerate 7nu(4) state by a Coriolis mechanism. A least
      squares analysis yields values for zero-order vibrational energies, rotational
      constants, and a Coriolis-coupling coefficient that are all consistent with
      expectations. Calculated relative intensities of SEP transitions, accounting for
      interference due to axis-switching effects, are also consistent with
      observations. Implications of the observed Coriolis resonance with regard to
      global acetylene vibrational dynamics are also discussed. Copyright 2000 Academic
      Press.

PMID- 10637114
TI  - The Hyperfine Structures of ScCl and ScF.
AB  - The Fourier transform microwave spectra of gaseous ScF and ScCl have been
      measured in their (1)Sigma(+) ground electronic states. Transitions have been
      observed for ScF (J = 1-0) and for both Sc(35)Cl and Sc(37)Cl (J = 1-0 and J = 2
      1) in the ground vibrational state, and for Sc(35)Cl (J = 1-0 and J = 2-1) in the
      first excited vibrational state. The nuclear quadrupole coupling constants of Sc
      and of both isotopes of Cl, the spin-rotation constants for all the nuclei and
      the nuclear spin-nuclear spin constants for both molecules, have been determined.
      From these hyperfine constants, the electronic structures of ScF and ScCl have
      been investigated and comparisons have been made to similar molecules. ScCl has
      been found to be highly ionic. For Sc(35)Cl, the equilibrium bond length has been
      reevaluated and the vibration frequency and dissociation energy have been
      estimated. A simple approach to account for the Sc quadrupole coupling constants
      has been shown to be flawed. Copyright 2000 Academic Press.

PMID- 10637115
TI  - Contact Transformations and Determinable Parameters in Spectroscopic Fitting
      Hamiltonians.
AB  - In recent least-squares fits of torsion-rotation spectra of acetaldehyde and
      methanol it was found possible to adjust more fourth-order parameters than would
      be expected from traditional contact-transformation considerations. To
      investigate this discrepancy between theory and practice we have carried out
      numerical fitting experiments on the simpler three-dimensional (three-Eulerian
      angle) asymmetric rotor problem, using J </= 20 unitless energy levels generated
      artificially from a full orthorhombic Hamiltonian with quadratic through octic
      operators in the angular momentum components. Results are analyzed using the
      condition number kappa of the least-squares matrix, which is a measure of its
      invertibility in the presence of round-off and other errors. When kappa is very
      large, parameters must be removed from the fit until kappa becomes acceptably
      small, corresponding to procedures which lead to reduced Hamiltonians in
      molecular spectroscopy. We find that under certain circumstances kappa can be
      decreased to an acceptable level for Hamiltonians which are only partially
      reduced when compared to Watson A and S reductions. Some insight into this
      behavior is obtained from classical mechanics and from the concept of delayed
      contact transformations. Transferring this numerical and algebraic understanding
      to the more complicated four-dimensional methyl-top internal rotor problem
      supports the empirical observation that presently existing data sets for methanol
      and acetaldehyde are most efficiently fit using partially reduced Hamiltonians
      and further suggests that expanding the methanol data set to transitions
      involving levels of higher J, K, and v(t) would favor even more strongly the use
      of partially reduced fourth-order Hamiltonians.

PMID- 10637116
TI  - Global Fit of Torsion-Rotational Transitions in the First Three Torsional States
      of CH(3)OD.
AB  - A global fit of the observed high-resolution microwave (MW), millimeter-wave
      (MMW), and Fourier transform far-infrared (FIR) spectra for CH(3)OD has been
      performed using a reduced torsion-rotational Hamiltonian that is obtained from
      the one-large-amplitude internal-rotation model. The CH(3)OD data set contains
      460 MW and MMW transitions with two or fewer quanta in the torsion, v(t) </= 2,
      and 2348 Fourier transform FIR transitions with v(t) </= 1 and J </= 21. The MW
      and MMW transitions have been fitted with a root-mean-square (rms) deviation of
      0.11 MHz (0.098 MHz for J </= 10) while FIR transitions have a rms deviation of
      0.0002 cm(-1). These deviations are approximately equal to the experimental
      uncertainties, indicating that the MW, MMW, and FIR spectral transitions have
      been fit to experimental accuracy. Copyright 2000 Academic Press.

PMID- 10637117
TI  - First Measurement of the Weak (0, 4) Band in the B(2)Sigma(+)(u)-X(2)Sigma(+)(g)
      System of (14)N(+)(2) by Collinear Fast-Ion-Beam Laser Spectroscopy.

PMID- 10637118
TI  - Rotational Spectrum of the MgN(13)C Radical.

PMID- 10637119
TI  - The Pure Rotational Spectrum of Yttrium Monoiodide.

PMID- 10637120
TI  - Effects of the new arginase inhibitor N(omega)-hydroxy-nor-L-arginine on NO
      synthase activity in murine macrophages.
AB  - In stimulated murine macrophage, arginase and nitric oxide synthase (NOS) compete
      for their common substrate, l-arginine. The objectives of this study were (i) to
      test the new alpha-amino acid N(omega)-hydroxy-nor-l-arginine (nor-NOHA) as a new
      selective arginase inhibitor and (ii) to elucidate the effects of arginase
      inhibition on l-arginine utilization by an inducible NOS. Nor-NOHA is about 40
      fold more potent than N(omega)-hydroxy-l-arginine (NOHA), an intermediate in the
      l-arginine/NO pathway, to inhibit the hydrolysis of l-arginine to l-ornithine
      catalyzed by unstimulated murine macrophages (IC(50) values 12 +/- 5 and 400 +/-
      50 microM, respectively). Stimulation of murine macrophages with interferon-gamma
      and lipopolysaccharide (IFN-gamma + LPS) results in clear expression of an
      inducible NOS (iNOS) and to an increase in arginase activity. Nor-NOHA is also a
      potent inhibitor of arginase in IFN-gamma + LPS-stimulated macrophage (IC(50)
      value 10 +/- 3 microM). In contrast to NOHA, nor-NOHA is neither a substrate nor
      an inhibitor for iNOS and it appears as a useful tool to study the interplays
      between arginase and NOS. Inhibition of arginase by nor-NOHA increases nitrite
      and l-citrulline accumulation for incubation times higher than 12 h, under our
      conditions. Our results allow the determination of the kinetic parameters of the
      two competitive pathways and the proposal of a simple model which readily
      explains the differences observed between experiments. This model readily
      accounts for the observed effects and should be useful to predict the
      consequences of arginase inhibition in the presence of an active NOS on l
      arginine availability.

PMID- 10637121
TI  - The reaction rates of NO with horseradish peroxidase compounds I and II.
AB  - In this study the reactions between nitric oxide (NO) and horseradish peroxidase
      (HRP) compounds I and II were investigated. The reaction between compound I and
      NO has biphasic kinetics with a clearly dominant initial fast phase and an
      apparent second-order rate constant of (7.0 +/- 0.3) x 10(5) M(-1) s(-1) for the
      fast phase. The reaction of compound II and NO was found to have an apparent
      second-order rate constant of k(app) = (1.3 +/- 0.1) x 10(6) M(-1) s(-1) or (7.4
      +/- 0.7) x 10(5) M(-1) s(-1) when measured at 409 nm (the isosbestic point
      between HRP and HRP-NO) and 419 nm (lambda(max) of compound II and HRP-NO),
      respectively. Interestingly, the reaction of compound II with NO is unusually
      high relative to that of compound I, which is usually the much faster reaction.
      Since horseradish peroxidase is prototypical of mammalian peroxidases with
      respect to the oxidation of small substrates, these results may have important
      implications regarding the lifetime and biochemistry of NO in vivo after
      inflammation where both NO and H(2)O(2) generation are increased several fold.

PMID- 10637123
TI  - Nitric oxide production is increased in patients with inflammatory myositis.
AB  - Nitric oxide (NO) production is increased in several inflammatory disorders. We
      have previously demonstrated higher levels of NO production among patients with
      rheumatoid arthritis and systemic lupus erythematosus. In this study we measured
      serum levels of nitrite and citrulline using calorimetric methods as surrogate
      markers of NO production among patients with inflammatory myositis (IM). Twenty
      patients with IM and 19 age- and sex-matched controls were studied. Serum nitrite
      levels were significantly higher among patients than among controls (986.6 +/-
      880 and 204.3 +/- 113.9 nmol/ml, respectively; P = 0.001). Serum citrulline
      levels, too, were significantly higher among patients than among controls (3755.7
      +/- 1905.5 and 189 +/- 177.2 nmol/ml, respectively; P < 0.0001). There was a
      positive correlation between steroid dosage and serum citrulline levels (r =
      0.51, P = 0.036) and a negative correlation between steroid dosage and disease
      duration (r = -0.54, P = 0.025). It was concluded that NO production is increased
      in patients with IM and those with more active disease, as indicated by higher
      steroid dosage, have higher serum citrulline levels.

PMID- 10637122
TI  - Generation of nitric oxide and possibly nitroxyl by nitrosation of
      sulfohydroxamic acids and hydroxamic acids.
AB  - Diazeniumdiolates (NONOates) and sulfohydroxamic acids are chemical entities that
      spontaneously generate nitric oxide (NO) and nitroxyl (HNO), respectively, at
      physiological pH and temperature. By combining the functional aspects of the
      NONOates with the hydroxamic acids and sulfohydroxamic acids, hybrid NONOate-type
      compounds that could theoretically generate nitroxyl or nitric oxide can be
      rationalized. Although the instability of these compounds, viz., the N
      nitrosohydroxamic acids and the N-nitrososulfohydroxamic acids, precluded their
      chemical characterization by actual isolation, their transient existence was
      deduced by identification of the products of their decomposition. Thus, treatment
      of benzohydroxamic acid (BHA) with limiting or excess nitrous acid (from NaNO(2)
      and H(3)PO(4)) gave rise to quantitative generation of N(2)O, possibly via HNO,
      based on the limiting reactant. Nitrosation of N-t-butyloxycarbonyl hydroxylamine
      gave similar results. The organic acid produced from BHA was identified as
      benzoic acid. No nitric oxide was detected from these reactions. In contrast,
      treatment of Piloty's acid (benzenesulfohydroxamic acid) and
      methanesulfohydroxamic acid (MSHA) with nitrous acid under the same conditions as
      above gave 36% of the theoretical quantity of NO from Piloty's acid and 47% of NO
      from MSHA, although finite quantities of HNO (measured as N(2)O) were also
      formed. The organic acid produced from Piloty's acid was identified by reverse
      phase HPLC as the redox product, benzenesulfinic acid.

PMID- 10637124
TI  - Evolution of streptozotocin-pancreatic damage in the rat: modulatory effect of
      endothelins on the nitridergic and prostanoid pathway.
AB  - Many lines of evidence indicate that an increased pancreatic production of nitric
      oxide (NO) and prostaglandins (PGs) is found in the pancreas of streptozotocin
      diabetic rats and that endothelins (ETs) are closely related to the nitridergic
      and prostanoid pathway in several tissues. In the present study the relationship
      between NO, ETs, and PGs has been explored in isolated pancreatic tissue from
      streptozotocin-diabetic rats. Pancreatic ET levels are higher in pancreatic
      tissues from diabetic (D) rats compared to control (C) animals. The addition of
      nitric oxide synthase (NOS) inhibitors (1 mM N(G)-nitro-l-arginine methyl ester,
      600 microM N(G)-monomethyl-l-arginine) in the incubating medium reduces and NO
      donors (SIN-1, 300 microM spermine suppress, NONOate 100 microM) increases ET
      levels in pancreatic slices from C and D animals. PGE(2) (10(-7) M) increases and
      indomethacin (10(-6) M) decreases ET pancreatic production only in D but not in C
      tissues when added into the incubating bath. When tissues are incubated in the
      presence of endothelin 1 (ET-1) (10(-7) M), NOS activity is higher in C pancreas,
      while the ET-receptor antagonist bosentan (B) decreases NOS levels in D but not
      in C tissues. When pancreatic arachidonic acid (AA) conversion to prostaglandins
      was explored, ET-1 increased PGF(2alpha), PGE(2), and TXB(2) levels in C but not
      in D tissues. B abolishes TXB(2) increment due to the diabetic state, but failed
      in modulating AA conversion to 6-keto PGF(1alpha), PGF2(alpha) and PGE(2) in D
      pancreas. Our results show an alteration in AA metabolism, ET production, and NO
      increment associated with pancreatic damage due to streptozotocin.

PMID- 10637125
TI  - Mechanism of extracellular thiol nitrosylation by N(2)O(3) produced by activated
      macrophages.
AB  - Reactive nitrogen intermediates are synthesized by activated macrophages. These
      molecules, and nitrous anhydride (N(2)O(3)) in particular, are known to be potent
      nitrosylating species. We investigated the role of macrophage-derived N(2)O(3) in
      extracellular nitrosylation. We used dilution experiments to demonstrate the
      intracellular production of N(2)O(3) and its export into the extracellular
      medium, with a rate constant k(ex) = 6.8 x 10(6) M s(-1). The kinetics of the
      competition between extracellular hydrolysis of N(2)O(3) and its reaction with
      added glutathione were also studied. We obtained a value of the rate constant
      k(GSH) for the latter reaction of 4.4 x 10(7) M(-1) s(-1), consistent with
      earlier determinations in cell-free systems. The implications of these results in
      human albumin nitrosylation were investigated. Nitrosylated albumin was detected
      in activated macrophages supernatants using an anti-NO-acetylated cysteine
      antibody. It was estimated that 10% of N(2)O(3) produced by activated cells
      participate in extracellular nitrosylation. N(2)O(3) thus appears to be a new
      effector molecule of the immune system, as an agent for the nitrosylation of
      albumin, the main nitric oxide carrier in vivo.

PMID- 10637126
TI  - Cyclic GMP reduces ventricular myocyte stunning after simulated ischemia
      reperfusion.
AB  - We tested the hypothesis that the second messenger activated by nitric oxide,
      cyclic GMP, would reduce the effects of myocyte stunning following simulated
      ischemia-reperfusion and that this was related to cyclic GMP protein kinase.
      Ventricular cardiac myocytes were isolated from New Zealand White rabbits (n =
      8). Cell shortening was measured by a video edge detector and protein
      phosphorylation was determined autoradiographically after SDS gel
      electrophoresis. Cell shortening data were acquired at: (i) baseline followed by
      8-Bromo-cGMP 10(-6) M (8-Br-cGMP) and then KT 5823 10(-6) M (cyclic GMP protein
      kinase inhibitor) and (ii) simulated ischemia (20 min of 95% N(2)-5% CO(2) at 37
      degrees C) followed by simulated reperfusion (reoxygenation) with addition of 8
      Br-cGMP 10(-6) M followed by KT 5823 10(-6) M, (iii) addition of 8-Br-cGMP prior
      to ischemia followed by the addition of KT 5823 10(-6) M after 30 min of
      reoxygenation. In the control group, 8-Br-cGMP 10(-6) M decreased percentage
      shortening (%short) (5.0 +/- 0.6 vs 3.8 +/- 0. 4) and the maximum velocity
      (V(max), microm/s) (48.6 +/- 6.9 vs 40.2 +/- 6.4). KT 5823 10(-6) M added after 8
      Br-cGMP partially restored %short (4.6 +/- 0.5) and V(max) (46.6 +/- 8.0). After
      stunning, baseline myocytes had decreased %short (3.4 +/- 0.2) and V(max) (36. 0
      +/- 4.2). After the addition of 8-Br-cGMP, the %short (2.7 +/- 0. 2) and V(max)
      (27.6 +/- 2.5) decreased further. The addition of KT 5823 did not change either
      the %short or the V(max). The myocytes with 8-Br-cGMP during ischemia had
      increased %short (4.2 +/- 0.2) and V(max) (37.2 +/- 3.4) when compared to the
      stunned group. The addition of KT 5823 did not significantly alter %short (3.3 +/
      0.4) or V(max) (29.2 +/- 5.0) in the myocytes pretreated with 8-Br-cGMP. Protein
      phosphorylation was increased by 8-Br-cGMP in control and stunned myocytes. KT
      5823 blocked this effect in control but not stunned myocytes, suggesting some
      change in the cyclic GMP protein kinase. Ischemia-reperfusion produced myocyte
      stunning that was reduced when 8-Br-cGMP was added prior to but not after
      ischemia.

PMID- 10637127
TI  - The hyperglycemic effect of S-nitrosoglutathione in the dog.
AB  - The present study investigates the pharmacological activity of the nitric oxide
      (NO) donor S-nitrosoglutathione (GSNO) on the plasma glucose and insulin levels
      in healthy normoglycemic dogs. The plasma nitrate and nitrite concentrations were
      measured by a commercial autoanalyzer and taken as the biochemical markers of in
      vivo nitric oxide formation. Plasma glucose levels were measured by the glucose
      oxidase method, while the insulin levels were determined by radioimmunoassay. The
      possible effect of the coadministration of ascorbic acid (vitamin C) and GSNO on
      plasma glucose levels was also examined. In healthy normoglycemic dogs,
      administration of 35 and 50 mg/kg of GSNO caused a dose-dependent increase in
      postprandial plasma glucose levels. The plasma glucose levels were significantly
      elevated at the 1.5-, 2.0-, and 2.5-h time intervals of the oral glucose
      tolerance test at both concentrations of GSNO (P < 0.05). These values were
      significantly higher than those obtained using captopril (control). Furthermore,
      coadministration of 35 mg/kg of GSNO and 50 mg/kg ascorbic acid enhanced the
      postprandial hyperglycaemic effect observed for the administration of only 35
      mg/kg of GSNO. There was a 35-100% increase in plasma nitrate concentration on
      administration of both doses of GSNO. Intravenous administration of GSNO (35
      mg/kg) and captopril (20 mg/kg) significantly decreased the mean arterial blood
      pressure and increased the heart rate. The blood pressure-lowering effect of
      these drugs was more pronounced on systolic than on diastolic blood pressure (P <
      0.05). These results suggests that in healthy normoglycaemic dogs: (a) nitric
      oxide released from GSNO increases postprandial plasma glucose levels and
      inhibits glucose-stimulated insulin secretion, (b) ascorbic acid enhances the
      postprandial hyperglycaemic effect of GSNO, probably by increasing the release of
      NO, and (c) GSNO decreases mean arterial blood pressure and increase heart rate
      in normotensive dogs.

PMID- 10637128
TI  - The effect of air pollution on exhaled nitric oxide of atopic and nonatopic
      subjects.
AB  - Levels of exhaled nitric oxide (NO) were determined in well-characterized atopic
      and nonatopic subjects on 4 days with a different level of outdoor air pollution.
      The two groups matched well regarding spirometric values, i.e., no difference
      with regard to FEV(1), FVC, and peak flow. On the 4 test days asymptomatic atopic
      subjects exhaled 1.5- to 2.4-fold higher levels of NO compared with nonatopic
      subjects. In both groups the increase in exhaled NO in response to air pollution
      was similar (2.5 times maximal increase, P < 0.01). In conclusion, atopic
      subjects exhale higher levels of NO compared with nonatopic subjects, but respond
      to a similar degree to increased levels of air pollution.

PMID- 10637129
TI  - Link between catecholamine and nitric oxide metabolism.

PMID- 10637130
TI  - Assessment of preferential T-helper 1 or T-helper 2 induction by low molecular
      weight compounds using the local lymph node assay in conjunction with RT-PCR and
      ELISA for interferon-gamma and interleukin-4.
AB  - The local lymph node assay (LLNA) is a new and promising test in mice used to
      identify contact allergens by means of dermal exposure. Experimentally this
      assay, which comprises a sensitizing phase only, is also used to identify
      respiratory allergens. Another, experimentally used test in mice to identify
      allergens is also based on dermal exposure, but comprises both a sensitizing and
      effector phase. In this latter test, it has been shown that contact allergens
      preferentially induce a T-helper 1 (TH1) response, whereas respiratory allergens
      preferentially induce a T-helper 2 (TH2) response. These responses can be
      discriminated on the basis of cytokine production, such as IFN-gamma, which is
      produced by TH1 cells, and IL-4, which is produced by TH2 cells. The aim of the
      study was to establish whether the LLNA was sufficient to not only identify
      allergens but also mark them as either a contact or a respiratory allergen. To
      this end, LLNA responses to the contact allergen dinitrochlorobenzene (DNCB) and
      the respiratory allergen trimellitic anhydride (TMA) were determined using IFN
      gamma and IL-4 mRNA expression and production as parameters. Topical application
      of TMA resulted in a threefold higher lymphocyte proliferation compared to DNCB 3
      and 5 days after the first application, while a similar proliferation was found
      from Day 7 and onward. RT-PCR showed a similar induction of IFN-gamma and IL-4
      mRNA expression. While both DNCB and TMA induced IFN-gamma production, TMA but
      not DNCB induced IL-4 production. Thus, only IL-4 production seemed a suitable
      parameter to discriminate between the two compounds. In a second study, the
      respiratory allergens toluene-2,4-diisocyanate (TDI) and phthalic anhydride (PA)
      were also assayed 7 days after the first application. Topical application of DNCB
      and PA resulted in a similar lymphocyte proliferation, while application of TMA
      and TDI resulted in a 1.8-fold higher proliferation. IFN-gamma production was
      similar for DNCB, TMA, and TDI, and fourfold lower for PA, while IL-4 production
      was similar for TMA, TDI, and PA, and 24-fold lower for DNCB. In summary, both
      studies showed induction of IL-4 production by respiratory allergens, with little
      or no induction by the contact allergen, holding promise for the possibility of
      identifying respiratory allergens within the LLNA by measuring IL-4 production 7
      days after the first application.

PMID- 10637131
TI  - Lung mucin production is stimulated by the air pollutant residual oil fly ash.
AB  - Human and animal exposure to particulate air pollution is correlated with airway
      mucus hypersecretion and increased susceptibility to infection. Seeking clues to
      the mechanisms underlying this pathology, we examined the effect of the
      particulate air pollutant residual oil fly ash (ROFA) on production of the major
      component of mucus, mucin, and the major antibacterial protein of the respiratory
      tract, lysozyme. We found that following in vitro exposure to ROFA, epithelial
      cells showed an increase in mucin (MUC5AC) and lysozyme (LYS) steady state mRNA.
      This upregulation was controlled at least partly at the level of transcription as
      shown by reporter assays. Experiments testing the ability of the major components
      of ROFA to mimic these effects showed that vanadium, a metal making up 18.8% by
      weight, accounted for the bulk of the response. A screen of signaling inhibitors
      showed that MUC5AC and LYS induction by ROFA are mediated by dissimilar signaling
      pathways, both of which are, however, phosphotyrosine dependent. Recognizing that
      the ROFA constituent vanadium is a potent tyrosine phosphatase inhibitor and that
      mucin induction by pathogens is phophotyrosine dependent, we suggest that
      vanadium-containing air pollutants trigger disease-like conditions by unmasking
      phosphorylation-dependent pathogen resistance pathways.

PMID- 10637132
TI  - Activation of parallel mitogen-activated protein kinase cascades and induction of
      c-fos by cadmium.
AB  - Cadmium is a toxic divalent cation that can initiate either mitogenic signals or
      apoptosis, possibly as a consequence of inducing different patterns of oncogene
      expression in different cells. We previously showed that Cd(2+) caused
      transcriptional activation of the c-fos protooncogene in mesangial cells (Wang
      and Templeton, J. Biol. Chem. 273, 73-79, 1998). The present study was undertaken
      to identify the signaling pathways that might be involved. Exposure to 10 microM
      CdCl(2) for 8 h caused a prolonged activation of Erk kinase and accumulation of c
      fos mRNA. Inhibition of Erk activation with PD98059 only partially inhibited c
      fos induction, indicating that additional pathways are involved. The c-Jun
      kinase/stress-activated protein kinase (SAPK) was also activated by Cd(2+). All
      three signals, i.e., Erk activity, SAPK activity, and c-fos mRNA levels in
      response to Cd(2+) showed a similar biphasic time course with an initial increase
      at 15-30 min and then a larger and more prolonged increase several hours later.
      Each signal also showed a similar concentration dependence, with less than 1
      microM Cd(2+) causing the initial increase but values above 3 microM being
      required for the prolonged phase. These events showed high specificity for
      Cd(2+); other divalent metals tested under the same conditions (Mg(2+), Mn(2+),
      Co(2+), Ni(2+), Cu(2+), Zn(2+), and Hg(2+)) were without significant effects. We
      conclude that Cd(2+) is a specific inducer of c-fos in mesangial cells, probably
      through activation of both Erk kinase and SAPK pathways. The similar time and
      concentration dependence of the response of both pathways to Cd(2+) suggests a
      common basis for activation.

PMID- 10637133
TI  - Class A type II scavenger receptor mediates silica-induced apoptosis in Chinese
      hamster ovary cell line.
AB  - Macrophage scavenger receptors are known to bind endotoxins, oxidized low-density
      lipoproteins (Ox-LDL), and other proteins with clustered negative charges. Recent
      evidence indicates some particulates may also bind to the scavenger receptor and
      initiate apoptosis. In this study, chinese hamster ovary (CHO) cells stabily
      transfected with the murine class A type II scavenger receptor (SR-A II) were
      exposed to crystalline silica to examine the role of this receptor in apoptosis.
      In a 24-h culture, silica (250 microg/ml) induced significant cell injury
      (necrosis and apoptosis) in transfected cells (MSR II) but not in the control
      cells (KA-7). This effect was specific to silica, as a control particle titanium
      dioxide had no cytotoxic effects on the MSR II cells at equal particle mass
      concentrations. Furthermore, silica-induced apoptosis in the MSR II cells could
      be eliminated by preincubating the cells with SR-A II antagonists: polyinosinic
      acid or maleylated bovine serum albumin. This study further supports the
      hypothesis that the SR-A II is directly involved with silica toxicity and that
      certain scavenger receptor ligands may have an important role in regulating
      macrophage apoptosis.

PMID- 10637134
TI  - Ethambutol-induced vacuolar changes and neuronal loss in rat retinal cell
      culture: mediation by endogenous zinc.
AB  - Ethambutol is an efficacious antituberculosis agent. However, its use has been
      limited by the occurrence of ocular toxicity. To investigate characteristics and
      possible mechanisms of ethambutol ocular toxicity, we used primary rat retinal
      cultures as a model. Primary rat retinal cultures were obtained from newborn
      Sprague-Dawley rats and used for experiments after maturation (DIV > or = 10).
      Cytopathologic changes were examined under light and electron microscopes. Thy-1
      (a membrane glycoprotein expressed by retinal ganglion neurons)-containing
      neurons and gamma-aminobutyric acid (GABA)-ergic neurons were identified
      immunocytochemically. Exposure of retinal cultures for 24-48 h to ethambutol
      induced cytoplasmic vacuolar changes and neuronal loss. Vacuolar changes were
      partially reversible with the termination of ethambutol exposure. Of neurons, Thy
      1(+) ganglion neurons were more vulnerable than GABA(+) neurons. Glutamate
      antagonists, an antioxidant (trolox), or cycloheximide, did not attenuate either
      vacuolar changes or neuronal loss. A cell-permeant zinc chelator N,N,N',N'
      tetrakis (2-pyridylmethyl) ethylenediamine (TPEN) markedly attenuated vacuolar
      degeneration and neuronal loss, while the addition of zinc augmented both. In rat
      retinal cultures, ethambutol induces reversible vacuolar degeneration as well as
      irreversible neuronal loss, more preferentially of Thy-1(+) ganglion neurons.
      Contrary to the current theories, ethambutol-induced retinal cytotoxicity in the
      present study is mediated not by excitotoxicity or zinc deficiency but by a
      mechanism requiring intracellular zinc. In addition, features of the ethambutol
      induced cell death were not consistent with those of apoptosis.

PMID- 10637135
TI  - Catechol metabolites of polychlorinated biphenyls inhibit the catechol-O
      methyltransferase-mediated metabolism of catechol estrogens.
AB  - The catechol metabolites of estradiol, 2- and 4-hydroxyestradiol (2-OHE(2) and 4
      OHE(2), respectively) are potent signaling molecules and are hypothesized to be
      central to estrogen-linked carcinogenesis. Methylation by catechol-O
      methyltransferase (COMT) is the principal means of catechol estrogen (CE)
      deactivation in the liver and other tissues. The present studies were conducted
      to determine the effects of PCBs and catechol metabolites of PCBs on the COMT
      mediated catabolism of 4-OHE(2) and 2-OHE(2) in vitro and in vivo. Liver
      homogenates of female Sprague-Dawley rats treated with Aroclor 1254 for 21 days
      (5 mg/kg/day) showed a 30 and 40% reduction of COMT activity toward 2-OHE(2) and
      4-OHE(2), respectively. Incubation of [(3)H]-beta-estradiol with these same liver
      homogenates, followed by HPLC analysis, demonstrated an elevation of CEs and a
      nearly complete reduction in levels of methylated catechol estrogens. In
      classical enzyme kinetics studies, COMT was demonstrated to have a high affinity
      for catechol PCBs, with K(m)'s approximately equivalent to those of CEs. Catechol
      PCBs were also potent inhibitors of CE O-methylation. These data suggest that
      PCBs may significantly alter the metabolism of catechol estrogens in vivo and
      that this effect may be mediated by catechol metabolites of PCBs. It is further
      speculated that methyltransferase inhibition by PCB catechols may contribute to
      PCB-mediated endocrine effects and liver carcinogenesis.

PMID- 10637136
TI  - Phenolphthalein metabolite inhibits catechol-O-methyltransferase-mediated
      metabolism of catechol estrogens: a possible mechanism for carcinogenicity.
AB  - Phenolphthalein (PT), used in over-the-counter laxatives, has recently been
      identified as a multisite carcinogen in rodents, but the molecular species
      responsible for the carcinogenicity is not known. A catechol metabolite of PT,
      hydroxyphenolphthalein (PT-CAT), was recently identified and may be the molecular
      species responsible for at least part of the toxicity/carcinogenicity of PT. We
      hypothesize that PT-CAT inhibits the enzyme catechol-O-methyltransferase (COMT)
      and therefore potentiates genotoxicity by either PT-CAT itself or the endogenous
      catechol estrogens (CEs) in susceptible tissues. The present studies were
      conducted to determine the effects of PT treatment and PT-CAT itself on the COMT
      mediated metabolism of 4- and 2-hydroxyestradiol both in vitro and in vivo.
      Female mice were treated with PT (50 mg/kg/d) for 21 days and then euthanized. PT
      CAT concentration in urine reached plateau levels by 7 days of exposure. An O
      methylated metabolite of PT-CAT was detected in feces. In vitro experiments
      demonstrated that PT treatment resulted in an increase in free CEs, which are
      normally cleared by COMT and a concurrent decrease in the capacity of hepatic
      catechol clearance by COMT. In vitro, PT-CAT was a substrate of COMT, with
      kinetic properties within the range measured with endogenous substrates. PT-CAT
      was an extremely potent mixed-type inhibitor of the O-methylation of the catechol
      estrogens, with 90-300 nM IC50s. The above data, when taken together, suggest
      that chronic administration of PT may enhance metabolic redox cycling of both PT
      CAT and the catechol estrogens and this, in turn, may contribute to PT-induced
      tumorigenesis.

PMID- 10637137
TI  - Oxalate toxicity in renal epithelial cells: characteristics of apoptosis and
      necrosis.
AB  - Studies in various tissues, including the kidney, have demonstrated that toxins
      elicit apoptosis under certain conditions and necrosis under others. The nature
      of the response has important consequences for the injured tissue in that
      necrotic cells elicit inflammatory responses, whereas apoptotic cells do not.
      Thus, there has been considerable interest in defining the mode of cell death
      elicited by known cytotoxins. The present studies examined the response of renal
      epithelial cells to oxalate, a metabolite excreted by the kidney that produces
      oxidant stress and death of renal cells at pathophysiological concentrations.
      These studies employed LLC-PK1 cells, a renal epithelial cell line from pig
      kidney and NRK-52E (NRK) cells, a line from normal rat kidney, and compared the
      effects of oxalate with those of known apoptotic agents. Changes in cellular and
      nuclear morphology, in nuclear size, in ceramide production, and in DNA integrity
      were assessed. The ability of bcl-2, an anti-apoptotic gene product, to attenuate
      oxalate toxicity was also assessed. These studies indicated that oxalate-induced
      death of renal epithelial cells exhibits several features characteristic of
      apoptotic cell death, including increased production of ceramide, increased
      abundance of apoptotic bodies, and marked sensitivity to the level of expression
      of the anti-apoptotic gene bcl-2. Oxalate-induced cell death also exhibits
      several characteristics of necrotic cell death in that the majority of the cells
      exhibited cellular and nuclear swelling after oxalate treatment and showed little
      evidence of DNA cleavage by TUNEL assay. These results suggest that toxic
      concentrations of oxalate trigger both forms of cell death in renal epithelial
      cells.

PMID- 10637138
TI  - Calmidazolium-induced rises in cytosolic calcium concentrations in Madin Darby
      canine kidney cells.
AB  - The effect of calmidazolium on Ca(2+) signaling in Madin Darby canine kidney
      (MDCK) cells was investigated using fura-2 as a Ca(2+) probe. Calmidazolium at 2
      5 microM increased [Ca(2+)](i) concentration dependently. The [Ca(2+)](i) rise
      induced by 2-5 microM calmidazolium comprised an immediate rise and a slow decay.
      External Ca(2+) removal partly inhibited the Ca(2+) signals, suggesting that
      calmidazolium activated external Ca(2+) influx and internal Ca(2+) release. In
      Ca(2+)-free medium, pretreatment with 3 microM calmidazolium abolished the Ca(2+)
      release induced by 1 microM thapsigargin, an endoplasmic reticulum Ca(2+) pump
      inhibitor, and, vice versa, pretreatment with thapsigargin inhibited
      calmidazolium-induced Ca(2+) release. This indicates that thapsigargin-sensitive
      Ca(2+) store was the source of calmidazolium-induced Ca(2+) release.
      Calmidazolium (3 microM) induced Mn(2+) quench of fura-2 fluorescence at 360 nm
      excitation wavelength, which was suppressed by 0.1 mM La(3+). Addition of 3 mM
      Ca(2+) increased [Ca(2+)](i) after pretreatment with 3-5 microM calmidazolium in
      Ca(2+)-free medium. This implies that calmidazolium activated concentration
      dependent capacitative Ca(2+) entry. Calmidazolium (3 microM) augmented the
      capacitative Ca(2+) entry induced by 1 microM thapsigargin or 0.1 mM ATP by 38%.
      Calmidazolium (3 microM)-induced Ca(2+) release was blocked by pretreatment with
      40 microM aristolochic acid and 2 microM U73122 (2 microM) to inhibit
      phospholipase A(2) and phospholipase, respectively, but pretreatment with 0.1 mM
      propranolol to inhibit phospholipase D had no effect. This suggests that
      calmidazolium induced internal Ca(2+) release in a manner dependent on
      phospholipases C- and A(2)-coupled events.

PMID- 10637139
TI  - Practical application of intravascular ultrasound in endovascular interventions.

PMID- 10637140
TI  - Preoperative cardiac assessment in patients with peripheral vascular disease: is
      it worthwhile?

PMID- 10637141
TI  - The Vein Graft Surveillance Trial: rationale, design and methods. VGST
      participants.
AB  - OBJECTIVES: to compare the amputation rates, quality of life and health care
      costs in patients receiving duplex ultrasound scanning against clinical
      surveillance following femoropopliteal and femorocrural vein bypass. DESIGN:
      multi-centre, prospective, randomised controlled trial. METHODS: 1200 patients
      with a patent vein graft at 30 days postoperatively will be randomised to either
      clinical or duplex follow-up. All patients are seen in an out-patient clinic at 6
      weeks, then 3, 6, 9, 12 and 18 months postoperatively. At each appointment
      patients are examined clinically; palpable pulses in the graft and crural
      vessels, presenting symptoms and their ankle-branchial pressure indices (ABPIs)
      measured. In the duplex group only, the results of the scan are monitored. The
      incidence of radiological and/or surgical interventions throughout the follow-up
      period are also noted. Quality of life is measured using the SF-36 and EuroQol
      questionnaires at the 6 and 18 month appointments. Hospital stays and resource
      use are documented for health economic analysis. RESULTS: the primary endpoint of
      this study is amputation or death from vascular causes; however, graft patency
      rates will also be compared between the groups. Quality of life and health
      economic data will be used to determine if there is any benefit in either arm in
      these outcomes between follow-up strategies. CONCLUSIONS: this large, randomised
      controlled trial will hopefully provide direct evidence on the benefit of duplex
      surveillance for vein grafts in terms of limb salvage, quality of life of the
      patients and cost-benefit to the purchaser.

PMID- 10637143
TI  - Length measurements of the aorta after endovascular abdominal aortic aneurysm
      repair.
AB  - BACKGROUND: successful endovascular repair of abdominal aortic aneurysms (AAA)
      generally leads to a decrease in aneurysm size. Theoretically, this may lead to
      foreshortening of the excluded segment. If so, vertically rigid endografts may
      dislocate over time and cover renal or hypogastric arteries. AIM: to assess
      length changes of the infrarenal aorta after endovascular AAA exclusion. PATIENTS
      AND METHODS: forty-four consecutive patients were scheduled for the EndoVascular
      Technologies endograft, a vertically non-rigid prosthesis which would potentially
      accommodate longitudinal changes. Twenty-four patients had completed at least 6
      months of follow-up. In 18/24 patients a decrease in size was established by
      aneurysm volume measurements at 6 months' follow-up. Helical computer tomography
      (CT) angiograms were processed on a workstation. Aortic lengths were measured
      along the central lumen line from the lower renal artery orifice to the native
      aortic bifurcation. The computer tomography angiogram (CTA) reconstruction
      thickness of 2 mm yields at least a 4-mm error for each length measurement.
      RESULTS: in the shrinking aneurysm group, the median length change was 0 mm
      (range -9 mm to +4 mm) at 6 months' follow-up (n =18) and also 0 mm (range -7 mm
      to +4 mm) at 12 months' follow-up ( n =10). In 16/18 patients, length changes
      remained within the measurement error range of 4 mm. CONCLUSION: in this group of
      shrinking aneurysms after endovascular AAA repair, foreshortening of the excluded
      aortic segment appears not to be a clinically significant problem.

PMID- 10637142
TI  - Abdominal aortic aneurysm measurements for endovascular repair: intra- and
      interobserver variability of CT measurements.
AB  - OBJECTIVES: to evaluate the intra- and interobserver variability in measurements
      of the aorta and iliac arteries in patients with abdominal aortic aneurysms
      (AAAs) considered for endovascular repair using computed tomography angiography
      (CTA). METHODS: the diameter of the neck, aneurysm, right and left iliac artery
      were measured by 5 observers in 10 consecutive patients. Measurements were
      performed on hard copy using a ruler and on a workstation using an electronic
      caliper. RESULTS: the intraobserver variability showed a decrease going from hard
      copy to workstation in the standard deviation of the differences of the paired
      observations for the neck from 3.54 mm to 1.18 mm; for the aorta from 4.16 to
      1.72 mm; for the right iliac from 1.87 to 1.01 mm; for the left iliac from 2.07
      to 0.87 mm. The interobserver variability showed a similar decrease for the neck
      in all ten pairs of observers; for the aorta in two, for the right iliac and left
      iliac in five. However, the difference between observers regularly exceeded 2 mm.
      CONCLUSION: the use of a workstation and electronic calipers results in lower
      intra- and interobserver variability. However, the results still show a
      clinically relevant difference between the observers. Therefore, it is necessary
      to develop an automatic observer-independent measurement technique.

PMID- 10637144
TI  - Abdominal aortic aneurysm wall mechanics and their relation to risk of rupture.
AB  - PURPOSE: to see whether aneurysmal aortic wall mechanics can be used as a
      predictor of abdominal aortic aneurysm (AAA) rupture. METHOD: among 285
      individuals, followed conservatively for AAA and monitored for aneurysm growth
      and wall mechanics on at least one occasion at our institution between January
      1991 and January 1998, eleven subsequently ruptured. Wall mechanics were
      estimated as stiffness (beta). This was calculated from diameter and pulsatile
      diameter change, determined non-invasively by an ultrasonic echo-tracking system
      and blood pressure obtained by the auscultatory method. The results were compared
      with those of 121 individuals electively operated on for AAA. RESULTS: no
      difference in aortic stiffness was found between those that subsequently ruptured
      (beta=35, median) compared to those non-ruptured (beta=38, median) AAAs
      (p=0.855). There was no difference in diameter in ruptured (58.8 mm) compared
      with non-ruptured (54.1 mm) AAAs (p=0.129). All ruptured AAAs showed an expansion
      of diameter over time. CONCLUSION: this study shows no difference in aneurysmal
      aortic wall mechanics in those AAAs that subsequently ruptured compared with
      electively operated AAAs. The results indicate that it is not possible to use
      aneurysmal aortic wall stiffness as a predictor of rupture.

PMID- 10637145
TI  - Reoperation for recurrent saphenofemoral incompetence: a prospective randomised
      trial using a reflected flap of pectineus fascia.
AB  - OBJECTIVE AND DESIGN: in 1978 Sheppard described using a flap of pectineus fascia
      in an attempt to reduce the further development of neovascularised veins at the
      saphenofemoral junction. The perceived benefits of this manoeuvre have not been
      tested by a prospective randomised trial. MATERIALS AND METHODS: consecutive
      patients with symptomatic recurrent varicose veins referred to a single
      consultant were examined for evidence of further reflux from the saphenofemoral
      junction. This was subsequently confirmed in forty limbs (thirty-seven patients)
      by descending venography. All had features of a neovascularised segment. These
      patients were treated by complete exposure and ligation of the recurrences
      arising from the common femoral vein, with or without the placement of a flap of
      pectineus fascia (prospectively randomised). The patients were assessed a minimum
      of eighteen months later by both clinical examination and duplex ultrasound
      scanning. RESULTS: six patients were lost to follow-up. This left seventeen limbs
      remaining in each half of the study. The characteristics in each group were
      broadly matched. CONCLUSIONS: this study failed to demonstrate any apparent
      benefit from the application of a flap of pectineus fascia. Most patients showed
      evidence of re-recurrence arising from the common femoral vein.

PMID- 10637146
TI  - Long-term results after recanalisation of chronic iliac artery occlusions by
      combined catheter therapy without stent placement.
AB  - OBJECTIVES: to evaluate the long-term outcome after recanalisation of chronic
      iliac artery occlusions by combined catheter therapy without stent placement.
      DESIGN: retrospective study. MATERIAL AND METHODS: between 1979 and 1995 75
      consecutive patients were treated (53 men, 22 women; mean age 63.1+/-13.7 years;
      mean length of the occluded segment 6.9+/-3.5 cm). The indication for treatment
      was incapacitating claudication (n=55) or chronic critical ischaemia (n=20). At
      follow-up clinical data, pulse volume and pressure measurements were recorded and
      duplex-sonography and/or angiography performed, if clinically indicated. RESULTS:
      mean follow-up was 7. 2+/-4.1 years. The primary clinical success rate was 64% at
      12 months, 57% at 4 years and remained stable for up to ten years. The secondary
      clinical success rate after 12 months was 83% and remained stable at 81% for up
      to 10 years. Peripheral embolisation as complication of the intervention occurred
      in 18 patients (24%) and was treated by percutaneous thromboembolectomy in 15
      patients during the same procedure. In the remaining three patients no
      intervention was necessary. One patient had to undergo surgery for a groin
      haematoma. CONCLUSIONS: recanalisation of segmental chronic iliac artery
      occlusions by catheter therapy without stent placement has favourable long-term
      results comparable to primary stent placement. Randomised controlled studies are
      required to determine the appropriate role of catheter therapy alone and primary
      or selective stenting for iliac artery occlusions.

PMID- 10637147
TI  - Endovascular treatment of abdominal aortic aneurysms in Norway: the first 100
      patients.
AB  - OBJECTIVES: to present the first 100 consecutive endograft implantations for
      abdominal aortic aneurysms (AAAs) in Norway. DESIGN: retrospective study of 100
      consecutive graft implantations, performed at five University Hospitals during
      1995 to 1997. MATERIAL: one hundred patients with a median age of 70 years were
      included. In all patients the Vanguard modular system (Boston Scientific Corp.)
      was used. Ninety-four of the 100 patients were treated under regional
      anaesthesia. A completion angiography was done to evaluate the position of the
      graft and whether endoleaks were present. RESULTS: two patients died within 30
      days, one due to cardiac insufficiency and another due to haemorrhage during the
      procedure. There were four early conversions to open repair. At discharge eight
      patients had an endoleak, while retrograde flow into the aneurysmal sac was
      observed in four patients. During the follow-up period one conversion to open
      repair became necessary due to graft migration. Four late leaks were all repaired
      successfully using endovascular techniques. Five cases of retrograde filling were
      detected and embolisation with coils was performed in two cases, while three were
      observed. Seven graft-limb occlusions occurred during the follow-up period and
      four of these required treatment. CONCLUSIONS: endovascular AAA repair should be
      regarded as an experimental treatment, although the short term results are
      promising. Close follow-up of patients with CT scans or arteriography is
      necessary.

PMID- 10637148
TI  - Fifteen-year experience of transperitoneal management of inflammatory abdominal
      aortic aneurysms.
AB  - OBJECTIVES: to assess the long-term outcome of patients with inflammatory
      abdominal aortic aneurysms. MATERIALS AND METHODS: over a fifteen-year period 598
      cases of abdominal aortic aneurysm were treated and, of these, 32 cases (5.3%)
      were inflammatory in nature. The diagnosis was made on preoperative (CT) computed
      tomography in fifteen cases. Twenty-six patients were symptomatic on presentation
      and ten cases were repaired on an emergency basis. Only six were repaired
      electively. The transabdominal transaortic approach without dissection on the
      nearby adherent structures was used routinely. RESULTS: there was one
      postoperative death from a respiratory arrest leading to a thirty-day mortality
      of 3.1%. Early graft thrombosis occurred in three cases (9.3%) and all underwent
      successful thrombectomy. Colonic ischaemia was encountered in one patient who
      later developed an aortoenteric fistula. Two patients suffered a non-fatal
      myocardial infarction postoperatively leading to an overall morbidity of 18.7%.
      CONCLUSIONS: patients with inflammatory aortic aneurysms fare worse than patients
      with aortic aneurysms in general. Preoperative suspicion assists in planning
      surgery. We believe that the transperitoneal approach with an anterolateral
      aortotomy and minimal dissection of adherent structures offers excellent results
      in dealing with this difficult group of patients.

PMID- 10637149
TI  - In vivo analysis of dynamic tensile stresses at arterial end-to-end anastomoses.
      Influence of suture-line and graft on anastomotic biomechanics.
AB  - OBJECTIVE: to determine the influence of an anastomotic suture line and a graft
      on dynamic tensile stresses of vascular end-to-end anastomoses in vivo. MATERIAL
      AND METHODS: the abdominal aorta of twelve 35-kg pigs was used as an experimental
      model. Simultaneous recordings of internal arterial diameter and pressure were
      performed on each pig at 3 successive stages: (1) The genuine artery (REF), (2)
      artery-artery (A-A) and (3) graft-artery (G-A) anastomosis at 1-mm increments in
      the immediate perianastomotic area. Thereby, RD (relative distension), CC
      (compliance coefficient), E(p)(dynamic pressure-strain elastic modulus) and
      hysteresis loop areas could be calculated for every measuring point. RESULTS: the
      graft was significantly stiffer than REF. A-A and G-A anastomoses were
      significantly less compliant than REF. Maximum E(p), minimum CC and hysteresis
      loop areas were found at the anastomotic line due to minimum anastomotic RD.
      Downstream of the G-A anastomosis, the RD, CC, E(p)and loop areas were
      significantly different from REF, but significantly different from A-A.
      CONCLUSION: an animal model for acute studies of mechanical properties of
      vascular end-to-end anastomoses was developed. The main determinant for
      anastomotic biomechanics was the suture-line itself.

PMID- 10637150
TI  - The value of a mortality-scoring system in the quality control of patients
      undergoing abdominal aortic surgery.
AB  - OBJECTIVES: to assess the quality of care of patients undergoing abdominal aortic
      surgery. MATERIALS: three hundred and forty-six patients undergoing surgery for
      aneurysmal or occlusive disease of whom 51 died. METHODS: we developed a
      mortality registration system to classify causes of death, to evaluate
      shortcomings in treatment, and to determine the extent of agreement between
      clinical diagnosis and necropsy findings. RESULTS: the main cause of death for 11
      patients (22%) was a poor clinical condition at admission, while 76% (n=39) of
      the patients died due to postoperative complications. Myocardial infarction was
      the most frequently encountered complication. Deficiencies in medical treatment
      were observed in 10 of the 51 deaths (20%). Autopsy was performed in 33 of the 51
      patients (65%), revealing in 10 cases (30%) a major discrepancy between pre- and
      postmortem findings. Six of the 10 autopsies revealed that a myocardial
      infarction had been missed during the postoperative period. CONCLUSIONS: autopsy
      reports are essential for accurately estimating complication rates as we observed
      discrepancies in 30% of cases.

PMID- 10637151
TI  - The progression of lower limb atherosclerosis is associated with IgA antibodies
      against Chlamydia pneumoniae.
AB  - OBJECTIVE: to study the influence of serologically diagnosed chronic infection
      with Chlamydia pneumoniae on the progression of lower limb atherosclerosis in a
      group of disposed men. MATERIAL AND METHODS: the highest systolic brachial and
      lowest systolic ankle blood pressures were followed for an average of 2.7 years
      in 129 men aged 65-73 years with conservatively treated small abdominal aortic
      aneurysms. Blood samples were taken to measure low-density lipoprotein and IgA
      and IgG titres of antibodies against C. pneumoniae by a microimmunofluorescence
      test. RESULTS: the prevalences of seropositivity varied from 43 to 83% depending
      on the definition. The ankle-brachial blood pressure index of the IgA
      seropositive [corrected] men decreases by 11%, while it decreased by 4.8% among
      IgA-seronegative men (p<0.05). The significant difference persisted in a multiple
      regression analysis adjusting for age, smoking, initial systolic ankle BP, and
      initial brachial systolic or diastolic BP, but disappeared after adjusting for
      the level of low-density lipoprotein. CONCLUSIONS: C. pneumoniae infection is
      associated with the progression of atherosclerosis.

PMID- 10637152
TI  - Haematuria and an abdominal aortic aneurysm--warning of an aortocaval fistula.

PMID- 10637153
TI  - Endovascular repair of an iatrogenic left common carotid to innominate vein
      fistula.

PMID- 10637154
TI  - Pseudo-aneurysm of a geniculate collateral artery complicating total knee
      replacement.

PMID- 10637155
TI  - A true aneurysm of the tibioperoneal trunk. Case report and literature review.

PMID- 10637156
TI  - The Stresst'er ergometer.

PMID- 10637157
TI  - Carotid artery occlusion.

PMID- 10637158
TI  - Estimation of claudication distance.

PMID- 10637159
TI  - Aortic grafting.

PMID- 10637160
TI  - Mixed leg ulcers.

PMID- 10637161
TI  - Complications after carotid endarterectomy.

PMID- 10637162
TI  - Endovascular repair of iliac aneurysms.

PMID- 10637170
TI  - Software review: atrium patient database software

PMID- 10637163
TI  - Results of thoracoscopic sympathetic trunk transection.

PMID- 10637172
TI  - Local movements evoked by chemical stimulation of the hind leg in the locust
      Schistocerca gregaria.
AB  - The behavioural responses of desert locusts, Schistocerca gregaria, to solutions
      of four behaviourally relevant chemicals (sodium chloride, sucrose, nicotine
      hydrogen tartrate and lysine glutamate) applied as droplets to the hind tarsus
      were analysed. All responses following within 1 s of chemical stimulation were
      local leg avoidance reflexes, and the probability of eliciting such a response
      increased in a dose-dependent manner with increasing concentration for all the
      chemicals tested. Chemical identity, however, critically determined the
      concentration threshold at which the different chemicals became an effective
      stimulus. For example, a 2.5 mmol l(-)(1) concentration of the secondary plant
      metabolite nicotine hydrogen tartrate (NHT), a potent feeding deterrent to
      locusts, was sufficient to evoke avoidance responses in 50 % of cases, whilst for
      the nutrients, sucrose and lysine glutamate, 250-500 mmol l(-)(1) of the chemical
      was needed to induce avoidance behaviour in 50 % of the locusts. NaCl was of
      intermediate effectiveness, with a 50 % response rate occurring at a
      concentration of approximately 50 mmol l(-)(1). The latency to the start of the
      response following stimulation was negatively correlated with the concentration
      of NaCl, but for the other chemicals concentration had no effect on latency. The
      duration of the avoidance behaviour decreased with increasing concentration for
      NaCl and more weakly for NHT, but not for the other chemicals. Adding a
      subthreshold concentration of sucrose to 50 mmol l(-)(1) NaCl decreased the
      incidence of response compared with 50 mmol l(-)(1) NaCl on its own. Experiments
      with other mixtures combining NaCl, sucrose and NHT indicate that the frequency
      and dynamics of the responses to chemical mixtures cannot be simply predicted
      from the responses to their individual constituents.

PMID- 10637173
TI  - Connections between thoraco-coxal proprioceptive afferents and motor neurons in
      the locust.
AB  - The position of the coxal segment of the locust hind leg relative to the thorax
      is monitored by a variety of proprioceptors, including three chordotonal organs
      and a myochordotonal organ. The sensory neurons of two of these proprioceptors,
      the posterior joint chordotonal organ (pjCO) and the myochordotonal organ (MCO),
      have axons in the purely sensory metathoracic nerve 2C (N2C). The connections
      made by these afferents with metathoracic motor neurons innervating thoraco-coxal
      and wing muscles were investigated by electrical stimulation of N2C and by
      matching postsynaptic potentials in motor neurons with afferent spikes in N2C.
      Stretch applied to the anterior rotator muscle of the coxa (M121), with which the
      MCO is associated, evoked sensory spikes in N2C. Some of the MCO afferent neurons
      make direct excitatory chemical synaptic connections with motor neurons
      innervating the thoraco-coxal muscles M121, M126 and M125. Parallel polysynaptic
      pathways via unidentified interneurons also exist between MCO afferents and these
      motor neurons. Connections with the common inhibitor 1 neuron and motor neurons
      innervating the thoraco-coxal muscles M123/4 and wing muscles M113 and M127 are
      polysynaptic. Afferents of the pjCO also make polysynaptic connections with motor
      neurons innervating thoraco-coxal and wing muscles, but no evidence for
      monosynaptic pathways was found.

PMID- 10637174
TI  - Identification of a ubiquitous family of membrane proteins and their expression
      in mouse brain.
AB  - A family of genes encoding membrane proteins with a unique structure has been
      identified in DNA and cDNA clones of various eukaryotes ranging from yeast to
      human. The nucleotide sequences of three novel cDNAs from Drosophila melanogaster
      and mouse were determined. The amino acid sequences of the two mouse proteins
      have human homologs. The gene (TMS1) encoding the yeast member of this family was
      disrupted, and the resulting mutant showed no significant phenotype under several
      stress conditions. The expression of the mouse genes TMS-1 and TMS-2 was examined
      by in situ hybridization of sections from brain, liver, kidney, heart and testis
      of an adult mouse as well as in a 1-day-old whole mouse. While the expression of
      TMS-2 was found to be restricted to the central nervous system, TMS-1 was also
      expressed in kidney and testis. The expression of TMS-1 and TMS-2 in the brain
      overlapped and was localized to areas associated with glutamatergic excitatory
      neurons, such as the hippocampus and cerebral cortex. High-magnification analysis
      indicated that both mRNAs are expressed in neurons. Semiquantitative analysis of
      mRNA expression was performed in various parts of the brain. The conservation,
      unique structure and localization in the mammalian brain of this novel protein
      family suggest an important biological role.

PMID- 10637175
TI  - Cloning and molecular characterisation of the trout (Oncorhynchus mykiss)
      vacuolar H(+)-ATPase B subunit.
AB  - The current model of transepithelial ion movements in the gill of freshwater fish
      incorporates an apically oriented vacuolar H(+)-ATPase (H(+)V-ATPase; proton
      pump) that is believed to facilitate both acid excretion and Na(+) uptake. To
      substantiate this model, we have cloned and sequenced a cDNA encoding the B
      subunit of the rainbow trout (Oncorhynchus mykiss) H(+)V-ATPase. The cloning of
      the B subunit enabled an examination by northern analysis of its tissue
      distribution and expression during external hypercapnia. Degenerate
      oligonucleotide primers to the B subunit of the H(+)V-ATPase were designed and
      used in a semi-nested polymerase chain reaction (PCR) to amplify an 810 base pair
      (bp) product from a trout gill/kidney cDNA library. This PCR product was cloned
      and sequenced and then used to screen the same cDNA library. The assembled 2262
      bp cDNA included an open reading frame coding for a deduced protein of 502 amino
      acid residues. A BLAST search of the GenBank nucleotide database revealed
      numerous matches to other vertebrate and invertebrate H(+)V-ATPase B subunits.
      Protein alignment demonstrated that the trout H(+)V-ATPase B subunit is more than
      85 % identical and more than 90 % similar to those in other vertebrate species.
      An initial analysis of H(+)V-ATPase mRNA tissue distribution revealed significant
      expression in blood. Although a comparison of perfused tissues (blood removed)
      with non-perfused tissues demonstrated no obvious contribution of the blood to
      total tissue H(+)-ATPase mRNA levels, all subsequent experiments were performed
      using perfused tissues. Levels of H(+)V-ATPase mRNA expression were high in the
      gill, kidney (anterior or posterior), intestine, heart and spleen, but lower in
      liver and white muscle. Exposure of the fish to 12 h of external hypercapnia
      (water P(CO2)=7. 5 mmHg; 1 kPa) was associated with a transient increase (at 2 h)
      in the levels of H(+)V-ATPase B subunit mRNA in gill and kidney; liver mRNA
      levels were unaffected. These results are consistent with the hypothesis of an
      apically localised plasma membrane H(+)V-ATPase in the freshwater trout gill and
      that the expression of this proton pump is increased during periods of acidosis,
      at least in part because of an increased steady-state level of H(+)V-ATPase mRNA.

PMID- 10637176
TI  - Patterns of white muscle activity during terrestrial locomotion in the American
      eel (Anguilla rostrata).
AB  - Eels (Anguilla rostrata) are known to make occasional transitory excursions into
      the terrestrial environment. While on land, their locomotor kinematics deviate
      drastically from that observed during swimming. In this study, electromyographic
      (EMG) recordings were made from white muscle at various longitudinal positions in
      eels performing undulatory locomotion on land to determine the muscle activity
      patterns underlying these terrestrial movements. As during swimming, eels
      propagate a wave of muscle activity from anterior to posterior during terrestrial
      locomotion. However, the intensity of EMG bursts is much greater on land (on
      average approximately five times greater than in water). In addition, anteriorly
      located musculature has higher-intensity EMG bursts than posteriorly located
      muscle during locomotion on land. EMG duty cycle (burst duration relative to
      undulatory cycle time) is significantly affected by longitudinal position during
      terrestrial locomotion, and duty cycles are significantly greater on land (0.4
      0.5 cycles) than in water (0. 2-0.3 cycles). Finally, as in swimming, a phase
      shift in the timing of muscle activity exists such that posteriorly located
      muscle fibers become activated earlier in their strain cycle than do more
      anteriorly located fibers. However, fibers become activated much later in their
      muscle strain cycle on land than in water. Therefore, it is clear that, while
      eels propagate a wave of muscle activity posteriorly to generate backward
      traveling waves that generate propulsive thrust both in water and on land, the
      specific patterns of timing and the intensity of muscle activity are
      substantially altered depending upon the environment. This suggests that physical
      differences in an animal's external environment can play a substantial role in
      affecting the motor control of locomotion, even when similar structures are used
      to generate the propulsive forces.

PMID- 10637177
TI  - The electric image in weakly electric fish: perception of objects of complex
      impedance.
AB  - Weakly electric fish explore the environment using electrolocation. They produce
      an electric field that is detected by cutaneous electroreceptors; external
      objects distort the field, thus generating an electric image. The electric image
      of objects of complex impedance was investigated using a realistic model, which
      was able to reproduce previous experimental data. The transcutaneous voltage in
      the presence of an elementary object is modulated in amplitude and waveform on
      the skin. Amplitude modulation (measured as the relative change in the local peak
      to-peak amplitude) consists of a 'Mexican hat' profile whose maximum relative
      slope depends on the distance of the fish from the object. Waveform modulation
      depends on both the distance and the electrical characteristics of the object.
      Changes in waveform are indicated by the amplitude ratio of the larger positive
      and negative phases of the local electric organ discharge on the skin. Using the
      peak-to-peak amplitude and the positive-to-negative amplitude ratio of this
      discharge, a perceptual space can be defined and correlated with the capacitance
      and resistance of the object. When the object is moved away, the perceptual space
      is reduced but keeps the same proportions (homothetically): for a given object,
      the positive-to-negative amplitude ratio is a linear function of the peak-to-peak
      amplitude. This linear function depends on the electrical characteristics of the
      object. However, there are 'families' of objects with different electrical
      characteristics that produce changes in the parameters of the local electric
      organ discharge that are related by the same linear function. We propose that
      these functions code the perceptual properties of an object related to its
      impedance.

PMID- 10637178
TI  - Rate-dependent changes in cell shortening, intracellular Ca(2+) levels and
      membrane potential in single, isolated rainbow trout (Oncorhynchus mykiss)
      ventricular myocytes.
AB  - The effects of increasing stimulation frequency (from 0.2 to 1.4 Hz) on the
      contractility, intracellular Ca(2+) concentration ([Ca(2+)](i)) and membrane
      potential of single ventricular myocytes isolated from the heart of rainbow trout
      (Oncorhynchus mykiss) were measured. Cell shortening, expressed as a percentage
      of resting cell length, was our index of contractility. The fluorescent Ca(2+)
      indicator Fura-2 was used to monitor changes in [Ca(2+)](i). Action potentials
      and L-type Ca(2+) currents (I(Ca)) were recorded using the whole-cell patch-clamp
      technique. Experiments were performed at 15 degrees C. Increasing the stimulation
      frequency caused a significant increase in diastolic [Ca(2+)](i) and a
      significant decrease in diastolic cell length and membrane potential. During
      systole, there was a significant fall in the amplitude of the [Ca(2+)](i)
      transient, cell shortening and action potential with a decrease in the duration
      of the action potential at both 20 % and 90 % repolarisation. Caffeine was used
      to assess the Ca(2+) content of the sarcoplasmic reticulum. We observed that
      sarcoplasmic reticulum Ca(2+) load was greater at 1.0 Hz than at 0.6 Hz, despite
      a smaller electrically evoked [Ca(2+)](i) transient. The amplitude of I(Ca) was
      found to decrease with increased stimulation frequency. At 0.6 Hz, electrically
      evoked [Ca(2+)](i) transients in the presence of 10 mmol l(-)(1) caffeine or 10
      micromol l(-)(1) ryanodine and 2 micromol l(-)(1) thapsigargin were reduced by
      approximately 15 %. We have described the changes in contractility, [Ca(2+)](i)
      and action potential configuration in a fish cardiac muscle system. Under the
      conditions tested (0.6 Hz, 15 degrees C), we conclude that the sarcoplasmic
      reticulum contributes at least 15 % of the Ca(2+) associated with the [Ca(2+)](i)
      transient. The rate-dependent decrease in contraction amplitude appears to be
      associated with the fall in the amplitude of the [Ca(2+)](i) transient. This, in
      turn, may be influenced by changes in the action potential configuration via
      mechanisms such as altered Ca(2+) efflux and Ca(2+) influx. In support of our
      conclusions, we present evidence that there is a rate-dependent decrease in
      Ca(2+) influx via I(Ca) but that the Ca(2+) load of the sarcoplasmic reticulum is
      not reduced at increased contraction frequencies.

PMID- 10637179
TI  - Attachment forces of ants measured with a centrifuge: better 'wax-runners' have a
      poorer attachment to a smooth surface.
AB  - The symbiotic ant partners of glaucous Macaranga ant-plants show an exceptional
      capacity to run on the slippery epicuticular wax crystals covering the plant stem
      without any difficulty. We test the hypothesis that these specialised 'wax
      runners' have a general, superior attachment capacity. We compared attachment on
      a smooth surface for 11 ant species with different wax-running capacities. The
      maximum force that could be withstood before an ant became detached was
      quantified using a centrifuge recorded by a high-speed video camera. This
      technique has the advantage of causing minimum disruption and allows measurements
      in very small animals. When strong centrifugal forces were applied, the ants
      showed a conspicuous 'freezing reflex' advantageous to attachment. Attachment
      forces differed strongly among the ant species investigated. This variation could
      not be explained by different surface area/weight ratios of smaller and larger
      ants. Within species, however, detachment force per body weight (F/W) scaled with
      the predicted value of W(-)(0.33), where W is body weight in newtons.
      Surprisingly, our results not only disprove the hypothesis that 'wax-runners'
      generally attach better but also provide evidence for the reverse effect.
      Superior 'wax-runners' (genera Technomyrmex and Crematogaster) did not cling
      better to smooth Perspex, but performed significantly worse than closely related
      congeners that are unable to climb up waxy stems. This suggests an inverse
      relationship between adaptations to run on wax and to attach to a smooth surface.

PMID- 10637180
TI  - Octopamine reverses the isolation-induced increase in trophallaxis in the
      carpenter ant Camponotus fellah.
AB  - Social deprivation is an unusual situation for ants that normally maintain
      continuous contact with their nestmates. When a worker was experimentally
      isolated for 5 days and then reunited with a nestmate, she engaged in prolonged
      trophallaxis. It is suggested that trophallaxis allows her to restore a social
      bond with her nestmates and to re-integrate into the colony, particularly via the
      exchange of colony-specific hydrocarbons. Octopamine reduced trophallaxis in
      these workers as well as hydrocarbon transfer between nestmates, but not
      hydrocarbon biosynthesis. Administration of serotonin to such 5-day-isolated ants
      had no effect on the percentage of trophallaxis. Administration of phentolamine
      alone, an octopamine antagonist, had no effect, but when co-administrated with
      octopamine it reduced the effect of octopamine alone and restored trophallaxis to
      control levels. Moreover, the observed effect of octopamine was not due to a non
      specific effect on locomotor activity. Therefore, we hypothesise that octopamine
      mediates behaviour patterns linked to social bonding, such as trophallaxis. On
      the basis of an analogy with the role of norepinephrine in vertebrates, we
      suggest that the levels of octopamine in the brain of socially deprived ants may
      decrease, together with a concomitant increase in their urge to perform
      trophallaxis and to experience social contacts. Octopamine administration may
      reduce this social deprivation effect, and octopamine could therefore be regarded
      as being partly responsible for the social cohesion between nestmates in ant
      colonies.

PMID- 10637181
TI  - Ecdysis of decapod crustaceans is associated with a dramatic release of
      crustacean cardioactive peptide into the haemolymph.
AB  - On the basis of detailed analyses of morphological characteristics and
      behavioural events associated with ecdysis in a crab (Carcinus maenas) and a
      crayfish (Orconectes limosus), a comprehensive substaging system has been
      introduced for the ecdysis stage of the moult cycle of these decapod crustaceans.
      In a remarkably similar stereotyped ecdysis sequence in both species, a passive
      phase of water uptake starting with bulging and rupture of thoracoabdominal
      exoskeletal junctions is followed by an active phase showing distinct behavioural
      changes involved in the shedding of the head appendages, abdomen and pereiopods.
      Together with an enzyme immunoassay for crustacean cardioactive peptide (CCAP),
      the substaging has been used to demonstrate a large, rapid and reproducible peak
      in haemolymph CCAP levels (increases of approximately 30-fold in the crab and
      more than 100-fold in the crayfish compared with intermoult titres) during the
      later stages of active ecdysis. We suggest that the release of CCAP (accumulated
      in late premoult) from the crab pericardial organs or the crayfish ventral nerve
      cord accounts for many of the changes in behaviour and physiology seen during
      ecdysis and that this neurohormone is likely to be of critical importance in
      crustaceans and other arthropods.

PMID- 10637182
TI  - Agonistic behaviour and biogenic amines in shore crabs Carcinus maenas.
AB  - To investigate the role of certain neurohormones in agonistic behaviour, fights
      were staged between pairs of size-matched male shore crabs Carcinus maenas, and
      blood samples were taken immediately after the contests had been resolved.
      Samples were also taken from these crabs at rest (before and after fighting) and
      after walking on a treadmill. A control group of crabs also had samples taken on
      each experimental day. Concentrations of tyramine, dopamine, octopamine,
      serotonin (5-HT) and norepinephrine were determined in each blood sample using a
      gas chromatography/mass spectrometry (GC-MS) system. Norepinephrine was not
      detectable in any of the samples, but the standards were recovered. Tyramine
      values were not significantly different between the control group and the fought
      group, so tyramine does not appear to be important in agonistic behaviour. A
      comparison between the control and fought groups shows that fighting had an
      effect on the concentrations of octopamine, dopamine and 5-HT, but exercise only
      had an effect on octopamine levels, which showed a reduction from resting values
      in both winners and losers. Resting and post-fight concentrations of octopamine,
      dopamine and 5-HT were higher in winners than in losers. 5-HT concentration
      increased in the blood of fought crabs from resting values, whereas dopamine
      concentration decreased. In winners, octopamine concentrations decreased from
      resting values, but in losers octopamine levels increased from resting
      concentrations. The escalatory behaviour or intensity of fighting performed by
      winners and losers was related to dopamine levels but not to those of octopamine
      or 5-HT. Therefore, there appears to be a link between relative concentrations of
      these three amines (dopamine, octopamine and 5-HT) and fighting ability; the
      effects are not simply a result of activity. The better competitors have higher
      concentrations of these three amines at rest and after fighting.

PMID- 10637183
TI  - Effects of temperature on escape jetting in the squid Loligo opalescens.
AB  - In Loligo opalescens, a sudden visual stimulus (flash) elicits a stereotyped,
      short-latency escape response that is controlled primarily by the giant axon
      system at 15 C. We used this startle response as an assay to examine the effects
      of acute temperature changes down to 6 C on behavioral and physiological aspects
      of escape jetting. In free-swimming squid, latency, distance traveled and peak
      velocity for single escape jets all increased as temperature decreased. In
      restrained squid, intra-mantle pressure transients during escape jets increased
      in latency, duration and amplitude at low temperature. Recordings of stellar
      nerve activity revealed repetitive firing of the giant motor axon accompanied by
      increased activity in the non-giant motor axons that run in parallel. Selective
      stimulation of giant and non-giant motor axons in isolated nerve-muscle
      preparations failed to show the effects seen in vivo, i.e. increased peak force
      and increased neural activity at low temperature. Taken together, these results
      suggest that L. opalescens is able to compensate escape jetting performance for
      the effects of acute temperature reduction. A major portion of this compensation
      appears to occur in the central nervous system and involves alterations in the
      recruitment pattern of both the giant and non-giant axon systems.

PMID- 10637184
TI  - Role of prey-capture experience in the development of the escape response in the
      squid Loligo opalescens: a physiological correlate in an identified neuron.
AB  - Although extensively used for biophysical studies, the squid giant axon system
      remains largely unexplored in regard to in vivo function and modulation in any
      biologically relevant context. Here we show that successful establishment of the
      recruitment pattern for the giant axon in the escape response elicited by a brief
      electrical stimulus depends on prey-capture experience early in life. Juvenile
      squid fed only slow-moving, easy-to-capture prey items (Artemia salina) develop
      deficits in coordinating activity in the giant axon system with that of a
      parallel set of non-giant motor axons during escape responses. These deficits are
      absent in cohorts fed fast-moving, challenging prey items (copepods). These
      results suggest that the acquisition of inhibitory control over the giant axon
      system is experience-dependent and that both prey-capture and escape behavior
      depend on this control.

PMID- 10637185
TI  - Comparison of a Ca(2+)-gated conductance and a second-messenger-gated conductance
      in rat olfactory neurons.
AB  - The effect of a rise in intracellular Ca(2+) concentration was analyzed in
      isolated rat olfactory neurons using a whole-cell patch-clamp technique.
      Intracellular dialysis of 1 mmol l(-)(1) Ca(2+) in a standard-K(+), low-Cl(-)
      internal solution (E(Cl)=-69 mV) from the patch pipette into the olfactory
      neurons induced a sustained outward current of 49+/-5 pA (N=13) at -50 mV in all
      the cells examined. The outward currents were inhibited by external application
      of 100 micromol l(-)(1) 5-nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB).
      External application of a Ca(2+) ionophore, 3 micromol l(-)(1) ionomycin, induced
      an inward current in three of eight cells whose voltages were clamped using the
      gramicidin-perforated technique, but ionomycin elicited an outward current in the
      other five cells, suggesting that natural intracellular Cl(-) concentration in
      the olfactory neurons was heterogeneous. While intracellular dialysis of 50
      micromol l(-)(1) inositol 1,4,5-trisphosphate (1,4,5-InsP(3)) in the standard
      K(+), low-Cl(-) internal solution induced the NPPB-sensitive outward current in
      31 % of cells, and 500 micromol l(-)(1) cAMP induced it in 21 % of cells, a large
      proportion of the cells displayed an inward current in response to 1,4,5-InsP(3)
      and cAMP. The results suggest that 1,4,5-InsP(3) and cAMP can elicit Ca(2+)
      dependent Cl(-) conductance and Ca(2+)-independent cation conductance in rat
      olfactory neurons.

PMID- 10637186
TI  - PACAP and nitric oxide inhibit contractions in the proximal intestine of the
      atlantic cod, Gadus morhua.
AB  - The possible inhibitory roles of pituitary adenylate cyclase-activating
      polypeptide (PACAP), vasoactive intestinal polypeptide (VIP) and nitric oxide in
      the control of intestinal motility were investigated in the Atlantic cod, Gadus
      morhua. Circular and longitudinal smooth muscle preparations developed
      spontaneous contractions that were inhibited by atropine (10(-)(5 )mol l(-)(1)).
      PACAP 27 and PACAP 38 (10(-)(7 )mol l(-)(1)) reduced the amplitude of the
      contractions but did not usually affect the resting tension. In the circular
      preparations, the mean active force developed (above resting level; +/- s.e.m.)
      was reduced from 0. 62+/-0.18 mN to 0.03+/-0.03 mN (N=10) by PACAP 27 and from
      0.53+/-0. 20 mN to 0.31+/-0.13 mN (N=7) by PACAP 38, while neither cod nor
      mammalian VIP (10(-)(10)-10(-)(6 )mol l(-)(1)) had any effect. In the
      longitudinal preparations, PACAP 27 reduced the force developed from 1.58+/-0.22
      mN to 0.44+/-0.25 mN (N=8) and PACAP 38 reduced it from 1.61+/-0.47 mN to 0.75+/
      0.28 mN (N=5). The nitric oxide donor sodium nitroprusside (NaNP) almost
      abolished the contractions in the circular preparations, reducing the mean force
      developed from 0. 47+/-0.05 mN to 0.02+/-0.06 mN (10(-)(6 )mol l(-)(1); N=9) and
      0+/-0. 07 mN (10(-)(5 )mol l(-)(1); N=8). In the longitudinal preparations, NaNP
      reduced the force developed from 2.03+/-0.36 mN to 0.33+/-0.22 mN (10(-)(6 )mol
      l(-)(1); N=8) and 0.19+/-0.30 mN (10(-)(5 )mol l(-)(1); N=8). The L-arginine
      analogue N(G)-nitro-L-arginine methyl ester (L-NAME; 3x10(-)(4 )mol l(-)(1))
      enhanced the contractions in both circular and longitudinal preparations,
      increasing the mean force developed from 0.51+/-0.12 mN to 0.94+/-0.21 mN (N=8)
      and from 1.49+/-0.36 mN to 3.34+/-0.67 mN (N=7), respectively. However,
      preincubation with L-NAME before a second addition of PACAP 27 (10(-)(7 )mol l(
      )(1)) did not affect the response to PACAP, neither did preincubation with the
      guanylate cyclase inhibitor 6-anilinoquinoline-5,8-quinone (LY83583; 10(-)(5 )mol
      l(-)(1)), while the inhibitory response to NaNP (3x10(-)(7 )mol l(-)(1)) was
      abolished by LY83583. The PACAP analogue PACAP 6-27 (3x10(-)(7 )mol l(-)(1)) had
      no effect on the response to either NaNP (3x10(-)(7 )mol l(-)(1)) or PACAP 27
      (10(-)(8 )mol l(-)(1)) in the circular preparations. These findings indicate the
      presence of both a cholinergic and a nitrergic tonus in the smooth muscle
      preparations of the cod. Although PACAP and NaNP both inhibit contractions, there
      is no evidence of any interactions between the two substances. In addition, NaNP,
      but not PACAP, probably acts via stimulating the production of cyclic GMP. In
      conclusion, both PACAP and nitric oxide may act as inhibitory transmitters, using
      distinct signalling pathways, in the control of intestinal motility in the
      Atlantic cod.

PMID- 10637187
TI  - The control of carrier frequency in cricket calls: a refutation of the subalar
      tegminal resonance/auditory feedback model.
AB  - The subalar-tegminal resonance/auditory feedback hypothesis attempts to explain
      how crickets control the carrier frequency (f(C)), the loudness and the spectral
      purity of their calls. This model contrasts with the 'clockwork cricket' or
      escapement model by proposing that f(C) is not controlled by the resonance of the
      cricket's radiators (the harps) but is instead controlled neurally. It suggests
      that crickets are capable of driving their harps to vibrate at any frequency and
      that they use a tunable Helmholtz-like resonator consisting of the tegmina and
      the air within the subalar space to amplify and filter the f(C). This model
      predicts that f(C) is variable, that call loudness is related to tegminal
      position (and subalar volume) and that low-density gases should cause f(C) to
      increase. In Anurogryllus arboreus, f(C) is not constant and varied by as much as
      0.8 % between pulses. Within each sound pulse, the average f(C) typically
      decreased from the first to the last third of a sound pulse by 9 %. When crickets
      called in a mixture of heliox and air, f(C) increased 1.07- to 1.14-fold above
      the value in air. However, if the subalar space were part of a Helmholtz-like
      resonator, then its resonant frequency should have increased by 40-50 %.
      Moreover, similar increases occurred in species that lack a subalar space
      (oecanthines). Experimental reduction of the subalar volume of singing crickets
      resulted neither in a change in f(C) nor in a change in loudness. Nor did
      crickets attempt to restore the subalar volume to its original value. These
      results disprove the presence of a subalar-tegminal resonator. The free resonance
      of freshly excised Gryllus rubens tegmina shifted by 1.09-fold when moved between
      air and a mixture of helium and air. Auditory feedback cannot be the cause of
      this shift, which is similar to the f(C) shifts in intact individuals of other
      species. Calculations show that the harp is 3.9-1.8 times more massive than the
      air that moves en masse with the vibrating harps. Replacing air with heliox-air
      lowers the mass of the vibrating system sufficiently to account for the f(C)
      shifts. These results re-affirm the 'clockwork cricket' (escapement) hypothesis.
      However, as realized by others, the harps should be viewed as narrow-band
      variable-frequency oscillators whose tuning may be controlled by factors that
      vary the effective mass.

PMID- 10637188
TI  - Song recognition in female bushcrickets Phaneroptera nana.
AB  - Unlike most acoustic systems evolved for pair formation, in which only males
      signal, in many species of phaneropterine bushcrickets both sexes sing, producing
      a duet. We used the duetting species Phaneroptera nana as a model to explore the
      cues in the male's song that elicit the female's phonoresponse. Different
      synthetic male songs (chirps containing 2-6 pulses) were presented to Ph. nana
      females, and their acoustic responses were recorded. The threshold of the female
      response is lowest at 16 kHz (best frequency), coinciding with the dominant
      frequency of the male song. The specific amplitude pattern of consecutive pulses
      in the song of the male is not a critical factor in his signal. That is, songs
      with both a normal and a reversed order of pulses equally elicit a female
      response. By systematically deleting pulses from the synthetic male chirp, we
      found that at least two pulses are needed to elicit a female reply. Under no
      choice conditions, increasing the number of pulses did not result in a higher
      probability of response and did not change the latency of the response; i.e. two
      pulses are necessary and sufficient to elicit a female response. The range of
      pulse duration that elicits a female response is 0.2-25 ms, and the inter-pulse
      silent interval ranges from 5 to 30 ms.

PMID- 10637189
TI  - Antidiuretic effects of a factor in brain/corpora cardiaca/corpora allata extract
      on fluid reabsorption across the cryptonephric complex of Manduca sexta.
AB  - Extracts of the brain/corpora cardiaca/corpora allata (Br/CC/CA) complex of
      Manduca sexta larvae elicit an antidiuretic effect, measured by an increase in
      fluid reabsorption across the cryptonephric complex of larval M. sexta.
      Separation of the extract by reversed-phase liquid chromatography gave two
      fractions with antidiuretic effects. The more potent of these two factors was
      further characterized for its effects on the cryptonephric complex. Its
      antidiuretic effect is not inhibited by bumetanide, a drug that inhibits M. sexta
      diuretic hormone (Mas-DH)-stimulated fluid reabsorption. These data indicate that
      the mechanism of the antidiuretic effect of the factor is different from that of
      Mas-DH on the cryptonephric complex. The basal reabsorption of the cryptonephric
      complex is blocked when treated on the lumen side with bafilomycin A(1), an
      inhibitor of the H(+)-ATPase, or with amiloride, an inhibitor of the H(+)/K(+)
      antiporter. However, the antidiuretic-factor-stimulated fluid reabsorption is not
      affected by either bafilomycin A(1) or amiloride. The increase in reabsorption
      triggered by the semi-purified factor can be inhibited by Cl(-) channel blockers
      or by removing Cl(-) from the lumen side of the cryptonephric complex. It appears
      that this factor activates a Cl(-) pump associated with the cryptonephric
      complex. Forskolin mimics the effect of this factor on fluid reabsorption, and
      the effect of forskolin is not inhibited by bumetanide. A selective and potent
      inhibitor of protein kinase A, H-89, also inhibits antidiuretic-factor-stimulated
      fluid reabsorption. Addition of the factor to cryptonephric complexes maintained
      in vitro caused a significant increase in cyclic AMP levels extracted from these
      tissues compared with values for controls. These data suggest that the
      antidiuretic effect of the factor in Br/CC/CA extract is mediated by cyclic AMP.

PMID- 10637190
TI  - Power production during steady swimming in largemouth bass and rainbow trout.
AB  - Steady swimming in fishes is powered by the aerobic or red muscle, but there are
      conflicting theories on the relative roles of the anterior and posterior red
      muscle in powering steady swimming. To examine how red muscle is used to power
      steady swimming in rainbow trout (Oncorhynchus mykiss), electromyographic (EMG)
      and sonomicrometry recordings were made of muscle activity in vivo. These data
      were used in in vitro work-loop studies of muscle power production. Data on in
      vitro power production were also collected for largemouth bass (Micropterus
      salmoides) red muscle from previously published data on in vivo muscle activity.
      The in vivo data collected from swimming trout were similar to those for other
      species. The anterior red muscle of these fish has the longest duty cycle, the
      smallest phase shift between the onset of EMG activity and maximum muscle length
      during each tailbeat and undergoes the smallest strain or length change. For both
      trout and largemouth bass, work-loop experiments indicate that the majority of
      power for steady swimming is generated by the posterior muscle, as has been
      observed in other species.

PMID- 10637191
TI  - Does membrane fluidity contribute to thermal compensation of beta-adrenergic
      signal transduction in isolated trout hepatocytes?
AB  - The potential role of compensatory adjustments to membrane components in
      determining the function of the (&bgr;)-adrenergic receptor/adenylyl cyclase
      ((&bgr;)-AR/AC) signal-transduction system was studied in isolated hepatocytes of
      5 degrees C- and 20 degrees C-acclimated rainbow trout Oncorhynchus mykiss. Rates
      of epinephrine-stimulated cyclic AMP (cAMP) production, although slowed (by a
      factor of 1.6- to 2.4-fold) by an acute drop in assay temperature from 20 to 5
      degrees C, were significantly temperature-compensated, being approximately
      twofold higher in hepatocytes of 5 degrees C- than of 20 degrees C-acclimated
      trout. Membrane order in the bilayer interior of hepatocyte plasma membranes (as
      assessed by fluorescence polarization of 1, 6-diphenyl-1,3,5-hexatriene) was
      consistently lower in cold- than in warm-acclimated trout, reflecting an efficacy
      of homeoviscous adaptation of approximately 50 %. Temperature-induced changes in
      plasma membrane fatty acid composition (i.e. an increase in the proportions of
      polyunsaturated fatty acids with acclimation to 5 degrees C) were consistent with
      both the observed changes in the order of the bilayer interior and the extent of
      homeoviscous adaptation. However, isothermal fluidization of the bilayer interior
      by the addition of benzyl alcohol (30 mmol l(-)(1)) decreased rather than
      increased the rate of cAMP production. Significantly more (1. 81-fold) beta
      adrenergic receptors were present in plasma membranes of hepatocytes from 5
      degrees C-acclimated (6. 23x10(4)+/-4206 receptors per cell; mean +/- s.e.m.,
      N=3) than 20 degrees C-acclimated fish (3.44x10(4)+/-4360 receptors per cell;
      N=3) when assayed at the acclimation temperature, whereas the equilibrium
      dissociation constants (K(d)) (13.73+/-4.33 nmol l(-)(1) at 5 degrees C; 9.75+/
      3.29 nmol l(-)(1) at 20 degrees C; N=3) were similar. On the basis of a strong
      correlation between beta-adrenoceptor number and the rate of cAMP production
      (r(2)=0. 956), regardless of assay or acclimation temperature, we conclude that
      modulation of receptor number is the primary acclimatory response of this signal
      transduction pathway to temperature change in trout liver.

PMID- 10637192
TI  - Thermal thresholds of lipid restructuring and delta(9)-desaturase expression in
      the liver of carp (Cyprinus carpio L.).
AB  - Cold acclimation induces a transient enzymatic activation of the acyl CoA
      (&Dgr;)(9)-desaturase in carp liver. We have determined thresholds for two
      underlying mechanisms; namely, the activation of latent enzyme and the induced
      synthesis of new desaturase. Carp were progressively cooled from 30 degrees C to
      23, 17 and 10 degrees C, where they were held for up to 5 days. Endoplasmic
      reticulum phospholipids showed substantial changes in fatty acid composition,
      with linear decreases in the proportion of saturates with temperature over the
      full range of cooling (11.3 % in phosphatidylcholine and 15.8 % in
      phosphatidylethanolamine). In the phosphatidyl-ethanolamine fraction, this was
      linked to increased proportions of monoenes, particularly 20:1(n-9). Modest
      cooling to 23 degrees C on day 1 induced a 2.5-fold transient increase in
      delta(9)-desaturase activity without any change in the amount of desaturase
      protein or transcript. Further cooling to 17 degrees C induced a greater and more
      sustained increase in desaturase activity, reaching sevenfold on day 5, with a 10
      to 20-fold increase in the amount of desaturase transcript. Extreme cooling to
      10 degrees C led to a very large, but transient, 40- to 50-fold increase in
      desaturase transcript amounts, a modest 40-50 % increase in desaturase protein
      but no further increase in activity over that observed at 17 degrees C. These
      results distinguish at least three mechanisms involved in cold-induced lipid
      restructuring; the activation of latent desaturase observed with gentle cooling,
      the induction of desaturase gene transcription and, finally, a third unidentified
      lipid compensatory mechanism that occurs with extreme cooling. The complex nature
      of cold-induced lipid restructuring also involves changes in the activity of
      other biosynthetic enzymes, including elongase and positional- and phospholipid
      specific acyltransferases.

PMID- 10637194
TI  - Circulation online only : january 18, 2000

PMID- 10637193
TI  - Soaring and non-soaring bats of the family pteropodidae (flying foxes, Pteropus
      spp.): wing morphology and flight performance.
AB  - On oceanic islands, some large diurnal megachiropteran bat species (flying foxes;
      Pteropus spp.) frequently use thermal or slope soaring during foraging flights to
      save energy. We compared the flight morphology and gliding/soaring performance of
      soaring versus non-soaring Pteropus species, one pair on American Samoa and one
      pair on the Comoro Islands, and two other soaring/flap-gliding species and one
      non-soaring species. We predicted that the soaring species should have a lower
      body mass, longer wings and, hence, lower wing loadings than those species that
      use mainly flapping flight. This would give a lower sinking speed during gliding,
      a higher glide ratio, and enable the bats to make tighter turns with lower
      sinking speeds than in the non-soaring species. We theoretically calculated the
      gliding and circling performances of both the soaring and non-soaring species.
      Our results show that there are tendencies towards longer wings and lower wing
      loadings in relation to body size in the gliding/soaring flying foxes than in the
      non-soaring ones. In the species-pair comparison of the soaring and non-soaring
      species on American Samoa and the Comoro Islands, the soarers on both islands
      turn out to have lower wing loadings than their non-soaring partners in spite of
      opposite size differences among the pairs. These characteristics are in
      accordance with our hypothesis on morphological adaptations. Most differences
      are, however, only significant at a level of P<0.1, which may be due to the small
      sample size, but overlap also occurs. Therefore, we must conclude that wing
      morphology does not seem to be a limiting factor preventing the non-soarers from
      soaring. Instead, diurnality in the soaring species seems to be the ultimate
      determinant of soaring behaviour. The morphological differences cause visible
      differences in soaring and gliding performance. The glider/soarers turn out to
      have lower minimum sinking speeds, lower best glide speeds and smaller turning
      radii than the non-soarers. When the wing measurements and soaring performance
      are normalized to a body mass of 0.5 kg for all species, the minimum sinking
      speed becomes significantly lower (P<0.05) in the three soaring and the one flap
      gliding species (0.63 m s(-)(1)) than in the three non-soaring species (0.69 m s(
      )(1)). Interestingly, the zones in the diagrams for the glide polars and circling
      envelopes of these similar-sized bats become displaced for the glider/soarers
      versus the non-soarers. The glide polars overlap slightly only at the gliding
      speeds appropriate for these bats, whereas the circling envelopes do not overlap
      at the appropriate bank angles and turning radii. This points towards adaptations
      for better gliding/soaring performance in the soaring and gliding species.

PMID- 10637195
TI  - Effect of intracoronary recombinant human vascular endothelial growth factor on
      myocardial perfusion: evidence for a dose-dependent effect.
AB  - BACKGROUND: Animal models of therapeutic angiogenesis have stimulated development
      of clinical application in patients with limited options for coronary
      revascularization. The impact of recombinant human vascular endothelial growth
      factor (rhVEGF) on myocardial perfusion in humans has not been reported. METHODS
      AND RESULTS: Fourteen patients underwent exercise (n=11), dobutamine (n=2), or
      dipyridamole (n=1) myocardial perfusion single photon emission CT (SPECT) before
      as well as 30 and 60 days after rhVEGF administration. After uniform processing
      and display, 2 observers blinded to the timing of the study and dose of rhVEGF
      reviewed the SPECT images. By a visual, semiquantitative 20-segment scoring
      method, summed stress scores (SSS) and summed rest scores (SRS) were generated.
      Although the SSS did not change from baseline to 30 days (21.6 versus 21.5;
      P=NS), the SRS improved after rhVEGF (13.2 versus 10.4; P<0.05). Stress and rest
      perfusion improved in >2 segments infrequently in patients treated with low-dose
      rhVEGF. However, 5 of 6 patients had improvement in >2 segments at rest and
      stress with the higher rhVEGF doses. Furthermore, although neither the SSS nor
      the SRS changed in patients treated with the low doses, the SRS decreased in the
      high-dose rhVEGF patients at 60 days (14.7 versus 10.7; P<0.05). Quantitative
      analysis was consistent with the visual findings but failed to demonstrate
      statistical significance. CONCLUSIONS: Although not designed to demonstrate
      rhVEGF efficacy, these phase 1 data support the concept that rhVEGF improves
      myocardial perfusion at rest and provide evidence of a dose-dependent effect.

PMID- 10637196
TI  - Carvedilol inhibits reactive oxygen species generation by leukocytes and
      oxidative damage to amino acids.
AB  - BACKGROUND: The purpose of this study was to test whether carvedilol has an
      antioxidant effect in humans in vivo. METHODS AND RESULTS: We administered 3.125
      mg of carvedilol twice daily to normal subjects for 1 week. ROS generation by
      polymorphonuclear leukocytes and mononuclear cells fell from 314+/-183.43 and
      303+/-116 mV to 185+/-157 and 189+/-63 mV (P<0.025), respectively. m-Tyrosine
      fell from 4.24+/-0.99 to 4.03+/-0.97 ng/mL (P=0.01), and o-tyrosine fell from
      4.59+/-1.10 to 4.24+/-0.99 ng/mL (P=0.004) in the absence of a change in
      phenylalanine concentrations. CONCLUSIONS: We conclude that carvedilol
      significantly inhibits ROS generation by leukocytes and oxidative conversion of
      phenylalanine to m- and o-tyrosine.

PMID- 10637197
TI  - Relationship of TIMI myocardial perfusion grade to mortality after administration
      of thrombolytic drugs.
AB  - BACKGROUND: Although improved epicardial blood flow (as assessed with either TIMI
      flow grades or TIMI frame count) has been related to reduced mortality after
      administration of thrombolytic drugs, the relationship of myocardial perfusion
      (as assessed on the coronary arteriogram) to mortality has not been examined.
      METHODS AND RESULTS: A new, simple angiographic method, the TIMI myocardial
      perfusion (TMP) grade, was used to assess the filling and clearance of contrast
      in the myocardium in 762 patients in the TIMI (Thrombolysis In Myocardial
      Infarction) 10B trial, and its relationship to mortality was examined. TMP grade
      0 was defined as no apparent tissue-level perfusion (no ground-glass appearance
      of blush or opacification of the myocardium) in the distribution of the culprit
      artery; TMP grade 1 indicates presence of myocardial blush but no clearance from
      the microvasculature (blush or a stain was present on the next injection); TMP
      grade 2 blush clears slowly (blush is strongly persistent and diminishes
      minimally or not at all during 3 cardiac cycles of the washout phase); and TMP
      grade 3 indicates that blush begins to clear during washout (blush is minimally
      persistent after 3 cardiac cycles of washout). There was a mortality gradient
      across the TMP grades, with mortality lowest in those patients with TMP grade 3
      (2.0%), intermediate in TMP grade 2 (4.4%), and highest in TMP grades 0 and 1
      (6.0%; 3-way P=0.05). Even among patients with TIMI grade 3 flow in the
      epicardial artery, the TMP grades allowed further risk stratification of 30-day
      mortality: 0.73% for TMP grade 3; 2.9% for TMP grade 2; 5.0% for TMP grade 0 or 1
      (P=0.03 for TMP grade 3 versus grades 0, 1, and 2; 3-way P=0.066). TMP grade 3
      flow was a multivariate correlate of 30-day mortality (OR 0.35, 95% CI 0.12 to
      1.02, P=0.054) in a multivariate model that adjusted for the presence of TIMI 3
      flow (P=NS), the corrected TIMI frame count (OR 1.02, P=0.06), the presence of an
      anterior myocardial infarction (OR 2.3, P=0.03), pulse rate on admission (P=NS),
      female sex (P=NS), and age (OR 1.1, P<0.001). CONCLUSIONS: Impaired perfusion of
      the myocardium on coronary arteriography by use of the TMP grade is related to a
      higher risk of mortality after administration of thrombolytic drugs that is
      independent of flow in the epicardial artery. Patients with both normal
      epicardial flow (TIMI grade 3 flow) and normal tissue level perfusion (TMP grade
      3) have an extremely low risk of mortality.

PMID- 10637198
TI  - Influence of a nonionic, iso-osmolar contrast medium (iodixanol) versus an ionic,
      low-osmolar contrast medium (ioxaglate) on major adverse cardiac events in
      patients undergoing percutaneous transluminal coronary angioplasty: A
      multicenter, randomized, double-blind study. Visipaque in Percutaneous
      Transluminal Coronary Angioplasty [VIP] Trial Investigators.
AB  - BACKGROUND: The potential merits and disadvantages of the use of ionic or
      nonionic contrast media in patients undergoing percutaneous transluminal coronary
      angioplasty (PTCA) have been the subjects of controversy. The present study was
      designed to evaluate the possible influence of both types of contrast media on
      major adverse cardiac events (MACE) in patients undergoing PTCA. METHODS AND
      RESULTS: In a randomized, parallel-group, double-blind study, 1411 patients
      received either iodixanol (a nonionic, iso-osmolar contrast medium) or ioxaglate
      (an ionic, low-osmolar contrast medium) during PTCA. A standardized
      anticoagulation regimen was followed. Patients were monitored in the hospital for
      2 days and followed-up at 1 month. The primary end point, a composite of MACE
      (death, stroke, myocardial infarction, coronary artery bypass grafting, and re
      PTCA) after 2 days, occurred in 4.3% of the total population, with no
      statistically significant difference between groups (iodixanol, 4.7%; ioxaglate,
      3.9%; P=0.45). Further, between 2-day and 1-month follow-ups, no significant
      difference (P=0.27) existed between the groups in the rates of MACE.
      Hypersensitivity reactions (P=0.007) and adverse drug reactions (P=0.002) were
      significantly less frequent in the iodixanol group. The only significant
      predicting factors for the occurrence of MACE were dissection/abrupt closure and
      country. CONCLUSIONS: No significant differences were observed between the
      iodixanol and ioxaglate groups with regard to MACE, although hypersensitivity and
      adverse drug reactions were significantly less frequent in patients who received
      iodixanol.

PMID- 10637199
TI  - Association of serology with the endovascular presence of Chlamydia pneumoniae
      and cytomegalovirus in coronary artery and vein graft disease.
AB  - BACKGROUND: Chemotherapeutic treatment for patients with symptomatic coronary
      artery disease to reduce cardiovascular events may be initiated in response to
      elevated antibody titers against Chlamydia pneumoniae or cytomegalovirus. How
      antibody titers are associated with the endovascular presence of these
      microorganisms is still unclear. METHODS AND RESULTS: Antibody titers against C
      pneumoniae (microimmunofluorescence) and cytomegalovirus (ELISA) in patients
      undergoing primary (coronary desobliterates, n=80) or repeated CABG (occluded
      vein grafts, n=45) were correlated with the endovascular presence of the 2
      microorganisms. C pneumoniae was detected by means of a nested polymerase chain
      reaction (PCR) and by culturing. Both conventional PCR and quantitative PCR were
      applied for detection of cytomegalovirus. C pneumoniae (PCR/culture) was detected
      in 19/9% (15/80 and 7/80) of coronary desobliterates and in 18/11% (8/45 and
      5/45) of occluded vein grafts. There was no statistical evidence that IgG values
      differed between patients with or without C pneumoniae detection who were
      undergoing primary CABG. In contrast, repeated-CABG patients with a positive PCR
      (P=0.0027) or C pneumoniae culture (P=0.0018) had distinctly elevated IgG titers
      compared with patients in whom C pneumoniae was not detected. Cytomegalovirus
      could not be detected in the examined specimens. CONCLUSIONS: Cytomegalovirus
      infection does not seem to be associated with advanced coronary artery lesions. C
      pneumoniae antibody titers are not associated with the endovascular presence of C
      pneumoniae in patients with coronary artery disease. The observed strong
      association between elevated IgG titers and the detection of C pneumoniae in
      occluded vein grafts warrants further investigation.

PMID- 10637200
TI  - Contrasting inotropic effects of endogenous endothelin in the normal and failing
      human heart: studies with an intracoronary ET(A) receptor antagonist.
AB  - BACKGROUND: Endothelin-1 (ET-1) is a potent positive inotrope in vitro, but its
      physiological effects on intrinsic myocardial contractile function in humans in
      vivo are unknown. Plasma ET-1 levels are elevated in heart failure, and ET-1 may
      be involved in the pathophysiology of this condition. However, its effects on
      contractile function of the failing human heart are also unknown. METHODS AND
      RESULTS: A specific ET(A) receptor antagonist, BQ123, was infused (40 nmol/min,
      16 minutes) into the left coronary artery in 8 patients with atypical chest pain
      (normal left ventricular ?LV function and coronary arteries) and 8 patients with
      nonischemic dilated cardiomyopathy (DCM) who were undergoing diagnostic
      catheterization. In normal subjects, BQ123 rapidly induced a significant
      reduction in LV dP/dt(max) (-270+/-71 mm Hg/s after 16 minutes; P<0.05) and in LV
      dP/dt at a developed pressure of 40 mm Hg (LV dP/dt(40)) (-179+/-54 mm Hg/s;
      P<0.05). In DCM patients, however, BQ123 caused no reductions in LV dP/dt(max)
      (62+/-49 mm Hg/s after 16 minutes) or LV dP/dt(40) (83+/-51 mm Hg/s;P<0.05
      compared with normal subjects). BQ123 had no effect on heart rate, LV relaxation,
      LV end-diastolic pressure, right atrial pressure, or pulmonary pressure in either
      patient group. CONCLUSIONS: Endogenous ET-1 has a tonic positive inotropic effect
      in normal subjects, independent of effects on the peripheral vasculature and
      unmasked by inhibition of ET(A) receptors. However, the effect of short-term
      ET(A) blockade in DCM patients was opposite to that in normal subjects, which
      suggests that ET-1 may cause negative inotropic effects in the failing heart.

PMID- 10637201
TI  - Insertion/deletion polymorphism in the angiotensin-converting enzyme gene affects
      heart weight.
AB  - BACKGROUND: Angiotensin (Ang) II, a major regulatory factor for left ventricular
      mass, is generated from Ang I by ACE. ACE levels are associated with an
      insertion/deletion (I/D) polymorphism in the ACE gene. The ACE polymorphism
      should result in varied Ang II concentrations and hence affect left ventricular
      mass. We therefore investigated whether ACE genotype is a predictor of heart
      weight. METHODS AND RESULTS: From 693 consecutive patients autopsied between 1994
      and 1998 in our hospital, patients with valvular disease, myocardial infarction,
      or cardiomyopathy were excluded. The remaining 443 autopsy patients were the
      subjects of our study. The heart weight at autopsy was corrected for body surface
      area. Genomic DNA was purified from the kidney, and ACE genotype was determined
      by polymerase chain reaction. Heart weight in the DD genotype (249. 9+/-49.9
      g/m(2)) was significantly higher than that in the ID (230. 0+/-51.2 g/m(2);
      P<0.05) and II (226.8+/-49.8 g/m(2); P<0.01) genotypes. Heart weight was also
      positively related to age (r=0.145, P<0.0001) and coronary stenosis index
      (r=0.147, P=0.0019). Multiple regression analysis showed that a history of
      hypertension (P<0.0001), age (P=0.0001), and DD genotype (P=0.0154) were
      independent predictors of heart weight. CONCLUSIONS: ACE genotype predicts
      cardiac mass; however, it was less effective than epigenetic factors such as
      hypertension or age.

PMID- 10637202
TI  - Relation of left ventricular diastolic properties to systolic function in
      arterial hypertension.
AB  - BACKGROUND: It is unclear whether impairment of left ventricular (LV) diastolic
      characteristics is independent of systolic dysfunction. METHODS AND RESULTS: To
      address this issue, 159 consecutive hypertensive patients (44+/-11 years, 78
      obese, 96 women) and 165 normotensive subjects (32+/-11 years, 84 obese, 110
      women) were studied with the use of Doppler echocardiography. After adjustment
      for age, body mass index (BMI), and sex, we found that ejection fraction (EF; M
      mode, z-derived) was higher in hypertensive (66. 6+/-5.2%) than in normotensive
      (63.9+/-4.4%, P<0.0001) subjects, whereas midwall shortening (MS) was lower
      (hypertensive patients 16. 9+/-2.0%, normotensive subjects 17.8+/-2.2%, P<0.02),
      even after correction for end-systolic wall stress (P<0.05). Isovolumic
      relaxation time (IVRT) was greater in hypertensive patients (103+/-14 ms) than in
      normotensive subjects (78+/-19 ms), as was deceleration time of E velocity and
      peak A velocity (all P<0.0001). In multivariate analysis, IVRT was unrelated to
      EF, but a negative relation was found with MS (P<0.001), independent of age, BMI,
      presence of arterial hypertension, LV geometry, and load (multiple R(2)=0.58).
      For comparable age, sex distribution, BMI, and blood pressure values,
      hypertensive patients with lower afterload-adjusted MS exhibited longer IVRT than
      patients with normal MS (P<0.005). However, IVRT remained higher than in
      normotensive control subjects after control for LV geometry and load.
      CONCLUSIONS: Doppler indices of delayed LV relaxation can be detected in the
      presence of normal or supranormal EF but are independently related to impaired
      MS. A less severely abnormal relaxation, however, can be also detected in the
      presence of normal midwall function, independent of LV geometry and load. Thus,
      diastolic abnormalities may occur before systolic dysfunction even when it is
      measured at the midwall.

PMID- 10637203
TI  - Destabilizing effects of mental stress on ventricular arrhythmias in patients
      with implantable cardioverter-defibrillators.
AB  - BACKGROUND: The incidence of sudden cardiac death increases in populations who
      experience disasters such as earthquakes. The physiological link between
      psychological stress and sudden death is unknown; one mechanism may be the direct
      effects of sympathetic arousal on arrhythmias. To determine whether mental stress
      alters the induction, rate, or termination of ventricular arrhythmias, we
      performed noninvasive programmed stimulation (NIPS) in patients with
      defibrillators and ventricular tachycardia (VT), which is known to be inducible
      and terminated by antitachycardia pacing, at rest and during varying states of
      mental arousal. METHODS AND RESULTS: Eighteen patients underwent NIPS in the
      resting-awake state (nonsedated). Ten underwent repeat testing during mental
      stress (mental arithmetic and anger recall). Induced VT was faster in 5 patients
      (P=0.03). VT became more difficult to terminate in 5 patients during mental
      stress; 4 required a shock (P=0.03). There was no change in ease of induction
      with mental stress. There was no evidence of ischemia on ECG or continuous
      ejection fraction monitoring. Eight patients received a shock in the resting
      awake state and did not perform mental stress. Four underwent repeat NIPS after
      sedation; 3 then had induced VT terminated with antitachycardia pacing. All
      patients with an increase in norepinephrine of >50% had alterations in VT that
      required shock for termination (P<0.01). CONCLUSIONS: Mental stress alters VT
      cycle length and termination without evidence of ischemia. This suggests that
      mental stress may lead to sudden death through the facilitation of lethal
      ventricular arrhythmias.

PMID- 10637204
TI  - Endothelium-derived nitric oxide contributes to the regulation of venous tone in
      humans.
AB  - BACKGROUND: Although nitric oxide (NO) is known to play an important part in the
      regulation of arterial tone, little is known about its role in veins. The aim of
      this study was to investigate the role of basal and stimulated NO activity in the
      regulation of tone of the human venous capacitance bed. METHODS AND RESULTS: We
      measured venous tone using radionuclide forearm venous plethysmography in 24
      healthy subjects with no cardiovascular risk factors. In 13 subjects, basal NO
      activity was assessed by measuring the effects on venous tone of an intra
      arterial infusion of the NO synthase inhibitor N-monomethyl-L-arginine (L-NMMA).
      In the remaining 11 subjects, stimulated NO activity was evaluated by measuring
      the effects of an intra-arterial infusion of incremental doses of carbachol,
      followed in a subgroup by coinfusion with L-NMMA. Infusion of carbachol caused
      dose-dependent venodilation, with a maximal reduction in forearm venous tone of
      40.1+/-12.5% (P<0.0001). Carbachol-induced venodilation was inhibited by L-NMMA
      (48.9+/-6.2% reversal of maximal venodilation, P<0.01). Infusion of L-NMMA alone
      caused venoconstriction (9.1+/-6.4% increase in venous tone, P=0.002).
      CONCLUSIONS: Human forearm capacitance veins exhibit both stimulated and basal NO
      activity, which indicates that NO contributes not only to the regulation of
      venous tone but also to resting venous tone in healthy human subjects.

PMID- 10637205
TI  - Oxidized low-density lipoproteins inhibit endothelial cell proliferation by
      suppressing basic fibroblast growth factor expression.
AB  - BACKGROUND: Hyperlipidemia inhibits proliferation of endothelial cells (ECs) in
      culture and angiogenesis in vivo and in arterial explants. Elucidation of the
      mechanisms may suggest novel therapies against atherosclerosis. METHODS AND
      RESULTS: Basic fibroblast growth factor (bFGF) expression and mitogenic effects
      were assessed in bovine aortic ECs incubated with oxidized LDL (ox-LDL). Compared
      with native LDL and lipoprotein-free controls, ox-LDL reduced bFGF mRNA levels in
      a time- and concentration-dependent manner, 100 microg/mL producing a maximum
      reduction of 40% to 50% within 24 to 48 hours. There were commensurate reductions
      in intracellular and extracellular bFGF concentrations, DNA and total RNA
      syntheses, and cell replication. FGF receptor 1 and beta-actin mRNA levels were
      unchanged. Ox-LDL accelerated bFGF mRNA degradation in actinomycin D-treated
      cells. However, inhibition of bFGF expression by ox-LDL was attenuated by
      cyclohexamide, indicating a requirement for continuous new protein synthesis for
      posttranscriptional destabilization. Reduced syntheses of DNA and total RNA were
      completely restored by bFGF but not by vascular endothelial growth factor.
      Inhibition of total RNA synthesis achieved by exposing cells to a bFGF
      neutralizing antibody was similar in magnitude to that induced by ox-LDL.
      CONCLUSIONS: Cytotoxic effects of ox-LDL on ECs are attributable in part to
      suppression of bFGF expression.

PMID- 10637206
TI  - High-efficiency, long-term cardiac expression of foreign genes in living mouse
      embryos and neonates.
AB  - BACKGROUND: The development of improved strategies for efficient and reproducible
      in vivo gene transfer into the murine heart will ultimately allow the
      intersection of somatic and germline gene transfer strategies to study complex
      features of cardiac biology and diseases. METHODS AND RESULTS: For embryonic gene
      transfer, an adenovirus vector expressing beta-galactosidase was injected in
      utero into the ventricular cavity of living embryos via microsurgical approaches.
      The injected embryos were developed to term, and efficient expression of the
      transgene was detected in all cell types in the heart. For postnatal cardiac gene
      transfer, adenovirus was injected into the cardiac ventricle of neonatal mice,
      resulting in efficient expression of the transgene in the outer layer of the
      myocardium as well as cardiomyocytes in the middle and inner layers of the
      cardiac wall. Mice examined after 3 weeks displayed a pattern of expression that
      completely mimicked the pattern seen after 3 days, and gene expression was also
      found after 6 months. The infected myocytes can be identified by coinfection of
      an adenovirus expressing green fluorescent protein without affecting their normal
      physiological function. CONCLUSIONS: We have developed a new strategy to achieve
      efficient and long-term foreign gene expression in both embryonic and postnatal
      mouse myocardium via direct intracardiac injection of recombinant adenovirus. The
      strategy should allow the functional assessment of the expression of dominantly
      acting exogenous genes, overexpression of wild-type genes, and Cre recombinase
      mediated gene ablations at the single-cell level in the context of the intact
      adult mouse myocardium.

PMID- 10637207
TI  - Dilated cardiomyopathy associated with simian AIDS in nonhuman primates.
AB  - BACKGROUND: Cardiomyopathy is being recognized with increasing frequency in
      patients with AIDS, yet the relationship between HIV infection and cardiac
      contractile dysfunction remains obscure. The purpose of the present study was to
      determine if infection with simian immunodeficiency virus (SIV) in nonhuman
      primates is associated with cardiac dysfunction and myocardial injury. METHODS
      AND RESULTS: Left ventricular size and function were determined by 2D
      echocardiography in 16 rhesus macaques before and at weekly intervals following
      infection with cloned pathogenic SIV(mac) 239 or the highly attenuated SIV(mac)
      239 nef deletion mutant. A second group of 15 rhesus macaques chronically
      infected with pathogenic (n=6) or nonpathogenic (n=9) virus were studied at >2
      years following infection. Cardiac tissues from 24 rhesus macaques chronically
      infected (>2 years) with pathogenic SIV were reviewed for evidence of cardiac
      pathology. Acute infection (<6 weeks) with either pathogenic or nonpathogenic SIV
      caused neither contractile dysfunction nor cardiac pathology. However, LV
      ejection fraction was significantly (P<0.05) depressed (43+/-7%) in rhesus
      macaques chronically infected with pathogenic SIV compared with rhesus macaques
      chronically infected with nonpathogenic SIV (61+/-3%). Furthermore, two thirds of
      rhesus macaques that succumbed to simian AIDS had myocardial pathology including
      lymphocytic myocarditis (n=9) and coronary arteriopathy (n=6), with complete
      vessel occlusion (n=4) and associated myocardial infarction and necrosis.
      CONCLUSIONS: This unique model is valuable in understanding the pathogenesis of
      cardiac injury associated with retroviral infection in a relevant nonhuman
      primate model of AIDS.

PMID- 10637208
TI  - Stable microreentrant sources as a mechanism of atrial fibrillation in the
      isolated sheep heart.
AB  - BACKGROUND: Atrial fibrillation (AF) has traditionally been described as
      aperiodic or random. Yet, ongoing sources of high-frequency periodic activity
      have recently been suggested to underlie AF in the sheep heart. Our objective was
      to use a combination of optical and bipolar electrode recordings to identify
      sites of periodic activity during AF and elucidate their mechanism. METHODS AND
      RESULTS: AF was induced by rapid pacing in the presence of 0.1 to 0.5 micromol/L
      acetylcholine in 7 Langendorff-perfused sheep hearts. We used simultaneous
      optical mapping of the right and left atria (RA and LA) and frequency sampling of
      optical and bipolar electrode recordings (including a roving electrode) to
      identify sites having the highest dominant frequency (DF). Rotors were identified
      from optical recordings, and their rotation period, core area, and perimeter were
      measured. In all, 35 AF episodes were analyzed. Mean LA and RA DFs were 14.7+/
      3.8 and 10.3+/-2.1 Hz, respectively. Spatiotemporal periodicity was seen in the
      LA during all episodes. In 5 of 7 experiments, a single site having periodic
      activity at the highest DF was localized. The highest DF was most often (80%)
      localized to the posterior LA, near or at the pulmonary vein ostium. Rotors
      (n=14) were localized on the LA. The mean core perimeter and area were 10.4+/-2.8
      mm and 3.8+/-2.8 mm(2), respectively. CONCLUSIONS: Frequency sampling allows
      rapid identification of discrete sites of high-frequency periodic activity during
      AF. Stable microreentrant sources are the most likely underlying mechanism of AF
      in this model.

PMID- 10637209
TI  - Effect of verapamil on long-term tachycardia-induced atrial electrical
      remodeling.
AB  - BACKGROUND: The effect of verapamil on long-term tachycardia-induced atrial
      electrical remodeling has not been reported. METHODS AND RESULTS: Forty-eight
      dogs were randomly divided into verapamil and control groups. The dogs in the
      verapamil group received verapamil 120 mg every day, those in the control group
      did not receive verapamil. Atrial effective refractory period (AERP),
      inducibility of atrial fibrillation (AF), and duration of AF were assessed before
      and after complete atrioventricular junction ablation with 1-day, 1-week, or 6
      week rapid atrial pacing (780 bpm). AERP shortening, AERP dispersion, AERP
      maladaptation, and inducibility of AF after 1-day pacing was significantly
      attenuated by verapamil. However, verapamil did not have any significant effect
      on these parameters in the dogs with 1-week or 6-week pacing. Verapamil did not
      have any significant effect on the conduction velocity in the dogs with 1-day, 1
      week, or 6-week pacing. Before rapid atrial pacing, verapamil significantly
      prolonged the duration of AF. In the dogs with 1-day pacing, the duration of AF
      measured immediately after termination of pacing was similar between the control
      and verapamil groups. However, in the dogs with 1-week or 6-week pacing, the
      duration of AF after pacing was significantly longer in the verapamil group.
      CONCLUSIONS: Verapamil cannot prevent long-term (1 and 6 weeks, respectively)
      tachycardia-induced changes of atrial electrophysiological properties.
      Furthermore, verapamil increases the duration of AF in the dogs either before or
      after long-term rapid atrial pacing.

PMID- 10637210
TI  - Current perspectives on statins.
AB  - Statins (HMG-CoA reductase inhibitors) are used widely for the treatment of
      hypercholesterolemia. They inhibit HMG-CoA reductase competitively, reduce LDL
      levels more than other cholesterol-lowering drugs, and lower triglyceride levels
      in hypertriglyceridemic patients. Statins are well tolerated and have an
      excellent safety record. Clinical trials in patients with and without coronary
      heart disease and with and without high cholesterol have demonstrated
      consistently that statins reduce the relative risk of major coronary events by
      approximately 30% and produce a greater absolute benefit in patients with higher
      baseline risk. Proposed mechanisms include favorable effects on plasma
      lipoproteins, endothelial function, plaque architecture and stability,
      thrombosis, and inflammation. Mechanisms independent of LDL lowering may play an
      important role in the clinical benefits conferred by these drugs and may
      ultimately broaden their indication from lipid-lowering to antiatherogenic
      agents.

PMID- 10637211
TI  - Images in cardiovascular medicine. IIb/IIIa receptor antagonists for failed
      rescue angioplasty.

PMID- 10637212
TI  - Dilemma of angiogenesis.

PMID- 10637213
TI  - In an emergency: at home or in the hospital.

PMID- 10637214
TI  - Attorneys argue FDA regulation of tobacco before Supreme Court.

PMID- 10637215
TI  - Do not forget the old in enthusiasm for the new and exotic.

PMID- 10637216
TI  - International team deciphers chromosome 22.

PMID- 10637217
TI  - US to tackle AIDS on the border.

PMID- 10637218
TI  - Varmus proposes guidelines for stem cell research.

PMID- 10637219
TI  - Angiotensin-converting enzyme tissue activity in the diffuse in-stent restenotic
      plaque.

PMID- 10637220
TI  - Nuclear and cytosolic events of light-induced, phytochrome-regulated signaling in
      higher plants.

PMID- 10637221
TI  - New structural motifs on the chymotrypsin fold and their potential roles in
      complement factor B.
AB  - Factor B and C2 are two central enzymes for complement activation. They are
      multidomain serine proteases and require cofactor binding for full expression of
      proteolytic activities. We present a 2.1 A crystal structure of the serine
      protease domain of factor B. It shows a number of structural motifs novel to the
      chymotrypsin fold, which by sequence homology are probably present in C2 as well.
      These motifs distribute characteristically on the protein surface. Six loops
      surround the active site, four of which shape substrate-binding pockets. Three
      loops next to the oxyanion hole, which typically mediate zymogen activation, are
      much shorter or absent. Three insertions including the linker to the preceding
      domain bulge from the side opposite to the active site. The catalytic triad and
      non-specific substrate-binding site display active conformations, but the
      oxyanion hole displays a zymogen-like conformation. The bottom of the S1 pocket
      has a negative charge at residue 226 instead of the typical 189 position. These
      unique structural features may play different roles in domain-domain interaction,
      cofactor binding and substrate binding.

PMID- 10637222
TI  - Flexibility, conformational diversity and two dimerization modes in complexes of
      ribosomal protein L12.
AB  - Protein L12, the only multicopy component of the ribosome, is presumed to be
      involved in the binding of translation factors, stimulating factor-dependent GTP
      hydrolysis. Crystal structures of L12 from Thermotogamaritima have been solved in
      two space groups by the multiple anomalous dispersion method and refined at 2.4
      and 2.0 A resolution. In both crystal forms, an asymmetric unit comprises two
      full-length L12 molecules and two N-terminal L12 fragments that are associated in
      a specific, hetero-tetrameric complex with one non-crystallographic 2-fold axis.
      The two full-length proteins form a tight, symmetric, parallel dimer, mainly
      through their N-terminal domains. Each monomer of this central dimer additionally
      associates in a different way with an N-terminal L12 fragment. Both dimerization
      modes are unlike models proposed previously and suggest that similar complexes
      may occur in vivo and in situ. The structures also display different L12 monomer
      conformations, in accord with the suggested dynamic role of the protein in the
      ribosomal translocation process. The structures have been submitted to the
      Protein Databank (http://www.rcsb.org/pdb) under accession numbers 1DD3 and 1DD4.

PMID- 10637223
TI  - Monoubiquitin carries a novel internalization signal that is appended to
      activated receptors.
AB  - Ubiquitin modification of signal transducing receptors at the plasma membrane is
      necessary for rapid receptor internalization and downregulation. We have
      investigated whether ubiquitylation alters a receptor cytoplasmic tail to reveal
      a previously masked internalization signal, or whether ubiquitin itself carries
      an internalization signal. Using an alpha-factor receptor-ubiquitin chimeric
      protein, we demonstrate that monoubiquitin can mediate internalization of an
      activated receptor that lacks all cytoplasmic tail sequences. Furthermore, fusion
      of ubiquitin in-frame to the stable plasma membrane protein Pma1p stimulates
      endocytosis of this protein. Ubiquitin does not carry a functional tyrosine- or
      di-leucine-based internalization signal. Instead, the three-dimensional structure
      of the folded ubiquitin polypeptide carries an internalization signal that
      consists of two surface patches surrounding the critical residues Phe4 and Ile44.
      We conclude that ubiquitin functions as a novel regulated internalization signal
      that can be appended to a plasma membrane protein to trigger downregulation.

PMID- 10637224
TI  - Involvement of ezrin/moesin in de novo actin assembly on phagosomal membranes.
AB  - The current study focuses on the molecular mechanisms responsible for actin
      assembly on a defined membrane surface: the phagosome. Mature phagosomes were
      surrounded by filamentous actin in vivo in two different cell types. Fluorescence
      microscopy was used to study in vitro actin nucleation/polymerization (assembly)
      on the surface of phagosomes isolated from J774 mouse macrophages. In order to
      prevent non-specific actin polymerization during the assay, fluorescent G-actin
      was mixed with thymosin beta4. The cytoplasmic side of phagosomes induced de novo
      assembly and barbed end growth of actin filaments. This activity varied
      cyclically with the maturation state of phagosomes, both in vivo and in vitro.
      Peripheral membrane proteins are crucial components of this actin assembly
      machinery, and we demonstrate a role for ezrin and/or moesin in this process. We
      propose that this actin assembly process facilitates phagosome/endosome
      aggregation prior to membrane fusion.

PMID- 10637225
TI  - Model for stathmin/OP18 binding to tubulin.
AB  - Stathmin/OP18 is a regulatory phosphoprotein that controls microtubule (MT)
      dynamics. The protein does not have a defined three-dimensional structure,
      although it contains three distinct regions (an unstructured N-terminus, N: 1-44;
      a region with high helix propensity, H 1: 44-89; and a region with low helix
      propensity, H 2: 90-142). The full protein and a combination of H 1 and H 2
      inhibits tubulin polymerization, while the combination of H 1 and the N-terminus
      is less efficient. None of the individual three regions alone are functional in
      this respect. However, all of them cross-link to alpha-tubulin, but only full
      length stathmin produces high-molecular-weight products. Mass spectrometry
      analysis of alpha-tubulin-stathmin/OP18 and its truncation products shows that
      full-length stathmin/OP18 binds to the region around helix 10 of alpha-tubulin, a
      region that is involved in longitudinal interactions in the MT, sequestering the
      dimer and possibly linking two tubulin heterodimers. In the absence of the N
      terminus, stathmin/OP18 binds to only one molecule of alpha-tubulin, at the top
      of the free tubulin heterodimer, preventing polymerization.

PMID- 10637226
TI  - Saccharomyces cerevisiae pex3p and pex19p are required for proper localization
      and stability of peroxisomal membrane proteins.
AB  - The mechanisms by which peroxisomal membrane proteins (PMPs) are targeted to and
      inserted into membranes are unknown, as are the required components. We show that
      among a collection of 16 Saccharomyces cerevisiae peroxisome biogenesis (pex)
      mutants, two mutants, pex3Delta and pex19Delta, completely lack detectable
      peroxisomal membrane structures and mislocalize their PMPs to the cytosol where
      they are rapidly degraded. The other pexDelta mutants contain membrane structures
      that are properly inherited during vegetative growth and that house multiple
      PMPs. Even Pex15p requires Pex3p and Pex19p for localization to peroxisomal
      membranes. This PMP was previously hypothesized to travel via the endoplasmic
      reticulum (ER) to peroxisomes. We provide evidence that ER-accumulated Pex15p is
      not a sorting intermediate on its way to peroxisomes. Our results show that Pex3p
      and Pex19p are required for the proper localization of all PMPs tested, including
      Pex15p, whereas the other Pex proteins might only be required for
      targeting/import of matrix proteins.

PMID- 10637227
TI  - A membrane-embedded glutamate is required for ligand binding to the multidrug
      transporter EmrE.
AB  - EmrE is an Escherichia coli multidrug transporter that confers resistance to a
      variety of toxins by removing them in exchange for hydrogen ions. The detergent
      solubilized protein binds tetraphenylphosphonium (TPP(+)) with a K(D) of 10 nM.
      One mole of ligand is bound per approximately 3 mol of EmrE, suggesting that
      there is one binding site per trimer. The steep pH dependence of binding suggests
      that one or more residues, with an apparent pK of approximately 7.5, release
      protons prior to ligand binding. A conservative Asp replacement (E14D) at
      position 14 of the only membrane-embedded charged residue shows little transport
      activity, but binds TPP(+) at levels similar to those of the wild-type protein.
      The apparent pK of the Asp shifts to <5.0. The data are consistent with a
      mechanism requiring Glu14 for both substrate and proton recognition. We propose a
      model in which two of the three Glu14s in the postulated trimeric EmrE
      homooligomer deprotonate upon ligand binding. The ligand is released on the other
      face of the membrane after binding of protons to Glu14.

PMID- 10637228
TI  - D-TACC: a novel centrosomal protein required for normal spindle function in the
      early Drosophila embryo.
AB  - We identify Drosophila TACC (D-TACC) as a novel protein that is concentrated at
      centrosomes and interacts with microtubules. We show that D-TACC is essential for
      normal spindle function in the early embryo; if D-TACC function is perturbed by
      mutation or antibody injection, the microtubules emanating from centrosomes in
      embryos are short and chromosomes often fail to segregate properly. The C
      terminal region of D-TACC interacts, possibly indirectly, with microtubules, and
      can target a heterologous fusion protein to centrosomes and microtubules in
      embryos. This C-terminal region is related to the mammalian transforming, acidic,
      coiled-coil-containing (TACC) family of proteins. The function of the TACC
      proteins is unknown, but the genes encoding the known TACC proteins are all
      associated with genomic regions that are rearranged in certain cancers. We show
      that at least one of the mammalian TACC proteins appears to be associated with
      centrosomes and microtubules in human cells. We propose that this conserved C
      terminal 'TACC domain' defines a new family of microtubule-interacting proteins.

PMID- 10637229
TI  - AHR38, a homolog of NGFI-B, inhibits formation of the functional ecdysteroid
      receptor in the mosquito Aedes aegypti.
AB  - In anautogenous mosquitoes, vitellogenesis, the key event in egg maturation,
      requires a blood meal. Consequently, mosquitoes are vectors of numerous
      devastating human diseases. After ingestion of blood, 20-hydroxyecdysone
      activates yolk protein precursor (YPP) genes in the metabolic tissue, the fat
      body. An important adaptation for anautogenicity is the previtellogenic
      developmental arrest (the state-of-arrest) preventing the activation of YPP genes
      in previtellogenic females prior to blood feeding. Here, we show that a retinoid
      X receptor homolog, Ultraspiracle (AaUSP), which is an obligatory partner in the
      functional ecdysteroid receptor, exists at the state-of-arrest as a heterodimer
      with the orphan nuclear receptor AHR38, a homolog of Drosophila DHR38 and nerve
      growth factor-induced protein B. Yeast two-hybrid and glutathione S-transferase
      pull-down assays demonstrate that AHR38 can interact strongly with AaUSP. AHR38
      also disrupts binding of ecdysteroid receptor to ecdysone response elements. Cell
      co-transfection of AHR38 with AaEcR and AaUSP inhibits ecdysone-dependent
      activation of a reporter gene by the ecdysteroid receptor. Co-immunoprecipitation
      experiments indicate that AaUSP protein associates with AHR38 instead of AaEcR in
      fat body nuclei at the state-of-arrest.

PMID- 10637230
TI  - Regulation of c-myc expression by IFN-gamma through Stat1-dependent and 
      independent pathways.
AB  - Interferons (IFNs) inhibit cell growth in a Stat1-dependent fashion that involves
      regulation of c-myc expression. IFN-gamma suppresses c-myc in wild-type mouse
      embryo fibroblasts, but not in Stat1-null cells, where IFNs induce c-myc mRNA
      rapidly and transiently, thus revealing a novel signaling pathway. Both tyrosine
      and serine phosphorylation of Stat1 are required for suppression. Induced
      expression of c-myc is likely to contribute to the proliferation of Stat1-null
      cells in response to IFNs. IFNs also suppress platelet-derived growth factor
      (PDGF)-induced c-myc expression in wild-type but not in Stat1-null cells. A gamma
      activated sequence element in the promoter is necessary but not sufficient to
      suppress c-myc expression in wild-type cells. In PKR-null cells, the
      phosphorylation of Stat1 on Ser727 and transactivation are both defective, and c
      myc mRNA is induced, not suppressed, in response to IFN-gamma. A role for Raf-1
      in the Stat1-independent pathway is revealed by studies with geldanamycin, an
      HSP90-specific inhibitor, and by expression of a mutant of p50(cdc37) that is
      unable to recruit HSP90 to the Raf-1 complex. Both agents abrogated the IFN-gamma
      dependent induction of c-myc expression in Stat1-null cells.

PMID- 10637231
TI  - A nuclear tyrosine phosphorylation circuit: c-Jun as an activator and substrate
      of c-Abl and JNK.
AB  - The nuclear function of the c-Abl tyrosine kinase is not well understood. In
      order to identify nuclear substrates of Abl, we constructed a constitutively
      active and nuclear form of the protein. We found that active nuclear Abl
      efficiently phosphorylate c-Jun, a transcription factor not previously known to
      be tyrosine phosphorylated. After phosphorylation of c-Jun by Abl on Tyr170, both
      proteins interacted via the SH2 domain of Abl. Surprisingly, elevated levels of c
      Jun activated nuclear Abl, resulting in activation of the JNK serine/threonine
      kinase. This phosphorylation circuit generates nuclear tyrosine phosphorylation
      and represents a reversal of previously known signalling models.

PMID- 10637232
TI  - Feedback-regulated degradation of the transcriptional activator Met4 is triggered
      by the SCF(Met30 )complex.
AB  - Saccharomyces cerevisiae SCF(Met30) ubiquitin-protein ligase controls cell cycle
      function and sulfur amino acid metabolism. We report here that the SCF(Met30
      )complex mediates the transcriptional repression of the MET gene network by
      triggering degradation of the transcriptional activator Met4p when intracellular
      S-adenosylmethionine (AdoMet) increases. This AdoMet-induced Met4p degradation is
      dependent upon the 26S proteasome function. Unlike Met4p, the other components of
      the specific transcriptional activation complexes that are assembled upstream of
      the MET genes do not appear to be regulated at the protein level. We provide
      evidence that the interaction between Met4p and the F-box protein Met30p occurs
      irrespective of the level of intracellular AdoMet, suggesting that the timing of
      Met4p degradation is not controlled by its interaction with the SCF(Met30)
      complex. We also demonstrate that Met30p is a short-lived protein, which
      localizes within the nucleus. Furthermore, transcription of the MET30 gene is
      regulated by intracellular AdoMet levels and is dependent upon the Met4p
      transcription activation function. Thus Met4p appears to control its own
      degradation by regulating the amount of assembled SCF(Met30) ubiquitin ligase.

PMID- 10637233
TI  - Identification of an erythroid-enriched endoribonuclease activity involved in
      specific mRNA cleavage.
AB  - Stability of the human alpha-globin mRNA is conferred by a ribonucleoprotein
      complex termed the alpha-complex, which acts by impeding deadenylation. Using our
      recently devised in vitro decay assay, we demonstrate that the alpha-complex also
      functions by protecting the 3'-untranslated region (3'-UTR) from an erythroid
      enriched, sequence-specific endoribonuclease activity. The cleavage site was
      mapped to a region protected by the alpha-complex and is regulated by the
      presence of the alpha-complex. Similar endoribonuclease cleavage products were
      also detected in erythroid cells expressing an exogenous alpha-globin gene.
      Nucleotide substitution of the target sequence renders the RNA refractory to the
      endoribonuclease activity. Insertion of the target sequence onto a heterologous
      RNA confers sequence-specific cleavage on the chimeric RNA, demonstrating the
      sequence specificity of this activity. We conclude that the alpha-complex
      stabilizes the alpha-globin mRNA in erythroid cells by a multifaceted approach,
      one aspect of which is to protect the 3'-UTR from specific endoribonuclease
      cleavage.

PMID- 10637235
TI  - Waiting for the definitive trial of hepatic arterial chemotherapy for colorectal
      cancer.

PMID- 10637234
TI  - A novel RNA binding protein, SBP2, is required for the translation of mammalian
      selenoprotein mRNAs.
AB  - In eukaryotes, the decoding of the UGA codon as selenocysteine (Sec) requires a
      Sec insertion sequence (SECIS) element in the 3' untranslated region of the mRNA.
      We purified a SECIS binding protein, SBP2, and obtained a cDNA clone that encodes
      this activity. SBP2 is a novel protein containing a putative RNA binding domain
      found in ribosomal proteins and a yeast suppressor of translation termination. By
      UV cross-linking and immunoprecipitation, we show that SBP2 specifically binds
      selenoprotein mRNAs both in vitro and in vivo. Using (75)Se-labeled Sec
      tRNA(Sec), we developed an in vitro system for analyzing Sec incorporation in
      which the translation of a selenoprotein mRNA was both SBP2 and SECIS element
      dependent. Immunodepletion of SBP2 from the lysates abolished Sec insertion,
      which was restored when recombinant SBP2 was added to the reaction. These results
      establish that SBP2 is essential for the co-translational insertion of Sec into
      selenoproteins. We hypothesize that the binding activity of SBP2 may be involved
      in preventing termination at the UGA/Sec codon.

PMID- 10637236
TI  - Randomized, multicenter trial of fluorouracil plus leucovorin administered either
      via hepatic arterial or intravenous infusion versus fluorodeoxyuridine
      administered via hepatic arterial infusion in patients with nonresectable liver
      metastases from colorectal carcinoma.
AB  - PURPOSE: To assess the efficacy and tolerability of three treatments for patients
      with documented adenocarcinoma of the colon and/or rectum who have undergone
      complete resection of primary tumor and have nonresectable liver metastases that
      do not exceed 75% of the liver volume. PATIENTS AND METHODS: A total of 168
      patients at 25 treatment centers were enrolled onto this prospective,
      multicenter, randomized study. The three treatment arms were as follows: (1)
      fluorouracil (5-FU)/leucovorin (LV) administered via hepatic arterial infusion
      (HAI), (2) 5-FU/LV administered via intravenous (IV) infusion, and (3)
      fluorodeoxyuridine (FUDR) administered via HAI. RESULTS: Median times to disease
      progression for the three treatment arms were as follows: 9.2 months for patients
      treated with HAI 5-FU/LV, 6.6 months for IV 5-FU/LV, and 5.9 months for HAI FUDR.
      Median survival times for patients treated with HAI 5-FU/LV, IV 5-FU/LV, and HAI
      FUDR were 18.7 months, 17.6 months, and 12.7 months, respectively. There was a
      nearly two-fold increase in time to progression in addition to a survival benefit
      among patients with an intrahepatic tumor burden of less than 25% who were
      treated with HAI 5-FU/LV. The most common adverse events were stomatitis, nausea
      and vomiting, skin irritation, diarrhea, and elevated serum levels of liver
      enzymes. Some patients exhibited severe reactions, including biliary sclerosis
      and chemical hepatitis. CONCLUSION: Although the use of HAI 5-FU/LV as a means of
      treating liver metastases after resection of colorectal carcinoma warrants
      further investigation, it cannot be recommended as a routine therapeutic measure
      at this time.

PMID- 10637237
TI  - Enhancement of fluorouracil uptake in human colorectal and gastric cancers by
      interferon or by high-dose methotrexate: An in vivo human study using noninvasive
      (19)F-magnetic resonance spectroscopy.
AB  - PURPOSE: To study whether two modulators, high-dose methotrexate (MTX) and
      interferon alfa-2a (IFNalpha-2a) will alter the intratumoral pharmacokinetics of
      fluorouracil (5-FU). PATIENTS AND METHODS: Five patients, two with gastric cancer
      and three with colorectal cancer, who had metastatic tumor nodules in their
      livers were studied dynamically in vivo after 5-FU injection. In a magnetic
      resonance imaging unit, noninvasive (19)F-magnetic resonance spectroscopy (MRS)
      was used to detect (19)F signals from 5-FU and its metabolites. RESULTS: The
      intratumoral half-life (t(1/2)) of 5-FU in these tumors ranged from 18.8 minutes
      to 42.3 minutes. Four of the five patients exhibited increases in the t(1/2) of 5
      FU after intravenous (IV) administration of MTX or IFNalpha-2a. In the two
      patients with gastric cancer who received IV high-dose MTX followed by IV 5-FU,
      increases were seen in either the total t(1/2) of 5-FU (41.8%) or in the t(1/2)
      of the alpha phase (150%). In the three patients with colorectal cancer who
      received IV IFNalpha-2a followed by IV 5-FU, the two patients with partial
      responses had increases in the t(1/2) of 5-FU of 41% and 30.2%, whereas the
      nonresponder had a nonsignificant increase (5.6%) in the t(1/2) of 5-FU.
      CONCLUSIONS: These results document that the in vivo modulation of the tumoral
      pharmacokinetics of 5-FU can be measured noninvasively by (19)F-MRS and suggest
      that such information correlates with subsequent clinical outcomes. The findings
      also indicate that IFNalpha-2a and high-dose MTX can increase the intratumoral 5
      FU in some patients. Such information, obtained prospectively in vivo, may assist
      in better individual cancer patient management and in developing novel drug
      combinations.

PMID- 10637238
TI  - Comparison of chemotherapy with chemohormonal therapy as first-line therapy for
      metastatic, hormone-sensitive breast cancer: An Eastern Cooperative Oncology
      Group study.
AB  - PURPOSE: Although hormonal therapy represents standard therapy for metastatic
      hormone-sensitive disease, many patients receive initial chemotherapy because of
      the location, bulk, or aggressiveness of their disease. It is uncertain whether
      simultaneous hormonal therapy provides additional benefit compared with
      chemotherapy alone. Eastern Cooperative Oncology Group trial E3186 was initiated
      to explore this question. PATIENTS AND METHODS: Between January 1988 and December
      1992, 231 patients with estrogen receptor (ER)-positive or ER-unknown metastatic
      breast cancer were randomized to receive either chemotherapy (cyclophosphamide,
      doxorubicin, and fluorouracil ?CAF) or chemohormonal therapy (CAF plus tamoxifen
      and Halotestin ?fluoxymesterone; Pharmacia-Upjohn, Kalamazoo, MI ?CAFTH) as front
      line therapy for metastatic breast cancer. Patients who experienced a complete
      response to induction therapy either received or did not receive maintenance
      cyclophosphamide, methotrexate, fluorouracil, prednisone, and TH as a secondary
      randomization. RESULTS: The response rates (complete response and partial
      response) of patients who received CAF and CAFTH were similar (69.2% v 68.9%,
      respectively; P =.99). Time to treatment failure (TTF) was slightly longer for
      patients who received chemohormonal therapy compared with chemotherapy alone
      patients (13.4 months v 10.3 months, respectively; P =.087), and TTF was
      significantly longer in ER-positive compared with ER-negative patients (17.4
      months v 10.3 months, respectively; P =.048). However, ER status had no effect on
      overall survival (30.0 months for CAF v 29.3 months for CAFTH). CONCLUSION: In
      patients with potentially hormone-sensitive metastatic breast cancer,
      chemohormonal therapy prolongs TTF for ER-positive patients without improving
      overall survival.

PMID- 10637239
TI  - HER-2/neu amplification in benign breast disease and the risk of subsequent
      breast cancer.
AB  - PURPOSE: The purpose of this study was to determine whether the presence of HER
      2/neu gene amplification and/or overexpression in benign breast disease was
      associated with an increased risk of subsequent breast cancer. PATIENTS AND
      METHODS: We conducted a nested case-control study of a cohort of women who were
      diagnosed with benign breast disease at the Mayo Clinic and who were subsequently
      observed for the development of breast cancer. Patients who developed breast
      cancer formed the case group, and a matched sample from the remaining cohort
      served as controls. Benign tissue samples from 137 cases and 156 controls and
      malignant tissues from 99 cases provided DNA or tissue for evaluation of HER
      2/neu amplification and protein overexpression. RESULTS: Among the controls,
      seven benign tissues (4.5%) demonstrated low-level HER-2/neu amplification,
      whereas 13 benign (9.5%) and 18 malignant (18%) tissue specimens from cases
      exhibited amplification. HER-2/neu amplification in benign breast biopsies was
      associated with an increased risk of breast cancer (odds ratio ?OR = 2.2; 95%
      confidence interval ?CI, 0.9 to 5.8); this association approached statistical
      significance. The risks for breast cancer associated with benign breast
      histopathologic diagnoses were OR = 1.1 (95% CI, 0.6 to 1.9) for lesions
      exhibiting proliferation without atypia and OR = 1.5 (95% CI, 0.4 to 5.6) for the
      diagnosis of atypical ductal hyperplasia. For women having both HER-2/neu
      amplification and a proliferative histopathologic diagnosis (either typical or
      atypical), the risk of breast cancer was more than seven-fold (OR = 7.2; 95% CI,
      0.9 to 60.8). Overexpression of the HER-2/neu protein product, defined as
      membrane staining in 10% or more of epithelial cells, was found in 30% of the
      breast tumors but was not detected in any of the benign breast tissues. Case
      patients who had HER-2/neu gene amplification in their malignant tumor were more
      likely to have had HER-2/neu amplification in their prior benign biopsy (P =.06,
      Fisher's exact test). CONCLUSION: Women with benign breast biopsies demonstrating
      both HER-2/neu amplification and a proliferative histopathologic diagnosis may be
      at substantially increased risk for subsequent breast cancer.

PMID- 10637240
TI  - Pilot trial of the safety, tolerability, and retinoid levels of N-(4
      hydroxyphenyl) retinamide in combination with tamoxifen in patients at high risk
      for developing invasive breast cancer.
AB  - PURPOSE: N-(4-hydroxyphenyl) retinamide (?4-HPR, Fenretinide; R.W. Johnson
      Pharmaceutical Research Institute, Springhouse, PA) and tamoxifen (TAM) have
      synergistic antitumor and chemopreventive activity against mammary cancer in
      preclinical studies. We performed a pilot study of this combination in women at
      high risk for developing breast cancer. PATIENTS AND METHODS: Thirty-two women
      were treated with four cycles of 4-HPR, 200 mg orally (PO) for 25 days of each 28
      day cycle, and TAM, 20 mg PO once daily for 23 months beginning after 1 month of
      4-HPR alone. Tolerability, dark adaptometry, tissue biopsies, and retinoid plasma
      concentrations (Cp) were evaluated. RESULTS: Symptomatic reversible nyctalopia
      developed in two patients (6%) on 4-HPR, but 16 (73%) of 22 patients had
      reversible changes in dark adaptation, which correlated with relative decrease in
      Cp retinol (P </=.01). Four patients stopped treatment for side effects, and 84%
      of patients had hot flashes. Other commonly reported (grade </= 2) reversible
      toxicities included skin and ocular dryness, fatigue, and mood changes. Serum
      high-density lipoprotein increased and cholesterol decreased from baseline to
      month 4. Baseline mean +/- SD Cp retinol was 708 +/- 280 ng/mL. Mean +/- SD Cp of
      4-HPR, N-(4-methoxyphenyl) retinamide (4-MPR), and retinol after 1 month of 4-HPR
      were 0.34 +/- 0.21 micromol/L, 0.28 +/- 0.21 micromol/L, and 282 +/- 127 ng/mL,
      respectively. Mean retinoid Cps did not change after 3 months of 4-HPR + TAM.
      CONCLUSIONS: TAM administration did not affect Cp 4-HPR or 4-MPR. Reversible
      nyctalopia correlated with relative decrease in Cp retinol but was not
      symptomatic for most patients. TAM + 4-HPR has acceptable tolerability for this
      high-risk cohort.

PMID- 10637241
TI  - Tamoxifen should be cost-effective in reducing breast cancer risk in high-risk
      women.
AB  - PURPOSE: To estimate the cost-effectiveness of tamoxifen in the prevention of
      breast cancer. PATIENTS AND METHODS: Clinical trial results of National Surgical
      Adjuvant Breast Program P-1 compared tamoxifen versus placebo in the prevention
      of breast cancer, and direct medical care costs were estimated from the Agency
      for Health Care Policy and Research and local sources. The base estimate of
      effectiveness included all women on the trial. RESULTS: For every 100 women
      treated for 5 years, 1.665 expected cancers would not be detected. If breast
      cancer death is fully prevented by this strategy, then the cost-effectiveness of
      tamoxifen compared with no intervention is $8,479 per additional year of life
      gained. If lifetime prevention of the risk of death from breast cancer exceeded
      17%, then the cost-effectiveness ratio would be less than $50,000 per year of
      life gained (a common benchmark). CONCLUSIONS: Tamoxifen for breast cancer
      prevention should be cost-effective under nearly all circumstances. Its use will
      require additional resources because it is not cost saving, but it fits within
      accepted guidelines.

PMID- 10637242
TI  - Cost-effectiveness of adding an electron-beam boost to tangential radiation
      therapy in patients with negative margins after conservative surgery for early
      stage breast cancer.
AB  - PURPOSE: Electron-beam boosts (EBB) are routinely added after conservative
      surgery and tangential radiation therapy (TRT) for early-stage breast cancer. We
      performed an incremental cost-utility analysis to evaluate their cost
      effectiveness. METHODS: A Markov model examined the impact of adding an EBB to
      TRT from a societal perspective. Outcomes were measured in quality-adjusted life
      years (QALYs). On the basis of the Lyon trial, the EBB was assumed to reduce
      local recurrences by approximately 2% at 10 years but to have no impact on
      survival. Patients' utilities were used to adjust for quality of life. Given the
      small absolute benefit of the EBB, baseline utilities were assumed to be the same
      with or without it, an assumption evaluated by Monte Carlo simulation. Direct
      medical, time, and travel costs were considered. RESULTS: Adding the EBB led to
      an additional cost of $2,008, an increase of 0.0065 QALYs and, therefore, an
      incremental cost-effectiveness ratio of over $300,000/QALY. In a sensitivity
      analysis, the ratio was moderately sensitive to the efficacy and cost of the EBB
      and highly sensitive to patients' utilities for treatment without it. Even if
      patients do value a small risk reduction, the mean cost-effectiveness ratio
      estimated by the Monte Carlo simulation remains high, at $70,859/QALY (95%
      confidence interval, $53,141 to $105,182/QALY). CONCLUSION: On the basis of
      currently available data, the cost-effectiveness ratio for the EBB is well above
      the commonly cited threshold for cost-effective care ($50,000/QALY). The EBB
      becomes cost-effective only if patients place an unexpectedly high value on the
      small absolute reduction in local recurrences achievable with it.

PMID- 10637243
TI  - Impact of young age on outcome in patients with ductal carcinoma-in-situ treated
      with breast-conserving therapy.
AB  - PURPOSE: We reviewed our institution's experience treating patients with ductal
      carcinoma-in-situ (DCIS) with breast-conserving therapy (BCT) to determine the
      impact of patient age on outcome. PATIENTS AND METHODS: From 1980 to 1993, 146
      patients were treated with BCT for DCIS. All patients underwent excisional
      biopsy, and 64% underwent re-excision. All patients received whole-breast
      irradiation to a median dose of 45 Gy. Ninety-four percent of patients received a
      boost to the tumor bed, for a median total dose of 60.4 Gy. All slides on every
      patient were reviewed by one pathologist. The median follow-up period was 7.2
      years. RESULTS: Seventeen patients developed an ipsilateral local recurrence, for
      5- and 10-year actuarial rates of 10.2% and 12.4%, respectively. The 10-year rate
      of ipsilateral failure was 26.1% in patients younger than 45 years of age versus
      8.6% in older patients (P =.03). On multivariate analysis, young age was
      independently associated with recurrence of the index lesion (true
      recurrence/marginal miss ?TR/MM failures), regardless of how it was analyzed (eg,
      < 45 years of age or as a continuous variable). In addition, young patients had a
      dramatically higher 10-year rate of invasive TR/MM failures (19.9% v 3.2%). In a
      separate multivariate analysis for the development of invasive TR/MM failures,
      only patient age and predominant nuclear grade were independently associated with
      recurrence. The relationship between excision volume and outcome was analyzed in
      the 95 patients who underwent re-excision. The 5-year actuarial rate of TR/MM
      failure was significantly worse only in young patients with smaller (< 40 mL) re
      excision volumes (33.3% v 9.1%; P =.02). In a separate multivariate analysis of
      only these 95 patients (25 of whom were < 45 years of age), the volume of re
      excision had the strongest association with outcome (P =.05). Patient age was no
      longer associated with local recurrence. CONCLUSION: These findings suggest that
      young patients with DCIS have a significantly greater risk of local recurrence
      after BCT that is independent of other previously defined risk factors. Our data
      also suggest that the extent of resection may in part be related to the less
      optimal results that are observed in these patients.

PMID- 10637244
TI  - Rapid hematopoietic recovery after coinfusion of autologous-blood stem cells and
      culture-expanded marrow mesenchymal stem cells in advanced breast cancer patients
      receiving high-dose chemotherapy.
AB  - PURPOSE: Multipotential mesenchymal stem cells (MSCs) are found in human bone
      marrow and are shown to secrete hematopoietic cytokines and support hematopoietic
      progenitors in vitro. We hypothesized that infusion of autologous MSCs after
      myeloablative therapy would facilitate engraftment by hematopoietic stem cells,
      and we investigated the feasibility, safety, and hematopoietic effects of culture
      expanded MSCs in breast cancer patients receiving autologous peripheral-blood
      progenitor-cell (PBPC) infusion. PATIENTS AND METHODS: We developed an efficient
      method of isolating and culture-expanding a homogenous population of MSCs from a
      small marrow-aspirate sample obtained from 32 breast cancer patients. Twenty
      eight patients were given high-dose chemotherapy and autologous PBPCs plus
      culture-expanded MSC infusion and daily granulocyte colony-stimulating factor.
      RESULTS: Human MSCs were successfully isolated from a mean +/- SD of 23.4 +/- 5.9
      mL of bone marrow aspirate from all patients. Expansion cultures generated
      greater than 1 x 10(6) MSCs/kg for all patients over 20 to 50 days with a mean
      potential of 5.6 to 36.3 x 10(6) MSCs/kg after two to six passages, respectively.
      Twenty-eight patients were infused with 1 to 2.2 x 10(6) expanded autologous
      MSCs/kg intravenously over 15 minutes. There were no toxicities related to the
      infusion of MSCs. Clonogenic MSCs were detected in venous blood up to 1 hour
      after infusion in 13 of 21 patients (62%). Median time to achieve a neutrophil
      count greater than 500/microL and platelet count >/= 20,000/microL untransfused
      was 8 days (range, 6 to 11 days) and 8.5 days (range, 4 to 19 days),
      respectively. CONCLUSION: This report is the first describing infusion of
      autologous MSCs with therapeutic intent. We found that autologous MSC infusion at
      the time of PBPC transplantation is feasible and safe. The observed rapid
      hematopoietic recovery suggests that MSC infusion after myeloablative therapy may
      have a positive impact on hematopoiesis and should be tested in randomized
      trials.

PMID- 10637245
TI  - European phase II study of rituximab (chimeric anti-CD20 monoclonal antibody) for
      patients with newly diagnosed mantle-cell lymphoma and previously treated mantle
      cell lymphoma, immunocytoma, and small B-cell lymphocytic lymphoma.
AB  - PURPOSE: Mantle-cell lymphoma (MCL), immunocytoma (IMC), and small B-cell
      lymphocytic lymphoma (SLL) are B-cell malignancies that express CD20 and are
      incurable with standard therapy. A multicenter phase II study was conducted to
      assess the toxicity and the overall response rates (RR) and complete response
      (CR) rates to rituximab (chimeric anti-CD20 monoclonal antibody). PATIENTS AND
      METHODS: Between January 1997 and January 1998, 131 patients with newly diagnosed
      MCL (MCL1; n = 34) and previously treated MCL (MCL2; n = 40), IMC (n = 28), and
      SLL (n = 29) received rituximab 375 mg/m(2)/wk for 4 weeks via intravenous
      infusion. Restaging studies were performed 1 and 2 months after treatment. An
      analysis of the duration of response was conducted in December 1998. RESULTS:
      Eleven patients were unassessable, including one who died of splenic rupture
      after the first infusion. The RR among the 120 assessable patients was 30% (36 of
      120 patients). The RR by histology was as follows: MCL1, 38%; MCL2, 37%; IMC,
      28%; and SLL, 14%. Ten patients, all with MCL, achieved CR. The median duration
      of response in MCL was 1.2 years. Immediate side effects were common and usually
      responded to adjustments in the infusion rate. There were 31 episodes of
      infection after treatment; most cases were mild. Cardiac arrhythmia and
      ophthalmologic side effects occurred in 10 and nine patients, respectively,
      including one case of severe loss of visual acuity. CONCLUSION: Single-agent
      rituximab has moderate activity in MCL and IMC but only limited activity in SLL.
      The duration of response in MCL was similar to that previously reported in
      follicular lymphoma. Its use in combination with cytotoxic chemotherapy to
      increase the CR rate is warranted in MCL and IMC.

PMID- 10637246
TI  - Factors that predict chemotherapy-induced myelosuppression in lymphoma patients:
      role of the tumor necrosis factor ligand-receptor system.
AB  - PURPOSE: To analyze factors that predict the occurrence of chemotherapy-induced
      myelosuppression and, in particular, the role of the tumor necrosis factor (TNF)
      ligand-receptor system in lymphoma patients at the beginning of their treatment.
      PATIENTS AND METHODS: We investigated the predictive factors for myelosuppression
      after the first course of chemotherapy in a cohort of 101 consecutive, previously
      untreated lymphoma patients receiving regimens that include doxorubicin and
      cyclophosphamide. Plasma samples were tested at baseline by enzyme-linked
      immunosorbent assay for TNF and its soluble receptors. Univariate and
      multivariate analyses were performed with a forward regression procedure that
      included all of the parameters that were found to be significant in the
      univariate analysis. The dose of chemotherapy and the prophylactic treatment with
      granulocyte colony-stimulating factor were deliberately included in this model.
      RESULTS: Sixty-seven patients experienced World Health Organization (WHO) grade 4
      neutropenia, and 37 patients experienced febrile neutropenia, which was
      responsible for WHO grade 2 through 4 infections in 23 patients. In
      multiparametric regression analysis, the occurrence of grade 4 neutropenia was
      associated with high doses of cyclophosphamide (odds ratio ?OR, 19.8; P =.008)
      and high levels of soluble p75-R-TNF (OR, 8.52; P =.001). The duration of grade 4
      neutropenia for more than 5 days was associated with the lack of hematopoietic
      growth factor administration (OR, 6.76; P =.004) and high levels of soluble p75-R
      TNF (OR, 5.84; P =.0023). The occurrence of febrile neutropenia was associated
      with high doses of cyclophosphamide (OR, 4.7; P =.007), altered performance
      status (OR, 18.8; P <.0001) and high levels of soluble p75-R-TNF (OR, 3.49; P
      =.029). CONCLUSION: This study indicates that in addition to the dose of
      chemotherapy and the administration of hematopoietic growth factors, poor
      performance status and high p75-R-TNF levels can predict the occurrence of
      chemotherapy-induced myelosuppression in lymphoma patients. This model may help
      in selecting patients for prophylactic growth factor administration.

PMID- 10637247
TI  - Treatment of primary progressive Hodgkin's and aggressive non-Hodgkin's lymphoma:
      is there a chance for cure?
AB  - PURPOSE: To determine differences in prognosis between primary progressive
      Hodgkin's disease (HD) and aggressive non-Hodgkin's lymphoma (NHL), we
      retrospectively analyzed patients with progressive lymphoma who were treated with
      different salvage chemotherapy regimens including high-dose chemotherapy (HDCT)
      followed by autologous stem-cell support (ASCT). PATIENTS AND METHODS: One
      hundred thirty-one patients with primary progressive lymphoma (HD, n = 67; NHL, n
      = 64) were enrolled. Primary progressive disease was defined as disease
      progression during first-line chemotherapy or only transient response (complete
      or partial response lasting </= 90 days) after induction treatment. Patients 60
      years or younger with progressive lymphoma were eligible to receive HDCT with
      ASCT. RESULTS: The overall response rate after salvage chemotherapy for patients
      with primary progressive HD and NHL was 33% and 15%, respectively. Twenty-five HD
      patients (37%) received HDCT. Most patients with NHL had progressive disease
      under salvage treatment, with only six patients (10%) receiving HDCT. Of those,
      only two patients were alive and in continuous complete remission 3 and 12 months
      after HDCT. No patient with NHL survived longer than 26 months after first
      diagnosis. Actuarial OS after 5 years was 19% for all HD patients; 53% for HD
      patients receiving HDCT, and 0% for patients who did not receive HDCT. In HD
      patients, multivariate regression analysis identified chemosensitive disease on
      salvage treatment (P =.0001) and HDCT (P =.031) as significant prognostic factors
      for freedom from treatment failure. Significant prognostic factors for OS are
      chemosensitive disease (P =.0005), HDCT (P =.039), and B symptoms at the time of
      progress (P =.046). CONCLUSION: There are striking differences in the prognosis
      of patients with progressive HD and aggressive NHL. The prognosis of progressive
      NHL patients is dismal. Most patients have rapidly progressive disease after
      salvage treatment and are, therefore, excluded from HDCT programs. In contrast,
      progressive HD patients can achieve long-term survival after HDCT.

PMID- 10637248
TI  - Comparison of preparative regimens in transplants for children with acute
      lymphoblastic leukemia.
AB  - PURPOSE: Preparative regimens involving total-body irradiation (TBI) produce
      significant late toxicities in some children who receive bone marrow transplants,
      including impaired growth and intellectual development. Busulfan is often used as
      an alternative to TBI, but there are few data regarding its relative efficacy.
      PATIENTS AND METHODS: We compared outcomes of HLA-identical sibling transplants
      for acute lymphoblastic leukemia (ALL) in children (< 20 years of age) who
      received cyclophosphamide plus TBI (CY/TBI) (n = 451) versus those who received
      busulfan plus cyclophosphamide (Bu/CY) (n = 176) for pretransplant conditioning.
      Patients received transplants between 1988 and 1995 and their results were
      reported to the International Bone Marrow Transplant Registry by 144
      participating institutions. The CY/TBI and Bu/CY groups did not differ in gender,
      immune phenotype, leukocyte count at the time of diagnosis, chromosome
      abnormalities, remission status, or length of initial remission. T-cell depletion
      was used more frequently in the CY/TBI group; the Bu/CY group included a higher
      proportion of children who were less than 5 years of age. The median follow-up
      period was 37 months. RESULTS: The 3-year probabilities of survival were 55% (95%
      confidence interval [CI], 50% to 60%) with TBI/CY and 40% (95% CI, 32% to 48%)
      with Bu/CY (univariate P =.003). The 3-year probabilities of leukemia-free
      survival were 50% (95% CI, 45% to 55%) and 35% (95% CI, 28% to 43%), respectively
      (univariate P =.005). In a multivariate analysis, the risks of relapse were
      similar in the two groups (relative risk [RR], 1.30 for Bu/CY v CY/TBI; P =.1).
      Treatment-related mortality was higher in the Bu/CY group (RR, 1.68; P =.012).
      Death and treatment failure (relapse or death, inverse of leukemia-free survival)
      were more frequent in the Bu/CY group (RR, 1. 39; P =.017 for death; RR, 1.42; P
      =.006 for treatment failure). CONCLUSION: These data indicate superior survival
      with CY/TBI conditioning, compared with Bu/CY conditioning, for HLA-identical
      sibling bone marrow transplants in children with ALL.

PMID- 10637249
TI  - New malignant diseases after allogeneic marrow transplantation for childhood
      acute leukemia.
AB  - PURPOSE: To determine the incidence of and risk factors for second malignancies
      after allogeneic bone marrow transplantation (BMT) for childhood leukemia.
      PATIENTS AND METHODS: We studied a cohort of 3, 182 children diagnosed with acute
      leukemia before the age of 17 years who received allogeneic BMT between 1964 and
      1992 at 235 centers. Observed second cancers were compared with expected cancers
      in an age- and sex-matched general population. Risks factors were evaluated using
      Poisson regression. RESULTS: Twenty-five solid tumors and 20 posttransplant
      lymphoproliferative disorders (PTLDs) were observed compared with 1.0 case
      expected (P <.001). Cumulative risk of solid cancers increased sharply to 11.0%
      (95% confidence interval, 2.3% to 19.8%) at 15 years and was highest among
      children at ages younger than 5 years at transplantation. Thyroid and brain
      cancers (n = 14) accounted for most of the strong age trend; many of these
      patients received cranial irradiation before BMT. Multivariate analyses showed
      increased solid tumor risks associated with high-dose total-body irradiation
      (relative risk [RR] = 3.1) and younger age at transplantation (RR = 3.7), whereas
      chronic graft-versus-host disease was associated with a decreased risk (RR =
      0.2). Risk factors for PTLD included chronic graft-versus-host disease (RR =
      6.5), unrelated or HLA-disparate related donor (RR = 7. 5), T-cell-depleted graft
      (RR = 4.8), and antithymocyte globulin therapy (RR = 3.1). CONCLUSION: Long-term
      survivors of BMT for childhood leukemia have an increased risk of solid cancers
      and PTLDs, related to both transplant therapy and treatment given before BMT.
      Transplant recipients, especially those given radiation, should be monitored
      closely for second cancers.

PMID- 10637250
TI  - Results and outcome of retroperitoneal lymph node dissection for clinical stage I
      embryonal carcinoma--predominant testis cancer.
AB  - PURPOSE: To determine the incidence of metastatic disease and usage of
      chemotherapy (adjuvant or metastatic) after primary retroperitoneal lymph node
      dissection (RPLND) in patients with clinical stage (CS) I embryonal carcinoma
      (EC)-predominant testicular cancer. EC predominance was defined as the presence
      of EC at a level greater than that of any other histologic diagnosis. PATIENTS
      AND METHODS: All CS I patients with nonseminomatous germ cell tumors who
      underwent RPLND at Indiana University from 1990 to 1995 were reviewed
      retrospectively. RESULTS: Two-year follow-up was available for 292 of 320
      patients. EC-predominant disease was found in 125 (42.8%) of 292. Eighty-five
      (68.0%) of 125 patients with EC-predominant disease had pathologic stage (PS) I,
      and 18 (21.2%) of this group of 85 relapsed. A significantly lower PS I relapse
      rate of 3% was found for patients who had non-EC-predominant disease (P <.0001).
      PS II disease was more frequent in patients with EC predominance, as 40 (32.0%)
      of 125 had retroperitoneal metastases, compared with 26 (15.6%) of 167 patients
      with a non-EC-predominant histologic diagnosis (P =.0024). Chemotherapy was
      administered to 48 (38.4%) of the 125 patients with CS I EC-predominant disease
      after RPLND. This included 25 CS I patients with PS II disease who received
      adjuvant chemotherapy in addition to 23 patients who subsequently required
      chemotherapy for relapse after RPLND. Ten (66. 6%) of 15 PS II EC-predominant
      patients were cured by surgery alone. Currently, all 125 EC-predominant patients
      are disease-free. CONCLUSION: Patients with CS I EC-predominant disease are at a
      relatively high risk for metastatic disease.

PMID- 10637251
TI  - Targeting superficial bladder cancer by the intravesical administration of copper
      67-labeled anti-MUC1 mucin monoclonal antibody C595.
AB  - PURPOSE: More effective intravesical agents are required to limit the recurrence
      and progression of superficial bladder cancer. This study assessed the ability of
      copper-67 ((67)Cu)-C595 murine antimucin monoclonal antibody to bind selectively
      to superficial bladder tumors when administered intravesically, with a view to
      its development for therapy. PATIENTS AND METHODS: Approximately 20 MBq of (67)Cu
      C595 monoclonal antibody was administered intravesically to 16 patients with a
      clinical indication of superficial bladder cancer. After 1 hour, the bladder was
      drained and irrigated. Tissue uptake was assessed by imaging and by the assay of
      tumor and normal tissues obtained by endoscopic resection. RESULTS: Tumor was
      correctly identified in the images of 12 of 15 patients who were subsequently
      found to have tumors. Assay of biopsy samples at 2 hours showed a mean tumor
      uptake of 59.4% of the injected dose per kilogram (SD = 48.0), with a tumor-to
      normal tissue ratio of 14.6:1 (SD = 20). After 24 hours (n = 5), this decreased
      to 4.3% of the injected dose per kilogram (SD = 2.9), with a tumor-to-normal
      tissue ratio of 1.8:1 (SD = 0.8). CONCLUSION: This study indicates a promising
      method for the treatment of superficial bladder cancer. Although the mean initial
      tumor uptake was high, effective therapy of bladder tumors will require an
      increased retention of the cytotoxic radionuclide in tumor tissue.

PMID- 10637252
TI  - Flavopiridol, a novel cyclin-dependent kinase inhibitor, in metastatic renal
      cancer: a University of Chicago Phase II Consortium study.
AB  - PURPOSE: Flavopiridol is the first cyclin-dependent kinase (cdk) inhibitor to
      enter clinical trials. Serum levels of flavopiridol obtained during phase I
      studies were sufficient to inhibit in vitro cancer cell growth. Because responses
      were observed in kidney cancer patients in the phase I trials, we performed a
      phase II trial of flavopiridol in this patient population. PATIENTS AND METHODS:
      Thirty-five minimally pretreated patients were accrued using a standard two-step
      mechanism. Flavopiridol (50 mg/m(2)/d) was administered by continuous infusion
      for 72 hours every 2 weeks, and response was evaluated every 8 weeks. Peripheral
      blood mononuclear cells (PBMCs) were collected at baseline, at completion of drug
      infusion, and on day 7 of the first therapy cycle, and cell cycle parameters
      after phytohemagglutinin and interleukin-2 stimulation were assessed. RESULTS:
      There were two objective responses (response rate = 6%, 95% confidence interval,
      1% to 20%). The most common toxicities were asthenia, occurring in 83% of
      patients (grade 3 or 4 in 9%), and diarrhea, occurring in 77% of patients (grade
      3 or 4 in 20%). Also, nine patients (26%) experienced grade 3 or 4 vascular
      thrombotic events, including one myocardial infarction, two transient neurologic
      ischemic attacks, four deep venous thrombosis, and two pulmonary emboli. Cell
      cycle studies did not reveal any effect of flavopiridol on stimulated PBMCs.
      CONCLUSION: Flavopiridol, at the dose and schedule administered in this trial, is
      ineffective in metastatic renal cancer. In addition to the diarrhea observed in
      phase I studies, we also observed a higher incidence of asthenia and serious
      vascular thrombotic events than expected.

PMID- 10637253
TI  - Clinical and immune responses in advanced melanoma patients immunized with an
      anti-idiotype antibody mimicking disialoganglioside GD2.
AB  - PURPOSE: To determine immune responses and toxicity to the anti-idiotype vaccine,
      as well as clinical responses and survival, we initiated a clinical trial for
      patients with advanced melanoma treated with an anti-idiotype antibody (TriGem)
      that mimics the disialoganglioside GD2. PATIENTS AND METHODS: Forty-seven
      patients with advanced melanoma received either 1-, 2-, 4-, or 8-mg doses of
      TriGem (Titan Pharmaceuticals Inc, South San Francisco, CA) mixed with QS-21
      adjuvant (Aquila Biopharmaceuticals, Inc, Worcester, MA) 100 microg
      subcutaneously weekly for 4 weeks and then monthly until disease progression.
      Median age was 57 years, there were 32 men and 15 women, 43% of patients had
      undergone prior therapy for metastatic disease, 55% had disease confined to soft
      tissue, and 45% had visceral metastasis. RESULTS: Hyperimmune sera from 40 of 47
      patients showed an anti-anti-idiotype (Ab3) response. Patient Ab3 was truly Ab1'
      because it specifically bound purified disialoganglioside GD2. The isotypic
      specificity of the Ab3 antibody consisted of predominantly immunoglobulin (Ig)G,
      and all IgG subclasses were represented. One patient had a complete response that
      persisted at 24 months, and 12 patients were stable from 14+ to 37+ months
      (median, 18+ months). Disease progression occurred in 32 patients on study from 1
      to 17 months (median, 5.5 months), and 21 have died at 1 to 16 months (median, 6
      months). The Kaplan-Meier-derived overall median survival has not been reached.
      Median survival has not been reached for the 26 patients with soft tissue disease
      only and was 13 months for 21 patients with visceral metastasis. Toxicity
      consisted of local reaction at the site of injection and mild fever and chills.
      CONCLUSION: TriGem has minimal toxicity and generates robust and specific IgG
      immune responses against GD2. Objective responses were minimal, but there may be
      a favorable impact on disease progression and survival that will require
      prospective randomized trials.

PMID- 10637254
TI  - p53 gene status as a predictor of tumor response to induction chemotherapy of
      patients with locoregionally advanced squamous cell carcinomas of the head and
      neck.
AB  - PURPOSE: To determine whether p53 gene status predicts tumor responses to
      platinum- and fluorouracil-based induction chemotherapy in locoregionally
      advanced squamous cell carcinomas of the head and neck. PATIENTS AND METHODS:
      Tumor responses of 105 patients were measured at the primary tumor site.
      Objective response and major response were defined by a 50% and 80% reduction in
      tumor size, respectively. All coding parts of p53 gene were directly sequenced.
      p53 expression in tumor cells was determined by immunohistochemistry. Human
      papillomavirus infection was detected by polymerase chain reaction. Odd ratios
      were adjusted by stepwise logistic regression analysis. RESULTS: p53 mutations,
      p53 expression, and tumor stage were sufficient to explain the variation in tumor
      responses to chemotherapy in multivariate models. p53 mutation was the only
      variable to significantly predict objective response (odds ratio, 0. 23; 95%
      confidence interval, 0.10 to 0.57; P =.002) and was the strongest predictor of
      major response (odds ratio, 0.29; 95% confidence interval, 0.11 to 0.74; P
      =.006). p53 expression (odds ratio, 0.39; 95% confidence interval, 0.16 to 0.98)
      and tumor stage (odds ratio, 0.31; 95% confidence interval, 0.10 to 0.96) also
      predicted major response. Specific mutations (contact mutations) accounted for
      much of the reduction in the risk of major response associated with overall
      mutations. In complementary analyses, p53 expression was weakly predictive of
      major response in the subgroup with wild-type p53, and p53 mutations also
      predicted histologic response. CONCLUSION: p53 gene mutations are strongly
      associated with a poor risk of both objective and major responses to
      chemotherapy. Contact mutations are associated with the lowest risk of major
      response to chemotherapy.

PMID- 10637255
TI  - Improving survival without reducing quality of life in small-cell lung cancer
      patients by increasing the dose-intensity of chemotherapy with granulocyte colony
      stimulating factor support: results of a British Medical Research Council
      Multicenter Randomized Trial. Medical Research Council Lung Cancer Working Party.
AB  - PURPOSE: The treatment of small-cell lung cancer patients with good performance
      status aims to improve survival. Dose-intensification could be a way to achieve
      improved survival but can be limited by neutropenia and thrombocytopenia.
      Preliminary, nonrandomized feasibility studies showed that doxorubicin,
      cyclophosphamide, and etoposide (ACE) could be given every 2 (instead of the
      usual 3) weeks with granulocyte colony-stimulating factor (G-CSF) (lenograstim;
      Chugai-Rh?one-Poulenc, Tokyo, Japan) support. The present multicenter randomized
      trial was designed to examine whether such dose-intensification improves survival
      while maintaining acceptable toxicity levels. PATIENTS AND METHODS: All patients
      were randomized to receive six cycles of ACE either every 3 weeks (control [C]
      group) or every 2 weeks with G-CSF (G group). The standard dose-intensity of ACE
      was increased by 50% in group G. RESULTS: Four hundred and three patients (G
      group: n = 201; C group: n = 202) were randomized. The received dose-intensity
      was 34% higher in the G group than in the C group. Complete response rates were
      40% for the G group and 28% for the C group (P =.02), and overall rates were 78%
      for the G group and 79% for the C group. Survival was longer in the G group
      (hazard ratio = 0.80; 95% confidence interval, 0.65 to 0.99; P =.04), survival
      rates for the G and C groups being 47% and 39% at 12 months and 13% and 8% at 24
      months, respectively. Metastasis-free survival, nonhematologic toxicity, and
      quality of life were similar in the two groups. In the G group, there was less
      neutropenia but more thrombocytopenia and more frequent blood and platelet
      transfusions. CONCLUSION: Increasing the dose-intensity of ACE with G-CSF support
      improved survival while maintaining acceptable toxicity.

PMID- 10637256
TI  - Phase I/II study of gemcitabine plus vinorelbine as first-line chemotherapy of
      non-small-cell lung cancer.
AB  - PURPOSE: To determine the maximum-tolerated dose of gemcitabine when combined
      with a fixed dose of vinorelbine in the treatment of non-small-cell lung cancer
      (NSCLC) and to evaluate in a phase II trial the activity of this combination.
      PATIENTS AND METHODS: Sixty-eight patients with stage IIIB/IV NSCLC were treated
      with vinorelbine at fixed dose of 30 mg/m(2) intravenously and gemcitabine at
      increasing dose levels from 800 to 1,500 mg/m(2) intravenously on days 1 and 8
      every 3 weeks. RESULTS: In phase I, dose-limiting toxicity occurred at the dosage
      of 1,500 mg/m(2) gemcitabine, with three of five patients developing grade 4
      thrombocytopenia. In phase II, with gemcitabine at 1,200 mg/m(2), 19 (36%) of 52
      assessable patients responded. Objective response was observed in 11 (39%) of 28
      patients with stage IIIB disease and in eight (33%) of 24 patients with stage IV.
      The median time to progression was 29 weeks (range, 2 to 41 weeks; 35 weeks and
      16 weeks for stages IIIB and IV, respectively), and median survival was 54 weeks
      (range, 2 to 84+ weeks; 63 weeks and 42 weeks for stages IIIB and IV,
      respectively). One-year survival was 64% for patients with stage IIIB disease and
      29% for those with stage IV. Clinical benefit response was observed in 29 (59%)
      of 49 assessable patients. Grade 4 leukopenia and thrombocytopenia were uncommon
      (6% and 8% of cases, respectively); however, grade 3/4 leukothrombocytopenia
      occurred more frequently in patients aged more than 70 years (52% and 24%,
      respectively). CONCLUSION: The combination of vinorelbine and gemcitabine is
      effective and tolerable in the treatment of NSCLC, thus deserving randomized
      trials with cisplatin combination regimens.

PMID- 10637257
TI  - Sex differences in fluorouracil-induced stomatitis.
AB  - PURPOSE: A meta-analysis of six North Central Cancer Treatment Group (NCCTG)
      trials involving patients receiving their first ever fluorouracil (5-FU)-based
      chemotherapy was undertaken to explore the association of sex with reports of the
      incidence and severity of stomatitis. PATIENTS AND METHODS: Data were obtained on
      a total of 731 patients (402 men and 329 women). Comparisons of incidence and
      severity rates and average stomatitis across sex were performed using standard
      binomial testing and t tests, respectively. Logistic regression analysis and a
      weighted analysis using data summarized to study level served as evidence of
      cross-validation. RESULTS: Women reported stomatitis both more often and with
      greater severity than did men. The incidence of any stomatitis for women was 63%
      versus 52% for men (P =.002). The incidence of severe or very severe stomatitis
      for men and women was 22% and 12%, respectively (P =. 0006). On average, women
      reported stomatitis of roughly 0.4 points higher than men on a 0 to 4 ordinal
      scale (P <.00001). Comparison of results across treatment and placebo arms was
      carried out to validate the initial findings. Logistic regression modelling
      further confirmed the results conditional on the presence of a number of
      potentially confounding covariates. Women were also 11% more likely than men to
      experience leukopenia of common toxicity criteria grade >/= 1, (70% v 59%,
      respectively; P <.00001) and grade 3+ (18% v 11%, respectively; P =.004).
      CONCLUSION: More women than men reported 5-FU-induced stomatitis. The precise
      mechanism resulting in different degrees of stomatitis across sex is not evident.

PMID- 10637258
TI  - Impact of quality of life on patient expectations regarding phase I clinical
      trials.
AB  - PURPOSE: Quality of life (QOL) is increasingly recognized as a critical cancer
      treatment outcome measure, but little is known about the impact of QOL on the
      patient decision-making process. A pilot study was conducted in an effort to (1)
      measure the expectations of patients, physicians, and research nurses regarding
      the potential benefits and toxicities from experimental and standard therapies,
      and (2) determine the relationship of QOL to patient perceptions regarding
      treatment options. METHODS: Thirty cancer patients enrolling in phase I clinical
      trials, their physicians, and their research nurses were administered
      questionnaires that assessed demographics, QOL, and treatment expectations.
      RESULTS: Compared with their physicians, patients overestimated potential
      benefits and toxicities from experimental therapy (mean expected benefit, 59.8% v
      23.8%, P <.01; mean expected toxicity, 29.8% v 16.0%, P <.01). Patients estimated
      a greater potential for benefit (59.8% v 36.8%, P <.01) and less potential for
      toxicity (29.8% v 45.6%, P =.01) for experimental therapy, compared with standard
      therapy. Short Form-36 general health perception correlated with patient
      perception of potential benefit from experimental therapy (r =.48, P =.01).
      CONCLUSION: Participants in phase I clinical trial have high expectations
      regarding the success of experimental therapy and discount potential toxicity.
      Patient QOL may affect the expectation of benefit from experimental therapy and,
      ultimately, treatment choice. Understanding the interactions between QOL and
      patient expectations may guide the development of improved strategies to present
      appropriate information to patients considering early-phase clinical trials.

PMID- 10637259
TI  - Content and quality of currently published phase II cancer trials.
AB  - PURPOSE: A number of statistical methods have been proposed for the design and
      analysis of phase II studies based on dichotomous outcomes. To investigate to
      what extent such methods are in current use, we conducted a survey of published
      studies. MATERIALS AND METHODS: We identified studies by conducting a
      computerized literature search of MEDLINE. We considered trials on systemic
      antineoplastic treatments described as phase II or pilot. The search was limited
      to articles written in English and published in 1997. RESULTS: Three hundred
      eight trials were identified. The majority, ie, 295 (95.8%), had been conducted
      as single-arm studies, with objective tumor response as the primary efficacy end
      point. An identifiable statistical design was reported for only 58 (19.7%) of
      these trials. The quality in reporting the statistical design and compliance with
      the design in carrying out the study or results interpretation were frequently
      poor. The frequency of reporting the statistical design was not shown to increase
      over the years of study start and was not associated with sample size or study
      duration. Instead, a significant association was found with trial results (which
      were less frequently positive among studies with a statistical design) and with
      the impact factor of the publishing journal. CONCLUSION: This survey shows that
      the quality of the statistical component of published phase II cancer trials is
      generally poor and raises suspicion that low quality is likely to bias study
      findings. Journals might improve the methodologic standard of published articles
      through a more vigilant reviewing policy.

PMID- 10637260
TI  - Comparison of young clinical investigators' accuracy and reproducibility when
      measuring pulmonary and skin surface nodules using a circumferential measurement
      versus a standard caliper measurement: American Association for Cancer
      Research/American Society of Clinical Oncology Clinical Trials Workshop.
AB  - PURPOSE: The clinical investigator must understand that errors in measuring
      tumors can greatly affect such clinical-trial end points as tumor response. We
      performed a prospective, controlled study of tumor measurements that compared
      circumferential measurements made with a loop planimeter with linear measurements
      made with a standard caliper. METHODS: Using a cross-over design, 76 clinical
      oncology fellows/junior oncology faculty members attending a Methods in Clinical
      Cancer Research Workshop sponsored by the American Association for Cancer
      Research and the American Society of Clinical Oncology measured five pulmonary
      nodule phantoms that ranged in size from 1.76 to 13.21 cm(2) and five surface
      nodule phantoms with sizes ranging from 2.3 to 12.9 cm(2). To perform these
      measurements, they used both a loop planimeter and a caliper. Forty-two and 40
      participants repeated measurements 3 days later on pulmonary and surface nodules.
      Accuracy, reproducibility, and time efficiency were evaluated. RESULTS: The
      linear caliper measurements overestimated pulmonary nodule and surface nodule
      size by a median of 37% and 23%, respectively. Circumferential loop planimeter
      measurements overestimated pulmonary nodule size and surface nodule size by a
      median of 8% and 17%, respectively. Interobserver reproducibility for the
      planimeter was greater than that for the caliper, as evidenced by thinner
      measurement interquartile ranges. Furthermore, intraobserver reproducibility was
      higher for the planimeter, with its variability being only 31.4% and 25.5% as
      large as that of the caliper when measuring the pulmonary and surface nodules,
      respectively. CONCLUSION: Circumferential measurements provide better accuracy,
      reproducibility, and speed in measuring both pulmonary and surface nodules than
      do perpendicular diameters.

PMID- 10637261
TI  - Docetaxel chemotherapy for pancreatic cancer: Do results support certainty?
      Italian Group for the Study of Gastrointestinal Tract Carcinomas.

PMID- 10637262
TI  - Tamoxifen and endometrial screening.

PMID- 10637263
TI  - Is the use of anti-androgen monotherapy appropriate in patients with advanced
      prostate cancer?

PMID- 10637264
TI  - Glutamine for irinotecan diarrhea.

PMID- 10637265
TI  - Role of OX40 signals in coordinating CD4 T cell selection, migration, and
      cytokine differentiation in T helper (Th)1 and Th2 cells.

PMID- 10637266
TI  - The molecular and cellular origins of Hodgkin's disease.

PMID- 10637267
TI  - A single amino acid determines the immunostimulatory activity of interleukin 10.
AB  - Cellular interleukin 10s (cIL-10s) of human and murine origin have extensive
      sequence and structural homology to the Epstein-Barr virus BCRF-I gene product,
      known as viral IL-10 (vIL-10). Although these cytokines share many
      immunosuppressive properties, vIL-10 lacks several of the immunostimulatory
      activities of cIL-10 on certain cell types. The molecular and cellular bases for
      this dichotomy are not currently defined. Here, we show that the single amino
      acid isoleucine at position 87 of cIL-10 is required for its immunostimulatory
      function. Substitution of isoleucine in cIL-10 with alanine, which corresponds to
      the vIL-10 residue, abrogates immunostimulatory activity for thymocytes, mast
      cells, and alloantigenic responses while preserving immunosuppressive activity
      for inhibition of interferon gamma production and prolongation of cardiac
      allograft survival. Conversely, substitution of alanine with isoleucine in vIL-10
      converts it to a cIL-10-like molecule with immunostimulatory activity. This
      single conservative residue alteration significantly affects ligand affinity for
      receptor; however, affinity changes do not necessarily alter specific activities
      for biologic responses in a predictable fashion. These results suggest complex
      regulation of IL-10 receptor-ligand interactions and subsequent biological
      responses. These results demonstrate that vIL-10 may represent a captured and
      selectively mutated cIL-10 gene that benefits viral pathogenesis by leading to
      ineffective host immune responses. The ability to manipulate the activity of IL
      10 in either a stimulatory or suppressive direction may be of practical value for
      regulating immune responses for disease therapy, and of theoretical value for
      determining what aspects of IL-10 activity are important for normal T cell
      responses.

PMID- 10637268
TI  - Neonatal tumor necrosis factor alpha promotes diabetes in nonobese diabetic mice
      by CD154-independent antigen presentation to CD8(+) T cells.
AB  - Neonatal islet-specific expression of tumor necrosis factor (TNF)-alpha in
      nonobese diabetic mice promotes diabetes by provoking islet-infiltrating antigen
      presenting cells to present islet peptides to autoreactive T cells. Here we show
      that TNF-alpha promotes autoaggression of both effector CD4(+) and CD8(+) T
      cells. Whereas CD8(+) T cells are critical for diabetes progression, CD4(+) T
      cells play a lesser role. TNF-alpha-mediated diabetes development was not
      dependent on CD154-CD40 signals or activated CD4(+) T cells. Instead, it appears
      that TNF-alpha can promote cross-presentation of islet antigen to CD8(+) T cells
      using a unique CD40-CD154-independent pathway. These data provide new insights
      into the mechanisms by which inflammatory stimuli can bypass CD154-CD40 immune
      regulatory signals and cause activation of autoreactive T cells.

PMID- 10637270
TI  - The role of apoptosis in the regulation of hematopoietic stem cells:
      Overexpression of Bcl-2 increases both their number and repopulation potential.
AB  - Hematopoietic stem cells (HSC) give rise to cells of all hematopoietic lineages,
      many of which are short lived. HSC face developmental choices: self-renewal
      (remain an HSC with long-term multilineage repopulating potential) or
      differentiation (become an HSC with short-term multilineage repopulating
      potential and, eventually, a mature cell). There is a large overcapacity of
      differentiating hematopoietic cells and apoptosis plays a role in regulating
      their numbers. It is not clear whether apoptosis plays a direct role in
      regulating HSC numbers. To address this, we have employed a transgenic mouse
      model that overexpresses BCL-2 in all hematopoietic cells, including HSC: H2K-BCL
      2. Cells from H2K-BCL-2 mice have been shown to be protected against a wide
      variety of apoptosis-inducing challenges. This block in apoptosis affects their
      HSC compartment. H2K-BCL-2-transgenic mice have increased numbers of HSC in bone
      marrow (2.4x wild type), but fewer of these cells are in the S/G(2)/M phases of
      the cell cycle (0.6x wild type). Their HSC have an increased plating efficiency
      in vitro, engraft at least as well as wild-type HSC in vivo, and have an
      advantage following competitive reconstitution with wild-type HSC.

PMID- 10637269
TI  - Cytotoxic T lymphocyte epitopes of HIV-1 Nef: Generation of multiple definitive
      major histocompatibility complex class I ligands by proteasomes.
AB  - Although a pivotal role of proteasomes in the proteolytic generation of epitopes
      for major histocompatibility complex (MHC) class I presentation is undisputed,
      their precise function is currently the subject of an active debate: do
      proteasomes generate many epitopes in definitive form, or do they merely generate
      the COOH termini, whereas the definitive NH(2) termini are cleaved by
      aminopeptidases? We determined five naturally processed MHC class I ligands
      derived from HIV-1 Nef. Unexpectedly, the five ligands correspond to only three
      cytotoxic T lymphocyte (CTL) epitopes, two of which occur in two COOH-terminal
      length variants. Parallel analyses of proteasomal digests of a Nef fragment
      encompassing the epitopes revealed that all five ligands are direct products of
      proteasomes. Moreover, in four of the five ligands, the NH(2) termini correspond
      to major proteasome cleavage sites, and putative NH(2)-terminally extended
      precursor fragments were detected for only one of the five ligands. All ligands
      are transported by the transporter associated with antigen processing (TAP). The
      combined results from these five ligands provide strong evidence that many
      definitive MHC class I ligands are precisely cleaved at both ends by proteasomes.
      Additional evidence supporting this conclusion is discussed, along with
      contrasting results of others who propose a strong role for NH(2)-terminal
      trimming with direct proteasomal epitope generation being a rare event.

PMID- 10637271
TI  - CC chemokine receptor (CCR)3/eotaxin is followed by CCR4/monocyte-derived
      chemokine in mediating pulmonary T helper lymphocyte type 2 recruitment after
      serial antigen challenge in vivo.
AB  - Isolated peripheral blood CD4 cells from allergic individuals express CC
      chemokine receptor (CCR)3 and CCR4 after expansion in vitro. In addition, human T
      helper type 2 (Th2) cells polarized in vitro selectively express CCR3 and CCR4 at
      certain stages of activation/differentiation and respond preferentially to the
      ligands eotaxin and monocyte-derived chemokine (MDC). However, controversy arises
      when the in vivo significance of this distinct expression is discussed. To
      address the functional role of CCR3/eotaxin and CCR4/MDC during the in vivo
      recruitment of Th2 cells, we have transferred effector Th cells into naive mice
      to induce allergic airway disease. Tracking of these cells after repeated antigen
      challenge has established that both CCR3/eotaxin and CCR4/MDC axes contribute to
      the recruitment of Th2 cells to the lung, demonstrating the in vivo relevance of
      the expression of these receptors on Th2 cells. We have shown that involvement of
      the CCR3/eotaxin pathway is confined to early stages of the response in vivo,
      whereas repeated antigen stimulation results in the predominant use of the
      CCR4/MDC pathway. We propose that effector Th2 cells respond to both CCR3/eotaxin
      and CCR4/MDC pathways initially, but that a progressive increase in CCR4-positive
      cells results in the predominance of the CCR4/MDC axis in the long-term
      recruitment of Th2 cells in vivo.

PMID- 10637272
TI  - Tumor necrosis factor alpha stimulates osteoclast differentiation by a mechanism
      independent of the ODF/RANKL-RANK interaction.
AB  - Osteoclast differentiation factor (ODF, also called RANKL/TRANCE/OPGL) stimulates
      the differentiation of osteoclast progenitors of the monocyte/macrophage lineage
      into osteoclasts in the presence of macrophage colony-stimulating factor (M-CSF,
      also called CSF-1). When mouse bone marrow cells were cultured with M-CSF, M-CSF
      dependent bone marrow macrophages (M-BMM phi) appeared within 3 d. Tartrate
      resistant acid phosphatase-positive osteoclasts were also formed when M-BMM phi
      were further cultured for 3 d with mouse tumor necrosis factor alpha (TNF-alpha)
      in the presence of M-CSF. Osteoclast formation induced by TNF-alpha was inhibited
      by the addition of respective antibodies against TNF receptor 1 (TNFR1) or TNFR2,
      but not by osteoclastogenesis inhibitory factor (OCIF, also called OPG, a decoy
      receptor of ODF/RANKL), nor the Fab fragment of anti-RANK (ODF/RANKL receptor)
      antibody. Experiments using M-BMM phi prepared from TNFR1- or TNFR2-deficient
      mice showed that both TNFR1- and TNFR2-induced signals were important for
      osteoclast formation induced by TNF-alpha. Osteoclasts induced by TNF-alpha
      formed resorption pits on dentine slices only in the presence of IL-1alpha. These
      results demonstrate that TNF-alpha stimulates osteoclast differentiation in the
      presence of M-CSF through a mechanism independent of the ODF/RANKL-RANK system.
      TNF-alpha together with IL-1alpha may play an important role in bone resorption
      of inflammatory bone diseases.

PMID- 10637273
TI  - Inhibition of Ca(2+) signaling by Mycobacterium tuberculosis is associated with
      reduced phagosome-lysosome fusion and increased survival within human
      macrophages.
AB  - Complement receptor (CR)-mediated phagocytosis of Mycobacterium tuberculosis by
      macrophages results in intracellular survival, suggesting that M. tuberculosis
      interferes with macrophage microbicidal mechanisms. As increases in cytosolic
      Ca(2+) concentration (?Ca(2+)(c)) promote phagocyte antimicrobial responses, we
      hypothesized that CR phagocytosis of M. tuberculosis is accompanied by altered
      Ca(2+) signaling. Whereas the control complement (C)-opsonized particle zymosan
      (COZ) induced a 4.6-fold increase in ?Ca(2+)(c) in human macrophages, no change
      in ?Ca(2+)(c) occurred upon addition of live, C-opsonized virulent M.
      tuberculosis. Viability of M. tuberculosis and ingestion via CRs was required for
      infection of macrophages in the absence of increased ?Ca(2+)(c), as killed M.
      tuberculosis or antibody (Ab)-opsonized, live M. tuberculosis induced elevations
      in ?Ca(2+)(c) similar to COZ. Increased ?Ca(2+)(c) induced by Ab-opsonized
      bacilli was associated with a 76% reduction in intracellular survival, compared
      with C-opsonized M. tuberculosis. Similarly, reversible elevation of macrophage
      ?Ca(2+)(c) with the ionophore A23187 reduced intracellular viability by 50%.
      Ionophore-mediated elevation of ?Ca(2+)(c) promoted the maturation of phagosomes
      containing live C-opsonized bacilli, as evidenced by acidification and
      accumulation of lysosomal protein markers. These data demonstrate that M.
      tuberculosis inhibits CR-mediated Ca(2+) signaling and indicate that this
      alteration of macrophage activation contributes to inhibition of phagosome
      lysosome fusion and promotion of intracellular mycobacterial survival.

PMID- 10637274
TI  - Arterial inflammation in mice lacking the interleukin 1 receptor antagonist gene.
AB  - Branch points and flexures in the high pressure arterial system have long been
      recognized as sites of unusually high turbulence and consequent stress in humans
      are foci for atherosclerotic lesions. We show that mice that are homozygous for a
      null mutation in the gene encoding an endogenous antiinflammatory cytokine,
      interleukin 1 receptor antagonist (IL-1ra), develop lethal arterial inflammation
      involving branch points and flexures of the aorta and its primary and secondary
      branches. We observe massive transmural infiltration of neutrophils, macrophages,
      and CD4(+) T cells. Animals appear to die from vessel wall collapse, stenosis,
      and organ infarction or from hemorrhage from ruptured aneurysms. Heterozygotes do
      not die from arteritis within a year of birth but do develop small lesions, which
      suggests that a reduced level of IL-1ra is insufficient to fully control
      inflammation in arteries. Our results demonstrate a surprisingly specific role
      for IL-1ra in the control of spontaneous inflammation in constitutively stressed
      artery walls, suggesting that expression of IL-1 is likely to have a significant
      role in signaling artery wall damage.

PMID- 10637275
TI  - Development of chronic inflammatory arthropathy resembling rheumatoid arthritis
      in interleukin 1 receptor antagonist-deficient mice.
AB  - Interleukin (IL)-1 is a proinflammatory cytokine that plays important roles in
      inflammation, host defense, and the neuro-immuno-endocrine network. IL-1 receptor
      antagonist (ra) is an endogenous inhibitor of IL-1 and is supposed to regulate IL
      1 activity. However, its pathophysiological roles in a body remain largely
      unknown. To elucidate the roles of IL-1ra, IL-1ra-deficient mice were produced by
      gene targeting, and pathology was analyzed on different genetic backgrounds. We
      found that all of the mice on a BALB/cA background, but not those on a C57BL/6J
      background, spontaneously developed chronic inflammatory polyarthropathy.
      Histopathology showed marked synovial and periarticular inflammation, with
      articular erosion caused by invasion of granulation tissues closely resembling
      that of rheumatoid arthritis in humans. Moreover, elevated levels of antibodies
      against immunoglobulins, type II collagen, and double-stranded DNA were detected
      in these mice, suggesting development of autoimmunity. Proinflammatory cytokines
      such as IL-1beta, IL-6, and tumor necrosis factor alpha were overexpressed in the
      joints, indicating regulatory roles of IL-1ra in the cytokine network. We thus
      show that IL-1ra gene deficiency causes autoimmunity and joint-specific
      inflammation and suggest that IL-1ra is important in maintaining homeostasis of
      the immune system. Possible involvement of IL-1ra gene deficiency in RA will be
      discussed.

PMID- 10637277
TI  - Critical role for CD8 in T cell receptor binding and activation by peptide/major
      histocompatibility complex multimers.
AB  - Recent data using MHC/peptide tetramers and dimers suggests that the T cell
      coreceptors, CD4 and CD8, although important for T cell activation, do not play a
      direct role in facilitating T cell receptor (TCR) binding to multivalent
      MHC/peptide ligands. Instead, a current model proposes that coreceptors are
      recruited only after a stable TCR-MHC/peptide complex has already formed and
      signaled. In contrast, we show using multimeric class I MHC/peptide ligands that
      CD8 plays a critical (in some cases obligatory) role in antigen-specific TCR
      binding. T cell activation, measured by calcium mobilization, was induced by
      multimeric but not monomeric ligands and also showed CD8 dependency. Our analysis
      using anti-CD8 antibodies revealed that binding to different epitopes of CD8 can
      either block or augment TCR-MHC/peptide interaction. These effects on TCR binding
      to high-affinity agonist ligands were even more pronounced when binding to
      multimeric low-affinity ligands, including TCR antagonists, was studied. Our data
      have important implications for the role of CD8 in TCR binding to MHC/peptide
      ligands and in T cell activation. In addition, our results argue against the view
      that multimeric MHC/peptide ligands bind directly and solely to the TCR; rather,
      our data highlight a pivotal contribution of CD8 for this association.

PMID- 10637276
TI  - Activation of the p38 mitogen-activated protein kinase pathway arrests cell cycle
      progression and differentiation of immature thymocytes in vivo.
AB  - The development of T cells in the thymus is coordinated by cell-specific gene
      expression programs that involve multiple transcription factors and signaling
      pathways. Here, we show that the p38 mitogen-activated protein (MAP) kinase
      signaling pathway is strictly regulated during the differentiation of CD4(-)CD8(
      ) thymocytes. Persistent activation of p38 MAP kinase blocks fetal thymocyte
      development at the CD25(+)CD44(-) stage in vivo, and results in the lack of T
      cells in the peripheral immune system of adult mice. Inactivation of p38 MAP
      kinase is required for further differentiation of these cells into CD4(+)CD8(+)
      thymocytes. The arrest of cell cycle in mitosis is partially responsible for the
      blockade of differentiation. Therefore, the p38 MAP kinase pathway is a critical
      regulatory element of differentiation and proliferation during the early stages
      of in vivo thymocyte development.

PMID- 10637278
TI  - A balance between positive and negative signals in cytotoxic lymphocytes
      regulates the polarization of lipid rafts during the development of cell-mediated
      killing.
AB  - Plasma membrane microdomains containing sphingolipids and cholesterol (lipid
      rafts) are enriched in signaling molecules. The cross-linking of certain types of
      cell surface receptors initiates the redistribution of these lipid rafts,
      resulting in the formation of signaling complexes. However, little is known about
      the regulation of the initial raft redistribution and whether negative regulatory
      signaling pathways target this phase of cellular activation. We used natural
      killer (NK) cells as a model to investigate the regulation of raft
      redistribution, as both positive and negative signals have been implicated in the
      development of their cellular function. Here we show that after NK cells form
      conjugates with sensitive tumor cells, rafts become polarized to the site of
      target recognition. This redistribution of lipid rafts requires the activation of
      both Src and Syk family protein tyrosine kinases. In contrast, engagement of
      major histocompatibility complex (MHC)-recognizing killer cell inhibitory
      receptors (KIRs) on NK cells by resistant, MHC-bearing tumor targets blocks raft
      redistribution. This inhibition is dependent on the catalytic activity of KIR
      associated SHP-1, a Src homology 2 (SH2) domain containing tyrosine phosphatase.
      These results suggest that the influence of integrated positive and negative
      signals on raft redistribution critically influences the development of cell
      mediated cytotoxicity.

PMID- 10637279
TI  - Tetracycline-controllable selection of CD4(+) T cells: half-life and survival
      signals in the absence of major histocompatibility complex class II molecules.
AB  - A system that allows the study, in a gentle fashion, of the role of MHC molecules
      in naive T cell survival is described. Major histocompatibility complex class II
      deficient mice were engineered to express Ealpha chains only in thymic epithelial
      cells in a tetracycline (tet)-controllable manner. This resulted in tet
      responsive display of cell surface E complexes, positive selection of CD4(+)8(-)
      thymocytes, and generation of a CD4(+) T cell compartment in a class II-barren
      periphery. Using this system, we have addressed two unresolved issues: the half
      life of naive CD4(+) T cells in the absence of class II molecules (3-4 wk) and
      the early signaling events associated with class II molecule engagement by naive
      CD4(+) T cells (partial CD3 zeta chain phosphorylation and ZAP-70 association).

PMID- 10637280
TI  - Impairment of antigen-presenting cell function in mice lacking expression of OX40
      ligand.
AB  - OX40 expressed on activated T cells is known to be an important costimulatory
      molecule on T cell activation in vitro. However, the in vivo functional
      significance of the interaction between OX40 and its ligand, OX40L, is still
      unclear. To investigate the role of OX40L during in vivo immune responses, we
      generated OX40L-deficient mice and a blocking anti-OX40L monoclonal antibody,
      MGP34. OX40L expression was demonstrated on splenic B cells after CD40 and anti
      immunoglobulin (Ig)M stimulation, while only CD40 ligation was capable of
      inducing OX40L on dendritic cells. OX40L-deficient and MGP34-treated mice
      engendered apparent suppression of the recall reaction of T cells primed with
      both protein antigens and alloantigens and a significant reduction in keyhole
      limpet hemocyanin-specific IgG production. The impaired T cell priming was also
      accompanied by a concomitant reduction of both T helper type 1 (Th1) and Th2
      cytokines. Furthermore, antigen-presenting cells (APCs) derived from the mutant
      mice revealed an impaired intrinsic APC function, demonstrating the importance of
      OX40L in both the priming and effector phases of T cell activation. Collectively,
      these results provide convincing evidence that OX40L, expressed on APCs, plays a
      critical role in antigen-specific T cell responses in vivo.

PMID- 10637281
TI  - Critical contribution of OX40 ligand to T helper cell type 2 differentiation in
      experimental leishmaniasis.
AB  - Infection of inbred mouse strains with Leishmania major is a well characterized
      model for analysis of T helper (Th)1 and Th2 cell development in vivo. In this
      study, to address the role of costimulatory molecules CD27, CD30, 4-1BB, and
      OX40, which belong to the tumor necrosis factor receptor superfamily, in the
      development of Th1 and Th2 cells in vivo, we administered monoclonal antibody
      (mAb) against their ligands, CD70, CD30 ligand (L), 4-1BBL, and OX40L, to mice
      infected with L. major. Whereas anti-CD70, anti-CD30L, and anti-4-1BBL mAb
      exhibited no effect in either susceptible BALB/c or resistant C57BL/6 mice, the
      administration of anti-OX40L mAb abrogated progressive disease in BALB/c mice.
      Flow cytometric analysis indicated that OX40 was expressed on CD4(+) T cells and
      OX40L was expressed on CD11c(+) dendritic cells in the popliteal lymph nodes of
      L. major-infected BALB/c mice. In vitro stimulation of these CD4(+) T cells
      showed that anti-OX40L mAb treatment resulted in substantially reduced production
      of Th2 cytokines. Moreover, this change in cytokine levels was associated with
      reduced levels of anti-L. major immunoglobulin (Ig)G1 and serum IgE. These
      results indicate that anti-OX40L mAb abrogated progressive leishmaniasis in
      BALB/c mice by suppressing the development of Th2 responses, substantiating a
      critical role of OX40-OX40L interaction in Th2 development in vivo.

PMID- 10637282
TI  - Lineage-restricted function of nuclear factor kappaB-inducing kinase (NIK) in
      transducing signals via CD40.
AB  - CD40 signaling in B cells and dendritic cells (DCs) is critical for the
      development of humoral and cell-mediated immunity, respectively. Nuclear factor
      kappaB (NF-kappaB)-inducing kinase (NIK) has been implicated as a central
      transducing kinase in CD40-dependent activation. Here, we show that although NIK
      is essential for B cell activation, it is dispensable for activation of DCs. Such
      data provide compelling evidence that different intermediary kinases are used by
      different cellular lineages to trigger NF-kappaB activation via CD40.

PMID- 10637283
TI  - Rare occurrence of classical Hodgkin's disease as a T cell lymphoma.
AB  - Recent work identified Hodgkin and Reed-Sternberg (H/RS) cells in classical
      Hodgkin's disease (cHD) as clonal progeny of mature B cells. Therefore, it is
      generally assumed that cHD homogenously represents a B cell lymphoma. In a subset
      of cHD, however, H/RS cells expressing T cell-associated proteins may be
      candidates for alternative lineage derivation. Single H/RS cells with cytotoxic T
      cell phenotype were micromanipulated from three cases of cHD and analyzed by
      single cell polymerase chain reaction for immunoglobulin heavy (IgH) and light
      chain (IgL) gene rearrangements, T cell receptor (TCR)-beta gene rearrangements,
      and germline configuration of the IgH and TCR-beta loci. H/RS cells from two
      cases of cHD harbored clonal, somatically mutated Ig gene rearrangements, whereas
      TCR-beta loci were in germline configuration. In contrast, H/RS cells from an
      additional case harbored clonal TCR-beta variable/diversity/joining (VDJ) and DJ
      gene rearrangements, whereas the IgH locus was in germline configuration on both
      alleles. Thus, in two cases of cHD with H/RS cells expressing cytotoxic T cell
      molecules, the tumor cells are derived from mature B cells that aberrantly
      express T cell markers. In a third case, however, H/RS cells were derived from a
      T cell, demonstrating that cHD can also occur as a T cell lymphoma.

PMID- 10637284
TI  - Clonal deleterious mutations in the IkappaBalpha gene in the malignant cells in
      Hodgkin's lymphoma.
AB  - Members of the nuclear factor (NF)-kappaB family of transcription factors play a
      crucial role in cellular activation, immune responses, and oncogenesis. In most
      cells, they are kept inactive in the cytosol by complex formation with members of
      the inhibitor of NF-kappaB (IkappaB) family, whose degradation activates NF
      kappaB in response to diverse stimuli. In Hodgkin's lymphoma (HL), high
      constitutive nuclear activity of NF-kappaB is characteristic of the malignant
      Hodgkin and Reed-Sternberg (H/RS) cells, which occur at low number in a
      background of nonneoplastic inflammatory cells. In single H/RS cells
      micromanipulated from histological sections of HL, we detect clonal deleterious
      somatic mutations in the IkappaBalpha gene in two of three Epstein-Barr virus
      (EBV)-negative cases but not in two EBV-positive cases (in which a viral oncogene
      may account for NF-kappaB activation). There was no evidence for IkappaBalpha
      mutations in two non-HL entities or in normal germinal center B cells. This study
      establishes deleterious IkappaBalpha mutations as the first recurrent genetic
      defect found in H/RS cells, indicating a role of IkappaBalpha defects in the
      pathogenesis of HL and implying that IkappaBalpha is a tumor suppressor gene.

PMID- 10637285
TI  - In vivo cytotoxic T lymphocyte elicitation by mycobacterial heat shock protein 70
      fusion proteins maps to a discrete domain and is CD4(+) T cell independent.
AB  - To gain insights into the mechanisms by which soluble heat shock protein (hsp)
      fusions can elicit CD8(+) cytotoxic T lymphocytes (CTLs) against the fusion
      partner, mycobacterial (Mycobacterium tuberculosis) hsp70 was dissected to
      ascertain whether a particular hsp domain is necessary, and knockout mice were
      used to determine whether the fusion protein's immunogenicity is dependent on
      CD4(+) T lymphocytes. We found that the ability to elicit CD8(+) CTLs depends on
      a discrete 200-amino acid protein domain, indicating that the fusion protein's
      immunogenicity for CD8(+) T cells does not require coupled chaperone function or
      peptide binding. Further, we found that ovalbumin (OVA).hsp70 fusion protein
      elicited anti-OVA CD8(+) CTLs about equally well in CD4 knockout and wild-type
      C57BL/6 mice, and also when the hsp70 was of murine (self) origin. The ability of
      hsp70 fusion proteins to elicit CD4-independent CTL responses suggests that hsp70
      fusion proteins may be useful for immunological prophylaxis and therapy against
      disease in CD4(+) T cell-deficient individuals.

PMID- 10637286
TI  - Regulation of mitotic inhibitor Mik1 helps to enforce the DNA damage checkpoint.
AB  - The protein kinase Chk1 enforces the DNA damage checkpoint. This checkpoint
      delays mitosis until damaged DNA is repaired. Chk1 regulates the activity and
      localization of Cdc25, the tyrosine phosphatase that activates the cdk Cdc2. Here
      we report that Mik1, a tyrosine kinase that inhibits Cdc2, is positively
      regulated by the DNA damage checkpoint. Mik1 is required for checkpoint response
      in strains that lack Cdc25. Long-term DNA damage checkpoint arrest fails in
      Deltamik1 cells. DNA damage increases Mik1 abundance in a Chk1-dependent manner.
      Ubiquitinated Mik1 accumulates in a proteasome mutant, which indicates that Mik1
      normally has a short half-life. Thus, the DNA damage checkpoint might regulate
      Mik1 degradation. Mik1 protein and mRNA oscillate during the unperturbed cell
      cycle, with peak amounts detected around S phase. These data indicate that
      regulation of Mik1 abundance helps to couple mitotic onset to the completion of
      DNA replication and repair. Coordinated negative regulation of Cdc25 and positive
      regulation of Mik1 ensure the effective operation of the DNA damage checkpoint.

PMID- 10637287
TI  - Efficient export of the vesicular stomatitis virus G protein from the endoplasmic
      reticulum requires a signal in the cytoplasmic tail that includes both tyrosine
      based and di-acidic motifs.
AB  - The vesicular stomatitis virus (VSV) G protein is a model transmembrane
      glycoprotein that has been extensively used to study the exocytotic pathway. A
      signal in the cytoplasmic tail of VSV G (DxE or Asp-x-Glu, where x is any amino
      acid) was recently proposed to mediate efficient export of the protein from the
      endoplasmic reticulum (ER). In this study, we show that the DxE motif only
      partially accounts for efficient ER exit of VSV G. We have identified a six-amino
      acid signal, which includes the previously identified Asp and Glu residues, that
      is required for efficient exit of VSV G from the ER. This six-residue signal also
      includes the targeting sequence YxxO (where x is any amino acid and O is a bulky,
      hydrophobic residue) implicated in several different sorting pathways. The only
      defect in VSV G proteins with mutations in the six-residue signal is slow exit
      from the ER; folding and oligomerization in the ER are normal, and the mutants
      eventually reach the plasma membrane. Addition of this six-residue motif to an
      inefficiently transported reporter protein is sufficient to confer an enhanced ER
      export rate. The signal we have identified is highly conserved among divergent
      VSV G proteins, and we suggest this reflects the importance of this motif in the
      evolution of VSV G as a proficient exocytic protein.

PMID- 10637288
TI  - Specific retrieval of the exocytic SNARE Snc1p from early yeast endosomes.
AB  - Many endocytosed proteins in yeast travel to the vacuole, but some are recycled
      to the plasma membrane. We have investigated the recycling of chimeras containing
      green fluorescent protein (GFP) and the exocytic SNARE Snc1p. GFP-Snc1p moves
      from the cell surface to internal structures when Golgi function or exocytosis is
      blocked, suggesting continuous recycling via the Golgi. Internalization is
      mediated by a conserved cytoplasmic signal, whereas diversion from the vacuolar
      pathway requires sequences within and adjacent to the transmembrane domain.
      Delivery from the Golgi to the surface is also influenced by the transmembrane
      domain, but the requirements are much less specific. Recycling requires the
      syntaxins Tlg1p and Tlg2p but not Pep12p or proteins such as Vps4p and Vps5p that
      have been implicated in late endosome-Golgi traffic. Subtle changes to the
      recycling signal cause GFP-Snc1p to accumulate preferentially in punctate
      internal structures, although it continues to recycle to the surface. The
      internal GFP-Snc1p colocalizes with Tlg1p, and immunofluorescence and
      immunoelectron microscopy reveal structures that contain Tlg1p, Tlg2p, and Kex2p
      but lack Pep12p and Sec7p. We propose that these represent early endosomes in
      which sorting of Snc1p and late Golgi proteins occurs, and that transport can
      occur directly from them to the Golgi apparatus.

PMID- 10637289
TI  - Is phosphorylation of the alpha1 subunit at Ser-16 involved in the control of
      Na,K-ATPase activity by phorbol ester-activated protein kinase C?
AB  - The alpha1 subunit of Na,K-ATPase is phosphorylated at Ser-16 by phorbol ester
      sensitive protein kinase(s) C (PKC). The role of Ser-16 phosphorylation was
      analyzed in COS-7 cells stably expressing wild-type or mutant (T15A/S16A and S16D
      E) ouabain-resistant Bufo alpha1 subunits. In cells incubated at 37 degrees C,
      phorbol 12, 13-dibutyrate (PDBu) inhibited the transport activity and decreased
      the cell surface expression of wild-type and mutant Na,K-pumps equally (
      approximately 20-30%). This effect of PDBu was mimicked by arachidonic acid and
      was dependent on PKC, phospholipase A(2), and cytochrome P450-dependent
      monooxygenase. In contrast, incubation of cells at 18 degrees C suppressed the
      down-regulation of Na,K-pumps and revealed a phosphorylation-dependent
      stimulation of the transport activity of Na,K-ATPase. Na,K-ATPase from cells
      expressing alpha1-mutants mimicking Ser-16 phosphorylation (S16D or S16E)
      exhibited an increase in the apparent Na affinity. This finding was confirmed by
      the PDBu-induced increase in Na sensitivity of the activity of Na,K-ATPase
      measured in permeabilized nontransfected COS-7 cells. These results illustrate
      the complexity of the regulation of Na,K-ATPase alpha1 isozymes by phorbol ester
      sensitive PKCs and reveal 1) a phosphorylation-independent decrease in cell
      surface expression and 2) a phosphorylation-dependent stimulation of the
      transport activity attributable to an increase in the apparent Na affinity.

PMID- 10637290
TI  - The catalytic activity of the Src family kinases is required to disrupt cadherin
      dependent cell-cell contacts.
AB  - Despite the importance of epithelial cell contacts in determining cell behavior,
      we still lack a detailed understanding of the assembly and disassembly of
      intercellular contacts. Here we examined the role of the catalytic activity of
      the Src family kinases at epithelial cell contacts in vitro. Like E- and P
      cadherin, Ca(2+) treatment of normal and tumor-derived human keratinocytes
      resulted in c-Yes (and c-Src and Fyn), as well as their putative substrate
      p120(CTN), being recruited to cell-cell contacts. A tyrosine kinase inhibitor
      with selectivity against the Src family kinases, PD162531, and a dominant
      inhibitory c-Src protein that interferes with the catalytic function of the
      endogenous Src kinases induced cell-cell contact and E-cadherin redistribution,
      even in low Ca(2+), which does not normally support stable cell-cell adhesion.
      Time-lapse microscopy demonstrated that Src kinase inhibition induced
      stabilization of transiently formed intercellular contacts in low Ca(2+).
      Furthermore, a combination of E- and P-cadherin-specific antibodies suppressed
      cell-cell contact, indicating cadherin involvement. As a consequence of contact
      stabilization, normal cells were unable to dissociate from an epithelial sheet
      formed at high density and repair a wound in vitro, although individual cells
      were still motile. Thus, cadherin-dependent contacts can be stabilized both by
      high Ca(2+) and by inhibiting Src activity in low (0.03 mM) Ca(2+) in vitro.

PMID- 10637292
TI  - Myosin-II tails confer unique functions in Schizosaccharomyces pombe:
      characterization of a novel myosin-II tail.
AB  - Schizosaccharomyces pombe has two myosin-IIs, Myo2p and Myp2p, which both
      concentrate in the cleavage furrow during cytokinesis. We studied the phenotype
      of mutant myosin-II strains to examine whether these myosins have overlapping
      functions in the cell. myo2(+) is essential. myp2(+) cannot rescue loss of
      myo2(+) even at elevated levels of expression. myp2(+) is required under specific
      nutritional conditions; thus myo2(+) cannot rescue under these conditions.
      Studies with chimeras show that the tails rather than the structurally similar
      heads determine the gene-specific functions of myp2(+) and myo2(+). The Myo2p
      tail is a rod-shaped coiled-coil dimer that aggregates in low salt like other
      myosin-II tails. The Myp2p tail is monomeric in high salt and is insoluble in low
      salt. Biophysical properties of the full-length Myp2p tail and smaller subdomains
      indicate that two predicted coiled-coil regions fold back on themselves to form a
      rod-shaped antiparallel coiled coil. This suggests that Myp2p is the first type
      II myosin with only one head. The C-terminal two-thirds of Myp2p tail are
      essential for function in vivo and may interact with components of the salt
      response pathway.

PMID- 10637291
TI  - The CEACAM1-L glycoprotein associates with the actin cytoskeleton and localizes
      to cell-cell contact through activation of Rho-like GTPases.
AB  - Associations between plasma membrane-linked proteins and the actin cytoskeleton
      play a crucial role in defining cell shape and determination, ensuring cell
      motility and facilitating cell-cell or cell-substratum adhesion. Here, we present
      evidence that CEACAM1-L, a cell adhesion molecule of the carcinoembryonic antigen
      family, is associated with the actin cytoskeleton. We have delineated the regions
      involved in actin cytoskeleton association to the distal end of the CEACAM1-L
      long cytoplasmic domain. We have demonstrated that CEACAM1-S, an isoform of
      CEACAM1 with a truncated cytoplasmic domain, does not interact with the actin
      cytoskeleton. In addition, a major difference in subcellular localization of the
      two CEACAM1 isoforms was observed. Furthermore, we have established that the
      localization of CEACAM1-L at cell-cell boundaries is regulated by the Rho family
      of GTPases. The retention of the protein at the sites of intercellular contacts
      critically depends on homophilic CEACAM1-CEACAM1 interactions and association
      with the actin cytoskeleton. Our results provide new evidence on how the Rho
      family of GTPases can control cell adhesion: by directing an adhesion molecule to
      its proper cellular destination. In addition, these results provide an insight
      into the mechanisms of why CEACAM1-L, but not CEACAM1-S, functions as a tumor
      cell growth inhibitor.

PMID- 10637293
TI  - Ultraviolet light induces redox reaction-mediated dimerization and
      superactivation of oncogenic Ret tyrosine kinases.
AB  - The c-RET proto-oncogene encodes a receptor-type tyrosine kinase, and its
      mutations in the germ line are responsible for the inheritance of multiple
      endocrine neoplasia type 2A (MEN2A) and 2B (MEN2B). Ret kinases are
      constitutively activated as a result of MEN2A mutations (Ret-MEN2A) or MEN2B
      mutations (Ret-MEN2B). Here we demonstrate that UV light (UV) irradiation induces
      superactivation of the constitutively activated Ret-MEN2A and Ret-MEN2B as well
      as activation of c-Ret. Before UV irradiation, small percentages of c-Ret (3-4%)
      and Ret-MEN2B (1-2%) and large percentages of Ret-MEN2A (30-40%) were dimerized
      through disulfide bonds. These dimerized Ret proteins were preferentially
      autophosphorylated, suggesting a close relation between up-regulated kinase
      activity and disulfide bond-mediated dimerization of Ret proteins. We found that
      UV irradiation promotes the disulfide bond-mediated dimerization of the Ret
      proteins, in close association with activation and superactivation of Ret
      kinases. UV irradiation also induced dimerization and activation of the
      extracellular domain-deleted mutant Ret (Ret-PTC-1). Interestingly, the levels of
      basic kinase activity and dimerization of Ret-PTC-1-C376A, in which cysteine 376
      in the tyrosine kinase domain of Ret-PTC-1 was replaced by alanine, were low and
      were not increased by UV irradiation. These results suggest that Ret-PTC-1
      cysteine 376 is one of possibly multiple critical target amino acids of UV for
      Ret kinase activation. Overexpression of Cu/Zn superoxide dismutase in cells as a
      result of gene transfection prevented both the UV-mediated promotion of
      dimerization and the superactivation of Ret-MEN2A kinase. These results suggest
      that the UV-induced free radicals in cells attack intracellular domains of Ret to
      dimerize the kinase proteins for superactivation.

PMID- 10637294
TI  - Tim18p is a new component of the Tim54p-Tim22p translocon in the mitochondrial
      inner membrane.
AB  - The mitochondrial inner membrane contains two separate translocons: one required
      for the translocation of matrix-targeted proteins (the Tim23p-Tim17p complex) and
      one for the insertion of polytopic proteins into the mitochondrial inner membrane
      (the Tim54p-Tim22p complex). To identify new members of the Tim54p-Tim22p
      complex, we screened for high-copy suppressors of the temperature-sensitive tim54
      1 mutant. We identified a new gene, TIM18, that encodes an integral protein of
      the inner membrane. The following genetic and biochemical observations suggest
      that the Tim18 protein is part of the Tim54p-Tim22p complex in the inner
      membrane: multiple copies of TIM18 suppress the tim54-1 growth defect; the
      tim18::HIS3 disruption is synthetically lethal with tim54-1; Tim54p and Tim22p
      can be coimmune precipitated with the Tim18 protein; and Tim18p, along with
      Tim54p and Tim22p, is detected in an approximately 300-kDa complex after blue
      native electrophoresis. We propose that Tim18p is a new component of the Tim54p
      Tim22p machinery that facilitates insertion of polytopic proteins into the
      mitochondrial inner membrane.

PMID- 10637295
TI  - LPP, an actin cytoskeleton protein related to zyxin, harbors a nuclear export
      signal and transcriptional activation capacity.
AB  - The LPP gene is the preferred translocation partner of the HMGIC gene in a
      subclass of human benign mesenchymal tumors known as lipomas. Here we have
      characterized the LPP gene product that shares 41% of sequence identity with the
      focal adhesion protein zyxin. LPP localizes in focal adhesions as well as in cell
      to-cell contacts, and it binds VASP, a protein implicated in the control of actin
      organization. In addition, LPP accumulates in the nucleus of cells upon treatment
      with leptomycin B, an inhibitor of the export factor CRM1. The nuclear export of
      LPP depends on an N-terminally located leucine-rich sequence that shares sequence
      homology with well-defined nuclear export signals. Moreover, LPP displays
      transcriptional activation capacity, as measured by GAL4-based assays.
      Altogether, these results show that the LPP protein has multifunctional domains
      and may serve as a scaffold upon which distinct protein complexes are assembled
      in the cytoplasm and in the nucleus.

PMID- 10637296
TI  - Differential induction of two p24delta putative cargo receptors upon activation
      of a prohormone-producing cell.
AB  - The p24 family consists of type I transmembrane proteins that are present
      abundantly in transport vesicles, may play a role in endoplasmic reticulum-to
      Golgi cargo transport, and have been classified into subfamilies named p24alpha, 
      beta, -gamma, and -delta. We previously identified a member of the p24delta
      subfamily that is coordinately expressed with the prohormone proopiomelanocortin
      (POMC) in the melanotrope cells of the intermediate pituitary during black
      background adaptation of the amphibian Xenopus laevis ( approximately 30-fold
      increase in POMC mRNA). In this study, we report on the characterization of this
      p24delta member (Xp24delta(2)) and on the identification and characterization of
      a second member (Xp24delta(1)) that is also expressed in the melanotrope cells
      and that has 66% amino acid sequence identity to Xp24delta(2). The two p24delta
      members are ubiquitously expressed, but Xp24delta(2) is neuroendocrine enriched.
      During black background adaptation, the amount of the Xp24delta(2) protein in the
      intermediate pituitary was increased approximately 25 times, whereas Xp24delta(1)
      protein expression was increased only 2.5 times. Furthermore, the level of
      Xp24delta(2) mRNA was approximately 5-fold higher in the melanotrope cells of
      black-adapted animals than in those of white-adapted animals, whereas
      Xp24delta(1) mRNA expression was not induced. Therefore, the expression of
      Xp24delta(2) specifically correlates with the expression of POMC. Together, our
      findings suggest that p24delta proteins have a role in selective protein
      transport in the secretory pathway.

PMID- 10637297
TI  - Mutants of the Yarrowia lipolytica PEX23 gene encoding an integral peroxisomal
      membrane peroxin mislocalize matrix proteins and accumulate vesicles containing
      peroxisomal matrix and membrane proteins.
AB  - pex mutants are defective in peroxisome assembly. The mutant strain pex23-1 of
      the yeast Yarrowia lipolytica lacks morphologically recognizable peroxisomes and
      mislocalizes all peroxisomal matrix proteins investigated preferentially to the
      cytosol. pex23 strains accumulate vesicular structures containing both
      peroxisomal matrix and membrane proteins. The PEX23 gene was isolated by
      functional complementation of the pex23-1 strain and encodes a protein, Pex23p,
      of 418 amino acids (47,588 Da). Pex23p exhibits high sequence similarity to two
      hypothetical proteins of the yeast Saccharomyces cerevisiae. Pex23p is an
      integral membrane protein of peroxisomes that is completely, or nearly
      completely, sequestered from the cytosol. Pex23p is detected at low levels in
      cells grown in medium containing glucose, and its levels are significantly
      increased by growth in medium containing oleic acid, the metabolism of which
      requires intact peroxisomes.

PMID- 10637298
TI  - Cell-specific activation of nuclear factor-kappaB by the parasite Trypanosoma
      cruzi promotes resistance to intracellular infection.
AB  - The transcription factor nuclear factor-kappaB (NF-kappaB) is central to the
      innate and acquired immune response to microbial pathogens, coordinating cellular
      responses to the presence of infection. Here we demonstrate a direct role for NF
      kappaB activation in controlling intracellular infection in nonimmune cells.
      Trypanosoma cruzi is an intracellular parasite of mammalian cells with a marked
      preference for infection of myocytes. The molecular basis for this tissue tropism
      is unknown. Trypomastigotes, the infectious stage of T. cruzi, activate nuclear
      translocation and DNA binding of NF-kappaB p65 subunit and NF-kappaB-dependent
      gene expression in epithelial cells, endothelial cells, and fibroblasts.
      Inactivation of epithelial cell NF-kappaB signaling by inducible expression of
      the inhibitory mutant IkappaBaM significantly enhances parasite invasion. T.
      cruzi do not activate NF-kappaB in cells derived from skeletal, smooth, or
      cardiac muscle, despite the ability of these cells to respond to tumor necrosis
      factor-alpha with NF-kappaB activation. The in vitro infection level in these
      muscle-derived cells is more than double that seen in the other cell types
      tested. Therefore, the ability of T. cruzi to activate NF-kappaB correlates
      inversely with susceptibility to infection, suggesting that NF-kappaB activation
      is a determinant of the intracellular survival and tissue tropism of T. cruzi.

PMID- 10637299
TI  - Evidence for a novel affinity mechanism of motor-assisted transport along
      microtubules.
AB  - In microtubule (MT) translocation assays, using colloidal gold particles coupled
      to monoclonal tubulin antibodies to mark positions along MTs, we found that
      relative motion is possible between the gold particle and an MT, gliding on
      dynein or kinesin. Such motion evidently occurred by an affinity release and
      rebinding mechanism that did not require motor activity on the particle. As the
      MTs moved, particles drifted to the trailing edge of the MT and then were
      released. Sometimes the particles transferred from one MT to another, moving
      orthogonally. Although motion of the particles was uniformly rearward, movement
      was toward the (-) or (+) end of the MT, depending on whether dynein or kinesin,
      respectively, was used in the assay. These results open possibilities for
      physiological mechanisms of organelle and other movement that, although dependent
      on motor-driven microtubule transport, do not require direct motor attachment
      between the organelle and the microtubule. Our observations on the direction of
      particle drift and time of release may also provide confirmation in a dynamic
      system for the conclusion that beta tubulin is exposed at the (+) end of the MT.

PMID- 10637300
TI  - Organization of the yeast Golgi complex into at least four functionally distinct
      compartments.
AB  - Pro-alpha-factor (pro-alphaf) is posttranslationally modified in the yeast Golgi
      complex by the addition of alpha1,6-, alpha1,2-, and alpha1,3-linked mannose to N
      linked oligosaccharides and by a Kex2p-initiated proteolytic processing event.
      Previous work has indicated that the alpha1,6- and alpha1,3-mannosylation and
      Kex2p-dependent processing of pro-alphaf are initiated in three distinct
      compartments of the Golgi complex. Here, we present evidence that alpha1,2
      mannosylation of pro-alphaf is also initiated in a distinct Golgi compartment.
      Linkage-specific antisera and an endo-alpha1,6-D-mannanase (endoM) were used to
      quantitate the amount of each pro-alphaf intermediate during transport through
      the Golgi complex. We found that alpha1,6-, alpha1,2-, and alpha1,3-mannose were
      sequentially added to pro-alphaf in a temporally ordered manner, and that the
      intercompartmental transport factor Sec18p/N-ethylmaleimide-sensitive factor was
      required for each step. The Sec18p dependence implies that a transport event was
      required between each modification event. In addition, most of the Golgi-modified
      pro-alphaf that accumulated in brefeldin A-treated cells received only alpha1,6
      mannosylation as did approximately 50% of pro-alphaf transported to the Golgi in
      vitro. This further supports the presence of an early Golgi compartment that
      houses an alpha1,6-mannosyltransferase but lacks alpha1,2-mannosyltransferase
      activity in vivo. We propose that the alpha1,6-, alpha1,2-, and alpha1,3
      mannosylation and Kex2p-dependent processing events mark the cis, medial, trans,
      and trans-Golgi network of the yeast Golgi complex, respectively.

PMID- 10637301
TI  - Characterization of alcohol-induced filamentous growth in Saccharomyces
      cerevisiae.
AB  - Diploid cells of the budding yeast Saccharomyces cerevisiae starved for nitrogen
      differentiate into a filamentous growth form. Poor carbon sources such as
      starches can also stimulate filamentation, whereas haploid cells undergo a
      similar invasive growth response in rich medium. Previous work has demonstrated a
      role for various alcohols, by-products of amino acid metabolism, in altering
      cellular morphology. We found that several alcohols, notably isoamyl alcohol and
      1-butanol, stimulate filamentous growth in haploid cells in which this
      differentiation is normally repressed. Butanol also induces cell elongation and
      changes in budding pattern, leading to a pseudohyphal morphology, even in liquid
      medium. The filamentous colony morphology and cell elongation require elements of
      the pheromone-responsive MAPK cascade and TEC1, whereas components of the
      nutrient-sensing machinery, such as MEP2, GPA2, and GPR1, do not affect this
      phenomenon. A screen for 1-butanol-insensitive mutants identified additional
      proteins that regulate polarized growth (BUD8, BEM1, BEM4, and FIG1),
      mitochondrial function (MSM1, MRP21, and HMI1), and a transcriptional regulator
      (CHD1). Furthermore, we have also found that ethanol stimulates
      hyperfilamentation in diploid cells, again in a MAPK-dependent manner. Together,
      these results suggest that yeast may sense a combination of nutrient limitation
      and metabolic by-products to regulate differentiation.

PMID- 10637302
TI  - The Rib43a protein is associated with forming the specialized protofilament
      ribbons of flagellar microtubules in Chlamydomonas.
AB  - Ciliary and flagellar microtubules contain a specialized set of three
      protofilaments, termed ribbons, that are composed of tubulin and several
      associated proteins. Previous studies of sea urchin sperm flagella identified
      three of the ribbon proteins as tektins, which form coiled-coil filaments in
      doublet microtubules and which are associated with basal bodies and centrioles.
      To study the function of tektins and other ribbon proteins in the assembly of
      flagella and basal bodies, we have begun an analysis of ribbons from the
      unicellular biflagellate, Chlamydomonas reinhardtii, and report here the
      molecular characterization of the ribbon protein rib43a. Using antibodies against
      rib43a to screen an expression library, we recovered a full-length cDNA clone
      that encodes a 42,657-Da polypeptide. On Northern blots, the rib43a cDNA
      hybridized to a 1. 7-kb transcript, which was up-regulated upon deflagellation,
      consistent with a role for rib43a in flagellar assembly. The cDNA was used to
      isolate RIB43a, an approximately 4.6-kb genomic clone containing the complete
      rib43a coding region, and restriction fragment length polymorphism analysis
      placed the RIB43a gene on linkage group III. Sequence analysis of the RIB43a gene
      indicates that the substantially coiled-coil rib43a protein shares a high degree
      of sequence identity with clones from Trypanosoma cruzi and Homo sapiens
      (genomic, normal fetal kidney, and endometrial and germ cell tumors) but little
      sequence similarity to other proteins including tektins. Affinity-purified
      antibodies against native and bacterially expressed rib43a stained both flagella
      and basal bodies by immunofluorescence microscopy and stained isolated flagellar
      ribbons by immuno-electron microscopy. The structure of rib43a and its
      association with the specialized protofilament ribbons and with basal bodies is
      relevant to the proposed role of ribbons in forming and stabilizing doublet and
      triplet microtubules and in organizing their three-dimensional structure.

PMID- 10637303
TI  - Dissociation from BiP and retrotranslocation of unassembled immunoglobulin light
      chains are tightly coupled to proteasome activity.
AB  - Unassembled immunoglobulin light chains expressed by the mouse plasmacytoma cell
      line NS1 (kappa(NS1)) are degraded in vivo with a half-life of 50-60 min in a way
      that closely resembles endoplasmic reticulum (ER)-associated degradation (). Here
      we show that the peptide aldehydes MG132 and PS1 and the specific proteasome
      inhibitor lactacystin effectively increased the half-life of kappa(NS1), arguing
      for a proteasome-mediated degradation pathway. Subcellular fractionation and
      protease protection assays have indicated an ER localization of kappa(NS1) upon
      proteasome inhibition. This was independently confirmed by the analysis of the
      folding state of kappa(NS1) and size fractionation experiments showing that the
      immunoglobulin light chain remained bound to the ER chaperone BiP when the
      activity of the proteasome was blocked. Moreover, kinetic studies performed in
      lactacystin-treated cells revealed a time-dependent increase in the physical
      stability of the BiP-kappa(NS1) complex, suggesting that additional proteins are
      present in the older complex. Together, our data support a model for ER
      associated degradation in which both the release of a soluble nonglycosylated
      protein from BiP and its retrotranslocation out of the ER are tightly coupled
      with proteasome activity.

PMID- 10637304
TI  - ATPase-defective mammalian VPS4 localizes to aberrant endosomes and impairs
      cholesterol trafficking.
AB  - The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal
      trafficking that couples membrane association to its ATPase cycle. To investigate
      the function of mammalian VPS4 in endosomal trafficking, we have transiently
      expressed wild-type or ATPase-defective human VPS4 (hVPS4) in cultured cells.
      Wild-type hVPS4 was cytosolic, whereas a substantial fraction of hVPS4 that was
      unable to either bind or hydrolyze ATP was localized to membranes, including
      those of specifically induced vacuoles. Vacuoles were exclusively endocytic in
      origin, and subsets of enlarged vacuoles stained with markers for each stage of
      the endocytic pathway. Sorting of receptors from the early endosome to the
      recycling compartment or to the trans-Golgi network was not significantly
      affected, and no mutant hVPS4 associated with these compartments. However, many
      hVPS4-induced vacuoles were substantially enriched in cholesterol relative to the
      endosomal compartments of untransfected cells, indicating that expression of
      mutant hVPS4 gives rise to a kinetic block in postendosomal cholesterol sorting.
      The phenotype described here is largely consistent with the defects in vacuolar
      sorting associated with class E vps mutants in yeast, and a role for mammalian
      VPS4 is discussed in this context.

PMID- 10637305
TI  - Functional coordination of three mitotic motors in Drosophila embryos.
AB  - It is well established that multiple microtubule-based motors contribute to the
      formation and function of the mitotic spindle, but how the activities of these
      motors interrelate remains unclear. Here we visualize spindle formation in living
      Drosophila embryos to show that spindle pole movements are directed by a
      temporally coordinated balance of forces generated by three mitotic motors,
      cytoplasmic dynein, KLP61F, and Ncd. Specifically, our findings suggest that
      dynein acts to move the poles apart throughout mitosis and that this activity is
      augmented by KLP61F after the fenestration of the nuclear envelope, a process
      analogous to nuclear envelope breakdown, which occurs at the onset of
      prometaphase. Conversely, we find that Ncd generates forces that pull the poles
      together between interphase and metaphase, antagonizing the activity of both
      dynein and KLP61F and serving as a brake for spindle assembly. During anaphase,
      however, Ncd appears to have no effect on spindle pole movements, suggesting that
      its activity is down-regulated at this time, allowing dynein and KLP61F to drive
      spindle elongation during anaphase B.

PMID- 10637306
TI  - Biogenesis of multilamellar bodies via autophagy.
AB  - Transfection of Mv1Lu mink lung type II alveolar cells with beta1-6-N
      acetylglucosaminyl transferase V is associated with the expression of large
      lysosomal vacuoles, which are immunofluorescently labeled for the lysosomal
      glycoprotein lysosomal-associated membrane protein-2 and the beta1-6-branched N
      glycan-specific lectin phaseolis vulgaris leucoagglutinin. By electron
      microscopy, the vacuoles present the morphology of multilamellar bodies (MLBs).
      Treatment of the cells with the lysosomal protease inhibitor leupeptin results in
      the progressive transformation of the MLBs into electron-dense autophagic
      vacuoles and eventual disappearance of MLBs after 4 d of treatment. Heterologous
      structures containing both membrane lamellae and peripheral electron-dense
      regions appear 15 h after leupeptin addition and are indicative of ongoing
      lysosome-MLB fusion. Leupeptin washout is associated with the formation after 24
      and 48 h of single or multiple foci of lamellae within the autophagic vacuoles,
      which give rise to MLBs after 72 h. Treatment with 3-methyladenine, an inhibitor
      of autophagic sequestration, results in the significantly reduced expression of
      multilamellar bodies and the accumulation of inclusion bodies resembling nascent
      or immature autophagic vacuoles. Scrape-loaded cytoplasmic FITC-dextran is
      incorporated into lysosomal-associated membrane protein-2-positive MLBs, and this
      process is inhibited by 3-methyladenine, demonstrating that active autophagy is
      involved in MLB formation. Our results indicate that selective resistance to
      lysosomal degradation within the autophagic vacuole results in the formation of a
      microenvironment propicious for the formation of membrane lamella.

PMID- 10637307
TI  - Reversible and irreversible unfolding of mitotic newt chromosomes by applied
      force.
AB  - The force-extension behavior of individual mitotic newt chromosomes was studied,
      using micropipette surgery and manipulation, for elongations up to 80 times
      native length. After elongations up to five times, chromosomes return to their
      native length. In this regime chromosomes have linear elasticity, requiring
      approximately 1 nN of force to be stretched to two times native length. After
      more than five times stretching, chromosomes are permanently elongated, with
      force hysteresis during relaxation. If a chromosome is repeatedly stretched to
      approximately 10 times native length and relaxed, a series of hysteresis loops
      are obtained that converge to a single reversible elastic response. For further
      elongations, the linear dependence of force on extension terminates at a force
      "plateau" of approximately 15-20 nN, near 30 times extension. After >30 times
      extensions, the elastic moduli of chromosomes can be reduced by more than 20
      fold, and they appear as "ghosts": swollen, elongated, and with reduced optical
      contrast under both phase and differential interference contrast imaging.
      Antibody labeling indicates that histone proteins are not being lost during even
      extreme extensions. Results are interpreted in terms of extension and failure of
      chromatin-tethering elements; the force data allow estimates of the number and
      size of such connectors in a chromosome.

PMID- 10637308
TI  - The N terminus of the transmembrane protein BP180 interacts with the N-terminal
      domain of BP230, thereby mediating keratin cytoskeleton anchorage to the cell
      surface at the site of the hemidesmosome.
AB  - In epidermal cells, the keratin cytoskeleton interacts with the elements in the
      basement membrane via a multimolecular junction called the hemidesmosome. A major
      component of the hemidesmosome plaque is the 230-kDa bullous pemphigoid
      autoantigen (BP230/BPAG1), which connects directly to the keratin-containing
      intermediate filaments of the cytoskeleton via its C terminus. A second bullous
      pemphigoid antigen of 180 kDa (BP180/BPAG2) is a type II transmembrane component
      of the hemidesmosome. Using yeast two-hybrid technology and recombinant proteins,
      we show that an N-terminal fragment of BP230 can bind directly to an N-terminal
      fragment of BP180. We have also explored the consequences of expression of the
      BP230 N terminus in 804G cells that assemble hemidesmosomes in vitro.
      Unexpectedly, this fragment disrupts the distribution of BP180 in transfected
      cells but has no apparent impact on the organization of endogenous BP230 and
      alpha6beta4 integrin. We propose that the BP230 N terminus competes with
      endogenous BP230 protein for BP180 binding and inhibits incorporation of BP180
      into the cell surface at the site of the hemidesmosome. These data provide new
      insight into those interactions of the molecules of the hemidesmosome that are
      necessary for its function in integrating epithelial and connective tissue types.

PMID- 10637309
TI  - Selective alterations in biosynthetic and endocytic protein traffic in Madin
      Darby canine kidney epithelial cells expressing mutants of the small GTPase Rac1.
AB  - Madin-Darby canine kidney (MDCK) cells expressing constitutively active Rac1
      (Rac1V12) accumulate a large central aggregate of membranes beneath the apical
      membrane that contains filamentous actin, Rac1V12, rab11, and the resident apical
      membrane protein GP-135. To examine the roles of Rac1 in membrane traffic and the
      formation of this aggregate, we analyzed endocytic and biosynthetic trafficking
      pathways in MDCK cells expressing Rac1V12 and dominant inactive Rac1 (Rac1N17).
      Rac1V12 expression decreased the rates of apical and basolateral endocytosis,
      whereas Rac1N17 expression increased those rates from both membrane domains.
      Basolateral-to-apical transcytosis of immunoglobulin A (IgA) (a ligand for the
      polymeric immunoglobulin receptor [pIgR]), apical recycling of pIgR-IgA, and
      accumulation of newly synthesized GP-135 at the apical plasma membrane were all
      decreased in cells expressing Rac1V12. These effects of Rac1V12 on trafficking
      pathways to the apical membrane were the result of the delivery and trapping of
      these proteins in the central aggregate. In contrast to abnormalities in apical
      trafficking events, basolateral recycling of transferrin, degradation of EGF
      internalized from the basolateral membrane, and delivery of newly synthesized
      pIgR from the Golgi to the basolateral membrane were all relatively unaffected by
      Rac1V12 expression. Rac1N17 expression had little or no effect on these
      postendocytic or biosynthetic trafficking pathways. These results show that in
      polarized MDCK cells activated Rac1 may regulate the rate of endocytosis from
      both membrane domains and that expression of dominant active Rac1V12 specifically
      alters postendocytic and biosynthetic membrane traffic directed to the apical,
      but not the basolateral, membrane.

PMID- 10637310
TI  - Vps52p, Vps53p, and Vps54p form a novel multisubunit complex required for protein
      sorting at the yeast late Golgi.
AB  - The late Golgi of the yeast Saccharomyces cerevisiae receives membrane traffic
      from the secretory pathway as well as retrograde traffic from post-Golgi
      compartments, but the machinery that regulates these vesicle-docking and fusion
      events has not been characterized. We have identified three components of a novel
      protein complex that is required for protein sorting at the yeast late Golgi
      compartment. Mutation of VPS52, VPS53, or VPS54 results in the missorting of 70%
      of the vacuolar hydrolase carboxypeptidase Y as well as the mislocalization of
      late Golgi membrane proteins to the vacuole, whereas protein traffic through the
      early part of the Golgi complex is unaffected. A vps52/53/54 triple mutant strain
      is phenotypically indistinguishable from each of the single mutants, consistent
      with the model that all three are required for a common step in membrane
      transport. Native coimmunoprecipitation experiments indicate that Vps52p, Vps53p,
      and Vps54p are associated in a 1:1:1 complex that sediments as a single peak on
      sucrose velocity gradients. This complex, which exists both in a soluble pool and
      as a peripheral component of a membrane fraction, colocalizes with markers of the
      yeast late Golgi by immunofluorescence microscopy. Together, the phenotypic and
      biochemical data suggest that VPS52, VPS53, and VPS54 are required for the
      retrograde transport of Golgi membrane proteins from an endosomal/prevacuolar
      compartment. The Vps52/53/54 complex joins a growing list of distinct
      multisubunit complexes that regulate membrane-trafficking events.

PMID- 10637311
TI  - Identification of filamin as a novel ligand for caveolin-1: evidence for the
      organization of caveolin-1-associated membrane domains by the actin cytoskeleton.
AB  - Reports on the ultrastructure of cells as well as biochemical data have, for
      several years, been indicating a connection between caveolae and the actin
      cytoskeleton. Here, using a yeast two-hybrid approach, we have identified the F
      actin cross-linking protein filamin as a ligand for the caveolae-associated
      protein caveolin-1. Binding of caveolin-1 to filamin involved the N-terminal
      region of caveolin-1 and the C terminus of filamin close to the filamin
      dimerization domain. In in vitro binding assays, recombinant caveolin-1 bound to
      both nonmuscle and muscle filamin, indicating that the interaction might not be
      cell type specific. With the use of confocal microscopy, colocalization of
      caveolin-1 and filamin was observed in elongated patches at the plasma membrane.
      Remarkably, when stress fiber formation was induced with Rho-stimulating
      Escherichia coli cytotoxic necrotizing factor 1, the caveolin-1-positive
      structures became coaligned with stress fibers, indicating that there was a
      physical link connecting them. Immunogold double-labeling electron microscopy
      confirmed that caveolin-1-labeled racemose caveolae clusters were positive for
      filamin. The actin network, therefore, seems to be directly involved in the
      spatial organization of caveolin-1-associated membrane domains.

PMID- 10637312
TI  - Functions and functional domains of the GTPase Cdc42p.
AB  - Cdc42p, a Rho family GTPase of the Ras superfamily, is a key regulator of cell
      polarity and morphogenesis in eukaryotes. Using 37 site-directed cdc42 mutants,
      we explored the functions and interactions of Cdc42p in the budding yeast
      Saccharomyces cerevisiae. Cytological and genetic analyses of these cdc42 mutants
      revealed novel and diverse phenotypes, showing that Cdc42p possesses at least two
      distinct essential functions and acts as a nodal point of cell polarity
      regulation in vivo. In addition, mapping the functional data for each cdc42
      mutation onto a structural model of the protein revealed as functionally
      important a surface of Cdc42p that is distinct from the canonical protein
      interacting domains (switch I, switch II, and the C terminus) identified
      previously in members of the Ras superfamily. This region overlaps with a region
      (alpha5-helix) recently predicted by structural models to be a specificity
      determinant for Cdc42p-protein interactions.

PMID- 10637313
TI  - Toxofilin, a novel actin-binding protein from Toxoplasma gondii, sequesters actin
      monomers and caps actin filaments.
AB  - Toxoplasma gondii relies on its actin cytoskeleton to glide and enter its host
      cell. However, T. gondii tachyzoites are known to display a strikingly low amount
      of actin filaments, which suggests that sequestration of actin monomers could
      play a key role in parasite actin dynamics. We isolated a 27-kDa tachyzoite
      protein on the basis of its ability to bind muscle G-actin and demonstrated that
      it interacts with parasite G-actin. Cloning and sequence analysis of the gene
      coding for this protein, which we named Toxofilin, showed that it is a novel
      actin-binding protein. In in vitro assays, Toxofilin not only bound to G-actin
      and inhibited actin polymerization as an actin-sequestering protein but also
      slowed down F-actin disassembly through a filament end capping activity. In
      addition, when green fluorescent protein-tagged Toxofilin was overexpressed in
      mammalian nonmuscle cells, the dynamics of actin stress fibers was drastically
      impaired, whereas green fluorescent protein-Toxofilin copurified with G-actin.
      Finally, in motile parasites, during gliding or host cell entry, Toxofilin was
      localized in the entire cytoplasm, including the rear end of the parasite,
      whereas in intracellular tachyzoites, especially before they exit from the
      parasitophorous vacuole of their host cell, Toxofilin was found to be restricted
      to the apical end.

PMID- 10637315
TI  - Association of mouse actin-binding protein 1 (mAbp1/SH3P7), an Src kinase target,
      with dynamic regions of the cortical actin cytoskeleton in response to Rac1
      activation.
AB  - Yeast Abp1p is a cortical actin cytoskeleton protein implicated in cytoskeletal
      regulation, endocytosis, and cAMP-signaling. We have identified a gene encoding a
      mouse homologue of Abp1p, and it is identical to SH3P7, a protein shown recently
      to be a target of Src tyrosine kinases. Yeast and mouse Abp1p display the same
      domain structure including an N-terminal actin-depolymerizing factor homology
      domain and a C-terminal Src homology 3 domain. Using two independent actin
      binding domains, mAbp1 binds to actin filaments with a 1:5 saturation
      stoichiometry. In stationary cells, mAbp1 colocalizes with cortical F-actin in
      fibroblast protrusions that represent sites of cellular growth. mAbp1 appears at
      the actin-rich leading edge of migrating cells. Growth factors cause mAbp1 to
      rapidly accumulate in lamellipodia. This response can be mimicked by expression
      of dominant-positive Rac1. mAbp1 recruitment appears to be dependent on de novo
      actin polymerization and occurs specifically at sites enriched for the Arp2/3
      complex. mAbp1 is a newly identified cytoskeletal protein in mice and may serve
      as a signal-responsive link between the dynamic cortical actin cytoskeleton and
      regions of membrane dynamics.

PMID- 10637314
TI  - Kinetic analysis of a molecular model of the budding yeast cell cycle.
AB  - The molecular machinery of cell cycle control is known in more detail for budding
      yeast, Saccharomyces cerevisiae, than for any other eukaryotic organism. In
      recent years, many elegant experiments on budding yeast have dissected the roles
      of cyclin molecules (Cln1-3 and Clb1-6) in coordinating the events of DNA
      synthesis, bud emergence, spindle formation, nuclear division, and cell
      separation. These experimental clues suggest a mechanism for the principal
      molecular interactions controlling cyclin synthesis and degradation. Using
      standard techniques of biochemical kinetics, we convert the mechanism into a set
      of differential equations, which describe the time courses of three major classes
      of cyclin-dependent kinase activities. Model in hand, we examine the molecular
      events controlling "Start" (the commitment step to a new round of chromosome
      replication, bud formation, and mitosis) and "Finish" (the transition from
      metaphase to anaphase, when sister chromatids are pulled apart and the bud
      separates from the mother cell) in wild-type cells and 50 mutants. The model
      accounts for many details of the physiology, biochemistry, and genetics of cell
      cycle control in budding yeast.

PMID- 10637316
TI  - A compilation of cellular transcription factor interactions with the HIV-1 LTR
      promoter.
AB  - The human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR)
      represents a model promoter system and the identification and characterisation of
      cellular proteins that interact with this region has provided a basic
      understanding about both general eukaryotic and HIV-1 proviral transcriptional
      regulation. To date a large number of sequence-specific DNA-protein interactions
      have been described for the HIV-1 LTR. The aim of this report is to provide a
      comprehensive, updated listing of these HIV-1 LTR interactions. It is intended as
      a reference point to facilitate on-going studies characterising the identity of
      cellular proteins interacting with the HIV-1 LTR and the functional role(s) of
      specific regions of the LTR for HIV-1 replication.

PMID- 10637317
TI  - Sp1 cooperates with c-Myc to activate transcription of the human telomerase
      reverse transcriptase gene (hTERT).
AB  - Telomerase activation is thought to be a critical step in cellular
      immortalization and carcinogenesis. The human telomerase catalytic subunit
      (hTERT) is a rate limiting determinant of the enzymatic activity of human
      telomerase. In the previous study, we identified the proximal 181 bp core
      promoter responsible for transcriptional activity of the hTERT gene. To identify
      the regulatory factors of transcription, transient expression assays were
      performed using hTERT promoter reporter plasmids. Serial deletion assays of the
      core promoter revealed that the 5'-region containing the E-box, which binds
      Myc/Max, as well as the 3'-region containing the GC-box, which binds Sp1, are
      essential for transactivation. The mutations introduced in the E-box or GC-box
      significantly decreased transcriptional activity of the promoter. Overexpression
      of Myc/Max or Sp1 led to significant activation of transcription in a cell type
      specific manner, while Mad/Max introduction repressed it. However, the effects of
      Myc/Max on transactivation were marginal when Sp1 sites were mutated. Western
      blot analysis using various cell lines revealed a positive correlation between c
      Myc and Sp1 expression and transcriptional activity of hTERT. Using fibroblast
      lineages in different stages of transformation, we found that c-Myc and Sp1 were
      induced to a dramatic extent when cells overcame replicative senescence and
      obtained immortal characteristics, in association with telomerase activation.
      These findings suggest that c-Myc and Sp1 cooperatively function as the major
      determinants of hTERT expression, and that the switching functions of Myc/Max and
      Mad/Max might also play roles in telomerase regulation.

PMID- 10637318
TI  - Association of a protein phosphatase 1 activity with the human factor C1 (HCF)
      complex.
AB  - We have screened a human cDNA expression library with a digoxygenin-labelled
      protein phosphatase 1 (PP1) probe to identify novel PP1 interacting proteins.
      Eleven cDNA clones were isolated, which included genes encoding two previously
      characterised and six novel PP1 binding proteins. Three of the cDNAs encoded a
      protein called host cell factor (HCF), which is an essential component of the
      cellular complex required for the transcription of the herpes simplex virus (HSV)
      immediate-early (IE) genes. We demonstrate that HCF and PP1 exist as a complex in
      nuclear extracts and that this complex is distinct from the form of HCF that
      associates with HSV VP16. The data suggest novel roles for HCF and PP1, which may
      be relevant to their functions in transcription and cell cycle progression.

PMID- 10637319
TI  - Analysis of the c-myc IRES; a potential role for cell-type specific trans-acting
      factors and the nuclear compartment.
AB  - The 5' UTR of c -myc mRNA contains an internal ribo-some entry segment (IRES) and
      consequently, c -myc mRNAs can be translated by the alternative mechanism of
      internal ribosome entry. However, there is also some evidence suggesting that c 
      myc mRNA translation can occur via the conventional cap-dependent scanning
      mechanism. Using both bicistronic and monocistronic mRNAs containing the c- myc
      5' UTR, we demonstrate that both mechanisms can contribute to c- myc protein
      synthesis. A wide range of cell types are capable of initiating translation of c-
      myc by internal ribosome entry, albeit with different efficiencies. Moreover, our
      data suggest that the spectrum of efficiencies observed in these cell types is
      likely to be due to variation in the cellular concentration of non-canonical
      translation factors. Interestingly, the c -myc IRES is 7-fold more active than
      the human rhinovirus 2 (HRV2) IRES and 5-fold more active than the
      encephalomyocarditis virus (EMCV) IRES. However, the protein requirements for the
      c -myc IRES must differ significantly from these viral IRESs, since an
      unidentified nuclear event appears to be a pre-requisite for efficient c -myc
      IRES-driven initiation.

PMID- 10637320
TI  - Prediction of transcription regulatory sites in Archaea by a comparative genomic
      approach.
AB  - Intragenomic and intergenomic comparisons of upstream nucleotide sequences of
      archaeal genes were performed with the goal of predicting transcription
      regulatory sites (operators) and identifying likely regulons. Learning sets for
      the detection of regulatory sites were constructed using the available
      experimental data on archaeal transcription regulation or by analogy with known
      bacterial regulons, and further analysis was performed using iterative profile
      searches. The information content of the candidate signals detected by this
      method is insufficient for reliable predictions to be made. Therefore, this
      approach has to be complemented by examination of evolutionary conservation in
      different archaeal genomes. This combined strategy resulted in the prediction of
      a conserved heat shock regulon in all euryarchaea, a nitrogen fixation regulon in
      the methanogens Methanococcus jannaschii and Methanobacterium thermoautotrophicum
      and an aromatic amino acid regulon in M.thermoautotrophicum. Unexpectedly, the
      heat shock regulatory site was detected not only for genes that encode known
      chaperone proteins but also for archaeal histone genes. This suggests a possible
      function for archaeal histones in stress-related changes in DNA condensation. In
      addition, comparative analysis of the genomes of three Pyrococcus species
      resulted in the prediction of their purine metabolism and transport regulon. The
      results demonstrate the feasibility of prediction of at least some transcription
      regulatory sites by comparing poorly characterized prokaryotic genomes,
      particularly when several closely related genome sequences are available.

PMID- 10637321
TI  - Structural analysis of DNA sequence: evidence for lateral gene transfer in
      Thermotoga maritima.
AB  - The recently published complete DNA sequence of the bacterium Thermotoga maritima
      provides evidence, based on protein sequence conservation, for lateral gene
      transfer between Archaea and Bacteria. We introduce a new method of periodicity
      analysis of DNA sequences, based on structural parameters, which brings
      independent evidence for the lateral gene transfer in the genome of T.maritima.
      The structural analysis relates the Archaea-like DNA sequences to the genome of
      Pyrococcus horikoshii. Analysis of 24 complete genomic DNA sequences shows
      different periodicity patterns for organisms of different origin. The typical
      genomic periodicity for Bacteria is 11 bp whilst it is 10 bp for Archaea.
      Eukaryotes have more complex spectra but the dominant period in the yeast
      Saccharomyces cerevisiae is 10.2 bp. These periodicities are most likely
      reflective of differences in chromatin structure.

PMID- 10637322
TI  - Structural basis for recognition of the RNA major groove in the tau exon 10
      splicing regulatory element by aminoglycoside antibiotics.
AB  - Drug-like molecules that bind RNA with sequence selectivity would provide
      valuable tools to elucidate gene expression pathways and new avenues to the
      treatment of degenerative and chronic conditions. Efforts at discovering such
      agents have been hampered, until recently, by the limited knowledge of RNA
      recognition principles. Several recent structures of aminoglycoside-RNA complexes
      have begun to reveal the structural basis for RNA-drug recognition. However, the
      absence of suitable chemical scaffolds known to bind the RNA major groove, where
      specificity could be provided by the diversity of functional groups exposed on
      the RNA bases, has represented a major obstacle. Here we report an investigation
      of the structural basis for recognition of an RNA stem-loop by neomycin, a
      naturally occurring aminoglycoside antibiotic. We found that neomycin binds the
      RNA stem-loop that regulates alternative splicing of exon 10 within the gene
      coding for human tau protein. Mutations within this splicing regulatory element
      destabilise the RNA structure and cause frontotemporal dementia and Parkinsonism
      linked to chromosome 17 (FTDP-17), an autosomal dominant condition leading to
      neurodegeneration and death. The three-dimensional structure of the RNA-neomycin
      complex shows interaction of the drug in the major groove of the short RNA
      duplex, where familial mutations cluster. Analysis of the structure shows how
      aminoglycosides and related drugs bind to the RNA major groove, adding to our
      understanding of the principles of drug-RNA recognition.

PMID- 10637323
TI  - Active site constraints in the hydrolysis reaction catalyzed by bacterial RNase
      P: analysis of precursor tRNAs with a single 3'-S-phosphorothiolate
      internucleotide linkage.
AB  - Endonucleolytic processing of precursor tRNAs (ptRNAs) by RNase P yields 3'-OH
      and 5'-phosphate termini, and at least two metal ions are thought to be essential
      for catalysis. To determine if the hydrolysis reaction catalyzed by bacterial
      RNase P (RNAs) involves stabilization of the 3'-oxyanion leaving group by direct
      coordination to one of the catalytic metal ions, ptRNA substrates with single 3'-
      S -phosphorothiolate linkages at the RNase P cleavage site were synthesized. With
      a 3'- S -phosphorothiolate-modified ptRNA carrying a 7 nt 5'-flank, a complete
      shift of the cleavage site to the next unmodified phosphodiester in the 5'
      direction was observed. Cleavage at the modified linkage was not restored in the
      presence of thiophilic metal ions, such as Mn(2+)or Cd(2+). To suppress aberrant
      cleavage, we also constructed a 3'- S -phosphorothiolate-modified ptRNA with a 1
      nt 5'-flank. No detectable cleavage of this substrate was seen in reactions
      catalyzed by RNase P RNAs from Escherichia coli and Bacillus subtilis,
      independent of the presence of thiophilic metal ions. Ground state binding of
      modified ptRNAs was not impaired, suggesting that the 3'- S -phosphorothiolate
      modification specifically prevents formation of the transition state, possibly by
      excluding catalytic metal ions from the active site.

PMID- 10637325
TI  - The ribosomal P-proteins of the medfly Ceratitis capitata form a heterogeneous
      stalk structure interacting with the endogenous P-proteins, in conditional P0
      null strains of the yeast Saccharomyces cerevisiae.
AB  - The genes encoding the ribosomal P-proteins CcP0, CcP1 and CcP2 of Ceratitis
      capitata were expressed in the conditional P0-null strains W303dGP0 and D67dGP0
      of Saccharomyces cerevisiae, the ribosomes of which contain either standard
      amounts or are totally deprived of the P1/P2 proteins, respectively. The presence
      of the CcP0 protein restored cell viability but reduced the growth rate. In the
      W303CcP0 strain, all four acidic yeast proteins were found on the ribosomes, but
      in notably less quantity, while a preferable binding of the YP1alpha/YP2betapair
      was established. In the absence of the endogenous P1/P2 proteins in the D67CcP0
      strain, the complementation capacity of the CcP0 protein was considerably
      reduced. The simultaneous expression of the three medfly genes resulted in
      alterations of the stalk composition: both the CcP1 and CcP2 proteins were found
      on the particles substituting the YP1alphaand YP2alpha proteins, respectively,
      but their presence did not alter the growth rate, except in the case of the
      YP1alpha/betadefective strain, where a helping effect on the binding of the
      YP2alphaand YP2betaproteins on the ribo-somes was confirmed. Therefore, the
      medfly ribosomal P-proteins complement the yeast P-protein deficient strains
      forming an heterogeneous ribosomal stalk, which, however, is not functionally
      equivalent to the endogenous one.

PMID- 10637324
TI  - Sequence-dependent variation in DNA minor groove width dictates orientational
      preference of Hoechst 33258 in A-tract recognition: solution NMR structure of the
      2:1 complex with d(CTTTTGCAAAAG)(2).
AB  - The solution structure of the dodecamer duplex d(CTTTTGCAAAAG)(2)and its 2:1
      complex with the bis -benzimidazole Hoechst 33258 has been investigated by NMR
      and NOE-restrained molecular dynamics (rMD) simulations. Drug molecules are bound
      in each of the two A-tracts with the bulky N-methylpiperazine ring of each drug
      located close to the central TG (CA) step, binding essentially to the narrow
      minor groove of each A-tract. MD simulations over 1 ns, using an explicit
      solvation model, reveal time-averaged sequence-dependent narrowing of the minor
      groove from the 3'-end towards the 5'-end of each TTTT sequence. Distinct
      junctions at the TpG (CpA) steps, characterised by large positive roll, low
      helical and propeller twists and rapid AT base pair opening rates, add to the
      widening of the groove at these sites and appear to account for the bound
      orientation of the two drug molecules with the N-methylpiperazine ring binding in
      the wider part of the groove close to the junctions. Comparisons between the free
      DNA structure and the 2:1 complex (heavy atom RMSD 1.55 A) reveal that these
      sequence-dependent features persist in both structures. NMR studies of the
      sequence d(GAAAAGCTTTTC)(2), in which the A-tracts have been inverted with the
      elimination of the TpG junctions, results in loss of orientational specificity of
      Hoechst 33258 and formation of multiple bound species in solution, consistent
      with the drug binding in a number of different orientations.

PMID- 10637326
TI  - Positional characterisation of false positives from computational prediction of
      human splice sites.
AB  - The performance of computational tools that can predict human splice sites are
      reviewed using a test set of EST-confirmed splice sites. The programs (namely
      HMMgene, NetGene2, HSPL, NNSPLICE, SpliceView and GeneID-3) differ from one
      another in the degree of discriminatory information used for prediction. The
      results indicate that, as expected, HMMgene and NetGene2 (which use global as
      well as local coding information and splice signals) followed by HSPL (which uses
      local coding information and splice signals) performed better than the other
      three programs (which use only splice signals). For the former three programs,
      one in every three false positive splice sites was predicted in the vicinity of
      true splice sites while only one in every 12 was expected to occur in such a
      region by chance. The persistence of this observation for programs (namely FEXH,
      GRAIL2, MZEF, GeneID-3, HMMgene and GENSCAN) that can predict all the potential
      exons (including optimal and sub-optimal) was assessed. In a high proportion
      (>50%) of the partially correct predicted exons, the incorrect exon ends were
      located in the vicinity of the real splice sites. Analysis of the distribution of
      proximal false positives indicated that the splice signals used by the algorithms
      are not strong enough to discriminate particularly those false predictions that
      occur within +/- 25 nt around the real sites. It is therefore suggested that
      specialised statistics that can discriminate real splice sites from proximal
      false positives be incorporated in gene prediction programs.

PMID- 10637327
TI  - The efficiency of Escherichia coli selenocysteine insertion is influenced by the
      immediate downstream nucleotide.
AB  - Selenocysteine (Sec) incorporation requires the TGA opal codon and a downstream
      Sec insertion sequence (SECIS), which can be partially randomized and cloned into
      M13 pIII fusion constructs for phage display. This combinatorial approach
      provides a convenient non-radioactive assay that couples phage production to opal
      suppression. Two SECIS libraries were prepared, with the immediate downstream
      nucleotide either randomized (TGAN) or fixed as thymidine (TGAT). The TGAN
      library resulted in a majority of clones with a downstream purine and selenium
      independent phage production, implicating the endo-genous tryptophan-inserting
      opal suppression pathway. Although the addition of sodium selenite to the growth
      medium did not affect phage production, it did increase the level of Sec
      insertion, as shown by the chemical reactivity of the resulting phage. The TGAT
      phage library yielded clones with strictly selenium-dependent phage production
      and reactivity consistent with the presence of Sec. These clones were prone to
      spontaneous mutation upon further propagation, however, resulting in loss of the
      selenium-dependent phenotype. We conclude that the immediate downstream
      nucleotide determines whether the endogenous opal suppression pathway competes
      with co-translational Sec insertion.

PMID- 10637328
TI  - The genes encoding endonuclease VIII and endonuclease III in Escherichia coli are
      transcribed as the terminal genes in operons.
AB  - Escherichia coli endonuclease VIII and endo-nuclease III are oxidative base
      excision repair DNA glycosylases that remove oxidized pyrimidines from DNA. The
      genes encoding these proteins, nei and nth, are both co-transcribed as the
      terminal genes in operons. nei is the terminal gene in an operon with four open
      reading frames that encode proteins of unknown function. This operon has two
      confirmed transcription initiation sites upstream of the first open reading frame
      and two transcript termination sites downstream of nei. nth is the terminal gene
      in an operon with seven open reading frames that encode proteins of unknown
      function. The six open reading frames immediately upstream of nth show homology
      to the genes rnfA, rnfB, rnfC, rnfD, rnfG and rnfE from Rhodobacter capsulatis.
      The rnf genes are required for nitrogen fixation in R.capsulatis and have been
      predicted to make up a membrane complex involved in electron transport to
      nitrogenase. The nth operon has transcription initiation sites upstream of the
      first and second open reading frames and a single transcript termination site
      downstream of nth. The order of genes in these operons has been conserved or
      partially conserved in other bacteria, although it is not known whether the genes
      are co-transcribed in these other organisms.

PMID- 10637329
TI  - Stabilities of intrastrand pyrimidine motif DNA and RNA triple helices.
AB  - Nucleic acid triple helices have provoked interest since their discovery more
      than 40 years ago, but it remains unknown whether such structures occur naturally
      in cells. To pursue this question, it is important to determine the stabilities
      of representative triple helices at physiological temperature and pH. Previous
      investigations have concluded that while both DNA and RNA can participate in the
      pyrimidine triplex motif under mildly acidic conditions, these structures are
      often relatively unstable at neutral pH. We are now explorin g the stability of
      intrastrand DNA and RNA pyrimidine motif triplexes at physiological temperature
      and pH. Duplex and triplex formation were monitored by thermal denaturation
      analysis, circular dichroism spectroscopy and gel shift experi-ments. Short
      intrastrand triplexes were observed to form in the pyrimidine motif in both DNA
      and RNA. In the presence of physiological concentrations of Mg(2+)and at
      physiological pH, all detected triplexes were sufficiently stable to persist at
      physiological temperature. If sequences specifying such intrastrand triplexes are
      encoded in genomes, the potential exists for the formation of stable structures
      in RNA or DNA in vivo.

PMID- 10637330
TI  - The virtues of self-binding: high sequence specificity for RNA cleavage by self
      processed hammerhead ribozymes.
AB  - Naturally occurring hammerhead ribozymes are produced by rolling circle
      replication followed by self-cleavage. This results in monomer-length catalytic
      RNAs which have self-complementary sequences that can occupy their trans -binding
      domains and potentially block their ability to cleave other RNA strands. Here we
      show, using small self-processed ribozymes, that this self-binding does not
      necessarily inhibit trans -cleavage and can result in greatly elevated
      discrimination against mismatches. We utilized a designed 63 nt circular DNA to
      encode the synthesis of a self-processed ribozyme, MDR63. Rolling circle
      transcription followed by self-processing produced the desired 63 nt ribozyme,
      which potentially can bind mdr-1 RNA with 9+9 nt of complementarity or bind
      itself with 4+5 nt of self-complementarity by folding back its ends to form
      hairpins. Kinetics of trans -cleavage of short complementary and mismatched RNAs
      were measured under multiple turnover conditions, in comparison to a standard 40
      nt ribozyme (MDR40) that lacks the self-complementary ends. The results show that
      MDR63 cleaves an mdr-1 RNA target with a k (cat)/ K (m)almost the same as MDR40,
      but with discrimination against mismatches up to 20 times greater. Based on
      folding predictions, a second self-processed ribozyme (UG63) having a single
      point mutation was synthesized; this displays even higher specificity (up to 100
      fold) against mismatches. The results suggest that self-binding ends may be
      generally useful for increasing sequence specificity of ribozymes.

PMID- 10637331
TI  - cis and trans factors affecting Mos1 mariner evolution and transposition in
      vitro, and its potential for functional genomics.
AB  - Mos1 and other mariner / Tc1 transposons move horizon-tally during evolution, and
      when transplanted into heterologous species can transpose in organisms ranging
      from prokaryotes to protozoans and vertebrates. To further develop the Drosophila
      Mos1 mariner system as a genetic tool and to probe mechanisms affecting the
      regulation of transposition activity, we developed an in vitro system for Mos1
      transposition using purified transposase and selectable Mos1 derivatives.
      Transposition frequencies of nearly 10(-3)/target DNA molecule were obtained, and
      insertions occurred at TA dinucleotides with little other sequence specificity.
      Mos1 elements containing only the 28 bp terminal inverted repeats were inactive
      in vitro, while elements containing a few additional internal bases were fully
      active, establishing the minimal cis -acting requirements for transposition. With
      increasing transposase the transposition frequency increased to a plateau value,
      in contrast to the predictions of the protein over-expression inhibition model
      and to that found recently with a reconstructed Himar1 transposase. This
      difference between the 'natural' Mos1 and 'reconstructed' Himar1 transposases
      suggests an evolutionary path for down-regulation of mariner transposition
      following its introduction into a naive population. The establishment of the cis
      and trans requirements for optimal mariner transposition in vitro provides key
      data for the creation of vectors for in vitro mutagenesis, and will facilitate
      the development of in vivo systems for mariner transposition.

PMID- 10637332
TI  - Selection of functional tRNA primers and primer binding site sequences from a
      retroviral combinatorial library: identification of new functional tRNA primers
      in murine leukemia virus replication.
AB  - Retroviral reverse transcription is initiated from a cellular tRNA molecule and
      all known exogenous isolates of murine leukemia virus utilise a
      tRNA(Pro)molecule. While several studies suggest flexibility in murine leukemia
      virus primer utilisation, studies on human immunodeficiency virus and avian retro
      viruses have revealed evidence of molecular adapt-ation towards the specific tRNA
      isoacceptor used as replication primer. In this study, murine leukemia virus tRNA
      utilisation is investigated by in vivo screening of a retroviral vector
      combinatorial library with randomised primer binding sites. While most of the
      selected primer binding sites are complementary to the 3'-end of tRNA((Pro)), we
      also retrieved PBS sequences matching four other tRNA molecules and demonstrate
      that Akv murine leukemia virus vectors may efficiently replicate using
      tRNA(Arg(CCU)), tRNA(Phe(GAA))and a hitherto unknown human tRNA(Ser(CGA)).

PMID- 10637333
TI  - Activation of c-myc promoter P1 by immunoglobulin kappa gene enhancers in Burkitt
      lymphoma: functional characterization of the intron enhancer motifs kappaB, E box
      1 and E box 2, and of the 3' enhancer motif PU.
AB  - Deregulated expression of the proto-oncogene c- myc in Burkitt lymphoma (BL)
      cells carrying a t(2;8) translocation is mediated by a synergistic interaction of
      the translocated immunoglobulin (Ig) kappa gene intron (kappaEi) and 3'
      (kappaE3') enhancers and characterized by a strong activation of the promoter P1.
      We have investigated the functional role of distinct kappa enhancer sequence
      motifs in P1 activation on both mini-chromosomes and reporter gene constructs.
      Stable and transient transfections of BL cells revealed critical roles of the
      kappaEi and kappaE3' elements kappaB and PU, respectively. Joint mutation of
      kappaB and PU completely abolished P1 activity, implying that an interaction of
      kappaB- and PU-binding factors is essential for the enhancer synergism. Mutation
      of the E box 1 and E box 2 motifs markedly decreased P1 activity in transient but
      not in stable transfection experiments. Co-expression of the NF-kappaB subunit
      p65(RelA) and Sp1, an essential factor for P1 transcription, in Drosophila
      melanogaster SL2 cells synergistically enhanced promoter activity. Our results
      support a model which proposes cross-talk between promoter and enhancer binding
      factors as the basic mechanism for kappa enhancer-mediated c- myc activation in
      BL cells.

PMID- 10637334
TI  - Isolation and characterization of human orthologs of yeast CCR4-NOT complex
      subunits.
AB  - The yeast CCR4-NOT protein complex is a global regulator of RNA polymerase II
      transcription. It is comprised of yeast NOT1 to NOT5, yeast CCR4 and additional
      proteins like yeast CAF1. Here we report the isolation of cDNAs encoding human
      NOT2, NOT3, NOT4 and a CAF1-like factor, CALIF. Analysis of their mRNA levels in
      different human tissues reveals a common ubiquitous expression pattern. A
      multitude of two-hybrid interactions among the human cDNAs suggest that their
      encoded proteins also form a complex in mammalian cells. Functional conservation
      of these proteins throughout evolution is supported by the observation that the
      isolated human NOT3 and NOT4 cDNAs can partially com-plement corresponding not
      mutations in yeast. Interestingly, human CALIF is highly homologous to, although
      clearly different from, a recently described human CAF1 protein. Conserved
      interactions of this factor with both NOT and CCR4 proteins and co
      immunoprecipitation experiments suggest that CALIF is a bona fide component of
      the human CCR4-NOT complex.

PMID- 10637335
TI  - Optimized synthesis of phosphorothioate oligodeoxyribonucleotides substituted
      with a 5'-protected thiol function and a 3'-amino group.
AB  - A new deprotection procedure enables a medium scale preparation of phosphodiester
      and phosphor-othioate oligonucleotides substituted with a protected thiol
      function at their 5'-ends and an amino group at their 3'-ends in good yield (up
      to 72 OD units/micromol for a 19mer phosphorothioate). Syntheses of 3'-amino
      substituted oligonucleotides were carried out on a modified support. A linker
      containing the thioacetyl moiety was manually coupled in two steps by first
      adding its phosphor-amidite derivative in the presence of tetrazole followed by
      either oxidation or sulfurization to afford the bis-derivatized oligonucleotide
      bound to the support. Deprotection was achieved by treating the fully protected
      oligonucleotide with a mixture of 2,2'-dithiodipyridine and concentrated aqueous
      ammonia in the presence of phenol and methanol. This proced-ure enables (i)
      cleavage of the oligonucleotide from the support, releasing the oligonucleotide
      with a free amino group at its 3'-end, (ii) deprotection of the phosphate groups
      and the amino functions of the nucleic bases, as well as (iii) transformation of
      the 5'-terminal S -acetyl function into a dithiopyridyl group. The bis
      derivatized phosphorothioate oligomer was further substituted through a two-step
      procedure: first, the 3'-amino group was reacted with fluorescein isothiocyanate
      to yield a fluoresceinylated oligo-nucleotide; the 5'-dithio-pyridyl group was
      then -quantitatively reduced to give a free thiol group which was then
      substituted by reaction with an N alpha-bromoacetyl derivative of a signal
      peptide containing a KDEL sequence to afford a fluoresceinylated peptide
      oligonucleotide conjugate.

PMID- 10637336
TI  - Characterization of Drosophila OVO protein DNA binding specificity using random
      DNA oligomer selection suggests zinc finger degeneration.
AB  - The Drosophila melanogaster ovo locus codes for several tissue- and stage
      specific proteins that all possess a common C-terminal array of four C(2)H(2)zinc
      fingers. Three fingers conform to the motif framework and are evolutionarily
      conserved; the fourth diverges considerably. The ovo genetic function affects
      germ cell viability, sex identity and oogenesis, while the overlapping svb
      function is a key selector for epidermal structures under the control of wnt and
      EGF receptor signaling. We isolated synthetic DNA oligomers bound by the OVO zinc
      finger array from a high complexity starting population and derived a
      statistically significant 9 bp long DNA consensus sequence, which is nearly
      identical to a consensus derived from several Drosophila genes known or suspected
      of being regulated by the ovo function in vivo. The DNA consensus recognized by
      Drosophila OVO protein is atypical for zinc finger proteins in that it does not
      conform to many of the 'rules' for the interaction of amino acid contact residues
      and DNA bases. Additionally, our results suggest that only three of the OVO zinc
      fingers contribute to DNA-binding specificity.

PMID- 10637337
TI  - Transcription-coupled DNA repair in yeast transcription factor IIE (TFIIE)
      mutants.
AB  - We examined the role of yeast transcription initiation factor IIE (TFIIE) in
      eukaryotic transcription-coupled repair (TCR), the preferential removal of DNA
      damage from the transcribed strands of genes over non-transcribed sequences.
      TFIIE can recruit the transcription initiation/repair factor TFIIH to the RNA
      polymerase II (RNA pol II) initiation complex to facilitate promoter clearance.
      Following exposure to UV radiation, the RNA pol II elongation complex is blocked
      at sites of UV-induced DNA damage, and may be recognized by nucleotide excision
      repair proteins, thus enabling TCR. The TFA1 gene encodes the large subunit of
      TFIIE. We determined how DNA repair is affected by TFA1 conditional mutations. In
      particular, we find proficient TCR in a heat-sensitive tfa1 mutant at the non
      permissive temperature during which growth is inhibited and overall RNA pol II
      transcription is reported to be inhibited. We demonstrate that transcription of
      the RPB2 gene was reduced, but readily detectable, in the heat-sensitive tfa1
      mutant at the non-permissive temperature and thereby prove that TCR does occur in
      an expressed gene in the absence of TFIIE in vivo. We demonstrate that TCR occurs
      even at low levels of transcription.

PMID- 10637338
TI  - Three different proteins recognize a multifunctional determinant that controls
      replication initiation, fork arrest and transcription in Tetrahymena.
AB  - Type I elements regulate the initiation of DNA replication, elongation of
      replication forks and transcription of the Tetrahymena thermophila rDNA
      minichromosome. Previous studies identified a 24 kDa protein, ssA-TIBF, which
      binds the A-rich strand of type I elements. Here we describe two additional type
      I element binding activities (native mol. wt approximately 65 and approximately
      250 kDa) that interact with DNA via previously unidentified 32 and 110 kDa
      polypeptides. The 65 kDa activity was purified to homogeneity and consists of a
      homodimer of a 32 kDa polypeptide. In contrast to the other type I element
      binding factors, the 65 kDa activity partitions preferentially to the nuclear
      fraction during isolation. Levels of the 65 kDa activity increase dramatically in
      starved cells, raising the possibility that it might negatively regulate
      replication or transcription. By comparison, the other two binding activities
      were elevated slightly during macronuclear development, when the rDNA was
      undergoing DNA replication. Previous studies indicate that the initiation of rDNA
      replication is regulated by long range interactions between dispersed type I
      elements. Competitive DNA binding or cooperative protein-protein interactions
      between the factors described here may play a regulatory role in replication or
      expression of the rDNA minichromosome.

PMID- 10637339
TI  - Nucleic acid mutation analysis using catalytic DNA.
AB  - The sequence specificity of the '10-23' RNA-cleaving DNA enzyme (deoxyribozyme)
      was utilised to discriminate between subtle differences in nucleic acid sequence
      in a relatively conserved segment of the L1 gene from a number of different human
      papilloma virus (HPV) genotypes. DNA enzymes specific for the different HPV types
      were found to cleave their respective target oligoribonucleotide substrates with
      high efficiency compared with their unmatched counterparts, which were usually
      not cleaved or cleaved with very low efficiency. This specificity was achieved
      despite the existence of only very small differences in the sequence of one
      binding arm. As an example of how this methodology may be applied to mutation
      analysis of tissue samples, type-specific deoxyribozyme cleavable substrates were
      generated by genomic PCR using a chimeric primer containing three bases of RNA.
      The RNA component enabled each amplicon to be cleavable in the presence of its
      matching deoxyribozyme. In this format, the specificity of deoxyribozyme cleavage
      is defined by Watson-Crick interactions between one substrate-binding domain (arm
      I) and the polymorphic sequence which is amplified during PCR. Deoxy-ribozyme
      mediated cleavage of amplicons generated by this method was used to examine the
      HPV status of genomic DNA derived from Caski cells, which are known to be
      positive for HPV16. This method is applicable to many types of nucleic acid
      sequence variation, including single nucleotide polymorphisms.

PMID- 10637340
TI  - Optimised ligation of oligonucleotides by thermal ligases: comparison of Thermus
      scotoductus and Rhodothermus marinus DNA ligases to other thermophilic ligases.
AB  - We describe the characterisation of four thermo-stable NAD(+)-dependent DNA
      ligases, from Thermus thermophilus (Tth), Thermus scotoductus (Ts), Rhodothermus
      marinus (Rm) and Thermus aquaticus (Taq), by an assay which measures ligation
      rate and mismatch discrimination. Complete libraries of octa-, nona- and
      decanucleotides were used as substrates. The assay comprised the polymerisation
      of oligo-nucleotides initiated from a 17 base 'primer', using M13mp18 ssDNA as
      template. Polymers of ligation products were analysed by polyacrylamide gel
      electro-phoresis. Under optimum conditions, the enzymes produced polymers ranging
      from 8 to 16 additions; there was variation between enzymes and the length of the
      oligonucleotides had a strong effect. The optimal total oligonucleotide
      concentration for each library was approximately 4 nmol. We compared the rates of
      ligation between the four ligases using an octanucleotide library as substrate.
      By this criterion, the Ts and Rm ligases are far more active compared to the more
      commonly available thermostable ligases.

PMID- 10637341
TI  - History of pediatric airway management.
AB  - The history of pediatric airway management is inseparable from the history of
      medicine in general. Advancing medical technology and improved childhood survival
      gave impetus for pioneering physicians with a vision for the future to branch out
      and develop the specialty of pediatric otolaryngology. Institutions and
      organizations committed to research, uncompromised care, and training have
      provided a firm foundation for the future growth and development of the
      specialty.

PMID- 10637342
TI  - Advances in pediatric airway radiology.
AB  - Radiologic evaluation of the airway has been used as a screening tool and an
      adjunct to endoscopy for many years. It provides noninvasive data on the
      structure of the airway while avoiding the risk of general anesthesia. In the
      past, standard radiographs provided only a shadow of the intricate anatomy of the
      pediatric airway. Not only have there been advances in static imaging but there
      now exists technology that enable noninvasive dynamic imaging and new techniques
      for image-guided intervention within the airway. This article focuses on four
      specific areas: airway fluoroscopy, functional swallow studies, controlled
      ventilation computed tomography, and interventional airway techniques.

PMID- 10637343
TI  - Anesthesia for pediatric airway endoscopy.
AB  - Anesthesia for endoscopic assessment and treatment of airway problems in infants
      and children requires a systematic and thoughtful approach. The anesthesiologist
      and otolaryngologist should have a sound knowledge of the causes of airway
      obstruction. The anesthesiologist must be aware of the instrumentation likely to
      be used and the endoscopist must be well informed about the principles of
      anesthesia. The choice of technique depends upon the needs for each patient, but
      in most cases, the safest and most controlled method is a gaseous induction with
      assisted spontaneous respiration and continued maintenance by the inhalational
      method, supplemented by topically applied local anesthesia.

PMID- 10637344
TI  - Pediatric obstructive sleep apnea syndrome.
AB  - Pediatric obstructive sleep apnea occurs in about 2% of children, and manifests
      as snoring, difficulty breathing, and witnessed apneic spells. Daytime symptoms
      include excessive sleepiness with poor performance and behavior problems. Severe
      forms may be associated with failure-to-thrive or death. The gold standard
      diagnostic procedure is overnight polysomnography and is indicated in high-risk
      patients. While most pediatric patients with obstructive sleep apnea can be
      treated with tonsillectomy and adenoidectomy; uvulopalatopharyngoplasty,
      tracheotomy, or other procedures are sometimes indicated. Nonsurgical treatment
      with continuous positive airway pressure is used in some children. Postoperative
      management in high-risk children includes careful perioperative monitoring and
      postoperative polysomnography.

PMID- 10637345
TI  - Endoscopic versus traditional approaches to choanal atresia.
AB  - With the introduction of endoscopic techniques and powered instrumentation for
      pediatric sinusitis, one would expect that the definitive treatment of congenital
      choanal atresia has been established. An international survey of pediatric
      otolaryngologists and the plethora of surgical approaches in the literature,
      however, indicate that there is still much controversy in its management. This
      article addresses this controversy between endoscopic and traditional approaches
      to neonatal bilateral bony choanal atresia and proposes guidelines for optional
      treatment.

PMID- 10637346
TI  - Congenital anomalies of the larynx and trachea.
AB  - A variety of congenital anomalies arise within the laryngeal or tracheal airway.
      Symptoms primarily include airway obstruction, hoarseness, and difficulty
      feeding. The diagnosis is typically made by a combination of clinical
      presentation, physical examination, and endoscopic evaluation. Definitive
      intervention may be necessary requiring endoscopic or open laryngeal surgery.
      Some of the more common congenital laryngeal and tracheal anomalies are discussed
      with respect to their diagnostic evaluation, clinical presentation, and
      management.

PMID- 10637347
TI  - Management of subglottic stenosis.
AB  - Evaluation and management of pediatric subglottic stenosis is complex and
      technically challenging. Laryngotracheal reconstruction has become the standard
      of care for symptomatic subglottic stenosis in children. Careful preoperative
      planning, meticulous surgery, and dedicated postoperative care are essential for
      a successful outcome. Early recognition and management of intraoperative and
      postoperative complications minimize their impact.

PMID- 10637348
TI  - Vocal cord paralysis in infants and children.
AB  - Vocal cord paralysis is the second most common cause of neonatal stridor.
      Recognition of laryngeal paralysis warrants further evaluation for an underlying
      etiology as it is frequently a manifestation of a multisystem anomaly. Initial
      intervention must concentrate on airway stabilization and treatment of any
      underlying conditions. Management strategies should be individualized and focus
      on maintenance of a safe and stable airway, acquisition of intelligible speech,
      and deglutition without aspiration.

PMID- 10637349
TI  - Pediatric gastroesophageal reflux and laryngopharyngeal reflux.
AB  - Pediatric gastroesophageal reflux (GER) and laryngopharyngeal reflux (LPR) have
      gained better recognition over the past few years. GER and LPR usually present as
      regurgitation, emesis, epigastric pain, failure to thrive, esophagitis, or
      stricture. Many patients suffer respiratory disorders associated with reflux.
      Classification of reflux, pathophysiology, manifestations of reflux, diagnosis,
      and management of the disease are discussed in this article.

PMID- 10637350
TI  - Advances in the management of major airway collapse: the use of airway stents.
AB  - The management of major airway collapse in the pediatric age group has evolved
      and continues to evolve over time. Tracheobronchomalacia, either primary or
      secondary, is still the most frequent cause of major airway collapse. This
      article reviews tracheobronchomalacia and discusses several treatment options;
      from traditional aortopexy to the more recent introduction of tracheobronchial
      stenting. Various types of stents are discussed and the authors' preferences are
      included.

PMID- 10637351
TI  - Tracheobronchial foreign bodies.
AB  - Aspirated and ingested foreign bodies continue to present challenges to
      otolaryngologists. The major issues involve the accurate diagnosis and speedy,
      safe retrieval of the foreign body. The accurate diagnosis may allude physicians
      because often the initial choking incidents are not witnessed and the delayed
      residual symptoms may mimic other common conditions. The retrieval of foreign
      bodies has been facilitated by technical improvements with the rod lens
      telescope, video endoscopy, a broad range of a variety of sized forceps, and
      safer anesthesia. This article reviews the clinical presentation, diagnostic work
      up, and appropriate management of foreign bodies in the aerodigestive tract.

PMID- 10637352
TI  - Pathogenesis and treatment of juvenile onset recurrent respiratory
      papillomatosis.
AB  - Juvenile onset recurrent respiratory papillomatosis is the most common cause of
      laryngeal tumors in children. This disease is caused by infection of the human
      papillomavirus, a virus whose complete genetic structure is now known. New, more
      directed agents show promise for improved control of papillomatosis in
      preliminary studies. Concurrently, there is an increasing awareness of methods to
      reduce surgical morbidity. At present, the role of preventive efforts including
      elective caesarian section remains uncertain.

PMID- 10637353
TI  - Hemangiomas and vascular malformations of the airway.
AB  - Hemangiomas are the most common neoplastic growth affecting the pediatric airway.
      The expected natural history includes a period of rapid growth followed by
      spontaneous involution. These patients often require treatment of the hemangioma
      in order to avoid the consequences of airway obstruction. In contrast, vascular
      malformations do not undergo spontaneous resolution. The clinical course and
      treatment options for children with vascular malformations are quite different
      from those with hemangioma. The clinical presentation, evaluation, management
      options, and expected outcomes for both of these lesions are discussed in this
      article.

PMID- 10637354
TI  - Targeting DNA secondary structures.
AB  - DNA secondary structures containing regions of single-stranded DNA have now been
      identified in the genomic DNA of a number of prokaryotic and eukaryotic species,
      including humans. Many of these secondary structures are associated with regions
      of DNA involved in regulation of transcription: promoters or upstream elements.
      The secondary structures involved appear likely to be hairpin or cruciform
      structures that may be recognition sites for binding of transcription factors. In
      the case of the coliphage N4 virion RNA polymerase, a defined hairpin in the
      polymerase promoter necessary for binding of the polymerase and regulation of
      transcription has been shown to be extruded under physiological conditions in
      plasmid DNA. The presence of single-stranded DNA in the promoters of several
      species suggests that regulatory hairpins may be involved in transcription of a
      number of genes. In support of this, hairpin- or cruciform-binding proteins have
      been identified from several species. These results imply that secondary
      structures in regulatory regions may be targets for drugs that bind and either
      block or enhance binding of proteins involved in transcription. In this review,
      we discuss the evidence for DNA secondary structures, particularly hairpins and
      cruciforms, in genomic DNA and review the studies to date of development of small
      molecules that can selectively bind these structures.

PMID- 10637355
TI  - Targeting DNA with triplexes.
AB  - The formation of intermolecular DNA triple helices offers the possibility of
      designing compounds with extensive sequence recognition properties which may be
      useful as antigene agents or tools in molecular biology. In these structures a
      third strand oligonucleotide binds in the DNA major groove, making specific
      contacts with substituents on the exposed faces of the base pairs. Although
      triplexes form with exquisite specificity their use suffers from several
      drawbacks. Two limitations of this approach, which are considered in this review
      are, firstly that conditions of low pH are necessary for formation of the C+*GC
      triplet, and secondly that these structures are often less stable than their
      duplex counterparts. This review outlines the strategies that have been employed
      to overcome these drawbacks. The pH problem is addressed by considering the
      various DNA base analogues that have been used to recognise GC base pairs in a pH
      independent fashion, and discusses the benefits and limitations of each analogue.
      Triplex stability can be increased by using novel base analogues, backbone
      modifications and the use of triplex-specific binding ligands.

PMID- 10637356
TI  - Topoisomerase I poisons and suppressors as anticancer drugs.
AB  - Inhibitors of topoisomerase I constitute a novel family of antitumor agents. The
      camptothecin derivatives topotecan and irinotecan represent new weapons in our
      arsenal for battling human cancer. These two drugs act specifically at the level
      of the topoisomerase I-DNA complex and stimulate DNA cleavage. This mechanism of
      action is not restricted to the camptothecins. Numerous topoisomerase I poisons
      including DNA minor groove binders such as Hoechst 33258 and DNA intercalators
      such as benzophenanthridine alkaloids and indolocarbazole derivatives have been
      discovered and developed. Another important group of topoisomerase I inhibitors
      contains drugs which prevent or reverse topoisomerase I-DNA complex formation.
      Many of these topoisomerase I suppressors are natural products (beta-lapachone,
      diospyrin, topostatin, topostin, flavonoids) which are believed to interact
      directly with the enzyme. This review is concerned with the different families of
      topoisomerase I poisons and suppressors. Their origin, chemical nature and
      mechanism of action are presented. The relationships between drug binding to DNA
      and topoisomerase I inhibition are discussed.

PMID- 10637357
TI  - Effects of cationic charge on three-dimensional structures of intercalative
      complexes: structure of a bis-intercalated DNA complex solved by MAD phasing.
AB  - We characterize intercalative complexes as either "high charge" and "low charge".
      In low charge complexes, stacking interactions appear to dominate stability and
      structure. The dominance of stacking is evident in structures of daunomycin,
      nogalamycin, ethidium, and triostin A/echinomycin. By contrast in a DNA complex
      with the tetracationic metalloporphyrin CuTMPyP4 [copper (II) meso-tetra(N-methyl
      4-pyridyl)porphyrin], electrostatic interactions appear to draw the porphyrin
      into the duplex interior, extending the DNA along its axis, and unstacking the
      DNA. Similarly, DNA complexes of tetracationic ditercalinium and tetracationic
      flexi-di show significant unstacking. Here we report x-ray structures of
      complexes of the tetracationic bis-intercalator D232 bound to DNA fragments
      d(CGTACG) and d(BrCGTABrCG). D232 is analogous to ditercalinium but with three
      methylene groups inserted between the piperidinium groups. The extension of the
      D232 linker allows it to sandwich four base pairs rather than two. In comparison
      to CuTMPyP4, flexi-di and ditercalinium, stacking interactions of D232 are
      significantly improved. We conclude that it is not sufficient to characterize
      intercalators simply by net charge. One anticipates strong electrostatic forces
      when cationic charge is focused to a small volume or region near DNA and so must
      consider the extent to which cationic charge is focused or distributed. In sum,
      ditercalinium, with a relatively short linker, focuses cationic charge more
      narrowly than does D232. So even though the net charges are equivalent,
      electrostatic charges are expected to be of greater structural significance in
      the ditercalinium complex than in the D232 complex.

PMID- 10637358
TI  - Targeting RNA with small molecules.
AB  - Therapeutic targeting of RNA is not as well-developed as with DNA and proteins,
      and the many structures and functions of RNA suggest that it is an underutilized
      target. As with DNA, RNA has heterocyclic bases and base pairs with a highly
      anionic backbone, but as with proteins, RNA can fold into complex tertiary
      structures that create unique binding pockets for small molecules. Aminoglycoside
      targeting of ribosomal RNA is a well-known success story, and mRNAs and tRNAs
      have also served as therapeutic targets as well as model systems for
      understanding RNA-ligand interactions. The unique, species-specific structures
      and chemistry involved in splicing and ribozyme activity makes this RNA function
      an attractive target, and inhibitors of ribozyme activity have been discovered.
      The numerous serious human diseases caused by RNA viruses highlight the
      importance of developing new compounds that can target RNA structures in viral
      genomes. Considerable effort has been directed at finding compounds that target
      HIV-1 RNAs that control viral replication and frameshifting. As part of these
      efforts very useful new assays have been developed for small molecule-RNA
      interactions. The assays have led to the discovery of new inhibitors for
      different steps in viral replication. The next phase of research in RNA targeting
      will not only focus on the discovery of new compounds, but also on how to develop
      small molecules with high affinity and selectively for RNA that can penetrate
      effectively into a wide array of cell types.

PMID- 10637359
TI  - Targeting multi-stranded DNA structures.
AB  - The design of agents targeted toward a structure-specific molecular recognition
      of DNA triplexes or tetraplexes ( quadruplexes ) is discussed, where such
      structures are relevant to antigene-based chemotherapies and the in situ cellular
      inhibition of telomerase function, respectively. Using principles that stem from
      the development of earlier synthetic duplex-binding ligands, together with recent
      findings that probe structure thermodynamic linkages and kinetic features of
      stability, a rational approach is developed to exploit the distinct molecular
      templates offered by these high-order nucleic acid biotarget systems. Such
      analytical techniques can usefully augment conventional drug design methods,
      particularly where detailed structural information is unavailable or the mode of
      binding to form a persistent DNA biotarget ligand complex is not established.
      Examples from the author s laboratory are used to illustrate structure-specific
      (or structure-preferential) recognition and subsequent stabilization of DNA
      triplexes using intercalative or groove-mediated binding mechanisms, and the
      successful targeting of DNA tetraplexes using planar extended-aromatic ligands.
      In each case, chemical manipulation of the molecule by exploiting either (i)
      geometric isomers, (ii) redistribution of charged groups and/or H-bond
      donors/acceptors, or (iii) optimization of intermolecular pi-overlap can be used
      to improve the affinity or specificity of the underlying DNA drug binding events.

PMID- 10637360
TI  - Molecular modeling and computer aided drug design. Examples of their applications
      in medicinal chemistry.
AB  - The development of new drugs with potential therapeutic applications is one of
      the most complex and difficult process in the pharmaceutical industry. Millions
      of dollars and man-hours are devoted to the discovery of new therapeutical
      agents. As, the activity of a drug is the result of a multitude of factors such
      as bioavailability, toxicity and metabolism, rational drug design has been
      utopias for centuries. Very recently, impressive technological advances in areas
      such as structural characterization of biomacromolecules, computer sciences and
      molecular biology have made rational drug design feasible. The aim of this review
      is to give an outline of studies in the field of medicinal chemistry in which
      molecular modeling has helped in the discovery process of new drugs. The emphasis
      will be on lead generation and optimization.

PMID- 10637361
TI  - Studies and syntheses of siderophores, microbial iron chelators, and analogs as
      potential drug delivery agents.
AB  - Siderophores (microbial iron chelators) play an extremely important role in
      microbial pathogenicity. Microbial uptake of siderophore-iron complexes through
      active transport systems allow microbes to survive and proliferate even under
      iron deficient environments during invasion of a host. Due to their structural
      complexity, unique iron (III) chelation, acquisition properties, and their
      therapeutic potential, siderophores have attracted much attention in a broad
      range of disciplines. Tremendous progress has been made in siderophore syntheses,
      in determination of the structures and functions of outer membrane receptors
      (e.g. FhuA and FepA), and in the mechanistic insight into siderophore-iron
      mediated active transport processes. One of the important practical applications
      of this active transport system is development of species-selective active drug
      transport (the Trojan Horse approach) to potentially treat infections due to drug
      resistant strains of microbes. Siderophore-drug conjugates have shown great
      potential in active drug delivery to target pathogenic microbes.

PMID- 10637362
TI  - Inhibitors of mammalian central nervous system selective amino acid transporters.
AB  - Central nervous system (CNS) selective amino acid transporters provide an
      important function in maintaining tonic extracellular levels of amino acids that
      act as neurotransmitters, synaptic modulators or neurotransmitter precursors.
      Small molecule inhibitors of these transporters have been postulated and in some
      cases demonstrated to be useful in the treatment of a range of CNS driven
      disorders such as epilepsy, anxiety, psychosis, depression, pain and
      neurodegenerative disease. Although much of the research to date in this field
      has focussed on inhibition of the gama-amino butyric acid (GABA) transporters
      more recent reports have also generated interest in modulation of glycine,
      glutamate and proline transporters. This article will review the current
      medicinal chemistry literature and structure activity relationships known for
      mammalian CNS selective amino acid transporters.

PMID- 10637363
TI  - Androgen receptor antagonists (antiandrogens): structure-activity relationships.
AB  - Prostate cancer, acne, seborrhea, hirsutism, and androgenic alopecia are well
      recognized to depend upon an excess or increased sensitivity to androgens or to
      be at least sensitive to androgens. It thus seems logical to use antiandrogens as
      therapeutic agents to prevent androgens from binding to the androgen receptor.
      The two predominant naturally occurring androgens are testosterone (T) and
      dihydrotestosterone (DHT). DHT is the more potent androgen in vivo and in vitro.
      All androgen-responsive genes are activated by androgen receptor (AR) bound to
      either T or DHT and it is believed that AR is more transcriptionally active when
      bound to DHT than T. The two classes of antiandrogens, presently available, are
      the steroidal derivatives, all of which possess mixed agonistic and antagonistic
      activities, and the pure non-steroidal antiandrogens of the class of flutamide
      and its derivatives. The intrinsic androgenic, estrogenic and glucocorticoid
      activities of steroidal derivatives have limited their use in the treatment of
      prostate cancer. The non-steroidal flutamide and its derivatives display pure
      antiandrogenic activity, without exerting agonistic or any other hormonal
      activity. Flutamide (89) and its derivatives, Casodex (108) and Anandron (114),
      are highly effective in the treatment of prostate cancer. The combination of
      flutamide and Anandron with castration has shown prolongation of life in prostate
      cancer. Furthermore, combined androgen blockade in association with radical
      prostatectomy or radiotherapy are very effective in the treatment of localized
      prostate cancer. Such an approach certainly raises the hope of a further
      improvement in prostate cancer therapy. However, all antiandrogens, developed so
      far display moderate affinity for the androgen receptor, and thus moderate
      efficacy in vitro and in vivo. There is thus a need for next-generation
      antiandrogens, which could display an equal or even higher affinity for AR
      compared to the natural androgens, and at the same time maintain its pure
      antiandrogenic activity, and thus providing improved androgen blockade using
      possibly antiandrogens alone.

PMID- 10637364
TI  - Propofol in anesthesia. Mechanism of action, structure-activity relationships,
      and drug delivery.
AB  - Propofol (2,6-diisopropylphenol) is becoming the intravenous anesthetic of choice
      for ambulatory surgery in outpatients. It is extensively metabolized, with most
      of the administered dose appearing in the urine as glucuronide conjugates.
      Favorable operating conditions and rapid recovery are claimed as the main
      advantages in using propofol, whereas disadvantages include a relatively high
      incidence of apnea, and blood pressure reductions. Besides a literature summary
      of the pharmacodynamics, pharmacokinetics, toxicology, and clinical use, this
      review provides a deeper discussion on the current understanding of mechanism of
      action and structure-activity relationships, and recent findings on drug delivery
      technologies as applied to the improvement of propofol formulations. The action
      of propofol involves a positive modulation of the inhibitory function of the
      neurotransmitter gama-aminobutyric acid (GABA) through GABAA receptors. Recent
      results from recombinant human GABAA receptor experiments and findings from the
      work exploring the effects at other receptors (e.g., glycine, nicotinic, and M1
      muscarinic receptors) are reviewed. Studies showing its antiepileptic and
      anxiolytic properties are also discussed. The structure-activity relationships
      (SAR) of series of alkylphenols and p-X-substituted congeners have been
      reinvestigated. Interestingly, unlike the other congeners tested sofar, p-iodo
      2,6-diisopropylphenol displayed anticonvulsant and anticonflict effects, but not
      sedative-hypnotic and anesthetic properties. Due to its high lipid-solubility,
      propofol was initially formulated as a solution with the surfactant Cremophor EL,
      but the occurrence of pain on injection and anaphylactoid reactions prompted to
      search for alternative formulations. Results from using cyclodextrins, water
      soluble prodrugs, and adopting Bodor's approach to the site-specific chemical
      delivery system (CDS), as well as the advantages provided by computer-controlled
      infusion systems, are examined in some detail.

PMID- 10637365
TI  - Molecular modelling and QSAR of reversible acetylcholines-terase inhibitors.
AB  - Acetylcholinesterase (AChE) inhibitors are an important class of medicinal agents
      useful for the treatment of Alzheimer s disease, glaucoma, myasthenia gravis and
      for the recovery of neuromuscular block in surgery. To rationalize the structural
      requirements of AChE inhibitors we attempt to derive a coherent AChE-inhibitor
      recognition pattern based on literature data of molecular modelling and
      quantitative structure-activity relationship (QSAR) analyses. These data are
      summarised from nearly all therapeutically important chemical classes of
      reversible AChE inhibitors, e.g., derivatives of physostigmine, tacrine,
      donepezil and huperzine A. Interactions observed from X-ray crystallography
      between these inhibitors and AChE have also been incorporated and compared with
      modelling and QSAR results. It is concluded that hydrophobicity and the presence
      of an ionizable nitrogen are the pre-requisites for the inhibitors to interact
      with AChE. However the mode of interaction i.e., the 3-dimensional (3D)
      positioning of the inhibitor in the active site of the enzyme varies among
      different chemical classes. It is also recognised that water molecules play
      crucial roles in defining these different 3D positioning. The information on AChE
      inhibitor interactions provided should be useful for future discovery of new
      chemical classes of AChE inhibitors, especially from De Novo design and hybrid
      construction.

PMID- 10637366
TI  - Synthesis of tacrine analogues and their structure-activity relationships.
AB  - Three man synthetic routes to analogues of tacrine are described: reaction of
      anthranilonitriles with cyclohexanone and other ketones, reaction of various
      anilines with alpha-cyanoketones, and reactions involving anilines and cyclic
      beta-ketoesters. Although tacrine has a wide range of pharmacological effects, it
      is best known as an inhibitor of cholinesterase enzymes. Many of the analogues
      that have been made have not been tested against acetylcholinesterase or
      butyrylcholinesterase activity. Consequently, there is limited information from
      which a detailed understanding of structure-activity relationships can be
      derived. However, some halogenated derivatives are not only more potent
      acetylcholinesterase inhibitors than tacrine, they are also more selective for
      acetylcholinesterase than for butyrylcholinesterase.

PMID- 10637367
TI  - Donepezil hydrochloride (E2020) and other acetylcholinesterase inhibitors.
AB  - A wide range of evidence shows that acetylcholinesterase (AChE) inhibitors can
      interfere with the progression of Alzheimer's disease (AD). The successful
      development of these compounds was based on a well-accepted theory that the
      decline in cognitive and mental functions associated with AD is related to the
      loss of cortical cholinergic neurotransmission. The earliest known AChE
      inhibitors, namely, physostigmine and tacrine, showed modest improvement in the
      cognitive function of Alzheimer's patients. However, clinical studies show that
      physostigmine has poor oral activity, brain penetration and pharmacokinetic
      parameters while tacrine has hepatotoxic liability. Studies were then focused on
      finding a new type of acetylcholinesterase inhibitor that would overcome the
      disadvantages of these two compounds. Donepezil hydrochloride inaugurates a new
      class of AChE inhibitors with longer and more selective action with manageable
      adverse effects. Currently, there are about 19 new Alzheimer's drugs in various
      phases of clinical development.

PMID- 10637368
TI  - Central selective acetylcholinesterase inhibitor with neurotrophic activity:
      structure-activity relationships of TAK-147 and related compounds.
AB  - A series of benzylamino inhibitors of acetylcholinesterase (AChE) have been
      designed based on a working hypothesis of the enzyme s active site. These
      compounds were tested for their inhibitory activities on AChE and potent
      inhibitors were further evaluated in terms of central selectivity. These studies
      led to a discovery of 3-[1-(phenylmethyl)-4-piperidinyl]-1-(2,3,4, 5-tetrahydro
      1H-1-benzazepin-8-yl)-1-propanone fumarate (TAK-147). Pharmacokinetic study has
      shown that the compound has high central selectivity, as demonstrated by rapid
      elimination from plasma and long-term existence in the brain. As a consequence,
      TAK-147 ameliorates impairments of learning and memory in various animal models
      without producing peripheral side effects. TAK-147 also activates the
      monoaminergic systems and energy metabolism. Furthermore, TAK-147 was revealed to
      have NGF-like neurotrophic activity on central cholinergic neurons at
      concentrations where it inhibits AChE activity. Therefore, TAK-147 is expected
      not only to ameliorate the clinical symptoms in Alzheimer s disease via AChE
      inhibition but to prevent or slow the progression of the disease via its
      neurotrophic action. TAK-147 is now under clinical trial as a therapeutic drug
      for Alzheimer s disease. This article reviews design and structure-activity
      relationships of TAK-147 and related compounds. Preclinical pharmacology of TAK
      147 is also summarized.

PMID- 10637369
TI  - Huperzine A, a potential therapeutic agent for treatment of Alzheimer's disease.
AB  - HupA is a potent, reversible and selective inhibitor of AChE with a rapid
      absorption and penetration into the brain in animal tests. It exhibits memory
      enhancing activities in animal and clinical trials. Compared to tacrine and
      donepezil, HupA possesses a longer duration of action and higher therapeutic
      index, and the peripheral cholinergic side effects are minimal at therapeutic
      doses. This review article deals with a comprehensive survey of the progress in
      chemical and pharmacological studies of HupA including the isolation and
      structure elucidation, pharmacological actions, total synthesis, SAR studies and
      the future development of HupA. Recently, it has been reported that HupA could
      reduce neuronal cell death caused by glutamate. The dual bio-activities of HupA
      would further enhance its value and potentiality as the therapeutic agent for
      Alzheimer s disease.

PMID- 10637370
TI  - Cathepsin K and the design of inhibitors of cathepsin K.
AB  - Cathepsin K, a cysteine protease of the papain family, was identified by
      sequencing complementary DNA libraries derived from osteoclasts. Cathepsin K can
      cleave bone proteins such as Type I collagen, osteopontin, and osteonectin. The
      localization and maturation of cathepsin K in activated osteoclasts have been
      characterized. Furthermore, mutation of the gene expressing cathepsin K in humans
      results in pycnodysostosis, an autosomal recessive condition, resulting in
      osteoprosis and increased bone fragility. Knockout of cathepsin K in the mouse
      also results in retarded bone matrix degradation and osteopetrosis. Together,
      these data demonstrate that inhibition of cathepsin K should result in a
      dimunition of osteoclast-mediated bone resorption. Several novel classes of
      cathepsin K inhibitors have been designed from X-ray co-crystal structures of
      peptide aldehydes bound to papain. The convergence of the design of novel
      inhibitors and the discovery of cathepsin K has created opportunities to further
      understand bone and cartilage biology as well as provide new therapeutic agents
      for the treatment of disease states in man such as osteoporosis.

PMID- 10637371
TI  - Therapeutic applications for ligands of retinoid receptors.
AB  - Synthetic retinoids, ligands for the RAR and RXR members of the steroid/thyroid
      superfamily of nuclear hormone receptors, are used for the treatment of
      psoriasis, acne, photoaging and cancer. Retinoid mechanisms of action for these
      conditions largely involve effects on epithelial differentiation and modulation
      of inflammation with some impact on the immune system. Retinoid medicinal
      chemistry in recent years has identified ligands highly specific for one of the
      three RAR subtypes (RAR-alpha) and for the RXR family of receptors, as well as
      antagonists for the RARs, RARalpha and the RXRs. Structure-activity relationships
      among the novel retinoid classes are reviewed along with potential therapeutic
      activities and side effects. RAR-alpha specific retinoids inhibit cancer cell
      growth but lack other retinoid toxicities, including skin irritation now ascribed
      to RAR-gama. RXR-specific retinoids lower blood glucose in animal models of type
      2 diabetes albeit with a potential for mild hypothyroidism. Function-selective
      retinoids, especially a class of RAR antagonists called inverse agonists, have
      unexpected gene regulatory activity. Given the diverse properties and tissue
      distributions of the retinoid receptors, synthesis of additional classes of
      receptor-specific and function-selective ligands has the potential to produce
      novel therapeutic applications.

PMID- 10637372
TI  - Progress in the development of inhibitors of SH2 domains.
AB  - SH2 domains are discrete structural motifs common to a variety of critical
      intracellular signaling proteins. Inhibitors of specific SH2 domains have become
      important therapeutic targets in the treatment and/or prevention of restenosis,
      cancers (including small cell lung), cardiovascular disease, osteoporosis,
      apoptosis among others. Considering the social and economic impact of these
      diseases significant attention has been focused on the development of potent and
      selective inhibitors of specific SH2 domains. In particular, considerable
      research has been performed on Src, PI 3-kinase, Grb2 and more recently, Lck. In
      this review, we will focus on progress in the development of inhibitors for these
      specific SH2 domains and evaluate potential future targets.

PMID- 10637373
TI  - Important hints in behavioural teratology of rodents.
AB  - The paper deals with the most important items regarding the improvement of
      quality of experimental procedures when testing drug effects on behaviour and
      development of commonly-used rodent species. Current-used test procedures for
      immature and adult rodents exposed early developmentally are briefly described
      and recent advances and difficulties in their hands-on interpretation are
      highlighted. Comparability of measures in human and animals for drug-effect
      assessment is also shortly discussed. It is then stressed that studies on rodents
      carried out in seminaturalistic and naturalistic settings may offer a highly
      profitable direction for future research in behavioural teratology and
      toxicology. A final paragraph is dedicated to the bioethical aspects arisen from
      the use of large number of rodents subjects in behavioural testing.

PMID- 10637374
TI  - Mode of action of anti-infective agents: focus on oxidative stress and electron
      transfer.
AB  - There is increasing evidence for involvement of oxidative stress (OS) in the
      mechanism of action of a wide variety of physiologically active materials. Often
      the reactive oxygen species (ROS) are generated by electron transfer (ET) or
      other routes mediated by free radicals. Principal ET functionalities are quinones
      (or precursors), metal complexes, aromatic nitro compounds (ArNO2), and
      conjugated imines. These moieties are commonly found in the structures of anti
      infective agents or their metabolites. In most cases, the ET functionalities
      display reduction potentials in the physiologically active range, i.e. more
      positive than approximately -0.5 V. Though the focus of this review is on OS and
      ET, a mode of action which emulates the natural immune system of the host, in
      some cases, this mechanism also appears to be involved in more generally accepted
      approaches, such as enzyme inhibition, adverse effects on membranes and DNA, or
      interference with DNA or protein synthesis. OS-ET represents a broad
      understanding of drug action that can aid in the design of new anti-infective
      agents. It is significant that a relatively simple unifying theme can be applied
      not only to the action of the predominant groups of anti-infective agents, but
      also more generally to other drug classes, toxins, carcinogens, enzymes, and
      hormones.

PMID- 10637376
TI  - Highlights of semi-synthetic developments from erythromycin A.
AB  - Earlier semi-synthetic studies of erythromycin A culminated in the discovery of
      two successful second generation macrolide antibiotics, azithromycin and
      clarithromycin, for the treatment of community-acquired bacterial infections.
      More recent structural modifications of erythromycin A have resulted in the
      discovery of novel ketolide antibiotics and new motilide prokinetic agents. This
      review is an account of the semi-synthetic developments from erythromycin A by
      chemical transformations.

PMID- 10637375
TI  - Hepatitis C virus infection: immune responsiveness and interferon-alpha
      treatment.
AB  - Hepatitis C virus (HCV) is responsible for most cases of posttransfusion
      hepatitis and sporadic or community-acquired non-A, non-B hepatitis. Different
      generations of enzyme-linked immunosorbent assay have been generated for
      detecting antibodies to HCV epitopes. HCV-RNA quantitative analysis has been
      developed by means of polymerase chain reaction technique. This approach is the
      only reliable method for HCV-RNA tissue localization, being helpful in early
      diagnosis. HCV infected liver is characterized by an inflammatory infiltrate
      including CD4+, CD8+, and B lymphocytes. Evidence has been provided that in HCV
      patients CD8+ cell response is associated with low level of viraemia and higher
      level of disease activity. CD4+ T cells exhibit specificity for the core antigen,
      also correlating with disease activity and viraemia. Costimulatory molecules,
      cytokines, oxygen radicals, the complex Fas/Fas-ligand and soluble class I HLA
      structures are discussed as putative cofactors involved in disease evolution.
      Various forms of interferon (IFN)-alpha have been evaluated for the treatment of
      patients with HCV infection. Initial enthusiasm has been attenuated by the
      evidence of a low sustained virological response rate and the constant side
      effects of IFN-alpha therapy in patients with chronic HCV disease. Among possible
      markers for predicting therapeutic outcome in HCV-positive individuals, anti-core
      antibodies correlate positively with response to IFN-alpha administration, as
      well as reduction of interleukin-2 serum levels has been detected in patients
      with a good therapeutic response. Association between HCV infection and
      autoimmune phenomena, also in relation to IFN-alpha therapy has been reported.
      Finally, results of the combined treatment with IFN-alpha/ribavirin are
      illustrated.

PMID- 10637377
TI  - Fungal cell wall inhibitors: emphasis on clinical aspects.
AB  - Invasive fungal infections, mainly caused by Candida and Aspergillus species, are
      an emerging cause of morbidity and mortality among all categories of
      immunocompromised patients. Currently available antifungal agents, both polyenes,
      flucytosine and (tri)azoles are hampered by serious infusion- or drug-related
      toxicity, by hazardous drug-drug interactions, or by pharmacokinetic problems and
      by the development of resistance, in vitro as well as in vivo. In recent years,
      several companies have become interested in antifungal drug development and have
      launched new compounds into preclinical and clinical trials. Some of these agents
      target the fungal cell wall in stead of the cell membrane. They exert their
      fungicidal action through inhibition of the synthesis of critical compounds of
      that fungal cell wall, not present in mammalian cells. Exciting and promising
      agents include inhibitors of beta-(1,3)-D-glucan synthase and inhibitors of
      chitin synthase. These drugs appear well tolerated in Phase I-II studies and will
      soon enter Phase III studies. This review wants to provide the clinical framework
      for assessing the utility of these agents compared to existing antifungals,
      thereby focusing on invasive fungal disease and emphasising the changing fungal
      epidemiology and susceptibility in immunocompromised hosts.

PMID- 10637378
TI  - What is the precise role of human MDR 1 protein in chemotherapeutic drug
      resistance?
AB  - Elucidating the molecular function of hu MDR 1 protein (also called P
      glycoprotein or P-gp 1) and the precise role this protein plays in clinically
      relevant tumor drug resistance remains a perplexing problem. Hundreds of reports
      over the past decades summarize a dizzying array of observations relevant to hu
      MDR 1 protein function. A dominant model in the MDR literature that is used to
      explain many observations is the well known "drug pump" model first suggested by
      Keld Dano in 1973 [1]. Although this model has proved useful in conceptualizing
      additional experiments, it violates fundamental laws of biology and chemistry and
      in well over a decade of intense effort, active outward drug pumping via hu MDR 1
      protein has still never been unequivocally measured. Also, in recent years it has
      become clear that the drug pump model cannot explain several important phenomena
      that are highly relevant to the cancer clinic. Thus, other models have also
      proved increasingly popular. One is the altered partitioning model, which does
      not violate fundamental laws, is consistent with the vast majority of available
      data, and has important predictive ability. This newer model has several novel
      facets that are relevant for cancer pharmacology, and that help explain phenomena
      not explained by the drug pump model. The basic principle of this model is that
      MDR proteins do not directly transport drugs, but that their altered expression
      leads to altered regulation of ion transport or signal transduction that is
      critical for setting key biophysical parameters of the cell (e.g. compartmental
      pH and membrane potentials) that dictate relative passive diffusion of drugs as
      well as important signal transduction linked to the cytotoxic actions of these
      drugs. Along with debate over the molecular details of hu MDR 1 function,
      additional controversy surrounds the precise role of hu MDR 1 in the clinic. Many
      investigators now debate the significance of its function (regardless of precise
      mechanism) with regard to "real" drug resistance phenotypes exhibited in the
      clinic. I believe that thorough debate on the pros and cons of various molecular
      models for hu MDR 1 function will help to address confusion over the clinical
      relevance of hu MDR1. In the current atmosphere of disappointment over the
      relative success of clinical trials based in large part on the logic of the drug
      pump model, it is important that we not lose sight of critical points. Namely, hu
      MDR 1 protein remains an extremely important window in on the complex pathways
      that lead to induced chemotherapeutic drug resistance. Exploring the rationale
      behind newer models for hu MDR 1 function leads to key predictions that can be
      tested.

PMID- 10637379
TI  - Genetically engineered monoclonal antibodies for direct anti-neoplastic treatment
      and cancer cell specific delivery of chemotherapeutic agents.
AB  - Classical therapeutic modalities such as surgery, radiation, and chemotherapy not
      only fail to cure the great majority of malignant tumors, but their employment
      often leads to severe and debilitating side effects. The severe cancer related
      morbidity is also in direct correlation with the use of x-radiation and
      chemotherapy, making them less than ideal forms of therapy. The development of
      hybridoma technology and the advances in monoclonal antibody (MoAB) production
      have revitalized the initial concept of Ehrlich concerning the existence of
      cancer cell-targeted, specific "magic bullets". Entirely new approaches to cancer
      therapy that are neoplastic cell-directed, and specifically lethal to malignant
      cells and less toxic to normal tissues are being observed and developed, adhering
      to the old prayer: "Destroy the diseased tissues, preserve the normal."
      Immunotherapy as a fourth modality of cancer therapy has already been developed
      and proven to be quite effective. Strategies for the employment of antibodies for
      anti-cancer immunotherapy include: 1) Immune reaction directed destruction of
      cancer cells; 2) Interference with the growth and differentiation of malignant
      cells; 3) Antigen epitope directed transport of anti-cancer agents to malignant
      cells; 4) Anti-idiotype vaccines; and 5) Development of engineered (humanized)
      mouse monoclonals for anti-cancer therapy. In addition, a variety of different
      agents (e.g. toxins, radionuclides, chemotherapeutic drugs) have been conjugated
      to mouse and human MoABs for selective delivery to cancer cells. Preclinical
      observations in athymic, nude mice using xenografted human cancers and mouse,
      anti-human MoABs were more than impressive and have lead to the development of
      clinical trials. Phase I studies established the safety of employing
      immunoconjugates in humans, but the in vivo therapeutic results were less
      impressive. The clinical use of mouse MoABs in humans is limited due to the
      development of a foreign anti-globulin immune response by the human host.
      Genetically engineered chimeric human-mouse MoABs have been developed by
      replacing the mouse Fc region with the human constant region. Moreover, the
      framework regions of variable domains of rodent immunoglobulins were also
      experimentally replaced by their human equivalents. These antibodies can also be
      designed to have specificities and effector functions determined by researchers,
      which may not appear in nature. The development of antibodies with two binding
      ends (bispecific antibodies) provided a great improvement in targeting cancer
      cells. The existing inadequacies of MoABs in immunotherapy may also be improved
      by increasing their efficiency with chemical coupling to various agents such as
      bacterial or plant toxins, radionuclides or cytotoxic drugs. The astonishing
      immunophenotypic (IP) heterogeneity of neoplastically transformed cells, the
      different cytotoxic activity associated with the moiety linked to given MoABs,
      and mostly the impressive genetic modulation capabilities of cancer cells still
      remain as yet unsolved difficulties in the present immunotherapy of human cancer.
      In writing this review article, one of our main goals is to encourage further
      clinical research with the use of genetically engineered rodent MoABs and various
      immunoconjugates in the treatment of human cancer, as well as the combination of
      such immunotherapy with the three conventional modalities of therapy. Finally, we
      propose that MoAB-based immunotherapy be accepted as a conventional form of
      therapy and employed not only in terminal cancer patients but also, for instance,
      during and following surgical resection.

PMID- 10637380
TI  - Mechanisms of anti-cancer agents: emphasis on oxidative stress and electron
      transfer.
AB  - A large body of evidence has accumulated indicating involvement of oxidative
      stress (OS) in the mode of action of various bioactive substances, including
      those of the immune system. The data for anticancer drugs (main and
      miscellaneous) are summarized herein. Although diverse origins pertain, reactive
      oxygen species (ROS) are frequently generated by redox cycling via electron
      transfer (ET) groups, such as quinones (or phenolic precursors), metal complexes
      (or complexors), aromatic nitro compounds (or reduced products) and conjugated
      imines (or iminium species). We believe it is not coincidental that these
      functionalities are frequently found in anticancer agents or their metabolites.
      Generally, the ET moieties display reduction potentials in the physiologically
      active range. Often ROS are also implicated in more traditional rationales,
      namely, enzyme inhibition, membrane or DNA insult, and interference with DNA or
      protein synthesis. A multi-faceted approach to mechanism appears to be the most
      logical. Significantly, the unifying theme of ET-OS also applies to other drug
      categories, as well as to toxins, carcinogens, hormones, and enzymes. Since this
      theoretical framework aids in our understanding of drug action, it can serve as a
      useful tool in the design of more active and safer pharmaceuticals.

PMID- 10637381
TI  - The importance of vitamin A in nutrition.
AB  - Preformed vitamin A (all-trans-retinol and its esters) and provitamin A (beta
      carotene) are essential dietary nutrients that provide a source of retinol. Both
      retinyl esters and beta-carotene are metabolized to retinol. The retinol-binding
      proteins on binding retinol provide a means for solubilizing retinol for delivery
      to target tissues and for regulating retinol plasma concentrations. Oxidation of
      retinol provides retinal, which is essential for vision, and retinoic acid, a
      transcription factor ligand that has important roles in regulating genes involved
      in cell morphogenesis, differentiation, and proliferation. The observations that
      vitamin A can produce cell and tissue changes similar to those found during
      neoplastic transformation and that vitamin supplementation can reverse this
      process indicated a potential role for vitamin A in cancer prevention. Thus far,
      correlative epidemiological studies on vitamin A use and cancer prevention have
      produced mixed results, as this review indicates. Apparently, in populations
      deficient in vitamin A (caused by an inadequate diet or tobacco use),
      supplementation programs appear to be effective in reducing cancer incidence. In
      groups already having sufficient dietary or supplemental vitamin A, cancer
      prevention by added vitamin A may not be particularly effective. The most likely
      reason for the low efficacy in the latter groups is that feedback mechanisms that
      increase retinol storage in the liver limit retinol plasma levels; whereas,
      supplementation at higher doses causes toxicity. In addition to serving as a
      metabolic source of retinol, beta-carotene, along with other dietary carotenoids,
      function as antioxidants that can prevent carcinogenesis by decreasing the levels
      of the free-radicals that cause DNA damage.

PMID- 10637382
TI  - Current and potential chemotherapeutic agents used for induction chemotherapy in
      the treatment of breast cancer.
AB  - A substantial proportion of breast cancers are large (<3 cm) or locally advanced
      (T3, T4, TXN2) at the time of initial presentation. The therapeutic goals that
      must be achieved in patients with such cancers are to obtain adequate local
      disease control so that surgery can be performed and to abolish occult distant
      metastases therefore improving survival. Over the past three decades conventional
      adjuvant chemotherapy regimens have been employed pre-operatively (neo-adjuvant
      or primary chemotherapy) to achieve these goals. Studies have now shown that the
      survival of patients who receive neo-adjuvant chemotherapy is comparable to that
      of those who receive the same chemotherapy regimen following surgery. It is also
      apparent that although clinical tumour response rates to neo-adjuvant
      chemotherapy may be high there is considerable scope for improvement in the
      corresponding pathological tumour response. Furthermore, data from major studies
      that have comprehensively evaluated the use of pre-operative chemotherapy now
      indicates that the pathological response of breast cancers following treatment is
      of far greater prognostic importance than the clinical response. Recent interests
      has focoused, therefore, on the implementation of more prolonged or dose
      intensive chemotherapy regimens with the aims of improving pathological response
      to treatment and ultimately overall survival. Newer antineoplastic agents are
      also becoming available that may be used alone or in combination with
      conventional therapies in order that tumor response may be improved. This review
      describes current and potential therapeutic agents that may be used for the
      induction therapy of breast cancer.

PMID- 10637383
TI  - Intravesical therapy of superficial bladder cancer.
AB  - Transurethral resection (TUR) of the superficial transitional cell carcinoma
      (TCC) of the bladder is known to be insufficient in controlling the disease
      because of the unacceptable rates of recurrence, progression and ultimate
      cystectomy. Adjuvant intravesical chemo-and/or immunotherapy is administered in
      an effort to enhance the efficacy of surgery alone. The initial tumor stage and
      grade, the multifocality of this cancer and the history of previous recurrences
      remain the determinant factors in survival. It is important to decide exactly
      which patients are at risk, and, therefore, do need treatment. Knowledge of the
      natural history of the disease will facilitate this decision making, although the
      natural history of TCC is largely unpredictable owing to tumor heterogeneity.
      Several cytotoxic and immune modifying agents have been used intravesically in
      different treatment schedules. However, despite their effectiveness, no consensus
      exists about the optimal antineoplastic regimen. The selection of the latter is a
      subject of continuous investigation. Intravesical treatment with cytotoxic drugs
      has been demonstrated to achieve an acceptable reduction in short- and
      intermediate-term recurrence rates, but has no proven ability in preventing
      disease progression to muscle-invasive cancer or prolonging survival. On the
      other hand, bacillus Calmette-Guerin (BCG) currently appears to be the most
      effective agent for intravesical use, especially in patients with high grade and
      stage neoplasms but the optimum strain, dosage and duration schedule have not
      been determined. Clinical trials have shown that BCG provides long-term
      protection from tumor recurrence, while there is evidence that it may favorably
      alter the progression rate of the disease with prolongation of survival. Toxicity
      of intravesical chemo- and immunotherapy still remains a major problem and
      attempts at reducing the dosage, and, thus, toxicity without affecting efficacy
      are underway. This review endeavors to present updated information on
      intravesical chemotherapy in treating superficial bladder cancer, the expanding
      role of intravesical immunotherapy, the recent work comparing various
      immunotherapeutic regimens with chemotherapeutic intravesical therapies, and the
      progress made towards achieving optimal treatment regimens.

PMID- 10637384
TI  - Heart transplantation in Asia.
AB  - BACKGROUND: The first clinical heart transplantation in Asia was performed by
      Wada in 1968. Due to cultural and religious problems, heart transplantation was
      rarely performed in Asia until 1987 and since then the number of heart
      transplantation has increased rapidly. This study was undertaken to investigate
      the results of heart transplantation in Asia. METHODS: Data was collected through
      the use of a questionnaire by mail. The questionnaire included information on the
      year when heart transplantation was started, the number of heart transplantations
      by year and country population, sex, age and diagnosis of recipients, causes of
      brain death of the donors, number of centers with an active heart transplantation
      programs, operative mortality and actuarial survival, brain death and organ
      transplant legislation. RESULTS: From July 17, 1987 to December 1996, 380
      patients received heart transplantation in Asia. Up to 1996, Taiwan had performed
      178 cases of heart transplantation. Thailand also started in 1987 and had 95
      cases. South Korea started in 1992 and had 65 cases. Singapore and India each had
      12 cases. Hong Kong 8 cases, China 7 cases, and the Philippines 3 cases, all
      started in the early 1990s. The recipient ages ranged from 1 to 70 years with a
      male to female ratio of 3 to 1. The one-month operative mortality rate ranged
      from 0 to 25% with an average of 7.4%. The one-year survival rate ranged from 0
      to 84% with an average of 78.8%. The 5-year survival rate ranged from 30 to 74.1%
      with an average of 67. 5%. CONCLUSION: Heart transplantation was well-established
      in most Asian countries, and the number was increasing. The result and survival
      rate of heart transplantation in Asia were comparable with that of the world
      series.

PMID- 10637385
TI  - Optimal pulse pressure of pulmonary circulation under bi-ventricular assist after
      cardiogenic shock.
AB  - In order to evaluate an appropriate pulse pressure of pulmonary circulation
      during bi-ventricular assist, an experimental study was carried out in swine. The
      cardiogenic shock model was made by the left anterior descending (LAD) ligation
      method. When the hear fibrillated due to acute myocardial infarction, both left
      and right hearts were supported by ventricular assist devices (VADs) for two
      hours. The left heart assist was operated with a pneumatic pulsatile ventricular
      assist device (VAD) and the right was operated with a pneumatic VAD or
      centrifugal pump. According to the pulse pressure of the pulmonary artery these
      models were divided into three groups: Low-P group (n = 3), in which a low pulse
      pressure (less than 20 mmHg) was made by VAD, High-P group (n = 5), in which over
      20 mmHg of pulse pressure was initiated. NP group (n = 10), in which nonpulsatile
      assist was done with a centrifugal pump. In pulmonary gas exchange, the Low-P
      group was superior to the other two groups. The average PaO2 was 214+/-57 mmHg in
      the Low-p group, and 117+/-41 mmHg and 148+/-81 mmHg in the NP group and High-P
      group respectively. In the pathological study, a remarkable extension of
      pulmonary lymphoducts was found in the High-P group. On the other hand, this
      change was not recognized in other groups. These results suggested that pulmonary
      microcirculation might deteriorate due to high pulse pressure of the pulmonary
      artery. We consider the most suitable pulmonary pulse pressure to be around 20
      mmHg to maintain normal pulmonary circulation.

PMID- 10637386
TI  - Cardiac afferents to the nucleus of the tractus solitarius: A WGA-HRP study in
      the rat.
AB  - Central distribution of the sensory fibers of the heart was investigated in the
      rat by the use of transganglionic transport of horseradish peroxidase (HRP).
      After the left intercostal thoracotomy was done under deep anesthesia and
      artificial respiration, wheat germ agglutinin-conjugated HRP (WGA-HRP) was
      injected into the left and right ventricular walls and the apex of the heart. HRP
      labeled fibers were observed to be distributed to the dorsomedial portion of the
      medulla oblongata through the vagal nerve. The labeled fibers were present in
      various subnuclei of the nucleus of the tractus solitarius (NTS) bilaterally at
      the level of +0.36 to -1.74 mm to the obex. However, the most conspicuous feature
      in the present study was that the labeled fibers were exclusively confined to the
      medial, ventrolateral and commissural NTS with some distribution to the
      dorsolateral NTS. Although the labeling in the medial and ventrolateral NTS was
      observed to extend rostrocaudally, it was of interest that the labeling in the
      medial NTS was divided into the ventral and dorsal parts at the level around the
      obex. Accumulation of the labeled fibers in the commissural NTS was found at the
      level caudal to the obex and these fibers were traced to the caudal portion of
      its subnucleus with a gradual decrease in number. This pattern of distribution of
      cardiac afferents in the NTS was considered to be peculiar to the rat, because it
      was quite different from that reported previously in the cat.

PMID- 10637387
TI  - Cardiac surgery in patients with dialysis-dependent renal disease.
AB  - This study was designed to evaluate the operative outcome of dialysis patients
      undergoing cardiac surgery. A retrospective review was performed of 28
      consecutive patients with end-stage renal disease dependent on maintenance
      hemodialysis (n = 26) or peritoneal dialysis (n = 2) who underwent
      cardiopulmonary bypass (CPB). The operations included isolated coronary artery
      bypass grafting (CABG) (n = 21), aortic valve replacement (n = 4) and CABG plus
      aortic valve replacement (n = 3). Seven operations were emergent or urgent. In 23
      patients, a heparin-coated (HC) circuit with reduced systemic heparinization was
      used for CPB. The hospital mortality was 7.1%. Complications occurred in 13
      patients (46%). Although thoracotomy for bleeding was required in 3 patients,
      only 1 had undergone CPB with an HC circuit. There were 7 late deaths. All
      survivors showed improvement in symptoms and overall functional status. The
      actuarial survival rates were 78% and 58% at 1 and 4 years, respectively. In the
      10 patients with diabetes mellitus, the 4-year survival rate was 50%. In the
      patients who underwent non-elective surgery, the survival rate was 29%. Cardiac
      surgery can be performed with increased but acceptable mortality in dialysis
      patients. Good symptomatic relief can be expected. Surgery should be performed
      before the general condition deteriorates.

PMID- 10637388
TI  - Eight year experience with the CarboMedics bileaflet valvular prosthesis.
AB  - Two hundred and two patients (97 female and 105 male; mean age: 45. 5+/-9 years)
      received CarboMedics bileaflet valves during a period of eight years. Ninety-one
      patients received mitral, 72 aortic and 39 aortic+mitral valve prosthesis.
      Tricuspid plasty and coronary artery bypass surgery were the concomitant
      operations in 17 and 12 patients, respectively. The mean follow-up period was
      24.7 months and the ratio was 91%. Overall operative mortality was 3.96% (8
      patients); 2.78% for aortic valve replacement (AVR), 3.29% for mitral valve
      replacement (MVR) and 7.7% for double valve replacement (DVR). The late mortality
      rate was 2.89% for AVR, 2.2% for MVR and 8. 3% for DVR. The main cause of
      mortality was low cardiac output. The overall survival rate was 91.5% in 2 years.
      The actuarial freedom from thromboembolism in 2 years was 97% for AVR, 95% for
      MVR and 84% for DVR. No mortality due to heamorrhagic events was observed.
      CarboMedics prosthetic heart valves may be used satisfactorily with a low
      incidence of valve-related morbidity and mortality.

PMID- 10637389
TI  - Assessment of coronary artery bypass surgery by exercise thallium imaging.
AB  - The purpose of this study was to assess the coronary artery bypass grafting
      (CABG) in exercise thallium-201 scintigraphy. The study was performed on 18
      consecutive patients undergoing elective surgery. We compared the results of the
      scintigraphic examinations, 1 week before and 1 month postoperatively. Of the 47
      bypass grafts, 20 (42. 6%) grafts contributed to the improvement of the ischemic
      areas and 38% of the bypass grafts did not change the scintigraphic patterns
      after surgery. Some bypass grafts had been performed on the stenotic arteries
      that dominated the areas which preoperatively showed normal exercise
      scintigraphic patterns yet were considered to worsen in the near future. Such
      grafts main contribution may be to protect and to increase the overall myocardial
      washout ratio for prevention of an enlargement of ischemic areas.

PMID- 10637390
TI  - Myocardial revascularization with modified T-graft using bilateral internal
      thoracic arteries.
AB  - OBJECTIVE: By using a T-graft configuration, the myocardium may be completely
      revascularized with bilateral internal thoracic arteries. This study aimed to
      evaluate the perioperative morbidity and mortality in a single surgeon's early
      experience with a modified T-graft using bilateral internal thoracic arteries.
      METHODS: Between October 1994 to April 1997, 200 consecutive patients mostly
      selected per protocol, received a T-graft with bilateral internal thoracic
      arteries for stable angina pectoris (n = 157) or unstable angina pectoris (n =
      43). The mean age of patients was 56 years (range of 36 to 78 years). There were
      171 males and 29 females. Forty-three patients had diabetes. Concomitant
      procedures were performed in 8 patients. RESULTS: In 190 patients (95%), total
      arterial revascularization of the myocardium was achieved solely by the use of
      bilateral internal thoracic arteries in a T-graft configuration and the number of
      anastomoses per patient averaged 4.2. Ten patients (5%) received supplemental
      saphenous veins in addition to T-grafts for low cardiac output (n = 3),
      intraoperative regional ischaemia (n = 2), postoperative myocardial ischaemia (n
      = 2) and inadequate conduits (n = 3). The 30-day mortality was 0.5%.
      Perioperative myocardial infarct occurred in 2 patients (1.0%). Reasons
      encountered for early re-operation included bleeding (n = 7), sternal dehiscence
      (n = 5), suppurative sternitis (n = 3) and myocardial ischaemia (n = 2). Twelve
      patients received inotropes and intraaortic balloon counterpulsation was employed
      in 3 patients. CONCLUSION: When bilateral internal thoracic arteries were used in
      a T-graft configuration, total arterial revascularization of the myocardium was
      achieved with an acceptably low morbidity and mortality.

PMID- 10637391
TI  - Repair of the left ventricular aneurysm: twenty-two years of experience with long
      term results.
AB  - METHODS: 1. All patients had preoperative investigations including coronary
      angiography and left ventriculography. 2. Clinical symptoms, functional outcome
      and survival rate were analyzed from medical records, patient's follow-up visits,
      and communications from the referring physicians. 3. All survivors were assessed
      for clinical functional status and survival rate at the most recent follow-up
      visits. MAIN OUTCOME MEASURES: long-term postoperative survival rate and the
      improvement of clinical outcomes. RESULTS: Repair of the left ventricular
      aneurysm alone was performed in 9 patients (19.15%). Repair of the left
      ventricular aneurysm combined with coronary artery bypass grafting was performed
      in 38 patients (80.85%). There was only one death (2.13%) in this study. There
      was a significant increase in the postoperative mean ejection fraction (EF) of
      the left ventricle (LV) of 16.83+/-4.93% (p < 0.01) when compared to the
      preoperative mean EF of the LV. Long-term follow-up of linear repair of the left
      ventricular aneurysm at a mean of 12.96 years was carried out. 78.13% of patients
      clinically improved according to the New York Heart Association (NYHA) functional
      class and Kaplan-Meier's method long-term survival rate of 66.61%. CONCLUSION:
      Left ventricular aneurysm was best managed by surgical repair with improvement in
      quality of life.

PMID- 10637392
TI  - Pseudotumor due to pulmonary infarction diagnosed by video-assisted thoracoscopic
      surgery.
AB  - We report a case of pulmonary infarction in a 50-year-old man who was referred
      for an asymptomatic coin lesion in the periphery of the right lower lobe.
      Computed tomography of the chest demonstrated a subpleural solitary nodule with
      spicular radiation. Video-assisted thoracoscopic surgery was performed to obtain
      a histological diagnosis. Thoracoscopic examination showed that the tumor was
      dark purple and the central portion was gray, indicating blood retention in the
      lung and necrotic and fibrotic tissue in the central portion. This is the first
      case of pseudotumor due to pulmonary infarction that was diagnosed by video
      assisted thoracoscopic resection.

PMID- 10637393
TI  - Thoracoscopic surgery for intralobar pulmonary sequestration.
AB  - A 47-year-old male with intralobar pulmonary sequestration successfully treated
      by thoracoscopic surgery was reported. Preoperative selective angiography
      revealed two aberrant arteries originating from the left infraphrenic artery.
      Under thoracoscopy, adhesive tissues around the sequestered lung were dissected,
      aberrant arteries were divided and the sequestered lung was resected. We
      considered that preoperative detailed analysis of the aberrant artery was very
      important to safely perform thoracoscopic procedures for pulmonary sequestration.

PMID- 10637394
TI  - Purulent pericarditis presenting as an extracardiac mass in a patient with
      untreated diabetes.
AB  - A 50-year-old man with symptoms of bi-ventricular heart failure was transferred
      to our hospital with a diagnosis of extracardiac tumor. He had a 10 year history
      of untreated diabetes. Chest computed tomography (CT) revealed an extracardiac
      mass in the right atrio-ventricular groove. Cardiac catheterization revealed an
      elevated mean right atrial pressure of 18 mmHg, mean pulmonary wedge pressure of
      16 mmHg, and the right ventricular pressure curve demonstrated typical dips and
      plateaus. At surgery, there was severe adhesion between the pericardium and
      epicardium, and the pericardium was severely thickened and contained turbid pus.
      In the left thoracic cavity, there was large amount of pleural effusion and pus.
      Therefore, the patient was diagnosed with purulent pericarditis caused by left
      empyema. The thickened pericardium at the anterior portion of the heart was
      resected, however resection of the remaining portion was abandoned because the
      adhesion was so tight. After surgery, the patient underwent irrigation of the
      heart and left thoracic cavity by 1% povidone iodine solution and 0.5 mg/ml of
      imipenem for 7 days. Bacteriologic culture of the pus from the pericardium
      revealed anaerobic gram negative bacteria. After 4 months of antibiotics
      infusion, his C reactive protein became negative and the patient was subsequently
      discharged from our hospital.

PMID- 10637395
TI  - Simultaneous repair of cardiovascular disorders and pectus deformity in a patient
      with Sprintzen-Goldberg syndrome: A case report.
AB  - We report a 12-year-old girl with Sprintzen-Goldberg syndrome (SGS) who was
      complicated with annuloaortic ectasia with aortic regurgitation, mitral valve
      prolapse with mitral regurgitation, and a severe pectus excavatum. In this
      patient, aortic root replacement, mitral valve replacement, and sternal elevation
      were simultaneously performed, and a version of Ravitch's procedure that was
      technically modified to support the sternum was used for sternal elevation. This
      modified sternal elevation technique gave excellent operative exposure, and
      maintained chest wall stability after the operation.

PMID- 10637396
TI  - Minimally invasive axillary-coronary artery bypass for acute occlusion of the
      coronary artery.
AB  - We performed minimally invasive axillary-coronary bypass using a reversed
      saphenous vein graft to treat a patient with acute occlusion of the left anterior
      descending artery after failed percutaneous transluminal coronary angioplasty
      (PTCA). For patients with acute myocardial ischemia, this procedure is useful to
      reduce the ischemic time and is less invasive. We believe this procedure may be
      an alternative intervention for selected patients with acute myocardial
      infarction or unstable angina after PTCA. However, a large series with sufficient
      follow-up and late angiography is required to evaluate the long-term patency and
      effectiveness of this approach.

PMID- 10637397
TI  - Cardiopulmonary bypass technique for treatment of renal cell carcinoma extending
      into the vena cava.
AB  - Cardiopulmonary bypass (CPB) is a unique technique used widely for renal cell
      carcinoma patients showing inferior vena cava invasion. We used a modification of
      CPB technique for 2 patients. These patients were managed with CPB without cross
      clamping and so without cold potassium cardioplegia. The primary tumor was a
      renal cell carcinoma propagating into the inferior vena cava and going into the
      right atrium as a thrombus in both patients. As a surgical procedure the urology
      team did nephrectomy and then with our clinical techniques we used CPB to cool
      the patients to 20 degrees C and decreased the flow to 500 ml/min/m2. The heart
      went into spontaneous ventricular fibrillation without using cross clamping and
      cardioplegia. Then we did atrial and inferior vena caval thrombectomy in a
      bloodless and visible operation field within a safe time interval. The aim of
      using this technique is to prevent myocardial injury and to protect the brain
      from hypoxia by using this low flow technique. This method can be used safely for
      the management of renal cell carcinomas and for some retroperitoneal malignancies
      associated with vena caval and atrial involvement.

PMID- 10637398
TI  - Late-life chronic depression: a 399-case study in private practice.
AB  - OBJECTIVE: Aims of the study were to find the prevalence of chronic depression in
      elderly patients compared with younger patients, and to compare chronic
      depression between elderly and younger patients, to find if there were clinical
      differences. A major feature of the study was the inclusion of a large number of
      bipolar II patients, usually not included in previous studies. METHODS: Three
      hundred and ninety-nine consecutive unipolar (N=200) and bipolar II (N=199)
      depression outpatients were interviewed with the Structured Clinical Interview
      for DSM-IV and depression rating scales in a private practice. RESULTS: Chronic
      depression was more common in elderly patients than in younger patients (53.6% vs
      40.1%, p=0.0299). Late-life chronic depression patients had later age at onset,
      longer duration of illness, fewer bipolar II cases, more unipolar cases and more
      relapses than younger chronic depression patients. CONCLUSIONS: Results suggest
      that late-life depression is more likely to be chronic than depression in younger
      patients. The subtyping of chronic depression according to age seems supported by
      a different age at onset and some clinical differences.

PMID- 10637399
TI  - Prevalence and correlates of parkinsonism in an institutionalized population of
      geriatric patients with chronic schizophrenia.
AB  - BACKGROUND: Geriatric patients with chronic schizophrenia are at increased risk
      for parkinsonism and cognitive impairment, but the relationship between the two
      has been insufficiently studied. OBJECTIVES: (1) To determine the prevalence of
      parkinsonism in a cohort of institutionalized geriatric patients with chronic
      schizophrenia (N=79). (2) To examine the relationship of parkinsonism to
      potentially relevant variables including cognitive functioning, positive and
      negative symptoms, sex, age, age at first hospitalization, psychopharmacological
      regimen and tardive dyskinesia (TD). METHOD: Tremor, rigidity and bradykinesia
      were rated on a five-point severity scale. Clinically significant parkinsonism
      was defined by the unambiguous presence of at least two of those signs. TD was
      assessed with the Modified Simpson Dyskinesia Scale. Schizophrenic symptoms were
      rated with the Positive and Negative Syndrome Scale, and cognitive functioning
      with the Mini-Mental State Examination and the Consortium to Establish a Registry
      for Alzheimer's Disease battery. RESULTS: The prevalence of parkinsonism was 19%
      and was significantly higher in women than in men. Age was a significant
      predictor of parkinsonism. Independent of age, bradykinesia was significantly
      correlated with MMSE, fluency and naming. Tremor, rigidity and medication status
      did not correlate with any cognitive variable assessed. Cognitive measures did
      not differ between subjects meeting and not meeting criteria for clinically
      significant parkinsonism. Rigidity and bradykinesia were significantly correlated
      with negative symptoms but no parkinsonism sign correlated with positive
      symptoms. Twelve subjects received ratings consistent with both TD and
      parkinsonism; however, no parkinsonian variable predicted the co-occurrence of
      TD. CONCLUSIONS: The present correlations suggest potential overlap among the
      neural substrates for bradykinesia, cognitive impairment and negative symptoms;
      however, further research is required to clarify that issue.

PMID- 10637400
TI  - Dementia in developing countries. A consensus statement from the 10/66 Dementia
      Research Group.
AB  - Less than one-tenth of all population-based research into dementia is directed
      towards the two-thirds or more of cases living in developing parts of the world.
      The 10/66 Dementia Research Group has been formed to redress this imbalance,
      encouraging active research collaboration between centres in different developing
      countries and between developed and developing countries. The 10/66 group
      consisted initially of researchers attending a symposium on dementia research in
      developing countries, held at the 1998 Alzheimer's Disease International
      conference. They noted a growing interest in this area, with many active
      researchers and others wishing to start new studies. There was felt to be an
      urgent need for more research: quantifying prevalence and incidence, exploring
      regional variations in international collaborations using harmonized
      methodologies, describing care arrangements for people with dementia, quantifying
      the impact on caregivers and evaluating the effectiveness of any newly
      implemented services. Methodological problems need to be addressed, particularly
      development of culture- and education-fair dementia diagnostic procedures. Good
      quality research can generate awareness, pioneer service development and
      influence policy.

PMID- 10637401
TI  - Methodological issues for population-based research into dementia in developing
      countries. A position paper from the 10/66 Dementia Research Group.
AB  - The 10/66 Dementia Research Group has been formed to promote good-quality,
      internationally comparable research into dementia in developing countries through
      active research collaboration. In this position paper, we review existing
      research into dementia prevalence in developing regions of the world. Seven
      methodologically robust studies were identified. The prevalence of dementia, age
      adjusted to the age structure of the Kerala population, ranged from 1.3% to 5.3%
      for all those aged 60 or over and from 1.7% to 5.2% for all those aged 65 and
      over. Two studies, from Ibadan, Nigeria and Ballabgarh, India, reported
      strikingly low prevalence figures. The reported prevalence for most studies was
      somewhat lower than the consistent figures for Europe reported by the EURODEM
      concerted action. Based on critical review of the literature, and on the
      practical research experience of members of the 10/66 group, recommendations have
      been made for procedure in the following areas: age limits for inclusion in
      dementia surveys, age ascertainment, sampling, scope for incidence studies,
      functional assessment and culture- and education-fair dementia diagnosis.

PMID- 10637402
TI  - Alzheimer's disease, depression and normal ageing: merit of simple psychomotor
      and visuospatial tasks.
AB  - INTRODUCTION: A brief psychometric test battery was used to differentiate
      Alzheimer's disease (AD) patients from patients with depression and healthy age
      matched control subjects. The purpose was to investigate the discriminative value
      of simple psychomotor and visuospatial tasks that were implemented in a computer
      assisted test battery. METHODS: Manumotoric coordination, discrimination reaction
      time and performance on a visuospatial pattern-matching task were assessed.
      Subjects were 30 patients with the diagnosis of probable AD (mild to moderate),
      22 patients with a major depression and 15 healthy normal control subjects.
      RESULTS: Discrimination reaction time separated the three groups most distinctly,
      but general level of cognitive functioning was a significantly confounding
      variable. There were no differences between the AD and the depressed patients
      when the MMSE was used as a covariate. Substantial deficiencies in manumotoric
      coordination were found in both demented and depressed patients. The visual
      pattern-matching task yielded longer reaction times in both patient groups than
      in the control group. CONCLUSION: Translated into neuropsychological terms, these
      data suggest deficiencies in basic central operations, a slowing of central
      information processing and attentional deficits in AD and depressed patients.
      Psychomotor tasks were able to distinguish effectively healthy elderly persons
      from AD and depressed patients. This test battery, however, appears to be limited
      in differentiating AD from depression.

PMID- 10637403
TI  - Clinical Lewy body dementia and the impact of vascular components.
AB  - OBJECTIVE: To study the prevalence of patients fulfilling the clinical consensus
      criteria for dementia with Lewy bodies (DLB) in a dementia population followed up
      with postmortem examination. To compare the clinical and neuropathological
      findings in the clinical Lewy body dementia (LBD) group with findings in a
      clinically defined group with Alzheimer's disease (AD). DESIGN: Medical records
      from 200 patients were studied retrospectively. Clinical consensus criteria for
      DLB and clinical criteria for other dementias were applied. SETTING: The majority
      of the cases were examined and cared for in psychogeriatric and psychiatric
      departments. PATIENTS: The patients, who died between 1985 and 1994, were part of
      a longitudinal dementia project. Each case was neuropathologically examined. Main
      outcome measures Prevalence of clinical signs and neuropathology was compared
      between the clinical groups. RESULTS: Forty-eight (24%) patients fulfilled the
      clinical criteria for DLB while 45 (22%) fulfilled the clinical criteria for
      Alzheimer's disease. The clinical LBD group had a higher Hachinski score compared
      to the clinical AD group. They also showed a tendency towards a 'frontal profile'
      with disinhibition, confusion, personality change and vocally disruptive
      behaviour. More than 80% of the AD and LBD groups respectively exhibited
      Alzheimer pathology. The LBD group had frontal white matter pathology and
      degeneration of the substantia nigra more often than the clinical AD group. Both
      LBD and AD groups showed a progressive and marked increase in severity of
      dementia and decrease in ADL capacity according to an evaluation based on the
      Berger scale and Katz index. The condition of the LBD group was significantly
      worse earlier in dementia. CONCLUSION: The results of this study indicate that
      patients fulfilling the clinical criteria for DLB also exhibit clinical features
      of possible vascular origin and a frontal profile. Subcortical vascular
      pathology, nigral degeneration and AD pathology in this group could partly
      explain the clinical features used to define DLB.

PMID- 10637404
TI  - Sustained cognitive improvement following treatment of Alzheimer's disease with
      donepezil.
AB  - OBJECTIVES: To audit response to the anticholinesterase inhibitor donepezil in
      patients referred to a specialist memory clinic, to identify possible means of
      targeting the drug more accurately. DESIGN: All referrals to the clinic who were
      assessed and treated against a protocol, with structured follow-up. SUBJECTS: All
      referrals of any age with the diagnosis of probable Alzheimer's disease, mild to
      moderately severe. Main outcome measures Cognitive improvement as measured by
      serial ADAS-cog and MMSE examinations. RESULTS: Two hundred and eight-two
      patients commenced on treatment, improved cognitive functioning in over 65% of
      patients reaching 3 months (N=184), 51% on intention to treat analysis (N=231),
      with significantly greater improvement (p=0.03) in those aged 65 and under. Carer
      reports of behavioural improvement not always linked to cognitive improvement.
      Trend to increased response in those on concomitant antidepressants. CONCLUSION:
      Three-month assessment for response prior to agreeing continuation of treatment
      selects a group who maintain their response. Younger patients should be targeted
      for early assessment and treatment.

PMID- 10637405
TI  - Validating screening instruments for cognitive impairment in older South Asians
      in the United Kingdom.
AB  - BACKGROUND: The numbers of older South Asians in the United Kingdom are rising.
      Investigation of their mental health has been neglected compared to their
      physical health. OBJECTIVES: This study aimed to determine the sensitivity and
      specificity of modified versions of two screening instruments for cognitive
      impairment (Mini-Mental State Examination and Abbreviated Mental Test) in a
      community-based population. DESIGN: Two-stage study comparing screening
      instruments against diagnostic interview. SETTING: South, central and north
      Manchester. SUBJECTS: Community-resident South Asians aged 60 years and over.
      METHODS: Subjects were approached via their general practitioners and interviewed
      at home. Sensitivity and specificity for the screening instruments were
      calculated using receiver operating characteristic (ROC) curve analysis. RESULTS:
      For the Gujarati population, the MMSE cutoff was >/=24 (sensitivity 100%,
      specificity 95%) and AMT>/=6 (sensitivity 100%, specificity 95%). For the
      Pakistani population, the MMSE cutoff was >/=27 (sensitivity 100%, specificity
      77%) and AMT>/=7 (sensitivity 100%, specificity 87%). CONCLUSIONS: Culturally
      modified versions of the Mini-Mental State Examination and Abbreviated Mental
      Test are acceptable and may have a high degree of sensitivity. They may assist
      with the recognition of cognitive impairment, if an appropriate cutoff is used.

PMID- 10637406
TI  - Psychometric behaviour of BDI in Alzheimer's disease patients with depression.
AB  - The psychometric properties of the Beck Depression Inventory (BDI) in subjects
      with Alzheimer's disease (AD) and depression have not been fully evaluated. Item
      endorsement patterns may be distorted by the presence of AD. This was tested by
      applying the BDI to a sample of 129 subjects with probable AD without depression
      and to 57 subjects with both probable AD and depression. It was found that the
      BDI under diagnoses depression in the context of AD. ROC curves for total BDI and
      cognitive and somatic items subsets showed low sensitivity and low areas under
      the curve indices. The results suggest that the BDI is not an ideal instrument to
      measure depression in AD. This may not result solely from the swing of the
      somatic items subset, but from other aspects which require further investigation.

PMID- 10637407
TI  - Severe and persistent regressive behaviour in three elderly subjects without
      cognitive decline.
AB  - The appearance of regressive behaviours in the elderly is relatively common.
      Among these regressive attitudes, there is a relatively high frequency of
      situations which mimic dementia in the absence of demonstrable organic
      alterations that justify the presence of a neurodegenerative profile. These
      generally stem from a primary psychiatric disorder and are referred to as
      'pseudodementia'. All these conditions, which are generally accompanied by a
      marked increase in dependency on the environment, are distinguished by the
      presence of cognitive impairment and behavioural traits typical of dementia but
      which are fully reversible on treatment of the primary psychiatric disorder. Here
      we describe three cases, characterized by their striking discrepancy between
      clinical profile, with pronounced behavioural alterations similar to dementia
      related conduct disorders, culminating in almost complete dependency on the
      environment, and almost stably intact cognitive performance (assessed through the
      MMSE), over a mean observation period of approximately five years.

PMID- 10637408
TI  - Age-associated changes in cognitive function in highly educated adults: emerging
      myths and realities.
AB  - The effects of education and continued intellectual engagement on age-associated
      cognitive change were investigated in a sample of 102 members of the professional
      and college communities in the metro Atlanta Georgia area (ages 30-76). All
      participants were administered a 60-minute battery that measured different
      aspects of memory, intelligence and cognitive performance. Age-associated
      declines in performance were detected on the digit symbol measure of
      intelligence. Conversely, positive but non-significant trends were detected on
      the picture completion, arithmetic and similarities subtests. Age effects were
      also noted on some measures of the Wisconsin Card Sorting Test and both versions
      of the Trail Making Test. The findings suggest that at least among the highly
      educated, certain cognitive abilities may receive some degree of amelioration as
      a consequence of continued intellectual engagement. However, the effects may be
      associated more with compensation rather than protection against the effects of
      ageing.

PMID- 10637409
TI  - The role of occupational therapy in dementia-C.O.P.E. (Caregiver options for
      practical experiences).
AB  - Occupational therapy is a profession that enables individuals to regain, maintain
      or promote function after an illness, injury or disability occurs. The basis of
      the profession's philosophy derives from a recognition of the importance of
      meaningful activity (occupation) in people's lives to support function, quality
      of life and the debilitating effects of inactivity. Occupational therapy enhances
      the abilities of individuals to engage in the following performance areas: (1)
      activities of daily living (eg eating, bathing, toileting, functional mobility)
      and instrumental activities of daily living (eg meal preparation, shopping,
      managing one's finances); (2) work and productive activities (eg care of others,
      educational and vocational activities); and (3) leisure to meet a variety of
      needs that are culturally meaningful to individuals and their significant others.
      In order to determine the etiologies of dysfunction in one or more performance
      areas, occupational therapists assess the following components of performance:
      sensorimotor, neuromusculoskeletal, motor, cognitive, and psychosocial. This
      assessment becomes the basis for tailoring treatment to individuals' needs and
      interests. When deficits and strengths in performance components and performance
      areas have been identified, occupational therapists work with clients/patients
      and their caregivers to reduce the barriers in daily functioning and facilitate
      maximum engagement in their environments, the human and physical context for
      daily living.

PMID- 10637410
TI  - In vitro stereoselective degradation of carprofen glucuronide by human serum
      albumin. Characterization of sites and reactive amino acids.
AB  - Acyl glucuronides formed from carboxylic acids can undergo hydrolysis, acyl
      migration, and covalent binding to proteins. In buffers at physiological pH, the
      degradation of acylglucuronide of a chiral NSAID, carprofen, consisted mainly of
      acyl migration. Acidic pH reduced hydrolysis and acyl migration, thus stabilizing
      the carprofen acyl glucuronides. Addition of human serum albumin (HSA) led to an
      increased hydrolysis of the conjugates of both enantiomers. This protein
      protected R-carprofen glucuronide from migration and therefore improved its
      overall stability. Hydrolysis was stereoselective in favor of the S conjugate.
      The protein domains and the amino acid residues likely to be responsible for the
      hydrolytic activity of HSA were deduced from the results of various
      investigations: competition with probes specific of binding sites, effects of pH
      and of chemical modifications of albumin. Dansylsarcosine (DS), a specific ligand
      of site II of HSA, impaired the hydrolysis, whereas dansylamide (DNSA) and
      digoxin, which are specific ligands of sites I and III, respectively, had no
      effect. The extent of hydrolysis by HSA strongly increased with pH, indicating
      the participation of basic amino acids in this process. The results obtained with
      chemically modified HSA suggest the major involvement of Tyr and Lys residues in
      the hydrolysis of glucuronide of S-carprofen, and of other Lys residues for that
      of its diastereoisomer.

PMID- 10637411
TI  - Preparation and evaluation of chiral stationary phases based on N, N-2,4-(or 4,6)
      disubstituted 4,5-(or 2,5)-dichloro-1, 3-dicyanobenzene.
AB  - Regioselective functionalization of 2,4,5,6-tetrachloro-1, 3-dicyanobenzene
      (TCDCB) by nucleophilic substitution of the chlorine at C(4) with L-Ala, L-Phe or
      L-Pro, followed by amide-bond formation to lipophilic amines containing strong pi
      donor group, and by final introduction of the spacer 3-aminopropyltriethoxysilyl
      (APTES), provided a number of new brush-type chiral selectors in the form of 1
      2:1 mixture of 2,4 and 4,6-di(alkyl)amino regioisomers (8/9, 10/11, 12/13, 14/15,
      20/21, 23/24). Linking these to silica gel (Nucleosil 100-5) gave new chiral
      stationary phases for HPLC columns (CSP I-CSP VI). Being strong pi-basic
      selectors, most of these columns exhibited good resolution properties for pi-acid
      test racemates (TR 1-TR 9), specifically rac 3, 5-dinitrobenzoyl-alpha-amino acid
      isopropyl-esters (DNB-AA). CSP V [1,3-dicyano-2,5(5,6)-dichloro-6(2)-(gamma'
      silica bound propylamino)-4-N-?[N-butyl]-N'-[(1R)-cyclohexylethyl]-N'-[napht
      hylmet hyl]acetamido?-aminobenzene] and particularly the dipeptide-containing CSP
      VI [2,5(5,6)-dichloro-6(2)-(gamma'-silica bound propylamino)-4-N-(3', 5'
      dimethylanilido)-L-alanyl-L-prolyl-aminobenzene] proved to have the highest
      efficiency, comparable with the best commercial brush-type columns with pi-donor
      properties. Further evidence revealed that multiple hydrogen bonding via the
      amide group in the chiral environment and pi-pi interaction play a major role in
      chiral recognition, whereas steric perturbations via nonbonding VDW interactions
      contribute substantially only to the resolution of CSP III [2,5(5,6)-dichloro
      6(2)-(gamma'-silica bound propylamino)-4-N-(cyclohexylamido)-L-alanyl
      aminobenzene]. This contribution is minor for the other CSPs.

PMID- 10637412
TI  - Absolute configuration of a diaryldiacyloxy spiroselenurane and resolution of a
      carbon analog.
AB  - The enantiomers of 3,3'-spirobi(3-selenaphthalide) (2) were obtained via direct
      separation by liquid chromatography on a chiral stationary phase. Determination
      of the absolute configuration was made by X-ray crystallography with the use of
      the anomalous dispersion technique. The first eluted (+)-form (lambda = 302 and
      365 nm) of 2 was found to have (S)-configuration. By a comparison of CD-spectra,
      the same (S)-configuration could be assigned to the (+)-forms of the sulfur (1)
      and tellurium (7) analogs of 2. An asymmetric dichloro-substituted spirobilactone
      (4) was also synthesized and separated into its enantiomers. Relative
      configurations between 4 and its parent compound (3) were established from the
      corresponding chiroptical data obtained. Chirality 12: 71-75, 2000.

PMID- 10637413
TI  - Regioselective template synthesis, X-ray structure, and chiroptical properties of
      a topologically chiral sulfonamide catenane.
AB  - The synthesis of a topologically chiral in,out-bis-sulfonamide catenane and its
      "dimer" are reported. The structures of the amide wheel and of the catenane were
      resolved by X-ray analysis. NMR-titration of the monosulfonamide-wheel yielded
      conclusive association constants supporting the proposed regioselective mechanism
      of the catenane formation. The enantioseparation of the catenane via chiral HPLC
      was successful. The enantiomers show pronounced Cotton effects in the aromatic
      region of the CD-spectrum. Since the template synthesis was carried out leading
      to the in-oriented sulfonamide-wheel blocked with an N-methyl group at its
      reactive sulfonamide functionality, the catenane represents the first
      monofunctional topologically chiral amide-based catenane. Reaction with 1,2-bis(2
      iodoethoxy)ethane led to a bis-catenane containing two topological units. The
      meso- and the RR/SS-isomers represent a new type of topological diastereomers.

PMID- 10637414
TI  - Reliable assay of extreme enantiomeric purity values by a new circular dichroism
      based HPLC detection system.
AB  - A new sensitive, selective, and versatile circular dichroism (CD)-based HPLC
      detection system was used for the validation of the enantiomeric purity assay in
      the quality control of chiral drugs upon nonchiral stationary phases. The
      precision and the accuracy of the method were checked for selected samples
      showing values of the anisotropy factor on the order of 10(-1) to 10(-4). Very
      high accuracy has been obtained also in the case of extreme enantiomeric purity
      values (</=1% or >/=99% e.p.) and of a low anisotropy factor (g = 2 x 10(-4))
      compound. The high selectivity of this detection system allows a selective
      monitoring of analytes in complex mixtures and makes the baseline stable.

PMID- 10637415
TI  - Solid phase synthesis and biological evaluation of enantiomerically pure wasp
      toxin analogues PhTX-343 and PhTX-12.
AB  - PhTX-343 and PhTX-12, analogues of the natural polyamine wasp toxin PhTX-433,
      were synthesised in 40-60% yields as pure enantiomers using solid phase synthesis
      techniques. Capillary electrophoresis procedures were developed for chiral
      separation and determination of enantiomeric purity (ee) of the enantiomers of
      PhTX-343 and PhTX-12. The methods were optimised with respect to chiral selector,
      buffer pH, and temperature around the capillary. Thus, rac-PhTX-343 was resolved
      using a separation buffer containing 30 mM heptakis-(2, 6-di-O-methyl)-beta
      cyclodextrin in 50 mM 6-aminocarproic acid (pH 4. 0) at 15 degrees C. rac-PhTX-12
      was not resolvable in this system, but could be resolved using a separation
      buffer containing 10% w/v of dextrin 10, a linear maltodextrin, in 50 mM 6
      aminocaproic acid (pH 4.0) at 15 degrees C. Using these methods, the optical
      purity of the synthetic enantiomers was determined to be ee > 99%. The
      enantiomers were also characterised by chiroptical methods. The antagonist
      potency of the enantiomers was tested on nicotinic acetylcholine receptors (human
      muscle-type nAChR) expressed in TE671 cells, ionotropic glutamate receptors in
      Xenopus laevis oocytes (expressing recombinant GluR1flop receptors), and locust
      muscle ionotropic glutamate receptors sensitive to quisqualate (qGluR). The
      potencies of each pair of enantiomers were similar (eudismic ratio close to 1).

PMID- 10637416
TI  - A novel approach for sensitivity enhancement in atmospheric pressure chemical
      ionisation liquid chromatography/mass spectrometry of chlorophylls.
AB  - Differences in the ionisation efficiency of chlorophylls and their phaeophytin
      counterparts result in lower sensitivity for atmospheric pressure chemical
      ionisation mass spectrometric detection of the former. Improvement in the
      sensitivity of detection of chlorophyll of around an order of magnitude at a
      concentration of 1 x 10(-6)mol L(-1) has been achieved using post-column addition
      of methanoic acid during analysis by liquid chromatography/mass spectrometry
      (LC/MS). The method gives linear response and is a simple strategy to improve
      sensitivity both for LC/MS and LC/MS/MS without loss of information relating to
      the precise nature of the tetrapyrrole distributions. Detection levels achieved
      exceed those obtained by absorbance detection.

PMID- 10637417
TI  - Continuous flow infrared matrix-assisted laser desorption/ionization with a
      solvent matrix
AB  - Continuous flow matrix-assisted laser desorption/ionization (MALDI) was
      demonstrated with infrared laser desorption and an ethanol matrix. A capillary
      was used to deliver an analyte solution dissolved in ethanol to a metal frit
      embedded in a sample stage. Typical flow rates were 1.7&mgr;L/min. An optical
      parametric oscillator tuned to 2.8&mgr;m was used for desorption and ionization,
      and mass analysis was achieved with a 1 m linear time-of-flight mass
      spectrometer. Flow injection studies were performed with low picomolar quantities
      of insulin and myoglobin in solutions containing 0.1 to 1.0% glycerol in ethanol.
      Copyright 2000 John Wiley & Sons, Ltd.

PMID- 10637419
TI  - Quantitative analysis of terbinafine (Lamisil) in human and minipig plasma by
      liquid chromatography tandem mass spectrometry.
AB  - A method using liquid chromatography/tandem mass spectrometry (LC/MS/MS) for the
      determination of terbinafine in human and minipig plasma has been developed and
      validated. The method used positive-ion mode for monitoring terbinafine, and used
      a stable isotope labelled terbinafine as the internal standard. Subsequent to
      acetonitrile protein precipitation, the supernatant was directly (unfiltered)
      injected onto the LC column (retention time approximately 4.3 min) for analysis.
      Interday and intraday accuracy and precision were assessed from the relative
      recoveries (observed concentration in percent of the nominal value) of spiked
      samples analyzed on three different days. The lower limit of quantitation (LLOQ)
      was 0.0679 ng/mL in human and minipig using a plasma sample volume of 0.08 mL.
      The method was fast, specific, and exhibited ruggedness. Furthermore, the use of
      turbulent flow chromatography (TurboFlow LC/MS/MS) coupled to mass spectrometry
      for direct analysis of terbinafine in plasma is discussed. The technique allowed
      direct introduction of plasma with satisfactory chromatographic peak shape and
      increased throughput.

PMID- 10637418
TI  - Peptide bond formation in gas-phase ion/molecule reactions of amino acids: a
      novel proposal for the synthesis of prebiotic oligopeptides.
AB  - There is a general fascination with regard to the origin of life on Earth. There
      is an intriguing possibility that prebiotic precursors of life occurred in the
      interstellar space and were then transported to the early Earth by comets,
      asteroids and meteorites. It is probable that some part of the prebiotic
      molecules may have been generated by gas-phase ion/molecule reactions. Here we
      show experimentally that gaseous ion/molecule reactions of the amino acids, Glu
      and Met, may promote the synthesis of protonated dipeptides such as (Glu-Glu)H(+)
      and (Glu-Met)H(+) and their chemical growth to larger protonated peptides.

PMID- 10637420
TI  - Optimization of the mass reflector parameters for direct ion extraction
AB  - The parameters of a mass reflector combined with direct ion extraction are
      optimized to reduce the time-of-flight spread caused by the initial velocity
      distribution of ions. Under the assumption that the initial ion velocity
      distribution is mass independent, one can find the mass range where the spread
      reaches its minimum by varying the electric field in the ion mirror. The mass
      dependence of this particular time-of-flight spread can be diminished when the
      electric field in the ion mirror changes with time. This was theoretically
      demonstrated for the mass region 5 x 10(3) < m < 10(5) Da, under conditions where
      the electric field in the mirror increases by approximately 20% during a time
      interval of several hundred microseconds. Copyright 2000 John Wiley & Sons, Ltd.

PMID- 10637421
TI  - Analysis of erythromycin by liquid chromatography/mass spectrometry using
      involatile mobile phases with a novel atmospheric pressure ionization source.
AB  - A critical limitation of electrospray ionization (ESI) liquid chromatography/mass
      spectrometry (LC/MS) sources is the susceptibility to blockage of interface
      orifices due to the deposition of involatile components from the sample and/or
      mobile phase. These components, including salts, buffers, and ion-pairing agents,
      can be essential to the performance of the chosen analytical method. We report
      here the performance enhancements provided by a novel atmospheric pressure
      ionization (API) source in the analysis of erythromycin A (ERY) using mobile
      phases that contain involatile components. The enhanced robustness of the new
      source is derived from the use of a continuous flow of aqueous solvent at the
      sampling cone orifice that maintains unobstructed ion transmission. The ESI mass
      spectral responses measured for ERY, using an LC separation that incorporates 10
      mM sodium phosphate with and without 10 mM octane sulfonate, were monitored by
      repeated injections over 13-15 h total analysis time. Minimal effects on ESI mass
      spectral responses (integrated peak area) or chromatographic performance (peak
      shape, retention time) were observed during these studies. In the absence of the
      aqueous cleaning flow, complete loss of mass spectral responses and total
      blocking of the sampling cone was observed in less than 30 min. Responses for ERY
      spiked into chicken and beef liver, and catfish muscle at or below the regulatory
      level of interest (100 ppb), were quantified by internal standard calibration
      using this procedure. These results demonstrate the ability of a novel API-MS ion
      source to perform analyses that require the use of involatile mobile phase
      additives.

PMID- 10637422
TI  - Mass spectrometry of the human pituitary proteome: identification of selected
      proteins.
AB  - The field of proteomics involves the combined application of advanced separation
      techniques, mass spectrometry, and bioinformatics tools to characterize proteins
      in complex biological mixtures. Here we report the identification of nine
      proteins from the human pituitary proteome, using the proteomics approach. The
      pituitary proteins were separated by two-dimensional electrophoresis, and were
      visualized by silver staining. The proteins of interest were subjected to in-gel
      digestion with trypsin, and the masses of the resulting peptides were determined
      by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.
      This tryptic mass map was used to identify the proteins through a search of a
      protein-sequence database. The identified proteins include important hormones,
      and enzymes with various catalytic activities. These proteins will be used to
      construct a two-dimensional reference database of the human pituitary. This
      database will be employed to study changes in the pituitary proteome that are
      associated with the formation of pituitary tumors.

PMID- 10637423
TI  - Determination of antimigraine compounds rizatriptan, zolmitriptan, naratriptan
      and sumatriptan in human serum by liquid chromatography/electrospray tandem mass
      spectrometry.
AB  - Development of a rapid, sensitive and selective method for the determination of
      antimigraine drugs from human serum is essential for understanding the
      pharmacokinetics of these drugs when administered concurrently. Solid phase
      extraction (SPE) using Oasis HLB was used to extract the drugs (sumatriptan,
      naratriptan, zolmitriptan and rizatriptan) and the internal standard bufotenine
      from serum. A method based on liquid chromatography/tandem mass spectrometry
      (LC/MS/MS) was developed and validated to simultaneously quantitate these
      antimigraine drugs from human serum. The precursor and major product ions of the
      analytes were monitored on a triple quadrupole mass spectrometer with positive
      ion electrospray ionization (ESI) in the multiple reaction monitoring (MRM) mode.
      The base peak in all the analytes is formed by alpha cleavage associated with
      protonation of the secondary amine. Mechanisms for the formation of the collision
      induced dissociation products of these antimigraine compounds are proposed.
      Linear calibration curves were generated from 1-100 ng/mL with all coefficients
      of determination greater than 0.99. The inter- and intraday precision (%RSD) were
      less than 9.3% and accuracy (%error) was less than 9.8% for all components. The
      limits of detection (LOD) for the method were 250 pg/mL for sumatriptan and 100
      pg/mL for the remaining analytes based on a signal-to-noise ratio of 3.

PMID- 10637424
TI  - Determination of methotrexate in human urine at trace levels by solid phase
      extraction and high-performance liquid chromatography/tandem mass spectrometry.
AB  - For biological monitoring of hospital personnel occupationally exposed to
      antineoplastic agents, highly sensitive and specific methods are required. In
      order to detect trace MTX urinary concentrations, a precise and accurate high
      performance liquid chromatography/tandem mass spectrometry (HPLC-MS/MS)
      procedure, incorporating solid phase extraction, has been developed. Urine
      samples were purified by solid phase extraction (SPE) on octadecyl bonded,
      endcapped silica SPE columns. After eluting with methanol, the solvent was
      evaporated obtaining a 25-fold concentration of the analyte. This procedure was
      validated by using 7-OHMTX as internal standard. Calibration curves had
      correlation coefficients always higher than 0.999, and the limit of detection was
      assessed at 0.2 microg L(-1). High specificity of the HPLC-MS/MS technique
      assures that no interfering substances are detected rather than the analyte of
      interest.

PMID- 10637425
TI  - Hydrogen-deuterium exchange reactions of cis- and trans-cyclopropane derivatives
      with D(2)O and CD(3)OD in the gas phase
AB  - Gas-phase hydrogen-deuterium (H/D) exchange reactions involving four isomeric
      cyclopropane derivatives were investigated under chemical ionization (CI)
      conditions, using D(2)O and CD(3)OD as reagent gases. There are abundant ions at
      [M + 1](+), [M + 2](+) and [M + 3](+) in the D(2)O and CD(3)OD positive-ion CI
      mass spectra of the two isomer pairs 1, 2 and 3, 4. Their CI mass spectra are
      identical with each pair, and so are the collision-induced dissociation (CID)
      spectra of ions [M + 1](+), [M + 2](+) and [M + 3](+) of each of the two isomer
      pairs. The CID spectra of [M + 1](+) ions indicate that they have common D/H
      exchange reactions within each pair, which take place between molecular ions and
      deuterium-labeling reagents to form the [M - H + D](+) ions. Those of their [M +
      2](+) ions show that they have common D/H exchange reactions within each pair,
      which form the [M(d1) + H](+) ions. Those of their [M + 3](+) ions show that they
      have common D/H exchange reactions within each pair, which take place between the
      [M(d1)] and deuterium-labeling reagents to produce [M(d2) + H](+) for the isomer
      pair 1, 2 and [M(d1) + D](+) for the isomer pair 3, 4. The number and position,
      and active order of the active hydrogen atoms of the isomer pairs 1, 2 and 3, 4
      were determined. Copyright 2000 John Wiley & Sons, Ltd.

PMID- 10637426
TI  - Mass spectrometric detection and identification of ortho, para-benzyltoluenes and
      oligotoluenes
AB  - Mass spectrometric detection and identification of ortho- and para-benzyltoluenes
      and oligotoluenes, C(21)-C(49), in several reaction mixtures was performed. Thus,
      the corresponding electron impact spectra were acquired and analyzed, this in
      addition to constant B/E linked scans and high-resolution data. Copyright 2000
      John Wiley & Sons, Ltd.

PMID- 10637427
TI  - p53 and its younger siblings.

PMID- 10637428
TI  - Inducible gene expression in apoptosis.

PMID- 10637429
TI  - Structure, function and regulation of p63 and p73.
AB  - The p53 tumor suppressor gene is one of the most frequently mutated genes in
      human cancers.1 p53 is a sequence-specific transcription factor and plays a
      critical role in activating the expression of genes involved in cell cycle arrest
      or apoptosis under conditions of genotoxic stress.2,3 For over two decades, p53
      was thought to be the only gene of its kind in the vertebrate genomes. This
      strong conviction, which was widely accepted in the p53 field, has now been
      proven to be incorrect. Two genes, referred to as p63 and p73, have been found to
      encode proteins that share a significant amino-acid identity in the
      transactivation domain, the DNA binding domain, and the oligomerization domain
      with p53. In the short period since their cloning, a number of investigators have
      reported on the structure, the function and the regulation of p63 and p73. This
      review summarizes the current information on the p63 and the p73 genes, with a
      focus on the differences between the three members in this newly defined p53-gene
      family.

PMID- 10637430
TI  - p53 family genes: structural comparison, expression and mutation.
AB  - The p53-related genes, p51/p63 and p73, have been isolated respectively from cDNA
      libraries of skeletal muscle and the brain, and their structural features and
      biological functions have been compared. High expression of p51A (TAp63gamma) in
      the skeletal muscle tissue drove us to investigate a differentiation-inducible
      myoblastic cell line which showed increased p51A expression after differentiation
      induction. Tissue-specific expression was further confirmed by reverse
      transcriptase-polymerase chain reaction (RT - PCR) using primers specific for
      DeltaN (TA-domain lacking p51), p51A, and p51B expression. p51A alone induced
      erythrodifferentiation when expressed in the erythroleukemia line (Tg-gp55-1-2-3)
      expressing a temperature-sensitive mutant of p53, and induced remarkable
      apoptosis when wild-type p53 expression was induced by the temperature shift to
      32 degrees C. Human p51A and p53 were introduced exogenously into the above
      erythroleukemia cells, and although their expression was rather low, both p51A
      and p53 proteins were induced by DNA-damaging treatment with UV and ActinomycinD.
      However, the protein-protein interactions analyzed by a yeast two-hybrid assay
      between p51 and p53, between p51 and p73, and between p51 and oncoproteins showed
      that p51 is functionally rather distant from p53. Extensive mutation analysis of
      p51/p63 in human tumors revealed only four mutations in 80 non-small cell lung
      carcinomas; two adenocarcinoma cases possessing Glu31His mutations in the
      transactivation domain (TA) domain, suggesting that p51/p63 is not a Knudson type
      tumor suppressor gene. Mutation and loss of heterozygosity (LOH) of p73,
      deregulated expression of p73 and loss of imprinting of p73 are also discussed.

PMID- 10637431
TI  - Regulation and activation of p53 and its family members.
AB  - Regulation of the p53 tumor suppressor protein occurs to a large extent through
      control of protein stability, and the MDM2 protein has been shown to play a key
      role in targeting p53 for degradation. Stress signals that activate the p53
      response lead to stabilization of p53 through inhibition of MDM2 mediated
      degradation, and it is becoming evident that a number of mechanisms exist to
      abrogate this activity of MDM2. Other members of the p53 protein family may also
      be regulated through protein stability, although MDM2 is not responsible for the
      degradation of p73. Nevertheless, interactions of p63 and p73 with MDM2 or p53
      have been described, suggesting that each of the p53-related proteins can play
      some role in regulating the activity of the others

PMID- 10637432
TI  - Structure and function in the p53 family.
AB  - The recent discovery of several p53 homologs has uncovered a p53 superfamily of
      transcription factors that can trigger cell cycle arrest and apoptosis. The
      challenge now is to understand the similarities and differences between family
      members especially in terms of their regulation and potential for physical or
      genetic interactions with one another. This review summarizes recent progress in
      understanding the structure-function relationship within the p53 family. The new
      family members, p63 and p73, have an additional conserved domain at their C
      termini which may have a regulatory function. The structure of this domain (a SAM
      domain) suggests that it is a protein-protein interaction module that may be
      involved in developmental processes. The oligomerization domains of p53 family
      members, while conserved in sequence and three-dimensional structure do not
      interact appreciably with other family members, but do mediate interactions
      between the multiple splice variants from an individual gene.

PMID- 10637433
TI  - Fas ligand, death gene.
AB  - The concept of death genes goes back to the early days of programmed cell death,
      when a researcher's model system was required to be dependent on transcription of
      the dying cell in order to qualify as apoptosis. In 1987 Andrew Wyllie,1 one of
      the pioneers of cell death research, outlined four 'cardinal elements' of
      apoptosis: one of which was a requirement for macromolecular synthesis. In the
      following years the complexity of the apoptotic process has become evident and
      while it is now clear that apoptosis does not have to rely on gene expression,
      the idea of death genes remains. Induction of an apoptotic cascade via activation
      of caspases, selective release of mitochondrial proteins and further activation
      of caspases, can be stimulated by engagement of the Fas surface molecule via
      membrane bound or soluble forms of Fas ligand (FasL). The FasL gene, which is
      often transcriptionally inactive, becomes activated in many forms of
      transcription/translation dependent apoptosis. Here we will discuss FasL as a
      candidate death gene.

PMID- 10637434
TI  - Glucocorticoid hormone-induced modulation of gene expression and regulation of T
      cell death: role of GITR and GILZ, two dexamethasone-induced genes.
AB  - Regulation of T-cell survival is a physiological process involved in determining
      the immune response development, and also the expansion of T-cell tumours.
      Glucocorticoid hormones (GCH) have been implicated as regulators of T-lymphocyte
      growth and differentiation. In particular, GCH which by themselves are apoptosis
      activators and induce T-cell death, can also counteract apoptosis activated by
      other stimuli, for example antigen-TCR interaction. A number of biochemical
      events constitute different GCH-activated death-triggering pathways and
      transcription activity regulation, either upstream and/or downstream in the
      pathways, is essential to apoptosis. Similarly, GCH-mediated inhibition of
      apoptosis also requires gene transcription regulation. In particular, between a
      number of GCH-induced genes, GITR and GILZ can inhibit apoptosis through
      interaction with mechanisms involved in T-cell survival regulation including the
      NF-kappaB transcription activity and the expression of the Fas/FasL system. These
      observations indicate that this GCH-activated dual effect, induction and/or
      inhibition of T-cell death, requires transcription regulation.

PMID- 10637435
TI  - Physiological apoptosis in hormone-dependent tissues: involvement of caspases.
AB  - Physiological apoptosis in mammals is a type of programmed cell death, an
      important element in the developmental repertoire ensuring tissue homeostasis and
      proper disposal of cells that are no longer needed, such as milk-producing
      epithelial cells in the mammary gland after lactation, luteal cells in the post
      partum Corpus luteum or secretory cells in the prostate after castration.
      Although incompletely described, apoptosis in hormone-dependent tissues is
      apparently initiated and executed using common biochemical strategies. These
      include survival pathways governed by local and systemic factors and hormones,
      diverse regulatory pathways and caspase-dependent execution pathways. Using an
      antibody that recognizes processed effector caspases or a fluorogenic caspase
      substrate, we present for the first time evidence that caspases are activated in
      the mammary gland, in the prostate and in the ovary at the time when apoptosis
      occurs. Most likely phagocytosis of apoptotic cells by neighboring cells may
      represent an important step, since only a modest involvement of professional
      phagocytes is apparent. Here, we will summarize and discuss recent data and will
      attempt to draw a generalized picture of how physiological apoptosis may occur in
      these organs.

PMID- 10637436
TI  - From PTK-STAT signaling to caspase expression and apoptosis induction.
AB  - The cell growth and survival can be regulated by cytokine induced signals.
      Nevertheless, the molecular mechanisms of signal transduction from cytokine
      receptors to mediators of cell growth and apoptosis are not well characterized.
      STAT (signal transducer and activator of transcription) proteins can be activated
      by protein tyrosine kinases (PTK) in response to a variety of cytokines. We have
      shown that STAT activation induces expression of caspases which may cause cells
      undergo apoptosis. A hypothesis is proposed that PTKSTAT signaling pathways can
      regulate induction of apoptosis in response to cytokines and other extracellular
      signals.

PMID- 10637437
TI  - Tumor suppression without differentiation or apoptosis by antisense cyclin D1
      gene transfer in K1735 melanoma involves induction of p53, p21WAF1 and superoxide
      dismutases.
AB  - In mammalian cells, terminal differentiation is mutually exclusive with
      proliferation. However, resistance to differentiation-inducing therapy requires
      alternative strategies to control poorly responsive tumors. We now show that
      retroviral transfer of the antisense cyclin D1 gene to differentiation-refractory
      K1735 melanoma leads to loss of in vivo tumorigenicity, shortened replicative
      ability, induction of the tumor suppressor p53 protein and of the cdk-inhibitor
      p21WAF1, increased beta-galactosidase pH 6.0 activity, and elevation in the ratio
      of superoxide dismutases to peroxidases, all properties associated with
      replicative senescence. However, pigmentation and tyrosinase expression,
      characteristic of differentiated melanocytic cells or apoptosis-associated PARP
      cleavage, were not increased by antisense cyclin D1 transduction. Our data
      suggests that targetting cyclin D1 inhibition suppresses melanoma tumorigenicity
      by promoting a cytostatic differentiation-independent pathway, mediated by
      activation of p53 and anti-oxidant functions.

PMID- 10637438
TI  - Interference with gene expression induces rapid apoptosis in p53-null T lymphoma
      cells.
AB  - Two p53-null T lymphoma cell lines proved to be highly sensitive to inhibition of
      gene expression. With either actinomycin D or cycloheximide, apoptosis commenced
      within 2 h, as indicated by loss of membrane integrity, degradation of certain
      proteins (including the phosphatase calcineurin) and DNA fragmentation. These
      effects were ablated by co-expression of Bcl-2 or co-incubation with the caspase
      inhibitor Z-VAD-fmk. These results suggest that the apoptotic machinery is in
      place in these cells but held in check by an unknown labile protein, which
      probably acts upstream of Bcl-2. Although cycloheximide can activate the JNK or
      p38 MAP kinases in some cells, neither was implicated here. However, disruption
      of phosphoinositide 3-kinase signaling may be involved, because the cells were
      also sensitive to wortmannin. The high sensitivity of the p53-null lymphoma cells
      to inhibitors of gene expression suggests that such inhibitors might prove useful
      in the cytotoxic therapy of certain tumors.

PMID- 10637439
TI  - Neurotrophin dependence mediated by p75NTR: contrast between rescue by BDNF and
      NGF.
AB  - During development, neurons pass through a critical phase in which survival is
      dependent on neurotrophin support. In order to dissect the potential role of
      p75NTR, the common neurotrophin receptor, in neurotrophin dependence, we
      expressed wild-type and mutant p75NTR in cells that do not express endogenous
      p75NTR or Trk family members (NIH3T3). Expression of wild-type p75NTR created a
      state of neurotrophin dependence: cells could be rescued by nerve growth factor
      (NGF), brain-derived neurotrophic factor (BDNF), or neurotrophin-3 (NT-3), but
      not by a mutant NGF that binds well to Trk A but poorly to p75NTR. Similarly,
      expression of p75NTR in human prostate cancer cells in culture rendered a
      metastatic tumor cell line (PC-3) sensitive to the availability of neurotrophins
      for survival. Moreover, expression of mutant p75NTR's in another neurotrophin
      insensitive cell line (HEK293T) showed that a domain within the intracellular
      domain governs alternate responses to neurotrophins: the carboxy terminus of the
      intracellular domain of p75NTR including the sixth alpha helix domain is
      necessary for rescue by BDNF, but not NGF. These results, when considered with
      previous studies of the timing of p75NTR expression, support the hypothesis that
      p75NTR is a mediator of neurotrophin dependence during the critical phase of
      developmental cell death and during the progression of carcinogenesis in prostate
      cancer.

PMID- 10637440
TI  - Novel targets for CNS gene therapy.

PMID- 10637441
TI  - Tipping the scales in favour of mitochondrial gene therapy.

PMID- 10637442
TI  - Intra-articular IL-4 gene therapy in arthritis: anti-inflammatory effect and
      enhanced th2activity.
AB  - Gene therapy has been explored as a potential method for treating chronic
      inflammatory diseases such as rheumatoid arthritis. To determine the efficacy of
      intra-articular IL-4 gene therapy in an animal model of arthritis using a
      retroviral vector, a retrovirus encoding rat IL-4 (DA-IL-4) was engineered,
      purified and concentrated to high titer (>/=109 CFU/ml). Infectivity and
      expression levels were demonstrated in vitro using cultured fibroblast-like
      synoviocytes. Efficacy was evaluated in the rat adjuvant arthritis model. DA-IL-4
      or DA-beta-gal retrovirus was injected into the intra-articular joint space of
      the right ankle on day 12 after immunization. Three days after joint injection,
      the injected paw contained increased levels of IL-4 compared with control or with
      the contralateral uninjected paw, demonstrating successful transgene expression.
      Surprisingly, 8 days after treatment IL-4 levels continued to increase in the
      injected and contralateral paw compared with DA-beta-gal-treated animals. Serum
      IL-4 levels were also elevated in DA-IL-4-treated rats. RT-PCR studies
      demonstrated that the transgene was expressed in the injected ankle but not in
      the contralateral joint. IL-4 gene therapy resulted in a significant reduction in
      paw swelling and decreased radiographic evidence of bone destruction. This is the
      first demonstration of successful intra-articular retroviral gene treatment using
      a therapeutic gene. In addition to its anti-inflammatory effect, this study
      supports the potential application of intra-articular gene therapy as a method
      for enhancing systemic Th2 function.

PMID- 10637443
TI  - Peptide nucleic acid delivery to human mitochondria.
AB  - Peptide nucleic acids (PNAs) are synthetic polynucleobase molecules, which bind
      to DNA and RNA with high affinity and specificity. Although PNAs have enormous
      potential as anti-sense agents, the success of PNA-mediated gene therapy will
      require efficient cellular uptake and sub-cellular trafficking. At present these
      mechanisms are poorly understood. To address this, we have studied the uptake of
      biotinylated PNAs into cultured cell lines using fluorescence confocal
      microscopy. In human myoblasts, initial punctate staining was followed by the
      release of PNAs into the cytosol and subsequent localisation and concentration in
      the nucleus. To determine whether PNAs could also be used as therapeutic agents
      for mtDNA disease, we attempted to localise PNAs to the mitochondrial matrix.
      When attached to the presequence peptide of the nuclear-encoded human cytochrome
      c oxidase (COX) subunit VIII, the biotinylated PNA was successfully imported into
      isolated organelles in vitro. Furthermore, delivery of the biotinylated peptide
      PNA to mitochondria in intact cells was confirmed by confocal microscopy. These
      studies demonstrate that biotinylated PNAs can be directed across cell membranes
      and to a specific sub-cellular compartment within human cells - highlighting the
      importance of these novel molecules for human gene therapy.

PMID- 10637445
TI  - Differential effects of glial cell line-derived neurotrophic factor (GDNF) in the
      striatum and substantia nigra of the aged Parkinsonian rat.
AB  - Injection of an adenoviral (Ad) vector encoding human glial cell line-derived
      neurotrophic factor (GDNF) protects dopaminergic (DA) neurons in the substantia
      nigra (SN) of young rats. As Parkinson's disease occurs primarily in aged
      populations, we examined whether chronic biosynthesis of GDNF, achieved by
      adenovirus-mediated delivery of a GDNF gene (AdGDNF), can protect DA neurons and
      improve DA-dependent behavioral function in aged (20 months) rats with
      progressive 6-OHDA lesions of the nigrostriatal projection. Furthermore, the
      differential effects of injecting AdGDNF either near DA cell bodies in the SN or
      at DA terminals in the striatum were compared. AdGDNF or control vector was
      injected unilaterally into either the striatum or SN. One week later, rats
      received a unilateral intrastriatal injection of 6-OHDA on the same side as the
      vector injection. AdGDNF injection into either the striatum or SN significantly
      reduced the loss of FG labelled DA neurons 5 weeks after lesion (P </= 0.05).
      However, only striatal injections of AdGDNF protected against the development of
      behavioral deficits characteristic of unilateral DA depletion. Striatal AdGDNF
      injections also reduced tyrosine hydroxylase fiber loss and increased amphetamine
      induced striatal Fos expression. These results demonstrate that increased levels
      of striatal, but not nigral, GDNF biosynthesis prevents DA neuronal loss and
      protects DA terminals from 6-OHDA-induced damage, thereby maintaining DA function
      in the aged rat.

PMID- 10637444
TI  - Liposome-mediated gene transfer into human basal cell carcinoma.
AB  - Direct intralesional injection of DNA encoding interferon-alpha2 (IFN-alpha2) was
      used in an effort to sustain local protein delivery for the treatment of human
      basal cell carcinoma (BCC). A novel model to study this malignancy was
      established by transplantation of human BCC tissue on to immunodeficient mice
      with a relatively high rate of engraftment and stable phenotype for superficial
      BCC (20 of 25; 80%). Gene transfer was significantly increased by using DNA
      liposome complexes (lipoplexes). Recombinant gene expression was detected
      predominantly in the epidermis and, to a lesser extent, in the dermis. Gene
      transfer of IFN-alpha2 using this method resulted in sustained production of IFN
      alpha2 protein and increased expression of a known IFN-inducible gene, the class
      II major histocompatibility (MHC) antigen, and induced BCC regression, presumably
      through a non-immune mechanism. Intralesional injection of DNA lipoplexes
      encoding IFN-alpha protein may therefore be applicable to the treatment of
      cutaneous BCC.

PMID- 10637446
TI  - Cancer gene therapy using a pro-apoptotic gene, caspase-3.
AB  - Caspase-3 is a member of the cysteine protease family, which plays a crucial role
      in apoptosis. We applied the human caspase-3 gene as a novel form of anticancer
      gene therapy. Overexpression of human caspase-3 alone could not induce apoptosis
      of tumor cell lines, but apoptosis was markedly enhanced by the addition of
      etoposide. In an AH130 liver tumor model, transduction of human caspase- 3, but
      not the empty vector, induced extensive apoptosis and reduced tumor volume when
      combined with etoposide administration. However, this effect was not observed
      with a Bcl-2 overexpressing tumor. In conclusion, caspase-3 gene transduction
      accompanied by an additional death stimulus may be a useful method of anticancer
      gene therapy, except for Bcl-2 overexpressing tumors.

PMID- 10637447
TI  - A sequence-specific gene correction by an RNA-DNA oligonucleotide in mammalian
      cells characterized by transfection and nuclear extract using a lacZ shuttle
      system.
AB  - The variability in gene conversion frequency by an RNA-DNA oligonucleotide (RDO)
      prompted us to develop a system as a means of measuring the conversion frequency
      rapidly and reproducibly. A shuttle vector was constructed to measure the
      frequency of targeted gene correction by RDO of the E. coli beta-galactosidase
      gene containing a single point mutation (G --> A), that resulted in inactivation
      of enzymatic activity. An RDO corrected the point mutation and restored the
      enzymatic activity, approximately 1%, determined by a histochemical staining in
      mammalian cells and by a color selection (blue or white) of bacteria transformed
      with Hirt DNA. In addition, we established an in vitro system capable of gene
      correction using nuclear extracts. CHO-K1 nuclear extracts corrected the point
      mutation approximately 0.1%, determined by bacterial transformation. Using the in
      vitro reaction, frequency of gene conversion in different cell types was
      measured. The embryonic fibroblasts from p53-/- mouse showed higher gene
      correction than that of the isogenic p53+/+ cells. Nuclear extracts from DT40
      cells, which have a higher homologous recombination rate than any other mammalian
      cells exhibited 0.1-0.6% of gene correction. These results indicated that
      recombination may be rate-limiting in gene conversion by RDO in cells with
      competent mismatch repair activities. Utilizing transfection and in vitro
      reaction, we demonstrated that such a shuttle system might be useful in comparing
      the frequency of targeting among different cell types and to investigate the
      mechanism of gene conversion by RDO.

PMID- 10637448
TI  - Gene gun-mediated DNA vaccination induces antitumor immunity against human
      papillomavirus type 16 E7-expressing murine tumor metastases in the liver and
      lungs.
AB  - DNA vaccination has emerged as an attractive approach for tumor immunotherapy.
      The aim of this study was to evaluate the potency of DNA vaccines in preventing
      and treating the liver and lung metastases of a human papillomavirus-16 (HPV-16)
      E7-expressing murine tumor (TC-1). We used the gene gun method to vaccinate
      C57BL/6 mice intradermally with DNA vaccines containing the HPV-16 E7 gene, the
      E7 gene linked to the sorting signals of the lysosome-associated membrane protein
      1 (Sig/E7/ LAMP-1), or the 'empty' plasmid vector. The in vivo antitumor immunity
      was analyzed in both tumor prevention and tumor regression experiments. In
      addition, cytotoxic T lymphocyte (CTL) assays, enzyme-linked immunospot assay and
      enzyme-linked immunoabsorbent assay were used to assess the E7-specific T cell
      mediated and humoral immunity. Mice vaccinated with Sig/E7/LAMP-1 DNA generated
      the strongest E7-specific CTL activities, the highest numbers of E7-specific CD8+
      cell precursors and the highest titers of E7-specific antibodies. While both E7
      DNA and Sig/E7/LAMP-1 DNA generated potent antitumor immunity in the liver and
      lung metastases models, the Sig/E7/LAMP-1 DNA was more potent under stringent
      conditions. DNA vaccination with E7-expressing plasmids was effective in
      controlling liver and lung metastases of an E7-expressing murine tumor. Our data
      suggest that antigen-specific DNA vaccination can potentially be applied to
      control liver and lung metastases of tumors with defined tumor-specific antigens.

PMID- 10637449
TI  - In vivo cell type-specific gene delivery with retroviral vectors that display
      single chain antibodies.
AB  - Cell type-specific gene delivery will be essential for in vivo gene therapy. Our
      laboratory has previously developed retroviral vector particles, derived from
      spleen necrosis virus, SNV, which display the antigen-binding site of an antibody
      on the viral surface. Such particles infected only human cells in vitro, which
      expressed a receptor recognized by the antibody. To test cell type-specific gene
      delivery in vivo, a mouse model system has been developed. Antibiotic resistant
      human target and non-target cells were injected into the peritoneum of SCID mice.
      Subsequently, a vector solution containing 106 infectious particles, which
      display scAs against the human her2neu cell surface protein, was injected. Cells
      were recovered from the peritoneum, subjected to antibiotic selection, and tested
      for the expression of a lacZ gene transduced by the retroviral vector. We found
      that human target cells, which express her2neu, were infected in vivo. However,
      neither human cells that do not express her2neu, nor normal mouse cells were
      infected by such viral particles. These data give proof of principle that
      retroviral vector-mediated, cell type-specific gene delivery can be obtained in
      vivo.

PMID- 10637450
TI  - Interferon-alpha gene therapy in combination with CD80 transduction reduces
      tumorigenicity and growth of established tumor in poorly immunogenic tumor
      models.
AB  - Interferon-alpha (IFN-alpha) or CD80 transduction of tumor cells individually
      reduces tumorigenicity and enhances antitumor responses. Here, we report that the
      combination of IFN-alpha and CD80 cancer gene therapy in poorly immunogenic
      murine tumor models, the colorectal adenocarcinoma cell line MC38, and the
      methylcholanthrene-induced fibrosarcoma cell line MCA205 reduces tumor growth
      more efficiently without affecting in vitro growth. Wild-type (WT), neomycin
      resistance (Neo) gene-, or CD80-transduced tumor cells grew progressively in all
      immunocompetent mice. In contrast, IFN-alpha-transduced MC38 or MCA205 cells were
      rejected in 13 of 15 and seven of 15 mice, respectively. Synergistic effects were
      observed when IFN-alpha- and CD80-transduced tumor cells were mixed and
      inoculated. These admixed cells were rejected by 14 of 15 (MC38) or seven of 15
      mice (MCA205), whereas, a mixture of IFN-alpha and Neo cells or CD80 and Neo
      cells led to tumors associated with progressive growth. Induction of long-lasting
      tumor immunity against WT tumor cells was demonstrated by rejection of a
      subsequent rechallenge in 10 of 13 (MC38) and six of seven (MCA205) tumor-free
      mice. The therapeutic efficacy with established WT MC38 tumors was shown when
      mice were treated with a vaccine consisting of repetitive injections of IFN-alpha
      and CD80-transduced MC38 cells into the contralateral flank (P < 0.01). This
      treatment was associated with accumulation of CD4+, CD8+ cells and dendritic
      cells within the established tumor, demonstrating induction of antitumor immune
      responses. Combination gene therapy using IFN-alpha and CD80 is an effective
      immune therapy of cancer and could be considered for clinical trials.

PMID- 10637451
TI  - Comparison between cationic polymers and lipids in mediating systemic gene
      delivery to the lungs.
AB  - Airway inflammation frequently found in congenital and acquired lung diseases may
      interfere with gene delivery by direct administration through either instillation
      or aerosol. Systemic delivery by the intravenous administration represents an
      alternative route of delivery that might bypass this barrier. A nonviral approach
      for transfecting various airway-derived cell lines in vitro showed that cationic
      polymers (PEI 22K and 25K) and lipids (DOTAP, GL-67/DOPE) are able to transfect
      with high efficiency the reporter genes firefly luciferase and E. coli lacZ.
      Notably, two properties predicted that cationic vectors would be useful for a
      systemic gene delivery approach to the lung: (1) transfection was not inhibited
      or increased when cells were incubated with cationic lipids or polymers in the
      presence of serum; and (2) cationic vectors protected plasmid DNA from DNase
      degradation. A single injection of DNA complexed to the cationic polymer PEI 22K
      into the tail vein of adult mice efficiently transfected primarily the lungs and
      to a lesser extent, heart, spleen, kidney and liver. The other vectors mediated
      lower to undetectable levels of luciferase expression in the lungs, with DOTAP >
      GL67/DOPE > PEI 25K > DOTMA/DOPE. A double injection protocol with a 15-min
      interval between the two doses of DOTAP/DNA complexes was investigated and showed
      a relevant role of the first injection in transfecting the lungs. A two log
      increase in luciferase expression was obtained either when the two doses were
      comprised of luciferase plasmid or when an irrelevant plasmid was used in the
      first injection. The double injection of luciferase/PEI 22K complexes determined
      higher transgene levels than a single dose, but a clear difference using an
      irrelevant plasmid as first dose was not observed. Using lacZ as a reporter gene,
      it was shown that only cells in the alveolar region, including type II
      penumocytes, stained positively for the transgene product.

PMID- 10637452
TI  - Increased level and duration of expression in muscle by co-expression of a
      transactivator using plasmid systems.
AB  - Skeletal muscle is an attractive target for gene therapies to treat either local
      or systemic disorders, as well as for genetic vaccination. An ideal expression
      system for skeletal muscle would be characterized by high level, extended
      duration of expression and muscle specificity. Viral promoters, such as the
      cytomegalovirus (CMV) promoter, produce high levels of transgene expression,
      which last for only a few days at high levels. Moreover, many promoters lack
      muscle tissue specificity. A muscle-specific skeletal alpha-actin promoter (SkA)
      has shown tissue specificity but lower peak activity than that of the CMV
      promoter in vivo. It has been reported in vitro that serum response factor (SRF)
      can stimulate the transcriptional activity of some muscle-specific promoters. In
      this study, we show that co- expression of SRF in vivo is able to up-regulate SkA
      promoter-driven expression about 10-fold and CMV/SkA chimeric promoter activity
      by five-fold in both mouse gastrocnemius and tibialis muscle. In addition, co
      expression of transactivator with the CMV/SkA chimeric promoter in muscle has
      produced significantly enhanced duration of expression compared with that shown
      by the CMV promoter-driven expression system. A dominant negative mutant of SRF,
      SRFpm, abrogated the enhancement to SkA promoter activity, confirming the
      specificity of the response. Since all the known muscle-specific promoters
      contain SRF binding sites, this strategy for enhanced expression may apply to
      other muscle-specific promoters in vivo.

PMID- 10637455
TI  - Keyword index volume 6 1999

PMID- 10637453
TI  - 1999 referees

PMID- 10637456
TI  - Neuronal and endothelial nitric oxide synthase isoforms: quantification of
      protein and mRNA in the normal rat penis.
AB  - Nitric oxide synthase (NOS) is an important enzyme for erection. We evaluated the
      content of neuronal (nNOS) and endothelial (eNOS) isoforms and their mRNA in the
      penis and major pelvic ganglion (MPG) of adult male rats by Western and Northern
      blot analysis. The cerebellum was evaluated as a control. nNOS protein and its
      mRNA were detected in abundance in the MPG, cerebellum, pelvic urethra and within
      the crura of the penis. In contrast, the penile urethra, neurovascular bundle and
      the shaft of penis contained smaller amounts of this protein. eNOS protein was
      most abundant in the penile and pelvic parts of the urethra, whereas a moderate
      level was found in the penile shaft, crura, neurovascular bundle, MPG and
      cerebellum. Similarly eNOS mRNA was abundant in the penile and pelvic parts of
      the urethra, MPG and cerebellum. Penile shaft, crura and neurovascular bundle
      showed moderate amounts of eNOS mRNA. In conclusion, nNOS and its mRNA are most
      abundant in the MPG and crura of penis whereas eNOS is most abundant in the
      urethra and to a lesser extent present in the penis. Importantly eNOS protein and
      mRNA were demonstrated in the MPG, where eNOS function has to be studied.

PMID- 10637457
TI  - Retrospective review of flow patterns following retropubic prostatectomy.
AB  - AIM OF THIS STUDY: We retrospectively evaluated penile inflows in 103 previously
      potent individuals who underwent standard nerve sparing radical retropubic
      prostatectomy (RRP) for the treatment of prostate cancer. No effort to identify
      or spare the accessory pudendal artery (APA) was made in any case. Our goal was
      to investigate the role of the accessory internal pudendal artery (APA) in the
      maintenance of erections in this population. We hypothesize that if the APA is
      present in a significant number of men, and its ligation significantly
      contributes to post-RRP impotence, then there should be an increased incidence of
      asymmetry between R/L cavernous arterial flows among post RRP patients with
      vascular impotence. MATERIALS AND METHODS: One hundred and three previously
      potent individuals complaining of persistent erectile dysfunction for at least
      six months after RRP were studied with color duplex Doppler, following age
      specific dosing of PGE1. Vascular assessment was performed before and after self
      stimulation, measuring peak systolic velocity (PSV), end diastolic velocity
      (EDV), and resistive index (RI). Erections were visually rated as inadequate
      (INA), adequate (ADE) for penetration, or excellent (EXC) with sustained rigidity
      for at least 20 min. Cavernous artery asymmetry (CAA) was defined as a >10 cm/s
      difference between right and left sided arterial flows. RESULTS: Mean duration
      between surgery and Doppler study was 14.7 months. 27 out of 103 (26%) of
      patients developed excellent rigidity consistent with isolated neurogenic
      impotence (PSV=32.0 cm/s, mean RI=0.95); 24 out of 103 (23%) had adequate
      vascular responses making it impossible to infer presence or absences of
      neurogenic impotence; 52 out of 103 (51%) had inadequate rigidity consistent with
      vascular insufficiency (PSV=23.7 cm/s, mean RI=0.66). We noted that of patients
      with EXC response, 48% (13 out of 27) had CAA. Among patients with severe inflow
      disease (INA responders), CAA was seen in only 21% of cases (11 out of 52).
      CONCLUSIONS: The incidence of APA has been reported as being from 4-70%, and its
      significance in the maintenance of erections has been questioned. Assuming that
      the APA provides significant inflow in some patients, we expected an increase in
      CAA in individuals in whom it was sacrificed. We found a higher incidence of CAA
      among post-RRP patients with normal vascular erectile responses to PGE1 (48%)
      compared to men with true vasculogenic impotence post-RRP (21%). These data do
      not support the importance of the APA in the maintenance of erections in the post
      RRP patient.

PMID- 10637458
TI  - Editorial comment

PMID- 10637459
TI  - Editorial comment

PMID- 10637460
TI  - Rigiscan versus snap gauge band measurements: is the extra cost justifiable?
AB  - Both RigiScan and the Snap Gauge band devices are used to objectively measure
      penile rigidity. The Snap Gauge band is the more simple and inexpensive of the
      two techniques. We investigated the correlation between the results obtained by
      both devices in order to evaluate whether the Snap Gauge band could be employed
      as the sole method of rigidity evaluation while not affecting the quality of
      diagnosis. Forty eight patients who were presented to our erectile dysfunction
      clinic used the two devices simultaneously, each according to the accepted
      protocols. Breakage of two and three strings of the Snap Gauge (good rigidity)
      correlated well with good tip and average rigidity as evaluated by the RigiScan.
      Snap gauge results also correlated with duration of erection, number of
      erections, the number of adequate erections, and the longest duration of erection
      measured by the RigiScan. Therefore, good rigidity according to the Snap Gauge
      test correlated well with the results of functional erections (number, rigidity,
      duration) as obtained by the RigiScan. The Snap Gauge band can be used to
      adequately evaluate penile rigidity. RigiScan measurements, which are more
      complicated and more expensive, should be reserved for selected patients in whom
      the results of the Snap Gauge band are inconclusive or when more detailed
      information is required.

PMID- 10637461
TI  - Editorial comment

PMID- 10637462
TI  - Development and evaluation of an abridged, 5-item version of the International
      Index of Erectile Function (IIEF-5) as a diagnostic tool for erectile
      dysfunction.
AB  - An abridged five-item version of the 15-item International Index of Erectile
      Function (IIEF) was developed (IIEF-5) to diagnose the presence and severity of
      erectile dysfunction (ED). The five items selected were based on ability to
      identify the presence or absence of ED and on adherence to the National Institute
      of Health's definition of ED. These items focused on erectile function and
      intercourse satisfaction. For 1152 men (1036 with ED, 116 controls) analyzed, a
      receiver operating characteristic curve indicated that the IIEF-5 is an excellent
      diagnostic test. Based on equal misclassification rates of ED and no ED, a cutoff
      score of 21 (range of scores, 5-25) discriminated best (sensitivity=0.98,
      specificity=0. 88). ED was classified into five severity levels, ranging from
      none (22-25) through severe (5-7). Substantial agreement existed between the
      predicted and 'true' ED classes (weighted kappa=0.82). These data suggest that
      the IIEF-5 possesses favorable properties for detecting the presence and severity
      of ED.

PMID- 10637463
TI  - Axial penile buckling forces vs Rigiscan radial rigidity as a function of
      intracavernosal pressure: why Rigiscan does not predict functional erections in
      individual patients.
AB  - AIM: An improved understanding of the relationship between radial and axial
      rigdity values would enable better appreciation of the clinical usefulness of
      RigiScantrade mark, the most widely utilized determination of erectile rigidity
      testing. Previous studies have shown that axial rigidity (measured by buckling
      forces) correlated well with radial rigidity (measured by RigiScantrade mark) for
      radial rigidity values below 60%. For radial rigidity exceeding 60%, there was
      poor correlation. Heretofore, there has been no physiologic explanation of this
      phenomenon. METHODS: During dynamic pharmacocavernosometry in 36 impotent
      patients, we investigated the relationship between axial buckling forces and
      RigiScan radial rigidity and, for the first time, how they both vary with
      pressure, (which we varied over over a wide functional range). In addition, we
      recorded multiple penile length and diameter values enabling us to relate, also
      for the first time, axial and radial rigidity to individual mechanical erectile
      tissue and penile geometric properties. RESULTS: Marked differences were found in
      the manner RigiScan radial rigidity units and axial buckling force magnitudes
      increased with increases in intracavernosal pressure values in each individual.
      The former asymptotically approached a maximum finite value while the latter
      increased continuously towards infinity. Based on data in this study, RigiScan
      radial rigidity values greater than 55% may be considered a necessary criteria
      for vaginal intromission capability in all partners but it is not a sufficient
      one. CONCLUSIONS: Axial and radial rigidity share a common dependency upon
      intracavernosal pressure, however, they are also dependent upon other unique
      physical determinants. For axial rigidity, additional dependent variables include
      cavernosal erectile tissue properties and penile geometry, while for radial
      rigidity, this may include tunical surface wall tension properties. Clinical
      devices which assess functional penile rigidity should utilize axial and not
      radial rigidity testing.

PMID- 10637465
TI  - Editorial comment

PMID- 10637464
TI  - Editorial comment

PMID- 10637466
TI  - Prosthesis implantation after radial free flap phalloplasty in patients with
      bladder exstrophy.
AB  - METHODS: Inflatable penile prosthesis were implanted into sensate radial free
      flap phalloplasties in two adult patients with bladder exstrophy. RESULTS:
      Neither patient reported loss of sensation, and both were able to inflate the
      prosthesis and engage in sexual intercourse three months later. CONCLUSION: The
      construction of a functional neophallus is well described however has not
      previously been reported in exstrophy patients who are suited to this procedure
      due to the presence of crura, and the absence of a neourethra. Scarring from
      previous reconstructive procedures however may make implantation difficult, and
      long-term follow up is required to evaluate this procedure in patients with
      bladder exstrophy.

PMID- 10637467
TI  - Testosterone supplementation in the aging male.
AB  - World-wide life expectancy at birth for men and women will have increased by
      about 20 y during 50 y period between 1950 and 2000. As a result, the proportion
      of the elderly population is expected to increase significantly in the 21st
      century. Despite this increase in longevity for men and women, men still have
      significantly shorter life expectancy of approximately 5 y. To further reduce and
      prevent debilitating disease and disability in elderly men, a question is whether
      any type of interventions, such as hormone replacement therapy, may play a role
      in improving the quality of life as proven in post-menopausal women. Men
      experience age-related decline of capability physically and mentally. Various
      symptoms, such as nervousness, depression, impaired memory, inability to
      concentrate, easy fatigability, insomnia, hot flushes, periodic sweating,
      reduction of muscle mass and power, bone ache, and sexual dysfunction, are
      related to this change. The fact that a number of age-related changes resemble
      features of various hormonal deficiency has led to worldwide interest in the use
      of various hormonal preparations in an effort to prevent the aging process in
      elderly men. Even though there have been opinions against hormonal
      supplementation in the aging male, preliminary studies defining the risk/benefit
      ratio of androgen supplementation appear to be encouraging. To understand
      testosterone supplementation in the aging male, this review will discuss the
      following important topics: physiology of male hormonal balance, changes in
      reproductive organs in elderly men, endocrine evaluation of the male,
      pharmacological effects of testosterone on target organs, available preparations
      for testosterone, and testosterone supplementation.

PMID- 10637468
TI  - Reply to 'The sexual health inventory for men (IIEF-5)' by JA Vroege.

PMID- 10637469
TI  - Publishers announcement

PMID- 10637470
TI  - A hypothesis for the pathogenesis of myelodysplastic syndromes: implications for
      new therapies.
AB  - To guide development of new clinical strategies, a review of recent
      investigations in the pathobiology of MDS was performed. Articles were identified
      through a Medline search. Studies, including reviews, are cited in the
      references. A multistep pathogenesis is proposed. (1) Targeted injury or mutation
      within hemopoietic stem cells may be followed by an immunologic response
      adversely affecting progenitor survival. (2) Accelerated proliferation and
      premature death of marrow cells is amplified by apoptogenic cytokines (TNF-alpha,
      Fas ligand). (3) Establishment of an abnormal clone associated with telomere
      shortening. (4) Disease progression associated with loss of tumor suppressor
      activity. Opportunities for therapeutic interventions are possible at each step.
      Comparisons between the proposed pathogenesis of MDS and severe aplastic anemia
      (SAA) are also presented. Leukemia (2000) 14, 2-8.

PMID- 10637471
TI  - Serine/threonine phosphorylation in cytokine signal transduction.
AB  - Over the past decade, the involvement of tyrosine kinases in signal transduction
      pathways evoked by cytokines has been intensively investigated. Only relatively
      recently have the roles of serine/threonine kinases in cytokine-induced signal
      transduction and anti-apoptotic pathways been examined. Cytokine receptors
      without intrinsic kinase activity such as interleukin-3 (IL-3), granulocyte
      macrophage colony-stimulating factor (GM-CSF) and the interferons were thought to
      transmit their regulatory signals primarily by the receptor-associated Jak family
      of tyrosine kinases. This family of tyrosine kinases activates STAT transcription
      factors, which subsequently transduced their signals into the nucleus to modulate
      gene expression. Cytokine receptors with intrinsic tyrosine kinase activity such
      as c-Kit were initially thought to transduce their signals independently of
      serine/threonine kinase cascades. Recently, both of these types of receptor
      signaling pathways have been shown to interact with serine/threonine kinase
      pathways as maximal activation of these tyrosine kinase regulated cascades
      involve serine/threonine phosphorylation modulated by, for example MAP kinases. A
      common intermediate pathway initiating from cytokine receptors is the
      Ras/Raf/MEK/ERK (MAPK) cascade, which can result in the phosphorylation and
      activation of additional downstream kinases and transcription factors such as
      p90Rsk, CREB, Elk and Egr-1. Serine/threonine phosphorylation is also involved in
      the regulation of the apoptosis-controlling Bcl-2 protein, as certain
      phosphorylation events induced by cytokines such as IL-3 are anti-apoptotic,
      whereas other phosphorylation events triggered by chemotherapeutic drugs such as
      Paclitaxel are associated with cell death. Serine/threonine phosphorylation is
      implicated in the etiology of certain human cancers as constitutive serine
      phosphorylation of STATs 1 and 3 is observed in chronic lymphocytic leukemia and
      can be inhibited by the chemotherapeutic drug fludarabine. Serine/threonine
      phosphorylation also plays a role in the etiology of immunodeficiencies.
      Activated STAT5 proteins are detected in reduced levels in lymphocytes recovered
      from HIV-infected individuals and immunocompromised mice. Serine/threonine
      phosphorylation may be an important target of certain chemotherapeutic drugs
      which recognize the activated proteins. This meeting report and mini-review will
      discuss the interactions of serine/threonine kinases with signal transduction and
      apoptotic molecules and how some of these pathways can be controlled by
      chemotherapeutic drugs. Leukemia (2000) 14, 9-21.

PMID- 10637472
TI  - Alpha-interferon improves survival and remission duration in P-190BCR-ABL
      positive adult acute lymphoblastic leukemia.
AB  - Treatment of P190BCR-ABL+ acute lymphoblastic leukemia (ALL) patients remains
      problematic: one possibility is to use biologic response modifiers such as alpha
      interferon (alpha-IFN), which is known to be active in chronic myeloid leukemia
      (CML). We used alpha-IFN to treat 10 adult P190BCR-ABL+ ALL patients (eight newly
      diagnosed; two in first relapse). All received a remission induction chemotherapy
      (modified L-20 protocol). Patients achieving morphological, immunological and
      cytogenetic complete remission (CR) were then submitted to a rotational
      consolidation regimen lasting 6 months. When no HLA-identical donor was
      available, patients aged <55 years underwent stem cell harvest followed by
      autologous transplantation; patients aged >/=55 years received standard
      maintenance treatment for 6 months. In the second year, maintenance treatment
      (all ages) was based on cycles of alpha-IFN (3 MU three times a week for 6 weeks)
      alternated with methotrexate/6-mercaptopurine continuously for up to 2 years from
      first demonstration of CR. Thereafter, patients maintaining CR had the same
      schedule of alpha-IFN (6 weeks on, 6 off). Eight patients (6/8 first diagnosis,
      2/2 relapsed) obtained morphological, immunological and cytogenetic CR with
      persistent molecular positivity. Two with an HLA-identical donor had allogeneic
      bone marrow transplantation. Six proceeded with chemotherapy: one experienced
      early relapse, three were autotransplanted, and two received maintenance. Five
      patients then received alpha-IFN as scheduled. All five are in continuous
      morphological and cytogenetic CR, with a longer mean duration of maintained
      morphological CR (mean 46 months; range: 20-88) than in previous reports of Ph+
      ALL patients treated with chemotherapy regimens (excluding allogeneic BMT). alpha
      IFN thus appears effective in this poor-risk subset of patients. This well
      tolerated IFN-containing maintenance treatment could be considered to reinforce
      intensified programs based on autologous stem cell transplantation as an
      alternative to allogeneic transplantation in P190BCR-ABL+ ALL patients (and by
      extension for Ph+ ALL patients) lacking an HLA-matched donor. Leukemia (2000) 14,
      22-27.

PMID- 10637473
TI  - Prognostic significance of the cell cycle inhibitor p27Kip1 in acute myeloid
      leukemia.
AB  - There are few molecular biologic determinants that are prognostic for patients
      with acute myeloid leukemia (AML). Hence, we examined whether cellular levels of
      the cyclin-dependent kinase inhibitor p27Kip1 in acute myeloid leukemia could be
      used to predict clinical outcome in AML. Using immunoblot analysis, levels of p27
      were assessed in blast cells from 72 AML patients who were registered and treated
      by the identical chemotherapy protocol. AML cases were classified into three
      groups on the basis of the percentage of the expression level of p27 compared to
      a control cell line. AML cases exhibiting p27 expression at low, moderate, and
      high levels were 43, 9, and 20 cases, respectively. No significant differences in
      the rates of complete remission (CR) were observed among the three groups.
      Although the level of p27 expression was not correlated with any other possible
      prognostic markers, such as age, white blood cell count, chromosome
      abnormalities, and FAB subclasses, patients with high p27 expression had a
      significantly increased disease-free survival (DFS) (78% vs 19%, P = 0.004). We
      further examined the expression of cyclin E at the protein level in all 72 AML
      cases. We observed a statistically significant correlation between a high cyclin
      E level and a high p27 level (P < 0.005). However, we failed to find any
      correlation between the rates of CR or DFS and cyclin E expression. The present
      study reveals that levels of p27 expression can be one of the useful prognostic
      molecular markers for AML. Leukemia (2000) 14, 28-33.

PMID- 10637474
TI  - Role of beta2 integrins in the prevention of apoptosis induction in chronic
      lymphocytic leukemia B cells.
AB  - Immunologically committed lymphocytes, especially mature, leukemic B cells,
      proliferate then accumulate without further cell division in chronic lymphocytic
      leukemia patients (CLL). These mature, leukemic B cells often produce
      autoantibodies. Under normal circumstances, immunologically committed lymphocytes
      that are autoreactive are deleted by a programmed cell death mechanism. In CLL
      cells, these mechanisms appear to be inhibited; therefore, cells accumulate
      rather than be destroyed. To understand the mechanism by which cell survival is
      selected over death in CLL cells, we studied the role of beta2 integrins and
      their ligands in the regulation of apoptosis. CLL cells were treated with
      monoclonal antibodies directed against beta2 integrins. Antibodies directed
      against the I-domain of the alpha chain of CD11b/CD18 inhibited apoptosis. The
      identity of the physiological ligand or counter-receptor for beta2 integrins that
      was required for the inhibition of apoptosis induction was sought. The ligand
      iC3b, but not ICAM-1 or fibrinogen, was identified as a ligand that could prevent
      apoptosis of CLL B cells. Free iC3b levels were elevated in CLL patients
      indicating that this ligand is available in vivowhere it may interact with beta2
      integrins on CLL B cells and sustain their viability by preventing activation of
      the programmed cell death pathway. Leukemia (2000) 14, 34-39.

PMID- 10637475
TI  - Chemosensitivity of B cell chronic lymphocytic leukemia and correlated expression
      of proteins regulating apoptosis, cell cycle and DNA repair.
AB  - B cell chronic lymphocytic leukemia (B-CLL) cannot be cured with conventional
      chemotherapy. This clinical enigma appears to be at least partially due to the
      fact that B-CLL cells are resistant to programmed cell death (apoptosis) and that
      they are arrested in G0/G1 phase of the cell cycle. The reasons for the
      dysregulation of these two key cellular events in B-CLL are unclear. The present
      study aimed at determining correlations between the expression levels of proteins
      regulating apoptosis, cell cycle and DNA repair in B-CLL cells and normal B
      cells. In addition, the differential sensitivity of B-CLL cells to drug-induced
      apoptosis was quantified. We show that in B-CLL cells levels of the death
      suppressor Bcl-2 correlated positively with those of the pro-apoptotic protein
      Bax and of the cyclin-dependent kinase (cdk) inhibitor p27Kip1. In B-CLL cells
      levels of the anti-apoptotic Bcl-xL showed a positive correlation with levels of
      the 80 kDa regulatory component (Ku80) of the DNA-dependent protein kinase that
      is involved in DNA double-stranded break repair. These correlations were not
      detected in normal B cells. The sensitivity of leukemic cells to FLUD but not to
      ADM, CPM or to DEX was reduced in pre-treated patients. These data support the
      hypothesis that in B-CLL cells death-modulators and molecules modulating cell
      cycle and DNA repair are regulated in a coordinated manner. Leukemia (2000) 14,
      40-46.

PMID- 10637476
TI  - Further elucidation of mechanism of resistance to vincristine in myeloid cells:
      role of hypochlorous acid in degradation of vincristine by myeloperoxidase.
AB  - Inherent resistance of myeloblasts to vincristine (VCR) has been related to the
      activity of myeloperoxidase (MPO) which can degrade VCR in the presence of
      hydrogen peroxide (H2O2). We investigated the relationship between VCR
      degradation and hypochlorous acid (HOCl) generation from the reaction of H2O2
      with chlorine (Cl) as catalyzed by MPO. A cell-free system, three human leukemia
      cell lines (CEM/CCRF, HL-60, U937) and 15 bone marrow samples from children with
      acute myeloid leukemia (AML) were studied. VCR cytotoxicity was evaluated by MTT
      assay and by quantitative measurement of apoptosis. In vitro levels of VCR in
      cell-free systems were measured by high performance liquid chromatography (HPLC),
      and intracellular HOCl levels by oxidation of 5-thio-2-nitrobenzoic acid with the
      accompanying decrease in the absorbency at 412 nm. VCR was degraded by increasing
      concentrations of HOCl in cell-free systems and this activity was inhibited by
      taurine, which is known to block HOCl activity. This finding was confirmed by the
      VCR cytotoxicity studies on cell lines. The HOCl-producing myeloblasts from
      patients were resistant to VCR. In five samples out of eight HOCl was also
      detected extracellularly. These results suggest that oxidation by HOCl may be the
      final step in VCR degradation catalyzed by MPO through its action on
      intracellular H2O2 and Cl. Leukemia (2000) 14, 47-51.

PMID- 10637477
TI  - Enhancement of retention and cytotoxicity of 2-chlorodeoxyadenosine in cultured
      human leukemic lymphoblasts by nitrobenzylthioinosine, an inhibitor of
      equilibrative nucleoside transport.
AB  - In leukemic cells exposed to 2-chlorodeoxyadenosine (2-CdA), levels of the
      nucleoside drug and its phosphate metabolites decay with time in the absence of
      external 2-CdA; an intrinsic part of this process is the efflux of 2-CdA. The
      effects of nitrobenzylthioinosine (NBMPR) and of dipyridamole (DPM), both potent
      inhibitors of es (e, equilibrative; s, sensitive to NBMPR) nucleoside transport
      processes, were studied in four lines of cultured leukemic lymphoblasts.
      Suspensions of 2-CdA-loaded cells were diluted 10-fold with 2-CdA-free medium to
      initiate the cellular 2-CdA decay processes, which followed a biexponential time
      course. When diluting media contained NBMPR or DPM, intracellular levels of 2-CdA
      and its metabolites were substantially increased (P < 0.001) compared with cells
      in media lacking the transport inhibitors, and 2-CdA loss followed a
      monoexponential time course. As a consequence, the AUCs (area under time-course
      plots of intracellular 2-CdA and its metabolites) were significantly (P < 0.001)
      lower in untreated control cells compared to inhibitor-treated cells. These
      results suggest that nucleoside transport processes contribute to the efflux of 2
      CdA from the cultured lymphoblasts. The cytotoxicity of 1-h exposure to 2-CdA of
      Reh-A2 and CCRF-CEM cells was enhanced three-fold by subsequent exposure to 0.5
      microM NBMPR relative to that of control cells subjected to the same
      manipulations without NBMPR exposure. However, before such a strategy may be
      considered to have a therapeutic application, careful examination of effects in
      normal lymphocytes and ex vivo leukemic lymphoblasts must first be undertaken.
      Leukemia (2000) 14, 52-60.

PMID- 10637479
TI  - Drug resistance factors in acute myeloid leukemia: a comparative analysis.
AB  - To compare the clinical relevance of drug resistance factors in de novo acute
      myeloid leukemia (AML), we determined their relationship to both response to
      induction chemotherapy and survival of the patients in univariate as well as
      multivariate analyses. The drug resistance factors immunocytochemically studied
      in 111 patients at the time of diagnosis included the lung resistance protein
      (LRP), P-glycoprotein (P-gp), multidrug resistance protein (MRP1) and bcl-2. In
      the univariate analyses, age (P = 0.005), karyotype (P = 0.03), LRP (P = 0.003),
      P-gp (P = 0.02) and bcl-2 (P = 0.03) predicted for response to induction
      chemotherapy, whereas MRP1 had no predictive value. Age (P = 0.05), karyotype (P
      = 0.05) and LRP (P = 0.03) retained their predictive value in the multivariate
      logistic regression analyses. With regard to overall survival, age (P = 0. 008),
      karyotype (P = 0.006), LRP (P = 0.001) and P-gp (P = 0.01) were of prognostic
      value in the univariate Cox regression analyses but only age (P = 0.01),
      karyotype (P = 0.02) and LRP (P = 0.01) retained their prognostic significance in
      the multivariate analyses. A risk score based on the number of independent
      prognostic factors allowed division of patients into four groups with different
      outcome. In these groups, the complete remission rates were 93%, 75%, 47% and
      33%, respectively, and median overall survival was 2.4, 1.2, 0.6 and 0.2 years,
      respectively. Thus, several drug resistance factors did predict outcome in the
      univariate analyses but LRP was the only drug resistance factor with independent
      predictive and prognostic significance. The proposed risk score might be useful
      for risk-adapted treatment in the future. Leukemia (2000) 14, 68-76.

PMID- 10637478
TI  - Incidence and prognostic significance of MDM2 oncoprotein overexpression in
      relapsed childhood acute lymphoblastic leukemia.
AB  - MDM2 overexpression by pediatric ALL cells at initial diagnosis has been linked
      to poor response to therapy. In the present study, we evaluated the incidence of
      MDM2 overexpression by ALL cells from pediatric patients at first relapse and
      compared MDM2 protein levels with in vitro response to adriamycin and with
      duration of initial complete remission (CR1). Since an important role of MDM2 in
      enhancing cell proliferation and survival appears to be inhibition of p53
      activity, we also evaluated the status of p53 in these patients' leukemic cells.
      MDM2 protein levels were determined by Western blot analysis of leukemic bone
      marrow cells obtained from 42 patients with B cell precursor (BCP) ALL who
      relapsed during or following therapy on standard POG ALL protocols. Twelve of 42
      (29%) cases have MDM2 levels >/=10-fold higher than those detected in normal bone
      marrow mononuclear (NMMC) cells, which express relatively low levels of protein.
      Thirty cases (71%) expressed MDM2 at levels <10-fold those in NMMC, including 24
      MDM2-negative cases (57%). P53 mutations were detected by single-strand
      conformation polymorphism analysis in two cases. Overexpression of MDM2 (>/=10
      fold) was significantly correlated with adriamycin resistance and decreased
      duration of CR1. Eight of 12 (75%) overexpressers showed high levels of in vitro
      resistance to adriamycin, compared to four of 30 (13%) non-overexpressers (P <
      0.005). The median CR1 for MDM2 overexpressers was 20.5 months (range: 3-75
      months) compared to 41 months (range: 8-98 months) for non-overexpressers (P <
      0.01). Four of 42 patients failed to achieve CR following re-induction: leukemic
      cells from three of these patients either overexpressed MDM2 or contained a
      mutant p53. These results indicate that overexpression of MDM2 plays a
      significant role in refractory pediatric ALL and is associated with early
      relapse, adriamycin resistance, and failure to respond to re-induction therapy.
      Leukemia (2000) 14, 61-67.

PMID- 10637480
TI  - The impact of differential binding of wild-type RARalpha, PML-, PLZF- and NPM
      RARalpha fusion proteins towards transcriptional co-activator, RIP-140, on
      retinoic acid responses in acute promyelocytic leukemia.
AB  - Retinoic acid receptor (RA) heterodimer (RAR/RXR) activities have been shown to
      be repressed by transcriptional co-repressor, SMRT/N-CoR, in the absence of the
      ligand while upon all-trans retionic acid (ATRA) treatment, SMRT/N-CoR is
      dissociated from RARalpha leading to gene expression by the recruitment of
      transcriptional co-activators to the transcriptional complex. The difference in
      response to ATRA therapy between acute promyelocytic leukemia (APL) patients with
      PML-RARalpha fusion and PLZF-RARalpha fusion has recently been found to be
      partially due to the strong association of the transcriptional co-repressor,
      SMRT/N-CoR, with PLZF domain. We demonstrate that SMRT association, as with PML
      RARalpha, can be released from NPM-RARalpha at pharmacological concentration of
      ATRA (10-6 M). Moreover, we show for the first time that the interaction between
      the transcriptional co-activator, RIP-140, and PML-, PLZF- or NPM-RARalpha fusion
      proteins can be positively stimulated by ATRA although they are less sensitive as
      compared with the wild-type RARalpha. Our results suggest that the dissociation
      of transcriptional co-repressors, SMRT/N-CoR, and recruitment of co-activators,
      eg RIP-140, to APL-associated fusion proteins constitute a common molecular
      mechanism in APL and underlie the responsiveness of the disease to RA therapy.
      Leukemia (2000) 14, 77-83.

PMID- 10637481
TI  - Intracellular forms of human NOTCH1 interact at distinctly different levels with
      RBP-jkappa in human B and T cells.
AB  - The cellular transcriptional repressor RBP-Jkappa associates with the Epstein
      Barr virus nuclear antigens (EBNAs) determined to be essential for transformation
      of human primary B lymphocytes. It was demonstrated through genetic analysis that
      interaction between the viral transactivator EBNA2 and RBP-Jkappa is essential
      for EBV immortalization of primary B lymphocytes. We have shown that the
      association of RBP-Jkappa with intracellular NOTCH1 differs significantly in B
      and T cells. Immunoprecipitation analyses with antibodies to both the
      intracellular forms of NOTCH1 and to RBP-Jkappa demonstrated that little or no
      RBP-Jkappa is associated with NOTCH1 in B cell lines compared to the RBP-Jkappa
      associated with NOTCH1 in T cell lines and was further demonstrated in human
      primary lymphocytes. Additionally, EBNA2 can compete with intracellular NOTCH1
      for binding to GST-RBP-Jkappa in vitro. Northern blot for the cellular gene hairy
      enhancer of split (HES1) demonstrated that HES1 is upregulated in the EBV
      transformed lymphoblastoid cells expressing high levels of EBNA2 and in a T cell
      line SupT1 overexpressing intracellular activated NOTCH1. Hence, EBNA2 may be
      able to compete for the available pool of RBP-Jkappa more effectively in human B
      cells than in T cells and provides a possible explanation for the ability of EBV
      to potently and efficiently infect and immortalize human B cells. Leukemia (2000)
      14, 84-92.

PMID- 10637482
TI  - Molecular analysis of the CALM/AF10 fusion: identical rearrangements in acute
      myeloid leukemia, acute lymphoblastic leukemia and malignant lymphoma patients.
AB  - The recurring translocation t(10;11)(p13;q14) which is found in acute myeloid
      leukemia (AML) and in acute lymphoblastic leukemia (ALL) results in the fusion of
      the putative transcription factor AF10 to CALM encoding a clathrin assembly
      protein. Previous studies using mainly fluorescence in situ hybridization (FISH)
      analysis have shown that the CALM/AF10 rearrangement is found in immature acute
      myeloid leukemia (AML) of subtype M0 and M1 and in T cell ALL. In this study we
      analyzed the CALM/AF10 and AF10/CALM fusion mRNAs in a series of three patients
      with AML, one patient with T-ALL and two patients with precusor T lymphoblastic
      lymphoma. In all six patients the breakpoint in CALM is at the 3' end of the
      coding region (nt1926/1927 or nt 2091/2092). Three breakpoints could be
      identified in AF10 (nt 588/589, nt 882/883 and nt 978/979). These data
      demonstrate that the CALM/AF10 fusions found in patients differ only slightly
      with respect to the portion of AF10 present and that there is no obvious
      difference between the fusions found in AML patients compared to those found in
      patients with lymphoid malignancies. Leukemia (2000) 14, 93-99.

PMID- 10637484
TI  - Increased frequency of dicentric chromosomes in therapy-related MDS and AML
      compared to de novo disease is significantly related to previous treatment with
      alkylating agents and suggests a specific susceptibility to chromosome breakage
      at the centromere.
AB  - Dicentric chromosomes are observed in many malignant diseases including
      myelodysplasia (MDS) and acute myeloid leukemia (AML) and have often been
      observed in a subset of these diseases, namely therapy-related MDS (t-MDS) and
      AML (t-AML). Using fluorescence in situ hybridization (FISH) with centromere
      specific probes, we investigated the frequency and type of dicentric chromosomes
      in 180 consecutive patients with t-MDS and t-AML and in 231 consecutive patients
      with de novo MDS and AML, whose karyotypes had been studied previously by
      conventional G-banding. Twenty-seven out of 180 patients with t-MDS or t-AML
      presented dicentric chromosomes compared to only seven out of 231 patients with
      de novo disease (P = 0.00003). A dic(1q;7p) was observed in 10 cases, a
      dic(5p;17q) was observed in six cases, whereas various isodicentric chromosomes
      were observed in six cases. Excluding these six cases with isodicentrics, all 25
      patients with dicentric chromosomes had involvement of at least one of the
      chromosome arms 1q, 5p, or 7p resulting in monosomy for 5q or 7q, and/or trisomy
      for 1q. Patients with dicentric chromosomes presented significantly more often as
      t-MDS compared to patients without dicentrics (P = 0.046), and the presence of a
      dicentric chromosome was significantly related to previous therapy with
      alkylating agents (P = 0.026). Thus, only one out of 27 patients with a dicentric
      chromosome had not previously received an alkylating agent. A specific
      susceptibility to breakage at the centromere after exposure to alkylating agents
      is suggested and may explain the frequent loss of whole chromosomes, in
      particular chromosomes 5 and 7 in t-MDS and t-AML, if the breaks are not followed
      by rejoining. Leukemia (2000) 14, 105-111.

PMID- 10637483
TI  - Identification and molecular characterization of CALM/AF10fusion products in T
      cell acute lymphoblastic leukemia and acute myeloid leukemia.
AB  - The t(10;11)(p12-p13;q14-q21) observed in a subset of patients with either acute
      lymphoblastic leukemia or acute myeloid leukemia has been shown to result in the
      fusion of AF10 on chromosome 10 with CALM (also named CLTH) on chromosome 11.
      AF10 was originally identified as a fusion partner of MLL in the t(10;11)(p12
      p13;q23) observed in myeloid leukemia. CALM is a newly isolated gene, cloned as
      the fusion partner of AF10 in the monocytoid cell line, U937. In order to
      understand the relationship between MLL, AF10, CALM and the leukemic process,
      fluorescence in situ hybridization and reverse transcriptase polymerase chain
      reaction were used to study a series of nine leukemia patients with a t(10;11).
      Six had myeloid leukemia (AML-M0, AML-M1, AML-M4 and AML-M5) and three had T cell
      lymphoblastic leukemia. We identified four different CALM/AF10 fusion products in
      five patients and AF10/CALM reciprocal message in one. We conclude that fusion of
      CALM and AF10 is a recurring abnormality in both lymphoid and myeloid leukemias
      of various types including AML-M5, and that the breakpoints in the two types of
      leukemia do not differ. Our data indicate that the CALM/AF10 fusion product on
      the der(10) chromosome is critical to leukemogenesis. Leukemia (2000) 14, 100
      104.

PMID- 10637485
TI  - Mutagen exposures and chromosome 3 aberrations in acute myelocytic leukemia.
AB  - Thirteen patients with acute myelocytic leukemia (AML) and with clonal
      aberrations involving chromosome 3 were studied. Three patients had monosomy 3,
      four had trisomy 3, and six had structural aberrations of chromosome 3. In the
      majority of cases chromosome 3 aberrations were parts of complex karyotypes, but
      in two patients, the abnormalities appeared as single aberrations, one as an
      interstitial deletion del(3)(p13p21) and the other as monosomy 3. All breakpoints
      of chromosome 3 were found in the fragile site regions 3p14.2, 3q21 and 3q26-27.
      All patients with monosomy 3 or structural aberrations of chromosome 3 and one of
      the four patients with trisomy 3 had been exposed to mutagens, such as
      occupational exposures to organic solvents and/or petroleum products or
      treatments with irradiation or antineoplastic agents. The association among
      mutagen exposure, structural chromosome 3 aberrations and fragile sites in AML
      may indicate that targeting of the mutagens to these sites is of importance for
      the etiology of the disease. Leukemia (2000) 14, 112-118.

PMID- 10637486
TI  - Jumping translocation in acute leukemia of myelomonocytic lineage: a case report
      and review of the literature.
AB  - Jumping translocation (JT) is a very rare cytogenetic event, occurring especially
      in cancer. We describe a case of secondary acute monocytic leukemia (AML5b) with
      a JT involving the 3q13-3qter segment and leading to a partial trisomy 3. Each
      clone with JT was associated with trisomy 8 or tetrasomy 8. The literature of JT
      in AML cases is reviewed: only 13 cases of AML associated with JT have been
      previously described, seven of which are AML4/5 FAB subtype. Jumping
      translocation involvement in leukemogenesis is discussed. Leukemia (2000) 14, 119
      122.

PMID- 10637487
TI  - Acute myeloid leukaemia triggering via CD40 induces leukocyte chemoattraction and
      cytotoxicity against allogenic or autologous leukemic targets.
AB  - The CD40 antigen is a member of the tumor necrosis factor receptor superfamily
      which interacts with its ligand and regulates the immune response via a dialogue
      between T-lymphocytes and antigen-presenting or tumor cells. Tumor triggering via
      CD40 exerts direct effects on cancer cells, which have mainly been investigated
      in terminally differentiated hematological malignancies such as low-grade
      lymphoma. We focused our attention on minimally differentiated acute myeloid
      leukemia (AML-M0), an aggressive hematological malignancy in which severe
      prognosis suggests the requirement for innovative therapeutic strategies. Here we
      demonstrate, for the first time to our knowledge, a CD40-triggered IL-8, RANTES
      and IL-12 secretion by leukemic cells. Supernatants from CD40-stimulated leukemia
      cells had chemoattractant effects on T-lymphocytes, natural killer cells and
      monocytes. Moreover, these supernatants, when complemented with low-dose IL-2,
      induced significant lymphokine-activated and natural killer cytotoxicity, leading
      to leukemia lysis both in allogenic HLA-matched and autologous settings.
      Stimulation of leukemia cells via CD40 could participate significantly to the
      anti-leukemia immune response by contributing to the development of an
      inflammatory response and to in situ cytotoxicity. Leukemia(2000) 14, 123-128.

PMID- 10637488
TI  - Treatment of refractory Hodgkin's lymphoma patients with an anti-CD25 ricin A
      chain immunotoxin.
AB  - The anti-CD25 immunotoxin RFT5.dgA was constructed by coupling the monoclonal
      antibody RFT5 via a sterically hindered disulfide linker to deglycosylated ricin
      A-chain and was administered to patients with relapsed Hodgkin's lymphoma in four
      bolus infusions over 7 days (day 1, 3, 5 and 7). The maximum tolerated dose in
      these patients as defined in a previous phase I study was 15 mg/m2. Subsequently,
      further patients were enrolled at the maximum tolerated dose and a total of 18
      patients were treated at this level. All patients had signs of progressive
      disease and were heavily pretreated. Side-effects in this trial were moderate and
      related to vascular leak syndrome. Five of 18 patients experienced NCI grade III
      toxicities including weakness, edema, dyspnea, and myalgia. Eleven of 16 (69%)
      patients receiving two or more cycles produced human anti-ricin antibodies and
      human anti-mouse antibodies (>/=1.0 microg/ml). Seventeen of 18 patients were
      evaluable for clinical response. These included two partial remissions. One
      patient demonstrated minor response and five patients stable diseases. We
      conclude that RFT5.dgA is of moderate clinical efficacy in this group of heavily
      pretreated refractory patients. Leukemia (2000) 14, 129-135.

PMID- 10637489
TI  - Anti-leukemic action of the novel agent MGI 114 (HMAF) and synergistic action
      with topotecan.
AB  - The illudin derivative MGI 114 (6-hydroxymethylacylfulvene or HMAF) is currently
      in phase II chemotherapeutic clinical trials for a variety of solid tumors. The
      illudins were originally thought to be potentially useful agents for myeloid
      leukemias, because hematopoietic tumor cells were markedly sensitive whereas
      normal bone marrow progenitors were relatively resistant to the cytotoxic effects
      of illudins. Due to the marked preclinical efficacy of MGI 114 against a variety
      of solid tumor xenografts, the current phase II human trials are restricted to
      solid tumor (breast, lung, colon, ovarian, pancreas, prostate, etc) malignancies.
      The present studies were undertaken to evaluate the efficacy of MGI 114 in the
      HL60/MRI myeloid leukemia xenograft. In addition, because of the reported
      synergistic cytotoxic activity between MGI 114 and the topoisomerase I inhibitor
      topotecan towards pediatric human tumor cell lines, we tested the activity of MGI
      114 and topotecan combinations against HL60 cells in vitro and the HL60/MRI
      myelocytic xenograft. Our results indicate that MGI 114 at maximum tolerated
      doses (MTD) of 7 mg/kg, five times per week for 3 weeks does display anti-myeloid
      leukemic properties in the HL60/MRI xenograft model which exceeds activity noted
      with other conventional agents (TGI > 70%). A marked therapeutic synergistic
      action was observed with MGI 114 and topotecan combinations of (1/2) MTD of each
      agent producing complete tumor remission in 50% of animals, without development
      of excessive or additive toxicity in animals. These results support further in
      vitro and clinical investigation into both the anti-myeloid leukemic activity of
      MGI-114, and the cooperative pharmacologic interaction noted between MGI-114 and
      topoisomerase I inhibitors. Leukemia (2000) 14, 136-141.

PMID- 10637490
TI  - Establishment and characterization of a new human megakaryoblastic cell line (SET
      2) that spontaneously matures to megakaryocytes and produces platelet-like
      particles.
AB  - A new factor-independent megakaryoblastic cell line, designated SET-2, was
      established from the peripheral blood of a patient with leukemic transformation
      of essential thrombocythemia (ET). SET-2 expressed CD 4, 7, 13, 33, 34, 36, 38,
      41, 61, 71, 117, 126, 130 and c-mpl. In addition, it spontaneously produced
      numerous platelet-like particles in liquid culture. These particles were shown to
      be the same size as normal platelets, and to express CD 36, 38, 41, 61 and 71.
      Proliferation of SET-2 was not influenced by thrombopoietin (TPO) and other
      hemopoietic cytokines. SET-2 was found to express the platelet-specific proteins
      such as platelet factor 4 and beta-thromboglobulin. The levels of expression were
      not altered by TPO. SET-2 also secreted interleukin-6 into the supernatants, as
      well as normal megakaryocytes. These results suggest that SET-2 spontaneously
      matures to megakaryocytes and produces platelet-like particles. These findings
      indicate that SET-2 may be useful for investigating the proliferation and
      differentiation mechanisms of leukemia cells and the role of c-mpl on
      megakaryoblasts, megakaryocytes, and platelets in ET. Leukemia (2000) 14, 142
      152.

PMID- 10637491
TI  - Expression of Flt3-ligand by the endothelial cell.
AB  - Flt3-ligand (FL) is a cytokine that is of paramount importance in the
      proliferation of primitive hematopoietic progenitors. In this study, we show that
      endothelial cells (EC) produce large amounts of soluble FL and express a membrane
      bound form of the molecule. Bone marrow microvascular EC also produce FL,
      suggesting that EC are an important source of FL in the bone marrow. High
      concentrations of FL in EC supernatants contrast with its undetectable levels in
      long-term bone marrow cultures. A single mRNA for FL is detected, suggesting that
      soluble FL derives from the membrane-bound species by proteolytic release. FL
      mRNA is stable with a half-life of about 3 h. II-1alpha increases FL mRNA levels
      and membrane and soluble FL expression. Glucocorticoids, known inhibitors for
      many hematopoietic growth factors do not down-regulate the expression of FL. On
      the contrary, GC increase the expression of both species of FL. The
      neutralization of FL in cocultures EC/ hematopoietic progenitors results in an
      acceleration of the maturation of the progenitors. IFN-alpha, MIP-1 alpha and TGF
      beta stimulate production of membrane-bound and soluble FL. This stimulation is
      essential to explain their modulatory effect on the generation of clonogenic
      cells in cocultures EC/hematopoietic progenitors. Leukemia (2000) 14, 153-162.

PMID- 10637492
TI  - Geographic heterogeneity of cellular characteristics of acute myeloid leukemia: a
      comparative study of Australian and Japanese adult cases.
AB  - We assessed a large number of adults (368 from Australia and 494 from Japan) with
      de novo acute myeloid leukemia (AML) to define the biological differences between
      the two populations. In this study, AML was classified using the French-American
      British (FAB) criteria into seven groups (M1-M7). M2 was more common in Japan
      than in Australia, whereas M4 occurred more frequently in Australia than in
      Japan. Other FAB subtypes were evenly distributed. Cytogenetically, Japanese M2
      displayed a higher frequency of t(8;21) than Australian (33.1% vs 15.3%, P <
      0.05). The t(15;17), inv/del(16), 11q23 aberrations and 5/7/8 abnormalities were
      seen at similar frequencies. Immunophenotypically, Japanese M4/M5 more frequently
      displayed CD13 and CD14 than Australian, whereas the stem cell markers, CD34 and
      HLA-DR were observed at a relatively higher rate in Australian M3 than in
      Japanese M3. The B cell antigen, CD19 was more frequently seen in Japanese M2
      than in Australian M2, but found more often in Australian M5 than in Japanese M5.
      In both populations, a close relationship was observed between the expression of
      CD19 and t(8;21). These findings suggest different biological characteristics of
      AML between the two populations, the main differences being generated by a higher
      frequency of t(8;21) chromosomal abnormality in Japanese AML. Leukemia(2000) 14,
      163-168.

PMID- 10637493
TI  - Ph-negative non-Hodgkin's lymphoma occurring in chronic phase of Ph-positive
      chronic myelogenous leukemia is defined as a genetically different neoplasm from
      extramedullary localized blast crisis: report of two cases and review of the
      literature.
AB  - This report describes two cases of Philadelphia chromosome-negative (Ph(-)) non
      Hodgkin's lymphomas (NHLs) recognized in patients with chronic phase Ph-positive
      (Ph(+)) chronic myelogenous leukemia (CML). Lymph node biopsy of patient 1 was
      initially diagnosed as diffuse large B cell non-Hodgkin's lymphoma (NHL, T cell
      rich variant), but at relapse showed immunoblastic features with a marked
      decrease of admixed lymphocyte components. Patient 2 presented with thickened
      parietal pleura which revealed a CD30-positive anaplastic large cell lymphoma
      showing null cell phenotype and genotype with abundant admixed neutrophils and
      lymphocytes. At the time of lymphoma diagnosis, the patients had CML for 33 and
      10 months, respectively. DNA obtained from bone marrow cells at the time of
      lymphoma diagnosis showed BCR/ABL gene rearrangements by both Southern blot
      analysis and reverse transcription polymerase chain reaction (RT-PCR), but lacked
      both immunoglobulin and T cell receptor gene rearrangements. BCR gene
      rearrangement and BCR/ABL fusion gene were also identified in lymph node and
      pleural biopsies by Southern blot and RT-PCR analysis, respectively. However,
      both biopsy specimens also contained reactive lymphocytes and neutrophils, and no
      fusion signals between BCR and ABL genes were identified in the hyperdiploid
      lymphoma cells of either case by fluorescence in situ hybridization (FISH). These
      data suggest the lymphoma cells in both cases were not genetically associated
      with BCR/ABL. Therefore, these cases were not diagnosed as an extramedullary
      localized blast crisis in CML, but as Ph(-) NHLs. This represents the first
      definitive demonstration of peripheral B cell lymphoma occurring by a separate
      genetic pathway, lacking BCR/ABL, in patients with Ph(+) CML. A review of the
      literature identified two different subtypes of malignant lymphomas arising in
      patients with an antecedent or concurrent diagnosis of CML. The most common are T
      cell lymphomas displaying an immature thymic phenotype, while peripheral B cell
      lymphomas are more rare. Our study shows, however, that 'Ph(+) NHL' occurring in
      CML or acute lymphocytic leukemia (ALL) may represent an unrelated neoplasm, even
      if standard cytogenetic analysis reveals a Ph(+) chromosome, and that FISH is
      required to confirm whether a localized lymphoid neoplasm is either a true
      extramedullary localized blast crisis or genetically distinct neoplasm.
      Leukemia(2000) 14, 169-182.

PMID- 10637494
TI  - De novo methylation of tumor suppressor gene p16/INK4a is a frequent finding in
      multiple myeloma patients at diagnosis.
AB  - The p16 gene competes with cyclin D for binding to CDK4/CDK6 and therefore
      inhibits CDK4/6 complex kinase activity, resulting in dephosphorylation of pRb
      and related G1 growth arrest. Inactivation of this gene has been involved in a
      variety of tumors by different mechanisms: homozygous/hemyzygous deletions, point
      mutations and methylation of a 5' CpG island into exon E1alpha of the p16 gene.
      Homozygous deletions have been rarely found in multiple myeloma (MM) and no point
      mutations have been reported. Two recent studies have reported a high prevalence
      of methylation in the exon E1alpha of the p16 gene, but included only a small
      number of cases. We have analyzed the methylation pattern of exon E1alpha of the
      p16 gene in 101 untreated MM and five primary plasma cell leukemias (PCL). A PCR
      assay, relying on the inability of some restriction enzymes to digest methylated
      sequences, was used to analyze the methylation status. Southern blot analysis was
      used to confirm these results. Forty-one of 101 MM patients (40.5%) as well as
      four of the five (80%) primary PCL patients had shown methylation of the exon
      E1alpha. Our study confirms that hypermethylation of the p16 gene is a frequent
      event in MM. Leukemia (2000) 14, 183-187.

PMID- 10637495
TI  - Agonist anti-gp130 transducer monoclonal antibodies are human myeloma cell
      survival and growth factors.
AB  - We have previously reported obtaining two monoclonal antibodies (mAb) against the
      human gp130 interleukin-6 (IL-6) transducer which made possible the dimerization
      of gp130 and the activation of several IL-6-driven functions when used together.
      We report here that these mAb induce gp130-mediated signaling in human myeloma
      cells and support the survival and the long-term growth of five IL-6-dependent
      human myeloma cell lines. Their agonist activity is not affected by neutralizing
      antibodies to IL-6 or IL-6R. These mAb induce a transient proliferation of
      primary myeloma cells from most patients with multiple myeloma. Again, IL-6
      inhibitors do not affect this agonist activity. By using highly purified primary
      myeloma cells, we found that these anti-gp130 mAb supported the long-term
      survival of primary myeloma cells from five patients with primary plasma cell
      leukemia but failed to induce their long-term growth. For patients with fulminant
      disease and secondary extramedullary proliferation, the antibodies supported a
      long-term survival and growth, and anti-gp130 mAb-dependent cell lines were
      obtained. For patients with medullary involvement only, a co-stimulatory signal
      is necessary, together with gp130 activation, to trigger cell survival and
      cycling. Leukemia (2000) 14, 188-197.

PMID- 10637496
TI  - p53 alterations in human leukemia-lymphoma cell lines: in vitroartifact or
      prerequisite for cell immortalization?
AB  - Alteration of the p53 gene is one of the most frequent events in human
      tumorigenesis. The inactivation of p53 tumor suppressor function can be caused by
      chromosome deletion, gene deletion, or mainly by point mutations. p53 mutations
      occur moderately often in hematopoietic malignancies. A significantly higher
      frequency of p53 alterations in cell lines vs primary samples has been observed
      for all types of malignant hematopoietic cell lines. It has been postulated that
      p53 gene abnormalities arise in cell lines during in vitro establishment of the
      culture or prolonged culture; but it is also conceivable that those cases that
      carry p53 mutations may be more suitable for in vitro establishment as permanent
      cell lines. We analyzed data on the p53 gene status in a panel of matched primary
      hematopoietic tumor cells and the respective cell lines derived from this
      original material. In 85% (53/62) of the pairs of matched primary cells and cell
      lines, the in vivo and in vitro data were identical (both with p53 wild-type or
      both with the same p53 mutation). In some instances, serial clinical samples (eg
      at presentation and relapse) and serial sister cell lines were available. These
      cases showed that a clinical sample at presentation often had a p53 wild-type
      configuration whereas the derived cell line and a relapse specimen carried an
      identical p53 point mutation. These findings suggest that a minor clone, at first
      undetectable by standard analysis, represents a reservoir for the outgrowth of
      resistant cells in vivo and also a pool of cells with a growth advantage in
      vitro, providing a significantly higher chance of immortalization in culture.
      This was further supported by studies employing mutant allele-specific gene
      amplifications, a technique which is significantly more sensitive (100- to 1000
      fold) than the commonly applied SSCP assay with a sensitivity threshold of about
      10% mutated cells within a pool of wild-type cells. Taken together, this analysis
      confirms the usefulness of human hematopoietic cell lines as in vitro model
      systems for the study of the biology of hematopoietic malignancies. It further
      underlines the notion that p53 gene alterations confer a survival advantage to,
      at least some, malignant cells in vitro and presumably also in vivo; however, it
      is highly unlikely that a p53 mutation alone would suffice for the
      immortalization of a cell line in vitro or tumor development in vivo. Leukemia
      (2000) 14, 198-206.

PMID- 10637497
TI  - Clonality analysis by methylation-specific PCR for the human androgen-receptor
      gene (HUMARA-MSP).
AB  - The human androgen-receptor gene (HUMARA) has been used for analysis of X
      chromosome inactivation (XCI) pattern because of a polymorphic short tandem
      repeat (STR) near the 5'-promoter region correlated with XCI. We introduce a
      novel method to analyze XCI pattern, named HUMARA methylation-specific PCR
      (HUMARA-MSP) assay, which analyzes methylation status of the HUMARA gene by
      bisulfite modification instead of a methylation-sensitive restriction enzyme.
      Although the original MSP method shows whether there is a methylated band or not,
      our HUMARA-MSP method identifies the patterns of methylated and unmethylated
      bands. Because this method identifies either unmethylated or methylated alleles
      in each PCR tube and shows opposite band patterns dependent on methylation
      status, we can assess the XCI pattern independently twice. This method can avoid
      false results by incomplete enzyme digestion and incomplete bisulfite
      modification will not affect the results. Extremely small quantities of samples,
      such as hematopoietic colonies, were also available for HUMARA-MSP assay. Because
      DNA modified by sodium bisulfite is also available for assessment of methylation
      status of other genes by setting specific primers for them, we performed the
      simultaneous assessment of clonality and aberrant hypermethylation of p15INK4B
      gene in myelodysplastic syndromes. These simultaneous assessments were easily
      possible and provided much information despite requiring only a small volume of
      DNA. The HUMARA-MSP assay may facilitate the analyses for pathogenesis of
      hematological disorders because of its simplicity, sensitivity and wide
      applicability. Leukemia (2000) 14, 207-212.

PMID- 10637498
TI  - Leukemia cell lines resistant to cytosine arabinoside, cyclophosphamide or
      daunomycin are equally sensitive to the drug acetyldinaline as the parental cell
      line.

PMID- 10637499
TI  - Sideroblastic anemia following treatment of chronic myeloid leukemia with
      busulfan.

PMID- 10637501
TI  - Duplex PCR facilitates the identification of immunoglobulin kappa (IGK) gene
      rearrangements in acute lymphoblastic leukemia.

PMID- 10637500
TI  - Nineteen cases of the t(1;22)(p13;q13) acute megakaryblastic leukaemia of
      infants/children and a review of 39 cases: report from a t(1;22) study group.

PMID- 10637502
TI  - Second treatment with fludarabine in a Waldenstrom's macroglobulinemia patient.

PMID- 10637503
TI  - Heterogeneity studies identify a subset of sporadic colorectal cancers without
      evidence for chromosomal or microsatellite instability.
AB  - Two apparently independent mechanisms of instability are recognized in colorectal
      cancer, microsatellite instability and chromosomal instability. Evidence from
      colorectal cancer cell lines indicates the presence of either, or both, types of
      instability in the vast majority. Here, we sought to determine the prevalence of
      such instability in primary sporadic colorectal cancers. Microsatellite
      instability was established by demonstration of ovel clonal, nongerm-line alleles
      in at least two of four tested loci. Chromosomal abnormalities were identified by
      comparative genomic hybridization (CGH) and flow cytometric analysis of nuclear
      DNA content. Tumours harbouring chromosomal instability were distinguished from
      those with stable but aneuploid karyotypes by comparing chromosomal defects at
      multiple sites throughout each cancer. This analysis allowed assessment of both
      the number of chromosomal abnormalities and their heterogeneity throughout the
      tumour. The results confirm that microsatellite instability is consistently
      associated with multiple, repeated changes in microsatellites throughout the
      growth of the affected colorectal carcinomas. There were also several carcinomas
      in which major structural or numerical abnormalities in chromosomes had clearly
      continued to arise during tumour growth. However, a substantial subset of tumours
      showed neither microsatellite instability nor multiple, major chromosomal
      abnormalities. We suggest that the development of a proportion of colorectal
      cancers proceeds via a different pathway of carcinogenesis not associated with
      either of the currently recognized forms of genomic instability.

PMID- 10637504
TI  - A role for PML and the nuclear body in genomic stability.
AB  - The PML gene of acute promyelocytic leukemia (APL) encodes a cell-growth and
      tumor suppressor. PML localizes to discrete nuclear bodies (NBs) that are
      disrupted in APL cells. The Bloom syndrome gene BLM encodes a RecQ DNA helicase,
      whose absence from the cell results in genomic instability epitomized by high
      levels of sister-chromatid exchange (SCE) and cancer predisposition. We show here
      that BLM co-localizes with PML to the NB. In cells from persons with Bloom
      syndrome the localization of PML is unperturbed, whereas in APL cells carrying
      the PML-RARalpha oncoprotein, both PML and BLM are delocalized from the NB into
      microspeckled nuclear regions. Treatment with retinoic acid (RA) induces the
      relocalization of both proteins to the NB. In primary PML-/- cells, BLM fails to
      accumulate in the NB. Strikingly, in PML-/- cells the frequency of SCEs is
      increased relative to PML+/+ cells. These data demonstrate that BLM is a
      constituent of the NB and that PML is required for its accumulation in these
      nuclear domains and for the normal function of BLM. Thus, our findings suggest a
      role for BLM in APL pathogenesis and implicate the PML NB in the maintenance of
      genomic stability.

PMID- 10637505
TI  - ERK activation induces phosphorylation of Elk-1 at multiple S/T-P motifs to high
      stoichiometry.
AB  - Elk-1, a member of the TCF family of Ets domain proteins, contains a C-terminal
      transcriptional activation domain with multiple copies of the MAPK core consensus
      sequence S/T-P. This region is phosphorylated by MAP kinases in vitro and in
      vivo, but the extent and kinetics of phosphorylation at the different sites have
      not been investigated in detail. We prepared antisera against the phosphorylated
      forms of residues T353, T363, T368, S383, S389 and T417. The antisera
      specifically recognize the phosphorylated Elk-1 C terminus and are specific for
      their cognate sites, as assessed by peptide competition and mutagenesis
      experiments. Analysis of cells stably expressing Elk-1 in vivo shows that
      following serum or TPA stimulation, residues T353, T363, T368, S383, S389 and
      T417 become phosphorylated with similar kinetics. Mutation of any one site does
      not prevent phosphorylation of the others. Mutation to alanine of S383, F378 or
      W379, which virtually abolishes transcriptional activation by Elk-1, does not
      affect phosphorylation of any sites tested. Analysis of Elk-1 using two
      dimensional gel electrophoresis shows that following ERK activation Elk-1
      receives at least six phosphates in addition to those present prior to
      stimulation. We propose that the Elk-1 C-terminal regulatory domain becomes
      stoichiometrically phosphorylated following growth factor stimulation.

PMID- 10637506
TI  - The breast cancer gene database: a collaborative information resource.
AB  - The Breast Cancer Gene Database (BCGD) is a compendium of molecular genetic data
      relating to genes involved in breast cancer, and which is freely available via
      the World Wide Web. The data in BCGD is extracted from the published biomedical
      research literature and stored as a collection of 'Facts', which in turn are
      collected into topical categories organized by gene. This organization
      facilitates quick searches and rapid retrievals of specific data such as gene
      characteristics, functions and role in oncogenesis, and is an important factor
      allowing for continuous updates. BCGD can be searched either by gene name or
      keyword. Data is deposited and retrieved from the database through a set of
      interactive Web forms, making it both platform-independent and universally
      accessible in facilitating worldwide collaborative authoring of the database.
      Data in BCGD is linked to other on-line resources such as Entrez, GeneCards and
      On-Line Mendelian Inheritance in Man. BCGD is located at
      http://mbcr.bcm.tmc.edu/ermb/bcgd/bcgd.html.

PMID- 10637507
TI  - Expression of activated CDC42 induces T cell apoptosis in thymus and peripheral
      lymph organs via different pathways.
AB  - CDC42, a Ras-related small GTP binding protein, is involved in diverse cellular
      functions in lymphocytes. We generated transgenic mice expressing constitutively
      active murine CDC42 (Q61L) under the control of the human CD2 promoter.
      Transgenic mice showed smaller thymi with a dramatic reduction of CD4+CD8+, CD4+
      and CD8+ thymocytes and with increase of CD4-CD8- thymocytes at CD25-CD44+ and
      CD25+ stage. A high percentage of the transgenic thymocytes were apoptotic,
      explaining the reduction of cellularity and size of the thymus. Mature T cells
      (TCR alphabeta+) in peripheral lymph organs, spleen and lymph node, were also
      dramatically reduced, and exhibited massive apoptosis. Expression of Fas and Fas
      ligand on both thymocytes and peripheral T cells was upregulated in transgenic
      mice, but the increased apoptosis in the thymus was independent of Fas (CD95),
      whereas peripheral spleen and lymph node T cell apoptosis was Fas dependent.
      Thus, activated CDC42 triggers distinct apoptotic pathways in thymocytes and
      peripheral T cells.

PMID- 10637508
TI  - MLL2, the second human homolog of the Drosophila trithorax gene, maps to 19q13.1
      and is amplified in solid tumor cell lines.
AB  - The Mixed Lineage Leukemia (MLL) gene is commonly involved in translocations in
      infantile leukemia and is amplified in some cases of adult myeloid leukemia. A
      homolog of MLL denoted MLL2, which represents the second human homolog of the
      Drosophila trithorax gene, was characterized by assembling ESTs, the KIAA0304
      cDNA clone, RT - PCR fragments and a new clone isolated from a cDNA phage library
      and compared to the available genomic sequence. The MLL2 gene maps to 19q13.1, a
      region of frequent rearrangement or amplification in solid tumors. MLL2 consists
      of an 8.5 - 9 kb transcript and spans 20 kb of genomic DNA. The predicted MLL2
      protein possesses all of the major domains defined in MLL and the two genes have
      a similar genomic structure. We find that MLL2 is amplified in two of 14
      pancreatic carcinoma cell lines and one of five glioblastoma cell lines and is a
      likely critical gene in 19q13.1 amplifications. It is also a candidate for
      chromosomal rearrangements involving this chromosome locus. MLL2 is one
      additional mammalian trithorax-group gene with involvement in human cancer.

PMID- 10637509
TI  - Molecular characterization of a zebrafish TCF ETS-domain transcription factor.
AB  - The ternary complex factor (TCF) subfamily of ETS-transcription factors represent
      key nuclear targets of the MAP kinase pathways. Members of this subfamily are
      classified by the presence of several conserved domains for DNA binding,
      interaction with SRF, interaction with MAP kinases and transcriptional
      activation. In this study we have isolated a further member of this subfamily
      (TCF-1) from zebrafish. The protein product of zebrafish TCF-1 (zTCF-1), shares
      sequence similarity with the mammalian TCFs in all four conserved domains, with
      highest overall similarity to SAP-1. Zebrafish TCF-1 is expressed throughout
      zebrafish embryonic development and exhibits typical TCF DNA binding
      characteristics, with the B-box being required for interaction with SRF. Of the
      mammalian TCFs, its DNA binding specificity resembles Elk-1. zTCF-1 is a target
      for both the growth factor/mitogen-activated and stress-activated MAP kinase
      cascades in vitro and in vivo. However, differential targeting occurs, with the
      profile of its activation closely resembling that of mammalian SAP-1. Together,
      our results demonstrate that the TCFs have been functionally conserved during
      vertebrate development.

PMID- 10637510
TI  - Identification of heterologous translocation partner genes fused to the BCL6 gene
      in diffuse large B-cell lymphomas: 5'-RACE and LA - PCR analyses of biopsy
      samples.
AB  - In order to elucidate the molecular mechanism(s) for BCL6 translocation, we
      identified translocational partner genes by subjecting clinical biopsy samples
      from patients with non-Hodgkin's lymphoma to 5'-rapid amplification of cDNA ends
      (5'-RACE). Sequence analysis of the 5'-RACE product revealed that the BCL6 gene
      was fused to the J segment of the immunoglobulin heavy chain (IgH) gene in about
      half of the cases, but in the other half, it was fused to heterologous partners,
      including the MHC class II transactivator (CIITA), pim-1, eukaryotic initiation
      factor 4AII (eif4AII), transferrin receptor (TFRR) and ikaros genes. Since
      analyses using genomic long and accurate (LA) - PCR revealed that the breakpoints
      in the partner gene were confined to the first intron or the second exon in all
      cases, the promoter and the first exon of the BCL6 gene were replaced by the
      promoter and the first or both the first and second exon of the partner gene. The
      breakpoint flanking sequences had no recombination signal sequences (RSSs) or chi
      sequences and were homologous with the switch region only when the BCL6 gene was
      fused to the IgH gene, suggesting that BCL6 translocation cannot be explained
      solely by mistakes of V(D)J, or chi-mediated or class-switch recombination, but
      rather another mechanism may also be required to explain the molecular mechanism
      for the promiscuous BCL6 translocation.

PMID- 10637511
TI  - The N-terminal domain of human TAFII68 displays transactivation and oncogenic
      properties.
AB  - In Ewing tumor, the (11;22) chromosomal translocation produces a chimeric
      molecule composed of the amino-terminal domain of EWS fused to the carboxyl
      terminal DNA-binding domain of FLI-1. Previously, we have identified a novel
      protein TAFII68, which is highly similar to EWS and another closely related
      protein TLS (also called FUS). We demonstrate that the N-terminus of TAFII68
      efficiently stimulates transcription when fused to two different DNA binding
      domains and that overexpression of TAFII68-FLI-1 chimeras in NIH3T3 cells leads
      to oncogenic transformation. We have also investigated the molecular mechanisms
      which could account for the transcriptional activation and the oncogenic
      transformation potential of the N-termini of TAFII68 and EWS. Thus, we have
      tested whether the artificial recruitment of components of the preinitiation
      complex (PIC) or a histone acetyltransferase (HAT) could bypass the requirement
      for the activation domains of either EWS or TAFII68. Recruitment of individual
      components of the transcription machinery or the GCN5 HAT is not sufficient to
      promote activation from FLI-1 responsive genes either in transfection experiments
      or in oncogenic transformation assays. These results suggest that the TAFII68 or
      EWS activation domains enhance a step after PIC formation in the transcriptional
      activation process.

PMID- 10637512
TI  - p53/T-antigen complex disruption in T-antigen transformed NIH3T3 fibroblasts
      exposed to oxidative stress: correlation with the appearance of a Fas/APO-1/CD95
      dependent, caspase independent, necrotic pathway.
AB  - Simian Virus 40 Large T-antigen expressed in NIH3T3 cells increases p53 level and
      interacts with this tumor suppressor to form large nuclear complexes. We show
      here that T-antigen sensitizes NIH3T3 cells to low doses of the oxidative stress
      inducer menadione. This oxidant increased p53 accumulation and disrupted p53/T
      antigen interaction, but not T-antigen/pRb, T-antigen/Hsc70 and p53/Hsc70
      complexes; a phenomenon inhibited by the anti-oxidant N-acetyl-cysteine. Analysis
      of several p53 downstream gene products revealed that the level of Fas receptor,
      which was sharply reduced by T-antigen expression, was drastically increased in
      response to menadione treatment. Menadione also induced a T-antigen dependent
      cleavage of Fas ligand. Analysis performed with Fas receptor antagonist antibody
      and metalloproteinases inhibitor revealed that menadione triggers a Fas-dependent
      death of a fraction of T-antigen expressing cells. This Fas pathway does not
      activate caspase 8 or 3, probably because of the inhibition induced by T-antigen,
      and leads to a necrotic cell death which contributes at least in part to the
      hypersensitivity of T-antigen transformed cells to oxidative stress.

PMID- 10637513
TI  - Integrin-linked kinase regulates phosphorylation of serine 473 of protein kinase
      B by an indirect mechanism.
AB  - The serine threonine kinase protein kinase B regulates cellular activities as
      diverse as glycogen metabolism and apoptosis. Full activation of protein kinase B
      requires 3-phosphoinositides and dual phosphorylation on threonine-308 and serine
      473. CaM-K kinase and 3-phosphoinositide dependent-kinase-1 phosphorylate
      threonine-308. Integrin-linked kinase reportedly phophorylates serine-473.
      Consistent with this, in a model COS cell system we show that expression of wild
      type integrin-linked kinase promotes the wortmannin sensitive phosphorylation of
      serine-473 of protein kinase B and its downstream substrates, and inhibits C2
      ceramide induced apoptosis. In contrast, integrin-linked kinase mutated in a
      lysine residue critical for function in protein kinases is inactive in these
      experiments, and furthermore, acts dominantly to block serine-473 phosphorylation
      induced by ErbB4. However, alignment of analogous sequences from different
      species demonstrates that integrin-linked kinase is not a typical protein kinase
      and identifies a conserved serine residue which potentially regulates kinase
      activity in a phosphorylation dependent manner. Mutation of this serine to
      aspartate or glutamate, but not alanine, in combination with the inactivating
      lysine mutation restores integrin-linked kinase dependent phosphorylation of
      serine-473 of protein kinase B. These data strongly suggest that integrin-linked
      kinase does not possess serine-473 kinase activity but functions as an adaptor to
      recruit a serine-473 kinase or phosphatase.

PMID- 10637515
TI  - Somatic frameshift mutations in the MBD4 gene of sporadic colon cancers with
      mismatch repair deficiency.
AB  - Defects of mismatch repair are thought to be responsible for carcinogenesis in
      hereditary non-polyposis colorectal cancer and about 15% of sporadic colon
      cancers. The phenotype is seen as microsatellite instability and is known to be
      caused either by mutations in mismatch repair genes or by aberrant methylation of
      these genes stabilizing their downregulation. Lack of repair of microsatellite
      sequence errors, created during replication, leads to a mutation-prone phenotype.
      Where mutations occur within mononucleotide tracts within exons they cause
      translation frameshifts, premature cessation of translation and abnormal protein
      expression. Such mutations have been observed in the TGFbetaRII, BAX, IGFIIR,
      MSH3 and MSH6 genes in colon and other cancers. We describe here frameshift
      mutations affecting the gene for the methyl-CpG binding thymine glycosylase,
      MBD4, in over 40% of microsatellite unstable sporadic colon cancers. The
      mutations all appear heterozygous but their location would ensure truncation of
      the protein between the methyl-CpG binding and glycosylase domains, thus
      potentially generating a dominant negative effect. It is thus possible that such
      mutations enhance mutation frequency at other sites in these tumours. A
      suggestion has been made that MBD4 (MED1) mutations may lead to an increased rate
      of microsatellite instability but this mechanism appears unlikely due to the
      nature of mutations we have found.

PMID- 10637514
TI  - An inhibitory switch derepressed by pbx, hox, and Meis/Prep1 partners regulates
      DNA-binding by pbx1 and E2a-pbx1 and is dispensable for myeloid immortalization
      by E2a-pbx1.
AB  - The Pbx/Exd family of homeodomain (HD) proteins contribute to the transcriptional
      and developmental roles of other Hox and Meis/Prep1/Hth HD proteins through
      heterodimer formation. E2a-Pbx1 is an oncogenic derrivative of Pbx1 produced by
      the t(1;19) translocation in pediatric pre-B cell acute lymphoblastic leukemia.
      E2a-Pbx1 heterodimerizes with Hox but not with Meis/Prep1 proteins, produces
      acute myeloid leukemia in mice, and blocks differentiation of cultured murine
      myeloid progenitors. Here, we characterize negative and positive regulatory
      sequences that flank the Pbx1 HD and determine their importance for myeloid
      immortalization by E2a-Pbx1. A 25 residue predicted alpha helix preceding the
      Pbx1 HD bound the HD and prevented both its binding to DNA and its ability to
      heterodimerize with Hox proteins. Addition of 39 residues N-terminal to this
      inhibitory helix exposed a Pbx dimerization interface that orchestrated
      cooperative DNA-binding of E2a-Pbx1 and all Pbx proteins as homodimers and
      heterdimers. Sequences inhibiting DNA-binding and mediating Pbx dimerization
      coincided with those reported to have nuclear export function. An additional 103
      residues N-terminal to the Pbx dimerization interface restored heterodimerization
      with Hox and Meis1/Prep1 proteins. This negative switch domain - comprised of the
      inhibitory helix and N-terminal regions required for its partner-mediated
      derepression - was dispensable for myeloid immortalization by E2a-Pbx1. While
      stabilizing the heterodimer, the 310 helix C-terminal to the Pbx1 HD was also
      dispensable for the ability of E2a-Pbx1 to heterodimerize with Hox proteins and
      immortalize myeloblasts. Retention of myeloid immortalization by E2a-Pbx1
      proteins lacking all Pbx1 sequences N- or C-terminal to the HD indicates that Hox
      proteins, or a yet undefined factor that binds the Pbx1 HD and derepresses DNA
      binding by the HD, cooperate with E2a-Pbx1 in myeloid immortalization.

PMID- 10637516
TI  - What for the future?

PMID- 10637517
TI  - Life course exposure and later disease: a follow-up study based on medical
      examinations carried out in Glasgow University (1948-68).
AB  - Evidence for the relationship between exposures in fetal life, infancy, childhood
      and early adulthood, and risk of chronic disease in later middle-age continues to
      accumulate. Further understanding of the associations between exposures acting
      over the life course and current morbidity and mortality in middle-age and later
      must depend upon the follow-up of previously established cohorts. This paper
      describes the design of, and background to, a follow-up of individuals who
      participated in a survey of student health in the University of Glasgow between
      1948 and 1968. 15 332 students, almost a quarter of whom were female, had
      detailed medical information collected from a doctor-administered questionnaire
      and physical examination. Participation was voluntary; approximately 50% of the
      student population took part and these students were rep-resentative of the
      entire student population. Data collected include: socio-demographic,
      behavioural, developmental, anthropometric, and clinical details, as well as
      details of medical history and family health and structure. Data are over 95%
      complete for most variables. Over 40% of students were examined on two or more
      occasions with 1026 students (6.8%) having four or more examinations. Over 90% of
      students were from social classes I-III. Eighty-two per cent (12 533/15 322) of
      the students have been traced and flagged through the National Health Service
      Central Register and attempts are on-going to increase this figure. Those study
      members who have been traced are representative of the original cohort. To date
      1111 (7.2%) of those traced have died. These data constitute a unique record of
      the health and physical development of a large cohort of students from Glasgow.
      Follow-up to investigate the relationship between indices of health and
      development, (height, weight, blood pressure), health behaviours and social
      circumstances in childhood and young adulthood, and mortality and morbidity in
      later adulthood is under way.

PMID- 10637518
TI  - Blood pressure and birthweight in first year university students aged 18-25.
AB  - There have been many papers examining the relationship between blood pressure and
      birthweight but although the association is clearly established in adults and
      children findings in adolescence and young adults have been inconsistent. The
      objective of this study was to examine the relationship between blood pressure
      and birthweight in young adults. The blood pressure of 1358 university students
      aged 18-25 was recorded at a screening medical examination and their birthweight
      from parental report. Using linear regression analysis, systolic blood pressure,
      after adjustment for age, weight and height, decreased by 2.00 mmHg (-3.8, -0.2)
      for every kg increase in birthweight in females. The relationship was negative
      but non-significant in males. Substituting body mass index (BMI) for weight in
      the regression analysis produced similar results. There was a smaller and non
      significant relationship between diastolic blood pressure and birthweight which
      is consistent with other studies. This study confirms the inverse relationship
      between systolic blood pressure and birthweight in young adults and provides some
      support for the hypothesis that undernutrition in utero contributes to the
      development of cardiovascular disease in adults.

PMID- 10637519
TI  - Ten-year trends in all-cause mortality and coronary heart disease mortality in
      socio-economically diverse neighbourhoods.
AB  - OBJECTIVE: Although all-cause mortality and coronary heart disease (CHD)
      mortality is declining in Sweden, as in most other countries in the
      industrialised world, we have limited information about the distribution and
      trends of mortality in deprived and affluent neighbourhoods. DESIGN: This study
      analyses the extent to which the decline in all-cause mortality and CHD mortality
      (over the age range 25-74 y) differs between affluent and deprived neighbourhoods
      during the decade 1984-1993. Incidence density ratios (IDR), estimated by Poisson
      regression, were calculated for small areas, grouped into population deciles, by
      both the care need index (CNI) and the Townsend deprivation score. On average,
      there were about 14 500 residents and 560 deaths in each decile over the period.
      SETTING: A large Swedish city. MAIN OUTCOME MEASURES: All-cause mortality and
      mortality from CHD. RESULTS: The most deprived neighbourhoods had the highest IDR
      for all-cause mortality and CHD mortality. Over the period from 1984-1988 to 1989
      1993 there was an overall decrease in all-cause mortality and CHD mortality,
      which was significantly higher in the most affluent areas. The mortality ratios
      for the most deprived neighbourhoods were almost three times higher than those of
      the most affluent areas. CONCLUSIONS: People liviing in more affluent
      neighbourhoods have had the benefit of most of the last decade's decline in CHD
      mortality.

PMID- 10637520
TI  - Using routine accident and emergency department data to describe local injury
      epidemiology.
AB  - All 17330 Accident and Emergency Department (A and E) attendances following
      injury (67% of all A and E attendances by residents of the EH54 postcode (the
      town of Livingston) at St John's Hospital during 1995 and 1996 were examined to
      study local accident epidemiology. The overall annual injury attendance rate for
      males (245.7/1000) and females (148.0/1000) and sex and age group analyses show
      recognised patterns reflecting occupation and domestic circumstances. Higher
      attendance rates were associated with greater deprivation and living close to the
      hospital. The unique injury coding system used by the hospital offers the
      potential to highlight particular injury types occurring within population sub
      groups. When linked with primary care and out-of-hours centre data, this could be
      useful in targeting preventive activities; this will be facilitated in this
      hospital, which will become part of a 'combined' acute and primary care trust
      from April 1999.

PMID- 10637521
TI  - Patterns of unintentional injury in childhood and their relation to socio
      economic factors.
AB  - OBJECTIVE: To estimate the rate of childhood injury resulting in attendance at
      Accident and Emergency Departments, to describe the types of accidents and
      injuries seen and to relate these to socio-economic indices for ward of
      residence. METHODS: Data were collected from Accident and Emergency records, on
      every fifth day for a year, for children 0-14 y, who attended following
      unintentional injury and were resident within the study area. RESULTS: 1147
      children fulfilled the inclusion criteria. The annual rate of attendance was
      138.2 per 1000. There was a higher rate of attendance in boys than in girls in
      all age groups and the gender difference was particularly marked for severe
      injuries. Social deprivation, measured by Townsend score, of ward of residence
      was a powerful predictor of risk of attendance; accounting for 33% of the
      variance between wards. CONCLUSION: Unintentional injury results in high rates of
      attendance at Accident and Emergency Departments although the rates in this
      community were substantially lower than those reported from elsewhere in the
      United Kingdom. Risk of injury was strongly related to social disadvantage.
      District based data collection can be used to facilitate the development of
      priorities and a locally applicable safety agenda for children.

PMID- 10637522
TI  - Environmental tobacco smoke interference in the assessment of the health impact
      of a municipal waste incinerator on children through urinary thioether assay.
AB  - The urinary elimination of thioethers urinary thioethers (UT) was studied in 83
      schoolchildren living in two different areas of the city of Mataro, with special
      attention paid to the influence of a waste incinerator and of the smoking habits
      of their parents. The mean UT values were 8.79+/-3.23 and 7.52+/-3.23 mmol/mol
      creatinine in the area close to the incinerator (A1) and in the area far away
      from it (A2) respectively (statistically n.s.). Children exposed to environmental
      tobacco smoke (ETS) at home presented increased levels of UT (8.60+/-3.11 vs
      5.93+/-3.22 mmol/mol creatinine; P=0.002). Considering the two exposures together
      (waste incinerator and ETS), no differences were found between the two areas
      studied (A1 and A2) in non-exposed (ETS) children, whereas slight differences
      were found when comparing highest ETS exposed children from the two areas (10.
      18+/-2.70 vs 8.00+/-3.42 mmol/mol creatinine; P=0.04). Exposure to ETS could
      affect health more than pollutants from a waste incinerator and may interfere
      with non-selective assays such as urinary thioethers.

PMID- 10637524
TI  - Effect of child labour on growth of children.
AB  - This community based group comparison study was undertaken to assess the effect
      of child labour on the growth of children. The study subjects were 223 child
      labourers aged between 8-15 y who were matched by age to an equal number of
      controls and pair matched for gender. The mean weight of the male child labourers
      and the controls increased from 23.8 (+/-5.9) to 41.2 (+/-9.7) kg and 23.9 (+/
      4.8) to 44.4 (+/-10.3) kg respectively, while mean height increased from 121.5
      (+/-12.6) to 151.9 (+/-10.6) cm and 122.0 (+/-8.4) to 154.8 (+/-10.8) cm
      respectively from 8-15 y. At older ages (12 y and above for weight and 14 y and
      above for height) the difference was statistically significant. The same was not
      observed for the female study subjects. Similarly standard deviation (s.d.)
      scores for weight for age and height for age of male comparison subjects was
      significantly (P<0.01) nearer to National Centre for Health Statistics (NCHS)
      standard than that of the child labourers. Body mass index (BMI) below normal
      value, that is, 18.5 was observed in significantly (P=0.0261) more child
      labourers 180 (80.7%) than controls 160 (71.1%). With increasing duration of
      employment BMI decreased from 18.1 (+/-3.5) to 17.3 (+/-2.2). Genital development
      was observed to be delayed significantly in male child labourers. Therefore, it
      can be concluded that labouring at a young age has a deleterious effect on the
      growth of the child.

PMID- 10637525
TI  - Health care for the disadvantaged: some preliminary observations of health
      centres in Trinidad and Tobago.
AB  - This study seeks to identify background characteristics of the people who utilise
      health centre services in Trinidad and Tobago and to investigate their
      perceptions of the services offered. Data were obtained through a survey of
      health centre users distributed throughout Trinidad and Tobago. Multi-stage
      sampling was used to select 1500 health centre users and structured interviews
      were conducted on regular clinic days by trained personnel. Results indicate that
      there are fairly high levels of patient satisfaction with health centres in
      Trinidad and Tobago and that the more disadvantaged groups (the elderly, women
      and the unemployed) utilise these services more frequently. Results also show
      variations with respect to care received, frequency of attendance, amount willing
      to pay, services that need improving and doctor's willingness to listen to
      problems.

PMID- 10637523
TI  - The relationship between maternal work and other socioeconomic factors and child
      health in Bangladesh.
AB  - The relationship between maternal work status, other socio-economic factors, and
      incidence of diarrhoea among children was studied using the Bangladesh
      Demographic and Health Survey (DHS) 1994 data. This study showed that 12.4% of
      children had suffered from diarrhoea in the two weeks preceding the survey. Of
      the women in the sample, 12% were working. Logistic regression analysis revealed
      that children of working mothers were 65% more likely to have had diarrhoea than
      children of non-working mothers. We also found that children of women who work
      seasonally were 8% less likely to have had diarrhoea than children of women who
      work all year. Women's higher education was found to be one of the important
      determinants related to childhood diarrhoea. Religion and ownership of land also
      appeared to be important factors affecting the incidence of diarrhoea in early
      childhood.

PMID- 10637526
TI  - Differential protective effect of bacillus Calmette-Guerin vaccine against
      multibacillary and paucibacillary leprosy in Nagpur, India.
AB  - For this paper we conducted a secondary data analysis to test the hypothesis that
      a linear trend exists in the protective effect of bacillus Calmette-Guerin (BCG)
      vaccine against types of leprosy. We used data from two previous case-control
      studies to perform an unmatched test for linear trend. We observed that both the
      studies revealed a significant linear trend (P<0.00001). One study that estimated
      an insignificant protective effect of BCG against paucibacillary leprosy showed a
      significant departure from linearity. We conclude that, the protective effect of
      BCG vaccination is differential across severity of leprosy as it brings about a
      shift in the immune response to a higher level of cell mediated immunity. We
      recommend that future studies dealing with the protective effect of BCG against
      leprosy should also conduct an analysis for trend.

PMID- 10637528
TI  - Evolution in health and disease

PMID- 10637527
TI  - Combined antiviral treatment in HIV infection. Is it value for money?
AB  - There is compelling evidence that combinations of antiretroviral drugs are
      significantly more effective than monotherapy and appear, at least in the short
      run, to offset problems caused by the rapid emergence of drug resistance which is
      characteristic of human immunodeficiency virus (HIV) infection.1,2 The routine
      prescribing of combination antiretroviral therapy appears to have contributed to
      a fall in HIV-related in-patient admissions, mortality and morbidity, with a
      concomitant increase in pharmacy costs. In this paper we have attempted to
      determine to what extent the reduction in direct hospital costs (reduced in
      patient admissions, diagnostic tests and management of complications) will offset
      the considerably increased pharmacy costs; by using Markhov modelling procedures
      together with locally gathered costs data.

PMID- 10637530
TI  - Keyword index to volume 113

PMID- 10637531
TI  - The respiratory effects of volatile organic compounds.
AB  - Volatile organic compounds (VOCs) have been implicated as causative agents in
      asthma and building-related illness. To determine whether a mixture of VOCs could
      impair lung function or cause airway inflammation among subjects without
      bronchial hyperresponsiveness, the authors conducted a randomized, crossover
      design trial of controlled human exposures to filtered air for four hours, VOCs
      at 25 mg/m(3) for four hours, and VOCs at 50 mg/m(3) for four hours, using a VOC
      mixture based on sampling of indoor environments. VOC exposures caused dose
      related increases in lower respiratory, upper respiratory, and non-respiratory
      symptoms, with no significant change in lung function (FEV(1);, FVC, or FEF(25
      75), nasal lavage cellularity or differential cell counts, induced sputum
      cellularity or differential cell counts, or biomarkers of airway inflammation,
      including IL-8, LTB(4), or albumin in nasal lavage or induced sputum samples.
      Atopic individuals had significantly reduced FEE(25-75 following exposure to VOCs
      at 50 mg/m(3), suggesting that these individuals may be more sensitive to the
      health effects of VOCs. The authors conclude that reductions in levels of VOCs to
      substantially less than 25 mg/m(3) are required if a "non-irritating" work
      environment is desired.

PMID- 10637532
TI  - Prevalence of assault and perception of risk of assault in urban public service
      employment settings.
AB  - This study describes the prevalence and correlates of physical assaults, threats
      of assault, and workers' perceptions of safety in selected urban employment
      settings. Questionnaires were mailed to a random sample of 1,763 persons working
      at various jobs and sites throughout Los Angeles County. Workers were asked to
      describe their work environments, their perceptions of personal safety at work,
      and physical assaults and threats they had experienced. Three percent of the
      respondents reported being assaulted within the previous year and 14% reported
      being threatened within the previous 30 days. Younger workers, more educated
      workers, and those who worked with clients or patients were more likely to report
      assaults. Approximately one third of those who reported threats or assaults
      described the perpetrator(s) as clients, patients, or persons in legal custody,
      and one third described the perpetrator(s) as co-workers or supervisors. Fifty
      two percent of the workers reported being concerned about their safety at work.

PMID- 10637533
TI  - Safety climate and its association with injuries and safety practices in public
      hospitals in Costa Rica.
AB  - In response to growing concern for occupational health and safety in the public
      hospital system in Costa Rica, a cross-sectional survey of 1,000 hospital-based
      health care workers was conducted in 1997 to collect baseline data that are being
      used to develop worker training programs in occupational health in Costa Rica.
      The objectives of this survey were to: 1) describe the safety climate within the
      national hospital system, 2) identify factors associated with safety, and 3)
      evaluate the relationship between safety climate and workplace injuries and
      safety practices of employees. The safety climate was found to be very poor. The
      two most significant predictors of safety climate were training and
      administrative support for safety. Safety climate was a statistically significant
      predictor of workplace injuries and safety practices, respectively, and there was
      an underreporting rate of 71% of workplace injuries. These findings underscore
      the need for improvement of the safety climate in the public hospital system in
      Costa Rica.

PMID- 10637534
TI  - Risk factors for work-related low back pain in the People's Republic of China.
AB  - A critical review was conducted of studies of work-related low back pain in the
      People's Republic of China. The published literature in both the English and
      Chinese languages from 1983 to 1997 was reviewed for studies that permitted the
      calculation of prevalence ratios. Thirty-five papers were identified initially,
      and after quality inclusion/exclusion criteria were applied, 16 (14 in Chinese
      and two in English) were selected for more detailed review. Prevalence ratios
      were statistically elevated in all but two of the selected studies. Prevalence
      ratios for individual groups ranged from 2.0 to 8.5 for bending and twisting, 1.5
      to 14.3 for static posture, 1.9 to 5.5 for whole-body vibration, and 2.6 to 9.4
      for low-temperature exposure. The literature was limited by the absence of
      standardized and robust measures of low-back-pain outcomes and exposures and by
      the omission of fundamental details from research reports. Even with these
      limitations, the review findings suggest that three physical risk factors, all
      well known in the international literature, are associated with the prevalence of
      low back pain in the People's Republic of China.

PMID- 10637535
TI  - Health-risk perception in the inner city community of Centro Habana, Cuba.
AB  - Perceptions of health risks were surveyed in the inner city of Centro Habana,
      Cuba. A questionnaire developed by community leaders and experts was administered
      to 348 residents to determine the level of perceived risk for each of 41 risk
      items. Ecologic-level data on morbidity, mortality, and environmental indicators
      were also gathered. Using factor analysis to reduce the dimensionality of the
      data, five factor groupings accounted for 60% of the variance, as follows: social
      environment (40.8%); infectious agents and other health-risk factors of immediate
      concern (6.1%); lifestyle risks (4. 9%); environmental sanitation (4.1%); and
      living conditions (3.3%). A relationship between the perception of risk and the
      ecologic data was found, with inconsistencies largely attributable to factors
      known to influence risk perception. The greatest concern identified throughout
      the municipality was housing conditions, highest in the neighborhood that had
      already begun to address this problem. The analysis was useful in planning
      targeted health promotion campaigns and prioritizing further interventions.
      Repeat evaluation of risk perception will be conducted following the completion
      of interventions.

PMID- 10637536
TI  - Musculoskeletal symptoms among women currently and formerly working in fish
      filleting plants.
AB  - The authors surveyed women currently or formerly working in fish-filleting plants
      to evaluate their musculoskeletal symptoms, using the standardized Nordic
      Questionnaire on musculoskeletal symptoms. The women's work consisted of cutting
      and trimming fish fillets, which were transported to and from the work stations
      by conveyor belts. The prevalence of musculoskeletal symptoms during the
      preceding 12 months was higher among former than current workers. The Mantel
      Haenszel odds ratio for symptoms of the fingers, ankles, and wrists hindering
      normal work during the preceding 12 months were 7.1 (95% CI 2.8-18.0), 5.3 (95%
      CI 1.3-21.5(, and 3.4 (95% CI 1. 3-8.8), respectively. The higher prevalence of
      musculoskeletal symptoms among those who had stopped working at the fish
      filleting plants than among those continuing to do so indicates a healthy-worker
      selection. There may be a causal relationship between musculoskeletal symptoms
      and ceasing to work at the plants.

PMID- 10637537
TI  - Comparison of N95 disposable filtering facepiece fits using bitrex qualitative
      and TSI Portacount quantitative fit testing.
AB  - As a means of evaluating the use of denatonium benzoate (bitrex) as a qualitative
      fit test agent with filtering facepiece respirators, the bitrex qualitative and
      TSI Protacount(R) quantitative fit-test methods were compared using N95 filtering
      facepieces. Seventy-nine paired tests (trial) were performed. Detection of bitrex
      during a qualitative fit test or measurement of a fit factor of <100 during a
      quantitative fit test constituted a failure. Qualitative and quantitative methods
      were performed using identical test protocols. Data were analyzed using pass/fail
      criteria, and matched-pair analysis methods were applied. The results of this
      study indicate that the use of bitrex during qualitative fit testing of N95
      disposable filtering facepieces results in an increase in failure and/or
      rejection in cases where a TSI Portacount (plus N95 companion accessory)
      quantitatively establishes an acceptable fit.

PMID- 10637538
TI  - Child labor and health: problems and perspectives.
AB  - Child labor remains a widespread problem. Although it can have positive effects,
      in some situations it has negative effects on health and development of the
      children. Although mainly a problem in developing countries, it is also possible
      to find child workers, some working in hazardous activities, in developed
      countries. The authors describe the child labor profiles in developed and
      developing countries, the principal occupations of children, and their
      concomitant hazards. They summarize the epidemiologic evidence for a greater
      impact of some occupational exposures on the health of children as compared with
      adults, and the theoretical concerns about the impact of child labor on health,
      and suggest policies that can be used to combat harmful child labor.

PMID- 10637539
TI  - Drug Discovery Today in 2000.

PMID- 10637540
TI  - Drug discovery today - and tomorrow.

PMID- 10637542
TI  - Protection against chemotherapy- and radiotherapy-induced cell damage.

PMID- 10637541
TI  - Targeting tumours with HSV.

PMID- 10637543
TI  - Selective arginine receptors as antiviral compounds and molecular probes.

PMID- 10637544
TI  - Adenovirus technology for gene manipulation and functional studies.
AB  - Recombinant adenoviral vectors are highly efficient at gene transfer in a broad
      spectrum of cell types and species, and have been used, both in vitro and in
      vivo, to achieve gain or loss of function in functional studies. In recent years,
      there have been several significant advances in adenovirus technologies,
      including new generations of vectors, improved production systems and
      sophisticated methods of delivery. In this review, recent progress and innovative
      applications are discussed to demonstrate the potential of the recombinant
      adenoviral vector as an effective tool in functional genomics.

PMID- 10637545
TI  - Approaches to higher-throughput pharmacokinetics (HTPK) in drug discovery.
AB  - With pressure on pharmaceutical companies to reduce time-to-market and improve
      the success rate of new drug candidates, higher-throughput pharmacokinetic (HTPK)
      support has become an integral part of many drug discovery programmes. This
      report details the amalgamation of robotics, new sample preparation technologies
      and highly sensitive and selective mass spectrometric detection systems to
      deliver the promise of HTPK. A historical perspective on automated bioanalysis
      with the current approaches and future prospects for the discipline are
      described.

PMID- 10637546
TI  - Emerging novel antifungal agents.
AB  - Promising new compounds have recently been identified in an effort to supplement
      the relatively sparse portfolio of antifungal drugs. Many of these compounds have
      defined mechanisms of action against fungal cells and have, in some cases, aided
      the identification of new selective targets in fungi. For most of these
      compounds, however, factors such as a narrow spectrum of activity, susceptibility
      to efflux pumps, protein binding, serum inactivation and poor pharmaceutical
      properties prevent their use in the clinic. Even so, these compounds are novel
      substrates for synthetic modifications that could lead to the discovery of future
      antifungal drugs.

PMID- 10637547
TI  - Monitor: molecules and profiles.
AB  - Monitor provides an insight into the latest developments in drug discovery
      through brief synopses of recent presentations and publications together with
      expert commentaries on the latest technologies. There are two sections: Molecules
      summarizes the chemistry and the pharmacological significance and biological
      relevance of new molecules reported in the literature and on the conference
      scene; Profiles offers commentary on promising lines of research, emerging
      molecular targets, novel technology, advances in synthetic and separation
      techniques and legislative issues.

PMID- 10637548
TI  - Combinatorial Chemistry.

PMID- 10637550
TI  - Validation of genomics-derived drug targets using yeast.

PMID- 10637549
TI  - New safer non-steroidal anti-inflammatory drugs?

PMID- 10637551
TI  - Microdomains in lymphocyte signalling: beyond GPI-anchored proteins.

PMID- 10637552
TI  - Immunobiology of vasoactive intestinal peptide (VIP)

PMID- 10637553
TI  - Limiting dilution analysis: from frequencies to cellular interactions.

PMID- 10637554
TI  - Is pathogenic humoral autoimmunity a Th1 response? Lessons from (for) myasthenia
      gravis.

PMID- 10637555
TI  - Interferon beta in multiple sclerosis: is IL-12 suppression the key?

PMID- 10637556
TI  - Immunopathology of schistosomiasis: a cautionary tale of mice and men.

PMID- 10637557
TI  - Neonatal immunity: how well has it grown up?

PMID- 10637558
TI  - Pancreatic islet xenotransplantation: the potential for tolerance induction.

PMID- 10637559
TI  - Suicide genes: past, present and future perspectives.

PMID- 10637560
TI  - Jumping or walking: which is better?

PMID- 10637561
TI  - Receptor editing (and the evolution of sex)

PMID- 10637562
TI  - A powerful role for B cells and autoantibodies in disease.

PMID- 10637563
TI  - FISHing for aneuploidies nets accurate results.

PMID- 10637564
TI  - Cancer research explosion imminent.

PMID- 10637565
TI  - PANDA identifies babies at risk of developing type 1 diabetes.

PMID- 10637566
TI  - Dissecting the risk factors for pre-eclampsia.

PMID- 10637567
TI  - Individual haploinsufficient loci and the complex phenotype of DiGeorge syndrome.

PMID- 10637568
TI  - DiGeorge syndrome: complex pathogenesis? Maybe, maybe not.

PMID- 10637569
TI  - DiGeorge syndrome: an enigma in mice and men.

PMID- 10637570
TI  - Causes and consequences of tumour acidity and implications for treatment.
AB  - Tumour cells have a lower extracellular pH (pHe) than normal cells; this is an
      intrinsic feature of the tumour phenotype, caused by alterations either in acid
      export from the tumour cells or in clearance of extracellular acid. Low pHe
      benefits tumour cells because it promotes invasiveness, whereas a high
      intracellular pH (pHi) gives them a competitive advantage over normal cells for
      growth. Molecular genetic approaches have revealed hypoxia-induced coordinated
      upregulation of glycolysis, a potentially important mechanism for establishing
      the metabolic phenotype of tumours. Understanding tumour acidity opens up new
      opportunities for therapy.

PMID- 10637572
TI  - RNA viruses: emerging vectors for vaccination and gene therapy.
AB  - The application of modern molecular techniques has profoundly influenced our
      understanding of virus function. As a consequence, virus biology is being
      directly applied to medical research. It is a reflection of the current pace of
      virology that we are now beginning to think of our ancient foes as useful and
      beneficial tools.

PMID- 10637571
TI  - Eotaxin and eosinophil recruitment: implications for human disease.
AB  - Eosinophils have been implicated in a broad range of diseases, notably allergic
      conditions (for example, asthma, rhinitis and atopic dermatitis) and other
      inflammatory disorders (for example, inflammatory bowel disease, eosinophilic
      gastroenteritis and pneumonia). These disease states are characterized by an
      accumulation of eosinophils in tissues. Severe tissue damage ensues as
      eosinophils release their highly cytotoxic granular proteins. Defining the
      mechanisms that control recruitment of eosinophils to tissues is fundamental to
      understanding these disease processes and provides targets for novel drug
      therapy. An important discovery in this context was the identification of an
      eosinophil-specific chemoattractant, eotaxin. Over the past six years there has
      been intensive investigation into the biological effects of eotaxin and its role
      in specific disease processes and this is the subject of this review.

PMID- 10637573
TI  - Recent advances in understanding the molecular basis of primary congenital
      hypothyroidism.
AB  - Primary congenital hypothyroidism is characterized by low levels of circulating
      thyroid hormones and raised levels of thyrotropin at birth. It can be either
      permanent or transitory. Most permanent cases (80-85%) result from alterations in
      the formation of the thyroid gland during embryogenesis (thyroid dysgenesis), and
      several were shown recently to be produced by mutations in genes responsible for
      the development of thyroid follicular cells (TITF1, TITF2, PAX8 and TSHR). Less
      frequently, congenital hypothyroidism is determined by defects in thyroid hormone
      synthesis (hormonogenesis defects). The latter are usually associated with
      goiter. Recently, the molecular mechanisms of two forms of hormonogenesis defects
      (iodine transport defects and Pendred syndrome) were elucidated.

PMID- 10637574
TI  - An animal model of attention deficit hyperactivity disorder.

PMID- 10637576
TI  - New insights into platyhelminth systematics and evolution.

PMID- 10637575
TI  - Parasitology: the dawn of a new millennium.

PMID- 10637577
TI  - Molecular helminthology moves forward.

PMID- 10637578
TI  - Molecular entomology in Africa.

PMID- 10637580
TI  - Journals, Sex Life and Swimmer's Itch Online.

PMID- 10637579
TI  - Anti-sleeping sickness drugs and cancer chemotherapy.

PMID- 10637581
TI  - Transglutaminase-catalyzed reactions in the growth, maturation and development of
      parasitic nematodes.
AB  - Parasitic nematodes cause several debilitating diseases in humans and animals.
      New drugs that are parasite specific and minimally toxic to the host are needed
      to counter these infections effectively. The identification and inhibition of
      enzymes that are vital for the growth and survival of parasites offer new
      approaches for developing effective chemotherapeutic agents. Several enzymes in
      nematodes fall into this category. Here, Ramaswamy Chandrashekar and Kapil Mehta
      examine in detail the role of transglutaminase, a protein-crosslinking enzyme, in
      the normal growth and development of nematodes, with an emphasis on filarial
      parasites.

PMID- 10637582
TI  - Websites of Interest.

PMID- 10637583
TI  - Maintaining the immunological balance in parasitic infections: a role for TGF
      beta?
AB  - Transforming growth factor beta (TGF-beta) is an important regulator of
      inflammation, being proinflammatory at low concentrations and anti-inflammatory
      at high concentrations. As such, TGF-beta might be important in maintaining the
      balance between control and clearance of infectious organisms on the one hand and
      prevention of immune-mediated pathology on the other. In this article,
      Fakhereldin Omer, Jorgen Kurtzhals and Eleanor Riley review the immunoregulatory
      properties of TGF-beta in the context of parasitic infections. Data from murine
      malaria infections suggest that TGF-beta modifies the severity of the disease,
      and a number of potential protective mechanisms are discussed. Evidence is
      accumulating that TGF-beta is important for the regulation of other host-parasite
      interactions and that parasites might directly influence TGF-beta-dependent
      pathways via the synthesis of TGF-beta or TGF-beta-receptor homologues.

PMID- 10637584
TI  - Extracellular matrix-induced signaling in Entamoeba histolytica: its role in
      invasiveness.
AB  - Entamoeba histolytica trophozoites can invade the mucosa of the host large
      intestine to cause disease. Here, Isaura Meza describes recent work indicating
      that the trophozoites respond to the binding of extracellular matrix proteins by
      activating receptor-mediated signal transduction pathways. Activation of
      phosphokinase C or adenylyl cyclase induces protein phosphorylation, actin gene
      expression and reorganization of the actin cytoskeleton to form adhesive
      structures that promote interaction with the substrate and the release of
      proteases. The release of proteases at the sites of contact, with the subsequent
      degradation of the substrate and generation of chemotactic peptides, facilitates
      locomotion and dissemination of the invading trophozoites.

PMID- 10637585
TI  - Malaria multigene families: the price of chronicity.
AB  - In this article, Georges Snounou, William Jarra and Peter Preiser discuss the
      survival strategy of malaria parasites in the light of a novel mechanism of
      clonal phenotypic variation recently described for a multigene family of
      Plasmodium yoelii yoelii. The 235 kDa rhoptry proteins (Py235) encoded by these
      genes may be involved in the selection of red blood cells for invasion by
      merozoites. The new mechanism may explain the ability of individual parasites to
      adapt to natural variations in red blood cell subsets, while ensuring that
      sufficient merozoites escape immune attack, thus maintaining a chronic infection
      for extended periods. This counterpoints the antigenic variation exemplified by
      PfEMP1 proteins (a large family of proteins derived from P. falciparum), which
      operates at the population level. The possibility of manipulating the expression
      of functionally similar genes in other Plasmodium species could lead to therapies
      aimed at reducing clinical severity without compromising the acquisition and
      maintenance of immunity.

PMID- 10637586
TI  - The targets of the lytic antibody response against Trypanosoma cruzi.
AB  - Trypanosoma cruzi trypomastigotes, but not epimastigotes, are normally resistant
      to the lytic effects of complement from vertebrate hosts susceptible to
      infection. This resistance facilitates parasite survival and infectivity. During
      the course of chronic infections, however, the vertebrate hosts produce
      antibodies that render the trypomastigotes sensitive to lysis, primarily via the
      alternative complement cascade and amplified by the classical pathway. Here,
      Greice Krautz, Jessica Kissinger and Antoniana Krettli summarize research on
      lytic antibodies, and on their respective target(s) on the T. cruzi surface.
      These targets are useful in tests aimed at the diagnosis of chronic Chagas
      disease for control of cure after specific treatment and for vaccine development.

PMID- 10637587
TI  - Cyclic AMP signaling in trypanosomatids.
AB  - Curative interference with signal transduction pathways is a spectacularly
      successful concept in many domains of modern pharmacology; indeed, the 'wonder
      drug' Viagra is but a humble inhibitor of a cyclic GMP (cGMP)-specific
      phosphodiesterase and, thus, interferes with cGMP-signaling in a strategic organ.
      In fact, about half of the 100 most successful drugs currently on the market act
      through modulating cellular signal transduction. Despite these encouraging
      findings, signal transduction pathways as potential drug targets in
      trypanosomatids have remained largely unexplored. However, what little is known
      indicates that adenylyl cyclases of trypanosomatids, and probably other enzymes
      of the cyclic nucleotide signaling pathways, are significantly different from
      their mammalian counterparts. Here, Christina Naula and Thomas Seebeck summarize
      what is known about cAMP signal transduction in trypanosomatids.

PMID- 10637589
TI  - Reply.

PMID- 10637588
TI  - More on protein glycosylation in the malaria parasite.

PMID- 10637590
TI  - On the use of single-cell fluorescence imaging for the measurement of
      intracellular ion concentrations.

PMID- 10637591
TI  - SCOPE-Malaria.

PMID- 10637592
TI  - How to survive in tomorrow's healthcare market.

PMID- 10637593
TI  - Anti-vascular targeting: a novel approach to cancer treatment.

PMID- 10637595
TI  - US licence for COMT inhibitor to boost levodopa effect in Parkinson's.

PMID- 10637594
TI  - Avoiding adverse modification of cardiac repolarization.

PMID- 10637596
TI  - Application of isothermal microcalorimetry in solid state drug development.
AB  - Microcalorimetry is an analytical technique that has found numerous applications
      within the pharmaceutical environment. In the realm of pharmaceutics, especially
      solid state pharmaceutics, the technique has proved to be an invaluable tool.
      This review addresses the solid state applications of microcalorimetry within the
      pharmaceutical industry, with a specific focus on stability, compatibility and
      amorphicity determinations.

PMID- 10637597
TI  - Human airway epithelial cell lines for in vitro drug transport and metabolism
      studies.
AB  - The pharmaceutical industry relies on appropriate in vitro models for the
      evaluation of drug absorption and metabolism. Despite increasing interest in drug
      delivery via the lung, there is currently no widely accepted cell culture model
      of the airway epithelium. This review considers the airway epithelium, the
      culture of airway epithelial cells and the need for cell lines which can model
      the airway epithelium. Three of the most promising human bronchial cell lines,
      16HBE14o-, Calu-3 and BEAS-2B, are reviewed, with emphasis on their recent
      application for the study of drug transport, drug metabolism and gene delivery.
      Current limitations and future directions for the development of these cell lines
      as models of the airway epithelium are discussed.

PMID- 10637598
TI  - Quantitative structure-property relationships in pharmaceutical research - Part
      1.
AB  - Quantitative structure-activity relationships (QSAR) have been applied for
      decades in the development of new drugs. Although a QSAR does not completely
      eliminate the trial and error factor involved in the development of a new drug,
      it certainly decreases the number of compounds synthesized by facilitating the
      selection of the most promising examples. The success of QSAR has tempted
      scientists, particularly in the pharmaceutical arena, to investigate
      relationships of molecular parameters with properties other than activity. The
      purpose of this two-part review is to provide a broad overview of the development
      of quantitative structure-property relationships (QSPR) and review the
      applications in pharmaceutical research. Part one discusses the advantages and
      limitations of QSPR, and various types of structural descriptors and properties,
      together with techniques to establish correlations between the two.

PMID- 10637599
TI  - Percutaneous penetration enhancers: local versus transdermal activity.
AB  - The stratum corneum, poses a formidable challenge to formulators of drug delivery
      systems. Several approaches have been utilized to facilitate entry of drugs into
      the lower skin layers. Traditionally, permeation enhancers were designed to
      deliver high drug concentrations across the skin into the systemic circulation.
      The use of many of these agents resulted in unpleasant or toxic side effects.
      However, in recent years there has been a search for compounds that exhibit low
      toxicity, and maintain their enhancing activity. More recently, there has been
      interest in agents that may be used in topical formulations to prevent the
      passage of active ingredients or excipients into the lower skin layers. These so
      called skin retardants have potential uses in many over-the-counter (OTC) skin
      formulations, such as sunscreens and pesticides, where the site of action is
      restricted to the skin surface or upper skin layers. Research in the area of
      permeation enhancement or retardation is yielding valuable insights into the
      structure-activity relationships of enhancers as well as retardants.

PMID- 10637600
TI  - Monitor: progress and profiles.
AB  - Monitor provides an insight into the latest developments in pharmaceutical
      science and technology through brief synopses of recent presentations,
      publications and patents, and expert commentaries on the latest technologies.
      There are two sections: Progress summarizes the latest developments in
      pharmaceutical process technology, formulation, analytical technology,
      sterilization, controlled drug delivery systems and regulatory issues; Profiles
      offers expert commentary on emerging technologies, novel processes and strategic,
      organizational and logistic issues underlying pharmaceutical R&D.

PMID- 10637601
TI  - Multiple physiological functions for multidrug transporter P-glycoprotein?
AB  - Multidrug resistance mediated by the drug-efflux protein P-glycoprotein (P-gp) is
      one mechanism that tumor cells use to escape death induced by chemotherapeutic
      drugs. Although it is irrefutable that P-gp can efflux xenobiotics out of cells,
      biological regulatory functions for P-gp in multicellular organisms have yet to
      be established firmly. Recent observations have challenged the notion that P-gp
      has evolved merely to efflux xenotoxins out of healthy cells and raised the
      possibility that P-gp and related transporter molecules might play a fundamental
      role in regulating cell differentiation, proliferation and survival.

PMID- 10637602
TI  - Dimerization in MAP-kinase signaling.
AB  - The stimulus-dependent nuclear localization of the extracellular-signal-
      regulated kinases ERK1 and ERK2 is required for many of their actions, including
      induction of neurites in PC12 cells and transformation of fibroblasts.
      Phosphorylation of ERK2 causes it to form dimers, and the most flexible portions
      of the ERK2 molecule provide the surfaces for dimerization. It is thought that
      dimerization promotes nuclear localization of ERK2 by its effects on import,
      export or retention in cytoplasmic and nuclear compartments. Dimerization might
      also influence substrate interactions.

PMID- 10637603
TI  - Thomas P. Singer (1920-1999)

PMID- 10637604
TI  - Cell-cycle regulatory proteins Hsl7p/Skb1p belong to the protein
      methyltransferase superfamily.

PMID- 10637605
TI  - The WIF module.

PMID- 10637606
TI  - Transcription factor series

PMID- 10637607
TI  - The many HATs of transcription coactivators.
AB  - Histone acetylation is closely linked to gene transcription. The identification
      of histone acetyltransferases (HATs) and the large multiprotein complexes in
      which they reside has yielded important insights into how these enzymes regulate
      transcription. The demonstration that HAT complexes interact with sequence
      specific activator proteins illustrates how these complexes target specific
      genes. In addition to histones, some HATs can acetylate non-histone proteins
      suggesting multiple roles for these enzymes.

PMID- 10637608
TI  - Regulating actin-filament dynamics in vivo.
AB  - The assembly and disassembly (i.e. turnover) of actin filaments in response to
      extracellular signals underlie a wide variety of basic cellular processes such as
      cell division, endocytosis and motility. The bulk turnover of subunits is 100-200
      times faster in cells than with pure actin, suggesting a complex regulation in
      vivo. Significant progress has been made recently in identifying and clarifying
      the roles of several cellular proteins that coordinately regulate actin-filament
      turnover.

PMID- 10637609
TI  - GHKL, an emergent ATPase/kinase superfamily.
AB  - An interesting recent development is the recognition of a novel ATP-binding
      superfamily that includes diverse protein families such as DNA topoisomerase II,
      molecular chaperones Hsp90, DNA-mismatch-repair enzymes MutL and histidine
      kinases. The most singular unifying feature of this superfamily is the
      unconventional Bergerat ATP-binding fold. The far-reaching significance of this
      commonality is still in the process of being explored.

PMID- 10637610
TI  - Intracellular copper routing: the role of copper chaperones.
AB  - Copper is required by all living systems. Cells have a variety of mechanisms to
      deal with this essential, yet toxic trace element. A recently discovered facet of
      homeostatic mechanisms is the protein-mediated, intracellular delivery of copper
      to target proteins. This routing is accomplished by a novel class of proteins,
      the 'copper chaperones'. They are a family of conserved proteins present in
      prokaryotes and eukaryotes, which suggests that copper chaperones are used
      throughout nature for intracellular copper routing.

PMID- 10637612
TI  - P2Y-receptor-ligand database.

PMID- 10637611
TI  - The GeneQuiz web server: protein functional analysis through the Web.

PMID- 10637613
TI  - The origin and the meaning of the little p in pH.

PMID- 10637614
TI  - What constrains the organization of the ventral temporal cortex?

PMID- 10637616
TI  - Lexical memory.

PMID- 10637615
TI  - Object-form topology in the ventral temporal lobeResponse to I. Gauthier (2000).

PMID- 10637617
TI  - Saccadic eye movements and cognition.
AB  - Scanning of the visual scene is an important selective process in visual
      perception. In this article we argue that eye-movement data provide an excellent
      on-line indication of the cognitive processes underlying visual search and
      reading. We outline some recent advances from physiological investigations of
      saccadic eye-movement control before focusing on eye-movement behaviour in visual
      search and reading studies. We consider factors that can affect the duration of
      fixations and the choice of saccade targets, emphasising continuities between
      biological and cognitive descriptions. We discuss different ways of measuring
      cognitive processing time from an eye-movement record and the relationship
      between attention and eye movements.

PMID- 10637618
TI  - Philosophical conceptions of the self: implications for cognitive science.
AB  - Several recently developed philosophical approaches to the self promise to
      enhance the exchange of ideas between the philosophy of the mind and the other
      cognitive sciences. This review examines two important concepts of self: the
      'minimal self', a self devoid of temporal extension, and the 'narrative self',
      which involves personal identity and continuity across time. The notion of a
      minimal self is first clarified by drawing a distinction between the sense of
      self-agency and the sense of self-ownership for actions. This distinction is then
      explored within the neurological domain with specific reference to schizophrenia,
      in which the sense of self-agency may be disrupted. The convergence between the
      philosophical debate and empirical study is extended in a discussion of more
      primitive aspects of self and how these relate to neonatal experience and
      robotics. The second concept of self, the narrative self, is discussed in the
      light of Gazzaniga's left-hemisphere 'interpreter' and episodic memory.
      Extensions of the idea of a narrative self that are consistent with neurological
      models are then considered. The review illustrates how the philosophical approach
      can inform cognitive science and suggests that a two-way collaboration may lead
      to a more fully developed account of the self.

PMID- 10637619
TI  - The recognition of mentalistic agents in infancy.
AB  - The ability to construe ourselves and others as agents with minds having mental
      states such as perceptions, attention, desires and beliefs, is critical to
      humans' social, linguistic, and cognitive competence. When and how this ability
      becomes available to us during development is therefore of particular theoretical
      importance. Historically, most work in this area has concentrated on the ability
      of three- and four-year-olds to predict and explain behaviors based on false
      beliefs. With recent advances in the methods available for studying cognition in
      pre-verbal infants however, more research is now focused on earlier age groups.
      In this review, arguments are presented for and against the presence of a
      rudimentary 'theory of mind' in infancy, with evidence discussed from three
      sources: (1) infants' active interactions with people; (2) infants' passive
      observations of people; and (3) infants' interactions with, and observations, of
      non-human agents.

PMID- 10637620
TI  - Exploring the natural foundations of religion.
AB  - A new cognitive approach to religion is bringing fresh insights to our
      understanding of how religious concepts are maintained, acquired and used to
      motivate and direct actions. This approach suggests that seemingly extraordinary
      thoughts and behaviours can be supported by quite ordinary cognition and may thus
      be termed 'natural'. Simultaneously, this research is expanding the domain of
      concepts and causal reasoning in general. This review examines recent research
      into religious rituals, communication and transmission of religious knowledge,
      the development of god-concepts in children, and the origins and character of
      religious concepts in adults. Together, these studies consistently emphasize and
      support the notion that the cultural phenomena typically labeled as 'religion'
      may be understood as the product of aggregated ordinary cognition. The new
      cognitive science of religion should eventually provide a fuller account of the
      distinctive and apparently extraordinary properties of religion.

PMID- 10637621
TI  - Origin of anterior patterning. How old is our head?
AB  - Most animals that display a bilateral symmetry (bilaterians) share homologous
      regulatory genes involved in head development. Recently, homologues of several of
      these genes have been cloned from animals that are radially organized, such as
      coral, sea anemones, jellyfish or hydra (cnidarians). Surprisingly, some of these
      are expressed apically and/or during apical patterning in hydrozoans, suggesting
      that head patterning is much older than previously thought.

PMID- 10637622
TI  - Mass spectrometry. From genomics to proteomics.
AB  - Large-scale DNA sequencing has stimulated the development of proteomics by
      providing a sequence infrastructure for protein analysis. Rapid and automated
      protein identification can be achieved by searching protein and nucleotide
      sequence databases directly with data generated by mass spectrometry. A high
      throughput and large-scale approach to identifying proteins has been the result.
      These technological changes have advanced protein expression studies and the
      identification of proteins in complexes, two types of studies that are essential
      in deciphering the networks of proteins that are involved in biological
      processes.

PMID- 10637623
TI  - Genome evolution. Gene fusion versus gene fission.

PMID- 10637624
TI  - The glnKamtB operon. A conserved gene pair in prokaryotes.

PMID- 10637626
TI  - Reply: certain uncertainties about the origin of the genetic code.

PMID- 10637625
TI  - The RNA world, the genetic code and the tRNA molecule.

PMID- 10637627
TI  - Cuticle collagen genes. Expression in Caenorhabditis elegans.
AB  - Collagen is a structural protein used in the generation of a wide variety of
      animal extracellular matrices. The exoskeleton of the free-living nematode,
      Caenorhabditis elegans, is a complex collagen matrix that is tractable to genetic
      research. Mutations in individual cuticle collagen genes can cause exoskeletal
      defects that alter the shape of the animal. The complete sequence of the C.
      elegans genome indicates upwards of 150 distinct collagen genes that probably
      contribute to this structure. During the synthesis of this matrix, individual
      collagen genes are expressed in distinct temporal periods, which might facilitate
      the formation of specific interactions between distinct collagens.

PMID- 10637628
TI  - TGF beta-related pathways. Roles in Caenorhabditis elegans development.
AB  - Genetic and molecular analysis in Caenorhabditis elegans has produced new
      insights into how TGF beta-related pathways transduce signals and the
      developmental processes in which they function. These pathways are essential
      regulators of dauer formation, body-size determination, male copulatory
      structures and axonal guidance. Here, we review the insights that have come from
      standard molecular genetic experiments and discuss how the recently completed
      genome sequence has contributed to our understanding of these pathways.

PMID- 10637629
TI  - Drosophila in cancer research. An expanding role.
AB  - In recent years, Drosophila researchers have developed powerful genetic
      techniques that allow for the rapid identification and characterization of genes
      involved in tumor formation and development. The high level of gene and pathway
      conservation, the similarity of cellular processes and the emerging evidence of
      functional conservation of tumor suppressors between Drosophila and mammals,
      argue that studies of tumorigenesis in flies can directly contribute to the
      understanding of human cancer. In this review, we explore the historical and
      current roles of Drosophila in cancer research, as well as speculate on the
      future of Drosophila as a model to investigate cancer-related processes that are
      currently not well understood.

PMID- 10637631
TI  - Introducing RefSeq and LocusLink: curated human genome resources at the NCBI.

PMID- 10637630
TI  - Morphogen gradients. A question of time or concentration?
AB  - Morphogens are secreted proteins that organize surrounding tissues into distinct
      territories and are thought to act as a function of a threshold of their
      concentration. Although it has been demonstrated that morphogens act directly on
      the cells and do not rely on secondary signalling relays, intracellular
      sequential induction mechanisms, which are dependent on a simple signalling
      instruction, have not been excluded. Here, we present an alternative model to
      account for the organizing properties of morphogens, and propose that initial
      exposure to signalling changes cell context, which in combination with continuing
      morphogen activity, results in the expression of novel targets.

PMID- 10637632
TI  - Expanding the prion model for the yeast [PSI+] element.

PMID- 10637634
TI  - Might Candida albicans be made to mate after all?

PMID- 10637635
TI  - Inhibition of prion-protein conversion: a therapeutic tool?

PMID- 10637636
TI  - Stress and sensitivity.

PMID- 10637637
TI  - Response from foster

PMID- 10637638
TI  - Pulling the channel in many dimensions.

PMID- 10637639
TI  - Serotype-converting bacteriophages and O-antigen modification in Shigella
      flexneri.
AB  - O-antigen modification (serotype conversion) in Shigella flexneri, which is an
      important virulence determinant, is conferred by temperate bacteriophages.
      Several serotype-converting phages have been isolated and preliminary
      characterization has identified the genes involved in O-antigen modification, and
      has also provided insight into the molecular biology of these phages.

PMID- 10637640
TI  - How does Mycobacterium leprae target the peripheral nervous system?
AB  - Mycobacterium leprae has the capacity to invade the peripheral nervous system and
      cause neuropathy. The molecular mechanisms responsible have remained unknown
      until recently. Identification of the endoneurial laminin-2 isoform and its
      receptor alpha-dystroglycan as neural targets of M. leprae has not only opened up
      a new area of scientific inquiry into the pathogenesis of neurological damage in
      leprosy, but has also revealed unexpected biological properties of these
      important host molecules.

PMID- 10637641
TI  - Phosphatases and kinases delivered to the host cell by bacterial pathogens.
AB  - The gram-negative type III secretion pathway translocates bacterial proteins
      directly into eukaryotic host cells, thus allowing a pathogen to interfere
      directly with host signalling pathways. Protein and inositol phosphatases and
      protein kinases have been identified as delivered effectors in three bacterial
      pathogens, Salmonella, Shigella and Yersinia, and it is expected that several
      more such type III effectors will be found.

PMID- 10637642
TI  - Microbial MIP channels.
AB  - MIP channels occur in all classes of organism ranging from bacteria to man. There
      are two major categories of MIP channels, aquaporins and glycerol facilitators,
      which facilitate the diffusion across biological membranes of water or glycerol
      and other uncharged compounds, respectively. As a result of their involvement in
      osmoregulation and metabolism, MIP channels are believed to affect a wide range
      of biological processes.

PMID- 10637643
TI  - An endogenous retrovirus and exogenous scrapie in a mouse model of aging.
AB  - As we enter the post-genomic era, there is an increasing need for accurate
      methods of identifying host and pathogen factors that contribute to bacterial,
      viral and fungal disease. In addition, there is a requirement for fast and
      precise techniques to evaluate potential therapies for the prevention of
      infectious diseases. The development of useful and cost-effective model systems
      will be crucial in advancing our knowledge of all aspects of microbial
      pathogenesis. In this series, we will learn of animal models used to investigate
      diseases caused by a wide variety of pathogens, including HIV, Vibrio cholerae
      and Pseudomonas aeruginosa. A description of a model system specifically designed
      to study intracellular pathogens will be presented, as will a variety of the
      techniques currently used to exploit other useful models of infection.
      Additionally, a description of the mathematical models used to analyse the
      population biology of human onchocerciasis will be discussed. The series begins
      with an intriguing look at the possible connections between an endogenous
      retrovirus, the infectious agent of scrapie and accelerated senescence in a mouse
      model of early aging.

PMID- 10637644
TI  - Rod pathways: the importance of seeing nothing, by Lindsay T. Sharpe and Andrew
      Stockman, Vol. 22, pp. 497-504.

PMID- 10637645
TI  - Corrigendum.

PMID- 10637646
TI  - Dopamine receptor partial agonists could address the duality of cocaine craving.

PMID- 10637647
TI  - Rational design of peptide agonists of cell-surface receptors.

PMID- 10637648
TI  - H3 receptor gene is cloned at last.

PMID- 10637650
TI  - The 'ABC' of GABA receptors.
AB  - In the conventional view, GABA acts at either ionotropic GABAA or metabotropic
      GABAB receptors. Recently, novel ionotropic GABA receptors that are composed of
      rho-subunits have been identified in the vertebrate retina. These bicuculline-
      and baclofen-insensitive GABA receptors are frequently called GABAC, following an
      early suggestion by Graham Johnston and colleagues. An IUPHAR committee has
      recommended that the term GABAC be avoided and subclassifies the retinal
      receptors as GABAA0r. However, new evidence regarding the pharmacology,
      structure, function, genetics and cellular localization of ionotropic GABA
      receptors strengthens the case for the existence of two major classes of these
      receptors, GABAA and GABAC.

PMID- 10637649
TI  - 5-HT modifiers as a potential treatment of asthma.
AB  - Increased levels of free 5-HT have been shown to be present in the plasma of
      symptomatic asthmatic patients compared with levels in asymptomatic patients. In
      addition, free 5-HT has been shown to correlate positively with clinical status
      and negatively with pulmonary function. These findings suggest that 5-HT might
      play a role in the pathophysiology of acute asthma. Accordingly, modifiers of the
      5-HT transmitter system such as compounds that affect the 5-HT transporter,
      prejunctional 5-HT receptors or postsynaptic 5-HT receptors might represent a
      novel treatment of asthma.

PMID- 10637651
TI  - Sensible use of antisense: how to use oligonucleotides as research tools.
AB  - In the past decade, there has been a vast increase in the amount of gene sequence
      information that has the potential to revolutionize the way diseases are both
      categorized and treated. Old diagnoses, largely anatomical or descriptive in
      nature, are likely to be superceded by the molecular characterization of the
      disease. The recognition that certain genes drive key disease processes will also
      enable the rational design of gene-specific therapeutics. Antisense
      oligonucleotides represent a technology that should play multiple roles in this
      process.

PMID- 10637652
TI  - Insights into ligand pharmacology using receptor-G-protein fusion proteins.
AB  - Production of chimeric DNAs in which the 5' end of G-protein alpha-subunits are
      linked directly to the 3' tail of a G-protein-coupled receptor has recently
      offered an unusual strategy to explore the detailed pharmacology of receptor-G
      protein interactions. Expression of such fusion proteins ensures a 1:1
      stoichiometry of receptor and G-protein expression and their proximity to each
      other. The capacity of such fusion proteins to be regarded as agonist-activated
      GTPases that allow simple enzyme kinetics to be applied to issues of ligand
      efficacy will be considered. In addition, the effects of point mutations, in both
      receptors and G proteins, on ligand function are particularly amenable to the
      types of robust quantitative analyses that can be produced using such fusion
      proteins.

PMID- 10637653
TI  - Integrin cell adhesion receptors and the concept of agonism.
AB  - Most cells are adherent and rely on adhesive interactions to regulate their
      shape, motility and growth. These interactions are critical for tissue integrity
      and homeostasis but they also contribute to many of the most common diseases in
      humans. The integrins are a key family of cell-surface receptors that mediate the
      downstream consequences of cell adhesion and are therefore prime targets for the
      development of therapeutic agents. In addition to their adhesive activity,
      integrins also exhibit several other classical features of signalling receptors.
      Sufficient evidence is now available to pose the question of whether integrins
      should be classified as true signalling receptors; this article both reviews this
      evidence and attempts to identify remaining gaps.

PMID- 10637654
TI  - Gibberellins and the Green Revolution.

PMID- 10637655
TI  - Heterologous expression for dominant-like gene activity.

PMID- 10637656
TI  - The effect of water motion on short-term rates of photosynthesis by marine
      phytoplankton.
AB  - Phytoplankton respond to variations in light intensity as they are mixed through
      the water column. Changes in pigment content are characteristic of the relatively
      slow response of 'sun-shade' photoacclimation that occurs on timescales typical
      of mixing in the open ocean. In estuaries, the variations are much faster and
      induce correspondingly rapid changes in the activity (rather than abundance) of
      different components of the photosynthetic apparatus. These components modulate
      light harvesting and Calvin cycle activity, or protect the pigment bed from
      excess energy absorption. When the protective capacity is exceeded,
      photoinhibition occurs. All these mechanisms modulate the rate of photosynthesis
      in situ.

PMID- 10637657
TI  - Floral induction and determination: where is flowering controlled?
AB  - Flowering is controlled by a variety of interrelated mechanisms. In many plants,
      the environment controls the production of a floral stimulus, which moves from
      the leaves to the shoot apex. Apices can become committed to the continuous
      production of flowers after the receipt of sufficient amounts of floral stimulus.
      However, in some plants, the commitment to continued flower production is
      evidently caused by a plant's commitment to perpetually produce floral stimulus
      in the leaves. Ultimately, the induction of flowering leads to the specification
      of flowers at the shoot apex. In Arabidopsis, floral specification and
      inflorescence patterning are regulated largely by the interactions between the
      genes TERMINAL FLOWER, LEAFY and APETALA1/CAULIFLOWER.

PMID- 10637658
TI  - Naturally occurring variation in Arabidopsis: an underexploited resource for
      plant genetics.
AB  - The definition of gene functions requires the phenotypic characterization of
      genetic variants. Currently, such functional analysis of Arabidopsis genes is
      based largely on laboratory-induced mutants that are selected in forward and
      reverse genetic studies. An alternative complementary source of genetic variation
      is available: the naturally occurring variation among accessions. The multigenic
      nature of most of this variation has limited its application until now. However,
      the use of genetic methods developed to map quantitative trait loci, in
      combination with the characteristics and resources available for molecular
      biology in Arabidopsis, allow this variation to be exploited up to the molecular
      level. Here, we describe the current tools available for the forward genetic
      analysis of this variation, and review the recent progress in the detection and
      mapping of loci and the cloning of large-effect genes.

PMID- 10637659
TI  - NMR adventures in the metabolic labyrinth within plants.
AB  - The era of metabolic engineering has begun, but there is only limited knowledge
      about metabolic fluxes and how they are regulated in plants. Particular
      challenges are the non-linearities between enzyme abundances, metabolite
      concentrations and metabolic fluxes, and the existence of metabolic networks that
      provide multiple routes between many important metabolites. NMR offers the means
      to distinguish and quantitate the fluxes along different routes to key
      metabolites. NMR can therefore help us understand and resolve the apparent
      paradox of, on the one hand, great metabolic flexibility evident in the natural
      responses of plants and, on the other hand, the unpredictable changes in
      metabolism reported in genetically engineered plants.

PMID- 10637660
TI  - How the deposition of cellulose microfibrils builds cell wall architecture.
AB  - Cell walls, the extracytoplasmic matrices of plant cells, consist of an ordered
      array of cellulose microfibrils embedded in a matrix of polysaccharides and
      glycoproteins. This construction is reminiscent of steel rods in reinforced
      concrete. How a cell organizes these ordered textures around itself, creating its
      own desirable environment, is a fascinating question. We believe that nature
      adopted an economical solution to this design problem: it exploits the
      geometrical constraints imposed by the shape of the cell and the limited space in
      which microfibrils are deposited, enabling the wall textures essentially to
      'build themselves'. This does not imply that the cell cannot control its wall
      texture. On the contrary, the cell has ample regulatory mechanisms to control
      wall texture formation by controlling the insertion of synthases and the distance
      between individual microfibrils within a wall lamella.

PMID- 10637661
TI  - Does a light-harvesting protochlorophyllide a/b-binding protein complex exist?
AB  - Recent in vitro studies have led to speculation that a novel light-harvesting
      protochlorophyllide a/b-binding protein complex (LHPP) might exist in dark-grown
      angiosperms. Structurally, it has been suggested that LHPP consists of a 5:1
      ratio of dark-stable ternary complexes of the light-dependent NADPH:
      protochlorophyllide oxidoreductases A and B containing nonphotoactive
      protochlorophyllide b and photoactive protochlorophyllide a, respectively.
      Functionally, LHPP has been hypothesized to play major roles in establishing the
      photosynthetic apparatus, in protecting against photo-oxidative damage during
      greening, and in determining etioplast inner membrane architecture. However, the
      LHPP model is not compatible with other studies of the pigments and the pigment
      protein complexes of dark-grown angiosperms. Protochlorophyllide b, which is
      postulated to be the major light-harvesting pigment of LHPP, has, for example,
      never been detected in etiolated seedlings. This raises the question: does LHPP
      exist?

PMID- 10637662
TI  - A new quantitative in vitro for the detection of latex-specific IgE antibodies.
AB  - Immediate-type hypersensitivity to latex allergens has resulted in anaphylactic
      shock and death in numerous reported cases. The allergenic proteins of latex are
      contained within the natural rubber extract of Hevea brasiliensis and are eluted
      into the final product during the manufacturing process. The quantity and types
      of latex allergens found in different latex products depends on the manufacturing
      process. Not all of these allergens are available for use in the latex prick skin
      test, and as a result, such tests may not be conclusive. Furthermore, application
      of such allergens to the skin of undiagnosed hypersensitive individuals may have
      harmful effects on their health. Therefore, it is important to be able to utilize
      in vitro methods, which reliably identify latex allergy without placing
      hypersensitive individuals at risk. We have developed a relatively simple and new
      enzyme immuno-assay (EIA) method for the detection of latex allergy. This in
      vitro method is quantitative and allows for the classification of allergy to
      latex in a short time. In comparative studies, ninety-nine serum specimens with
      documented clinical history of latex allergy were tested by this method, and the
      results paralleled those of the skin prick test performed by an independent
      group. The data showed that the specificity and sensitivity of our assay
      approaches 97.5% and 100%, respectively. We conclude that, by using a simple
      assay, the detection of specific IgE to latex proteins may be valuable for
      screening individuals and for the diagnosis of allergy to latex.

PMID- 10637663
TI  - [Solenophagy and telmophagy: biting mechanisms among various hematophagous
      insects].
AB  - Blood-sucking insects do not all take blood from the host in the same way.
      Mechanisms are different according to capillary feeding or pool feeding and this
      explains the differences between clinical reactions. A better knowledge of the
      insect biology is helpful for an aetiological diagnosis. So, in the case of an
      allergic reaction, procedures of complementary investigations will be optimised.

PMID- 10637664
TI  - [Prevalence of allergy to cockroaches in the African intertropical zone. Review
      of the literature].
AB  - The epidemiology of environmental allergens and their role in respiratory
      pathology remains poorly understood in sub-Sahara Africa. The aim of this work
      was to measure the frequency of sensitivity to cockroach allergens of subjects
      with chronic respiratory affections in the Ivory Coast. We recruited
      consecutively 140 patients, adults and infants, who had asthma, rhinitis or
      sinusitis over a period of 20 months, in a hospital environment. The patients
      were prepared by a clinical questionnaire on atopy (personal and familial
      antecedents), systemic prick tests for common environmental allergens
      (cockroaches, mites, moulds). Our results indicated that the mean age of the
      children was 8 years and that of the adults 26 years (with extremes of 3 and 53
      years). The proportion of patients with positive prick tests to cockroaches was
      30.7% (43 cases). In asthmatics it was 16.5%. When asthma was associated with an
      ORL focus, 41.9% was found and in isolated ORL pathology 19.5%. Existence of
      familial atopy was found in 72% of cases. Discomfort from domestic dust was shown
      on questioning by 88.4% of cases. In 81.4% of cases positivity of the prick test
      to cockroaches was accompanied by a positive reaction to mites. Those who were
      only sensitive to cockroaches were less than 10%. Types II and III asthma were
      2/3 in the asthmatic patients. In conclusion, the cockroaches were in the second
      rank of pneumoallergens that are implicated in sensitization and in the
      perpetuation of allergic respiratory symptoms, after the mites. These two factors
      were often associated in our patients and are consequently seen with a strong
      allergenic potential that is exercised by the interior environment.

PMID- 10637665
TI  - [Draft of the Aix-en Provence pollen calendar].
AB  - Because of some divergences between the pathologics of Aix and the pollinic
      accounts found by the spore-trap of Marseilles, a spore-trap has been installed
      since the beginning of 1997 in Aix hospital to prove that these two sites are
      specific for pollen identification and dates of pollinisation as well. After
      three years of measures, the correlation between the vegetation of Aix and the
      pathological symptoms is established. They are coherent with those published in
      other sound European countries and confirm the "mediterreean" feature of Aix.

PMID- 10637666
TI  - [Health in Vietnam between two eras].

PMID- 10637667
TI  - [Medical structures in Vietnam].
AB  - In Vietnam, medical structures are organized according to administrative areas.
      The large cities are divided into sectors each with several quarters. Each region
      of the country is divided into districts grouping together several small towns.
      Each small town or city quarter has an infirmary and the districts or city
      sectors have a small hospital. Larger hospitals are located in the different
      regions or large cities. Primary patient care is provided by the infirmaries
      which can refer to small district or quarter hospitals; the more severe cases are
      then referred to the regional or large city hospitals. Students entering medical
      school are selected among secondary school graduates by a special entry
      examination. After a 6-years medical curriculum, hospital interns are chosen by
      an internship examination. Internship lasts 3 years for all specialties.
      Specialists and general practitioners work in hospitals or state medical
      services. Private practice is authorized after working hours.

PMID- 10637668
TI  - [Ocular manifestations of Behcet's disease].
AB  - Ocular complications of Behcet's disease are considered one of the major criteria
      upon which the diagnosis is based. The ocular disease is characterized by
      repeated, explosive ocular inflammatory attacks which can healed spontaneously.
      During in-between attacks there is little or no evidence of inflammation in the
      eyes. The anterior segment can be involved alone presenting as a severe anterior
      uveitis with hypopyon. Posterior pole involvement is often sight threatening
      presenting as recurrent retinal vaso-occlusive disease. The fundus changes most
      frequently encountered are hyperhemia of the optic nerve, macular edema, retinal
      edema, vascular sheathing retinal exudate, and retinal hemorrhages. Complications
      of the inflammation include retinal and optic disc atrophy, neovascular glaucoma,
      vitreous hemorrhage, retinal detachment. Treatment is with topical steroids,
      systemic medications, including corticosteroids, colchicine, and
      immunosuppressive drugs. These complications are sight threatening and require a
      close follow up and a collaboration between ophthalmologists and Internal
      Medicine physicians.

PMID- 10637669
TI  - [Dermato-mucosal manifestations of Behcet's disease].
AB  - Oral and genital aphthae are the main clinical dermatologic manifestations of
      Behcet's disease. They look like those that occur in other aphthosis. Cutaneous
      lesions include pseudofolliculitis, folliculitis, erythema nodosum-like lesions,
      Sweet's-like lesions and pyoderma gangrenosum-like lesions. Histologically, these
      lesions are frequently perivascular with proeminent infiltrates of neutrophils
      and/or lymphocytes. Hypersensibility to needle pricks is explored by the pathergy
      test which sensibility is highly variable depending on the countries. When there
      is no systemic lesions requiring oral corticosteroids or immunosuppressive
      therapy, colchicine, aspirine, or dapsone may be prescribed. Thalidomide is
      sometimes required if aphthosis is refractory to other treatments despite its
      neurotixic and teratogenic effects.

PMID- 10637670
TI  - [Cardiovascular manifestations of Behcet's disease].
AB  - Vascular involvement in Behcet's disease, recognized since 1946, is peculiar
      since it occurs in young subjects with no vascular risk factor. Recurrent
      phlebitis, sometimes associated with fever and biological signs of inflammation,
      commonly involve the large vessels (superior and inferior vena cava, hepatic
      veins) and cerebral veins. Arterial involvement was more recently identified and
      is expressed by thrombosis, stenosis and/or aneurysms diversely associated.
      Aneurysms, true "arterial aphthae", may be multifocal and can involve all
      arterial territories with a clear preference for the abdominal aorta and the
      pulmonary arteries (Hughes-Stovin syndrome). Mortality is significant due to
      rupture and the risk of recurrence. Cardiac involvement includes coronary artery
      disease which merits attention since it affects young subjects and is often
      expressed by myocardial infarction or angina; all three tunics can be involved;
      mortality is high: 20% in the months or years following diagnosis. A few cases of
      recurrent pericarditis have been reported. Myocardiopathy can be of inflammatory
      nature or secondary to coronary artery disease. Endocardiac involvement may be
      limited to valve disease or spread to the ventricular wall. Endomyocardial
      fibrosis is exceptional and usually associated with intracavitary thrombus
      formation. Coagulation disorders have been reported but they cannot explain the
      different thrombotic manifestations which are probably the consequence of an
      abnormal response of the vascular endothelial cells.

PMID- 10637671
TI  - [Neurologic manifestations of Behcet's disease].
AB  - Neurological involvement in Behcet's disease, the cause of the disease's severe
      functional sequellae, is reported in 5.3 to 30% of cases. Coagulation disorders
      have been reported but they cannot explain the different thrombotic
      manifestations which are probably the consequence of an abnormal response of the
      vascular endothelial cells. Neurological manifestations include: a) dural sinus
      thrombosis which can be diagnosed by angio-MRI and whose prognosis is improved
      with the use of anticoagulants; b) exceptional lesions to arteries supplying the
      brain; c) aseptic meningitis and meningo-encephalitis; and d) exceptionally,
      solitary spinal cord involvement and peripheral disease. Neurological involvement
      can occur early or late after development of skin and mucosal signs and when
      inaugural make mislead diagnosis. The spinal tap usually gives objective evidence
      of lymphocyte meningitis. MRI is nonspecific, but the T2 and Flair sequences can
      evidence hypersignal areas, preferentially in the brain stem, basal nuclei, and
      subtentorial white matter with no preference for the periventricular regions.
      Spontaneous aggravation is the rule and the neurological prognosis is severe
      (dementia, pseudo-bulbar syndrome, loss of independence). Treatment is similar to
      that used for vasculitis and is aimed initially at reducing the inflammation with
      corticosteroids and at preventing relapse with the adjunction of an
      immunosuppressor. Results are better when treatment begins early; restitutio ad
      integrum has been observed. Duration of treatment is poorly defined:
      immunosuppressors have been proposed for a minimal duration of 2 years;
      corticosteroid therapy can be tapered off but interruption would expose to
      relapse. A maintenance therapy is advisable and, in our opinion, should be
      proposed indefinitely combining colchicine (1 to 2 mg/d), anti-aggregate doses of
      aspirin, and low-dose corticosteroids (1/10 mg/kg/d).

PMID- 10637672
TI  - [Rheumatic manifestations of Behcet's disease].
AB  - Rheumatologic manifestations are common in Behcet's disease. Joint involvement
      takes the third place after mucocutaneous and ocular lesions and can be the
      inaugural manifestation. Monoarthritis and oligoarthritis affect essentially
      knees and ankles, with a marked male bias. They usually run an acute or recurrent
      course, with chronic forms being rare. Polyarthritis is not rare and involves the
      large limb joints and the small joints of the hands and feet. Arthritis in
      Behcet's disease heels usually without sequelea and the aggressive treatment is
      not necessary. Unusual forms include arthritis with deformities and/or
      destruction, pseudogout, rupture of popliteal cyst (imitating deep vein
      thrombosis) and myositis. The association with spondylarthropathy is not common.
      Behcet's disease is rarely associated with rheumatoid arthritis, Sjogren's
      syndrome, systemic lupus erythematosus, relapsing polychondritis and amyloidosis.
      Children are more likely than adults to have joint manifestations and
      polyarthritis. CONCLUSION: Joint manifestations are common in Behcet's disease.
      Their unusual forms deserve to be known since they can raise diagnostic problems
      when they are inaugural.

PMID- 10637673
TI  - [Behcet's disease: pediatric features].
AB  - There is an increased awareness about the pediatric aspects of Behcet's disease
      (BD) in the world literature. Recent surveys of patients have outlined peculiar
      features in this age group such as recurrent attacks of fever and abdominal pain.
      Considered to be uncommon in childhood, uveitis have a very severe course. The
      higher frequency of familial cases and the genetic anticipation suggest that the
      genetic component plays a major role in the early expression of the disease.
      Pediatric aspects of BD including different categories of patients, are not
      definitely characterized. Indeed it is now necessary to distinguish the pediatric
      group (BD completed before 16 years) from the "juvenile" group (adult patients
      with first symptoms before 16 years).

PMID- 10637674
TI  - The management of Behcet's syndrome.
AB  - Behcet's syndrome (BS), originally described as a triad of oral aphthae, genital
      ulcerations and uveitis, is a systemic vasculitis that is prevalent in the Middle
      east, Far East and in the Mediterranean basin. It is characterized by a
      heightened state of inflammation although the main drive that initiates and
      sustains this is not yet elucidated. Suppression of this inflammatory state
      constitutes the major goal of treatment and therapy is tailored according to the
      specific manifestations observed. We now have considerable more insight on drug
      management of BS compared to 20 years ago. Particularly, within the recent past
      we have learned to use more rationally the agents that were already available to
      us. This is especially true for azathioprine, cyclosporin A, thalidomide and
      colchicine. Promising data are also being collected with alpha-interferon. With
      these agents, significant progress has been achieved in the management of uveitis
      and mucocutaneous symptoms but treatment issues related to thrombotic problems,
      major vessel involvement and neurological disease have not yet been resolved.

PMID- 10637675
TI  - Localized subcutaneous Nocardia farcinica abscess in a woman with overlap
      syndrome between systemic scleroderma and polymyositis.
AB  - Nocardia farcinica is an increasingly common cause of human infection in Europe.
      We observed an isolated nodular subcutaneous abscess due to N. farcinica in the
      forearm of a young patient with overlap syndrome between systemic sclerosis and
      polymyositis. Despite in vitro resistance to trimethoprim-sulfamethoxazole, this
      oral combination completely resolved the lesion within 3 weeks and was maintained
      for 6 months. The spectrum of cutaneous nocardiosis in the immunocompromised host
      is discussed.

PMID- 10637676
TI  - Fact versus fancy concerning the multimodal treatment study for attention-deficit
      hyperactivity disorder.
AB  - Findings from the Multimodal Treatment Study of Children With Attention-Deficit
      Hyperactivity Disorder (ADHD), the MTA, have been much discussed but frequently
      misinterpreted or mischaracterized. Misinterpretations regarding the specific
      nature of and rationale for the study design, the effectiveness of the
      behavioural treatment arm, the possible advantages of combined treatments over
      single-component (medication management or behavioural therapy) interventions,
      and the feasibility and applicability of MTA treatments for "real-world"
      practitioners are addressed. Careful interpretation of the MTA findings suggests
      that for ADHD symptoms, carefully crafted medication-management approaches are
      superior to behavioural treatment and to routine community care that includes
      medication. For non-ADHD areas of functioning (for example, social skills,
      academic performance), combined treatments may offer modest advantages over
      single-component approaches. Longer-term outcomes past 14 months of intensive MTA
      treatments (as well as their relative effectiveness with respect to each other)
      remain unknown, pending further MTA analyses. The MTA treatments by and large
      consisted of evidence-based "best practices." Thus, rather than characterizing
      these treatments as infeasible, the substantially superior outcomes of these
      treatments (versus routine clinical care) across diverse settings should help set
      the standard for future treatment practices in real-world settings. Despite
      important study limitations, the MTA study, by virtue of its size, scope, and
      length; parallel-groups design; explicit use of manualized, evidence-based
      treatments; and comprehensive range of outcome assessments sets an important
      benchmark for future trials testing new treatments for childhood ADHD and defines
      a new standard for optimal outcomes that can be achieved with the best of
      clinical care.

PMID- 10637677
TI  - The NIMH multimodal treatment study for attention-deficit hyperactivity disorder:
      just say yes to drugs alone?
AB  - The outcome, merits, and limitations of the Multimodal Treatment Study for
      Children With Attention-Deficit Hyperactivity Disorder (ADHD), the MTA study, are
      described and discussed. Consideration is given to design issues that make the
      MTA a landmark study for clinicians and researchers working with ADHD children.
      These include the large, heterogeneous sample, the state-of-the-art treatment,
      the lengthy treatment period, the extensive documentation of treatment manuals,
      and the attention paid to treatment fidelity and adherence. Also highlighted are
      facets of the design that predisposed the study in favour of a differentially
      positive outcome for pharmacological relative to behavioural treatment. Primary
      among these is the fact that outcome was measured 4-6 months after the intensive
      phase of behaviour treatment and after therapeutic contact with the behaviour
      therapist had ended but while medication treatment was active and in its most
      intensive phase. Finally, the outcome for the combined treatment condition in the
      MTA is discussed in the context of the extant literature and directions for
      future research.

PMID- 10637678
TI  - Lessons from large trials: the MTA study as a model for evaluating the treatment
      of childhood psychiatric disorder.
AB  - OBJECTIVE: To review the methodology of the Multimodal Treatment Study of
      Children With Attention-Deficit Hyperactivity Disorder (ADHD), the MTA study, and
      its implications for the design of future child mental health treatment studies.
      METHOD: The characteristics of large-scale studies envisioned by trialists
      engaged in cardiovascular and cancer research provide the framework for reviewing
      key elements of the MTA study--objectives, research questions, measurement,
      sampling, and exposure to treatment--and discussing important methodological
      decisions the MTA investigators had to make. RESULTS: The MTA study is a complex,
      standardized, carefully implemented, randomized control trial. Review of the MTA
      study indicated that future studies should be aligned clearly with either
      effectiveness or efficacy objectives but not both. Questions selected for study
      should be simple, clear, and important. Measurement, sampling, and data
      collection must adhere to the principle of simplicity to ensure maximum
      participation. All methodological decisions should be geared to attaining the
      research objectives: in effectiveness trials, this means evaluating treatments
      that have a high potential for dissemination if proven successful and recruiting
      only new referrals from child mental health settings. CONCLUSIONS: The MTA study
      has raised the standard for technical excellence in child treatment research and
      will draw attention to some fundamental issues in large-scale child treatment
      studies, including articulating objectives and questions, setting priorities for
      measurement and sampling, and identifying treatments for evaluation that have a
      high probability of dissemination if found effective.

PMID- 10637679
TI  - In the wake of the MTA: charting a new course for the study and treatment of
      children with attention-deficit hyperactivity disorder.
AB  - This paper considers 3 questions addressed by the National Institute of Mental
      Health's Collaborative Multimodal Treatment Study of Children With Attention
      Deficit Hyperactivity Disorder (ADHD), the MTA study, of pharmacological and
      behavioural interventions for 7- to 9-year-old ADHD children. First, do
      behavioural interventions represent a viable treatment option for families of
      children with ADHD? Second, what are the relative benefits of behavioural and
      pharmacological interventions? Finally, are there advantages to combining
      behavioural and pharmacological interventions for children with ADHD? In the
      absence of secondary analyses, the MTA's primary intent-to-treat analyses
      released to date are difficult to interpret. While behavioural interventions
      represented a viable option for many families, the doses achieved via systematic
      titration and follow-up medication-management protocols yielded larger effect
      sizes on unblinded primary symptom reports than did behavioural treatments or the
      medication management used by most families in the community control conditions.
      Finally, while combined medication and behavioural management demonstrates some
      benefits, a more definitive conclusion awaits a detailed presentation of
      secondary analyses and follow-up data.

PMID- 10637680
TI  - Attention-deficit hyperactivity disorder in children and youth: a quantitative
      systematic review of the efficacy of different management strategies.
AB  - OBJECTIVE: To obtain estimates of the relative efficacy of 3 main treatment
      strategies for attention-deficit hyperactivity disorder (ADHD) in children and
      youth (age < 18 years). METHODS:  DESIGN: quantitative systematic review of
      randomized trials. SUBJECTS: 999 patients with ADHD from 26 randomized trials.
      INTERVENTIONS: medications alone, behavioural interventions alone, and a
      combination of these 2 modalities. MAIN OUTCOME MEASURE: differences in scores
      between treatment groups on commonly used teacher- and parent-completed behaviour
      rating scales. RESULTS: Medication-only therapy was efficacious in ADHD.
      Behavioural therapies used alone appeared not to be efficacious in ADHD.
      Combination therapy was more efficacious than placebo or no treatment for parent
      but not teacher ratings, not more efficacious than drug therapy alone, and more
      efficacious than behavioural treatments alone based on parent but not teacher
      ratings. CONCLUSION: Though stimulant medications were found to be an effective
      treatment strategy for ADHD in children and youth, it proved difficult to assess
      the relative benefits of behavioural interventions alone and combined medication
      and behavioural therapy because of the paucity of treatment studies other than
      medication-only treatment studies and heterogeneity of various kinds that exist
      in relation to ADHD studies and treatments.

PMID- 10637681
TI  - Appropriateness of psychostimulant prescription to children: theoretical and
      empirical perspectives.
AB  - OBJECTIVES: 1) To consider study designs for evaluating how appropriately
      stimulant medications are prescribed to children. 2) To investigate
      appropriateness by seeking evidence of consensus around how stimulant management
      should be undertaken, collecting and reviewing evidence of actual physician
      practice in relation to use of stimulants, and evaluating the closeness of fit
      between recommended and actual practice. METHOD: Electronic databases and other
      published and unpublished material were searched for the decade 1987-1997 to
      identify 1) authoritative recommendations for medical management of attention
      deficit hyperactivity disorder (ADHD) and 2) surveys of physician practice.
      Available information was analyzed qualitatively for commonalities and trends and
      for concordance between recommendations and practice. RESULTS: Despite
      differences in emphasis between experts, common themes were identifiable
      regarding prerequisites and follow-up for use of stimulants. Overall, it was rare
      to find physician practice in accordance with expert recommendations more than
      70% of the time, suggesting that management may be suboptimal in at least 30% of
      children treated with medication for ADHD. Across surveys, consistent differences
      appear in physician practice patterns related to practice type. Management by
      specialist consultants approximates standards recommended by experts, while
      management by primary care practitioners diverges from these standards.
      CONCLUSIONS: There are grounds for concern about the quality and appropriateness
      of medical management for children with ADHD. The methodology used in this study
      holds promise for wider application, with planning and refinement. There is a
      need to find ways to improve care for children with ADHD provided by primary care
      physicians.

PMID- 10637682
TI  - The treatment of attention-deficit hyperactivity disorder: an annotated
      bibliography and critical appraisal of published systematic reviews and
      metaanalyses.
AB  - CONTEXT: The Agency for Health Care Policy and Research charged the McMaster
      Evidence-based Practice Center with conducting a comprehensive systematic review
      of the literature on the treatment of attention-deficit hyperactivity disorder
      (ADHD), with input from various groups of stakeholders. One strategy used to
      avoid duplication of work included a critical appraisal of existing systematic
      reviews and metaanalyses. OBJECTIVE: To identify and appraise published
      metaanalyses and systematic reviews on the treatment of ADHD and to produce an
      annotated bibliography. DATA SOURCES: Medline, Cumulative Index in Nursing and
      Allied Health (CINAHL), Healthstar, Psycinfo, and Embase were searched to
      September 1998; the Cochrane Database (1998 issue 3), selected Internet sites,
      and the files of investigators were also reviewed. STUDY SELECTION: Review
      articles described as systematic reviews or metaanalyses or including a Methods
      section were identified independently by 3 reviewers. DATA EXTRACTION: Two
      reviewers extracted, by consensus, relevant information on the name,
      methodological quality, ADHD-related aspects (comorbid disorders, family
      characteristics) of those reviews; data on the population, study setting,
      interventions, and outcomes evaluated by the reviews were also retrieved.
      RESULTS: Thirteen reviews, published from 1982 to 1998, were included. Eight
      included metaanalysis and 5 a qualitative review. Nonpharmacological treatments
      were mentioned in 6 reviews and combination therapies in 3. One review focused on
      the treatment of adults. Forty-seven drugs and 20 adverse effects were mentioned.
      Most reviews had major methodological flaws. CONCLUSIONS: Most published
      systematic reviews and metaanalyses on the treatment of ADHD have limited value
      for guiding clinical, policy, and research decisions. A rigorous, systematic
      review following established methodological criteria is warranted.

PMID- 10637683
TI  - Aggressive behaviour in children with Tourette syndrome and comorbid attention
      deficit hyperactivity disorder and obsessive-compulsive disorder.
AB  - BACKGROUND: Aggressive behaviour, defined as sudden, explosive outbursts of rage,
      has been reported as a clinical problem in approximately 23% to 40% of Tourette
      syndrome (TS) patients (1-5). Attention-deficit hyperactivity disorder (ADHD) and
      obsessive-compulsive disorder (OCD) are also reported in 50% to 70% of TS
      patients (6). OBJECTIVE: To investigate whether aggressive behaviour was
      associated with TS directly or found primarily in TS with comorbid ADHD or OCD.
      METHOD: Aggressive behaviour in 33 nonmedicated patients with TS (ages 6 to 14
      years) and 6 healthy control subjects (ages 7 to 12 years) was examined by
      semistructured interview and multiinformant questionnaires. RESULTS: Aggression
      subscales on Achenbach's Child Behavior Checklist (CBCL) completed by parents and
      Teacher's Report Form (TRF) completed by teachers distinguished the TS-only and
      control groups from the group with TS + Comorbidity (P < 0.046, and P < 0.016)
      after adjusting for tic severity and age. The conduct disorder subscale on the
      Conners Parent Rating Scale (CPRS) was also significantly higher (P < 0.005) in
      the TS + comorbidity group than in the TS-only or control groups, with more
      problems reported in the older children. CONCLUSIONS: These findings provide
      additional evidence that aggressive behaviour observed in children with TS may be
      associated with comorbid ADHD or OCD (6), independent of tic severity or age.
      This is consistent with the clinical observation that most TS patients have only
      minimal symptoms, which do not interfere with their daily functioning.

PMID- 10637684
TI  - Parental knowledge of attention-deficit hyperactivity disorder and opinions of
      treatment options: impact on enrollment and adherence to a 12-month treatment
      trial.
AB  - OBJECTIVE: This study examines the relationship between parents' knowledge of
      attention-deficit hyperactivity disorder (ADHD) and opinions of treatment and
      their impact on enrolment in and adherence to both pharmacological and
      nonpharmacological interventions for children with ADHD. METHOD: Participants in
      the study were the parents of 81 children who reached diagnostic criteria for
      ADHD and who were referred to a treatment study of ADHD involving stimulant
      medication and parent groups. The mothers completed a modified version of the
      ADHD Knowledge and Opinion Scale (AKOS) prior to receiving diagnostic feedback
      and prior to the families' decisions to participate in a 12-month randomized
      trial (medication [methylphenidate or placebo] and parent groups [training or
      support]). Treatment enrolment and adherence were monitored over the 12-month
      trial, and families who remained in the study at 12 months completed another
      modified AKOS. RESULTS: A higher level of knowledge of ADHD was found to be
      related to more favourable opinions of parent groups but not of medication.
      Moreover, parents who were more knowledgeable about ADHD were more likely to
      enroll in both pharmacological and nonpharmacological treatments. Adherence to
      pharmacological and nonpharmacological treatments was not predicted by parental
      knowledge of ADHD or opinions of the treatment. CONCLUSION: Parents' knowledge of
      ADHD and opinions of treatments play a significant role in enrollment in
      treatments for their children with ADHD. Providing information to parents
      regarding ADHD prior to offering treatment modalities could have a favourable
      impact on treatment enrollment and hence treatment adherence.

PMID- 10637685
TI  - Is it time for a Canadian Institute of Mental Illness and Mental Health Research?

PMID- 10637687
TI  - Bipolar II and unipolar atypical depression.

PMID- 10637686
TI  - Improvement of obsessions and compulsions with clozapine in an individual with
      schizophrenia.

PMID- 10637688
TI  - Citalopram: a rapid-onset selective serotonin reuptake inhibitor?

PMID- 10637689
TI  - Neurobiology of early antecedents of adult health problems.

PMID- 10637690
TI  - [The surgeon as expert witness in the quality-malpractice spiral].

PMID- 10637691
TI  - [Must the poor die younger? Health care costs explode. Savings create need.
      Experiences from foreign countries].

PMID- 10637692
TI  - [Palliative surgery].

PMID- 10637693
TI  - [Palliative therapy of gastrointestinal obstruction].
AB  - Gastrointestinal obstruction is a frequently observed emergency with tumor
      patients. In addition to tumor relapse, the development of a second tumor or
      intraperitoneal tumor spreading, and benign alterations in advanced tumor stages
      (radiogenic stenosis, adhesions) may also be the cause for the obstruction. The
      main objective of therapy is an attempt to eliminate the intestinal obstruction
      through surgery. If this is not possible because of advanced intra-abdominal
      tumor expansion, several endoscopic or interventional radiology methods, and
      drugs are available, that are used on an individual basis and based on prevailing
      experience to relieve the patient's condition.

PMID- 10637694
TI  - [Palliative measures in the hepatobiliary-pancreatic system].
AB  - Malignant tumors of the hepatobiliopancreatic system are not curable in > 60%.
      For this reason, palliation plays an important therapeutic role. Indications are
      mainly obstructive jaundice, duodenal obstruction and pain. Assessment of the
      tumor's morphology and resectability is often possible only by surgical
      exploration. If necessary and feasible, non-curable malignancies are treated
      synchronously during this operation. In preoperatively proven distant metastases
      or local non-resectability, interventional procedures are preferred. They are
      efficient, at least primarily, and mostly correlated with little patient
      discomfort. A surgical biliary bypass obviously leads to improved long-term
      palliation. Especially in Klatskin tumors, palliative resection may be useful.
      Generally the patients benefit from palliation depends on minor therapeutic
      discomfort and long-lasting control of symptoms.

PMID- 10637695
TI  - [Value of tumor debulking in gastrointestinal tumors].
AB  - Tumor debulking of gastrointestinal tumors for the reduction of tumor mass is
      intended to improve subsequent treatment efficacy. However, in advanced malignant
      disease, this therapy is often associated with increased morbidity and lethality.
      Adjuvant therapies cannot be initiated when needed. Therefore, long-term survival
      remains unaffected. Advances in biomedical science provide preliminary
      explanations for these therapeutic problems. Modern therapeutic concepts like
      neoadjuvant therapy for locally advanced tumors are based on these findings. The
      probability of complete R0 resections, necessary to improve long-term survival,
      can be enhanced by these therapies. The ongoing prospective neoadjuvant studies
      for gastrointestinal tumors are already very encouraging.

PMID- 10637696
TI  - [Metastases compromising physical stability].
AB  - Multimodal therapy of tumor patients with osseous metastases is an
      interdisciplinary task. The surgical treatment requires optimal integration, in
      terms of timing and extent of the procedure, into the overall treatment plan. In
      addition to surgery, modern therapeutic approaches include systemic
      chemotherapeutic, hormonal and immunological therapy, radiotherapy, and other
      drug therapy (i.e. biophosphonates). We use classical stabilization methods with
      plates and bone cement or intramedullary nailing and also new implants with
      angular stability like an internal fixator and modular endoprothesis systems in
      operative therapy. Such stabilizing systems allow bridging of tumor defects in
      almost all parts of the skeleton. The ultimate goal of any treatment and
      especially of operative intervention is a mobile patient with little or no pain
      and a good quality of life.

PMID- 10637697
TI  - [Supportive measures in palliation: pain therapy and nutrition].
AB  - Pain relief and nutritional support represent two main efforts of palliative
      medicine. A considerable proportion of surgical patients might not be treated
      with adequate analgetic medication. Those patients are often treated too late,
      too short or with an insufficient amount of drug. Particularly if the treatment
      goal is palliation problems of drug abuse are of less importance. However,
      randomized trials aiming at best pain relief have rarely been carried out in
      oncological patients. Psychological factors (suffering, affective aspects) have
      to be borne in mind when deciding upon pain treatment. The surgeon often knows
      best the local problem inducing pain whether it is due to intestinal obstruction,
      infiltration of bone and joints, arising from the viscera, or resulting from
      nerve compression. This information is of utmost value to select the most
      appropriate treatment. Parenteral, local, or regional measures to relief pain can
      be combined with chemical neurolysis. Receptor-specific drugs may be the
      analgetics of the future. Regarding nutritional support the patient's acceptance
      must be respected. Other guidelines concern life expectancy, nutritional status,
      or intestinal function and influence the decision whether or not nutritional
      support should be offered. Enteral feeding should always be the treatment of
      first choice due to economical and logistic reasons but also due to the fact that
      translocation of bacteria and endotoxin can be minimised with this technique.

PMID- 10637698
TI  - [Esophageal replacement by interposition of pedicled ascending colon flap
      supplied by the inferior mesenteric artery].
AB  - OBJECTIVE: Colon interposition for esophageal replacement is indicated in
      patients with benign esophageal disease, in patients who require an esophago
      gastrectomy for a potential cure and in patients in whom the stomach is no longer
      available for replacement because of preceding surgery. METHODS: In 30 patients
      we performed colon interposition grafts for esophageal replacement using a
      modified technique. This technique includes ligation of the middle and right
      colic artery, thereby creating an interposition graft of the whole ascending
      colon which receives blood exclusively from the left colic artery. The main
      advantage of this procedure is the length of the interposition graft. Preparation
      of the left colic flexure is no longer required. Nineteen patients had an
      esophagectomy, 11 patients an esophago-gastrectomy. RESULTS: Minor complications
      in this unselected patient group occurred six times (20%), and major
      complications were observed in seven patients (23.3%). Frequency of anastomotic
      leakage amounted to 13.3%, hospital mortality to 10%. CONCLUSION: Frequency of
      postoperative complications and hospital mortality of patients in whom a modified
      colon interposition was done is comparable with published data of unselected
      patient groups, which had either a standard colon interposition graft for
      esophageal replacement or a gastric pull-through procedure.

PMID- 10637699
TI  - [Temporary closure of interposed intestine in treatment of anastomotic dehiscence
      in esophageal surgery].
AB  - INTRODUCTION: Though resections of the esophagus are performed today with a
      mortality of below 10% anastomotic leakages still represent a serious threat
      especially when located intrathoracically. METHODS: In cases with intrathoracic
      leakage and severe septic disease the interposed intestinum was interrupted by
      staples within the abdomen in order to inhibit bile and intestinal reflux to the
      anastomosis. Care was taken not to hurt the mesentery. RESULTS: Of 102 patients
      with adenocarcinoma of the gastroesophageal junction and the distal esophagus 48
      were treated with cervical anastomosis and stomach or colon interposition.
      Anastomotic leakages occurred in 12.5% of cases and were cured without special
      measures. In 54 patients an intrathoracic anastomosis was done using small
      intestine or colon for interposition. Four cases (7.4%) with anastomotic leakage
      and severe septic disease were recorded. In these patients the interposed
      intestine was interrupted. The anastomotic leakage healed. With small intestine
      interposition a spontaneous reopening of the staples was observed after 6 weeks.
      Total mortality up to the time of discharge in 102 patients was 2%. No patient
      died because of anastomotic leakage. CONCLUSIONS: With the method of interruption
      of the interposed intestine anastomotic leakages in esophageal surgery can be
      cured. The effect is based on the prevention of intestinal reflux to the
      anastomosis. With small intestine interposition a spontaneous reopening of the
      interruption can be expected after 6 weeks.

PMID- 10637700
TI  - [Crohn disease of the esophagus].
AB  - INTRODUCTION: Since the landmark report by Crohn, Ginzburg and Oppenheimer in
      1932, the spectrum of involvement of Crohn's disease has expanded to include the
      entire digestive tract from mouth to anus. The involvement of the esophagus by
      Crohn's disease is very rare. METHODS: We report a 41-year-old male patient with
      severe Crohn's disease of the distal esophagus with a fistula to the right
      bronchial system. RESULTS: After a long period of nutritional support we
      performed a transthoracic esophagectomy and a Nissen fundoplication.
      Postoperatively his course was complicated by pneumonia and withdrawal symptoms.
      CONCLUSIONS: Esophagectomy is indicated in Crohn's disease of the esophagus with
      severe stricture or fistula formations.

PMID- 10637701
TI  - [Surgery of stomach carcinoma--established and controversial procedures.
      Retrospective 1-year analysis with discussion of current aspects].
AB  - BACKGROUND: Current problems in gastric cancer surgery concern the extent of
      gastric resection, the need for abdominal evisceration, the degree of
      lymphadenectomy, and optimal preoperative tumor staging procedure. PATIENTS AND
      METHODS: In a restrospective analysis, data on epidemiology, extent of surgery,
      histopathology, postoperative complications, mortality, and survival in 284
      gastric cancer patients were evaluated. RESULTS: Our results are in favor of
      subtotal gastrectomy performed for all T stages located in the distal or middle
      third, provided that a tumor-free margin of 5 cm in intestinal type and 10 cm in
      diffuse Lauren's type tumor can be achieved. Additional organ resections are
      indicated only if direct tumor invasion has occurred, and should not be part of
      an extended lymphadenectomy procedure. The degree of lymph node removal should be
      guided by the primary tumor site. Multimodal therapeutic approaches and high
      postoperative mortality after exploratory laparotomy justify the use of
      diagnostic laparoscopy in T3/4 tumors and if diagnostic scans suggest possible
      tumor spread. CONCLUSION: Even though surgery for gastric cancer is well
      standardized, a tailored surgical approach to different extent of gastric cancer
      appears warranted.

PMID- 10637702
TI  - [Gastrointestinal quality of life after duodenopancreatectomy in pancreatic
      carcinoma. Preliminary results of a prospective randomized study:
      pancreatoduodenectomy or pylorus-preserving pancreatoduodenectomy].
AB  - BACKGROUND: The Whipple operation (PD) is the standard operation in patients with
      cancer of the head of the pancreas and the periampullary region. However, the
      pylorus-preserving duodenopancreatectomy (PPPD) is supposed to be superior in
      gastrointestinal function. METHODS: In a prospective randomized trial (October
      1994-October 1998) PD and PPPD were compared in terms of global and
      gastrointestinal quality of life, operation time, duration of hospital stay,
      transfusions and perioperative morbidity. Quality of life was analyzed under
      standardized conditions (EORTC-QLQ-30) pre- and postoperatively (weeks 2, 6, 12,
      24, 36, 48, and 60). RESULTS: A duodenopancreatectomy was performed in 48
      patients because of cancer of the head of the pancreas (n = 38) and the
      periampullary region (n = 10) (PD, n = 24; PPPD, n = 24). The PD and PPPD groups
      did not differ according to age, gender or UICC stage. Operation time was shorter
      in the PPPD group (206 +/- 48 vs 306 +/- 54 min) (P < 0.05). Morbidity did not
      differ between the two groups (PPPD 20% vs PD 30%, P > 0.05). While there was no
      difference in global quality of life, gastrointestinal quality of life was
      postoperatively increased in the PPPD group regarding appetite, nausea and
      diarrhea (P < 0.05). While the preoperative body weight was reached after 6
      months in 85% of the PPPD group (n = 20), this was true in only 60% of the PD
      group (n = 14) (P < 0.05). CONCLUSION: PPPD seems to be associated with a better
      postoperative gastrointestinal quality of life than PD.

PMID- 10637703
TI  - [Preoperative MR mammography in breast carcinoma. Effect on operative treatment
      from the surgical viewpoint].
AB  - INTRODUCTION: In a prospective study the diagnostic validity of magnetic
      resonance mammography (MRM) as well as its impact on the choice of the operative
      procedure in the treatment of breast cancer was examined. In 125 patients who
      were suspected of having breast cancer by clinical examination, ultrasound, and X
      ray mammography, additional bilateral MRM was performed. Of special interest was
      the diagnostic potential of MRM with regard to multifocal, multicentric and
      contralateral lesions. METHODS: After a complete resection all lesions diagnosed
      by the various conventional methods were examined patho-histologically. In 112
      patients, complete data were available to calculate the sensitivity and the
      specificity of each method as well as to correlate its results with the
      pathohistological findings. RESULTS: In 91 cases, a breast carcinoma was
      diagnosed by conventional methods, with a sensitivity/specificity of 73%/67% for
      clinical examination, of 58%/86% for ultrasound, and of 89%/20% for X-ray
      mammography. In this preselected series of patients with a prevalence of 81.25%
      the diagnosis established by the various methods was confirmed by MRM with
      sensitivity of 96.7% and specificity of 19%. Forty-six additional suspicious
      lesions were found only by MRM, of which 28 were malignant (25 multifocal or
      multicentric and 3 contralateral carcinomas), and 18 benign. The rate of false
      positive MRM results was 18%. Due to the MRM findings, the therapeutic procedure
      was changed from breast preservation to mastectomy in 14.3%. CONCLUSION: Not only
      for the differential diagnosis of discrepant findings between X-ray mammography
      and ultrasound, but especially for the diagnosis of multifocal or multicentric
      lesions, MRM seems to be the method of choice. Consequently, MRM plays an
      important role in planning the operative procedure in breast cancer patients,
      especially in the context of breast preservation. To ensure optimal use of this
      new diagnostic tool high technical standards, proper expertise on the part of the
      examining radiologist, and effective cooperation among the involved disciplines
      (radiology, pathology, surgery) must be guaranteed.

PMID- 10637704
TI  - [Effect of transanal excision on rate of recurrence of stage I rectal carcinoma
      in comparison with radical resection methods].
AB  - INTRODUCTION: In the case of T1 low-risk rectal cancer, transanal excision is an
      established method. Now the question arises whether we can also treat higher
      stages, i.e. T1 high-risk and T2 tumors, by transanal excision with an acceptable
      recurrence rate. METHOD: The hospital notes of 152 patients treated by radical
      resection and transanal excision were examined retrospectively with special
      regard to the rate of recurrence after an average follow-up of 9.5 years.
      RESULTS: Twenty-five patients were treated by rectal exstirpation, 105 by
      anterior resection. In 22 cases local tumor excision was performed: in 12 T1
      carcinomas with curative intent and in 10 T2 carcinomas as a minimally invasive
      procedure for high-risk patients. Recurrence rates were between 8% and 9% in the
      three different groups. CONCLUSIONS: We recommend transanal excision with
      curative intent only in T1 low-risk tumors. Local excision is seen as an
      alternative minimally invasive treatment for patients in poor general condition
      with T2 carcinomas.

PMID- 10637705
TI  - [Experiences in surgery of proctologic diseases in patients with HIV infection].
AB  - Individuals who are seropositive for the human immunodeficiency virus (HIV) often
      suffer from disorders affecting the anorectum, but unfortunately the best kind of
      treatment frequently seems questionable. In a retrospective investigation we
      reviewed 29 HIV-positive patients with anorectal lesions who had experienced a
      proctologic operation. Our impression correlates with other findings according to
      which HIV-positive patients in advanced stages have a poorer post-operative
      outcome in terms of morbidity and survival than patients in an early CDC disease
      stage. This implies that the indication for a proctologic operation in an
      immunocompromised state has to be considered carefully.

PMID- 10637706
TI  - [Thoracoscopic therapy of pleural empyema after pneumonectomy].
AB  - In a 4-year period two right-sided empyemas occurred following a total of 39
      pneumonectomies for lung cancer. In another case pneumonectomy was performed for
      left-sided lung cancer with concomitant empyema as an emergency procedure in a
      patient referred from an outside hospital. Empyema was treated with repeated
      thoracoscopic debridements and intermittent lavage with polyvinylpyrrolidine
      iodine solution and streptocinase/streptodornase. Three to seven thoracoscopies
      were required to sterilize the pleural cavity. After a median follow-up of 14
      months all three patients are well and without any evidence of infection. VATS is
      suitable for definitive treatment of postpneumonectomy empyema and is associated
      with excellent functional and cosmetic results.

PMID- 10637707
TI  - [Minimal invasive video-assisted vein preparation (Endoscopic vein harvesting
      EVH) in peripheral bypass surgery].
AB  - Saphenous vein harvesting remains a 20% source of morbidity in patients who
      require lower extremity bypass or coronary artery bypass grafting. In an attempt
      to reduce the complications associated with this procedure, minimally invasive
      video-assisted vein harvesting is propagated. The technique uses currently
      available endoscopic equipment with mechanical retraction to dissect the great
      saphenous vein with two limited incisions. The dissection is visualized on the
      video monitor to isolate and control side branches by clips. The vein is removed
      for reverse arterial bypass grafting or dissection is completed for an in situ
      bypass procedure. Initial experience with ten patients undergoing peripheral
      bypass procedures showed a mean vein-preparation time of 60 min. Two of seven in
      situ bypass procedures were complicated by side branch damage controlled through
      longer skin incision. After a mean follow-up of 12 months, all bypasses are
      patent. Taking our own experience as well as that reported in the literature into
      consideration, aspects of cost-effectiveness are discussed.

PMID- 10637708
TI  - [Foreign body granuloma of the head of the pancreas caused by a fish bone--a rare
      differential diagnosis in head of the pancreas tumor].
AB  - Despite highly developed scanning methods there is no absolute certainty of
      delineating malignant pancreatic tumor from chronic pancreatitis. Pancreatitis
      caused by foreign bodies has occasionally been mentioned in literature. Our
      report is on the first case of a foreign body granuloma of the pancreatic head
      caused by a fish-bone transduodenally perforating the pancreas. On preoperative
      CT and ultrasound as well as by intraoperative inspection and palpation the
      lesion appeared malignant, so we saw the indication for Whipple's operation.
      Although the histological examination showed a benign state, taking into account
      the generally bad prognosis, in case of suspected malignant pancreatic tumor we
      plead for resection as the only possible form of curative therapy.

PMID- 10637709
TI  - [Free intraperitoneal clip as the cause of mechanical ileus of the small
      intestine].
AB  - In the last 10 years the use of mechanical stapling devices in endoscopic surgery
      have found wide-spread application and acceptance. Even one of the most common
      surgical operations, the appendectomy, is done regularly laparoscopically.
      Therefore, utilization of endostaples is commonplace and often results in the
      spillage of fired staples beyond the margin tissue. We report the case of a 23
      year-old patient who developed the clinical signs of bowel obstruction 2 weeks
      after laparoscopical appendectomy. An exploratory laparotomy was subsequently
      performed. At the time of exploration, a single band was identified that draped
      over the ilium central affixed to a staple. The staple was removed and the
      obstruction relieved without bowel resection. The patient had an uncomplicated
      recovery. We believe that the cause of this mechanical bowel obstruction was a
      loose staple.

PMID- 10637710
TI  - [Epithelioid hemangioma of the popliteal artery].
AB  - We report the case of a 37-year-old patient with an epithelioid haemangioma
      arising from the third segment of the popliteal artery and the tibio-peroneal
      trunk. As far as we know this is the first description of this tumour originating
      in an artery of this order. One year after excision of the tumour mass and
      vascular reconstruction the patient has recovered and shows no evidence of
      recurrence. Clinical manifestation and morphological characteristics of this rare
      lesion are described in this article.

PMID- 10637711
TI  - [Treatment of shaft fractures during the growth period].

PMID- 10637712
TI  - Seafood allergy: tropomyosins and beyond.
AB  - Hypersensitive reactions to seafood is one of the most common food allergies.
      Despite years of intensive studies, the reasons why some people are allergic to
      seafood is still unclear. The growing demand for seafood and the subsequent
      increasing risk of seafood allergy in the population at large make it important
      to elucidate the molecular basis of seafood allergy and identify the seafood
      allergens at the molecular level. Here, we discuss the clinical symptoms,
      physiological mechanisms, current findings of the immunological and molecular
      basis of shellfish allergy as well as future directions for the prevention of
      shellfish allergy. Interestingly, identified seafood allergens belong to a group
      of muscle proteins, namely the parvalbumins in codfish and tropomyosin in
      crustaceans. In addition, there is strong immunological evidence that tropomyosin
      is a cross-reactive allergen among crustaceans and mollusks. The molecular
      cloning, expression and biochemical characterization of seafood allergens will
      continue to provide valuable tools in the further understanding of the mechanisms
      of seafood allergy as well as the future development of immunomodulation regimen.

PMID- 10637713
TI  - The role of gastric acid and Helicobacter pylori in the natural course of
      duodenal ulcer.
AB  - This study was conducted using roxatidine acetate or Mylanta combined with
      metronidazole and amoxicillin to evaluate the role of acid and Helicobacter
      pylori in the natural course of the duodenal ulcer. Eighty-three patients with H.
      pylori positive duodenal ulcers were randomly allocated into one of four
      treatment groups. Group A: roxatidine 75 mg hs for 8 weeks; Group B: the same as
      group A + metronidazole 250 mg and amoxicillin 250 mg qid for 1 week on the 3rd
      week; Group C: Mylanta (combined hydroxide of magnesium and aluminum) 20 ml qid
      for 8 weeks; Group D: the same as group C + metronidazole 250 mg and amoxicillin
      250 mg qid for 1 week on the 3rd week. Repeated endoscopies were performed on the
      8th week post the initial treatment and the sixth and 12th month post the
      termination of treatment, or, at the earliest recurrence of symptoms. Eradication
      of H. pylori was considered to be successful if the culture, histology and CLO
      test all showed negative. The ulcer healing rates of Groups A, B, C and D were
      95%, 100%, 61% and 86%, respectively, with a significant difference between A and
      C. The eradication rates of groups B and D were 81% and 62%, respectively,
      without any significant difference. The 12 months cumulative ulcer recurrence
      rates were 72%, 15%, 80% and 22%, respectively, with a significant difference
      between each paired groups with and without antibiotics. In conclusions,
      roxatidine is effective in the healing of duodenal ulcer. One-week roxatidine
      based triple therapy is powerful in the eradication of H. pylori. Potent acid
      suppression is sufficient to heal the duodenal ulcer. Eradication of H. pylori
      can potentiate ulcer healing under insufficient acid suppression. A causal role
      for H. pylori in recurrent duodenal ulcer is strongly supported by a much lower
      recurrence of ulcer in H. pylori free patients.

PMID- 10637714
TI  - Mutation analysis of pertussis toxin promoter.
AB  - The improving of the expression efficiency of a pertussis toxin (PT) promoter was
      believed to be a critical issue for the production of PT in acellular vaccine
      development. In this study, we have isolated a PT promoter region from the genome
      of a pertussis strain ATCC 9340. Based on the promoter sequence, a series of
      mutant PT promoters have been generated and subjected to in vitro gel shift
      analysis and in vivo reporter beta-galactosidase activity study. As compared with
      the wild type promoter, the mutation of the ribosome binding sequence or -10
      element, to the respective consensus sequence derived from strong bacterial
      promoters, resulted in an enhancement of its interaction with two cellular
      proteins, and a slightly higher beta-galactosidase activity (1.3 fold). Whereas,
      the change of either upstream inverse repeats or 20-bp direct repeats to a
      certain complete repeat significantly promoted the formation of another DNA
      protein-complex, and exhibited an 1.8 fold beta-galactosidase activity. These
      findings would have provided a mutation target for making a more efficient PT
      production pertussis strain.

PMID- 10637715
TI  - Sex differences in pediatric systemic lupus erythematosus: a retrospective
      analysis of 135 cases.
AB  - A retrospective review of 135 patients with systemic lupus erythematosus (SLE)
      (24 boys and 111 girls) under age 18 at the National Taiwan University Hospital
      (NTUH) from 1989 to 1998 was done. The aim of this retrospective study was to
      compare the differences in the age at diagnosis, clinical, laboratory features
      and survival among both sexes. The female to male ratio was 4.6:1. The mean age
      at the time of diagnosis was 13.7 years (range, 8y5m-18y) for male patients and
      13.7 years (range, 6y1m-18y) for female patients. There was no significant
      differences in the mean age of diagnosis between the sexes. It was found that
      there were no significant differences in the clinical and laboratory features
      between male and female patients except for the prevalence of oral ulcers,
      alopecia and anti-SSA antibodies which were more frequent in the female group.
      The cumulative 5- and 10-year survival rates were 80.2% and 65%, respectively;
      male patients appeared to have a better survival, yet it did not reach any
      statistical significance. Univariate analysis showed that gender is not a
      significant factor on prognosis in pediatric SLE. Although abnormal creatinine
      was associated with poor mortality, it was not statistically significant on
      multivariate analysis.

PMID- 10637716
TI  - Penicillin-nonsusceptible Streptococcus pneumoniae infections in children.
AB  - The emergence of penicillin-nonsusceptible Streptococcus pneumoniae (PNSSP) has
      brought a new clinical challenge. In Taiwan, reports of the prevalence and
      clinical features of PNSSP infections in children are limited. This study
      reviewed the resistance patterns of all clinical isolates of S. pneumoniae
      obtained from patients under 17 years of age from January 1993 through July 1998
      in a medical center. Their clinical features and treatment responses were
      analyzed, with special attention paid to those patients with invasive PNSSP
      infections. Totally, 170 clinical isolates of S. pneumoniae were obtained from
      168 patients aged under 17 years. Among those infections, there were 56 sinusitis
      (including 4 sinusitis with bacteremia), 44 pneumonia (including 23 pneumonia
      with bacteremia or empyema), 23 otitis media (including 5 otitis media with
      bacteremia), 9 simple bacteremia, 9 conjunctivitis, 8 meningitis, 4 peritonitis,
      3 skin infections and the other 14 isolates were colonization. One hundred eleven
      isolates (65.3%) showed reduced penicillin susceptibility by the disk diffusion
      method. A trend of increasing percentiles of PRSP was noted: 27.3% (3/11) in
      1993, 37.5% (9/24) in 1994, 55.5% (10/18) in 1995, 77.5% (31/40) in 1996, 66.0%
      (31/47) in 1997, and 87.1% (27/31) in 1998. Minimum inhibitory concentration
      (MIC) determinations by the E-test showed some of the isolates were
      intermediately resistant. Prior antibiotic usage was associated with a higher
      incidence of PNSSP infections. However, most children responded well to
      antimicrobial treatment.

PMID- 10637717
TI  - Investigation of an outbreak of Pseudomonas putida using antimicrobial
      susceptibility patterns, pulsed-field gel electrophoresis of genomic DNA and
      restriction fragment length polymorphism of PCR-amplified rRNA operons.
AB  - Seventeen Pseudomonas putida isolates were investigated which were collected from
      the urine specimens of 14 patients and one reflectrometer by comparing
      antimicrobial susceptibility patterns, pulsed-field gel electrophoresis (PFGE) of
      genomic DNA, and restriction fragment length polymorphism (RFLP) of PCR-amplified
      rRNA operons. Three susceptibility patterns were defined by testing 22
      antimicrobial agents, with 14 isolates resistant to all agents. PFGE of XbaI
      genomic DNA fragments divided the 17 isolates into 9 distinct types. One type,
      seen in 6 isolates showing identical patterns of approximately 35 fragments of 10
      to 350 kb, was defined as the outbreak strain. Another 4 types, in a total of 6
      isolates, were considered closely related to the outbreak strain; 2 types in 1
      isolate each were possibly related to the outbreak strain; and 2 types in a total
      of 3 isolates were different from the outbreak strain. All 12 outbreak or closely
      related isolates were from patients in the surgical intensive care unit and a
      surgical ward, and were different from isolates in other wards, clearly
      indicating an outbreak of P. putida. Only two types were defined by the RFLP of
      4.5 kb PCR-amplified rRNA operons; one type was seen in 15 isolates, while the
      other was seen in only 2 isolates. In conclusion, PFGE of genomic DNA is a highly
      discriminatory and reproducible method for epidemiological typing of P. putida.

PMID- 10637718
TI  - Susceptibility testing and clinical effect of fusidic acid in oxacillin-resistant
      Staphylococcus aureus infections.
AB  - One hundred and six oxacillin-resistant Staphylococcus aureus (ORSA) isolates
      collected from various clinical specimens at Mackay Memorial Hospital during the
      period from 1997 to 1998 were tested. The MICs of fusidic acid against ORSA
      isolates were in the range of 0.06 microgram/mL to 4 micrograms/mL. There was
      only one ORSA isolate (0.9%) resistant to fusidic acid in this study. Twenty-four
      patients with ORSA infection were enrolled into the study between July 1997 to
      June 1998. Four patients without the evidence of sepsis received oral fusidic
      acid only. The other 20 patients with sepsis received intravenous glycopeptide
      first, and then the oral fusidic acid for 7 to 10 days. Oral fusidic acid was
      used for mild ORSA infection and achieved satisfactory clinical outcome. In
      severe ORSA infection, it was found that sequential therapy with fusidic acid had
      relapsed in three patients. We concluded that oral fusidic acid achieved a
      satisfactory outcome in our patients with mild ORSA infection. In such cases,
      fusidic acid may provide an effective alternative treatment of choice. The rare
      side effect of granulocytopenia and jaundice was noted in our case series. The
      side effect may be not so rare as previously thought, if it had been carefully
      looked for.

PMID- 10637719
TI  - Urinary tract infection in children.
AB  - Two hundred and eighty-five children under 15 years old (169 boys and 116 girls)
      who had urinary tract infection (UTI) were admitted to our hospital during the
      period July 1995 to June 1998. Clinical presentation, laboratory data and image
      studies were recognized and analyzed. Most patients were younger than 2 years of
      age. Fever is the most common sign, especially in young children. With the
      urinary dipstick test a low positive rate of nitrite reaction (34.7%) was found.
      E. coli is the most common pathogen and exclusively resistant to ampicillin
      (90.2%). The E. coli is also relatively resistant to
      trimethoprim/sulfamethoxazole (57.1%). Voiding cystourethrogram was performed in
      187 cases, in which 24.6% of those patients showed vesicoureteric reflux. Ninety
      eight children received 99mTc-dimercaptosuccinic acid renal scans and 62 cases
      (63.3%) had abnormal findings compatible with pyelonephritis. The positive
      predictive values by renal ultrasonography for vesicoureteric reflux and
      pyelonephritis are 30.7% and 78.9%, respectively. In pyelonephritis patients,
      only 37% also had a vesicoureteric reflux. The fever duration and clinical
      inflammatory parameters were evaluated in all patients. Longer febrile periods
      are the risk of vesicoureteric reflux and pyelonephritis, and a high C-reactive
      protein concentration indicates the risk of pyelonephritis. In conclusion, fever
      was the most common sign in young UTI children who had a low positive nitrite
      reaction rate in the dipstick test. E. coli was the most common pathogen with a
      high ampicillin resistance in Taiwan. Only 37% pyelonephritis patients had
      refluxing nephropathy. It is indicated that pyelonephritis is not always
      attributed to reflux of infected urine. A longer febrile period and a high C
      reactive protein level are good indicators for prediction of the risk of
      pyelonephritis in UTI patients.

PMID- 10637720
TI  - [Immunity against diphtheria in Taiwan].
AB  - The vaccination of combined diphtheria, pertussis, and tetanus (DPT) vaccine
      provides good immunity against childhood diphtheria in Taiwan. However, a waning
      protective antibody level has been observed with an increase in age. Therefore,
      we assessed diphtheria immunoglobulin (DIG) level in Taipei City as
      representatives of urban dwellers and in King-Shan County as representatives of
      rural dwellers to evaluate the status of immunity against diphtheria in the
      population of Taiwan. In total, 1239 serum samples collected from the resident
      population, age 0-91 years, were detected by toxin neutralization test with VERO
      cells. The DIG level > or = 0.01 IU/mL was considered to be seropositive and > or
      = 0.1 IU/mL was considered to be fully protective. The positive rate and fully
      protective rate for all persons were 79.9% and 36.6%, respectively. The age
      specific positive rate and fully protective rate for children under 14 years of
      age were 97.0% and 78.0%, for 20-29 years of age group, were 38.0% and 8.3%,
      respectively, to be the lowest record among tested age groups. Then, both rates
      increased proportionately with age. Among those birth cohorts born in the
      diphtheria immunization era (since 1955), the antibody levels were inversely
      correlated with age, suggesting a decreased opportunity for exposure to natural
      diphtheria infection in the recent years and the duration of the vaccine
      inoculation. This finding indicates the need of a booster vaccination for young
      adults to ensure a full term protection and a long lasting diphtheria control.

PMID- 10637721
TI  - Porphyromonas gingivalis bacteremia and subhepatic abscess after renal
      transplantation: a case report.
AB  - A uremic patient developed subhepatic abscess, Porphyromonas gingivalis
      bacteremia and cytomegalovirus viremia after a renal transplantation in mainland
      China. P. gingivalis infection has been reported to cause gingivitis and
      periodontitis. Bacteremia due to P. gingivalis, however, has not been reported in
      the literature. We report herein a case of subhepatic abscess and bacteremia due
      to P. gingivalis in a renal transplant recepient who was treated successfully
      with the well functioning renal graft.

PMID- 10637722
TI  - Genital tuberculosis with peritonitis mimicking Meigs' syndrome: a case report.
AB  - A 19-year-old girl presented with genital tuberculosis (TB) complicated with
      peritonitis and pleural effusion. In addition to oligomenorrhea, her initial
      presentation included symptoms of intermittent high fever, exertional dyspnea,
      productive cough and body weight loss. Acid-fast bacilli were identified by
      sputum culture. She continued to suffer from persistent abdominal discomfort and
      body weight loss after eight months of anti-TB treatment. Finally, exploratory
      laparotomy was performed under the suspicion of Meigs' syndrome or TB
      peritonitis. Operative findings included diffusely granulomatous change over the
      peritoneum, ovaries, endometrium, intestine and liver. Histologic examination of
      the ovaries and endometrium showed caseous necrosis associated with Langhan's
      giant cells and epithelial cells. Acid-fast stain revealed numerous acid-fast
      bacilli. She was discharged after two months of anti-TB treatment. Anti-TB
      therapy was continued for one year after discharge. During 3 years of post
      discharge follow up, she was free of abdominal discomfort and had given birth to
      two healthy children.

PMID- 10637723
TI  - [Evolution of the hand].
AB  - The skeleton of the human hand has its evolutionary origin in the anterior fin of
      primitive fishes following a reduction process. Starting with 20 to 30 elements,
      the number of bones reduces to eight. This does not follow a continuous pattern
      but is influenced by environmental factors. This becomes particularly evident
      when considering the development of the opposition of the thumb. The muscles of
      the hand evolve from dorsal and palmar compact plates which are divided into two
      layers. The differentiation process follows the development of the fingers. The
      development of the individual hand is controlled by a group of homeobox genes.
      Comparable genes are found in many different species. The more recent evolution
      of the hand can be understood as the expression of the development of the brain.
      Therefore, the hand is a direct tool of our consciousness. It is a main source of
      differentiated tactile sensations as well as a precise working organ. Gestures,
      finally, are direct expressions of our personality.

PMID- 10637724
TI  - [Pulleys of the tendon sheath of the flexor pollicis longus muscle].
AB  - The fibrous wall of the flexor tendon sheath of the thumb is reinforced by
      pulleys similar to those in the fingers. As cited in the literature, there are
      two annular pulleys A 1 and A 2 and one oblique pulley. On the basis of our
      investigations, this distribution was found only in 10%. In 90%, the proximal (A
      1) and the distal pulley (A 2) can be seen. However, between these two annular
      pulleys a Y-shaped fiber complex can be dissected at the level of the base and
      the shaft of the proximal phalanx. This complex can be further divided into an
      annular part (proximal) and an oblique part (distal). The annular part is
      associated with the tendon insertion of the adductor pollicis muscle. The oblique
      part arises distal from the annular part from the ulnar side of the tendon
      sheath, running to the radial side of the proximal phalanx interwoven with the
      interphalangeal joint capsule and the palmar plate. Some fiber strands
      continually pass into the cutaneous ligaments of Cleland. Thin accessory pulley
      fibers were found between the annular pulley A 1 and the annular part of the Y
      shaped fiber complex in 9.5% and in 20.6% between the oblique part and the
      annular pulley A 2.

PMID- 10637726
TI  - [Value of clinical diagnosis in carpal tunnel syndrome].
AB  - The aim of this study was to examine sensitivity and specificity of Durkan test
      in 54 patients with carpal tunnel syndrome confirmed by electrophysiological
      testing, as compared to a control group of 54 patients without clinical signs of
      the syndrome. Sensitivity and specificity of Durkan test alone, as well as in
      combination with Phalen test and Hoffmann-Tinel test, were determined. The
      sensitivity of Durkan test was 0.87, its specificity was 0.96. The sensitivity of
      Phalen test was 0.85 with a specificity of 0.96. It was discovered that the
      combination of Phalen with Durkan test achieved a sensitivity of 0.94 and a
      specificity of 0.96, thus equalling the respective values for
      electrophysiological testing (nerve conduction velocity, electromyography) which
      so far is regarded as the golden standard diagnostic test for carpal tunnel
      syndrome. If Hoffmann-Tinel test is included as a further clinical parameter,
      then both sensitivity and specificity reach 0.96. This study, therefore, raises
      the question of whether costly electrophysiological testing is in fact necessary
      before surgery for carpal tunnel syndrome, when the clinical tests have already
      proven positive.

PMID- 10637725
TI  - [Effect of pre-degeneration of peripheral nerves on plasticity of cultivated
      Schwann cells and their cell number in vitro].
AB  - Predegeneration of peripheral nerve grafts is known to improve axonal
      regeneration in the sciatic nerve of the rat. Predegeneration involves sectioning
      the donor nerve in situ for a period of time prior to harvesting in order to
      allow Wallerian degeneration to take place. It is suggested that proliferating
      Schwann cells are responsible for this regeneration-promoting effect due to an
      increased production and accumulation of trophic factors. The aim of this study
      was to evaluate whether the proliferation of Schwann cells is increased after
      various predegeneration periods and whether predegeneration does affect the
      production of trophic factors. The rat's sciatic nerve was transsected distal to
      the spinal ganglion. Predegeneration was allowed to take place for one, two,
      three and four days and one, two and three weeks, respectively. The nerve was
      resected and prepared for Schwann cell cultivation. Cells cultivated from the
      contralateral untreated nerve served as control. S100 immunostaining, nerve
      growth factor (NGF), and N-cadherin were used to characterize Schwann cells.
      Viability was assessed by fluoresceine fluorescence staining. Proliferation index
      was determined by BrdU DNA incorporation. Cultivation of cells harvested from
      predegenerated nerves indicated an increased proliferation of Schwann cells
      compared to the control. Proliferation effects depended on the period of
      predegeneration. A higher cell yield was obtained as early as 24 hours and up to
      three weeks after predegeneration. Optimal proliferation was seen after one week
      of predegeneration. The rapid expansion of Schwann cell populations oppressed the
      development of contaminating fibroblasts. NGF and N-cadherin were expressed by
      all S100-positive cells. Predegeneration did not affect viability. The determined
      high mitotic activity of predegenerated Schwann cells in combination with an
      early onset of proliferation may explain the regenerating-promoting effect of
      predegenerated nerve grafts. The expression of both NGF and N-cadherin in the
      predegenerated cultures indicates a high level of plasticity with
      dedifferentiation capacity, which in turn promotes neural regeneration.
      Predegeneration allows a proliferation of Schwann cells without concomitant
      pharmacological treatment. Thus, predegeneration of peripheral nerves is
      considered to be a highly efficacious method if a high yield of activated Schwann
      cells is desired within a short period of time. This may become relevant in the
      future of repair of peripheral nerve lesions, when autologous Schwann cells with
      their capacity to provide neurotrophines and cell adhesion molecules are used as
      cellular prostheses to bridge nerve gaps.

PMID- 10637727
TI  - [Bowers hemi-resection-interposition arthroplasty for treatment of post-traumatic
      arthrosis of the distal radio-ulnar joint after distal radius fractures].
AB  - Arthrosis of the distal radioulnar joint (DRUJ) is a common problem following
      fractures of the distal radius. The treatment options include the hemiresection
      interposition technique (Bowers procedure) or Kapandji-Sauve procedure. In a
      retrospective study, we assessed the results of the Bowers procedure. MATERIAL
      AND METHODS: From 1992 to 1997, 24 patients were treated by the hemiresection
      interposition technique (Bowers procedure) for arthrosis of the DRUJ following
      fracture of the distal radius. The average follow-up time was 30.5 (9 to 55)
      months. RESULTS: The average preoperative pronation was 67 degrees, the
      supination 45 degrees. Postoperatively, we found a pronation of 80 degrees and a
      supination of 62 degrees. Grip-strength compared to the opposite site could be
      improved from 38 to 57% postoperatively. Pain was reduced markedly in 78% of the
      patients. However, ten patients developed a postoperative instability of the
      distal ulna. In only two patients did painful instability necessitate revision
      procedures. CONCLUSION: The hemiresection-interposition technique is a salvage
      procedure for the destroyed DRUJ, leading to good clinical results in most
      patients. Painful instability of the distal ulna and remaining functional
      deficits can be the reasons for failure. Therefore, adequate primary reduction of
      fractures of the distal radius or secondary reconstruction of the anatomy is
      necessary to prevent secondary arthrosis of the DRUJ.

PMID- 10637728
TI  - [Rib cartilage transplant in arthrosis of the thumb basal joint].
AB  - The method and the results of costal cartilage replacement for the trapezium are
      described. The idea was to find an alternative method for trapezium implant
      arthroplasty. From 1995, 47 patients were treated by this technique, 42 patients
      could be examined. There were good results in function and no case of shortening
      of the thumb. Except of two, all patients were satisfied.

PMID- 10637729
TI  - [Metastasizing chondrosarcoma of the pisiform bone: a case report].
AB  - We report about a chondrosarcoma of the pisiform in a 39-year-old man. 1.5 years
      after exstirpation of the tumor, an extended recurrence developed. Two years
      after the first operation, an amputation was performed at midshaft of the upper
      arm. One year later, multiple metastases in both lungs were found.

PMID- 10637730
TI  - [Clinical aspects and therapy of benign symmetrical lipomatosis--Madelung
      disease].
AB  - The clinical picture, diagnosis, therapy, and theories on the etiology of benign
      symmetric lipomatosis (Madelung disease) are outlined. Personal experience from
      62 operations on 28 patients is compared to the literature. Up to now, there is
      only palliative surgical treatment for this sporadically appearing disease of
      unknown etiology. Liposuction--a less traumatic treatment--has considerably
      facilitated the treatment of the circumscribed fatty hyperplasias. The surgical
      characteristics of different anatomical regions are pointed out.

PMID- 10637731
TI  - [Orthotopic cartilage transplantation. Morphologic, angiography and histochemical
      studies of the vitality of free septum transplants].
AB  - Orthotopic cartilage transplantation is a technique frequently used in modern
      septal surgery. The prerequisite for a stable long-term result is viability of
      the transplanted cartilage. Therefore, we studied the healing process
      histologically, angiographically, and histochemically. We found a characteristic
      picture. Due to chondronal structure of the cartilage, the healing process varied
      in time and location. Reintegration took place by chondroneogenesis, commencing
      at the inner perichondrium. Reintegration depended directly on the distance of
      the cartilage cells to the surrounding vessels. Histochemically, we found an
      intact respiratory chain in the mitochondria and thus, we were able to
      demonstrate the preservation of viability in orthotopic transplanted cartilage.

PMID- 10637732
TI  - [Reconstruction of nose defects by combined multiple flap-plasties and
      stabilization with cartilage transplants].
AB  - In the reconstruction of nasal defects, the method of choice involves flaps from
      the immediate surroundings (nose, cheek, forehead), because of their superior
      skin colour and texture match. In defects involving all layers of the nose, the
      inner lining and the nasal skeleton must also be reconstructed. These procedures
      are often performed in several steps, with incision and elevation of flaps,
      implantation of cartilage and skin-grafting of the donor site (prefabricating).
      By using one flap to replace the missing skin and a second flap for inner lining,
      a stabilizing cartilage graft can be inserted primarily. Using this "sandwich
      technique", subtotal nose reconstructions can be performed in a single stage as
      well. Between 1986 and 1996, 23 patients underwent nasal reconstructions using
      local flaps. Our reconstructive concept is demonstrated by means of several
      clinical cases.

PMID- 10637733
TI  - [Tripier bridge flap technique for lower eyelid reconstruction].
AB  - Defects of the lower lid are more common than defects of the upper lid. Various
      methods for reconstruction of the lower lid have been published; we prefer the
      method of Tripier. The inner lining is reconstructed using a composite graft from
      the nose, and the outer defect is covered by a myocutaneous bridge flap from the
      upper lid. We have used this technique for defects of different sizes and have
      obtained good functional and aesthetic results.

PMID- 10637734
TI  - [Breast reconstruction with the deep inferior epigastric perforator vein flap].
AB  - Aside from existing advantages for reconstruction of an amputated breast with a
      free versus a pedicled TRAM-flap, small parts of the rectus abdominis muscle
      still must be sacrificed to secure blood perfusion of the flap. The deep inferior
      epigastric perforator flap (DIEP-flap) was recently introduced to overcome this
      disadvantage in autogenous breast reconstruction. Morbidity of the donor site
      should be minimized, since this technique avoids fascia or muscle defects. Eight
      patients underwent ten autogenous breast reconstructions with a DIEP-flap. Four
      flaps were performed for immediate and six flaps for delayed reconstructions. The
      internal thoracic artery and vein were used as recipient vessels in seven cases,
      the thoracodorsal vessels were utilized in three cases. The average operating
      time was 4.5 hours for unilateral and 6.9 hours for bilateral reconstructions.
      Two flaps developed total flap necrosis. One was due to a technical error during
      dissection, another flap developed an arterial thrombosis on postoperative day 5.
      The remaining flaps healed without problems. Subjectively, patients had far less
      complaints about the donor site in the lower abdomen compared to a free TRAM
      flap, suggesting a lower morbidity in this area with the DIEP-flap.

PMID- 10637735
TI  - [Concurrent platinum-based chemotherapy and radiotherapy for locally advanced
      bladder cancer].
AB  - Eight patients with locally advanced bladder cancer who were not candidates for
      radical cystectomy or concurrent intra-arterial chemotherapy and radiotherapy
      were treated with combined platinum-based chemotherapy and radiation therapy. Six
      of the eight patients (75%) achieved a clinical complete response (CR). The
      effect of therapy in four patients whose histopathological responses were
      evaluated was effect grade 3. One of the eight patients died of treatment-related
      myelosuppression. The other two patients died of intercurrent disease, while the
      remaining five patients are alive with preservation of a functional bladder. The
      2-year overall survival rate was 87.5%. Adverse events due to chemotherapy were
      mainly bone marrow suppression. Those caused by radiation therapy were rectal
      irritability. We considered concurrent platinum-based chemotherapy and
      radiotherapy useful for the treatment of locally advanced bladder cancer.

PMID- 10637736
TI  - [Clinical results of interstitial laser coagulation for benign prostatic
      hyperplasia using diode laser].
AB  - Interstitial laser coagulation (ILCP) is currently considered to be one of the
      avenues for treatment of benign prostatic hyperplasia (BPH). The efficacy and
      effectiveness of the treatment, however, have not been well clarified. Here we
      report the outcome of treatment in benign prostatic hyperplasia using ILCP.
      Twenty patients with BPH who underwent interstitial laser coagulation using a
      diode laser between March and December 1998 were investigated. Our results showed
      that there are significant improvements in prostate symptom score and quality of
      life index after the treatment. According to the efficacy criteria, 70% of the
      patients showed clinical improvement of both scores at 1 month, and more than 90%
      of the patients at 3 months. The reduction of prostate volume was observed after
      1 month of treatment and continued for 6 months. The improvement on peak flow
      rate was observed in 50% of the patients at 3 months and in 73.3% of the patients
      at 6 months. The overall efficacy rates were 62.5%, 85.0% and 100% of the
      patients at 1, 3 and 6 months, respectively. In all 20 patients the complications
      were minimal. No blood transfusion was required in any patients. However, one
      patient experienced both epididymitis and prostatic abscess and was treated with
      conservative therapy. In conclusion, interstitial laser coagulation using a diode
      laser is a very effective means for the treatment of benign prostatic
      hyperplasia. Because of its less invasive nature, we strongly recommend that ILCP
      be the major way of treatment for benign prostatic hyperplasia.

PMID- 10637737
TI  - [A case of renal cell carcinoma associated with von Hippel-Lindau disease and the
      necessity for family genetic diagnosis].
AB  - We report a 47-year-old man who had bilateral renal cell carcinoma (RCC)
      associated with von Hippel-Lindau (VHL) disease. Surgical resection of
      hemangioblastomas and left nephrectomy for RCC had been done previously. This
      time, a small RCC was found in his right kidney and enucleation was performed to
      preserve renal function. His mother had retinal angioma, hemangioblastoma, and
      bilateral RCC. Hemangioblastoma was also found in his daughter. Genetic diagnosis
      was performed in his family and a germline VHL mutation was recognized. For
      improvement of the prognosis of VHL disease, genetic diagnosis and early clinical
      assessment are important.

PMID- 10637738
TI  - [Inverted papilloma of the renal pelvis: report of a case].
AB  - Inverted papilloma of the upper urinary tract is a rare lesion. To our knowledge,
      we report here the 32nd case of inverted papilloma of the renal pelvis. A 50-year
      old man presented with asymptomatic gross hematria. Excretory urography showed a
      filling defect in the left upper calyx. Computerized tomography showed a poorly
      enhanced low-density area within the renal pelvis. Since radiographic findings
      suggested a renal pelvic tumor, the patient underwent total nephroureterectomy.
      Unexpectedly, a 3 x 2.5 cm polypoid tumor of the renal pelvis was consistent with
      inverted papilloma. Since this benign lesion is extremely rare within the upper
      tract and its radiographic characteristics closely resemble those of urothelial
      carcinoma, the preoperative diagnosis of inverted papilloma of the upper tract
      cannot be conclusively established even by modern imaging techniques. Therefore
      treatment consistent with that for urothelial carcinoma should be applied in this
      disease entity.

PMID- 10637739
TI  - [A case of vesicovaginal fistula with vaginal stone].
AB  - The patient, a 51-year-old woman developed urinary incontinence after an
      abdominal hysterectomy 3 years earlier. She was referred to our hospital
      complaining of urine leakage from her vagina after spontaneous passage of a
      stone. Drip infusion pyelography and cystography demonstrated a vesicovaginal
      fistula. She underwent repair of the fistula with an abdominal procedure. The
      stone was composed of magnesium ammonium phosphate.

PMID- 10637740
TI  - [An experience of indwelling of a urethral stent (Urolume Wallstent) for urethral
      stricture accompanying pelvic fracture in a young man].
AB  - The patient was a 15-year-old boy, who sustained pelvic fracture and complete
      disruption of the urethra in a traffic accident. The previous doctor performed
      two-staged treatment for complete disruption of the urethra, which ended in
      postoperative urethral stricture. We performed two sessions of endoscopic
      operations and a pull-through procedure, but the procedures were not effective.
      Five years later, a urethral stent was indwelt. Urolume Wallstent of AMS, Co,
      Ltd. was used as the urethral stent. At 4 months, the stent started to be
      enveloped in the urethral epithelia and no complications have been found in
      particular. However, detention of a permanent-type stent in a young man such as
      ours remains a controversial issue and long-term follow-up is needed.

PMID- 10637741
TI  - [Giant testicular tumor: a case report].
AB  - We report a case of giant testicular tumor. A 30-year-old man visited our
      department complaining of a painless swelling of the right scrotal contents. In
      chest X-ray and abdominal computerized tomography (CT) there were no abnormal
      findings. Serum alpha-fetoprotein, human chorionic gonadotropin and lactate
      dehydrogenase levels were normal. Right high orchiectomy was performed. The size
      of the removed specimen was 13.5 x 8.5 x 7.5 cm, and weight 530 g. The
      pathological diagnosis was immature teratoma. The patient has received no further
      therapy. There has been no recurrence for 7 months postoperatively.

PMID- 10637742
TI  - [In Process Citation]

PMID- 10637743
TI  - [Results of chemotherapy and salvage surgery for advanced testicular cancer].
AB  - Since 1980, 73 patients with advanced testicular cancer have been treated with
      chemotherapy and 43 patients received post-chemotherapy (salvage) surgery. The
      median age of all patients was 31 years old, ranging from 17 to 63 years. The
      histology of the primary testicular tumor was pure seminoma in 23 patients and
      non-seminoma in 50 patients. According to the Japan Urological Association
      classification, 38 patients were classified as stage II and 35 patients as stage
      III. As first-line chamotherapy, 52 patients were treated with PVB regimen
      (cisplatin, vinblastin, bleomycin), 16 patients with PEB (cisplatin, etoposide,
      bleomycin) and 5 patients with VAB-6 (vinblastine, actinomycin-D, bleomycin,
      cisplatin, cyclophosphamide). Thirty (41%) of the 73 patients achieved a complete
      response (CR) with chemotherapy alone and 63 (86%) achieved no evidence of
      disease (NED) with salvage treatment. As second-line chemotherapy, 16 patients
      were treated with PE (cisplatin, etoposide), or VIP (etoposide, ifosfamide,
      cisplatin) or VeIP (vinblastine, ifosfamide, cisplatin). One of the 16 patients
      achieved CR and 11 (69%) patients achieved NED. As salvage surgery,
      retroperitoneal lymphnode dissection (RPLND) was performed in 22 patients, RPLND
      with thoracotomy in 7 cases and thoracotomy alone in 4 cases. Necrosis was found
      in surgical specimens of 24 (56%) patients, mature teratoma in 6 (14%) and
      residual cancer in 13 (30%). Ninety-six percent and 100% of the patients with
      necrosis and mature teratoma survived with NED, respectively, but only 54% of the
      patients with residual carcinoma survived despite further treatment. Residual
      cancer was still found in 8 of the 32 (25%) marker normalized cases. Residual
      cancer could not reliably be predicted or discriminated from necrosis or mature
      teratoma by the prognostic criteria. Therefore, salvage surgery remains essential
      in the treatment of advanced testicular cancer.

PMID- 10637744
TI  - [Treatment of advanced testicular cancer and toxicity of chemotherapy].
AB  - To assess the efficacy and toxicity of chemotherapy for advanced germ cell
      tumors, 115 patients with testicular and extragonadal germ cell tumors were
      reviewed. Five-year survival rates of 19 seminoma patients and 96 non-seminoma
      patients were 84% and 68%, respectively. According to the analysis using three
      sets of prognostic criteria, Indiana University Classification, International
      Germ Cell Consensus Classification and K Classification, the 5-year survival rate
      of poor-prognosis patients was 42-45%. BEP regimen (bleomycin, etoposide and
      cisplatin) salvaged with VIP (etoposide, ifosfamide and cisplatin) would be the
      standard therapy for advanced germ cell tumors since high-dose chemotherapy had
      no advantage on survival over the standard-dose regimen. Early serious toxicities
      were observed in 18 patients (15.7%), including pulmonary fibrosis, respiratory
      distress, and sepsis. Poor performance status and prior radiotherapy were risk
      factors for fatal adverse effects. In terms of late toxicites, out of 76 patients
      in complete remission for at least one year after cessation of chemotherapy, 31
      had numbness of extremities and 29 had tinnitus. Serial semen analyses of 38
      patients showed continuous azoospermia or severe oligozoospermia in 22. These
      data indicated that less toxic therapy was required for good-risk patients to
      improve the quality of life, while more intensive therapy for poor-risk patients
      to be cured. Several prognostic criteria should be utilized to properly
      distinguish good- from poor-risk patients, and decide how to treat each patient.

PMID- 10637745
TI  - [Quality of life in patients with testicular cancer after high orchiectomy,
      radiation therapy or chemotherapy].
AB  - We evaluated the physical or psychosocial states of testicular cancer patients
      receiving orchiectomy, radiation therapy and chemotherapy to assess their quality
      of life during and after treatment. The subjects were 33 post-treatment patients
      with testicular cancer who responded to the questionnaire we mailed to them. The
      quality of life score during chemotherapy showed a decrease, which was
      accompanied by gastrointestinal symptoms induced by anti-cancer drugs. With
      regard to the difference in adjuvant treatment types, the surveillance group
      showed the highest score in the satisfaction of daily life. Moreover, married
      patients tended to be satisfied with daily life more than non-married patients.
      With regard to sexual or erectile function, scores of testicular cancer patients,
      especially in the retroperitoneal lymph node dissection group, were inferior to
      these of normal volunteers. In conclusion, the physical or psychosocial states
      after treatment for testicular cancer depend not only on treatment type but also
      marriage status.

PMID- 10637746
TI  - [Clinical study of high-dose chemotherapy with peripheral blood stem cell
      transplantation for poor-risk germ cell tumor].
AB  - Between January 1997 and December 1998, six patients with germ cell tumor were
      treated with high-dose CEC: carboplatin (1,500 mg/m2), etoposide (1,200 mg/m2)
      and cyclophosphamide (100 mg/kg), followed by peripheral blood stem cell
      transplantation (PBSCT) at Nagoya University Hospital. Four patients received one
      cycle of high-dose CEC and two received two cycles. The reasons why the high-dose
      CEC was administered included: 1) refractory to the induction chemotherapy
      (AFP/beta-HCG elevated during the induction chemotherapy or prolonged half-life
      of each marker) in three patients, 2) relapse in two patients, and 3)
      consolidation in one with unresectable mediastinal residual tumor. There were no
      treatment-related deaths and grade 1 hepatotoxicity occurred in one (17%)
      patient. The median duration (range) from PBSCT until a granulocyte count of
      500/microL and a platelet count of 50,000/microL was 8.5 (8-11) and 11 (9-16)
      days, respectively. Of the six patients studied, 5 responded to the treatment;
      two achieved a complete response (CR) and three achieved a partial response (PR).
      One patient achieving a CR and two achieving a PR remained in complete remission
      after 23 to 24 months of follow-up, while the remaining patients with a CR, a PR
      and an incomplete response died of the disease. High-dose CEC could be
      administered without serious toxicity but the effectiveness of high-dose CEC for
      the poor-risk patients with germ cell tumor needs to be further investigated.

PMID- 10637747
TI  - [Clinical results of super high-dose chemotherapy with peripheral blood stem cell
      transplantation for patients with advanced germ cell tumor].
AB  - We examined the clinical results of super high-dose chemotherapy with peripheral
      blood stem cell transplantation (PBSCT) in 14 patients with poor-risk advanced
      germ cell tumors. The mean number of nadir white blood cells was 205 +/-
      126/microliter; the mean period of number of white blood cells fewer than
      1,000/microliter was at 8-10 days (mean +/- SD; 9.2 +/- 0.92). The nadir number
      of blood platelet cells was 1.7 +/- 0.70 x 10(4)/microliter; the mean period of
      number of platelet cells fewer than 5 x 10(4)/microliter was at 12.6 +/- 2.17
      days. Of 10 patients treated with super high-dose chemotherapy with PBSCT as
      induction therapy, 8 patients (80%) showed that the serum tumor marker returned
      within the normal range after super high-dose chemotherapy. Of 8 patients, 7
      underwent resection of the residual tumor. Surgical or pathological CR was
      obtained in 5 of these 7 patients, 4 patients of whom were alive with no evidence
      of disease 29 to 49 months after initial consultation: the other patient died
      with recurrence 20 months after initial visit. On the other hand, super high-dose
      chemotherapy with PBSCT was performed for one patient as consolidation, and for 3
      patients with recurrence. Of these 4 patients, one died from disease 6 months
      after detection of recurrence. The other 3 patients were alive with no evidence
      of disease at 7-37 months after initial visit. The 1- and 3-year disease-free
      survival rates were 88% and 72%, respectively. In conclusion, super high-dose
      chemotherapy with PBSCT can be done safely and could be useful for patients with
      poor-risk germ cell tumor.

PMID- 10637748
TI  - [High-dose chemotherapy with peripheral blood stem cell autotransplantation for
      patients with poor-risk testicular germ cell tumors--pilot study of the Japan
      Blood Cell Transplantation Study Group].
AB  - The efficacy and toxicity of a single cycle of high-dose chemotherapy with
      peripheral blood stem cell autotransplantation (PBSCT) in patients with poor-risk
      testicular germ cell tumors (GCT) enrolled in the Japan Blood Cell
      Transplantation Study Group was investigated. Previously untreated poor-risk
      testicular GCT patients were treated with BEP therapy (cisplatin, etoposide and
      bleomycin) with or without high-dose chemotherapy (carboplatin, etoposide and
      ifosphamide) followed by PBSCT. Patients were qualified for a change to high-dose
      chemotherapy if elevated serum tumor markers (human chorionic gonadotropin-beta,
      alpha-fetoprotein and lactate dehydrogenase) was observed after 3 cycles of BEP
      therapy. Eighteen patients were treated with BEP therapy alone and 16 with BEP
      and high-dose chemotherapy. At the completion of high-dose chemotherapy, all
      tumor markers had returned to normal in 6 patients. Among them, 1 had only
      teratoma found at resection and 5 had carcinoma resected. Nine patients who had
      persistent elevation of any tumor marker were treated with high-dose chemotherapy
      or another anticancer drug. Thirteen are alive (81%) and 9 (56%) are continuously
      disease-free at a median follow up of 11 months. The median time from PBSCT to a
      granulocyte count > 500/microL was 9.5 days and to a platelet count >
      50,000/microL was 13 days.

PMID- 10637749
TI  - [The salvage chemotherapy for refractory testicular cancer with novel anticancer
      agents].
AB  - Despite the generally high cure rate in patients with metastatic testicular
      cancer, 20% to 30% of treated patients will become candidates for salvage
      chemotherapy. We reviewed the recent salvage chemotherapy trials of refractory
      diseases. CPT-11 is a new derivative of camptothecin and has activity in a
      variety of solid tumors. We evaluated the antitumor effect of combination
      chemotherapy using CDDP and CPT-11 against refractory testicular cancer. Fourteen
      patients who failed to achieve complete remission with salvage chemotherapy were
      treated with combination chemotherapy with CPT-11 and CDDP or 254-S (nedaplatin)
      as third line chemotherapy. Six patients remain alive and disease-free and 5
      patients died of disease. The combination of CPT-11 and either CDDP or nedaplatin
      was significantly more effective than other salvage therapy regimens such as VIP.
      Paclitaxel, ifosfamide, etoposide regimens were also effective in patients with
      refractory testicular tumors. We concluded that these combination regimens
      demonstrated significant activity against refractory testicular tumor and further
      investigation is warranted.

PMID- 10637750
TI  - Work, stress, and disability.

PMID- 10637751
TI  - Short-term disability, sickness absence, and social gradients in the Whitehall II
      Study.

PMID- 10637752
TI  - Chronic psychosocial stress at work and cardiovascular disease: the role of
      effort-reward imbalance.

PMID- 10637753
TI  - Workers' compensation, mental health claims, and political economy.

PMID- 10637754
TI  - Back pain: delimiting the problem in the next millennium.

PMID- 10637755
TI  - Precarious employment and workers' compensation.

PMID- 10637756
TI  - Therapeutic and anti-therapeutic consequences of workers' compensation.

PMID- 10637757
TI  - Privatization of workers' compensation: will the cure kill the patient?

PMID- 10637758
TI  - Social inequalities in occupational health and health care for work-related
      injuries and illnesses.

PMID- 10637759
TI  - Overall pattern of health care and social welfare use by injured workers in the
      British Columbia cohort.

PMID- 10637760
TI  - Workers' compensation and psychiatric injury definition.

PMID- 10637761
TI  - Finances

PMID- 10637762
TI  - Plexins, semaphorins, and scatter factor receptors: a common root for cell
      guidance signals?
AB  - Semaphorins, the plexin family of semaphorin receptors, and scatter factor
      receptors share evolutionarily conserved protein modules, such as the semaphorin
      domain and Met Related Sequences (MRS). All these proteins also have in common a
      role in mediating cell guidance cues. During development, scatter factor
      receptors control cell migration, epithelial tubulogenesis, and neurite
      extension. Semaphorins and their receptors are known signals for axon guidance;
      they are also suspected to regulate developmental processes involving cell
      migration and morphogenesis, and have been implicated in immune function and
      tumor progression. Scatter factors and secreted semaphorins are diffusible
      ligands, whereas membrane-bound semaphorins signal by cell-cell interaction. Cell
      guidance control by semaphorins requires plexins, alone or in a receptor complex
      with neuropilins. Semaphorins, besides their role in axon guidance, are expected
      to have multiple functions in morphogenesis and tissue remodeling by mediating
      cell-repelling cues through plexin receptors.

PMID- 10637763
TI  - Peptide binding inhibits aggregation of soluble MHC class II in solution.
AB  - Affinity-purified major histocompatability complex (MHC) class II molecules are
      known to bind antigenic peptide in vitro. This peptide-bound MHC class II is
      known to undergo a change in structure upon stable binding of antigenic peptide.
      Previous results from our, and other laboratories, have suggested a relationship
      between MHC class II structure and peptide association that enables class II to
      enter into a stable conformation upon peptide binding. In this report we describe
      that stable binding of high-affinity antigenic peptide to MHC class II molecule
      results in transition of aggregated purified MHC class II proteins to a stable
      heterodimeric state. Such transition was demonstrated by using purified human HLA
      DR2 class II molecule and high-affinity myelin basic protein (MBP) 83-102)Y83
      peptide. Highly aggregated purified DR2 (high molecular weight; HMW) was first
      separated from heterodimer (low molecular weight: LMW) in the presence of 50-fold
      molar excess of MBP(83-102)Y83 peptide. We then show that the aggregated HMW
      preparation can be successfully converted into a stable dimer by further
      incubation with MBP(83-102)Y83 and changing various binding parameters such as
      pH, temperature, reducing agent, and peptide concentrations. Under optimized
      conditions, the highly aggregated inactive DR2 molecules can be completely loaded
      with the antigenic peptide. The transformed heterodimers with bound peptide
      prepared by this method are biologically active, as shown by their ability to
      induce the production of gamma-interferon by SS8T-transformed human T cells.
      These results suggest that in solution, MHC class II molecules may be aggregated
      in the absence of bound peptide. Such aggregated MHC class II molecules can be
      converted to stable and biologically active heterodimers in the presence of high
      affinity antigenic peptide.

PMID- 10637764
TI  - Molecular cloning, sequencing, and expression of two late proteins of
      bacteriophage MB78.
AB  - Bacteriophage MB78, a virulent phage of Salmonella typhimurium, does not allow
      other phages, such as P22 and 9NA, to grow in its presence. A detailed physical
      map of this phage has been constructed in our laboratory. In an ongoing effort to
      understand the genetics of this interesting phage, various genes were
      characterized. Here, we report cloning, sequencing, and expression of two late
      proteins, coded in a SalI-HindIII fragment (SH9), by using the minicell
      expression system. Further, we performed a kinetic study of phage proteins by
      infection the host LT2 cells and compared the proteins produced, with proteins
      obtained by the minicell expression system. Both sets of proteins run exactly
      parallel and migrated as 14- and 15-kDa proteins on a polyacrylamide gel. The
      synthesis of these two proteins started 15 min after infection with MB78 and was
      prominent after 45 min. One of the proteins exhibited 57% homology to the
      structural protein of mycobacteriophage L5.

PMID- 10637765
TI  - Lucigenin luminescence elicited by microsomes and its modulation by nitroazole
      compounds.
AB  - The lucigenin luminescence elicited by rat liver microsomes and its modulation by
      the nitroazole compounds metronidazole and sanazole (drug AK-2123), as well as
      the rates of lucigenin-dependent NADPH consumption and cytochrome c reduction,
      were studied. The obtained data suggest that the luminescence can be the result
      of univalent lucigenin reduction by microsomal NAD(P)H-reductases, generation of
      superoxide anion radical in the redox cycle of lucigenin radicals, dioxetane
      formation by (di)oxygenases, and catalytic action of cytochrome P450 heme on
      dioxetane decomposition, followed by light emission.

PMID- 10637766
TI  - Thiolation of low-Mr phosphotyrosine protein phosphatase by thiol-disulfides.
AB  - Thiol-disulfides cause a time- and a concentration-dependent inactivation of the
      low-M(r) phosphotyrosine protein phosphatase (PTP). We demonstrated that six of
      eight enzyme cysteines have similar reactivity against 5,5'
      dithiobis(nitrobenzoic acid): Their thiolation is accompanied by enzyme
      inactivation. The inactivation of the enzyme by glutathione disulfide also is
      accompanied by the thiolation of six cysteine residues. Inorganic phosphate, a
      competitive enzyme inhibitor, protects the enzyme from inactivation, indicating
      that the inactivation results from thiolation of the essential active-site
      cysteine of the enzyme. The inactivation is reversed by dithiothreitol. Although
      all PTPs have three-dimensional active-site structures very similar to each other
      and also have identical reaction mechanisms, the thiol group contained in the
      active site of low-M(r) PTP seems to have lower reactivity than that of other
      PTPs in the protein thiolation reaction.

PMID- 10637767
TI  - Construction of murine phage antibody library and selection of ricin-specific
      single-chain antibodies.
AB  - A murine phage antibody library containing 1.7 x 10(8) independent clones was
      constructed and then screened by affinity panning of anti-ricin antibody
      fragments. First, mRNA was purified from the total RNA extracted from fresh
      spleens of nonimmunized mice of Kunming, and then the total antibody variable
      region cDNA was amplified via reverse transcription-polymerase chain reaction.
      Gene fragments encoding VH and VL were amplified and assembled into a single gene
      by using a DNA linker encoding a pentadecapeptide (Gly4Ser)3 through primary PCR.
      Finally the recombinant DNA fragments were cloned into the phagemid pCANTAB 5E
      vector and electroporated into Escherichia coli TG1. The recombinant phage
      particles displaying functional single-chain fragment variable regions (scFvs)
      were rescued by reinfection of helper phage M13KO7, thus constructing a murine
      antibody library. Two ricin-specific scFvs strains were selected from the phage
      antibody library by using affinity panning. The target antigen, ricin, was
      biotinylated with photobiotin and the biotin-labeled ricin interacted with the
      phage antibody library. Subsequent addition of streptavidincoated paramagnetic
      beads isolated the biotinylated ricin-binding phage particle complex. Washing,
      elution, and reinfection of the isolated complex then proceeded sequentially.
      After six rounds of panning, 2 strains of the 34 clones were verified to show
      greater specific affinity to ricin.

PMID- 10637768
TI  - Isolation and characterization of a new trypsin inhibitor from Crotalaria paulina
      seeds.
AB  - A new trypsin inhibitor (CPTI) has been isolated from Crotalaria paulina seeds.
      Purification of the inhibitor was carried out by gel filtration, ion-exchange
      chromatography, and subsequent reversed-phase HPLC. The presence of a single
      polypeptide chain, with a molecular mass of 20 kDa and isoelectric point 4.0, was
      detected. The trypsin inhibitor had a Ki value of 4.5 x 10(-8) M and was capable
      of acting on human, bovine, and porcine trypsin and weakly on bovine
      chymotrypsin. Amino acid analysis showed that CPTI has a high content of
      aspartate, glutamate, leucine, serine, and glycine, having 177 amino acid
      residues in its composition. These data suggest that the protein belongs to the
      Kunitz-type trypsin inhibitors.

PMID- 10637769
TI  - Phosphoserine aminotransferase, the second step-catalyzing enzyme for serine
      biosynthesis.
AB  - As a step toward analyzing the serine biosynthetic pathway in mammals, we have
      studied the properties of phosphoserine aminotransferase, the second step
      catalyzing enzyme. The K(m) values for 3-phosphohydroxypyruvate and L
      phosphoserine are 5 and 35 microM, respectively, and those for glutamate and
      alpha-ketoglutarate are 1.2 and 0.8 mM, respectively. The product inhibition
      studies strengthened the support for a ping-pong mechanism and allowed evaluation
      of Ki values for the four substrates. The equilibrium constant evaluated from the
      kinetic parameters is approximately 40. Additionally, some physical properties
      relative to the bound coenzyme and the secondary structure were investigated. The
      results are consistent with a structural relationship between the Escherichia
      coli enzyme and the mammalian enzyme. The mammalian enzyme has specific kinetic
      parameters, the determination of which is a prerequisite to analyzing the serine
      biosynthetic pathway in mammals.

PMID- 10637770
TI  - Glucose erythrocyte transporter in women with breast cancer: changes in lipid
      composition of erythrocyte membrane.
AB  - Women with breast cancer show altered blood glucose compartmentation compared
      with healthy women, with lower concentrations in plasma and similar
      concentrations in blood cells. The goal of this paper was to study whether this
      pattern was the result of changes in the erythrocyte glucose transporter and, if
      so, to assess the possible changes in lipid environment of the erythrocyte
      membrane. In 12 women with different degrees of breast cancer and 12 age-matched
      healthy women, the lipid composition of erythrocyte membrane and erythrocyte
      glucose transport were studied. Women with breast cancer showed changes in both
      the kinetic variables and the lipid environment of the glucose transporter, in
      keeping with an increase in fluidity of the erythrocyte membrane. The results
      obtained would account, in part, for the changes in glucose compartmentation.

PMID- 10637771
TI  - Effect of 13-hydroperoxyoctadecadienoic acid on the supply of arachidonic acid
      for prostaglandin synthesis from arachidonoyl-CoA mediated by the cytosolic or
      microsomal acyl-CoA hydrolase in rabbit kidney medulla.
AB  - The effects of 13-hydroperoxyoctadecadienoic acid (13-HPODE) on the cytosolic or
      microsomal acyl-CoA hydrolase (ACH) activity in rabbit kidney medulla and on the
      ACH-mediated prostaglandin (PG) formation from arachidonoyl-CoA (AA-CoA) were
      examined. 13-HPODE (10, 20, and 50 microM) had no effect on the cytosolic ACH
      activity but significantly inhibited the activity of the microsomal enzyme (43
      57% inhibition). PG formation was measured as follows: AA-CoA (20 nmol) was
      preincubated with the cytosolic or microsomal fraction (as the source of ACH) in
      the presence or absence of 13-HPODE for 5 min at 37 degrees C, followed by
      incubation with the microsomal fraction (as the source of PG-synthesizing
      enzymes), hydroquinone and reduced glutathione for 5 min at 37 degrees C, and the
      PGs formed were measured by HPLC, with use of 9-anthryldiazomethane for
      derivatization. 13-HPODE reduced the PG formation when the microsomal fraction,
      but not the cytosolic fraction, was used as the source of ACH (10, 20, and 50
      microM; 28-55% inhibition). These results suggest that 13-HPODE may modulate PG
      levels in rabbit kidney medulla by inhibiting the microsomal ACH activity.

PMID- 10637772
TI  - Microsomal carbonyl reductase responsible for reduction of 4-phenyl-3-buten-2-one
      in rats.
AB  - trans-4-Phenyl-3-buten-2-one (PBO), a flavoring additive, was transformed to the
      carbonyl-reduced product, trans-4-phenyl-3-buten-2-ol (PBOL) by rat liver
      microsomes, but not by liver cytosol, in the presence of NADH or NADPH. PBOL
      formed was identified by comparison with an authentic sample. The reductase
      activity was not inhibited by quercitrin, an inhibitor of cytosolic carbonyl
      reductase. The carbonyl reduction product of PBO by liver microsomes was
      identified as the R-enantiomer of PBOL by HPLC analysis. Rat blood also exhibited
      the carbonyl reductase activity in the presence of NADH or NADPH, but to a lesser
      extent.

PMID- 10637773
TI  - Investigation of the orientation of purple membrane sheets in Langmuir-Blodgett
      films by a quartz crystal microbalance.
AB  - By means of the quartz crystal microbalance (QCM), a convenient method was
      developed to determine the degree of orientation of purple membrane (PM) sheets
      on the air/water interface. Langmuir-Blodgett films from both wild-type and SH
      mutant PM (bR D36C) were vertically deposited on the surface of gold-sputtered AT
      cut quartz crystals. The shift of resonance frequency of the QCM during a special
      washing protocol allowed us to differentiate between physically adsorbed PM
      fragments and any PM attached to the gold surface via chemical bonds. By washing
      with organic solvents, complete desorption of the wild-type PM was achieved,
      whereas for the SH-mutant, approximately 60% of the PM fragments could not be
      detached from the surface. These PM sheets should be oriented with the
      cytoplasmic side facing the water subphase to that their SH-groups can chemically
      bind to the gold surface of the quartz plate.

PMID- 10637775
TI  - [Regional meeting of the Japanese Circulation Society. Japan. 1999. Abstracts].

PMID- 10637774
TI  - On the mode of inhibition of eukaryotic protein synthesis by ADP-ribosylation of
      elongation factor 2.
AB  - The exchange of free guanine nucleotides with guanine nucleotides bound to
      elongation factor 2 (EF-2) and to the EF-2-ribosome complex, and the effect of
      ADP-ribosylation of the EF-2 thereon, were investigated by nitrocellulose filter
      assay. Under the experimental conditions, stoichiometric amounts of guanine
      nucleotides were bound, in particular, to ternary complexes of EF-2 with biphasic
      kinetics. The exchange kinetics were similarly biphasic in all cases. Ribosomes
      appeared to have variable effects on the exchange kinetics, depending on the type
      of nucleotide bound. Thus, in their presence, the rate and magnitude of the fast
      exchange of nucleotides revealed increasing values in the order GTP (GXP) > GTP
      gamma S > GDP. ADP-ribosylation had no inhibitory effect on the binding of
      guanine nucleotides to EF-2 or to the EF-2-ribosome complex but reduced
      significantly the fast exchange of GTP (GXP) and GTP gamma S bound to the EF-2
      ribosome complex. The effect of ADP-ribosylation on the fast exchange of GDP in
      binary and ternary complexes was less pronounced. The mechanism of inhibition of
      protein synthesis by ADP-ribosylation of EF-2 is discussed in view of these data.

PMID- 10637776
TI  - [General toxicity study of gadobenate dimeglumine formulation (E7155) (1)--single
      dose intravenous and intracisternal toxicity study in rats].
AB  - Gadobenate dimeglumine formulation (E7155) was evaluated for its general toxicity
      potential following a single intravenous and intracisternal administration to
      rats. Dosage levels tested were 3.3, 4.5, 6.0 and 8.0 mmol/kg at the injection
      rate of 6 ml/min and 7.50, 8.89, 10.54 and 12.50 mmol/kg at 1 ml/min for the
      intravenous administration route, and 0.15, 0.21, 0.29 and 0.40 mmol/kg for the
      intracisternal administration route. Parameters measured during the 14-day
      observation period were mortality, clinical signs and macroscopic examination.
      After intravenous administration at the injection rate of 6 ml/min, twitches,
      respiratory blocking and prostration were observed at 6.0 mmol/kg, and dyspnoea
      and sedation at 3.3 and 4.5 mmol/kg. Deaths occurred within 1 min after
      administration at 6.0 mmol/kg and above. LD50 values were 7.97 mmol/kg in males
      and 6.22 mmol/kg in females. After intravenous administration at the injection
      rate of 1 ml/min, shallow breathing, twitches and sedation were observed at 7.50
      mmol/kg and above and respiratory arrest at 8.89 mmol/kg. Deaths occurred within
      1 min after administration at 8.89 mmol/kg and above. LD50 values were 9.0
      mmol/kg in males and 9.7 mmol/kg in females. After intracisternal administration,
      symptoms consisted of sedation, staggering gait, dyspnoea, twitches and ataxia at
      0.15 mmol/kg and above, prostration, paralysis of forelimbs, and/or hind limbs
      and chromodacryorrhea at 0.21 mmol/kg, and convulsions at 0.29 mmol/kg and above.
      Deaths occurred within 7 days after administration at 0.21 mmol/kg and within 5
      min at 0.29 mmol/kg and above. LD50 values were 0.42 mmol/kg in males and 0.25
      mmol/kg in females.

PMID- 10637777
TI  - [General toxicity study of gadobenate dimeglumine formulation (E7155) (2)--Single
      dose intravenous toxicity study in dogs].
AB  - Gadobenate dimeglumine formulation (E7155) was given by single intravenous
      injection to 4-5 month-old beagle dogs at doses of 2 or 6 mmol/kg. Treatment was
      followed by a 14-day observation period in order to evaluate the test article's
      toxicity. The male and female dogs at 6 mmol/kg vomited and showed reddened gums
      and ears as clinical signs. One male dog at 6 mmol/kg was euthanized
      approximately 23 hr after administration due to its very poor clinical condition,
      which included an unwillingness to move, pale gums and weak pulse. Body weight
      was decreased at 6 mmol/kg, and also slightly at 2 mmol/kg. Decreased food
      consumption was noted both at 2 and 6 mmol/kg. Hematology for the euthanized male
      at 6 mmol/kg showed increases in the total white blood cell count, packed cell
      volume, hemoglobin and red cell count and a decrease in the platelet count.
      Biochemistry showed a dose-related increase in alkaline phosphatase, GPT and GOT
      at 2 and 6 mmol/kg. Males and females at 6 mmol/kg showed increases in bilirubin,
      calcium and urea, and a reduction in glucose. Females at 6 mmol/kg also showed a
      reduction in total protein. Urinalysis showed an increase in pH at 2 mmol/kg and
      above. For females at 6 mmol/kg, an increase in urine volume and a decrease in
      specific gravity and osmolality were noted. An increase in relative liver and
      kidney weights was recorded for males and females dosed at 6 mmol/kg. For the
      euthanized male at 6 mmol/kg, postmortem examination revealed a pale liver with
      rounded edges and an accentuated lobular pattern, and dark material on the gastro
      intestinal mucosal surface. In macroscopic pathology, the male at 6 mmol/kg
      revealed single liver cell necrosis, minimal early hyperplasia in small biliary
      ductules, inflammatory cells in the sinusoidal and portal tracts, centrilobular
      inflammatory cells, diffuse vacuolation of the hepatocytes and sinusoidal
      dilatation in the liver, and cortical tubular vacuolation in the kidneys. In the
      female dog treated at 6 mmol/kg, hyperplasia in the small biliary ductules,
      inflammatory cells in the portal tracts, diffuse vacuolation of hepatocytes and
      sinusoidal dilatation were seen in the liver, and increases in the severity of
      cortical tubular basophilia, cortical tubular dilatation and cortical tubular
      casts were detected in the kidney. Based on these results, the lethal dose of
      E7155 was set at 6 mmol/kg. It is also concluded that a dose of 2 mmol/kg was
      tolerated in the beagle dog after a single injection followed by a 14-day
      observation period.

PMID- 10637778
TI  - [General toxicity study of gadobenate dimeglumine formulation (E7155) (3)--4-week
      repeated dose intravenous toxicity study followed by 4-week recovery period in
      rats].
AB  - A 4-week repeated dose toxicity study of gadobenate dimeglumine formulation
      (E7155) was conducted in Sprague-Dawley rats to assess its non-clinical safety.
      E7155 was administered intravenously at doses of 0.3, 1.0 and 3.0 mmol/kg/day to
      male and female rats once a day during 4 weeks. The reversibility of toxicity was
      evaluated during a 4-week recovery period at 3.0 mmol/kg/day. At 0.3 mmol/kg/day
      and higher, vacuolation of the cortical epithelium was seen in the kidneys and an
      increase in the incidence of local damage at the injection sites. In the 1.0 and
      3.0 mmol/kg/day male and female groups, scabbing/ulceration of the tail at the
      injection sites, macroscopic pale/thickened fundic mucosa in the stomachs,
      vacuolation of the urinary bladder, and mucosal mineralization with epithelial
      hyperplasia of the glandular stomach were found. In the 1.0 and 3.0 mmol/kg/day
      male group and 3.0 mmol/kg/day female group, increases of water consumption and
      urinary potassium excretion, increased kidney weight and enlargement of the
      kidneys were observed. In the 3.0 mmol/kg/day male and female group, hepatocyte
      necrosis with inflammatory cells in the liver and epithelial degranulation in the
      interlobular ducts of the salivary glands were found. In addition, in the 3.0
      mmol/kg/day male group, increases in plasma sodium and decreases of urinary
      sodium and chloride excretion, and degenerative changes in the testes and
      epididymides were observed. After the 4-week recovery period, except for an
      increase in urinary potassium excretion, increased kidney weights and changes in
      the testes and epididymides, all of the above findings had complete or partial
      recovery. Vacuolation of renal tubular cells was common, expected, and known as
      an adaptive change of treatment with hypertonic solutions, and an increase in the
      incidence of local damage at the injection sites was due to irritation by
      repeated intravenous dosing with hypertonic solutions. Therefore, these changes
      were not toxic changes. In conclusion, the dose level of 0.3 mmol/kg/day should
      be regarded as the No Observed Adverse Effect Level (NOAEL) after repeated
      administration of E7155 in rats.

PMID- 10637779
TI  - [General toxicity study of gadobenate dimeglumine formulation (E7155) (4)--4-week
      repeated dose intravenous toxicity study followed by 4-week recovery period in
      dogs].
AB  - Gadobenate dimeglumine formulation (E7155), at doses of 0 (physiological saline),
      0.25, 0.5, 1 and 2 mmol/kg/day of body weight, was administered intravenously to
      male and female beagle dogs once daily for 4 consecutive weeks in order to
      evaluate the subacute toxicity of the test article. Reversibility of toxicity was
      evaluated during a 4-week recovery period at 1 and 2 mmol/kg/day. No
      toxicologically significant changes were observed at 0.25 and 0.5 mmol/kg/day. In
      animals receiving 1 or 2 mmol/kg/day, transient swelling and redness of the
      facial and eye areas, lethargy, decreased activity, emesis, retching, watery or
      unformed stool, decreased body weight or body weight gain, decreased food
      consumption, decreased hematocrit and hemoglobin concentration, increased APTT,
      increases in plasma ALP, GPT or gamma-GT, decreased plasma inorganic phosphorus,
      total protein or albumin, increased liver or kidney weight, subacute inflammatory
      infiltrates, loss of centrilobular hepatocytes or hepatocellular cytoplamic
      vacuolation in the liver, vacuoles in the epithelial cells of the renal tubles
      and/or hypocellularity in the bone marrow were seen. The results of toxicokinetic
      analysis showed that systemic exposure was similar in males and females, and
      there was no accumulation of the test material over the treatment period,
      although AUC tended to be enhanced by slightly more than the proportionate dose
      increase. These effects were recovered or tended to be reversed after a post
      dosing period for 4 weeks. In conclusion, the No Observed Adverse Effect Level
      (NOAEL) was 0.5 mmol/kg/day.

PMID- 10637780
TI  - [Reproductive and developmental toxicity study of gadobenate dimeglumine
      formulation (E7155) (1)--Fertility study in male rats by intravenous
      administration].
AB  - The influence of gadobenate dimeglumine formulation (E7155) on general
      reproductive performance and fertility in male rats of the Sprague-Dawley strain
      was assessed in this study. E7155 was administered by intravenous injection at a
      dosage of 0.3, 1.0, or 2.0 mmol/kg/day to groups of 22 male rats for 13 weeks.
      Control animals received 0.9% sterile physiological saline throughout the same
      period. After four weeks of treatment, each male was paired with an untreated
      female of the same strain. Each male was paired again after 10 weeks of treatment
      with another untreated female of the same strain. All females were killed on Day
      14 of gestation for examination of pregnancy status. No significant toxicological
      signs associated with systemic exposure to E7155 were observed. There were no
      effects of treatment with E7155 on body weight gain, food consumption,
      macroscopic findings, reproductive organ weights and sperm count or sperm
      motility in male rats. Mating performance after pairing at Weeks 4 and 10 of
      treatment as well as litter size and number of survival embryos on Day 14 of
      gestation were not affected by paternal treatment with E7155. From these results,
      the No Observed Adverse Effect Level (NOAEL) of E7155 was 2.0 mmol/kg/day for
      general and reproductive toxicity parameters in male rats treated with E7155 and
      for development in their embryos.

PMID- 10637781
TI  - [Reproductive and developmental toxicity study of gadobenate dimeglumine
      formulation (E7155) (2)--Combined study of effects on fertility and embryo-fetal
      toxicity in female rats by intravenous administration].
AB  - The influence of gadobenate dimeglumine formulation (E7155) on fertility and
      general reproductive performance and embryo-fetal development was assessed in
      female Sprague-Dawley rats. E7155 was administered by intravenous injection at a
      dose of 0.3, 1.0 or 2.0 mmol/kg/day to groups of 22 female rats for 15 days
      before pairing. Treatment was continued throughout mating and up to Day 17 of
      gestation. Control animals received 0.9% sterile physiological saline throughout
      the same period. All females were killed on Day 20 of gestation for examination
      of their uterine contents. There were no toxic clinical signs of treatment. The
      body weight and food consumption of females before pairing and during gestation
      were not affected by treatment. Estrous cycles, mating performance, litter size
      and fetal weight, survival and development were also not affected by treatment.
      Based on the above results, the No Observed Adverse Effect Level (NOAEL) of E7155
      was 2.0 mmol/kg/day for general toxicologic effects and reproduction of female
      rats and the development of their fetuses.

PMID- 10637783
TI  - [Mutagenicity study of gadobenate dimeglumine formulation (E7155) (1)--Reverse
      mutation assays in S. typhimurium and E. coli tester strains].
AB  - The ability of gadobenate dimeglumine formulation (E7155) to cause gene mutations
      was assessed in five strains of Salmonella typhimurium (TA100, TA1535, TA98,
      TA1538, and TA1537) and a strain of Escherichia coli (CM891; WP2, uvrA-, pKM101)
      using the Ames test (agar plate assay). The results suggest that E7155 is non
      mutagenic towards these bacterial tester strains.

PMID- 10637782
TI  - [Reproductive and developmental toxicity study of gadobenate dimeglumine
      formulation (E7155) (3)--Study of embryo-fetal toxicity in rabbits by intravenous
      administration].
AB  - Gadobenate dimeglumine formulation (E7155) was daily administered by intravenous
      injection at 0.3, 0.9 or 2.0 mmol/kg/day to mated NZW female rabbits (20/group)
      to assess the effect on embryo-fetal development. Treatment with 2.0 mmol/kg/day
      caused initial, notable loss of body weight and reduction in food consumption.
      Slightly reduced body weight gain and food intake were recorded at 0.9
      mmol/kg/day. There were no obvious adverse effects in dams given E7155 at 0.3
      mmol/kg/day. There was a slightly higher incidence of early intrauterine deaths
      at 0.9 and 2.0 mmol/kg/day. Morphological examination of fetuses at 2.0
      mmol/kg/day revealed small eye/microphthalmia and/or retinal irregularities in
      three fetuses from three separate litters. There was also an increase in the
      incidence of additional and/or fused sternebral centres and 20-thoracolumbar
      vertebrae at this dosage. From these results, the No Observed Adverse Effect
      Level (NOAEL) for general toxicity of dams and embryo-fetal development was 0.3
      mmol/kg/day.

PMID- 10637784
TI  - [Mutagenicity study of gadobenate dimeglumine formulation (E7155) (2)--Chromosome
      aberration test with human lymphocytes in culture].
AB  - The mutagenic potential of gadobenate dimeglumine formulation (E7155) was studied
      by the chromosome aberration test in cultured human lymphocytes. Human
      lymphocytes were exposed to E7155 at 0.078-10 mM both in the presence and absence
      of S9 mix derived from rat livers. Three dose levels (2.5-10 mM) were selected
      for the metaphase analysis. E7155 induced no increase in the incidence of
      aberrant cells or polyploid cells in any treatments both in the presence and
      absence of metabolic activation. Thus, it is concluded that E7155 has shown no
      evidence of clastogenic or polyploidy-inducing activity under these experimental
      conditions.

PMID- 10637785
TI  - [Mutagenicity study of gadobenate dimeglumine formulation (E7155) (3)-
      Micronucleus test in rat bone marrow cells].
AB  - The mutagenic potential of gadobenate dimeglumine formulation (E7155) was studied
      by the micronucleus test in rats. Single intraperitoneal injection of E7155 to
      Sprague Dawley rats at the dose of 5295.2 mg/kg (5 mmol/kg) did not induce any
      statistically significant increase in the frequency of micronucleate cells in the
      bone marrow sampled after 18, 42 and 66 hr from time of administration.

PMID- 10637786
TI  - [Muscular irritation study of gadobenate dimeglumine formulation (E7155) in
      rabbits].
AB  - To examine the local muscular irritation potency of gadobenate dimeglumine
      formulation (E7155), E7155 was injected into the right vastus lateralis muscle of
      male Kbl:JW rabbits, and saline as the negative control was injected into the
      left muscle. Half of the animals were subjected to necropsy at 2 or 14 days after
      administration. The muscles were examined macroscopically and
      histopathologically. Also, 0.425 w/v% and 1.7 w/v% acetic acid solutions were
      used as a positive control. In macroscopic observation, hemorrhage with white or
      brown coloration was seen in the muscles treated with E7155 at 2 days after
      administration, and white coloration was seen in one case at 14 days after
      administration. In histopathological examination, slight or moderate hemorrhage,
      edema, cellular infiltration, degeneration of muscle fibers and necrosis of
      muscle fibers were seen in the muscles treated with E7155 at 2 days after
      administration, and very slight to slight cellular infiltration, degeneration of
      muscle fibers, fibrosis, calcification of muscle fibers and foreign body giant
      cells were seen in the muscles treated with E7155 at 14 days after
      administration. The changes in the muscle caused by E7155 were definitely less
      than those caused by the 1.7 w/v% acetic acid solution at both 2 and 14 days, and
      slightly less and definitely less than those caused by the 0.425 w/v% acetic acid
      solution at 2 days and 14 days after administration, respectively. The changes
      caused by E7155 were more severe than those caused by saline. It was concluded
      that the local muscular irritation potency of E7155 could be classified at Grade
      2.

PMID- 10637787
TI  - [No Europe without video display terminals].

PMID- 10637788
TI  - [Binocular vision and video display terminal work].

PMID- 10637789
TI  - [Eye diseases and work at video display terminals].

PMID- 10637790
TI  - [Vision disorders in work at video display terminals caused by poor gaze
      orientation].

PMID- 10637791
TI  - [Visual prosthesis for the blind: justifiable hope? Yes, but ...].

PMID- 10637792
TI  - [1999 German Future Award: ophthalmologic project in the final selection].

PMID- 10637793
TI  - [Criteria for evaluating and publishing refractive surgery interventions].

PMID- 10637794
TI  - [Clinical 12-month outcome with the foldable, hydrophobic acrylic lens AMO
      AR40NB].
AB  - BACKGROUND: More and more foldable acrylic lenses are implanted besides silicone
      and polymethylmethacrlyate (PMMA) lenses through small incision unfolding in the
      capsular bag. Complications were observed such as forceps marks, surface
      scratches and so called glistenings. Therefore, a profound clinical evaluation of
      a former by Ioptex marketed acrylic lens which has been readapted by Allergan
      also with regard to a special developed injector seemed to be necessary. PATIENTS
      AND METHODS: Forty-four patients were enrolled within 14 days in a one-year,
      unilateral, non-comparative, open clinical study implanted with the AMO AR40NB
      hydrophobic acrylic IOL. This foldable acrylic IOL with biconvex optic design and
      extruded polymethylmethacrylate (PMMA) haptics (AR40) was implanted either using
      a folding forceps or the AMO AR40NB Insertion System through a temporal limbal
      hinged incision of 3.2 to 3.5 mm. RESULTS: One-year postoperatively, 85% (28/33)
      best corrected distance visual acuity (BSCVA) of 0.5 (20/40) or better was
      reported, with 39% (13/33) reported BSCVA of 1.0 (20/20) or better. Those not
      achieving 0.5 or better suffered from either macular degeneration or other
      ophthalmic pathologies. There were no reports of surgical complications and ease
      of lens insertion was rated by the surgeon better than most in 98% of all cases.
      There were no persistent adverse events. CONCLUSION: Results from this study of
      the AR40 demonstrate good clinical performance characteristics as well as better
      implantation with the injector Unfolder Sapphire.

PMID- 10637795
TI  - [Etiology of non-penetrating corneal injuries].
AB  - BACKGROUND: Non-penetrating injuries of the cornea are frequent. Complications
      like corneal infiltrations, or corneal ulcera, may follow. MATERIAL AND METHODS:
      This prospective study included 144 patients with non-penetrating corneal
      injuries. Records contained epidemiological data, field of activity, profession,
      cause of the injury, and stress during the trauma. RESULTS: 97% of the patients
      were men, 78% of the injuries occurred during working hours, 41% of the patients
      were from metal working professions, 73% of the accidents happened with grinding
      machines and drilling machines. Only 6.9% of patients weared adequate glasses.
      The cause of trauma was deflection and working without glasses. In 32% of
      patients stress played a role in the cause of injuries. CONCLUSIONS: Most of the
      corneal, non penetrating injuries happened during the working hours by
      deflection, and by neglecting safety glasses. With the use of safety glasses the
      number of corneal non-penetrating injuries could definitely be reduced.

PMID- 10637796
TI  - [Ultrasound biomicroscopy diagnosis of congenital glaucoma].
AB  - BACKGROUND: In children with congenital glaucoma the assessment of the anterior
      chamber and the chamber angle might be difficult since scarring and opacities of
      the cornea are often seen. The purpose of our study was to reveal in vivo-
      morphology of the anterior segment in patients with congenital glaucoma and
      opaque cornea. PATIENTS AND METHODS: In 46 eyes of 23 children with different
      degrees of corneal opacities we performed ultrasoundbiomicroscopy (UBM) of the
      anterior chamber after having performed a complete ophthalmological examination
      in general anesthesia. RESULTS: Massive abnormalities of the anterior segment
      morphology were detected in 5 eyes with completely cloudy cornea. In eyes with
      partial opacity of the cornea, UBM gave additional information concerning the
      anterior chamber angle topography, as iris remnants in aniridia, or anterior
      synechia. CONCLUSION: Especially in cases with extensive corneal opacities the
      UBM allows us to get morphological and topographic information about the anterior
      segment and helps to establish an individual strategy for surgical management.

PMID- 10637797
TI  - [Staining the lens capsule with trypan blue for visualizing capsulorhexis in
      surgery of mature cataracts].
AB  - BACKGROUND: A capsulorhexis may be difficult to perform in the absence of a red
      fundus reflex. PATIENTS AND METHODS: After application of 0.3 mL trypan blue
      0.1%, a quick and homogeneous staining of the anterior lens capsule was obtained
      in 100 patients with a mature cataract, to visualize the capsulorhexis during a
      phacoemulsification procedure. RESULTS: No adverse reactions related to the dye
      were observed up to 18 months after surgery. CONCLUSION: Trypan blue staining of
      the anterior lens capsule may therefore be a safe technique to facilitate the
      performance of a capsulorhexis in the absence of a red fundus reflex.

PMID- 10637798
TI  - [Cataract extraction combined with trans-pupillary silicone oil drainage by
      planned posterior capsulorhexis].
AB  - BACKGROUND: A cataract is frequently observed after pars plana vitrectomy with
      silicone oil endotamponade. PATIENTS AND METHODS: Forty-three consecutive
      patients underwent cataract surgery combined with transpupillary removal of
      silicone oil. After phacoemulsification of the lens material through a
      sclerocorneal tunnel incision, a planned posterior capsulorhexis with a diameter
      of 3-4 mm was performed. By injecting saline through the capsulorhexis into the
      vitreous cavity, the silicone oil was rinsed out. Widening of the sclerocorneal
      tunnel facilitated the drainage of the silicone oil through the pupil and tunnel.
      After ophthalmoscopic evaluation of the fundus, a plano-convex PMMA posterior
      chamber lens was implanted into the capsular bag or ciliary sulcus, and the
      corneoscleral tunnel was closed by a 10-0 nylon suture. RESULTS: Depending on the
      underlying retinal disease the visual acuity improved in some eyes. Silicone oil
      bubbles left behind in the vitreous cavity were smaller than 0.5 mm in diameter.
      Persisting corneal decompensation or a clinically detectable cystoid macular
      edema related to cataract surgery did not occur. Due to the posterior
      capsulorhexis, secondary cataract did not develop postoperatively. Small
      postoperative vitreous hemorrhages resolved during the first three post-operative
      days. Retinal detachment recurred in 11 eyes (11/42 or 26.2%). In one eye,
      dislocation of the pseudophacos occurred which had to be corrected surgically.
      Since the pars plana region remained untouched, direct retinal lesions in the
      periphery of the fundus or marked vitreous hemorrhages were not encountered.
      CONCLUSIONS: Silicone oil removal can be combined with cataract surgery with
      transpupillary drainage of the silicone oil.

PMID- 10637799
TI  - [Long-term outcome of gliomas of the visual pathway in type 1 neurofibromatosis].
AB  - BACKGROUND: Optic gliomas are frequently associated with neurofibromatosis type 1
      (NF1) and belong to the diagnostic criteria of NF1. Different growth rates
      require differentiated strategies for screening and observation. PATIENTS AND
      METHODS: 29 patients (25 children < 11 years, 4 adults > 18 years) with visual
      pathway tumors and NF1 were examined neurologically, ophthalmogically, by means
      of MRI and VEP. Results were set into context with preceding investigations (mean
      follow up time 6.5 years). RESULTS: 11 children showed a stable condition, 14 an
      unfavorable process with substantial loss of vision. Children with an unfavorable
      process showed a lower age at diagnosis (3.2 versus 5.8 years; p < 0.05), more
      frequently strabism (11/14 versus 1/11; p < 0.05), optic atrophy (12/14 versus
      1/11; p < 0.05), pathological VEP (9/9 versus 2/10; p = 0.001), visual field
      defects (9/9 versus 1/9) and involvement of the optic chiasm (11/14 versus 3/11;
      p < 0.05) than children with a stable condition. 3 of 4 adults had no visual
      symptoms despite involvement of the optic chiasm. CONCLUSIONS: The crucial
      prognostic factor is the patient's age at the time of diagnosis. Optic gliomas
      which become symptomatic in early childhood (< 6 years) grow rapidly and require
      frequent ophthalmologic investigations and MRI. Tumors diagnosed in late
      childhood (> 6 years) do not progress, allowing for gradual extension of
      intervals between ophthalmological investigations.

PMID- 10637800
TI  - [Long-term radiation damage to the skin and eye after combined beta- and gamma-
      radiation exposure during the reactor accident in Chernobyl].
AB  - BACKGROUND: In April 1986, numerous reactor workers and firemen were exposed to
      high doses of ionizing radiation during the Chernobyl nuclear power plant
      accident. Apart from high ambient gamma-ray exposures they received inhomogeneous
      contamination with beta-rays from fission products, resulting in severe skin
      exposure. PATIENTS AND METHODS: Sixteen of these so called Liquidators were
      repeatedly examined between 1991 and 1996. Their doses ranged from 0.35 to 9 Gy,
      partly confirmed by determination of chromosomal aberrations. Ophthalmologic
      examination included non-subjective assessment of lenticular radiation damage
      with an electronic Scheimpflug camera system. Digital image analysis allowed the
      comparison of opacification units to previous and normal findings. RESULTS: Four
      Liquidators had posterior subcapsular opacifications in different degrees, one
      presented only after cataract extraction. One patient had dense corticonuclear
      cataracts and pseudoexfoliation-like changes. Three men had severe dry eye
      syndrome. Eight men had no ocular complications. Retinal radiation damages were
      absent. 15 Liquidators suffered from severe chronic cutaneous radiation damage,
      which led to amputations in 3 cases. CONCLUSIONS: A relation between ocular and
      dermatological findings was not expected and could, in fact, not be seen. The
      comparison of posterior subcapsular opacification and doses revealed no distinct
      relation, although it indicates a correlation that is here not quantified. The
      doses represent organ doses for the bone marrow which is primarily exposed to
      deeper penetrating gamma-radiation. Thus they need not be correlated with
      combined beta- and gamma-doses in organs such as skin and eye because the
      superficial exposure due to beta-radiation may differ greatly form the whole body
      exposure as reflected in bone marrow doses.

PMID- 10637801
TI  - [Ocular pulse amplitude, intraocular pressure and beta blocker/carbonic anhydrase
      inhibition in combined therapy of primary open-angle glaucoma].
AB  - BACKGROUND: Beyond intraocular pressure (IOP, German abbreviation: IOD) ocular
      perfusion is increasingly discussed in the pathogenesis of the glaucomas. The
      present study was designed to investigate for ocular pulse amplitude (OPA) in
      primary open angle glaucoma patients with elevated intraocular pressure (POAG,
      German abbreviation: POWG) following application of timolol, a beta-blocker and
      dorzolamide a topical carbonic anhydrase inhibitor. METHODS: OPA (Ocular Blood
      Flow System, OBF Labs U.K.) IOP, heart rate, systolic and diastolic brachial
      artery pressures were measured before and 4 weeks following application of
      timolol and additional 4 weeks following application of a timolol/dorzolamide
      combination in 14 POAG patients. RESULTS: Following administration of timolol,
      IOP was highly significantly reduced in drug treated POAG eyes; this effect was
      additively enhanced by dorzolamide. Timolol did not affect OPA, whereas
      dorzolamide significantly increased OPA in drug treated POAG eyes. Systemic
      perfusion parameters were unchanged. CONCLUSION: Timolol and dorzolamide
      drastically reduced IOP, in addition dorzolamide increased OPA in POAG, an ocular
      microcirculatory effect which may further help to improve prognosis of POAG.

PMID- 10637802
TI  - [No contamination of medical personnel by desflurane and nitrous oxide inhalation
      anesthetics during surgical interventions in ophthalmology].
AB  - BACKGROUND: Possible health hazards from chronical exposure to inhalational
      anesthetics cannot definitively be excluded. PATIENTS AND METHODS: Trace
      concentrations of nitrous oxide and desflurane were continuously every 90 seconds
      determined in the breathing zone of both ophthalmologist and anesthesiologist
      during strabism surgery in 20 children by a infrared spectrometer. RESULTS:
      During anesthesia, the surgeon was exposed to the inhalational agents used, but
      concentrations were well within the legal limits. CONCLUSIONS: Despite minor
      occupational exposure of the operating room staff during the operative
      procedures, inhalational anesthesia in ophthalmologic operative procedures can be
      considered safe from the standpoint of modern work place laws and health care
      regulations.

PMID- 10637803
TI  - [Intraocular invasion of melanoma of the conjunctiva].
AB  - BACKGROUND: The treatment of a localised conjunctival melanoma usually requires
      local excision combined with cryotherapy, brachytherapy and/or local
      chemotherapy. CASE REPORT: A 71 year old woman suffering from a conjunctival
      melanoma located at the limbus of her left eye was treated by local excision and
      cryotherapy. After this therapeutic procedure two recurrences occurred which had
      been again treated by excision and cryotherapy and finally brachytherapy.
      Nevertheless, a third recurrent tumor developed and was treated again with deep
      lamellar sclerectomy and keratectomy. During this procedure the anterior chamber
      was opened inadvertently in a tiny spot. Some months later an intraocular
      invasion of the melanoma was diagnosed clinically and the eye had to be
      enucleated 5 years after the first treatment. Histological examination revealed
      extended melanoma growth into iris, ciliary body, anterior choroid, and tumor
      cell seedings in the antertior chamber. CONCLUSIONS: Removing a conjunctival
      melanoma especially such a tumor growing at the limbus, the surgeon has to pay
      attention not to open the anterior chamber during sclerectomy and keratectomy.
      The possibility that prior local surgical excision aided the intraocular
      extension is discussed.

PMID- 10637804
TI  - [Periphlebitis retinae, uveitis and cystoid maculopathy in a patient with
      multiple sclerosis].
AB  - PATIENT: A 44-year-old woman has a history of multiple sclerosis since 20 years.
      Besides recurrent numbness she had many instances of optic nerve neuritis which
      has led to a pronounced optic atrophy on her left eye. Additionally, she has
      developed recurrent iridocyclitis on her right eye. This was the reason why she
      was referred to our outpatient department for evaluation. Ophthalmic examination
      revealed an iridocyclitis associated with a multifocal retinal periphlebitis and
      severe cystoid macular edema in her right eye. CONCLUSION: Patients with multiple
      sclerosis develop in approximately 30% of cases retinal periphlebitis which may
      rarely be associated with anterior uveitis or cystoid macular edema as observed
      in our patient.

PMID- 10637805
TI  - [Deep penetrating nevus of the eyelid].
AB  - BACKGROUND: A 52-year-old woman was evaluated for a pigmented tumor in her right
      lower eyelid, which has developed over the last year. The tumor measured 3 x 4
      mm. The patient's ophthalmologic and medical history was normal. Clinically, a
      malignant melanoma was suspected, and an excision was carried out in local
      anesthesia. The histopathology was suggestive for a deep penetrating nevus.
      CONCLUSION: Deep penetrating nevus is a variant of benign pigmented nevi with
      deep dermal and subcutaneous involvement. The pattern should be recognized and
      differentiated form malignant melanoma.

PMID- 10637806
TI  - [Idiopathic sclero-choroid calcification].
AB  - BACKGROUND: Idiopathic sclerochoroidal calcification (ISC) is an unusual, benign
      disorder occurring at the level of the posterior choroidea and sclera. Clinical
      differential diagnosis includes choroidal osteoma, choroidal metastasis,
      choroidal melanoma, choroidal amelanotic naevus and choroiditis. PATIENT: A 61
      year old man was referred with the diagnosis of multifocal choroidal tumor in
      both eyes. Fundoscopy showed bilateral yellow lesions located near the
      superotemporal arcade. RESULTS: Fluorescein angiography shows the late staining
      of the choroidal lesions. Ultrasonographically highly reflective lesions
      (sclerochoroidal placoid lesions at the sclero-choroidal interface in the CT)
      confirms the clinical diagnosis. The serum calcium and phosphate metabolism is
      normal. CONCLUSION: The Idiopathic Sclerochoroidal Calcification (ISC) is a rare
      echographical differential diagnosis to the choroidal osteoma. ISC is a
      heterotopic calcification of the posterior pole in both eyes, usually located
      near the superotemporal arcade.

PMID- 10637807
TI  - [H. Laqua: Comment on the contribution by Widder et. al. Senile macular
      degeneration].

PMID- 10637808
TI  - [Neurology 2000. From the molecule to the system].

PMID- 10637809
TI  - [Differential orthostatic dysregulation disorders diagnosis].
AB  - Orthostatic circulatory disorders are frequently the cause of orthostatic
      intolerance, syncope or dangerous falls. A sufficient therapy should be based on
      a differential diagnosis by means of an active standing test or a tilt-table
      test. Three typical pathological reactions of blood pressure and heart rate can
      be differentiated. The hypoadrenergic orthostatic hypotension is characterised by
      an immediate drop in blood pressure (systolic drop > 20 mmHg below base line
      within 3 min) with or without compensatory tachycardia. It is caused by
      peripheral or central sympathetic dysfunction. Tachycardia (> 30 beats per minute
      above base line within 10 min) without significant blood pressure drop but with a
      fall of cerebral blood flow indicates a postural tachycardia syndrome. In
      general, there is no further somatic dysfunction. Increased venous pooling is
      thought to be the assumed pathomechanism. A reflex mechanism evokes the
      neurocardiogenic syncope after a certain time of standing: sympathetic inhibition
      yields a strong blood pressure drop and vagal activation bradycardia. Proved
      therapies include use of the mineralocorticoide fludrocortison (hypoadrenergic
      orthostatic hypotension), of the alpha-agonist midodrin (postural tachycardia
      syndrome) and of beta-blockers (neurocardiogenic syncope).

PMID- 10637810
TI  - [Hereditary motor-sensory neuropathies (Charcot-Marie-Tooth syndrome) and related
      neuropathies. Current classification and genotype-phenotype correlation].
AB  - Charcot-Marie-Tooth (CMT) disease is the most common inherited disorder of the
      peripheral nervous system with an incidence of 40:100,000. Clinically, it is
      characterized by distal muscle weakness and wasting, primarily of the legs and
      later of the arms, foot deformity, diminished or absent tendon reflexes, and mild
      to-moderate sensory loss. Molecular genetic studies over the past 2 decades have
      revealed the genetic heterogeneity of this disorder and the identification of
      different genes or gene loci, respectively. Therefore, a current CMT
      classification though constantly changing due to ongoing detection of further
      genetic defects must take into consideration both phenotypic and genotypic
      criteria. Since certain clinical features appear to be associated with specific
      genetic subtypes, we provide a detailed description of characteristic phenotypic
      variants to facilitate differential diagnosis and allow more precise referral to
      subsequent genetic investigations.

PMID- 10637811
TI  - [Neurologic diseases and pregnancy].
AB  - Neurological diseases during and following pregnancy represent a small subgroup
      of all neurological diseases. They can be divided into three groups. 1) Diseases
      which existed already before pregnancy or which appear just by chance during this
      phase like migraine, multiple sclerosis, myasthenia gravis, epilepsy, brain
      tumors or Guillain-Barre syndrome. 2) Diseases that can appear without pregnancy
      but which display a higher incidence in connection with pregnancy. Cerebral
      ischemia, intracerebral hemorrhage, subarachnoidal hemorrhage, intracranial
      venous thrombosis and compression neuropathies belong to this group. 3)
      Preeclampsia/eclampsia, HELLP syndrome, amniotic fluid embolism and pituitary
      apoplexy are diseases with neurological symptoms which occur only with pregnancy.
      The pregnancy itself can imply some restrictions or even a contraindication
      concerning diagnosis and therapy of these diseases. The decision in favour or
      against diagnostic or therapeutic approaches is determined by possible effects on
      the fetus and by potential danger resulting from not recognizing or not treating
      such a disease.

PMID- 10637812
TI  - [Aging in parts? Systemic aging of the nervous system].
AB  - Neurons of the central nervous system in general do not multiply after birth.
      Therefore, no replacement or biological renewal of individual cells affected by
      aging or death is possible. Morphological changes occurring in the aging brain
      are found substantially more pronounced in neurodegenerative diseases. Systemic
      degenerations of selective brain areas in these disorders, e.g. in Alzheimer's,
      Parkinson's, Huntington's disease or in amyotrophic lateral sclerosis, may be
      considered as models of accelerated aging and may allow to study the genetic and
      environmental influences of selective aging and cell death in modules of the
      central nervous system. Although neurodegenerative diseases are disparate
      disorders on the basis of their symptomatology and the anatomic distribution of
      pathologic lesions, they actually share key attributes with respect to
      biochemical and cellular determinants of selective vulnerability. Most
      strikingly, many show a conversion of disease specific and only recently
      identified proteins into unsoluble aggregates which form intra- or extracellular
      deposits. These protein aggregates may, over time, affect neuronal function,
      eventually leading to neurodegeneration and neurodegenerative pathology. The
      pathological process is counterbalanced by protective mechanisms that may loose
      their efficacy during normal aging. This could explain the late onset of even the
      inherited neurodegenerative disorders. Since the expression of disease-specific
      proteins is often not restricted to the affected brain areas (as exemplified by
      the expression of polyglutamine containing proteins in trinucleotide repeat
      disorders in non-affected brain areas and even outside the brain), the anatomical
      specificity of the degenerative process may be determined by associated binding
      proteins. Therapeutic strategies include the reinforcement of physiological
      defense mechanisms and intervention at early phases of the pathological
      biochemistry of disease specific proteins.

PMID- 10637813
TI  - [Indications of cerebral micro-hemorrhage in MRI. Comparative histological
      findings and possible clinical significance].
AB  - Increased use of gradient echo T2*-weighted gradient echo sequences in magnetic
      resonance imaging (MRI) of patients suffering from primary ICH called attention
      to foci of signal loss which were suggested to represent remnants of cerebral
      microbleeds. In a post mortem correlative MR and histopathological study we
      provide support for this notion. We found areas of signal loss on gradient echo
      T2*-weighted sequences in 7 out of 11 brains of patients who had died of
      intracerebral hematoma. Histopathologically, these areas represented hemosiderin
      deposits indicating previous extravasation of blood. To provide data about the
      prevalence of these MRI findings in a healthy elderly population a subgroup of
      participants of the Austrian Stroke Prevention Study was analyzed. We detected
      foci of signal loss on gradient echo T2*-weighted sequences in 18 out of 280
      volunteers (6.4%). MR-based evidence of previous microbleeds may indicate a
      potentially higher risk of suffering from intracerebral bleeding which could have
      therapeutic implications for the treatment of acute stroke and for secondary
      prevention. This hypothesis will have to be tested in future prospective trials.

PMID- 10637814
TI  - [Noninvasive protocol for surgical treatment of focal epilepsies].
AB  - We present a non-invasive epilepsy surgery protocol, which includes EEG-video
      monitoring, magnetic resonance imaging (MRI), interictal positron emission
      tomography (PET) and ictal single photon emission computerized tomography
      (SPECT). According to this non-invasive protocol 50 of 173 patients with
      medically intractable focal epilepsy underwent resective surgery. The
      localization of the epileptogenic zone was based on the congruence of the
      localizing results of EEG-video-monitoring, MRI, interictal PET and ictal SPECT.
      46 (92%) of the patients had temporal and 4 (8%) had extratemporal epilepsies.
      78% (n = 39) of all patients operated according to our non-invasive protocol were
      postoperatively completely or almost seizure free. Extramesiotemporal resections
      could be carried out without invasive EEG-recording if the epileptogenic zone was
      not adjacent to the eloquent cortex. We conclude from our results that in a
      considerable number of patients with medically intractable particularly temporal
      focal epilepsies, resective epilepsy surgery can be based on non-invasive EEG
      evaluations and the risk of invasive recordings can be avoided.

PMID- 10637815
TI  - [Grand mal series after Ecstasy abuse].
AB  - The consumption of the jet set drug Ecstasy (3,4-methylenedioxymetamphetamine,
      abbreviated to MDMA) by young people is increasing markedly. Parallel to this
      development, there is a large number of reports on severe neurological,
      psychiatric and medical complications following the use of Ecstasy. Seizures are
      among the most common clinical complications of the CNS following the ingestion
      of Ecstasy. Our report presents the case of a 21-year-old patient, who had a
      series of grand mal seizures after taking 12 tablets of Ecstasy. 36 hours after
      ingestion the substance MDMA was demonstrated at a level of 300 ng/ml in the
      serum and CSF. Following treatment with Clonazepam and under an adequate level of
      carbamazepine, no further seizures occurred. The diagnosis was difficult because
      the patient initially denied the consumption of drugs and the routine
      toxicological screening does not contain the substance MDMA.

PMID- 10637816
TI  - [Neurological spectrum of pre-eclampsia and eclampsia].
AB  - Preeclampsia is a disorder specific to pregnancy which can affect all maternal
      organs. Cerebral involvement with the occurrence of convulsions is the defining
      factor for eclampsia. The most prominent signs of cerebral dysfunction include
      headache, hyperreflexia, visual disturbances, confusion and/or altered state of
      consciousness. Patients usually recover completely however some patients remain
      disabled due to cerebrovascular damage. Intracerebral and subarachnoidal
      hemorrhage are severe however rare complications of eclampsia. TCD investigations
      regularly find vasospasm in all great cerebral arteries. Reversible hypodense
      lesions in the white matter on early CT-scans and increased signal intensities on
      T2-weighted MRT images indicate local edema. The etiology of preeclampsia and
      eclampsia remains unknown and its current pathophysiology is still hypothetical.
      The clinical picture may best be explained by an endothelial dysfunction with
      increased vascular sensitivity to circulating pressure agents as well as by a
      structural endothelial lesion with fluid loss from the intravascular compartment.

PMID- 10637817
TI  - [Tiagabine and non-convulsive status epilepticus].
AB  - A case report is given to draw attention to the risk of the occurrence of
      nonconvulsive status epilepticus (NCSE) under the anticonvulsant tiagabine in
      higher doses and doses increases. The patient who had no previous history of
      status epilepticus developed several NCSE shortly after administration of
      tiagabine. This represents strong evidence of a causal relationship. Also, in
      experimental studies it has been shown that in higher doses a disequilibrium
      between glial and neuronal GABA uptake may aggravate the failure of GABA
      inhibition thus explaining this adverse side-effect.

PMID- 10637818
TI  - [Involvement of the peripheral nervous system in Crohn disease].
AB  - In medical literature peripheral neurological disorders are associated with
      Crohn's disease only in particular cases. We report on two patients who suffering
      from Crohn's disease developed an acute Guillain-Barre syndrome or a
      polyneuropathy associated with myositis. Two weeks after a 65-year old female
      patient developed a serious Guillain-Barre syndrome, a haemorrhagical Crohn's
      colitis was diagnosed. Within a few weeks the specific therapy led to a
      satisfying recovery. A 45-year old female had suffered from Crohn's disease since
      12 years. Within 8 weeks she developed a serious sensorimotor mixed axonal and
      demyelinating neuropathy and a granulomatous myositis. After treatment with
      steroids her signs constantly decreased. These observations as well as a
      literature review show that polyneuropathy and Guillain-Barre syndrome can be
      associated with chronic inflammatory bowel diseases. Our results suggest that
      peripheral neurological signs could be regarded as a possible extraintestinal
      manifestation of inflammatory bowel disease.

PMID- 10637819
TI  - [Clenbuterol in amyotrophic lateral sclerosis. No indication for a positive
      effect].
AB  - The anabolic effects of clenbuterol have been recognized for a long time.
      Clenbuterol augments the expression of specific muscle proteins with a
      differential effect on type I and type II fibres. Furthermore, clenbuterol
      induces the synthesis of endogenous nerve growth factor (NGF) and may itself be a
      myotrophic factor released by neuron endings. Side effects include tremor and
      headache and dose dependent abnormalities of laboratory values (hypokalemia,
      hypoglycemia). After long-term medication increasing fatigue of muscles has been
      observed. Decreased expression of beta 2-adrenergic receptors may limit the
      expected functional improvement. The efficacy of clenbuterol as symptomatic
      treatment of amyotrophic lateral sclerosis has not been proved. Controlled
      treatment trials are warranted to assess this question.

PMID- 10637820
TI  - [Mechanisms for the development of intracranial hemorrhage. Possible implications
      for thrombolysis in cerebral infarct].
AB  - The role of cerebral hemorrhagic transformation, either as clinically silent
      hemorrhagic infarction or disastrous parenchymal hemorrhage, is crucial for any
      risk/benefit analysis of thrombolysis. Especially, thrombolysis in acute ischemic
      stroke increases the risk of severe, life-threatening hemorrhagic complications
      up to 10 times compared to untreated controls. In this paper, previous proposed
      concepts for the development of intracerebral hemorrhage and hemorrhagic
      transformation are presented. The role of the cerebral microvasculature will be
      emphasized. In experimental focal cerebral ischemia a significant loss of basal
      lamina components of the cerebral microvessels has been demonstrated. This loss
      in vessel wall integrity is associated with the development of petechial
      hemorrhage. The mechanisms for this microvascular damage may include the plasmin
      generated laminin degradation, matrix metalloproteinases activation, and the
      transmigration of leukocytes through the vessel wall. The attenuation of the
      microvascular integrity loss with subsequent reduction in hemorrhage is
      theoretically possible 1) by an improvement in the definition of an individual
      time window of therapy (by means of imaging techniques), 2) by a biochemical
      quantification of the basal lamina damage to avoid dangerous interventions, and
      3) by pharmacological strategies to protect the basal lamina during thrombolysis.

PMID- 10637821
TI  - [Comment on the contribution by Ostertag and Warnke. Neuronavigation].

PMID- 10637822
TI  - [First faculty chair for neurology in Germany. Comments on an editorial by Th.
      Brandt].

PMID- 10637823
TI  - [Considerations of DGPPN (German Society of Psychiatry, Psychotherapy and
      Neurology) regarding future curriculum patterns in graduate education regulations
      in the psychiatric-psychotherapeutic specialty].

PMID- 10637824
TI  - Pharmacotherapy of stimulant dependence: one of Japan's greatest public health
      challenges.
AB  - Stimulant dependence has become a major public health problem in the world over
      the last 15 years, and pharmacotherapies have been evolved based on our
      understanding of the neurobiological alterations induced by these drugs. Among
      the stimulants cocaine and amphetamine are the most common dependencies, and they
      share several common pathophysiologies in producing disease and in guiding
      medication approaches to treatment--neurotransmitter re-normalization, reversal
      of cerebral perfusion abnormalities and peripheral cocaine blockers. First is
      neurotransmitter re-normalization. A relative catecholamine deficiency occurs
      following prolonged abuse of cocaine and amphetamine due to transporter
      upregulation and receptor downregulation. This abnormality in dopamine and
      serotonin neurotransmission appears to be associated with depression and has
      supported antidepressant treatments to re-normalize neurotransmission.
      Dopaminergic and serotonergic agonists have also been given to re-normalize
      neurotransmission, but in contrast to substitution therapies such as methadone,
      LAAM or buprenorphine for opioids, these approaches have had limited success in
      unselected cocaine dependent patients. As a correlary approach to substitution,
      however, aspects of dopamine function can be augmented by dopamine beta
      hydroxylase inhibitors such as disulfiram to increase the aversive properties of
      stimulants and decrease their abuse. The second medication approach relates to
      cerebral perfusion defects and associated cognitive deficits due to
      vasoconstriction and abnormalities in platelets, which can respond to
      antiplatelet therapies as well as excitatory amino acid (EAA) antagonists. These
      EAA antagonists can prevent neuronal damage that is due to the release of EAA
      during cerebral ischemia induced by stimulant use. Finally, peripheral blockade
      treatment for cocaine may be possible using a newly developed active vaccine that
      blocks the uptake of cocaine from the bloodstream into the brain. Its potential
      efficacy has been shown in rodents that decrease their self-administration of
      cocaine when immunized with this vaccine, and preliminary human studies support
      its safety and immunogenicity. In summary, stimulant pharmacotherapy has made
      great progress in developing treatments based on understanding the neurobiology
      of these abused drugs, but these pharmacotherapies must be delivered in the
      context of appropriate behavioral and cognitive psychotherapies, which are also
      rapidly evolving.

PMID- 10637825
TI  - [Study on a comparison of clinical presentations of nicotine and other types of
      substance dependence].

PMID- 10637826
TI  - [Current status of abuse and dependence on medications at psychiatric
      facilities].

PMID- 10637827
TI  - [Current topics on regulation of dependence-inducing drugs].

PMID- 10637828
TI  - [Comparative study on smoking habits of patients with schizophrenia or manic
      depressive psychoses].

PMID- 10637829
TI  - [Psychiatric diseases and smoking].

PMID- 10637830
TI  - [Epidemiology of antianxiety and tranquilizing agent dependence in Japan].

PMID- 10637831
TI  - [Biological mechanism of drug dependence--with special reference to intracerebral
      endozepine].

PMID- 10637832
TI  - [Clinical presentation of anti-anxiety and tranquilizing agent dependence].

PMID- 10637833
TI  - [Status of patients on antidepressants or tranquilizing agents for extended
      periods--results of a survey conducted by Kitasato University Hospital].

PMID- 10637834
TI  - A comparison of drug withdrawal symptoms with cigarette smoking.

PMID- 10637835
TI  - [T-cell interferon-gamma, tumor necrosis factor-alpha and interleukin-6 receptor
      binding in patients with multiple sclerosis. Effects of interferon-beta-1b
      treatment].
AB  - INTRODUCTION: Multiple sclerosis (MS) is a T-cell-mediated demyelinating disease
      of the central nervous system (CNS), in which the cytokine network may be
      deranged. Interferon (IFN)-gamma, interleukin (IL)-6, and tumor necrosis factor
      (TNF)-alpha are cytokines with several effects on the neuroimmune system.
      Specific IFN-gamma, IL-6, and TNF-alpha receptors have been found on human
      lymphocytes and other cell types. PATIENTS AND METHODS: We assayed IFN-gamma, TNF
      alpha, and IL-6 binding on peripheral blood T cells from MS patients, as compared
      with healthy subjects. T cells from MS patients have significantly less IFN-gamma
      receptors, and more TNF-alpha and IL-6 receptors than those from controls. Such
      receptors are of the same type in patients and healthy subjects. By comparing MS
      patients' subgroups with each other, significant differences in mean Bmax values
      have been found between patients in a stable phase and those in relapse, and
      between stable patients and those in an evolutive phase. As far as IL-6 binding
      is concerned, significant differences in mean Bmax values were observed only
      between patients in stable phase and those in relapse. RESULTS: T lymphocytes
      from untreated MS patients, which had significantly smaller amounts of IFN-gamma
      receptors than those from controls, and more TNF-alpha and IL-6 receptors than
      controls showed a significant increase in IFN-gamma binding, and a significant
      decrease in TNF-alpha and IL-6 binding after a 3-month IFN-beta 1b treatment. T
      cell IFN-gamma Bmax values were even higher, and those of TNF-alpha and IL-6 were
      lower after 6 months. CONCLUSION: We discuss these results in terms of MS
      immunopathophysiology, since activated T cells have decreased IFN-gamma, and
      increased TNF-alpha and IL-6 receptor amounts.

PMID- 10637836
TI  - [Acquired epileptic aphasia].
AB  - OBJECTIVE: To evaluate clinical and EEG features, as well as treatment and
      progression in fifteen patients with a diagnosis of acquired epileptic aphasia.
      PATIENTS AND METHODS: The population comprised nine male and six female patients,
      whose mean age was 14.5 (r = 8.11-20 years). All were on routine antiepileptic
      drugs. Inclusion criteria were acute, subacute or chronic aphasia, lacking signs
      of motor deficit or demonstrable brain lesion, but displaying bilateral spikes or
      generalized spike-wave discharges. Throughout, sleep and waking EEG,
      neuroimaging, brainstem auditory evoked potentials and neuro-psychological
      evaluations were performed. Cortical brainstem auditory evoked potentials were
      carried out in ten cases. RESULTS: Median age at onset of verbal auditory agnosia
      was 5.6 years (r = 1.1-8.6 years), which eleven cases developed epileptic
      seizures at a median age of five years. Waking and sleep EEG were abnormal but
      brainstem auditory evoked potentials were normal throughout. Cortical brainstem
      auditory evoked potentials in ten patients displayed P300 wave and vertex
      potential alterations. Five cases received 1-3 mg/kg/day prednisone during 6-12
      months, with almost complete speech recovery in four. At the last follow-up,
      language impairment was mild in five patients, moderate in five and severe in
      three, while two children recovered normal speech. CONCLUSIONS: Early acquired
      epileptic aphasia treatment is advisable with valproic acid, benzodiazepines or
      ethosuximide alone or in combinations, supplementary with corticoids for at least
      six months in the absence of clinical response and/or EEG improvement. Globally,
      seven out of fifteen patients overcame their speech disorder.

PMID- 10637837
TI  - [Dementia syndrome and risk factors in adults older than 60 years old residing in
      Habana].
AB  - INTRODUCTION: The dementias and Alzheimer's disease are a growing problem in
      countries with a long life expectancy. OBJECTIVE: To find the prevalence of the
      dementia syndrome in the population aged over 60 years in the municipality of
      Marianao, La Habana, during the first three months of 1998, and the relationship
      with certain associated biosocial factors. PATIENTS AND METHODS: A descriptive
      transversal study in which 799 elderly persons were assessed in their homes, out
      of a population of 22,590 elderly persons, by means of conglomerate sampling in
      two stages. In the same way, we selected a sample from the municipality of Bauta
      representing 340 adults. The probable diagnosis of dementia syndrome or
      Alzheimer's disease was based on criteria of DSM III R and NINCDS-ADRDA. A second
      analytical phase was done by studying cases and witnesses. Univariate and
      multivariate hypothesis tests were done by means of the multiple logistic
      regression method. RESULTS AND CONCLUSIONS: The prevalence of the dementia
      syndrome was 8.2% (6.27-10.42); and that of Alzheimer's disease and vascular
      dementia was 5.13% and 1.93% respectively. Age, female sex, previous clinical
      history and no spouse (due to widowhood or being single), were risk factors in
      this population. Early detection of the dementia syndrome allows development of
      projects to intervene in old people to actively improve their state of health and
      socio-familial adaptation.

PMID- 10637838
TI  - [Early mitochondrial encephalomyopathy due to complex IV deficiency consistent
      with Alpers-Huttenlocher syndrome: report of two cases].
AB  - INTRODUCTION: Complex IV or cytochrome c oxidase (COX) deficiency is the most
      common disorder involving complexes of the respiratory chain in the pediatric
      age. Exceptionally, it has been reported in association with Alpers syndrome or
      Alpers disease, and with its variant named progressive neuronal degeneration with
      liver disease or Alpers-Huttenlocher syndrome. OBJECTIVE: To report the cases of
      two infants with mitochondrial encephalomyopathy due to COX deficiency in whom
      the clinical, biochemical, neurophysiologic and neuroimaging characterization
      suggested an associated Alpers-Huttenlocher syndrome. CLINICAL CASES: Two no
      related males, one with noncontributory family history and the other with third
      grade consanguineous parents developed refractory seizures from age 20 and 60
      days, respectively. Additionally, myoclonic fits accounted on evolution of the
      condition. In the first case, serial EEG recordings showed low amplitude
      polyspikes, polyspike waves and very slow waves of high amplitude alternating
      with a trace of burst-suppression activity. In the second case, a right
      preponderant but also bilateral low amplitude polyspikes, polyspike waves and
      occasional desynchronization of basal trace were recorded. In both, a rapidly
      progressive cerebral atrophy, neurological deterioration with pyramidal signs,
      and tendency to microcephaly, ensued. Accompanying to this clinical picture,
      minor hepatic dysfunction, elevated protein levels in the CSF, lactic acidosis
      and COX deficiency in muscle homogenate were demonstrated. In the first case,
      moreover, cortical blindness and severe hepatic failure occurred while receiving
      valproate, in spite of concomitant L-carnitine therapy. CONCLUSIONS: We believe
      that the reported cases are consisted with Alpers-Huttenlocher syndrome
      associated with mitochondrial encephalomyopathy due to COX deficiency.
      Nevertheless, early myoclonic encephalopathy, a condition related in same cases
      with poliodistrophy, must be keep in mind as a possible diagnosis in case 1.

PMID- 10637839
TI  - [Perinatal intracranial hemorrhage due to immune thrombocytopenia].
AB  - INTRODUCTION: Immune neonatal thrombocytopenia is caused by maternal antibodies
      (IgG) passing across the placenta, with subsequent destruction of foetal
      platelets. There are two forms, the iso-aloimmune forms, with an incidence of
      intracranial hemorrhage (ICH) in the neonatal period of 10-20%, and the
      autoimmune form with an incidence of only 1%. OBJECTIVE: To review the patients
      with this condition in a neonatal unit. CLINICAL CASES: During the past 12 years,
      three patients with ICH due to immune thrombocytopenia were attended in the
      neonatal unit. Three newborn babies had ICH (two intrauterine, at 30 and 33 weeks
      of gestation, and one postnatal) secondary to immune thrombocytopenia (two
      aloimmune and one autoimmune). Two births were by caesarean section and one was
      vaginal. All three had thrombocytopenia at birth (12,000; 23,000 and 56,000
      platelets/mm3). Immunological study of the platelets from the patients with
      aloimmune thrombocytopenia showed the absence of HPA-1a in their mothers. The
      patients were treated with gammaglobulins and platelets. Intracranial hemorrhage
      was confirmed on neuroimaging in all cases. A porencephalic cyst was seen to have
      formed in two cases. The clinical course was satisfactory in two patients.
      However, the third patient had severe motor impairment and died 9 months later.
      In all three patients the PEV were altered and two had reduced visual acuity.
      CONCLUSIONS: 1. Perinatal ICH due to immune thrombocytopenia is uncommon, but
      potentially serious. 2. We suggest that cranial ecographic studies should be done
      in all newborn babies with immune thrombocytopenia even when no neurological
      disorder is seen. 3. Early diagnosis and suitable treatment may help to reduce
      the neurological sequelae. 4. The neurological complications are due to
      intraparenchymatous hemorrhage, and visual sequelae are frequent.

PMID- 10637840
TI  - [Hyperperfusion syndrome as a complication of percutaneous transluminal
      angioplasty of the internal carotid artery].
AB  - INTRODUCTION: The hyperperfusion syndrome (HS) is described as an infrequent
      complication of carotid endarterectomy. It may also occur in percutaneous
      transluminal carotid angioplasty with a similar causal mechanism and clinical
      features to those seen in HS related to carotid endarterectomy. CLINICAL CASE: We
      describe the case of a 69 year old man who developed HS at the time of
      transluminal carotid angioplasty and 'stenting' of symptomatic, pre-occlusive
      stenosis of the left internal carotid artery. This complication was not detected
      on the postoperative arteriography. On CT the presence of a hemispheric hematoma
      was confirmed. It is thought that HS is caused by a fault in autoregulation of
      the cerebral blood flow following correction of vascular stenosis in previously
      ischemic territory. CONCLUSIONS: Most of the early complications of transluminal
      carotid angioplasty are ischemic. HS is rare but is a possible complication of
      transluminal carotid angioplasty and therefore meticulous control of the blood
      pressure is necessary. A CT scan after any atypical complication of angioplasty
      may be considered to be essential.

PMID- 10637841
TI  - [Behavioral and neuropsychological phenotype of the 48XXYY syndrome: a
      longitudinal study of a case].
AB  - INTRODUCTION: The 48XXYY syndrome is a clinical condition which has been little
      studied from the neuropsychological and neuropsychiatric points of view. We have
      not found any follow-up studies in the literature. The treatment used to date has
      not been successful. CLINICAL CASE: We made a longitudinal study of a boy with
      the 48XXYY syndrome. Neuropsychiatric evaluation was done when he was 6, 8, 10
      and 12 years old. The course followed, both in conduct (bulimia, anorexia,
      disinhibition, depression, social isolation and heteroaggressivity) and in
      neuropsychology (evaluated using WISC-R and the Continuous Performance Test), was
      of progressive deterioration of sustained attention and also on the subscales of
      comprehension, arithmetic, similarities, vocabulary and WIS-R keys. On EEG there
      was hypofrontality and theta-delta activity in the occipito-parieto-temporal
      regions of both hemispheres. In the brainstem a low voltage IV wave was seen in
      the OI. The metabolic alterations were: hyperserotoninemia and hyperuricemia. On
      CAT there were lesions giving increased signals in the occipital horns.
      Prescription of risperidone at a dose of 2 mg/day led to improved behavior (with
      less heteroaggressivity and social isolation) and improved neurocognition
      (arithmetic, similarities and keys) with no modification of EEG activity.
      CONCLUSIONS: From the neuropsychological and behavior measurements and the
      clinical data in the bibliography, we suggest (for the first time) that there is
      a conduct and neuropsychological phenotype corresponding to this syndrome,
      although confirmation of this will require a larger number of longitudinal
      studies. Risperidone at a low dosage has been shown to be effective in
      controlling alterations of conduct and neuropsychology.

PMID- 10637842
TI  - [Sphenoid metastasis mimicking a meningioma as the initial feature of
      adenocarcinoma of the prostate].
AB  - INTRODUCTION: Presentation of adenocarcinoma of the prostate as an intracranial
      metastasis is uncommon. This metastasis tends to be seen in the sphenoid bone,
      and in this case it is difficult to differentiate radiologically from a
      meningioma. Because this cancer is treatable, the differential diagnosis must be
      resolved as soon as possible. CLINICAL CASE: A 72 year old man presented with a
      rapidly progressive left parasellar syndrome. On neuroimaging there was a tumour
      at the level of the left lesser wing of the sphenoid, which was isodense and iso
      intense and also showed homogeneous uptake of contrast material. On angiography
      the circulation was pathological with homogeneous delayed filling. The initial
      diagnosis was meningioma of the lesser wing of the sphenoid. Months later the
      patient complained of bone and respiratory problems. At this time plain chest X
      ray was compatible with carcinomatous lymphangitis. Therefore, tumour markers
      were studied and for the first time the specific prostatic antigen was
      investigated and found to be raised. Although there were no symptoms of
      prostatism, per rectum there was a malignant prostatic mass. In spite of complete
      hormone block, his illness followed an unfavorable course. At necropsy there was
      adenocarcinoma of the papillary prostate and a metastasis in the left lesser wing
      of the sphenoid. CONCLUSIONS: In elderly men, detection of a sphenoid tumour,
      which radiologically may appear to be a meningioma and although prostatism has
      not been diagnosed, the possibility of prostatic metastasis should be considered.
      Per rectum examination and specific prostatic antigen determination should be
      done in these patients.

PMID- 10637843
TI  - [Cerebellar syndrome and peripheral neuropathy as manifestations of infection by
      HTLV-1 human T-cell lymphotropic virus].
AB  - INTRODUCTION: Type I human T-cell lymphotropic virus (HTLV-I) is a retrovirus
      with affinity for CD4 cells. This infection may give rise to a broad spectrum of
      disorders including T-cell leucemia/lymphoma, the myelopathy/tropical spastic
      paraparesis complex (M/TSP), and to a lesser extent, uveitis, arthritis,
      polymyositis and peripheral neuropathy. M/TSP is a progressive, chronic
      myelopathy characterized by spasticity, hypereflexia, muscle weakness and
      sphincter disorders. Much less frequently it may precede, or give rise to, a
      cerebellar syndrome with ataxia and intention tremor. CLINICAL CASE: We describe
      the case of a 13 year old adolescent girl who presented with a neurological
      syndrome which had started with tremor of the head and limbs, ataxia, dysmetria,
      frequent falls and sphincter disorders. During the two and a half years that she
      had had this illness she had developed spastic paraparesis of the legs and had
      repeated urinary infections. Serology of blood and CSF was positive for HTLV-I
      using the ELISA technique and confirmed by Western-blot. EMG showed predominantly
      axonal sensomotor neuropathy. A neurogenic bladder was detected on functional
      urodynamic studies. On MR there was moderate atrophy of the thoracic spinal cord
      and slight alterations of the subcortical white matter. CONCLUSIONS: The presence
      of a cerebellar syndrome or neuropathy of uncertain origin, in endemic areas,
      should lead to the inclusion of HTLV-I infection in the differential diagnosis,
      even in the absence of pyramidal symptoms or defined M/TSP. Maternal
      seropositivity supports the hypothesis of mother-daughter transmission during
      lactation.

PMID- 10637844
TI  - [Progressive supranuclear palsy: neurological, neuropathological and
      neuropsychological aspects].
AB  - INTRODUCTION: Progressive supranuclear palsy is a syndrome characterized by
      supranuclear ophthalmoplegia, pseudobulbar paralysis, dysarthria, dystonic
      rigidity of neck and trunk and other cerebellar and pyramidal symptoms. In this
      article we review the principal neurological, neuropathological, neurochemical,
      clinical, therapeutic and neuropsychological aspects of progressive supranuclear
      palsy. DEVELOPMENT: Although progressive supranuclear palsy is usually included
      with the subcortical dementias, some neuropathological and neuroimaging findings
      show cortical involvement, which casts doubt on this classification. In
      accordance with these findings, recent neuropsychological studies have shown the
      presence of frontal changes (dysexecutive syndrome) and impaired verbal fluency,
      together with slight alterations in attention, bradypsyche, changes in long term
      memory and changes in mood and personality. CONCLUSION: From a neuropsychological
      point of view, progressive supranuclear palsy may be considered to be a
      subcortical-cortical disorder.

PMID- 10637845
TI  - [Epidemiological, clinical and prognostic aspects of subarachnoid hemorrhage in
      Segovia].
AB  - INTRODUCTION: Subarachnoid hemorrhage is a disorder commonly seen as a
      neurological emergency, with an incidence of 11-19/100,000 persons; 12% of the
      patients die without seeking medical attention, 63% die during the first year and
      72% during the first five years. OBJECTIVE: To describe the epidemiological,
      clinical and prognostic factors of subarachnoid hemorrhage. PATIENTS AND METHODS:
      We made a retrospective study of the cases of primary subarachnoid hemorrhage
      occurring in the province of Segovia between January 1993 and November 1997. The
      patients presented with a clinical history compatible with subarachnoid
      hemorrhage which was confirmed by cranial CT and/or lumbar puncture. Angiography
      of the supra-aortic trunks was done to detect vascular malformations. The
      patients were classified according to clinical grades on the criteria of Hunt and
      Hess. RESULTS: There were 54 primary subarachnoid hemorrhages (29 men and 25
      women); the average age was 59 years. The average annual incidence was 7/100,000
      persons; 59% were at Hunt and Hess stage I-II. Headache was the presenting
      symptom in 67% of the patients. The patients with normal CT scans (20%) were of
      lower clinical grade and consulted later; 4% had further bleeding and all these
      died. There were associated neurological complications in 46% and systemic
      complications in 28%. Of the 44 arteriographies done, in 14 there were positive
      findings, 11 aneurysms (five were embolized and five treated surgically), and
      three arteriovenous malformations (two treated surgically). On discharge 7% had
      severe neurological sequelae. Mortality during the acute phase was 13%.
      CONCLUSIONS: Subarachnoid hemorrhage is still a serious condition, with a high
      rate of mortality during the acute phase (13%) and of sequelae (20%). The
      clinical grade and cranial CT findings were the main factors in prognosis.

PMID- 10637846
TI  - [Confused dream-like state and hypophyseal apoplexy: neurovascular hypothesis].
AB  - INTRODUCTION: Pituitary apoplexy has been defined classically as a nosologic
      syndrome of predominant headache, visual deficits and decreased level of
      consciousness, but there are not any psychopathological associations described in
      the scientific literature directly related to it. The disorder of sensorium or
      arousal is a variable sign, with a rank of features from moderated lethargy to
      coma and stupor, revealing a torpid evolution. CLINICAL CASE: We present a case
      with behavioral changes, mental dissociation and temporal illusions. In turn,
      infections or endocrinologic morbidity are rejected; it is estimated a
      nosological difference of confused-oneiric psychosis in a neurovascular context.
      CONCLUSIONS: In the neuroanatomical context, an acceptable hypothesis for this
      emotional semiology would be the effect of diaschisis on hypothalamic and
      hypophyseal fibers in connection with limbic system/hippocampus. There could be,
      in addition, a demonstration of the relationship between this hypophyseal
      hypothalamic system and the rhinencephalic or vegetative brain, the seat of
      behavioral activity.

PMID- 10637847
TI  - [Determination of Doppler parameters in the study of basal cerebral veins: basal
      vein of Rosenthal and middle cerebral vein].
AB  - INTRODUCTION: To date, little attention has been paid to the study of the venous
      system by means of transcranial Doppler ultrasound. The objective of our study
      was to learn how to localize cerebral blood flow and find the normal values of
      different ultrasonographic parameters. PATIENTS AND METHODS: We studied 20
      healthy persons in whom the arterial system of the circle of Willis had
      previously been shown to be normal. Transcranial Doppler scan was done with the
      person lying face upwards, using a transtemporal 2 MHz catheter. In the study we
      included persons in whom at least one of the two veins could be studied
      unilaterally. RESULTS: We studied twelve men and eight women aged between 25 and
      78 years. The basal vein of Rosenthal, localized bilaterally in 70% of the cases,
      was identified as a wave of low pulsation between segments P1 and P2 of the
      posterior cerebral artery, going away from the catheter at a speed of about 11
      cm/second. The middle cerebral vein was found bilaterally in only 35% of the
      cases as a wave near to the middle cerebral artery but in the opposite direction,
      at an average velocity of approximately 11.7 cm/second and of low pulsation.
      CONCLUSIONS: In spite of the technical problems, which can be solved using
      contrast agents, it is possible to study the cerebral venous system by means of
      transcranial Doppler. Our Unit is the first in Spain to show this. We therefore
      wish to promote the use of transcranial Doppler in cerebral venous disorders.

PMID- 10637848
TI  - [Leukocytes and primary intracerebral hemorrhage].
AB  - INTRODUCTION AND OBJECTIVE: The association between the leucocyte count and
      prognosis observed in ischemic cerebrovascular disease and subarachnoid
      hemorrhage has rarely been reported in primary intracerebral hemorrhage. The
      objective of our study is to assess the importance of the number of leukocytes in
      the peripheral blood during the first 24 hours for prognosis of mortality.
      PATIENTS AND METHODS: We made a prospective analysis of supratentorial primary
      intracerebral hemorrhages seen during the first 24 hours during the period 1987
      1994. We evaluated the relationship between age, sex, size of hematoma, blood
      found in the ventricles, level of consciousness on admission, survival and
      prognosis after 30 days, level of glucaemia, arterial hypertension and leucocyte
      count. RESULTS: We considered 186 primary intracerebral hemorrhages (64% men and
      36% women); the average age was 64 years (Standard Deviation: 10 years). There
      were 63% deep and 37% lobar hemorrhages. Thirty five percent of the patients
      died. Leucocytosis was associated with survival (p = 0.003), prognosis (p =
      0.0005) and intraventricular bleeding (p = 0.03). We found a significant
      relationship between the size of the hematoma (r = 0.256; df = 186; p < 0.0001),
      level of glycaemia on admission (r = 0.282; df = 186; p < 0.0001), level of
      consciousness (r = -0.263; df = 186, p < 0.0001) and leukocyte count.
      CONCLUSIONS: The peripheral blood leucocyte count was significantly associated
      with prognosis and increased mortality. It may therefore be considered to be
      another parameter of bad prognosis in primary intracerebral hemorrhage.

PMID- 10637849
TI  - [Analysis of the echocardiographic findings in young patients with cerebral
      ischemia].
AB  - INTRODUCTION: When we consider the importance of cardioembolism in the aetiology
      of cerebral ischaemia in young adults, echocardiography, both transthoracic and
      transesophageal, becomes of increasing diagnosis importance. We analyze its
      usefulness and contribution to the reduction in the number of cerebral ischemias
      of unknown origin. PATIENTS AND METHODS: We selected persons aged between 14 and
      45 years who had had cerebral ischaemia during the period between January 1991
      and April 1998. The protocol for the diagnosis of stroke in young persons was
      applied to all of them together with transthoracic echocardiography whenever
      there was the possibility of embologenous cardiopathy followed by transesophageal
      echocardiography when the transthoracic echocardiography was not diagnostic.
      RESULTS: In 114 identified cases, 98 transthoracic echocardiographs were done, of
      which 14 were diagnostic, together with 32 transesophagic echocardiograms, which
      showed nine cases of embologenous cardiopathy not detected on transthoracic
      echography. The most frequent diagnoses were: prolapsed mitral valve (14); patent
      foramen ovale (8); mitral stenosis (5) and interauricular septal aneurysm (4). A
      total of 31 patients were diagnosed as having a previously unrecognized
      cardioembolic origin of their illness. CONCLUSIONS: The diagnostic usefulness of
      transthoracic echography was 22.45% (9.18% were false negatives), and 28.12% for
      transesophagic echocardiography. These reduced the diagnosis of ischaemia of
      unknown origin by 32.69% and 20% respectively. Besides, in 75% of the patients
      with a patent foramen ovale and 100% of those with interauricular septal
      aneurysms, no other possible cause for their condition was found. Transthoracic
      echocardiography is a technique to be recommended in all cases of cerebral
      ischaemia of unknown origin in young adults. Its usefulness may be enhanced by
      transesophagic ultrasonography when diagnosis cannot be definitely made on
      transthoracic echosonography alone.

PMID- 10637850
TI  - [Spinal cord infarction/ischemia].
AB  - INTRODUCTION: Vascular pathology is considered to be uncommon, with a much lower
      incidence than cerebral vascular pathology. PATIENTS AND METHODS: We reviewed the
      clinical histories of patients with a clinical diagnosis of spinal cord
      infarction-ischemia attended by the Neurology Department and the Neuropaediatric
      section at our centre between 1990 and 1997. We analyzed the clinical and
      investigational findings and compared them with those in the literature. RESULTS:
      We studied the cases of 12 patients (nine adults and three children). There was
      only one case in which no etiological factor of any type was found to justify the
      spinal vascular condition. All the children had had surgery to repair coarctation
      of the aorta. The most frequent clinical presentation was of paraparesis
      paraplegia with signs of involvement of the anterior spinal artery. MR was done
      in all cases, except in that of an adult who was diagnosed on arteriography. The
      adults were studied by means of MR during the first 24-48 hours after onset of
      the condition. In five cases this was normal. In two of the latter cases, MR was
      repeated and alterations were seen in one whilst the other was not satisfactory.
      In the other three cases MR was not repeated since in two there was clinical
      improvement and in the other excessive technical problems. On discharge the
      children had not improved at all although the six adults improved completely or
      almost completely. CONCLUSIONS: In general, our findings are comparable to those
      in the literature. We consider that the diagnosis is basically clinical and
      differential diagnosis should be made with other spinal disorders. MR is helpful,
      although early use does not show changes which help in diagnosis.

PMID- 10637851
TI  - [A validity study of continuous Doppler].
AB  - INTRODUCTION: Ultrasound is regularly used for the detection of carotid stenosis
      which can be treated surgically. This technique includes continuous Doppler,
      which together with study of blood flow in the orbit is very useful and should be
      used systematically, not only in certain cases. We present a study of the
      usefulness of this technique in our Cerebral Vascular Pathology Laboratory.
      PATIENTS AND METHODS: We selected 708 patients studied sequentially over 10 years
      with continuous Doppler and conventional angiography (gold standard). The data
      obtained independently with each technique were compared in order to establish
      the degree of concordance between them and the corresponding indicators of
      validity. Contingency tables were drawn up for different cut-off points
      corresponding to the different degrees of stenosis (50, 70 and 100%). The
      parameters for validity (sensitivity, specificity, predictive value and
      precision) were calculated in each case. RESULTS: The percentage coincidence of
      the two techniques was 91.95%. At the cut-off points there was a high degree of
      precision (> 94.35%). The specificity and negative predictive value of Doppler
      compared with angiography was over 95% and 96% respectively. CONCLUSIONS: The
      validity markers obtained in our laboratory support the technique using
      continuous Doppler as the ideal non-invasive diagnostic method for carotid
      stenosis and this means that its systematic use is to be recommended in patients
      with suspected extracranial carotid disease. Moreover, the low cost of the
      equipment used as compared with other more sophisticated techniques should lead
      to its more widespread use as a first-line diagnostic method in all Neurology
      departments.

PMID- 10637853
TI  - [Multiple sclerosis in Cuba: results of a questionnaire].

PMID- 10637852
TI  - [Cerebral infarct in systemic lupus erythematosus].
AB  - INTRODUCTION AND OBJECTIVE: Systemic lupus erythematosus is a syndrome of
      variable clinical and immunological expression, which may affect any organ.
      Stroke is an uncommon complication of systemic lupus erythematosus, attributed to
      many different etiopathogenic mechanisms such as early atherosclerosis,
      coagulopathy, vasculitis, cardiogenic embolism, etc. Our objectives were to
      analyze the incidence, clinical and immunological characteristics of this
      condition and to evaluate the therapeutic approach and evolution. CLINICAL CASES:
      We present the cases of six patients with cerebral infarcts who also had systemic
      lupus erythematosus. The frequency of cerebral infarct in our series of systemic
      lupus erythematosus was 6%. The average age was 45 years (range 13-67). All the
      cerebral infarcts occurred whilst the systemic lupus erythematosus was active.
      There were positive antiphospholipid antibodies in three of the patients and two
      patients had potentially embologenic cardiopathy (33%). Fifty percent of the
      patients required treatment with cyclophosphamide for their severe systemic
      disease and 66% received anticoagulants for an antiphospholipid syndrome and/or
      suspected thromboembolism. The clinical course was satisfactory in all cases but
      the one who died. CONCLUSIONS: The incidence of cerebral infarct in relation to
      systemic lupus erythematosus is low, and generally appears during advanced,
      active phases of the disease. The many etiopathogenic mechanisms involved
      generally act together so that it is difficult to say which is the main cause,
      especially in elderly patients. Amongst these mechanisms is the presence of
      antiphospholipid antibodies, detection of which is essential in this condition,
      and cardiogenic embolism. The evolution depends mainly on the multi-organ
      involvement and how early immunosuppressive and/or anticoagulant treatment is
      started.

PMID- 10637854
TI  - [Enterobacter cloacae related meningitis].

PMID- 10637855
TI  - [Lewy bodies dementia: new data for the understanding of neuroimaging].
AB  - INTRODUCTION: The criteria for diagnosis of dementia with Lewy bodies (DLB) do
      not include neuroimaging, and few reports have been published on this. OBJECTIVE:
      To report our observations of cerebral CAT and MR studies in 25 patients with
      probable DLB. PATIENTS AND METHODS: Measurement of the surface of the cerebral
      lobes and the hippocampal region in two axial sections on CAT and MR and three
      coronal sections on MR. Our controls were 27 persons with probable Alzheimer's
      disease and 30 healthy persons of the same age group. RESULTS: The size of the
      frontal, parietal and temporal lobes in DLB is intermediate between the values
      found in Alzheimer's disease and those found in asymptomatic persons, but without
      significant differences from these. Atrophy of the hippocampal region seen in DLB
      is significant as compared with healthy persons, but not when compared with those
      with Alzheimer's disease, in whom it was greater still. In the patients in whom
      DLB was still not an advanced stage, there was no atrophy of the occipital lobes,
      in spite of other observers having found hypoactivity of these lobes on SPECT and
      PET. CONCLUSION: In the sample studied, structural imaging techniques were not
      useful in the diagnosis of DLB.

PMID- 10637856
TI  - [Telephone consultation in child neurology practice: quantification and
      contents].
AB  - INTRODUCTION: The workload of telephone consultations has been scarcely studied
      except at the Emergency Units, in spite of the considerable amount of time
      consumed by the task in normal practice. OBJECTIVE: To asses the workload of
      telephone consultations in a Neuropediatric Unit, during normal working hours.
      METHODS: A prospective analysis of all calls received during a year, at the out
      patient hospital-based neuropediatric clinic. RESULTS: 150-200 telephone
      consultations were received every month, decreasing during the holiday seasons.
      They amount to two thirds of the face-to-face contacts at the clinic, during the
      same period of time, and require about 10% of our day-time working hours.
      Disorders more likely to produce the calls: epilepsy (40%), mental retardation
      (19%), cerebral palsy (11%), all others with a frequency lower than 5%. These
      percentages, and those of hydrocephalus, autism and spina bifida, are similar to
      those encountered in normal practice, while headaches, speech delay,
      hyperactivity, syncopes, etc. produced half the number of calls expected;
      myopathies doubled the number of calls expected. The monthly frequency of calls
      varied significatively, along the year, for epilepsy, mental retardation,
      hyperactivity, migraine and autism. Calls were made especially by the family
      (49%), but it depends of the purpose and the patient's diagnosis. The purpose was
      most frequently to consult about the symptomatology of the illness; treatments
      produced 7% of calls; and discussion about citations, 19.5%, regardless of the
      diagnosis. CONCLUSION: In neuropediatric practice, telephone consultations should
      be recognized and provided for in order to manage effectively the clinical
      demand.

PMID- 10637857
TI  - [Neurocysticercosis and epilepsy in Cuba].
AB  - INTRODUCTION: Neurocysticercosis is one of the main causes of epilepsy in the
      tropics, particularly in Central and South America. OBJECTIVES: To report the
      only five patients diagnosed in a tertiary care institution as having
      neurocysticercosis and its relation to epilepsy. PATIENTS AND METHODS: We made a
      retrospective study, reviewing the clinical histories of patients admitted to the
      Instituto de Neurologia y Neurocirugia of La Habana, Cuba, over 25 years up to
      1989, to determine those with neurocysticercosis. RESULTS: We found only five
      patients, representing a frequency of 0.01% of all admissions. We discuss the
      origin of these cases and their possible place of infection, showing that this is
      almost non-existent in Cuba since three of the cases were of foreigners and there
      was evidence that the two Cubans had acquired the disease abroad. The correlation
      between neurocysticercosis and epilepsy (4 of 5 cases) was assessed. The main
      symptoms were analyzed: the three most important, in order, were tonic-clonic
      convulsions, headache and motor deficit respectively. The epileptic seizures were
      classified as secondary generalized partial seizures (symptomatic partial
      epilepsy secondary to cysticercosis). The clinical form, when the site is
      considered, was inactive, with intraparenchymatous and meningeal (mixed)
      calcifications in one case. CONCLUSION: We assess the elements which permit
      diagnosis, the efficacy of anti-helminth treatment and the drugs used to treat
      epilepsy and cerebral oedema, the prognosis as a function of the diagnosis and
      the treatment.

PMID- 10637858
TI  - [Fatal familial insomnia: clinical, laboratory and pathological features].
AB  - INTRODUCTION: Fatal familial insomnia (FFI) is a hereditary disease caused by
      prions and characterized by mutations in the gene of the prion protein. Its
      clinical, neuropathological and biomolecular properties make this a distinctive
      and worrying disorder. PATIENTS AND METHODS: We studied the clinical and
      laboratory findings of 14 patients belonging to three Italian and two French
      families. The genetic analysis done on all patients showed a mutation of codon
      178 and polymorphism of codon 129 in both mutant and non-mutant alleles. RESULTS:
      The signs and symptoms at the start of the disease were: changes in the sleeping
      waking cycle, oniric episodes and frequent waking, dysautonomia, sphincter
      disorders and impotence in men, transitory diplopia and dysarthria,
      osteotendinous hyper-reflexia and myoclonias not associated with
      electroenchephalographic activity. The middle stages of the illness were
      associated with worsening of the oniric state, dysautonomia, dysarthria and
      dysphagia and the presence of pyramidal disorders. Finally the patient dies
      suddenly, either fully awake or following a final comatose state. CONCLUSIONS:
      FFI, a disorder caused by prions, is a worrying illness. It is characterized by
      severe alteration in the sleep-waking cycle and other autonomic and endocrine
      circadian functions. It is still necessary to discover a treatment for this
      dramatic, invariably fatal disease, although considerable progress has been made
      since it was first described barely ten years ago.

PMID- 10637859
TI  - [Ischemic anoxic cerebral crises in children. Electrophysiological aspects].
AB  - INTRODUCTION: Ischemic anoxic cerebral crises are linked to cardio-inhibition in
      response to vagal hypersensitivity which causes cerebral ischemic. OBJECTIVE: In
      this paper we proposed to describe the clinical and electrophysiological features
      seen during the ocular compression test. PATIENTS AND METHODS: We studied 200
      children with clinical findings suggesting ischemic anoxic cerebral crises with
      positive results on ocular compression testing. RESULTS: The ocular compression
      test provoked signs and symptoms, on average, in between 48.5% and 62.5% of the
      patients; generalized hypotonia and loss of consciousness were the most frequent
      signs. We found that the presence of clinical changes depended on the duration of
      the pause in heartbeat. There was also an association between the duration of the
      pause in heartbeat and the electroencephalographic findings. CONCLUSIONS:
      Identification of a state of vagal hypersensitivity is of considerable value in
      the positive differential diagnosis of cerebral crises in children, and of
      definite prognostic value.

PMID- 10637860
TI  - [A multidisciplinary approach to the management of cerebral vascular
      malformations].
AB  - INTRODUCTION: Cerebral vascular malformations (CVM) are a heterogeneous group of
      lesions. One way of classifying them is according to histological criteria,
      clinical features, imaging findings, electroencephalography and distinctive
      pathology. OBJECTIVES: To report the results obtained in 16 patients clinically
      diagnosed as having CVM and operated on in the Centro Internacional de
      Restauracion Neurologica (La Habana, Cuba) between March 1995 and October 1998.
      We also consider the usefulness of diagnostic tools for neurosurgical management
      and anatomo-pathological diagnosis. PATIENTS AND METHODS: We review the clinical
      findings, images, electroencephalograms and diagnostic histology of 16 patients.
      The gender distribution was 10 men and 6 women who were aged between 9 and 48
      years. Stereotaxic resection guided by CAT and angiography was done in all cases.
      RESULTS: The predominant symptoms were headache and generalized tonic-clonic
      convulsions. CAT and angiography were helpful in determining the clinical
      diagnosis and location. The most frequent electroencephalographic finding was
      focal slowing associated with inactive epileptiform disorders. Histological study
      showed that there were 3 cases of arteriovenous malformations (AVM), one angioma
      cavernosa and one mixed vascular malformation (AVM plus angioma cavernosa). The
      malformation was not resected (it was treated with a clip) in the remaining case.
      CONCLUSION: Our results show the importance of structural imaging studies and
      their relationship to functional studies in the presumptive diagnosis of CVM
      corroborated by post-operative histological diagnosis.

PMID- 10637861
TI  - [Visual evoked potentials in children with tension headaches and migraine].
AB  - OBJECTIVE: To determine whether visual evoked potentials (VEP) change, and to
      what degree, in different types of headache (migraine with or without aura, or
      tension headache). PATIENTS AND METHODS: We made a transversal study of 78
      children (aged 3-14 years) studied between March 1997 and August 1998, classified
      into three groups according to HIS diagnostic criteria of 1988 and HIS-R 1997. A
      VEP of geometric pattern was done using the recording technique recommended by
      the International Society in their standards for VEP and the reference values
      were used for an amplitude of less than 5 microV and a latency of P100 +/- 15 ms.
      The qualitative variable was frequency, and the quantitative variables were the
      mean and the standard deviation. We studied the association between qualitative
      variables using the chi-squared test and the differences in means between the
      groups with ANOVA. All differences were considered to be statistically
      significant when p < 0.05. RESULTS: Girls made up 55%, with an average age of
      8.84 years and a standard deviation of 3 years. There were no statistically
      significant differences in the mean of the VEP findings between the different
      types of headache with regard to amplitude (p = 0.975) and latency (p = 0.941).
      Neither were there any significant differences in the response to VEP in the
      different types of headache as far as sex and age were concerned, with p = 0.268
      and p = 0.147 respectively. CONCLUSION: Our results show no statistically
      significant differences and do not support the idea of using VEP as a
      neurophysiological method for studying headaches and differentiating the various
      types.

PMID- 10637862
TI  - [Sepsis and antibiotic prophylaxis in stereotaxic neurosurgery].
AB  - INTRODUCTION: Stereotaxic surgery is becoming increasingly important because of
      the possibility of approaching the deep zones of the brain with less risk. It is
      in daily use in cerebral tumours and in the functional surgery of Parkinson's
      disease. The use of antibiotic prophylaxis in neurosurgery is controversial,
      although in many centres, including ours, all patients receive it. OBJECTIVE: To
      study the pre-operative clinical characteristics analysing the antibiotic
      prophylaxis used, septic complications seen and their management. PATIENTS AND
      METHODS: In this study we included 93 patients with neurosurgical disorders
      operated on using a stereotaxic approach in the Neurosurgical Department of the
      Centro Internacional de Restauracion Neurologica (Cuba) during 1997 and 1998, in
      which antibiotic prophylaxis was used and septic patients detected. The variables
      studied included age, sex, neurological disorders, surgical operations done and
      the antibiotic used for prophylaxis. We analysed the test of clinical criteria
      for sepsis in all patients. RESULTS: We found that a greater number of patients
      operated on had had functional surgery, which showed its importance as an
      alternative surgical method in Parkinson's disease. There was satisfactory use of
      antibiotic prophylaxis with a reduction in the rate of nosocomial infection; most
      infections were seen in the lower respiratory tract. CONCLUSION: These results
      support the hypothesis of use of antibiotic prophylaxis in stereotaxic surgery to
      achieve a reduction in intra-hospital infections in surgical patients.

PMID- 10637863
TI  - [Cystic hemangioblastoma of the spinal bulb].
AB  - INTRODUCTION: Hemangioblastomas are histologically benign tumors that comprise 8%
      12% of all posterior fossa lesions in the adult. Brain stem hemangioblastomas may
      be solid or cystic tumors, and surgical removal of these tumors is usually
      possible and is the optimal treatment. We describe a case of hemangioblastoma in
      the medulla oblongata diagnosed with MRI. Using microsurgery technic a total
      excision of this intramedullary tumor was performed. CLINICAL CASE: A 37-year-old
      woman with a 3-months history of progressive dysphagia and occipital headache.
      Neurological examination at the time of admission revealed bilateral horizontal
      nystagmus, paresis of cranial nerves IX, X and XII, motor weakness of the four
      extremities. A MRI revealed a cystic intramedullary tumor. Using a suboccipital
      craniectomy the tumor was totally removed. CONCLUSIONS: Cystic hemangioblastomas
      of the medulla oblongata represent a small segment in the spectrum of brain stem
      tumors. Surgical removal of these tumors can be accomplished successfully with a
      low risk of neurological injury.

PMID- 10637864
TI  - [Susac syndrome: clinical and diagnostic approach. A new case report].
AB  - INTRODUCTION: The Susac syndrome is made up of the clinical triad:
      encephalopathy, visual and hearing defects. It is caused by microangiopathy of
      unknown origin affecting the small arteries of the brain, retina and cochlea. It
      is very uncommon. It mainly affects young women. The course of the illness is
      usually monophasic and self-limiting. The deficit of visual acuity is caused by
      occlusion of tributaries of the retinal artery. The auditory defect is bilateral
      and symmetrical, and particularly affects medium and low frequencies. NMR is of
      great diagnostic value, showing multiple lesions in the grey and white matter.
      Our case gives more data regarding the evolution of this condition and the
      contribution of cerebral SPECT to diagnosis, the results of systemic treatment,
      use of hyperbaric oxygen and reflections on the physiopathology of the process.
      CLINICAL CASE: We present the clinical case of a young woman who presented with
      psychiatric symptoms and migraine followed by clinical encephalopathy and
      acute/subacute coma. There were also visual and auditory deficits. Other types of
      systemic disease were ruled out. CONCLUSIONS: Findings on SPECT suggested the
      presence of a microangiopathic disorder of the brain. The patient responded to
      systemic treatment with cortico-steroids. The encephalopathy resolved in a few
      days and two months later she had resumed her former daily activities. Treatment
      with hyperbaric oxygen definitely reduced visual sequelae.

PMID- 10637866
TI  - [C6-C7 subluxation and the importance of simple radiology in the emergency
      department. A case report and literature review].
AB  - INTRODUCTION: Post-traumatic fractures and luxations of the cervical spine are
      commonest in young patients. A good basic radiological study of the region
      between the occipitocervical joint and the first thoracic vertebra is essential.
      The antialgic spasm which causes the shoulders to be raised means that their
      image is superimposed on that of the cervico-dorsal vertebrae hiding the latter.
      Suitable technical measures should be taken for X-ray images of this area. If
      these are not satisfactory, computerized tomography (CT) or magnetic resonance
      (MR) are indicated. CLINICAL CASE AND CONCLUSIONS: We present the case of a
      twenty year old woman who presented after cervical hyperextension due to a road
      traffic accident. She had been attended in the Emergency Department of another
      hospital, where she went complaining of bilateral cervicobrachial pain. Plain
      antero-posterior and lateral X-rays were done showing as far as C6. The patient
      was discharged on analgesics and muscle relaxants. Her symptoms did not improve
      so she was sent for rehabilitation. Even so, she became paraplegic three months
      later. On MR subluxation of C6-C7, an extradural intraspinal space-occupying
      lesion and osteolysis of C7 were seen. An emergency operation was done. The C7
      vertebra was removed together with a very vascular mass. Histological study
      showed that it was a giant cell tumour. Subsequently, the patient recovered
      movement of her legs and radiotherapy was started.

PMID- 10637865
TI  - [Parry-Romberg progressive facial hemiatrophy: pathogenic and evolutionary
      considerations with regards to a case followed up for a long period of time].
AB  - INTRODUCTION: The Parry-Romberg syndrome is a clinical condition in which there
      is progressive facial hemiatrophy which may be associated with neurological,
      ocular, cutaneous and auto-immune disorders. It is of unknown aetiology, although
      many theories have been put forward. CLINICAL CASE: We present a case of left
      facial hemiatrophy associated with ipsilateral lingual hemiatrophy and signs of
      cortico-cerebellar dysfunction, the neuroimaging findings (NMR) and clinico
      radiological follow-up covered a period of over 10 years. CONCLUSION: The data on
      the clinical course and neuroimaging, together with our review of the literature,
      suggest that the Parry-Romberg syndrome may be considered to be a dysgenetic
      process which may originate during the first stages of CNS embryogenesis.

PMID- 10637867
TI  - [Spontaneous intracranial hypotension].
AB  - INTRODUCTION AND CLINICAL CASE: A 38 year old woman, with no previous history of
      trauma, presented complaining of interscapular pain followed by pulsating
      headache clearly related to posture, alleviated on lying down and worse on
      standing up. Subsequently, she also complained of diplopia. On examination there
      was paresia of the left sixth cranial nerve. Low opening pressure on lumbar
      puncture confirmed the presence of intracranial hypotension. The protein level of
      the cerebrospinal fluid was slightly raised. On CT the cortical sulci and small
      ventricles had disappeared. Cerebral MR (without gadolinium) showed marked
      diffuse meningeal hyper-intensity and apparent absence of the basal cisterni.
      Isotopic cisternography showed a pattern compatible with hypotension, without
      signs of fistulas. On spinal MR no spinal meningeal defects were seen. With
      conservative treatment the patient improved in a few days and the headache and
      diplopia disappeared. The absence of traumatism or spinal operations mean that
      the hypotension may be considered to be spontaneous. We discuss the CSF,
      neuroimaging and cisternography findings characteristic of the spontaneous
      intracranial hypotension syndrome. CONCLUSION: Unawareness of this syndrome, the
      particular neuroimaging changes and the usual CSF anomalies may lead to confusion
      over diagnosis, leading to the use of invasive techniques unsuitable for a
      condition which often has a good prognosis and in which the symptoms resolve in a
      few days or weeks with conservative treatment.

PMID- 10637868
TI  - [Neuropsychological implications of Crouzon syndrome: a case report].
AB  - INTRODUCTION: Crouzon syndrome (CS) has traditionally been associated with
      moderated mental retardation. However, very few studies have quantified in these
      patients the degree of this mental retardation, and even less research has been
      carried out to evidenciate the typical neuropsychological profile, including
      affective, cognitive and executive functions. CLINICAL CASE: We present a single
      case-study of a 16 year-old, right-handed female affected of CS.
      Neuropsychological functions assessed included attention, concentration, memory,
      visual perception, language, arithmetic processes, praxis, executive functions,
      reasoning and general intelligence. Deficient results have been obtained in
      learning and memory, attention, language, graphic praxis, comprehension of social
      situations and executive functions (frontal lobes). Nevertheless, the patient
      kept within normal limits her spatial and temporal orientation, visual
      perception, visual-spatial and manipulative abilities and arithmetic processes.
      CONCLUSIONS: Results suggest that the intellectual defect in CS is not general
      and uniform and that some intellectual abilities are preserved, while others are
      affected in different degrees. The importance of carrying out a thorough
      neuropsychological assessment in these cases is emphasized.

PMID- 10637869
TI  - [Delayed central pain associated with a sub-insular hematoma followed by parieto
      occipital tumor. Favorable effects of chronic stimulation of the ventral
      posterior thalamic nucleus].
AB  - INTRODUCTION: Dejerine and Roussy reported thalamic syndrome, chronic pain after
      a vascular lesion in the thalamus, in 1906. Posterior clinical observations
      allowed know that the same clinical picture can be observed after lesions in
      other parts of the central nervous system. Due to the fact that the more frequent
      etiology is vascular, nowadays the term central poststroke pain syndrome is
      preferred. CLINICAL CASE: We report a patient who suffered a left subinsular
      hematoma when he was 62 years old. Four years later he started complaining
      burning constant pain in the right side of the body with crisis of lancinating
      pain. Also allodynia was observed in the face and right arm. MRI disclosed a
      necrotic lesion at the level of the left subinsular region. CONCLUSIONS: The
      lancinating pain and the allodynia were properly controlled by deep brain
      stimulation with an electrode placed stereotactically at the level of VPL nucleus
      of the left thalamus. Five months later there was a recurrence of the pain, a CT
      disclosed a tumour in the parietal region with an important shift of the midline
      and migration of the electrode out the thalamus. A biopsy disclosed tumoral
      necrosis. The pathophysiology of the central poststroke pain and effectivity of
      the deep brain stimulation in this cases are discussed.

PMID- 10637870
TI  - [Coma associated with migraine].
AB  - INTRODUCTION: Basilar migraine is a particular form of migraine with an aura in
      which crises of headache are accompanied by symptoms of dysfunction in the
      vertebro-basilar territory, including alteration of consciousness in the form of
      stupor or coma. CLINICAL CASES: We report four patients, three men of 14, 17 and
      83 years of age and one woman of 21. All had previous histories of migraine and
      presented with transitory episodes of coma. During the coma, the woman woke up
      spontaneously with intense bulimia. In the three men, it was seen, on injecting
      flumazenil, that the state of consciousness and the EEG returned to normal
      transiently. Neuroimaging studies (CT and MR) were normal in all patients.
      CONCLUSIONS: Migraine-coma is an exceptional, emergency condition in which
      structural, infectious, toxic and metabolic pathology of the Central Nervous
      System should be ruled out. As well as in patients with basilar migraine, the
      association of migraine and coma may also be seen in patients with familial
      hemiplegic migraine and CADASIL and MELAS syndromes. It may be that gabaergic
      mechanisms are involved in the theoretical dysfunction of the ascending reticular
      activating system causing alteration of consciousness, since in the three
      patients in whom flumazenil was injected, there was a response.

PMID- 10637871
TI  - [The use of corticosteroids in cryptogenic palsy of the third cranial nerves. A
      case report].
AB  - INTRODUCTION: In spite of the rarity of isolated paralysis of the third cranial
      nerves in infancy, we present an acquired cryptogenic case which had an
      excellent, rapid response to treatment with corticosteroids started three months
      after onset of the condition. CLINICAL CASE: A girl aged three and a half years,
      with no significant past clinical history, presented with a third cranial nerve
      syndrome of sudden onset, with divergent squint and right ptosis, but no changes
      in pupil reactivity. All the complementary tests done were normal. After three
      months of observation, since the condition persisted, treatment was started with
      oral prednisone 2 mg/kg/day for three months. The ptosis disappeared in two
      weeks, and two years after treatment was stopped has not reappeared. The absence
      of pain would suggest that this was not a Tolosa-Hunt syndrome, although pain
      free episodes have been described. The absence of alteration in pupil reactions
      is against, although does not exclude, compression of the third cranial nerve.
      This finding, together with the spectacular response to corticosteroids would
      support the diagnosis of inflammation limited to the motor fibres, probably due
      to a viral infection. CONCLUSION: We conclude that corticosteroids may be
      considered in the treatment of cryptogenic cranial neuropathy, once other
      possible aetiologies have been excluded, with the object of modulation of the
      theoretical immune mechanisms involved.

PMID- 10637872
TI  - [Carotidynia as a form of presentation of paraxysmal hemicrania].
AB  - INTRODUCTION: Paroxysmal hemicrania is a well-defined clinical condition about
      which many articles have been published. Attempts have been made to explain the
      response of this illness to indomethacin, suggesting its possible cervical
      origin. In some patients it is set off by stimulation of certain trigger zones
      situated in this region. The exceptional radiation of the pain seen in our
      patient clearly supports this theory. CLINICAL CASE: A 34 year old man with a
      past history of a similar but briefer episode 5 years previously presented to us.
      He complained of repeated episodes of stabbing pain with no obvious cause. The
      pain started at the base of the neck and radiated along the right carotid vessels
      to the cheek, base of the nose and ipsilateral eye. This was accompanied by
      injection of the conjunctivae, tears, nasal congestion and nasal discharge. Each
      episode lasted 15 to 30 minutes and was repeated 20 to 25 times a day without any
      particular relation to the time of day. The neurological examination, MR and
      angio-MR were normal. Before being seen by us he had been treated with prednisone
      and verpamil without effect. Indomethacin at a dose of 100 mg/day controlled the
      problem completely. CONCLUSIONS: We report a case of paroxysmal hemicrania with a
      spontaneous description of pain starting at the base of the neck and radiating
      along the carotid vessels. We consider this clinical description to be of
      interest since it supports the theories of a cervicogenic origin of this type of
      headache.

PMID- 10637873
TI  - [Axolemmal transporters for neurotransmitter uptake].
AB  - INTRODUCTION AND OBJECTIVE: Neurotransmission is a fundamental process in
      interneuronal communication. It starts with the release of the neurotransmitter
      following a nerve impulse and ends either by uptake by specific specific
      transporters or by metabolization to an inactive compound. In this review we will
      consider the molecular, ion dependence and electrogenic properties of the
      axolemal transporters for neurotransmitters and also the pathological
      consequences of their impairment as well as the drugs that can interact with
      them. DEVELOPMENT: Most axolemmal transporters have been cloned and grouped into
      two large families according to their molecular characteristics and electrogenic
      properties: 1. Those dependent on Na+/Cl- include transporters of GABA,
      noradrenaline, dopamine, serotonin, choline, proline, betaine, glycine and
      taurine, and 2. Those dependent on Na+/K+, which include the transporters of
      glutamate, alanine, serine and cysteine. CONCLUSIONS: The clonation of
      transporters has permitted (and will continue to permit) the correlation of
      molecular alterations of transporters with different neuro-degenerative disorders
      (e.g. multiple sclerosis, Parkinson's disease, Alzheimer's disease), with brain
      lesions (e.g. cerebral ischemia, status epilepticus) and with psychiatric
      alterations (e.g. schizophrenia, depression). In this respect, chemical synthesis
      of new selective drugs which interact with the different systems for uptake of
      neurotransmitters will offer new approaches to the treatment of many disorders of
      the central nervous system which still have no satisfactory drug treatment.

PMID- 10637874
TI  - [Anticoagulants: when, which, how, how much, until when: these are still the
      questions. I].
AB  - OBJECTIVE: To analyze the available data in the literature so as to suggest a
      scheme for use when anticoagulating patients with ischemic vascular disease.
      DEVELOPMENT: We analyzed the most relevant publications on the use of
      anticoagulation in cerebrovascular disease, published since 1940. Studies and
      meta-analysis of anticoagulation--oral, intravenous using heparin and
      subcutaneous using low molecular weight heparin--in acute and recurrent stroke.
      This data on anticoagulation was then applied to different aspects of
      cerebrovascular disease such as disease of the great intracranial and
      extracranial vessels (dissection, occlusion and intraluminal thrombus), the
      penetrating vessels, venous system, hypercoagulation states and particular
      therapeutic uses such as anticoagulation in cerebral hemorrhage, and the use of
      thrombolytic agents. CONCLUSIONS: Anticoagulants are frequently used in
      cerebrovascular disease in spite of the lack of studies giving first level
      support of its efficacy (randomized studies with low false positive and false
      negative errors) and the fact that some studies have failed to confirm the
      efficacy of this treatment. With the analysis presented, we have tried to show
      that the failure to define the role of anticoagulants is mainly due to
      limitations in design of the methods used in the studies carried out. The basic
      shortcoming has been the search for one single treatment which could be effective
      for the entire spectrum of cerebrovascular disease.

PMID- 10637875
TI  - [Current concepts regarding the cerebellum and cognition].
AB  - OBJECTIVE: To review the main cognitive processes regulated by the cerebellum and
      the anatomical circuits involved in their clinical correlation. DEVELOPMENT: The
      cerebellum is generally regarded as a regulator of motor function with a key role
      in movement coordination. Clinical evidence of the relation of the cerebellum to
      neural functions typically considered as cortical, is supplied by several
      neuropsychological alterations detected in both degenerative disorders and acute
      insult to the region such as vascular event and surgery. More anatomical circuits
      between the cerebellum and several cortical areas and limbic system, with the
      ventral pons region as main afference and efference relay of all these pathways.
      Cerebellar structures that are phylogenetically older such as the floculonodullar
      lobe, vermix, fastigial nuclei and globus nuclei have a tight relationship to
      emotional control and autonomic manifestations. More complex circuits are founded
      in the regulation of learning, motor planning and language. Functional imaging
      studies have helped to confirm the relationship between the cerebellum and memory
      processes, finding a selective activation of lateral regions during to cerebellar
      damage, such a frontal like syndromes, memory deficits and aphasia and even
      though dysmetria with incoordination between mental process velocity and its
      motor execution. CONCLUSIONS: All the data from clinical and functional studies
      indicate that the cerebellum has a central co-ordinating function not only of
      movement but also regulating thought. The cerebellum should, therefore, be
      reconsidered as a complex neurone system at much the same level as the more
      advanced cortical structures.

PMID- 10637876
TI  - [Neuronal membrane and aging. Electrophysiological aspects].
AB  - INTRODUCTION: The cell membranes are formed of lipids and proteins. Because of
      their hydrophobic nature, phospholipids separate the intracellular from the
      extracellular medium. DEVELOPMENT: The extracellular medium is a solution
      enriched with sodium ions, whilst the intracellular medium is rich in potassium
      ions. In accordance with the laws of chemistry, the asymmetric distribution of
      ions causes a small potential difference between the inside and outside of the
      cell. All the cells of the human body show this small difference in potential of
      about -60 mV. Another component of the cell membranes are proteins. Some of these
      -the ion pumps or ATPases--maintain the asymmetric distribution of the ions.
      Other membrane proteins--the ion channels--permit the selective passage of ions
      between the intracellular and extracellular media. Electrophysiological
      techniques (patch clamp) applied at a cellular level allow us to measure the
      passage of ions across a single molecule. Each ion channel permits the passage of
      a single ionic species. The cells contain ion channels which are transiently
      permeable to the ions of sodium, potassium, calcium and chlorine. One of the
      characteristic properties of neurons is that they are excitable cells. Neuronal
      excitability depends on the ion channels. The neurons show different electrical
      behavior during the different phases of life. The changes in the electrical
      activity of the neurons are determined by the activity of the ion channels and
      their interaction with the liquid surrounding them. CONCLUSIONS: Investigations
      are being done to relate the changes in behavior of the ion channels with the
      process of aging of the neurone membranes.

PMID- 10637877
TI  - [About protocols, regulations and guidelines in clinical practice. Spanish
      Society of Pediatric Neurology].
AB  - OBJECTIVE: In order to increase the awareness and perception of guidelines as a
      helpful tool in clinical practice, a description of its main features,
      foundations and social context is provided. DEVELOPMENT: Protocols, algorithms
      and guidelines are defined as instruments to improve patient care without
      interfering with the clinician's criteria regarding a particular patient. They
      are supported by the Evidence Based Medicine, and its development follows precise
      rules. Guidelines are the product of high quality research, made public through
      Medline, research that is previously evaluated in a specified manner. The level
      of evidence determines the strength of the recommendation. The effects of
      guidelines on the health status of patients are one of the subjects of the
      outcomes assessment methodology. They have some limitations but they contribute
      to avoid arbitrary practice and to reduce practice variability among
      professionals. Their contribution to the present health system management and to
      optimized resources utilization is decisive. CONCLUSIONS: At present, clinical,
      scientific and management practices are closely related. Guidelines have a role
      in the three aspects of the Health System.

PMID- 10637878
TI  - [Chronic anterior laxity of the knee treated with free patellar graft and extra
      articular lateral plasty: 10-year follow-up of 148 cases].
AB  - PURPOSE OF THE STUDY: Assess long-term subjective, functional and radiographic
      outcome after free patellar graft and extra-articular lateral plasty for chronic
      anterior laxity of the knee. PATIENTS AND METHODS: 148 cases of chronic anterior
      laxity of the knee treated by free patellar graft and extra-articular lateral
      Lemaire plasy were reviewed after a mean follow-up of 11.5 years (range 10-15
      years). A complete work-up was performed in all cases at 4 years postsurgery to
      assess objective, sport, function and radiographic outcome (objective laxity and
      osteoarthritic status). RESULTS: Subjectively, 65 p. 100 of the patients were
      very satisfied and 24 p. 100 were satisfied. According to the IKDC
      classification, functional outcome was in class A in 22 p. 100 and in class B in
      49 p. 100. All failures (14 p. 100) except one occurred during the first year.
      When the meniscus was healthy or repaired, the failure rate was only 4 p. 100.
      Two principal factors favoring failure were severe laxity (meniscectomy) and poor
      femoral position. Residual laxity measured on the lateral view in the one-leg
      weight bearing position was 3.3 mm in the overall series, 2.4 mm for cases with
      isolated anterior laxity, and 4 mm for chronic laxities. Residual laxity was
      higher if the medial meniscus was totally or partially removed. There was no
      change between the 4th and 11th year of follow-up. A secondary meniscectomy was
      performed in 5 p. 100 of the cases despite renewed sports activity in 80 p. 100
      of the cases. Osteoarthritic degeneration was the most important factor for less
      favorable outcome: 42 p. 100 of the cases developed preosteoarthitis or
      osteoarthritis. Joint degeneration occurred almost exclusively in patients who
      had undergone medial meniscectomy. Only 2 p. 100 of the patients with a healthy
      or repaired meniscus developed osteoarthritis. When the anterior laxity was the
      only anomaly, the functional result was very excellent, with renewed sports
      activity. Even in cases with persistent residual laxity, there were almost no
      failures or secondary meniscal lesions if the femoral position was correct.
      DISCUSSION: For chronic laxity, free patellar graft alone cannot avoid a high
      rate of failure and/or joint degeneration, particularly favored by an incorrect
      femoral position. Improved results can only be achieved by preserving the
      meniscus and possibly associating a lateral or medial plasty whose effect remains
      to be evaluated.

PMID- 10637879
TI  - [Anterior cruciate ligament function: a non-invasive quantitative technique].
AB  - PURPOSE OF THE STUDY: The purpose of the study was to develop a new non-invasive
      and quantitative method for evaluation of the anterior cruciate ligament
      function. PATIENTS AND METHODS: The new method was tested in 24 asymptomatic
      subjects and in 58 patients (39 males and 19 females) with arthroscopically
      proven unilateral rupture of the anterior cruciate ligament. Anterior
      displacement of the tibia with the knee in 20 degrees flexion was achieved by
      using a redesigned device, constructed originally for stress-radiography, and
      detected by a 3-D optical motion analysis system. RESULTS: In the normal group,
      the average difference (d) in anterior displacement of the tibia between the left
      and the right side under a displacement force of 250N was 0.56 mm (range 0.1 mm
      to 1.9 mm) or 17 p. 100 (range 2 p. 100 to 64 p. 100), while in patients the
      average difference (d) in anterior displacement of the tibia between the injured
      and uninjured side under a displacement force of 250N was 4.02 mm (range 0.6 mm
      to 9.4 mm) or 133.6 p; 100 (range 26 p. 100 to 451 p. 100). By the criteria for
      false negative results, i.e. the maximum value of the parameter d in normal
      subjects (1.9 mm and 64 p. 100), 10 p. 100 of the patients (6 patients) fell into
      the normal group. According to the criteria of false positive results, i.e. the
      minimum value of the parameter d in patients (0.6 mm and 26 p. 100), 17 p. 100 of
      the normal subjects (4 normal subjects) fell into the group of patients. The
      achieved level of differentiation is in the similar range as the most frequently
      used present methods. DISCUSSION: The main advantage of the newly developed
      noninvasive optical measurement technique is that the direction of force and the
      amplitude and site of application are accurately defined and documented, and that
      dislocation movement of the tibia towards the femur during the application of a
      growing force is continuously monitored with the 3-D optical system and that it
      allows for several consecutive assessments based on statistical data.

PMID- 10637880
TI  - [Laxity and functional results of Miller-Galante total knee prosthesis with
      posterior cruciate ligament sparing after a 6-year follow-up].
AB  - PURPOSE OF THE STUDY: The preservation of the posterior cruciate ligament (PCL)
      was introduced in total knee arthroplasty to improve the quadriceps efficiency
      and the range of flexion in stairs. The purpose of this study was to determine if
      these goals were achieved with the Miller-Galante total knee prothesis and to
      assess the relation between knee laxity and function. MATERIALS AND METHOD: We
      assessed retrospectively the results of 48 consecutive Miller-Galante with PCL
      retaining. Four patients were excluded: 2 died, 2 lost to follow-up. Forty-four
      prostheses were evaluated in 38 patients mean aged 65 (33-79). The preoperative
      HSS score was 41 +/- 12.4 [21-63]. All the components were cemented with patellar
      resurfacing (25 metal-backed, 19 polyethylene). Stressed X-rays with Telos device
      were performed to assess frontal and antero-posterior laxity. All radiographic
      measurements were carried out with a digitizer (Orthographics). RESULTS: After 6
      years of follow-up, 8 prostheses (18.1 p. 100) were already revised because of:
      1) 3 excessive anterior tibial translations and severe polyethylene wear; 2) 5
      femoro-patellar disorders. These last 5 knees (4 patellar metal-backed) had a
      greater patellar thickness [(25 mm +/- 1.2) (p = 0.01)]. The mean HSS knee score
      for the 36 remaining prostheses was 73.8 +/- 11.3 (35-92). Only 5 patients were
      able to climb stairs without support. The mean mechanical axis was 2.3 degrees in
      varus, but 81 percent of the knees were at 5 degrees around neutral position. The
      mean laxity in valgus was 4 degrees +/- 2.3 degrees [1-10], and 4.1 degrees +/-
      2.1 degrees [1-9] in varus. The mean anterior tibial translation was 5.3 mm +/- 5
      [1-17] and posterior laxity was 4.7 mm +/- 2.5 [1-10]. HSS knee score was lowered
      by 9 points when frontal laxity (valgus + varus) was greater than 5 degrees (p =
      0.01), and by 9.8 points when posterior laxity was 5 mm or more (p = 0.02). The
      mean thickness of the patella was 22 mm +/- 2.3 [16-27]. DISCUSSION: These
      results were unsatisfactory considering the high revision rate and the low
      functional score observed despite of a correct implant positioning. The major
      challenge for PCL retaining (i.e. free stair climbing) was achieved in few cases.
      The wide range of posterior laxity underlined the difficulties to control PCL
      tension. On the other hand, PCL tension has to be controlled as it could
      influence knee function. Patello-femoral disorders was the main reason for
      revision surgery and an insufficient patellar bone resection may be contributive.
      Sagittal anterior laxity was the second reason for revision and it should be
      carefully detected as it could drive to catastrophic polyethylene wear.
      CONCLUSION: The advantages of PCL retaining were not demonstrated with this low
      constrained design. Surgical control of PCL tension could give a wide range of
      posterior laxity. Sagittal femoral-tibial laxity and femoro-patellar disorders
      should be detected before severe polyethylene wear. These results advocates for:
      1) more congruent designs with PCL retaining or for PCL substituting designs, 2)
      improvement of patello-femoral design.

PMID- 10637881
TI  - [Role of arthroscopy in the treatment of pyogenic arthritis of the knee in
      adults. Report of 16 cases].
AB  - PURPOSE OF THE STUDY: The goal of this study was to determine the place and the
      limit of the arthroscopic management of septic knee arthritis. This procedure is
      an alternative treatment to needle aspiration and to open arthrotomy drainage.
      MATERIAL AND METHODS: Sixteen adult patients were treated between 1993 and 1997
      for pyogenic septic arthritis of the knee. The duration of symptoms prior to
      arthroscopic debridement was 4.5 days (range, one to 14 days). In 8 patients the
      infection was hematogenous. 5 patients had post-operative infection, 2 had post
      traumatic infection and one infection followed an intraarticular injection. All
      the patients were treated by arthroscopic debridement and irrigation of the knee.
      A partial synovectomy of the anterior compartment was carried out in 4 cases in
      which the infection diagnosis was delayed. In 6 patients with resistant germ or
      early unfavorable course (clinically or biologically), an early iterative
      arthroscopy was performed between 2 and 7 days after the first procedure. The
      medical treatment consisted in a double systemic antibiotherapy for an average
      duration of 4 weeks, followed by oral treatment for 3 weeks. The patients were
      encouraged to mobilize their knee as soon as C Reactiv Protein was normal
      (average 3 weeks, 0 to 12). RESULTS: The average follow up was 20.5 months (2 to
      60). Two elderly patients died, one directly related to knee infection. One
      patient with prior patella osteosynthesis had a recurrent infection 10 months
      after the arthroscopy. Thirteen out of 14 patients had an excellent or good
      functional result. DISCUSSION: Arthroscopic drainage is a valuable alternative
      procedure for the treatment of the septic arthritis. Arthroscopic treatment leads
      to a more effective infectious result than needle aspiration procedure and the
      functional result is better than with open drainage. Septic arthritis in the
      elderly or in patients with multiple organ failure have a poor prognosis. The
      treatment of pyoarthrosis of the knee must be aggressive and we frequently
      propose an iterative arthroscopic drainage, specially in case of delayed
      treatment, early unfavorable course or multiresistant germ.

PMID- 10637882
TI  - [Experimental comparative study of 3 systems of osteosynthesis for proximal
      humeral fractures. Preliminary study of the mechanical properties of conserved
      trabecular bone].
AB  - PURPOSE OF THE STUDY: We have compared three systems for osteosynthesis of
      proximal humeral fractures on a four-fragment fracture model: Plate with
      tuberosity screwing (P), Kirschner wires with bone sutures (K) and an original
      implant, the "bilboquet" (Stryker) (B), composed of a hook for the head supported
      on a diaphyseal stem. MATERIAL AND METHODS: Because of the unavailability of
      fresh human material, we have turned to embalmed bones after having shown, on
      cancellous femoral head bone, the little influence of our method Vs freezing
      conservation. Settings were tested in compression. We measured their mechanical
      resistance judged on the ultimate strength and on the slope (displacement/load),
      to this limit. We similarly analyzed by video recording displacement of the
      different fragments according to four components (head slipping, its lateral
      displacement, its see-saw and the separation of tuberosities), to show the weak
      points of the three systems. RESULTS AND DISCUSSION: K was more deformable (p <
      0.001) that P and B (average slopes in mm/100N to 0.67 for K, 0.42 for P and 0.43
      for B). The ultimate strength differed but not significantly (average values in
      Newton to 1223 for K, 1601 for P and 1721 for B). We also showed for the three
      techniques, the significant correlation between slopes and bony densities. Video
      analysis showed that P opposed lateral displacement of the head and separation of
      tuberosities better, the resistance to slipping and see-saw seems to be
      improvable by greater divergence of screws or a modification of the plate (mini
      canon). B opposed slipping and see-saw better but its weak point was the risk of
      articular break-in of the hook, by defect of resistance to lateral displacement,
      that for us could be limited by a less peripheral position of teeth or a
      modification of their form. K is indeed the least effective of the four
      components but we think that it would be improvable by using, for example, a
      centro-medullary technique, allowing an internal cortical support.

PMID- 10637883
TI  - [Retrospective study of 23 arthrolyses of the elbow for post-traumatic stiffness:
      result predicting factors].
AB  - INTRODUCTION: The goal of the study was to determine the results of elbow
      arthrolysis for post-traumatic stiffness, and to identify factors governing the
      result of that procedure. PATIENTS AND METHODS: Between 1984 and 1997, 26 elbow
      arthrolysis were performed. Twenty-three patients were retrospectively assessed
      by an independent examiner, 3 patients were lost for follow-up. The mean age at
      surgery was 41 years. The traumatisms responsible for stiffness were: 5 elbow
      dislocations, 7 radial head fractures, 3 olecranon fractures, 8 humeral palette
      fractures. The surgical approach was 2 times posterior, 9 times lateral, 12 times
      combined (posterior and lateral). The surgical approach was chosen according to
      the preoperative analysis of the stiffness factors and the scars in case of
      previous surgery. RESULTS: At follow-up (85 months (12-144)), 5 patients were
      very satisfied, 17 patients were satisfied and one patient was not satisfied. Six
      patients had discomfort in daily gesture. Ten patients had no pain, 6 had pain
      while effort and 7 had climatic pain. Two ulnar palsies existing at arthrolysis
      did not improve after neurolysis and anterior ulnar nerve transposition. Range of
      motion increased in every sector of mobility, and at follow-up mean ROM was: 121
      degrees flexion, -31 degrees extension, 69 degrees pronation and 65 degrees
      supination. The average absolute benefit in flexion-extension was about 38
      degrees. The average relative (flexion-extension) benefit according to Merle
      d'Aubigne was about 44%. At follow-up, the average pronation-supination was
      higher than 100 degrees. The range of motion was not correlated to the type of
      injury, to the surgical management, nor to the type of rehabilitation program.
      Likewise, the delay between traumatism and arthrolysis had no influence on the
      result. On the other hand, the range of motion was directly correlated to the
      preoperative mobility and mobility obtained just after surgery (p = 0.001).
      However, the range of motion at follow-up was slightly decreased (5 degrees to 15
      degrees) compared to the mobility obtained just after surgery. DISCUSSION: The
      final range of motion was mainly related to the severity of the preoperative
      stiffness. We noticed that few patients were bothered in daily gestures, in spite
      of a relative stiffness. The type of injury did not seem to influence the final
      result. Elbow arthrolysis remains a mobilizing technique giving reliable long
      lasting results. CONCLUSION: The range of motion obtained after arthrolysis
      performed because of elbow post-traumatic contracture is mainly related to
      preoperative stiffness. By comparing with postoperative range of motion, a loss
      of 5 degrees to 10 degrees can be predicted.

PMID- 10637884
TI  - [Direct cost assessment of wrist fractures].
AB  - PURPOSE OF THE STUDY: The cost effectiveness of wrist fractures in 1996 at Pitie
      Salpetriere Hospital in Paris has been thoroughly analysed. The purpose of this
      retrospective study was to identify the factors responsible for the variation in
      the treatment cost of those fractures. MATERIAL AND METHODS: Cost, hospital stay,
      functional status, ASA score and surgical treatment were analysed in 53 patients
      with a median age of 57 years. RESULTS: The mean cost per patient was 6,120 FF
      divided as follows: 26.1% for pre-operative care, 36.4% for surgical procedures,
      37.5% for post-operative care. The mean hospital stay was 4.3 days. The cost of
      personnel (43%) and medical investigations (35%) were the two main sources of
      hospital expenses beside medical materials (12.5%), hostelry (5.5%), and drugs
      (4%). DISCUSSION: The duration of hospital stay, the age and the type of the
      fracture were the only factors that affected statistically the mean cost per
      patient. Furthermore, factors related to the patient as sex, place of residence
      prior to admission, functional status, ASA score, had no influence on cost
      variation. CONCLUSION: Therefore, the best way to reduce the cost of wrist
      fractures management is to minimize the hospital stay before and after surgical
      procedure to avoid a lengthy and costly hospital stay and to minimize the abuse
      utilisation of systematic medical investigations.

PMID- 10637885
TI  - [Chondrosarcoma secondary to multiple cartilage diseases. Study of 29 clinical
      cases and review of the literature].
AB  - PURPOSE OF THE STUDY: Several studies have demonstrated better prognosis of
      chondrosarcomas arising in hereditary multiple exostosis or Ollier's disease. The
      aim of this study was to evaluate their clinical, radiological and histological
      features and compare their prognosis with other chondrosarcomas. MATERIAL AND
      METHODS: We reviewed twenty nine secondary chondrosarcomas among seventeen
      patients with osteochondroma (group A), and eight with Ollier's disease (group
      B). These tumors represented 12 p. 100 of all chondrosarcomas treated between
      1950 and 1994 in Cochin Hospital. Two group B patients successively developed
      three multicentric chondrosarcomas. Twenty six resections (eight intra and
      eighteen extra-lesional), two disarticulations and one amputation were performed
      as primary treatment. The average follow-up of the study was 10.5 years. The
      results were evaluated by means of survival curves. The significance of the
      difference between the curves was determined by the log-rank test. RESULTS: The
      mean age of malignant change was 36 years old. The most frequent tumoral site was
      the innominate bone for group A and the femur for group B. In three cases,
      radiographs showed no malignant features. All chondrosarcomas were classified as
      grade 1 or 2. The ten-year survival rate was 82 p. 100 with no significant
      difference between the two groups. The survival rates were significantly
      different after carcinologic surgery (extra-lesional resection or amputation) and
      contaminated surgery (intralesional resection), with 5 and 88 p. 100 of local
      recurrences respectively. DISCUSSION AND CONCLUSION: These secondary
      chondrosarcomas represent about 10 p. 100 of all chondrosarcomas. They appear 15
      years earlier. According to O'Neal and Ackerman classification, most of the
      tumors are well-differentiated (60 p. 100 grade I, 39 p. 100 grade II and 1 p.
      100 grade III). Carcinologic surgery is generally curative. Ten-year survival
      rate is 94 p. 100. With equivalent grade and surgery, their prognosis is better
      as compared to primary chondrosarcomas.

PMID- 10637886
TI  - [Repair of cartilage defects. Technical aspects].
AB  - Efficacious treatment of chondral and osteochondral defects of the weight bearing
      surfaces represents a real challenge for the orthopaedic surgeon. Treatment
      options for full thickness cartilage defects are discussed in this paper. Poor
      biomechanical characteristics of the reparative fibrocartilage promoted by
      "traditional resurfacing techniques" provide only moderate clinical outcome in
      the treatment of such lesions. During the last decade several new efforts have
      been expressed to provide a hyaline or hyaline-like gliding surface for a full
      thickness defected area on the weight bearing surface. Among several surgical
      procedures, autologous osteochondral transplantation methods, including
      osteochondral mosaicplasty, chondrocyte transplantation, periosteal and
      perichondrial resurfacement and allograft transplantation are the favoured "new
      methods". Experimental background, operative techniques and clinical results of
      these new procedures are detailed in this overview. According to the early and
      medium term experiences of these methods it seems that a hyaline or hyaline-like
      resurfacement of the defected area can provide a more durable gliding surface and
      a better clinical outcome than the so called "traditional resurfacing
      techniques". Autologous osteochondral mosaicplasty--as an easy, one-step
      procedure, providing a relatively quick rehabilitation--can be an alternative in
      the treatment of small and medium sized lesions. Excellent clinical outcome, low
      costs of the treatment and short rehabilitation time represent the main
      advantages of this method. Autologous chondrocyte transplantation seems to be a
      promising option in the treatment of larger full thickness defects but requires
      relatively expensive two-step procedure and longer rehabilitation period. Both of
      the above mentioned techniques have femoral, tibial, patellofemoral and talar
      applications as well. According to the present recommendations transplantation of
      osteochondral allografts can be indicated at massive osteochondral lesions. There
      are less experiences with the clinical use of periosteal and perichondrial
      resurfacing techniques and biomaterials. Beside the promising early and medium
      term results of these methods the authors express that a successful treatment of
      the full-thickness cartilage damages of the weight bearing surfaces depends not
      only the way of the cartilage repair but on the treatment of the underlying cause
      as well. According to this statement for an effective treatment of full thickness
      defects on the weight bearing surfaces requires careful patient selection,
      complex operative plan and well organized treatment course.

PMID- 10637887
TI  - [Postero-medial elastic stable intramedullary nailing for anteriorly displaced
      distal diaphyso-metaphyseal fractures of the radius in children].
AB  - PURPOSE: To suggest a mechanically satisfying method to stabilize the unfrequent
      distal diaphyso-metaphyseal fractures of the radius, when they are anteriorly
      displaced, avoiding the classical use of an anterior osteosynthesis by plate and
      screws. MATERIAL AND METHODS: Ten cases of postero medial Elastic Stable
      Intramedullary Nailing are presented. Technically, a small postero medial
      approach with gentle retraction of extensors tendons is used. Then a hole is
      drilled through the postero medial metaphysis of the distal radius. A present
      wire is introduced intramedullary, directing its elastic forces in a postero
      lateral way, fighting against the displacement. DISCUSSION: The instability of
      this fracture often requires an osteosynthesis. Plating needs a larger incision
      and a direct control of the fracture (danger of injure of the growth plate,
      scar). Retrograd nailing through the proximal end of the bone can injure nerves.
      Then, postero medial Elastic Stable Intramedullary Nailing can be useful for
      stabilization of the diaphysometaphyseal fractures of the radius.

PMID- 10637888
TI  - [Chondroma of the soft tissues of the hand. Report of a recurrent case].
AB  - A twenty six-year-old man presented a mass of the fifth left finger. X Ray and
      pathological examination after surgical treatment showed an extraskeletal
      chondroma. One month later, this tumor recurred, leading to a second surgical
      procedure. At one year follow up there was no evidence of new recurrence. A
      review of the literature shows that recurrence of this type of tumor is extremely
      rare. Also, it stresses the importance of a proper diagnosis which allows an
      appropriate treatment initially and after a recurrence.

PMID- 10637890
TI  - [Henri Dejour (1930-1998)].

PMID- 10637889
TI  - [Primary bone leiomyosarcoma. Anatomo-clinical, immunohistochemical, and
      ultrastructural study].
AB  - A variety of tissues in bone can be the origin of neoplastic primitive lesions.
      Consequently, it can be the site of various sarcomas of tissue type, incursing
      leiomyosarcoma. The leiomyosarcoma of the bone is considered as primitive after
      exclusion either a bony extension of a soft tissue tumor of vicinity or the
      presence of a leiomyosarcoma elsewhere. We report a case of a primary
      leiomyosarcoma arising on the left femur of a 40-year-old woman. The diagnosis
      was confirmed by immuno-histochemistry and electron microscopic study. A bloc
      resection followed by a prothesis was performed. The patient underwent a
      fractioned postoperative radiotherapy with a total dose of 75 Gy. The
      postoperative course one year later revealed local recurrence and pulmonary
      metastases. Despite the resection of pulmonary metastases and the amputation of
      left lower limb, the patient had developed local recurrence on the stump of
      amputated limb and was on the outside of all therapeutic resource. In this
      report, we present the clinicopathologic, immuno-histochemical and
      ultrastructural profiles of these rare primary bone tumors.

PMID- 10637891
TI  - [Pleuropulmonary endometriosis].
AB  - Endometriosis is a condition where endometrial and cytogenic chorion glands lie
      outside the uterine cavity. The underlying pathophysiological mechanisms remain
      unclear. Pelvic localizations are common, but more distant localizations in
      cutaneous, neurological or thoracic sites are exceptional. Symptoms following the
      menstrual cycle suggest the diagnosis. Bronchopulmonary endometriosis is
      exceptional. The diagnosis is suggested by the presence of recurrent hemoptysis
      following the menstrual cycle. Distal lesions are exceptionally visible to the
      endoscope. Chest x-ray and CT can visualize the lesion as a nodule with variable
      size depending on the menstrual cycle. Positive diagnosis is obtained at
      excision. The characteristic feature of catamenial pneumothorax is recurrent
      pneumothorax in the fourth decade of life, almost always on the right and
      coincident with menses but with no other signs. The diagnosis is clinical and
      radiological. Endometriomas appear as hypodense nodules on CT scan if they are
      larger than one centimeter. A homogeneous hypersignal is seen on the MRI.
      Thoracoscopy or thoracotomy may be necessary; the endopleural aspect is specific.
      The hypothesized pathogenic mechanism involves an air passage from the genital
      tract via breaches in the diaphragm. Treatment is based on medical or surgical
      pleural synthesis and hormone therapy for several months.

PMID- 10637892
TI  - [Current aspects of lymphangioleiomyomatosis].
AB  - Lymphoangioleiomyomatosis (LAM) is a characteristic diffuse proliferation of
      abnormal smooth muscle fibers predominantly developing in the lung and leading to
      cystic destruction. An almost totally specific marker, HMB45, is available. This
      monoclonal antibody labels cells of the melanocyte line, LAM cells and renal
      angiomyolipoma cells. The antigen carried by all these cell lines is probably gp
      100 involved in melanogenesis. Two gene loci are formally implicated in the
      pathogenesis of Bourneville tuberous sclerosis (BTS): TSC1 (9q 34.3) and TSC2
      (16p 13.3). The TSC2 locus could be implicated in the pathogenesis of pulmonary
      LAM. LAM and BTS have similar clinical and histological features and could be two
      different phenotypic forms, distinguished strictly on a nosological basis, of the
      same disease. The hormone-dependence theory is suggested on the basis of purely
      clinical arguments, particularly the almost exclusive female predominance,
      generally during the period of genital activity. Certain counter arguments have
      also been put forward and consequently, since no in vitro cell culture model or
      animal model of LAM is available, it is not really possible to verify the
      hypothesis. Epidemiological data have been recently acquired in France with the
      constitution of the GERM"O"P registry of LAM cases in France. Recent
      technological progress in imaging techniques has also been helpful for earlier,
      more precise diagnosis. HMB45 immunolabeling improves diagnostic sensitivity on
      small tissue fragments obtained with transbronchial biopsies. The course of LAM
      appears to be different in certain patient subgroups. Certain patients develop
      rapidly fatal disease in months or years while in the majority of patients the
      disease is much less aggressive for years. A minority of patients also have very
      slowly evolving disease sometimes diagnosed after menopause. Lung transplantation
      remains the ultimate treatment in case of life-threatening prognosis.

PMID- 10637893
TI  - [Pleuropulmonary metastases of female cancers].
AB  - Pleuropulmonary metastasis occurs in 30 to 50% of all patients with cancer.
      Certain metastases occur specifically in females: breast and ovary cancer. There
      are six different clinical presentations of bronchopulmonary metastases: unique
      or multiple nodular images, mediastinal nodes, carcinomatous lymphangitis,
      bronchial metastasis, tumoral emboli, and metastatic bronchiolo-alveolar
      metastatic cancer. When the primary cancer is not known, a minimum number of
      investigations are needed: thyroid and pelvic ultrasound, mammography, colonscopy
      for certain cases, alfa-fetoprotein assay, neuron-specific enolase and beta HCG.
      Metastatic pleurisy accounts for 45% of all cases of pleurisy. In women,
      neoplastic pleural effusions result from breast cancer (37%), genitourinary tract
      cancer (20%), and lung cancer (15%).

PMID- 10637894
TI  - [The lung and benign diseases of the ovary].
AB  - Two main benign diseases of the ovary which can simulate advanced stage cancer of
      the ovary are described. The first is Meigs' syndrome, a triad of benign ovarian
      tumor, usually an ovarian fibroma, ascitis, and pleural effusion with complete
      disappearance of serous exsudative effusions with surgical resection of the
      ovarian tumor. The second is ovarian hyperstimulation syndrome following
      ovulation induction with exogenous gonotropins for the treatment of infertility.
      This syndrome associates significant ovarian enlargement, hyperestrogenism and
      latent or clinically patent serous exsudative effusions; it usually resolves with
      suggestive measures and rest.

PMID- 10637895
TI  - [Smoking in women in France].
AB  - Surveillance of smoking behavior and study of consequences of smoking on the
      health of the French population, and particularly the female population, is a
      public health priority. The amount of tobacco consumed can be determined from
      sales figures and from surveys. Globally, tobacco sales increased through 1985.
      According to the available surveys, the proportion of regular smokers has varied
      little as smoking rate has decreased in men and increased in women. The decrease
      occurred in all age groups for men and increased only in the 25-49 year age group
      for women. Smoking is the cause of 60,000 deaths per year in France, 57,000 in
      the male population and 3,000 in the female population. Despite reinforced
      legislation (The Veil and Evin laws) which is unfortunately poorly applied,
      tobacco consumption has not decreased greatly. Funding levels for anti-smoking
      campaigns are totally insignificant compared with the efforts of the tobacco
      industry to promote their products. However, the beneficial health effect of
      stopping smoking is truly great since the risk depends much more on the duration
      of smoking than on the number of daily cigarettes. In addition, the delay between
      the cause and consequence is long, the consequences of the increase in tobacco
      smoking among young women over the last 20 years will not become visible until 20
      to 40 years from now. One could wonder why so little effort has been put into
      anti-smoking campaigns despite the readily available data clearly warranting
      their promotion.

PMID- 10637896
TI  - [Specific features of bronchial cancer in women].
AB  - Deaths related to lung cancer in females are now more frequent than those related
      to breast cancer in North America. The French situation is far from this one but
      starting from a very low incidence-plateau there is now a significant growing
      frequency and the sex-ratio is lowering. Even if smoking is, like in males, the
      most important cause of lung cancer, there are at least 25% of lung cancers in
      female for which indoor pollution, diet, previous history of respiratory diseases
      are important risk factors. These factors vary according to the geographical area
      and period. The role of environmental tobacco smoke exposure is now quite certain
      in female non-smokers. Distribution of histological subtypes differs considerably
      with a large predominance of adenocarcinoma in females and more small-cell lung
      carcinomas in smokers. Female sex appears to be an independent favourable
      prognostic factor. All these female-male differences in patients with lung cancer
      suggest that lung cancer in females is a somewhat different entity from lung
      cancer in males.

PMID- 10637897
TI  - [Influence of female sex on asthma].
AB  - Asthma in women has characteristic features related to hormone secretion.
      Classically, the prevalence of asthma is higher in boys than in girls. Data in
      the literature are not all in agreement with this hypothesis and it would appear
      that for cultural and social reasons, asthma is under-diagnosed in young girls.
      In the premenstrual context, sex hormones have a clear effect as reported in the
      literature in 30 to 40% of asthmatic women. Aggravation occurs readily in
      patients with severe disease. During pregnancy, asthma can influence outcome
      unfavorably. It is advisable to follow these pregnancies closely and encourage
      good self-monitoring to minimize risks for the mother and fetus. In the peri- and
      post-menopausal period, asthma may worsen in women with prior disease. The rate
      of disease onset during this period is also higher than in other age groups.
      Hormone replacement therapy can have an unfavorable effect on the incidence of
      asthma during this period.

PMID- 10637899
TI  - [Modifications of respiratory function during pregnancy].
AB  - During pregnancy, changes in the thoracic configuration subsequent to progressive
      increase in the abdominal volume have a moderate effect on respiratory function.
      The cephalic displacement of the diaphragm reduces the expiratory reserve volume
      and the residual volume. The main consequence is an increase in the closing
      volume of the airways due to the fact that the lower residual functional capacity
      occurs during the tidal volume. The increase in the closing volume decreases the
      ventilation of the adjacent alveolar areas which could explain an increased
      heterogenicity of the ventilation-perfusion ratios. Increased tidal volume is
      almost always observed during pregnancy and is the cause of hyperventilation and
      a major increase in alveolar ventilation which can reach 70% of the post partum
      value. This hyperventilation is probably due to increased chemosensitivity of the
      CO2 respiratory centers induced by the hyperprogesteronism observed during
      pregnancy.

PMID- 10637898
TI  - [Influence of female sex on the respiratory manifestations of connective tissue
      disease].
AB  - Connective tissue diseases predominating in females include disseminated lupus
      erythematosus, antiphospholipid syndrome, primary pulmonary hypertension,
      Sjogren's syndrome, and rheumatoid arthritis. Pulmonary involvement is not
      uncommon and clinical expression may be modified by pregnancy. In addition, a
      certain number of drugs used for their treatment have an effect on fertility and
      pregnancy. We review here these different aspects and female-specific diagnostic
      and therapeutic features of connective tissue diseases.

PMID- 10637900
TI  - [Thoracic radiology in pregnant women].
AB  - Radiological explorations of the thorax raise a certain number of risks for the
      mother and infant which should be well recognized by the pneumologist.
      Irradiation is the major risk and can be evaluated in comparison with other risks
      of radiation. We recall the dosimetric system based on the effective dose
      expressed in Sievert (Sv). The risks of irradiation are described. The dangers
      related to contrast agents are discussed. Each type of thoracic imaging is then
      considered from the standpoint of the technique, risks involved and means of
      radioprotection. Precise indications for each technique are given in detail for
      pregnant women. We review rapidly the physiological and pathological signs and
      symptoms observed during pregnancy and propose a practical attitude for ordering
      radiographic explorations.

PMID- 10637901
TI  - [Development of acute and chronic respiratory diseases during pregnancy].
AB  - Physiological respiratory and hormonal changes occurring during pregnancy result
      in increased oxygen consumption related to fetal growth. The increase in the
      maternal basal metabolism leads to hyperventilation and increased cardiac output.
      This explains why pathological respiratory or cardiovascular conditions existing
      prior to pregnancy can rapidly worsen during the course of the pregnancy.
      However, even if no cardiorespiratory disease exists prior to pregnancy, an
      inhalation lung disease, pre-eclampsia or sepsis can lead to pulmonary edema due
      to the increased plasma volume in the pregnant woman. These different
      pathological situations as well as infectious lung diseases are discussed here.
      We examine the evolution of respiratory function during the course of labor,
      delivery and the post-partum period. In addition, pregnancy also has an effect on
      chronic respiratory disease, particularly asthma.

PMID- 10637902
TI  - [Sarcoidosis and pregnancy].
AB  - If well managed, pregnancy in women with sarcoidosis is usually carried to term
      with no problem, excepting rare contraindications. There is no specific risk for
      the embryo-fetus. Fertility is unchanged. Pregnancy can be contraindicated in
      case of respiratory failure due to heart failure or central nervous system
      disorders. A vital capacity less than 100 ml or pulmonary hypertension
      contraindicate pregnancy. Pregnancy should be discouraged during a period of
      active disease progression., but pregnancy in itself does not aggravate
      sarcoidosis. A flare up 3 to 6 months after delivery is not unusual. Therapeutic
      indications are the same as outside pregnancy, corticosteroid therapy being the
      only proven treatment during this period. Methotrexate and antimalaria drugs are
      contraindicated. Methotrexate, even with low weekly doses has a teratogenic
      effect, particularly between 6 and 8 weeks gestation. Likewise, congenital
      anomalies have been described with antimalaria drugs although the risk is less
      than with methotrexate.

PMID- 10637903
TI  - [Drugs for respiratory tropism and pregnancy].
AB  - The pharmokinetics of drugs used to treat lung disease in pregnant women undergo
      changes due to the physiological variations induced by pregnancy. Dosage must
      therefore be adapted; increased doses are often required for the treatment of
      severe lung infections. Most drugs used for lung disease have a teratogenic
      potential and thus carry a risk for the fetus. Drugs used for asthma usually
      present little risk for the fetus. Administration by inhalation is particularly
      well adapted as it limits systemic diffusion. Excessively high doses can however
      lead to neonatal toxicity. Penicillins, cephalosporins and erythromycin have been
      shown to be well tolerated and are the choice antibiotics. Aminoglycosides
      require careful monitoring due to the risk of renal and auditory toxicity.
      Fluoroquinolones, sulfamides and tetracyclines should be avoided. Available data
      on recent compounds such as the new macrolides (azithromycin, clarithromycin) are
      too limited for recommending their use during pregnancy. In case of resistant
      tuberculosis, it is sometimes necessary to prescribe a second choice anti
      tuberculosis drug with known or suspected fetal toxicity.

PMID- 10637904
TI  - [Pulmonary auscultation revisited?].

PMID- 10637905
TI  - [Use of the helium-oxygen mixture in pneumology practice].
AB  - Therapeutic use of the helium-oxygen mixture (heliox) was first reported in 1934.
      Medical use was further restricted to physiological studies. Density and
      viscosity of Heliox are very different from those of air or oxygen. This can
      explain how Heliox can induce modifications in the airway flow. In diseases of
      the main or small airways (upper airway obstruction, chronic obstructive
      pulmonary disease, asthma), such modifications could induce a diminution in the
      resistive component of the work of breathing and therefore protect against the
      risk of developing a respiratory failure. This explains a renewed interest of
      clinicians for Heliox since the beginning of the eighties. To date, the good
      tolerance of heliox seems to be well established. Inversely, scientific
      validation of the therapeutic indications of the mixture in airway diseases are
      lacking. Moreover, potential therapeutic indications of the mixture are not
      restricted to airway diseases. Various applications, such as adult respiratory
      distress syndrome, pneumothorax, fiberoptic bronchoscopy, and mechanical
      ventilation, are suggested by preliminary reports. Obtaining a synthetic vision
      of older and more recent studies is the purpose of this review.

PMID- 10637906
TI  - [Pulmonary stethacoustic nomenclature: Why not a worldwide consensus?].
AB  - In order to found the stethacoustic nomenclature on objective facts, we suggest
      to express lung sounds in a way taking first into account acoustical physics.
      Indeed the physicoacoustical definition of lung sounds has to take place before
      its psychoacoustical definition. Acoustical physics identifies only four kinds of
      vibrations: simple and complex periodical vibrations, transient and continuous
      non periodical vibrations. Lung sounds are bound to fall into one of those four
      categories. Phonopneumograms in time and frequency domain allow an objective
      classification of breath and adventitious lung sounds and introduce a
      simplification into the nomenclature which recognizes only four sorts of lung
      sounds, all of them included in these two categories: 1 degree breath sounds
      include normal and bronchial breath sounds, 2 degrees adventitious sounds include
      crackles (for every discontinuous sound) and wheezes (for every continuous
      sound). Objective parameters add their specific characteristics in terms of
      pitch, complexity, Hz-frequency, timing in the respiratory cycle and duration.
      The proposal of a new nomenclature is justified because it is supported by
      measurable physical phenomena. The solution of semantic problems should enable
      clinicians to progress toward a worldwide consensus.

PMID- 10637907
TI  - [Intensive care and respiratory sleep disorders].
AB  - The study of respiratory sleep disorders in intensive care is a developing field.
      Indeed sleep pathology concerns not only pneumologists and neurophysiologists but
      also numerous specialties including medicosurgical resuscitation. The advent of
      "portable" appliances should facilitate access to polysomnography (PSG) for
      diagnosis of sleep respiratory disorders (RDS) in the intensive care unit. This
      examination can be appropriate in two separate circumstances. RDS in life
      threatening situations (generally respiratory and/or cardiac failure) or when RDS
      is worsened by the specific conditions of intensive care units: "intensive care
      induced RDS". In both cases, easy diagnosis of RDS by PSG allows adjustment of
      the treatment (corrections of iatrogenic factors, continuous positive airway
      pressure [CPAP], noninvasive ventilation [NIV], oxygen [O2]. A specific treatment
      of the well documented RDS is most desirable, as the patients are considered to
      be at high risk for endotracheal intubation. If diagnosis of RDS is not made
      during the acute phase, the intensive care physician should be informed of the
      clinical and paraclinical elements leading to prescription of a delayed
      polysomnography in order to reduce the risk of further vital distress.

PMID- 10637908
TI  - [Allergologic explorations in children].
AB  - Guidelines to the multitude of allergologic tests are defined. But, in practical
      experience, skin prick test are the first and the best test for allergy
      diagnosis. Positive skin prick test refer to sensitization in accordance with
      clinical history.

PMID- 10637909
TI  - [Postpneumonectomy syndrome in adults: description and therapeutic propositions
      apropos of 8 cases].
AB  - BACKGROUND: Adult post-pneumonectomy syndrome can be defined as an extrinsic
      compression of the main bronchus or a lobe bronchus on the aorta resulting from
      excessive mediastinal deviation after pneumonectomy. PATIENTS: Eight cases in
      adults are reported. The delay to symptom onset was a mean 34 months. Three
      patients complained of increased dyspnea and 5 patients experienced a must more
      rapid course with adult respiratory distress syndrome in 1. Fibroscopy and chest
      CT confirmed the diagnosis of extrinsic compression of the main bronchus or a
      lobe bronchus. RESULTS: In the first 2 patients, endoscopic treatment with an
      endobronchial prosthesis was unsuccessful. The mediastinum was recentered in the
      following patients using an inflatable prosthesis positioned in the pneumonectomy
      cavity. Clinical improvement was achieved in all patients. Fibroscopy and chest
      CT confirmed the reduction in bronchial compression. DISCUSSION: Early diagnosis
      and mediastinal recentering are required for good outcome. Surveillance after
      pneumonectomy should include a search for mediastinal deviation and its
      consequences, particularly concerning the permeability of the remaining bronchi.

PMID- 10637910
TI  - [Profiles of 939 patients with obstructive sleep apnea syndrome treated with
      continuous positive pressure].
AB  - The aim of this study was to analyze the characteristics of patients on long-term
      continuous positive pressure therapy for obstructive sleep apnea in order to
      determine the efficacy, observance, tolerance, degree of patient satisfaction and
      patient quality of life using the Nottingham scale. A questionnaire was sent to
      939 patients treated for at least six months in 11 centers. Factorial analysis of
      multiple correspondences and two classification analyses were used to establish
      patient profiles. Factorial analysis evidenced a relationship between patient
      satisfaction, reduced symptoms, observance and tolerance. The classification
      analyses distinguished three groups. Group A (n = 596) included primarily men
      (93%) who were satisfied with the treatment (99%) and showed good observance.
      Group B (n = 284) was characterized by patient satisfaction, observance, improved
      symptoms and lower quality of life than group A. Group C was composed of older
      patients who were satisfied with their treatment and showed good observance but
      who had no notable improvement in their symptoms. In conclusion, this study
      pointed out the difficulty in defining which patients with obstructive sleep
      apnea would benefit most from continuous positive pressure therapy. Good
      observance is not a sufficient criterion for therapeutic efficacy.

PMID- 10637911
TI  - [Acute respiratory Chlamydia pneumoniae infections in adults. Value of direct
      gene amplification diagnosis].
AB  - Chlamydia pneumoniae has been established recently as an important human
      respiratory pathogen. The aim of this study was to define the incidence of
      Chlamydia pneumoniae in acute respiratory infections by evaluating its presence
      in posterior nasopharyngeal aspirates or broncho-alveolar lavage specimens by
      polymerase chain reaction-hybridization (PCR-EIA) as well as the titres of
      specific antibodies in serum by a rELISA test and a micro-immunofluorescence
      (MIF) test. 68 adults patients were investigated. Eight patients (11.8%) were
      positive by either rELISA or PCR-EIA or both, with an infection rate of 5
      patients with community-acquired pneumonia, 2 asthmatic patients and 1 patients
      with an exacerbation of chronic obstructive pulmonary disease. Serological
      evidence of acute infection was found in four of these patients with rELISA test
      and in three others with MIF test. PCR-EIA detected Chlamydia pneumoniae DNA in
      four patients, but there were concordant results with rELISA and PCR-EIA in only
      one patient. In conclusion, Chlamydia pneumoniae appears to be a common etiologic
      agent of acute respiratory infections in adults. The discrepancy between
      serological test and PCR-EIA results reflects the difficulties in routine
      laboratory diagnosis of Chlamydia pneumoniae. The ambiguous results of
      serological tests from a single serum sample assess the utility of PCR for prompt
      diagnosis. When PCR is negative or no feasible, a second serology to 15/21 days
      of interval is necessary. Further studies with optimised techniques must be
      developed.

PMID- 10637912
TI  - [Chemically-induced paraneoplastic hyperleukocytic lung].
AB  - Dyspnea is the principal clinical feature of pulmonary leukostasis, a syndrome
      called "poumon hyperleucocytaire" in French. It is a common complication of
      chronic myeloid leukemia. In the course of pulmonary carcinoma, leukocytosis is
      frequently noted. One of the etiologies is a paraneoplastic syndrome with
      production of colony stimulating factor. We report a case of pulmonary
      hyperleukostasis following antineoplastic chemotherapy for pulmonary carcinoma.

PMID- 10637913
TI  - [A further case of tracheal paraganglioma].
AB  - Paragangliomas, or chemodectomas, are neuro-endocrine tumors of the neural type,
      derived from extra-adrenal paraganglia. Tracheal localizations are rare. We
      report the case of a patient with a paraganglioma of the upper part of the
      trachea. The tumor was totally removed by means of the resection of the
      subglottic trachea and anastomosis. Surgery is the treatment of such lesions, but
      can be difficult in cases of subglottic or juxta-carinal localizations.

PMID- 10637914
TI  - [Intramural hematoma of the esophagus: a rare diagnosis].
AB  - We describe three cases of spontaneous intramural hematoma of the esophagus, a
      rare pathology. The combination of chest pain, dysphagia and hematemesis and
      often the existence of hemostasis disorders or fragility of the mucosa, or trauma
      of the esophagus, should evoke the diagnosis. Radiology (thoracic scan, barium
      swallowing) and esophagoscopy enable confirmation of the diagnosis, permitting
      conservative treatment and simple spontaneous course of this pathology.

PMID- 10637915
TI  - [Association of sarcoidosis and hemorrhagic rectocolitis in an insulin-dependent
      diabetic].
AB  - Ulcerative colitis and sarcoidosis are seldom associated. A 33-year-old diabetic
      man developed simultaneously a rectitis and a non-productive cough leading to the
      diagnosis of ulcerative colitis and sarcoidosis. These diagnoses are discussed
      because of the possible gastrointestinal lesions from sarcoidosis or the
      respiratory disorders due to ulcerative colitis. Some pathophysiological evidence
      can be found in this case in favor of a non-fortuitous association.

PMID- 10637916
TI  - [Acute pleurisy revealing post-myocardial infarction syndrome].
AB  - We report a case of Dressler's syndrome in which the diagnosis was made following
      an investigation of pleurisy which the laboratory data revealed as inflammatory.
      A myocardial infarction which had occurred two months earlier had passed
      unnoticed. The principal value of this case was to draw attention to the syndrome
      which may initially be a pleurisy but also clinically the picture may mimic
      pneumonia, both alone or together may be associated with classical pericarditis.
      Pleurisy occurs in Dressler's syndrome but it is rarely the presenting diagnosis
      as the cardiac picture tends to predominate.

PMID- 10637917
TI  - [Peritoneal fistulization in pleural aspergillosis associated with skin lesions].
AB  - This report describes the development of a pleuroperitoneal fistula complicating
      pleural aspergillosis in a 63-year old non-immunocompromised man treated with
      itraconazole. The patient presented a confluent granuloma of the abdomen while an
      abscess of the abdominal wall was disclosed. Skin involvement, usually described
      in disseminated aspergillosis, has not been reported in pleuropulmonary
      aspergillosis.

PMID- 10637918
TI  - [Phantom thoracic opacity].
AB  - The etiology of the respiratory distress syndrome is dominated by pulmonary edema
      and the septic shock. We report a rare etiology of a respiratory distress
      secondary to a rupture of a well treated tuberculous latero-tracheal adenopathy.
      A 24-year-old woman was treated a year ago for a peripheral and mediastinal lymph
      node tuberculosis confirmed by the biopsy of a left supra clavicular adenopathy,
      by two months of isoniazid-rifampicin-pyrazinamide-ethambutol and seven months of
      isoniazid-rifampicin. The patient completed 9 month treatment with a good
      clinical and radiology course. Two months after stopping the antibacillary
      treatment, the patient was admitted to an intensive care unit with a respiratory
      distress syndrome requiring both intubation and artificial ventilation. The
      bronchial aspiration brought back plain pus. The telethorax from admission was
      normal and the retrospective history suggested the diagnostic of a ganglio
      bronchial fistula which was confirmed by bronchial fibroscopy demonstrating right
      latero-tracheal fistula. The course was good with recovery of consciousness on
      the seventh day. Direct bacilloscopies and culture were negative. The digestive
      fibroscopy was normal. Finally, fistulization of a tuberculous adenopathy must be
      considered among the etiologies of respiratory distress even in a patient
      appropriately treated for mediastinal lymph node tuberculosis.

PMID- 10637919
TI  - [Is thoracic computed tomography really implicated in the etiology of breast
      cancer?].

PMID- 10637920
TI  - [Comments on the guidelines of the French-Language Society of Pneumology on the
      use of serum tumor markers in the management of primary bronchial cancers.
      Restatement].

PMID- 10637921
TI  - [Cortico-basal degeneration].
AB  - Cortico-basal degeneration (CBD) has recently emerged as a distinctive entity of
      the Parkinson-plus syndromes but presents with great clinical and
      anatomopathological heterogeneity. The purpose of this review is to increase
      awareness of the syndrome and facilitate its recognition in both typical and
      unusual cases. We will herein review the 398 cases found in the English and
      French literature with their clinical, laboratory and pathological features.

PMID- 10637922
TI  - [Absence status epilepsy].
AB  - Absence status (AS), or "Petit Mal status" is a polymorphic condition that can
      complicate many epileptic syndromes. Diagnosis is difficult on the basis of
      clinical semiology alone, and requires emergency EEG. Although heterogeneous, the
      most typical ictal pattern is constituted by slow generalized rhythmic spike
      waves (SW) or polyspike-waves (PSW) complexes. In a number of cases, clinical and
      EEG normalization is obtained after intravenous (i.v.) benzodiazepine (BZ)
      injection. In some difficult cases, neuropsychological investigations before and
      after BZ injection is useful: a significant improvement of the neuropsychological
      score should occur following BZ injection. On a nosographic point of view,
      literature data indicate that 4 types of AS may be recognized. Typical AS occurs
      as part of an idiopathic generalised epilepsy most often characterized by
      absences. Isolated impairment of consciousness, at times with subtle jerks of the
      eyelids, is the essential symptomatology. The EEG correlates with repetitive
      absence seizures and shows symmetric and bilateral synchronous SW or PSW
      complexes faster than 3 Hz. The immediate prognosis is excellent. Atypical AS
      occurs in patients with symptomatic or cryptogenic generalized epilepsies and is
      characterized by a fluctuating confusional state with more prominent tonic and/or
      myoclonic and/or lateralized ictal manifestations than occur in typical AS. The
      EEG shows continuous or intermittent diffuse irregular slow SW or PSW complexes.
      The immediate prognosis is guarded, as these episodes tend to recur and to be
      resistant to medication. "De novo" absence status of late onset is characterized
      by toxic or metabolic precipitating factors in middle-aged or elderly subjects
      with no previous history of epilepsy. Patients often have a history of
      psychiatric illness with multiple psychotropic drug intake. The electroclinical
      characteristics and the immediate prognosis are variable. These episodes of AS
      generally represent acute symptomatic seizures and may not recur if the
      triggering factors can be controlled or corrected. Long-term antiepileptic drugs
      may thus not be needed. Absence status with focal characteristics occur in
      subjects with a pre-existing or newly developing partial epilepsy, most often of
      extra-temporal origin. The EEG shows bilateral but often asymmetric ictal
      discharges. The immediate prognosis is variable. Some of these cases are
      difficult to distinguish from complex partial status epilepticus of frontal lobe
      origin.

PMID- 10637923
TI  - [Writing disorder using a word processor: role of the left hand].
AB  - A young female secretary developed a writing disorder, exclusively expressed when
      using a word processor, following an ischemic vascular event involving the insula
      and the right posterior parietal region. There was no disturbance of laterality.
      The neurological examination, completed by neuropsychological tests eliminated
      any persistent phasic or gnostic disorders. The analysis of the text produced
      revealed abnormalities leading to the conclusion that the left hand was
      responsible for all the errors observed. A sensorimotor integration disorder
      produced a melokinetic apraxia which appeared to be the cause of the writing
      disorder which would have most likely remained unknown had the subject not been a
      secretary.

PMID- 10637925
TI  - [Sleep apnea syndrome and stroke in the elderly population].
AB  - The objective was to compare the prevalence of sleep apnea syndrome (SAS) in
      elderly individuals with a history of stroke to the one in individuals, matched
      by age and sex with a history of insomnia. To determine if previous subjective
      sleep complaints in the elderly are associated with stroke. A cross-sectional
      study with subsequent 3-year follow-up was designed in an acute geriatric
      inpatient unit. 19 subjects with documented stroke and 21 subjects with insomnia
      were included. All participants were assessed with a sleep questionnaire, an
      overnight polysomnographic examination including a recording of respiratory
      movements, and pulse oximetry. SAS was diagnosed in 68.4 p. 100 in the stroke
      group compared with 28.6 p. 100 in the insomnia group (p = 0.01). The median
      apnea/hypopnea index was significantly higher in the stroke group: 25 events per
      hour versus 2 in the insomnia group (p = 0.01). The median lowest oxygen
      saturation was not significantly different in the two groups (p = 0.3). Snoring
      and previous daytime sleepiness were both correlated with stroke (p = 0.05, p =
      0.003). Among sleep complaints and cardiovascular risk factors, only a history of
      diabetes and previous daytime sleepiness were found to be significantly
      associated with stroke (p = 0.01, p = 0.002). Mortality was higher in SAS
      subjects (58.8 p. 100) than in non SAS subjects (33 p. 100). The difference was
      not statistically significant (p = 0.14), but a tendency could be noticed. SAS is
      a common finding in elderly individuals after a stroke. Physicians must be aware
      of the risks of prescribing sedatives and anxiolytics to these patients.

PMID- 10637924
TI  - [Posture and gait modulation using sensory or attentional cues in Parkinson's
      disease. A possible approach to the mechanism of episodic freezing].
AB  - Parkinsonian patients have difficulties for walking as well as for adapting their
      posture following a voluntary or automatic movement that will disturb their
      equilibrium. Furthermore, in Parkinson's disease, the patients can suffer for
      motor blockades (or freezing) in which the movement is like frozen during its
      execution. These motor blockades can occur during gait initiation, turning round,
      as well as during the walking through apertures or small passages, but with a
      high variability as inter-individual as intra-individual. Cognitive, attentional
      or sensory stimulation--especially visual information--can interact directly on
      these motor blockades, either positively inhibiting them or negatively inducing
      them. The different modulation factors of locomotion as well as posture, in
      Parkinsonian patient and in healthy elderly, and the special case of the motor
      blockades in Parkinsonian patients are reviewed here. We also examine the effects
      of L-DOPA with respect to each of these factors. In the conclusion, the
      modulation of gait, posture, and freezing are discussed in term of mechanisms
      involved or hypothesis recently proposed.

PMID- 10637926
TI  - [Neuromuscular disease: health care accessibility in the Nord-Pas-de- Calais
      region].
AB  - A survey was conducted to estimate accessibility to current diagnostic techniques
      for patients with neuromuscular disease living in the Nord-Pas-de-Calais. In
      association with the "Association francaise contre les myopathies", we invited
      200 adults with neuromuscular disease to fill out a questionnaire concerning
      diagnosis of their neuromuscular disease and medical and paramedical follow-up.
      Each subject answered the questionnaire anonymously providing data on
      sociodemographic items, diagnosis and medical and paramedical follow-up. The
      results showed a lack of follow-up for lung disease whereas respiratory failure
      is known as a frequent complication of neuromuscular disease. Genetic counselling
      was not suggested often enough. A large proportion (80 p. 100) of the patients
      had had physiotherapy. Whereas cardiomyopathy and orthopedic buckling with
      subsequent decreased autonomy are observed in 90 p. 100 of patients with Duchenne
      muscular dystrophy, only 42 p. 100 of the patients with this disease were
      followed by a cardiologist and a physical therapists. We suggest more cooperation
      between specialists in order to improve medical care for patients with
      neuromuscular diseases.

PMID- 10637927
TI  - [Sunct syndrome: case report and literature review].
AB  - The case of a woman with short neuralgiform paroxysmal attacks located in orbital
      periorbital area and associated with autonomic features of ten years duration is
      reported. This headache syndrome is compared with trigeminal neuralgia involving
      the first branch of the nerve. Duration, intensity, spreading of the pain and
      presence of accompanying ipsilateral vasomotor phenomena may be of help in the
      differential diagnosis. According to the latest reports, sex distribution which
      passed from 17 men/2 women to 18/6 and effect of the carbamazepine on pain would
      not appear to have an effect. Nevertheless other reports are needed to
      distinguish these two clinical syndromes and to develop an etiological and
      pathogenesis hypothesis.

PMID- 10637928
TI  - [Primary intramedullary spinal cord lymphoma in HIV patients. MRI aspects].
AB  - We report a case of an immunocompetent man who developed primary spinal
      intramedullary malignant lymphoma. This condition occurs in about 0.9 p. 100 of
      primary central nervous system non-Hodgkin lymphomas in non-AIDS patients.
      Magnetic resonance imaging was nonspecific but suggestive. Like the brain
      localization, prognosis is poor. Because of the high frequency of recurrence,
      usually confined to the central nervous system with neuraxis dissemination,
      treatment must be delivered to the entire neuraxis. But more effective treatment
      strategies with radiotherapy-chemotherapy combinations will be needed.
      Feasibility and toxicity patterns remain to be determined.

PMID- 10637929
TI  - [Krouamania causing an acute subdural hematoma of arterial origin].
AB  - We report a case of arteriolar subdural hematoma caused by Jedba assimilated to
      Krouamania. We discuss the pathophysiological mechanism of subdural bleeding, the
      clinical symptoms, the characteristics of such hematomas and the therapeutical
      management.

PMID- 10637930
TI  - [Craniocerebral actinomycosis].

PMID- 10637931
TI  - [Neurotrophins and the central nervous system].

PMID- 10637932
TI  - [Alzheimer's disease in the European setting].

PMID- 10637933
TI  - Genetic and environmental factors in Alzheimer's disease.
AB  - In recent years, considerable progress has been made in unraveling the etiology
      of Alzheimer's disease (AD). Dominant mutations have been identified, in the beta
      amyloid precursor protein gene (APP), and in two homologous genes presenilin 1
      (PSEN-1) and presenilin 2 (PSEN-2). The contribution of these mutations to the
      occurrence of AD in the general population is estimated to be lower than 1p. 100.
      A genetic risk factor of more importance on the population level is the
      Apolipoprotein E (APOE) gene that may explain up to 17p. 100 of the prevalence of
      AD in the general population. It is clear that other yet unknown genes must be
      involved in the etiology of AD. Two loci on chromosome 12 have been suggested,
      but no consistent effect could be found. Important progress with regard to non
      genetic risk factors concerns the role of vascular and endocrine factors in the
      pathogenesis. Of major interest for the prevention of AD will be the interaction
      of genetic and non-genetic risk factors. Large scale, long term follow-up
      studies, ongoing at present, may clarify this issue.

PMID- 10637934
TI  - [Alzheimer's disease: lesions and their progression].
AB  - Alzheimer disease appears to be a stereotyped mode of reaction of the central
      nervous system to various types of aggression such as different mutations
      involving various proteins, trisomy 21 or repeated head trauma as in dementia
      pugilistica. Rather than a disease, it appears to be a clinicopathological
      syndrome due to various causes. Lesions may be considered under 3 headings:
      neurofibrillary pathology, A beta peptide deposits and loss (neuronal and
      synaptic). Neurofibrillary pathology includes the neurofibrillary tangle, the
      crown of the senile plaque and the neuropil threads. All those lesions are
      characterized by the same ultrastructure--i.e. the accumulation of paired helical
      filaments--and the same immunohistochemistry: they are labelled by antibodies
      directed against the tau proteins. The amyloid deposits, present in the core of
      the senile plaque and in the vascular walls, are made of a 40 to 42 amino-acids
      long peptide, named A beta, derived from the amyloid precursor protein (APP).
      Antibodies directed against the A beta peptide also label diffuse deposits that
      are devoid of the tinctorial affinities and of the biochemical properties of
      amyloid substances. Those diffuse deposits are insufficient to cause dementia
      since they may be observed in high density in aged people without intellectual
      deterioration. Neuronal loss occurs after neurofibrillary pathology. The role of
      the synaptic pathology remains discussed. Besides tau proteins, A beta peptide
      and APP, several other proteins may play an important role: apolipoprotein E
      which could act as a chaperone protein, inducing or facilitating the formation of
      amyloid, presenilins 1 and 2, mutated in some cases of familial Alzheimer
      disease, alpha-synuclein which is present in the Lewy bodies found in Parkinson
      disease and in dementia with Lewy bodies. The A beta deposits are diffusely
      distributed in the cerebral cortex; the neurofibrillary changes have a
      hierarchical distribution. The progression of the neurofibrillary pathology in
      the various cortical areas follow a stereotyped sequence that may help to grade
      the severity of the disease. Progression may take decades. The relations between
      aging and Alzheimer disease are still poorly understood. Frequency of Alzheimer
      type lesions in old people could suggest that they are the inevitable burden of
      age, but this has been discussed.

PMID- 10637935
TI  - Pathogenesis of Alzheimer's disease and dementia.
AB  - The pathogenesis of Alzheimer's disease is far from clear since it is still
      undetermined whether and how extracellular beta-protein and cytoskeletal
      degeneration of neurons, which are colocalized in the association neocortex of
      Alzheimer patients, are related to one another. By using beta-protein and other
      derivatives of the precursor protein, efforts to cause cell lesions comparable to
      neurofibrillary degeneration have been fruitless. However, the view that the
      amyloid issued from the polymerisation of beta-protein is neurotoxic, remains the
      most attractive. To fully explore this hypothesis, attention should be paid to
      neurons that participate in neocortical circuits and to factors that may
      influence their vulnerability, whether selective or not, to beta-protein and
      associated proteins.

PMID- 10637936
TI  - Diagnosis of early Alzheimer's disease.
AB  - Current criteria for the diagnosis of Alzheimer's disease require that the
      patient also fulfils the criteria for dementia. This means inevitably that the
      disease is well-established. As treatments become available there is an important
      need for early diagnosis. There are two components to diagnosis; the recognition
      that cognitive performance is below that which would be anticipated for the
      individual and secondly to relate this to a specific disease process. Research
      studies need to identify the very earliest changes i.e. before symptoms commence.
      Such studies have focused on at risk populations either by virtue of age or a
      positive family history. Both groups have demonstrated that memory is the salient
      early feature, particularly verbal memory, impairment of which may precede overt
      symptoms by many years. The other major approach has been that of neuroimaging.
      Group studies of at risk individuals, for example for those who carry an apoE4
      allele, have shown relative biparietal, bitemporal hypometabolism in the at risk
      group. Similarly, structural neuroimaging may show hippocampal atrophy at an
      early stage. Serial studies to determine rate of change, may be more valuable
      than single cross-sectional studies. Recent techniques of positional matching and
      registration allow precise quantitation of rates of cerebral atrophy which may be
      useful in early diagnosis.

PMID- 10637937
TI  - [Neuropsychological aspects of Alzheimer's disease].
AB  - This analysis is centered on the study of cognitive disorders in Alzheimer's
      Disease (AD), mainly for major neuropsychological functions. We insist on the
      heterogeneity of the clinical picture especially in the early stages of the
      illness, when deficits of episodic memory and executive functions are prevalent.
      We consider that studying early stages of the illness is necessary to delineate
      the diagnostic signs, to validate the new therapeutic experiments, to predict
      stages of decline.

PMID- 10637938
TI  - Psychotic symptoms, aggression and restlessness in dementia.
AB  - The current article reviews the literature pertaining to psychosis, aggression
      and restlessness in dementia sufferers examining frequency, course and
      associations as well as treatment considerations. All of these problems are
      highly prevalent, with a high impact upon dementia sufferers and their carers.
      Although there has been an expansion in this literature over the last few years
      there are still very few studies describing the natural course of behavioural and
      psychological symptoms in dementia (BPSD) and a paucity of data relating to non
      Alzheimer dementias. Several large treatment studies have recently been
      completed, but there are still very few double blind controlled trials focusing
      upon BPSD in particular respect to non-pharmacological interventions.

PMID- 10637939
TI  - PET studies and cholinergic therapy in Alzheimer's disease.
AB  - Alzheimer's disease (AD) is one of the most devastating brain disorders of
      elderly humans. The last decade has witnessed a steadily increasing effort
      directed at discovery of the etiology of the disease and development of
      pharmacological treatment stategies. Symptomatic treatment mainly focussing on
      cholinergic therapy has been clinical evaluated by randomized, double-blind,
      placebo controlled, parallel group studies measuring performance based tests of
      cognitive function, activity of daily living and behavior. Significant progress
      has been made in recent years to develop and apply functional brain imaging
      techniques allowing early diagnosis of dementia and evaluation of treatment
      efficacy. Positron emission tomography (PET) is a suitable method for functional
      studies of pathological changes in brain which as a clinical instrument not
      solely reveal dysfunctional changes early in the course of the disease but also
      may provide a deep insight into the functional mechanisms of new potential drug
      treatment strategies. The advantage with PET is the capacity not only to measure
      changes in glucose metabolism, cerebral blood flow but also to obtain further
      insight into neuronal communicative processes (transmitter/receptor interactions)
      in brain and pharmacokinetic events and drug mechanisms. PET studies have so far
      revealed disturbances in some neuroreceptor systems in brain of AD patients. A
      significant correlation can be observed between the impairment of nicotinic
      receptors in the temporal cortex and the cognitive impairment of AD patients.
      Cholinergic drugs including cholinesterase inhibitors such as physostigmine,
      tacrine, velnacrine as well as the acetylcholine releaser linopiridine have been
      reported to increase the cerebral blood flow in AD patients both after acute and
      fairly short period of treatment. Increase in cerebral glucose metabolism has
      also been measured following fairly long periods of treatment with cholinesterase
      inhibitors (months). The cholinergic nicotinic and muscarinic receptors do also
      respond to treatment with cholinesterase inhibitors in AD patients. An
      improvement of the nicotinic receptors has been found in cortical regions
      following treatment with cholinesterase inhibitors and nerve growth factors (NGF)
      to AD patients. Functional PET activation studies performed simultaneously with
      memory tasks will provide further valuable insight into the mechanisms of action
      of new drug, how they interact and can improve the efficacy of memory processes
      in AD brains.

PMID- 10637940
TI  - Vascular dementia today.
AB  - This decade witnessed a resurgence of interest in vascular dementia (VaD) as an
      increasingly important cause of senile dementia. Although definitions of dementia
      in general, and of VaD in particular, are still controversial recent diagnostic
      criteria for VaD acknowledge that pathogenetic mechanisms different from multi
      infarct dementia are important in dementia causation. These include subcortical
      strokes, mainly lacunes, global hypoxic-ischemic events during acute stroke, and
      ischemic periventricular white matter lesions of the Binswanger type. These
      lesions tend to be manifested primarily by alterations of frontal executive
      function control. The importance of these ischemic vascular lesions in the
      clinical expression of Alzheimer's disease (AD) in very old subjects has also
      been recognized. Clinically, VaD may present in two forms: Acute VaD includes
      large-vessel infarction, and lacunar dementia due to small-vessel disease,
      including thalamic and caudate strokes. Subacute VaD includes Binswanger's
      disease (BD), cerebral angiopathy with leukoencephalopathy and CADASIL. The
      discovery of CADASIL, a genetic form of VaD mapped to chromosome 19 as a mutation
      of the Notch 3 gene, opened research avenues into the pathogenesis of BD.
      Finally, epidemiological evidence suggests that it may be possible to prevent VaD
      -and perhaps degenerative senile dementia--by controlling hypertension and other
      vascular risk factors. These findings offer hope for prevention of this growing
      public health problem.

PMID- 10637941
TI  - [Progressive focal cortical atrophies].
AB  - Progressive focal cortical atrophies are degenerative conditions characterised by
      the insidious onset and gradual exacerbation of an impairment in a single
      cognitive domain related to circumscribed cerebral atrophy. Several focal
      cortical syndromes with deficits in the realm of cognition are reviewed:
      progressive impairment of language (primary progressive aphasia), speech
      (progressive anarthria), semantic memory (semantic dementia), episodic memory
      (pure progressive amnesia), vision (progressive perceptual or visuo-spatial
      deficits) and gesture (progressive apraxia). These conditions are histologically
      heterogeneous and can be associated with focal non-specific neuronal loss and
      gliosis with some spongiform changes (non-specific lesions), pathological
      features of Pick's disease (inclusion bodies and swollen neurones) or Alzheimer's
      disease (AD) (senile plaques and neurofibrillary tangles). A relationship between
      neuropsychological profiles and lesional types emerges from this review of the
      literature. Non-fluent primary progressive aphasia, semantic dementia and
      progressive anarthria are usually associated with non-specific lesions and Pick
      type pathology. Progressive disorders of episodic memory and progressive visuo
      spatial deficits are more often related to AD. If adequate clinical
      characterisation can determine the underlying disorder, it appears even more
      important to establish the neuropsychological profile in patients with cortical
      degenerative disease. Progressive deficits of only one domain of cognition may
      well be due to preferential involvement of anatomically and functionally defined
      neural systems and could therefore be considered as "system atrophies". There
      remains no doubt that these syndromes are particularly well suited models for
      studies on the relationship between cerebral functions and their neural
      substrate.

PMID- 10637942
TI  - [Organization of memory centers and prospects].
AB  - The concept of memory centers is based on a multidisciplinary approach to memory
      disorders and dementia, especially Alzheimer's disease, a public health
      challenge. The first memory centers were established in the 80s in the US and the
      British Isles. The aims of these centers are to make a diagnosis (and to reassure
      the 'worried well'), to detect dementia, to provide a service for their
      management, to educate care takers, to evaluate new therapies, and to contribute
      to clinical and basic research. Follow-up is crucial. The first memory centers
      all experienced long delay to diagnosis of dementia and found that Alzheimer's
      disease was the first cause of consultation. These observations led to the
      creation of such centers in many countries. A survey of 20 French memory centers
      defined the "ideal memory center": an identified structure with a clinic and a
      day-care unit for diagnosis and follow-up, with neurological, psychological,
      psychiatric, and geriatric skills. It must be part of a medical and social
      network for the management of dementia and participate in a network of memory
      centers at the regional and national level. Relationships between dementia and
      somatic diseases, frequent in demented patients, are still poorly known. Dementia
      interferes with the clinical expression, the management, and the prognosis of
      somatic diseases, some of which, such as cardiovascular conditions, are possibly
      linked with dementia. Conversely, somatic diseases may rapidly worsen the
      cognitive state and induce delirium, leading to hospitalization. Medical wards
      are not all appropriate. Memory centers must also be involved in these care,
      educational and research issues.

PMID- 10637943
TI  - [Influence on diagnosis of Helicobacter pylori infection in 13C urea breath test
      of existence of dead space gas].
AB  - The 13C-urea breath test is a noninvasive analysis for the detection of
      Helicobacter pylori infection and is valuable for judging the effects of
      antimicrobial treatment. Up to date the most popular technique for 13C-urea
      breath test: UBT, is performed by collecting expired gas into an aluminum bag,
      but the result is considered to be influenced in the diagnosis of Helicobacter
      pylori infection by the existence of anatomical dead space gas. We therefore
      introduced a new technique to measure 13CO2 and 12CO2 continuously during
      expiration, identified the correct alveolar gas, and excluded the effect of
      anatomical dead space. Subjects were 127 males and 8 females. We compared the
      diagnostic accuracy of these aluminum bag and continuous measurement methods. We
      adopted serological IgG positive and barium-meal study positive cases as a gold
      standard for the diagnosis. Diagnostic accuracy by continuous measurement was
      superior to that by the aluminum bag method. We should pay attention to the
      existence of anatomical dead space for accurate diagnosis. Continuous measurement
      is important in the collection of end tidal expired gas in order to make an
      accurate diagnosis.

PMID- 10637944
TI  - [Actual conditions of occupational health activities in small-scale enterprises
      in Japan: system for occupational health, health management and demands by small
      scale enterprises].
AB  - In order to clarify the real conditions of occupational health services (OHS) in
      small-scale enterprises (SSEs) in Japan, we analyzed questionnaires recovered
      from 765 SSEs in the area of a city neighboring Osaka City (recovery rate,
      69.3%). The SSEs included 358 SSEs with 1 to 4 workers (46.8% of total SSEs), 203
      with 5 to 9 (26.5%), 163 with 10 to 29 (21.3%) and 41 with 30 to 49 (5.4%). The
      main types of businesses were manufacturing (374, 48.9% of total SSEs),
      wholesale/retail trade/restaurants (153, 20.0%), community, social and personal
      services (132, 17.3%) and construction (72, 9.4%). Health examinations were
      performed in 47.7% of SSEs. The reason for the lack of examinations were
      "shortage of time" (33.3% of SSEs lacking health examination) and "employees do
      not want to be examined" (28.1%). Some health promotion measures were conducted
      in 29.2% of SSEs. Health examination (59.0% of SSEs), health promotion (36.5%),
      measure of mental health (25.9%) and information service for employers and
      employees (25.5%) were demanded by SSEs as OHS. Financial subsidies and
      economical incentives were demanded by 46.4% and 28.8% of SSEs, respectively.
      Regional occupational health center in this area was poorly known among SSEs
      (8.2%), but health examination (48.4%), information service (37.5%), assessment
      of work method and advice to improve (19.8%) and environment measurement (12.4%)
      are demanded of the center by SSEs.

PMID- 10637945
TI  - [Disseminated intravascular coagulation after acute hepatic injury in rats
      induced by 1,3-dichloro-2-propanol].

PMID- 10637946
TI  - [Change in a teacher's hoarseness caused by school lessons].

PMID- 10637947
TI  - [Effect of the long distance truck driving in Hokkaido on cardiovascular system].
AB  - We took the blood pressure and ECG of 8 male truck drivers who drive long
      distances in Hokkaido and observed the conditions under which they work. Most of
      their driving routes included steep passes, and the weather and the road
      conditions became worse in winter. Their tasks were not only the driving and
      waiting but also such manual labor as loading, etc. The mean driving distance of
      one route was 705 km and it ranged from 159 km to 1,210 km. The mean number of
      working hours was 27.8 h, and it ranged from 9.2 h to 46.9 h. Blood pressure was
      higher when driving or loading than when resting or on a day off. The mean
      systolic blood pressure was over 140 mmHg in 6 cases, and arrhythmia occurred
      frequently in 4 cases during driving or loading. In 2 cases, in which the driver
      met with accident, the blood pressure was remarkably high and arrhythmia occurred
      frequently. Most drivers worked for a very long time in poor conditions and
      environment. The results of our study suggested that such a heavy work load will
      affect the cardiovascular system.

PMID- 10637948
TI  - [Lipid-lowering therapy in patients with coronary disease: proportion of patients
      requiring treatment according to recommendations of the Swiss Society of
      Cardiology].
AB  - BACKGROUND: Recent studies have confirmed that treatment with lipid-lowering
      drugs decreases cardiovascular morbidity and mortality in primary as well as
      secondary prevention of cardiovascular diseases. In 1999, new Swiss
      recommendations for treatment with lipid-lowering drugs have been published. We
      therefore performed a study to estimate the proportion of patients with coronary
      artery disease requiring lipid-lowering drugs. METHODS: We included 637 patients
      with coronary heart disease who were referred for coronary angiography during
      1991-1993. We calculated the proportion of patients requiring lipid-lowering
      drugs according to the new Swiss guidelines, and compared them with European and
      US guidelines. RESULTS: According to the 1999 Swiss recommendations, 79% of the
      study population would have qualified for lipid-lowering treatment (males 80%,
      females 78%; patients aged up to 69 years 80%, patients aged 70 years and over
      73%). Agreement with both the Recommendations of the Second Joint Task Force of
      European and other Societies on Coronary Prevention, and the ACC/AHA Guidelines
      for Management of Patients with Acute Myocardial Infarction, was 96% (Kappa 0.79
      and 0.83 respectively). CONCLUSION: A large proportion of patients with coronary
      artery disease qualifies for treatment with lipid-lowering drugs. The new Swiss
      recommendations closely agree with European and US guidelines.

PMID- 10637949
TI  - [International Stroke Trial Switzerland: some epidemiologic data].
AB  - Randomised trials provide the best evidence on the effects of treatment on a
      particular disease. They can also provide valuable data on outcome. In the
      present article, data from 1631 Swiss patients randomised in the International
      Stroke Trial (IST) are presented. Baseline characteristics and outcome in the
      Swiss patients were compared with the 17,804 patients randomised in other
      countries. On average, compared with other countries, Swiss patients were: 2.5
      years older (CI: 1.9-3.1; p < 0.001); more likely to have presented with total
      anterior circulation infarcts (28 vs 23%); less likely to have lacunar strokes
      (16 vs 25%; p < 0.00001); more likely to be randomised and treated early (within
      3 hours, 7 vs 4%, and within 6 hours, 25 vs 15%; p < 0.00001). However, Swiss
      patients were more likely to be dead or dependent 6 months after the stroke (66.9
      vs 62.2%; p < 0.00001). The difference in death or dependency was almost entirely
      explained by the difference in age and baseline severity of strokes. These data
      highlight the difficulties inherent in between-country comparisons of outcome
      after stroke. They also emphasise the need for international multicentre trials
      to use methods of randomisation (either stratification or minimisation), as IST
      did, to ensure balance of prognostic factors within each participating country;
      to do otherwise might confound the assessment of the effect of treatment.

PMID- 10637950
TI  - [Pulmonary artery malformations].
AB  - We report on two patients with pulmonary arteriovenous malformations (PAVM). An
      almost asymptomatic young man and an elderly woman with severe dyspnoea
      illustrate paradigmatically various aspects of the clinical manifestation,
      diagnostic approach and treatment of this rare disorder. New aspects with respect
      to genetics, diagnosis and therapy are discussed. PAVM are often manifestations
      of hereditary teleangiectasia, which also affect blood vessels of the skin,
      mucous membranes, brain and liver. Transcatheter embolotherapy is a safe,
      effective and minimally invasive treatment option, which seems to be replacing
      surgical resection as first-line therapy in many cases.

PMID- 10637952
TI  - [Residual changes after varicella pneumonia].

PMID- 10637951
TI  - [Identification and genetic counseling of people with HNPCC (hereditary
      nonpolyposis colorectal cancer): old and new research goals].
AB  - Hereditary non-polyposis colorectal cancer (HNPCC) is a relatively common
      autosomal dominantly inherited predisposition leading to a familial occurrence of
      cancer of the colon, rectum, endometrium and some other organs. Cancer mortality
      can be significantly reduced by appropriate intervention. The diagnosis of HNPCC
      is suspected on the basis of early onset and multiple foci of colorectal cancer
      (CRC), in many cases affecting the proximal part of the colon, and of endometrial
      cancer. It may be confirmed by molecular genetic analysis of the mismatch repair
      genes, especially hMLH1 and hMSH2. In spite of considerable progress in the
      understanding of hereditary colon cancer, many questions which are of basic
      importance for the identification and appropriate genetic counselling of gene
      carriers remain to be answered. HNPCC defined on clinical and genealogical
      grounds is by no means identical with the presence of mutated mismatch-repair
      genes. This impedes the identification of persons/families at increased cancer
      risk. Mutations of other, mainly as yet unidentified genes may lead to a similar
      phenotype. Not only heterogeneity of the predispositions underlying CRC, but also
      penetrance and expressivity of the identifiable mutations of the MMR-genes, have
      been explored only superficially. The process of carcinogenesis in the colon can
      follow different routes depending on the genetic background of the patients. Its
      investigation will open up new possibilities of cancer prevention. In addition,
      genetic counselling must be developed into a more "evidence"-based medical
      undertaking. These gaps in the understanding of hereditary CRC and in the care of
      persons at risk can only be overcome through structured collaboration between
      family doctors, medical specialists such as gastroenterologists, oncologists and
      surgeons, medical geneticists and basic researchers.

PMID- 10637953
TI  - [Depression and anxiety].
AB  - Depression and anxiety disorders are among the most common psychiatric disorders
      in the general population and in daily practice of a general practitioner. Only a
      few years ago these disorders have been diagnosed either as "depression" or as
      "neurosis" in case of anxiety disorders. Since standardised diagnostic manuals
      have been available, it has been possible to differentiate between several
      depressive and anxiety disorders, which need a specific treatment. This change in
      the psychiatric diagnostic system is basing on psychiatric research results in
      the field of clinical diagnostics, biological psychiatry and epidemiology. This
      article provides guidance in diagnosis, differential diagnosis of depression and
      anxiety disorders and their therapy basing on international accepted treatment
      algorithms. Reviewed topics should make easy recognition and therapy possible for
      the general practitioner.

PMID- 10637954
TI  - [Dysthymia: a chronic illness and its treatment].
AB  - Dysthymia is a chronic disease with a high psychosocial burden. Age of onset
      frequently is in young adulthood. It is clinically characterized by very mild but
      continuous chronic depressive symptoms. The quality of symptoms seems to be
      similar to episodic depressive disorders, but the severity criteria for major
      depression are not fulfilled. After more than 2 years of dysthymia a depressive
      episode may occur (double depression). Neurobiological and genetic findings
      indicate a relation of dysthymia to affective disorders. Antidepressants are
      proven to be effective without a difference between various types of drugs.
      Psychotherapy is also proven to be effective (e.g. behaviour therapy) and should
      be prescribed in combination or alone, if a patient refused to take drugs.
      Because of the preferable side-effect profile of newer antidepressant compounds,
      they should be prescribed as first choice. A prophylactic treatment for 2 years
      is recommended. The dose of antidepressants should be in the therapeutic range
      for treatment of major depression.

PMID- 10637955
TI  - [Therapy refractory depression].
AB  - Patients who fail in an adequate trial of a standard antidepressant drug
      (corresponding to 150 mg/d imipramine over a minimal period of 4 weeks) are
      defined as treatment resistant. According to these guidelines a substantial
      number of patients is not sufficiently treated and, thus, should be reassessed
      for dosage and length of antidepressant medications. If patients fail to a
      sufficient treatment a response may be achieved if they are switched to an
      alternative drug and/or if biochemically differently acting antidepressants are
      combined. Furthermore, an increasingly popular approach to handle treatment
      resistance is the use of augmentation strategies. Among these, lithium and
      thyroid T3 are the most well studied with the most consistently positive results.
      As non-pharmacological augmentation approach partial sleep deprivation has proved
      to be effective in combination with antidepressant medication. Finally, patients
      who had no or only a partial response to several treatments with antidepressants
      may benefit from electroconvulsive therapy.

PMID- 10637956
TI  - [Long-term treatment of depressive illnesses].
AB  - Depressive and bipolar disorders are affective disorders of chronic nature
      characterized by the occurrence of depressive episodes with or without manic
      episodes. Pharmacologic treatment must not be stopped with remission, i.e.
      cessation of depressive symptoms. Relapse prevention must be carried on over 4-6
      months, in many cases maintenance therapy has to be continued for years if not
      lifelong. Treatment strategies include antidepressants, lithium and
      anticonvulsants for all of which efficacy in long-term treatment of depression
      has been shown. In this phase of therapy information and motivation--besides
      periodical clinical and drug level checks--in order to establish compliance in
      patients remain important tasks of treating physicians.

PMID- 10637957
TI  - [Therapeutic sleep deprivation and phototherapy].
AB  - Since ancient times the influence of chronobiological factors on the
      pathogenesis, course, and treatment of depression has been well known. Amongst
      antidepressive treatment strategies two are based on chronobiological knowledge:
      therapeutic sleep deprivation, which exerts a rapid and dramatic, albeit usually
      short-lasting, improvement of mood in the majority of patients with major
      depressive disorder, and light therapy with full-spectrum bright light. About
      sixty percent of all depressed patients improve after a single night of total or
      partial sleep deprivation. It has been shown that a combination of
      pharmacotherapy with antidepressants and sleep deprivation is superior to
      pharmacotherapy alone. Moreover, sleep deprivation has proved to hasten the onset
      of action of antidepressant medication and repeated sleep deprivation can also be
      an efficient treatment strategy in drug refractory depression. Light therapy with
      bright artificial light is especially beneficial in patients with a fall/winter
      pattern of depressive symptomatology that has been termed seasonal affective
      disorder. Similar to sleep deprivation, bright light therapy is characterized by
      a fast onset of antidepressant action and by the exertion of additive properties
      to antidepressive medication. Bright light therapy, beginning in the morning
      after partial sleep deprivation, is able to prevent the depressive relapse after
      the next night of sleep in sleep deprivation responders.

PMID- 10637958
TI  - [Clinical value of electroconvulsive therapy in treatment of depression].
AB  - The electroconvulsive therapy (ECT), which provokes a generalized epileptic
      seizure by an electrical stimulus, was first administered in 1938 and performed
      without anesthesia during thirty years. Nowadays, ECT is carried out using brief
      anesthesia (preferably methohexital) and skeletal muscle relaxation
      (succinylcholine) to avoid fearful complications like bone and muscle fractures.
      ECT is a safe treatment without absolute contraindications; the treatment risk
      corresponds to the risk of general anesthesia. ECT is indicated in depression,
      mania and schizophrenia. It plays an important role in the treatment of therapy
      resistant, severely ill patients with affective disorders, suicidal drive,
      delusional symptoms, vegetative dysregulation, inanition and catatonic symptoms.
      The response rate (remission or marked improvement) is about 70%. Usually ECT is
      performed 3 times per week, resulting in an ECT course with a total number of 6
      to 12 single treatments. Within 2 or 3 weeks a substantial improvement can be
      expected. Further controlled studies are required with regard to antidepressive
      and/or antipsychotic continuation therapy after successful ECT course. Brief
      pulse stimulation, unilateral nondominant electrode placement and individual
      stimulus titration with respect to seizure threshold (EEG monitoring is
      required!) can minimize cognitive side effects. The apprehension that ECT could
      cause prolonged amnesia and structural brain damage has not been confirmed by the
      available scientific data. Modern brain imaging methods could elicit the until
      now unknown mode of action of ECT.

PMID- 10637959
TI  - [Rheumatic diseases].

PMID- 10637960
TI  - [Lofgren syndrome].
AB  - A short review on incidence, prevalence, possible causes and pathologic findings
      in sarcoidosis is given. Especially the symptomatology, differential diagnosis
      and therapy will be described. Finally some data on 10 patients with this
      syndrome will be presented.

PMID- 10637961
TI  - [From acute to chronic pain (in rheumatic diseases)].
AB  - Pain and functional restriction are the main factors leading the patient to the
      physician. For these patients quality of life is reduced a lot. Pain is a
      subjective experience and it cannot be objectivated easily. Pain experience
      lasting more than 3 to 6 months is considered to be chronic. Its causes are
      individually different and encompass the peripheral nociception, biochemical
      changes of the neurotransmitters in the spinal range and events in the
      subcortical and cortical region. For a successful treatment, the proper
      understanding of the perception and experience of pain is a preliminary condition
      for the physician and the patient.

PMID- 10637962
TI  - [Non-steroidal anti-inflammatory drugs and cyclooxygenase-2-specific inhibitors].
AB  - The discovery of two isoenzymes of cyclooxygenase--COX-1 and COX-2--in the late
      eighties was followed by an intensive looking for drugs, which inhibit
      specifically COX-2 and have no influence on COX-1. After some years of trial and
      error it is now possible to measure the inhibition-capacity--e.g. of Rofecoxib,
      Celecoxib and all the conventional NSAIDs--in a human blood assay. New insights
      into localisation, expression and physiological function of COX-2 followed. We
      now are able to differentiate between "conventional" NSAIDs and COX-2 specific
      inhibitors (CSI, COXIBS), as a new class of substances. CSI firstly inhibit COX
      1/COX-2 to a different extent and in a different manner. Secondly they have a
      different profile concerning unwanted--especially gastrointestinal--side effects.
      Further experiences and investigations have to confirm and establish this
      positive risk/benefit ratio.

PMID- 10637963
TI  - [Use of topical non-steroidal anti-inflammatory drugs in aggravated and
      decompensated arthroses].
AB  - Pain in osteoarthritis of the big weight bearing joints is either derived from
      periarticular ligaments, tendons, fascias, muscles, bursae--periarthropathy as
      sign of decompensation or from the reactive synovitis with or without effusion.
      NSAIDs (ibuprofen, diclofenac, indometacin, some salicylates, etofenamate and
      piroxicam) have demonstrated relevant advantages of the percutaneous route over
      the systemic one in soft tissue rheumatism. NSAIDs, mentioned above, locally
      administered as cream, gel or spray, quickly penetrate through the corneal layer
      of the skin and the site of application, reach highly effective concentrations in
      subcutis, fascias, tendons, ligaments and muscles, less in joint-capsule and 
      fluid indicating direct penetration. The blood levels of topical NSAIDs are
      extremely low with no systemic side effects, especially no gastric toxicity;
      however, local skin irritation is observed (1 to 2%). In contrast to this,
      systemic (oral) NSAIDs lead primarily via high blood levels to a lower
      concentration--only one tenth--in periarticular soft tissues with a high
      incidence of side effects. In conclusion the percutaneous application of certain
      NSAIDs has become a well established therapeutic regimen in painful
      osteoarthritis and in all other inflammatory degenerative and posttraumatic
      alterations of soft tissue structure.

PMID- 10637964
TI  - [IgA rheumatoid factor and prognosis in chronic polyarthritis].
AB  - We determined the prognostic value of IgA rheumatoid factor in patients with
      rheumatoid arthritis. The results show clearly that only patients with high
      titers of IgARF during their course had an unfavorable prognosis determined by
      functional status and mortality.

PMID- 10637965
TI  - [Adhesion molecule ICAM-1 in patients with chronic polyarthritis--effects of
      inpatient rehabilitation].
AB  - In rheumatoid arthritis (RA) the adhesion molecule ICAM-1 mediates the adhesion
      of leucocytes following subsequent transendothelial migration including
      interactions and adhesion of several cell types such as fibroblasts, T
      lymphocytes and synoviocytes. Significantly increased ICAM-1 levels were measured
      in the acute phase of RA. The correlation of ICAM-1 levels with the pteridine
      neopterin (p < or = 0.01) may reflect the role of this adhesion molecule in
      modulation of immune responses. Despite the significantly higher levels of acute
      phase reactions parallel to the elevated ICAM-1 levels, no correlations were
      found between ICAM-1 and erythrocyte sedimentation rate (ESR), C-reactive protein
      (CRP) and serum-Amyloid A (SAA). During an in-patient multidisciplinary
      rehabilitation programme the levels of ICAM-1 in serum and the majority of all
      investigated laboratory and clinical parameters such as ESR, CRP, SAA,
      fibrinogen, pain, swollen and painful joint count, morning stiffness and health
      assessment questionnaire improved.

PMID- 10637966
TI  - [Anti-TNF-alpha therapy as a new option in treatment of rheumatoid arthritis?].
AB  - Due to intensive research in the field of cytokines during the last decade the
      knowledge of cytokine mediated processes has increased intensively. Modulation or
      even inhibition of the inflammatory cascade gave hope to effective therapeutic
      possibilities in sepsis or autoimmune diseases, particularly in rheumatoid
      arthritis (RA). Interestingly the application of biological immunomodulating
      substances could not increase the prognosis in sepsis, sometimes even
      deterioration occurred. However, in inflammatory bowel diseases and RA
      substantial efficacy could be revealed. Since blockade of II-1 or II-2 led to
      some beneficial results, but also sometimes to significant toxicity, TNF-alpha
      blockade gave hope to constitute a promising therapeutical target. Since the
      efficacy of a monoclonal anti-TNF-alpha antibody and a recombinant soluble TNF
      receptor p75 fusion protein had been demonstrated in animal studies and in vitro,
      these results could be confirmed in controlled multicenter trials, showing
      significant improvement of patients according to Paulus and/or ACR criteria.
      However, a final assessment of therapeutical TNF-alpha blockade in RA cannot be
      given yet, since the tolerability in long-term application, particularly with
      respect to the risk of infections and the induction of malignancies and
      antibodies (e.g. drug induced lupus erythematosus) has to be observed carefully
      for longer times. Also the cost effectiveness of this new therapeutic approach
      needs further investigations.

PMID- 10637967
TI  - [Panalgesia and the fibromyalgia concept].
AB  - Fibromyalgia is a chronic soft tissue pain syndrome characterized by the presence
      of widespread musculosceletal aching, tender points at characteristic sites,
      fatigue and poor sleep. Associated disorders are restless leg syndrome, irritable
      bowel syndrome, irritable bladder syndrome, cognitive dysfunction, cold
      intolerance, multiple sensitivities and dizziness. Despite the superficial
      appearance of normality, many fibromyalgia patients have difficulties with
      remaining competitive in the work force. Impressive resurgence of research had
      been done about fibromyalgia in a better understanding in the neurobiology of
      chronic pain. The results demonstrate that sensory disorders processing at a
      central level are in part involved in fibromyalgia. These findings also influence
      the management of the disease with the tendency to a multidisciplinary
      therapeutical concept.

PMID- 10637968
TI  - [Electromyography biofeedback therapy in fibromyalgia].
AB  - Nineteen patients with fibromyalgia underwent a course of treatment with EMG
      biofeedback (EMG-BFB) technique. On completion of treatment, there was a
      statistically significant lowering of sensitivity to pain at pressure points
      typical for fibromyalgia (p = 0.017), which could be observed also 2 months after
      completion of treatment. In addition, there was a reduction both in the affective
      (p = 0.04) and in the sensory (p = 0.007) components of pain. Furthermore, there
      was a statistically significant improvement in the accompanying disease
      parameters of sleep disturbance (p = 0.004) and head ache (p = 0.031). Since EMG
      BFB training might contribute not only to a reduction of pain and muscle tension
      but also to an improvement of quality of life, it can be recommended as part of a
      multimodal pain therapy in fibromyalgia patients.

PMID- 10637969
TI  - [Results of a multidisciplinary rehabilitation concept in patients with chronic
      lumbar syndromes].
AB  - The aim of our pilot study was to evaluate the influence of a multidisciplinary
      rehabilitation programme on various parameters of pain and function in 88
      patients suffering from chronic low back pain caused by disc herniation (46
      patients) or after lumbar discectomy (42 patients). We used an exercise-based
      multidisciplinary programme during a four-week in-patient treatment: active
      physiotherapy, exercise training and back school, organized in group therapies
      combined with passive techniques of physiotherapy (heat, massage, electrotherapy,
      medicated bath) with a daily duration of treatment exceeding three hours.
      Symptoms and functions improved simultaneously with the reduction of pain. The
      results of the visual analogue scale improved significantly in both groups
      (conservatively treated group p < 0.0001, after lumbar discectomy p < 0.005). As
      for the McGill pain questionnaire, however, only the group with conservatively
      treated disc herniations changed significantly for the better. We found an
      improvement in Roland-Morris' disability questionnaire in both groups, which
      reached statistical significance only in the group after lumbar discectomy.
      Forward-backward bending (kyphometer measurement as described by Debrunner),
      ameliorated significantly in both groups. Our results indicate that an exercise
      based multidisciplinary rehabilitation programme can improve pain and function
      even in patients suffering from definitely chronic low back pain caused by disc
      herniation or after lumbar discectomy.

PMID- 10637970
TI  - [Routine examinations in the densitometry department].
AB  - The authors describe observations on the basis of the high number of patients at
      their osteodensitometry clinic. They found that in ankylosing spondylitis
      vertebral osteodensity would not be practical to be taken into account for
      estimating osteopenia. They suggest the "slicing" method of the 4th lumbar
      vertebra, taking into consideration the middle slice only. The second part of
      their study proved that daughters of their patients, suffering from osteoporosis
      with fractured vertebra, had significantly lower osteodensity as compared with
      the age and menstrual cycle-matched controls.

PMID- 10637971
TI  - [Quantitative scintigraphy of the sacroiliac joints].
AB  - Effects of gender and age on quantitative sacroiliac joint imaging are discussed
      controversially. In most investigations the number of controls has been small and
      might not exactly reflect the change of sacroiliac/sacral (SI/S) ratios related
      to different age and gender. The aim of our study was to evaluate the changes
      SI/S ratios according to age and gender. In 125 patients without any history of
      either diseases or complaints of the sacroiliac joints a bone scintigraphy was
      obtained and the SI/S ratios were calculated. We observed a significant negative
      correlation of SI/S index with age. After separation into 4 different age groups
      a significant decline of the ratios could be shown. There were no significant
      differences between male and female patients. We conclude that the influence of
      age on SI/S ratios is substantial. But also many other factors like patient
      position, algorithm of SI/S ratio calculation, the time interval between
      application of the radiopharmaceutical and data acquisition may exert effects on
      SI/S ratios. It seems necessary for each department to evaluate their own age
      related reference values of SI/S ratios.

PMID- 10637972
TI  - [RHEUMexpert: a documentation and expert system for rheumatic diseases].
AB  - A computer assisted documentation of signs and findings in rheumatic diseases is
      described. This documentation was developed by the Austrian Society for
      Rheumatology and thought to be a minimal standard for the use by general
      practitioners. In addition, a knowledge-based basic differential diagnosis
      support was developed, which differentiates between major groups of rheumatic
      diseases as inflammatory spine diseases, mechanical or metabolic reasons for
      spine disorders, inflammatory joint diseases, degenerative or metabolic joint
      diseases, soft tissue diseases. This presentation describes the results of an
      evaluation of 75 typical case histories and a second study where 252 case
      histories were documented retrospectively in this new system. The results of the
      first showed a pretty good discrimination between the described groups of
      different diagnoses (sensitivity between 71 and 100 percent for all groups with
      the exception of metabolic joint diseases, specificity between 75 and 94
      percent). The second--retrospective--documentation and diagnostic support showed
      much weaker results (sensitivity for major groups 74-76 percent). The reasons for
      the different outcomes are discussed: On the one hand, signs and symptoms from
      case reports could not be transferred completely in the new documentation, as
      some findings retrospectively could not be defined sharp enough. On the other
      hand the study showed, that the sensitivity of well defined disorders as
      inflammatory joint diseases (exp. rheumatoid arthritis) reaches almost 100
      percent, whereas it is as low as 50 percent in some other diseases (e.g. gout)
      whose characteristic findings and symptoms are suppressed by treatment (drug
      medication) in many cases. The results show that computer based documentation of
      rheumatic diseases facilitates the systematized and standardised documentation of
      patient data. However, a few modifications of the knowledge base as well as the
      knowledge representation formalisms are necessary to achieve a better performance
      in differential diagnostic support.

PMID- 10637973
TI  - [Refugee children].

PMID- 10637974
TI  - [Haptic perception and EEG changes in anorexia nervosa].
AB  - OBJECTIVES: We predicted that due to diminished somatosensory integrative
      ability, the anorectic patients would have problems reproducing haptic stimuli.
      In addition we sought to determine whether EEGs from anorectic patients (AN) and
      the healthy controls (CO) would show discrepancies between the two groups during
      haptic explorations in theta-power over the right parietal region. METHOD: EEG
      power (theta-power) data of AN (n = 13) and CO (n = 13) were analyzed during
      haptic exploration tasks and rest intervals. The haptic explorations consisted of
      palpating the structure of six sunken reliefs in sequence with both hands, eyes
      closed. After each exploration the structure was drawn on a piece of paper.
      RESULTS: The reproductions of haptic stimuli submitted by the anorectic patients
      were of notably poorer quality than those of the healthy controls. During rest
      intervals and haptic explorations, spectral power was generally lower in the AN
      group in comparison to the healthy controls. Significant theta-power differences
      between groups showed over the right parietal cortex during haptic explorations.
      The decrease in EEG power in the anorectic patients in the theta bands across the
      right parietal region during haptic exploration tasks could be interpreted as a
      minor activation of visuo-spatial regions. The results of the haptic explorations
      as well as the EEG-power changes indicate a cortical dysfunction and deficits in
      somatosensory integration processing in anorexia nervosa patients.

PMID- 10637975
TI  - [Exclusion of receptive speech disorders with the ADOS (Autism Diagnostic
      Observation Schedule)].
AB  - OBJECTIVE: The purpose of our pilot study was to assess the reliability and
      diagnostic validity of the Autism Diagnostic Observation Schedule (ADOS). The
      usefulness of the schedule in the differentiation between children with autism
      and children with a severe specific receptive language disorder is examined.
      METHOD: Eight boys with early infantile autism and eight age- and IQ-matched boys
      with a specific receptive language disorder were examined with the ADOS. The
      reliability of the instrument was assessed using the ratings of eight pairs of
      raters. The agreement between diagnostic classification based on the ADOS ICD-10
      algorithm and the independent clinical psychiatric diagnosis of two experts was
      used as the measure of validity. RESULTS: The reliability of the different ADOS
      items proved to be good among experienced raters. Various ADOS items clearly
      discriminate both groups. Using the ADOS ICD-10 algorithm, the clinical diagnosis
      of infantile autism could be confirmed for five of the eight children in this
      group. None of the children with the clinical diagnosis of a receptive language
      disorder was identified as autistic according to the algorithm. CONCLUSIONS: In
      the hands of experienced raters the ADOS is a reliable diagnostic instrument. It
      can support the differentiation between autism and specific receptive language
      disorder, but additional parent information is needed to confirm the diagnosis.

PMID- 10637976
TI  - [Heart and liver transplantation in adolescents. Results of an expert survey].
AB  - OBJECTIVE: What counseling concepts do experts use? How do they describe the
      quality of life following the transplantation? How do they judge the psychosocial
      development of transplanted adolescents? METHOD: Four physicians and two
      psychologists, all working in the field of heart or liver transplantation, were
      interviewed. The evaluation was conducted according to Mayring's Qualitative
      Content Analysis. RESULTS: Counseling adolescent patients in the face of a
      transplantation is described as very difficult, as it is hard to estimate the
      extent to which they can anticipate the implications of surgery. Although from a
      medical point of view the quality of life improves, restrictions concerning
      psychosocial development persist. The relationship between the physician and the
      patient in the field of transplantation appears to be extraordinarily close.
      DISCUSSION: It became clear that the experts are highly interested in
      psychological research concerning transplantation in adolescents and that they
      prefer the use of qualitative methods in quality-of-life research. Additionally,
      the results stress the need for the development of psychological counseling
      concepts for this group of patients.

PMID- 10637977
TI  - [Encopresis: review of the literature 1988 to 1998].

PMID- 10637978
TI  - [History of child psychiatry in the USA. From social reform and psychoanalysis to
      psychiatry of the family].

PMID- 10637979
TI  - [Tuberous sclerosis and organic bipolar disorder in a 15-year-old adolescent].
AB  - We present the case of a 15-year-old girl with tuberous sclerosis who developed
      rapid cycling bipolar disorder under treatment with the anticonsulvant
      oxcarbazepine. Because of first occurrence of grand mal-seizures combined
      treatment with Valproate became necessary, but failed to prevent relapses of
      bipolar disorder. Mood stabilization was noticed under additional treatment with
      lithium, which was complicated by an increase of serum potassium.

PMID- 10637980
TI  - [Use of metric indices in anorexia nervosa].

PMID- 10637981
TI  - Synthesis of selected aminodeoxy analogues of galabiose and globotriose.
AB  - Six aminodeoxy 2-(trimethylsilyl)ethyl (Me3SiEt) glycoside analogues of galabiose
      (4'- and 6'-aminodeoxy) and globotriose (6"-, 4"-, 2"-, and 6'-aminodeoxy) were
      synthesized by glycosylation of protected Me3SiEt galactoside and lactoside
      acceptors with azido-substituted monosaccharide donors, followed by reduction of
      the azido groups and removal of the protecting groups.

PMID- 10637982
TI  - Synthesis of some aglycon analogs of globotriosylceramide.
AB  - Seven aglycon analogs of globotriosylceramide were synthesized by glycosylation
      of suitable functionalized alcohols with peracetylated globotriose
      trichloroacetimidate, followed by further transformations of the aglycon and
      removal of the protecting groups.

PMID- 10637983
TI  - Synthesis of selected aminodeoxy analogs of globotriosylceramide.
AB  - Four aminodeoxy analogs of globotriosylceramide (6"-, 4"-, 2"-, and 6'
      aminodeoxy) were synthesized by glycosylation of 3-O-benzoylated azidosphingosine
      with the corresponding aminodeoxy-globotriose trichloroacetimidate, followed by
      reduction of the azido group, N-acylation with 1-adamantaneacetic acid, and
      removal of the protecting groups.

PMID- 10637985
TI  - Towards regioselective synthesis of oligosaccharides by use of alpha-glucosidases
      with different substrate specificity.
AB  - alpha-Glucosidase from two microbial sources, Bacillus stearothermophilus and
      Brewer's yeast, has been used to catalyze transglycosylation reactions and a
      comparative study was carried out to determine the regioselectivity of this
      reaction. Bacterial alpha-glucosidase exhibited higher transfer activity with
      maltose and was able to synthesize tri- and tetrasaccharides in high yield (27%).
      In the case of yeast enzyme, only trisaccharides were synthesized in lower yield.
      Structure analysis of transglycosylation products by means of GC-MS and NMR
      spectroscopy revealed a correlation between the hydrolytic substrate specificity
      and the regioselectivity of transglycosylation reaction. Higher substrate
      specificity of bacterial enzyme, however, influenced its transglucosylation
      activity toward other saccharide acceptors.

PMID- 10637984
TI  - The synthesis and evaluation of novel sialic acid analogues bound to matrices for
      the purification of sialic acid-recognising proteins.
AB  - A novel N-acetylneuraminic acid analogue, 2-S-(5'-aminopentyl) 5-acetamido-3,5
      dideoxy-2-thio-D-glycero-alpha-D-galacto-2- nonulopyranosidonic acid, as well as
      the thiosialoside 2-S-(2'-aminoethyl) 5-acetamido-3,5-dideoxy-2-thio-D-glycero
      alpha-D-galacto-2- nonulopyranosidonic acid, have been synthesised and
      successfully coupled to CNBr-activated Sepharose 4B through the terminal amino
      group. The resultant affinity resins have proved efficient in purifying a number
      of sialic acid-recognising proteins such as Vibrio cholerae sialidase, sialidase
      L from leech, trans-sialidase from Trypanosoma cruzi, and sialyltransferases from
      rat liver, all in high yield.

PMID- 10637986
TI  - Chemical and immunochemical studies of the O-antigen from enteropathogenic
      Escherichia coli O158 lipopolysaccharide.
AB  - The O-specific polysaccharide isolated from Escherichia coli O158 smooth
      lipopolysaccharide contains L-rhamnose, D-glucose and 2-acetamido-2-deoxy-D
      galactose in the molar ratios 1:2:2. Studies on composition, methylation analysis
      and specific degradations together with a 1H and 13C NMR spectral study
      established that the O-antigen is built up from a pentasaccharide repeating unit
      having the following structure: [formula: see text] The most effective inhibitory
      part of the oligosaccharide from E. coli O158 lipopolysaccharide has been
      serologically characterized by an ELISA-inhibition study using different sugars.
      The results showed that methyl alpha- and beta-D-GalpNAc are the most effective
      inhibitors among the monosaccharides tested, while the main antibody specificity
      lies on the main-chain trisaccharide repeating unit.

PMID- 10637987
TI  - Low-molecular-weight dextran derivatives (f-CMDB) enter the nucleus and are
      better cell-growth inhibitors compared with parent CMDB polymers.
AB  - Carboxymethyldextrans-benzylamide (CMDB) are dextran derivatives that are
      statistically substituted with carboxymethyl and benzylamide groups. These
      molecules display a variety of biological effects, one of which is their
      inhibitory activity against mammary tumor cell growth, both in vitro and in vivo.
      We and others have previously shown that the effects of CMDB on cell growth are
      related to their ability to interact with the growth factor FGF-2. The binding
      modifies the conformation of FGF-2, leading to the suppression of its mitogenic
      activity. Here, the method previously reported to fragment natural polysaccharide
      fucans has been applied to CMDB (80,000 g/mol). f-CMDB (fragmented CMDB) of
      molecular weights from 6000 to 20,000 g/mol were found to be more potent
      inhibitors of MCF7 mammary tumor cell growth than high-molecular-weight CMDB.
      Confocal microscopy experiments using CMDB and f-CMDB labeled with the
      fluorophore DTAF (5-([4,6-dichlorotriazine-2-yl]amino) fluorescein) indicate that
      only low-molecular-weight f-CMDB penetrate into the nucleus of MCF7 cells. It is
      thus assumed that the better inhibitory properties demonstrated by f-CMDB,
      compared with CMDB, are related to their better ability to penetrate the nucleus
      and interact with nuclear targets, including topoisomerase II. The DNA relaxation
      properties of the latter are inhibited in vitro by both CMDB and f-CMDB. These
      findings could help us to develop models of low-molecular-weight oligosaccharide
      derivatives exhibiting better antiproliferative and antitumor properties.

PMID- 10637988
TI  - Understanding biological and social influences on religious affiliation,
      attitudes, and behaviors: a behavior genetic perspective.
AB  - Although the transmission of religiousness has been assumed to be purely
      cultural, behavior genetic studies have demonstrated that genetic factors play a
      role in the individual differences in some religious traits. This article reviews
      the extant behavior genetic literature and presents new analyses from the
      "Virginia 30,000" on the causes of variation in religious affiliation, attitudes,
      and practices, and relates these to personality as construed by Eysenck. Results
      indicate that religious affiliation is primarily a culturally transmitted
      phenomenon, whereas religious attitudes and practices are moderately influenced
      by genetic factors. Further, Eysenck's personality traits do not mediate genetic
      influences on religiousness, but significant negative genetic correlations are
      found between church attendance and liberal sexual attitudes. Implications and
      possibilities for future studies are discussed.

PMID- 10637989
TI  - Religion, personality, and aging: a life span perspective.
AB  - A life span model of development provides the framework for examining the
      relation between religion and personality in aging persons. This article
      emphasizes the interplay of constancy and change in adult religious life.
      Important contextual factors that influence religion and personality are noted. A
      discussion of generativity and ego integrity shows how the maturing personality
      can embrace religiously motivated acts of justice and mercy as well as a
      deepening of spiritual life. Also discussed are the ways religion encourages
      generativity and ego integrative processes. The article concludes with
      suggestions for future studies of religion, personality, and aging utilizing a
      life span model of development.

PMID- 10637990
TI  - Religion and the forgiving personality.
AB  - Forgiveness is a concept with deep religious roots. It is also a basic social and
      psychological phenomenon. In this article, we explore the links between
      forgiveness and religion by surveying how they are linked in the major
      monotheistic world religions, and how they appear to be linked empirically. In
      attempting to account for the current body of empirical findings, we propose four
      potential substantive and methodological explanations that should be explored in
      future studies. Because the concept of forgiveness is (a) both spiritual and
      social-psychological in nature, and (b) possibly linked to some measures of human
      health and well-being (concerns that have traditionally been of interest to both
      reseachers in personality and researchers in religion), the concept of
      forgiveness could be an important common ground for future research on the
      interface of religion and personality.

PMID- 10637991
TI  - Virtue, personality, and social relations: self-control as the moral muscle.
AB  - Morality is a set of rules that enable people to live together in harmony, and
      virtue involves internalizing those rules. Insofar as virtue depends on
      overcoming selfish or antisocial impulses for the sake of what is best for the
      group or collective, self-control can be said to be the master virtue. We analyze
      vice, sin, and virtue from the perspective of self-control theory. Recent
      research findings indicate that self-control involves expenditure of some limited
      resource and suggest the analogy of a moral muscle as an appropriate way to
      conceptualize virtue in personality. Guilt fosters virtuous self-control by
      elevating inter-personal obligations over personal, selfish interests. Several
      features of modern Western society make virtue and self-control especially
      difficult to achieve.

PMID- 10637992
TI  - Mainstream personality psychology and the study of religion.
AB  - In this commentary, I make some general observations about the study of
      personality and religion and some specific comments about individual articles
      from the perspective of contemporary personality psychology. Most of the authors
      represented here treat religion as a domain of human experience and behavior that
      can be understood in terms of familiar personality principles and processes. I
      therefore urge greater attention to the Five-Factor Model of personality traits,
      especially Openness to Experience, in understanding religious phenomena.
      Mainstream psychologists, including longitudinal researchers, behavior
      geneticists, and epidemiologists, should consider the inclusion of religious
      variables in their research designs.

PMID- 10637993
TI  - [Heart failure. A public health problem].

PMID- 10637994
TI  - [Assessment of quality of care in heart failure].
AB  - OBJECTIVES: To evaluate the presence of predetermined quality aspects in the
      management of hearth failure inside an Internal Medicine Department. METHODS:
      Prospective study under protocol of 200 patients admitted to our Internal
      Medicine Department under diagnosis of hearth failure from july 97 to july 98.
      RESULTS: Every patient of our study had an anamnesis, physical examination, chest
      radiology and electrocardiography. Only 42.4% had an electrocardiography. Hearth
      failure etiology was determined in only 62.6% (30% isquemic, 22% hypertensive, 6%
      mixed, 30% valvulopathy, 9% specific myocardiopathy, 3% others). 47.5% of the
      patients were functionally classified after NYHA (I 2.7%, II 58%, III 35.4%, IV
      3.6%). Treatment and drug dosing were adequate in 85.5% (diuretics 91%, ACEI 42%,
      digitalis 36%, nitrates 56%, inotropic drugs 2%, betablockers and calcium
      antagonists 1%). 13% of the patients were admitted to the hospital more than
      three times a year. Mortality rate was 18% and 19% of them were older than 70
      years old. CONCLUSIONS: Quality management indicators were acceptably present in
      our study. We must insist on etiologic diagnosis and NYHA classification as a way
      of improving care.

PMID- 10637995
TI  - [Poor therapeutic management of patients with heart failure: study of
      readmissions at a general hospital].
AB  - BACKGROUND: To assess the measures used in Chronic Heart Failure (HF) in ours
      medium, and medical control of patients before and after readmissions to
      hospital. METHODS: Retrospective study was made in aleatory sample of 153
      patients with readmissions for HF, during a one year period (January to December
      1996). We took details of age, sex, number of readmission, aetiology of
      cardiopathy, ejection fraction of left ventricle, functional status, previous and
      posterior to discharge treatments and the medical control. RESULTS: There was not
      medical control previous of readmission in 22.2% of patients. There was not
      coordination with other medical care after discharge in 19.6%. The etiology of
      cardiopathy was unknown in 14% of patients and do not performed the
      echocardiography in 22.2%. There was systolic dysfunction 66.3%. More used drugs
      was diuretics; previous (91.5%) and after (83%) discharge. ACE-Inhibitors was
      used in 49.3% of patients with systolic dysfunction, previous of readmission
      (only in 26.5% to correct dose). After discharge was used in 68% and 16.4% to
      correct dose. We analyzed others therapies as dietary sodium poor (44.4%) and
      suitable exercise (0.7%). CONCLUSIONS: We observed the underutilization of ACE
      Inhibitors in patients with ventricular dysfunction, and de unsuitable medical
      control in patients with HF. There are relatively high percent of patients
      without correct valuation after multiple rehospitalizations.

PMID- 10637996
TI  - [Prognostic value of the nutrition status and pro-inflammatory cytokines (IL-1,
      TNF-alpha and IL-6) in critically ill patients].
AB  - OBJECTIVE: Prognosis of hospitalized patients depends on the status of nutrition,
      the intensity of the biologic inflammatory response or acute phase response
      (APR), triggered by cytokine, and the illness severity. These factors have been
      shown closely related, as cytokine causes malnutrition and organ failure. AIM: to
      analyze which of these factors are related to mortality and, by multivariate
      analysis, which of them have an independent predictive value. METHOD: We include
      119 patients admitted to a semi-intensive care unit. Nutritional assessment was
      performed by mid arm anthropometrics, serum albumin, transferrin, IGF-I, and
      subjective nutritional evaluation; we also determine acute phase proteins and
      cytokine IL-1, TNF alpha and IL-6. Severity of illness was assessed by organ
      failure. The only end point considered was death or survival until discharge of
      hospital. RESULTS: The following data were related to increased mortality:
      impaired alimentary habits and nutritional subjective assessment, raised serum
      levels of IL-6 and neutrophil differential count, decreased lymphocyte count,
      hemoglobin and serum transferrin levels, a negative PPD and the presence of
      sepsis, shock or organ failure. At multivariate analysis (stepwise logistic
      regression) only nutritional variables, sepsis and organ failure data showed an
      independent predictive value, whereas IL-6 was displaced by organ failure data.
      CONCLUSION: Regarding prognosis, severity of illness and nutritional status have
      independent predictive value, whereas IL-6 was displaced, probably because it is
      closely related to the inflammatory response and to organ failure.

PMID- 10637997
TI  - [Antithrombotic treatment in non-rheumatic atrial fibrillation. Do we follow the
      recommendations of clinical trials?].
AB  - OBJECTIVES: Several clinical trials have demonstrated that antithrombotic
      treatment may be effective in prevention of stroke in nonrheumatic atrial
      fibrillation (AF). The aim of this study was to assess if we follow clinical
      trial recommendations in community practice. METHODS: We analyzed 225 medical
      records of patients diagnosed of nonrheumatic AF in Caceres, during February and
      March 1998. Patients who were contraindicated to follow antiagreggation or anti
      coagulation treatment were excluded. We compared patients with and without
      antithrombotic treatment with different demographic characteristics and embolic
      risk factors. RESULTS: 205 patients were included in the study, 149 (72.6%) had
      high embolic risk. 62 (30.2%) followed anticoagulation, 94 (45.8%)
      antiaggregation treatment, 5 (2.4%) both treatment and 49 (24%) were not
      receiving therapy. We didn't findings differences between age, sex, presence of
      ischemic heart disease, hypertension and congestive heart failure in last three
      months compared with the patients in respect to the group of patients with
      anticoagulation and antiaggregation therapy or without it. We determinate as well
      that previous stroke and echocardiographical finds (valve disease, valve
      calcification, ventricular dysfunction) were more frequent in the anticoagulation
      and antiaggregate patients than in those without therapy. CONCLUSION: A high
      range of nonrheumatic AF patients take any kind of antithrombotic preventive
      therapy, though a great number of patients with high embolic risk could still get
      benefits from anticoagulation therapy. We should considerate in the therapy
      assessment some other clinical characteristics as hypertension, isquemic heart
      disease and heart failure apart from echocardiographical findings.

PMID- 10637998
TI  - [Wegener's granulomatosis presenting with ARDS and acute kidney failure with
      neutrophil anticytoplasmic+ antibodies].
AB  - We report a case of adult respiratory distress syndrome (ARDS) associate to renal
      failure in a patient labeled of "round pneumonia" some weeks before. An open
      biopsy was made that only showed typical findings of ARDS. The patient was
      treated with corticosteroids and cyclophosphamide because of cANCA positivity. We
      discuss the utility of this determination in Wegener disease and we conclude that
      this determination should be made in this clinical setting and start
      immunosuppressive treatment when cANCA is positive.

PMID- 10637999
TI  - [Cushing's syndrome secondary to bronchial carcinoid tumor: contribution of
      gammagraphy with 111In-DTPA octreotide in the localization diagnosis].
AB  - Bronchial carcinoid (BC) is a rare etiology of Cushing syndrome, and difficulties
      in differential diagnosis with Cushing's disease are often present. We report two
      cases in which octreotide scintigraphy was an important diagnostic tool. The
      first patient showed a 1 cm non-specific pulmonary nodule on CT scan that was
      positive on scintigraphy, being confirmed by surgery. The second case was a man
      that had been operated but not cured of an ACTH secreting BC that continued with
      high ACTH levels and negative localization imaging studies. A subsequent
      scintigraphy showed a positive image suggestive of recurrence. Octreotide
      scintigraphy may be considered in patients with suspicion of ectopic ACTH
      syndrome although a positive image in CT scan be present.

PMID- 10638000
TI  - [Toxic megacolon presenting as Crohn's disease].
AB  - We introduce a young patient, without history of inflammatory bowel disease
      (I.B.D.) who started with an acute gastroenteritis, which in the following days
      progressed to a toxic megacolon. The patient had come to hospital with nausea,
      vomiting, fever and liquid, explosive diarrhoea without pathologic products.
      There was no clinical remission with astringent diet, hydroelectrolitic
      reposition and antidiarrheic opiates. The patient was admitted in hospital when
      he had blood in the diarrhoea. This progressed to a toxic megacolon in three days
      and the patient had to be operated on urgently. The surgeons found perforations
      in the colon and the pathologists diagnosed Crohn disease. Even without previous
      E.B.D. history we reached the diagnosis from the clinical and analytical data and
      the plain abdominal radiology. It was impossible to confirm the diagnosis with a
      colonoscopy because of the high risk of perforation. In cases like this, early
      surgery may save the life of the patient.

PMID- 10638001
TI  - [Hyperthyroidism secondary to antidepressive treatment with fluoxetine].
AB  - We present two clinical cases about patients whose previous psychiatric
      diagnostic was depressive syndrome, that's why they were treated with fluoxetine.
      After a large period of time using this medication both cases developed a
      secondary hyperthyroidism to that treatment.

PMID- 10638002
TI  - [Simultaneous presentation of actinomycosis and metastatic pharyngeal carcinoma].
AB  - Although actinomycosis frequently presents as a pseudotumoral syndrome, the
      simultaneous diagnosis of actinomycosis and cancer is exceptional. Actinomycosis
      can occur as an opportunistic infection secondary to the antineoplastic treatment
      and even the cancer itself can act as facilitating factor. We report a patient
      who was diagnosed simultaneously of advanced oropharinx cancer (T4-N1-M0) and
      actinomycosis associated to the tumoral mass. This exceptional association and
      the importance of its early diagnosis justify the communication of the case.

PMID- 10638003
TI  - [Spinal cord compression caused by metastasis of soft tissue hepatocarcinoma].
AB  - More than 90% of hepatocellular carcinoma (HCC) arise in a chronical hepatitis.
      When HCC is diagnosed, most of the patients have symptoms in relation to
      cirrhosis of the liver. Spread metastases are not frequent and the extension to
      soft tissues is exceptional. We reported a 55 year old patient who had alcoholic
      cirrhosis and HCC with quickly development. The onset was a spinal cord
      compression due to soft tissues epidural metastases, seated at paravertebral
      zone. Plain radiographs and radionuclide bone scans were normal; diagnosis was
      achieved by magnetic resonance imaging and fine-needle aspiration cytology of the
      tumor. We have found no bibliographic reference on spinal cord compression due to
      soft tissues metastases from HCC. We want to point out the importance of
      including soft tissues metastases in differential diagnosis for radiculopathies
      with normal radiography and radionuclide scanning in patients at risk,
      considering also patients with hepatocellular carcinoma.

PMID- 10638004
TI  - [Prevention of venous thromboembolism: unfractionated heparins and low-molecular
      weight heparins. Analysis of these 2 options].
AB  - Traditionally, it has been recommended that the prevention of venous
      thromboembolic disease (VTD) be treated, subcutaneously, with heparins, be they
      fractionated (UH) or low molecular weight (LMWH). While it has been expected that
      the latter would prove the more effective, numerous clinical studies have
      confirmed that there are no appreciable differences between either, given the
      results obtained in the prevention of VTD, or of bleeding, or of death. It
      therefore appears logical to think that the moment has arrived to consider
      substituting the old, conventional heparins, for the new LMWH. In order to
      attempt to answer this question, we have undertaken a revision of the main meta
      analysis published, wherein both heparins have been comparatively employed; thus
      we analyze their mechanisms of action, their pharmacokinetics differences, and
      their adverse effects, as well as the type of patients, both at the time of
      initiation and continuation of tromboprophylaxis with heparins. Using currently
      available data, it can be inferred that LMWH are as safe and effective as the UH
      in the prevention of VTD. Moreover, there are a series or added advantages, such
      as no unnecessary laboratory controls, and the easy dosification and
      administration, both to patient as well as nursing staff.

PMID- 10638005
TI  - [Hypercoagulation markers in myocardial infarction].

PMID- 10638006
TI  - [Arthritis induced by antihepatitis B vaccine].

PMID- 10638007
TI  - [Treatment of visceral leishmaniasis in patients with antimonials: is there a
      maximal dose?].

PMID- 10638008
TI  - [Incomplete POEMS syndrome?].

PMID- 10638009
TI  - [Fat embolism syndrome with cerebral involvement shown with magnetic resonance].

PMID- 10638010
TI  - [Treatment with anti-Rh (D) immunoglobulin in thrombopenia associated with viral
      infection].

PMID- 10638011
TI  - [Alveolar hemorrhage caused by cryoglobulinemia associated with hepatitis C virus
      infection].

PMID- 10638012
TI  - [Spontaneous hematoma of the rectus sheath and essential thrombocytosis].

PMID- 10638013
TI  - [Remission following verapamil use in acromegalic patient with heart failure].

PMID- 10638014
TI  - [Assessment of thyroid function in the cirrhotic patient: a good clinical
      practice].

PMID- 10638015
TI  - [Clinical and etiologic features of hepatocarcinoma in Sicily].
AB  - Hepatocellular carcinoma is a neoplasia with a high degree of malignancy and a
      quite unfavorable prognosis, and its frequency has tripled over the last 30
      years. The aim of this study was to shed further light on some epidemiological
      and clinical aspects of hepatocellular carcinoma, on the basis of experience with
      a wide ranging patient population. We included 179 patients (127 males, 52
      females, age range 31-86 years), diagnosed with hepatocellular carcinoma between
      January 1993 and December 1998. For each patient we recorded age, sex,
      coexistence and cause of cirrhosis, severity of cirrhosis, stage of
      hepatocellular carcinoma, serum markers of viral hepatitis (hepatitis B surface
      antigen and hepatitis C virus antibodies) and serum levels of alpha-fetoprotein.
      Hepatocellular carcinoma was associated with hepatitis C virus in 72% of
      patients, with hepatitis B virus in 10%, with combined infection in 3% and with
      negative viral markers in 15%. Mean age at diagnosis was significantly higher in
      the hepatitis C virus infection patients than in the combined infection patients
      (p < 0.04); the male/female ratio was 2.1:1 in the hepatitis C virus and 8:1 in
      the hepatitis B virus subjects. At hepatocellular carcinoma diagnosis, 175 out of
      179 patients had liver cirrhosis with a significantly higher severity in patients
      with negative viral markers than in those with positive viral markers (p < 0.02).
      The stage of hepatocellular carcinoma at diagnosis was very advanced: in 103 out
      of 179 cases (58%) neoplasia was stage IV, with a stage I diagnosis in only 14
      out of 179 (8%) cases. All the combined (hepatitis B and C virus) cases were
      diagnosed at stage IV, while hepatocellular carcinoma cases in patients with
      negative viral markers were diagnosed at earlier stages (66% stages I-II). Serum
      alpha-fetoprotein levels were above the normal limit (20 ng/mL) in 72% of
      patients; however, only 30% (54/179) had alpha-fetoprotein values > 400 ng/mL.
      These data confirm some previous epidemiological and clinical evidence concerning
      hepatocellular carcinoma (mean age at diagnosis, male/female ratio, severity of
      pre-existing liver disease, frequency of an associated hepatitis C and/or
      hepatitis B virus infection). Data based on such a large population, moreover,
      aid clarification of some still unresolved points such as the utilization of
      alpha-fetoprotein values in diagnosing hepatocellular carcinoma.

PMID- 10638016
TI  - [Viral hepatitis A with atypical course. Clinical, biochemical, and virologic
      study of 7 cases].
AB  - The aim of our study was to assess the clinical, biochemical and virological
      profile of patients with atypical viral hepatitis A (protracted, relapsed and
      cholestatic forms). Five patients with the relapsed form and 2 patients with the
      cholestatic form were studied among 95 patients hospitalized in our Division of
      Infectious Diseases for viral hepatitis A during the years 1988 to 1998. A
      relapse was defined by a decrease in serum alanine transaminase levels > or = 50%
      followed by a > or = 50% increase in the minimal value. The protracted form was
      defined by elevated serum alanine transaminase levels for more than 6 months. The
      cholestatic form was defined by the highest value of bilirubinemia above 15 mg/dL
      or by a persistent jaundice for more than 8 weeks. All 5 of the protracted
      relapsed forms had a biphasic course: the median time between onset and relapse
      of the disease was 8 weeks, and serum aminotransferase activities returned to the
      normal range within an average of 45 weeks after relapse. The two cholestatic
      forms were characterized by a very high level of bilirubinemia (24.58 and 19.03
      mg/dL) and by protracted jaundice with itching (3 and 8 months). All patients
      were tested for hepatitis B and C, Cytomegalovirus and Epstein-Barr virus, with
      negative results. In short, viral hepatitis A is a benign, self-limiting disease
      which usually resolves in a few weeks. In a non-negligible percentage of cases (3
      21%), however, it can assume atypical forms, which are more serious in patients
      with chronic liver diseases.

PMID- 10638017
TI  - Decreased surface antigen density on lymphocytes of elderly humans.
AB  - The aim of our study was to analyze some poorly investigated and controversial
      aspects of senescent lymphocyte phenotype and functions. We examined 100 healthy
      aging individuals, divided into 4 age groups, and 30 young controls, correlating
      lymphocyte responsiveness to mitogenic stimulation with membrane phenotypic
      pattern and surface molecular densities of the main functional lymphoid markers.
      Stability of values in the period of study was established. No age-related
      differences in the parameters evaluated were detected among aging subjects.
      Phytohemagglutinin-induced lymphocyte proliferation was found severely impaired
      (about halved) in all elderly individuals with respect to controls. There was no
      significant difference between elderly group and controls in CD2, CD3, CD4, CD8,
      CD19, CD25 and HLA-DR antigen distribution. CD56 positive cell percentages were
      slightly decreased in the elderly groups. In apparent correlation with reduced
      lymphocyte responsiveness, CD2, CD3, CD4 and CD8 molecular densities, to
      different extents, were found relevantly (about 1 to 3-fold) lower in all aging
      groups than in controls. We could not ascertain if those antigens were poorly
      synthesized, defectively transported to membrane or shed in excess. However, we
      suggest that decreased surface molecular densities of antigens involved in
      functional processes of immune responses may be responsible for an abnormal
      costimulatory pattern during lymphocyte activation, leading to apoptotic rather
      than proliferative signals in a greater proportion of cells than normal.

PMID- 10638018
TI  - [Chlamydia pneumoniae and atherosclerosis].
AB  - There is widespread consensus that atherosclerosis is an inflammatory disease.
      Between possible pathogenetic mechanisms, infective hypothesis has received
      increasing attention. Researches have recently focused their attention on the
      role of Chlamydia pneumoniae, a gram-negative intracellular organism, as
      infection by this bacterium has been demonstrated frequently associated with
      atherosclerosis. This review attempts to analyze and critically evaluate
      available data of the literature about the association between Chlamydia
      pneumoniae and atherosclerosis in order to provide updated elements of judgement
      concerning a possible future revolutionary scenario: the consideration of
      atherosclerosis as an infective disease, susceptible to prevention and treatment
      by means of antimicrobial therapy. More than twenty sero-epidemiological studies
      have found a two-fold or greater risk of cardiovascular events in subjects with
      serological evidence of Chlamydia pneumoniae infection. The organism has been
      identified in over 50% of atherosclerotic plaques examined by various
      histopathological techniques, while it has been only rarely found in normal
      artery tissues; moreover, viable Chlamydia pneumoniae has recently been isolated
      from coronary and carotid atherosclerotic plaques. Several experimental studies
      have shown that the biological properties of Chlamydia pneumoniae can explain its
      potential role in initiating and/or modulating plaque formation. The most
      relevant issue, i.e. the possibility of preventing or slowing progression of the
      disease with antimicrobial treatment, is still unsolved: only data from
      experimental studies on animals and four small intervention trials on humans are
      available, and their encouraging results require confirmation in larger
      prospective studies. In conclusion, while the association between Chlamydia
      pneumoniae and atherosclerosis seems to be established, it is still uncertain
      whether or not the organism plays a causal role in atherosclerosis and its
      complications. It is hoped that the results of wide scale clinical intervention
      trials with antibiotics for the secondary prevention of atherosclerotic diseases
      now in progress will clarify this problem.

PMID- 10638019
TI  - Pathogenetic factors and clinical elements in ascites and hepatorenal syndrome
      during liver cirrhosis.
AB  - Ascites is the most frequent major complication of liver cirrhosis. Even if a
      significant decrease in renal clearances may be observed in the first stages of
      chronic active hepatitis, true renal impairment, often with the typical signs of
      hepatorenal syndrome, only occurs in patients with ascites, especially when tense
      and refractory. Experimental and clinical data suggest the presence of primary
      sodium and water retention, perhaps as a consequence of an increase in
      intrahepatic hydrostatic pressure. The abnormal sodium retention leads to plasma
      volume expansion, followed by decreased peripheral vascular resistances and
      increased cardiac output. This second stage concords with the peripheral arterial
      vasodilation theory, characterized by an increase in total blood volume, but with
      a decrease in effective arterial blood volume. This discrepancy leads to the
      activation of sympathetic nervous and renin-angiotensin-aldosterone systems. This
      activation, while protective against splanchnic and systemic vasodilation,
      provoked by the increased availability of nitric oxide and other vasodilating
      substances, induces renal vasoconstriction. This phenomenon can be considered as
      the basis of the progressive renal failure that leads to hepatorenal syndrome,
      favored by progressive exhaustion of the renal autacoid vasodilating substances.
      The first therapeutic approach to ascites is sequential and based on diuretic
      administration. Subsequently, paracentesis with albumin infusion is carried out,
      as well as transjugular intrahepatic portosystemic shunting, surgical
      portosystemic shunting, and liver transplantation: these procedures are essential
      for the treatment of hepatorenal syndrome.

PMID- 10638020
TI  - Clinical relevance of serum cryoglobulins in hemophilic patients with hepatitis C
      virus infection.
AB  - Twenty-four hemophilic patients positive for hepatitis C virus were evaluated for
      the presence of serum cryoglobulins and associated symptoms. Eight (33.3%) of
      them had serum cryoglobulins (type II mixed cryoglobulinemia in all cases). The
      average time lapse between infection and appearance of serum cryoglobulins was
      14.4 years (range 7-22 years). Two (25%) out of the 8 patients presented
      symptoms: one had systemic vasculitis, the other mild purpura. Hemophiliacs are a
      particularly suitable model for studying cryoglobulinemia in patients with
      hepatitis C virus infection since the onset of the infection is known and there
      is a long-term follow-up period.

PMID- 10638021
TI  - The relationship between splenic marginal zone B-cell lymphoma and chronic liver
      disease associated with hepatitis C virus infection.
AB  - An etiologically important role has been suggested for hepatitis C virus
      infection in the development of low-grade B-cell non-Hodgkin's lymphoma, such as
      splenic marginal zone B-cell lymphoma. We present a study of 3 patients with
      splenic marginal zone B-cell lymphoma and chronic hepatitis C, and describe
      clinical, histologic, and immunohistochemical features and the response to
      therapy in these cases. All 3 patients underwent splenectomy, polychemotherapy
      and alpha-interferon therapy. The first patient achieved complete remission; the
      second died of hepatic failure and anasarca 3 months after admission; as this
      writing, the third remains in complete remission 4.5 years after diagnosis. In
      the second patient, a long latency period of chronic hepatitis C virus infection
      was observed. Our data indicate that when early detection of the disease is
      possible, splenic marginal zone B-cell lymphoma has a relatively favorable
      prognosis. Our results could furthermore suggest an etiologic role for hepatitis
      C virus infection in the development of splenic B-cell lymphoma through multistep
      cooperating events. A fuller understanding of the virus-related mechanisms of
      lymphoproliferation could contribute significantly to the development of new
      therapeutic strategies.

PMID- 10638022
TI  - [Ascites as preeminent manifestation of primary hypothyroidism. Clinical case].
AB  - The case of an adult male who came to clinical evaluation because of an abundant
      ascites without any obvious cardiac or hepatic explanation is reported. The
      exudative characteristics of the ascitic fluid, the elevated serum-ascites
      albumin gradient, some electrocardiographic anomalies, hypercholesterolemia and a
      slight macrocytic anemia prompted a clinical diagnosis of probable
      hypothyroidism. This was also due to an anamnesis of remote antithyroid
      radiometabolic treatment. The serum hormone levels and the ultrasonogram of the
      gland confirmed the diagnosis. Hormonal substitutive therapy led to thyroid
      stimulating hormone normalization and to a progressive decrease of the ascites,
      that eventually disappeared. This case, which involves a rare manifestation of
      hypothyroidism, underscores the need to consider thyroid diseases in the
      differential diagnosis of ascites and to include thyroid-stimulating hormone
      dosage among the laboratory tests to be ordered when suspicious clinical or
      biochemical data are present (mainly, the exudative aspect of the ascites).

PMID- 10638023
TI  - Primary adrenal non-Hodgkin's lymphoma associated with autoimmune hemolytic
      anemia: a case diagnosed by ultrasound-guided fine needle biopsy.
AB  - Primary localized adrenal non-Hodgkin's lymphomas are extremely rare. Only 28
      observations have been reported so far, all with a very poor prognosis: a median
      survival of 12.5 weeks. The authors report the case of a 78-year-old male with
      primary non-Hodgkin's lymphoma of the right adrenal gland. Disease onset was
      characterized by severe autoimmune hemolytic anemia, and diagnosis was made by
      echo-guided biopsy. The patient was admitted to our Department with severe
      autoimmune hemolytic anemia; the hemoglobin value was 6.5 g/dL and both indirect
      and direct Coombs' tests were positive. Steroid treatment with methylprednisolone
      2 mg/kg/day did not improve the hemolytic process. Abdominal ultrasound
      examination disclosed a right hypoechogenic suprarenal mass of 10 x 9 cm; imaging
      techniques such as computed tomography and magnetic resonance imaging were not
      useful in the etiologic diagnosis of the right suprarenal mass; fine needle
      aspiration and tissue-core biopsy revealed low-grade non-Hodgkin's lymphoma.
      Staging procedures, including clinical examination, total body computed
      tomography scan, bone-marrow biopsy, gallium scan, abdominal magnetic resonance
      imaging, did not disclose other sites of involvement and strongly supported a
      diagnosis of primary non-Hodgkin's lymphoma of the right adrenal gland. Hormone
      assays were within normal limits. The patient was treated with chemotherapy,
      cyclophosphamide-vincristine-prednisone regimen, with good regression of the
      adrenal mass after 6 courses, and normalization of hemoglobin level and
      negativity of Coombs' tests. The importance of this case lies in the very rare
      occurrence of this disease, its association with autoimmune hemolytic anemia, the
      diagnosis made by ultrasound-guided biopsy, and good response to treatment with
      respect to cases reported in the literature. The patient remains in clinical
      remission 12 months after onset of the disease.

PMID- 10638024
TI  - [Environmental and animal hygiene--an indispensable subject for veterinary
      education?].
AB  - Based on conference reports, publications, and personal experiences in the field
      of veterinary environmental hygiene in Germany and abroad, the question is
      discussed whether the subjects environmental and animal hygiene have to be
      considered as indispensable subjects for the curricula in veterinary education or
      only play a secondary role as a fringe area of veterinary medicine. The analysis
      and evaluation of the relevant literature have shown that this subject has gained
      an extraordinary significance for science and practice during the last 4-5
      decades. Due to its close interconnections with related fields of science like
      agriculture, human medicine, biology, ecology, engineering sciences and economics
      the veterinary environmental and animal hygiene has reached such a high standing
      that it is now an indispensable component of veterinary education in Germany.

PMID- 10638025
TI  - [The impact of suboptimal animal husbandry practices on animal health and
      economic profitability using the example of tie-in and loose housing system of
      dairy cattle].
AB  - In this study of two common housing systems of dairy cattle, the tie-in system
      and the loose housing system, check lists were created to evaluate whether these
      husbandry systems fulfill the needs of the animals. Furthermore, a combination of
      questionnaires and interviews were employed to assess the qualification of dairy
      stockmen to handle the animals. These checklists should provide a useful tool for
      those persons involved in the examination of husbandry systems, both by providing
      a written record and by providing a clear outline of all the points that need to
      be covered during such an examination. The study, done in the way of an
      explorative analysis of data, included 22 farms (14 with tie-in systems and 8
      with loose housing systems) and a total of 802 animals. With regard to the
      economic effects of poor management and housing conditions, several interesting
      and statistically noteworthy correlations emerged. TIE-IN SYSTEM: Positive
      correlations were found between severity of behavioural abnormalities (behave)and
      number of injuries due to husbandry system (injury); injury and number of
      inseminations per pregnancy (preg); injury and age of cow (age); preg and cell
      count of milk (cell). Negative correlations were found between cell and milk
      yield (milk) as well as between the qualification of stockmen (equal) and
      inappropriate technical design of the housing environment (tech). LOOSE HOUSING
      SYSTEM: Positive correlations existed between behave and injury, and between tech
      and injury. Negative correlations were found between milk and cell, equal and
      tech, and milk and age. The magnitudes of these correlations were quantified by
      means of linear regression analysis. Comparison of the two husbandry systems
      revealed that while the loose housing systems is associated with significantly
      more problems related to tech, it is associated with significantly fewer problems
      related to injury. It seems that in this housing system cows are better able to
      avoid injury since they are allowed to move freely. No significant differences in
      behavior were found between the two husbandry systems. The present study shows
      the importance of proper technical design of housing environments, both in
      relation to animal welfare and to economic profitability.

PMID- 10638026
TI  - [Structures and possibilities of herd management on the example of respiratory
      enzootic infection of calves].
AB  - With the keeping of cattle in bigger herds problems arise, which require a
      modified veterinary approach. In stead of and in addition to the treatment of
      individual animals improvement of hygiene, intensification of prophylaxis, fast
      recognition (herd diagnostics) and interregional comparability have to be
      established. Beside the conventional field veterinarian, who is consulted on
      request primarily for the treatment of single animals, specialists in team
      practices as an alternative, permanently employed veterinarians or firm contracts
      with a health service up to integrated herd control are thinkable. The
      clarification and control of infectious diseases of the respiratory tract in
      cattle operations require an exact analysis of the environmental conditions and
      the identification of etiologic agents. Special attention has to be drawn to the
      evaluation of the barn climate and the respective taking of samples concerning
      the actual disease situation.

PMID- 10638027
TI  - [The use of molecular fingerprinting techniques in environmental hygiene].
AB  - The analysis of epidemiological pathways for the transmission of pathogens via
      the environment is a fundamental task in the field of environmental hygiene. The
      task demands for a precise differentiation between isolates. This can be done by
      sophisticated techniques for differentiation which are based on phenotypic or
      genotypic features. The fingerprinting of DNA is a powerful tool in this context.
      A survey is given for different kinds of RFLP-analysis, plasmid profiling, and
      PCR fingerprinting as well regarding their principles, methodical variations and
      published applications. Notable limitations of the applications are also
      discussed.

PMID- 10638028
TI  - [Reduction efficiencies of a biofilter and a bio-scrubber as bio-aerosols in two
      piggeries].
AB  - Biofilters and bioscrubbers are ultimate tools to control odour emissions from
      animal houses in pig and poultry production. Little is known about the efficiency
      of these devices to remove airborne particulate pollutants such as dust,
      microorganisms and endotoxins from the exhaust air of animal houses. Preliminary
      results of a one year field campaign in two piggeries show that the biofilter
      reduces the number of particles in the exhaust air by 79 to 96%. The efficiency
      of the bioscrubber was 22% only. The biofilter reduced the amount of mesophilic
      bacteria by 11% and 71%, respectively, the amount of thermotolerant fungi by 71%.
      The concentration of endotoxin and mesophilic fungi in the clean air after the
      bioscrubber was 3.8 times resp. 2.7 times higher than in the air of the piggery.
      The washing water which is regularly recirculated in both systems was highly
      contaminated with varying amounts of air contaminants. It seems that the quality
      of the washing water distinctly influences the reduction efficiency of both
      systems.

PMID- 10638029
TI  - [Effect of aerobic fermentation on the survival of Salmonella typhimurium (DT
      104) and Escherichia coli in swine liquid manure].
AB  - In this study aerobic-thermophilic fermentation of untreated liquid pig manure
      was examined for the potential of inactivating pathogenic microorganisms. As
      microbial tracer organisms, Salmonella typhimurium DT 104 and Escherichia coli
      were used. An effective reduction of survival of these microorganisms could be
      demonstrated by aerobic fermentation at temperatures of 50 degrees C for at least
      3 h. However, these optimal process conditions without the need of additional
      heating, can only be achieved by microbial substrate reduction. In contrast to
      the impact of temperature on hygienization processes, alteration of the pH value
      which occurs during fermentation had no or little influence on the tenacity of
      the tracer bacteria. Even under mesophilic reaction conditions the influence of
      the pH value was not measurable. A technical realisation of such an aerobic
      thermophilic fermentation process for prophylactic disinfection is questionable
      since a large technical expenditure is necessary to control ammonia emission.
      Effective partial reduction of nitrogen, phosphate, and free carbon in liquid
      manure requires retention times of at least 48 h. However, thermophilic reaction
      conditions may ensure an effective hygienization of the final fermentation
      products.

PMID- 10638030
TI  - [Nature and frequency of the existence of mold fungi in garbage cans for
      biological waste and the resultant airborne spore pollution].
AB  - In organic waste, numerous mold fungi and other microorganisms develop sometimes
      within a few hours only which decompose the organic material already in the
      collecting containers generating heat and odor. With regard to the emission of
      mold fungus spores out of garbage cans for bio-waste and the potential
      environmental-hygienic danger connected with it, considerable worries have been
      expressed recently. A wide spectrum of mold fungi can be found in bio-waste in
      strongly varying concentrations. No noticeable difference could be ascertained
      between the settlement structure areas and the cities respectively as to the
      fungus concentration in the bio-waste substrate. A. fumigatus and A. niger can be
      recommended as leading spores for the behavior of the total concentration of
      fungi in the bio-waste due to their frequency of detection and their seasonal
      dynamism. The intensity of the air spore pollution through emission of mold
      fungus spores correlates closely with the climatic conditions, such as variations
      of temperature, relative humidity and solar radiation. The airborne release of
      mold fungus spores out of garbage cans for bio-waste and the formation of a
      respective exposure connected with it is judged as harmless for healthy persons.
      Risk patients and persons having a weakened immune system or assumed to have such
      a one due to an existent basic illness and/or other reasons should avoid any
      handling of bio-waste as well as any other waste if possible.

PMID- 10638031
TI  - [Analysis of the influence of temperature on the stability of sex steroids in cow
      feces].
AB  - Up to the present natural and synthetic steroids have only rarely been considered
      a cause of disturbances of sexual behavior and anomalies of sex organs. The
      increasing environmental contamination with chemicals showing estrogenic effects
      underlines the importance of further investigations in that matter. Therefore,
      the concentrations of estrogens and progesterone in the faeces of cattle were
      examined over a 13 weeks period. The values obtained are presented as equivalents
      of the standard substances estrone and 4-pregnene-20 beta-ol-3-one. The samples
      were stored in a refrigerator or incubator at temperatures of 5 degrees C and 30
      degrees C, respectively, and the investigations were carried out by using an
      enzyme-immunoassay. Estrogen and progesterone concentrations decreased more
      rapidly when incubation was performed at 30 degrees C as compared to storage at 5
      degrees C, and estrogen values declined more slowly than those of progesterone.
      When keeping the samples at 5 degrees C the estrogen concentrations decreased to
      below the basal values only beyond the eleventh week of storage. In contrast,
      comparable concentrations were already obtained during the third week of the
      experiment if the samples were stored at 30 degrees C. Progesterone levels
      decreased to below the basal values during the fourth week of storage at 5
      degrees C and during the second week at 30 degrees C.

PMID- 10638032
TI  - Serum antibodies against particular antigens of Borrelia burgdorferi sensu
      stricto and their potential in the diagnosis of canine Lyme borreliosis.
AB  - Dog sera (n = 118) were tested for antibodies recognizing Borrelia (B.)
      burgdorferi sensu stricto strain B31 (ATCC 35210) antigens. In total, 18 of the
      dog sera gave positive results in a whole cell sonicate ELISA (WCS ELISA). These
      positive sera were further evaluated by immunoblot assay, utilizing a whole
      bacterial lysate as antigens. 94.4% (17 of 18) of the dog sera reacted with
      immunodominant antigens at 20-22 kDa (protein C, pC), 31 kDa (outer surface
      protein A, OspA), 34 kDa (outer surface protein B, OspB), 41 kDa (flagellin), 60
      kDa ("common antigen"), and/or 100 kDa (presumably p100). Sera recognizing pC (20
      22 kDa) and antigens > 94 kDa always detected the highest number of antigen
      bands, indicating the specificity of those antigens in serological diagnosis. The
      results clearly demonstrate that the WCS ELISA is a useful tool for testing sera
      of dogs for antibodies against B. burgdorferi. However, positive results should
      be confirmed by immunoblot, using WCS as antigen. According to the presented
      data, we recommend criteria for B. burgdorferi immunoblots using dog sera as
      follows: sera have to be considered as positive if they detect the 41 kDa
      flagellin, and two of the 5 immunodominant antigens, namely > 94 kDa (presumably
      p100), 60 kDa ("common antigen"), 34 kDa and 29-31 kDa (OspB and OspA,
      respectively) and 20-22 kDa (pC). If sera only recognize the 41 kDa flagellin,
      this result is equivocal, requiring testing a second serum sample 4 to 8 weeks
      later.

PMID- 10638033
TI  - [Rumen fermentation and digestibility of nutrients studied by the addition of Ca
      soaps of palm oil fatty acids and their analogous fatty acids in the sheep
      model].
AB  - The ruminally fistulated sheep was used as a model to study the effects of fat
      supplementation (Ca-soaps and free long chain fatty acids from palm oil) on rumen
      physiology and digestibility of the nutrients. The animals were fed with a
      typical ration of hay and concentrate supplying nutrients according to
      maintenance levels. The following results should be pointed out: The addition of
      free fatty acids and their Ca-soaps induced a retarded recovery of postprandially
      decreased pH-values in ruminal fluid. This retardation was more pronounced after
      addition of free long chain fatty acids than with their Ca-soap-analogous acids.
      Compared to the control, the concentration of short chain fatty acids was
      depressed by fat addition in the period 2 hours after feed intake. The release of
      ammonia in the first period after feed intake was reduced by fat addition. A lack
      of synchronity could be observed in this post-prandial period in ruminal fluid
      between concentration of short chain fatty acids and ammonia. This effect was
      most obvious with supplementation of unprotected fatty acids. This might be one
      reason for the better tolerance of Ca soaps from palm oil fatty acids. Formation
      of hydrides, branched chains and transforms proceeds more effectively with free
      fatty acids than with their analogous forms of Ca-soaps. The well-known effect of
      depression of digestibility of nutrients due to fat supplementation was--under
      present conditions--quite low. This might be different in lactating dairy cows
      with higher levels of feed intake. With high feed intake, passage time is
      reduced. This will affect digestibility and interactions with fat
      supplementation.

PMID- 10638034
TI  - Lupus for the non-rheumatologist.

PMID- 10638035
TI  - Family intervention in psychosis: who needs it?

PMID- 10638036
TI  - Work outcomes in family-aided assertive community treatment: vocational
      rehabilitation for persons with psychotic disorders.

PMID- 10638037
TI  - [Family psychoeducational treatment in schizophrenia: love for foreigners or
      application of evidence-based interventions?].

PMID- 10638038
TI  - [Cost of psychiatric patients by disability type].
AB  - OBJECTIVE: The study of the relation between treatment costs and disability of
      psychiatric patient groups. DESIGN: Perspective assessment of costs and
      disability of 1371 adult psychiatric patients in charge at two Operative
      Psychiatric Units (OPU), followed during an average period of 9 months. Data are
      related to all OPU's psychiatric services, including ambulatory, full or half
      residential and psychiatric departments of acute hospital services. SETTING: OPUs
      of Magenta (MI) and Desio (MI). METHOD: The disability level has been measured by
      Health of the Nation Outcome Scales (HoNOS) filled in at the inclusion of the
      patient in the study and every three-months on average thereafter. Besides other
      HoNOSs have been filled in both at admission and discharge from psychiatric
      departments of acute hospitals, Residential Centres of psychiatric Therapies and
      Rehabilitation and Guarded Communities. All patients have been grouped using the
      main psychiatric diagnosis (first digit ICD-10) and the maximum disability level
      shown in the whole period of the study. Direct costs of publicly financed
      psychiatric services have only been considered. Their attribution to each patient
      has been made applying standard costs or tariffs (diagnostic procedures) to the
      data perspectively collected by the regional Register and a purposely designed
      protocol. RESULTS: Total cost of 1371 patients has been 9771.1 million lire with
      a cost per patient of 7,127,000 lire (sd 19,499,000) and a cost per "day in
      charge" of 27,172 lire (sd 68,358). The cost per day has been found unrelated
      with the length of observed time frame. At the inclusion the mean level of
      disability has been 4.26 points (sd 3.73) and 3.19 points (sd 3.26) at the end of
      the study. Its value, measured at maximum level shown by each problem in the
      whole period of study, has been 6.00 points (sd 4.64). Disability and treatment
      cost of each patient did result directly related (r = 0.626, p = 0.0001). All
      patients have been grouped in 12 classes with a significant (p = 0.0001) overall
      difference on both their disability level and treatment cost. CONCLUSIONS: All
      adult psychiatric patients could be grouped in disability related classes which
      sometimes have also a different treatment cost. A study on a greater number of
      patients is needed to confirm these results. It may also provide a more reliable
      basis for a new financing system of psychiatric services.

PMID- 10638039
TI  - [Mental disorder and the use of public psychiatric services in the foreign
      population in the Canton Ticino region].
AB  - OBJECTIVE: To verify if the foreign population resident in the Canton Ticino,
      differs in the use of public psychiatric services and in the type of mental
      disorder presented, with respect to the Swiss population. DESIGN: Research
      completed on subjects Swiss and foreign, over 19 years old, and resident in the
      Canton Ticino, who during 1995 spent at least one day admitted at the psychiatric
      hospital or had at least one contact with the out-patient services. SETTING:
      Public psychiatric services of the Canton's sociopsychiatric organisation. MAIN
      OUTCOME MEASURES: For the Swiss, Italian and other non-Italian foreigners, the
      standardised annual rates of in- and outpatient prevalence and first admission
      and first outpatient contact were calculated, both totals and per diagnostic
      categories (ICD-10). RESULTS: The group of non-Italian foreigners presents higher
      total standardised annual rates of in-patient prevalence and first admission and
      above all, of first admission, with respect to the Swiss and Italian groups;
      furthermore, with respect to the other two groups it presents higher first
      admission rates for the schizophrenic syndromes (F2) in men and for mental
      disorders due to psychoactive substances (F1) in women. Whereas for first
      outpatient contacts the other foreigners present higher rates in neurotic
      syndromes (F4) in men, and affective syndromes (F3) in women. CONCLUSIONS: The
      results seem to confirm the presence of higher levels of mental disorder in non
      Italian foreigners, above all for certain nationalities, with respect to Swiss
      and Italians. It is possible that the presence of a substantial offer of
      psychiatric services from the private sector may have caused an underestimation
      of the actual rate of mental disorder above all in the Swiss group and to a minor
      extent in that of the Italians.

PMID- 10638041
TI  - [Epidemiology of pancreatic cancer].

PMID- 10638040
TI  - A pharmacoeconomic evaluation of major depressive disorder (Italy).
AB  - OBJECTIVE: To determine the most cost-effective oral therapy for the treatment of
      Major Depressive Disorder (MDD) in Italy. METHOD: We conducted a pharmacoeconomic
      evaluation based on a decision analytic model that examined the treatment of
      major depressive disorder (MDD) in Italy. The analysis compared the serotonin
      norepinephrine reuptake inhibitor (SNRI), venlafaxine extended-release
      (venlafaxine XR), to selective serotonin reuptake inhibitors (SSRIs) and
      tricyclic antidepressants (TCAs). A meta-analysis was performed to determine the
      clinical rates of success. The meta-analytic rates were applied to the decision
      analytic model to calculate the expected cost and expected outcomes for each anti
      depressant comparator. Cost-effectiveness was determined using the expected
      values for both a successful outcome, and a composite measure of outcome termed
      'symptom-free days'. A policy analysis was conducted to estimate the financial
      impact to the Servizio Sanitario Nazionale (SSN). RESULTS: Treatment of MDD with
      venlafaxine XR yielded the highest overall efficacy rates for outpatients (73.7%)
      versus SSRIs (61.4%) and TCAs (59.3%), and inpatients (62.3%) versus SSRIs
      (58.6%) and TCAs (58.2%). Venlafaxine XR had the lowest dropout rates due to lack
      of efficacy (4.8%) versus SSRIs (8.4%) and TCAs (6.8%), and adverse drug
      reactions (10.9%) versus SSRIs (17.4%) and TCAs (23.1%). Initiating treatment of
      MDD with venlafaxine XR yielded the lowest expected cost for outpatients and for
      inpatients. The total resulting savings for the SSN at a 5% venlafaxine XR
      utilization was estimated between L 963 million and L 3,210 million. CONCLUSION:
      This study confirms that venlafaxine XR is generally a cost-effective treatment
      of MDD. Additionally, the results of this investigation suggest that increased
      utilization of venlafaxine XR will favorably impact the SSN.

PMID- 10638042
TI  - [Molecular genetics of human pancreatic cancer].

PMID- 10638043
TI  - [Premalignant conditions, presentation forms, and clinical profile of pancreatic
      carcinoma].

PMID- 10638044
TI  - [The laboratory in the diagnosis of pancreatic cancer].

PMID- 10638045
TI  - [Current role of imaging techniques in the study of pancreatic carcinoma].

PMID- 10638046
TI  - [Surgical treatment of pancreatic carcinoma].

PMID- 10638047
TI  - [Adjuvant and palliative treatment of pancreatic cancer].

PMID- 10638048
TI  - [Guidelines for the diagnosis and treatment of pancreatic cancer].

PMID- 10638050
TI  - Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: a case example in
      developmental disabilities.
AB  - Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency is a rare autosomal
      recessive disorder with varied expression, from severe hypoglycemia and possible
      sudden infant death to neurosensory deficits secondary to the acute onset. The
      neurosensory deficits can include clinical features such as seizure disorders,
      mental retardation, neuropathy, and retinopathy. The basic defect is the lack of
      the LCHAD enzyme in the liver, which is necessary for fatty acid metabolism. The
      condition is usually precipitated by infection and dehydration. A case example of
      a preschooler with LCHAD deficiency is presented to show the complexity of this
      disorder and resultant developmental disabilities. Implications for nursing
      practice, education, and research are discussed in relation to the needs of
      families with complex, developmental disabilities.

PMID- 10638049
TI  - Key issues in chronic illness research: lessons from the study of children with
      diabetes.
AB  - Issues and controversies in chronic illness research are discussed, with data and
      examples from a program of research dealing with children and adolescents with
      diabetes. The key differences that demand consideration include prevalence,
      developmental issues, measurement, cultural issues, the lack of viable models,
      use of controls, the importance of the family, and ethical concerns.

PMID- 10638051
TI  - Out of their element: fathers of children who are "not the same".
AB  - The purpose of this research was to ascertain the meaning of fathering for
      fathers of children with congenital anomalies. The human becoming theory was the
      theoretical perspective for this descriptive-exploratory study. Findings showed
      that fathering for these participants is a desire to grasp the situation, mingled
      with disturbing feelings, while facing one's limits and gives rise to comforting
      views. Comfortable-uncomfortable ways of being with others emerge as fathering
      shifts one from the familiar to the unfamiliar, surfacing the joy-sorrow of the
      always-changing "now" and the unpredictable "not yet." Implications for further
      research and practice are also discussed.

PMID- 10638052
TI  - Pain in hospitalized children: pediatric nurses' beliefs and practices.
AB  - A descriptive design was used to gather information regarding nurses' beliefs and
      documentation practices related to pain assessment and management in children.
      Pediatric nurses (n = 260) from eight hospital units completed a child and pain
      survey. Nurses' pain-related documentations on children (n = 153) were also
      examined. Results showed inconsistency between what nurses believe about pain
      assessment and management and their documentation of practice. Nurses believed
      that assessment is the first step toward alleviating pain in children. However,
      it was not evident in their documentations that nurses used developmentally
      appropriate tools for assessment or for evaluation of children's responses to
      pain management strategies.

PMID- 10638053
TI  - Children's fears.
AB  - The purpose of this article is to provide nurses with a comprehensive literature
      review of children's fears and to offer interventions that help children cope
      with fear. Children's normal fear development and the importance of developmental
      considerations in the assessment, diagnosis, and treatment of fear are also
      explored. A preventive model based on the work of Robinson and colleagues
      highlights several approaches to assist children in dealing with fear. This model
      provides consultation and counseling strategies that the nurse may use to help
      children develop control, self-worth, and security. This model may also be used
      to explore areas of normative developmental fears.

PMID- 10638054
TI  - Enhancing leadership abilities for pediatric nurses: strategies for the 21st
      century.

PMID- 10638055
TI  - Nursing activities and outcomes of care in the assessment, management, and
      documentation of children's pain.
AB  - This study describes how assessment and documentation of children's acute
      postoperative pain is managed by nurses in university hospitals in Finland. A
      survey was conducted of 303 nurses working in children's wards of university
      affiliated hospitals, and at the same time a retrospective chart review of 50
      consecutive cases of operation of acute appendicitis was carried out. Charts were
      analyzed by content analysis, and the results of the survey are reported with
      percentage distribution and nonparametric statistical calculations. The results
      indicate that nurses assess pain mainly by observing the child's behavior and
      changes in physiology. Pain measurement instruments are rarely used, and nurses
      do not recognize them. The documentation of pain care is unsystematic and does
      not support the continuity of care. There is a clear need for development of
      assessment and documentation practices in the studied hospitals. Future research
      should look at the postoperative care of pain at home as well as care in non
      university-affiliated hospitals.

PMID- 10638056
TI  - How shall we treat the children in the 21st century?

PMID- 10638057
TI  - Tanner VI.

PMID- 10638058
TI  - Imipramine in burn patients.

PMID- 10638059
TI  - Hallucinations in nonpsychotic children.

PMID- 10638060
TI  - Reasons for adolescent suicide attempts.

PMID- 10638061
TI  - More on the DICA.

PMID- 10638062
TI  - Telepsychiatric consultation for ADHD in the primary care setting.

PMID- 10638063
TI  - Priapism associated with venlafaxine use.

PMID- 10638064
TI  - Introduction--research psychiatric diagnostic interviews for children and
      adolescents.

PMID- 10638065
TI  - NIMH Diagnostic Interview Schedule for Children Version IV (NIMH DISC-IV):
      description, differences from previous versions, and reliability of some common
      diagnoses.
AB  - OBJECTIVE: To describe the National Institute of Mental Health Diagnostic
      Interview Schedule for Children Version IV (NIMH DISC-IV) and how it differs from
      earlier versions of the interview. The NIMH DISC-IV is a highly structured
      diagnostic interview, designed to assess more than 30 psychiatric disorders
      occurring in children and adolescents, and can be administered by "lay"
      interviewers after a minimal training period. The interview is available in both
      English and Spanish versions. METHOD: An editorial board was established in 1992
      to guide DISC development and ensure that a standard version of the instrument is
      maintained. Preliminary reliability and acceptability results of the NIMH DISC-IV
      in a clinical sample of 84 parents and 82 children (aged 9-17 years) drawn from
      outpatient child and adolescent psychiatric clinics at 3 sites are presented.
      Results of the previous version in a community sample are reviewed. RESULTS:
      Despite its greater length and complexity, the NIMH DISC-IV compares favorably
      with earlier versions. Alternative versions of the interview are in development
      (the Present State DISC, the Teacher DISC, the Quick DISC, the Voice DISC).
      CONCLUSIONS: The NIMH DISC is an acceptable, inexpensive, and convenient
      instrument for ascertaining a comprehensive range of child and adolescent
      diagnoses.

PMID- 10638066
TI  - The Child and Adolescent Psychiatric Assessment (CAPA).
AB  - OBJECTIVE: To describe the Child and Adolescent Psychiatric Assessment (CAPA).
      The base interview covers the age range from 9 to 17 years. METHOD: The interview
      glossary that provides detailed operational definitions of symptoms and severity
      ratings is described, and psychometric data and further developments of the
      interview are presented. RESULTS: Across 5,962 parent-child interviews, the core
      sections of the CAPA (psychiatric symptoms, functional impairment, demographics,
      family structure and functioning) took on average 59 minutes for children and 66
      minutes for parents. Test-retest reliability for diagnoses ranged from kappa =
      0.55 for conduct disorder (CD) to kappa = 1.0 for substance abuse/dependence.
      Validity as judged by 10 different criteria was good. Developments of the CAPA
      include a shorter "gateway" version using core symptoms as screen items, a
      Spanish version, and versions for twin studies, use with young adults (YAPA), and
      preschool-age children (PAPA). CONCLUSIONS: There is a place in both research and
      clinical settings for a rigorously operationalized interview (such as the CAPA)
      that focuses on ensuring that respondents understand what is being asked and on
      clearly defining levels of symptom severity and functional impairment.

PMID- 10638067
TI  - Historical development and present status of the schedule for affective disorders
      and schizophrenia for school-age children (K-SADS).
AB  - OBJECTIVES: To review the historical development, reliability, validity,
      administrative characteristics, and uses of the Schedule for Affective Disorders
      and Schizophrenia for School-Age Children (K-SADS). METHOD: The various past and
      current K-SADS editions were reviewed as was the literature describing their
      uses. RESULTS: Three DSM-IV-compatible versions of the K-SADS are in general use,
      1 present state (K-SADS-P IVR) and 2 epidemiological editions (K-SADS-E and K
      SADS-P/L). All 3 interviews provide a current diagnostic assessment. The K-SADS-P
      IVR also evaluates the worst past episode during the preceding year, while the K
      SADS-E and -P/L provide a lifetime diagnosis. The K-SADS-E and -P/L are primarily
      categorical diagnostic interviews while the K-SADS-P IVR, which also measures
      symptom severity, can be used to monitor treatment response. All editions have
      good rater reliability. However, the quality of the validating data set for the K
      SADS is limiting. CONCLUSIONS: The K-SADS is a viable interview schedule to
      assess current, past, and lifetime diagnostic status in children and adolescents.
      It is has the potential to further aide in the validation of psychiatric
      disorders. The substantial rater training required for reliable administration
      and the need for more validation work remain its drawbacks.

PMID- 10638068
TI  - Diagnostic interview for children and adolescents (DICA)
AB  - OBJECTIVE: To describe the evolution of the Diagnostic Interview for Children and
      Adolescents (DICA) as well as the goals of the instrument and the issues
      surrounding its use. METHOD: Administration procedures, psychometric properties,
      and comparisons with other measures are reviewed. RESULTS: The DICA, once
      considered a structured interview, can now be used in a semistructured format. It
      displays good reliability and works well with younger children. CONCLUSION: The
      DICA is a useful measure for both research and clinical settings, and it provides
      a reliable tool for assessing psychiatric information in children and
      adolescents.

PMID- 10638069
TI  - Interview schedule for children and adolescents (ISCA).
AB  - OBJECTIVE: To describe the development, use, and psychometric properties of the
      semistructured, symptom-oriented Interview Schedule for Children and Adolescents
      (ISCA) and its versions suitable for reevaluation. METHOD: Data are summarized on
      the reliability, construct validity, and predictive validity of symptom ratings
      and resultant diagnoses, and information regarding the feasibility of a version
      of the ISCA for young adult subjects is presented. RESULTS: The evidence suggests
      that these instruments yield reliable symptom ratings and diagnoses relevant to a
      wide range of syndromes and diagnoses over time and that the ISCA is useful with
      psychiatric and pediatric medical populations. CONCLUSIONS: The ISCA and its
      follow-up versions are useful clinical tools in research focusing on
      developmental psychopathology.

PMID- 10638070
TI  - Children's Interview for Psychiatric Syndromes (ChIPS).
AB  - OBJECTIVE: To describe the development and summarize the psychometric properties
      of the Children's Interview for Psychiatric Syndromes (ChIPS). METHOD: ChIPS is a
      highly structured interview designed for use by trained lay interviewers in
      children aged 6-18 years. It screens for 20 Axis I disorders as well as
      psychosocial stressors. Questions use simple language and short sentence
      structure to enhance subject comprehension and cooperation. The interview is
      based on DSM-IV and results are presented in a concise, easy-to-interpret manner.
      There are both child and parent versions. The psychometric properties of each
      version were studied. RESULTS: A series of 5 studies has demonstrated the
      validity of the DSM-III, DSM-III-R, and DSM-IV versions of the ChIPS as well as
      the validity of the P-ChIPS (parent version). Administration time is relatively
      brief, averaging 49 minutes for inpatients, 30 minutes for outpatients, and 21
      minutes for a community-based sample. CONCLUSIONS: ChIPS can be used as a
      screening instrument to maximize a clinician's efficiency, as a diagnostic
      instrument in clinical research, and as a training instrument to help mental
      health professionals learn psychiatric diagnosis. It can also be used in
      epidemiological research.

PMID- 10638071
TI  - The Dominic-R: a pictorial interview for 6- to 11-year-old children.
AB  - OBJECTIVE: To review the Dominic-R and the Terry questionnaires, respectively,
      for white and African-American children, both DSM-III-R-based, and more recent
      DSM-IV-based computerized versions. METHOD: Five papers describing the
      development, content, validation studies, and establishment of the diagnostic
      cutpoints of these instruments are reviewed. The instruments are pictorial, fully
      structured, and designed to assess mental disorders in children 6 to 11 years of
      age. Symptom descriptions complement the visual stimulus, providing better
      information-processing than visual or auditory stimuli alone. Cognitive
      immaturity of young children bars frequency, duration, and age-of-onset
      measurements, restricting correspondence with DSM criteria. DSM-IV (computerized
      versions) and DSM-III-R (paper versions) disorders being assessed include
      specific (simple) phobias, separation anxiety, generalized anxiety (overanxious),
      depression/dysthymia, attention-deficit hyperactivity, oppositional defiant, and
      conduct disorder. RESULTS: Test-retest reliability of symptoms and symptom scores
      and criterion validity against clinical judgment support the visual-auditory
      combination of stimuli to assess child mental health. CONCLUSION: Intended for
      clinical, epidemiological, and screening purposes, these instruments are short
      and simple. Although it only approximates DSM-III-R and DSM-IV criteria, the
      pictorial format permits young children to be reliable informants about their
      mental health.

PMID- 10638072
TI  - Pictorial Instrument for Children and Adolescents (PICA-III-R).
AB  - OBJECTIVE: The Pictorial Instrument for Children and Adolescents (PICA-III-R) is
      presented as part of a comprehensive review of the tools used to diagnose
      psychiatric disorders in children and adolescents. METHOD: The PICA-III-R's
      development, content, initial psychometric properties, and directions for use are
      described. RESULTS: The PICA-III-R assesses all DSM-III-R Axis I psychiatric
      disorders in children aged 6 to 16 years, categorically (diagnosis present or
      absent) and dimensionally (range of severity). It comprises 137 pictures
      organized in modules that cover 5 diagnostic categories, including disorders of
      anxiety, mood, psychosis, disruptive behavior, and substance abuse. Its initial
      psychometric properties are promising, with good internal consistency,
      significant discriminative power for diagnoses, and sensitivity to changes.
      CONCLUSIONS: Despite great interest expressed by child and adolescent
      psychiatrists, further testing has not been possible for practical reasons
      unrelated to the scientific importance of such work. Although it needs to be
      modified to follow DSM-IV criteria, the PICA-III-R can be of significant help to
      child and adolescent psychiatrists, for clinical as well as research diagnostic
      purposes. In addition, it can be used for the assessment of non-English-speaking
      or hearing/speech-impaired children.

PMID- 10638073
TI  - Internal representations: predicting anxiety from children's play narratives.
AB  - OBJECTIVE: This research uses children's story-stem play narratives to examine
      whether certain specified internal representations of self and experiences will
      predict later childhood anxiety. METHOD: Thirty-five nonclinical children were
      studied from 5 to 6 years of age. Narratives of the 5-year-old children were
      coded for negative expectations of self, others, and experiences. Parents and
      teachers completed the Child Behavior Checklist and Teacher's Report Form when
      the children were 5 and 6 years of age. Mothers completed the anxiety section of
      the Diagnostic Interview Schedule for Children when the children were 6 years of
      age. Parental anxiety and child temperament were also measured. RESULTS: Five
      year-old child negative expectations significantly predicted
      mother/father/teacher reports of internalizing and anxiety symptoms and mother
      reports of separation anxiety, overanxious, and social phobia/avoidant disorder
      symptoms in the children at 6 years of age, even when anxiety and internalizing
      symptoms at 5 years of age were entered first in the regression equations. Child
      negative expectations predicted later anxiety in these analyses better than
      parental anxiety and child temperament. CONCLUSIONS: Child negative expectations
      may be a risk factor or a mechanism for the development of later anxiety.
      Children's narratives may be useful for examining such representations and
      identifying children at risk.

PMID- 10638074
TI  - Posttraumatic stress in children exposed to family violence and single-event
      trauma.
AB  - OBJECTIVE: To examine posttraumatic stress disorder (PTSD) and other comorbid
      forms of psychopathology in a sample of children exposed to chronic abuse and
      single-event trauma. METHOD: School-age children (N = 337) were assessed for
      exposure to traumatic events (family violence, violent crime, death or illness of
      someone close to child, accidents) and posttraumatic stress symptoms. Children
      and mothers received structured diagnostic interviews to assess child
      psychopathology. RESULTS: Children from violent households were no more likely to
      report an extrafamilial traumatic stressor than children from nonviolent homes.
      Among the children reporting a traumatic event, 24.6% met the diagnostic criteria
      for PTSD. The leading precipitating event for PTSD symptoms was death or illness
      of someone close to the child (log odds = 4.3). Family violence, violent crime,
      but not accidents also resulted in PTSD. Children with PTSD displayed comorbidity
      across different symptom classes, most notably phobias and separation anxiety.
      CONCLUSIONS: Both type I and type II trauma can result in PTSD in about one
      quarter of children. Children with posttraumatic stress symptoms had many other
      forms of comorbid psychopathology, indicating a global and diffuse impact of
      trauma on children.

PMID- 10638075
TI  - Case study: suprasellar germinoma presenting with psychotic and obsessive
      compulsive symptoms.
AB  - This case describes a 13-year-old boy who had a suprasellar germinoma involving
      the bilateral basal ganglia. His presenting symptoms included left-sided
      weakness, diabetes insipidus, a decline in academic functioning as well as
      psychotic and obsessive-compulsive symptoms. His neuroradiological findings and
      clinical symptoms lend support to the potential role of the basal ganglia in
      psychotic and obsessive-compulsive symptomatology.

PMID- 10638076
TI  - Genetics of childhood disorders: X. Huntington disease.

PMID- 10638077
TI  - Summary of the practice parameters for the assessment and treatment of children
      and adolescents who are sexually abusive of others. American Adademy of Child and
      Adolescent Psychiatry.
AB  - This summary provides an overview of the assessment and treatment recommendations
      contained in the Practice Parameters for the Assessment and Treatment of Children
      and Adolescents Who are Sexually Abusive of Others. The parameters were written
      to aid clinicians in the assessment and treatment of children and adolescents
      with symptoms of sexually abusive behavior. The assessment and treatment of
      children and adolescents with sexually abusive behavior requires an understanding
      of normal sexual development. A multiplicity of biological and psychosocial
      factors determines the child's sexual development, gender role, sexual
      orientation, patterns of sexual arousal, sexual cognitions, sexual socialization,
      and the integration of sexual and aggressive patterns of behavior. The
      individual's sexuality evolves in concert and as a result of interaction with
      family, ethnic, social, and cultural influences. These parameters summarize what
      we know about the epidemiology and phenomenology of sexually abusive youths and
      provide guidelines for the assessment and the selection of treatment
      interventions for these youths. Essential considerations in the assessment and
      treatment of sexually abusive youths, as well as the different categories of
      sexually abusive youths which should be recognized and which influence treatment
      decisions, are presented. The spectrum of currently available psychosocial and
      biological treatments will be summarized.

PMID- 10638078
TI  - Controlling tobacco menace: now or never.

PMID- 10638079
TI  - Sports sponsorship by cigarette companies influences the adolescent children's
      mind and helps initiate smoking: results of a national study in India.
AB  - To estimate the effect of large scale tobacco sponsorship of cricket, a study was
      conducted on children's knowledge and perceptions about smoking and their impact
      on subsequent smoking uptake. Twelve nations played 36 matched in the Wills World
      Cup-1996 cricket series over one month during which Wills (a cigarette brand) was
      extensively advertised by live broadcast to a 2-billion viewers with WILLS logo
      on the players' T-shirts and playground, newspapers, magazines, and hoardings. An
      anonymous structured questionnaire including 4 knowledge based questions about
      tobacco, 4 about perceptions directly promoted by Wills and 10 questions related
      to wrong perceptions about smoking was administered by class teachers six months
      after the series. A total of 5822 children (65% boys and 35% girls) in Grade 10,
      aged 13-17 years (median 14) were selected. Smokers increased from 137 (2.4%)
      before the series to 649 (11.1%) after the series. The smoking initiation rate
      was 2.04% (13/636) in children with full knowledge and no wrong perceptions, 7.8%
      (48/618) among those with less knowledge and no wrong perceptions. Among those
      with less knowledge but believing in at least 2 of Wills related perceptions and
      3 of the smoking related perceptions the rate for smoking initiation was 20.55%
      (127/618). The sponsorship appeared to have a similar effect on initiation rates
      in both sexes despite the strong social taboo against girls smoking in India.
      Wrong perceptions about smoking promoted by tobacco sponsorship increases smoking
      initiation amongst both boys and girls even when they are aware of the risks
      involved. The study suggests that education, without bans on advertisements is
      unlikely to stop initiation of smoking among children.

PMID- 10638080
TI  - A profile of lung cancer patients in Hyderabad.
AB  - One hundred and sixty cases of bronchogenic carcinoma were retrospectively
      analysed. Male to female ratio was 8.4:1, common age group being 40-60 years. The
      most common (38%) radiological presentation was mass lesion. The predominant
      histological cell type was squamous cell carcinoma (67%). Most of the patients
      presented in an advanced stage of the disease of inoperability. The study
      underlines the various diagnostic madalities in diagnosing lung cancer and
      emphasises the need for practising doctors to keep in mind the possibilities of
      bronchogenic carcinoma in all cases of unresolved pneumonia and mass lesion on
      chest x-ray especially in high risk patients.

PMID- 10638081
TI  - Carcinoma of oesophagus--aetiological factors and epidemiology: an overview.
AB  - Tobacco and alcohol, opium, hot tea and food, bracken and tannins, plant
      irritants, fungal infection, nitrosamines, nitrates and nitrites, moldy foods and
      mycotoxins and dietary deficiencies have received attention as aetiological
      factors for carcinoma of oesophagus. Global epidemiology and epidemiology at the
      national level show that it has marked regional pattern with steep gradients and
      marked variations among countries and provinces suggesting a strong aetiological
      role of environmental risk factors. The aetiological agents for carcinoma of
      oesophagus appear to be many which may act together or successively upon the
      oesophagus.

PMID- 10638082
TI  - Prevalence of chronic bronchitis in urban population of Kashmir.
AB  - Population based survey was conducted in an urban area of Kashmir comprising 629
      males and 511 females. Majority (27.9%) of individuals studied were in the age
      group of < 40 years. Prevalence of chronic bronchitis was more in the age group
      of 70 years and above (14.12%), in smokers the prevalence was 7.55% and in people
      living in poorly ventilated dwellings it was 10.56%.

PMID- 10638083
TI  - Tobacco smoking and hypertension.
AB  - Coronary artery diseases is rapidly increasing in our part of the world. The
      South Asian ethnic groups are especially vulnerable to coronary artery disease.
      The two most striking features of coronary artery disease in the South Asian
      population are extreme prematurity and severity of the disease, both resulting
      from the malignant atherosclerosis that begins at an earlier age than in other
      population. Triple vessel disease and complicated lesions are not common even in
      young people and follow a malignant course. The most important aspect of
      prevention is to identify individuals with high risk of coronary artery disease
      at an early age and aggressive modification of risk factors. Tobacco smoking and
      hypertension are the two most important risk factors for coronary heart disease
      and stroke. Both of these risk factors have very high prevalence in India, Nepal
      and other countries of this region. There is a synergistic interaction of tobacco
      smoking with hypertension and high blood cholesterol which greatly increase
      coronary heart disease risk as well as sudden death and stroke.

PMID- 10638084
TI  - Mouth cancer in India: a new epidemic?
AB  - Oral cancer has been traditionally described as a major form of cancer in India
      although on the basis of cancer registry data, it was thought that the incidence
      has decreased. There are several recent reports in the literature, however,
      predicting an increase in mouth cancer incidence in India. This prediction is
      based upon observation of an increasing prevalence of oral submucous fibrosis,
      especially in younger individuals, caused by gutka, an industrially manufactured
      food item. A comparison of the age distribution of recently reported oral
      submucous fibrosis cases and incident cases reported in the past clearly
      establishes that the disease is now occurring at much younger ages. A comparison
      of the age specific incidence rates of mouth cancer (ICD 143-5) during 1983-87
      and 1995 in the city of Ahmedabad shows that the incidence has significantly
      increased in the younger population (< 50 years). Since tongue cancer (ICD 141)
      does not show a similar increase, it is concluded that the increase in mouth
      cancer incidence is real. Urgent public health measures are required to curb this
      new but avoidable epidemic.

PMID- 10638085
TI  - Tobacco epidemic.

PMID- 10638086
TI  - Health facts.

PMID- 10638087
TI  - Some facts on global tobacco use.

PMID- 10638088
TI  - Country profile: India.

PMID- 10638089
TI  - The benefits of quitting smoking.

PMID- 10638090
TI  - Smoking cessation programmes.

PMID- 10638091
TI  - Pharmacological aids to smoking cessation.

PMID- 10638092
TI  - Specific targets of cessation efforts.

PMID- 10638093
TI  - Self-directed smoking cessation.

PMID- 10638094
TI  - Helping smokers quit (a guide for primary care clinicians).

PMID- 10638095
TI  - Types of tobacco products.

PMID- 10638096
TI  - Smoking is hazardous to health.

PMID- 10638097
TI  - Eagle-Barrett syndrome.

PMID- 10638098
TI  - Successful treatment of dapsone poisoning using commercially available methylene
      blue crystals.

PMID- 10638099
TI  - Open labelled evaluation of injection Manyana (a combination of diclofenac +
      pitofenone + fenpiverinium) in ureteric, biliary and intestinal spasm--a
      preliminary report.
AB  - To study the efficacy and safety of a parenteral formulation of 'Manyana' (a
      combination of diclofenac + pitofenone + fenpiverinium) in ureteric, biliary and
      intestinal colic, an open labelled study was conducted at two centres. A total of
      206 patients were enrolled and evaluated for decrease in pain with time on a
      visual analogue scale. A statistically significant difference was observed in
      pain within 30 minutes of drug administration and the pain relief lasted for as
      long as 24 hours post dosing. The study shows definite synergism between the
      antispasmodics pitofenone and fenpiverinium with the NSAID-diclofenac, reducing
      the prostaglandin levels and also the spasm related to colic.

PMID- 10638100
TI  - Heart valve prosthesis: better than the best.

PMID- 10638101
TI  - Cardiovascular effects of yellow oleander ingestion.
AB  - Yellow oleander (Thevetia neriifolia) is a commonly grown tree found widely in
      Eastern India. The seeds of yellow oleander are highly poisonous and contain
      three glycosides--thevetin, thevetoxin and peruvoside. Yellow oleander seed
      ingestion is usually with suicidal intent in Eastern India. Manifestations range
      from mild to potentially fatal. It has significant cardiovascular effects with
      varying rhythm abnormalities. Effects of yellow oleander seed ingestion (YOI)
      were studied in 300 patients from 1986 to 1990 at BS Medical College, Bankura.
      Majority i.e., 246 (82%) were females and 226 (75.33%) were young in the age
      group 11-20 years. Most reported for treatment 6 to 8 hours after ingestion of
      seeds. The number of seeds swallowed varied from half to fifteen. Two hundred and
      ninety-two (97.33%) ingested seeds in the crushed form; 156 (52%) were
      asymptomatic, 92 (30.66%) had vomiting and 36 (12%) had palpitation. In
      electrocardiogram (ECG), 138 (46%) revealed varying types of arrhythmias
      including sinus bradycardia in 68 cases (49.27%). Ischaemic changes were present
      in 118 cases (39.33%). Number of seeds ingested did not bear any relationship
      with ECG changes in YOI. All 14 cases of death were autopsied. Subendocardial and
      perivascular haemorrhage with focal myocardial oedema was present in all. Median
      hospital stay was 5 days (range 2 to 24). During discharge, 256 (85.33%) had
      normal ECG, 14 (4.66%) had sinus bradycardia and 16 (5.33%) demonstrated
      ischaemic changes.

PMID- 10638102
TI  - Pharmacologic support of circulation in patients undergoing cardiac surgery.
AB  - Maintenance of adequate oxygen balance to all tissues is one of the primary
      objectives when dealing with patients undergoing cardiac surgery. Cardiac output
      is one of the major components of oxygen delivery so that its maintenance is an
      important consideration. Due to pre-operative cardiac lesion and myocardial
      dysfunction secondary to the events related to cardiac surgery and
      cardiopulmonary by-pass, circulatory support by pharmacological or mechanical
      means is frequently required after surgery. Therefore, inotropes and vasodilators
      are used to improve the myocardial performance after cardiac surgery.
      Epinephrine, dopamine and dobutamine are commonly used inotropes. Dopexamine and
      phosphodiesterase inhibitors such as amrinone, milrinone and enoximone are some
      of the newer agents that have been introduced in clinical practice. Amongst the
      vasodilators, sodium nitroprusside and nitroglycerin are commonly used. Alpha
      adrenergic blockers such as phentolamine and phenoxybenzamine and calcium channel
      blockers such as diltiazem are some other vasodilators that can be used. Many
      units still regard epinephrine as an inotrope of choice and use its predominant
      beta agonist effect in the dose range of 0.02 to 0.04 mg/kg/minute. Some prefer
      dobutamine and others a combination of inotrope and vasodilator or an inodilator.
      Phosphodiesterase inhibitors can be useful in certain situations such as pre
      existing ventricular dysfunction or when stunning of the myocardium is suspected
      with down regulation of beta receptors. Dopamine is useful in the renal
      vasodilating dose to improve renal perfusion and improve output. There is no
      ideal inotrope at present and each one has its own drawbacks. The clinician must
      learn to use the inotropes (especially the newer ones) based on his own clinical
      experience.

PMID- 10638103
TI  - Evolution of strategies in the non-pharmacologic management of atrial
      fibrillation: a review.
AB  - Atrial fibrillation is the commonest amongst all sustained cardiac dysrhythmias.
      Besides in its idiopathic form seen in the elderly, it may co-exist with other
      cardiac disorders, especially rheumatic valvular heart disease. No
      pharmacotherapeutic combination has yet succeeded in comprehensively addressing
      the three detrimental sequelae of atrial fibrillation viz, the subjective
      discomfort of an irregular heartbeat, compromised cardiac haemodynamics caused by
      the loss of synchronous atrioventricular contraction, and the stasis of blood
      flow in the left atrium threatening thrombo-embolism. Percutaneous catheter
      interventions, too, have been equally unsuccessful. However, several innovative
      surgical solutions have been designed in the laboratory as well as in clinical
      setting. The most successful amongst these is the Maze III procedure. It is a
      complex operation which deploys a number of predesignated incisions in both atria
      along with cryolesions applied at certain vantage points. The objective is to
      interrupt micro re-entrant circuits in the atria while ensuring that the SA node
      is able to generate and propagate the sinus impulse through both atria. In spite
      of its immense success, the prolonged duration of myocardial ischaemia and
      cardiopulmonary by-pass, especially when accompanied by associated valve related
      procedures have come in the way of its popularity. Efforts are underway to
      replicate the Maze radiofrequency incisions using radiofrequency energy to
      produce equally efficient intramural ablation within a much shorter time.
      Catheters capable of creating contiguous multiple transmural linear lesions are
      being developed to facilitate rapid ablation of atria. Their induction is likely
      to significantly reduce the surgical duration, thus making the Maze procedure
      more popular. Thus it is evident that for the moment the onus and privilege of
      'curing' atrial fibrillation will rest with the cardiac surgeons.

PMID- 10638104
TI  - Anaesthetic management of port-access minimally invasive cardiac surgery.
AB  - Minimally invasive cardiac surgery is the talk of the day among anaesthetists and
      cardiothoracic surgeons. Port-access minimally invasive cardiac surgery was
      performed among 116 patients at Loyola University Medical Center since July,
      1997. This technology uses a system of 5-channel internal jugular vein and
      femoral artery/vein catheters and cannulae to provide a closed chest
      cardiopulmonary by-pass permitting the heart to be arrested and protected with
      cardioplegic solution in a manner equivalent to used that in open cardiac
      surgery. Out of 116 patients, 2 experienced coronary sinus rupture for which they
      were converted to standard conventional approach. All patients had done well
      postoperatively. The advantages of this method include less postoperative
      discomfort, decreased hospitalisation and reduced health care costs. Concern
      exists regarding technical results which according to some are not equivalent to
      conventional method.

PMID- 10638105
TI  - Current status of cardiac anaesthesia.
AB  - Cardiac anaesthesia continues to advance at a rapid pace. Many innovations in
      monitoring and pharmacology have wide application in patients with cardiac
      disease. In recent years many new cardiac procedures have been introduced to
      improve results and reduce cost. Anaesthesia for these procedures (e.g., mid-cab,
      port-access) requires special training and experience so as to reduce morbidity
      and mortality. Recently short acting anaesthetic agents are used to permit early
      extubation as a part of fast tracking. Constant vigilance and monitoring are
      necessary to handle potentially dangerous situations and avoid complications.

PMID- 10638106
TI  - Oesophageal atresia--the touch stone of paediatric surgery.
AB  - Paediatric surgery has been grappling with oesophageal atresia with or without
      tracheo-oesophageal fistula for over 300 years. A very brief resume of the
      history of evolution of its treatment, anatomical types, clinical features and
      basic principles of treatment have been outlined. The immediate and long term
      complications have also been highlighted. The results of surgical treatment of
      this birth defect have tremendously improved in developed countries over last two
      decades, but the results in developing countries are yet to match that. The
      prevalent reasons for this discrepancy are also discussed.

PMID- 10638107
TI  - Advances in perfusion technology--an overview.
AB  - The introduction of minimally invasive approaches to cardiac surgery offered the
      opportunity to reduce patient's pain associated with median stemotomy as well as
      infection and postoperative bleeding. This technique required the use of one
      small venous cannula necessitating the implementation of kinetic assisted venous
      drainage (KAVD). However, KAVD proved costly due to the use of a centrifugal pump
      and could be de-primed if air was introduced into the venous line. Vacuum
      assisted venous drainage (VAVD), an easy to learn technique, was proved to be a
      better, safe and less expensive alternative as it required lower prime and small
      cannulae. Blunt trauma could also be avoided as large cannulae were not used.

PMID- 10638108
TI  - Role of thoracic surgery in pulmonary tuberculosis.
AB  - Surgery in pulmonary tuberculosis in one form or other gives good results.
      Indications for surgery include drug resistant pulmonary tuberculosis, massive
      recurrent haemoptysis, post-tuberculosis bronchiectasis or destroyed lung,
      empyema with or without bronchopleural fistula and for diagnostic purposes. In
      all cases a clear indication for surgery is mandatory. Processes of surgery
      include lung resection, thoracoplasty, decortication, thoracotomy and biopsy,
      thoracoscopy and ib resection for pleurocutaneous flap procedures. Adequate
      postoperative management is very important. Complications like atelectasis and
      pneumonia, empyema, bronchopleural fistula, wound infection, cachexia, etc, add
      morbidity and prolonged hospital stay.

PMID- 10638110
TI  - Torture--global issue of concern.

PMID- 10638109
TI  - Comparative efficacy and tolerability of nimesulide and piroxicam in
      osteoarthritis with specific reference to chondroprotection: a double blind
      randomised study.
AB  - The aim of the study was to assess the efficacy, tolerability and
      chondroprotection afforded by nimesulide, a selective cyclooxygenase-2 inhibitor
      and piroxicam in a randomised, double blind, controlled clinical trial in 90
      patients suffering from osteoarthritis of the knee joint. A significant
      improvement in the osteoarthritis severity index at 2 weeks (p < 0.01) and an
      improvement in physicians assessment of global arthritic condition at 4 weeks (p
      < 0.01) was seen with both the treatments. A significant decrease in articular
      index of joint tenderness (p < 0.05) at 8 weeks and in self assessment of
      handicap at 4 weeks (p < 0.05), in comparison to baseline, was observed only in
      patients receiving nimesulide. Rescue therapy was required by a greater
      percentage of patients being administered piroxicam. Functional capacity improved
      in 64% of the patients on nimesulide and 74.5% of the patients receiving
      piroxicam. Adverse effects were observed in 6 patients on nimesulide and 9
      patients receiving piroxicam. No significant difference was found in any of the
      efficacy and tolerability parameters between the two treatment groups. Magnetic
      resonance imaging evaluation of the knee joint of 10 patients showed no
      significant change in the articular cartilage and associated joint structures
      after 6 months of therapy with both the treatments. The results show that
      nimesulide and piroxicam are comparable in efficacy and tolerability in patients
      suffering from osteoarthritis.

PMID- 10638111
TI  - Sex oriented torture--an overview.
AB  - Sexual torture was prevalent in ancient times. It may take place in any form
      e.g., violence against sexual organs, physical sexual assault and mental sexual
      assault. There are many examples of sexual torture throughout the world.
      Indonesia in 1998 riot has witnessed several cases of sexual tortures. There are
      always some forms of motives in sexual torture. Methods employed in sexual
      torture are many--with or without using instruments or animals. The revival or
      moral values in the society, respect for women, sanctity of the family, respect
      for individual's dignity and awakening at social levels can meet the challenge.

PMID- 10638112
TI  - Medical ethics and torture.
AB  - Incidence of human right abuse and torture is increasing. The role of a doctor in
      torture is highlighted citing various declarations of different medical
      communities. Torture is generally accepted as unethical and all international
      organisations warned doctors against participation in torture.

PMID- 10638113
TI  - Gender bias torture in place of work.
AB  - Gender bias torture specially sexual harassment of women at the work place is now
      a hard reality, the ultimate form of control that repressed men, especially those
      in position of authority, can have today. They are generally being allowed to get
      away with it. Mainly because women are fearful and totally unorganized,
      managements are complacent and the law takes much too long to work if it ever
      does. Global picture is horrifying. Child abuse, women abuse and even some men
      are sexually abused. The fear of loss of job, hostility at work and social stigma
      still prevent women from complaining about sexual harassment. It has been
      recognized as human rights violation by the Supreme Court which has even drawn up
      legally binding guidelines directing employers to implement preventive and
      remedial measures in the work place.

PMID- 10638114
TI  - Legal aspect of medical practice.
AB  - Practice of medicine does not involve its curative aspect alone only, but also it
      is concerned with its legal nee medicolegal aspect relating to (a) doctor-patient
      relationship, (b) doctor-doctor relationship, (c) doctor-state relationship in
      relation to the duties of a doctor, obligation to his patients apart from legal
      aspect of medical practice including infamous conduct, medical negligence,
      malpractices, etc. State medicine envisages proper code of conduct of registered
      medical practitioners to guide and regulate their professional activities, to
      protect the community at large from quacks and charlatans against malpractice.
      Medical jurisprudence connotes legal aspect of medical practice.

PMID- 10638115
TI  - Role of doctors in prevention of torture.
AB  - Torture is taking place since time immemorial. Doctors can take important part in
      elimination of this social evil. Torture is deliberate, systematic or wanton
      infliction of physical or mental suffering by one or more persons to force
      another person or torture victim to make confession or giving information.
      Torture happens to occur in 3 forms--physical, mental and/or sexual. Doctors
      working in prisons, police or paramilitary/military forces are most likely to
      confront with torture and they should follow the medical ethics, codes and
      conventions in true sense. MCI, IMA, WMA should play their role in educating,
      motivating and supporting doctors in confronting torture. NHRC and IMA should co
      operate each other to protect human rights.

PMID- 10638116
TI  - Methaemoglobinaemia in nitrobenzene poisoning--a case report.
AB  - A 24-year-old female of nitrobenzene poisoning presented with features of
      methaemoglobinaemia. She was treated with oral methylene blue and intravenous
      ascorbic acid and responded favourably from 3rd day onwards. The case is reported
      in details.

PMID- 10638117
TI  - Contusion of lungs.
AB  - A 16 years old male with history of beating by army personnel was admitted in the
      hospital with the complaints of chest pain and breathlessness. After about 5
      hours of admission, the patient died in spite of treatment with analgesics,
      antibiotics, fluids and oxygen inhalation. The autopsy report showed multiple
      bruises on different body parts and there were contusions on the lungs showing
      impression of rib patterns. Histological examination showed alveoli filled with
      blood and cellular infiltrate in interalveolar and interstitial spaces.

PMID- 10638118
TI  - Lithium neurotoxicity at therapeutic level--a case report.
AB  - A 30 years old Hindu male presenting with symptoms of lithium toxicity. On
      investigation, serum lithium level was found to be 0.5 meq/l. Though toxicity at
      this level of lithium is unusual, still neurotoxicity happened to be the cause of
      his hospital admission. He was debarred from taking lithium further and
      carbamazepine was started as mood elevator. He responded favourably.

PMID- 10638119
TI  - Expectation from a civilized administration in our plight.

PMID- 10638120
TI  - Cyclosporine trough levels in renal graft recipients.
AB  - Blood Trough Levels (TL) of cyclosporine (CyA) [the drug panimun bioral
      cyclosporine oral solution USP--modified. Panacea Biotec Ltd], were monitored in
      103 renal transplant patients who were receiving CyA orally. Two hundred and
      sixty-two blood concentrations of CyA were determined using a validated HPLC
      assay over a period of two years. Mean dose from week 1 until 2 years ranged from
      7.65 +/- 0.9 to 2.73 +/- 0.8 mg/kg. Mean blood CyA levels ranged from 197.4 +/-
      87.5 to 205.9 +/- 113.5. The TL concentration changes versus dose reduction were
      not markedly different after 2-4 weeks and remained within therapeutic range.
      Stabilised concentrations were achieved after first month. We conclude that the
      blood TL of CyA were in the nominal therapeutic range suitable for renal
      transplant patients.

PMID- 10638121
TI  - The people: the government, its health policy and role of IMA.

PMID- 10638122
TI  - Testicular biopsy in infertility.
AB  - Eighty-eight infertile couples attended the infertility clinic. Semen analysis
      was abnormal in 64 cases. The cases were divided into 3 groups according to sperm
      count:Group I (count zero), group II (count < 20 million/ml) and group III (20-50
      million/ml). The morphology of testicular biopsy categorised into 5 groups were
      normal--10(15.63%), hypospermatogenesis--42(65.63%), the Sertoli cell only
      syndrome--2(3.13%), maturation arrest--2(3.13%) and tubular hyalinization-
      8(12.50%). Quantitative analysis of biopsies was done using mean Johnson
      score(MJS) and Silber score(SS). The morphology in any single section was not
      uniform but of mixed type. Normal spermatogenesis in azoospermics indicated
      bilateral ductal obstruction. As compared to MJS, SS showed a more direct
      correlation between number of mature spermatids per tubular cross section and
      sperm count in unobstructed cases.

PMID- 10638123
TI  - Role of computed tomography in spinal trauma.
AB  - Twenty patients admitted for spinal trauma were studied with computed tomography
      (CT) scan. All the patients had initial routine plain radiographs in the
      anteroposterior and lateral views. Ten patients sustained injury due to fall from
      height, 7 suffered road side accident, 2 had injury due to fall of weight on back
      and one suffered due to slip on floor. Twelve patients had injury at multiple
      levels. Twenty-four vertebral bodies were involved in 20 patients, 10 had
      fracture of posterior elements only. Neurological deficit occurred in 16
      patients. CT scan provided more information than plain radiography, which missed
      vertebral body fracture in 2 out of 24 instances and spinal canal compromise in 7
      out of 12 patients. CT scan detected posterior element injuries better and in
      greater detail in all cases.

PMID- 10638124
TI  - Rheumatic fever in children.
AB  - Rheumatic fever (RF) and rheumatic heart disease (RHD) are major public health
      problems in developing countries. A prospective study carried out in a large
      general hospital showed that carditis was the predominant feature in first attack
      and also the recurrence of RF but that recurrence was associated with more severe
      manifestations. Echocardiography picked up cases of subclinical carditis.
      Presence of congestive cardiac failure in association with carditis always led to
      chronic RHD. Recurrence occurred only when patient defaulted penicillin
      prophylaxis. The overall recurrence rate was 0.026 per patient.

PMID- 10638125
TI  - Bronchopulmonary absorption of aerosolised insulin.
AB  - Seven non-insulin dependent diabetes mellitus (NIDDM) patients aged 48 to 78
      years, inhaled approximately 10 to 20 units of aerosolised insulin (human
      actrapid) by nebuliser. In 5 cases, approximately 10 units of insulin aerosol
      inhalation was given 4 hours after breakfast. Blood glucose level started falling
      after 15 minutes with a maximum fall at 45 minutes to 1 hour. In 2 cases insulin
      aerosol inhalation was given 2 hours after lunch. The first dose of 10 units of
      insulin did not show any significant change in blood glucose level at 30 minutes.
      A second dose of 10 units of insulin aerosol was inhaled after 30 minutes and
      blood glucose level started falling in a pattern similar to the first group of
      patients. The first dose appears to withhold the rise of blood glucose in the
      postprandial phase and the second dose lowers the blood glucose level. The result
      is compared with placebo inhalation and there is a significant fall of blood
      glucose level with insulin aerosol inhalation. It admits of little doubt that
      insulin is absorbed from the bronchopulmonary mucosa.

PMID- 10638126
TI  - Assessment of the need for a training course in rational use of drugs: a cross
      sectional pilot study.
AB  - Rational use of drugs means need-based use of them keeping in mind the
      pathological status, therapeutic indices, drugs interactions and adverse drug
      reactions. Lacunae in the existing undergraduate curriculum cause irrational use
      of drugs. The present study was undertaken among 2,200 fresh medical graduates
      from all over the country with a list of questionnaire distributed among them and
      analysing the answers. The aim was to ascertain the adequacy of present
      undergraduate curriculum on pharmacology in equipping the doctors on rational use
      of drugs and to assess the need and feasibility of Refresher's course. More than
      half (55%) replied prescriptions were not truly rational. Ninety-eight per cent
      opened Refresher's course is beneficial in rational prescribing. This cross
      sectional survey could provide a glimpse of existing undergraduate pharmacology
      curriculum and its impact on rational prescribing practice. The Refresher's
      course in the early internship period involving the clinical departments and
      department of pharmacology is suggested.

PMID- 10638127
TI  - Congenital urethral fistula.
AB  - A 3-year-old male child was presented with the history of passage of urine coming
      from the undersurface of penis and its tip since birth. An opening was present on
      the ventral aspect of midshaft of penis through which a catheter could be passed.
      It was diagnosed as urethral fistula which was managed surgically.

PMID- 10638128
TI  - Subacute sclerosing panencephalitis in a case of aqueductal stenosis.
AB  - A 14-year-old boy presented with history of deterioration of scholastic
      performance, altered behaviour, difficulty in walking and repeated falls since
      last 2-3 months. He had history of delayed milestones and at 11 months developed
      febrile rashes. On investigations, MRI showed compensated hydrocephalus with
      aqueductal stenosis. EEG suggested subacute sclerosing panencephalitis (SSPE).
      CSF was positive for measles antibody titre. This case of aqueductal stenosis
      with SSPE is very interesting for its diagnostic dilemma.

PMID- 10638129
TI  - Blood brain barrier and ageing.

PMID- 10638130
TI  - Cyclosporin A monotherapy in young Indian aplastic anaemia patients.

PMID- 10638131
TI  - Comparative study of nifedipine CD retard 30 tablets vs enalapril in patients of
      uncomplicated essential hypertension.

PMID- 10638133
TI  - Noonan's syndrome.

PMID- 10638132
TI  - Papillary adenofibroma of cervix.

PMID- 10638134
TI  - Lymphoblastic lymphoma--T cell variant.

PMID- 10638135
TI  - Retro-orbital hydatid cyst.

PMID- 10638136
TI  - A unique cause of male dyspareunia.

PMID- 10638137
TI  - Solitary neurofibroma causing nasal obstruction.

PMID- 10638138
TI  - Primary liposarcoma of the mediastinum.

PMID- 10638139
TI  - Pathophysiology, diagnosis and treatment of Clostridium difficile infection.
AB  - Clostridium difficile infection has become in recent years an important
      nosocomial threat. Prevention of the spread of C. difficile infection among long
      term hospitalized patients is a major challenge since C. difficile spores can
      persist indefinitely in the hospital environment. Following antibiotic therapy
      that disrupts the normal bacterial flora of the colon, C. difficile can colonize
      the large intestine. The bacteria releases two large protein toxins that bind to
      colonocytes and mediate an acute inflammatory diarrhea characterized by an
      abundant exudate rich in neutrophils and proteins that in some cases can form the
      typical "pseudomembrane". C. difficile infection shows a spectrum of severity
      from asymptomatic carrier to fulminant acute pseudomembraneous colitis. The gold
      standard for the laboratory diagnosis of C. difficile infection is the stool
      cytotoxin test, however recently developed immunoassays represent a good
      alternative. The treatment of C. difficile infection is based on the severity of
      the clinical picture. In patients with mild diarrhea discontinuation of the
      causing antibiotic can be an adequate therapeutic approach, whereas patients with
      more severe symptoms require antibiotic therapy or, in the most severe
      infections, even colectomy.

PMID- 10638140
TI  - Contribution of lumbrical muscle activity to the paradoxical extension phenomenon
      induced by injuries to the finger flexor tendons.
AB  - The "Extensor habitus" phenomenon occurs in finger flexor tendon injuries and
      consists of a paradoxical extension of the interphalangeal joints after an
      attempt to flex the finger. The mechanism of extension is considered to be a
      contraction of the flexor digitorum profundus that is then transmitted via the
      lumbrical muscle structure to the extensor expansion. Using electromyography, we
      recorded the lumbrical muscle activity during the paradoxical extension
      phenomenon to determine whether the lumbrical muscle contributed to this event.
      Two patterns of electromyographical activity of the lumbrical muscle were
      observed. Group I (6 fingers) displayed electrical activities in the lumbrical
      muscle during flexion tasks, while group II (12 fingers) did not. In group I, the
      lesions were mainly located in zone V, and the response to range of motion
      exercises was satisfactory. In group II, nearly all of the lesion were located in
      zone II, and half of the cases required additional surgical interventions. Group
      II appeared to exhibit the "Extensor habitus" phenomenon, while group I exhibited
      an "Extensor habitus-like phenomenon." To distinguish between these two
      phenomena, an electromyographical examination of the lumbrical muscle must be
      performed.

PMID- 10638141
TI  - Antitumor effects of an interferon-loaded silicone formulation in human renal
      cell carcinoma in nude mice.
AB  - Conventional therapy for renal cell carcinoma using interferon (IFN) has shown
      limited antitumor action. The IFN-loaded silicone formulation (IFN-SF) is a
      sustained-release formulation of human lymphoblastoid IFN, with a medical grade
      silicone elastomer used as the carrier material. We evaluated the antitumor
      effect of IFN-SF on human renal cell carcinoma cell line (KU-2) transplanted to
      nude mice. The treatment was started when the tumor nodules had grown 6 to 8 mm
      in diameter. IFN-SF, on an aqueous solution of IFN, was given by subcutaneous or
      peritumoral injection. Antitumor effects were evaluated according to tumor
      weights calculated as (long diameter) x (short diameter)2/2 in 7 groups
      consisting of 6 mice each. Serum IFN levels remained detectable up to 30 days
      after subcutaneous injection of IFN-SF. IFN-SF administered by the subcutaneous
      and peritumor route significantly inhibited growth of the tumor when compared
      with tumor growth in the untreated mice and mice treated with aqueous IFN
      solution. IFN-SF had equivalent inhibitory effects on tumor growth by peritumor
      and subcutaneous injection. Results indicated that the use of IFN-SF could reduce
      the frequency of injections and provide better treatment of patients with renal
      cell carcinoma because of its long-acting effect when it is used systemically.

PMID- 10638142
TI  - Pathogenesis of alcoholic liver disease: newer mechanisms of injury.
AB  - The understanding of how alcohol damages the liver has expanded substantially
      over the last decade. In particular, the genetics of alcoholism, the genesis of
      fatty liver, the role of oxidant stress, interactions between endotoxin and the
      Kupffer cell, and the factors that control activation of the hepatic stellate
      cell (HSC) have been the focus of a great deal of research. Genetic mechanisms
      for increasing the risk of alcoholism include alterations in alcohol metabolizing
      enzymes as well as neurobiological differences between individuals. The
      development of fatty liver may involve both redox forces, oxidative stress, and
      alterations in peroxisome proliferator activated receptor function. Oxidative
      stress is now known to involve both microsomal and mitochondrial systems. Recent
      studies implicate stimulation of Kupffer cells by portal vein endotoxin as a
      cause of release of cytokines and chemokines, hepatocyte hyper-metabolism, and
      activation of HSC. These actions appear to be in part gender-dependent and may
      explain the susceptibility of women to alcoholic liver disease. Activation of HSC
      underlies liver fibrosis and cirrhosis of all types; control of this activation
      might permit control of the progression of fibrosis. These advances suggest a
      number of new approaches as therapy for alcoholic liver injury.

PMID- 10638143
TI  - Infratemporal fossa approaches to the lateral skull base.
AB  - The infra-temporal fossa approach is one of the lateral approaches to the skull
      base. It is indicated for the treatment of tumors such as glomus tumor, petrous
      apex cholesteatoma, chondroma, lower cranial nerve neuroma and nasopharyngeal
      cancer. In the present paper, we described the surgical anatomy of the lateral
      skull base and the indications for the infra-temporal fossa approach with its
      variants. We showed the hints and pitfalls in the procedures. Five illustrative
      cases are also presented.

PMID- 10638144
TI  - Uterine reconstruction for complete septate uterus.
AB  - In the period between 1990-1995, six women with complete septate uterus presented
      to our clinic and underwent uterine reconstruction using our own unique
      procedure, a method we independently developed using the Jones & Jones procedure
      and the Thompkins procedure for reference. Five of these 6 cases later became
      pregnant, and to date, they have given birth to 7 newborns. Because of a very
      high rate of successful postoperative pregnancy, we were convinced that uterine
      reconstruction is useful for complete septate uterus.

PMID- 10638145
TI  - A two-year-old female with methylmalonic acidemia and progressive low density
      lesions in the basal ganglia on CT scans.

PMID- 10638146
TI  - [Video-assisted thoracic surgery in the treatment of spontaneous pneumothorax].
AB  - BACKGROUND: The aim of this study was to evaluate the surgical indications and
      the results of a series of 107 patients treated by video-assisted thoracic
      surgery for spontaneous pneumothorax with a minimum follow-up of 12 months.
      METHODS: From January 1991 to December 1997, 107 patients (86 male and 21 female
      patients) mean age 28 years (range 14-78), underwent VATS for treatment of
      spontaneous pneumothorax. RESULTS: Seventy-five patients had primary spontaneous
      pneumothorax (PSP) and thirty-two patients had secondary spontaneous pneumothorax
      (SSP). Bullous area was not seen in 26 patients with PSP. Ninety-nine patients
      were treated with wedge stapled resection of the bullous area or of the apex
      (when no bullous area was seen) and some form of pleurodesis, whereas 8 patients
      with PSP were treated only with pleurodesis. Among these 8 patients, two
      presented recurrence. Two patients with PSP and 8 patients with SSP were treated
      by apical pleurectomy: no one developed recurrence. The other 97 were treated
      with electrocoagulation of the parietal pleura. Conversion to a thoracotomy was
      necessary in 4 patients (12.5%) because of massive pleural adhesions. There were
      no postoperative deaths. A complication developed in 3 patients (4%) with PSP and
      in 5 patients (17.8%) with SSP, whose procedure was ended by VATS. The duration
      of systematic postoperative drainage was 3.8 +/- 0.9 (range 3-15 days) for the
      group of patients with PSP and 6 +/- 2.1 (range 4-23 days) for the group of
      patients with SSP. The duration of the hospital stay was 5.6 +/- 1.4 (range 4-15)
      and 8.4 +/- 2.3 (range 6-18) in patients with PSP and SSP respectively. Follow-up
      analysis revealed 2 (2.66%) ipsilateral recurrent pneumothorax in 75 patients
      treated for PSP. Among 26 patients with SSP, whose procedure was completed by
      VATS, 2 recurrences (7.7%) were observed. CONCLUSIONS: Surgical treatment by VATS
      is a valid alternative to open thoracotomy in patients with PSP and will be the
      treatment of choice because, with increased experience of surgeons, it will yield
      the same results as standard operative therapy but with the advantages of the
      minimally invasive operation. The usefulness of VATS in patients with SSP remains
      to be defined.

PMID- 10638147
TI  - [Treatment of parastomal colostomy hernia].
AB  - BACKGROUND: Parastomal hernias are the most common cause of in patients
      surgically with stomy reoperation treated. METHODS: Treatment of parastomal
      hernias has been faced through two kind of technics: the first one consisted in
      the translocation of colostomy, the second one was placing around the colostomic
      hole a marlex mesh which was inserted at muscular structure level. From January
      1993 to May 1997 we treated 8 patients affected by paracolostomic hernia
      associated to laparocele. The laparocele was treated according Rives' technique
      with the prosthesis positioned in the properitoneal site. The parastomal hernia
      was treated with translocation of the colostomy in 3 cases; in the other patients
      a plastic surgery of the colostomic orifice was made using polypropylene little
      bandages in properitoneal site. RESULTS: In the postoperative period the
      complications concerned a single case of skin parcellar necrosis, that healed
      spontaneously with medications and a case of prolonged serous secretion the mean
      follow-up was 2 years from the wound. CONCLUSIONS: In our experience the use of
      marlex mesh may be effective in treatment of parastomal hernia only a patient
      treated with translocation of the stoma showed a recurrence of parastomal hernia.
      The positioning of the prosthesis at properitoneal level is subject to a lower
      incidence of recurrent parastomal hernia.

PMID- 10638148
TI  - [Diagnostic protocol of thyroid nodules used in a surgical case series (409
      cases)].
AB  - BACKGROUND: The introduction of ultrasonography and fine needle biopsy (FNB) has
      changed the approach towards thyroid pathology. At the Division of Surgical
      Oncology of the National Institute for Cancer Research in Genoa we use a complex
      diagnostic system for the selection of patients affected by thyroid pathologies.
      Our aim is to analyze this methodology and find the best diagnostic procedure for
      the individual patient. METHODS: Between January 1982 and June 1997, 2500
      patients (pts) were found to be affected by thyroid pathologies. The diagnostic
      procedures for thyroid pathologies are: physical examination and anamnesis,
      scintigraphy, ultrasonography, fine needle biopsy, blood dosages, radiography of
      trachea and aesophagus; some cases require Computerized Tomography of the neck
      and Magnetic Nuclear Resonance. At the end of the examinations 409 pts underwent
      surgery; we will be evaluating the diagnostic system of these patients. RESULTS:
      We found from our data, that the group with the highest incidence of malignant
      tumors is characterized by a large number of instrumental examinations. In fact,
      55/73 pts underwent all the instrumental exams, and in 21.1% a malignant tumor
      was found. These data are interesting, but more important is that only 409
      patients out of 2500 underwent surgery 16.3%. CONCLUSIONS: We believe that one
      single instrumental examination is not enough to detect the characteristic of a
      thyroid nodule; the three most important examinations, scintigraphy,
      ultrasonography and cytology, would make it possible to select those cases which
      need a surgical approach. We believe that the 20% incidence in these cases can be
      considered good result, considering that the incidence of malignant tumors in
      thyroid pathologies is about 5% and that in these cases although the tumors were
      not malignant, they were operated on for functional or mechanical disorder.

PMID- 10638149
TI  - [Primary retroperitoneal tumors. Treatment modality and prognostic factors].
AB  - BACKGROUND: Primary Retroperitoneal Tumors (PRT) form a heterogeneous group of
      malignant mesenchymal and neuroectodermal neoplasms making up only 1% of all
      solid neoplasms. METHODS: From 1965 to 1997, 27 patients (16 females and 9 males,
      age range 19-79 years) underwent operations at the General and Cardiovascular
      Institute of University of Milan for primary retroperitoneal tumors (22 malignant
      and 5 benign, sarcomas represented 68% of all malignant tumors). A retrospective
      analysis of these patients was performed to determine the prognostic parameters
      associated with a favourable prognosis. All patients were admitted with severe
      abdominal pain or a palpable mass, other symptoms included fewer and weight loss.
      The median duration of symptoms before presentation was 16 months (range 15 days
      5 years). Before surgical treatment abdominal and pulmonary CT scanning and MRN
      were undertaken on all patients with PRT to define the size of the tumor and the
      involvement of other retroperitoneal structures. RESULTS: Complete resection was
      possible in 54% of malignant tumors (n = 12), incomplete resection was performed
      in 14% (n = 3) and in 31% (n = 7) only biopsy was possible. Recurrent tumor
      developed in 25% of patients with total resection (n = 3), (median time to
      recurrence 5 years). Independent treatment variables (size, signs and symptoms,
      histopathologic findings and grade) and treatment-dependent variables (type of
      surgical treatment and adjuvant chemotherapy) were analyzed. Patients with
      complete resection had a 12 month survival of 100% (n = 12) compared to 50% (n =
      1) for those undergoing partial resection and 14.2% (n = 1) for those with simple
      biopsy. A 24-month survival of the patients undergoing complete resection was 25%
      (n = 3). Median survival for type of surgical treatment was 28 months for
      complete resection compared to 14 months for partial resection and only 8 months
      for biopsy. Twelve-months survival for tumor grade was 100% (n = 7) for low grade
      tumor (G1), compared to 66.6% (n = 4) for median differentiated tumors (G2), and
      37.5% (n = 3) for high grade tumors (G3). Twenty-four-months survival was 28.5%
      (n = 2) for low grade tumors compared to 16.6% (n = 1) of median differentiated
      tumors. High grade tumors were associated with a 35-month median survival time
      compared to 17 months for median differentiated tumors and 10 months for low
      grade tumors. Other variables (histopathologic findings, size, symptoms) had not
      significant impact on survival. Operative mortality rate was 3.7% (n = 1). The
      overall 2 years survival rate in patients with totally resected tumors was 25% (n
      = 3), (2G1, 1G2), while the 5 year survival rate was 16.6% (n = 2), (2G1).
      CONCLUSIONS: Complete surgical excision and low grade of the tumor are the most
      important parameters of survival. Recurrent disease is a vexing problem; a
      careful and prolonged follow-up based on the use of CT and MRN is recommended.

PMID- 10638150
TI  - [Long-term central venous access. Experience with 173 cases].
AB  - BACKGROUND: Utility of long term central venous accesses. METHODS: Personal
      experience in 173 long term central venous accesses (a.v.c.) performed from
      January 1990 to December 1997 in 172 patients mostly affected by neoplastic
      disease is reported. The device used was totally implantable in 102 cases (59%):
      82 Port (80.3%), 20 Chrono-infusors (20.7%); in 71 cases (41%) an external
      tunnellized catheter (c.v.c.). Percutaneous way with Seldinger procedure was
      performed in 168 cases (97.3%), left subclavian vein was preferred in 118 cases
      (68.2%). RESULTS: The overall complications in this series were about 7.4%: early
      4% (5 accidental arterial punctures, 2 pneumothoraxes), late 3.4% (1 subcutaneous
      pocket infection, 3 cutaneous necrosis, 1 venous catheter dislocation and 1
      migration). No significative differences in terms of complications were reported
      between totally implantable devices and external tunnellized catheter.
      CONCLUSIONS: The reasons of a low rate of complications in our series are to be
      found in the perfect aseptic condition of the operating room, the positioning of
      the a.v.c. under constant fluoroscopic control and a good management during the
      postoperative care of the a.v.c. The indications and the economic aspect for each
      kind of device used (c.v.c. or totally implantable a.v.c.) are then discussed and
      the conclusion drawn that for short term therapy, up to six months, (hematologic
      patients of this series) the external tunnellized catheter should be advisable,
      while for long term therapy administration (solid tumors and parenteral
      nutrition) totally implanted device should be recommended.

PMID- 10638151
TI  - [Kidney and urinary tract injuries. Experience with 113 cases].
AB  - BACKGROUND: Trauma of the kidney and urinary tract is not rare in emergency
      surgery and the related treatment needs today high competence and
      interdisciplinary approach. Aim of the study was to analyze the personal
      experience in order to find differences in the treatment during the last years
      especially for trauma of the kidney. METHODS: The authors report 113 cases of
      kidney or urinary tract trauma out of 16,569 patients admitted in emergency
      between 1981 and 1995. Fifty patients (44%) underwent surgery. Thirty patients
      (26%) underwent surgery for kidney trauma but in only 5 (16%) conservative
      surgery for partial damage was possible. Section of the ureter occurred in one
      patient. Ten patients had a rupture of the bladder and 9 the rupture of urethra.
      The cause of trauma was a gunshot wound in 11 patients (22%). Nineteen patients
      (38%) had also damage to other organs. RESULTS: The results show absence of
      morbidity or mortality related with urinary tract trauma. CONCLUSIONS: The
      analysis of these cases shows that the improvement of diagnostic possibilities
      allowed the reduction of surgical interventions especially for kidney trauma.

PMID- 10638152
TI  - [Assessment and treatment of incidentally discovered adrenal tumors].
AB  - An incidentally discovered adrenal mass involves two main questions: the first is
      the evaluation of the hormonal activity of incidentalomas, that by definition are
      considered clinically silent. The second problem is to establish preoperatively
      the biologic behaviour of the masses, whether they are benign or malignant. An
      essential endocrinological screening of these masses includes the 24 hour urine
      VMA determination, serum potassium level, and a 1 mg overnight dexamethasone
      suppression test. Furthermore, the recent observation of a possible partial
      deficit of 21-hydroxylase suggests the advantage of 17-hydroxyprogesterone dosage
      after ACTH stimulation. At present no biochemical or radiologic markers can
      reliably distinguish benign from malignant masses. For this reason the
      association of imaging study with scintigraphy seems to be helpful, providing
      "concordant" or "discordant" patterns with CT images. As regard to therapeutic
      indications, the resection of all hypersecretive masses, proved malignant or
      increased in diameter tumors is suggested. As regards to biochemically silent
      lesions, the tumor size has been deemed to be the most helpful determinant of the
      nature although controversy remains over the size cutoff below which the masses
      can safely be presumed to be benign and therefore observed. The threshold to
      proceed surgically has been based on the perceived risk of cancer balanced
      against the operative risk. However it seems reasonable to recommend excision or
      surgical exploration for hormonally silent tumors greater than 3 cm, particularly
      in younger patients. According to personal opinion the laparoscopic approach
      might represent the gold standard in the treatment of incidentally discovered
      adrenal masses.

PMID- 10638153
TI  - [Microsurgical repair of iatrogenic injuries of the recurrent laryngeal nerve].
AB  - In this retrospective study the functional results of microsurgical repair of
      iatrogenic recurrent nerve lesions (10 patients) faced during years 1983 through
      1995 have been analysed. Different parameters were considered (thyroid disease,
      previous thyroid surgery, microsurgical reconstruction technique, time between
      surgical damage and microsurgery). Furthermore, a thorough review has been made
      on the medical literature on subjects such as surgical anatomy of the cervical
      region, microsurgical nerve repair techniques, and clinical results of
      microsurgery in different authors experiences.

PMID- 10638154
TI  - [Partial resection of the tracheal wall and introverting tracheoplasty].
AB  - A tracheal tumor involving roughly the half circumference of the tracheal wall
      and 3.5 cm length, was resected preserving the part of the tracheal cylinder not
      invaded by the tumor; reconstruction was carried out by an introverting
      tracheoplasty. This reconstruction technique, already successfully carried out in
      main bronchus resections, allowed iuxtapositioning of the tracheal rims very
      firmly without tension, the maneuvers for laryngeal or carenal release being not
      necessary.

PMID- 10638155
TI  - [Sclerosing peritonitis. A complication of LeVeen peritoneovenous shunt].
AB  - Sclerosing peritonitis (abdominal cocoon syndrome) is a rare chronic affection of
      the peritoneum; its etiology is multifactorial and it affects all ages.
      Capsulating membranes seem to grow from a poorly cellular connective deposition
      in many layers on the intestinal peritoneum and are casually detected by surgery
      or autopsy. The placement of the peritoneovenous shunt can favour the deposition
      of fibrin on the visceral peritoneum, determining the formation of sclerosing
      membranes. When mechanical occlusion occurs, surgery is the choice therapy in
      order to remove the obstacle and, if possible, the membranes as well.

PMID- 10638156
TI  - [Surgical treatment of internal duodenal diverticulum. Report of 2 clinical
      cases].
AB  - Internal duodenal diverticulum is a rare disease. Nowadays, less than 100 cases
      are reported in Western literature. Even if it is a pathology of malformative
      origin, the first clinical manifestations occur quite always during the III
      decade. Main symptom is a violent, suddenly arisen, abdominal colic, often
      associated with meals and with spontaneous remission. Frequency of accesses is
      variable in time; in most serious cases, colics are so close to cause a
      considerable reduction of nutrition. Among diagnostical means, very useful are Rx
      enema (that offers pathognomonical images) and endoscopy, by which the formation
      can be visualized directly and its connection with papilla can be delineated. In
      some rare cases, differential diagnosis has to be made with cystic dilatations of
      bile duct, and particularly with type III according to Alonso-Lej classification
      or choledochocele. When such a distinction is not possible, differential
      diagnosis will be made on the basis of histological examination of the type of
      mucosa present in the internal aspect of the diverticulum. Therapy of symptomatic
      forms is surgery. The technique of choice is transduodenal diverticulectomy.
      Cannulation of bile duct is a useful means to found the papilla during
      intervention, to protect duodenal suture in the postoperative period and to
      control it radiologically. Two cases of internal duodenal diverticulum operated
      on in the last 2 years are described and diagnostical and therapeutical items are
      discussed.

PMID- 10638157
TI  - [Necrotizing fasciitis. A diagnostic and therapeutic challenge].
AB  - A case of necrotizing fasciitis of the upper limb caused by group A streptococcal
      infection and a case with an abscess of the hand caused by staphylococcus aureus,
      are presented. The anatomo-pathological and clinical differences between the two
      different types of infection are underlined and stress is laid on the
      excruciating pain, the high temperature and the rapidly spreading inflammatory
      necrotizing evolution of the first case. More than the anatomo-pathological
      findings of a necrotic area the authors consider more important, the rapidity and
      the severity of the infection, that can evolve into a toxic shock-like syndrome,
      and the microbiological isolation of the streptococcus type A. On the basis of
      personal experience and of an accurate review of the literature, a therapeutical
      protocol is proposed based on an aggressive surgical approach, prompt specific
      antibiotic treatment and daily control of the lesions.

PMID- 10638158
TI  - [Intestinal anastomosis in urology. Comparison of techniques].
AB  - BACKGROUND: Three different intestinal anastomosis were compared during
      reconstructive urologic surgery; time, cost and incidence of complications were
      evaluated. METHODS: From November 1993 to February 1997, 45 patients (43 males
      and 2 females) were submitted to ileal resection to fashion 30 ileal neobladder,
      8 ileal conduits and 7 augmentation ileocystoplasties. The patients were
      randomized in 3 groups. In the first group the intestinal continuity was
      performed by BAR; the second one was treated by GIA stapling device; the last
      underwent a manual suture with interrupted stitches double layer (vicryl).
      RESULTS: The mean follow-up was 18 months. The mean time of canalization was 6.3
      days. The complications were: one intestinal subocclusion (group 1); one
      abdominal wound infection (group 2); one anastomotic leak and one pulmonary
      embolism (group 3). The mean time of anastomosis was 18, 12 and 39 minutes
      respectively. The average total cost was 915,000 lire in group 1; 1,280,000 lire
      in group 2; 632,000 lire in group 3. CONCLUSIONS: The conclusion is drawn that
      mechanical devices (BAR and stapler) are more convenient and advisable in
      reconstructive urologic surgery, for their quickness, effectiveness and final
      total cost.

PMID- 10638159
TI  - [Peripheral anesthesia techniques in surgery of the arm].
AB  - BACKGROUND: This report deals with the techniques of peripheral anaesthesia used
      by the Authors for surgical treatment of lesions of the upper extremity. METHODS:
      Plexus brachial block anaesthesia using a supraclavicular approach was performed
      for arm, forearm and hand surgery, axillary block anaesthesia for forearm and
      hand surgery, while block anaesthesia was employed for wrist and hand injuries.
      Local anaesthetics as Bupivacaine 0.5% and Mepivacaine 2% without Epinephrine
      were used. RESULTS: In 95% of the cases the results were satisfactory, in 5% (not
      cooperating and young patients, long operations, incomplete block anaesthesia) it
      was necessary to perform a general anaesthesia. CONCLUSIONS: Surgeons and
      patients well accepted these techniques of anaesthesia because of: less bleeding
      during the operation, easy surgical performance, high percentage of success in
      reimplantations, absence of side effects due to narcosis, better recovery of
      psycho-physical conditions and long lasting postoperative analgesia.

PMID- 10638160
TI  - [Evaluation of Ron and Met proto-oncogene expression in epithelial ovarian
      tumors].
AB  - BACKGROUND: Epithelial ovarian cancer is the most lethal gynecologic neoplasia.
      Up to date, little is known about its biology, and this makes even more difficult
      the definition of new therapies and the finding of early diagnostic methods. In
      this study, the expression of two oncogenes, Ron and Met, whose role in cancer
      progression has already been shown, and the possible clinical implication of
      their presence in the neoplastic tissue have been evaluated. METHODS: Forty-eight
      ovarian cancer specimens, 5 borderline lesions, 4 benign ovarian tumors and 2
      normal ovaries were analyzed; from frozen tissue, Rna was extracted and cDna
      obtained by a RT-PCR (Retrotranscriptase-Polymerase Chain Reaction). Finally, the
      cDna was assayed for the presence of the Ron and the Met gene by another PCR. The
      results were correlated with clinicopathological parameters, and patient
      survival. RESULTS: Ron expression was shown in 56% of malignant lesions, and in
      60% of borderline ones, while Met expression was detected in 54 and 60%,
      respectively. No statistically significant correlation was found between Ron and
      Met expression and clinicopathological features, such as histotype, grading,
      staging, residual tumor after debulking surgery, and response to chemotherapy,
      while a strong correlation (p = 0.001) was observed between overexpression of one
      of the oncogenes and the concomitant expression of the other. CONCLUSIONS: Even
      if residual tumor after debulking surgery was the most relevant prognostic
      factor, this study showed new data about the concomitant expression of Ron and
      Met oncogenes, which may suggest their cooperative role in ovarian cancer
      progression.

PMID- 10638161
TI  - [Critical review of colpo-histological results in cervix pathology].
AB  - BACKGROUND: The objective of this paper was to evaluate the role of squamous
      metaplasia in the determination of certain colposcopic appearances. METHODS: One
      thousand four hundred and six infertile outpatients, attending assisted
      reproduction techniques, underwent a "first level" colposcopy. Two hundred fifty
      nine abnormal transformation zones were biopsied and the histologic diagnoses
      were subdivided as follows: squamous metaplasia, squamous metaplasia +
      koilocytosis, isolated koilocytosis, condyloma, CIN + HPV, cervicitis. RESULTS:
      Two hundred forty seven cases out of 259 biopsied colposcopic findings (95.4%)
      were colposcopically classified as grade 1 abnormal transformation zone (thin
      white epithelium, regular mosaic and punctuation). The correlation between 247
      grade 1 abnormal transformation zone colposcopic patterns and histologic
      diagnosis revealed 105 (42.5%) histologic findings described as squamous
      metaplasia that resulted immature in 63% of these samples. Between 132 (53.4%)
      cases that presented a pattern of human papillomavirus infection (condyloma,
      squamous metaplasia + koilocytosis or isolated koylocitosis), quite two thirds
      (62%) were described as condylomas, one third (31%) as squamous metaplasia
      associated with koylocitosis and only 7% as isolated koylocitosis. In conclusion,
      42.5% of target biopsies performed on low grade abnormal transformation of the
      cervix revealed squamous metaplasia, more than half of them revealed one of HPV
      infection forms, while only 2% represented cervical intraepithelial neoplasia.
      CONCLUSIONS: Among the low risk female population, one out of two cases of
      colposcopically low grade pattern should be considered indicative of squamous
      metaplasia. The results obtained confirm that colposcopic evaluation is unable to
      distinguish between immature metaplastic transformation of the epithelium and
      metaplastic epithelium with initial neoplastic transformation.

PMID- 10638162
TI  - Markers of tubular damage in pre-eclampsia.
AB  - BACKGROUND: The aaim of this study is to investigate the tubular damage markers
      in pre-eclampsia and in pregnancy induced hypertension (PIH). METHODS: This
      transversal study involved 111 women admitted to the Department of Obstetric and
      Gynaecology, University Hospital, Padua (Italy) and was conducted from the 24th
      week until delivery: 23 had normal pregnancies, 54 manifest pre-eclampsia, and 34
      manifested pregnancy-induced hypertension (PIH) without superimposed pre
      eclampsia. The following laboratory tests were performed: U-alpha 1
      microglobulin, U-NAG, uric acid and microalbuminuria. The four groups were
      compared using the Mann-Whitney test and the Kruskall-Wallis test for multiple
      comparisons. A value of p < 0.05 was considered as statistically significant.
      RESULTS: As for the markers of tubular damage, the values for urinary NAG were
      significantly lower in the control group (0.97 U/mmol Creat) than in the pre
      eclampsia group (2.89 U/mmol Creat), and the PIH group (2.12 U/mmol Creat) (p <
      0.01). Values for urinary alpha 1-microglobulin were higher in the pre-eclampsia
      group (4.03 U/mmol Creat) than in the control (0.74 U/mmol Creat), and PIH groups
      (1.88 U/mmol Creat) (p < 0.01). As for the markers of glomerular damage, the
      values of microalbuminuria were higher in the pre-eclampsia group (134
      micrograms/min) than in the control (9.4 micrograms/min), and PIH groups (10
      micrograms/min), (p < 0.05). Uric acid, the marker of glomerular and tubular
      damage, was higher in the pre-eclampsia group (0.27 mmol/L) than in the control
      (0.20 mmol/L), and PIH groups (0.24 mmol/L), (p < 0.05). CONCLUSIONS: In pre
      eclampsia there is a tubular and glomerular damage to point out by an increased
      urinary excretion of NAG. In pre-eclampsia, an increase of urinary alpha 1
      microglobulin excretion may be considered to be partly due to the overloading of
      the tubule and partly due to a mixed glomerular and tubular lesion.

PMID- 10638163
TI  - [The cardiotocographic service during pregnancy. Reports on operative procedures
      used at different centers of the National area].
AB  - BACKGROUND: Aim of the paper is to verify the presence of operative procedures
      and their differences in the use of cardiotocography during pregnancy by some
      sample Centres in the national area. METHODS: From the year-book AOGOI 1997, 50
      Operative Units of Obstetrics and Gynecology were chosen and sent a
      questionnaire, duly prepared, in order to get the following information: presence
      of a specific Cardiotocographic Service during pregnancy and its supply; number
      of patients and way of making appointments; duration and frequency of controls;
      type of reporting; type of cardiotocographs used; behaviour in emergency cases
      and possible combined diagnostics. RESULTS: Most of the Centres interviewed (64%)
      have their own Cardiotocographic Service which may be used in the morning by
      appointment. The patients have generally physiological pregnancies at term. Some
      differences were observed among the Centres concerning the period of the first
      control and the frequency of the following ones. The average number of antepartal
      non-stress tests has been of 3.9 with a very wide range (1-10). Only in 23.5 and
      in 12.7% of the cases a cardiotocographic control is required starting from the
      40th and 41st week respectively. In the remaining cases (63.8%) controls are to
      be effected between the 34th and the 39th week. The average duration of the
      cardiotocographic recording changes if computerized appliances are used; in any
      case, the most likely duration is between 21 and 30 minutes. Doubtful reports per
      year were more when using non-computerized cardiotocography (10.8% vs 7.08%). In
      most of the Centres, a system of reporting on a final evaluating form, enclosed
      to the cardiotocogram, is used and in 72% of the cases the Centre may give an
      echographic and echofluximetric combined evaluation. Almost the total of the
      sample interviewed solved the problem of "emergencies" by entrusting the medical
      and paramedical staff of the Obstetrics Department, with controls. CONCLUSIONS:
      Antepartal Cardiotocography has nowadays become a means of control widely spread
      also in physiological pregnancy. In fact, most of the sample Centres have their
      own ambulatory Service. The same operative procedures were not followed by these
      Services and the solution of running problems (admission of users) varies in each
      Centre according to the number of users and the availability of means and staff.

PMID- 10638164
TI  - [The antioxidants (coenzyme Q10) in materno-fetal physiopathology].
AB  - BACKGROUND: Coenzyme Q10 (ubidecarenone) is a torpeniod molecule mainly located
      in bacterial and mitochondrial membranes. It is a part of a specific enzyme
      system and acts primarily on the transport of electrons in the mitochondrial
      respiratory chain. It performs an antioxidant action. We studied both fetal and
      maternal coenzyme Q10 plasma levels in physiological conditions and also in the
      presence of some pathologies. METHODS: As regards the maternal side, we selected
      483 pregnancies, performing 615 blood samples, and divided them into four groups:
      A: physiological pregnancies; B: spontaneous abortions; C: threatened abortions;
      D: threatened late abortions and threatened pre-term deliveries. We then selected
      61 pregnancies which differed from the previous ones and determined Q10 levels in
      fetal samples obtained by cordocentesis. We divided a control group from
      pathological groups: intra-uterine growth retardation (IUGR); Rh-isoimmunization
      (with intra-uterine transfusion), non immune fetal hydrops, fetal malformations.
      Coenzyme Q10 levels were determined in only one laboratory by high-performance
      liquid chromatography (HPLC). Coenzyme Q10 concentrations were expressed as
      mg/ml, the data as the mean + SD. Statistical analysis was performed employing a
      linear regression model and the student "t"-test. RESULTS: After working out a
      normality curve of CoQ10 levels in maternal blood, we noticed that the levels of
      Coenzyme Q10 were low in spontaneous abortions, in threatened late abortions and
      in threatened pre-term deliveries. We determined the value of 0.3 mg/ml as a
      cutoff to differentiate the fetal from the adult values. Moreover, CoQ10 values
      turned out to be increased only in fetuses affected by non-immune fetal hydrops.
      CONCLUSIONS: Accordingly, we can say that maternal CoQ10 plasma levels can be
      considered as a marker of pathological uterine contractile activity. There is a
      substantial increase in CoQ10 fetal plasma levels in fetuses affected by hypoxic
      hypoxia and also in those affected by non-immune fetal hydrops.

PMID- 10638165
TI  - [Fetal malformations and chromosome abnormalities diagnosed at the Center of
      Prenatal Diagnosis of the University of Aquila in the 1995-1998 triennium].
AB  - BACKGROUND: Over the past few years numerous techniques have been developed,
      allowing an evaluation of fetal physiopathology that was unthinkable until
      recently. The authors describe 20 cases of fetal malformations and chromosomal
      abnormalities diagnosed by scan and amniocentesis at the Centre for Diagnosis and
      Obstetric Prophylaxis at L'Aquila University. METHODS: Between January 1995 and
      April 1998 a total of 1180 amniocentesis and 4000 obstetric scans were performed
      in a group of 1650 pregnant women. RESULTS: Of the patients examined using
      ultrasound scan, 8 presented manifest fetal pathologies, of which 5 were
      associated with chromosome abnormalities: 1) left ventricular hypoplasia, common
      atrium, tricuspid dysplasia; 2) omphalocele; 3) Morgagni-Stewart-Morel syndrome;
      4) plurilobate cystic hygroma; 5) duodenal atresia; 6) Dandy-Walker syndrome; 7)
      cystic hygroma and hydrops; 8) cystic hygroma, hydrops, cardiopathy and Dandy
      Walker syndrome. Among the pregnant women undergoing amniocentesis without a
      prior diagnosis of fetal malformation, 12 presented pathological fetal
      karyotypes: 2 cases of Turner's syndrome; 2 cases of Edward's syndrome; 2 cases
      of Klinefelter's syndrome, of deletion of a stretch of chromosome 8; 1 case of
      Down's syndrome; 2 cases of supernumerary marker chromosome; 1 twin pregnancy
      with Klinefelter's syndrome in one twin and paracentric inversion of chromosome
      13 in the other; 1 twin pregnancy with a small supernumerary marker chromosome in
      both twins. CONCLUSIONS: Ultrasonography often enables the diagnosis of
      congenital abnormalities not associated with chromosome pathologies. However,
      karyotype studies play an essential role in pregnancies with a high genetic risk.

PMID- 10638166
TI  - [Periconceptual folic acid intake by Sicilian couples at a risk of recurrence of
      NTD].
AB  - BACKGROUND AND AIM: The authors aimed to evaluate the frequency with which
      pregnant Sicilian women with a high risk of recurring neural tube defects (NTD)
      attending the Ultrasonography and Prenatal Diagnosis Clinic in the Department of
      Diagnosis and Treatment at Ospedale S. Bambino in Catania were aware of the
      preventive effect of folic acid supplements during the periconceptional period
      and whether they therefore took folic acid supplements before the next pregnancy.
      METHODS: All pregnant women undergoing ultrasonography between January 1997 and
      December 1998 were interviewed. It was noted whether any earlier offspring had
      suffered from NTD or whether relatives (sisters, brothers, parents) had also
      suffered from the same experience. They were also asked whether they knew about
      the preventive effect of periconceptional folic acid supplements on the
      development of NTD, whether their pregnancy was planned and whether they had
      taken periconceptional folic acid supplements and, if so, at what dose. RESULTS:
      Eighteen couples were identified as being at risk for recurring NTD, in 3 cases
      owing to an earlier pregnancy resulting in NTD (2 cases of spina bifida and 1
      case of anencephaly) with a negative family history for NTD; a further 15 couples
      showed a positive family history for NTD. None of the women were aware of the
      preventive effect of acid folic supplements during the periconceptional period on
      the development of NTD. Out of 11 programmed pregnancies, none of the pregnant
      women took folic acid during the periconceptional phase. CONCLUSIONS: Pregnant
      Sicilian women at risk for recurring NTD interviewed by the authors were not
      aware of the possible prevention of NTD using folic acid supplements during the
      periconceptional phase.

PMID- 10638167
TI  - Benign ovarian fibroma associated with free peritoneal fluid and elevated serum
      CA 125 levels.
AB  - This paper reports the clinical case of a patient with ovarian neoplasia, ascites
      effusion, and elevated serum CA 125 levels (411 U/ml). This condition simulated a
      malignant pathology on the grounds of preoperative diagnostic examinations.
      Surgical investigation diagnosed an ovarian fibroma and ascites. Ascites was
      resolved rapidly and the serum CA 125 levels decreased after surgical neoplasia
      removal. An ovarian neoplasia associated with ascites effusion and elevated serum
      CA 125 levels (also in the presence of suspect ecographic and tomographic
      features) do not necessarily imply a malignant neoplasia.

PMID- 10638168
TI  - [Congenital factor XIII deficiency in pregnancy. A case report].
AB  - Congenital factor XIII deficiency is a rare hemorrhagic syndrome with an altered
      fibrin stability, hemorrhagic diathesis and habitual abortions. After a short
      introduction, a case report is described and the clinical differences between
      plasmatic and platelet deficiency pointed out.

PMID- 10638169
TI  - Variables affecting salivary Streptococcus mutans counts in a cohort of 12-year
      old subjects.
AB  - BACKGROUND: Several factors such as toothbrushing, diet, acidogenic potential of
      the mutans streptococci strain and site of the carious lesion can modify the
      salivary Streptococcus mutans (Sm) counts. In the present investigation the
      effect of some behavioural, clinical and microbiological variables on Sm salivary
      counts was evaluated in a cohort of 12-year-olds. METHODS: Forty subjects were
      examined by two calibrated examiners (GC, AL). The number of surfaces either
      decayed occlusal, decayed smooth or filled and the number of bleeding sextants,
      (clinical index for oral hygiene) were reported. Saliva was collected using a
      tongue depressor and was plated onto mitis salivarius agar with bacitracin and
      20% sucrose. The presumptive Sm colonies were counted and the concentrations were
      logarithmically transformed. One Sm strain per subject was identified and the
      cariogenic potential evaluated as the minimum pH value recorded, during 5 hrs of
      incubation in 5% sucrose solution. The children's parents or guardians completed
      a questionnaire concerning the frequency of toothbrushing, the consumption of
      sweet foods and soft drinks and at what age the children started brushing their
      teeth. The effect of the explanatory variables on Sm count logarithms was
      evaluated by stepwise multiple regression. RESULTS: The regressors with
      significant additional explanatory power were cariogenic potential (b = -1.335, p
      = 0.00001, R2 increment = 0.312), decayed smooth surfaces (b = -0.456, p = 0.009,
      R2 increment = 0.114) and bleeding sextants (b = -0.113, p = 0.004, R2 increment
      = 0.062), whereas the power of filled surfaces was marginally significant (p =
      0.08). CONCLUSIONS: On the basis of these results, it is suggested that
      acidogenicity is not only a cariogenic factor, but also a factor promoting
      colonization of oral sites by Sm, especially in subjects with a high frequency of
      sugar consumption.

PMID- 10638170
TI  - [Changes in the mouth mucosa in patients with chronic inflammatory intestinal
      diseases].
AB  - BACKGROUND: Oral mucosa and periodontal lesions occurrence in Inflammatory Bowel
      Disease (IBD), Ulcerative Colitis (UC) and Crohn Disease (CD). METHODS: This
      study involved 100 patients examined for 5 years (1990/1995), with a clinical and
      histopathological diagnosis of CD (21 patients) and UC (79 patients). RESULTS:
      The analysis of the data obtained, from our sample, showed that 5 patients out of
      100 presented aphtha minor lesions; in 3 cases the diagnosis was, respectively,
      of two neoformations of the genian mucosa--which turned out to be a papilloma and
      a fibroma--and a retro-commissural leukoplakia, degree OIN I. The 50% of our
      patients presented parodontal lesions, oral candidosis in 15 out of 67 patients
      who presented a whitish coating on the back of the tongue. CONCLUSIONS: The
      results of this investigation, lessen the importance of an association between
      IBD and oral diseases.

PMID- 10638171
TI  - Pulpo-dentin protection: the biocompatibility of materials most commonly used in
      restorative work. A literature review.
AB  - The complexity and importance of the biological structures that form the so
      called pulpal dentinal complex call for considerable accuracy during restorative
      procedures. In practice this means accurate techniques and appropriate dental
      materials, able to combine protective and restorative qualities, and above all,
      offering biocompatibility. In order to analyze this property, a number of
      international studies suggest the use of sequential tests divided into three
      different levels: initial tests, secondary tests and usage tests in the form of
      in vivo and in vitro tests to observe and simulate the biological reactions to
      dental materials used in particular tissues. The authors publish a review of the
      literature regarding the biocompatibility of intermediate materials regarded as
      useful aids in restorative dental practice; these include paints, liners and
      cavity bases made from Ca(OH)2, ZOE cements, zinc phosphate, polycarboxylic
      compounds, glass ionomers, bonding agents and mordents. The chemical, biological,
      clinical and utilization parameters are outlined for each compound, paying
      special attention to the problem of biocompatibility and indicating the pulpal
      reactions reported over the past decade in connection with their use. In
      conclusion, while waiting for a standard international document to codify
      evaluation methods and classify the results obtained, these experimental data can
      be used to programme a more correct and safer use of materials.

PMID- 10638172
TI  - [Non-Hodgkin lymphoma of the maxilla. Report of a case].
AB  - Lymphomas are primitive neoplasias of the lympho-reticular system and are
      classified into two principal categories: Hodgkin's lymphoma (HL) and Non
      Hodgkin's Lymphoma (NHL) each classified into low, medium and high grades,
      according to their clinical and cytological characteristics. The treatment and
      prognosis of such neoplasias vary according to the distribution of the illness
      and to the moment of initial diagnosis. In NHL, treatment depends prevalently on
      the histological subtype. Over the last few years it has been possible to
      associate to defined nosographic entities a characteristic phenotype, and to
      formulate a phenotypical classification of chronic lymphoproliferating illnesses.
      The classification of the Working Formulation subdivides lymphomas into groups of
      increasing malignancy. In histological sections, non-Hodgkins lymphomas are
      relatively homogeneous, uniformly cellular and dominated by malign lymphocytes.
      The symptomatology of NHL can vary according to the different location. The
      clinical manifestation of NHL can be in the form of swelling or ulceration. In
      contrast with lymphonodal lymphoma, in which the spread through blood to distant
      lymphonodal regions or extra lymphonodal areas is rapid, the extra lymphonodal
      ones show a clinical course of illness comparable with those of carcinomas. The
      authors present the case of a 89 year-old patient with an ulcerated, non painful
      swelling in the upper right alveolar maxillary region, showing slow development,
      soft consistency and indefinite edges; this lesion did not affected the normal
      physiological functions of the stomatognathic apparatus, thus explaining why the
      patient had noticed the appearance of the process two years prior to the visit
      but had not reported it. The pathological case-history shows traumas at the site
      of the lesions due to dentures. At the moment of the visit, the
      ortopathomographic examination of the upper and lower dental arch shows the
      presence of a lesion in the right maxillary region, radiographically opaque, with
      ill-defined margins and signs of continuity with the homolateral maxillary sinus.

PMID- 10638173
TI  - [Method of functional impression in prosthetic treatment with distal extension
      with dental-mucosal support].
AB  - Having examined the biomechanical problems regarding free-end tooth-tissue borne
      dentures caused by the different resilience of denture support structures and
      changes in the resilience of fibre-mucosa, and having reviewed the impression
      methods now in use, the authors describe a functional impression method used to
      obtain a clinical and instrumental record of the individual conditioning of fibre
      mucosa support by functional occlusal stress. The aim was to reduce the
      resilience of fibre-mucosa to levels comparable to periodontal and articular
      levels. The purpose was to achieve an optimal functional morphology of the
      prosthetic occlusal surface in order to guarantee the static and dynamic
      equilibrium of the denture. The authors describe a protocol based on weekly
      relining sessions and clinical and instrumental controls performed at every other
      session until optimal results have been obtained. Instrumental tests were carried
      out using the computerised occlusal analyser: T-SCAN version II. The authors used
      this device to measure the redistribution of occlusal forces acting on the
      occlusal surface in an antero-posterior and latero-lateral direction in
      subsequent sessions and the corresponding position of the centre of forces in the
      central area. In line with the results of earlier studies carried out by other
      researchers, the authors confirm that when maximum conditioning of the fibre
      mucosa support is achieved, it only retains a slight residual elasticity.

PMID- 10638174
TI  - The role of apoptosis and bcl-2 protein in topical treatment of oral leukoplakia
      with isotretinoin.
AB  - BACKGROUND: This study evaluates the role of bcl-2 protein, as well as, of
      apoptotic bodies in the topical treatment of oral leucoplakia with 13-cis
      retinoic acid (isotretinoin). To test this role, a clinical, histological and
      immunohistochemical study of the treated lesions was carried out, so as to verify
      the role of apoptosis and its genetic control mechanism of the development,
      progression and therapy of preneoplastic lesions. METHODS: A Double-blind study
      was carried out on 15 patients afflicted with oral leukoplakia. They were treated
      daily (3 topical applications) with 0.1% isotretinoin gel or a placebo for 4
      months. Afterwards, the patients treated with placebo were administered the
      active medication for an additional 4 month period. RESULTS: All the patients,
      with the exception of one patient who was lost to follow-up, who finished the
      treatment, showed a marked improvement of the dimension and the clinical aspect
      of the lesions (3 total remission, 11 improvement of the size and clinical
      appearance of the lesion of 50% or more). The immunohistochemical analysis for
      bcl-2 protein showed a weak positive reaction of the level in the basal membrane
      of the specimens collected before the pharmacological treatment; after the
      pharmacological treatment almost all the specimens with the exception of one,
      tested completely negative for bcl-2 protein. In the specimens collected before
      the pharmacological treatment only a few apoptotic bodies were observed, while
      after treatment the samples showed a noticeable increase of apoptotic bodies.
      CONCLUSIONS: A statistical analysis showed that the difference in the positive
      reaction to bcl-2 protein between the 2 groups is not statistically significant
      (p = 0.132). On the other hand, the difference in the count of apoptotic bodies
      between the 2 groups is statistically significant (p = 0.0193).

PMID- 10638175
TI  - [Bcl-2, p53, Ki-67 and apoptotic index in cancerous and precancerous lesions of
      the oral mucosa].
AB  - BACKGROUND: In this study an immunohistochemical analysis of both normal and
      pathological tissues was made to investigate the expression of some factors
      involved in genic regulation mechanisms of apoptosis. METHODS: In normal mucosa,
      in leukoplakia, in mild and severe dysplasia and in high, mild and low grade
      cancer a bcl-2, p53, and Ki 67 evaluation was made using immunostaining
      techniques; also an evaluation of apoptotic index was carried out. Seventy-two
      biopsies were made in 12 patients with normal mucosa, 12 affected by leukoplakia,
      12 by dysplasia (6 mild, 6 severe), 12 by low grade, 12 by mild grade and 12 by
      high grade cancer. > t RESULTS: The immunohistochemical analysis pointed out that
      there was weak bcl-2 expression in normal mucosa and in preneoplastic lesions and
      less more in severe dysplasia while bcl-2 was discreetly detectable in oral
      tumors. P53 was not detectable in normal mucosa and weakly expressed in
      preneoplastic lesions, presenting a peak in severe dysplasia. These results
      showed an interesting inverse relation between bcl-2 and p53 expression in severe
      dysplasia. Ki 67 expression results to be weak in normal mucosa, in preneoplastic
      lesions and in mild dysplasia, while it reaches the maximum level in severe
      dysplasia and in tumors. CONCLUSIONS: In all the samples the apoptotic index
      expression showed the same features of the Ki 67 protein. These results were
      achieved through statistically analysis carried out with the U Mann Whitney test.

PMID- 10638176
TI  - [Screening for prostate cancer: reasons for, reasons against].

PMID- 10638177
TI  - [24 Hour arterial pressure in insulin-dependent diabetics and non-insulin
      dependent diabetics with preserved renal function].
AB  - BACKGROUND: The aim of the study was to value the behaviour of systolic (S) and
      diastolic (D) arterial pressure (AP)/24 hrs in a group of diabetic patients
      insulin-dependent (IDDM) and non insulin-dependent (NIDDM) with preserved renal
      function. METHODS: We examined 65 diabetic patients (aged 39.1 +/- 23.3), 33 IDDM
      (aged 18.2 +/- 7.5; years of diabetes: 5.8 +/- 4.9) and 32 NIDDM (aged 60.7 +/-
      11.4; years of diabetes: 7.2 +/- 7.5). In all of them we computed BMI and
      determined creatinine clearance, glycosylated haemoglobin A, total and HDL
      associated cholesterol, triglyceridemia, middle glycemia and microalbuminuria. AP
      measurement was performed by 24 hrs monitoring (periodicity 15') using a Takeda
      2420 measurer. Chronobiological characteristics of AP were analysed by
      statistical method of cosinor according to Halberg, examining if there was or not
      a blood pressure circadian rhythm (PCR) (p < 0.05) and its characteristics
      represented by the mesor, the amplitude and the acrophase. Moreover the patients
      were subjected to a diet with fixed contents of sodium (130 mEq/day) and
      afterwards we drew (every 4 hours) renin (R), aldosterone (A1) and atrial
      natriuretic factor (ANF) which were analysed with cosinor's method. The purpose
      was not to compare the two populations, not homogeneous between them and not
      different only for the years of diabetes, but to study their blood pressure
      behaviour, the rhythm, the order of the indicated hormones for possible
      pathogenetic connections. RESULTS: NIDDM presented higher blood pressure values
      (PAS 134.2 +/- 3.5 and PAD 80.9 +/- 2 mmHg) than IDDM (PAS 116.6 +/- 1 and PAD
      66.4 +/- 1.7 mmHg), still in limits of substantial normality. The acrophase was
      in the midday for NIDDM (PAS 11:25', PAD 12:06') and in the early afternoon for
      IDDM (PAS 14:15', PAD 14:06'). Analysing the trend of the AP in the single cases,
      PCR was present in 70% and absent in 30% of IDDM while it was persistent in 56%
      and disappeared in 44% of NIDDM. IDDM without PCR differed from those with it in
      years of diabetes (p < 0.001), body weight (p < 0.02), BMI (p < 0.01),
      triglyceridemia (p < 0.05), all more elevated, as well as in higher PAS and PAD
      (p < 0.001) and in higher concentration of ANF (p < 0.05). The same comparison
      was done in NIDDM. Patients without PCR were older (p < 0.025), had higher PAS (p
      < 0.025) and PAD (p < 0.001) and also a more activated ANF (p < 0.001).
      CONCLUSIONS: This hormonal anomaly may be ascribed to a lower excretion of sodium
      with consequent expansion of extracellular volume due to antinatriuretic action
      of insulin often found at high plasmatic levels particularly in NIDDM.

PMID- 10638178
TI  - [Rare renal tumors (neoplasms other than conventional renal cell carcinoma).
      Clinico-pathologic aspects and review of the literature].
AB  - The clinical and pathological findings in 94 patients with surgically confirmed
      renal neoplasm from 1990 to 1998 have been retrospectively reviewed and a
      literature review is made. The heterogeneous group of rare renal tumours has been
      particularly considered: renal oncocytoma and oncocytomatosis, renal
      angiomyolipoma and renal medullary fibroma; chromophobe renal cell carcinoma
      (RCC), papillary RCC, multiple primary malignant RCC, hereditary RCC, renal
      sarcoma and sarcomatoid RCC, renal malignant fibrous histiocytoma, renal
      hemangiopericytoma and renal lymphoma.

PMID- 10638179
TI  - Penile metastasis from carcinoma of the prostate in a patient with high serum
      prostate specific antigen levels.
AB  - Prostatic carcinoma metastasizing to the penis is rare. Prognosis is poor with
      survival ranging from 1 to 24 months. A patient with prostate cancer and a serum
      Prostate Specific Antigen (PSA) level over 200 ng/ml, submitted to radical
      retropubic prostatectomy (RRP) and after 2 months presenting with two painful
      nodules in the penis, is described.

PMID- 10638180
TI  - [Uretero-arterial fistula as a complication of vascular surgery].
AB  - Urinary fistulae between ureter and iliac arteries are very uncommon. A case of
      fistula connecting ureter and bypass between iliac and femoral arteries is
      reported. This kind of surgical complication, due to arterial lesion during coxo
      femoral arthroprosthesis implant has never been reported in the literature.

PMID- 10638181
TI  - [A rare case of acute scrotum. Thrombophlebitis from ectasia of the left
      pampiniforme plexus].
AB  - The acutely painful scrotum may be due to testicular torsion, twisted testicular
      appendages, twisted spermatic cord or epididymitis. Most rarely it occurs as a
      result of a testicular trauma, orchitis, idiopathic scrotal edema, idiopathic
      infarction of testis and vaginalis tunica or testicular neoplasm; a spontaneous
      thrombosis of the spermatic vein vessels is quite unusual. A rare case of
      thrombosis of a dilated pampiniform plexus which occurred in a 6 year-old child
      is reported and its clinical presentation, diagnosis and treatment is discussed.
      The difficulty in making such a diagnosis is stressed since thrombosis of the
      spermatic vein is quite a rare entity; a conservative approach is suggested as a
      treatment of choice whenever a definite diagnosis is made, otherwise surgical
      intervention (ligation of the spermatic vein, if necessary) is required in order
      to rule out any other urologic emergency.

PMID- 10638182
TI  - [Cavernous adrenal hemangioma. Observation of a case and the problem of
      differential diagnosis].
AB  - Cavernous hemangiomas of adrenal gland are rare. A case of adrenal hemangioma
      discovered by chance and removed surgically is reported. A review of the
      literature is also made.

PMID- 10638183
TI  - [The effectiveness of long-term treatment of severe secondary hyperparathyroidism
      with intravenous calcitriol].
AB  - AIMS: To evaluate the efficacy of intravenous calcitriol as a means of
      significantly reducing plasma PTH in long-term hemodialysis with severe
      hyperparathyroidism. METHODS:  EXPERIMENTAL DESIGN: prospective study. FOLLOW-UP:
      12 months. SETTING: hospital hemodialysis centre. PATIENTS: 14 chronic
      hemodialysis patients, 6 males and 8 females, mean dialytic age 6.3 +/- 2.7
      years, mean age 65.3 +/- 10.5 years, PTH-I > 500 pg/ml; normal serum calcium,
      serum phosphate, serum aluminium; normal or increased alkaline phosphatase; signs
      of hyperparathyroidism on hand X-ray; non-responder to oral calcitriol; 12
      patients completed the study. TREATMENT: intravenous calcitriol 6 micrograms/week
      post-dialysis, half dose during the study of 7 patients; preventive calcium salt
      suspension; reduced calcium in dialysis bath, low dose aluminium hydroxide and
      intravenous disodium clodronate to treat and prevent hyperphosohoremia and
      hypercalcemia. FINDINGS: in basal conditions: PTH-I, total serum calcium, serum
      phosphate, total alkaline phosphatase, serum aluminum, ultrasonography, neck
      scintigraphy; serum calcium, serum phosphate, alkaline phosphatase each week in
      the first 45 days, every 2 weeks up until the third month, every month until the
      twelfth month; PTH-I every 3 months, serum aluminium after 12 months. RESULTS:
      Reduction of PTH-I from 1006 + 363 to 303 + 136 pg/ml in 12 patients who
      completed the study, with occasional, controllable hypercalcemia and
      hyperphosphoremia; dropout 2/14 (14.2%). CONCLUSIONS: Intravenous calcitriol is
      an efficious and easily managed long-term treatment for hemodialysed patients who
      would otherwise undergo parathyroidectomy.

PMID- 10638185
TI  - [The 27th annual meeting of the Japanese Society of Clinical Immunology. Tochigi,
      Japan. October 6-8, 1999. Abstracts].

PMID- 10638186
TI  - Risk factors and pathogenesis of atherosclerotic lesion.

PMID- 10638184
TI  - ["Classic" vs autolubricant catheterization for endovesicular chemotherapy.
      Preliminary experience].
AB  - AIM: The aim of this study was to evaluate the frequency of urinary tract
      infections (UTI) after catheterisation for instillation comparing two systems:
      the "classic" method and the catheterisation using a new autolubricant device:
      EasiCath Coloplast. METHODS: During the period of endovesical chemotherapy
      (between 4 and 48 weeks), 22 patients (6 females and 18 males) were studied, aged
      between 53 and 78 years old. We have performed 139 instillations using Nelaton Ch
      14 or 12 type catheters lubricated with gel based on lidocaine, neomicyn and
      fluocinolone ("classic" method). Instead 135 patients have been treated with
      autolubricant devices according to the manufacturer's instructions. After 48
      hours from instillation, a total of 274 catheterisation have been examined using
      urine tests and urine culture with antibiogram. We administered a 5-point visual
      analogic score to the patients weighing the post-instillation dysuria. RESULTS:
      With "classic" method UTI frequency is 7.19% (10/139). The most common pathogen
      has been E. coli (7/10). With autolubricant catheters UTI frequency is 2.96
      (4/135). Klebsiella, Enterobacter, as well as E. coli (2/4) have been identified
      as pathogen. All patients with infections have been treated with targeted
      antibiotics based on the antibiogram. CONCLUSIONS: We have observed the people
      with autolubricant catheters left more comfort then those undergoing to the
      "classic" catheterisation. The frequency of post-catheterisation, dysuria was
      also reduced. Our data show that the new method is safer and easier to handle
      then the "classic" one. Moreover, common anaesthetic/antibiotic lubricant have
      important bacteriostatic effects that reduce the BCG viability.

PMID- 10638187
TI  - The short-term effects of tamsulosin in Japanese men with benign prostatic
      hyperplasia.
AB  - We evaluated the short-term effects of tamsulosin in treating benign prostatic
      hyperplasia. Twenty-seven patients, aged 57 to 86 years (mean 68.4); complaining
      of obstructive urinary symptoms who had received no previous treatment for such
      symptoms were orally administered 0.2 mg of tamsulosin for 4 weeks. Symptoms
      (total AUA symptom score and AUA symptom subscores) and objective parameters
      including peak and average flow rate, and post-void residual urine rate were
      evaluated before and after 1, 2 and 4 weeks of treatment. The mean total AUA
      symptom score and the mean AUA symptom subscores for incomplete emptying and weak
      stream were significantly decreased after only 1 week of treatment. The mean AUA
      symptom subscores for intermittency, urgency and nocturia were significantly
      decreased after 4 weeks of treatment. The mean AUA symptom subscores for
      frequency and hesitancy were unchanged after 4 weeks of treatment. The mean peak
      and average flow rate, and post-void residual urine rate were significantly
      improved after only 1 week of treatment. In conclusion, tamsulosin improved not
      only objective parameters but also symptoms only 1 week after the start of
      treatment.

PMID- 10638189
TI  - [Cardiac catheterization by a transradial approach].

PMID- 10638188
TI  - [QT dispersion in premature beats produced by extrastimuli from the right atrium
      and right ventricle].
AB  - The difference between the maximum and minimum QT interval measured from a 12
      lead electrocardiogram was defined as an index of spatial inhomogeneous
      repolarization of the ventricular myocardium. The causal relationship between QT
      dispersion and incidence of ventricular arrhythmias has been pointed out in
      various heart diseases, but until now it was discussed mainly related to sinus
      rhythm. QT dispersion in extrasystole may be more important in the development of
      arrhythmias. We examined 5 cases (mean age 34 +/- 12 years) with a history of
      paroxysmal supraventricular tachycardia, who underwent electrophysiologic study.
      Both atrial and ventricular premature stimuli were given at a basic cycle length
      of 600 msec respectively. The QT interval and the ventricular activation time
      (VAT) (period from premature test stimulus to the summit of QRS) of the premature
      beats were measured in a simultaneously recorded 12-lead electrocardiogram. QT
      dispersion (the difference between the longest QT interval and the shortest QT
      interval) and VAT dispersion (the difference between the longest VAT and the
      shortest VAT) were measured. In atrial premature beats, there were no significant
      changes in the QT dispersion or VAT dispersion when the coupling interval of the
      premature beats was shortened. In the ventricular premature beats, however, both
      the QT dispersion and the VAT dispersion tended to increase with the shortening
      of the coupling interval. We concluded that only a short coupled ventricular
      premature beat induces greater QT and VAT dispersion. A ventricular couplet with
      short coupling interval may contribute to the development of ventricular
      tachyarrhythmias.

PMID- 10638190
TI  - [Clinical epidemiology of primary hyperlipidemia in Japanese population, in
      comparison with western populations].
AB  - For the last years cardiovascular diseases are the major causes of deaths in
      Japan. The increase in the frequency of hyperlipidemia is thought to be the
      background factor of this trend. In this article, the characteristics of clinical
      epidemiology of hyperlipidemia in Japanese population will be reviewed, in
      comparison with the studies from Western populations. Regarding phenotypes, type
      IV hyperlipidemia is dominant in Japanese men, while type II is most frequent in
      Western populations. The differences in the serum cholesterol levels between
      Japanese population and Western one have got smaller year after year. The
      epidemiological study of hyper HDL cholesterolemia, which is characteristic of
      Japanese, will be also reviewed.

PMID- 10638191
TI  - [Guideline for diagnosis and management of hyperlipidemia for prevention of
      atherosclerosis in Japan].
AB  - Coronary heart disease (CHD) mortality and plasma cholesterol level have
      increased in Japan. There has been evidence indicating that cholesterol-lowering
      is effective in secondary and primary prevention of CHD. Hypercholesterolemia has
      been defined as over 220 mg/dl, and over 140 mg/dl for LDL-cholesterol. These
      levels were determined on the base of the evidence observed in Japan. The
      subjects are divided as follows, A: no CHD and no other risk factors, B: no CHD
      and at least one risk factor, C: manifest CHD. The treatment levels of LDL
      cholesterol are 140 mg/dl for category A, 120 mg/dl for B and 100 mg/dl for C.
      Although drug therapy may be necessary when LDL-cholesterol level is over 120
      mg/dl in category C, life-style modification is most important in category A and
      B.

PMID- 10638192
TI  - [Molecular mechanism of insulin resistance in hyperlipidemia].
AB  - Several types of abnormal lipoprotein particles are observed in patients with
      insulin resistance: elevated VLDL-triglycerides, remnant lipoprotein, small dense
      LDL, reduced HDL-cholesterol. These patterns are caused by environmental and
      genetic factors that alter the lipoprotein metabolism. These lipoprotein
      abnormalities cause insulin resistance through several factors which decrease LPL
      and PPAR gamma, on the other hand increase ACS and MTP. It is considered that
      increased plasma level of FFA will closely associated with these factors and
      their regulations. Secretion of TNF-alpha from adipocytes increases in obesity
      and closely relates to the pathogenesis of insulin resistance. But the genetic
      mechanisms are not still clear. More studies about genetic factors which affect
      to lipoprotein metabolism will be needed and should be considered about the role
      on insulin resistance.

PMID- 10638193
TI  - [Endothelial injury by oxidized LDL].
AB  - Recent progress in the research of oxidized LDL has revealed that this
      lipoprotein causes not only foam cell transformation of macrophages but also
      several endothelial dysfunction, and the effects on endothelial cells are also
      involved with the process of atherogenesis. Receptors for oxidized LDL on
      endothelial cells, such as LOX-1 and SREC, have been cloned and their
      characteristics are now under investigation. In addition to lowering plasma
      cholesterol level, it is expected that new strategies to prevent atherosclerosis
      is established by focusing on the endothelial injury caused by oxidized LDL.

PMID- 10638194
TI  - [Postprandial lipemia as an atherosclerotic risk factor and fat tolerance test].
AB  - Most of our lives are spent in the postprandial state, during which vessel walls
      are exposed to triglyceride rich lipoproteins-namely, chylomicron and chylomicron
      remnants. Recent studies showed that coronary artery disease patients even with
      normal fasting lipid levels had higher concentrations of postprandial
      lipoproteins than patients without coronary artery disease. Postprandial
      lipoprotein responses are influenced by various factors such as the
      postabsorptive concentrations of plasma triglycerides, lipoprotein lipase
      activity, polymorphisms of apolipoprotein B and apolipoprotein E, dietary fatty
      acid contents. Oral fat tolerance test is performed to see the postprandial
      lipoprotein responses. Triglycerides, apolipoprotein B, retinyl-palmitate and
      remnant like particles in plasma and subfractionated triglyceride rich
      lipoproteins are measured.

PMID- 10638195
TI  - [The role of apolipoprotein E in the pathogenesis of Alzheimer disease].
AB  - Alzheimer disease (AD) is by far the most common cause of dementia in humans.
      Massive accumulation of senile plaques and neurofibrillary tangles are
      characteristic neuropathological manifestations of the disease. Recent
      investigations have revealed the presence of apolipoprotein E (apoE) in these
      structures. Furthermore, APOE4, a specific allele of the apoE gene, is frequently
      associated with sporadic AD and late-onset familial AD. Now, APOE4 has been
      established as being a major risk factor for AD. Although apoE is one of numerous
      plasma lipoproteins, it is of particular interest because, unlike other
      lipoproteins that are mainly synthesized in the liver, apoE is also synthesized
      in astrocytes and oligodendrocytes in the central nervous system. Furthermore,
      apoE plays an important role in the regeneration and degeneration of neurons.
      Recent studies have indicated the possibility that APOE4 accelerates the
      deposition of amyloid beta protein, which is a major component of senile plaques
      in AD brains.

PMID- 10638196
TI  - [Sterol regulatory element binding protein that controls cholesterol metabolism].
AB  - Sterol regulatory element-binding proteins, designated as SREBP-1 and -2, are
      synthesized as membrane-bound proteins. They are localized on the endoplasmic
      reticulum membrane and the nuclear envelope, and activated by a two-step
      proteolytic processing. The NH2-terminal processed forms are released in the
      cytosol only when the intracellular cholesterol level is low, and translocated to
      the nucleus, resulting in the stimulation of transcription of the target genes.
      The transcriptional regulation requires either Sp1 or NF-Y, which binds its
      specific DNA-binding site close to the SREBP-binding site. On the contrary, the
      transcription of the MTP (Microsomal Triglyceride transfer Protein) gene is down
      regulated by SREBPs without any participation of either Sp1 or NF-Y.

PMID- 10638197
TI  - [The role of microsomal triglyceride transfer protein in metabolism of apo B
      containing lipoprotein].
AB  - Microsomal triglyceride transfer protein (MTP) plays a central role on secretion
      of lipoprotein from the liver and the intestine. MTP catalyzes the transfer of
      triglyceride, cholesteryl ester and phosphatidylcholine between membranes and
      lipoproteins. In human, defect of MTP activity, result from mutations encoding
      the MTP large subunit, is the primary cause of abetalipoproteinemia. To
      investigate the association between hyperlipidemia with obese and MTP, We used
      Otsuka Long-Evans Tokushima Fatty rat, an animal model of obesity with visceral
      fat accumulation, hyperlipidemia. In animals, very-low density lipoprotein
      triglyceride levels were elevated compared with the control rats. Hepatic mRNA
      levels of acyl-coenzyme A synthetase, and MTP were also elevated. These results
      suggest that the enhanced expression of both ACS and MTP genes associated with
      visceral fat accumulation may be involved in the pathogenesis of hyperlipidemia
      in obese animal models.

PMID- 10638198
TI  - [The LDL receptor family].
AB  - The LDL receptor family is known to bind and internalize apoE-rich lipoproteins,
      and thought to play a role in lipoprotein metabolism. The recently identified new
      members showed the structural heterogeneity in the family, and molecular
      biological approach using animal models revealed the essential biological
      function in neural development. These increasing novel findings suggest that the
      LDL receptor family is a cluster of multifunctional receptors for intracellular
      signal transduction, neuron migration and vascular smooth muscle cell
      proliferation, as well as lipoprotein incorporation.

PMID- 10638199
TI  - [Scavenger receptor family].
AB  - After the proposal of scavenger pathway hypothesis, a family of genes have been
      discovered. Here we show the precise properties of the first cloned scavenger
      receptor class A type I and II. Then the profiles of other members of scavenger
      receptors including lectin receptors are shown briefly.

PMID- 10638200
TI  - [The family of HDL receptor].
AB  - Several HDL binding proteins have recently cloned and their roles in HDL
      metabolism have been gradually elucidated. HBP (vigilin), which lacks a
      transmembrane domain, is responsive to cell cholesterol levels, however, its
      physiological roles remain unknown. SR-B1, a member of the class B scavenger
      receptor, has been reported to bind with not only oxidized LDL but also HDL. The
      level of SR-B1 expression correlates with both the selective cholesterol transfer
      into cells and cholesterol efflux from cells. These data suggest that SR-B1 plays
      important roles in steroid hormone production. HB2 shows high sequence homology
      with ALCAM (activated leukocyte-cell adhesion molecule). When overexpressed with
      HB2, HDL binding is increased in the cells. After PMA-induced differentiation of
      monocytes into macrophages, HB2 mRNA is elevated, which correlates with increased
      binding of HDL, but is down-regulated by cholesterol loading of macrophages.
      However, physiological role of HB2 also remains unknown.

PMID- 10638201
TI  - [Human apolipoprotein B48 receptor].
AB  - Unique candidate receptor membrane binding proteins, MBP 200 and 235, were
      identified in human monocyte-macrophages. The MBP binds and internizes
      chylomicrons, triglyceride (TG)-rich VLDL, and VLDL devoid of apo E, but not
      acetyl LDL, via a domain in apo B48. The MBP is named apo B48 receptor because
      the receptor-binding domain is within apo B48. The apo B48 receptor differs from
      the scavenger receptor family and LDL receptor family because it does not bind
      acetyl LDL and it binds VLDL devoid of apo E by an apo E-independent mechanism.
      Immunohisto-chemical studies indicate colocalization of anti-apo B48 receptor Ab
      and monocyte-macrophage specific Ab in human atherosclerotic lesion foam cells.
      This suggests that apo B48 receptor may contribute to foam cell formation and
      atherosclerosis in abnormal state with elevated TG-rich lipoproteins.

PMID- 10638202
TI  - [Recent advanced knowledges related with lipoprotein metabolism].
AB  - This article aims to highlight recent advanced knowledges in enzymes and transfer
      protein in lipoprotein metabolism, including lipoprotein lipase (LPL), hepatic
      triglyceride lipase (HTGL), lecithin: cholesterol acyltransferase (LCAT) and
      cholesteryl ester transfer protein (CETP). In addition to its traditional role in
      the hydrolysis of lipoproteins, recent studies have revealed other functions of
      LPL and HTGL which may serve as ligands of cell surface receptors and/or
      proteoglycans. Clinical studies also have demonstrated new aspects in genetic
      polymorphism of both enzymes related with coronary artery disease. Several animal
      models have provided exact functions of LCAT and CETP which play an important
      role of reverse cholesterol transport. Clinical approach of CETP deficiency may
      be useful to identify the mechanism of atherosclerosis.

PMID- 10638203
TI  - [Genetic disorders causing abnormal LDL-cholesterol levels].
AB  - Various epidemiological studies and lipid intervention trials have revealed that
      serum LDL-cholesterol level correlates to the incidence in ischemic heart
      disease, and decreasing the level can prevent cardiac events. Inherited diseases
      causing abnormal LDL-cholesterol levels are discussed in this article, including
      their animal models. Familial hypercholesterolemia, familial ligand-defective
      apolipoprotein B100, familial combined hyperlipidemia and cholesterol ester
      storage disease result in elevation of serum LDL-cholesterol. On the other hand,
      serum LDL-cholesterol is decreased in abetalipoproteinemia and familial
      hypobetalipoproteinemia. The development of genetic engineering technology has
      elucidated the mechanism of these genetic disorders and elaborated their animal
      models. Although most of them cause atherosclerotic or psychoneurological
      diseases, fundamental therapy remains to be established, such as gene therapy.

PMID- 10638204
TI  - [Hypo- and hyper alphalipoproteinemia and genetic abnormalities in reverse
      cholesterol transport system].
AB  - The risk of atherosclerosis has been known to be inversely correlated with the
      plasma concentration of high-density lipoprotein (HDL)-cholesterol, and we now
      know HDL plays a protective role against atherosclerosis. The most important
      mechanism, by which HDL could exert their anti-atherogenic role, is certainly the
      removal of excess cholesterol from peripheral cells and its transport to the
      liver, a process commonly called "reverse cholesterol transport system". In this
      system, many proteins are involved, i.e., ABC1, LCAT, CETP, HTGL and SR-BI.
      Abnormalities of these proteins reduce the efficacy of the system, and cause
      abnormalities of HDL and atherosclerosis. In this paper, we review the recent
      findings on the molecular mechanism of reverse cholesterol transport system, and
      then discuss hypo- and hyperalphalipoproteinemia, which are caused by genetic
      abnormalities of the key players.

PMID- 10638205
TI  - [Analysis of lipoproteins].
AB  - Most of serum lipids are transported in lipoprotein particles, such as
      chylomicron, VLDL, IDL and HDL. These lipoprotein fractions were classified
      according to density distribution by analytical ultracentrifugation. LDL-C and
      HDL-C are generally determined by precipitation method or homogeneous method as a
      most basic lipoprotein analysis. In order to diagnose the hyperlipidemia,
      electrophoretic method (agarose or polyacrylamide) is used. More detailed
      analysis of lipoprotein is examined by ultracentrifugation and high performance
      liquid chromatography.

PMID- 10638206
TI  - [Method for remnant lipoproteins--quantitative analysis of serum remnant-like
      particle cholesterol (RLP-C)].
AB  - The important role of remnant lipoprotein, which is linked up to serum insulin,
      in the development of atherosclerosis is well known. So, measurement of remnant
      has a benefit as the indicator of cardiovascular disease-risk. Recently, Nakajima
      et al have developed a simple, rapid assay method, using a immunoaffinity gel
      mixture of anti-apo B-100 and anti-apo A1 monoclonal antibodies coupled with
      Sepharose 4B. The apoprotein composition of RLP which is unbound with mixed gel
      is as similar to apo-E rich VLDL. Clinical significance of RLP-C has been already
      indicated by many reports.

PMID- 10638207
TI  - [New clinical application of direct and chemical measurement of low density
      lipoprotein cholesterol-estimation of compositional changes in triglyceride-rich
      lipoprotein fraction].
AB  - Recently several new direct assay systems for chemical measurement of LDL
      cholesterol (Ch) have been developed. These systems allow us to estimate LDL-Ch
      value even in samples under non-fasting condition as well as samples from
      prominent hypertriglyceridemics without ultracentrifugation. Since it is possible
      that the difference between LDL-Ch value measured using new direct method and
      that calculated using Friedewald's formula can indicate compositional
      abnormalities of triglyceride-rich lipoprotein (TGRL) fraction (if VLDL-Ch equal
      to 1/5 of plasma triglyceride, this difference must always be zero), this
      difference (estimated remnant-Ch) may represent the presence of remnant or
      intermediate density lipoprotein (IDL) fraction. LDL-Ch is not detected by means
      of this direct method (LDL-EX, Denka Seiken Co.) in the eluate of the affinity
      column, which contains anti-apoA1 and anti-B100 antibody, indicating that RLP
      fraction can be excluded from the assay system. Estimated remnant-Ch correlated
      well with RLP-Ch, IDL-Ch and apoE. Furthermore, there is no significant
      correlation between LDL-Ch measured by LDL-EX and Lp(a), indicating that this
      direct assay system does not include Lp(a) in plasma. Thus, this new direct assay
      method for LDL-Ch enables us to measure LDL-Ch value with ease and also to
      estimate compositional abnormalities of TGRL fraction and/or appearance of
      remnant or IDL fraction without ultracentrifugation.

PMID- 10638208
TI  - [Oxidized LDL in patients with coronary heart disease and normal subjects].
AB  - Basic research has provided strong evidence that oxidation of LDL plays an
      important role in the progression of atherosclerotic vascular disease. The levels
      of plasma oxidized two-density lipoprotein (ox-LDL) were measured by sandwich
      ELISA using the monoclonal antibody (DLH3) recognized oxidatively modified
      lipoproteins and the anti-human apolipoprotein B monoclonal antibody in healthy
      subjects and patients with coronary heart disease (CHD). Plasma ox-LDL could be
      detected in normal subjects and patients with CHD. No sex-related difference was
      observed in normal subjects. The levels of ox-LDL in the forties and fifties were
      higher than those in the thirties and twenties. The levels of plasma ox-LDL were
      significantly higher in patients with CHD than in controls. There was no
      difference between the levels of ox-LDL of patients with single vessel disease
      and those with multivessel disease. These results suggest that elevated levels of
      oxidized LDL may be a marker for CHD.

PMID- 10638209
TI  - [Primary hyperchylomicronemia and gene defects].
AB  - Primary Hyperchylomicronemia is known as a syndrome in which the accumulation of
      chylomicron occurs in the circulation. The main clinical symptoms of this
      disorder are the huge increase in plasma trigriceride and cholesterol, and the
      presence of xanthomatous eruption, lipemia retinalis, hepatosplenomegaly, and the
      complication of acute pancreatitis. With gene analysis, a deficiency of
      lipopreteinlipase (LPL) or apolipoprotein C-II is revealed as a main cause of
      primary chylomicronemia. Furthermore, in some cases, abnormalities of remnant
      receptors, the presence of antibody against LDL, apolipoprotein C-II, and LDL
      receptor are reported as causes of chylomicronemia syndrome. In the present
      paper, we summarized the major gene polymorphism and characteristics of clinical
      symptom of these disease.

PMID- 10638210
TI  - [Autoimmune hyperchylomicronemia].
AB  - The concept of autoimmune hyperlipidemia was proposed originally by Beaumont et
      al. Since then, hyperlipidemic patients with autoantibodies to circulating
      lipoproteins as well as enzymes related to lipoprotein metabolism have been
      documented. However, the mechanism remains speculative except in a few cases. We
      described a patient with autoimmune hyperchylomicronemia due to autoantibodies
      against lipoproteins lipase and hepatic triglyceride lipase. We also identified a
      hyperlipidemic case with inhibitory monoclonal antibodies against low density
      lipoprotein binding to fibroblasts and multiple myeloma. These data suggest that
      screening of patients with nonfamilial hyperlipidemia, especially those with
      associated autoimmune diseases, may result in the identification of other such
      patients.

PMID- 10638211
TI  - [Genotype-phenotype correlations in familial hypercholesterolemia].
AB  - The low-density lipoprotein (LDL) receptor gene mutations cause familial
      hypercholesterolemia (FH), which was characterized by increased levels of LDL
      cholesterol and premature coronary atherosclerosis. Molecular genetic study of FH
      showed extreme heterogeneity in their underlying LDL receptor gene mutations, and
      suggested that this heterogeneity is responsible for the variability of its
      clinical manifestations. Since 1988, we have identified 11 mutations (10 novel
      and 1 previously reported) in the LDL receptor gene among 201 unrelated FH
      families in Hokuriku district, Japan. However, they explained only 38.8% of the
      patients suggesting that a more efficient mutation screening method should be
      developed. Through mutation detection, a genetically-determined mild type of FH
      (homozygotes with relative longevity and normocholesterolemic heterozygotes) was
      found in a case in which exons 2 and 3 were eliminated by a 10 kb deletion
      (Tonami-2). In addition, cholesterol-lowering drug therapy was significantly more
      effective in heterozygous patients with the P664L mutation (Kanazawa-2) compared
      to those with a 6 kb deletion including exon 15 (Tonami-1). These observations
      indicate that FH patients should be managed based on the results of their gene
      analyses.

PMID- 10638212
TI  - [Familial combined hyperlipidemia].
AB  - Familial combined hyperlipidemia (FCHL) is the most common genetic hyperlipidemia
      of unknown etiology. FCHL is characterized by a variable phenotype of both
      hypercholesterolemia and hypertriglyceridemia in proband and family members.
      While, the genetic basis for FCHL has not been characterized, recently, linkage
      analysis of Finnish FCHL family indicated major gene locus on chromosome 1q21-23.
      We review recent progress of genetics of FCHL.

PMID- 10638213
TI  - [Primary hypertriglyceridemia].
AB  - Familial hypertriglyceridemia has been suggested to be an autosomal dominant
      condition with age-dependent penetrance, but so far the underlying defective gene
      has not been elucidated. LPL gene and apolipoprotein A-I/C-III/A-IV gene cluster
      might be involved in familial clustering of hypertriglyceridemia. Heterozygous
      LPL deficiencies caused by several types of gene mutation are known to result in
      a partial defect in catabolism of VLDL, occurring mild to moderate
      hypertriglyceridemia. However, although the mutation of LPL gene results in
      reduced lipolytic activity, this type of dyslipidemia appears to manifest only if
      VLDL-TG production is also increased. These suggest that overproduction of VLDL
      TG is a more important cause of hypertriglyceridemia than is the LPL deficiency.
      Moreover, families with a clustering of hypertriglyceridemia are known to be at
      increased risk of hyperinsulinemia due to impaired insulin sensitivity. Impaired
      insulin sensitivity and hyperinsulinemia are the major determinants of excessive
      VLDL-TG synthesis and dyslipidemia. Taken together, abnormally high production of
      VLDL-TG seemed to be the major factor in causing familial hypertriglyceridemia,
      but clearance capacity can play an important role in determining the severity of
      the TG elevation.

PMID- 10638214
TI  - [Remnant hyperlipidemia and gene polymorphism].
AB  - Remnant lipoproteins are intermediate metabolites of triglyceride-rich
      lipoproteins, such as chylomicron (CM) and very-low density lipoprotein (VLDL) in
      the circulation. Several lines of evidence have suggested that remnant
      lipoproteins are atherogenic. It is well known that some of the inherited
      dyslipidemias cause remnant hyperlipidemia and are accompanied with marked skin
      and tendon xanthomas, corneal arcus and premature or accelerated atherosclerosis.
      Among them, lipid abnormalities, clinical features and gene polymorphism of
      familial dyslipoproteinemia and hepatic lipase deficiency were reviewed. Even if
      one has affected alleles associated with these disorders, sometimes abnormal
      lipid profiles are difficult to reveal in the overnight fasting plasma. So, a
      tolerance test like a fat overloading may be required to elucidate such
      abnormalities.

PMID- 10638215
TI  - [Familial apolipoprotein A-I variants].
AB  - Apolipoprotein (apo) A-I is the major apolipoprotein of HDL and is a single
      polypeptide chain with 243 amino acid residues. Familial apo A-I deficiency is a
      rare metabolic disorder of which 13 cases have been characterized at the
      molecular level. However, in subjects with apo A-I deficiency, coronary artery
      disease is not always present. To date, more than 40 genetically determined
      structural variants of apo A-I have been identified. Seven apo A-I mutations have
      been identified to cause hereditary amyloidosis. In our laboratory, we
      characterized ten apo A-I variants, including apo A-I(Vall56Glu) Oita. A minority
      of structural variants were associated with altered HDL cholesterol levels or
      increased risk for cardiovascular disease.

PMID- 10638216
TI  - [Multiple risk factor syndrome].
AB  - Insulin resistance predisposes to the development of a cluster of abnormalities
      including glucose intolerance, hyperlipidemia, and hypertension, which may relate
      to the excess intra-abdominal fat deposits. The cluster of abnormalities
      increases a risk of atherosclerosis and comprises multiple risk factor syndrome
      (MRFS). Though many suspectable candidate genes of MRFS was analyzed, there is no
      compelling candidate gene by itself for MRFS. Simultaneous existence of polygenic
      and environmental factors may induce MRFS resulting in atherosclerosis.

PMID- 10638217
TI  - [Primary and secondary prevention of atherosclerotic disease by lipid-lowering
      therapies].
AB  - Epidemiological studies have shown close relationships between serum cholesterol
      levels and incidences of coronary heart disease (CHD). Primary and secondary
      prevention trials with cholesterol lowering have shown definite corresponding
      reductions in CHD. 4S in secondary prevention and WOS in primary prevention of
      hypercholesterolemic patients, CARE and LIPID in secondary prevention and CAPS in
      primary prevention in patients with average serum cholesterol levels have shown
      reduction of CHD. LDL-apheresis is more effective than medical treatment in
      heterozygous FH patients with CHD. Gemfibrozil is effective in secondary
      prevention of low HDL-cholesterolemic patients. Thus, for primary and secondary
      prevention of CHD the lower serum cholesterol level is the better.

PMID- 10638218
TI  - [Effectiveness and practice of dietary therapy and exercise].
AB  - Dietary therapy and physical activity are cornerstones for lipid lowering and
      prevention of cardiovascular disease. The efficacy of dietary therapy has been
      established in several primary and secondary prevention studies. Exercise is
      believed to be useful to prevent atherosclerosis, but there has been no mega
      trial performed. The beneficial effect of physical activity may be mediated in
      several ways, such as reduction in VLDL, increase in HDL, reduction in body
      weight and reduction in blood pressure. According to the guideline of Japan
      Atherosclerosis Society, dietary modification is recommended to perform in three
      steps and practical use of the guideline was described. For exercise, aerobic
      activity, such as brisk walking, jogging, swimming and bicycling are recommended.
      Intensity, amount and frequency of exercise were described.

PMID- 10638219
TI  - [HMG-CoA reductase inhibitors: anti-atherosclerotic effects other than lipid
      lowering].
AB  - Several clinical prevention trials have firmly established that normalization of
      elevated serum cholesterol levels by 3-hydroxy-3-methylglutaryl-coenzyme A(HMG
      CoA) reductase inhibitors reduces the incidence of coronary events. Four HMG-CoA
      reductase inhibitors are now available for clinical use in Japan, and two others,
      under development, are expected to have strong lipid-lowing effects including
      triglycerides. Indeed, HMG-CoA reductase inhibitors exert direct anti
      atherosclerotic effects, independently of their hypocholesterolemic properties.
      Recently many putative anti-atherogenic effects have been demonstrated, such as
      improvement in endothelial function, up-regulation of endothelial nitric oxide
      synthase activity, reduction of platelet thrombus formation, inhibition of
      monocyte chemotaxis or smooth muscle cell proliferation, and immunosuppressive
      effect. Moreover, HMG-CoA reductase inhibitors have shown the induction of cell
      death in vitro, by a pathway involving apoptosis. In conclusion, HMG-CoA
      reductase inhibitors may play more important roles, in addition to their well
      established efficacy and cost effectiveness in reducing hypercholesterolemia.

PMID- 10638220
TI  - [Fibric acid derivatives].
AB  - Fibric acid derivatives show remarkable reduction of triglyceride rich
      lipoproteins and increment of high density lipoproteins. Recently, it is revealed
      that fibrate activate the nuclear peroxisome proliferator-activated receptor
      (PPAR) alpha and thereby alter the transcription of genes controlling lipoprotein
      metabolism. Additionally, fibrates inhibit the activation of aortic smooth muscle
      cells and lower the plasma fibrinogen concentration, which are also anti
      atherogenic factors. Many prevention studies revealed that fibrates prevent
      ischemic heart disease of hyperlipidemic patients, suggesting not only high level
      of low-density-lipoprotein cholesterol but hypertriglyceridemia, low high-density
      lipoprotein cholesterol level and high level of fibrinogen may be the definite
      risks of atherosclerosis.

PMID- 10638221
TI  - [Mechanisms of anti-atherogenic action of probucol].
AB  - Probucol has been recognized to have antioxidant properties as well as lipid
      lowering effects, and contribute to prevention of atherosclerosis.
      Pharmacologically, this agent has shown several unique actions, and a lot of
      investigations have been reported regarding the mechanisms. Recently, it has been
      reported that probucol increases selective uptake of high density lipoprotein
      cholesterol esters by the medium of the class B, type I scavenger receptor (SR
      BI), and that antioxidant potent may inhibit the restenosis of post coronary
      angioplasty. This review attempts to focus on the mechanism of antioxidant and
      HDL-lowering effects of probucol.

PMID- 10638222
TI  - [Antioxidants and cardiovascular disease].
AB  - Oxygen-free radical reactions have been implicated in many chronic diseases,
      including atherosclerotic cardiovascular disease (CVD). Epidemiologic studies
      have demonstrated an association between increased intake of naturally occurring
      antioxidant vitamins such as vitamin E and vitamin C and reduced morbidity and
      mortality from CVD. By contrast, most of the completed randomized trial did not
      show any clear reduction in CVD. However, the trials were not specifically
      designed to assess CVD, did not provide data on nonfatal CVD, may have had
      insufficient treatment durations, and used suboptimal vitamin E doses. Despite
      the lack of a general consensus, recent data reinforce the concept that the
      regular intake of antioxidants present in foods limits the progression of
      atherosclerotic CVD.

PMID- 10638223
TI  - [Development of new antiatherosclerotic agents--ACAT inhibitors and CETP
      inhibitors].
AB  - Development of new antiatherosclerotic agents were reviewed focusing on ACAT
      inhibitors and CETP inhibitors. ACAT inhibitors enhance intracellular degradation
      of VLDL in hepatocytes. Cholesterol absorption in small intestine is inhibited by
      ACAT inhibitors. Thus, ACAT inhibitors reduce plasma cholesterol levels. In
      atherosclerotic lesions, ACAT inhibitors suppress foam cell formation
      (cholesteryl ester accumulation) in macrophages. Since ACAT inhibitors have
      multiple anti-atherogenic effects, they are considered future drugs controlling
      hypercholesterolemia and atherosclerosis. CETP inhibitors are expected to
      increase HDL and decrease LDL. Although the patients with CETP deficiency show
      high level of HDL, recent studies showed that they are not necessarily resistant
      to atherosclerosis. The strategy to inhibit CETP for suppressing atherosclerosis
      has not been established.

PMID- 10638224
TI  - [Efficacy of hormone replacement therapy on hyperlipidemia].
AB  - In women, serum lipid levels and the incidence of myocardial ischemia increase
      after menopause. Deficiency of estrogen is believed to be the cause of these
      epidemiological phenomena. On the other hand, hormone replacement therapy(HRT),
      has prevailed in developed countries. Estrogen is replaced to ease climacteric
      disorders, and retard bone loss. Many clinical studies cleared the effect of HRT
      on lipids, in which total and LDL-C (cholesterol) decreased, and HDL-C increased.
      TG increased by conjugated equilin estrogen but not by transdermal estradiol. In
      our study, hepatic triglyceride lipase(HTGL) was suppressed by HRT, but
      lipoprotein lipase(LpL) was not suppressed. HRT decreases coronary artery
      diseases, but it is still controversial whether HRT is efficient in patients who
      already have heart disease.

PMID- 10638225
TI  - [LDL-apheresis--clinical indication and utility].
AB  - LDL-apheresis is now sprended as a special technique for reducing serum
      cholesterol in drug-resistant patients with severe hypercholestrolemia. It's
      indication should be limited to homozygous familial hypercholesterolemia (FH) and
      lipid-uncontrollable heterozygous FH cases with coronary artery disease. Long
      term effectiveness of LDL-apheresis on coronary events and lesions was
      established. This method may be useful to prevent graft vessel disease in
      patients with heart transplantation in the future. The clinical efficacy of this
      method may be induced not only by the removal of large amount of cholesterol but
      also by the resistance of LDL-oxidation or the improvement of endothelium
      dependent vasodilatation.

PMID- 10638226
TI  - [Gene therapy of hyperlipoproteinemia].
AB  - Gene therapy is an ultimate treatment of inherited diseases. Hyperlipoproteinemia
      is largely genetically determined. In particular, familial hypercholesterolemia
      (FH) is one of the most prevalent genetic diseases which result from the mutated
      LDL receptor. Retrovirus-mediated ex vivo gene transfer of the LDL receptor has
      been tested in homozygotes of FH. The outcome was far from a success in terms of
      the improvement of hypercholesterolemia. Experimentally, LDL receptor knockout
      mice have been widely used as a model of FH. Manipulation of several genes which
      are distinct from the LDL receptor in these animals has proven to have
      cholesterol-lowering effects. Further development of vector is needed to obtain
      practically satisfactory results in humans.

PMID- 10638227
TI  - [First brain dead donor heart transplantation under new legislation in Japan and
      future aspects of heart transplantation in Japan].
AB  - After the brain death and organ transplantation law was settled in 1997, the
      first case of heart transplantation (HTx) was carried out successfully. The
      patient was 47 year-old male with hypertrophic cardiomyopathy of dilated phase
      and on Novacor Implantable LVAS for 4 months. The distance from the donor
      hospital was about 200 km taking 2 hours for transport, and total ischemic time
      was 3 hours and 24 minutes. The post-transplant course was smooth. The patient
      was discharged on 75 postoperative day. We described current status of HTx in
      Japan and worldwide and discussed current problems and future aspects of HTx in
      Japan.

PMID- 10638228
TI  - [Pediatric quality circles moderated by child psychiatrists--a suitable quality
      assurance measure in basic psychosomatic care?].
AB  - The important role of pediatricians in private practice for the care of
      psychologically noticeable children makes it seem necessary to implement quality
      assurance measures. As part of an integrated project for quality assurance in
      psychosomatic basic care the pediatricians in the medical care district Gottingen
      were offered two quality circles for two years which in contrast to the original
      concept were conducted by child psychiatrists. The evaluation of this offer by
      the participating pediatricians after one year (n = 16) and after the end (n =
      15) yielded very positive results regarding the structural characteristics of the
      quality circles (such as length of sessions, subject selection, moderation,
      working atmosphere) and also the general usefulness of such a quality assurance
      measure. The increase in competence regarding practical skills (diagnostics,
      treatment in the own practice, referee indication, forming the physician-patient
      relationship) however, was evaluated as being less pronounced. The attractiveness
      of a quality circle modified by continuously integrating a child
      psychiatrist/psychotherapist was confirmed by the results of a national survey.
      In another survey the participating pediatricians documented cases where they
      suspected psychological problems before the quality circles began and after the
      first year. Sensitivity and specificity of the pediatricians' assessments
      increased at the second evaluation point which is a sign for an increased
      diagnostic competency of pediatricians.

PMID- 10638229
TI  - [Familial alcohol abuse in the context of sexual and physical abuse offenses by
      male adolescents and young adults].
AB  - This study investigated whether and to what extent defined samples of young male
      offenders (sexual and assault offences) differ with regard to the effects of
      alcohol abuse in their families. Thirty-eight young men had sexually assaulted
      women of their own age or older, 36 subjects had sexually abused children and 33
      had committed assault offences. The incidence of alcohol abuse of mothers was the
      same in all groups. The alcohol abuse of fathers was most common in the group of
      assault offences and least common in the group of sexual offences against women
      of the same age or older. In contrast, alcohol abuse of the delinquent young men
      after the age of 14 years and the influence of alcohol at the time of offence
      were virtually identical in the group of sexual offences against women and
      assault offences, whereas alcohol abuse and the influence of alcohol at the time
      of offence were only rarely observed among the sexual offences against children.
      Analysis of alcohol abuse and violence in the intrafamilial context revealed a
      different and possibly specific profile for each group: Paternal alcohol abuse
      was associated with alcohol abuse of the son (sexual offences, women victims),
      with expulsion from school (sexual offences, child victims), and with the
      influence of alcohol at the time of offence (assault-offences). Such profiles may
      be helpful in the assessment of the offence and in interventions aimed at
      preventing relapse: with regard to the degree of alcohol abuse, with regard to
      the respective delinquent development and with regard to the interaction of the
      two disorders.

PMID- 10638231
TI  - [Surgical treatment of obesity].

PMID- 10638230
TI  - [Physical and psychological status of 60-70-year-old citizens of Bern with
      neurotic symptoms in childhood--a study over more than 50 years (Emmental
      cohort)].
AB  - The present study was undertaken to assess the influence of childhood variables
      (physical and emotional) to later well-being in a group of rural Swiss (Emmental
      Cohort). Our study is the first prospective cohort over a time period of more
      than 50 years. It includes 1537 children who were listed and assessed in 1942
      (T1) because they had difficulties in school or were otherwise behaviorally
      disturbed. In 1995 (T2) more than 60% of the initial population could be
      reassessed by our study group. We found more subjects at T2 who had been rated as
      intelligent at T1. More subjects responding to T2 belonged to a higher social
      class, were more anxious, and had more psychosocial problems at T1. Social income
      at T2 is correlated to the social class at T1. More subjects have died since who
      were rated at T1 as being less intelligent, less neurotical, and having higher
      psychosocial problems. Twice as many men died than women. The emotional situation
      at T2 is significantly correlated to psychological well-being at T1. The somatic
      complaints at T2 correlate significantly to neurotic symptoms in childhood (T1).
      The more intelligent the children were rated at T1, the less emotional and
      somatic complaints were voiced at T2 and the better the psychic well-being was
      rated (T2). In addition, the former social milieu (T1) significantly determined
      somatic and psychological complaints at T2. Our data discern a significant
      correlation between actual status and former childhood variables more than 50
      years later in a rural Swiss cohort (Emmental Cohort).

PMID- 10638232
TI  - [Diagnosis and ambulatory treatment of patients with community-acquired
      pneumonia: variability of complementary tests and study of the effectiveness of
      roxithromycin. Study Group on Ambulatory Treatment of Community-Acquired
      Pneumonia (NACTA)].
AB  - BACKGROUND: Community-acquired pneumonia (CAP) has been the subject of a number
      of studies. Nevertheless, studies focused on effectiveness of therapy and
      variability of diagnostic tests are scarce. PATIENTS AND METHODS: Observational
      study of the diagnostic methodology used in patients attending hospital Emergency
      Departments for possible CAP and assessment of effectiveness and reliability of
      empiric ambulatory therapy with roxithromycin (150 mg/12 h, for a minimum of ten
      days). The only mandated complementary tests included PA and lateral chest X-ray
      views and blood count. Microbiological tests were left to the discretion of the
      attending physician. Clinical and biological follow-up of the patient consisted
      of three outpatient visits. RESULTS: The study was conducted at 18 spanish
      hospitals from October 1997 to March 1998. The final total of patients with CAP
      enrolled was 161 (75 women and 86 men). Three patients required hospital
      admission. In a 3% of patients the Gram staining of the sputum specimen was
      performed; in 53% of patients blood cultures were obtained (3.4% were positive)
      and in 23% of patients serological determinations are performed (16.7% were
      positive). The final microbiological results led to the disclosure of the
      etiologic agent of CAP in 5.5% of patients. In only one patient did the results
      prompt a change in antibiotic therapy. The clinical course was favorable in 92.5%
      of patients. In 12 patients (7.5%) a change of antibiotic was made or a second
      antibiotic was added. The mean therapy duration with roxithromycin was 11.9 days
      (range: 7-22 days). In five patients (3.1%), the observed adverse events were
      attributed to roxithromycin, and in no case was discontinuation of therapy
      necessary. CONCLUSIONS: The variability of diagnostic tests used in patients with
      CAP is remarkable but their yield is of little effect. Patients with CAP
      candidates for ambulatory therapy can receive empiric antibiotic therapy with
      roxithromycin. In this series, roxithromycin had a high clinical effectiveness
      and was well tolerated.

PMID- 10638233
TI  - [Pyogenic liver abscess: changes in etiology, diagnosis and treatment over 18
      years].
AB  - BACKGROUND: There are no detailed studies in our country on the impact of modern
      imaging techniques on diagnosis, treatment and prognosis of pyogenic liver
      abscesses. MATERIAL AND METHODS: All patients with the diagnosis of PLA from 1981
      to 1998 were included in the study. The study was divided in two periods: 1981 to
      1989 and 1990 to 1998. RESULTS: Compared with the first time period, the
      following was observed from 1990 to 1998: the mean age was higher (52 versus 65
      years, p = 0.006), infections with identified source increased (33% versus 74%, p
      = 0.003), diagnosis was earlier (13 versus 3 days, p = 0.0002), modern imaging
      techniques were used more frequently (17% versus 96%, p = 0.002), the proportion
      of recovered microorganisms increased (53% versus 88%, p = 0.002), as well as use
      of percutaneous drainage (0% versus 37%, p = 0.002) and the prognosis was better
      (mortality rate 40% versus 10%, p = 0.01). CONCLUSIONS: Relevant changes were
      observed among patients in our hospital in the nineties regarding epidemiology,
      management and prognosis of PLAs. Part of these changes are due to a higher use
      of new imaging techniques.

PMID- 10638234
TI  - [Epidemic outbreak of tularemia in Palencia].
AB  - BACKGROUND: Tularemia can become a health problem after its recent emergence in
      Spain. OBJECTIVE: To describe the clinico-epidemiologic characteristics of a
      tularemia outbreak occurred in Palencia (October 1997 to March 1998). DESIGN:
      Case-control study. MATERIAL AND METHODS: A clinico-epidemiologic survey was
      conducted. The Chi square test and the Student "t" test were used and a logistic
      regression analysis was made. The diagnosis was made by serology
      (microagglutination or macroagglutination) or culture. RESULTS: There were 151
      cases; 74.5% of cases were confirmed or likely. The ulceroglandular was the most
      common clinical form of the disease (49%) and 23.2% of patients required hospital
      admission; 93.4% of patients had exposure to hares, and 86.7% of them handled
      them. Higher risk practices included skinning (adjusted OR: 3.9; 95% CI [1.03
      14.7]; p = 0.04) and cutting/cooking (adjusted OR: 2.7; 95% CI [1.01-6.7]; p =
      0.03). Streptomycin therapy was used for 51.6% of cases. CONCLUSIONS: The clinico
      epidemiologic surveillance of this disease in Spain is necessary.

PMID- 10638235
TI  - [Clinical profile and prognosis of bacteremia in patients with cirrhosis based on
      the Child-Pugh classification].
AB  - The characteristics of 70 cases of bacteremia in cirrhotic patients were studied
      according to the Child-Pugh classification as severity marker of liver
      involvement. Factors influencing on prognosis were determined. For a comparative
      analysis, 1,006 cases of bacteremia in non-cirrhotic patients were included.
      Sixteen patients corresponded to group A, 23 to group B and 31 to group C in the
      Child-Pugh classification. Patients in group A had a predominance of extra
      enteric microorganisms, mainly Staphylococcus aureus (37.5%; p = 0.02), well
      defined source (urinary tract, respiratory tract, skin) and good prognosis
      (mortality rate 6.2%). In contrast, patients in group C had a high recovery rate
      of Escherichia coli (41.9%) and pneumococcus (19.3%), undetermined source (51.6%;
      p = 0.05), ascites (83.9%), with or without concomitant peritonitis (41.1%; p =
      0.03) and poor prognosis (mortality rate 48.3%; p = 0.008). The characteristics
      of patients in group B were similar to those of patients in group C but prognosis
      was as in patients in group A. The immediate mortality rate in the studied
      patients was 26%. The parameter which best predicted survival in the multivariate
      analysis was the Child-Pugh classification.

PMID- 10638236
TI  - [Rheumatologic manifestations of chronic graft vs host disease. 4 case reports].
AB  - A description is given of four patients with the diagnosis of chronic graft
      versus-host disease (cGVHD) who developed articular manifestations during the
      clinical course. One of the patients developed advanced lesions of scleroderma.
      The rheumatologic changes of the disease as well as other affections of organs,
      complications and prophylaxis are reviewed.

PMID- 10638237
TI  - [Association of multiple myeloma and solid neoplasms: analysis of 13 cases].
AB  - BACKGROUND: The diagnosis of second malignancies in patients with multiple
      myeloma is uncommon. It is debatable whether this tumor is in itself a risk
      factor for the incidence of second malignancies. Etiopathogenic factors which
      might account for this association were analyzed. MATERIALS AND METHODS:
      Retrospective analysis of a series of 210 patients with myeloma controlled by a
      Medical Oncology Department from 1984 to 1998. After searching for the diagnosis
      of a second malignancy, thirteen patients were identified with both diagnoses. A
      descriptive statistical study was elaborated as well as an analysis of survival.
      RESULTS: There were seven males and six females, with a mean age at diagnosis of
      69 years (57-80). The Durie-Salmon stages at diagnosis were: I-A (3), I-B (1), II
      A (4), III-A (4). Associated solid malignancies included: hepatocarcinoma (2),
      prostate adenocarcinoma (2), soft tissue sarcoma (2), lung adenocarcinoma (1),
      cholangiocarcinoma (1), breast carcinoma (1), endometrial carcinoma (2) and
      bladder carcinoma (1). At diagnosis, seven of the solid malignancies were
      metastatic. At the time of this analysis, eleven patients had died, eight because
      of progression of the solid cancer, two because of progression of myeloma and one
      because of therapy toxicity. Two patients are still alive with stability of the
      myeloma and solid malignancy controlled after surgical resection. CONCLUSIONS:
      The association was observed in 6.2% of patients with myeloma and occurs at an
      advanced age. IgG myelomas and in early stages predominated. Solid malignancies
      were diagnosed in advanced stages in most cases. A short term high mortality rate
      was observed due to progression of the solid malignancy. The frequency of the
      association did not seem to be higher than the overall incidence of second
      malignancies in patients with cancer.

PMID- 10638238
TI  - [Indications and use of omeprazole in esophago-gastro-duodenal diseases].

PMID- 10638239
TI  - [New prospects in genetics of obesity].

PMID- 10638240
TI  - [Research on diagnostic tests].

PMID- 10638241
TI  - [Large hepatomegaly of neoplastic appearance].

PMID- 10638242
TI  - [Patient with antecedents of anxiety-depression syndrome].

PMID- 10638243
TI  - [Pain the left iliac fossa in a patient without relevant pathological
      antecedents].

PMID- 10638244
TI  - [Von Recklinghausen's disease and abdominal mass].

PMID- 10638245
TI  - [67-year-old man with pruriginous skin lesions and long-course splenomegaly].

PMID- 10638246
TI  - [A 15-year-old male patient with connective tissue disease admitted for arterial
      hypertension and convulsions].

PMID- 10638247
TI  - [Aortic aneurysm and multiple venous thrombosis as initial manifestation of
      Behcet's disease].

PMID- 10638248
TI  - [Coexistence of breast cystosarcoma phyllodes and bilateral in situ lobular
      carcinoma].

PMID- 10638249
TI  - [Mononucleosis syndrome caused by hepatitis A virus].

PMID- 10638250
TI  - [Transverse myelitis caused by Brucella].

PMID- 10638251
TI  - [A new case of malignant pseudothyroiditis].

PMID- 10638252
TI  - [Dapsone and panniculitis due to alpha 1-antitrypsin deficiency].

PMID- 10638253
TI  - [Hyperlipidemia in patients with HIV infection treated with protease inhibitors].

PMID- 10638254
TI  - [Marked increase of serum ferritin in alcoholic patients and its normalization in
      abstinence].

PMID- 10638255
TI  - [Dental identification. The medical duty of confidentiality within the framework
      of the identification of unknown dead persons].

PMID- 10638256
TI  - [The type testing of light-polymerization equipment, II: the 1998 status].
AB  - In this study 16 different light curing units, available on the Swiss market,
      were tested for their features, radiant power and light distribution across the
      face of the curing tip and components like integrated radiometer, timer and
      cooling device. The basis of this study was the test protocol published in the
      november edition (11/1999). The features of the light curing units differed from
      one another. The Optilux 500 had all conceivable features that it could be
      designated the standard in features. If all these technical options are necessary
      has to be decided by the consumer. However, the components such as the timer,
      radiometer and voltage stabilizer are important because they influence the time
      of irradiation and the radiant power. The radiant power (mW) i.e., the radiance
      (mW/cm2) were measured in 2 spectral areas which are important for visible light
      polymerisation. The absolute values for the standard curing tip at a voltage of
      230 V lay between 143.4 and 389.7 mW for the wavelengths between 400-520 nm and
      between 17.7 and 41.8 mW for the wavelengths between 462-472 nm. The resultant
      specific radiance values were between 268.3 and 862.6 mW/cm2 in the broad
      spectrum of 400-520 nm and 33.5 and 95.4 mW/cm2 in the narrow spectrum of 462-472
      nm. Where the standard curing tips were replaced by guides with other diameters,
      tips with larger entrances showed more radiant power, light guides with smaller
      exits also showed more radiance. Turbo tips have larger entrances than exits and
      therefore combine both positive effects. The intensity wasn't distributed equally
      across the face of the curing light guide. Characteristically there was a
      concentric distribution of the intensity, with the maximum found in the centre
      and a decrease to the margin. Corresponding to the radiance values, curing light
      tips with decreasing diameters showed more homogeneous distribution patterns.
      Only Turbo tips showed worse distribution. Comparing the light intensity at a
      voltage of 207 V and 244 V to the normal voltage of 230 V it was found that not
      all curing units had an integrated voltage stabilizer. Just 9 out of the 16
      tested units had an integrated radiometer. Comparison of the evaluated radiance
      values to the values given by the integrated radiometer revealed an agreement in
      just two cases. The marginal values, programmed by the manufacturer varied
      between 70 and 300 mw/cm2 and lie therefore, too low.

PMID- 10638257
TI  - [Current status and overview of genome analysis--a new strategy for the analysis
      of etiology of neuropsychiatric diseases].

PMID- 10638258
TI  - [Mechanism involved in substance dependence--from the view point of the reward
      system].

PMID- 10638259
TI  - [Functional and morphological studies of schizophrenia].

PMID- 10638260
TI  - [Cognitive remediation of schizophrenia--with special reference to SST (social
      skills training)].

PMID- 10638261
TI  - [Japanese Society of Biological Psychiatry--biological studies of affective
      disturbances--recent progress].

PMID- 10638262
TI  - [Lethal poisoning with ethyl alcohol and its surrogates in various regions of the
      Russian Federation].
AB  - The index of lethal poisoning with ethyl alcohol and its surrogates in Russia
      remains one of the highest in the world. It is explained by high alcohol
      consumption in Russia (about 15 liters of pure alcohol per capita annually),
      consumption of mainly strong beverages (about 80%), extensive sales of
      adulterated strong alcoholic beverages (more than 25%), virtually no preventive
      work in the population, and other causes. The index of lethal poisoning with
      alcohol and its surrogates in the country and its regions is one of the most
      important parameters in evaluation of the socioeconomic well-being of the
      population.

PMID- 10638263
TI  - [Modern concepts of adipocere formation mechanisms].
AB  - Biochemical parameters of transformation of fresh subcutaneous fat into adipocere
      have been studied in experiment. Activation of lipid peroxidation is a
      significant component of the mechanism of adipocere transformation, which is
      proven by a drastic increase in the level of Schiff's bases in adipocere in
      comparison with subcutaneous fat. The concentrations of myristic, palmitic, and
      stearic fatty acids increase during the formation of adipocere, while the content
      of linoleic acid decreases in comparison with the unchanged human subcutaneous
      fat.

PMID- 10638264
TI  - [Morphological sign of cardiac ventricle fibrillation].
AB  - An early sign of cardiac ventricle fibrillation is described: numerous surface
      cracks in the myocardial fibers. The formation of cracks is the initial stage of
      myocardial fiber fragmentation. The cracks are detected by polarization
      microscopy in the absence of fragmentation or in myocardial sites without focal
      fragmentation.

PMID- 10638265
TI  - [Medicosocial aspects of sexual abuse crimes in Arkhangel'sk].
AB  - The criminological and victim sides of sexual abuse crimes in Archangelsk are
      analyzed and the data are compared with the data for Russia and for St.
      Petersburg. Seasonal patterns of rapes and violations and the most vulnerable age
      of victims have been determined. Flaws in the resolutions on expert evaluations
      in cases with social abuse are analyzed.

PMID- 10638266
TI  - [Morphologic changes in spinal cord of patients with spinal injuries who died in
      hospital].
AB  - Morphologic changes in the spine have been investigated in patients with spinal
      injuries who died in hospital. The incidence of injuries has been evaluated as
      9.3% of mechanical injuries. Purposeful search for possible injuries increased
      the rate of detection of injuries of the spine and the cord. Spinal cord can be
      impaired without involving the osseous formations and spinal ligaments. Edema of
      the cord tissue develops during the early period of injury and prevents the
      detection of injuries, persisting for a long time after the injury. Edemas are
      detected even in subjects who died at the site of accident.

PMID- 10638267
TI  - [Specific features of kidney injuries altered by disease].
AB  - The degree of development of subcutaneous fat and muscles of the back, filling of
      the gastrointestinal tract, increase in intra-abdominal pressure, and
      pathological processes, specifically, cysts, hydronephrosis, tumors, pelvic
      stones, etc., play a significant role in the development of renal injuries. A
      case with a kidney rupture resultant from a slight trauma in a 19-year-old
      soldier is presented. Analysis of nephrectomy, review and intravenous excretory
      urography, and pathological examination of the removed kidney showed third-stage
      hydronephrosis. This diagnosis was significant for evaluation of the severity of
      corporal injuries and for determining the punishment for the guilty subject.

PMID- 10638268
TI  - [Evaluation of injuries features inflicted by shots from gas guns by emission
      spectral analysis].
AB  - The authors describe a methodological approach to emission spectral analysis of
      material evidences aimed at evaluating the regularities of deposition of the shot
      metals at the site of injuries inflicted by gas guns. Injuries inflicted by
      gunshots with chemical cartridges and with shot cartridges, with and without
      obstructions, from different distances have been examined. The detected
      regularities may be useful in forensic medical expert evaluations by means of
      emission spectral analysis in cases with gas gunshots.

PMID- 10638269
TI  - [Crystallographic analysis of liquor for diagnosis and life-time evaluation of
      craniocerebral injury].
AB  - Liquor specimens were examined by crystallography in 136 patients with
      craniocerebral injuries of different severity, hospitalized at the neuroinjury
      department of Kaliningrad Emergency Hospital and in 12 normal subjects in 1997
      1998. The crystallograms were evaluated by a sum of signs, as a result of which
      specific patterns of colony growth in health and craniocerebral injury of
      different severity were obtained.

PMID- 10638271
TI  - [Utilization of a block module training program in forensic medical training].

PMID- 10638270
TI  - [Use of proteases to improve the sensitivity of ABO antigen detection by
      absorption-elution test in analysis of human excretion traces].
AB  - The highest sensitivity of the absorption-elution test for detection of A, B, and
      H antigens in human excretion traces was observed when the excretion traces were
      treated with protease C and lidase (hyaluronidase) and standard erythrocytes for
      analysis of the resultant eluates were treated with protease C. Cross-reactions
      of sera with antigens of contralateral specificity were ruled out by simple
      dilution of the sera; the reliability of antigen detection was not lost due to
      pronounced increase in the sensitivity of modified absorption-elution test.

PMID- 10638272
TI  - [Certification of specialists in forensic medical service].

PMID- 10638273
TI  - [Criteria fo forensic medical expert evaluation of male subjects in sexual crimes
      and civil cases. Ministry of Public Health].

PMID- 10638274
TI  - [Antitubercular agents].
AB  - The personally experienced development of chemotherapy for tuberculosis during
      the last half century represents some highlights of new knowledges and practical
      successes: the discovery of antituberculosis drugs; the comprehension of their
      actions and side effects; the exploration of mechanisms of resistance against
      antituberculosis agents; the evaluation of therapeutic and epidemiologic
      consequences of resistant strains; the decoding of the mycobacterial genetic
      structure. For different economic, social and psychologic reasons, the worldwide
      results of the battle against tuberculosis are not nearly as good as possible.
      AIDS is only a partial factor of this failure.

PMID- 10638275
TI  - [Antibiotics, new pathogens, new drug resistance].
AB  - The 20th century is the century of the discovery of numerous pathogenic
      microorganisms. It is also the century of discovery of antimicrobial drugs and
      the beginning of the antibiotic era. While the development of antifungal drugs
      and of antivirals is on its rise, many infectious disease physicians and
      microbiologists feel that we might be on the edge of the beginning of the post
      antibiotic era--50 years after antibiotic use in man and animals. Antibiotics
      have certainly been a major progress in modern medicine. Mortality and morbidity
      from many infectious diseases have been substantially reduced by effective
      antimicrobial therapy. The use of antibiotics has also been a prerequisite for
      major advances in clinical oncology, transplantation medicine, and surgery. The
      emergence and spread of resistant pathogens, however, has necessitated the
      development of broader and more active drugs and has resulted in excessive
      antimicrobial drug use with consequent selective pressure. Every 3rd patient
      admitted to a hospital is given antibiotics--often in the form of stepwise
      escalated therapy eventually including combinations of expensive agents. If the
      aim is to minimize the emergence of resistance and to contain costs, a much more
      critical indication for antimicrobial drug therapy will be necessary. Also,
      programmes on a local, regional, and perhaps even national level will be needed
      to help rationalize antimicrobial drug use.

PMID- 10638276
TI  - [Vaccinations].
AB  - Vaccines are amongst the most cost effective interventions in medicine. Optimal
      implementation of actually available vaccines would markedly increase the
      enormous benefits for mankind achieved so far. Biotechnology has allowed
      improvement of old and engineering of new vaccines. However, there is still
      urgent need for vaccines against pathogens with a global morbidity and mortality
      toll. The challenges for the 21st century to close the increasing gap between
      developed and developing countries are bound to biology, finances, cooperation
      and solidarity.

PMID- 10638277
TI  - [Immunosuppressive drugs--useful confusion of the 20th century?].
AB  - In the second part of the twentieth century, four categories of immunosuppressive
      agents have been developed: glucocorticosteroids, cytotoxic drugs, antibody
      reagents and agents interfering with the action or expression of cytokines. The
      emerging field of immunosuppression allows now to perform successfully organ
      transplantation and to control most of the immunologically mediated disease
      states during the acute, less so during the chronic phase. Unfortunately, all the
      immunosuppressive agents used today are nonspecific. As a consequence,
      opportunistic infections and the development of malignancies are expected side
      effects. Clinicians introduced these new agents with enthusiasm into practice.
      Immunosuppressive agents are mostly used for so-called autoimmune diseases, i.e.
      entities of unknown etiology. Considering the tremendous side effects of
      immunosuppressive agents, the question arises whether in the future research
      should focus more on the discovery of the cause of these immune-mediated disease
      states than on the development of further agents designed to relieve symptoms of
      autoimmune diseases. Two areas might be promising for future research in this
      field: 1. the definition of mechanisms accounting for the genetic predisposition
      and 2. the assessment of the triggers (infectious diseases and/or antigenes)
      causing so-called auto-immune diseases.

PMID- 10638278
TI  - [Aspirin].
AB  - Acetylsalicylic acid (aspirin) was the first synthetized drug 100 years ago.
      Whereas other drugs have disappeared a long time ago, aspirin has stood the test
      of time and is one of the most important drugs at the turn of this century.
      Initially it was used for its analgesic, antipyretic and antiphlogistic
      properties. They are due to the acetylation of the cyclooxygenase and hence an
      inhibition of prostaglandin synthesis. At higher doses aspirin inhibits
      interleukin expression induced by nuclear factor-kappa B. Aspirin is the
      prototype of nonsteroidal antiinflammatory drugs, which are currently challenged
      by the development of specific inhibitors of cyclooxygenase isoform 2 (COX-2),
      which must, however, first prove their efficacy and safety in clinical trials.
      The inhibition of platelet aggregation by aspirin has only been recognized in the
      second half of the century. It is due to an inhibition of thromboxane A2
      synthesis because of an irreversible cyclooxygenase blockade in platelets.
      Aspirin has been found to reduce the incidence and death rate of cardiovascular
      and cerebrovascular events and is nowadays the cornerstone of any secondary
      prevention in vascular diseases. Newer antiaggregatory agents such as
      ticlopidine, clopidogrel or IIb/IIIa-blockers have been developed. Most often
      they are used in conjunction with aspirin and their place has yet to be defined.
      New modes of action of aspirin continue to be found. Recent examples are an
      improvement of endothelial dysfunction or a reduced incidence of colorectal
      cancers. It is therefore likely that aspirin will continue to be a very useful
      and cheap drug for a very large population and will meet the interest of
      researchers for many more decades.

PMID- 10638279
TI  - [Psychotropic drugs].
AB  - With the introduction of the antipsychotic compound Chlorpromazine in the early
      1950s began the era of psychotropic drugs. These include a large number of
      different classes of compounds. They have been clearly demonstrated to be more
      effective than placebo in the treatment of psychiatric disorders. Anxiolytic and
      hypnotic drugs are the most commonly prescribed agents. In the past decade many
      new antidepressants and antipsychotics with a more favorable side-effect profile
      have been introduced onto the market, and have dramatically widened our
      possibilities to improve the course of the various psychiatric disorders. The
      administration of psychotropic drugs is primarily syndrome-related. So far,
      specific causal therapy is not available.

PMID- 10638280
TI  - [Therapeutic milestones in tumor therapy].
AB  - The treatment of cancer has witnessed dramatic improvement throughout the 20th
      century. All three classical pillars of cancer therapy, tumour surgery, radiation
      oncology and medical oncology have provided impressive results which early in our
      century had not been anticipated to this extent. Particular mile stones of
      treatment include the discovery that prostate cancer is a hormone-sensitive
      tumour and the development of curative chemotherapy for many haematological
      neoplasms, or advanced testicular cancer. Adjuvant systemic treatment has led to
      significant improvement in the prognosis of patients with breast cancer and other
      solid tumours. More recently preoperative chemotherapy is gaining an important
      role in particular disorders such as non-small cell lung cancer. The most
      fascinating advances, however, have originated from our improved understanding of
      the molecular and cellular basis of malignancy. The development of monoclonal
      antibodies targeting specific tumour antigens, tumour vaccines and cancer gene
      therapy are all clinically relevant results of diligent basic and translational
      experimental cancer research.

PMID- 10638281
TI  - [Gene technology drugs and gene therapy].
AB  - The principles of recombinant DNA technology are illustrated based on the biology
      of somatic cells with transcription of chromosomal DNA into messenger RNA and its
      translation into protein. Recombinant DNA technology allows the cloning,
      identification and characterization of genes and their expression with the
      production of medically relevant proteins. The products of recombinant DNA
      technology are cloned genes on the one hand. These may be useful for molecular
      diagnosis and gene therapy. On the other hand they comprise recombinant proteins
      which may be useful in the diagnosis, therapy and prevention of human diseases.

PMID- 10638282
TI  - Second degree burn from a toe warmer.

PMID- 10638283
TI  - Reducing trauma through organ and tissue donation education.

PMID- 10638284
TI  - Preventing trauma through CHILD SAFE.

PMID- 10638285
TI  - Technology opens new doors for trauma and care.

PMID- 10638286
TI  - Taking trauma care to the next level.

PMID- 10638287
TI  - Unique system examines firearm injury data. Looking behind the bullets.

PMID- 10638288
TI  - Basketball injuries in a rural area.
AB  - This study was conducted to determine the frequency and nature of basketball
      injuries occurring in a rural setting. More than 6000 patients with sports
      related injuries presented to a rural emergency department between June 1, 1988
      and June 1, 1994. Of these patients, 1189 (19% of the total) were injured playing
      basketball. A chart abstraction form was utilized to retrospectively review
      injuries noting demographics, types and sites of injuries, as well as referral
      and treatment plans. Approximately two-thirds (66.4%) of those injured were
      males, with most injuries (53%) occurring during school-related activities.
      Almost four-fifths (78%) of injuries occurred between the ages of 10 and 19. The
      ankle (33.1%) was the body site most commonly injured, followed in frequency by
      finger injuries (19.3%), sprains and strains, which accounted for the majority
      (55%) of injuries. The most common mechanism of injury was recorded in which no
      contact with other players occurred (37.4%). The vast majority (99%) of injuries
      were managed as outpatients. The majority of cases (72%) were expected to recover
      within 2 weeks. Similarities were noted regarding sites of injury and age of
      distribution of patients when compared to the previous studies.

PMID- 10638289
TI  - The availability of extrinsic handgun locking devices in a defined metro area.
AB  - Extrinsic safety devices, such as trigger locks, have been central in the recent
      state discussions on how to reduce firearm injuries. The actual prevalence of
      handgun locking devices in the consumer market, however, is unknown. This study
      catalogued the extrinsic safety devices available from handgun dealers and
      discount retail chains in Milwaukee, WI. We found that all locations studied (n =
      13) stock at least 1 type of extrinsic safety device. A total of 21 unique models
      of safety devices were stocked by the 13 locations, with trigger locks being the
      most common (n = 9). Other types of devices included lock-boxes (n = 5), cable
      locks (n = 4), hammer locks (n = 1), barrel locks (n = 1), and a rubber slide
      strap (n = 1). Handgun owners in the Milwaukee metro area have a selection of
      extrinsic handgun safety devices available from handgun dealers and discount
      retailers. However, there does not appear to be a consistent availability on type
      of device.

PMID- 10638290
TI  - Accidental pediatric ingestion, hospital charges and failure to utilize a poison
      control center.
AB  - PROBLEM: Telephone contact with a poison control center may determine that
      accidental poison ingestion may not pose a risk of developing adverse clinical
      effect. Over 50% of reported human poisonings occur in children less than 6 years
      old. Yet most of these accidental childhood ingestions do not produce clinical
      toxicity. Such nontoxic ingestions can be managed by telephone rather than
      treated in a health care facility. This study evaluated the clinical effects
      produced, and the cost of emergency department care, versus obtaining telephone
      advice from a poison control center, following accidental poison ingestion in
      children age 6 and under. METHODS: 1 year review of all cases of accidental
      ingestion in children 6 years and under evaluated in a pediatric emergency
      department. Utilizing the hospital's poison control center criteria, cases were
      grouped as nontoxic (no risk of adverse effect) or toxic (significant risk for
      adverse effect). Groups were compared for demographics, clinical effect,
      dispositions, charges. RESULTS: 467 cases were seen; 141 met nontoxic criteria.
      Toxicity was not related to race or gender. Children age 2 and less accounted for
      the majority of cases (p = .003) [table: see text] Estimated poison control
      center costs are less than $25 per telephone call. CONCLUSION: Significant
      charges are billed to health care payers when an emergency department is utilized
      as the primary means of evaluating children with nontoxic ingestions. Utilization
      of a poison control center as the initial means of intervention following an
      accidental pediatric ingestion results in significant savings in health care
      expenditures.

PMID- 10638291
TI  - Hospitalizations for vehicle associated injuries in Wisconsin.
AB  - Computerized data from the Wisconsin Office of Health Care Information (OHCI) was
      utilized to evaluate the epidemiology of vehicle associated injuries treated in
      acute care Wisconsin hospitals in 1997. There were 6043 vehicle associated
      injuries which required hospitalization in Wisconsin in 1997, a rate of 141 per
      100,000 males and 91 per 100,000 females. Seventy-eight percent of these were
      motor vehicle traffic related (8% of which involved collisions with pedestrians),
      9% were motor vehicle non-traffic related and 6% were pedal cycle related. This
      study demonstrates how the risk of these various types of vehicle related
      injuries varied with age, gender, and county of residence, and describes the
      distribution of morbidity associated with each type. The information described in
      this paper may be useful in developing hypotheses regarding the causes of vehicle
      related injuries in Wisconsin, and ultimately lead to the development of
      interventions which will decrease morbidity, mortality, and costs due to vehicle
      related injuries.

PMID- 10638292
TI  - Prevention and control of influenza by Wisconsin family physicians: a WReN
      supported study.
AB  - PROBLEM: Although patients infected with influenza commonly present to family
      physicians, little is known about the usual clinical practices utilized by these
      physicians regarding influenza. METHODS: A 1-page questionnaire was mailed to a
      random sample of Wisconsin family physicians. Responses were used to describe
      current management style and evaluate for possible relationships between
      management style and demographic and practice variables. RESULTS: Completed
      questionnaires were obtained from 89 (29%) physicians. Influenza was perceived as
      a moderately important and frequent illness. Physicians estimated that 66% of
      their high-risk patients received immunization. Antiviral medications were
      infrequently used, mostly for older patients and those with comorbid conditions.
      The news media, other physicians and public health officials were the most common
      sources of information on influenza. CONCLUSIONS: Family physicians utilize
      current guidelines for prevention and control of influenza. Improvements can be
      made in mechanisms to identify high-risk patients and improved access to
      surveillance reports.

PMID- 10638293
TI  - The changing face of emergency medicine in Wisconsin.

PMID- 10638294
TI  - Nurse adoption campaign promotes mammography.

PMID- 10638295
TI  - Effects of dietary substitution with raw and heat-treated cowpea (Vigna
      unguiculata) on intestinal transport and pancreatic enzymes in the pig.
AB  - Tropical grain legumes represent potentially important feed for farm animals.
      However, diarrhoea and poor growth performance have been reported, due to the
      various anti-nutritional factors they contain. This study addressed in particular
      whether dietary cowpea impaired the growth of pigs, whether the small intestinal
      Na+/D-glucose coabsorptive transport capacity was decreased, whether the Cl-
      secretory capacity was increased, and, finally, whether these parameters were
      affected by heat treatment of cowpea. Pigs, 4 weeks old, were fed for 3 weeks
      with one of three diets: (i) standard soy, (ii) 75% of soy substituted with raw
      cowpea, or (iii) 75% of soy substituted with heat-treated cowpea. The absorptive
      and secretory capacities of the jejunum and ileum were measured with the Ussing
      chamber technique. Weight gain, feed intake, pancreatic protein and enzyme
      concentrations and levels of the blood hormones glucagon and cholecystokinin were
      also measured. The Na+ transport capacity was measured as the increase in short
      circuit current (Isc) when D-glucose was added to the luminal side in the Ussing
      chambers. Isc was significantly higher in the jejunum from raw cowpea-fed pigs
      than in the jejunum from standard soy-fed pigs, with no difference between the
      two cowpea-fed groups. The phosphodiesterase inhibitor theophylline was
      subsequently added bilaterally, and the increase in Isc indicated the cAMP
      depedent Cl- secretory capacity. In the jejunum this was significantly higher in
      raw and heat-treated cowpea-fed pigs than in standard soy-fed pigs. In contrast,
      there were no differences in the ileal transport capacities. There were no
      differences in the pancreatic protein and trypsin concentrations or the blood
      hormones, but the raw cowpea-fed pigs had significantly lower pancreatic amylase
      than standard soy-fed pigs. Weight gain and feed intake were lowest in the cowpea
      fed groups, with no significant difference between the two groups. In conclusion,
      the hypothesis of impaired small intestinal absorption of D-glucose and Na+ as
      causing malabsorption, and therefore impaired growth, during cowpea substitution
      in the feed may be firmly rejected. The increased Cl- secretory capacity,
      although moderate, may contribute to the higher incidence of post-weaning
      diarrhoea in cowpea-fed pigs, as observed in other studies. Additionally, the
      decreased food intake, feed conversion and weight gain were unaffected by heat
      treatment, further suggesting involvement of heat-stable anti-nutritional
      factors.

PMID- 10638296
TI  - Bovine dermatophilosis and its influencing factors in central Ethiopia.
AB  - A study of bovine cutaneous dermatophilosis was carried out on a total of 6530
      animals under different management systems. Of the 6530 animals examined, 334
      (5.1%) were found to be positive. A significantly (P > 0.01) higher breed
      susceptibility was found in Holstein-Friesian cattle (12.8%) than in the local
      zebu (4.8%). The prevalence of the disease on feed-lots, a ranch, traditional
      farms and urban dairy farms was 2.9%, 4.2%, 7.1% and 12.8% respectively.
      Management and breed differences were found to be very important risk factors
      associated with the disease. However, other factors, including ticks, were also
      found to be apparently associated with the disease, indicating a complex
      interplay of several factors in the pathogenesis of dermatophilosis. Possible
      measures to be taken into account in the control of the disease are suggested.

PMID- 10638297
TI  - Spiramycin, oxytetracycline and sulphamonomethoxine contents of eggs and egg
      forming tissues of laying hens.
AB  - Spiramycin (SP), oxytetracycline (OTC) or sulphamonomethoxine (SMM) was fed to
      laying hens at a dietary level of 400 p.p.m. for 7 successive days. After 7 days
      of medicated feed, the concentrations of SP, OTC and SMM were determined in the
      blood, liver, ovary, oviducts (magnum and isthmus plus shell gland) and eggs
      (albumen and yolk) by high-performance liquid chromatography. Of the three drugs,
      OTC showed the lowest content in the above tissues and eggs, while the reverse
      was true for SMM. Low concentrations of SP were measured in the blood, whereas
      contents in the liver and the oviducts were relatively much higher.

PMID- 10638298
TI  - Comparison of xylazine and lidocaine effects for analgesia and cardiopulmonary
      functions following lumbosacral epidural injection in goats.
AB  - The present study was carried out in order to compare the effects of xylazine and
      lidocaine on analgesia and cardiopulmonary parameters following epidural
      injection in goats. Twelve healthy Small East African goats of both sexes (mean
      +/- SD; 15.6 +/- 1.9 kg body weight) were used. The goats were randomly assigned
      to two groups of five and seven animals. The first group (n = 5) was given 2%
      lidocaine-HCl at 4400 micrograms/kg body weight. The second group (n = 7) was
      administered 2% xylazine-HCl at 150 micrograms/kg body weight. All drugs were
      diluted in 5 ml of sterile water and were injected epidurally through the
      lumbosacral interspace with the injection taking over 20 s. Both drugs induced
      analgesia within 5 min. Signs of sedation, cardiopulmonary changes and lateral
      recumbency developed within 5-7 min after administration of epidural xylazine.
      Tail flaccidity and hind limb paralysis developed 3 min after epidural
      administration of lidocaine. The time from recumbency to regaining normal stance
      was 60 and 158 min for xylazine- and lidocaine-treated animals respectively.
      Xylazine induced adequate analgesia of the flank and perineum, which extended to
      the head and forelimbs. In contrast, lidocaine induced adequate bilateral flank
      and perineal analgesia extending up to the third thoracic vertebra. For both
      drugs, analgesia of the flank and perineum persisted for the entire 180-min
      observational period. Epidural injection of xylazine and lidocaine caused
      variable depression effects on the cardiopulmonary values but was not so low as
      to cause concern. It is concluded that lumbosacral epidural injection of xylazine
      at 150 micrograms/kg body weight in 5 ml of water for injection offers the most
      desirable sedation and analgesia of the flank and perineum. The longer duration
      of analgesia may be useful for postoperative analgesia and relief of continuous
      straining in goats.

PMID- 10638299
TI  - Non-specific immunity and ketone bodies. I: In vitro studies on chemotaxis and
      phagocytosis in ovine neutrophils.
AB  - The in vitro effects of the ketone bodies beta-OH-butyrate (2.4 or 4.8 mmol/l)
      and acetoacetate (2.4 or 4.8 mmol/l) on the uptake of latex particles (1.09
      microns) and chemotaxis were investigated in ovine neutrophils. Because the
      acetoacetate used was a lithium salt, the effect of 2.4 or 4.8 mmol/l lithium
      chloride was also tested. Neutrophils from eight non-lactating, non-pregnant ewes
      were studied. The uptake of latex particles, as measured by a spectrophotometric
      method, showed wide individual variation. The phagocytotic activity was
      unaffected by 2.4 mmol/l ketone bodies and LiCl, but it was significantly
      inhibited by 4.8 mmol/l beta-OH-butyrate and activated by 4.8 mmol/l LiCl. The
      latter result could be masking an inhibitory effect of acetoacetate. Chemotactic
      movements of neutrophils, as evaluated in a modified Boyden chamber using
      homologous zymosan-activated serum (ZAS) as a chemoattractant, were slightly but
      significantly reduced by a 2.4 mmolar concentration of the ketone bodies,
      administered singly or simultaneously, and by LiCl. We conclude therefore that
      the inhibitory effect of lithium-acetoacetate could be due to its lithium
      component. The 4.8 mmol/l dose of acetoacetate and beta-OH butyrate significantly
      decreased chemotaxis only when both compounds were added simultaneously. No
      effect of 4.8 mmol/l LiCl was observed. These results suggest that ketone bodies,
      in particular beta-OH butyrate, could directly influence particle uptake and
      chemotaxis in neutrophils. Although other factors could decrease the efficiency
      of the immune system in ketotic ruminants, the effects of the ketone bodies on
      neutrophils functions may explain the high frequency of infectious disease during
      'ketotic syndrome'. The immunomodulatory effect of lithium needs to be evaluated
      further and it should be considered when testing lithium compounds.

PMID- 10638300
TI  - Measurement of glucocorticoid metabolite concentrations in faeces of domestic
      livestock.
AB  - After 14C-labelled cortisol infusion in ponies and pigs, faecal samples were
      collected. Extraction of 0.5 g faeces with 5 ml 80-90% methanol yielded the
      highest radioactivity in the supernatant. Most of the metabolites were ether
      soluble. After high performance liquid chromatography (HPLC), the presence of
      immunoreactive metabolites was demonstrated by measuring each HPLC fraction using
      enzyme immunoassays for cortisol, corticosterone and 11-oxoaetiocholanolone. Only
      the assay for 11-oxoaetiocholanolone revealed peaks with co-eluting
      radioactivity. For biological validation of the test system, adrenocorticotrophic
      hormone (ACTH) and dexamethasone were injected intravenously successively in both
      species (n = 6). Cortisol concentration in blood and the 11-oxoaetiocholanolone
      immunoreactive substances in faeces were determined. In horse faeces, basal
      values of 2.3-35.2 nmol/kg were measured. After ACTH administration, an increase
      (more than 200% above basal values) of these metabolites was seen about 1 day
      after ACTH administration. After dexamethasone injection the levels decreased,
      reaching minimum concentrations 2 days after administration. In pigs, an increase
      in these metabolites was measured in only three animals after ACTH; dexamethasone
      did not cause a decrease. The stability of the samples after defecation was
      tested by storing samples from cows, horses and pigs at room temperature. It was
      shown that there was a significant increase in the concentration of measured
      cortisol metabolites in bovine, equine and porcine faeces after storage for 1 h,
      4 h and 24 h, respectively. In frozen samples this effect was diminished after
      thawing samples at 40 degrees C; thawing the samples at 95 degrees C prevented an
      increase in immunoreactive substances.

PMID- 10638301
TI  - Age-related morphometry of equine incisors.
AB  - In the present study the age-related morphological characteristics of 948 equine
      incisors were investigated. After extraction, total incisival length and root
      length were measured at the vestibular side of the teeth. Equine incisors reach
      their maximal length 2-3 years after eruption. Notwithstanding severe occlusal
      wear, this maximal length is maintained during most of the horses' life due to
      prolonged root formation. Root formation, at the rate of 2.5 mm per year, starts
      at the age of 5-6 years and continues until the age of 17. As the root of the
      incisor develops, its apical foramen narrows and changes position. In young
      horses the apical foramen is situated at the apex of the tooth, whereas in older
      individuals it is located at the mesial, distal, or lingual side of the tooth at
      a distance of 5-15 mm from the dental apex. In horses aged over 20 years apical
      foramina are still present. Radiographic imaging is a good method with which to
      obtain reliable information concerning the total incisival length and the size
      and position of the apical foramen.

PMID- 10638302
TI  - 1999 Index to volume 59.

PMID- 10638303
TI  - Society of Critical Care Medicine 29th Educational and Scientific Symposium.
      Orlando, Florida, USA. February 11-15, 2000. Abstracts.

PMID- 10638304
TI  - Joint Congress of the British Society for Immunology and the British Society for
      Allergy and Clinical Immunology. Harrogate, United Kingdom, 30 November -3
      December 1999. Abstracts.

PMID- 10638305
TI  - Delta Society to explore influence of animals on human health.

PMID- 10638306
TI  - Veterinarians: a missing LINK.

PMID- 10638307
TI  - Multistate surveillance system in place for West Nile virus.

PMID- 10638308
TI  - Rabies vaccine labeling and the wolf hybrid.

PMID- 10638309
TI  - Telling "the truth".

PMID- 10638310
TI  - Regarding euthanasia.

PMID- 10638311
TI  - Believes veterinarians should help shelters.

PMID- 10638312
TI  - What is your diagnosis? A soft-tissue mass in the thoracic cavity between the
      heart and the right crus of the diaphragm.

PMID- 10638313
TI  - Emotional distress, punitive damages, and the veterinarian--some judicial
      responses.

PMID- 10638314
TI  - Evaluating the economic and noneconomic impacts of the veterinary medical
      profession in Michigan.
AB  - This study reaffirms the diversity and breadth of the veterinary profession. As
      it turns out, some of the furthest-reaching impacts of the veterinary medical
      profession were largely non-quantifiable. The veterinary medical profession had a
      substantial direct economic impact in Michigan during 1995. The total economic
      contribution of the veterinary medical profession to Michigan during 1995 that
      was attributable to expenditures on salaries, supplies, services, and their
      multiplier effect was approximately $500 million. In addition, the profession was
      associated with nearly 8,500 jobs (combined professional and lay positions). The
      veterinary medical profession was also considered to have an impact on the
      prosperity of the live-stock, equine, and pet food industries in Michigan, even
      though the economic contribution in these areas could not be directly quantified.
      Economic well-being of the individual businesses in these industries is directly
      related to the health and productivity of the associated animals, and
      improvements in output or productivity that accompany improved animal health
      likely carry substantial economic benefits in these sectors. In addition,
      progressive animal health management provides a crucial method of managing risk
      in the animal industries. Similarly, although the economic contribution could not
      be quantified, the veterinary medical profession enhances the safety and quality
      of human food through research, regulation, and quality assurance programs in
      livestock production, minimizing the risk of drug residues and microbial
      contamination. During 1995, approximately 5.3 million Michigan residents
      benefitted from the physical, psychological, and emotional well-being that
      accompanies companion animal ownership. By preserving the health and longevity of
      companion animals, veterinarians sustain and enhance these aspects of the human
      animal bond. As Michigan enters a new century, it is likely that the state's
      veterinary medical profession will continue to make a highly valued societal
      contribution. Pets, equines, and food animals will continue to have prominent
      roles in Michigan for the foreseeable future, as will the human-animal bond, food
      safety, and medical research. Clearly, for economic and noneconomic reasons, it
      will be in the interest of the people of Michigan to seek opportunities to
      maintain and enhance the vitality of the state's veterinary medical profession.
      It was our hope that results of this study would provide university
      administrators, legislators, MVMA executives, and others with information needed
      to justify the ongoing provision of public support for the veterinary medical
      profession. In addition, we expect that the results will supply useful material
      for public relations and marketing campaigns by the MVMA and the Michigan State
      University College of Veterinary Medicine and will provide the media with public
      interest stories to promote the veterinary profession. Although this study
      considered the economic and noneconomic impacts of the veterinary medical
      profession only in Michigan, the results can provide an important reference point
      for educators, policy markers, and legislators in other states. In addition, this
      study could serve as a methodologic model for veterinary organizations in other
      states, or at the national level, to emulate.

PMID- 10638315
TI  - Association between results of ambulatory electrocardiography and development of
      cardiomyopathy during long-term follow-up of Doberman pinschers.
AB  - OBJECTIVE: To characterize ambulatory electrocardiographic results of overtly
      healthy Doberman Pinschers and determine associations between those results and
      development of dilated cardiomyopathy. DESIGN: Cohort study. ANIMALS: 114 (58
      male, 56 female) overtly healthy Doberman Pinschers without echocardiographic
      evidence of cardiac disease on initial examination. PROCEDURE: Echocardiograms
      and 24-hour ambulatory electrocardiograms (Holter recordings) were obtained
      initially and at variable intervals. The status (live vs dead) of all dogs was
      known at least 2 years and as long as 10 years after initial examination (mean
      [+/- SD] follow-up time, 4.33 +/- 1.84 years). Associations between development
      of dilated cardiomyopathy and number of ventricular premature contractions (VPC),
      age, and sex were determined. RESULTS: 55 dogs (48%) did not have VPC on initial
      Holter recordings, and only 8 dogs had > 50 VPC/24 hours. The likelihood that a
      dog would have VPC was associated with increasing age and being male. At least 1
      VPC/24 hours, and in particular, > 50 VPC/24 hours or > or = 1 couplet or triplet
      of VPC/24 hours, were predictive of subsequent development of dilated
      cardiomyopathy. Fifty-four dogs (47%) developed dilated cardiomyopathy; 12 were
      still alive at the end of the study, and 42 had died. Twenty-five of these 42
      dogs died after the onset of congestive heart failure (CHF), 15 died suddenly
      before the onset of overt CHF, and 2 died of noncardiac causes. More males
      developed dilated cardiomyopathy than females, and dogs that died suddenly were
      approximately 1 year younger than those that developed CHF. CONCLUSIONS AND
      CLINICAL RELEVANCE: Results of high-quality Holter recordings may be used to
      identify overtly healthy Doberman Pinschers that are at a high risk for dilated
      cardiomyopathy.

PMID- 10638316
TI  - Incidence of and breed-related risk factors for gastric dilatation-volvulus in
      dogs.
AB  - OBJECTIVE: To compare incidence of and breed-related risk factors for gastric
      dilatation-volvulus (GDV) among 11 dog breeds (Akita, Bloodhound, Collie, Great
      Dane, Irish Setter, Irish Wolfhound, Newfoundland, Rottweiler, Saint Bernard,
      Standard Poodle, and Weimaraner). DESIGN: Prospective cohort study. ANIMALS:
      1,914 dogs. PROCEDURE: Owners of dogs that did not have a history of GDV were
      recruited at dog shows, and the dog's length and height and depth and width of
      the thorax and abdomen were measured. Information concerning the dogs' medical
      history, genetic background, personality, and diet was obtained from owners, and
      owners were contacted by mail and telephone at approximately 1-year intervals to
      determine whether dogs had developed GDV or died. Incidence of GDV based on the
      number of dog-years at risk was calculated for each breed, and breed-related risk
      factors were identified. RESULTS AND CLINICAL RELEVANCE: Incidence of GDV for the
      7 large (23 to 45 kg [50 to 99 lb]) and 4 giant (> 45 kg [> 99 lb]) breeds was 23
      and 26 cases/1,000 dog-years at risk, respectively. Of the 105 dogs that
      developed GDV, 30 (28.6%) died. Incidence of GDV increased with increasing age.
      Cumulative incidence of GDV was 5.7% for all breeds. The only breed-specific
      characteristic significantly associated with a decreased incidence of GDV was an
      owner-perceived personality trait of happiness.

PMID- 10638317
TI  - Familial glomerulonephropathy in a litter of beagles.
AB  - Membranoproliferative glomerulonephropathy was diagnosed in 5 of 7 adult Beagles
      from the same litter. Dogs were raised in more than 1 area of the United States.
      One died without evidence of renal disease when it was 3 years old. At 8 years of
      age, 2 dogs developed signs of uremia, including polyuria, polydipsia, and
      infrequent episodes of anorexia and vomiting. Serum biochemical variables and
      urine specific gravity values were consistent with renal azotemia. Both dogs had
      proteinuria. Although healthy, 3 of the 4 remaining Beagles had proteinuria. Of
      these 3, only 1 was azotemic. Membranoproliferative glomerulonephritis was
      diagnosed on the basis of results of histologic examination of renal biopsy
      specimens from 4 of the dogs. Electron microscopy performed on 3 of the renal
      biopsy specimens revealed identical lesions, consisting of an extremely thickened
      glomerular basement membrane with multilaminar splitting. Immunoglobulin or
      amyloid deposits were not detected. On the basis of similar clinicopathologic
      abnormalities, common genetic background, and identical histopathologic and
      electron microscopic findings, familial renal disease was diagnosed. Additional
      studies involving other related Beagles are needed to identify the hereditary
      nature of membranoproliferative glomerulonephropathy in Beagles.

PMID- 10638318
TI  - Intrathoracic and concurrent orthopedic injury associated with traumatic rib
      fracture in cats: 75 cases (1980-1998).
AB  - OBJECTIVE: To characterize rib, intrathoracic, and concurrent orthopedic
      injuries, and prognosis associated with traumatic rib fracture in cats. DESIGN:
      Retrospective study. ANIMALS: 75 cats. PROCEDURE: Medical records from January
      1980 to August 1998 were examined for cats with traumatic rib fracture.
      Signalment, cause of trauma, interval from trauma to evaluation at a veterinary
      teaching hospital, referral status and date, method of diagnosis, duration of
      hospitalization, number and location of rib fractures, presence of flail chest,
      costal cartilage involvement, intrathoracic and concurrent orthopedic injury, and
      clinical outcome were reviewed. RESULTS: Median age was 3 years. Twenty-five
      (58%) cats with reported cause of trauma were injured by interaction with another
      animal. Forty-seven (78%) cats that were treated survived. Cats that died had a
      median duration of hospitalization of < 1 day. Ten (13%) cats had flail chest.
      Sixty-five (87%) cats had intrathoracic injury (median, 2 injuries). Nine (100%)
      cats without detected intrathoracic injury that were treated survived. Thirty
      five (47%) cats had concurrent orthopedic injury. Cats with flail chest, pleural
      effusion, or diaphragmatic hernia were significantly more likely to die than cats
      without each injury. CONCLUSIONS AND CLINICAL RELEVANCE: Traumatic rib fracture
      in cats is associated with intrathoracic and concurrent orthopedic injury.
      Aggressive treatment of cats with traumatic rib fracture is warranted, because
      the prognosis is generally favorable. Diagnosis and treatment of intrathoracic
      injury associated with traumatic rib fracture in cats should precede management
      of concurrent orthopedic injury.

PMID- 10638319
TI  - Risk factors for acquired myasthenia gravis in cats: 105 cases (1986-1998).
AB  - OBJECTIVE: To determine prevalence of initial clinical signs and risk factors for
      acquired myasthenia gravis (MG) in cats. DESIGN: Retrospective case-control
      study. ANIMALS: 105 cats from the United States, Canada; and the United Kingdom
      with a confirmed diagnosis of acquired MG and 510 cats with other neuromuscular
      disorders, including generalized weakness, megaesophagus, and dysphagia (control
      group). PROCEDURES: Records were retrieved from a data-base containing results of
      serum samples tested for acetylcholine receptor antibodies. Signalment, including
      breed, age, and state or country of origin, month of onset, and initial clinical
      signs were obtained. An acetylcholine receptor antibody titer > 0.3 nmol/L was
      diagnostic for acquired MG. Unconditional logistic regression was used for
      statistical analysis. RESULTS: Compared with mixed-breed cats, the breed with the
      highest relative risk of acquired MG was the Abyssinian (including Somali).
      Significant differences between sexes were not detected. There was no compelling
      evidence for a difference in risk of developing MG between states or countries.
      Relative risk increased after 3 years of age. The most common clinical signs were
      generalized weakness without megaesophagus and weakness associated with a cranial
      mediastinal mass. Focal signs, including megaesophagus and dysphagia without
      signs of generalized weakness, were also evident. CONCLUSIONS AND CLINICAL
      RELEVANCE: A breed predisposition for acquired MG in Abyssinians (and related
      Somalis) was observed. Clinical signs were variable and included generalized
      weakness, megaesophagus, and dysphagia. A cranial mediastinal mass was commonly
      associated with MG in cats.

PMID- 10638320
TI  - Prognosis for presumed feline vaccine-associated sarcoma after excision: 61 cases
      (1986-1996).
AB  - OBJECTIVE: To evaluate time to first recurrence (TFR) and overall survival in
      cats with presumed vaccine-associated sarcomas (VAS) treated with excision.
      DESIGN: Retrospective study. ANIMALS: 61 cats with presumed VAS. PROCEDURE:
      Medical records of cats that received excision as the only initial treatment for
      presumed VAS were reviewed to evaluate prognosis. Overall survival curves and TFR
      were determined. RESULTS: Median TFR was 94 days. Median TFR for tumors treated
      with excision performed at a referral institution (274 days) was significantly
      longer than that for tumors excised by a referring veterinarian (66 days).
      Radical first excision yielded significantly longer median TFR (325 days) than
      did marginal first excision (79 days). Cats with tumors located on the limbs had
      longer median TFR (325 days) than cats with tumors located in other sites (66
      days). Median overall survival time was 576 days. Significant differences in
      survival times between groups were not detected. Few cats (13.8%) receiving only
      surgical treatment had long-term (> 2 years) survival. CONCLUSIONS AND CLINICAL
      RELEVANCE: Radical first excision of presumed VAS is essential for extended TFR.
      Current recommendations for vaccination of the distal portions of the extremities
      are appropriate, because this practice permits radical excision of tumors
      (amputation) that develop at vaccination sites; however, surgery alone is seldom
      curative.

PMID- 10638321
TI  - Efficacy of florfenicol for treatment of naturally occurring infectious bovine
      keratoconjunctivitis.
AB  - OBJECTIVE: To determine the efficacy of florfenicol for treatment of calves with
      naturally occurring infectious bovine keratoconjunctivitis (IBK). DESIGN:
      Randomized controlled field trial. ANIMALS: 63 beef calves and 80 dairy calves
      between 4 and 12 months of age. PROCEDURE: Calves were randomly assigned to 1 of
      3 treatment groups. Calves in the SC treatment group received a single dose of
      florfenicol (40 mg/kg [18.2 mg/lb of body weight), SC, on day 0. Calves in the IM
      treatment group received florfenicol (20 mg/kg [9.1 mg/lb]), IM, on days 0 and 2.
      Calves in the control group received injections of saline solution (0.9% NaCl),
      IM, on days 0 and 2. Calves were reevaluated every other day for 20 days after
      treatment. RESULTS: Corneal ulcers healed by day 20 in 48 of 49 (98%) calves
      treated with florfenicol IM, 39 of 42 (93%) calves treated with florfenicol SC,
      and 33 of 52 (63%) control calves. CONCLUSIONS AND CLINICAL RELEVANCE:
      Florfenicol administered SC (1 dose) or IM (2 doses 48 hours apart) was effective
      for treatment of calves with naturally occurring IBK.

PMID- 10638322
TI  - Cytogenetic survey of Holstein bulls at a commercial artificial insemination
      company to determine prevalence of bulls with centric fusion and chimeric
      anomalies.
AB  - OBJECTIVE: To determine prevalence of Holstein bulls with chromosomal anomalies,
      particularly the 1/21 centric fusion (CF), at a commercial artificial
      insemination (AI) company in the United States. DESIGN: Cross-sectional
      cytogenetic prevalence study. ANIMALS: All 606 Holstein bulls at a commercial AI
      company were cytogenetically screened to detect CF, chimerism, and other
      chromosomal abnormalities. PROCEDURE: Lymphocytes from heparinized blood samples
      were cultured by standard cytogenetic techniques, and chromosome spreads were
      prepared for microscopic examination. Chromosomal abnormalities were detected by
      examining 10 chromosome spreads per bull. Pedigree analysis was performed.
      RESULTS: None of the bulls had any type of CF. However, 6 bulls were identified
      as chimeras (i.e., contained lymphocytes with male [XY] and female [XX]
      chromosomes). One bull was sire or maternal grandsire to 85 of the bulls tested,
      and 739 of 1,212 (61%) sire and maternal-grandsire possibilities were accounted
      for by just 18 bulls. CONCLUSIONS AND CLINICAL RELEVANCE: Analysis of these
      results supports previous indications that CF is extremely rare in Holstein
      bloodlines available commercially via AI in the United States. However, chimeric
      bulls are more common, and they reportedly have decreased reproductive
      performance. Therefore, identification of chimeric sires in the AI facility
      reported here and the possibility of de novo onset of CF at any time indicates
      that early cytogenetic screening should be encouraged for prospective bulls
      intended for use in AI programs.

PMID- 10638324
TI  - Cumulative indexes of volumes 1-49.

PMID- 10638325
TI  - British Pharmacological Society meeting. University of Leeds. 8-10 September
      1999. Abstracts.

PMID- 10638323
TI  - Hypernatremia in neonatal elk calves: 30 cases (1988-1998).
AB  - OBJECTIVE: To characterize hypernatremia in neonatal elk calves, including
      clinical signs, incidence, physical examination findings, and possible causes.
      DESIGN: Retrospective case series. ANIMALS: 26 neonatal elk calves were examined;
      4 calves were evaluated twice, for a total of 30 examinations. PROCEDURE: Medical
      records were reviewed for signalment, history, physical examination findings,
      results of diagnostic tests, and response to treatment. Hypernatremia was defined
      as serum sodium concentration > 153 mEq/L. RESULTS: Hypernatremia was diagnosed
      in 14 calves and was significantly associated with diarrhea, high WBC count, high
      anion gap, and high serum concentrations of albumin, chloride, creatinine, and
      urea. Hypernatremia was not significantly associated with survival, but high
      serum albumin concentration and rectal temperature were significantly associated
      with survival of calves. Animals given antibiotics and electrolyte solutions
      orally prior to evaluation were significantly more likely to die than those
      untreated. Dehydration was a common reason for evaluation but was not
      significantly associated with survival. CONCLUSIONS AND CLINICAL RELEVANCE:
      Hypernatremia was significantly associated with diarrhea. Treatment of diarrheic
      elk calves is often the same as that used in bovine calves with diarrhea;
      however, bovine calves are commonly hypo- or normonatremic. Our experience
      suggests that treatment protocols used in bovine calves are unsatisfactory for
      elk calves. The rate at which serum sodium concentration is reduced should be <
      1.7 mEq Na/L/h to avoid development of neurologic signs associated with
      iatrogenically induced cerebral edema.

PMID- 10638327
TI  - 2nd International Symposium on Hepatology. Beijing, China, December 5-9, 1999.
      Abstracts.

PMID- 10638326
TI  - Digestive Disease Week. Thailand 1999. 5th Asia-Pacific American
      Gastroenterological Association Conference and 40th Annual Gastroenterological
      Association of Thailand Conference. Chiang Mai, Thailand, 12-16 December 1999.
      Abstracts.

PMID- 10638328
TI  - Eicosanoids and other Bioactive Lipids in Cancer, Inflammation and Related
      Diseases. 6th International Conference. Boston, Massachussetts, USA. September 12
      15, 1999. Abstracts.

PMID- 10638329
TI  - Pan-American Congress of Psychosocial and Behavioral Oncology. New York, New
      York, USA. October 20-23, 1999. Abstracts.

PMID- 10638330
TI  - Quantitative analysis of alpha 1(I) and alpha 1(III) procollagen mRNA expression
      in systemic sclerosis skin tissue--an in situ hybridization study.
AB  - Human alpha 1(I) and alpha 1(III) procollagen mRNA expression in skin tissue from
      15 systemic sclerosis (SSc) patients and from 7 normal control subjects was
      quantitatively analyzed using in situ hybridization. The grains accumulating in
      each area, representing procollagen mRNA expression per cell, were counted. To
      normalize the results from each subject, the number of cells and the number of
      grains per cell were divided by the area of the skin specimen (in square
      millimeters). The number of cells per square millimeter expressing alpha 1(I) and
      alpha 1(III) procollagen mRNA in SSc skin was significantly elevated compared
      with normal control skin (both P < 0.01). The number of grains per cell per
      square millimeter expressing alpha 1(III) procollagen mRNA in SSc skin was also
      significantly elevated compared with normal control skin (P < 0.01). The
      relationship between procollagen mRNA expression and the histological findings in
      SSc was also studied. The numbers of cells and grains per cell per square
      millimeter expressing alpha 1(I) procollagen mRNA in fibrotic zone SSc skin were
      significantly elevated compared with normal control skin (both P < 0.01). The
      numbers of cells and grains per cell per square millimeter expressing alpha
      1(III) procollagen mRNA in SSc skin were significantly elevated compared with
      normal control skin (both P < 0.01) and with border zone SSc skin (number of
      cells P < 0.01, number of grains P < 0.05). These results indicate an increase in
      the number of cells showing elevated expression of alpha 1(I) and alpha 1(III)
      procollagen mRNA, and a close relationship between alpha 1(I) and alpha 1(III)
      procollagen mRNA expression and the histological findings in SSc.

PMID- 10638331
TI  - Matrix metalloproteinases (MMPs) are required for re-epithelialization of
      cutaneous wounds.
AB  - Matrix metalloproteinases (MMPs) are neutral zinc-dependent endopeptidases with
      substrate specificity for most extracellular matrix molecules. MMPs participate
      in physiological and pathological biological processes. In wound repair, several
      MMPs are upregulated in migrating epithelium although the biological significance
      of their presence is unknown. To elucidate the role of MMPs in epithelial
      migration of cutaneous wounds, a broad-spectrum synthetic MMP inhibitor (GM 6001,
      10 mg/ml) was applied topically to partial-thickness wounds in domestic pigs to
      inhibit endogenous MMPs. The concentration of solubilized GM 6001 in wound fluid
      obtained from treated porcine wounds was 0.06 mg/ml (150 microM) as determined by
      high-performance liquid chromatography. Zymographic analysis showed that GM 6001
      solubilized at this concentration abolished almost completely all enzymatic
      activity present in wound fluid. Epithelial coverage, assessed morphometrically,
      after 66 h of treatment was significantly decreased (P = 0.002) in GM 6001
      treated wounds (50.0 +/- 29.6%, mean +/- SD, n = 6) compared with wounds treated
      with the vehicle (a hydrogel) alone (87.4 +/- 10.6%, n = 6). Topical GM 6001 did
      not influence the degree of dermal inflammatory cell infiltrate or the in vivo
      incorporation of 5-bromo-2'-deoxyuridine (as a measure of epithelial
      proliferation in the wounds) indicating that the reduced re-epithelialization
      with GM 6001 was not due to interference with the inflammatory response or
      epithelial proliferation. Our results suggest that MMPs are directly involved and
      necessary in epithelial resurfacing of moist skin wounds.

PMID- 10638332
TI  - Wound healing of human skin transplanted onto the nude mouse after a superficial
      excisional injury: human dermal reconstruction is achieved in several steps by
      two different fibroblast subpopulations.
AB  - It has been established that human skin grafted onto the nude mouse is able to
      regenerate after being subjected to a full-thickness wound. In the present work,
      we sought to determine the cells involved in the connective tissue repair process
      following superficial wounding. Two months after transplantation, superficial
      wounds were made at the center of the graft using mechanical dermabrasion. At
      various times thereafter, ranging from 2 days to 6 weeks, healing grafts were
      harvested and processed for immunohistological study with species-specific and
      cross-reacting antibodies directed against human or mouse antigens. The grafted
      human skin regenerated according to the following series of events. First, the
      human dermis underneath the scab became devoid of human fibroblasts while the
      surrounding human dermis preserved its own characteristics. The TUNEL reaction on
      earlyphase healing wounds indicated that apoptosis occurred steadily within this
      area and could be the mechanism by which cells disappeared. Moreover, cell death
      was reduced when the wound was covered with an occlusive dressing. The human
      dermis beneath the wound was then invaded by mouse cells which deposited type I
      collagen on the human extracellular matrix and produced mouse granulation tissue
      at the surface above it. Human keratinocytes migrated over the mouse granulation
      tissue to reconstruct the epidermis. Eventually, the mouse granulation tissue was
      progressively invaded by human fibroblasts, which formed a human neodermis. The
      overall process appeared to depend upon several successive epithelial-mesenchymal
      interactions, which were not species-specific. This suggests that myofibroblasts
      arise from a specific subpopulation of fibroblasts, probably located at the
      interface between the dermis and adipose tissue, and that the granulation tissue
      is eventually remodeled by another population of fibroblasts present in the human
      dermis.

PMID- 10638333
TI  - Tissue engineering with HaCaT cells and a fibroblast cell line.
AB  - Most skin models consist of primary cells. Our aim was to develop a highly
      reproducible skin model consisting only of cell lines to investigate irradiation
      effects. The spontaneously immortalized human keratinocyte line HaCaT is known
      for its capacity for epidermal differentiation. As an organotypic coculture,
      HaCaT cells were grown air-exposed on top of a dermis equivalent consisting of a
      murine fibroblast cell line (L929) in collagen. The technique for the preparation
      of this coculture system is described. After 3 weeks a multilayered epithelium
      with signs of differentiation developed. The expression of several markers for
      differentiation and basal membrane formation were compared with those of healthy
      human skin by immunohistochemical staining. In the epithelium of the skin model
      several cytokeratins, especially keratin 10, and involucrin were expressed
      comparable to normal skin. Laminin expression was found along the basal zone of
      the epithelium. BrdU labeling indicating proliferation was mainly found in the
      basal parts of the epithelium. Differentiated cells showing DNA fragmentation
      were detected in the upper parts of the epithelium by the TUNEL assay.
      Fluorescence in situ hybridization was used to discriminate between HaCaT and
      L929 cells in the coculture. Some L929 cells growing on top of the epithelium
      could be detected. This might have been due to an invasion of highly
      proliferating L929 cells and might be one of the limits of tissue engineering
      with cell lines. In conclusion, the organotypic coculture used as a skin model is
      a promising additional tool for addressing specific research questions.

PMID- 10638334
TI  - Phosphatidylcholine-specific phospholipase C, but not phospholipase D, is
      involved in pemphigus IgG-induced signal transduction.
AB  - The precise mechanism of the acantholysis after pemphigus IgGs bind to desmoglein
      (Dsg) 3 and/or Dsg 1 on the cell surface is as yet unknown. We have previously
      reported that pemphigus IgG (P-IgG) causes a transient increase in intracellular
      calcium and inositol 1,4,5-trisphosphate concentration, and subsequent activation
      of protein kinase C (PKC) in DJM-1 cells, a squamous cell carcinoma line. In
      order to see whether phosphatidylcholine (PC)-specific phospholipase C (PLC) or
      phospholipase D (PLD) is involved in the P-IgG-induced signaling process, the
      production of 1,2-diacylglycerol (DAG) and phosphatidylbutanol (PBut), a
      potential marker for the determination of PLD activity in the presence of
      butanol, was determined in DJM-1 cells. A biphasic accumulation of DAG, which
      consisted of a first transient phase and a second sustained phase, was observed.
      The second phase of DAG accumulation was profoundly inhibited by pretreatment
      with D609, a selective inhibitor of PC-PLC, but not by propranolol, an inhibitor
      of phosphatidate phosphohydrolase. Pemphigus serum after preadsortion of
      antibodies to Dsg 3 and Dsg 1 with recombinant Dsg 3 and Dsg 1 did not show
      formation of DAG. PBut was not generated following the addition of P-IgG. In
      addition, the levels of [3H]phosphocholine, a direct metabolite of PC-PLC, were
      elevated after the addition of P-IgG. These results suggest that the PC-PLC
      pathway plays a major role in P-IgG-induced transmembrane signaling by causing
      prolonged generation of DAG, which may lead to long-term activation of PKC.

PMID- 10638335
TI  - Accelerated proliferation of epidermal keratinocytes by the transgenic expression
      of the platelet-activating factor receptor.
AB  - Transgenic mice overexpressing platelet-activating factor receptor (PAFR) have
      abnormal pigmentation of the ear and the tail, which can progress to melanocytic
      tumors as the mice age. Histologically, epidermal hyperproliferation and
      increases in dermal melanocytes are evident. Examination of these transgenic mice
      at various ages revealed hyperproliferation of the epidermis even 2 weeks after
      birth which developed as the mice aged. Dermal melanocytes also increased in
      number with growth. Expression of the PAFR transgene was found in keratinocytes
      and not in melanocytes, thereby suggesting that PAF does not play a direct role
      in proliferation of melanocytes. Topical application of a cream containing
      WEB2086, a specific PAFR antagonist, to the ear and the dorsal skin significantly
      suppressed the number of BrdU-positive cells in PAFR transgenic mice. These
      results suggest that PAF plays a modulatory role in the growth of epidermal
      keratinocytes. PAFR transgenic mice would be a useful model for investigations of
      skin diseases related to altered proliferation of epidermal keratinocytes
      including psoriasis.

PMID- 10638336
TI  - Overexpression of circulating vascular endothelial growth factor (VEGF) in
      leukocytoclastic vasculitis.

PMID- 10638337
TI  - Massage and ultrasound as therapeutic modalities in exercise-induced muscle
      damage.

PMID- 10638338
TI  - Dietary creatine monohydrate supplementation.
AB  - This paper summarizes and interprets the research published about physiological
      aspects of dietary supplementation with creatine monohydrate and the effects on
      physical performance. A nitrogenous molecule that occurs naturally in the flesh
      consumed by meat-eaters, creatine is also synthesized endogenously and is stored
      primarily in skeletal muscle. The research literature in which direct
      measurements of muscle creatine content have been reported indicates that most,
      but not all, subjects respond to "creatine loading" by increasing the total
      intramuscular concentration of creatine, including the concentration of
      phosphocreatine. The factors that affect muscle creatine stores are reviewed, as
      are the widely ranging results on physical performance. The mechanism of action
      by which increased intramuscular creatine could enhance performance is not yet
      clear. Original speculation was that increased phosphocreatine levels prior to
      commencing exercise, in conjunction with higher free creatine concentration,
      would prolong the time required until performance-limiting levels of
      phosphocreatine were reached during intense exercise. It was also speculated that
      restoration of phosphocreatine levels between bouts of such exercise would be
      more rapid. More recent studies question such speculation. This review includes a
      discussion of what is known about the health risks and side-effects associated
      with creatine loading. The paper concludes with speculation about the
      unprecedented attention given to creatine supplementation by recreational and
      competitive athletes and the media.

PMID- 10638339
TI  - Fatty acid transporters (FABPpm, FAT, FATP) in human muscle.
AB  - Recently, a number of putative LCFA transporters have been identified: fatty acid
      binding protein (FABPpm), fatty acid translocase (FAT/CD36), and fatty acid
      transport protein (FATP). We have demonstrated, for the first time, that
      transcripts of all three putative LCFA transporters (FAT mRNA, FATP mRNA, and
      mAspAT/FABPpm mRNA) are present in human skeletal muscle.

PMID- 10638340
TI  - Acute hormonal responses to a single bout of heavy resistance exercise in trained
      power lifters and untrained men.
AB  - The purpose of this study was to investigate the acute responses of both stress
      and fluid regulatory hormones to a single bout of resistance exercise in both
      trained and untrained men. Seven competitive power lifters (PL) and 12 untrained
      subjects (UT) performed one set of the leg press exercise to exhaustion at 80% of
      their respective one-repetition maximum. Blood samples were obtained twice prior
      to exercise (at P1 and P2), immediately postexercise (IP), and at 5 minutes
      postexercise (5PE). Compared to P1 and P2, plasma epinephrine, norepinephrine,
      dopamine, atrial peptide, osmolality, and blood lactic acid increased
      significantly (p < or = 0.05) at IP. Plasma epinephrine, norepinephrine, atrial
      peptide, and blood lactic acid concentrations remained elevated at 5PE compared
      to P1 and P2. Plasma renin activity and angiotensin II were significantly
      elevated at 5PE compared to P1, P2, and IP, and this increase was significantly
      greater in PL compared to UT at 5PE. These data indicate that an acute bout of
      resistance exercise dramatically affects secretion of stress and fluid regulatory
      hormones.

PMID- 10638341
TI  - Nasal dilator strips delay the onset of oral route breathing during exercise.
AB  - The external nasal dilator strip (ENDS) device (Breathe Right, CNS Inc.,
      Chanhassen, MN, USA) has been adopted by athletes to promote nasal route
      breathing during exercise. We studied the influence of ENDS on the switching
      point from nasal-only to oro-nasal breathing during exercise in 4 healthy men
      (age 25 +/- 2 yrs, mean +/- SEM) and 5 women (age 30 +/- 5 yrs). Resting
      inspiratory nasal airflow resistance decreased from 0.33 +/- 0.02 kPa/L/s without
      ENDS to 0.22 +/- 0.01 kPa/L/s with ENDS (p < 0.01). ENDS delayed the onset of oro
      nasal breathing such that the time from commencement of exercise to switching
      increased by 15.2%, and maximum levels of inspiratory nasal airflow and
      ventilation achieved prior to switching increased by 14.9% and 14.3%,
      respectively (all p < 0.05). We conclude that, in normal healthy subjects, ENDS
      does promote nasal route breathing during exercise, but any delay in the onset of
      oral route breathing during a progressive exercise task appears relatively small.

PMID- 10638342
TI  - Weight relapsers, maintainers, and controls: metabolic and behavioural
      differences.
AB  - The present investigation was undertaken to describe selected factors associated
      with the maintenance of body weight in three groups of women: relapsers (regained
      weight after losing weight), maintainers (maintained weight loss), and controls
      (weight stable). The following physiological variables were also assessed:
      resting energy expenditure (REE), serum glucose, insulin, leptin,
      triiodothyronine (T3), and body composition. As well, participants completed the
      interviewer-administered Weight Maintenance Questionnaire (WMQ). Overall,
      relapsers were older and heavier than maintainers and controls. As well, BMI, sum
      of-four skinfolds, waist and arm circumference, serum leptin, and insulin levels
      were significantly greater for relapsers than for maintainers and controls. There
      were no differences between maintainers and controls in any of the parameters
      measured. Although relapsers revealed a history of weight cycling, the weight
      loss strategies and exercise habits of maintainers and relapsers did not differ.
      The data suggest that the higher body mass and fat mass in relapsers may explain
      the physiological differences between relapsers and maintainers.

PMID- 10638343
TI  - Development of a hockey-specific, skate-treadmill VO2 max protocol.
AB  - The purpose of this study was to investigate a protocol for the determination of
      VO2 max utilizing a motor-driven skate treadmill (ST). On separate days, 6 male
      hockey players completed a ST and a cycle ergometer (BK) VO2 max protocol. The
      results showed no significant difference between the ST and BK protocols for
      relative (60.4 +/- 5.09 vs. 59.0 +/- 8.31 ml.kg-1.min-1) and absolute VO2 max
      values (4.51 +/- 0.50 vs. 4.39 +/- 0.59 L.min-1), respectively. Significantly
      higher HR max was recorded during the ST protocol (202.3 +/- 4.27 vs. 200.7 +/-
      4.55 b.min-1) (p < 0.05). Peak VE and VT were nonsignificant between the two
      conditions. However, peak f was higher for the ST protocol (63.0 +/- 7.56 vs.
      60.2 +/- 7.76 breath.min-1) (p < 0.05). Although the physiological response to
      both protocols was similar, the ST protocol replicates a hockey stride, which may
      provide more applicable information for the development of training programs.

PMID- 10638344
TI  - The optimal joint angle for adductor pollicis force production in men and women.
AB  - The purpose of this study was to determine the joint angle that allows for the
      greatest MVC and evoked twitch forces from the adductor pollicis (AP), and also
      whether there is a gender difference in either the above forces or the optimum
      thumb angle. Ten men (25.2 yrs) and 10 women (27.6 yrs) participated. The
      nondominant hand was placed palm-down with the thumb fixed at four angles of
      abduction (55, 70, 85, 100 degrees). Male MVC forces were significantly greater
      than female, and there was no significant effect of joint angle on MVC force in
      either gender. For the evoked twitch, men were significantly stronger than women
      when tested at the 100 and 85 degrees angles, and a significant effect was found
      for joint angle such that the lowest twitch force occurred at 55 degrees. Men
      also tended to have a greater rate of force development than women (p = 0.07).
      These data suggest that studies using the AP muscle in stimulated and voluntary
      paradigms should use a thumb angle between 70 and 100 degrees of abduction, or
      approximately 85 degrees, and that the same angle can be used for both men and
      women.

PMID- 10638345
TI  - The state of EEG biofeedback therapy (EEG operant conditioning) in 2000: an
      editor's opinion.

PMID- 10638346
TI  - A review of EEG biofeedback treatment of anxiety disorders.
AB  - Alpha, theta and alpha-theta enhancements are effective treatments of the anxiety
      disorders (Table 1). Alpha suppression is also effective, but less so (Table 2).
      Perceived success in carrying out the task plays an important role in clinical
      improvement. Research is needed to find out how much more effective they are than
      placebo, and which variables are important for efficacy. Variables needing study
      are: duration of treatment, type and severity of anxiety, number and type of EEG
      waveforms used, pretreatment with other kinds of feedback, position and number of
      electrodes, and presence of concomitant medication.

PMID- 10638347
TI  - An EEG biofeedback protocol for affective disorders.

PMID- 10638348
TI  - The treatment of addictive disorders by brain wave biofeedback: a review and
      suggestions for future research.

PMID- 10638349
TI  - Self regulation of electrocortical activity in schizophrenia and schizotypy: a
      review.
AB  - Contrary to the belief that schizophrenic patients will be unable to learn self
      control of electrocortical activity due to attentional and motivational deficits,
      the two studies which have investigated this, both involving operant conditioning
      of slow cortical potentials, have demonstrated that self regulation can take
      place. This was particularly true of a study of interhemispheric control.
      Learning difficulties were found to be more to do with sustaining motivation
      towards the end of sessions or training programs, rather than in initial
      learning. Schizotypical features in the normal population have in the case of
      anhedonia been associated with slower learning, while withdrawn introversion has
      been associated with faster learning. In view of the affirmative evidence and
      advances in understanding the functional significance of electroencephalographic
      (EEG) rhythms, the undertaking of therepeutic regimens with electrocortical
      operant conditioning is warranted in the schizophrenia spectrum.

PMID- 10638350
TI  - Treatment of attention deficit hyperactivity disorder with neurotherapy.
AB  - Significant public health concerns exist regarding our current level of success
      in treating ADHD. Medication management is very helpful in 60-70% of patients.
      Side effects, lack of compliance and the fact that stimulant medications cannot
      be given late in the day limit the benefits largely to school hours. While
      stimulants improve behavior and attention, less of an effect has been noted on
      academic and social performance. Continuing concerns exist about long-term
      safety, and studies on long-term cardiovascular and neurophysiological effects
      have not been carried out. Neurotherapy for ADHD offers an effective alternate
      for patients whose treatment is limited by side effects, poor medication response
      and in cases in which the patients and/or their parents refuse to consider
      medications. Studies indicate clinical improvement is largely related to
      measurable improvements in the EEG signature, evidenced by declining theta/beta
      ratios over frontal/central cortex and/or reduced theta/alpha band amplitudes.

PMID- 10638351
TI  - EEG operant conditioning (biofeedback) and traumatic brain injury.
AB  - A review is presented of the currently sparse literature about EEG operant
      conditioning or biofeedback as a treatment to reduce symptomology and patient
      complaints following a traumatic brain injury. The paper also evaluates the
      general use of quantitative EEG (QEEG) to assess traumatic brain injury and to
      facilitate EEG biofeedback treatment. The use of an age matched reference
      normative QEEG database and QEEG discriminant function are presented as a method
      to evaluate the nature or neurological basis of a patient's complaints as well as
      to individualize an efficient and optimal feedback protocol and to help evaluate
      the efficacy of the biofeedback therapy. Univariate and multivariate statistical
      issues are discussed, different classes of experimental designs are described and
      then a "double blind" research study is proposed in an effort to encourage future
      research in the area of EEG biofeedback for the treatment and rehabilitation of
      traumatic brain injury.

PMID- 10638352
TI  - Basic concepts and clinical findings in the treatment of seizure disorders with
      EEG operant conditioning.
AB  - Two issues concerning sensorimotor EEG operant conditioning, or biofeedback, as a
      therapeutic modality for the treatment of seizure disorders are the focus of this
      review. The first relates to the question of whether relevant physiological
      changes are associated with this procedure. This question is addressed through
      review of an extensive neurophysiological literature that is likely unfamiliar to
      many clinicians but that documents both immediate and sustained functional
      changes that are consistent with elevation of seizure thresholds. The second
      focuses on the clinical efficacy of this method and whether it should carry the
      designation of "experimental". This designation is challenged through an
      assessment of over 25 years of peer-reviewed research demonstrating impressive
      EEG and clinical results achieved with the most difficult subset of seizure
      patients.

PMID- 10638353
TI  - Effects of leukotrienes and prostaglandins on cochlear blood flow in the
      chinchilla.
AB  - Prostaglandins (PGs) such as PGE2 and PGI2 are vasodilators, and leukotrienes
      (LTs) such as LTB4 and LTC4 are vasoconstrictors. Our previous studies have shown
      that salicylate ototoxicity is associated with decreased levels of PGs and
      increased levels of LTs. We hypothesized that vasodilating PGs increase cochlear
      blood flow and vasoconstricting LTs decrease cochlear blood flow. PGE2, Iloprost
      (a PGI2 analog), LTB4, and LTC4 were applied to the round window membranes of
      chinchillas and cochlear blood flow was measured with a laser Doppler flowmeter.
      PGE2 increased cochlear blood flow, while LTC4 decreased cochlear blood flow.
      This findings show that vasodilating PGs may have therapeutic implications for
      sensorineural hearing loss and/or vertigo by increasing cochlear blood flow.
      Vasoconstricting LTs may cause hearing loss by decreasing cochlear blood flow.

PMID- 10638354
TI  - Middle ear mucosa changes following exposure to Pseudomonas aeruginosa exotoxin
      A.
AB  - Pseudomonas aeruginosa exotoxin A (1 microgram/20 microliters) was instilled into
      the middle ear cavity in the rat. Morphological changes of the mucosa were
      analyzed after various intervals using light (LM) and transmission electron
      microscopy (TEM). An inflammatory cell reaction was seen in which there was a
      predominance of polymorphonuclear leukocytes (PMNs) and mononuclear cells that
      were mostly lymphocytes and monocytes/macrophages. Epithelial cells often showed
      signs of metaplasia and hyperplasia, followed by degradation through necrosis
      and/or apoptosis, resulting in denudation of the submucosal layer. A
      characteristic feature was the physical interaction between intraepithelial
      lymphocytes and epithelial cells. Lymphocytes adhering to the cell coat of
      epithelial cells showed signs of directed secretion that seemed to end in
      necrosis or apoptosis of the target cell. These changes occurred simultaneously
      with phagocytosis of cells and cell debris by PMNs and macrophages.
      Ultrastructural analysis suggested that intraepithelial, lymphocyte-mediated
      cytolysis and apoptosis may be important events in degradation of the epithelium
      following exposure to Pseudomonas sp. exotoxin. These findings indicate that
      denuding of the lamina propria may facilitate the penetration of toxin into the
      labyrinth, thus explaining subsequent inner ear damage.

PMID- 10638355
TI  - Electrocochleographic documentation of temporal findings of speech perception in
      normal and hearing-impaired individuals.
AB  - Compound action potentials (CAPs) evoked by the short Japanese syllables /a/ and
      /ka/ were recorded by extratympanic electrocochleography in 17 subjects with
      normal hearing (17 ears) and 34 patients with sensorineural hearing losses (35
      ears) to investigate the temporal aspects of speech coding for perception. In
      normal ears, three characteristics were found common to the temporal patterns of
      all CAPs: (1) a prominent CAP at the beginning of both stimuli; (2) periodic CAPs
      with the same interval as the pitch period through the vowel part of both
      stimuli; (3) absence of a prominent CAP at the onset of voice. These
      characteristics may help to produce consonant recognition. Among the subjects
      with sensorineural hearing loss, some ears showed the following two
      characteristics different from those with normal hearing: (1) a significantly
      lower CAP at the onset of both stimuli than in those with normal hearing; (2)
      decay of CAPs during the voiced part. These findings may result in abnormal
      loudness perception in sensorineural hearing loss as produced by loudness
      recruitment and pathological adaptation. Such different temporal patterns of CAPs
      may have an adverse influence on the speech discrimination of patients with
      sensorineural hearing impairments.

PMID- 10638356
TI  - Twenty years of experience with Marullo's supraglottic laryngectomy.
AB  - We present a follow-up study of 142 patients on whom we performed supraglottic
      laryngectomy (SL) with an anterior subperichondral approach using Marullo's
      technique, which was described in 1975. Between January 1976 and December 1992,
      142 patients (age range, 35-73 years) with squamous cell carcinoma of the
      supraglottic larynx were treated with SL or extended SL (ESL) and ipsilateral or
      bilateral neck dissections with or without postoperative radiotherapy. All cases
      were staged according to the 1997 UICC TNM classification. Survival was defined
      by the Kaplan-Meyer method and showed an overall survival of 77% and a local
      control rate of 78%. Regarding functional rehabilitation, the mean nasogastric
      tube-removal time was 16 days (range, 10-39 days) for SL and 23 days (range, 11
      102 days) for ESL. Voice quality was very satisfactory after SL, while the voice
      was often harsh or breathy after ESL with postoperative radiotherapy. The overall
      oncologic and functional results obtained with Marullo's SL were very similar to
      those obtained with the classic Alonso's operation and demonstrated that this
      technique makes it possible to reach "en bloc" supraglottic sites and the
      hyothyroepiglottic space. We consider the operation to be safe and simple to
      perform, provided the sub-perichondral plane is correctly identified. This
      approach allows the surgeon easily to reach the correct transverse level above
      the anterior commissure of the vocal cords. Inferiorly, the resection cuts
      through the floor of the ventricle and is considered to be the safe oncologic
      plane for pure supraglottic lesions. This technique has also been used
      successfully in extended resections to treat tumors involving the base of the
      tongue, pyriform sinus and one arytenoid.

PMID- 10638357
TI  - Neoglottic vibration in tracheoesophageal shunt phonation.
AB  - The purpose of the present study was to examine vibratory patterns of the
      neoglottis and to ascertain the neoglottic conditions that could cause failure in
      tracheoesophageal shunt phonation. We studied 30 tracheoesophageal shunt speakers
      while using "trap-door" type voice prostheses. Videostroboscopy was undertaken to
      investigate vibratory patterns of the neoglottis during phonation of the
      sustained vowel sound /e/ in these patients. The voice qualities of the patients
      were judged perceptually. A regular neoglottic vibration was observed in 21
      patients. Nine patients had irregular neoglottic vibrations. In this latter
      group, two patients had incomplete neoglottic closures with breathy voices, four
      patients had multiple contacts of several mucosal walls with rough voices, and
      three patients had tight neoglottic closures with strained voices. During
      stroboscopic evaluation of tracheoesophageal shunt phonation, regularity of the
      neoglottic vibration may be the most significant finding. These findings show
      that it is as important to evaluate neoglottic vibration in alaryngeal voicing as
      it is to study glottic vibration in laryngeal voicing. Stroboscopic examination
      may be a help to elucidate a cause of failure in cases of poor tracheoesophageal
      shunt speech.

PMID- 10638358
TI  - A fatal case of craniofacial necrotizing fasciitis.
AB  - A case of fatal craniofacial necrotizing fasciitis is described in a 72-year-old
      diabetic woman and management is discussed. Progressive infection of the eyelids
      occurred with involvement of the right side of the face. Computed tomography
      revealed soft tissue swelling. Antibiotic treatment was started and debridement
      performed; histopathology showed acute inflammation and thrombosis of the
      epidermis and dermis. Despite treatment, scepticemia occurred, resulting in death
      less than 48 h after presentation. At this time extensive necrosis had developed
      in the superficial fascia with undermining and gangrene of surrounding tissues.
      Streptococcus and Staphylococcus were the pathogens involved. Poor prognosis in
      similar patients has been associated with extensive infection, involvement of the
      lower face and neck, delayed treatment, advanced age, diabetes and vascular
      disease.

PMID- 10638359
TI  - Cervical necrotizing fasciitis.
AB  - Necrotizing fasciitis is a severe soft tissue infection that results in necrosis
      of the fasciae and subcutaneous tissues; the infection can quickly prove fatal.
      Although involvement of the head and neck is rare, causes are usually odontogenic
      or pharyngeal but can also be insect bites, local trauma, burns or surgery. We
      present a clinical case of a 31-year-old Italian woman with cervical necrotizing
      fasciitis having an uncommon presentation. While under treatment, the patient's
      husband was admitted for necrotizing fasciitis of the medial fasciae of his left
      leg subsequent to an insect sting. The causes, diagnosis and treatment of
      necrotizing fasciitis are reviewed.

PMID- 10638360
TI  - Expression of intermediate filament proteins in benign lesions of the oral
      mucosa.
AB  - Immunohistochemistry with monospecific antibodies was used to study the
      expression patterns of cytokeratins (Cks) and vimentin in non-dysplastic lesions
      of the oral cavity, including lichen planus and fibromas. In hyperplastic
      lesions, Ck expression did not deviate significantly from the normal non
      keratinizing squamous epithelium of the oral cavity. Hyperkeratotic lesions
      showed pronounced aberrations in their Ck profile. These lesions were
      characterized by extended expression of the keratinization marker Ck 10, the
      basal cell Ck 14 and the hyperproliferation-associated Ck 16 in the suprabasal
      compartment. The stratification markers Cks 4 and 13 showed a decreased
      expression. Coexpression of Cks and vimentin was found in lesions having
      accumulations of inflammatory cells in the subepithelial cell layer. These
      changes are felt to characterize benign mucosal lesions without dysplasia and
      might be helpful for distinguishing these lesions from potentially malignant
      ones.

PMID- 10638361
TI  - A comparative study of age and degree of facial nerve recovery in patients with
      Bell's palsy.
AB  - The purpose of this study was to investigate if there is any relationship between
      the age of a patient and the degree of facial nerve recovery in patients with
      Bell's palsy. Between 1987 and 1995 250 patients with peripheral idiopathic
      facial nerve palsy were examined at the ENT Clinic of the University of Ioannina.
      In this group 134 were male and 116 were female. The patients' ages ranged from 4
      to 80 years and had an average of 47.7 years. The average age of the male
      patients was 46.5 years and that of the female patients was 49.1 years. In the
      overall group of 250 patients 129 presented with a paralysis of the right facial
      nerve and 121 on the left. There was no case of bilateral palsies. When comparing
      the age of the patients and the degree of recovery, measuring age was associated
      with a decrease in complete recovery. While the percentage of complete recovery
      between age 4 and 50 years varied from 83% to 74%, respectively, the percentage
      of complete recovery decreased to less than 54% at age 80. Our results show that
      the age of the patient is a very important factor for facial nerve recovery.

PMID- 10638362
TI  - Use of the laryngeal mask to evaluate a laryngeal web.

PMID- 10638363
TI  - Reading and spelling disorders: clinical features and causes.
AB  - Developmental dyslexia (specific reading and specific spelling disorder) is
      thought to stem from specific features in cognitive processing strongly related
      to biological maturation of the central nervous system which interact with non
      biological learning conditions. The specific learning disorder should not be
      accounted for by mental age, gross neurological deficits, emotional disturbances
      or inadequate schooling. As a clinical guideline, the child's level in reading
      and spelling must be significantly below that expected for the population of
      children of the same mental age. The persistence rate is high and dyslexia is
      often associated with psychiatric problems. The etiology is not known. From the
      biological point of view, dyslexia is supposed to have a neurological basis.
      Neuroanatomical, neurophysiological, and neuropsychological correlates have been
      studied by means of autopsy, brain imaging, neurophysiological and
      neuropsychological methods. There is good evidence that dyslexia is determined by
      heritable cognitive components of reading and spelling processing. Experimental
      research focuses on characteristics of brain structure and cognitive skills
      related to the central nervous systems of auditory-phonological and visual
      information processing.

PMID- 10638364
TI  - The influence of different diagnostic approaches on familial aggregation of
      spelling disability.
AB  - The influence of different diagnostic approaches on familial aggregation of
      spelling disability was investigated in three studies. In the first study, in a
      sample of 32 dyslexic children and their families, we found significantly
      increased rates of spelling-disabled sibs and parents by applying the IQ
      discrepancy criterion. There was no evidence for the assumption that IQ
      discrepancy and low achievement criteria define different subgroups of spelling
      disorder regarding familial aggregation. In the second study, in a sample of 79
      adults, it could be demonstrated that questionnaire data can be used as an
      appropriate method to classify adult probands as spelling disabled with a correct
      classification rate above 87%. In the third study, a subgroup of dyslexic boys
      could be characterized by a lack of the N1-component in visual evoked potentials
      which was most prominent in those boys whose spelling scores were more than 1.5
      standard deviations below their intelligence level. This subgroup could be
      interesting also for genetic research.

PMID- 10638365
TI  - A candidate phenotype for familial dyslexia.
AB  - The probative analysis of genotype-phenotype relations in familial dyslexia
      requires operationally defined psychobiological outcome variables that are not
      confounded by cultural differences of orthography or other factors that may
      influence the clinical ascertainment and diagnosis of dyslexia. Timing precision,
      as expressed in coordinated motor action, was used as an objective behavioral
      measure that can be mapped on current knowledge of central nervous system
      functions as well as on the most salient non-reading deficits in developmental
      dyslexia. Dyslexia families with four distinct pedigrees and a normally reading
      reference group were the study subjects. The results indicated that impaired
      timing precision in bimanual coordination and in motor speech were transmitted
      vertically in affected members of about half of dyslexia families. Motor
      coordination deficits were associated with a disposition to make dysphonemic
      spelling errors. It is proposed that impaired timing precision identifies a
      behavioral phenotype in some familial dyslexia subtypes. The detailed analysis of
      coarticulation in speech production may be one pathway by which impaired timing
      precision in motor action impinges on reading and writing deficits in
      developmental dyslexia.

PMID- 10638366
TI  - The role of phonological awareness, speech perception, and auditory temporal
      processing for dyslexia.
AB  - There is strong evidence that auditory processing plays a major role in the
      etiology of dyslexia. Auditory temporal processing of non-speech stimuli, speech
      perception, and phonological awareness have been shown to be influential in
      reading and spelling development. However, the relationship between these
      variables remains unclear. In order to analyze the influence of these three
      auditory processing levels on spelling, 19 dyslexic and 15 control children were
      examined. Significant group differences were found for all speech variables, but
      not for any non-speech variable. Structural equation modeling resulted in a
      fairly simple model with direct paths to the respective next lower level. One
      additional path from preattentive speech processing to spelling had to be
      included in order to improve the model fit. These results strengthen the role of
      speech and phonological processing for the etiology in dyslexia.

PMID- 10638367
TI  - Sampling strategies for model free linkage analyses of quantitative traits:
      implications for sib pair studies of reading and spelling disabilities to
      minimize the total study cost.
AB  - One approach to establish linkage is based on allele sharing methods for sib
      pairs. In recent years the use of selected sib pairs to increase power for
      mapping quantitative traits in humans has been discussed intensively. In this
      paper the different basic principles for sib pair sampling proposed in the
      literature are made evident. Implications for ascertainment schemes of sib pairs
      to minimize the total study cost in linkage analyses on reading and spelling
      disabilities are discussed.

PMID- 10638368
TI  - Linkage analysis and genetic models in dyslexia--considerations pertaining to
      discrete trait analysis and quantitative trait analyses.
AB  - We used simulation studies to assess the relative powers of various autosomal
      dominant models of inheritance for dyslexia.

PMID- 10638369
TI  - Linkage analysis in heterogeneous and complex traits.
AB  - Linkage analysis is generally carried out under single-gene models, while complex
      traits are thought to be under the control of multiple interacting genes. Current
      issues related to linkage analysis for complex traits are discussed. It is argued
      that linkage analyses should be carried out for sub-phenotypes, in addition to
      classical "affected-unaffected" phenotypes. Correlations for phenotypes among
      family members are often computed on the basis of extreme phenotypes of a
      proband, which results in biased estimates. Methods for ascertainment corrections
      are recommended. A generalized version of heterogeneity analysis is introduced
      and are shown to provide an effective single-locus analysis for complex traits.

PMID- 10638370
TI  - A genome-wide search strategy for identifying quantitative trait loci involved in
      reading and spelling disability (developmental dyslexia).
AB  - Family and twin studies of developmental dyslexia have consistently shown that
      there is a significant heritable component for this disorder. However, any
      genetic basis for the trait is likely to be complex, involving reduced
      penetrance, phenocopy, heterogeneity and oligogenic inheritance. This complexity
      results in reduced power for traditional parametric linkage analysis, where
      specification of the correct genetic model is important. One strategy is to focus
      on large multigenerational pedigrees with severe phenotypes and/or apparent
      simple Mendelian inheritance, as has been successfully demonstrated for speech
      and language impairment. This approach is limited by the scarcity of such
      families. An alternative which has recently become feasible due to the
      development of high-throughput genotyping techniques is the analysis of large
      numbers of sib-pairs using allele-sharing methodology. This paper outlines our
      strategy for conducting a systematic genome-wide search for genes involved in
      dyslexia in a large number of affected sib-pair familites from the UK. We use a
      series of psychometric tests to obtain different quantitative measures of reading
      deficit, which should correlate with different components of the dyslexia
      phenotype, such as phonological awareness and orthographic coding ability. This
      enable us to use QTL (quantitative trait locus) mapping as a powerful tool for
      localising genes which may contribute to reading and spelling disability.

PMID- 10638371
TI  - Reading disability: evidence for a genetic etiology.
AB  - A review of evidence for genetic influences on reading disabilities (RD) is
      presented, with focus on twin study design and sib-pair linkage techniques.
      DeFries-Fulker multiple regression analyses result in significant estimates of
      heritability for group deficits on several reading and language measures.
      Structural equation modeling techniques reveal the presence of significant common
      and independent genetic effects on individual differences on reading skills.
      Finally, linkage techniques confirm a candidate locus for RD on chromosome 6.

PMID- 10638372
TI  - Genetic linkage analysis with dyslexia: evidence for linkage of spelling
      disability to chromosome 15.
AB  - Dyslexia (reading and spelling disability) is one of the most frequently
      diagnosed disorders in childhood. Twin studies of dyslexia have indicated that
      deficits in spelling are substantially heritable and that the heritability of
      spelling deficits is higher than the heritability of reading deficits. We
      conducted a linkage study for spelling disability in seven multiplex families
      from Germany. Following previously reported linkage findings of components of
      dyslexia to chromosome 6p21-p22 and 15q21, we genotyped 26 microsatellite markers
      covering all of chromosome 6, and 13 microsatellite markers covering all of
      chromosome 15. While the chromosome 6 data were negative, results from chromosome
      15 markers supported a locus on 15q21. The highest two-point LOD score was 1.26
      with marker D15S143 at theta = 0. A multipoint LOD score of 1.78 (p = 0.0042) was
      achieved with a maximum at D15S132. Thus, our results provide independent support
      for a dyslexia gene on the long arm of chromosome 15.

PMID- 10638373
TI  - Facilitation of the withdrawal reflex by repeated transcutaneous electrical
      stimulation: an experimental study on central integration in humans.
AB  - In the present human study, we aimed to investigate the facilitation of both the
      subjective pain responses, and the withdrawal reflex to consecutive
      transcutaneous electrical stimuli as measures of temporal summation. The
      frequency (0.5-20 Hz) and intensity (0.4-0.8 times the reflex threshold, xRT) of
      the electrical stimuli were systematically varied. When using repeated
      stimulation, the stimulus intensity that evoked pain was lower than that required
      by a single stimulus (temporal summation). Temporal summation leading to pain was
      found to depend significantly upon both frequency and intensity (e.g. stimulation
      at 1 Hz caused summation at 0.8 x RT, whereas stimulation at 20 Hz caused
      summation at 0.6 x RT). The strongest reflex facilitation, and hence the
      strongest pain intensity was obtained for stimulation at 10-20 Hz at an intensity
      of 0.8 x RT. In conclusion, the results of the present human study demonstrate
      clearly that a stimulus that is perceived as a localised, repetitive tactile tap
      can be integrated and cause severe pain. This suggests that pathologically
      generated sparse nociceptive afferent activity causes strong pain by central
      integration. This might be one mechanism to explain why clinical conditions can
      become excruciatingly painful despite the fact that the pathophysiological
      changes seem to be marginal (e.g. minor nerve trauma).

PMID- 10638374
TI  - Time course for strength and muscle thickness changes following upper and lower
      body resistance training in men and women.
AB  - The purpose of this study was to investigate the time course of skeletal muscle
      adaptations resulting from high-intensity, upper and lower body dynamic
      resistance training (WT). A group of 17 men and 20 women were recruited for WT,
      and 6 men and 7 women served as a control group. The WT group performed six
      dynamic resistance exercises to fatigue using 8-12 repetition maximum (RM). The
      subjects trained 3 days a week for 12 weeks. One-RM knee extension (KE) and chest
      press (CP) exercises were measured at baseline and at weeks 2, 4, 6, 8, and 12
      for the WT group. Muscle thickness (MTH) was measured by ultrasound at eight
      anatomical sites. One-RM CP and KE strength had increased significantly at week 4
      for the female WT group. For the men in the WT group, 1 RM had increased
      significantly at week 2 for KE and at week 6 for CP. The mean relative increases
      in KE and CP strength were 19% and 19% for the men and 19% and 27% for the women,
      respectively, after 12 weeks of WT. Resistance training elicited a significant
      increase in MTH of the chest and triceps muscles at week 6 in both sexes. There
      were non-significant trends for increases in quadriceps MTH for the WT groups.
      The relative increases in upper and lower body MTH were 12%-21% and 7%-9% in the
      men and 10%-31% and 7%-8% in the women respectively, after 12 weeks of WT. These
      results would suggest that increases in MTH in the upper body are greater and
      occur earlier compared to the lower extremity, during the first 12 weeks of a
      total body WT programme. The time-course and proportions of the increase in
      strength and MTH were similar for both the men and the women.

PMID- 10638375
TI  - Elastic properties of muscle-tendon complex in long-distance runners.
AB  - The purpose of this study was to investigate the elastic properties of muscle
      tendon complex (MTC) in knee extensor muscles and the capacity for elastic energy
      utilization in long-distance runners (LDR) by comparing with data obtained from
      untrained individuals (CON). The elongation (L) of the tendon and aponeurosis of
      vastus lateralis muscle during isometric knee extension was determined by real
      time brightness mode ultrasonography, while the subjects developed a gradually
      increasing torque from 0 (relaxed) to maximal effort (MVC) within 7 s. In
      addition, performances in two kinds of maximal vertical jumps, i.e. squatting
      (SJ) and counter-movement jumps (CMJ), were measured. The relationship between L
      muscle and force (F) was curvilinear and consisted of an initial region (toe
      region), characterized by a large increase in L with increasing F, immediately
      followed by a linear region. The slope of the regression equation for the L-F
      relationship in the range 50%-100% of MVC was defined as an index of MTC
      compliance, where the rate of the changes in L to that in muscle F at every 10%
      of MVC became almost constant. The maximal L (Lmax) and MTC compliance were
      significantly lower in LDR than in CON: 29.9 (SD 3.9) mm in LDR compared to 33.3
      (SD 5.5) mm in CON for Lmax and 1.55 (SD 0.25) x 10(-2) mm.N-1 in LDR compared to
      1.88 (SD 0.82) x 10(-2) mm.N-1 in CON for MTC compliance. Also, LDR showed
      significantly less elastic energy absorption (Ee) than CON, defined as the area
      below the L-F relationship curve from 0 to 100% of MVC. Not only jump heights but
      also the differences between the heights in SJ and CMJ, expressed as the
      percentage of the height in SJ, were significantly lower in LDR than in CON. The
      augmentation with counter-movement was significantly correlated to either MTC
      compliance (r = 0.554, P < 0.05) or Ee (r = 0.563, P < 0.05). Thus, the present
      results would indicate that MTC of vastus lateralis muscle is less compliant and
      its potential for energy storage during MTS lengthening is lower in LDR than
      untrained individuals. These elastic profiles of vastus lateralis muscle in LDR
      may be associated with their lower performances during CMJ.

PMID- 10638376
TI  - Intermittent runs at the velocity associated with maximal oxygen uptake enables
      subjects to remain at maximal oxygen uptake for a longer time than intense but
      submaximal runs.
AB  - Interval training consisting of brief high intensity repetitive runs (30 s)
      alternating with periods of complete rest (30 s) has been reported to be
      efficient in improving maximal oxygen uptake (VO2max) and to be tolerated well
      even by untrained persons. However, these studies have not investigated the
      effects of the time spent at VO2max which could be an indicator of the benefit of
      training. It has been reported that periods of continuous running at a velocity
      intermediate between that of the lactate threshold (vLT) and that associated with
      VO2max (vVO2max) can allow subjects to reach VO2max due to an additional slow
      component of oxygen uptake. Therefore, the purpose of this study was to compare
      the times spent at VO2max during an interval training programme and during
      continuous strenuous runs. Eight long-distance runners took part in three maximal
      tests on a synthetic track (400 m) whilst breathing through a portable,
      telemetric metabolic analyser: they comprised firstly, an incremental test which
      determined vLT, VO2max [59.8 (SD 5.4) ml.min-1; kg-1], vVO2max [18.5 (SD 1.2)
      km.h-1], secondly, an interval training protocol consisting of alternately
      running at 100% and at 50% of vVO2max (30 s each); and thirdly, a continuous high
      intensity run at vLT + 50% of the difference between vLT and vVO2max [i.e. v
      delta 50: 16.9 (SD 1.00) km.h-1 and 91.3 (SD 1.6)% vVO2max]. The first and third
      tests were performed in random order and at 2-day intervals. In each case the
      subjects warmed-up for 15 min at 50% of vVO2max. The results showed that in more
      than half of the cases the v delta 50 run allowed the subjects to reach VO2max,
      but the time spent specifically at VO2max was much less than that during the
      alternating low/high intensity exercise protocol [2 min 42 s (SD 3 min 09 s) for
      v delta 50 run vs 7 min 51 s (SD 6 min 38 s) in 19 (SD 5) interval runs]. The
      blood lactate responses were less pronounced in the interval runs than for the v
      delta 50 runs, but not significantly so [6.8 (SD 2.2) mmol.l-1 vs 7.5 (SD 2.1)
      mmol.l-1]. These results do not allow us to speculate as to the chronic effects
      of these two types of training at VO2max.

PMID- 10638377
TI  - Effects of moderate dietary manipulation on intermittent exercise performance and
      metabolism in women.
AB  - The aim of the current study was to examine the effect of a moderate alteration
      in pre-exercise diet composition on the performance of, and metabolic response
      to, intermittent treadmill exercise in a group of normally menstruating females.
      Eight recreationally active women performed two intermittent, incremental
      exercise trials, one preceded by 2 days of a high [61 (1)%] carbohydrate (CHO)
      diet and the other by 2 days of a low [31 (1)%] CHO diet. Oxygen uptake (VO2) was
      measured during, and blood samples were obtained immediately after, each bout for
      the determination of blood lactate, glucose, glycerol, plasma free fatty acids
      and plasma ammonia. Performance, as assessed by time to exhaustion in the final
      bout, was found to be similar whether preceded by a high- or low-CHO diet [median
      (range): 28.0 (18-54) s, 29 (18-54) s, respectively]. No significant between
      trial differences were found in VO2, heart rate, or any of the blood metabolites.
      The results of the current, study indicate that moderate alterations of pre
      exercise diet do not affect intermittent, high-intensity exercise performance in
      women, despite some evidence of an alteration in the pattern of the metabolic
      response to exercise.

PMID- 10638378
TI  - Influence of muscle temperature during fatiguing work with the first dorsal
      interosseous muscle in man: a 31P-NMR spectroscopy study.
AB  - Six healthy subjects rapidly lifted and lowered a small (250 g) weight with the
      first dorsal interosseous muscle (FDI) of one hand while the work performed was
      recorded continuously until fatigue (defined as losing the ability to continue
      lifting). Work was recorded in units of chart recorder trace displacement from
      baseline (centimeters) as an isotonic transducer followed the movement of the
      weight. In all experiments, the temperature of the hand was first adjusted by
      immersion in a controlled-temperature water bath. In the warmest condition, the
      skin surface temperature over the FDI was 30.5(0.30) degrees C [mean (SE)]. After
      moderate cooling, this surface temperature was 21.5(0.16) degrees C. Cooling
      significantly reduced the time taken to reach fatigue and more than halved the
      work capacity. An intermediate degree of cooling was also used in four subjects,
      showing that most of the effects seen were changing incrementally. Before work,
      and at fatigue, intracellular metabolic conditions in the FDI were studied by
      phosphorus nuclear magnetic resonance (31P-NMR) spectroscopy, with occlusion of
      the blood flow maintained during measurements. The mean intracellular pH of the
      FDI was also calculated. The changes observed were all consistent with the fact
      that intense work requires energy which must be derived largely from
      intracellular stores of phosphocreatine and glycogen. Less work made less demand
      upon reserves, and created lower concentrations of waste products and by
      products. The observations did not, however, allow us to explain why fatigue
      occurred at a particular point or why work capacity was reduced by cooling.

PMID- 10638379
TI  - Changes in cross-sectional area in human exercising and non-exercising skeletal
      muscles.
AB  - This research was performed to study how the cross-sectional area (CSA) changes
      in the skeletal muscles of exercising (E-leg) and contralateral non-exercising (N
      leg) legs and to evaluate to what extent changes in CSA mirror changes in blood
      flow or extravascular water displacement. Seven healthy volunteers performed
      plantar flexion exercise at three different exercise intensities for 10 min each.
      Six plantar flexions followed by a 2-s rest in between allowed repeated
      measurement of the blood flow to the lower limbs by duplex ultrasonography in the
      popliteal artery and CSA by magnetic resonance imaging. The CSA was measured
      using manual planimetry at rest and after 3 and 9 min of the exercise periods.
      The CSA increased in the E-leg by 4.5% and decreased in the N-leg by -2.4%, from
      rest to highest exercise intensity. Post-exercise imaging of the E-leg showed a
      bi-phasic recovery of CSA with a rapid phase followed by a slower phase while the
      blood flow very rapidly returned almost to basal. The time course of the post
      exercise decrease indicated that about 50% of the increase in CSA at the highest
      exercise intensity might have been a result of extravascular water displacement
      and 50% of an increase in the vasculature volume related to the flow increase.
      The CSA reduction in N-leg seems to have been related to vasoconstriction,
      probably mainly of the capacitance vessels since blood flow was not reduced.

PMID- 10638380
TI  - Specificity of treadmill and cycle ergometer tests in triathletes, runners and
      cyclists.
AB  - The objective of this study was to evaluate the viability of using a single test
      in which cardiorespiratory variables are measured, to establish training
      guidelines in running and/or cycling training activities. Six triathletes (two
      females and four males), six runners (two females and four males) and six males
      cyclists, all with 5.5 years of serious training and still involved in racing,
      were tested on a treadmill and cycle ergometer. Cardiorespiratory variables
      [e.g., heart rate (HR), minute ventilation, carbon dioxide output (VCO2)] were
      calculated relative to fixed percentages of maximal oxygen uptake (VO2max; from
      50 to 100%). The entire group of subjects had significantly (P < 0.05) higher
      values of VO2max on the treadmill compared with the cycle ergometer [mean (SEM)
      4.7 (0.8) and 4.4 (0.9) l.min-1, respectively], and differences between tests
      averaged 10.5% for runners, 6.1% for triathletes and 2.8% for cyclists. A three
      way analysis of variance using a 3 x 2 x 6 design (groups x tests x intensities)
      demonstrated that all factors yielded highly significant F-ratios (P < 0.05) for
      all variables between tests, even though differences in HR were only 4 beats.min
      1. When HR was plotted against a fixed percentage of VO2max, a high correlation
      was found between tests. These results demonstrate that for triathletes, cyclists
      and runners, the relationship between HR and percentage of VO2max, obtained in
      either a treadmill or a cycle ergometer test, may be used independently of
      absolute VO2max to obtain reference HR values that can be used to monitor their
      running and/or cycling training bouts.

PMID- 10638381
TI  - Saliva immunoglobulins in elite women rowers.
AB  - Saliva immunoglobulins (sIgA, sIgG, and sIgM) and upper respiratory tract
      infection (URTI) rates were evaluated in 20 elite female rowers and 19
      nonathletes. Also, the influence of carbohydrate versus placebo beverage
      consumption on saliva immunoglobulin responses to rowing training sessions was
      measured in 15 rowers and in 5 non-exercising rowers. Saliva samples were
      collected 1 day before, and 5-10 min and 1.5 h after rowing or rest. Pre-exercise
      sIgA (but not sIgG or sIgM) concentration was 77% higher in the rowers compared
      to nonathletes (P < 0.001). Health records kept over 2 months revealed mean 5.2
      (SEM 1.2) and 3.3 (SEM 1.1) days with URTI symptoms for the rowers and controls,
      respectively. For all 39 subjects, and for the 20 rowers separately, no
      significant correlation was found between URTI symptoms or insulin, cortisol, and
      growth hormone concentrations and pre-exercise or exercise-related changes in
      saliva immunoglobulin concentrations or secretion rates. The patterns of change
      in saliva immunoglobulin concentration and secretion rate did not differ between
      the carbohydrate and placebo rowing trials, or between exercised and rested
      athletes. These data indicated an increased sIgA concentration in the female
      elite rowers compared to the nonathletes, no association between saliva
      immunoglobulins and URTI, and no effect of a normal 2-hour training session or
      carbohydrate ingestion on saliva immunoglobulin concentrations or secretion
      rates.

PMID- 10638382
TI  - In vivo 4-androstene-3,17-dione and 4-androstene-3 beta,17 beta-diol
      supplementation in young men.
AB  - To determine if known androgenic hormone precursors for testosterone in the
      androgen pathway would be readily transformed to testosterone, eight male
      subjects [mean age 23.8 (SEM 3) years, bodymass 83.1 (SEM 8.7) kg, height 175.6
      (SEM 8.5) cm] underwent a randomized, double-blind, cross-over, placebo
      controlled oral treatment with 200 mg of 4-androstene-3,17-dione (delta 4), 4
      androstene-3 beta,17 beta-diol (delta 4 Diol), and placebo (PL). The periods of
      study were separated by 7 days of washout. Blood was drawn at baseline and
      subsequently every 30 min for 90 min after treatment. Analysis revealed mean area
      under-the-curve (AUC) serum delta 4 concentrations to be higher during delta 4
      treatment [2177 (SEM 100) nmol.l-1] than delta 4Diol [900 (SEM 96) nmol.l-1] or
      PL [484 (SEM 82) nmol.l-1; P < 0.0001]. The delta 4 treatment also revealed a
      significant effect on total testosterone with a mean AUC [1632.5 (SEM 121) nmol.l
      1] that was greater than PL [1418.5 (SEM 131) nmol.l-1; P < 0.05] but not
      significantly different from those observed after delta 4Diol treatment [1602.9
      (SEM 119) nmol.l-1; P = 0.77]. Free testosterone concentrations followed a
      similar pattern where mean AUC for the delta 4 treatment [6114.0 (SEM 600) pmol.l
      1] was greater than after PL [4974.6 (SEM 565) pmol.l-1; P < 0.06] but not
      significantly different from those observed after delta 4Diol [5632.0 (SEM 389)
      pmol.l-1; P = 0.48]. The appearance and apparent conversion to total and free
      testosterone over 90 min was stronger for the delta 4 treatment (r = 0.91, P <
      0.045) than for delta 4Diol treatment (r = 0.69, NS) and negatively correlated
      for PL (r = -0.90, P < 0.02). These results would suggest that delta 4, and
      perhaps delta 4Diol, taken by month are capable of producing in vivo increases in
      testosterone concentrations in apparently healthy young men as has already been
      observed in women after treatment with delta 4.

PMID- 10638383
TI  - Difference in human cardiovascular response between upright and supine recovery
      from upright cycle exercise.
AB  - Cardiovascular responses were examined in seven healthy male subjects during 10
      min of recovery in the upright or supine position following 5 min of upright
      cycle exercise at 80% peak oxygen uptake. An initial rapid decrease in heart rate
      (fc) during the early phase of recovery followed by much slower decrease was
      observed for both the upright and supine positions. The average fc at the 10th
      min of recovery was significantly lower (P < 0.05) in the supine position than in
      the upright position, while they were both significantly greater than the
      corresponding pre-exercise levels (each P < 0.05). Accordingly, the amplitude of
      the high frequency (HF) component of R-R interval variability (by spectrum
      analysis) in both positions was reduced with a decrease in mean R-R interval, the
      relationship being expressed by a regression line--mean R-R interval = 0.006 x HF
      amplitude + 0.570 (r = 0.905, n = 28, P < 0.001). These results would suggest
      that the slower reduction in fc following the initial rapid reduction in both
      positions is partly attributable to a retardation in the restoration of the
      activity of the cardiac parasympathetic nervous system. Post-exercise upright
      stroke volume (SV, by impedance cardiography) decreased gradually to just below
      the pre-exercise level, whereas post-exercise supine SV increased markedly to a
      level similar to that at rest before exercise. The resultant cardiac output (Qc)
      and the total peripheral vascular resistance (TPR) in the upright and supine
      positions returned gradually to their respective pre-exercise levels in the
      corresponding positions. At the 10th min of recovery, both average SV and Qc were
      significantly greater (each P < 0.005) in the supine than in the upright
      position, while average TPR was significantly lower (P < 0.05) in the supine than
      in the upright position. In contrast, immediately after exercise, mean blood
      pressure dropped markedly in both the supine and upright positions, and their
      levels at the 10th min of recovery were similar. Therefore we concluded that
      arterial blood pressure is maintained relatively constant through various
      compensatory mechanisms associated with fc, SV, Qc, and TPR during rest and
      recovery in different body positions.

PMID- 10638384
TI  - Axon reflexes in human cold exposed fingers.
AB  - Exposure of fingers to severe cold induces cold induced vasodilatation (CIVD).
      The mechanism of CIVD is still debated. The original theory states that an axon
      reflex causes CIVD. To test this hypothesis, axon reflexes were evoked by
      electrical stimulation of the middle fingers of hands immersed in water at either
      5 degrees C or 35 degrees C. Axon reflexes were pronounced in the middle finger
      of the hand in warm water, but absent from the hand in cold water, even though
      the stimulation was rated as "rather painful" to "painful". These results showed
      that axon reflexes do not occur in a cold-exposed hand and thus are unlikely to
      explain the CIVD phenomenon.

PMID- 10638385
TI  - Peripheral and brachial blood pressure during standardized occupation-related
      tests in normotensive and mild hypertensive men and women.
AB  - We investigated the usefulness of peripheral blood pressure (BP) measurement in
      the assessment of strain in occupational physiology. Our hypothesis was that the
      brachial and peripheral BP reflect physiologically different events under various
      occupation-related demands in normotensive (NT) and hypertensive (HT) people. A
      group of 20 female and 20 male subjects with unmedicated mild hypertension that
      had been diagnosed by ambulatory blood pressure monitoring [awake time
      systolic/diastolic BP (BPs/BPd) 142.9 (SD 11.3)/86.4 (SD 6.2) mmHg] and 40 NT
      matched by age and sex [BPs/BPd 120.0 (SD 9.8)/75.6 (SD 5.9) mmHg] attended a
      laboratory session to undertake mental arithmetic tasks, a fingergrip test and
      submaximal cycle ergometry. Brachial and peripheral BP as well as heart rate were
      measured using a sphygmomanometer and an continuously automatic blood pressure
      measuring device on the finger, respectively. The peripheral BPs was higher than
      brachial BPs, BPd was similar for peripheral and brachial BP except during cycle
      ergometry. Associations between the levels of brachial and peripheral BP depended
      on demands and did not explain more than 42% of the common variance. The highest
      correlations between the two BP methods were observed during habituation,
      recovery and mental demands, and weak correlations during cycle ergometry. For
      peripheral BPs and BPd we found significant correlations in all phases of the
      test (r = 0.58 to 0.86, P < 0.001), also in ergometry (NT r = 0.62, P < 0.001, HT
      r = 0.53, P < 0.001), in contrast to the brachial BP. Peripheral BP
      differentiated the two BP groups (57.5%-72.5% correctly classified) which had
      been grouped by daily measurement of brachial BP, but brachial BP was superior in
      this respect with 65.0%-87.5% being correctly classified. These results supported
      the suggestion that the combined measurement of peripheral and brachial BP
      provides complementary information regarding physiological changes in NT and HT
      in different situations.

PMID- 10638386
TI  - Changes in stiffness induced by hindlimb suspension in rat Achilles tendon.
AB  - The aim of this study was to measure the effects of hindlimb suspension on
      mechanical properties of the rat Achilles tendon. Adult male Wistar rats were
      randomly assigned to groups to be either suspended, or a control. After 21 days,
      Achilles tendons were removed for mechanical analysis. Classical tests of tensile
      performance were made, and mechanical parameters were derived from a stress
      strain relationship. The tendons of animals that had been suspended presented
      values for maximal stress and tangent modulus which were 37.5% (P < 0.01) and 41%
      (P < 0.01), respectively, lower than the tendons of the control rats. In a
      similar way, the energy absorption capacity had largely decreased in animals that
      had been suspended. However, the maximal strain was similar in the two groups.
      These results showed that hindlimb suspension in rats has an important
      detrimental effect on mechanical properties of the Achilles tendon. Differences
      in tendon stiffness obtained here, along with those found by other investigators,
      encourage the hypothesis that homeostatic responses of soft tissues are due to
      changes in limb loadings. This study may be useful in providing a better
      understanding of the adaptation of human skeletal muscle when exposed to
      microgravity.

PMID- 10638387
TI  - Assessment of the efficacy and safety of paracetamol, ibuprofen and nimesulide in
      children with upper respiratory tract infections.
AB  - OBJECTIVE: The aim of this study was to assess and compare the efficacy and
      tolerability of paracetamol, ibuprofen and nimesulide in children with upper
      respiratory tract infections (URTIs). METHODS: Ninety children with acute URTIs
      and fever were enrolled to the study. The patients were allocated to three
      groups. The first group was treated with paracetamol 10 mg/kg thrice daily; the
      second group with ibuprofen 10 mg/kg thrice daily; and the third group received
      nimesulide 2.5 mg/kg twice daily for 5 days. RESULTS: The anti-pyretic activity
      of nimesulide was greater and more rapid than either paracetamol or ibuprofen.
      The number of patients with normal temperature was significantly greater in the
      first 2 days for the nimesulide group. The improvement in cough for the
      paracetamol group was better than the others. CONCLUSION: The results of this
      study demonstrated that the anti-pyretic effectiveness of nimesulide is better
      than paracetamol and ibuprofen in febrile children with URTIs. However, new
      studies in larger paediatric populations are required to explore the anti
      inflammatory effect of nimesulide.

PMID- 10638388
TI  - Influence of food intake on electrocardiograms of healthy male volunteers.
AB  - OBJECTIVE: To study the influence of food intake on electrocardiogram (ECG)
      variables (heart rate, QT-, QTc-, PR-intervals, QRS-time) and morphological
      alterations of the T-waves in 12 healthy male volunteers. METHODS: The study was
      of open, three-period crossover design. On each occasion, all subjects fasted
      from midnight. During two of the study periods, the subjects were given a
      standardised meal at 1.5 h and 5.5 h after the baseline assessments,
      respectively, whereas, during the third period, they remained fasting for the
      entire study period of about 9 h. ECG and blood pressure were recorded at
      baseline and thereafter every hour for 8 h. RESULTS: No ECG changes were observed
      following the fasting condition, whereas a clear change in ECG and an increased
      heart rate were recorded in response to the meal intake during the other two
      periods. The most prominent ECG effect was the change in the size and shape of
      the T-waves, which were described as flattened to biphasic and, occasionally,
      negative. These alterations were most pronounced in the precordial leads V4 to V6
      in the ECG recording immediately following the meal intake, with a gradual return
      to baseline conditions over 4-5 h. Moreover, a transient increase of supine
      systolic blood pressure was also recorded in response to the meal intake.
      CONCLUSIONS: The intake of a meal can cause clear and consistent ECG changes in
      healthy male subjects, comprising increases in heart rate as well as alterations
      in the size and shape of the T-waves (flattened to biphasic and, occasionally,
      negative). Also, a post-meal increase in the supine systolic blood pressure was
      recorded.

PMID- 10638389
TI  - Fluvastatin reduces endothelin secretion of cultured human umbilical vein
      endothelial cells.
AB  - OBJECTIVE: Fluvastatin is an agent of a new lipid lowering drug class, the 3
      hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, which seems to elicit
      direct effects on the vasculature. METHODS: The effect of fluvastatin on
      endothelin secretion in endothelial cell cultures from human umbilical veins was
      investigated. RESULTS: Fluvastatin significantly reduced endothelin secretion by
      13% at a concentration of 10(-8) M, by 41% at 10(-7) M and by 62% at 10(-6) M.
      CONCLUSION: Since endothelin is a potent vasoconstrictor which may be associated
      with the aetiology of cardiovascular diseases, the reduction of its synthesis by
      fluvastatin may contribute to the beneficial effects of this substance on the
      cardiovascular system.

PMID- 10638390
TI  - Experimental, extrapolated and truncated areas under the concentration-time curve
      in bioequivalence trials.
AB  - OBJECTIVE: The extrapolated area under the concentration-time curve (AUC0
      infinity) for any drug is considered by operating guidelines as the primary
      parameter related to the extent of absorption in single-dose bioavailability and
      bioequivalence trials. Not more than 20% should be added to the experimental AUC
      (AUC0-t) in the extrapolating procedure. However, in certain specific cases, it
      is problematic and, in other cases, impossible to respect the above requirement.
      It was intended to demonstrate that truncated AUC or AUC0-t would be used in
      bioequivalence trials when the AUC cannot be extrapolated. METHODS: AUC0-t and
      truncated AUC were compared at various time intervals with AUC0-infinity in a
      series of 19 single-dose bioequivalence trials covering 15 different drugs, each
      carried out on 12-24 healthy volunteers. Point estimators and 90% confidence
      intervals in the 0.80-1.25 and 0.70-1.43 ranges were statistically processed
      using log-transformed parameters. RESULTS: In all the trials considered,
      overlapping point estimators and 90% confidence intervals were invariably
      obtained, regardless of the AUC used. CONCLUSION: The use of AUC0-t or truncated
      AUC may be considered an ancillary procedure in bioequivalence trials when AUC
      cannot be extrapolated. This occurs with most extended-release formulations,
      endogenous substances, and poorly absorbed drugs. It also occurs in trials with
      one or more poor metabolisers, with drugs possessing very long elimination half
      lives, and with bioassays having problems of sensitivity that preclude
      sufficiently precise plasma concentration measurement over the required sampling
      period.

PMID- 10638391
TI  - Pharmacokinetic and pharmacodynamic effects of YM087, a combined V1/V2
      vasopressin receptor antagonist in normal subjects.
AB  - OBJECTIVE: The pharmacokinetic and pharmacodynamic properties of YM087, (4'-[(2
      methyl-1,4,5,6- tetrahydroimidazo[4,5-d][1]benzazepin-6-yl)-carbonyl]-2-p
      henylbenzanilide monohydrochloride), a new orally active, dual V1/V2 receptor
      antagonist were characterised in healthy normotensive subjects. METHODS: Six
      subjects were randomly allocated to receive, at 1-week intervals, a single oral
      dose of 60 mg YM087 and a single i.v. dose of 50 mg YM087 in an open-label,
      crossover study. RESULTS: YM087 had an oral bioavailability of 44% and a short
      half-life. Upon oral and i.v. administration of YM087, a significant sevenfold
      increase in urine flow rate and a fall in urinary osmolality (from 600 mosmol/l
      to less than 100-mosmol/l) were observed with a peak effect 2 h after drug intake
      suggesting effective vasopressin V2 receptor blockade. Simultaneously,
      significant increases in plasma osmolality (from 283 +/- 1.3 mosmol/l to 288 +/-
      1.0 mosmol/l after i.v. and from 283 +/- 2.1 mosmol/l to 289 +/- 1.7-mosmol/l
      after oral administration) and vasopressin levels (from 1.5 +/- 0.3 pg/ml to 3.7
      +/- 0.6 pg/ml after i.v. and from 0.9 +/- 0.1 pg/ml to 3.9 +/- 0.7 pg/ml after
      oral administration) were found. When administered i.v., YM087 inhibited the
      vasopressin-induced skin vasoconstriction, suggesting a blockade of V1 receptors.
      However, the YM087-induced antagonism of V1 receptors was less pronounced than V2
      receptor blockade. CONCLUSION: These data show that YM087 is an effective dual
      V1/V2 receptor antagonist in man.

PMID- 10638392
TI  - Arterial/venous plasma nicotine concentrations following nicotine nasal spray.
AB  - BACKGROUND AND OBJECTIVES: Arterial (A) and venous (V) plasma nicotine and
      cotinine concentrations were measured after nasal nicotine spray in tobacco
      smokers of both genders. The hypothesis for this research was that a greater A/V
      difference in plasma nicotine would be present in males than females because
      males have greater skeletal muscle mass to bind nicotine. SUBJECTS AND METHODS:
      Nine male and nine female healthy adult smokers were studied. They all abstained
      from use of tobacco overnight for 10 h or more prior to the study. Nicotine nasal
      spray was given in doses of 1-2.5 mg total, with half in each nostril while the
      subject was supine. Both A and V blood samples were obtained prior to and 3, 6,
      10, 15, 20, and 30 min post-nasal nicotine spray. RESULTS AND CONCLUSIONS: Nasal
      nicotine administration produced greater A than V plasma levels. There were no
      gender differences in A/V nicotine concentrations, disproving the above
      hypothesis, suggesting that other physiochemical factors besides skeletal muscle
      mass must be involved. Heart rate increases correlated well with arterial plasma
      nicotine levels (r = 0.77). Males had less variance than females in the expected
      increase in arterial plasma nicotine concentrations with increased number of
      nasal sprays. Although there was considerable overlap, mean A cotinine
      concentrations were consistently slightly larger than V concentrations.

PMID- 10638393
TI  - Pharmacokinetics of intravenous N-acetylcysteine in pre-term new-born infants.
AB  - BACKGROUND: Reactive oxygen species have been considered to play a role in
      several clinical complications in pre-term infants. The aim of this study was to
      determine the pharmacokinetics of intravenous N-acetylcysteine in pre-term
      neonates. This information is needed to evaluate the use of N-acetylcysteine as
      an antioxidant in this patient group. METHODS: N-acetylcysteine was infused
      intravenously in ten patients (gestational age 24.9-31.0 weeks, weight 500-1384
      g) for 24 h (3.4-4.6 mg/kg/h), starting 2.0-11.2 h from birth (study I) and in
      six patients (gestational age 25.9-29.7 weeks, weight 520-1335 g) for 6 days (0.3
      1.3 mg/kg/h), starting at the age of 24 h (study II). Arterial plasma N
      acetylcysteine and cyst(e)ine concentrations were determined from timed samples
      taken during (study I and II) and after (study I) the N-acetylcysteine infusion.
      RESULTS: In study I, the mean elimination half-life of N-acetylcysteine was 11 h
      (range 7.8-15.2 h). The mean plasma clearance of N-acetylcysteine was 37 ml/kg/h
      (range 13-62 ml/kg/h) and the mean volume of distribution was 573 ml/kg (range
      167-1010 ml/kg). The plasma clearance and volume of distribution correlated with
      weight (r = 0.81, P < 0.01, and r = 0.78, P < 0.01, respectively) and with
      gestational age (r = 0.71, P < 0.05, and r = 0.64, P < 0.05, respectively). In
      study II, the steady-state concentration of N-acetylcysteine was reached in 2-3
      days in five of six patients during a constant infusion. CONCLUSIONS: The
      pharmacokinetics of N-acetylcysteine in pre-term infants depend markedly on
      weight and gestational age. The elimination of N-acetylcysteine is much slower in
      pre-term new-borns than in adults.

PMID- 10638394
TI  - Limited-sampling strategy models for estimating the area under the plasma
      concentration-time curve for amlodipine.
AB  - OBJECTIVE: Develop and validate limited-sampling strategy (LSS) models for
      estimating the area under the plasma concentration versus time curve (AUC) of
      amlodipine, using data from a bioequivalence study. METHODS: Sixteen healthy
      volunteers received single 5-mg oral doses of amlodipine, as reference or test
      formulation, at a 14-day interval, in a randomized, crossover protocol. Plasma
      concentrations of amlodipine (n = 288), measured by mass spectrometry, were used
      to develop LSS models. RESULTS: Linear regression analysis of the AUC0-72 and a
      "jack-knife" validation procedure revealed that LSS models based on two sampling
      times (12 h and 48 h) predict accurately (R2 = 0.99; bias < 0.01%; precision =
      0.03%) the AUC0-72 of amlodipine for each formulation. Validation tests indicate
      that the 2-point LSS model developed for the reference formulation predicts
      accurately (R2 > 0.90): (a) the individual AUC0-72 for the test formulation in
      the same group of volunteers; (b) the individual AUC0-72 for the same reference
      formulation in another bioequivalence study in Brazilian volunteers; (c) the
      average AUC0-72 reported in seven additional international studies performed
      under protocols similar to the present investigation; (d) the individual AUC0-72
      corresponding to concentration data points provided by a first-order
      compartmental pharmacokinetic model, when the relative values of either the
      absorption rate (Kabs) or the bioavailability (F) model parameters were set at
      0.85 or 0.6, of their respective original values. CONCLUSIONS: The 2-point LSS
      models developed in the current study predict accurately the AUC of amlodipine
      under a variety of experimental conditions and, thus, may be valuable for
      exploring the relationships between the pharmacokinetics and pharmacodynamics of
      this calcium antagonist, at reduced costs of sample acquisition and analysis, and
      avoiding sampling at "unsociable" hours.

PMID- 10638395
TI  - Drug extrapyramidal side effects. CYP2D6 genotypes and phenotypes.
AB  - OBJECTIVE: Among Caucasians, a lack of cytochrome P450 enzyme CYP2D6 is observed
      in 5-10% of individuals, named poor metabolizers (PMs). A consequence may be an
      impaired metabolism of many drugs such as most of the psychotropic drugs with an
      increased risk of drug side effects. This enzyme is also involved in the
      metabolism of endogenous compounds, including neurotransmitters such as dopamine
      and dopamine-related neurotransmitters which play a role in the mechanism of
      action of extrapyramidal drug side effects. The present study investigates
      whether patients who have developed and those who have not developed
      extrapyramidal drug side effects differ in their CYP2D6 genotypes and phenotypes.
      METHODS: The CP2D6 genotype (method involving restriction length fragment
      polymorphism and polymerase chain reaction-single strand conformation
      polymorphism) was determined in 65 drug-treated in-patients, and the CYP2D6
      phenotype (with dextromethorphan probe) in 62 of them. Two groups were
      constituted, one with 22 patients who had developed extrapyramidal drug side
      effects, and the second with 43 patients without such side effects. RESULTS: In
      the whole population, there was an over-representation of PM phenotypes--more
      marked in the first group than the second (45% vs 14%). Concerning the genotypes,
      we observed that the percentage of functional alleles (with extensive metabolic
      capacity) was higher in group 2, whereas the percentage of nonfunctional alleles
      (without metabolic activity) was higher in group 1; this frequency difference was
      only marginally significant (chi 2 5.95; P < 0.0509; degrees of freedom = 2).
      Consequently, there was a higher percentage of genotypes with no (extensive)
      functional alleles in the group of patients suffering from extrapyramidal side
      effects than in the other group (P < 0.00001). CONCLUSION: CYP2D6-impaired
      metabolic capacity may be a contributory factor in extrapyramidal drug side
      effects.

PMID- 10638396
TI  - Effect of orlistat on blood cyclosporin concentration in an obese heart
      transplant patient.
AB  - OBJECTIVE: We detected markedly decreased cyclosporin blood levels in a heart
      transplanted patient after the gastrointestinal lipase inhibitor orlistat was
      accidentally added to the treatment program to control for his obesity.
      Therefore, we determined cyclosporin plasma concentration time kinetics with and
      without orlistat reexposition in this patient. METHODS: Plasma concentration time
      kinetics of whole blood cyclosporin levels in an obese heart-transplant patient
      were measured using a standard monoclonal fluorescence polarisation immunoassay.
      Results were obtained in hourly intervals up to 12 h without and with co-therapy
      of 3 x 120 mg orlistat (Xenical, Roche Ltd., Switzerland). The orlistat re
      exposition was started the day before taking blood samples. RESULTS: Cyclosporin
      trough levels (98 ng/ml vs 52 ng/ml), maximum concentrations (532 ng/ml vs 74
      ng/ml) and the area under the blood drug concentration-time curve (2832 ng h ml-1
      vs 700 ng h ml-1) were greatly reduced with orlistat. CONCLUSIONS: Orlistat
      markedly decreased blood cyclosporin concentrations, possibly due to an
      interference with its absorption in the small intestine. To avoid potential
      dangerous under-immunosuppression, orlistat should not be used in patients taking
      cyclosporin.

PMID- 10638397
TI  - Prediction of aminoglycoside distribution space in neonates by multiple frequency
      bioelectrical impedance analysis.
AB  - OBJECTIVE: Aminoglycoside antibiotics have a narrow margin of safety between
      therapeutic and toxic levels. The current study used multiple frequency
      bioelectrical impedance analysis to develop prediction equations for gentamicin
      distribution space in neonates. METHODS: Gentamicin pharmacokinetic parameters
      and bioimpedance were measured in 14 infants in the neonatal intensive care unit.
      Stepwise regression analysis was used to develop predictive models, using
      impedance quotients (F2/R), weight and gestational age as variables, whose
      predictive performance was then tested in a second group of ten infants. RESULTS:
      The prediction model with the smallest bias and highest concordance correlation
      was that which included F2/R0 and weight. This bias of 50 ml or 6.7% was less
      than half of that found using a model including weight alone. CONCLUSION: A
      bioelectrical impedance-based prediction equation for prediction of gentamicin
      distribution space in neonates was produced. Although this prediction equation
      represents only a small improvement over that using weight alone, this is of
      clinical significance due to the narrow margin between therapeutic and toxic
      levels for gentamicin. A clinical trial to confirm the value of this methodology
      is now warranted.

PMID- 10638398
TI  - Bioavailability of intranasal formulations of dihydroergotamine.
AB  - OBJECTIVE: A comparison of the pharmacokinetic properties of two novel intranasal
      preparations of dihydroergotamine mesilate (DHEM) with a commercially available
      intranasal preparation. METHODS: Two intranasal formulations of DHEM in
      combination with randomly methylated beta-cyclodextrin (RAMEB) were prepared.
      Subsequently, in an open, randomised, crossover study in nine healthy volunteers,
      the following medication was administered: 2 mg DHEM/2% RAMEB nasal spray (= two
      puffs of 100 microliters); 2 mg DHEM/4 mg RAMEB nasal powder; 2 mg Diergo nasal
      spray (= four puffs of 125 microliters); 0.5 mg DHEM i.m., and 2 mg DHEM solution
      p.o. RESULTS: No statistically significant differences were found in maximum
      plasma concentration (Cmax), time to reach Cmax (tmax), area under plasma
      concentration-time curve (AUC0-8 h), Frel(t = 8 h) and Cmax/AUC(t = 8 h) for the
      three intranasal preparations. The relative bioavailabilities of the DHEM/RAMEB
      nasal spray, the DHEM/RAMEB nasal powder and the commercially available DHEM
      nasal spray were 25%, 19% and 21%, respectively, in comparison with i.m.
      administration. The relative bioavailability after oral administration was 8%.
      CONCLUSION: The pharmacokinetic properties of the novel intranasal preparations
      are not significantly different from the commercially available nasal spray.
      Advantages of the DHEM/RAMEB nasal spray are (1) less complicated handling, (2)
      reduction of the number of puffs and (3) a preference by the volunteers.

PMID- 10638399
TI  - Opioid consumption in Spain--the significance of a regulatory measure.
AB  - OBJECTIVE: To investigate the impact of new regulatory measures on opioid
      consumption in Spain during the period 1985-1998. METHODS: A search in the ECOM
      (Especialidades Consumo de Medicamentos) database of the Ministry of Health was
      made for the 1985-1998 period. This database contains information about drug
      preparations prescribed in primary care in the National Health System in Spain.
      RESULTS: Since 1985-1998, the overall opioid consumption has increased tenfold,
      from 94.7 DDD (defined daily dose) per million inhabitants per day to more than
      1000 DDD. For the five drugs that require a special prescription form (morphine,
      methadone, pethidine, tilidine and fentanyl), the consumption has increased 13.5
      fold. CONCLUSION: A huge increase in opioid consumption has occurred. In this
      increase, changes in supply and, to a lesser extent, regulatory measures have
      played an important role.

PMID- 10638400
TI  - Pharmacoepidemiology of psychotropic drugs in patients with severe mental
      disorders in Italy. Italian Collaborative Study Group on the Outcome of Severe
      Mental Disorders.
AB  - OBJECTIVE: To describe the epidemiology of psychotropic drug use in a sample of
      Italian outpatient psychiatric services. METHODS: Drug-utilisation survey
      conducted within the framework of a broader prospective follow-up study with 67
      Italian outpatient psychiatric services. RESULTS: The data concern 2322 patients
      recruited over a 3-year period. Three-quarters of the cohort were prescribed
      antipsychotic drugs, one-half received benzodiazepines and nearly one-third
      received antidepressants. The trends in drug use from 1994 to 1997 show that for
      patients with schizophrenia there has been a decrease in the prescription of
      typical neuroleptics: the use of haloperidol passed from 56% to 42.4% and that of
      chlorpromazine dropped from 13.5% to 6.1%; during the same period, an increasing
      use of the atypical compound risperidone was observed. Among patients suffering
      from unipolar affective psychosis, the prescriptions of tricyclic antidepressants
      (TCAs) and selective serotonin reuptake inhibitors (SSRIs) have not changed in
      time, while the proportion of patients receiving neuroleptic drugs has increased
      from 41% to 45.2%. In addition, the use of antiepileptic drugs and lithium
      increased, irrespective of diagnosis. Almost 40% of the patients on psychotropic
      drugs received three or more drugs. Finally, a positive association was found
      between the number of prescribed compounds and the daily dose administered.
      CONCLUSION: These data indicate that in the absence of a rational approach to
      drug use, a symptomatic approach is generally adopted, by which common sense,
      experience, information provided by non-independent agencies and other cultural
      parameters play an important role in the prescription strategy.
      Pharmacoepidemiology should more often consider the use of drugs as a dependent
      variable, to be investigated within the context of other clinical, cultural,
      social and setting-related parameters; this approach would enable a more
      comprehensive assessment of prescribing practices and strategies in routine
      clinical care.

PMID- 10638402
TI  - Nuclear medicine and thyroid cancer.

PMID- 10638401
TI  - Interethnic and interindividual variabilities of platelet sulfotransferases
      activity in Italians and Finns.
AB  - OBJECTIVE: The aim of this investigation was to see whether there was interethnic
      variability in the platelet activities of catechol- and phenol sulfotransferases
      in Italians and Finns. METHODS: The activities of catechol- and phenol
      sulfotransferases were measured in platelets obtained from 103 Italian and 74
      Finnish individuals. Blood donors were obtained from healthy volunteers free from
      drugs and without apparent disease. The activities of catechol- and phenol
      sulfotransferases were measured with 60 microM dopamine and 4 microM 4
      nitrophenol as substrates, respectively. RESULTS: The activity of catechol
      sulfotransferase was not gender dependent and the median estimates (pmol/min/mg)
      were 9.10 in Italians and 6.37 in Finns (P = 0.0018). The activity of phenol
      sulfotransferase activity was gender dependent in Finns but not in Italians. The
      median estimates (pmol/min/mg) were 3.81 in Finnish men and 1.18 in Finnish women
      (P = 0.0007). In Italian men and women, the median estimates (pmol/min/mg) of
      phenol sulfotransferase activity were 1.25 and 1.24, respectively (NS).
      CONCLUSION: This study shows that platelet catechol sulfotransferase activity is
      greater in Italians than Finns and that the activity of phenol sulfotransferase
      is gender regulated in Finns but not in Italians. Thus, interethnic differences
      exist in platelet sulfotransferases between Italians and Finns.

PMID- 10638403
TI  - Thallium-201 gated single-photon emission tomography for the assessment of left
      ventricular ejection fraction and regional wall motion abnormalities in
      comparison with two-dimensional echocardiography.
AB  - Simultaneous assessment of myocardial perfusion and function by gated single
      photon emission tomography (GS) after a single tracer injection provides
      incremental information and is feasible with technetium-99m sestamibi. The
      present study validated the use of GS with thallium-201 for the assessment of
      left ventricular ejection fraction (LVEF) and regional wall motion by comparison
      with two-dimensional (2D) echocardiography (echo), which has not been done
      before. After injection of 111 MBq 201Tl at peak bicycle exercise (n = 55) or
      pharmacological stress (n = 17), GS was acquired 15 (post stress) and 120 min
      post injection (rest) on a double-head camera. An automatic algorithm (QGS) was
      used for processing. Echo (Acuson Sequoia C256) was performed immediately after
      rest GS. LVEFs assessed by GS and echo were correlated. The overall and segmental
      sensitivity and specificity of GS for the detection of regional wall motion
      abnormalities (WMAs) were calculated, echo serving as the gold standard.
      Perfusion abnormalities were scored. The success rate of the automatic algorithm
      was 100%, and visually assessed image quality was good to excellent in 88% of
      cases. Post-stress and rest LVEF as assessed by GS were highly correlated (r =
      0.91). Good correlations were obtained between post-stress LVEF (GS) and rest
      LVEF (echo) and between rest LVEF (GS) and rest LVEF (echo) (r = 0.76 and 0.86
      respectively). In patients with a reduced LVEF of less than 50% (n = 23), these
      correlations were even better (r = 0.84 and 0.89 respectively). Regional wall
      motion abnormalities (WMAs) were identified by GS with high sensitivity and
      specificity (88%-100% and 82%-98% respectively) and were directly related to the
      extent and severity of stress as well as of resting perfusion defects. It is
      concluded that GS with 201Tl is a feasible and reliable tool for the evaluation
      of patients with compromised left ventricular function in the context of coronary
      artery disease, and thus improves diagnosis and prognostic stratification.
      Regional WMAs were identified with high diagnostic accuracy and the method may
      prove helpful for the detection of myocardial viability.

PMID- 10638404
TI  - Gated single-photon emission tomography imaging protocol to evaluate myocardial
      stunning after exercise.
AB  - This study was designed to apply ECG-gating to stress myocardial perfusion single
      photon emission tomography (SPET) for the evaluation of myocardial stunning after
      exercise. Technetium-99m sestamibi was selected as the perfusion agent and a
      rest/exercise 1-day protocol was employed. Fourteen patients without coronary
      stenosis and 33 patients with coronary stenosis were enrolled in the study. We
      carried out three data acquisitions with ECG-gating: a 15-min data acquisition
      starting 30 min after the rest injection (AC1), a 5-min acquisition starting 5
      min after the stress injection (AC2) and a 15-min acquisition starting 20 min
      after the stress injection (AC3). Calculation of left ventricular ejection
      fraction (LVEF) values was performed by means of automatic determination of the
      endocardial surface for all gating intervals in the cardiac cycle. Measured
      global EF values in 14 patients without coronary stenosis were 52.3% +/- 7.6%
      (AC1), 60.6% +/- 8.9% (AC2) and 55.6% +/- 5.6% (AC3), and those in 11 patients
      with severe ischaemia were 53.6% +/- 8.0% (AC1), 45.6% +/- 12.1% (AC2) and 49.7%
      +/- 10.7%. The magnitude of the depression of post-stress LVEF relative to the
      rest LVEF correlated with the severity of ischaemia (r = 0.594, P = 0.002), and
      segments manifesting post-stress functional depression were associated with
      ischaemic segments showing reversible perfusion defects. Stress myocardial
      perfusion SPET with ECG-gating is a feasible method for the evaluation of
      myocardial stunning as well as exercise-induced ischaemia.

PMID- 10638405
TI  - Fluorine-18 fluorodeoxyglucose positron emission tomography in thyroid cancer:
      results of a multicentre study.
AB  - The aim of this multicentre study was to evaluate the clinical significance of
      fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) in
      differentiated thyroid carcinoma and to compare the results with both iodine-131
      whole-body scintigraphy (WBS) and technetium-99m 2-methoxyisobutylisonitrile
      (MIBI) or thallium-201 chloride (Tl) scintigraphy. Whole-body PET imaging using
      FDG was performed in 222 patients: 134 with papillary tumours, 80 with follicular
      tumours and 8 with mixed-cell type tumours. Finally, for each case an overall
      clinical evaluation was done including histology, cytology, thyroglobulin level,
      ultrasonography, computed tomography and subsequent clinical course, to allow a
      comparison with functional imaging results. Sensitivity of FDG-PET was 75% and
      85% for the whole patient group (n = 222) and the group with negative radioiodine
      scan (n = 166), respectively. Specificity was 90% in the whole patient group.
      Sensitivity and specificity of WBS were 50% and 99%, respectively. When the
      results of FDG-PET and WBS were considered in combination, tumour tissue was
      missed in only 7%. Sensitivity and specificity of MIBI/Tl were 53% and 92%,
      respectively (n = 117). We conclude that FDG-PET is a sensitive method in the
      follow-up of thyroid cancer which should be considered in all patients suffering
      from differentiated thyroid cancer with suspected recurrence and/or metastases,
      and particularly in those with elevated thyroglobulin values and negative WBS.

PMID- 10638406
TI  - A head-to-head comparison between technetium-99m-tetrofosmin and technetium-99m
      MIBI scintigraphy to evaluate suspicious breast lesions.
AB  - The aim of this study was to assess the diagnostic value of technetium-99m
      tetrofosmin and technetium-99m-MIBI in a head-to-head comparison. Both
      radiopharmaceuticals are routinely used for detecting breast cancer. In a
      prospective, open, diagnostic trial, the two radiopharmaceuticals were
      administered randomly on different days to the same 101 women suffering from 103
      breast tumours. Planar images and single photon emission computer tomography
      (SPET) were performed. After histological examination of the tumours,
      sensitivity, specificity and positive and negative predictive value were
      compared. 99mTc-tetrofosmin and 99mTc-MIBI showed low sensitivity in planar
      images (44% vs 46%, respectively). SPET improved sensitivity (70% vs 69%,
      respectively). Specificity in planar images was 83% and 87%, and it was even
      lower using SPET (70% vs 78%, respectively). Positive predictive value in planar
      images was 76% vs 81%, and it was not changed by SPET. Negative predictive value
      was low in planar images (54% vs 57%, respectively), but it was improved by using
      SPET (65% vs 67%, respectively). In conclusion, 99mTc-tetrofosmin and 99mTc-MIBI
      scintigraphy show similar diagnostic value in assessing suspicious breast
      lesions.

PMID- 10638407
TI  - Evaluation of small-bowel transit for solid and liquid test meal in healthy men
      and women.
AB  - Evaluation of severe functional gastrointestinal motility disorders requires an
      investigation of the entire gastrointestinal tract. This should be possible with
      a single radionuclide imaging study. The purpose of this study was (1) to define
      normal values of small-bowel transit in men and women and (2) to assess a
      possible difference between gender or test meal, since it has been shown that
      women have slower gastric emptying than men, and gastric emptying of solids is
      slower than liquids. A standard gastric-emptying test for a solid (technetium-99m
      sulphur colloid, 230 Kcal) and liquid (indium-111 DTPA water) test meal was
      performed in 12 healthy male and 12 healthy female volunteers. After 135 min, the
      volunteer was placed in the supine position for static imaging of the abdomen
      every 15 min for 6 h. Decay and crossover-corrected geometric mean gastric
      emptying data were fit to a modified power exponential function to determine the
      10% stomach emptying time for solids and liquids separately. An ROI was drawn
      around the caecum and ascending colon to determine the arrival time of at least
      10% of the solid and liquid test meal. Ten percent small-bowel transit time (10%
      SBTT) and orocaecal transit time (OCTT) were calculated. The OCTT for males and
      females, respectively for solids and liquids, are 294.6 +/- 18.8; 301.3 +/- 24.5;
      294.6 +/- 18.8 and 301.3 +/- 24.5 min. The 10% SBTT for males and females,
      respectively for solids and liquids, are 280.3 +/- 18.4; 280.6 +/- 24.0; 288.2 +/
      18.9 and 297.4 +/- 24.4 (mean +/- SEM) min. We observed a simultaneous transfer
      of solids and liquids from the terminal ileum to caecum (correlation coefficient
      0.90). There is no statistically significant difference in SBTT between gender or
      solids and liquids. In contrast to the gastric-emptying time, the SBTT of solids
      and liquids were not significantly different nor was a gender difference found.
      Determination of the OCTT seems to be the simplest and most accurate approach to
      measure SBTT. Since ileocaecal transfer occurs as a bolus phenomenon, a 111In
      labelled test meal can also be used for the determination of colon transit in a
      single imaging study protocol.

PMID- 10638408
TI  - Limited sensitivity of iodine-123-2-hydroxy-3-iodo-6-methoxy-N-[(1-ethyl-2
      pyrrolidinyl)methyl ] benzamide whole-body scintigraphy in patients with
      malignant melanoma: a comparison with thallium-201 imaging.
AB  - The aim of this prospective study was to assess the diagnostic value of iodine
      123-2-hydroxy-3-iodo-6-methoxy-N-[(1-ethyl-2-pyrrolidinyl)methyl] benzamide
      (IBZM) whole-body imaging in comparison to thallium-201 scintigraphy in patients
      with metastatic malignant melanoma. Ten patients with suspected or proven
      locoregional metastases of malignant melanoma underwent whole-body scintigraphy
      both with 201Tl and 123I-IBZM prior to scheduled surgery. Whole-body scans and
      planar scintigrams were acquired at 5 min and 30 min after injection of 100 MBq
      201Tl and at 10 min, 2 h, 4 h and 24 h after injection of 185 MBq 123I-IBZM. Ten
      out of 12 melanoma metastases, both melanotic and amelanotic as proven
      histologically, were detected by 201Tl with a sensitivity of 83%. 123I-IBZM
      showed tracer uptake only in 3 melanotic metastases (sensitivity: 25%) with a
      maximum tumor-to-background ratio within 4 h, while none of the amelanotic
      metastases was IBZM-positive. All lesions localized by 123I-IBZM showed tracer
      uptake of 201Tl as well, while 201Tl-negative lesions were also negative with
      IBZM. Because of the poor results of IBZM, the study was terminated after an
      interim evaluation of 10 patients. 123I-IBZM is a tracer with only moderate
      sensitivity in melanotic melanoma lesions, suggesting that this method has no
      clinical value as a routine investigation in melanoma patients. In comparison,
      our previous results with 201Tl whole-body scintigraphy yielded a significantly
      higher sensitivity of about 80% in patients with locoregional melanoma metastases
      and may thus offer considerable potential in non-PET melanoma imaging.

PMID- 10638409
TI  - "Ecstasy"-induced changes of cerebral glucose metabolism and their correlation to
      acute psychopathology. An 18-FDG PET study.
AB  - The aim of this study was to determine the acute effects of the "Ecstasy"
      analogue MDE (3,4-methylene dioxyethamphetamine) on cerebral glucose metabolism
      (rMRGlu) of healthy volunteers and to correlate neurometabolism with acute
      psychopathology. In a randomized double-blind trial, 15 healthy volunteers
      without a history of drug abuse were examined with fluorine-18-deoxyglucose
      (18FDG) positron emission tomography (PET) 110-120 min after oral administration
      of 2 mg/kg MDE (n = 7) or placebo (n = 8). Two minutes prior to radiotracer
      injection, constant cognitive stimulation was started and maintained for 32 min
      using a word repetition paradigm to ensure constant and comparable mental
      conditions during cerebral glucose uptake. Individual brain anatomy was
      represented using Tl-weighted 3D flash magnetic resonance imaging (MRI), followed
      by manual regionalization into 108 regions of interest and PET/MRI overlay. After
      absolute quantification of rMRGlu and normalization to global metabolism,
      normalized rMRGlu under MDE was compared to placebo using the Mann-Whitney U
      test. Acute psychopathology was assessed using the Positive and Negative Syndrome
      Scale (PANSS) and rMRGlu was correlated to PANSS scores according to Spearman.
      MDE subjects showed significantly decreased rMRGlu in the bilateral frontal
      cortex: left frontal posterior (-7.1%, P < 0.05) and right prefrontal superior (
      4.6%, P < 0.05). On the other hand, rMRGlu was significantly increased in the
      bilateral cerebellum (right: +10.1%, P < 0.05; left: +7.6%, P < 0.05) and in the
      right putamen (+6.2%, P < 0.05). There were positive correlations between rMRGlu
      in the middle right cingulate and grandiosity (r = 0.87, P < 0.05), both the
      right amygdala (r = 0.90, P < 0.01) and the left posterior cingulate (r = 0.90, P
      < 0.01) to difficulties in abstract thinking, and the right frontal inferior (r =
      0.85, P < 0.05), right anterior cingulate (r = 0.93, P < 0.01), and left anterior
      cingulate (r = 0.85, P < 0.05) to attentional deficits. A negative correlation
      was found between the left frontal operculum (Broca's area) and attentional
      deficits (r = -0.85, P < 0.05). The present study revealed acute neurometabolic
      changes under the "Ecstasy" analogue MDE, indicating a frontostriatocerebellar
      imbalance paralleling other psychotropic substances or various psychiatric
      disorders.

PMID- 10638410
TI  - Absolute quantitation of iodine-123 epidepride kinetics using single-photon
      emission tomography: comparison with carbon-11 epidepride and positron emission
      tomography.
AB  - Epidepride labelled with iodine-123 is a suitable probe for the in vivo imaging
      of striatal and extrastriatal dopamine D2 receptors using single-photon emission
      tomography (SPET). Recently, this molecule has also been labelled with carbon-11.
      The goal of this work was to develop a method allowing the in vivo quantification
      of radioactivity uptake in baboon brain using SPET and to validate it using
      positron emission tomography (PET). SPET studies were performed in Papio anubis
      baboons using 123I-epidepride. Emission and transmission measurements were
      acquired on a dual-headed system with variable head angulation and low-energy
      ultra-high resolution (LEUHR) collimation. The imaging protocol consisted of one
      transmission measurement (24 min, heads at 90 degrees), obtained with two sliding
      line sources of gadolinium-153 prior to injection of 0.21-0.46 GBq of 123I
      epidepride, and 12 emission measurements starting 5 min post injection. For
      scatter correction (SC) we used a dual-window method adapted to 123I. Collimator
      blurring correction (CBC) was done by deconvolution in Fourier space and
      attenuation correction (AT) was applied on a preliminary (CBC) filtered back
      projection reconstruction using 12 iterations of a preconditioned, regularized
      minimal residual algorithm. For each reconstruction, a calibration factor was
      derived from a uniform cylinder filled with a 123I solution of a known
      radioactivity concentration. Calibration and baboon images were systematically
      built with the same reconstruction parameters. Uncorrected (UNC) and (AT), (SC +
      AT) and (SC + CBC + AT) corrected images were compared. PET acquisitions using
      0.11-0.44 GBq of 11C-epidepride were performed on the same baboons and used as a
      reference. The radioactive concentrations expressed in percent of the injected
      dose per 100 ml (% ID/100 ml) obtained after (SC + CBC + AT) in SPET are in good
      agreement with those obtained with PET and 11C-epidepride. A method for the in
      vivo absolute quantitation of 123I-epidepride uptake using SPET has been
      developed which can be directly applied to other 123I-labelled molecules used in
      the study of the dopamine system. Further work will consist in using PET to model
      the radioligand-receptor interactions and to derive a simplified model applicable
      in SPET.

PMID- 10638411
TI  - Cytogenetic damage after 131-iodine treatment for hyperthyroidism and thyroid
      cancer. A study using the micronucleus test.
AB  - To detect the incidence and persistence of potential chromosome damage induced by
      iodine-131 therapy, we applied the cytokinesis-block micronucleus assay to
      peripheral blood lymphocytes from hyperthyroidism and thyroid cancer patients
      treated with 131I. Two groups of patients were evaluated in a longitudinal study;
      one group was composed of 47 hyperthyroid patients and the other of 39 thyroid
      cancer patients. In the hyperthyroidism group, the micronuclei frequency was
      determined before 131I therapy and 1 week, 1 month and 3 months after it.
      Furthermore, an additional sample was taken from a subgroup of 17 hyperthyroidism
      patients 6 months after treatment. In the thyroid cancer group, the analysis was
      also conducted over time, and four samples were studied: before treatment and 1
      week, 6 months and 1 year later. Simultaneously, a cross-sectional study was
      performed with 70 control subjects and 54 thyroid cancer patients who had
      received the last therapeutic dose 1-6 years before the present study. In the
      hyperthyroidism group a significant increase in the micronuclei average was found
      over time. In the sample obtained 6 months after therapy, the micronuclei mean
      frequency was practically the same as in the sample taken 3 months before. In the
      thyroid cancer group a twofold increase in the frequency of micronuclei was seen
      1 week after therapy. Although this value decreased across time, the micronuclei
      frequency obtained 1 year after 131I therapy remained higher than the value found
      before it. Concerning the data from the cross-sectional study, a significant
      increase in the frequency of micronuclei was detected in the subgroup of thyroid
      cancer patients treated between 1 and 3 years before the current study. These
      results indicate that exposure to 131I therapy induces chromosome damage in
      peripheral lymphocytes and that the cytokinesis-block micronucleus assay is
      sensitive enough to detect the genetic damage by exposure to sufficiently high
      levels of radiation from internal radioactive sources.

PMID- 10638412
TI  - Evaluation of radioiodinated medium chain fatty acids as new diagnostic agents
      for the determination of hepatic viability.
AB  - Radiopharmaceuticals which reflect beta-oxidation in hepatocytes will provide
      useful information on the prognosis after surgery or on the efficacy of
      treatment, since beta-oxidation is the main pathway responsible for adenosine
      triphosphate in hepatocytes. We have previously developed [1-11C]octanoate as a
      diagnostic agent for determination of hepatic viability by means of positron
      emission tomography (PET). The goal of the present study was to develop a new
      radiopharmaceutical for single-photon emission tomography (SPET), which has the
      advantage of being more widely used than PET. To this end, two radioiodinated
      omega-(4-iodophenyl)-medium chain fatty acids, p-iodophenylvaleric acid (IPVA)
      and p-iodophenylenanthic acid (IPEA), were synthesized and evaluated as
      radiopharmaceuticals for determination of hepatic viability. Metabolite analyses
      in vitro and in vivo and a biodistribution study in normal mice indicated that
      both compounds were taken up by the liver actively and metabolized by beta
      oxidation. However, these studies also indicated that IPEA is more suitable as an
      imaging agent than IPVA. Based on these results, SPET imaging studies were
      performed in normal and hepatitis model rats using [123I]IPEA. The time-activity
      curves of the liver showed two-phase clearance of radioactivity in both normal
      and hepatitis model rats, but the clearance was delayed depending on the severity
      of hepatitis. Furthermore, the clearance rate of the first phase was correlated
      with the ATP level in hepatocytes, which was used as an index of the energy
      production capacity of hepatocytes. In conclusion, IPEA was metabolized
      predominantly by beta-oxidation, and the clearance of IPEA from the liver was
      closely associated with the ATP concentration in the liver. Thus, [123I]IPEA is a
      potentially useful new radiopharmaceutical for diagnosis of hepatic viability
      based on energy metabolism.

PMID- 10638413
TI  - Fluorine-18 fluorodeoxyglucose dual-head positron emission tomography in the
      detection of recurrent differentiated thyroid cancer: preliminary results.
AB  - In the follow-up of patients with thyroid cancer, it may be very difficult to
      identify the site of recurrence in the presence of persistently elevated or
      rising thyroglobulin (Tg) levels and negative iodine-131 whole-body scintigraphy
      (WBS). The aim of this study was to assess the feasibility of employing fluorine
      18 fluorodeoxyglucose and a dual-head positron emission tomography (PET) camera
      to detect recurrent thyroid cancer in patients with elevated Tg levels and
      negative 131I WBS. Eleven patients suspect of having recurrent thyroid cancer
      (five males, six females; mean age 47 years; range 26-73 years) were studied with
      both 131I WBS and FDG using a dual-head PET camera. The suspicion that these
      patients had recurrent thyroid cancer was based on elevated Tg levels. Thyroid
      stimulating hormone (TSH) and Tg levels as well as antibodies to Tg were measured
      3 weeks after the withdrawal of tri-iodothyronine. In patients in whom
      pathological uptake was seen on the PET images but who had no signs of recurrent
      thyroid cancer on WBS, ultrasonography and/or computed tomography or magnetic
      resonance imaging was performed followed by fine-needle aspiration cytology. The
      mean Tg and TSH levels after discontinuation of L-thyroxine were 156 ng/ml (range
      4-815 ng/ml) and 84 mU/l (range 43-159 mU/l), respectively. None of the patients
      had antibodies to thyroglobulin. In seven out of ten patients with negative 131I
      WBS, FDG PET showed focally increased uptake in the head and neck region. In one
      patient, the site of increased uptake on the PET images corresponded with the
      site of increased 131I uptake. Malignancies with a diameter less than 1 cm (n =
      3) were not depicted by either CT or US. It is concluded that detection of
      recurrent thyroid cancer by means of FDG dual-head PET is feasible in patients
      with elevated Tg concentrations and negative 131I WBS. The results justify a
      prolongation of the study.

PMID- 10638414
TI  - Quantitation in planar renal scintigraphy: which mu value should be used?
AB  - The attenuation coefficient value mu used by different authors for quantitation
      in planar renal scintigraphy varies greatly, from the theoretical value of 0.153
      cm-1 (appropriate for scatter-free data) down to 0.099 cm-1 (empirical value
      assumed to compensate for both scatter and attenuation). For a 6-cm-deep kidney,
      such variations introduce up to 30% differences in absolute measurement of kidney
      activity. Using technetium-99m phantom studies, we determined the mu values that
      would yield accurate kidney activity quantitation for different energy windows
      corresponding to different amounts of scatter, and when using different image
      analysis approaches similar to those used in renal quantitation. With the 20%
      energy window, it was found that the mu value was strongly dependent on the size
      of the region of interest (ROI) and on whether background subtraction was
      performed: the mu value thus varied from 0.119 cm-1 (loose ROI, no background
      subtraction) to 0.150 cm-1 (kidney ROI and background subtraction). When using
      data from an energy window that could be considered scatter-free, the mu value
      became almost independent of the image analysis scheme. It is concluded that: (1)
      when performing background subtraction, which implicitly reduces the effect of
      scatter, the mu value to be used for accurate quantitation is close to the
      theoretical mu value; (2) if the acquired data were initially corrected for
      scatter, the appropriate mu value would then be the theoretical mu value,
      whatever the image analysis scheme.

PMID- 10638415
TI  - Labelling of platelets with indium-111 oxine and technetium-99m
      hexamethylpropylene amine oxime: suggested methods. International Society of
      Radiolabelled Blood Elements (ISORBE).

PMID- 10638416
TI  - Cell irradiation caused by diagnostic nuclear medicine procedures: dose
      heterogeneity and biological consequences.
AB  - Most radionuclides used for diagnostic imaging emit Auger electrons (technetium
      99m, iodine-123, indium-111, gallium-67 and thallium-201). Their very short range
      in biological tissues may lead to dose heterogeneity at the cellular level with
      radiobiological consequences. This report describes the dosimetric models used to
      calculate the mean dose absorbed by the cell nucleus from Auger radionuclides.
      The techniques used to determine the biodistribution of radiopharmaceuticals at
      the subcellular level are also described and compared. Published examples of
      cellular dosimetry computations performed with radiotracers are reviewed in
      various clinical settings. Finally, the biological implications of the
      subcellular localization of Auger emitters are examined. While a number of
      efforts have been made to obtain dosimetric models and to estimate subcellular
      distribution of radioactivity, little is known of the cellular dosimetry of most
      radiopharmaceuticals used in diagnostic imaging. However, biological examples of
      selective radiotracer uptake have been shown, leading to extremely strong cell
      cell dose heterogeneity. Furthermore, radiobiological experiments show that the
      biological effects of Auger emitters incorporated into DNA can be severe, with
      relative biological effectiveness greater than 1 compared with external X-rays.
      These findings clearly show that the assessment of biological risks associated
      with internal administration of diagnostic radiopharmaceuticals must focus not
      only on target organs as a whole, but also on the cellular level. This review
      proposes the most appropriate model for dosimetric computations (cellular or
      conventional) according to the subcellular distribution of radiotracers. The
      radionuclide of choice and the general strategy used to design new diagnostic
      radiopharmaceuticals are also discussed.

PMID- 10638417
TI  - Estimation of differential renal function by means of 99mTc-MAG3: integral method
      or Rutland-Patlak plot?

PMID- 10638418
TI  - Value of attenuation correction for the predictive accuracy of thallium-201
      reinjection imaging.

PMID- 10638419
TI  - Investigation of physical phenomena affecting scintigraphic images.

PMID- 10638420
TI  - Contamination hazard due to iodine-131 therapy for thyrotoxicosis.

PMID- 10638421
TI  - Bone scintigraphy with 99mTc-MDP formulated by a novel, simple and rapid
      sonication method: clinical results.

PMID- 10638422
TI  - The neural substrate of the vestibulocollic reflex. What needs to be learned.
AB  - The purpose of this review is to assess the role of short-latency pathways in the
      vestibulocollic reflex (VCR). First the current knowledge about the disynaptic
      and trisynaptic pathways linking semicircular canal and otolith afferents with
      cat neck motoneurons is summarized. We then discuss whether these pathways are
      sufficient or necessary to produce the responses observed in neck muscles by
      natural vestibular stimulation and conclude that they are neither. Finally,
      alternate pathways are considered, most likely involving reticulospinal fibers,
      which are an important part of the neural substrate of the VCR.

PMID- 10638423
TI  - Intracortical origin of the short latency facilitation produced by pairs of
      threshold magnetic stimuli applied to human motor cortex.
AB  - Under certain conditions, EMG responses evoked by pairs of transcranial magnetic
      stimuli over the motor cortex are larger than the sum of the responses to each
      stimulus given alone. This occurs with interstimulus intervals of around 1.3, 2.5
      and 4.3 ms and could be due to interaction between the responses to each stimulus
      at either the cortex or spinal cord. We recorded the descending volleys set up by
      such pairs of stimuli from the cervical epidural space of five patients implanted
      with chronic stimulators for pain control. Interstimulus intervals of 1, 1.2, 1.4
      and 2 ms were used to investigate the first peak of facilitation. Enhanced EMG
      responses occurred after pairs of stimuli at 1, 1.2 and 1.4 ms, and these were
      accompanied by larger and more numerous descending volleys than expected from the
      sum of each stimulus alone. We conclude that facilitatory interaction between the
      stimuli can occur within the cerebral cortex. This may involve elements that
      produce repetitive I-wave activity in response to a single stimulus.

PMID- 10638424
TI  - Tests of two hypotheses to account for different-sized saccades during
      disjunctive gaze shifts.
AB  - Rapid shifts of the point of visual fixation between objects that lie in
      different directions and at different depths require disjunctive eye movements.
      We tested whether the saccadic component of such movements is equal for both eyes
      (Hering's law) or is unequal. We compared the saccadic pulses of abducting and
      adducting movements when horizontal gaze was shifted from a distant to a near
      target aligned on the visual axis of one eye (Muller paradigm) in ten normal
      subjects. We similarly compared horizontal saccades made between two distant
      targets lying in the same field of movement as during the Muller paradigm tests,
      and between targets lying symmetrically on either side of the midline, at near
      side of the midline, at near or far. We measured the ratio of the amplitude of
      the movements of each eye in corresponding directions due to the saccadic
      component, as well as corresponding ratios of peak velocity and peak
      acceleration. In response to a Muller test paradigm requiring about 17 degrees of
      vergence, the change in position of the unaligned eye was typically twice the
      size of the corresponding movement of the aligned eye. The ratio of peak
      velocities for the unaligned/aligned eyes was about 1.5, which was greater than
      for saccades made between distant targets. The ratio of peak acceleration for
      unaligned/aligned eyes was about 1.0 during shifts from near to far and about 1.3
      for shifts from far to near, these values being similar to corresponding ratios
      for saccades between distant targets. These measurements of peak acceleration
      indicate that the saccadic pulses sent to each eye during the Muller paradigm are
      more equal than would be deduced by comparing the changes in eye position. We
      retested five subjects to compare directly the peak acceleration of saccades made
      during the Muller paradigm with similar-sized "conjugate" saccades made between
      targets at optical infinity. Saccades made during the Muller paradigm were
      significant slower (P < 0.005) than similar-sized conjugate saccades; this
      indicated that the different-sized movements during Muller paradigm are not
      simply due differences in saccadic pulse size but are also influenced by the
      concurrent vergence movement. A model for saccade-vergence interactions, which
      incorporates equal saccadic pulses for each eye, and differing contributions from
      convergence and divergence, accounts for many of these findings.

PMID- 10638425
TI  - The role of the pedunculopontine region in basal-ganglia mechanisms of akinesia.
AB  - The akinesia of Parkinsonism is relieved by pallidotomy and subthalamic
      nucleotomy, but not by thalamotomy. Therefore, this disabling symptom probably
      depends upon connections other than the pallidalthalamocortical tracts, possibly
      efferents of the medial pallidum descending to the upper brainstem. We have
      previously demonstrated akinesia in the normal monkey following radiofrequency
      lesioning in the region of the pedunculopontine nucleus (PPN), one of the primary
      targets for descending pallidal outflow. Here, we confirm that selectively
      destroying neurones in the PPN area, whilst sparing fibres of passage, results in
      an akinetic state in normal macaques.

PMID- 10638426
TI  - Tactile impoverishment and sensorimotor restriction deteriorate the forepaw
      cutaneous map in the primary somatosensory cortex of adult rats.
AB  - We investigated the effects of sensory deprivation on the forepaw representation
      in the primary somatosensory cortex (SI) in the adult rat. Cortical maps were
      constructed from high-resolution multiunit recordings of the response of layer IV
      neurons to somatosensory stimuli. The main features of the forepaw representation
      were described in terms of areal extent and topography of the cortical map, and
      sensory submodality, size, and location of the receptive field (RF) of small
      clusters of the cortical neurons. After being weaned, two groups of Long-Evans
      rats were housed in a standard (SE) or impoverished (IE) environment for 65-115
      days. A third group of SE rats was subjected to severe sensorimotor restriction
      (SR) of one forepaw for 7 days or 14 days, by using a one-sleeved cast. A
      concomitant effect of unilateral forelimb immobilization was a forced use of the
      nonrestricted forelimb in postural balance. The maps of both forepaws were
      derived 24 h after the cast was removed and the animal was allowed normal limb
      use. In a fourth group, SE rats experienced a 7-day immobilization followed by
      symmetrical limb use for 7 days before we mapped the hemisphere contralateral to
      the casted limb. For the SE and IE rats, the total areal extent of the cutaneous
      forepaw representation was similar, but IE rats exhibited a significant expansion
      of cortical islets serving high-threshold, presumably noncutaneous inputs, which
      were included in the cutaneous maps. In addition, SI neurons of IE rats had
      greatly enlarged glabrous, but not hairy, skin RFs. For the SR rats, the areal
      extent of the cutaneous map of the casted forepaw decreased by about 50%, after
      both 7- and 14-day forelimb immobilization. Large cortical sectors presumed to be
      formerly activated by cutaneous inputs were driven by high-threshold inputs that
      disrupted the somatotopic representation of the forepaw skin surfaces. These
      "emergent" representational sectors were topographically organized. By contrast,
      the areal extent and topography of the non-casted forepaw representation did not
      differ from those of SE rats. The size of glabrous RFs on the casted forepaw was
      similar to that of SE rats. On the contrary, glabrous RFs on the noncasted
      forepaw of SR rats were larger than those on their casted forepaw. The size of
      hairy RFs was not altered by the forelimb restriction. Interestingly, alteration
      of the somatotopic features of the casted forepaw map persisted after 7 days of
      symmetric use of the forelimbs. The present study demonstrates that continuous
      sensory experience is needed for the organizational features of SI maps to be
      maintained.

PMID- 10638427
TI  - Negligible role of catecholaminergic receptors in the anteroventral third
      ventricular region in mediating vasopressin-releasing and cardiovascular actions
      of prostaglandin E2.
AB  - The aim of this study was to pursue the roles of the catecholamine receptors in
      the anteroventral third ventricular region (AV3V), a cerebral site engaged in
      various stress responses, in prostaglandin (PG) E2-evoked vasopressin (AVP)
      release and cardiovascular action. Experiments were conducted in conscious rats
      in which cerebral and vascular cannulae had been implanted chronically. Local
      infusion (0.5 microliter, 1 min) of dopamine (150 nmol), a D1-dopaminergic
      agonist SKF 38393 (17 nmol) and an alpha-adrenergic agonist phenylephrine (150
      nmol), as well as PGE2 (7 nmol), into the AV3V enhanced plasma AVP 5 min later,
      without affecting plasma osmolality and electrolytes. In contrast to the
      increases in both arterial pressure and heart rate observed when PGE2 was
      applied, dopamine and SKF 38393 did not affect these variables, and phenylephrine
      elevated only arterial pressure. The AV3V infusion of a beta-agonist
      isoproterenol (100 nmol) did not change plasma AVP, although it decreased
      arterial pressure and increased heart rate. The increase in plasma AVP by
      dopamine was not blocked by the preinfusion of the D2-antagonist sulpiride (13
      nmol) into the AV3V 10 min before, but was abolished by that of the D1-antagonist
      SCH-23390 (8 nmol). The effects of phenylephrine on both plasma AVP and the blood
      pressure were prevented by the preadministration of the alpha-antagonist
      phenoxybenzamine (13 nmol). However, the pretreatments with phenoxybenzamine,
      sulpiride or SCH 23390 did not inhibit the responses of AVP, arterial pressure
      and heart rate caused by PGE2. These antagonists were without significant effect
      on AVP and other variables when given alone. The infusion sites of PGE2 and the
      other drugs identified histologically included the AV3V structures such as the
      organum vasculosum laminae terminalis or its vicinity, median preoptic nucleus,
      medial preoptic nucleus and periventricular hypothalamic nucleus. Dopamine or
      phenylephrine administered into the cerebral ventricle at the same dose as used
      in the AV3V application did not exert a significant effect on plasma AVP,
      arterial pressure and heart rate. These results suggest that catecholamine
      receptors in the AV3V may not be involved in the AVP-secreting, tachycardiac and
      pressor responses evoked by topical action of PGE2 on this area, despite their
      ability to influence hormone release and cardiovascular function.

PMID- 10638428
TI  - Nitric oxide and the cerebral-blood-flow response to somatosensory activation
      following deafferentation.
AB  - The single-vibrissa stimulation model in the rat was utilized to study the
      microvascular coupling between functional activation and local cerebral blood
      flow (LCBF) in both normal cortex and in cortex that had been peripherally
      deafferented. In addition, the role of chronic nitric oxide synthase (NOS)
      inhibition on the LCBF response to vibrissa stimulation was examined. One-day-old
      rats underwent deafferentation of all vibrissae on one side of the face, sparing
      C3, and received daily administration of either saline or N omega-nitro-L
      arginine (L-NA). After seven weeks of treatment, LCBF was measured
      autoradiographically in conscious rats with [14C]N-isopropyl-p-iodoamphetamine
      while C3 was stimulated bilaterally. Stimulation produced a greater increase in
      LCBF in the deafferented cortex of both the saline (30.4%) and L-NA treated
      (25.7%) animals than in the intact cortex (19.9% and 16%, respectively). The area
      of activation of LCBF (0.176 mm2) was comparable to the area metabolically
      activated (0.149 mm2), and the increase in area of LCBF activation following
      deafferentation (169%) was smaller than the increase in area that was
      metabolically activated (287%). Chronic inhibition of NOS did not alter the
      spatial extent of the blood-flow response.

PMID- 10638429
TI  - Anticipatory postural adjustments are associated with single vertical jump and
      their timing is predictive of jump amplitude.
AB  - This study was carried out to determine the existence and the specificity of
      anticipatory postural adjustments (APA) associated with vertical jump. Single
      vertical jump is an upward-oriented movement with identical initial and final
      postures. A consistent backward shift of the center of pressure (CP) clearly
      demonstrated the existence of APA. This shift mainly resulted from a soleus (SO)
      deactivation and tibialis anterior (TA) activation. As in gait initiation, the
      main role of APA associated with vertical jump is to create the necessary
      disequilibrium to initiate the movement. A comparison of CP and CG (center of
      gravity) forward shifts between single jump and tip-toe rising allowed us to
      propose that forward disequilibrium ends when a critical CP position is reached.
      As in gait initiation, the duration of jump's APA was several hundreds of
      milliseconds. This showed that when the role of the APA is to create the initial
      disequilibrium, their duration is greater than when their role is to compensate
      for the forthcoming postural disturbance due to the movement. Since the goal of
      the voluntary movement was to jump at a given height, one expected that this
      parameter could be programmed. APA's timing depended on the amplitude of the
      vertical jump: the time of onset of SO deactivation and TA activation and that of
      backward CP shift were dependent on the peak amplitude of the jump. Nevertheless,
      there was no relationship between the backward CP shift amplitude and the
      vertical impulse. Thus, it appears that the amplitude of the jump is not fully
      programmed but must be adjusted after the onset of the movement, i.e., there is a
      sequential programming of forward and upward movement. It is also of interest to
      stress that the SO-TA synergy, which is shown here to be at the basis of the APA
      associated with single vertical jump, has been also found in many forward
      oriented movements. Thus, the present data reinforce the idea that SO-TA synergy
      is part of a functional synergy used by the central nervous system to simplify
      the postural motor command.

PMID- 10638430
TI  - The contribution of fast corticospinal input to the voluntary activation of
      proximal muscles in normal subjects and in stroke patients.
AB  - Although it is well known that the corticospinal system exerts more influence
      over distal (hand and fingers) than proximal (elbow and shoulder) upper limb
      muscles, differences in the importance of this system for voluntary activation of
      these muscle groups have not been demonstrated directly. Two investigations were
      carried out to provide a quantitative comparison of the contribution of fast
      corticospinal inputs to voluntary activity in proximal and distal muscles of
      normal subjects. The first study confirmed that the rate of increase in the
      amplitude of EMG responses to transcranial magnetic stimulation (TMS) with
      voluntary activation of the muscles was significantly greater in a hand muscle
      (first dorsal interosseous, 1DI) than in biceps, which was in turn greater than
      that for deltoid. The second study demonstrated that this result reflected a
      genuine difference in corticospinal influence over these muscles and was not due
      to differences in the pattern and type of motor unit recruitment in proximal vs
      distal muscles. The voluntary activation of a pair of low-threshold single motor
      units (SMUs) in 1DI and deltoid was compared with their response to TMS. In both
      muscles only a small amount of additional effort was required to recruit the
      second SMU; increments were typically within 1% of maximum voluntary contraction,
      as assessed from EMG measurements. Subjects were asked to voluntarily discharge
      the lower threshold SMU at a steady rate, and then the threshold of responses of
      this SMU and that of the second unit to TMS were determined. In 1DI, only small
      increments in TMS intensity above the threshold for the first SMU were required
      to activate the second unit [mean 1.4% maximum stimulator output (MSO), SD +/-
      1.0%, n = 7 subjects]. In contrast, in deltoid a significantly greater intensity
      increase was needed (mean 6%, SD +/- 1.2%, MSO n = 7, P < 0.001). Similar results
      were obtained when TMS thresholds of motor unit pairs were assessed in relaxed
      subjects. These experiments support the hypothesis that the fast corticospinal
      input that can be activated by TMS is of greater importance for the voluntary
      activation of hand than of shoulder muscles. This hypothesis served as a basis
      for testing deltoid responses in three stroke patients. In two patients smaller
      responses to TMS were obtained on the affected side than on the unaffected side
      during the production of equivalent voluntary contractions, suggesting that the
      patients achieved these contractions using inputs other than the fast
      corticospinal elements excited by TMS.

PMID- 10638431
TI  - Strategies of segmental stabilization during gait in Parkinson's disease.
AB  - This study compared the postural strategies adopted by patients with Parkinson's
      disease (PD; n = 16) during locomotion to those of elderly controls (n = 16). We
      focused mainly on the head and trunk stabilization modes in sagittal and frontal
      planes. Subjects were asked to walk at their natural speed on an uniformly gray,
      flat ground. Gait data were recorded before and 1 h after L-dopa intake and were
      analyzed by an automatic motion analyser (Elite system). The modes of segmental
      stabilization adopted by each group were determined by means of the anchoring
      index, associated with cross-correlation functions between angular movements of
      pairs of segments. The major findings were: (a) PD patients generally had shorter
      step length, greater step width, and slower gait velocity than the healthy
      elderly. (b) No difference in angular dispersion of any anatomical segment
      studied was observed between the two groups. (c) PD patients had adopted a
      strategy of head stabilization on the shoulder ("en bloc" functioning of the head
      shoulder unit) about the roll axis only. (d) PD patients displayed head and
      shoulder angular movements around the roll axis that were more correlated than
      those of controls, confirming their more en bloc functioning. (e) Shoulder and
      hip were equally stabilized in space in the two groups around the roll axis. (f)
      There was no difference between the two groups about the pitch axis where an en
      bloc functioning of the whole trunk was shown. These results are discussed with
      respect to the similarities observed between the visuo-locomotor PD performances
      and those of children.

PMID- 10638432
TI  - Bilateral cortical control of the human anterior digastric muscles.
AB  - Transcranial magnetic stimulation (TCMS) was used to determine the organization
      of cortical motor projections to the anterior digastric muscles in 12 normal
      human subjects. Two distinct types of potentials were evoked in anterior
      digastric with a figure-of-eight coil. A short-latency (3 ms) response appeared
      bilaterally on the surface electromyogram (EMG), but only ipsilaterally on
      intramuscular recordings: this was the result of direct stimulation of the
      ipsilateral trigeminal motor root. Motor evoked potentials (MEPs) were elicited
      in the anterior digastric muscles at variable onset latencies of around 10 ms by
      stimulation of scalp areas antero-lateral to the area for the first dorsal
      interosseous muscle of the hand. These were evoked bilaterally in relaxed
      anterior digastric muscles in six of the seven subjects. In the other subject,
      the responses in the relaxed muscle were exclusively ipsilateral. However, when
      the anterior digastric muscles were contracted, the responses were bilateral in
      all subjects. TCMS and spike-triggered averaging revealed that the bilateral
      responses were not due to the branching of axons from individual digastric
      motoneurones to muscles on each side. Because the digastric motor nucleus may
      contain separate populations of ipsi- and contralateral projecting motoneurones,
      it was necessary to study single motor-unit responses to TCMS to demonstrate a
      bilateral corticobulbar projection. The responses of 17 single motor units in the
      anterior digastric muscle to TCMS were recorded. All were activated by
      contralateral stimulation. Approximately 80% were also activated by ipsilateral
      TCMS, although one well-characterised motor unit was inhibited by ipsilateral
      TCMS. When bilateral activation was present, the ipsilateral responses were more
      secure than the contralateral responses, which may indicate an additional
      interneurone in the pathway to the contralateral motoneurone. The major
      conclusions from this study are that (1) the cortical representation of the
      anterior digastric muscle is antero-lateral to hand muscles; (2) the cortical
      projection to the anterior digastric muscles is bilateral; (3) the corticobulbar
      projection is stronger contralaterally than ipsilaterally but may involve at
      least one additional synapse; and (4) anterior digastric motoneurones do not
      branch to innervate the muscles bilaterally.

PMID- 10638433
TI  - Relation between torque history, firing frequency, decruitment levels and force
      balance in two flexors of the elbow.
AB  - By means of intramuscular electromyographic recordings, we studied the firing
      frequencies and recruitment/decruitment thresholds of individual motor units in
      two elbow flexors, the biarticular biceps brachii muscle and the monoarticular
      brachioradialis muscle. Subjects had to perform isometric contractions with
      increasing elbow flexion torque until a specific peak torque level was reached.
      The torque level was kept constant for 6 s during which firing frequencies were
      measured. Then the torque was decreased to a lower level and, after 3 s, firing
      frequencies were again measured for 6 s. By repeating this procedure, the torque
      level was decreased stepwise until the motor unit under study stopped firing. The
      last level before the unit stopped firing was considered to be the decruitment
      torque level. We measured the firing frequency at recruitment and decruitment,
      the torque-frequency relationship and the recruitment and decruitment torque
      thresholds after various levels of peak torque. In the biceps, both the firing
      frequencies at a specific torque level and the decruitment torque level itself
      were independent of the peak torque. In the brachioradialis, however, firing
      frequencies at a specific torque level decreased and decruitment torque levels
      increased after subjects generated higher peak torques. Thus, in this muscle
      firing frequencies as well as decruitment thresholds show hysteresis effects. The
      result indicates a shift of force from the brachioradialis muscle during
      recruitment to the biceps muscle during decruitment. This shift is smaller than
      was concluded from previous studies in which decruitment threshold levels for the
      brachioradialis muscle were assumed to be independent of force history. Moreover,
      we found that in both muscles decruitment firing frequencies were lower than
      recruitment frequencies and they were independent of the peak torque level. In
      order to analyse the effect of the peak torque level on the distribution of force
      over the two muscles, we performed a model study in which we simulated the
      activation-frequency relation of two elbow flexors: a biceps-like and
      brachioradialis-like muscle, each contributing equally to the elbow torque during
      recruitment. In addition, we analysed how the different behaviour of the biceps
      and the brachioradialis during decruitment alters their contribution to the total
      torque production and how this redistribution is caused. The model study shows
      that the shift in contribution to the total torque is not constant during the
      relaxation phase and is not caused by a simple mechanism like a shift of
      activation from one muscle to another. Furthermore, changes limited to the muscle
      in which hysteresis is present do not seem to be sufficient to explain the
      experimental results.

PMID- 10638434
TI  - The parafascicular nucleus and two-way active avoidance: effects of electrical
      stimulation and electrode implantation.
AB  - To evaluate whether electrical stimulation of the parafascicular nucleus (PF) can
      improve short-term (24 h) and/or long-term (21 days) retention of two-way active
      avoidance, rats were implanted with an electrode at this nucleus (experimental
      groups) or above it (control groups). After a single 30-trial acquisition
      session, experimental groups were submitted to a 10-min session of electrical
      stimulation. Results showed that the simple implantation of an electrode at the
      posterior PF enhanced by itself the acquisition of two-way active avoidance, in
      such a way that the subsequent stimulation of this region may have been unable to
      further improve the performance of the rats. On the other hand, parafascicular
      stimulation improved the 24-h retention of the task in a site-specific way, since
      this effect was mainly seen after stimulation of the central PF region. The
      facilitative effect on 24-h retention could also depend on the level of
      performance achieved during the acquisition session, because this improvement was
      only evidenced in poorly learning animals. No effects were found on 21-day
      retention. The present results confirm the involvement of the PF in learning and
      memory and the functional heterogeneity of this nucleus.

PMID- 10638435
TI  - Visual search of heading direction.
AB  - When we move along we frequently look around. How quickly and accurately can we
      gaze in the direction of heading? We studied the temporal aspects of heading
      perception in expanding and contracting patterns simulating self-motion. Center
      of flow (CF) eccentricity was 15 degrees. Subjects had to indicate the CF by
      making a saccade to it. A temporal constraint on the response time was
      introduced, because stimuli were presented briefly (1 s). On average, subjects
      needed two saccades to find the CF. Initial saccades covered about 50-60% of the
      distance between the fixation point and the CF. Subjects underestimated the
      eccentricity of the CF. The systematic radial error ranged from -2.4 degrees to 
      4.9 degrees. The systematic tangential error was small (about 0.5 degree). The
      variable radial error ranged from 2.7 degrees to 4.6 degrees. We found a relation
      between saccade onset time and saccade endpoint error. Saccade endpoint error
      decreased with increasing saccade onset time, suggesting that saccades were often
      fired before the heading processing had been completed. From the saccade onset
      times, saccade endpoint errors and an estimate for the saccadic dead time
      (interval prior to the saccade during which modification is impossible 70 ms), we
      estimated the heading processing time (HPT 0.43 s). In three out of four
      subjects, HPT was longer for trials simulating backward movement than for trials
      simulating forward movement. For each saccade we determined whether it reduced
      the distance error. The second saccade reduced the error more effectively per
      time unit than the initial saccade. On the basis of this finding, we suggest that
      visual processing that occurs during the saccadic dead time of the first saccade
      is used in the preparation of the second saccade.

PMID- 10638436
TI  - Online steering: coordination and control of body center of mass, head and body
      reorientation.
AB  - Steering is an integral component of adaptive locomotor behavior. Along with
      reorientation of gaze and body in the direction of intended travel, body center
      of mass must be controlled in the mediolateral plane. In this study we examine
      how these subtasks are sequenced when steering is planned early or initiated
      under time constraints. Whole body kinematics were monitored as individuals were
      required to change their direction of travel by varying amounts when visually
      cued either at the beginning of the walk or one stride before. The analyses
      focused on the transition stride from one travel direction to another. Timing of
      changes (with respect to first right foot contact) in trunk roll angle, head and
      trunk yaw angle, and right foot displacement in the mediolateral plane were
      analyzed. The magnitude of these measures along with right and left foot
      placement at the beginning and right foot placement at the end of the transition
      stride were also analyzed. The results show the CNS uses two mechanisms, foot
      placement and trunk roll motion (piking action about the hip joint in the frontal
      plane), to move the center of mass towards the new direction of travel in the
      transition stride, preferring to use the first option when planning can be done
      early. Control of body center of mass precedes all other changes and is followed
      by initiation of head reorientation. Only then is the rest of the body
      reorientation initiated.

PMID- 10638437
TI  - Human orientation and movement control in weightless and artificial gravity
      environments.
AB  - Our goal is to summarize what has been learned from studies of human movement and
      orientation control in weightless conditions. An understanding of the physics of
      weightlessness is essential to appreciate the dramatic consequences of the
      absence of continuous contact forces on orientation and posture. Eye, head, arm,
      leg, and whole body movements are discussed, but only experiments whose results
      seem relatively incontrovertible are included. Emphasis is placed on
      distinguishing between virtually immediate adaptive compensations to
      weightlessness and those with longer time courses. The limitations and
      difficulties of performing experiments in weightless conditions are highlighted.
      We stress that when astronauts and cosmonauts return from extended space flight
      they do so with both physical "plant" and neural "controller" structurally and
      functionally altered. Recent developments in adapting humans to artificial
      gravity conditions are discussed as a way of maintaining sensory-motor and
      structural integrity in extended missions involving transitions between different
      force environments.

PMID- 10638438
TI  - Activity of respiratory laryngeal motoneurons during fictive coughing and
      swallowing.
AB  - Membrane potential changes and discharges from 28 laryngeal motoneurons were
      recorded intracellularly in the caudal nucleus ambiguus of decerebrate, paralyzed
      and ventilated cats. Electrical activities were recorded from 17 expiratory
      laryngeal motoneurons (ELMs) with maximal depolarizing membrane potential in
      early expiration, and from 11 inspiratory laryngeal motoneurons (ILMs) with
      maximal depolarizing membrane potential in inspiration. Activities during
      breathing were compared with those observed during fictive coughing and
      swallowing evoked by electrical stimulation of the superior laryngeal nerves.
      These non-respiratory behaviors were evidenced in paralyzed animals by
      characteristic discharge patterns of the phrenic, abdominal nerves and pharyngeal
      branch of the vagus nerve. We recorded the activity of 11 ELMs and 5 ILMs during
      coughing in which ELMs, but not ILMs, exhibited increased membrane depolarization
      and discharge frequencies. Membrane depolarization and discharge frequencies of
      all ELMs were also significantly increased during swallowing. In addition,
      membrane depolarization of most ELMs (15/17) was preceded by a short-lasting
      hyperpolarization due to chloride-dependent inhibitory mechanisms occurring at
      the onset of swallowing. Out of 10 ILMs tested during swallowing, 7 exhibited
      membrane depolarization, preceded in 5 cases by a short-lasting
      hyperpolarization. Discharge frequencies of ILMs were significantly reduced
      during swallowing. The same pattern of phasic activities of ILMs and ELMs was
      observed during coughing and breathing, suggesting the involvement of similar
      excitatory pathways in both behaviors. These results imply that the duration of
      activation and the discharge frequency of neurons of the central generator for
      breathing that drive laryngeal motoneurons are enhanced during coughing. During
      swallowing, in addition to central excitatory mechanisms, laryngeal motoneurons
      are subjected to an initial inhibition of unknown origin. This inhibition
      probably contributes to the temporal organization of the swallowing motor
      sequence.

PMID- 10638439
TI  - Distance estimation in the visual and visuomotor systems.
AB  - Previous work has demonstrated that monocular vision affects the kinematics of
      skilled visually guided reaching movements in humans. In these experiments, prior
      to movement onset, subjects appeared to be underestimating the distance of
      objects (and as a consequence, their size) under monocular viewing relative to
      their reaches made under binocular control. The present series of experiments was
      conducted to assess whether this underestimation was a consequence of a purely
      visual distance underestimation under monocular viewing or whether it was due to
      some implicit inaccuracy in calibrating the reach by a visuomotor system normally
      under binocular control. In a purely perceptual task, a group of subjects made
      similar explicit distance estimations of the objects used in the prehension task
      under monocular and binocular viewing conditions, with no time constraints. A
      second group of subjects made these explicit distance estimations with only 500
      ms views of the objects. No differences were found between monocular and
      binocular viewing in either of these explicit distance-estimation tasks. The
      limited-views subjects also performed a visually guided reaching task under
      monocular and binocular conditions and showed the previously demonstrated
      monocular underestimation (in that their monocular grasping movements showed
      lower peak velocities and smaller grip apertures). A distance underestimation of
      4.1 cm in the monocular condition was computed by taking the y intercepts of the
      monocular and binocular peak velocity functions and dividing them by a common
      slope that minimised the sum of squares error. This distance underestimation was
      then used to predict the corresponding underestimation of size that should have
      been observed in the monocular reaches--a value closely approximating the
      observed value of 0.61 cm. Taken together, these results suggest that the
      monocular underestimation in the prehension task is not a consequence of a purely
      perceptual bias but rather it is visuomotor in nature--a monocular input to a
      system that normally calibrates motor output on the basis of binocular vision.

PMID- 10638440
TI  - Cutaneomotor integration in humans is somatotopically organized at various levels
      of the nervous system and is task dependent.
AB  - Integration of tactile afferent signals with motor commands is crucial for the
      performance of purposeful movements such as during manipulation of an object in
      the hand. To study the somatotopic organization of sensorimotor integration we
      applied electrical peripheral conditioning stimuli to a digit located near
      (homotopic stimulation) or distant from (heterotopic stimulation) relaxed or
      isometrically contracted intrinsic hand muscles at variable time intervals prior
      to transcranial magnetic stimulation (TMS). Cutaneous stimulation has previously
      been shown to modulate the amplitude of the motor evoked potential (MEP) and to
      shorten the duration of the silent period (SP) evoked by TMS. In relaxed target
      muscles the time-dependent modulation of TMS-evoked motor responses by homotopic
      conditioning stimulation differed from modulation by heterotopic stimulation.
      Similar differences in the modulation pattern evoked by homotopic and heterotopic
      conditioning stimulation were observed for two distinct target muscles of the
      hand (abductor digiti minimi, abductor pollicis brevis muscle). Differences in
      modulation were maximal when the conditioning stimulation was applied 25-30 ms
      and 150-200 ms prior to TMS. Comparison of the modulation of the amplitudes of
      MEPs evoked by transcranial electrical stimulation (TES) and the modulation of
      those evoked by TMS suggests that differences between homotopic and heterotopic
      stimulation originate subcortically at 25- to 30-ms and, at least partially,
      cortically at 150- to 200-ms interstimulus intervals. In isometrically contracted
      intrinsic hand muscles the degree to which the SP was shortened reflected the
      location and the timing of the conditioning stimulus. Shortening was maximal when
      the conditioning stimulus was applied nearest to the contracted target muscle and
      20 ms prior to the test stimulus. In contrast to the SP duration, the MEP size in
      voluntarily contracted target muscles was unaffected by the location of the
      conditioning stimulus. The somatotopic gradient of SP shortening was abolished
      when the two target muscles were simultaneously activated isometrically.
      Together, our findings suggest that somatotopy of input-output relationships is
      implemented at both a spinal and a cortical level in the human central nervous
      system and may also depend on the motor task involved.

PMID- 10638441
TI  - Neuroprotective effects of the novel brain-penetrating antioxidant U-101033E and
      the spin-trapping agent alpha-phenyl-N-tert-butyl nitrone (PBN).
AB  - Literature on the therapeutic efficacy of free radical scavengers suggests that
      drugs that are able to cross the blood-brain barrier are more effective in
      protecting the brain from ischemic damage. However, the exact mechanisms by which
      brain-penetrating antioxidants act have yet not been delineated. We compared the
      neuroprotective potential of the newly discovered pyrrolopyrimidine U-101033E
      with that of alpha-phenyl-N-tert-butyl nitrone (PBN) and investigated their
      influence on cerebral blood flow. Thirty male Sprague-Dawley rats were subjected
      to 90 min of middle cerebral artery (MCA) occlusion by an intraluminal filament.
      Local cerebral blood flow (LCBF) was bilaterally recorded by laser Doppler
      flowmetry. Neurological deficits were quantified daily. Infarct volume was
      assessed after 7 days. MCA occlusion reduced ipsilateral LCBF to 20-30% of
      baseline. After reperfusion, postischemic hyperemia was followed by a decrease in
      LCBF to about 70% of baseline. There was no difference in LCBF among groups. U
      101033E improved neurological function and reduced infarct volume by 52% (P <
      0.05). Improvement of neurological function and reduction of infarct volume (
      25%) in animals treated with PBN was not significant. We conclude that U-101033E
      has superior neuroprotective properties compared with PBN. Neither drug improves
      blood flow during ischemia and 1 h of reperfusion. The mechanisms by which these
      brain-penetrating antioxidants act remain to be clarified.

PMID- 10638442
TI  - Interactions between first- and second-order motion revealed by optokinetic
      nystagmus.
AB  - A previous study has suggested that second-order motion is ineffective at driving
      optokinetic nystagmus (OKN) when presented alone. First- and second-order motion
      cues interact in creating the perception of motion. Is there an interaction
      between first- and second-order cues in the control of eye movements? We
      presented combinations of first- and second-order cues moving in the same or
      opposite directions and measured the eye movements evoked, to look for a
      modification of the oculomotor response to first-order motion by simultaneously
      presented second-order cues. Dynamic random noise was used as a carrier for first
      and second-order drifting gratings (13.4 degrees/s; 0.25 cycles/degree; 64 x 48
      degrees screen viewed at 28.5 cm). Second-order gratings were defined by spatial
      modulation of the luminance flicker frequency of noise pixels of constant
      contrast (50%). A first-order, luminance-defined grating (13.4 degrees/s; 0.25
      cycles/degree; variable contrast from 4-50%) was moved in either the same or the
      opposite direction. Eye movements were recorded by video-oculography from six
      subjects as they looked straight ahead. The gain (eye velocity/stimulus velocity)
      of first-order-evoked OKN increased with contrast. The presence of flicker
      defined second-order motion in the opposite direction attenuated this OKN below a
      first-order contrast of 15%, although it had little effect at higher contrasts.
      When first- and second-order motion were in the same direction, there was an
      enhancement of the OKN response. We conclude that second-order motion can modify
      the optokinetic response to simultaneously presented first-order motion.

PMID- 10638443
TI  - Density of perfused brain capillaries in the aged rat during the wake-sleep
      cycle.
AB  - Structural and functional age-related changes in brain vasculature might affect
      the cerebral microcirculation. The present study evaluated the density of
      perfused brain capillaries and the perfusion fraction (perfused/existing
      capillaries) in aged rats (24 months) during the states of the wake-sleep cycle
      (quiet wakefulness, quiet sleep, active sleep) characterized by different levels
      of brain activation. The number of perfused capillaries was determined by
      intravascular injection of the fluorescent marker Evans Blue; histochemical
      staining of the capillary endothelium identified the alkaline-phosphatase (AP)
      reactive quota of the anatomical population. No sleep-related changes in perfused
      capillary density were found, and the perfusion fraction in the AP-stained sub
      population was high and stable (95%) across the sleep-wake cycle: changing levels
      of brain activation during sleep do not affect functional capillary density in
      aged rats.

PMID- 10638444
TI  - Medullary reticular formation activity during ingestion and rejection in the
      awake rat.
AB  - The consummatory components of ingestion and rejection, organized in the caudal
      brainstem, include licking, swallowing, and the oral phase of rejection (gaping).
      Studies employing electrical-stimulation induced motor activity have localized
      interneurons controlling these complex motor patterns to the medullary reticular
      formation (RF), but the characteristics of these neurons during more naturally
      induced behavior are unknown. The purpose of the present study was to record the
      activity profiles of RF neurons during licking, swallowing, and oral rejection in
      response to gustatory stimulation. Two-hundred and two neurons recorded from
      awake, freely moving rats were broadly classified as orally related (67%) or non
      orally related (33%). Orally related neurons included a large number that were
      rhythmically active during licking (n = 76; 38%). These "lick-rhythmic" neurons
      were widely distributed in the RF, but were concentrated in the caudal medullary
      reticular formation adjacent to the hypoglossal nucleus (Probst's region) and
      further rostral in the intermediate zone (IRt) of the RF. An analysis of
      autocorrelations determined that lick-rhythmic neurons in these regions were more
      closely coupled to licking than to lick-rhythmic neurons more lateral in the
      parvocellular RF (PCRt). In addition to neurons with weak lick-rhythmic activity,
      the PCRt also contained a disproportionate number of neurons with orosensory or
      mixed oro-sensorimotor properties. These data provide evidence for functional
      specialization within different regions of the medullary RF. A high proportion of
      lick-rhythmic neurons also showed differential activity associated with
      swallowing (41%) and/or gaping (75%), further suggesting that the different
      components of ingestion and rejection share brainstem substrates instead of being
      produced by unique subsets of interneurons.

PMID- 10638446
TI  - Constitutive NF-kappa B activity is modulated via neuron-astroglia interaction.
AB  - NF-kappa B is found in many neuronal cell types in different states of activity.
      This study aimed to define which conditions induce constitutive NF-kappa B
      activity in cultured hippocampal neurons using activity-specific antibody
      staining. In co-culture with astroglia, hippocampal neurons were devoid of
      activated NF-kappa B. In these co-cultures, NF-kappa B could not be activated via
      kainate or glutamate. In contrast, separating neurons from the glial compartment
      resulted in a time-dependent increase of activated neuronal NF-kappa B. In this
      line, activation of NF-kappa B by kainate or glutamate is very effective in
      freshly separated cultures, but inhibited when the cultures are reassembled after
      stimulation. These findings suggests that a neuronal-glial interaction may
      regulate gene expression via NF-kappa B.

PMID- 10638445
TI  - Changes in nerve growth factor levels in dorsal root ganglia and spinal nerves in
      a rat neuropathic pain model.
AB  - The purpose of this study was to measure the changes in levels of nerve growth
      factor (NGF) in dorsal root ganglia (DRG) and spinal nerves with the aim of
      investigating the role of NGF in a rat neuropathic pain model. Nerve injuries
      were made by tight ligation of the left L5 and L6 spinal nerves using 6-0 silk
      thread in male Sprague-Dawley rats. Before surgery and 1, 3, 5, 7, and 14 days
      after surgery, tissue samples collected included the L3-6 DRGs bilaterally,
      segments of the ipsilateral L5-6 spinal nerves proximal and distal to ligation
      sites, and corresponding sites of the contralateral L3-6 and the ipsilateral L3-4
      spinal nerves. NGF levels in the DRGs of the injured spinal nerves (the left L5
      and L6) did not change significantly from control values. The spinal nerve
      segments distal to ligation sites had higher levels of NGF than the control
      values. Unlesioned sites did not show any significant changes in NGF levels. The
      increase of NGF in distal segments of injured spinal nerves may be due to an
      accumulation of retrogradely transported NGF. The maintenance of NGF levels in
      the DRGs that had lost peripheral connections may reflect local synthesis after
      nerve injury.

PMID- 10638447
TI  - A complementary relationship between wake and REM sleep in the auditory system: a
      pre-sleep increase of middle-ear muscle activity (MEMA) causes a decrease of MEMA
      during sleep.
AB  - Since some evidence has supported a complementary relationship between waking and
      REM-sleep eye movement (variations in frequency, amplitude, or direction of
      waking saccades have been found to inversely affect the corresponding parameters
      of rapid eye movements), the present study assessed whether this relationship can
      also be shown for other phasic components of REM sleep, such as middle-ear muscle
      activity (MEMA), as a consequence of an increase of middle-ear reflex frequency
      during pre-sleep wake. Ten subjects were studied in three consecutive nights (one
      adaptation, one baseline, one experimental). In the experimental night, subjects
      underwent a 2-h pure-tone (1000 Hz, 90 dB SPL) auditory stimulation and MEMA was
      monitored every 15 min; noise exposure during daytime was also controlled.
      Results show that MEMA frequency during REM sleep significantly decreased during
      the experimental nights compared with baseline nights, while each sleep variable
      as well as mean daily auditory input did not present any significant difference
      between baseline and experimental nights. Results suggest that the complementary
      relationship between wake and REM sleep is not bounded to oculomotor activity,
      but it may also be extended at least to middle-ear muscle phasic activity.

PMID- 10638448
TI  - The International Society of Gynecological Pathologists. Its founding and early
      years.
AB  - The International Society of Gynecological Pathologists was founded in 1976 to
      facilitate an exchange of knowledge about gynecological disease throughout the
      world. The Society moved quickly to schedule companion meetings with established
      international and regional pathology and gynecology societies, including the
      International Academy of Pathology, its United States-Canadian Division, and the
      International Federation of Gynecology and Obstetrics, and to sponsor smaller
      meetings within individual countries. In 1981 the Society founded this journal,
      and in 1983, at the invitation of the World Health Organization, it assumed the
      responsibility of revising the WHO classifications of tumors of the female
      genital tract. The foundation of the Society appears to have been solid in view
      of its present robust health.

PMID- 10638449
TI  - Histopathologic grading of ovarian carcinoma: a review and proposal.
AB  - The histopathologic grade of ovarian epithelial carcinoma has generally been
      found to be of prognostic significance, but the grading system used has varied
      among published reports, and often has not been specified at all. The major
      proposed grading systems are reviewed, and a new system is proposed, which is
      modeled on the Nottingham system of breast cancer grading and is designed to be
      applied to all invasive epithelial carcinomas of the ovary. Results obtained in
      studies using this system are presented. When grading is compared with
      histopathologic typing of ovarian carcinoma, the latter is less valuable in
      predicting survival but better at predicting tumor responsiveness to
      chemotherapy, and can also suggest the chemotherapeutic agents to be used. Thus,
      both grade and type should be specified in the surgical pathology report for any
      ovarian carcinoma.

PMID- 10638450
TI  - Human papillomaviruses and cervical neoplasia: a model for carcinogenesis.
AB  - Human papillomaviruses are etiologic for cervical cancers and their pathologic
      precursors. As presented in this review, pathologic, epidemiologic, and molecular
      data all support a working model that accounts for the pathogenetic role of these
      viruses in cervical neoplasia. Diagnostic criteria and classification systems are
      discussed in light of this model. These insights point to a potential change in
      clinical screening systems for cervical cancer. In addition, vaccine trials for
      oncogenic HPVs have begun. In the long term, these trials may hold promise as
      truly specific preventive therapy for this common human cancer.

PMID- 10638451
TI  - Early invasive adenocarcinoma of the uterine cervix.
AB  - In an attempt to determine the natural history of early invasive adenocarcinoma
      of the cervix, defined as depth of invasion of 5 mm or less, an extensive review
      of the literature was undertaken, together with recent unpublished material of
      the author. Many of the cases had to be extracted from series dealing with
      microinvasive squamous cell carcinoma. The pons asinorum for the pathologist is
      the differentiation between adenocarcinoma in situ and early invasion. The
      criteria for microinvasion are: 1.) obvious invasion to 5 mm or less; 2.) usually
      complete obliteration of the normal endocervical crypts; 3.) extension beyond the
      normal glandular field; and 4.) a stromal response characteristic of invasive
      carcinoma. Not all of these criteria are present in every case. In all 436 cases
      were collected. Allowing for vagueness of reports, 126 patients were treated by
      radical hysterectomy, and none had parametrial involvement. No cases of adnexal
      tumors were found in the 155 patients in whom one or both ovaries were removed.
      Of the 219 patients with pelvic lymph node dissection, five (2%) had metastasis.
      There were 15 recurrences and six tumor-related deaths in the 436 patients. Only
      21 patients had conization as the only treatment, and none has suffered a
      recurrence. It appears that early invasive adenocarcinoma behaves in the same way
      as its squamous counterpart. Cold knife conization is acceptable treatment only
      when the cone biopsy has been adequately sampled and the margins are free,
      especially when preservation of fertility is an issue. Loop excision procedures
      obscure depth of invasion and margins and are not acceptable either for diagnosis
      or therapy. Multicentricity does not appear to require cylindrical cones. If
      hysterectomy is contemplated, removal of the adnexa, per se, is unnecessary.

PMID- 10638452
TI  - The pathology of uterine smooth muscle tumors and mixed endometrial stromal
      smooth muscle tumors: a selective review with emphasis on recent advances.
AB  - This review focuses on the pathology of uterine smooth muscle tumors (SMTs), with
      a particular emphasis on those studies published in the past 15 years that have
      expanded our knowledge of these tumors which still present diagnostic challenges
      for the pathologist. Leiomyoma variants, leiomyosarcoma, SMTs of low or uncertain
      malignant potential, epithelioid SMTs, SMTs with unusual growth patterns, and
      mixed endometrial stromal-SMTs are discussed.

PMID- 10638453
TI  - The role of electron microscopy in gynecological pathology.
AB  - Electron microscopy, as a diagnostic method, has been available to pathologists
      for about half a century. Its use in studying normal and abnormal gynecological
      tissues has been applied during the second half of that period, and many works on
      specific female genital topics have been published. Several of those subjects are
      worthy of citing in a review of the present type. Clear cell carcinoma has been
      revealed to be a mullerian, rather than a wolffian, derivative. Small cell
      carcinoma of the ovary with hypercalcemia is comprised of cells shown
      ultrastructurally to be epithelial, but unlike surface epithelial cells, germ
      cells, sex-cord cells, or neuroendocrine cells. Further electron microscopic
      studies provided evidence that these small cell tumors are not adult diffuse
      granulosa cell tumors, endometrioid stromal tumors, primitive neuroectodermal
      tumors, or numerous other primary and metastatic small cell tumors. Electron
      microscopy has also been useful in determining that not all signet-ring cell
      tumors of the ovary are stromal, and that there are multiple types of signet-ring
      (vacuolated) cells in ovarian tumors. Smooth muscle tumors are well known to have
      multiple light microscopic phenotypes, and electron microscopy has proven to be
      diagnostic in many of these cases, especially in epithelioid smooth muscle
      tumors. A number of other gynecological neoplasms that have been better defined
      by electron microscopic studies are described. Embryology and histogenesis are
      other areas of study in which electron microscopy has been a major contributor of
      new information at the subcellular level. Electron microscopy, solely or in
      harmony with clinical information, light microscopy, and immunohistochemistry,
      has been and is a valuable tool for the pathologist in the study of histogenesis
      and accurate diagnosis of gynecological lesions.

PMID- 10638454
TI  - Dusting off old books: comments on classic gynecologic pathology books of
      yesteryear.
AB  - Selected outstanding books from the older literature on gynecological pathology
      are reviewed with emphasis on drawing attention to the abundant helpful
      information and outstanding illustrations that are worthy of review by present
      day pathologists. The first three works are Cancer of the Uterus, Myomata of the
      Uterus, and Adenomyoma of the Uterus by Thomas S. Cullen. The senior author of
      the second book is Howard A. Kelly even though he did not have any role in the
      preparation of the text; he was given senior authorship by Dr. Cullen as a token
      of appreciation to his mentor. The next book, Fibroids and Allied Tumors by
      Cuthbert Lockyer, is particularly noteworthy for the quality of the numerous
      color illustrations. The final book on the uterus is The Cervix Uteri and Its
      Diseases by C. Frederic Fluhmann. It provides detailed coverage of the normal and
      pathologic aspects of the cervix, including the endocervical clefts (glands) and
      their abnormalities. The next three books are on the ovary: Ovarian Tumors by
      Samuel H. Geist, Atlas of Ovarian Tumors by Gemma Barzilai, and Endocrine
      Pathology of the Ovary by John McLean Morris and Robert E. Scully. The first is
      notable for the quality of the coverage of clinical and gross aspects of ovarian
      tumors and the second for the quality of the description of the microscopic
      features. The third book expanded the range of functioning ovarian tumors by
      showing that this could be a feature of tumors not usually considered hormonally
      active and also discussed in detail the endocrine function of non-neoplastic
      lesions. The final two books cover general gynecological pathology: Manual of
      Obstetrical and Gynaecological Pathology by John H. Teacher and Gynecological and
      Obstetrical Pathology by Emil Novak. Both have particularly outstanding coverage
      of normal histology and non-neoplastic lesions.

PMID- 10638455
TI  - History of gynecological pathology. VII. Dr. Elizabeth Hurdon.

PMID- 10638456
TI  - [A clinicobacteriologic study on clavulanic acid/amoxicillin in pediatric acute
      otitis media].
AB  - We carried out clinical and bacteriological studies on clavulanic
      acid/amoxicillin and amoxicillin in pediatric acute otitis media at 14 general
      practice settings. The results are summarized as follows. 1. The major isolated
      organisms from content of middle ear effusion were Streptococcus pneumoniae
      31.8%, Haemophilus influenzae 35.8% and Moraxella subgenus Branhamella
      catarrhalis 1.5%. Similar results were observed for the major isolates organisms
      from content of nasopharynx Streptococcus pneumoniae 31.1%, Haemophilus
      influenzae 33.9% and Moraxella subgenus Branhamella catarrhalis 19.2%. 2. 42.2%
      of S. pneumoniae isolated from middle ear effusion were drug resistant S.
      pneumoniae (PISP, PRSP) and they were increasing year by year. 3. 46.7% of S.
      pneumoniae isolated from nasopharyngeal swab were drug resistant S. pneumoniae
      (PISP, PRSP) and they were increasing year by year. The incidence of drug
      resistant S. pneumoniae isolated from all cases and organisms were 26.3% and
      14.5%, respectively. 4. On MIC90, antimicrobial activity of CVA/AMPC against
      Streptococcus pneumoniae, Haemophilus influenzae and Moraxella subgenus
      Branhamella catarrhalis was superior to SBTPC. 5. In the evaluation of clinical
      efficacy, bacteriological efficacy and utility, CVA/AMPC-treated group was
      significantly superior to AMPC-treated group. 6. Adverse reactions were observed
      in 22% of CVA/AMPC-treated group, involving diarrhea and loose stool.

PMID- 10638457
TI  - [A clinicobacteriologic study on clavulanic acid/amoxicillin in pediatric
      sinusitis].
AB  - We carried out clinical and bacteriological studies on clavulanic
      acid/amoxicillin and amoxicillin in pediatric sinusitis at 11 general practice
      settings. The results are summarized as follows. 1. The major isolated organisms
      from content of middle meatus were Streptococcus pneumoniae 32.2%, Haemophilus
      influenzae 32.0% and Moraxella subgenus Branhamella catarrhalis 25.1%. Similar
      results were observed for the major isolates from nasopharynx. 2. 62.1% of S.
      pneumoniae isolated were drug resistant S. pneumoniae (PISP, PRSP) and they were
      increasing year by year. 3. Drug resistant S. pneumoniae was isolated from 38.6%
      of all cases. 4. Regarding MIC90, CVA/AMPC showed superior antimicrobial activity
      against Streptococcus pneumoniae, Haemophilus influenzae and Moraxella subgenus
      Branhamella catarrhalis. 5. The clinical efficacy, bacteriological efficacy and
      utility of CVA/AMPC-treated group were 78%, 58% and 72.8%, respectively, and they
      were significantly superior to AMPC-treated group. 6. Adverse reactions were
      observed in 11.2% of CVA/AMPC group, involving diarrhea and stool loose and there
      was no statistical deference from those of AMPC group.

PMID- 10638458
TI  - Research on screening and diagnosis in autism: a work in progress.
AB  - In June 1998, the National Institutes of Health Autism Coordinating Committee
      (NIH/ACC) invited representatives of 13 major medical and other professional
      academies and associations and six national autism parent research organizations
      to review research data on screening and diagnosis of autism spectrum disorders.
      Ten review papers and more than 4,000 publications were consulted in this effort.
      This paper highlights some promising areas for research identified in this
      process. One of the highest priorities is the search for the ultimate diagnostic
      indicator, a biological marker(s), for example, genetic, metabolic, immunologic,
      neurologic, that will distinguish autism unequivocally from other developmental
      disabilities. In the interim, research on infant screening and diagnosis might
      lower the threshold age for diagnosis to 8-12 months. The role of sensory-motor
      disorders in early diagnosis needs further research. Earlier and better diagnosis
      of co-occurring, potentially treatable disorders, including epileptic and
      epileptiform disorders, has implications both for diagnosis and treatment.
      Pharmacogenetic and pharmacogenomic research strategies could help diagnose
      subtypes and responders versus nonresponders to potential treatments. Better
      endpoints and outcome measures are needed, including improved procedures for
      cognitive and neuropsychological testing, more knowledge about verbal and
      nonverbal communication milestones, and less invasive and more sensitive
      neuroimaging measures. Critical questions remain regarding regression after
      apparently normal development, and about possible environmental precipitants.
      Finally, field trials of the reliability and validity of screening and diagnosis
      using the newly developed practice guidelines are needed.

PMID- 10638460
TI  - A review of the diagnostic methods reported in the Journal of Autism and
      Developmental Disorders.
AB  - This review summarizes subject selection and diagnostic procedures documented in
      the Journal of Autism and Developmental Disorders. One hundred forty-two
      empirical articles published between February 1993 and April 1997 were examined.
      Reviewers independently evaluated articles using a coding instrument developed by
      the authors. Results indicated that a majority of researchers reported the use of
      one or more standard diagnostic criteria in classifying their subjects. However,
      numerous studies did not report the methods by which the diagnostic criteria were
      quantified or applied. Additionally, there was a lack of clear specification of
      inclusion and exclusion criteria for comorbid disorders. Improving the
      documentation of diagnostic practices in research on autism will benefit
      researchers and practitioners.

PMID- 10638461
TI  - Childhood disintegrative disorder.
AB  - Childhood disintegrative disorder (CDD) is a clinical syndrome characterized by
      disintegration of mental functions and regression of acquired language and
      intellectual functions after a period of normal development typically of 3 to 4
      years. Although recognized for many years, research on this condition is less
      advanced than that in autism. Epidemiological data are limited but the condition
      is much less common than autism. The relationship of this condition to autism
      remains the topic of debate. Neuropathological and other medical conditions are
      sometimes associated with the disorder but contrary to earlier belief this is not
      typical. Collaborative research would facilitate our understanding of this
      condition.

PMID- 10638462
TI  - A normed study of face recognition in autism and related disorders.
AB  - Although the interpretation of studies of face recognition in older children,
      adolescents, and adults with autism is complicated by the fact that participating
      samples and adopted methodologies vary significantly, there is nevertheless
      strong evidence indicating processing peculiarities even when task performance is
      not deficient. Much less is known about face recognition abilities in younger
      children with autism. This study employed a well-normed task of face recognition
      to measure this ability in 102 young children with autism, pervasive
      developmental disorder not otherwise specified (PDDNOS), and non-PDD disorders
      (mental retardation and language disorders) matched on chronological age and
      nonverbal mental age, and in a subsample of 51 children divided equally in the
      same three groups matched on chronological age and verbal mental age. There were
      pronounced deficits of face recognition in the autistic group relative to the
      other nonverbally matched and verbally matched groups. Performance on two
      comparison tasks did not reveal significant differences when verbal ability was
      adequately controlled. We concluded that young children with autism have face
      recognition deficits that cannot be attributed to overall cognitive abilities or
      task demands. In contrast to controls, there was a lower correlation between
      performance on face recognition and nonverbal intelligence, suggesting that in
      autism face recognition is less correlated with general cognitive capacity.
      Contrary to our expectation, children with PDDNOS did not show face recognition
      deficits.

PMID- 10638463
TI  - Diagnosed with autism about 6 month ago.

PMID- 10638464
TI  - Nutrition and metabolic support in the 21st century.
AB  - New approaches to nutritional support are necessary to test therapies that may
      potentially enhance outcomes. Such approaches include the move to rely on the
      enteral route for nutrient delivery, the ability to reduce exogenous calories in
      our nutritional support systems, the need to utilize nutrients for their
      pharmacological effects, the ability to use growth factors to enhance nutrient
      efficacy, and the ability to institute nutritional supplementation before
      elective operations, thus practicing preventative nutrition. Testing these
      approaches in the years to come should allow us to identify modalities that will
      permit us to move away from nutritional therapy as a supportive modality and use
      it as a primary or secondary method of patient care.

PMID- 10638465
TI  - Prospective randomized controlled trials: when the gold in the gold standard
      isn't pure.

PMID- 10638459
TI  - The screening and diagnosis of autistic spectrum disorders.
AB  - The Child Neurology Society and American Academy of Neurology recently proposed
      to formulate Practice Parameters for the Diagnosis and Evaluation of Autism for
      their memberships. This endeavor was expanded to include representatives from
      nine professional organizations and four parent organizations, with liaisons from
      the National Institutes of Health. This document was written by this
      multidisciplinary Consensus Panel after systematic analysis of over 2,500
      relevant scientific articles in the literature. The Panel concluded that
      appropriate diagnosis of autism requires a dual-level approach: (a) routine
      developmental surveillance, and (b) diagnosis and evaluation of autism. Specific
      detailed recommendations for each level have been established in this document,
      which are intended to improve the rate of early suspicion and diagnosis of, and
      therefore early intervention for, autism.

PMID- 10638467
TI  - Physicochemical stability of two types of intravenous lipid emulsion as total
      nutrient admixtures.
AB  - BACKGROUND: Recent data have demonstrated that total nutrient admixtures (TNAs)
      are unstable when the percentage of fat (PFAT) globules >5 microm in diameter
      constitute >0.4% of the total fat present and therefore can be considered
      pharmaceutically unfit for human administration. METHODS: We studied five
      nutritionally balanced TNAs using two different products of different oil
      composition designed to feed adult patients weighing 40 to 80 kg in 10 kg
      increments, which were given in final volumes equal to 25 mL/kg. Final
      concentrations of amino acids, dextrose, and lipids were held constant for each
      weight level. To provide cationic stress within clinical limits, calcium and
      magnesium were given in amounts equal to three times the usual daily dose, at 15
      mmol each. Five TNAs were made in duplicate and for each product (n = 20) and
      studied over 5 days. Lipid droplet counts were determined by laser light
      extinction and conducted at five intervals; immediately after preparation at time
      1 (T1), after 4 days at 4 degrees C +/- 2 degrees C (T2), and then at 6 (T3), 24
      (T4), and 30 (T5) hours during storage at 25 degrees C +/- 1 degree C. At T3, a
      simulated patient infusion, set at a rate to deliver the entire volume over the
      next 24 hours, was begun. Samples taken at T3, T4, and T5, equal to 0, 18, and 24
      hours, respectively, of the simulated patient infusion, were collected from the
      terminal infusion port of the i.v. administration set. Mean particle size (MPS)
      was determined by dynamic light scatter at T1, T3, and T5. Dependent variable
      analyses included the PFAT globules > 1.75 and 5 microm and MPS. A repeated
      measure two-way ANOVA assessing treatment and time was performed. RESULTS: The
      MCT/LCT-based TNAs had significantly fewer enlarged fat globules >1.75 microm (p
      < .0001) and >5 microm (p = .046), and smaller MPS (p < .0001) than TNAs made
      with the pure LCT emulsion. Of the 20 TNAs studied, 4 demonstrated visible
      evidence of instability (ie, heavy creaming or free oil), each occurring on day 5
      only with the 70- and 80-kg LCT-based TNAs, and no evidence of instability with
      admixtures prepared from MCT/LCT lipid emulsions (chi2 analysis: p < .05).
      CONCLUSIONS: Because the final macronutrient concentrations were held constant,
      the instability seen with the LCT-based TNAs of higher volumes may result from
      dilution of the electrolyte concentrations that unfavorably alters the electrical
      double layer and irreversibly commits the emulsion to an unstable state. The
      greater physicochemical stability achieved with the MCT/LCT-based TNAs, in turn,
      likely results from the smaller lipid droplet sizes, which may be an inherent
      property of MCTs.

PMID- 10638466
TI  - Perioperative total parenteral nutrition in malnourished, gastrointestinal cancer
      patients: a randomized, clinical trial.
AB  - BACKGROUND: Clinical trials investigating the potential benefits of perioperative
      total parenteral nutrition (TPN) for reducing the risk of surgery in malnourished
      cancer patients have yielded controversial results. METHODS: Ninety elective
      surgical patients with gastric or colorectal tumors and weight loss of 10% or
      more of usual body weight were randomly assigned to 10 days of preoperative and 9
      days of postoperative nutrition vs a simple control group. The daily per kilogram
      body weight TPN regimen included 34.6 +/- 6.3 kcal nonprotein and 0.25 +/- 0.04 g
      nitrogen per kilogram in a volume of 42.6 +/- 7.3 mL of fluid. The glucose-to-fat
      calorie ratio was 70:30. Control patients did not receive preoperative nutrition
      but received 940 kcal nonprotein plus 85 g amino acids postoperatively. RESULTS:
      Complications occurred in 37% of the patients receiving TPN vs 57% of the control
      patients (p = .03). Noninfectious complications mainly accounted for this
      difference, which was 12% vs 34%, respectively (p = .02). Mortality occurred in
      only 5 of the control group patients (p = .05). The total length of
      hospitalization for TPN patients was longer than for control (p = .00), whereas
      the length of postoperative stay in the two groups did not differ significantly.
      CONCLUSIONS: This study shows that 10 days of preoperative TPN that is continued
      postoperatively is able to reduce the complication rate by approximately one
      third and to prevent mortality in severely malnourished patients with
      gastrointestinal cancer.

PMID- 10638468
TI  - Electronic parenteral and enteral nutrition.
AB  - BACKGROUND: With reports of deleterious effects of total parenteral nutrition
      (TPN) in adults in addition to our surveys, which indicated that 1/4, and as many
      as 1/2, of US academic medical centers were using excess glucose in TPN, our
      objective was to devise a computer program to optimize nutrients in parenteral
      and enteral nutrition in adult and pediatric patients. METHODS: From review of
      the literature, body composition, including total body water and body cell mass
      (BCM), were calculated from large published databases. A computer program, based
      on a previous algorithm, was developed to determine optimum parenteral and
      enteral nutritional support, based on calculated BCM as the reference.
      Flexibility to permit any nutrients, in accordance with individual patient
      requirements, was included. RESULTS: With entry of simple anthropometric values
      and an average stress factor equivalent to 20% greater than the Harris-Benedict
      energy calculation, energy and nutrients were calculated for TPN as follows:
      amino acids, 3.4 g/kg BCM/d; carbohydrate, 12 g/kg BCM/d; and fat for remaining
      energy, usually 2.3 g/kg BCM/d. The program, available on any personal computer,
      is available using Netscape 3.0 or higher or from Microsoft Internet Explorer
      4.0, at http://epen.kumc.edu. It permits rapid calculation and display of body
      composition values, a standardized TPN formula, an alternate TPN prescription,
      enteral nutrition options, a section that explains the calculations, and a list
      of references. CONCLUSIONS: The program, http://epen.kumc.edu, provides rapid
      definition of the TPN or enteral prescription for adult and pediatric patients,
      with reduced likelihood of providing excessive glucose and energy in parenteral
      or enteral nutrition.

PMID- 10638469
TI  - Induction of a catabolic state in rats by dexamethasone: dose or time dependency?
AB  - BACKGROUND: Daily injections of dexamethasone (DEX) given to adult rats are a
      recognized but nonstandardized model of stress. The aim of this work was to
      establish a reproducible and accurate model of stress in adult rats by chronic
      injection of DEX in order to standardize it. For this purpose, the effect of the
      duration of treatment and the effect of DEX dose were tested. To help understand
      the mechanisms of the catabolic effect of DEX, the study was extended to the
      metabolism of glutamine (GLN). In experiment 1, 60 male Sprague-Dawley rats (3
      months old) were divided into 8 groups of 6 rats: groups G3, G5, G7, and G9
      received 1.50 mg/kg/d of DEX by intraperitoneal (i.p.) injection for 3, 5, 7, or
      9 days, respectively. Groups G3PF, G5PF, G7PF, or G9PF were pair-fed to groups
      G3, G5, G7, or G9, respectively. Group AL (n = 12) was healthy rats fed ad
      libitum. RESULTS: In treated rats, nitrogen balance reached its lowest value at
      day 5. After 9 days treatment by DEX, the catabolic state was reduced. An
      increase in GLN-synthetase activity and a decrease in muscle GLN content were
      related to DEX per se not to DEX-induced anorexia. In experiment 2, 25 rats were
      divided into 5 groups of 5 animals. Groups G0.75, G1.50, and G2.50 received 0.75,
      1.50, and 2.50 mg/kg/d, respectively, of DEX by i.p. injection for 5 days. Group
      PF was pair-fed to group G2.50 and group AL was control rats. RESULTS: DEX
      induced a decrease in nitrogen balance that was dose-independent. GLN-synthetase
      activity was increased maximally in gastrocnemius by 0.75 mg/kg. CONCLUSIONS:
      Five days of treatment by DEX and a dose of 0.75 mg/kg/d induced a marked
      catabolic state.

PMID- 10638470
TI  - Lipid peroxidation of intravenous lipid emulsions and all-in-one admixtures in
      total parenteral nutrition bags: the influence of trace elements.
AB  - An iodometric titration was used to assess the influence of a daily portion of
      trace elements on lipid peroxidation of pure lipid emulsions and lipid-containing
      all-in-one (AIO) admixtures by measuring the peroxide value (PV; mmol
      peroxides/L). A pure lipid emulsion (Intralipid 20%; Pharmacia & Upjohn,
      Dubendorf, Switzerland) was stored in ethylvinylacetate bags under light
      protection (LP) at 40 degrees C with and without trace elements. In absence of
      trace elements the PV of Intralipid 20% was significantly lower (day 14: 2.77 vs
      18.04; p < .001). After the same time period with the same storage conditions the
      drop in pH was two times higher in presence of trace elements (1.54 vs 0.77). In
      an AIO admixture with LP stored at 2 degrees C to 8 degrees C, trace elements
      increased the PV from 0.04 to 0.19 mmol/L (day 29; p < .01). The drop in pH was
      0.01 and 0.02 units, respectively. When stored at 20 degrees C to 30 degrees C
      and exposed to daylight, the PV of the AIO admixture containing trace elements
      reached 1.92 compared with 0.52 in their absence (day 19; p < .001) with a pH
      drop of 0.03 and 0.11, respectively (day 29). Although trace elements led to a
      much higher drop in pH in pure lipid emulsions, no obvious influence on the pH of
      AIO admixtures was demonstrated. To minimize lipid peroxidation, AIO admixtures
      should be stored light-protected and refrigerated without trace elements. The
      latter should be added immediately before administration or should be given
      separately.

PMID- 10638471
TI  - Decreased in vitro fluoroquinolone concentrations after admixture with an enteral
      feeding formulation.
AB  - BACKGROUND: The purpose of this study was to determine if mixing of
      fluoroquinolones with a common enteral feeding formulation, Ensure (Ross Products
      Division, Abbott Laboratories, Columbus, OH), would alter the measured in vitro
      quinolone concentrations over a 24-hour period. METHODS: Tablets of ciprofloxacin
      (500 mg), levofloxacin (500 mg), and ofloxacin (300 mg) were crushed and mixed
      with 240 mL of Ensure, water and calcium chloride (500 mg/L), water and magnesium
      chloride (200 mg/L), water and calcium chloride and magnesium chloride, and water
      alone. Fluoroquinolone concentrations of the mixtures were measured, via high
      performance liquid chromatography, at baseline and serially over 24 hours.
      Experiments were performed in duplicate, at three temperatures (5 degrees C, 25
      degrees C, and 37 degrees C). RESULTS: Average decreases of 82.5% +/- 1.5% for
      ciprofloxacin, 61.3% +/- 5.2% for levofloxacin, and 45.7% +/- 10.1% for ofloxacin
      (mean +/- 95% CI) were observed in vitro for Ensure over the two experimental
      sets at baseline. Serial analysis revealed no further significant change in any
      of the quinolone concentrations over the remaining 24-hour period. No significant
      decrease was noted with the quinolones when mixed in water and calcium, water and
      magnesium, water and calcium and magnesium, or water alone. This phenomenon
      appears to be unaffected by time and temperature. CONCLUSIONS: These data suggest
      there is an immediate and significant loss of fluoroquinolone when mixed with
      Ensure. An explanation for the loss of fluoroquinolone remains unclear.

PMID- 10638472
TI  - Increased intestinal permeability after upper gastrointestinal surgery during
      enteral nutrition.

PMID- 10638473
TI  - Laparoscopic gastric bypass: a new approach or a new procedure?

PMID- 10638474
TI  - Mechanisms of weight loss after surgery for clinically severe obesity.
AB  - Surgical treatment of clinically severe obesity is becoming more established
      within the medical and lay communities, with a variety of procedures currently
      being performed. Little has been published concerning and comparing the metabolic
      effects produced by these procedures and the mechanisms by which they produce
      weight loss. This article reviews the physiology of weight loss induced by semi
      starvation and other proposed mechanisms of surgically induced weight loss.

PMID- 10638475
TI  - Financial status does not predict weight loss after bariatric surgery.
AB  - BACKGROUND: Lower socioeconomic status and poor funding are thought to be
      associated with suboptimal outcome after bariatric surgery. We undertook this
      study to determine if funding status is a predictor of outcome in patients
      undergoing bariatric surgery. METHODS: The medical records of 131 consecutive
      patients who underwent vertical banded gastroplasty (VBG) for clinically severe
      obesity (BMI >40 kg/m2) were reviewed. Patients were divided into three groups
      based on insurance status: (1) commercially insured/traditional indemnity
      programs; (2) entitlement programs (Medicare), and (3) medically indigent
      (Medicaid or no funding). Data is mean +/- SD. Data was analyzed using ANOVA and
      Student t-test. RESULTS: The three groups had similar preoperative weight. Mean
      BMI was 39 +/- 13, 42 +/- 15, 41 +/- 11 at 1 year, and 40 +/- 13, 43 +/- 16, 45
      +/- 16 at 2 years postoperatively for the insured, entitlement, and indigent
      groups, respectively. CONCLUSION: After standard preoperative evaluation and
      screening, patients loss weight following VBG independent of insurance status.
      Source of funding should, therefore, not preclude patients from undergoing
      bariatric surgery. Patients with limited financial resources can expect similar
      outcomes as patients with commercial insurance.

PMID- 10638476
TI  - Gastroesophageal reflux in obesity: the effect of lap-band placement.
AB  - BACKGROUND: Gastroesophageal reflux disease (GERD) is a common condition which is
      often aggravated by morbid obesity. Lap-Band surgery provides effective weight
      loss in the morbidly obese. There have been several reports that gastric banding
      causes or aggravates reflux. The aim of this study was to evaluate the effect of
      Lap-Band placement on GERD. METHODS: All patients with a significant history of
      GERD who had a Lap-Band inserted over a 2-year period were evaluated
      postoperatively to assess any change in impact on reflux. Resolution required
      absence of reflux symptoms and no anti-reflux drug therapy. RESULTS: There were
      48 (16%) of 274 consecutive patients with a significant history of reflux
      esophagitis requiring regular therapy preoperatively. The median age was 39
      (range 23-58) and M:F ratio was 5:43. We confirm a high prevalence of GERD in
      patients with morbid obesity: 17% with symptoms requiring regular therapy
      (Community Norm 7%). Total resolution of all reflux symptoms occurred in 36 (76%)
      patients, improvement in 7 (14%), no change in 3 (6%), and aggravation of
      symptoms in 2 (4%). Patients with severe and moderate symptoms had similar
      improvement. Resolution or improvement was reported soon after surgery.
      CONCLUSION: Rapid and major improvement in symptoms of GERD occurs after Lap-Band
      placement. The placement of the band probably acts directly to reduce reflux.
      This result contrasts with reports which have found gastric banding causes or
      aggravates GERD.

PMID- 10638477
TI  - Role of radiologic contrast studies in the early postoperative period after
      bariatric surgery.
AB  - BACKGROUND: Radiologic contrast studies have been used routinely to rule out
      gastrointestinal (GI) leaks and to evaluate gastric emptying after bariatric
      surgery. The aim of the study was to evaluate the value of this study in the
      diagnosis of early complications. PATIENTS AND METHODS: 100 morbidly obese
      patients underwent bariatric surgery at our institution in a 7 year period. An
      upper GI series was routinely performed 48 to 72 hours after surgery. Clinical
      and radiologic records were reviewed, analyzing demographic characteristics, type
      of surgery, radiologic findings, and clinical evolution with emphasis on the
      presence of leaks. RESULTS: Mean age was 36 +/- 10 years; there were 68 women and
      32 men. Mean body mass index (BMI) was 48 +/- 10 kg/m2. All radiologic
      examinations ruled out the presence of leaks and showed adequate gastroesophageal
      emptying. One patient with normal postoperative x-ray studies developed a small
      GI fistula after starting liquid diet. CONCLUSIONS: Contrast radiologic studies
      permit good visualization of the gastric anatomy after bariatric surgery. They
      usually confirm adequate gastric emptying, but might be unable to demonstrate
      small gastric leaks.

PMID- 10638478
TI  - Complications after vertical gastroplasty with artificial pseudopylorus in the
      treatment of morbid obesity: a 7-year experience.
AB  - BACKGROUND: Vertical gastroplasty with artificial pseudopylorus (VGAP) was
      designed to reduce the complication rate of other forms of gastroplasty. The
      purpose of this study was to analyze the complications of this approach for 7
      years of surgical practice. METHODS: A total of 156 morbidly obese patients (BMI
      41-81 kg/m2) who underwent VGAP were analyzed retrospectively in terms of early
      and late complications and gastroplasty failure. RESULTS: The early complication
      rate, operative and systemic, was 6.40% (10 patients) and the late complication
      rate was 12.16% (19 patients). Early complications: We observed two gastric leaks
      and subphrenic abscess formation with one gastrocutaneous fistula, one severe
      intraabdominal hemorrhage, one evisceration, two serious wound hematomas, one
      lobar pneumonia, one massive pulmonary embolism and two nodular erythemas. Late
      complications: There were two prepyloric ulcers, one pseudopyloric ulcer with
      stoma stenosis, seven wound hernias, four pseudopyloric dilatations with suture
      rejection and gastroplasty failure, and five staple-line dehiscences with
      endostomach channel formation and gastroplasty failure. One patient (0.64%) died
      from massive pulmonary embolism. CONCLUSIONS: The early and late complication
      rate was acceptable in this series. The applied technique of VGAP is simple,
      safe, and helps avoid many complications caused by the other forms of
      gastroplasty.

PMID- 10638479
TI  - Quality-of-life outcome after laparoscopic adjustable gastric banding for morbid
      obesity.
AB  - BACKGROUND: The definition of success and failure of a bariatric procedure should
      include weight loss as well as improvement of comorbidity and quality-of-life
      (QoL) assessment. QoL measures changes in physical, functional, mental, and
      social health in order to evaluate benefits of new programs and interventions.
      MATERIAL AND METHODS: From April 1995 until March 1999, 287 patients underwent
      laparoscopic adjustable silicone gastric banding (LASGB) at Northwest Hospital
      Frankfurt a.M. (Germany). In this study, 100 of 287 patients (preoperative mean
      BMI 48.3 kg/m2; mean age 35.2 years) with a follow-up >18 month were evaluated.
      All patients underwent anonymous questionnaire (26 questions with a maximum score
      of 60) about different aspects of QoL outcome after LSAGB. RESULTS: In this
      study, 4 of 100 patients refused to give an answer to the QoL questions.
      Therefore 96 patients were evaluated. The QoL auto-evaluation of the patients
      shows that QoL generally improved after surgery in 92%. Using the scoring system,
      44% of patients have excellent, 52% good, and only 4% bad results. The 4 patients
      who refused had to be classified as failure. General acceptance of LSAGB is wide,
      but gastrointestinal side effects are recognizable in more than 78% of operated
      patients. Successful weight loss is followed by an improvement of comorbidities.
      CONCLUSIONS: Safe, effective bariatric procedures increase the quality of life in
      morbidly obese patients markedly. Bariatric surgeons are committed to support and
      help their patients until they reach a new quality of life after obesity surgery.

PMID- 10638480
TI  - Internal hernias and gastric perforation after a laparoscopic gastric bypass.
AB  - A 27-year-old woman underwent laparoscopic Rouxen-Y gastric bypass. A retrocolic
      retrogastric herniation of most of the small bowel and later a gastric
      perforation due to internal hernia at the mesenteric defect of the jejuno
      jejunostomy occurred. These unusual, but not rare, complications are directly
      related to the neoanatomy that follows gastric bypass and can lead to rapidly
      progressing and life-threatening situations. Proper evaluation of clinical signs
      and symptoms, early abdominal CT scan, and urgent operative intervention are
      mandatory to achieve a successful outcome.

PMID- 10638481
TI  - Reversal of drug resistance in sarcoma-45 by the new calmodulin antagonist-
      trihydrochloride of [1,2,5-trimethyl-4-phenyl-4-beta-[N-(beta-ethylamino)-N-4'
      methoxybe nzy l]-ethylamino] piperidine (AR-2).
AB  - The anti-drug resistance effect of three derivatives (AR-1, AR-2 and AR-3) of
      [1,2,5-trimethyl-4-phenyl-4-beta-(N,N-disubstituted-ethylamino)] piperidines,
      that were evaluated as calcium and calmodulin antagonists, was studied on
      doxorubicin (ADM) and vincristine (VCR) resistant Sarcoma-45 inoculated rats.
      Treatment with ADM (5 mg/kg) or VCR (3 mg/kg) alone, as well as with AR-1, AR-2
      or AR-3 (50 mg/kg) alone, had no effect on tumor growth. However, AR-2 in dose 50
      mg/kg (calmodulin antagonist), but not AR-1 and AR-3 (calcium channel blocker),
      administered with ADM (5 mg/kg) or VCR (3 mg/kg), significantly suppressed tumor
      growth 80% and 70%, respectively. Two rats treated with ADM/AR-2 and one treated
      with VCR/AR-2 were cured. 170 kDa protein was purified from sarcoma-45 tumor
      cells to apparent homogeneity by successive steps of phosphocellulose, DEAE
      cellulose, and AR-2-coupled sepharose chromatography. The protein proved to be
      immunopositive with the P-glycoprotein-specific monoclonal antibody. It is
      concluded that the effect of AR-2 can be explained by both hydrophobic and
      electrostatic interaction with a protein target (170 kDa P-glycoprotein) in
      resistant sarcoma-45 tumor cell's membrane.

PMID- 10638482
TI  - Activity of doxorubicin covalently bound to a novel human serum albumin
      microcapsule.
AB  - Doxorubicin is widely used in the treatment of human malignancies, however is
      associated with significant cardiac, bone marrow and gastro-intestinal toxicity.
      Delivery systems may ameliorate this toxicity and increase treatment specificity
      by increasing the proportion of drug delivered to sites of disease. We have
      developed a novel preparation of doxorubicin (Dox) covalently linked to a heat
      stabilised human serum albumin microparticle (HSAM) carrier (median particle
      diameter of 4 microm) and assessed its activity in 4 malignant cell lines.
      MATERIALS AND METHODS: Doxorubicin microcapsules were compared with free
      doxorubicin in the rat carcinoma cell line, WRC256, and the human lines, OVCAR3,
      MCF7 and the Dox resistant MCF7/Dox, using a cell counting technique. IC50 were
      calculated from regression analysis of the resulting survival curves. Endocytosis
      of the microcapsules by cells in culture was observed. The rate of microcapsule
      uptake was assessed using dual wavelength filtered fluorescence microscopy and
      flow cytometry. RESULTS: The mean IC50 following incubation with the Dox
      microcapsules was around 5 times greater than Dox for WRC256 (p < 0.001), MCF7 (p
      < 0.01) and for OVCAR3 (p < 0.01). MCF7/Dox was significantly more sensitive to
      Dox microcapsules than free Dox (p = 0.034). A negative correlation between the
      rate of microcapsule uptake and the IC50 values for each cell line in culture
      exists (r = -0.96, p = 0.04). CONCLUSIONS: We conclude that: 1) Doxorubicin
      microcapsules retain activity in vitro and appear to overcome p-glycoprotein
      mediated Dox resistance. 2) The observed activity of Dox microcapsules correlates
      with the rate of particle uptake. Further studies in animal tumour models are in
      progress.

PMID- 10638483
TI  - Anti-angiogenic activity of selected receptor tyrosine kinase inhibitors,
      PD166285 and PD173074: implications for combination treatment with photodynamic
      therapy.
AB  - Angiogenesis, the formation of new blood vessels from an existing vasculature, is
      requisite for tumor growth. It entails intercellular coordination of endothelial
      and tumor cells through angiogenic growth factor signaling. Interruption of these
      events has implications in the suppression of tumor growth. PD166285, a broad
      spectrum receptor tyrosine kinase (RTK) inhibitor, and PD173074, a selective
      FGFR1TK inhibitor, were evaluated for their anti-angiogenic activity and anti
      tumor efficacy in combination with photodynamic therapy (PDT). To evaluate the
      anti-angiogenic and anti-tumor activities of these compounds, RTK assays, in
      vitro tumor cell growth and microcapillary formation assays, in vivo murine
      angiogenesis and anti-tumor efficacy studies utilizing RTK inhibitors in
      combination with photodynamic therapy were performed. PD166285 inhibited PDGFR
      beta-, EGFR-, and FGFR1TKs and c-src TK by 50% (IC50) at concentrations between 7
      85 nM. PD173074 displayed selective inhibitory activity towards FGFR1TK at 26 nM.
      PD173074 demonstrated (>100 fold) selective growth inhibitory action towards
      human umbilical vein endothelial cells compared with a panel of tumor cell lines.
      Both PD166285 and PD173074 (at 10 nM) inhibited the formation of microcapillaries
      on Matrigel-coated plastic. In vivo anti-angiogenesis studies in mice revealed
      that oral administration (p.o.) of either PD166285 (1-25 mg/kg) or PD173074 (25
      100 mg/kg) generated dose dependent inhibition of angiogenesis. Against a murine
      mammary 16c tumor, significantly prolonged tumor regressions were achieved with
      daily p.o. doses of PD166285 (5-10 mg/kg) or PD173074 (30-60 mg/kg) following PDT
      compared with PDT alone (p<0.001). Many long-term survivors were also noted in
      combination treatment groups. PD166285 and PD173074 displayed potent anti
      angiogenic and anti-tumor activity and prolonged the duration of anti-tumor
      response to PDT. Interference in membrane signal transduction by inhibitors of
      specific RTKs (e.g. FGFR1TK) should result in new chemotherapeutic agents having
      the ability to limit tumor angiogenesis and regrowth following cytoreductive
      treatments such as PDT.

PMID- 10638484
TI  - RAS inhibitors in hematologic cancers: biologic considerations and clinical
      applications.
AB  - As the molecular mechanisms responsible for the development and propagation of
      cancer are becoming elucidated, the nascent field of gene-directed therapy is
      emerging. Recently, several investigators have described inhibitors of the Ras
      protein. This molecule has been targeted because RAS is one of the most commonly
      mutated oncogenes in human neoplasia. In this review, we will discuss the role of
      Ras in the pathogenesis of hematologic neoplasms, and the biology behind the
      development of novel compounds which specifically suppress Ras function.

PMID- 10638486
TI  - A new statistical method for dose-finding based on efficacy and toxicity in early
      phase clinical trials.
AB  - Most statistical methods for dose-finding in phase I clinical trials determine a
      maximum tolerable dose based on toxicity while ignoring efficacy. Most phase II
      designs assume that an acceptable dose has been determined and aim to estimate
      treatment efficacy, possibly with early stopping rules for safety monitoring. The
      purpose of this paper is to describe a new statistical strategy for dose-finding
      in single-arm clinical trials where patient outcome is characterized in terms of
      both response and toxicity. The strategy, which may be considered a phase I/II
      hybrid, was first proposed by Thall and Russell [1] and subsequently modified by
      Thall [2]. The underlying mathematical model expresses the probabilities of
      response and toxicity as interdependent functions of dose. The method is based on
      fixed standards for the minimum probability of response and the maximum
      probability of toxicity appropriate for the particular trial. The best acceptable
      dose is chosen for each successive patient cohort adaptively, based on the fixed
      standards and the dose-outcome data from patients treated previously in the
      trial. The scientific goals are to select one best acceptable dose for future
      patients and to estimate the response and toxicity probabilities at that dose, or
      to stop the trial early if it becomes sufficiently unlikely that any dose is both
      safe and efficacious. An application of the method to a trial of donor lymphocyte
      infusion as salvage therapy for chemo-refractory AML/MDS patients is described.
      To illustrate the method's flexibility and potential breadth of application, two
      additional examples are provided, including a hypothetical trial in which a 5%
      response rate is of interest.

PMID- 10638485
TI  - Ethical issues in the development of new agents.
AB  - In the early drug development process for cancer therapy, several ethical
      dilemmas result from the use of cancer patients with advanced disease as the
      subjects of research in clinical trials studying agents of unknown toxicity
      and/or efficacy. Although several accepted ethical principles guide the behavior
      of involved physicians and investigators, many of these principles are allowed to
      be violated in order to achieve the overall goal of clinical research in
      improving medical care for future patients. Informed consent has been a process
      viewed by many as a mechanism which protects potentially vulnerable patients from
      harm in the clinical trial process. However, the ability of the traditionally
      regulated process of obtaining informed consent for clinical research may be
      inadequate to ensure appropriate understanding of the purposes and the goals of
      early clinical trial research by potentially vulnerable advanced cancer patients.
      This creates further dilemmas with regard to physician-investigator and patient
      subject communications. In the setting of phase I trials, where the specific goal
      of the research is to obtain toxicity information regarding a new potential
      anticancer agent, many heightened ethical conflicts are present. The fact that
      patients do not participate in these studies as a result of altruism, and that
      their main goals of participation are intensely therapeutic, create issues that
      may be in direct conflict with the research purpose of phase I trials. As well,
      the presence of therapeutic intentions on the part of involved physician
      investigators creates challenging issues when one realizes the very low
      likelihood of benefit for individual patients participating in these studies.
      Within the phase II setting, the statistical constraints placed on new drug
      trials and, again, the low likelihood of benefit for participating-subjects, also
      creates challenging dilemmas. These statistical requirements may be in direct
      conflict with involved clinicians' attitudes and beliefs regarding potential
      efficacy of an agent in this setting. As well, these issues become problematic
      when thinking about the desired structure and outcome for informed consent in
      phase II anticancer trials. The ability to conduct clinical research on advanced
      cancer patients using agents of unknown efficacy and toxicity is a daunting
      privilege granted to physicians and accompanying institutions. The weight of this
      privilege should not be underestimated, and involved physician-investigators
      should be aware of the significant ethical challenges involved in appropriately
      and successfully conducting this form of research.

PMID- 10638487
TI  - Phase II trial of menogaril in non-Hodgkin's lymphomas: a Southwest Oncology
      Group trial.
AB  - PURPOSE: To assess the efficacy and toxicity of menogaril against non-Hodgkin's
      lymphoma (NHL) in a group of previously treated patients. PATIENTS AND METHODS:
      Sixty-two eligible patients with a histologic diagnosis of NHL were enrolled, 35
      of who had intermediate or high-grade histologies and 27 of who had low-grade
      lymphomas. Patients with intermediate or high-grade lymphomas had received only 1
      prior chemotherapy regimen, while patients with low-grade histologies had
      received 1 or 2 prior chemotherapy regimens. Menogaril was administered at 160
      mg/m2 intravenously over 1 hour, once every 28 days. RESULTS: Among the 35
      patients with intermediate or high-grade lymphomas who were evaluable for
      response, 6 of 35 patients achieved a partial response (PR) for a response rate
      of 17% (95% confidence interval: 7%-34%). Median survival in this group of
      patients was 13 months. For those patients with low-grade lymphoma, 5 of 26
      patients achieved a PR for a response rate of 19% (95% confidence interval: 6%
      38%). No complete responses were observed in either patient group. The incidence
      of serious (grade 3 or 4) toxicity for those with intermediate/high-grade and low
      grade lymphomas was 43% and 44%, respectively. Most of these toxic effects
      consisted of reversible myelosuppression. Menogaril was discontinued in 2
      patients due to prolonged neutropenia. Cardiotoxicity was observed in 4 patients,
      requiring discontinuation of the drug in 1 patient. No treatment-related deaths
      occurred and the overall toxicity was felt to be acceptable. CONCLUSION: The
      observed antitumor activity of single agent menogaril against both
      intermediate/high-grade and low-grade lymphomas was modest. Further exploration
      of this agent in patients with non-Hodgkin's lymphomas does not seem warranted.

PMID- 10638488
TI  - A phase II trial of homoharringtonine and caracemide in the treatment of patients
      with advanced large bowel cancer.
AB  - Twenty-four previously untreated, ambulatory patients with advanced colorectal
      carcinoma were treated with either caracemide (11 patients) or homoharringtonine
      (13 patients). No objective responses were observed in any of the treatment
      cohorts. Caracemide was well tolerated with the exception of one death due to
      sepsis. On the homoharringtonine arm one patient died of pulmonary sepsis, one
      patient experienced grade 4 leukopenia requiring more than 4 weeks of recovery,
      and an additional patient developed grade 4 renal failure. These severe and
      unexpected complications caused early termination of accrual to the
      homoharringtonine arm of the study. These agents have no activity in the
      treatment of advanced colorectal carcinoma.

PMID- 10638489
TI  - Phase II clinical trial of didemnin B in patients with recurrent or refractory
      anaplastic astrocytoma or glioblastoma multiforme (NSC 325319).
AB  - The activity of didemnin B, a natural product derived from the Caribbean Tunic
      was assessed in 16 patients with Glioblastoma multiforme. Didemnin B was
      administered intravenously by a short infusion at a dose of 4.3 mg/m2 and
      subsequently escalated to 6.3 mg/m2. No anti-tumor activity was observed.
      Toxicity consisted of fatigue, weakness, stomatitis, mild blood count changes,
      nausea and vomiting and occasional fever. Based on these results further studies
      with didemnin B in patients with Glioblastoma multiforme are not recommended.

PMID- 10638490
TI  - Phase II trial of suramin in patients with metastatic renal cell carcinoma.
AB  - This study was conducted to assess the efficacy and toxicity of suramin
      administered using a fixed dose schedule in patients with advanced renal cell
      carcinoma. Fourteen eligible patients with advanced renal cell carcinoma were
      enrolled and treated on a fixed dose schedule of suramin administered over 12
      weeks. Suramin was administered by intravenous infusions over 1 hour. None of the
      13 evaluable patients demonstrated an objective response. Only 3 patients
      completed the 12-week therapy course, with the majority developing progressive
      disease on therapy. The fixed dosage schedule was well tolerated with minimal to
      moderate toxicity. Suramin in this fixed dose schedule is well tolerated but has
      no activity in advanced renal cell carcinoma.

PMID- 10638491
TI  - Phase II study of paclitaxel in combination with mitoxantrone and
      ifosfamide/mesna for patients with relapsed or refractory non-Hodgkin's lymphoma
      after failure to cytarabine/cisplatin combination.
AB  - PURPOSE: Evaluate response, duration of response, and toxicity of paclitaxel in
      combination with other drugs known to be effective in non-Hodgkin's lymphoma
      (NHL). METHODS: Thirty-eight patients with relapsed/refractory NHL who had been
      exposed to doxorubicin as well as the cytarabine-cisplatin combinations received
      Mesna 1.33 gm/M2/D daily days 1, 2, 3 i.v. over 1 hour; ifosfamide 1.33 gm/M2/D
      daily days 1, 2, 3 i.v. over 1 hour (same bag); Novantrone 8 mg/M2/D i.v. day 1;
      and Taxol 27.5 mg/M2/D daily days 1, 2, 3, 4 by continuous 24-hour intravenous
      infusion. Premedication for Taxol included dexamethasone, diphenhydramine, and
      cimetidine on day 1. RESULTS: Of 35 evaluable patients, 9 (26%) achieved a
      complete response and 7 (20%) a partial response for a total response rate of
      46%. The median failure-free and overall survival times were 2 and 10 months,
      respectively. Major toxicity was hematologic with a median absolute neutrophil
      nadir of 196/mm3. Only 10% of the cycles were associated with a grade 3-4
      infection. CONCLUSION: MINT is an active and safe regimen for relapsed/refractory
      NHL that have failed both an Adriamycin-containing regimen and a
      cytarabine/cisplatin-containing regimen.

PMID- 10638492
TI  - Weight loss and diarrhea in a research dog.

PMID- 10638493
TI  - Experimental models of peripheral neuropathies.
AB  - BACKGROUND AND PURPOSE: Peripheral neuropathies, disorders of peripheral nerves,
      result from genetic alterations or from metabolic, inflammatory, infectious, or
      chemical insults. Experimental animal models, spontaneous or induced, exist for
      many of the common human peripheral neuropathies. Recent advances in human
      genetics have led to identification of several specific gene defects involved in
      heritable neuropathies and have allowed reproduction of the molecular defects in
      experimental animals. METHODS: Genetic modifications in mice and rats, similar to
      those seen in humans, along with animal models of specific gene defects are
      presented and discussed. RESULTS AND CONCLUSION: Chemotherapeutic agents
      administered to affected animals mimic the dose-dependent neuropathies similar to
      those seen in humans. Availability of the experimental animal models has been
      invaluable to an understanding of the pathogenesis of disease and the development
      of new treatments.

PMID- 10638494
TI  - Pathogenesis of guinea pig adenovirus infection.
AB  - BACKGROUND AND PURPOSE: The existence of guinea pig adenovirus (GPAdV) has been
      suspected on the basis of histopathologic findings, but the virus has not yet
      been isolated. In susceptible animals, it may cause severe bronchopneumonia and
      death. Adenovirus-like inclusion bodies have been observed in the lungs of
      animals with clinical disease. Prevalence of the infection is unknown. Recently,
      a polymerase chain reaction (PCR) assay was described that was able to
      selectively detect GPAdV. METHODS: To investigate the pathogenesis of GPAdV, we
      inoculated eight guinea pigs with GPAdV; eight control animals were sham
      inoculated. The PCR assay was used to trace the infection. In a second
      experiment, transmission of GPAdV from an experimentally infected animal to five
      immune-naive cohorts was examined. RESULTS: None of the infected animals
      developed clinical disease. The GPAdV could be detected by PCR analysis of nasal
      swab specimens on days 6 through 15 after infection. Infective virus could be
      recovered from the nasal mucosa during this period (as determined by inoculation
      of immune-naive animals). The virus was transmitted from an experimentally
      infected animal to two of five immune-naive cage mates. CONCLUSION: The GPAdV may
      cause transient subclinical upper respiratory tract infection that may descend to
      the lungs.

PMID- 10638495
TI  - Herpesvirus papio 2: alternative antigen for use in monkey B virus diagnostic
      assays.
AB  - BACKGROUND AND PURPOSE: Serologic testing for antibody to monkey B virus (BV) in
      macaque sera is problematic due to the biohazardous nature of BV and BV antigens.
      Herpesvirus papio 2 (HVP2), a herpesvirus of baboons, is more closely related
      genetically and antigenically to BV than is human herpes simplex virus 1 (HSV1).
      The potential for use of HVP2 relative to HSV1 as an alternative test antigen for
      detection of anti-BV antibody in macaque sera was assessed. METHODS: Standard
      ELISA formats were developed, using BV-, HVP2-, and HSV1-infected cell extracts.
      Performance of the HVP2 and HSV1 tests was assessed relative to that of the BV
      test. RESULTS: Using the BV antigen ELISA, 349 sera from 7 macaque species were
      tested, and results were classified as positive (253), negative (94), or suspect
      (2). The ELISA using HVP2 antigen detected 98.0% of BV-positive sera (248 of
      253), whereas the HSV1-based ELISA detected only 96.0% (243 of 253). All three
      ELISAs identified the same two samples as suspect, and the HSV1 ELISA identified
      three additional BV-positive sera as suspect. CONCLUSIONS: The HVP2 antigen-based
      ELISA was equal in sensitivity and specificity to the BV antigen-based ELISA and
      was superior to the HSV1 ELISA for detection of BV-positive macaque sera. In
      addition, the HVP2 ELISA has greater laboratory safety, compared with BV antigen
      use for ELISA testing.

PMID- 10638496
TI  - Effect of weaning time and associated management practices on postweaning chronic
      diarrhea in captive rhesus monkeys (Macaca mulatta).
AB  - OBJECTIVE: Our purpose was to assess the extent to which early weaning and other
      weaning-management factors affect development of postweaning chronic diarrhea in
      captive rhesus monkeys at the California Regional Primate Research Center between
      1992 and 1995. METHODS: Data for weaning, management, and onset of diarrhea were
      obtained from daily records. The Cox proportional hazard model was used to assess
      whether the risk of chronic diarrhea was related to early weaning. RESULTS:
      Monkeys that were lighter at weaning had a threefold increase in risk of
      postweaning chronic diarrhea (P = 0.07), compared with that in heavier monkeys.
      An episode of preweaning diarrhea increased the risk of postweaning chronic
      diarrhea twofold (P = 0.08). Relocation of monkeys to outdoor facilities in the
      fall was associated with a fivefold decrease in risk (P < 0.001), compared with
      that of other seasons, and weaning in 1993 was associated with a twofold decrease
      in risk, compared with that of other years (P = 0.04). CONCLUSIONS: Multiple
      factors need to be considered for prevention of postweaning chronic diarrhea,
      including weaning weight, preweaning diarrhea, season weaned, and weaning
      conditions that change from year to year.

PMID- 10638497
TI  - Distribution of Helicobacter pylori in a Mongolian gerbil gastric ulcer model.
AB  - BACKGROUND AND PURPOSE: To the authors' knowledge, histopathologic changes
      associated with early H. pylori infection and ulceration have not been
      established. We examined presence of H. pylori infection in an acetic acid
      induced gastric ulcer (AAU) model in Mongolian gerbils. METHODS: Sixty Mongolian
      gerbils were used as an AAU model, and another 60 gerbils were studied as a
      control (non-AAU) group. All animals were orally administered H. pylori, then
      were evaluated by use of histologic and bacteriologic examinations. RESULTS:
      Helicobacter pylori were scattered on the surface mucous gel layer and in the
      pyloric gland gastric were pits; inflammation seen at the early stages later
      extended to the mucosa of the fundic gland area. The organisms were predominantly
      observed in the AAU model, but findings were comparable to those in controls at
      1, 3, 7, 14, 28, or 56 days. Evaluation with regard to viable bacterial numbers
      reflected the histologic aspects, that the pyloric gland area had more viable
      counts than did the fundic gland area. Carbohydrate composition of mucin differed
      between pyloric and fundic gland areas. These findings shed light on L-fucose
      related to the H. pylori adhesive factor abundant in mucin of the pyloric gland
      area. CONCLUSIONS: Findings for this ulcer model of Helicobacter pylori infection
      make it useful for the study of onset of infection and screening of anti-ulcer
      agents.

PMID- 10638498
TI  - Open-thorax guinea pig model for defibrillation.
AB  - BACKGROUND AND PURPOSE: Guinea pigs are used as models for study of ventricular
      tachyarrhythmias (VT); however, the tachyarrhythmia often is transient and does
      not persist. We developed an open-thorax guinea pig model of sustained
      ventricular fibrillation (VF). METHODS: Bilateral thoracotomy was performed on
      eight guinea pigs weighing 865 to 1,464 g, and two sutures were positioned in the
      right ventricular apex for the purpose of pacing. Two methods were used to induce
      VF: a 50-Hz burst (normal pacing), and an initial 15 beats at 70% of the R-R
      interval followed by a 100-Hz burst for 84 beats (rapid pacing). Fifteen attempts
      at inducing VF were performed by use of each method. Blood pressure was recorded
      before and after development of VF, which was defined as VT with mean blood
      pressure consistently <10 mm Hg. A final observation was obtained using the
      normal pacing method without defibrillation. RESULTS: Use of both methods
      successfully induced VF. A significant relationship between body weight >1,021 g
      and ability to sustain and survive VF was detected. CONCLUSION: The guinea pig is
      a useful rodent model for the study of VF and defibrillation.

PMID- 10638499
TI  - Evaluation of cynomolgus (Macaca fascicularis) and rhesus (Macaca mulatta)
      monkeys as experimental models of acute Q fever after aerosol exposure to phase-I
      Coxiella burnetii.
AB  - BACKGROUND AND PURPOSE: Q fever is a disease of humans. Vaccines to prevent this
      disease have demonstrated efficacy in rodents and must also be evaluated for
      efficacy in a nonhuman primate model. Preliminary to vaccine efficacy
      experiments, cynomolgus and rhesus monkeys were evaluated as suitable
      experimental models of acute Q fever. METHODS: Both species of monkeys were
      challenged with aerosolized 10(5) virulent phase-I Coxiella burnetii Henzerling
      strain, and clinical and serologic responses were determined. RESULTS:
      Radiographic changes were observed in seven of eight monkeys of both species;
      however, changes in cynomolgus monkeys tended to be more significant. Between 7
      and 10 days after challenge, all rhesus monkeys and 88% of cynomolgus monkeys
      were bacteremic. Sequential increases in antibody responses to C. burnetii phase
      I and phase-II whole cells and phase-I lipopolysaccharide were observed in both
      species. Although the maximal rectal temperature increase was similar in both
      species, duration of fever was slightly longer in rhesus monkeys. Clinical
      features were similar to those described in human acute Q fever patients.
      CONCLUSIONS: On the basis of the more pronounced radiographic changes in
      cynomolgus monkeys, we favor use of this species for future studies of vaccine
      efficacy.

PMID- 10638500
TI  - Insulin replacement therapy for the rat model of streptozotocin-induced diabetes
      mellitus.
AB  - OBJECTIVE: This study was conducted to compare various strategies for insulin
      replacement therapy in the streptozotocin-induced diabetic rat model. METHODS:
      Control and diabetic Sprague Dawley rats were fed ad libitum, blood glucose
      concentration was measured twice daily, and outcome was assessed over the final 5
      days of a 10-day treatment period, with adjustment of insulin dosage toward the
      goal of normal glucose values. RESULTS: All insulin regimens induced weight gain
      at least comparable to that of controls, but glucose regulation differed. It was
      not possible to normalize glucose values by use of protamine zinc insulin (PZI)
      or Ultralente insulin given once daily. In contrast, PZI and neutral protamine
      Hagedorn (NPH) insulin given twice daily provided glucose values comparable to
      those in controls, whereas glucose values were modestly higher in response to a
      70% human insulin isophane suspension and 30% soluble human insulin solution (70/
      30 insulin) given twice daily. Attempted normalization of glucose values was
      limited by hypoglycemia, which was most common after administration of PZI once
      daily, and least common after 70/30 insulin given twice daily. Dosage
      requirements for Ultralente insulin were four- to fivefold higher than those for
      all other insulins. CONCLUSION: In streptozotocin-diabetic rats, normal weight
      gain can be achieved by treatment with PZI insulin once daily, but attainment of
      near-normal glucose values requires administration of PZI, NPH, or 70/ 30 insulin
      twice daily. Ultralente insulin may have reduced bioeffectiveness in this animal
      model.

PMID- 10638502
TI  - Comparison of two systems for tibial external fixation in rabbits.
AB  - BACKGROUND AND PURPOSE: Use of rabbits in orthopedic investigations is common. In
      this study, focus is on factors that influence bone healing and on distraction
      osteogenesis. Biomechanical characteristics of two external fixator systems
      (Orthofix device and Hoffmann device) for long bones were tested. METHODS: Twelve
      freshly dissected tibiae were obtained from six skeletally mature New Zealand
      White rabbits, and four-point bending stiffness in two planes (90 and 180 degrees
      to the fixator pins) and torsional stiffness and strength of the bone-fixator
      complex were evaluated by use of a material testing machine. RESULTS: In four
      point bending, Orthofix device had higher stiffness and strength, compared with
      Hoffmann device. When the load was applied 180 degrees to the pins, both devices
      had higher stiffness, compared with that at 90 degrees. In torsional testing,
      Orthofix device had significantly higher stiffness and strength. CONCLUSIONS:
      Significant differences in structural properties between the two systems were
      evident. Loading direction and gap conditions were important factors in
      determining properties of the systems. Therefore, type of external fixation
      system and fixation technique should be considered when designing experiments,
      using the rabbit long bone model.

PMID- 10638501
TI  - Peripheral blood progenitor cell mobilization and leukapheresis in pigs.
AB  - BACKGROUND AND PURPOSE: The pig is being investigated as an organ donor for
      humans. Induction of immunologic tolerance to pig tissues in primates would
      overcome the major immunologic barriers to xenotransplantation. A proven method
      of inducing tolerance to allografts is by the induction of mixed hematopoietic
      chimerism by bone marrow transplantation. We are therefore investigating
      induction of mixed hematopoietic chimerism in the pig-to-baboon model. METHODS:
      To obtain large numbers of pig hematopoietic cells, leukapheresis was used to
      collect blood cell products in miniature swine (n = 5) after progenitor cell
      mobilization by use of a course of hematopoietic growth factors (cytokines),
      consisting of porcine interleukin 3, porcine stem cell factor, and human
      granulocyte colony-stimulating factor. RESULTS: Cytokine therapy and
      leukapheresis were well tolerated. Cytokine therapy increased the total white
      blood cell count and allowed large numbers of leukocytes (60 x 10(10)) to be
      obtained by apheresis, of which approximately 0.1% were granulocyte-erythrocyte
      monocyte-megakaryocyte colony-forming units (CFU-GEMMs), which are considered to
      be representative of hematopoietic progenitors with multi-lineage potential.
      CONCLUSIONS: The combination of cytokine therapy and leukapheresis enables
      hematopoietic progenitor cells to be obtained safely from miniature swine.

PMID- 10638503
TI  - Comparison of three treatments for control of ear mites in ferrets.

PMID- 10638504
TI  - Effects of histamine, carbachol, and methacholine on maximal expiratory lung
      mechanics in goats.

PMID- 10638505
TI  - Depressive effects of anesthesia or sedation on exocrine pancreatic function in
      pigs.

PMID- 10638506
TI  - Pathologic changes associated with use of tribromoethanol (avertin) in the
      Sprague Dawley rat.

PMID- 10638507
TI  - Major histocompatibility haplotype does not impact the course of experimentally
      induced murine vaginal candidiasis.

PMID- 10638508
TI  - Pulmonary complications of HIV disease. Introduction.

PMID- 10638509
TI  - Epidemiology and risk of pulmonary disease.
AB  - Although pulmonary diseases are important causes of illness and death in patients
      with human immunodeficiency virus (HIV) infection, advances in treatment and the
      demographics of HIV-infected populations are changing their incidence and
      manifestations. The rates of acquires immune deficiency syndrome (AIDS)- related
      mortality and opportunistic infections have fallen drastically since the
      introduction of highly active antiretroviral therapy (HAART) in 1996. The risk of
      developing specific disorders is related to the degree of immunosuppression, HIV
      risk group, area of residence, and use of antiretroviral treatments and
      prophylaxis against common infections. HIV-infected drug users are at increased
      risk for developing bacterial pneumonia and tuberculosis. Bronchitis and
      sinusitis occur commonly in the general population, but more frequently in HIV
      infected persons. With progressive immunocompromise, the risk of developing
      bacterial pneumonia, Pneumocystis carinii pneumonia, and tuberculosis increases.

PMID- 10638510
TI  - Screening and noninvasive testing for pulmonary disease.
AB  - Although detection of preclinical disease using screening tests is desirable if
      earlier treatment improves outcome, the available data show no morbidity or
      mortality benefit using chest radiography, sputum analysis for Pneumocystis
      carinii and acid-fast bacilli, or serial measurements of single-breath carbon
      monoxide diffusing capacity to detect pulmonary disease in asymptomatic persons
      with HIV. It seems prudent to evaluate asymptomatic patients periodically with a
      careful history and focused physical examination and to perform only those tests
      that are likely to alter the plan of management such as tuberculin skin testing,
      CD4 lymphocyte measurement, and measurement of viral burden. Noninvasive
      diagnostic studies including chest radiography, arterial blood gas analysis,
      induced or expectorated sputum analysis, exercise testing, and nuclear scans
      should be performed if new pulmonary symptoms are observed. The use of these
      tests should be guided by the clinical presentation and followed, when necessary,
      by the appropriate invasive studies.

PMID- 10638511
TI  - Bronchoscopic techniques for the diagnosis of pulmonary complications of HIV
      infection.
AB  - Bronchoscopy has played the central role in defining the spectrum of pulmonary
      disorders that occur in patients with HIV infection. Transbronchial biopsy (TBB)
      and bronchoalveolar lavage (BAL) both have high yields in the diagnosis of
      Pneumocystis carinii pneumonia (PCP) and other infections. Paradoxically, despite
      our knowledge and experience using bronchoscopy, controversy still exists
      regarding whether to attempt to make a bronchoscopic diagnosis in most patients
      with suspected PCP who have negative sputum studies or whether to administer
      initial empiric therapy and reserve invasive diagnostic techniques for patients
      who have a response. I prefer establishing a diagnosis as soon as possible
      because bronchoscopy is safe and because the patient may not have PCP and may
      become too ill to have bronchoscopy after a few days of ineffective therapy. A
      second controversy relates to the necessity of including routine TBB in addition
      to BAL during bronchoscopy. Although biopsies increase the risk of pneumothorax
      and hemorrhage, they add to the diagnostic yield in PCP and other infections.
      They are also necessary to provide tissue specimens for diagnosing noninfectious
      pulmonary disorders such as Kaposi's sarcoma and lymphocytic and nonspecific
      pneumonitis.

PMID- 10638512
TI  - Bacterial pneumonia.
AB  - Bacterial pneumonia is significantly more common in persons who are HIV-infected
      than in the general population and is most common among injection drug users and
      in persons with advanced HIV disease and immunosuppression. The clinical features
      of bacterial pneumonia are similar to those in HIV-seronegative persons, but
      bacteremia is more common. When a pathogen is identified, Streptococcus
      pneumoniae is consistently the most common, occurring in 20% to 70% of cases.
      Haemophilus influenzae, Staphylococcus aureus, Escherichia coli, and other gram
      negative organisms are mainly responsible for the remainder of bacterial
      pneumonia episodes in the United States, Central Africa, Australia, and England.
      In some studies, Chlamydia pneumoniae was recognized as a common cause in persons
      with early HIV disease, whereas Pseudomonas aeruginosa is recognized as a
      community- and hospital-acquired lower respiratory tract pathogen in patients
      with severe immunosuppression. Although antimicrobial therapy is frequently
      empiric, it should be tailored to the severity of illness, local prevalence of
      infections, resistance patterns, or when an etiologic agent is identified. The
      treatment response is similar in patients with and without HIV infection, but
      bacterial pneumonia may accelerate the progression of HIV disease. Preventative
      measures include use of the polyvalent pneumococcal vaccine, especially early in
      the course of HIV infection, when it is most likely to be effective. The
      incidence of bacterial pneumonia is also reduced in HIV-seropositive persons who
      use trimethoprim-sulfamethoxazole to prevent Pneumocystis carinii pneumonia.

PMID- 10638513
TI  - Pneumocystis carinii pneumonia.
AB  - Throughout the epidemic, Pneumocystis carinii pneumonia (PCP) has been the most
      common AIDS-defining opportunistic infection in the United States. With the
      widespread use of highly active antiretroviral therapy (HAART) and prophylaxis in
      patients known to be at risk, the incidence of PCP in patients with AIDS has
      declined dramatically. However, it is still seen regularly in patients with
      previously undiagnosed human immunodeficiency virus (HIV) infection, those who do
      not comply with prophylactic medications, and in occasional cases of failure of
      prophylaxis. Despite many years of study, our understanding of the biology,
      ecology, and pathogenesis of PCP is inadequate. Clinically, PCP in AIDS tends to
      be a less acute and milder illness than PCP in other types of immunocompromised
      hosts. Although the radiograph typically shows bilateral diffuse granular
      opacities, many other patterns are seen. Trimethoprim-sulfamethoxazole is the
      preferred drug for treating and preventing PCP, but toxicity limits its use. The
      choice of treatment is influenced by the severity of illness and relative
      toxicities of antipneumocystis agents. Adjunctive corticosteroid therapy is
      recommended for patients with moderate or severe disease. The success of HAART
      has prompted investigators to question whether prophylaxis against PCP and other
      opportunistic infections is necessary in patients who respond with a rise in CD4
      lymphocyte counts and suppression of HIV replication.

PMID- 10638514
TI  - Tuberculosis in patients with human immunodeficiency virus infection.
AB  - Tuberculosis (TB) is the major opportunistic infection of human immunodeficiency
      virus (HIV)-infected persons worldwide. Human immunodeficiency virus infection is
      the most potent known risk factor for reactivation of latent Mycobacterium
      tuberculosis infection, and TB disease appears to increase the rate of HIV
      progression. Pulmonary disease is seen in most patients, including a large
      proportion of those with extrapulmonary disease. Failure to suspect TB and to
      order the appropriate diagnostic tests is the most common reason for diagnostic
      delays. With advancing HIV infection, tuberculin skin test reactivity decreases
      along with reactivity to nonspecific antigens such as mumps, tetanus toxoid, and
      Candida; anergy testing need not be a routine component of tuberculosis screening
      of HIV-infected persons. The diagnosis depends on identifying the organism on
      smears or cultures; direct amplification tests may facilitate rapid
      identification of M. tuberculosis, but the relatively low sensitivity in smear
      negative specimens limits their use. Also, these tests must be used in
      conjunction with the clinical assessment, and they must always be performed in
      conjunction with microscopy and standard culture. Shorter courses of combination
      preventive therapy of patients with latent tuberculous infection are effective,
      but the potential advantages of improved adherence and reduced costs of shorter
      courses should be balanced with an increased risk secondary to ongoing TB
      exposure in areas with a high TB prevalence. Six months of treatment for active
      tuberculosis is recommended, unless the response of a particular patient is slow
      or otherwise suboptimal. The use of highly active antiretroviral therapy (HAART)
      made a remarkable impact on the course or HIV disease, but raises several issues
      with respect to HIV-related TB. Drug interactions necessitate either a non
      rifamycin-based regimen or a rifabutin-based regimen in patients on HAART treated
      for TB.

PMID- 10638515
TI  - Cytomegalovirus pneumonia.
AB  - Cytomegalovirus (CMV) pneumonia is a major cause of morbidity and mortality in
      allogeneic bone marrow transplant and lung transplant recipients. However, its
      role as a cause of lung disease in patients with the human immunodeficiency virus
      (HIV) is controversial. Although CMV can be isolated from lung specimens in
      patients with HIV-associated respiratory illness, it is rarely the causative
      pathogen. Most adults with HIV infection have latent CMV infection of many
      tissues including the lung, and most cases of CMV pneumonia are believed to be
      caused by reactivation secondary to severe immunocompromise. The clinical
      presentation of pneumonia caused by CMV pneumonia is similar to that of
      Pneumocystis carinii, with fever, cough, hypoxemia, and diffuse radiographic
      opacities. Although the two infections can not be differentiated on clinical
      grounds alone, the presence of extrapulmonary CMV disease and the use of recent
      cytotoxic chemotherapy or corticosteroids suggests the diagnosis of CMV
      pneumonia. Although approximately 60% of cases respond initially to anti-CMV
      therapy, the disease is associated with progression and high early mortality,
      probably related to severe underlying immunosuppression.

PMID- 10638516
TI  - Thoracic surgical spectrum of HIV infection.
AB  - The thoracic surgeon is often called on to diagnose or treat a variety of
      disorders associated with human immunodeficiency virus (HIV) infection. Surgical
      mediastinal exploration through cervical and anterior approaches is a safe and
      valuable modality in appropriately selected patients with unexplained mediastinal
      lymphadenopathy. Open lung biopsy is used in a small subset of HIV-infected
      patients with undiagnosed diffuse or multifocal pulmonary disease, with an
      anticipated diagnostic yield of more than 70%. The biopsy can be performed either
      thoracoscopically or via thoracotomy, based on the expertise and discretion of
      the surgeon. Open lung biopsy should be used very selectively and in patients
      with bronchoscopically confirmed diagnoses who are failing optimal medical
      therapy, because the impact on outcome is minuscule and because open lung biopsy
      is best avoided altogether in patients with established respiratory failure.
      Patients with acquired immune deficiency syndrome (AIDS) have an increased
      incidence of pneumothorax, often associated with Pneumocystis carinii pneumonia.
      Depending on the clinical scenario, tube thoracostomy, pleurodesis, or
      pleurectomy may be used. Thoracic empyema in AIDS patients requires urgent
      intercostal drainage and close clinical surveillance to discern the need for
      decortication or rib resection and open drainage. A surgical approach to pyogenic
      lung abscess or invasive aspergillosis is occasionally useful. Although it is
      controversial whether the incidence of lung cancer is increased in patients with
      HIV infection, HIV-positive patients with early stage nonsmall-cell lung cancer
      who are otherwise surgical candidates should undergo resection, especially in the
      era of highly active antiretroviral therapy.

PMID- 10638517
TI  - Intensive care of patients with HIV infection.
AB  - Despite the improvements in the prognosis associated with the development of
      highly active antiretroviral therapy (HAART), more than 410,000 people in the
      United States were reported to have died from acquired immune deficiency syndrome
      (AIDS) by the end of 1998. The number of people living with human
      immunodeficiency virus (HIV) infection and AIDS in the United States continues to
      increase, estimated at more than 370,000 in 1998, and there is good reason for
      optimism that HIV infection may be a controllable disease in many people.
      Nevertheless, an estimated 27,000 persons still died of AIDS in the United States
      in 1997, and AIDS is still a leading cause of death in the age group 25 to 44
      years. Despite the dramatic treatment advances for HIV infection and improving
      survival following an AIDS diagnosis, many patients still present with life
      threatening complications of HIV infection for three major reasons. Highly active
      antiretroviral therapy and prophylaxis against Pneumocystis carinii and other
      infections are not effective in all patients, despite rigorous adherence to
      treatment. Others adhere to these therapies poorly. Finally, many patients
      present with advanced disease, unaware that they have HIV infection until they
      develop a serious opportunistic infection. Therefore, the AIDS epidemic and its
      burden of illness will continue, and decisions regarding the appropriateness of
      intensive care for individual patients will be inevitable. The impact of AIDS in
      Africa and Asia is far more devastating than in the United States and Europe, and
      most HIV-infected persons in the world live in the underdeveloped nations where
      intensive care is often unavailable. This article will deal with intensive care
      in patients with HIV in developed nations.

PMID- 10638518
TI  - Infection control in pulmonary and critical care medicine.
AB  - During the routine care of patients, pulmonary and critical care specialist may
      have significant exposure to respiratory infections and potentially infectious
      body fluids such as blood and pleural fluid. Bronchoscopy and intensive care
      services often require close contact with patients and the use of sharp devices
      required for intravascular catheterization. Rendering such care places physicians
      at risk for acquiring agents such as human immunodeficiency virus (HIV),
      hepatitis viruses, and Mycobacterium tuberculosis. As of December 1998, 188 cases
      of occupational transmission of HIV to health care workers (HCWs) in the United
      States have been reported to the Centers for Disease Control. Most documented
      cases of seroconversion involve percutaneous injury involving blood, with the
      greatest risks being associated with injury from a hollow-bore needle that has
      been in an infected patient's vein or artery. Because thousands of HIV-infected
      persons are unaware of their infection, HCWs must consider all patients to be
      infected with HIV and improve work practices accordingly. Nevertheless,
      elimination of all exposures is impossible, and postexposure prophylaxis with
      combination antiretroviral therapy is recommended for persons deemed a high risk
      of contracting HIV. Pulmonary specialists are at high risk of exposure to
      tuberculosis; proper precautions include isolation of patients with suspected
      tuberculosis and the use of DMF-HEPA respirator masks, especially while
      performing procedures like bronchoscopy. Contaminated bronchoscopes have been
      implicated in transmission and "pseudoinfection" of tuberculosis and
      nontuberculous mycobacteria, underscoring the need for rigorous cleaning and
      disinfection practices.

PMID- 10638519
TI  - Multiple pulmonary masses as a presentation of abscesses.

PMID- 10638520
TI  - The RAS genes: a homeostatic device in Saccharomyces cerevisiae longevity.
AB  - The genetic analysis of the yeast replicative life span has revealed the
      importance of metabolic control and resistance to stress. It has also illuminated
      the pivotal role in determining longevity that the RAS genes play by the
      maintenance of homeostasis. This role appears to be performed by the coordination
      of a variety of cellular processes. Metabolic control seems to occupy a central
      position among these cellular processes that include stress resistance. Some of
      the features of metabolic control in yeast resemble the effects of the daf
      pathway for adult longevity in Caenorhabditis elegans and the metabolic
      consequences of selection for extended longevity in Drosophila melanogaster, as
      well as some of the features of caloric restriction in mammals. The distinction
      between dividing and nondividing cells is proposed to be less important for the
      aging process than generally believed because these cell types are part of a
      metabolic continuum in which the total metabolic capacity determines life span.
      As a consequence, the study of yeast aging may be helpful in understanding
      processes occurring in the aging brain.

PMID- 10638521
TI  - Mutations in signal transduction proteins increase stress resistance and
      longevity in yeast, nematodes, fruit flies, and mammalian neuronal cells.
AB  - Mutations in Ras and other signal transduction proteins increase survival and
      resistance to oxidative stress and starvation in stationary phase yeast,
      nematodes, fruit flies, and in neuronal PC12 cells. The chronological life span
      of yeast, based on the survival of nondividing cells in stationary phase, has
      allowed the identification and characterization of long-lived strains with
      mutations in the G-protein Ras2. This paradigm was also used to identify the in
      vivo sources and targets of reactive oxygen species and to examine the role of
      antioxidant enzymes in the longevity of yeast. I will review this model system
      and discuss the striking phenotypic similarities between long-lived mutants
      ranging from yeast to mammalian neuronal cells. Taken together, the published
      studies suggest that survival may be regulated by similar fundamental mechanisms
      in many eukaryotes and that simple model systems will contribute to our
      understanding of the aging process in mammals.

PMID- 10638522
TI  - Mechanisms of life span determination in Caenorhabditis elegans.
AB  - Molecular analysis of several gerontogenes of Caenorhabditis elegans has led to
      the discovery of at least two life span-controlling pathways. An insulin-like
      signaling cascade consisting of proteins encoded by the genes daf-2, age-1, akt
      1, akt-2, daf-16 and daf-18 regulates dauer diapause, reproduction, and
      longevity. This pathway regulates all three processes systemically. daf-12
      interacts with it, affecting dauer diapause and longevity. Life span extension
      mediated by this pathway probably results from the activation of an enhanced life
      maintenance program, which is normally operative during dauer diapause. A
      different mechanism is specified by the clock genes clk-1, clk-2, clk-3 and gro
      1, which regulate metabolic activity and the pace of many temporal processes
      including longevity. There is some controversy as to whether the life span
      extension observed in these mutants requires the activity of daf-16. All known
      gerontogenes appear to confer resistance to environmental stress, usually
      multiple stress factors, including oxidative stress, high temperature, and
      exposure to ultraviolet radiation. Caloric restriction extends longevity
      substantially, and may act by activating the enhanced life-maintenance program.

PMID- 10638523
TI  - The spe-10 mutant has longer life and increased stress resistance.
AB  - We investigated the life span of spe-10 mutant nematodes. We also tested
      resistance of spe-10 mutants to ultraviolet (UV) light, heat, and paraquat and
      examined the relationship between resistance to UV light and the fertility defect
      of these animals. The spe-10 mutation significantly increased mean life span.
      Additionally, the mutation significantly increased resistance to both UV light
      and to heat. Resistance to paraquat was not significantly different from that of
      wild-type, nor were any dauers formed at 27 degrees C. No significant correlation
      was found between the UV resistance and the fertility defect, nor was the UV
      resistance attributable to a hormetic effect. These results reinforce the
      importance of stress resistance in specifying increased life span and indirectly
      suggest that this fertility defect is not a direct cause of life span extension.

PMID- 10638524
TI  - P13-kinase inhibition induces dauer formation, thermotolerance and longevity in
      C. elegans.
AB  - The effects of 2-(4-Morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002), an
      inhibitor of mammalian phosphatidylinositol 3-OH kinase, was tested on an insulin
      signaling-like pathway in the nematode Caenorhabditis elegans. Populations of C.
      elegans were treated with LY294002 at different stages of the life cycle, and its
      effects on development, thermotolerance and longevity were assessed. At
      concentrations of 160 microM and above, LY294002 significantly induced both dauer
      formation and thermotolerance. Treatment of adult worms also resulted in a small,
      but significant, increase in life span. The results presented are consistent with
      the view that a neuroendocrine signaling pathway functions in adult worms to
      determine stress resistance and longevity.

PMID- 10638525
TI  - Stress resistance and longevity in selected lines of Drosophila melanogaster.
AB  - Five independent populations (lines) of Drosophila melanogaster were selected for
      female starvation resistance. Females and males from the selected lines were
      relatively starvation resistant when compared to flies from five control lines.
      Moreover, flies from selected lines were resistant to other stresses:
      desiccation, acetone fumes, ethanol fumes, and paraquat (a source of oxygen
      radicals). Data from a variety of previous studies indicate an association
      between stress resistance and longevity. In this context, the present study
      addressed the question of whether flies from the stress-resistant lines were
      relatively long-lived. Replicate population cages from each selected and control
      line were used to assess longevity. Neither females nor males from the selected
      lines were relatively long-lived. In at least some cases, stress resistance may
      be necessary, but not sufficient, for longevity.

PMID- 10638526
TI  - Motorneurons, reactive oxygen, and life span in Drosophila.
AB  - Aging and life span are widely recognized, but poorly understood, aspects of
      basic biology. Fortunately, genetic approaches to understanding the mechanisms
      governing these processes are beginning to bear fruit. One line of investigation
      has established that incompletely reduced forms of oxygen, arising as by-products
      of respiration and cellular catabolism, play an important, and perhaps universal,
      role in aging and life span determination. An important refinement of this model
      of aging, suggested by recent experiments in our laboratory, is that the critical
      nexus of the relationship between reactive oxygen species and life span is highly
      localized and, in fact, may reside principally in the motorneuron. Here we
      analyze the strengths and weaknesses of the reactive oxygen species/motorneuron
      model of aging by comparing the studies on which it is based, which used the
      approach of targeted transgene expression in Drosophila, with studies from other
      laboratories using different genetic approaches, principally mutation and
      selection. The results encourage the view that an understanding of the mechanisms
      that underlie this widely recognized aspect of basic biology is within our grasp.

PMID- 10638527
TI  - CuZn-SOD promoter-driven expression in the Drosophila central nervous system.
AB  - The aim of this study was to ascertain the status of CuZn superoxide dismutase
      (CuZn-SOD) expression in the central nervous system of Drosophila melanogaster.
      Immunoblot analysis of dissected tissue extracts revealed low levels of the CuZn
      SOD protein in adult brains relative to other adult and larval tissues. To
      explore further this observation, three different reporter constructs containing
      different elements of the CuZn-SOD promoter domain were used for the generation
      of transgenic flies. A high level of reporter gene expression occurred during the
      second wave of neurogenesis (third instar and early pupal stages) in scattered,
      proliferating neuroblasts (NBs) and in proliferation centers of the optic lobe.
      In mature, postmitotic neurons, this expression was lower relative to other
      tissues. In adult flies, at all ages examined, there was little if any detectable
      reporter gene expression in cells of the central nervous system. These results
      suggest that one of the key components of the antioxidant defenses, CuZn-SOD, is
      quite low in postmitotic neural tissue, rendering it particularly susceptible to
      oxidative damage during aging.

PMID- 10638528
TI  - Sequence requirements for upregulated expression of Drosophila hsp70 transgenes
      during aging.
AB  - hsp70 protein and hsp70:lacZ fusion reporters are upregulated during aging and in
      response to oxidative stress in the thorax of Drosophila. hsp70 expression was
      increased during aging in each of seven different Drosophila genetic backgrounds
      tested, 2.6-4.8-fold. DNA sequence requirements were investigated by analysis of
      nine distinct hsp70:lacZ fusion reporter constructs in multiple independent
      transgenic lines. hsp70 sequences -194 to +276 supported an average 2.7-fold
      increase during aging. This increase was reduced or eliminated by deletion or
      point mutation of the heat shock response elements, consistent with a
      transcriptional mechanism. Similar sequence requirements were observed for
      increased expression in response to catalase null mutation as a model of
      oxidative stress. hsp70 5'UTR sequences were required for efficient basal
      expression of transgenes, but were not sufficient to confer detectable
      upregulation during aging. Inclusion of additional hsp70 coding region sequences
      from +276 to + 1011 created a larger hsp70:lacZ fusion protein and had two
      effects: dramatic reduction of the overall expression level of the fusion
      protein, and an additional three to fourfold upregulation during aging. These
      results suggest that the coding region sequences reduce fusion protein abundance
      and that this negative effect decreases as a function of age. The data support a
      model for increased expression of hsp70 transgenes during aging involving both
      transcriptional and posttranscriptional components.

PMID- 10638529
TI  - AlphaMUPA mice: a transgenic model for increased life span.
AB  - AlphaMUPA is a line of transgenic mice that, compared with their wild type (WT)
      counterparts, spontaneously eat less (approximately 20%) and live longer (average
      approximately 20%), thus resembling dietary-restricted (DR) mice. Here, we show
      that body temperature was significantly reduced in alphaMUPA compared with WT
      throughout a wide range of ages. Plasma corticosterone was significantly higher
      in young alphaMUPA compared to young WT; however, it significantly declined in
      aged alphaMUPA, but not in aged WT. In addition, age-associated thymus involution
      occurred in alphaMUPA as it did in WT. Thus alphaMUPA mice appear to largely
      resemble, but also to somewhat differ from diet-restricted animals. We also
      report on four new transgenic lines that, like alphaMUPA, produced in the brain
      the mRNA that encodes the extracellular protease urokinase (uPA); however,
      transgenic uPA expression was most extensive and widespread in the alphaMUPA
      brain, where it also occurred in the hypothalamus. AlphaMUPA was also the only
      line that ate less, but also showed another characteristic, high frequency leg
      muscle tremor seen only at unstable body states. We hypothesize that transgenic
      uPA in the brain could have caused the alphaMUPA phenotypic alterations. Thus
      alphaMUPA offers a unique transgenic model of inherently reduced eating to
      investigate the homeostatic state of delayed aging at the systemic and single
      cell levels.

PMID- 10638530
TI  - Mitochondrial DNA rearrangements in aging human brain and in situ PCR of mtDNA.
AB  - Deletions of the mitochondrial DNA (mtDNA) have been shown to accumulate with age
      in a variety of species regardless of mean or maximal life span. This implies
      that such mutations are either a molecular biomarker of senescence or that they
      are more causally linked to senescence itself. One assay that can be used to
      detect these mtDNA mutations is the long-extension polymerase chain reaction
      assay. This assay amplifies approximately 16 kb of the mtDNA in mammalian
      mitochondria and preferentially amplifies mtDNAs that are either deleted or
      duplicated. We have applied this assay to the aging human brain and found a
      heterogeneous array of rearranged mtDNAs. In addition, we have developed in situ
      polymerase chain reaction to detect mtDNA within individual cells of both the
      mouse and the human brain as a first step in identifying and enumerating cells
      containing mutant mtDNAs in situ.

PMID- 10638531
TI  - Evaluation of an Internet-based decision-support system for applying the ATS/CDC
      guidelines for tuberculosis preventive therapy.
AB  - Preventive therapy for patients infected with tuberculosis (TB) remains an
      important component of TB control. To guide physicians in applying preventive
      therapy, the American Thoracic Society and Centers for Disease Control (ATS/CDC)
      developed guidelines based on PPD reactivity and on pretest probability of
      infection. The guidelines have become complex, and many clinicians find them
      challenging to apply. The authors developed a computerized decision-support
      system to assist clinicians in applying the ATS/CDC guidelines. This tool,
      published on the World Wide Web using hypertext markup language, delivers patient
      specific recommendations based on physician-delivered patient-specific
      information. Four local TB experts derived eight TB infection scenarios and
      validated the web-based tool, which was tested for effectiveness using general
      internal medicine residents, randomly divided into two groups. Group A (n = 12)
      used the web-based tool and group B (n = 17) used pre-existing understanding of
      the guidelines and/or written resources to determine the need for preventive
      therapy in the case scenarios. Group A correctly used therapy in 92/96 possible
      cases (95.8%), group B in only 77/136 (56.6%) (p < 0.001). Group A required a
      mean of three mouse-clicks and 1.5 minutes per scenario to reach their choices,
      and they rated the web-based tool both intuitive and effective. These data
      demonstrate that a computer-based decision-support system for applying TB
      treatment guidelines can be delivered over the Internet and provide an efficient
      and effective resource for clinicians.

PMID- 10638532
TI  - What questions do patients with curable prostate cancer want answered?
AB  - PURPOSE: To determine the questions that recently diagnosed early-stage prostate
      cancer patients think should be addressed with patients like themselves. STUDY
      POPULATION: 56 patients diagnosed as having early-stage prostate cancer within
      the previous year. METHODS: Surveys distributed to the patients included 93
      questions that might be considered important. Respondents judged the importance
      (essential/desired/no opinion/avoid) of addressing each question, and indicated
      why those "essential" or "desired" were important. RESULTS: 38 patients (68%)
      responded. Agreement on question importance, overall, was rather poor (mean
      41.6%, kappa 0.17). There were, however, 20 questions that at least 67% of the
      respondents agreed were essential to address and 12 that they agreed were not
      essential. No question was relevant to the treatment decisions of more than 50%
      of respondents, but 91 questions were relevant to at least one respondent's
      decision. CONCLUSIONS: Although there was enough agreement to define a core set
      of questions that should be addressed with most patients, each of the remaining
      questions was also considered essential to some people. The core set, therefore,
      would not be adequate to satisfy any one patient's essential information needs.
      Whereas most questions would be needed to cover all patients' decision needs,
      only some are needed for any given patient. Such variability in information needs
      means that the subjective standard is the only viable legal standard for judging
      the adequacy of provision of information for the treatment decision.

PMID- 10638533
TI  - Decision analyses for prophylactic replacement of the Bjork-Shiley convexo
      concave heart valve: an evaluation of assumptions and estimates.
AB  - Bjork-Shiley convexo-concave (BScc) mechanical heart valves have a risk of outlet
      strut fracture. Decision-analytic models may support decision making regarding
      prophylactic replacement to avert the disastrous consequences of fracture.
      Assumptions and estimates from previous analyses were evaluated to develop an
      accurate new decision model, incorporating updated follow-up experience from
      2,263 patients with BScc valves implanted between 1979 and 1985 in The
      Netherlands. The authors focus on estimation of fracture risks (50 events) and
      survival (883 deaths, excluding fractures). In previous analyses, fracture risk
      was estimated with widely varying combinations of patient, valve, and production
      characteristics. Two analyses assumed a constant fracture hazard during follow
      up, while data from the present study suggest that risk decreases with increasing
      age during follow-up. An additive excess-risk model was applied in two analyses
      to estimate survival. The assumption of a constant additive excess risk was not
      supported by the Dutch data, which suggest that the life expectancies of patients
      currently alive with BScc valves may be shorter than previously believed. Based
      on the revised decision model, over 90% of the currently alive Dutch BScc valve
      patients do not benefit from replacement, since the fracture risk causes only a
      minor reduction of remaining life expectancy. The variation in essential
      assumptions of previous decision analyses directly affected the indication for
      prophylactic replacement. This study shows how detailed statistical analyses may
      guide modeling choices in a decision analysis.

PMID- 10638534
TI  - Does clinical error contribute to unnecessary antibiotic use?
AB  - Patient expectations and physician attitudes are often cited as factors in the
      overuse of antibiotics. This study examined whether clinical error might also be
      important. In treating 517 patients with sore throat, family physicians estimated
      the probability that group A streptococcus infection was present. Two thirds of
      antibiotics prescribed were to culture-negative patients and therefore considered
      unnecessary. Physicians overestimated the probability that a group A
      streptococcal infection was present by an average 33.2% in these cases, compared
      with 6.9% otherwise (p < 0.001). The rate of unnecessary prescribing was 5.1%
      when the physician estimate differed from the true probability of a group A
      streptococcal infection by <10%, 16.0% for an error of 10-29%, 35.6% for an error
      of 30-49%, and 78.3% when the chance of the infection was overestimated by 50% or
      more. Clinical error in estimating the likelihood of group A streptococcal
      infection probably contributes to unnecessary antibiotic use in patients with
      sore throat.

PMID- 10638535
TI  - Further explorations of medical decisions for individuals and for groups.
AB  - BACKGROUND: Important discrepancies between clinical practice and health policy
      may be related to the ways in which physicians and others make decisions about
      individuals and groups. Previous research has found that physicians and
      laypersons asked to consider an individual patient generally make different
      decisions than those asked to consider a group of comparable patients, but this
      discrepancy has not been observed in more recent studies. This study was designed
      to explore possible reasons for these findings. METHODS: Prospective jurors (N =
      1,013) each made a recommendation regarding a risky treatment for an incurable
      blood condition. Perspective (individual vs group) was crossed with uncertainty
      frame (probability vs frequency) and response wording (original vs revised) in a
      2 x 2 x 2 between-participants design. RESULTS: When the strength of
      participants' recommendations was considered, the effects of perspective,
      uncertainty frame, and response wording were not statistically significant. When
      recommendations were dichotomized, participants in the revised-response-wording
      conditions were more likely to recommend treatment to the group than to the
      individual. CONCLUSIONS: These results conflict with previous findings for this
      scenario and suggest that reported differences between decisions for individuals
      and decisions for groups are not robust.

PMID- 10638536
TI  - Decision making of clinical teams: communication patterns and diagnostic error.
AB  - This study examined the discussion of information among mixed-status clinical
      teams while constructing differential diagnoses. Twenty-four ad hoc teams, each
      consisting of a resident, an intern, and a third-year medical student, were given
      two hypothetical patient cases to discuss and diagnose. Prior to discussion, team
      members individually viewed different versions of a videotaped interview with a
      "patient" (trained actor). Each videotape contained some information that was
      present in all three versions (shared information) and some that was present in
      only that version (unique information). In addition, half of the time, the cases
      were constructed so that the unique information that appeared in only one tape
      was crucial for a correct diagnosis (a "hidden profile" condition). After viewing
      the videotapes, team members met to discuss the case and develop a differential
      diagnosis. Discussions were videotaped and analyzed. Overall, shared information
      was mentioned more often than unique information (p < 0.0001). Furthermore, teams
      offered incorrect diagnoses significantly more often for hidden-profile cases
      than for control cases (p < 0.01). The teams' overreliance on previously shared
      information (inability to appropriately utilize unique information) was
      detrimental when a correct diagnosis demanded the inclusion of such information.
      Clinical discussions that require the consideration of uniquely held information
      may be susceptible to error.

PMID- 10638537
TI  - Measuring post-decision satisfaction.
AB  - Measuring satisfaction with a decision after a choice has been made is
      particularly important for difficult choice situations where there is no "right"
      decision and/or where long-term consequences are uncertain. While others have
      developed instruments that primarily focus on clinical decisions, the authors
      developed a scale-the decision-attitude scale-in the context of consumers' choice
      of health plan. They examined the reliability and validity of this scale using
      data from a sample of state employees. While the decision-attitude scale has been
      applied to a health-plan-choice problem only, it can be applied to a variety of
      other health-related decision problems, because it shares a core set of items
      with the existing Satisfaction with Decision Scale. The authors identify and
      discuss the similarities and differences between the two scales. They also
      observe that each scale uncovers an additional construct not addressed by the
      other, suggesting that the concept of post-decision satisfaction is
      multidimensional. A new instrument combining items from both scales may prove the
      best measure of decision satisfaction for a variety of health-related decision
      problems.

PMID- 10638538
TI  - Unstable preferences: a shift in valuation or an effect of the elicitation
      procedure?
AB  - OBJECTIVE: Many studies suggest that impaired health states are valued more
      positively when experienced than when hypothetical. This study investigated to
      what extent this discrepancy occurs and examined four possible explanations: non
      corresponding description of the hypothetical health state, new understanding due
      to experience with the health state, valuation shift due to a new status quo, and
      instability of preference. PATIENTS AND METHODS: Fifty-five breast cancer
      patients evaluated their actually experienced health state, a radiotherapy
      scenario, and a chemotherapy control scenario before, during, and after
      postoperative radiotherapy. Utilities were elicited by means of a visual analog
      scale (VAS), a chained time tradeoff (TTO), and a chained standard gamble (SG).
      RESULTS: The discrepancy was found for all methods and was statistically
      significant for the TTO (predicted utilities: 0.89, actual utilities: 0.92, p <
      or = 0.05). During radiotherapy, significant differences (p < or = 0.01) were
      found between the utilities for the radiotherapy scenario and the actual health
      state by means of the VAS and the SG, suggesting non-corresponding description as
      an explanation. The utilities of the radiotherapy scenario and the chemotherapy
      control scenario remained stable over time, and thus new understanding, valuation
      shift, and instability could be ruled out as explanations. CONCLUSION: Utilities
      obtained through hypothetical scenarios may not be valid predictors of the value
      judgments of actually experienced health states. The discrepancy in this study
      seems to have been due to differences between the situations in question (non
      corresponding descriptions).

PMID- 10638539
TI  - Can the standard gamble be used to determine utilities for uncertain health
      states? An example using postoperative maintenance therapy in Crohn's disease.
AB  - The objective of this study was to determine whether patients with Crohn's
      disease (CD) value the absolute reduction in postoperative recurrence risk
      attributable to therapy with mesalamine (5-ASA). One hundred subjects evaluated
      state A (taking 5-ASA; 25% risk of recurrence), state B (not taking 5-ASA; 40%
      risk of recurrence), and state C (100% risk of recurrence) by rank order, visual
      analog scale (VAS), and standard gamble (SG). Sixty-five of 91 patients (71%)
      with completed and usable questionnaires had the same preference order for state
      A (25% risk), state B (40% risk), and state C (100% risk) on both the VAS and the
      SG. The mean scores for state A (25% risk), state B (40% risk), and state C (100%
      risk), respectively, were 67.5, 49.8, and 19.8 on the VAS and 0.977, 0.972, and
      0.910 on the SG. Subgroup analyses using stepwise logistic regression showed that
      risk attitude seemed to be predictive of subjects' preferences for 5-ASA. These
      results suggest that most subjects seem to value the 15% absolute risk reduction
      offered by 5-ASA. Furthermore, the SG seems to be a feasible method for measuring
      utilities for uncertain health states in patients with CD.

PMID- 10638540
TI  - A time-tradeoff method for cost-effectiveness models applied to radiology.
AB  - PURPOSE: The wait tradeoff (WTO) is a simple time-tradeoff method designed for
      temporary health states that uses a realistic and intuitive interface for the
      patient/subject. This method was tested by assessing patients' preferences for
      magnetic resonance angiography (MRA) versus x-ray angiography (XRA). MATERIALS
      AND METHODS: The WTO was tested by telephone interview in 38 patients with
      atherosclerotic peripheral vascular disease, all having previously undergone both
      MRA and XRA. At indifference point, patients were ambivalent about having MRA or
      XRA and immediate treatment, versus having a waiting period for test results and
      treatment after a hypothetical "ideal test" that entailed no pain or risk.
      RESULTS: The patients were willing to wait a mean of 42.1 days after the ideal
      test for results and treatment, as opposed to XRA. They were willing to wait only
      16.1 days as opposed to MRA. This difference in waiting times was significant (p
      = 0.0001) and indicates a clear preference for MRA, in agreement with known
      literature. CONCLUSION: The WTO method assesses preferences for these radiologic
      tests in an intuitive fashion that does not invoke artificial or irrelevant
      health states. This approach may also prove useful for other testing situations
      or short-term treatments being evaluated for cost-effectiveness.

PMID- 10638541
TI  - How HIV treatment advances affect the cost-effectiveness of prevention.
AB  - OBJECTIVE: The cost-effectiveness of an HIV prevention program depends, in part,
      on its potential to avert HIV-related medical care costs. Recent advances in
      antiretroviral therapy have made HIV/AIDS treatment both more effective and more
      costly, which might make HIV prevention either more or less cost-effective. The
      objective of the present study was to explicate the relationship between the
      effectiveness and costs of HIV treatment and the cost-effectiveness of HIV
      prevention programs. METHODS: A basic analytic framework was used to compare the
      cost-effectiveness of HIV prevention interventions with respect to different
      HIV/AIDS medical care scenarios. Algebra was used to calculate a cost
      effectiveness threshold that distinguishes prevention programs that become more
      cost-effective when therapeutic advances simultaneously increase or decrease the
      cost and effectiveness of treatment from those that become less cost-effective.
      Recent estimates of the costs and consequences of combination antiretroviral
      therapy were used to illustrate the calculation method. RESULTS: The advent of
      combination antiretroviral therapies for HIV has increased the cost-effectiveness
      of some, but not all, HIV prevention interventions. CONCLUSIONS: Whether a
      particular prevention program becomes more or less cost-effective as a
      consequence of advancements in the medical treatment of HIV/AIDS depends upon the
      specific characteristics of both the program and the therapy.

PMID- 10638542
TI  - Improved statistical classification methods in computerized psychiatric
      diagnosis.
AB  - BACKGROUND: Mainstream psychiatric diagnosis involves mainly sequential, expert
      system-derived, logical decision rules. Among the few statistical classification
      methods that have been sporadically evaluated are Bayes, k-nearest neighbor, and
      discriminant analysis classifiers. METHODS: A statistical classification method
      based on artificial neural networks (ANN) with task-specific constrained
      architectures was applied to a sample of 796 clinical interviews, where the
      symptom evaluation and the diagnostic judgments were made using the Psychiatric
      State Examination (PSE) system. The proposed constrained ANN (CANN) method was
      compared with other statistical classification methods. RESULTS: CANN was found
      to be superior to all other considered methods, having an overall "correct"
      classification rate of 80% when applied to test data. Similarly, the concordance
      coefficients of agreement with the PSE diagnostic categories were all very high.
      Among the other used methods, discriminant analysis had slightly inferior
      performance but better generalization capability. CONCLUSIONS: The proposed CANN
      method has a definite utility in psychiatric diagnosis and requires further
      evaluation, perhaps alongside other standard classification systems and/or with
      larger samples.

PMID- 10638543
TI  - An assessment of methods to combine published survival curves.
AB  - PURPOSE: To assess the accuracies of different techniques for combining published
      survival curves, for use in disease modeling applications. METHODS: Five methods
      were identified: 1) iterative generalized least-squares (IGLS), 2) meta-analysis
      of failure-time data with adjustment for covariates (MFD), 3) nonlinear
      regression (NLR), 4) log relative risk (LRR), and 5) weighted LRR (w-LRR). Each
      method was used to combine the survival curves from eight single-arm Phase II
      trials of chemotherapy in 918 patients with advanced non-small-cell lung cancer
      (NSCLC). The resulting summary curves were compared with the curve calculated
      from the corresponding individual patient data (IPD). RESULTS: All methods were
      able to produce accurate summary survival curves statistically similar to the IPD
      derived curve. Maximum discrepancies ranged from 1.8% to 4.7%. MFD appeared to be
      the most accurate when censoring information was complete. Characteristics of the
      component trials that adversely affected the accuracies of the different
      techniques were 1) a high proportion of censored observations (MFD); 2)
      variability in the length of follow-up (IGLS, NLR, LRR, w-LRR); and 3) the
      heterogeneity of the treatment results (NLR, w-LRR). CONCLUSIONS: All methods
      were able to accurately reproduce summary survival curves from the published
      literature. The best method depends on characteristics of the data and the
      purpose of the analysis.

PMID- 10638544
TI  - Feasibility and effects of decision aids.
AB  - Decision aids for patients have recently been introduced in health care. A
      literature review was conducted to address the following research questions: 1)
      which types of decision aids have been developed?; 2) to what extent are they
      feasible, and acceptable to patients and health care providers?; 3) do decision
      aids affect the decision-making process and patients' outcomes? Thirty non
      controlled (e.g., one-group-only designs) and controlled studies (e.g.,
      randomized experimental designs) were identified. Decision aids were found to be
      feasible and acceptable to patients and to increase the agreement between
      patients' values and decisions and patients' knowledge. The effects of decision
      aids on decisions and on patients' outcomes, including decision uncertainty,
      satisfaction, and health, have rarely been addressed. When studied, the
      beneficial effects of decision aids on these outcomes appear to be rather modest.
      Implications for future development of decision aids and the design of studies
      are discussed.

PMID- 10638545
TI  - Clinical decision-support systems: evaluating the evaluation.

PMID- 10638546
TI  - Information disclosure and beyond: how do patients understand and use the
      information they report they want?

PMID- 10638547
TI  - Uncertainty in decision models analyzing cost-effectiveness.

PMID- 10638548
TI  - Law and ethics.

PMID- 10638549
TI  - Judgmental psychology.

PMID- 10638550
TI  - Thar's gold in your patient's NG! Hold the scalpel, hold the endoscope, hold the
      trochars.

PMID- 10638551
TI  - Mortality with percutaneous endoscopic gastrostomy.

PMID- 10638552
TI  - An overview of special considerations in the evaluation and management of the
      geriatric patient.
AB  - As the population ages, physicians will care for increasing numbers of older
      patients. Promoting independence is a major goal of care. Gastrointestinal
      dysfunction is often caused by chronic disease, medications, and lifestyle
      exposures, rather than to age alone. A useful approach to the older patient
      focuses on maintaining function and avoiding complications.

PMID- 10638553
TI  - Gender role and irritable bowel syndrome: literature review and hypothesis.
AB  - Studies examining the prevalence of irritable bowel syndrome (IBS) consistently
      show that women outnumber men in both patient and nonpatient populations.
      However, because IBS does affect both women and men, it is important to examine
      and to understand gender similarities and differences in the expression of this
      complex disorder. Studies that have explored gender differences have focused
      their investigations on prevalence and health seeking behavior, physical and
      psychological symptomotology, and abuse history. This article reviews and
      summarizes the findings from those studies. As well, whereas the literature
      examining differences between men and women with IBS has focused on distinctions
      based on the biological sex of study participants, this article offers an
      alternate approach to the exploration of gender differences. The concept of
      gender role, defined as generalizations about appropriate male and female traits
      that are associated with masculinity and femininity, may further our
      understanding of IBS in both women and men.

PMID- 10638554
TI  - A multispecialty approach to the diagnosis and management of pancreatic cancer.
AB  - This article reviews recent developments in pancreatic cancer research and offers
      a multispecialty perspective on the diagnosis and management of this challenging
      disease. Current findings in the molecular biology of the disease and their
      implications for management are examined, as well as development in diagnostic
      techniques, including helical computed tomography (CT), magnetic resonance
      imaging (MRI), magnetic resonance cholangio-pancreatography (MRCP), and,
      particularly, endoscopic ultrasound-guided fine-needle aspiration. Surgical
      management, the role of adjuvant/neoadjuvant chemoradiation therapy, and the
      critical importance of accurate preoperative imaging are also addressed in this
      review. Palliative techniques, including endoscopic stenting for malignant
      obstructive jaundice and chemotherapy for locally advanced and metastatic
      disease, are discussed, and results of recent clinical trials in pancreatic
      cancer are summarized. Finally, future directions for research are identified.

PMID- 10638555
TI  - Congenital esophageal stenosis in adults.
AB  - OBJECTIVE: Congenital esophageal stenosis is thought to be a rare disease
      confined to infancy and childhood with only a few case reports in adults
      described. METHODS: We report five patients between the ages of 19 and 46 yr who
      presented with this disorder over a 2-yr period. RESULTS: Patients had been
      labeled with reflux strictures, webs, or as idiopathic in the past. All patients
      had chronic solid food dysphagia, some since early childhood. The location of the
      stricture varied, occurring in the mid or proximal esophagus in four, but
      throughout the esophagus in one. Radiographic and endoscopic appearance was a
      smooth concentric stricture or multiple rings, sometimes tracheal in appearance.
      Endosonography was performed in two patients, both of whom had focal
      circumferential hypoechoic wall thickening with disruption of the normal layer
      pattern corresponding to the areas of luminal narrowing. All patients dilated had
      good symptomatic response, with resolution of symptoms up to 6 months in follow
      up. CONCLUSIONS: We suggest that congenital esophageal stenosis does occur in
      adults and may be underrecognized. Its endosonographic appearance is described.

PMID- 10638556
TI  - Proximal migration of esophageal acid perfusions during waking and sleep.
AB  - OBJECTIVE: Proximal acid migration resulting from gastroesophageal reflux has
      been implicated in aerodigestive complaints and disorders. This study was
      designed to investigate the effects of acid volume, posture, and sleep on
      proximal esophageal acid migration (drop in pH to <4.0). METHODS: The study was
      performed in 15 healthy adults. A distal esophageal acid perfusion technique to
      simulate gastroesophageal reflux was used. Esophageal acid perfusions of 1 ml and
      3 ml were accomplished at a site 5 cm above the proximal border of the lower
      esophageal sphincter in the upright and supine positions during waking, and
      during polysomnographically monitored sleep. Esophageal pH was recorded by two
      sensors located in the mid- and proximal esophagus at 10 and 15 cm above the
      lower esophageal sphincter. RESULTS: Acid volume clearly increased the incidence
      of migration to the mid and proximal sensors during both waking and sleep, and
      also significantly increased acid clearance time. Posture failed to significantly
      affect the incidence of acid migration and acid clearance. Sleep clearly enhanced
      migration to the proximal pH sensor of even those perfusions as small as 1 ml.
      For instance, 40% of 1 ml perfusions during sleep migrated to the proximal sensor
      compared with <1% during waking. Acid clearance times were significantly longer
      during sleep as measured by the mid- and proximal esophageal pH sensors.
      CONCLUSIONS: In healthy individuals, volume enhances the likelihood of migration
      to both mid- and proximal esophagus, and significantly prolongs clearance time in
      the waking state. Posture appears to be a less significant parameter with regard
      to both the incidence of acid migration and acid clearance. Sleep is a
      significant risk factor for acid migration to the proximal esophagus for even
      minute volumes, and markedly prolongs acid clearance.

PMID- 10638557
TI  - Clinical and manometric features of the lower esophageal muscular ring.
AB  - OBJECTIVE: In contrast to the well-recognized Schatzki's ring, the lower
      esophageal muscular ring remains a poorly defined entity. The purpose of this
      study is to report on the clinical features of three patients with lower
      esophageal muscular rings and review the literature on this disorder, to better
      understand its importance as a cause of dysphagia. METHODS: Three patients
      presenting to the West Roxbury VA Medical Center were identified as having a
      contractile, focal narrowing in the distal esophagus by upper GI series. Clinical
      histories were obtained and endoscopic and manometric evaluations were performed.
      RESULTS: The three patients had symptoms consisting of chronic, intermittent
      dysphagia for both liquids and solids. The results of barium swallows and upper
      endoscopic examinations were similar and revealed a focal, thick constriction of
      variable luminal diameter located a few centimeters above the squamocolumnar
      junction. Esophageal motility testing revealed peristaltic, high-amplitude, long
      duration, and multiple peaked contractions. Lower esophageal sphincter function
      was normal. The patients derived partial or only temporary relief of dysphagia
      with esophageal dilation with rigid dilators. All three patients had significant
      symptomatic responses to anticholinergic agents. CONCLUSIONS: Lower esophageal
      muscular rings are an uncommon but important cause of dysphagia. Significant
      esophageal motility abnormalities can be found in symptomatic patients.
      Distinguishing the lower esophageal muscular ring from the Schatzki's ring is
      important because of differences in the treatment and outcome of the two
      conditions.

PMID- 10638558
TI  - The long-term reinfection rate and the course of duodenal ulcer disease after
      eradication of Helicobacter pylori in a developing country.
AB  - OBJECTIVE: The aim of this study was to evaluate the effect of Helicobacter
      pylori (H. pylori) eradication on the natural history of duodenal ulcer disease
      and the reinfection rate after treatment in a developing country. METHODS: A
      total of 111 H. pylori-infected patients with duodenal ulcer were treated with
      either omeprazole or famotidine plus two antibiotics for 2 wk. Those failed to
      respond to treatment were retreated with bismuth-based triple therapy. RESULTS:
      The radication rate was 76% (95% CI: 67-83%). Eventually, H. pylori was
      eradicated in 96 of the 111 patients (86%), who were followed-up clinically and
      endoscopically for a mean of 37.2 months. The cumulative reinfection rate after
      eradication (Kaplan-Meier) was 8%+/-3% in yr 1, 11%+/-4% in yr 2, and 13%+/-4% in
      yr 3. Nine of the 12 reinfections occurred during yr 1. Recurrence of duodenal
      ulcer was detected in five patients (5.2%), all of them during yr 1 of follow-up.
      Histologically, gastritis scores (according to the Sydney system) improved
      significantly after eradication. CONCLUSIONS: In a high prevalence setting, H.
      pylori eradication and early reinfection rates after treatment are similar to
      rates observed in a low prevalence environment, whereas the late reinfection rate
      seems to be higher. However, up to 3 yr after treatment, most treated patients
      are free of H. pylori infection and/or ulcer activity. Even longer follow-up
      studies are necessary to determine whether specific retreatment policies are
      necessary to maintain long term eradication in developing countries.

PMID- 10638559
TI  - Twenty-four-hour intragastric pH: tolerance within 5 days of continuous
      ranitidine administration.
AB  - OBJECTIVE: To investigate further the phenomenon of pharmacological tolerance to
      H2-receptor antagonists, we undertook a study of the antisecretory effect of
      ranitidine with continuous daily administration. METHODS: A total of 28 healthy
      male volunteers were given ranitidine 150 mg q.i.d. for 5 days. Twenty-four-hour
      intragastric pH monitoring was performed predosing and on days 1 and 5 of
      ranitidine administration. Serial blood samples were collected on days 1 and 5 of
      ranitidine administration for pharmacokinetics. RESULTS: Mean 24-h intragastric
      pH was 2.62 predosing, 4.22 on day 1 of ranitidine administration and 3.28 on day
      5 (p = 0.001, ranitidine day 1 vs. day 5). Intragastric pH was >3, 4, and 5 for
      69.9%, 54.3%, and 35.9%, respectively, on day 1 of ranitidine administration and
      was 45.8%, 30.1%, and 20.8% on day 5 (p<0.005 for each comparison). Subjects'
      Helicobacter pylori status did not affect the antisecretory effect of ranitidine.
      There was no alteration in ranitidine pharmacokinetics to account for its reduced
      antisecretory effect. CONCLUSION: This study has demonstrated a statistically
      significant reduction in the antisecretory effect of ranitidine within 5 days of
      continuous administration which is not explained by altered ranitidine
      pharmacokinetics. This is further evidence for the development of a form of
      pharmacological tolerance to an H2-receptor antagonist within a few days of
      continuous daily dosing.

PMID- 10638560
TI  - Pantoprazole versus ranitidine in the treatment of duodenal ulcer: a multicenter
      study in Brazil.
AB  - OBJECTIVE: The aim of this study was to compare the effectiveness and tolerance
      of pantoprazole versus ranitidine in the treatment of duodenal ulcers in the
      Brazilian population. METHODS: A total of 222 patients with active duodenal
      ulcers (DU) were randomly allocated to a double dummy blind treatment, either
      with ranitidine (RAN) 300 mg (111, aged from 20-68 yr old, 56 female) or with
      pantoprazole (PANT) 40 mg (111 patients, 18-70 yr old, 45 female). After a 2-wk
      course of treatment, each patient was clinically and endoscopically assessed for
      ulcer healing. Failure to heal required a further 2-wk course of treatment and a
      new evaluation thereafter. RESULTS: In all, 77 of the 103 patients in the PANT
      group (74.8%) and 42 of the 94 patients in the RAN group (44.7%) who completed
      the study had ulcer healing after one 2-wk treatment course, and an additional 23
      in the PANT group (22.3%) and 28 in the RAN group (29.8%) after the second 2-wk
      treatment course, totaling 100 (97.1%) and 70 (74.5%), respectively. Therapeutic
      gain in favor of pantoprazole was significant both at the end of the first and
      the second 2-wk treatment course (p<0.001). At 2 wk, symptoms remission was
      significantly higher in the PANT group (97.6%) than with the RAN group (77.5%)
      (p<0.001). The Intention-to-treat analysis showed results statistically similar
      to those observed in the per-protocol analysis. Minor adverse events were
      reported by four patients in the PANT group and three in the RAN group. No
      relevant laboratory abnormalities were seen. No patient withdrew from the study
      due to adverse events. CONCLUSIONS: Our results show that pantoprazole is more
      effective than ranitidine in the treatment of duodenal ulcer providing faster
      ulcer healing in most patients (97.1%), in 4 wk. Adverse events were rare and
      were similar in both groups, and had no influence on the therapeutic outcome.

PMID- 10638561
TI  - The impact of functional gastrointestinal disorders on quality of life.
AB  - OBJECTIVE: The impact of functional gastrointestinal disorders (FGIDs) on quality
      of life is unknown. We aimed to evaluate whether FGIDs impair quality of life in
      terms of mental and physical functioning in patients and nonpatients. METHODS: A
      random sample of 4500 subjects, representative of the Australian population, were
      mailed a questionnaire on gastrointestinal symptoms in the past 12 months.
      Quality of life was assessed using the valid SF-12, in which the lower the
      scores, the greater the impairment of quality of life. The response rate was 72%.
      RESULTS: Among those fulfilling Rome I criteria for a diagnosis of a FGID (n =
      1006) versus those not having a FGID (n = 1904) (healthy controls), there was a
      significant association with impaired mental (43.9 vs. 48.1) and physical (47.7
      vs. 51.6) functioning. Mental functioning (43.3 vs. 44.9) and physical
      functioning (46.0 vs. 50.5) was significantly more impaired in patients versus
      nonpatients with a FGID. Furthermore, nonpatients with a FGID had more impaired
      mental and physical functioning than healthy controls. CONCLUSION: FGIDs impair
      quality of life, particularly in those that consult for health care.

PMID- 10638562
TI  - Evaluation of rapid antibody tests for the diagnosis of Helicobacter pylori
      infection.
AB  - OBJECTIVE: The aim of this study was to compare the performance characteristics
      of one serum and four whole blood rapid antibody tests for Helicobacter pylori
      infection. METHODS: A total of 97 outpatients referred for endoscopic evaluation
      of dyspepsia were included. Antral biopsies were obtained for histology and rapid
      urease test. Serum was tested with an enzyme-linked immunoassay (HM-CAP) and a
      rapid serology test (FlexSure HP). A commercially available 13C-urea breath test
      was performed. Capillary blood obtained by fingerstick was tested with FlexSure
      HP, QuickVue, Accustat, and StatSimple pylori tests. Sensitivity, specificity,
      and accuracy of each rapid test was calculated relative to a criterion standard
      of histological gastritis and at least two of the four following tests positive:
      identifiable organisms on specially stained slides, rapid urease test, urea
      breath test, or serum immunoassay. RESULTS: A total of 30 patients (31%) were
      infected. The FlexSure HP Serum, and FlexSure HP, QuickVue, Accustat, and
      StatSimple pylori whole blood tests had sensitivities of 90%, 87%, 83%, 76%, and
      90%; specificities of 94%, 90%, 96%, 96%, and 98%, and accuracies of 93%, 88%,
      92%, 87%, and 96%, respectively. Sensitivities were not statistically different.
      StatSimple pylori was more specific than FlexSure HP whole blood (p<0.03), and
      more accurate than FlexSure whole blood (p<0.024) and Accustat (p< 0.01). Serum
      immunoassay was significantly more sensitive (97%) than FlexSure whole blood,
      QuickVue, and Accustat (p<0.01), but its specificity (95%) was not statistically
      different from the rapid tests. CONCLUSION: Rapid antibody testing provides an
      accurate diagnosis of H. pylori infection. In general, these tests are less
      sensitive than, but as specific as, standard serology.

PMID- 10638563
TI  - Standardization of a simplified scintigraphic methodology for the assessment of
      gastric emptying in a multicenter setting.
AB  - OBJECTIVE: Scintigraphy remains the gold standard to study gastric emptying. The
      technique is onerous and normal values vary between centers. Standardized
      protocols, although desirable, are not presently available. We validated a
      simplified scintigraphic protocol in a multicenter setting. METHODS: In 69
      healthy volunteers from seven Canadian institutions, gastric emptying of a
      standard meal (99mTc-labeled beef liver) was assessed by scintigraphy every 10
      min for 1 h, then every 20 min for the next 2 h. Gastric retention was fitted to
      a power exponential model, Prop(t) = (-(kappat)beta) with Prop(t) = proportion of
      retention at time t, either using all 13 time intervals (conventional technique)
      or using measurements at 0, 1, 2, and 3 h (simplified technique). RESULTS: The
      power exponential model yielded identical emptying curves and T 1/2 values with
      both techniques. Gastric emptying was more rapid in men than in women < 35 yr
      (p<0.01) and in younger than in older men (p<0.005). Gastric emptying was slower
      in women from Quebec than in women from Ontario (p<0.04). Gastric retention was
      similar at 1, 2, and 3 h among the seven centers. Gastric emptying of a beef
      liver meal was slower than that of a low fat egg substitute (p<0.03).
      CONCLUSIONS: A simpler scintigraphic approach, using four rather than 13 samples,
      provides results comparable to those of the conventional technique. This simpler
      approach provides an economical, yet accurate, alternative to the techniques
      presently used and is applicable to a multicenter setting.

PMID- 10638564
TI  - H. pylori in the pathogenesis of duodenal ulcer: interaction between duodenal
      acid load, bile, and H. pylori.
AB  - OBJECTIVE: Helicobacter pylori (H. pylori) growth is inhibited by bile yet it can
      grow in the duodenal bulb and cause ulcer disease. The aim of this study was to
      test the effect of bile on H. pylori viability and growth and to determine
      whether acidification of bile reduces its inhibitory activity. METHODS: Fresh
      human bile was collected at laparotomy and tested for inhibitory activity of H.
      pylori using broth dilution assays. Six clinical isolates of H. pylori obtained
      from patients with duodenal ulcer were used for each experiment. The bile was
      diluted from 1:3 to 1:192; its inhibitory effect on H. pylori was tested before
      and after acidification, treatment with cholestyramine, or chloroform. Bile was
      acidified to a pH of 2-6, centrifuged at 8000 rpm for 20 min to remove
      precipitated bile acids, and the supernatant pH readjusted. Controls included BHI
      broth without bile (positive control) and bile that was acidified to pH 2 and
      neutralized without centrifugation. RESULTS: Human bile inhibited H. pylori
      growth in a dose dependent manner. Growth of all strains was supported for all
      strains only at a dilution of 1:192. In contrast, after acidification to pH < or
      =5 and centrifugation to remove precipitated bile acids, all strains grew at a
      bile dilution of 1:12. Neither chloroform extraction of lipids, nor acidification
      without centrifugation removed the inhibitory action of bile. In contrast,
      cholestyramine sequestration of bile acids completely removed all inhibitory
      activity. CONCLUSIONS: The duodenal acid load may be the critical factor to
      explain the ability of H. pylori to colonize the duodenal bulb by precipitating
      glycine-conjugated bile salts. The combination of a high duodenal acid load and
      H. pylori infection is likely the critical event in the pathogenesis of H. pylori
      related duodenal ulcer disease.

PMID- 10638565
TI  - Long-term effects of pyloromyotomy on pyloric motility and gastric emptying in
      humans.
AB  - OBJECTIVE: The aim of this study was to determine the long term effects of
      pyloromyotomy for infantile hypertrophic pyloric stenosis (IHPS) on gastric
      emptying and pyloric motility. METHODS: Concurrent measurements of gastric
      emptying and antropyloroduodenal pressures were performed in six volunteers (aged
      24-26 yr) who had had pyloromyotomy performed in infancy because of IHPS, and in
      six normal subjects. Subjects were studied on 2 days, once sitting and once in
      the left lateral position. Gastric emptying of 300 ml 25% dextrose labeled with
      20 MBq 99mTc sulfur colloid was measured. Antropyloroduodenal motility was
      evaluated with a sleeve/multiple sidehole manometric assembly, which was also
      used to deliver an intraduodenal triglyceride infusion at 1.1 kcal/min for 60
      min, starting 30 min after ingestion of the dextrose. RESULTS: In both body
      positions, gastric emptying and intragastric distribution of the drink did not
      differ between the two groups. In both groups and postures, the amount emptied
      was less during intraduodenal lipid infusion. The number (p<0.01) and amplitude
      (p<0.02) of isolated pyloric pressure waves (IPPWs) was greater in the control
      subjects, whereas basal pyloric pressure was greater in the pyloromyotomy
      subjects (p<0.02). In both groups, the rate of gastric emptying in the sitting
      position was related to the number of IPPWs (r> or =0.40, p<0.05), but not to
      basal pyloric pressure. CONCLUSIONS: These results indicate that, in adults who
      have had pyloromyotomy for IHPS in infancy, patterns of pyloric motility are
      abnormal; pyloric tone is higher, whereas the number and amplitude of phasic
      pyloric pressure waves are less. In contrast, the overall rate of gastric
      emptying of a nutrient liquid meal is normal. These observations are consistent
      with the concept that the stomach has the capacity to compensate for changes in
      pyloric motility to minimize effects on gastric emptying.

PMID- 10638566
TI  - Symptomatic benefit 1-3 years after H. pylori eradication in ulcer patients:
      impact of gastroesophageal reflux disease.
AB  - OBJECTIVES: Eradication of Helicobacter pylori (H. pylori) infection markedly
      reduces the recurrence of duodenal and gastric ulcers. However, there is little
      information regarding its efficacy in resolving dyspeptic symptoms in ulcer
      patients. The primary aim of this study was to assess the effect of eradicating
      H. pylori infection on dyspeptic symptoms in ulcer patients. The secondary aim
      was to identify predictors of symptomatic response to H. pylori eradication.
      METHODS: A total of 97 dyspeptic patients with active duodenal and/or gastric
      ulceration associated with H. pylori infection and unrelated to NSAID use had the
      severity and character of their dyspeptic symptoms measured before and again 1-3
      yr after H. pylori eradication therapy. RESULTS: Pretreatment, the median
      dyspepsia score was 12 (4-16). Posttreatment, 55% of those eradicated of H.
      pylori had resolution of dyspepsia (score <2) compared with 18% of those not
      eradicated of the infection (95% CI for difference, 11-62%). Of the ulcer
      patients 31% had symptoms and/or endoscopic evidence of coexisting
      gastroesophageal reflux disease (GERD) at initial presentation and this
      influenced the symptomatic response to eradication of H. pylori. Of the 22
      patients with heartburn or acid reflux as the predominant presenting symptom, but
      no endoscopic esophagitis, only 27% experienced resolution of dyspepsia after H.
      pylori eradication, compared with 68% of the 59 without those as predominant
      symptoms (95% CI for difference, 18-63%). Only one of the five patients with
      coexisting endoscopic esophagitis at initial presentation experienced resolution
      of dyspepsia after H. pylori eradication. Symptomatic benefit was unrelated to
      time lapsed since the infection was eradicated. Only three of 50 subjects
      developed de novo GERD symptoms after eradication of H. pylori, whereas 21 of 36
      subjects experienced resolution of GERD symptoms after eradication of the
      infection. CONCLUSIONS: A substantial proportion of ulcer patients have symptoms
      and/or signs of coexisting GERD at initial presentation and this reduces the
      symptomatic benefit from H. pylori eradication. However, we have found no
      evidence that eradicating H. pylori induces de novo GERD symptoms in ulcer
      patients.

PMID- 10638567
TI  - The quality of care for Medicare patients with peptic ulcer disease.
AB  - OBJECTIVE: The aim of this study was to examine quality of care for hospitalized
      Medicare beneficiaries with peptic ulcer disease. METHODS: Collaborating with
      five Peer Review Organizations, we used 1995 Medicare claim files to select
      samples of inpatients with a principal diagnosis of peptic ulcer disease. Quality
      of care indicators developed by content experts included percentages for ulcer
      patients tested for Helicobacter pylori (H. pylori); biopsied patients who
      received tissue tests; H. pylori-positive patients who received appropriate
      therapy; and ulcer patients screened for preadmission nonsteroidal anti
      inflammatory drug (NSAID) use and counseled about risks. RESULTS: Of 2,644
      patients eligible for medical record review, 56% were tested for H. pylori, and
      73% of those testing positive were treated appropriately; 84% of patients with
      endoscopic biopsies received a tissue test for H. pylori; 74% of patients were
      screened for preadmission NSAID use, 24% had documented counseling of NSAID use,
      and only 2% had documented counseling on the ulcer risk of NSAID use.
      Statistically significant regional variation occurred in four of six quality
      indicators. Outpatient records were reviewed for 529 patients to document prior
      outpatient H. pylori in this population; only 2% (n = 12) were tested for H.
      pylori in the year before admission. CONCLUSIONS: Opportunities exist to improve
      quality of care by testing for and treating H. pylori in hospitalized Medicare
      beneficiaries with peptic ulcer disease and to improve screening for NSAIDs and
      counseling on ulcer risks.

PMID- 10638568
TI  - Antral-type mucosa in the gastric incisura, body, and fundus (antralization): a
      link between Helicobacter pylori infection and intestinal metaplasia?
AB  - OBJECTIVES: Helicobacter pylori is a carcinogen; gastric carcinoma involves a
      multistep process from chronic gastritis to atrophy, intestinal metaplasia, and
      dysplasia. The aims of this study were to determine the types of mucosa at
      different gastric sites in H. pylori-infected and uninfected patients, and
      whether the presence of antral-type mucosa in the incisura, body, and fundus is
      associated with gastric atrophy and intestinal metaplasia. METHODS: Two hundred
      and sixty-eight patients with dyspepsia were enrolled. Eight biopsies (i.e.,
      antrum x3, body x2, fundus x2, and incisura x1) were obtained. One antral biopsy
      was used for the CLO-test. Three (each from the antrum, body, and fundus) were
      cultured. The remaining biopsies were examined histologically according to the
      updated Sydney System after staining with hematoxylin and eosin and Giemsa. A
      validated serological test was also applied. RESULTS: Overall, 113 (42%) patients
      were infected with H. pylori. At the incisura, antral-type mucosa was more
      prevalent in infected than in uninfected patients (84% vs. 18%; odds ratio [OR] =
      23.9, 95% confidence interval [CI] 12.5-45.8; p<0.001). Atrophic gastritis and
      intestinal metaplasia at the incisura was present in 19.5% and 13.3%,
      respectively, of infected, and 4.5% and 3.2%, respectively, of uninfected
      patients (both p<0.01). Moreover, atrophic gastritis at the incisura was
      associated with the presence of antral-type mucosa at the site (termed
      antralization); the prevalence of atrophic gastritis was 19.5% (24/123) in the
      presence of antralization, whereas the rate was 2.1% (3/145) without
      antralization (OR = 11.4, 95% CI 3.4-39.2; p<0.001). Similarly, at the incisura,
      16.3% (20/123) of "antralized" cases and 1.4% (2/145) of "unantralized" cases had
      intestinal metaplasia (OR = 13.8, 95% CI, 3.2-60.7; p<0.001). The association
      between antralization at gastric body and fundus also appeared to be associated
      with atrophic gastritis and intestinal metaplasia at these sites. CONCLUSIONS:
      Atrophic gastritis and intestinal metaplasia occurs predominantly at the gastric
      antrum and incisura with H. pylori infection. Antralization of the gastric
      incisura is a common event in H. pylori-infected patients, and appears to be
      associated with an increased risk of atrophic gastritis and intestinal
      metaplasia.

PMID- 10638569
TI  - Ampullary obstruction monitoring in acute gallstone pancreatitis: a safe,
      accurate, and reliable method to detect pancreatic ductal obstruction.
AB  - OBJECTIVE: The aim of this study was to determine the value of ordinary clinical
      and laboratory data, including the monitoring of ampullary gallstone obstruction
      in the early phases of the disease, in the diagnosis of acute gallstone
      pancreatitis (AGP). METHODS: One hundred and thirty-two patients were studied.
      The inclusion criteria were admission within 48 h from the onset of symptoms,
      clinical presentation compatible with AGP, bile-free gastric aspirate, elevation
      of serum amylase and bilirubin, and ultrasonographic demonstration of
      cholelithiasis. Monitoring of ampullary obstruction included severity of pain,
      presence of bile in the gastric aspirate, and serial serum bilirubin
      determinations. The clinical diagnosis of AGP was confirmed or excluded by
      surgical exploration, and that of ampullary obstruction by intraoperative
      cholangiography (IOC) or endoscopic retrograde cholangiopancreatography (ERCP).
      RESULTS: The overall accuracy of the diagnostic tests for AGP was high:
      sensitivity, 0.94; specificity, 0.99; positive predictive value, 0.95; and
      negative predictive value, 0.99. Detection of spontaneous ampullary decompression
      was correct in 100% of the patients, and that of ampullary obstruction, in 61%.
      The accuracy of this test was sensitivity, 1.0; specificity, 0.92; positive
      predictive value, 0.61; and negative predictive value, 1.0. CONCLUSIONS: Clinical
      criteria and ordinary laboratory determinations are sufficiently accurate to
      discriminate between patients with AGP and those with other acute abdominal
      pathologies. Careful monitoring of patients' pain, quality of nasogastric
      aspirate, and serum bilirubin level can accurately identify the few cases with
      persistent ampullary obstruction. Those patients can then be selected for
      intervention to restore the ampullary patency and prevent progression of acute
      pancreatitis.

PMID- 10638570
TI  - Percutaneous endoscopic gastrostomy: high mortality rates in hospitalized
      patients.
AB  - OBJECTIVE: Percutaneous endoscopic gastrostomy (PEG) is a widely used method for
      insertion of a gastrostomy tube in patients who are unable to eat but have a
      normally functioning gut. Complications have been described, especially in
      fragile, debilitated patients, and 30-day mortality rates of 4.1-26% have been
      reported. We assessed the outcome of PEG tube placement for inpatients and
      outpatients, based on morbidity, mortality, and long-term survival. METHODS: We
      reviewed the medical records of all patients who underwent PEG at our institution
      between January 1, 1995 and December 31, 1996. Four groups of patients were
      compared: Group 1, patients from nursing homes; Group 2, hospitalized patients;
      Group 3, hospitalized patients matched to Group 2 for diseases, except mental
      disorder, and not treated with PEG; and Group 4, the general hospital population
      matched for age. RESULTS: A total of 114 PEG tubes were inserted in 114 patients,
      47 from Group 1, 67 from Group 2. Eighty-seven percent of patients in Group 1
      underwent PEG because of dementia, versus 46% of Group 2 (p<0.001). The mortality
      rate was five times higher in Group 2 than in Group 3 (p<0.001). The 30-day
      mortality was seven times higher in Group 2 than in Group 1, twice that in Group
      3, and five times higher than in Group 4 (p = 0.002 and p<0.001, respectively).
      When intention-to-treat analyses were applied to the data, 19/48 patients died
      (39.5%) in Group 1, and 60/83 (72.0%) died in Group 2, (p<0.001). CONCLUSIONS:
      Patients hospitalized with acute illness are at high risk for serious adverse
      events after PEG insertion and this procedure should be avoided.

PMID- 10638571
TI  - Hypoalbuminemia is a poor predictor of survival after percutaneous endoscopic
      gastrostomy in elderly patients with dementia.
AB  - OBJECTIVE: Percutaneous endoscopic gastrostomy (PEG) is widely used for long-term
      enteral nutrition in patients with dementia and inadequate oral intake, although
      its benefit in prolonging the survival of the patient is not clear. Patients are
      often referred for PEG placement after a significant weight loss or fall in serum
      albumin. It is not known whether this delay in referral adversely affects the
      survival. Our aim was to determine the survival after PEG placement in patients
      with inadequate oral intake secondary to cognitive impairment and to determine
      whether-the nutritional parameters at the time of placement of PEG predict
      survival. METHODS: After excluding patients with cancer, cerebrovascular accident
      (CVA), and anoxic encephalopathy, 56 consecutive patients with dementia and
      inadequate oral intake were included in the study. The following parameters were
      analyzed to predict survival benefit: demographics, reason for admission to the
      hospital, nutritional indices, Karnofsky performance status before and after PEG,
      comorbid medical illnesses, and complications after PEG. A control group was
      selected from patients admitted to the geriatric division who did not receive
      PEG. Patients with CVA, cancer, and anoxic encephalopathy were also excluded in
      the control group. Both groups were followed-up for 6 months. RESULTS: One
      patient was lost to follow-up and complete data were available for 55 patients.
      The control group of 33 patients was comparable to the patients in age, gender,
      and comorbid illnesses. During a 6-month follow-up period, the mortality was 44%
      among patients and 26% among controls (p = 0.03). The only factor that predicted
      poor survival in patients at 6 months was a serum albumin of <2.8 g/dl. The
      predictive value of low serum albumin was higher in patients with sepsis on
      hospital admission and in patients younger than 85 yr. The mean serum albumin of
      the patients was significantly lower than the control group (p = 0.0001).
      CONCLUSIONS: Only 50% of demented patients with inadequate oral intake are likely
      to survive beyond 6 months after PEG placement. No improvement in performance
      status is likely to occur in any patient. These limited benefits should be
      realized before initiating PEG feeding. Since the survival in the age-matched
      control group with a higher mean serum albumin was better than in the patients
      who had PEG, there may be some benefit in performing PEG before the onset of
      severe hypoalbuminemia.

PMID- 10638572
TI  - Diagnostic value of push-type enteroscopy: a report from India.
AB  - OBJECTIVE: We sought to assess the diagnostic value of push-type enteroscopy in
      relation to indications. METHODS: Ninety-nine consecutive patients (mean age,
      42+/-15 yr; 65 men) with suspected small bowel disorders underwent push
      enteroscopy. The indications were chronic diarrhea (n = 54), obscure
      gastrointestinal (GI) bleeding (n = 21), abdominal pain (n = 10), abnormal
      radiological studies of small bowel (n = 5), iron deficiency anemia (n = 5), and
      others (n = 4). Push enteroscopy was performed using the Olympus SIF-10 (160-cm)
      enteroscope. RESULTS: Endoscopic examination of the jejunum was successful in all
      the patients, except one with a distal duodenal stricture. The length of the
      jejunum examined ranged from 10 to 70 cm. The time taken to complete the
      procedure varied from 2 to 30 min. Lesions were found in nine (42.8%) patients
      with obscure GI bleeding; six (28.5%) had worms (Ascaris lumbricoides [n = 3],
      Ankylostoma duodenale [n = 3]) in the jejunum, producing multiple erosions and
      bleeding points. In the chronic diarrhea group, a diagnosis was made in 13 (24%)
      patients on enteroscopic visualization and jejunal histology: celiac disease (n =
      6), tropical sprue (n = 3), Crohn's disease (n = 1), secondary lymphangiectasia
      (n = 1), strongyloidiasis (n = 1), and nodular lymphoid hyperplasia with
      giardiasis (n = 1). In patients with abdominal pain, enteroscopy provided a
      diagnosis in one (10%) patient. No positive diagnosis could be made on
      enteroscopy in patients with iron deficiency anemia and abnormal radiological
      studies of small bowel. CONCLUSION: Push-type enteroscopy is a useful test in the
      evaluation of patients with obscure GI bleeding and chronic diarrhea. In
      developing countries, in patients with obscure GI bleeding, the presence of worms
      in the jejunum is an important finding on enteroscopy. Tropical sprue,
      giardiasis, and strongyloidiasis are distinct findings in patients with chronic
      diarrhea in the present series.

PMID- 10638573
TI  - Role of ERCP in asymptomatic orthotopic liver transplant patients with abnormal
      liver enzymes.
AB  - OBJECTIVE: The safety and efficacy of endoscopic retrograde
      cholangiopancreatography (ERCP) in the evaluation and management of biliary tract
      complications after orthotopic liver transplantation (OLT) have been previously
      demonstrated. However, the role of ERCP in evaluating asymptomatic OLT patients
      with abnormal liver enzymes with a previously normal biliary tree remains poorly
      defined. We sought to assess the utility of ERCP in this subset of patients.
      METHODS: A retrospective analysis of-asymptomatic OLT patients with abnormal
      liver enzymes evaluated by ERCP was undertaken. In addition to ERCP, all these
      patients had a diagnostic abdominal Doppler ultrasound, and a percutaneous liver
      biopsy. All patients had choledochocholedochostomy at the time of transplant and
      normal T-tube cholangiograms 3 months postoperatively. A radiologist, blinded to
      clinical findings, interpreted the ultrasound as normal, biliary dilation, or
      vascular abnormalities. The same radiologist interpreted ERCP findings. A
      pathologist, blinded to clinical findings, graded liver biopsies as normal,
      diagnostic, or abnormal but nondiagnostic. RESULTS: Twenty-two patients underwent
      23 ERCPs. Twenty-two of the 23 ERCPs were normal (96%), and one abnormal ERCP
      finding did not explain the liver enzyme abnormality. Liver biopsy was diagnostic
      in 13 of 22 (57%) and in each case the ERCP was normal. The remaining 10 liver
      biopsies were abnormal but nondiagnostic. Ultrasound was abnormal in five of 22
      cases, but in the three cases suggesting biliary dilation, the ERCP was
      interpreted as normal. CONCLUSION: Routine use of ERCP in evaluation of
      asymptomatic OLT patients with liver function test abnormalities and normal
      cholangiograms at 3 months was not diagnostically useful. In this subset of
      patients, liver biopsy was usually abnormal and frequently diagnostic and should
      be the initial invasive diagnostic procedure.

PMID- 10638574
TI  - The SIBDQ: further validation in ulcerative colitis patients.
AB  - OBJECTIVE: The Inflammatory Bowel Disease Questionnaire (IBDQ) is an instrument
      that assesses quality of life in patients with inflammatory bowel disease. It has
      32 items in four domains. The short form of the IBDQ (SIBDQ) was developed in
      Canadian Crohn's disease patients for use in clinical practice. Patients with
      ulcerative colitis might require a different form of the SIBDQ. Our aim was to
      design and validate a SIBDQ for patients with ulcerative colitis and to compare
      this to the Crohn's SIBDQ. METHODS: We recruited 122 patients with colitis as an
      initial sample. Using linear regression modeling, the 10 items that best
      predicted the total IBDQ score were identified. The colitis and Crohn's versions
      of the SIBDQ were compared by univariate linear regression with the total IBDQ
      score in two other cohorts of colitis patients. RESULTS: Ten items explained 97%
      of the variance of the total IBDQ score in our first cohort. These were items 1
      and 9 (bowel); 7, 11, 21, 30 (emotional); 2 and 10 (systemic); and 12 and 28
      (social). Only three items were shared with the Crohn's SIBDQ. The R2 for both
      SIBDQs with the total IBDQ score in the other cohorts were very high (> or
      =0.95), although the Colitis SIBDQ showed better internal consistency.
      CONCLUSIONS: The development of a SIBDQ for patients with ulcerative colitis did
      not reveal any clear advantage over the original version of the SIBDQ. Further
      studies are required to determine the role of the SIBDQ in routine clinical
      practice.

PMID- 10638575
TI  - Correlation of symptom criteria with perception thresholds during rectosigmoid
      distension in irritable bowel syndrome patients.
AB  - OBJECTIVE: Due to a lack of reliable biological markers, the diagnosis of
      irritable bowel syndrome (IBS) is based on symptom criteria. The possible
      physiological correlates of these criteria are not known. Our aims were to
      identify correlations of currently used IBS symptom criteria with distinct
      alterations in visceral perception. METHODS: Forty-two IBS patients (51% women)
      with a mean age of 39.5+/-1.4 yr, were included; 64% of patients were recruited
      from advertisement and 36% were clinic referrals. Patients completed a bowel
      symptom questionnaire, which included the Rome criteria and symptom severity
      ratings. Rectal discomfort thresholds were evaluated in all patients and in 19
      controls, using a nonbiased tracking protocol consisting of phasic rectal balloon
      distensions before (PreTh) and after (PostTh) repetitive, high-pressure sigmoid
      distensions. We assessed the effect of each Rome criteria and symptom severity on
      PreTh and PostTh. RESULTS: IBS symptom severity was reported as moderate in 38.1%
      and as severe in 61.9% of patients. Overall, lower thresholds were observed in
      IBS patients than in controls (PreTh: 28.2+/-1.7 vs. 36.3+/-2.8 mm Hg, p<0.05;
      PostTh: 25.3+/-1.5 vs. 34.2+/-2.7 mm Hg, p<0.01). When assessing the effect of
      Rome criteria on rectal thresholds, we found that patients with hard/lumpy stools
      had lower thresholds than those without them, whereas patients with loose watery
      stools had higher thresholds than those who lacked them (both p<0.05). The
      lowering of rectal discomfort thresholds after sigmoid stimulation was observed
      regardless of the presence or absence of any Rome criteria or symptom severity.
      CONCLUSION: Although a decrease in rectal discomfort thresholds after sigmoid
      stimulation is seen in IBS regardless of specific symptoms, baseline and
      postsigmoid stimulation thresholds are lower in IBS patients with constipation
      related symptoms.

PMID- 10638576
TI  - Risk factors for irritable bowel syndrome: role of analgesics and food
      sensitivities.
AB  - OBJECTIVE: Symptoms of irritable bowel syndrome (IBS) are reported by 10% of the
      general population; however, evaluation of traditional risk factors has not
      provided any insight into the pathogenesis of this condition. The objective of
      this study was to identify additional risk factors for irritable bowel syndrome.
      METHODS: A valid self-report questionnaire that records the gastrointestinal (GI)
      symptoms required for a diagnosis of IBS, self-reported measures of potential
      risk factors, and a psychosomatic symptom checklist was mailed to an age-and
      gender-stratified random sample of Olmsted County, Minnesota residents aged 30-64
      yr. A logistic regression model that adjusted for age, gender, and psychosomatic
      symptom score was used to identify factors significantly associated with IBS.
      RESULTS: A total of 643 (72%) of 892 eligible subjects returned the survey. IBS
      symptoms were reported by 12% of the respondents. IBS was significantly
      associated with use of analgesics (acetaminophen, aspirin, or nonaspirin
      nonsteroidal antiinflammatory drugs) for reasons other than IBS, reporting a food
      allergy or sensitivity, and ratings of somatic symptoms. No association was
      detected for age, gender, body mass index, smoking history, alcohol use,
      educational level, exposure to pets in the household, or water supply. Among
      subjects reporting the use of just one type of analgesic, IBS was associated with
      acetaminophen but not aspirin or nonaspirin nonsteroidal antiinflammatory drugs
      used alone. The odds of having IBS were higher among subjects reporting more
      reasons for taking analgesics and intolerance to a higher number of foods.
      CONCLUSIONS: IBS is significantly associated with analgesic use. However, this is
      confounded by other somatic pain complaints. IBS symptoms are associated with the
      reporting of many food allergies or sensitivities. The role of food-induced
      symptoms in IBS requires further investigation.

PMID- 10638577
TI  - Comparative, open, randomized trial of the efficacy and tolerance of slow-release
      5-ASA suppositories once daily versus conventional 5-ASA suppositories twice
      daily in the treatment of active cryptogenic proctitis: French Pentasa Study
      Group.
AB  - OBJECTIVE: The efficacy and tolerance of slow-release 5-ASA suppositories
      (Pentasa 1 g/day) were compared with those of conventional 5-ASA suppositories
      (Rowasa 0.5 g b.i.d.). METHODS: Two hundred and fifty-one (251) patients
      presenting with an exacerbation of cryptogenic proctitis were randomized.
      Clinical activity and rectal lesions were measured at days 1 and 14 (and at day
      21 for patients not in remission at day 14), and each patient had to fill out a
      daily diary card (checklist). RESULTS: Results are given for slow-release and
      classical suppositories, respectively. The reduction in symptoms and lesions was
      identical in both groups. Treatment was continued until day 21 in 36% versus 33%
      of the patients, and minor or moderate side effects occurred in 5.6% versus 6.3%
      (NS). The tolerance of the suppositories was rated as satisfactory every day by
      77% versus 54% (p = 0.001), and early suppository expulsion occurred in 0.5%
      versus 3.4% (p = 0.001). CONCLUSIONS: The treatments were equally effective and
      both were well tolerated. However, the advantages of the slow-release
      suppositories were that patients exhibited greater tolerance and early expulsion
      was less frequent.

PMID- 10638578
TI  - Appendectomy and the development of ulcerative colitis: results of a metaanalysis
      of published case-control studies.
AB  - OBJECTIVE: Numerous epidemiological studies have been performed to determine risk
      factors that might contribute to the development of ulcerative colitis (UC).
      Recent studies have focused on the role of appendectomy in the disease's
      pathogenesis. This report aims to review and analyze the degree of evidence from
      recent published studies. METHODS: Medline and Embase databases were scrutinized
      for studies published between 1987 and January 1999. Reference lists from
      published articles, reviews, and abstracts from major gastrointestinal (GI)
      meetings were also reviewed. All studies specifically designed to evaluate the
      association between appendectomy and UC were selected. Thirteen studies that
      satisfied our selection criteria were evaluated by metaanalysis. RESULTS: The 13
      case-control studies collectively gathered evidence from 2770 patients with UC
      and 3352 controls. Combining the results of the individual studies gave an
      overall odds ratio of 0.307 (95% confidence interval [CI] = 0.249-0.377) in favor
      of appendectomy (p<0.0001). This suggests that appendectomy gives a 69% reduction
      in the risk of developing UC (95% CI = 62%-75%). The test for heterogeneity (of
      all 13 studies) was not significant (chi2 = 16.213, d.f. = 12, p>0.10). The
      influence of potential confounding factors (mainly smoking) on these results
      could be excluded. CONCLUSIONS: The review of the literature and the metaanalysis
      of the selected studies suggest that the inverse association between appendectomy
      and UC is strong and consistent. Further studies are needed to establish whether
      a causal relationship exists.

PMID- 10638579
TI  - Impact of surgery for Crohn's disease on health-related quality of life.
AB  - OBJECTIVE: When patients with Crohn's disease (CD) express concerns about their
      disease, they emphasize worries about surgery. However, most studies about the
      impact of surgery in CD on health-related quality of life (HRQOL) have compared
      postsurgical changes on HRQOL relative to HRQOL before surgery, not taking into
      account the influence of CD activity on HRQOL. Our aim was to assess whether
      surgical treatment of CD modifies HRQOL, compared with inactive CD, active CD, or
      healthy controls. METHODS: Outcomes of 29 CD patients in remission with a
      previous bowel resection were compared with those from 42 clinically active CD
      patients and 48 patients with medically induced remission. A reference control
      group of 63 healthy individuals was also studied. HRQOL was measured by the
      Inflammatory Bowel Disease Questionnaire (IBDQ), the Psychological General Well
      Being Index (PGWBI), and the EuroQol. RESULTS: Active CD patients scored the
      lowest on the IBDQ. Both operated and nonoperated inactive CD patients had lower
      HRQOL scores than controls in overall IBDQ and in all five domains. However,
      neither global score, digestive, systemic, emotional, social, or functional
      dimensions differed significantly between operated and nonoperated inactive CD
      patients. PGWBI and the visual analog scale of the EuroQol were also similar in
      both groups of inactive CD patients (103 [range, 94-107] vs. 103 [97-106] and 90
      [73-87] vs. 82 [76-84]), but significantly higher than in active CD. CONCLUSIONS:
      HRQOL is impaired in active CD, and improves during remission irrespective of
      whether it had been achieved medically or surgically. Our results suggest that to
      improve HRQOL it is more important to achieve remission than the approach, drugs
      or surgery, chosen.

PMID- 10638580
TI  - Risk of fractures in celiac disease patients: a cross-sectional, case-control
      study.
AB  - OBJECTIVES: Although osteopenia and osteoporosis are well-recognized
      complications of celiac disease, no controlled studies have been done to assess
      the prevalence of fractures in a large cohort of patients. The objectives of this
      study were to determine the prevalence of bone fractures and vertebral
      deformities in celiacs and to analyze the relationship between fractures and
      clinical data of patients. METHODS: We studied 165 patients with a well
      established diagnosis of celiac disease. A similar number of age- and gender
      matched control subjects with functional GI disorders were evaluated. The design
      of the study was cross-sectional, with a retrospective historical review through
      a personal interview of all subjects. All patients underwent bone mineral density
      measurement by dual-energy, x-ray absorptiometry and spinal x-ray. Vertebral
      deformities were determined by visual inspection of spinal x-rays and by
      morphometric analysis. RESULTS: Among celiacs, 41 patients (25%) referred have
      had from one to five fractures in the peripheral skeleton. On the contrary, only
      14 (8%) control subjects experienced fractures. This difference was highly
      significant (odds ratio, 3.5; 95% confidence interval [CI], 1.8-7.2; p<0.0001).
      Although inspection of spinal x-rays showed evidence of vertebral deformities in
      the lumbar spine in only two patients, a more detailed examination of lateral x
      rays using morphometric criteria detected lumbar spine vertebral deformities in
      nine (five also had fractures in the peripheral skeleton) and in four controls
      (odds ratio, 2.8; 95% CI, 0.7-11.5; p = NS). Eighty percent of fractures were
      detected before the diagnosis of celiac disease or in patients who were
      noncompliant with the gluten-free diet; only 7% of patients experienced fractures
      after starting treatment. Regression analysis adjusted for multiple comparisons
      showed that patients with fractures were diagnosed with celiac disease later
      (p<0.06) and remained undiagnosed for more prolonged periods (p<0.05). There was
      a trend, which did not reach statistical significance, for a lower bone mineral
      density in the lumbar spine and total skeleton among patients with fractures.
      CONCLUSIONS: This study has demonstrated that patients with celiac disease had a
      high prevalence of bone fractures in the peripheral skeleton. Most of these
      events occurred before diagnosis or while patients were noncompliant with gluten
      containing diet. Our results suggest that early diagnosis and effective treatment
      of celiac disease were the most relevant measures to protect patients from the
      risk of fractures.

PMID- 10638581
TI  - Resistance to activated protein C and low levels of free protein S in Greek
      patients with inflammatory bowel disease.
AB  - OBJECTIVE: Patients with inflammatory bowel disease (IBD) frequently suffer from
      thromboembolic events. A recently identified mechanism for thrombophilia, the
      poor anticoagulant response to activated protein C, has been suggested as one of
      the leading risk factors for thrombosis. The aim of this study was to evaluate
      the frequency of thrombophilic abnormalities, including activated protein C
      resistance (APCR), in Greek patients with ulcerative colitis (UC) and Crohn's
      disease (CD). METHODS: Forty-eight patients with UC, 36 with CD, and 61 matched
      healthy controls (HC) were studied. Cases with presence of lupus anticoagulant,
      use of anticoagulants or heparin, and pregnancy were excluded. Disease activity
      in CD was evaluated by use of the Crohns Disease Activity Index (CDAI) score and
      in UC by the Truelove-Witts grading system. Plasma levels of protein C, free
      protein S, antithrombin III (AT-III), activated protein C resistance (APCR), and
      fibrinogen were determined in IBD patients, as well as in HC. All the cases and
      controls with abnormal APCR were further studied by genetic testing for the
      factor V Leiden mutation. RESULTS: Mean fibrinogen levels in UC and CD patients
      were significantly elevated (p<0.0001), compared with HC. The mean values of free
      protein S, as well as mean APCR, were significantly lower in UC and CD patients
      than in the HC (p<0.0001). Seven (five UC and two CD) of 84 IBD patients (8.3%)
      and three of the HC (4.9%) had the factor V Leiden mutation. No significant
      difference was observed for the other thrombophilic parameters. Fibrinogen levels
      and profound free protein S deficiency were found related to disease activity.
      CONCLUSIONS: Thrombophilic defects are common in Greek patients with IBD and they
      could interfere either in the disease manifestation or in the thrombotic
      complications.

PMID- 10638582
TI  - Right colonic involvement is associated with severe forms of ischemic colitis and
      occurs frequently in patients with chronic renal failure requiring hemodialysis.
AB  - OBJECTIVE: The aim of this study was to identify factors associated with severe
      outcome in patients with ischemic colitis. METHODS: The files of 60 consecutive
      inpatients (34 women, 26 men, mean age 67 yr) with ischemic colitis were
      reviewed. The following data were analyzed: age, sex, smoking, medications,
      history of cardiovascular disease, metabolic disease, chronic renal failure and
      hemodialysis, the time elapsed between the first symptoms and the diagnosis, and
      the site and extension of their colonic involvement. Patients were divided into
      two groups according to outcome: those with severe disease, including those who
      died from ischemic colitis (n = 3) or who required surgical resection (n = 21);
      and those with mild forms of colitis who were treated successfully without
      surgery (n = 36). The two groups were compared by means of univariate and
      multivariate analysis to identify factors associated with unfavorable outcomes.
      Only patients who had a complete examination of the colon (n = 51) were entered
      into the statistical analysis. RESULTS: By univariate analysis, chronic renal
      failure (p = 0.03), hemodialysis (p = 0.01), short delay between symptoms and
      diagnosis (p = 0.01), and right colonic involvement (p = 0.002) were
      significantly more common in the patients with severe colitis. By logistic
      regression, right colonic involvement was the only factor independently
      associated with severity (p = 0.01). Right-sided lesions were present in 82% of
      patients on dialysis but in only 26% of patients not on dialysis (p = 0.0005).
      CONCLUSIONS: Right colonic involvement is associated with severe forms of
      ischemic colitis and occurs frequently in patients with chronic renal failure
      requiring hemodialysis.

PMID- 10638583
TI  - Hepatic tissue endothelin-1 levels in chronic liver disease correlate with
      disease severity and ascites.
AB  - OBJECTIVES: Plasma endothelin-1 (ET-1) levels are increased in patients with
      cirrhosis and ET-1 production is increased in the liver itself during
      experimental injury. These data suggest a possible role for this vasoactive
      peptide in intrahepatic microcirculatory changes that contribute to the
      pathogenesis of portal hypertension in cirrhosis. Therefore the aims of this
      study were to determine whether ET-1 levels were abnormal in the livers of
      patients with cirrhosis and to investigate possible clinical correlates of
      altered hepatic ET-1 in cirrhosis. METHODS: Liver specimens were obtained from
      explants at the time of liver transplantation in 62 cirrhotic patients; 49
      without pretransplantation transjugular intrahepatic portosystemic shunt (TIPS)
      and 13 with pretransplantation TIPS. The presence of ascites was evaluated by
      physical examination and ultrasonography. Control specimens consisted of livers
      with normal morphology obtained from patients who died from nonliver-related
      causes. Hepatic ET-1 was measured by enzyme immunoassay. RESULTS: Hepatic ET-1
      levels in cirrhotics without (0.17 pg/mg liver tissue) or with TIPS (0.12 pg/mg)
      were higher than in control patients [0.04 pg/mg (p = 0.02 for ET-1 levels in
      cirrhotics with or without TIPS vs. control)]. In cirrhotics without ascites who
      had not had TIPS, ET-1 levels (0.07 pg/mg [0.04-1.00]) were similar to those of
      the controls. In contrast, ET-1 content was increased in cirrhotics with small
      (0.11 pg/mg; p = 0.0002) and moderate-to-large (0.69 pg/mg; p = 0.0002) amounts
      of ascites compared to patients without ascites. There was a modest correlation
      between ET-1 levels and Child-Pugh score (correlation coefficient 0.32; p = 0.03)
      and ET-1 levels were significantly higher in patients with Child-Pugh score of 13
      or greater (0.88 pg/mg; p = 0.02) than in those with Child-Pugh score of 12 or
      less (0.16 pg/mg). CONCLUSIONS: Hepatic tissue ET-1 levels are increased in the
      liver of patients with cirrhosis. This increase appears to be proportional to the
      severity of both liver disease and ascites. These data raise a possible role for
      ET-1 in modulation of intrahepatic resistance in cirrhotic portal hypertension.

PMID- 10638584
TI  - The utility of CA 19-9 in the diagnoses of cholangiocarcinoma in patients without
      primary sclerosing cholangitis.
AB  - OBJECTIVES: The diagnosis of cholangiocarcinoma is often difficult, making
      management approaches problematic. A reliable serum tumor marker for
      cholangiocarcinoma would be a useful additional diagnostic test. Previous studies
      have demonstrated that elevated serum concentrations of CA 19-9, a tumor
      associated antigen, have good sensitivity and specificity for cholangiocarcinoma
      in patients with primary sclerosing cholangitis. However, the value of this tumor
      marker for cholangiocarcinoma unassociated with primary sclerosing cholangitis is
      unclear. Thus, the aims of this study were to determine the usefulness of a serum
      CA 19-9 determination in the diagnosis of de novo cholangiocarcinoma. METHODS: We
      prospectively measured serum CA 19-9 concentrations in patients with
      cholangiocarcinoma (n = 36), nonmalignant liver disease (n = 41), and benign bile
      duct strictures (n = 26). Serum CA 19-9 concentrations were measured by an
      immunoradiometric assay (CIS Bio International) without knowledge of the clinical
      diagnosis. RESULTS: The sensitivity of a CA 19-9 value >100 U/ml in diagnosing
      cholangiocarcinoma was 53%. When compared with the nonmalignant liver disease and
      the benign bile duct stricture groups, the true negative rates were 76% and 92%,
      respectively. Patients with unresectable cholangiocarcinoma had significantly
      greater mean CA 19-9 concentrations compared to patients with resectable
      cholangiocarcinoma. CONCLUSIONS: These data suggest that the serum CA 19-9
      determination is a useful addition to the available tests for the differential
      diagnosis of cholangiocarcinoma.

PMID- 10638585
TI  - Alcohol levels are increased in social drinkers receiving ranitidine.
AB  - OBJECTIVE: Ranitidine increases blood alcohol concentrations by decreasing the
      first pass metabolism of ethanol. The effect of ranitidine on alcohol levels has
      been found to be variable when using large doses of alcohol or conditions in
      which its first pass metabolism is known to be minimal. Despite a consensus that
      the drug increases alcohol levels after small doses of ethanol, this effect has
      been considered inconsequential, because of the low alcohol levels. However,
      social drinking comprises repetitive consumption of small doses of alcohol and
      the ranitidine effect could thereby be potentiated. METHODS: To study this
      factor, alcohol levels were determined by breath analysis in nine men (social
      drinkers), after four drinks of 0.15 g/kg ethanol given postprandially every 45
      min, before and after ranitidine (150 mg b.i.d. for 7 days). RESULTS: Their blood
      alcohol increased with repeated doses, reaching peak values of 24+/-3 mg/dl
      before ranitidine and 33+/-2 after ranitidine (p = 0.04). In seven of the nine
      subjects blood alcohol exceeded 25 mg/dl, a level at which impairment of judgment
      and of finely tuned skills occurs and which exceeds legal limits of driving in
      some European countries. Moreover, the high levels persisted for a longer time
      with than without the drug. These effects were associated with a 62% decrease in
      first pass metabolism. CONCLUSION: Under conditions mimicking social drinking,
      ranitidine increases blood alcohol to levels known to impair psychomotor skills
      needed for driving.

PMID- 10638586
TI  - Bacterial peritonitis after elective endoscopic variceal ligation: a prospective
      study.
AB  - OBJECTIVE: Endoscopic variceal ligation is becoming the therapy of choice for
      esophageal varices, replacing endoscopic variceal sclerotherapy. The latter is
      associated with a 5-53% incidence of port-procedural bacteremia and a 0.5-3%
      incidence of peritonitis, whereas the former carries a 3-6% risk of bacteremia.
      However, the incidence of peritonitis after variceal ligation has not been well
      studied. This prospective study is designed to investigate the risk of developing
      bacteremia and bacterial peritonitis after elective endoscopic variceal ligation.
      METHODS: Sixty-seven patients with esophageal varices and ascites secondary to
      liver cirrhosis underwent elective endoscopic variceal ligation. Before the
      procedure, ascitic fluid was drawn under ultrasound guidance and sent for cell
      counts, Gram stain, and cultures. Two to 4 days afterward, a repeat ascitic fluid
      sample was sent for the same studies whether or not the patient had symptoms or
      signs suggestive of infection. Blood cultures were drawn both immediately before
      and after the endoscopic ligation procedure. RESULTS: Of 67 subjects, 11
      developed asymptomatic bacteremia with Gram-positive commensals. However, none of
      them progressed to peritonitis. Two patients who did not have bacteremia
      developed mild febrile peritonitis with Escherichia coli and were successfully
      treated with oral antibiotics. No other infectious complications were noted.
      CONCLUSIONS: There is a significant risk of asymptomatic bacteremia and bacterial
      peritonitis after elective variceal ligation. The peritonitis does not seem to be
      related to the bacteremia, as patients who had bacteremia did not develop
      peritonitis and vice versa. In addition, the involved organisms were quite
      different. Unlike the bacteremia, postligation peritonitis may be a consequence
      of severe liver cirrhosis rather than the procedure itself. The clinical
      significance of postligation bacteremia is doubtful. With regard to peritonitis,
      in our opinion the use of prophylactic antibiotics should be reserved for
      patients with Child's C class cirrhosis, a recent history of variceal bleeding, a
      past history of bacterial peritonitis, or a comorbid immunosuppressive condition.

PMID- 10638587
TI  - Treatment of advanced hepatocellular carcinoma with tamoxifen and the correlation
      with expression of hormone receptors: a prospective randomized study.
AB  - OBJECTIVES: A prospective randomized study was performed to test the hypothesis
      that tamoxifen might improve the survival of patients with advanced
      hepatocellular carcinoma (HCC) and to correlate the response of treatment with
      the expression of hormone receptors. METHODS: One hundred nineteen patients with
      advanced and otherwise untreatable HCC were included in a placebo-controlled,
      single-blind trial. The patients were randomized to tamoxifen group (61 patients)
      and control group (58 patients) and were prescribed with a daily dose of 30 mg of
      tamoxifen and placebo, respectively. Immunohistochemical tests for estrogen and
      progesterone receptors were performed on the tumor tissues obtained from 66
      patients. All patients were closely monitored and the survival outcome of the two
      groups of patients was compared and stratified according to the hormonal receptor
      status. RESULTS: There was no difference in the 1-month mortality rates (32.8%
      vs. 43.1%, p = 0.246) and the median survival (44 days vs. 41 days, p = 0.703)
      between the tamoxifen group and the control group. Furthermore, the expression of
      hormone receptors in the tumors did not affect the survival outcome of the
      patients treated with tamoxifen. None of the patients who survived longer than 3
      months had tumor that had partial response to tamoxifen treatment on follow-up
      imaging study. CONCLUSIONS: Tamoxifen has no efficacy in the treatment of
      patients with advanced HCC and response to treatment was not affected by the
      expression of hormone receptors.

PMID- 10638588
TI  - Cost-effective analysis of hepatitis A prevention in Ireland.
AB  - OBJECTIVE: The purpose of this study was to determine the most cost-effective
      prevention strategy against hepatitis A virus (HAV) infection for healthcare
      workers and the general population at risk in Ireland. METHODS: Four prevention
      strategies were compared: active immunization with Havrix Monodose (1440E.U);
      screening for anti-HAV antibody and then vaccinating; passive immunization;
      screening for anti-HAV antibody and then passive immunization. The cost-effective
      ratio was calculated for each prevention strategy. Threshold analysis,
      sensitivity analysis, and model extension to include indirect cost from work days
      lost and secondary attack rates through horizontal transmission were also
      derived. RESULTS: The medical costs were lowest and the infection rate highest
      when no preventive action was taken. Vaccination was most cost effective when the
      prevalence of immunity was 45% or less, reducing the infection rate by 98% when
      compared to nonprevention. Screening before vaccination was most cost effective
      when the prevalence of immunity was greater than 45%. Passive immunization and
      screening before passive immunization were not comparable to the other strategies
      in cost effectiveness. Sensitivity analysis showed that the cost-effective ratio
      for vaccination was dependent on vaccine price, incidence of HAV, and prevalence
      of immunity in the target group. Extending the model to include indirect costs
      further increased the cost effectiveness of vaccination. CONCLUSION: The best
      cost-effective strategy relates to target group immunity. Where HAV immunity is
      45% or less, vaccination is the strategy of choice and when immunity is greater
      than 45%, then screening followed by vaccination should be used. This study can
      be used to provide a framework within which choices can be made to achieve better
      health for less cost.

PMID- 10638589
TI  - Increased frequency of interferon-gamma-producing peripheral blood CD4+ T cells
      in chronic hepatitis C virus infection.
AB  - OBJECTIVES: To determine the profile of cytokine secretion by CD4+ T helper (Th)
      cells in chronic hepatitis C virus (HCV) infection, we used flow cytometry to
      determine the percentage of interferon (IFN)-gamma and interleukin (IL)-4
      producing cells from CD4+ T lymphocytes in peripheral blood obtained from
      patients chronically infected with HCV. METHODS: Peripheral blood mononuclear
      cells isolated from 89 HCV infected subjects (22 asymptomatic carriers, 56
      patients with chronic hepatitis, and 11 patients with liver cirrhosis) and 24
      healthy controls were stained with surface CD4 and intracellular IFN-gamma and IL
      4. Serum soluble IL-2 receptor (sIL-2R) levels were analyzed by ELISA. RESULTS:
      The frequency of IFN-gamma producing CD4+ cells in asymptomatic HCV carriers,
      patients with chronic hepatitis, and patients with liver cirrhosis were
      significantly higher than those of healthy controls (p<0.01, respectively). In
      contrast, the percentages of IL-4-producing CD4+ cells were very low, and there
      were no significant correlations with disease progression. A significant
      elevation in serum sIL-2R levels was found in chronic HCV infection compared to
      healthy controls, and serum sIL-2R levels significantly correlated with the
      frequency of IFN-gamma-producing cells. CONCLUSIONS: In HCV infected subjects,
      both serum sIL-2R and IFN-gamma are increased in chronic HCV infection no matter
      the stage of disease, meaning they are no different in asymptomatic carriers,
      patients with chronic hepatitis, and patients with liver cirrhosis, and that Th1
      cytokine or Th1 cells may participate in the pathogenesis of liver damage in
      chronic HCV infection.

PMID- 10638590
TI  - Ascites and spontaneous bacterial peritonitis in fulminant hepatic failure.
AB  - OBJECTIVE: Although presence of ascites has been reported in patients with
      fulminant hepatic failure (FHF), spontaneous bacterial peritonitis (SBP) has not
      been studied in a large group of such patients. Hence, the present study was
      conducted to evaluate the prevalence and prognostic significance of ascites and
      SBP in FHF patients. METHODS: Two hundred ninety-eight consecutive patients (mean
      age 32.9+/-14.8 yr) with FHF were studied. There were 133 (44.6%) men and 165
      (55.4%) women. Acute viral hepatitis accounted for 91.6% of the patients and were
      analyzed in the present study. RESULTS: Ascites was clinically detected in 79
      (28.9%) patients. The patients with ascites were older (p = 0.005), had longer
      jaundice-encephalopathy interval (p<0.0000001), lesser grade of encephalopathy on
      admission (p = 0.0000043), and a lower incidence of raised intracranial pressure
      on admission (p = 0.0007). Patients with ascites had significantly lower serum
      albumin (p = 0.021), ALT (p = 0.0005), AST (p = 0.00017), and PT (p = 0.002) on
      admission than in patients without ascites. Multivariate logistic regression
      analysis showed that jaundice-encephalopathy interval (> or =14 days) and serum
      albumin (< or =2.5 g/dl) were the only independent predictors of ascites. SBP was
      detected in 14 (17.7%) patients (neutrocytic culture positive, 4; neutrocytic
      culture negative, 9; and monomicrobial bacterascites, 1). Escherichia coli was
      identified in three patients. Survival was no different between patients with and
      those without ascites and also between patients with and those without SBP.
      CONCLUSIONS: Ascites is a frequent accompaniment of FHF and is complicated by
      SBP. Jaundice-encephalopathy interval of 14 days or more and serum albumin (< or
      =2.5 g/dl) on admission predicts the development of ascites in these patients.

PMID- 10638591
TI  - Role of hepatitis B virus in non-B, non-C chronic liver disease: in vitro
      proliferation and interferon-gamma production of peripheral blood mononuclear
      cells in response to hepatitis B core antigen and its relation to hepatitis
      activity.
AB  - OBJECTIVE: Although hepatitis B virus (HBV) DNA has been detected in the sera of
      patients with chronic liver disease with neither hepatitis B surface antigen nor
      antihepatitis C virus antibody (non-B, non-C [NBNC] CLD), whether HBV has some
      pathogenic role in NBNC CLD has not been made clear. METHODS: To investigate the
      significance of HBV DNA in NBNC CLD, we performed in vitro stimulation assays of
      peripheral blood mononuclear cells (PBMCs) in response to hepatitis B core
      antigen (HBcAg) in 17 NBNC CLD patients. RESULTS: HBV DNA with an 8-nucleotide
      deletion in the core promoter region was detected in 13 (76%) of the 17 patients
      by nested polymerase chain reaction. Interferon-gamma (IFN-gamma) production and
      proliferation of PBMCs of HBV DNA-positive patients showed a significant increase
      in response to HBcAg. The histological activity of hepatitis was also found to be
      significantly associated with the magnitude of IFN-gamma production and
      proliferation of PBMCs in response to HBcAg. Although five (38%) of the 13 HBV
      DNA-positive NBNC CLD patients had anti-HBs and/or anti-HBc, there was no
      difference in response of PBMCs to HBcAg between the HBV DNA-positive and 
      negative groups. CONCLUSION: Our observation suggests that HBV may have a
      pathogenic role in HBV DNA-positive NBNC CLD, even in those patients without any
      serological markers of HBV.

PMID- 10638592
TI  - A new therapeutic approach for the treatment of cystic echinococcosis:
      percutaneous albendazole sulphoxide injection without reaspiration.
AB  - OBJECTIVE: In this experimental study, the effectiveness of intracystic injection
      of albendazole sulfoxide solution was investigated as a new approach to
      percutaneous treatment in liver hydatid disease. METHODS: Ten naturally infected
      sheep were selected and divided into two groups: a treatment group (n = 7), and a
      control group (n = 3). Intracystic injection of albendazole sulfoxide was
      performed in the first group, whereas the control group received intracystic
      distillated water injection instead. No reaspiration was performed in any group.
      RESULTS: During the follow-up period of 6 months, serial sonographic examination
      revealed a significant decrease in the cyst size, progressive solidification, and
      complete separation of the germinal and the laminated membranes of hydatid cysts
      from the pericysts in the treatment group. In the control group, diameters and
      volumes of cysts were increased. All procedures were done without any
      complications. During the follow-up-period, liver function tests were normal.
      After 6 months, all sheep were killed and were examined for macroscopic and
      microscopic changes. Pathological examination showed pericyst hyalinization,
      inflammatory cells in the cyst wall, degeneration of laminated and germinal
      membranes, and necrotic material in the cyst cavity. No viable protoscoleces or
      daughter cysts were observed. CONCLUSION: Albendazole sulfoxide injection as a
      scolecidal agent in the percutaneous treatment of cystic echinococcosis seems to
      be effective in this animal model. Further studies are suggested to evaluate the
      effectiveness of this procedure in human subjects.

PMID- 10638593
TI  - Expression of brain-type glycogen phosphorylase is a potentially novel early
      biomarker in the carcinogenesis of human colorectal carcinomas.
AB  - OBJECTIVE: Our previous studies have demonstrated the significant role of brain
      type glycogen phosphorylase (BGP) in the carcinogenesis of gastric carcinoma. The
      aims of the present study were to investigate the expression of BGP in colorectal
      carcinoma as well as the timing of this expression in the adenoma-carcinoma
      sequence (ACS), in comparison with the overexpression of p53 protein. We also
      sought to identify this marker in the particular colorectal mucosa bearing de
      novo carcinoma. METHODS: The expression of BGP and p53 protein in colorectal
      carcinoma using affinity purified specific anti-human BGP antibody (Ab) and anti
      p53 Ab was studied using 96 resected specimens. Further investigation to examine
      the timing of BGP expression in comparison with p53 overexpression was carried
      out using 13, 18, eight, and 16 specimens of adenoma with mild, moderate, and
      severe dysplasia, and carcinoma in adenoma, respectively. The BGP
      immunohistochemistry in whole resected human colorectal mucosa (two with
      carcinoma and one with ulcer) was carried out using specific anti-BGP and anti
      p53 Ab. RESULTS: The BGP visualized by immunohistochemistry was commonly present
      in colorectal carcinoma (83.3%). The expression of this molecule during ACS
      showed excellent correlation with the increased dysplasia and was found before
      p53 overexpression, whereas no BGP expression was seen in the normal human large
      intestine remote from the cancer foci. Positive staining in overtly normal
      looking colonic mucosa was observed mainly around carcinomas without any adenoma
      component. CONCLUSIONS: The present study is the first to localize the BGP
      molecule in colorectal carcinoma, adenoma, and normal mucosa. It is suggested
      that BGP is a novel biomarker for carcinogenesis in both the pathways of ACS and
      the de novo colorectal carcinoma.

PMID- 10638594
TI  - The description of outcomes in Medicare patients hospitalized with peptic ulcer
      disease.
AB  - OBJECTIVE: The objective of this study was to describe outcomes of care for
      Medicare patients hospitalized with peptic ulcer disease from 1992 through 1997
      and to identify factors related to cost, length of stay, and readmission rates.
      METHODS: General descriptive statistics were obtained from Medicare inpatient
      claims data by year, endoscopy grouping, diagnosis related group code, and
      principal diagnosis code. From abstracted clinical data, associations were
      derived for length of stay, readmission rates, and the following processes of
      care: screening or treatment for Helicobacter pylori; screening for nonsteroidal
      antiinflammatory drug (NSAID) use; and the performance of endoscopy. The Acute
      Physiology and Chronic Health Evaluation method was used to estimate patient
      health status for the study. RESULTS: During the 6-yr study, there were 878,212
      claims, which constituted 1.3% of the total Medicare claims. The total Medicare
      payment for peptic ulcer claims was estimated at $4.8 billion. The inpatient
      mortality rate was 4.5%. Readmission rates remained relatively constant during
      the study period but decreased significantly when NSAID screening was documented
      during the hospitalization. Admission rates, length of stay, and mortality
      declined progressively during the study period. A reduction in length of stay of
      approximately 1 day was observed when screening or treatment for H. pylori,
      screening for NSAID use, or the performance of endoscopy was documented.
      CONCLUSIONS: Peptic ulcer disease has an important impact on the Medicare
      population with respect to cost, recurrence, and mortality. Adherence to selected
      processes of care is associated with shorter length of stay and lower readmission
      rates.

PMID- 10638595
TI  - Pap boat.

PMID- 10638596
TI  - Hepatotoxicity due to troglitazone: report of two cases and review of adverse
      events reported to the United States Food and Drug Administration.
AB  - Two patients (a 48-year-old woman and a 62-year-old man) developed clinical and
      laboratory signs of hepatotoxicity due to troglitazone (Rezulin), a
      thiazolidinedione used in treatment of diabetes mellitus. There was no clear
      clinical evidence of drug allergy, although the woman experienced colitis before
      the onset of recognized hepatotoxicity. Liver biopsies showed bridging necrosis
      and fibrosis in the woman and hepatitis with granuloma formation in the man. The
      abnormalities in liver chemistries resolved promptly upon cessation of the drug.
      Cases involving 46 patients reported to the United States Food and Drug
      Administration are also reviewed. Troglitazone is a useful new oral
      antihyperglycemic agent, but in about 1.9% of patients hepatotoxicity has
      occurred, which may be severe and even fatal. Frequent monitoring of serum liver
      chemistries in patients taking the drug is essential.

PMID- 10638597
TI  - Tamoxifen-induced transient multifocal hepatic fatty infiltration.
AB  - Tamoxifen is one of the most commonly used anticancer medications. Hepatic damage
      secondary to tamoxifen treatment is rare. Tamoxifen-induced multifocal hepatic
      fatty infiltration has not been reported previously. This report describes one
      case of steatohepatitis caused by tamoxifen in an elderly woman with a history of
      breast cancer. The patient had multifocal hepatic fatty infiltration secondary to
      tamoxifen therapy. After tamoxifen was discontinued, the features of multifocal
      hepatic fatty infiltration on CT improved dramatically, and hepatic transaminases
      normalized.

PMID- 10638598
TI  - Intestinal pseudo-obstruction and acute pandysautonomia associated with Epstein
      Barr virus infection.
AB  - We report the association of neurological and intestinal disorders with the
      reactivation of Epstein-Barr virus (EBV) in a child. This previously healthy 13
      yr-old boy presented with pharyngitis and acute abdominal ileus. Laparotomy
      excluded a mechanical obstruction. Postoperatively, he suffered from prolonged
      intestinal obstruction, pandysautonomia, and encephalomyelitis. Histological
      examination of the appendix and a rectal biopsy taken 3 months after the onset
      showed an absence of ganglion cells (appendix) and hypoganglionosis (rectum),
      with a mononucleate inflammatory infiltrate in close contact with the myenteric
      neural plexuses. EBV-PCR was positive in the blood and cerebrospinal fluid, and
      in situ hybridization with the Epstein-Barr virus encoded RNA probe showed
      positive cells throughout the appendix wall including the myenteric area, in a
      mesenteric lymph node, and in the gastric biopsies. EBV spontaneous lymphocytic
      proliferation was noted in the blood. The serology for EBV showed previous
      infection but anti-early antigen antibodies were present. No immunodeficiency was
      found. Neurological and GI recovery occurred after 6 months of parenteral
      nutrition and bethanechol. The omnipresence of EBV associated with the
      neurointestinal symptoms suggest that the virus was the causal agent. This is the
      first documented case of acquired hypoganglionnosis due to EBV reactivation.

PMID- 10638599
TI  - The striking effect of hyperbaric oxygenation therapy in the management of
      chronic idiopathic intestinal pseudo-obstruction.
AB  - Chronic idiopathic intestinal pseudo-obstruction is one of the disorders that is
      most refractory to medical and surgical treatment. Even when patients are given
      nutritional support, including total parenteral nutrition, obstructive symptoms
      seldom disappear. We report a case of chronic idiopathic intestinal pseudo
      obstruction, due to myopathy, in which hyperbaric oxygenation therapy was
      strikingly effective. The presence of myopathy was histologically confirmed on
      the surgically resected jejunal specimen. Hyperbaric oxygenation resulted not
      only in relief of the patient's obstructive symptoms but also in a rapid decrease
      of abnormally accumulated intestinal gas. At last, he could resume oral intake
      without any critical adverse effects. These observations strongly suggest that
      hyperbaric oxygenation can be an effective therapy in the management of chronic
      idiopathic intestinal pseudo-obstruction.

PMID- 10638600
TI  - Metastatic jejunal VIPoma: beneficial effect of combination therapy with
      interferon-alpha and 5-fluorouracil.
AB  - The VIPoma syndrome is rare. It is usually caused by a neuroendocrine tumor
      located in the pancreas. Somatostatin analogs and interferon-a can be helpful in
      the symptomatic control of the disease, but the efficacy of chemotherapy in
      metastatic disease is limited. We report the case of a 32-yr-old patient who had
      a primary intestinal VIPoma with peritoneal carcinomatosis and hepatic
      metastases. Somatostatin analogs and conventional chemotherapy regimens were not
      effective on VIPoma syndrome and tumor progression. The combination of 5-
      fluorouracil and interferon-alpha was associated with a major clinical
      improvement and tumor regression. Further investigations should evaluate the
      place of such a combination as a first line treatment for patients with
      metastatic neuroendocrine tumors.

PMID- 10638601
TI  - Acute small bowel pseudo-obstruction due to AL amyloidosis: a case report and
      literature review.
AB  - Amyloidosis may uncommonly present with intestinal pseudo-obstruction. Previous
      reports have described an acute presentation with AA amyloid and a more chronic
      syndrome with AL amyloid. We report the case of a 78-yr-old man who presented
      with clinical and radiographic features of an acute small bowel obstruction and
      who, at laparotomy, was found to have intestinal pseudo-obstruction due to AL
      amyloidosis. We believe this case represents the first report of acute pseudo
      obstruction from AL amyloidosis; awareness of this presentation may facilitate
      earlier diagnosis.

PMID- 10638602
TI  - Isolated abdominal vasculitis as an atypical presentation of Wegener's
      granulomatosis.
AB  - Although current classifications characterize vasculitic syndromes based upon the
      size of the vessels involved, the histopathology, and the presence or absence of
      antineutrophil cytoplasmatic antibodies ANCA (1-3), those occasional patients
      with vasculitis whose features are not typical may evade diagnosis and effective
      treatment. We report one such patient who presented with bilateral refractory
      uveitis and abdominal angina who had a positive C-ANCA. Because of his atypical
      presentation, this patient's disease progressed over 8 yr despite an extensive
      gastrointestinal evaluation, before a diagnosis of vasculitis was established
      angiographically, and immunosuppressive therapy was begun.

PMID- 10638603
TI  - Precipitation of iron overload and hereditary hemochromatosis after successful
      treatment of celiac disease.

PMID- 10638604
TI  - Cholangiopathy and intrahepatic stones in sickle cell disease: coincidence or
      ischemic cholangiopathy?
AB  - Hepatic and bile duct involvement are common in sickle cell disease. This article
      reports the case of a young woman with cholangiopathy, homozygous sickle cell
      disease, and protracted anemia. We suggest that sickle cell disease was directly
      responsible for ischemic cholangiopathy through anoxia.

PMID- 10638605
TI  - Rapid onset of massive ascites as the initial presentation of systemic lupus
      erythematosus.
AB  - Ascites in systemic lupus erythematosus (SLE) is rarely massive, and either
      accompanies the typical manifestations of active disease or results from
      nephrotic syndrome, protein-losing enteropathy, constrictive pericarditis, and
      conditions unrelated to lupus. Marked ascites has been attributed to chronic
      lupus peritonitis, characterized by the insidious onset of massive, painless
      ascites and unrelated to disease activity. Regardless of the etiology, ascites
      typically has a gradual onset and occurs after a diagnosis of SLE has been made.
      We describe a young woman presenting with the rapid development of massive
      ascites as the initial manifestation of SLE.

PMID- 10638606
TI  - Neostigmine infusion: new standard of care for acute colonic pseudo-obstruction?
AB  - This study was designed to assess the efficacy of i.v. infusion of neostigmine in
      patients with acute colonic pseudo-obstruction, which was defined as colonic
      distention with a cecal diameter of at least 10 cm on plain radiographs and no
      radiographic evidence of mechanical obstruction. Patients who failed to respond
      to conventional management (nothing by mouth, nasogastric suction, postural
      changes, i.v. fluids, electrolyte replacement, and discontinuation of any drugs
      that affect colonic motility) for 24 h were included in the study. Those with
      bradycardia (heart rate <60/min), hypotension (systolic blood pressure <90 mm
      Hg), active bronchospasm, clinical or radiographic evidence of perforation,
      history of partial colonic resection, active gastrointestinal bleeding,
      pregnancy, or serum creatinine >3 mg/dL were excluded. Twenty patients were
      included in this prospective, randomized, double-blind, placebo-controlled study.
      Eleven patients received neostigmine 2.0 mg i.v. over 3-5 min with
      electrocardiographic monitoring, and 10 received placebo. Patients were evaluated
      for immediate clinical response (passage of flatus or stools associated with
      decreased abdominal distention within 30 min) and sustained response with
      decreased abdominal girth and reduced colonic dilation on radiographs 3 h after
      infusion. Ten patients in the neostigmine group had an immediate clinical
      response (median time, 4 min) compared to none in the placebo group (p<0.001).
      Three patients in the neostigmine group (27%) and eight in the placebo group
      (80%) failed to show sustained improvement 3 h after infusion (p = 0.04). Eight
      patients (one-neostigmine; seven-placebo) who failed to respond received open
      label treatment with neostigmine. Seven patients responded; one patient from the
      placebo group failed and eventually required colonic resection. In conclusion,
      from a total of 18 patients treated with neostigmine, 17 (94%) had immediate
      clinical response, and 16 (89%) did not have recurrent colonic dilation. The most
      common side effect was crampy abdominal pain reported in 13 patients, although
      usually mild (nine). Symptomatic bradycardia requiring atropine occurred in two
      patients. Two patients in the neostigmine group died, but death was felt not to
      be related to acute colonic pseudo-obstruction or its treatment.

PMID- 10638607
TI  - Optimal treatment for localized esophageal cancer still uncertain.
AB  - These articles both report the results of multi-institutional, randomized, phase
      3 trials for the treatment of patients with localized (T1-3 N0-1 M0) esophageal
      squamous cell carcinoma (SCC) or esophageal adenocarcinoma. Both studies were
      initiated and coordinated by the Radiation Therapy Oncology Group (RTOG) but
      included patients enrolled by other study groups as well. Cooper et al. report
      late follow-up results for the RTOG 85-01 trial that was conducted between 1986
      and 1990. This trial randomized patients to either radiation therapy (RT) alone
      (RT, 64 Gy in 32 fractions over 6.4 wk, n = 62) or combined RT and chemotherapy
      (50 Gy in 25 fractions over 5 wk, plus cisplatin 75 mg/m2 i.v. on first day of wk
      1, 5, 8, and 11, and continuous infusion fluorouracil (5FU) 1 g/m2 per day on the
      first 4 days of the same weeks, n = 61). Most (82%) of the patients had SCC.
      Eight percent of the cohort randomly assigned to combined modality therapy
      experienced acute life-threatening toxic effects, and an additional 2% died as a
      direct consequence of treatment. The randomized trial was halted in 1990 when an
      interim analysis found a highly significant difference in survival favoring the
      combined therapy group, after which 73 consecutive patients were enrolled into a
      nonrandomized study offering only the combined therapy regimen. At 5-yr of follow
      up, the overall survival rate for the combined therapy group in the randomized
      study was 26% (95% CI, 15-37%) compared with 0% for RT alone. In the
      nonrandomized study, the 5-yr overall survival rate was 14% (95% CI, 6-23%). The
      histopathological type of tumor did not significantly influence survival. Cooper
      et al. now report that 22% of the randomized combined modality group survived at
      least 8 yr after treatment, and that there were no deaths caused by esophageal
      cancer after 5 yr post-treatment. The study reported by Kelsen et al. included
      440 patients with esophageal adenocarcinoma (n = 236) or SCC (n = 204) randomized
      to either preoperative chemotherapy plus esophagectomy or to esophagectomy alone.
      The chemotherapy regimen consisted of three cycles of preoperative cisplatin and
      5FU and two cycles after operation for responding patients. Doses were higher
      than those used in the RTOG 85-01 trial. Although radiation therapy was not part
      of the treatment plan, it could be given in some circumstances. There was no
      significant difference in median survival (14.9 months for chemotherapy plus
      surgery compared with 16.1 months for surgery alone), and there were also no
      significant differences in 1-yr, 2-yr, 3-yr, or disease-free survival rates.
      There were no significant differences in survival between patients with
      adenocarcinoma and those with SCC. A clinical response to chemotherapy, as
      assessed by barium contrast radiography, was found in 19% of patients who
      received chemotherapy. A complete pathological response was found in 2.5% of
      patients. There was no significant increase in operative complications in the
      chemotherapy treated group.

PMID- 10638608
TI  - Collating collagenous colitis cases.
AB  - Between 1980 and 1993, collagenous colitis was diagnosed in 56 patients at UCLA.
      These authors evaluated the histology of almost 300 biopsies from these patients
      to further clarify the relationship between diagnostic histology and site of
      biopsy. As expected, their patients were predominately women (71%), with a mean
      age at diagnosis of 59 yr. Chronicity of diarrheal symptoms ranged from 3 months
      to 15 yr. Diagnostic subepithelial collagen thickness was variable throughout the
      colon. The highest yield was in transverse colon (83%), right colon (70%), and
      lowest in rectosigmoid (66%). Diagnostic collagen thickness was >15 microm in
      most biopsies, but was detected most readily when >30 microm--a threshold the
      authors suggest increases the diagnostic com-fort level. They recommend flexible
      sigmoidoscopy as adequate for diagnosis of most patients with collagenous
      colitis, noting colonoscopy is often used to clarify diagnosis, i.e., when only
      mild or focal colitis is seen distally.

PMID- 10638610
TI  - Systemic lupus erythematosus after alpha-interferon therapy for chronic hepatitis
      C: a case report and review of the literature.

PMID- 10638609
TI  - Garlic and Helicobacter pylori.

PMID- 10638611
TI  - Streptokinase-induced jaundice due to hemolysis in a G-6PD-deficient patient.

PMID- 10638612
TI  - Peri-PEG cellulitis as a prelude to button extrusion.

PMID- 10638613
TI  - Spontaneous rectus sheath hematoma and an anterior pelvic hematoma as a
      complication of anticoagulation.

PMID- 10638614
TI  - Acute upper gastrointestinal hemorrhage from an ulcer on a Nissen fundoplication.

PMID- 10638615
TI  - 13C-urea breath test using infrared spectroscopy: practical recommendations.

PMID- 10638616
TI  - Domperidone versus metoclopramide in the treatment of diabetic gastroparesis.

PMID- 10638617
TI  - The transmission of Helicobacter pylori via exposure to common sources outweighs
      the person-to-person contact among spouses in developing countries.

PMID- 10638618
TI  - Is malaria chemoprophylaxis also effective against Crohn's disease?

PMID- 10638619
TI  - Age, Helicobacter pylori, and/or CagA antibodies as a pre-endoscopic screening
      policy.

PMID- 10638620
TI  - Crohn's disease epidemiology at the turn of the century-solving the puzzle.

PMID- 10638621
TI  - Probiotics for the hemodynamic alterations of patients with liver cirrhosis.

PMID- 10638622
TI  - Socioeconomics of Crohn's disease: a review of epidemiology and an etiological
      hypothesis.

PMID- 10638623
TI  - Combination therapy of bezafibrate and ursodeoxycholic acid in primary biliary
      cirrhosis: a preliminary study.

PMID- 10638624
TI  - Cytomegalovirus infection in AIDS presenting as a rectal mass.

PMID- 10638625
TI  - Female workforce participation, use of oral contraceptives, and the sex ratio of
      Crohn's disease incidence.

PMID- 10638626
TI  - Dilation of benign esophageal strictures.

PMID- 10638627
TI  - Re: Duplicate publication.

PMID- 10638628
TI  - Behavioral and biochemical studies of dichloromethane fraction from the Areca
      catechu nut.
AB  - The dichloromethane fraction from Areca catechu was found to inhibit monoamine
      oxidase type A isolated from the rat brain with an IC50 of 665 +/- 65.1
      microg/ml. Studies with pharmacological models of depression, i.e., forced swim
      and tail-suspension tests, indicated that it caused significant reduction in the
      immobility time similar to that of moclobemide (a selective inhibitor of MAO-A)
      without causing a significant change in motor performance. Alkaloids such as
      arecaidine, arecoline, and a few other constituents, reported to be present in
      Areca catechu were also tested, but none of them were found to inhibit MAO.
      Present study suggests that the dichloromethane fraction from A. catechu
      possesses antidepressant property via MAO-A inhibition.

PMID- 10638630
TI  - Lesion of the median raphe nucleus: a combined behavioral and microdialysis study
      in rats.
AB  - The purpose of the present study was to investigate the behavioral consequences
      and the neurochemical correlates of a 5,7-dihydroxytryptamine (5,7-DHT) lesion of
      the median raphe nucleus (MRN) in rats. Anxiety-related behavior was assessed in
      the elevated plus maze test on days 5, 14, and 21 after lesioning. In general,
      behavior of MRN-lesioned rats was unchanged when compared with sham-lesioned or
      untreated controls. Neurochemically, microinjection of 5,7-DHT into the MRN
      resulted in 87.5% depletion of hippocampal 5-HT content. Using the in vivo
      microdialysis technique, the exposure of 5,7-DHT-lesioned rats to the elevated
      plus-maze failed to increase extracellular 5-HT release (94%) in the hippocampus,
      as shown in sham-lesioned (150%) or untreated controls (194%). Moreover,
      application of fenfluramine (10 mg/kg, i.p.) evoked a 10-fold increase in
      hippocampal extracellular 5-HT levels in sham-lesioned animals, whereas in 5,7
      DHT lesioned rats 5-HT was only slightly increased. The results demonstrate, that
      a marked reduction of 5-HT release from the MRN is not necessarily accompanied by
      anxiolytic-like behavior.

PMID- 10638629
TI  - Gabaergic-benzodiazepine system is involved in the crotoxin-induced anxiogenic
      effect.
AB  - The behavioral effects of crotoxin (CTX), the major component of Crotalus
      durissus terrificus venom, were studied in rats submitted to the open field,
      holeboard, and social interaction tests. CTX (100, 250, and 500 microg/kg, i.p.)
      was administered 2 h before the tests. In the open field, CTX reduced ambulation
      (250 microg/kg) and rearing (250 and 500 microg/kg) and increased grooming (100
      and 250 microg/kg) and freezing (250 microg/kg). In the holeboard and social
      interaction, all the CTX doses evaluated decreased, respectively, head dip and
      head dipping, and social interaction time. The CTX-induced behavioral alterations
      could be attributed to its neuromuscular transmission blockade, but this
      possibility was ruled out because CTX (250 and 500 microg/kg, i.p., 2 h before
      the rotarod test) was unable to modify the rotarod performance of rats. The
      involvement of the benzodiazepine receptor in the CTX-induced behavioral
      alterations was investigated through the pretreatment (30 min before the tests,
      i.p.) of the animals with diazepam (1.2 mg/kg), or flumazenil (4 and 10 mg/kg).
      Both diazepam and flumazenil antagonized the CTX-induced behavioral alterations
      in the open field, holeboard, and social interaction tests. This study
      demonstrated that: (1) CTX is an anxiogenic compound; and (2) the gabaergic
      benzodiazepine system may play a role in the CTX-induced anxiogenic effect.

PMID- 10638631
TI  - Hypothermia inhibits pentylenetetrazol kindling and prevents kindling-induced
      deficit in shuttle-box avoidance.
AB  - In this study, we evaluated the effects of hypothermic exposure on
      pentylenetetrazol (PTZ) kindling and the resulting deficit of shuttle-box
      avoidance learning in rats. Additionally, to acknowledge neuronal cell loss, we
      estimated the number of toluidine blue-positive cells in different brain regions
      after PTZ kindling and hypothermia exposure in comparison to different
      normothermic and hypothermic controls. To obtain hypothermic conditions over a
      period of up to about 3 h, 30 min after PTZ application the animals were treated
      with 5 mg/kg chlorpromazine (CP) and 25 min later exposed to 15 degrees C cold
      water for 5 min. Under these conditions the rectal and the striatal temperature
      were reduced up to a maximum of 5 degrees C. The additional injection of CP did
      not influence the development of PTZ kindling. Animals treated with PTZ/CP and
      exposed to hypothermia did not reach the criterion for kindling. Furthermore,
      this group of animals did not demonstrate any learning deficit. Forty-eight hours
      after the last kindling application the number of toluidine blue-stained cells
      was decreased in the investigated brain regions (hippocampal CA1 and CA3 sector,
      hilus, and cingular cortex) of kindled rats. Hypothermia protected from cell
      damage in the hippocampal CA3 sector and in the hilus. Results suggest that the
      inhibiting effect of hypothermia on the development of kindling and the following
      learning deficit possibly resulted from the suppression of cell damage in
      distinct brain structures on PTZ-kindled rats.

PMID- 10638632
TI  - The D3 antagonist PNU-99194A potentiates the discriminative cue produced by the
      D3 agonist 7-OH-DPAT.
AB  - Based on correlations between potencies of various dopamine D2/D3 agonists to
      substitute for the 7-OH-DPAT discriminative cue and their in vitro (mitogenesis
      test) potencies, it has been suggested that the 7-OH-DPAT cue is mediated by
      activity at the D3 subtype. We sought to verify that the 7-OH-DPAT cue could be
      blocked by PNU-99194A, a commercially available preferential D3 antagonist. Rats
      were trained (FR10 two-lever, food-reinforced schedule) to press one lever
      following 7-OH-DPAT (0.1 mg/kg i.p.) and the other lever following saline. Rats
      were then tested with various doses of 7-OH-DPAT alone or in combination with PNU
      99194A. 7-OH-DPAT (0.003 to 0.3 mg/kg) engendered dose-dependent substitution;
      PNU-99194A (1 to 10 mg/kg) failed to antagonize the cue induced by 0.1 mg/kg of 7
      OH-DPAT and, at 10 mg/kg, given in combination with 0.003 to 0.1 mg/kg of 7-OH
      DPAT, PNU-99194A markedly shifted the 7-OH-DPAT dose-effect curve to the left,
      i.e., potentiated the 7-OH-DPAT cue. If PNU-99194A is a preferential D3
      antagonist, the present data do not confirm the previous hypothesis that the 7-OH
      DPAT cue is mediated by the D3 subtype.

PMID- 10638633
TI  - Hypoexpression of benzodiazepine receptors in the amygdala of neophobic BALB/c
      mice compared to C57BL/6 mice.
AB  - The distribution of benzodiazepine receptors in the brain of neophobic BALB/c
      mice was studied by autoradiographic analysis using [3H]-diazepam and compared to
      that of the same receptors of the "nonemotional" C57BL/6 mice. This technique
      revealed no significant interstrain difference except for a lower density of
      diazepam binding sites in the amygdala of BALB/c mice. Therefore, the expression
      of benzodiazepine receptors in the amygdala of the two strains of mice were
      quantified by binding studies on brain membranes. The amygdala of BALB/c mice
      exhibited a fivefold decrease in the density of benzodiazepine receptors compared
      to C57BL/6 mice. These results suggest that the trait anxiety (neophobia) that
      characterizes BALB/c mice could be due, at least in part, to a genetic modulation
      of benzodiazepine receptor expression in the amygdala, a structure known to be
      strongly involved in fear behavior.

PMID- 10638634
TI  - Prenatal morphine exposure alters N-methyl-D-aspartate- and kainate-induced
      seizures in adult male rats.
AB  - The purpose of the present study was to investigate whether prenatal exposure to
      morphine has effects on excitatory amino acid-induced seizures. Adult male rats,
      exposed on embryonic days 11-18 to saline or morphine, were injected with N
      methyl-D-aspartate (NMDA) (150, 175, 200, 225, and 250 mg/kg) or kainic acid (KA)
      (15 or 20 mg/kg) in adulthood to assess the occurrence and latency to onset of
      stereotypy and seizures. The latency to onset of stereotypy was significantly
      increased after 175 mg/kg, and decreased after 200 mg/kg of NMDA in morphine
      exposed animals. The lowest dose of NMDA (150 mg/kg) induced seizures in
      prenatally saline-treated control male rats but not in the morphine-exposed male
      rats. In the KA-injected group, prenatally morphine-exposed males had shorter
      latency to onset of wet-dog shakes, but there were no effects on the latency to
      onset of clonic seizures. The data suggest that prenatal morphine exposure has
      long-term effects on seizure susceptibility and the onset of stereotypy in the
      excitatory amino acid-induced seizure models.

PMID- 10638635
TI  - Modulation of the discriminative stimulus effects of d-amphetamine by mu and
      kappa opioids in squirrel monkeys.
AB  - It has been reported that the discriminative stimulus effects of cocaine in
      squirrel monkeys can be potentiated by mu opioid agonists and attenuated by kappa
      opioid agonists. The purpose of this study was to extend these observations by
      examining the effects of mu and kappa opioids agonists on the discriminative
      stimulus effects of d-amphetamine (AMPH). Five squirrel monkeys were trained to
      discriminate 0.3 mg/kg of AMPH (i.m.) from saline using a stimulus
      termination/avoidance task. AMPH and cocaine substituted dose dependently for the
      AMPH training stimulus in all five monkeys. The AMPH training dose was completely
      antagonized by 0.1 mg/kg of the D1 dopamine antagonist SCH 39166. When
      administered alone, the kappa agonist U69,593 substituted partially or completely
      for AMPH in four of five monkeys, the kappa agonist enadoline substituted
      completely for AMPH in two of five monkeys, and morphine substituted completely
      for AMPH in one monkey. In all five monkeys, pretreatment with some doses of
      U69,593 or enadoline attenuated the discriminative stimulus effects of AMPH;
      however, some doses of U69,593 and enadoline also potentiated the effects of AMPH
      in at least two monkeys. Morphine pretreatment potentiated the discriminative
      stimulus effects of AMPH in three monkeys and either attenuated or did not alter
      these effects in two monkeys. Morphine pretreatment did not significantly alter
      the discriminative stimulus effects of cocaine except in one monkey. These data
      indicate large individual differences in the abilities of mu and kappa opioid
      agonists to alter the discriminative stimulus effects of AMPH.

PMID- 10638636
TI  - Kappa opioid-induced diuresis in female vs. male rats.
AB  - Kappa opioid agonists may produce dissimilar discriminative and analgesic effects
      in female vs. male subjects. The present study was conducted to determine whether
      a prototypic physiological effect of kappa agonists--diuresis--also differs
      between the sexes. When data were not corrected for individual differences in
      body weight, the kappa agonists U69,593 (0.03-3.0 mg/kg), U50,488 (0.3-10 mg/kg),
      (-)-bremazocine (0.001-0.1 mg/kg) and (-)-pentazocine (1-10 mg/kg), as well as a
      nonopioid diuretic, furosemide (1-10 mg/kg) produced significantly greater
      diuresis in normally hydrated, age-matched males than females; however, there was
      no sex difference in the diuretic effect of butorphanol (0.3-3.0 mg/kg), or in
      the antidiuretic effect of the mu agonist morphine (1.0-5.6 mg/kg, in water
      loaded rats). In contrast, when data were corrected for individual difference in
      body weight, U69,593, U50,488, (-)-bremazocine, (-)-pentazocine, and furosemide
      produced nearly equivalent diuresis/kg in females and males, whereas butorphanol
      produced slightly greater diuresis/kg, and morphine produced significantly less
      antidiuresis/kg, in females than males. U69,593-induced diuresis was highly
      similar in males and females of similar body weight (i.e., different ages).
      U69,593 effects were dose-dependently antagonized by the kappa antagonist nor
      binaltorphimine in both sexes, indicating a common, kappa receptor-mediated
      mechanism of action. (-)-Bremazocine was slightly more potent in suppressing
      vasopressin in 24-h water-deprived males than females. These results suggest that
      the greater diuretic effects of kappa receptor-selective opioid agonists in male
      rats are primarily due to males' larger body size (greater body water) relative
      to age-matched females, but may also be attributed to slightly greater
      vasopressin suppression in males.

PMID- 10638637
TI  - Antinociceptive activity of derivatives of improgran and burimamide.
AB  - Improgan, a compound related to H2 and H3 antagonists, induces antinociception in
      rodents after intraventricular administration. Characteristics of improgan and
      its congeners include: (a) morphine-like antinociception on thermal and
      mechanical tests in two species; (b) no impairment of motor coordination or
      locomotor activity; (c) evidence for a novel, nonopioid mechanism that is
      independent of known histamine receptors; (d) lack of tolerance with daily
      dosing; and (e) unique structure-activity relationships (SARs). Presently, the
      antinociceptive activity of several new derivatives of improgan was investigated
      in rats. Among compounds similar to burimamide, VUF4577 (possessing a two-carbon
      side chain) and VUF4582 (an N-phenyl derivative of VUF4577) induced complete,
      dose- and time-dependent antinociception on the hot-plate and tail-flick tests
      with no behavioral side effects. These compounds (with ED50 values of 71-117
      nmol) were approximately twice as potent as burimamide itself (a four-carbon
      derivative). Two other derivatives in which the thiourea group (C=S, known to
      cause human toxicity) was replaced by either nitroethene (C=CH-NO2, VUF5405) or
      urea (C=O, VUF5407) also showed effective, potent antinociception on both assays.
      The latter compound is the most potent improgan-like drug discovered to date
      (ED50 = 71 nmol). Furthermore, positional isomers of antinociceptive compounds
      either lacked activity (VUF5394) or induced toxicity (VUF5393), revealing a high
      degree of pharmacological specificity. Although the mechanism of improgan
      antinociception remains unknown, the present results show promise for the further
      development of safe, effective, and potent pain-relieving compounds.

PMID- 10638638
TI  - Glutamatergic control of food intake in pigeons: effects of central injections of
      glutamate, NMDA, and AMPA receptor agonists and antagonists.
AB  - The possible involvement of glutamatergic mechanisms in the control of food
      intake was studied in free-feeding and in 24-h food-deprived (FD24) pigeons for 1
      h after intracerebroventricular (i.c.v.) treatment with glutamate (Glu, 0, 50,
      150, 300, and 600 nmol). Glu injections dose dependently induced decreases (30
      65%) in food intake (FI) and feeding duration (FD), and increases in latency to
      start feeding (LSF) in FD24 animals, but not in free-feeding ones. None of these
      treatments affected noningestive behaviors (locomotion, sleep, and preening). In
      FD24 pigeons, i.c.v. treatments with N-methyl-D-aspartic acid (NMDA, 0.1, 1, 4,
      8, or 16 nmol) or D,L-alpha-amino-3-hydroxy-isoxazole proprionic acid (AMPA, 0.1,
      1, 4, or 8 nmol) decreased FI and FD, but left LSF unchanged compared to vehicle
      treated FD24 controls. Kainic acid (0.1, 0.5, and 1 nmol), or [trans-(1S,3R)-ACPD
      (5NH4OH)] (ACPD, 0.1, 1, 4, 8, and 16 nmol) left unchanged the ingestive profile
      of FD24 pigeons. Pretreatment with the NMDA receptor antagonist MK-801 (15 nmol)
      and the AMPA-kainate receptor antagonist CNQX (390 nmol), 20 min before an i.c.v.
      injection of Glu (300 nmol) induced a partial blockade of the Glu-induced
      decreases in FI and FD and completely inhibited the Glu-induced increase in LSF
      in FD24 pigeons. I.c.v. injections of MK-801 (30 nmol) and of CNQX (780 nmol)
      increased FI and FD and reduced LSF in free-feeding pigeons. A lower dose of MK
      801 (15 nmol) increased FI and FD, but not LSF. Conversely, a lower dose of CNQX
      (390 nmol) reduced LSF without changing FI or FD. These findings indicate the
      involvement of Glu as a chemical mediator in the regulation of food intake in the
      pigeon, possibly acting on multiple central mechanisms in this species through
      NMDA- and AMPA-sensitive Glu receptors.

PMID- 10638639
TI  - The paradox of 5-methoxy-N,N-dimethyltryptamine: an indoleamine hallucinogen that
      induces stimulus control via 5-HT1A receptors.
AB  - Stimulus control was established in rats trained to discriminate either 5-methoxy
      N,N-dimethyltryptamine (3 mg/kg) or (-)-2,5-dimethoxy-4-methylamphetamine (0.56
      mg/kg) from saline. Tests of antagonism of stimulus control were conducted using
      the 5-HT1A antagonists (+/-)-pindolol and WAY-100635, and the 5-HT2 receptor
      antagonist pirenperone. In rats trained with 5-MeO-DMT, pindolol and WAY-100635
      both produced a significant degree of antagonism of stimulus control, but
      pirenperone was much less effective. Likewise, the full generalization of 5-MeO
      DMT to the selective 5-HT1A agonist [+/-]-8-hydroxy-dipropylaminotetralin was
      blocked by WAY-100635, but unaffected by pirenperone. In contrast, the partial
      generalization of 5-MeO-DMT to the 5-HT2 agonist DOM was completely antagonized
      by pirenperone, but was unaffected by WAY-100635. Similarly, in rats trained with
      (-)-DOM, pirenperone completely blocked stimulus control, but WAY-100635 was
      inactive. The results obtained in rats trained with (-)-DOM and tested with 5-MeO
      DMT were more complex. Although the intraperitoneal route had been used for both
      training drugs, a significant degree of generalization of (-)-DOM to 5-MeO-DMT
      was seen only when the latter drug was administered subcutaneously. Furthermore,
      when the previously effective dose of pirenperone was given in combination with 5
      MeO-DMT (s.c.), complete suppression of responding resulted. However, the
      combination of pirenperone and WAY-100635 given prior to 5-MeO-DMT restored
      responding in (-)-DOM-trained rats, and provided evidence of antagonism of the
      partial substitution of 5-MeO-DMT for (-)-DOM. The present data indicate that 5
      MeO-DMT-induced stimulus control is mediated primarily by interactions with 5
      HT1A receptors. In addition, however, the present findings suggest that 5-MeO-DMT
      induces a compound stimulus that includes an element mediated by interactions
      with a 5-HT2 receptors. The latter component is not essential for 5-MeO-DMT
      induced stimulus control, but is revealed in animals tested or trained with a 5
      HT2-selective agonist such as (-)-DOM. Based upon the present data, we conclude
      that 5-MeO-DMT differs from DOM with respect to the serotonergic element that
      mediates stimulus control in the rat, but that it shares with DOM a functionally
      significant interaction with 5-HT2 receptors.

PMID- 10638640
TI  - Conditioned suppression with cocaine as the unconditioned stimulus.
AB  - A conditioned-suppression procedure was used to study drug conditioning using
      cocaine as the unconditioned stimulus (UCS). Rats were first trained to nose poke
      for food-reinforcement during daily 60-min sessions. At least 1 week following
      jugular vein catheterization, a 5-min tone-light compound stimulus was presented
      30 min into the food-reinforcement session. Two minutes after the onset of the
      stimulus, either 0 (saline), 1.0, 3.0 or 5.6 mg/kg cocaine, was administered i.v.
      to separate groups of rats. For another group, the stimulus was presented, and
      the 5.6 mg/kg dose of cocaine was injected in an unpaired fashion (i.e., at
      different times). After 5 days of training a test was given with the tone-light
      stimulus presented alone. No disruption of responding during the tone-light
      stimulus was observed in the saline and 1.0 mg/kg cocaine groups or for the
      unpaired group. When the tone-light stimulus was paired with 5.6 mg/kg cocaine;
      however, it produced nearly a 50% reduction in responding, which then gradually
      extinguished when the stimulus was presented alone for 5 days. The 3.0 mg/kg
      cocaine group produced intermediate suppression. When the tone-light compound
      stimulus was shortened to 70 s and the interstimulus interval (ISI) was 0, 30, or
      60 s in three separate groups of rats, the most robust conditioned suppression
      was observed at the 60 s ISI. Therefore, the conditioned suppression procedure,
      using 3.0 or 5.6 mg/kg i.v. cocaine doses as the UCS, produced robust
      conditioning effects comparable to other drugs and more conventional reinforcers.
      The conditioned suppression procedure may be a useful model for studying the
      classically conditioned effects of cocaine.

PMID- 10638641
TI  - Gender differences in the reinforcing properties of morphine.
AB  - The purpose of the present studies was to examine whether gender differences
      could be observed in an important aspect of morphine's pharmacology: its
      reinforcing properties. Our results showed that morphine served as a positive
      reinforcing agent in both male and female rats in a place conditioning paradigm,
      but that the dose-response curves displayed marked sex-related differences. At
      doses from 0.2 up to 10.0 mg/kg, morphine induced an equally strong preference
      for the drug-associated chamber in males and females. However, as the dose was
      increased from 10-17.5 mg/kg, morphine ceased to act as a positive reinforcer in
      males. In contrast, a very strong preference for the morphine-associated chamber
      was still observed in females at doses up to 30 mg/kg. No gender differences in
      the blood and brain levels of morphine were observed subsequent to morphine
      administration during the conditioning phase, suggesting that pharmacokinetic
      factors were not involved in the sex-related differences observed. Consequently,
      these results suggest that there are intrinsic sex-linked differences in the
      doses of morphine that can induce a preference for the drug-associated chamber in
      a place-conditioning paradigm that are most likely related to differences in the
      sensitivity of the central nervous system to morphine's reinforcing properties in
      males and females.

PMID- 10638642
TI  - Intake of a palatable sucrose solution modifies the actions of spiradoline, a
      kappa opioid receptor agonist, on analgesia and feeding behavior in male and
      female rats.
AB  - Previous research has shown that rats consuming a sucrose solution and chow are
      more sensitive to the analgesic actions of morphine, a selective mu opioid
      agonist, and the anorectic actions of opioid antagonists, than rats eating only
      chow. However, from these data, it cannot be determined if sucrose intake only
      modifies the behavioral consequences of drugs that act at the mu opioid receptor,
      or if the sugar also alters the actions of opioid drugs that act at other opioid
      receptor subtypes. Thus, the present experiments examined the effects of sucrose
      intake on the actions of spiradoline, a selective kappa opioid agonist, on
      analgesia and food intake in male and female Long-Evans rats. In Experiment 1,
      male and female rats consumed either chow, a 32% sucrose solution and water, or
      only chow and water. After 3 weeks, antinociceptive responses on the tail-flick
      test were determined after spiradoline injections (0.0, 0.3, 1.0, and 3.0 mg/ kg,
      s.c.). Rats fed sucrose were more sensitive to the analgesic actions of
      spiradoline than rats fed only chow. In Experiment 2, drug-naive male and female
      rats were maintained under the same dietary conditions as in Experiment 1. Food
      intake was measured 1, 2, 4, and 6 h after spiradoline injections (0.0, 0.3, 1.0,
      and 3.0 mg/kg, s.c.). Spiradoline led to significant dose-related decreases in
      food intake for males and females in both dietary conditions. However, the
      anorectic effects of the drug were more pronounced in rats fed sucrose than in
      those eating only chow. These results support the hypothesis that intake of
      palatable foods and fluids alters the activity of the endogenous opioid system.

PMID- 10638643
TI  - Chlordiazepoxide-induced spatial learning deficits: dose-dependent differences
      following prenatal malnutrition.
AB  - The sensitivity of prenatally protein-malnourished rats to the amnestic
      properties of the benzodiazepine (BZ) receptor agonist, chlordiazepoxide (CDP),
      was studied in the male offspring of rats provided with a protein-deficient diet
      (6% casein) for 5 weeks prior to mating and throughout pregnancy. Rats were
      tested during acquisition of the submerged platform version of the Morris water
      maze task using three systemic doses of CDP (3.2, 5.6, and 7.5 mg/kg i.p.) at two
      ages (day 30 and day 90). At 30 days, prenatally malnourished rats showed less
      sensitivity to the amnestic effect of the 5.6-mg/kg dose when compared with well
      nourished controls by displaying shorter swim paths during acquisition and a more
      selective search of the target quadrant upon removal of the platform (probe
      trial). At 90 days, prenatally malnourished rats again showed less sensitivity to
      CDP at a dose of 5.6 mg/kg, but more sensitivity to the 3.2-mg/kg dose (indicated
      on the probe trial). No obvious relationship was identified between the
      nutritional group differences in behavioral sensitivity to CDP at 90 days and
      their BZ receptor density in the hippocampus or medial septum. It can be
      concluded that prenatal malnutrition alters the amnestic response to CDP in a
      dose-dependent and developmentally specific manner, thus providing further
      support for functional changes within the GABAergic system subsequent to
      malnutrition.

PMID- 10638644
TI  - Effect of lidocaine on harmaline-induced tremors in the rat.
AB  - The present study was undertaken to investigate the effect of lidocaine on
      harmaline-induced tremors in the rat. Four groups of Wistar rats weighing 45-50 g
      were injected with harmaline (50 mg/kg i.p.) for inducing experimental tremors.
      The rats in group 1 served as control, whereas the animals in groups 2, 3, and 4
      were also given lidocaine i.p. at doses of 12.5, 25, and 50 mg/kg, respectively,
      10 min after the onset of tremors (therapeutic study). In a separate four groups
      of animals intraperitoneal lidocaine injection was given 10 min before harmaline
      (prophylactic study) in the same dose regimen as mentioned above. The latency of
      onset, intensity, and duration of tremor and electromyographic responses were
      recorded. Lidocaine dose dependently attenuated harmaline-induced tremors in
      rats. The latency period was increased, and duration and intensity of harmaline
      induced tremors was reduced by lidocaine. Our electromyography (EMG) study also
      revealed a decrease in the amplitude of harmaline-induced tremors in lidocaine
      treated rats. In conclusion, the results of this study clearly suggest beneficial
      effects of lidocaine in harmaline-induced tremors.

PMID- 10638645
TI  - Behavioral and hormonal effects of centrally injected "anxiogenic" neuropeptides
      in growing pigs.
AB  - Records of behavior (alertness, posture, oro-nasal responses, activity level, and
      vocalization pattern) were made in prepubertal pigs (n = 6) during a 60-min
      period following central injections of equimolar (21 nmol) doses of porcine CRH
      (pCRH), urocortin (UCN), octadecaneuropeptide (ODN), or saline vehicle (SAL).
      Blood samples were also collected at 15-min intervals before, during, and after
      the test, and used to determine plasma cortisol, prolactin, and growth hormone
      concentrations. The pigs became excited and highly active after pCRH, and to a
      lesser extent following UCN administration, but were subdued when given ODN or
      SAL. None of the peptides significantly affected prolactin or growth hormone
      release, but both UCN, and especially pCRH, increased cortisol concentrations.
      The emotional responses induced by pCRH and UCN are consistent with observations
      in rodents, which indicate that centrally administered CRH-like peptides have
      anxiogenic effects. In contrast, ODN, which inhibits benzodiazepine binding at
      the GABA(A) receptor and is anxiogenic in rodents, lowered plasma cortisol and
      had no overt behavioral effects. Hence, at the dose administered, there was no
      evidence to indicate that ODN acted as an anxiogen in this species.

PMID- 10638646
TI  - The allocentric place discrimination task is selectively and highly dependent on
      the central muscarinic system in rats.
AB  - The allocentric place discrimination task (APDT) is useful in evaluating working
      memory separately from and simultaneously with motivation, motor and sensory
      ability. Muscarinic acetylcholine receptor antagonist scopolamine has been shown
      to selectively impair the accuracy of APDT without changing swimming speed,
      distance, and still time. For further evaluation of other neurotransmitters'
      roles in the APDT, pharmacological manipulations were performed. Neither diazepam
      3.0 mg/kg, mecamylamine 10 mg/kg, haloperidol 0.5 mg/kg, nor 8-OH DPAT 1.0 mg/kg
      affected accuracy of place discrimination. Two kinds of responses were observed
      following the administration of MK-801 0.3 mg/kg: the accuracy of rats for longer
      swimming distance tended to decrease, and the accuracy of rats for normal
      swimming distance did not change. Therefore, NM-801 did not seem to affect the
      working memory selectively. In addition, neither flumazenil 10 mg/kg, ondansetron
      0.3 mg/kg nor R(-)-alpha-metylhistamine 10 mg/kg attenuated the scopolamine
      induced deficits. These results suggest that the central muscarinic receptors are
      selectively and highly important in the APDT.

PMID- 10638647
TI  - Strain differences in neuropathic hyperalgesia.
AB  - The purpose of this study was to investigate strain-related differences in the
      onset and maintenance of thermal hyperalgesia following the induction of
      peripheral nerve injury in two inbred strains of rats (Fischer 344 and Lewis) and
      two outbred strains of rats (Sprague-Dawley and Wistar). Neuropathic pain was
      induced via unilateral ligation of the left sciatic nerve with chromic gut
      sutures. A plantar analgesia meter was used to measure paw-withdrawal latency
      from the ligated vs. unligated hind paws of inbred vs. outbred strains of rats to
      investigate strain-related differences in nerve injury-induced thermal
      hyperalgesia. The results demonstrated no significant effects of animal strain on
      presurgical paw-withdrawal latency values. Following the sciatic nerve ligation
      (SNL) surgery, a significant hyperalgesic response was elicited from the Sprague
      Dawley and Wistar rats (outbred strains) for at least 28 days. Conversely, data
      analyses from the inbred strains failed to demonstrate significant hyperalgesic
      responses to peripheral nerve injury, with the exception of postsurgical day 10.
      These data emphasize the importance of considering the strain of the rat being
      investigated before extrapolating the results from animals experiments to
      treatment strategies for humans with chronic neuropathic pain.

PMID- 10638648
TI  - Delta-opioid and 5-HT3 receptor antagonist effects on ethanol reward and
      discrimination in C57BL/6 mice.
AB  - The effects of the receptor antagonists MDL 72222 (MDL, 5-HT3) and naltrindole
      (delta-opioid) on ethanol reward and its discrimination were examined in ethanol
      preferring C57BL/6 (C57) mice. MDL attenuated lever responding for 12% ethanol
      delivered on a fixed-ratio 8 reinforcement schedule at a dose that did not
      influence responding for water reward, thus confirming a previous report that ICS
      205-930 reduced ethanol reward for Long-Evans rats. Our study in combination with
      the reduced ethanol consumption reported for C57 mice injected with odansetron
      indicates that 5-HT3 receptor systems are involved in mediating behavior directed
      toward obtaining ethanol as well as its consumption. By attenuating the rewarding
      effects of ethanol or of ethanol conditioned cues (e.g., the operant
      environment), 5-HT3 antagonists may be useful in the treatment of alcohol abuse.
      The 5-HT3 antagonist effects in this study are comparable with the effects of
      naltrexone on ethanol reward in C57 mice, although higher doses were required to
      reduce operant responding for ethanol reward. In contrast to the 5-HT3 antagonist
      and naltrexone effects, naltrindole, an antagonist with greater specificity for
      the delta-opioid receptor, was without effect on ethanol reward. This result and
      recent reports for rats and monkeys suggests that the general antagonists might
      be more efficacious in attenuating ethanol reward. Both MDL and naltrindole
      produced only slight reductions in the ethanol discriminative cue, suggesting
      that the rewarding and discriminative effects of ethanol are not likely mediated
      by identical neural mechanisms as previously suggested.

PMID- 10638649
TI  - Caffeine during sleep deprivation: sleep tendency and dynamics of recovery sleep
      in rats.
AB  - The adenosine antagonist caffeine disrupts sleep, but whether caffeine promotes
      wakefulness by interfering with the expression of sleep or by attenuating
      sleepiness is unknown. The ability of caffeine to reduce sleep tendency in rats
      was directly tested by quantifying the number of stimuli needed to maintain
      wakefulness during sleep deprivation for 6 h after systemic caffeine treatment.
      In addition, the influence of caffeine on the dynamics between nonrapid-eye
      movement (NREM) and rapid-eye-movement (REM) sleep was investigated by comparing
      the magnitude and time course of the compensatory sleep responses for 42 h
      postsleep deprivation. Caffeine significantly reduced the attempts to sleep
      during sleep deprivation, F(1,9) 8.83, p = 0.0157; 44.9% of vehicle), but did not
      change compensatory slow-wave activity during recovery sleep. During the initial
      recovery phase, caffeine suppressed compensatory REM sleep and reduced, but did
      not block, compensatory NREM sleep duration and continuity. By 42 h postsleep
      deprivation, the amount of NREM recovered (70.0% of deficit) did not differ from
      vehicle. In contrast, the REM sleep deficit recovered after caffeine (100%) was
      more than after vehicle (43.9%). Thus, caffeine slowed the rate of compensatory
      sleep after sleep deprivation, as indexed by the duration of sleep states and
      sleep continuity.

PMID- 10638650
TI  - Role of the laterodorsal tegmental nucleus in scopolamine- and amphetamine
      induced locomotion and stereotypy.
AB  - Scopolamine (1.5 mg/kg; i.p.) or amphetamine (3 mg/kg; i.p.) increases locomotion
      and stereotyped behavior patterns in rats. Previous studies suggest that
      scopolamine acts via muscarinic receptors near the midbrain-pons border. In this
      study, unilateral microinjections in N-methyl-scopolamine (2.5-10 microg) into
      the laterodorsal tegmental nucleus (LDT) increased locomotion. Bilateral
      ibotenate lesions of the LDT attenuated scopolamine-induced locomotion by 68% 7
      days postlesion, and by 35% 28 days postlesion. LDT lesions reduced scopolamine
      induced stereotypy less than locomotion. The sensitization to amphetamine
      observed on repeated tests was attenuated by LDT lesions for stereotypy, but not
      for locomotion. These findings suggest that scopolamine induces locomotion
      largely, but not exclusively, by blocking muscarinic receptors in LDT.

PMID- 10638651
TI  - Scopolamine augments the efficacy of physostigmine against soman poisoning in
      guinea pigs.
AB  - The efficacy of the subchronically administered cholinesterase-inhibitor
      physostigmine (PHY) (0.025 mg/kg/h) either with or without the muscarinergic
      receptor antagonist scopolamine (SCO) (0.018 mg/kg/h) in counteracting soman
      induced lethality and incapacitation were determined in guinea pigs. This was
      tested in animals that either received atropine sulphate (AS, 17.4 mg/kg i.m.) or
      no postintoxication therapy. Behavioral and neurophysiological readout systems
      were used to measure postintoxication incapacitation. Only the pretreatment with
      PHY alone did not offer any protection against 2x LD50 soman intoxication.
      Animals that received the complete treatment (PHY + SCO + AS) did not show any
      abberations in the performance of learned behavior. The use of AS after soman
      intoxication resulted in an increase of the startle response, whereas the
      addition of SCO to the pretreatment led to a more persistent duration of the
      effect in time. In case one has to rely completely on the pretreatment, the
      addition of SCO to PHY is life-saving. However, some postintoxication
      incapacitation is still present. Therefore, the pretreatment regime may perhaps
      further be improved by the addition of a nicotinic antagonist.

PMID- 10638652
TI  - Feeding and 8-OH-DPAT-related release of serotonin in the rat lateral
      hypothalamus.
AB  - Based on the different effects of somatodendritic 5-HT1A agonist 8-OH-DPAT on
      food intake whether given to food-deprived rats or freely feeding rats, we
      hypothesized that the effects of 8-OH-DPAT on extracellular serotonin (5-HT) in
      the lateral hypothalamus (LH) will interfere with different feeding states,
      eventually resulting in different patterns of 5-HT release. In a microdialysis
      study we measured extracellular 5-HT in the LH after 8-OH-DPAT under four
      experimental conditions, i.e., in freely feeding rats with no food available,
      freely feeding rats with access to food, in food-deprived rats with no food
      available, and in food-deprived rats with good available after treatment. The
      results show a significant decrease of 5-HT release after 300 microg/kg 8-OH-DPAT
      (i.p.) in freely feeding rats. This effect is not seen when food is provided
      after drug treatment. In contrast, the same dose of 8-OH-DPAT has no effect on 5
      HT release in food-deprived rats. In addition, providing food after drug
      treatment does not change the release pattern significantly in food-deprived
      rats, suggesting more complexity in the underlying mechanisms. The present study
      describes the effects of 8-OH-DPAT on 5-HT release in the LH, depending on
      feeding conditions and feeding-related behavioral states.

PMID- 10638653
TI  - A nicotine conjugate vaccine reduces nicotine distribution to brain and
      attenuates its behavioral and cardiovascular effects in rats.
AB  - Vaccination of animals to elicit drug-specific antibodies, or the passive
      transfer of such antibodies from other animals, can reduce the behavioral effects
      of drugs such as cocaine and heroin. To study the potential application of this
      approach to treating nicotine dependence, IgG was isolated from rabbits immunized
      with a nicotine-protein conjugate vaccine. Anesthetized rats received immune IgG
      containing nicotine-specific antibodies (Nic-IgG) or control-IgG i.v.. Thirty
      minutes later, rats received nicotine at 0.03 mg/kg i.v., equivalent on an mg/kg
      basis to the nicotine intake from two cigarettes by a smoker. Compared to control
      IgG, Nic-IgG reduced the brain nicotine concentration in a dose-related manner
      (65% reduction at the highest IgG dose). Pretreatment with Nic-IgG also reduced
      the distribution to brain of five repeated doses of nicotine (equivalent to the
      nicotine intake from 10 cigarettes) administered over 80 min. To study blood
      pressure effects, rats received control-IgG or Nic-IgG 1 day prior to
      administering nicotine. Nicotine-induced systolic blood pressure increases were
      attenuated by Nic-IgG in a dose-related manner, and were almost completely
      blocked by the highest Nic-IgG dose. Pretreatment with Nic-IgG also completely
      prevented the nicotine-induced stimulation of locomotor activity observed in rats
      receiving control-IgG. Nic-IgG did not prevent locomotor activation from cocaine,
      demonstrating its specificity for nicotine. These data demonstrate that the
      administration of nicotine-specific antibodies can reduce or prevent some of the
      pharmacokinetic, cardiovascular, and behavioral consequences of nicotine in rats.
      Effects were observed at nicotine doses and nicotine serum concentrations equal
      to or exceeding those typically associated with nicotine exposure in cigarette
      smokers. A potential role for immunization in the treatment of nicotine
      dependence is suggested.

PMID- 10638655
TI  - Computer-based imaging and interventional MRI: applications for neurosurgery.
AB  - Advances in computer technology and the development of open MRI systems
      definitely enhanced intraoperative image-guidance in neurosurgery. Based upon the
      integration of previously acquired and processed 3D information and the
      corresponding anatomy of the patient, this requires computerized image-processing
      methods (segmentation, registration, and display) and fast image integration
      techniques. Open MR systems equipped with instrument tracking systems, provide an
      interactive environment in which biopsies and minimally invasive interventions or
      open surgeries can be performed. Enhanced by the integration of multimodal
      imaging these techniques significantly improve the available treatment options
      and can change the prognosis for patients with surgically treatable diseases.

PMID- 10638654
TI  - Computer aided surgery with special focus on neuronavigation.
AB  - The term computer aided surgery (CAS) is now mainly used for an intraoperative
      navigation within the body combining a 3D-digitizer with preoperative CT/MR
      imaging. This method has become indispensable in neurosurgery for the removal of
      deep-seated and/or critically located intracranial tumors and vascular
      malformations. Also ENT surgery within the paranasal sinuses and setting of
      pedicle screws in orthopedic surgery profit greatly from the high targeting
      precision of CAS. And still a growing number of surgical disciplines are
      employing this method. Today infrared-optical 3D-digitizers are state of the art,
      but electromagnetic spatial digitizing using novel, miniature localizers is
      promising, too. The results of our CAS study 1994-mid-1997 with 50 patients
      suffering from small intracranial lesions are presented.

PMID- 10638656
TI  - The quality of functional MR images in patients with brain tumors: influences of
      neurological disorders and tumor location.
AB  - The aim of our study was to investigate the influence of neurological disorders,
      and the influence of tumor and perifocal edema location on functional magnetic
      resonance imaging (fMRI) quality. fMRI quality tended to be better the closer the
      tumor and the perifocal edema were located to the pmc. Hemipareses and seizures
      had no significant influence on fMRI quality. Therefore, hemiparetic patients do
      not have to be excluded beforehand. The evaluation of time courses is essential
      before using z-maps to localize eloquent brain regions preoperatively.

PMID- 10638657
TI  - A low-cost PCI-bus-based ultrasound system for use in image-guided neurosurgery.
AB  - A low-cost PCI-bus-based ultrasound sub-system has been developed and integrated
      into the image-guided neurosurgery system currently in use at the Cleveland
      Clinic. Two software applications have been developed that integrate real-time
      ultrasound images with preoperative MR and CT data sets. By tracking the position
      of the ultrasound probe during surgery, it is possible to display a real time
      ultrasound image and the corresponding (preoperative) oblique CT or MR slice.
      This provides immediate positional feedback to the neurosurgeon during the
      surgical procedure.

PMID- 10638658
TI  - Rapid protyping technology in medicine--basics and applications.
AB  - Using medical models built with Rapid Prototyping (RP) technologies represents a
      new approach for surgical planning and simulation. These techniques allow one to
      reproduce anatomical objects as 3D physical models, which give the surgeon a
      realistic impression of complex structures before a surgical intervention. The
      shift from the visual to the visual-tactile representation of anatomical objects
      introduces a new kind of interaction called 'touch to comprehend'. As can be
      seen, from the presented case studies of maxillo-cranio-facial surgery, the RP
      models are very well suited for use in the diagnosis and the precise preoperative
      simulation of skeleton modifying interventions.

PMID- 10638659
TI  - Perspective volume rendered motion: gaining insights virtually.
AB  - Since modern imaging modalities deliver huge amounts of data the visualization
      techniques utilized must emphasize the structures of interest. To compare them,
      the different visualization techniques are regressed to a common ground whereby
      their strengths and weaknesses can be revealed. Perspective, lighting, color and
      motion support the real world look and feel. Virtual 3D techniques allow the
      observer to move through 3D images of anatomy almost in real time. In virtual
      cisternoscopy this concept is applied to 3D data of the head to reveal a closer
      look at the cerebral vessels. The more realistic presentation of the 3D data
      allows for higher efficiency.

PMID- 10638660
TI  - MR diagnosis of vein of Galen aneurysmal malformations using virtual
      cisternoscopy.
AB  - Vein of Galen aneurysmal malformations (VGAMs) are rarely seen intracranial
      congenital vascular malformations with extremely complex vascular architectures.
      We present two newborns with an unclear intracranial mass being discovered in
      routine intrauterine ultrasonography. Magnetic resonance imaging (MRI) and
      magnetic resonance angiography (MRA) identified these lesions as VGAMs. Besides
      conventional MRA analysis, "virtual cisternoscopy"-a special kind of virtual
      endoscopy combining perspective volume rendering and motion-was applied to assess
      the intracranial vasculature. One newborn was treated by means of interventional
      neuroradiology with coiling of the median prosencephalic vein. The clinical
      outcome in this case was excellent. The other will undergo interventional therapy
      shortly.

PMID- 10638661
TI  - Caspases -2, -3, -6, and -9, but not caspase-1, are activated in sepsis-induced
      thymocyte apoptosis.
AB  - Sepsis induces extensive lymphocyte cell death that may contribute to immune
      depression and morbidity/mortality in the disorder. bcl-2 is a member of a new
      class of oncogenes that prevents cell death from an array of noxious stimuli.
      Transgenic mice that overexpress BCL-2 in T lymphocytes are resistant to sepsis
      induced T cell apoptosis, and mortality was decreased in sepsis. The purpose of
      this study was to identify key initiator and executioner "caspases" involved in
      sepsis-induced lymphocyte apoptosis and to determine if BCL-2 acts prior to
      caspase activation. Thymi were removed 5-22 h post-cecal ligation and puncture
      (CLP) or sham surgery. Apoptosis was evaluated in thymocytes by annexin-V FITC
      labeling and flow cytometry. Caspase-1 activity was determined by western blot
      analysis of the procaspase protein and p20 subunit of the activated caspase;
      activities of caspases -2, -6, and -9 were determined by colorimetric assays
      using specific substrates conjugated to a color reporter molecule. Caspase-3
      activity was determined both by western blot and by a fluorogenic assay in which
      a fluorescent compound was generated. Thymocytes from CLP mice had markedly
      increased apoptosis and activation of caspases -2, -3, -6, and -9 in comparison
      with thymocytes of sham-operated mice. Caspase-1 was not activated. BCL-2
      prevented sepsis-induced thymocyte apoptosis and inhibited activation of all
      caspases. We conclude that sepsis causes activation of multiple caspases and that
      BCL-2 acts upstream as an inhibitor of caspase activation. The pattern of caspase
      activation suggests a mitochondrial mediated pathway.

PMID- 10638663
TI  - Protective effects of N-acetylcysteine and rutin on the lipid peroxidation of the
      lung epithelium during the adult respiratory distress syndrome.
AB  - This study investigates the effects of N-acetylcysteine (NAC) and rutin on the
      lung oxidative burden of patients with early adult respiratory distress syndrome
      (ARDS). The protection was evaluated by measuring expired ethane and
      malondialdehyde (MDA), and oxidized (GSSG) and reduced glutathione (GSH) in the
      epithelial lining fluid of 36 patients who developed ARDS less than 24 hours
      before enrollment in the study. The patients were randomly assigned to 3 groups,
      receiving 250 mL 5% dextrose in water (group 1), NAC 50 mg/kg body weight in 5%
      dextrose (group 2), and NAC 50 mg/kg + rutin 5 mg/kg in 5% dextrose (group 3).
      Ethane and MDA concentrations were significantly reduced in the treatment groups
      after day 6. GSH was 30% increased in the treatment groups. No significant
      variations were observed in the control group until day 9. The trial confirms
      that NAC and rutin are efficient in protecting the lungs of patients with ARDS.

PMID- 10638662
TI  - IL-1beta induction of NF-kappaB activation in human intestinal epithelial cells
      is independent of oxyradical signaling.
AB  - IL-1beta stimulation of cultured epithelial cells induces the degradation of
      IkappaBalpha and the consequent nuclear translocation of NF-lambdaB, a critical
      proinflammatory transcription factor in the mucosal host immune response. The
      role of reactive oxygen intermediates, serine protease activity, and tyrosine
      kinase activity in the activation of NF-kappaB is weakly conserved across various
      cell lineages and has not been defined in human enterocytes, a major target of
      oxidant stress in sepsis, thermal injury, and hemorrhagic shock. We report here
      that in Caco-2BBe cells, a transformed human colon cancer cell line with features
      of small intestinal epithelial cells in culture, exposure to oxidant stress
      (hydrogen peroxide 1-10 mM) did not induce NF-kappaB activation. Similarly,
      scavenging of free radicals and oxidants by pyrrolidine dithiocarbamate and
      dimethyl sulfoxide did not block IL-1beta-induced IkappaBalpha degradation and NF
      kappaB activation. Genistein, a nonspecific tyrosine kinase inhibitor, also had
      no effect on IL-1beta-mediated effects on NF-kappaB. Serine protease inhibition
      by tosyl-lysine-chloromethylketone and tosyl-phenylalanine-chloromethylketone
      inhibited IkappaBalpha degradation and NF-kappaB activation stimulated by IL
      1beta. Our data highlight the strong divergence between epithelial and
      mononuclear cells in the signal transduction pathways relating IL-1beta
      stimulation and NF-kappaB nuclear translocation.

PMID- 10638664
TI  - Cecal ligation and double puncture impairs heat shock protein 70 (HSP-70)
      expression in the lungs of rats.
AB  - Induction of the heat shock response may improve outcome from pathophysiological
      disturbances. This improvement is associated with and believed to result from
      expression of heat shock protein (HSP)-70. Therefore, we examined the temporal
      expression of HSP-70 in an animal model of acute respiratory distress syndrome
      (ARDS) secondary to fecal peritonitis. Specifically, we hypothesize that sepsis
      in rats impairs pulmonary HSP-70 expression. ARDS was induced in adolescent rats
      via cecal ligation and double puncture (2CLP). Sham-operated animals served as
      controls. Lung tissue was collected 0, 3, 6, 16, 24, and 48 h after 2CLP and sham
      operation. Northern blot hybridization analysis was performed to detect steady
      state HSP-70 messenger ribonucleic (mRNA) levels. HSP-70 protein levels were
      determined via immunoblotting and immunohistochemistry. Mortality after 2CLP was
      50% at 24 h and 75% at 48 h. Northern blot hybridization analysis revealed no
      significant change in steady-state HSP-70 mRNA levels in lung at any time after
      2CLP. HSP-70 steady-state mRNA levels increased after sham operation and was
      higher than values in 2CLP at 6, 16, and 24 h. HSP-70 protein levels did not
      change over time in either group. Thus, the expression of HSP-70 does not change
      after 2CLP. Although lack of an increase in protein levels may be adaptive after
      sham operation, it is not appropriate after 2CLP. Therefore, failed HSP-70
      expression represents a form of pulmonary epithelial dysfunction that may
      contribute to lung injury in sepsis.

PMID- 10638665
TI  - Magnolol attenuates peroxidative damage and improves survival of rats with
      sepsis.
AB  - Reactive oxygen species and peroxidative damage are implicated in the
      pathophysiology of sepsis. Magnolol is a compound extracted from the Chinese
      medicinal herb Magnolia officinalis and has multiple pharmacological effects,
      notably antioxidant functions. To determine whether magnolol can modulate the
      course of sepsis, survival rate and biochemical parameters were analyzed in rats
      with sepsis with various treatment protocols. Magnolol at doses ranging from 10(
      9) g/kg to 10(-5) g/kg was administered either before or after induction of
      sepsis by cecal ligation and puncture. Magnolol did not modulate the course of
      sepsis induced by two cecal punctures. When one cecal puncture was performed, a
      moderately evolving type of sepsis was induced, and the survival rate of affected
      rats was significantly improved by pretreatment with 10(-7) g/kg magnolol. The
      beneficial effect was partially retained if magnolol was administered 6 hours
      after onset of sepsis when a higher dose (10(-5) g/kg) was used. The intensity of
      lipid peroxidation in plasma, liver, and lung of septic rats was also attenuated
      in a treatment-dependent manner. Magnolol at this dose range exerted these
      beneficial effects probably through its antioxidant efficacy. These significant
      results may suggest magnolol as a candidate agent for the treatment of sepsis.

PMID- 10638666
TI  - Stored red blood cells selectively activate human neutrophils to release IL-8 and
      secretory PLA2.
AB  - Packed red blood cell (PRBC) transfusion has been invoked previously with
      immunosuppression and increased infections, but it has now been demonstrated that
      stored PRBCs (>14 days) can prime PMNs and provoke multiple organ failure.
      Recently, the role of PMNs in the genesis of MOF has been extended to their
      release of inflammatory cytokines, notably IL-1, IL-8, TNFalpha, and secretory
      phospholipase A2 (sPLA2). We hypothesize that stored PRBCs can act as a second
      event via stimulating the release of inflammatory cytokines from PMNs. Isolated
      human PMNs were incubated for 24 h in RPMI with either 20% fresh plasma or plasma
      from 42 day old PRBC (day of outdate) and release of IL-8, IL-1beta, TNFalpha,
      and sPLA2 were measured. Plasma from stored PRBCs contained small amounts of IL
      8, sPLA2, and TNFalpha (102.1 +/-5.6 pg/ml, 87.6+/-6.0 pg/ml and 9.7+/-.7 pg/ml).
      Levels of IL-1beta were below detection (<1 pg/ml). Day 42 PRBC plasma stimulated
      significant PMN release of both IL-8 and sPLA2 as compared to both control and
      day 0 plasma (*P < .05), but PRBC plasma did not stimulate PMN release of either
      IL-1beta or TNFalpha. Transfused blood is emerging as an inflammatory agent that
      is capable of producing PMN priming. In this study we have demonstrated that PRBC
      plasma selectively activates PMNs to release both IL-8 and sPLA2. Thus,
      transfusion of PRBCs may represent a preventable inflammatory insult via
      modification of both blood banking and transfusion practices.

PMID- 10638667
TI  - Serine/threonine phosphorylation in cellular signaling for alveolar macrophage
      phagocytic response to endotoxin.
AB  - Protein serine/threonine (ser/thr) phosphorylation is an early signaling event in
      macrophage activation. We investigated the changes in stress-activated protein
      kinase/c-Jun NH2-terminal kinase (SAPK/JNK) activity and effects of phosphatase
      inhibition on alveolar macrophage (AM) function in rats challenged with
      intratracheal endotoxin. Animals were sacrificed 90 min post intratracheal
      lipopolysaccharide (LPS, 100 microg/rat) challenge. AMs were incubated with or
      without phosphatase inhibitors at 37 degrees C for 30 min. Phagocytosis, CD18
      expression, SAPK/JNK and phosphatase activities of AMs were determined. LPS
      challenge activated SAPK/JNK activity and enhanced phagocytosis of AMs without
      altering phosphatase activity in these cells. Inhibition of phosphatase 1 and 2A
      activity with okadaic acid and calyculin A exerted a bi-phasic effect on AM
      phagocytic function. Okadaic acid at a concentration of 1 microM increased the
      mean channel fluorescence intensity (MCF) and the percentage of cells engaged in
      phagocytosis (percent phagocytosis) in AMs from saline-treated rats. This
      inhibitor at concentrations of 0.5 and 1 microM enhanced both the MCF and percent
      phagocytosis of AMs from LPS-challenged rats. Calyculin A at a concentration of
      10 nM increased the MCF phagocytosis of AMs from LPS-challenged rats. At higher
      concentrations (20 and 30 nM), calyculin A showed a suppression on both the MCF
      and percent phagocytosis of AMs in both saline and LPS groups. AM CD18 expression
      was not altered following LPS challenge. Phosphatase inhibitors at doses that
      enhanced AM phagocytosis showed either no effect (okadaic acid) or inhibition
      (calyculin A) of AM CD18 expression. These results suggest that ser/thr
      phosphorylation and dephosphorylation participate in mediating the phagocytic
      response of AMs to LPS.

PMID- 10638668
TI  - Cyclooxygenase 2 (COX-2) gene activation is regulated by cyclic adenosine
      monophosphate.
AB  - Prostaglandin E2 production by tissue-fixed macrophages (Mphi) after severe
      injury contributes to an enhanced susceptibility to infection and sepsis. The
      purpose of this study was to investigate the effect of cyclic adenosine
      monophosphate (cAMP) on prostaglandin (PGE2) production and cyclooxygenase II
      (COX-2) gene activation in LPS-stimulated macrophages (Mphi). RAW264.7 cells, a
      mouse Mphi cell line, were exposed to various concentrations of dibutyryl cAMP +/
      lipopolysaccharide (10 microg/mL) stimulation. Total Mphi ribonucleic acid (RNA)
      was harvested for the determination of COX-2 messenger RNA (mRNA) with mouse
      complementary deoxyribonucleic acid (cDNA) by Northern blot assay. Mphi
      supernatant was collected for the measurement of tumor necrosis factor (TNF) by
      L929 bioassay and PGE2 by enzyme-linked immunosorbent assay (ELISA),
      respectively. Mphi NFkappaB activity was determined by electrophoretic mobility
      shift assays (EMSA). Dibutyryl cAMP significantly inhibited TNF production by LPS
      stimulated Mphi. Dibutyryl cAMP (1 mM) alone induced PGE2 production. Dibutyryl
      cAMP (100 microM and 1 mM) also augmented PGE2 production by LPS-stimulated Mphi.
      Dibutyryl cAMP had similar effect on Mphi COX-2 mRNA expression and NFkappaB
      activity. Our data demonstrate that cAMP modulates Mphi TNF production and
      upregulates COX-2 gene and PGE2 production.

PMID- 10638669
TI  - Prevention of early myocardial depression in hyperdynamic endotoxemia in dogs.
AB  - In our study the pathomechanism of sepsis-induced early myocardial depression was
      investigated. We determined the effects of the inducible nitric oxide synthase
      inhibitor and free radical scavenger mercaptoethylguanidine (MEG) on the
      myocardial contractility, the endothelial and inducible nitric oxide synthase
      (eNOS and iNOS) activities, and the activation and tissue accumulation of
      polymorphonuclear leukocytes in hyperdynamic endotoxemia in dogs. Group 1 served
      as endotoxemic control. Mean arterial pressure and cardiac output were measured,
      myocardial contractility was estimated from the end-systolic pressure-diameter
      relationship. The eNOS, iNOS and myeloperoxidase activities were determined on
      myocardial biopsy samples, and the free radical-producing capacity of
      granulocytes was measured from separated cells. The effect of MEG on the in vitro
      free radical production of isolated granulocytes was measured by
      chemiluminometry. Endotoxin induced a hyperdynamic circulatory reaction and
      significant myocardial depression. The myocardial eNOS activity was significantly
      increased 4 h after induction of endotoxemia and remained elevated, the iNOS
      activity was increased only 8 h after endotoxemia induction. The free radical
      producing capacity and the myocardial accumulation of the granulocytes were
      significantly increased. In group 2, MEG treatment selectively inhibited the iNOS
      activity, prolonged the hyperdynamic circulatory reaction, prevented myocardial
      depression and decreased the activation and tissue accumulation of granulocytes.
      The compound dose-dependently decreased the in vitro activation of previously
      resting granulocytes. Our study demonstrates that iNOS do not contribute to the
      early cardiac failure in endotoxemia. MEG selectively inhibits iNOS in vivo, but
      its beneficial effects are rather related to the decreases in leukocyte and free
      radical-mediated myocardial dysfunction during early endotoxemia.

PMID- 10638670
TI  - Oxidative stress precedes circulatory failure induced by 35-GHz microwave
      heating.
AB  - Sustained whole-body exposure of anesthetized rats to 35-GHz radio frequency
      radiation produces localized hyperthermia and hypotension, leading to circulatory
      failure and death. The physiological mechanism underlying the induction of
      circulatory failure by 35-GHz microwave (MW) heating is currently unknown. We
      hypothesized that oxidative stress may play a role in the pathophysiology of MW
      induced circulatory failure and examined this question by probing organs for 3
      nitrotyrosine (3-NT), a marker of oxidative stress. Animals exposed to low
      durations of MW that increased colonic temperature but were insufficient to
      produce hypotension showed a 5- to 12-fold increase in 3-NT accumulation in lung,
      liver, and plasma proteins relative to the levels observed in control rats that
      were not exposed to MW. 3-NT accumulation in rats exposed to MW of sufficient
      duration to induce circulatory shock returned to low, baseline levels. Leukocytes
      obtained from peripheral blood showed significant accumulation of 3-NT only at
      exposure levels associated with circulatory shock. 3-NT was also found in the
      villus tips and vasculature of intestine and within the distal tubule of the
      kidney but not in the irradiated skin of rats with MW-induced circulatory
      failure. The relationship between accumulation in liver, lung, and plasma
      proteins and exposure duration suggests either that nitro adducts are formed in
      the first 20 min of exposure and are then cleared or that synthesis of nitro
      adducts decreases after the first 20 min of exposure. Taken together, these
      findings suggest that oxidative stress occurs in many organs during MW heating.
      Because nitration occurs after microwave exposures that are not associated with
      circulatory collapse, systemic oxidative stress, as evidenced by tissue
      accumulation of 3-NT, is not correlated with circulatory failure in this model of
      shock.

PMID- 10638671
TI  - Effect of genetic disruption of poly (ADP-ribose) synthetase on delayed
      production of inflammatory mediators and delayed necrosis during myocardial
      ischemia-reperfusion injury.
AB  - The nuclear enzyme poly (ADP ribose) synthetase (PARS) has been shown to play an
      important role in the pathogenesis of various forms of ischemia or reperfusion
      injury and circulatory shock. Recent studies demonstrated that inhibition or
      genetic inactivation of PARS is beneficial in the early phase of myocardial
      reperfusion injury. The aim of the present study was to investigate whether
      inactivation of PARS influences the delayed myocardial necrosis and the
      production of the proinflammatory cytokine tumor necrosis factor alpha
      (TNFalpha), the anti-inflammatory cytokine interleukin-10 (IL-10), and the free
      radical nitric oxide in the late stage of myocardial reperfusion injury. The
      results demonstrate that genetic disruption of PARS provides marked protection
      against the delayed myocardial ischemia and reperfusion injury. In addition, in
      the absence of functional PARS, a suppression of TNFalpha, IL-10, and nitric
      oxide production was found. These findings provide direct evidence that PARS
      activation participates in the development of delayed cell injury and delayed
      mediator production in myocardial reperfusion injury.

PMID- 10638672
TI  - Myocardial reperfusion: leukocyte accumulation in the ischemic and remote non
      ischemic regions.
AB  - Neutrophil accumulation in the first hour of myocardial reperfusion was assessed
      in dog hearts submitted to ischemia with and without necrosis. In anesthetized
      dogs, the left anterior descending coronary artery was occluded for 20 min (group
      IS-20 n = 7) and for 90 min (group IS-90 n = 6). Immediately after reperfusion,
      99m Tc-Ceretec (Exametazime-Amersham) labeled neutrophils were injected into a
      central vein and 60 min later the dogs were killed. The left ventricle was
      isolated, weighed, and sliced. Six sections, 3 from normal and 3 from reperfused
      regions, were divided into endocardial and epicardial layers. Myocardial and
      blood radiometry were used to evaluate the neutrophil accumulation during
      reperfusion. The differences between leukocyte accumulation in both groups were
      assessed comparing the ischemic/normal relations in the endocardial and
      epicardial layers. A second comparison considered myocardium/blood relations to
      allow the evaluation of differences between remote normal myocardial areas of the
      two experimental groups. In dogs submitted to 20 min of ischemia, leukocytes
      accumulated significantly more (P < 0.01) in the reperfused myocardium as
      compared with the non-ischemic region. The increase occurred both in the
      endocardial (1.49+/-0.20) and epicardial (1.48+/-0.29) regions. After 90 min
      ischemia, leukocyte accumulation was more intense and predominant in endocardium
      where there was a 4-fold (3.97+/-1.28) increase over the non-ischemic region,
      while in the epicardium this relation was only 2.5-fold (2.56+/-0.98). In the
      remote non-ischemic myocardium, leukocyte accumulation was greater in dogs
      submitted to 90 min of ischemia compared to the 20 min group (P < 0.01), without
      distinction between endocardial and epicardial layers. This accumulation in
      territories of non-culprit coronary arteries may be related to the blood flow
      abnormalities and matrix structure changes that occur in these regions during the
      development of an acute myocardial infarction and its natural repair.

PMID- 10638673
TI  - Altered endothelin receptor subtype expression in hepatic injury after
      ischemia/reperfusion.
AB  - This study was performed to determine whether ischemia/reperfusion (I/R) injury
      in rat liver results in alterations in endothelin receptor expression. Hepatic
      ischemia was produced in rats for 60 min followed by 6 or 24 h reperfusion.
      Portal inflow pressure was increased (7.38+/-0.60 mmHg) at 24 hours after
      reperfusion. Serum ALT increased significantly at both 6 and 24 h (6 h; 258.3+/
      74.3, 24 h; 243.1+/-74.8 IU/L). Portal vascular response to an endothelin-B
      receptor agonist (IRL 1620) was significantly increased in the I/R livers
      compared to control and this was potentiated by L-NAME. IRL 1620 also caused LDH
      release from I/R livers but not controls. LDH release after IRL 1620 in I/R
      livers correlated with increased portal pressure response. To determine whether
      the altered response might be the result of altered endothelin receptor
      expression, livers were harvested after reperfusion and total endothelin binding
      sites were determined by competitive binding with ET-1. Proportion of endothelin
      receptor subtypes (ET(A)/ET(B)) was determined using the ET(A) antagonist BQ-610
      (1 microM) and ET(B) agonist IRL-1620 (100 nM). There were no significant changes
      in Kd but Bmax for endothelin-1 was decreased in I/R group especially non
      ischemic lobe at 24 h. ET(A) receptors were significantly decreased whereas ET(B)
      receptors were increased. These changes were more pronounced at 24 h after
      reperfusion than at 6 h. Interestingly, the changes in ET receptors was observed
      identically both in ischemic and non-ischemic lobes (ischemic lobe ET(A) 41.9%,
      ET(B) 51%; non-ischemic lobe ET(A) 38.8%, ET(B) 49.5%). These results indicate
      that the major functional endothelin receptor subtype upregulated in I/R is the
      ET(B) receptor and that this upregulation may contribute to microvascular
      dysregulation and hepatic injury.

PMID- 10638674
TI  - Intramucosal pH and endotoxin and cytokine release in severe acute pancreatitis.
AB  - It has been postulated that in severely ill patients splanchnic hypoperfusion may
      cause endotoxin release from the gut, and this leakage of endotoxin into the
      circulation can trigger the cascade of inflammatory cytokines. We tested this
      hypothesis in 9 patients with acute severe pancreatitis by monitoring gastric
      intramucosal pH (pHi) as measure of splanchnic hypoperfusion at 12-h intervals
      trying to correlate it to endotoxin and cytokine release. Only 3 of 59 samples,
      obtained from 3 patients contained circulating endotoxin. Thirteen of 15 plasma
      samples drawn at pHi <7.20 did not contain endotoxin. The pHi was significantly
      lower in patients who subsequently developed 3 or more organ failures (P =
      0.0017, analysis of variance). Although endotoxemia was only occasionally found,
      most patients had measurable interleukin 1beta (IL-1beta), interleukin 6 (IL-6),
      interleukin 8 (IL-8), and interleukin 10 (IL-10) in their plasma. Concentrations
      of IL-6, IL-8, and IL-10 on admission correlated to degree of organ dysfunction
      as measured by the multiple organ system failure score (P = 0.035, r = 0.74; P =
      0.010, r = 0.91; P = 0.021, r = 0.82, respectively). In conclusion, patients with
      acute, severe pancreatitis often have splanchnic hypoperfusion and produce a wide
      array of cytokines despite a rare occurrence of endotoxemia.

PMID- 10638675
TI  - Isoforms of troponin in normal and diseased myocardium.
AB  - The regulatory protein troponin (Tn) located on actin filament consists of three
      subunits: TnT--binds troponin to tropomyosin, TnC--binds divalent calcium ions,
      and TnI--affects myosin-actin interactions. Tn subunits display several molecular
      and calcium binding variations. During ontogenetic development of cardiac and
      skeletal muscles the synthesis of multiple isoforms of Tn subunits was detected.
      Expression of Tn isoforms and the extent of phosphorylation of both TnT and TnI
      via protein kinase C or protein kinase A under different pathological situations
      (e.g. ischemia, congenital heart disease, heart failure) can affect the Ca2+
      stimulated contraction function and the myofibrillar ATPase activity of the
      heart.

PMID- 10638676
TI  - Acetylcholine and bradykinin induce paradoxically amplified hypotensive response
      in hypertensive NO-deficient rats.
AB  - The hypotensive response to acetylcholine and bradykinin was studied in rats with
      NO synthase activity inhibited for a short period of 2 h or a long period of 6
      weeks. N(G)-nitro-L-arginine-methyl ester (L-NAME) was used as NO synthase
      inhibitor (given in a dose of 50 mg/kg either into the jugular vein, or daily in
      drinking water). Blood pressure was measured in the right carotid artery by a
      Statham pressure transducer in acute experiments, and on the tail artery by the
      plethysmographic method weekly in chronic experiments. During both the short- and
      long-lasting NO synthase inhibition blood pressure rose significantly. The heart
      rate decreased significantly in rats treated with L-NAME for 6 weeks.
      Surprisingly, the hypotensive responses to acetylcholine and bradykinin were
      present in both experimental groups. Paradoxically, the hypotensive responses to
      all three doses of acetylcholine were remarkably enhanced in rats with NO
      synthase inhibition lasting 6 weeks, in comparison to both age-matched controls
      and to rats subjected to short-lasting NO synthase inhibition. The blockade of
      muscarinic receptors by atropine abolished the hypotensive response to
      acetylcholine but not to bradykinin. The hypothetical mechanisms underlying this
      unexpected paradoxical phenomenon of cardiovascular control are discussed.

PMID- 10638677
TI  - Influence of active immunization against angiotensin AT1 or AT2 receptor on
      hypertension development in young and adult SHR.
AB  - The influence of long-lasting blockade of angiotensin AT1 or AT2 receptors by
      antibody against the particular receptor peptides on blood pressure and relative
      heart and kidney weight was studied in spontaneously hypertensive rats (SHR).
      Young and adult SHR were repeatedly immunized against the sequence 14-23 of
      angiotensin AT1 receptor from the age of either 1 or 3 months. Other groups of
      young and adult SHR were immunized against the sequences 37-43 and 106-116 of
      angiotensin AT2 receptor. Synthetic peptides conjugated to bovine gamma globulin
      were used as antigens. After 5 months of immunization, blood pressure was
      measured by the direct method. All immunized animals produced antibodies against
      the particular peptides. At the end of immunization, the blood pressure was
      significantly decreased in SHR immunized in youth against angiotensin AT1
      receptor peptide, although no difference in heart and kidney hypertrophy was
      observed compared to sham-immunized SHR. The immunization against angiotensin AT1
      receptor peptide in adulthood as well as the immunization against angiotensin AT2
      receptor peptides in youth or in adulthood affected neither blood pressure nor
      heart and kidney weight. No influence of immunization on the studied parameters
      was observed in normotensive WKY rats. Angiotensin AT1 receptors play a more
      important role in the pathogenesis of spontaneous hypertension than angiotensin
      AT2 receptors. The blockade of angiotensin AT1 receptors by active immunization
      against the receptor peptide attenuated hypertension development in young SHR but
      did not modify the already established hypertension in adult SHR.

PMID- 10638678
TI  - Determination of the glomerular filtration rate (GFR): methodological problems,
      age-dependence, consequences of various surgical interventions, and the influence
      of different drugs and toxic substances.
AB  - Determinations of renal clearance of fluorescein isothiocyanate (FITC)-inulin
      were used for assessing the glomerular filtration rate (GFR) in rats and to
      characterize factors influencing the glomerular filtration capacity. In
      anesthetized rats, GFR develops after birth up to day 30. Thereafter, GFR remains
      relatively constant for up to 3 months of age and drops continuously until the
      8th month. GFR can be determined in utero, already one day before birth, however,
      only at a very low level. It increases significantly on the first day of life.
      Even at this time the effect of furosemide on GFR can be proven. After reduction
      of renal mass, GFR is decreased in dependence on the extent of kidney tissue
      removal. However, within 2 days after unilateral nephrectomy (NX) or one week
      after 5/6 NX, GFR reaches values about 3/4 of the controls with two intact
      kidneys. Furthermore, the compensation of GFR after renal ischemia reaches 80% of
      baseline values after one week. On the other hand, GFR is enhanced after bile
      duct ligation as a model of hepato-renal failure. It has been shown in previous
      experiments that pretreatment with hormones can stimulate renal tubular transport
      processes. Pretreatment with dexamethasone or triiodothyronine after 5/6 NX
      improves glomerular filtration capacity whereas in animals with ligated bile
      ducts dexamethasone seems to prevent the increase in GFR. After subchronic
      treatment with epidermal growth factor (EGF) GFR is significantly reduced. A
      continuous infusion of amino acids does not change GFR in the controls but
      enhances the filtration capacity in EGF-treated rats. But immediately after bolus
      injection of amino acids GFR also increases significantly in the controls.
      Diuretics such as furosemide, most nephrotoxic agents (cyclosporine A [CsA],
      heavy metals) and imidazole reduce the GFR significantly. Diltiazem reported to
      act nephroprotectively in CsA nephrotoxicity in human beings was without
      beneficial effect in rats. This could be due to species differences in GFR
      because the rat is one of the species with the highest glomerular filtration
      capacity.

PMID- 10638679
TI  - Methodological aspects of measuring amino acid uptake in studies with porcine
      jejunal brush border membrane vesicles.
AB  - With L-glutamine, as a representative amino acid this study was undertaken to
      examine the effects of substrate concentrations on initial and equilibrium amino
      acid uptake and intravesicular volume determined with porcine jejunal brush
      border membrane vesicles prepared by Mg2+-aggregation and differential
      centrifugation. Transport measurements (24 degrees C) were conducted by the rapid
      filtration manual procedure. Glutamine uptake was shown to occur into an
      osmotically-active space ranging between 1.09-1.58 microl/mg protein with little
      non-specific membrane binding. At different concentrations (in parentheses), the
      duration of initial glutamine uptake in both Na+ gradient and Na+-free conditions
      was 10 s (0.01 mM), 15 s (0.17 mM), and 20 s (1.9 and 9.4 mM), respectively.
      Substrate concentrations affected the duration of initial uptake, with lower
      substrate concentrations giving shorter duration for initial amino acid uptake.
      At different substrate concentrations (in parentheses), the time required to
      reach equilibrium glutamine uptake was 5 min (0.01 mM), 10 min (0.17 mM), and 60
      min (1.9 and 9.4 mM), respectively. Thus, substrate concentrations also affected
      the time required to reach equilibrium uptake. The higher the substrate
      concentration, the longer the incubation time needed to reach equilibrium amino
      acid uptake. At the glutamine concentrations of 0.01, 0.17, 1.9, and 9.4 mM, the
      average intravesicular volume was estimated to be 1.58+/-0.21, 1.09+/-0.28,
      1.24+/-0.18, and 1.36+/-0.21 microl/mg protein, respectively. Substrate
      concentrations had no effect (p>0.05) on the intravesicular volume of membrane
      vesicles. In conclusion, in the experiments on amino acid transport kinetics
      measured with the rapid filtration manual procedure, the incubation time used for
      measuring the initial uptake rate should be determined from the time course
      experiments conducted at the lowest substrate concentration used, whereas the
      intravesicular volume can be obtained from equilibrium uptake measured at any
      substrate concentrations.

PMID- 10638680
TI  - Local vasodilatation with metacholine, but not with nitroprusside, increases
      forearm glucose uptake.
AB  - Insulin is known to increase blood flow in parallel to glucose uptake in skeletal
      muscle. However, it is not known if an increase in blood flow by itself is
      associated with an increase in glucose uptake in the absence of hyperinsulinemia.
      To investigate further this matter, the effect of increased blood flow on forearm
      glucose uptake was studied in the fasting state during intra-arterial infusions
      of two different vasodilators, metacholine and nitroprusside, in 19 hypertensive
      subjects. Both metacholine (4 microg/min) and nitroprusside (10 microg/min)
      increased resting forearm blood flow, measured by venous occlusion
      plethysmography, to a similar degree (180 % and 170 %, respectively, p<0.0001 for
      both). However, metacholine infusion increased the forearm glucose uptake from
      2.0+/-0.9 (S.D.) during rest to 5.5+/-3.0 umol/min/100 ml tissue (p<0.0001),
      while no significant change in glucose uptake was seen during nitroprusside
      infusion (2.3+/-1.4 micromol/min/100 ml tissue). In conclusion, vasodilatation
      induced by metacholine, but not by nitroprusside, increased glucose uptake in the
      forearm of hypertensive patients. Thus, an increase in forearm blood flow does
      not necessarily improve glucose uptake in the forearm during the fasting state.

PMID- 10638681
TI  - Effects of olive oil on superoxide dismutase activity in the brain of newborn and
      young female rats.
AB  - Changes in the activity of brain antioxidant superoxide dismutases (SOD) were
      followed in newborn and young female rats 8, 15, 30, 45, 60 and 75 days after
      birth treated with olive oil. In newborn rats, the content of brain cytosol SOD
      (CuZnSOD) and mitochondrial SOD (MnSOD) decreased after treatment with olive oil.
      However, in the brain of rats aged 8 days this effect was lost. The suppressive
      effect of olive oil on these enzymes reappeared again in 15-day-old rats. In rats
      aged one month, only the activity of CuZnSOD was reduced after olive oil
      treatment. In the brain of rats aged 45, 60 and 75 days, neither MnSOD nor
      CuZnSOD were affected by olive oil. The different effects of olive oil on the
      brain SOD, during ontogeny suggest that profound changes in the susceptibility of
      nervous tissue antioxidant enzymes to olive oil take place during sexual
      maturation.

PMID- 10638682
TI  - Global brain dynamics of transient visual evoked potentials.
AB  - The independent component analysis was applied to multichannel transient visual
      evoked potentials elicited by a high contrast pattern-reversal and motion-onset
      (motion velocity of 7 and 23 deg/s). Three overlapping independent components
      with different topographical distribution over the scalp were described. The
      first component displayed similar timing in response to all three stimuli (40-200
      ms) but was a different in shape and scalp projection. This activation component
      is considered to reflect the stimulus properties. The second component (100-227
      ms), related to negativity at about 160 ms, can be referred to visual processing
      of motion. The last component, attributed to positivity at 230 ms dominates in
      the fronto-central area and might represent a cognitive process.

PMID- 10638683
TI  - Surface changes in type II pneumocytes isolated from rats during the cultivation.
AB  - Type II cells isolated from the rat lung were maintained in culture for 8 days.
      The activity of alkaline phosphatase and lectin binding properties were studied.
      The alkaline phosphatase activity and the number of lamellar bodies were
      continually decreasing during the studied time period. The profile of lectin
      binding (Maclura pomifera and Ricinus communis) did not change during the
      cultivation.

PMID- 10638684
TI  - Non-quantal acetylcholine release is increased after nitric oxide synthase
      inhibition.
AB  - After anticholinesterase treatment, depolarization of the postsynaptic muscle
      membrane by about 5 mV develops due to non-quantally released acetylcholine from
      the motor nerve terminal and can be revealed as hyperpolarization by the addition
      of curare (H-effect). The H-effect increases significantly to 8.7 mV after
      inhibition of NO-synthase by L-nitroarginine methylester (L-NAME) whilst no
      changes in the amplitude and frequency of quantal miniature endplate potentials
      are observed.

PMID- 10638685
TI  - Dextran enhances calcium-induced aggregation of phosphatidylserine liposomes:
      possible implications for exocytosis.
AB  - We have studied the calcium-induced aggregation of phosphatidylserine liposomes
      in the presence of various concentration of a high-molecular water-soluble
      polysaccharide dextran. It has been shown that threshold concentrations of
      calcium necessary to induce liposome aggregation in the presence of approximately
      1 mM concentration of dextran is about one order lower than in the absence of
      dextran. Soluble intracellular polymers may thus play an important role in the
      process of exocytosis.

PMID- 10638686
TI  - The common cDNA and amino acid sequences of the CD14 (myeloid cell-specific
      leucine-rich glycoprotein) receptor.
AB  - The CD14 receptor is a myeloid cell specific receptor, which plays a role in the
      recognition of lipopolysaccharides (endotoxins of gram-negative bacteria) and
      cell stimulation. To date, several sequences of the cDNA of the CD14 receptor
      have been described. We sought to establish whether the substitutions C(230)-->G,
      and G(560)-->A are polymorphic or if they result from a PCR or sequencing error.
      Using two mismatched PCRs, we confirmed (on 75 unrelated probands) that the
      substitutions are not due to common polymorphisms. The common cDNA sequence has
      the C in position 230 and G in position 560. This corresponds to the amino acids
      Ala and Cys in positions 77 and 187, respectively.

PMID- 10638687
TI  - Acute effect of hydrochlorothiazide on renal calcium and magnesium handling in
      postmenopausal women.
AB  - A single 50 mg dose of hydrochlorothiazide (HCTZ) decreases the urinary excretion
      of calcium (U(Ca)V), clearance (C(Ca)) and fractional excretion (FE(Ca)) of
      calcium. This is accompanied by an increase of total calcium and ionized calcium
      (Ca2+) concentrations in the serum. On the other hand, HCTZ increases fractional
      excretion of magnesium (FE(Mg)) and decreases serum Mg2+ concentrations.
      Moreover, HCTZ decreases markedly clearance of phosphate (C(Pi)) and fractional
      excretion of phosphate (FE(Pi)) and increases serum phosphate (Pi) concentrations
      in healthy postmenopausal women. It is concluded that intrinsic renal cellular
      control promptly uncouples calcium and magnesium tubular reabsorption even
      without K+ depletion.

PMID- 10638688
TI  - New approaches to screening for cervical cancer in high-risk populations.

PMID- 10638689
TI  - Toward an understanding of biomaterial infections: a complex interplay between
      the host and bacteria.

PMID- 10638690
TI  - Moderate hyperhomocysteinemia and cardiovascular disease.

PMID- 10638691
TI  - Infrared spectroscopic study of cervical smears in patients with HIV:
      implications for cervical carcinogenesis.
AB  - Patients with HIV have an increased incidence of cervical cancer, necessitating
      increased surveillance. Infrared spectroscopy (IRS) has the potential of aiding
      the diagnosis of cervical neoplasia and also of providing clues into its
      pathogenesis. We studied by IRS cervical scrapings from 22 HIV-infected and 23
      control women; 8 of the former and none of the latter had dysplasia. The infrared
      spectra followed three patterns, designated pattern I (similar to that previously
      associated with normal cervical samples), pattern II (intermediate between
      patterns I and III), and pattern III (associated with cervical neoplasia).
      Compared with HIV-negative controls, HIV-infected women had a higher prevalence
      of pattern III and a lower prevalence of pattern II; these differences were
      statistically significant (P = .015 by chi2 analysis). Similar spectroscopic
      changes were present even when only the cytologically normal samples from HIV
      positive and HIV-negative women were analyzed. We speculate that these changes
      may reflect early structural changes associated with cervical neoplasia that are
      not detectable cytologically. The infrared spectra in the region 950 to 1,300 cm(
      1) could not differentiate cervical samples from HIV-infected and uninfected
      patients. The potential practical applications of IRS in HIV cervical disease are
      discussed.

PMID- 10638692
TI  - Identification of plasma proteins adsorbed on hemodialysis tubing that promote
      Staphylococcus aureus adhesion.
AB  - Risk factors for Staphylococcus aureus infections in patients undergoing
      hemodialysis include underlying disease, material-induced host defects, and the
      presence of vascular access catheters. To determine the specific contribution of
      various potentially adsorbed plasma components in promoting S aureus adhesion to
      shunt tubing during chronic hemodialysis, we quantified their respective amounts
      by Western immunoblotting and densitometry and estimated their individual
      adhesion-promoting activities with specific adhesion-modified bacterial mutants.
      Fibrinogen, which was the only component consistently present in tubing protein
      extracts from all patients, was adsorbed in significantly higher amounts on
      predialyzer than on postdialyzer tubing segments. In contrast, fibronectin and
      von Willebrand factor were irregularly present in patients' tubing, whereas
      vitronectin or thrombospondin remained undetectable in all samples. The
      contribution of fibrinogen in promoting S aureus attachment to hemodialysis
      tubing was demonstrated by (1) the significantly lower adhesion of a cIfA mutant
      of strain Newman compared with its parent; (2) the increased attachment of strain
      8325-4 after complementation with the cloned cIfA gene on the multicopy plasmid
      pCF4; and (3) the general tendency for strains Newman and 8325-4(pCF4) to express
      higher attachment on predialyzer compared with postdialyzer tubing segments in
      relationship with the higher content of fibrinogen on the former material.
      However, the specific S aureus attachment-promoting activity of both prefilter
      and postfilter tubing-adsorbed fibrinogen were much lower than that of the native
      in vitro-adsorbed protein and may reflect masking or inactivation of the in vivo
      adsorbed protein by unknown mechanisms.

PMID- 10638693
TI  - Staphylococcus aureus adherence to thrombin-treated endothelial cells is mediated
      by fibrinogen but not by platelets.
AB  - Recent studies emphasize the role of blood constituents in Staphylococcus aureus
      (S. aureus) adherence to subendothelial extracellular matrix. In the present
      study, the adherence of two strains of S. aureus (ATCC 29213 and RN 6390) grown
      to a postexponential phase to cultured human umbilical vein endothelial cells (EC
      304) was examined. Under flow conditions (600 s(-1)), pretreatment of endothelial
      cells (ECs) with human alpha-thrombin (2 U/mL) significantly (2- to 4-fold)
      increased bacterial adherence to ECs. Adherence of both S. aureus strains to
      thrombin-treated ECs was similarly higher in the presence of whole blood,
      platelet-rich plasma, or platelet-poor plasma when compared with Tris-buffered
      saline solution (TBS). Platelet inactivation in whole blood by prostaglandin E1
      did not reduce the adherence rate. When ATCC 29213 bacteria were suspended in TBS
      containing increasing concentrations of fibrinogen at near-physiologic ranges
      (0.25 to 2 mg/mL), a dose-dependent increase in S. aureus adherence to thrombin
      activated ECs was observed that reached a maximum level of about 12-fold.
      Fibronectin used at the above physiologic concentrations (12.5 to 100 microg/mL)
      enhanced bacterial adherence up to 2-fold. Von Willebrand factor (1 IU/mL) did
      not support bacterial adherence to ECs, either alone or in combination with
      fibrinogen. Inhibition of fibrin formation either by the Gly-Pro-Arg-Pro peptide
      or by hirudin increased bacterial adherence by 50% and 90%, respectively.
      Blockage of either ICAM-I, alpha5beta1, or alphavbeta3 receptors on ECs by
      appropriate monoclonal antibodies resulted in substantial inhibition of bacterial
      adherence (by 42%, 65%, and 72%, respectively). Preincubation of S. aureus with a
      fibrinogen gamma-chain binding domain peptide led to 65% inhibition of adherence
      to ECs in the presence of fibrinogen. In contrast, preincubation of bacteria with
      the Arg-Gly-Asp-Ser peptide failed to affect their adherence. The data suggest
      that S. aureus adherence to the EC surface was (1) significantly enhanced by
      thrombin treatment of ECs, (2) not mediated by platelets, and (3) mediated by
      plasma fibrinogen, which binds to the bacteria via the C-terminus gamma-chain
      binding domain but not via the Arg-Gly-Asp sequence.

PMID- 10638694
TI  - Effect of gamma-L-glutamyl-L-dopa on phosphate excretion.
AB  - gamma-L-glutamyl-L-DOPA (gludopa) is a dopamine prodrug that is relatively
      specific for the kidney. Because dopamine is phosphaturic, the present study
      compared the phosphaturic effects of the infusion of equimolar doses of gludopa
      (n = 8), L-DOPA (n = 8), and gamma-L-glutamyl-L-tyrosine (glutyrosine, n = 6).
      Glutyrosine was used as a control to evaluate the effect of the glutamyl portion
      of gludopa on phosphate excretion. Sprague-Dawley rats (350 to 400 g) were
      anesthetized with 5-sec-butylethyl-2-thyobarbituric acid (Inactin; 100 mg/kg, IP)
      and underwent thyroparathyroidectomy. Clearances were taken during the infusion
      of normal saline vehicle, followed by the infusion of gludopa, L-DOPA, or
      glutyrosine, all infused at the rate of 10 nmol/kg bolus and 0.8 nmol/kg/min
      (iv). To determine the contribution of glutamyl derivative to phosphate
      excretion, gludopa or L-DOPA was infused in the presence of SCH23390, a DA-1
      receptor antagonist. Gludopa infusion significantly increased dopamine excretion
      (from 1.9+/-0.2 ng/min to 17.0+/-3.9 ng/min, delta15.0+/-3.9 ng/min, P < .008)
      and fractional excretion of phosphate (from 2.6%+/-0.6% to 34.8%+/-1.8%,
      delta32.0%+/-1.6%, P < .001). L-DOPA infusion significantly increased dopamine
      excretion (from 1.4+/- 0.4 ng/min to 9.7+/-1.6 ng/min, delta8.3+/-1.5 ng/min, P <
      .001) and fractional excretion of phosphate (from 1.7%+/-0.6% to 8.2%+/-2.0%,
      delta6.4%+/-1.5%, P < .004). Glutyrosine infusion significantly increased
      fractional excretion of phosphate (from 2.8%+/-0.8% to 17.5%+/-5.2%, delta14.6%+/
      4.8%, P < .03) without changing dopamine excretion (delta0.5+/-0.2 ng/min).
      Infusion of gludopa in the presence of SCH23390 increased fractional excretion of
      phosphate (from 5.7%+/-2.5% to 12.6%+/-3.5%, delta6.8%+/-2.3%, n = 6, P < .03),
      whereas SCH23390 completely blocked the phosphaturic effect of L-DOPA. We
      conclude that gamma-L-glutamyl-L-DOPA is more phosphaturic than L-DOPA in the rat
      because of the combined effects of dopamine and the glutamyl moiety.

PMID- 10638695
TI  - First human studies with a high-molecular-weight iron chelator.
AB  - The release of free, reactive iron from cellular iron stores has been implicated
      as an important contributor to tissue damage in a variety of clinical situations,
      including ischemia and reperfusion injury, hemorrhagic shock, and burn injury.
      Deferoxamine mesylate (DFO), the only iron chelator currently approved for
      clinical use, is used for the treatment of iron overload, including acute iron
      poisoning and treatment of chronic iron overload in transfusion-dependent anemias
      such as beta-thalassemia. However, it is not suitable for acute care situations
      because of its toxicity, primarily hypotension when given at high intravenous
      doses, and its short plasma half-life. We have produced a high-molecular-weight
      iron chelator by chemically coupling DFO to hydroxyethyl starch. This novel
      chelator (HES-DFO) was administered to healthy male subjects by intravenous
      infusion over a 4-hour period. The drug was well tolerated, and signs of DFO
      acute toxicity were not observed. Maximum plasma chelator levels of approximately
      3 mmol/L were achieved with HES-DFO, which is more than an order of magnitude
      higher than has been reported with injections of DFO. Drug residence time in
      plasma was markedly prolonged, with an initial half-life of 22 to 33 hours.
      Urinary iron excretion was 7.1 +/- 2.2 mg in 48 hours in the highest dose group,
      as compared with 0.06 +/- 0.15 mg in control subjects who received normal saline
      infusions. Intravenous infusion of HES-DFO is well tolerated, produces
      substantial and prolonged plasma chelator levels, and markedly stimulates urinary
      iron excretion.

PMID- 10638696
TI  - Thrombin receptor activating peptide (SFLLRN) potentiates shear-induced platelet
      microvesiculation.
AB  - Shear-induced activation of platelets plays a major role in vascular thrombosis.
      Shear stress tends to increase both platelet aggregation and procoagulant
      activity. One mechanism for increased procoagulant activity is promotion of the
      transbilayer movement of anionic phospholipids from the inner to the outer
      leaflet of the platelet membrane bilayer. This is accompanied by vesiculation of
      the platelet membrane, resulting in the formation of procoagulant membrane
      particles called microvesicles. In this study we have examined the effect of
      various platelet agonists on shear-induced platelet microvesiculation and the
      development of platelet procoagulant activity. Normal citrated whole blood was
      subjected to laminar shear rate up to 12,500 sec(-1) (shear stress approximately
      375 dyne/cm2) in a cone-and-plate viscometer, and the formation of platelet
      microvesicles was measured by flow cytometry under different conditions. Elevated
      levels of shear stress induced significant microvesiculation. We investigated the
      effects of adenosine diphosphate, epinephrine, thromboxane A2 analog, collagen,
      and thrombin receptor activation peptide (SFLLRN) on shear-induced platelet
      microvesiculation. The thrombin peptide significantly increased shear-induced
      microvesicle formation. In contrast, under similar conditions, the other agonists
      had no significant effect on shear-induced microvesiculation. These studies
      suggest that thrombin formed in the vicinity of primary hemostatic plugs in areas
      of elevated shear stress may have a major role in the propagation of thrombi by
      potentiating shear-induced platelet microvesiculation.

PMID- 10638697
TI  - Effects of hemoglobin-based oxygen-carrying solutions in anesthetized rats with
      acute ischemic renal failure.
AB  - The effects of three hemoglobin solutions were compared with those of iso-oncotic
      human serum albumin in rats with ischemic renal failure and sham-operated
      controls. Unmodified and alpha-alpha cross-linked hemoglobins both increase mean
      arterial pressure and systemic vascular resistance and reduce cardiac output
      substantially and to a comparable extent. In contrast, omicron-raffinose cross
      linked hemoglobin has no deleterious effect on any of these parameters. In sham
      operated rats unmodified hemoglobin reduces the glomerular filtration rate (GFR)
      by approximately 30%, whereas neither of the two cross-linked hemoglobins has any
      adverse effect on GFR in this group. None of the three hemoglobin solutions
      exacerbated the degree to which GFR was reduced by ischemia-reperfusion injury.
      Also, the degree of tubular necrosis induced by ischemia-reperfusion injury was
      also comparable in all groups. We conclude the following: (1) omicron-raffinose
      cross-linking, but not alpha-alpha cross-linking, ameliorates the effects of
      unmodified hemoglobin on vascular resistance and cardiac output; (2) both forms
      of cross-linking reduce the nephrotoxicity exhibited by unmodified hemoglobin in
      sham-operated rats; and (3) none of the hemoglobin solutions exacerbate renal
      injury induced by ischemia-reperfusion.

PMID- 10638698
TI  - Endogenous prostaglandins modulate chloride secretion by prairie dog gallbladder.
AB  - In addition to concentrating bile, the gallbladder secretes chloride (Cl-) and
      mucus into its lumen. We recently observed that gallbladder Cl- secretion is
      increased in prairie dogs during the formation of cholesterol crystals, a period
      of altered mucosal prostaglandin synthesis. Pathologic Cl- secretion is
      characteristic of other epithelial disorders such as cystic fibrosis and
      hypercalciuric nephrolithiasis and may be important in gallstone pathogenesis. We
      hypothesized that concentrations of endogenous prostaglandin E2 (PGE2) found
      during experimental gallstone formation may mediate increased Cl- secretion by
      prairie dog gallbladder. Prairie dog gallbladders were harvested by
      cholecystectomy and mounted in Ussing chambers. Unidirectional transepithelial Cl
      , Na+, and H20 fluxes were measured before and after inhibition of endogenous
      prostaglandin synthesis with 10 micromol/L indomethacin. Gallbladders were then
      exposed to increasing concentrations of PGE2 to a maximal dose of 1 micromol/L,
      as found in animals with gallstones. Standard electrophysiologic parameters were
      recorded simultaneously. Indomethacin increased mucosal resistance and stimulated
      gallbladder Na+ and Cl- absorption. These effects were rapidly reversed by PGE2.
      PGE2 promoted Cl- secretion and decreased mucosal Na+ absorption at
      concentrations found in the gallbladder bile of animals with gallstones.
      Endogenous prostaglandin metabolism modulates gallbladder Cl- secretion and may
      promote changes in Cl- transport associated with cholelithiasis.

PMID- 10638699
TI  - Dietary manipulation of delta-6-desaturase modifies phospholipid arachidonic acid
      levels and the urinary excretion of calcium and oxalate in the rat: insight in
      calcium lithogenesis.
AB  - An anomalous n-6 polyunsaturated fatty acid composition in plasma and erythrocyte
      membrane phospholipids, namely increased levels of arachidonic acid (AA), has
      been reported in calcium nephrolithiasis and has been proposed to play an
      important role in its pathogenesis. To confirm this, in rats we modified
      phospholipid AA levels by dietary manipulation of the delta-6-desaturase, the
      rate-limiting enzyme of the fatty acid biosynthetic pathway, and evaluated the
      effect on cellular and renal functions predisposing to lithogenesis. Increased AA
      levels led to conditions at risk for nephrolithiasis: higher oxalate flux and
      lower sodium cotransport in erythrocytes and a rise in urinary prostaglandin E2,
      calcium, sodium, and oxalate levels; reduced AA levels reversed these changes. In
      vitro, in human erythrocytes the incorporation of exogenous AA into membranes
      increased band 3 protein phosphorylation directly activating the Ser/Thr protein
      kinase CK1 and induced a parallel raise in band 3-mediated oxalate transport.
      These findings demonstrate the pivotal role of phospholipid AA in modulating
      erythrocyte and renal transport of calcium and oxalate.

PMID- 10638700
TI  - Peripheral blood erythrocyte parameters in hemochromatosis: evidence for
      increased erythrocyte hemoglobin content.
AB  - We studied peripheral blood erythrocyte parameters and HFE genotypes in 94
      hemochromatosis probands and 132 white, normal control subjects. Mean red blood
      cell counts in probands and control subjects were not significantly different.
      However, mean values of hemoglobin, hematocrit, mean corpuscular volume (MCV),
      mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration
      (MCHC) were significantly higher in C282Y/C282Y probands (n = 60) than in wild
      type control subjects (n = 65). Probands with other HFE genotypes also had
      increased mean erythrocyte parameters (other than red blood cell count).
      Peripheral blood smears prepared before therapeutic phlebotomy revealed that
      erythrocytes in many probands had increased diameters and were well filled with
      hemoglobin. Erythrocyte parameters were similar in C282Y/C282Y probands with and
      without hepatomegaly, elevated serum concentrations of hepatic enzymes, hepatic
      cirrhosis, diabetes mellitus, arthropathy, or hypogonadism. Among C282Y/C282Y
      probands, significantly greater values of MCV (but not other erythrocyte
      parameters) occurred among those who had transferrin saturation values of 75% or
      greater or iron overload at diagnosis. After iron depletion, the mean MCV, MCH,
      and MCHC values of C282Y/C282Y probands decreased but remained significantly
      greater than values in wild-type control subjects. Mean values of prephlebotomy
      MCH and MCHC concentrations were lower in HLA-A3-positive than in HLA-A3-negative
      C282Y/C282Y probands. We conclude that increased values of mean hemoglobin,
      hematocrit, MCV, MCH, and MCHC in hemochromatosis probands are caused primarily
      by increased iron uptake and hemoglobin synthesis by immature erythroid cells.
      Mechanisms of iron uptake by erythrocytes that could explain these results are
      discussed.

PMID- 10638701
TI  - Adherence of staphylococci.

PMID- 10638702
TI  - The cross-species antiviral activities of different IFN-tau subtypes on bovine,
      murine, and human cells: contradictory evidence for therapeutic potential.
AB  - It is claimed that interferon-tau (IFN-tau) has broad cross-species reactivity
      and less cytotoxicity than other type I IFN when used at high concentration
      either in vitro or in living animals. It can also amelioriate the development of
      experimental allergic encephalomyelitis (EAE) without the usual side effects of
      IFN therapy in mice autoimmunized with myelin basic protein. For these reasons,
      IFN-tau may have therapeutic potential in humans. Here, the antiviral (AV)
      activities of eight different recombinant IFN-tau were compared with those of
      several bovine, human, and murine type I IFN on bovine MDBK cells, murine L929
      cells, and human WISH cells. The data show that only one of the IFN-tau, OvIFN
      tau4, has broad cross-species reactivity. It was comparable in this respect to
      HuIFN-omega1 and HuIFN-alpha1. The other IFN-tau, including the variant form
      (OvIFN-tau1mod) tested by others in cytotoxicity experiments and for its ability
      to protect mice against EAE, had relatively weak AV activity on mouse and human
      cells. It is possibly because this particular bioengineered form of IFN-tau binds
      the common type I receptor of these two species with such low affinity that it
      lacks cytotoxic effects. The basis for its potent anti-EAE activity is unclear,
      but it seems possible that it does not involve the type I IFN receptor.

PMID- 10638703
TI  - Biologic and binding activities of IFN-alpha subtypes in ACHN human renal cell
      carcinoma cells and Daudi Burkitt's lymphoma cells.
AB  - Nine interferon-alpha subtypes, IFN-alpha1, IFN-alpha2, IFN-alpha5, IFN-alpha7,
      IFN-alpha8, IFN-alpha10, IFN-alpha14, IFN-alpha17, and IFN-alpha21, were
      separated from purified human lymphoblastoid IFN. We tested their inhibitory
      effects on cell growth and replication of Semliki Forest virus (SFV) and
      vesicular stomatitis virus (VSV) and their induction of 2',5'-oligoadenylate
      synthetase (2', 5'-OAS) in ACHN renal cell carcinoma cells. In terms of all three
      activities, the nine subtypes had similar relative activities, with IFN-alpha10
      the most active and IFN-alpha1 the least. Their relative effects on cell growth
      were similar in two other human cell lines, SK-LU-1 lung cancer cells and KU-2
      renal cell carcinoma cells, whereas cells of the Daudi Burkitt lymphoma line
      behaved quite differently, being highly sensitive to all the nine subtypes. The
      relative effects with ACHN cells correlated well with their relative binding
      affinities. However, each of the subtypes bound to both ACHN and Daudi cells to
      almost the same extent. This suggests that their profound inhibitory effects on
      the growth of Daudi cells are amplified at some stage in the signal transduction
      pathway or in the expression of genes that results from binding to the IFN-alpha
      receptor.

PMID- 10638704
TI  - IFN-gamma induction of p21(WAF1) is required for cell cycle inhibition and
      suppression of apoptosis.
AB  - Interferons (IFN) inhibit the growth of tumor cells by blocking the progression
      of their cell cycle. Recently, we showed that this cell cycle inhibition
      correlates with the ability of IFN to upregulate the cyclin-dependent kinase
      inhibitor p21(WAF1). This, however, is not proof of a causal relationship. Using
      p21(WAF1)-deficient cells derived from the HCT116 colon adenocarcinoma cell line,
      we now show that p21(WAF1) is indeed responsible for the antiproliferative
      effects of the type II IFN, IFN-gamma. IFN-gamma upregulated p21(WAF1) expression
      in a p53-independent manner, decreased cyclin-dependent kinase 2 activity, and
      inhibited entry into the S phase of the cell cycle in p21+/+ but not in p21-/-
      HCT116 cells. We additionally found that the lack of p21(WAF1) expression
      resulted in an increase in the ability of IFN-gamma to induce apoptosis, as
      reflected by an earlier induction of DNA fragmentation and caspase 3 activity in
      p21-/- cell. Our results indicate that p21(WAF1) expression is necessary for IFN
      gamma-mediated cell cycle inhibition and suppression of IFN-gamma-induced
      apoptosis.

PMID- 10638705
TI  - Cooperation between transcription factor AP-1 and NF-kappaB in the induction of
      interleukin-8 in human pancreatic adenocarcinoma cells by hypoxia.
AB  - The expression of interleukin-8 (IL-8) has been shown to play an important role
      in the growth and metastasis of human pancreatic cancer. In the present study, we
      investigated the regulation of IL-8 gene expression by hypoxic environments.
      Exposure of the human pancreatic cancer cells COLO357 and FG to hypoxia in
      culture resulted in a time-dependent increase in steady-state levels of IL-8 mRNA
      and IL-8 protein secretion. The induction of IL-8 expression was correlated with
      transcriptional activation of the IL-8 gene. Deletion and point mutation analyses
      of the IL-8 promoter revealed that both AP-1 and NF-kappaB binding sites were
      necessary for IL-8 induction by hypoxia. Consistently, hypoxia induced both AP-1
      and NF-kappaB activity. These data suggest that hypoxic environments upregulate
      the IL-8 gene via cooperation of NF-kappaB and AP-1 and contribute to the
      progression and metastasis of human pancreatic cancer.

PMID- 10638706
TI  - Cytokine production from murine CD4 and CD8 cells after mannan-MUC1 immunization.
AB  - Immunotherapy with oxidized mannan-MUC1 fusion protein (M-FP) leads to a T1
      immune response characterized by the generation of cytotoxic T lymphocytes (CTL),
      few antibodies, secretion of interleukin-2 (IL-2), IL-12, and interferon-gamma
      and tumor protection. Immunotherapy with reduced M-FP or fusion protein (FP)
      alone leads to a T2 immune response characterized by the generation of MUC1
      antibodies, few CTL, IL-4 secretion, and no tumor protection. In these studies,
      cytokine production from T cells was measured from cultures containing whole
      spleens. We now report the cytokine secretion patterns from spleen cells
      separated into CD4+ and CD8+ T cells obtained from mice immunized with either
      oxidized M-FP, reduced M-FP or FP, or the simultaneous administration of oxidized
      M-FP and FP. Immunization with oxidized M-FP led to the secretion of T1 cytokines
      from CD8+ T cells (IL-2, IFN-gamma, and tumor necrosis factor-alpha [TNF-alpha])
      and from CD4+ T cells (IL-2 and IFN-gamma). IL-12 production, presumably from
      activated macrophages, was observed in CD8+ but not CD4+ cultures. Immunization
      with either reduced M-FP or FP led to the secretion of predominantly T2 cytokines
      from CD4+ T cells (IL-4 and IL-10) and IL-2 production in both CD4+ and CD8+ T
      cell cultures. The simultaneous immunization of both oxidized M-FP and FP led to
      the production of both T1 and T2 cytokines from CD8+ T cells (IL-2, IFN-gamma,
      and TNF-alpha) and CD4+ cells (IL-2, IFN-gamma, IL-4, and IL-10) and IL-12
      production in CD8+ cultures that is, both types of immune responses could occur
      together. The results demonstrate that the cellular immune response observed in
      oxidized M-FP-immunized mice is indeed dependent on the T1 cytokine profile
      secreted by CD8+ T cells, and the simultaneous production of both T1 and T2
      cytokines is not cross-inhibitory.

PMID- 10638707
TI  - Transient gene transfer of non-ELR chemokines to rodent lung induces mononuclear
      cell accumulation and activation.
AB  - The in vivo function of the CXC chemokines interferon-inducible protein-10 (IP
      10) and monokine induced by gamma (MIG) was examined using replication-deficient
      adenoviral vectors expressing human IP-10 (AdIP-10) or murine MIG (AdMIG).
      Intratracheal and intranasal administration of AdIP-10 or AdMIG into rats and
      mice produced transient chemokine overexpression from the bronchial epithelium.
      IP-10 concentrations in the bronchoalveolar lavage fluid (BAL) of AdIP-10-treated
      animals showed peak expression (>2 ng/ml) 24-48 h after AdIP-10 administration.
      Dramatic transient increases in BAL cellularity (macrophages, monocytes,
      lymphocytes, and neutrophils) were observed in AdIP-10-treated and AdMIG-treated
      animals, and histologic examination of AdIP-10-treated lungs revealed transient
      infiltrations of mononuclear cells primarily localized around the bronchus and
      extending throughout the lung parenchyma. However, in immunocomprised SCID mice,
      only increases in natural killer cell populations were detected in BAL following
      AdIP-10 intranasal administration, indicating that monocyte/macrophage and
      neutrophil accumulation was likely the result of factors released from activated
      lymphocytes.

PMID- 10638708
TI  - Induction of antitumor immunity with modified autologous cells expressing
      membrane-bound murine cytokines.
AB  - Development of cytokine gene-modified autologous tumor vaccines must take into
      account the strictly paracrine physiology of cytokines whose expression at the
      tumor microenvironment is important for the successful induction of tumor
      specific immunity. In this study, we investigated the efficacy of a tumor vaccine
      composed of inactivated autologous cells transfected with two plasmid vectors
      encoding a mutant membrane-bound murine granulocyte-macrophage colony-stimulating
      factor (MuGM-CSF) and murine interferon-gamma (MuIFN-gamma). Expression of both
      cytokines as cell surface ligands on the highly metastatic D122 clone of Lewis
      lung carcinoma led to abrogation of their tumorigenicity and metastatic
      phenotype. More importantly, vaccination with irradiated tumor cells expressing
      the membrane-bound GM-CSF and IFN-gamma induced a cytotoxic T lymphocyte (CTL)
      response that protected syngeneic mice against a subsequent challenge with D122
      cells as a primary tumor in preimmunized mice as well as against lung metastasis
      developing after surgical removal of the primary tumor in naive mice. Autologous
      cells expressing the membrane-bound GM-CSF and IFN-gamma exhibited comparable
      efficacy as an antimetastatic vaccine to a vaccine composed of transfectants
      expressing wild-type secreted cytokine molecules. These results indicate that
      membrane-bound cytokines can cause enhanced immunogenicity when transfected into
      tumor cells for the induction of antitumor immunity.

PMID- 10638710
TI  - The antifibrogenic effects of liposome-encapsulated IFN-alpha2b cream on skin
      wounds.
AB  - Interferons (IFN), including IFN-alpha2b, have been used as antifibrogenic
      factors to modulate the excessive production of extracellular matrix (ECM)
      associated with dermal fibroproliferative disorders. This study was conducted to
      examine the ability of a dermal cream containing liposome-encapsulated IFN
      alpha2b (LIPO+IFN) to affect the synthesis of ECM in open and reepithelialized
      wounds. Full-thickness skin wounds in 32 female Hartley guinea pigs (6 wounds per
      animal, 3 on each side) were made with an 8-mm biopsy punch. Each wound on the
      right side received 3,000 U LIPO+IFN, whereas wounds on the left side received
      cream containing empty liposomes. Histologic examination revealed a significant
      reduction in scar formation in LIPO+IFN-treated but not in vehicle-treated
      wounds. Northern analysis showed reductions in type I procollagen mRNA in healed
      wounds treated with LIPO+IFN (day 4 groups: 1596.9 +/- 207 vs. 3710.2 +/- 493
      densitometry units, p < 0.01, n = 8). This was consistent with a reduction in the
      concentration of collagen in the tissue, assayed as 4-hydroxyproline (day 4
      group: 38.5 +/- 3.8 vs. 54.5 +/- 3.9 microg per tissue, p < 0.01, n = 8). Even
      when applied to reepithelialized wounds, LIPO+IFN caused a marked reduction in
      type I collagen mRNA (1938.5 +/- 579 vs. 4085.7 +/- 1271 densitometry units, p <
      0.01, n = 8). These findings support the concept of the early topical use of this
      antifibrogenic agent for treatment of dermal fibroproliferative disorders, such
      as hypertrophic scars.

PMID- 10638709
TI  - Synergistic induction of mouse serum amyloid A3 promoter by the inflammatory
      mediators IL-1 and IL-6.
AB  - Serum amyloid A (SAA), one of the major acute-phase proteins, increases several
      hundredfold in concentration in plasma following acute inflammation, primarily as
      a result of a 200-fold increase in its transcription rate. We have previously
      demonstrated that a 350-bp promoter fragment from the mouse SAA3 gene could
      confer conditioned medium-induced expression in cultured cells. The induction is
      mediated through a 42-bp distal response element (DRE) consisting of three
      functional regulatory elements. In this study, we show that interleukin-1 (IL-1)
      is the major cytokine in the conditioned medium responsible for SAA3 induction,
      and the induction by IL-1 can be effectively blocked by H-7, a protein kinase C
      inhibitor. Although IL-6 alone had no effect on SAA3 promoter activity, the
      addition of IL-6 and IL-1 resulted in dramatic synergistic activation of the
      reporter gene. We further show that the DRE is both necessary and sufficient to
      confer synergistic induction by IL-1 and IL-6. Moreover, individual mutation of
      the three regulatory elements within DRE either abolished or drastically reduced
      the synergistic induction. Our results indicate that synergistic activation of
      SAA3 promoter by IL-1 and IL-6 is achieved through integration of signals
      triggered by these two cytokines onto the DRE and that all three functionally
      distinct regulatory elements in the DRE are required to effectively and fully
      activate SAA3 gene transcription.

PMID- 10638712
TI  - Sociocultural influences on body image and body change methods.

PMID- 10638711
TI  - Common mental disorders, suicidality and use of health care services during late
      adolescence in Finland.

PMID- 10638714
TI  - Parental underestimates of adolescent risk behavior: a randomized, controlled
      trial of a parental monitoring intervention.
AB  - OBJECTIVES: To develop and evaluate an intervention (ImPACT) seeking to increase
      monitoring (supervision and communication) by parents and guardians of African
      American youth regarding high risk and protective behaviors; and to develop an
      instrument to assess parental monitoring, the Parent-Adolescent Risk Behavior
      Concordance Scale. DESIGN/INTERVENTION: This research was a randomized,
      controlled longitudinal study. Baseline (preintervention), and 2 and 6 months
      postintervention data were obtained via a talking MacIntosh computer regarding
      youth and parent perceptions of youth involvement in 10 risk behaviors, parental
      monitoring and youth-parent communication, and condom-use skills. Intervention
      parents and youth received the ImPACT program and a video emphasizing parental
      supervision and discussion, followed by a structured discussion and role-play
      emphasizing key points. Control parents and youth received an attention-control
      program on goal-setting, which also included an at-home video and discussion.
      PARTICIPANTS: A total of 237 parents and one each of their youth (ages 12-16
      years) recruited from eight public housing developments located in a city in the
      mid-Atlantic region. RESULTS: Similarity of youth and parental reporting on the
      Parent-Adolescent Risk Behavior Concordance Scale was positively correlated with
      protective behaviors, perceived parental monitoring, and good parent-youth
      communication. At baseline, parents significantly underestimated their youth's
      risk behaviors. However, 2 and 6 months postintervention, the ImPACT program
      increased similarity of reports by youth and their parents of youth involvement
      in risk and protective behaviors. In addition, at 6 months postintervention,
      intervention (compared to control) youths and parents also demonstrated higher
      levels of condom-use skills. CONCLUSION: Parental monitoring interventions such
      as ImPACT should be given to parents in conjunction with more traditional youth
      centered risk-reduction interventions.

PMID- 10638713
TI  - Abstinence-based programs for prevention of adolescent pregnancies. A review.

PMID- 10638715
TI  - Do friendships change behaviors, or do behaviors change friendships? Examining
      paths of influence in young adolescents' alcohol use.
AB  - PURPOSE: This study examined support for models of peer influence, which
      postulates that young adolescents whose friends use alcohol will also engage in
      that behavior, and of peer selection, whereby young adolescents seek out friends
      whose drinking behavior is similar to their own. METHODS: Data for this study are
      from 1804 adolescents participating in Project Northland, a school- and community
      based alcohol use prevention trial. Using latent variable structural equation
      modeling, a series of models examined directions of influence between participant
      alcohol use and friend drug use over three points in Grades 7, 8, and 9. RESULTS:
      Findings indicated that higher levels of friends' drug use led to increased
      participant alcohol use. The reverse-order relationship (i.e., greater
      participant involvement in alcohol leading to more drug use among friends) was
      not supported by these data. Finally, best-fitting models supported the notion
      that both participants' alcohol use and the alcohol and other drug use of friends
      were highly stable over time. CONCLUSIONS: Similarity in drinking behavior among
      adolescent friends may be more related to processes of peer influence than to
      processes of peer selection. Findings support the utility of alcohol use
      prevention programs that equip younger teens with skills to resist peer
      influences to use alcohol.

PMID- 10638716
TI  - Does the camera add 10 pounds? Media use, perceived importance of appearance, and
      weight concerns among teenage girls.
AB  - PURPOSE: To examine the relationship between use of electronic media and
      perceived importance of appearance and weight concerns among adolescent girls.
      METHODS: Physical measures and self-report surveys were obtained from 837 ninth
      grade girls attending pubs lic high schools in San Jose, California (mean age =
      14.9 +/- 0.47 years; 36% Latino, 24% White, 22% Asian, 8% Black, 10% other).
      Correlational and multiple regression analyses were performed with ethnicity,
      body mass index (BMI), perceived importance of appearance, weight concerns, and
      media use (based on self-reported average weekly use of television, videotapes,
      video and computer games, and music videos). RESULTS: Total media use was not
      significantly related to perceived importance of appearance or weight concerns.
      When media use was separated into distinct media genres, only hours of watching
      music videos was related to perceived importance of appearance and weight
      concerns (r = 0.12, p < .001, and r = .08, p < .05, respectively). In
      multivariate analyses, after controlling for BMI and ethnicity, no media use
      variables were significantly associated with either perceived importance of
      appearance or weight concerns. CONCLUSIONS: Frequent music video use may be a
      risk factor for increased perceived importance of appearance and increased weight
      concerns among adolescent girls.

PMID- 10638717
TI  - Influences on adolescents' decision to postpone onset of sexual intercourse: a
      survival analysis of virginity among youths aged 13 to 18 years.
AB  - BACKGROUND: Previous research has focused on risk factors associated with early
      onset of sexual intercourse among adolescents. This study hypothesizes that
      protective factors identified for other health compromising behaviors are also
      protective against early onset of sexual intercourse. The study sample included
      26,023 students in grades 7-12 (87.5% white, 52.5% male) who did not report a
      history of sexual abuse in a statewide survey of adolescent health in 1988.
      METHODS: Bivariate analyses were stratified into early (13-14 years), middle (15
      16 years) and late (17-18 years) adolescence and by gender. Cox proportional
      hazards survival analysis, stratified by gender, was used to determine risk and
      protective factors associated with delayed onset of sexual intercourse. RESULTS:
      Variables showing a significant bivariate association with lower levels of sexual
      activity across all age groups and genders were: dual-parent families, higher
      socioeconomic status (SES), better school performance, greater religiosity,
      absence of suicidal thoughts, feeling adults or parents cared, and high parental
      expectations. High levels of body pride were associated with higher levels of
      sexual activity for all age and gender groups. In the multivariate survival
      analyses, variables significantly associated with delayed onset of sexual
      activity for both males and females included: dual-parent families, higher SES,
      residing in rural areas, higher school performance, concerns about the community,
      and higher religiosity. High parental expectations were a significant protective
      factor for males but not for females. CONCLUSION: While many protective factors
      are not subject to intervention, the present analyses indicate that teen
      pregnancy prevention may be enhanced by addressing family and educational
      factors.

PMID- 10638718
TI  - Chondroblastoma: an unusual cause of knee pain in the adolescent.
AB  - Chondroblastoma is a rare, benign bone tumor that may mimic an orthopedic
      infection. Characteristic clinical features include specific radiographic
      findings, predilection for the adolescent age group, and long bone epiphyseal
      involvement. This case of chondroblastoma is unusual because of aggressive
      findings on radiographic studies which underscore the need to obtain hip
      radiographs on adolescent patients with knee pain.

PMID- 10638719
TI  - Substance use in high school students in New South Wales, Australia, in relation
      to language spoken at home.
AB  - PURPOSE: To examine for the first time adolescent substance use by ethnicity,
      given the high proportion of migrants from non-English-speaking countries in New
      South Wales, (NSW), Australia. METHODS: Data from four surveys of NSW secondary
      school students in 1983, 1986, 1989, and 1992 were used for this analysis. The
      prevalence of substance use by whether English was spoken at home was stratified
      by sex and age using data from the most recent survey year. Adjusted odds ratios
      and 95% confidence intervals were produced by simultaneous logistic regression,
      adjusting for sex, age group, and the interaction term of sex and age for each of
      these substances, and for each survey year separately. Data from 1989 and 1992
      were pooled together to examine rates of substance use by ethnic subgroups which
      reflect migration patterns. RESULTS: The prevalence of smoking and alcohol and
      illicit drug use was consistently lower among NSW adolescents speaking a language
      other than English at home, compared with those speaking English at home in all
      survey years. Only the prevalence of solvent sniffing was higher among younger
      adolescents speaking a language other than English at home. Students from
      Southeast Asia showed consistently lower rates of usage of all substances
      compared to all other groups. CONCLUSIONS: There may be different opportunities
      for the prevention of adolescent substance use among native English speakers to
      be gained from non-English-speaking cultures.

PMID- 10638720
TI  - An Australian study of adolescents with cystic fibrosis: perceived supportive and
      nonsupportive behaviors from families and friends and psychological adjustment.
AB  - PURPOSE: To identify and compare perceived supportive and nonsupportive behaviors
      exhibited by family members and friends toward adolescents with cystic fibrosis
      (CF), and to examine the relationships between supportive and nonsupportive
      behaviors and adolescents' psychological adjustment. METHOD: Participants were 35
      adolescents with CF attending the Women's and Children's Hospital in South
      Australia. Perceived supportive and nonsupportive behaviors were assessed using
      an adapted version of the Chronic Disease Support Interview. The psychological
      adjustment of the adolescents was assessed using the Youth Self Report Form.
      Repeated-measures analyses of variance were performed to compare the support
      provided by family members and friends. Multiple regression analyses assessed the
      contribution of supportive and nonsupportive behaviors for the prediction of
      psychological adjustment. RESULTS: Family members provided more tangible support
      than friends who, conversely, provided more companionship support. Overall,
      family members scored higher than friends on ratings for supportive behaviors. No
      differences were observed between family members and friends on ratings for
      nonsupportive behaviors. Rating of nonsupportive behaviors for family members was
      found to be the strongest predictor of psychological adjustment. CONCLUSIONS:
      Family members and friends provide different types of support. Family members
      provide more tangible help with treatment tasks and adolescents provide more
      companionship. Overall, this study demonstrated the importance of addressing
      nonsupportive as well as supportive behaviors when investigating the impact of
      support on the psychological adjustment of adolescents with a chronic illness.

PMID- 10638721
TI  - Assessment of body perception among Swedish adolescents and young adults.
AB  - PURPOSE: To assess body perception in adolescents and young adults without
      anorexia nervosa. METHOD: Using a visual size estimation technique, perceived
      body size was estimated in four groups of Swedish adolescents and young adults
      without anorexia nervosa (86 males and 95 females). Perceived body size was
      estimated at nine different body sites comparing these estimations to real body
      size. RESULTS: The results show that 95% of males and 96% of females
      overestimated their body size (mean overestimation: males +22%, females +33%).
      The overestimations were greatest in females. The greatest overestimations were
      made of the waist (males +31%, females +46%), buttocks (males +22%, females
      +42%), and thighs (males +27%, females +41%). CONCLUSIONS: The results indicate
      that overestimation of body size may be a general phenomenon in adolescents and
      young adults in a country such as Sweden, implying a similar, but less pronounced
      distortion of body image as in individuals with anorexia nervosa.

PMID- 10638722
TI  - Resolutions to enhance confident creativity.

PMID- 10638723
TI  - Europe lifts patent embargo on transgenic plants and animals.

PMID- 10638724
TI  - Big gains for biology and IT in Japanese science budget.

PMID- 10638725
TI  - 'US politicians have fallen in love with basic research'.

PMID- 10638727
TI  - 'I have reported on astonishing achievements in times of hardship'.

PMID- 10638726
TI  - 'Japan's scientists must learn to take action'.

PMID- 10638728
TI  - 'If knowledge is king, we may need a republican revolution'.

PMID- 10638729
TI  - Do we need a huge new centre to annotate the human genome?

PMID- 10638730
TI  - How nature itself uses genetic modification.

PMID- 10638731
TI  - Millennial highlights...from Gerbert d'Aurillac to Watson and Crick.

PMID- 10638733
TI  - Optics adapt to the whole sky

PMID- 10638732
TI  - Making waves in physics. Three wave singularities from the miraculous 1830s

PMID- 10638734
TI  - Living on the edge.

PMID- 10638736
TI  - A bright future for dark matter

PMID- 10638737
TI  - Taking the temperature of slabs

PMID- 10638735
TI  - Caspases find a new place to hide.

PMID- 10638739
TI  - Durable catalysts for cleaner air

PMID- 10638738
TI  - Telomeric tethers.

PMID- 10638740
TI  - Marine iguanas shrink to survive El Nino.

PMID- 10638741
TI  - Biogeography of the Indonesian coelacanths.

PMID- 10638742
TI  - Extrapolating movement without retinal motion.

PMID- 10638743
TI  - Numerical memory span in a chimpanzee.

PMID- 10638744
TI  - Explaining the T-wave shape in the ECG.

PMID- 10638745
TI  - The language of covalent histone modifications.
AB  - Histone proteins and the nucleosomes they form with DNA are the fundamental
      building blocks of eukaryotic chromatin. A diverse array of post-translational
      modifications that often occur on tail domains of these proteins has been well
      documented. Although the function of these highly conserved modifications has
      remained elusive, converging biochemical and genetic evidence suggests functions
      in several chromatin-based processes. We propose that distinct histone
      modifications, on one or more tails, act sequentially or in combination to form a
      'histone code' that is, read by other proteins to bring about distinct downstream
      events.

PMID- 10638747
TI  - Adaptive-optics corrections available for the whole sky
AB  - Adaptive-optics systems can in principle allow a telescope to achieve performance
      at its theoretical maximum (limited only by diffraction), by correcting in real
      time for the distortion of starlight by atmospheric turbulence. For such a system
      installed on an 8-m-class telescope, the spatial resolution and sensitivity could
      be up to 100 times better than conventional imaging. Adaptive-optics corrections
      have hitherto been achieved only for regions of the sky within a few arcseconds
      of a bright reference source. But it has been proposed theoretically that by
      using multiple guide stars, the tomography of atmospheric turbulence could be
      probed and used to extend adaptive-optics corrections to the whole sky. Here we
      report the experimental verification of such tomographic corrections, using three
      off-axis reference stars approximately 15 arcsec from the central star. We used
      the observations of the off-axis stars to calculate the deformations of the
      wavefront of the central star, and then compare them with the real measured
      values. This tomographic approach is found to reduce variations in the wavefront
      by approximately 92%. Our result demonstrates that a serious barrier to achieving
      diffraction-limited seeing over the whole sky has been removed.

PMID- 10638746
TI  - Crystal structure of the hereditary haemochromatosis protein HFE complexed with
      transferrin receptor.
AB  - HFE is related to major histocompatibility complex (MHC) class I proteins and is
      mutated in the iron-overload disease hereditary haemochromatosis. HFE binds to
      the transferrin receptor (TfR), a receptor by which cells acquire iron-loaded
      transferrin. The 2.8 A crystal structure of a complex between the extracellular
      portions of HFE and TfR shows two HFE molecules which grasp each side of a
      twofold symmetric TfR dimer. On a cell membrane containing both proteins, HFE
      would 'lie down' parallel to the membrane, such that the HFE helices that
      delineate the counterpart of the MHC peptide-binding groove make extensive
      contacts with helices in the TfR dimerization domain. The structures of TfR alone
      and complexed with HFE differ in their domain arrangement and dimer interfaces,
      providing a mechanism for communicating binding events between TfR chains. The
      HFE-TfR complex suggests a binding site for transferrin on TfR and sheds light
      upon the function of HFE in regulating iron homeostasis.

PMID- 10638748
TI  - Infrared spectrum of an extremely cool white-dwarf star
AB  - White dwarfs are the remnant cores of stars that initially had masses of less
      than 8 solar masses. They cool gradually over billions of years, and have been
      suggested to make up much of the 'dark matter' in the halo of the Milky Way. But
      extremely cool white dwarfs have proved difficult to detect, owing to both their
      faintness and their anticipated similarity in colour to other classes of dwarf
      stars. Recent improved models indicate that white dwarfs are much more blue than
      previously supposed, suggesting that the earlier searches may have been looking
      for the wrong kinds of objects. Here we report an infrared spectrum of an
      extremely cool white dwarf that is consistent with the new models. We determine
      the star's temperature to be 3,500 +/- 200 K, making it the coolest known white
      dwarf. The kinematics of this star indicate that it is in the halo of the Milky
      Way, and the density of such objects implied by the serendipitous discovery of
      this star is consistent with white dwarfs dominating the dark matter in the halo.

PMID- 10638749
TI  - Tunnelling between the edges of two lateral quantum Hall systems
AB  - The edge of a two-dimensional electron system in a magnetic field consists of one
      dimensional channels that arise from the confining electric field at the edge of
      the system. The crossed electric and magnetic fields cause electrons to drift
      parallel to the sample boundary, creating a chiral current that travels along the
      edge in only one direction. In an ideal two-dimensional electron system in the
      quantum Hall regime, all the current flows along the edge. Quantization of the
      Hall resistance arises from occupation of N one-dimensional edge channels, each
      contributing a conductance of e2/h. Here we report differential conductance
      measurements, in the integer quantum Hall regime, of tunnelling between the edges
      of a pair of two-dimensional electron systems that are separated by an atomically
      precise, high-quality, tunnel barrier. The resultant interaction between the edge
      states leads to the formation of new energy gaps and an intriguing dispersion
      relation for electrons travelling along the barrier: for example, we see a
      persistent conductance peak at zero bias voltage and an absence of tunnelling
      features due to electron spin. These features are unexpected and are not
      consistent with a model of weakly interacting edge states. Remnant disorder along
      the barrier and charge screening may each play a role, although detailed
      numerical studies will be required to elucidate these effects.

PMID- 10638750
TI  - Magnetic trapping of neutrons
AB  - Accurate measurement of the lifetime of the neutron (which is unstable to beta
      decay) is important for understanding the weak nuclear force and the creation of
      matter during the Big Bang. Previous measurements of the neutron lifetime have
      mainly been limited by certain systematic errors; however, these could in
      principle be avoided by performing measurements on neutrons stored in a magnetic
      trap. Neutral-particle and charged-particle traps are widely used for studying
      both composite and elementary particles, because they allow long interaction
      times and isolation of particles from perturbing environments. Here we report the
      magnetic trapping of neutrons. The trapping region is filled with superfluid 4He,
      which is used to load neutrons into the trap and as a scintillator to detect
      their decay. Neutrons in the trap have a lifetime of 750(+330)(-200) seconds,
      mainly limited by their beta decay rather than trap losses. Our experiment
      verifies theoretical predictions regarding the loading process and magnetic
      trapping of neutrons. Further refinement of this method should lead to improved
      precision in the neutron lifetime measurement.

PMID- 10638751
TI  - Reverse microemulsion synthesis of nanostructured complex oxides for catalytic
      combustion
AB  - Catalysts play an important role in many industrial processes, but their use in
      high-temperature applications-such as energy generation through natural gas
      combustion, steam reforming and the partial oxidation of hydrocarbons to produce
      feedstock chemicals--is problematic. The need for catalytic materials that remain
      stable and active over long periods at high operation temperatures, often in the
      presence of deactivating or even poisoning compounds, presents a challenge. For
      example, catalytic methane combustion, which generates power with reduced
      greenhouse-gas and nitrogen-oxide emissions, is limited by the availability of
      catalysts that are sufficiently active at low temperatures for start-up and are
      then able to sustain activity and mechanical integrity at flame temperatures as
      high as 1,300 degrees C. Here we use sol-gel processing in reverse microemulsions
      to produce discrete barium hexa-aluminate nanoparticles that display excellent
      methane combustion activity, owing to their high surface area, high thermal
      stability and the ultrahigh dispersion of cerium oxide on the their surfaces. Our
      synthesis method provides a general route to the production of a wide range of
      thermally stable nanostructured composite materials with large surface-to-volume
      ratios and an ultrahigh component dispersion that gives rise to synergistic
      chemical and electronic effects, thus paving the way to the development of
      catalysts suitable for high-temperature industrial applications.

PMID- 10638752
TI  - Forecasting Andean rainfall and crop yield from the influence of El Nino on
      Pleiades visibility
AB  - Farmers in drought-prone regions of Andean South America have historically made
      observations of changes in the apparent brightness of stars in the Pleiades
      around the time of the southern winter solstice in order to forecast interannual
      variations in summer rainfall and in autumn harvests. They moderate the effect of
      reduced rainfall by adjusting the planting dates of potatoes, their most
      important crop. Here we use data on cloud cover and water vapour from satellite
      imagery, agronomic data from the Andean altiplano and an index of El Nino
      variability to analyse this forecasting method. We find that poor visibility of
      the Pleiades in June-caused by an increase in subvisual high cirrus clouds-is
      indicative of an El Nino year, which is usually linked to reduced rainfall during
      the growing season several months later. Our results suggest that this centuries
      old method of seasonal rainfall forecasting may be based on a simple indicator of
      El Nino variability.

PMID- 10638753
TI  - Channelized fluid flow in oceanic crust reconciles heat-flow and permeability
      data
AB  - Hydrothermal fluid circulation within the sea floor profoundly influences the
      physical, chemical and biological state of the crust and the oceans. Circulation
      within ridge flanks (in crust more than 1 Myr old) results in greater heat loss
      and fluid flux than that at ridge crests and persists for millions of years,
      thereby altering the composition of the crust and overlying ocean. Fluid flow in
      oceanic crust is, however, limited by the extent and nature of the rock's
      permeability. Here we demonstrate that the global data set of borehole
      permeability measurements in uppermost oceanic crust defines a trend with age
      that is consistent with changes in seismic velocity. This trend-which indicates
      that fluid flow should be greatly reduced in crust older than a few million years
      would appear to be inconsistent with heat-flow observations, which on average
      indicate significant advective heat loss in crust up to 65 Myr old. But our
      calculations, based on a lateral flow model, suggest that regional-scale
      permeabilities are much higher than have been measured in boreholes. These
      results can be reconciled if most of the fluid flow in the upper crust is
      channelized through a small volume of rock, influencing the geometry of
      convection and the nature of fluid-rock interaction.

PMID- 10638754
TI  - A highly unsaturated fatty acid predicts carbon transfer between primary
      producers and consumers.
AB  - The factors that regulate energy transfer between primary producers and consumers
      in aquatic ecosystems have been investigated for more than 50 years. Among all
      levels of the food web (plants, herbivores, carnivores), the plant-animal
      interface is the most variable and least predictable link. In hypereutrophic
      lakes, for example, biomass and energy transfer is often inhibited at the
      phytoplankton-zooplankton link, resulting in an accumulation of phytoplankton
      biomass instead of sustaining production at higher trophic levels, such as fish.
      Accumulation of phytoplankton (especially cyanobacteria) results in severe
      deterioration of water quality, with detrimental effects on the health of humans
      and domestic animals, and diminished recreational value of water bodies. We show
      here that low transfer efficiencies between primary producers and consumers
      during cyanobacteria bloom conditions are related to low relative
      eicosapentaenoic acid (20:5omega3) content of the primary producer community.
      Zooplankton growth and egg production were strongly related to the primary
      producer 20:5omega3 to carbon ratio. This indicates that limitation of
      zooplankton production by this essential fatty acid is of central importance at
      the pelagic producer-consumer interface.

PMID- 10638755
TI  - The Santa Barbara Basin is a symbiosis oasis.
AB  - It is generally agreed that the origin and initial diversification of Eucarya
      occurred in the late Archaean or Proterozoic Eons when atmospheric oxygen levels
      were low and the risk of DNA damage due to ultraviolet radiation was high.
      Because deep water provides refuge against ultraviolet radiation and early
      eukaryotes may have been aerotolerant anaerobes, deep-water dysoxic environments
      are likely settings for primeval eukaryotic diversification. Fossil evidence
      shows that deep-sea microbial mats, possibly of sulphur bacteria similar to
      Beggiatoa, existed during that time. Here we report on the eukaryotic community
      of a modern analogue, the Santa Barbara Basin (California, USA). The Beggiatoa
      mats of these severely dysoxic and sulphidic sediments support a surprisingly
      abundant protistan and metazoan meiofaunal community, most members of which
      harbour prokaryotic symbionts. Many of these taxa are new to science, and both
      microaerophilic and anaerobic taxa appear to be represented. Compared with nearby
      aerated sites, the Santa Barbara Basin is a 'symbiosis oasis' offering a new
      source of organisms for testing symbiosis hypotheses of eukaryogenesis.

PMID- 10638756
TI  - Mortality of sea lions along the central California coast linked to a toxic
      diatom bloom.
AB  - Over 400 California sea lions (Zalophus californianus) died and many others
      displayed signs of neurological dysfunction along the central California coast
      during May and June 1998. A bloom of Pseudo-nitzschia australis (diatom) was
      observed in the Monterey Bay region during the same period. This bloom was
      associated with production of domoic acid (DA), a neurotoxin that was also
      detected in planktivorous fish, including the northern anchovy (Engraulis
      mordax), and in sea lion body fluids. These and other concurrent observations
      demonstrate the trophic transfer of DA resulting in marine mammal mortality. In
      contrast to fish, blue mussels (Mytilus edulus) collected during the DA outbreak
      contained no DA or only trace amounts. Such findings reveal that monitoring of
      mussel toxicity alone does not necessarily provide adequate warning of DA
      entering the food web at levels sufficient to harm marine wildlife and perhaps
      humans.

PMID- 10638757
TI  - Dynamic biogeography and conservation of endangered species.
AB  - As one moves from the core to the periphery of a species' geographical range,
      populations occupy less favourable habitats and exhibit lower and more variable
      densities. Populations along the periphery of the range tend to be more
      fragmented and, as a result, are less likely to receive immigrants from other
      populations. A population's probability of extinction is directly correlated with
      its variability and inversely correlated with density and immigration rate. This
      has led to the prediction that, when a species becomes endangered, its
      geographical range should contract inwards, with the core populations persisting
      until the final stages of decline. Convinced by these logical but untested
      deductions, conservation biologists and wildlife managers have been instructed to
      avoid the range periphery when planning conservation strategies or allocating
      resources for endangered species. We have analysed range contraction in 245
      species from a broad range of taxonomic groups and geographical regions. Here we
      report that observed patterns of range contraction do not support the above
      predictions and that most species examined persist in the periphery of their
      historical geographical ranges.

PMID- 10638758
TI  - Reduced vas deferens contraction and male infertility in mice lacking P2X1
      receptors.
AB  - P2X1 receptors for ATP are ligand-gated cation channels, present on many
      excitable cells including vas deferens smooth muscle cells. A substantial
      component of the contractile response of the vas deferens to sympathetic nerve
      stimulation, which propels sperm into the ejaculate, is mediated through P2X
      receptors. Here we show that male fertility is reduced by approximately 90% in
      mice with a targeted deletion of the P2X1 receptor gene. Male mice copulate
      normally--reduced fertility results from a reduction of sperm in the ejaculate
      and not from sperm dysfunction. Female mice and heterozygote mice are unaffected.
      In P2X1-receptor-deficient mice, contraction of the vas deferens to sympathetic
      nerve stimulation is reduced by up to 60% and responses to P2X receptor agonists
      are abolished. These results show that P2X1 receptors are essential for normal
      male reproductive function and suggest that the development of selective P2X1
      receptor antagonists may provide an effective non-hormonal male contraceptive
      pill. Also, agents that potentiate the actions of ATP at P2X1 receptors may be
      useful in the treatment of male infertility.

PMID- 10638759
TI  - Turning of nerve growth cones induced by localized increases in intracellular
      calcium ions.
AB  - Guidance of developing axons involves turning of the motile tip, the growth cone,
      in response to a variety of extracellular cues. Little is known about the
      intracellular mechanism by which the directional signal is transduced. Ca2+ is a
      key second messenger in growth cone extension and has been implicated in growth
      cone turning. Here I report that a direct, spatially restricted elevation of
      intracellular Ca2+ concentration ([Ca2+]i) on one side of the growth cone by
      focal laser-induced photolysis (FLIP) of caged Ca2+ consistently induced turning
      of the growth cone to the side with elevated [Ca2+]i (attraction). Furthermore,
      when the resting [Ca2+]i at the growth cone was decreased by the removal of
      extracellular Ca2+, the same focal elevation of [Ca2+]i by FLIP induced
      repulsion. These results provide direct evidence that a localized Ca2+ signal in
      the growth cone can provide the intracellular directional cue for extension and
      is sufficient to initiate both attraction and repulsion. By integrating local and
      global Ca2+ signals, a growth cone could thus generate different turning
      responses under different environmental conditions during guidance.

PMID- 10638760
TI  - Calcium signalling in the guidance of nerve growth by netrin-1.
AB  - Pathfinding by growing axons in the developing nervous system is guided by
      diffusible or bound factors that attract or repel the axonal growth cone. The
      cytoplasmic signalling mechanisms that trigger the responses of the growth cone
      to guidance factors are mostly unknown. Previous studies have shown that the
      level and temporal patterns of cytoplasmic Ca2+ can regulate the rate of growth
      cone extension in vitro and in vivo. Here we report that Ca2+ also mediates the
      turning behaviour of the growth cones of cultured Xenopus neurons that are
      induced by an extracellular gradient of netrin-1, an established diffusible
      guidance factor in vivo. The netrin-1-induced turning response depends on Ca2+
      influx through plasma membrane Ca2+ channels, as well as Ca2+-induced Ca2+
      release from cytoplasmic stores. Reduction of Ca2+ signals by blocking either of
      these two Ca2+ sources converted the netrin-1-induced response from attraction to
      repulsion. Activation of Ca2+-induced Ca2+ release from internal stores with a
      gradient of ryanodine in the absence of netrin-1 was sufficient to trigger either
      attractive or repulsive responses, depending on the ryanodine concentration used.
      These results support the model that cytoplasmic Ca2+ signals mediate growth-cone
      guidance by netrin-1, and different patterns of Ca2+ elevation trigger attractive
      and repulsive turning responses.

PMID- 10638761
TI  - Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by
      amyloid-beta.
AB  - Apoptosis, or cellular suicide, is important for normal development and tissue
      homeostasis, but too much or too little apoptosis can also cause disease. The
      family of cysteine proteases, the so- called caspases, are critical mediators of
      programmed cell death, and thus far 14 family members have been identified. Some
      of these, such as caspase-8, mediate signal transduction downstream of death
      receptors located on the plasma membrane. Others, such as caspase-9, mediate
      apoptotic signals after mitochondrial damage. Stress in the endoplasmic reticulum
      (ER) can also result in apoptosis. Here we show that caspase-12 is localized to
      the ER and activated by ER stress, including disruption of ER calcium homeostasis
      and accumulation of excess proteins in ER, but not by membrane- or mitochondrial
      targeted apoptotic signals. Mice that are deficient in caspase-12 are resistant
      to ER stress-induced apoptosis, but their cells undergo apoptosis in response to
      other death stimuli. Furthermore, we show that caspase-12-deficient cortical
      neurons are defective in apoptosis induced by amyloid-beta protein but not by
      staurosporine or trophic factor deprivation. Thus, caspase-12 mediates an ER
      specific apoptosis pathway and may contribute to amyloid-beta neurotoxicity.

PMID- 10638762
TI  - Anti-inflammatory cyclopentenone prostaglandins are direct inhibitors of IkappaB
      kinase.
AB  - NF-kappaB is a critical activator of genes involved in inflammation and immunity.
      Pro-inflammatory cytokines activate the IkappaB kinase (IKK) complex that
      phosphorylates the NF-kappaB inhibitors, triggering their conjugation with
      ubiquitin and subsequent degradation. Freed NF-kappaB dimers translocate to the
      nucleus and induce target genes, including the one for cyclo-oxygenase 2 (COX2),
      which catalyses the synthesis of pro-inflammatory prostaglandins, in particular
      PGE. At late stages of inflammatory episodes, however, COX2 directs the synthesis
      of anti-inflammatory cyclopentenone prostaglandins, suggesting a role for these
      molecules in the resolution of inflammation. Cyclopentenone prostaglandins have
      been suggested to exert anti-inflammatory activity through the activation of
      peroxisome proliferator-activated receptor-gamma. Here we demonstrate a novel
      mechanism of antiinflammatory activity which is based on the direct inhibition
      and modification of the IKKbeta subunit of IKK. As IKKbeta is responsible for the
      activation of NF-kappaB by pro-inflammatory stimuli, our findings explain how
      cyclopentenone prostaglandins function and can be used to improve the utility of
      COX2 inhibitors.

PMID- 10638763
TI  - Nuclear pore complexes in the organization of silent telomeric chromatin.
AB  - The functional regulation of chromatin is closely related to its spatial
      organization within the nucleus. In yeast, perinuclear chromatin domains
      constitute areas of transcriptional repression. These 'silent' domains are
      defined by the presence of perinuclear telomere clusters. The only protein found
      to be involved in the peripheral localization of telomeres is Yku70/Yku80. This
      conserved heterodimer can bind telomeres and functions in both repair of DNA
      double-strand breaks and telomere maintenance. These findings, however, do not
      address the underlying structural basis of perinuclear silent domains. Here we
      show that nuclear-pore-complex extensions formed by the conserved TPR homologues
      Mlp1 and Mlp2 are responsible for the structural and functional organization of
      perinuclear chromatin. Loss of MLP2 results in a severe deficiency in the repair
      of double-strand breaks. Furthermore, double deletion of MLP1 and MLP2 disrupts
      the clustering of perinuclear telomeres and releases telomeric gene repression.
      These effects are probably mediated through the interaction with Yku70. Mlp2
      physically tethers Yku70 to the nuclear periphery, thus forming a link between
      chromatin and the nuclear envelope. We show, moreover, that this structural link
      is docked to nuclear-pore complexes through a cleavable nucleoporin, Nup145. We
      propose that, through these interactions, nuclear-pore complexes organize a
      nuclear subdomain that is intimately involved in the regulation of chromatin
      metabolism.

PMID- 10638764
TI  - Three-dimensional structure of the ion-coupled transport protein NhaA.
AB  - Ion-coupled membrane-transport proteins, or secondary transporters, comprise a
      diverse and abundant group of membrane proteins that are found in all organisms.
      These proteins facilitate solute accumulation and toxin removal against
      concentration gradients using energy supplied by ion gradients across membranes.
      NhaA is a Na+/H+ antiporter of relative molecular mass 42,000, which is found in
      the inner membrane of Escherichia coli, and which has been cloned and
      characterized. NhaA uses the H+ electrochemical gradient to expel Na+ from the
      cytoplasm, and functions primarily in the adaptation to high salinity at alkaline
      pH. Most secondary transporters, including NhaA, are predicted to have 12
      transmembrane helices. Here we report the structure of NhaA, at 7 A resolution in
      the membrane plane and at 14 A vertical resolution, determined from two
      dimensional crystals using electron cryo-microscopy. The three-dimensional map of
      NhaA reveals 12 tilted, bilayer-spanning helices. A roughly linear arrangement of
      six helices is adjacent to a compact bundle of six helices, with the density for
      one helix in the bundle not continuous through the membrane. The molecular
      organization of NhaA represents a new membrane-protein structural motif and
      offers the first insights into the architecture of an ion-coupled transport
      protein.

PMID- 10638765
TI  - Educational programmes for people with rheumatoid arthritis: a prediction of the
      future.

PMID- 10638766
TI  - Needle arthroscopy of the knee with synovial biopsy sampling: technical
      experience in 150 patients.
AB  - Needle arthroscopy is an office-based technique allowing direct visualisation of
      the knee cavity and selective sampling of the synovial membrane. We performed
      needle arthroscopy in 150 patients with synovitis of the knee (1) to evaluate the
      diagnostic potential in early arthritis, (2) to perform therapeutic lavage in
      persistent inflammatory synovitis and (3) to assess the balance between technical
      feasibility, safety and patient comfort on the one hand, and the relevance of the
      obtained macro- and microscopic information for diagnosis and research purposes
      on the other. After disinfection of the leg and local anaesthesia of the skin and
      joint, a 1.8-2.7 mm needle arthroscope was introduced into the knee. Synovial
      fluid was aspirated and lavage of the joint cavity was performed to allow
      macroscopic evaluation of hyperaemia and hypertrophy of the synovial membrane.
      Biopsies were taken at inflamed sites, followed by another lavage to remove blood
      and debris. Needle arthroscopy of the knee is a simple and easy to perform
      technique made particularly attractive by the local anaesthesia and the
      ambulatory setting. It allows good macroscopic evaluation of synovial
      inflammation and selective sampling of the synovial membrane. Biopsies are
      suitable for RNA and DNA extraction, bacterial or lymphocyte culture, and cell
      isolation. Because samples were sometimes too small for representative histology,
      we switched from a 1.8 mm to a 2.7 mm biopsy forceps with good results. In nearly
      all cases the arthroscopy was well tolerated. Moreover, some patients reported
      relief of symptoms and even improvement of mobility after lavage of the inflamed
      joint. No major complications were noted. It was concluded that needle
      arthroscopy of the knee is a simple, safe and well-tolerated technique, with
      promising perspectives as a diagnostic, scientific and possibly therapeutic tool
      in rheumatic diseases.

PMID- 10638767
TI  - Clinical features of spondyloarthropathy in Chinese and native Indonesians.
AB  - The prevalence of spondyloarthropathy (SpA) in Chinese Indonesians is much higher
      than in native Indonesians. This is due to HLA-B27 subtype differences. In the
      present study we re-examined the clinical features of SpA in Indonesians to see
      whether, besides the HLA-B27 subtype differences, other factors affect the
      frequency of SpA. Seventy two patients with SpA were re-examined. The patients
      came from two clinics for rheumatic diseases. The overall entry ratio of Chinese
      to native Indonesians was 1:2. Ankylosing spondylitis (AS) was more frequent
      among the Chinese (n = 32, 94% B27 positive) than among the native Indonesians (n
      = 5, 40% B27 positive). HLA-B27 subtyping was performed on 22 of the 37 HLA-B27
      positive AS patients. Twenty Chinese were positive for B*2704 and two native
      Indonesians were B*2705 positive. The clinical features of AS and reactive
      arthritis (ReA) showed no differences between the two populations and were
      similar to the clinical descriptions in other parts of the world. In conclusion,
      it can be stated that in spite of HLA-B27 subtype differences the clinical
      features of SpA in Chinese and native Indonesians are fully comparable.

PMID- 10638768
TI  - Familial Mediterranean fever and acute rheumatic fever: a pathogenetic
      relationship?
AB  - The frequency of acute rheumatic fever (ARF) in patients with familial
      Mediterranean fever (FMF) was documented and the effects of preceding
      streptococcal infections on the exacerbation of FMF were determined. In the first
      part of the study, 162 individuals with FMF were investigated for a history of
      ARF in a retrospective study. In the second part of the study, antistreptolysin-O
      (ASO) titres were measured in 130 individuals with FMF. Thirty-six patients had
      an arthritic attack (group A1), 55 patients had a typical FMF attack without
      arthritis (group A2) and 39 patients were in the attack-free interval (group B)
      during the investigation. Nine patients with FMF (5.5%) were considered to have
      ARF and three of them (1.85%) also had rheumatic heart disease. This prevalence
      of rheumatic heart disease in FMF is higher than that of the normal population
      (0.65%) reported in Turkey. Elevated ASO titres were found in 75%, 42% and 38% of
      the patients in groups A1, A2 and B, respectively. These percentages were found
      to be significantly higher in group A1 than in both groups A2 (p<0.01) and B
      (p<0.01). We concluded that patients with FMF might be more prone to the late
      complications of streptococcal infections.

PMID- 10638769
TI  - Spot urine concentrations of type I collagen cross-linked N-telopeptides and
      deoxypyridinoline in psoriatic arthritis.
AB  - The main objectives of this study were to investigate whether the spot urine
      concentrations of type I collagen cross-linked N-telopeptides (NTx) and
      deoxypyridinoline (Dpd) can be used to distinguish between active and suppressed
      disease in psoriatic arthritis (PsA) and to study the relationship between these
      markers of bone resorption and disease activity indices. Using enzyme-linked
      immunosorbent assays, concentrations of NTx and Dpd were estimated in spot urine
      samples from 25 patients with active disease, 10 patients with suppressed disease
      and 35 age- and sex-matched healthy control subjects. In patients with active
      disease, urine concentrations of NTx and Dpd were significantly elevated
      (p<0.001) compared with healthy controls and there were no significant
      differences (p>0.05) when compared with those with suppressed disease. In active
      disease, there was no significant positive correlation between urinary NTx and
      erythrocyte sedimentation rate (ESR) (r = 0.025, p>0.05) nor between Dpd and ESR
      (r = -0.208, p>0.05). In conclusion, NTx and Dpd concentrations in spot urine
      have no association with disease activity in patients with PsA.

PMID- 10638770
TI  - Intravenous cyclophosphamide pulse therapy for the treatment of lung disease
      associated with scleroderma.
AB  - Until recently, renal crisis was the most significant cause of morbidity and
      mortality in patients with scleroderma (SSc). Nowadays, following the
      introduction of angiotensin-converting enzyme inhibitors used in renovascular
      hypertension, pulmonary fibrosis and pulmonary hypertension have become the most
      common causes of death in SSc. Consequently, the early diagnosis and treatment of
      pulmonary fibrosis is essential to improve morbidity and mortality in SSc
      patients. The aim of this study was to investigate the effect of intravenous
      cyclophosphamide pulse therapy in patients with SSc and evidence of active
      alveolitis assessed on a high resolution computed tomographic (HRCT) scan, and to
      compare the effect of cyclophosphamide pulse therapy with oral therapy. Sixteen
      consecutive patients with SSc were allocated alternately to the two treatment
      groups. Eight patients were treated with monthly cyclophosphamide pulse therapy
      (750 mg/ m2) for 12 months; the other eight patients were treated with oral
      cyclophosphamide (2-2.5 mg/kg/day) for the same period. All patients received
      concurrently prednisone (10 mg/day). Pulmonary function tests and HRCT scans were
      performed before therapy and at 6 and 12 months. In the oral cyclophosphamide
      group, three patients with a grade I pattern showed regression of disease extent.
      In the other five patients (one with grade II and four with grade III) the
      pattern and extent of disease remained stable during the study. No statistical
      differences were found in forced expiratory volume in 1 s, forced vital capacity
      and total lung capacity during the study period. The diffusing capacity for
      carbon monoxide increased significantly between baseline and 12 months (p =
      0.043). In the cyclophosphamide pulse therapy group, seven patients with a grade
      I pattern showed regression of disease extent at 6 months (p = 0.018) and 12
      months (p = 0.012). One patient with grade III remained stable during the study.
      In both groups the regression of the extent of disease estimated on HRCT was due
      to a decrease in the ground glass appearance. The extent of the reticular
      appearance remained stable throughout the study. Our results indicate that
      cyclophosphamide pulse therapy is effective in suppressing active alveolitis
      (ground glass appearance). Although in this study it is not possible to compare
      pulse therapy with oral therapy because of the different pattern seen on HRCT
      between the two groups, it seems that oral therapy is also effective in
      suppressing active alveolitis. Neither regimen improved pulmonary involvement
      when the reticular appearance predominated over the ground glass appearance on
      HRCT. It is concluded that either pulse or oral cyclophosphamide therapy may
      improve the outcome of SSc patients.

PMID- 10638772
TI  - Haemophilic; arthropathy: assessment of quality of life after total knee
      arthroplasty.
AB  - The goal of this study was to examine how the known effects of total knee
      arthroplasty (TKA) on clinical outcome parameters translate into improved quality
      of life, as measured with validated condition-specific and generic questionnaires
      (Knee Society Score, WOMAC, SF-12, transition questions), addressing physical,
      mental and social health. Eleven patients (13 knees) undergoing TKA from 1986 to
      1994, with the diagnosis of severe haemophilic arthropathy of the knee, were
      followed-up over a 4-year period on average. TKA was found to reduce the burden
      of disease to levels similar to patients with osteoarthritis undergoing hip
      arthroplasty. Clinical and functional improvement after TKA translated into a
      substantial and significant increase in quality of life and patient satisfaction,
      found in objective as well as in patient-perceived measures. However, the
      physical functional ability did not reach the same level as in the corresponding
      population not affected by haemophilia, due to residual symptoms and impairment
      of other joints.

PMID- 10638771
TI  - Clinico-laboratory characteristics of patients with dermatomyositis accompanied
      by rapidly progressive interstitial lung disease.
AB  - The clinico-laboratory features of 16 patients with dermatomyositis (DM) were
      compared between patients with accompanying rapidly progressive interstitial lung
      disease (RP-ILD, n = 7) and those with chronic interstitial lung disease (C-ILD,
      n = 9), and also between deceased (seven RP-ILD and three C-ILD) and living
      patients (six C-ILD). The extent of muscle weakness of the extremities and
      frequency of autoantibody positivity were significantly lower in DM patients with
      RP-ILD than in DM patients with C-ILD. Furthermore, significantly lower serum
      creatine kinase/lactate dehydrogenase levels (0.26+/-0.27) were found in the 10
      patients who died than in the six living patients (1.21+/-1.09). A higher
      CD4+/CD8+ T-lymphocyte ratio in the peripheral blood (3.51+/-2.65) was detected
      in the four DM patients with RP-ILD who died than in the six living DM patients
      with C-ILD (1.22+/-0.49).

PMID- 10638773
TI  - Sympathetic skin response in scleroderma, scleroderma overlap syndromes and
      inflammatory myopathies.
AB  - Sympathetic skin response (SSR), a non-invasive method for evaluation of the
      autonomic nervous system, was studied in 57 patients with various connective
      tissue disorders: scleroderma, dermatomyositis, polymyositis, scleromyositis and
      unclassified collagenoses. The patients were divided into three main groups:
      scleroderma (SSc), myositis or other inflammatory myopathy (M) and scleromyositis
      (ScM). The aim of the study was to detect abnormalities of the SSR in the
      connective tissue diseases, to define the pattern for each group and to evaluate
      the usefulness of SSR in detection of subclinical impairment of sympathetic
      cholinergic function. In the myositis group, an abnormal SSR was found in 88% of
      patients; the main abnormality was absence of the response from the lower limbs
      (in 50% of patients). In scleroderma, the SSR was abnormal in 77% of patients,
      consisting mainly of absence of the response from the lower limbs, whereas
      responses from the upper limbs were normal. In scleromyositis, the SSR was
      abnormal in 80% of patients, the most frequent finding was an increase in latency
      in one limb. The SSR changes were most pronounced in connective tissue disorders
      with myositis or inflammatory myopathy. The SSR, although non-disease-specific,
      because of its sensitivity, seems to be useful in the assessment of the
      abnormalities of the autonomic nervous system in scleroderma and inflammatory
      myopathies. The study showed a very high prevalence of autonomic nervous system
      dysfunction in connective tissue diseases associated with myopathy or myositis,
      displaying no clinical symptoms of autonomic system involvement.

PMID- 10638774
TI  - Coexistence of hereditary multiple exostoses and ankylosing spondylitis.
AB  - We report a 50-year-old male patient with hereditary multiple exostoses (HME) and
      ankylosing spondylitis (AS). This is the first case reporting the coexistence of
      HME and AS. Our patient has multiple exostoses around the knee, elbow and wrist
      joints. At the age of 40 years, pain in the lower back associated with morning
      stiffness lasting about an hour and improving with exercise began. His son also
      has hereditary multiple exostoses but has no sign of AS. HME is an autosomal
      dominant disorder. AS has a remarkably strong association with the
      histocompatibility antigen HLA-B27. Owing to the different genetic mechanisms, it
      is not possible to differentiate between coincidence and association. Coexistence
      of HME and AS in our patient probably represents a coincidence rather than a real
      association.

PMID- 10638775
TI  - Localised hyaline vascular type of Castleman's disease mimicking adult-onset
      Still's disease.
AB  - A previously healthy 18-year-old boy presented with daily spiking fever,
      polyarthritis, and evanescent skin rashes, as well as hepatomegaly and Raynaud's
      phenomena for 2 months. He was initially diagnosed with adult-onset Still's
      disease (AOSD). During the period of follow-up, intermittent fever and migratory
      polyarthritis persisted and an insidiously growing mass over the right axillary
      region was noted 1 year after the diagnosis of AOSD. Excisional biopsy of the
      mass revealed a group of lymph nodes with histological features of the hyaline
      vascular type of Castleman's disease. The patient's symptoms disappeared soon
      after excision of the lymph nodes. evanescent rash, lymphadenopathy,
      hepatosplenomegaly and serositis [5]. A clinical picture compatible with the
      diagnosis of AOSD has not been described in the localised hyaline vascular type
      of Castleman's disease. We report such a case in an 18-year-old male patient who
      presented prolonged fever and polyarthritis with an initial diagnosis of AOSD.
      The diagnosis of hyaline vascular type of Castleman's disease was made 1 year
      later, when the patient developed an insidiously growing mass over the right
      axilla.

PMID- 10638776
TI  - Calcitriol-mediated hypercalcaemia and increased interleukins in a patient with
      sarcoid myopathy.
AB  - In this report we describe a patient with Sjogren's syndrome (SS) and calcitriol
      mediated hypercalcaemia. Initially, there was no clinical evidence of
      sarcoidosis. The patient had hypercalcaemia associated with increased calcitriol
      serum levels; circulating interleukin-6 and tumour necrosis factor alpha levels
      were also elevated. At the beginning, therapy with clodronate was effective in
      decreasing the serum calcium levels. However, the serum calcitriol decreased only
      after chloroquine treatment was added. After 2 years of therapy, the patient
      developed progressive and extensive muscle weakness. A muscle biopsy revealed a
      very prominent non-caseating granulomatous myopathy. Corticosteroid therapy was
      then instituted. Although both chloroquine and corticosteroid therapy were
      associated with decreased serum interleukin and calcitriol levels, only
      corticosteroid therapy was effective in treating the sarcoid myopathy. The role
      of cytokines in calcitriol mediated hypercalcaemia is discussed.

PMID- 10638777
TI  - Vertebral and rib sarcoidosis: long-term clinical remission with methotrexate.
AB  - We describe a patient with bilateral hilar lymphadenopathy shown on a chest
      radiograph and supraclavicular lymphadenopathy. Biopsy of a supraclavicular lymph
      node showed non-caseating granulomas. A diagnosis of sarcoidosis was made and no
      treatment was given. One year later she complained of cervical and lumbar pain
      and decreasing strength of the right hand. Magnetic resonance imaging of the
      spine showed multiple lesions within the vertebral bodies of six vertebrae, and
      thoracic computed tomography showed partial destruction of the first right rib. A
      biopsy of the second lumbar vertebra demonstrated non-caseating granulomas.
      Corticosteroid treatment was unsuccessful and long-term remission of the symptoms
      was achieved with a weekly low dose of methotrexate.

PMID- 10638778
TI  - Focal myositis: magnetic resonance imaging findings and peripheral arterial
      administration of prednisolone.
AB  - We report two patients with biopsy-proven focal myositis, successfully treated
      with a peripheral arterial injection of low-dose prednisolone. Spin-echo T2
      weighted magnetic resonance images helped to identify affected muscles and proved
      to be useful for monitoring treatment.

PMID- 10638779
TI  - Coexisting Behcet's syndrome and spondyloarthritis.
AB  - A patient suffering from Behcet's syndrome and undifferentiated spondyloarthritis
      developed dactylitis and psoriasis over the next three years.

PMID- 10638780
TI  - Polyarteritis nodosa and cytomegalovirus: diagnosis by polymerase chain reaction.
AB  - We investigated the occurrence of an active cytomegalovirus (CMV) infection in
      patients with polyarteritis nodosa (PAN). Eleven patients with PAN were screened
      for the presence of CMV-DNA in their blood using the polymerase chain reaction
      (PCR). Serum anti-CMV IgG and anti-CMV IgM antibodies were determined by enzyme
      linked immunosorbent assays (ELISA). The ELISA for IgM was negative in all cases
      whereas that for IgG was positive in eight cases. Only one patient was positive
      for CMV-DNA by PCR. He presented with myalgia, polyarthralgia, fever and weight
      loss, suggesting PAN activity. CMV infection was uncommon in our series of
      patients with PAN, despite disease activity and immunosuppressor therapy. The
      finding of a transient CMV infection in one case at the beginning of PAN activity
      suggests that CMV may be involved in the pathogenesis of PAN.

PMID- 10638781
TI  - Substance abuse and criminality.
AB  - Substance abuse issues and the law have become intricately linked over the years.
      This article reviews the current research underlying the association between
      substance abuse and crime, and provides an overview of the pertinent issues in
      conducting a substance abuse evaluation in the forensic context. The epidemiology
      of substance abuse and crime is reviewed, exploring the association between crime
      and specific psychoactive substances. Clinical considerations underlying the
      association are discussed, with specific attention paid to the pharmacological
      effects of psychoactive substances and to the role of substance use in
      individuals with serious associated psychopathology. Diagnostic and etiological
      issues that are important in differentiating substance abuse from criminality are
      considered in the context of conducting forensic evaluations. Finally, key
      components of a forensic substance abuse evaluation are presented.

PMID- 10638782
TI  - The physician-assisted suicide policy dilemma: a pilot study of the views and
      experiences of Connecticut physicians.
AB  - Development of fully informed public policy regarding physician-assisted suicide
      (PAS) requires a thorough understanding of the experiences, attitudes, and
      beliefs of physicians with respect to this issue. This study gathered data on
      physician characteristics, attitudes toward PAS, factors influencing attitudes
      toward PAS, and sensitivity to the role of depression in a sample of 397
      psychiatrists, internists, and family practitioners in Connecticut. Central
      considerations included: the influence of religious values, professional
      discipline and practice patterns, and ability to diagnose depression in a single
      evaluation. Psychiatrists were significantly more likely to be supportive of PAS
      than were internists or family practitioners. Most respondents expressed concern
      regarding the influence of depression on PAS requests. A subset of physicians
      endorse PAS yet do not share such concern about risks, suggesting substantial
      challenges for policy-makers.

PMID- 10638783
TI  - Attorneys' pressures on the expert witness: early warning signs of endangered
      honesty, objectivity, and fair compensation.
AB  - While most attorneys practice ethically and treat their retained experts fairly,
      there are a few that do otherwise. The authors describe "early warning signs" of
      the likelihood that the attorneys attempting to retain the psychiatric expert
      witness may compromise the expert's honesty and striving for objectivity. Experts
      themselves may have certain vulnerabilities that interfere with their ability to
      detect those early warning signs. Recommendations for the expert are offered.

PMID- 10638784
TI  - The unconditional release of mentally ill offenders from indefinite commitment: a
      study of Missouri insanity acquittees.
AB  - Using a database of all Missouri insanity acquittees committed on July 1, 1997 (N
      = 873) and all insanity acquittees unconditionally released from 1986 through
      1997 (N = 193), this study calculated the lengths of commitment and identified
      variables associated with the unconditional release of insanity acquittees from
      indefinite commitment by the mental health and criminal justice systems. The
      study found that 85 percent of insanity acquittees were still under commitment 5
      years after acquittal and 76 percent 10 years after acquittal. Factors that
      decreased the odds of being unconditionally released included never having been
      married; having a psychotic disorder, a mood disorder, a substance abuse
      disorder, or mental retardation/borderline intellectual functioning; and having
      committed a serious crime. These results support achievement of the intended goal
      of Missouri's insanity acquittee statute, which is to maximize public safety
      considerations, but have had the unintended effect of increasing the inpatient
      insanity acquittee population, resulting in fewer resources for voluntary
      patients.

PMID- 10638785
TI  - Psychiatric testimony and the "reasonable person" standard.
AB  - The aim of this article is to explore the boundaries of psychiatric testimony in
      criminal cases. In a series of vignettes, the author describes applications of
      psychiatric testimony in nontraditional areas. These are criminal cases in which
      the defendant-who was not mentally ill-acted in response to a situation that
      would tend to trigger violence in many persons: protection of self or others. In
      scenarios involving self-defense, duress, and passion/provocation, the dynamics
      involve interpersonal situations that give rise to behavior that may be entirely
      foreign to the defendant but that could not have been avoided. The law looks at
      these matters through a "reasonable person" standard: what the ordinary citizen
      would have done. In principle, there is often no need for expert testimony,
      because judges and jurors are presumed able to assess reasonableness,
      justification, or provocation. The trier of fact, however, could use a
      psychiatric explanation to assess culpability. The author discusses the cases in
      terms of application and admissibility.

PMID- 10638787
TI  - The Americans with Disabilities Act and deinstitutionalization of the chronically
      mentally ill.

PMID- 10638786
TI  - Assaultive eye injury and enucleation.
AB  - An especially dangerous behavior observed in some forensic and security hospital
      populations is assaultive eye gouging. Although a number of case reports in the
      literature concern auto-enucleation, gouging out the eyes of another is virtually
      unmentioned. We present a case series of eye gougers (n = 10) gathered through
      clinical contributions from several forensic populations in the United States and
      Russia. Four subjects were psychotic during the eye-gouging episode, one was only
      mentally retarded, and five, who were neither psychotic nor retarded,
      deliberately injured victims' eyes during acts of extreme sexual violence.

PMID- 10638788
TI  - Canadian landmark case, Smith v. Jones, supreme court of Canada: confidentiality
      and privilege suffer another blow.

PMID- 10638789
TI  - U.S. v. Greer: longer sentences for malingerers.

PMID- 10638790
TI  - Some reflections on racial profiling.

PMID- 10638791
TI  - "The color of suspicion": race profiling or racism?

PMID- 10638792
TI  - Psychoanalytic perspectives on racial profiling.

PMID- 10638793
TI  - The forensic psychiatrist as expert witness in malpractice cases.

PMID- 10638794
TI  - The forensic psychiatrist as expert witness in malpractice cases.

PMID- 10638795
TI  - Dietary protein and the reproductive performance of cows.
AB  - Increasing a cow's intake of dietary protein intake can increase its milk
      production, but can also reduce its fertility. This paper reviews the effects of
      increasing dietary protein on the fertility of the dairy cow, and the mechanisms
      that may produce them. The effects vary widely, but all stages of the
      reproductive cycle from the return to cyclicity after parturition, to the
      survival of the embryo, may be affected. However, the underlying cause of the
      link between protein intake and fertility is unclear. Fertility could be reduced
      by a direct toxic effect of protein breakdown products, but alternatively the
      increased energy demand for their metabolism could be responsible. The effect of
      protein degradability is also uncertain. Excess rumen degradable protein is
      commonly associated with reduced fertility, but similar effects are produced by
      diets that contain excess rumen undegradable protein. Increasing the intake of
      protein of all degradabilities has significantly different effects on blood
      biochemistry than a reduction in the intake of energy, suggesting that not all
      the effects of protein are due to energy imbalance. The primary site of action of
      the effect is also unclear. Limited evidence suggests that it is localised to the
      reproductive system, but effects on the pituitary and hypothalamus, as well as
      the ovary and uterus, have all been postulated. It is also uncertain what toxic
      principle is involved. Ammonia, nitrate and urea have all been suggested, but
      there is no conclusive evidence. Although a high protein intake has been
      postulated to have an effect on fertility for over 30 years, the evidence remains
      inconclusive, and the aetiology and pathogenesis of the effect remain obscure.

PMID- 10638796
TI  - Clinical and pathological observations on natural infections of cryptosporidiosis
      and flagellate protozoa in leopard geckos (Eublepharis macularius).
AB  - A group of adult leopard geckos (Eublepharis macularius) which had been losing
      weight for several months were found to be infected with Cryptosporidium species.
      Histological and electron microscopical investigations on the intestines of five
      of the lizards revealed the presence of large numbers of the developmental stages
      of Cryptosporidium species attached to the mucosal surface of the lower
      intestine, and large numbers of flagellate protozoa, suspected to be
      predominantly Trichomonas species, in the gut lumen. The clinical signs were
      attributed to the presence of one or both types of parasites.

PMID- 10638797
TI  - Effects of Fasciola gigantica infection on growth and nutrient utilisation of
      buffalo calves.
AB  - The effects of Fasciola gigantica infection on bodyweight gain, dry matter
      intake, digestibility of nutrients and feed conversion efficiency in buffalo
      calves were investigated. Nine male buffalo calves of the Murrah breed, aged 12
      to 15 months with a mean (se) bodyweight of 166 (12.5) kg, were randomly assigned
      to groups of five (group 1) and four (group 2). The animals in group 1 were given
      1000 viable, mature metacercariae of F gigantica orally, while the animals in
      group 2 served as uninfected controls. They were stall fed on diets containing a
      concentrate mixture and ad libitum wheat straw and were maintained by standard
      management practices for a period of 165 days after infection. The average daily
      liveweight gain of the infected animals was 110.6 g, compared with 439.4 g in the
      uninfected controls, and was associated with the appearance and establishment of
      immature flukes in hepatic bile ducts. The feed conversion efficiency declined
      significantly (P<0.01) from 41 days after infection and was lowest at the end of
      the experiment. F gigantica infection did not influence the digestibility of the
      nutrients. The impaired feed conversion efficiency was mainly due to a reduction
      in dry matter intake due to inappetence.

PMID- 10638798
TI  - Inheritance of multifocal retinal dysplasia in the golden retriever in the UK.

PMID- 10638799
TI  - Survey on parasite control in dairy cattle in northern Germany.

PMID- 10638800
TI  - Spermatocele in a common noctule (Nyctalus noctula).

PMID- 10638801
TI  - Unusual manifestation of tuberculosis in an ostrich (Struthio camelus).

PMID- 10638802
TI  - Severe foot lesions in sheep.

PMID- 10638803
TI  - Polyorchidism in a dog.

PMID- 10638804
TI  - Cattle identification.

PMID- 10638805
TI  - Baroreflex failure following radiation therapy for nasopharyngeal carcinoma.
AB  - The authors present a 51-year-old man with right-sided nasopharyngeal carcinoma
      who was treated for regional lymph node involvement by bilateral radiation
      therapy of the neck. Six years later he presented with episodic complaints of
      headache, flushing, and palpitations accompanied by elevations of blood pressure.
      Examination of arterial baroreflex function indicated selective afferent carotid
      sinus denervation. Cross spectral analysis of spontaneous heart rate and blood
      pressure variability showed decreased arterial baroreflex sensitivity (6.5 ms/mm
      Hg). Twenty-four hour measurements of blood pressure and heart rate variability
      showed labile hypertension during normal daytime activities. Baroreflex failure
      in this patient probably represents a late complication of bilateral radiation
      therapy of the neck.

PMID- 10638806
TI  - Autonomic nervous system disorders in stroke.
AB  - Disturbances of the autonomic nervous system are common in patients with various
      cerebrovascular diseases. They are attributed to damage of the central autonomic
      network, particularly in the frontoparietal cortical areas and in the brain stem,
      or to a disruption of the autonomic pathways descending from the hypothalamus via
      the mesencephalon, pons, and medulla to the spinal cord. The most common clinical
      problems include abnormalities in heart rate and blood pressure regulation,
      reflecting cardiovascular autonomic dysfunction, and asymmetric sweating with
      cold hemiplegic limbs, reflecting changes in the sudomotor and vasomotor
      regulatory systems. Bladder and bowel dysfunction and impotence are also frequent
      complaints after stroke, but the present knowledge concerning their prevalence
      and clinical significance is still limited. Cardiovascular autonomic dysfunction,
      which is mainly related to increased sympathetic activity, is most evident in the
      acute phase of stroke, whereas other autonomic disorders, such as abnormal
      sweating, are long-standing or even irreversible. In addition to the well
      established sympathetic hyperfunction, abnormalities of the parasympathetic
      nervous system may also contribute to the autonomic imbalance after stroke.
      Reliable recognition of autonomic dysfunction using quantitative analysis methods
      is important, because these disturbances are not only subjectively disabling and
      uncomfortable, but they may also be prognostically unfavorable. Moreover,
      quantitative measurements also form the ground for successive treatment of
      various stroke-related autonomic disorders.

PMID- 10638807
TI  - Autonomic function in patients with chronic fatigue syndrome.
AB  - Subtle signs of autonomic dysfunction and orthostatic intolerance have been
      reported in patients with chronic fatigue syndrome (CFS). To assess
      cardiovascular autonomic function noninvasively in an unselected group of
      patients with CFS, we examined responsiveness to several cardiovascular reflex
      tests in 37 CFS patients and 38 healthy control subjects. Blood pressure and
      heart rate (HR) were recorded continuously by a Finapres device before and during
      forced breathing, standing up, Valsalva maneuver, and sustained handgrip exercise
      (HG). In addition, a mental arithmetic test was carried out and questionnaires to
      assess the severity of CFS symptoms were completed. At rest, there were no
      significant differences in blood pressure or in HR between the two groups. The in
      and expiratory difference in HR tended to be lower in CFS patients (28.4 +/-
      10.5 beats) than in healthy controls (32.2 +/- 9.5) (p = 0.11). The maximal
      increase in HR during standing up was not significantly different between the CFS
      group (37.6 +/-8.9 beats) and the control group (40.2 +/- 8.9 beats). There were
      no significant differences between both groups with regard to the Valsalva ratio,
      but the systolic and diastolic blood pressure responses were significantly larger
      in CFS patients, despite the fact that many CFS patients were not able to sustain
      the Valsalva maneuver. The HR response to MA was significantly less in the CFS
      group (22.6 +/- 9.9) than in the control group (29.5 +/- 16.7) (p < 0.05),
      suggesting impaired cardiac sympathetic responsiveness to mental stress. The
      lower HR responses could not be explained by the level of concentration in the
      CFS group. During HG exercise, the hemodynamic responses were lower in the CFS
      group than in the control group, but this might be attributed to the lower level
      of muscle exertion in CFS patients. There were no significant differences between
      CFS patients with and without symptoms of autonomic dysfunction regarding the
      hemodynamic responses to the cardiovascular reflex tests. The findings of the
      study suggest that there are no gross alterations in cardiovascular autonomic
      function in patients with CFS.

PMID- 10638808
TI  - Patients' choice of portable folding chairs to reduce symptoms of orthostatic
      hypotension.
AB  - Patients with neurogenic orthostatic hypotension may use portable folding chairs
      to prevent or reduce symptoms of low blood pressure. However, a concomitant
      movement disorder may limit the use of these chairs in daily living. In this
      prospective study, 13 patients with orthostatic hypotension, balance disturbance
      associated with motor disability, or both examined three commercially available
      portable folding chairs. A questionnaire was used to document the characteristics
      in chair design that were relevant for satisfactory use to these patients.
      Armrests, seat width, and an adjustable sitting height were found to be important
      features of a portable folding chair. One chair was selected by 11 of 13 patients
      to fit most needs.

PMID- 10638809
TI  - Autonomic cardiovascular control in children with obstructive sleep apnea.
AB  - Autonomic cardiorespiratory control changes with sleep-wake states and is
      influenced by sleep-related breathing disorders. Power spectrum (PS) analysis of
      instantaneous fluctuations in heart rate (HR) is used to investigate the role of
      the autonomic nervous system (ANS) in cardiorespiratory control. The two spectral
      regions of interest are the low frequency component (LF) and high frequency
      component (HF). The aim of the present study was to investigate the autonomic
      cardiorespiratory control in children with obstructive sleep apnea (OSA)
      syndrome. We studied 10 children with OSA versus 10 normal children. All subjects
      underwent whole night polysomnography. Spectral analysis of the HR and breathing
      signals was performed for 256 second long, artifact-free epochs in each sleep
      wake state. The LF power was higher in the OSA group compared with control
      subjects for all states, reflecting enhanced sympathetic activity in OSA
      subjects. The results indicated sympathetic predominance during REM sleep in all
      subjects and parasympathetic predominance in slow wave sleep only in controls.
      The autonomic balance (LF/HF) was significantly higher in OSA patients than in
      control subjects, at all stages during night sleep, and while awake before sleep
      onset. An index of overall autonomic balance (ABI) was computed for each subject
      and correlated well with the measured respiratory disturbance index (RDI).

PMID- 10638810
TI  - Adrenergic autoreceptors.

PMID- 10638811
TI  - Multiple single unit recording in the cortex of monkeys using independently
      moveable microelectrodes.
AB  - Simultaneous recording from multiple single neurones presents many technical
      difficulties. However, obtaining such data has many advantages, which make it
      highly worthwhile to overcome the technical problems. This report describes
      methods which we have developed to permit recordings in awake behaving monkeys
      using the 'Eckhorn' 16 electrode microdrive. Structural magnetic resonance images
      are collected to guide electrode placement. Head fixation is achieved using a
      specially designed headpiece, modified for the multiple electrode approach, and
      access to the cortex is provided via a novel recording chamber. Growth of scar
      tissue over the exposed dura mater is reduced using an anti-mitotic compound.
      Control of the microdrive is achieved by a computerised system which permits
      several experimenters to move different electrodes simultaneously, considerably
      reducing the load on an individual operator. Neurones are identified as pyramidal
      tract neurones by antidromic stimulation through chronically implanted
      electrodes; stimulus control is integrated into the computerised system. Finally,
      analysis of multiple single unit recordings requires accurate methods to correct
      for non-stationarity in unit firing. A novel technique for such correction is
      discussed.

PMID- 10638812
TI  - Miniature carrier with six independently moveable electrodes for recording of
      multiple single-units in the cerebellar cortex of awake rats.
AB  - Ensemble recording in cerebellar cortex of awake rats presents unique
      methodological challenges not encountered when recording from the cerebral cortex
      or from deep brain structures with more homogeneous cell populations. Compared to
      the cerebral cortex, removal of dura over the cerebellum evokes pronounced
      swelling, and insertion of multiple closely spaced electrodes in the cerebellar
      cortex causes considerable dimpling (Welsh JP, Schwartz C. Multielectrode
      recording from the cerebellum. In: Nicolelis MAL, editor. Methods for Neural
      Ensemble Recordings, CRC Methods in Neuroscience Series. Boca Raton, FL: CRC
      Press LLC, 1999, pp. 79-100). Also, a repetitious and well-defined neural circuit
      characterizes the cerebellar cortex across its entire surface. With conventional
      multi-electrode methods, such as chronically implanted bundles or arrays of
      microwires, the risk of disrupting the cerebellar cytoarchitecture is high. In
      most conventional multi-electrode systems, electrodes have rather low impedance
      and cannot be moved independently after implantation. These limitations make
      proper unit isolation, necessary to identify each of the recorded cerebellar
      units, very difficult. We designed a lightweight (14 g), miniature (base plate:
      19 x 23 mm; total height: 16 mm) multi-electrode system to allow for the chronic
      implantation of six independently moveable sharp electrodes with high impedance,
      in the cerebellar cortex. The six electrodes are arranged in a 2 x 3 matrix
      (inter-electrode distance: 0.6 mm). At any time after the implantation the
      vertical position of each individual electrode can be adjusted by screwing spring
      loaded electrode heads up or down. The system preserves the integrity of the
      cerebellar cytoarchitecture, and enables easy isolation and identification of
      individual cerebellar units in awake, freely moving rats.

PMID- 10638813
TI  - Simultaneous multi-site recordings and iontophoretic drug and dye applications
      along the trigeminal system of anesthetized rats.
AB  - A multi-electrode system that permits simultaneous recordings from multiple
      neurons and iontophoretic applications at two or three different brain sites
      during acute experiments is described. This system consists of two or three
      microdrive terminals, each of which includes four electrodes that can be moved
      independently and used for both extracellular recordings and microiontophoretic
      drug administration. Drug applications were performed during standard
      extracellular recordings of multiple single-units via specialized combined
      electrodes (CEs), which enable ejection of neuroactive substances and recording
      of neuronal activity from the same electrode. With this system, we were able to
      successfully record simultaneously from different levels (brainstem, thalamus,
      and cortex) of the vibrissal ascending pathway of the anesthetized rat. Herein,
      examples of simultaneous recordings from the brainstem and thalamus and from the
      thalamus and cortex are presented. An effect of iontophoretic applications of
      agonists and antagonists of metabotropic glutamate receptors (mGluRs) in the
      thalamus is demonstrated, and the extent of drug diffusion in the barrel cortex
      is demonstrated with biocytin. This new multi-electrode system will facilitate
      the study of transformations of sensory information acquired by the whiskers into
      cortical representations.

PMID- 10638814
TI  - Interaction between spike waveform classification and temporal sequence
      detection.
AB  - In vivo extracellular recordings have allowed researchers to study the response
      properties of neurons to behaviorally relevant stimuli. In this paper we use
      multiple tetrode recordings from the hippocampus of the freely behaving rat to
      show that the action potential amplitude of a given cell can vary in a systematic
      and activity dependent manner over behaviorally relevant time scales. Since the
      discrimination algorithms used by experimenters to isolate cells from
      extracellular recordings are based on differences in waveforms, we show how these
      systematic changes in waveform shape can lead to non-random errors in single cell
      isolation. We further demonstrate that these non-random errors can lead to
      apparent temporal ordering effects between neurons in the absence of any specific
      temporal relationship. A firm understanding of these naturally occurring
      physiological changes is therefore critical for the evaluation of higher order
      phenomena such as the temporally correlated firing of ensembles of neurons.

PMID- 10638815
TI  - The distribution of neuronal population activation (DPA) as a tool to study
      interaction and integration in cortical representations.
AB  - In many cortical areas, simple stimuli or task conditions activate large
      populations of neurons. We hypothesize that such populations support processes of
      interaction within parametric representations and integration of multiple sources
      of input and we propose to study these processes using distributions of
      population activation (DPAs) as a tool. Such distributions can be viewed as
      neuronal representations of continuous stimulus or task parameters. They are
      built from basis functions contributed by each neuron. These functions may be
      explicitly chosen based on tuning curves or receptive field profiles. Or they may
      be determined by minimizing the distance between chosen target distributions and
      the constructed DPAs. In both cases, construction of the DPA is based on a set of
      reference conditions in which the stimulus or task parameters are sampled
      experimentally. In a second step, basis functions are kept fixed, and the DPAs
      are used to explore time dependent processing, interaction and integration of
      information. For instance, stimuli which simultaneously specify multiple
      parameter values can be used to study interactions within the parametric
      representation. We review an experiment, in which the representation of retinal
      position is probed in this way, revealing fast excitatory interactions among
      neurons representing similar retinal positions and slower inhibitory interactions
      among neurons representing dissimilar retinal positions. Similarly, DPAs can be
      used to analyze different sources of input that are fused within a parametric
      representation. We review an experiment in which the representation of the
      direction of goal-directed arm movements in motor and premotor cortex is studied
      when prior and current information about upcoming movement tasks are integrated.

PMID- 10638816
TI  - Detecting unitary events without discretization of time.
AB  - In earlier studies we developed the 'Unitary Events' analysis (Grun S. Unitary
      Joint-Events in Multiple-Neuron Spiking Activity: Detection, Significance and
      Interpretation. Reihe Physik, Band 60. Thun, Frankfurt/Main: Verlag Harri
      Deutsch, 1996.) to detect the presence of conspicuous spike coincidences in
      multiple single unit recordings and to evaluate their statistical significance.
      The method enabled us to study the relation between spike synchronization and
      behavioral events (Riehle A, Grun S, Diesmann M, Aertsen A. Spike synchronization
      and rate modulation differentially involved in motor cortical function. Science
      1997;278:1950-1953.). There is recent experimental evidence that the timing
      accuracy of coincident spiking events, which might be relevant for higher brain
      function, may be in the range of 1-5 ms. To detect coincidences on that time
      scale, we sectioned the observation interval into short disjunct time slices
      ('bins'). Unitary Events analysis of this discretized process demonstrated that
      coincident events can indeed be reliably detected. However, the method looses
      sensitivity for higher temporal jitter of the events constituting the
      coincidences (Grun S. Unitary Joint-Events in Multiple-Neuron Spiking Activity:
      Detection, Significance and Interpretation. Reihe Physik, Band 60. Thun,
      Frankfurt/Main: Verlag Harri Deutsch, 1996.). Here we present a new approach, the
      'multiple shift' method (MS), which overcomes the need for binning and treats the
      data in their (original) high time resolution (typically 1 ms, or better).
      Technically, coincidences are detected by shifting the spike trains against each
      other over the range of allowed coincidence width and integrating the number of
      exact coincidences (on the time resolution of the data) over all shifts. We found
      that the new method enhances the sensitivity for coincidences with temporal
      jitter. Both methods are outlined and compared on the basis of their analytical
      description and their application on simulated data. The performance on
      experimental data is illustrated.

PMID- 10638817
TI  - Single-trial estimation of neuronal firing rates: from single-neuron spike trains
      to population activity.
AB  - We present a method to estimate the neuronal firing rate from single-trial spike
      trains. The method, based on convolution of the spike train with a fixed kernel
      function, is calibrated by means of simulated spike trains for a representative
      selection of realistic dynamic rate functions. We derive rules for the optimized
      use and performance of the kernel method, specifically with respect to an
      effective choice of the shape and width of the kernel functions. An application
      of our technique to the on-line, single-trial reconstruction of arm movement
      trajectories from multiple single-unit spike trains using dynamic population
      vectors illustrates a possible use of the proposed method.

PMID- 10638818
TI  - Using partial directed coherence to describe neuronal ensemble interactions.
AB  - This paper illustrates the use of the recently introduced method of partial
      directed coherence in approaching how interactions among neural structures change
      over short time spans that characterize well defined behavioral states. Central
      to the method is its use of multivariate time series modelling in conjunction
      with the concept of Granger causality. Simulated neural network models were used
      to illustrate the technique's power and limitations when dealing with neural
      spiking data. This was followed by the analysis of multi-unit activity data
      illustrating dynamical change in the interaction of thalamo-cortical structures
      in a behaving rat.

PMID- 10638819
TI  - Testing non-linearity and directedness of interactions between neural groups in
      the macaque inferotemporal cortex.
AB  - Information processing in the visual cortex depends on complex and context
      sensitive patterns of interactions between neuronal groups in many different
      cortical areas. Methods used to date for disentangling this functional
      connectivity presuppose either linearity or instantaneous interactions,
      assumptions that are not necessarily valid. In this paper a general framework
      that encompasses both linear and non-linear modelling of neurophysiological time
      series data by means of Local Linear Non-linear Autoregressive models (LLNAR) is
      described. Within this framework a new test for non-linearity of time series and
      for non-linearity of directedness of neural interactions based on LLNAR is
      presented. These tests assess the relative goodness of fit of linear versus non
      linear models via the bootstrap technique. Additionally, a generalised definition
      of Granger causality is presented based on LLNAR that is valid for both linear
      and non-linear systems. Finally, the use of LLNAR for measuring non-linearity and
      directional influences is illustrated using artificial data, reference data as
      well as local field potentials (LFPs) from macaque area TE. LFP data is well
      described by the linear variant of LLNAR. Models of this sort, including lagged
      values of the preceding 25 to 60 ms, revealed the existence of both uni- and bi
      directional influences between recording sites.

PMID- 10638820
TI  - Principal component analysis of neuronal ensemble activity reveals
      multidimensional somatosensory representations.
AB  - Principal components analysis (PCA) was used to define the linearly dependent
      factors underlying sensory information processing in the vibrissal sensory area
      of the ventral posterior medial (VPM) thalamus in eight awake rats. Ensembles of
      up to 23 single neurons were simultaneously recorded in this area, either during
      long periods of spontaneous behavior (including exploratory whisking) or
      controlled deflection of single whiskers. PCA rotated the matrices of correlation
      between these n neurons into a series of n uncorrelated principal components
      (PCs), each successive PC oriented to explain a maximum of the remaining
      variance. The fact that this transformation is mathematically equivalent to the
      general Hebb algorithm in linear neural networks provided a major rationale for
      performing it here on data from real neuronal ensembles. Typically, most
      information correlated across neurons in the ensemble was concentrated within the
      first 3-8 PCs. Each of these was found to encode distinct, and highly significant
      informational factors. These factor encodings were assessed in two ways, each
      making use of fact that each PC consisted of a matrix of weightings, one for each
      neuron. First, the neurons were rank ordered according to the locations of the
      central whiskers in their receptive fields, allowing their weightings within
      different PCs to be viewed as a function of their position within the whisker
      representation in the VPM. Each PC was found to define a distinctly different
      topographic mapping of the cutaneous surface. Next, the PCs were used to weight
      sum the neurons' simultaneous activities to create population vectors (PVs). Each
      PV consisted of a single continuous time series which represented the expression
      of each PC's 'magnitude' in response to stimulation of different whiskers, or
      during behavioral events such as active tactile whisking. These showed that each
      PC functioned as a feature detector capable of selectively predicting significant
      sensory or behavioral events with far greater statistical reliability than could
      any single neuron. The encoding characteristics of the first few PCs were
      remarkably consistent across all animals and experimental conditions, including
      both spontaneous exploration and direct sensory stimulation: PC1 positively
      weighted all neurons, mainly according to their covariance. Thus it encoded
      global magnitude of ensemble activity, caused either by combined sensory inputs
      or intrinsic network activity, such as spontaneous oscillations. PC2 encoded
      spatial position contrast, generally in the rostrocaudal dimension, across the
      whole cutaneous surface represented by the ensemble. PC3 more selectively encoded
      contrast in an orthogonal (usually dorsoventral) dimension. A variable number of
      higher numbered PCs encoded local position contrast within one or more smaller
      regions of the cutaneous surface. The remaining PCs typically explained residual
      'noise', i.e. the uncorrelated variance that constituted a major part of each
      neuron's activity. Differences in behavioral or sensory experience produced
      relatively little in the PC weighting patterns but often changed the variance
      they explained (eigenvalues) enough to alter their ordering. These results argue
      that PCA provides a powerful set of tools for selectively measuring neural
      ensemble activity within multiple functionally significant 'dimensions' of
      information processing. As such, it redefines the 'neuron' as an entity which
      contributes portions of its variance to processing not one, but several tasks.

PMID- 10638821
TI  - Independent component analyses for quantifying neuronal ensemble interactions.
AB  - The goal of this study was to compare how multivariate statistical methods for
      dimension reduction account for correlations between simultaneously recorded
      neurons. Here, we describe applications of principal component analysis (PCA) and
      independent component analysis (ICA) (Cardoso J-F, Souloumiac A. IEE-Proc F
      1993;140:362-70; Hyvarinen A, Oja E. Neural Comput 1997;9:1483-92; Lee TW,
      Girolami M, Sejnowski TJ. Neural Comp 1999;11:417-41) to neuronal ensemble data.
      Simulated ensembles of neurons were used to compare how well the methods above
      could account for correlated neuronal firing. The simulations showed that
      'population vectors' defined by PCA were broadly distributed over the neuronal
      ensembles; thus, PCA was unable to identify independent groupings of neurons that
      shared common sources of input. By contrast, the ICA methods were all able to
      identify groupings of neurons that emerged due to correlated firing. This result
      suggests that correlated neuronal firing is reflected in higher-order
      correlations between neurons and not simply in the neurons' covariance. To assess
      the significance of these methods for real neuronal ensembles, we analyzed data
      from populations of neurons recorded in the motor cortex of rats trained to
      perform a reaction-time task. Scores for PCA and ICA were reconstructed on a bin
      by-bin basis for single trials. These data were then used to train an artificial
      neural network to discriminate between single trials with either short or long
      reaction-times. Classifications based on scores from the ICA-based methods were
      significantly better than those based on PCA. For example, scores for components
      defined with an ICA-based method, extended ICA (Lee et al., 1999), classified
      more trials correctly (80.58+/-1.25%) than PCA (73.14+/-0.84%) for an ensemble of
      26 neurons recorded in the motor cortex (ANOVA: P < 0.005). This result suggests
      that behaviorally relevant information is represented in correlated neuronal
      firing and can be best detected when higher-order correlations between neurons
      are taken into account.

PMID- 10638822
TI  - The characterization of the effect of locally applied N-methylquipazine, a 5-HT3
      receptor agonist, on extracellular dopamine levels in the anterior medial
      prefrontal cortex in the rat: an in vivo microdialysis study.
AB  - In this study, we examined the effect of n-methylquipazine (NMQ), which is a
      putative 5-hydroxytryptamine3(5-HT3)receptor agonist, on the extracellular
      concentrations of dopamine (DA) and one of its metabolites, dihydroxyphenylacetic
      acid (DOPAC), in the anterior medial prefrontal cortex (AmPFc) of awake, freely
      moving rats. The administration of NMQ via the perfusion fluid produced a
      concentration-dependent (10-1,000 microM) increase in extracellular DA levels in
      the AmPFc. In contrast, NMQ produced a decrease in the extracellular
      concentrations of DOPAC. The increase in extracellular DA levels returned to
      baseline after the removal of NMQ from the perfusate. The increase in
      extracellular DA levels in the AmPFc produced by 100 microM of NMQ was markedly
      attenuated by either the coadministration of tetrodotoxin (1 microM), which
      inhibits axonal impulse flow, or the depletion of extracellular Ca2+ by removing
      CaCl2 and adding EDTA to the perfusate. The intradialysate administration of the
      5-HT3 antagonist BRL 46470A produced a concentration-dependent (10-1,000 microM)
      decrease in extracellular DA levels, and this effect was reversible on removal
      from the perfusate. In contrast, ondansetron (500 and 1,000 microM), which is
      another 5-HT3 receptor antagonist, produced a transient increase followed by a
      sustained decrease in extracellular DA levels. The preinfusion of 10 microM of
      BRL 46470 followed by coperfusion of BRL 46470A with 50 or 100 microM of NMQ via
      the dialysis probe did not significantly attenuate the increase of NMQ in
      extracellular DA levels in the AmPFc. The administration of the selective 5-HT2
      receptor MDL 100907 (1 mg/kg, i.p.) also did not alter the increase in basal DA
      levels produced by 100 microM of NMQ. The pretreatment of rats with alpha-methyl
      p-tyrosine produced a significant attenuation in the NMQ-induced increase in
      extracellular DA levels, suggesting that the elevation by NMQ of DA levels is
      dependent on newly synthesized stores of DA. Overall, these results suggest that
      the increase in AmPFc DA levels by NMQ is probably not mediated by its
      interaction with the 5-HT3 receptor.

PMID- 10638824
TI  - Iodinated PK 11195 as an ex vivo marker of neuronal injury in the lesioned rat
      brain.
AB  - In order to study the potentials of indirect and direct detection of neuronal
      damages in humans by single photon emission computerized tomography (SPECT), we
      compared ex vivo cerebral biodistribution of [125I]PK 11195 with that of
      [125I]TISCH in a rat model of unilateral striatal excitotoxic lesion. Experiments
      on in vitro binding with [3H]PK 11195 as a ligand for peripheral type
      benzodiazepine binding sites (PTBBS) and [3H]SCH 23390 as a ligand for dopamine
      D1 receptors were also performed to validate our experimental model. We observed
      a very high increase in the PTBBS and a dramatic decrease in the D1 receptors on
      the lesioned striatum compared to the intact side. Moreover, we showed that
      [125I]PK 11195 bound specifically to PTBBS in lesioned cerebral areas ex vivo 5
      days after striatal infusion of quinolinic acid (600 nmoles). Increases of 192%,
      168%, and 30% were obtained in the striatum, the cortex, and the hippocampus,
      respectively, on the lesioned side. These results showed that iodinated PK 11195
      bound specifically to PTBBS ex vivo and that this binding was dramatically
      increased at the sites of brain lesion. This ligand could therefore be suitable
      to detect brain injuries in humans by SPECT, complementing the information given
      by ligands which image loss in a specific neuron population.

PMID- 10638823
TI  - Comparison of two fluorine-18 labeled benzamide derivatives that bind reversibly
      to dopamine D2 receptors: in vitro binding studies and positron emission
      tomography.
AB  - The purpose of the present set of studies was to characterize, in vitro and in
      vivo, two benzamide analogues, 2,3-dimethoxy-N-[1-(4
      fluorobenzyl)piperidin4yl]benzamide (MBP) and 4'-fluoroclebopride (FCP), for
      studying dopamine D2 receptors with Positron Emission Tomography (PET). In vitro
      binding studies were conducted to determine the affinities of MBP and FCP to the
      three subtypes of dopamine D2 receptors: D2(long), D3, and D4 receptors. MBP was
      found to have a high affinity (Ki = 1-8 nM) for all three subtypes of the D2
      receptor, whereas FCP had nanomolar affinity (Ki approximately 5.5 nM) for
      D2(long) and D3 receptors, and a lower affinity for D4 receptors (Ki = 144 nM).
      In vitro binding studies also revealed that MBP had a relatively high affinity
      for rho1 receptors (Ki = 11 nM) compared to FCP (Ki = 340 nM). PET imaging
      studies were conducted in rhesus monkeys with the fluorine-18 labeled analogues
      of each compound. Both [18F]MBP and [18F]FCP displayed reversible binding
      kinetics during the 3 h time course of PET. [18F]FCP was found to have a higher
      basal ganglia:cerebellum ratio and lower variability in the rate of washout from
      D2 receptors in vivo relative to [18F]MBP. Neither radiotracer was found to
      produce radiolabeled metabolites capable of crossing the blood-brain barrier. The
      high rho1 binding affinity and low basal ganglia:cerebellum ratio of [18F]MBP
      indicate that this ligand may not be suitable for quantitative studies of D2
      receptors. The results from the in vitro and in vivo studies indicate that
      [18F]FCP is a promising ligand for studying D2 receptors with PET.

PMID- 10638825
TI  - Nitrogen-based drugs are not essential for blockade of monoamine transporters.
AB  - In brain, monoamine transporters are principal targets of widely used therapeutic
      drugs including antidepressants, methylphenidate (Ritalin), and the addictive
      drug cocaine. Without exception, these transport blocking agents contain an amine
      nitrogen. A prevalent view and untested premise is that an amine nitrogen is
      needed to bind to the same counterion on the transporter as does the amine
      nitrogen of the monoamine neurotransmitter. We report that several compounds
      without nitrogen (8-oxa-bicyclo-3-aryl-[3.2.1] octanes, or aryloxatropanes) are
      active at monoamine transporters. One of these, tropoxane (0-914), bound with
      high affinity to the dopamine (IC50: 3.35 +/- 0.39 nM), serotonin (IC50: 6.52 +/-
      2.05 nM), and norepinephrine (IC50: 20.0 +/- 0.3 nM) transporters in monkey
      brain, the human striatal dopamine transporter (IC50: 5.01 +/- 1.74 nM), and
      blocked dopamine transport (IC50: 7.2 +/- 3.0 nM) in COS-7 cells transfected with
      the human dopamine transporter. These unique compounds require a revision of
      current concepts of the drug binding domains on monoamine transporters, open
      avenues for discovery of a new generation of drugs and raise the issue of whether
      mammalian transporters and receptors may respond to, as yet, undiscovered non
      amine bearing neurotransmitters or drugs.

PMID- 10638826
TI  - Pharmacological actions of the atypical antipsychotic drug clozapine: a review.
AB  - Clozapine [8-chloro- 11-(4-methyl- 1-piperazinyl)-3H-dibenzo (b,e)(1,4)
      diazepine], or clozaril, is a member of the dibenazepine class of antipsychotic
      drugs. Initially, studies in animals using a number of neurochemical,
      biochemical, electrophysiological, and behavioral paradigms indicated that
      clozapine was markedly different from various typical antipsychotic drugs such as
      haloperidol and chlorpromazine. Subsequently, clinical studies have shown that
      clozapine is effective in ameliorating the core symptoms, as well as the negative
      symptoms, in schizophrenia. However, clozapine has a much lower propensity for
      inducing neurological side effects after acute or repeated administration
      compared to various typical neuroleptics. Furthermore, clozapine is
      therapeutically effective in treating about 30% of schizophrenic patients who are
      resistant to standard antipsychotic drugs. Based on the above information,
      clozapine has been designated an atypical antipsychotic drug. However, at this
      time, it is not entirely clear why clozapine is such a unique antipsychotic drug.
      To date, there has not been a comprehensive review regarding clozapine's
      pharmacological profile. Therefore, we will review clozapine's profile in the
      following areas: 1) affinity for neurotransmitter receptors in the brain; 2)
      electrophysiology (in vivo, single-cell recording and iontophoresis; in vitro
      studies); 3) in vivo microdialysis and voltammetry; 4) monoamine turnover or
      metabolism; 5) intermediate early gene expression; 6) positron emission
      tomography studies; and 7) molecular biological studies. We will also compare and
      contrast clozapine's acute and chronic effects, and discuss the merits of various
      hypotheses that have been put forward to explain clozapine's unique profile.

PMID- 10638827
TI  - Fenfluramine-induced loss of serotonin transporters in baboon brain visualized
      with PET.
AB  - The present study sought to determine whether or not Positron Emission Tomography
      (PET) with the newly developed positron emitting serotonin (5-HT) transporter
      ligand, (+)[11C]McN-5652, could be used to detect fenfluramine-induced 5-HT
      neurotoxicity in the brain of living primates (baboons). Six PET imaging studies
      were performed: three before treatment with fenfluramine (5 mg/kg, s.c., twice
      daily for 4 days) and three after (18, 45, and 81 days after treatment). The dose
      of fenfluramine used in this study (5 mg/kg) is known to produce 5-HT
      neurotoxicity in primates, and to be approximately two times higher than a dose
      of fenfluramine reported to produce small and inconsistent weight loss in baboons
      (2 mg/kg). Following fenfluramine treatment, marked lasting reductions in
      regional brain specific binding of (+)[11C]McN-5652 were found by means of PET.
      Findings with PET corresponded well with post-mortem neurochemical findings
      indicative of serotonergic neurotoxicity (lasting depletions of regional brain 5
      HT, 5-HIAA, and 5-HT uptake sites). These results suggest that PET imaging with
      (+)[11C]McN-5652 will be useful for evaluating the 5-HT neurotoxic potential of
      fenfluramine and related drugs in living humans.

PMID- 10638828
TI  - Cocaine doses equivalent to those abused by humans occupy most of the dopamine
      transporters.

PMID- 10638829
TI  - Mapping nicotinic acetylcholine receptors with PET.

PMID- 10638830
TI  - Ex vivo propagation and characterization of lymphocytes from rejecting rat-kidney
      allografts.
AB  - Today, most clinically used methods for analysis of alloreactivity in organ
      transplantation are based on humoral immunity. In order to study the cellular
      alloresponse, a rat kidney transplantation model with culturing of graft
      infiltrating lymphocytes was developed. Kidney transplantations between inbred
      rat strains were performed with the animals initially immunosuppressed with
      cyclosporine. In order to initiate acute cellular rejection, immunosuppression
      was withdrawn after 10 days. Infiltrating lymphocytes were analysed using an in
      vitro culture system, allowing cells to propagate from the biopsies to culture
      medium. The propagated cells were counted and analysed for subtype activation
      markers and donor-specificity using flow cytometry and a proliferation assay.
      Syngeneically transplanted animals and animals given constant immunosuppression
      upon transplantation were used as controls. During rejection, significantly more
      T lymphocytes were propagating from the biopsies compared to controls. A higher
      percentage of the propagated T lymphocytes in the rejection group expressed
      activation markers [CD25 and major histocompatibility complex (MHC) class II
      antigen] compared to spleen- and peripheral blood T lymphocytes from the same
      individuals. Propagated mononuclear cells from biopsies in the rejection group
      were proliferating and showed donor-specific reactivity whereas mononuclear
      spleen cells from animals in the same group did not show this donor specificity.
      In conclusion, we have presented a rat kidney allotransplantation model with in
      vitro propagation of graft-infiltrating, activated and donor-specific T
      lymphocytes. This technique offers a possibility to study cellular reactivity in
      allotransplantation.

PMID- 10638831
TI  - Syngeneic renal transplantation increases the number of renal dendritic cells in
      the rat.
AB  - Dendritic cells participate in the regulation of CD4 and CD8 T cells during
      transplant rejection. Understanding what causes increased numbers of dendritic
      cells to appear in the renal transplant is therefore important. We performed
      syngeneic renal transplants between rats. We used the monoclonal antibody OX62 to
      detect dendritic cells, and OX6 to detect major histocompatability complex (MHC)
      Class II in the renal transplant. One week after transplant, dendritic cells
      appeared. This indicates that the injury of transplantation itself is sufficient
      to increase the number of dendritic cells in the kidney in a model where there is
      no alloreactivity.

PMID- 10638832
TI  - Intragraft platelet-derived growth factor-alpha and transforming growth factor
      beta1 during the development of accelerated graft vascular disease after clinical
      heart transplantation.
AB  - This study was to determine whether the growth factors platelet-derived growth
      factor-alpha (PDGF-alpha) and transforming growth factor-beta1 (TGF-beta1)
      contribute to the development of graft vascular disease (GVD) after clinical
      heart transplantation. We analysed intragraft PDGF-alpha and TGF-beta1 messenger
      RNA (mRNA) expression levels by competitive template reverse transcriptase
      polymerase chain reaction (RT-PCR). Endomyocardial biopsies (EMB) were obtained
      at 1 and 9 months post-transplant from cardiac allograft recipients with (n = 11)
      and without (n = 11) angiographic evidence of GVD at 1 year. In 1-month EMB,
      comparable TGF-beta1 mRNA levels were found in patients with and without GVD at 1
      year (p = 0.84, Mann-Whitney U-test). In contrast, in 9-month EMB during the
      development of GVD, intragraft mRNA levels of both PDGF-alpha (p = 0.08) and TGF
      beta1 (p = 0.03) were higher in patients with GVD after the first year compared
      to patients without GVD. These results suggest that intragraft PDGF-alpha and TGF
      beta1 play a role in the pathogenesis of accelerated GVD after clinical heart
      transplantation.

PMID- 10638833
TI  - Idarubicin-145-2C11-F(ab')2 promotes peripheral tolerance and reduces chronic
      vascular disease in mouse cardiac allografts.
AB  - In order to reduce the toxic effects of the T cell activating anti-CD3 monoclonal
      antibody, 145-2C11, F(ab')2 fragments were prepared by pepsin digestion. These
      fragments were then used as non-immunosuppressive carriers for the cytotoxic drug
      idarubicin (IDA), to reduce toxicity of both the monodonal antibodies (mAb) and
      the drug and to increase the specificity of drug delivery. The IDA-145-2C11
      F(ab')2 immunoconjugate was tested for specificity by fluorometry. 145-2C11
      intact antibody, 145-2C11 F(ab')2 and IDA conjugates of the antibody and F(ab')2
      were used to treat CBA recipients of BALB/c vascularized cardiac allografts. Mice
      with hearts surviving >100 days were challenged with donor and third party
      (C57BL/6) skin grafts. Although both antibody and F(ab')2 blocked the binding of
      145-2C11-FITC to CBA spleen cells, only the intact antibody caused sustained
      depletion of CD3 cells in vivo. 145-2C11 F(ab')2 blocked cell surface CD3 within
      30 min, but was cleared in 24 h without depletion of CD3 cells from the spleen.
      In BALB/c to CBA cardiac allografts (rejected in 12-17 days), IDA-145-2C11
      F(ab')2 (0.2 mg/20 g mouse i.p. at the time of transplantation) induced >100
      days' allograft survival and specific tolerance, in contrast to the equivalent
      dose of 145-2C11 F(ab')2 (mean survival 25 days). Hearts from IDA-145-2C11
      F(ab')2-treated mice at >100 days showed decreased cellular infiltration and less
      chronic vascular disease than long-surviving hearts from mice treated with an
      alternative antibody, KT3. Thus, F(ab')2 prepared from 145-2C11 provided a
      suitable CD3-specific, nonimmunosuppressive carrier for IDA. This immunoconjugate
      was more effective against both acute and chronic rejection than other conjugates
      or whole antibody. IDA-145-2C11 F(ab')2 is an effective, nontoxic tolerogen in
      the mouse cardiac allograft model.

PMID- 10638834
TI  - In vitro reactivity of allospecific cytotoxic T lymphocytes does not explain the
      taboo phenomenon.
AB  - Matching for human leucocyte antigens (HLA) is important for graft survival in
      kidney transplantation. Nevertheless, most patients receive a kidney graft with
      multiple HLA mismatches. Some of these mismatches seem to be more harmful than
      others. By studying the effect of single HLA mismatches in the context of the
      patients' own HLA, we have previously identified donor/recipient combinations
      with a significantly higher incidence of early graft failure, the so-called taboo
      combinations. In the present study we investigated whether a higher cytotoxic T
      lymphocyte (CTL) response towards taboo mismatches may be involved in this
      phenomenon. CTL reactivity was determined both in taboo and control combinations
      by in vitro CTL precursor assays, using peripheral blood mononuclear cells and
      proximal tubular epithelial cells as target cells. Inhibition studies with CD8
      antibody as well as Cyclosporin A were performed to identify high avidity and
      primed CTLs. Furthermore, in committed CTLp assays indirect recognition of the
      taboo mismatch was tested using synthetic peptides. The CTL precursor frequencies
      in taboo combinations were always lower than the CTL precursor frequencies in
      control combinations. No difference in avidity and activation status of the CTLs
      could be detected when taboo combinations were compared with the controls. In the
      committed CTLp assays no reactivity towards any of the synthetic peptides was
      observed. The significantly poorer graft survival of taboo combinations cannot be
      explained by a higher number of donor-specific CTLs. Furthermore, the avidity or
      activation status of these CTLs does not provide a clue to the taboo phenomenon.

PMID- 10638835
TI  - Stable prodrugs of n-butyric acid: suppression of T cell alloresponses in vitro
      and prolongation of heart allograft survival in a fully allogeneic rat strain
      combination.
AB  - n-Butyric acid has previously been shown in vitro to suppress T cell
      alloresponses and beyond that to induce a state of alloantigen-specific
      hyporesponsiveness suggesting a potential relevance for suppressing alloresponses
      also in vivo. The clinical use of butyrate salt derivatives, however, is limited
      by an extremely short half-life due to rapid metabolism. This prompted us to
      investigate the effect of butyric acid derivatives with prolonged residence time
      in vivo on T cell alloresponses in vitro and further to explore the
      immunosuppressive capacity of esterified n-butyric acid in vivo. First, the
      effect of three butyric acid esters, i.e. glucose pentabutyrate, diacetone
      glucose butyrate and tributyrin on T cell proliferation in a human mixed
      lymphocyte culture (MLC) was evaluated. All three derivatives were found to
      inhibit T cell alloresponses in a concentration-dependent manner. Based on the
      ED50 values, glucose pentabutyrate was found to be most effective in inhibiting T
      cell alloreactivity in vitro (11 microM), followed by diacetone glucose butyrate
      (122 microM), tributyrin (146 microM) and sodium butyrate (539 microM). Because
      of its favourable in vitro properties, glucose pentabutyrate was chosen for in
      vivo experiments. To test the effect of this compound on allograft survival in
      vivo, in the second part of this study, heterotopic heart transplants were
      performed in a high responder fully allogeneic rat strain combination (Brown
      Norway to Lewis strain rats). We found that intraperitoneal (i.p.) injection of
      glucose pentabutyrate at 500 mg/kg/day (day 0 and daily up to 12 days
      posttransplant) induced a significant prolongation of allograft survival as
      compared to animals treated with vehicle (glycerol formal, i.p.) alone (14.1+/
      6.3 versus 9.6+/-3.2 days, p = 0.036), whereby at lower dosage (100 mg/kg/day) no
      such effect was observed (10.2+/-2.1 days, p = 0.21). Our findings suggest that
      stable prodrugs of n-butyric acid might have potential clinical relevance for
      inhibiting alloresponses in vivo.

PMID- 10638836
TI  - Expression patterns of integrin receptors and extracellular matrix proteins in
      chronic rejection of human liver allografts.
AB  - The beta1-integrin family of adhesion molecules is supposed to mediate cell-to
      matrix interactions involved in a variety of immune reactions, especially in
      those associated with tissue remodelling. In an attempt to determine the role of
      beta1-integrins in the initiation and maintenance of fibrotic deposition observed
      in chronic rejection after liver transplantation, we immunohistochemically
      analysed the expression of different extracellular matrix components and the very
      late antigen (VLA) family of beta1-integrins in 11 samples of chronically
      rejected human liver allografts and compared results to findings in acutely
      rejected transplants and nontransplanted chronic inflammatory livers. In contrast
      to normal liver specimens, chronically rejected human liver allografts displayed
      a general overexpression of matrix components along sinusoids throughout the
      tissue and an additional characteristic accumulation in pericentral areas.
      Accordingly, VLA-1, -5 and -6 demonstrated a linear upregulation or de novo
      expression on sinusoidal lining cells, VLA-1 and VLA-4 additionally displayed
      concentration within pericentral fibrotic deposits. VLA-2 and -3 were only
      sporadically found. In accordance with findings in chronic rejection, chronic
      inflammatory livers showed overexpression of VLA-1, -5 and -6 within sinusoids
      and accumulation of VLA-1 and -4 in fibrotic septa. In contrast, acutely rejected
      allografts displayed slight overexpression of ECM components without
      characteristic accumulates, hence beta1-integrins were seen to be equally
      distributed throughout the parenchyma. Altogether, our analysis showed an
      upregulation of integrin receptors which corresponded to the extent of ECM
      deposition and thus suggested an important role for these molecules in the
      iniation of fibrosis observed in these specimens. Individual integrins showed
      different expression patterns within sinusoids and fibrotic areas, indicating
      distinct roles in differential stages of matrix accumulation, but induction
      patterns were generally similar in chronic inflammatory and chronically rejected
      livers, suggesting independence of the underlying disease.

PMID- 10638837
TI  - A comparison of primary endothelial cells and endothelial cell lines for studies
      of immune interactions.
AB  - The purpose of this study was to assess the suitability of using endothelial cell
      (EC) lines for studies of endothelial/immune interactions. The immortal human EC
      lines HMEC-1, ECV304 and EaHy926 were compared to human umbilical vein
      endothelial cells (HUVEC) for constitutive and induced expression of surface
      antigens known to be involved in interactions with T cells. These cell lines were
      also compared to HUVEC in transendothelial migration assays. Flow cytometry was
      used to measure cell surface expression of platelet/endothelial cell adhesion
      molecule-1 (PECAM-1), intercellular adhesion molecule-1 (ICAM-1), vascular cell
      adhesion molecule-1 (VCAM-1), E-selectin, major histocompatibility complex (MHC)
      class I and MHC class II, CD40, CD95 (fas) and lymphocyte function associated
      antigen-3 (LFA-3) before and after treatment with the cytokines tumour necrosis
      factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma). Polymerase chain
      reaction (PCR) was used to detect expression of the MHC class II transactivator.
      Significant differences were found in the ability to respond to cytokines between
      HUVEC and the cell lines, the greatest differences being induction of VCAM-1 and
      E-selectin in response to TNF-alpha and induction of MHC class II antigens in
      response to IFN-gamma. Thus unlike HUVEC, induction of VCAM-1 and E-selectin was
      not detectable on EaHy926 and ECV304 and barely detectable on HMEC-1. MHC class
      II antigens were not induced on ECV304 in response to IFN-gamma and nor was the
      class II transactivator (CIITA). Unlike HUVEC and the other cell lines, ECV304
      were constitutively negative for PECAM-1. Constitutive and induced expression of
      MHC class I, ICAM-1, LFA/3, CD40 and fas were most conserved between the cell
      lines and showed little difference to HUVEC. The migration of peripheral blood
      mononuclear cells (PBMC) through all cell lines was significantly reduced
      compared to through HUVEC, suggesting that there is a functional difference
      between the cell lines with regard to interactions with lymphocytes. In
      conclusion this study has demonstrated significant differences in the ability of
      endothelial cell lines to respond to cytokines compared to primary HUVEC
      cultures. In particular ECV304 compares very poorly with HUVEC. Whether these
      differences are caused by immortalization procedures or reflect heterogeneity of
      EC arising from different vascular beds is discussed.

PMID- 10638838
TI  - TGF-beta gene polymorphism does not influence the rise in creatinine following
      cardiac transplantation.

PMID- 10638839
TI  - Estimating environmental exposures to sulfur dioxide from multiple industrial
      sources for a case-control study.
AB  - This paper first discusses how population exposures to environmental pollutants
      are estimated from environmental monitoring data and the problems that are
      encountered in estimating risk from pollutants on the basis of ecologic studies.
      We then present a technique of estimating individualized exposures to an
      atmospheric pollutant, sulfur dioxide (SO2), through atmospheric transport
      modeling for a case-control study. The transport model uses the quantities of SO2
      released from 30 geographically identified industrial facilities and
      meteorological data (wind speed and direction) to predict the downwind ground
      level concentrations of SO2 at geographically identified residences, receptors,
      of 797 study subjects. A distribution of facility SO2 emissions, uncertainties in
      effective stack height, and model uncertainty are incorporated to examine the
      uncertainty in the predicted versus ambient monitoring SO2 levels, and to
      generate an exposure uncertainty distribution for both the cases and controls.
      The transport model's accuracy is evaluated by comparing recorded ambient
      measurements of SO2 with the model's predicted SO2 estimates at geographically
      identified ambient monitoring stations.

PMID- 10638840
TI  - A new carbon monoxide occupational dosimeter: results from a worker exposure
      assessment survey.
AB  - The LBNL/QGI occupational carbon monoxide (CO) dosimeter (LOCD), a new,
      inexpensive CO passive sampler, was field-validated in an occupational exposure
      assessment study in the Moscone Convention Center (MCC) in San Francisco, CA in
      January, 1997. The LOCD measures time-weighed-average (TWA) CO exposures from 10
      to 800 parts per million hours (ppm h; accuracy +/- 20%; precision 10 ppm h).
      This device represents a major improvement over currently available low-cost
      personal CO monitors. At the MCC, over 1000 workers set up and remove
      exhibitions. Forty propane-powered forklifts moved materials throughout the
      42,000 m2 of exhibit halls. Diesel truck emissions enter the building via three
      internal underground loading docks. The LOCD was used to measure 154 worker
      exposures on 3 days. Sampler performance was compared to a standard method at 15
      fixed sites. The geometric mean (GM) of all 154 exposures was 7 ppm (geometric
      standard deviation (GSD) = 1.6); 10% of the exposures was 10 ppm or more. Dock
      Walkers and Forklift Operators had the highest exposures (maximum = 34 ppm) with
      GM (GSD) of 9 (1.7) and 9 (1.6) ppm, respectively. Attendants and
      Installer/Decorators had the lowest exposures with GMs of 6 (1.6) and 7 (1.4),
      respectively. The Cal/OSHA personal exposure limit for CO is 25 ppm time-weighted
      average (TWA).

PMID- 10638841
TI  - Comparisons of seasonal fungal prevalence in indoor and outdoor air and in house
      dusts of dwellings in one Northeast American county.
AB  - Fungi cause allergies and many other adverse health effects. In this study, we
      characterized the nature and seasonal variation of fungi inside and outside homes
      in the Greater New Haven, Connecticut area. Three indoor air samples (in the
      living room, bedroom, and basement) and one outdoor sample were collected by the
      Burkard portable air sampler. House dust samples were collected in the living
      room by a vacuum cleaner. The mold concentrations varied widely from house to
      house in both indoor and outdoor air. No significant difference (p>0.05) in
      concentration and type of fungi between living room and bedroom or by season was
      observed. Both concentration and type of fungi were significantly higher (p<0.05)
      in the basement than other indoor areas and outdoor air in winter. The type of
      fungi in living room, bedroom, and outdoor air were found to have significant
      changes among seasons, but there was no significant difference for the basement
      among seasons. Cladosporium spp. was dominant in both indoor and outdoor air in
      summer. Penicillium and Aspergillus were dominant in indoor air in winter, but
      neither was dominant in any season in outdoor air. The type of fungi and their
      concentrations in house dust samples were not representative of those isolated in
      indoor air. In dust samples, more Mucor, Wallemia, and Alternaria species, but
      less Aspergillus, Cladosporium, and Penicillium species were found in all
      seasons. Air sampling in spring or fall in every suspected house is suggested for
      year-round fungal exposure assessment.

PMID- 10638842
TI  - Indoor air exposure to volatile compounds emitted by paints: experiment and
      model.
AB  - To describe the evaporation of organic solvents from paints and the resulting
      indoor concentrations, a mathematical model and an indoor paint experiment are
      presented. The model describes painting in terms of an increasing area of paint
      during application and two compartments of paint once applied. Evaporation of
      organic solvents is driven by the vapor pressure of the organic solvent. The
      experiment revealed concentrations of n-alkanes in indoor air, during painting,
      and 3 days thereafter. To compare experimental results to model predictions,
      model parameters were measured at the start of the experiment. Diffusional
      exchange between paint compartments and fraction of paint applied to the upper
      compartment were set by expert judgment. Model predictions and experimental
      results were in agreement, although the timing of the concentration peak appeared
      difficult to predict.

PMID- 10638843
TI  - Missing annual external radiation dosimetry data among Hanford workers.
AB  - Epidemiological studies of workers employed at the Hanford Site have been
      underway for nearly 30 years. Although the external radiation dosimetry program
      at Hanford has been fairly comprehensive, some workers included in previous
      epidemiological analyses have periods of employment during which there are
      missing annual external radiation dosimetry records. In this report, employment
      history records and annual external dosimetry records have been used to
      investigate the extent of missing annual external dosimetry records for workers
      at the Hanford facility. A "nearby" procedure for estimating values for missing
      annual external dosimetry records was evaluated. Among the 33,459 workers who
      were employed at least 180 days and had at least one annual external dosimetry
      record, annual external dosimetry records were missing for 8% of the years of
      employment (32,323 missing annual external dosimetry records). Missing annual
      external dosimetry records were more common for female Hanford workers than for
      male workers, and for workers employed in the early years of Hanford's operation
      than for workers employed in later years of operation. The nearby procedure
      provided reliable estimates of values for missing annual external dosimetry
      records. Using this procedure, 18,937.5 mSv were estimated for missing annual
      external dosimetry records; this was 2% of the total recorded cumulative external
      radiation dose for these workers. Missing annual external dosimetry records
      should be considered as a potential source of bias and uncertainty in
      investigations of radiation-cancer associations among Hanford workers.

PMID- 10638844
TI  - Spatial and temporal measurements of NO2 in an urban area using continuous mobile
      monitoring and passive samplers.
AB  - This paper describes the use of a continuous mobile monitor and passive samplers
      to estimate the spatial distribution of NO2 in an urban area for the purpose of
      siting a continuous monitor to measure population exposure. Monitoring sites were
      sites selected based on the State and Local Air Monitoring Stations (SLAMS) and
      National Air Monitoring Station (NAMS) siting criteria required by the U.S.
      Environmental Protection Agency (U.S. EPA). SLAMS monitoring objectives define
      scales in which the NO2 concentration and land use are homogeneous. The SLAMS
      scales relevant to NO2 monitoring for NAMS NO2 monitoring sites are neighborhood
      (0.5 to 4 km), and urban (several to 50 km). SLAMS siting objectives also define
      four categories of sites: highest concentration, representative concentration,
      impacts of major sources, and background sites. Mobile monitoring with a Scintrex
      LMA-3 luminal monitor was used on a neighborhood scale to measure the NO2
      concentration at sites that covered a large geographical area. Passive samplers
      were then located at candidate mobile monitoring locations for long-term sampling
      which covered the neighborhood to the urban scale. These two methods complement
      each other by combining short-term continuous measurements and integrated long
      term measurements which reflect the National Ambient Air Quality Standard for NO2
      which is based on an annual average. The neighborhood site with the highest
      concentration was not only in the area of highest population density, but was
      also representative of the larger urban scale. The magnitude of this urban scale
      is approximately 20 km.

PMID- 10638845
TI  - Ozone emissions from a "personal air purifier".
AB  - Ozone emissions were measured above a "personal air purifier" (PAP) designed to
      be worn on a lapel, shirt pocket, or neck strap. The device is being marketed as
      a negative ion generator that purifies the air. However, it also produces ozone
      within the person's immediate breathing zone. In order to assess worst-case
      potential human exposure to ozone at the mouth and nose, we measured ozone
      concentrations in separate tests at 1, 3, 5, and 6 in. above each of two PAPs in
      a closed office. One PAP was new, and one had been used slightly for 3 months.
      Temperature, relative humidity, atmospheric pressure, room ozone concentration,
      and outdoor ozone concentration also were measured concurrently during the tests.
      Average ozone levels measured directly above the individual PAPs ranged from 65
      71 ppb at 6 in. above the device to 268-389 ppb at 1 in. above the device. Ozone
      emission rates from the PAPs were estimated to be 1.7-1.9 microg/minute. When
      house dust was sprinkled on the top grid of the PAPs, one showed an initial peak
      of 522 ppb ozone at 1 in., and then returned to the 200-400 ppb range. Room ozone
      levels increased by only 0-5 ppb during the tests. Even when two PAPs were left
      operating over a weekend, room ozone levels did not noticeably increase beyond
      background room ozone levels. These results indicate that this "PAP," even
      without significant background ozone, can potentially elevate the user's
      exposures to ozone levels greater than the health-based air quality standards for
      outdoor air in California (0.09 ppm, 1-hour average) and the United States (0.08
      ppm, 8-hour average).

PMID- 10638846
TI  - Investigations of the proximity effect for pollutants in the indoor environment.
AB  - More than a dozen indoor air quality studies have reported a large discrepancy
      between concentrations measured by stationary indoor monitors (SIMs) and personal
      exposure monitors (PEMs). One possible cause of this discrepancy is a source
      proximity effect, in which pollutant sources close to the respondent cause
      elevated and highly variable exposures. This paper describes three sets of
      experiments in a home using real-time measurements to characterize and quantify
      the proximity effect relative to a fixed distant location analogous to a SIM. In
      the first set of experiments, using sulfur hexafluoride (SF6) as a continuously
      emitting tracer pollutant from a point source, measurements of pollutant
      concentrations were made at different distances from the source under different
      air exchange rates and source strengths. A second set of experiments used a
      continuous point source of carbon monoxide (CO) tracer pollutant and an array of
      high time resolution monitors to collect simultaneous concentration readings at
      different locations in the room. A third set of experiments measured particle
      count density and particle-bound polycyclic aromatic hydrocarbon (PAH)
      concentrations emitted from a continuous particle point source (an incense stick)
      using two particle counters and two PAH monitors, and included human activity
      periods both before and during the source emission period. Results from the SF6
      and CO experiments show that while the source is emitting, a source proximity
      effect can be seen in the increases in the mean and median and in the variability
      of concentrations closest to the source, even at a distance of 2.0 m from the
      source under certain settings of air exchange rate and source strength. CO
      concentrations at locations near the source were found to be higher and more
      variable than the predictions of the mass balance model. For particles emitted
      from the incense source, a source proximity effect was evident for the fine
      particle sizes (0.3 to 2.5 microm) and particle-bound PAH up to at least 1.0 m
      from the source. Analysis of spatial and temporal patterns in the data for the
      three tracer pollutants reveal marked transient elevations of concentrations as
      seen by the monitor, referred to as "microplumes," particularly at locations
      close to the source. Mixing patterns in the room show complex patterns and
      directional effects, as evidenced by the variable intensity of the microplume
      activity at different locations. By characterizing the spatial and temporal
      variability of pollutant concentrations in the home, the proximity effect can be
      quantified, leading to improved indoor monitoring designs and models of human
      exposure to air pollutants.

PMID- 10638847
TI  - The effect of cigar smoking on indoor levels of carbon monoxide and particles.
AB  - To provide new information on environmental tobacco smoke (ETS) levels from
      cigars, we conducted three types of experiments: (1) Measurements of carbon
      monoxide (CO) during 15 controlled experiments in an office where several cigar
      brands were machine-smoked; (2) Measurements of CO or respirable suspended
      particles (RSP) and particle-bound polycyclic aromatic hydrocarbons (PAH) in a
      residence where two cigars were smoked by a person; and (3) Measurements of CO
      during two studies at cigar social events (where there were up to 18 cigars being
      smoked at a time) in which an investigator wore a concealed personal exposure
      monitor. Average concentrations of CO at the cigar social events were comparable
      to, or larger than, those observed on a freeway during rush hour traffic. A mass
      balance model that has been used successfully to predict ETS from cigarettes is
      used in this paper to obtain CO, RSP, and PAH emission factors (emission rate
      [mg/min], total mass emitted [mg], and emissions per mass smoked [mg/g]). The
      calculated emission factors show that the cigar can be a stronger source of CO
      than the cigarette. In contrast, the cigar may have fewer emissions of RSP and
      PAH per gram of consumed tobacco than the cigarette, but its size and longer
      smoking time results in greater total RSP and PAH emissions than for a single
      cigarette.

PMID- 10638848
TI  - Techniques of CT colonography (virtual colonoscopy).
AB  - Colorectal cancer is a leading cause of death in older adults, which usually
      involves a long-term progressive change of normal mucosa into adenomatous polyps
      and then cancer. The detection and treatment of this disease in an early stage
      can lead to a cure in most cases by simply removing the polyp. Computed
      tomographic colonography (CTC), also referred to as virtual colonoscopy (VC), is
      a recent advance that gives an intraluminal visualization of the colon that is
      similar to endoscopy. VC requires fast 3D display (at least 10 frames/sec) of the
      colon's mucosal surface on a computer screen. Spiral/helical computer tomography
      is used to gather 3D volume data prior to display. CTC has been demonstrated to
      be promising for colorectal cancer screening. Studies on unraveling of the colon
      are underway to map the convoluted tubular structure into a straightened and
      flattened image volume for global visualization. In this article, we review the
      current status of CTC with an emphasis on image processing and visualization
      algorithms. Clinical assessment results of existing techniques are summarized.
      Practical issues and future perspectives are also discussed.

PMID- 10638849
TI  - Engineering manual and electric powered wheelchairs.
AB  - The sophistication required to develop and properly configure a wheelchair is
      illustrated by the amount and complexity of the research being conducted. At this
      time there appears to be between 1.5 and 2.0 million full-time wheelchair users
      within the United States. The reliance of the user on the wheelchair and the
      amount of time in the wheelchair provide significant challenges for the
      wheelchair design engineer. Currently there are a wide variety of wheelchair
      designs that are commercially available. These wheelchairs accommodate a variety
      of people's needs, and represent significant progress. The current trend among
      manufacturers of manual wheelchairs seems to be cost-reduction engineering. The
      ergonomics of long-term wheelchair use are critical to the advancement of
      wheelchair design and to the clinical selection of wheelchairs. Electric powered
      wheelchairs appear to be progressing faster than nearly all other types of
      wheelchairs. This is due to the availability of computing power with low cost
      microcontrollers and associated peripherals. The greater range and availability
      of sensors are also making changes into the design of electric powered
      wheelchairs. The interaction between an electric powered wheelchair and the user
      can be extremely complex. In many cases, individual solutions are necessary. One
      of the more challenging questions is determining the abilities of the user
      required to drive an electric powered wheelchair effectively. There have been
      substantial improvements in the engineering of all wheelchairs. However, there
      remain significant issues to be addressed.

PMID- 10638850
TI  - Biomechanical basis of vascular tissue engineering.
AB  - Blood vessels develop under the influence of mechanical stresses and strains and
      remodel in response to alterations in these factors. It has long been
      hypothesized that mechanical stresses and strains contribute to the development
      of vascular diseases such as atherosclerosis and hypertrophy. A large number of
      studies have been conducted to verify this hypothesis and have demonstrated that
      increased tensile stress and strain due to hypertension may induce and/or
      facilitate vascular hypertrophy, and oscillatory low fluid shear stress and/or
      altered shear gradients due to eddy blood flow may initiate and/or promote focal
      atherosclerosis and intimal hyperplasia. A variety of cellular components,
      including growth-related factors, cell membrane proteins and lipids,
      intracellular signaling molecules and transcriptional factors, and immediate
      early genes and mitogenic genes, have been shown to mediate these mechanical
      stress-related pathological processes. These discoveries suggest that a
      modulation of tensile and fluid shear stresses and strains, if possible, may
      prevent mechanical stress-induced pathological changes in blood vessels and thus
      constitute a foundation for the development of vascular engineering approaches.
      Recent studies have demonstrated by using an experimental vein graft model that
      biomechanical engineering approaches can be used to reduce tensile stress and
      strain due to exposure to arterial blood pressure and to prevent eddy blood flow
      in vein grafts. Such engineering modulations significantly reduced the rate of
      focal intimal hyperplasia and medial and adventitial hypertrophy in vein grafts.
      These preliminary studies have provided convincing evidence for further
      development of vascular biomechanical engineering approaches. In this article,
      the background, principles, clinical potentials, as well as the limitations of
      vascular biomechanical engineering are discussed.

PMID- 10638851
TI  - A survey of medical image registration.
AB  - The purpose of this paper is to present a survey of recent (published in 1993 or
      later) publications concerning medical image registration techniques. These
      publications will be classified according to a model based on nine salient
      criteria, the main dichotomy of which is extrinsic versus intrinsic methods. The
      statistics of the classification show definite trends in the evolving
      registration techniques, which will be discussed. At this moment, the bulk of
      interesting intrinsic methods is based on either segmented points or surfaces, or
      on techniques endeavouring to use the full information content of the images
      involved.

PMID- 10638852
TI  - A scheme for automatically building three-dimensional morphometric anatomical
      atlases: application to a skull atlas.
AB  - We present a general scheme for automatically building a morphometric anatomical
      atlas. We detail each stage of the method, including the non-rigid registration
      algorithm, three-dimensional line averaging and statistical processes. We apply
      the method to obtain a quantitative atlas of skull crest lines. Finally, we use
      the resulting atlas to study a craniofacial disease; we show how we can obtain
      qualitative and quantitative results by contrasting a skull affected by a
      mandible deformation with the atlas.

PMID- 10638853
TI  - An advanced system for the simulation and planning of orthodontic treatment.
AB  - This paper presents a new system for three-dimensional (3-D) orthodontic
      treatment planning and movement of teeth. We describe a computer vision technique
      for the acquisition and processing of 3-D images of the profile of hydrocolloid
      dental imprints. Profile measurement is based on the triangulation method which
      detects deformation of the projection of a laser line on the dental imprints. The
      system is computer-controlled and designed to achieve depth and lateral
      resolutions of 0.1 and 0.2 mm, respectively, within a depth range of 40 mm. The 3
      D image of the imprint is segmented in order to identify different teeth. Two
      operators are presented: one for the detection of molars and premolars based on a
      directional gradient, and one for incisors and canines based on 3-D registration
      with dental models contained in a database. We apply these 3-D dental models to
      simulate the 3-D movement of teeth, including rotations, during orthodontic
      treatment. With this objective, we have developed an original simplified model of
      arch-wire behaviour and a viscoplastic behaviour law for the alveolar bone in
      order to simulate teeth displacements during orthodontic treatment. The
      contribution of the paper is part of a diagnosis system (called MAGALLANES) that
      is designed to replace manual measurement methods, which use costly plaster
      models, with computer measurement methods and teeth movement simulation using
      cheap hydrocolloid dental wafers. This procedure will reduce the cost and
      acquisition time of orthodontic data and facilitate the conduct of
      epidemiological studies.

PMID- 10638854
TI  - An efficient motion estimator with application to medical image registration.
AB  - Image registration is a very important problem in computer vision and medical
      image processing. Numerous algorithms for registering single and multi-modal
      image data have been reported in these areas. Robustness as well as computational
      efficiency are prime factors of importance in image data registration. In this
      paper, a robust/reliable and efficient algorithm for estimating the
      transformation between two image data sets of a patient taken from the same
      modality over time is presented. Estimating the registration between two image
      data sets is formulated as a motion-estimation problem. We use a hierarchical
      optical flow motion model which allows for both global as well as local motion
      between the data sets. In this hierarchical motion model, we represent the flow
      field with a B-spline basis which implicitly incorporates smoothness constraints
      on the field. In computing the motion, we minimize the expectation of the squared
      differences energy function numerically via a modified Newton iteration scheme.
      The main idea in the modified Newton method is that we precompute the Hessian of
      the energy function at the optimum without explicitly knowing the optimum. This
      idea is used for both global and local motion estimation in the hierarchical
      motion model. We present examples of motion estimation on synthetic and real data
      (from a patient acquired during pre- and post-operative stages) and compare the
      performance of our algorithm with that of competing ones.

PMID- 10638855
TI  - Hypothesis: is low prenatal vitamin D a risk-modifying factor for schizophrenia?
AB  - The central nervous system is increasingly being recognised as a target organ for
      vitamin D via its wide-ranging steroid hormonal effects and via the induction of
      various proteins such as nerve growth factor. This paper proposes that low
      maternal vitamin D may impact adversely on the developing foetal brain, leaving
      the affected offspring at increased risk of adult-onset schizophrenia. The
      hypothesis can parsimoniously explain diverse epidemiological features of
      schizophrenia, such as the excess of winter births, increased rates of
      schizophrenia in dark-skinned migrants to cold climates, the increased rate of
      schizophrenia births in urban versus rural setting, and the association between
      prenatal famine and schizophrenia. Studies that will allow rejection of the
      hypothesis are proposed.

PMID- 10638856
TI  - Lateralized brain dysfunction in schizophrenia: a comparison with patients with
      lateralized structural lesions.
AB  - A comparison was made among participants with schizophrenia and those with
      structural lateralized or diffuse brain damage in order to determine the extent
      to which the cognitive profile of the schizophrenia sample resembled the profiles
      obtained from patients with left-hemisphere, right-hemisphere, and diffuse brain
      damage. The Halstead-Reitan Neuropsychological Battery was used as the testing
      procedure. The data were subjected to discriminant analysis in order to obtain
      frequencies of predicted classification of the participants with schizophrenia
      into schizophrenia, left-hemisphere, right-hemisphere, and diffuse groups. Half
      of the participants with schizophrenia were classified into the schizophrenia
      group. The other half was evenly distributed across the left-hemisphere, right
      hemisphere, and diffuse brain damage groups. There was not a disproportionately
      large number of participants classified into the left-hemisphere group.
      Comparisons among these four predicted groups were accomplished for each of the
      Halstead-Reitan Battery measures using one-way analysis of variance. The
      comparison of the subtest scores among the predicted groups indicated that the
      patients classified into the left-hemisphere group were characterized by a
      pattern of language dysfunction thought to be developmental in nature, and an
      abnormal lack of asymmetry in tapping speed favoring the right hand.

PMID- 10638857
TI  - Visual scanpaths in schizophrenia: is there a deficit in face recognition?
AB  - There is substantial evidence that schizophrenics have deficits in face
      processing. We hypothesised that this difficulty is due to abnormalities in the
      visual scanning of faces. The specificity of these abnormalities to recognisable
      faces, the effect of task difficulty and their relationships to three primary
      symptom dimensions were examined. An infrared corneal reflection technique was
      used to record the visual scanpaths of 63 schizophrenics and 60 non-psychiatric
      controls while viewing non-degraded ('recognisable') and degraded ('not
      recognisable') faces. In the concurrent recognition task, subjects were asked to
      select the previously viewed face from among seven (exposure 1) or three
      (exposure 2) options. Both groups were unable to accurately recognise degraded
      faces, but schizophrenics were less accurate than controls for non-degraded faces
      in the more difficult task condition. Schizophrenics maintained a relatively
      'restricted' scanpath style across both faces, but scanpath disturbances were
      most apparent for non-degraded faces. Analysis of fixation distribution to non
      degraded faces showed that, unlike controls, schizophrenics did not concentrate
      their fixations on salient features. Scanpath aberrations showed only minimal
      associations with symptom dimensions. These results suggest that schizophrenic
      individuals have a specific deficit in the visual scanning of faces, that is a
      distinct case of a fundamental problem in complex object processing.

PMID- 10638858
TI  - Wisconsin Card Sorting Test deficits in schizotypic individuals.
AB  - The present study investigates executive functioning in schizotypic college
      students and control subjects using the Wisconsin Card Sorting Test (WCST).
      Inhibitory control and working memory, two aspects of executive functioning, were
      examined in deviantly high scorers on the Perceptual Aberration and Magical
      Ideation Scales (n=97), high scorers on the revised Social Anhedonia Scale
      (n=58), and in control subjects (n=104). The schizotypic groups displayed
      significantly more perseverative errors and achieved fewer categories than the
      control group. The two schizotypic groups did not differ from each other. We
      identified a subset of schizotypic individuals who also produced clinically
      deviant WCST profiles. The findings support the hypothesis that executive
      function deficits may precede the onset of schizophrenia and related illnesses.

PMID- 10638859
TI  - Altered adhesion, proliferation and death in neural cultures from adults with
      schizophrenia.
AB  - The causes of schizophrenia are unknown, but there is evidence linking subtle
      deviations in neural development with schizophrenia. Embryonic brain development
      cannot be studied in an adult with schizophrenia, but neurogenesis and early
      events in neuronal differentiation can be investigated throughout adult life in
      the human olfactory epithelium. Our past research has demonstrated that neuronal
      cultures can be derived from biopsy of the human adult olfactory epithelium. In
      the present study, we examined mechanisms related to neurogenesis and neuronal
      differentiation in adults with schizophrenia versus well controls. Forty biopsies
      were collected under local anaesthesia from ten individuals with DSM III-R
      schizophrenia and ten age- and sex-matched well controls. All patients, except
      one, were receiving antipsychotic medication at the time of the biopsy.
      Immunostaining for neuronal markers indicated that neurogenesis occurred in the
      biopsies from both patients and controls since all contained cells expressing
      tubulin and/or olfactory marker protein. The major findings of this study are: 1.
      biopsies from patients with schizophrenia showed a significantly reduced ability
      to attach to the culture slide: 29.9% of patient biopsies attached compared to
      73.5% of control biopsies; 2. biopsies from patients with schizophrenia had a
      significantly greater proportion of cells undergoing mitosis: 0.69% in the
      patients compared to 0.29% in the controls; and 3. dopamine (10 microM)
      significantly increased the proportion of apoptotic cells in the control cultures
      but significantly decreased the proportion in patients' cultures.

PMID- 10638860
TI  - Cortical gray matter deficit in patients with bipolar disorder.
AB  - BACKGROUND: cortical gray matter volume deficit and ventricular enlargement are
      well documented in schizophrenia, but their presence in bipolar disorder is less
      well established. METHODS: global cortical gray matter, white matter and sulcal
      CSF, as well as lateral and third ventricular volume measures, were derived from
      axial MRI brain images obtained on age-matched bipolar (n=9), schizophrenic
      (n=9), and control (n=16) subjects. All subjects were free of history of alcohol
      or other substance dependence. RESULTS: relative to controls, bipolar patients
      had widespread volume deficits of cortical gray matter but not of cortical white
      matter. Schizophrenic patients had an even more severe cortical gray matter
      deficit and greater sulcal and lateral ventricular enlargement than the bipolar
      patients. CONCLUSIONS: this group of patients with bipolar disorder had a
      widespread deficit of cortical gray matter similar to, but less pronounced than,
      that observed in patients with schizophrenia.

PMID- 10638861
TI  - Age at onset and sex differences in corpus callosum area in schizophrenia.
AB  - Previous research on neuropsychological function among schizophrenia patients
      suggests that typical onset males (first psychiatric hospital admission before
      age 25) and typical onset females (first admission after age 25) may exhibit less
      lateralization of behavioral function ('hypolateralization') than atypical onset
      males and atypical onset females. To explore whether these differences were
      reflected in corpus callosum area, brain morphometric data from a large sample of
      subjects diagnosed with schizophrenia were analyzed. Typical onset females and
      typical onset males were compared to atypical onset females and atypical onset
      males on corpus callosum area. While neither sex nor onset effect on total corpus
      callosum area was statistically significant, analysis of standard subregions of
      the corpus callosum revealed a significant interaction effect on the posterior
      20% area of the corpus callosum, with typical onset women having particularly
      large corpora callosa. The anterior 50% area did not differ among the groups. The
      results are discussed in terms of the role of anomalies in the integration and
      hemispheric transfer of information as underlying mechanisms of schizophrenia.

PMID- 10638862
TI  - Obstetric complications in schizophrenia, schizoaffective disorder and normal
      comparison subjects.
AB  - Previous studies have indicated that obstetric complications (OCs) may be risk
      factors for schizophrenia, but findings are inconsistent, and data about other
      diagnostic groups are relatively scarce. We compared the obstetric histories of
      subjects with schizophrenia, major affective disorder and normal controls. Our
      subjects included 61 schizophrenia, 26 schizoaffective, 28 major affective
      disorder patients and 21 normal controls. OCs were rated on the McNeil-Sjostrom
      Scale using data from mothers reports and for a subsample from hospital and birth
      certificate records. The frequency of OCs did not differ statistically between
      diagnostic groups at any stage or for the three stages combined. OCs of at least
      level 4 were found in 69% of schizophrenia patients, 62% of schizoaffective
      patients, 68% of major affective disorder patients and 71% of the normal
      comparison group. OCs of at least level 5 were found in 23% of schizophrenia
      patients, 23% of schizoaffective patients, 21% of the major affective disorder
      patients and 14% of the normal comparison group. Our findings indicate that the
      etiologic significance of OCs may not be specific to schizophrenia.

PMID- 10638863
TI  - Negative parkinsonian, depressive and catatonic symptoms in schizophrenia: a
      conflict of paradigms revisited.
AB  - BACKGROUND: To study the interrelationship pattern of negative, depressive,
      parkinsonian and catatonic symptoms over an exacerbation phase of schizophrenia.
      METHOD: Forty-five inpatients with a DSM-IV diagnosis of schizophrenia or
      schizophreniform disorder were assessed at admission and discharge for negative,
      depressive, parkinsonian and catatonic symptoms. A subsample of patients
      unmedicated at admission (n=23) was specifically analyzed. RESULTS: Negative,
      parkinsonian and catatonic symptoms correlated significantly at both assessment
      points, as did their mean changes over the episode. At admission, depressive
      symptoms did not correlate with negative, parkinsonian or catatonic symptoms, but
      they did at discharge. Changes of depressive symptoms over the episode did not
      correlate with changes of the other groups of symptoms. In the patients who were
      unmedicated at admission, ratings of nonakinetic parkinsonism, unlike ratings of
      akinetic parkinsonism, worsened significantly after neuroleptic treatment.
      CONCLUSIONS: While negative, parkinsonian and catatonic symptoms are highly
      related features, depressive symptoms seem to be a relatively independent
      dimension of psychopathology in schizophrenia. Non-akinetic parkinsonian symptoms
      may be more useful than the akinetic symptoms in distinguishing primary from drug
      induced negative symptoms.

PMID- 10638864
TI  - The effects of typical antipsychotics, clozapine, and risperidone on
      neuropsychological test performance in schizophrenia.

PMID- 10638865
TI  - Span of apprehension in adolescents with schizophrenia or ADHD.

PMID- 10638866
TI  - What's it like to be mentally ill?

PMID- 10638867
TI  - Aerobic capacity in adult dermatomyositis/polymyositis patients and healthy
      controls.
AB  - OBJECTIVE: Assessment of myositis patients has relied on symptoms, strength
      testing, and serum muscle enzyme activity. Recently, functional assessments and
      evaluation of strength by dynamometry and of disease activity by magnetic
      resonance imaging have also been added. Aerobic testing in selected patients has
      been considered useful. DESIGN: Case-control study. SETTING: University Hospital,
      Vienna, Austria. PATIENTS: Twenty-two subjects (8 outpatients with chronic
      dermatomyositis and 3 outpatients with chronic polymyositis, and 11 healthy
      controls) participated, allowing the identification of 11 case-control pairs
      matched by age (+/-3 years) and gender (mean age, 48+/-14 yrs; ratio of women to
      men, 18/4). MAIN OUTCOME MEASURES: Target parameters were peak oxygen uptake
      (peak VO2) to estimate aerobic exercise capacity and peak isometric torque for
      muscle strength. Creatine phosphokinase (CPK) was measured to assess elevation of
      muscle enzymes. RESULTS: The mean peak VO2 in patients with
      dermatomyositis/polymyositis was 15.3 mL/min/kg (SD = 5.8) and in the healthy
      controls 28.7 mL/min/kg (SD = 7.8). Cardiorespiratory capacity expressed as peak
      VO2 was thus significantly reduced at 53% (p = .0001) of the control value.
      Muscle strength expressed as peak isometric torque was significantly lower (p =
      .01) in patients (mean 148+/-73 Nm) when compared to the control group (mean
      261+/-99 Nm). In myositis patients peak VO2 and peak isometric torque correlate
      well with each other (r = .7631; p = .0001), but not at all with serum CPK levels
      (r = .056; p = .869). CONCLUSION: Peak VO2 is significantly diminished in
      patients with dermatomyositis/polymyositis, compared with age- and sex-matched
      controls. Serum CPK did not significantly correlate with VO2. Aerobic exercise
      testing may be a useful assessment parameter in selected patients with
      dermatomyositis/ polymyositis.

PMID- 10638868
TI  - Contractures secondary to immobility: is the restriction articular or muscular?
      An experimental longitudinal study in the rat knee.
AB  - OBJECTIVES: To measure articular structures' contribution to the limitation of
      range of motion after joint immobility. STUDY DESIGN: Experimental, controlled
      study involving 40 adult rats that had one knee joint immobilized in flexion for
      durations of 2, 4, 8, 16, and 32 weeks; 20 rats underwent a sham procedure. The
      angular displacement was measured both in flexion and extension at three
      different torques. Myotomy of transarticular muscles allowed isolation of the
      arthrogenic component of the contracture. RESULTS: A contracture developed in all
      immobilized knees. The articular structures were incrementally responsible for
      the limitation in range of motion (from 12.6 degrees +/-6.7 degrees at 2 weeks to
      51.4 degrees +/-5.4 degrees at 32 weeks). The myogenic restriction
      proportionately decreased over time (from 20.1 degrees +/-8.4 degrees at 2 weeks
      to only 0.8 degrees +/-7.2 degrees at 32 weeks). The increase in the arthrogenic
      component of contracture was predominant in extension. CONCLUSION: This study
      quantified the increasing role of arthrogenic changes in limiting the range of
      motion of joints after immobility, especially as the period of immobility
      extended past 2 weeks. These data provide a better understanding of joint
      contracture development and can be used to guide therapeutic approaches.

PMID- 10638869
TI  - Influencing factors and ambulation outcome in patients with dual disabilities of
      hemiplegia and amputation.
AB  - OBJECTIVE: To determine the ambulatory outcome and predictive factors of
      successful ambulation training in patients with both hemiplegia and lower
      extremity amputation. DESIGN: A retrospective study. SETTING: A rehabilitation
      center of a university hospital. PATIENTS: Twenty-three patients with dual
      disabilities consecutively admitted to the rehabilitation center from 1984 to
      1994. MAIN OUTCOME MEASURES: Ambulatory outcome was measured using physical
      therapists' and physicians' notes at discharge or the last available clinical
      visit. Ambulation ability was graded as community and noncommunity ambulation,
      which included indoor ambulation and nonambulation. Several clinical features
      were reviewed to assess their association with ambulation outcome. RESULTS: About
      two thirds of the 23 patients could be trained to be ambulatory: 10 (43.8%)
      achieved community ambulation and 5 (21.7%) achieved indoor ambulation. Of the
      clinical factors, only mental status showed a statistically significant
      association with good ambulation outcome (p<.05). When odds ratios were
      considered, several factors, including mild motor involvement, transtibial
      amputation, amputation before cerebrovascular accident, age younger than 60
      years, and the presence of ipsilateral hemiplegia and amputation, showed trends
      toward association with increased ambulation achievement, although these
      associations were not statistically significant. CONCLUSION: Impaired mental
      status seemed to be the most influential negative predictive factor of achieving
      community ambulation. If subjects with dual disabilities are properly selected,
      satisfactory results of ambulation training will be obtained.

PMID- 10638870
TI  - Bladder volume determination: portable 3-D versus stationary 2-D ultrasound
      device.
AB  - OBJECTIVE: To investigate how accurately a portable three-dimensional (3-D)
      scanner and a multipurpose two-dimensional (2-D) real-time scanner determined
      bladder volumes. STUDY DESIGN: Prospective, controlled clinical trial, single
      blind, crossover design. SETTING AND PARTICIPANTS: Twenty-three inpatients with
      permanent bladder catheters participated voluntarily in this study. METHODS: The
      bladders of 20 patients were filled through an indwelling catheter with 60, 110,
      160, 210, and 260 mL sterile normal saline. Volumes were measured twice with each
      device. Measurements were compared with the actual bladder volumes. RESULTS: The
      2-D device showed better reproducibility, particularly at lower bladder volumes.
      The 3-D scanner showed a significant difference between the two measurements at
      160 mL (p<.05) and had poor reproducibility at 110, 210, and 260 mL. Both devices
      overestimated actual bladder volume at fillings of <160 mL and underestimated it
      at fillings of > or =160 mL. The range between the 25th and 75th percentiles was
      always larger for the 3-D scanner, except for the 210 mL reading. CONCLUSION:
      Both devices showed sufficient accuracy for clinical practice. Ultrasound
      measurements of >110 mL should be followed by catheterization to detect
      potentially harmful bladder volumes.

PMID- 10638871
TI  - Urinary incontinence and stroke outcomes.
AB  - OBJECTIVE: To examine the relation of urinary incontinence to functional status
      and discharge destination in stroke rehabilitation patients. DESIGN: Historical
      cohort. SETTING: Freestanding, not-for-profit rehabilitation hospital.
      PARTICIPANTS: Nonrandom sampling. The charts of all admissions to the stroke
      rehabilitation unit were screened to identify patients with a medical diagnosis
      of completed stroke occurring 2 to 4 weeks before admission to rehabilitation,
      documented evidence of urinary incontinence at least daily the first 2 days after
      admission, and Functional Independence Measure (FIM) bladder sphincter score of 5
      or less. Ninety patients met the inclusion criteria. MAIN OUTCOME MEASURES: FIM,
      change in FIM scores from admission to discharge, weekly FIM gains, and discharge
      destination. RESULTS: Continence status at discharge was not associated with
      discharge destination, but did predict total FIM score at discharge and the
      change in FIM scores from admission to discharge. Subjects who regained
      continence had higher weekly FIM gains on all subscales except Communication. A
      critical area of difference between the groups was in Social Cognition scores.
      The time interval from stroke greatly influenced the findings; in patients
      evaluated 14 to 18 days after stroke differences between continent and
      incontinent subjects were found only in Social Cognition scores, whereas in
      patients evaluated 27 to 30 days after stroke differences were found in Self-Care
      and Sphincter Control scores. CONCLUSION: Further investigation into cognitive
      characteristics should be undertaken with a more comprehensive tool appropriate
      for an impaired population.

PMID- 10638872
TI  - Active and passive scapulohumeral movement in healthy persons: a comparison.
AB  - OBJECTIVES: Clinical studies investigating shoulder complaints have found that
      active exercises and passive manipulation are not equally effective treatments,
      perhaps because active and passive movements align the individual shoulder girdle
      components differently. This study sought to investigate whether a significant
      difference exists in scapulohumeral rhythm of the healthy shoulder when the
      humerus is elevated actively or passively. STUDY DESIGN: Both shoulders of 10
      healthy volunteers (9 men; mean age 50 yrs) were studied using an electromagnetic
      coordinate system to locate the position of the scapula relative to the humerus
      and trunk. Scapula position in three dimensions was recorded at 10 degrees
      intervals during active and passive humeral elevation in the coronal plane
      between 10 degrees and 50 degrees. Each shoulder was measured three times.
      RESULTS: Analysis of variance showed that in all three planes of scapula movement
      (lateral rotation, backward tip, and retraction) the components of variance
      attributable to the differences in active and passive movement were less than 5%.
      CONCLUSIONS: During humeral elevation between 10 degrees and 50 degrees no
      significant difference exists between active and passive shoulder complex motion
      in healthy individuals. These findings may help to explain why passive
      manipulation is an effective treatment for shoulder complaints.

PMID- 10638873
TI  - Back and hip extensor activities during trunk flexion/extension: effects of low
      back pain and rehabilitation.
AB  - OBJECTIVE: To compare lumbar paraspinal, gluteus maximus, and biceps femoris
      muscle function during sagittal trunk flexion and extension in patients with
      chronic low back pain and healthy control subjects, and to assess the influence
      of rehabilitation in the back pain patients. DESIGN: A cross-sectional study
      comparing chronic low back pain patients and healthy controls, and a prospective
      follow-up in back pain patients during rehabilitation. SETTING: Physical medicine
      and rehabilitation clinic. SUBJECTS: Nineteen women with chronic low back pain,
      and 19 women without pain (controls). INTERVENTION: Five-week active outpatient
      rehabilitation (1 hour three times a week) guided by a physiotherapist, followed
      by 5-week self-motivated exercise at home. OUTCOME MEASURES: Subjects performed
      sagittal trunk flexion and extension while surface electromyogram was bilaterally
      recorded of paraspinal (L1-L2 level), gluteus maximus, and biceps femoris
      muscles. The muscle activity was assessed from the average electromyogram and the
      relative muscle activation onsets and their duration were calculated. RESULTS:
      During early flexion, lumbar paraspinal and biceps femoris were activated
      simultaneously before gluteus maximus. At the end of flexion and during extension
      all investigated muscles were activated and relaxed in order. Lumbar paraspinal
      and biceps femoris muscles were activated in a similar order in low back pain
      patients and healthy controls during flexion and extension. However, the duration
      of gluteus maximus activity was shorter in the back pain patients than in
      controls during the trunk flexion (p<.05), and it ended earlier during extension.
      Active rehabilitation did not change the muscle activities of lumbar paraspinal
      and biceps femoris in the back pain patients, but in the measurements after
      rehabilitation the onset of gluteus maximus activity occurred later in flexion
      and earlier in extension. CONCLUSIONS: The activity of the gluteus maximus muscle
      during the flexion-extension cycle was reduced in patients with chronic low back
      pain. The gluteal muscles should be taken into consideration in the
      rehabilitation of these patients.

PMID- 10638874
TI  - Compensatory advantages of toe walking.
AB  - OBJECTIVES: The study's hypothesis is that toe walking requires less peak muscle
      strength distally about the ankle and knee compared with normal heel-toe walking
      and thus may have compensatory advantages for patients with upper motor neuron
      injury and distal muscle weakness. DESIGN: Motion analysis and force platform
      data were collected in able-bodied subjects during toe walking and normal
      walking. Sagittal plane joint torques reflecting muscle force requirements and
      joint powers reflecting nonisometric muscle contraction were compared between the
      two conditions using paired t tests, applying a Bonferroni correction for
      multiple comparisons. SETTING: A gait laboratory. SUBJECTS: Seventeen able-bodied
      adults, 9 of whom were ballet dancers. MAIN OUTCOME MEASURES: Peak hip, knee, and
      ankle joint torque and power variables during walking. RESULTS: Peak ankle
      plantarflexor torque and ankle power generation during terminal stance and
      preswing were reduced (p<.001), as compared with normal heel-toe walking. The
      normal ankle dorsiflexor torque at initial contact-and the knee extensor torque
      and knee power generation during loading response were all essentially absent
      during toe walking. Hip extensor torque and hip power generation during the
      loading response phase were greater for toe walking (p<.001). CONCLUSION: Toe
      walking may require less ankle plantarflexor, ankle dorsiflexor, and knee
      extensor strength than normal heel-toe walking and thus may have compensatory
      advantages for patients with upper motor neuron injury and distal lower extremity
      weakness.

PMID- 10638875
TI  - Intrasession reliability of the "center of pressure minus center of mass"
      variable of postural control in the healthy elderly.
AB  - OBJECTIVES: To estimate the intrasession reliability of a single measure of the
      biomechanical variable "center of pressure minus center of mass" (COP-COM) to
      determine, first, how many trials must be averaged to obtain a reliable measure
      of postural stability, and second, the minimal metrically detectable change of
      the COP-COM. PARTICIPANTS: Community-living, healthy, elderly people over 60
      years of age (n = 7). DESIGN: Measurements were made in double leg stance, eyes
      open condition. Nine successive trials, with rests between, were carried out for
      each subject. DATA ANALYSIS: Intraclass correlation coefficients (ICCs). MAIN
      OUTCOME MEASURE: The biomechanical variable COP-COM, which represents the
      distance between the center of pressure and the center of mass, was measured from
      two force platforms and three position sensors. RESULTS: The ICCs obtained for
      one measure of the COP-COM were .79 in the anterior-posterior (AP) direction and
      .69 in mediolateral (ML) direction. With four trials, the COP-COM variable is
      reliable at .94 in the AP direction and .90 in the ML direction. Minimal
      metrically detectable changes were .10 mm (AP) and .16 mm (ML). CONCLUSION: Using
      four repetitions of the COP-COM variable provides a reliable measurement of
      postural stability.

PMID- 10638876
TI  - Adjuvant physical therapy versus occupational therapy in patients with reflex
      sympathetic dystrophy/complex regional pain syndrome type I.
AB  - OBJECTIVE: To investigate the effectiveness and cost of physical therapy (PT) or
      occupational therapy (OT) in patients with reflex sympathetic dystrophy (RSD).
      DESIGN: Prospective randomized controlled trial, with 1 year follow-up. SETTING:
      Two university hospitals. PATIENTS: One hundred thirty-five patients who had been
      suffering from RSD of one upper extremity for less than 1 year. INTERVENTIONS:
      Patients were assigned to PT, OT, or a control group (social work). MAIN OUTCOME
      MEASURES: Improvement in impairment level sumscore (ISS) over 1 year (Student's t
      test). A difference of 5 ISS points between the groups was defined as being
      clinically relevant. Furthermore, severity of disability and handicap was
      measured and tested exploratively (Wilcoxon; alpha = .05), and cost-effectiveness
      of the groups was calculated. RESULTS: PT and, to a lesser extent, OT resulted in
      a significant and also more rapid improvement in the ISS as compared with
      controls (6 and 4 ISS points, respectively). On a disability level, a positive
      trend was found in favor of OT. On a handicap level, no differences were found
      between the groups. PT had an advantage over OT regarding the cost-effectiveness
      ratio. CONCLUSION: In different ways PT and OT each contribute to the recovery
      from RSD of the upper extremity.

PMID- 10638877
TI  - Interrater reliability of judgments of the centralization phenomenon and status
      change during movement testing in patients with low back pain.
AB  - OBJECTIVE: To determine the interrater reliability of judgments of status change,
      including the centralization phenomenon during examination of the lumbar spine,
      and to determine the effects of training and experience on reliability. DESIGN: A
      videotape study of judgments by physical therapists and physical therapy students
      of the results of movement testing during the examination of patients with low
      back pain. SETTING: Outpatient physical therapy clinic. PATIENTS: Patients
      receiving physical therapy treatment for low back pain. INTERVENTION: Patients
      with low back pain were videotaped while performing a variety of movement tests
      including single, repeated, and sustained movements. Forty licensed physical
      therapists and 40 physical therapy students were provided with operational
      definitions of the three potential judgments of status change with movement
      testing; centralization, peripheralization, status quo. All therapists and
      students viewed the videotape and made a judgment regarding the patient's status
      change in response to the test. MAIN OUTCOME MEASURE: Percentage agreement and
      kappa coefficient values for agreement. RESULTS: Interrater reliability was
      excellent for the total sample of examiners (kappa = .793), for the licensed
      physical therapists (kappa = .823), and for the students (kappa = .763).
      CONCLUSIONS: Judgments of status change are reliable when operational definitions
      are provided. Clinical experience does not appear to substantially improve
      reliability.

PMID- 10638878
TI  - Total head excursion and resting head posture: normal and patient comparisons.
AB  - OBJECTIVE: To determine whether significant differences existed between normal
      and patient groups on three postural measurements: anterior-posterior total head
      excursion (THE), resting head posture in sitting (RHPsit), and resting head
      posture in standing (RHPstd). SUBJECTS: Forty-two healthy subjects, 13 men and 29
      women between the ages of 20 and 60 years, were matched to 42 patients according
      to gender and age. DESIGN: Measurements of THE, RHPsit, and RHPstd were taken for
      each subject. Patients were measured during their initial evaluation and had neck
      pain as a primary or secondary complaint. RESULTS: A two-way multivariate
      analysis of variance followed by two-way analyses of variance showed that normal
      subjects had a significantly (p<.05) greater THE than did the patients and that
      men (patients and controls) scored significantly higher (p<.05) than women
      (patients and controls) on both THE and RHPstd. CONCLUSION: Clinical assessment
      of patients with cervical pain should focus on cervical mobility rather than
      resting head posture. Head/neck posture is different for males and females and
      they should not be judged by the same standard.

PMID- 10638879
TI  - Muscle activation after supervised exercises in patients with rotator tendinosis.
AB  - OBJECTIVE: To determine whether pain reduction induced by supervised exercises
      over several months results in increased maximal force and muscle activation.
      DESIGN: Before-after trial. PARTICIPANTS: Ten patients with unilateral rotator
      tendinosis and more than 3 months' duration of pain. INTERVENTION: Supervised
      exercises for 3 to 6 months. OUTCOME MEASURES: Maximal abduction force, muscle
      activation by surface electromyogram (EMG), and pain were assessed during brief
      maximal voluntary isometric contractions (MVC) before and after fatigue. EMG and
      pain were assessed during sustained submaximal contraction, performed with the
      shoulder 45 degrees abducted. The testing protocol was performed before and after
      supervised exercises. RESULTS: In the afflicted shoulder, resting pain was
      reduced after supervised exercises and no longer differed from the unafflicted
      side. The increase in pain during contraction was almost the same before and
      after treatment. MVC force increased, but significant side differences remained.
      EMG increased for trapezius and deltoid muscles in both afflicted and unafflicted
      arms. Fatigue development and recovery was unaltered by the exercise regimen.
      CONCLUSIONS: Pain reduction after supervised exercises was associated with an
      improved MVC force, but the side difference in maximal force generation was
      maintained. Muscle activity during maximal contraction increased in both the
      afflicted and unafflicted sides.

PMID- 10638880
TI  - The relation between stress fractures and bone mineral density: evidence from
      active-duty Army women.
AB  - OBJECTIVE: To determine if bone mineral density (BMD) is associated with the
      probability of stress fractures in premenopausal women. DESIGN: Case-control
      study. SETTING: Large Army post, Fort Lewis, WA. PARTICIPANTS: Twenty-seven
      active duty Army women with documented stress fractures within the last 2 years
      and 158 female controls. METHODS AND MAIN RESULTS: All subjects were examined and
      interviewed. BMD of the femoral neck and posteroanterior lumbar spine (L2-L4) was
      measured using dual energy X-ray absorptiometry. Univariate comparisons revealed
      no significant differences in BMD of the femoral neck or lumbar spine between
      groups. Women with stress fractures had a significantly higher exercise intensity
      (428 vs 292 minutes per week, p<.05) and were more likely to be entry-level
      enlisted soldiers (63% vs. 44%, p<.05) than those without stress fractures.
      Multivariate analyses revealed a strong negative association between femoral neck
      BMD and the probability of stress fractures (lower BMD, higher risk). Exercise
      intensity and body mass index had a significant positive effect on BMD of the
      femoral neck and lumbar spine, yet both were associated with an increased
      probability of stress fractures. CONCLUSIONS: Femoral neck BMD was significantly
      associated with the probability of stress fractures. Optimal training programs
      should balance the beneficial indirect effect of increased exercise (through
      increased BMD) with its detrimental direct effect on stress fractures.

PMID- 10638881
TI  - Electrically stimulated elbow extension in persons with C5/C6 tetraplegia: a
      functional and physiological evaluation.
AB  - OBJECTIVE: To measure the effect of electrically stimulated triceps on elbow
      extension strength, range of motion, and the performance of overhead reaching
      tasks. SETTING: Clinical research laboratory. PARTICIPANTS: Four individuals with
      spinal cord injuries at the C5 or C6 motor level. INTERVENTIONS: The
      participants, who already had an implanted upper extremity neuroprosthesis, were
      provided with elbow extension through functional electrical stimulation (FES) of
      the triceps brachii. MAIN OUTCOME MEASURES: Comparisons of stimulated elbow
      extension to voluntary elbow extension: (1) evaluations of impairment such as
      range of motion and strength; (2) performance of a set of functional overhead
      reaching tasks that required elbow extension; (3) a usage survey (conducted by
      telephone) to examine use of triceps stimulation in the home and community.
      RESULTS: All participants achieved greater range of motion and strength of elbow
      extension with stimulated triceps versus without. Overall functional task
      performance improved in 100% of the tasks tested for all but one participant, who
      showed improvement in 60% of the tasks. Participants reported using the triceps
      in at least one activity for at least 90% of the days the neuroprosthesis was
      donned.

PMID- 10638882
TI  - Organizational strategy influence on visual memory performance after stroke:
      cortical/subcortical and left/right hemisphere contrasts.
AB  - OBJECTIVE: To examine how organizational strategy at encoding influences visual
      memory performance in stroke patients. DESIGN: Case control study. SETTING:
      Postacute rehabilitation hospital. PARTICIPANTS: Stroke patients with right
      hemisphere damage (n = 20) versus left hemisphere damage (n = 15), and stroke
      patients with cortical damage (n = 11) versus subcortical damage (n = 19). MAIN
      OUTCOME MEASURES: Organizational strategy scores, recall performance on the Rey
      Osterrieth Complex Figure (ROCF). RESULTS: Results demonstrated significantly
      greater organizational impairment and less accurate copy performance (i.e.,
      encoding of visuospatial information on the ROCF) in the right compared to the
      left hemisphere group, and in the cortical relative to the subcortical group.
      Organizational strategy and copy accuracy scores were significantly related to
      each other. The absolute amount of immediate and delayed recall was significantly
      associated with poor organizational strategy scores. However, relative to the
      amount of visual information originally encoded, memory performances did not
      differ between groups. CONCLUSIONS: These findings suggest that visual memory
      impairments after stroke may be caused by a lack of organizational strategy
      affecting information encoding, rather than an impairment in memory storage or
      retrieval.

PMID- 10638883
TI  - A kinematic study of contextual effects on reaching performance in persons with
      and without stroke: influences of object availability.
AB  - OBJECTIVE: To examine the effects of context on reaching performance in
      neurologically impaired and intact populations. Context was varied by the
      presence or absence of objects used to complete a task. DESIGN: A counterbalanced
      repeated-measures design. SETTING: A motor control laboratory in a university
      setting. PARTICIPANTS: Fourteen persons with stroke and 25 neurologically intact
      adults. INTERVENTIONS: Each participant was tested under two conditions: the
      presence of the object, in which the participant reached forward with the
      impaired arm (or corresponding arm) to scoop coins off the table into the other
      hand; and the absence of the object, in which the participant reached forward to
      the place where the coins would be placed in the condition of object present.
      MAIN OUTCOME MEASURES: Kinematic Variables of movement time, total displacement,
      peak velocity, percentage of reach where peak velocity occurs, and movement units
      (derived from acceleration data) for reaching tasks. RESULTS: The condition of
      using real objects elicited kinematically better performance of reaching
      movements than the condition of performing movements without relevant objects
      present. Better performance was reflected by shorter movement time, less total
      displacement, higher peak velocity, greater percentage of reach where peak
      velocity occurs, and fewer movement units. CONCLUSION: The results of this study
      showed that the condition of object present elicited better performance of
      movements represented by kinematic variables than the condition of object absent.
      The clinical implication is that the use of real and functional objects might be
      an effective way of facilitating efficient, smooth, and coordinated movement with
      the impaired arm in persons with stroke. This study, however, should be
      replicated and extended to confirm the validity of its findings and to allow for
      generalization in various functional activities.

PMID- 10638884
TI  - Endurance training in patients with chronic obstructive pulmonary disease: a
      comparison of high versus moderate intensity.
AB  - PURPOSE: To create a maximum tolerated 45-minute aerobic training program for
      patients with chronic obstructive pulmonary disease (COPD) and to compare its
      outcomes with those of commonly prescribed moderate exercise. DESIGN:
      Prospective, randomized trial. SETTING: A work physiology laboratory. PATIENTS
      AND METHODS: The maximum exercise intensities that 7 COPD patients could sustain
      for 45 minutes were determined on a bilevel exercise ergometer. The patients then
      exercised 45 minutes daily, 5 days a week for 6 weeks, working 2.03+/-0.4 kJ/kg
      per session. They were matched with 6 COPD patients who pushed an O2 cart for 45
      minutes daily, 5 days a week for 6 weeks, working 1.44+/-.35 kJ/kg per session.
      RESULTS: A 45 minute maximal regimen was established by alternating 1-minute peak
      exercise at peak VO2-levels with 4 minutes at the ventilatory anaerobic threshold
      or at 40% of peak VO2. Maximal bilevel training significantly decreased dyspnea
      at rest (p< or =.01) and the blood lactate level during submaximal exercise
      (p<.001), and increased peak VO2 and total physical work (p<.01), maximum
      inspiratory and expiratory pressures (p<.01), and grip and forearm strength and
      endurance (p<.01). The training also increased maximum voluntary ventilation
      while decreasing the ventilatory equivalent during exercise (p<.001). The O2 cart
      pushers significantly improved only on the 12-minute walk (p<.05). CONCLUSIONS: A
      maximally intense anaerobic exercise program can be created for most COPD
      patients that can significantly improve both skeletal and respiratory muscle
      strength and endurance as well as dyspnea and physiologic parameters.

PMID- 10638885
TI  - Goal-directed secondary motor tasks: their effects on gait in subjects with
      Parkinson disease.
AB  - OBJECTIVE: To investigate the effects of secondary motor tasks of three levels of
      difficulty on the spatial and temporal parameters of gait in subjects with
      Parkinson disease (PD) compared with control subjects. DESIGN: A two-group
      repeated measures design using a sample of convenience. Subjects performed 10
      meter gait trials walking (1) freely, (2) carrying a tray, and (3) carrying a
      tray with four plastic glasses. SETTING: Subjects were tested in the gait
      laboratory at Kingston Centre, Victoria, Australia. SUBJECTS: Twelve subjects
      with PD and 12 control subjects matched for age, height, and sex were recruited
      from the Movement Disorders Clinic at Kingston Centre. OUTCOME MEASURES: Gait
      speed, stride length, cadence, and the proportion of the walking cycle spent in
      double limb support were measured in moderately disabled subjects with PD and
      control subjects. RESULTS: For all of the walking conditions, subjects with PD
      walked more slowly (F(1,22) = 16.54, p = .001, partial nu2 = .429) and with
      shorter steps (F(1,22) = 15.07, p = .001, partial nu2 = .406) than control
      subjects. In addition there were significant group by condition interaction
      effects for gait speed (F(2, 44) = 4.42, p = .018, partial nu2 = .167) and stride
      length (F(2, 44) = 4.95, p = .012, partial nu2 = .184). There was little
      deterioration in gait when subjects in either group carried a tray while walking
      compared with free walking; however, when required to carry four plastic glasses
      on the tray while walking, subjects in the PD group showed marked deterioration
      in gait speed (t(11) = 3.19, p = .009, alpha = .025) and stride length (t(11) =
      3.82, p = .003, alpha = .025). Performance in the control subjects changed only
      marginally across the conditions. CONCLUSION: Subjects with moderate disability
      in PD experience considerable difficulty when they are required to walk while
      attending to a complex visuomotor task involving the upper limbs.

PMID- 10638886
TI  - Abnormal bone and calcium metabolism in patients after stroke.
AB  - OBJECTIVE: To review how mineral stores and endocrine factors affect bone mass in
      poststroke patients immobilized by hemiparesis. DATA SOURCES: Computer databases
      and published indexes. STUDY SELECTION: Case-control studies of hemiparetic
      poststroke patients examined regarding bone metabolism. DATA EXTRACTION:
      References were obtained from MEDLINE; all data concerning the objective were
      used. DATA SYNTHESIS: Bone loss occurs in affected extremities after stroke.
      Immobilization from hemiplegia causes hypercalcemia. Insufficiency or deficiency
      of 25-hydroxyvitamin D (25-OHD) is very common in stroke patients and may be
      caused by poor dietary intake, decreased sunlight exposure, or both. Compensatory
      hyperparathyroidism may not occur because hypercalcemia inhibits the parathyroid
      glands even when 25-OHD is in the insufficient range. However,
      hyperparathyroidism does occur when 25-OHD is in the deficient range, in which
      case the parathyroid response to hypovitaminosis D overrides effects of
      hypercalcemia. Increased bone resorption was observed during the first year after
      stroke, declining to normal during the second year. During the first year,
      determinants of bone mineral density (BMD) in hands affected by hemiplegia were
      age, severity of hemiplegia, duration of paralysis, serum calcium concentration,
      and 25-OHD concentration. In the second year, BMD determinants on the hemiplegic
      side were severity of hemiplegia and 25-OHD concentration, whereas 25-OHD
      concentration was the only BMD determinant on the intact side. Administering
      1alpha-hydroxyvitamin D3, vitamin K2, or ipriflavone ameliorated osteopenia on
      both sides and decreased the frequency of hip fracture on the hemiplegic side.
      CONCLUSIONS: Bone remodeling and determinants of bone mass for the affected and
      unaffected sides after stroke differ between the first and subsequent years.

PMID- 10638887
TI  - Serum positive botulism with neuropathic features.
AB  - A 32-year-old man presented with multiple cranial neuropathies and his serum was
      positive for botulism type B. However, serial electrodiagnostic studies were
      consistent with a primarily neuropathic process, such as Fisher syndrome, rather
      than a neuromuscular junction disorder. Electrodiagnostic study findings in
      patients with presumed neuromuscular junction disorders may mimic findings
      suggestive of a neuropathic process, or the bioassay for botulism may be falsely
      positive in patients with Fisher Syndrome.

PMID- 10638888
TI  - Deep venous thrombosis and pulmonary embolism as a complication of bed rest for
      low back pain.
AB  - A case of bilateral lower extremity deep venous thrombosis and pulmonary embolism
      as a complication of bed rest prescribed for an acute low back pain episode is
      presented. A 29-year-old woman with low back pain was prescribed more than 2
      weeks of bed rest, during which she developed progressive bilateral lower
      extremity complaints that were ascribed to nerve root irritation. Her symptoms
      were initially treated with physical therapy and epidural steroid injections. A
      Doppler examination and ventilation-perfusion scan revealed extensive deep venous
      thromboses and mismatches consistent with pulmonary embolism. This case
      illustrates an unusual extraspinal source of lower extremity symptoms associated
      with low back pain and further supports the role of early mobilization in the
      treatment of back pain.

PMID- 10638889
TI  - Intraoperative SSEP detection of ulnar nerve compression or ischemia in an obese
      patient: a unique complication associated with a specialized spinal retraction
      system.
AB  - OBJECTIVE: To report a case of peripheral nerve compression caused by a
      specialized spinal retraction system, the Thompson-Farley retractor system, that
      most likely would not have been detected without intraoperative monitoring of the
      ulnar nerve. DESIGN: Bilateral median and peroneal nerve somatosensory evoked
      potentials (SSEPs) were monitored continuously during a C5 corpectomy, as was
      core body temperature. RESULTS: Within minutes after cervical soft-tissue
      retraction, the left ulnar nerve SSEP began to decline in amplitude. Peroneal
      nerve SSEPs were normal throughout the surgery; core body temperature remained at
      36 degrees +/- 0.2 degrees C. After much effort to reposition the patient, the
      SSEPs returned to baseline and the Thompson-Farley system was replaced by a self
      retracting system. CONCLUSIONS: To our knowledge, this is the first report of
      peripheral nerve compression caused by the Thompson-Farley retractor system. Even
      with careful positioning on the operating table, obese patients may be
      particularly at risk for upper arm compression. Continuous monitoring of SSEPs is
      suggested to prevent postoperative morbidity.

PMID- 10638890
TI  - Halogenated anesthetics and human myocardium.

PMID- 10638891
TI  - Use and abuse of neonatal neurobehavioral testing.

PMID- 10638892
TI  - Minidose bupivacaine-fentanyl spinal anesthesia for surgical repair of hip
      fracture in the aged.
AB  - BACKGROUND: Spinal anesthesia for surgical repair of hip fracture in the elderly
      is associated with a high incidence of hypotension. The synergism between
      intrathecal opioids and local anesthetics may make it possible to achieve
      reliable spinal anesthesia with minimal hypotension using a minidose of local
      anesthetic. METHODS: Twenty patients aged > or = 70 yr undergoing surgical repair
      of hip fracture were randomized into two groups of 10 patients each. Group A
      received a spinal anesthetic of bupivacaine 4 mg plus fentanyl 20 microg, and
      group B received 10 mg bupivacaine. Hypotension was defined as a systolic
      pressure of < 90 mmHg or a 25% decrease in mean arterial pressure from baseline.
      Hypotension was treated with intravenous ephedrine boluses 5-10 mg up to a
      maximum 50 mg, and thereafter by phenylephrine boluses of 100-200 microg.
      RESULTS: All patients had satisfactory anesthesia. One of 10 patients in group A
      required ephedrine, a single dose of 5 mg. Nine of 10 patients in group B
      required vasopressor support of blood pressure. Group B patients required an
      average of 35 mg ephedrine, and two patients required phenylephrine. The lowest
      recorded systolic, diastolic, and mean blood pressures as fractions of the
      baseline pressures were, respectively, 81%, 84%, and 85% versus 64%, 69%, and 64%
      for group A versus group B. CONCLUSIONS: A "minidose" of 4 mg bupivacaine in
      combination with 20 microg fentanyl provides spinal anesthesia for surgical
      repair of hip fracture in the elderly. The minidose combination caused
      dramatically less hypotension than 10 mg bupivacaine and nearly eliminated the
      need for vasopressor support of blood pressure.

PMID- 10638893
TI  - Cerebral hemodynamic effects of morphine and fentanyl in patients with severe
      head injury: absence of correlation to cerebral autoregulation.
AB  - BACKGROUND: The current study investigates the effects of morphine and fentanyl
      upon intracranial pressure and cerebral blood flow estimated by cerebral
      arteriovenous oxygen content difference and transcranial Doppler sonography in 30
      consecutive patients with severe head injury in whom cerebrovascular
      autoregulation previously had been assessed. METHODS: Patients received morphine
      (0.2 mg/kg) and fentanyl (2 microg/kg) intravenously over 1 min but 24 h apart in
      a randomized fashion. Before study, carbon dioxide reactivity and autoregulation
      were assessed. Intracranial pressure, mean arterial blood pressure, and cerebral
      perfusion pressure were repeatedly monitored for 1 h after the administration of
      both opioids. Cerebral blood flow was estimated from the reciprocal of
      arteriovenous oxygen content difference and middle cerebral artery mean flow
      velocity using transcranial Doppler sonography. RESULTS: Although carbon dioxide
      reactivity was preserved in all patients, 18 patients (56.7%) showed impaired or
      abolished autoregulation to hypertensive challenge, and only 12 (43.3%) had
      preserved autoregulation. Both morphine and fentanyl caused significant increases
      in intracranial pressure and decreases in mean arterial blood pressure and
      cerebral perfusion pressure, but estimated cerebral blood flow remain unchanged.
      In patients with preserved autoregulation, opioid-induced intracranial pressure
      increases were not different than in those with impaired autoregulation.
      CONCLUSIONS: The authors conclude that both morphine and fentanyl moderately
      increase intracranial pressure and decrease mean arterial blood pressure and
      cerebral perfusion pressure but have no significant effect on arteriovenous
      oxygen content difference and middle cerebral artery mean flow velocity in
      patients with severe brain injury. No differences on intracranial pressure
      changes were found between patients with preserved and impaired autoregulation.
      Our results suggest that other mechanisms, besides the activation of the
      vasodilatory cascade, also could be implicated in the intracranial pressure
      increases seen after opioid administration.

PMID- 10638894
TI  - Incidence of venous air embolism during craniectomy for craniosynostosis repair.
AB  - BACKGROUND: Investigations to determine the incidence of venous air embolism in
      children undergoing craniectomy for craniosynostosis repair have been limited,
      although venous air embolism has been suspected as the cause of hemodynamic
      instability and sometimes death. A precordial Doppler ultrasonic probe is an
      accepted method for detection of venous air embolism and is readily available at
      most institutions. METHODS: A prospective study was conducted using a precordial
      Doppler ultrasonic probe in children undergoing craniectomy for craniosynostosis
      repair. The Doppler signal was continuously monitored intraoperatively for
      characteristic changes of venous air embolism. A recording was made of the
      precordial Doppler probe pulses, which was later reviewed by a
      neuroanesthesiologist, blinded to the intraoperative events. This information was
      correlated with the intraoperative events and episodes of venous air embolism
      were graded. RESULTS: Twenty-three patients were enrolled in the study during the
      2-yr study period. Nineteen patients (82.6%) demonstrated 64 episodes of venous
      air embolism; six patients (31.6%) had hypotension associated with venous air
      embolism. Thirty-two episodes of hypotension were demonstrated in eight patients
      (34.7%). None of the patients developed cardiovascular collapse. CONCLUSION: The
      incidence of venous air embolism in our study of 23 children undergoing
      craniectomy for craniosynostosis was 82.6%. Though most episodes of venous air
      embolism during craniosynostosis repair are without hemodynamic consequences, the
      preemptive placement of a precordial Doppler ultrasonic probe is a noninvasive,
      economic, and safe method for the detection of venous air embolism. Prompt
      recognition may allow for the early initiation of therapy, thereby decreasing
      morbidity and mortality rates related to venous air embolism.

PMID- 10638895
TI  - Hemodynamic effects of synchronized high-frequency jet ventilation compared with
      low-frequency intermittent positive-pressure ventilation after myocardial
      revascularization.
AB  - BACKGROUND: The purpose of this prospective study was to examine the effect on
      cardiac performance of selective increases in airway pressure at specific points
      of the cardiac cycle using synchronized high-frequency jet ventilation (sync
      HFJV) delivered concomitantly with each single heart beat compared with
      controlled mechanical ventilation in 20 hemodynamically stable, deeply sedated
      patients immediately after coronary artery bypass graft. METHODS: Five 30-min
      sequential ventilation periods were used interspersing controlled mechanical
      ventilation with sync-HFJV twice to control for time and sequencing effects. Sync
      HFJV was applied using a driving pressure, which generated a tidal volume
      resulting in gas exchanges close to those obtained on controlled mechanical
      ventilation and associated with the maximal mixed venous oxygen saturation.
      Hemodynamic variables including cardiac output, mixed venous oxygen saturation
      and vascular pressures were recorded at the end of each ventilation period.
      RESULTS: The authors found that in 20 patients, hemodynamic changes induced by
      controlled mechanical ventilation and by sync-HFJV were similar. Cardiac index
      did not change (mean +/- SD for controlled mechanical ventilation: 2.6 +/- 0.7 l
      x min(-1) x m(-2); for sync-HFJV: 2.7 +/- 0.7 l x min(-1) x m(-2); P value not
      significant). This observation persisted after stratification according to
      baseline left-ventricular contractility, as estimated by ejection fraction.
      CONCLUSIONS: The authors conclude that after coronary artery bypass graft, if gas
      exchange values are maintained within normal range, sync-HFJV does not result in
      more favorable hemodynamic support than controlled mechanical ventilation. These
      findings contrast with the beneficial effects of sync-HFJV, resulting in marked
      hypocapnia, on cardiac performance observed in patients with terminal left
      ventricular failure.

PMID- 10638896
TI  - Neuromuscular effects of mivacurium in 2- to 12-yr-old children with burn injury.
AB  - BACKGROUND: Burned patients are usually resistant to the neuromuscular effects of
      nondepolarizing relaxants, mostly because of receptor changes. The magnitude of
      the resistance is related to burn size and time after burn. Mivacurium is a
      muscle relaxant, degraded by plasma cholinesterase, whose enzyme activity is
      decreased in burns. The present study tested the hypothesis that burn-induced
      depressed plasma cholinesterase activity counteracts the receptor-mediated
      resistance, resulting in a lack of resistance to mivacurium. METHODS: Burned
      patients (n = 23), aged 2-12 yr, subclassified into burns of 10-30% or > 30% of
      body surface, were studied at < or = 6 days and again at 1-12 weeks after burn if
      possible. Thirteen additional patients served as controls. Neuromuscular
      variables monitored included onset and recovery following bolus dose, continuous
      infusion rates required to maintain 95 +/- 4% paralysis, and recovery rates
      following infusion. RESULTS: The onset times of maximal twitch suppression were
      not different between burns and controls, but recovery to 25% of baseline twitch
      height was prolonged in patients with > 30% burn irrespective of time after
      injury. The continuous infusion rates to maintain twitch suppression at 95 +/- 4%
      were not different between groups. The recovery indices, including train-of-four
      to > 75%, 25-75%, or 5-95% in burned patients, were similar or prolonged compared
      with controls. The prolonged recovery in burned patients was inversely related to
      plasma cholinesterase activity (R2 = 0.86, r = -0.93, P < 0.001), and the
      decreased plasma cholinesterase activity was related to burn size and time after
      burn. CONCLUSIONS: A normal mivacurium dosage (0.2 mg/kg) effects good relaxation
      conditions in burned patients, with an onset time similar to that in controls.
      This finding contrasts with the response seen with other nondepolarizing drugs,
      higher doses of which are required to effect paralysis. The decreased metabolism
      of mivacurium, resulting from depressed plasma cholinesterase activity, probably
      counteracts the receptor-mediated potential for resistance. Because
      succinylcholine is contraindicated in burned patients, larger doses of
      nondepolarizing agents are advocated to effect rapid onset of paralysis. This
      generalization does not hold for mivacurium. diatrics; plasma cholinesterase;
      relaxant resistance; succinylcholine, alternative to.)

PMID- 10638897
TI  - Automated detection of gastric luminal partial pressure of carbon dioxide during
      cardiovascular surgery using the Tonocap.
AB  - BACKGROUND: A new automated system of air tonometry (Tonocap; Datex Ohmeda,
      Helsinki, Finland) allows for frequent (every 15 min) measurement of gastric
      luminal partial pressure of carbon dioxide. Its use has not been described in
      cardiac surgical patients. METHODS: One hundred patients undergoing coronary
      artery bypass graft or cardiac valve surgery were enrolled in a prospective
      cohort study. After anesthetic induction and insertion of a TRIP NGS Catheter
      (Datex Ohmeda), measurements of gastric luminal partial pressure of carbon
      dioxide were obtained using the Tonocap, and gastric mucosal pH (pHi) was
      calculated. The main outcome measure was postoperative complication, defined as
      either in-hospital death or prolonged postoperative hospitalization (> 14 days).
      RESULTS: Four patients (4%) died, all of multiple-system organ failure, one each
      on postoperative days 9, 26, 46, and 121. Postoperative complication occurred in
      18 patients (18%), all of whom exhibited persistent dysfunction of at least one
      organ system. Perioperatively, an abnormal pHi (< 7.32) and gastric luminal minus
      arterial partial pressure of carbon dioxide gap (> 8 mmHg) occurred in 66% and
      70% of patients, respectively. Predictors of postoperative complication included
      postoperative pHi (P = 0.001), gastric luminal partial pressure of carbon dioxide
      (P = 0.022), and gastric luminal minus arterial partial pressure of carbon
      dioxide gap (P = 0.013). In contrast, arterial base excess (P > 0.4) and
      routinely measured hemodynamic variables (e.g., heart rate, blood pressure) were
      either less predictive compared with Tonocap-derived variables or not predictive.
      CONCLUSIONS: Despite a low mortality rate, patients undergoing cardiac surgery
      exhibited high incidences of prolonged hospitalization and postoperative
      morbidity. The Tonocap was easy to use, particularly compared with saline
      tonometry. Several Tonocap-derived variables were predictive of postoperative
      complications consistent with previously published data using saline tonometry.

PMID- 10638898
TI  - Propofol for monitored anesthesia care: implications on hypoxic control of
      cardiorespiratory responses.
AB  - BACKGROUND: Hypoxia has a dual effect on ventilation: an initial period of
      hyperventilation, the acute hypoxic response, is followed after 3-5 min by a slow
      decline, the hypoxic ventilatory decline. Because of hypoxic ventilatory decline,
      subsequent acute hypoxic responses are depressed. In this study, the influence of
      a sedative concentration of propofol on ventilation was studied if hypoxia was
      sustained and intermittent. METHODS: Ten healthy young male volunteers performed
      two hypoxic tests without and with a target controlled infusion of propofol. The
      sustained hypoxic test consisted of 15 min of isocapnic hypoxia followed by 2 min
      of normoxia and 3 min of hypoxia. The test of hypoxic pulses involved six
      subsequent exposures to 3 min hypoxia followed by 2 min of normoxia. The
      bispectral index of the electroencephalogram was measured to obtain an objective
      measure of sedation. RESULTS: Blood propofol concentrations varied among subjects
      but were stable over time (mean blood concentration 0.6 microg/ml). The sustained
      hypoxic test showed that propofol decreased acute hypoxic response by
      approximately 50% and that the magnitude of hypoxic ventilatory decline relative
      to acute hypoxic response was increased by > 50%. Propofol increased the
      depression of the acute hypoxic response after 15 min of hypoxia by approximately
      25%. In control and propofol studies, no hypoxic ventilatory decline was
      generated during exposure to hypoxic pulses. The bispectral index-acute hypoxic
      response data suggest that subjects were either awake (with minimal effect on
      acute hypoxic response) or sedated (with 50-60% reduction of acute hypoxic
      response). CONCLUSIONS: The depression of acute hypoxic response results from an
      effect of propofol at peripheral or central sites involved in respiratory control
      or secondary to the induction of sedation or hypnosis by propofol. The relative
      increase in hypoxic ventilatory decline is possibly related to propofol's action
      at the gamma-aminobutyric acid A (GABA(A)) receptor complex, causing increased
      GABAergic inhibition of ventilation during sustained (but not intermittent)
      hypoxia.

PMID- 10638899
TI  - Influence of age on hypnotic requirement, bispectral index, and 95% spectral edge
      frequency associated with sedation induced by sevoflurane.
AB  - BACKGROUND: Aging is associated with a reduction in anesthetic requirements. The
      effects of age on the electroencephalographic response to inhalational anesthesia
      have not been well documented. The objective of the present study was to
      determine the influence of age on hypnotic requirement and
      electroencephalographic derivatives such as bispectral index and 95% spectral
      edge frequency associated with sedation induced by sevoflurane. METHODS: Ninety
      six patients were randomly allocated into one of three age groups A, B, and C,
      ranging in age from 18-39 yr, 40-64 yr, and 65-85 yr, respectively. Patients in
      each group were sedated with sevoflurane at two predetermined concentrations
      ranging between 0.45% and 0.85%. The relationship between sevoflurane
      concentration and response to a verbal command, as well as the relationships
      between response and bispectral index and 95% spectral edge frequency, was
      determined. RESULTS: Multiple regression analysis showed that end-tidal
      sevoflurane concentration and age significantly affected both bispectral index
      and 95% spectral edge frequency. ED50 values of sevoflurane concentration for
      loss of consciousness, defined as no response to verbal command, were different
      between groups A and C: 0.72 (95% confidence interval: 0.68-0.75) versus 0.59
      (95% confidence interval: 0.56-0.62). However, the same effective values of
      bispectral index and 95% spectral edge frequency at this same clinical end point
      did not differ. CONCLUSIONS: Increasing age reduced sevoflurane requirements to
      suppress responses to a verbal command but did not change bispectral index and
      95% spectral edge frequency associated with this end point, and in a population
      with a wide age range, bispectral index would predict depth of sedation better
      than end-tidal sevoflurane concentration.

PMID- 10638901
TI  - Left-molar approach improves the laryngeal view in patients with difficult
      laryngoscopy.
AB  - BACKGROUND: The molar approach of laryngoscopy is reported to improve glottic
      view in sporadic cases of difficult laryngoscopy. The authors studied the effect
      of molar approaches and optimal external laryngeal manipulation (OELM) using the
      Macintosh blade. METHODS: A series of 1,015 adult patients who underwent general
      anesthesia and tracheal intubation was studied. Laryngoscopy was carried out
      using a Macintosh no. 3 or 4 standard blade. Three consecutive trials of direct
      laryngoscopy using the midline and left- and right-molar approaches were carried
      out under full muscle relaxation with optimal head and neck positioning. The best
      glottic views were recorded for each approach with and without OELM. RESULTS:
      Difficult laryngoscopy with a midline approach accounted for 6.5% (66 cases)
      before OELM and 1.97% (20 cases) after OELM. A left-molar approach with OELM
      further reduced difficult laryngoscopy to seven cases (P < 0.001 vs. midline
      approach with OELM); a right-molar approach with OELM reduced difficult
      laryngoscopy to 18 cases (P = 0.48). CONCLUSIONS: The left-molar approach with
      OELM improves the laryngeal view in patients with difficult laryngoscopy.

PMID- 10638900
TI  - Effect of epidural blockade on protein, glucose, and lipid metabolism in the
      fasted state and during dextrose infusion in volunteers.
AB  - BACKGROUND: To interpret correctly the results from studies performed during
      surgery and anesthesia it is necessary to dissect the separate effect of the
      anesthetic technique itself. The purpose of this study was to investigate the
      metabolic effects of epidural blockade (T7-S1) with bupivacaine 0.25% after 12 h
      fasting and during administration of 4 mg x kg(-1) x min(-1) dextrose in six
      healthy volunteers. METHODS: Each volunteer was assigned to randomly undergo a 6
      h multiple stable isotope infusion study (3 h fasted, 3 h dextrose infusion) with
      or without epidural blockade. L-[1-13C]leucine, [6,6-2H2]glucose, and [1,1,2,3,3
      2H5]glycerol were infused to measure protein synthesis, breakdown, and amino acid
      oxidation; glucose production and clearance; and lipolysis. Plasma concentrations
      of glucose, lactate, glycerol, free fatty acids, insulin, and glucagon were
      determined. RESULTS: Epidural blockade with bupivacaine had no influence on
      protein oxidation, breakdown and synthesis, glucose production, glucose clearance
      and lipolysis in the fasted state. Plasma concentrations of metabolic substrates
      and hormones also were not affected. Dextrose infusion significantly increased
      glucose clearance and plasma concentrations of glucose and insulin, while
      endogenous glucose production and lipolysis decreased to a similar degree in both
      groups. Protein synthesis, breakdown, and oxidation did not change during
      dextrose infusion. CONCLUSIONS: Epidural blockade with bupivacaine in the absence
      of surgery has no effect on fasting protein, glucose, and lipid metabolism.
      Epidural blockade does not modify the inhibitory influence of dextrose
      administration on endogenous glucose production and lipolysis.

PMID- 10638902
TI  - Concentration-effect relationship of intravenous lidocaine on the allodynia of
      complex regional pain syndrome types I and II.
AB  - BACKGROUND: Several lines of evidence suggest that neuropathic pain (including
      Complex Regional Pain Syndrome [CRPS] I and CRPS II) is mediated in part by an
      increase in the density of voltage-sensitive sodium channels in injured axons and
      the dorsal root ganglion of injured axons. This study sought to characterize the
      effects of intravenous lidocaine (a sodium channel blocker) on acute sensory
      thresholds within the painful area and the size of the painful area in patients
      suffering from CRPS I and II. METHODS: This study used a randomized, double
      blind, placebo-controlled design in 16 subjects suffering from CRPS I and II with
      a prominent allodynia. Each subject received an intravenous infusion of lidocaine
      and diphenhydramine separated by 1 week. A computer-controlled infusion pump
      targeted stair-step increases in plasma levels of lidocaine of 1, 2, and 3
      microg/ml. At baseline and at each plasma level, spontaneous and evoked pain
      scores and neurosensory testing within the painful area were measured. The
      neurosensory testing consisted of thermal thresholds, tactile thresholds and the
      area of allodynia to punctate, and stroking and thermal stimuli. RESULTS:
      Intravenous lidocaine and diphenhydramine had no significant effect on the cool,
      warm, or cold pain thresholds. However, lidocaine caused a significant elevation
      of the hot pain thresholds in the painful area. Intravenous lidocaine caused a
      significantly decreased response to stroking and cool stimuli in the allodynic
      area. There was also a significant decrease in pain scores to cool stimuli at all
      plasma levels and the spontaneous pain at the highest plasma level. CONCLUSIONS:
      This study demonstrates that intravenous lidocaine affects pain in response to
      cool stimuli more than mechanical pain in subjects with neuropathic pain. There
      is a lesser effect on spontaneous pain and pain induced by stroking stimuli and
      no effect on the pain induced by punctate stimuli.

PMID- 10638903
TI  - Temperature-dependent pharmacokinetics and pharmacodynamics of vecuronium.
AB  - BACKGROUND: The authors evaluated the influence of temperature on the
      pharmacokinetics and pharmacodynamics of vecuronium because mild core hypothermia
      doubles its duration of action. METHODS: Anesthesia was induced with alfentanil
      and propofol and maintained with nitrous oxide and isoflurane in 12 healthy
      volunteers. Train-of-four stimuli were applied to the ulnar nerve, and the
      mechanical response of the adductor pollicis was measured. Volunteers were
      actively cooled or warmed until their distal esophageal temperatures were in one
      of four ranges: < 35.0 degrees C, 35.0-35.9 degrees C, 36.0-36.9 degrees C, and >
      or = 37.0 degrees C. With temperature stabilized, vecuronium was infused at 5
      microg x kg(-1) x min(-1) until the first response of each train-of-four had
      decreased by 70%. Arterial blood (for vecuronium analysis) was sampled at
      intervals until the first response recovered to at least 90% of its prevecuronium
      level. Vecuronium, 20 microg x kg(-1) x min(-1), was then infused for 10 min, and
      arterial blood was sampled at intervals for up to 7 h. Population-based nonlinear
      mixed-effects modeling was used to examine the effect of physical characteristics
      and core temperature on vecuronium pharmacokinetics and pharmacodynamics.
      RESULTS: Decreasing core temperature over 38.0-34.0 degrees C decreases the
      plasma clearance of vecuronium (11.3% per degrees C), decreases the rate constant
      for drug equilibration between plasma and effect site (0.023 min(-1) per degrees
      C), and increases the slope of the concentration-response relationship (0.43 per
      degrees C). CONCLUSIONS: Our results show that reduced clearance and rate of
      effect site equilibration explain the increased duration of action of vecuronium
      with reducing core temperature. Tissue sensitivity to vecuronium is not
      influenced by core temperature.

PMID- 10638904
TI  - Racemic ketamine decreases muscle sympathetic activity but maintains the neural
      response to hypotensive challenges in humans.
AB  - BACKGROUND: Cardiovascular stimulation and increased catecholamine plasma
      concentrations during ketamine anesthesia have been attributed to increased
      central sympathetic activity as well as catecholamine reuptake inhibition in
      various experimental models. However, direct recordings of efferent sympathetic
      nerve activity have not been performed in humans. The authors tested the
      hypothesis that racemic ketamine increases efferent muscle sympathetic activity
      (MSA) and maintains the muscle sympathetic response to hypotensive challenges.
      METHODS: Muscle sympathetic activity was recorded by microneurography in the
      peroneal nerve of six healthy subjects before and during anesthesia with racemic
      ketamine (2 mg/kg intravenously plus 30 microg x kg(-1) x min(-1)). Catecholamine
      plasma concentrations, heart rate, and blood pressure were also determined.
      Muscle sympathetic neural responses to a hypotensive challenge were assessed by
      injection of sodium nitroprusside (2-10 microg/kg) before and during ketamine
      anesthesia. In the final step, increased arterial pressure observed during
      ketamine anesthesia was adjusted to preanesthetic baseline by sodium
      nitroprusside infusion (1-6 microg x kg(-1) x min(-1)). RESULTS: Ketamine
      significantly decreased MSA burst frequency (mean +/- SD, 18 +/- 9 bursts/min to
      9 +/- 8 bursts/min) and burst incidence (26 +/- 11 bursts/100 heart beats to 9 +/
      6 bursts/100 heart beats). However, when increased mean arterial pressure (85 +/
      8 mmHg to 121 +/- 20 mmHg) was normalized to the awake baseline by sodium
      nitroprusside, MSA recovered (25 +/- 18 bursts/min; 23 +/- 14 bursts/100 heart
      beats). During ketamine anesthesia, both epinephrine (15 +/- 10 pg/ml to 256 +/-
      193 pg/ml) and norepinephrine (250 +/- 105 pg/ml to 570 +/- 270 pg/ml) plasma
      concentrations significantly increased, as did heart rate (67 +/- 13 beats/min to
      113 +/- 15 beats/min). Hypotensive challenges similarly increased MSA both in the
      awake state and during ketamine anesthesia. CONCLUSIONS: During increased
      arterial blood pressure associated with ketamine, sympathetic discharge to muscle
      blood vessels decreases at the same time that plasma concentrations of
      norepinephrine increase. When this increase in arterial blood pressure is
      reversed, MSA during ketamine is not changed from preketamine baseline
      recordings. Finally, hypotensive challenges still evoke an unchanged sympathetic
      reflex response. Thus, our results do not support the assumption that ketamine
      anesthesia increases sympathetic nerve activity in a generalized fashion.

PMID- 10638905
TI  - Patient-controlled interscalene analgesia with ropivacaine 0.2% versus patient
      controlled intravenous analgesia after major shoulder surgery: effects on
      diaphragmatic and respiratory function.
AB  - BACKGROUND: The authors compared the effects of patient-controlled interscalene
      analgesia (PCIA) with ropivacaine 0.2% and patient-controlled intravenous
      analgesia (PCIVA) with opioids on hemidiaphragmatic excursion and respiratory
      function after major shoulder surgery. METHODS: Thirty-five patients scheduled
      for elective major shoulder surgery were prospectively randomized to receive
      either PCIA or PCIVA. All patients received an interscalene block before surgery.
      In the PCIA group, a catheter was introduced between the anterior and middle
      scalene muscles. Six hours after the initial block, patients received for 48 h
      either a continuous infusion of 0.2% ropivacaine through the interscalene
      catheter at a rate of 5 ml/h plus a bolus dose of 3 or 4 ml with a lockout time
      of 20 min (PCIA group) or a continuous intravenous infusion of nicomorphine at a
      rate or 0.5 mg/h plus a bolus dose of 2 or 3 mg with a lockout time of 20 min
      (PCIVA group). Hemidiaphragmatic excursion and respiratory function were assessed
      with the patient in a 45 degrees semirecumbent position the day before the
      operation and 20 min (in the operating room), 24 h, and 48 h after the initial
      block by means of ultrasonography and spirometry, respectively. Pain relief was
      regularly assessed, side effects were noted, and patient satisfaction was rated 6
      h after the end of the study. RESULTS: Hemidiaphragmatic excursion was similar in
      the two groups 20 min after interscalene block. Hemidiaphragmatic excursion was
      increased in the PCIA group on the nonoperated side 24 and 48 h after the
      interscalene block (P < 0.05). Pulmonary function was similar in the two groups
      at each time. Pain was better controlled in the PCIA group at 12 and 24 h (P <
      0.05). The incidence of nausea and vomiting were 5.5% versus 60% for the PCIA and
      PCIVA groups, respectively (P < 0.05). Patient satisfaction was greater in the
      PCIA group (P < 0.05). CONCLUSIONS: The use of PCIA or PCIVA techniques to
      provide analgesia after major shoulder surgery is associated with similar effects
      on respiratory function. In the PCIA group, hemidiaphragmatic excursion showed a
      significantly greater amplitude 24 and 48 h after the initial block on the
      nonoperated side. The PCIA technique provided better pain control, a lower
      incidence of side effects, and a higher degree of patient satisfaction.

PMID- 10638906
TI  - Stellate ganglion block modifies the distribution of lymphocyte subsets and
      natural-killer cell activity.
AB  - BACKGROUND: Recent investigations suggest that the sympathetic nervous system
      affects the immune system. This study examined whether stellate ganglion block
      (SGB) affects the immune response, specifically the distribution of lymphocyte
      subsets and natural-killer (NK) cell activity. METHODS: Ten volunteers received
      three different treatments in random order at 7-day intervals: (1) SGB with 7 ml
      of 1% lidocaine; (2) an identical volume of normal saline injected at the same
      site as SGB; and (3) an identical volume of 1% lidocaine injected
      intramuscularly. Blood samples were drawn before and 30 min after treatment. The
      distribution of lymphocyte subsets was analyzed, and NK cell activity was
      measured. Plasma concentrations of epinephrine, norepinephrine,
      adrenocorticotropic hormone, and cortisol were measured. RESULTS: Any value in
      the normal saline and intramuscular treatments did not change significantly.
      After SGB, the plasma concentrations of epinephrine and norepinephrine decreased
      significantly (P < 0.01), but adrenocorticotropic hormone and cortisol values
      were unchanged. Increases were observed in the proportion of B cells (from 18.4
      +/- 3.0% to 20.0 +/- 3.8%; P < 0.01) and T cells (from 64.2 +/- 4.1% to 67.1 +/-
      4.2%; P < 0.01). A decrease in the proportion of NK cells was observed (from 13.4
      +/- 2.7% to 9.8 +/- 2.2%; P < 0.01). The proportion of CD4+ cells increased (P <
      0.01), and that of CD8+ cells decreased (P < 0.01), so that the CD4+ cell/CD8+
      cell ratio increased (P < 0.01). The proportion of CD29+ (helper-inducer T) cells
      increased (P < 0.05), but that of CD45RA+ (suppressor-inducer T) cells did not
      change. NK cell activity decreased significantly (from 33.6 +/- 8.3% to 29.1 +/-
      7.6%; P < 0.01). CONCLUSIONS: A small but significant alteration in lymphocyte
      subsets and in NK cell activity by SGB indicates that local sympathetic nerve
      block may modulate the immune response.

PMID- 10638907
TI  - In vitro effects of desflurane, sevoflurane, isoflurane, and halothane in
      isolated human right atria.
AB  - BACKGROUND: Direct myocardial effects of volatile anesthetics have been studied
      in various animal species in vitro. This study evaluated the effects of
      equianesthetic concentrations of desflurane, sevoflurane, isoflurane, and
      halothane on contractile parameters of isolated human atria in vitro. METHODS:
      Human right atrial trabeculae, obtained from patients undergoing coronary bypass
      surgery, were studied in an oxygenated (95% O2-5% CO2) Tyrode's modified solution
      ([Ca2+]o = 2.0 mM, 30 degrees C, stimulation frequency 0.5 Hz). The effects of
      equianesthetic concentrations (0.5, 1, 1.5, 2, and 2.5 minimum alveolar
      concentration [MAC]) of desflurane, sevoflurane, isoflurane, and halothane on
      inotropic and lusitropic parameters of isometric twitches were measured. RESULTS:
      Isoflurane, sevoflurane, and desflurane induced a moderate concentration
      dependent decrease in active isometric force, which was significantly lower than
      that induced by halothane. In the presence of adrenoceptor blockade, the
      desflurane-induced decrease in peak of the positive force derivative and time to
      peak force became comparable to those induced by isoflurane. Halothane induced a
      concentration-dependent decrease in time to half-relaxation and a contraction
      relaxation coupling parameter significantly greater than those induced by
      isoflurane, sevoflurane and desflurane. CONCLUSIONS: In isolated human atrial
      myocardium, desflurane, sevoflurane, and isoflurane induced a moderate
      concentration-dependent negative inotropic effect. The effect of desflurane on
      time to peak force and peak of the positive force derivative could be related to
      intramyocardial catecholamine release. At clinically relevant concentrations,
      desflurane, sevoflurane, and isoflurane did not modify isometric relaxation.

PMID- 10638908
TI  - Neuronal nitric oxide synthase mediates halothane-induced cerebral microvascular
      dilation.
AB  - BACKGROUND: The causes of volatile anesthetic-induced cerebral vasodilation
      include direct effects on smooth muscle and indirect effects via changes in
      metabolic rate and release of mediators from vascular endothelium and brain
      parenchyma. The role of nitric oxide and the relative importance of neuronal and
      endothelial nitric oxide synthase (nNOS and eNOS, respectively) are unclear.
      METHODS: Rat brain slices were superfused with oxygenated artificial
      cerebrospinal fluid. Hippocampal arteriolar diameters were measured using
      computerized videomicrometry. Vessels were preconstricted with prostaglandin
      F2alpha (PGF2alpha; halothane group) or pretreated with 7-nitroindazole sodium (7
      NINA, specific nNOS inhibitor, 7-NINA + halothane group) or N-nitro-L-arginine
      methylester (L-NAME; nonselective NOS inhibitor, L-NAME + halothane group) and
      subsequently given PGF2alpha to achieve the same total preconstriction as in the
      halothane group. Increasing concentrations of halothane were administered and
      vasodilation was calculated as a percentage of preconstriction. RESULTS:
      Halothane caused significant, dose-dependent dilation of hippocampal microvessels
      (halothane group). Inhibition of nNOS by 7-NINA or nNOS + eNOS by L-NAME
      similarly attenuated halothane-induced dilation at 0.6, 1.6, and 2.6% halothane.
      The dilation (mean +/- SEM) at 1.6% halothane was 104 +/- 10%, 65 +/- 6%, and 51
      +/- 9% in the halothane, 7-NINA + halothane and L-NAME + halothane groups,
      respectively. The specificity of 7-NINA was confirmed by showing that
      acetylcholine-induced dilation was not inhibited by 7-NINA but was converted to
      constriction by L-NAME. CONCLUSIONS: At clinically relevant concentrations,
      halothane potently dilates intracerebral arterioles. This dilation is mediated,
      in part, by neuronally derived nitric oxide. Endothelial NOS does not play a
      major role in halothane-induced dilation of hippocampal microvessels.

PMID- 10638909
TI  - Effects of intravenous anesthetics on Ca2+ sensitivity in canine tracheal smooth
      muscle.
AB  - BACKGROUND: Halothane and other volatile anesthetics relax airway smooth muscle
      in part by decreasing the amount of force produced for a particular intracellular
      calcium concentration (the Ca2+ sensitivity) during muscarinic receptor
      stimulation. In this study, ketamine, propofol, and midazolam were evaluated to
      determine whether the inhibitory effect of volatile anesthetics on this signal
      transduction pathway is a general property of other types of anesthetic drugs.
      METHODS: A beta-escin permeabilized canine tracheal smooth muscle preparation was
      used. Ketamine, propofol, and midazolam, in concentrations producing near-maximal
      relaxation in intact airway smooth muscle (200 microM, 270 microM, and 100
      microM, respectively), were applied to permeabilized muscles stimulated with
      calcium in either the absence or the presence of muscarinic receptor stimulation
      provided by acetylcholine. The effect of halothane also was evaluated. RESULTS:
      Confirming previous studies, halothane (0.75 mM) decreased calcium sensitivity
      during muscarinic receptor stimulation. None of the intravenous anesthetics
      studied affected Ca2+ sensitivity, either in the absence or the presence of
      muscarinic receptor stimulation. CONCLUSIONS: Intravenous anesthetics in high
      concentrations directly relax canine tracheal smooth muscle without affecting
      Ca2+ sensitivity. The inhibition of agonist-induced increases in Ca2+ sensitivity
      of canine tracheal smooth is not a common property of anesthetics, but is unique
      to volatile agents.

PMID- 10638910
TI  - Effect of spinal morphine after long-term potentiation of wide dynamic range
      neurones in the rat.
AB  - BACKGROUND: Studies have shown that long-term increase in the excitability of
      single wide dynamic range neurones in the spinal dorsal horn of rats may be
      induced after tetanic stimulation to the sciatic nerve. This sensory event is
      possibly an in vivo counterpart of long-term potentiation, described in the
      brain. This study investigated whether this phenomenon occurs in the halothane
      anesthetized rat and whether the antinociceptive effects of spinally administered
      morphine are altered when tested on the enhanced activity. METHODS: Single unit
      extracellular recordings were made in three different groups of halothane
      anesthetized rats (n = 6 in each group). In group 1, the evoked neuronal
      responses of wide dynamic range neurones by a single electrical stimulus to the
      peripheral nerve were recorded every 4 min, for 1 h before (baseline) and for 3 h
      after brief high-frequency conditioning stimulation of the sciatic nerve. In
      group 2, morphine was applied onto the spinal cord after long-term potentiation
      had been established. Increasing concentrations of morphine were added until the
      C fiber-evoked responses were abolished; this was followed by naloxone reversal.
      In group 3, the same protocol as in group 2 was used except a waiting period
      substituted for the electrical conditioning. RESULTS: The C fiber-evoked
      responses were significantly increased (P < 0.001) after conditioning compared
      with baseline and those in control animals. Further, significantly higher
      concentrations of morphine (P = 0.008) were needed to abolish the C fiber-evoked
      responses in tetanized animals than in control animals. Naloxone reversed the
      effects of morphine to the predrug potentiated baseline in group 2, showing that
      opioids do not block the maintenance of spinal long-term potentiation.
      CONCLUSIONS: Long-term potentiation of C fiber-evoked responses also can be
      induced in halothane-anesthetized rats, and morphine seems to have less potency
      during such conditions. These data suggest that long-term potentiation-like
      mechanisms may underlie some forms of hyperalgesia associated with a reduced
      effect of morphine.

PMID- 10638911
TI  - Tonic blocking action of meperidine on Na+ and K+ channels in amphibian
      peripheral nerves.
AB  - BACKGROUND: Among opioids, meperidine (pethidine) also shows local anesthetic
      activity when applied locally to peripheral nerve fibers and has been used for
      this effect in the clinical setting for regional anesthesia. This study
      investigated the blocking effects of meperidine on different ion channels in
      peripheral nerves. METHODS: Experiments were conducted using the outside-out
      configuration of the patch-clamp method applied to enzymatically prepared
      peripheral nerve fibers of Xenopus laevis. Half-maximal inhibiting concentrations
      were determined for Na+ channels and different K+ channels by nonlinear least
      squares fitting of concentration-inhibition curves, assuming a one-to-one
      reaction. RESULTS: Externally applied meperidine reversibly blocked all
      investigated channels in a concentration-dependent manner, i.e., voltage
      activated Na+ channel (half-maximal inhibiting concentration, 164 microM),
      delayed rectifier K+ channels (half-maximal inhibiting concentration, 194
      microM), the calcium-activated K+ channel (half-maximal inhibiting concentration,
      161 microM), and the voltage-independent flicker K+ channel (half-maximal
      inhibiting concentration, 139 microM). Maximal block in high concentrations of
      meperidine reached 83% for delayed rectifier K+ channels and 100% for all other
      channels. Meperidine blocks the Na+ channel in the same concentration range as
      the local anesthetic agent lidocaine (half-maximal inhibiting concentration, 172
      microM) but did not compete for the same binding site as evaluated by competition
      experiments. Low concentrations of meperidine (1 nM to 1 microM) showed no
      effects on Na+ channels. The blockade of Na+ and delayed rectifier K+ channels
      could not be antagonized by the addition of naloxone. CONCLUSIONS: It is
      concluded that meperidine has a nonselective inhibitory action on Na+ and K+
      channels of amphibian peripheral nerve. For tonic Na+ channel block, neither an
      opioid receptor nor the the local anesthetic agent binding site is the target
      site for meperidine block.

PMID- 10638912
TI  - Spinal cord bioavailability of methylprednisolone after intravenous and
      intrathecal administration: the role of P-glycoprotein.
AB  - BACKGROUND: High-dose intravenously administered methylprednisolone has been
      shown to improve outcome after spinal cord injury. The resultant glucocorticoid
      induced immunosuppression, however, results in multiple complications including
      sepsis, pneumonia, and wound infection. These complications could be reduced by
      techniques that increase the spinal bioavailability of intravenously administered
      methylprednisolone while simultaneously decreasing plasma bioavailability. This
      study aimed to characterize the spinal and plasma bioavailability of
      methylprednisolone after intravenous and intrathecal administration and to
      identify barriers to the distribution of methylprednisolone from plasma into
      spinal cord. METHODS: The spinal and plasma pharmacokinetics of intravenous (30
      mg/kg bolus dose plus 5.4 mg x kg(-1) x h(-1)) and intrathecal (1-mg/kg bolus
      dose plus 1 mg x kg(-1) x h(-1)) methylprednisolone infusions were compared in
      pigs. In addition, wild-type mice and P-glycoprotein knockout mice were used to
      determine the role of P-glycoprotein in limiting spinal bioavailability of
      methylprednisolone. RESULTS: Despite the greater intravenous dose, concentrations
      of methylprednisolone in pig spinal cord were far higher and plasma
      concentrations much lower after intrathecal administration. After intraperitoneal
      administration in the mouse, the concentrations of methylprednisolone in muscle
      were not different between mice expressing P-glycoprotein (2.39 +/- 1.79
      microg/g) and those lacking P-glycoprotein (2.83 +/- 0.46 microg/g). In contrast,
      methylprednisolone was undetectable in spinal cords of wild-type mice, whereas
      concentrations in spinal cords of P-glycoprotein-deficient mice were similar to
      those in skeletal muscle (2.83 +/- 0.27 microg/g). CONCLUSIONS: These pig studies
      demonstrate that the spinal cord bioavailability of methylprednisolone is poor
      after intravenous administration. The studies in knockout mice suggest that this
      poor bioavailability results from P-glycoprotein-mediated exclusion of
      methylprednisolone from the spinal cord.

PMID- 10638913
TI  - Sevoflurane does not inhibit human platelet aggregation induced by thrombin.
AB  - BACKGROUND: Sevoflurane reportedly inhibits adenosine diphosphate-induced
      platelet aggregation by suppressing thromboxane A2 formation. The increase in
      intracellular calcium concentration that fosters platelet aggregation, however,
      is also induced by other cell signaling pathways, such as activation of the
      production of inositol 1,4,5-triphosphate by thrombin. The current study aimed to
      clarify the net influence of sevoflurane on thrombin-induced platelet
      aggregation. METHODS: Washed platelets were stimulated by thrombin after
      incubation with 0.5, 1.0, or 1.5 mM sevoflurane, halothane, or isoflurane.
      Aggregation curves were measured by an aggregometer. Intracellular calcium
      concentration was measured fluorometrically using fura-2. Calcium mobilization
      via plasma membrane calcium channels and the dense tubular system was assessed
      differentially. Intracellular inositol 1,4,5-triphosphate was measured by
      radioimmunoassay. RESULTS: Halothane significantly suppressed aggregation ratios
      at 5 min compared with those in controls (89 +/- 7%) to 71 +/- 10% (1.0 mM) and
      60 +/- 11% (1.5 mM) and the increase in intracellular calcium concentration
      (controls, 821 +/- 95 nM vs. 440 +/- 124 nM [1.0 mM] or 410 +/- 74 nM [1.5 mM]).
      Halothane also significantly inhibited release of calcium from the dense tubular
      system (controls, 220 +/- 48 nM vs. 142 +/- 31 nM [1.0 mM]). Neither sevoflurane
      nor isoflurane produced a net change in aggregation ratios, intracellular calcium
      concentration, or calcium mobilization. Halothane (1 mM) significantly suppressed
      inositol 1,4,5-triphosphate concentrations, whereas neither 1 mM isoflurane nor 1
      mM sevoflurane had any effect. CONCLUSIONS: Although sevoflurane has been
      reported to inhibit human platelet aggregation induced by weak agonists such as
      adenosine diphosphate, it does not inhibit human platelet aggregation induced by
      strong agonists such as thrombin.

PMID- 10638914
TI  - Effects of pentobarbital and isoflurane on conditioned learning after transient
      global cerebral ischemia in rabbits.
AB  - BACKGROUND: The acquisition of a conditioned eyeblink response has been used
      extensively to study the neurologic substrates of learning and memory. We
      examined the effects of the anesthetics isoflurane and pentobarbital, or
      hypothermia (30 degrees C), on the ability of rabbits to acquire an eyeblink
      conditioned response after 6.5 min of cerebral ischemia. METHODS: New Zealand
      white rabbits (n = 48) were randomly assigned to sham, normothermic, hypothermic,
      isoflurane, or pentobarbital groups. In the normothermic, hypothermic,
      isoflurane, and pentobarbital groups, 6.5 min of global cerebral ischemia was
      produced. In animals randomized to the isoflurane and pentobarbital groups, a
      pattern of burst suppression was achieved on the electroencephalogram before the
      start of the ischemic episode. Animals in the hypothermia group were cooled to 30
      degrees C before ischemia. Seven days after ischemia, eyeblink training was
      started using an audible tone presented for 100 ms as the conditioned stimulus.
      The unconditioned stimulus was an air puff directed at the cornea. The delay
      between the end of conditioned stimulus and the start of the unconditioned
      stimulus (the trace interval) was 300 ms in duration. A conditioned response was
      defined as an eyeblink that was initiated during the trace interval. Eighty
      trials per day and 15 days of training were delivered. RESULTS: Neurologic
      deficits were greatest in the normothermia group, and these animals also had
      fewer conditioned responses than those in the sham, hypothermia, or pentobarbital
      groups. Animals in the isoflurane group had an intermediate number of conditioned
      responses that was not significantly different from the normothermia group.
      CONCLUSIONS: This study demonstrates that a brief episode of cerebral ischemia
      results in the impairment of associative learning. Hypothermia and burst
      suppressive doses of pentobarbital were able to improve neurobehavioral outcome
      as measured by ability to acquire a trace conditioned response.

PMID- 10638916
TI  - Lack of whole-body pharmacokinetic differences of halothane enantiomers in the
      rat.
AB  - BACKGROUND: Halothane is made and used as a racemate (an equimolar mixture of R-
      and S- enantiomers). This study was initiated to determine whether there were
      demonstrable enantiomeric differences in the whole-body pharmacokinetics of
      halothane that might have significance for studies in which racemate is used.
      METHODS: Adult male Wistar rats were exposed to halothane vaporized in the
      atmosphere of a closed constant volume chamber supplied with O2 commensurate with
      CO2 production. Concentrations of halothane enantiomers were measured by a
      specific gas chromatography-mass spectrometry method. Experiments were performed
      at four initial concentrations of halothane (0.1%, 0.5%, 1.0%, and 1.5% vol/vol).
      Enantiomeric differences in whole-body pharmacokinetics were assessed indirectly
      from the relative chamber atmosphere concentrations of halothane enantiomers.
      RESULTS: Concentrations of halothane decreased biphasically. The initial more
      rapid decrease was interpreted as incorporating absorption, distribution, and
      clearance; the slower decrease was interpreted as principally incorporating
      metabolic clearance. The ratio of concentrations of the two halothane enantiomers
      and of the ratios of the respective areas under the concentration-time curves
      remained constant without differing from unity at any time at any concentration
      of halothane. The dose-normalized areas under the concentration-time curves for
      the concentrations 0.1%, 0.5%, and 1.0% did not differ; that for 1.5% was
      significantly greater, suggesting nonlinear clearance, but the values did not
      differ significantly between enantiomers at any concentration. CONCLUSIONS: As
      there were no significant differences in concentrations of the two enantiomers in
      the chamber atmosphere, enantioselectivity was not demonstrated in the whole-body
      pharmacokinetics of halothane.

PMID- 10638915
TI  - Endotracheal cardiac output monitor.
AB  - BACKGROUND: The endotracheal cardiac output monitor (ECOM) is a new device that
      uses an endotracheal tube with multiple electrodes to measure cardiac output
      (CO). It measures the changes in electrical impedance caused by pulsatile blood
      flow in the aorta. The system was tested for safety and efficacy in 10 swine.
      METHODS: Swine (60-80 kg) were chronically instrumented with a transit time flow
      probe on the ascending aorta and vascular occluders on the vena cava and
      pulmonary artery. After a minimum recovery of 4 days, the animals were
      anesthetized and intubated with an ECOM endotracheal tube. CO measurements from
      the ECOM system were compared to transit time flow probe measurements using
      linear regression and Bland-Altman analysis. Three different inotropic states
      were studied: (1) baseline; (2) increased (dobutamine); and (3) decreased
      (esmolol). CO was changed at each inotropic state by impeding left ventricular
      filling with the vena cava or pulmonary artery occluders. CO values between 0 and
      15 l/min were studied. Pigs were studied for 24 h consecutively. RESULTS: There
      was no deterioration of the impedance signal with time and no tracheal injury
      from the ECOM electrodes. There is a linear relationship between the ECOM and
      transit time flow probe CO between 0 and 15 l/min (slope = 0.94; intercept = 0.15
      l/min; R2= 0.77). The mean difference between the two measures (bias) is 0.15
      l/min and the SD is 1.34 l/min. The limits of agreement are -2.53 to 2.82 l/min.
      CONCLUSION: Endotracheal CO monitor is a promising technology that needs further
      evaluation in clinical trials.

PMID- 10638917
TI  - Bupivacaine inhibits baroreflex control of heart rate in conscious rats.
AB  - BACKGROUND: Because exposure to intravenously administered bupivacaine may alter
      cardiovascular reflexes, the authors examined bupivacaine actions on baroreflex
      control of heart rate in conscious rats. METHODS: Baroreflex sensitivity (pulse
      interval vs. systolic blood pressure in ms/mmHg) was determined before, and 1.5
      and 15.0 min after rapid intravenous administration of bupivacaine (0.5, 1.0, and
      2.0 mg/kg) using heart rate changes evoked by intravenously administered
      phenylephrine or nitroprusside. The actions on the sympathetic and
      parasympathetic autonomic divisions of the baroreflex were tested in the presence
      of a muscarinic antagonist methyl atropine and a beta-adrenergic antagonist
      atenolol. RESULTS: Within seconds of injection of bupivacaine, mean arterial
      pressure increased and heart rate decreased in a dose-dependent manner.
      Baroreflex sensitivity was unaltered after administration of 0.5 mg/kg
      bupivacaine. In addition, 1 mg/kg bupivacaine at 1.5 min depressed phenylephrine
      evoked reflex bradycardia (0.776 +/- 0.325 vs. 0.543 +/- 0.282 ms/mmHg, P < 0.05)
      but had no effect on nitroprusside-induced tachycardia. Bupivacaine (2 mg/kg),
      however, depressed reflex bradycardia and tachycardia (phenylephrine, 0.751 +/-
      0.318 vs. 0.451 +/- 0.265; nitroprusside, 0.839 +/- 0.256 vs. 0.564 +/- 0.19
      ms/mmHg, P < 0.05). Baroreflex sensitivity returned to prebupivacaine levels by
      15 min. Bupivacaine (2 mg/kg), in the presence of atenolol, depressed baroreflex
      sensitivity (phenylephrine, 0.633 +/- 0.204 vs. 0.277 +/- 0.282; nitroprusside,
      0.653 +/- 0.142 vs. 0.320 +/- 0.299 ms/mmHg, P < 0.05). In contrast, bupivacaine
      did not alter baroreflex sensitivity in the presence of methyl atropine.
      CONCLUSIONS: Bupivacaine, in clinically relevant concentrations, inhibits
      baroreflex control of heart rate in conscious rats. This inhibition appears to
      involve primarily vagal components of the baroreflex-heart rate pathways.

PMID- 10638918
TI  - Time-dependent pressure distortion in a catheter-transducer system: correction by
      fast flush.
AB  - BACKGROUND: Distortion of the pressure wave by a liquid-filled catheter
      transducer system leads most often to an overestimation in systolic arterial
      blood pressure in pulmonary and systemic circulations. The pressure distortion
      depends on the catheter-transducer frequency response. Many monitoring systems
      use either mechanical or electronic filters to reduce this distortion. Such
      filters assume, however, that the catheter-transducer frequency response does not
      change over time. The current study aimed to study the changes with time of the
      catheter-transducer frequency response and design a flush procedure to reverse
      these changes back to baseline. METHODS: An in vitro setup was devised to assess
      the catheter-transducer frequency response in conditions approximating some of
      those met in a clinical environment (slow flushing, 37 degrees C, 48-h test).
      Several flush protocols were assessed. RESULTS: Within 48 h, catheter-transducer
      natural frequency decreased from 17.89 +/- 0.36 (mean +/- SD) to 7.35 +/- 0.25
      Hz, and the catheter-transducer damping coefficient increased from 0.234 +/-
      0.004 to 0.356 +/- 0.010. Slow and rapid flushing by the flush device built into
      the pressure transducer did not correct these changes, which were reversed only
      by manual fast flush of the transducer and of the catheter. These changes and
      parallel changes in catheter-transducer compliance may be explained by bubbles
      inside the catheter-transducer. CONCLUSIONS: Catheter-transducer-induced blood
      pressure distortion changes with time. This change may be reversed by a manual
      fast flush or "rocket flush" procedure, allowing a con. stant correction by a
      filter.

PMID- 10638919
TI  - Comparative contractile effects of halothane and sevoflurane in rat aorta.
AB  - BACKGROUND: Volatile anesthetic agents have been shown to have contractile
      effects in vascular tissues during specific conditions. This study compared
      contractile effects of halothane and sevoflurane in rat aorta treated with
      verapamil. This study also tried to elucidate the mechanism of the contraction.
      METHODS: Endothelium-denuded rat thoracic aorta was used for recording of
      isometric tension and measurement of influx of 45Ca2+. All experiments were
      performed in the presence of verapamil. In recording of tension, rings were
      precontracted with a submaximum dose of phenylephrine, followed by exposure to
      halothane or sevoflurane. For measurement of influx of 45Ca2+, rat aortic strips
      were exposed to phenylephrine and then to additional halothane or sevoflurane.
      Influx of Ca2+ was estimated by incubating the strips in 45Ca2+-labeled solution
      for 2 min. RESULTS: Halothane (0.5-4.0%) induced contraction in a dose-dependent
      manner, whereas sevoflurane (1-4%) had no effect on tension. Influx of 45Ca2+ was
      strongly enhanced by halothane at 1% and 2%, but only slightly at 4%, and was not
      affected by 1-4% sevoflurane. SK&F 96365, a blocker of voltage-independent Ca2+
      channels, abolished contraction and influx of 45Ca2+ by 1% halothane. Depletion
      of Ca2+ from the sarcoplasmic reticulum with ryanodine or thapsigargin reduced
      the contraction induced by halothane at 4% but not that at 1% and 2%. CONCLUSION:
      Halothane is suggested to cause contraction by enhancing influx of Ca2+ via
      voltage-independent Ca2+ channels at concentrations up to 2% and by inducing
      release of Ca2+ at 4%. Sevoflurane (1-4%) is devoid of these contractile effects.

PMID- 10638920
TI  - Excitatory synaptic transmission mediated by NMDA receptors is more sensitive to
      isoflurane than are non-NMDA receptor-mediated responses.
AB  - BACKGROUND: Effects of volatile anesthetic agents on N-methyl-D-aspartate (NMDA)
      receptor-mediated excitatory synaptic transmission have not been well
      characterized. The authors compared effects produced by halothane and isoflurane
      on electrophysiologic properties of NMDA and non-NMDA receptor-mediated synaptic
      responses in slices from the rat hippocampus. METHODS: Field excitatory
      postsynaptic potentials (fEPSPs) in the CA1 area were recorded with extracellular
      electrodes after electrical stimulation of Schaffer-collateral-commissural fiber
      inputs. NMDA or non-NMDA receptor-mediated fEPSPs were pharmacologically isolated
      using selective antagonists. Clinically relevant concentrations of halothane or
      isoflurane were applied to slices in an artificial cerebrospinal fluid perfusate.
      Paired pulse facilitation was used as a measure of presynaptic effects of the
      anesthetic agents. RESULTS: Clinically relevant concentrations of halothane (1.2
      vol% approximately 0.35 mM) depressed fEPSP amplitudes mediated by NMDA receptors
      and non-NMDA receptors to a similar degree (mean +/- SD: 63.3 +/- 14.0% of
      control, n = 5; 60.2 +/- 7.3% of control, n = 7, respectively). In contrast,
      isoflurane (1.4 vol% approximately 0.50 mM) preferentially depressed fEPSP
      amplitudes mediated by NMDA receptors (44.0 +/- 7.4% of control, n = 6, P <
      0.001) compared with those for non-NMDA receptors (68.7 +/- 5.4% of control n =
      6), indicating a selective, additional postsynaptic effect. Paired pulse
      facilitation of fEPSPs was increased significantly by both anesthetic agents from
      1.37 +/- 0.13 to 1.91 +/- 0.25 (n = 5, P < 0.05 for halothane) and from 1.44 +/-
      0.04 to 1.64 +/- 0.08 (n = 5, P < 0.01 for isoflurane), suggesting that
      presynaptic mechanisms are also involved in fEPSP depression produced by the
      anesthetic agents. Neither rise times nor decay times of fEPSPs were changed in
      the presence of the anesthetic agents. CONCLUSIONS: These results indicate that
      fEPSPs mediated by postsynaptic NMDA receptors are more sensitive to clinically
      relevant concentrations of isoflurane than are non-NMDA receptor-mediated
      responses, but this selective effect was not observed for halothane. Both agents
      also appeared to depress release of glutamate from nerve terminals via
      presynaptic actions.

PMID- 10638921
TI  - The Neurologic and Adaptive Capacity Score: a systematic review of its use in
      obstetric anesthesia research.

PMID- 10638922
TI  - John Snow's practice of obstetric anesthesia.
AB  - The influence of Queen Victoria on the acceptance of obstetric anesthesia has
      been overstated, and the role of John Snow has been somewhat overlooked. It was
      his meticulous, careful approach and his clinical skills that influenced many of
      his colleagues, Tyler-Smith and Ramsbotham and the Queen's own physicians. The
      fact that the Queen received anesthesia was a manifestation that the conversion
      of Snow's colleagues had already taken place. This is not to say that this
      precipitated a revolution in practice. Medical theory may have changed, but
      practice did not, and the actual number of women anesthetized for childbirth
      remained quite low. This, however, was a reflection of economic and logistical
      problems, too few women were delivered of newborn infants during the care of
      physicians or in hospitals. Conversely, it is important to recognize that John
      Snow succeeded in lifting theoretical restrictions on the use of anesthesia.

PMID- 10638923
TI  - Approaches to the prevention of perioperative myocardial ischemia.
AB  - Goals for the perioperative management of patients with coronary artery disease
      include: * Prevent increases in sympathetic nervous system activity: reduce
      anxiety preoperatively; prevent stress response and release of catecholamines by
      appropriate use of opioids or volatile anesthetics and beta-adrenoceptor
      antagonists; beta-blocker therapy should be initiated before and continued during
      and after the surgical procedure. * Decrease heart rate: reduction in heart rate
      increases oxygen supply to ischemic myocardium and reduces oxygen demand; the use
      of beta-blockers is the most effective means to reduce or attenuate deleterious
      increases in heart rate. * Preserve coronary perfusion pressure: decreases in
      diastolic arterial pressure in the presence of severe coronary artery stenoses
      will lead to decreases in blood flow; preservation of perfusion pressure by
      administration of fluid or phenylephrine or a reduction in anesthetic
      concentration may be critical. * Decrease myocardial contractility: reduces
      myocardial oxygen demand and can be accomplished with beta-adrenoceptor
      antagonists or volatile anesthetics. * Precondition myocardium against stunning
      and infarction: in the future, this may accomplished by stimulating the adenosine
      triphosphate- dependent potassium channel with agents such as volatile
      anesthetics and opioid delta1-receptor agonists.

PMID- 10638924
TI  - Mandibular osteoma: a case of impossible rigid laryngoscopy.

PMID- 10638926
TI  - Life-threatening upper airway obstruction caused by oxygen administration with a
      nasal catheter.

PMID- 10638925
TI  - Use of recombinant hirudin in patients with heparin-induced thrombocytopenia with
      thrombosis requiring cardiopulmonary bypass.

PMID- 10638927
TI  - Hemodynamic and metabolic alterations in response to graded exercise in a patient
      susceptible to malignant hyperthermia.

PMID- 10638928
TI  - Use of intravenous cosyntropin in the treatment of postdural puncture headache.

PMID- 10638930
TI  - Oropharyngeal burn in a newborn baby: new complication of light-bulb
      laryngoscopes.

PMID- 10638929
TI  - Detection of basophil activation by flow cytometry in patients with allergy to
      muscle-relaxant drugs.

PMID- 10638931
TI  - Comparison of epidural ropivacaine and bupivacaine in combination with sufentanil
      for labor.

PMID- 10638932
TI  - Therapeutic window after spinal cord trauma is longer than after spinal cord
      ischemia.

PMID- 10638933
TI  - Relative potencies of ropivacaine and bupivacaine.

PMID- 10638934
TI  - Anemia and arterial partial pressure of oxygen.

PMID- 10638935
TI  - Ropivacaine: drug of choice? Or not?

PMID- 10638936
TI  - Acidity and particulate characteristics of aspirated material may affect the
      severity of pneumonitis.

PMID- 10638937
TI  - Another application of dual-lung capnography.

PMID- 10638938
TI  - A case of Fournier's gangrene contraindicating spinal anesthesia.

PMID- 10638939
TI  - Was chloroform produced before 1831?

PMID- 10638940
TI  - Is there still a role for prostatic acid phosphatase? CSCC Position Statement.
      Canadian Society of Clinical Chemists.

PMID- 10638941
TI  - Antioxidant enzymes and human diseases.
AB  - OBJECTIVES: To describe the importance of the antioxidant enzymes superoxide
      dismutase, glutathione peroxidase, and catalase working together in human cells
      against toxic reactive oxygen species, their relationship with several
      pathophysiologic processes and their possible therapeutic implications.
      CONCLUSIONS: Reactive oxygen species (ROS) are involved in the cell growth,
      differentiation, progression, and death. Low concentrations of ROS may be
      beneficial or even indispensable in processes such as intracellular signaling and
      defense against micro-organisms. Nevertheless, higher amounts of ROS play a role
      in the aging process as well as in a number of human disease states, including
      cancer, ischemia, and failures in immunity and endocrine functions. As a
      safeguard against the accumulation of ROS, several nonenzymatic and enzymatic
      antioxidant activities exist. Therefore, when oxidative stress arises as a
      consequence of a pathologic event, a defense system promotes the regulation and
      expression of these enzymes.

PMID- 10638943
TI  - Biochemical differentiation of the porphyrias.
AB  - OBJECTIVES: To differentiate the porphyrias by clinical and biochemical methods.
      DESIGN AND METHODS: We describe levels of blood, urine, and fecal porphyrins and
      their precursors in the porphyrias and present an algorithm for their biochemical
      differentiation. Diagnoses were established using clinical and biochemical data.
      Porphyrin analyses were performed by high performance liquid chromatography.
      RESULTS AND CONCLUSIONS: Plasma and urine porphyrin patterns were useful for
      diagnosis of porphyria cutanea tarda, but not the acute porphyrias.
      Erythropoietic protoporphyria was confirmed by erythrocyte protoporphyrin assay
      and erythrocyte fluorescence. Acute intermittent porphyria was diagnosed by
      increases in urine delta-aminolevulinic acid and porphobilinogen and confirmed by
      reduced erythrocyte porphobilinogen deaminase activity and normal or near-normal
      stool porphyrins. Variegate porphyria and hereditary coproporphyria were
      diagnosed by their characteristic stool porphyrin patterns. This appears to be
      the most convenient diagnostic approach until molecular abnormalities become more
      extensively defined and more widely available.

PMID- 10638942
TI  - Fucosylation of IgG heavy chains is increased in rheumatoid arthritis.
AB  - OBJECTIVES: Glycosylation of IgG was suggested to be important in the etiology of
      rheumatoid diseases. Most studies addressed the amount of galactose, but recently
      we showed that fucose is highly increased in the juvenile chronic arthritis. The
      objective of this study was to determine fucosylation of IgG heavy chains in
      patients with rheumatoid arthritis (RA). DESIGN AND METHODS: IgG was purified
      from sera of 29 RA patients and 17 matching controls using ammonium sulfate
      precipitation and ion exchange. Heavy chains were separated by denaturing
      polyacrylamide gel electrophoresis and their fucosylation analysed using fucose
      specific UEA I lectin. RESULTS: Fucose was found to be approximately 40%
      increased in RA patients with very high statistical significance (p = 0.00095).
      CONCLUSIONS: Fucose on IgG heavy chains is significantly increased in patients
      with rheumatoid arthritis.

PMID- 10638944
TI  - Cis-platinum-induced immunosuppression: relationship to melatonin in human
      peripheral blood mononuclear cells.
AB  - OBJECTIVES: The purpose of this study was to investigate the immunomodulatory
      effect of melatonin (MLT) on human peripheral blood mononuclear cells (PBMC) and
      to address its effects on Cis-platinum (CDDP)-induced cytotoxicity. METHODS AND
      RESULTS: The obtained data from this study revealed that treatment of cells with
      MLT (100 microg/ml) for 24 h enhanced cell viability. When cells were exposed to
      CDDP (5 microg/ml), cell proliferation in response to phytohaemagglutinin (PHA)
      stimulation was reduced by 49.63% compared to control cells as detected by 3[H]
      thymidine uptake. Furthermore, Cis-platinum significantly depleted intracellular
      glutathione (GSH) levels by approximately 47% below that of untreated cells and
      led to apoptotic changes in the target cells as evidenced by DNA fragmentation
      (45% compared to 5% in control cells as measured by diphenylamine assay). DNA
      fragmentation was also confirmed by agarose gel electrophoresis. However, MLT
      enhanced cell proliferation by approximately 8.63% above the control values, and
      counteracted the antiproliferative effect of CDDP. The GSH levels were
      significantly increased in response to MLT (71% above control values) and it
      protected the cells against GSH depletion induced by CDDP. Moreover, DNA
      fragmentation and laddering produced by CDDP were significantly reduced or even
      disappeared when the cells were pretreated with MLT or the latter was
      simultaneously added with CDDP. CONCLUSIONS: The findings from this study
      indicated that melatonin is a potent immunomodulatory hormone that protects PBMC
      against cis-platinum-induced immunosuppressive effects. These effects might
      improve the patients' response to cis-platinum therapy and, therefore, their
      survival rates.

PMID- 10638945
TI  - New developments in the standardization of total prostate-specific antigen.
AB  - OBJECTIVE: Analytical evaluation of the calibration of three recently launched
      assays for the measurement of total prostate-specific antigen, i.e., IMx Total
      PSA (Abbott), Elecsys PSA (Roche), and IMMULITE 3rd Generation PSA (DPC). DESIGN
      AND METHODS: For accuracy assessment two reference materials were applied namely,
      Stanford 90:10 PSA Calibrator and Certified Reference Material 613 Prostate
      Specific Antigen. Dilutions of these preparations were analyzed with all assays.
      In addition, clinical specimens from known prostate cancer or benign prostate
      hyperplasia patients and samples taken from an ongoing prostate cancer screening
      study were used for comparison. RESULTS: Application of the Stanford Calibrator
      revealed results well within 10% of the calculated values for all assays.
      Regarding the CRM Calibrator only the IMx Total PSA proved to approach the line
      of identity. The IMMULITE results differed about 40% and the Elecsys about 18%
      from the calculated values. The comparison with clinical specimens showed
      statistically different results for the combination IMMULITE-IMx and for IMMULITE
      Elecsys. The regression lines for both collections were: y(IMx) = 0.86x(IMMULITE)
      +0.12 (n = 104, r = 0.970, Sy/x = 0.883 microg/L) and y(Elecsys) =
      0.98x(IMMULITE) +0.38 (n = 97, r = 0.976, Sy/x = 0.733 microg/L). In the lower
      measuring range (PSA <5.0 microg/L) as measured with the screening samples (n =
      43), these differences were less pronounced. CONCLUSION: In analytical sense a
      difference was found for both reference preparations in the assays studied.
      Clinically, despite improvements in methodology, results for total prostate
      specific antigen are still not interchangeable. The possible consequences need to
      be elaborated.

PMID- 10638946
TI  - Determination of cytosolic citrulline and nitrate as indicators of nitric oxide
      in bladder cancer: possible association with basic fibroblast growth factor.
AB  - BACKGROUND: Nitric Oxide (NO) and nitrosamines have been implicated in bladder
      carcinogenesis. Apart from its implication in carcinogenesis, NO contributes to
      the regulation of tumor angiogenesis via angiogenic peptides exemplified by basic
      fibroblast growth factor (bFGF). OBJECTIVES AND METHODS: In order to examine NO
      pattern in normal, schistosomal, and malignant bladder cytosols, we have used a
      combined approach by measuring nitrate and the amino acid citrulline. The results
      were correlated to bFGF, which were measured in bladder cytosols by an EIA
      method. RESULTS: Comparison between normal, schistosomal, and malignant bladder
      groups showed that patients with schistosomiasis and bladder cancer had
      significantly higher cytosolic nitrate, citrulline, and bFGF levels. There were
      no apparent correlations between these investigated parameters and tumor
      histologic features. The level of citrulline was strongly correlated to nitrate
      level and both were correlated to bFGF level in bladder cancer and
      schistosomiasis groups. CONCLUSIONS: Our findings indicate that NO and bFGF were
      significantly elevated in schistosomiasis and bladder cancer compared to normal
      bladders. Moreover, the consistent association of NO with bFGF found in the
      present work, support the hypothesis that the angiogenic peptide bFGF may be
      modulated by NO and suggest a useful target in antiangiogenic therapy in bladder
      cancer.

PMID- 10638947
TI  - Serum levels of tetranectin, intercellular adhesion molecule-1 and interleukin-10
      in B-chronic lymphocytic leukemia.
AB  - BACKGROUND AND OBJECTIVE: The fibrinolytic regulator tetranectin (TN), in
      association with the circulating intercellular adhesive molecule-1 (cICAM-1) and
      interleukin -10 (IL-10), may be involved in the metastatic cascade of B-chronic
      lymphocytic leukemia (B-CLL). Our aim was to investigate the potential usefulness
      of these molecules as prognostic markers in B-CLL. DESIGN AND METHODS: Therefore,
      TN, cICAM-1, and IL-10 were assessed (ELISA) in the serum of 53 B-CLL patients,
      classified in Binet A, B, and C stages in comparison with those in 45 healthy
      subjects (HS). RESULTS: TN was significantly lower in B-CLL patients than in HS
      (9.63 [8.75-11.51] mg/L, 13.75 [12.56-14.64] ng/mL, respectively, p<10(-5)),
      being lower (p = 0.05) in B and C stage patients (subgroup B+C) than in A stage
      ones (subgroup A). cICAM-1 levels were significantly higher in B-CLL patients
      than in HS (475.86 [355.86-593.79] ng/mL vs. 225.62 [118.49-312.83] ng/mL,
      respectively, p<10(-5)) with a tendency for higher levels in subgroup B+C than in
      subgroup A. A significant correlation of cICAM-1 with lactate dehydrogenase (LDH)
      (r(s) = 0.532, p = 0.049), and a significant increase in cICAM-1 in B-CLL with
      diffuse bone marrow infiltration (BMI) compared to that in B-CLL with nondiffuse
      BMI (624.48 [557.24-726.55] ng/mL vs. 480.34 [368.96-590.34] ng/mL, respectively,
      p = 0.0172) were found. A significant negative correlation between TN and cICAM-1
      (r = -0.5017, p = 0.0001) was observed. IL-10 was detected in all B-CLL patients
      and in no HS (7.37 [5.30-10.55] pg/mL), being higher (p = 0.0153) in C than in A
      stage patients. A significant correlation of IL-10 with TN and cICAM-1 in
      subgroup B+C (r(s) = -0.659 [p = 0.014] and r = 0.679 [p = 0.011], respectively)
      was found. CONCLUSIONS: The abovementioned findings and good performance
      characteristics of TN and cICAM-1 in B-CLL suggest the potential usefulness of
      these adhesive/recognition molecules as prognostic markers in B-CLL. The
      implication of these molecules along with IL-10 in the disease process deserves
      further study.

PMID- 10638948
TI  - Increased mortality in hemodialyzed patients with elevated serum troponin T: a
      one-year outcome study.
AB  - OBJECTIVES: To determine the significance of elevated serum troponin T (cTnT)
      occurring in hemodialysis patients in the absence of clinical evidence of acute
      coronary ischemia. DESIGN AND METHODS: Twelve-month follow-up of cohort of 172
      hemodialyzed patients with known serum cTnT concentration. The cohort consisted
      of patients undergoing hemodialysis in a hospital unit over a 5-month period,
      with one to four measurements of cTnT. The main outcome measure was death. Cause
      of death was determined by autopsy in six patients. RESULTS: Of the 31 deaths, 12
      were due to acute coronary disease, 14 were noncoronary, and 5 were undefined.
      Death rates of patients with cTnT <0.1, 0.1-0.2, and >0.2 microg/L were 9.9%
      (11/111), 32.4% (12/37), and 33.3% (8/24), respectively. The increase in death
      rate with cTnT > or =0.1 microg/L was significant (p<0.001) for noncoronary
      deaths, but not for acute coronary deaths. The risk ratios for noncoronary deaths
      in the subgroups were: nondiabetics 6.6 (95% CI 1.9-23.6), patients with no
      coronary artery disease 7.3 (1.6-32.4), patients with no peripheral vascular
      disease 8.9 (2.0-39.7), and hypertensives 9.0 (1.1-76.5). Significant increase in
      coronary deaths was seen only in patients without hypertension and those aged >
      or =50 years. The risk ratios for these groups were 9.3 (1.2-74.3) and 3.3 (1.0
      10.6), respectively. CONCLUSIONS: Serum cTnT is a potential prognostic marker of
      mortality in hemodialyzed patient, with increase in death from coronary and
      noncoronary causes.

PMID- 10638949
TI  - Usefulness of monitoring beta-glucuronidase in pleural effusions.
AB  - BACKGROUND: The objective of the study was to evaluate the additional value of
      beta-glucuronidase (BGD), a lysosomal enzyme in the analysis of transudative and
      exsudative pleural effusions, especially between malignant and non-malignant
      effusions. DESIGN AND METHODS: Pleural fluid samples obtained from four
      respective diagnostic groups: transudates parapneumonic effusions, malignant
      effusions or pleuritis carcinomatosa, and empyema were evaluated. RESULTS: Beta
      glucuronidase was significantly different between transudative and exsudative
      effusions (p<0.001) as well as between parapneumonic and malignant effusions
      (p<0.03), parapneumonic effusions and empyema (p<0.002), and malignant and
      empyema (p<0.002), respectively. Logistic regression analysis yielded a weak
      discrimination between the parapneumonic and malignant groups. CONCLUSIONS: Beta
      glucuronidase activity differed between pleural effusions of various origin.
      However, including BGD in the biochemical work-up of pleural effusions did not
      reveal discriminatory value in the assessment of the classification of these
      effusions.

PMID- 10638950
TI  - Serum beta-glucuronidase activity in a population of ex-coalminers.
AB  - BACKGROUND: The aim of this study was to investigate whether BGD activity is of
      additional value in the assessment of pulmonary inflammation caused by coal dust
      exposure. DESIGN AND METHODS: Ex-coalminers were included in this study. Forty
      eight healthy male subjects, without a relevant medical history, were used as
      controls. RESULTS: In ex-coalminers serum BGD activity was higher compared to the
      control group. Moreover, ex-coalminers with a normal chest radiograph and normal
      serum LDH demonstrated elevated serum BGD compared to the control group. However,
      no relation was found in the total group of ex-coalminers between serum BGD
      activity and pulmonary function parameters. CONCLUSIONS: Our study adds in vivo
      human evidence to the already existing animal data that BGD is a potential
      biomarker useful in monitoring pulmonary inflammation caused by coal dust
      exposure.

PMID- 10638951
TI  - Blood selenium levels in healthy Indian subjects and patients with rheumatoid
      arthritis.

PMID- 10638952
TI  - False positive analytical interference of cardiac troponin I assays: an important
      consideration for method selection.

PMID- 10638953
TI  - Lipid peroxides and antioxidant status in serum of patients with angiographically
      defined coronary atherosclerosis.

PMID- 10638954
TI  - Increase in CSF NGF concentration is positively correlated with poor prognosis of
      postoperative hydrocephalic patients.

PMID- 10638955
TI  - Improved diagnosis of sickle cell mutation by a robust amplification refractory
      polymerase chain reaction.

PMID- 10638956
TI  - Position paper by the UKCCCR elderly cancer patients in clinical trials working
      group.

PMID- 10638957
TI  - Economics of stem cell transplantation for lymphoma: counting the cost of living.

PMID- 10638958
TI  - Optimizing cancer care: specialization, coordination and cooperation.

PMID- 10638959
TI  - Involvement of APC and K-ras mutation in non-polypoid colorectal tumorigenesis.
AB  - The aim of this study was to clarify the role of APC and K-ras mutations in non
      polypoid colorectal tumorigenesis. DNA from 63 adenomas (31 polypoid, 17
      superficial elevated, 15 superficial depressed), 66 submucosally invasive
      carcinomas (47 polypoid, 19 non-polypoid) and 34 advanced carcinomas were
      examined for K-ras codon 12 point mutations and APC mutations in the mutation
      cluster region. K-ras mutation: the frequency in superficial depressed adenomas
      was lower than that in polypoid adenomas (0% vs 31%: P= 0.018). The frequency in
      non-polypoid carcinomas was lower than that in polypoid carcinomas (11% vs 56%: P
      = 0.0008), and was relatively low compared with that in polypoid adenomas (11% vs
      31%). APC mutation: the frequency in superficial depressed adenomas was lower
      than that in polypoid adenomas (7% vs 43%: P = 0.016), and that in polypoid
      carcinomas was similar to that in non-polypoid carcinomas. Polypoid adenomas,
      polypoid carcinomas and advanced carcinomas had almost the same frequency. There
      may be some pathway other than the conventional adenoma-carcinoma sequence in
      development of non-polypoid carcinomas. The precursors of most non-polypoid
      carcinomas are considered to be de novo or superficial depressed adenomas. In
      this non-polypoid pathway, APC mutation seems to be requisite but K-ras mutation
      not. It is possible that new APC mutations are acquired after the development of
      superficial depressed adenomas.

PMID- 10638960
TI  - Preferential down-regulation of phospholipase C-beta in Ewing's sarcoma cells
      transfected with antisense EWS-Fli-1.
AB  - EWS-Fli-1, a fusion gene found in Ewing's sarcoma and primitive neuro-ectodermal
      tumour (PNET), encodes a transcriptional activator and promotes cellular
      transformation. We have made stable Ewing's sarcoma cells expressing antisense
      EWS-Fli-1 transcripts by transfecting the antisense EWS-Fli-1 expression plasmid.
      These cells showed partial loss of endogenous EWS-Fli-1 proteins and suppression
      of the cell growth. To elucidate the molecular mechanisms underlying the growth
      inhibition, we examined the changes of signal transducing proteins by immunoblot
      analysis in Ewing's sarcoma cells stably expressing antisense EWS-Fli-1
      transcripts. Western blotting of the cell proteins revealed that expressions of
      phospholipase Cbeta2 and beta3 (PLCbeta2, PLCbeta3), and also protein kinase C
      alpha and beta (PKCalpha, beta) were significantly reduced by transfecting with
      antisense EWS-Fli-1. The inositol phosphates production by bradykinin (BK), but
      not platelet-derived growth factor (PDGF), was suppressed in these cells. These
      results suggest that the PLCbeta2 and PLCbeta3 may play a role in tumour
      proliferation in Ewing's sarcoma cells.

PMID- 10638961
TI  - Phosphoglycerate mutase, 2,3-bisphosphoglycerate phosphatase, creatine kinase and
      enolase activity and isoenzymes in breast carcinoma.
AB  - We have compared the levels of phosphoglycerate mutase (EC 5.4.2.1), 2,3
      bisphosphoglycerate phosphatase (EC 3.1.3.13), creatine kinase (EC 2.7.3.2) and
      enolase (EC 4.2.1.11) activities and the distribution of their isoenzymes in
      normal breast tissue and in breast carcinoma. Tumour tissue had higher
      phosphoglycerate mutase and enolase activity than normal tissue. Creatine kinase
      activity was higher in seven out of 12 tumours. In contrast 2,3
      bisphosphoglycerate phosphatase activity was lower. Phosphoglycerate mutase,
      enolase and 2,3-bisphosphoglycerate phosphatase presented greater changes in the
      oestrogen receptor-negative/progesterone receptor-negative breast carcinomas than
      in the steroid receptor-positive tumours. Determined by electrophoresis, type BB
      phosphoglycerate mutase, type BB creatine kinase and alpha alpha-enolase were the
      major isoenzymes detected in normal breast tissue. Types alpha gamma and gamma
      gamma enolase, types MB and MM phosphoglycerate mutase were detected in much
      lower proportions. In tumours a decrease of phosphoglycerate mutase isoenzymes
      possessing M-type subunit and some increase of enolase isoenzymes possessing
      gamma-type subunit was observed. No detectable change was observed in the
      creatine kinase phenotype.

PMID- 10638962
TI  - Inhibition of I kappaB-alpha phosphorylation at serine and tyrosine acts
      independently on sensitization to DNA damaging agents in human glioma cells.
AB  - Molecular mechanisms and/or intrinsic factors controlling cellular
      radiosensitivity are not fully understood in mammalian cells. The recent studies
      have suggested that nuclear factor kappaB (NF-kappaB) is one of such factors. The
      activation and regulation of NF-kappaB are tightly controlled by IkappaB-alpha, a
      cellular inhibitory protein of NF-kappaB. Most importantly, phosphorylation
      regulates activity of the inhibitor IkappaB-alpha, which sequesters NF-kappaB in
      the cytosol. Two different pathways for the phosphorylation of IkappaB-alpha are
      demonstrated, such as serine (at residues 32 and 36) and tyrosine (at residue 42)
      phosphorylations. To assess a role of the transcription factor, NF-kappaB, on
      cellular sensitivity to DNA damaging agents, we constructed three different types
      of expression plasmids, i.e. S-IkappaB (mutations at residues 32 and 36), Y
      IkappaB (mutation at residue 42) and SY-IkappaB (mutations at residues 32, 36 and
      42). The cell clones expressing S-IkappaB and Y-IkappaB proteins became sensitive
      to X-rays as compared with the parental and vector-transfected cells. The cell
      clones expressing SY-IkappaB were further radiosensitive. By the treatment with
      herbimycin A, an inhibitor of phosphorylation, the X-ray sensitivity of cells
      expressing SY-IkappaB did not change, while that of the cells expressing S
      IkappaB and Y-IkappaB and the parental cells was enhanced. Change in the
      sensitivity to adriamycin and UV in those clones was very similar to that in the
      X-ray sensitivity. The inhibition of IkappaB-alpha phosphorylation at serine and
      tyrosine acts independently on the sensitization to X-rays, adriamycin and UV.
      These findings suggest that the transcriptional activation induced by NF-kappaB
      may play a role in the DNA damage repair. The present study proposes a
      possibility that the inactivation of NF-kappaB by inhibition of both serine and
      tyrosine phosphorylations may be useful for the treatment of cancer in radio- and
      chemotherapies.

PMID- 10638963
TI  - Depletion of protein kinase C (PKC) by 12-O-tetradecanoylphorbol-13-acetate (TPA)
      enhances platinum drug sensitivity in human ovarian carcinoma cells.
AB  - Down-regulation of protein kinase C (PKC) by 12-Otetradecanoylphorbol-13-acetate
      (TPA) enhances the sensitivity of human ovarian carcinoma 2008 cells to various
      types of platinum compounds such as cisplatin (DDP), carboplatin and (-)-(R)-2
      aminomethylpyrrolidine (1,1-cyclobutanedicarboxylato)-platinum(II) monohydrate
      (DWA) by a factor of two- to threefold. TPA enhanced the sensitivity of the DDP
      resistant 2008/C13*5.25 subline to each of these three drugs to the same extent
      as for the 2008 cells. The extent of PKC down-regulation and drug sensitization
      depended on the duration of TPA exposure; maximum effect was achieved with a 48 h
      pretreatment. Sensitization was TPA concentration-dependent and was maximal at
      0.05 microM TPA. 2008 cells expressed only the PKCalpha and PKCzeta isoforms.
      Western blot analysis revealed that whereas the expression of PKCalpha was
      reduced by TPA the level of PKCzeta was not affected. These results suggest that
      PKCalpha is the isotype responsive to TPA in these cells and that platinum drug
      sensitivity can be modulated by this isoform alone. In parallel to its effect on
      PKCalpha, TPA decreased cellular glutathione content by 30 +/- 3 (standard
      deviation (s.d.) % in 2008 cells and by 41 +/- 3 (s.d.) % in 2008/C13*5.25 cells.
      TPA also increased accumulation of DDP and DWA by 70%, although this effect was
      limited to the 2008/C13*5.25 cells. TPA rendered 2008 and 2008/C13*5.25 cells
      resistant to cadmium chloride by a factor of 3.7 and 3.6-fold respectively,
      suggesting a significant increase in cellular metallothionein content. Although
      the mechanism of TPA induced sensitization is not yet fully understood, this
      study points to a central role for PKCalpha in modulating platinum drug
      sensitivity.

PMID- 10638964
TI  - Androgen receptor protein is down-regulated by basic fibroblast growth factor in
      prostate cancer cells.
AB  - Interactions between polypeptide growth factors and the androgen receptor (AR)
      are important for regulation of cellular events in carcinoma of the prostate.
      Basic fibroblast growth factor (bFGF), the prototype of heparin-binding growth
      factors, and the AR are commonly expressed in prostate cancer. bFGF diminished
      prostate-specific antigen protein in the supernatants of androgen-stimulated
      human prostate cancer cells LNCaP by 80%. In the present study, we asked whether
      the bFGF effect on prostate-specific antigen is preceded by action on AR
      expression. LNCaP cells were treated with bFGF and AR protein expression was
      determined by immunoblotting and ligand binding assay. bFGF down-regulated AR
      protein in a dose-dependent manner showing a maximal effect at 50 ng ml(-1) both
      in the presence or absence of dihydrotestosterone. Down-regulation of AR protein
      expression occurred already after 8 h of bFGF treatment and a maximal inhibition
      was observed 24 h after addition of bFGF to culture media. As AR expression can
      be reduced by an increase in intracellular calcium levels, we investigated
      whether the bFGF effect on AR protein is mediated by this mechanism. Calcium
      release from intracellular stores and store-operated calcium influx after
      treatment with either bFGF or calcium ionophore A 23187 were measured by single
      cell fluorescence technique. The ionophore A 23187 was able to induce calcium
      influx and an increase in cytoplasmic calcium concentration in LNCaP cells. In
      contrast, bFGF was incapable of eliciting a similar effect. In contrast to AR
      protein, AR mRNA levels were not affected by bFGF as shown by semiquantitative
      reverse transcription polymerase chain reaction. In summary, these studies show
      that bFGF is a potent negative regulator of AR protein expression in the human
      prostate cancer cell line LNCaP.

PMID- 10638965
TI  - Anti-HER2 antibody enhances the growth inhibitory effect of anti-oestrogen on
      breast cancer cells expressing both oestrogen receptors and HER2.
AB  - Anti-oestrogen is effective for the treatment of oestrogen receptor (ER)-positive
      breast carcinomas, but most of these tumours become resistant to anti-oestrogen.
      It has been suggested that anti-oestrogen therapy may induce a HER2 signalling
      pathway in breast cancer cells and this may cause resistance to anti-oestrogen.
      Thus, it is conceivable that combined therapy with anti-oestrogen and anti-HER2
      antibody might be more effective. In the present study, we investigated the
      effect of combined treatment with a humanized anti-HER2 monoclonal antibody,
      rhumAbHER2 (trastuzumab), and an anti-oestrogen, ICI 182,780, on the cell growth
      of three human breast cancer cell lines which respectively express different
      levels of ER and HER2. The combined treatment enhanced the growth inhibitory
      effect on ML-20 cells, which express a high level of ER and a moderate level of
      HER2, but showed no additive effect on either KPL-4 cells, which express no ER
      and a moderate level of HER2, or MDA-MB-231 cells, which express no ER and a low
      level of HER2. It is also suggested that both the antibody and anti-oestrogen
      induce a G1-S blockade and apoptosis. These findings indicate that combined
      treatment with anti-HER2 antibody and anti-oestrogen may be useful for the
      treatment of patients with breast cancer expressing both ER and HER2.

PMID- 10638966
TI  - The effects of exogenous growth factors on matrix metalloproteinase secretion by
      human brain tumour cells.
AB  - Matrix metalloproteinases (MMPs) are a growing family of zinc-dependent
      endopeptidases that are capable of degrading various components of the
      extracellular matrix. These enzymes have been implicated in a variety of
      physiological and pathological conditions including embryogenesis and tumour
      invasion. The synthesis of many MMPs is thought to be regulated by growth
      factors, cytokines and hormones. In this study, we investigated the effects of
      five exogenous growth factors known to be expressed by gliomas [epidermal growth
      factor (EGF), basic growth factor (bFGF), transforming growth factor beta (TGF
      beta1,2) and vascular endothelial growth factor (VEGF)].on MMP-2 and MMP-9
      expression in an ependymoma, two grade III astrocytomas, a grade III
      oligoastrocytoma and a benign meningioma. Zymogram analysis revealed that the
      effects of the growth factors depended upon the cell lines used in the study.
      Growth factors generally up-regulated MMP-2 and MMP-9 expression in the gliomas
      but were least effective in the meningioma; the effect being most prominent with
      TGF-beta1 and TGF-beta2 in all the cell lines. It is hypothesized that paracrine
      growth factor interplay may be crucial in the regulation of MMP expression by
      glioma invasion of the normal brain.

PMID- 10638968
TI  - Chromosomal alterations in the clonal evolution to the metastatic stage of
      squamous cell carcinomas of the lung.
AB  - Comparative genomic hybridization (CGH) was applied to squamous cell carcinomas
      (SCC) of the lung to define chromosomal imbalances that are associated with the
      metastatic phenotype. In total, 64 lung SCC from 50 patients were investigated,
      25 each with or without evidence of metastasis formation. The chromosomal
      imbalances summarized by a CGH histogram of the 50 cases revealed deletions most
      frequently on chromosomes 1p21-p31, 2q34-q36, 3p, 4p, 4q, 5q, 6q14-q24, 8p, 9p,
      10q, 11p12-p14, 13q13-qter, 18q12-qter and 21q21. DNA over-representations were
      most pronounced for chromosomes 1q11-q25, 1q32-q41, 3q, 5p, 8q22-qter, 11q13,
      12p, 17q21-q22, 17q24-q25, 19, 20q and 22q. In ten cases, paired samples of
      primaries and at least one metastasis were analysed. The comparison revealed a
      considerable chromosomal instability and genetic heterogeneity; however, the CGH
      pattern indicated a clonal relationship in each case. The difference in
      histograms from the metastatic and non-metastatic tumour groups was most useful
      in pinpointing chromosomal imbalances associated with the metastatic phenotype,
      indicating that the deletions at 3p12-p14, 3p21, 4p15-p16, 6q24-qter, 8p22-p23,
      10q21-qter and 21q22, as well as the over-representations at 1q21-q25, 8q, 9q34,
      14q12 and 15q12-q15, occurred significantly more often in the metastatic tumour
      group. The comparison of the paired samples confirmed these findings in
      individual cases and suggested distinct genetic changes, in particular the
      extension of small interstitial deletions, during tumour progression.
      Importantly, metastasis-associated lesions were frequently detectable in the
      primary tumour providing a method of identifying patients at risk for tumour
      dissemination. Individual profiles and histograms are accessible at our web site
      http://amba.charite.de/cgh.

PMID- 10638967
TI  - Targeted photodestruction of human colon cancer cells using charged 17.1A chlorin
      e6 immunoconjugates.
AB  - The goal of this study was to develop a strategy for the selective destruction of
      colorectal cancer cells. Towards this end, photoimmunoconjugates were prepared
      between the anti-colon cancer monoclonal antibody 17.1A and the photosensitizer
      (PS) chlorin(e6) (c(e6)). Polylysine linkers bearing several c(e6) molecules were
      covalently attached in a site-specific manner to partially reduced IgG molecules,
      which allowed photoimmunoconjugates to bear either cationic or anionic charges.
      The conjugates retained immunoreactivity as shown by enzyme-linked immunosorbent
      assays and by competition studies with native antibody. The overall charge on the
      photoimmunoconjugate was an important determinant of PS delivery. The cationic
      photoimmunoconjugate delivered 4 times more c(e6) to the cells than the anionic
      photoimmunoconjugate, and both 17.1A conjugates showed, in comparison to non
      specific rabbit IgG conjugates, selectivity for antigen-positive target cells.
      Illumination with only 3 J cm(-2) of 666 nm light reduced the number of colony
      forming cells by more than 90% for the cationic 17.1A conjugate and by 73% for
      the anionic 17.1A conjugate after incubation with 1 microM c(e6) equivalent of
      the respective conjugates. By contrast, 1 microM free c(e6) gave only a 35%
      reduction in colonies. These data suggest photoimmunoconjugates may have
      applications in photoimmunotherapy where destruction of colorectal cancer cells
      is required.

PMID- 10638970
TI  - The cost-effectiveness of high dose chemotherapy in the treatment of relapsed
      Hodgkin's disease and non-Hodgkin's lymphoma.
AB  - As part of an NHS Executive Trent regional initiative we considered the role and
      cost-effectiveness of high dose chemotherapy in the treatment of relapsed
      Hodgkin's disease and non-Hodgkin's lymphoma. The key trials and case series show
      an additional patient benefit of 0.8-1.1 life years over standard chemotherapy.
      We estimate incremental cost per life year gained of 12 800 pound silver-17 600
      pound silver, which reduces further if long-term benefits are considered. High
      dose chemotherapy in these conditions is both life-saving and cost-effective.

PMID- 10638969
TI  - Comparison of different methods of intracerebral administration of
      radioiododeoxyuridine for glioma therapy using a rat model.
AB  - The Auger electron emitting agent 5-[125I]iodo-2'-deoxyuridine (i.e. [125I]IUdR)
      holds promise for the treatment of residual glioma after surgery because this
      thymidine analogue kills only proliferating cells. However, malignant cells which
      are not synthesizing DNA during exposure to the radiopharmaceutical will be
      spared. To determine whether tumour incorporation of [125I]IUdR could be enhanced
      by protracted administration, we used a C6 cell line, growing in the brains of
      Wistar rats, as a glioma model and compared three methods of intracerebral
      delivery of [125I]IUdR. Twenty-four hours after administration of drug,
      autoradiography of brain sections demonstrated nuclear uptake of the
      radiopharmaceutical in cells throughout tumour while normal brain cells remained
      free of radioactivity. The [125I]IUdR labelling indices (% +/- s.e.m.) achieved
      were 6.2 (0.4) by single injection, 22.5 (4.1) using a sustained release polymer
      implant (poly(lactide-co-glycolide)) and 34.3 (2.0) by mini-osmotic pump. These
      results emphasize the need for a sustained delivery system as a prerequisite for
      effective treatment. These findings are also encouraging for the development of a
      sustained release system for radiolabelled IUdR for use in the treatment of
      intracranial tumours, particularly in the immediate postoperative setting.

PMID- 10638971
TI  - Antibodies to heat shock protein 90 in osteosarcoma patients correlate with
      response to neoadjuvant chemotherapy.
AB  - Autoantibodies to the heat shock protein 90 (Hsp 90) have been reported as
      prognostic marker in breast cancer patients. Sera from 20 high-grade osteosarcoma
      patients were tested at the time of diagnosis by enzyme-linked immunosorbent
      assay. Presence of anti-Hsp90 antibodies correlated with a better response to
      neoadjuvant chemotherapy (P < 0.01), whereas the absence correlated with
      development of metastases. These data suggest that anti-Hsp90 antibodies might be
      of predictive value in human osteosarcoma.

PMID- 10638972
TI  - Preservation of tumour oxygen after hyperbaric oxygenation monitored by magnetic
      resonance imaging.
AB  - Hyperbaric oxygen (HBO) has been proposed to reduce tumour hypoxia by increasing
      the dissolved molecular oxygen in tissue. Using a non-invasive magnetic resonance
      imaging (MRI) technique, we monitored the changes in MRI signal intensity after
      HBO exposure because dissolved paramagnetic molecular oxygen itself shortens the
      T1 relation time. SCCVII tumour cells transplanted in mice were used. The
      molecular oxygen-enhanced MR images were acquired using an inversion recovery
      preparation fast low angle shot (IR-FLASH) sequence sensitizing the paramagnetic
      effects of molecular oxygen using a 4.7 tesla MR system. MR signal of muscles
      decreased rapidly and returned to the control level within 40 min after
      decompression, whereas that of tumours decreased gradually and remained at a high
      level 60 min after HBO exposure. In contrast, the signal from the tumours in the
      normobaric oxygen group showed no significant change. Our data suggested that MR
      signal changes of tumours and muscles represent an alternation of extravascular
      oxygenation. The preserving tumour oxygen concentration after HBO exposure may be
      important regarding adjuvant therapy for cancer patients.

PMID- 10638973
TI  - Large-scale UK audit of blood transfusion requirements and anaemia in patients
      receiving cytotoxic chemotherapy.
AB  - Cancer patients receiving cytotoxic chemotherapy often become anaemic and may
      require blood transfusions. A large-scale audit of patients with a variety of
      solid tumours receiving chemotherapy at 28 specialist centres throughout the UK
      was undertaken to quantify the problem. Data were available from 2719 patients
      receiving 3206 courses of cytotoxic chemotherapy for tumours of the breast (878),
      ovary (856), lung (772) or testis (213). Their mean age was 55 years (range 16
      87). Overall, 33% of patients required at least one blood transfusion but the
      proportion varied from 19% for breast cancer to 43% for lung. Sixteen per cent of
      patients required more than one transfusion (7% for breast, 22% in lung). The
      mean proportion of patients with Hb < 11 g dl(-10 rose over the course of
      chemotherapy from 17% before the first cycle, to 38% by the sixth, despite
      transfusion in 33% of patients. Of the patients receiving transfusions, 25%
      required an inpatient admission and overnight stay. The most common symptoms
      reported at the time of transfusion were lethargy, tiredness and breathlessness.
      Further research is needed to evaluate the role of blood transfusions in patients
      receiving cytotoxic chemotherapy.

PMID- 10638974
TI  - Treatment of unresectable, locally advanced pancreatic adenocarcinoma with
      combined radiochemotherapy with 5-fluorouracil, leucovorin and cisplatin.
AB  - The aim of the study was to evaluate the effectiveness and safety of a combined
      treatment modality including systemic chemotherapy with 5-fluorouracil (FU),
      leucovorin, cisplatin and external beam radiotherapy in patients with locally
      advanced pancreatic cancer. Systemic chemotherapy consisted of FU 400 mg m(-2)
      and leucovorin 20 mg m(-2) both given as intravenous bolus injection on days 1-4,
      plus cisplatin 20 mg m(-2) administered as 90-min infusion on days 1-4. Treatment
      courses were repeated every 4 weeks x 6 unless prior evidence of progressive
      disease. Radiation therapy using megavolt irradiation of > or = 6 MV photons with
      a 3- or 4-field technique was delivered during the second and third chemotherapy
      course, that was reduced in dose by 25%. Between October 1994 and July 1996, a
      total of 38 patients were entered onto this trial, all of whom were assessable
      for toxicity and survival. Eighteen of these (47%) had objective remissions to
      combined radiochemotherapy, including four CR (11%), 13 (34%) had stable disease
      and seven patients (18%) showed tumour progression during treatment. The median
      progression-free interval of the entire study population was 10 months (range 3
      32), and median overall survival was 14.0 months (range 3-45+ months); 53% of all
      patients were alive at 12 months, and 18% of patients were alive at 24 months
      respectively. Severe haematological side-effects comprised neutropenia in 18%,
      thrombocytopenia in 8% and anaemia in 11%. The most frequent non-haematological
      side-effects were nausea/vomiting (WHO grade 3: 18%), and diarrhoea (grade 3:
      13%). This combined radiochemotherapy regimen was tolerable and effective in
      patients with locally advanced pancreatic cancer. Since therapeutic results, in
      fact, compare favourably with other series, including surgical treatment of
      potentially resectable tumours, further evaluation of combined treatment
      modalities in the neoadjuvant setting seems warranted.

PMID- 10638976
TI  - Variations in activin receptor, inhibin/activin subunit and follistatin mRNAs in
      human prostate tumour tissues.
AB  - The possible role of activin in the regulation of malignant prostatic growth was
      studied using RNAase protection assays of activin receptors, inhibin/activin
      subunits and follistatin mRNAs in the human prostatic carcinoma cell lines LNCaP
      FGC, -R and -LNO, in human prostatic carcinoma xenografts and in human prostatic
      tissue. Activin receptor types IA (ActRIA), IB (ActRIB), IIA (ActRIIA) and IIB
      (ActRIIB) mRNAs were generally expressed in prostate epithelial cells, with
      significantly lower levels of ActRIB mRNA in prostate tumour material when
      compared to non-malignant tissue (P < 0.05; Mann-Whitney U-test). Inhibin/activin
      betaA- and betaB-subunit mRNA expression was also found in prostate tissue.
      Androgen-independent xenografts expressed significantly lower amounts of betaB
      subunit mRNA when compared to androgen-dependent xenografts (P< 0.05). While
      betaB-subunit mRNA was expressed by LNCaP-FGC and -LNO cells, virtually no
      expression was found in the androgen-independent LNCaP-R line. Inhibin alpha
      subunit mRNA levels were low or undetectable in all samples investigated.
      Follistatin mRNA was undetectable in LNCaP-sublines, while low levels were found
      in prostatic tissues. In androgen-independent LNCaP-R cells, activin inhibited
      cell growth in a dose-dependent manner. These results suggest that prostate
      tumour progression is accompanied by a decrease of the inhibitory effect of
      locally produced activin by either a decrease in the expression of activin betaB
      subunit mRNA or by a decrease of ActRIB mRNA levels.

PMID- 10638975
TI  - A phase II study of cisplatin and 5-fluorouracil with concurrent
      hyperfractionated thoracic radiation for locally advanced non-small-cell lung
      cancer: a preliminary report from the Okayama Lung Cancer Study Group.
AB  - A recent meta-analysis and randomized studies have demonstrated that combined
      chemoradiotherapy is associated with a survival advantage for selected patients
      with locally advanced unresectable non-small-cell lung cancer (NSCLC). We
      conducted a phase II study of combined chemoradiotherapy to find a more effective
      combination of drugs and radiation than those previously reported for such
      patients. Between January 1994 and November 1996, 50 previously untreated
      patients with locally advanced unresectable NSCLC (stage IIIA with N2 or IIIB
      disease) were entered in this study. Patients were required to have Eastern
      Cooperative Oncology Group performance status < or = 2, age < or = 75 years and
      adequate organ function. Treatment consisted of three cycles of cisplatin (20 mg
      m(-2), days 1-5) and 5-fluorouracil (5-FU) (500 mg m(-2), days 1-5) every 4
      weeks, and concurrent hyperfractionated thoracic radiation (1.25 Gy twice daily,
      with a 6-h interfraction interval; total radiation dose, 62.5-70 Gy). Of the 50
      patients entered, 37 (74%) responded to this chemoradiotherapy, including two
      (4%) with complete response. By a median follow-up time of 41.0 months, 35
      patients had died and 15 were still alive. The median time to progression for
      responding patients was 14.1 months (range, 2.6-51.3+ months). The median
      survival time was 18.7 months, with a survival rate of 66.0% at 1 year, 46.0% at
      2 years and 27.6% at 3 years. Survival outcome was strongly affected by the
      extent of nodal involvement (median survival time, 27.4 months for N0-2 disease
      (n = 37) vs 10.7 months for N3 disease (n = 13); P = 0.007). The major toxicities
      of treatment were leukopenia and neutropenia (> or = Grade 3, 58% and 60%
      respectively). Other toxicities of > or = Grade 3 included thrombocytopenia
      (26%), anaemia (26%), nausea/vomiting (16%) and radiation oesophagitis (6%).
      Treatment-related death occurred for one patient. Our findings suggest that
      cisplatin and 5-FU in combination with concurrent hyperfractionated thoracic
      radiation is effective and feasible for the treatment of locally advanced
      unresectable NSCLC. The short-term survival in this study appeared to be more
      encouraging than those of similar chemoradiation trials. A randomized trial will
      be needed to compare the combination of cisplatin and 5-FU with other platinum
      based regimens together with concurrent hyperfractionated thoracic radiation. In
      addition, in future studies, inclusion criteria for N3 disease with or without
      supraclavicular involvement should be reconsidered to correctly evaluate the
      effect of combined chemoradiotherapy for locally advanced unresectable NSCLC.

PMID- 10638977
TI  - Correlation of positive RT-PCR for tyrosinase in peripheral blood of malignant
      melanoma patients with clinical stage, survival and other risk factors.
AB  - The clinical value of the reverse transcription polymerase chain reaction (RT
      PCR) assay for tyrosinase in peripheral blood of melanoma patients is still under
      debate. A total of 212 blood samples from 212 melanoma patients in all clinical
      stages (AJCC) were examined. Erythrocytes were lysed prior to RNA extraction by
      phenol precipitation from 2.7 ml of blood. cDNA for tyrosinase PCR was
      synthesized using random hexamers. Positive tyrosinase RT-PCR results were
      obtained in 11% of 106 stage I patients, 18% of 56 stage II patients, 31% of 26
      stage III patients and 67% of 24 stage IV patients. After a median follow-up of
      36 months (range 26-41), stage III patients with positive RT-PCR for tyrosinase
      had a shortened disease-free interval as compared to negative patients (P <
      0.01). In stage IV patients, median overall survival was 8 months in case of a
      positive RT-PCR in contrast to 12 months in case of a negative test. While
      univariate analysis showed sex and primary tumour location associated with
      positive RT-PCR, multiple regression analysis revealed clinical stage and
      detection of tyrosinase transcripts in peripheral blood as best prognostic
      factors. Hazard ratios for disease-free survival were 19.7 (confidence interval
      (CI) 8.53-45.5, P = 0.0001) for metastatic vs primary disease and 2.96 (CI 1.49
      5.89, P = 0.002) for positive vs negative tyrosinase RT-PCR. The corresponding
      hazard ratios for overall survival were 97.0 (CI 12.7-741, P = 0.0001) and 4.33
      (CI 1.69-11.1, P= 0.002). Our results emphasize the importance of tyrosinase RT
      PCR testing in peripheral blood.

PMID- 10638978
TI  - Bombesin family receptor and ligand gene expression in human colorectal cancer
      and normal mucosa.
AB  - Bombesin-like peptides and their receptors are widely distributed throughout the
      gut and are potential mitogens for a number of gastrointestinal (GI) cancers. We
      have analysed the expression of bombesin-like peptides and their receptor
      subtypes in normal and neoplastic colorectal tissue. Expression was analysed by
      reverse transcription polymerase chain reaction (RT-PCR) using receptor and
      ligand subtype-specific primers and then expression localized by in situ
      hybridization (ISH) with riboprobes synthesized by in vitro transcription of
      cloned PCR product. Colorectal cancer tissue and matched normal mucosa from 23
      patients were studied. Two of these patients had synchronous adenomatous polyps
      and two had synchronous hepatic metastases which were also studied. An additional
      two patients with adenomatous polyps were studied along with matched normal
      mucosa. Gastrin releasing peptide (GRP) receptor and ligand expression was
      present in all samples but with overall greater expression in the tumour samples.
      Neuromedin B (NMB) receptor expression was not detectable. NMB ligand was
      detected in all but one mucosal sample with overall overexpression in the tumour
      samples. Bombesin receptor subtype 3 (BRS-3) receptor expression was not
      detectable. These data support the possibility that GRP may be an autocrine
      growth factor in colorectal cancer.

PMID- 10638979
TI  - Promoter region methylation does not account for the frequent loss of expression
      of the Fas gene in colorectal carcinoma.
AB  - Expression of the apoptosis-promoting Fas gene is frequently reduced or lost
      during the development of colorectal carcinoma. However, loss of heterozygosity
      at the Fas locus or Fas gene rearrangements do not account for the loss of
      expression of Fas, raising the possibility that methylation of the Fas promoter
      may inhibit gene expression in colorectal carcinomas. We have examined the Fas
      promoter region CpG island for evidence of hypermethylation in colorectal
      tumours. Forty-seven specimens of colorectal adenoma and carcinoma, as well as
      six samples of normal colonic mucosa, were examined by Southern blotting for
      methylation at HpaII and Cfol sites in this region. No methylation was detected
      in any of the specimens, suggesting that hypermethylation is not primarily
      responsible for the loss of expression of the Fas gene during colorectal
      tumorigenesis.

PMID- 10638980
TI  - p53 mutations as a marker of malignancy in bladder washing samples from patients
      with bladder cancer.
AB  - The diagnosis and follow-up of patients with bladder cancer rely on invasive
      procedures (cystoscopy with biopsy). Polymerase chain reaction (PCR)-based
      technologies may allow the sensitive detection of cancer-related genetic
      mutations in exfoliated tumour material, potentially allowing the development of
      less invasive techniques. This pilot study investigated the feasibility of
      detecting mutations in exons 5-8 of the p53 gene using single-stranded
      conformational polymorphism (SSCP) analysis in bladder-washing specimens from
      patients with bladder cancer. Bladder-washing samples (31) were collected from
      patients (27) with bladder cancer. An abnormal additional SSCP band was detected
      in five samples from five different patients suggesting the presence of a p53
      mutation. In all five cases the same abnormal SSCP pattern was demonstrated in
      samples of the corresponding bladder tumour. In one case bladder washings were
      available from the same patient on two separate occasions with one washing
      demonstrating a mutation and the other not. In two further cases a mutation was
      demonstrated in the bladder tumour but not in the corresponding washing. It is
      concluded that it is possible to detect and characterize p53 mutations in bladder
      washing samples from patients with bladder cancer. Improved sensitivity in
      detecting mutations in a sample containing a mixture of normal and malignant
      cells may lead to the clinical applicability of molecular methods of disease
      monitoring.

PMID- 10638981
TI  - Overexpression of stathmin in breast carcinomas points out to highly
      proliferative tumours.
AB  - We recently discovered that stathmin was overexpressed in a subgroup of human
      breast carcinomas. Stathmin is a cytosolic phosphoprotein proposed to act as a
      relay integrating diverse cell signalling pathways, notably during the control of
      cell growth and differentiation. It may also be considered as one of the key
      regulators of cell division for its ability to destabilize microtubules in a
      phosphorylation-dependent manner. To assess the significance of stathmin
      overexpression in breast cancer, we evaluated the correlation of stathmin
      expression, quantified by reverse transcription polymerase chain reaction, with
      several disease parameters in a large series of human primary breast cancer (n =
      133), obtained in strictly followed up women, whose clinico-pathological data
      were fully available. In agreement with our preliminary survey, stathmin was
      found overexpressed in a subgroup of tumours (22%). In addition, overexpression
      was correlated to the loss of steroid receptors (oestrogen, P = 0.0006;
      progesterone, P = 0.008), and to the Scarff-Bloom-Richardson histopathological
      grade III (P= 0.002), this latter being ascribable to the mitotic index component
      (P= 0.02). Furthermore studies at the DNA level indicated that stathmin is
      overexpressed irrespective of its genomic status. Our findings raise important
      questions concerning the causes and consequences of stathmin overexpression, and
      the reasons of its inability to counteract cell proliferation in the
      overexpression group.

PMID- 10638982
TI  - Screening for BRCA2 mutations in 81 Dutch breast-ovarian cancer families.
AB  - We have analysed 81 families with a history of breast and/or ovarian cancer for
      the presence of germline mutations in BRCA2 with a number of different mutation
      screening techniques. The protein truncation test (PTT) for exons 10 and 11
      detected four different frame-shifting mutations in six of these families. Four
      of the remaining 75 families had given positive linkage evidence for being due to
      BRCA2. In these families the entire coding region was analysed by single-strand
      conformational polymorphism, leading to the detection of a non-sense and a splice
      site mutation in two of them. While these studies were in progress, Southern
      analysis of BRCA1 revealed that in our study-population of 81 families, 15
      families were segregating either the exon 13 or exon 22 deletion in BRCA1 (Petrij
      Bosch et al (1997) Nat Genet 17: 341-345). This prompted us to examine BRCA2 in
      the remaining 58 families by Southern analysis, using two different restriction
      enzymes. No aberrations were found in the restriction patterns. Thus, contrary to
      BRCA1, large genomic rearrangements within the BRCA2 gene do not represent a
      major mutation mechanism among Dutch breast cancer families.

PMID- 10638983
TI  - Expression of cytokeratin 20 in thyroid carcinomas and peripheral blood detected
      by reverse transcription polymerase chain reaction.
AB  - We investigated a nested reverse transcriptase polymerase chain reaction (RT-PCR)
      system to detect CK20 mRNA in thyroid carcinomas, benign thyroid diseases and
      peripheral blood to improve diagnosis of thyroid carcinoma and to detect
      disseminated tumour cells. Frozen tissue samples of 46 thyroid carcinomas and 30
      benign thyroid diseases (14 multinodular goiters, 14 follicular adenomas, two
      Hashimoto's thyroiditis) were obtained intraoperatively. Preoperative blood
      samples were drawn from 31 patients with thyroid cancer, nine patients with
      benign thyroid disorders and 20 healthy volunteers. Nine out of nine medullary,
      9/12 follicular, 7/19 papillary and 2/6 anaplastic carcinomas expressed CK20
      transcripts. CK20 mRNA was undetectable in 30 tissue sections of benign thyroid
      diseases. Circulating tumour cells were found in the blood of 3/8 patients with
      medullary carcinoma, 2/8 patients with follicular carcinoma, 2/11 patients with
      papillary carcinoma and 1/4 patients with an anaplastic carcinoma. Nine blood
      samples of patients with benign thyroid diseases and 20 healthy volunteers tested
      negative. For the first time CK20 mRNA could be detected in tissue sections of
      thyroid carcinomas and peripheral blood samples of patients with thyroid cancer.
      It was not detectable in benign thyroid diseases. Our results therefore strongly
      suggest that CK20 RT-PCR assays may improve the diagnosis of thyroid carcinoma
      and is able to detect circulating tumour cells in peripheral blood of thyroid
      carcinoma patients.

PMID- 10638984
TI  - Eukaryotic initiation factor-4E in superficial and muscle invasive bladder cancer
      and its correlation with vascular endothelial growth factor expression and tumour
      progression.
AB  - Vascular endothelial growth factor (VEGF) is an important factor mediating tumour
      angiogenesis. VEGF mRNA is differentially expressed in bladder cancer with high
      expression in superficial tumours (stage pTa and pT1) contrasting with low
      expression in muscle invasive tumours (stage > or = pT2). To investigate
      mechanisms regulating VEGF expression in bladder cancer, VEGF mRNA and protein
      were measured in normal bladder (n = 12) and primary bladder cancers (n = 57).
      VEGF protein levels correlated with mRNA expression in normal bladder (r = 0.68,
      P = 0.02) and bladder cancer (r = 0.46, P = 0.0007). Whilst VEGF mRNA expression
      was threefold higher in superficial compared to muscle invasive bladder cancers
      (P = 0.0001) there was no difference in VEGF protein (P = 0.81). Accordingly, the
      median protein:mRNA ratios increased more than 15-fold with increasing tumour
      stage (P < 0.0001) suggesting translational regulation. Expression of the
      eukaryotic initiation factor-4E (elF-4E), a factor implicated in the
      translational regulation of VEGF, was greater in tumours than normal bladder (P <
      0.0001) and correlated with VEGE protein:mRNA ratios (n = 43, r = 0.54, P =
      0.0004) pointing to its role in the regulation of VEGF. In superficial tumours (n
      = 37) high expression of eIF-4E was associated with a poor prognosis and reduced
      stage progression-free survival (P = 0.04, Cox proportional hazards model). The
      study demonstrates that eIF-4E may be involved in translational regulation of
      VEGF in bladder cancer and might have a role as a prognostic factor in bladder
      cancer.

PMID- 10638985
TI  - Histamine, mast cells and tumour cell proliferation in breast cancer: does
      preoperative cimetidine administration have an effect?
AB  - Endogenous histamine has been shown to effect growth mechanisms in experimental
      mammary carcinomas via H2 membrane receptors (Cricco et al, 1994). Both H1 and H2
      binding sites are present in human mammary glands but only 75% malignant
      carcinomas express H2 receptors (Lemos et al, 1995). The presence of mast cells
      around tumour tissue raises questions concerning the source of histamine in
      breast tumour tissue. While cimetidine, an H2 antagonist, has been shown to
      influence the presence of tumour infiltrating lymphocytes (TIL) in colorectal
      cancer (Adams and Morris, 1994, 1997) that was not found to be the case in breast
      cancer (Ng et al, 1995). In recent studies tumour cell proliferation, as measured
      by Ki-67 antibody labelling, has been seen as an additional prognostic indicator
      in breast cancer (Railo et al, 1993, 1997; Ferno, 1998; Schauer et al, 1998). We
      investigated the possibility that cimetidine may influence tumour proliferation
      by blocking the growth-promoting effects of histamine. No relationship between
      preoperative cimetidine administration and tumour cell proliferation was seen
      overall. A weak correlation was seen between tissue histamine content and mast
      cell count which was not influenced by cimetidine. Tumour cell proliferation
      correlated well with other prognostic indicators such as grade and
      differentiation.

PMID- 10638986
TI  - Application of an original RT-PCR-ELISA multiplex assay for MDR1 and MRP, along
      with p53 determination in node-positive breast cancer patients.
AB  - The long-term prognostic value of tumoural MDR1 and MRP, along with p53 and other
      classical parameters, was analysed on 85 node-positive breast cancer patients
      receiving anthracycline-based adjuvant therapy. All patients underwent tumour
      resection plus irradiation and adjuvant chemotherapy (the majority receiving
      fluorouracil-epirubicin-cyclophosphamide). Median follow-up for the 54 alive
      patients was 7.8 years. Mean age was 53.7 years (range 28-79) and 54 patients
      were post-menopausal. MDR1 and MRP expression were quantified according to an
      original reverse transcription polymerase chain reaction multiplex assay with
      colourimetric enzyme-linked immunosorbent assay detection (beta2-microglobulin as
      control). P53 protein was analysed using an immunoluminometric assay (Sangtec).
      MDR1 expression varied within an 11-fold range (mean 94, median 83), MRP within a
      45-fold range (mean 315, median 242) and p53 protein from the limit of detection
      (0.002 ng mg(-1)) up to 35.71 ng mg(-1) (mean 1.18, median 0.13 ng mg(-1)). P53
      protein was significantly higher in oestrogen receptor (ER)-negative than in ER
      positive tumours (P = 0.039). The higher the p53, the lower the MDR1 expression
      (P = 0.015, r= -0.27). P53 was not linked to progesterone receptor (PR) status, S
      phase fraction, or MRP Significantly greater MDR1 expression was observed in
      grade I tumours (P = 0.029). No relationship was observed between MDR1 and MRP.
      Neither MDR1 nor MRP was linked to ER or PR status. Unlike MDR1, MRP was
      correlated with the S phase: the greater the MRP, the lower the S phase (P =
      0.006, r = -0.42). Univariate Cox analyses revealed that MDR1, MRP, p53 and S
      phase had no significant influence on progression-free or specific survival. A
      tendency suggested that the greater the p53, the shorter the progression-free
      survival (P = 0.076 as continuous and 0.069 as dichotomous).

PMID- 10638987
TI  - Bcl-w expression in colorectal adenocarcinoma.
AB  - We have found that the anti-apoptotic Bcl-2 family protein, Bcl-w, was frequently
      expressed in colorectal adenocarcinomas, with 69/75 showing positive staining
      with anti-Bcl-w IgG. Adenomas demonstrated a much lower frequency of Bcl-w
      expression (only 1 of 17), as did adenocarcinomas from other epithelial tissues
      such as breast (0/8), stomach (1112) and cervix (0/12). Bcl-w status could be
      related to the histopathological classification of the tumours, with TNM stage
      III tumours showing significantly higher levels of expression than tumours of
      better prognostic grade (at P = 0.009). Those patients with node involvement also
      had tumours with significantly elevated levels of Bcl-w (at P = 0.02), compared
      to those which were node-negative. The results suggest that Bcl-w could play a
      general role in the progression from adenoma to adenocarcinoma in the colorectal
      epithelium. Currently, more data are being collected to allow us to assess the
      importance of Bcl-w for disease progression and patient survival.

PMID- 10638988
TI  - Evidence for the differential expression of a variant EGF receptor protein in
      human prostate cancer.
AB  - Earlier studies have demonstrated an unexplained depletion of the epidermal
      growth factor receptor (EGFR) protein expression in prostatic cancer. We now
      attribute this phenomenon to the presence of a variant EGFR (EGFRvIII) that is
      highly expressed in malignant prostatic neoplasms. In a retrospective study,
      normal, benign hyperplastic and malignant prostatic tissues were examined at the
      mRNA and protein levels for the presence of this mutant receptor. The results
      demonstrated that whilst EGFRvIII was not present in normal prostatic glands, the
      level of expression of this variant protein increased progressively with the
      gradual transformation of the tissues to the malignant phenotype. The selective
      association of high EGFRvIII levels with the cancer phenotype underlines the role
      that this mutant receptor may maintain in the initiation and progression of
      malignant prostatic growth, and opens the way for new approaches in the
      management of this disease including gene therapy.

PMID- 10638989
TI  - Butyrate regulates E-cadherin transcription, isoform expression and intracellular
      position in colon cancer cells.
AB  - Cell-to-cell adhesion, an important event in differentiation, is impaired during
      advanced stages of tumorigenesis. In this study, we examined the possible
      regulation of cell-adhesion proteins by the differentiation agent butyrate in
      LS174T and HM7 cells, two types of human colon cancer cells that differ in their
      ability to produce mucin and colonize the liver of experimental animals. The more
      aggressive, high-mucin-producing cell line (HM7), a clone selected from LS174T
      cells, showed a scattered and undifferentiated ultramorphological appearance and
      low basal alkaline phosphatase activity; the proteins beta-catenin and E
      cadherin, as detected by immunostaining, were expressed in the cells' nuclei. All
      of these properties were significantly less pronounced in the less aggressive,
      low-mucin-producing LS174T cells. In both cell lines, butyrate treatment enhanced
      cell-to-cell interaction, alkaline phosphate activity, translocation of beta
      catenin and E-cadherin from the nuclei to the membrane junctions, and
      transcription and translation of the 120-kDa E-cadherin isoform, but not of its
      100-kDa isoform. Analysis of possible mechanisms of E-cadherin up-regulation
      revealed that butyrate induces the release of nuclear proteins from the E
      cadherin promoter sequence, reducing transcription repression. We suggest that
      butyrate activates E-cadherin transcription through translocation of nuclear
      transcription factors bearing specific repressor activity. We surmise that
      abrogation of nuclear 100-kDa E-cadherin and beta-catenin expression following
      butyrate treatment is related to the control of E-cadherin gene transcription.

PMID- 10638990
TI  - Risk factors for oral and pharyngeal cancer in women: a study from Italy and
      Switzerland.
AB  - We analysed two case-control studies of women from Italy and Switzerland,
      including 195 cases of oral and pharyngeal cancers and 1113 controls. The
      multivariate odds ratio was 4.6 for heavy smokers and 2.7 for high alcohol
      intake. Vegetables, fruit, beta-carotene and wholegrain foods were inversely,
      butter and retinol directly, related to risk.

PMID- 10638991
TI  - Multiple cancer site comparison of adjusted survival by hospital of treatment: an
      East Anglian study.
AB  - We performed a preliminary investigation into which hospitals would benefit from
      investment and development, and which should have services restricted, with
      respect to the implementation of the Calman-Hine strategy of specialist cancer
      care. A retrospective study approach was used implementing uniform definitions
      for colon, rectal, breast, melanoma, bladder and ovarian cancers. A total of 14
      527 cases registered by the East Anglian cancer registry and diagnosed between
      1989 and 1993 were included. The cases were analysed in two age groups (< 75, 75+
      years) and two hospital groups: group 1, those treated at hospitals with
      radiotherapy and oncology departments; group 2, other district general hospitals.
      Adjusted hazard ratios derived from Cox's proportional hazards model and adjusted
      conditional survival curves were presented. We found that after adjustment for
      age, sex and tumour stage at diagnosis, survival up to 5 years after diagnosis
      was usually worse in group 2 hospitals and significantly so for patients aged <
      75 years with breast, ovarian and rectal tumours. Hospital workload produced
      little significant effect independently from hospital group. Analysing the
      selected cancer sites using uniform definitions and consistent staging supports
      the view that the strategy proposed in the Calman-Hine report is likely to be
      beneficial, but particular priority for change should be given to younger
      patients with breast, ovarian and rectal tumours.

PMID- 10638992
TI  - Sample size calculation for clinical trials: the impact of clinician beliefs.
AB  - The UK Medical Research Council (MRC) randomized trial of gastric surgery, ST01,
      compared conventional (D1) with radical (D2) surgery. Sample size estimation was
      based upon the consensus opinion of the surgical members of the design team,
      which suggested that a change in 5-year survival from 20% (D1) to 34% (D2) could
      be realistic and medically important. On the basis of these survival rates, the
      sample size for the trial was 400 patients. However, this trial was exceptional
      in the way that a survey of surgeons' opinions was made at the start of the
      trial, in 1986, and again before results were analysed but after termination of
      the trial in 1994. At the initial survey, the three surgeons from the trial
      steering committee and 23 other surgeons experienced in treating gastric
      carcinoma were given detailed questionnaires. They were asked about the expected
      survival rate in the D1 group, anticipated difference in survival from D2
      surgery, and what difference would be medically important and influence future
      treatment of patients. The consensus opinion of those surveyed was that there
      might be a survival improvement of 9.4%. In 1994, prior to closure of the trial,
      and before any survival information was disclosed, the survey was repeated with
      21 of the original 26 surgeons. At this second survey, the opinion of the trial
      steering committee was that 9.5% difference was more realistic. This was in
      accord with the opinion of the larger group, which remained little changed since
      1986. The baseline 5-year D1 survival was thought likely to be about 32%, which
      corresponded closely to the actual survival of recruited patients. Revised sample
      size calculations suggested that, on the basis of these more recent opinions,
      between 800 and 1200 patients would have been required. Both surveys assessed the
      level of treatment benefit that was deemed to be sufficient for causing surgeons
      to change their practice. This showed that the 13% difference in survival used as
      the study target was clinically relevant, but also indicated that many clinicians
      would remain unwilling to change their practice if the difference is only 9.5%.
      The experience of this carefully designed trial illustrates the problems of
      designing long-term, randomized trials. It raises interesting questions about the
      common practice of basing sample size estimates upon the beliefs of a trial
      design committee that may include a number of enthusiasts for the trial
      treatment. If their opinion of anticipated effect sizes drives the design of the
      trial, rather than the opinion of a larger community of experts that includes
      sceptics as well as enthusiasts, there is likely to be a serious miscalculation
      of sample size requirements.

PMID- 10638993
TI  - Radiation risk and mammographic screening of women from 40 to 49 years of age:
      effect on breast cancer rates and years of life.
AB  - The aim of this study was to evaluate the carcinogenic risks associated with
      radiation in mass mammographic screening. Assessment was in terms of breast
      cancer mortality and years of life for a hypothetical cohort of 100 000 women.
      Data were obtained on incidence, mortality and life expectancy for the female
      population of Stockholm. With a screening interval of 18 months at ages 40-49
      years, a total absorbed dose to the breast of 13 mGy per invited woman; and an
      annual breast cancer reduction of 25% per year 7 years from screening start, the
      net number of years gained was at least 2800. However, using the highest absorbed
      dose reported in routine mammographic screening in Sweden (approximately 3 mGy
      per view), and the highest reported radiation risk in the literature, a programme
      entailing annual screening with 2 views would require at least a 20% annual
      reduction in breast cancer mortality to give a net benefit in both the number of
      years of life gained and number of breast cancer deaths avoided. This observation
      supports the conclusion that exposures with low absorbed dose are essential when
      performing mass screening with mammography among young women.

PMID- 10638994
TI  - Gender differences in lung cancer risk by smoking: a multicentre case-control
      study in Germany and Italy.
AB  - Several studies in the past have shown appreciably higher lung cancer risk
      estimates associated with smoking exposure among men than among women, while more
      recent studies in the USA report just the opposite. To evaluate this topic in a
      European population we conducted a case-control study of lung cancer in three
      German and three Italian centres. Personal interviews and standardized
      questionnaires were used to obtain detailed life-long smoking and occupational
      histories from 3723 male and 900 female cases and 4075 male and 1094 female
      controls. Lung cancer risk comparing ever-smokers with never-smokers was higher
      among men (odds ratios (OR) adjusted for age and centre = 16.1, 95% confidence
      interval (CI) 12.8-20.3) than among women (OR = 4.2, CI 3.5-5.1). Because the
      smoking habits of women were different from men, we conducted more detailed
      analyses using comparable levels of smoking exposure. After restriction to
      smokers and adjustment for other smoking variables, risk estimates did not differ
      appreciably between genders. The analysis of duration of smoking (0-19, 20-39,
      40+ years) adjusted for cigarette consumption and time since quitting smoking
      revealed similar risk estimates in men (OR = 1.0, 3.3 [CI 2.6-4.2], 4.1 [CI 3.1
      5.6]) and women (OR = 1.0, 2.7 [CI 1.7-4.1], 3.3 [CI 1.9-5.8]). The same was true
      of the analysis of average or cumulative smoking consumption, and also of
      analyses stratified by different histological types. We conclude that for
      comparable exposure to tobacco smoke, the risk of lung cancer is comparable in
      women and men.

PMID- 10638995
TI  - Patterns of infection and day care utilization and risk of childhood acute
      lymphoblastic leukaemia.
AB  - To investigate if decreased exposure to common childhood infections is associated
      with risk of childhood acute lymphoblastic leukaemia (ALL) we conducted a case
      control study of 1842 newly diagnosed and immunophenotypically defined cases of
      ALL under age 15, and 1986 matched controls in the US. Data regarding day care,
      sibship size and common childhood infections were obtained through parental
      interviews. Data were analysed stratified by leukaemia lineage and separately for
      'common' childhood ALL (age 2-5 years, CD19, CD10-positive). Neither attendance
      at day care nor time at day care was associated with risk of ALL overall or
      'common' ALL. Ear infections during infancy were less common among cases, with
      odds ratios of 0.86, 0.83, 0.71 and 0.69 for 1, 2-4, 5+ episodes, and continuous
      infections respectively (trend P = 0.026). No effect of sibship size or birth
      interval was seen. With one exception (ear infections), these data do not support
      the hypothesis that a decrease in the occurrence of common childhood infection
      increases risk of ALL.

PMID- 10638997
TI  - Survival in renal cell carcinoma: a randomized evaluation of tamoxifen vs
      interleukin-2, alpha-interferon (leucocyte) and tamoxifen.

PMID- 10638996
TI  - Height-related risk factors for prostate cancer.
AB  - Previous studies have reported that adult height is positively associated with
      the risk of prostate cancer. The authors carried out a population-based case
      control study involving 317 prostate cancer cases and 480 controls to further
      investigate the possibility that height is more strongly associated with
      advanced, compared with localized forms of this disease. Since the inherited
      endocrine factors, which in part determine height attained during the growing
      years, may influence the risk of familial prostate cancer later in life, the
      relationship with height was also investigated for familial versus sporadic
      prostate cancers. Adult height was not related to the risk of localized prostate
      cancer, but there was a moderate positive association between increasing height
      and the risk of advanced cancer (relative risk (RR) = 1.62; 95% confidence
      interval (CI) 0.97-2.73, upper versus lowest quartile, P-trend = 0.07). Height
      was more strongly associated with the risk of prostate cancer in men with a
      positive family history compared with those reporting a negative family history.
      The RR of advanced prostate cancer for men in the upper height quartile with a
      positive family history was 7.41 (95% CI 1.68-32.67, P-trend = 0.02) compared
      with a reference group comprised of men in the shortest height quartile with a
      negative family history. Serum insulin-like growth factor-1 levels did not
      correlate with height amongst men with familial or sporadic prostate cancers.
      These findings provide evidence for the existence of growth-related risk factors
      for prostate cancer, particularly for advanced and familial forms of this
      disease. The possible existence of inherited mechanisms affecting both somatic
      and tumour growth deserves further investigation.

PMID- 10638998
TI  - Hereditary factors in basal cell carcinoma of the skin: a population-based cohort
      study in twins.

PMID- 10638999
TI  - The relation of gelatinase (MMP-2 and -9) expression with distant site metastasis
      and tumour aggressiveness in colorectal cancer.

PMID- 10639000
TI  - The history of inhibitors of angiotensin converting enzyme.
AB  - This review paper by Sir John Vane, The Nobel Prize Laureate for the first time
      reveals the insides of discovery of inhibitors of angiotensin converting enzyme
      (ACE-1), presently known as important drugs for the treatment of hypertension,
      congestive heart failure and coronary artery disease.

PMID- 10639001
TI  - The role of endothelium in antithrombotic effect of the renin-angiotensin system
      blockade.
AB  - Drugs blocking the renin - angiotensin system, angiotensin converting enzyme
      inhibitors and AT1 receptor antagonists, among many pharmacological effects may
      exert an antithrombotic action. The mechanisms, which mediate their
      antithrombotic activity are associated with enhanced nitric oxide and
      prostacyclin release or with attenuation of angiotensin II action (Fig. 1, 2).
      Nevertheless, endothelium plays an important role in this process linking the
      renin-angiotensin and fibrinolysis / coagulation systems.

PMID- 10639002
TI  - Coronary vascular endothelium-myocyte interactions in protection of the heart by
      ischaemic preconditioning.
AB  - Because ischaemia preconditioning is a general phenomenon - it is present in
      almost all tissues and organs - we must look for a mechanism which involves cell
      types common to all organs. The hypothesis outlined below is that endothelial
      cells, in response to a brief ischaemic stimulus, release protective mediators
      which (in the heart) diffuse to cardiac myocytes to increase resistance to a
      subsequent ischaemic stress. These substances include nitric oxide, generated
      through initial bradykinin release, and prostacyclin. The evidence includes
      measurement of mediator release and the pharmacological attenuation of the
      antiarrythmic effects of preconditioning by blockade of bradykinin receptors and
      inhibition of nitric oxide production.

PMID- 10639003
TI  - The third pathway: endothelium-dependent hyperpolarization.
AB  - In response to various neurohumoral substances endothelial cells release nitric
      oxide (NO), prostacyclin and produce hyperpolarization of the underlying vascular
      smooth muscle cells, possibly by releasing another factor termed endothelium
      derived hyperpolarizing factor (EDHF). EDHF-mediated responses are sensitive to
      the combination of two toxins, charybdotoxin plus apamin, but do not involve ATP
      sensitive or large conductance calcium-activated potassium channels. As
      hyperpolarization of the endothelial cells is required in order to observe
      endothelium-dependent hyperpolarization, and electrical coupling through myo
      endothelial gap junctions may explain the phenomenon. An alternative explanation
      is that the hyperpolarization of the endothelial cells causes an efflux of
      potassium that in turn activates the inwardly rectifying potassium conductance
      and the Na+/K+ pump of the smooth muscle cells. Endothelial cells produce
      metabolites of the cytochrome P450-monooxygenase that activate BKCa, and induce
      hyperpolarization of coronary arterial smooth muscle cells. The elucidation of
      the mechanism underlying endothelium-dependent hyperpolarization and the
      discovery of specific inhibitors of the phenomenon are prerequisite for the
      understanding of the physiological role of this alternative endothelial pathway
      involved in the control of vascular tone in health and disease.

PMID- 10639004
TI  - Endothelial no release caused by red wine polyphenols.
AB  - Epidemiological studies have suggested that moderate consumption of red wine
      might reduce the risk of cardiovascular disease. Red Wine Polyphenolic Compounds
      (RWPC), a complex extract obtained from red wine, causes endothelium-dependent
      vasorelaxation in rat aortic rings pre-contracted with noradrenaline. This effect
      is associated with marked formation of NO in the vessel (directly shown by
      electron paramagnetic resonance spectroscopy) and it is abolished by the NO
      synthase inhibitor N(G)-nitro-L-arginine methylester (300 microM). It is mimicked
      by some defined polyphenols (like the anthocyanin delphinidin) but not by others
      (malvidin, cyanidin, quercetin, catechin, epicatechin), despite close structures.
      In addition, RWPC causes an extracellular Ca(2+)-dependent increase in [Ca2+]i in
      endothelial but not in smooth muscle cells. The efficiency of RWPC in inducing NO
      production in the aorta and increase in [Ca2+]i, in endothelial cells is
      comparable to those of carbachol and bradykinine, respectively. These findings
      provide evidence that RWPC and polyphenols with selective structures can activate
      an undefined target in endothelial cells. The resulting increase in [Ca2+]i
      activation of NO-synthase and enhanced formation of NO may be involved in
      cardiovascular protection.

PMID- 10639005
TI  - Endotoxin-endothelium interactions in "low-perfusion state" research.
AB  - LPS/endotoxin provokes a plethora of pathological events some of which may be
      considered as examples of "low perfusion state". These are discussed here. It is
      well known that hypotension and refractoriness to vasocostrictors are the
      hallmark of endotoxic shock. Nevertheless, there are some vascular beds, such as
      mesenteric circulation, that respond with vasoconstriction - not vasodilation to
      endotoxin. Aminoguanidine, an inhibitor of NOS-2, blocks endotoxin- induced
      increase of resistance in mesenteric bed and endotoxin-induced translocation of
      bacteria through the gut wall. It is postulatede that endotoxin has
      antiarrythmogenic action due to the release of nitric oxide and increase in
      intracellular cGMP levels. Although we demonstrate that endotoxin increases
      nitric oxide formation in spleen and liver, its contribution to the injury of
      these organs by endotoxin is not fully established. In addition, we present our
      immunochemistry data on nitrotyrosine formation in the liver and spleen of
      endotoxin-treated animals.

PMID- 10639006
TI  - Biphasic response to lipopolysaccharide from E. coli in the isolated ventilated
      blood-perfused rat lung.
AB  - We characterised early circulatory and respiratory responses to
      lipopolysaccharide from E. coli (LPS, serotype 0127:B8) in the isolated,
      ventilated and perfused rat lung preparation. Lungs were isolated from
      anaesthetised Wistar rats and perfused with full blood, platelet rich plasma
      (PRP), platelet poor plasma (PPP) or Krebs-Henseleit solution (KH). LPS (300
      microg/ml) injected into the blood-perfused lung induced a characteristic
      biphasic response consisting of an immediate, transient decrease in respiratory
      tidal volume and an increase in pulmonary perfusion pressures followed by a
      delayed decrease in respiratory tidal volume. An immediate
      respiratory/circulatory response to LPS was of considerable magnitude only in
      full blood-perfused lung whereas the delayed response was fully expressed
      irrespective whether blood, PRP, PPP or KH was used for the lung perfusion.
      Immediate respiratory/circulatory response was inhibited by WEB 2170 (100
      microM), a PAF receptor antagonist, and by camonagrel (300 microM), a TXA2
      synthase inhibitor, but not by MK 571 (100 microM), a cysteinyl leukotriene
      receptor antagonist. Delayed respiratory response was inhibited by camonagrel
      only. In summary, we demonstrated that the immediate coupled
      respiratory/circulatory response is mediated by blood cell-derived PAF and TXA2
      whereas the delayed uncoupled respiratory response is mediated by lung parenchyma
      derived TXA2.

PMID- 10639007
TI  - Cysteinyl-leukotriene receptors in pulmonary vessels.
AB  - Two categories of cysteinyl-leukotrienes have been proposed, namely, CysLT1 and
      CysLT2. These receptors are found not only on the vascular smooth muscle but also
      on the endothelium. Activation of the receptor(s) on vascular smooth muscle
      provokes contraction whereas activation of the receptors on the endothelium
      produces contraction and/or relaxation. These endothelium dependent effects are
      due to the release of both contractile and relaxant factors derived from the
      endothelium. While factors derived from either the cyclooxygenase or nitric oxide
      pathways are involved, in some vascular preparations other mediators such as
      endothelin may be involved. However, in isolated human pulmonary vascular
      preparations, this appears not to be the case and presently the nature and origin
      of the contractile factor remains to be established.

PMID- 10639008
TI  - Nitric oxide release from normal and dysfunctional endothelium.
AB  - The endothelium plays a critical role in maintaining vascular tone by releasing
      vasoconstrictor and vasodilator substances. Endothelium - derived nitric oxide
      (NO) is a vasodilator rapidly inactivated by superoxide (O2-) found in
      significant quantities. The porphyrinic sensor (0.5-8 microm diameter) and
      chemiluminescence methods were used to measure NO and (O2-) respectively. Effects
      of hypertension, low density lipoprotein (LDL), and heart preservation on the
      release of NO and O2- were delineated. In the single endothelial cell (rat aorta)
      NO concentration was the highest in the cell membrane decreasing exponentially
      with distance from cell, and becoming undetectable beyond 50 microm and 25 microm
      for normotensive (WKY) and hypertensive (SHR) rats respectively. The endothelium
      of SHR released 40% less NO (300+/-25 nmol L(-1)) than that of normotensive rats
      (500+20 nmol L(-1)), due to the higher production of O2- in SHR rats. An
      exponentially decreasing NO production (from 1.20 +/- 0.15 to 0.16 +/- 0.05
      micromol (L-1)) and concomitant increase of O2- generation (from 10 +/- 0.3 to
      300 +/- 25 nmol L(-1) were observed in left ventricle of stored (eight hours)
      rabbit heart. Native and oxidized low density lipoproteins (nLDL and oxLDL)
      inhibited NO generation and increased O2- production. The local depletion of the
      L-arginine substrate may disarrange the nitric oxide synthase, leading to
      production of O2- from oxygen.

PMID- 10639009
TI  - Enhanced expression of leptin following acute gastric injury in rat.
AB  - Leptin, a product of ob-gene plays an important role in the regulation of food
      intake. Recently, leptin expression has been detected in gastric epithelium, but
      the physiologic role of gastric leptin remains unknown. The purpose of this study
      was: 1) to determine the effect of gastric injury by ethanol and aspirin on the
      expression of leptin in gastric mucosa and 2) to investigate whether exogenous
      leptin affects the integrity of gastric mucosa exposed to noxious agents such as
      ethanol or aspirin. In Wistar rats the acute gastric lesions were induced by
      intragastric application of 1.5 ml of 75% ethanol or acidified aspirin (100 mg/kg
      in 0.2 N HCl). Rats were divided into two groups and pretreated either with
      leptin (1-10 microg/kg i.p.) or vehicle (saline). Rats were anesthetized 1 h
      after i.g. induction of acute gastric lesions and the gastric blood flow (GBF)
      was measured by H2 gas clearance method. Then the rats were sacrificed, the
      stomach was excised and the mean lesions area was assessed by planimetry. In
      addition, mRNA and protein expression for leptin was analyzed in the gastric
      mucosa by reverse transcription polymerase chain reaction (RT-PCR) and Western
      blot, respectively. Both ethanol and acidified aspirin induced acute gastric
      lesions and led to significant reduction in GBF. In the intact gastric mucosa,
      the mRNA and protein expression for leptin was small but detectable. The exposure
      of gastric mucosa to noxious agents such as ethanol and aspirin was associated
      with markedly increased expression for gastric leptin at mRNA and protein level.
      Application of 75% ethanol or acidified aspirin caused wide-spread mucosal
      lesions. The pretreatment with exogenous leptin reduced dose-dependently these
      ethanol or aspirin-induced gastric lesions. The protective effects of exogenous
      leptin were accompanied by a significant attenuation of the fall of GBF. We
      conclude that: 1) Exogenous leptin exerts potent gastroprotective and hyperemic
      actions on gastric mucosa, and 2) Acute injury of gastric mucosa is associated
      with increased expression of leptin suggesting a possible role of this peptide in
      mediating of repair process in injured gastric mucosa.

PMID- 10639010
TI  - Thienopyridines: effects on cultured endothelial cells.
AB  - In cultured endothelial cells harvested from human umbilical vein (HUVEC) or
      bovine aorta (BAEC) the 30 min incubation with calcium ionophore A 23187 (1
      microM) or ticlopidine (100 microM) caused an increase in nitrite generation in
      HUVEC from basal 227 +/- 37 to 372 +/- 60 or to 325 +/- 33 pmoles per 10(6)
      cells, respectively, and in BAEC from basal 182 +/- 17 to 378 +/- 18 or to 423 +/
      66 pmoles per 106 cells (n = 6), respectively. Calcium ionophore A 23187 (1
      microM) or ticlopidine (100 microM) next to 30 min incubation with BAEC increased
      release of 6-keto-PGF 1alpha from basal level of 9.4 +/- 1.8 to 96.2 +/- 5.1 or
      to 99.5 +/- 10.2 pmoles per 10(6) cells, respectively. The pretreatment with
      aspirin (300 microM) cut down this rise to 4.2 +/- 0.1 pmoles per 10(6) cells (n
      = 8). Basal cytoplasmic calcium levels, [Ca2+]i, in immortalised HUVEC cell line 
      ECV304, HUVEC and BAEC were 47.7 +/- 3.3 nM (n = 53), 68.3 +/- 5.0 nM (n = 30)
      and 53.1 +/- 3.0 nM (n = 15), respectively. In these cultured endothelial cells
      calcium ionophore A 23187 (0.1 microM) produced net maximum rise in [Ca2+]i by
      157 +/-27 nM (n = 16)[ ECV304], by 107 +/- 58 nM (n=4) [HUVEC], and by 231.0 +/-
      41.3 nM (n = 8) [BAEC], respectively, while ticlopidine (30 microM) produced net
      maximum rise in [Ca2+]i by 30.0 +/- 3.2 nM (n=9)[ECV304], 48.8 +/- 15.6 nM (n =
      4)[HUVEC] and 28.4 +/- 5.4 nM (n = 8)[BAEC], respectively. Effect of ticlopidine
      on [Ca2+]i was not only weaker than that of calcium A 23187 but also its maximum
      appeared after a lag period that was 2 3 times longer than that for A23187. In
      ECV304 clopidogrel at concentrations of 10, 30 and 100 microM produced maximum
      increment of [Ca2+]i by 16.5 +/- 3.8 nM (n = 7), 47.0 +/- 6.9 nM (n = 8) and 67.2
      +/- 8.3 nM (n = 8), respectively. Incubation of BAEC with A23187 (microM),
      ticlopidine or clopidogrel (100 microM) for 2 h did not influence viability of
      cultured endothelial cells. We claim that thienopyridines, independently of their
      delayed anti-platelet properties ex vivo do release NO and PGI2 from cultured
      endothelial cells in vitro. The above endothelial action of thienopyridines might
      be mediated by a rise in [Ca2+]i, however, this possibility has not been proved.

PMID- 10639011
TI  - Reversal of the postischaemic suppression of coronary function in perfused guinea
      pig heart by ischaemic preconditioning.
AB  - In the isolated guinea pig hearts suppression of endothelium-dependent
      (Acetylcholine, Substance P, postocclusive hyperaemia) and endothelium
      independent (Sodium nitroprusside, PGE1) responses after 30 min subglobal
      ischaemia (reduction of coronary flow to 5%) were analysed in hearts which were
      not preconditioned or preconditioned by various protocols. Preconditioning
      consisted of single 5 min ischaemia (IP5) or single 10 min ischaemia (IP10) or
      double 5 min ischaemia (IP5 + 5). Thirty minutes of ischaemia followed by
      reperfusion reduced both endothelium-dependent and endothelium-independent
      responses approximately by 30-50% and slightly suppressed basal coronary flow by
      10%. IP5 and IP5 + 5 protected against postischaemic suppression of responses to
      NaNP but not against postischaemic impairment of SP, ACh, and POH responses. The
      endothelium-dependent responses and postischaemic suppression of basal coronary
      flow were protected by IP10 only. In summary, in the isolated guinea pig heart
      the 30-min ischaemia impairs vasodilator responses to both endothelium-dependent
      and endothelium-independent agents. Ischaemic preconditioning protects both
      endothelial and smooth muscle cells function against this impairment, though
      endothelial cells require a more extensive preconditioning to put in motion
      protective mechanisms than smooth muscle cells do. Independent mechanisms of IP
      in endothelial cells and in smooth muscle cells are suggested.

PMID- 10639012
TI  - Effect of ischemic preconditioning on endothelial dysfunction and granulocyte
      adhesion in isolated guinea-pig hearts subjected to ischemia/reperfusion.
AB  - It has been demonstrated that ischemic preconditioning (IPC) affords protection
      against the post-ischemic endothelial dysfunction. Here, a hypothesis was tested
      that IPC, by protecting the endothelium, prevents also the adherence of
      granulocytes (PMNs) in the post-ischemic heart. Langendorff-perfused guinea-pig
      hearts were subjected to 30 min ischemia/30 min reperfusion (IR) and peritoneal
      PMNs were infused between 15 and 25 min of the reperfusion. Acetylcholine (ACh)
      induced coronary vasodilatation and nitrite outflow were used to measure
      endothelial function and coronary flow response to sodium nitroprusside (SNP)
      served as a measure of endothelium-independent vascular function. The endothelial
      adherence of PMNs to the coronary microvessels was assessed in histological
      preparation of the myocardium. In the hearts subjected to IR, ACh-induced
      vasodilatation and nitrite outflow were reduced by 55% and 69%, respectively, SNP
      response remained unaltered, and 22% of microvessels were occupied by PMNs, as
      compared to 2% in the sheam perfused hearts. These alterations were attenuated by
      IPC (3 x 5 min ischemia). A selectin blocker, sulfatide, prevented IR-induced
      PMNs adherence and did not affect the responses to ACh and SNP. These data
      demonstrate that IR leads to the endothelial dysfunction and to the selectin
      mediated PMNs adhesion in the isolated guinea-pig and that IPC attenuates both
      alterations. We speculate that the pro-adhesive effect of IR is secondary to the
      endothelial injury and that the anti-PMNs action represents a novel
      cardioprotective mechanism of IPC.

PMID- 10639013
TI  - Effects of nitric oxide and prostacyclin on deformability and aggregability of
      red blood cells of rats ex vivo and in vitro.
AB  - Although many diseases of the heart and circulatory system have been linked with
      insufficient deformability and increased aggregability of red blood cells, there
      are only a few drugs which can modulate these biological functions of
      erythrocytes. Here, we show evidences that iloprost, stable prostacyclin analogue
      and SIN-1, active metabolite of molsidomine which spontaneously releases NO, may
      be sufficient pharmacological tools for modulating red blood cell deformability
      and aggregability. Deformability of red blood cells was measured by shear stress
      laser diffractometer (Rheodyn SSD) and expressed in percent of red blood cell
      deformability index (DI). MA-1 (Myrenne) erythrocyte aggregometer was used for
      photometric measurements of aggregability in arbitrary units (MEA) of mean extent
      of aggregation. Experiments were carried out on rats ex vivo and in vitro using
      whole rat blood or isolated erythrocytes. Ex vivo SIN-1 (infusion 2 mg/kg/min
      i.v.) and iloprost (bolus injection 10 microg/kg i.v.) significantly improved
      erythrocyte deformability and aggregability at 5-15 min after administration. L
      NAME (10 mg/kg i.v.)- inhibitor of nitric oxide synthase, and aspirin (1 mg/kg
      i.v.) caused worsening of deformability of erythrocytes in experiments ex vivo.
      Studies in vitro also revealed improvement of red blood cell deformability and
      aggregability by SIN-1 (3 microM, 15 min incubation at 22 degrees C) or iloprost
      (1 microM, 15 min incubation at 22 degrees C) and this phenomenon appeared not
      only in whole blood but also in isolated red cells. It is concluded that NO- and
      prostacyclin-induced improvement of red blood cell deformability and
      aggregability results from direct action of these compounds on erythrocytes. NO
      donors and iloprost could be useful in the treatment of disorders of blood
      fluidity.

PMID- 10639014
TI  - Cross talk between NO and cyclic nucleotide phosphodiesterases in the modulation
      of signal transduction in blood vessel.
AB  - An increase in cAMP and/or cGMP induces vasodilation which could be potentiated
      by endothelium or NO-donors. Cyclic nucleotide phosphodiesterases (PDE) are
      differently distributed in vascular tissues. cAMP hydrolyzing PDE isozymes in
      endothelial cells are represented by PDE2 (cGMP stimulated-PDE) and PDE4 (cGMP
      insensitive-PDE), whereas in smooth muscle cells PDE3 (cGMP inhibited-PDE) and
      PDE4 are present. To investigate the role of NO in vasodilation induced by PDE
      inhibitors, we studied the effects of PDE3- or PDE4-inhibitor alone and their
      combination on cyclic nucleotide levels, on relaxation of precontracted aorta and
      on protein kinase implication. Furthermore, the direct effect of dinitrosyl iron
      complex (DNIC) was studied on purified recombinant PDE4B. The results show that:
      1) in endothelial cells PDE4 inhibition may up-regulate basal production of NO,
      this effect being potentiated by PDE2 inhibition; 2) in smooth muscle cGMP
      produced by NO inhibits PDE3 and increases cAMP level allowing PDE4 to
      participate in vascular contraction; 3) protein kinase G mediates the relaxing
      effects of PDE3 or PDE4 inhibition. 4) DNIC inhibits non competitively PDE4B
      indicating a direct effect of NO on PDE4 which could explain an additive
      vasodilatory effect of NO. A direct and a cGMP related cross-talk between NO and
      cAMP-PDEs, may participate into the vasomodulation mediated by cAMP activation of
      protein kinase G.

PMID- 10639015
TI  - Positive and negative outcomes of L-arginine therapy in cardiovascular diseases.
AB  - The author reviews controlled clinical investigation on the effectiveness of L
      arginine in cardiovascular diseases. Positive results were observed in
      hyperlipidemic subjects and in patients with a critical stage of the peripheral
      arterial occlusive disease. Patients with stable ischemic heart disease responded
      to L-arginine to some extent, while results of L-arginine therapy in congestive
      heart failure are inconsistent. Null effects if L-arginine has been documented in
      essential hypertension.

PMID- 10639016
TI  - COX-2 is not involved in thromboxane biosynthesis by activated human platelets.
AB  - The occurrence of aspirin resistance has been inferred by the assessment of
      platelet aggregation ex vivo in patients with ischemic vascular syndromes taking
      aspirin. Since aspirin is a weak inhibitor of the inducible isoform of
      prostaglandin H synthase (COX-2), it was suggested that COX-2 may play a role in
      aspirin resistance. However the cellular source(s) of COX-2 possibly responsible
      for aspirin resistance remains unknown. Recently, the expression of the inducible
      isoform of COX-2 in circulating human platelets was reported. To investigate the
      possible contribution of COX-2 expression in platelet thromboxane (TX)
      biosynthesis, we have compared the inhibitory effects of NS-398 and aspirin,
      selective inhibitors of COX-2 and COX-1, respectively, on prostanoid biosynthesis
      by thrombin-stimulated platelets vs lipopolysaccharide (LPS)stimulated monocytes
      (expressing high levels of COX-2) isolated from whole blood of healthy subjects.
      NS-398 was 180-fold more potent in inhibiting monocyte COX-2 activity than
      platelet TXB2 production. In contrast, aspirin (55 micromol/L) largely suppressed
      platelet TXB2 production without affecting monocyte COX-2 activity. By using
      specific Western blot techniques, we failed to detect COX-2 in platelets while
      COX-1 was readily detectable. Our results argue against the involvement of COX-2
      in TX biosynthesis by activated platelets and consequently dispute platelet COX-2
      expression as an important mechanism of aspirin resistance.

PMID- 10639017
TI  - Mineralocorticoid action.
AB  - The physiology of mineralocorticoid action, particularly with respect to
      epithelial sodium transport, is well defined. A full understanding of the
      molecular basis of mineralocorticoid action has however proven to be more
      elusive. In the last decade insights into structural and functional aspects of
      the mineralocorticoid receptor combined with emerging details of the components
      of the mediators of the sodium flux has resulted in a clearer picture. This
      review focuses on two aspects of these new developments; the mineralocorticoid
      receptor and putative aldosterone induced proteins.

PMID- 10639018
TI  - (17alpha,20E/Z)-iodovinyl- and 16alpha-iodP618-homoestradiol derivatives:
      synthesis and evaluation for estrogen receptor imaging.
AB  - Three new 125I-radioiodinated estrogens featuring a 13beta-ethyl instead of the
      natural 13beta-methyl group, i.e. 18-homoestradiols, were synthesized and
      evaluated as potential estrogen receptor imaging agents. The 16alpha-iodo-18
      methylestradiol and the 125I-labeled analog were synthesized from the
      corresponding 16beta-bromo analog by the halogen-exchange method. The cis
      bromohydrin precursor was obtained by bromination of an estrone enolacetate,
      followed by epimerization and reduction. The isomeric (17alpha,20E/Z)-iodovinyl
      18-methylestradiols were prepared via the vinyltin intermediates. Treatment of 18
      methyl-17alpha-ethynylestradiol with tri-n-butyltin hydride, in the presence of
      azobisisobutyronitrile as catalyst and heating at 90-100 degrees C afforded the
      (17alpha,20E)-tri-n-butylstannyl isomer as the major product. Changing the
      catalyst for triethyl borane, at room temperature, mainly gave the 20Z-isomer.
      The nca 125I-labeled analogs were obtained from their corresponding tin
      intermediates upon treatment with [125I]NaI in the presence of H2O2. The 16alpha
      [125I]iodo- and isomeric (17alpha,20E/Z)-[125I]iodovinyl-18-methylestradiols were
      evaluated for estrogen receptor-mediated uterine uptake in immature female rats.
      Homologation of the C13-methyl group did improve the uterine uptake of the
      iodovinyl derivatives, but also increased blood retention, resulting in lower
      target uptake ratios. In the case of the 16alpha-iodo analog uterine retention
      decreased upon C13-homologation.

PMID- 10639019
TI  - Isolation and structure elucidation of new cytotoxic steroids from the gorgonian
      Leptogorgia sarmentosa.
AB  - The gorgonian Leptogorgia sarmentosa contains three new steroids, (20S)-20
      hydroxycholestane-3,16-dione (1), (16S, 20S)-16,20-dihydroxycholestan-3-one (2),
      and (20S)-20-hydroxycholest-1-ene-3,16-dione (3) together with a known related
      compound (4). Their structures were defined by spectroscopic analysis. The new
      steroids exhibited significant cytotoxicity against four tumor cell lines (ED50 =
      1 microg/ml).

PMID- 10639020
TI  - The use of deuterium-labeled cortisol for in vivo evaluation of renal 11beta-HSD
      activity in man: urinary excretion of cortisol, cortisone and their A-ring
      reduced metabolites.
AB  - This study describes a new approach using stable isotope methodology in
      evaluating 11beta-HSD activities in vivo based on urinary excretion of cortisol,
      cortisone, and their A-ring reduced metabolites. The method involved the
      measurement of deuterium-labeled cortisol and its deuterium-labeled metabolites
      by GC/MS simultaneously with endogenous cortisol, cortisone, and their A-ring
      reduced metabolites after oral administration of deuterium-labeled cortisol to
      normal human subjects. This stable isotope approach offered unique advantages in
      assessing the appropriateness of measuring unconjugated and total (unconjugated +
      conjugated) cortisol, cortisone, and their A-ring reduced metabolites in urine as
      indices of renal 11beta-HSD2 activity in man. Our results strongly support that
      the measurement of urinary unconjugated cortisol and cortisone is a significant
      advance in assessing 11beta-HSD2 activity.

PMID- 10639021
TI  - Influence of oral dehydroepiandrosterone (DHEA) on urinary steroid metabolites in
      males and females.
AB  - Oral dehydroepiandrosterone (DHEA) replacement therapy may have a multitude of
      potential beneficial effects and exerts its action mainly via peripheral
      bioconversion to androgens (and estrogens). A daily dose of 50-mg DHEA has been
      shown by us and others to restore low endogenous serum DHEA concentrations to
      normal youthful levels followed by an increase in circulating androgens and
      estrogens. As the hepatic first-pass effect may lead to a non physiological
      metabolism of DHEA after oral ingestion we studied the influence of two single
      DHEA doses (50 and 100 mg) on the excretion of steroid metabolites in 14 elderly
      males [age 58.8+/-5.1 years (mean +/- SEM)] with endogenous DHEAS levels <1500
      ng/ml and in 9 healthy females (age 23.3+/-4.1 years) with transient suppression
      of endogenous DHEA secretion induced by dexamethasone (dex) pretreatment (4x0.5
      mg/day/4 days). Urinary steroid profiles in the elderly males were compared to
      the steroid patterns found in 15 healthy young men (age 28.9+/-5.1 years). In the
      females the results were compared to their individual baseline excretion without
      dex pretreatment. Urinary steroid determinations were carried out by
      semiautomatic capillary gas-liquid chromatography. In both genders DHEA
      administration induced significant increases in urinary DHEA (females: baseline
      vs. 50 mg vs. 100 mg: 361+/-131 vs. 510+/-264 vs. 1541+/-587 microg/day; males:
      placebo vs. 50 mg vs. 100 mg: 434+/-154 vs. 1174+/-309 vs. 4751+/-1059
      microg/day) as well as in the major DHEA metabolites androsterone (A) and
      etiocholanolone (Et). Fifty mg DHEA led to an excretion of DHEA and its
      metabolites only slightly above baseline levels found in young females and in
      young men, respectively, whereas 100 mg induced clearly supraphysiological
      values. After 50 mg DHEA the ratios of urinary DHEA metabolites (A/DHEA, Et/DHEA)
      were not significantly different between elderly males vs. young male volunteers
      and young healthy females versus their individual baseline levels. In conclusion,
      an oral dose of 30 to 50 mg DHEA restores a physiological urinary steroid profile
      in subjects with DHEA deficiency without evidence for a relevant hepatic first
      pass effect on urinary metabolites.

PMID- 10639022
TI  - Development of a plasma 17alpha-hydroxyprogesterone time resolved-fluorescence
      immunoassay involving a new biotinylated tracer.
AB  - A biotinylated 17alpha-hydroxyprogesterone probe (3) was prepared from 17alpha
      hydroxyprogesterone-3-carboxymethyloxime and conjugate obtained by acylation of
      biotinylaminopropylammonium trifluroacetate. This new tracer was used in the
      development of a 17alpha-hydroxyprogesterone time-resolved fluoroimmunoassay
      using streptavidin-europium. The new method was compared to a long-standing
      radioimmunoassay method and found to be more sensitive and economical.

PMID- 10639023
TI  - Novel steroid spiro enones: condensation of prednisolone derivatives with diethyl
      oxalate.
AB  - In a continuing effort to discover potent anti-inflammatory steroids without
      systemic side effects, diethyl oxalate was condensed with the 17beta-ketol side
      chain of prednisolone derivatives. Prednisolone gave the most interesting result
      in forming a novel spiro enone with alpha-hydroxy and beta-carboxylic ester
      substitutions, and a facile one-pot procedure has been established for the
      synthesis of this highly functionalized spiro enone structure. The spiro products
      were tested for their binding potency to the RAW 264.7 macrophage glucocorticoid
      receptor, for their effect on LPS-induced nitric oxide generation in RAW 264.7
      cells, and for their inhibition of rats ear edema induced by croton oil. The new
      compounds showed weak activities in all of the bioassays. Because the
      corresponding acid metabolites of two representative spiro enone esters gave no
      activity in either the binding assay or the nitric oxide generation test, the
      novel steroids are probably antedrugs. The reduced potency as compared to their
      parent compounds suggests that the rigid spiro structure is unfavorable to anti
      inflammatory activities. Molecular modeling studies confirm that the spiro enones
      adopt a rigid planar geometry with the ester group in the plane.

PMID- 10639024
TI  - Incomplete segregation of endorgan-specific vestibular ganglion cells in mice and
      rats.
AB  - The endorgan-specific distribution of vestibular ganglion cells was studied in
      neonatal and postnatal rats and mice using indocarbocyanine dye (DiI) and dextran
      amines for retrograde and anterograde labeling. Retrograde DiI tracing from the
      anterior vertical canal labeled neurons scattered throughout the whole superior
      vestibular ganglion, with denser labeling at the dorsal and central regions.
      Horizontal canal neurons were scattered along the dorsoventral axis with more
      clustering toward the dorsal and ventral poles of this axis. Utricular ganglion
      cells occupied predominantly the central region of the superior vestibular
      ganglion. This utricular population overlapped with both the anterior vertical
      and horizontal canals' ganglion cells. Posterior vertical canal neurons were
      clustered in the posterior part of the inferior vestibular ganglion. The saccular
      neurons were distributed in the two parts of the vestibular ganglion, the
      superior and inferior ganglia. Within the inferior ganglion, the saccular neurons
      were clustered in the anterior part. In the superior ganglion, the saccular
      neurons were widely scattered throughout the whole ganglion with more numerous
      neurons at the posterior half. Small and large neurons were labeled from all
      endorgans. Examination of the fiber trajectory within the superior division of
      the vestibular nerve showed no clear lamination of the fibers innervating the
      different endorgans. These results demonstrate an overlapping pattern between the
      different populations within the superior ganglion, while in the inferior
      ganglion, the posterior canal and saccular neurons show tighter clustering but
      incomplete segregation. This distribution implies that the ganglion cells are
      assigned for their target during development in a stochastic rather than
      topographical fashion.

PMID- 10639025
TI  - Eye movements during torso rotations in labyrinthine-defective subjects.
AB  - The aim of this study was to examine whether the chronic loss of vestibular
      function modifies perceptual and oculomotor responses during torso rotations in
      darkness. Subjects (4 patients with complete vestibular loss and 7 healthy
      volunteers) were seated on a rotating chair. Stimuli consisted of sinusoidal
      chair rotations (+/-30 degrees, 0.1 Hz and 0.011 Hz). We used 2 conditions: space
      stationary head (neck stimulation) and space stationary head and shoulders (torso
      stimulation). Horizontal eye deviations and slow component of eye movements were
      analysed. The results showed that eye movements and perception of head motion in
      space during neck stimulation were similar to those during torso stimulation both
      in normal and labyrinthine-defective (LD) subjects. During low-frequency chair
      rotations (0.011 Hz) all subjects perceived illusory head or head and shoulder
      rotation in space (as if the lower part of the body was stationary relative to
      the room) and shifted their gaze in the direction of illusory head rotation. In
      these conditions there was no significant difference in eye movements between
      normal and LD subjects. During higher frequency chair rotations (0.1 Hz), LD
      subjects had significantly larger eye deviations as well as increases in the gain
      of the slow component of eye movements relative to normals. In these conditions
      patients mostly perceived illusory head or head and shoulder rotation in space
      while normal subjects mainly perceived the head as stationary in space. The
      results indicate that 1) neck and torso rotations can evoke similar ocular
      responses in LD subjects, 2) the chronic loss of vestibular function modifies the
      representation of axial body segment motion relative to space.

PMID- 10639026
TI  - Chronic unilateral loss of otolith function revealed by the subjective visual
      vertical during off center yaw rotation.
AB  - Assessing the subjective visual vertical, SVV, in a static upright position is an
      easy clinical test in which a deviation of some 10 degrees from true vertical
      indicates an acute loss of unilateral (otolithic) vestibular function on the side
      to which the SVV is tilted. Because this deviation of the SVV is compensated
      during the following months, patients with chronic unilateral vestibular loss do
      no longer differ from normal subjects. This study presents an experimental set-up
      that allows for clear detection of compensated chronic loss of unilateral
      otolithic function by testing the SVV. 21 normals and 17 unilaterally vestibular
      deafferentiated (UVD) patients (vestibular neurectomies) were first rotated on a
      human centrifuge about an earth vertical yaw axis through the midsagittal plane
      of the head (240 degrees/s). This induced tilts of the gravito-inertial force
      (GIF) vectors, which differed at the two inner ears by 8 degrees. During constant
      velocity rotation, the subjects were moved in pseudo-randomized steps laterally
      up to 16 cm apart from the rotation axis, inducing roll tilts of the GIF vectors
      up to 16 degrees. Normal subjects set their SVV to pre-centrifugation values at
      positions with the midsagittal plane of their head close to the rotation axis,
      while chronic UVD patients indicated pre-centrifugation values during positions
      with the rotation axis 5.9 +/- 2.5 cm paramedian on the side of the intact ear.
      Tilts of the GIF vectors shifted the SVV with a gain of 0.70 in normals and only
      0.32 in UVD patients. Roll gains for laterally directed GIF vectors relative to
      the intact inner ear did not differ from medially directed roll gains in the UVD
      patients. The roll gains observed in this experimental set-up were lower than
      those observed with static body tilts or during eccentric rotation with a larger
      radius, which might be at least partially due to conflicting stimulation between
      otolithic and extra-vestibular cues.

PMID- 10639027
TI  - Predicting control mechanisms for human head stabilization by altering the
      passive mechanics.
AB  - The purpose of this study was to clarify the mechanisms controlling head and neck
      stabilization in the horizontal (yaw) and vertical (pitch) planes by changing the
      passive mechanics of the head-neck motor system. Angular velocities of the head
      and trunk in space were recorded in seated subjects during external perturbations
      of the trunk with pseudorandom sum-of-sines (SSN) stimuli. Four subjects in yaw
      and nine subjects in pitch actively stabilized their heads in the dark, and
      performed a mental distraction task in the dark both with and without a weight
      atop the head. In yaw, the behavior of the head was found to change relatively
      little with added inertia. As adding inertia to a passive mechanical system
      should cause substantial changes in dynamics, we inferred that neural mechanisms
      were invoked to maintain the constant response dynamics. A mathematical model of
      head-neck control was applied to predict the relative influence of the
      vestibulocollic and cervicocollic reflexes, and of inertia, stiffness, and
      viscosity. Using optimization methods to fit the model to experimental data, we
      identified stiffness and vestibulocollic reflex gain as the primary contributors
      to the control of head stabilization in space. In pitch, increasing inertia
      accentuated phase shifts at higher frequencies. Because our pitch model was
      insufficiently constrained, we only simulated responses due to passive mechanics.
      Model simulation predicted unstable head motion at all test frequencies. Subjects
      were able to compensate for trunk motion at most frequencies, however, suggesting
      that neural components were modulated to exert compensatory responses both with
      and without additional weight.

PMID- 10639028
TI  - EquiTest modification with shank and hip angle measurements: differences with age
      among normal subjects.
AB  - The Sensory Organization Test protocol of the EquiTest system (NeuroCom
      International, Clackamas Oregon) tests utilization of visual, vestibular, and
      proprioceptive sensors by manipulating the accuracy of visual and/or
      somatosensory inputs during quiet stance. In the standard Sensory Organization
      Test, both manipulation of sensory input (sway-referencing) and assessment of
      postural sway are based on ground reaction forces measured from a forceplate. The
      purpose of our investigation was to examine the use of kinematic measurements to
      provide a more direct feedback signal for sway-referencing and for assessment of
      sway. We compared three methods of sway-referencing: the standard EquiTest method
      based on ground reaction torque, kinematic feedback based on servo-controlling to
      shank motion, and a more complex kinematic feedback based on servo-controlling to
      follow position of the center of mass (COM) as calculated from a two-link
      biomechanical model. Fifty-one normal subjects (ages 20-79) performed the
      randomized protocol. When using either shank or COM angle for sway-referencing
      feedback as compared to the standard EquiTest protocol, the Equilibrium Quotient
      and Strategy Score assessments were decreased for all age groups in the platform
      sway-referenced conditions (SOT 4, 5, 6). For all groups of subjects, there were
      significant differences in one or more of the kinematic sway measures of shank,
      hip, or COM angle when using either of the alternative sway-referencing
      parameters as compared to the standard EquiTest protocol. The increased
      sensitivities arising from use of kinematics had the effect of amplifying
      differences with age. For sway-referencing, the direct kinematic feedback may
      enhance ability to reduce proprioceptive information by servo-controlling more
      closely to actual ankle motion. For assessment, kinematics measurements can
      potentially increase sensitivity for detection of balance disorders, because it
      may be possible to discriminate between body sway and acceleration and to
      determine the phase relationship between ankle and hip motion.

PMID- 10639029
TI  - The role of vision on postural strategy evaluated in patients affected by
      congenital nystagmus as an experimental model.
AB  - The role of vision in postural control is crucial and is strictly related to the
      characteristics of the visual stimulus and to the performance of the visual
      system. The purpose of this investigation was to evaluate the effects of
      chronically reduced visual cues upon postural control in patients affected by
      Congenital Nystagmus (CN). These patients have developed since birth a postural
      strategy mainly based on vestibular and somatosensorial cues. Fifteen patients
      affected by CN and 15 normal controls (NC) were enrolled in the study and
      evaluated by means of dynamic posturography. The overall postural control in CN
      patients was impaired as demonstrated by the equilibrium score and by the changes
      of the postural strategy. This impairment was even more enhanced in CN than in NC
      group when somatosensorial cues were experimentally reduced. An aspecific pattern
      of visual impairment and a pathological composite score were also present. Our
      data outline that in patients affected by CN an impairment of the postural
      balance is present especially when the postural control relies mainly on visual
      cues. Moreover, a decrease in accuracy of the somatosensory cues has a
      proportionally greater effect on balance than it has on normal subjects.

PMID- 10639030
TI  - Matrix-assisted laser desorption/ionization mass spectrometry of carbohydrates.
AB  - This review describes the application of matrix-assisted laser
      desorption/ionization (MALDI) mass spectrometry to carbohydrate analysis and
      covers the period 1991-1998. The technique is particularly valuable for
      carbohydrates because it enables underivatised, as well as derivatised compounds
      to be examined. The various MALDI matrices that have been used for carbohydrate
      analysis are described, and the use of derivatization for improving mass spectral
      detection limits is also discussed. Methods for sample preparation and for
      extracting carbohydrates from biological media prior to mass spectrometric
      analysis are compared with emphasis on highly sensitive mass spectrometric
      methods. Quantitative aspects of MALDI are covered with respect to the
      relationship between signal strength and both mass and compound structure. The
      value of mass measurements by MALDI to provide a carbohydrate composition is
      stressed, together with the ability of the technique to provide fragmentation
      spectra. The use of in-source and post-source decay and collision-induced
      fragmentation in this context is described with emphasis on ions that provide
      information on the linkage and branching patterns of carbohydrates. The use of
      MALDI mass spectrometry, linked with exoglycosidase sequencing, is described for
      N-linked glycans derived from glycoproteins, and methods for the analysis of O
      linked glycans are also covered. The review ends with a description of various
      applications of the technique to carbohydrates found as constituents of
      glycoproteins, bacterial glycolipids, sphingolipids, and glycolipid anchors.

PMID- 10639031
TI  - Safety and pharmacokinetics of a new liposomal liver-specific contrast agent for
      CT: results of clinical testing in nonpatient volunteers.
AB  - RATIONALE AND OBJECTIVES: To evaluate the safety and pharmacokinetics of BR21, a
      liposome-encapsulated iomeprol formulation, in nonpatient volunteers. METHODS:
      This was a single-blind, placebo-controlled, ascending dose study in 30 adult,
      male nonpatient volunteers, randomized to receive a single intravenous bolus (2
      mL/s) of BR21 (0.5, 1.0, 1.5, 2.0, and 2.5 mL/kg, four volunteers per dose level)
      or matched volumes of placebo (0.9% saline, 10 volunteers). The safety controls
      performed consisted of preand postdose complete physical examinations,
      measurement of vital signs, electrocardiographic controls, clinical laboratory
      investigations (hematology, serum chemistry, and urinalysis), and monitoring of
      adverse events. The safety controls and monitoring of subjects for adverse events
      continued up to 7 days after the dose. For pharmacokinetic analysis, the
      determination of total iomeprol content was performed by a high-performance
      liquid chromatography assay procedure in blood, urine, and fecal samples
      collected before the dose and serially after the dose, up to 120 hours. RESULTS:
      No serious adverse events occurred throughout the study. All nonserious adverse
      events were minor and mild in intensity and rapidly resolved without treatment.
      No difference in the incidence of adverse events was observed among the various
      doses of BR21 and between BR21 and placebo. There were no clinically significant
      changes in vital signs, electrocardiographic parameters, or clinical laboratory
      findings. Iomeprol blood level decay can be described by a three-exponential
      function, consistent with a distribution phase (range, t1/2 0.12-0.21 hours), a
      fast elimination phase (range, t1/2 1.2-1.5 hours), and a slow elimination phase
      from a deep compartment (range, t1/2 3.3-4.5 hours). There was an apparent
      linearity in the relation between the area under the curve and the dose. Urinary
      elimination of unchanged iomeprol accounted for 89% to 90% of injected dose
      within 24 hours. CONCLUSIONS: BR21 appeared to be safe and well tolerated in
      nonpatient subjects. Its pharmacokinetic profile was compatible with nonspecific
      distribution into the extracellular fluid space and specific distribution into a
      deep compartment.

PMID- 10639032
TI  - Synthesis, characterization, and imaging performance of a new class of
      macrocyclic hepatobiliary MR contrast agents.
AB  - RATIONALE AND OBJECTIVES: To investigate the effect of substituent lipophilicity,
      substituent position, and overall charge on the hepatobiliary clearance and
      tolerance of a series of aromatic ring-containing macrocyclic Gd chelates to
      select a candidate compound for evaluation as a hepatobiliary imaging agent.
      METHODS: Hepatobiliary clearance was studied in rats. Tissue distribution and
      tolerance were studied in mice. Imaging was performed in cats, rabbits, and
      Rhesus monkeys using T1-weighted pulse sequences or T1-weighted breath-hold pulse
      sequences. RESULTS: All the compounds were excreted bimodally. Gd-2,5-BPA-DO3A
      (15d) was found to have the optimal combination of hepatobiliary clearance (47%
      in rats, 29% in mice) and tolerance (minimum lethal dose 5.0 mmol/kg). Initial
      imaging studies in cats demonstrated the feasibility of Gd-2,5-BPA-DO3A for
      hepatic imaging. In rabbits with implanted VX-2 adenocarcinoma as a model for
      metastatic liver disease, Gd-2,5-BPA-DO3A provided sustained hepatic signal
      intensity (SI) enhancement and lesion conspicuity over a 120-minute imaging time
      course. In Rhesus monkeys with normal liver function, Gd-2,5-BPA-DO3A afforded
      sustained hepatic SI enhancement and a time-dependent increase in gallbladder SI
      over the entire 90-minute imaging time course. CONCLUSIONS: Gd-2,5-BPA-DO3A
      provides dramatic and sustained SI enhancement of hepatic tissue in cats,
      rabbits, and Rhesus monkeys that was superior in all respects to the
      extracellular space MRI agent, Gd-HP-DO3A, that was employed as a control.

PMID- 10639033
TI  - Hepatocellular carcinoma: correlation between gadobenate dimeglumine-enhanced MRI
      and pathologic findings.
AB  - RATIONALE AND OBJECTIVES: To correlate the appearance of hepatocellular carcinoma
      on delayed (60 minutes) postcontrast T1-weighted gradient echo images with the
      mode of action of gadobenate dimeglumine (Gd-BOPTA) and the anatomic and
      pathologic characteristics of the lesions. METHODS: A total of 34 patients with
      hepatocellular carcinoma and varying degrees of diffuse liver disease were
      studied. T2-weighted spin echo and T1-weighted spin echo and gradient echo images
      were acquired before and 60 minutes after the intravenous administration of 0.1
      mmol/kg Gd-BOPTA. Qualitative and quantitative evaluations of the images were
      performed and correlated with histologic findings. The quantitative evaluation,
      performed on T1-weighted gradient echo images, looked at the percentage increase
      of liver enhancement after Gd-BOPTA administration, the lesion-to-liver
      contrast/noise (C/N) ratio before and after Gd-BOPTA administration, and the C/N
      variation after Gd-BOPTA administration. Qualitative assessment considered the
      morphologic features of the lesions as well as the visual variation of contrast
      before and after Gd-BOPTA administration. Finally, a histologic evaluation was
      made of the degree of differentiation of the lesions and of the presence of fatty
      metaplasia, necrosis, bile, or intratumoral peliosis. RESULTS: Among the
      parameters affecting lesion identification were the extent of liver function,
      degree of vascularization, residual functionality of the tumor cells, and
      characteristics of the neoplastic tissue. Positive correlations (Spearman
      coefficients = 0.359 and 0.393, respectively) were observed precontrast between
      the degree of liver failure and the amount of contrast noise, and postcontrast
      between the amount of intralesional fatty metaplasia and the extent to which
      lesion conspicuity worsened after Gd-BOPTA administration. An inverse correlation
      (Spearman coefficient = -0.330) was observed between the degree of lesion
      differentiation and the visible appearance after Gd-BOPTA administration, with
      well-differentiated lesions tending toward worsened conspicuity postcontrast. A
      statistically significant difference (P = 0.001) was observed in the mean
      precontrast C/N ratio for lesions later showing unchanged conspicuity and worse
      conspicuity on postcontrast images, respectively. Marked variation (P = 0.019)
      was also observed between Child A and B cirrhotic patients for the degree of
      hepatic enhancement on postcontrast images. CONCLUSIONS: The results suggest that
      liver parenchyma signal intensity is influenced by the extent to which liver
      function is compromised, that residual hepatocytic functionality permits Gd-BOPTA
      uptake by certain lesions and that this uptake might subsequently impair the
      observed C/N ratio on delayed images, and that the worsening of lesion
      conspicuity on postcontrast images is influenced also by high quantities of
      intralesional fatty metaplasia.

PMID- 10639034
TI  - Pharmacokinetics of 1M gadobutrol in patients with chronic renal failure.
AB  - RATIONALE AND OBJECTIVES: To investigate the pharmacokinetics of 1M gadobutrol as
      a new neutral MR contrast agent in patients with impaired renal function.
      METHODS: Twenty-one patients with impaired renal function and any indication for
      a contrast-enhanced MRI were enrolled into this prospective study and classified
      in two subgroups according to their creatinine clearance (group 1, 30-80 mL/ min;
      group 2, 30 mL/min or less, not requiring dialysis). Eleven patients were
      assigned to the lower dose of 0.1 mmol Gd/kg and 10 patients to the higher dose
      of 0.3 mmol Gd/kg. To calculate pharmacokinetic parameters, urine and venous
      blood samples were drawn at baseline and up to 72 hours for group 1 and 120 hours
      for group 2 after administration of gadobutrol. RESULTS: The predominant
      extracellular distribution of gadobutrol at steady state did not change according
      to the degree of renal impairment. The mean elimination half-life of gadobutrol
      increased to 7.4 +/- 2.6 hours (0.1 mmol/kg) and 5.4 +/- 1.5 hour (0.3 mmol/kg)
      in group 1 and to 17.9 +/- 6.2 hours (0.1 mmol/kg) and 20.4 +/- 16.9 hours (0.3
      mmol/kg) in group 2, compared with 1.5 hours in healthy volunteers. The relation
      between serum (tbeta) and urine (t(elim)) elimination half-lives, as well as
      total serum and renal clearance, indicated renal elimination as the main pathway
      of elimination. The recovery of gadobutrol in the urine of group 1 was complete
      within 72 hours for both dosage levels. Patients with severe renal impairment
      showed a mean recovery of 80.1% (0.1 mmol/kg) and 85.3% (0.3 mmol/kg) within the
      observation period of 120 hours. CONCLUSIONS: The half-life of gadobutrol is
      prolonged in patients with impaired renal function, but elimination by means of
      the kidneys is the predominant route.

PMID- 10639035
TI  - Pilot MR evaluation of pharmacokinetics and relaxivity of specific blood pool
      agents for MR angiography.
AB  - RATIONALE AND OBJECTIVES: To evaluate the use of two new blood pool contrast
      agents (P760, P775) compared with a low-molecular-weight gadolinium chelate in MR
      angiography. METHODS: The r1 efficiency of P760 was evaluated in vitro at 1.5 T;
      3D abdominal contrast-enhanced MR angiography with qualitative analysis was
      compared in four rabbits after injection of incremental doses of P760 and in one
      rabbit after Gd-DOTA. A dynamic MR study was performed using a 2D T1-weighted
      turbo-flash MR sequence after injection of P760, P775, and Gd-DOTA. Each compound
      was tested at equivalent doses in three rabbits to assess r1 efficiency.
      Quantitative analysis of signal intensity in the aorta, the inferior vena cava,
      the renal cortex, and the medulla was performed. RESULTS: In vitro, the r1
      efficiency of P760 was 23.3 mmol(-1) x L x sec(-1) at 1.5 T. Injection of a dose
      of P760 10 times less than Gd-DOTA allowed similar vessel visualization. The
      signal intensity peak and first-pass contrast kinetics in the aorta and the
      inferior vena cava were similar with the three products. Compared with P760 and
      Gd-DOTA, P775 allowed a greater renal cortex signal intensity at the first pass
      and a faster decrease on delayed images. CONCLUSIONS: The superior r1 efficiency
      of P760 and P775 was confirmed in vitro and in vivo at 1.5 T compared with Gd
      DOTA, and P775 proved to be a rapid-clearance blood pool agent.

PMID- 10639036
TI  - Development of a tumor-targeting MR contrast agent using the high-affinity folate
      receptor: work in progress.
AB  - RATIONALE AND OBJECTIVES: Macromolecular contrast agents enhance tumors by means
      of active or passive targeting. Active targeting requires surface receptors. Many
      tumors of epithelial origin express the high-affinity folate receptor (hFR),
      including ovarian tumors. The objective of this research was to enhance tumors
      that express hFR using macromolecular contrast agents conjugated to folic acid.
      METHODS: The authors prepared a folate-conjugated dendrimer polychelate by
      attaching folic acid to a fourth-generation ammonia-core polyamidoamine
      dendrimer. The remaining amines were reacted with 2-(4-isothiocyanatobenzyl)-6
      methyldiethylenetriamine pentaacetic acid. Relaxivity measurements (r1 and r2)
      and MRI were conducted at 4.7 T. RESULTS: The dendrimer r2 exceeded that of Gd-HP
      DO3A by 8.2 times at 4.7 T. It increased the tumor percentage contrast
      enhancement, 24 hours after injection, of T2-weighted images by 33%. CONCLUSIONS:
      This new agent accumulates in tumors expressing hFR. These results do not
      differentiate between active and passive targeting mechanisms. Receptor-negative
      tumors suggest a mechanism other than a nonspecific blood pool effect.

PMID- 10639037
TI  - Pulse inversion imaging of liver blood flow: improved method for characterizing
      focal masses with microbubble contrast.
AB  - RATIONALE AND OBJECTIVES: To create a microbubble contrast image of vessels that
      lie below the resolution of an ultrasound system, a technique is required that
      detects preferentially the agent echo, rejecting that from tissue. Harmonic
      imaging exploits the nonlinear behavior of microbubbles but forces a compromise
      between image sensitivity and axial resolution. The authors describe and evaluate
      a new method that overcomes this compromise and improves contrast imaging
      performance: pulse inversion imaging. METHODS: Sequences of pulses of alternate
      phase are transmitted into tissue and their echoes summed. A prototype scanner
      equipped with pulse inversion was used to image phantoms and 16 patients with
      focal liver masses. RESULTS: Pulse inversion images show contrast sensitivity and
      resolution superior to that of harmonic images. Vessels can be imaged at an
      incident power sufficiently low to avoid destroying the agent, allowing unique
      visualization of tumor vasculature. Distinct patterns were seen in hemangiomas,
      metastases, and hepatocellular carcinomas. CONCLUSIONS: Pulse inversion imaging
      is an improved bubble-specific imaging method that extends the potential of
      contrast ultrasonography.

PMID- 10639038
TI  - Infusion versus bolus of an ultrasound contrast agent: in vivo dose-response
      measurements of BR1.
AB  - RATIONALE AND OBJECTIVES: To determine the efficacy of an ultrasound contrast
      agent infusion using Doppler intensitometry estimation of backscatter enhancement
      in blood. METHODS: Multiple intravenous injections of BR1 (SonoVue) were
      performed in chronic dog studies, using bolus (0.05-2 mL) and infusion (3-40 mL/h
      during 6 minutes) administration. The pulsed Doppler signal from the femoral
      artery was recorded and analyzed for mean Doppler power and integrated fractional
      enhancement. RESULTS: For bolus injection, time-intensity curves exhibited a
      rapid first pass (peak 30 dB for 0.45 mL) followed by a slower washout.
      Integrated fractional enhancement exhibited a linear relation with the dose (R2 =
      0.99). For infusion administration, peak enhancement increased with the infusion
      rate from 8 to 22 dB. At rates exceeding 30 mL/h, the enhancement was stable with
      a plateau-like pattern. CONCLUSIONS: Infusion of BR1 is easily achieved and
      allows the duration of enhancement to be increased as long as desired. Stable
      enhancement is obtained for rates greater than 30 mL/h.

PMID- 10639039
TI  - Human pharmacokinetics and safety evaluation of SonoVue, a new contrast agent for
      ultrasound imaging.
AB  - RATIONALE AND OBJECTIVES: To assess in humans the pharmacokinetics of SonoVue, a
      new echo contrast agent based on stabilized sulfur hexafluoride (SF6)
      microbubbles and to provide additional safety and tolerability information on the
      compound. METHODS: The blood kinetics and pulmonary elimination of SF6 after
      intravenous bolus injection of two dosage levels (0.03 and 0.3 mL/kg) of SonoVue
      were evaluated in 12 healthy subjects (7 men, 5 women). In addition, safety and
      tolerability were evaluated by monitoring vital signs, adverse effects,
      discomfort, and physical examination and laboratory parameters associated with
      the SonoVue injection. RESULTS: The blood kinetics of SF6 was not dose dependent.
      SF6 was rapidly removed from the blood by the pulmonary route, with 40% to 50% of
      the injected dose eliminated within the first minute after administration and 80%
      to 90% eliminated by 11 minutes after administration; the elimination was similar
      in men and women and independent of dose. Both dosages were well tolerated. No
      adverse effects were observed immediately or during the 24-hour follow-up period.
      CONCLUSIONS: SonoVue was shown to be rapidly removed from the blood. The route of
      SF6 elimination was by means of the lungs in the expired air. SonoVue appeared to
      be safe and well tolerated in healthy subjects.

PMID- 10639040
TI  - The use of a thrombus-specific ultrasound contrast agent to detect thrombus in
      arteriovenous fistulae.
AB  - RATIONALE AND OBJECTIVES: To evaluate the use of a new thrombus-specific
      ultrasound contrast agent, MRX-408, in the ultrasonic detection of thrombus in
      arteriovenous (AV) fistulae. METHODS: Six purpose-bred mongrels with two AV
      fistulae each were imaged with gray-scale ultrasound 7 weeks after graft
      implantation before and after the intravenous bolus injection of MRX-408 (a GPIIb
      receptor-targeted ultrasound contrast agent). Pre- and postcontrast videotaped
      segments were randomized and reviewed by four radiologists blinded to the
      presence of thrombus in the grafts. RESULTS: After the use of MRX-408, there was
      improved visualization of thrombus within the grafts (P < 0.0001). This was due
      to the enhancement of the thrombus (P < 0.0001). The improved visualization and
      contrast enhancement were more marked in the grafts that contained thrombus
      nonhyperechoic to surrounding soft tissues. CONCLUSIONS: MRX-408 demonstrated
      better visualization of thrombus within AV fistulae. This was shown in both
      patent and occluded grafts. These results are encouraging and suggest that this
      contrast agent merits further development.

PMID- 10639041
TI  - Leriche memorial lecture. The fate of arterial transplantation or the death of
      the microcosm.

PMID- 10639042
TI  - Variation in vascular activity in the United Kingdom: an analysis of five
      regions.
AB  - BACKGROUND: The aim of this study was to define variations in vascular activity
      that may exist between different demographic regions of the UK. METHODS: Five
      regions were studied. Data were obtained on OPCS codes for vascular surgery 1994
      95 from the Department of Health or Welsh Office. Mortality and cause of death
      statistics were calculated for each region from OPCS data. RESULTS: Ranges of
      vascular reconstruction, iliac and superficial femoral artery angioplasty and
      major amputation were 26.2-44, 10.5-23.0 and 11.5-15.7 per 100,000 population,
      respectively. The highest rates of amputation were seen in areas of high standard
      mortality and highest death rate from atheroma and ischaemic heart disease. Rates
      of amputation also rose in proportion to the number of men in the population aged
      > 60 years. CONCLUSION: Variations exist in vascular activity between different
      regions. This may be caused by demographic differences in the population. It
      needs to be considered when calculating the number of vascular surgeons required
      in different areas of the country.

PMID- 10639043
TI  - Lower extremity revascularization without contrast arteriography: a prospective
      study of operation based upon duplex mapping.
AB  - This study prospectively assessed the results of lower extremity surgical
      revascularization, which was performed on the basis of duplex arterial mapping in
      selected patients without preoperative contrast arteriography. Criteria were
      developed for patient selection. Among 158 patients requiring surgery for lower
      extremity ischemia over a 24-month period, 24 (15%) were selected for operation
      without current preoperative arteriography. Aorto-iliac and infrainguinal duplex
      arterial mapping were performed in an laboratory that was accredited by the
      Intersocietal Commission for Accreditation of Vascular Laboratories. Indications
      for surgery were minor gangrene (11), rest pain (7), or claudication (6).
      Operations included femoropopliteal bypass (14), femoral endarterectomy (9) and
      femoral-femoral bypass (1). Mean length of stay was 4.5 +/- 2.0 days. Ankle
      brachial index improved from 0.49 +/- 0.12 to 0.80 +/- 0.15 (P < 0.05). Primary
      patency was 91.7 +/- 9.4% and assisted primary patency was 100% at 18 months.
      There was no graft occlusion or limb loss. Mean follow-up was 16.7 +/- 7.0
      months. These preliminary data support the safety and durability of duplex-guided
      lower extremity surgical revascularization without arteriography in selected
      cases. Success in a broader application of this approach requires the continuing
      development of patient selection criteria.

PMID- 10639044
TI  - Endoluminal pulse oximetry of the sigmoid colon and the monitoring of the colonic
      circulation.
AB  - Colonic ischaemia is a frequently observed serious complication following
      abdominal aortic reconstruction. For adequate treatment of this disorder, early
      diagnosis and resection of the diseased colon is essential. The purpose of this
      study was to evaluate a new method, based on pulse oximetry, to detect colonic
      ischaemia at an early preclinical stage. During a 7-year period (1989-1995)
      colonoscopy and pulse oximetry were performed in all patients at risk of colonic
      ischaemia: complicated acute or elective aortic reconstructions, colostomies with
      superficial necrosis and in patients who underwent uncomplicated aortic
      reconstruction and non-ischaemic colonic problems (n = 90). The sensitivity,
      specificity and positive predictive values, and negative predictive value, were
      calculated. All patients, except four for whom an acute relaparotomy was
      necessary, subsequently underwent colonoscopy combined with endoluminal pulse
      oximetry. Of the 90 patients, 30 had colonic ischaemia according to endoscopy (n
      = 26) or relaparotomy (n = 4), and in 33 patients the absence of pulsatile signal
      was detected by means of pulse oximetry. Thus, in three patients, pulse oximetry
      was falsely positive for colonic ischaemia. The calculated sensitivity and
      specificity of pulse oximetry were 100 and 95%, respectively. In comparison to
      other methods used for early detection of colonic ischaemia, pulse oximetry
      appears to be a promising method for the evaluation and monitoring of colonic
      ischaemia because it is non-invasive and easy to apply with a high sensitivity
      and specificity.

PMID- 10639045
TI  - The incorporation of a stent-graft into the porcine aorta and the inflammatory
      response to the endoprosthesis.
AB  - The fate of a non-sutured anastomosis and the inflammatory response to an
      endoprosthesis in a porcine aorta was determined. Self-expanding aorto-aortic
      endovascular prostheses were deployed into the infrarenal aorta of Large White
      pigs by the transfemoral route, in accordance with Home Office regulations.
      Animals were followed up at intervals to 1 year. The aortas were explanted and
      specimens were subjected to light microscopy. Thirteen animals, mean weight 103
      kg, underwent placement of a prosthesis. There was early evidence of a neointima
      at 4 weeks and a well-developed neointima by 12 weeks, with complete
      incorporation of the endoprosthesis. The early acute inflammatory reaction seen
      at 4 weeks had become chronic by 12 and was largely absent by 26 weeks. There was
      no evidence of atypia. Complete incorporation of the non-sutured anastomosis is
      seen in this model. The acute inflammatory reaction to the prosthesis seen at 4
      weeks had largely subsided by 26 weeks.

PMID- 10639046
TI  - Experimental determination of the safe minimum perfusion flow rate for low-flow
      hypothermic cardiopulmonary bypass.
AB  - This study investigated the safe minimum perfusion flow rate for low-flow
      hypothermic cardiopulmonary bypass in a canine model. The adequacy of cerebral
      oxygenation was determined from the adenosine concentration, the oxygen
      saturation of cerebral venous blood and brain oxyhemoglobin level. In experiment
      1, nine beagles were cooled on bypass to a nasopharyngeal temperature of 18
      degrees C and the perfusion flow rate was reduced in a stepwise fashion every 30
      min from 100 to 50, 30, 20 and 10 ml/kg per min. In experiment 2, six beagles
      were cooled on bypass as in experiment 1, and flow was maintained at 30 ml/kg per
      min for 120 min. At a perfusion flow rate of 30 ml/kg per min, adequate cerebral
      oxygenation was maintained for 120 min. In contrast, perfusion flow rates of 20
      and 10 ml/kg per min were associated with cerebral ischemia.

PMID- 10639047
TI  - Low-potassium University of Wisconsin solution for cardioplegia: improved
      protection of the isolated ischemic neonatal rabbit heart.
AB  - Recovery of cardiac function and high-energy phosphates following ischemia and
      reperfusion were determined for hearts perfused with low potassium University of
      Wisconsin solution, high potassium University of Wisconsin solution, St Thomas'
      solution, or subjected to hypothermia alone. Isolated hearts were arrested for
      either 3 h at 15 degrees C or 6 h at 20 degrees C (n = 7 for each group) with one
      of the four solutions and then reperfused. Aortic flow after ischemic arrest at
      20 degrees C was 40.3 +/- 13.3%, 79.3 +/- 10.0%, 64.3 +/- 11.9% and 43.9 +/-
      15.9% of control values for high potassium University of Wisconsin solution, low
      potassium University of Wisconsin solution, St Thomas' solution and hypothermia
      alone, respectively. Similar results were observed in hearts subjected to
      ischemic arrest at 15 degrees C. Myocardial adenosine triphosphate and creatine
      phosphate after reperfusion tended to be higher in the low potassium University
      of Wisconsin solution group. It is concluded that low potassium University of
      Wisconsin solution may provide reliable cardioplegia during surgery that requires
      prolonged cardiac arrest in neonates and infants.

PMID- 10639048
TI  - Comparison of reoperation findings of the Carpentier-Edwards (standard)
      bioprosthesis and the St Jude bioimplant (formerly Liotta) in the mitral
      position.
AB  - Between 1986 and 1996, 50 patients with Carpentier-Edwards porcine bioprostheses
      and 211 with a St Jude bioprosthesis underwent reoperation because of structural
      valve deterioration. Structural valve deterioration was defined as an intrinsic
      abnormality of the prosthesis (leaflet disruption, calcification, leaflet
      thickening, etc.) that caused stenosis or regurgitation found on physical
      examination and echocardiography. Fifteen of the Carpentier-Edwards bioprosthesis
      group were male and 35 were female. Eighty-two of the St Jude group were male and
      129 female. The mean age at reoperation was 33.88 +/- 10.31 years (range 19-70)
      for the Carpentier-Edwards group and 39.03 +/- 9.97 years (range 20-70) for the
      St Jude group. The average duration was 94.32 +/- 3.83 months for the Carpentier
      Edwards group and 73.76 +/- 1.44 months for the St Jude group (P < 0.001). The
      mean aortic cross-clamp time was 67.4 min (minimum 32, maximum 210) for the St
      Jude group and 63.21 min (minimum 36, maximum 230) for the Carpentier-Edwards
      group. Reoperative hospital mortality was 10% (5/50) in the Carpentier-Edwards
      group and 7.1% (15/211) in the St Jude group (P > 0.05). Late failure modes of
      the bioprostheses were defined for the purposes of this study as calcification,
      stenosis and torn leaflets. Of the Carpentier-Edwards group, seven patients (14%)
      developed calcification, six patients (12%) developed stenosis and 13 patients
      (26%) developed leaflet tears. Of the St Jude group, the incidences were 22
      patients (10%), 67 patients (31.8%) and 87 patients (41%), respectively. This
      study indicates that the Carpentier-Edwards bioprosthesis is more durable than
      the St Jude. The St Jude bioprosthesis tended to develop leaflet tears and linear
      calcification in female patients, and nodular calcification in male patients.

PMID- 10639049
TI  - Calcification tendency of various biological aortic valves in an experimental
      animal model.
AB  - The present study aimed at investigating the influence of fixation methods on the
      ultrastructure and calcium content of five different aortic biovalves. Biovalves
      subcutaneously implanted in Wistar rats for 12 weeks demonstrated significant
      differences in their calcium contents. Using Scheffe tests, two different groups
      of biovalves could be distinguished: (i) valves with high calcium content, such
      as Toronto-SPV (165 +/- 42 mg/g dry tissue) and Intact (193 +/- 36 mg/g dry
      tissue), and (ii) valves with low calcium content, such as Mosaic (2.7 +/- 1.8
      mg/g dry tissue), Freestyle (2.3 +/- 1.1 mg/g dry tissue) and Hancock-II (3.6 +/-
      1.2 mg/g dry tissue) (P < 0.05). All biovalves with an ultrastructurally
      preserved endothelium exhibited a low calcification tendency. The data suggest
      that if the endothelium is lost as a result of the fixation procedure, then
      calcification can only be prevented by appropriate anticalcification methods.

PMID- 10639050
TI  - Preconditioning and proximal ligation did not influence the outcome of direct
      internal mammary artery bypass grafting in a canine model.
AB  - The aim of this study was to assess the need for preconditioning and/or exclusion
      of competitive flow in minimally invasive coronary bypass grafting procedures
      (MICAB), to prevent early graft occlusion. Eight mongrel dogs (+/- 25 kg) were
      operated on under intravenous anaesthesia (sodium thiopenthal 15 mg/kg) and
      maintained with Halothan 1-2% and Pancurorium. A direct anastomosis between the
      left internal mammary artery and the left anterior descending coronary artery was
      performed, via anterior distal sternotomy, on the beating heart. Four dogs were
      preoperatively randomly conditioned by intravenous bolus injection of Diltiazem
      (0.0025 g/kg) prior to the procedure and after (meanwhile the left internal
      mammary artery takedown, the proximal coronary artery was snared during 15 min).
      In the absence of ECG changes or rhythm disturbances, a direct anastomosis of the
      left internal mammary artery and the left anterior descending coronary artery was
      performed. In four control dogs, direct MICAB procedure was done without
      preconditioning. The proximal left anterior descending coronary artery was
      occluded upstream of the arteriotomy in two dogs from both groups to exclude
      competitive flow from the native coronary artery. All the procedures were
      successful, except for one conditioned dog that sustained preoperative transmural
      anterior myocardial infarction. Cardiac enzymes (CK and CKMB) rose in all groups
      immediately after the procedure; this was not statistically significant between
      groups. All survivors were angiographically controlled after 6 to 8 weeks. They
      showed good patency of all grafts (mean thrombolysis in myocardial infarction
      flow equals 2.86). There was perfect matching between the left internal mammary
      artery and left anterior descending coronary artery in the conditioned and
      proximal occluded group, which was contrary to the competitive flow in the
      control groups between the open left anterior descending coronary artery and the
      left internal mammary artery graft. Permeability of the left internal mammary
      artery grafts are not influenced by preconditioning nor exclusion of competitive
      flow in the MICAB technique for the canine model. Graft diameter and flow are
      merely the result of outflow conditions. In one case, preconditioning was
      followed by fatal myocardial infarction.

PMID- 10639051
TI  - The concept of long term potentiation of transmission at synapses.
AB  - The phenomenon of long term potentiation (LTP) of synaptic transmission, whereby
      a series of conditioning trains of impulses potentiate the size of synaptic
      potentials for periods in excess of hours, was discovered in the mammalian
      hippocampus by Lomo [1966, Acta Physiol. Scand. 68(Suppl. 277), 128] and
      subsequently characterized by Bliss and Lomo (1970, J. Physiol. 207, 61P). The
      search for the underlying mechanisms of LTP makes for fascinating reading. The
      induction of associative LTP was shown by Collingridge et al. (1982, J. Physiol.
      334, 33-46) to be dependent on the presence of N-methyl-D-aspartate receptors,
      following the discovery of these receptors by Watkins and Evans (1981, A. Rev.
      Pharmac. Toxic. 21, 165-204). There has, however, been continuing controversy as
      to whether the maintenance phase of LTP over periods of hours may be attributed
      to an increase in the amount of transmitter released or to an increase in the
      number of glutamate receptors or both. There is more agreement on the important
      role or protein kinases in the maintenance phase of LTP. The role of LTP in
      memory is just now being elucidated.

PMID- 10639052
TI  - The cause of neuronal degeneration in Alzheimer's disease.
AB  - Alzheimer's disease is associated with a specific pattern of pathological changes
      in the brain that result in neurodegeneration and the progressive development of
      dementia. Pathological hallmarks common to the disease include beta-amyloid
      plaques, dystrophic neurites associated with plaques and neurofibrillary tangles
      within nerve cell bodies. The exact relationship between these pathological
      features has been elusive, although it is clear that beta-amyloid plaques precede
      neurofibrillary tangles in neocortical areas. Examination of the brains of
      individuals in the preclinical stage of the disease have shown that the earliest
      form of neuronal pathology associated with beta-amyloid plaques resembles the
      cellular changes that follow structural injury to axons. Thus, the development of
      beta-amyloid plaques in the brain may cause physical damage to axons, and the
      abnormally prolonged stimulation of the neuronal response to this kind of injury
      ultimately results in the profound cytoskeletal alterations that underlie
      neurofibrillary pathology and neurodegeneration. Therapeutically, inhibition of
      the neuronal reaction to physical trauma may be a useful neuroprotective strategy
      in the earliest stages of Alzheimer's disease.

PMID- 10639053
TI  - Herpes virus latency in sensory ganglia--a comparison with endogenous neuronal
      gene expression.
AB  - Central to infection by a majority of DNA viruses is the expression of encoded
      proteins that modify cell cycle. Viruses such as SV40 and Adenovirus viruses
      encode proteins that interact directly, or indirectly, with key cell cycle
      proteins such as CBP300 and the retinoblastoma gene product. However, neurons do
      not have a cell cycle as we generally describe it and this is also reflected in
      the difficulty in obtaining immortalised neuronal cultures. The replication
      strategies of viruses that infect post-mitotic cells such as neurons may be
      different from infection of other somatic cells. The life cycle for viral latency
      or slow infection of neurons appears to involve silencing or restricting
      expression of the viral genome until such times as dictated by the environment.
      These signals from the environment usually reflect cell stress, otherwise the
      cell appears to tolerate the existence of the virus genome. We will review the
      genomic structure of alphaherpesviruses in neurons and transcriptional control
      mechanisms that may regulate expression. Where appropriate we will contrast and
      compare virus and endogenous neuronal gene expression.

PMID- 10639054
TI  - Voltage-gated calcium channels in autonomic neuroeffector transmission.
AB  - Calcium influx through voltage-gated calcium channels (VGCCs) is required for
      neurotransmitter release. Recent research has characterised several
      pharmacologically and electrophysiologically distinct VGCC subtypes, some of
      which are involved in neurotransmitter release. Transmitter release from
      autonomic neurons can be coupled to calcium entry through N-, P/Q- and/or R-type
      VGCCs; the precise combination of VGCC subtypes appears to vary according to the
      neurotransmitter, tissue and species. L-type channels rarely appear to be
      important in autonomic neurotransmitter release. There does not appear to be a
      general rule regarding the nature of the VGCCs coupled to release of a particular
      transmitter in different tissues or species. Release of the same neurotransmitter
      from different populations of neurons often reveals a different pattern of
      involvement of VGCCs. Transmitters released from the same population of neurons
      are sometimes coupled to calcium influx through different VGCC subtypes. However,
      release of transmitters thought to be co-localised within vesicles is coupled to
      calcium influx through the same VGCCs. The role of VGCC subtypes in transmitter
      release can be altered by mode of nerve stimulation. Different VGCC subtypes may
      be coupled to transmitter release at low versus high electrical stimulation
      frequencies, or in response to potassium depolarization or chemical stimulation.
      In certain disease processes, voltage-gated calcium channels on autonomic neurons
      can be targeted; for example antibodies to P/Q-type VGCCs in Lambert-Eaton
      myasthenic syndrome downregulate VGCCs, thereby inhibiting autonomic
      neuroeffector transmission.

PMID- 10639055
TI  - Genitourinary chlamydial infection: a reappraisal and hypothesis.
AB  - Our understanding of genitourinary chlamydial infection and disease remains
      limited. That natural defences and/or apparently adequate treatments leave some
      patients with latent disease is suspected. There is, however, no consensus as to
      its nature. Furthermore, many patients, most obviously males, presenting with
      similar or identical symptoms and signs remain unexplained in microbiological
      terms; this in spite of many years of dedicated research endeavour. The recent
      trend towards an impasse has coincided with a growing acquaintance with the
      immunobiology and immunopathology of chlamydial infections. The time would seem
      to have arrived for a reappraisal of available clinical and laboratory
      observations. A hypothesis with research suggestions is presented for discussion.

PMID- 10639056
TI  - Evaluation of self-taken samples for the presence of genital Chlamydia
      trachomatis infection in women using the ligase chain reaction assay.
AB  - The aim of this study was to evaluate the sensitivity and acceptability of self
      taken vulval-introital (VI) samples, first-catch urine (FCU) samples and
      clinician-obtained cervical samples for the presence of genital Chlamydia
      trachomatis infections in women using the ligase chain reaction (LCR) assay. One
      hundred and four patients were enrolled, of whom 54 patients had chlamydial DNA
      in at least one of the samples tested. The sensitivity of the cervical sample was
      96.3%, vulval-introital sample in LCR buffer 92.6%, vulval-introital swab
      collected dry 88.9%, FCU stored at +2-8 degrees C 81.5%, FCU stored at room
      temperature 77.8% and FCU stored with 2% w/v boric acid at room temperature
      87.0%. Self-taken vulval-introital LCR samples were shown to be an acceptable
      alternative to a clinician-obtained LCR sample. The addition of boric acid may
      overcome the need for a continuous cold chain for FCU samples.

PMID- 10639057
TI  - Intestinal protozoa in homosexual men in Edinburgh.
AB  - Our objective was to determine the prevalence of intestinal protozoa in
      homosexual men attending a sexually transmitted diseases (STD) clinic, to compare
      it with the prevalence in a previous study from the same clinic, and to examine
      the relationship, if any, between the presence of protozoa and sexual practices.
      Men who consecutively attended the clinic and who gave a history of having had
      recent sexual contact with another male were invited to provide a stool sample
      for protozoological examination. Diarrhoeal samples were examined by direct
      microscopy for trophozoites and cysts and, after staining, for Cryptosporidium
      spp. In all cases, a modified formol-ether method was used to concentrate
      protozoal cysts before microscopy. One hundred and seventy-five of the 257 men
      invited to participate in the study provided a stool sample. At least one species
      of protozoan was found in 99 (57%) men. Giardia intestinalis was identified in
      only 5 (3%) men. Blastocystis hominis was found in 46 (26%) men, but the presence
      of this protozoan was not associated with diarrhoea. Other than the prevalence of
      Entamoeba dispar/histolytica and G. intestinalis, which remained unchanged, the
      proportion of men who harboured the non-pathogenic protozoa was significantly
      increased from 1981/82. A correlation between oral-anal sex or peno-insertive or
      peno-receptive anal intercourse and the prevalence of protozoa was not found.
      There was also no correlation between the number of species of protozoa carried
      and these sexual practices. The presence of protozoa was not associated with a
      history of foreign travel or sexual contact with a man who had recently travelled
      outside the UK. The study showed that, although the prevalence of infection is
      low, giardiasis is still transmissible amongst homosexual men. A correlation
      between individual sexual practices and the prevalence of intestinal protozoa was
      not found.

PMID- 10639058
TI  - Condom shape: a neglected factor influencing use and acceptability? UK Family
      Planning Research Network.
AB  - Improving condom acceptability amongst users is one way to enhance efficacy. This
      study aimed to test whether or not the shape of a condom influenced users'
      perceptions of condom acceptability as measured through their ratings of condom
      comfort, sensitivity and security. Four types of condoms were tested which had 3
      different shapes, and one of which also had a small diameter. Participants were
      recruited at 15 UK Family Planning Research Network Clinics and one Student
      Health Centre in England and Wales in late 1997. A total of 1193 people initially
      volunteered to take part and of these 204 men and 251 women completed the trial,
      giving an overall response rate of 38%. Results suggest that both men and women
      were able to detect differences in the shapes of the condoms and that differences
      led to preference for a particular condom type. Similar proportions preferred a
      straight-sided, a flared and a contoured condom, whilst the smaller, contoured
      condom was preferred by a minority of respondents. To optimize consistent condom
      use, providers should consider encouraging users to try a range of condoms to
      ensure that they are using the one most suitable for them.

PMID- 10639059
TI  - A retrospective study of the addition of ciprofloxacin to clarithromycin and
      ethambutol in the treatment of disseminated Mycobacterium avium complex
      infection.
AB  - Disseminated Mycobacterium avium complex (DMAC) infection is associated with
      increased morbidity and mortality in HIV-infected individuals. The combination
      antibiotic regimens containing clarithromycin can decrease symptoms and improve
      survival in patients with DMAC, however, optimal therapy remains to be defined.
      Quinolones have been widely used in the treatment of DMAC but their utility has
      not been established. A retrospective cohort study of DMAC infection was
      established in a metropolitan hospital providing comprehensive care to over 3000
      HIV-infected individuals. Medical records of patients with DMAC diagnosed at the
      Parkland Memorial Hospital from 1991 to 1994 were reviewed for therapeutic
      regimens for DMAC, concomitant therapy for HIV and Pneumocystis carinii
      prophylaxis and date of death. Subjects were included if they were treated with
      clarithromycin and ethambutol. Cases were defined as those patients who received
      more than 30 days of ciprofloxacin as therapy for DMAC in addition to the other
      drugs that they received. The primary endpoint was the time to death from the
      data of DMAC diagnosis. Covariates effecting survival were analysed through the
      Cox proportional hazards model. Eighty-nine subjects with DMAC who were treated
      with clarithromycin and ethambutol were identified. Fifty-eight received
      ciprofloxacin in addition to clarithromycin and ethambutol. The time to death was
      significantly better in those subjects who were treated with ciprofloxacin than
      those who were not (489 days vs 281 days, P=0.01). The sole significant predictor
      of improved survival on Cox proportional hazards model was ciprofloxacin therapy.
      Subjects treated with combination of clarithromycin, ethambutol and ciprofloxacin
      had improved survival over those treated with clarithromycin and ethambutol
      alone.

PMID- 10639060
TI  - HIV-related malignancies: community-based study using linkage of cancer registry
      and HIV registry data.
AB  - For people immunosuppressed by human immunodeficiency virus (HIV), we expect an
      increase in cancer incidence similar to that documented in transplant patients.
      We examined the cancer spectrum in an HIV-infected cohort, specifically
      malignancies not currently associated with acquired immunodeficiency syndrome
      (AIDS), in relation to the general population. Cancer incidence data for
      residents of Harris County, Texas, diagnosed between 1975 and 1994, were linked
      to HIV/AIDS registry data by Soundex code and date of birth to identify
      malignancies in an HIV-infected cohort of 14,986 persons. Incidence of cancer in
      this cohort was compared to the general population by standardized incidence
      ratio (SIR) analysis. From the HIV-infected cohort, 2289 persons (15%) were
      identified as having one or more malignancies, with 97% occurring in males. The
      linkage alone identified 29.5% of the malignancies, of which only 28.7% were
      diagnosed in males. Adjusting for age, HIV-infected men and women had incidences
      of cancer that were 16.7 [95% confidence interval (CI) 16.1-17.3] and 2.9 (95% CI
      2.3-3.7) times that expected for the general population of Harris County, Texas.
      Besides Kaposi's sarcoma, non-Hodgkin's lymphoma, cervix cancer and brain
      lymphoma, non-AIDS related malignancies of Hodgkin's lymphoma, non-melanotic skin
      cancer in males and colon cancer in females, exhibited significant SIRs of 5.6
      (95% CI 3.6-8.4), 6.9 (95% CI 4.8-9.5) and 4.0 (95% CI 1.1-10.2). Increased
      incidences of lung, prostate and breast malignancies were not seen in this HIV
      cohort. Persons infected with HIV appear to be at increased risk for the non-AIDS
      related malignancies, Hodgkin's lymphoma, non-melanotic skin cancer in males and
      colon cancer in females.

PMID- 10639061
TI  - Relationship between human papillomavirus (HPV) genotyping and genital neoplasia
      in HIV-positive patients of Santos City, Sao Paulo, Brazil.
AB  - Among HIV-positive women, infection with multiple human papillomavirus (HPV)
      types is known to be more frequent and persistent, as well as a greater
      prevalence of high-grade genital lesions. This study aims to characterize, for
      the first time in Brazil, HPV presence and types among HIV-positive women of a
      high-risk population for genital intraepithelial neoplasia (GIN) development. A
      non-anonymous, voluntary, cross-sectional epidemiological survey was conducted,
      from June 1996 to April 1997, among 141 HIV-positive women followed at the Center
      of Reference in AIDS (CRAIDS). They were submitted to gynaecological examination,
      cytological screening and biopsies whenever necessary, for GIN and HPV DNA
      detection through polymerase chain reaction (PCR) technique. Positive HPV DNA
      were found in 80.8% patients. Two or more HPV types were detected in 45% of the
      samples. The most frequent HPV types detected were 16, 18 (30.5%); 61, 53
      (24.4%), and non-identified types (18.7%). According to the oncogenic potential,
      34.8% were considered of high-risk types. Among these HIV-positive patients, a
      great variety of HPV types, including high-risk types, was found in anogenital
      environment, as well as among young women, a great prevalence of high-grade
      genital lesions. Thus, it should strengthen the need for a periodical careful
      gynaecological examination among those women.

PMID- 10639062
TI  - Usefulness of information from the unlinked anonymous prevalence monitoring
      programme for HIV in England and Wales: survey of planners of HIV/AIDS services.
AB  - The aim of this study was to evaluate whether information from the Unlinked
      Anonymous Prevalence Monitoring Programme for HIV in England and Wales is useful
      to planners of HIV/AIDS services. The study involved 2 stages: examination of
      1997 AIDS Control Act Reports for England and Wales, and a telephone
      questionnaire survey of local planners of HIV/AIDS services. Forty-eight out of
      55 health authorities (87.3%) found information from the programme to be useful
      in general; 37/55 (67.3%) found the information useful for targeting of health
      promotion; 35/55 (63.6%) found the information useful for assessing the
      effectiveness of preventive measures aimed at reducing the spread of HIV; and
      28/55 (50.9%) found the information useful for planning of medical or social
      services. If information from the programme was no longer available, 36/55
      (65.5%) said it would make some difference to local planning, although 12/55
      (21.8%) said it would make no difference. Local planners were generally
      supportive of the programme, and complaints were mostly directed at funding and
      timeliness of the reports.

PMID- 10639064
TI  - The cellular immune system in female patients with or without genital warts: a
      study of peripheral white blood cell components.
AB  - The immune system plays a vital role in the fight against infections. The
      commonest viral infections treated in the genitourinary medicine (GUM)
      departments are genital warts. Knowledge about the status of the immune system in
      these patients may help in their clinical management. This study compares the
      values of various blood cell components in the peripheral blood of 2 groups of
      female patients--those with genital warts against those without genital warts.
      The mean monocyte count was lower among patients with genital warts.

PMID- 10639063
TI  - HIV-infected workers deported from the Gulf States: impact on Southern Pakistan.
AB  - HIV prevalence is still very low in Pakistan, but its south Asian location and
      subgroups with recognized lifestyle risk factors suggest that Pakistan will
      experience expanded diffusion of HIV. We report the frequency of HIV infections
      identified by the AIDS Control Programme on the Sindh province of Pakistan. Most
      HIV-positive cases currently reported to the Sindh AIDS Control Programme are
      found among Pakistani workers deported from the Gulf States and among foreigners.
      The 58 returned workers with HIV represent 61 to 86% of reported cases in any
      given year during the 1996-1998 period. Five wives of returning workers have been
      identified with HIV. Expatriate workers in the Gulf States are tested for HIV
      routinely, unlike other subgroups in Pakistan. Considering the risk of HIV/AIDS
      due to regular introduction of HIV from returned workers, and the limited
      awareness surrounding sexual health and HIV/STD transmission issues in Pakistan,
      intervention programmes targeted at overseas workers need to be implemented to
      control the expansion of the HIV epidemic in Pakistan.

PMID- 10639065
TI  - Characteristics of HIV-infected men with low serum testosterone levels.
AB  - Low levels of serum testosterone may have negative implications on morbidity in
      HIV-infected men. The purpose of this study was to determine demographic and
      clinical characteristics that predict low serum testosterone among men attending
      our HIV clinic. A cross-sectional study of 587 HIV-positive male patients who
      presented at the Louisiana State University HIV Outpatient (HOP) Clinic between
      August 1997 and January 1999 was conducted. Demographic and clinical
      characteristics were collected and analysed. Of the 587 men studied, 119 (20.3%)
      had a serum testosterone level below 400 ng/dl. Significantly more men with low
      serum testosterone levels had a presence of opportunistic infection (especially
      HIV wasting syndrome, oesophageal candidiasis, or dementia), CD4+ cell counts
      below 200 cells/mm3, or were taking megestrol acetate. Early detection of low
      serum testosterone will allow for expedient testosterone supplementation therapy,
      which could improve morbidity and quality of life for HIV-infected men.

PMID- 10639066
TI  - Saccharomyces cerevisiae oesophagitis in an HIV-infected patient.

PMID- 10639067
TI  - Carcinoma of the penis preceded by Zoon's balanitis.

PMID- 10639068
TI  - Acceptability of the female condom amongst commercial sex workers in Thailand and
      Cote d'Ivoire.

PMID- 10639069
TI  - Acquiring scientific information in the 21st century(1)

PMID- 10639070
TI  - Soluble molybdenum blues-"des Pudels Kern".
AB  - The earlier tremendous interest in molybdenum blue solutions-an enigma for
      generations of chemists-became even more pronounced when it turned out that the
      basic building units correspond to giant wheel-shaped clusters with
      nanostructured cavities, displaying exceptional aesthetic beauty. This discovery
      will stimulate new ideas in supramolecular chemistry, colloid chemistry, and
      materials science. The giant wheels represent nanosensors and nanoreactors,
      enabling the initiation of chemical processes at different positions, like a
      "structured landscape", and can even be used as robust synthons for the
      construction of compounds with typical solid-state structure, a situation
      comparable to crystal engineering.

PMID- 10639071
TI  - Glycosidase mechanisms: anatomy of a finely tuned catalyst.
AB  - In order to accelerate the hydrolysis of glycosidic bonds by factors approaching
      10(17)-fold, glycosidases have evolved finely tuned active sites optimally
      configured for transition-state stabilization. Structural analyses of various
      enzyme complexes representing stable intermediates along the reaction coordinate,
      in conjunction with detailed mechanistic studies on wild-type and mutant enzymes,
      have delineated the contributions of nucleophilic and general acid/base
      catalysis, as well as the roles of noncovalent interactions, to these impressive
      rate enhancements.

PMID- 10639072
TI  - Transition states for surface-catalyzed chemistry.
AB  - Fluorine substituent effects have been used to probe the nature of the transition
      states for the several elementary reaction steps occurring on metal surfaces. The
      reactions described include beta-hydrogen elimination in adsorbed alkoxide and
      alkyl groups, coupling of alkyl groups, and dehalogenation of alkyl chloride and
      iodides. The substituent effect method can provide a connection between
      heterogeneous catalysis, surface science, and computational molecular simulation
      of surface reactions.

PMID- 10639073
TI  - Monolayer-protected cluster molecules.
AB  - In this report, we evaluate the present state of the rapidly emerging field of
      monolayer-protected cluster (MPC) molecules with regard to their synthesis and
      monolayer functionalization, their core and monolayer structure, their
      composition, and their properties. Finally, we canvass some of the important
      remaining research opportunities involving MPCs.

PMID- 10639074
TI  - Nanoshocks in molecular materials.
AB  - Nanoshocks are tiny but powerful laser-driven shock waves that can be used to
      produce large-amplitude compression in molecular materials on the picosecond time
      scale. When coupled with ultrafast molecular spectroscopy, the molecular response
      to nanoshocks can be probed in detail. Simple molecular systems (anthracene
      crystals) are used to characterize the nanoshock pulses. Well-characterized
      nanoshocks are used to study complex phenomena such as shock-induced chemical
      reactions, shock-induced orientation of energetic solids, and shock compression
      of organic polymers and proteins.

PMID- 10639075
TI  - Synthesis and reactivities of cubane-type sulfido clusters containing noble
      metals.
AB  - Cubane-type sulfido clusters containing noble metals are newcomers compared with
      the corresponding clusters of the first transition series metals and molybdenum,
      which have been extensively studied in relation to metalloenzymes and industrial
      hydrodesulfurization catalysts. This Account reviews the recent progress in
      studies on the synthesis and reactivities of these noble metal cubane-type
      clusters. One of the goals in this new area lies in development of the unique
      catalysis of the noble metals embedded in the robust and redox-active cubane-type
      cores. Rational synthetic approaches indispensable to the preparation of such
      effective cluster catalysts are discussed to a significant extent.

PMID- 10639076
TI  - One-dimensional polymers and mesogens incorporating multiple bonds between metal
      atoms.
AB  - A synthetic strategy aimed at incorporating metal-metal multiple bonds into one
      dimensional polymers and liquid crystals is outlined. Specific examples taken
      from the use of dimetal tetracarboxylates, where the metals are molybdenum and
      tungsten, are presented. Depending upon the organic linking group, the one
      dimensional polymers may be conducting or charge-storing, and the
      characterization of discrete dimers of "dimers" is used to illustrate this. The
      thermotropic and other physicochemical properties of mesogenic M(2)(O(2)CR)(4)
      compounds can be related to the intermolecular M(2)- - -O interactions as a
      function of M and R.

PMID- 10639077
TI  - Editorial: What's New

PMID- 10639078
TI  - Synthesis of bioadhesive lectin-HPMA copolymer-cyclosporin conjugates.
AB  - An amino group containing cyclosporin A (CsA) derivative has been synthesized and
      conjugated to N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer via an aromatic
      azo bond, which can be specifically cleaved by azoreductase activity in colon to
      release the drug for the treatment of colon diseases. Lectins, peanut (Arachis
      hypogea) agglutinin (PNA) and wheat germ agglutinin (WGA), have been conjugated
      to HPMA copolymer-CsA derivative conjugates (PCsA), respectively, to give
      bioadhesive conjugates. The PNA and WGA are the targeting proteins that can bind
      to diseased colon tissue and healthy tissue, respectively. There were on average
      four P(CsA) copolymer chains attached on one WGA molecule with a drug content of
      16.0 wt % and five P(CsA) copolymer chains attached on one PNA molecule with a
      drug content of 11.5 wt %. The incubation of a P(CsA) copolymer with the rat
      cecal contents resulted in the cleavage of the azo bond and release of the
      cyclosporin derivative. The biological evaluation of the conjugates is under way.

PMID- 10639079
TI  - Hydrogen gas evolution and carbon dioxide fixation with visible light by
      chlorophyllin coupled with polyethylene glycol.
AB  - Chlorophyllin a was conjugated with alpha-(3-aminopropyl)-omega
      methoxypoly(oxyethylene), PEG-NH(2), to form the PEG-chlorophyllin conjugate
      through acid-amide bonds. The PEG-chlorophyllin conjugate was stable toward light
      illumination under anaerobic condition in comparison with chlorophyllin a. The
      conjugate catalyzed the reduction of methyl viologen in the presence of 2
      mercaptoethanol and the evolution of hydrogen gas in the presence of methyl
      viologen (an electron carrier), 2-mercaptoethanol (an electron donor) and
      hydrogenase (Scheme 1). Furthermore, the PEG-chlorophyllin conjugate catalyzed
      the photoreduction of NADP(+) or NAD(+) in the presence of ascorbate as an
      electron donor and ferredoxin-NADP(+) reductase as the coupling enzyme. Utilizing
      the reducing power of NADPH generated by the PEG-chlorophyllin conjugate under
      the illumination, CO(2) fixation was accomplished by the synthesis of malate
      (C(4)) from pyruvate (C(3)) and CO(2) in the presence of malic enzyme (Scheme 2).
      These reactions mentioned above did never proceed in dark or without each enzyme.

PMID- 10639080
TI  - Synthesis of polyamide oligomers based on 14-amino-3,6,9, 12
      tetraoxatetradecanoic acid.
AB  - A series of oligomers of polyamides based on 14-amino-3,6,9, 12
      tetraoxatetradecanoic acid monomers (ATTAn) was synthesized. These materials were
      designed as monodisperse analogues of poly(ethylene glycol) for use in biomedical
      applications where reproducible behavior is important. Synthesis of the monomer
      was evaluated using two routes. For small-scale preparations, tetraethylene
      glycol (TEG) was monoprotected with dihydropyran, converted to an alkoxide, and
      alkylated with ethyl bromoacetate. On larger scales, TEG was alkylated directly
      by treatment with sodium, followed by ethyl bromoacetate. The amine function was
      introduced by mesylation followed by treatment with sodium azide. Reduction of
      the azide to amino groups was performed over Pd/C using either hydrogen or formic
      acid as proton sources. Assembly of the oligomers was accomplished using standard
      DCC/NHS chemistry and an iterative dimerization sequence after appropriate
      deprotection of a pair of monomers. The amino group was protected by retaining
      the azido group as a latent amine. A series of ATTAn oligomers was prepared (n =
      1-8). A lipid conjugate of the octamer, ATTA8-DSPE, was synthesized.

PMID- 10639081
TI  - Noncovalent adducts of poly(ethylene glycols) with proteins.
AB  - A new method of preparation of noncovalent complexes between poly(ethylene
      glycol) (PEG) and proteins (alpha-chymotrypsin (ChT), lysozyme, bovine serum
      albumine) under high pressure has been developed. The involvement of polymer in
      the complexes was proved using (3)H-labeled PEG. The composition of the complexes
      (the number of polymer chains per one ChT molecule) depends on the molecular mass
      of PEG and decreases with the increase in molecular mass from 300 to 4000,
      whereas the portion of the protein (wt %) in complexes does not depend on the
      molecular mass of incorporated PEG and corresponds to approximately 70 wt %. The
      kinetic constants for enzymatic hydrolysis of N-benzoyl-L-tyrosine ethyl ester
      and azocasein catalyzed by the PEG-ChT complexes are identical with the
      corresponding values for the native ChT. According to the data obtained by the
      method of circular dichroism, the enzyme in the complexes fully retains its
      secondary structure. The steric availability of PEG polymer chains in the
      complexes was evaluated by their complexation with alpha-cyclodextrin (CyD) or
      polymer derivatives of beta-CyD modified with PEG (PEG-beta-CyD). In contrast to
      free PEG, only part of PEG polymer chains ( approximately 10%) interact with
      alpha-CyD. Thus, the complexation of PEG with ChT proceeds by means of multipoint
      interaction with surface groups of the protein globule located far from the
      active site and results in the sufficient decrease in the availability of polymer
      chains. The complexes between PEG chains in PEG-protein adducts and PEG-beta-CyD
      may be considered as a novel type of dendritic structures.

PMID- 10639082
TI  - Phospholipid-model membrane interactions with branched polypeptide conjugates of
      a hepatitis A virus peptide epitope.
AB  - To establish correlation between structural properties (charge, composition, and
      conformation) and membrane penetration capability, the interaction of epitope
      peptide-carrier constructs with phospholipid model membranes was studied. For
      this we have conjugated a linear epitope peptide, (110)FWRGDLVFDFQV(121) (110
      121), from VP3 capside protein of the Hepatitis A virus with polylysine-based
      branched polypeptides with different chemical characteristics. The epitope
      peptide elongated by one Cys residue at the N-terminal [C(110-121)] was attached
      to poly[Lys-(DL-Ala(m)()-X(i)())] (i < 1, m approximately 3), where x = o(AK),
      Ser (SAK), or Glu (EAK) by the amide-thiol heterobifunctional reagent, 3-(2
      pyridyldithio)propionic acid N-hydroxy-succinimide ester. The interaction of
      these polymer-[C(110-121)] conjugates with phospholipid monolayers and bilayers
      was studied using DPPC and DPPC/PG (95/5 mol/mol) mixture. Changes in the
      fluidity of liposomes induced by these conjugates were detected by using two
      fluorescent probes 1,6-diphenyl-1,3, 5-hexatriene (DPH) and sodium anilino
      naphthalene sulfonate (ANS). The binding of conjugates to the model membranes was
      compared and the contribution of the polymer component to these interactions were
      evaluated. We found that conjugates with polyanionic/EAK-[C(110-121)] or
      polycationic/SAK-[C(110-121)], AK-[C(110-121)]/character were capable to form
      monomolecular layers at the air/water interface with structure dependent
      stability in the following order: EAK-[C(110-121)] > SAK-[C(110-121)] > AK-[C(110
      121)]. Data obtained from penetration studies into phospholipid monolayers
      indicated that conjugate insertion is more pronounced for EAK-[C(110-121)] than
      for AK-[C(110-121)] or SAK-[C(110-121)]. Changes in the fluorescence intensity
      and in polarization of fluorescent probes either at the polar surface (ANS) or
      within the hydrophobic core (DPH) of the DPPC/PG liposomes suggested that all
      three conjugates interact with the outer surface of the bilayer. Marked
      penetration was documented by a significant increase of the transition
      temperature only with the polyanionic compound/EAK-[C(110-121)]. Taken together,
      we found that the binding/penetration of conjugates to phospholipid model
      membranes is dependent on the charge properties of the constructs. Considering
      that the orientation and number of VP3 epitope peptides attached to branched
      polypeptides were almost identical, we can conclude that the structural
      characteristics (amino acid composition, charge, and surface activity) of the
      carrier have a pronounced effect on the conjugate-phospholipid membrane
      interaction. These observations suggest that the selection of polymer carrier for
      epitope attachment might significantly influence the membrane activity of the
      conjugate and provide guidelines for adequate presentation of immunogenic
      peptides to the cells.

PMID- 10639083
TI  - Structure of a synthetic glucose derived advanced glycation end product that is
      immunologically cross-reactive with its naturally occurring counterparts.
AB  - Glucose reacts nonenzymatically with the amino groups of proteins to form stable,
      cross-linking adducts called advanced glycation end products or AGEs. While
      several lines of evidence have established that AGEs accumulate in tissues and
      contribute to the pathological sequelae of diabetes and aging, the identity of
      the major cross-link(s) that forms in vivo has remained enigmatic. This has been
      considered to be due to the labile nature and to the low fluorescence properties
      of this cross-link, despite the fact that fluorescence has been generally
      associated with AGE formation in vivo. Accordingly, the few AGE adducts that have
      been isolated thus far from proteins in vivo or from model systems in vitro have
      been found to account for only a fraction of the glucose-derived cross-links that
      occur in tissues. This situation has been further underscored by the development
      of a well-characterized class of antibodies that recognize in vivo AGEs but which
      fail to react with the structurally defined AGEs that have been identified to
      date. This particular class of anti-AGE antibodies has proven valuable in the
      quantification of AGE-modified forms of hemoglobin, low-density lipoprotein
      (LDL), and beta-amyloid peptide, and can provide prognostic information on the
      course of certain diabetic complications. To obtain insight into the structure of
      this immunoreactive, AGE adduct, we used an anti-AGE antibody (RU) as a probe to
      isolate novel AGE(s) that formed within a reaction mixture of glucose and the
      model glycation substrate, N(alpha)-CBZ-Arg-Lys. HPLC purification of an
      immunoreactive fraction that accumulated in this preparation showed the presence
      of a compound that was determined by (1)H NMR and electrospray ionization mass
      spectrometry (ESI-MS) to be a stable, imidazole-based cross-link (termed arginine
      lysine imidazole or ALI). The properties of ALI, immunoreactivity, acid-lability,
      nonfluorescence, and inhibition of formation by aminoguanidine, suggest that ALI
      is likely to typify an important class of the AGE cross-links that form in vivo.

PMID- 10639084
TI  - Exchange transfusion with albumin-heme as an artificial O2-infusion into
      anesthetized rats: physiological responses, O2-delivery, and reduction of the
      oxidized hemin sites by red blood cells.
AB  - Human serum albumin (HSA) incorporating synthetic hemes, the tetrakis(o
      pivalamido)phenylporphinatoiron(II) derivative (FeP), is an artificial
      hemoprotein (HSA-FeP) which is able to reversibly bind and release dioxygen under
      physiological conditions (in aqueous media, pH 7.4, 37 degrees C) like hemoglobin
      and myoglobin. Physiological responses to exchange transfusion with HSA-FeP
      solution [[HSA], 5 g/dL; FeP/HSA, 4 (mol/mol)] into rats after hemodilution and
      hemorrhage (Hct, about 10%) has been evaluated. The declined mean arterial
      pressure (MAP) and blood flow after a 70% exchange with HSA and the further 40%
      bleeding of blood were significantly recovered up to about 90% of the baseline
      values by the injection of HSA-FeP. Furthermore, the renal cortical O(2)-tensions
      and skeletal tissue O(2)-tensions were also increased, indicating the in vivo
      O(2)-delivery of HSA-FeP. Autoxidation of ferrous Fe(II)P to ferric Fe(III)P was
      retarded in the blood stream; the half-lifetime of the dioxygenated FeP
      [tau(1/2)(O(2))] in vivo was 4.1 h [cf. 1.0 h (in vitro)]. It has been found that
      autooxidized Fe(III)P was certainly reduced in the whole blood suspension.
      Physiological concentrations of ascorbic acid continuously provided by red blood
      cells probably rereduces Fe(III)P, leading to the apparent long lifetime of the
      dioxygenated species of FeP.

PMID- 10639085
TI  - Novel method for covalent fluorescent labeling of plasmid DNA that maintains
      structural integrity of the plasmid.
AB  - We have developed a chemical strategy for covalent coupling of fluorophores to
      plasmid DNA. A p-azido-tetrafluoro-benzyl-lissamine conjugate was synthesized and
      purified. This conjugate was used to covalently associate fluorescent molecules
      to plasmid DNA by photoactivation. In contrast to nick-translated plasmid DNA,
      plasmid-lissamine conjugates appeared on gel as supercoiled DNA. Reporter gene
      was expressed after transfection of the plasmid-lissamine conjugates in NIH 3T3
      cells, although gene transfer efficiency was decreased by 60% as compared with
      unlabeled DNA. Intracellular traffic of plasmid-lissamine conjugates was studied
      in transfected cells. After cytoplasmic microinjection, fluorescent plasmid did
      not diffuse from the site of injection and appeared to be progressively degraded
      in the cytoplasm.

PMID- 10639086
TI  - Synthesis and physicochemical characterization of a series of hemoglobin-based
      oxygen carriers: objective comparison between cellular and acellular types.
AB  - A series of hemoglobin (Hb)-based O(2) carriers, acellular and cellular types,
      were synthesized and their physicochemical characteristics were compared. The
      acellular type includes intramolecularly cross-linked Hb (XLHb), polyoxyethylene
      (POE)-conjugated pyridoxalated Hb (POE-PLP-Hb), hydroxyethylstarch-conjugated Hb
      (HES-XLHb), and glutaraldehyde-polymerized XLHb (Poly-XLHb). The cellular type is
      Hb-vesicles (HbV) of which the surface is modified with POE (POE-HbV). Their
      particle diameters are 7 +/- 2, 22 +/- 2, 47 +/- 17, 68 +/- 24, and 224 +/- 76
      nm, respectively, thus all the materials penetrate across membrane filters with
      0.4 microm pore size, though only the POE-HbV cannot penetrate across the filter
      with 0.2 microm pore size. These characteristics of permeability are important to
      consider an optimal particle size in microcirculation in vivo. POE-PLP-Hb ([Hb] =
      5 g/dL) showed viscosity of 6.1 cP at 332 s(-1) and colloid osmotic pressure
      (COP) of 70.2 Torr, which are beyond the physiological conditions (human blood,
      viscosity = 3-4 cP, COP = ca. 25 Torr). XLHb and Poly-XLHb showed viscosities of
      1.0 and 1.5 cp, respectively, which are significantly lower than that of blood.
      COP of POE-HbV is regulated to 20 Torr in 5% human serum albumin (HSA). HES-XLHb
      and POE-HbV/HSA showed comparable viscosity with human blood. Microscopic
      observation of human red blood cells (RBC) after mixing blood with POE-PLP-Hb or
      HES-XLHb disclosed aggregates of RBC, a kind of sludge, indicating a strong
      interaction with RBC, which is anticipated to modify peripheral blood flow in
      vivo. On the other hand, XLHb and POE-HbV showed no rouleaux or aggregates of
      RBC. The acellular Hbs (P(50) = 14-32 Torr) have their specific O(2) affinities
      determined by their structures, while that of the cellular POE-HbV is regulated
      by coencapsulating an appropriate amount of an allosteric effector (e.g., P(50) =
      18, 32 Torr). These differences in physicochemical characteristics between the
      acellular and cellular types indicate the advantages of the cellular type from
      the physiological points of view.

PMID- 10639087
TI  - Bioluminescence and secondary structure properties of aequorin mutants produced
      for site-specific conjugation and immobilization.
AB  - Aequorin is one of several photoproteins that emits visible light upon binding to
      calcium ions. It has been widely used as a Ca(2+)-indicator and as an alternative
      highly sensitive bioluminescent label in binding assays. The apoprotein of
      aequorin binds an imidazopyrazine compound (coelenterazine) and molecular oxygen
      to form a stable photoprotein complex. Upon addition of calcium, the photoprotein
      undergoes a conformational change leading to the oxidation of the chromophore
      with the release of CO(2) and blue light. To gain more information of structure
      function relationships within the photoprotein that will aid in the design of
      mutants suitable for site-specific conjugation and immobilization, polymerase
      chain reaction (PCR)-based site-directed mutagenesis was employed to produce five
      different aequorin mutants. The five mutants included a cysteine-free mutant and
      four other mutants with single cysteine residues at selected positions within the
      protein. The aequorin mutants exhibited different bioluminescence emission
      characteristics with two mutants showing a decrease in relative light production
      in comparison to the cysteine-free mutant. Additionally, circular dichroism (CD)
      spectra revealed that the single amino acid substitutions made for two of the
      aequorin mutants did alter their secondary structures.

PMID- 10639088
TI  - Dye-pair reporter systems for protein-peptide molecular interactions.
AB  - Modifying a linear peptide near each terminus with a fluorescent dye can make it
      able to signal its own binding to a protein. As originally described, the dye
      pair is composed of fluorescein and tetramethylrhodamine [Wei, A.-P., Blumenthal,
      D. K., and Herron, J. N. (1994) Anal. Chem. 66, 1500-1506]. This paper shows that
      it may also be two molecules of tetramethylrhodamine. In aqueous solution, mutual
      affinity of the dyes causes fluorescence-quenching contact between them. When the
      peptide is bound by an antibody or cleaved by a proteinase, or when acetonitrile
      is added, dye-to-dye contact decreases and fluorescence increases 3-15-fold. When
      five peptides of 4-20 amino acid residues were doubly modified with
      tetramethylrhodamine, each product had the absorption spectrum of a
      tetramethylrhodamine dimer. As the peptides were not known to have special
      conformational features, self-affinity of the dye appeared to be the main cause
      of dimerization. Disruption of the dye dimers by acetonitrile suggested that
      dimerization of the dye(s) in aqueous solution was largely an effect of
      hydrophobicity. Dye-tagged peptides were used in fluorometric assays for two
      peptide-protein interactions. First, a peptide from type II collagen recognized
      by a monoclonal antibody was derivatized with two different dye pairs. The
      monoclonal bound each modified peptide, disrupting dye-to-dye contact and
      increasing fluorescence up to 4-fold. Second, a phosphopeptide recognized by an
      SH2 domain was tagged with fluorescein and tetramethylrhodamine, and its binding
      to the SH2 domain was detected through fluorescence. Doubly dye-tagged peptides
      offer a direct, solution-phase assay for protein-peptide binding.

PMID- 10639089
TI  - Site-specific polymer-streptavidin bioconjugate for pH-controlled binding and
      triggered release of biotin.
AB  - Low molecular weight copolymers of acrylic acid (AAc) and N-isopropylacrylamide
      (NIPAAm) have been synthesized with reactive OH groups at one end, using a chain
      transfer polymerization technique. The copolymer displays both pH and temperature
      sensitivity over a wide and useful range of pHs and temperatures, which permits
      both pH and temperature control of polymer conformation. This copolymer has been
      conjugated to a specific cysteine thiol site inserted by genetic engineering near
      the recognition site of streptavidin (SAv). In this paper, we demonstrate that
      this bioconjugate can provide pH control of biotin binding to and triggered
      release from the mutant SAv. These actions are relevant to affinity separations,
      biosensors, diagnostics, enzyme processes, and targeted delivery of drugs or
      chemical agents, labels, and other signals.

PMID- 10639090
TI  - Reduced immunogenicity of beta-lactoglobulin by conjugation with carboxymethyl
      dextran.
AB  - We prepared two beta-lactoglobulin (beta-LG)-carboxymethyl dextran (CMD)
      conjugates (Conj. 10A and Conj. 10B) by using a water-soluble carbodiimide to
      decrease the immunogenicity of beta-LG. The molar ratios of beta-LG to CMD in the
      conjugates were 5:1 (Conj. 10A) and 2:1 (Conj. 10B). The beta-LG-CMD conjugates
      maintained the retinol-binding activity of native beta-LG. Intrinsic fluorescence
      study indicated that shielding of the surface of beta-LG by CMD occurred in each
      conjugate, which was eminent in Conj. 10B. A local conformational change around
      (125)Thr-(135)Lys (alpha-helix) in each conjugate was detected by ELISA with
      monoclonal antibodies. The denaturation temperature of beta-LG evaluated by
      differential scanning calorimetry was greatly enhanced in each conjugate. The
      anti-beta-LG antibody response was markedly reduced after immunization with the
      beta-LG-CMD conjugates in BALB/c, C57BL/6, and C3H/He mice. We determined the B
      cell epitopes of beta-LG and each conjugate recognized in these mice and found
      that the linear epitope profiles of the beta-LG-CMD conjugates were similar to
      those of beta-LG, while the antibody response for each epitope was dramatically
      reduced. The reduced immunogenicity of beta-LG was most marked in the case of
      Conj. 10B, which contained more CMD than Conj. 10A, and was effectively shielded
      by CMD. We concluded that masking of epitopes by CMD is responsible for the
      decreased immunogenicity of the beta-LG in these conjugates.

PMID- 10639091
TI  - Caged single and double strand breaks.
AB  - Ionizing radiation and radiomimetic drugs such as bleomycin, calichieamycin,
      neocarzinostatin chromophore, and other synthetic agents can produce both single
      and double strand breaks in DNA. The ability to study the structure-activity
      relationships of single and double-strand break repair, lethality, and
      mutagenesis in vivo is complicated by the numerous types and sites of DNA
      cleavage products that can be induced by such agents. The ability to "cage" such
      breaks in DNA might help to further such studies and additionally afford a
      mechanism for activating and deactivating nucleic acid based drugs and probes.
      The major type of single strand break induced by ionizing radiation is a 3'- and
      5'-phosphate terminated single nucleotide gap. Previously, a caged strand break
      of this type had been developed that was designed to produce the 5'-phosphate
      directly upon irradiation with 366 nm light, and the 3'-phosphate by a subsequent
      beta-elimination reaction [Ordoukhanian, P., and Taylor, J.-S. (1995) J. Am.
      Chem. Soc. 117, 9570]. Unfortunately, the release of the 3'-phosphate group was
      quite slow at pH 7. To circumvent this problem, a second caged strand break has
      been developed that produces the 3'-phosphate directly upon irradiation, and the
      5'-phosphate by a subsequent beta-elimination reaction. When this caged strand
      break was used in tandem with the previous caged strand break, 5'- and 3'
      phosphate terminated gaps could be directly produced by irradiation with 366 nm
      light. These caged single strand breaks were also incorporated in tandem into
      hairpin substrates to demonstrate that they could be used to cage double strand
      breaks. These caged single strand breaks should be generally useful for
      generating site-specific DNA single and double strand breaks and gaps, using
      wavelengths and doses of light that are nondetrimental to biological systems.
      Because the position of the single strand break can be varied, it should now be
      possible to examine the effect of the sequence context and cleavage pattern of
      single and double strand breaks on the lethality and mutagenicity of this
      important class of DNA damage.

PMID- 10639092
TI  - Controlled template-assisted assembly of plasmid DNA into nanometric particles
      with high DNA concentration.
AB  - A series of novel cationic detergents that contain cleavable hydrophilic
      isothiuronium headgroups was synthesized, and their utility in controlled
      assembly of plasmid DNA into small stable particles with high DNA concentration
      investigated. The detergents have alkyl chains of C(8)-C(12) and contain
      hydrophilic isothiuronium headgroups that give relatively high critical micelle
      concentration (CMC) to the detergents (>10 mM). The isothiuronium group masks a
      sulfhydryl group on the detergent and can be cleaved in a controlled manner under
      basic conditions to generate a reactive thiol group. The thiol group can undergo
      a further reaction after the detergents have accumulated on a DNA template to
      form a disulfide-linked lipid containing two alkyl chains. The pH-dependent
      kinetics of cleavage of the isothiuronium group, the CMC of the surfactants, the
      formation of the complexes, and the transfection efficiency of the DNA complexes
      have been investigated. Using the C(12) detergent, a approximately 6 kilo
      basepair plasmid DNA was compacted into a small particle with an average diameter
      of around 40 nm with a approximately -13 mV zeta-potential at high DNA
      concentration (up to 0.3 mg/mL). The compounds were well tolerated in cell
      culture and showed no cytotoxicity under their CMCs. Under appropriate
      conditions, the small particle retained transfection activity.

PMID- 10639093
TI  - Radio-LC-MS for the characterization of 99mTc-labeled bioconjugates.
AB  - This report describes the first example of using radio-LC-MS for determining the
      composition of (99m)Tc radiopharmaceuticals at the tracer level. The in-line
      radiometric detector is a useful addition to a standard LC-MS and provides direct
      correlation between the MS data and the radioactive species in a
      radiopharmaceutical kit. Complexes [(99m)Tc(HYNICtide)(tricine)(L)] (RP444, L =
      TPPTS; RP445, L = TPPDS; and RP446, L = TPPMS) were prepared using a decayed
      generator eluant. All the ternary ligand (99m)Tc complexes show the expected
      monoprotonated molecular ions, (M + 1)(+), and diprotonated molecular ions, (M +
      2)(2+). The LC-MS spectral data support the proposed structure and are consistent
      with those obtained for their corresponding (99)Tc analogues. Ternary ligand
      complexes [(99m)Tc(HYNICtide)(tricine)(L)] (L = ISONIC-HE and ISONIC-Sorb) are
      neutral, and the molecular weights are also lower than that of RP444. Using a
      fresh generator eluant (24 h prior elution), only 1-2 mCi of (99m)Tc [(7 x 10(
      )(12))-(1.5 x 10(-)(11)) mol of technetium complex] are required to obtain a
      reasonably clean mass spectrum. Radio-LC-MS is a quick and accurate analytical
      tool for characterization of (99m)Tc radiopharmaceuticals at the tracer level.

PMID- 10639094
TI  - Differential reactivity of maleimide and bromoacetyl functions with thiols:
      application to the preparation of liposomal diepitope constructs.
AB  - The comparative reactivity of maleimide and bromoacetyl groups with thiols (2
      mercaptoethanol, free cysteine, and cysteine residues present at the N-terminus
      of peptides) was investigated in aqueous media. These studies were performed (i)
      with water-soluble functionalized model molecules, i.e., polyoxyethylene-based
      spacer arms that could also be coupled to lipophilic anchors destined to be
      incorporated into liposomes, and (ii) with small unilamellar liposomes carrying
      at their surface these thiol-reactive functions. Our results indicate that an
      important kinetic discrimination (2-3 orders of magnitude in terms of rate
      constants) can be achieved between the maleimide and bromoacetyl functions when
      the reactions with thiols are performed at pH 6.5. The bromoacetyl function which
      reacts at higher pH values (e.g., pH 9.0) retained a high chemoselectivity; i.e.,
      under conditions where it reacted appreciably with the thiols of, e.g., HS
      peptides, it did react with other nucleophilic functions such as alpha- and
      epsilon-amino groups or imidazole, which could also be present in peptides. This
      differential reactivity was applied to design chemically defined and highly
      immunogenic liposomal diepitope constructs as synthetic vaccines, i.e., vesicles
      carrying at their surface two different peptides conjugated each to a specific
      amphiphilic anchor. This was realized by coupling sequentially at pH 6.5 and 9.0
      two HS-peptides to preformed vesicles containing lipophilic anchors
      functionalized with maleimide and bromoacetyl groups [Boeckler, C., et al. (1999)
      Eur. J. Immunol. 29, 2297-2308].

PMID- 10639095
TI  - Collagen cross-links. Synthesis of immunoreagents for development of assays for
      deoxypyridinoline, a marker for diagnosis of osteoporosis.
AB  - (+)-Deoxypyridinoline (Dpd, 2) is a cross-link of bone collagen, which is
      released and excreted in urine during process of bone resorption. It has been
      shown that this bone collagen degradation product, Dpd (2) is a useful marker for
      diagnosis of osteoporosis and other metabolic bone diseases. In this paper, the
      design and synthesis of two immunogens (3, 4) via of conjugation of succinimidyl
      ester (14) to carrier protein, bovine serum albumin, or keyhole limphet
      hemocyanin, was presented. Additionally, fluorescent (5) and chemiluminescent (6)
      tracers were prepared from (-)-acid (13) via in situ activation and subsequent
      reaction with 6-Fln-CH(2)NH(2) (17) or Acr-NH(2) (18) and hydrolysis. The key
      hapten (-)-acid (13) was prepared by quaternization of 3-hydroxypyridine
      derivative (S,S)-(-)-11 with iodide (S)-(-)-10 followed by selective hydrolysis.
      These immunreagents (immunogens 3 and 4 and tracers 5 and 6) are useful for the
      development of sensitive and high throughput immunoassays, such as FPIA and CLIA
      for Dpd (2).

PMID- 10639096
TI  - Signal transduction by G-proteins, rho-kinase and protein phosphatase to smooth
      muscle and non-muscle myosin II.
AB  - We here review mechanisms that can regulate the activity of myosin II, in smooth
      muscle and non-muscle cells, by modulating the Ca2+ sensitivity of myosin
      regulatory light chain (RLC) phosphorylation. The major mechanism of Ca2+
      sensitization of smooth muscle contraction and non-muscle cell motility is
      through inhibition of the smooth muscle myosin phosphatase (MLCP) that
      dephosphorylates the RLC in smooth muscle and non-muscle. The active, GTP-bound
      form of the small GTPase RhoA activates a serine/threonine kinase, Rho-kinase,
      that phosphorylates the regulatory subunit of MLCP and inhibits phosphatase
      activity. G-protein-coupled release of arachidonic acid may also contribute to
      inhibition of MLCP acting, at least in part, through the Rho/Rho-kinase pathway.
      Protein kinase C(s) activated by phorbol esters and diacylglycerol can also
      inhibit MLCP by phosphorylating and thereby activating CPI-17, an inhibitor of
      its catalytic subunit; this mechanism is independent of the Rho/Rho-kinase
      pathway and plays only a minor, transient role in the G-protein-coupled mechanism
      of Ca2+ sensitization. Ca2+ sensitization by the Rho/Rho-kinase pathway
      contributes to the tonic phase of agonist-induced contraction in smooth muscle,
      and abnormally increased activation of myosin II by this mechanism is thought to
      play a role in diseases such as high blood pressure and cancer cell metastasis.

PMID- 10639097
TI  - The 4'lysine in the putative channel lining domain affects desensitization but
      not the single-channel conductance of recombinant homomeric 5-HT3A receptors.
AB  - The 5-HT3 receptor is a transmitter-gated ion channel of the Cys-loop
      superfamily. Uniquely, 5-HT3 receptor subunits (5-HT3A and 5-HT3B) possess a
      positively charged lysine residue within the putative channel lining M2 domain
      (4' position). Using whole cell recording techniques, we examined the role of
      this residue in receptor function using wild-type (WT) and mutant 5-HT3A receptor
      subunits of murine origin transiently expressed in human embryonic kidney (HEK
      293) cells. WT 5-HT3A receptors mediated rapidly activating currents in response
      to 5-HT (10-90 % rise time, 103 ms; EC50, 2.34 microM; Hill coefficient, nH,
      2.87). The currents rectified inwardly, reversed in sign at a potential of -9 mV
      and desensitized in the continuous presence of agonist (half-time of
      desensitization, t(1/2), 2.13 s). 5-HT3A receptor subunits in which the 4'lysine
      was mutated to arginine, glutamine, serine or glycine formed functional
      receptors. 5-HT EC50 values were approximately 2-fold lower than for WT 5-HT3A
      receptors, but Hill coefficients, kinetics of current activation, rectification,
      and reversal potentials were unaltered. Each of the mutants desensitized more
      slowly than the WT 5-HT3A receptor, with the arginine and glycine mutations
      exhibiting the greatest effect (5-fold reduction). The rank order of effect was
      arginine > glycine > serine > glutamine. The single-channel conductance of the WT
      5-HT3A receptor, as assessed by fluctuation analysis of macroscopic currents, was
      390 fS. A similar value was obtained for the 4'lysine mutant receptors. Thus it
      appears unlikely that 4'lysine is exposed to the channel lumen. Mutation of
      residues immediately adjacent to 4'lysine to glutamate or lysine resulted in lack
      of receptor expression or function. We conclude that 4'lysine does not form part
      of the channel lining, but may play an important role in 5-HT3 receptor
      desensitization.

PMID- 10639098
TI  - Inactivation of P2X2 purinoceptors by divalent cations.
AB  - 1. P2X2 channels are activated by extracellular ATP. Despite being commonly
      described as non-desensitizing, P2X2 receptors do desensitize or inactivate. In
      the unspliced, 472 amino acid isoform of the P2X2 receptor, inactivation required
      membrane disruption and the presence of extracellular Ca2+. 2. The ability to
      inactivate whole-cell currents developed slowly after breaking in. In contrast,
      currents from excised patches exhibited rapid (approximately 100 ms) inactivation
      with a dependence on extracellular Ca2+, ATP and voltage. 3. The inactivation
      rate increased with the fourth power of [Ca2+] suggesting that the functional
      channel may be a tetramer. Ca2+ had both a higher affinity and a larger Hill
      coefficient for inactivation than Mg2+, Ba2+ or Mn2+. Trivalent cations at
      concentrations up to the solubility product of ATP had no effect. The change in
      apparent co-operativity with ionic species suggests the presence of
      experimentally unresolved ligand-insensitive kinetic steps. 4. Based on the weak
      voltage dependence of inactivation and the lack of effect of intracellular Ca2+
      buffers, the Ca2+-binding sites are probably located near the extracellular
      surface of the membrane. 5. The recovery from inactivation was slow, with a time
      constant of approximately 7 min. 6. Ca2+-sensitive inactivation only appeared
      when the membrane was disrupted in some manner. Treatment with actin and
      microtubule reagents did not induce inactivation, suggesting that an intact
      cytoskeleton is not necessary. 7. Inactivation rates observed in different patch
      configurations suggest that the induction of Ca2+-dependent inactivation was due
      to the loss of a diffusible cofactor located in the membrane or the cytoplasm.

PMID- 10639099
TI  - Kinetic and mutational analysis of Zn2+ modulation of recombinant human
      inhibitory glycine receptors.
AB  - 1. The effects of Zn2+ on glycine receptor (GlyR) currents were analysed in
      Xenopus oocytes and human embryonic kidney cells expressing homomeric human wild
      type and mutant alpha1 subunit GlyRs. 2. Low concentrations (10 microM) of
      extracellular Zn2+ converted the partial agonist taurine into a high-efficacy
      agonist. Concentration-response analysis showed that the EC50 for taurine
      decreased whereas the Hill coefficient increased under these conditions. In
      contrast, 50-500 microM Zn2+ showed an increased EC50 value and reduced maximal
      inducible taurine currents. The potency of competitive antagonists was not
      affected in the presence of Zn2+. 3. Single-channel recording from outside-out
      patches revealed different kinetics of glycine- and taurine-gated currents. With
      both agonists, Zn2+ altered the open probability of the alpha1 GlyR without
      changing its unitary conductance. Low Zn2+ concentrations (5 microM) increased
      both the opening frequency and mean burst duration, whereas higher Zn2+
      concentrations (> 50 microM) reduced GlyR open probability mainly by decreasing
      the open frequency and the relative contribution of the longest burst of the
      single-channel events. 4. Site-directed mutagenesis of the GlyR alpha1 subunit
      identified aspartate 80 and threonine 112 as important determinants of Zn2+
      potentiation and inhibition, respectively, without affecting potentiation by
      ethanol. 5. Our data support the view that Zn2+ modulates different steps of the
      receptor binding and gating cycle via specific allosteric high- and low-affinity
      binding sites in the extracellular N-terminal region of the GlyR alpha1 subunit.

PMID- 10639100
TI  - Novel action of BAPTA series chelators on intrinsic K+ currents in rat
      hippocampal neurones.
AB  - 1. Whole-cell recordings were made from rat CA1 neurones in brain slices. When
      electrodes contained diazo-2 (2 mM) or dibromo BAPTA (1 mM) a large steady-state
      outward current (hundreds of picoamps) developed within 5 min of breakthrough at
      a VH of -60 mV. BAPTA itself (1 mM) caused qualitatively similar but smaller
      effects. 2. The outward current was accompanied by increased conductance with a
      null potential close to the calculated K+ equilibrium potential (EK) of -110 mV.
      Development of outward current occurred concurrently with progressive loss of
      slow AHP tail current (IsAHP) evoked by brief depolarizations. The peak latency
      of IsAHP increased during the onset of chelator action. 3. The persistent outward
      current was reversibly inhibited by noradrenaline (10 microM) or isoprenaline (2
      5 microM), and completely prevented by 8-bromoadenosine 3',5' cyclic
      monophosphate (8-Br cAMP; 100 microM) or QX-314 (10 mM) in recording electrodes.
      After development of outward current, diazo-2 photolysis caused inward current
      and decreased conductance. Both flash- and noradrenergic-sensitive responses were
      inwardly rectifying outward currents with null potentials close to EK. 4. The
      outward current induced by dibromo BAPTA was not blocked by internal EGTA (10
      mM). However, experiments incorporating Ca2+ influx or Ca2+ loading of the buffer
      indicate that Ca2+ facilitated the outward current. 5. The outward currents
      induced by dibromo BAPTA or diazo-2 were not associated with significant changes
      in resting [Ca2+]i. Regions of the cell contributing to the outward current were
      deduced from measurements of fura-2 diffusion. These were compared with regions
      of [Ca2+]i elevation during IsAHP. 6. These results are consistent with the
      hypothesis that the BAPTA series Ca2+ buffers can activate those Ca2+-activated
      K+ channels that underlie the slow AHP, without the predicted elevation of bulk
      [Ca2+]i. Therefore these results cannot be interpreted solely in terms of Ca2+
      concentration changes, although the observations illustrate a novel,
      investigative role for these compounds in the study of Ca2+-dependent processes.

PMID- 10639101
TI  - Substantial depletion of the intracellular Ca2+ stores is required for
      macroscopic activation of the Ca2+ release-activated Ca2+ current in rat
      basophilic leukaemia cells.
AB  - 1. Tight-seal whole-cell patch clamp experiments were performed to examine the
      ability of different intracellular Ca2+ mobilising agents to activate the Ca2+
      release-activated Ca2+ current (ICRAC) in rat basophilic leukaemia (RBL-1) cells
      under conditions of weak cytoplasmic Ca2+ buffering. 2. Dialysis with a maximal
      concentration of inositol 1,4,5-trisphosphate (IP3) routinely failed to activate
      macroscopic ICRAC in low buffer (0.mM EGTA, BAPTA or dimethyl BAPTA), whereas it
      activated the current to its maximal extent in high buffer (10 mM EGTA). Dialysis
      with a poorly metabolisable analogue of IP3, with ionomycin, or with IP3 and
      ionomycin all failed to generate macroscopic ICRAC in low Ca2+ buffering
      conditions. 3. Dialysis with the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA)
      pump blocker thapsigargin was able to activate ICRAC even in the presence of low
      cytoplasmic Ca2+ buffering, albeit at a slow rate. Exposure to IP3 together with
      the SERCA blockers thapsigargin, thapsigargicin or cyclopiazonic acid rapidly
      activated ICRAC in low buffer. 4. Following activation of ICRAC by intracellular
      dialysis with IP3 and thapsigargin in low buffer, the current was very selective
      for Ca2+ (apparent KD of 1 mM) Sr2+ and Ba2+ were less effective charge carriers
      and Na+ was not conducted to any appreciable extent. The ionic selectivity of
      ICRAC was very similar in low or high intracellular Ca2+ buffer. 5. Fast Ca2+
      dependent inactivation of ICRAC occurred at a similar rate and to a similar
      extent in low or high Ca2+ buffer. Ca2+-dependent inactivation is not the reason
      why macroscopic ICRAC cannot be seen under conditions of low cytoplasmic Ca2+
      buffering. 6. ICRAC could be activated by combining IP3 with thapsigargin, even
      in the presence of 100 microM Ca2+ and the absence of any exogenous Ca2+
      chelator, where ATP and glutamate represented the only Ca2+ buffers in the
      pipette solution. 7. Our results suggest that a threshold exists within the IP3
      sensitive Ca2+ store, below which intraluminal Ca2+ needs to fall before ICRAC
      activates. Possible models to explain the results are discussed.

PMID- 10639102
TI  - Modulation of CICR has no maintained effect on systolic Ca2+: simultaneous
      measurements of sarcoplasmic reticulum and sarcolemmal Ca2+ fluxes in rat
      ventricular myocytes.
AB  - 1. The effects of modulating Ca2+-induced Ca2+ release (CICR) in single cardiac
      myocytes were investigated using low concentrations of caffeine (< 500 microM) in
      reduced external Ca2+ (0.5 mM). Caffeine produced a transient potentiation of
      systolic [Ca2+]i (to 800 % of control) which decayed back to control levels. 2.
      Caffeine decreased the steady-state sarcoplasmic reticulum (SR) Ca2+ content. As
      the concentration of caffeine was increased, both the potentiation of the
      systolic Ca2+ transient and the decrease in SR Ca2+ content were increased. At
      higher concentrations, the potentiating effect decayed more rapidly but the rate
      of recovery on removal of caffeine was unaffected. 3. A simple model in which
      caffeine produces a fixed increase in the fraction of SR Ca2+ which is released
      could account qualitatively but not quantitatively for the above results. 4. The
      changes in total [Ca2+] during systole were obtained using measurements of the
      intracellular Ca2+ buffering power. Caffeine initially increased the fractional
      release of SR Ca2+. This was followed by a decrease to a level greater than that
      under control conditions. The fraction of systolic Ca2+ which was pumped out of
      the cell increased abruptly upon caffeine application but then recovered back to
      control levels. The increase in fractional loss is due to the fact that, as the
      cytoplasmic buffers become saturated, a given increase in systolic total [Ca2+]
      produces a larger increase in free [Ca2+] and thence of Ca2+ efflux. 5. These
      results confirm that modulation of the ryanodine receptor has no maintained
      effect on systolic Ca2+ and show the interdependence of SR Ca2+ content,
      cytoplasmic Ca2+ buffering and sarcolemmal Ca2+ fluxes. Such analysis is
      important for understanding the cellular basis of inotropic interventions in
      cardiac muscle.

PMID- 10639103
TI  - Activation of a Ca2+-permeable cation channel produces a prolonged attenuation of
      intracellular Ca2+ release in Aplysia bag cell neurones.
AB  - 1. Brief synaptic stimulation, or exposure to Conus textile venom (CtVm),
      triggers an afterdischarge in the bag cell neurones of Aplysia. This is
      associated with an elevation of intracellular calcium ([Ca2+]i) through Ca2+
      release from intracellular stores and Ca2+ entry through voltage-gated Ca2+
      channels and a non-selective cation channel. The afterdischarge is followed by a
      prolonged (approximately 18 h) refractory period during which the ability of both
      electrical stimulation and CtVm to trigger afterdischarges or elevate [Ca2+]i is
      severely attenuated. By measuring the response of isolated cells to CtVm, we have
      now tested the contribution of different sources of Ca2+ elevation to the onset
      of the prolonged refractory period. CtVm induced an increase in [Ca2+]i in both
      normal and Ca2+-free saline, in part by liberating Ca2+ from a store sensitive to
      thapsigargin or cyclopiazonic acid, but not sensitive to heparin. 3. In the
      presence of extracellular Ca2+, the neurones became refractory to CtVm after a
      single application but recovered following approximately 24 h, when CtVm could
      again elevate [Ca2+]i. However, this refractoriness did not develop if CtVm was
      applied in Ca2+-free saline. Thus, elevation of [Ca2+]i alone does not induce
      refractoriness to CtVm-induced [Ca2+]i elevation, but Ca2+ influx triggers this
      refractory-like state. 4. CtVm produces a depolarization of isolated bag cell
      neurones. To determine if Ca2+ influx through voltage-gated Ca2+ channels,
      activated during this depolarization, caused refractoriness to CtVm-induced
      [Ca2+]i elevation, cells were depolarized with high external potassium (60 mM),
      which produced a large increase in [Ca2+]i. Nevertheless, subsequent exposure of
      the cells to CtVm produced a normal response, suggesting that Ca2+ influx through
      voltage-gated Ca2+ channels does not induce refractoriness. 5. As a second test
      for the role of voltage-gated Ca2+ channels, these channels were blocked with
      nifedipine. This drug failed to prevent the onset of refractoriness to CtVm
      induced [Ca2+]i elevation, providing further evidence that Ca2+ entry through
      voltage-gated Ca2+ channels does not initiate refractoriness. 6. To examine if
      Ca2+ entry through the CtVm-activated, non-selective cation channel caused
      refractoriness, neurones were treated with a high concentration of TTX, which
      blocks the cation channel. TTX protected the neurones from the refractoriness to
      [Ca2+]i elevation produced by CtVm in Ca2+-containing medium. 7. Using clusters
      of bag cell neurones in intact abdominal ganglia, we compared the ability of
      nifedipine and TTX to protect the cells from refractoriness to electrical
      stimulation. Normal, long-lasting afterdischarges could be triggered by
      stimulation of an afferent input after a period of exposure to CtVm in the
      presence of TTX. In contrast, exposure to CtVm in the presence of nifedipine
      resulted in refractoriness. 8. Our data indicate that Ca2+ influx through the non
      selective cation channel renders cultured bag cell neurones refractory to
      repeated stimulation with CtVm. Moreover, the refractory period of the
      afterdischarge itself may also be initiated by Ca2+ entry through this cation
      channel.

PMID- 10639104
TI  - Mechanisms that regulate [Ca2+]i following depolarization in rat systemic
      arterial smooth muscle cells.
AB  - 1. We have used the patch-clamp technique in combination with fluorimetric
      recording to study the mechanisms that regulate intracellular Ca2+, [Ca2+]i,
      following depolarization in cells isolated from the rat femoral artery. 2.
      Depolarization to 0 mV from a holding potential of -70 mV increased [Ca2+]i.
      Little Ca2+ release from sarcoplasmic reticulum, SR, was detected during
      depolarization since application of 30 microM ryanodine, a Ca2+-release
      inhibitor, had no significant effect on total Ca2+ buffering power. 3. Upon
      repolarization to -70 mV, 7 out of 13 cells showed three phases of Ca2+ removal;
      an initial rapid first phase, a slow second phase, and a faster third phase. Six
      cells, in which Ca2+ recovered quickly, lacked the third phase. The third phase
      was also absent in cells treated with a SR Ca2+-pump inhibitor, cyclopiazonic
      acid. 4. The peak first-phase Ca2+ removal rate observed upon repolarization to 
      70 mV was significantly reduced in cells treated with a mitochondrial Ca2+ uptake
      inhibitor, carbonyl cyanide m-chlorophenylhydrazone. However, an ATP-synthase
      inhibitor, oligomycin B, had no significant effect. 5. The Ca2+ removal rate was
      little affected by clamping the cell at +120 mV rather than -70 mV, suggesting
      that Ca2+ removal processes are largely voltage independent. Also, little inward
      current was associated with Ca2+ clearance, indicating that Ca2+ removal does not
      involve an electrogenic process. 6. Our results suggest that Ca2+-induced Ca2+
      release contributes little to the elevation of Ca2+ in these cells. The SR Ca2+
      pump may contribute to Ca2+ removal over a low [Ca2+]i range in cells where
      [Ca2+]i remains high for long enough, while mitochondrial Ca2+ uptake may be
      important when [Ca2+]i is high.

PMID- 10639105
TI  - Functional organization of climbing fibre projection to the cerebellar anterior
      lobe of the rat.
AB  - 1. The input characteristics and distribution of climbing fibre field potentials
      evoked by electrical stimulation of various parts of the skin were investigated
      in the cerebellum of barbiturate anaesthetized rats. 2. Climbing fibre responses
      were recorded in sagittally oriented microelectrode tracks across the
      mediolateral width of the anterior lobe. Climbing fibres with similar response
      latencies and convergence patterns terminated in sagittal bands with widths of
      0.5-1.5 mm. The principal organization of the anterior lobe with respect to input
      characteristics and locations of sagittal zones was similar to that in the cat
      and ferret. Hence, the sagittal bands in the rat were tentatively named the a, b,
      c1, c2 and d1 zones. 3. In contrast to the cat and ferret, the a zone of the rat
      was characterized by short latency ipsilateral climbing fibre input. Furthermore,
      it was divisible into a medial 'a1' zone with convergent, proximal input and a
      lateral 'ax' zone with somatotopically organized input. A forelimb area with
      similar location and input characteristics as the X zone of the cat was found,
      but it formed an integral part of the ax zone. A somatotopic organization of
      ipsilateral, short latency climbing fibre input was also found in the c1 zone. 4.
      Rostrally in the anterior lobe, climbing fibres activated at short latencies from
      the ipsilateral side of the body terminated in a somatotopically organized
      transverse band which extended from the midline to the lateral end of the
      anterior lobe. 5. The absence of the C3 and Y zones may be interpreted as a
      reflection of differences in the organization of the motor systems in the rat as
      compared with the cat. Skilled movements, which in the cat are controlled by the
      C1, C3 and Y zones via the anterior interposed nucleus, may in the rat be partly
      controlled by the ax zone via the rostrolateral part of the fastigial nucleus.

PMID- 10639106
TI  - Inhibition of nitric oxide synthase augments the positive inotropic effect of
      nitric oxide donors in the rat heart.
AB  - 1. In this investigation we studied the effects of nitric oxide on contractility
      and heart rate in normal saline-perfused rat hearts where shear stress-induced
      endothelial NO synthesis substantially contributes to total cardiac NO
      production. In addition, we sought to estimate the concentrations of exogenous NO
      producing inotropic effects. 2. We investigated the effects of glyceryl
      trinitrate (GTN), S-nitroso-d,l-penicillamine (SNAP), sodium (Z)-1-(N, N
      diethylamino)diazen-1-ium-1,2-diolat (DEA/NO), and DEA/NO in the presence of the
      NO synthase inhibitor Nomega-nitro-L-arginine (L-NA) in constant-flow-perfused
      spontaneously beating rat Langendorff hearts and in rat working hearts. 3. In
      Langendorff hearts, GTN (10 nM to 100 microM, n = 32) induced a positive
      inotropic response that plateaued at 1 microM GTN with a maximal rate of increase
      of left ventricular pressure during ventricular contraction (+dP/dtmax) of 6. 33
      +/- 2.56 % (n = 11, P < 0.5). Similarly, both spontaneous NO donors (0.1 nM to 1
      microM, corresponding to approximately 0.03-0.3 microM NO) induced a positive
      inotropic response of 10.6 +/- 3.1 % (SNAP; n = 15, P < 0.05) and 11.5 +/- 2.7 %
      (DEA/NO, n = 15, P < 0. 05). 4. The positive inotropic effect of SNAP and DEA/NO
      progressively declined from 1 microM to 100 microM of the NO donors
      (corresponding to approximately 0.3-30 microM NO). 5. In the isolated working rat
      heart, 0.1 microM DEA/NO induced an increase of +dP/dtmax of 7.5 +/- 2.5 % (n =
      9, P < 0.05). Inhibition of NO synthase by L-NA produced a 4-fold increase in
      this effect of DEA/NO. 6. We suggest that physiological NO concentrations support
      myocardial performance. In normal rat hearts the positive inotropic effect of NO
      appears to be almost maximally exploited by the endogenous NO production.

PMID- 10639107
TI  - Purinergic and cholinergic neuro-neuronal transmission underlying reflexes
      activated by mucosal stimulation in the isolated guinea-pig ileum.
AB  - 1. We present evidence that adenosine triphosphate (ATP) plays a major role in
      excitatory neuro-neuronal transmission in ascending and descending reflex
      pathways to the longitudinal (LM) and circular muscle (CM). 2. A partitioned bath
      was used for the pharmacological isolation of a segment of guinea-pig ileum (
      approximately 6 cm in length), allowing drugs to be selectively applied to an
      intermediate region between the region where mucosal stimulation was applied and
      that where mechanical recordings were made. 3. Brush stroking the mucosa (3
      strokes) elicited a synchronous contraction of the LM and CM both above
      (ascending excitation) and below (descending excitation) the site of stimulation.
      All reflexes were abolished when tetrodotoxin (1 microM) was applied to the
      intermediate chamber. 4. Hexamethonium (300 microM) added to the intermediate
      chamber abolished the ascending contraction in 15 % of oral preparations (from 26
      preparations, 18 animals) and the descending contraction in 13% of anal
      preparations studied (from 53 preparations, 48 animals). In the remaining 85% of
      oral preparations, hexamethonium usually attenuated the oral contraction of the
      LM and CM. However, in the remaining 87% of anal preparations, hexamethonium had
      no effect on the anal contraction of the LM and CM. 5. Oral and anal reflexes
      that were hexamethonium resistant were either abolished or attenuated by the
      further addition of the P2 purinergic receptor antagonist pyridoxal phosphate-6
      azophenyl-2',4'-disulphonic acid (PPADS, 10 microM) or alpha,beta-methylene ATP
      (50-100 microM) to the intermediate chamber. 6. 1,1-Dimethyl-4-phenyl
      piperazinium iodide (DMPP, 20 microM) or alpha,beta-methylene ATP (50-100 microM)
      stimulated both ascending and descending excitatory pathways, when applied to the
      intermediate chamber. 7. In conclusion, ascending and descending neuro-neuronal
      transmission in excitatory nervous pathways to the LM and CM is complex and
      clearly involves neurotransmitter(s) other than acetylcholine (ACh). We suggest
      mucosal stimulation releases ACh and ATP in both ascending and descending
      excitatory reflex pathways that synapse with excitatory motoneurons to the LM and
      CM.

PMID- 10639109
TI  - PNAS Early Edition.

PMID- 10639108
TI  - Function of skeletal muscle tissue formed after myoblast transplantation into
      irradiated mouse muscles.
AB  - 1. Pretreatment of muscles with ionising radiation enhances tissue formation by
      transplanted myoblasts but little is known about the effects on muscle function.
      We implanted myoblasts from an expanded, male-donor-derived, culture (i28) into X
      ray irradiated (16 Gy) or irradiated and damaged soleus muscles of female
      syngeneic mice (Balb/c). Three to 6 months later the isometric contractile
      properties of the muscles were studied in vitro, and donor nuclei were visualised
      in muscle sections with a Y chromosome-specific DNA probe. 2. Irradiated sham
      injected muscles had smaller masses than untreated solei and produced less twitch
      and tetanic force (all by about 18 %). Injection of 106 myoblasts abolished these
      deficiencies and innervation appeared normal. 3. Cryodamage of irradiated solei
      produced muscle remnants with few (1-50) or no fibres. Additional myoblast
      implantation led to formation of large muscles (25 % above normal) containing
      numerous small-diameter fibres. Upon direct electrical stimulation, these muscles
      produced considerable twitch (53 % of normal) and tetanic forces (35 % of normal)
      but innervation was insufficient as indicated by weak nerve-evoked contractions
      and elevated ACh sensitivity. 4. In control experiments on irradiated muscles,
      reinnervation was found to be less complete after botulinum toxin paralysis than
      after nerve crush indicating that proliferative arrest of irradiated Schwann
      cells may account for the observed innervation deficits. 5. Irradiation appears
      to be an effective pretreatment for improving myoblast transplantation. The
      injected cells can even produce organised contractile tissue replacing whole
      muscle. However, impaired nerve regeneration limits the functional performance of
      the new muscle.

PMID- 10639110
TI  - Lysozyme among the Lilliputians.

PMID- 10639111
TI  - Bax-induced apoptotic cell death.

PMID- 10639112
TI  - Antitumorigenic actions of growth hormone-releasing hormone antagonists.

PMID- 10639113
TI  - Another hormone-sensitive triglyceride lipase in fat cells?

PMID- 10639114
TI  - Chemistry and biology.

PMID- 10639115
TI  - Quantum groups with invariant integrals.
AB  - Quantum groups have been studied intensively for the last two decades from
      various points of view. The underlying mathematical structure is that of an
      algebra with a coproduct. Compact quantum groups admit Haar measures. However, if
      we want to have a Haar measure also in the noncompact case, we are forced to work
      with algebras without identity, and the notion of a coproduct has to be adapted.
      These considerations lead to the theory of multiplier Hopf algebras, which
      provides the mathematical tool for studying noncompact quantum groups with Haar
      measures. I will concentrate on the *-algebra case and assume positivity of the
      invariant integral. Doing so, I create an algebraic framework that serves as a
      model for the operator algebra approach to quantum groups. Indeed, the theory of
      locally compact quantum groups can be seen as the topological version of the
      theory of quantum groups as they are developed here in a purely algebraic
      context.

PMID- 10639116
TI  - The operator algebra approach to quantum groups.
AB  - A relatively simple definition of a locally compact quantum group in the C*
      algebra setting will be explained as it was recently obtained by the authors. At
      the same time, we put this definition in the historical and mathematical context
      of locally compact groups, compact quantum groups, Kac algebras, multiplicative
      unitaries, and duality theory.

PMID- 10639117
TI  - Architecture with designer atoms: simple theoretical considerations.
AB  - The distinct electronic states of assemblies of metallic quantum dots are
      discussed in a simple approximation where each dot is mimicked as an "atom" that
      carries one valence electron. Because of their large size, the charging energy of
      the dots, I = energy required to add another electron, is much smaller than for
      ordinary atoms. The Coulomb blocking of charge migration is therefore easier to
      overcome. For the theory, however, this is a challenge, because ionic states,
      which are typically higher in energy, come down, so the density of electronic
      states is high, and special methods need to be adapted. Quantum dots are prepared
      by wet chemical methods and accordingly are not quite identical. They will have a
      size distribution that can be narrow (when the dots can be assembled into an
      ordered array) or broad. Other sources of disorder are packing imperfections,
      which are characteristic of a wider size distribution, ligand deformations, and
      chemical unevenness. Two experimental control parameters are the size of the dots
      and the spacing between them. We discuss the combined effects of the low charging
      energy and disorder and examine the distinct electronic phases that can be
      realized.

PMID- 10639118
TI  - A highly efficient and robust cell-free protein synthesis system prepared from
      wheat embryos: plants apparently contain a suicide system directed at ribosomes.
AB  - Current cell-free protein synthesis systems can synthesize proteins with high
      speed and accuracy, but produce only a low yield because of their instability
      over time. Here we describe the preparation of a highly efficient but also robust
      cell-free system from wheat embryos. We first investigated the source of the
      instability of existing systems in light of endogenous ribosome-inactivating
      proteins and found that ribosome inactivation by tritin occurs already during
      extract preparation and continues during incubation for protein synthesis.
      Therefore, we prepared our system from extensively washed embryos that are devoid
      of contamination by endosperm, the source of tritin and possibly other
      inhibitors. In a batch system, we observed continuous translation for 4 h, and
      sucrose density gradient analysis showed formation of large polysomes, indicating
      high protein synthesis activity. When the reaction was performed in a dialysis
      bag, enabling the continuous supply of substrates together with the continuous
      removal of small byproducts, translation proceeded for >60 h, yielding 1-4 mg of
      enzymatically active proteins, and 0.6 mg of a 126-kDa tobacco mosaic virus
      protein, per milliliter of reaction volume. Our results demonstrate that plants
      contain endogenous inhibitors of translation and that after their elimination the
      translational apparatus is very stable. This contrasts with the common belief
      that cell-free translation systems are inherently unstable, even fragile. Our
      method is useful for the preparation of large amounts of active protein as well
      as for the study of protein synthesis itself.

PMID- 10639119
TI  - Highly mutagenic replication by DNA polymerase V (UmuC) provides a mechanistic
      basis for SOS untargeted mutagenesis.
AB  - When challenged by DNA-damaging agents, Escherichia coli cells respond by
      inducing the SOS stress response, which leads to an increase in mutation
      frequency by two mechanisms: translesion replication, a process that causes
      mutations because of misinsertion opposite the lesions, and an inducible mutator
      activity, which acts at undamaged sites. Here we report that DNA polymerase V
      (pol V; UmuC), which previously has been shown to be a lesion-bypass DNA
      polymerase, was highly mutagenic during in vitro gap-filling replication of a
      gapped plasmid carrying the cro reporter gene. This reaction required, in
      addition to pol V, UmuD', RecA, and single-stranded DNA (ssDNA)-binding protein.
      pol V produced point mutations at a frequency of 2.1 x 10(-4) per nucleotide
      (2.1% per cro gene), 41-fold higher than DNA polymerase III holoenzyme. The
      mutational spectrum of pol V was dominated by transversions (53%), which were
      formed at a frequency of 1.3 x 10(-4) per nucleotide (1. 1% per cro gene), 74
      fold higher than with pol III holoenzyme. The prevalence of transversions and the
      protein requirements of this system are similar to those of in vivo untargeted
      mutagenesis (SOS mutator activity). This finding suggests that replication by pol
      V, in the presence of UmuD', RecA, and ssDNA-binding protein, is the basis of
      chromosomal SOS untargeted mutagenesis.

PMID- 10639120
TI  - Acceleration of oligomerization, not fibrillization, is a shared property of both
      alpha-synuclein mutations linked to early-onset Parkinson's disease: implications
      for pathogenesis and therapy.
AB  - The Parkinson's disease (PD) substantia nigra is characterized by the presence of
      Lewy bodies containing fibrillar alpha-synuclein. Early-onset PD has been linked
      to two point mutations in the gene that encodes alpha-synuclein, suggesting that
      disease may arise from accelerated fibrillization. However, the identity of the
      pathogenic species and its relationship to the alpha-synuclein fibril has not
      been elucidated. In this in vitro study, the rates of disappearance of monomeric
      alpha-synuclein and appearance of fibrillar alpha-synuclein were compared for the
      wild-type (WT) and two mutant proteins, as well as equimolar mixtures that may
      model the heterozygous PD patients. Whereas one of the mutant proteins (A53T) and
      an equimolar mixture of A53T and WT fibrillized more rapidly than WT alpha
      synuclein, the other (A30P) and the corresponding equimolar mixture with WT
      fibrillized more slowly. However, under conditions that ultimately produced
      fibrils, the A30P monomer was consumed at a comparable rate or slightly more
      rapidly than the WT monomer, whereas A53T was consumed even more rapidly. The
      difference between these trends suggested the existence of nonfibrillar alpha
      synuclein oligomers, some of which were separated from fibrillar and monomeric
      alpha-synuclein by sedimentation followed by gel-filtration chromatography.
      Spheres (range of heights: 2-6 nm), chains of spheres (protofibrils), and rings
      resembling circularized protofibrils (height: ca. 4 nm) were distinguished from
      fibrils (height: ca. 8 nm) by atomic force microscopy. Importantly, drug
      candidates that inhibit alpha-synuclein fibrillization but do not block its
      oligomerization could mimic the A30P mutation and thus may accelerate disease
      progression.

PMID- 10639121
TI  - Proapoptotic BH3-only Bcl-2 family members induce cytochrome c release, but not
      mitochondrial membrane potential loss, and do not directly modulate voltage
      dependent anion channel activity.
AB  - Through direct interaction with the voltage-dependent anion channel (VDAC),
      proapoptotic Bcl-2 family members such as Bax and Bak induce apoptogenic
      mitochondrial cytochrome c release and membrane potential (Deltapsi) loss in
      isolated mitochondria. Using isolated mitochondria, we showed that Bid and Bik,
      BH3-only proteins from the Bcl-2 family, induced cytochrome c release but not
      Deltapsi loss. Unlike Bax/Bak, the cytochrome c release induced by Bid/Bik was
      Ca(2+)-independent, cyclosporin A-insensitive, and respiration-independent.
      Furthermore, in contrast to Bax/Bak, Bid/Bik neither interacted with VDAC nor
      directly affected the VDAC activity in liposomes. Consistently, Bid/Bik induced
      apoptosis without Deltapsi loss, whereas Bax induced apoptosis with Deltapsi
      loss. These findings indicated the involvement of a different mechanism in BH3
      only, protein-induced apoptogenic cytochrome c release.

PMID- 10639122
TI  - Molecular cloning of a 10-deacetylbaccatin III-10-O-acetyl transferase cDNA from
      Taxus and functional expression in Escherichia coli.
AB  - The cDNA clone for a 10-deacetylbaccatin III-10-O-acetyl transferase, which
      catalyzes formation of the last diterpene intermediate in the Taxol biosynthetic
      pathway, has been isolated from Taxus cuspidata. By using consensus sequences
      from an assembly of transacylases of plant origin and from many deduced proteins
      of unknown function, a homology-based PCR cloning strategy was employed to
      amplify initially a 911-bp gene fragment of the putative taxane C-10 hydroxyl
      acetyl transferase from Taxus. This amplicon was used to screen a cDNA library
      constructed from mRNA isolated from methyl jasmonate-induced Taxus cells, from
      which the full-length 10-deacetylbaccatin III-10-O-transacetylase sequence was
      obtained. Expression of the ORF from pCWori(+) in Escherichia coli JM109 afforded
      a functional enzyme, as determined by (1)H-NMR and MS verification of the product
      baccatin III derived from 10-deacetylbaccatin III and acetyl CoA. The full-length
      cDNA has an ORF of 1,320 bp corresponding to a deduced protein of 440 residues
      with a calculated molecular weight of 49,052, consistent with the size of the
      operationally soluble, monomeric, native acetyl transferase. The recombinant
      acetyl transferase has a pH optimum of 7.5, has K(m) values of 10 microM and 8
      microM for 10-deacetylbaccatin III and acetyl CoA, respectively, and is
      apparently regiospecific toward the 10-hydroxyl group of the taxane ring. Amino
      acid sequence comparison of 10-deacetylbaccatin III-10-O-acetyl transferase with
      taxadienol-5-O-acetyl transferase and with other known acyl transferases of plant
      origin indicates a significant degree of similarity between these enzymes (80%
      and 64-67%, respectively).

PMID- 10639123
TI  - The crystal structure of calcium-free human m-calpain suggests an electrostatic
      switch mechanism for activation by calcium.
AB  - Calpains (calcium-dependent cytoplasmic cysteine proteinases) are implicated in
      processes such as cytoskeleton remodeling and signal transduction. The 2.3-A
      crystal structure of full-length heterodimeric [80-kDa (dI-dIV) + 30-kDa
      (dV+dVI)] human m-calpain crystallized in the absence of calcium reveals an oval
      disc-like shape, with the papain-like catalytic domain dII and the two calmodulin
      like domains dIV+dVI occupying opposite poles, and the tumor necrosis factor
      alpha-like beta-sandwich domain dIII and the N-terminal segments dI+dV located
      between. Compared with papain, the two subdomains dIIa+dIIb of the catalytic unit
      are rotated against one another by 50 degrees, disrupting the active site and the
      substrate binding site, explaining the inactivity of calpains in the absence of
      calcium. Calcium binding to an extremely negatively charged loop of domain dIII
      (an electrostatic switch) could release the adjacent barrel-like subdomain dIIb
      to move toward the helical subdomain dIIa, allowing formation of a functional
      catalytic center. This switch loop could also mediate membrane binding, thereby
      explaining calpains' strongly reduced calcium requirements in vivo. The activity
      status at the catalytic center might be further modulated by calcium binding to
      the calmodulin domains via the N-terminal linkers.

PMID- 10639124
TI  - Evidence for a linear search in bimolecular 3' splice site AG selection.
AB  - In most eukaryotic introns the 3' splice site is defined by a surprisingly short
      AG consensus found a variable distance downstream of the branch site. Exactly how
      the spliceosome determines which AG to use, however, is not well understood.
      Previously we showed that when the branch site and 3' splice site AG are supplied
      by separate RNA molecules, there is a strong preference for use of the 5'-most AG
      in the 3' splice site-containing RNA. Here we show that this apparent 5'-->3'
      directionality holds even when this RNA contains four tandem repeats of a 6-nt
      sequence containing AG. Exactly the same pattern of 3' splice site choice was
      observed when the same tandem repeats were incorporated into a full-length
      splicing substrate. When the 3' splice site AG is supplied by a separate RNA,
      that RNA must be linear with an unobstructed 5' end. Similarly, the branch
      containing RNA must be truncated immediately 3' to the polypyrimidine tract. A
      model is presented that incorporates these observations and reconciles previously
      proposed mechanisms for 3' splice site selection.

PMID- 10639125
TI  - NifS-directed assembly of a transient [2Fe-2S] cluster within the NifU protein.
AB  - The NifS and NifU proteins from Azotobacter vinelandii are required for the full
      activation of nitrogenase. NifS is a homodimeric cysteine desulfurase that
      supplies the inorganic sulfide necessary for formation of the Fe-S clusters
      contained within the nitrogenase component proteins. NifU has been suggested to
      complement NifS either by mobilizing the Fe necessary for nitrogenase Fe-S
      cluster formation or by providing an intermediate Fe-S cluster assembly site. As
      isolated, the homodimeric NifU protein contains one [2Fe-2S](2+, +) cluster per
      subunit, which is referred to as the permanent cluster. In this report, we show
      that NifU is able to interact with NifS and that a second, transient [2Fe-2S]
      cluster can be assembled within NifU in vitro when incubated in the presence of
      ferric ion, L-cysteine, and catalytic amounts of NifS. Approximately one
      transient [2Fe-2S] cluster is assembled per homodimer. The transient [2Fe-2S]
      cluster species is labile and rapidly released on reduction. We propose that
      transient [2Fe-2S] cluster units are formed on NifU and then released to supply
      the inorganic iron and sulfur necessary for maturation of the nitrogenase
      component proteins. The role of the permanent [2Fe-2S] clusters contained within
      NifU is not yet known, but they could have a redox function involving either the
      formation or release of transient [2Fe-2S] cluster units assembled on NifU.
      Because homologs to both NifU and NifS, respectively designated IscU and IscS,
      are found in non-nitrogen fixing organisms, it is possible that the function of
      NifU proposed here could represent a general mechanism for the maturation of Fe-S
      cluster-containing proteins.

PMID- 10639126
TI  - In vivo selection of functional ribosomes with variations in the rRNA-binding
      site of Escherichia coli ribosomal protein S8: evolutionary implications.
AB  - The highly conserved nature of rRNA sequences throughout evolution allows these
      molecules to be used to build philogenic trees of different species. It is
      unknown whether the stability of specific interactions and structural features of
      rRNA reflects an optimal adaptation to a functional task or an evolutionary trap.
      In the work reported here, we have applied an in vivo selection strategy to
      demonstrate that unnatural sequences do work as a functional replacement of the
      highly conserved binding site of ribosomal protein S8. However, growth
      competition experiments performed between Escherichia coli isolates containing
      natural and unnatural S8-binding sites showed that the fate of each isolate
      depended on the growth condition. In exponentially growing cells, one unnatural
      variant was found to be equivalent to wild type in competition experiments
      performed in rich media. In culture conditions leading to slow growth, however,
      cells containing the wild-type sequence were the ultimate winner of the
      competition, emphasizing that the wild-type sequence is, in fact, the most fit
      solution for the S8-binding site.

PMID- 10639127
TI  - Modifications of proteins by polyunsaturated fatty acid peroxidation products.
AB  - The ability of unsaturated fatty acid methyl esters to modify amino acid residues
      in bovine serum albumin (BSA), glutamine synthetase, and insulin in the presence
      of a metal-catalyzed oxidation system [ascorbate/Fe(III)/O(2)] depends on the
      degree of unsaturation of the fatty acid. The fatty acid-dependent generation of
      carbonyl groups and loss of lysine residues increased in the order methyl
      linoleate < methyl linolenate < methyl arachidonate. The amounts of alkyl
      hydroperoxides, malondialdehyde, and a number of other aldehydes that accumulated
      when polyunsaturated fatty acids were oxidized in the presence of BSA were
      significantly lower than that observed in the absence of BSA. Direct treatment of
      proteins with various lipid hydroperoxides led to a slight increase in the
      formation of protein carbonyl derivatives, whereas treatment with the
      hydroperoxides together with Fe(II) led to a substantial increase in the
      formation of protein carbonyls. These results are consistent with the proposition
      that metal-catalyzed oxidation of polyunsaturated fatty acids can contribute to
      the generation of protein carbonyls by direct interaction of lipid oxidation
      products (alpha,beta-unsaturated aldehydes) with lysine residues (Michael
      addition reactions) and also by interactions with alkoxyl radicals obtained by
      Fe(II) cleavage of lipid hydroperoxides that are formed. In addition, saturated
      aldehydes derived from the polyunsaturated fatty acids likely react with lysine
      residues to form Schiff base adducts.

PMID- 10639128
TI  - Direct localization of a beta-subunit domain on the three-dimensional structure
      of Escherichia coli RNA polymerase.
AB  - To identify the location of a domain of the beta-subunit of Escherichia coli RNA
      polymerase (RNAP) on the three-dimensional structure, we developed a method to
      tag a nonessential surface of the multisubunit enzyme with a protein density
      easily detectable by electron microscopy and image processing. Four repeats of
      the IgG-binding domain of Staphylococcus aureus protein A were inserted at
      position 998 of the E. coli RNAP beta-subunit. The mutant RNAP supported E. coli
      growth and showed no apparent functional defects in vitro. The structure of the
      mutant RNAP was determined by cryoelectron microscopy and image processing of
      frozen-hydrated helical crystals. Comparison of the mutant RNAP structure with
      the previously determined wild-type RNAP structure by Fourier difference analysis
      at 20-A resolution directly revealed the location of the inserted protein domain,
      thereby locating the region around position 998 of the beta-subunit within the
      RNAP three-dimensional structure and refining a model for the subunit locations
      within the enzyme.

PMID- 10639129
TI  - Specific chemical and structural damage to proteins produced by synchrotron
      radiation.
AB  - Radiation damage is an inherent problem in x-ray crystallography. It usually is
      presumed to be nonspecific and manifested as a gradual decay in the overall
      quality of data obtained for a given crystal as data collection proceeds. Based
      on third-generation synchrotron x-ray data, collected at cryogenic temperatures,
      we show for the enzymes Torpedo californica acetylcholinesterase and hen egg
      white lysozyme that synchrotron radiation also can cause highly specific damage.
      Disulfide bridges break, and carboxyl groups of acidic residues lose their
      definition. Highly exposed carboxyls, and those in the active site of both
      enzymes, appear particularly susceptible. The catalytic triad residue, His-440,
      in acetylcholinesterase, also appears to be much more sensitive to radiation
      damage than other histidine residues. Our findings have direct practical
      implications for routine x-ray data collection at high-energy synchrotron
      sources. Furthermore, they provide a direct approach for studying the radiation
      chemistry of proteins and nucleic acids at a detailed, structural level and also
      may yield information concerning putative "weak links" in a given biological
      macromolecule, which may be of structural and functional significance.

PMID- 10639130
TI  - Sequence-specific binding of counterions to B-DNA.
AB  - Recent studies by x-ray crystallography, NMR, and molecular simulations have
      suggested that monovalent counterions can penetrate deeply into the minor groove
      of B form DNA. Such groove-bound ions potentially could play an important role in
      AT-tract bending and groove narrowing, thereby modulating DNA function in vivo.
      To address this issue, we report here (23)Na magnetic relaxation dispersion
      measurements on oligonucleotides, including difference experiments with the
      groove-binding drug netropsin. The exquisite sensitivity of this method to ions
      in long-lived and intimate association with DNA allows us to detect sequence
      specific sodium ion binding in the minor groove AT tract of three B-DNA
      dodecamers. The sodium ion occupancy is only a few percent, however, and
      therefore is not likely to contribute importantly to the ensemble of B-DNA
      structures. We also report results of ion competition experiments, indicating
      that potassium, rubidium, and cesium ions bind to the minor groove with similarly
      weak affinity as sodium ions, whereas ammonium ion binding is somewhat stronger.
      The present findings are discussed in the light of previous NMR and diffraction
      studies of sequence-specific counterion binding to DNA.

PMID- 10639131
TI  - Landscape approaches for determining the ensemble of folding transition states:
      success and failure hinge on the degree of frustration.
AB  - We present a method for determining structural properties of the ensemble of
      folding transition states from protein simulations. This method relies on
      thermodynamic quantities (free energies as a function of global reaction
      coordinates, such as the percentage of native contacts) and not on "kinetic"
      measurements (rates, transmission coefficients, complete trajectories);
      consequently, it requires fewer computational resources compared with other
      approaches, making it more suited to large and complex models. We explain the
      theoretical framework that underlies this method and use it to clarify the
      connection between the experimentally determined Phi value, a quantity determined
      by the ratio of rate and stability changes due to point mutations, and the
      average structure of the transition state ensemble. To determine the accuracy of
      this thermodynamic approach, we apply it to minimalist protein models and compare
      these results with the ones obtained by using the standard experimental procedure
      for determining Phi values. We show that the accuracy of both methods depends
      sensitively on the amount of frustration. In particular, the results are similar
      when applied to models with minimal amounts of frustration, characteristic of
      rapid-folding, single-domain globular proteins.

PMID- 10639132
TI  - Mechanism of the single-headed processivity: diffusional anchoring between the K
      loop of kinesin and the C terminus of tubulin.
AB  - A motor-domain construct of KIF1A, a single-headed kinesin superfamily protein,
      was demonstrated to take more than 600 steps before detaching from a microtubule.
      However, its molecular mechanism remained unclear. Here we demonstrate the
      nucleotide-dependent binding between the lysine-rich, highly positively charged
      loop 12 of the KIF1A motor domain (K-loop) and the glutamate-rich, highly
      negatively charged C-terminal region of tubulin (E-hook). This binding did not
      contribute in the strong binding state but only in the weak binding state. This
      binding was demonstrated to be essential for the single-headed processivity by
      functioning as the anchor for the one-dimensional simple Brownian movement in the
      weak binding state. This Brownian movement will allow the small KIF1A motor
      domain to span the distance between the binding sites on microtubule and also
      will give the diffusive nature to the movement of single KIF1A molecules. These
      observations quantitatively fitted well to the predictions made from our Brownian
      motor model on the mechanism of the single-headed processive movement.

PMID- 10639133
TI  - RNA folding energy landscapes.
AB  - Using a statistical mechanical treatment, we study RNA folding energy landscapes.
      We first validate the theory by showing that, for the RNA molecules we tested
      having only secondary structures, this treatment (i) predicts about the same
      native structures as the Zuker method, and (ii) qualitatively predicts the
      melting curve peaks and shoulders seen in experiments. We then predict
      thermodynamic folding intermediates. For one hairpin sequence, unfolding is a
      simple unzipping process. But for another sequence, unfolding is more complex. It
      involves multiple stable intermediates and a rezipping into a completely non
      native conformation before unfolding. The principle that emerges, for which there
      is growing experimental support, is that although protein folding tends to
      involve highly cooperative two-state thermodynamic transitions, without
      detectable intermediates, the folding of RNA secondary structures may involve
      rugged landscapes, often with more complex intermediate states.

PMID- 10639134
TI  - CopA: An Escherichia coli Cu(I)-translocating P-type ATPase.
AB  - The copA gene product, a putative copper-translocating P-type ATPase, has been
      shown to be involved in copper resistance in Escherichia coli. The copA gene was
      disrupted by insertion of a kanamycin gene through homologous recombination. The
      mutant strain was more sensitive to copper salts but not to salts of other
      metals, suggesting a role in copper homeostasis. The copper-sensitive phenotype
      could be rescued by complementation by a plasmid carrying copA from E. coli or
      copB from Enterococcus hirae. Expression of copA was induced by salts of copper
      or silver but not zinc or cobalt. Everted membrane vesicles from cells expressing
      copA exhibited ATP-coupled accumulation of copper, presumably as Cu(I). The
      results indicate that CopA is a Cu(I)-translocating efflux pump that is similar
      to the copper pumps related to Menkes and Wilson diseases and provides a useful
      prokaryotic model for these human diseases.

PMID- 10639135
TI  - Regulation of expanded polyglutamine protein aggregation and nuclear localization
      by the glucocorticoid receptor.
AB  - Spinobulbar muscular atrophy and Huntington's disease are caused by polyglutamine
      expansion in the androgen receptor and huntingtin, respectively, and their
      pathogenesis has been associated with abnormal nuclear localization and
      aggregation of truncated forms of these proteins. Here we show, in diverse cell
      types, that glucocorticoids can up- or down-modulate aggregation and nuclear
      localization of expanded polyglutamine polypeptides derived from the androgen
      receptor and huntingtin through specific regulation of gene expression. Wild-type
      glucocorticoid receptor (GR), as well as C-terminal deletion derivatives,
      suppressed the aggregation and nuclear localization of these polypeptides,
      whereas mutations within the DNA binding domain and N terminus of GR abolished
      this activity. Surprisingly, deletion of a transcriptional regulatory domain
      within the GR N terminus markedly increased aggregation and nuclear localization
      of the expanded polyglutamine proteins. Thus, aggregation and nuclear
      localization of expanded polyglutamine proteins are regulated cellular processes
      that can be modulated by a well-characterized transcriptional regulator, the GR.
      Our findings suggest approaches to study the molecular pathogenesis and selective
      neuronal degeneration of polyglutamine expansion diseases.

PMID- 10639136
TI  - Drob-1, a Drosophila member of the Bcl-2/CED-9 family that promotes cell death.
AB  - The Bcl-2/CED-9 family of proteins, which includes both antiapoptotic and
      proapoptotic members, plays key regulating roles in programmed cell death. We
      report here the identification and characterization of Drob-1, the first
      Drosophila member of the Bcl-2/CED-9 family to be isolated. Drob-1 contains four
      conserved Bcl-2 homology domains (BH1, BH2, BH3, and BH4) and a C-terminal
      hydrophobic domain. Ectopic expression of Drob-1 in the developing Drosophila eye
      resulted in a rough-eye phenotype. Furthermore, when overexpressed in Drosophila
      S2 cells, Drob-1 induced apoptosis accompanied by elevated caspase activity. This
      Drob-1-induced cell death, however, could not be antagonized by baculovirus p35,
      a broad-spectrum caspase inhibitor. Drob-1 was localized to the intracytoplasmic
      membranes, predominantly to the mitochondrial membranes, and a mutant Drob-1
      lacking the hydrophobic C terminus lost both its mitochondrial localization and
      its proapoptotic activity. These results suggest that Drob-1 promotes cell death
      by inducing both caspase-dependent and -independent pathways at the mitochondria.
      Our identification of Drob-1 and further genetic analysis should provide
      increased understanding of the universal mechanisms by which the Bcl-2/CED-9
      family members and other related proteins regulate apoptosis.

PMID- 10639137
TI  - The putative tumor suppressors EXT1 and EXT2 form a stable complex that
      accumulates in the Golgi apparatus and catalyzes the synthesis of heparan
      sulfate.
AB  - Hereditary multiple exostoses, a dominantly inherited genetic disorder
      characterized by multiple cartilaginous tumors, is caused by mutations in members
      of the EXT gene family, EXT1 or EXT2. The proteins encoded by these genes, EXT1
      and EXT2, are endoplasmic reticulum-localized type II transmembrane glycoproteins
      that possess or are tightly associated with glycosyltransferase activities
      involved in the polymerization of heparan sulfate. Here, by testing a cell line
      with a specific defect in EXT1 in in vivo and in vitro assays, we show that EXT2
      does not harbor significant glycosyltransferase activity in the absence of EXT1.
      Instead, it appears that EXT1 and EXT2 form a hetero-oligomeric complex in vivo
      that leads to the accumulation of both proteins in the Golgi apparatus.
      Remarkably, the Golgi-localized EXT1/EXT2 complex possesses substantially higher
      glycosyltransferase activity than EXT1 or EXT2 alone, which suggests that the
      complex represents the biologically relevant form of the enzyme(s). These
      findings provide a rationale to explain how inherited mutations in either of the
      two EXT genes can cause loss of activity, resulting in hereditary multiple
      exostoses.

PMID- 10639139
TI  - A Rab11-containing rapidly recycling compartment in macrophages that promotes
      phagocytosis.
AB  - Macrophages are specialized cells of the immune system that exhibit a prodigious
      capacity for phagocytosis. The ability of macrophages to internalize a
      substantial proportion of their plasma membrane during phagocytosis indicates
      that they possess a mechanism for the rapid renewal of plasma membrane. We
      examined the role of endocytic membrane recycling in promoting phagocytosis. In
      contrast to many other cell types, macrophages lack a morphologically distinct
      peri-centriolar recycling compartment but instead demonstrate an extensive
      network of transferrin receptor-positive tubules and vesicles that participated
      in recycling. The rate of transferrin recycling in thioglycollate-elicited murine
      peritoneal macrophages (thio-macrophages) was exceedingly rapid, with exocytic
      rate constants that were 2- to 3-fold higher than those of most other cells.
      Because the GTPase Rab11 has been implicated in transferrin recycling in other
      cells, we determined its role in transferrin recycling and phagocytosis in
      macrophages. Macrophages expressing epitope-tagged Rab11 demonstrated the
      presence of Rab11 in several intracellular membrane compartments, including
      endosomes and nascent phagosomes. Expression of Rab11 25N, a GTP binding
      deficient allele of Rab11, led to a decreased rate of transferrin efflux and
      impaired Fc(gamma)R-mediated phagocytosis, where Fc(gamma)R is the receptor for
      the Fc portion of IgG. In contrast, expression of Rab11 70L, a GTPase-deficient
      allele of Rab11, led to an increased rate of transferrin efflux and enhanced
      phagocytosis. We conclude that macrophages have adapted a rapidly mobilizable,
      endocytic compartment to enhance phagocytosis. Rab11 participates in the
      recruitment of this compartment to the macrophage cell surface.

PMID- 10639138
TI  - Calnuc, an EF-hand Ca(2+) binding protein, specifically interacts with the C
      terminal alpha5-helix of G(alpha)i3.
AB  - Calnuc (nucleobindin) was previously shown to be present both in the cytosol and
      in the Golgi and to be the major Golgi Ca(2+) binding protein. In this study we
      verified the existence of the cytosolic pool of calnuc and investigated its
      interaction with G(alpha)i3. Cytosolic calnuc was released by mild digitonin
      permeabilization. In pulse-chase experiments, the two pools of calnuc had
      different mobilities, suggesting different posttranslational modifications. That
      calnuc interacts with G(alpha)i3 in vivo was verified by the finding that
      G(alpha)i3 could be crosslinked intracellularly to calnuc and co
      immunoprecipitated from NIH 3T3 cells stably overexpressing either activated
      (Q204L) or inactivated (G203A) G(alpha)i3. Binding was Ca(2+) and Mg(2+)
      dependent. Calnuc and G(alpha)i3-GFP codistributed primarily in the Golgi region.
      By yeast two-hybrid analysis, the binding site on G(alpha)i3 for calnuc was
      mapped to the C-terminal region because removal of the last 12 amino acids (but
      not 11) abolished the interaction. Peptide competition indicated that calnuc,
      with its coiled-coil domain constituted by the two EF-hands, binds to
      G(alpha)i3's C-terminal alpha5-helix. These results demonstrate that calnuc may
      play an important role in G protein- and Ca(2+)-regulated signal transduction
      events.

PMID- 10639140
TI  - A method for detecting abasic sites in living cells: age-dependent changes in
      base excision repair.
AB  - Apurinic/apyrimidinic (AP) sites are common DNA lesions that arise from
      spontaneous depurination or by base excision repair (BER) of modified bases. A
      biotin-containing aldehyde-reactive probe (ARP) [Kubo, K., Ide, H., Wallace, S.
      S. & Kow, Y. W. (1992) Biochemistry 31, 3703-3708] is used to measure AP sites in
      living cells. ARP penetrates the plasma membrane of cells and reacts with AP
      sites in DNA to form a stable ARP-DNA adduct. The DNA is isolated and treated
      with avidin-horseradish peroxidase (HRP), forming a DNA-HRP complex at each
      biotin residue, which is rapidly separated from free avidin-HRP by selective
      precipitation with a DNA precipitating dye (DAPER). The number of AP sites is
      estimated by HRP activity toward chromogenic substrate in an ELISA assay. The
      assay integrates the AP sites formed by the different glycosylases of BER during
      a 1-h incubation and eliminates artifactual depurination or loss of AP sites
      during DNA isolation. The assay was applied to living cells and nuclei. The
      number of AP sites after a 1-h incubation in old IMR90 cells was about two to
      three times higher than that in young cells, and the number in human leukocytes
      from old donors was about seven times that in young donors. The repair of AP
      sites was slower in senescent compared with young IMR90 cells. An age-dependent
      decline is shown in the activity of the glycosylase that removes methylated bases
      in IMR90 cells and in human leukocytes. The decline in excision of methylated
      bases from DNA suggests an age-dependent decline in 3-methyladenine DNA
      glycosylase, a BER enzyme responsible for removing alkylated bases.

PMID- 10639141
TI  - Position-dependent linkages of fibronectin- integrin-cytoskeleton.
AB  - Position-dependent cycling of integrin interactions with both the cytoskeleton
      and extracellular matrix (ECM) is essential for cell spreading, migration, and
      wound healing. Whether there are regional changes in integrin concentration,
      ligand affinity or cytoskeleton crosslinking of liganded integrins has been
      unclear. Here, we directly demonstrate a position-dependent binding and release
      cycle of fibronectin-integrin-cytoskeleton interactions with preferential binding
      at the front of motile 3T3 fibroblasts and release at the endoplasm-ectoplasm
      boundary. Polystyrene beads coated with low concentrations of an integrin-binding
      fragment of fibronectin (fibronectin type III domains 7-10) were 3-4 times more
      likely to bind to integrins when placed within 0.5 microns vs. 0.5-3 microns from
      the leading edge. Integrins were not concentrated at the leading edge, nor did
      anti-integrin antibody-coated beads bind preferentially at the leading edge.
      However, diffusing liganded integrins attached to the cytoskeleton preferentially
      at the leading edge. Cytochalasin inhibited edge binding, which suggested that
      cytoskeleton binding to the integrins could alter the avidity for ligand beads.
      Further, at the ectoplasm-endoplasm boundary, the velocity of bead movement
      decreased, diffusive motion increased, and approximately one-third of the beads
      were released into the medium. We suggest that cytoskeleton linkage of liganded
      integrins stabilizes integrin-ECM bonds at the front whereas release of
      cytoskeleton-integrin links weakens integrin-ECM bonds at the back of
      lamellipodia.

PMID- 10639142
TI  - Heritability of fitness in a wild mammal population.
AB  - Classical population genetics theory predicts that selection should deplete
      heritable genetic variance for fitness. We show here that, consistent with this
      prediction, there was a negative correlation between the heritability of a trait
      and its association with fitness in a wild population of red deer (Cervus
      elaphus) and there was no evidence of significant heritability of total fitness.
      However, the decline in heritability was caused, at least in part, by increased
      levels of residual variance in longevity and, hence, in total fitness: in this
      population, longevity is known to be heavily influenced by environmental factors.
      Other life history traits that were not associated with longevity, such as
      average annual breeding success, had higher heritabilities. Coefficients of
      additive genetic variance differed markedly between traits, but highly skewed
      measures, such as male breeding success, generally had greater coefficients of
      variance than morphometric traits. Finally, there were significant maternal
      effects in a range of traits, particularly for females.

PMID- 10639143
TI  - Functional evolution of the Ultrabithorax protein.
AB  - The Hox genes have been implicated as central to the evolution of animal body
      plan diversity. Regulatory changes both in Hox expression domains and in Hox
      regulated gene networks have arisen during the evolution of related taxa, but
      there is little knowledge of whether functional changes in Hox proteins have also
      contributed to morphological evolution. For example, the evolution of greater
      numbers of differentiated segments and body parts in insects, compared with the
      simpler body plans of arthropod ancestors, may have involved an increase in the
      spectrum of biochemical interactions of individual Hox proteins. Here, we compare
      the in vivo functions of orthologous Ultrabithorax (Ubx) proteins from the insect
      Drosophila melanogaster and from an onychophoran, a member of a sister phylum
      with a more primitive and homonomous body plan. These Ubx proteins, which have
      been diverging in sequence for over 540 million years, can generate many of the
      same gain-of-function tissue transformations and can activate and repress many of
      the same target genes when expressed during Drosophila development. However, the
      onychophora Ubx (OUbx) protein does not transform the segmental identity of the
      embryonic ectoderm or repress the Distal-less target gene. This functional
      divergence is due to sequence changes outside the conserved homeodomain region.
      The inability of OUbx to function like Drosophila Ubx (DUbx) in the embryonic
      ectoderm indicates that the Ubx protein may have acquired new cofactors or
      activity modifiers since the divergence of the onychophoran and insect lineages.

PMID- 10639145
TI  - Heterochromatic deposition of centromeric histone H3-like proteins.
AB  - Centromeres of most organisms are embedded within constitutive heterochromatin,
      the condensed regions of chromosomes that account for a large fraction of complex
      genomes. The functional significance of this centromere-heterochromatin
      relationship, if any, is unknown. One possibility is that heterochromatin
      provides a suitable environment for assembly of centromere components, such as
      special centromeric nucleosomes that contain distinctive histone H3-like
      proteins. We describe a Drosophila H3-like protein, Cid (for centromere
      identifier) that localizes exclusively to fly centromeres. When the cid upstream
      region drives expression of H3 and H2B histone-green fluorescent protein fusion
      genes in Drosophila cells, euchromatin-specific deposition results. Remarkably,
      when the cid upstream region drives expression of yeast, worm, and human
      centromeric histone-green fluorescent protein fusion proteins, localization is
      preferentially within Drosophila pericentric heterochromatin. Heterochromatin
      specific localization also was seen for yeast and worm centromeric proteins
      constitutively expressed in human cells. Preferential localization to
      heterochromatin in heterologous systems is unexpected if centromere-specific or
      site-specific factors determine H3-like protein localization to centromeres.
      Rather, the heterochromatic state itself may help localize centromeric
      components.

PMID- 10639144
TI  - Distinct genetic profiles in colorectal tumors with or without the CpG island
      methylator phenotype.
AB  - Colorectal cancers (CRCs) are characterized by multiple genetic (mutations) and
      epigenetic (CpG island methylation) alterations, but it is not known whether
      these evolve independently through stochastic processes. We have recently
      described a novel pathway termed CpG island methylator phenotype (CIMP) in CRC,
      which is characterized by the simultaneous methylation of multiple CpG islands,
      including several known genes, such as p16, hMLH1, and THBS1. We have now studied
      mutations in K-RAS, p53, DPC4, and TGFbetaRII in a panel of colorectal tumors
      with or without CIMP. We find that CIMP defines two groups of tumors with
      significantly different genetic lesions: frequent K-RAS mutations were found in
      CIMP(+) CRCs (28/41, 68%) compared with CIMP(-) cases (14/47, 30%, P = 0.0005).
      By contrast, p53 mutations were found in 24% (10/41) of CIMP(+) CRCs vs. 60%
      (30/46) of CIMP(-) cases (P = 0.002). Both of these differences were independent
      of microsatellite instability. These interactions between CIMP, K-RAS mutations,
      and p53 mutations were preserved in colorectal adenomas, suggesting that they
      occur early in carcinogenesis. The distinct combinations of epigenetic and
      genetic alterations in each group suggest that activation of oncogenes and
      inactivation of tumor suppressor genes is related to the underlying mechanism of
      generating molecular diversity in cancer, rather than simply accumulate
      stochastically during cancer development.

PMID- 10639146
TI  - Double trans-chromosomic mice: maintenance of two individual human chromosome
      fragments containing Ig heavy and kappa loci and expression of fully human
      antibodies.
AB  - The use of a human chromosome or its fragment as a vector for animal transgenesis
      may facilitate functional studies of large human genomic regions. We describe
      here the generation and analysis of double trans-chromosomic (Tc) mice harboring
      two individual human chromosome fragments (hCFs). Two transmittable hCFs, one
      containing the Ig heavy chain locus (IgH, approximately 1.5 Mb) and the other the
      kappa light chain locus (Igkappa, approximately 2 Mb), were introduced into a
      mouse strain whose endogenous IgH and Igkappa loci were inactivated. In the
      resultant double-Tc/double-knockout mice, substantial proportion of the somatic
      cells retained both hCFs, and the rescue in the defect of Ig production was shown
      by high level expression of human Ig heavy and kappa chains in the absence of
      mouse heavy and kappa chains. In addition, serum expression profiles of four
      human Ig gamma subclasses resembled those seen in humans. They mounted an antigen
      specific human antibody response upon immunization with human serum albumin, and
      human serum albumin-specific human monoclonal antibodies with various isotypes
      were obtained from them. These results represent a generation of mice with
      "humanized" loci by using the transmittable hCFs, which suggest that the Tc
      technology may allow for the humanization of over megabase-sized, complex loci in
      mice or other animals. Such animals may be useful not only for studying in vivo
      functions of the human genome but also for obtaining various therapeutic
      products.

PMID- 10639147
TI  - Plasmid copy-number control and better-than-random segregation genes of pSM19035
      share a common regulator.
AB  - Transcription initiation of the copy-number control and better-than-random
      segregation genes of the broad-host-range and low-copy-number plasmid pSM19035
      are subjected to repression by the autoregulated pSM19035-encoded omega product
      in Bacillus subtilis cells. The promoters of the copS (Pcop1 and Pcop2), delta
      (Pdelta), and omega (Pomega) genes have been mapped. These promoters are embedded
      in a set of either seven copies of a 7-bp direct repeat or in a block consisting
      of two 7-bp direct repeats and one 7-bp inverted repeat; the blocks are present
      either two or three times. The cooperative binding of omega protein to the
      repeats on the Pcop1, Pcop2, Pdelta, and Pomega promoters represses transcription
      initiation by a mechanism that does not exclude sigma(A)RNAP from the promoters.
      These results indicate that omega protein regulates plasmid maintenance by
      controlling the copy number on the one hand and by regulating the amount of
      proteins required for better-than-random segregation on the other hand.

PMID- 10639148
TI  - IL-18 regulates IL-1beta-dependent hepatic melanoma metastasis via vascular cell
      adhesion molecule-1.
AB  - Proinflammatory cytokines, including IL-1beta and tumor necrosis factor-alpha
      (TNF-alpha), promote cancer cell adhesion and liver metastases by up-regulating
      the expression of vascular cell adhesion molecule-1 (VCAM-1) on hepatic
      sinusoidal endothelium (HSE). In this study, hepatic metastasis after
      intrasplenically injected mouse B16 melanoma (B16M) cells was reduced 84-95% in
      mice with null mutations for either IL-1beta or the IL-1beta-converting enzyme
      (ICE, caspase-1) compared with wild-type mice. On day 12, 47% of wild-type mice
      were dead compared with 19% of either IL-1beta or ICE-deficient mice. In vitro,
      conditioned medium from B16M cells (B16M-CM) induced the release of TNF-alpha and
      IL-1beta from cultures of primary murine HSE. The effect of B16M-CM on HSE
      resulted in increased numbers of B16M cells adhering to HSE, which was completely
      abrogated by a specific inhibitor of ICE, anti-IL-18 or IL-18-binding protein.
      Exogenous IL-18 added to HSE also increased the number of adhering melanoma
      cells; however, this was not affected by IL-1 receptor blockade or TNF
      neutralization but rather by anti-VCAM-1. These results demonstrate a role for IL
      1beta and IL-18 in the development of hepatic metastases of B16M in vivo. In
      vitro, soluble products from B16M cells stimulate HSE to sequentially release TNF
      alpha, IL-1beta, and IL-18. The IL-18 cytokine increases expression of VCAM-1 and
      the adherence of melanoma cells.

PMID- 10639149
TI  - Involvement of decidual Valpha14 NKT cells in abortion.
AB  - The immunological mechanisms that regulate abortion are largely unknown. Here, we
      found that a distinct subset of lymphocytes, Valpha14 NKT cells expressing an
      invariant antigen receptor encoded by Valpha14/Jalpha281 and Vbeta7 segments,
      accumulated in the decidua during pregnancy and provoked abortion upon
      stimulation with alpha-galactosylceramide (alpha-GalCer), a specific ligand for
      Valpha14 NKT cells. The alpha-GalCer-mediated abortion was not observed in
      Valpha14 NKT-, IFN-gamma-, tumor necrosis factor alpha-, or perforin-knock-out
      mice and appeared to be due to the degeneration of embryonic trophoblasts
      mediated by the activated Valpha14 NKT cells whose perforin-dependent killing and
      production of IFN-gamma and tumor necrosis factor alpha were essential. The
      possible role of the decidual Valpha14 NKT cells in the pathogenesis of abortion
      is discussed.

PMID- 10639150
TI  - Enzymatic reduction of disulfide bonds in lysosomes: characterization of a gamma
      interferon-inducible lysosomal thiol reductase (GILT).
AB  - Proteins internalized into the endocytic pathway are usually degraded. Efficient
      proteolysis requires denaturation, induced by acidic conditions within lysosomes,
      and reduction of inter- and intrachain disulfide bonds. Cytosolic reduction is
      mediated enzymatically by thioredoxin, but the mechanism of lysosomal reduction
      is unknown. We describe here a lysosomal thiol reductase optimally active at low
      pH and capable of catalyzing disulfide bond reduction both in vivo and in vitro.
      The active site, determined by mutagenesis, consists of a pair of cysteine
      residues separated by two amino acids, similar to other enzymes of the
      thioredoxin family. The enzyme is a soluble glycoprotein that is synthesized as a
      precursor. After delivery into the endosomal/lysosomal system by the mannose 6
      phosphate receptor, N- and C-terminal prosequences are removed. The enzyme is
      expressed constitutively in antigen-presenting cells and induced by IFN-gamma in
      other cell types, suggesting a potentially important role in antigen processing.

PMID- 10639152
TI  - T cell receptor interactions with class I heavy-chain influence T cell selection.
AB  - The interaction of the T cell receptor (TCR) with peptide in the binding site of
      the major histocompatibility complex molecule provides the basis for T cell
      recognition during immune surveillance, repertoire development, and tolerance.
      Little is known about the extent to which repertoire selection is influenced
      directly by variation of the structure of the class I heavy chain. We find that
      the 2C TCR, normally positively selected in the context of the K(b) molecule, is
      minimally selected into the CD8 lineage in the absence of antigen-processing
      genes. This finding underscores the importance of peptides in determining the
      positive-selecting class I ligands in the thymus. In contrast, K(bm3), a variant
      class I molecule that normally exerts a negative selection pressure on 2C-bearing
      T cells, positively selects 2C transgenic T cells into the CD8 lineage in an
      antigen-processing gene-deficient environment. These findings indicate that
      structural changes in the heavy chain can have direct influence in T cell
      recognition, from which we conclude that the nature of TCR interaction with class
      I heavy chain influences the array of TCRs selected during development of the
      functional adult repertoire.

PMID- 10639151
TI  - Pathogen-specific loss of host resistance in mice lacking the IFN-gamma-inducible
      gene IGTP.
AB  - Interferon-gamma (IFN-gamma) is critical for defense against pathogens, but the
      molecules that mediate its antimicrobial responses are largely unknown. IGTP is
      the prototype for a family of IFN-gamma-regulated genes that encode 48-kDa GTP
      binding proteins that localize to the endoplasmic reticulum. We have generated
      IGTP-deficient mice and found that, despite normal immune cell development and
      normal clearance of Listeria monocytogenes and cytomegalovirus infections, the
      mice displayed a profound loss of host resistance to acute infections of the
      protozoan parasite Toxoplasma gondii. By contrast, IFN-gamma receptor-deficient
      mice have increased susceptibility to all three pathogens. Thus, IGTP defines an
      IFN-gamma-regulated pathway with a specialized role in antimicrobial resistance.

PMID- 10639153
TI  - Prevention of passively transferred experimental autoimmune myasthenia gravis by
      a phage library-derived cyclic peptide.
AB  - Many pathogenic antibodies in myasthenia gravis (MG) and its animal model,
      experimental autoimmune MG (EAMG), are directed against the main immunogenic
      region (MIR) of the acetylcholine receptor (AcChoR). These antibodies are highly
      conformation dependent; hence, linear peptides derived from native receptor
      sequences are poor candidates for their immunoneutralization. We employed a phage
      epitope library to identify peptide-mimotopes capable of preventing the
      pathogenicity of the anti-MIR mAb 198. We identified a 15-mer peptide
      (PMTLPENYFSERPYH) that binds specifically to mAb 198 and inhibits its binding to
      AcChoR. A 10-fold increase in the affinity of this peptide was achieved by
      incorporating flanking amino acid residues from the coat protein as present in
      the original phage library. This extended peptide (AEPMTLPENYFSERPYHPPPP) was
      constrained by the addition of cysteine residues on both ends of the peptide,
      thus generating a cyclic peptide that inhibited the binding of mAb 198 to AcChoR
      with a potency that is three orders of magnitude higher when compared with the
      parent library peptide. This cyclic peptide inhibited the in vitro binding of mAb
      198 to AcChoR and prevented the antigenic modulation of AcChoR caused by mAb 198
      in human muscle cell cultures. The cyclic peptide also reacted with several other
      anti-MIR mAbs and the sera of EAMG rats. In addition, this peptide blocked the
      ability of mAb 198 to passively transfer EAMG in rats. Further derivatization of
      the cyclic peptide may aid in the design of suitable synthetic mimotopes for
      modulation of MG.

PMID- 10639154
TI  - Anti-IL-9 vaccination prevents worm expulsion and blood eosinophilia in Trichuris
      muris-infected mice.
AB  - Production of neutralizing anti-IL-9 antibodies was induced in mice by
      immunization with mouse IL-9 coupled to ovalbumin. In the six mouse strains
      tested, a strong and long-lasting anti-IL-9 response developed with seric
      inhibitory titers of 10(-3) to 10(-5), as measured in an in vitro IL-9-dependent
      cell proliferation assay. In vivo, this immunization completely abrogated the
      increase in mast-cell protease-1 levels as well as the eosinophilia observed in
      mice after implantation of an IL-9-secreting tumor. We took advantage of this
      method to assess the role of IL-9 in infections with nematode Trichuris muris,
      where IL-9 production correlates with the resistant phenotype. C57BL/6 mice,
      which normally expel the parasite, became susceptible after anti-IL-9
      immunization, demonstrating that IL-9 plays a critical role in this model. In
      addition, neutralization of IL-9 also inhibited parasite-induced blood
      eosinophilia. Taken together, the present data demonstrate the potency of our
      strategy to antagonize IL-9 in vivo and shows that this cytokine plays a major
      role in resistance against T. muris infection.

PMID- 10639155
TI  - Cloning and characterization of IL-17B and IL-17C, two new members of the IL-17
      cytokine family.
AB  - IL-17 is a T cell-derived cytokine that may play an important role in the
      initiation or maintenance of the proinflammatory response. Whereas expression of
      IL-17 is restricted to activated T cells, the IL-17 receptor is found to be
      widely expressed, a finding consistent with the pleiotropic activities of IL-17.
      We have cloned and expressed two novel human cytokines, IL-17B and IL-17C, that
      are related to IL-17 ( approximately 27% amino acid identity). IL-17B mRNA is
      expressed in adult pancreas, small intestine, and stomach, whereas IL-17C mRNA is
      not detected by RNA blot hybridization of several adult tissues. No expression of
      IL-17B or IL-17C mRNA is found in activated T cells. In a survey of cytokine
      induction, IL-17B and IL-17C stimulate the release of tumor necrosis factor alpha
      and IL-1beta from the monocytic cell line, THP-1, whereas IL-17 has only a weak
      effect in this system. No induction of IL-1alpha, IL-6, IFN-gamma, or granulocyte
      colony-stimulating factor is found in THP-1 cells. Fluorescence-activated cell
      sorter analysis shows that IL-17B and IL-17C bind to THP-1 cells. Conversely, IL
      17B and IL-17C are not active in an IL-17 assay or the stimulation of IL-6
      release from human fibroblasts and do not bind to the human IL-17 receptor
      extracellular domain. These data show that there is a family of IL-17-related
      cytokines differing in patterns of expression and proinflammatory responses that
      may be transduced through a cognate set of cell surface receptors.

PMID- 10639156
TI  - Benzo[a]pyrene carcinogenicity is lost in mice lacking the aryl hydrocarbon
      receptor.
AB  - The contribution of the aryl hydrocarbon receptor (AhR) in induction of a battery
      of xenobiotic-metabolizing enzymes has been studied extensively. However, no
      direct proof has been obtained that it plays a role in modulating carcinogenesis.
      To address the question of whether AhR is required for tumor induction, we have
      investigated the response of AhR-deficient mice to benzo[a]pyrene (B[a]P), a
      widely distributed environmental carcinogen. B[a]P treatment induced expression
      of the cytochrome P450 gene Cyp1a1 in the skin and liver of AhR-positive mice
      bearing +/+ and +/- genotypes and did not induce expression of the cytochrome
      P450 gene Cyp1a1 in AhR-null mice in either skin or liver. In contrast, Cyp1a2
      gene expression was positive in liver irrespective of the presence or absence of
      the AhR gene, or B[a]P treatment, although its inducibility was lost in the AhR(
      /-) mouse. All AhR-positive male mice of both +/+ and +/- genotypes that received
      subcutaneous injection of B[a]P (2 mg) on the first and the eighth days had
      developed subcutaneous tumors at the site of injection at the end of the 18-week
      experiment. In contrast, no tumors were apparent in any of the AhR-deficient
      mice. Likewise, topical application of B[a]P (200 microg) at weekly intervals to
      the skin of female mice for 25 weeks produced skin tumors only in the AhR
      positive mice. Thus the carcinogenic action of B[a]P may be determined primarily
      by AhR, a transcriptional regulator of the gene for CYP1A1. The results of the
      present study provide direct evidence that AhR is involved in carcinogenesis.

PMID- 10639157
TI  - Drug target validation: lethal infection blocked by inducible peptide.
AB  - Genome projects are generating large numbers of potential new targets for drug
      discovery. One challenge is target validation, proving the usefulness of a
      specific target in an animal model. In this paper, we demonstrate a new approach
      to validation and assay development. We selected in vitro specific peptide
      binders to a potential pathogen target. By inducing the expression of a selected
      peptide in pathogen cells causing a lethal infection in mice, the animals were
      rescued. Thus, by combining in vitro selection methods for peptide binders with
      inducible expression in animals, the target's validity was rigorously tested and
      demonstrated. This approach to validation can be generalized and has the
      potential to become a valuable tool in the drug discovery process.

PMID- 10639158
TI  - Targeted disruption of hormone-sensitive lipase results in male sterility and
      adipocyte hypertrophy, but not in obesity.
AB  - Hormone-sensitive lipase (HSL) is known to mediate the hydrolysis not only of
      triacylglycerol stored in adipose tissue but also of cholesterol esters in the
      adrenals, ovaries, testes, and macrophages. To elucidate its precise role in the
      development of obesity and steroidogenesis, we generated HSL knockout mice by
      homologous recombination in embryonic stem cells. Mice homozygous for the mutant
      HSL allele (HSL-/-) were superficially normal except that the males were sterile
      because of oligospermia. HSL-/- mice did not have hypogonadism or adrenal
      insufficiency. Instead, the testes completely lacked neutral cholesterol ester
      hydrolase (NCEH) activities and contained increased amounts of cholesterol ester.
      Many epithelial cells in the seminiferous tubules were vacuolated. NCEH
      activities were completely absent from both brown adipose tissue (BAT) and white
      adipose tissue (WAT) in HSL-/- mice. Consistently, adipocytes were significantly
      enlarged in the BAT (5-fold) and, to a lesser extent in the WAT (2-fold),
      supporting the concept that the hydrolysis of triacylglycerol was, at least in
      part, impaired in HSL-/- mice. The BAT mass was increased by 1.65-fold, but the
      WAT mass remained unchanged. Discrepancy of the size differences between cell and
      tissue suggests the heterogeneity of adipocytes. Despite these morphological
      changes, HSL-/- mice were neither obese nor cold sensitive. Furthermore, WAT from
      HSL-/- mice retained 40% of triacylglycerol lipase activities compared with the
      wild-type WAT. In conclusion, HSL is required for spermatogenesis but is not the
      only enzyme that mediates the hydrolysis of triacylglycerol stored in adipocytes.

PMID- 10639159
TI  - Adenoviral gene transfer of SERCA2a improves left-ventricular function in aortic
      banded rats in transition to heart failure.
AB  - In human and experimental models of heart failure, sarcoplasmic reticulum Ca(2+)
      ATPase (SERCA2a) activity is decreased, resulting in abnormal calcium handling.
      The disturbances in calcium metabolism have been shown to contribute
      significantly to the contractile dysfunction observed in heart failure. We
      investigated whether increasing SERCA2a expression can improve ventricular
      function in an animal model of heart failure obtained by creating ascending
      aortic constriction in rats. After 19-23 wk of banding during the transition from
      compensated hypertrophy to heart failure (documented by >25% decrease in
      fractional shortening), rats were randomized to receive either an adenovirus
      carrying the SERCA2a gene (Ad.SERCA2a, n = 13) or beta-galactosidase (Ad.betagal,
      n = 14) by using a catheter-based technique. The failing hearts infected with Ad.
      betagal were characterized by a significant decrease in SERCA2a expression and a
      decrease in SERCA2a activity compared with nonfailing sham-operated rats (n =
      11). In addition, these failing hearts had reduced left-ventricular systolic
      pressure, maximal rate of left-ventricular pressure rise and decline (+dP/dt, 
      dP/dt), and rate of isovolumic relaxation (tau). Overexpression of SERCA2a
      restored both SERCA2a expression and ATPase activity to nonfailing levels.
      Furthermore, rats infected with Ad.SERCA2a had significant improvement in left
      ventricular systolic pressure, +dP/dt, -dP/dt, and rate of isovolumic relaxation
      (tau) normalizing them back to levels comparable to sham-operated rats. In this
      study, we show that in an animal model of heart failure where SERCA2a protein
      levels and activity are decreased and severe contractile dysfunction is present,
      overexpression of SERCA2a in vivo restores both systolic and diastolic function
      to normal levels.

PMID- 10639160
TI  - Intestinal trefoil factor confers colonic epithelial resistance to apoptosis.
AB  - Intestinal trefoil factor (ITF) is an essential regulator of colonic epithelial
      restitution, the rapid migration of colonocytes over mucosal wounds. High levels
      of ITF are frequently present in colorectal cancers and derived cell lines.
      Mucosal restitution requires the detachment of epithelium from substrate, which
      would be expected to induce apoptosis. However, mice deficient in ITF showed an
      increase in colonocyte apoptosis unaccompanied by changes in expression of
      receptor-related (TNFR/Fas) or stress-related (Bcl-family) cell death regulators.
      An ITF-expressing colonic (HT-ITF1) cell line was resistant to apoptosis induced
      by serum starvation and ceramide. Exogenous ITF also protected another human
      colonic carcinoma-derived cell line (HCT116) and a nontransformed rat intestinal
      epithelial cell line (IEC-6) from apoptosis. This effect was abrogated by
      wortmannin and tyrphostin A25, indicating the potential involvement of
      phosphatidylinositol 3-kinase and epidermal growth factor (EGF) receptor
      activation. Expression of phosphorylated Akt, which lies downstream of
      phosphatidylinositol 3-kinase activation, was elevated in this HT-29-ITF line.
      p53-dependent cell death in the AGS human gastric cancer cell line after
      etoposide was similarly inhibited by transient expression of ITF but not a C
      terminal truncation mutant of ITF, and it required functional
      phosphatidylinositol 3-kinase and EGF receptor. These findings support a central
      role for ITF in the maintenance of intestinal mucosal continuity, and conversely
      demonstrate the potential for ITF expression to confer resistance of colorectal
      tumors to therapy.

PMID- 10639161
TI  - Functional deletion of the CCR5 receptor by intracellular immunization produces
      cells that are refractory to CCR5-dependent HIV-1 infection and cell fusion.
AB  - Studies of naturally occurring polymorphisms of the CCR5 gene have shown that
      deletion of the functional receptor or reduced expression of the gene can have
      beneficial effects in preventing HIV-1 infection or delaying disease. Because
      these polymorphisms are found in otherwise healthy people, strategies that aim to
      prevent or limit expression of CCR5 should be beneficial in the treatment of HIV
      1 disease. To test this approach we have developed a CCR5-specific single-chain
      antibody that was expressed intracellularly and retained in the endoplasmic
      reticulum. This CCR5-intrabody efficiently blocked surface expression of human
      and rhesus CCR5 and thus prevented cellular interactions with CCR5-dependent HIV
      1 and simian immunodeficiency virus envelope glycoprotein. Intrabody-expressing
      cells were shown to be highly refractory to challenge with R5 HIV-1 viruses or
      infected cells. These results suggest that gene therapy approaches that deliver
      this intracellular antibody could be of benefit to infected individuals. Because
      the antibody reacts with a conserved primate epitope on CCR5 this strategy can be
      tested in nonhuman lentivirus models of HIV-1 disease.

PMID- 10639162
TI  - Cationic microparticles: A potent delivery system for DNA vaccines.
AB  - An approach involving the preparation of biodegradable microparticles with a
      cationic surface was developed to improve the delivery of adsorbed DNA into
      antigen-presenting cells after i.m. injection. The microparticles released intact
      and functional DNA over 2 weeks in vitro. In addition, the microparticles induced
      higher levels of marker gene expression in vivo. After i.m. immunization, the
      microparticles induced significantly enhanced serum antibody responses in
      comparison to naked DNA. Moreover, the level of antibodies induced by the
      microparticles was significantly enhanced by the addition of a vaccine adjuvant,
      aluminum phosphate. In addition, in contrast to naked DNA, the cationic
      microparticles induced potent cytotoxic T lymphocyte responses at a low dose.

PMID- 10639163
TI  - ABCG1 (ABC8), the human homolog of the Drosophila white gene, is a regulator of
      macrophage cholesterol and phospholipid transport.
AB  - Excessive uptake of atherogenic lipoproteins such as modified low-density
      lipoprotein complexes by vascular macrophages leads to foam cell formation, a
      critical step in atherogenesis. Cholesterol efflux mediated by high-density
      lipoproteins (HDL) constitutes a protective mechanism against macrophage lipid
      overloading. The molecular mechanisms underlying this reverse cholesterol
      transport process are currently not fully understood. To identify effector
      proteins that are involved in macrophage lipid uptake and release, we searched
      for genes that are regulated during lipid influx and efflux in human macrophages
      using a differential display approach. We report here that the ATP-binding
      cassette (ABC) transporter ABCG1 (ABC8) is induced in monocyte-derived
      macrophages during cholesterol influx mediated by acetylated low-density
      lipoprotein. Conversely, lipid efflux in cholesterol-laden macrophages, mediated
      by the cholesterol acceptor HDL(3), suppresses the expression of ABCG1.
      Immunocytochemical and flow cytometric analyses revealed that ABCG1 is expressed
      on the cell surface and in intracellular compartments of cholesterol-laden
      macrophages. Inhibition of ABCG1 protein expression using an antisense strategy
      resulted in reduced HDL(3)-dependent efflux of cholesterol and choline
      phospholipids. In a comprehensive analysis of the expression and regulation of
      all currently known human ABC transporters, we identified an additional set of
      ABC genes whose expression is regulated by cholesterol uptake or HDL(3)-mediated
      lipid release, suggesting a potential function for these transporters in
      macrophage lipid homeostasis. Our results demonstrating a regulator function for
      ABCG1 in cholesterol and phospholipid transport define a biologic activity for
      ABC transporters in macrophages.

PMID- 10639164
TI  - An in vivo approach showing the chemotactic activity of leukotriene B(4) in acute
      renal ischemic-reperfusion injury.
AB  - Neutrophil migration protects the body against foreign invasion. Sequestration
      and activation of neutrophils, however, require stringent regulation because they
      may also cause tissue damage by the release of lysosomal enzymes and reactive
      oxygen species. The activity of various chemoattractants [e.g., leukotriene B(4)
      (LTB(4)), interleukin-8, and complements] has been documented by in vitro assays,
      whereas in vivo data have been limited mostly to histology. To examine in an in
      vivo model the chemotactic activity and subsequent tissue infiltration and the
      role of a specific chemoattractant, LTB(4), we used a rat renal ischemia
      reperfusion injury model. Fluorescence-labeled Chinese hamster ovary (CHO) cells
      stably expressing the LTB(4) receptor (CHO-BLT) were able to accumulate along
      with neutrophils in the postischemic kidney, in contrast to vector control CHO
      cells. Furthermore, LTB(4) antagonists that protect against the decrease in renal
      function and diminish the tissue myeloperoxidase activity also led to the marked
      decrease in the number of CHO-BLT cells and neutrophils. Thus, LTB(4) alone
      appears sufficient to cause cells to migrate into postischemic tissues, and its
      dominant role in reperfusion injury has been demonstrated. The utilization of
      transfectants to pinpoint the role of LTB(4) in these in vivo experiments
      suggests their potential use with other ligands and/or in other pathological
      conditions.

PMID- 10639166
TI  - Extracellular protein kinase A as a cancer biomarker: its expression by tumor
      cells and reversal by a myristate-lacking Calpha and RIIbeta subunit
      overexpression.
AB  - Overexpression of cAMP-dependent protein kinase (PKA) type I isozyme is
      associated with cell proliferation and neoplastic transformation. The presence of
      PKA on the external surface of LS-174T human colon carcinoma cells has been
      shown. Here, we show that cancer cells of various cell types excrete PKA into the
      conditioned medium. This extracellular PKA (ECPKA) is present in active, free
      catalytic subunit (C subunit) form, and its activity is specifically inhibited by
      PKA inhibitory protein, PKI. Overexpression of the Calpha or RIalpha subunit gene
      of PKA in an expression vector, which up-regulates intracellular PKA type I,
      markedly up-regulates ECPKA expression. In contrast, overexpression of the
      RIIbeta subunit, which eliminates PKA type I, up-regulates PKA type II, and
      reverts the transformed phenotype, down-regulates ECPKA. A mutation in the Calpha
      gene that prevents myristylation allows the intracellular PKA up-regulation but
      blocks the ECPKA increase, suggesting that the NH(2)-terminal myristyl group of
      Calpha is required for the ECPKA expression. In serum of cancer patients, the
      ECPKA expression is up-regulated 10-fold as compared with normal serum. These
      results indicate that the ECPKA expression is an ordered cellular response of a
      living cell to actively exclude excess intracellular PKA molecules from the cell.
      This phenomenon is up-regulated in tumor cells and has an inverse relationship
      with the hormone dependency of breast cancer. Thus, the extracellular PKA may
      serve as a potential diagnostic and prognostic marker for cancer.

PMID- 10639165
TI  - Stability of cytotoxic luteinizing hormone-releasing hormone conjugate (AN-152)
      containing doxorubicin 14-O-hemiglutarate in mouse and human serum in vitro:
      implications for the design of preclinical studies.
AB  - Recently, we developed a series of cytotoxic peptide conjugates containing 14-O
      glutaryl esters of doxorubicin (DOX) or 2-pyrrolino-DOX (AN-201). Serum
      carboxylesterase enzymes (CE) can partially hydrolyze these conjugates in the
      circulation, releasing the cytotoxic radical, before the targeting is complete.
      CE activity in serum of nude mice is about 10 times higher than in human serum.
      Thus, we found that the t(1/2) of AN-152, an analog of luteinizing hormone
      releasing hormone (LH-RH) containing DOX, at 0.3 mg/ml is 19. 49 +/- 0.74 min in
      mouse serum and 126.06 +/- 3.03 min in human serum in vitro. The addition of a CE
      inhibitor, diisopropyl fluorophosphate (DFP), to mouse serum in vitro
      significantly (P < 0. 01) prolongs the t(1/2) of AN-152 to 69.63 +/- 4.44 min.
      When DFP is used in vivo, 400 nmol/kg cytotoxic somatostatin analog AN-238
      containing AN-201 is well tolerated by mice, whereas all animals die after the
      same dose without DFP. In contrast, DFP has no effect on the tolerance of AN-201.
      A better tolerance to AN-238 after DFP treatment is due to the selective uptake
      of AN-238 by somatostatin receptor-positive tissues. Our results demonstrate that
      the suppression of the CE activity in nude mice greatly decreases the toxicity of
      cytotoxic hybrids containing 2-pyrrolino-DOX 14-O-hemiglutarate and brings this
      animal model closer to the conditions that exist in humans. The use of DFP
      together with these peptide conjugates in nude mice permits a better
      understanding of their mechanism of action and improves the clinical
      predictability of the oncological and toxicological results.

PMID- 10639167
TI  - Aortic wall damage in mice unable to synthesize ascorbic acid.
AB  - By inactivating the gene for L-gulono-gamma-lactone oxidase, a key enzyme in
      ascorbic acid synthesis, we have generated mice that, like humans, depend on
      dietary vitamin C. Regular chow, containing about 110 mg/kg of vitamin C, is
      unable to support the growth of the mutant mice, which require L-ascorbic acid
      supplemented in their drinking water (330 mg/liter). Upon withdrawal of
      supplementation, plasma and tissue ascorbic acid levels decreased to 10-15% of
      normal within 2 weeks, and after 5 weeks the mutants became anemic, began to lose
      weight, and die. Plasma total antioxidative capacities were approximately 37%
      normal in homozygotes after feeding the unsupplemented diet for 3-5 weeks. As
      plasma ascorbic acid decreased, small, but significant, increases in total
      cholesterol and decreases in high density lipoprotein cholesterol were observed.
      The most striking effects of the marginal dietary vitamin C were alterations in
      the wall of aorta, evidenced by the disruption of elastic laminae, smooth muscle
      cell proliferation, and focal endothelial desquamation of the luminal surface.
      Thus, marginal vitamin C deficiency affects the vascular integrity of mice unable
      to synthesize ascorbic acid, with potentially profound effects on the
      pathogenesis of vascular diseases. Breeding the vitamin C-dependent mice with
      mice carrying defined genetic mutations will provide numerous opportunities for
      systematic studies of the role of antioxidants in health and disease.

PMID- 10639168
TI  - Rapid antibody responses by low-dose, single-step, dendritic cell-targeted
      immunization.
AB  - We have compared the kinetics of antibody responses in conventional and dendritic
      cell-targeted immunization by using a model antigen in mice. Targeting was
      achieved by linking the reporter antigen (polyclonal goat anti-hamster antibody)
      to N418, a hamster mAb that binds to the CD11c molecule on the surface of murine
      dendritic cells. Intradermal injection of submicrogram quantities of goat anti
      hamster antibody complexed to mAb N418 elicited goat antibody-specific serum IgG
      in mice. Antigen-specific IgG titers were detectable by day 5, with titers that
      ranged from 1:1000 to 1:100,000 by day 7. In contrast, when the goat antigen was
      injected alone or in the presence of a hamster antibody control to form
      nontargeted complexes, goat-specific serum IgG was undetectable at day 7.
      Additional control experiments showed that the interaction between the model
      antigen and mAb N418 is required for amplification of the serum antibody
      response. These studies demonstrate that a single-step, facilitated-delivery of
      small amounts of protein antigen to dendritic cells in vivo can give very rapid
      and high antibody responses. The approach may be particularly useful for
      vaccination immediately before or just after exposure to a pathogen and may
      enhance the utility of subunit antigens as immunogens.

PMID- 10639169
TI  - Specific chromosome 1 breaks induced by human cytomegalovirus.
AB  - Human cytomegalovirus (HCMV) is the major viral cause of birth defects and a
      serious problem for immunocompromised individuals. Here we show that infection of
      cells with HCMV during the S-phase of the cell cycle results in two specific
      chromosome 1 breaks at positions 1q42 and 1q21. We demonstrate that purified
      virions, and not infected cell supernatant alone, are responsible for the damage.
      In addition, we show that the specific breaks occur when different sources of
      fibroblasts and strains of HCMV are used. Incubation of the virus with
      neutralizing antibody prevents the induction of breaks. However, UV-inactivated
      virus is as efficient as untreated virus in inducing specific damage to
      chromosome 1. Thus, there is a requirement for viral adsorption/penetration, but
      not new viral gene expression. This HCMV-mediated induction of site-specific
      damage in actively dividing cells may provide clues for the development of
      neurological defects in the congenitally infected infant.

PMID- 10639170
TI  - Genetic analysis of a bacterial genetic exchange element: the gene transfer agent
      of Rhodobacter capsulatus.
AB  - An unusual system of genetic exchange exists in the purple nonsulfur bacterium
      Rhodobacter capsulatus. DNA transmission is mediated by a small bacteriophage
      like particle called the gene transfer agent (GTA) that transfers random 4.5-kb
      segments of the producing cell's genome to recipient cells, where allelic
      replacement occurs. This paper presents the results of gene cloning, analysis,
      and mutagenesis experiments that show that GTA resembles a defective prophage
      related to bacteriophages from diverse genera of bacteria, which has been adopted
      by R. capsulatus for genetic exchange. A pair of cellular proteins, CckA and
      CtrA, appear to constitute part of a sensor kinase/response regulator signaling
      pathway that is required for expression of GTA structural genes. This signaling
      pathway controls growth-phase-dependent regulation of GTA gene messages, yielding
      maximal gene expression in the stationary phase. We suggest that GTA is an
      ancient prophage remnant that has evolved in concert with the bacterial genome,
      resulting in a genetic exchange process controlled by the bacterial cell.

PMID- 10639171
TI  - Loss of BETA2/NeuroD leads to malformation of the dentate gyrus and epilepsy.
AB  - BETA2/NeuroD is a homologue of the Drosophila atonal gene that is widely
      expressed during development in the mammalian brain and pancreas. Although
      studies in Xenopus suggest that BETA2/NeuroD is involved in cellular
      differentiation, its function in the mammalian nervous system is unclear. Here we
      show that mutant mice homozygous for a deletion at the BETA2/NeuroD locus fail to
      develop a granule cell layer within the dentate gyrus, one of the principal
      structures of the hippocampal formation. To understand the basis of this
      abnormality, we analyzed dentate gyrus development by using immunocytochemical
      markers in BETA2/NeuroD-deficient mice. The early cell populations in the dentate
      gyrus, including Cajal-Retzius cells and radial glia, are present and appear
      normally organized. The migration of dentate precursor cells and newly born
      granule cells from the neuroepithelium to the dentate gyrus remains intact.
      However, there is a dramatic defect in the proliferation of precursor cells once
      they reach the dentate and a significant delay in the differentiation of granule
      cells. This leads to malformation of the dentate granule cell layer and excess
      cell death. BETA2/NeuroD null mice also exhibit spontaneous limbic seizures
      associated with electrophysiological evidence of seizure activity in the
      hippocampus and cortex. These findings thus establish a critical role of
      BETA2/NeuroD in the development of a specific class of neurons. Furthermore,
      failure to express BETA2/NeuroD leads to a stereotyped pattern of pathological
      excitability of the adult central nervous system.

PMID- 10639172
TI  - ATM is a cytoplasmic protein in mouse brain required to prevent lysosomal
      accumulation.
AB  - We previously generated a mouse model with a mutation in the murine Atm gene that
      recapitulates many aspects of the childhood neurodegenerative disease ataxia
      telangiectasia. Atm-deficient (Atm-/-) mice show neurological defects detected by
      motor function tests including the rota-rod, open-field tests and hind-paw
      footprint analysis. However, no gross histological abnormalities have been
      observed consistently in the cerebellum of any line of Atm-/- mice analyzed in
      most laboratories. Therefore, it may be that the neurologic dysfunction found in
      these animals is associated with predegenerative lesions. We performed a detailed
      analysis of the cerebellar morphology in two independently generated lines of Atm
      /- mice to determine whether there was evidence of neuronal abnormality. We found
      a significant increase in the number of lysosomes in Atm-/- mice in the absence
      of any detectable signs of neuronal degeneration or other ultrastructural
      anomalies. In addition, we found that the ATM protein is predominantly
      cytoplasmic in Purkinje cells and other neurons, in contrast to the nuclear
      localization of ATM protein observed in cultured cells. The cytoplasmic
      localization of ATM in Purkinje cells is similar to that found in human
      cerebellum. These findings suggest that ATM may be important as a cytoplasmic
      protein in neurons and that its absence leads to abnormalities of cytoplasmic
      organelles reflected as an increase in lysosomal numbers.

PMID- 10639173
TI  - Direct evidence for local oscillatory current sources and intracortical phase
      gradients in turtle visual cortex.
AB  - Visual stimuli induce oscillations in the membrane potential of neurons in
      cortices of several species. In turtle, these oscillations take the form of
      linear and circular traveling waves. Such waves may be a consequence of a
      pacemaker that emits periodic pulses of excitation that propagate across a
      network of excitable neuronal tissue or may result from continuous and possibly
      reconfigurable phase shifts along a network with multiple weakly coupled neuronal
      oscillators. As a means to resolve the origin of wave propagation in turtle
      visual cortex, we performed simultaneous measurements of the local field
      potential at a series of depths throughout this cortex. Measurements along a
      single radial penetration revealed the presence of broadband current sources,
      with a center frequency near 20 Hz (gamma band), that were activated by visual
      stimulation. The spectral coherence between sources at two well-separated loci
      along a rostral-caudal axis revealed the presence of systematic timing
      differences between localized cortical oscillators. These multiple oscillating
      current sources and their timing differences in a tangential plane are
      interpreted as the neuronal activity that underlies the wave motion revealed in
      previous imaging studies. The present data provide direct evidence for the
      inference from imaging of bidirectional wave motion that the stimulus-induced
      electrical waves in turtle visual cortex correspond to phase shifts in a network
      of coupled neuronal oscillators.

PMID- 10639174
TI  - Kinetics of exocytosis and endocytosis at the cochlear inner hair cell afferent
      synapse of the mouse.
AB  - Hearing in mammals relies on the highly synchronous synaptic transfer between
      cochlear inner hair cells (IHCs) and the auditory nerve. We studied the
      presynaptic function of single mouse IHCs by monitoring membrane capacitance
      changes and voltage-gated Ca(2+) currents. Exocytosis initially occurred at a
      high rate but then slowed down within a few milliseconds, despite nearly constant
      Ca(2+) influx. We interpret the observed secretory depression as depletion of a
      readily releasable pool (RRP) of about 280 vesicles. These vesicles are probably
      docked close to Ca(2+) channels at the ribbon-type active zones of the IHCs.
      Continued depolarization evoked slower exocytosis occurring at a nearly constant
      rate for at least 1 s and depending on "long-distance" Ca(2+) signaling.
      Refilling of the RRP after depletion followed a biphasic time course and was
      faster than endocytosis. RRP depletion is discussed as a mechanism for fast
      auditory adaptation.

PMID- 10639175
TI  - Atm and Bax cooperate in ionizing radiation-induced apoptosis in the central
      nervous system.
AB  - Ataxia-telangiectasia is a hereditary multisystemic disease resulting from
      mutations of ataxia telangiectasia, mutated (ATM) and is characterized by
      neurodegeneration, cancer, immune defects, and hypersensitivity to ionizing
      radiation. The molecular details of ATM function in the nervous system are
      unclear, although the neurological lesion in ataxia-telangiectasia becomes
      apparent early in life, suggesting a developmental origin. The central nervous
      system (CNS) of Atm-null mice shows a pronounced defect in apoptosis induced by
      genotoxic stress, suggesting ATM functions to eliminate neurons with excessive
      genomic damage. Here, we report that the death effector Bax is required for a
      large proportion of Atm-dependent apoptosis in the developing CNS after ionizing
      radiation (IR). Although many of the same regions of the CNS in both Bax-/- and
      Atm-/- mice were radioresistant, mice nullizygous for both Bax and Atm showed
      additional reduction in IR-induced apoptosis in the CNS. Therefore, although the
      major IR-induced apoptotic pathway in the CNS requires Atm and Bax, a p53
      dependent collateral pathway exists that has both Atm- and Bax-independent
      branches. Further, Atm- and Bax-dependent apoptosis in the CNS also required
      caspase-3 activation. These data implicate Bax and caspase-3 as death effectors
      in neurodegenerative pathways.

PMID- 10639176
TI  - Constraining the subunit order of rod cyclic nucleotide-gated channels reveals a
      diagonal arrangement of like subunits.
AB  - Retinal rod cyclic nucleotide-gated channels are composed of alpha and beta
      subunits. We have explored possible subunit arrangements by expressing tandemly
      linked dimers of both subunits and examining their responses to three different
      modulating agents. Channels formed from either alpha-beta or beta-alpha
      heterodimers had functional properties similar to those formed from coexpressed
      alpha and beta monomers and to native channels. These results point to an alpha
      beta-alpha-beta arrangement. To ensure that heterodimers had not flipped around,
      we coexpressed alpha-alpha dimers with an excess of either beta monomers or beta
      beta dimers. Our data indicate that heteromultimers do not form efficiently in an
      alpha-alpha-beta-beta arrangement. Thus, we propose that native rod cyclic
      nucleotide-gated channels are arranged with like subunits diagonally opposed:
      alpha-beta-alpha-beta.

PMID- 10639177
TI  - Dynamics of dendritic calcium transients evoked by quantal release at excitatory
      hippocampal synapses.
AB  - Synaptic N-methyl-D-aspartate (NMDA) receptors detect coincident pre- and
      postsynaptic activity and play a critical role in triggering changes in synaptic
      strength at central synapses. Despite intensive study of synaptic plasticity,
      relatively little is known about the magnitude and duration of calcium
      accumulation caused by unitary events at individual synapses. We used
      fluorescence imaging to detect NMDA receptor-mediated miniature synaptic calcium
      transients (MSCTs) caused by spontaneous release of synaptic vesicles in
      dendrites of cultured hippocampal neurons. MSCTs originated focally in dendritic
      regions <1 microm in length and decayed with a time constant of 0.35 +/- 0.03 s.
      Multiple occurrences of MSCTs recorded at single sites had fluctuating
      amplitudes, with a coefficient of variation of 0.34. From the reduction in the
      spatial spread of MSCTs with decreasing concentration of indicator dye, we
      estimated that the dominant endogenous calcium buffer in dendrites is relatively
      immobile (diffusion coefficient between 10 and 50 microm(2)/s). We conclude that
      calcium rise caused by spontaneous quantal synaptic NMDA receptor activation (i)
      is variable, (ii) lasts for a time period briefer than previous measurements
      indicate, and (iii) is confined by endogenous calcium buffers to local dendritic
      regions even when synapses are not on spines.

PMID- 10639178
TI  - Effect of G protein heterotrimer composition on coupling of neurotransmitter
      receptors to N-type Ca(2+) channel modulation in sympathetic neurons.
AB  - Voltage-dependent (VD) inhibition of N-type Ca(2+) channels is mediated primarily
      by neurotransmitter receptors that couple to pertussis toxin (PTX)-sensitive G
      proteins (such as G(o) and G(i)). To date, however, the composition of
      heterotrimeric complexes, i.e., specific Galphabetagamma combinations, capable of
      coupling receptors to N-type Ca(2+) channels has not been defined. We addressed
      this question by heterologously expressing identified Galphabetagamma
      combinations in PTX-treated rat sympathetic neurons and testing for
      reconstitution of agonist-mediated VD inhibition. The heterologously expressed
      Galpha subunits were rendered PTX-insensitive by mutating the codon specifying
      the ADP ribosylation site. The following results were obtained from this
      approach. (i) Expression of Galpha(oA), Galpha(oB), and Galpha(i2) (along with
      Gbeta(1)gamma(2)) reconstituted VD inhibition mediated by alpha(2)-adrenergic,
      adenosine, somatostatin, and prostaglandin E(2) receptors. Conversely, expression
      of Galpha(i1) and Galpha(i3) was ineffective at restoring coupling. (ii) Coupling
      efficiency, as determined from the magnitude of reconstituted Ca(2+) current
      inhibition, depended on both the receptor and Galpha subtype. The following rank
      order of coupling efficiency was observed: Galpha(oA) = Galpha(oB) > Galpha(i2)
      for alpha(2)-adrenergic receptor; Galpha(i2) > Galpha(oA) = Galpha(oB) for
      adenosine and prostaglandin E(2) receptors; and Galpha(oB) = Galpha(i2) >
      Galpha(oA) for the somatostatin receptor. (iii) In general, varying the
      Gbetagamma composition of Galpha(oA)-containing heterotrimers had little effect
      on the coupling of alpha(2)-adrenergic receptors to the VD pathway. Taken
      together, these results suggest that multiple, diverse Galphabetagamma
      combinations are capable of coupling neurotransmitter receptors to VD inhibition
      of N-type Ca(2+) channels. Thus, if exquisite Galphabetagamma-coupling
      specificity exists in situ, it cannot arise solely from the inherent inability of
      other Galphabetagamma combinations to form functional signaling complexes.

PMID- 10639179
TI  - Temporal dynamics of cortical representation for action.
AB  - Brain-imaging studies have shown that the human Broca's region and precentral
      motor cortex are activated both during execution of hand actions and during
      observation of similar actions performed by other individuals. We aimed to
      clarify the temporal dynamics of this cortical activation by neuromagnetic
      recordings during execution, on-line imitation, and observation of right-hand
      reaching movements that ended with a precision pinch of the tip of a
      manipulandum. During execution, the left inferior frontal cortex [Brodmann's area
      (BA) 44] was activated first (peak approximately 250 ms before the pinching);
      this activation was followed within 100-200 ms by activation in the left primary
      motor area (BA4) and 150-250 ms later in the right BA4. During imitation and
      observation, the sequence was otherwise similar, but it started from the left
      occipital cortex (BA19). Activation was always strongest during action imitation.
      Only the occipital activation was detected when the subject observed the
      experimenter reaching his hand without pinching. These results suggest that the
      left BA44 is the orchestrator of the human "mirror neuron system" and is strongly
      involved in action imitation. The mirror system matches action observation and
      execution and probably contributes to our understanding of actions made by
      others.

PMID- 10639180
TI  - Theta oscillations index human hippocampal activation during a working memory
      task.
AB  - Working memory (WM) is the ability to retain and associate information over brief
      time intervals. Functional imaging studies demonstrate that WM is mediated by a
      distributed network including frontal and posterior cortices, hippocampus, and
      cerebellum. In rodents, the presentation of stimuli in a WM task is followed by a
      reset of the phase of hippocampal theta. In this paper we report the observation
      of a similar phenomenon in normal human subjects. Neuromagnetic responses were
      recorded during presentation of a set of digits and a subsequent probe of the
      retained items. All stimuli were presented with a fixed temporal pattern. We
      observed phase reset of approximately 7 Hz theta in left hippocampus
      approximately 120 ms after probe stimuli, whereas reset of theta in right
      hippocampus was visible approximately 80 ms prior to these anticipated stimuli.
      The duration of stimulus-locked theta increased with memory load, with a limiting
      value of approximately 600 ms for 5-7 retained items. We suggest that, as in
      rats, stimulus-locked theta may index involvement of human hippocampal networks
      in the cognitive processing of sensory input. The anticipatory phase reset of
      theta indicates involvement of hippocampus in right hemisphere and cerebellar
      timing networks. Hippocampal structures are essential for orientation to
      perturbations in the sensory scene, a function that requires use of a context
      established by a constellation of stimuli. We suggest that the initiation and
      maintenance of stimulus-locked hippocampal theta observed here may facilitate
      processing of potentially salient and/or novel input with respect to a context
      established by the contents of WM.

PMID- 10639181
TI  - Biochemically based design of cyclooxygenase-2 (COX-2) inhibitors: facile
      conversion of nonsteroidal antiinflammatory drugs to potent and highly selective
      COX-2 inhibitors.
AB  - All nonsteroidal antiinflammatory drugs (NSAIDs) inhibit the cyclooxygenase (COX)
      isozymes to different extents, which accounts for their anti-inflammatory and
      analgesic activities and their gastrointestinal side effects. We have exploited
      biochemical differences between the two COX enzymes to identify a strategy for
      converting carboxylate-containing NSAIDs into selective COX-2 inhibitors.
      Derivatization of the carboxylate moiety in moderately selective COX-1
      inhibitors, such as 5,8,11,14-eicosatetraynoic acid (ETYA) and arylacetic and
      fenamic acid NSAIDs, exemplified by indomethacin and meclofenamic acid,
      respectively, generated potent and selective COX-2 inhibitors. In the
      indomethacin series, esters and primary and secondary amides are superior to
      tertiary amides as selective inhibitors. Only the amide derivatives of ETYA and
      meclofenamic acid inhibit COX-2; the esters are either inactive or nonselective.
      Inhibition kinetics reveal that indomethacin amides behave as slow, tight-binding
      inhibitors of COX-2 and that selectivity is a function of the time-dependent
      step. Site-directed mutagenesis of murine COX-2 indicates that the molecular
      basis for selectivity differs from the parent NSAIDs and from diarylheterocycles.
      Selectivity arises from novel interactions at the opening and at the apex of the
      substrate-binding site. Lead compounds in the present study are potent inhibitors
      of COX-2 activity in cultured inflammatory cells. Furthermore, indomethacin
      amides are orally active, nonulcerogenic, anti-inflammatory agents in an in vivo
      model of acute inflammation. Expansion of this approach can be envisioned for the
      modification of all carboxylic acid-containing NSAIDs into selective COX-2
      inhibitors.

PMID- 10639182
TI  - Overexpression of angiotensin II type I receptor in cardiomyocytes induces
      cardiac hypertrophy and remodeling.
AB  - Angiotensin II (AII) is a major determinant of arterial pressure and volume
      homeostasis, mainly because of its vascular action via the AII type 1 receptor
      (AT1R). AII has also been implicated in the development of cardiac hypertrophy
      because angiotensin I-converting enzyme inhibitors and AT1R antagonists prevent
      or regress ventricular hypertrophy in animal models and in human. However,
      because these treatments impede the action of AII at cardiac as well as vascular
      levels, and reduce blood pressure, it has been difficult to determine whether AII
      action on the heart is direct or a consequence of pressure-overload. To determine
      whether AII can induce cardiac hypertrophy directly via myocardial AT1R in the
      absence of vascular changes, transgenic mice overexpressing the human AT1R under
      the control of the mouse alpha-myosin heavy chain promoter were generated.
      Cardiomyocyte-specific overexpression of AT1R induced, in basal conditions,
      morphologic changes of myocytes and nonmyocytes that mimic those observed during
      the development of cardiac hypertrophy in human and in other mammals. These mice
      displayed significant cardiac hypertrophy and remodeling with increased
      expression of ventricular atrial natriuretic factor and interstitial collagen
      deposition and died prematurely of heart failure. Neither the systolic blood
      pressure nor the heart rate were changed. The data demonstrate a direct
      myocardial role for AII in the development of cardiac hypertrophy and failure and
      provide a useful model to elucidate the mechanisms of action of AII in the
      pathogenesis of cardiac diseases.

PMID- 10639183
TI  - Modulation of nucleotide sensitivity of ATP-sensitive potassium channels by
      phosphatidylinositol-4-phosphate 5-kinase.
AB  - ATP-sensitive potassium channels (K(ATP) channels) regulate cell excitability in
      response to metabolic changes. K(ATP) channels are formed as a complex of a
      sulfonylurea receptor (SURx), a member of the ATP-binding cassette protein
      family, and an inward rectifier K(+) channel subunit (Kir6.x). Membrane
      phospholipids, in particular phosphatidylinositol (PI) 4,5-bisphosphate (PIP(2)),
      activate K(ATP) channels and antagonize ATP inhibition of K(ATP) channels when
      applied to inside-out membrane patches. To examine the physiological relevance of
      this regulatory mechanism, we manipulated membrane PIP(2) levels by expressing
      either the wild-type or an inactive form of PI-4-phosphate 5-kinase (PIP5K) in
      COSm6 cells and examined the ATP sensitivity of coexpressed K(ATP) channels.
      Channels from cells expressing the wild-type PIP5K have a 6-fold lower ATP
      sensitivity (K(1/2), the half maximal inhibitory concentration, approximately 60
      microM) than the sensitivities from control cells (K(1/2) approximately 10
      microM). An inactive form of the PIP5K had little effect on the K(1/2) of wild
      type channels but increased the ATP-sensitivity of a mutant K(ATP) channel that
      has an intrinsically lower ATP sensitivity (from K(1/2) approximately 450 microM
      to K(1/2) approximately 100 microM), suggesting a decrease in membrane PIP(2)
      levels as a consequence of a dominant-negative effect of the inactive PIP5K.
      These results show that PIP5K activity, which regulates PIP(2) and PI-3,4,5-P(3)
      levels, is a significant determinant of the physiological nucleotide sensitivity
      of K(ATP) channels.

PMID- 10639184
TI  - Plant organ size control: AINTEGUMENTA regulates growth and cell numbers during
      organogenesis.
AB  - The control of cell proliferation during organogenesis plays an important role in
      initiation, growth, and acquisition of the intrinsic size of organs in higher
      plants. To understand the developmental mechanism that controls intrinsic organ
      size by regulating the number and extent of cell division during organogenesis,
      we examined the function of the Arabidopsis regulatory gene AINTEGUMENATA (ANT).
      Previous observations revealed that ANT regulates cell division in integuments
      during ovule development and is necessary for floral organ growth. Here we show
      that ANT controls plant organ cell number and organ size throughout shoot
      development. Loss of ANT function reduces the size of all lateral shoot organs by
      decreasing cell number. Conversely, gain of ANT function, via ectopic expression
      of a 35S::ANT transgene, enlarges embryonic and all shoot organs without altering
      superficial morphology by increasing cell number in both Arabidopsis and tobacco
      plants. This hyperplasia results from an extended period of cell proliferation
      and organ growth. Furthermore, cells ectopically expressing ANT in fully
      differentiated organs exhibit neoplastic activity by producing calli and
      adventitious roots and shoots. Based on these results, we propose that ANT
      regulates cell proliferation and organ growth by maintaining the meristematic
      competence of cells during organogenesis.

PMID- 10639186
TI  - PC-SPES: a unique inhibitor of proliferation of prostate cancer cells in vitro
      and in vivo .
AB  - BACKGROUND: Management of prostate cancer that has spread beyond the capsule is a
      difficult problem. Innovative and nontoxic approaches to the disease are urgently
      required. Recently, a commercially available herbal mixture called PC-SPES showed
      potent antitumor activities on a variety of malignant cells in vitro. METHODS: PC
      SPES was evaluated for its ability to inhibit clonal growth, and to induce cell
      cycle arrest of three human prostate cancer cell lines (LNCaP, PC-3, and DU 145).
      Western blot analysis examined the effect of PC-SPES on levels of p21(waf1),
      p27(kip1), Bcl-2, and E-cadherin in the three cell lines; and telomerase activity
      was examined by telomeric repeat amplification protocol (TRAP) assay.
      Furthermore, the effect of oral PC-SPES (250 mg/kg/day) on growth of PC-3 and DU
      145 tumors present in male BNX nu/nu triple immunodeficient mice was studied.
      LNCaP cells were not analyzed in mice because they grow only with difficulty in
      these immunodeficient mice. RESULTS: PC-SPES markedly inhibited clonal growth of
      LNCaP, PC-3, and DU 145 prostate cancer cells, with a 50% inhibition (ED50) at
      approximately 2 microl/ml. Pulse-exposure studies showed that a 5-day pulse
      exposure to PC-SPES (2 microl/ml) in liquid culture achieved a 50% inhibition of
      PC-3 clonal growth in soft agar, suggesting that the growth inhibition mediated
      by the extracts remained after removal of PC-SPES. Cell cycle analysis using the
      prostate cancer cell lines found that PC-SPES induced a significant increase in
      the number of cells in G0-G1 and G2/M, with a concomitant decrease in the number
      of cells in S phase. PC-SPES (2 microl/ml, 4 days) increased slightly the levels
      of p21(waf1) in the three cell lines, decreased by 40% the levels of Bcl-2 in PC
      3, and the levels of p27(kip1) and E-cadherin and telomerase were unchanged in
      each of the lines. In vivo treatment with oral PC-SPES of male BNX mice having DU
      145 tumors produced significant inhibition of their growth (P < 0.001), with no
      objective side effects including blood chemistries, weights, or autopsy analysis.
      The PC-SPES showed no statistical effect on the in vivo growth of PC-3 cells.
      CONCLUSIONS: PC-SPES inhibits clonal proliferation of human prostate cancer cells
      both in vitro and in vivo, using a murine model.

PMID- 10639185
TI  - An Arabidopsis histone H2A mutant is deficient in Agrobacterium T-DNA
      integration.
AB  - Agrobacterium tumefaciens genetically transforms plant cells by transferring a
      portion of the bacterial Ti-plasmid, the T-DNA, to the plant and integrating the
      T-DNA into the plant genome. Little is known about the T-DNA integration process,
      and no plant genes involved in integration have yet been identified. We
      characterized an Arabidopsis mutant generated by T-DNA insertional mutagenesis,
      rat5, that is resistant to Agrobacterium root transformation. rat5 contains two
      copies of T-DNA integrated as a tandem direct repeat into the 3' untranslated
      region of a histone H2A gene, upstream of the polyadenylation signal sequence.
      Transient and stable beta-glucuronidase expression data and assessment of the
      amount of T-DNA integrated into the genomes of wild-type and rat5 Arabidopsis
      plants indicated that the rat5 mutant is deficient in T-DNA integration. We
      complemented the rat5 mutation by expressing the RAT5 histone H2A gene in the
      mutant plant. Overexpression of RAT5 in wild-type plants increased Agrobacterium
      transformation efficiency. Furthermore, transient expression of a RAT5 gene from
      the incoming T-DNA was sufficient to complement the rat5 mutant and to increase
      the transformation efficiency of wild-type Arabidopsis plants.

PMID- 10639187
TI  - Contrasting effects of aspirin on prostate cancer cells: suppression of
      proliferation and induction of drug resistance .
AB  - BACKGROUND: Aspirin is widely used as a preventive measure against occlusive
      vascular diseases. Since the age group in which aspirin use has become prevalent
      is similar to the one presenting with prostate cancer, we decided to examine the
      potential effects of aspirin on prostate cancer. METHODS: We studied the effects
      of plasma-attainable concentrations of aspirin (0.5-2 mM) on the human prostate
      cancer cell lines LNCaP, PC-3, and DU 145, employing cytotoxicity assays and flow
      cytometric analyses. RESULTS: Incubation with aspirin for 3 days reduced cellular
      proliferation by up to 35-55% in each cell line studied, but induced a tripling
      of the percentage of cells expressing P-glycoprotein (an efflux pump conferring
      multidrug resistance) only in the LNCaP cells. Both effects were dose-dependent.
      The effect on P-glycoprotein expression was reflected in the induction of
      resistance against adriamycin cytotoxicity. Furthermore, this protective effect
      of aspirin was reversed by a specific P-glycoprotein inhibitor, PSC833. The
      cellular expression of P-glycoprotein returned to normal within 3 days following
      the removal of aspirin. Aspirin did not affect the cell cycle distribution of
      LNCaP cells. CONCLUSIONS: This study suggests that aspirin enhances the ability
      of androgen-responsive prostate cancer cells to resist chemotherapeutic drugs.
      These findings could potentially have significant clinical ramifications for
      prostate cancer patients taking aspirin shortly before or during chemotherapeutic
      sessions.

PMID- 10639188
TI  - Measurement of complexed PSA in the differential diagnosis between prostate
      cancer and benign prostate hyperplasia .
AB  - BACKGROUND: To enhance the specificity of PSA in diagnosis of cancer, several
      approaches have been evaluated, having in common the study of fractions of PSA.
      The aim of this study was to evaluate the usefulness of complexed PSA in the
      differential diagnosis between benign prostate hyperplasia (BPH) and prostate
      cancer. METHODS: We determined the concentrations of complexed PSA (Bayer,
      Tarrytown, NY) and total PSA (Tandem-R Assay, Hybritech Incorporated, San Diego,
      CA) in 196 patients with BPH and in 55 patients with prostate cancer. Likewise,
      the percentage of free PSA (Wallac, Turku, Finland) was determined for 124 of
      these patients. RESULTS: The specificity of complexed PSA was found to be greater
      than that of total PSA for the cutoff values corresponding to sensitivities of
      80%, 85%, and 90%. Similarly, the area under the curve obtained by receiver
      operating curve analysis was greater for complexed PSA than for total PSA,
      although significant differences were not observed. The diagnostic usefulness of
      complexed PSA in the differential diagnosis between BPH and prostate cancer was
      found to be lower than the percentage of free PSA. CONCLUSIONS: We believe that
      differential diagnosis with complexed PSA between BPH and prostate cancer is of
      little use, due to low efficacy when PSA results are extreme.

PMID- 10639189
TI  - STAT3 mediates IL-6-induced neuroendocrine differentiation in prostate cancer
      cells .
AB  - BACKGROUND: In the human prostate cancer cell line LNCaP, interleukin (IL)-6 has
      been shown to regulate both growth and neuroendocrine (NE) differentiation. We
      recently observed that IL-6 mediated growth arrest in LNCaP by activating STAT 3.
      Since differentiation and growth arrest are often associated processes, we
      investigated whether STAT3 also mediated NE differentiation in this prostate
      cancer cell line. METHODS: We treated previously characterized clones LNCaP-neo
      (neomycin-resistant LNCaP) and LNCaP-SF (LNCaP-STAT3 dominant negative mutant)
      with IL-6 and screened for NE differentiation by observing morphological changes
      and immunoblotting for two NE markers, neuron-specific enolase (NSE) and
      chromogranin A (ChA). To characterize further the role of STAT3 in growth arrest
      and differentiation, we transfected a wild-type STAT3 vector into PC-3 cells and
      generated a subclone PC-3-S3. In this clone, we assessed differentiation by
      observing morphological changes and determined growth responses by cell counting
      and clonogenic assays. RESULTS: We observed that IL-6 induced formation of
      neurite extensions, morphologic features associated with NE differentiation, and
      enhanced expression of neuronal markers ChA and NSE in LNCaP-neo cells. In
      contrast, LNCaP-SF, possessing a dominant negative mutant form of STAT3,
      exhibited no characteristics of IL-6 induced NE differentiation. Furthermore,
      expression of a constitutively phosphorylated wild-type STAT3 in PC-3 cells
      inhibited growth and induced the formation of neurite extensions and NSE
      expression. CONCLUSIONS: These results indicate that STAT3 is a mediator of both
      NE differentiation and growth inhibition in LNCaP and PC-3, suggesting a
      connection between growth inhibition and NE differentiation in prostate cancer.

PMID- 10639190
TI  - Mitochondrial aconitase gene expression is regulated by testosterone and
      prolactin in prostate epithelial cells .
AB  - BACKGROUND: m-aconitase catalyzes the first step leading to the oxidation of
      citrate via the Krebs cycle. It is a constituitive enzyme in virtually all
      mammalian cells, found in excess, and is considered to be a regulatory or
      regulated enzyme. In contrast to these general relationships, prostate secretory
      epithelial cells possess a uniquely limiting mitochondrial (m-) aconitase which
      minimizes the oxidation of citrate. This permits the unique prostate function of
      accumulating and secreting extraordinarily high levels of citrate. Previous
      animal studies demonstrated that testosterone and prolactin regulate the level of
      m-aconitase specifically in citrate-producing prostate cells. The present studies
      were conducted to determine if testosterone and prolactin regulated the
      expression of the m-aconitase gene in prostate cells, and to determine the effect
      of the hormones on human prostate cells. METHODS: The studies were conducted with
      freshly prepared rat ventral, rat lateral, and pig prostate epithelial cells, and
      with the human malignant cell lines LNCaP and PC-3. The effects of 1 nM
      testosterone and 3 nM prolactin on the level of m-aconitase mRNA and on the
      transcription rate of m-aconitase were determined. RESULTS: The studies revealed
      that both prolactin and testosterone increase the levels of m-aconitase mRNA and
      the transcription rates of m-aconitase in rat ventral prostate cells, pig
      prostate cells, and human malignant prostate cells (LNCaP and PC-3). In contrast,
      both hormones decreased the level of m-aconitase mRNA and repressed m-aconitase
      gene transcription in rat lateral prostate cells. The hormonal regulation of m
      aconitase corresponded with the levels of m-aconitase enzyme, m-aconitase
      activity, and citrate oxidation. CONCLUSIONS: In addition to the constitutive
      expression of m-aconitase, the m-aconitase gene is testosterone- and prolactin
      regulated in specifically targeted prostate cells. The hormonal regulation of m
      aconitase gene expression and biosynthesis of m-aconitase provide a regulatory
      mechanism for the oxidation of citrate, and consequently, the level of net
      citrate production by prostate. The hormonally increased expression and
      biosynthesis of m-aconitase in human malignant cells might be involved in the
      increased citrate oxidation associated with the development of true malignant
      cells in prostate cancer.

PMID- 10639191
TI  - Prostatic involution in men taking finasteride is associated with elevated levels
      of insulin-like growth factor-binding proteins (IGFBPs)-2, -4, and -5 .
AB  - BACKGROUND: Insulin-like growth factor-binding proteins (IGFBPs)-2, -4, and -5
      are associated with upregulation of apoptosis in the ovary. The purpose of this
      study was to assess the roles of IGF-I and IGFBPs during involution of the
      prostate. Frozen and fixed tissue was collected by transurethral prostatectomy
      from Caucasian men, aged 52-82 years, scheduled for prostatectomy for benign
      prostatic hyperplasia, who took either placebo (n = 7) or the 5alpha-reductase
      inhibitor finasteride for 6 days to 6 years (n = 15) prior to surgery. METHODS:
      Intraprostatic androgen levels were measured by radioimmunoassay. Tissues were
      immunostained for IGF-I and IGFBP-2, -3, -4, and -5, and staining was quantitated
      by computerized image analysis. Serial sections were stained for markers of
      apoptosis (TUNEL and tissue transglutaminase) and IGFBP-2, -4, or -5. RESULTS:
      IGF-I staining was significantly decreased in the medium-term (18-43 days)
      treatment group and remained so for the duration of the study (P = 0.026). IGFBP
      3 staining was unchanged in the early and medium-term treatment groups; however,
      a transient earlier rise in the level of this proapoptotic protein cannot be
      ruled out. The percentage of epithelial cell area staining positively for IGFBP-2
      increased significantly, from 1.6 +/- 0.5 in the placebo group to 12.0 +/- 2.0 (P
      < 0.0001), and 7.6 +/- 1.9 (P = 0.003) in the short (6-13 days) and medium-term
      treatment groups, respectively. IGFBP-4 staining increased from 2.2 +/- 0.6 to
      9.8 +/- 1.9 (P < 0.0001) and 7.4 +/- 1.2 (P = 0.004) in the short and medium-term
      groups, respectively, and IGFBP-5 staining increased from 0.2 +/- 0.1 to 3.8 +/-
      2.0 (P = 0.004) in the medium-term group. The results from serial sections showed
      that IGFBP-2 and -4 costained with markers of apoptosis, while IGFBP-5 did not.
      CONCLUSIONS: These results indicate that IGFBP-2, -4, and -5 are associated with
      prostatic involution. Because of the timing and distribution of expression, we
      hypothesize that IGFBP-2 and -4 have a role as signals for apoptosis, but that
      IGFBP-5 likely does not.

PMID- 10639192
TI  - Crystal structure of human prostatic acid phosphatase .
AB  - BACKGROUND: Prostatic acid phosphatase (hPAP) is a major product of the human
      prostate gland, yet its physiological substrate remains unknown. METHODS: Human
      PAP, purified from semen, was crystallized using polyethylene glycol as the
      precipitant and its crystal structure was determined using X-ray diffraction. The
      structure was refined at 3.1 A resolution to R = 16% and R(free) = 27%. RESULTS:
      The structure of hPAP is similar to that of other known histidine phosphatases,
      and the positions of its catalytic residues are conserved. N-linked carbohydrates
      are present at each of the possible glycosylation sites. It appears that high
      mannose chains are attached to Asn 62 and Asp 301, while complex chains are at
      Asn 188. CONCLUSIONS: The similarity of the three-dimensional structures of rat
      PAP and human PAP indicates that the mechanistic analyses of the catalytic
      mechanism proposed for the rat enzyme should be extended to the human enzyme
      without reservations. The crystallographic data allowed the correlation of
      attachment sites of N-linked carbohydrate chains with a given carbohydrate type.
      The carbohydrates of the protein produced in the prostate cells and in the
      baculovirus expression system appear to differ at the site of complex
      carbohydrates attachment.

PMID- 10639193
TI  - PSP94 (or beta-microseminoprotein) is a secretory protein specifically expressed
      and synthesized in the lateral lobe of the rat prostate .
AB  - BACKGROUND: Prostatic secretory protein of 94 amino acids (PSP94), also called
      beta-microseminoprotein, is a small, nonglycosylated protein, rich in cysteine
      residues. It was first isolated as a major protein from human seminal plasma.
      Subsequently, its homologous proteins were identified, and their cDNAs or genes
      have been cloned in primates, pigs, and rodents. METHODS: The present study
      investigated the expression pattern of PSP94 in the normal Noble rat prostate
      gland by nonradioactive in situ hybridization, Northern blotting, RT-PCR, Western
      blotting, and immunohistochemistry. Its expression in the mouse prostate gland
      was also examined by in situ hybridization. RESULTS: The results of in situ
      hybridization, and Northern and Western blot analyses, showed that the expression
      of rat PSP94 was prostate-specific. It was highly expressed in the lateral
      prostatic lobe, moderate in the dorsal lobe, weak in the coagulating gland, and
      negative in the ventral lobe and seminal vesicle. Its specific expression in the
      rat prostate gland was further confirmed by RT-PCR analysis of prostatic and
      nonprostatic organ tissues. Its mRNA transcripts were not detected in the
      urinary, digestive, and respiratory tracts, male and female reproductive organs,
      muscles, brain, and kidney. Its molecular mass was estimated to be 14.5 kDa by
      Western blotting. Similar prostate-specific expression of PSP94 was also observed
      by in situ hybridization in the lateral lobe, but not in the dorsal and ventral
      lobe, of the mouse prostate gland. CONCLUSIONS: Rat PSP94 is a major secretory
      protein highly expressed and synthesized by the lateral lobe of both rat and
      mouse prostate glands, and moderately expressed in the dorsal lobe of the rat
      prostate gland.

PMID- 10639194
TI  - Identification of a superimmunoglobulin gene family member overexpressed in
      benign prostatic hyperplasia .
AB  - BACKGROUND: Benign prostate hyperplasia (BPH), a nonmalignant disease with an
      increasing rate of occurrence associated with advancing age, requires auxiliary
      markers to help identify its presence and distinguish its progression from
      prostate cancer. METHODS: Hybridoma technology was used to generate an antibody
      against a BPH antigen, which was subsequently characterized by Western blot
      analysis, sequence homology, and RT-PCR. RESULTS: A BPH-associated protein,
      designated P25/26, was identified that showed a strong sequence similarity with
      superimmunoglobulin family members, overexpressed in BPH, with lower expression
      observed in both normal and prostate cancer tissues. CONCLUSIONS: Further studies
      appear warranted to assess the role that this and other superimmunoglobulin
      family members may have in the pathogenesis of BPH, and to determine if these
      glycoproteins have any clinical utility in the differential diagnosis or
      therapeutic monitoring of BPH.

PMID- 10639195
TI  - Interleukin-6 induces prostate cancer cell growth accompanied by activation of
      stat3 signaling pathway .
AB  - BACKGROUND: Interleukin-6 (IL-6) is a pleiotropic cytokine that regulates growth
      and differentiation of various types of malignant tumors, including prostate
      carcinomas. The levels of IL-6 are elevated in sera of patients with metastatic
      prostate cancer. In this study, we evaluate the role of IL-6 in the growth
      regulation of prostate cancer cells. METHODS: Expression of IL-6 and its
      receptors in human prostate cancer cells was measured by ELISA and RT-PCR. The
      effects of IL-6 on cell growth were evaluated by ectopically expressing IL-6 cDNA
      into IL-6-negative LNCaP human prostate cancer cells. Stat3 DNA binding
      activities were analyzed by electromobility shift assay and supershift assay.
      RESULTS: Expression of IL-6 was detected in the androgen-insensitive prostate
      cancer cell lines (i.e. , TSU, PC3, and DU145), but not in the androgen-sensitive
      LNCaP cell line. IL-6 receptors, including both IL-6-specific receptor alpha
      chain and gp130 signal transducer, are expressed in all human prostate cancer
      cell lines (i.e., LNCaP, TSU, PC3, and DU145). Overexpression of IL-6 by
      ectopically expressing IL-6 into IL-6-negative LNCaP human prostate cancer cells
      significantly increased clonogenic ability and cell proliferation in vitro
      compared to the IL-6-negative parental LNCaP cells and the antisense controls.
      This growth stimulation by IL-6 was accompanied by activation of the Stat3
      signaling transduction pathway. CONCLUSIONS: IL-6 is an autocrine growth factor
      for LNCaP human prostate cancer cells; the effects of IL-6 on prostate cancer
      cell growth are mediated through the Janus kinase-signal transducers and
      activators of transcription (JAK-STAT) signaling pathway.

PMID- 10639196
TI  - Calcium, lycopene, vitamin D and prostate cancer.

PMID- 10639197
TI  - Total plasma antioxidant capacity in cystic fibrosis.
AB  - Several studies have demonstrated ongoing oxidative stress in cystic fibrosis
      (CF). With the complexity of the antioxidant network, measurement of individual
      antioxidants does not necessarily assess how they work in combination. One
      measure that has been proposed as a gauge of total plasma antioxidant capacity is
      the Trolox-equivalent antioxidant capacity (TEAC) of plasma. We decided to look
      at plasma TEAC levels in children with CF, and relate this measure to their
      nutritional status, lung function, and blood measurements of several known
      antioxidants. We hypothesized that values in general would be lower than healthy
      control values, especially during acute pulmonary exacerbations. Twenty-nine
      children were evaluated, five of whom were during an acute pulmonary
      exacerbation. Height and weight, expiratory spirometry, and lung volumes were
      assessed, as were serum concentrations of vitamins A and E, uric acid, albumin,
      and lymphocyte glutathione (GSH) concentrations. TEAC values for nonhospitalized
      patients (1.40 +/- 0. 20 mmol/L) were not different from laboratory control
      values (1.35 +/- 0.11 mmol/L), but greater than values for hospitalized patients
      (1.09 +/- 0.17 mmol/L). TEAC correlated with anthropometric values (height: r =
      0.39, P < 0.03; weight: r = 0.50, P < 0.01; body mass index: r = 0.47, P < 0.01),
      and pulmonary function (forced expiratory volume in 1 sec: r = 0.43, P < 0.02;
      residual volume/total lung capacity: r = -0.42, P < 0.03), but not with age.
      Univariate correlation with blood measurements demonstrated a significant
      correlation of TEAC with uric acid (r = 0.49, P < 0.02), but not with albumin,
      vitamins A or E, or lymphocyte GSH. Multiple regression analysis demonstrated a
      correlation between TEAC and uric acid, albumin, and lymphocyte GSH in the non
      hospitalized group (r(2) = 0.38, P < 0.03). We conclude that TEAC appears to
      represent a mixed antioxidant response, rather than response to a single
      antioxidant. While being responsive to oxidative stress, the mechanism of the
      response may differ between clinical situations, such that the clinical
      significance of changes in plasma TEAC remains to be defined.

PMID- 10639198
TI  - Association between parental perception of children's vulnerability to illness
      and management of children's asthma.
AB  - This study examined the relationship between asthma management strategies used by
      parents and parental perception of children's vulnerability to illness. Home
      interviews were conducted with 101 parents of children previously hospitalized
      with asthma. The child vulnerability scale (CVS) was employed to assess parents'
      perception of their children's vulnerability to illness. The asthma severity
      index (ASI) was used to measure the frequency and intensity of asthma symptoms
      experienced by children in the preceding 12 months. Five markers of parental
      asthma management were assessed: (i) school absences; (ii) visits to the general
      practitioner (GP); (iii) visits to the emergency room (ER); (iv)
      hospitalizations; and (v) whether children are using a regular preventer. After
      controlling for the frequency and intensity of children's asthma symptoms,
      parents who perceived that their children were more vulnerable to medical illness
      were significantly more likely to keep their children home from school (P =
      0.01), were more likely to take their children to the GP for acute asthma care (P
      = 0.02), and were more likely to be giving their children regular preventer
      medication (P = 0.02). In contrast, the use of tertiary pediatric care services
      was not significantly associated with parental perceptions of their children's
      vulnerability. The results suggest that parental attitudes and beliefs about the
      vulnerability of their children to illness were associated with greater use of GP
      services by parents and more frequent school absences for children. The use of
      hospital services by parents appeared to be more strongly associated with the
      actual level of children's asthma symptoms than their vulnerability to illness.

PMID- 10639199
TI  - Ventilation inhomogeneity assessed by nitrogen washout and ventilation-perfusion
      mismatch by capnography in stable and induced airway obstruction.
AB  - Few studies have been published on gas distribution in the lung during acute and
      stable airway obstruction in children. Multiple breath nitrogen (N(2)) washout is
      an established method for assessing ventilation inhomogeneity, while the tidal
      breathing capnogram may be used as an indicator of ventilation-perfusion
      (V(')(A)/Q) mismatch. We hypothesized that significant V(')(A)/Q mismatch is not
      seen in stable airway obstruction unless obstruction is severe, and that stable
      and induced airway obstruction of similar severity would result in different
      degrees of V(')(A)/Q mismatch. To test this hypothesis, we performed spirometry
      measurements of forced expiratory volume in 1 sec (FEV(1)), multiple breath N(2)
      washout, and tidal breathing capnography in 11 young patients (9-30 years) with
      cystic fibrosis, 37 asthmatic patients (8-18 years), and 34 healthy subjects (7
      20 years). Lung function was measured at rest, after airway obstruction induced
      by cold dry air hyperventilation or methacholine challenge, and after beta(2)
      agonist treatment. V(')(A)/Q mismatch was assessed from the slopes of the phases
      II and III of the capnogram. We observed a normal capnogram during stable
      obstruction of moderate severity despite significant ventilation inhomogeneity.
      In patients with severe stable obstruction and in those with induced airway
      obstruction significant ventilation inhomogeneity and pathological capnograms
      were seen. Induced airway obstruction, resulted in a more pathological capnogram
      than stable obstruction of similar severity. beta(2)-agonist treatment reduced
      ventilation inhomogeneity, but did not improve the capnogram. Our findings are
      compatible with the presence of an efficient pulmonary blood flow regulatory
      mechanism that adequately compensates for chronic ventilation inhomogeneity of
      moderate severity, but not for severe or sudden airway obstruction.

PMID- 10639200
TI  - Epidermal growth factor and lung development in the offspring of the diabetic
      rat.
AB  - Fetuses of diabetic mothers who were exposed to excessive glucose show delayed
      maturation. Under these conditions, altered growth factor expression or signaling
      may have important regulatory influences. We examined the role of epidermal
      growth factor (EGF) in lung development and maternal diabetes in the rat. In
      order to evaluate the possible role of glucose for the expression of EGF and the
      growth of lung tissue, we performed in vitro studies with organotypic cultures of
      fetal alveolar cells obtained from control rats. Compared to pups of normal rats,
      the newborn rats of untreated diabetic rats had reduced body weight, but normal
      lung weight relative to body weight. The air:mesenchyme ratio and the average
      size of alveoli per mm(2) lung tissue were reduced. The immunoreactivity (IR) of
      EGF, which was quantified using a computerized image analysis system, appeared
      with increased intensity and was associated with a reduced intensity of
      surfactant protein A-IR. The only difference observed between pups of treated
      diabetic rats and controls was a decrease in the lung weight:body weight ratio.
      In organotypic cultures, the presence of 13 mmol/L glucose in the cell media
      increased immunoreactive staining against EGF, but decreased the incorporation of
      thymidine as compared to the results obtained with alveolar cells grown in a
      normophysiological concentration of glucose (3 mmol/L). Addition of EGF increased
      the thymidine incorporation only in cells grown in 3 mM glucose. These findings
      may indicate immaturity of the lungs of pups of untreated diabetic rats, and
      subtle alterations in the lungs of pups from treated diabetic rats. The results
      also suggest that glucose plays a role in the expression of EGF, and that cells
      exposed to high concentrations of glucose are less responsive to EGF.

PMID- 10639201
TI  - Airway reactivity following repeated milk aspiration in rabbits.
AB  - Asthma and gastroesophageal reflux (GER) are commonly associated disorders.
      Microaspiration is one possible link between these processes. The purpose of this
      study was to assess methacholine reactivity following repeated small-volume
      aspiration such as may occur with GER. This was also correlated with airway
      cytology. Five weekly intratracheal instillations of either milk (N = 8) or
      saline sham controls (N = 7) in volumes of 0.25 mL/kg were performed in
      anesthetized rabbits. Transpulmonary pressure, flow, tidal volume, central
      airways resistance, and dynamic lung compliance were measured in anesthetized and
      paralyzed animals at baseline, after 2 and 5 weeks of instillation, and 3 weeks
      after the last instillation. Doubling concentrations of methacholine were given
      until a 50% or greater increase in resistance occurred (PC50R). Bronchial
      washings for cytological evaluation were performed after the physiologic
      measurements and before each instillation. There were no significant differences
      in airway reactivity between baseline and all subsequent observation points
      within each of the two groups. However, methacholine responsiveness was
      significantly higher in the milk group before the final instillation (PC50R =
      5.84 vs. 12.97 mg/mL, P = 0.03) and at recovery (PC50R = 6.40 vs. 10.56 mg/mL, P
      = 0.047) when compared to saline controls. This was associated with a higher
      neutrophil percentage (P = 0.01) at 5 weeks, and eosinophil percentage (P = 0.05)
      at recovery in the bronchial wash specimens from the milk group. These results
      show that repeated small-volume aspiration of milk in rabbits causes persistent
      inflammation and is associated with greater airway reactivity when compared to
      sham controls. This inflammation was accompanied by either increased neutrophils
      or eosinophils in bronchial lavage specimens. These findings lend support to a
      possible role of microaspiration in association with increased airway reactivity
      in patients with GER.

PMID- 10639202
TI  - Evaluation of pulsed and breath-synchronized nebulization of budesonide as a
      means of reducing nebulizer wastage of drug.
AB  - The aim of this open, randomized, crossover study was to compare the inhaled mass
      of budesonide suspension delivered by nebulization, using constant output, breath
      synchronized, or pulsed jet nebulization techniques. The inhaled mass was defined
      as the amount of drug deposited on a filter between the inspiratory port of the
      nebulizer and the face mask or mouthpiece used by the subjects. The breath
      synchronized nebulization delivered aerosol during the whole inspiration, whereas
      the pulsed nebulization was adjusted to deliver aerosol for up to 1 sec from the
      start of inspiration. Budesonide suspensions, 2 mL of 0.5 mg mL(-1), or 2 mL of
      0.25 mg mL(-1), in single-dose respules, were used (AstraZeneca R&D Lund, Lund,
      Sweden). Eleven children (7 boys, age range 2.5-5.8 years) with either a clinical
      suspicion or a confirmed diagnosis of asthma and 11 healthy adolescents and
      adults (6 male, age range 13-52 years) were enrolled. With constant output
      nebulization, the median inhaled mass of budesonide was about 17.6% (range 9.6
      21.2%) of the nominal dose (i. e., dose of drug in the respule per label claim)
      in adolescents and adults, and 18.1% in children (15.7-21.4%). With pulsed
      nebulization the median inhaled mass increased to 23.4% (22.0-28.1%) in children
      and to 32.8% (24.8-38.0%) in adolescents and adults (P < 0.001). With breath
      synchronized nebulization median inhaled mass increased to 30.1% (21.7-28.1%) in
      children, but was unchanged (30.8%, 27.0-38. 0%) in adolescents and adults. The
      mode of nebulization (i.e., constant or breath-synchronized) had a statistically
      significant effect on the inhaled mass in children and adolescents or adults (P <
      0.001). There was a statistically significant difference in inhaled mass between
      the breath-synchronized and pulsed nebulization in children only (P < 0.05). The
      results support the use of breath-synchronized but not pulsed nebulization with
      conventional nebulizers. The results of pulsed nebulization in children warrants
      further clinical studies.

PMID- 10639203
TI  - Air leaks from the respiratory tract in mechanically ventilated children with
      severe respiratory disease.
AB  - Our objectives were to evaluate the frequency of air leaks (AL) from the
      respiratory tract (pneumothorax, pneumomediastinum, pneumoperitoneum,
      subcutaneous emphysema) in critically ill children on mechanical ventilation (MV)
      for severe respiratory diseases, and to examine whether AL could be correlated
      with specific clinical events or ventilator settings. The study constitutes a
      retrospective cohort of 80 consecutive critically ill children receiving MV for
      severe respiratory diseases between 1986 and 1993. Patients (mean age 2.9 +/- 0.6
      years, 49 males and 31 females), were admitted to the Pediatric Intensive Care
      Unit (PICU) with acute respiratory syndrome (ARDS) (27%), asthma (15%),
      bronchiolitis (10%), pneumonia (21%), pulmonary congenital diseases (9%), or
      foreign body aspiration (18%). Patients were divided into two groups; those with
      AL (n=22) and those without air-leaks (non-AL) (n = 58). Air leaks developed in
      22 of 80 patients or in 27.5%. Survival was significantly lower in the AL group,
      compared to the non-AL group (41% vs. 76%, P < 0.01). The odds ratio that a
      patient with multiple organ system failure (MOSF) or infection would develop AL
      was 2.96 and 2.19, respectively. Candida and Pseudomonas species were recovered
      with significantly higher frequency in the AL group compared with the non-AL
      group (P < 0.025). There was a strong positive correlation between the incidence
      of AL and high ventilatory pressures (PIP 36 vs. 29.7 cm H(2)O, P < 0.001), or
      large tidal volumes (V(T) 12 vs. 9 mL/kg, P < 0.05), suggesting that large
      volumes might elicit injury to the pulmonary epithelium. Multiple logistic
      regression analysis showed that only V(T) was independently associated with the
      development of AL in children with primary severe respiratory disease (r(2) = 
      0.38, P = 0.01). In conclusion, MV will produce AL, particularly when high peak
      airway pressures (barotrauma) or large tidal volumes (volotrauma) are delivered
      by the ventilator. Sepsis, MOSF, and lung superinfection with Pseudomonas or
      Candida species may be also important factors in the development of AL in
      critically ill children.

PMID- 10639204
TI  - Sleep-disordered breathing in Duchenne muscular dystrophy: a preliminary study of
      the role of portable monitoring.
AB  - Although Duchenne muscular dystrophy (DMD) is often associated with sleep
      disordered breathing (SDB), it is not standard clinical practice to routinely
      test this population for SDB, and the optimal timing and methodology for such
      testing has not been established. Our objectives were: 1) to examine the
      concordance between laboratory polysomnography (PSG) and two portable monitoring
      systems, and 2) to identify clinical factors associated with the onset of SDB. We
      performed a cross-sectional pilot study of patients with DMD who were 6 years of
      age or older, and who were registered at the Alberta Children's and Calgary
      General Hospitals. Patient symptom and functional rating scores were calculated,
      and pulmonary function tests, awake oxygen saturation, and capillary blood gases
      were obtained. PSG was performed according to standard methods, and results were
      compared with Snoresat(R) (Saga Tech Electronics, Inc.) and EdenTec(R) (Nellcor
      Puritan Bennett) portable home monitors. Eleven boys were studied. Ten of 11
      subjects had normal awake oxygen saturation and capillary blood gases. Median
      forced vital capacity (FVC) was 70% of predicted values (15-104%). PSG identified
      3 boys with severe hypoventilation occurring throughout REM sleep. Reported
      symptom severity did not predict the patients with significant SDB. All 3 boys
      with SDB had a severe functional disability and severely reduced FVCs. Portable
      monitoring in the home identified all patients with abnormal PSG. One additional
      patient was falsely identified by the EdenTec(R) monitor. We conclude that
      initial results using Snoresat(R) or EdenTec(R) monitoring equipment for the
      identification of SDB are promising, but further validation of portable home
      monitoring is required in this group of patients.

PMID- 10639205
TI  - Pulmonary manifestations of neuromuscular disease with special reference to
      Duchenne muscular dystrophy and spinal muscular atrophy.
AB  - Deterioration of respiratory function in patients with neuromuscular disorders is
      primarily responsible for the high mortality associated with these diseases. A
      review of Duchenne muscular dystrophy and spinal muscular atrophy, the leading
      neuromuscular disorders affecting children, will be followed by a critical
      analysis of the various pathophysiological mechanisms underlying respiratory
      manifestations in these patients. Among such mechanisms, the role of muscular
      weakness in preservation of lung function, mucociliary clearance, gas exchange at
      rest and during exercise, and respiratory control during wakefulness and sleep
      will be examined in detail. In addition, the potential benefits of respiratory
      muscle training and of early diagnosis and clinical intervention will be
      delineated. This review underscores the importance of periodic assessment of
      pulmonary function during wakefulness and sleep in children affected by
      neuromuscular diseases as an essential component of multidisciplinary care aimed
      at improving long-term morbidity, survival, and quality of life.

PMID- 10639206
TI  - Severe pulmonary disease in association with Crohn's disease in a 13-year-old
      girl.
AB  - Pulmonary manifestations of Crohn's disease are infrequent in adults and even
      less common in children. Our literature search found only a few cases of Crohn's
      disease causing pulmonary manifestations in children. We report on the case of a
      13-year-old girl in whom severe pulmonary disease was found four years after the
      onset of Crohn's disease. Open lung biopsy uncovered bronchiolitis obliterans and
      granulomatous lung disease. Aggressive treatment has yielded gradual improvement.
      This case emphasizes the importance of recognizing the association, the
      differential diagnosis, and treatment implications.

PMID- 10639207
TI  - Severe allergic bronchopulmonary aspergillosis in an infant with cystic fibrosis
      and her asthmatic father.
AB  - An infant with cystic fibrosis and her asthmatic father were diagnosed as
      suffering from allergic bronchopulmonary aspergillosis (ABPA). Cystic fibrosis
      was diagnosed in the infant at 6 weeks of age, and gene mutations were
      W1282X/G542X. She was diagnosed definitively as suffering from ABPA at age 3.5
      years, but had suggestive symptoms from age 11 months. This may be the youngest
      age described to date for ABPA. The child responded well to systemic steroid
      therapy, but remained steroid-dependent over the next 4 years. Treatment with
      itraconazole enabled a marked reduction in steroid dosage. The father was an
      asthmatic, and a heterozygote for the cystic fibrosis transmembrane regulator
      (CFTR) mutation W1282X. He had a normal sweat test, atopy, and moderate
      reversible airway obstruction. There was no proven exposure to Aspergillus in the
      home environment. The importance of considering the diagnosis of ABPA even in
      infancy, the therapeutic dilemmas, and the possible role of abnormal CFTR
      function in the development of ABPA are discussed.

PMID- 10639208
TI  - Selected abstracts

PMID- 10639209
TI  - Issues Regarding the Use of Heparin Following Streptokinase Therapy.
AB  - The success of thrombolytic therapy is dependent upon the balance of fibrinolytic
      activity and procoagulant activity. Streptokinase produces fibrin degradation
      products that have anticoagulant effects and may potentially protect against
      reocclusion. However, streptokinase also activates platelets and thrombin, and
      the prothrombotic effects may be more marked than after administration of
      recombinant tissue plasminogen activator (rt-PA). Administration of high-dose,
      delayed subcutaneous heparin after streptokinase and aspirin has been shown to
      have some benefits and some risks. The benefits and risks of adding intravenous
      heparin to aspirin and streptokinase have not been clearly defined.

PMID- 10639210
TI  - Thrombolysis in Acute Myocardial Infarction Complicated by Cardiogenic Shock.
AB  - The adverse impact of the development of cardiogenic shock in the setting of
      acute myocardial infarction was first described by Killip and Kimball in 1967.
      While the in-hospital mortality rate in patients with myocardial infarction and
      no evidence of heart failure was only 6%, the mortality rate in those patients
      who developed cardiogenic shock was 81%. Despite advances in cardiovascular care
      and therapy since that initial report, including universal institution of cardiac
      care units, advances in hemodynamic monitoring, new inotropic and vasodilating
      agents, and even increasing utilization of thrombolytic therapy, the mortality
      from acute myocardial infarction, when complicated by cardiogenic shock, remains
      disturbingly high, and cardiogenic shock remains the leading cause of death of
      hospitalized patients following acute myocardial infarction.The grave prognosis
      associated with this condition has resulted in increased interest in potential
      therapeutic interventions, particularly in the area of reperfusion therapy.
      Several studies suggest that, in contrast to the beneficial effects of
      thrombolytic therapy in most patient populations suffering acute myocardial
      infarction, mortality rates are not decreased in those patients with cardiogenic
      shock at the time of lytic administration. Thrombolytic administration does,
      however, appear to lead to a modest reduction in the percent of patients with
      myocardial infarction who will subsequently develop cardiogenic shock during
      hospitalization.Reperfusion rates with lytic therapy in patients with cardiogenic
      shock are disappointingly low, in the range of 42-48%, significantly lower than
      those achieved in patients without cardiogenic shock. These low perfusion rates
      may, in part, be explained by decreased coronary blood flow and perfusion
      pressure in patients with left ventricular pump failure.Although promising as
      adjunctive therapy, it is unclear whether institution of balloon counterpulsation
      has any long-term benefit in patients with cardiogenic shock treated with
      thrombolytic therapy. Whether other or additional interventions, such as coronary
      angioplasty and coronary artery bypass graft (CABG), decrease mortality rates in
      patients with cardiogenic shock remains to be determined.

PMID- 10639211
TI  - Antithrombotic Therapy during Percutaneous Coronary Intervention.
AB  - Ischemic complications of percutaneous coronary intervention occur commonly and
      are among the major limitations of the procedure. Both platelets and thrombin
      play an essential role in the response to the arterial injury that follows
      coronary intervention and in the pathophysiology of the ischemic complications of
      the procedure. Aspirin and heparin are essential treatments for the patient
      undergoing coronary intervention. Novel thrombin and platelet inhibitors are
      being developed that may be useful for improving both acute and long-term
      clinical outcomes of percutaneous coronary intervention.

PMID- 10639212
TI  - Thrombolytic Therapy for Acute Myocardial Infarction in Patients with Prior
      Coronary Bypass Surgery: Results from the Thrombolysis in Myocardial Infarction
      (TIMI) 4 Trial.
AB  - Little data exist on the value of intravenous thrombolysis for acute myocardial
      infarction in patients with previous coronary bypass surgery. The Thrombolysis In
      Myocardial Infarction (TIMI) 4 trial was a randomized study comparing tissue
      plasminogen activator, anistreplase, or a combination in patients with evolving
      myocardial infarction; patients with previous coronary bypass surgery were not
      excluded. Coronary angiography was performed 90 minutes and 18-36 hours after
      randomization, a myocardial perfusion scan was performed at 18-36 hours and
      predischarge, and a radionuclide ventriculogram was obtained predischarge.
      Angiographic and clinical outcome variables were determined in patients with and
      without a history of coronary bypass surgery. A total of 416 patients were
      randomized and 13 of them had previous bypass surgery; of these, 6 had an
      occluded vein graft as the infarct-related vessel. The incidence of TIMI grade 3
      flow at 90 minutes was lower in patients with previous coronary surgery as
      compared with controls (42% vs. 49%), and overall patency was significantly lower
      (50% vs. 77%, p = 0.04). This trend persisted at 18-36 hours after randomization.
      Furthermore, patients with previous coronary surgery had more thrombus in their
      infarct-related arteries, especially with occlusion of a vein graft (83% vs. 32%,
      p = 0.04) and higher rates of recurrent ischemia (15% vs. 8%) and recurrent
      infarction (23% vs. 5%, p = 0.03) than controls. Thus, in patients with previous
      coronary bypass surgery intravenous thrombolysis yields results that are inferior
      to those achieved in patients without such a history and alternative methods of
      reperfusion should be considered.

PMID- 10639213
TI  - Clinical Utility of Electrocardiographic ST-Segment Area for Predicting
      Unsatisfactory Outcomes Following Thrombolytic Therapy.
AB  - The bedside surface 12-lead electrocardiogram is a mainstay in the early
      diagnostic evaluation of patients with suspected acute myocardial infarction. The
      presence of ST-segment elevation exceeding 1.0 mm in two or more anatomically
      associated leads is a reliable marker of myocardial injury and, when considered
      along with concomitant ST-segment depression, reflects the extent of myocardial
      injury. Mounting evidence also suggests that prolonged repolarization is a marker
      of injury and predicts the likelihood of malignant ventricular arrhythmias. We
      questioned whether a measure of both ST-segment duration and deviation (ST
      deviation area) would offer additional prognostic information. Methods/Results:
      Admission electrocardiograms from 200 consecutive patients with ischemic chest
      pain accompanied by ST-segment elevation in whom thrombolytic therapy was given
      within 6 hours from symptom onset were analyzed. The sum of ST-segment elevation
      (Sigma ST elevation) and ST-segment deviation (Sigma ST deviation) were
      calculated, as was the sum of ST-segment deviation area (Sigma ST deviation
      area). All ST measurements were performed 60 msec after the J point. Computerized
      planimetry was used to calculate ST-segment area. Sigma ST deviation and Sigma ST
      deviation area remained constant over time. Patients with large deviations (Sigma
      ST elevation > 20 mm (odds ratio 2.14, p = 0.02) and Sigma ST deviation area >
      150 (odds ratio 1.92, p = 0.02) had a higher incidence of in-hospital
      unsatisfactory clinical outcome (defined as death, congestive heart failure,
      cardiogenic shock, recurrent myocardial infarction, or the need for coronary
      revascularization). These relationships were present for both inferior and
      anterior infarctions. Sigma ST deviation area correlated closely with Sigma ST
      elevation (r = 0.92; p = 0.0001) and significantly but much less strongly with
      the sum of Q waves (r = 0.18; p = 0.01). By univariate analysis, only site of
      infarction (p = 0.01), Sigma ST deviation area (p = 0.04), and the sum of Q waves
      (p = 0.005) were identified as predictors of a poor clinical outcome. The sum of
      Q waves was identified by multivariate analysis as the best independent predictor
      of an unsatisfactory clinical outcome. Conclusions: A clinician's ability to
      provide optimal care is influenced strongly by the availability of diagnostic and
      prognostic information. In the evaluation of patients with acute myocardial
      infarction, ST-segment deviation area derived from the admission surface
      electrocardiogram can be used to risk-stratify patients. The full clinical
      potential of this measure is unknown and will require further evaluation.

PMID- 10639215
TI  - 1994 Joint European and World Congress of Cardiology: An Overview in the Field of
      Thrombosis and Thrombolysis.

PMID- 10639214
TI  - Dynamic Nature of Thrombin Generation, Fibrin Formation, and Platelet Activation
      in Unstable Angina and Non-Q-Wave Myocardial Infarction.
AB  - Thrombin and platelets are directly involved in arterial thrombosis, typically
      occurring at sites of atherosclerotic plaque rupture among patients with acute
      coronary syndromes. Understanding the dynamic nature of pathologic thrombosis has
      important clinical implications. Methods: Fibrinopeptide A (FPA), thrombin
      antithrombin complexes (TAT), and prothrombin activation fragment 1.2 (F1.2),
      plasma markers of fibrin formation (thrombin activity) and thrombin generation,
      and platelet activation, determined by the recognition of a surface-expressed
      platelet alpha-granule protein, P-selectin, using flow cytometry, were measured
      in 36 consecutive patients with unstable angina and non-Q-wave myocardial
      infarction participating in the Thrombolysis In Myocardial Ischemia (TIMI) III B
      trial. Results: Thrombin generation (TAT 12.1 +/- 17.8 ng/ml vs. 3.4 +/- 1.0
      ng/ml; F1.2 0.19 +/- 0.14 nmol/l vs. 0.12 +/- 0.8 nmol/l), fibrin formation (FPA
      15.8 +/- 23.5 ng/ml vs. 7.5 +/- 2.3 ng/ml), and platelet activation) 10.6 +/-
      2.4% vs. 2.5 +/- 2.0%) were increased significantly in patients compared with
      healthy, age-matched controls (p < 0.01). Fibrin formation, represented by plasma
      FPA levels, did not correlate with the percentage of activated platelets (r = 
      .10, p = 0.69). Thrombin generation and platelet activation also did not
      correlate. A statistically insignificant trend between TAT and platelet
      activation was observed (r =.42, p = 0.07); however, even with TAT levels in
      excess of 20 ng/ml (nearly sixfold greater than normal healthy controls) platelet
      activation was increased by only 1.7-fold. Conclusions: Thrombin generation,
      fibrin formation, and platelet activation are increased modestly among patients
      with unstable angina and non-Q-wave myocardial infarction. Despite the
      involvement of platelets and coagulation proteins in arterial thrombotic
      processes, their relative contributions may vary, providing a pathophysiologic
      basis for the dynamic expression of di sease and response to treatment observed
      commonly in clinical practice.

PMID- 10639216
TI  - 1994 American Heart Association Scientific Sessions at a Glance.

PMID- 10639217
TI  - Lethal Myocardial "Reperfusion Injury": The Opinions of Good Men.

PMID- 10639220
TI  - Myocardial Reperfusion Injury: From Bench to Bedside.

PMID- 10639221
TI  - Reperfusion Phenomena Suggestive of Reperfusion Injury in Patients with Acute
      Myocardial Infarction.

PMID- 10639222
TI  - Myocardial Reperfusion Injury.

PMID- 10639219
TI  - Reperfusion Injury: Does It Exist and Does It Have Clinical Relevance?
AB  - Although reperfusion is an absolute prerequisite for the survival of ischemic
      tissue, it is not necessarily without hazard. Many (but not all) cardiologists
      are of the opinion that some components of reperfusion may be detrimental and
      able to inflict injury over and above that attributable to the ischemia. In this
      article we define four sequelae of reperfusion that might be designated as
      "reperfusion injury." We identify possible underlying mechanisms and consider
      whether any of these forms of reperfusion injury are of clinical relevance.

PMID- 10639218
TI  - Reperfusion Injury: Basic Concepts and Protection Strategies.
AB  - Prolonged ischemia such as that following myocardial infarction or occurring
      during long-term coronary bypass procedures causes serious damage to the
      myocardium. Early reperfusion is an absolute prerequisite for the survival of
      ischemic tissue. However, reperfusion has been referred to as the "double edged
      sword" because reperfusing ischemic myocardium carries with it a component of
      injury known as reperfusion injury. Reperfusion injury includes a number of
      events, such as reperfusion arrhythmias, myocardial infarction, stunning,
      vascular damage, and endothelial dysfunction. The underlying mechanism of
      reperfusion injury is not entirely known, but the existing evidence suggests that
      oxygen free radicals generated during the first few minutes of reflow lead to
      damage of cellular membranes, intracellular calcium overload, and uncoupling of
      excitation-contraction coupling. Although controversial, free radical scavengers,
      in general, are highly effective in the attenuation of reperfusion injury in
      animal models. Newer endogenous protection strategies, which include ischemic and
      heat shock preconditioning, are known to reduce reperfusion injury following
      ischemia.

PMID- 10639223
TI  - Lethal Myocardial Reperfusion Injury: Fact or Fiction?

PMID- 10639224
TI  - Does "Lethal Reperfusion Injury" Exist?

PMID- 10639225
TI  - Lethal Myocardial "Reperfusion Injury"

PMID- 10639226
TI  - Reperfusion Injury: Idle Curiosity or Therapeutic Vector?

PMID- 10639227
TI  - Endothelial Dysfunction as a Trigger for Ischemia-Reperfusion Injury.

PMID- 10639228
TI  - Apoptosis: A New Mechanism of Lethal Myocardial "Reperfusion Injury"?

PMID- 10639229
TI  - Lethal Myocardial Reperfusion Injury: Does it Exist, Should We Treat It?

PMID- 10639230
TI  - Lethal Reperfusion Injury in Regionally Ischemic, Reperfused Porcine Hearts?

PMID- 10639231
TI  - Reperfusion Injury in Humans: Existence, Clinical Relevance, Mechanistic
      Insights, and Potential Therapy.

PMID- 10639232
TI  - Clinical Perspectives on Lethal Reperfusion Injury.

PMID- 10639233
TI  - Existence and Clinical Relevance of Lethal Myocardial "Reperfusion Injury"

PMID- 10639234
TI  - Lethal Myocardial "Reperfusion Injury": The Views of a Cardiac Surgeon.

PMID- 10639235
TI  - Does Lethal Reperfusion Injury Exist in Cardiac Surgery?

PMID- 10639236
TI  - Is "Lethal Reperfusion" an Oxymoron?

PMID- 10639237
TI  - Does Lethal Myocardial Reperfusion Injury Exist?

PMID- 10639238
TI  - Reperfusion Stimulated Inflammatory Response: Role in Lethal Reperfusion Injury.

PMID- 10639239
TI  - Does Reperfusion Injury Exist?

PMID- 10639240
TI  - Reperfusion Injury: Significance and Prospects for Treatment.

PMID- 10639241
TI  - Direct Demonstration in Dogs of the Absence of Lethal Reperfusion Injury.

PMID- 10639242
TI  - Does Lethal Myocardial Reperfusion Injury Exist? A Controversy that is Unlikely
      to Be Settled in our Lifetime.

PMID- 10639243
TI  - Little Evidence for Lethal Reperfusion Injury to Cardiomyocytes.

PMID- 10639244
TI  - Reperfusion Injury: An Opinionated View.

PMID- 10639245
TI  - Lethal Reperfusion Injury: Does It Exist and Does It Matter?

PMID- 10639246
TI  - The Unknown Reality of Vague Lethal Reperfusion Injury.

PMID- 10639247
TI  - Does Lethal Reperfusion Injury Interfere with Myocardial Salvage?

PMID- 10639248
TI  - Lethal "Reperfusion Injury": Is It a Real Entity?

PMID- 10639249
TI  - Does Reperfusion per se Kill Myocytes in the Heart?

PMID- 10639250
TI  - "Reperfusion Injury" and Myocardial Protection by Cardioplegia: An Opinion.

PMID- 10639251
TI  - Myocardial Reperfusion Injury: The Case Against Shadow Boxing.

PMID- 10639252
TI  - W(h)ither Myocardial Reperfusion Injury?

PMID- 10639253
TI  - Lethal Reperfusion Injury: Does Anyone Still Care?

PMID- 10639254
TI  - Reperfusion Injury: Fact, Fiction, or Simply Unresolvable?

PMID- 10639255
TI  - Lethal Myocardial Reperfusion Injury: A Right Target for the Clinician?

PMID- 10639256
TI  - The Cardiac Surgeon's Perspective on Lethal Myocardial "Reperfusion Injury"

PMID- 10639258
TI  - The Open-Artery Hypothesis: Introduction.

PMID- 10639257
TI  - The Open-Artery Hypothesis: An Overview.
AB  - The open artery hypothesis postulates salutary effects distinct from myocardial
      salvage referable to infarct related arterial patency. Short and long term
      clinical trials, as well as studies in animal models have suggested clinical
      benefit in patients with sustained infarct related arterial patency. Mechanisms
      of benefit are not entirely clear, but probably relate to mitigation of post
      infarction left ventricular remodeling and improvement in several
      electrophysiologic parameters. The effect of infarct related arterial patency on
      post infarction prognosis, presumed mechanisms of benefit and noninvasive
      assessment of arterial patency are summarized in this review.

PMID- 10639259
TI  - Acute Coronary Syndromes: Molecular Basis for Cardiac Risk Factors.

PMID- 10639260
TI  - Pathobiology of Myocardial Necrosis.

PMID- 10639262
TI  - Adjunctive Pharmacologic Treatment: Focus on the Development of Low Molecular
      Weight Heparins.

PMID- 10639261
TI  - Pathobiology and Clinical Impact of Reperfusion Injury.
AB  - Reperfusion injury refers to cellular death or dysfunction caused by restoration
      of blood flow to previously alchemic tissue. This should be differentiated from
      the normal reparative processes that follow an ischemic insult. Four types of
      reperfusion injury have been described in the literature: (1) lethal reperfusion
      injury, (2) nonlethal reperfusion injury, (myocardial stunning), (3) reperfusion
      arrhythmias, and (4) vascular injury (including the "no-reflow" phenomenon).
      There is continued debate whether reperfusion itself is capable of killing viable
      myocytes, which otherwise would have survived the ischemic insult. However, there
      is firm evidence for the existence of myocardial stunning following various
      ischemic syndromes, including reperfusion therapy for acute myocardial
      infarction, unstable angina pectoris, vasospastic angina, effort-induced
      ischemia, coronary artery bypass surgery, and cardiac transplantation.
      Reperfusion arrhythmia is more common after short ischemic episodes than after
      long ischemic periods. Thus, while reperfusion arrhythmias in the setting of
      acute myocardial infarction are relatively rare, reperfusion arrhythmias may be
      an important cause of sudden death. The "no-reflow" phenomenon has been described
      following reperfusion in patients with acute myocardial infarction. Three major
      components have been proposed as mediators of reperfusion injury: (1) oxygen free
      radicals, (2) the complement system, and (3) neutrophils. Numerous experimental
      studies have shown short-term benefit by blocking various stages of the
      postischemic inflammatory response. Oxygen free radicals scavengers, complement
      inhibition, leukocyte depletion, and the use of antibodies against various
      adhesion molecules have shown a reduction of infarct size in many
      ischemic/reperfusion experimental models. However, many of these agents failed to
      show a benefit in the clinical setting. Moreover, the long-term benefit of such
      intervention is still unknown.

PMID- 10639263
TI  - Assessment of Regional Viability in the Infarct Zone Following Myocardial
      Infarction.
AB  - The goal of reperfusion strategies in patients with acute myocardial infarction
      is to salvage myocardium within the infarct zone at risk from the acute
      occlusion. The status of wall motion and thickening within the infarct zone is an
      imprecise guide to the extent of salvage and viability within the infarct zone,
      based on the well-described phenomenon of myocardial stunning. However, knowledge
      of significant salvage and preserved viability within an infarct zone soon after
      infarction has important implications regarding clinical decision making for
      catheterization and potential revascularization: given preserved viability,
      restoration of normal coronary flow in the setting of a severe residual stenosis
      or occlusion would be expected to result in significant recovery of regional, and
      possibly global left ventricular function, with attendant implications for
      prognosis and outcome.This review will critically explore imaging techniques
      regarding their ability to discern myocardial viability within the infarct zone
      soon after myocardial infarction, including electrocardiography, angiography,
      echocardiography, and radionuclide studies of myocardial perfusion, metabolism
      and cell membrane integrity.

PMID- 10639264
TI  - Invasive Strategies to Achieve Infarct-Related Artery Patency.
AB  - Randomized trials of reperfusion therapy completed over the past decade have
      engendered the open-artery hypothesis. Collectively, patients with patent infarct
      related arteries have fewer complications of their myocardial infarction,
      salutary effects on ventricular remodeling, and better survival. Thrombolytic
      therapy has been widely regarded as the most appropriate initial therapy for
      acute myocardial infarction (AMI), particularly in the community setting. At
      institutions with the appropriate resources and expertise, primary angioplasty
      may be the treatment of choice for patients with AMI presenting within 6 hours.
      Mechanical reperfusion strategies such as angioplasty are quite effective and may
      be more appropriate for selected patient populations, such as those in
      cardiogenic shock or who have compelling contraindications to thrombolytic
      therapy. For these patients, timely mechanical reperfusion can lead to prompt
      hemodynamic stability and significant improvement in prognosis. Balloon
      angioplasty, and to a lesser extent other mechanical interventions, are effective
      therapy for patients with failed thrombolysis or recurrent spontaneous ischemia
      after initial reperfusion therapy. Elective mechanical revascularization after
      AMI can be performed with a high degree of success, a low rate of complication,
      and a good long-term outcome, but there are no compelling data to support routine
      angioplasty, ostensibly to create an "open artery", for patients with clinical
      reperfusion and no spontaneous or inducible ischemia. Finally, all interventions,
      whether chemical or mechanical, will be required to be cost effective as well as
      clinically effective. As we move to a managed care environment in the latter half
      of this decade, value will replace technology as the prominent influence in
      American medicine.

PMID- 10639266
TI  - The Open Artery: Electrophysiologic Considerations.
AB  - Prompt opening of the infarct-related artery reduces mortality and subsequent
      morbid events. Not all benefit of timely thrombolysis or angioplasty appears to
      be accounted for by myocardial preservation. A favorable modification of the
      electrophysiologic postinfarction milieu by a patent infarct-related artery has
      been proposed to help explain this improved outcome. This review investigates the
      support for such a hypothesis. Long-term follow-up data from controlled trials is
      scarce but suggests that episodes of life-threatening ventricular arrhythmias and
      sudden cardiac death are less frequent after thrombolysis with a patent infarct
      related artery. The preponderance of data investigate the modification of
      postinfarction risk stratification parameters, including the signal-averaged
      electrocardiogram, assessment of heart-rate variability, response to programmed
      extrastimuli, and dispersion of refractoriness. Reduction of the incidence of
      late potentials after thrombolysis has been reported by many, but not all,
      investigators. Differences in signal-averaging technique and timing may help
      explain the disparity of findings. A patent infarct-related artery is associated
      with a reduction in late potential incidence. Heart-rate variability, a measure
      of autonomic balance, appears to be improved in those high-risk patients who
      receive thrombolysis. Likewise, most investigators reported an association of
      improved heart-rate variability with a patent infarct-related artery. QT interval
      dispersion, a measure of ventricular arrhythmic risk, declines as antegrade
      infarct-related artery flow improves. High-risk patients undergoing programmed
      extrastimuli have a lower incidence of inducibility and an improved response to
      pharmacologic therapy after thrombolysis or with a patent infarct-related artery.
      The mechanisms of arterial flow's modulation of electrophysiologic substrate
      remains to be elucidated. Long-term follow-up of large post-infarction
      populations will be necessary to demonstrate benefit conclusively.

PMID- 10639265
TI  - Coronary Artery Patency and Survival in Clinical Trials.
AB  - Central to many of the major advances seen in the treatment of acute myocardial
      infarction over the last 15 years has been the concept that reperfusion by
      thrombolytic therapy, by producing early patency of an infarct-related artery,
      salvages myocardium and preserves left ventricular function. Large clinical
      trials have confirmed the mortality benefits of thrombolytic therapy, which has
      become the standard worldwide treatment. It is increasingly evident that complete
      reperfusion (TIMI 3 flow) is needed to achieve the optimum patient outcome. In
      addition, the benefits of microvascular reperfusion are now being recognized. The
      evaluation of new regimens and therapies to improve early patency are exciting
      current developments. Recently it has been shown for the first time that late
      patency of the infarct-related artery is an independent predictor of survival.
      This extension of the open-artery theory has major implications for both the
      treatment of acute myocardial infarction and future thrombolytic and
      revascularization policies for surviving patients.

PMID- 10639268
TI  - Key References in the Open-Artery Hypothesis.

PMID- 10639267
TI  - Early, Complete Infarct Vessel Patency: Arriving at a Gold Standard for Future
      Clinical Investigation in Myocardial Reperfusion.
AB  - Early clinical trials of thrombolytic therapy in the setting of acute myocardial
      infarction (AMI) demonstrated that early angiographic reperfusion correlated with
      improved survival. This supported the open-artery hypothesis that early
      reperfusion decreases infarct size, improves left ventricular function, and
      improves survival. Two subsequent comparative thrombolytic trials showed no
      difference in left ventricular function or survival between agents with different
      rates of reperfusion. Additionally, reduction in mortality was demonstrated
      without improvement in left ventricular function and with the late administration
      of thrombolytic therapy. Therefore, there was a real question as to the
      importance of infarct vessel patency, and its relation to clinical outcome. This
      article discusses the various markers of coronary artery patency, their relation
      to clinical outcome, and how they reflect perfusion at the tissue level. The
      coronary angiogram gives a snapshot view of the infarct-related artery (IRA) that
      does not reflect the dynamic process of vessel reocclusion and recanalization.
      The patent artery is therefore "open" at only a given time frame, and may undergo
      cyclic or complete reocclusion. Angiographically characterized flow has been
      demonstrated to be more clinically meaningful. The GUSTO-I trial was designed to
      test the open-artery hypothesis. This trial confirmed that improved early IRA
      patency and optimal (TIMI-3) flow correlated with improved survival. The presence
      of TIMI-3 flow in the IRA has consistently demonstrated significant improvement
      in patient morbidity and mortality, and conversely, less than optimal, but still
      "patent" (TIMI-2) flow in the IRA correlates with clinical outcomes observed in
      patients with occluded infarct vessels. Even TIMI-3 flow in the IRA does not
      always confirm perfusion of the myocardium at risk. Therefore, the "patent" IRA
      can be subsequently compromised by intermittent patency, reocclusion, less than
      TIMI-3 flow, and a "no-reflow" effect at the tissue level. The development of
      accurate, reliable non-invasive markers of IRA patency is crucial. This would
      allow a more selective application of invasive and interventional techniques to
      restore patency to the IRA. The merits and faults of these noninvasive markers
      are discussed. The ideal gold standard for establishing the adequacy of therapy
      in AMI is one that could detect rapid, complete, and sustained coronary
      reperfusion with adequate myocardial perfusion. Current technologic achievements
      allow an approach to this ideal; however, as of 1997, the coronary angiogram
      demonstrating TIMI-3 flow represents the clinically proven standard of optimal
      therapeutic efficacy.

PMID- 10639269
TI  - The Essence Trial: Efficacy and Safety of Subcutaneous Enoxaparin in Unstable
      Angina and Non-Q-Wave MI: A Double-Blind, Randomized, Parallel-Group, Multicenter
      Study Comparing Enoxaparin and Intravenous Unfractionated Heparin: Methods and
      Design.
AB  - Antithrombotic therapy reduces the risk of recurrent ischemic events in patients
      with unstable angina. The primary aim of the ESSENCE trial is to evaluate the
      efficacy of enoxaparin (low molecular weight heparin) versus unfractionated
      heparin, plus aspirin, in patients with rest angina or non-Q-wave infarction.
      This is a randomized, double-blind, placebo-controlled study of 3180 patients
      comparing enoxaparin, 1 mg/kg sc bid, with unfractionated heparin via continuous
      iv infusion to maintain the aPTT at 2 x control. Patients within 24 hours of the
      onset of acute myocardial ischemia without ST elevation are eligible, and trial
      therapy is administered for a minimum of 48 hours to a maximum of 8 days. Primary
      endpoints analyzed are death, myocardial infarction (MI), or recurrent angina at
      14 days. Currently 3019 patients have been randomized in 10 countries. The mean
      age is 64 years, 33% are female, and 46% have had a prior MI. The overall event
      rates at 14 days are 1.7% mortality, 5.9% subsequent MI, and 17% recurrent
      angina. The composite triple endpoint rate is 23.6%. Recruitment should be
      complete by June 1996. The methods and design of the study are presented in this
      article.

PMID- 10639270
TI  - Prospective Comparison of Patient Characteristics and Outcome of Non-prior
      Aspirin Users versus Aspirin Users with Unstable Angina or Non-Q-Wave Myocardial
      Infarction Treated with Combination Antithrombotic Therapy.
AB  - The objective of this study was to determine if aspirin users presenting with
      acute coronary syndromes are at higher risk for subsequent clinical events. In a
      trial evaluating combination antithrombotic therapy in resting angina or non-Q
      wave myocardial infarction (MI), patients were prospectively dichotomized on
      admission into nonprior versus recent aspirin users. Then 105 nonprior users and
      144 users were randomized to treatment with aspirin plus heparin/warfarin for 12
      weeks. Recurrent myocardial ischemia occurring during the 12-week follow-up
      period was defined as recurrent angina (with electrocardiographic changes or
      prompting coronary revascularization), MI, or death. Prior aspirin users had a
      significantly higher incidence of previous MI, prior bypass grafting, beta
      blocker use, or hypertension (p </= 0.003) and were more likely to present with
      unstable angina as opposed to non-Q-wave MI. (p </= 0.008). The cumulative
      probability of recurrent ischemic endpoints for nonprior versus recent users was
      10% versus 21% at 14 days (log rank p = 0.03), and 19% versus 29%, at 12 weeks (p
      = 0.06). Using the Cox model, adjusting for variables significantly associated
      with outcome, aspirin use remained a significant predictor of 14-day outcome (p =
      0.04) but not of 12-week outcome (p = 0.06). In conclusion, even after adjusting
      for significant differences in baseline variables, aspirin users presenting with
      rest angina or non-Q-infarction have a worse short-term prognosis in spite of
      maximal medical therapy.

PMID- 10639271
TI  - Rescue PTCA Following Failed Thrombolysis and Primary PTCA: A Retrospective Study
      of Angiographic and Clinical Outcome.
AB  - Evidence is increasing that a patent culprit artery improves the prognosis of
      patients with acute myocardial infarction (AMI). Primary percutaneous
      transluminal coronary angioplasty (PTCA) has shown to be more effective than
      thrombolytic therapy alone. How effective is rescue PTCA after failed
      thrombolytic treatment? In a retrospective analysis, 176 consecutive patients
      with AMI and TIMI 0 or 1 perfusion grade were included. Patients had either
      rescue PTCA after failed thrombolysis (100 patients) or primary PTCA (76
      patients). Angiographic data and in-hospital and 1-year outcome were analyzed.
      Comparison of baseline data of the two groups showed a higher proportion of long
      standing angina and use of nitrates and aspirin in the primary PTCA group. Also,
      the delay between the onset of pain and PTCA was not significantly different,
      with a mean of 222 minutes for rescue PTCA and 245 minutes for primary PTCA (p =
      0.52). The angiographic outcomes in the rescue PTCA group and the primary PTCA
      group were identical: The intervention was successful (TIMI 3 flow and residual
      stenosis <50%) in 86.0% and 85.5%, respectively. Complication rates of the
      procedure were also similar, except for bleeding complications. Blood transfusion
      was only needed after rescue PTCA in 3.0% versus 0.0% in primary PTCA patients.
      Clinical outcomes during hospital stay in terms of death rate (4.0% and 6.6%),
      reinfarction (6.0% and 3.9%), recurrent angina (16.0% and 11.8%), and repeat
      interventions were comparable, as was the first-year outcome. Failed PTCA was the
      most important predictor of a poor 1-year outcome; 28.0% died after failed PTCA
      versus 4.6% after successful PTCA (p < 0.001). In this retrospective analysis of
      176 AMI patients, angiographic and clinical outcome, including a 1-year follow-up
      in patients who had rescue PTCA after failed thrombolysis, were of the same
      magnitude of patients in whom primary PTCA was performed. These findings suggest
      that in this subset the outcome of patients with rescue PTCA because of failed
      thrombolysis is good and is comparable with patients who underwent primary PTCA.

PMID- 10639272
TI  - Low-Dose Vitamin K Therapy in Excessively Anticoagulated Patients: A Dose-Finding
      Study.
AB  - Rapid reduction of excessively high international normalized ratio (INR) values
      into the therapeutic range is necessary in patients who must be maintained on
      oral anticoagulants but who present with an overdose. We prospectively studied
      the effect of observation alone versus escalating low doses of intravenous
      vitamin K on 23 patients presenting with no overt evidence of hemorrhage and INR
      values in excess of 10. Two of six patients observed without intervention
      developed spontaneous hemorrhage. Only one of the observed patients and none of 4
      patients given 100-200 ug-vitamin K had INR values less than 5.0 by 24 hours.
      Three of the four patients receiving 500 ug of vitamin K had INR values less than
      5.0, with two of these being less than 3.5 within the first 24 hours. Nine
      patients receiving 1000 ug of vitamin K had INR values between 1.7 and 3.5 by 24
      hours. In none of these nine patients did the INR subsequently normalize, and
      there were no difficulties re-establishing anticoagulant therapy. No adverse
      effects were noted in any of the patients receiving intravenous vitamin K. We
      recommend 1000 ug of intravenous vitamin K as a safe and effective means of
      rapidly reversing excessively anticoagulated patients presenting with INR values
      greater than 10 units.

PMID- 10639273
TI  - Adjunctive Therapy with an Antithrombotic Drug Can Prevent Reocclusion and Induce
      Residual Thrombus Reduction After Percutaneous Transcatheter Angioplasty of the
      Thrombotic Lesions.
AB  - Acute reocclusion after successful angioplasty is a severe complication. The
      preventive effects of heparin, the synthetic antithrombin, argtroban, and the
      defibrinogenating agent batroxobin on reocclusion after balloon angioplasty of
      thrombotic occlusions were evaluated in canine iliac arteries. After the 2-hour
      old thrombus was evaluated by angiography and angioscopy, percutaneous
      transcatheter angioplasty (PTA) was performed on the thrombotic stenosis. We used
      one of the three agents, heparin (100 U/kg), the antithrombin argatroban (0.3
      mg/kg), or the defibrinogenating agent batroxobin (0.3 U/kg). Then angioscopy and
      angiography were performed before, just after, and 2 hours after PTA. After PTA,
      angiography revealed a marked reduction in percent stenosis in all groups (from
      88 +/- 8% to 24 +/- 4% in the heparin group, from 79 +/- 7% to 26 + 11% in the
      argatroban group and from 89 +/- 12% to 32 +/- 7% in the batroxobin group). At 2
      hours after PTA, angiography demonstrated a greater reduction in percent stenosis
      with argatroban (from 26 +/- 11% to 9 +/- 3%) and batroxobin (from 32 +/- 7% to
      10 +/- 8%), and maintenance of percent stenosis reduced by PTA with heparin (from
      24 +/- 5% to 28 +/- 9%) when compared with the significant reversal of percent
      obstruction in the control side. Angioscopic visualization also demonstrated a
      similar trend. These results show that these antithrombotic drugs have a
      preventive effect on reocclusion after balloon angioplasty for thrombotic
      obstruction.

PMID- 10639274
TI  - Synthesis and structure-activity relationships of new 1, 3-disubstituted
      cyclohexanes as structurally rigid leukotriene B(4) receptor antagonists.
AB  - A series of 1-hydroxy-3-?3-hydroxy-7-phenyl-1-hepten-1-yl cyclohexane acetic acid
      derivatives was designed based on postulated active conformation of leukotriene
      B(4) (LTB(4)) and evaluated as human cell surface LTB(4) receptor (BLTR)
      antagonists. Binding was determined through ?(3)HLTB(4) displacement from human
      neutrophils and receptor antagonistic assays by in vitro measurements of
      inhibition of leukocyte chemotaxis induced by LTB(4). On the basis of these
      assays, a structure-affinity relationship was investigated. Optimization of the
      acid chain length and omega-substitution of a phenyl group on the lipophilic tail
      were shown to be critical for binding activity. These modifications led to the
      discovery of compounds with submicromolar potency and selective BLTR antagonism.
      The most potent compound 3balpha (IC(50) = 250 nM) was found to significantly
      inhibit oedema formation in a topical model of phorbolester-induced inflammation.
      Substantial improvement of in vitro potency was achieved by modification of the
      carboxylic acid function leading to the identification of the N,N-dimethylamide
      series. Compound 5balpha, free of agonist activity, displayed higher potency in
      receptor binding with an IC(50) of 40 nM. These results support the hypothesis
      that the spatial relationship between the carboxylic acid and allylic hydroxyl
      functions is crucial for high binding affinity with BLTR.

PMID- 10639275
TI  - Na(+)-glucose cotransporter (SGLT) inhibitors as antidiabetic agents. 4.
      Synthesis and pharmacological properties of 4'-dehydroxyphlorizin derivatives
      substituted on the B ring.
AB  - In our studies of Na(+)-glucose cotransporter (SGLT) inhibitors as antidiabetic
      agents, a series of novel 4'-dehydroxyphlorizin derivatives substituted on the B
      ring was prepared and their effects on urinary glucose excretion were evaluated
      in rats. Introduction of only a small alkyl group at the 4'-position increased
      the activity, and 3-(benzo?bfuran-5-yl)-2',6'-dihydroxy-4'-methylpropiophenone 2'
      O-beta-D-glucopyranoside (4) showed the most potent effect. To overcome
      hydrolysis of compound 4 by beta-glucosidase in the digestive tract, the OH
      groups on the glucose moiety of compound 4 were modified. Three prodrugs (5, 42,
      and 55) were more potent than the parent compound 4 by oral administration, and
      finally 3-(benzo?bfuran-5-yl)-2',6'-dihydroxy-4'-methylpropiophenone 2'-O-(6-O
      methoxycarbonyl-beta-D-glucopyranoside) (5) was selected as a new promising
      candidate. Compound 5 was metabolized mainly by liver esterase to the active form
      (4), which was about 10 times more potent than 5 in inhibiting SGLT. In oral
      glucose tolerance test in db/db mice, compound 5 dose-dependently suppressed the
      elevation of glucose levels. Single administration of 5 reduced hyperglycemia
      concurrently with increase of glucose excretion into urine in diabetic KK-A(y)
      mice. Furthermore, compound 5 suppressed the elevation of blood glucose levels
      but did not lower it below the normal level even in fasted conditions in KK-A(y)
      mice. Additionally, long-term treatment with 5 dose-dependently reduced
      hyperglycemia and HbA1c in KK-A(y) mice. These pharmacological data strongly
      suggest that compound 5 has a therapeutic potential in the treatment of NIDDM.

PMID- 10639277
TI  - Molecular recognition of modified adenine nucleotides by the P2Y(1)-receptor. 2.
      A computational approach.
AB  - The molecular recognition of C2- or C8-substituted ATP derivatives by the P2Y(1)
      receptor (P2Y(1)-R) is analyzed using ab initio quantum mechanical calculations.
      Parameters that may determine ligand specificity toward P2Y(1)-R were examined on
      reduced models and correlated with the biochemical data for the parent compounds.
      These include tautomerism and protonation energy in the gas and aqueous phases,
      as well as molecular electrostatic potential (MEP) and dipole moment vector. The
      calculated electronic parameters cannot explain the inactivity of the C8
      substituted ATP derivatives, nor the difference in activity among the C2
      substituted ATP analogues. These results indicate that neither tautomerism nor
      changes in the electronic distribution of the adenine ring play a major role in
      determining binding specificity of adenine nucleotides to the receptor. It is
      suggested that the higher potency of the C2-substituted ATP derivatives, compared
      to ATP, might be due to interaction between the C2 side chain heteroatom and the
      receptor. Furthermore, the interaction of the C2 alkyl side chain with a
      hydrophobic pocket at the receptor binding site is suggested. In addition, NMR
      data in the companion paper indicate that the inactivity of the C8-substituted
      ATP analogues may be due to steric and conformational, rather than electronic,
      effects.

PMID- 10639276
TI  - Molecular recognition of modified adenine nucleotides by the P2Y(1)-receptor. 1.
      A synthetic, biochemical, and NMR approach.
AB  - The remarkably high potencies of 2-thioether-adenine nucleotides regarding the
      activation of the P2Y(1)-receptor (P2Y(1)-R) in turkey erythrocyte membranes
      represent some of the largest substitution-promoted increases in potencies over
      that of a natural receptor ligand. This paper describes the investigation
      regarding the origin of the high potency of these P2Y(1)-R ligands over that of
      ATP. For this study, an integrated approach was employed combining the synthesis
      of new ATP analogues, their biochemical evaluation, and their SAR analysis
      involving NMR experiments and theoretical calculations. These experiments and
      calculations were performed to elucidate the conformation and to evaluate the
      electronic nature of the investigated P2Y(1)-R ligands. ATP analogues synthesized
      included derivatives where C2 or C8 positions were substituted with electron
      donating groups such as ethers, thioethers, or amines. The compounds were tested
      for their potency to induce P2Y(1)-R-mediated activation of phospholipase C in
      turkey erythrocytes and Ca(2+) response in rat astrocytes. 8-Substituted ATP and
      AMP derivatives had little or no effect on phospholipase C or on calcium levels,
      whereas the corresponding 2-substituted ATP analogues potently increased the
      levels of inositol phosphates and ?Ca(2+)(i). AMP analogues were ineffective
      except for 2-butylthio-AMP which induced a small Ca(2+) response. P2Y(1)-R
      activity of these compounds was demonstrated by testing these ligands also on
      NG108-15 neuroblastoma x glioma hybrid cells. NMR data together with theoretical
      calculations imply that steric, rather than electronic, effects play a major role
      in ligand binding to the P2Y(1)-R. Hydrophobic interactions and H-bonds of the C2
      substituent appear to be important determinants of a P2Y(1)-R ligand affinity.

PMID- 10639278
TI  - Comparative molecular field analysis of fungal squalene epoxidase inhibitors.
AB  - Comparative molecular field analysis (CoMFA) of fungal squalene epoxidase
      inhibitors exhibiting antifungal activity reported in terms of minimum inhibitory
      concentration (MIC) was performed. Ninety-two molecules belonging to different
      chemical classes, namely terbinafine analogues, benzylamines,
      homopropargylamines, and carbon analogues were divided into training set and test
      set. The initial conformations of the inhibitors obtained from molecular dynamics
      simulations for 50 ps in aqueous solution were used in the study. Out of three
      charges used in the study, Gasteiger-H]uckel charges result in models with good
      internal predictivity. Initial analysis of 92 molecules (analysis A) resulted in
      models with low predictive r(2) values for activity against three organisms. This
      data set was modified by exclusion of 13 molecules, and analysis was performed
      again. This analysis of 79 molecules (analysis B) resulted in improvement in
      predictivity of the CoMFA models and cross-validated r(2) values of 0.583, 0.509,
      and 0.502 for Candida albicans, Aspergillus fumigatus, and Trichophyton
      mentagrophytes, respectively. These models were used to predict the activities of
      the molecules belonging to the test set. The models from analysis B show better
      correlative and predictive properties than analysis A. Comparison of CoMFA
      contour maps for activity against three different fungi revealed differentiating
      structural requirements.

PMID- 10639279
TI  - Exploring the structure-activity relationships of [1-(4-tert-butyl-3'
      hydroxy)benzhydryl-4-benzylpiperazine] (SL-3111), a high-affinity and selective
      delta-opioid receptor nonpeptide agonist ligand.
AB  - SL-3111 [1-(4-tert-butyl-3'-hydroxy)benzhydryl-4-benzylpiperazine] is a de novo
      designed, high-affinity and selective nonpeptide peptidomimetic agonist of the
      delta-opioid receptor. In a previous report we had described the unique
      biological characteristics of this ligand and also a need for further structural
      evaluation.(6) To pursue this, we have introduced a completely different
      heterocyclic template (2 and 3), which, based on molecular modeling studies, may
      present the required structural features to properly orient the pharmacophore
      groups. We also have made more subtle changes to the original piperazine scaffold
      (5 and 11). The biological activities of these compounds revealed an important
      participation of the scaffold in the ligand-receptor interaction. To further
      explore functional diversity on the scaffold, we have maintained the original
      piperazine ring and introduced four different functionalities at position 2 of
      the heterocyclic ring (15a-d; a = CH(2)-O-CH(2)-Ph; b = Me; c = CH(2)Ph; d =
      CH(2)OH). The biological activities observed for these compounds showed a very
      interesting trend in terms of the steric effects of the groups introduced at this
      position. A decrease of almost 2000-fold in affinity and potency at the delta
      receptor was observed for 15c compared with 15b. This difference may be explained
      if we postulate that the bioactive conformation of these peptidomimetics is close
      to the minimal energy conformations calculated in our study. On the basis of
      these findings we have realized the importance of this position to further
      explore and simplify the structure of future generations of peptidomimetic
      ligands.

PMID- 10639280
TI  - Design and structure-activity relationship of a new class of potent VEGF receptor
      tyrosine kinase inhibitors.
AB  - A series of substituted 4-anilinoquinazolines and related compounds were
      synthesized as potential inhibitors of vascular endothelial growth factor (VEGF)
      receptor (Flt and KDR) tyrosine kinase activity. Enzyme screening indicated that
      a narrow structure-activity relationship (SAR) existed for the bicyclic ring
      system, with quinazolines, quinolines, and cinnolines having activity and with
      quinazolines and quinolines generally being preferred. Substitution of the
      aniline was investigated and clearly indicated that small lipophilic substituents
      such as halogens or methyl were preferred at the C-4' position. Small
      substituents such as hydrogen and fluorine are preferred at the C-2' position.
      Introduction of a hydroxyl group at the meta position of the aniline produced the
      most potent inhibitors of Flt and KDR tyrosine kinases activity with IC(50)
      values in the nanomolar range (e.g. 10, 12, 13, 16, and 18). Investigation of the
      quinazoline C-6 and C-7 positions indicates that a large range of substituents
      are tolerated at C-7, whereas variation at the C-6 is more restricted. At C-7,
      neutral, basic, and heteroaromatic side chains led to very potent compounds, as
      illustrated by the methoxyethoxy derivative 13 (IC(50) < 2 nM). Our inhibitors
      proved to be very selective inhibitors of Flt and KDR tyrosine kinase activity
      when compared to that associated with the FGF receptor (50- to 3800-fold).
      Observed enzyme profiles translated well with respect to potency and selectivity
      for inhibition of growth factor stimulated proliferation of human umbilical vein
      endothelial cells (HUVECs). Oral administration of selected compounds to mice
      produced total plasma levels 6 h after dosing of between 3 and 49 microM. In vivo
      efficacy was demonstrated in a rat uterine oedema assay where significant
      activity was achieved at 60 mg/kg with the meta hydroxy anilinoquinazoline 10.
      Inhibition of growth of human tumors in athymic mice has also been demonstrated:
      compound 34 inhibited the growth of established Calu-6 lung carcinoma xenograft
      by 75% (P < 0.001, one tailed t-test) following daily oral administration of 100
      mg/kg for 21 days.

PMID- 10639281
TI  - Modeling of amino-terminal domains of group I metabotropic glutamate receptors:
      structural motifs affecting ligand selectivity.
AB  - On the basis of a new sequence alignment between the amino terminal domains of
      mGlu1 and mGlu5 receptor subtypes and leucine/isoleucine/valine binding protein
      (LIVBP), three-dimensional models of the binding sites of the two group I
      metabotropic glutamate receptor subtypes were constructed. The 3D-models thus
      obtained showed a high degree of similarity. In the region of the putative
      binding site, identified by Ser165 and Thr188 (mGlu1) or Ser152 and Thr175
      (mGlu5), the only nonconserved residue is Pro369 (mGlu1), which is substituted by
      Gln356 in mGlu5. Although not directly involved in ligand binding, these residues
      may provide a subtle difference in the steric environment of the two active sites
      that may account for the observed subgroup selectivity of recently reported
      ligands.

PMID- 10639282
TI  - Selective inhibitors of glial GABA uptake: synthesis, absolute stereochemistry,
      and pharmacology of the enantiomers of 3-hydroxy-4-amino-4,5,6,7-tetrahydro-1,2
      benzisoxazole (exo-THPO) and analogues.
AB  - 3-Methoxy-4,5,6,7-tetrahydro-1,2-benzisoxazol-4-one (20a), or the corresponding 3
      ethoxy analogue (20b), and 3-chloro-4,5,6, 7-tetrahydro-1,2-benzisothiazol-4-one
      (51) were synthesized by regioselective chromic acid oxidation of the respective
      bicyclic tetrahydrobenzenes 19a,b and 50, and they were used as key intermediates
      for the syntheses of the target zwitterionic 3-isoxazolols 8-15 and 3
      isothiazolols 16 and 17, respectively. These reaction sequences involved
      different reductive processes. Whereas (RS)-4-amino-3-hydroxy-4,5,6,7-tetrahydro
      1,2-benzisoxazole (8, exo-THPO) was synthesized via aluminum amalgam reduction of
      oxime 22a or 22b, compounds 9, 11-13, and 15-17 were obtained via reductive
      aminations. Compound 10 was synthesized via N-ethylation of the N-Boc-protected
      primary amine 25. The enantiomers of 8 were obtained in high enantiomeric
      purities (ee >/= 99.1%) via the diastereomeric amides 32 and 33, synthesized from
      the primary amine 23b and (R)-alpha-methoxyphenylacetyl chloride and subsequent
      separation by preparative HPLC. The enantiomers of 9 were prepared analogously
      from the secondary amine 27. On the basis of X-ray crystallographic analyses, the
      configuration of oxime 22a was shown to be E and the absolute configurations of (
      )-8 x HCl and (+)-9 x HBr were established to be R. The effects of the target
      compounds on GABA uptake mechanisms in vitro were measured using a rat brain
      synaptosomal preparation and primary cultures of mouse cortical neurons and glia
      cells (astrocytes). Whereas the classical GABA uptake inhibitor, (R)-nipecotic
      acid (2), nonselectively inhibits neuronal (IC(50) = 12 microM) and glial (IC(50)
      = 16 microM) GABA uptake and 4,5,6,7-tetrahydroisoxazolo?4,5-cpyridin-3-ol (1,
      THPO) shows some selectivity for glial (IC(50) = 268 microM) versus neuronal
      (IC(50) = 530 microM) GABA uptake, exo-THPO (8) was shown to be more potent as an
      inhibitor of glial (IC(50) = 200 microM) rather than neuronal (IC(50) = 900
      microM) GABA uptake. This selectivity was more pronounced for 9, which showed
      IC(50) values of 40 and 500 microM as an inhibitor of glial and neuronal GABA
      uptake, respectively. These effects of 8 and 9 proved to be enantioselective, (R)
      (-)-8 and (R)-(+)-9 being the active inhibitors of both uptake systems. The
      selectivity of 9 as a glial GABA uptake inhibitor was largely lost by replacing
      the N-methyl group of 9 by an ethyl group, compound 10 being an almost equipotent
      inhibitor of glial (IC(50) = 280 microM) and neuronal (IC(50) = 400 microM) GABA
      uptake. The remaining target compounds, 11-17, were very weak or inactive as
      inhibitors of both uptake systems. Compounds 9-13 and 15 were shown to be
      essentially inactive against isoniazide-induced convulsions in mice after
      subcutaneous administration. The isomeric pivaloyloxymethyl derivatives of 9,
      compounds 43 and 44, were synthesized and tested as potential prodrugs in the
      isoniazide animal model. Both 43 (ED(50) = 150 micromol/kg) and 44 (ED(50) = 220
      micromol/kg) showed anticonvulsant effects, and this effect of 43 was shown to
      reside in the (R)-(+)-enantiomer, 45 (ED(50) = 44 micromol/kg). Compound 9 also
      showed anticonvulsant activity when administered intracerebroventricularly
      (ED(50) = 59 nmol).

PMID- 10639283
TI  - Synthesis, characterization, and structure-activity relationships of amidine
      substituted (bis)benzylidene-cycloketone olefin isomers as potent and selective
      factor Xa inhibitors.
AB  - Factor Xa (FXa) is a trypsin-like serine protease that plays a key role in blood
      coagulation linking the intrinsic and extrinsic pathways to the final common
      pathway of the coagulation cascade. During our initial studies, we observed
      facile photochemical conversion of the known FXa/tPA inhibitor, BABCH ?(E,E)-2, 7
      bis(4-amidinobenzylidene)cycloheptan-1-one, 1a, to the corresponding (Z,Z) olefin
      isomer, 1c (FXa K(i) = 0.66 nM), which was over 25,000 times more potent than the
      corresponding (E,E) isomer (1a, FXa K(i) = 17 000 nM). In order to determine the
      scope of this observation, we expanded on our initial investigation through the
      preparation of the olefin isomers in a homologous series of cycloalkanone rings,
      4-substituted cyclohexanone analogues, and modified amidine derivatives. In most
      cases the order of potency of the olefin isomers was (Z,Z) > (E,Z) > (E,E) with
      the cycloheptanone analogue (1c) showing the most potent factor Xa inhibitory
      activity. In addition, we found that selectivity versus thrombin (FIIa) can be
      dramatically improved by the addition of a carboxylic acid group to the
      cycloalkanone ring as seen with 8c (FXa K(i) = 6.9 nM, FIIa K(i) > 50,000 nM).
      Compounds with one or both of the amidine groups substituted with N-alkyl
      substituents or replaced with amide groups led to a significant loss of activity.
      In this report we have demonstrated the importance of the two amidine groups, the
      cycloheptanone ring, and the (Z,Z) olefin configuration for maximum inhibition of
      FXa within the BABCH template. The results from this study provided the
      foundation for the discovery of potent, selective, and orally active FXa
      inhibitors.

PMID- 10639284
TI  - Design, synthesis, and biological evaluation of matrix metalloproteinase
      inhibitors derived from a modified proline scaffold.
AB  - The synthesis and structure-activity relationship (SAR) studies of a series of
      proline-based matrix metalloproteinase inhibitors are described. The data reveal
      a remarkable potency enhancement in those compounds that contain an sp(2) center
      at the C-4 carbon of the ring relative to similar, saturated compounds. This
      effect was noted in compounds that contained a functionalized oxime moiety or an
      exomethylene at C-4, and the potencies were typically <10 nM for MMP-3 and <100
      nM for MMP-1. Comparisons were then made against compounds with similar
      functionality where the C-4 carbon was reduced to sp(3) hybridization and the
      effect was typically an order of magnitude loss in potency. A comparison of
      compounds 14 and 34 exemplifies this observation. An X-ray structure was obtained
      for a stromelysin-inhibitor complex which provided insights into the SAR and
      selectivity trends observed within the series. In vitro intestinal permeability
      data for many compounds was also accumulated.

PMID- 10639285
TI  - 2-(diethylamino)thieno1,3oxazin-4-ones as stable inhibitors of human leukocyte
      elastase.
AB  - A series of 2-(diethylamino)thieno1,3oxazin-4-ones was synthesized and evaluated
      in vitro for inhibitory activity toward human leukocyte elastase (HLE). The
      Gewald thiophene synthesis was utilized to obtain several ethyl 2-aminothiophene
      3-carboxylates. These precursors were subjected to a five-step route to obtain
      thieno2,3-d1,3oxazin-4-ones bearing various substituents at positions 5 and 6.
      Both thieno2,3-d and thieno3,2-d fused oxazin-4-ones possess extraordinary
      chemical stability, which was expressed as rate constants of the alkaline
      hydrolysis. The kinetic parameters of the HLE inhibition were determined. The
      most potent compound, 2-(diethylamino)-4H-1benzothieno2,3-d1,3oxazin-4-one,
      exhibited a K(i) value of 5.8 nM. 2-(Diethylamino)thieno1, 3oxazin-4-ones act as
      acyl-enzyme inhibitors of HLE, similar to the inhibition of serine proteases by
      4H-3,1-benzoxazin-4-ones. The isosteric benzene-thiophene replacement accounts
      for an enhanced stability of the acyl-enzyme intermediates.

PMID- 10639286
TI  - Inhibition of Trypanosoma cruzi trypanothione reductase by acridines: kinetic
      studies and structure-activity relationships.
AB  - Series of 9-amino and 9-thioacridines have been synthesized and studied as
      inhibitors of trypanothione reductase (TR) from Trypanosoma cruzi, the causative
      agent of Chagas' disease. The compounds are structural analogues of the acridine
      drug mepacrine (quinacrine), which is a competitive inhibitor of the parasite
      enzyme, but not of human glutathione reductase, the closest related host enzyme.
      The 9-aminoacridines yielded apparent K(i) values for competitive inhibition
      between 5 and 43 microM. The most effective inhibitors were those with the
      methoxy and chlorine substituents of mepacrine and NH(2) or
      NHCH(CH(3))(CH(2))(4)N(Et)(2) at C9. Detailed kinetic analyses revealed that in
      the case of 9-aminoacridines more than one inhibitor molecule can bind to the
      enzyme. In contrast, the 9-thioacridine derivatives inhibit TR with mixed-type
      kinetics. The kinetic data are discussed in light of the three-dimensional
      structure of the TR-mepacrine complex. The conclusion that structurally very
      similar acridine compounds can give rise to completely different inhibition
      patterns renders modelling studies and quantitative structure-activity
      relationships difficult.

PMID- 10639287
TI  - Probes for narcotic receptor mediated phenomena. 26. Synthesis and biological
      evaluation of diarylmethylpiperazines and diarylmethylpiperidines as novel,
      nonpeptidic delta opioid receptor ligands.
AB  - We recently reported (+)-4-?(alphaR)-alpha-?(2S,5R)-4-allyl-2, 5-dimethyl-1
      piperazinyl?-3-methoxybenzyl-N,N-diethylbenzamide (1b, SNC80) as a novel
      nonpeptidic delta receptor agonist and explored the structure-activity
      relationships (SAR) of a series of related derivatives. We have found that delta
      binding activities and selectivity showed little change when the 3-methoxy group
      in 1b was removed or replaced by the other substituents, whereas the N, N
      diethylbenzamide group is important for interaction with the delta receptor.
      Extensive modification of the piperazine nucleus led to the synthesis of a new
      series of N, N-diethyl(alpha-piperazinylbenzyl)benzamides (2, 3a-e), N, N
      diethyl(alpha-piperidinyl or piperidinylidenebenzyl)benzamides (4a, 5a-c, 6a-b),
      and related derivatives (4b, 7a-c). Several compounds (2, 3a, 3e, 6a) strongly
      bound to the delta receptor with K(i) values in the low nanomolar range. On the
      other hand, the binding affinities of these compounds for the mu and kappa
      receptors were negligible, indicating excellent delta opioid receptor subtype
      selectivity. The two nitrogen atoms on the piperazine nucleus showed different
      SAR in the interaction of this series of compounds at the delta receptor.
      Nitrogen N(4) appears to be an important structural element and is essential for
      electrostatic interaction, while N(1) seems to be unnecessary for recognition at
      the delta receptor.

PMID- 10639289
TI  - Synthesis and biological evaluation of dihydrobenzofuran lignans and related
      compounds as potential antitumor agents that inhibit tubulin polymerization.
AB  - A series of 19 related dihydrobenzofuran lignans and benzofurans was obtained by
      a biomimetic reaction sequence involving oxidative dimerization of p-coumaric,
      caffeic, or ferulic acid methyl esters, followed by derivatization reactions. All
      compounds were evaluated for potential anticancer activity in an in vitro human
      disease-oriented tumor cell line screening panel that consisted of 60 human tumor
      cell lines arranged in nine subpanels, representing diverse histologies. Leukemia
      and breast cancer cell lines were relatively more sensitive to these agents than
      were the other cell lines. Compounds 2c and 2d, but especially 2b (methyl (E)-3
      ?2-(3, 4-dihydroxyphenyl)-7-hydroxy-3-methoxycarbonyl-2, 3-dihydro-1-benzofuran-5
      ylprop-2-enoate), the dimerization product of caffeic acid methyl ester,
      containing a 3',4'-dihydroxyphenyl moiety and a hydroxyl group in position 7 of
      the dihydrobenzofuran ring, showed promising activity. The average GI(50) value
      (the molar drug concentration required for 50% growth inhibition) of 2b was 0.3
      microM. Against three breast cancer cell lines, 2b had a GI(50) value of <10 nM.
      Methylation, reduction of the double bond of the C(3)-side chain, reduction of
      the methoxycarbonyl functionalities to primary alcohols, or oxidation of the
      dihydrobenzofuran ring to a benzofuran system resulted in a decrease or loss of
      cytotoxic activity. Compound 2b inhibited mitosis at micromolar concentrations in
      cell culture through a relatively weak interaction at the colchicine binding site
      of tubulin. In vitro it inhibited tubulin polymerization by 50% at a
      concentration of 13 +/- 1 microM. The 2R, 3R-enantiomer of 2b was twice as active
      as the racemic mixture, while the 2S,3S-enantiomer had minimal activity as an
      inhibitor of tubulin polymerization. These dihydrobenzofuran lignans (2-phenyl
      dihydrobenzofuran derivatives) constitute a new group of antimitotic and
      potential antitumor agents that inhibit tubulin polymerization.

PMID- 10639288
TI  - Tyrosine kinase inhibitors. 16. 6,5,6-tricyclic benzothieno[3, 2-d]pyrimidines
      and pyrimido[5,4-b-] and -[4,5-b]indoles as potent inhibitors of the epidermal
      growth factor receptor tyrosine kinase.
AB  - Several elaborations of the fundamental anilinopyrimidine pharmacophore have been
      reported as potent and selective inhibitors of the epidermal growth factor
      receptor (EGFr) tyrosine kinase. This paper reports on a series of inhibitors
      whereby some 6,5-bicyclic heteroaromatic systems were fused through their C-2 and
      C-3 positions to this anilinopyrimidine pharmacophore. Although the resulting
      tricycles did not produce the enormous potency of some of the (5/6),6,6-bicyclic
      systems, the best of them had IC(50)s for the EGFr TK around 1 nM. Investigation
      of 4-position side chains in the indolopyrimidines confirmed that m-bromoaniline
      was an optimal substituent for potency. Investigation of substitution within the
      C-(benzo)ring of benzothienopyrimidines confirmed that introduction of an extra
      ring can change sharply the effects of substituents when compared to similar
      bicyclic nuclei, and only two substituents were found which even moderately
      enhanced inhibitory activity over the parent compound for this series.

PMID- 10639290
TI  - Combined effect of platination and intercalation upon DNA binding of novel
      cytotoxic Pt-bis(naphthalimide) complexes.
AB  - The reaction of platinum salts with bis(naphthalimide), compound 1, yielded two
      Pt-bis(naphthalimide) complexes, compounds 2 and 3 which differ from each other
      in their leaving groups being 1,1-cyclobutane dicarboxylate or chloride,
      respectively. The testing of the cytotoxic activity of compounds 2 and 3 against
      several tumor cell lines indicated that both compounds may be endowed with
      important antineoplastic properties since they circumvent cisplatin resistance.
      At similar rates of DNA platination (r(b) = 0.025), compounds 2 and 3 unwind
      supercoiled pUC8 DNA by (48 +/- 2) degrees. Altogether, these data suggest (i)
      that the cytotoxic activity of compounds 2 and 3 may be due to a combined effect
      of platination and intercalation and (ii) that the bis(naphthalimide) ligand is a
      suitable "carrier" that favors DNA targeting by cis-Pt(II) centers.

PMID- 10639291
TI  - Novel, potent, semisynthetic antimalarial carba analogues of the first-generation
      1,2,4-trioxane artemether.
AB  - Ten novel, second-generation, fluorinated ether and ester analogues of the potent
      first-generation analogues artemether (4a) and arteether (4b) have been designed
      and synthesized. All of the compounds demonstrate high antimalarial potency in
      vitro against the chloroquine-sensitive HB3 and -resistant K1 strains of
      Plasmodium falciparum. The most potent derivative 8 was 15 times more potent than
      artemisinin (2) against the HB3 strain of P. falciparum. In vivo, versus
      Plasmodium berghei in the mouse, selected derivatives were generally less potent
      than dihydroartemisinin with ED(50) values of between 5 and 8 mg/kg. On the basis
      of the products obtained from the in vitro biomimetic Fe(II)-mediated
      decomposition of 8, the radical mediator of biological activity of this series
      may be different from that of the parent drug, artemisinin (2).

PMID- 10639292
TI  - Cardiac marker elevation after cardioversion: sorting out chicken and egg.

PMID- 10639293
TI  - Sex differences in outcome following community-based cardiopulmonary arrest.

PMID- 10639294
TI  - Is the exercise test of use in post-menopausal women with unstable coronary
      artery disease?

PMID- 10639295
TI  - Amiodarone after acute myocardial infarction.

PMID- 10639296
TI  - Do statins and hormonal replacement therapy in combination reduce cardiovascular
      risk in postmenopausal women?

PMID- 10639297
TI  - The not so obvious truth.

PMID- 10639298
TI  - Continuing medical education in cardiology: the ESC perspective. European Society
      of Cardiology.

PMID- 10639299
TI  - Reuse of coronary angioplasty balloon catheters: yes or no?

PMID- 10639300
TI  - Effects of simvastatin only or in combination with continuous combined hormone
      replacement therapy on serum lipid levels in hypercholesterolaemic post
      menopausal women.
AB  - AIMS: To evaluate the effects of simvastatin only or combined with continuous
      hormone replacement therapy on the serum lipid profile in hypercholesterolaemic
      post-menopausal women. METHODS AND RESULTS: One hundred hypercholesterolaemic
      post-menopausal women were given either simvastatin 10 mg daily together with
      oestrogen 0.625 mg and medroxyprogesterone 2.5 mg daily (HRT+simvastatin group)
      (n:50) or simvastatin 10 mg daily (simvastatin only group) (n:50) in a
      prospective manner. Serum total, low density lipoprotein, and high density
      lipoprotein cholesterol and triglyceride levels were measured at baseline, at 3
      and 6 months. The initial mean (+/-SD) cholesterol values were as follows for the
      HRT+simvastatin group and the simvastatin only group, respectively: total
      cholesterol 240. 0+/-28.0 and 248.9+/-28.2 mg x dl(-1); low density lipoprotein
      cholesterol 174.7+/-25.6 and 175.1+/-25.9 mg x dl(-1); high density lipoprotein
      cholesterol 37.2+/-5.0 and 39.9+/-7.3 mg x dl(-1). Compared with the baseline,
      total and low density lipoprotein cholesterol levels decreased; and high density
      lipoprotein cholesterol levels increased significantly at 3 and 6 months in both
      groups. However, the mean percent reduction in total cholesterol and low density
      lipoprotein cholesterol was significantly greater in the HRT+ simvastatin group
      compared with the simvastatin only group both at 3 months (12.3+/-7.0% vs 8.9+/
      6.2%;P<0.01; and 19.0+/-10.6% vs 13.2+/-10.4%;P< 0.005, respectively) and at 6
      months (14.6+/-7.7% vs 11.3+/-7.4%;P<0.05 and 23.3+/-9.7% vs 15.8+/
      12.3%;P<0.005, respectively). The mean percent increase in serum high density
      lipoprotein cholesterol concentrations was also significantly greater in the
      HRT+simvastatin group compared with the simvastatin only group at both times
      (14.6+/-11.8% vs 9.8+/-11.8%;P<0.005, at 3 months, and 21.3+/-15.2% vs 11.1+/
      12.5;P<0.005, at 6 months, respectively). Furthermore, significantly more
      patients in the HRT+simvastatin group than in the simvastatin only group attained
      their target treatment goals dictated by the National Cholesterol Education
      Program Adult Treatment Panel II Guidelines. Although the mean percent decrease
      in triglyceride levels was significantly greater in the HRT+simvastatin group at
      3 months, the significance disappeared at 6 months. CONCLUSION: The combination
      of simvastatin and continuous combined hormone replacement therapy seems to be
      more effective than simvastatin only in the treatment of hypercholesterolaemia in
      post-menopausal women.

PMID- 10639301
TI  - Morbidity and mortality following early administration of amiodarone in acute
      myocardial infarction. GEMICA study investigators, GEMA Group, Buenos Aires,
      Argentina. Grupo de Estudios Multicentricos en Argentina.
AB  - AIMS: The objective of this study was to ascertain the effect of intravenous and
      oral amiodarone on morbidity and mortality in patients during the first hours
      after the onset of an acute myocardial infarction. METHODS AND RESULTS: A cohort
      of 1073 patients admitted to the CCU within 24 h of the onset of symptoms of an
      acute myocardial infarction and heart failure (Killip and Kimball A-B) were
      randomized to receive amiodarone (n=542) or placebo (n=531) for 6 months. Because
      of the higher mortality, on an interim analysis, from a 'high dose' of amiodarone
      or placebo (516 patients) the protocol was changed to a 'low dose' or placebo
      (557 patients). Mortality with high doses of amiodarone was 16.30% vs 10.16% in
      the placebo group (P=0.04), whereas mortality with low doses was 6.61% vs 9.47%
      in the control group (P=0.20). Several non-fatal adverse effects were observed in
      108 and 73 patients treated with amiodarone and placebo, respectively.
      CONCLUSION: This study demonstrated that early administration of amiodarone in
      low doses to patients with an acute myocardial infarction may be used only if
      life-threatening arrhythmia justify its prescription. Conversely, when given in
      high doses, it might increase mortality.

PMID- 10639302
TI  - Mortality of patients admitted with a suspected acute myocardial infarction in
      whom the diagnosis is not confirmed.
AB  - AIMS: To examine the survival of patients admitted with a suspected acute
      myocardial infarction in whom the diagnosis was not confirmed ('possible
      myocardial infarction'). METHODS AND RESULTS: A cohort study based on the
      Nottingham Heart Attack Register of 1716 sequential patients discharged alive
      from two acute teaching hospitals following admission in 1992. The main outcome
      was mortality following hospital discharge after 5 years of follow-up. Survival
      of the cohort of patients in whom myocardial infarction was suspected but not
      confirmed was 58% (95% C.I. 56 to 60%) after 5 years of follow-up, compared with
      an expected survival of 76% in an age/sex matched general population. Patients
      with ECG abnormalities that were not diagnostic of myocardial infarction had a 5
      year survival of 56%, compared with 77% in those without such changes
      (P<0.00001). In the 703 patients who died in the first 5 years of follow-up, the
      cause of death was cardiovascular in at least 53% of cases. Survival following
      hospital discharge was worse than that in patients discharged alive in the same
      year following a confirmed myocardial infarction (63% vs 69% after 4 years of
      follow-up P=0.0016). CONCLUSION: Patients in this study had a substantially
      increased risk of death in the 5 years after discharge from hospital, compared
      with an age- and sex-matched population, and worse than patients discharged
      following a confirmed myocardial infarction. Almost half of those with ECG
      changes at the time of their admission died over the next 5 years. As over half
      of all deaths in this cohort were due to cardiovascular causes, further work is
      needed to identify patients at high and low risk of subsequent mortality who may
      warrant investigation and treatment following hospital discharge.

PMID- 10639303
TI  - Identifying the risk of death following hospital discharge in patients admitted
      with a suspected acute myocardial infarction in whom the diagnosis is not
      confirmed.
AB  - AIMS: To describe clinical factors, available at the time of discharge, that
      predicted survival of patients admitted with a suspected acute myocardial
      infarction in whom the diagnosis was not confirmed. METHODS AND RESULTS: A cohort
      study based on the Nottingham Heart Attack Register of 1716 sequential patients
      discharged alive from two acute teaching hospitals following admission in 1992.
      The main outcome was identification of high and low mortality risk groups over 5
      years of follow-up. Overall 5-year survival was 58% (95% CI 56 to 60%). Having
      abnormal cardiac enzyme changes or an abnormal ECG that was insufficient to meet
      established diagnostic criteria of myocardial infarction, or both, identified
      three groups with a 5 year survival of 77%, 60% or 51%. Multivariate methods were
      used to develop a risk score from seven variables available at the time of
      discharge (age, sex, past history of myocardial infarction, ECG abnormalities,
      cardiac enzyme abnormalities, Killip score of 2 or 3 on admission and being
      discharged on a diuretic). Quartiles of this risk score then identified four
      groups with 5 year survival ranging from 89% to 25%. CONCLUSION: Among the study
      cohort, it was possible to identify subgroups with a markedly different risk of
      subsequent mortality from clinical indicators that were readily available at the
      time of hospital discharge. Risk stratification has the potential to improve
      targeting of subsequent secondary preventive efforts, but further work is
      required to ascertain whether cardiovascular risk can be modified through a more
      intensive approach to management.

PMID- 10639304
TI  - Myocardial infarction in diabetic vs non-diabetic subjects. Survival and infarct
      size following therapy with sulfonylureas (glibenclamide)
AB  - AIMS: Sulfonylureas may interfere with 'ischaemic preconditioning' and worsen the
      prognosis in diabetic patients with acute myocardial infarction. METHODS AND
      RESULTS: Three hundred and fifty-seven non-diabetic patients admitted with acute
      myocardial infarction to one hospital over 6.5 years (72 deaths, in-hospital
      mortality 20.2%) were compared to 245 Type 2 diabetic patients categorized as
      having taken sulfonylureas (glibenclamide 7+/-3 mg x day(-1); n = 76, 25 deaths =
      32.9%;P = 0.025), not having taken sulfonylureas (n = 89, 29 deaths = 33.0%;P =
      0.012), and newly diagnosed as having diabetes (n = 80, 20 deaths = 25.0%).
      Survival was significantly different (log-rank test: P = 0.03). Increments in
      creatine kinase and creatine kinase(MB)activity were higher in non-diabetic
      patients (P<0.01). CONCLUSIONS: In-hospital mortality in Type 2 diabetic patients
      is higher than in non-diabetic patients suffering acute myocardial infarction
      regardless of whether or not they had been treated with sulfonylureas.
      Glibenclamide does not enlarge myocardial necroses.

PMID- 10639305
TI  - Early symptom-limited exercise test for risk stratification in post menopausal
      women with unstable coronary artery disease. FRISC study group. Fragmin during
      Instability in Coronary Artery Disease.
AB  - AIMS: The exercise test is considered less reliable in women than in men both for
      diagnostic and prognostic purposes. The value, however, of the exercise test
      might vary with the population that is examined, the way the test is performed
      and which exercise test variables are taken into consideration in the analysis.
      The aim of the study was to evaluate an early symptom-limited exercise test as a
      tool for risk stratification in women with unstable coronary artery disease
      admitted to the coronary care unit. METHODS AND RESULTS: Of the 543 women in the
      FRISC I study, 395 stabilized on medical treatment and performed a symptom
      limited exercise test 5-8 days after inclusion. Sixteen patients with a cardiac
      event before the scheduled exercise test were excluded. During the 6 months
      follow-up 17% of the women who did not perform the exercise test and 9% of the
      395 women who did, died or had a myocardial infarction (P<0.01). Multivariate
      stepwise logistic regression analysis was performed to assess the value of
      clinical variables and findings at the predischarge exercise test to predict
      cardiac events. Based on the exercise test results three risk groups were
      identified with an event rate of 19%, 9% and 1%, respectively. The exercise test
      was better than any of the tested clinical variables in predicting cardiac
      events. CONCLUSION: Women with unstable coronary artery disease who do not
      stabilize within a few days have a high event rate early during follow-up. For
      women who are medically stabilized, considering not only variables like ST
      depression and chest pain but also parameters reflecting the cardiac performance
      such as maximal workload and increase in rate-pressure product, an early symptom
      limited exercise test is a good predictor of future cardiac events.

PMID- 10639306
TI  - Sex differences in outcome following community-based cardiopulmonary arrest.
AB  - AIMS: To determine whether men and women suffering cardiopulmonary arrest differ
      in terms of survival and risk factors for survival. METHODS AND RESULTS: A
      prospective cohort study, using the Heartstart (Scotland) database, was
      undertaken on all 22 161 people suffering community-based cardiopulmonary arrest
      in Scotland between 1988 and 1997. The outcomes studied were death at the arrest
      scene, death before admission, death in hospital and death at any point up to
      discharge. Univariate analysis, using chi-square and Mann-Whitney U tests, was
      used to compare men and women in terms of patient characteristics, management and
      outcome. Multivariate logistic regression analysis was used to determine the
      association between sex and outcome after adjustment for case-mix. Sex
      differences in outcome varied over time. Women had a poorer risk profile than
      men. They were older (P<0.0001) and less likely to have shockable rhythms
      (P<0.0001). Despite this, they were more likely to survive to admission
      (P<0.0001). However, thereafter, women were more likely to die in hospital
      (P<0.01). There was no significant difference between the sexes in overall case
      fatality rates to discharge. CONCLUSION: Women have a better early prognosis than
      men. However, this represents a postponement of death, rather than avoidance.

PMID- 10639308
TI  - ESC news and appointments

PMID- 10639307
TI  - Serum troponins T and I after elective cardioversion.
AB  - AIMS: To describe the pattern of release of five myocardial proteins after
      elective cardioversion. METHODS AND RESULTS: We measured serum levels of the
      myocardial proteins creatine kinase, creatine kinase MB mass, myoglobin, troponin
      T and troponin I serially from baseline to 24 h after 72 elective cardioversion
      attempts. The total energy used for attempted cardioversion was 408+/-318 J
      (range 50 to 1280 J). Maximal creatine kinase levels (median 232 IU x l(-1),
      interquartile range 91 to 1152 IU x l(-1)) occurred at 24 h and correlated with
      the total energy delivered (r=0.75, P<0.0001). The peak creatine kinase MB mass
      levels exceeded the discrimination level for myocardial injury (>/=5 microg x l(
      1)) in seven patients (10%). The peak myoglobin levels were elevated (>85 microg
      x l(-1)) in 40 patients (56%) and correlated with the peak creatine kinase levels
      (r=0.83, P<0.0001). Troponin T reached the discrimination level (0.10 microg x l(
      1)) in one patient with a serum creatinine level of 0.16 mmol x l(-1)and severe
      left ventricular impairment. Twelve patients had baseline troponin I levels above
      our prespecified discrimination level of 0.4 microg x l(-1)(range 0.4 to 3.1
      microg x l(-1)), which did not increase after cardioversion. In two patients the
      levels rose from <0.4 microg x l(-1) to 0.5 microg x l(-1) and 0.6 microg x l(-1)
      respectively. CONCLUSIONS: Troponin T levels do not rise after elective
      cardioversion. The minor increases in troponin I may reflect our choice of
      discrimination level. Cardiac troponins are useful in determining whether
      arrhythmias requiring emergency cardioversion are primary or secondary to
      myocardial infarction.

PMID- 10639309
TI  - Identification of two major virion protein genes of white spot syndrome virus of
      shrimp.
AB  - White Spot Syndrome Virus (WSSV) is an invertebrate virus, causing considerable
      mortality in shrimp. Two structural proteins of WSSV were identified. WSSV
      virions are enveloped nucleocapsids with a bacilliform morphology with an
      approximate size of 275 x 120 nm, and a tail-like extension at one end. The
      double-stranded viral DNA has an approximate size 290 kb. WSSV virions, isolated
      from infected shrimps, contained four major proteins: 28 kDa (VP28), 26 kDa
      (VP26), 24 kDa (VP24), and 19 kDa (VP19) in size, respectively. VP26 and VP24
      were found associated with nucleocapsids; the others were associated with the
      envelope. N-terminal amino acid sequences of nucleocapsid protein VP26 and the
      envelope protein VP28 were obtained by protein sequencing and used to identify
      the respective genes (vp26 and vp28) in the WSSV genome. To confirm that the open
      reading frames of WSSV vp26 (612) and vp28 (612) are coding for the putative
      major virion proteins, they were expressed in insect cells using baculovirus
      vectors and analyzed by Western analysis. A polyclonal antiserum against total
      WSSV virions confirmed the virion origin of VP26 and VP28. Both proteins
      contained a putative transmembrane domain at their N terminus and many putative N
      and O-glycosylation sites. These major viral proteins showed no homology to
      baculovirus structural proteins, suggesting, together with the lack of DNA
      sequence homology to other viruses, that WSSV may be a representative of a new
      virus family, Whispoviridae.

PMID- 10639310
TI  - HPV11 mutant virus-like particles elicit immune responses that neutralize virus
      and delineate a novel neutralizing domain.
AB  - Characterization of the regions of human papillomaviruses (HPVs) that elicit
      neutralizing immune responses supports studies on viral infectivity and provides
      insight for the development and evaluation of prophylactic vaccines. HPV11 is a
      major etiologic agent of genital warts and a likely vaccine candidate. A
      conformationally dependent epitope for the binding of three neutralizing
      monoclonal antibodies (mAbs) has been mapped to residues G(131)T(132) of the L1
      major capsid protein. The mAbs bind L1 only when it is assembled into virions or
      into virus-like particles (VLPs) that mimic the capsid structure. We were
      interested in identifying other domains of L1 that elicit neutralizing responses.
      To this end, we have generated a panel of mAbs against VLPs derived from HPV11 L1
      harboring a G131S substitution. The new mAbs are unlike the neutralizing mAbs
      previously mapped to residues G(131)T(132) in that they bind both prototype and
      HPV11:G131S mutant VLPs. Some of the new mAbs neutralized virus in vitro. We have
      mapped epitopes for three of these new mAbs, as well as a neutralizing mAb
      generated against HPV11 virions, by measuring binding to HPV6 VLPs substituted
      with HPV11-like amino acids. Two regions are critical: one defined by HPV11 L1
      residues 263-290 and the other by residues 346-349. mAbs H11.H3 and H11.G131S.G3
      bind HPV6 VLPs with substitutions derived from the 346-349 region; in addition,
      H11.G131S.G3 binds HPV6 VLPs with substitutions derived only from the 263-290
      region. Although H11.H3 does not bind HPV6 VLPs with substitutions derived from
      the 263-290 region, binding to HPV6 VLPs is enhanced when both sets of
      substitutions are present. mAbs H11.G131S.I1 and H11.G131S.K5 bind HPV6 VLPs with
      the 263-290 substitutions, but show little binding to HPV6 VLPs with the 346-349
      substitutions. However, binding to HPV6 VLPs is enhanced when substitutions at
      both regions are present. The 346-349 region has not previously been described as
      eliciting a neutralizing response for any HPV type. In addition, the work
      demonstrates a complex binding site contributed by two distinct regions of L1.

PMID- 10639311
TI  - Cell cycle-dependent stimulation of the HIV-1 promoter by Tat-associated CAK
      activator.
AB  - Activation of the HIV-1 promoter by the virally encoded Tat protein is
      characterized by efficient processive transcription, mediated by host cell
      factors that are tethered to the promoter with the Tat-TAR RNA complex.
      Importantly, viral gene activation has been shown to be stimulated in
      mitogenically induced cells, although the link between cell cycle regulation and
      viral gene activation is unclear. We reported a Tat-associated CAK/CTD kinase
      from mitogenically induced primary human T-cells (TTK) (S. Nekhai et al., 1997,
      J. Virol. 71, 7436-7441). Here, biological activity of the kinase has been
      studied by direct microinjection at the individual-cell level. The TTK-dependent
      Tat response is maximal during G1 phase as shown by co-injection with Tat protein
      in cells synchronized at the various stages of the cell cycle. The cell cycle
      dependence of the Tat response was confirmed by inhibiting G0 --> G1 progression
      with the expression of dominant negative mutant Ras(Asn17) or the cyclin
      dependent kinase CDK4. The results support a mechanism whereby transactivation of
      the HIV promoter is regulated by cell growth signal transduction pathways that
      target the Tat cofactor.

PMID- 10639312
TI  - Defining parameters for successful immunocytotherapy of persistent viral
      infection.
AB  - Persistent infections with viruses such as HIV, Epstein-Barr virus,
      cytomelagovirus, and hepatitis B and C viruses continue to be major human health
      problems. Immunocytotherapy for persistent viral infections has proven successful
      in animal models but less effective in humans. While the requirement of antigen
      specific CD8(+) T cells is known, the precise role of CD4(+) T cells as regards
      specific priming, numbers needed, and interaction with CD8(+) T cells is less
      clear. To address these issues, we used a mouse model of persistent virus
      infection in which adoptive transfer of T cells effectively purges virus from all
      tissues. We demonstrate that (1) inclusion of antigen-specific CD4(+) in addition
      to CD8(+) T cells is mandatory for efficient and long-term virus control. Neither
      naive nor CD4(+) T cells with specificity for a different virus are sufficient.
      (2) The minimal numbers of virus-specific T cells required for virus clearance
      from sera and tissues are 350,000 virus-specific CD8(+) and 7000 virus-specific
      CD4(+) T cells or approximately 5 x 10(7) CD8(+) and as few as 1 x 10(6) CD4(+) T
      cells per square meter of body surface area, a CD8:CD4 ratio of 50:1. (3)
      Production of interferon-gamma, obligatory for resolution of persistent
      infection, is dependent on the interaction of virus-specific CD4(+) and CD8(+) T
      cells. (4) Maintenance of CD8(+) T cell effector functions after adoptive
      transfer is directly proportional to the amount of cotransferred, virus-specific
      CD4(+) T cells.

PMID- 10639313
TI  - Mutagenesis of murine cytomegalovirus using a Tn3-based transposon.
AB  - A transposon derived from Escherichia coli Tn3 was introduced into the genome of
      murine cytomegalovirus (MCMV) to generate a pool of viral mutants. We analyzed
      three of the constructed recombinant viruses that contained the transposon within
      the M25, M27, and m155 open reading frames. Our studies provide the first direct
      evidence to suggest that M25 and M27 are not essential for viral replication in
      mouse NIH 3T3 cells. Studies in cultured cells and Balb/c mice indicated that the
      transposon insertion is stable during viral propagation both in vitro and in
      vivo. Moreover the virus that contained the insertion mutation in M25 exhibited a
      titer similar to that of the wild-type virus in the salivary glands, lungs,
      livers, spleens, and kidneys of the Balb/c mice that were intraperitoneally
      infected with these viruses. These results suggest that M25 is dispensable for
      viral growth in these organs and the presence of the transposon sequence in the
      viral genome does not significantly affect viral replication in vivo. The Tn3
      based system can be used as a mutagenesis approach for studying the function of
      MCMV genes in both tissue culture and in animals.

PMID- 10639314
TI  - Identification of a novel expressed open reading frame situated between genes
      U(L)20 and U(L)21 of the herpes simplex virus 1 genome.
AB  - An open reading frame (ORF) situated between the U(L)20 and U(L)21 genes encodes
      a protein designated as U(L)20.5. The U(L)20.5 ORF lies 5' and in the same
      orientation as the U(L)20 ORF. The expression of the U(L)20.5 ORF was verified by
      RNase protection assays and by in-frame insertion of an amino acid sequence
      encoding an epitope of an available monoclonal antibody. The tagged U(L)20.5
      protein colocalized in small dense nuclear structures with products of the
      alpha22/U(S)1.5, U(L)3, and U(L)4 genes. Expression of the U(L)20.5 gene was
      blocked in cells infected and maintained in the presence of phosphonoacetate,
      indicating that it belongs to the late, or gamma(2), kinetic class. U(L)20.5 is
      not essential for viral replication inasmuch as a recombinant virus made by
      insertion of the thymidine kinase gene into the U(L)20.5 ORF replicates in all
      cell lines tested [J. D. Baines, P. L. Ward, G. Campadelli-Fiume, and B. Roizman
      (1991) J. Virol. 65, 6414-6424]. The genomic location of the recently discovered
      genes illustrates the compact nature of the viral genome.

PMID- 10639315
TI  - Implication of the C-terminal domain of nef protein in the reversion to
      pathogenicity of attenuated SIVmacBK28-41 in macaques.
AB  - We have analyzed the nef gene sequences amplified from 12 macaques presenting
      various patterns of infection with SIVmacBK28-41, a clone derived from attenuated
      SIVmacBK28. We have observed seven mutation hot spots at positions 56, 75, 432,
      588, 680, 699, and 779. The major alteration was a thymidine insertion at
      position 699, leading to a frameshift in the SIVmacBK28-41 nef gene and changing
      the last 15 amino acids of Nef into a 31-amino-acid-long C-terminal domain nearly
      identical to that encoded by pathogenic SIVmac239 and SIVmac251. The insertion
      was found at early time points in proviruses obtained from rapid progressor
      macaques, after 2 years postinfection in progressors, and rarely or only after 4
      years postinfection in nonprogressors. Fixation of the other mutations occurred
      only after insertion of thymidine 699. Phylogenetic analysis demonstrated that
      the nef genes isolated from progressors evolved from the allele present in
      SIVmacBK28-41 to alleles present in SIVmac239 or SIVmac251, whereas nef sequences
      from nonprogressors stayed clustered with that of the inoculated molecular clone.
      These data stress the importance of the C-terminal extremity of the Nef protein
      of SIVmac239 or SIVmac251 in viral pathogenesis.

PMID- 10639316
TI  - Evidence for participation of RNA 1-encoded elicitor in Cowpea mosaic virus
      mediated concurrent protection.
AB  - The cowpea (Vigna unguiculata) line Arlington, inoculated with Cowpea mosaic
      virus (CPMV), showed no symptoms, and no infectivity or accumulation of capsid
      antigen was detected at several days after inoculation. Coinoculation, but not
      sequential inoculation, of CPMV with similar concentrations of another Comovirus;
      Cowpea severe mosaic virus (CPSMV), resulted in reduced numbers of CPSMV-induced
      lesions. This apparent, CPMV-mediated reduction in number of CPSMV-induced
      infection centers was termed concurrent protection. We report results obtained by
      inoculating two nearly isogenic cowpea lines derived from a CPMV-susceptible
      cowpea crossed to Arlington, one line CPMV-susceptible and the other resistant.
      The CPMV virions B and M, encapsidating genomic RNAs 1 and 2, respectively, were
      extensively purified by gradient centrifugation. In the CPMV-resistant cowpea,
      either CPMV or CPMV B affected concurrent protection against CPSMV and against
      two distinct non-Comoviruses: Cherry leafroll virus and Southern bean mosaic
      virus. Adding CPMV M to the inoculum did not enhance CPMV-B-mediated protection.
      CPMV B was ineffective in protecting CPMV-susceptible cowpea. We postulate that
      CPMV-mediated concurrent protection is elicited in CPMV-resistant cowpea by a
      CPMV RNA-1-encoded factor and acts to reduce accumulation or spread of CPMV and
      certain coinoculated challenging viruses in or from the inoculated cell.
      Coinoculated CPMV did not protect CPMV-resistant cowpea against Tomato bushy
      stunt virus or Cucumber mosaic virus.

PMID- 10639317
TI  - Characterization of the U(L)33 gene product of herpes simplex virus 1.
AB  - The U(L)33 protein is one of six genes (including U(L)6, U(L)15, U(L)17, U(L)28,
      and U(L)32) required for cleavage of viral concatemeric DNA into unit-length
      genomes and packaging of the virus genomes into preformed capsids. The U(L)25
      gene product is dispensable for cleavage of viral DNA but essential for packaging
      of DNA into capsids. A polyclonal antiserum was produced against an affinity
      purified protein containing the full-length U(L)33 gene product of herpes simplex
      virus 1 fused to glutathione-S-transferase. A protein of approximate M(r) 19,000
      that reacted with the antiserum was detected in immunoblots of herpes simplex
      virus 1-infected cellular lysates. This protein was not detected in lysates of
      mock-infected cells or cells infected with a mutant virus containing a stop codon
      in U(L)33, indicating that the 19,000 M(r) protein is the product of the U(L)33
      open reading frame. The U(L)33 gene product was not detected in purified virions
      or capsids. Accumulation of the U(L)33 protein to detectable levels required
      viral DNA synthesis, indicating that the protein was regulated as a late gene.
      Indirect immunofluorescence analysis demonstrated that U(L)33 protein accumulated
      predominantly within replication compartments in the central domains of infected
      cell nuclei and within the cytoplasm. Localization of the U(L)33 gene product in
      replication compartments was maintained in cells infected with a variety of
      cleavage/packaging mutants.

PMID- 10639318
TI  - Cell growth regulatory and antiviral effects of the P69 isozyme of 2-5 (A)
      synthetase.
AB  - Among the many interferon-induced proteins that carry out multiple cellular
      functions of interferons is the family of enzymes called 2'-5' oligoadenylate
      synthetases. We examined the anticellular and antiviral activities of a specific
      member of that family, the P69 isozyme. P69 was expressed in human cells by
      transfection and shown to be localized primarily in the endoplasmic reticulum.
      For further studies, permanent cell lines expressing different levels of P69 or
      an enzymatically inactive mutant were isolated. Constitutive P69 expression
      caused inhibition of replication of encephalomyocarditis virus but not of
      vesicular stomatitis virus, Sendai virus, or reovirus. Increasing levels of P69
      expression also caused increasing perturbations in cell growth properties. There
      was increasing accumulations of the P69-expressing cells in the G1 phase of the
      cell cycle; cell-doubling time was increased by P69 expression; and there were
      many multinucleated cells in the P69-expressing line, indicating a defect in
      cytokinesis.

PMID- 10639319
TI  - DNA vaccination with vaccinia virus L1R and A33R genes protects mice against a
      lethal poxvirus challenge.
AB  - Previously we found that passive transfer of monoclonal antibodies (MAbs)
      specific to either the vaccinia virus (VACV) L1R or A33R gene product protected
      mice from challenge with VACV. The L1R-specific MAbs, which bind the
      intracellular mature virion (IMV), neutralized virus in cell culture, whereas the
      A33R-specific MAbs, which bind extracellular enveloped virions (EEV), did not. To
      investigate whether a protective response could be generated by vaccination with
      these genes, we constructed and evaluated DNA vaccines expressing the VACV L1R
      and/or A33R genes under control of a cytomegalovirus promoter. Mice were
      vaccinated with DNA-coated gold beads by using a gene gun and then challenged
      with VACV (strain WR) intraperitoneally. Mice vaccinated with L1R alone developed
      neutralizing antibodies and were partially protected. Mice vaccinated with a
      combination of both genes loaded on the same gold beads developed a robust anti
      A33R response; however, no neutralizing antibody response was detected, and the
      mice were not protected. In contrast, when mice were vaccinated with L1R and A33R
      loaded on different gold beads, neutralizing (presumably anti-L1R) and anti-A33R
      antibody responses were detected, and protection was markedly improved. Our
      results indicated that vaccination with both L1R and A33R proteins, intended to
      evoke mechanistically distinct and complementary forms of protection, was more
      effective than vaccination with either protein by itself.

PMID- 10639320
TI  - African swine fever virus EP153R open reading frame encodes a glycoprotein
      involved in the hemadsorption of infected cells.
AB  - The open reading frame EP153R, located within the EcoRI E' fragment of the
      African swine fever (ASF) virus genome, is predicted to encode a membrane protein
      of 153 amino acids that presents significant homology to the N-terminal region of
      several CD44 molecules. EP153R contains multiple putative sites for N
      glycosylation, phosphorylation, and myristoylation, a central transmembrane
      region, a C-type animal lectin-like domain, and a cell attachment sequence.
      Transcription of EP153R takes place at both early and late times during the virus
      infection. The disruption of the gene, achieved by insertion of the marker gene
      LacZ within EP153R, did not change either the in vitro virus growth rate or the
      virus-sensitive/resistant condition of up to 17 established cell lines, but
      abrogated the hemadsorption phenomenon induced in ASF virus-infected cells. As
      the sequence and expression of the ASF virus protein pEP402R, a CD2 homolog
      responsible for the adhesion of erythrocytes to susceptible cells, was unaffected
      in cultures infected with the EP153R deletion mutant, we conclude that the gene
      EP153R is needed to induce and/or maintain the interaction between the viral CD2
      homolog and its corresponding cell receptor.

PMID- 10639321
TI  - Poliovirus protease 3C(pro) kills cells by apoptosis.
AB  - The tetracycline-based Tet-Off expression system has been used to analyze the
      effects of poliovirus protease 3C(pro) on human cells. Stable HeLa cell clones
      that express this poliovirus protease under the control of an inducible, tightly
      regulated promoter were obtained. Tetracycline removal induces synthesis of 3C
      protease, followed by drastic morphological alterations and cellular death.
      Degradation of cellular DNA in nucleosomes and generation of apoptotic bodies are
      observed from the second day after 3C(pro) induction. The cleavage of poly(ADP
      ribose) polymerase, an enzyme involved in DNA repair, occurs after induction of
      3C(pro), indicating caspase activation by this poliovirus protease. The 3C(pro)
      induced apoptosis is blocked by the caspase inhibitor z-VAD-fmk. Our findings
      suggest that the protease 3C is responsible for triggering apoptosis in
      poliovirus-infected cells by a mechanism that involves caspase activation.

PMID- 10639322
TI  - Alastrim smallpox variola minor virus genome DNA sequences.
AB  - Alastrim variola minor virus, which causes mild smallpox, was first recognized in
      Florida and South America in the late 19th century. Genome linear double-stranded
      DNA sequences (186,986 bp) of the alastrim virus Garcia-1966, a laboratory
      reference strain from an outbreak associated with 0.8% case fatalities in Brazil
      in 1966, were determined except for a 530-bp fragment of hairpin-loop sequences
      at each terminus. The DNA sequences (EMBL Accession No. Y16780) showed 206
      potential open reading frames for proteins containing >/=60 amino acids. The
      amino acid sequences of the putative proteins were compared with those reported
      for vaccinia virus strain Copenhagen and the Asian variola major strains India
      1967 and Bangladesh-1975. About one-third of the alastrim viral proteins were
      100% identical to correlates in the variola major strains and the remainder were
      >/=95% identical. Compared with variola major virus DNA, alastrim virus DNA has
      additional segments of 898 and 627 bp, respectively, within the left and right
      terminal regions. The former segment aligns well with sequences in other
      orthopoxviruses, particularly cowpox and vaccinia viruses, and the latter is
      apparently alastrim-specific.

PMID- 10639323
TI  - Patterned entry and egress by Epstein-Barr virus in polarized CR2-positive
      epithelial cells.
AB  - In polarized epithelium direction of viral entry and release correlates with
      proclivity of a virus to establish local versus systemic infection. The Epstein
      Barr virus (EBV), whose principal tissue reservoir is B lymphocytes, also has
      disease manifestations in epithelium, suggesting intertissue spread potentially
      influenced by epithelial cell polarity. We stably transfected the B lymphocyte
      EBV receptor (CR2/CD21) into Madin-Darby canine kidney (MDCK) epithelial cells
      used extensively to study effects of cell polarity on infection by both DNA and
      RNA viruses. CR2/CD21 was detected on both apical and basolateral surfaces of
      polarized MDCK cells, with predominant expression basolaterally. However,
      infectivity was up to four-fold greater apically, suggesting that endogenous cell
      surface molecules, sorted asymmetrically onto polarized plasma membranes, may be
      involved in EBV entry into MDCK cells. EBV gp350/220, a replicative cycle
      glycoprotein added to the virus envelope on egress through the cell membrane, was
      immunolocalized by confocal microscopy to basolateral cell surfaces only. Apical
      entry of EBV with subsequent basolateral release of newly replicated virus favors
      systemic infection by viral dissemination to underlying lymphocytic aggregations.
      Under conditions of long-term culture, latent EBV was not stably maintained in
      these cells, suggesting that the epithelial phase of acute EBV infection may be
      transient.

PMID- 10639324
TI  - Polarization of cell growth in yeast. I. Establishment and maintenance of
      polarity states.
AB  - The ability to polarize is a fundamental property of cells. The yeast
      Saccharomyces cerevisiae has proven to be a fertile ground for dissecting the
      molecular mechanisms that regulate cell polarity during growth. Here we discuss
      the signaling pathways that regulate polarity. In the second installment of this
      two-part commentary, which appears in the next issue of Journal of Cell Science,
      we discuss how the actin cytoskeleton responds to these signals and guides the
      polarity of essentially all events in the yeast cell cycle. During the cell
      cycle, yeast cells assume alternative states of polarized growth, which range
      from tightly focused apical growth to non-focused isotropic growth. RhoGTPases,
      and in particular Cdc42p, are essential to guiding this polarity. The
      distribution of Cdc42p at the cell cortex establishes cell polarity. Cyclin
      dependent protein kinase, Ras, and heterotrimeric G proteins all modulate yeast
      cell polarity in part by altering the distribution of Cdc42p. In turn, Cdc42p
      generates feedback signals to these molecules in order to establish stable
      polarity states and coordinate cytoskeletal organization with the cell cycle.
      Given that many of these signaling pathways are present in both fungi and
      animals, they are probably ancient and conserved mechanisms for regulating
      polarity.

PMID- 10639325
TI  - The cell biology of osteoclast function.
AB  - Osteoclasts are multinucleated cells responsible for bone resorption. They have
      developed an efficient machinery for dissolving crystalline hydroxyapatite and
      degrading organic bone matrix rich in collagen fibers. When initiating bone
      resorption, osteoclasts become polarized, and three distinct membrane domains
      appear: a ruffled border, a sealing zone and a functional secretory domain.
      Simultaneously, the cytoskeleton undergoes extensive re-organisation. During this
      process, the actin cytoskeleton forms an attachment ring at the sealing zone, the
      membrane domain that anchors the resorbing cell to bone matrix. The ruffled
      border appears inside the sealing zone, and has several characteristics of late
      endosomal membrane. Extensive vesicle transport to the ruffled border delivers
      hydrochloric acid and proteases to an area between the ruffled border and the
      bone surface called the resorption lacuna. In this extracellular compartment,
      crystalline hydroxyapatite is dissolved by acid, and a mixture of proteases
      degrades the organic matrix. The degradation products of collagen and other
      matrix components are endocytosed, transported through the cell and exocytosed
      through a functional secretory domain. This transcytotic route allows osteoclasts
      to remove large amounts of matrix-degradation products without losing their tight
      attachment to underlying bone. It also facilitates further processing of the
      degradation products intracellularly during the passage through the cell.

PMID- 10639326
TI  - TGF-(beta)1 maintains hematopoietic immaturity by a reversible negative control
      of cell cycle and induces CD34 antigen up-modulation.
AB  - Somatic stem cells are largely quiescent in spite of their considerable
      proliferative potential. Transforming growth factor-(beta)1 (TGF-(beta)1) appears
      to be a good candidate for controlling this quiescence. Indeed, various mutations
      in the TGF-beta signalling pathway are responsible for neoplasic proliferation of
      primitive stem/progenitor cells in human tissues of various origins. In
      hemopoietic single cell culture assays, blocking autocrine and endogeneous TGF
      (beta)1 triggers the cell cycling of high proliferative potential
      undifferenciated stem/progenitor cells. However, it has never been demonstrated
      whether TGF-(beta)1 has an apoptotic effect or a differentiating effect on these
      primitive cells, as already described for more mature cells. Using single cell
      experiments both in liquid or semi-solid culture assays and dye tracking
      experiments by flow cytometry, we demonstrate that low, physiological
      concentrations of TGF-(beta)1, which specifically maintain primitive human
      hemopoietic stem/progenitor cells in quiescence, have a reversible effect and do
      not induce apoptosis. We moreover demonstrate that these low concentrations
      prevent the rapid loss of the mucin-like protein CD34, a most common marker of
      immature hematopoietic stem/progenitor cells, which is progressively lost during
      differentiation. TGF-(beta)1 not only up-modulated the CD34 antigen before S
      phase entry but also maintained a high level of CD34 expression on cells which
      had escaped cell cycle inhibition, suggesting that proliferation inhibition and
      differentiation control by TGF-(beta)1 may be independent. These data provide
      additional evidence that TGF-(beta)1 acts as a key physiological factor ensuring
      the maintenance of a stem cell reserve.

PMID- 10639327
TI  - Low-affinity LFA-1/ICAM-3 interactions augment LFA-1/ICAM-1-mediated T cell
      adhesion and signaling by redistribution of LFA-1.
AB  - Although ICAM-3 is implicated in both adhesion and signal transduction events of
      leukocytes, its low affinity for LFA-1 compared to other ligands of LFA-1 has
      puzzled many investigators. Here we investigated the role of ICAM-3 in supporting
      LFA-1-mediated ICAM-1 binding and subsequently cell signaling. We observed that
      although ICAM-3 binds poorly to LFA-1 expressed on resting T cells, it
      specifically facilitates and increases LFA-1-mediated adhesion to the high
      affinity ligand of LFA-1, ICAM-1. We demonstrate that low-affinity binding of LFA
      1 to ICAM-3 together with ICAM-1 alters the cell surface distribution of LFA-1
      dramatically, inducing large clusters of LFA-1 that facilitate ICAM-1 binding
      after LFA-1 activation. We found that LFA-1-mediated ICAM-1 cell-cell
      interactions such as T cell proliferation greatly depend on low affinity LFA
      1/ICAM-3 interactions that enhance stable LFA-1/ICAM-1 cell-cell contact. Taken
      together, these data demonstrate that low affinity LFA-1 binding to ICAM-3
      regulates strong LFA-1/ICAM-1-mediated adhesion by driving LFA-1 into clusters to
      facilitate cell-cell interactions that take place in the immune system.

PMID- 10639328
TI  - Phosphorylation of neurofilament heavy chain side-arms by stress activated
      protein kinase-1b/Jun N-terminal kinase-3.
AB  - Neurofilaments comprise three subunit proteins; neurofilament light, middle and
      heavy chains (NF-L, NF-M and NF-H). The carboxy-terminal domains of NF-M and NF-H
      form side-arms that project from the filament and that of NF-H contains multiple
      repeats of the motif lys-ser-pro, the serines of which are targets for
      phosphorylation. The level of phosphorylation on the lys-ser-pro repeats varies
      topographically within the cell; in cell bodies and proximal axons, the side-arms
      are largely non-phosphorylated whereas in more distal regions of axons, the side
      arms are heavily phosphorylated. Here we show that stress activated protein
      kinase 1b (SAPK1b), a major SAPK in neurones will phosphorylate NF-H side-arms
      both in vitro and in transfected cells. These studies suggest that SAPK1b targets
      multiple phosphorylation sites within NF-H side-arms. Additionally, we show that
      glutamate treatment induces activation of SAPK1b in primary cortical neurones and
      increased phosphorylation of NF-H in cell bodies. This suggests that glutamate
      causes increased NF-H phosphorylation at least in part by activation of stress
      activated protein kinases.

PMID- 10639329
TI  - Targets of extinction: identification of genes whose expression is repressed as a
      consequence of somatic fusion between cells representing basal and luminal
      mammary epithelial phenotypes.
AB  - The use of somatic cell hybrids has led to an increased understanding of the
      'negative' regulation of cellular phenotype. Using somatic cell hybrids
      constructed between human breast cells that represent differing stages of
      malignancy but also display differing phenotypes from the same tissue, we present
      experimental results suggesting that luminal epithelial characteristics are
      controlled by repressive mechanisms. Fusion of HBL 100 cells, non-tumorigenic and
      characteristic of the basal cell lineage, with MCF-7 or MDA-MB-468 malignant
      breast cancer cells, characteristic of the luminal lineage, resulted in hybrid
      cells that displayed the phenotype of the HBL 100 cells. Using representational
      difference analysis, a panel of genes whose expression was repressed in the
      hybrid between HBL 100 and MDA-MB-468 was identified. This analysis revealed
      markers of luminal epithelial cells to be repressed, including Ep-CAM,
      cytokeratin 19 and E-cadherin. These markers were found to be coordinately re
      expressed in variant hybrid cells indicating that the observed repression is
      reversible. Integrin (alpha)(v)(beta)(3) expression was found to be in mutual
      exclusivity to the luminal epithelial markers, thereby revealing a bidirectional
      'switch' in the pattern of gene expression in this system. Finally, the
      expression of Ep-CAM was found to be lost in heterokaryons produced by fusion of
      HBL 100 and MCF-7 or MDA-MB-468 cells suggesting that the extinction of this gene
      in hybrid cells is the consequence of a trans-acting factor(s) synthesized by the
      HBL 100 cells. These data suggest that a number of markers of luminal cell
      differentiation in the mammary gland can be controlled through negative
      mechanisms and that such control of phenotype is highly coordinated.

PMID- 10639330
TI  - Functional interaction between E-cadherin and alphav-containing integrins in
      carcinoma cells.
AB  - We have demonstrated the possibility of cross-talk between E-cadherin and alphav
      integrins in breast carcinoma cells. Using the function-blocking anti-alphav
      monoclonal antibody 17E6, applied to monolayer cultures of breast cancer lines,
      it was found that treatment of cells possessing detergent-insoluble (implying
      attachment to the actin cytoskeleton) E-cadherin resulted in the adoption of a
      spheroid configuration of cell growth. This effect was dependent upon not just
      alphav occupancy but also receptor aggregation. Thus in vitro alphav-dependent
      adhesion suppresses E-cadherin-mediated morphological changes. To investigate
      whether manipulation of E-cadherin would, conversely, modulate integrin activity
      we introduced a dominant-negative E-cadherin construct into one of the lines,
      ZR75-1, giving rise to the cell line ZR-E2R1. Surface expression of endogenous E
      cadherin was downregulated (by around 25%), whereas beta-catenin levels were
      increased two- to threefold in ZR-E2R1 cells. There was also a highly significant
      increase in migration of ZR-E2R1 cells (relative to control cells) toward
      vitronectin (P<0.001), but not toward collagen type I, fibronectin or laminin.
      Such increased migration could be abrogated totally by antibody blockade of
      alphavbeta5 and alphavbeta1 integrins. There was no detectable change in alphav
      integrin levels. These data suggest that the introduction of a dominant-negative
      E-cadherin mutant into ZR75-1, in addition to a loss of cohesion, generates a
      signal (or signals) which increases migration towards vitronectin through
      increased activity of alphav integrins.

PMID- 10639331
TI  - Inhibition of chondrocyte differentiation in vitro by constitutive and inducible
      overexpression of the c-fos proto-oncogene.
AB  - We have investigated the role of c-Fos in chondrocyte differentiation in vitro
      using both constitutive and inducible overexpression approaches in ATDC5
      chondrogenic cells, which undergo a well-defined sequence of differentiation from
      chondroprogenitors to fully differentiated hypertrophic chondrocytes. Initially,
      we constitutively overexpressed exogenous c-fos in ATDC5 cells. Several stable
      clones expressing high levels of exogenous c-fos were isolated and those also
      expressing the cartilage marker type II collagen showed a marked decrease in
      cartilage nodule formation. To investigate further whether c-Fos directly
      regulates cartilage differentiation independently of potential clonal variation,
      we generated additional clones in which exogenous c-fos expression was tightly
      controlled by a tetracycline-regulatable promoter. Two clones, DT7.1 and DT12.4
      were capable of nodule formation in the absence of c-fos. However, upon induction
      of exogenous c-fos, differentiation was markedly reduced in DT7.1 cells and was
      virtually abolished in clone DT12.4. Pulse experiments indicated that induction
      of c-fos only at early stages of proliferation/differentiation inhibited nodule
      formation, and limiting dilution studies suggested that overexpression of c-fos
      decreased the frequency of chondroprogenitor cells within the clonal population.
      Interestingly, rates of proliferation and apoptosis were unaffected by c-fos
      overexpression under standard conditions, suggesting that these processes do not
      contribute to the observed inhibition of differentiation. Finally, gene
      expression analyses demonstrated that the expression of the cartilage markers
      type II collagen and PTH/PTHrP receptor were down-regulated in the presence of
      exogenous c-Fos and correlated well with the differentiation status. Moreover,
      induction of c-fos resulted in the concomitant increase in the expression of fra
      1 and c-jun, further highlighting the importance of AP-1 transcription factors in
      chondrocyte differentiation. These data demonstrate that c-fos overexpression
      directly inhibits chondrocyte differentiation in vitro, and therefore these cell
      lines provide very useful tools for identifying novel c-Fos-responsive genes that
      regulate the differentiation and activity of chondrocytes.

PMID- 10639332
TI  - Developmentally regulated activity of CRM1/XPO1 during early Xenopus
      embryogenesis.
AB  - In this work, we have investigated the role of CRM1/XPO1, a protein involved in
      specific export of proteins and RNA from the nucleus, in early Xenopus
      embryogenesis. The cloning of the Xenopus laevis CRM1, XCRM1, revealed remarkable
      conservation of the protein during evolution (96.7% amino acid identity between
      Xenopus and human). The protein and mRNA are maternally expressed and are present
      during early embryogenesis. However, our data show that the activity of the
      protein is developmentally regulated. Embryonic development is insensitive to
      leptomycin B, a specific inhibitor of CRM1, until the neurula stage. Moreover,
      the nuclear localization of CRM1 changes concomitantly with the appearance of the
      leptomycin B sensitivity. These data suggest that CRM1, present initially in an
      inactive form, becomes functional before the initiation of the neurula stage
      during gastrula-neurula transition, a period known to correspond to a critical
      transition in the pattern of gene expression. Finally, we confirmed the gastrula
      neurula transition-dependent activation of CRM1 by pull-down experiments as well
      as by the study of the intracellular localization of a green fluorescent protein
      tagged with a nuclear export signal motif during early development. This work
      showed that the regulated activity of CRM1 controls specific transitions during
      normal development and thus might be a key regulator of early embryogenesis.

PMID- 10639333
TI  - Penaeidins, antimicrobial peptides with chitin-binding activity, are produced and
      stored in shrimp granulocytes and released after microbial challenge.
AB  - Penaeidins are members of a new family of antimicrobial peptides isolated from a
      crustacean, which present both Gram-positive antibacterial and antifungal
      activities. We have studied the localization of synthesis and storage of
      penaeidins in the shrimp Penaeus vannamei. The distribution of penaeidin
      transcripts and peptides in various tissues reveals that penaeidins are
      constitutively synthesized and stored in the shrimp haemocytes. It was shown by
      immunocytochemistry, at both optical and ultrastructural levels, that the
      peptides are localized in granulocyte cytoplasmic granules. The expression and
      localization of penaeidins were further analysed in shrimp subjected to microbial
      challenge. We found that (1) penaeidin mRNA levels decrease in circulating
      haemocytes in the first 3 hours following stimulation and (2) an increase in
      plasma penaeidin concentration occurs after microbial challenge, together with
      (3) a penaeidin immunoreactivity in cuticular tissue, which can be related to the
      chitin-binding activity we demonstrate here for penaeidins.

PMID- 10639334
TI  - Endothelial cell retraction is induced by PAK2 monophosphorylation of myosin II.
AB  - The p21-activated kinase (PAK) family includes several enzyme isoforms regulated
      by the GTPases Rac1 and Cdc42. PAK1, found in brain, muscle and spleen, has been
      implicated in triggering cytoskeletal rearrangements such as the dissolution of
      stress fibers and reorganization of focal complexes. The role of the more widely
      distributed PAK2 in controlling the cytoskeleton has been less well studied.
      Previous work has demonstrated that PAK2 can monophosphorylate the myosin II
      regulatory light chain and induce retraction of permeabilized endothelial cells.
      In this report we characterize PAK2's morphological and biochemical effect on
      intact endothelial cells utilizing microinjection of constitutively active PAK2.
      Under these conditions we observed a modification of the actin cytoskeleton with
      retraction of endothelial cell margins accompanied by an increase in
      monophosphorylation of myosin II. Selective inhibitors were used to analyze the
      mechanism of action of PAK2. Staurosporine, a direct inhibitor of PAK2, largely
      prevented the action of microinjected PAK2 in endothelial cells. Butanedione
      monoxime, a non-specific myosin ATPase inhibitor, also inhibited the effects of
      PAK2 implicating myosin in the changes in cytoskeletal reorganization. In
      contrast, KT5926, a specific inhibitor of myosin light chain kinase was
      ineffective in preventing the changes in morphology and the actin cytoskeleton.
      The additional finding that endogenous PAK2 associates with myosin II is
      consistent with the proposal that cell retraction and cytoskeletal rearrangements
      induced by microinjected PAK2 depend on the direct activation of myosin II by
      PAK2 monophosphorylation of the regulatory light chain.

PMID- 10639335
TI  - Dose-dependent linkage, assembly inhibition and disassembly of vimentin and
      cytokeratin 5/14 filaments through plectin's intermediate filament-binding
      domain.
AB  - Plectin, the largest and most versatile member of the cytolinker/plakin family of
      proteins characterized to date, has a tripartite structure comprising a central
      200 nm-long (&agr;)-helical rod domain flanked by large globular domains. The C
      terminal domain comprises a short tail region preceded by six highly conserved
      repeats (each 28-39 kDa), one of which (repeat 5) contains plectin's intermediate
      filament (IF)-binding site. We used recombinant and native proteins to assess the
      effects of plectin repeat 5-binding to IF proteins of different types.
      Quantitative Eu(3+)-based overlay assays showed that plectin's repeat 5 domain
      bound to type III IF proteins (vimentin) with preference over type I and II
      cytokeratins 5 and 14. The ability of both types of IF proteins to self-assemble
      into filaments in vitro was impaired by plectin's repeat 5 domain in a
      concentration-dependent manner, as revealed by negative staining and rotary
      shadowing electron microscopy. This effect was much more pronounced in the case
      of vimentin compared to cytokeratins 5/14. Preassembled filaments of both types
      became more and more crosslinked upon incubation with increasing concentrations
      of plectin repeat 5. However, at high proportions of plectin to IF proteins,
      disassembly of filaments occurred. Again, vimentin filaments proved considerably
      more sensitive towards disassembly than those composed of cytokeratins 5 and 14.
      In general, IFs formed from recombinant proteins were found to be slightly more
      responsive towards plectin influences than their native counterparts. A dose
      dependent plectin-inflicted collapse and putative disruption of IFs was also
      observed in vivo after ectopic expression of vimentin and plectin's repeat 5
      domain in cotransfected vimentin-deficient SW13 (vim(-)) cells. Our results
      suggest an involvement of plectin not only in crosslinking and stabilization of
      cytoskeletal IF networks, but also in regulation of their dynamics.

PMID- 10639336
TI  - Control of extracellular matrix assembly by syndecan-2 proteoglycan.
AB  - Extracellular matrix (ECM) deposition and organization is maintained by
      transmembrane signaling and integrins play major roles. We now show that a second
      transmembrane component, syndecan-2 heparan sulfate proteoglycan, is pivotal in
      matrix assembly. Chinese Hamster Ovary (CHO) cells were stably transfected with
      full length (S2) or truncated syndecan-2 lacking the C-terminal 14 amino acids of
      the cytoplasmic domain (S2deltaS). No differences in the amount of matrix
      assembly were noted with S2 cells, but those expressing S2deltaS could not
      assemble laminin or fibronectin into a fibrillar matrix. The loss of matrix
      formation was not caused by a failure to synthesize or externalize ECM components
      as determined by metabolic labeling or due to differences in surface expression
      of alpha5 or beta1 integrin. The matrix assembly defect was at the cell surface,
      since S2deltaS cells also lost the ability to rearrange laminin or fibronectin
      substrates into fibrils and to bind exogenous fibronectin. Transfection of
      activated alphaIIbalphaLdeltabeta3 integrin into alpha(5)-deficient CHO B2 cells
      resulted in reestablishment of the previously lost fibronectin matrix. However,
      cotransfection of this cell line with S2deltaS could override the presence of
      activated integrins. These results suggest a regulatory role for syndecan-2 in
      matrix assembly, along with previously suggested roles for activated integrins.

PMID- 10639337
TI  - Type 1 protein phosphatase is required for maintenance of cell wall integrity,
      morphogenesis and cell cycle progression in Saccharomyces cerevisiae.
AB  - GLC7 encodes the catalytic subunit of type 1 protein serine/threonine phosphatase
      (PP1) in the yeast Saccharomyces cerevisiae. Here we have characterized the
      temperature-sensitive glc7-10 allele, which displays aberrant bud morphology and
      an abnormal actin cytoskeleton at the restrictive temperature. At 37 degrees C
      glc7-10 strains accumulated a high proportion of budded cells with an unmigrated
      nucleus, duplicated spindle pole bodies, a short spindle, delocalized cortical
      actin and 2C DNA content, indicating a cell cycle block prior to the metaphase to
      anaphase transition. glc7-10 was suppressed by growth on high osmolarity medium
      and exhibited temperature-sensitive cell lysis upon hypo-osmotic stress. Pkc1p,
      the yeast protein kinase C homolog which is thought to regulate the Mpk1p MAP
      kinase pathway involved in cell wall remodelling and polarized cell growth, was
      found to act as a dosage suppressor of glc7-10. Although neither activation of
      BCK1 (MEKK) by the dominant BCK1-20 mutation nor increased dosage of MKK1 (MEK)
      or MPK1 (MAP kinase) mimicked PKC1 as a glc7-10 dosage suppressor, extra copies
      of genes encoding upstream components of the Pkc1p pathway such as ROM2, RHO2,
      HCS77/WSC1/SLG1 and MID2 also suppressed glc7-10 effectively. Conversely,
      mpk1delta glc7-10 and bck1delta glc7-10 double mutants displayed a synthetic cell
      lysis defect compared with each single mutant and glc7-10 was hypersensitive to
      reduced PKC1 function, displaying highly aberrant morphologies and inviability
      even at the normally permissive temperature of 26 degrees C. Dephosphorylation by
      PP1 therefore functions positively to promote cell integrity, bud morphology and
      polarization of the actin cytoskeleton and glc7-10 cells require higher levels of
      Pkc1p activity to sustain these functions.

PMID- 10639338
TI  - Saccharomyces cerevisiae Arc35p works through two genetically separable
      calmodulin functions to regulate the actin and tubulin cytoskeletons.
AB  - Analysis of the arc35-1 mutant has revealed previously that this component of the
      Arp2/3 complex is involved in organization of the actin cytoskeleton. Further
      characterization uncovered a cell division cycle phenotype with arrest as large
      budded cells. Cells with correctly positioned metaphase spindles accumulated at
      the restrictive temperature. The observed metaphase arrest most likely occurs by
      activation of the spindle assembly checkpoint, because arc35-1 was synthetically
      lethal with a deletion of BUB2. Arc35p activity is required late in G(1) for its
      cell cycle function. Both the actin and microtubule defects of arc35-1 can be
      suppressed by overexpression of calmodulin. Analysis of a collection of ts cmd1
      mutants for their ability to suppress the actin and/or microtubule defect
      revealed that the two defects observed in arc35-1 are genetically separable.
      These data suggest that the actin defect is probably not the cause of the
      microtubule defect.

PMID- 10639339
TI  - Evidence for a novel pathway for the targeting of a Saccharomyces cerevisiae
      peroxisomal protein belonging to the isomerase/hydratase family.
AB  - We, and others, have identified a novel Saccharomyces cerevisiae peroxisomal
      protein that belongs to the isomerase/hydratase family. The protein, named Dci1p,
      shares 50% identity with Eci1p, a delta(3)-cis-delta(2)-trans-enoyl-CoA isomerase
      that acts as an auxiliary enzyme in the beta-oxidation of unsaturated fatty
      acids. Both of these proteins are localized to peroxisomes, and both contain
      motifs at their amino- and carboxyl termini that resemble peroxisome targeting
      signals (PTS) 1 and 2. However, we demonstrate that the putative type 1 signaling
      motif is not required for the peroxisomal localization of either of these
      proteins. Furthermore, the correct targeting of Eci1p and Dci1p occurs in the
      absence of the receptors for the type 1 or type 2 peroxisome targeting pathway.
      Together, these data suggest a novel mechanism for the intracellular targeting of
      these peroxisomal proteins.

PMID- 10639340
TI  - S. pombe sporulation-specific coiled-coil protein Spo15p is localized to the
      spindle pole body and essential for its modification.
AB  - Spindle pole bodies in the fission yeast Schizosaccharomyces pombe are required
      during meiosis, not only for spindle formation but also for the assembly of
      forespore membranes. The spo15 mutant is defective in the formation of forespore
      membranes, which develop into spore envelopes. The spo15(+)gene encodes a protein
      with a predicted molecular mass of 223 kDa, containing potential coiled-coil
      regions. The spo15 gene disruptant was not lethal, but was defective in spore
      formation. Northern and western analyses indicated that spo15(+) was expressed
      not only in meiotic cells but also in vegetative cells. When the spo15-GFP fusion
      gene was expressed by the authentic spo15 promoter during vegetative growth and
      sporulation, the fusion protein colocalized with Sad1p, which is a component of
      spindle pole bodies. Meiotic divisions proceeded in spo15delta cells with
      kinetics similar to those in wild-type cells. In addition, the morphology of the
      mitotic and meiotic spindles and the nuclear segregation were normal in
      spo15delta. Intriguingly, transformation of spindle pole bodies from a punctate
      to a crescent form prior to forespore membrane formation was not observed in
      spo15delta cells. We conclude that Spo15p is associated with spindle pole bodies
      throughout the life cycle and plays an indispensable role in the initiation of
      spore membrane formation.

PMID- 10639341
TI  - Reversible programming of pluripotent cell differentiation.
AB  - We have undertaken an in vitro differentiation analysis of two related,
      interconvertible, pluripotent cell populations, ES and early primitive ectoderm
      like (EPL) cells, which are most similar in morphology, gene expression, cytokine
      responsiveness and differentiation potential in vivo to ICM and early primitive
      ectoderm, respectively. Pluripotent cells were differentiated in vitro as
      aggregates (embryoid bodies) and the appearance and abundance of cell lineages
      were assessed by morphology and gene expression. Differentiation in EPL cell
      embryoid bodies recapitulated normal developmental progression in vivo, but was
      advanced in comparison to ES cell embryoid bodies, with the rapid establishment
      of late primitive ectoderm specific gene expression, and subsequent loss of
      pluripotent cell markers. Nascent mesoderm was formed earlier and more
      extensively in EPL cell embryoid bodies, and resulted in the appearance of
      terminally differentiated mesodermal cell types prior to and at higher levels
      than in ES cell embryoid bodies. Nascent mesoderm in EPL cell embryoid bodies was
      not specified but could be programmed to alternative fates by the addition of
      exogenous factors. EPL cells remained competent to form primitive endoderm even
      though this is not the normal fate of primitive ectoderm in vivo. The
      establishment of primitive ectoderm-like gene expression and inability to
      participate in embryogenesis following blastocyst injection is therefore not
      directly associated with restriction in the ability to form extra-embryonic
      lineages. However, the EPL cell embryoid body environment did not support
      differentiation of primitive endoderm to visceral endoderm, indicating the lack
      of an inductive signal for visceral endoderm formation deduced to originate from
      the pluripotent cells. Similarly, the inability of EPL cells to form neurons when
      differentiated as embryoid bodies was attributable to perturbation of the
      differentiation environment and loss of inductive signals rather than a
      restricted differentiation potential. Reversion of EPL cells to ES cells was
      accompanied by restoration of ES cell-like differentiation potential. These
      results demonstrate the ability of pluripotent cells to adopt developmentally
      distinct, stable cell states with altered differentiation potentials.

PMID- 10639342
TI  - Correlation between the resistance genotype determined by multiplex PCR assays
      and the antibiotic susceptibility patterns of Staphylococcus aureus and
      Staphylococcus epidermidis.
AB  - Clinical isolates of Staphylococcus aureus (a total of 206) and S. epidermidis (a
      total of 188) from various countries were tested with multiplex PCR assays to
      detect clinically relevant antibiotic resistance genes associated with
      staphylococci. The targeted genes are implicated in resistance to oxacillin
      (mecA), gentamicin ?aac(6')-aph(2"), and erythromycin (ermA, ermB, ermC, and
      msrA). We found a nearly perfect correlation between genotypic and phenotypic
      analysis for most of these 394 strains, showing the following correlations: 98%
      for oxacillin resistance, 100% for gentamicin resistance, and 98.5% for
      erythromycin resistance. The discrepant results were (i) eight strains found to
      be positive by PCR for mecA or ermC but susceptible to the corresponding
      antibiotic based on disk diffusion and (ii) six strains of S. aureus found to be
      negative by PCR for mecA or for the four erythromycin resistance genes targeted
      but resistant to the corresponding antibiotic. In order to demonstrate in vitro
      that the eight susceptible strains harboring the resistance gene may become
      resistant, we subcultured the susceptible strains on media with increasing
      gradients of the antibiotic. We were able to select cells demonstrating a
      resistant phenotype for all of these eight strains carrying the resistance gene
      based on disk diffusion and MIC determinations. The four oxacillin-resistant
      strains negative for mecA were PCR positive for blaZ and had the phenotype of
      beta-lactamase hyperproducers, which could explain their borderline oxacillin
      resistance phenotype. The erythromycin resistance for the two strains found to be
      negative by PCR is probably associated with a novel mechanism. This study
      reiterates the usefulness of DNA-based assays for the detection of antibiotic
      resistance genes associated with staphylococcal infections.

PMID- 10639343
TI  - Comparison of three methods of determining MICs for filamentous fungi using
      different end point criteria and incubation periods.
AB  - Three different methods were used to determine the in vitro activities of
      amphotericin B, ketoconazole, itraconazole, and flucytosine against 30 isolates
      of different genera of filamentous fungi. MICs were determined visually, with or
      without agitation, and spectrophotometrically by using a broth microdilution
      method. For amphotericin B, there was one end point reading criterion (the
      minimum concentration of antifungal that inhibited 100% of growth), but for
      azoles and flucytosine there were two (the minimum concentrations that inhibited
      50 and 75% of fungal growth, respectively) after 48 and 72 h of incubation. All
      tests were performed in triplicate. An intraclass correlation coefficient (ICC)
      was used to evaluate the reproducibility of each of the methods and the
      correlation among them. The reproducibility of the three methods was very high
      (ICC of 0.808 to 0.992), particularly in the case of azoles and flucytosine. In
      general, the degree of reproducibility was highest for azoles and amphotericin B
      after 72 h of incubation and for flucytosine after 48 h of incubation. The degree
      of correlation among the three methods was very high (ICC of >0.98) with all of
      the antifungals under all the conditions tested. The end point reading criteria
      and the time of incubation affected neither the reproducibility of the methods
      nor their correlation, and their effect on MICs was statistically significant.

PMID- 10639344
TI  - Immunization with the Candida albicans membrane fraction and in combination with
      fluconazole protects against systemic fungal infections.
AB  - We studied the immunogenicity of a membrane fraction prepared from Candida
      albicans cells called C. albicans membrane antigen (CMA). The present study
      revealed that CMA immunization has antifungal activity in mouse models of
      systemic fungal infection. Immunization of mice by subcutaneous injections of CMA
      with incomplete Freund adjuvant induced resistance to infections caused not only
      by C. albicans but also by Aspergillus fumigatus. The level of resistance to
      candidiasis was as high as that induced by whole-cell immunization. The acquired
      resistance to candidiasis in the mice immunized with CMA was not diminished by
      immunosuppressive treatment with cyclophosphamide. The level of resistance to
      fungal infections was superior to that given by fluconazole (FLC) treatment alone
      and highly enhanced by the combination with FLC. When CD4(+) cells in CMA
      immunized mice were depleted by a monoclonal antibody, the antifungal activity
      induced by the combination of CMA and FLC was significantly reduced. These
      results indicate that immunization with CMA is useful for preventing systemic
      fungal infections and in combination with FLC for increasing resistance after
      infection.

PMID- 10639345
TI  - Helicobacter pylori uptake and efflux: basis for intrinsic susceptibility to
      antibiotics in vitro.
AB  - We previously demonstrated (M. M. Exner, P. Doig, T. J. Trust, and R. E. W.
      Hancock, Infect. Immun. 63:1567-1572, 1995) that Helicobacter pylori has at least
      one nonspecific porin, HopE, which has a low abundance in the outer membrane but
      forms large channels. H. pylori is relatively susceptible to most antimicrobial
      agents but less susceptible to the polycationic antibiotic polymyxin B. We
      demonstrate here that H. pylori is able to take up higher basal levels of the
      hydrophobic fluorescent probe 1-N-phenylnaphthylamine (NPN) than Pseudomonas
      aeruginosa or Escherichia coli, consistent with its enhanced susceptibility to
      hydrophobic agents. Addition of polymyxin B led to a further increase in NPN
      uptake, indicative of a self-promoted uptake pathway, but it required a much
      higher amount of polymyxin B to yield a 50% increase in NPN uptake in H. pylori
      (6 to 8 microg/ml) than in P. aeruginosa or E. coli (0.3 to 0.5 microg/ml),
      suggesting that H. pylori has a less efficient self-promoted uptake pathway.
      Since intrinsic resistance involves the collaboration of restricted outer
      membrane permeability and secondary defense mechanisms, such as periplasmic beta
      lactamase (which H. pylori lacks) or efflux, we examined the possible role of
      efflux in antibiotic susceptibility. We had previously identified in H. pylori
      11637 the presence of portions of three genes with homology to potential
      restriction-nodulation-division (RND) efflux systems. It was confirmed that H.
      pylori contained only these three putative RND efflux systems, named here hefABC,
      hefDEF, and hefGHI, and that the hefGHI system was expressed only in vivo while
      the two other RND systems were expressed both in vivo and in vitro. In uptake
      studies, there was no observable energy-dependent tetracycline, chloramphenicol,
      or NPN efflux activity in H. pylori. Independent mutagenesis of the three
      putative RND efflux operons in the chromosome of H. pylori had no effect on the
      in vitro susceptibility of H. pylori to 19 antibiotics. These results, in
      contrast to what is observed in E. coli, P. aeruginosa, and other clinically
      important gram-negative bacteria, suggest that active efflux does not play a role
      in the intrinsic resistance of H. pylori to antibiotics.

PMID- 10639346
TI  - Efficacy of a new cream formulation of mupirocin: comparison with oral and
      topical agents in experimental skin infections.
AB  - A new cream formulation of mupirocin developed to improve patient compliance was
      compared with systemic and topical antibiotics commonly used to treat primary and
      secondary skin infections. A mouse surgical wound model infected with
      Staphylococcus aureus or Streptococcus pyogenes was used. Topical treatment was
      applied at 4 and 10 h postinfection or oral treatment at a clinically relevant
      dose was administered 4, 8, and 12 h postinfection; treatments were continued
      three times daily for a further 3 days. Mupirocin cream was significantly more
      effective than (P < 0.01; two of eight studies) or not significantly different
      from (six of eight studies) mupirocin ointment in reducing bacterial numbers.
      Mupirocin cream was similar in efficacy to oral flucloxacillin but significantly
      more effective (P < 0.001) than oral erythromycin. It was also similar in
      efficacy to cephalexin against S. pyogenes but superior against S. aureus (P <
      0.01). Mupirocin cream had a similar efficacy to fusidic acid cream against S.
      aureus but was significantly superior against S. pyogenes (P < 0.01). A hamster
      impetigo model infected with S. aureus was also used. Topical or oral treatment
      was administered at 24 and 30 h postinfection (also 36 h postinfection for oral
      therapy) and then three times daily for a further 2 days. On day 5, mupirocin
      cream was significantly more effective than mupirocin ointment in one study (P <
      0.01) and of similar efficacy in the other two studies. Mupirocin cream was not
      significantly different from fusidic acid cream or neomycin-bacitracin cream, but
      it was significantly superior (P < 0.01) to oral erythromycin and cephalexin.
      Mupirocin cream was as effective as, or superior to, oral and other topical
      agents commonly used for skin infections.

PMID- 10639347
TI  - Ultrastructure of Achilles tendons of rats treated with ofloxacin and fed a
      normal or magnesium-deficient diet.
AB  - Fluoroquinolones can cause tendinitis and tendon rupture. However, toxicological
      as well as clinical information on quinolone-induced tendopathy is scarce. We
      performed extensive electron microscopic studies with Achilles tendon specimens
      from ofloxacin-treated rats. The drug was given at a dose of 1,200 mg/kg (body
      weight) orally. Juvenile Wistar rats received one or three oral doses each of
      1,200 mg of ofloxacin/kg (body weight)/day. Three days after treatment, the
      tenocytes of their Achilles tendons showed degenerative alterations, such as
      multiple vacuoles and vesicles in the cytoplasm that had developed due to
      swellings and dilatations of cell organelles. Other indications of cell
      degradation were the occurrence of cell debris and cell detachment from the
      extracellular matrix accompanied by a loss of cell-matrix interaction. The
      tenocytes of juvenile Wistar rats that had been treated at day 36 with a single
      oral dose of 1,200 mg of ofloxacin/kg (body weight) and sacrificed either 3 or 6
      months later exhibited similar degenerative alterations. The number of
      degenerative alterations of tenocytes after ofloxacin treatment was considerably
      higher in rats that had received a magnesium-deficient diet than in rats with
      normal magnesium status. Of the adult rats that had been treated once, 5 times,
      and 10 times with ofloxacin and killed 1 day later, only those with the 10-times
      treatment showed a significantly increased number of degeneratively altered
      tenocytes. In summary, effects observed in tendons show similar pathological
      features as described earlier in cartilage, indicating that quinolone-induced
      arthropathy and quinolone-induced tendopathy probably are different clinical
      manifestations of the same toxic effect on cellular components of connective
      tissue structures.

PMID- 10639348
TI  - Antibiotic resistance in Campylobacter strains isolated from animals, foods, and
      humans in Spain in 1997-1998.
AB  - Colonization by Campylobacter strains was investigated in human, broiler, and pig
      fecal samples from 1997-1998, as well as in foods of animal origin, and
      antibiotic susceptibility testing was carried out for these strains.
      Campylobacter strains were isolated in the foods of animal origin (55 of 101
      samples; 54.4%), intestinal samples from broilers (85 of 105; 81%), and pigs (40
      of 45; 88.9%). A total of 641 Campylobacter strains were isolated from 8,636
      human fecal samples of clinical origin (7.4%). Campylobacter jejuni was the most
      frequently isolated species from broilers (81%) and humans (84%), and
      Campylobacter coli was most frequently isolated from pigs (100%). An extremely
      high frequency of ciprofloxacin resistance was detected among Campylobacter
      strains, particularly those isolated from broilers and pigs (99%), with a
      slightly lower result for humans (72%); cross-resistance with nalidixic acid was
      almost always observed. A higher frequency of resistance to erythromycin (81.1%),
      ampicillin (65.7%), gentamicin (22.2%), and amikacin (21.6%) was detected in C.
      coli strains isolated from pigs compared to those isolated from humans (34.5,
      29.3, 8.6, and 0%, respectively). A low frequency of erythromycin resistance was
      found in C. jejuni or C. coli isolated from broilers. A greater resistance to
      ampicillin and gentamicin (47.4 and 11.9%, respectively) was detected in C.
      jejuni isolated from broilers than in human strains (38 and 0.4%, respectively).
      Beta-lactamase production was found in 81% of the Campylobacter strains tested,
      although 44% of them were characterized as ampicillin susceptible. The increasing
      rates of Campylobacter resistance make advisable a more conservative policy for
      the use of antibiotics in farm animals.

PMID- 10639350
TI  - A population pharmacokinetic model for vancomycin in pediatric patients and its
      predictive value in a naive population.
AB  - The objectives of this study were to (i) construct a population pharmacokinetic
      (PK) model able to describe vancomycin (VAN) concentrations in serum in pediatric
      patients, (ii) determine VAN PK parameters in this population, and (iii) validate
      the predictive ability of this model in a naive pediatric population. Data used
      in this study were obtained from 78 pediatric patients (under 18 years old). PK
      analyses were performed using compartmental methods. The most appropriate model
      was chosen based on the evaluation of pertinent graphics and calculation of the
      Akaike information criterion test. The population PK analysis was performed using
      an iterative two-stage method. A two-compartment PK model using age, sex, weight,
      and serum creatinine as covariates was determined to be the most appropriate one
      to describe serum VAN concentrations. The quality of fit was very good, and the
      distribution of weighted residuals was found to be homoscedastic (Wilcoxon signed
      rank test). Fitted population PK parameters (mean +/- standard deviation) were as
      follows: central clearance (0.1 +/- 0.05 liter/h/kg), central volume of
      distribution (0.27 +/- 0.07 liter/kg), peripheral volume of distribution (0.16 +/
      0.07 liter/kg), and distributional clearance (0.16 +/- 0.07 liter/kg). The
      predictive ability of the developed model (including the above-mentioned
      covariates) was evaluated in a naive population of 19 pediatric patients. The
      predictability was very good. Precision (+/-95% confidence interval [CI]) (peak,
      4.1 [+/-1.4], and trough, 2.2 [+/-0.7]) and bias (+/-95% CI) (peak, -0.58 [+/
      2.2], and trough, 0.63 [+/-1.1] mg/liter) were significantly (P < 0.05) superior
      to those obtained using a conventional method (precision [+/-95% CI]: peak, 8.03
      [+/-2. 46], and trough, 2.7 [+/-0.74]; bias: peak, -7.1 [+/-2.9], and trough, 
      1.35 [+/-1.2] mg/liter). We propose the use of this population PK model to
      optimize VAN clinical therapies in our institution and others with similar
      patient population characteristics.he object

PMID- 10639349
TI  - Reversion of the glycopeptide resistance phenotype in Staphylococcus aureus
      clinical isolates.
AB  - The recent identification of glycopeptide intermediate-resistant Staphylococcus
      aureus (GISA) clinical isolates has provided an opportunity to assess the
      stability of the glycopeptide resistance phenotype by nonselective serial passage
      and to evaluate reversion-associated cell surface changes. Three GISA isolates
      from the United States (MIC of vancomycin = 8 microg/ml) and two from Japan (MICs
      of vancomycin = 8 and 2 microg/ml) were passaged daily on nutrient agar with or
      without vancomycin supplementation. After 15 days of passage on nonselective
      medium, vancomycin- and teicoplanin-susceptible revertants were obtained from
      each GISA isolate as determined by broth dilution MIC. Revertant isolates were
      compared with parent isolates for changes in vancomycin heteroresistance, capsule
      production, hemolysis phenotype, coagulase activity, and lysostaphin
      susceptibility. Several revertants lost the subpopulations with intermediate
      vancomycin resistance, whereas two revertants maintained them. Furthermore,
      although all of the parent GISA isolates produced capsule type 5 (CP5), all but
      one revertant tested no longer produced CP5. In contrast, passage on medium
      containing vancomycin yielded isolates that were still intermediately resistant
      to vancomycin, had no decrease in the MIC of teicoplanin, and produced detectable
      CP5. No consistent changes in the revertants in hemolysis phenotype, lysostaphin
      susceptibility, or coagulase activities were discerned. These data indicate that
      the vancomycin resistance phenotype is unstable in clinical GISA isolates.
      Reversion of the vancomycin resistance phenotype might explain the difficulty in
      isolating vancomycin-resistant clinical isolates from the blood of patients who
      fail vancomycin therapy and, possibly, may account for some of the difficulties
      in identifying GISA isolates in the clinical laboratory.

PMID- 10639351
TI  - Comparative antimicrobial activities of the newly synthesized quinolone WQ-3034,
      levofloxacin, sparfloxacin, and ciprofloxacin against Mycobacterium tuberculosis
      and Mycobacterium avium complex.
AB  - WQ-3034 is a newly synthesized acidic fluoroquinolone. We assessed its in vitro
      activity against Mycobacterium tuberculosis and M. avium complex using
      levofloxacin (LVFX), ciprofloxacin (CPFX), sparfloxacin (SPFX), and KRM-1648
      (KRM) as reference drugs. The MICs of these agents were determined by the agar
      dilution method with 7H11 medium. The MICs at which 50 and 90% of the test
      strains were inhibited (MIC(50)s, and MIC(90)s, respectively) for the test
      quinolones for rifampin (RMP)-susceptible M. tuberculosis strains were in the
      order SPFX < LVFX </= WQ-3034 </= CPFX, while those for RMP-resistant M.
      tuberculosis strains were in the order SPFX </= WQ-3034 </= LVFX < CPFX. The MICs
      of KRM for RMP-susceptible M. tuberculosis were much lower than those of the test
      quinolones, while the MIC(90) of KRM for RMP-resistant M. tuberculosis strains
      was higher than those of the quinolones. The MIC(50)s and MIC(90)s of the test
      drugs for M. avium were in the order KRM < SPFX < CPFX </= WQ-3034 </= LVFX,
      while those for M. intracellulare were in the order KRM < SPFX < WQ-3034 LVFX </=
      CPFX. Next, we compared the antimicrobial activities of the test drugs against M.
      tuberculosis organisms residing in cells of the Mono Mac 6 macrophage (Mphi)-like
      cell line (MM6-Mphis) and of the A-549 type II alveolar cell line (A-549 cells).
      When drugs were added at the concentration that achieves the maximum
      concentration in blood, progressive killing or inhibition of the M. tuberculosis
      organisms residing in MM6-Mphis and A-549 cells was observed in the order KRM >
      SPFX >/= LVFX > WQ-3034 > CPFX. The efficacies of all quinolones against
      intracellular M. tuberculosis organisms were significantly lower in A-549 cells
      than in MM6-Mphis. WQ-3034 at the MIC caused more marked growth inhibition of
      intramacrophage M. tuberculosis than did LVFX. These findings indicate that the
      in vitro anti-M. tuberculosis activity of WQ-3034 is greater than that of CPFX
      and is comparable to that of LVFX.

PMID- 10639352
TI  - Multiple antibiotic resistance in Stenotrophomonas maltophilia: involvement of a
      multidrug efflux system.
AB  - Clinical strains of Stenotrophomonas maltophilia are often highly resistant to
      multiple antibiotics, although the mechanisms of resistance are generally poorly
      understood. Multidrug resistant (MDR) strains were readily selected by plating a
      sensitive reference strain of the organism individually onto a variety of
      antibiotics, including tetracycline, chloramphenicol, ciprofloxacin, and
      norfloxacin. Tetracycline-selected MDR strains typically showed cross-resistance
      to erythromycin and fluoroquinolones and, in some instances, aminoglycosides. MDR
      mutants selected with the other agents generally displayed resistance to
      chloramphenicol and fluoroquinolones only, although two MDR strains (e.g., K1385)
      were also resistant to erythromycin and hypersusceptible to aminoglycosides. Many
      of the MDR strains expressed either moderate or high levels of a novel outer
      membrane protein (OMP) of ca. 50 kDa molecular mass, a phenotype typical of MDR
      strains of Pseudomonas aeruginosa hyperexpressing drug efflux systems. Indeed,
      the 50-kDa OMP of these S. maltophilia MDR strains reacted with antibody to OprM,
      the outer membrane component of the MexAB-OprM MDR efflux system of P.
      aeruginosa. Similarly, a ca. 110-kDa cytoplasmic membrane protein of these MDR
      strains also reacted with antibody to the MexB component of the P. aeruginosa
      pump. The outer and cytoplasmic membranes of several clinical S. maltophilia
      strains also reacted with the anti-OprM and anti-MexB antibodies. N-terminal
      amino acid sequencing of a cyanogen bromide-generated peptide of the 50-kDa OMP
      of MDR strain K1385, dubbed SmeM (Stenotrophomonas multidrug efflux), revealed it
      to be very similar to a number of outer membrane multidrug efflux components of
      P. aeruginosa and Pseudomonas putida. Deletion of the L1 and L2 beta-lactamase
      genes confirmed that these enzymes were responsible for the bulk of the beta
      lactam resistance of K1385 and its parent. Still, overexpression of the MDR
      efflux mechanism in an L1- and L2-deficient derivative of K1385 did yield a
      modest increase in resistance to a few beta-lactams. These data are consistent
      with the MDR efflux mechanism(s) playing a role in the multidrug resistance of S.
      maltophilia.

PMID- 10639353
TI  - Characterization of passage-selected vancomycin-resistant Staphylococcus aureus
      strains of diverse parental backgrounds.
AB  - A series of 12 Staphylococcus aureus strains of various genetic backgrounds,
      methicillin resistance levels, and autolytic activities were subjected to
      selection for the glycopeptide-intermediate S. aureus (GISA) susceptibility
      phenotype on increasing concentrations of vancomycin. Six strains acquired the
      phenotype rapidly, two did so slowly, and four failed to do so. The vancomycin
      MICs for the GISA strains ranged from 4 to 16 microg/ml, were stable to 20
      nonselective passages, and expressed resistance homogeneously. Neither ease of
      acquisition of the GISA phenotype nor the MIC attained correlated with
      methicillin resistance hetero- versus homogeneity or autolytic deficiency or
      sufficiency. Oxacillin MICs were generally unchanged between parent and GISA
      strains, although the mec members of both isogenic methicillin-susceptible and
      methicillin-resistant pairs acquired the GISA phenotype more rapidly and to
      higher MICs than did their susceptible counterparts. Transmission electron
      microscopy revealed that the GISA strains appeared normal in the absence of
      vancomycin but had thickened and diffuse cell walls when grown with vancomycin at
      one-half the MIC. Common features among GISAs were reduced doubling times,
      decreased lysostaphin susceptibilities, and reduced whole-cell and zymographic
      autolytic activities in the absence of vancomycin. This, with surface
      hydrophobicity differences, indicated that even in the absence of vancomycin the
      GISA cell walls differed from those of the parents. Autolytic activities were
      further reduced by the inclusion of vancomycin in whole-cell and zymographic
      studies. The six least vancomycin-susceptible GISA strains exhibited an increased
      capacity to remove vancomycin from the medium versus their parent lines. This
      study suggests that while some elements of the GISA phenotype are strain
      specific, many are common to the phenotype although their expression is
      influenced by genetic background. GISA strains with similar glycopeptide MICs may
      express individual components of the phenotype to different extents.

PMID- 10639354
TI  - Antipneumococcal activities of gemifloxacin compared to those of nine other
      agents.
AB  - The activities of gemifloxacin compared to those of nine other agents was tested
      against a range of penicillin-susceptible and -resistant pneumococci by agar
      dilution, microdilution, time-kill, and post-antibiotic effect (PAE) methods.
      Against 64 penicillin-susceptible, 68 penicillin-intermediate, and 75 penicillin
      resistant pneumococci (all quinolone susceptible), agar dilution MIC(50)s (MICs
      at which 50% of isolates are inhibited)/MIC(90)s (in micrograms per milliliter)
      were as follows: gemifloxacin, 0.03/0.06; ciprofloxacin, 1.0/4.0; levofloxacin,
      1.0/2. 0; sparfloxacin, 0.5/1.0; grepafloxacin, 0.125/0.5; trovafloxacin, 0.
      125/0.25; amoxicillin, 0.016/0.06 (penicillin-susceptible isolates), 0.125/1.0
      (penicillin-intermediate isolates), and 2.0/4.0 (penicillin-resistant isolates);
      cefuroxime, 0.03/0.25 (penicillin-susceptible isolates), 0.5/2.0 (penicillin
      intermediate isolates), and 8.0/16.0 (penicillin-resistant isolates);
      azithromycin, 0.125/0.5 (penicillin-susceptible isolates), 0. 125/>128.0
      (penicillin-intermediate isolates), and 4.0/>128.0 (penicillin-resistant
      isolates); and clarithromycin, 0.03/0.06 (penicillin-susceptible isolates),
      0.03/32.0 (penicillin-intermediate isolates), and 2.0/>128.0 (penicillin
      resistant isolates). Against 28 strains with ciprofloxacin MICs of >/=8
      microg/ml, gemifloxacin had the lowest MICs (0.03 to 1.0 microg/ml; MIC(90), 0.5
      microg/ml), compared with MICs ranging between 0.25 and >32.0 microg/ml (MIC(90)s
      of 4.0 to >32.0 microg/ml) for other quinolones. Resistance in these 28 strains
      was associated with mutations in parC, gyrA, parE, and/or gyrB or efflux, with
      some strains having multiple resistance mechanisms. For 12 penicillin-susceptible
      and -resistant pneumococcal strains (2 quinolone resistant), time-kill results
      showed that levofloxacin at the MIC, gemifloxacin and sparfloxacin at two times
      the MIC, and ciprofloxacin, grepafloxacin, and trovafloxacin at four times the
      MIC were bactericidal for all strains after 24 h. Gemifloxacin was uniformly
      bactericidal after 24 h at </=0.5 microg/ml. Various degrees of 90 and 99%
      killing by all quinolones were detected after 3 h. Gemifloxacin and trovafloxacin
      were both bactericidal at two times the MIC for the two quinolone-resistant
      pneumococci. Amoxicillin at two times the MIC and cefuroxime at four times the
      MIC were uniformly bactericidal after 24 h, with some degree of killing at
      earlier time points. Macrolides gave slower killing against the seven susceptible
      strains tested, with 99.9% killing of all strains at two to four times the MIC
      after 24 h. PAEs for five quinolone-susceptible strains were similar (0.3 to 3.0
      h) for all quinolones, and significant quinolone PAEs were found for the
      quinolone-resistant strain.

PMID- 10639355
TI  - Substitutions in the eyelet region disrupt cefepime diffusion through the
      Escherichia coli OmpF channel.
AB  - The Escherichia coli OmpF porin is a nonspecific channel involved in the membrane
      translocation of small hydrophilic molecules and especially in the passage of
      beta-lactam antibiotics. In order to understand the dynamic of charged-compound
      uptake through bacterial porins, specific charges located in the E. coli OmpF
      channel were mutated. Substitutions G119D and G119E, inserting a protruding
      acidic side chain into the pore, decreased cephalosporin and colicin
      susceptibilities. Cefepime diffusion was drastically altered by these mutations.
      Conversely, substitutions R132A and R132D, changing a residue located in the
      positively charged cluster, increased the rate of cephalosporin uptake without
      modifying colicin sensitivity. Modelling approaches suggest that G119E generates
      a transverse hydrogen bond dividing the pore, while the two R132 substitutions
      stretch the channel size. These charge alterations located in the constriction
      area have differential effects on cephalosporin diffusion and substantially
      modify the profile of antibiotic susceptibility.

PMID- 10639356
TI  - Regional prophylaxis with teicoplanin in monolateral or bilateral total knee
      replacement: an open study.
AB  - From January 1991 to June 1997, patients undergoing primary elective monolateral
      or bilateral total knee replacement (TKR) were consecutively enrolled in a
      prospective, open clinical study on the efficacy and safety of regional
      prophylaxis with teicoplanin (TEC). Those scheduled for monolateral TKR (115
      patients) received 400 mg of TEC in 100 ml of saline as a 5-min infusion into a
      foot vein of the leg to be operated on immediately after the tourniquet was
      inflated to 400 mm Hg (ca. 50 kPa). For patients undergoing bilateral surgery (45
      patients), regional administration of TEC was also repeated for the second knee
      operation. Follow-up ranged from a minimum of 2 years to 8 years. None of the
      patients experienced local or systemic adverse effects following regional
      administration of TEC. In the immediate postoperative and 2-year follow-up
      periods, only one superficial infection of the primary site attributable to
      intraoperative contamination (prophylaxis failure) out of the 205 prostheses
      implanted was observed. Deep infections involving the prosthesis did not occur.
      Infectious complications at distant sites were observed in nine cases (urinary
      tract infection due to Escherichia coli in eight cases, and Salmonella
      enteritidis gastroenteritis in one case) in the immediate postoperative period;
      they all were rapidly cured after antibiotic treatment. A delayed prosthetic
      infection, related to hematogenous spread of the etiological agent and therefore
      not considered a prophylactic failure, was observed in a patient who had
      undergone TKR 5 years before. Regional administration of TEC in monolateral and
      bilateral TKR appears to be a safe and valuable prophylactic technique.

PMID- 10639357
TI  - Engineering the specificity of antibacterial fluoroquinolones: benzenesulfonamide
      modifications at C-7 of ciprofloxacin change its primary target in Streptococcus
      pneumoniae from topoisomerase IV to gyrase.
AB  - We have examined the antipneumococcal mechanisms of a series of novel
      fluoroquinolones that are identical to ciprofloxacin except for the addition of a
      benzenesulfonylamido group to the C-7 piperazinyl ring. A number of these
      derivatives displayed enhanced activity against Streptococcus pneumoniae strain
      7785, including compound NSFQ-105, bearing a 4-(4-aminophenylsulfonyl)-1
      piperazinyl group at C-7, which exhibited an MIC of 0.06 to 0.125 microg/ml
      compared with a ciprofloxacin MIC of 1 microg/ml. Several complementary
      approaches established that unlike the case for ciprofloxacin (which targets
      topoisomerase IV), the increased potency of NSFQ-105 was associated with a target
      preference for gyrase: (i) parC mutants of strain 7785 that were resistant to
      ciprofloxacin remained susceptible to NSFQ-105, whereas by contrast, mutants
      bearing a quinolone resistance mutation in gyrA were four- to eightfold more
      resistant to NSFQ-105 (MIC of 0.5 microg/ml) but susceptible to ciprofloxacin;
      (ii) NSFQ-105 selected first-step gyrA mutants (MICs of 0.5 microg/ml) encoding
      Ser-81-to-Phe or -Tyr mutations, whereas ciprofloxacin selects parC mutants; and
      (iii) NSFQ-105 was at least eightfold more effective than ciprofloxacin at
      inhibiting DNA supercoiling by S. pneumoniae gyrase in vitro but was fourfold
      less active against topoisomerase IV. These data show unequivocally that the C-7
      substituent determines not only the potency but also the target preference of
      fluoroquinolones. The importance of the C-7 substituent in drug-enzyme contacts
      demonstrated here supports one key postulate of the Shen model of quinolone
      action.

PMID- 10639359
TI  - Effect of a bis-benzyl polyamine analogue on Pneumocystis carinii.
AB  - Pneumocystis carinii is the causative agent of P. carinii pneumonia (PCP), an
      opportunistic infection associated with AIDS and other immunosuppressed
      conditions. Although polyamine metabolism of this fungus has been shown to be a
      chemotherapeutic target, this metabolism has not been thoroughly investigated.
      Reported here is the effect of one polyamine analogue, N, N'-bis[3
      [(phenylmethyl)amino]propyl]-1,7-diaminoheptane (BBS), on P. carinii. BBS
      inhibits the growth of P. carinii in culture, but at concentrations higher than
      those required to inhibit the growth of other pathogens. However, BBS is at least
      as active in an animal model of PCP as in other models of diseases studied. BBS
      causes some reduction in P. carinii polyamine content and polyamine biosynthetic
      enzyme activities, but the effect is less than that observed with other pathogens
      and very much less than the effect of the polyamine biosynthesis inhibitor DL
      alpha-difluoromethylornithine. BBS enters P. carinii cells via a polyamine
      transporter, unlike all other cells that have been studied. P. carinii cells do
      not remove the benzyl groups of BBS, as is reported for mammalian cells. The most
      likely mode of action is displacement of natural polyamines. Overall, the
      activity of BBS provides further evidence that polyamines and polyamine
      metabolism are rational targets for the development of drugs to treat PCP.
      Because the details of BBS-P. carinii interaction differ from those of other
      cells studied, polyamine analogues may provide a highly specific treatment for
      PCP.

PMID- 10639358
TI  - Molecular genetic analysis of nucleotide polymorphisms associated with ethambutol
      resistance in human isolates of Mycobacterium tuberculosis.
AB  - Ethambutol (EMB) is a central component of drug regimens used worldwide for the
      treatment of tuberculosis. To gain insight into the molecular genetic basis of
      EMB resistance, approximately 2 Mb of five chromosomal regions with 12 genes in
      75 epidemiologically unassociated EMB-resistant and 33 EMB-susceptible
      Mycobacterium tuberculosis strains isolated from human patients were sequenced.
      Seventy-six percent of EMB-resistant organisms had an amino acid replacement or
      other molecular change not found in EMB-susceptible strains. Thirty-eight (51%)
      EMB-resistant isolates had a resistance-associated mutation in only 1 of the 12
      genes sequenced. Nineteen EMB-resistant isolates had resistance-associated
      nucleotide changes that conferred amino acid replacements or upstream potential
      regulatory region mutations in two or more genes. Most isolates (68%) with
      resistance-associated mutations in a single gene had nucleotide changes in embB,
      a gene encoding an arabinosyltransferase involved in cell wall biosynthesis. The
      majority of these mutations resulted in amino acid replacements at position 306
      or 406 of EmbB. Resistance-associated mutations were also identified in several
      genes recently shown to be upregulated in response to exposure of M. tuberculosis
      to EMB in vitro, including genes in the iniA operon. Approximately one-fourth of
      the organisms studied lacked mutations inferred to participate in EMB resistance,
      a result indicating that one or more genes that mediate resistance to this drug
      remain to be discovered. Taken together, the results indicate that there are
      multiple molecular pathways to the EMB resistance phenotype.

PMID- 10639360
TI  - Mechanisms of artemisinin resistance in the rodent malaria pathogen Plasmodium
      yoelii.
AB  - Artemisinin and its derivatives are important new antimalarials which are now
      used widely in Southeast Asia. Clinically relevant artemisinin resistance has not
      yet been reported but is likely to occur. In order to understand how the malaria
      parasite might become resistant to this drug, we studied artemisinin resistance
      in the murine malaria parasite Plasmodium yoelii. The artemisinin-resistant
      strain (ART), which is approximately fourfold less sensitive to artemisinin than
      the sensitive NS strain, accumulated 43% less radiolabeled drug in vitro (P <
      0.01). Within the parasite, the drug appeared to react with the same parasite
      proteins in both strains. The translationally controlled tumor protein, one of
      the artemisinin target proteins, did not differ between the strains. No DNA
      sequence difference was found, but the resistant strain was found to express 2.5
      fold-more protein than the sensitive strain (P < 0.01). Thus, the phenotype of
      artemisinin resistance in P. yoelii appears to be multifactorial.

PMID- 10639361
TI  - Candida albicans mutants deficient in respiration are resistant to the small
      cationic salivary antimicrobial peptide histatin 5.
AB  - Histatins are a group of small cationic peptides in human saliva which are well
      known for their antibacterial and antifungal activities. In a previous study we
      demonstrated that histatin 5 kills both blastoconidia and germ tubes of Candida
      albicans in a time- and concentration-dependent manner at 37 degrees C, whereas
      no killing was detected at 4 degrees C. This indicated that killing activity
      depends on cellular energy. To test histatin 5 killing activity at lower cellular
      ATP levels at 37 degrees C, respiratory mutants, or so-called petite mutants, of
      C. albicans were prepared. These mutants are deficient in respiration due to
      mutations in mitochondrial DNA. Mutants were initially identified by their small
      colony size and were further characterized with respect to colony morphology,
      growth characteristics, respiratory activity, and cytochrome spectra. The killing
      activity of histatin 5 at the highest concentration was only 28 to 30% against
      respiratory mutants, whereas 98% of the wild-type cells were killed. Furthermore,
      histatin 5 killing activity was also tested on wild-type cells in the presence of
      the respiratory inhibitor sodium azide or, alternatively, the uncoupler carbonyl
      cyanide m-chlorophenylhydrazone. In both cases histatin 5 killing activity was
      significantly reduced. Additionally, supernatants and pellets of cells incubated
      with histatin 5 in the presence or absence of inhibitors of mitochondrial ATP
      synthesis were analyzed by sodium dodecyl sulfate gel electrophoresis. It was
      observed that wild-type cells accumulated large amounts of histatin 5, while wild
      type cells treated with inhibitors or petite mutants did not accumulate
      significant amounts of the peptide. These data showed first that cellular
      accumulation of histatin 5 is necessary for killing activity and second that
      accumulation of histatin 5 depends on the availability of cellular energy.
      Therefore, mitochondrial ATP synthesis is required for effective killing activity
      of histatin 5.

PMID- 10639362
TI  - New gene cassettes for trimethoprim resistance, dfr13, and Streptomycin
      spectinomycin resistance, aadA4, inserted on a class 1 integron.
AB  - In a previous survey of 357 trimethoprim-resistant isolates of aerobic gram
      negative bacteria from commensal fecal flora, hybridization experiments showed
      that 25% (90 of 357) of the isolates failed to hybridize to specific
      oligonucleotide probes for dihydrofolate reductase types 1, 2b, 3, 5, 6, 7, 8, 9,
      10, and 12. Subsequent cloning and sequencing of a plasmid-borne trimethoprim
      resistance gene from one of these isolates revealed a new dihydrofolate reductase
      gene, dfr13, which occurred as a cassette integrated in a site-specific manner in
      a class 1 integron. The gene product shared 84% amino acid identity with dfr12
      and exhibited a trimethoprim inhibition profile similar to that of dfr12. Gene
      probing experiments with an oligonucleotide probe specific for this gene showed
      that 12.3% (44 of 357) of the isolates which did not hybridize to probes for
      other dihydrofolate reductases hybridized to this probe. Immediately downstream
      of dfr13, a new cassette, an aminoglycoside resistance gene of the class AADA
      ?ANT(3")(9)-I, which encodes streptomycin-spectinomycin resistance, was
      identified. This gene shares 57% identity with the consensus aadA1 (ant(3")-Ia)
      and has been called aadA4 (ant(3")-Id). The 3' end of the aadA4 cassette was
      truncated by IS26, which was contiguous with a truncated form of Tn3. On the same
      plasmid, pUK2381, a second copy of IS26 was associated with sul2, which suggests
      that both integrase and transposase activities have played major roles in the
      arrangement and dissemination of antibiotic resistance genes dfr13, aadA4,
      bla(TEM-1), and sul2.

PMID- 10639363
TI  - High-level expression of chromosomally encoded SHV-1 beta-lactamase and an outer
      membrane protein change confer resistance to ceftazidime and piperacillin
      tazobactam in a clinical isolate of Klebsiella pneumoniae.
AB  - We describe Klebsiella pneumoniae 15571, a clinical isolate resistant to
      ceftazidime MIC = 32 microg/ml) and piperacillin-tazobactam (MICs = 1,024 and 128
      microg/ml). K. pneumoniae 15571 expresses a single beta-lactamase with a pI of
      7.6. However, when cloned in a high-copy-number vector in Escherichia coli, this
      bla(SHV-1) gene did not confer resistance to ceftazidime, a spectrum consistent
      with the nucleotide sequence, which was nearly identical to those of previously
      described bla(SHV-1) genes. Outer membrane protein (OMP) analysis of K.
      pneumoniae 15571 revealed a decrease in the quantity of a minor 45-kDa OMP in
      comparison to that in K. pneumoniae 44NR, a low-level ampicillin-resistant strain
      that also expresses a chromosomally determined bla(SHV-1). Crude beta-lactamase
      enzyme extracts from K. pneumoniae 15571 produced roughly 200-fold more beta
      lactamase activity than K. pneumoniae 44NR. Northern hybridization analysis
      revealed that this difference was explainable by quantifiable differences in
      transcription of the bla(SHV-1) gene in the two strains. Primer extension
      analysis of bla(SHV-1) mRNA from K. pneumoniae 15571 and 44NR indicated that the
      transcriptional start sites were identical in the two strains. DNA sequencing of
      the promoter regions upstream of the of bla(SHV-1) open reading frames in the two
      K. pneumoniae strains revealed an A-->C change in the second position of the -10
      region in K. pneumoniae 44NR compared to that in 15571. Site-directed mutagenesis
      of the cloned K. pneumoniae 15571 bla(SHV-1), in which the A in the second
      position of the 15571 -10 region was changed to a C, resulted in a substantial
      lowering of the MIC of ampicillin. When the levels of beta-lactamase enzyme
      expression in E. coli were compared, the bla(SHV-1) downstream of the altered -10
      region produced 17-fold less beta-lactamase enzyme. These results indicate that
      elevated levels of ceftazidime resistance can result from a combination of
      increased enzyme production and minor OMP changes and that levels of
      chromosomally encoded SHV-1 beta-lactamase production can vary substantially with
      a single-base-pair change in promoter sequence.

PMID- 10639364
TI  - Discovery of novel antifungal (1,3)-beta-D-glucan synthase inhibitors.
AB  - The increasing incidence of life-threatening fungal infections has driven the
      search for new, broad-spectrum fungicidal agents that can be used for treatment
      and prophylaxis in immunocompromised patients. Natural-product inhibitors of cell
      wall (1,3)-beta-D-glucan synthase such as lipopeptide pneumocandins and
      echinocandins as well as the glycolipid papulacandins have been evaluated as
      potential therapeutics for the last two decades. As a result, MK-0991
      (caspofungin acetate; Cancidas), a semisynthetic analogue of pneumocandin B(o),
      is being developed as a broad-spectrum parenteral agent for the treatment of
      aspergillosis and candidiasis. This and other lipopeptide antifungal agents have
      limited oral bioavailability. Thus, we have sought new chemical structures with
      the mode of action of lipopeptide antifungal agents but with the potential for
      oral absorption. Results of natural-product screening by a series of newly
      developed methods has led to the identification of four acidic terpenoid (1,3)
      beta-D-glucan synthase inhibitors. Of the four compounds, the in vitro antifungal
      activity of one, enfumafungin, is comparable to that of L-733560, a close
      analogue of MK-0991. Like the lipopeptides, enfumafungin specifically inhibits
      glucan synthesis in whole cells and in (1,3)-beta-D-glucan synthase assays,
      alters the morphologies of yeasts and molds, and produces a unique response in
      Saccharomyces cerevisiae strains with point mutations in FKS1, the gene which
      encodes the large subunit of glucan synthase.

PMID- 10639365
TI  - Toxicity of LY303366, an echinocandin antifungal, in mice pretreated with
      glucocorticoids.
AB  - LY303366 is a semisynthetic derivative of the echinocandin class. During
      preclinical studies, lethal toxicity was observed in DBA/2 mice pretreated with a
      cortisone acetate dose followed by treatment with LY303366 at doses ranging from
      12.5 to 50 mg/kg of body weight/day given intraperitoneally (i.p.). In the
      cortisone-treated, uninfected controls, 90% given LY303366 at 50 mg/kg died.
      Deaths occurred only in steroid-treated mice. In additional experiments,
      uninfected DBA/2 and CD-1 mice were pretreated with different glucocorticoids.
      Dosages were adjusted for comparative potency with cortisone and were given at
      one, two, or five times the equivalent cortisone dosage of 5 mg prior to
      treatment with LY303366 at 25 mg/kg/day given i.p. Lethal toxicity occurred in
      DBA/2 mice given hydrocortisone (1x or 2x), triamcinolone (1x or 5x), and
      cortisone. However, no mice pretreated with 1x or 5x dexamethasone died. In CD-1
      mice, deaths occurred only in those given 5x triamcinolone; three of five died 2
      days after the cessation of 10 days of LY303366 treatment. The causes of the
      deaths and why inbred DBA/2 mice are more sensitive than outbred CD-1 mice to the
      combined lethal effects of LY303366 and some glucocorticoids could not be
      determined histologically and remain unexplained. This is the first report of
      this toxicity of combination glucocorticoids and LY303366. Whether a similar
      toxicity might apply to the other compounds in the echinocandin class of
      antifungals and the species specificity require additional study. In addition,
      the clinical relevance of these observations in steroid-treated patients to the
      clinical safety of LY303366 and other echinocandins needs to be determined.

PMID- 10639367
TI  - Acquisition of chloramphenicol resistance by the linearization and integration of
      the entire staphylococcal plasmid pC194 into the chromosome of Streptococcus
      pneumoniae.
AB  - Chloramphenicol resistance in Streptococcus pneumoniae was associated with cat,
      which has 100% identity with cat(pC194) from Staphylococcus aureus. Inverse PCR
      with primers specific for pC194 confirmed that in some isolates the entire
      staphylococcal plasmid was present in the S. pneumoniae chromosome, with
      linearization having occurred between cat(pC194) and the origin of replication.

PMID- 10639366
TI  - Genes for production of the enediyne antitumor antibiotic C-1027 in Streptomyces
      globisporus are clustered with the cagA gene that encodes the C-1027 apoprotein.
AB  - C-1027, the most potent member of the enediyne antitumor antibiotic family, is
      produced by Streptomyces globisporus C-1027 and consists of an apoprotein
      (encoded by the cagA gene) and a nonpeptidic chromophore. The C-1027 chromophore
      could be viewed as being derived biosynthetically from a benzoxazolinate, a
      deoxyamino hexose, a beta-amino acid, and an enediyne core. By adopting a
      strategy for cloning of the C-1027 biosynthesis gene cluster by mapping a
      putative dNDP-glucose 4,6-dehydratase (NGDH) gene to cagA, we have localized 75
      kb of contiguous DNA from S. globisporus. DNA sequence analysis of two regions of
      the cloned gene cluster revealed two genes, sgcA and sgcB, that encode an NGDH
      enzyme and a transmembrane efflux protein, respectively, and confirmed that the
      cagA gene resides approximately 14 kb upstream of the sgcAB locus. The
      involvement of the cloned gene cluster in C-1027 biosynthesis was demonstrated by
      disrupting the sgcA gene to generate C-1027-nonproducing mutants and by
      complementing the sgcA mutants in vivo to restore C-1027 production. These
      results represent the first cloning of a gene cluster for enediyne antitumor
      antibiotic biosynthesis and provide a starting point for future genetic and
      biochemical investigations of C-1027 biosynthesis.

PMID- 10639368
TI  - Identification of a cyclase gene dictating the C-9 stereochemistry of
      anthracyclines from Streptomyces nogalater.
AB  - Nogalamycin is an anthracycline antibiotic produced by Streptomyces nogalater.
      Its aglycone has a unique stereochemistry (7S, 9S, 10R) compared to that of most
      other anthracyclines (7S, 9R, 10R). The gene snoaL, encoding a nogalonic acid
      methyl ester cyclase for nogalamycin, was used to generate nogalamycinone,
      demonstrating that the single cyclase dictates the C-9 stereochemistry of
      anthracyclines.

PMID- 10639369
TI  - Influence of shaking on antifungal susceptibility testing of Cryptococcus
      neoformans: a comparison of the NCCLS standard M27A medium, buffered yeast
      nitrogen base, and RPMI-2% glucose.
AB  - Cryptococcus neoformans is a nonfermentative yeast that requires oxygen for
      growth. The shaking of culture media achieves good oxygenation, promoting the
      growth of cryptococci. In this study, three test media (RPMI 1640, RPMI 1640-2%
      glucose, and buffered yeast nitrogen base ?BYNB) recommended in the National
      Committee for Clinical Laboratory Standards M27A standard were examined. Growth
      abilities and minimum inhibitory concentrations (MICs) in microplates incubated
      at 35 degrees C for 48 h were determined. The results indicated that shaking and
      an inoculum size of 10(5) CFU/ml yielded optimal growth of this yeast. Compared
      to RPMI 1640, supplementation of RPMI 1640 with 2% glucose did not significantly
      improve growth of C. neoformans and resulted in an 8.7-h delay of exponential
      growth. Cryptococcal growth in RPMI 1640 at 24 h was notably better than that in
      RPMI-2% glucose, although by 48 h the growths were comparable. The MIC range of
      amphotericin B observed for the C. neoformans strains grown in RPMI 1640 with or
      without glucose was too narrow to allow the separation of susceptible and
      resistant strains based on clinical outcome. The widest ranges of MICs of
      flucytosine and fluconazole were obtained with BYNB. This work demonstrates the
      need for a new antifungal susceptibility test for C. neoformans.

PMID- 10639370
TI  - Effects of MS-8209, an amphotericin B derivative, on tumor necrosis factor alpha
      synthesis and human immunodeficiency virus replication in macrophages.
AB  - Amphotericin B derivatives, such as MS-8209, have been evaluated as a therapeutic
      approach to human immunodeficiency virus (HIV) infection. We show that MS-8209,
      like amphotericin B, increases tumor necrosis factor alpha (TNF-alpha) mRNA
      expression and TNF-alpha production and consequently HIV replication in human
      macrophages. These effects confirm the pharmacological risk associated with the
      administration of amphotericin B or its derivatives to HIV-infected patients.

PMID- 10639371
TI  - Distribution of lipid formulations of amphotericin B into bone marrow and fat
      tissue in rabbits.
AB  - The distribution of the three currently available lipid formulations of
      amphotericin B (AmB) into bone marrow and fat tissue was evaluated in noninfected
      rabbits. Groups of four animals each received either 1 mg of AmB deoxycholate (D
      AmB) per kg of body weight per day or 5 mg of AmB colloidal dispersion, AmB lipid
      complex, or liposomal AmB per kg per day for seven doses. Plasma, bone marrow,
      fat, and liver were collected at autopsy, and AmB concentrations were determined
      by high-performance liquid chromatography. At the investigated dosages of 5
      mg/kg/day, all AmB lipid formulations achieved at least fourfold-higher
      concentrations in bone marrow than did standard D-AmB at a dosage of 1 mg/kg/day.
      Concentrations in bone marrow were 62 to 76% of concurrent AmB concentrations in
      the liver. In contrast, all AmB formulations accumulated comparatively poorly in
      fat tissue. The results of this study show that high concentrations of AmB can be
      achieved in the bone marrow after administration of lipid formulations,
      suggesting their particular usefulness against disseminated fungal infections
      involving the bone marrow and against visceral leishmaniasis.

PMID- 10639372
TI  - The macrolide-lincosamide-streptogramin B resistance determinant from Clostridium
      difficile 630 contains two erm(B) genes.
AB  - The ErmB macrolide-lincosamide-streptogramin B (MLS) resistance determinant from
      Clostridium difficile 630 contains two copies of an erm(B) gene, separated by a
      1.34-kb direct repeat also found in an Erm(B) determinant from Clostridium
      perfringens. In addition, both erm(B) genes are flanked by variants of the direct
      repeat sequence. This genetic arrangement is novel for an ErmB MLS resistance
      determinant.

PMID- 10639373
TI  - In vitro development of resistance to telithromycin (HMR 3647), four macrolides,
      clindamycin, and pristinamycin in Streptococcus pneumoniae.
AB  - The ability of 50 sequential subcultures in subinhibitory concentrations of
      telithromycin (HMR 3647), azithromycin, clarithromycin, erythromycin A,
      roxithromycin, clindamycin, and pristinamycin to select for resistance was
      studied in five macrolide-susceptible and six macrolide-resistant pneumococci
      containing mefE or ermB. Telithromycin selected for resistance less often than
      the other drugs.

PMID- 10639374
TI  - Role of the PDR gene network in yeast susceptibility to the antifungal antibiotic
      mucidin.
AB  - Yeast strains disrupted in the PDR1, PDR3, or PDR5 gene, but not in SNQ2,
      exhibited higher sensitivity to mucidin (strobilurin A) than did the isogenic
      wild-type strains. Different gain-of-function mutations in the PDR1 and PDR3
      genes rendered yeast mutants resistant to this antibiotic. Mucidin induced PDR5
      expression, but the changes in the expression of SNQ2 were only barely
      detectable. The results indicate that PDR5 provides the link between
      transcriptional regulation by PDR1 and PDR3 and mucidin resistance of yeast.

PMID- 10639375
TI  - Detection of florfenicol resistance genes in Escherichia coli isolated from sick
      chickens.
AB  - Florfenicol is an antibiotic approved for veterinary use in cattle in the United
      States in 1996. Although this drug is not used in poultry, we have detected
      resistance to florfenicol in clinical isolates of avian Escherichia coli.
      Molecular typing demonstrated that the florfenicol resistance gene, flo, was
      independently acquired and is plasmid encoded.

PMID- 10639376
TI  - Efficacy of the cyclodextrin liquid preparation of itraconazole in treatment of
      denture stomatitis: comparison with itraconazole capsules.
AB  - This study investigated the efficacy of a cyclodextrin solution of itraconazole
      in the treatment of Candida-associated denture stomatitis. It was found that the
      liquid and capsule preparations of itraconazole were equally effective adjuncts
      in the treatment of this condition. However, the side effect profile indicates
      that capsules are the preferred formulation.

PMID- 10639378
TI  - Mechanisms of resistance to quinupristin-dalfopristin among isolates of
      Enterococcus faecium from animals, raw meat, and hospital patients in Western
      Europe.
AB  - Twenty-eight quinupristin-dalfopristin-resistant isolates of Enterococcus faecium
      from hospital patients and nonhuman sources in European countries were studied.
      High-level resistance (MICs, >/=32 microg/ml) was associated with the presence of
      vat(E) (satG) (14 isolates ?50%) or vat(D) (satA) (6 isolates ?21%). These genes
      were not detected in eight (29%) isolates with lower levels of quinupristin
      dalfopristin resistance (MICs, 4 to 16 microg/ml). This suggests the presence of
      further mechanisms of resistance to quinupristin-dalfopristin in E. faecium.

PMID- 10639377
TI  - Cloning, nucleotide sequencing, and analysis of the gene encoding an AmpC beta
      lactamase in Acinetobacter baumannii.
AB  - A clinical strain of Acinetobacter baumannii (strain Ab RYC 52763/97) that was
      isolated during an outbreak in our hospital and that was resistant to all beta
      lactam antibiotics tested produced three beta-lactamases: a TEM-1-type (pI, 5.4)
      plasmid-mediated beta-lactamase, a chromosomally mediated OXA-derived (pI, 9.0)
      beta-lactamase, and a presumptive chromosomal cephalosporinase (pI, 9.4). The
      nucleotide sequence of the chromosomal cephalosporinase gene shows for the first
      time the gene encoding an AmpC beta-lactamase in A. baumannii. In addition, we
      report here the biochemical properties of this A. baumannii AmpC beta-lactamase.

PMID- 10639379
TI  - Identification and characterization of the point mutation which affects the
      transcription level of the chromosomal 3-N-acetyltransferase gene of Streptomyces
      griseus SS-1198.
AB  - We determined the molecular basis for the enhanced expression of the aac(3)-Xa
      gene encoding an aminoglycoside 3-N-acetyltransferase in Streptomyces griseus. A
      C-->T substitution was identified at the putative promoter of the mutant gene.
      RNA analyses demonstrated that the substitution caused a marked increase in the
      production of the gene-specific transcripts. Therefore, it seemed very likely
      that the aac(3)-Xa gene was activated by the substitution resulting in the
      emergence of a stronger promoter.

PMID- 10639380
TI  - In vitro activity of the new triazole BMS-207147 against Aspergillus species in
      comparison with itraconazole and amphotericin B.
AB  - The in vitro activity of BMS-207147 against 80 clinical isolates of Aspergillus
      was compared with that of itraconazole and amphotericin B, using a validated
      microtiter method. Geometric mean MICs (in microg/ml) were as follows: 1.71 for
      BMS-207147, 0.67 for itraconazole, and 0.63 for amphotericin B. The range of
      concentrations of each drug was 0.125 to >16 microg/ml. Aspergillus fumigatus was
      significantly more susceptible to BMS-207147 (P < 0. 05) than A. terreus and A.
      flavus. No BMS-207147-resistant A. fumigatus isolates were identified, though
      eight itraconazole-resistant (MIC, >8 microg/ml) isolates were. BMS-207147 is
      active against Aspergillus spp. at slightly high concentrations compared with
      itraconazole and amphotericin B.

PMID- 10639381
TI  - Molecular characterization of the beta-lactamases from clinical isolates of
      Moraxella (Branhamella) catarrhalis obtained from 24 U.S. medical centers during
      1994-1995 and 1997-1998.
AB  - The beta-lactamases from 403 Moraxella (Branhamella) catarrhalis clinical
      isolates obtained during 1994-1995 and 1997-1998 U.S. multicenter surveillance
      studies were characterized by isoelectric focusing. The overall prevalences of
      the BRO-1 and BRO-2 enzymes among beta-lactamase-positive isolates were estimated
      to be 97.5 and 2.5%, respectively. The minimum inhibitory concentrations (MICs)
      of ampicillin for all BRO-2-producing isolates were </=1 microg/ml; however,
      numerous beta-lactamase-positive isolates for which the ampicillin MICs were </=1
      microg/ml produced the BRO-1 enzyme (88. 1%).

PMID- 10639382
TI  - In vitro activity of ABT-773, a new ketolide, against recent clinical isolates of
      Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis.
AB  - The in vitro activity of ABT-773 was evaluated against Streptococcus pneumoniae,
      Haemophilus influenzae, and Moraxella catarrhalis isolates. ABT-773 was the most
      active antimicrobial tested against S. pneumoniae. ABT-773 and azithromycin were
      equivalent in activity against H. influenzae and M. catarrhalis and more active
      than either clarithromycin or erythromycin.

PMID- 10639383
TI  - Failure of short-course ceftriaxone chemotherapy for multidrug-resistant typhoid
      fever in children: a randomized controlled trial in Pakistan.
AB  - The precise duration of therapy of multidrug-resistant (MDR) typhoid with broad
      spectrum cephalosporins is uncertain. We prospectively randomized 57 children
      with culture-proven MDR typhoid to receive treatment with intravenous ceftriaxone
      (CRO) (65 mg/kg of body weight/day) for 7 days (short course; n = 29) or 14 days
      (conventional; n = 28). The response to therapy, as evaluated by the serial
      monitoring of the typhoid morbidity score and bacteriological clearance, was
      comparable between groups. In contrast to the conventional therapy, 14% of the
      children receiving CRO for 7 days had a confirmed bacteriological relapse within
      4 weeks of stopping therapy.

PMID- 10639384
TI  - Characterization of TEM-56, a novel beta-lactamase produced by a Klebsiella
      pneumoniae clinical isolate.
AB  - TEM-56 produced by a Klebsiella pneumoniae clinical isolate is a novel beta
      lactamase of isoelectric point 6.4 that confers a moderate resistance level to
      expanded-spectrum cephalosporins. The amino acid sequence deduced from the
      corresponding bla gene showed two amino acid replacements with respect to the TEM
      2 sequence: Glu-104 to Lys and His-153 to Arg. This enzyme showed catalytic
      properties close to those of TEM-18. Thus, TEM-56 appears as a new TEM mutant, an
      intermediary between TEM-18 and the extended-spectrum beta-lactamase TEM-21.

PMID- 10639385
TI  - Resistance to mercury and antimicrobial agents in Streptococcus mutans isolates
      from human subjects in relation to exposure to dental amalgam fillings.
AB  - Resistance to cefuroxime, penicillin, tetracycline, and mercury is reported for
      839 Streptococcus mutans isolates from 209 human study subjects. The MICs of
      these drugs did not differ for isolates from one dental amalgam group and two
      nonamalgam subsets: a group with no known exposure to amalgam and a group whose
      members had their amalgam fillings removed.

PMID- 10639386
TI  - In vitro activities of rabeprazole, a novel proton pump inhibitor, and its
      thioether derivative alone and in combination with other antimicrobials against
      recent clinical isolates of Helicobacter pylori.
AB  - The MICs of rabeprazole sodium (RPZ), a newly developed benzimidazole proton pump
      inhibitor (PPI), against 133 clinical Helicobacter pylori strains revealed a
      higher degree of activity than the another two PPIs, lansoprazole and omeprazole.
      Time-kill curve assays of RPZ, when combined with amoxicillin, clarithromycin, or
      metronidazole, disclosed that synergistic effects were demonstrated in
      combination with each antibiotic examined. Moreover, no apparent antagonistic
      effect appeared among all of the strains tested.

PMID- 10639387
TI  - Prevalence of gyrA, gyrB, parC, and parE mutations in clinical isolates of
      Streptococcus pneumoniae with decreased susceptibilities to different
      fluoroquinolones and originating from Worldwide Surveillance Studies during the
      1997-1998 respiratory season.
AB  - From 8,419 worldwide clinical isolates of Streptococcus pneumoniae obtained
      during 1997-1998, 69 isolates with reduced susceptibility or resistance to
      fluoroquinolones (FQs) were molecularly characterized. For the isolates in this
      prevalence study, only parC (Ser-79-->Tyr) and gyrA (Ser-81-->Phe or Tyr)
      mutations, especially in combination, were found to contribute significantly to
      resistance. These mutations influenced the FQ MICs to varying degrees, although
      the rank order of activity remains independent of mutation type, with
      ciprofloxacin the least active, followed by levofloxacin,
      gatifloxacin/grepafloxacin/moxifloxacin/sparfloxaci n/trovafloxacin, and
      clinafloxacin/sitafloxacin. Efflux likely plays a crucial role in reduced
      susceptibility for new hydrophilic FQs.

PMID- 10639388
TI  - In vitro activities of ketoconazole, econazole, miconazole, and Melaleuca
      alternifolia (tea tree) oil against Malassezia species.
AB  - The in vitro activities of ketoconazole, econazole, miconazole, and tea tree oil
      against 54 Malassezia isolates were determined by agar and broth dilution
      methods. Ketoconazole was more active than both econazole and miconazole, which
      showed very similar activities. M. furfur was the least susceptible species. M.
      sympodialis, M. slooffiae, M. globosa, and M. obtusa showed similar
      susceptibilities to the four agents.

PMID- 10639390
TI  - Editorial announcement

PMID- 10639389
TI  - In vitro interaction of terbinafine with itraconazole against clinical isolates
      of Scedosporium prolificans.
AB  - In order to develop new approaches for the chemotherapy of invasive infections
      caused by Scedosporium prolificans, the in vitro interaction between itraconazole
      and terbinafine against 20 clinical isolates was studied using a checkerboard
      microdilution method. Itraconazole and terbinafine alone were inactive against
      most isolates, but the combination was synergistic against 95 and 85% of isolates
      after 48 and 72 h of incubation, respectively. Antagonism was not observed. The
      MICs obtained with the terbinafine-itraconazole combination were within levels
      that can be achieved in plasma.

PMID- 10639391
TI  - Visual function and brain organization in non-decussating retinal-fugal fibre
      syndrome.
AB  - Functional neuroimaging, psychophysical and electrophysiological investigations
      were performed in a patient with non-decussating retinal-fugal fibre syndrome, an
      inborn achiasmatic state in which the retinal projections of each eye map
      entirely to the ipsilateral primary visual cortex. Functional magnetic resonance
      imaging (fMRI) studies showed that for monocularly presented simple visual
      stimuli, only the ipsilateral striate cortex was activated. Within each
      hemisphere's striate cortex, the representation of the two hemifields overlapped
      extensively. Despite this gross miswiring, visual functions that require precise
      geometrical information (such as vernier acuity) were normal, and there was no
      evidence for the confounding of visual information between the overlapping ipsi
      lateral and contralateral representations. Contrast sensitivity and velocity
      judgments were abnormal, but their dependence on the orientation and velocity of
      the targets suggests that this deficit was due to ocular instabilities, rather
      than the miswiring per se. There were no asymmetries in performance observed in
      visual search, visual naming or illusory contour perception. fMRI analysis of the
      latter two tasks under monocular viewing conditions indicated extensive bilateral
      activation of striate and prestriate areas. Thus, the remarkably normal visual
      behavior achieved by this patient is a result of both the plasticity of visual
      pathways, and efficient transfer of information between the hemispheres.

PMID- 10639392
TI  - Experience-dependent plasticity of rat barrel cortex: redistribution of activity
      across barrel-columns.
AB  - The redistribution of neuronal activity across rat barrel cortex following an
      alteration in whisker usage has been investigated. In adult rats, two mystacial
      vibrissae - D(2) and one neighbor, D(1) or D(3) - were left intact while all
      other vibrissae on that side of the snout were clipped. Neurons in contralateral
      barrel cortex were sampled with a microelectrode array 3.5 days later.
      Stimulation of clipped vibrissae produced a narrow spatial distribution of
      cortical activity, whereas stimulation of intact vibrissae produced a widened
      spatial distribution. Simultaneous recordings from multiple cortical barrel
      columns suggest that changes in the effective connectivity between barrel-columns
      may partially account for this redistribution of sensory responses. Evidence is
      also presented for a second mechanism, a release from inhibition in sensory
      deprived cortical areas. A model is therefore proposed where these two mechanisms
      operate together to regulate the cortical distribution of evoked activity.

PMID- 10639393
TI  - Auditory cortical responses to the interactive effects of interaural intensity
      disparities and frequency.
AB  - Under natural conditions, stimuli reaching the two ears contain multiple acoustic
      components. Rarely does a stimulus containing only one component (e.g. pure tone
      burst) exist outside the realm of the laboratory. For example, in sound
      localization the simultaneous presence of multiple cues (spectral content, level,
      phase, etc.) serves to increase the number of available cues and provide the
      listener with more information, thereby helping to reduce errors in locating the
      sound source. The present study was designed to explore the relationship between
      two acoustic parameters: stimulus frequency and interaural intensity disparities
      (IIDs). By varying both stimulus frequency and IIDs for each cell, we hoped to
      gain insight into how multiple cues are processed. To this end, we examined the
      responses of neurons in cat primary auditory cortex (AI) to determine if their
      sensitivity to IIDs changed as a function of stimulus frequency. IIDs ranging
      from +30 to -30 dB were presented at different frequencies (frequency was always
      the same in the two ears). We found that approximately half of the units examined
      exhibited responses to IIDs that varied as a function of stimulus frequency (i.e.
      displayed some form of IID x Freq dependency). The remaining units displayed IID
      responses that were not clearly related to stimulus frequency.

PMID- 10639394
TI  - Mapping morphology of the corpus callosum in schizophrenia.
AB  - The nature and extent of callosal morphological alterations in schizophrenia
      remain unresolved. A parametric surface modeling approach using magnetic
      resonance (MR) images was employed. This provided spatially accurate
      representations of midsagittal callosal surfaces in schizophrenic patients (n =
      25; 15 males) and normal controls (n = 28; 15 males). Areas of functionally
      relevant callosal channels and measures reflecting callosal shape were visualized
      and compared across groups. To register neuroanatomical landmarks surrounding the
      corpus callosum, each three-dimensional MR volume was scaled according to
      Talairach AC-PC distance, and raw distances included as covariates in
      multivariate analyses. Results revealed: (i) a marked vertical displacement of
      the corpus callosum in patients (P < 0.01); (ii) increases in curvature of
      superior and inferior callosal surfaces (P < 0.001); and (iii) significant
      increases in maximum widths in anterior and posterior regions in male patients
      compared to male controls; as well as (iv) increased patterns of callosal
      variability in female patients but no effects of diagnosis between female groups.
      These findings demonstrate a clear index of structural neuropathology in male
      schizophrenic patients. Displacement and curvature increases were highly
      correlated with structural differences in surrounding neuroanatomical regions,
      including increased volume of the lateral ventricles (P < 0.01).

PMID- 10639395
TI  - Neurotrophic factors protect cortical synaptic terminals against amyloid and
      oxidative stress-induced impairment of glucose transport, glutamate transport and
      mitochondrial function.
AB  - Previous studies have shown that several different neurotrophic factors can
      prevent death of cortical and hippocampal neurons induced by excitotoxic and
      oxidative insults in cell culture and in vivo. Because neuronal degeneration may
      be initiated by alterations occurring in synaptic compartments in disorders
      ranging from Alzheimer's disease to stroke, we tested the hypothesis that
      neurotrophic factors can exert direct protective actions at the level of the
      synapse. We now report that a nine amino acid bioactive fragment of activity
      dependent neurotrophic factor (ADNF-9) enhances basal glucose and glutamate
      transport, and attenuates oxidative impairment of glucose and glutamate transport
      induced by amyloid beta-peptide and Fe(2+), in neocortical synaptosomes.
      Preservation of transporter function required only short-term (1-2 h)
      pretreatments. Basic fibroblast growth factor (bFGF) was also effective in
      suppressing oxidative impairment of synaptic transporter functions, while nerve
      growth factor (NGF) was less effective. Additional analyses showed that ADNF-9,
      bFGF and NGF suppress oxidative stress and mitochondrial dysfunction induced by
      amyloid beta-peptide and Fe(2+) in synaptosomes. Our data suggest that ADNF-9 can
      act locally in synaptic compartments to suppress oxidative stress and preserve
      function of glucose and glutamate transporters. Such synapto-protective actions
      suggest roles for activity-dependent trophic signaling in preventing degeneration
      of neuronal circuits, and indicate possible therapeutic applications of agents
      that stimulate local synaptic (transcription-independent) neurotrophic factor
      signaling pathways.

PMID- 10639396
TI  - Organization of nonprimary motor cortical inputs on pyramidal and nonpyramidal
      tract neurons of primary motor cortex: An electrophysiological study in the
      macaque monkey.
AB  - To elucidate the functions of nonprimary motor cortical (nPMC) areas whose
      afferents synapse onto output neurons of the primary motor cortex (PMC), we
      examined the responses of pyramidal tract neurons (PTNs) and non-PTNs (nPTNs) to
      electrical stimulation in the three nPMCs, the supplementary motor area (SMA) and
      the dorsal and ventral divisions of the premotor cortex (PMd and PMv), with
      extracellular unit recording in alert monkeys. Typical responses of PTNs to nPMC
      stimulation were early orthodromic excitatory responses followed by inhibitory
      responses. Among 27 PTNs tested by constructing peri-stimulus time histograms, 19
      (70.4%) showed inhibitory responses to stimulation in all of the nPMC areas. In
      contrast, 5/33 PTNs (15.2%) and 10/72 nPTNs (13.9%) showed excitatory responses
      to stimulation in all of the nPMCs. The inhibitory responses of PTNs were
      mediated by inhibitory interneurons, some of which may correspond to nPTNs in the
      superficial layers of the PMC. These interneurons probably possess widely
      extended axons and nonspecifically inhibit multiple PTNs in layer V. The
      excitatory and inhibitory influences, and the patterns of convergence of inputs
      from the nPMCs onto the PTNs, are important to understand motor control by the
      nPMC-PMC-spinal cord pathway.

PMID- 10639397
TI  - Cognitive response profile of the human fusiform face area as determined by MEG.
AB  - Activation in or near the fusiform gyrus was estimated to faces and control
      stimuli. Activation peaked at 165 ms and was strongest to digitized photographs
      of human faces, regardless of whether they were presented in color or grayscale,
      suggesting that face- and color-specific areas are functionally separate.
      Schematic sketche evoked approximately 30% less activation than did face
      photographs. Scrambling the locations of facial features reduced the response by
      approximately 25% in either hemisphere, suggesting that configurational versus
      analytic processing is not lateralized at this latency. Animal faces evoked
      approximately 50% less activity, and common objects, animal bodies or sensory
      controls evoked approximately 80% less activity than human faces. The (small)
      responses evoked by meaningless control images were stronger when they included
      surfaces and shading, suggesting that the fusiform gyrus may use these features
      in constructing its face-specific response. Putative fusiform activation was not
      significantly related to stimulus repetition, gender or emotional expression. A
      midline occipital source significantly distinguished between faces and control
      images as early as 110 ms, but was more sensitive to sensory qualities. This
      source significantly distinguished happy and sad faces from those with neutral
      expressions. We conclude that the fusiform gyrus may selectively encode faces at
      165 ms, transforming sensory input for further processing.

PMID- 10639398
TI  - Horizontal synaptic connections in monkey prefrontal cortex: an in vitro
      electrophysiological study.
AB  - In monkey dorsolateral prefrontal cortex (PFC), long-distance, horizontally
      oriented intrinsic axon collaterals interconnect clusters of pyramidal neurons in
      the supragranular layers. In order to study the electrophysiological responses
      mediated by these long-distance projections, an in vitro slice preparation of
      monkey PFC was used to obtain whole-cell patch clamp recordings from layer 3
      pyramidal neurons. Using in vivo tracer injections, we found that long-distance
      projections were well preserved in PFC slices cut in the coronal plane.
      Postsynaptic currents were evoked by low-intensity electrical extracellular
      stimulation applied successively to 20-30 discrete sites located up to 2200
      micron lateral to the recorded cell. Several criteria were applied to
      discriminate between mono- and polysynaptic responses. Long-distance monosynaptic
      connections were mediated by fibers with relatively slow conduction velocity
      (0.14 m/s). Excitatory postsynaptic currents (EPSCs) evoked by stimulation of
      short- or long-distance horizontal connections did not differ in kinetic
      properties. The majority (77%) of the 35 layer 3 PFC neurons studied were
      monosynaptic targets of long-distance connections. EPSCs mediated by long
      distance connections had amplitudes that were similar or even larger than short
      distance EPSCs, suggesting that excitatory input provided by the former was
      relatively robust. For most neurons (87.5%) in which a full complement of
      monosynaptic EPSCs was evoked by multisite stimulation, the EPSC amplitude as a
      function of stimulation distance from the recorded cells exhibited statistically
      significant peaks. The spacing between peaks was similar to the spacing between
      interconnected clusters of neurons observed in previous anatomical studies. The
      results show that long-distance excitatory connections constitute a significant
      intrinsic pathway of synaptic communication in layer 3 of monkey PFC.

PMID- 10639399
TI  - Functional dissociation between medial and lateral prefrontal cortical
      spatiotemporal activation in negative and positive emotions: a combined fMRI/MEG
      study.
AB  - The orbitofrontal cortex has been cytoarchitectonically and connectionally
      subdivided into a medial and a lateral part which are assumed to subserve
      distinct functions in emotional processing. However the exact spatiotemporal
      mechanisms of negative and positive emotional processing in medial and lateral
      orbitofrontal cortex remain unclear. We therefore investigated spatiotemporal
      orbitofrontal and prefrontal cortical activation patterns during emotional
      stimulation in a combined fMRI/MEG study. We investigated 10 healthy subjects, 5
      women and 5 men. Positive and negative pictures from the International Affective
      Picture system (IAPS) were used for emotional stimulation, whereas neutral and
      gray pictures were taken as control conditions. fMRI/MEG measurements covered the
      whole frontal lobe and a time window between -2000 and +200 ms around motor
      responses (right index finger extension) associated with each picture. Positively
      and negatively correlated activities were determined in various
      prefrontal/frontal cortical regions in fMRI. Isocontour maps and single dipoles
      in MEG were analyzed in 50 ms time windows ranging from -2000 to +200 ms. Dipoles
      and fMR images were mapped on three-dimensional anatomical MRI so that anatomical
      localization of single dipoles and regional fMRI activity could be compared. Both
      negative and positive emotional conditions differed from non-emotional control
      conditions by strong orbitofrontal and lateral prefrontal activation as well as
      by the presence of early magnetic fields (-1700 to +1100 ms). Negative emotional
      processing was characterized by strong medial orbitofrontal activation and
      earlier (-1700 ms), stronger and more medially oriented orbitofrontal dipoles. In
      contrast positive emotional processing showed a rather strong activation in
      lateral prefrontal cortex with later (-1500 ms), weaker and more laterally
      oriented orbito and prefrontal dipoles. Negative emotional processing can be
      characterized by strong and early medial orbitofrontal cortical activation,
      whereas positive emotional processing showed rather later and weaker activation
      in lateral orbitofrontal/prefrontal cortex. Such a functional dissociation
      between medial and lateral orbito-frontal/prefrontal cortex during negative and
      positive emotional processing lends further support to the assumption of a
      functional subdivision in the orbitofrontal cortex.

PMID- 10639400
TI  - A peptide permease mutant of Mycobacterium bovis BCG resistant to the toxic
      peptides glutathione and S-nitrosoglutathione.
AB  - Oligopeptides play important roles in bacterial nutrition and signaling. Using
      sequences from the available genome database for Mycobacterium tuberculosis
      H37Rv, the oligopeptide permease operon (oppBCDA) of Mycobacterium bovis BCG was
      cloned from a cosmid library. An opp mutant strain was constructed by homologous
      recombination with an allele of oppD interrupted by kanamycin and streptomycin
      resistance markers. The deletion was complemented with a wild-type copy of the
      opp operon. Two approaches were taken to characterize the peptide transporter
      defect in this mutant strain. First, growth of wild-type and mutant strains was
      monitored in media containing a wide variety of peptides as sole source of carbon
      and/or nitrogen. Among 25 peptides ranging from two to six amino acids in length,
      none was capable of supporting measurable growth as the sole carbon source in
      either wild-type or mutant strains. The second approach exploited the resistance
      of permease mutants to toxic substrates. The tripeptide glutathione (gamma
      glutamyl-L-cyteinylglycine [GSH]) is toxic to wild-type BCG and was used
      successfully to characterize peptide uptake in the opp mutant. In 2 mM GSH,
      growth of the wild-type strain is inhibited, whereas the opp mutant is resistant
      to concentrations as high as 10 mM. Similar results were found with the
      tripeptide S-nitrosoglutathione (GSNO), thought to be a donor of NO in mammalian
      cells. Using incorporation of [(3)H]uracil to monitor the effects of GSH and GSNO
      on macromolecular synthesis in growing cells, it was demonstrated that the opp
      mutant is resistant, whereas the wild type and the mutant complemented with a
      wild-type copy of the operon are sensitive to both tripeptides. In uptake
      measurements, incorporation of [(3)H]GSH is reduced in the mutant compared with
      wild type and the complemented mutant. Finally, growth of the three strains in
      the tripeptides suggests that GSH is bacteriostatic, whereas GSNO is
      bacteriocidal.

PMID- 10639401
TI  - Molecular characterization of Mycoplasma arthritidis membrane lipoprotein MAA1.
AB  - Genes encoding the Mycoplasma arthritidis surface-exposed lipoprotein MAA1 were
      cloned and sequenced from MAA1-expressing strains 158p10p9 and PG6, from a low
      adherence (LA) variant derived from 158p10p9 that expresses a truncated version
      of MAA1 (MAA1Delta) and from two MAA1-negative strains, 158 and H39. The deduced
      amino acid sequences of maa1 from 158p10p9 and PG6 predicted, respectively, 86.5-
      and 86.4-kDa basic, largely hydrophilic lipoproteins with 29-amino-acid signal
      peptides and predicted cleavage sites for signal peptidase II (Ala-Ala-Ala
      downward arrowCys). The truncation in the LA variant resulted from a G-->T
      substitution at nucleotide 695, which created a premature stop codon. This, in
      turn, generated a predicted 26.6-kDa prolipoprotein (23.6 kDa after processing),
      consistent with an M(r) of approximately 24,000 calculated for MAA1Delta.
      Similarly, absence of MAA1 expression in H39 and 158 resulted from C-->A
      substitutions at nucleotide 208, generating premature stop codons at that site in
      both strains.

PMID- 10639402
TI  - Urease as a virulence factor in experimental cryptococcosis.
AB  - Urease catalyzes the hydrolysis of urea to ammonia and carbamate and has been
      found to be an important pathogenic factor for certain bacteria. Cryptococcus
      neoformans is a significant human pathogenic fungus that produces large amounts
      of urease; thus we wanted to investigate the importance of urease in the
      pathogenesis of cryptococcosis. We cloned and sequenced the genomic locus
      containing the single-copy C. neoformans urease gene (URE1) and used this to
      disrupt the native URE1 in the serotype A strain H99. The ure1 mutant strains
      were found to have in vitro growth characteristics, phenoloxidase activity, and
      capsule size similar to those of the wild type. Comparison of a ure1 mutant with
      H99 after intracisternal inoculation into corticosteroid-treated rabbits revealed
      no significant differences in colony counts recovered from the cerebrospinal
      fluid. However, when these two strains were compared in both the murine
      intravenous and inhalational infection models, there were significant differences
      in survival. Mice infected with a ure1 strain lived longer than mice infected
      with H99 in both models. The ure1 strain was restored to urease positivity by
      complementation with URE1, and two resulting transformants were significantly
      more pathogenic than the ure1 strain. Our results suggest that urease activity is
      involved in the pathogenesis of cryptococcosis but that the importance may be
      species and/or infection site specific.

PMID- 10639403
TI  - Increased Escherichia coli phagocytosis in neutrophils that have transmigrated
      across a cultured intestinal epithelium.
AB  - The functionality of polymorphonuclear leukocytes (PMNs) once they migrate into
      the digestive lumen is still ill defined. More specifically, phagocytic function
      and bactericidal action of PMNs after transepithelial migration have not received
      much attention. The aim of the present study is to compare PMN behavior before
      and after transepithelial migration, in particular (i) phagocytosis and
      bactericidal activity; (ii) expression of surface molecules, particularly those
      involved in phagocytosis; and (iii) apoptosis. Cultured human intestinal
      epithelial T84 cell monolayers were used. The effect of transepithelial migration
      on phagocytosis was evaluated by immunofluorescence and electron microscopy and
      by flow cytometric assessment of the engulfment of a strain of Escherichia coli
      transfected with the green fluorescent protein. Superoxide production by PMNs was
      investigated by luminol-mediated chemiluminescence. Expression of various surface
      molecules on PMNs was evaluated by flow cytometry, while PMN apoptosis was
      assayed by morphologic changes and DNA fragmentation. E. coli phagocytosis by the
      PMNs was markedly increased after transepithelial migration without modification
      of superoxide production. CD11b/CD18 and CD47 expression was increased upon PMN
      transmigration, whereas CD16 expression was decreased and CD29, CD46, CD49e,
      CD49f, CD55, CD59, CD61, CD95 levels remained unchanged. Apoptosis in
      transmigrated PMNs was slightly advanced and was observed after 12 h compared to
      16 h for nontransmigrated PMNs. In conclusion, the phagocytic capacity of the
      PMNs is augmented after transepithelial migration, with a dramatic increase in
      the level of CD11b/CD18 and preservation of the superoxide production. These
      results suggest a higher bactericidal activity of the PMNs once they have
      translocated into the digestive lumen.

PMID- 10639404
TI  - Requirement for CD4(+) T lymphocytes in host resistance against Cryptococcus
      neoformans in the central nervous system of immunized mice.
AB  - The importance of cell-mediated immunity (CMI) and CD4(+) T lymphocytes in host
      resistance against Cryptococcus neoformans is well documented and is exemplified
      by the high susceptibility to progressive infection with this pathogen of AIDS
      patients with reduced CD4(+) T-cell numbers. Although much has been learned about
      the role of CMI in the clearance of C. neoformans from the lungs and other
      internal organs, less is known about the protective mechanisms in the brain, the
      organ most frequently involved with a fatal outcome of cryptococcosis. We
      hypothesized that host resistance mechanisms against C. neoformans in the central
      nervous system (CNS) were similar to those outside the CNS (i.e., gamma
      interferon [IFN-gamma], CD4(+) T cells, and others). To test this hypothesis, we
      used a murine model of cryptococcal meningitis whereby cryptococci are introduced
      directly into the CNS. In experiments where mice were immunized to mount an
      anticryptococcal CMI response, our results indicate that immunization induced
      protective mechanisms that could be detected in the CNS by inhibition of the
      growth of viable yeast cells. Flow cytometric analyses of leukocytes in brain and
      spinal cord homogenates revealed that T lymphocytes, macrophages, and neutrophils
      accumulated in C. neoformans-infected brains of immune mice. In vivo depletion of
      CD4(+) T cells, but not CD8(+) T cells, resulted in significantly reduced
      leukocyte accumulation in the brains of immune mice. Furthermore, depletion of
      CD4(+) T cells or neutralization of IFN-gamma exacerbated CNS infection in immune
      mice, suggesting a critical role for CMI mechanisms in acquired protection in the
      CNS.

PMID- 10639405
TI  - Cleavage of a recombinant human immunoglobulin A2 (IgA2)-IgA1 hybrid antibody by
      certain bacterial IgA1 proteases.
AB  - To understand more about the factors influencing the cleavage of immunoglobulin
      A1 (IgA1) by microbial IgA1 proteases, a recombinant human IgA2/IgA1 hybrid
      molecule was generated. In the hybrid, termed IgA2/A1 half hinge, a seven-amino
      acid sequence corresponding to one half of the duplicated sequence making up the
      IgA1 hinge was incorporated into the equivalent site in IgA2. Insertion of the
      IgA1 half hinge into IgA2 did not affect antigen binding capacity or the
      functional activity of the hybrid molecule, as judged by its ability to bind to
      IgA Fcalpha receptors and trigger respiratory bursts in neutrophils. Although the
      IgA2/A1 hybrid contained only half of the IgA1 hinge, it was found to be cleaved
      by a variety of different bacterial IgA1 proteases, including representatives of
      those that cleave IgA1 in the different duplicated halves of the hinge, namely,
      those of Prevotella melaninogenica, Streptococcus pneumoniae, S. sanguis,
      Neisseria meningitidis types 1 and 2, N. gonorrhoeae types 1 and 2, and
      Haemophilus influenzae type 2. Thus, for these enzymes the recognition site for
      IgA1 cleavage is contained within half of the IgA1 hinge region; additional
      distal elements, if required, are provided by either an IgA1 or an IgA2
      framework. In contrast, the IgA2/A1 hybrid appeared to be resistant to cleavage
      with S. oralis and some H. influenzae type 1 IgA1 proteases, suggesting these
      enzymes require additional determinants for efficient substrate recognition.

PMID- 10639406
TI  - Expression of the Helicobacter pylori ureI gene is required for acidic pH
      activation of cytoplasmic urease.
AB  - ureI encodes an integral cytoplasmic membrane protein. It is present in the
      urease gene cluster of Helicobacter pylori and is essential for infection and
      acid survival, but its role is unknown. To determine the function of UreI
      protein, we produced H. pylori ureI deletion mutants and measured the pH
      dependence of urease activity of intact and lysed bacteria and the effect of urea
      on the membrane potential. We also determined ureI expression, urease activity,
      and the effect of urea on membrane potential of several gastric and nongastric
      Helicobacter species. ureI was found to be present in the genome of the gastric
      Helicobacter species and absent in the nongastric Helicobacter species studied,
      as determined by PCR. Likewise, Western blot analysis confirmed that UreI was
      expressed only in the gastric Helicobacter species. When UreI is present, acidic
      medium pH activation of cytoplasmic urease is found, and urea addition increases
      membrane potential at acidic pH. The addition of a low concentration of detergent
      raised urease activity of intact bacteria at neutral pH to that of their
      homogenates, showing that urease activity was membrane limited. No acidic pH
      activation or urea induced membrane potential changes were found in the
      nongastric Helicobacter species. The ureI gene product is probably a pH activated
      urea transporter or perhaps regulates such a transporter as a function of
      periplasmic pH.

PMID- 10639407
TI  - Characterization of the cell adhesion site of Trypanosoma cruzi metacyclic stage
      surface glycoprotein gp82.
AB  - The surface glycoprotein gp82, expressed in the insect-stage metacyclic
      trypomastigotes of Trypanosoma cruzi, has been implicated in mammalian cell
      invasion. Here we have characterized the cell adhesion site of gp82 by using
      recombinant proteins and synthetic peptides based on gp82. The recombinant
      protein Del-4/8, lacking 65 amino acids of gp82 central domain (at positions 257
      to 321), was virtually devoid of cell-binding activity and lacked the ability to
      inhibit parasite invasion, in contrast to J18, the construct containing the full
      length gp82 sequence (amino acids 1 to 516). Constructs with shorter deletions,
      i.e., Del-4 (deleted from 257 to 271) and Del-8 (deleted from 293 to 321), bound
      to target cells to a significantly lesser degree than did J18. The sites deleted
      in recombinant proteins Del-4 and Del-8 contained acidic amino acids critical for
      cell adhesion. Thus, the cell-binding capacity of protein Del-E/D, lacking the
      glutamic acid (259/260) and aspartic acid (303/304) pairs, was negligible, as was
      its capacity to inhibit parasite internalization. Of a set of synthetic peptides
      spanning the gp82 central domain, a 22-mer hybrid peptide, p4/8, formed by two
      noncontiguous sequences (at positions 257 to 273 and 302 to 306) and containing
      the four acidic residues, competed with the binding of J18 protein to target
      cells and significantly inhibited ( approximately 60%) the penetration of
      parasites. This peptide, generated by the juxtaposition of sequences that are
      separated by a hydrophobic stretch in the linear molecule, appears to be
      mimicking a conformation-dependent cell-binding site of gp82. Experiments of
      antibody competition with a set of 20-mer overlapping peptides mapped the epitope
      for 3F6, a monoclonal antibody directed to gp82 that inhibits parasite invasion,
      to the sequence represented by peptide p3 (244 to 263), which has a partial
      overlap with the cell adhesion site.

PMID- 10639409
TI  - Host cellular immune response to pneumococcal lung infection in mice.
AB  - Although there is substantial evidence that pneumolysin is an important virulence
      factor in pneumococcal pneumonia, relatively little is known about how it
      influences cellular infiltration into the lungs. We investigated how the
      inability of mutant pneumococci to produce pneumolysin altered the pattern of
      inflammation and cellular infiltration into the lungs. The effect on bacterial
      growth in the lungs also was assessed. There were three phases of growth of wild
      type bacteria in the lungs: a decline followed by a rapid increase and then
      stasis or decline. The absence of pneumolysin was associated with a more rapid
      early decline and then a much slower increase in numbers. The pattern of
      inflammatory-cell accumulation also had distinct stages, and the timing of these
      stages was influenced by the presence of pneumolysin. Neutrophils began to
      accumulate about 12 to 16 h after infection with wild-type pneumococci. This
      accumulation occurred after the early decline in pneumococcal numbers but
      coincided with the period of rapid growth. Following infection with pneumococci
      unable to make pneumolysin, neutrophil influx was slower and less intense.
      Coincident with the third stage of pneumococcal growth was an accumulation of T
      and B lymphocytes at the sites of inflammation, but the accumulation was not
      associated with an increase in the total number of lymphocytes in the lungs.
      Lymphocyte accumulation in the absence of pneumolysin occurred but was delayed.

PMID- 10639408
TI  - Genital antibody responses in mice after intranasal infection with an attenuated
      candidate vector strain of Bordetella pertussis.
AB  - Intranasal administration of live attenuated Bordetella pertussis, from which the
      pertussis toxin gene has been deleted, has previously been shown to give rise to
      high levels of serum immunoglobulin G (IgG) antibodies against both the
      protective antigen filamentous hemagglutinin (FHA) and heterologous antigens
      genetically fused to FHA. Here, we extend these results by demonstrating that
      anti-FHA IgA and IgG antibodies are also produced in the genital tract of mice,
      both in the vagina and in the uterus, after a single intranasal administration of
      B. pertussis. By comparing the immune responses induced after infection with wild
      type virulent B. pertussis with that induced by infection with an attenuated
      pertussis toxin-deficient strain, we conclude that pertussis toxin produced by
      the virulent bacteria does not modify antibody production to FHA in the genital
      tract of B. pertussis-infected mice. The intranasal infection with either the
      attenuated or the virulent B. pertussis strain also led to the development of
      immunologic memory that could be efficiently boosted with purified FHA
      administered either intranasally or intravaginally to give rise to a significant
      increase in the levels of specific IgA and IgG produced locally in the genital
      tract, as well as of specific antibodies in the serum. These observations suggest
      that attenuated B. pertussis could be a promising vector for intranasal
      administration to induce antibody responses against antigens from sexually
      transmitted pathogens fused to FHA.

PMID- 10639410
TI  - T-Cell epitopes and human leukocyte antigen restriction elements of an
      immunodominant antigen of Blastomyces dermatitidis.
AB  - Humans infected with the dimorphic fungus Blastomyces dermatitidis develop strong
      T-lymphocyte responses to WI-1, an immunodominant antigen that has been shown to
      elicit protective immunity in mice. In the present study, the T-cell epitopes of
      WI-1 and human leukocyte antigen (HLA) restricting elements that display them
      were investigated. Peripheral blood mononuclear cells (PBMC) from 37 patients
      with a confirmed history of blastomycosis were tested for a response to WI-1 in
      primary proliferation assays; PBMC from 35 (95%) responded. Six patients whose
      PBMC proliferated strongly in response to WI-1 (defined as a stimulation index
      greater than 50) were tested further for responses to subcloned, recombinant
      fragments of the antigen. These patients responded chiefly to sequences within
      the N terminus and the 25-amino-acid tandem repeat. Cloned CD4(+) T cells from an
      infected individual were used to delineate more precisely the peptide epitopes in
      the fragments and HLA restricting elements that present them. A majority of the T
      cell clones recognized an epitope spanning amino acids 149 to 172 within the N
      terminus, displayed by HLA-DR 15. A minority of the clones, which have been shown
      to perform a cytolytic function in vitro, recognized an epitope in the tandem
      repeat displayed by HLA-DPw4, an uncommon restricting element. Tandem repeat
      epitopes required display by the beta chain of DPw4 heterodimers. Thus, human T
      cells with different functions in vitro also recognize distinct regions of WI-1,
      raising the possibility that HLA restricting elements that present them could
      modulate immunity during blastomycosis by selection and display of WI-1 peptides.

PMID- 10639411
TI  - Acquired, but not innate, immune responses to Streptococcus pneumoniae are
      compromised by neutralization of CD40L.
AB  - Streptococcus pneumoniae is a significant pathogen of young children and the
      elderly. Systemic infection by pneumococci is a complex process involving several
      bacterial and host factors. We have investigated the role of CD40L in host
      defense against pneumococcal infection. Treatment of mice with MR-1 antibody
      (anti-CD154/CD40L) markedly reduced antibody responses to the pneumococcal
      protein PspA, elicited by immunization of purified protein or whole bacteria. In
      mice immunized with whole bacteria, MR-1 treatment reduced antibody responses to
      capsular polysaccharides but not cell wall polysaccharides. MR-1 did not suppress
      antibody responses to isolated capsular polysaccharides but did reduce the
      production of antibody to a capsular polysaccharide-protein conjugate, indicating
      that when presented in the context of whole bacteria, the humoral response to
      capsular polysaccharides is partially T-cell dependent. Despite the reduction of
      the protective humoral responses to pneumococcal infection, administration of MR
      1 had no effect on sepsis, lung infection, or nasal carriage in nonimmune mice
      inoculated with virulent pneumococci. Thus, short-term neutralization of CD40L
      does not compromise innate host defenses against pneumococcal invasion.

PMID- 10639412
TI  - Defective hyphal development and avirulence caused by a deletion of the SSK1
      response regulator gene in Candida albicans.
AB  - In a previous study, we reported the isolation and characterization of the two
      component response regulator SSK1 gene of Candida albicans. This gene is a
      structural but not a functional homolog of the SSK1 and mcs4(+) genes of
      Saccharomyces cerevisiae and Schizosaccharomyces pombe, respectively. In the
      present study, we have constructed and phenotypically characterized Deltassk1
      mutants of C. albicans. The results confirmed our previous observation that
      CaSSK1, unlike SSK1 or mcs4(+), does not regulate cellular responses to either
      osmotic or oxidative stress. Instead, Deltassk1 null strains showed severely
      reduced hyphal formation on serum agar and were totally defective in hyphal
      development on other solid media, such as medium 199 (pH 7.5) and Spider medium.
      In contrast, under conditions of low nitrogen availability on solid media,
      Deltassk1 null strains dramatically hyperinvaded the agar. However, while forming
      germ tubes and hyphae in liquid media similar to those of the wild type,
      Deltassk1 null strains flocculated in a manner similar to that of Deltachk1 two
      component histidine kinase mutants, which we have previously described. Finally,
      virulence studies indicated that SSK1 is essential for the pathogenesis of C.
      albicans, suggesting that the Ssk1p response regulator could be a good target for
      antifungal therapy.

PMID- 10639413
TI  - Cloning and characterization of vuuA, a gene encoding the Vibrio vulnificus
      ferric vulnibactin receptor.
AB  - The ability of Vibrio vulnificus to acquire iron from the host has been shown to
      correlate with virulence. Many iron transport genes are regulated by iron, and in
      V. vulnificus, transcriptional regulation by iron depends on the fur gene. The N
      terminal amino acid sequence of a 72-kDa iron-regulated outer membrane protein
      purified from a V. vulnificus fur mutant had 53% homology with the first 15 amino
      acids of the mature protein of the Vibrio cholerae vibriobactin receptor, ViuA.
      In this report, we describe the cloning, DNA sequence, mutagenesis, and analysis
      of transcriptional regulation of the structural gene for VuuA, the vulnibactin
      receptor of V. vulnificus. Analysis of the DNA sequence of the vuuA promoter
      region demonstrated a sequence identical to the upstream Fur box of V. cholerae
      viuA. Northern blot analysis showed that the transcript was strongly regulated by
      iron. The amino acid sequence of VuuA was 74% identical to the sequence of V.
      cholerae ViuA and was homologous to those of several TonB-dependent outer
      membrane receptors. An internal deletion of the V. vulnificus vuuA gene resulted
      in the loss of expression of the 72-kDa protein and the loss of the ability to
      use transferrin or vulnibactin as a source of iron. This mutant showed reduced
      virulence in an infant mouse model. Introduction of a plasmid containing the
      complete viuA coding sequence and 342 bp of upstream DNA into the mutant restored
      ferric vulnibactin and ferric transferrin utilization to the mutant.

PMID- 10639414
TI  - Nonpolar inactivation of the hypervariable streptococcal inhibitor of complement
      gene (sic) in serotype M1 Streptococcus pyogenes significantly decreases mouse
      mucosal colonization.
AB  - Group A Streptococcus (GAS) is a human pathogen that commonly infects the upper
      respiratory tract. GAS serotype M1 strains are frequently isolated from human
      infections and contain the gene encoding the hypervariable streptococcal
      inhibitor of complement protein (Sic). It was recently shown that Sic variants
      were rapidly selected on mucosal surfaces in epidemic waves caused by M1 strains,
      an observation suggesting that Sic participates in host-pathogen interactions on
      the mucosal surface (N. P. Hoe, K. Nakashima, S. Lukomski, D. Grigsby, M. Liu, P.
      Kordari, S.-J. Dou, X. Pan, J. Vuopio-Varkila, S. Salmelinna, A. McGeer, D. E.
      Low, B. Schwartz, A. Schuchat, S. Naidich, D. De Lorenzo, Y.-X. Fu, and J. M.
      Musser, Nat. Med. 5:924-929, 1999). To test this idea, a new nonpolar mutagenesis
      method employing a spectinomycin resistance cassette was used to inactivate the
      sic gene in an M1 GAS strain. The isogenic Sic-negative mutant strain was
      significantly (P < 0.019) impaired in ability to colonize the mouse mucosal
      surface after intranasal infection. These results support the hypothesis that the
      predominance of M1 strains in human infections is related, in part, to a Sic
      mediated enhanced colonization ability.

PMID- 10639415
TI  - Construction and characterization of an effector strain of Streptococcus mutans
      for replacement therapy of dental caries.
AB  - An effector strain has been constructed for use in the replacement therapy of
      dental caries. Recombinant DNA methods were used to make the Streptococcus mutans
      supercolonizing strain, JH1140, lactate dehydrogenase deficient by deleting
      virtually all of the ldh open reading frame (ORF). To compensate for the
      resulting metabolic imbalance, a supplemental alcohol dehydrogenase activity was
      introduced by substituting the adhB ORF from Zymomonas mobilis in place of the
      deleted ldh ORF. The resulting clone, BCS3-L1, was found to produce no detectable
      lactic acid during growth on a variety of carbon sources, and it produced
      significantly less total acid due to its increased production of ethanol and
      acetoin. BCS3-L1 was significantly less cariogenic than JH1140 in both
      gnotobiotic- and conventional-rodent models. It colonized the teeth of
      conventional rats as well as JH1140 in both aggressive-displacement and
      preemptive-colonization models. No gross or microscopic abnormalities of major
      organs were associated with oral colonization of rats with BCS3-L1 for 6 months.
      Acid-producing revertants of BCS3-L1 were not observed in samples taken from
      infected animals (reversion frequency, <10(-3)) or by screening cultures grown in
      vitro, where no revertants were observed among 10(5) colonies examined on pH
      indicator medium. The reduced pathogenic potential of BCS3-L1, its strong
      colonization potential, and its genetic stability suggest that this strain is
      well suited to serve as an effector strain in the replacement therapy of dental
      caries in humans.

PMID- 10639416
TI  - Neisseria meningitidis expressing transferrin binding proteins of Actinobacillus
      pleuropneumoniae can utilize porcine transferrin for growth.
AB  - Homologous recombination was used to generate a number of mutants of serogroup B
      Neisseria meningitidis B16B6 with the following characteristics: (i) an inability
      to bind human or porcine transferrin because of loss of both transferrin binding
      proteins (Tbp) A and B [strain B16B6(Str(r))/tbpA(-)B(-)] and (ii) an ability to
      bind porcine transferrin but not human transferrin [strain
      B16B6(Str(r))/tbpA(ap)B(ap)] due to replacement of the meningococcal Tbp with the
      Tbp of Actinobacillus pleuropneumoniae. During construction of the
      B16B6(Str(r))/tbpA(ap)B(ap) strain, transformants expressing only TbpA or TbpB of
      A. pleuropneumoniae were isolated [strains B16B6(Str(r))/tbpA(ap)B(-) and
      B16B6(Str(r))/tbpA(-)B(ap)]. Expression of the A. pleuropneumoniae Tbp in N.
      meningitidis B16B6 was iron regulated and expressed under the control of the
      meningococcal promoter. The relative abilities of the meningococcal transformants
      to bind porcine transferrin were in the order B16B6(Str(r))/tbpA(ap)B(ap) >
      B16B6(Str(r))/tbpA(ap)B(-) > B16B6(Str(r))/tbpA(-)B(ap). Of these transformants,
      only B16B6(Str(r))/tbpA(ap)B(ap) could grow in the presence of porcine
      transferrin as the sole iron source, achieving a growth rate similar to that of
      the B16B6 parent strain in the presence of human transferrin.

PMID- 10639417
TI  - Early induction of interleukin-12 by human monocytes exposed to Cryptococcus
      neoformans mannoproteins.
AB  - Interleukin-12 (IL-12) production by human monocytes stimulated with
      mannoproteins (MPs) of Cryptococcus neoformans was investigated. The results
      reported show that secreted or cell-associated MPs induce an early and
      significant production of IL-12. MPs show different capabilities to
      quantitatively affect IL-12 production; MP2, an 8. 2-kDa MP purified from the
      culture supernatant of C. neoformans, appears to be the most potent stimulator.
      Cytochalasin B inhibits both internalization and IL-12 induction by MP. In
      addition, a drastic reduction of IL-12 was observed when monocytes were cultured
      in the absence of normal human serum or treated with soluble mannan. Early
      production of IL-12 promotes early secretion of gamma interferon by T cells but
      does not influence the magnitude of the MP-induced lymphoproliferative response.
      Overall our results identify cryptococcal antigens responsible for rapid and
      potent induction of IL-12 in monocytes. MPs appear to regulate IL-12 secretion by
      internalization via the endocytic pathway and by interaction with monocyte
      receptors or serum factors.

PMID- 10639418
TI  - Isolation, affinity purification, and identification of piglet small intestine
      mucosa receptor for enterotoxigenic Escherichia coli k88ac+ fimbriae.
AB  - An affinity chromatography technique was utilized to isolate and purify the
      receptors of Escherichia coli K88ac(+) fimbriae from the mucus of the small
      intestines of newborn piglets. Purified K88ac+ fimbriae were covalently
      immobilized onto a beaded agarose matrix (Sepharose 4B). The immobilized fimbriae
      were used for the affinity purification of the K88ac+ receptors. Only two major
      proteins were tightly and specifically bound to the immobilized fimbriae after
      the column containing bound receptor was washed exhaustively with a buffer
      containing a high concentration of salt and a detergent. The receptors were
      eluted as a single component at a low pH. The isolated proteins were then
      subjected to enzyme-linked immunosorbent assay, sodium dodecyl sulfate
      polyacrylamide gel electrophoresis, and Western blot (immunoblot) analyses. The
      two proteins were of high purity, were responsible for nearly all of the fimbrial
      binding capacity of the crude mucus, and had molecular masses of 26 and 41 kDa.
      The method for isolation of E. coli binding proteins is simple and yields
      purified intestinal receptors in a single chromatographic run. The intestinal
      mucus of different piglets has different proportions of the two receptor
      proteins.

PMID- 10639419
TI  - Adherence of platelets to Candida species in vivo.
AB  - The in vivo interactions of platelets with Candida species yeast cells were
      investigated in a murine model. Mice were injected intravenously via the lateral
      caudal vein, and blood drawn by periorbital puncture was collected in phosphate
      buffered saline-formaldehyde to avoid in vitro platelet activation. The study of
      the clearance of blastoconidia of Candida albicans and Candida glabrata showed
      that these cells disappeared quickly from the bloodstream. Microscopic
      observation of blood samples, stained by Calcofluor white or May Grunwald Giemsa,
      demonstrated the rapid attachment of platelets to fungal elements of all the
      Candida spp. tested. The attachment of murine platelets to C. albicans cells,
      observed by scanning electron microscopy, revealed morphological changes. The
      platelets lost their discoid shape, generated pseudopodia, and flattened against
      the yeast cells. The reversibility of platelet binding to C. albicans by
      chelating agents suggests a cation-dependent link. In contrast, the fixation of
      C. glabrata and Candida tropicalis was not modified by chelating agents. The
      mechanisms involved in the in vivo adherence of platelets to Candida cells may
      therefore differ according to the species of Candida.

PMID- 10639421
TI  - A major cell surface antigen of Coccidioides immitis which elicits both humoral
      and cellular immune responses.
AB  - Multinucleate parasitic cells (spherules) of Coccidioides immitis isolates
      produce a membranous outer wall component (SOW) in vitro which has been reported
      to be reactive with antibody from patients with coccidioidal infection, elicits a
      potent proliferative response of murine immune T cells, and has immunoprotective
      capacity in a murine model of coccidioidomycosis. To identify the antigenic
      components of SOW, the crude wall material was first subjected to Triton X-114
      extraction, and a water-soluble fraction derived from this treatment was examined
      for protein composition and reactivity in humoral and cellular immunoassays.
      Protein electrophoresis revealed that the aqueous fraction of three different
      isolates of C. immitis each contained one or two major glycoproteins (SOWgps),
      distinguished by their molecular sizes, which ranged from 58 to 82 kDa. The
      SOWgps, however, showed identical N-terminal amino acid sequences, and each was
      recognized by sera from patients with C. immitis infection. Antibody raised
      against the purified 58-kDa glycoprotein (SOWgp58) of the Silveira isolate was
      used for Western blot and immunolocalization analyses. Expression of SOWgp was
      shown to be parasitic phase specific, and the antigen was localized to the
      membranous SOW. The water-soluble fraction of SOW and the purified SOWgp58 were
      tested for the ability to stimulate proliferation of human peripheral monocytic
      cells (PBMC). The latter were obtained from healthy volunteers with positive skin
      test reaction to spherulin, a parasitic-phase antigen of C. immitis, and from
      volunteers who showed no skin test reaction to the same antigen. The SOW
      preparations stimulated proliferation of PBMC from skin test-positive but not
      skin test-negative donors, and the activated cells secreted gamma interferon,
      which is indicative of a T helper 1 pathway of immune response. Results of this
      study suggest that SOWgp is a major parasitic cell surface-expressed antigen that
      elicits both humoral and cellular immune responses in patients with coccidioidal
      infection.

PMID- 10639420
TI  - Neutrophils play a protective nonphagocytic role in systemic Mycobacterium
      tuberculosis infection of mice.
AB  - Evidence showing that neutrophils play a protective role in the host response to
      infection by different intracellular parasites has been published in the past few
      years. We assessed this issue with regard to the infection of mice with
      Mycobacterium tuberculosis. We found a chronic recruitment of neutrophils to the
      infection foci, namely, to the peritoneal cavity after intraperitoneal infection
      and to the spleen and liver after intravenous inoculation of the mycobacteria.
      However, bacilli were never found associated with the recruited neutrophils but
      rather were found inside macrophages. The intravenous administration of the
      antineutrophil monoclonal antibody RB6-8C5 during the first week of infection led
      to selective and severe neutropenia associated with an enhancement of bacillary
      growth in the target organs of the mice infected by the intravenous route. The
      neutropenia-associated exacerbation of infection was most important in the liver,
      where a bacterial load 10-fold higher than that in nonneutropenic mice was found;
      the exacerbation in the liver occurred both during and after the neutropenic
      period. Early in infection by M. tuberculosis, neutropenic mice expressed lower
      levels of mRNAs for gamma interferon and inducible nitric oxide synthase in the
      liver compared to nondepleted mice. These results point to a protective role of
      neutrophils in the host defense mechanisms against M. tuberculosis, which occurs
      early in the infection and is not associated with the phagocytic activity of
      neutrophils but may be of an immunomodulatory nature.

PMID- 10639422
TI  - Expression of chemokine genes in murine macrophages infected with Orientia
      tsutsugamushi.
AB  - Scrub typhus, caused by Orientia tsutsugamushi infection, is characterized by
      local as well as systemic inflammatory manifestations. Inflammation is initiated
      by O. tsutsugamushi-infected macrophages and endothelial cells in the dermis. We
      investigated the regulation of chemokine induction in macrophage cell line
      J774A.1 in response to O. tsutsugamushi infection. The mRNAs for macrophage
      inflammatory proteins 1alpha/beta (MIP-1alpha/beta), MIP-2, and macrophage
      chemoattractant protein 1 were induced within 30 min, and their levels showed a
      transitory peak for 3 to 12 h. However, the lymphotactin, eotaxin, gamma
      interferon-inducible protein 10, and T-cell activation gene 3 mRNAs were not
      detected by RNase protection assays. Heat-killed O. tsutsugamushi induced a
      similar extent of chemokine responses. Induction of the chemokine genes was not
      blocked by the eukaryotic protein synthesis inhibitor cycloheximide, suggesting
      that de novo synthesis of host cell protein is not required for these
      transcriptional responses. The induction of chemokine mRNAs by O. tsutsugamushi
      was blocked by the inhibitors of NF-kappaB activation. Furthermore, O.
      tsutsugamushi induced the nuclear translocation and activation of NF-kappaB.
      These results demonstrate that heat-stable molecules of O. tsutsugamushi induce a
      subset of chemokine genes and that induction involves activation of the
      transcription factor NF-kappaB.

PMID- 10639423
TI  - Identification of Cowdria ruminantium antigens that stimulate proliferation of
      lymphocytes from cattle immunized by infection and treatment or with inactivated
      organisms.
AB  - Cowdria ruminantium is an obligate intracellular pathogen that causes heartwater
      in ruminants. Several findings suggest that T cells play an important role in
      protection against the disease. In order to identify which proteins are involved
      in T-cell immunity, C. ruminantium proteins were fractionated by continuous-flow
      electrophoresis and tested for their ability to stimulate lymphocyte
      proliferation in vitro. C. ruminantium-infected endothelial cell lysates were
      fractionated at between 11 and 38 kDa and 50 and 168 kDa on 15 and 7% acrylamide
      gels, respectively. In an attempt to stimulate the natural infective process,
      peripheral blood mononuclear cells (PBMC) were obtained from two cattle rendered
      immune by infection and treatment and assayed in proliferation assays with
      fractionated proteins. In a parallel study, four cattle were immunized with
      inactivated C. ruminantium to determine whether their lymphocytes also responded
      to fractionated proteins. Proliferation assays after immunization by infection
      and treatment detected no C. ruminantium-specific proliferation in vitro after
      one vaccination. Proliferation was observed, however, between 1 and 4 weeks after
      challenge. This was followed by a period of no detectable response, after which
      the response reappeared. PBMC from animals immunized with inactivated organisms
      proliferated specifically in response to antigen soon after the first
      immunization. Only C. ruminantium proteins with low molecular masses of 11, 12,
      14 to 17, and 19 to 23 kDa induced proliferative responses by lymphocytes from
      all six animals. These protein fractions may have potential as vaccine antigens.

PMID- 10639424
TI  - Matrix metalloproteinases contribute to brain damage in experimental pneumococcal
      meningitis.
AB  - The present study was performed to evaluate the role of matrix metalloproteinases
      (MMP) in the pathogenesis of the inflammatory reaction and the development of
      neuronal injury in a rat model of bacterial meningitis. mRNA encoding specific
      MMPs (MMP-3, MMP-7, MMP-8, and MMP-9) and the inflammatory cytokine tumor
      necrosis factor alpha (TNF-alpha) were significantly (P < 0.04) upregulated,
      compared to the beta-actin housekeeping gene, in cortical homogenates at 20 h
      after infection. In parallel, concentrations of MMP-9 and TNF-alpha in
      cerebrospinal fluid (CSF) were significantly increased in rats with bacterial
      meningitis compared to uninfected animals (P = 0.002) and showed a close
      correlation (r = 0.76; P < 0. 001). Treatment with a hydroxamic acid-type MMP
      inhibitor (GM6001; 65 mg/kg intraperitoneally every 12 h) beginning at the time
      of infection significantly lowered the MMP-9 (P < 0.02) and TNF-alpha (P < 0.02)
      levels in CSF. Histopathology at 25.5 +/- 5.7 h after infection showed neuronal
      injury (median [range], 3.5% [0 to 17.5%] of the cortex), which was significantly
      (P < 0.01) reduced to 0% (0 to 10.8%) by GM6001. This is the first report to
      demonstrate that MMPs contribute to the development of neuronal injury in
      bacterial meningitis and that inhibition of MMPs may be an effective approach to
      prevent brain damage as a consequence of the disease.

PMID- 10639425
TI  - CD4(+) T-cell subsets that mediate immunological memory to Mycobacterium
      tuberculosis infection in mice.
AB  - We have studied CD4(+) T cells that mediate immunological memory to an
      intravenous infection with Mycobacterium tuberculosis. The studies were conducted
      with a mouse model of memory immunity in which mice are rendered immune by a
      primary infection followed by antibiotic treatment and rest. Shortly after
      reinfection, tuberculosis-specific memory cells were recruited from the
      recirculating pool, leading to rapidly increasing precursor frequencies in the
      liver and a simultaneous decrease in the blood. A small subset of the
      infiltrating T cells was rapidly activated (<20 h) and expressed high levels of
      intracellular gamma interferon and the T-cell activation markers CD69 and CD25.
      These memory effector T cells expressed intermediate levels of CD45RB and were
      heterogeneous with regard to the L-selectin and CD44 markers. By adoptive
      transfer into nude mice, the highest level of resistance to a challenge with M.
      tuberculosis was mediated by CD45RB(high), L-selectin(high), CD44(low) cells.
      Taken together, these two lines of evidence support an important role for memory
      cells which have reverted to a naive phenotype in the long-term protection
      against M. tuberculosis.

PMID- 10639426
TI  - A novel Leishmania infantum recombinant antigen which elicits interleukin 10
      production by peripheral blood mononuclear cells of patients with visceral
      leishmaniasis.
AB  - We report here the characterization of a novel Leishmania infantum protein termed
      papLe22 (22-kDa potentially aggravating protein of Leishmania). A positive clone
      from a cDNA library was identified by serum of a visceral leishmaniasis (VL)
      patient. Full-length cDNA obtained using rapid amplification of cDNA ends-PCR
      codes for a 22-kDa protein. In L. infantum promastigotes an endogenous nuclear
      protein of 14-kDa electrophoretic mobility was found by using an antiserum
      prepared against the fusion protein glutathione S-transferase-papLe22. Its
      expression was also shown in L. infantum amastigotes and in Leishmania major and
      Leishmania guyanensis promastigotes. VL patients' sera showed anti-papLe22
      immunoglobulin M (IgM) and IgG reactivities, indicating that a primary response
      against the leishmanial protein papLe22 accompanied acute VL manifestations.
      Specific IgG levels were correlated with patients' clinical status. The presence
      of IgG1, IgG2, and IgG3 subclasses suggested a mixed Th1- and Th2-type response;
      there was no correlation between subclass reactivity and the disease course. The
      recombinant papLe22 specifically activated interleukin-10 production by VL
      patients' peripheral blood mononuclear cells collected at diagnosis and after
      treatment-induced cure, indicating its contribution to VL pathogenesis and
      concomitant immunosuppression and its potential role in the reactivation of
      latent parasites. As a dominant immunogen, papLe22 might be used as a vaccine
      component, provided that the vaccination protocol directs the response toward the
      Th1 pattern.

PMID- 10639427
TI  - Streptococcus suis serotype 2 interactions with human brain microvascular
      endothelial cells.
AB  - Streptococcus suis serotype 2 is a worldwide causative agent of many forms of
      swine infection and is also recognized as a zoonotic agent causing human disease,
      including meningitis. The pathogenesis of S. suis infections is poorly
      understood. Bacteria circulate in the bloodstream in the nonimmune host until
      they come in contact with brain microvascular endothelial cells (BMEC) forming
      the blood-brain barrier. The bacterial polysaccharide capsule confers
      antiphagocytic properties. It is known that group B streptococci (GBS) invade and
      damage BMEC, which may be a primary step in the pathogenesis of neonatal
      meningitis. Interactions between S. suis and human endothelial cells were studied
      to determine if they differ from those between GBS and endothelial cells.
      Invasion assays performed with BMEC and human umbilical vein endothelial cells
      demonstrated that unlike GBS, S. suis serotype 2 could not invade either type of
      cell. Adherence assays showed that S. suis adhered only to BMEC, whereas GBS
      adhered to both types of cell. These interactions were not affected by the
      presence of a capsule, since acapsular mutants from both bacterial species
      adhered similarly compared to the wild-type strains. Lactate dehydrogenase
      release measurements indicated that some S. suis strains were highly cytotoxic
      for BMEC, even more than GBS, whereas others were not toxic at all. Cell damage
      was related to suilysin (S. suis hemolysin) production, since only suilysin
      producing strains were cytotoxic and cytotoxicity could be inhibited by
      cholesterol and antisuilysin antibodies. It is possible that hemolysin-positive
      S. suis strains use adherence and suilysin-induced BMEC injury, as opposed to
      direct cellular invasion, to proceed from the circulation to the central nervous
      system.

PMID- 10639428
TI  - Role of serotype-specific polysaccharide in the resistance of Streptococcus
      mutans to phagocytosis by human polymorphonuclear leukocytes.
AB  - To clarify the role of cell surface components of Streptococcus mutans in
      resistance to phagocytosis by human polymorphonuclear leukocytes (PMNs), several
      isogenic mutants of S. mutans defective in cell surface components were studied
      with a luminol-enhanced chemiluminescence (CL) assay, a killing assay, and a
      transmission electron microscope. The CL responses of human PMNs to mutant Xc11
      defective in a major cell surface antigen, PAc, and mutant Xc16 defective in two
      surface glucosyltransferases (GTF-I and GTF-SI) were the same as the response to
      the wild-type strain, Xc. In contrast, mutant Xc24R, which was defective in
      serotype c-specific polysaccharide, induced a markedly higher CL response than
      the other strains. The killing assay showed that human PMNs killed more Xc24R
      than the parent strain and the other mutants. The transmission electron
      microscopic observation indicated that Xc24R cells were more internalized by
      human PMNs than the parental strain Xc. These results may be reflected by the
      fact that strain Xc24R was more phagocytosed than strain Xc. The CL response of
      human PMNs to a mutant defective in polysaccharide serotype e or f was similar to
      the response to Xc24R. Furthermore, mutants defective in serotype-specific
      polysaccharide were markedly more hydrophobic than the wild-type strains and the
      other mutants, suggesting that the hydrophilic nature of polysaccharides may
      protect the bacterium from phagocytosis. We conclude that the serotype-specific
      polysaccharide, but not the cell surface proteins on the cell surface of S.
      mutans, may play an important role in the resistance to phagocytosis.

PMID- 10639429
TI  - Effects of reproductive hormones on experimental vaginal candidiasis.
AB  - Vulvovaginal candidiasis (VVC) is an opportunistic mucosal infection caused by
      Candida albicans that affects large numbers of otherwise healthy women of
      childbearing age. Acute episodes of VVC often occur during pregnancy and during
      the luteal phase of the menstrual cycle, when levels of progesterone and estrogen
      are elevated. Although estrogen-dependent experimental rodent models of C.
      albicans vaginal infection are used for many applications, the role of
      reproductive hormones and/or their limits in the acquisition of vaginal
      candidiasis remain unclear. This study examined the effects of estrogen and
      progesterone on several aspects of an experimental infection together with
      relative cell-mediated immune responses. Results showed that while decreasing
      estrogen concentrations eventually influenced infection-induced vaginal titers of
      C. albicans and rates of infection in inoculated animals, the experimental
      infection could not be achieved in mice treated with various concentrations of
      progesterone alone. Furthermore, progesterone had no effect on (i) the induction
      and persistence of the infection in the presence of estrogen, (ii) delayed-type
      hypersensitivity in primary-infected mice, or (iii) the partial protection from a
      secondary vaginal infection under pseudoestrus conditions. Other results with
      estrogen showed that a persistent infection could be established with a wide
      range of C. albicans inocula under supraphysiologic and near-physiologic (at
      estrus) concentrations of estrogen and that vaginal fungus titers or rates of
      infection were similar if pseudoestrus was initiated several days before or after
      inoculation. However, the pseudoestrus state had to be maintained for the
      infection to persist. Finally, estrogen was found to reduce the ability of
      vaginal epithelial cells to inhibit the growth of C. albicans. These results
      suggest that estrogen, but not progesterone, is an important factor in hormone
      associated susceptibility to C. albicans vaginitis.

PMID- 10639430
TI  - Occurrence of severe destructive lyme arthritis in hamsters vaccinated with outer
      surface protein A and challenged with Borrelia burgdorferi.
AB  - Arthritis is a frequent and major complication of infection with Borrelia
      burgdorferi sensu stricto. The antigens responsible for the induction of
      arthritis are unknown. Here we provide direct evidence that a major surface
      protein, outer surface protein A (OspA), can induce arthritis. Hamsters were
      vaccinated with 30, 60, or 120 microg of recombinant OspA (rOspA) in aluminum
      hydroxide and challenged with B. burgdorferi sensu stricto isolate 297 or C-1-11.
      Swelling of the hind paws was detected in 100, 100, and 50% of hamsters
      vaccinated with 30, 60, or 120 microg of rOspA, respectively. In addition,
      arthritis developed in 57% of hamsters vaccinated with a canine rOspA vaccine
      after infection with B. burgdorferi sensu stricto. When the canine rOspA vaccine
      was combined with aluminum hydroxide, all vaccinated hamsters developed arthritis
      after challenge with B. burgdorferi sensu stricto. Histopathologic examination
      confirmed the development of severe destructive arthritis in rOspA-vaccinated
      hamsters challenged with B. burgdorferi sensu stricto. These findings suggest
      that rOspA vaccines should be modified to eliminate epitopes of OspA responsible
      for the induction of arthritis. Our results are important because an rOspA
      vaccine in aluminum hydroxide was approved by the Food and Drug Administration
      for use in humans.

PMID- 10639431
TI  - Cytokine expression and production by purified Helicobacter pylori urease in
      human gastric epithelial cells.
AB  - Cytokines have been proposed to play an important role in Helicobacter pylori
      associated gastroduodenal diseases, but the exact mechanism of the cytokine
      induction remains unclear. H. pylori urease, a major component of the soluble
      proteins extracted from bacterial cells, is considered to be one of the virulence
      factors for the inflammation in the gastric mucosa that is produced in H. pylori
      infection. However, the response of human gastric epithelial cells to the
      stimulation of urease has not been investigated. In the present study, we used
      human gastric epithelial cells in a primary culture system and examined whether
      H. pylori urease stimulates the gastric epithelial cells to induce
      proinflammatory cytokines by reverse transcription-PCR and enzyme-linked
      immunosorbent assay. First, by using peripheral blood mononuclear cells (PBMC)
      and a gastric cancer cell line (MKN-45 cells), we confirmed the ability of
      purified H. pylori urease to induce the production of proinflammatory cytokines.
      Furthermore, we demonstrated that the human gastric epithelial cells produced
      interleukin-6 (IL-6) and tumor necrosis factor alpha, but not IL-8, following
      stimulation with purified urease. The patterns of cytokine induction differed
      among human PBMC, MKN-45 cells, and human gastric epithelial cells. These results
      suggest that the human gastric epithelial cells contribute to the induction of
      proinflammatory cytokines by the stimulation of H. pylori urease, indicating that
      the epithelial cells were involved in the mucosal inflammation that accompanied
      H. pylori infection.

PMID- 10639432
TI  - Mucosally induced immunoglobulin E-associated inflammation in the respiratory
      tract.
AB  - The purpose of the present study was to determine the immunologic responses,
      particularly immunopathologic reactions, associated with nasal immunization with
      the mucosal adjuvant, cholera toxin (CT). BALB/c mice were nasally immunized with
      tetanus toxoid (TT) combined with CT, and the responses of these mice were
      determined. After nasal immunization, mice produce a serum antibody response,
      primarily of the immunoglobulin G (IgG) isotype of predominantly IgG1 subclass,
      against both TT and CT. Along with the antibody responses, we also found that
      inflammatory reactions, which could be potentially fatal, developed within the
      lung. Furthermore, IgE responses were also induced after nasal immunization, and
      these responses were associated with the detection of interleukin 5 in the serum.
      Thus, nasal immunization with TT plus CT likely results in the activation of Th2
      cells, which may contribute to serious immunopathologic reactions in the lung.

PMID- 10639433
TI  - Epitope mapping of immunogenic and adhesive structures in repetitive domains of
      Mycoplasma bovis variable surface lipoproteins.
AB  - The family of variable surface lipoproteins (Vsps) of the bovine pathogen
      Mycoplasma bovis includes some of the most immunogenic antigens of this
      microorganism. Vsps were shown to undergo high-frequency phase and size
      variations and to possess extensive reiterated coding sequences extending from
      the N-terminal end to the C-terminal end of the Vsp molecule. In the present
      study, mapping experiments were conducted to detect regions with immunogenicity
      and/or adhesion sites in repetitive domains of four Vsp antigens of M. bovis,
      VspA, VspB, VspE, and VspF. In enzyme-linked immunosorbent assay experiments,
      sera obtained from naturally infected cattle showed antibodies to different
      repeating peptide units of the Vsps, particularly to units R(A)1, R(A)2, R(A)4.1,
      R(B)2.1, R(E)1, and R(F)1, all of which were found to contain immunodominant
      epitopes of three to seven amino acids. Competitive adherence trials revealed
      that a number of oligopeptides derived from various repeating units of VspA,
      VspB, VspE, and VspF partially inhibited cytoadhesion of M. bovis PG45 to
      embryonic bovine lung cells. Consequently, putative adherence sites were
      identified in the same repeating units (R(A)1, R(A)2, R(A)4.1, R(B)2.1, R(E)1,
      and R(F)1) and in R(F)2. The positions and lengths of the antigenic determinants
      were mostly identical to those of adhesion-mediating sites in all short repeating
      units, whereas in the considerably longer R(F)1 unit (84 amino acid residues),
      there was only one case of identity among four immunogenic epitopes and six
      adherence sites. The identification of epitopes and adhesive structures in
      repetitive domains of Vsp molecules is consistent with the highly immunogenic
      nature observed for several members of the Vsp family and suggests a possible
      function for these Vsp molecules as complex adherence-mediating regions in
      pathogenesis.

PMID- 10639434
TI  - Mannose-binding lectin binds to a range of clinically relevant microorganisms and
      promotes complement deposition.
AB  - Mannose-binding lectin (MBL) is a collagenous serum lectin believed to be of
      importance in innate immunity. Genetically determined low levels of the protein
      are known to predispose to infections. In this study the binding of purified MBL
      to pathogens isolated from immunocompromised children was investigated by flow
      cytometry. Diverse Candida species, Aspergillus fumigatus, Staphylococcus aureus,
      and beta-hemolytic group A streptococci exhibited strong binding of MBL, whereas
      Escherichia coli, Klebsiella species, and Haemophilus influenzae type b were
      characterized by heterogeneous binding patterns. In contrast, beta-hemolytic
      group B streptococci, Streptococcus pneumoniae, and Staphylococcus epidermidis
      showed low levels of binding. Bound MBL was able to promote C4 deposition in a
      concentration-dependent manner. We conclude that MBL may be of importance in
      first-line immune defense against several important pathogens.

PMID- 10639435
TI  - Biochemical and immunological characterization of MP65, a major mannoprotein
      antigen of the opportunistic human pathogen Candida albicans.
AB  - In the search of the antigenic determinants of a 65-kDa mannoprotein (MP65) of
      Candida albicans, tryptic fragments of immunoaffinity-purified MP65 preparations
      were tested for their ability to induce lymphoproliferation of human peripheral
      blood mononuclear cells (PBMC). Five major peptides (T1 to T5) were shown to
      induce a vigorous proliferation of PBMC from the majority of the eight healthy
      human subjects tested. With the use of synthetic peptides, critical amino acid
      sequences of the two most immunoactive (T1 and T2) peptides were determined.
      Similar to what was found for the MP65 molecule, no PBMC multiplication was
      induced by the antigenic peptides in cultures of naive cord blood cells. The
      amino acid sequence analysis of tryptic and chymotryptic peptides of MP65
      demonstrated a substantial homology with the deduced sequences of two cell wall
      proteins of Saccharomyces cerevisiae, encoded by the genes YRM305C and YGR279C.
      However, the antigenic peptides were those showing the least similarity with the
      corresponding regions of the above proteins. In particular, the
      lymphoproliferation-inducing sequence of the T1 peptide scored only 20% identity
      with the homologous regions of S. cerevisiae proteins. Besides disclosing the
      amino acid sequence of MP65, this study provides an initial characterization of
      some of its antigenic determinants, as well as of synthetic peptides of potential
      use to detect specific immune responses against MP65, a major target of
      anticandidal cell-mediated immunity in humans.

PMID- 10639436
TI  - Inflammatory mediators in dengue virus infection in children: interleukin-8 and
      its relationship to neutrophil degranulation.
AB  - The chemokine interleukin-8 (IL-8) has chemoattractant activity for neutrophils
      and is able to activate and degranulate these cells. We investigated whether IL-8
      may exert these effects in children with dengue virus infection. Circulating
      levels of IL-8, neutrophilic elastase (a constituent of the azurophilic granula
      of neutrophils), and lactoferrin, released from specific granula, were measured
      in 186 children with dengue virus infection, 33 healthy children as negative
      controls and 11 children with bacterial infections as positive controls. Levels
      of IL-8 on admission were elevated in 71% of the dengue patients, while the
      elastase and lactoferrin levels were increased in 68 and 17% of patients,
      respectively. These levels were significantly higher than in healthy children (P
      < 0.05) for IL-8 and elastase but not for lactoferrin (by the Wilcoxon-Mann
      Whitney [WMW] U test). Similar levels of IL-8 were found in patients with
      bacterial infections. Levels of IL-8 and elastase in patients with shock were
      significantly higher than in patients without shock (P = 0.02; WMW), but those of
      lactoferrin were not. IL-8 correlated with elastase and lactoferrin (r = 0.19 and
      P = 0.009 versus r = 0.24 and P = 0.001, respectively; two-tailed Spearman rank
      correlation). Thus, IL-8 levels are increased in most patients with dengue virus
      infection and correlate with degranulation of neutrophils as well as with some
      clinical and hemodynamic variables. These findings suggest a role for IL-8 in the
      pathogenesis of dengue virus infection.

PMID- 10639437
TI  - Identification of an antigen localized to an apparent septum within dividing
      chlamydiae.
AB  - The process of chlamydial cell division has not been thoroughly investigated. The
      lack of detectable peptidoglycan and the absence of an FtsZ homolog within
      chlamydiae suggest an unusual mechanism for the division process. Our laboratory
      has identified an antigen (SEP antigen) localized to a ring-like structure at the
      apparent septum within dividing chlamydial reticulate bodies (RB). Antisera
      directed against SEP show similar patterns of antigen distribution in Chlamydia
      trachomatis and Chlamydia psittaci RB. In contrast to localization in RB, SEP in
      elementary bodies appears diffuse and irregular, suggesting that the distribution
      of the antigen is developmental-stage specific. Treatment of chlamydiae with
      inhibitors of peptidoglycan synthesis or culture of chlamydiae in medium lacking
      tryptophan leads to the formation of nondividing, aberrant RB. Staining of
      aberrant RB with anti-SEP reveals a marked redistribution of the antigen. Within
      C. trachomatis-infected cells, ampicillin treatment leads to high levels of SEP
      accumulation at the periphery of aberrant RB, while in C. psittaci, treatment
      causes SEP to localize to distinct punctate sites within the bacteria. Aberrancy
      produced via tryptophan depletion results in a different pattern of SEP
      distribution. In either case, the reversal of aberrant formation results in the
      production of normal RB and a redistribution of SEP to the apparent plane of
      bacterial division. Collectively these studies identify a unique chlamydial-genus
      common and developmental-stage-specific antigen that may be associated with RB
      division.

PMID- 10639438
TI  - Enzymatic properties of dipeptidyl aminopeptidase IV produced by the periodontal
      pathogen Porphyromonas gingivalis and its participation in virulence.
AB  - Porphyromonas gingivalis is a major pathogen associated with adult periodontitis.
      We cloned and sequenced the gene (dpp) coding for dipeptidyl aminopeptidase IV
      (DPPIV) from P. gingivalis W83, based on the amino acid sequences of peptide
      fragments derived from purified DPPIV. An Escherichia coli strain overproducing
      P. gingivalis DPPIV was constructed. The enzymatic properties of recombinant
      DPPIV purified from the overproducer were similar to those of DPPIV isolated from
      P. gingivalis. The three amino acid residues Ser, Asp, and His, which are thought
      to form a catalytic triad in the C-terminal catalytic domain of eukaryotic DPPIV,
      are conserved in P. gingivalis DPPIV. When each of the corresponding residues of
      the enzyme was substituted with Ala by site-directed mutagenesis, DPPIV activity
      significantly decreased, suggesting that these three residues of P. gingivalis
      DPPIV are involved in the catalytic reaction. DPPIV-deficient mutants of P.
      gingivalis were constructed and subjected to animal experiments. Mice injected
      with the wild-type strain developed abscesses to a greater extent and died more
      frequently than those challenged with mutant strains. Mice injected with the
      mutants exhibited faster recovery from the infection, as assessed by weight gain
      and the rate of lesion healing. This decreased virulence of mutants compared with
      the parent strain suggests that DPPIV is a potential virulence factor of P.
      gingivalis and may play important roles in the pathogenesis of adult
      periodontitis induced by the organism.

PMID- 10639439
TI  - Streptococcus sobrinus antigens that react to salivary antibodies induced by
      tonsillar application of formalin-killed S. sobrinus in rabbits.
AB  - We previously found that tonsillar application of antigen induces a strong
      antibody response to Streptococcus sobrinus in saliva and blood plasma. Rabbits
      immunized against S. sobrinus by tonsillar application were highly resistant to
      experimental dental caries triggered by oral inoculation of living S. sobrinus
      organisms with sucrose. In the present study, we examined the reaction of S.
      sobrinus antigens to the antibodies induced by the tonsillar application of S.
      sobrinus AHT-k in rabbits and compared them to those antibodies induced by
      intramuscular injection. In an enzyme-linked immunosorbent assay using ultrasonic
      fragments from mutans group streptococci, the saliva and blood plasma selectively
      reacted to S. sobrinus AHT-k (serotype g) and serologically related streptococci
      (serotypes a, d, and h) in the sixth week after tonsillar application, whereas
      the blood plasma in the sixth week after intramuscular injection reacted to the
      unrelated streptococci (serotypes b, c, e, and f) in addition to the
      aforementioned streptococci. The antibody reactivity induced after tonsillar
      application was not lost after treatment of the antigen with heat or proteinase
      digestion, whereas these treatments resulted in a 70% decrease of the antibody
      reactivity induced by intramuscular injection. The inhibition by haptenic sugars
      and the decrease in immunoreactivity by heat treatment and proteinase digestion
      suggested that 80% of the antibodies induced by tonsillar application reacted to
      saccharides. These saccharide antigens appeared to be involved in a specific
      reaction with S. sobrinus-specific streptococci and a selective reaction with
      serologically related streptococci. These antigens are probably involved in
      anticaries reactions in experimental dental caries.

PMID- 10639440
TI  - Expression and immunogenicity of hemagglutinin A from Porphyromonas gingivalis in
      an avirulent Salmonella enterica serovar typhimurium vaccine strain.
AB  - Porphyromonas gingivalis is a major etiologic agent of periodontitis, a chronic
      inflammatory disease that ultimately results in the loss of the supporting
      tissues of the teeth. Previous work has demonstrated the usefulness of avirulent
      Salmonella enterica serovar Typhimurium strains as antigen delivery systems for
      protective antigens of pathogens that colonize or cross mucosal surfaces. In this
      study, we constructed and characterized a recombinant S. enterica serovar
      Typhimurium avirulent vaccine strain which expresses hemagglutinin A and carries
      no antibiotic resistance markers. HagA, a major virulence-associated surface
      protein, is a potentially useful immunogen that contains an antigenic epitope
      which, in humans, elicits an immune response that is protective against
      subsequent colonization by P. gingivalis. The hagA gene, including its promoter,
      was cloned into a balanced-lethal Salmonella vector and transferred to the
      vaccine strain. Heterologous expression of HagA was demonstrated in both
      Escherichia coli JM109 and S. enterica serovar Typhimurium vaccine strain
      chi4072. The HagA epitope was present in its native configuration as determined
      by immunochemistry and immunoelectron microscopy. Purified recombinant HagA was
      recognized by sera from mice immunized with the S. enterica serovar Typhimurium
      vaccine strain. The HagA-specific antigen of the vaccine was also found to be
      recognized by serum from a periodontal patient. This vaccine strain, which
      expresses the functional hemagglutinin protein, induces a humoral immune response
      against HagA and may be useful for developing a protective vaccine against
      periodontal diseases associated with P. gingivalis.

PMID- 10639441
TI  - The cytotoxic T-lymphocyte epitope of the Plasmodium falciparum circumsporozoite
      protein also modulates the efficiency of receptor-ligand interaction with
      hepatocytes.
AB  - Malaria sporozoites are transmitted from the mosquito salivary gland to host
      hepatocytes within minutes of an infectious bite. The circumsporozoite protein
      (CS), which covers the surface of Plasmodium sporozoites, functions during these
      minutes in the targeting of host liver cells. The protein's potentially important
      role in an antimalaria vaccine has spawned interest in both the host immune
      responses to the parasite's presence and the actual functional role of the
      protein in the targeting of host liver cells. Here we show that the region of CS
      known to elicit a cytotoxic T-lymphocyte (CTL) response to irradiated sporozoites
      also, somewhat ironically, mediates the receptor-ligand interaction essential to
      parasite invasion of the host. Hence, the structure of CS represents a balance of
      potentially counterdirectional forces. Polymorphism in the CTL epitope appears to
      be a product of this balanced state as opposed to an "arms race" as it is so
      often portrayed. The conceptual difference between the theories regarding the
      maintainance of polymorphism in CTL epitopes may have significant implication for
      vaccine design.

PMID- 10639442
TI  - Absence of SpeB production in virulent large capsular forms of group A
      streptococcal strain 64.
AB  - Passage in human blood of group A streptococcal isolate 64p was previously shown
      to result in the enhanced expression of M and M-related proteins. Similarly, when
      this isolate was injected into mice via an air sac model for skin infection,
      organisms recovered from the spleens showed both increased expression of M and M
      related proteins and increased skin-invasive potential. We show that these
      phenotypic changes were not solely the result of increased transcription of the
      mRNAs encoding the M and M-related gene products. Rather, the altered expression
      was associated with posttranslational modifications of the M and M-related
      proteins that occur in this strain, based on the presence or absence of another
      virulence protein, the streptococcal cysteine protease SpeB. The phenotypic
      variability also correlates with colony size variation. Large colonies selected
      by both regimens expressed more hyaluronic acid, which may explain differences in
      colony morphology. All large-colony variants were SpeB negative and expressed
      three distinct immunoglobulin G (IgG)-binding proteins in the M and M-related
      protein family. Small-colony variants were SpeB positive and bound little IgG
      through their M and M-related proteins because these proteins, although made,
      were degraded or altered in profile by the SpeB protease. We conclude that
      passage in either human blood or a mouse selects for a stable, phase-varied
      strain of group A streptococci which is altered in many virulence properties.

PMID- 10639443
TI  - Activation of human peripheral blood mononuclear cells by nonpathogenic bacteria
      in vitro: evidence of NK cells as primary targets.
AB  - The interaction of commensal bacteria with immunocompetent cells may occur in
      definite compartments of the mucosal immune system, as limited translocation
      through the epithelial barrier cannot be excluded. In this study the stimulation
      of human peripheral blood mononuclear cells and purified lymphocyte subsets by
      nonpathogenic gram-positive lactobacilli (Lactobacillus johnsonii and
      Lactobacillus sakei) and gram-negative Escherichia coli was investigated. The
      various bacterial strains induced a differential cytokine pattern. Whereas L.
      johnsonii and L. sakei strongly induced gamma interferon (IFN-gamma) and
      interleukin-12 (IL-12), E. coli and lipopolysaccharide (LPS) preferentially
      induced IL-10 after 16 h of stimulation. Expression of activation antigens CD69
      and CD25 was observed on (CD3(-) CD56(+)) natural killer (NK) cells after
      stimulation of total human peripheral blood mononuclear cells. All bacteria
      mediated the proliferation of human peripheral blood mononuclear cells, and the
      strongest proliferative response was observed with L. johnsonii. Purified CD4(+),
      CD8(+), and CD19(+) lymphocyte subsets were not activated upon bacterial
      stimulation but showed normal response to a mitogenic stimulus. In contrast,
      purified NK cells upregulated the IL-2Ralpha chain (CD25) and underwent
      proliferation when stimulated by L. johnsonii. E. coli and LPS were less
      effective in inducing proliferation. Expression of CD25 or secretion of IFN-gamma
      from purified NK cells was significantly increased in the presence of bacterially
      primed macrophages, indicating that full activation required both bacterium- and
      cell contact-based signals derived from accessory cells.

PMID- 10639444
TI  - Immunogenicity of the B monomer of Escherichia coli heat-labile toxin expressed
      on the surface of Streptococcus gordonii.
AB  - The B monomer of the Escherichia coli heat-labile toxin (LTB) was expressed on
      the surface of the human oral commensal bacterium Streptococcus gordonii.
      Recombinant bacteria expressing LTB were used to immunize BALB/c mice
      subcutaneously and intragastrically. The LTB monomer expressed on the
      streptococcal surface proved to be highly immunogenic, as LTB-specific
      immunoglobulin G (IgG) serum titers of 140,000 were induced after systemic
      immunization. Most significantly, these antibodies were capable of neutralizing
      the enterotoxin in a cell neutralization assay. Following mucosal delivery,
      antigen-specific IgA antibodies were found in feces and antigen-specific IgG
      antibodies were found in sera. Analysis of serum IgG subclasses showed a clear
      predominance of IgG1 when recombinant bacteria were inoculated subcutaneously,
      while a prevalence of IgG2a was observed upon intragastric delivery, suggesting,
      in this case, the recruitment of a Th1 type of immune response.

PMID- 10639445
TI  - Disruption of the genes encoding antigen 85A and antigen 85B of Mycobacterium
      tuberculosis H37Rv: effect on growth in culture and in macrophages.
AB  - The mechanism of pathogenesis of Mycobacterium tuberculosis is thought to be
      multifactorial. Among the putative virulence factors is the antigen 85 (Ag85)
      complex. This family of exported fibronectin-binding proteins consists of members
      Ag85A, Ag85B, and Ag85C and is most prominently represented by 85A and 85B. These
      proteins have recently been shown to possess mycolyl transferase activity and
      likely play a role in cell wall synthesis. The purpose of this study was to
      generate strains of M. tuberculosis deficient in expression of the principal
      members of this complex in order to determine their role in the pathogenesis of
      M. tuberculosis. Constructs of fbpA and fbpB disrupted with the kanamycin
      resistance marker OmegaKm and containing varying amounts of flanking gene and
      plasmid vector sequences were then introduced as linear fragments into H37Rv by
      electroporation. Southern blot and PCR analyses revealed disruption of the
      homologous gene locus in one fbpA::OmegaKm transformant and one fbpB::OmegaKm
      transformant. The fbpA::OmegaKm mutant, LAa1, resulted from a double-crossover
      integration event, whereas the fbpB::OmegaKm variant, LAb1, was the product of a
      single-crossover type event that resulted in insertion of both OmegaKm and
      plasmid sequences. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and
      Western blot analysis confirmed that expression of the disrupted gene was not
      detectable in the fbpA and fbpB mutants. Analysis of growth rates demonstrated
      that the fbpB mutant LAb1 grew at a rate similar to that of the wild-type parent
      in enriched and nutrient-poor laboratory media as well as in human (THP-1) and
      mouse (J774.1A) macrophage-like cell lines. The fbpA mutant LAa1 grew similarly
      to the parent H37Rv in enriched laboratory media but exhibited little or no
      growth in nutrient-poor media and macrophage-like cell lines. The targeted
      disruption of two genes encoding mycolyl transferase and fibronectin-binding
      activities in M. tuberculosis will permit the systematic determination of their
      roles in the physiology and pathogenesis of this organism.

PMID- 10639446
TI  - Helicobacter felis infection is associated with lymphoid follicular hyperplasia
      and mild gastritis but normal gastric secretory function in cats.
AB  - The relationship of Helicobacter felis, a bacterium observed in the stomachs of
      cats, to gastric disease is unclear. The objective of this study was to determine
      if H. felis infection alters gastric histopathology, proinflammatory cytokine
      expression, and secretory function and evokes a humoral immune response in cats.
      Five specific-pathogen-free (SPF) Helicobacter-free cats were studied before and
      for 1 year after oral inoculation with H. felis (ATCC 49179). Four SPF H. felis
      uninfected cats served as controls. The stomachs of all five H. felis-inoculated
      cats became colonized, as determined by urease activity, histopathology, PCR,
      culture, and transmission electron microscopy of serial gastric biopsies at 0, 3,
      5, 8, and 12 months. Uninoculated cats remained Helicobacter free. Lymphoid
      follicular hyperplasia, atrophy, and fibrosis were observed primarily in the
      pylorus of infected cats. Mild mononuclear inflammation was detected in both
      infected and uninfected cats, but was more extensive in infected cats, with
      pangastric inflammation, eosinophilic infiltrates, and cardia gastritis observed
      only in infected cats. No upregulation of antral mucosal interleukin 1alpha (IL
      1alpha), IL-1beta, or tumor necrosis factor alpha was detected by reverse
      transcription-PCR in any cat. The gastric secretory axes, assessed by fasting
      plasma gastrin, antral mucosal gastrin and somatostatin immunoreactivity, and
      pentagastrin-stimulated gastric acid secretion, were similar in both infected and
      uninfected cats. Gradual seroconversion (immunoglobulin G) was observed in four
      of five infected cats, with enzyme-linked immunosorbent assay values reaching 4x
      to 12x baseline 12 months postinfection. These findings indicate that H. felis
      infection in cats induces lymphoid follicular hyperplasia, mild gastritis, and
      seroconversion, but is associated with normal gastric secretory function.

PMID- 10639447
TI  - ESAT-6 subunit vaccination against Mycobacterium tuberculosis.
AB  - The ESAT-6 antigen from Mycobacterium tuberculosis is a dominant target for cell
      mediated immunity in the early phase of tuberculosis (TB) in TB patients as well
      as in various animal models. The purpose of our study was to evaluate the
      potential of ESAT-6 in an experimental TB vaccine. We started out using dimethyl
      dioctadecylammonium bromide (DDA), an adjuvant which has been demonstrated to be
      efficient for the induction of cellular immune responses and has been used
      successfully before as a delivery system for TB vaccines. Here we demonstrate
      that, whereas immune responses to both short-term-culture filtrate and Ag85B are
      efficiently induced with DDA, this adjuvant was inefficient for the induction of
      immune responses to ESAT-6. Therefore, we investigated the modulatory effect of
      monophosphoryl lipid A (MPL), an immunomodulator which in different combinations
      has demonstrated strong adjuvant activity for both cellular and humoral immune
      responses. We show in the present study that vaccination with ESAT-6 delivered in
      a combination of MPL and DDA elicited a strong ESAT-6-specific T-cell response
      and protective immunity comparable to that achieved with Mycobacterium bovis BCG.

PMID- 10639448
TI  - Intranasal immunization of mice with a mixture of the pneumococcal proteins PsaA
      and PspA is highly protective against nasopharyngeal carriage of Streptococcus
      pneumoniae.
AB  - Acquisition of pneumococci is generally from carriers rather than from infected
      individuals. Therefore, to induce herd immunity against Streptococcus pneumoniae
      it will be necessary to elicit protection against carriage. Capsular
      polysaccharide-protein conjugates, PspA, and PsaA are known to elicit some
      protection against nasopharyngeal carriage of pneumococci but do not always
      completely eliminate carriage. In this study, we observed that PsaA elicited
      better protection than did PspA against carriage. Pneumolysin elicited no
      protection against carriage. Immunization with a mixture of PsaA and PspA
      elicited the best protection against carriage. These results indicate that PspA
      and PsaA may be useful for the elicitation of herd immunity in humans. As PspA
      and pneumolysin are known to elicit immunity to bacteremia and pneumonia, their
      inclusion in a mucosal vaccine may enable such a vaccine to prevent invasive
      disease as well as carriage.

PMID- 10639449
TI  - Alkyl hydroperoxide reductases C and D are major antigens constitutively
      expressed by Mycobacterium avium subsp. paratuberculosis.
AB  - Antigens characteristic for Mycobacterium avium subspecies paratuberculosis were
      identified by crossed immunoelectrophoresis (CIE) and by absorbing out cross
      reactive antigens by using a polyclonal and polyvalent Mycobacterium avium
      subspecies avium antiserum. Two antigens were present in M. avium subsp.
      paratuberculosis and not detected in Mycobacterium avium subsp. avium. They were
      identified as antigens 17 and 20 in a CIE reference system for M. avium subsp.
      paratuberculosis antigens. Purified antigen 20 was identified as alkyl
      hydroperoxide reductase C (AhpC) while the N-terminal part of purified antigen 17
      showed 80% homology with alkyl hydroperoxide reductase D (AhpD) of Mycobacterium
      tuberculosis. AhpC had a nonreduced mobility in sodium dodecyl sulfate
      polyacrylamide gel electrophoresis corresponding to a molecular mass of 45 kDa
      and is probably a homodimer linked with disulfide bridges in its native form.
      AhpD had a mobility corresponding to 19 kDa. Monospecific rabbit antiserum
      against AhpC and AhpD reacted with 9 strains of M. avium subsp. paratuberculosis
      but not with 20 other mycobacterial strains except for a Mycobacterium gordonae
      strain, against which a weak cross-reactive band was produced. Goats
      experimentally infected with M. avium subsp. paratuberculosis had strong gamma
      interferon (IFN-gamma) responses toward both AhpC and AhpD, and they also had
      antibodies against AhpC. The ability of AhpC and AhpD to induce IFN-gamma
      production shows that these proteins potentially could be used in future vaccines
      or in diagnostic assays. These results further show that AhpC and AhpD are
      immunologically important proteins which are constitutively and highly expressed
      in M. avium subsp. paratuberculosis without the bacteria being submitted to
      oxidative stress and that the specificities of antigens can be a matter of
      different levels of protein expression in various species as well as distinct
      structural differences.

PMID- 10639450
TI  - Priming of a beta-galactosidase (beta-GAL)-specific type 1 response in BALB/c
      mice infected with beta-GAL-transfected Leishmania major.
AB  - To determine whether an ongoing response to Leishmania major would affect the
      response to a non-cross-reacting, non-leishmanial antigen, susceptible BALB/c
      mice and resistant C3H mice were infected with L. major parasites expressing
      Escherichia coli beta-galactosidase (beta-GAL); this parasite was designated L.
      major-betaGAL. BALB/c and C3H mice responded to infection with L. major-betaGAL
      by mounting a CD4 T-cell response to both parasite antigens and to the reporter
      antigen, beta-GAL. The phenotypes of these T cells were characterized after
      generating T-cell lines from infected mice. As expected, BALB/c mice responded to
      infection with L. major-betaGAL by producing interleukin 4 in response to the
      parasite and C3H mice produced gamma interferon (IFN-gamma) in response to the
      parasite and beta-GAL. Interestingly, however, BALB/c mice produced IFN-gamma in
      response to beta-GAL. Taken together, these results demonstrate that priming of
      IFN-gamma-producing cells can occur in BALB/c mice despite the fact the animals
      are simultaneously mounting a potent Th2 response to L. major.

PMID- 10639451
TI  - Analysis of a gene cluster of Enterococcus faecalis involved in polysaccharide
      biosynthesis.
AB  - Previously, we described a gene cluster of Enterococcus faecalis OG1RF that
      produced an antigenic polysaccharide when cloned in Escherichia coli. The
      polysaccharide antigen was not detectable in E. faecalis strains, however. Here,
      we show by reverse transcriptase-PCR that the 16 genes in this region are
      transcribed in OG1RF. Gene disruption of orfde4, encoding a putative glycosyl
      transferase, and orfde6, a putative dTDP-rhamnose biosynthesis gene, generated
      two OG1RF mutants. The mutants showed delayed killing and a higher 50% lethal
      dose in a mouse peritonitis model. In addition, two mucoid E. faecalis isolates
      from patients with chronic urinary tract infections were found to produce the
      polysaccharide antigen.

PMID- 10639452
TI  - The tprK gene is heterogeneous among Treponema pallidum strains and has multiple
      alleles.
AB  - We have previously shown that the TprK antigen of T. pallidum, Nichols strain, is
      predominantly expressed in treponemes obtained 10 days after infection and that
      the hydrophilic domain of TprK is a target of opsonic antibodies and confers
      significant protection against homologous challenge. The T. pallidum genome
      sequence reported the presence of a single copy of the tprK gene in the Nichols
      strain. In the present study we demonstrate size heterogeneity in the central
      portions of the TprK hydrophilic domains of 14 treponemal isolates. Sequence
      analysis of the central domains and the complete open reading frames (ORFs) of
      the tprK genes confirms this heterogeneity. Further, multiple tprK sequences were
      found in the Nichols-defined tprK locus in three isolates (Sea 81-4, Bal 7, and
      Bal 73-1). In contrast, only a single tprK sequence could be identified in this
      locus in the Nichols strain. Alignment of the DNA and deduced amino acid
      sequences of the whole tprK ORFs shows the presence of seven discrete variable
      domains flanked by highly conserved regions. We hypothesize that these
      heterogeneous regions may be involved in antigenic heterogeneity and, in
      particular, evasion of the immune response. The presence of different tprK
      alleles in the tprK locus strongly suggests the existence of genetically
      different subpopulations within treponemal isolates.

PMID- 10639453
TI  - Persistent Cryptococcus neoformans pulmonary infection in the rat is associated
      with intracellular parasitism, decreased inducible nitric oxide synthase
      expression, and altered antibody responsiveness to cryptococcal polysaccharide.
AB  - Fungal pathogens are notorious for causing chronic and latent infections, but the
      mechanism by which they evade the immune response is poorly understood. A major
      limitation in the study of chronic fungal infection has been the lack of suitable
      animal models where the infection is controlled and yet persists. Pulmonary
      Cryptococcus neoformans infection in rats results in a diffuse pneumonitis that
      resolves without dissemination or scarring except for the persistence of
      interstitial and subpleural granulomas that harbor viable cryptococci inside
      macrophages and epithelioid cells. Infected rats are asymptomatic but remain
      infected for as long as 18 months after inoculation with C. neoformans.
      Containment of infection is associated with granuloma formation that can be
      partially abrogated by glucocorticoid administration. Using this model, we
      identified several features associated with persistent infection in the rat lung,
      including (i) localization of C. neoformans to discrete, well-organized
      granulomas; (ii) intracellular persistence of C. neoformans within macrophages
      and epithelioid cells; (iii) reduced inducible nitric oxide synthase expression
      by granulomas harboring C. neoformans; and (iv) reduced antibody responses to
      cryptococcal polysaccharide. The results show that maintenance of persistent
      infection is associated with downregulation of both cellular and humoral immune
      responses.

PMID- 10639454
TI  - Lack of a role of cytotoxic necrotizing factor 1 toxin from Escherichia coli in
      bacterial pathogenicity and host cytokine response in infected germfree piglets.
AB  - Some Escherichia coli strains isolated from intestinal or extraintestinal
      infections in pigs produce cytotoxic necrotizing factor 1 (CNF1). In order to
      analyze the role of CNF1 in the pathogenesis of porcine colibacillosis, newborn
      colostrum-deprived germfree piglets were orally inoculated with a wild-type CNF1
      producing strain (M623) or with an isogenic cnf1 mutant (M623DeltaCNF1). The two
      isogenic strains induced a high mortality with similar lung and serosal
      inflammatory lesions, indicating that both strains were pathogenic in these
      piglets. Bacterial counts in various organs of inoculated piglets revealed an
      intestinal predisposition of M623 and M623DeltaCNF1 strains for the cecum and
      colon. Extraintestinal organs (lungs, liver, spleen, and kidney) were also
      colonized by both strains. Similar colonization of intestinal and extraintestinal
      tissues in animals inoculated with either strain was observed, except in the
      ileum, where M623 showed a higher colonization than M623DeltaCNF1. Intestinal
      (ileum and colon), extraintestinal (lung and kidney), and immune (mesenteric
      lymph nodes and spleen) tissues were sampled at 1 day postinoculation and
      analyzed for cytokine expression by a reverse transcriptase PCR technique.
      Inoculation with E. coli M623 induced an enhanced expression of inflammatory
      cytokines (interleukin-1alpha [IL-1alpha], tumor necrosis factor alpha, and IL
      12p40) in the intestinal organs compared to uninoculated piglets or piglets
      inoculated with nonpathogenic intestinal E. coli 862B, which is also able to
      colonize the intestinal tract. There was little difference in cytokine transcript
      levels in the intestinal and extraintestinal organs in piglets inoculated with E.
      coli strains M623 or M623DeltaCNF1, except in the ileum, where IL-1alpha and IL-8
      mRNA levels correlated with bacterial colonization. Expression of regulatory
      cytokines (gamma interferon and IL-4) was weak in immune tissues from piglets
      inoculated with M623 or M623DeltaCNF1. Taken together, our data indicate that the
      CNF1-producing strain, M623, is pathogenic and induces inflammatory cytokine
      expression in germfree, colostrum-deprived piglets. Nevertheless, in this model,
      the CNF1 toxin does not appear to be a major factor for pathogenicity or cytokine
      response, as demonstrated by the use of an isogenic cnf1 mutant.

PMID- 10639455
TI  - Comparative analysis of antibody responses against HSP60, invariant surface
      glycoprotein 70, and variant surface glycoprotein reveals a complex antigen
      specific pattern of immunoglobulin isotype switching during infection by
      Trypanosoma brucei.
AB  - During Trypanosoma brucei infections, the response against the variant surface
      glycoprotein (VSG) of the parasite represents a major interaction between the
      mammalian host immune system and the parasite surface. Since immune recognition
      of other parasite derived factors also occurs, we examined the humoral host
      response against trypanosome heat shock protein 60 (HSP60), a conserved antigen
      with an autoimmune character. During experimental T. brucei infection in BALB/c
      mice, the anti-HSP60 response was induced when parasites differentiated into
      stumpy forms. This response was characterized by a stage-specific immunoglobulin
      isotype switching as well as by the induction of an autoimmune response. Specific
      recognition of trypanosome HSP60 was found to occur during the entire course of
      infection. Immunoglobulin G2a (IgG2a) and IgG2b antibodies, induced mainly in a T
      cell-independent manner, were observed during the first peak of parasitemia,
      whereas IgG1 and IgG3 antibodies were found at the end of the infection, due to a
      specific T-cell-mediated response. Comparative analysis of the kinetics of anti
      HSP60, anti-invariant surface glycoprotein 70 (ISG70), and anti-VSG antibody
      responses indicated that the three trypanosome antigens give rise to specific and
      independent patterns of immunoglobulin isotype switching.

PMID- 10639456
TI  - Impact of heterogeneity within cultured cells on bacterial invasion: analysis of
      Pseudomonas aeruginosa and Salmonella enterica serovar typhi entry into MDCK
      cells by using a green fluorescent protein-labelled cystic fibrosis transmembrane
      conductance regulator receptor.
AB  - The cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride ion
      channel that also serves as a receptor for entry of Pseudomonas aeruginosa and
      Salmonella enterica serovar Typhi into epithelial cells. To evaluate
      heterogeneity in CFTR protein expression in cultured cells and the effect of
      heterogeneity on internalization of different P. aeruginosa and serovar Typhi
      strains, we used two-color flow cytometry and confocal laser microscopy to study
      bacterial uptake by Madin-Darby canine kidney (MDCK) type I epithelial cells
      stably expressing a green fluorescent protein (GFP)-CFTR fusion construct (MDCK
      GFP-CFTR cells). We found a strong correlation between cell size and GFP-CFTR
      protein expression, with 60 to 70% of cells expressing low levels of GFP-CFTR
      protein, 20 to 30% expressing intermediate levels, and <10% expressing high
      levels. The cells were sorted into low-, intermediate-, or high-level producers
      of CFTR protein; in vitro growth of each sorted population yielded the same
      distribution of CFTR protein expression as that in the original population. Cells
      expressing either low or high levels of CFTR protein internalized bacteria
      poorly; maximal bacterial uptake occurred in the cells expressing intermediate
      levels of CFTR protein. Treatment of MDCK cells with sodium butyrate markedly
      enhanced the production of CFTR protein without increasing cell size; butyrate
      treatment also increased the proportion of cells with internalized bacteria.
      However, there were fewer bacteria per butyrate-treated cell and, for P.
      aeruginosa, there was an overall decrease in the total level of bacterial uptake.
      The most highly ingested bacterial strains were internalized by fewer total MDCK
      GFP-CFTR cells, indicating preferential bacterial uptake by a minority of
      epithelial cells within a given culture. Confocal fluorescence microscopy showed
      that P. aeruginosa and serovar Typhi induced cytoplasmic accumulation of CFTR
      protein close to the plasma membrane where the bacteria were adherent. These
      results show that within a population of MDCK-GFP-CFTR cells, there are cells
      with markedly different abilities to ingest bacteria via CFTR, the majority of
      the P. aeruginosa and serovar Typhi cells are ingested by the one-fourth to one
      third of the cells that exhibit an intermediate size and level of CFTR protein
      expression, and overexpression of the CFTR receptor does not increase total
      bacterial uptake but rather allows more epithelial cells to ingest fewer total
      bacteria.

PMID- 10639457
TI  - GAA trinucleotide repeat region regulates M9/pMGA gene expression in Mycoplasma
      gallisepticum.
AB  - Mycoplasma gallisepticum, the cause of chronic respiratory infections in the
      avian host, possesses a family of M9/pMGA genes encoding an adhesin(s) associated
      with hemagglutination. Nucleotide sequences of M9/pMGA gene family members
      indicate extensive sequence similarity in the promoter regions of both the
      transcribed and silent genes. The mechanism that regulates M9/pMGA gene
      expression is unknown, but studies have revealed an apparent correlation between
      gene expression and the number of tandem GAA repeat motifs located upstream of
      the putative promoter. In this study, transposon Tn4001 was used as a vector with
      the Escherichia coli lacZ gene as the reporter system to examine the role of the
      GAA repeats in M9/pMGA gene expression in M. gallisepticum. A 336-bp M9 gene
      fragment (containing the GAA repeat region, the promoter, and the translation
      start codon) was amplified by PCR, ligated with a lacZ gene from E. coli, and
      inserted into the Tn4001-containing plasmid pISM2062. This construct was
      transformed into M. gallisepticum PG31. Transformants were filter cloned on agar
      supplemented with 5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside (X-Gal) to
      monitor lacZ gene expression on the basis of blue/white color selection. Several
      cycles of filter cloning resulted in cell lineages in which lacZ gene expression
      alternated between the On and Off states in successive generations of progeny
      clones. The promoter regions of the M9-lacZ hybrid genes of individual progeny
      clones were amplified by PCR and sequenced. The only differences between the
      promoter regions of the blue and white colonies were in the number of GAA
      repeats. Clones that expressed lacZ had exactly 12 tandem copies of the GAA
      repeat. Clones that did not express lacZ invariably had either more than 12 (14
      to 16) or fewer than 12 (5 to 11) GAA repeats. Southern analysis of M.
      gallisepticum chromosomal DNA confirmed that the phase-variable expression of the
      lacZ reporter gene was not caused by Tn4001 transposition. These data strongly
      indicate that changes in the length of the GAA repeat region are responsible for
      regulating M9/pMGA gene expression.

PMID- 10639458
TI  - A Mycobacterium ulcerans toxin, mycolactone, causes apoptosis in guinea pig
      ulcers and tissue culture cells.
AB  - Mycobacterium ulcerans is the causative agent of Buruli ulcer, a tropical
      ulcerative skin disease. One of the most intriguing aspects of this disease is
      the presence of extensive tissue damage in the absence of an acute inflammatory
      response. We recently purified and characterized a macrolide toxin, mycolactone,
      from M. ulcerans. Injection of this molecule into guinea pig skin reproduced cell
      death and lack of acute inflammatory response similar to that seen following the
      injection of viable bacteria. We also showed that mycolactone causes a cytopathic
      effect on mouse fibroblast L929 cells that is characterized by cytoskeletal
      rearrangements and growth arrest within 48 h. However, these results could not
      account for the extensive cell death which occurs in Buruli ulcer. The results
      presented here demonstrate that L929 and J774 mouse macrophage cells die via
      apoptosis after 3 to 5 days of exposure to mycolactone. Treatment of cells with a
      pan-caspase inhibitor can inhibit mycolactone-induced apoptosis. We demonstrate
      that injection of mycolactone into guinea pig skin results in cell death via
      apoptosis and that the extent of apoptosis increases as the lesion progresses.
      These results may help to explain why tissue damage in Buruli ulcer is not
      accompanied by an acute inflammatory response.

PMID- 10639459
TI  - Phenotypic switching in Candida glabrata involves phase-specific regulation of
      the metallothionein gene MT-II and the newly discovered hemolysin gene HLP.
AB  - Although Candida glabrata has emerged in recent years as a major fungal pathogen,
      there have been no reports demonstrating that it undergoes either the bud-hypha
      transition or high-frequency phenotypic switching, two developmental programs
      believed to contribute to the pathogenic success of other Candida species. Here
      it is demonstrated that C. glabrata undergoes reversible, high-frequency
      phenotypic switching between a white (Wh), light brown (LB), and dark brown (DB)
      colony phenotype discriminated on an indicator agar containing 1 mM CuSO(4).
      Switching regulates the transcript level of the MT-II metallothionein gene(s) and
      a newly discovered gene for a hemolysin-like protein, HLP. The relative MT-II
      transcript levels in Wh, LB, and DB cells grown in the presence of CuSO(4) are
      1:27:81, and the relative transcript levels of HLP are 1:20:35. The relative MT
      II and HLP transcript levels in cells grown in the absence of CuSO(4) are 1:20:30
      and 1:20:25, respectively. In contrast, switching has little or no effect on the
      transcript levels of the genes MT-I, AMT-I, TRPI, HIS3, EPAI, and PDHI. Switching
      of C. glabrata is not associated with microevolutionary changes identified by the
      DNA fingerprinting probe Cg6 and does not involve tandem amplification of the MT
      IIa gene, which has been shown to occur in response to elevated levels of copper.
      Finally, switching between Wh, LB, and DB occurred in all four clinical isolates
      examined in this study. As in Candida albicans, switching in C. glabrata may
      provide colonizing populations with phenotypic plasticity for rapid responses to
      the changing physiology of the host, antibiotic treatment, and the immune
      response, through the differential regulation of genes involved in pathogenesis.
      More importantly, because C. glabrata is haploid, a mutational analysis of
      switching is now feasible.

PMID- 10639461
TI  - Effects of the immunoglobulin A1 protease on Neisseria gonorrhoeae trafficking
      across polarized T84 epithelial monolayers.
AB  - We previously demonstrated that the Neisseria IgA1 protease cleaves LAMP1
      (lysosome-associated membrane protein 1), a major integral membrane glycoprotein
      of lysosomes, thereby accelerating its degradation rate in infected A431 human
      epidermoid carcinoma cells and resulting in the alteration of lysosomes in these
      cells. In this study, we determined whether the IgA1 protease also affects the
      trafficking of Neisseria gonorrhoeae across polarized T84 epithelial monolayers.
      We report that N. gonorrhoeae infection of T84 monolayers, grown on a solid
      substrate or polarized on semiporous membranes, also results in IgA1 protease
      mediated reduction of LAMP1. We demonstrate that iga mutants in two genetic
      backgrounds exited polarized T84 monolayers in fewer numbers than the
      corresponding wild-type strains. Finally, we present evidence that these mutants
      have a statistically significant and reproducible defect in their ability to
      traverse T84 monolayers. These results add to our previous data by showing that
      the IgA1 protease alters lysosomal content in polarized as well as unpolarized
      cells and by demonstrating a role for the protease in the traversal of epithelial
      barriers by N. gonorrhoeae.

PMID- 10639460
TI  - Isolation of Neisseria gonorrhoeae mutants that show enhanced trafficking across
      polarized T84 epithelial monolayers.
AB  - Initiation of a gonococcal infection involves attachment of Neisseria gonorrhoeae
      to the plasma membrane of an epithelial cell in the mucosal epithelium and its
      internalization, transepithelial trafficking, and exocytosis from the basal
      membrane. Piliation and expression of certain Opa proteins and the immunoglobulin
      A1 protease influence the transcytosis process. We are interested in identifying
      other genetic determinants of N. gonorrhoeae that play a role in transcellular
      trafficking. Using polarized T84 monolayers as a model epithelial barrier, we
      have assayed an N. gonorrhoeae FA1090 minitransposon (mTn) mutant bank for
      isolates that traverse the monolayer more quickly than the isogenic wild-type
      (WT) strain. From an initial screen, we isolated four mutants, defining three
      genetic loci, that traverse monolayers significantly more quickly than their WT
      parent strain. These mutants adhere to and invade cells normally and do not
      affect the integrity of the monolayer barrier. Backcrosses of the mutations into
      the WT FA1090 strain yielded mutants with a similar fast-trafficking phenotype.
      In two mutants, the mTns had inserted 370 bp apart into the same locus, which we
      have named fit, for fast intracellular trafficker. Backcrosses of one of these
      mutants into the MS11A genetic background also yielded a fast-trafficking mutant.
      The fit locus contains two overlapping open reading frames, fitA and fitB, whose
      deduced amino acid sequences have predicted molecular weights of 8.6 and 15.3,
      respectively. Neither protein contains a signal sequence. FitA has a potential
      helix-turn-helix motif, while the deduced sequence of FitB offers no clues to its
      function. fitA or fitB homologues are present in the genomes of Pseudomonas
      syringae and Rhizobium meliloti, but not Neisseria meningitidis. Replication of
      the MS11A fitA mutant in A431 and T84 cells is significantly accelerated compared
      to that of the isogenic WT strain. In contrast, growth of this mutant in liquid
      media is normal. Taken together, these results strongly suggest that traversal of
      N. gonorrhoeae across an epithelial barrier is linked to intracellular bacterial
      growth.

PMID- 10639462
TI  - Mutants of Listeria monocytogenes defective in In vitro invasion and cell-to-cell
      spreading still invade and proliferate in hepatocytes of neutropenic mice.
AB  - Listeria monocytogenes mutants defective in the actA gene, the plcB gene, and the
      inlA and inlB genes were less virulent when injected intravenously into BALB/c
      mice. The growth of these strains as well as of the virulent wild-type strains
      was increased by treating mice with a neutrophil-specific depleting monoclonal
      antibody, RB6-8C5. Histologic examination of the livers of the treated animals
      showed intrahepatocytic proliferation of the listeriae in all cases. Our data
      show that more than one pathway exists that allows L. monocytogenes to invade
      parenchymal cells. One pathway most likely involves the actA and plcB gene
      products, and a second one probably involves the internalins.

PMID- 10639464
TI  - Evaluation of the virulence of a Streptococcus pneumoniae neuraminidase-deficient
      mutant in nasopharyngeal colonization and development of otitis media in the
      chinchilla model.
AB  - Considerable evidence has implicated Streptococcus pneumoniae neuraminidase in
      the pathogenesis of otitis media (OM); however, its exact role has not been
      conclusively established. Recently, an S. pneumoniae neuraminidase-deficient
      mutant, DeltaNA1, has been constructed by insertion-duplication mutagenesis of
      the nanA gene of S. pneumoniae strain D39. The relative ability of DeltaNA1 and
      the D39 parent strain to colonize the nasopharynx and to induce OM subsequent to
      intranasal inoculation and to survive in the middle ear cleft after direct
      challenge of the middle ear were evaluated in the chinchilla model.
      Nasopharyngeal colonization data indicate a significant difference in the ability
      of the DeltaNA1 mutant to colonize as well as to persist in the nasopharynx. The
      neuraminidase-deficient mutant was eliminated from the nasopharynx 2 weeks
      earlier than the D39 parent strain. Both the parent and the mutant exhibited
      similar virulence levels and kinetics during the first week after direct
      inoculation of the middle ear. The DeltaNA1 neuraminidase-deficient mutant,
      however, was then completely eliminated from the middle ear by day 10
      postchallenge, 11 days before the D39 parent strain. Data from this study
      indicate that products of the nanA gene have an impact on the ability of S.
      pneumoniae to colonize and persist in the nasopharynx as well as the middle ear.

PMID- 10639463
TI  - Identification of immunodominant antigens from Helicobacter pylori and evaluation
      of their reactivities with sera from patients with different gastroduodenal
      pathologies.
AB  - Colonization of the gastric mucosa by Helicobacter pylori is the major cause of
      gastroduodenal pathologies in humans. Studying the outcome of the humoral immune
      response directed against this gastric pathogen may contribute substantially to
      vaccine development and to the improvement of diagnostic techniques based on
      serology. By using two-dimensional gel electrophoresis, 29 proteins from H.
      pylori G27 were identified which strongly react with sera derived from H. pylori
      infected patients suffering from different gastroduodenal pathologies. These
      antigens were characterized by mass spectrometry and proved to correspond to
      products of open reading frames predicted by the H. pylori genome sequence. The
      comparison of the antigenic patterns recognized by these sera revealed no
      association of specific H. pylori antigens with antibodies in patients with
      particular gastroduodenal pathologies.

PMID- 10639466
TI  - Functional conservation of the polysaccharide biosynthetic protein WbpM and its
      homologues in Pseudomonas aeruginosa and other medically significant bacteria.
AB  - WbpM is a highly conserved protein involved in synthesis of the O antigens of
      Pseudomonas aeruginosa. Homologues of this protein have been identified in a
      large number of bacteria, and they can be divided into two subfamilies: subfamily
      1, including WbpM, contains large proteins ( approximately 600 amino acids),
      while subfamily 2, typified by HP0840 (FlaA1) of Helicobacter pylori, contains
      smaller proteins ( approximately 350 amino acids) homologous to the C termini of
      proteins in subfamily 1. Analysis of knockout mutants of wbpM in P. aeruginosa
      serotypes O3, O10, O15, and O17 showed that although all 20 serotypes of P.
      aeruginosa possess wbpM, it is not universally required for O-antigen
      biosynthesis. Homologous genes from Bordetella pertussis (wlbL), Staphylococcus
      aureus (cap8D), and H. pylori (flaA1) complemented a P. aeruginosa O5 wbpM mutant
      to various degrees. These conserved proteins may represent interesting targets
      for the design of inhibitors of bacterial exopolysaccharide biosynthesis.

PMID- 10639465
TI  - Identification of the operon for the sorbitol (Glucitol)
      Phosphoenolpyruvate:Sugar phosphotransferase system in Streptococcus mutans.
AB  - Transposon mutagenesis and marker rescue were used to isolate and identify an 8.5
      kb contiguous region containing six open reading frames constituting the operon
      for the sorbitol P-enolpyruvate phosphotransferase transport system (PTS) of
      Streptococcus mutans LT11. The first gene, srlD, codes for sorbitol-6-phosphate
      dehydrogenase, followed downstream by srlR, coding for a transcriptional
      regulator; srlM, coding for a putative activator; and the srlA, srlE, and srlB
      genes, coding for the EIIC, EIIBC, and EIIA components of the sorbitol PTS,
      respectively. Among all sorbitol PTS operons characterized to date, the srlD gene
      is found after the genes coding for the EII components; thus, the location of the
      gene in S. mutans is unique. The SrlR protein is similar to several
      transcriptional regulators found in Bacillus spp. that contain PTS regulator
      domains (J. Stulke, M. Arnaud, G. Rapoport, and I. Martin-Verstraete, Mol.
      Microbiol. 28:865-874, 1998), and its gene overlaps the srlM gene by 1 bp. The
      arrangement of these two regulatory genes is unique, having not been reported for
      other bacteria.

PMID- 10639467
TI  - Relationship of blood group determinants on Helicobacter pylori
      lipopolysaccharide with host lewis phenotype and inflammatory response.
AB  - As Lewis a (Le(a)) and Lewis b (Le(b)) blood group antigens are isoforms of Lewis
      x (Le(x)) and Lewis y (Le(y)) and are expressed in the gastric mucosa, we
      evaluated whether the patterns of expression of Le(x) and Le(y) on Helicobacter
      pylori lipopolysaccharides reflected those of host expression of Le(a) and Le(b).
      When 79 patients (secretors and nonsecretors) were examined for concordance
      between bacterial and host Le expression, no association was found (chi(2) =
      5.734, 3 df, P = 0.125), nor was there a significant difference between the
      amount of Le(x) or Le(y) expressed on isolates from ulcer and chronic gastritis
      patients (P > 0.05). Also, the effect of host and bacterial expression of Le
      antigens on bacterial colonization and the observed inflammatory response was
      assessed. In ulcer patients, Le(x) expression was significantly related to
      neutrophil infiltration (r(s) = 0.481, P = 0.024), whereas in chronic gastritis
      patients significant relationships were found between Le(x) expression and H.
      pylori colonization density (r(s) = 0.296, P = 0.03), neutrophil infiltrate (r(s)
      = 0.409, P = 0. 001), and lymphocyte infiltrate (r(s) = 0.389, P = 0.002).
      Furthermore, bacterial Le(y) expression was related to neutrophil (r(s) = 0.271,
      P = 0.033) and lymphocyte (r(s) = 0.277, P = 0.029) infiltrates. Thus, although
      no evidence of concordance was found between bacterial and host expression of Le
      determinants, these antigens may be crucial for bacterial colonization, and the
      ensuing inflammatory response appears, at least in part, to be influenced by Le
      antigens.

PMID- 10639468
TI  - Construction of urease-negative mutants of Yersinia enterocolitica serotypes O:3
      and o:8: role of urease in virulence and arthritogenicity.
AB  - Yersinia enterocolitica serotype O:3 and O:8 urease-negative mutants unable to
      express the 19-kDa beta subunit of urease were constructed and tested for
      virulence and arthritogenicity. Our results indicate that urease is needed for
      full virulence in oral infections and that it is not an arthritogenic factor in
      the rat model.

PMID- 10639469
TI  - Molecular characterization of a new variant of toxin-coregulated pilus protein
      (TcpA) in a toxigenic non-O1/Non-O139 strain of Vibrio cholerae.
AB  - A toxigenic non-O1/non-O139 strain of Vibrio cholerae (10259) was found to
      contain a new variant of the toxin-coregulated pilus (TCP) protein gene (tcpA) as
      determined by PCR and Southern hybridization experiments. Nucleotide sequence
      analysis data of the new tcpA gene in strain 10259 (O53) showed it to be about 74
      and 72% identical to those of O1 classical and El Tor biotype strains,
      respectively. The predicted amino acid sequence of the 10259 TcpA protein shared
      about 81 and 78% identity with the corresponding sequences of classical and El
      Tor TcpA strains, respectively. An antiserum raised against the TCP of a
      classical strain, O395, although it recognized the TcpA protein of strain 10259
      in an immunoblotting experiment, exhibited considerably less protection against
      10259 challenge compared to that observed against the parent strain.
      Incidentally, the tcpA sequences of two other toxigenic non-O1/non-O139 strains
      (V2 and S7, both belonging to the serogroup O37) were determined to be almost
      identical to that of classical tcpA. Further, tcpA of another toxigenic non
      O1/non-O139 strain V315-1 (O nontypeable) was closely related to that of El Tor
      tcpA. Analysis of these results with those already available in the literature
      suggests that there are at least four major variants of the tcpA gene in V.
      cholerae which probably evolved in parallel from a common ancestral gene.
      Existence of highly conserved as well as hypervariable regions within the
      sequence of the TcpA protein would also predict that such evolution is under the
      control of considerable selection pressure.

PMID- 10639470
TI  - Capsular polysaccharide is a major complement resistance factor in
      lipopolysaccharide O side chain-deficient Klebsiella pneumoniae clinical
      isolates.
AB  - We have previously demonstrated the existence of Klebsiella pneumoniae clinical
      isolates deficient in the lipopolysaccharide O side chain, the major factor for
      resistance to complement-mediated killing in this bacterial species. These
      isolates are complement resistant, and their mechanisms to resist complement were
      investigated by selecting transposon-generated complement-sensitive mutants. One
      mutant with a drastically reduced capacity to grow in nonimmune human serum
      carried the transposon inserted in an open reading frame of a gene cluster
      involved in capsule synthesis. This mutant produced less capsule, bound more
      molecules of the complement component C3, and was more sensitive to complement
      mediated and opsonophagocytic killings than was the parent strain. Four
      additional clinical isolates representing four different K serotypes were
      studied, and results showed that capsular polysaccharide is a major complement
      resistance factor in these O side chain-deficient isolates.

PMID- 10639471
TI  - Phagocytosed Bordetella pertussis fails to survive in human neutrophils.
AB  - Previous studies have reported that phagocytosed Bordetella pertussis survives in
      human neutrophils. This issue has been reexamined. Opsonized or unopsonized
      bacteria expressing green fluorescent protein (GFP) were incubated with adherent
      human neutrophils. Phagocytosis was quantified by fluorescence microscopy, and
      the viability of phagocytosed bacteria was determined by colony counts following
      treatment with polymyxin B to kill extracellular bacteria. Only 1 to 2% of the
      phagocytosed bacteria remained viable. Opsonization with heat-inactivated immune
      serum reduced the amount of attachment and phagocytosis of the bacteria but did
      not alter survival rates. In contrast to previous reports, these data suggest
      that phagocytosed B. pertussis bacteria are killed by human neutrophils.

PMID- 10639472
TI  - Acquired immunity to Chlamydia pneumoniae is dependent on gamma interferon in two
      mouse strains that initially differ in this respect after primary challenge.
AB  - The role of gamma interferon (IFN-gamma) in a Chlamydia pneumoniae mouse model
      was studied by in vivo neutralization in two inbred mouse strains. During primary
      C. pneumoniae infection, neutralization of IFN-gamma increased both the numbers
      of bacteria and the pneumonia score in the lungs of C57BL/6 mice but not BALB/c
      mice. During reinfection, the bacterial counts in the lungs were increased by IFN
      gamma neutralization in both mouse strains. Thus, the effect of IFN-gamma
      neutralization was dependent on the genetic background in primary infection.
      However, IFN-gamma appeared to be equally important in both mouse strains during
      reinfection.

PMID- 10639473
TI  - Candida albicans-derived beta-1,2-linked mannooligosaccharides induce
      desensitization of macrophages.
AB  - Candida albicans beta-1,2-oligomannosides stimulate macrophage tumor necrosis
      factor alpha (TNF-alpha) but not NO release. This stimulation desensitized
      macrophages by altering beta-1, 2-oligomannoside-dependent TNF-alpha production
      and lipopolysaccharide-dependent TNF-alpha and NO secretion. Desensitization was
      not related to tyrosine phosphorylation signal transduction but was transferred
      by culture supernatants in which arachidonic acid derivatives were evidenced.

PMID- 10639474
TI  - Intranasal immunization with Toxoplasma gondii SAG1 induces protective cells into
      both NALT and GALT compartments.
AB  - Intranasal (i.n.) immunization with the SAG1 protein of Toxoplasma gondii plus
      cholera toxin (CT) provides protective immunity. The aim of this study was to
      analyze the cellular activation of several mucosal compartments after i.n.
      immunization. Cervical and mesenteric lymph node (CLN and MLN, respectively)
      lymphoid cell and intraepithelial lymphocyte (IEL) passive transfer experiments
      were performed with CBA/J mice immunized i.n. with SAG1 plus CT. CLN and MLN
      cells and IEL isolated 42 days after immunization conferred protective immunity
      on naive recipient mice challenged with strain 76K T. gondii, as assessed by the
      reduction in the number of brain cysts. There were proliferative specific
      responses in nose-associated lymphoid tissue and the CLN and MLN cells from mice
      immunized with SAG1 plus CT, but no cytokine was detectable. Thus, protective
      immunity is associated with a specific cellular response in the nasal and
      mesenteric compartments after i.n. immunization.

PMID- 10639475
TI  - Two allelic forms of the aureolysin gene (aur) within Staphylococcus aureus.
AB  - Proteinases of Staphylococcus aureus are emerging as potential virulence factors
      which may be involved in the pathogenecity of staphylococcal diseases. We
      describe here the structure of the gene encoding the metalloproteinase referred
      to as aureolysin. This gene occurs in two allelic forms and is strongly conserved
      among S. aureus strains, implying the possibility that the proteinase may have
      important housekeeping functions.

PMID- 10639476
TI  - Optimizing the germfree mouse model for in vivo evaluation of oral Vibrio
      cholerae vaccine and vector strains.
AB  - The germfree mouse model of Vibrio cholerae infection can be used to judge immune
      responses to V. cholerae vaccine and vector strains. In the original model, a
      single oral inoculation was administered on day 0, a booster oral inoculation was
      administered on day 14, and immune responses were analyzed with samples collected
      on day 28. Unfortunately, immune responses in this model frequently were low
      level, and interanimal variability occurred. In order to improve this model, we
      evaluated various primary and booster V. cholerae inoculation schedules. The most
      prominent systemic and mucosal antibody responses were measured in mice that
      received a multiple primary inoculation series on days 0, 2, 4, and 6 and booster
      inoculations on days 28 and 42. These modifications result in improved
      preliminary evaluation of V. cholerae vaccine and vector strains in mice.

PMID- 10639478
TI  - Use of lambda phage S and R gene products in an inducible lysis system for Vibrio
      cholerae- and Salmonella enterica serovar typhimurium-based DNA vaccine delivery
      systems.
AB  - Novel methods for adapting DNA vaccine technology to the prevention of mucosal
      diseases are greatly needed. Here we show that regulated expression of phage
      lambda lysis genes S and R causes dramatic lysis of both Vibrio cholerae and
      Salmonella enterica serovar Typhimurium cells with concomitant release of plasmid
      DNA into the surrounding media. We also used single and double DNase mutant
      strains to show that secreted V. cholerae DNases can adversely affect the
      integrity of DNA molecules released upon lysis. These results suggest that
      incorporation of lambda SR-mediated lysis constructs and DNA stabilizing
      mutations into candidate live attenuated bacterial vaccines offers a promising
      approach for the development of effective mucosal DNA delivery vectors for
      humans.

PMID- 10639477
TI  - Comparison of the roles of calcineurin in physiology and virulence in serotype D
      and serotype A strains of Cryptococcus neoformans.
AB  - The calcineurin gene was cloned and disrupted in serotype D strains of
      Cryptococcus neoformans. Serotype A and serotype D calcineurin mutants were
      inviable at 37 degrees C and avirulent in mice, whereas only serotype A mutants
      were cation stress sensitive. Thus, calcineurin plays conserved and divergent
      roles in serotype A and serotype D strains.

PMID- 10639479
TI  - MTSA-10, the product of the Rv3874 gene of Mycobacterium tuberculosis, elicits
      tuberculosis-specific, delayed-type hypersensitivity in guinea pigs.
AB  - In a search for new skin test reagents specific for tuberculosis, we found that
      the antigen encoded by gene Rv3874 of Mycobacterium tuberculosis elicited delayed
      type hypersensitivity in M. tuberculosis-infected guinea pigs but not in control
      animals immunized with Mycobacterium bovis bacillus Calmette-Guerin (BCG) or
      Mycobacterium avium. The antigen, which was named MTSA-10 (for M. tuberculosis
      specific antigen 10), is a prime candidate for a component of a new tuberculin
      that will allow discrimination by a skin test of latent M. tuberculosis infection
      from vaccination with BCG or from sensitization with environmental,
      nontuberculous mycobacteria.

PMID- 10639480
TI  - Human monocyte receptors involved in tumor necrosis factor responses to group B
      streptococcal products.
AB  - Several group B streptococcal products have been previously found to stimulate
      human monocytes to produce tumor necrosis factor alpha. In order to identify the
      receptors involved in these responses, monocytes were stimulated with purified
      group- or type-specific carbohydrates or lipoteichoic acid in the presence of
      anti-receptor monoclonal antibodies, soluble CD14, or lipopolysaccharide-binding
      protein. Results indicate that CD14 plays an important role in tumor necrosis
      factor alpha responses to all of the stimuli tested. Moreover, both CD14 and
      complement receptor type 3 may be involved in responses to the group-antigen.

PMID- 10639482
TI  - Specificity controls for immunocytochemical methods.
AB  - Immunocytochemistry is used for antibody localization of proteins in cells and
      tissues. The specificity of the results depends on two independent criteria: the
      specificity of the antibody and of the method used. The antibody specificity is
      best determined by immunoblot and or immunoprecipitation. Absorption of the
      antibody with a protein does not determine that the antibody would have bound to
      the same protein in the tissue, and therefore is not a good control for antibody
      specificity. The specificity of the method is best determined by both a negative
      control, replacing the primary antibody with serum, and a positive control, using
      the antibody with cells known to contain the protein. With the increasing use of
      immunocytochemistry, it is important to be aware of the appropriate controls
      needed to show specificity of the labeling. (J Histochem Cytochem 48:163-165,
      2000)

PMID- 10639481
TI  - Role of listeriolysin O in cell-to-cell spread of Listeria monocytogenes.
AB  - Listeria monocytogenes is a facultative intracellular bacterial pathogen that
      escapes from a host vacuolar compartment and grows rapidly in the cytosol.
      Listeriolysin O (LLO) is a secreted pore-forming protein essential for the escape
      of L. monocytogenes from the vacuole formed upon initial internalization.
      However, its role in intracellular growth and cell-to-cell spread events has not
      been testable by a genetic approach. In this study, purified six-His-tagged LLO
      (HisLLO) was noncovalently coupled to the surface of nickel-treated LLO-negative
      mutants. Bound LLO mediated vacuolar escape in approximately 2% of the mutants.
      After 5.5 h of growth, cytosolic bacteria were indistinguishable from wild-type
      bacteria with regard to formation of pseudopod-like extensions, here termed
      listeriopods, and spread to adjacent cells. However, bacteria in adjacent cells
      failed to multiply and were found in double-membrane vacuoles. Addition of bound
      LLO to mutants lacking LLO and two distinct phospholipases C (PLCs) also resulted
      in spread to adjacent cells, but these triple mutants became trapped in multiple
      membrane vacuoles that are reminiscent of autophagocytic vacuoles. These studies
      show that neither LLO nor the PLCs are necessary for listeriopod formation and
      uptake of bacteria into neighboring cells but that LLO is required for the escape
      of L. monocytogenes from the double-membrane vacuole that forms upon cell-to-cell
      spread.

PMID- 10639483
TI  - Inverse expression of peroxisomes and connexin-43 in the granulosa cells of the
      quail follicle.
AB  - Studying the regulation of peroxisome (Px) expression could improve our
      understanding of human peroxisomal disorders. The granulosa of the largest
      preovulatory quail follicles proved to be a relevant model because (a) Px
      expression changes according to the follicular maturation stage and (b) Px
      expression varies regionally according to the distance of the granulosa relative
      to the germinal disc region containing the female gamete (oocyte). The question
      was asked whether Px expression is related to the extent of metabolic cell
      coupling and whether zonal Px variation is causally related to oocytal factors.
      This was evaluated by the presence of catalase and Cx-43 (marker proteins for
      peroxisomes and gap junctions, respectively) and by in vitro experiments with
      granulosa explants. The data obtained show that the expression of Cx-43 and Px is
      inversely correlated both temporally and spatially. Uncoupling of gap junctions
      results in an upregulation of alpha-catalase immunofluorescence. This is in
      agreement with reports that gap junctions are often negatively affected by Px
      proliferators. The zonal gradient in Px expression appears to be imposed by the
      oocyte, as is the case for steroidogenesis and proliferative capacity in the
      granulosa epithelium. (J Histochem Cytochem 48:167-177, 2000)

PMID- 10639484
TI  - Ocrl1, a PtdIns(4,5)P(2) 5-phosphatase, is localized to the trans-Golgi network
      of fibroblasts and epithelial cells.
AB  - PtdIns(4,5)P(2) and PtdIns(4,5)P(2) 5-phosphatases play important roles in
      diverse aspects of cell metabolism, including protein trafficking. However, the
      relative importance of the PtdIns(4,5)P(2) 5-phosphatases in regulating
      PtdIns(4,5)P(2) levels for specific cell processes is not well understood. Ocrl1
      is a PtdIns(4,5)P(2) 5-phosphatase that is deficient in the oculocerebrorenal
      syndrome of Lowe, a disorder characterized by defects in kidney and lens
      epithelial cells and mental retardation. Ocrl1 was originally localized to the
      Golgi in fibroblasts, but a subsequent report suggested a lysosomal localization
      in a kidney epithelial cell line. In this study we defined the localization of
      ocrl1 in fibroblasts and in two kidney epithelial cell lines by three methods:
      immunofluorescence, subcellular fractionation, and a dynamic perturbation assay
      with brefeldin A. We found that ocrl1 was a Golgi-localized protein in all three
      cell types and further identified it as a protein of the trans-Golgi network
      (TGN). The TGN is a major sorting site and has the specialized function in
      epithelial cells of directing proteins to the apical or basolateral domains. The
      epithelial cell phenotype in Lowe syndrome and the localization of ocrl1 to the
      TGN imply that this PtdIns(4,5)P(2) 5-phosphatase plays a role in trafficking. (J
      Histochem Cytochem 48:179-189, 2000)

PMID- 10639485
TI  - Distribution of IkappaB proteins in gastric mucosa and other organs of mouse and
      gerbil.
AB  - The NF-kappaB/IkappaB complex is a major transcription regulator of inflammatory
      and immune responses. Helicobacter pylori infection causes chronic inflammation
      in gastric mucosa by inducing dissociation of the inhibitory IkappaB protein from
      the complex with a resulting increased expression of interleukin (IL)-8. To
      clarify which of several known IkappaB proteins could be involved in this
      inflammatory response, we undertook immunohistochemical examination of normal
      mouse stomach as well as other murine tissues for comparison, using polyclonal
      antibodies specific for alpha-, beta-, gamma-, and in-isoforms of IkappaB. The
      results showed strong immunoreactivity for the alpha-isoform in parietal cells
      and for the beta-isoform in pit cells of the stomach, along with the presence of
      these proteins in various other sites. Comparative staining revealed a similar
      but not identical distribution of IkappaB proteins in the Mongolian gerbil, a
      rodent model for H. pylori infection. The findings suggest that the alpha- and
      beta-isoforms are dominant IkappaB proteins in gastric parietal and foveolar
      cells, respectively, and point to a role for these transcription regulators in
      modulating pathological responses in stomach and other organs. (J Histochem
      Cytochem 48:191-199, 2000)

PMID- 10639486
TI  - Laminin chains in developing and adult human myotendinous junctions.
AB  - In addition to being the specialized site for transmission of force from the
      muscle to the tendon, the myotendinous junction (MTJ) also plays an important
      role in muscle splitting during morphogenesis. An early event in the formation of
      the MTJ is a regional deposition of basement membranes. We used
      immunocytochemistry to investigate the distribution of laminin chains during the
      development of MTJs in human limb muscle at 8-22 weeks of gestation (wg) and in
      adult MTJs. We used polyclonal antibodies and a new monoclonal antibody (MAb)
      against the human laminin alpha1 G4/G5 domains. At 8-10 wg, laminin alpha1 and
      laminin alpha5 chains were specifically localized to the MTJ. Laminin alpha1
      chain remained restricted to the MTJ at 22 wg as the laminin beta2 chain had
      appeared, whereas the laminin alpha5 chain became deposited along the entire
      length of the myotubes from 12 wg. In the adult MTJ, only vestigial amounts of
      laminin alpha1 and laminin alpha5 chains could be detected. On the basis of co
      distribution data, we speculate that laminin alpha1 chain in the forming MTJ
      undergoes an isoform switch from laminin 1 to laminin 3. Our data indicate a
      potentially important role for laminin alpha1 chain in skeletal muscle formation.
      (J Histochem Cytochem 48:201-209, 2000)

PMID- 10639487
TI  - Localization of S-adenosylhomocysteine hydrolase in the rat kidney.
AB  - S-adenosylhomocysteine (SAH) hydrolase is a cytosolic enzyme present in the
      kidney. Enzyme activities of SAH hydrolase were measured in the kidney in
      isolated glomeruli and tubules. SAH hydrolase activity was 0.62 +/- 0.02 mU/mg in
      the kidney, 0.32 +/- 0.03 mU/mg in the glomeruli, and 0.50 +/- 0.02 mU/mg in
      isolated tubules. Using immunohistochemical methods, we describe the localization
      of the enzyme SAH hydrolase in rat kidney with a highly specific antibody raised
      in rabbits against purified SAH hydrolase from bovine kidney. This antibody
      crossreacts to almost the same extent with the SAH hydrolase from different
      species such as rat, pig, and human. Using light microscopy, SAH hydrolase was
      visualized by the biotin-streptavidin-alkaline phosphatase immunohistochemical
      procedure. SAH hydrolase immunostaining was observed in glomeruli and in the
      epithelium of the proximal and distal tubules. The collecting ducts of the cortex
      and medulla were homogeneously stained. By using double immunofluorescence
      staining and two-channel immunofluorescence confocal laser scanning microscopy,
      we differentiated the glomerular cells (endothelium, mesangium, podocytes) and
      found intensive staining of podocytes. Our results show that the enzyme SAH
      hydrolase is found ubiquitously in the rat kidney. The prominent staining of SAH
      hydrolase in the podocytes may reflect high rates of transmethylation. (J
      Histochem Cytochem 48:211-218, 2000)

PMID- 10639488
TI  - Osteoclastic tartrate-resistant acid phosphatase (Acp 5): its localization to
      dendritic cells and diverse murine tissues.
AB  - Tartrate-resistant acid phosphatase (TRAP) is a histochemical marker of the
      osteoclast. It is also characteristic of monohistiocytes, particularly alveolar
      macrophages, and is associated with diverse pathological conditions, including
      hairy cell leukemia and AIDS encephalopathy. To study the biology of this enzyme,
      we investigated its expression and activity in mouse tissues. Confocal
      fluorescence studies showed that TRAP is localized to the lysosomal compartment
      of macrophages. In adult mice, high activities of the enzyme were demonstrated in
      bone, spleen, liver, thymus, and colon, with lower amounts in lung, stomach,
      skin, brain, and kidney. Trace amounts were detected in testis, muscle, and
      heart. Expression of TRAP mRNA was investigated in tissue sections by in situ
      hybridization and protein expression was monitored by histochemical staining or
      immunohistochemically. TRAP is widely expressed in many tissues, where it is
      associated with cells principally originating from the bone marrow, including
      those of osteoclast/macrophage lineage. The cellular distribution of TRAP mRNA
      and enzyme antigen in the tissues corresponds closely to that of cells staining
      with an antibody directed to the CD80 (B7) antigen. Therefore, to confirm its
      putative localization in dendritic cells, isolated bone marrow dendritic cells
      were matured in culture. These co-stained strongly for TRAP protein and the CD80
      antigen. These studies demonstrate that TRAP is a lysosomal enzyme that is found
      in diverse murine tissues, where it is expressed in dendritic cells as well as
      osteoclasts and macrophages, as previously shown. (J Histochem Cytochem 48:219
      227, 2000)

PMID- 10639489
TI  - Nidogen-1. Expression and ultrastructural localization during the onset of
      mesoderm formation in the early mouse embryo.
AB  - Nidogen-1, a key component of basement membranes, is considered to function as a
      link between laminin and collagen Type IV networks and is expressed by
      mesenchymal cells during embryonic and fetal development. It is not clear which
      cells produce nidogen-1 in early developmental stages when no mesenchyme is
      present. We therefore localized nidogen-1 and its corresponding mRNA at the light
      and electron microscopic level in Day 7 mouse embryos during the onset of
      mesoderm formation by in situ hybridization, light microscopic immunostaining,
      and immunogold histochemistry. Nidogen-1 mRNA was found not only in the cells of
      the ectoderm-derived mesoderm but also in the cytoplasm of the endoderm and
      ectoderm, indicating that all three germ layers express it. Nidogen-1 was
      localized only in fully developed basement membranes of the ectoderm and was not
      seen in the developing endodermal basement membrane or in membranes disrupted
      during mesoderm formation. In contrast, laminin-1 and collagen Type IV were
      present in all basement membrane types at this developmental stage. The results
      indicate that, in the early embryo, nidogen-1 may be expressed by epithelial and
      mesenchymal cells, that both cell types contribute to embryonic basement membrane
      formation, and that nidogen-1 might serve to stabilize basement membranes in
      vivo. (J Histochem Cytochem 48:229-237, 2000)

PMID- 10639490
TI  - Human articular chondrocytes express osteogenic protein-1.
AB  - This study demonstrates for the first time that human articular chondrocytes
      express osteogenic protein-1 (OP-1). OP-1 was originally purified from bone
      matrix and was shown to induce cartilage and bone formation. Both OP-1 protein
      and message were present in human normal and osteoarthritic (OA) cartilages. OP-1
      mRNA was upregulated in OA cartilage compared with normal adult tissues. However,
      the level of mature OP-1 protein in the same OA tissues was downregulated,
      whereas the pro-OP-1 remained high. Moreover, these two forms of OP-1 were
      localized in an inverted manner. Mature OP-1 was primarily detected in the
      superficial layer, whereas the pro-form was mostly in the deep layer of
      cartilage. The presence of pro- and mature OP-1 in extracts of normal and OA
      cartilages was confirmed by Western blotting. These findings imply that articular
      chondrocytes continue to express and synthesize OP-1 throughout adulthood. The
      observed patterns of the distribution of pro- and mature OP-1 also suggest
      differences in the processing of this molecule by normal and OA chondrocytes and
      by the cells in the superficial and deep layers. Distinct distribution of OP-1
      and its potential activation in deep zones and regions of cloning in OA
      cartilages may provide clues to the potential involvement of endogenous OP-1 in
      repair mechanisms. (J Histochem Cytochem 48:239-250, 2000)

PMID- 10639491
TI  - The lysosomotropic agent monodansylcadaverine also acts as a solvent polarity
      probe.
AB  - The autofluorescent substance monodansylcadaverine has recently been reported as
      a specific in vivo marker for autophagic vacuoles. However, the mechanism for
      this specific labeling remained unclear. Our results reveal that the common model
      of ion trapping in acidic compartments cannot completely account for the observed
      autophagic vacuole staining. Because autophagic vacuoles are characterized by
      myelin-like membrane inclusions, we tested whether this lipid-rich environment is
      responsible for the staining properties of monodansylcadaverine. In in vitro
      experiments using either liposomes or solvents of different polarity,
      monodansylcadaverine showed an increased relative fluorescence intensity in a
      hydrophobic environment as well as a Stokes shift dependent on the solvent
      polarity. To test the effect of autophagic vacuoles or autophagic vacuole lipids
      on monodansylcadaverine fluorescence, we isolated autophagic vacuoles and
      purified autophagic vacuole lipids depleted of proteins. Entire autophagic
      vacuoles and autophagic vacuole lipids had the same effect on
      monodansylcadaverine fluorescence properties, suggesting lipids as the
      responsible component. Our results suggest that the in vivo fluorescence
      properties of monodansylcadaverine do not depend exclusively on accumulation in
      acidic compartments by ion trapping but also on an effective interaction of this
      molecule with autophagic vacuole membrane lipids. (J Histochem Cytochem 48:251
      258, 2000)

PMID- 10639492
TI  - Glial fibrillary acidic protein (GFAP)-like immunoreactivity in rat endocrine
      pancreas.
AB  - The study of intermediate filament expression in the pancreatic epithelium has
      been previously focused almost exclusively on cytokeratins. Transient vimentin
      immunoreactivity has also been detected in duct cells of rat fetal pancreas. Here
      we report that, in rat pancreas, intense GFAP-like immunoreactivity is detectable
      in a subpopulation of endocrine cells located in the periphery of the islet of
      Langerhans. In addition, staining appeared to be preferentially localized to the
      apical pole of the cells. Two different polyclonal antibodies were employed in
      this study, with analogous results. Staining of consecutive sections with anti
      GFAP, anti-glucagon, and anti-somatostatin antibodies demonstrates that GFAP-like
      immunoreactivity is present in glucagon-secreting cells. The relevance of this
      finding is discussed. (J Histochem Cytochem 48:259-265, 2000)

PMID- 10639493
TI  - The affinity binding sites of pancreatic bile salt-dependent lipase in pancreatic
      and intestinal tissues.
AB  - In previous studies, we have shown that the bile salt-dependent lipase (BSDL)
      associates with the Grp94 molecular chaperone, an association that appears to
      play essential roles in the folding of BSDL. More recently, combined biochemical
      and immunocytochemical investigations were carried out to show that the transport
      of BSDL occurs via an association with the Grp94 all along the pancreatic
      secretory route (ER-Golgi-granules). The Grp94-BSDL complex is secreted with the
      pancreatic juice into the acinar lumen and reaches the duodenal lumen, where it
      is internalized by enterocytes. The dissociation of the complex could take place
      within the endosomal compartment because BSDL continues further on its way to the
      basolateral membrane of the enterocyte. To localize the affinity binding sites of
      pancreatic BSDL in pancreatic and duodenal tissues, we have used an affinity-gold
      ultrastructural technique. BSDL coupled to gold particles appears to interact
      with specific sites in tissue sections. This was confirmed by another indirect
      morphological approach using biotin-labeled BSDL and streptavidin-gold complexes
      on tissue sections. We have shown that BSDL associates with sites in the
      pancreatic secretory pathway compartments and in the microvilli, the endosomal
      compartment, and the basolateral membrane of enterocytes. By biochemical
      approaches, biotin-labeled BSDL displayed affinities with proteins of 180-190 kD
      in both pancreatic and duodenal tissues. We have also shown that the Grp94-BSDL
      complexes, which are insensitive to denaturing conditions, are present in
      pancreatic homogenate but not in duodenal lysate. Thus, BSDL is able to bind
      protein complexes formed by either BSDL-Grp94 or Grp94 dimers. (J Histochem
      Cytochem 48:267-276, 2000)

PMID- 10639494
TI  - Epithelial Dlx-2 homeogene expression and cementogenesis.
AB  - The Dlx-2 (distal-less gene) homeoprotein transcription factor controls early
      tooth development but has not been studied during the late stages of
      biomineralization. Transgenic mice containing a Dlx-2/LacZ reporter construct
      were used to map the Dlx-2 expression pattern in cementoblasts, the dental cells
      most closely related to bone cells and therefore suggested to be uniquely
      positioned osteoblasts. During initial root formation, marked expression of Dlx-2
      was evident in molar and incisor root epithelium, whereas dental papilla and
      follicle were negative. Dlx-2 was expressed in this epithelium from the apical
      loop to the area of its disruption. During acellular cementum formation in both
      incisors and molars, Dlx-2 expression was observed in the majority of
      differentiated cementoblasts from the apical region to the erupting zones. During
      cellular cementum formation, the presence of which characterizes growth-limited
      molars, Dlx-2 expression was restricted to the innermost cementoblasts and
      entrapped cementocytes. These data further support the hypothesis of a complex
      origin and fate of cementum-forming cells, as previously suggested by the
      expression patterns of a set of mesenchymal and epithelial markers, notably
      ameloblastin as shown here. Dlx-2 expression might constitute a landmark of
      cementoblast subpopulations of epithelial origin. (J Histochem Cytochem 48:277
      283, 2000)

PMID- 10639495
TI  - PCR-derived ssDNA probes for fluorescent in situ hybridization to HIV-1 RNA.
AB  - We developed a simple and rapid technique to synthesize single-stranded DNA
      (ssDNA) probes for fluorescent in situ hybridization (ISH) to human
      immunodeficiency virus 1 (HIV-1) RNA. The target HIV-1 regions were amplified by
      the polymerase chain reaction (PCR) and were simultaneously labeled with dUTP.
      This product served as template for an optimized asymmetric PCR (one-primer PCR)
      that incorporated digoxigenin (dig)-labeled dUTP. The input DNA was subsequently
      digested by uracil DNA glycosylase, leaving intact, single-stranded, digoxigenin
      labeled DNA probe. A cocktail of ssDNA probes representing 55% of the HIV-1
      genome was hybridized to HIV-1-infected 8E5 T-cells and uninfected H9 T-cells.
      For comparison, parallel hybridizations were done with a plasmid-derived RNA
      probe mix covering 85% of the genome and a PCR-derived RNA probe mix covering 63%
      of the genome. All three probe types produced bright signals, but the best signal
      to-noise ratios and the highest sensitivities were obtained with the ssDNA probe.
      In addition, the ssDNA probe syntheses generated large amounts of probe (0.5 to 1
      microg ssDNA probe per synthesis) and were easier to perform than the RNA probe
      syntheses. These results suggest that ssDNA probes may be preferable to RNA
      probes for fluorescent ISH. (J Histochem Cytochem 48:285-293, 2000)

PMID- 10639496
TI  - PS-100 and NF 70-200 double immunolabeling for human digital skin meissner
      corpuscle 3D imaging.
AB  - For detailed study of complex structures such as corpuscular mechanoreceptors,
      confocal microscopy can be used with multiple immunolabeling that identifies
      specifically different subcomponents. In addition, anatomic interpretation is
      enhanced by three-dimensional reconstruction. Confocal laser micrographs,
      reconstructed from serial images 1 microm thick of human skin Meissner corpuscles
      simultaneously immunostained for neurofilaments (NF 70-200) and protein S-100 (PS
      100), clearly reveal the complex 3D relationship between Schwann-related lamellar
      cells immunoreactive for PS-100 and the nerve fibers marked by NF 70-200. The
      nerve fiber, after branching into the corpuscle, divides into several
      ramifications, presenting discoidal expansions and flattened fringed sections.
      The mean nerve diameter was 4 microm +/- 1 (2-5 microm) and the mean size of the
      discoidal expansions was 15 microm +/- 1 (7-30 microm). Corpuscle size varied
      from 30-140 +/- 1 microm in length and from 20-60 +/- 1 microm in diameter. This
      study confirms the presence of neural discoidal areas in Meissner's corpuscles,
      which are probably involved to some extent with the transduction process. Despite
      the accuracy of immunolabeling and imaging, an extracorpuscular neural network
      was never observed in the vicinity of corpuscles, thus giving doubt as to their
      existence. (J Histochem Cytochem 48:295-302, 2000)

PMID- 10639497
TI  - Quantitative immunohistochemistry by measuring cumulative signal strength using
      commercially available software photoshop and matlab.
AB  - Currently available techniques for performing quantitative immunohistochemistry
      (Q-IHC) rely upon pixel-counting algorithms and therefore cannot provide
      information as to the absolute amount of chromogen present. We describe a novel
      algorithm for true Q-IHC based on calculating the cumulative signal strength, or
      energy, of the digital file representing any portion of an image. This algorithm
      involves subtracting the energy of the digital file encoding the control image
      (i.e., not exposed to antibody) from that of the experimental image (i.e.,
      antibody-treated). In this manner, the absolute amount of antibody-specific
      chromogen per pixel can be determined for any cellular region or structure. (J
      Histochem Cytochem 48:303-311, 2000)

PMID- 10639498
TI  - MEMORANDUM FOR: science writers and editors on the journal press list : current
      FTC guidelines may underestimate amounts of tar and nicotine smokers receive

PMID- 10639499
TI  - MEMORANDUM FOR: science writers and editors on the journal press list :
      BCAR1/p130Cas gene is involved in tamoxifen resistance seen in breast cancer

PMID- 10639500
TI  - It's time for a change: cigarette smokers deserve meaningful information about
      their cigarettes.

PMID- 10639501
TI  - How is tamoxifen's action subverted?

PMID- 10639502
TI  - Incipient angiogenesis.

PMID- 10639503
TI  - Pricing human genes: the patent rush pushes on.

PMID- 10639504
TI  - Gene rights

PMID- 10639505
TI  - Gene therapy death--"everyone has to share in the guilt".

PMID- 10639506
TI  - Gene protocols

PMID- 10639507
TI  - Stat bite: Recent trends in U.S. cigar consumption.

PMID- 10639508
TI  - Cancer survivor issues are all in the family.

PMID- 10639509
TI  - Cancer's impact and the best time for intervention

PMID- 10639510
TI  - NCI moves to ensure research confidentiality

PMID- 10639511
TI  - Doses of nicotine and lung carcinogens delivered to cigarette smokers.
AB  - BACKGROUND: Cigarette smoke yields of tar and nicotine obtained under the Federal
      Trade Commission (FTC)-specified machine-smoking protocol (35-mL puff volume
      drawn for 2 seconds once per minute) may not accurately reflect the delivery of
      toxins and carcinogens to the smoker. We conducted this study to obtain more
      realistic estimates of exposure to components of cigarette smoke that affect lung
      cancer risk. METHODS: We used a pressure transducer system to evaluate puffing
      characteristics for 133 smokers of cigarettes rated by the FTC at 1.2 mg of
      nicotine or less (56 smokers of low-yield cigarettes [</=0.8 mg of nicotine per
      cigarette] and 77 smokers of medium-yield cigarettes [0.9-1.2 mg of nicotine per
      cigarette]). We programmed measurements from a randomly chosen subset of 72 of
      these smokers into a piston-type machine to generate smoke from each smoker's
      usual brand of cigarettes for assays of nicotine, carbon monoxide, tar, and the
      lung cancer-causing agents 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and
      benzo[a]pyrene. The FTC protocol was also used to assess levels of targeted
      components in the 11 brands most frequently smoked by study subjects. RESULTS:
      Compared with the FTC protocol values, smokers of low- and medium-yield brands
      took in statistically significantly larger puffs (48.6 and 44.1 mL, respectively)
      at statistically significantly shorter intervals (21.3 and 18.5 seconds,
      respectively), and they drew larger total smoke volumes than specified in the FTC
      parameters. They received, respectively, 2.5 and 2.2 times more nicotine and 2.6
      and 1.9 times more tar than FTC-derived amounts, as well as about twofold higher
      levels of benzo[a]pyrene and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.
      Smokers of medium-yield cigarettes compared with smokers of low-yield cigarettes
      received higher doses of all components. CONCLUSIONS: The FTC protocol
      underestimates nicotine and carcinogen doses to smokers and overestimates the
      proportional benefit of low-yield cigarettes. Thus, FTC-based nicotine medication
      doses prescribed/recommended for smoking cessation may need to be reassessed.

PMID- 10639512
TI  - BCAR1, a human homologue of the adapter protein p130Cas, and antiestrogen
      resistance in breast cancer cells.
AB  - BACKGROUND: Treatment of breast cancer with the antiestrogen tamoxifen is
      effective in approximately one half of the patients with estrogen receptor
      positive disease, but tumors recur frequently because of the development of
      metastases that are resistant to tamoxifen. We have previously shown that
      mutagenesis of human estrogen-dependent ZR-75-1 breast cancer cells by insertion
      of a defective retrovirus genome caused the cells to become antiestrogen
      resistant. In this study, we isolated and characterized the crucial gene at the
      breast cancer antiestrogen resistance 1 (BCAR1) locus. METHODS/RESULTS: Transfer
      of the BCAR1 locus from retrovirus-mutated, antiestrogen-resistant cells to
      estrogen-dependent ZR-75-1 cells by cell fusion conferred an antiestrogen
      resistant phenotype on the recipient cells. The complete coding sequence of BCAR1
      was isolated by use of exon-trapping and complementary DNA (cDNA) library
      screening. Sequence analysis of human BCAR1 cDNA predicted a protein of 870 amino
      acids that was strongly homologous to rat p130Cas-adapter protein. Genomic
      analysis revealed that BCAR1 consists of seven exons and is located at chromosome
      16q23.1. BCAR1 transcripts were detected in multiple human tissues and were
      similar in size to transcripts produced by retrovirus-mutated ZR-75-1 cells.
      Transfection of BCAR1 cDNA into ZR-75-1 cells again resulted in sustained cell
      proliferation in the presence of antiestrogens, confirming that BCAR1 was the
      responsible gene in the locus. CONCLUSIONS: Overexpression of the BCAR1 gene
      confers antiestrogen resistance on human ZR-75-1 breast cancer cells.
      Overexpression of BCAR1 in retrovirus-mutated cells appears to result from
      activation of the gene's promoter. The isolation and characterization of this
      gene open new avenues to elucidating mechanisms by which the growth of human
      breast cancer becomes independent of estrogen.

PMID- 10639513
TI  - Bcar1/p130Cas protein and primary breast cancer: prognosis and response to
      tamoxifen treatment.
AB  - BACKGROUND: The product of the Bcar1/p130Cas (breast cancer resistance/p130Crk
      associated substrate) gene causes resistance to antiestrogen drugs in human
      breast cancer cells in vitro. To investigate its role in clinical breast cancer,
      we determined the levels of Bcar1/p130Cas protein in a large series of primary
      breast carcinomas. METHODS: We measured Bcar1/p130Cas protein in cytosol extracts
      from 937 primary breast carcinomas by western blot analysis. The levels of
      Bcar1/p130Cas protein were tested for associations and trends against
      clinicopathologic and patient characteristics, the lengths of relapse-free
      survival and overall survival (n = 775), and the efficacy of first-line treatment
      with tamoxifen for recurrent or metastatic disease (n = 268). RESULTS:
      Bcar1/p130Cas levels in primary tumors were associated with age/menopausal status
      and the levels of estrogen receptor and progesterone receptor. In univariate
      survival analysis, higher Bcar1/p130Cas levels were associated with poor relapse
      free survival and overall survival (both two-sided P =.04; log-rank test for
      trend). In multivariate analysis, a high level of Bcar1/p130Cas was independently
      associated with poor relapse-free survival and overall survival. The response to
      tamoxifen therapy in patients with recurrent disease was reduced in patients with
      primary tumors that expressed high levels of Bcar1/p130Cas. In multivariate
      analysis for response, Bcar1/p130Cas was independent of classical predictive
      factors, such as estrogen receptor status, age/menopausal status, disease-free
      interval, and dominant site of relapse. CONCLUSION: Patients with primary breast
      tumors expressing a high level of Bcar1/p130Cas protein appear to experience more
      rapid disease recurrence and have a greater risk of (intrinsic) resistance to
      tamoxifen therapy. Thus, measurement of Bcar1/p130Cas may provide useful
      prognostic information for patients with primary or metastatic breast cancer.

PMID- 10639514
TI  - Physical activity and breast cancer risk in women aged 20-54 years.
AB  - BACKGROUND/METHODS: Although several studies have suggested that physical
      activity is associated with a decreased risk of breast cancer, such a decrease
      has not been found consistently, perhaps because physical activity was assessed
      in different ways and for restricted periods. Few studies have assessed the risk
      of breast cancer in relation to lifetime physical activity. We used data from a
      population-based, case-control study, including 918 case subjects (aged 20-54
      years) and 918 age-matched population control subjects, to examine associations
      between breast cancer risk and physical activity at ages 10-12 years and 13-15
      years, lifetime recreational activity, and title of longest held job. RESULTS:
      Women who were more active than their peers at ages 10-12 years had a lower risk
      of breast cancer (odds ratio [OR] = 0.68; 95% confidence interval [CI] = 0.49
      0.94). Women who had ever engaged in recreational physical activity had a reduced
      risk of breast cancer compared with inactive women (OR = 0.70; 95% CI = 0.56
      0.88). Neither very early recreational activity (before age 20 years) nor recent
      activity (last 5 years) was associated with a greater reduction in risk than
      recreational activity in the intermediate period. Furthermore, women who started
      recreational activities after age 20 years and women who started earlier and
      continued their activities throughout adult life experienced a similar reduction
      in risk. Lean women, i.e., women with a body mass index (weight in kg/[height in
      m](2)) less than 21. 8 kg/m(2), appeared to have a lower risk associated with
      recreational physical activity than women with a body mass index greater than
      24.5 kg/m(2) (OR = 0.57 [95% CI = 0.40-0.82] and OR = 0. 92 [95% CI = 0.65-1.29],
      respectively). CONCLUSIONS: Our findings support the hypothesis that recreational
      physical activity is associated with a decreased risk of breast cancer. Physical
      activity in early or recent life does not appear to be associated with additional
      beneficial effects.

PMID- 10639515
TI  - Cost of care for patients in cancer clinical trials.
AB  - BACKGROUND: Information on the costs of medical care for patients enrolled in
      clinical trials is needed by policymakers evaluating ways to facilitate clinical
      research in a managed care environment. We examined the direct costs of medical
      care for patients enrolled in cancer clinical trials at a large health
      maintenance organization (HMO). METHODS: Costs for 135 patients who entered 22
      cancer clinical trials (including 12 breast cancer trials) at Kaiser Permanente
      in Northern California, from 1994 through 1996 were compared with costs for 135
      matched control subjects who were not enrolled in such trials. Cancer registry
      data and medical charts were used in matching the control subjects to the trial
      enrollees with respect to cancer site, stage, date of diagnosis, age, sex, and
      trial eligibility. The direct costs of medical care were compared between trial
      enrollees and the control subjects for a 1-year period, with data on costs and
      utilization of services obtained from Kaiser Permanente databases and medical
      charts. RESULTS: Mean 1-year costs for the enrollees in trials were 10% higher
      than those for the control subjects ($17 003 per enrollee compared with $15 516
      per control subject; two-sided P =.011). The primary component of this difference
      was a $1376 difference in chemotherapy costs ($4815 per trial enrollee versus
      $3439 per control subject; two-sided P<.001). Costs for the 11 enrollees in
      trials that had a bone marrow transplant (BMT) arm were approximately double the
      costs for their matched control subjects (borderline significance: two-sided
      P=.054). The $15 041 mean cost for the enrollees in trials without BMT was
      similar to the $15 186 mean cost for their matched control subjects. CONCLUSIONS:
      Participation in cancer clinical trials at a large HMO did not result in
      substantial increases in the direct costs of medical care.

PMID- 10639516
TI  - Initial stages of tumor cell-induced angiogenesis: evaluation via skin window
      chambers in rodent models.
AB  - BACKGROUND: There is a paucity of information about events that follow
      immediately after tumor cells are triggered to initiate the process of
      angiogenesis (the formation of new blood vessels). Such information is relevant
      to the issue of when micrometastases vascularize and has implications for the
      accessibility of micrometastases to various treatments. In this study, we
      attempted to monitor events at the initiation of angiogenesis at the earliest
      possible stage of tumor growth in vivo. METHODS: Two different rodent mammary
      tumor cell lines, R3230Ac from the Fischer 344 rat and 4T1 from the BALB/c mouse,
      were stably transfected with a gene that encodes an enhanced version of green
      fluorescence protein (GFP). GFP-labeled R3230Ac or 4T1 cells (about 20-50 cells)
      were implanted into dorsal skinfold window chambers of Fischer 344 rats or BALB/c
      mice, respectively. Tumor angiogenesis was then monitored serially and
      noninvasively for up to 4 weeks. RESULTS: Clear evidence of modification of the
      host vasculature was observed when tumor mass reached approximately 60-80 cells,
      and functional new blood vessels were seen when tumor mass reached roughly 100
      300 cells. Individual tumor cells exhibited a chemotaxis-like growth pattern
      toward the pre-existing host vasculature. When ex-flk1 (a soluble, truncated
      vascular endothelial cell growth factor receptor protein known to be
      antiangiogenic) was injected with the tumor cells, the initial angiogenic and
      tumor growth activities were inhibited considerably, indicating that angiogenesis
      inhibitors may halt tumor growth even before the onset of angiogenesis.
      CONCLUSION: Angiogenesis induced by tumor cells after implantation in the host
      begins at a very early stage, i.e., when the tumor mass contains roughly 100-300
      cells. Identification of chemotactic signals that initiate tumor cell migration
      toward the existing vasculature may provide valuable targets for preventing tumor
      progression and/or metastases.

PMID- 10639517
TI  - Ser-249 p53 mutations in plasma DNA of patients with hepatocellular carcinoma
      from The Gambia.
AB  - BACKGROUND: A selective mutation, an arginine-to-serine substitution in codon
      249, of the p53 gene has been identified as a "hotspot" mutation in
      hepatocellular carcinoma (HCC). This mutation occurs in populations that are
      exposed to aflatoxins and have a high prevalence of hepatitis B virus carriers.
      We evaluated whether this mutation could be detected in cell-free DNA isolated
      from the plasma of subjects from The Gambia to detect this mutation that is
      strongly associated with HCC. METHODS: Fifty-three patients with HCC, 13 patients
      with cirrhosis, and 53 control subjects were prospectively recruited from The
      Gambia. Sixty patients, of non-African origin, with various liver pathologies
      were also selected from France. DNA was extracted and purified from 200-microL
      aliquots of plasma. The Ser-249 p53 mutation was detected by restriction
      endonuclease digestion of polymerase chain reaction products from exon 7 and was
      confirmed by direct sequencing of the amplified DNA. RESULTS: The Ser-249 p53
      mutation was detected in plasma DNA from 19 (36%) of the 53 patients with HCC,
      two (15%) of the 13 patients with cirrhosis, and three (6%) of the 53 control
      subjects. This mutation was not detected in any plasma DNA from the European
      patients. The adjusted odds ratio for having the mutation was 16.4 (95%
      confidence interval = 3.0-90.5) for patients with HCC compared with the control
      subjects. CONCLUSION: The Ser-249 p53 mutation in plasma DNA is strongly
      associated with HCC in Gambian patients. This mutation was also detected at a
      much lower prevalence in plasma DNA from Gambian patients with cirrhosis and in
      Gambian control subjects, findings that may lead to the earlier detection of HCC.
      Use of the Ser-249 p53 mutation should facilitate further molecular epidemiologic
      studies on the development of HCC.

PMID- 10639518
TI  - Intake of flavonoids and lung cancer.
AB  - BACKGROUND: To investigate the possible relationship between intake of flavonoids
      powerful dietary antioxidants that may also inhibit P450 enzymes-and lung cancer
      risk, we conducted a population-based, case-control study in Hawaii. METHODS: An
      in-person interview assessed smoking history and usual intake of 242 food items
      for 582 patients with incident lung cancer and 582 age-, sex-, and ethnicity
      matched control subjects. Subjects who donated a blood sample were genotyped for
      the P450 enzyme variant allele CYP1A1*2 by use of a polymerase chain reaction
      based method. Logistic regression analysis was used to compute odds ratios (ORs)
      and 95% confidence intervals (CIs). All P values are two-sided. RESULTS: After
      adjusting for smoking and intakes of saturated fat and beta-carotene, we found
      statistically significant inverse associations between lung cancer risk and the
      main food sources of the flavonoids quercetin (onions and apples) and naringin
      (white grapefruit). The lung cancer OR for the highest compared with the lowest
      quartile of intake was 0.5 (95% CI = 0.3-0.9) for onions (P for trend =.001) and
      0.6 (95% CI = 0.4-1.0) for apples (P for trend =.03). The OR for the highest
      compared with the lowest tertile of intake for white grapefruit was 0.5 (95% CI =
      0.2-0.9) (P for trend =.02). No association was found for important food sources
      of other flavonoids. Using published food-composition data for flavonoids, we
      found an inverse association between intake of quercetin and risk of lung cancer
      (P for trend =.07) that appears consistent with associations for its food
      sources. The effect of onions was particularly strong against squamous cell
      carcinoma (a cell type specifically associated with CYP1A1*2 in our study) and
      was modified by the CYP1A1 genotype, suggesting that CYP1A1 may play a role in
      this association. CONCLUSION: If replicated, particularly in prospective studies,
      these findings would suggest that foods rich in certain flavonoids may protect
      against certain forms of lung cancer and that decreased bioactivation of
      carcinogens by inhibition of CYP1A1 should be explored as underlying mechanisms.

PMID- 10639519
TI  - More about: Tumor angiogenesis as a prognostic assay for invasive ductal breast
      carcinoma.

PMID- 10639520
TI  - Bacterial hotspots and cancer gene therapy.

PMID- 10639521
TI  - Re: Possible role of ovarian epithelial inflammation in ovarian cancer.

PMID- 10639523
TI  - Role of atrial septostomy in the treatment of pulmonary vascular disease.

PMID- 10639524
TI  - Emergency pre-hospital management of patients admitted with acute asthma.
AB  - BACKGROUND: Little is known about the management of acute asthma prior to
      hospital admission. Pre-hospital treatment of patients referred to hospital with
      acute asthma was therefore studied in 150 patients divided into three groups:
      those in the Edinburgh Emergency Asthma Admission Service (EEAAS) who can contact
      an ambulance and present directly to respiratory services when symptoms arise (n
      = 38), those under continuing supervision at a hospital respiratory outpatient
      clinic (n = 54), and those managed solely in primary care (n = 58). METHODS:
      Standardised admission forms detailing aspects of pre-hospital management, case
      records, GP referral letters, and ambulance patient transport forms were
      analysed. RESULTS: In each group airflow obstruction had improved upon arrival at
      hospital, the effect being most marked in patients transported by ambulance (p<0.
      001) and in those receiving nebulised beta(2) agonists prior to admission
      (p<0.005). However, 25% of patients arrived without having nebulised beta(2)
      agonists and 37% without having glucocorticoids. EEAAS patients were least likely
      to receive nebulised beta(2) agonists before arrival at hospital (p<0.05). This
      observation was attributable to a tendency for these patients to travel to
      hospital by car rather than by ambulance. CONCLUSIONS: There is an important
      shortfall in administration of bronchodilators and glucocorticoids for acute
      asthma before arrival at hospital. Ambulances equipped with nebulised
      bronchodilators provide the optimal mode of transport to hospital for patients
      with acute asthma. In Edinburgh ambulances are not being used by a significant
      proportion of the population with asthma, possibly because of the mistaken belief
      that personal transport arrangements reduce journey time to hospital.

PMID- 10639525
TI  - Diet, lung function, and lung function decline in a cohort of 2512 middle aged
      men.
AB  - BACKGROUND: A prospective cohort study of 2512 Welshmen aged 45-59 living in
      Caerphilly in 1979-1983 was used to investigate associations between diet and
      lung function. METHODS: At baseline (phase I) and at five year follow up (phase
      II), forced expiratory volume in one second (FEV(1)) was measured using a
      McDermott spirometer and dietary data were obtained using a semi-quantitative
      food frequency questionnaire. RESULTS: Good lung function, indicated by high
      maximum FEV(1) given age and height, was associated with high intakes of vitamin
      C, vitamin E, beta-carotene, citrus fruit, apples, and the frequent consumption
      of fruit juices/squashes. Lung function was inversely associated with magnesium
      intake but there was no evidence of an association with fatty fish. Following
      adjustment for confounders including body mass index, smoking history, social
      class, exercise, and total energy intake, only the associations with vitamin E
      and apples persisted, with lung function estimated to be 39 ml (95% confidence
      interval (CI) 9 to 69) higher for vitamin E intakes one standard deviation (SD)
      apart and 138 ml higher (95% CI 58 to 218) for those eating five or more apples
      per week compared with non-consumers. Decline in lung function between phases was
      not significantly associated with the changing intakes of apples or vitamin E. An
      association between high average apple consumption and slow decline in lung
      function lost significance after adjustment for confounders. CONCLUSIONS: A
      strong positive association is seen between lung function and the number of
      apples eaten per week cross sectionally, consistent with a protective effect of
      hard fruit rather than soft/citrus fruit. The recent suggestion that such effects
      are reversible was not supported by our longitudinal analysis.

PMID- 10639526
TI  - Use of nitric oxide inhalation in chronic obstructive pulmonary disease.
AB  - BACKGROUND: Inhalation of nitric oxide with oxygen could be a promising treatment
      in patients with chronic obstructive pulmonary disease (COPD) and pulmonary
      hypertension. However, the current methods of delivery of NO are cumbersome and
      unsuitable for long term use. The present study was undertaken to investigate the
      safety and efficacy of a mixture of nitric oxide (NO) and oxygen administered via
      a nasal cannula for 24 hours in patients with oxygen dependent COPD. METHODS:
      Twenty five parts per million (ppm) of NO was administered by inhalation combined
      with supplemental oxygen at a flow rate of 2 l/min via a nasal cannula for 24
      hours to 11 ambulatory men with stable, oxygen dependent COPD. Room air with
      supplemental oxygen at 2 l/min was administered in an identical manner for
      another 24 hours as control therapy in a randomised, double blind, crossover
      fashion to all patients. Pulmonary function tests, exercise tolerance, dyspnoea
      grade, and lung volumes were measured at baseline, 24, and 48 hours. Pulmonary
      artery pressure (PAP), cardiac output (CO), pulmonary vascular resistance (PVR),
      arterial blood gas tensions, and minute ventilation were measured at baseline,
      after 30 minutes and 24 hours of breathing NO and oxygen. Venous admixture ratio
      (Qs/Qt) and dead space ratio (Vd/Vt) were also calculated. Concentrations of
      nitrogen dioxide (NO(2)) and NO in the inhaled and ambient air were monitored
      continuously. Differences in pulmonary function, arterial blood gas tensions,
      pulmonary haemodynamics, exercise tolerance, and dyspnoea between oxygen and NO
      breathing periods were analysed for significance using paired t tests. RESULTS: A
      significant (p<0.05) fall was observed in PVR (183.1 (116.05) and 137.2 (108.4)
      dynes.s.cm(-3) before and after breathing NO for 24 hours, respectively) with NO
      administration without significant changes in symptoms, pulmonary function,
      arterial oxygen tension, or exercise tolerance. CONCLUSIONS: NO at a
      concentration of 25 ppm blended with oxygen can be safely administered by nasal
      cannula for 24 hours without significant adverse effects and lowers PVR in stable
      patients with COPD receiving long term oxygen therapy.

PMID- 10639527
TI  - Relation of sputum inflammatory markers to symptoms and lung function changes in
      COPD exacerbations.
AB  - BACKGROUND: Although it is presumed that exacerbations of chronic obstructive
      pulmonary disease (COPD) are associated with increased airway inflammation, there
      is little information available on inflammatory markers during an exacerbation
      and the relationship with severity or time course of recovery. A study was
      undertaken to investigate the sputum cell and cytokine characteristics of COPD
      when stable and during an exacerbation. METHODS: Induced sputum samples from 57
      patients with moderate to severe COPD were analysed (44 samples were taken during
      a stable period and 37 during an exacerbation). The patients recorded daily
      symptoms on diary cards. Cell counts and sputum levels of interleukin (IL)-6 and
      IL-8 were measured. RESULTS: Patients with >/=3 exacerbations/year had higher
      median stable sputum levels of IL-6 (110 (95% CI 11 to 215) pg/ml) and IL-8 (6694
      (95% CI 3120 to 11995) pg/ml) than those with </=2 exacerbations/year (22 (95% CI
      12 to 93) and 1628 (95% CI 607 to 4812) pg/ml, respectively). Median IL-6 levels
      were increased during exacerbations compared with stable conditions. The levels
      of IL-6 during exacerbations were related to the presence of a cold and to the
      total cell count and eosinophil and lymphocyte numbers, while IL-8 was positively
      correlated with all sputum cell counts. Sputum cell counts and cytokine levels
      during an exacerbation did not predict the size and duration of lung function
      changes in the exacerbation. CONCLUSIONS: Patients with more frequent
      exacerbations have higher baseline sputum cytokine levels, which may predict the
      frequency of future exacerbations.

PMID- 10639528
TI  - Genetic susceptibility to chronic obstructive pulmonary disease in Koreans:
      combined analysis of polymorphic genotypes for microsomal epoxide hydrolase and
      glutathione S-transferase M1 and T1.
AB  - BACKGROUND: Although smoking is the major causal factor in the development of
      chronic obstructive pulmonary disease (COPD), only 10-20% of chronic heavy
      cigarette smokers develop symptomatic COPD which suggests the presence of genetic
      susceptibility. This genetic susceptibility to COPD might depend on variations in
      enzyme activities that detoxify cigarette smoke products such as microsomal
      epoxide hydrolase (mEPHX) and glutathione-S transferase (GST). As there is
      increasing evidence that several genes influence the development of COPD,
      multiple gene polymorphisms should be investigated to find out the genetic
      susceptibility to COPD. METHODS: The genotypes of 83 patients with COPD and 76
      healthy smoking control subjects were determined by polymerase chain reaction
      (PCR) followed by restriction fragment length polymorphism (PCR-RFLP) for the
      mEPHX gene, and multiplex PCR for GST M1 and GST T1 genes. The frequencies of
      polymorphic genotypes of mEPHX, GST M1, and GST T1 genes were compared both
      individually and in combination in patients with COPD and healthy smokers.
      RESULTS: No differences were observed in the frequency of polymorphic genotypes
      in exons 3 and 4 of mEPHX, GST M1, and GST T1 genes between patients with COPD
      and healthy smokers. The frequencies of any combination of these genotypes also
      showed no differences between the COPD group and the control group. CONCLUSIONS:
      Genetic polymorphisms in mEPHX, GST M1, and GST T1 genes are not associated with
      the development of COPD in Koreans.

PMID- 10639529
TI  - Effect of oral mexiletine on the cough response to capsaicin and tartaric acid.
AB  - BACKGROUND: The effect of the orally active local anaesthetic mexiletine on the
      cough response to two different tussive agents, a C-fibre ending stimulator
      capsaicin and a chemostimulant tartaric acid, was examined in normal subjects.
      METHODS: The cough threshold, defined as the lowest concentration of capsaicin
      (C(5)-CP) or tartaric acid (C(5)-TA) causing five or more coughs, and histamine
      induced bronchoconstriction were measured three hours after a single oral dose of
      300 mg mexiletine or placebo in 14 normal subjects. RESULTS: Mexiletene in a mean
      (SE) serum concentration of 0.99 (0. 04) microg/ml significantly increased C(5)
      TA from a geometric mean (SE) of 32.0 (1.27) mg/ml with placebo to 49.9 (1.34)
      mg/ml, but C(5)-CP did not differ significantly between treatment with mexiletine
      (12.2 (1.33) microM) and placebo (14.9 (1.23) microM). CONCLUSIONS: These results
      suggest that the cough response to capsaicin and tartaric acid may be mediated in
      part via different neural pathways.

PMID- 10639530
TI  - Tuberculosis diagnosed during pregnancy: a prospective study from London.
AB  - BACKGROUND: A study was undertaken to characterise the presentation of
      tuberculosis in pregnancy and the difficulties in diagnosis in an area of the UK
      with a high incidence of tuberculosis. METHODS: A prospective case series was
      investigated at Northwick Park Hospital, a university affiliated district general
      hospital in Brent and Harrow health authority in north-west London which
      incorporates a regional infectious diseases unit. Patients diagnosed with
      tuberculosis over the study period were included if the onset of symptoms
      occurred during pregnancy. RESULTS: Thirteen patients were diagnosed during a 30
      month period from December 1995 to May 1998 during which 9069 mothers were
      delivered, a prevalence of 143.3/100 000 deliveries. Symptoms began at a median
      of 22 weeks gestation (range 9-40 weeks). All patients were recent immigrants of
      Indian subcontinent or Somali origin and their median duration of residence in
      the UK was 31 months (range 1-72). Prevalence broken down for racial origin of
      mothers was 466.3/100 000 for mothers of black African origin and 239.1/100 000
      for mothers of Indian origin. Nine of the 13 patients had extrapulmonary
      tuberculosis. Four patients with widely disseminated disease had a negative
      Mantoux response and five with localised disease had a strongly positive Mantoux
      response. HIV co-infection was absent. The median delay between the onset of
      symptoms and diagnosis was seven weeks (range 2-30). The response to standard
      treatment was excellent and all patients were cured. CONCLUSIONS: Tuberculosis
      occurring in pregnancy is common in recent immigrants. Diagnosis during pregnancy
      is delayed because the disease is frequently extrapulmonary with few symptoms.

PMID- 10639531
TI  - Diagnosis of pneumococcal pneumonia by polymerase chain reaction (PCR) in whole
      blood: a prospective clinical study.
AB  - BACKGROUND: Streptococcus pneumoniae is the leading cause of community acquired
      pneumonia; however, only a small proportion of cases can be detected by
      conventional methods. The ability of the polymerase chain reaction (PCR) test
      performed on whole blood samples to identify patients with pneumococcal pneumonia
      was investigated. METHODS: One hundred and fourteen consecutive adult patients
      with community acquired pneumonia were evaluated by a wide battery of diagnostic
      tests in order to determine the aetiology. Blood samples from these patients and
      50 controls were also tested by the nested PCR test to detect selected
      pneumolysin gene fragments of S pneumoniae. RESULTS: The patients were divided
      into four groups: (1) 40 patients with pneumococcal pneumonia in 22 of whom (55%)
      the PCR was positive (eight of 11 with bacteraemia and 14 of 29 without); (2) 30
      with pneumonia due to other pathogens in all of whom the PCR was negative; (3) 44
      with pneumonia of unknown aetiology in 14 of whom (32%) PCR was positive, and (4)
      50 controls in whom the PCR test was positive in two (4%). Thus, the sensitivity
      of the test was 55% and the specificity 100% (81% if positive PCR tests among
      undiagnosed patients are considered as false positive results). CONCLUSION: PCR
      applied to whole blood samples appears to be a sensitive and very specific
      diagnostic test for identifying patients with pneumococcal pneumonia with a
      potential application in clinical practice.

PMID- 10639532
TI  - Increase in exhaled carbon monoxide during exacerbations of cystic fibrosis.
AB  - BACKGROUND: Non-invasive assessment of inflammation is likely to be useful in the
      management of cystic fibrosis (CF). Exhaled carbon monoxide (CO) concentrations
      are increased in patients with clinically stable CF. A study was undertaken to
      determine whether this marker of oxidative damage is further increased during
      exacerbations of the disease. METHODS: Exhaled CO concentrations were measured in
      12 healthy non-smoking control subjects (six men) of mean (SE) age 37 (2) years
      with forced expiratory volume in one second (FEV(1)) 95 (1)% predicted and in 44
      patients with CF (20 men) of mean (SE) age 29 (1) years with FEV(1) 56 (3)%
      predicted using an on-line CO analyser. RESULTS: Twenty nine patients were in a
      stable condition while 15 had clinically defined respiratory exacerbations
      (increased cough and production of sputum, change in the quality of the sputum,
      shortness of breath, sensation of chest congestion, and deterioration of FEV(1))
      and represented the unstable group. Exhaled CO concentrations were 2.0 (0.15) ppm
      in the control group, were increased in the stable CF group to 2.7 (0.13) ppm
      (differences between means -0.67 (0.22), 95% confidence interval (CI) 0.22 to
      1.12, p<0.01) and further increased in the unstable group to 4.8 (0.3) ppm
      (differences between means -2.15 (0.32), 95% CI 1.50 to 2.79, p<0.001). A
      significant correlation was found between the deterioration in FEV(1) and exhaled
      CO concentrations. CONCLUSIONS: This study shows that the measurement of exhaled
      CO is of potential value as an indicator of exacerbations in patients with CF and
      could be used as a simple method to monitor the course of the disease.

PMID- 10639533
TI  - Adult familial cryptogenic fibrosing alveolitis in the United Kingdom.
AB  - BACKGROUND: Familial cases of cryptogenic fibrosing alveolitis (CFA) have
      previously been reported; however, the prevalence and genetic background of this
      disorder are not known. The clinical and epidemiological findings of 25 families
      identified within the UK are reported. METHODS: Adult pulmonary physicians in the
      UK were asked to identify all families under their care in which two or more
      individuals had been diagnosed with fibrosing alveolitis of unknown cause. A
      detailed structured questionnaire was sent to each proband to delineate possible
      environmental/occupational exposures and to obtain complete pedigree data.
      Physicians were also asked to provide clinical and diagnostic information.
      RESULTS: Twenty five families were identified comprising 67 cases. Suitable data
      for analysis were available for 21 families (57 cases). The male:female ratio was
      1. 75:1 (p<0.05). A high resolution computed tomographic (HRCT) scan was
      performed in 93% and a diagnosis of CFA confirmed on biopsy specimens in 32%. The
      mean age at diagnosis was 55.5 (2.5) years. Fifty percent of cases were ever
      smokers and 18% had been diagnosed as asthmatic. Exposure to known fibrogenic
      agents was recorded by 36% of patients. Clinical signs/symptoms and histological
      findings were indistinguishable from non-familial cases. CONCLUSIONS: This study
      represents the largest cohort of familial CFA cases reported to date and confirms
      a prevalence of 1.34 cases per 10(6) in the UK population. Although rare, such
      cases represent an important subgroup in which a genetic susceptibility to
      pulmonary fibrosis is particularly evident. Familial patients are younger at
      diagnosis but otherwise indistinguishable from non-familial cases. The mode of
      inheritance is as yet unclear but a number of genetic loci are likely to be
      involved and are the subject of ongoing studies.

PMID- 10639534
TI  - Role of E-selectin in bleomycin induced lung fibrosis in mice.
AB  - BACKGROUND: Bleomycin (BLM), a well known anti-cancer drug, often causes acute
      lung injury and fibrosis by mechanisms that are not well understood. It is
      suspected that some proteases and active oxygen species generated from
      inflammatory cells cause the lung injury and subsequent lung fibrosis. It was
      therefore hypothesised that inhibition of adhesion of inflammatory cells to the
      endothelium might prevent these developments. METHODS: BLM (100 mg/kg) was
      injected into the tail veins of ICR mice to evaluate the induction of E-selectin,
      an adhesion molecule known to induce neutrophil attachment on endothelial cells.
      E-selectin mRNA induction was detected by reverse transcriptase polymerase chain
      reaction (RT-PCR). The myeloperoxidase (MPO) activities in the lung tissues of
      BLM treated and control mice were compared to evaluate neutrophil infiltration.
      Pathological changes in the lungs of soluble E-selectin transgenic mice (TG) and
      their TG negative (non-TG) littermates after BLM treatment were also compared.
      Serum samples of TG mice and non-TG mice were tested for their ability to block
      the binding of sialyl Lewis(x) to recombinant E-selectin in vitro. RESULTS: E
      selectin mRNA was maximally induced at six hours after BLM treatment in the ICR
      mice. The soluble form of E-selectin which can competitively inhibit the binding
      of sialylated antigens on inflammatory cells to E- and P-selectins on the
      endothelium was detected in the serum of TG mice. BLM induced lung fibrosis
      occurred in non-TG mice but not in TG mice. This result confirms the finding that
      the serum of TG mice inhibits the binding of sialyl Lewis(x) to E-selectin in
      vitro. CONCLUSION: E-selectin plays an essential role in BLM induced lung
      fibrosis through the induction of neutrophil and other inflammatory cell
      accumulation, and soluble E-selectin may be of use in the prophylactic treatment
      of lung fibrosis.

PMID- 10639535
TI  - Do hospital physicians have a role in reducing antibiotic prescribing in the
      community?

PMID- 10639537
TI  - Alveolar haemorrhage in a case of high altitude pulmonary oedema.
AB  - A case of high altitude pulmonary oedema (HAPE) in a climber who made a rapid
      ascent on Mt McKinley (Denali), Alaska is described. The bronchoalveolar lavage
      (BAL) fluid contained increased numbers of red blood cells and an abundance of
      haemosiderin laden macrophages consistent with alveolar haemorrhage. The timing
      of this finding indicates that alveolar haemorrhage began early during the
      ascent, well before the onset of symptoms. Although evidence of alveolar
      haemorrhage has been reported at necropsy in individuals dying of HAPE, previous
      reports have not shown the same abundance of haemosiderin laden macrophages in
      the BAL fluid. These findings suggest that alveolar haemorrhage is an early event
      in HAPE.

PMID- 10639536
TI  - Pleuropulmonary manifestations of systemic lupus erythematosus.

PMID- 10639538
TI  - Xanthoma disseminatum with respiratory tract involvement and fatal outcome.
AB  - Xanthoma disseminatum (XD) is a rare mucocutaneous xanthomatosis classified as a
      benign form of non-Langerhans' cell histiocytosis. The case history is presented
      of a 61 year old woman with XD who developed dyspnoea and spirometric features of
      airflow obstruction. Bronchoscopy and computed tomography confirmed involvement
      of the large and medium sized bronchi and she subsequently died from acute
      respiratory failure. The post-mortem findings and the importance of respiratory
      tract disease in this unusual condition are discussed.

PMID- 10639539
TI  - Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on
      cardiovascular events in high-risk patients.
AB  - BACKGROUND: Angiotensin-converting-enzyme inhibitors improve the outcome among
      patients with left ventricular dysfunction, whether or not they have heart
      failure. We assessed the role of an angiotensin-converting-enzyme inhibitor,
      ramipril, in patients who were at high risk for cardiovascular events but who did
      not have left ventricular dysfunction or heart failure. METHODS: A total of 9297
      high-risk patients (55 years of age or older) who had evidence of vascular
      disease or diabetes plus one other cardiovascular risk factor and who were not
      known to have a low ejection fraction or heart failure were randomly assigned to
      receive ramipril (10 mg once per day orally) or matching placebo for a mean of
      five years. The primary outcome was a composite of myocardial infarction, stroke,
      or death from cardiovascular causes. The trial was a two-by-two factorial study
      evaluating both ramipril and vitamin E. The effects of vitamin E are reported in
      a companion paper. RESULTS: A total of 651 patients who were assigned to receive
      ramipril (14.0 percent) reached the primary end point, as compared with 826
      patients who were assigned to receive placebo (17.8 percent) (relative risk,
      0.78; 95 percent confidence interval, 0.70 to 0.86; P<0.001). Treatment with
      ramipril reduced the rates of death from cardiovascular causes (6.1 percent, as
      compared with 8.1 percent in the placebo group; relative risk, 0.74; P<0.001),
      myocardial infarction (9.9 percent vs. 12.3 percent; relative risk, 0.80;
      P<0.001), stroke (3.4 percent vs. 4.9 percent; relative risk, 0.68; P<0.001),
      death from any cause (10.4 percent vs. 12.2 percent; relative risk, 0.84;
      P=0.005), revascularization procedures (16.3 percent vs. 18.8 percent; relative
      risk, 0.85; P<0.001), cardiac arrest (0.8 percent vs. 1.3 percent; relative risk,
      0.62; P=0.02), [corrected] heart failure (9.1 percent vs. 11.6 percent; relative
      risk, 0.77; P<0.001), and complications related to diabetes (6.4 percent vs. 7.6
      percent; relative risk, 0.84; P=0.03). CONCLUSIONS: Ramipril significantly
      reduces the rates of death, myocardial infarction, and stroke in a broad range of
      high-risk patients who are not known to have a low ejection fraction or heart
      failure.

PMID- 10639540
TI  - Vitamin E supplementation and cardiovascular events in high-risk patients.
AB  - BACKGROUND: Observational and experimental studies suggest that the amount of
      vitamin E ingested in food and in supplements is associated with a lower risk of
      coronary heart disease and atherosclerosis. METHODS: We enrolled a total of 2545
      women and 6996 men 55 years of age or older who were at high risk for
      cardiovascular events because they had cardiovascular disease or diabetes in
      addition to one other risk factor. These patients were randomly assigned
      according to a two-by-two factorial design to receive either 400 IU of vitamin E
      daily from natural sources or matching placebo and either an angiotensin
      converting-enzyme inhibitor (ramipril) or matching placebo for a mean of 4.5
      years (the results of the comparison of ramipril and placebo are reported in a
      companion article). The primary outcome was a composite of myocardial infarction,
      stroke, and death from cardiovascular causes. The secondary outcomes included
      unstable angina, congestive heart failure, revascularization or amputation, death
      from any cause, complications of diabetes, and cancer. RESULTS: A total of 772 of
      the 4761 patients assigned to vitamin E (16.2 percent) and 739 of the 4780
      assigned to placebo (15.5 percent) had a primary outcome event (relative risk,
      1.05; 95 percent confidence interval, 0.95 to 1.16; P=0.33). There were no
      significant differences in the numbers of deaths from cardiovascular causes (342
      of those assigned to vitamin E vs. 328 of those assigned to placebo; relative
      risk, 1.05; 95 percent confidence interval, 0.90 to 1.22), myocardial infarction
      (532 vs. 524; relative risk, 1.02; 95 percent confidence interval, 0.90 to 1.15),
      or stroke (209 vs. 180; relative risk, 1.17; 95 percent confidence interval, 0.95
      to 1.42). There were also no significant differences in the incidence of
      secondary cardiovascular outcomes or in death from any cause. There were no
      significant adverse effects of vitamin E. CONCLUSIONS: In patients at high risk
      for cardiovascular events, treatment with vitamin E for a mean of 4.5 years had
      no apparent effect on cardiovascular outcomes.

PMID- 10639542
TI  - The value of routine preoperative medical testing before cataract surgery. Study
      of Medical Testing for Cataract Surgery.
AB  - BACKGROUND: Routine preoperative medical testing is commonly performed in
      patients scheduled to undergo cataract surgery, although the value of such
      testing is uncertain. We performed a study to determine whether routine testing
      helps reduce the incidence of intraoperative and postoperative medical
      complications. METHODS: We randomly assigned 19,557 elective cataract operations
      in 18,189 patients at nine centers to be preceded or not preceded by a standard
      battery of medical tests (electrocardiography, complete blood count, and
      measurement of serum levels of electrolytes, urea nitrogen, creatinine, and
      glucose), in addition to a history taking and physical examination. Adverse
      medical events and interventions on the day of surgery and during the seven days
      after surgery were recorded. RESULTS: Medical outcomes were assessed in 9408
      patients who underwent 9626 cataract operations that were not preceded by routine
      testing and in 9411 patients who underwent 9624 operations that were preceded by
      routine testing. The most frequent medical events in both groups were treatment
      for hypertension and arrhythmia (principally bradycardia). The overall rate of
      complications (intraoperative and postoperative events combined) was the same in
      the two groups (31.3 events per 1000 operations). There were also no significant
      differences between the no-testing group and the testing group in the rates of
      intraoperative events (19.2 and 19.7, respectively, per 1000 operations) and
      postoperative events (12.6 and 12.1 per 1000 operations). Analyses stratified
      according to age, sex, race, physical status (according to the American Society
      of Anesthesiologists classification), and medical history revealed no benefit of
      routine testing. CONCLUSIONS: Routine medical testing before cataract surgery
      does not measurably increase the safety of the surgery.

PMID- 10639543
TI  - A Medical Mystery.

PMID- 10639541
TI  - Supplemental perioperative oxygen to reduce the incidence of surgical-wound
      infection.
AB  - BACKGROUND: Destruction by oxidation, or oxidative killing, is the most important
      defense against surgical pathogens and depends on the partial pressure of oxygen
      in contaminated tissue. An easy method of improving oxygen tension in adequately
      perfused tissue is to increase the concentration of inspired oxygen. We therefore
      tested the hypothesis that the supplemental administration of oxygen during the
      perioperative period decreases the incidence of wound infection. METHODS: We
      randomly assigned 500 patients undergoing colorectal resection to receive 30
      percent or 80 percent inspired oxygen during the operation and for two hours
      afterward. Anesthetic treatment was standardized, and all patients received
      prophylactic antibiotic therapy. With use of a double-blind protocol, wounds were
      evaluated daily until the patient was discharged and then at a clinic visit two
      weeks after surgery. We considered wounds with culture-positive pus to be
      infected. The timing of suture removal and the date of discharge were determined
      by the surgeon, who did not know the patient's treatment-group assignment.
      RESULTS: Arterial oxygen saturation was normal in both groups; however, the
      arterial and subcutaneous partial pressure of oxygen was significantly higher in
      the patients given 80 percent oxygen than in those given 30 percent oxygen. Among
      the 250 patients who received 80 percent oxygen, 13 (5.2 percent; 95 percent
      confidence interval, 2.4 to 8.0 percent) had surgical-wound infections, as
      compared with 28 of the 250 patients given 30 percent oxygen (11.2 percent; 95
      percent confidence interval, 7.3 to 15.1 percent; P=0.01). The absolute
      difference between groups was 6.0 percent (95 percent confidence interval, 1.2 to
      10.8 percent). The duration of hospitalization was similar in the two groups.
      CONCLUSIONS: The perioperative administration of supplemental oxygen is a
      practical method of reducing the incidence of surgical-wound infections.

PMID- 10639544
TI  - The physiology of parathyroid hormone-related protein.

PMID- 10639545
TI  - Ingestion of toxic substances by children.

PMID- 10639546
TI  - Case records of the Massachusetts General Hospital. Weekly clinicopathological
      exercises. Case 2-2000. A 74-year-old man with painless jaundice 10 years after
      renal transplantation.

PMID- 10639547
TI  - ACE inhibition in cardiovascular disease.

PMID- 10639548
TI  - Prevention of surgical-wound infections.

PMID- 10639549
TI  - More preoperative assessment by physicians and less by laboratory tests.

PMID- 10639551
TI  - Correction: Priming with Human Chorionic Gonadotropin before Retrieval of
      Immature Oocytes in Women with Infertility Due to the Polycystic Ovary Syndrome.

PMID- 10639552
TI  - Correction: Students' Knowledge of and Attitudes about Female Circumcision in
      Egypt.

PMID- 10639550
TI  - Rethinking the role of tube feeding in patients with advanced dementia.

PMID- 10639553
TI  - Pediatric asthma epidemiology: incidence, morbidity, and mortality.
AB  - Despite significant advances in understanding the pathophysiology of asthma and
      the development of pharmacologic agents for treatment, asthma prevalence,
      morbidity, and mortality continue to increase in most countries. This Article
      focuses on the epidemiology of asthma, specifically on the prevalence, incidence,
      morbidity, and mortality associated with pediatric asthma.

PMID- 10639554
TI  - Pathophysiology of asthma.
AB  - Asthma is a complex, multifactorial disease. Although airway reactivity,
      inflammation, and increased mucus secretion are agreed on universally as the
      central components of asthma, the pathophysiology of each of these is complex.
      This Article reviews the physiologic events resulting in symptoms of asthma. The
      contributions of genetics and environment to the development of the asthma
      phenotype are discussed. Gastroesophageal reflux and environmental allergies are
      prevalent conditions in asthmatic patients and often act as significant triggers
      for asthma symptoms.

PMID- 10639555
TI  - Pediatric pulmonary function testing.
AB  - Pulmonary function testing is an essential component in the diagnosis and
      monitoring of the pediatric asthmatic. Very young children are capable of
      performing spirometry, lung Volumes, airway mechanics, and other testing.
      Obtaining valid test results in children is dependent on multiple factors
      including equipment selection, environment, technologist training and competence
      level, and the child's developmental age. Multiple test methods are discussed to
      assess the degree of airway obstruction and reversibility.

PMID- 10639556
TI  - Drugs used in the treatment of asthma: a review of clinical pharmacology and
      aerosol drug delivery.
AB  - The selection and titration of pharmacologic agents are essential in the
      treatment of asthma. This Article focuses on the primary medications used in the
      treatment of reactive airway disease. The recent advances in the technology of
      devices used to administer aerosolized medications are also reviewed.

PMID- 10639557
TI  - Pediatric asthma disease management.
AB  - The prevalence of asthma in children in the United States is estimated at more
      than 5% of the population, and it has risen more than 40% in the previous decade.
      Several guidelines for the management of acute and chronic asthma exist, and they
      all emphasize several basic components including state-of-the-art pharmacologic
      treatment, trigger avoidance, and patient self-management skills. This Article
      highlights the necessary components for pediatric asthma disease management to
      insure a smooth continuum of care across all disciplines and settings.

PMID- 10639558
TI  - Home care.
AB  - As soon as the pediatric asthmatic leaves the hospital, emergency department, or
      physician's office, the provision of their care is in the hands of a parent or
      guardian, or themselves. Patients often require more intensive intervention by a
      health care professional. The respiratory therapist is a logical physician
      extender in the home. This Article explores home-based asthma disease management
      programs that are respiratory-therapist directed.

PMID- 10639559
TI  - Ambulatory management of pediatric asthma.
AB  - Asthma is the most common chronic inflammatory disease of childhood. While
      specialists should care for the most severe individuals with this disease, the
      bulk of pediatric asthma care rests in the hands of the primary care physician.
      This Article details information that should be incorporated into the evaluation
      and management of the pediatric asthma patient in the ambulatory setting. Through
      the adoption of proper assessment and monitoring techniques in conjunction with
      optimal treatment strategies, our pediatric asthma patients should be able to
      attain the quality of life that all children deserve.

PMID- 10639560
TI  - Emergency care of asthma.
AB  - Children with asthma frequently receive care in the emergency department (ED).
      The factors associated with presentation to the ED are complex and must be
      considered when developing a treatment plan and disposition. The diagnosis and
      assessment must be rapid and focused, and treatment must be initiated promptly.
      Objective measures should be used where possible to assess the response to
      therapy and determine readiness for discharge. This Article reviews the essential
      components of diagnosis, assessment, and treatment of pediatric asthma in the ED,
      and it reviews the key elements of discharge planning.

PMID- 10639561
TI  - Acute inpatient care of status asthmaticus.
AB  - The hospital management of status asthmaticus includes aggressive use of a
      limited armamentarium of medications. Understanding the appropriate use of
      available medications is key. Proper assessment of the severity of an acute
      episode and response to applied therapies is essential for optimum outcomes
      without undue delays in treatment and excessive costs. Ensuring that all patients
      discharged from the hospital receive an individualized treatment plan for the
      management of chronic stable, worsening, and acute asthma can help prevent future
      hospitalizations.

PMID- 10639562
TI  - Mechanical ventilation for children with status asthmaticus.
AB  - Status asthmaticus is the most common diagnosis leading to hospital admission in
      childhood. Most of these patients respond well to oxygen, steroids, beta
      agonists, anticholinergics, and other medications. The few patients who develop
      respiratory failure from severe status asthmaticus pose many challenges to those
      supporting them in the intensive care unit. This Article discusses the
      pathophysiology of asthma and how that relates to appropriate ventilator
      management. Alternative therapies are briefly discussed.

PMID- 10639563
TI  - Profile of genetic alterations and tumorigenicity of human breast cancer cells.
AB  - The profile of genetic alterations in four breast carcinoma cell lines, SK-BR-3,
      BT-474, MDA-MB361 and ZR-75-1 was examined by comparative genomic hybridization,
      G-band karyotyping, reverse chromosome painting and fluorescence in situ
      hybridization of single-copy genes. These lines are aneuploid with complex
      structural rearrangements and have DNA copy-number imbalances involving multiple
      sites that include amplification of ERBB-2 and MYC proto-oncogenes which are
      implicated in breast cancer pathogenesis. A novel site of high level
      amplification was mapped on chromosome 15. All lines were tumorigenic in nude
      mice, however, the latency and the incidence of tumor formation varied; SK-BR-3
      and MDA-MB361 produced tumors in a shorter time and had a higher total number of
      genomic imbalances compared to BT-474 and ZR-75-1 cells. Tumor cell behavior in
      vivo was not reflected by the rate of in vitro cell proliferation.
      Underrepresentation on the long arm of chromosome 18 was the sole alteration that
      correlated with an increased tumorigenicity. Chromosome 18q is rich in tumor
      suppressor genes and its loss is prevalent in primary node-positive breast
      tumors. Cell lines with monoclonal populations preserve the genetic
      characteristics of the primary tumor and their use may facilitate the detection
      of specific alterations associated with breast cancer progression.

PMID- 10639564
TI  - S100P calcium-binding protein overexpression is associated with immortalization
      of human breast epithelial cells in vitro and early stages of breast cancer
      development in vivo.
AB  - The mechanism of cell immortalization of human breast epithelial cells leading to
      neoplastic transformation is not clear. The isolation and characterization of a
      spontaneously immortalized human breast epithelial cell line, MCF-10F, have
      provided a valuable tool to identify genes involved in this process. Using the
      technique of differential display, we have identified seven cDNA bands
      differentially displayed in the MCF-10F cells when compared with the mortal S130
      cells from which MCF-10F was originated. One of these bands was isolated and
      cloned. Sequence analysis revealed 99% homology to the EF-hand calcium-binding
      protein S100P (Placental). The clone was overexpressed in the immortal cell line
      MCF-10F when compared to the mortal counterpart S130 or other primary cultures of
      human breast epithelial cells. In addition, it was highly expressed in chemically
      transformed breast epithelial cell lines (BP1E and D3. 1), breast cancer cell
      line T47D, as well as in three invasive ductal carcinomas when compared to their
      normal adjacent tissue. The S100P protein was localized by immunohistochemistry,
      using a monoclonal antibody against the same amino acid sequence of the gene
      cloned, in ductal hyperplasias, in situ and invasive ductal carcinoma, but not in
      the normal tissues. We concluded that S100P overexpression is an early event that
      might play an important role in the immortalization of human breast epithelial
      cells in vitro and tumor progression in vivo.

PMID- 10639565
TI  - Detection of ornithine decarboxylase mRNA in human breast cancer MCF-7 cells by
      in situ RT-PCR.
AB  - We have studied the expression of ornithine decarboxylase (ODC) mRNA by in situ
      hybridization and in situ RT-PCR in human breast cancer MCF-7 cell line. In situ
      RT-PCR demonstrated the overexpression of ODC mRNA, localized over the cytoplasm,
      while a very low signal was detected by in situ hybridization. Our findings
      indicate that in situ RT-PCR could represent a useful tool to study different
      levels of ODC expression in normal and tumor tissues. Since ODC expression is
      regulated by c-Myc oncoprotein, this model could be useful to monitor in vivo the
      effects of new anti-neoplastic molecules, specific inhibitors of c-Myc.

PMID- 10639566
TI  - Structures and comparison of genomic and complementary DNAs of mouse MSSP, a c
      Myc binding protein.
AB  - Two cDNAs encoding mouse MSSP and Scr3 were cloned. Both proteins, like those in
      humans, share significant homology of the region near the N-terminus containing
      the RNA-binding protein, RNP, while little homology exists near the C-terminal
      region of the proteins. Expression of mouse MSSP and Scr3 in mouse tissues were
      examined by Northern blot hybridization and both mRNAs were ubiquitously
      expressed in all the tissues except for testis, where the smaller sizes of MSSP
      mRNAs, but not Scr3 mRNA, were highly expressed. Then, the genomic DNA of mouse
      MSSP was cloned. Mouse genomic MSSP gene was comprised of at least 13 exons over
      the region spanning 60 kb. Furthermore, a chromosome location of human MSSP gene
      was identified at 2q24 by FISH mapping.

PMID- 10639567
TI  - Overexpression of vascular endothelial growth factor164 and its co-receptor
      neuropilin-1 in estrogen-induced rat pituitary tumors and GH3 rat pituitary tumor
      cells.
AB  - We have shown previously that the VEGF system plays a crucial role in regulation
      of tumor angiogenesis during the development of estrogen-induced prolactin
      secreting pituitary tumors in Fisher 344 rats. Studies also suggested that both
      endothelial and non-endothelial cells expressed VEGF. However, several questions
      concerning the VEGF signals in regulation of estrogen-induced angiogenesis in rat
      pituitary remained unanswered. VEGF exists in a number of isoforms in human and
      rodent tissue (i.e., VEGF206h/205r, VEGF189h/188r, VEGF165h/164r, VEGF145h/144r
      and VEGF121) that differ in their molecular masses and biological activities. The
      VEGF isoforms bind with two tyrosine-kinase receptors, KDR/flk-1 and flt-1. In
      addition, VEGF165 binds with a newly identified co-receptor, neuropilin-1, which
      is expressed in human endothelial cells and several types of non-endothelial
      cells including tumor cells. The present study was undertaken to elucidate which
      isoforms of VEGF are predominantly expressed in normal Fisher 344 rat
      pituitaries, estrogen-induced prolactin secreting rat pituitary tumors and in
      prolactin secreting rat pituitary tumor cell line (GH3 cell line). To identify
      the isoform, RT-PCR with primer pairs derived from exon 1 and exon 8 of the VEGF
      gene, cloning, sequencing and Western blot analysis were performed. The status of
      neuropilin-1 in the rat pituitaries (normal and transformed) and GH3 pituitary
      tumor cell line has also been investigated using RT-PCR and Western blot
      analysis. These studies demonstrate that normal rat pituitaries, estrogen-induced
      rat pituitary tumors and GH3 pituitary tumor cells expressed VEGF164 and co
      receptor, neuropilin-1. The VEGF164 was the predominant form in all of these
      cells. The VEGF164 and neuropilin-1 mRNA and protein levels were significantly
      higher in the estrogen-induced pituitary tumors and GH3 tumor cell line, as
      compared to normal pituitary. The data suggest that both VEGF164 and neuropilin-1
      may actively participate in modulation of tumor angiogenesis and the development
      of pituitary tumors in Fisher 344 rats.

PMID- 10639568
TI  - Cyclin D1 overexpression in esophageal dysplasia: a possible biomarker for
      carcinogenesis of esophageal squamous cell carcinoma.
AB  - There is controversy as to whether esophageal squamous dysplasia is a pre
      cancerous lesion or a non-cancerous lesion. In this study, we conducted an
      immunohistochemical investigation of cyclin D1, retinoblastoma (Rb), p16INK4 and
      p27KIP1 expression in 36 squamous dysplasias and 34 early squamous cell
      carcinomas of the esophagus. The frequency of cyclin D1 overexpression was
      similar in dysplasias and early cancers (30% vs. 35%). Loss of p16INK4 and
      p27KIP1 expression was less frequent in dysplasias than in early cancers (p=0.005
      and 0.001, respectively). Loss of Rb protein expression was not detected in
      dysplasia and rarely observed in early cancer (7%). The proliferation cell
      nuclear antigen index increased from moderate dysplasia to mucosal invasive
      carcinoma and was correlated significantly with the expression of cyclin D1,
      p16INK4 and p27KIP1 (p=0.0001, 0.003, and 0.007, respectively). Thus, this study
      found that cyclin D1 overexpression starts early in dysplasia and could be a
      useful marker for its malignant potentiality while reduction of p16INK4 and
      p27KIP1 occurs during the transformation from dysplasia to cancer. These findings
      suggest that esophageal dysplasia should be treated as a precancerous lesion.

PMID- 10639569
TI  - Cancer immunomodulation by carbohydrate ligands for the lymphocyte receptor NKR
      P1.
AB  - Natural killer (NK) and T cells express a superfamily of proteins with structural
      features of C-type lectins. Recombinantly prepared soluble form of rat NKR-P1
      (CD161) recognized carbohydrate GalNac and GlcNac moieties. Ganglioside GM2 and
      heparin related-IS oligosaccharides representing the high affinity ligands for
      this receptor, increased the sensitivity of targets for killing by the rat
      effectors isolated from blood and spleen in vitro. Based on these results, we
      investigated in vivo the possible therapeutic effect of GM2 and IS carried by
      liposomes during induced rat colorectal carcinogenesis. The reduction of cancer
      incidence versus the controls (50% vs 88.88%), approached the 5-fluorouracil
      treatment (41.66%).

PMID- 10639570
TI  - Modulation of transforming growth factor beta1 gene expression in the mammary
      gland by insulin-like growth factor I and octreotide.
AB  - Transforming growth factor beta1 (TGF-beta1) has been shown to exhibit anti
      proliferative activity for mammary gland epithelial cells and for human breast
      cancer cells. Insulin-like growth factor I (IGF-I), in contrast, is a well
      characterized mitogenic and anti-apoptotic factor involved in mammary gland
      physiology. In order to examine the hypothesis that IGF-I suppresses TGF-beta1
      expression in the mammary gland, we studied the effect of various manipulations
      of the growth hormone - IGF-I axis on TGF-beta1 mRNA abundance. Administration of
      IGF-I to intact animal suppressed TGF-beta1 mRNA levels in a dose-dependent
      manner to approximately 20% of control levels. Administration of the somatostatin
      analogue octreotide in a manner previously shown to acutely suppress the growth
      hormone - IGF-I axis increased mammary gland TGF-beta1 expression approximately 3
      fold. Transgenic mice overexpressing growth hormone expressed TGF-beta1 in the
      mammary gland at only approximately 12% of the level of control animals, while
      mice IGF-I deficient due to the mutation expressed TGF-beta1 at slightly higher
      levels than control animals. The large differences in TGF-beta1 expression
      between control and GH-transgenic animals were correlated with major differences
      in architecture of the mammary gland, while the appearance of mammary glands of
      normal and animals was similar. These data document a previously unrecognized
      relationship between TGF-beta1 and IGF-I physiology in the mammary gland, and
      suggest a novel mechanism by which somatostatin analogues influence the
      proliferative behaviour of breast epithelial cells.

PMID- 10639571
TI  - Assessment of secondary necrosis of Jurkat cells using a new microscopic system
      and double staining method with annexin V and propidium iodide.
AB  - Using a new system developed by us for acquiring microscopic images
      automatically, we compared the morphological changes that apoptotic cells undergo
      with changes in the staining pattern of annexin V-enhanced green fluorescent
      protein (AV-EGFP) and propidium iodide (PI) in individual cells. Jurkat cells
      were treated with 5 mM CaCl2 alone, anti-Fas antibody and heating at 42 degrees C
      for 30 min or 46 degrees C for 60 min, and then were incubated in medium with 5
      mM CaCl2. Time-lapse DNA fragmentation analysis and morphological observation
      revealed that the anti-Fas antibody and heating at 42 degrees C for 30 min
      induced typical apoptosis in the cells, and heating at 46 degrees C for 60 min
      induced typical necrosis. Time-lapse observation of individual cells stained with
      AV-EGFP and PI confirmed that apoptotic cells were stained at first with AV-EGFP
      alone, and thereafter also with PI when the cellular membrane ruptured and the
      cell underwent secondary necrosis. Most of the cells which underwent necrosis
      were stained simultaneously with AV-EGFP and PI. There was a significant time
      interval between the staining of individual cells with AV-EGFP, indicating
      apoptosis, and staining of these cells with PI, which indicated the occurrence of
      secondary necrosis. These results suggest that time-lapse examinations are
      necessary to distinguish apoptosis, secondary necrosis and necrosis in cells from
      one another. This study presents direct evidence that apoptotic cells undergo
      secondary necrosis, which could be recognized with PI.

PMID- 10639572
TI  - Quantification of micrometastases in lymph nodes of colorectal cancer using real
      time fluorescence polymerase chain reaction.
AB  - The expression of carcinoembryonic antigen (CEA) mRNA was assessed in 102 lymph
      nodes (LNs) obtained from seven colorectal cancer patients by both the
      conventional non-quantitative RT-PCR and quantitative RT-PCR. The number of CEA
      expressing cells was calculated compared with CEA-expressing MKN-45 cell line as
      a standard control. Using the quantitative RT-PCR, the relative number of CEA
      expressing cells ranged between 1.3x103 and 5.7x106 in 16 histologically positive
      LNs and between 2.3x101 and 8.1x105 in 10 histologically negative and RT-PCR
      positive LNs. In both histologically and RT-PCR negative LNs, the relative cell
      number was <4.0x102. Our results demonstrated that quantifying the amount of
      metastasis might enhance the reliability of RT-PCR detection assay as a
      diagnostic tool for the detection of cancer micrometastases.

PMID- 10639573
TI  - NADPH/quinone oxidoreductase is a priority target of glioblastoma chemotherapy.
AB  - We attempted to determine a target of chemotherapy specific to glioblastoma cells
      to ensure a favorable response to anticancer drugs, through comparison in
      biologic nature related to drug resistance with other types of cancer cells.
      Using 13 human cancer cell lines including 3 glioblastoma lines, gene expression
      analysis and biochemical quantitative assay were performed for a total of 12
      properties, which have been linked to drug action. Although most of genes related
      to drug resistance, such as MDR1, MRP, MGMT and GSTpi, were overexpressed in
      T98G, U-373MG, and U-251MG glioblastoma cells, Topo I (topoisomerase I)
      expression was relatively low and alpha- and beta-TUB (tubulin) expression was
      comparable to other types of 10 cell lines. The glioblastoma cell lines also
      showed an increased expression of NADPH/quinone oxidoreductase gene (NQO1), but
      the respective enzyme NQO activated MMC. Among the drugs targeting such
      properties, MMC was more active than Topo I inhibitors and docetaxel (TXT) due to
      the lack of other sensitivity (resistance) determinants. Differing from MMC, MGMT
      was shown to participate in the resistance of Topo I inhibitors (CPT-11, SN-38
      and DX-8951f), while GSTpi and MDR1 were involved in docetaxel (TXT) resistance.
      MMC was also more active than ACNU and CDDP in the three glioblastoma cells. NQO
      may be a priority target of glioblastoma chemotherapy suitable for biochemical
      nature of the cells, and expression analysis of NQO1, alpha-TUB, beta-TUB, MGMT,
      MDR1 and GSTpi may help to seek a truly active drug against glioblastomas.

PMID- 10639575
TI  - Effect of a novel vitamin D3 analog, EB1089, on G1 cell cycle regulatory proteins
      in HL-60 cells.
AB  - Progression of cell cycle in eukaryotes is regulated by a series of the cyclin
      dependent kinases (CDKs) and cyclin-dependent kinase inhibitors (CDKIs). It has
      been shown that 1,25(OH)2D3 is able to arrest cell cycle at G1 phase in malignant
      cells including HL-60 cells. EB1089 is a novel 1,25(OH)2D3 analog that has more
      potent antileukemic properties with reduced hypercalcemic effect in vitro and in
      vivo than 1,25(OH)2D3. In the present study, we examined the effect of EB1089 on
      HL-60 cells at the protein levels of several G1 regulatory proteins. Exposure of
      HL-60 cells to EB1089 (1x10-8 M) for 3 days showed the G1 block by FACS analysis.
      The level of p21 was markedly induced in HL-60 cells treated with EB1089 at 24 h,
      and p27 were progressively increased in a time-dependent manner. The expressions
      of CDK2 and CDK6 were down-regulated during G1 block of HL-60 cells, and CDK4 is
      progressively elevated. In addition, level of cyclin D1 was increased in a time
      dependent manner, however, no change of cyclin E was noted through the G1 to S
      traverse. Immunoprecipitation study demonstrated that p27 did not bind to CDK2,
      CDK4 and CDK6 in EB1089-treated HL-60 cell extracts. In contrast, complexes
      immunoprecipitated from EB1089-treated HL-60 cells with antibodies CDK2 and CDK6
      contained higher amounts of immunodetectable p21 protein compared to untreated HL
      60 cells, whereas no detectable change was noted with anti-CDK4 antibody.
      Furthermore, the kinase activities of CDK2 and CDK6 were decreased while little
      change was observed in CDK4 activity. These data indicated that p21 protein is a
      strong candidate for the control of G1 progression in EB1089-treated HL-60 cells,
      and its major target molecules are CDK2 and CDK6.

PMID- 10639574
TI  - Regulation of the activity and polymerization status of recombinant human
      cytosolic thymidine kinase by thiols and ATP.
AB  - The cDNA clone encoding human thymidine kinase (hTK), was expressed in E. coli
      using a prokaryotic expression vector, pKK 223-3. The kinetics of the recombinant
      hTK (rhTK) were similar to those of cytosolic TK but not of mitochondrial TK.
      rhTK was highly purified in the presence of either ATP or dithiothreitol (DTT).
      The specific activity of rhTK purified in the presence of ATP [rhTK(ATP)] was
      lower than that of rhTK purified in the presence of DTT [rhTK(DTT)]. Activity of
      the purified rhTK(ATP) was enhanced by addition of thiols including DTT,
      cysteine, homocysteine and beta-mercaptoethanol but inhibited by various
      sulfhydryl reagents such as 5,5'-dithio-bis(2-nitrobenzoic acid). Hence, it was
      suggested that rhTK is a thiol-type enzyme. Apparent Mr of purified rhTK(ATP) was
      100 kDa, which corresponds to the size of a tetramer (25 kDa subunit), while that
      of purified rhTK(DTT) was 50 kDa, the size of a dimer. The tetramer form of
      rhTK(ATP) was converted to the dimer by replacement of ATP by DTT. On the other
      hand, the dimer form of rhTK(DTT) was converted to the tetramer by addition of
      ATP. Thus, the catalytic activity of human cytosolic TK might be regulated by
      thiols as well as ATP via its polymerization status.

PMID- 10639576
TI  - Cisplatin-resistance involves the defective processing of MEKK1 in human ovarian
      adenocarcinoma 2008/C13 cells.
AB  - Cisplatin has been widely used as a chemotherapeutic agent to treat different
      types of tumors. However, its use is limited by the ability of the tumor cells to
      develop cisplatin-resistance. The molecular lesion that produces cisplatin
      resistance is poorly understood. In this report, we show that cisplatin activates
      a robust apoptotic pathway involving the activation of JNK and p38MAPK whereas it
      fails to elicit such a response in cisplatin-resistant 2008/C13 cells. Analysis
      of the defective apoptotic pathway in 2008/C13 cells indicates that these cells
      are deficient in the proteolytic activation of MEKK1 by caspase-3. The blunted
      activity of caspase-3 appears to be closely related to the increased levels of
      the anti-apoptotic protein Bcl-xL seen in the resistant cells. These studies, for
      the first time, demonstrate that inadequate caspase-3 processing and MEKK1
      activation can lead to a drug-resistant phenotype.

PMID- 10639577
TI  - Peptide amidating activity in human bronchoalveolar lavage fluid: relationship to
      lung cancer, inflammation and infection.
AB  - The most common post-translational modification of peptide hormones, present in
      half of all neuroendocrine (NE) peptides, is alpha-amidation and this is
      necessary for the biological activity of the peptides. Peptides are alpha
      amidated by the action of two enzymes: peptidylglycine alpha-hydroxylating
      monooxygenase (PHM) and peptidylamidoglycolate lyase (PAL). As the common pathway
      for the formation of amidated peptides, the enzymes may provide a better
      indication of the NE status of a tumour or tissue than the presence of any single
      amidated peptide. PHM and PAL enzyme activities were measured in 39 BL fluid
      specimens from patients undergoing bronchoscopy for diagnosis of lung cancer. The
      assays revealed that PHM levels were higher in a group of specimens from patients
      undergoing bronchoscopy for chest infection, inflammation, asthma, or pneumonia
      compared to a group of specimens in which malignant cells were seen. The presence
      of elevated levels of amidating enzymes in specimens with non-cancerous
      conditions may reflect events of promotional phase cancer biology occurring
      simultaneously with inflammatory and infectious processes.

PMID- 10639578
TI  - Genistein induced molecular changes in a squamous cell carcinoma of the head and
      neck cell line.
AB  - Epidemiological studies have shown lower incidence of breast and prostate cancers
      in Asian populations consuming a traditional diet rich in soy. Protection from
      these cancers was attributed to the isoflavones, particularly genistein and
      daidzein found in vivo as the major metabolites of soy isoflavones. However, the
      role of isoflavones in head and neck cancer is less clear. In our previous
      studies we reported that genistein can induce cell growth inhibition by arresting
      the cells at S/G2-M phases, and also induces apoptosis in HN4 squamous cell
      carcinoma of the head and neck cell line (HNSCC). In this report we show that
      these changes are accompanied by the down-regulation of Cdk1, and CyclinB1, and
      up-regulation of the cyclin dependent kinase (Cdk) inhibitor p21WAF1, which may
      be responsible for the induction of cell cycle arrest and apoptosis. The evidence
      for the induction of apoptosis was supported by the appearance of DNA ladder as
      reported previously, and further supported by our current results on the cleavage
      of poly-ADP-ribose polymerase (PARP), hallmark of apoptosis. This was also
      accompanied by the up-regulation of Bax, with modest down-regulation of Bcl-2
      protein expression, which changes the balance between pro- and anti-apoptosis
      molecules in favor of pro-apoptosis. Furthermore, we also observed down
      regulation and degradation of Cdc25C, which is a marker of cell proliferation,
      and plays important role in CyclinB-Cdk1 complex activation. The down-regulation
      followed by the degradation of Cdc25C is an indicator of G2/M arrest and anti
      proliferation effects of genistein. Collectively, these data provide strong
      molecular evidence for the anti-tumor activity of genistein in HNSCC cells.

PMID- 10639579
TI  - AMY-1 is a trigger for the erythrocyte differentiation of K562 cells.
AB  - We have reported that a novel c-Myc binding protein, AMY-1, stimulated the
      transcription activity of c-Myc and was translocated from cytoplasm to nuclei in
      a c-Myc-dependent manner. Here, the role of AMY-1 in cell differentiation was
      examined. AMY-1 expression was up-regulated after differentiation induction of
      human K562 cells to erythrocyte cells by AraC, while c-Myc expression was rapidly
      down-regulated. K562 cell lines expressing exogenous AMY-1 were established, and
      these cells expressed a high level of epsilon-globin mRNA, a marker gene
      necessary for erythrocyte cell differentiation, without differentiation
      induction. The addition of AraC rapidly initiated differentiation in these cell
      lines, which continued to differentiate to erythrocyte cells possessing a high
      level of hemoglobin even after the decrease in AMY-1 expression. These results
      suggest that AMY-1 is a trigger for K562 cells to differentiate to erythrocyte
      cells and that AMY-1 may have a function independent of or different from c-Myc.

PMID- 10639580
TI  - Human colon cancer cells express multiple glycoprotein ligands for E-selectin.
AB  - The interaction between the colon tumor cell surface and the endothelial cell
      layer is an important component of tumor intravasation, extravasation, and
      metastasis. Multiple studies suggest that tumor cells may bind to E-selectin
      expressed on endothelial cells during these processes. To identify possible E
      selectin ligands on tumor cells that may participate in this mechanism, we used E
      selectin-Ig chimera affinity chromatography to isolate glycoproteins from the
      human colon cancer cell line Colo-205. Binding of these cells to E-selectin was
      specific, required the presence of calcium, and could be blocked by antibodies
      against E-selectin. We identified LAMP-1 (lysosomal membrane glycoprotein-1),
      LAMP-2, and two high molecular weight glycoproteins (>400 kDa and 300 kDa) as the
      main E-selectin ligands on Colo-205 cells. Treatment of the cells with N
      glycanase and O-sialoglycoprotease abolished their binding to E-selectin. The
      high MW glycoproteins contained sialyl Lewis X and/or sialyl Lewis A
      glycoconjugates, and appeared to be either alternatively spliced or alternatively
      glycosylated forms of MUC-1 (mucin-1).

PMID- 10639581
TI  - TGF-beta1 secreted by gastric fibroblasts up-regulates CD44H expression and
      stimulates the peritoneal metastatic ability of scirrhous gastric cancer cells.
AB  - Gastric fibroblast-derived conditioned medium and TGF-beta1 stimulated the
      adhesion ability of scirrhous gastric cancer cells to mesothelial cells, but not
      that of well-differentiated gastric cancer cells. The CD44H expression of
      scirrhous gastric cancer cells was significantly up-regulated by gastric
      fibroblast-derived CM and TGF-beta1. The stimulated adhesion ability and CD44H
      expression was significantly inhibited by anti TGF-beta1 neutralizing antibody.
      These findings suggested that TGF-beta1 secreted by gastric fibroblasts up
      regulated the CD44H expression of scirrhous gastric cancer cells, which resulted
      in the stimulation of the adhesion ability of scirrhous gastric cancer cells to
      the mesothelium, and increased the peritoneal dissemination potential. These
      results might explain one of the reasons why scirrhous gastric carcinomas develop
      frequent peritoneal dissemination.

PMID- 10639582
TI  - Newcastle disease virus activates macrophages for anti-tumor activity.
AB  - Newcastle Disease Virus (NDV), an agent with interesting immune stimulatory and
      anti-tumor activity, was investigated for its capacity to activate anti-tumor
      activity in murine macrophages in vitro and in vivo. Direct macrophage activation
      was seen under a variety of experimental conditions using two different strains
      of NDV, different sources of macrophages (spleen and peritoneum) and different
      strains of mice (DBA/2, C57BL/6, 615). Various macrophage enzymes (ADA, iNOS,
      lysozyme, acid phosphatase) became upregulated and anti-tumor effector molecules
      such as nitric oxide (NO) and TNF-alpha were found in the supernatant. NDV
      activated macrophages performed anti-tumor activity in vitro such as anti-tumor
      cytostasis and anti-tumor cytotoxicity. The cytotoxic anti-tumor activity was
      broad and active against all tumor lines tested including mammary carcinoma, lung
      carcinoma, mastocytoma and immune escape variants (lymphoma). Macrophage
      activation via BCG/LPS also caused a broad range anti-tumor cytotoxic activity
      while activation via mixed lymphocyte culture conditioned medium had restricted
      anti-tumor activity. Anti-tumor activity of NDV activated macrophages could be
      transfered in vivo. Transfer of macrophages which had not been appropriately
      activated exerted either no effect or a tumor growth augmenting effect. Repeated
      intravenous transfer of NDV activated macrophages exerted a significant
      suppressive effect on pulmonary metastases in a mammary carcinoma tumor model as
      well as in a lung carcinoma model. Taken together these results demonstrate that
      NDV can strongly activate macrophages to perform anti-tumor activities in vitro
      and in vivo.

PMID- 10639583
TI  - Angiogenesis inhibitor TNP-470 suppresses the progression of experimentally
      induced hepatocellular carcinoma in rats.
AB  - We evaluated the effects of angiogenesis inhibitor, TNP-470, on hepatocellular
      carcinoma (HCCs) induced by a choline-deficient L-amino acid defined (CDAA) diet
      in rats. Male Fisher 344 rats were fed CDAA for 68 weeks. Rats were treated by
      subcutaneous injection of TNP-470 (15 mg/kg) or saline (control) three times per
      week from 53 to 68 weeks. At the end of the experiment, we determined the
      frequency and size of HCCs and glutathione S-transferase placental form (GSTP)
      positive lesions, histology of liver cirrhosis, liver function, and liver weight
      per body weight. We also determined, using histologic and immunohistochemical
      semiquantification analyses, the degree of vascularity, apoptosis and
      proliferation in HCC and adjacent tissues. Treatment with TNP-470 resulted in a
      reduction of the size and frequency of HCC compared to untreated rats. However,
      TNP-470 did not influence the histology of liver cirrhosis and liver function.
      The liver weight per body weight of TNP-470-treated rats was slightly heavier in
      comparison with that of the controls. Treatment with TNP-470 significantly
      reduced tumor vascularity relative to the controls. There were no significant
      differences in the Ki-67 labeling index of HCCs between TNP-470 treated and
      control rats. The frequency of apoptotic hepatoma cells in TNP-470-treated rats
      was higher than in control rats. Our results indicate that TNP-470 suppresses the
      progression of CDAA-induced HCCs in rats through inhibition of angiogenesis, and
      suggest that TNP-470 might be useful clinically for HCCs.

PMID- 10639584
TI  - Patterns of genomic imbalances in human solid tumors (Review).
AB  - Based on comparative studies on CGH-detected genomic imbalances in head and neck
      squamous cell carcinomas and in ovarian tumors it was supposed that the patterns
      of genomic imbalances in human tumors are not only related to the oncogenic
      progress and tumor progression or specific for the tissue of origin, but also
      could be influenced by environmental (mutagenic) factors present in the
      environment of the evolving cancer. To base this hypothesis on a more solid
      ground, data obtained by use of comparative genomic hybridization (CGH) which
      were reported up to early 1999 from a large variety of more than 2400 human solid
      tumors, representing 18 different organs of origin or physical localizations,
      were collected and comparatively analyzed. Patterns of inter- and intra
      chromosomal distribution of DNA sequence copy number changes pointed to high
      conformity on several chromosomal segments, but also revealed striking
      differences between the tumor types, the latter suggesting tumor specific, tissue
      specific and/or environment specific influences on the generation of genomic
      imbalance in human neoplasia. The clinical relevance of these findings must be
      examined further on by increasing the studied material.

PMID- 10639585
TI  - Molecular analysis of the human myeloperoxidase promoter region.
AB  - Myeloperoxidase (MPO) is a granule protein, transiently expressed during the
      promyelocyte stage of myeloid differentiation. It is transcribed in a stage and
      lineage specific manner. Studies of MPO gene regulation can help to elucidate the
      mechanism of normal and abnormal myeloid differentiation. Our preliminary data
      indicated the lack of basal promoter activity in the region immediately 5' to the
      MPO cDNA. Here, we report the results of the detailed molecular studies of the
      human MPO promoter region. To locate potential promoter elements active in HL60
      cells, we made promoter deletion constructs ranging in size from 200 bp to 4.5 kb
      of the 5' region of the hMPO gene, cloned into the chloramphenicol acetyl
      transferase (CAT) reporter vector. Following electroporation of the promoter
      constructs into HL60 cells, CAT enzyme production was found only in the construct
      containing approximately the 1 kb region upstream of the reported MPO cDNA. A
      separate set of constructs was made to look for putative MPO enhancer elements.
      Several fragments upstream of the MPO promoter showed prominent transactivation
      of the TK promoter, indicating a possible enhancer. Tissue specificity of MPO
      promoter fragments was determined in myeloid cells arrested either before
      induction of MPO expression (KG1), during MPO expression (HL60), or after it had
      ceased (U937), as well as in non-MPO expressing non-myeloid cells. The construct
      containing an approximate 1000 bp fragment of the 5' region of MPO was found to
      direct CAT expression only in HL60 cells. The 3'-truncations of this promoter
      region resulted in loss of tissue-specificity, while the promoter activity
      remained largely unchanged. A negative regulatory element was found upstream of
      the MPO promoter which repressed heterologous promoters in all the tested cell
      lines. Enhancer elements showed no tissue- or stage-specificity that were
      characteristic for native MPO gene. Sequence analysis of the putative MPO
      promoter region showed a number of potential transcription factor binding sites.
      Of special interest is the region containing the purine-rich site that can bind
      proteins from the ets-family of transcription factors and a duplicate GATA-like
      site. When inserted upstream of a reporter containing the minimal Herpes simplex
      viral thymidine kinase (HSV-TK) promoter (into pBL2CAT plasmid) this site
      strongly activated the TK promoter in transfected myeloid cells. Further studies
      showed that oligonucleotides derived from the MPO promoter region bind multiple
      proteins in a band-shift assay. Taken together, our experiments located the
      regulatory elements important for human MPO gene expression in HL60
      promyelocytes.

PMID- 10639586
TI  - Inhibition of the mitogen activated protein kinase pathway potentiates radiation
      induced cell killing via cell cycle arrest at the G2/M transition and
      independently of increased signaling by the JNK/c-Jun pathway.
AB  - The ability of low dose ionizing radiation (2 Gy) to modulate the activities of
      the mitogen activated protein kinase (MAPK) and c-Jun NH2-terminal kinase (JNK1)
      cascades in human monocytic leukemia (U937/pREP4) cells and in cells over
      expressing dominant negative c-Jun (TAM67) (U937/TAM67) was investigated.
      Radiation exposure caused prolonged ( approximately 1 h) MAPK activations in U937
      cells. In contrast, low dose irradiation weakly modulated JNK1 activity in these
      cells. Inhibition of the MAPK pathway by use of the specific MEK1/2 inhibitor (10
      microM PD98059) in both U937/pREP4 and U937/TAM67 cells prior to radiation
      exposure permitted strong prolonged radiation-induced activations of JNK1.
      Expression of TAM67 decreased the ability of radiation to cause apoptosis
      compared to control transfected cells. However, combined MEK1/2 inhibition and
      radiation exposure in both cell types caused a large decrease in suspension
      culture growth and a large increase in apoptosis, when compared to either
      treatment alone. Reduced proliferation after combined irradiation and PD98059
      treatment in both cell types correlated with prolonged cell cycle arrest in G2/M
      phase. Prolonged growth arrest was abolished when MEK1/2 inhibitor was removed 6
      h following irradiation, which was associated with a reduction in apoptosis. The
      ability of MEK1/2 inhibition to cause prolonged G2/M growth arrest was reduced in
      U937 cells stably transfected with a p21Cip-1/WAF1 antisense construct
      (U937/p21AS). This data correlated with an enhancement of radiation-induced
      apoptosis and a reduced ability of MEK1/2 inhibition to potentiate apoptosis.
      Collectively our data demonstrate that inhibition of MEK1/2 function increases
      the radiation sensitivity of U937 cells, independently of c-Jun function, and
      decreases the ability of these cells to recover from the radiation-induced G2/M
      cell cycle checkpoint arrest. In addition, our data also demonstrate that the
      ability of MEK1/2 inhibition to potentiate radiation-induced cell death in U937
      cells in part requires an ability of cells to express low levels of p21Cip
      1/WAF1.

PMID- 10639587
TI  - Phthalocyanine 4-photodynamic therapy induces ceramide generation and apoptosis
      in acid sphingomyelinase-deficient mouse embryonic fibroblasts.
AB  - Photodynamic therapy (PDT), a novel cancer treatment using a photosensitizer and
      visible light, produces an oxidative stress in cells that can lead to apoptosis.
      PDT with the phthalocyanine photosensitizer Pc 4 (Pc 4-PDT), causes increased
      generation of ceramide, a lipid mediator, and subsequent induction of apoptosis
      in various cell types. Formation of ceramide by acid sphingomyelinase (ASMase) in
      response to stress has been implicated in apoptotic cell death. We assessed the
      role of ASMase in photocytotoxicity using mouse embryonic fibroblasts (MEFs)
      isolated from ASMase knockout (k/o) and wild-type (wt) mice. Exposure of wt or
      k/o MEFs to Pc 4-PDT led to increased caspase-3 activity and subsequent
      apoptosis. Similarly, ceramide levels were elevated in both cell types post-PDT.
      We suggest that in MEFs, ASMase is dispensable for ceramide accumulation and
      induction of apoptosis after Pc 4-PDT.

PMID- 10639588
TI  - RNA-protein interactions in the control of stability and localization of
      messenger RNA (review).
AB  - Growing evidence demonstrates the importance of regulating mRNA localization,
      stability and translation, in the control of gene expression, both in development
      and in differentiated cells. The signals responsible for specific regulation of
      mRNA metabolism reside in the RNA message itself: both 5' and 3' to the coding
      region, all transcripts contain variable lengths of untranslated sequences (5'
      UTR and 3'-UTR) which contain the binding sites for a number of RNA-binding
      proteins (RBPs). Most RBPs assemble on the message at the moment of
      transcription, thus determining the future fate of the transcript from the very
      beginning. We discuss possible mechanisms through which mRNA, leaving from the
      nucleus as an RNA-protein complex, might reach its final intracellular
      destinations and how its access to the translational apparatus might be regulated
      in time and space. We also focus on a few known examples of aberrant RNA-protein
      interactions associated with human diseases, including cancer.

PMID- 10639589
TI  - Anti-human immunodeficiency virus type 1 of a two-strand-system targeted to the
      polypurine tract.
AB  - The polypurine tract (PPT) is highly conserved among the known human
      immunodeficiency virus (HIV)-1 strains, and is a possible target for triplex
      formation. We show the effects of triple-helix formation by assays of primer
      extension inhibition in vitro, using a two-strand-system (FTFOs) targeted to the
      PPT of HIV-1. The two-stranded composition of a triple-helix is thermodynamically
      and kinetically superior to the three-strand-system. The FTFOs inhibited the RT
      activity in a sequence-specific manner, i.e., the triplex actually formed at the
      PPT and blocked the RT. The FTFOs containing the phosphorothioate groups at the
      antisense sequences showed greater 3'-exonuclease resistance. In the observation
      of the FITC-DsDGloopT5-37 with MOLT-4 cells by a confocal laser scanning
      microscope, diffuse fluorescence was apparently observed in the cytoplasm and
      nucleus. However, weak fluorescence was observed within the cytoplasm and nucleus
      of MOLT-4 cells treated with the antisense phosphorothioate oligonucleotides (S
      ODN-gag-AUG). In HIV-1 infected MOLT-4 cells, the FTFOs containing the
      phosphorothioate groups at the antisense sequence sites and guanosine rich parts
      within the third Hoogsteen base pairing sequence inhibit the replication of HIV-1
      more effectively than the antisense oligonucleotides, indicating sequence
      specific inhibition of HIV-1 replication.

PMID- 10639590
TI  - Epitope analysis and utility of monoclonal antibodies to native and recombinant
      human thymidylate synthase.
AB  - The expression of thymidylate synthase (TS) in human cancer tissues has been
      suggested to be a prognostic factor for patients receiving 5-fluorouracil-based
      chemotherapy. We generated monoclonal antibodies to both recombinant and native
      TS and analyzed the epitopes on the TS molecule. Two monoclonal antibodies were
      obtained from recombinant human TS proteins (RTSMA1 and RTSMA2) and two
      monoclonal antibodies raised to native TS in human cancers (NTSMA1 and NTSMA2)
      were obtained, and were found to have a high affinity and specificity for TS
      proteins. To identify the human TS epitope that these monoclonal antibodies
      recognized, we constructed plasmids to produce full-length and two partially
      deleted TS proteins fused to glutathion-S-transferase (GST). Western blot
      analysis showed that RTSMA1 and 2 only reacted with full-length TS and NTSMA1 and
      2 reacted with all three recombinant TS proteins, suggesting that the epitopes of
      the former were located at C-terminal sites (D186-V313), and those of the latter
      were at N-terminal sites (M1-M61). The RTSMA 1 and 2 epitopes were more
      accurately mapped using 8 oligopeptides to the region of I267 to L282 which was
      situated at the surface of the TS protein. Highly sensitive detection of human TS
      was also possible by sandwich ELISA using a combination of different types of
      antibody rather than a single type. In conclusion, different type monoclonal
      antibodies to human TS protein may contribute to the detection of TS in cancer
      patients.

PMID- 10639591
TI  - Ionizing radiation-induced apoptosis in human lymphoma cell lines differing in
      p53 status.
AB  - Most of malignant lymphomas have been shown to be relatively radiosensitive
      clinically, but some, especially recurrent ones, are frequently highly
      radioresistant. To clarify the origin of the difference, we examined ionizing
      radiation (IR)-induced apoptosis in three closely related human lymphoma cell
      lines (DL-40, DL-95, and DL-110) that differ in p53 status. DL-95 and DL-110
      cells have a wild-type p53, whereas DL-40 cells carry a T to G transition in exon
      5 of the p53 gene, resulting in a change of Cys to Phe at codon 176. Irradiation
      of DL-40 cells (mutant-type p53) with 5 Gy gamma-rays resulted in delayed
      apoptosis with membrane changes (annexin-V expression) 13 h after IR, and caspase
      3 activation 23 h after IR, whereas apoptotic response was not identified in DL
      95 cells until 48 h after IR in spite of their normal p53 status. Concerning DL
      110 cells, delayed and reduced apoptotic response was revealed both
      microscopically and by DNA fragmentation assay. These results suggested that IR
      induced apoptosis in DL-40 cells is mediated by a mechanism involving the caspase
      3 cascade of the p53-independent pathway, and that some unknown mechanism
      inhibited IR-induced apoptosis in existence of wild-type p53, especially for DL
      95 cells.

PMID- 10639592
TI  - All-trans retinoic acid modulates fas expression and enhances chemosensitivity of
      human medulloblastoma cells.
AB  - Retinoic acid (RA) can promote human medulloblastoma cells Med-3 toward
      differentiation but is not sufficient to induce cell death, suggesting its
      limited effect on medulloblastomas. On the other hand, the differentiated tumour
      cells have been supposed to be more sensitive to chemotherapeutic drugs. To
      elucidate this possibility for medulloblastoma cells, 10 microM/l RA, 1.0
      microg/ml cisplatin (CP) and their half-dosage combinations were utilized in this
      study to treat Med-3 cells and their influences in cell proliferation, morphology
      and death patterns were evaluated. In parallel, the expressions of Fas and its
      ligand (FasL) were analyzed by immunocytochemical staining and Western blot
      hybridization. Anti-Fas antibody was used to incubate the Med-3 cells pretreated
      by 10 microM/l RA or 1.0 microg/ml CP. It was revealed that RA and CP could
      inhibit cell growth but rarely induce apoptosis. Combination of half doses each
      of RA and CP effectively caused most of tumour cells to die of apoptosis within 6
      days. FasL molecules in 29 kDa and 37 kDa were detected in Med-3 cells with and
      without the treatments. The Fas molecule around 30 kDa and located in the
      cytoplasm was found in the normally cultured cells and the cells treated by CP.
      An additional 45 kDa Fas band with the appearance of its cell surface labeling
      was detected in the cells treated by 10 microM/l RA and by 5 microM/l RA + 0.5
      microg/ml CP. The anti-Fas antibody could efficiently induce apoptosis only in
      the cell populations pretreated by RA. Our data thus suggest that RA can enhance
      the chemosensitivity of human medulloblastoma Med-3 cells presumably via
      modulating the Fas expression pattern. The RA/CP combined regimen would be a
      potential therapeutic approach for medulloblastomas.

PMID- 10639593
TI  - Grb10 proteins in insulin-like growth factor and insulin receptor signaling
      (review).
AB  - The adapter protein Grb10 belongs to a superfamily of related proteins that
      include Grb7, Grb14 and the Caenorhabtidis elegans Mig10. The available data on
      Grb10 proteins suggest a role of these adapters in signaling downstream of
      several receptor tyrosine kinases. In the present review the focus is on the
      interaction between Grb10 proteins and the insulin-like growth factor
      receptor/insulin receptor, and the role of Grb10 in IGF-I/insulin-induced
      mitogenesis is discussed, considering that the data available are also partially
      discordant.

PMID- 10639594
TI  - The alteration of mitochondria is an early event of arsenic trioxide induced
      apoptosis in esophageal carcinoma cells.
AB  - It is accepted that inorganic arsenic trioxide is an inducer of apoptosis for
      many types of cancer. Our previous studies have demonstrated that arsenic
      trioxide induces apoptosis of esophageal carcinoma cells. Administration of
      arsenic trioxide results in the inhibition of growth and survival of tumor cells.
      Esophageal carcinoma cells treated with arsenic trioxide for 3 days demonstrated
      a typical morphological appearance of apoptosis. To further examine molecular
      mechanism of arsenic trioxide induced apoptosis of esophageal carcinoma cells, we
      have investigated the early changes of the apoptotic cell induced by arsenic
      trioxide. Our results indicated that arsenic trioxide induced apoptosis of
      esophageal carcinoma cells occurs as early as 2 h after treatment. Annexin-v
      staining has further proved that the phosphatidylserine is exposed at 2 h. The
      early morphological change of arsenic trioxide treated cells was in the
      mitochondria. Arsenic trioxide treated cells displayed aggregated mitochondria.
      It induces accumulation of high electron-density amorphous substances, swollen
      and disruption of mitochondria in oesophageal carcinoma cells after 2 h
      treatment. The alteration of mitochondria induced by arsenic trioxide seems to
      occur before the condensation of chromatin. Thus, our data demonstrated that the
      primary target of arsenic trioxide induced apoptosis of esophageal carcinoma
      cells may be the mitochondria. It is possible that arsenic trioxide is a
      mitochondriotoxic agent.

PMID- 10639595
TI  - Absence of microsatellite instability in primary myelodysplastic syndrome.
AB  - Using polymerase chain reaction (PCR), we examined a panel of 10 microsatellite
      markers (BAT26, BAT40, D2S123, D4S171, D8S87, D10S197, D12S89, Tp53, D18S58,
      PLCpr) covering nine chromosomal arms for microsatellite instability (MSI) in 29
      patients with primary MDS. Bone marrow DNA was compared with corresponding
      constitutional DNA derived from buccal epithelial cells. Apart from BAT26 and
      BAT40 that were mononucleotide (poly A) repeats, the others were dinucleotide
      (CA) repeats. The patients comprised 10 cases of refractory anemia (RA), three
      cases of refractory anemia with ringed sideroblasts (RARS), nine cases of
      refractory anemia with excess of blasts (RAEB), four cases of refractory anemia
      with excess of blasts in transformation (RAEBt), and three cases of chronic
      myelomonocytic leukemia (CMML). Serial samples were available in seven patients,
      in which four showed transformation into higher disease grade or acute myeloid
      leukemia (AML). Genetic alterations at one locus (three at D2S123, one at D4S171)
      were evident in four cases, and loss of heterozygosity at Tp53 was detected in
      one case. Accordingly, none of the 29 patients with primary MDS nor the seven
      with disease progression in this study exhibited MSI. This shows that MSI may not
      be important in the pathogenesis or progression of MDS in contrast to other
      genetic mechanisms, notably recurrent chromosomal abnormalities that dysregulate
      the expression or function of genes controlling cell growth, differentiation and
      apoptosis.

PMID- 10639596
TI  - Bryostatin 1 induces ubiquitination and proteasome degradation of Bcl-2 in the
      human acute lymphoblastic leukemia cell line, Reh.
AB  - The ubiquitin-mediated proteolytic system has been implicated in the turnover of
      a number of intracellular proteins. In the present study, we investigated the
      novelty and potential role of bryostatin 1, a macrocyclic lactone isolated from
      the marine bryozoan, Bugula neritina, in inducing the ubiquitin-mediated
      proteolysis of the oncoprotein Bcl-2. Immunoprecipitation and immunoblotting
      analyses revealed that Bcl-2 is ubiquitinated following exposure of the acute
      lymphoblastic leukemia (ALL) cell line Reh to 1 nM bryostatin 1. Bcl-2 protein
      rapidly decreases to 50% of that recorded in the control after 24 h of bryostatin
      1 treatment. In the subsequent 24 h, Bcl-2 protein again rapidly decreases to 6%
      of its pre-bryostatin 1 level at which time a plateau is reached and maintained
      for another 72 h. Furthermore, ubiquitin-Bcl-2 conjugates are detected in
      untreated as well as bryostatin 1 treated cells, indicating that ubiquitin
      dependent proteolysis plays a role in the normal turnover of Bcl-2. However,
      ubiquitin-Bcl-2 conjugates increase in a time-dependent manner following
      bryostatin 1 treatment. Lactacystin, which inhibits the proteinase activities of
      the proteasome, inhibited the bryostatin 1-induced decrease of Bcl-2 protein. The
      effect of bryostatin 1 on the proteolytic efficiency of the 26S proteasome in Reh
      cell extracts was also investigated and shown to increase following 1 h of
      bryostatin 1 treatment. Proteolytic activity reached its highest point by 3 h,
      and subsequently returned to control levels by 12 h, post-bryostatin 1 treatment.
      In addition, bryostatin 1 treatment of the Reh cell line decreased expression of
      bcl-2 mRNA within 3 h. However, bcl-2 mRNA expression returned after 24 h. We
      speculate that this decrease in mRNA together with increased 26S proteolytic
      activity accounts for the initial rapid decrease recorded in Bcl-2 protein. These
      findings indicate that bryostatin 1 treatment of Reh ALL cells decreases Bcl-2
      expression through two processes: a) enhanced Bcl-2 protein degradation through
      the activation of the ubiquitin-proteasome pathway and b) decreased bcl-2 mRNA
      expression.

PMID- 10639598
TI  - Vascularization is decreased in pulmonary adenocarcinoma expressing brain
      specific angiogenesis inhibitor 1 (BAI1).
AB  - Brain-specific angiogenesis inhibitor 1 (BAI1) is a novel angioinhibitory factor.
      We examined BAI1 gene expression in 48 pulmonary adenocarcinoma specimens by RT
      PCR. Vascular density (number and measurement area) was immunohistochemically
      evaluated in tumor specimens using anti-CD34 monoclonal antibody. BAI1 gene
      expression was detected in 38 of 48 pulmonary adenocarcinomas (79. 2%). Vascular
      number and measurement area were significantly decreased in the BAI1-positive
      pulmonary adenocarcinomas (19.3+/-4. 4/microm2 and 1.7+/-0.6%) as compared with
      those in the BAI1-negative carcinomas (75.5+/-42.7/microm2 and 5.5+/-1.5%) (Mann
      Whitney U-test, p=0.0017). These results suggest that BAI1 expression may inhibit
      stromal vascularization in pulmonary adenocarcinoma.

PMID- 10639597
TI  - Different expression of positive and negative regulators of hepatocyte growth in
      growing and shrinking hepatic lobes after portal vein branch ligation in rats.
AB  - Portal vein branch embolization is often performed before hepatectomy to prevent
      postoperative liver failure. It is, however, still not clear how the embolized
      lobe shrinks and the non-embolized lobe proliferates in counterbalance. We
      investigated the expression of positive and negative regulators of hepatocyte
      growth to clarify the mechanisms of liver growth and atrophy in a rat portal vein
      ligation (PVL) model compared with partial hepatectomy (PH). A significant
      increase in DNA synthesis within the non-ligated lobe reached a peak at 36 h, a
      delay of 12 h as compared with PH, while no increase occurred in the ligated
      lobe. Expression of hepatocyte growth factor mRNA remarkably increased in the non
      ligated growing lobe between 6 and 24 h, but was only slightly elevated in the
      ligated shrinking lobe. Contrarily, negative regulators of hepatocyte
      proliferation, such as TGF-beta1 and IL-1beta, were strongly expressed in the
      ligated shrinking lobe. Thus, the changes of portal venous flow and/or pressure
      caused by PVL may contribute to induction of different kinds of growth factors
      between the ischemic and non-ischemic lobes; these factors possibly regulate
      liver regeneration and atrophy after PVL.

PMID- 10639599
TI  - Expression of cell cycle regulators and growth factor/receptor systems in gastric
      carcinoma in young adults: association with Helicobacter pylori infection.
AB  - We studied the expression of cell cycle regulators and growth factor-receptor
      systems in gastric carcinoma in young adults and tried to clarify the specific
      alterations associated with H. pylori. We studied 33 young patients (18-29 years
      old, mean age 26.4) with gastric carcinoma. The patients were classified into two
      groups according to the degree of atrophic gastritis. Then we examined the
      expression of p53, cripto, cyclin-E, c-met, c-erbB2 and TGF-alpha
      immunohistochemically and compared the results between the two groups. The
      results were compared with 66 sex-, tumor histology-, and depth-matched elder
      controls (36-86 years old, mean age 64.0). H. pylori was judged by Giemsa
      staining. Seventeen patients had atrophic changes in the corpus (Group A), while
      16 showed superficial gastritis or normal mucosa (Group S). All 17 patients of
      Group A showed H. pylori infection, while the 3 of the 16 members of Group S did
      not have H. pylori. p53 overexpression was observed more frequently in Group S
      (88%) than in Group A (41%, p<0.05). In the 3 patients without H. pylori
      infection, all carcinoma specimens showed p53 overexpression. Overexpression of
      cyclin-E was detected in 4 patients from Group S. On the other hand, cripto was
      observed more frequently in Group A than in Group S. No obvious differences were
      observed in c-erbB2, TGF-alpha and c-met expression. Overall, p53 overexpression
      was detected more frequently in younger than in older patients, whereas cripto
      expression was less detected. These results suggest that p53 and cyclin-E may act
      in an H. pylori-independent or -adjunctive manner for gastric carcinogenesis.
      Cripto expression might be correlated tightly with H. pylori infection.

PMID- 10639600
TI  - The opioid growth factor receptor in human head and neck squamous cell carcinoma.
AB  - Carcinoma of the head and neck is the sixth leading cause of cancer in the world,
      and the third most common neoplasia in developing countries. More than 90% of
      head and neck cancers are squamous cell carcinomas (SCCHN). Approximately half of
      the patients afflicted die within 5 years of diagnosis and survival rates for
      cancer of the upper aero-digestive tract have not changed in 25 years. The opioid
      growth factor (OGF), ?Met5-enkephalin, inhibits the growth of SCCHN in vitro and
      in vivo, and acts in a receptor-mediated fashion. Receptor binding assays using
      CAL-27 human SCCHN cells in culture and ?3H-?Met5-enkephalin were employed to
      identify and characterize the receptor responsible for the growth-regulatory
      effects of OGF. Specific and saturable binding was recorded, and Scatchard
      analysis showed that the data were consistent for a single binding site with a
      binding affinity (Kd) of 5.0+/-0.9 nM and maximal binding capacity (Bmax) of
      47.5+/-1.7 fmol/mg protein. Subcellular fractionation studies determined that the
      optimal binding occurred with the nuclear fraction. Competition experiments
      demonstrated that cold ?Met5-enkephalin was at least 7-fold greater than ligands
      selective for classical opioid receptors. Binding was detected in 4 other SCCHN
      cell lines. Receptor number in xenografts of CAL-27 was decreased almost 5-fold
      compared to the same cells grown in vitro. Binding to radiolabeled ?Met5
      enkephalin was recorded in SCCHN obtained from surgical resections. The function,
      pharmacological and biochemical characteristics, distribution and subcellular
      location of OGF binding in human SCCHN were consonant with the OGF receptor
      (OGFr).

PMID- 10639601
TI  - Genomic structure of the human tetratricopeptide repeat-containing gene, TTC4,
      from chromosome region 1p31 and mutation analysis in breast cancers.
AB  - Loss of heterozygosity (LOH) in 1p31 is a frequent genetic alteration in breast
      tumors indicating the site of a tumor suppressor gene. We recently isolated a new
      member of the human tetratricopeptide repeat-containing family of genes, TTC4,
      which maps to this region. Other members of this gene family have been implicated
      in tumorigenesis suggesting that TTC4 may represent a breast cancer tumor
      suppressor gene. We now report the exon/intron structure of TTC4 and single
      strand conformation polymorphism (SSCP) analysis of DNA from 20 sporadic breast
      tumors. Although polymorphic variations were identified no mutations affecting
      the open reading frame of TTC4 were detected. Since the overall region of
      chromosome 1p31 which undergoes LOH can be relatively large, excluding
      involvement of newly isolated genes from this region in breast cancer
      tumorigenesis is an important process for the successful identification of the
      critical gene. Understanding the structure of TTC4 now makes mutation analysis
      possible for other cancers and diseases that map to this region.

PMID- 10639602
TI  - Serum total cholesterol and triglycerides levels in patients with lung cancer.
AB  - Epidemiological studies indicate that low serum total cholesterol level may
      increase the risk of death due to cancer, mainly lung cancer. The aim of our
      study was to evaluate serum levels of total cholesterol (TC) and triglycerides
      (TG) in patients with squamous cell and small cell lung cancer and their
      dependence on the histological type and the clinical stage of the neoplasm. Lung
      cancer patients (n=135) and healthy controls (n=39) entered the study. All lung
      cancer patients had higher rate of hypocholesterolemia and lower TC and TG levels
      than the control group. TC concentration was lower in lung cancer patients and in
      both histological types in comparison with the control group, TG level was lower
      only in patients with squamous cell lung cancer. There were no statistically
      significant differences of TC and TG levels between the histological types, or
      between the clinical stages of each histological type.

PMID- 10639603
TI  - The challenge of CMTX and connexin 32 mutations.

PMID- 10639604
TI  - Prognosis of neuropathy with monoclonal gammopathy.

PMID- 10639605
TI  - The surgical treatment of spasticity.
AB  - Many neurosurgical procedures have been designed for or applied to the treatment
      of spasticity arising from different disorders, including cerebral palsy;
      traumatic, ischemic, or hypoxic brain injury, multiple sclerosis, and spinal cord
      injury. Neurosurgical procedures are primarily aimed at reducing spasticity by
      interrupting the stretch reflex at various sites along the spinal reflex arc or
      attempting to increase the centrally mediated inhibitory influence on the pool of
      motor neurons in the anterior horn. Surgical interventions for spasticity can be
      classified into peripheral ablative procedures, such as rhizotomy or peripheral
      neurectomy, and central ablative procedures, such as cordectomy, myelotomy, or
      stereotactic procedures. Non-ablative procedures include peripheral nerve or
      motor point blocks, the implantation of cerebellar or spinal stimulators, and the
      implantation of subdural catheters for infusion of pharmacologic agents to
      increase inhibitory activity. Several proposed mechanisms for spasticity are
      reviewed so that the rationale for the various surgical interventions for
      spasticity described may be better understood.

PMID- 10639606
TI  - Long-term clinical and neurophysiological follow-up of patients with peripheral,
      neuropathy associated with benign monoclonal gammopathy.
AB  - The incidence of hematological malignancy in patients with monoclonal gammopathy
      of undetermined significance (MGUS) has been assessed as 17% to 25%. To ascertain
      whether this is true of neuropathy associated with MGUS, a long-term (5-42 years)
      retrospective clinical and neurophysiological follow-up was conducted in 50 cases
      (immunoglobulin M [IgM], n = 38; IgG, n = 11; IgA, n = 1). Only three patients
      developed hematological malignancy. Of 25 survivors with IgM paraproteinemia, 7
      had myelin-associated glycoprotein antibodies with typical clinical features.
      Evoked distal muscle amplitudes were significantly smaller than for the other
      paraprotein classes. Preferential distal demyelination manifested by relative
      prolongation of distal motor latency was not apparent in the cases of long
      duration. Two patients with IgM antidisialosyl antibodies and cold agglutinating
      activity had a large fiber neuropathy with intermittent oculofacial involvement.
      Both responded to intravenous immunoglobulin. Findings in the remaining patients
      were varied. Recognition of IgM subgroups is important both for prognosis and
      possible response to treatment.

PMID- 10639607
TI  - Muscle phosphorus magnetic resonance spectroscopy oxidative indices correlate
      with physical activity.
AB  - The purpose of this study was to assess the effect of physical deconditioning on
      skeletal muscle's oxidative metabolism as evaluated by phosphorus-31 magnetic
      resonance spectroscopy ((31)P MRS). Twenty-seven subjects without muscle disease,
      representing a wide range of fitness levels, were evaluated with (31)P MRS.
      Spectra were obtained at rest and during recovery from in-magnet exercise. The
      data show a significant correlation between maximum resting metabolic equivalent
      (MET) score and the following (31)P MRS recovery indices: adenosine diphosphate
      and phosphocreatine recovery half-time; initial phosphocreatine resynthesis rate;
      calculated estimation of mitochondrial capacity; pH at end of exercise; and
      phosphocreatine depletion. In addition, significant differences between the
      deconditioned and conditioned group were found for all of the aforementioned
      recovery indices. At rest, only the inorganic phosphate concentration was
      significantly different between the two groups. These data indicate that physical
      activity level should be taken into account when assessing patients' oxidative
      metabolism with (31)P MRS.

PMID- 10639608
TI  - Unusual electrophysiological findings in X-linked dominant Charcot-Marie-Tooth
      disease.
AB  - X-linked Charcot-Marie-Tooth disease (CMTX) is the second most common form of
      Charcot-Marie-Tooth disease. Variable histopathological and nerve conduction
      velocity (NCV) results have suggested either a primary demyelinating or axonal
      polyneuropathy. We identified five individuals across three generations in a
      family with CMTX associated with a mutation in the gene coding for connexin 32.
      All individuals were studied by clinical neurological examination, DNA analysis,
      and nerve conduction studies. The proband (1174/KD) also underwent a sural nerve
      biopsy. As expected, all the affected males were more clinically affected than
      the females. All affected males and obligate female carriers exhibited some
      electrophysiological characteristics of demyelination. However, striking
      heterogeneity of nerve conduction velocities was seen. This family shows that
      CMTX is a heterogeneous and distinctly nonuniform demyelinating polyneuropathy,
      the severity of which varies with sex and age. Such electrophysiological
      variability is unique among hereditary neuropathies.

PMID- 10639609
TI  - Tolerability of recombinant-methionyl human neurotrophin-3 (r-metHuNT3) in
      healthy subjects.
AB  - This phase I, double-blind, randomized, placebo-controlled study evaluated the
      safety of single and multiple (daily for 7 days) subcutaneous administrations of
      recombinant-methionyl human neurotrophin-3 (r-metHuNT3) in healthy human
      volunteers at seven doses, ranging from 3 to 500 microg/kg/day. No serious or
      life-threatening adverse events occurred. The most frequently recorded adverse
      effects were mild injection-site pain, diarrhea, and elevation of liver function
      tests. No change in neurologic function was noted with these dosing regimens. We
      conclude that r-metHuNT3 is safe and well tolerated in the dosages used in this
      study.

PMID- 10639610
TI  - Statistical motor unit number estimation: reproducibility and sources of error in
      patients with amyotrophic lateral sclerosis.
AB  - The reliability of motor unit number estimation (MUNE) for assessment of the long
      term course of ALS is dependent on the reproducibility of the technique. We
      report our results with the statistical method of MUNE on the ulnar
      nerve/hypothenar muscle in 16 ALS patients who were studied on 52 occasions. On
      each occasion, MUNE was performed twice with one electrode placement and once
      with a different placement. For each MUNE, mean surface motor unit potential
      amplitude was determined within three different recording ranges or windows at
      different stimulus intensities. The MUNE results had excellent reproducibility
      with coefficients of variation of 19% and test-retest correlation coefficients
      from 0.75 to 0.86. With examination of sources for variability, the
      reproducibility of statistical MUNE is not affected by minor variation in
      stimulation and recording electrode placement but may be improved by modifying
      methods for recording window selection. The high reproducibility of statistical
      MUNE supports its reliability for estimating the rate of motor unit loss in ALS.

PMID- 10639611
TI  - Abnormal movements in complex regional pain syndrome: assessment of their nature.
AB  - Abnormal movements may be a clinical feature in complex regional pain syndrome
      (CRPS), but their basic nature is unclear. Between August 1989 and September
      1998, patients fulfilling diagnostic criteria for CRPS (I or II) and displaying
      abnormal movements were entered into a prospective study. Fifty-eight patients,
      39 women and 19 men, met entry criteria; 47 had sustained a minor physical injury
      at work. The patients exhibited various combinations of dystonic spasms, coarse
      postural or action tremor, irregular jerks, and, in one case, choreiform
      movements. Patients underwent rigorous clinical and laboratory evaluation aimed
      at characterizing their neurological disturbance. Surprisingly, no case of CRPS
      II but only cases of CRPS type I displayed abnormal movements. In addition to an
      absence of evidence of structural nerve, spinal cord, or intracranial damage, all
      CRPS I patients with abnormal movements typically exhibited pseudoneurological
      (nonorganic) signs. In some cases, malingering was documented by secret
      surveillance. This study highlights abnormal movements in CRPS as constituting a
      key clinical feature that differentiates CRPS I from CRPS II. They are
      consistently of somatoform or malingered origin, signaling an underlying
      psychoneurological disorder responsible for the entire CRPS profile.

PMID- 10639612
TI  - Impact of plasma exchange on indices of demyelination in chronic inflammatory
      demyelinating polyradiculoneuropathy.
AB  - We studied the impact of plasma exchange (PE) on indices of primary demyelination
      in patients of the Canadian multicenter trial of PE in chronic inflammatory
      demyelinating polyneuropathy (CIDP). Individual motor nerves (median, ulnar,
      peroneal, tibial) were studied: distal motor latencies (DMLs), proximal and
      distal compound muscle action potential (M-wave) amplitudes, negative peak areas
      and durations, and motor conduction velocities (CVs). Proximal M-wave amplitudes
      in individual motor territories, particularly in the ulnar nerve (from below
      elbow, above elbow, and axillary stimulating sites) demonstrated significant
      improvement with PE, but not sham exchange. Proximal ulnar M-wave areas also had
      significant improvement with PE. Trends toward improvement of individual nerve
      motor CVs, M-wave durations, and DMLs did not achieve statistical significance.
      Proximal M-wave amplitudes, particularly in the ulnar motor territory, and
      proximal M-wave areas (providing a measure of conduction block) were the most
      sensitive indices of improvement conferred by PE in CIDP. In individual patients,
      these indices may help judge the efficacy of therapy.

PMID- 10639613
TI  - Usefulness of hand rehabilitation after carpal tunnel surgery.
AB  - The purpose of this randomized trial was to assess the clinical evolution after
      carpal tunnel release in subjects with long-term carpal tunnel syndrome. The
      evaluation criteria were symptom occurrence, motor performance, and delay in
      returning to work. A total of 100 subjects were assessed four times (prior to
      surgery, and 12 days, 1 month, and 3 months after surgery) using the Boston
      carpal tunnel questionnaire, the nine-hole peg test (NHPT), and the Jebsen-Taylor
      test (JTT). Subjects were randomized to a rehabilitation program or to a
      progressive home exercise program. No difference in symptom occurrence between
      the two groups was detected after 1 and 3 months. One month after surgery, only
      patients in the first group showed motor dexterity improvement according to NHPT
      and JTT scores. At the 3-month follow-up, the two groups did not differ but the
      group undergoing rehabilitation showed a shorter return-to-work interval. A
      rehabilitation approach after hand surgery is clinically relevant to accelerate
      recovery but neither modifies functional recovery nor reduces symptom occurrence.

PMID- 10639614
TI  - Macro-EMG and muscle biopsy of paretic foot dorsiflexors in Charcot-Marie-Tooth
      disease.
AB  - Twelve patients with Charcot-Marie-Tooth disease type 1 (CMT1) and 11 with type 2
      (CMT2), with a clinically similar range of muscle weakness of foot dorsiflexion,
      were subjected to macroelectromyographic (macro-EMG) examination and muscle
      biopsy of the tibialis anterior (TA) muscle in order to elucidate the denervation
      reinnervation process in the two CMT forms. The macro-EMG examination showed
      higher median amplitude values and median area values for the CMT1 patients, with
      a mean value of 1,515 +/- 1,222 microV and 3,953 +/- 2,613 microV. ms,
      respectively, than for the CMT2 patients, with a mean value of 865 +/- 971 microV
      and 2,525 +/- 2,575 microV. ms, respectively. When corrected for muscle fiber
      area, the difference was statistically significant for amplitude (P < 0.01) and
      area (P < 0.05). For CMT1 patients, the increase of macro-EMG potentials varied
      from 2 to 14 times and for CMT2 patients from less than 1 to 8 times larger than
      corresponding age-matched values. Muscle biopsies of TA showed that the type I
      fiber percentage was significantly higher (P < 0.05) in the CMT1 patients (99 +/-
      2.2%) than in the CMT2 patients (86 +/- 12.3%). Morphometric data showed a
      significantly higher (P < 0.05) mean type I fiber area in the CMT2 patients
      (8,130 +/- 4,721 microm(2)) when compared with the CMT1 patients (5,066 +/- 3,431
      microm(2)). The present data indicate that denervation in CMT1 is associated with
      prominent collateral reinnervation but only minor muscle fiber changes, whereas
      in CMT2 there is only minor collateral reinnervation but prominent muscle fiber
      changes including significant muscle fiber hypertrophy.

PMID- 10639615
TI  - Malignant hyperthermia: fatigue characteristics of skeletal muscle.
AB  - Although the defects in cellular Ca(2+) homeostasis associated with malignant
      hyperthermia (MH) have been extensively studied, the functional consequences of
      the MH mutation are not clear. We used continuous and intermittent high-frequency
      stimulation to determine whether this mutation might alter the fatigue resistance
      of muscle from MH susceptible (MHS) pigs. Force decline with 10 s continuous
      stimulation (150 Hz) was significantly less in MHS muscle (58.4 +/- 1.0%) than in
      normal muscle (50.5 +/- 3.0%). With intermittent stimulation, there was no
      significant difference in tension decline between muscle types. Post-stimulation
      twitch and tetanus responses were similar in MHS and normal muscles except: 1)
      twitch potentiation was significantly greater in normal muscle after continuous
      stimulation, and 2) recovery of tetanic tension was slowed in MHS muscle.
      Although the MH defect does not cause major functional abnormalities, subtle
      differences in MHS muscle response to fatiguing stimulation are apparent.
      Therefore, it is unlikely the work capacity of MH patients would be limited by
      any MH associated defect within the muscle.

PMID- 10639616
TI  - Relation between maximum discharge rates on electromyography and motor unit
      number estimates.
AB  - To improve quantitative assessment of motor unit recruitment by standard
      concentric needle electromyography (CNEMG), hypothenar muscles of 22 healthy
      subjects, 18 with denervation, and 10 with a myopathy were studied. Discharge
      rates of motor units were measured in CNEMG recordings comprising action
      potentials of, at most, 4 motor units. Motor unit number estimation (MUNE) was
      done using the manual incremental method. In controls, the upper 95% limit of the
      discharge rate was 16.2/s. In all subjects, a strong nonlinear correlation
      between the number of motor units and the maximal discharge rate was found (r =
      0.88, P < 0.0001). Increased discharge rates were found in all but one of the
      paretic muscles with denervation, but in none of the myopathic muscles.
      Measurement of the discharge rate is a simple and reliable procedure. If the
      discharge rate is high in a hypothenar muscle, loss of motor units can be
      inferred. Moreover, the discharge rate value gives an estimate of the number of
      motor units in that muscle. Thus, we suggest that maximal discharge rate be
      included in electromyographic reports.

PMID- 10639617
TI  - HGF is an autocrine growth factor for skeletal muscle satellite cells in vitro.
AB  - Muscle satellite cell activation following injury is essential for muscle repair,
      and hepatocyte growth factor/scatter factor (HGF) was the first growth factor
      shown to be able to stimulate activation and early division of adult satellite
      cells in culture and in muscle tissue. In addition, HGF was shown to be present
      in uninjured and injured skeletal muscle. Experiments in this report demonstrate
      that cultured satellite cells also synthesize and secrete HGF. Reverse
      transcription-polymerase chain reaction (RT-PCR) was used to demonstrate the
      presence of HGF mRNA in cultured adult satellite cells as early as 12 h from the
      time of plating. Message content was detectable at early times in culture and
      appeared to increase between 36 and 48 h. HGF protein expression was demonstrated
      during this time period by immunofluorescence localization; HGF was localized to
      mononucleated cells and multinucleated myotubes. HGF message was not detectable
      in muscle-derived fibroblast clones, and fibroblast-like cells in satellite cell
      cultures were negative for HGF by immunofluorescence analysis. Furthermore,
      Western blot analysis revealed the presence of HGF in satellite cell culture
      conditioned medium, associated with the cell surface and inside cells. Finally,
      the addition of neutralizing HGF antibodies during the proliferation phase in
      culture (42-90 h) significantly reduced cell proliferation. These experiments
      indicate that HGF is expressed by cultured satellite cells and that endogenous
      HGF from satellite cells can act in an autocrine fashion. Because HGF plays a
      central role in satellite cell activation, it is likely that direct
      administration of HGF into damaged muscle may represent a potentially useful
      approach for stimulating muscle repair. This approach may also be useful in
      enhancing the efficiency of myoblast transplantation in vivo.

PMID- 10639618
TI  - Thalamic potentials evoked by motor point stimulation.
AB  - We studied thalamic potentials elicited by stimulation of the extensor digitorum
      communis muscle motor point during stereotactic surgery for movement disorders.
      In 6 patients with Parkinson's disease and 1 with cerebral palsy, muscle afferent
      evoked thalamic potentials (METPs) were recorded in the ventral intermediate
      (Vim) nucleus. METPs consisted of three peaks with an average latency of 11.02 +/
      0.80 ms for initial positive peak (PI), 13.04 +/- 0.58 ms for negative (N), and
      14.30 +/- 0.87 ms for later positive peak (PII). These METPs were different from
      those evoked by median nerve stimulation. No peaks corresponding to the N20
      component of the somatosensory evoked potential were recorded from C3 or C4 scalp
      electrodes. The METP amplitudes in the ventrolateral (VL) nucleus were markedly
      lower than those in the Vim nucleus. These findings suggest that METPs in the Vim
      nucleus are responses that occur via the fast conducting group Ia afferent fibers
      rather than somatosensory afferent fibers.

PMID- 10639620
TI  - Quantitative analysis of reflex inhibition in single motor units in human
      masseter muscle: effects of stimulus intensity.
AB  - Inhibitory reflex responses to electrical stimulation of the mental nerve were
      studied in recordings from single motor units (SMU) in the human masseter muscle.
      A new analytical technique for spike train data was used. Electrical stimuli were
      delivered to the mental nerve when the SMU fired with two consecutive inter-spike
      intervals (ISIs) within the range of 90 ms to 110 ms. Stimuli were delivered with
      increasing stimulus delays after the preceding SMU action potential (AP). Sham,
      non-painful, and painful stimulus intensities were applied. The post-stimulus
      firing probability of the SMU was progressively decreased among the three
      conditions. Analysis of the relation between stimulus delays and ISI for the
      first post-stimulus APs revealed a linear relation which was shifted upward, and
      the slope was increased with increasing stimulus intensity. This may be explained
      by a differential effect of the increasing stimulus intensity on the duration and
      amplitude of the inhibitory post-synaptic potential. The methods used in the
      present study provide a useful means of quantifying the effects of motoneuron
      excitability in detail.

PMID- 10639619
TI  - Sensory involvement in spinal-bulbar muscular atrophy (Kennedy's disease).
AB  - Spinal-bulbar muscular atrophy (SBMA) is a rare X-linked neuronopathy associated
      with an abnormal representation of androgen receptors in the nervous system.
      Standard nerve conduction and histopathological studies have disclosed the
      involvement of large myelinated sensory fibers in the spinal nerves of SBMA
      patients. Little is known about the involvement of small sensory neurons and
      trigeminal nerves. Laser evoked potentials (LEPs) were studied in 6 unrelated
      patients with SBMA; 5 of these patients also underwent trigeminal reflex
      recordings, and 3 a sural nerve biopsy. LEPs were markedly abnormal, indicating a
      dysfunction in pain pathways. Given the sparing of small fibers in the sural
      nerve specimens, we hypothesize a dysfunction in spinothalamic cells, possibly
      due to an abnormal representation of the androgen receptors. Except for the jaw
      jerk, all the trigeminal reflexes were markedly abnormal. Since the afferents for
      the jaw-jerk have their cell body within the central nervous system instead of
      the ganglion, the selective sparing of the jaw-jerk indicates a trigeminal
      ganglionopathy.

PMID- 10639621
TI  - Isolated superior oblique palsies with electrophysiologically documented
      brainstem lesions.
AB  - Over a 13.5-year period, we observed 10 patients with isolated superior oblique
      palsies in whom electrophysiological abnormalities indicated brainstem lesions.
      In 7 patients unilateral masseter reflex abnormalities were seen, and were
      located on the side of the superior oblique palsy in 2 patients and on the
      opposite side in 5 patients. Two patients had slowed gain of following eye
      movements to the side contralateral to the superior oblique palsy. Slowed
      adduction saccades in the eye contralateral to the superior oblique palsy were
      seen in 1 patient. Clinical improvement was frequently (in 7 of 10 patients)
      associated with improvement or normalization of electrophysiologic findings.
      Magnetic resonance imaging (MRI) was normal, showing no evidence of brainstem
      lesions in 6 patients. Unilateral superior oblique palsy may be the only clinical
      sign of a brainstem lesion. Although such a cause may be underdiagnosed if based
      on MRI-documented lesions only, it remains a rare condition.

PMID- 10639622
TI  - Brachial plexopathy in diabetic ketoacidosis.
AB  - We report the clinical and electrodiagnostic findings of a 39-year-old patient
      who presented with severe, bilateral and asymmetrical, axon-loss brachial
      plexopathies occurring in the midst of diabetic ketoacidosis. This patient's
      unusual presentation is not consistent with the rare diabetic polyradiculopathy
      of the upper extremities usually occurring in association with diabetic
      amyotrophy.

PMID- 10639623
TI  - Focal myopathy induced by chronic heroin injection is reversible.
AB  - We report a patient who developed a focal myopathy with prominent contractures of
      his thigh muscles induced by chronic heroin injection. Muscle biopsy and magnetic
      resonance imaging (MRI) were indicative of a fibrotic and inflammatory process.
      Treatment with steroids, D-penicillamine, and physical therapy led to full
      functional recovery within 6 months. Sequential electromyographic (EMG) studies
      and muscle biopsies showed evidence of regenerating muscle fibers and absence of
      inflammatory cells. We conclude that heroin-induced focal myopathy is reversible
      and that combination therapy with D-penicillamine and steroids may be useful.

PMID- 10639624
TI  - Stability of N20 onset or peak latency in median somatosensory evoked potentials.
AB  - We analyzed onset and peak latencies of the N20 response of median nerve
      somatosensory evoked potentials (SEPs) in 21 healthy subjects by simultaneous
      recordings with noncephalic or ear reference from multiple scalp sites. The
      cortical onset was defined as the fork at which the contralateral parietal and
      frontal or ipsilateral parietal waves diverged. We found the N20 onset unchanged
      between noncephalic and ear reference recordings, or among the recordings around
      the contralateral centroparietal scalp. The N20 peak was prolonged when the
      recording position moved posteriorly. We suggest that N20 onset latency is more
      stable than N20 peak.

PMID- 10639626
TI  - Rhabdomyolysis as the presenting manifestation of calciphylaxis.
AB  - A 43-year-old woman was admitted with progressive leg pains and weakness and was
      found to have rhabdomyolysis. Prior to this admission the patient had
      hypercalcemia, but this returned to normal following treatment with calcitonin.
      During the hospitalization, she developed the syndrome of calciphylaxis
      consisting of necrotic skin and muscle associated with vascular calcification.
      This is the first case report of rhabdomyolysis caused by calciphylaxis in a
      patient without chronic renal failure.

PMID- 10639625
TI  - Chronic demyelinating hypertrophic brachial plexus neuropathy.
AB  - A patient with unilateral, painless, chronic progressive upper limb sensorimotor
      deficit showed electrophysiological evidence of a focal demyelinating neuropathy
      with almost complete conduction block across the brachial plexus. Magnetic
      resonance imaging disclosed marked brachial plexus hypertrophy. Intravenous
      immunoglobulin led to fast and complete recovery, maintained by intermittent
      perfusions. Hypertrophic brachial plexus neuropathy can be a presentation of
      focal chronic inflammatory demyelinating polyradiculoneuropathy. Objective and
      quantitative assessment of hand function is useful to evaluate treatment results
      and to optimize treatment regimens.

PMID- 10639627
TI  - ALS and myasthenia: An unusual association in a patient treated with riluzole.

PMID- 10639628
TI  - Clinical improvement following interferon-alpha alone as an initial treatment in
      CIDP.

PMID- 10639629
TI  - Muscle fiber conduction velocity in arg1239his mutation in hypokalemic periodic
      paralysis.

PMID- 10639630
TI  - AAEM news and comments

PMID- 10639631
TI  - The TIMI 9b and GUSTO IIb Trials and the "Thrombin Hypothesis"
AB  - The "thrombin hypothesis" proposes that the clinical outcome of patients with
      unstable angina or acute myocardial infarction (MI) is related to the degree of
      thrombin inhibition, with greater inhibition resulting in improved outcome. Two
      recent trials (TIMI 9b and GUSTO IIb) tried to test this hypothesis by
      randomizing 15,000 patients with MI or unstable angina to a 3-to-5 day
      intravenous administration of either the powerful thrombin inhibitor hirudin, or
      standard heparin. In both studies, after 30 days, there was no significant
      difference in the rates of death or nonfatal infarction between the 2 treatment
      arms. More than one reason may explain these findings. In both trials the
      anticoagulant regimens were carefully tailored to prevent excessive bleeding
      complications and to achieve a predetermined level of efficacy, as measure by
      aPTT. It is possible that similar aPTTs and similar bleeding rates will result in
      similar clinical outcomes, regardless of the anticoagulant agent used. It is also
      possible that patients already receiving fibrinolytic drugs and aspirin did not
      derive such additional thrombolytic benefit from anticoagulants to compensate for
      the increased bleeding risk associated with their use. Finally, thrombin may not
      always play the crucial role that has been attibuted to it: marked thrombin
      generation may occur only in subgroups of patients, or as a secondary response to
      a primary trigger that fails to be antagonized by antithrombin therapy or that re
      emerges after stopping treatment. The true role played by anticoagulants in the
      management of acute coronary syndromes is not clear from TIMI 9b or GUSTO IIb
      because neither study included a control group not receiving anticoagulants.
      These trials, however, raise important issues that deserve further investigation:
      for example, the definition of what drives thrombin generation in patients with
      acute coronary syndromes and the identification of possible subgroups of patients
      deriving true clinical benefit from anticoagulant therapy.

PMID- 10639632
TI  - The Narrow Therapeutic Index of Thrombin Inhibition: Implications for Newer
      Antithrombotic Therapies.
AB  - Recent trials have compared direct thrombin inhibitors with heparin as adjunctive
      therapy with thrombolysis for acute myocardial infarction or as antithrombotic
      therapy following coronary angioplasty. The results suggest that these agents are
      comparable to heparin in terms of efficacy, and can be safely administered;
      however, like that of heparin, the therapeutic index of direct thrombin
      inhibitors is narrow. Thus, one must excercise caution in trial design and data
      interpretation from studies of these antithrombotic agents in patients with acute
      coronary syndromes. The potential applicability of these agents to patients with
      acute coronary syndromes, the appropriate dosing regimen, and the patient
      population in whom the therapeutic index is optimal all await further study.

PMID- 10639633
TI  - Thrombin Hypothesis: The TIMI 9B and GUSTO IIB Trials Have Successfully
      Disproven/Proven the Thrombin Hypothesis.
AB  - The direct thrombin inhibitor, hirudin, was tested in two trials. The TIMI 9B
      trial randomized patients receiving thrombolytic therapy for acute myocardial
      infarction to receive hirudin or heparin. The GUSTO IIB trial randomized patients
      with or without electrocardiographic ST-segment elevation (i.e. thrombolytic- and
      non-thrombolytic-eligible patients). In the combined trials at 30 days there was
      a non-significant 14% reduction in myocardial infarction, but no effect on
      mortality. There are a number of factors in these two trials, including dose
      selection, timing of administration and duration of drug therapy, that may have
      led to an underestimate of the potential benefits of hirudin. Further trials are
      therefore required to test the thrombin hypothesis.

PMID- 10639634
TI  - Reexamination of the Thrombin Hypothesis: What We Have Learned from TIMI 9B and
      GUSTO IIb.

PMID- 10639635
TI  - Hirudin in Acute Coronary Syndromes: When Cents Override Good Sense.
AB  - Two large multicenter clinical trials comparing heparin with hirudin in the
      management of patients with acute coronary syndromes have recently been
      completed. Direct thrombin inhibition was reported to result in only a modest
      reduction in the incidence of primary endpoint in GUSTO IIb, and to be of no
      demonstrable benefit in TIMI 9b. However, closer examination of the performance
      of hirudin in these trials suggests it to have been harshly judged. Hirudin
      provided a consistently more reliable anticoagulant effect than heparin, was
      associated with a comparable risk of bleeding and minimal risk of allergy.
      Furthermore, direct thrombin inhibition was more effective in preventing events
      in patients with unstable angina and non-Q wave infarction, and resulted in a
      significant reduction in the incidence of reinfarction among all facets of the
      acute coronary syndromes. There was in addition a striking benefit of combining
      hirudin with streptokinase in patients with acute myocardial infarction. Based on
      these data, there is little doubt that hirudin rather than heparin should form
      the foundation on which to base future strategies for management of the acute
      coronary syndromes.

PMID- 10639636
TI  - Primary Angioplasty Is the Ideal Treatment for Acute Myocardial Infarction.

PMID- 10639637
TI  - Primary PTCA: Possibly the Best, Often the Only Choice for Reperfusion in Acute
      Myocardial Infarction.
AB  - Primary PTCA is at least as effective as intravenous thrombolysis for the
      management of acute myocardial infarction. When the capability for primary PTCA
      exists, it is also a very cost-effective treatment, allowing earlier hospital
      discharge, reduced readmissions and reduced risks of recurrent ischemia and
      infarction. Finally, many patients with acute myocardial infarction either have
      contraindications to thrombolysis or fail to fulfill the clinical and ECG
      criteria for thrombolysis. In these patients, the only possible reperfusion
      therapy is primary PTCA: it is potentially applicable to all patients with
      ongoing acute myocardial infarction, without contraindications, which may lead to
      a substantial increase in the proportion of acute myocardial infarction patients
      receiving reperfusion therapy. Its use is limited by logistical problems:
      permanent availability of interventional cardiology facilities and staff, need
      for secondary transfer of patients from primary care centers. Currently, it
      appears reasonable to use pre-hospital medical systems as often as possible to
      triage patients excluded from thrombolysis as well as the most severe
      thrombolysis-eligible to centers able to perform primary PTCA round the clock,
      which exist in nearly every large urban center. When the patient is thrombolysis
      eligible and is within a center in which interventional facilities and
      experienced teams are immediately available, both treatments are legitimate,
      although primary PTCA may be favored both in terms of outcome and cost.
      Conversely, when the patient has no contraindication to thrombolysis and cannot
      be treated rapidly in a center with interventional capabilities, thrombolytic
      therapy should remain the preferred treatment.

PMID- 10639639
TI  - Low-Molecular-Weight Heparin in the Initial Treatment of Proximal Deep Vein
      Thrombosis.
AB  - Intravenous unfractionated heparin followed by oral warfarin is the current
      standard of care for the treatment of acute venous thrombosis. More recently,
      several low-molecular-weight heparin preparations have been shown to be as
      effective and safe as unfractionated heparin for the initial therapy of acute
      proximal vein thrombosis. These drugs have a number of advantages over
      unfractionated heparin, and will undoubtedly replace the current standard for the
      initial treatment of venous thromboembolism.

PMID- 10639638
TI  - Thrombolytic Therapy: The Treatment of Choice in Acute Myocardial Infarction.

PMID- 10639640
TI  - Low-Molecular-Weight Heparin Should Replace Unfractionated Heparin for Treatment
      of Venous Thrombosis and Unstable Angina.

PMID- 10639641
TI  - Adjunctive Antiplatelet Therapy in Acute Myocardial Infarction: The Road to
      Improved Infarct-Related Artery Patency.
AB  - A direct relationship exists between infarct artery patency and survival in
      patients with acute myocardial infarction. Currently available thrombolytic
      regimens produce 90 minute patency rates on the order of 80%. Preliminary trials
      suggest that adjunctive anti-platelet therapy with glycoprotein IIb/IIIa
      inhibitors, in conjunction with thrombolytic therapy, may significantly improve
      90 minute infarct related artery patency and thereby survival, in patients with
      acute myocardial infarction.

PMID- 10639642
TI  - The Prothrombinase Complex: Assembly and Function.

PMID- 10639643
TI  - Deep Venous Thrombosis: Early Discharge Strategies and Outpatient Management.
AB  - Conventional management of acute deep venous thrombosis (DVT) consists of
      initiating continuous infusion intravenous unfractionated heparin (UFH) for 5
      days in the hospital as well as warfarin. Low-molecular-weight heparins (LMWHs)
      appear to confer similar protection against recurrent DVT compared with UFH but
      exhibit prolonged bioavailability, increased ease of dosing, and fewer side
      effects. The advent of LMWH has resulted in increased numbers of patients
      undergoing initial management of acute DVT with only several days of
      hospitalization. While 3-month follow-up studies with LMWH demonstrate similar
      efficacy and safety to UFH, longer term experience with these new agents is
      necessary to determine their optimal use and safety. We suggest a system for
      triage in the initial management of DVT patients for: (1) complete outpatient
      management with LMWH, or (2) short-term hospitalization for initiation of LMWH,
      or (3) 5-day hospitalization for treatment with UFH. A review of DVT management
      with LMWH and algorithms for each of these pathways are provided.

PMID- 10639645
TI  - Thrombolytic Therapy in Acute Myocardial Infarction: Management Algorithms.

PMID- 10639646
TI  - Physicians' Use of Heparin Following Thrombolytic Therapy: An International
      Perspective.
AB  - Background: The current prevalence, timing, and route of heparin use after
      thrombolytic therapy for acute myocardial infarction both within and outside the
      United States (U.S.) have not been extensively studied. Method: An 18-item
      questionnaire was mailed to cardiologists and emergency medicine practitioners in
      the U.S. and to physicians in 5 countries considering participation in an
      international trial of thrombolytic therapy. Results: Almost all used some form
      of heparin after recombinant tissue-plasminogen activator; 8% withheld heparin
      after streptokinase. Non-U.S. physicians used subcutaneous heparin more
      frequently than did U.S. physicians (26% vs. 4%). Time to heparin initiation
      varied greatly. Most physicians used the activated partial thromboplastin time to
      monitor anticoagulation, although there was little consensus about the
      appropriate way to determine the efficacy of heparin therapy. Conclusions: This
      survey shows considerable disagreement about the preferred administration of
      heparin among physicians treating patients with myocardial infarction. This lack
      of agreement reflects uncertainty about how heparin therapy should be used. When
      the results of well-designed clinical trials examining the optimal dosing,
      timing, and monitoring of heparin therapy have been published, perhaps the
      clinical community can reach a consensus.

PMID- 10639644
TI  - Current and Practical Management of Acute Myocardial Infarction.

PMID- 10639647
TI  - Thrombophilia in Patients with Hypertriglyceridemia.
AB  - Objectives: To investigate a possible relationship between hypertriglyceridemia
      and the coagulation system, a Cardiovascular Risk Factor Two-township Study was
      conducted in Taiwan. Design: A case-control study. This longitudinal, prospective
      study focused on the evolution of cardiovascular disease risk factors with
      emphasis on haemostatic factors. Subjects: Hypertriglyceridemic subjects
      (triglyceride <2.26 mmoll+1, n = 327) and age-matched normal controls from a
      population screening program. Main outcome measures: Haemostatic parameters
      measured in this study included prothrombin time (PT), activated partial
      thromboplastin time (aPTT), fibrinogen, factors VIIc and VIIIc, and antithrombin
      III and plasminogen levels. Results: In our male hypertriglyceridemic subjects,
      aPTT was not significantly reduced, while significant elevations of factor VIIIc,
      factor VIIc, and plasminogen and antithrombin-III levels were noted. In the
      female hypertriglyceridemic subjects, the elevation of factor VIIc, factor VIIIc,
      and plasminogen and antithrombin-III levels was highly-significant, whereas aPTT
      was not significantly reduced. Unexpectedly, the levels of the established
      coronary risk factor, fibrinogen, did not show a statistically different change.
      Similar to previous data, our hypertriglyceridemic subjects also presented with
      hyperinsulinemia, glucose intolerance, upper body obesity, and elevated blood
      pressure. Conclusions: Despite the fact that in population studies, triglycerides
      do not consistently appear to be an independent risk factor for coronary heart
      disease, our data suggest that a pronounced increase in triglycerides warrants
      aggressive therapy, because this increase may be associated with a
      hypercoagulable state. This phenomenon contributes another perspective to the
      study of higher cardiovascular mortality in hypertriglyceridemic subjects.

PMID- 10639648
TI  - Platelet Glycoprotein IIb/IIIa Integrin Blockade in Coronary Artery Disease:
      Current State of the Art.
AB  - Platelets have been shown to play an important role in the pathogenesis of
      atherosclerosis, acute coronary syndromes, and ischemic complications after
      percutaneous coronary intervention. Fibrinogen binding via platelet surface
      glycoprotein (GP) IIb/IIIa receptors constitutes the "final pathway" in platelet
      aggregation leading to thrombus formation. The GP IIb/IIIa receptor inhibitors, a
      new class of antiplatelet agents that have emerged in recent years, show great
      promise in reducing complications of coronary angioplasty and acute coronary
      syndromes. This review will examine the biology of platelet GP IIb/IIIa
      receptors, the various classes of GP IIb/IIIa receptor antagonists, the results
      of the latest clinical trials, and their implications in current clinical
      practice.

PMID- 10639649
TI  - In vivo microdialysis of painful achilles tendinosis.

PMID- 10639650
TI  - Healing of the patellar tendon donor defect created after central-third patellar
      tendon autograft harvest. A long-term histological evaluation in the lamb model.
AB  - Patellar tendon donor defect (PTDD) healing after patellar tendon autograft
      (PTA), was evaluated in 12 lambs (24 knees), by means of conventional histology,
      immunohistochemistry and image analysis. The results of this study indicate that
      the PTDD is replaced by a tissue that does not assume the histological
      characteristics of a normal patellar tendon. Both the Hoffa fat pad (HFP) and the
      paratenon play an important role in the healing process, although qualitative and
      quantitative chronological differences were found, which supports the concept of
      a "two-time process". The HFP initiates the repair process, and is the main
      active proliferative tissue compartment during the first week. Once the process
      is established, the paratenon and, in particular, its synovial lining, starts
      proliferative activity and virtually substitutes that of the HFP, which rapidly
      loses activity in a few days. Moreover, donor-site morbidity after PTA could be
      the result of histological changes in the patellar tendon and environs in only a
      few cases. We have found inflammatory and neural changes in the refilled PTDD
      that could explain the anterior knee pain after PTA. Likewise, we have observed
      loss of Golgi corpuscles in the refilled PTDD, which could lead to proprioceptive
      loss after ACL reconstruction with PTA. Finally, we have observed shrinkage of
      the PTDD scar that could contribute to the etiopathogenia of a patella infera.

PMID- 10639651
TI  - The quadriceps tendon cyst: an uncommon cause of chronic anterior knee pain.
AB  - The causes of knee pain are manifold. One of the uncommon causes of chronic
      anterior knee pain are cysts and ganglia. Magnetic resonance imaging not only
      reveals the intra-articular pathology but also accurately depicts such cystic
      structures about the knee. As part of this case report, a cyst of the lateral
      border of the quadriceps tendon is presented as a cause of such discomfort.
      Although cystic lesions around the knee are a common clinical problem, the
      described location is rare. After surgical revision of the lateral border of the
      quadriceps tendon and excision of the cyst, the patient was found to be
      asymptomatic.

PMID- 10639652
TI  - Locked lateral patellar dislocation: a rare case of irreducible patellar
      dislocation requiring open reduction.
AB  - Irreducible patellar dislocations are rare injuries, but those that do occur are
      mainly directed intra-articularly. In this case, a 53-year-old woman sustained a
      locked lateral patellar dislocation when falling from a chair. A preoperative CT
      scan revealed bony avulsions at the insertion of the vastus medialis muscle, the
      medical retinaculum, and partial disruption of the ligamentum patellae from the
      apex patellae. Open reduction was necessary and the torn structures were
      reattached with anchor systems and sutures. Postoperative management included
      intensive physiotherapy. At 1 year after surgery, the patient was without
      swelling or pain and had a normal gait, but flexion was restricted to 120
      degrees. All postoperative radiographs showed the patella correctly placed in the
      femoral groove.

PMID- 10639653
TI  - Etiological aspects in osteochondritis dissecans patellae.
AB  - In a retrospective study probable etiological factors of rare cases of
      osteochondritis dissecans of the patella were analyzed. Anamnestic data and data
      obtained from standardized roentgenography in the anterior-posterior, axial, and
      lateral views of the patella were evaluated. Anamnestic data provided no evidence
      of the etiology in addition to the fact that several patients mentioned a single
      or multiple trauma. In contrast to this, evaluation of the roentgenograms showed
      that most of the patients with osteochondritis patellae exhibited a flat
      articular surface of the patella (types I and V in Hertel's classification) and a
      distinct accumulation of the patellae with greater lateral than medial facet
      (types II and III in Wiberg's classification). Furthermore, the axial shape of
      the patellar groove exhibited a distinct accumulation of type III trochleae,
      representing a hypoplasia of the medial and hyperplasia of the lateral part of
      the trochlea. Evaluation of the lateromedial patellar alignment revealed in a
      distinct accumulation of grade II dislocation medially and laterally. Although
      the data were obtained from a rather small number of patients, in our opinion
      these results support the theory of biomechanical induction of osteochondritis
      dissecans patellae. Further dynamic analyses are needed to clarify biodynamic
      effects on the patella and the patellofemoral joint.

PMID- 10639654
TI  - Effectiveness of physiotherapy after meniscectomy.
AB  - To evaluate the effect of physiotherapy after partial arthroscopic meniscectomy,
      we performed a prospective, randomised and partially blinded study. This pilot
      study was performed from October 1996 to June 1997. The control group received
      the standard treatment, consisting of verbal and written advice and exercises.
      The physiotherapy group performed exercises according to a dynamic protocol under
      the supervision of a physiotherapist. During a 3-week period, nine treatment
      sessions were given of 30 min each. Twenty patients, who had undergone
      arthroscopic meniscectomy without any other pathology of the knee, were
      randomised into two groups of ten patients each. The effects of therapy were
      evaluated by a blinded observer. We measured the distance and height of one-leg
      jumps (hops), the VAS pain scale, the Tegner and Lysholm scores and the SARS/FORS
      score. Recovery and satisfaction with the treatment were also evaluated. The
      effect measurements were performed at 7 (T1), 14 (T2), 21 (T3) and 28 days (T4)
      following surgery. Statistical analysis was performed with the Student's t-test.
      The physiotherapy group showed significantly better results than the control
      group regarding the SARS score, the hop test and the distance jumps. Moreover,
      the measurements showed clear progression in favour of the physiotherapy group.
      In conclusion, exercising under the supervision of a physiotherapist led to high
      patient satisfaction and good functional rehabilitation after partial
      arthroscopic meniscectomy.

PMID- 10639655
TI  - Which stabilization technique corrects anatomy best in patients with AC
      separation? An experimental study.
AB  - In ten human cadaveric shoulder specimens four different parameters were
      documented prior to, and after, dissecting all passive stabilizers. These
      included the vertical, horizontal and mediolateral acromioclavicular distance, as
      well as the clavicular rotation. In addition, the same parameters were documented
      after acromioclavicular (AC) reconstruction using eight different techniques. The
      results showed a good reconstruction of the vertical ac-distance. Most of the
      techniques, especially the coracoid-sling procedure, led to a significant
      anterior displacement of the clavicle in relation to the scapula. To a lesser
      degree, most of the conventional procedures also resulted in a lateralization of
      the acromion and/or clavicular rotation. A bone anchor system for distal fixation
      in the base of the coracoid process and a medialized hole in the clavicle
      restored anatomy best. This new technique therefore is recommended for anatomical
      AC-reconstruction.

PMID- 10639656
TI  - Fractures of the fifth metatarsal in basketball players.
AB  - A prospective nonrandomized study was made of 17 basketball players with
      fractures of the proximal third of the shaft of the fifth metatarsal. Eight had
      acute fractures, which were treated with a cast without weight-bearing, and the
      other nine had stress fractures for which percutaneous compression screwing was
      initially used. In the first group, union was obtained in four cases in an
      average of 9 weeks, with resumption of sport by 12 weeks. Three had a good
      outcome and the fourth was fair. The other four cases, which had not healed after
      12 weeks of immobilization, were subsequently treated using compression screws.
      Resumption of sport was achieved 20-24 weeks after the fracture. Two of these had
      a good result; in the other two the results were fair. Of the nine patients with
      stress fractures in which a screw was inserted, all healed between 8 and 14 weeks
      and returned to sport within 7-12 weeks. Seven had a good result and the other
      two only fair. There was one intraoperative complication, but no postoperative
      complications, such as nonunion or refracture, were observed. Even if the non
      operative treatment is able to provide a good result, immobilization without
      weight-bearing does not guarantee healing. In this series, percutaneous screw
      fixation was able to achieve successful healing in a short period of time. Thus,
      this procedure seems to be preferable for primary treatment of this lesion in
      athletes.

PMID- 10639657
TI  - In situ microdialysis in tendon tissue: high levels of glutamate, but not
      prostaglandin E2 in chronic Achilles tendon pain.
AB  - This investigation was to our knowledge the first to use the microdialysis
      technique to study concentrations of substances in a human tendon. In four
      patients (mean age 40.7 years) with a painful nodule in the Achilles tendon
      (chronic Achilles tendinosis) and in five controls (mean age 37.2 years) with
      normal Achilles tendons (confirmed by ultrasonography) the local concentrations
      of glutamate and prostaglandin E2 were measured under resting conditions. A
      standard microdialysis catheter was inserted into the Achilles tendon under local
      anesthesia. Sampling was performed every 15 min over a 4-h period. The results
      showed significantly higher concentrations of glutamate in tendons with
      tendinosis than in normal tendons (196 +/- 59 vs. 48 +/- 27 mumol/l, P < 0.05),
      and there were no significant changes in glutamate concentration over the period
      of investigation. There were no significant differences in the mean
      concentrations of prostaglandin E2 (83 +/- 22 vs. 54 +/- 24 pg/ml) between
      tendons with tendinosis and normal tendons. In conclusion, in situ microdialysis
      appears a useful method to study certain metabolic events in tendon tissue. The
      higher concentrations of the excitatory neurotransmitter glutamate in Achilles
      tendons with a painful nodule may possibly be involved in the pain mechanism in
      this chronic condition. Furthermore, there were no signs of inflammation in the
      tendons with painful nodules, as indicated by the normal prostaglandin E2 levels.

PMID- 10639658
TI  - 'Infectious web'.
AB  - The infection-related web-sites discussed in this issue include sites on the
      Campylobacter jejuni genome, Toxoplasma-expressed sequence tags (ESTs),
      Salmonella infections, the history and biology of tuberculosis, both DNA and RNA
      vaccines, and interactions between cytomegalovirus and antibodies.

PMID- 10639659
TI  - Contrast-enhanced MR angiography of the craniocervical vessels: a review.
AB  - The use of MR angiography (MRA) with injection of contrast medium enables imaging
      of a large volume with a very short acquisition time, providing angiographic
      images similar to those obtained with catheter angiography. This makes possible
      investigation of patients in the acute phase of stroke, with examination of the
      entire length of the cervical arteries from the aortic arch to the circle of
      Willis. However, the parameters of the sequence must be carefully chosen to
      optimise image quality, with a compromise between spatial resolution, acquisition
      time and image contrast. An overview of the technical aspects is presented,
      including current developments. Different protocol strategies are discussed,
      including their advantages and limits. Finally, we review the preliminary results
      of contrast-enhanced MRA for assessment of atherosclerotic lesions of supra
      aortic vessels.

PMID- 10639660
TI  - Conservative management of extra-axial hematomas diagnosed by CT.
AB  - Our purpose was to assess the role of serial CT in recently traumatized patients
      with clinically stable extra-axial intracranial hematomas (EACH) and a midline
      shift of less than 0.5 cm. A retrospective review of 91 imaging studies in 41
      patients (with 45 EACH) was done to assess the time between trauma and CT; the
      presence and type of skull fracture; the volume, type, and location of the EACH;
      the presence of associated edema and/or contusion. Over a 19-day follow-up, 11%
      of the dense EACH increased in volume and 27% decreased. An adjacent skull
      fracture was seen most frequently in patients with a decrease in EACH volume.
      Clinical data remain the key to determining the need for neurosurgical
      intervention in patients with EACH. Follow-up CT afforded no data which altered
      the medical management of these patients. However, it may be said to have alerted
      the clinician to an increase in the size of the EACH in 11% of cases, which could
      mandate close observation of this group.

PMID- 10639661
TI  - Visual analysis of serial T2-weighted MRI in multiple sclerosis: intra- and
      interobserver reproducibility.
AB  - We evaluated the effect of consensus formation and training on the agreement
      between observers in scoring the number of new and enlarging multiple sclerosis
      (MS) lesions on serial T2-weighted MRI studies. The baseline and month 9 MRI
      studies of 16 patients with a range of MRI activity were used (dual-echo
      conventional spin-echo sequence, TR 2000, TE 34 and 90 ms, 5 mm contiguous
      slices, inplane resolution 1 mm). First, the serial studies were visually
      analysed for the presence of new and enlarging lesions, on two occasions, by five
      experienced observers, without adopting any consensus strategy and in isolation.
      Next, the observers met to identify the common sources of inconsistencies in
      reporting between observers and formulate consensus rules. Finally, a further
      independent reading session was performed on the same MRI dataset, this time
      applying the consensus rules. Agreement between observers was assessed using
      kappa scores. Without the consensus rules, interobserver kappa scores for the
      first and second reading sessions for new lesions were only 0.51 and 0.39
      respectively; agreement for enlarging lesions was even worse. The mean
      intraobserver kappa score for new lesions was higher at 0.72, reflecting the fact
      that the observers were consistently applying their individual assessment
      strategies. Application of the consensus rules did not lead to a significant
      improvement in inter observer kappas; the kappa scores adopting the guidelines
      were 0.46 and 0.21 for new and enlarging lesions respectively. Consensus
      guidelines thus did not improve the reproducibility of visual analysis of serial
      T2-weighted MRI, and the level of agreement between observers remained only
      moderate. Suboptimal repositioning is likely to be a major source of residual
      variability and this suggests a future role for image registration strategies;
      until then, a single observer, or pair of observers working in consensus, should
      be used in MS studies.

PMID- 10639662
TI  - Clinical single-shot diffusion-weighted MRI of the human brain on a short-bore
      medium-field imager.
AB  - Diffusion-weighted MRI (DWI) is becoming important for assessment of acute
      stroke. Until recently single-shot DWI required expensive technology such as
      echoplanar imaging (EPI) available only at some research sites. A new medium
      field (1.0 T) short-bore MR imager has been developed with which DWI data sets
      can be acquired. We prospectively studied 169 patients on this 1.0 T commercial
      system. After conventional imaging, DWI was performed with a single-shot multi
      slice sequence with b values 0 an 900 s/mm2, and with the gradients switched in
      three directions. The apparent diffusion coefficients were calculated with online
      calculation software. There were 50 patients with totally normal MRI, and 17 had
      strokes, these strokes were detected as areas of high signal on the images at a
      maximal b value. There was a drop in the ADC in ischaemic regions: in sub-acute
      infarcts, the values were between 0.41 and 0.531 x 10(-3) mm2/s. In old infarcts
      the ADC was 1.15 x 10(-3) mm2/s. Cerebrospinal fluid (CSF) gave low signal
      whereas areas in the brain had more intermediate intensities (CSF: 3.00; deep
      white matter: 0.75, cortical grey matter: 0.80, basal ganglia (thalamus): 0.70
      and cerebellar white matter: 0.65 x 10(-3) mm2/s. Anisotropy was detected as
      areas of restricted diffusion along the tracts. These preliminary data show that
      DWI can be acquired successfully on a medium-field short-bore system. This should
      allow the technique to be implemented at more sites, therefore facilitating the
      diagnosis of acute stroke and rendering early intervention feasible.

PMID- 10639663
TI  - Progressive multifocal leukoencephalopathy demonstrating contrast enhancement on
      MRI and uptake of thallium-201: a case report.
AB  - We describe a patient with AIDS who presented with focal neurological symptoms,
      and who had contrast-enhancing brain lesions on MRI which demonstrated increased
      thallium-201 uptake on SPECT. These findings were consistent with lymphoma;
      however, brain biopsy established a diagnosis of progressive multifocal
      leukoencephalopathy (PML). To our knowledge, this is the first reported case of
      PML with increased thallium-201 uptake on brain SPECT.

PMID- 10639664
TI  - Unusual MRI findings in lymphocytic hypophysitis with central diabetes insipidus.
AB  - We report an unusual case of lymphocytic hypophysitis, which proved to be cystic
      at surgery.

PMID- 10639665
TI  - A rare, complex developmental anomaly of the atlas: embryological and
      radiological considerations.
AB  - We report a patient with disseminated malignancy and a complex anomaly of C1 and
      C2 in whom CT confirmed the developmental nature of the bony abnormalities.

PMID- 10639666
TI  - Spinal epidural abscess: correlation between MRI findings and outcome.
AB  - Our purpose was to determine if specific MRI findings in spinal epidural abscess
      (SEA), at the time of diagnosis, are associated with the clinical outcome. The
      clinical records and MRI studies of 18 patients with SEA were reviewed and follow
      up was obtained from the outpatient medical record, telephone interview, or both.
      The association between findings on contrast-enhanced MRI and clinical outcome
      (weakness, neck or back pain, and incomplete functional recovery) was evaluated.
      With univariate analysis, narrowing of 50% or more of the central spinal canal (P
      = 0.03), peripheral contrast-enhancement (P = 0.05), and abnormal spinal cord
      signal intensity (P = 0.05) were associated with weakness at follow-up.
      Persistent neck or back pain was associated with spinal canal narrowing (P =
      0.02), peripheral contrast-enhancement (P = 0.02), and an abscess longer than 3
      cm (P = 0.04) on MRI. Incomplete clinical recovery was associated with both
      abscess length (P = 0.01) and the severity of canal narrowing (P = 0.01). Abscess
      length, enhancement pattern, and severity of canal narrowing can be incorporated
      in a grading system that can be used to predict outcome.

PMID- 10639667
TI  - Hyperacute spinal subdural haematoma as a complication of lumbar spinal
      anaesthesia: MRI.
AB  - We report two cases of hyperacute spinal subdural haematoma secondary to lumbar
      spinal anaesthesia, identified with MRI. Prompt diagnosis of this infrequent,
      potentially serious complication of spinal anaesthesia is essential, as early
      surgical evacuation may be needed. Suggestive MRI findings in this early phase
      include diffuse occupation filling of the spinal canal with poor delineation of
      the spinal cord on T1-weighted images, and a poorly-defined high-signal lesion
      with a low-signal rim on T2-weighted images.

PMID- 10639668
TI  - The efficacy of CT arteriography for spinal arteriovenous fistula surgery:
      technical note.
AB  - We performed helical computed tomography with contrast injection into feeding
      arteries through a selectively introduced microcatheter to provide precise
      definition of the vascular and bony structure of the spine in patients with
      spinal arteriovenous fistula. This selective CT arteriography reliably showed
      structures including abnormal epi- and intradural feeding arteries, the fistula,
      perimedullary draining veins and surrounding vertebrae preoperatively with a
      minimal contrast medium load. This technique can facilitate safe, minimally
      invasive surgical obliteration of the fistula and a favorable outcome.

PMID- 10639669
TI  - Mitochondrial diseases in children: neuroradiological and clinical features in 17
      patients.
AB  - Mitochondrial diseases result from structural, biochemical or genetic defects of
      mitochondria, which contain the respiratory chain. They usually affect children
      and young adults. We report the CT and MRI findings in 17 patients under 14 years
      of age, the youngest reported to date, with various mitochondrial diseases.
      Although imaging studies may be normal negative in the early stages, follow-up
      usually shows many abnormalities, which depend on clinical status and the
      disease. We have recognised a spectrum of findings that can be divided into four
      patterns: nonspecific myelin lesions (8/17); grey-matter nuclei involvement
      (6/17); a leukodystrophic pattern; and calcification of the brain (1/17),
      although mixed forms, particularly myelin and grey-matter lesions are frequent.

PMID- 10639670
TI  - Changes in brain water diffusion during childhood.
AB  - We studied the changes in brain water diffusion in childhood as seen on diffusion
      weighted MRI in 30 children from 1 day of life to 17 years to provide a data base
      and to investigate the correlation of diffusion changes with known patterns of
      white matter maturation. The apparent diffusion coefficient (ADC) and apparent
      anisotropy (AA) were calculated in numerous regions of the brain to include major
      white matter tracts and gray matter. ADC and AA values were directly related to
      the structural maturity and compactness of the white matter tracts and changed
      with aging in a way that predated early myelination markers such as signal change
      on T1- or T2-weighted images. Diffusion of water is sensitive to structural
      changes in the brain such as white matter maturation and may be useful in
      investigating white matter disorders.

PMID- 10639671
TI  - MRI and proton spectroscopy in a child with Rasmussen's encephalitis. Case
      report.
AB  - The greater sensitivity of magnetic resonance spectroscopy (MRS) compared with
      MRI to brain abnormalities in Rasmussen's encephalitis was demonstrated in a 3
      year-old boy. The patient, with symptoms, signs and morphological findings
      consistent with Rasmussen's encephalitis, was followed with MRI and MRS over 30
      months. That metabolic changes can be disclosed by MRS before the development of
      symptoms or signs was demonstrated as pathological spectra were found not only in
      the diseased left hemisphere but also in the morphologically normal right
      hemisphere before any neurological disturbance of that side.

PMID- 10639672
TI  - MRI in 3-methylglutaconic aciduria type 1.
AB  - MRI in a young child with 3-methylglutaconic aciduria type 1 showed signal
      abnormalities in the basal ganglia which progressed despite successful treatment.

PMID- 10639673
TI  - Sydenham's chorea: MRI and proton spectroscopy.
AB  - We present the MRI and proton spectroscopy findings in a child with clinical
      diagnosis of Sydenham's chorea. MRI showed high signal in the caudate nuclei and
      putamina on T2-weighted images. We believe that the spectra showed an abnormality
      in the number and/or function of neurons, lipids from cellular breakdown
      (cytolytic effect of antibodies), aminoacids (related to the presence of
      antibodies in the neostriatum), and sugars (also related to the presence of
      antibodies). The spectroscopy features correlate well with the histopathology and
      biochemistry of this rare disorder.

PMID- 10639674
TI  - Central structure preservation of the reversal sign.
AB  - We report serial changes of central structure preservation of the reversal sign
      in a case of child abuse. The serial CT images show that the relatively spared
      attenuation at the basal ganglia, thalami, and posterior fossa develops before
      the occurrence of transtentorial herniation. This finding makes the theory that
      central preservation of the reversal sign is due to pressure relief after
      transtentorial herniation less convincible.

PMID- 10639675
TI  - Cerebellopontine angle pilocytic astrocytoma mimicking acoustic schwannoma.
AB  - We describe a case of pilocytic astrocytoma of the cerebellum mimicking an
      acoustic schwannoma. The tumour protruded into the porus acusticus and enlarged
      the internal auditory meatus, which is a quite unusual characteristic of glial
      tumours.

PMID- 10639676
TI  - Endovascular therapy of arteriovenous fistulae with electrolytically detachable
      coils.
AB  - We report our experience in using Guglielmi electrolytically detachable coils
      (GDC) alone or in combination with other materials in the treatment of
      intracranial or cervical high-flow fistulae. We treated 14 patients with
      arteriovenous fistulae on brain-supplying vessels--three involving the external
      carotid or the vertebral artery, five the cavernous sinus and six the dural
      sinuses--by endovascular occlusion using electrolytically detachable platinum
      coils. The fistula was caused by trauma in six cases. In one case Ehlers-Danlos
      syndrome was the underlying disease, and in the remaining seven cases no
      aetiology could be found. Fistulae of the external carotid and vertebral arteries
      and caroticocavernous fistulae were reached via the transarterial route, while in
      all dural fistulae a combined transarterial-transvenous approach was chosen. All
      fistulae were treated using electrolytically detachable coils. While small
      fistulae could be occluded with electrolytically detachable coils alone, large
      fistulae were treated by using coils to build a stable basket for other types of
      coil or balloons. In 11 of the 14 patients, endovascular treatment resulted in
      complete occlusion of the fistula; in the remaining three occlusion was subtotal.
      Symptoms and signs were completely abolished by this treatment in 12 patients and
      reduced in 2. On clinical and neuroradiological follow-up (mean 16 months) no
      reappearance of symptoms was recorded.

PMID- 10639677
TI  - Women's health policy and the U.S. Women's Soccer team.

PMID- 10639678
TI  - Pelvic inflammatory disease after tubal sterilization: a review.
AB  - Exceptions ot the common notion that tubal occlusion protects from recurrent
      pelvic inflammatory disease (PID) do exist. Since 1975, 71 cases of salpingitis
      and 38 tubo-ovarian abscesses (TOA) in sterilized women have been published. The
      majority of cases of salpingitis after previous tubal occlusion (SPOT) developed
      more than a year after either laparoscopic or laparotomy sterilization
      procedures. For tubo-ovarian abscess after previous tubal occlusion (TOAPOT),
      this time interval ranged from several weeks to almost two decades. Most cases of
      salpingitis showed inflammation of both tubal segments. When only one segment was
      involved, it was generally the proximal segment. The appearance of the TOAPOT at
      the time of surgery was typical to TOA. The symptoms of salpingitis were not
      different from symptoms in any other case of PID, and those associated with
      TOAPOT were typical of TOA. Laboratory findings included leucocytosis and growth
      of Neisseria gonorrohoea and Chlamydia trachomatis from the cervix, the infected
      tube, and the peritoneal fluid. Pus cultures obtained from cases of TOAPOT grew
      mixed or single organisms. Detailed histopathologic studies in tubal specimens
      after the failure of an occlusion procedure are available from cases with no
      infection. They have demonstrated distortion, loss of musculature, and loss of
      lumen configuration, all of which may have been the result of compromised blood
      supply to the tube. These findings may be extrapolated to cases of SPOT and
      TOAPOT, assuming similar changes may be present before the development of
      infection. The mechanisms by which infection may develop in previously occluded
      tubes are divided into three groups: The first group consists of situations where
      there is persistence of free passage between the proximal and distal portions of
      the tube. These include toboperitoneal fistula, spontaneous anastomosis at the
      occlusion site, recanalization of the occluded site, incomplete tubal occlusion
      due to a faulty surgical technique or rupture of the weakened tubal wall. The
      second group consists of infections initiated by the surgical procedure itself,
      such as introduction of pathogens at surgery, exacerbation of chronic PID, and
      ascending infection secondary to surgical manipulation. In the third group, the
      infection is initiated systemically by hematogeneous spread, lymphatic spread, or
      change in immunologic status.

PMID- 10639679
TI  - Epidemiologic issues of sexually transmitted diseases in sexual assault victims.
AB  - The objective of this study was to investigate the epidemiologic aspects of
      sexually transmitted diseases (STDs) in victims of sexual assault and to discuss
      the methodological issues in determining risk of STD acquisition. We performed a
      comprehensive review of the medical literature to determine the prevalence of
      STDs in victims of sexual assault. A MEDLINE search and a search of
      bibliographies of published manuscripts was performed to discover relevant
      articles published in the English language. Studies were included in our review
      if they provided estimates of the prevalence of infection with Neisseria
      gonorrhoeae, Chlamydia trachomatis, Treponema pallidum, Trichomonas vaginalis, or
      human papillomavirus (HPV). The main outcome measure was prevalence rates of STDs
      in victims of sexual assault. It is difficult to determine the rate of newly
      acquired STDs from sexual assault. In the populations studied the prevalence of
      STDs can be summarized as follows: N. gonorrhoeae 0.0 to 26.3 percent; C.
      trachomatis 3.9 to 17 percent; T. pallidum 0.0 to 5.6 percent; T. vaginalis 0.0
      to 19.0 percent; and HPV 0.6 to 2.3 percent. We conclude that prevalence
      estimates vary widely depending on the population studied and known risk factors
      for STDs. Given the limited follow-up rates in this population, preventive
      treatment for STDs in addition to emergency contraception should be offered in
      most instances. TARGET AUDIENCE: Obstetricians & Gynecologists, Family
      Physicians. LEARNING OBJECTIVES: After completion of this article, the reader
      will be able to estimate the prevalence of STD transmission from an act of sexual
      assault, to describe the various types of STDs that a sexual assault victim is at
      risk for, and to explain the role of preventive therapy in this setting.

PMID- 10639680
TI  - Intracytoplasmic sperm injection: what are the risks?
AB  - Intracytoplasmic sperm injection, a relatively new technique used at the time of
      in vitro fertilization to fertilize human oocytes, has provided couples with very
      severe male factor infertility the ability to conceive their own biologic
      children. Many men with severe oligospermia or azoospermia can now pass their
      genes on to their progeny, an event that might not have been possible for them
      just a few years ago. Recent studies now suggest that there may be genetic and
      developmental differences in some children conceived through intracytoplasmic
      sperm injection. It is likely that genetic testing and counseling will be
      recommended for all couples with male factor infertility in the near future.
      TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians. LEARNING
      OBJECTIVES: After completion of this article, the reader will be able to describe
      the various indications for the use of ICSI in the treatment of infertility, to
      identify the potential long-term risks associated with the use of ICSI, and to
      estimate the rate of chromosomal abnormalities in this population of infertile
      patients.

PMID- 10639681
TI  - Radiotracer imaging of dopaminergic transmission in neuropsychiatric disorders.
AB  - This article will review the capabilities and accomplishments of radiotracer
      imaging with single photon emission computed tomography (SPECT) and positron
      emission tomography (PET) to measure pre-, post-, and "intra-synaptic" aspects of
      dopaminergic (DAergic) neurotransmission. The presynaptic site can be labeled
      with probes for the dopamine transporter (DAT) or the synthetic enzyme aromatic L
      amino acid decarboxylase ("dopa decarboxylase"). The postsynaptic sites can be
      labeled with probes for either the dopamine D1 receptor (D1R) or the dopamine D2
      receptor (D2R). The "synaptic" measurements are made indirectly by measurements
      of the interaction/displacement of receptor tracers by endogenous dopamine (DA).
      Agents are used which either release (e.g., amphetamine) or deplete (e.g., alpha
      methyl-paratyrosine (AMPT), an inhibitor of tyrosine hydroxylase) tissue stores
      of DA. The application of these paradigms will be reviewed with special emphasis
      to neuropsychiatric diseases such as schizophrenia and idiopathic Parkinson's
      disease (IPD).

PMID- 10639682
TI  - Dose-response curves and time-course effects of selected anticholinergics on
      locomotor activity in rats.
AB  - RATIONALE: In order to facilitate direct comparisons of anticholinergic drug
      effects on activity, nine drugs were tested in one laboratory using a
      standardized procedure. OBJECTIVE: The present study compared the effects of
      aprophen hydrochloride, atropine sulfate, azaprophen hydrochloride, benactyzine
      hydrochloride, biperiden hydrochloride, diazepam, procyclidine hydrochloride,
      scopolamine hydrobromide, and trihexyphenidyl hydrochloride on activity levels in
      rats. METHODS: Both fine motor activity (reflecting smaller movements) and
      ambulatory activity (reflecting larger movements) were recorded for 23 h
      following drug administration in food-restricted rats. All drugs were
      administered during the light period of the photocycle. RESULTS: Atropine,
      azaprophen, biperiden, scopolamine, and trihexyphenidyl increased both
      ambulations and fine motor activity significantly during the first hour post
      injection, but the increased activity levels returned to vehicle control levels
      within 2-6 h post-injection. Benactyzine and procyclidine only increased fine
      motor activity significantly above vehicle control levels and activity levels
      returned to vehicle control levels within 2-3 h. Finally, aprophen and diazepam
      generally did not increase measures of activity significantly above vehicle
      controls at the dose ranges examined. CONCLUSIONS: Based on potencies relative to
      scopolamine, the potency of the drugs could be ranked as follows: scopolamine >
      trihexyphenidyl > biperiden > azaprophen > procyclidine > benactyzine > atropine
      > aprophen. The comparison of drug effects on activity may be useful in selecting
      anticholinergic drug therapies with a minimal range of side effects. In addition,
      these data may reduce the number of anticholinergic drugs that need to be tested
      in comparison studies involving more complex behavioral tests.

PMID- 10639683
TI  - Cocaine-opioid interactions in groups of rats trained to discriminate different
      doses of cocaine.
AB  - RATIONALE: The growing abuse of cocaine combined with morphine-like opiates
      ("speedballs") in human addicts has prompted efforts to characterize the roles of
      different opioid receptor subtypes in mediating their combined effects. Previous
      drug discrimination studies in rats have been inconsistent in showing significant
      interactions between cocaine and opioid agonists in subjects trained to
      discriminate a relatively high dose of cocaine from vehicle. It is known,
      however, that the training dose of cocaine can play a key role in drug
      substitution and drug-interaction profiles and, therefore, training rats to
      discriminate a relatively low dose of cocaine may influence its interactions with
      opioid agonists. OBJECTIVES: The objectives of this study were to examine the
      degree to which a relatively high (10 mg/kg) versus a relatively low (3.0 mg/kg)
      cocaine training dose influenced the interactions between cocaine and either the
      mu opioid agonist morphine or the kappa opioid agonist U50,488. METHODS:
      Substitution tests with cumulative doses of cocaine, morphine and U50,488 were
      conducted, as were studies in which selected doses of morphine or U50,488 were
      administered prior to cumulative doses of cocaine. RESULTS: In substitution
      tests, cocaine was 2.9 times more potent under the low- than the high-dose
      training condition. Morphine substituted fully for cocaine in the majority of
      subjects trained to discriminate the low, but not the high, dose of cocaine.
      U50,488 engendered mainly saline-lever responses under both training conditions.
      In pretreatment studies, morphine enhanced and U50,488 attenuated the
      discriminative stimulus effects of cocaine in low-dose, but not high-dose,
      trained rats. In low-dose trained rats, cocaine was five- to eightfold more
      potent after morphine and three- to fourfold less potent after U50,488
      pretreatments. CONCLUSIONS: The results demonstrate that cocaine-opioid
      interactions are dependent on the training dose of cocaine in rats and suggest an
      opposing influence of mu and kappa opioid receptors in modifying the
      discriminative stimulus effects of cocaine.

PMID- 10639684
TI  - Lorazepam impairs both visual and auditory perceptual priming.
AB  - RATIONALE: Lorazepam has been repeatedly shown to impair both explicit memory and
      perceptual priming, a form of implicit memory, in the visual domain. However, the
      effects of this benzodiazepine on priming in other perceptual domains, such as
      auditory priming, have never been explored. OBJECTIVE: The present study
      investigated whether the deleterious effects of lorazepam on perceptual priming
      are restricted to the visual domain, or if they could be extended to the auditory
      domain. METHODS: Thirty-two healthy volunteers were randomly assigned to two
      parallel groups, placebo and lorazepam 0.038 mg/kg. The drug was administered
      orally, following a double-blind procedure. In the same subjects, perceptual
      priming was assessed in the auditory and visual domains using similar word-stem
      completion tasks, and explicit memory was explored using a free-recall task.
      RESULTS: Lorazepam markedly reduced free-recall performance for visually and
      auditorily presented words. Lorazepam equally impaired visual and auditory
      priming. In the auditory word-stem completion task, prior presentation of a word
      facilitated perception of its stem in the placebo group. This facilitation effect
      was not observed in the lorazepam group. The lorazepam-induced impairment of
      priming was not due to sedation or explicit contamination. CONCLUSION: These
      results indicate that the deleterious effects of lorazepam on priming are not
      restricted to the visual modality, but extend to the auditory modality.

PMID- 10639685
TI  - Initiation of ethanol self-administration in the rat using sucrose substitution
      in a sipper-tube procedure.
AB  - RATIONALE: The concepts of appetitive and consummatory behaviors provide a
      framework for examining ethanol-drinking behavior. However, traditional studies
      of ethanol self-administration using dipper procedures make separating the
      appetitive from the consummatory components difficult. OBJECTIVE: This study
      compared the ability to initiate ethanol self-administration using a new sipper
      tube self-administration procedure with the older established sucrose
      substitution initiation model that employed dipper presented reinforcement. The
      new model was developed to allow for an assessment of the appetitive and
      consummatory components in ethanol self-administration. METHODS: For the sipper
      tube procedure, the rats were initiated to self-administer ethanol using a
      sucrose-substitution procedure that provided limited access to a sipper tube
      containing ethanol. This procedure required the completion of a fixed ratio
      requirement (FR4) in order to gain access to a sipper tube for 20 min. Initially,
      a 20% sucrose solution with no ethanol was provided in the sipper tube. Over
      sessions, the concentration of sucrose was reduced and the ethanol concentration
      increased, until 10% ethanol in water was the solution presented. A second group
      of animals was initiated to self-administer ethanol using the dipper-presentation
      procedure employed in our laboratory for many years. This group was used for
      comparison of the effectiveness of initiation in the sipper-tube procedure.
      RESULTS: Following initiation, the sipper-tube rats self-administered 10% ethanol
      in water with intakes averaging 0.75 g/kg during the 20-min drinking period.
      Increasing the ethanol concentrations as high as 20%, increased intakes as high
      as 1.5 g/kg. The ethanol intakes observed were similar to those obtained with the
      dipper initiation procedure but occurred in one-third of the time. CONCLUSIONS:
      The sipper-tube procedure employed here results in similar ethanol self
      administration behavior as has been found with a dipper presentation procedure.
      More importantly, however, it allows for a separation of the appetitive and
      consummatory components of ethanol self-administration. This separation may prove
      useful for examining the strength of ethanol-seeking behaviors without the
      confound of increasing levels of ethanol interacting with the appetitive seeking
      behaviors.

PMID- 10639686
TI  - Growth hormone response to baclofen in patients with mania: a pilot study.
AB  - RATIONALE: Growth hormone (GH) response to a challenge with a GABAB receptor
      agonist, baclofen, is considered to provide an in vivo index of hypothalamic
      GABAB receptor function in humans. OBJECTIVES: The purpose of this study was to
      explore the role of GABAB receptors in the pathophysiology of mania by measuring
      plasma GH response to baclofen in ten manic patients and ten matched healthy
      controls. METHODS: After obtaining blood samples for baseline GH levels, a single
      dose of 20 mg baclofen was administered orally to all the subjects, and further
      blood samples were obtained at 30-min intervals for the following 3 h. RESULTS:
      We found that baclofen administration led to a significant increase in GH release
      both in manic patients and healthy controls, but the GH response to baclofen in
      manic patients was significantly enhanced when compared to healthy controls.
      CONCLUSIONS: Our results suggest that manic patients may have an up-regulated
      hypothalamic GABAB receptor function. However, in light of the limitations
      including small sample size and absence of placebo control, our results should be
      viewed as preliminary. Further studies with a larger number of manic patients and
      a placebo control design are needed to replicate our finding before any firm
      conclusion can be drawn.

PMID- 10639687
TI  - Cocaine-seeking produced by experimenter-administered drug injections: dose
      effect relationships in rats.
AB  - RATIONALE: Relapse to drug taking is a major obstacle to the effective treatment
      of cocaine abuse. Animal studies have determined that various drugs are able to
      reinstate extinguished drug-taking behavior. OBJECTIVES: This study was designed
      to determine whether there is specificity in the ability of drugs to lead to
      cocaine-seeking and to compare potency and efficacy of a variety of drug primes.
      Another objective was to compare the effect of drugs with a primary dopaminergic
      mechanism with those having a secondary effect on dopaminergic substrates.
      METHODS: Following acquisition of cocaine self-administration, the ability of
      injections of cocaine (5.0-20.0 mg/kg), amphetamine (0.30-3.0 mg/kg),
      methylphenidate (2.0-20.0 mg/kg), nicotine (0.0375-0.60 mg/kg), caffeine (1.25
      20.0 mg/kg), morphine (0.10-10.0 mg/kg) or delta 9THC (0.3-3.0 mg/kg) to
      reinstate extinguished drug taking was measured. Tests were conducted in a single
      day and were comprised of three phases. The first phase consisted of a 60-min
      period of cocaine self-administration. During phase 2, the cocaine solution was
      replaced with saline and responding was extinguished during the next 3-h period.
      During phase 3, in which saline again was the only solution available for self
      administration, responding was monitored for 3-8 h following an injection of a
      drug prime. RESULTS: Reinstatement was produced by experimenter-administered
      injections of cocaine, amphetamine, methylphenidate and caffeine but not
      nicotine, morphine or delta 9THC. The potency and efficacy of cocaine,
      methylphenidate and caffeine were comparable, whereas amphetamine was more potent
      and efficacious. Cocaine seeking occurred primarily during the first hour
      following the injection. CONCLUSIONS: These findings suggest that cocaine seeking
      is only produced following administration of specific drugs. It is suggested that
      effective drug primes are those that produce a discriminative stimulus that
      generalizes to the stimulus produced by the reinforcing effects of cocaine.

PMID- 10639688
TI  - Selective destruction of brain serotonin neurons by 5,7-dihydroxytryptamine
      increases responding for a conditioned reward.
AB  - RATIONALE: Previously, we have shown that increasing 5-hydroxytryptamine (5-HT)
      activity attenuates responding for conditioned reward (CR), and the response
      potentiating effect of d-amphetamine on this behaviour. OBJECTIVES: The present
      experiments examined the effects of reducing 5-HT function on responding for CR.
      METHODS: In experiment 1, thirsty rats were trained to associate a CS+ with water
      delivery. The neurotoxin 5,7-DHT was then injected into the dorsal and median
      raphe nuclei. Subsequently, rats were treated with intraaccumbens d-amphetamine
      (1, 3, 10 micrograms) or saline and given access to two levers. One lever
      delivered the CS+ (now termed a CR), while the other was inactive. In experiment
      2, the lesion was carried out prior to conditioning, and approach behaviour to
      the water magazine was measured during CS+ periods. Subsequently, rats were
      allowed to respond for the CS. In experiment 3, non-deprived rats learned to
      associate a CS+ with 10% sucrose; these animals also experienced a CS- which was
      not paired with sucrose. During a test phase responses on the two levers
      delivered either the CS+ or the CS-. RESULTS: 5,7-DHT substantially reduced 5-HT
      levels in striatum and hippocampus. In experiment 1, responding for the CR was
      enhanced by both d-amphetamine and 5-HT depletion in an additive fashion. In
      experiments 2 and 3, the discriminative control over behaviour exerted by the CS+
      was not affected by 5-HT depletion. However, compared to control animals 5-HT
      depleted rats showed higher levels of operant responding for the CR. CONCLUSIONS:
      Serotonin depletion selectively enhances responding for CR. Although 5-HT
      depletion did not potentiate the effects of d-amphetamine, it is suggested that
      CRs activate the mesolimbic dopamine system, and that removal of an inhibitory
      influence of 5-HT on the activity of this system results in increased responding
      for CR in 5,7-DHT-treated rats.

PMID- 10639689
TI  - Cytochrome P450 2D6 genotype and steady state plasma levels of risperidone and 9
      hydroxyrisperidone.
AB  - The role of the polymorphic cytochrome P450 2D6 (CYP2D6) in the metabolism of
      risperidone to its major active metabolite, 9-hydroxyrisperidone (9-OH
      risperidone), has been documented after single oral doses of the drug. In this
      study, the influence of the CYP2D6 polymorphism on the steady-state plasma
      concentrations of risperidone and 9-OH-risperidone was investigated. Thirty-seven
      schizophrenic patients on monotherapy with risperidone, 4-8 mg/day, were
      genotyped by RFLP and PCR for the major functional variants of the CYP2D6 gene.
      Steady state plasma levels of risperidone and 9-OH-risperidone were analysed by
      HPLC. Based on the genotype analysis, three patients were classified as
      ultrarapid metabolizers (UM) with an extra functional CYP2D6 gene, 16 were
      homozygous extensive metabolizers (EM), 15 heterozygous EM and three poor
      metabolizers (PM). The median steady-state plasma concentration-to-dose (C/D)
      ratios of risperidone were 0.6, 1.1, 9.7 and 17.4 nmol/l per mg in UM, homozygous
      EM, heterozygous EM and PM, respectively, with statistically significant
      differences between PM and the other genotypes (P < 0.02). The C/D of 9-OH
      risperidone also varied widely but was not related to the genotype. The
      risperidone/9-OH-risperidone ratio was strongly associated with the CYP2D6
      genotype, with the highest ratios in PM (median 0.79). Heterozygous EM also had
      significantly higher ratios than homozygous EM (median value 0.23 versus 0.04; P
      < 0.01) or UM (median 0.03; P < 0.02). No significant differences were found in
      the C/D of the sum of the plasma concentrations of risperidone and 9-OH
      risperidone between the genotype groups. In conclusion, the steady-state plasma
      concentrations of risperidone and the risperidone/9-OH-risperidone ratio are
      highly dependent on the CYP2D6 genotype. However, as risperidone and 9-OH
      risperidone are considered to have similar pharmacological activity, the lack of
      relationship between the genotype and the sum of risperidone and 9-OH-risperidone
      indicates that the CYP2D6 polymorphism may be of limited importance for the
      clinical outcome of the treatment.

PMID- 10639690
TI  - Modulation of craving by cues having differential overlap with pharmacological
      effect: evidence for cue approach in smokers and social drinkers.
AB  - RATIONALE: An increased risk of drug intake produced by drug cues may reflect the
      fact that the cues are withdrawal-like or aversive, reflecting a conditioned
      adaptation to the drug's acute effects. More recent work suggests that they may
      also be appetitive, signalling the goal characteristics of drug taking.
      OBJECTIVE: These opposing mechanisms were tested in dependent smokers and in
      social drinkers by examining the motivational nature of drug cues that overlap
      differentially with the acute effects of the drug. METHODS: Pictures of different
      phases of smoking or alcohol drinking were presented to deprived and non-deprived
      smokers, to never smokers and non-deprived smokers or to social drinkers. Desire
      for cigarettes or alcohol and momentary pleasure and arousal were measured after
      viewing an experimental picture or a pleasant, neutral or unpleasant control
      scene. RESULTS: High desire for smoking was evoked by pictures of preparation for
      and actual smoking but not by scenes of the end of smoking, although the latter
      were best correlated with acute drug effect. This pattern was not affected by
      overnight smoke deprivation, it was seen in different smokers but not in never
      smokers and it was replicated in social drinkers using pictures of alcohol
      consumption. Moreover, scenes evoking high desire to consume did not evoke states
      of momentary unpleasantness and they were seen as relaxing and not arousing.
      Control pictures had a minimal effect on desire to consume. CONCLUSIONS: In line
      with incentive models of drug cues, cues based on pictures of drug intake may be
      conditioned stimuli encoding cue approach and preparation for consumption.

PMID- 10639691
TI  - Dopamine transporter and D2-receptor density in late-onset alcoholism.
AB  - RATIONALE: Late onset type 1 alcoholism has been suggested to be associated with
      an underlying dopaminergic defect. Therefore, it is relevant to study both
      postsynaptic D2-receptor and presynaptic dopamine transporter (DAT) densities
      among alcoholics. OBJECTIVE: We investigated DAT densities, along with striatal
      and extrastriatal dopamine D2-receptor densities, in nine nonviolent late-onset
      male alcoholics, who had no major mental disorder nor antisocial personality
      disorder (ASPD), and nine healthy controls. METHODS: [123I]PE2I and
      [123I]epidepride were used in SPECT imaging. RESULTS: DAT occupancy ratios
      (striatum/cerebellum) were significantly lower among alcoholics than in controls.
      Extrastriatal D2-receptor occupancy ratios (temporal pole/cerebellum) were not
      significantly different between the groups. CONCLUSIONS: Striatal presynaptic DAT
      densities are decreased among type 1 alcoholics, and this finding is not
      associated with recent alcohol abuse.

PMID- 10639692
TI  - Acute effect of glucose tablets on desire to smoke.
AB  - RATIONALE: Previous research suggests that glucose may reduce desire to smoke
      during periods of abstinence but a definitive test is needed. OBJECTIVE: The
      present study aimed to determine whether a single administration of oral glucose
      would reduce desire to smoke in abstaining smokers. METHODS: Thirty-eight smokers
      attended the laboratory in the afternoon having not smoked since the previous
      evening. They rated their desire to smoke immediately before and at 5-min
      intervals for 20 min after chewing four 3-g glucose tablets (experimental group)
      or four matched placebo tablets (control group). RESULTS: Ratings of desire to
      smoke decreased to a greater extent in the experimental than the control group.
      The effect was apparent after 10 min. There was no difference between the groups
      in terms of feeling "sick" or "satisfied". CONCLUSION: A single dose of glucose
      has a relatively rapid and detectable effect on desire to smoke and the effect is
      not mediated by feeling sick. Glucose tablets may be useful in helping to control
      desire to smoke during periods of abstinence.

PMID- 10639693
TI  - Caffeine and prepulse inhibition of the acoustic startle reflex.
AB  - RATIONALE: A stimulus presented immediately prior to a startle reflex-eliciting
      stimulus inhibits the startle reflex. This is termed prepulse inhibition (PPI)
      and is postulated to index automatic and controlled attentional processing of the
      prepulse. OBJECTIVE: Two experiments investigated the effect of 0, 2, and 4 mg/kg
      oral caffeine on PPI of the acoustic startle eyeblink reflex across stimulus
      onset asynchronies (SOAs) ranging from 30 to 420 ms. In experiment 1, acoustic
      prepulses were used and automatic attention was investigated, whereas in
      experiment 2, acoustic and tactile prepulses were used and automatic and
      controlled attention was investigated. Controlled attention was investigated by
      instructing the subjects to attend to one stimulus (attended stimulus) and not to
      another stimulus (non-attended stimulus). METHODS: Caffeine was administrated to
      human subjects in within-subjects designs (n = 24 and n = 18). Startle reflexes
      to 100 dB noise were recorded by electromyography. A mood scale and readings of
      blood pressure indexed arousal. RESULTS: Caffeine increased the indexes of
      arousal. There were, however, no significant main effects of caffeine on startle,
      nor did caffeine significantly interact with any other variable. Attended
      acoustic prepulses increased PPI at the 120 ms and longer SOAs. Caffeine 4 mg/kg
      abolished this difference between attended and non-attended stimuli. Attended
      tactile prepulses facilitated startle at short SOAs, and caffeine reduced
      facilitation of startle by tactile prepulses. CONCLUSIONS: Caffeine did not
      facilitate automatic attention. Caffeine 4 mg/kg abolished the effect of
      controlled attention on PPI. Facilitation of startle by attended acoustic
      prepulses is best explained by facilitation of motoneurons in the facial nucleus.

PMID- 10639694
TI  - Self-administration of intravenous amphetamine: effect of nucleus accumbens CCKB
      receptor activation on fixed-ratio responding.
AB  - RATIONALE: The mesolimbic dopamine (DA) system is implicated in psychostimulant
      drug self-administration. The neuropeptide cholecystokinin (CCK) is co-localised
      with DA and inhibits nucleus accumbens (NAcc) DAergic neurotransmission via CCKB
      receptors. OBJECTIVES: The present experiment was designed to examine the effects
      of intra-NAcc CCKB receptor stimulation on fixed-ratio (FR) amphetamine self
      administration. METHODS: Wistar rats with intravenous catheters and NAcc cannulae
      were trained to self-administer amphetamine under a FR3 schedule of
      reinforcement. Animals performing stable self-administration were microinjected
      with pentagastrin and assessed during 3-h sessions. RESULTS: Intra-NAcc
      pentagastrin dose dependently increased amphetamine intake. CONCLUSIONS: These
      results are consistent with the notion that NAcc CCKB receptor activation
      attenuates amphetamine reward.

PMID- 10639695
TI  - Selective impairment in the recognition of anger induced by diazepam.
AB  - RATIONALE: Facial expressions appear to be processed by at least partially
      separable neuro-cognitive systems. Given this functional specialization of
      expression processing, it is plausible that these neurocognitive systems may also
      be dissociable pharmacologically. OBJECTIVE: The present study therefore compared
      the effects of diazepam (15 mg) with placebo upon the ability to recognize
      emotional expressions. METHODS: A double blind, independent group design was used
      to compare the effects of diazepam and matched placebo in 32 healthy volunteers.
      Participants were presented morphed facial expression stimuli following a
      paradigm developed for use with patients with brain damage and asked to name one
      of the six basic emotions (sadness, happiness, anger, disgust, fear and
      surprise). RESULTS: Diazepam selectively impaired subjects' ability to recognize
      angry expressions but did not affect recognition of any other emotional
      expression. CONCLUSIONS: The findings are interpreted as providing further
      support for the suggestion that there are dissociable systems responsible for
      processing emotional expressions. It is suggested that these findings may have
      implications for understanding paradoxical aggression sometimes elicited by
      benzodiazepines.

PMID- 10639696
TI  - Dosage of inhaled nitric oxide: a simple method for experimental studies.
AB  - Few studies on treatment with inhaled nitric oxide (NOi) have been carried out in
      small laboratory animals yet, since commercially available dosing devices are not
      appropriate in this setting for technical or financial reasons. The aim of our
      study was to establish and validate a simple, cost-effective system for the
      application of NOi in small animals. The system mixes NOi with constant-flow
      inspiratory gas. A gas blender allows for a mixture of nitrogen, oxygen, and NO
      dissolved in nitrogen. A formula using the desired inspiratory oxygen fraction
      and the desired concentration of NOi as independent variables derives a somewhat
      higher inspiratory oxygen fraction, which is preset using an oximeter. Then the
      flow of NO in nitrogen is started, lowering the inspiratory oxygen fraction to
      the initially desired value, thereby adding NOi in the desired concentration. The
      method was validated by 153 adjustments, covering a variety of oxygen fractions
      and concentrations of NOi. NOi was measured by chemiluminescence as reference
      method. A close correlation (R = 0.994) was found, and the regression line was
      close to the line of identity with y = -0.0994 + 1.048x. No systematic errors
      could be identified. We conclude that the method described may serve as a simple,
      cost-effective way to administer NOi to small animals.

PMID- 10639697
TI  - Beta-adrenergic signalling and threshold adrenaline concentration for induction
      of fibrillation in the perfused heart pretreated with antihypertensive drugs.
AB  - Recent investigations have shown that antihypertensive drug treatment leads to
      enhanced myocardial beta-adrenoceptor sensitivity. This study was therefore
      conducted to establish whether or not such hypersensitivity might trigger
      myocardial arrhythmia subsequent to adrenaline exposure. Adult male Wistar rats
      (n = 6 per group) were treated with either placebo (vehicle), metoprolol (2.40
      mg.kg-1.day-1), timolol (0.075 mg.kg-1.day-1), verapamil (5.50 mg.kg-1.day-1) or
      enalapril (0.50 mg.kg-1.day-1) for 20 consecutive days. Hearts were excised and
      perfused ad modum Langendorff in the presence of an adrenaline gradient (0-300
      nM) for 20 min with either 3.0 mM or 5.9 mM of potassium in the perfusion buffer.
      Adrenaline threshold concentration (ATC, nanomolar) at myocardial fibrillation
      was recorded, as well as tissue cAMP contents, beta-adrenoceptor number, G
      protein levels and signalling effector enzyme activities. The main findings were:
      (1) ATC and cAMP levels were affected in hearts perfused with low-concentration
      potassium buffer only. In terms of ATC, the beneficial effect of each drug
      regimen appeared to be in the rank order of: placebo = enalapril > verapamil >
      timolol > metoprolol. There was an inverse correlation between ATC and myocardial
      cAMP contents at the start of fibrillation; (2) Subsequent to fibrillation, beta
      adrenoceptor number, hormone-elicited adenylate cyclase activities and Gs
      alpha:Gi2 alpha-ratio were no different from preperfusion values; (3) Significant
      inverse correlations between beta 1-adrenoceptor numbers and ATC were observed.
      We conclude that alterations in beta-adrenoceptor number, G proteins and cAMP
      induced by antihypertensive drugs are predictive of the myocardial sensitivity to
      adrenaline in terms of time to continuous and irrevocable fibrillation.

PMID- 10639698
TI  - Implementation of the microdialysis method in the hamster dorsal skinfold
      chamber.
AB  - The aim of this study was to implement the microdialysis method, a well
      established technique for measuring the local concentration of neurotransmitters
      and metabolites in the brain, in the dorsal skinfold chamber of the awake
      hamster. First, the effects of implanted, nonperfused microdialysis probes on the
      microcirculation were examined. Skinfold chambers were prepared with and without
      probes. Two and 3 days later, the following parameters were assessed: diameter,
      red blood cell (RBC) velocity, macromolecular leakage, leukocyte rolling
      fraction, and adherent leukocytes in venules, diameter and macromolecular leakage
      in arterioles, and functional capillary density (FCD). No significant differences
      between the animals of the two groups were observed in any of the parameters on
      either day. Second, the interstitial lactate concentration was measured at two
      perfusion rates in groups with and without a 4-h tourniquet ischemia. The
      induction of ischemia resulted in a significant increase in lactate concentration
      over the control values in the tissue within 1 h to 8000 +/- 860 microM, where it
      remained until the reperfusion, at which point the concentration returned to
      control values within 1 h. The microdialysis method provides the opportunity to
      measure the concentration of metabolites in the extravascular space of the
      hamster dorsal skinfold chamber.

PMID- 10639699
TI  - Multivariate regression analysis of the influence of aortic pressure, end
      diastolic pressure, and heart rate on left ventricular relaxation in isolated
      ejecting rat and guinea pig hearts.
AB  - The effect of moderate changes of peak aortic and end-diastolic pressure and of
      heart rate on the left ventricular relaxation of isolated working rat and guinea
      pig hearts was investigated by multivariate regression analysis. Each of these
      three independent variables was set to three different levels, yielding 27 sets
      of data by combination in each experiment. Relaxation was quantified by the
      maximum pressure fall velocity (min LVdP/dt) and by the time constant tau of left
      ventricular isovolumic pressure fall. tau was obtained by fitting that pressure
      curve to the three-parametric exponential regression model p(t) = P infinity +
      (P0-P infinity) exp (-t/tau) and to an extended four-parametric model p(t) = P
      infinity + (P0-P infinity) exp [(-t/(tau 0 + r tau t)]. The influence of the
      three independent variables on min LVdP/dt, tau, and r tau was checked by
      analysis of variance and quantified by standardized regression coefficients
      obtained by trivariate regression analysis. A positive dependence of min LVdP/dt
      on precedent maximum pressure and of the three-dimensionally (but not four
      dimensionally) estimated tau on beat interval length are the only unequivocally
      significant effects of the investigated hemodynamic changes on the lusitropic
      parameters min LVdP/dt and tau. Principal species differences do not occur. It is
      concluded that considerable lusitropic effects seen especially in pharmacologic
      studies must be attributed to intrinsic effects of the substance rather than to
      hemodynamic changes caused by the substance if the former remain moderate. The
      four-dimensionally calculated tau is slightly more often found to be independent
      of the investigated hemodynamic parameters than the usual three-dimensional
      estimate. This may indicate higher reliability of the four-dimensional regression
      model of isovolumic pressure fall.

PMID- 10639700
TI  - Alterations in superoxide dismutase, glutathione peroxidase and catalase
      activities in experimental cerebral ischemia-reperfusion.
AB  - Free radicals are thought to be the most important cause of the reperfusion
      injury subsequent to ischemia. The antioxidant status of the tissue affected by
      ischemia-reperfusion is of great importance for the primary endogenous defense
      against the free radical induced injury. This investigation was performed to
      evaluate the antioxidant enzyme capacity of the brain tissue in the ischemia
      reperfusion period using an experimental global moderate (penumbral) ischemia
      model on rat brains. Experiments were performed on 45 male Sprague Dawley rats.
      Ischemia was induced by bilateral vertebral arteries cauterization and temporary
      bilateral carotid arteries occlusion and sustained for 10 minutes. At the end of
      ischemia (0 min reperfusion) and various reperfusion periods (20 min, 60 min, 240
      min), rats were decapitated and brains were frozen in liquid nitrogen. Changes in
      the intracellular antioxidant enzyme (superoxide dismutase, glutathione
      peroxidase and catalase) activities were assessed in the rat brain tissues, by
      spectrophotometric methods. In all moderate ischemia-reperfusion groups,
      superoxide dismutase activities were found to have decreased significantly
      compared to the sham operated controls (P < 0.05). During ischemia superoxide
      dismutase activity was lowered to 31% of that of the control group. The decreases
      were more significant in reperfusion groups, particularly in 60 min reperfusion
      (40%). Relatively smaller but still significant diminution was observed in
      glutathione peroxidase activities (P < 0.05). The ratio of diminution was
      striking in 20 min and 60 min reperfusion groups with 26% of the sham operated
      rats. Conversely, moderate ischemia-reperfusion caused significant increase in
      catalase activities (P < 0.05). The increment was 63% of the preischemic level
      with 10 min of moderate ischemia. In conclusion, activities of the major
      antioxidant enzymes were changed significantly in moderate brain ischemia
      reperfusion. These results suggest that the disturbance in oxidant-antioxidant
      balance might play a part in rendering the tissue more vulnerable to free radical
      induced injuries.

PMID- 10639701
TI  - The effect of oral protease administration in the rat remnant kidney model.
AB  - It has been demonstrated that intraperitoneal administration of proteolytic
      enzymes ameliorates the progression of renal diseases in various animal models.
      In the present study, we employed the rat remnant kidney model to study the
      effectiveness of oral administration of proteases. Twenty male Wistar rats
      underwent sham operation (CTRL), while 25 were subjected to 5/6 nephrectomy (5/6
      NX). Rats were randomised into placebo (PL) (2 ml tap water/day by gavage), or
      Phlogenzym (E; fixed mixture of trypsin 2.42 mg, bromelain 4.54 mg, and rutozid
      5.04 mg added as antioxidant, in 2 ml tap water daily by gavage) treated group.
      Duration of the study was 45 days. Rats were pair-fed. Enzyme treatment exerted
      salutary effects on various functional and morphological parameters. Proteinuria
      was higher in both 5/6 NX group rats throughout the study. Administration of
      proteases ameliorated its rise effectively (data at sacrifice: CTRL-PL 6.27 +/-
      1.25, CTRL-E 9.27 +/- 0.99, 5/6 NX-PL 74.04 +/- 21.33, 5/6 NX-E 39.09 +/- 7.93
      mg/24 h; P < 0.01). Increased urinary excretion of the fibrogenic cytokine
      transforming growth factor (TGF-beta 1) was improved, too (CTRL-PL 0.349 +/-
      0.051, CTRL-E 0.693 +/- 0.230, 5/6 NX-PL 3.044 +/- 0.540, 5/6 NX-E 1.390 +/-
      0.238 ng/mumol creatinine; P < 0.05). At sacrifice, tubulointerstitial fibrosis
      was less pronounced in E-treated rats. Correspondingly, the volume fraction of
      tubulointerstitial tissue in the renal cortex was improved in 5/6 NX-E rats (CTRL
      PL 9.9 +/- 0.2, CTRL-E 10.0 +/- 0.2, 5/6 NX-PL 17.9 +/- 1.8, 5/6 NX-E 13.8 +/-
      0.9%; P < 0.05). The protein/DNA ratio in isolated glomeruli and tubules, as an
      estimate of glomerular matrix accumulation and hypertrophy of tubules, was
      enhanced in 5/6 NX groups and a tendency towards lower values was observed after
      E treatment. Renal function as evaluated by serum creatinine and urea levels was
      not influenced by the enzyme therapy. No between-group differences in blood
      pressure were observed. In summary, oral administration of proteolytic enzymes
      improved proteinuria and urinary TGF-beta 1 excretion, as well as the severity of
      tubulointerstitial fibrosis without signs of toxicity.

PMID- 10639702
TI  - An additional dose of cefazolin for intraoperative prophylaxis.
AB  - We examined the pancreatic tissue concentrations of cefazolin in ten patients
      undergoing pancreatectomy, and determined the optimal intraoperative time to
      deliver a repeat dose of cefazolin. An intravenous bolus dose of 1 g cefazolin
      was administered at the time of skin incision. Peripheral blood, subcutaneous
      adipose tissue, and peritoneal samples were obtained intraoperatively every hour
      for 4 h after the antibiotic was first administered, and pancreatic tissue
      samples were obtained at the time of pancreatectomy. To determine adequate tissue
      levels of cefazolin, minimum inhibitory concentrations (MIC) were measured for
      four bacterial species, namely 360 isolates of methicillin-sensitive
      Staphylococcus aureus (MSSA), 204 isolates of Klebsiella pneumoniae, 314 isolates
      of Escherichia coli, and 30 isolates of Streptococcus spp. The antibiotic
      concentrations in adipose tissue and peritoneum 3 h after the administration of
      cefazolin were lower than the MIC80 for K. pneumoniae, E. coli, and Streptococcus
      spp. Most pancreatic tissue samples showed antibiotic concentrations greater than
      the MIC80 for these bacterial species; however, those from four patients
      complicated by severe chronic pancreatitis, massive intraoperative bleeding, or
      obesity showed concentrations lower than the MIC80. Thus, we recommend that a
      second dose of cefazolin be given 3 h after the first administration to maintain
      adequate levels of antibiotic activity.

PMID- 10639703
TI  - Detection of a rectocele-like prolapse in the colonic J-pouch using pouchography:
      cause or effect of evacuation difficulties?
AB  - The functional outcome after a low anterior resection for rectal cancer is
      improved by a colonic J-pouch reconstruction. One functional problem with J
      pouches is difficulty in evacuation, which is more common with large
      reconstructions. Since rectoceles are common findings on defecography in patients
      with evacuation difficulties, we proposed that a rectocele-like prolapse may be
      thus found in patients with large J-pouches. Pouchography was used to identify a
      rectocele-like prolapse (RP) in 26 patients with a 10-cm J-pouch (10-J group) and
      27 patients with a 5-cm J-pouch (5-J group). Pouchography was performed at 3
      months, 1 year, and 2 years after surgery. Functional assessments were performed
      1 year postoperatively. Clinical function was evaluated using a questionnaire.
      The evacuation function was evaluated by the balloon expulsion and saline
      evacuation test. No patients had an RP at 3 months or 1 year after surgery. An RP
      was significantly more common in the 10-J group than in the 5-J group at 2 years
      after surgery (P = 0.0374). An evacuation difficulty was significantly more
      common in the 10-J group than in the 5-J group. The evacuation function in the 10
      J group was also significantly inferior to that in the 5-J group. An RP appearing
      2 years after surgery is more common in patients with evacuation difficulties and
      large colonic J-pouch reconstructions.

PMID- 10639704
TI  - The effect of vaginal delivery on the pelvic floor.
AB  - This study was undertaken to determine the effects of vaginal deliveries on
      anorectal function, and to analyze the possible clinical, physiological, and
      radiological risk factors predisposing to damage of the pelvic floor musculature.
      We studied 25 consecutive women with a mean age of 32 years old, 3 months after
      vaginal delivery, 17 of whom were primiparae and 8, multiparae. The symptoms of
      anal incontinence were assessed, and anorectal manometry, rectal sensation, and
      radiological measurements of the anorectal angle and pelvic floor position at
      rest, on squeezing, and on straining were performed. As a control, six
      nulliparous women underwent the same examinations. Pelvic floor descent in both
      the primiparae and multiparae was significantly greater at rest and on squeezing
      than that in the nulliparous women. Furthermore, pelvic floor descent on
      straining was greater in the multiparae than in the nulliparous women (P =
      0.028). An analysis of the 17 primiparae showed that prolonged duration of the
      second stage of labor and third-degree perineal tears were important factors
      predisposing to pelvic floor descent. In fact, 3 of the 17 primiparae (17%) had
      anal incontinence. These findings indicate that vaginal delivery may cause pelvic
      floor descent, an obtuse anorectal angle, and bowel symptoms.

PMID- 10639705
TI  - Endo-organ full-thickness excision for gastric cancer: report of a case.
AB  - We performed endo-organ full thickness gastric excision to treat a high-risk
      patient with T2 gastric cancer. The patient, a 75-year-old white man with a
      gastric adenocarcinoma located just below the gastroesophageal junction, had a
      history of chronic obstructive pulmonary disease and cor pulmonale, and developed
      markedly elevated pulmonary artery pressures under general anesthesia. The less
      invasive endo-organ approach was utilized because of these severe morbidities.
      The carcinoma was staged laparoscopically, then removed utilizing the full
      thickness endo-organ excision technique. This case report serves to demonstrate
      that full thickness endo-organ gastric excision may be indicated not only for
      certain early gastric cancers, but also for high-risk patients who cannot
      tolerate open surgery due to advanced age or serious illness.

PMID- 10639706
TI  - T-cell dysfunction in a patient with short bowel syndrome: report of a case.
AB  - We describe herein the case of a 48-year-old man who underwent emergency massive
      resection of the small intestine due to strangulated ileus, which led to short
      bowel syndrome (SBS) as he was left with 7 cm of jejunum and 8 cm of ileum. We
      evaluated the immune function in this patient, focusing particular attention on T
      cell-mediated immunity. Biochemical and nutritional parameters, including
      minerals and trace elements, indicated that the patient was in relatively good
      health; however, the proliferative response to mitogen and tumor necrosis factor
      alpha production in response to the anti-CD3 monoclonal antibody in peripheral
      blood lymphocytes (PBL) were impaired compared with age-matched postgastrectomy
      patients and healthy donors. Moreover, the expression of T-cell receptor (TCR)
      zeta, which is involved in signal transduction and the subsequent activation of T
      cells, was downregulated in this patient compared with that in the age-matched
      postgastrectomy patients and healthy donors. These observations suggest that T
      cell function was disturbed in our patient, and that this dysfunction was
      associated with the decreased expression of TCR zeta molecules.

PMID- 10639707
TI  - Delivery of a normal newborn after intensive medical treatment for an acute
      exacerbation of ulcerative colitis during pregnancy: a case report.
AB  - A 28-year-old woman developed an acute exacerbation of chronic ulcerative colitis
      in the second trimester of pregnancy. She was treated by intensive medical
      treatment with intravenous prednisolone, betamethasone enema, oral
      salazosulfapyridine, intravenous ceftazitim, and total parenteral nutrition. The
      acute relapse subsided after 73 days of the treatment and a normal female newborn
      weighing 2,208 g was delivered vaginally after 40 weeks' gestation. Our
      experience showed that the intensive medical therapy did not impair either the
      course of the pregnancy or the fetal outcome.

PMID- 10639708
TI  - Metastatic seeding of bile duct carcinoma in the transhepatic catheter tract:
      report of a case.
AB  - We describe herein the case of a 51-year-old woman in whom metastatic tumor
      seeding of the percutanenous transhepatic biliary drainage tract occurred
      following a pancreatoduodenectomy for carcinoma of the distal common bile duct.
      An abdominal computed tomography scan done 6 months after the initial operation
      detected a hepatic lesion located at the site of the previous percutaneous
      transhepatic biliary drainage tract. Implantation of bile duct carcinoma in the
      drainage tract was diagnosed, and the recurrent tumor was successfully resected
      by performing a subsegmentectomy of segment 3 and removal of the adjacent
      abdominal wall. At present, 5 years and 4 months after the second resection, the
      patient is in good health without any signs of recurrence. This case report
      demonstrates that an aggressive surgical approach should be performed for tumor
      seeding of a transhepatic biliary catheter tract.

PMID- 10639709
TI  - Solid cystic tumor of the pancreas in elderly men: report of a case.
AB  - Solid cystic tumor of the pancreas is a primary pancreatic neoplasm of unknown
      etiology that most commonly occurs in young women and ordinarily contains
      hemorrhagic tissue. We report herein the unusual case of a 75-year-old man found
      to have a solid cystic tumor in the body and tail of the pancreas, who is the
      oldest such male patient to be documented in Japan. The results of laboratory
      data and imaging studies indicated that the patient had a nonfunctioning islet
      tumor or solid cystic tumor of the pancreas, and distal pancreatectomy with
      splenectomy was performed. The diagnosis of solid cystic tumor was confirmed
      based on macroscopic and histological findings of the resected pancreatic tumor.
      The patient is currently in good health, without any signs of tumor recurrence 1
      year and 4 months after his operation. A total of 181 cases of solid cystic
      tumors of the pancreas reported in the Japanese literature, including our case,
      were reviewed to evaluate the clinical differences between patients aged 50 years
      or over and those younger than 50 years.

PMID- 10639710
TI  - Laparoscopic splenectomy for a giant splenic epidermoid cyst: report of a case.
AB  - The use of laparoscopic splenectomy has increased in recent years, primarily for
      patients with idiopathic thrombocytopenic purpura (ITP). We describe herein the
      first known case of a laparoscopic splenectomy to be performed in Japan for a
      patient with a giant splenic epidermoid cyst. A 26-year-old woman presented to
      our hospital with the major complaint of a feeling of abdominal fullness. Prior
      to surgery, an ultrasound-guided splenic cyst puncture was conducted for
      diagnostic purposes as well as to reduce the size of the cyst. The carbohydrate
      antigen 19-9 (CA 19-9) level was found to be elevated in the cystic contents and
      in the serum. Under laparoscopic guidance, the splenic vessels were ligated using
      a device for extracorporeal ligation, then divided. After the resected spleen had
      been placed in a retrieval bag, it was delivered out of the abdominal cavity
      without fragmentation. Following surgery, the patient's serum CA 19-9 level
      returned to normal. Splenic epidermoid cysts are most often encountered in young
      women, and laparoscopic surgery to remove cysts of this type is both minimally
      invasive and excellent from a cosmetic standpoint. Thus, laparoscopic surgery
      should be considered as the method of choice for the majority of patients
      diagnosed with a splenic epidermoid cyst.

PMID- 10639711
TI  - Application of intravascular ultrasonography for intracaval tumor thrombectomies
      in adrenal metastasis from hepatocellular carcinoma: report of two cases.
AB  - Intracaval tumor thrombus is one of the characteristic features of advanced
      hepatocellular carcinoma. To formulate an appropriate operative strategy for
      removing intracaval tumor thrombi, it is of great importance to accurately
      diagnose the location, any invasion into the wall of the vena cava, and the
      extent of intracaval tumor spread. Intravascular ultrasonographic imaging is a
      novel technology that enables the precise catheter-based assessment of the
      dimensions and morphology of the vascular structure and any lesions. We have
      applied this technology to the diagnosis of intracaval tumor thrombi originating
      from adrenal metastasis secondary to hepatocellular carcinomas. This modality was
      thus found to be useful in determining the best operative procedure for removing
      tumor thrombi in the inferior vena cava.

PMID- 10639712
TI  - Laparoscopic adrenalectomy for solitary metachronous adrenal metastasis from lung
      cancer: report of a case.
AB  - We report herein the case of a 69-year-old man who underwent laparoscopic
      adrenalectomy for a solitary adrenal metastasis 10 months after a left lower
      lobectomy for T2N1M0 lung cancer. A 30 x 20 mm tumor was found in the left
      adrenal gland, and dissected using an ultrasonically activated scalpel.
      Histological examination revealed metastatic squamous cell carcinoma. The patient
      recovered uneventfully and his condition is now stable 18 months after the second
      operation, with no evidence of local recurrence or metastatic disease. Although
      laparoscopic resection for malignant adrenal tumors is still controversial, we
      consider that laparoscopic adrenalectomy may be an optional treatment for
      metastatic adrenal tumors, provided the tumor is solitary, small in size, and
      well-localized. To our knowledge, only 14 cases of laparoscopic adrenalectomy for
      malignant tumors have been reported to date; however, this is the first case of
      successful laparoscopic adrenalectomy for a metastasis from lung cancer.

PMID- 10639713
TI  - Handlebar hernia with intra-abdominal extraluminal air presenting as a novel form
      of traumatic abdominal wall hernia: report of a case.
AB  - An 18-year-old male was admitted to our Emergency Department with a traumatic
      abdominal wall hernia (TAWH) of the left lower quadrant (LLQ) after suffering
      hypogastric blunt injury and urogenital lacerations in a motorcycle accident.
      Upright chest X-ray showed a small amount of right infradiaphragmatic free air,
      and a computed tomographic (CT) scan demonstrated an abdominal wall hernia. At
      surgery, no impairment was found in the digestive tract, and an abdominal
      herniorrhaphy was performed. It is suggested that the free air had passed through
      a connection between the scrotal laceration and the contralateral abdominal
      defect via the subcutaneous space and was palpated as emphysema. This is a new
      type of TAWH, which suggests that blunt abdominal trauma may result in negative
      pressure in the subcutaneous and peritoneal cavity, and this could reflect the
      pathophysiology of TAWH.

PMID- 10639714
TI  - Diaphragm reconstruction with autologous fascia lata: report of a case.
AB  - When the diaphragm is excised so widely that the defect cannot be closed directly
      during an operation on either thoracic or epigastric tumors, a reconstruction of
      the defect is necessary. We used harvested autologous fascia lata to reconstruct
      the diaphragm in a patient undergoing a pleuropneumonectomy with a partial
      diaphragmatic resection for malignant mesothelioma.

PMID- 10639715
TI  - Descending necrotizing mediastinitis with sternocostoclavicular osteomyelitis and
      partial thoracic empyema: report of a case.
AB  - We present herein the case of a 50-year-old woman in whom descending necrotizing
      mediastinitis originating from an anterior neck abscess spread to the left upper
      bony thorax, resulting in osteomyelitis of the left sternocostoclavicular
      articulation and left partial thoracic empyema. Transcervical mediastinal
      irrigation and drainage was performed with aggressive antibiotic therapy,
      followed by resection of the left sternocostoclavicular joint and debridement of
      the anterior mediastinum. The patient had an uneventful postoperative course, and
      her left arm and shoulder mobility was well preserved.

PMID- 10639716
TI  - Right axillary arterial perfusion for a ruptured type B aortic dissection: report
      of a case.
AB  - The results of surgical treatment for a ruptured type B aortic dissection remain
      far from satisfactory. It is believed that additional perfusion from the right
      axillary artery might be more beneficial than perfusion from only the femoral
      artery during surgery for a ruptured thoracic aneurysm. The right axillary
      perfusion is more likely to perfuse the vital organs proximal to the ruptured
      area, and thus avoid retrograde emboli. In addition, if the open proximal method
      is performed, then the right axillary perfusion is able to facilitate the
      evacuation of air from the aortic lumen. We present herein the case of a patient
      in whom a ruptured type B acute aortic dissection was successfully treated by
      applying right axillary perfusion through a left thoracotomy.

PMID- 10639717
TI  - Total aortic replacement for aortitis syndrome: report of a case.
AB  - We report herein the case of a 35-year-old woman who was administered steroid
      therapy based on a diagnosis of aortitis syndrome. Despite this treatment, the
      symptoms of cardiac failure gradually progressed, and she was referred to our
      hospital to undergo surgery. Preoperative evaluations revealed a large aneurysm
      extending from the ascending aorta to the thoracoabdominal aorta. A two-staged
      total aortic replacement was carried out and postoperative digital subtraction
      angiography showed excellent reconstruction of the entire aorta.

PMID- 10639718
TI  - Penetration by a huge abdominal aortic aneurysm into the lumbar vertebrae: report
      of a case.
AB  - We report herein the case of a 64-year-old man who underwent urgent surgery for a
      huge abdominal aortic aneurysm (AAA) with severe lumbago. At surgery, a defect in
      the posterior wall of the AAA, through which the adjacent lumbar vertebrae was
      seen after removal of intraluminal thrombi, was encountered with no evidence of
      blood leakage. This is a rare case of AAA that eroded the posterior wall and
      exposed the vertebrae.

PMID- 10639719
TI  - Molecular structure and functional role of vascular tight junctions.
AB  - Interendothelial tight junctions regulate paracellular permeability and maintain
      cell polarity. The assembly and remodeling of tight junctions are examined,
      focusing on the molecular interactions between tight junction components and
      their functional role in endothelial biology. The molecular structures of two
      subcellular organelles related to tight junctions, the intercalated disks in
      cardiomyocytes and the slit diaphragms in glomerular podocytes, are discussed.

PMID- 10639720
TI  - Evolving functions of apolipoprotein AIV: from birds to mammals.
AB  - Apolipoprotein (apo) AIV is a serum protein that displays particularly vivid
      dynamics regarding its distribution among the various plasma lipoprotein and
      nonlipoprotein fractions. This article discusses two main aspects. First, the
      general functional properties of apo AIV as a highly mobile and versatile
      apolipoprotein, delineated in mammalian species, are described. Second, the
      implications of the fact that not only mammals, but also the chicken, express apo
      AIV are highlighted. Given the differences in certain lipid metabolic pathways
      between mammals and birds, the structure and functions of apo AIV may have
      evolved into distinct functions in different amniotes.

PMID- 10639721
TI  - Systemic gene therapy for cardiovascular disease.
AB  - Systemic gene therapy involves the transfer into the body of a gene whose protein
      product reaches the blood and has a beneficial effect on a patient. Both
      retroviral and adenovirus-associated viral vectors have resulted in stable but
      only moderate systemic levels of blood proteins. Adenoviral vectors have resulted
      in very high levels of expression that diminishes over days or weeks. Hepatic
      gene therapy has achieved levels of the anticoagulant protein C in blood that
      would protect against spontaneous thromboses in homozygous protein-C deficiency,
      and levels of tissue plasminogen activator that can lyse pulmonary emboli.
      Hypercholesterolemia has been ameliorated transiently by transfer of the low
      density lipoprotein receptor gene into the livers of animals with familial
      hypercholesterolemia or by promoting lipid transfer via a variety of alternative
      mechanisms. Hypertension has been reduced by the transfer of genes for kallikrein
      or atrial natriuretic peptide into the liver, or by expressing antisense for the
      angiotensin II type I receptor after intravenous injection in neonates. Finally,
      fasting but not fed hyperglycemia has been ameliorated in animal models of
      diabetes by transfer of an insulin gene into the liver or by expression of
      insulin from implanted fibroblasts. Gene therapy has the potential to treat these
      cardiovascular diseases. However, improvements in levels of long-term expression
      and the ability to regulate expression in response to physiologic changes will be
      required before this approach will be implemented for most of these disorders in
      humans.

PMID- 10639722
TI  - Enhancement of vitamin-K-dependent protein function by modification of the gamma
      carboxyglutamic acid domain: studies of protein C and factor VII.
AB  - Vitamin-K-dependent proteins are found in both the pro- and anti-coagulation
      cascades, and their use in coagulation therapies is expanding rapidly. The
      vitamin-K-dependent, gamma-carboxyglutamic acid (Gla)-containing regions of
      proteins in this family are homologous and are responsible for membrane
      association. Site-directed mutations that enhance the membrane affinity of
      protein C, an anticoagulant, and of factor VII, a procoagulant, have been
      identified. These protein C and Factor VII mutants show enhanced activity in many
      assays, offering opportunities to study the role of membrane in blood clotting
      reactions and proteins that may have greater therapeutic value.

PMID- 10639723
TI  - A novel megakaryocyte differentiation factor from mouse placenta.
AB  - Megakaryocyte differentiation and subsequent platelet production are regulated by
      a network of growth factors and cytokines. We hypothesized that pregnancy
      specific regulatory factors also may participate in the modulation of
      megakaryocytopoiesis and thrombopoiesis. We identified a mouse placental
      prolactin-like protein hormone with an activity similar to interleukin 6 in
      targeting megakaryocytes and inducing cell differentiation. The receptor for this
      placental hormone is present on megakaryocytes from pregnant and nonpregnant
      female mice and from male mice, and from humans, suggesting that this signaling
      pathway (if not necessarily this particular ligand) is broadly functional both in
      terms of physiologic state and evolution. Thus, studying the biologic activities
      of the large family of placental prolactin-like proteins represents a potentially
      valuable approach to the discovery of novel hematopoietic signaling pathways.

PMID- 10639724
TI  - Current status of acrolein as a lipid peroxidation product.
AB  - There is increasing evidence that aldehydes generated endogenously during lipid
      peroxidation contribute to the pathophysiologic effects associated with oxidative
      stress in cells and tissues. A number of reactive lipid aldehydes, such as 4
      hydroxy-2-alkenals and malondialdehyde, have been implicated as causative agents
      in cytotoxic processes initiated by the exposure of biologic systems to oxidizing
      agents. Recently, acrolein (CH2 = CH-CHO), a ubiquitous pollutant in the
      environment, was identified as a product of lipid peroxidation reactions. The
      basis for this finding is an experimental approach that provides a measure of
      acrolein bound to lysine residues of protein. The identification of acrolein as
      an endogenous lipid-derived product suggests an examination of the possible role
      of this aldehyde as a mediator of oxidative damage in a variety of human
      diseases.

PMID- 10639725
TI  - New aspect of the research on limb-girdle muscular dystrophy 2A: a molecular
      biologic and biochemical approach to pathology.
AB  - p94, a muscle-specific member of the calpain family, also called calpain3
      (CAPN3), has been identified as the gene product responsible for limb-girdle
      muscular dystrophy type 2A (LGMD2A). To elucidate the molecular mechanism of
      LGMD2A, the effects of missense point mutations found in LGMD2A on the unique
      properties of p94 were studied. All of the mutants examined to date lose their
      proteolytic activity against fodrin, a cytoskeletal protein, strongly suggesting
      that of the specific properties of p94, the loss of protease activity is the
      prime cause of LGMD2A. Studies of LGMD2A and p94 suggest a novel molecular
      mechanism for muscular dystrophy, showing that a combined pathologic and
      biochemical approach is effective.

PMID- 10639726
TI  - Spatial and temporal organization in ventricular fibrillation.
AB  - Ventricular fibrillation (VF) is the leading heart rhythm alteration that results
      in sudden cardiac death, yet the detailed mechanisms of the arrhythmia remain
      elusive. Fibrillation has been defined as "turbulent" cardiac electrical
      activity, which conjures up the idea of totally random and disorganized
      activation of the ventricles. I review theoretical concepts and recently
      published results based on a newly developed algorithm, "two-dimensional phase
      mapping," which demonstrates that VF is not random and may be analyzed
      quantitatively. The approach is based on video imaging of voltage-sensitive dye
      fluorescence to record transmembrane potential simultaneously from 20,000 sites
      on the epicardial surface of rabbit and sheep ventricles. During VF, activity
      shows a strong periodic component centered near approximately 500 beats/min.
      Phase maps reveal that VF depends on the organization of electrical waves around
      a small number of "phase singularities" that have relatively short lifespans and
      form as a result of interactions of wavefronts with obstacles in their paths.
      Overall, the evidence demonstrates that there is a high degree of temporal and
      spatial organization in cardiac fibrillation. The results may pave the way for a
      better understanding of the mechanisms of VF in normal, as well as in diseased,
      hearts.

PMID- 10639727
TI  - Annexin II: a mediator of the plasmin/plasminogen activator system.
AB  - The annexins constitute a family of calcium-dependent membrane binding proteins.
      Recently, annexin II has been shown to accelerate the activation of the clot
      dissolving protease plasmin by complexing with the plasmin precursor plasminogen
      and with tissue plasminogen activator. Binding of plasminogen to annexin II is
      inhibited by the atherogenic lipoprotein, lipoprotein(a), while binding of tissue
      plasminogen activator to annexin II is blocked by the thiol amino acid
      homocysteine. Formation of the plasminogen/tissue plasminogen activator/annexin
      II complex may represent a key regulatory mechanism in fibrinolytic surveillance.

PMID- 10639728
TI  - Cardiac and skeletal muscle development in P19 embryonal carcinoma cells.
AB  - Mouse P19 embryonal carcinoma cells are pluripotent stem cells that can be
      maintained in culture in an undifferentiated state or can be induced to
      differentiate in vitro into multiple cell types. P19 cells aggregated in the
      presence of dimethylsulfoxide differentiate into spontaneously beating
      cardiomyocytes and bipolar skeletal myocytes that exhibit the biochemical and
      physiologic properties of their embryonic equivalents. P19 cells can be readily
      manipulated genetically, resulting in the loss or over-expression of a gene of
      interest. Because of this versatility, the P19 system is suited for examining the
      molecular mechanisms controlling the developmental decisions of stem cells
      differentiating into the skeletal or cardiac muscle lineage.

PMID- 10639729
TI  - Neuronal death after brain injury. Models, mechanisms, and therapeutic strategies
      in vivo.
AB  - Neuronal damage in the central nervous system leads to primary cell death,
      induced directly by the trauma, and delayed secondary death of neurons, the
      latter depending on environmental changes, lack of metabolic and trophic supply,
      and altered gene transcription. While primary death of neurons occurring within a
      short time after trauma is not a realistic target for therapy, secondary cell
      death might be prevented by new neuroprotective strategies. Although there are
      increasing data concerning cell rescue after ischemic and traumatic brain injury
      through the last decade, the mechanisms that underlie secondary death of neurons
      following lesion are still incompletely understood and are now the subject of a
      more detailed investigation. In this review, we want to give an overview on what
      is known about the molecular mechanisms of delayed ischemic and traumatic
      neuronal death in vivo and about promising neuroprotective treatment strategies
      that might be of future clinical relevance or have already entered clinical
      trials.

PMID- 10639730
TI  - The Canoe protein is necessary in adherens junctions for development of
      ommatidial architecture in the Drosophila compound eye.
AB  - Rhabdomeres of the Drosophila melanogaster canoemisl mutant ommatidia were
      twisted, branched, and often fused to each other. A considerable proportion of
      rhabdomeres were found to have fallen below the retinal basement membrane.
      Electron-microscopic observations of the mutant ommatidia revealed that
      microvilli, the subcellular structures composing the rhabdome, were normal. As
      was the case with partial loss-of-function mutations in the canoe locus,
      overexpression of the wild-type canoe transgene driven by the heat shock promoter
      or sevenless enhancer in the wild-type canoe background caused malformation of
      the rhabdomeres in the adult ommatidia. Immunolabeling of the Canoe protein in
      the pupal retinae showed that it was accumulated in adherens junctions in
      photoreceptor rhabdomeres at high concentrations, as well as in pigment cells,
      bristle cells, and the interjunctional region of photoreceptors at a lower level.
      In the canoe mutant ommatidia, the Canoe protein concentration was dramatically
      decreased in adherens junctions, while it was maintained at a level comparable
      with the wild-type flies in the interjunctional region. Since Canoe or its
      mammalian homolog AF-6 is known to bind to F-actin and Ras, we suggest the
      possibility that Canoe couples Ras signaling with cytoskeleton, thereby
      supporting the straight elongation of rhabdomeres required for development of a
      regular array of ommatidia.

PMID- 10639731
TI  - Olfactory neuron-specific expression of NeuroD in mouse and human nasal mucosa.
AB  - Human olfactory neuroepithelium (OE) is situated within the olfactory cleft of
      the nasal cavity and has the characteristic property of continually regenerating
      neurons during the lifetime of the individual. This regenerative ability of OE
      provides a unique model for neuronal differentiation, but little is known about
      the structure and biology of human olfactory mucosa. Thus, to better understand
      neurogenesis in human OE, we studied the expression of olfactory marker protein
      (OMP), TrkB and NeuroD in human nasal biopsies and autopsy specimens and compared
      these data with those obtained from normal and regenerating mouse OE. We show
      that NeuroD and TrkB are coordinately expressed in human OE. Thus, by using these
      markers we have been able to extend the known boundaries of the human OE to
      include the inferior middle turbinate. In normal mouse OE, TrkB and OMP
      expression overlap in cells closest to the superficial layer, but TrkB is
      expressed more strongly in the lower region of this layer. In contrast, NeuroD
      expression is more basally restricted in a region just above the globose basal
      cells. These characteristic expression patterns of OMP, TrkB and NeuroD were also
      observed in the regenerating mouse OE induced by axotomy. These results support a
      role of NeuroD and brain-derived neurotrophic actor (BDNF), the preferred ligand
      for TrkB, in the maintenance of the olfactory neuroepithelium in humans and mice.

PMID- 10639732
TI  - Localisation of phosphatidylethanolamine-binding protein in the brain and other
      tissues of the rat.
AB  - Phosphatidylethanolamine-binding protein (PEBP) is a highly-conserved 21- to 23
      kDa basic protein that shows preferential affinity in vitro for
      phosphatidylethanolamine. Previous studies have focussed on PEBP in the brain and
      male reproductive tract where it has been proposed to play a role in membrane
      biogenesis. In the present more comprehensive study, rat PEBP transcripts and
      protein have been found to be expressed in all tissues examined, although the
      levels vary considerably between tissues. However, at the cellular level, PEBP
      expression is enigmatic, being restricted to a diverse range of highly
      specialised neuronal and non-neuronal cell types. The nature of this diversity,
      ranging from oligodendrocytes to plasma cells, whilst not precluding a role for
      PEBP in membrane biogenesis in some cell types, would imply that this is not the
      major function in others.

PMID- 10639733
TI  - Elevated Fos-like immunoreactivity in the brains of postpartum female prairie
      voles, Microtus ochrogaster.
AB  - This study investigated the expression of the protein product of the immediate
      early gene c-fos in the brains of female prairie voles (Microtus ochrogaster) in
      association with pregnancy and postparturient activities including maternal
      behavior, lactation and postpartum estrus. Fos expression was assessed in female
      voles that were late in pregnancy, nonpregnant or at one of three different times
      postpartum (0-8, 12-24, and 24-48 h, respectively). A significant increase in the
      number of cells displaying Fos immunoreactivity (Fos-ir) was observed during the
      0-8 h and 12-24 h postpartum time periods in the accessory olfactory bulbs,
      medial preoptic area, hypothalamus (specifically, the supraoptic nucleus, ventro
      medial hypothalamus, and paraventricular nucleus), lateral septum, bed nucleus of
      the stria terminalis, and primary somatosensory area of the brain. The number of
      Fos-ir cells decreased after 24 h postpartum. There were no significant changes
      in Fos-ir cell numbers in the primary olfactory bulbs, hippocampus, or caudate
      putamen. The neural activation of the medial preoptic area, accessory olfactory
      bulbs, hypothalamus, and bed nucleus is consistent with reports in rats of Fos
      induction associated with the onset of maternal behavior. In voles postpartum
      estrous behavior begins and ends 0-12 h after parturition. Maternal behavior,
      including lactation, is initiated at the same time but persists for several
      weeks. The highest Fos-ir cell numbers reported here coincide with the timing of
      postpartum estrous behavior in this species.

PMID- 10639734
TI  - VIP-, galanin-, and neuropeptide-Y-immunoreactive fibers in the chicken carotid
      bodies after various types of denervation.
AB  - The chicken carotid body receives numerous branches from the vagus nerve,
      especially distal (nodose) ganglion, and the recurrent laryngeal nerve. Dense
      networks of peptidergic nerve fibers immunoreactive for substance P, calcitonin
      gene-related peptide (CGRP), galanin, vasoactive intestinal peptide (VIP) and
      neuropeptide Y are distributed in and around the carotid body. Substance-P- and
      CGRP-immunoreactive fibers projecting to the chicken carotid body mainly come
      from the vagal ganglia. In the present study, various types of denervation
      experiments were performed in order to clarify the origins of VIP-, galanin- and
      neuropeptide-Y-immunoreactive fibers in the chicken carotid bodies. After nodose
      ganglionectomy, midcervical vagotomy or excision of the recurrent laryngeal
      nerve, VIP-, galanin- and neuropeptide-Y-immunoreactive fibers were unchanged in
      the carotid body region. Furthermore, these peptidergic fibers remained
      unaffected even by removal of the nodose ganglion in conjunction with severance
      of the recurrent laryngeal nerve that induced a marked decrease in TuJ1
      immunoreactive fibers in the carotid body region. VIP-, galanin- and neuropeptide
      Y-immunoreactive fibers are densely distributed around the arteries supplying the
      carotid body in normal chickens. The peptidergic fibers around the arteries were
      also unaffected after the denervation experiments. However, after removal of the
      14th cervical ganglion of the sympathetic trunk, which lies close to the
      vertebral artery on the root of the brachial plexus and issues prominent branches
      to the artery, VIP-, galanin- and neuropeptide-Y-immunoreactive fibers almost
      disappeared in the carotid body region. The ganglion contained many VIP-, galanin
      and neuropeptide-Y-immunoreactive neurons. Thus it is clear that VIP-, galanin-
      and neuropeptide-Y-immunoreactive fibers in the chicken carotid body region are
      mainly derived from the 14th cervical sympathetic ganglion via the vertebral
      artery.

PMID- 10639735
TI  - Distribution of P2X receptors in the rat adrenal gland.
AB  - The distribution of each of the seven subtypes of ATP-gated P2X receptors was
      investigated in the adrenal gland of rat utilizing immunohistochemical techniques
      with specific polyclonal antibodies to unique peptide sequences of P2X1-7
      receptors. A small number of chromaffin cells showed positive immunoreaction for
      P2X5 and P2X7, with the relative occurrence of P2X7-immunoreactive chromaffin
      cells exceeding that of P2X5. The preganglionic nerve fibres that form terminal
      plexuses around some chromaffin cells showed P2X1 immunoreactivity. Intrinsic
      adrenal neurones were observed to be positively stained for P2X2 and P2X3
      receptors. P2X2 immunoreactivity occurred in several neurones found singly or in
      groups in the medulla, while only a small number of neurones were immunoreactive
      for P2X3. Adrenal cortical cells were positively immunostained for P2X4-7.
      Immunoreactivity for P2X4 was confined to the cells of the zona reticularis,
      while P2X5-7 immunoreactivities occurred in cells of the zona fasciculata. The
      relative occurrence of immunoreactive cortical cells of the zona fasciculata was
      highest for P2X6, followed by P2X7 and then P2X5. The smooth muscle of some
      capsular and subcapsular blood vessels showed P2X2 immunoreactivity. The specific
      and widespread distribution of P2X receptor subtypes in the adrenal gland
      suggests a significant role for purine signalling in the physiology of the rat
      adrenal gland.

PMID- 10639737
TI  - Localization of 28-kDa peroxiredoxin in rat epithelial tissues and its
      antioxidant properties.
AB  - Peroxiredoxins are a novel family of antioxidant proteins that specifically
      prevent enzymes from metal-catalyzed oxidation. The localization of a member of
      the mono-cystein subfamily of peroxiredoxins, the 28-kDa protein, in different
      rat tissues and its antioxidant properties were investigated. By immunoblotting,
      the 28-kDa peroxiredoxin was found to be most highly concentrated in olfactory
      epithelium and present in all tissues tested (skin, lung, trachea, kidney, womb,
      and brain). Immunostaining with rabbit polyclonal antibody raised against the 28
      kDa peroxiredoxin revealed the particularly high level of the 28-kDa
      peroxiredoxin immunoreactivity in air-contacting areas (apical regions and mucus
      of the olfactory and respiratory epithelium and skin epidermis), which are
      continually exposed to numerous air-borne reactive oxygen species. In the apical
      regions of the olfactory and respiratory epithelium, the 28-kDa-peroxiredoxin
      immunogold labeling outlined microvilli and cilia and was mainly located in
      sustentacular cells and in respiratory and goblet cells, as electron-microscopic
      analysis revealed. In skin epidermis, the 28-kDa peroxiredoxin immunoreactivity
      was confined to the granular layer and specifically concentrated in sebaceous
      glands of hair follicle. In situ hybridization with 33P-labeled antisense RNA
      probe revealed the expression of the 28-kDa peroxiredoxin mRNA in tissues with a
      high level of the 28-kDa peroxiredoxin immunoreactivity. Immunodepletion of the
      28-kDa peroxiredoxin profoundly decreased the antioxidant activity of the
      olfactory tissue extract.

PMID- 10639736
TI  - Secretory organelles in ECL cells of the rat stomach: an immunohistochemical and
      electron-microscopic study.
AB  - ECL cells are numerous in the rat stomach. They produce and store histamine and
      chromogranin-A (CGA)-derived peptides such as pancreastatin and respond to
      gastrin with secretion of these products. Numerous electron-lucent vesicles of
      varying size and a few small, dense-cored granules are found in the cytoplasm.
      Using confocal and electron microscopy, we examined these organelles and their
      metamorphosis as they underwent intracellular transport from the Golgi area to
      the cell periphery. ECL-cell histamine was found to occur in both cytosol and
      secretory vesicles. Histidine decarboxylase, the histamine-forming enzyme, was in
      the cytosol, while pancreastatin (and possibly other peptide products) was
      confined to the dense cores of granules and secretory vesicles. Dense-cored
      granules and small, clear microvesicles were more numerous in the Golgi area than
      in the docking zone, i.e. close to the plasma membrane. Secretory vesicles were
      numerous in both Golgi area and docking zone, where they were sometimes seen to
      be attached to the plasma membrane. Upon acute gastrin stimulation, histamine was
      mobilized and the compartment size (volume density) of secretory vesicles in the
      docking zone was decreased, while the compartment size of microvesicles was
      increased. Based on these findings, we propose the following life cycle of
      secretory organelles in ECL cells: small, electron-lucent microvesicles (pro
      granules) bud off the trans Golgi network, carrying proteins and secretory
      peptide precursors (such as CGA and an anticipated prohormone). They are
      transformed into dense-cored granules (approximate profile diameter 100 nm) while
      still in the trans Golgi area. Pro-granules and granules accumulate histamine,
      which leads to their metamorphosis into dense-cored secretory vesicles. In the
      Golgi area the secretory vesicles have an approximate profile diameter of 150 nm.
      By the time they reach their destination in the docking zone, their profile
      diameter is between 200 and 500 nm. Exocytosis is coupled with endocytosis
      (membrane retrieval), and microvesicles in the docking zone are likely to
      represent membrane retrieval vesicles (endocytotic vesicles).

PMID- 10639738
TI  - Dual immunofluorescence labeling with cell-specific markers localizes BRCA1 in
      both basal and luminal epithelial cells in primary outgrowth from noncancerous
      mammary ductal and alveolar preparations.
AB  - The role played by either of the two differentiated mammary epithelial cell types
      in human breast cancer progression is currently not defined. This work addresses
      the question of whether the mammary tumor suppressor gene product BRCA1 is
      localized in basal and/or luminal epithelial cells in noncancerous outgrowth
      cultured from breast organoids. Primary epithelial cell outgrowths from ductal
      and alveolar preparations were directly employed to facilitate small-scale
      analysis under conditions closely approximating intact tissue. BRCA1
      immunofluorescence was detected for the most part in cell nuclei of the
      epithelial outgrowth when using confocal microscopy. Nuclear staining was
      punctate in the cells with higher labeling intensity. Only minimal nonspecific
      staining was observed with mouse IgG as a negative primary antibody control or
      with primary antibody against the cell membrane receptor ErbB2, reported to be
      expressed in breast cancer, but was either not detectable or weakly expressed in
      normal breast tissue. Dual labeling was used to distinguish which epithelial cell
      type(s) stains for BRCA1. Primary monoclonal antibody against vimentin was used
      to identify basal cells, while antibody against cytokeratin 19 was used to
      identify luminal cells. Monoclonal antibody against BRCA1 was used for colabeling
      with each of these markers. Epifluorescence microscopy revealed BRCA1
      immunoreactivity in both basal and luminal interphase cells. BRCA1
      immunofluorescence was diffusely located about the chromosome mass during
      mitosis.

PMID- 10639739
TI  - Characterization and regulation of peptidylglycine alpha-amidating monooxygenase
      (PAM) expression in H9c2 cardiac myoblasts.
AB  - Peptidylglycine alpha-amidating monooxygenase (PAM), which catalazyes the two
      step formation of bioactive alpha-amidated peptides from their glycine-extended
      precursors, has been found in H9c2 myoblasts. The expression of PAM has been
      evaluated in H9c2 cells. Northern blot analysis and amplification of fragments
      derived from rat PAM by the reverse transcription/polymerase chain reaction
      method has demonstrated the presence of rPAM-1, -2, -3, -3a and -3b mRNA
      transcripts. These forms of PAM mRNA may be generated by alternative splicing.
      PAM mRNA levels are increased to 160 +/- 12% of control values by treatment with
      dexamethasone but are unchanged during triiodothyronine incubation of the cells.
      PAM activity is very low, which is not comparable to the high levels found in
      adult atrium tissue. Western blot analysis has demonstrated 86-, 76-, and 46-kDa
      PAM proteins in the particulate fraction. The soluble fraction contains major PAM
      proteins of 110, 86, and 46 kDa. In situ hybridization studies with 35S-labeled
      full length RNA antisense transcripts of rat PAM-1 cDNA have localized
      autoradiographic grains around the nucleus. Our data clearly demonstrate PAM
      expression in H9c2 rat heart cells, suggesting the ability of these cardiac cells
      to make bioactive alpha-amidated hormones and/or neuropeptides.

PMID- 10639740
TI  - Ecto-ATPase activity in the rat cardiac muscle: biochemical characteristics and
      histocytochemical localization.
AB  - We used a combined biochemical and histocytochemical approach to study ecto
      ATPase in the rat cardiac muscle. The reaction medium employed for
      histocytochemical detection was optimized in biochemical assays to achieve the
      highest enzyme activity and lowest inhibition by the capture agent used for
      visualization of the reaction product. Approximately 70% of the enzyme activity
      was retained in samples after the fixation procedure. Divalent cations stimulated
      ecto-ATPase. High activity was detectable within a wide pH range.
      Histocytochemical reaction was observed at sites at which extracellular ATP can
      potentially exert its actions on the cardiac muscle: nerve endings, plasma
      membranes of cardiac myocytes and capillary endothelial cells, and T-tubules.
      Product of the reaction was found exclusively at the outer surface of the cells.
      In controls, enzyme activity was abolished by diethyl pyrocarbonate and slightly
      stimulated by digitonin and concanavalin A, whereas sodium orthovanadate, N
      ethylmaleimide, and sodium azide yielded no effect. Our results support the view
      that cardiac ecto-ATPase is involved in important physiological functions and
      suggest that its activity may be regulated by the release of ATP from nerve
      endings.

PMID- 10639741
TI  - Dynamics of rat liver ecto-ATPase during development suggests its involvement in
      bile acid efflux. A cytochemical view.
AB  - We studied cytochemical localization of ectoadenosine triphosphatase in the rat
      liver during development from 15-day-old fetus to 4-week-old and adult animal.
      First signs of the enzyme activity were found in some of the primitive bile
      canaliculi of 15-day-old fetuses. The majority of canaliculi, however, did not
      reveal any reaction product. Although intensity of the cytochemical reaction
      increased at 20 days of gestation, it still remained relatively low. Intensity of
      the reaction increased significantly and its product became readily detectable in
      the liver of newborn rats. Liver of 1-, 2-, and 4-week-old animals showed strong
      reaction for ecto-ATPase at the luminal surface of the plasma membrane of the
      bile canaliculi. Liver of adult rats contained a prominent reaction product
      similar to that seen in newborns, 1-, 2-, and 4-week-old animals. At all stages
      of fetal development, as well as in postnatal and adult rats, reaction was found
      only within the hepatic bile canalicular system and exclusively at the luminal
      surface of the canalicular plasma membrane. Using diethyl pyrocarbonate (DEPC), a
      specific inhibitor of ecto-ATPase activity, cytochemical reaction was blocked in
      all examined samples. Results of the present study, taken together with
      established biochemical and immunological data, provide conclusive morphological
      evidence in support of the view that canalicular ecto-ATPase is involved in bile
      acid efflux.

PMID- 10639743
TI  - Visualization of acidic compartments in cultured osteoclasts by use of an
      acidotrophic amine as a marker for low pH.
AB  - Using the acidotrophic amine 3-(2,4-dinitroanillino)-3'-amino-N
      methyldipropylamine (DAMP) as a marker for low pH and immunofluorescence
      cytochemistry, we examined acidic compartments of osteoclasts cultured on cover
      glasses or bone slices, where they could resorb the bone surface, forming
      resorptive lacunae. DAMP-positive structures were seen as vesicular and tubular
      forms in the cytoplasm, indicating lysosomes and endosomes. Not only the
      osteoclastic cytoplasm but also the extracellular area around the ruffled border
      and resorptive lacunae were stained with DAMP, suggesting acidic regions.
      Immunofluorescence was localized predominantly on the substratum side of actively
      resorbing osteoclasts, whereas an evenly distributed staining pattern was seen in
      the nonactive cell. The most intensive reaction was seen at the advancing front
      of resorptive lacunae within the actively resorbing osteoclasts. The distribution
      pattern of DAMP seemed to be correlated with the osteoclastic activity, since
      osteoclasts exhibit alternating resorption and migration phases during the bone
      remodeling cycle. In this culture system, the resorptive lacunae were left behind
      after the osteoclasts had completed resorption and migrated along the bone
      surface. These exposed resorptive lacunae were also stained with DAMP, which were
      presumably kept at an acidic pH. The effect of treatment with monensin,
      chloroquine, ammonium chloride, or nigericin was varied in terms of the
      immunoreactivity for DAMP, but not complete abolition of the staining was
      obtained. Weak bases such as chloroquine or ammonium chloride inhibited both
      intra- and extracellular immunoreactivity. Immunoreactivity for the vacuolar type
      of proton ATPase (V-ATPase) was demonstrable in the cytoplasm of the osteoclasts
      but was weakened by the addition of bafilomycin. Immunofluorescence of the
      resorptive lacunae was still retained even after the treatment with bafilomycin
      and acetazolamide. Besides, both bafilomycin and acetazolamide reversibly
      inhibited cellular acidity as judged by DAMP immunocytochemistry, which agrees
      with the fact that ostoeclastic acidification results from the action of vacuolar
      proton-pump ATPase coupled with carbonic anhydrase.

PMID- 10639742
TI  - A method of tracking donor cells after simulated autologous transplantation: a
      study using synovial cells of transgenic rats.
AB  - A transgenic rat was used as a transplantation donor to simulate autologous
      transplantation. The sex-matched transplantation between a female transgenic and
      a wild-type rat can theoretically be regarded as an autologous transplantation
      due to the genetic agreement of these rats except for the non-protein-producing
      transgenes. Transgene-containing synovial cells were tracked in the joint using
      this autologous transplantation model. The transgenes in the donor synovial cells
      were detected using in situ hybridization (ISH), while mitotic activities were
      simultaneously examined by immunodetection of 5-bromo-2'-deoxyuridine (BrdU). A
      defect was generated in the knee joint capsule of a Fischer 344 (wild-type) rat.
      The synovium of a transgenic rat was sutured to the defect of the wild-type rat
      in group 1 and was allowed to free float in the joint in group 2. A large number
      of BrdU-labeled, transgene-containing synovial cells were detected in both groups
      at 3 days. The number of these cells then decreased, but they could still be
      identified even at 4 weeks after autologous transplantation. These results
      indicated that transplanted synovial cells were viable in the joint for at least
      4 weeks. Furthermore, the transgenic rat was shown to be an effective animal
      model for distinguishing the extrinsic from the intrinsic cells in the cellular
      intermixed tissues in vivo. The combined method of ISH for detecting transgene
      containing cells and the immunohistochemistry of BrdU for detecting proliferating
      cells was also shown to be effective for tracking the viability of extrinsic
      cells after autologous transplantation.

PMID- 10639744
TI  - Existence of a dense reticular meshwork surrounding the nephron inducer in
      neonatal rabbit kidney.
AB  - While more and more humoral factors involved in nephrogenesis are being
      discovered, there is no detailed knowledge of the morphological structures at the
      interface of the nephron inducer and the surrounding mesenchyme. For that reason
      we examined this area in the cortex of neonatal rabbit kidneys by scanning
      electron-microscopical and transmission electron-microscopical techniques. Our
      interest was focused on the basal aspect of the collecting duct ampulla and the
      surrounding competent mesenchyme, where morphogenic signals are to be exchanged
      during nephron induction. Close contact between these two tissues involved in
      nephrogenesis is assumed to allow direct cellular contact or diffusion of soluble
      factors across a short distance. Our data, however, show the presence of a dense
      fibrillar meshwork around the collecting duct ampulla, spatially separating the
      inducer and the competent mesenchyme during nephron induction.

PMID- 10639745
TI  - Comparative analysis of FMRFamide-like immunoreactivity in caiman (Caiman
      crocodilus) and turtle (Trachemys scripta elegans) brains.
AB  - The distribution of FMRFamide (FMRFa)-like peptides in caiman (Caiman crocodilus)
      and turtle (Trachemys scripta elegans) brains was studied by
      immunohistochemistry. In both species, distinct groups of FMRFa-like
      immunoreactive (ir) perikarya were present in the medial septal nucleus,
      accumbens nucleus, nucleus of the diagonal band of Broca, suprachiasmatic area,
      lateral hypothalamic area, and periventricular hypothalamic nucleus. A few FMRFa
      ir neurons in the hypothalamic area were located in the neuroepithelial cell
      lining of the third ventricle. FMRFa-ir fibers were scattered in all major areas
      of the brain, from the olfactory bulbs to the rhombencephalon. They formed dense
      aggregates in the medial septal area, basal telencephalon, median eminence, and
      infundibulum, and adjacent to the fourth ventricle. The most obvious difference
      between the FMRFa-ir systems in caimans and turtles concerned the number of
      nuclei that contained neurons with this immunoreactivity. Eight such clusters
      were present in the caiman brain, whereas thirteen clusters were found in the
      turtle brain. The turtle also displayed scattered FMRFa-ir somata in the anterior
      olfactory nucleus, striatum, lateral septal nucleus, medial and lateral cortex,
      medial forebrain bundle, lateral preoptic area, and lateral geniculate nucleus.
      In the caiman brain, a few FMRFa-ir neurons were noted in the ventrolateral area
      of the pallial commissure and an even smaller number of ir neurons was found
      dispersed in the optic tracts. Neither formed nuclear aggregates. The results are
      compared with those described for other vertebrates.

PMID- 10639746
TI  - Immunocytological localization of dopamine in the guinea pig retina.
AB  - We examined dopaminergic neurons in the guinea pig retina; antisera against
      tyrosine hydroxylase (TH), dopamine beta-hydroxylase (DBH), phenylethanolamine N
      methyltransferase (PNMT) and an antiserum against gamma-aminobutyric acid (GABA)
      were used. In the present study, two types of amacrine cells were labeled with an
      anti-TH antiserum. However, no DBH and PNMT immunoreactivities were seen. The
      type 1 cell had a larger-sized soma located in the inner nuclear layer with
      processes ramifying mainly in stratum 1 of the inner plexiform layer (IPL). The
      type 2 cell had a smaller-sized soma and processes branching in stratum 3 of the
      IPL. The mean densities were 56.4 +/- 11.5/mm2 for the type 1 cell and 166.6 +/-
      30.3/mm2 for the type 2 cell. Double immunocytochemistry using an antiserum
      against GABA revealed that while none of the type 1 cells showed GABA
      immunoreactivity, all of the type 2 cells displayed GABA immunoreactivity. Our
      results suggest that, in the guinea pig retina, the type 1 amacrine cells are
      pure dopaminergic and the type 2 cells are dopaminergic elements that use GABA as
      their second transmitter.

PMID- 10639747
TI  - Synthesis and antiviral studies of unsaturated analogues of isomeric
      dideoxynucleosides.
AB  - Novel isomeric dideoxynucleosides with unsaturation in the carbohydrate moiety
      have been synthesized. For example, isod4A was synthesized through a
      rearrangement reaction involving a cyclonucleoside. Support for the structures of
      both purine and pyrimidine d4 compounds came from UV, NMR, HRMS and single
      crystal X-ray data. Interestingly, the single crystal X-ray data for isod4C shows
      that the base is almost orthogonal to the carbon-carbon double bond of the sugar
      moiety. Consistent with this is the observation that the UV data of this compound
      does not show a bathochromic shift compared to the saturated compound implying
      that the pi-bond is not in conjugation with the pyrimidine base.

PMID- 10639748
TI  - Intramolecular glycosylation to form 4-methoxy-2,6-dioxopyrimidine nucleosides
      via O6,5'-cyclonucleosides.
AB  - Lewis-acid promoted intramolecular N1 glycosylation to form the novel O6,5'
      cyclonucleoside 1a occurs in high yield from the corresponding acyclic thiophenyl
      glycoside 12. The relative stability of the O6,5' tether compared with O2,5' and
      O2,3' tethers is reported. Cleavage of the anhydro bond was effected with aqueous
      base to yield the 4-methoxybarbituric acid nucleoside analogue 14.

PMID- 10639749
TI  - Synthesis and biological evaluation of 9-(beta-L-arabinofuranosyl)adenine.
AB  - For the first time, the stereospecific synthesis of 9-(beta-L-arabinofuranosyl)
      adenine was carried out. Unfortunately, and unlike its "natural" D-counterpart
      Vidarabine, this L-enantiomer did not show significant activity when evaluated
      against a broad range of viruses.

PMID- 10639750
TI  - Acyclic sugar analogs of triciribine: lack of antiviral and antiproliferative
      activity correlate with low intracellular phosphorylation.
AB  - Triciribine and triciribine monophosphate have antiviral and antiproliferative
      activity at low or submicromolar concentrations. In an effort to improve and
      better understand this activity, we have synthesized a series of acyclic analogs
      and evaluated them for activity against select viruses and cancer cell lines. We
      conclude that the rigid ribosyl ring system of triciribine must be intact in
      order to be phosphorylated and to obtain significant antiviral and
      antiproliferative activity.

PMID- 10639751
TI  - Synthesis, cytotoxic effect and antiviral activity of 1-(beta-D-arabinofuranosyl)
      5-bromo-N4-substituted cytosine and 1-(beta-D-arabinofuranosyl)-5-bromo-4
      methoxypyrimidin-2(1H)-one derivatives.
AB  - A convenient and mild synthesis of 5-bromo-N4-substituted-1-(beta-D
      arabinofuranosyl)cytosine and 5-bromo-O4-methyl-1-(beta-D
      arabinofuranosyl)pyrimidin-2(1H)-one derivatives by selective
      oxyfunctionalization of the corresponding 4-thionucleosides with 3,3
      dimethyldioxirane is reported. The cytotoxicity and the antiviral activity
      against parainfluenza 1 (Sendai virus) of all new synthesized products are also
      reported.

PMID- 10639752
TI  - Synthesis of di- and tri-substituted adenosine derivatives and their affinities
      at human adenosine receptor subtypes.
AB  - The synthesis of 2-(hex-1-ynyl)adenosine derivatives substituted at the N6-
      and/or 5'-position was carried out on the basis that 2-(hex-1-ynyl)adenosine-5'-N
      ethyluronamide (HENECA, 2) showed good affinity and different degree of
      selectivity for rat adenosine receptors. All new compounds were tested in
      radioligand binding and adenylyl cyclase assays with recently cloned human A1,
      A2A, A2B, and A3 adenosine receptors.

PMID- 10639753
TI  - L-nucleoside analogues as potential antimalarials that selectively target
      Plasmodium falciparum adenosine deaminase.
AB  - The L-stereoisomer analogues of D-coformycin selectively inhibited P. falciparum
      adenosine deaminase (ADA) in the picomolar range (L-isocoformycin, Ki 7 pM; L
      coformycin, Ki 250 pM). While the L-nucleoside analogues, L-adenosine, 2,6
      diamino-9-(L-ribofuranosyl)purine and 4-amino-1-(L-ribofuranosyl)pyrazolo[3,4-d]
      pyrimidine were selectively deaminated by P. falciparum ADA, L-thioinosine and L
      thioguanosine were not. This is the first example of 'non-physiological' L
      nucleosides that serve as either substrates or inhibitors of malarial ADA and are
      not utilised by mammalian ADA.

PMID- 10639754
TI  - Inhibitory potency of 5-benzyluracil, 5-phenylcytosine and 5-phenylpyrimidin-2
      one nucleosides against uridine phosphorylase from mouse leukemic L1210 cells.
AB  - The inhibitory activity of a series of novel sugar-modified nucleosides derived
      from 5-benzyluracil, 5-phenylcytosine and 5-phenylpyrimidin-2-one against uridine
      phosphorylase purified from mouse leukemic L-1210 cells was investigated.
      Significant activity was encountered with O2,2'-anhydro-5-benzylcytidine
      hydrochloride, 2',3'-dideoxy-5-benzyluridine, 2',3'-dideoxy-4-thiouridine and
      alpha- and beta-anomers of 5-benzyl-1-(2-deoxy-D-arabino-hexopyranosyl)uracil.

PMID- 10639755
TI  - Oligonucleotide conjugated to linear and branched high molecular weight
      polyethylene glycol as substrates for RNase H.
AB  - Two conjugates of an anti-HIV oligonucleotide (ODN) with different high molecular
      weight monomethoxy polyethylene glycols (MPEGs) have been tested for their
      activity as substrate towards RNase H. The MPEG does not impede the formation of
      the regular hybrid duplex with the target RNA sequence as pointed out by the
      persistence of the RNase H activity; thus, these derivatives stimulate the
      hydrolysis of RNA by the enzyme at the same site and with the same extent of
      cleavage as the native sequence.

PMID- 10639756
TI  - Introduction of 6-formylcytidine into a Myb binding sequence.
AB  - Single 6-formylcytidine was introduced into a oligonucleotide duplex (23 mers) as
      a substitute for thymidine in the Myb binding sequence of 3'-TTGAC-5'. The
      modified duplex showed Tm of 67 degrees C, which was six degrees lower than the
      Tm of the native duplex. Binding affinity of the 23-mers to the Myb protein was
      estimated by electrophoretic mobility shift assays, and the binding was almost
      completely abolished.

PMID- 10639757
TI  - Stereoselective synthesis of beta-L-2',3'-dideoxy- and L-2',3'-didehydro-2',3'
      dideoxy purine nucleosides.
AB  - beta-L-2',3'-Dideoxy- and L-2',3'-didehydro-2',3'-dideoxy purine nucleosides have
      been synthesized via a highly stereoselective method of glycosylation by the
      condensation of L-2-(phenylselenyl)-2,3-dideoxyribose derivative with silylated
      heterocyclic base.

PMID- 10639758
TI  - Antileukotriene drugs: have these truly arrived?

PMID- 10639759
TI  - Video assisted thoracoscopic surgery (VATS) in the diagnosis of intrathoracic
      pathology: initial experience.
AB  - We report our experience with the use of video-assisted thoracoscopic surgery
      [VATS] in the diagnosis of intrathoracic disease of unknown origin. In the last
      two years, 32 patients (18 males) underwent this procedure for diagnostic
      purposes. Of them, 18 patients had lung pathology, eight mediastinal and six
      pleural disease. All attempts at achieving a tissue diagnosis were unrewarding.
      In all of them, diagnostic thoracotomy was being contemplated to procure tissue
      for histopathological diagnosis. Diagnostic thoracoscopy was successful in
      providing tissue diagnosis in all the patients with lung disease; seven of the
      eight patients with mediastinal pathology and five of the six patients with
      pleural lesions. Diagnostic thoracoscopy was associated with minimal morbidity,
      short hospital stay, better cosmetic result and quicker return to work as
      compared to conventional thoracotomy. We conclude that video-assisted
      thoracoscopy is an excellent diagnostic tool to confirm tissue diagnosis in
      patients with undiagnosed chest diseases.

PMID- 10639760
TI  - Decreased sodium-potassium and calcium adenosine triphosphatase activity in
      asthma: modulation by inhaled and oral corticosteroids.
AB  - The activation of both the inflammation-producing cells and the airway smooth
      muscle in asthma is believed to be a phenomenon dependent on the intracellular
      calcium. The activity of Na+ K+ ATPase and Ca2+ ATPase, enzymes responsible for
      regulating the intracellular calcium concentrations has been reported to be
      decreased in asthma. An increase in plasma lysophosphatidylcholine (LPC), which
      is known to be a pro-inflammatory compound and has an inhibitory effect on the
      two ATPases has also been reported. Corticosteroids are potent antiinflammatory
      drugs very effective in the treatment of asthma. The effect of long-term (12
      weeks) treatment with inhaled beclomethasone dipropionate (BDP) and short-term (1
      week) treatment with oral prednisolone on the activity of the two ATPases and
      intracellular calcium in leukocytes and plasma LPC levels was investigated. Both
      the treatments resulted in an improvement in lung function accompanied by an
      increase in the activities of the ATPases and a decrease in the intracellular
      calcium and LPC levels. It was concluded that increase in the activities of Na+
      K+ ATPase and Ca2+ ATPase and a consequent lowering of intracellular calcium, and
      a lowering of plasma LPC may underlie the beneficial effect of corticosteroids in
      asthma.

PMID- 10639761
TI  - Experimental pulmonary fluorosis.
AB  - An experimental study was undertaken to observe effects of fluoride ingestion on
      lung tissue. The study was conducted on 15 albino rabbits of either sex and
      experimental fluorosis was induced by daily oral administration of sodium
      fluoride (NaF) solution. Rabbits were divided into three groups according to the
      quantity of fluoride ingestion: Group A: rabbits fed with 10 mg/kg/day NaF, Group
      B: 20 mg/kg/day NaF; and Group C: controls. After six months, the rabbits were
      sacrificed and their lung tissue was submitted for histopathological examination
      and fluoride content estimation. On gross examination, pale areas on the surface
      and dark brown congested areas on cut-section of lungs were seen in rabbits of
      groups A and B. Histopathological changes of alveolar haemorrhage, congestion,
      edema fluid, necrosis of alveolar epithelium, distortion of alveolar architecture
      and desquamation of epithelium of respiratory tract with damage to tracheal
      cartilage were observed in these groups. These changes were more marked in group
      B rabbits. Fluoride content of lung tissue homogenate was significantly higher in
      groups A and B (mean 1.206 ppm and 1.978 ppm respectively) as compared to control
      (0.1585 ppm). It was concluded that prolonged fluoride ingestion damages
      pulmonary tissues of rabbits. To the best of our knowledge, effect of chronic
      fluoride ingestion on lungs has not been reported in the literature, therefore,
      we had undertaken this study to analyse the effect of chronic fluoride ingestion
      on lungs.

PMID- 10639762
TI  - Preoperative pulmonary evaluation.

PMID- 10639763
TI  - Concomitant azygos fissure and Kartagener's syndrome with pulmonary tuberculosis.

PMID- 10639764
TI  - Tuberculous mediastinitis: a rare presentation.
AB  - Granulomatous mediastinitis is a rare condition, and tuberculosis and fungal
      infections are the most important causes of this potentially lethal condition.
      Tuberculous mediastinitis usually presents with fever, cough, dyspnoea and
      rarely, florid features of obstruction to intra-thoracic structures are seen. A
      case of tuberculous mediastinitis presenting as a suprasternal lump, a rare
      presentation, is described here.

PMID- 10639765
TI  - Primary intrapulmonary teratoma presenting as pyothorax.
AB  - A female patient presented with empyema thoracis and was planned for
      decortication. Peroperatively a cystic mass was found in the left lower lobe
      which was resected and diagnosed as a case of teratoma of lung on
      histopathological examination. This unusual case of primary intrapulmonary
      teratoma is being reported here.

PMID- 10639766
TI  - Primary mediastinal hydatid cyst.
AB  - An unusual case of primary mediastinal echinococcosis in a young female presented
      with non-specific symptoms. On examination, she had signs of Horner's syndrome
      and mild superior vena cava compression. She was operated successfully. The final
      diagnosis could only be made on the operating table and confirmed by
      histopathology. Hydatid cyst in mediastinum is uncommon but because of
      surrounding vital structures and potential of its complete cure should be
      explored without delay.

PMID- 10639767
TI  - Malignant pleural mesothelioma without asbestos exposure.
AB  - A 45-year-old male, non smoker and lecturer by profession was diagnosed as an
      advanced case of bilateral mesothelioma involving lung and pleura. He was never
      exposed to asbestos, which makes it a rare case.

PMID- 10639768
TI  - Bacteriology of bronchial secretions in non-tubercular lower respiratory tract
      infections.
AB  - Fifty samples of bronchial secretions collected from patients of non-tubercular
      lower respiratory tract infections through fiberoptic bronchoscopy (FOB) were
      cultured both for aerobic and anaerobic organisms. Thirty-three (66%) samples
      yielded bacteria. Out of these, thirty were isolated in pure culture and from
      three, a mixed growth of aerobic and anaerobic micro-organisms was obtained.
      Aerobic bacteria were the predominant isolates. Stephylococcus aureus (10),
      pseudomonas (9) and streptococcus pneumoniae (8) were the major aerobic isolates.
      Ciprofloxacin was found to be the most effective drug against aerobes and
      metronidazole against anaerobes in vitro susceptibility tests.

PMID- 10639769
TI  - Phase contrast microscopy: utility in obstetrics and gynaecology.

PMID- 10639770
TI  - Acridine orange stained blood wet mounts for fluorescent detection of malaria.
AB  - The age old Romanowsky stained thick blood smear examination for malarial
      parasites may fail to reveal the low parasitaemia. The commercial 'QBC' like
      acridine orange stained capillary tube preparation has a limitation of precise
      species identification and the detection of extra-erythrocytic parasites. Hence,
      the present study was aimed to improve malarial parasite detection by using
      acridine orange to stain large blood drops in the form of wet coverglass mounts.
      The acridine orange stained blood wet mounts over 2420 suspected malaria cases
      from Indore city were examined under fluorescent microscope and the results
      compared with the Leishman's stained thick blood smears in a blind study. The
      positivity of malarial parasites reported by the modified acridine orange
      staining was 248 against 109 by Leishman's stained thick blood smears. The
      modified acridine orange stained method is simple, instant and more efficient,
      requires less scanning time and skill, allows scanning of larger blood volume (75
      ul) at lower magnification and the morphological details at higher magnification
      helps to make the precise species identification.

PMID- 10639771
TI  - Evaluation of thyroid hormones in chronic renal failure.
AB  - When chronic renal failure becomes advanced, the serum levels of most hormones
      are altered because of several interplaying mechanisms. This study was carried
      out to evaluate the level of total thyroxine (T4), triiodothyronine (T3) and
      thyrotropin (TSH) in 96 clinically euthyriod patient with chronic renal failure
      and 25 healthy individual as control. The patients were grouped into two groups,
      62 patient on conservative management and 34 patients on chronic haemodialysis.
      The patient of both groups showed significant decrease in total T3 and T4 level
      as compared to normal control. Serum TSH level were similar in both groups as
      well as in control and were with in normal limit except 3 patients on
      conservative management which showed TSH level above normal chronic haemodialysis
      did not have positive effect in alteration of serum T3, T4 and TSH level.

PMID- 10639772
TI  - Cloning and expression of a cell wall associated protein gene of Mycobacterium
      tuberculosis.
AB  - Genomic library of Mycobacterium tuberculosis (SIHV) was constructed into T7
      promoter based vector pBluescript II KS (+/-) in Escherichia coil. The expression
      of mycobacterial antigens from recombinants was detected by immunoscreening using
      E-coli-preabsorbed hyperimmune rabbit anti-M tuberculosis cell wall associated
      proteins serum. Among 980 clones tested by immunoscreening, a clone pJJ5 was
      found to produce mycobacterial antigen. This clone was further characterized by
      immunoblotting and found to produce a 36 kDa of cell wall associated antigen
      Detection of antibodies response to this antigen in the serum of the majority of
      the individuals with tuberculosis indicates that this antigen is capable of
      stimulating a humoral immune response.

PMID- 10639773
TI  - Quality assurance programme in haematology at a teaching hospital in the eastern
      region of Nepal.
AB  - Quality assurance in haematology laboratory is intended to ensure the reliability
      of the laboratory tests. A quality assurance programme has two main aspects,
      namely, internal quality control and external quality assessment. A two year
      experience of quality assurance in haematology laboratory at B.P. Koirala
      Institute of Health Sciences, Nepal, is presented here. As a part of internal
      quality control, test results in the laboratory were scrutinized before release
      on a daily basis. Inconsistent result were checked for the given values with
      control material. In addition, the laboratory is a participant of the 'External
      Haematology Quality Assurance Programme' conducted by WHO regional reference
      centre at AIIMS, New Delhi, India. Variations related to errors in manual and
      autopipetting, calibration and inter-observer differences have been noted from
      time to time and rectified. The programme has helped us to deliver quality
      service in haematology laboratory at BPKIHS.

PMID- 10639774
TI  - Diagnostic distinction between unusual malignant tumors of gall bladder by
      histochemistry and antigenic phenotype.
AB  - In a review of 79 cases of gall bladder malignancy, nineteen cases were labelled
      as unusual tumors while sixty were diagnosed as adenocarcinoma. Alcian blue, PAS,
      Grimelius' and Masson trichrome stains were done. Expression of EMA, CEA and
      desmin was assessed (PAP). Histological subtype was revised, in eleven cases out
      of 19. Five tumors initially diagnosed as squamous cell carcinoma were found to
      be positive for mucin and CEA and hence were reclassified as adenosquamous
      carcinoma. Three undifferentiated carcinomas and two malignant carcinoids were
      labelled as adenocarcinoma and composite tumor respectively. Positive reactivity
      with CEA and alcian blue PAS and absence of AFP helped in differentiating one
      giant cell carcinoma from hepatocellular carcinoma. No definite marker could be
      identified in one case of malignant mesenchymal tumor. Histochemistry and
      immunohistochemistry also helped in confirming the diagnosis of three cases of
      carcinoma in situ, one of malignant carcinoid and three of clear cell carcinoma.

PMID- 10639775
TI  - Diagnosis of hydatid disease of abdomen and thorax by ultrasound guided fine
      needle aspiration cytology.
AB  - Five cases of hydatid disease of abdomen and thorax were diagnosed by fine needle
      aspiration cytology (FNAC) under ultrasound guidance. The age of patients ranged
      from 25-50 years, with a median age of 37 years. Male to female ratio was 2:3.
      None of the cases were clinically diagnosed as hydatid disease, but
      ultrasonography raised suspicion in two cases. The location of cyst in four cases
      was liver and one aspiration was done from lung. Smears from all cases showed
      features consistent with hydatid disease. None of the patients showed any
      untoward allergic reaction following FNAC.

PMID- 10639776
TI  - Pneumatosis cystoides intestinalis--a case report.

PMID- 10639777
TI  - Medullary thyroid carcinoma with melanin production--a case report.
AB  - Melanin production in medullary thyroid carcinomas is rare. The present case
      illustrates melanin and other atypical features of medullary carcinoma of the
      thyroid in a fifty year old female. The diagnosis was suggested on the
      cytomorphological features seen on fine needle aspiration cytology smears. On
      histo-pathological examination the tumor was extensively pigmented with frequent
      mitosis. Amyloid was conspicuously scarce. Confirmation of diagnosis was done by
      immunohistochemical positivity for calcitonin and HMB-45 on tissue sections. The
      case is being presented in view of its rarity and distinct immunoreactivity.
      Review of literature is done and the implications of such dual positivity in the
      histogenesis and divergent phenotype of this tumor are discussed.

PMID- 10639778
TI  - Neonatal candidial endocarditis--a rare manifestation of systemic candidiasis.
AB  - Infective candidial endocarditis in four premature neonates is reported. These
      occurred as a complication of systemic candidiasis. Vegetations were present on
      the right side of the heart in two cases and both sides in the other two.
      Diagnosis requires a high degree of clinical suspicion. Mortality rate is high
      despite appropriate therapy.

PMID- 10639779
TI  - Retroperitonial, teratoma as fetus in fetu--a case report.
AB  - We report a rare case of Retroperitonial teratoma containing Axial Skeleton long
      bone. Jaw, pelvis & scapula in a 27 yrs old male. Aberration in monozygotic
      twinning may rarely present as Fetus in Fetu. Rarer is presentation in Adult.

PMID- 10639780
TI  - An overview of PSA/free PSA with special reference to recent trends in diagnosis
      of prostatic cancer.

PMID- 10639781
TI  - Redefining status of pathology and microbiology.

PMID- 10639782
TI  - Redefining status of pathology and microbiology.

PMID- 10639783
TI  - Prevalence of Acinetobacter anitratus in urinary isolates at G.M and associated
      hospitals.

PMID- 10639784
TI  - [Clinical evaluation of VATS lobectomy for lung cancer].
AB  - Thoracoscopic lobectomy is now recognized as a possible less invasive surgical
      option for stage I primary non-small cell lung cancer. We have widely used
      thoracoscopic procedure for surgical diagnosis of lung nodules especially in lung
      peripheral region as well as resection of primary lung cancer. Results of 47
      thoracoscopic lobectomy during last 5 years were compared with 24 standard
      lobectomy under postero-lateral thoracotomy. There were no significant
      differences in the duration of surgery, post-operative hospital stay,
      intraoperative blood loss and post-operative survival. All but three patients who
      were diagnosed as n 2 disease or tumor with extrapulmonary extension post
      operatively are surviving at the time of survey. We conclude that thoracoscopic
      lobectomy is safe and less invasive procedure compared to standard thoracotomy.
      We believe it can provide sufficient outcome for stage I non-small cell lung
      cancer.

PMID- 10639785
TI  - [Assessment of systematic nodal dissection by VATS lobectomy for lung cancer].
AB  - The feasibility of the complete systematic nodal dissection by the video-assisted
      thoracic surgery was prospectively assessed in 22 cases of clinical stage I lung
      cancer (16 right, 6 left cases). Resection of the designated lobe with the
      mediastinal lymph node dissection was carried out by the small thoracotomy with
      the aid of the thoracoscope, followed by the standard surgery to verify the
      completeness of systematic nodal dissection. Although residual lymph nodes were
      found in 14 of 22 cases, the residual rate was 2.9% and 2.7% by the number and
      2.3% and 2.1% by the weight in right and left cases, respectively. Average time
      and hemorrhage for performing the procedure were 196 minutes, 216.7 minutes and
      157.5 g, 145 g in right and left cases, respectively. As a consequence,
      sufficient systematic nodal dissection in lung cancer was suggested to be
      feasible by VATS lobectomy.

PMID- 10639786
TI  - [Thoracoscopic lobectomy (non rib-spreading method): versus a video assisted
      lobectomy and a conventional thoracotomy].
AB  - We analyzed 33 thoracoscopic lobectomy (non rib-spreading method: NR) cases and
      33 video assisted lobectomy (VA) cases and 49 posterolateral thoracotomy (PL)
      cases, regarding post-operative changes in the serum enzyme levels, operative
      bleeding, required analgesic treatments, changes in the respiratory function and
      other factors. Regarding the post/pre-operative ratio of creatinin phosphokinase,
      bleeding and analgesic treatment NR was showed significantly lower levels than
      the other two methods. Regarding the post/pre-operative ratio of vital capacity
      of the lung NR was significantly less than PL for every six months after the
      operation. With NR the mean number of dissected mediastinal nodes was 14.2 +/-
      7.4 which was not significantly different from VA and PL. We thus concluded that
      NR caused less thoracotomic damage and especially far less restrictive damage to
      the respiratory function than both PL and VA. NR may also result in a better
      quality of life than VA and PL. The node dissection required for NR is also not
      considered to be inferior to that for PL because the number of dissected nodes
      for NR was not significantly different from that for PL. Therefore, in cases
      presenting with clinical stage I primary lung cancer NR is thus considered to be
      indicated in order to obtain an improved post-operative quality of life.

PMID- 10639787
TI  - [Video-assisted minithoracotomy versus conventional posterolateral thoracotomy
      for performing lobectomy of lung carcinomas].
AB  - This study was performed to evaluate the advantages of video-assisted
      minithoracotomy over conventional posterolateral thoracotomy for performing
      lobectomy of lung carcinomas. Thirty-two patients with clinical T1N0M0 non-small
      cell lung carcinoma underwent lobectomy with R2a mediastinal lymphadenectomy. Of
      these, sixteen patients underwent posterolateral thoracotomy (between April 1994
      and November 1995: T group), and sixteen patients underwent video-assisted
      thoracic surgery (between December 1997 and April 1999: V group). No significant
      differences were found in the two groups with respect to the total number of
      mediastinal lymph nodes dissected (T group: 16.9 +/- 8.7. V group: 14.3 +/- 7.2)
      or operative time (T group: 182.3 +/- 48.8 min, V group: 174.9 +/- 28.8 min). The
      intraoperative blood loss was significantly less in the V group (T group: 222.3
      +/- 107.1 ml, V group: 143.3 +/- 92.6 ml, p < 0.05), and the postoperative max
      CPK was also less (T group: 1,484 +/- 496, V group: 785 +/- 327, p < 0.0001).
      Duration of chest tube drainage (T group: 11.3 +/- 3.6 days, V group: 7.9 +/- 2.7
      days) and the requirement of epidural analgesia (T group: 6.7 +/- 2.2 days, V
      group: 5.0 +/- 0.8 days) were less in the V group (p < 0.01), and the length of
      postoperative hospitalization as also shorter in the V group (T group: 26.3 +/-
      8.3 days, V group: 20.6 +/- 4.1 days, p < 0.05). In conclusion, video-assisted
      minithoracotomy is less invasive than posterolateral thoracotomy for performing
      lobectomy of lung carcinomas, and has an advantage in that it improves the
      postoperative quality of life.

PMID- 10639788
TI  - [Safety of video-assisted thoracic surgical (VATS) lobectomy without rib
      spreading for low respiratory function patients].
AB  - We performed VATS Lobectomies without rib spreading on 3 low respiratory function
      patients (FEV1.0 < 1.2 l) with primary lung cancer. Their post-operative courses
      were uneventful. During the 3 post-operative months, VC, FEV1.0, PF, and MVV did
      not decrease for the lost lung volume, while DLco decreased considerably.

PMID- 10639789
TI  - [Technical evaluation of video-assisted lung resection for lung cancer].
AB  - There are two major problems including indications and techniques in video
      assisted lung resection for lung cancer. The current technique of video-assisted
      lung resection have various troublesome procedures as compared with conventional
      open thoracic surgery. We have designed a new thoracoscopic instrument as a
      ligation device. Between September 1997 and August 1999, 15 patients with early
      lung cancer underwent video-assisted lobectomy (VAL). In 5 patients, VAL was
      performed through skin incisions of 3 cm using this new device and at extraction
      of the resected lung the skin incision was elongated minimally (Group A). In 10
      patients, a skin incision of 6-8 cm was made enough to perform VAL without the
      new device at the beginning of the operation (Group B). Total length of skin
      incisions (TLS) and total postoperative pleural discharge (TPD) were measured.
      TLS was 7.2 +/- 1.47 cm in group A, 11.9 +/- 4.50 cm in group B (p = 0.029). TPD
      was 492 +/- 256 ml in group A, 1.132 +/- 591 ml in group B (p = 0.032). TPD might
      be thought as an index of invasion of VAL and it was difficult to decrease TPD
      significantly. The new device made it possible to feel the ligature tension when
      the device was in touch with the chest wall. In a result, the device improved
      technical procedure of VAL and contributed toward less invasive surgery.

PMID- 10639790
TI  - [A therapeutic metastasectomy of pulmonary metastases by VATS].
AB  - The use of VATS to perform diagnostic metastasectomy is uniformly accepted, but
      the role of therapeutic VATS metastasectomy remains controversial. We
      retrospectively compared the value of therapeutic metastasectomy by VATS with
      that by open thoracotomy in the management of pulmonary metastatic tumors. The
      forty-six patients who underwent a complete metastasectomy of pulmonary
      metastatic tumors were divided into groups: one group in which metastasectomy was
      performed by VATS (VATS group; 23 cases, 25 operations) and another group in
      which metastasectomy was performed by open thoracotomy (Thoracotomy group 23
      cases, 26 operations). Here, complete metastasectomy means compete resection of
      all tumors, which were detected by preoperative high resolution computed
      tomography in both groups and also by intraoperative manipulation in the
      thoracotomy group, without positive lesions of the surgical margin. The groups
      were matched with respect to preoperative clinical characteristics (age, sex,
      primary lesion, disease-free interval) and histological findings (maximum tumor
      size, number of metastatic tumors, minimum distance between surgical margin and
      tumor edge). The cumulative survival one-year and three-year rates were 83.5 and
      83.5% in the VATS group, and 89.5 and 77.5% in the thoracotomy group,
      respectively. The cumulative one-year and three-year non-recurrence rates were
      72.3 and 68.0% in the VATS group and 83.9 and 63.8% in the thoracotomy group,
      respectively. There were no significant differences between the two groups. We
      conclude that pulmonary metastasectomy by VATS can be used safely not only as a
      diagnostic but also therapeutic tool if complete resection is done following
      diagnosis by preoperative high resolution computed tomography.

PMID- 10639791
TI  - [Video-assisted thoracic surgery (VATS) for metastatic lung tumor: comparison
      with thoracotomy].
AB  - Effectiveness and present problems of video-assisted thoracic surgery (VATS) for
      metastatic lung tumor were investigated by comparing 14 cases (16 operations) of
      VATS with 16 cases (19 operations) of conventional thoracotomy during the same
      period. VATS was favorably selected in the solitary metastasis. The cases who had
      small tumor diameter less than 3 cm and shorter distance from viseral pluera to
      the tumor surface than tumor diameter were advantageous for only thoracoscopic
      procedure to do the safe and sure resection. Regarding to the tumor number, we
      detected another tumor intraoperatively in 2 of 16 cases (12.5%) of VATS and 6 of
      19 cases (31.6%) of thoracotomy. Multiple metastases had the tendency to have the
      differences of the tumor number between preoperation and intraoperation.
      Prognosis is very good until now, but the recurrence rate was high (64.5%) and
      one case had the recurrence at the surgical margin. VATS for metastatic tumor is
      very effective, but it is important not to hesitate to do the mini-thoracotomy
      and convert to conventional thoracotomy for safe and sure resection.

PMID- 10639792
TI  - [Minimal invasive surgery in heart valve diseases].

PMID- 10639793
TI  - [A simultaneous operation on coronary artery disease and abdominal aortic
      aneurysm during extracorporeal circulation in patient with impaired left
      ventricular function].
AB  - A 74-year-old man had an previous antero-septal and inferior myocardial
      infarction and an abdominal aortic aneurysm (AAA) 48 mm in diameter. Coronary
      angiography showed obstruction of the left anterior descending artery and of the
      right coronary artery, and 95% stenosis of the circumflex artery. The value of an
      ejection fraction of the left ventricle was 33%, measured by left
      venticulography. CABG and replacement of the aneurysm were performed
      simultaneously, because of the necessity of an intra-aortic balloon pumping
      (IABP) due to the impaired left ventricular function. First, CABG was performed
      under cardiac arrest. After declamping the ascending aorta, subsequently,
      replacement of AAA was performed while extracorporeal circulation (ECC) assisted
      heart beating. Weaning from ECC was smooth, and the operation was successful
      without using IABP. The patient was discharged 32 days after the operation.
      Consequently, cardiopulmonary bypass during AAA operation could decrease heart
      loads when hemodynamic states change in aortic clamping or after declamping. A
      simultaneous operation of CABG and AAA using ECC is safe and effective for
      impaired left ventricular function.

PMID- 10639794
TI  - [A case report of pulmonary embolectomy for acute pulmonary thromboembolism
      without extra-corporeal circulation].
AB  - A 69-year-old man complaining of abrupt dyspnea was admitted by ambulance. Acute
      massive pulmonary thromboembolism was diagnosed by pulmonary arteriography but
      after PAG cardiac standstill developed. Infusing of heparin and tPA immediately,
      cardiopulmonary resuscitation was successful after 5 minutes. Repeated PAG showed
      that thrombus in the right intermediate pulmonary artery was not detected, but
      was still detected in the left main pulmonary artery. The emergency embolectomy
      of left main pulmonary artery was performed without extracorporeal circulation
      and massive thrombi were removed. Mechanical respiratory support was required and
      we suffered from the frequent bleeding of the air way for one night. The patient
      was discharged about one month without any complaints.

PMID- 10639795
TI  - [A case of left ventricular rupture and left ventricular-right atrial
      communication after mitral valve re-replacement].
AB  - We report a case of left ventricular rupture and left ventricular-right atrial
      communication after mitral valve re-replacement. A 53-year-old man was admitted
      to our hospital for a primary tissue failure of mitral xenograft. On June 4,
      1997, he underwent mitral valve re-replacement. At 12 post operative day, he was
      suffered from unexpected dyspnea. The transesophageal echocardiography showed
      floated mitral valve and left ventricular-right atrial communication. The
      emergent operation was done. At the operation, posterior mitral annulus was
      disrupted and the disruption reached to a membranous septum. A communication was
      directly closed, mitral annulus was repaired with perigard and one size smaller
      mitral valve was implanted. The patient was discharged and returned to social
      life.

PMID- 10639796
TI  - [Cardiac tamponade due to ruptured intramural hematoma of the ascending aorta: a
      case report].
AB  - A 72-year-old man with a history of hypertension for 20 years was admitted with
      symptoms of acute aortic dissection. Computed tomography showed a crescentic
      thickening of the ascending aortic wall, suggesting an intramural hematoma.
      Sixteen hours after admission, he underwent urgent repair of the ascending aorta
      because of cardiac tamponade. We inspected the inside of the aorta from the
      aortic valve to the arch. Subadventitial hematoma due to hemorrhage from the
      outer media was confirmed. Rupture of the vasa vasorum was thought to be an
      initiating mechanism. The affected aortic wall was simply resutured and was not
      replaced with a graft because the intima was intact and the media was not
      dissected and the aortic wall was considered to be tolerable to normal blood
      pressure. The patient continues to do well 18 months following operation. An
      intramural hematoma of the ascending aorta should be regarded as a precursor of
      imminent rupture or classic dissection.

PMID- 10639797
TI  - [Should arterial grafts be used for urgent coronary artery bypass surgery?].
AB  - It is not clear whether arterial grafts should be used for emergency or urgent
      coronary artery bypass grafting (CABG) because harvest of internal thoracic
      arteries (ITAs) is not easy under urgent conditions and the blood flow through
      the ITAs may be inadequate immediately after CABG. The purpose of this study was
      to assess whether the use of arterial grafts in urgent CABG affects the outcome
      adversely or not. Twenty consecutive patients who underwent urgent CABG within 48
      hours following coronary angiography at our institute between July 1991 and
      October 1998 were reviewed. The patients who underwent CABG with associated
      procedures were excluded. Among these subjects, 11 patients received at least one
      arterial graft. Only 1 patient died of subarachnoidal hemorrhage, and the
      hospital mortality rate was 5.0%. According to the overall survival rate, cardiac
      death-free rate, and cardiac-event-free rate, the long-term outcome was much
      better in the patients with arterial grafts than those with saphenous vein grafts
      alone. We suggest that arterial grafts should be used even for urgent CABGs since
      the use of arterial grafts may not affect operative results adversely and will
      confer better long-term benefits.

PMID- 10639798
TI  - [Mediastinal mature teratoma perforated into the pericardial sac: a case report].
AB  - Mature teratomas occasionally rupture into adjacent organs such as lung,
      bronchus, mediastinum and pericardial sac. However, perforation into the
      pericardial sac is rare. We experienced a case of mediastinal mature teratoma
      perforated into the pericardial sac. A 16-year-old man was admitted to our
      hospital due to sudden severe anterior chest pain. Chest X-ray showed a mass
      shadow in the right middle lung field. Chest CT scan and MRI demonstrated a
      heterogeneous mass with fat component in the right anterior mediastium adjacent
      to the pericardium. Some squamous cells were obtained from the mass by CT guided
      percutaneous needle biopsy. Operation was performed with the diagnosis of
      mediastinal teratoma. The mass adhered to the pericardium and turbid pericardial
      effusion was noted. The mass was removed with the pericardium. The mass was 9 x
      6.5 x 6 cm in size, which contained yellow sebaceous material and a tuft of white
      hair. The pathological diagnosis of the mass was mature cystic teratoma with
      perforation into the pericardial sac.

PMID- 10639799
TI  - [A case report: Carpentier-Edwards porcine bioprosthesis malfunction due to the
      stent dehiscence at 17 years after the implantation in the mitral position].
AB  - A 53-year-old female had undergone mitral valve replacement with Carpentier
      Edwards (C-E) porcine bioprosthesis for mitral valve regurgitation at the other
      hospital in November, 1981. Postoperative clinical course was uneventful, since
      she was referred from the other hospital in 1990. In December, 1997, she had
      sudden complaint of shortness of breath on effort, and the chest X-ray showed
      pulmonary congestion and increase of cardio-thoracic ratio. Echocardiography and
      catheterization revealed severe mitral regurgitation due to bioprosthesis
      malfunction and aortic valve regurgitation. Combined mitral and aortic valve
      replacement was successfully performed with mechanical valves in February, 1998.
      The explanted C-E porcine bioprosthesis showed the commissural dehiscence from
      only one of the three stents without any leaflet perforation, commissural tear,
      pannus overgrowth, impaired leaflet mobility and leaflet deterioration or
      calcification. This case suggested the variety of malfunction of C-E porcine
      bioprosthesis and the limitation of its long-term durability.

PMID- 10639800
TI  - [A case of spontaneous pneumothorax in pregnancy].
AB  - Spontaneous pneumothorax rarely happened in woman compared to man generally.
      Furthermore, it is said that spontaneous pneumothorax in the pregnancy is very
      rare. We experienced a case of spontaneous pneumothorax in 32 weeks gestation.
      She complains chest pain and dyspnea in hospital because of medication to urgent
      premature. Throcar catheter has been placed after delivery. Video assisted
      thoracoscopic bullectomy was performed on the next day of the delivery and
      discharged 5 days after operation. Treatment of spontaneous pneumothorax in
      pregnancy was believed to be difficult, but she delivered safely because of being
      under the tube drainage. We believed that the tube drainage during pregnancy or
      the operation were recommended for these cases because of security of mother and
      embryo.

PMID- 10639801
TI  - New rules authorizing physicians to delegate the prescribing of controlled
      substances present significant legal liability exposure.

PMID- 10639802
TI  - When medicine goes .com.

PMID- 10639803
TI  - Lessons from the Burns Clinic experience.

PMID- 10639804
TI  - Telemedicine speeds up on information superhighway.

PMID- 10639805
TI  - Thriving under managed care.

PMID- 10639806
TI  - Looking back on the 20th century.

PMID- 10639807
TI  - Clinical use of stents for carotid artery disease.
AB  - Over the last 5 years, the clinical use of intravascular stents for treatment of
      carotid artery pathology has become more prevalent and the spectrum of potential
      indications has widened. Endovascular stenting is providing an alternative to
      surgical endarterectomy for treatment of cervical carotid artery atherosclerotic
      disease. This has prompted a North American, randomized, controlled clinical
      trial directly comparing these two therapies. In this article we review the major
      surgical endarterectomy trials that currently provide the scientific rationale
      for revascularization of carotid artery occlusive disease, critically evaluate
      the evidence supporting the application of endovascular stenting procedures for
      the treatment of occlusive and nonocclusive disease of the extracranial and
      intracranial carotid artery, consider the current clinical indications for use of
      stents in the carotid artery, and discuss current equipment, technique, and
      potential procedure-related complications.

PMID- 10639808
TI  - Postoperative anticonvulsant prophylaxis for patients treated for cerebral
      aneurysms.
AB  - The incidences of postoperative seizures and side effects were evaluated in 193
      patients with cerebral aneurysm who received anticonvulsant prophylaxis and
      underwent 224 craniotomies for cerebral aneurysms between 1993 and 1995. The
      patients were 73 males and 120 females aged between 31 and 80 years. One hundred
      and sixteen patients had ruptured cerebral aneurysms and 108 had unruptured
      aneurysms. Phenytoin followed by valproic acid were administered. Early
      postoperative seizures occurred in five patients (4 with ruptured and 1 with
      unruptured aneurysms) within 14 days after surgery. Late postoperative seizures
      occurred in four different patients with ruptured aneurysms more than 14 days
      after surgery. The presence of cortical lesions detected by cerebral computed
      tomography and occurrence of symptomatic vasospasm were correlated with the
      occurrence of early postoperative seizure (p < 0.05). Three of the four patients
      with late postoperative seizure had cortical lesions and two were receiving
      continued medication. Side effects that warranted discontinuation of therapy were
      seen in the follow-up period in 12.9% of patients. Anticonvulsant prophylaxis is
      not recommended due to the higher incidence of side effects than seizure, except
      in patients in poor clinical condition for the purpose of brain protection.
      Otherwise, anticonvulsant medication should be initiated at the time of the
      initial seizure attack.

PMID- 10639809
TI  - Anterior approach for dumbbell type cervical neurinoma.
AB  - A one-stage anterior approach was performed in four patients for total removal of
      dumbbell type neurinoma at the cervical level. In each case, the neurinoma
      compressed the spinal cord in the cervical canal, developed anteriorly through
      the intervertebral foramen, and compressed the vertebral artery. A conventional
      cervical anterior approach at the tumor site was performed, followed by
      confirmation of the tumor located outside the spinal canal. After identification
      of the vertebral artery, corpectomy was carried out and the extradural component
      of the tumor was resected. In cases with a portion of the tumor located also
      within the dura mater, the dura mater was opened for removal of the intradural
      tumor. We found the anterior approach to be effective for the total removal of
      some kinds of cervical dumbbell type neurinomas.

PMID- 10639810
TI  - Prediction of effectiveness of shunting in patients with normal pressure
      hydrocephalus by cerebral blood flow measurement and computed tomography
      cisternography.
AB  - Measurement of cerebral blood flow (CBF) and computed tomography (CT)
      cisternography were performed in 37 patients with a tentative diagnosis of normal
      pressure hydrocephalus (NPH) to predict their surgical outcome. The mean CBF of
      the whole brain was measured quantitatively by single photon emission computed
      tomography with technetium-99m-hexamethylpropylene amine oxime before surgery.
      The results of CT cisternography were classified into four patterns: type I, no
      ventricular stasis at 24 hours; type II, no ventricular stasis with delayed
      clearance of cerebral blush; type III, persistent ventricular stasis with
      prominent cerebral blush; type IV, persistent ventricular stasis with diminished
      cerebral blush and/or asymmetrical filling of the sylvian fissures. The mean CBF
      was significantly lower than that of age-matched controls (p < 0.005). Patients
      with a favorable outcome had a significantly higher mean CBF than patients with
      an unfavorable outcome (p < 0.005). Patients with the type I pattern did not
      respond to shunting. Some patients with type II and III patterns responded to
      shunting but improvement was unsatisfactory. Patients with type IV pattern
      responded well to shunting, and those with a mean CBF of 35 ml/100 g/min or over
      achieved a favorable outcome. The combination of CBF measurement and CT
      cisternography can improve the prediction of surgical outcome in patients with
      suspected NPH.

PMID- 10639811
TI  - Cavernous angioma of the internal acoustic meatus--case report.
AB  - A 39-year-old female presented with an intrameatal cavernous angioma manifesting
      as hearing loss and tinnitus in the right ear which progressed over 8 months.
      Magnetic resonance (MR) images revealed an intrameatal lesion as ultra-high
      intensity, nearly as bright as cerebrospinal fluid, on the T2-weighted images,
      and isointensity on the T1-weighted images. Computed tomography (CT) showed the
      mass accompanied by stippled patterns of calcification. The patient underwent
      surgery under a diagnosis of calcified acoustic neurinoma. Histological studies
      were compatible with cavernous angioma. Intrameatal cavernous angioma is a rare
      disease which requires differential diagnosis from the more common neurinoma or
      meningioma in this location. Intrameatal lesion with ultra-high intensity on T2
      weighted MR imaging and stippled patterns of calcification on CT is more likely
      to be cavernous angioma than acoustic neurinoma. These neuroimaging features are
      important information in deciding the treatment strategy.

PMID- 10639812
TI  - Postpartum dissecting aneurysm of the superior cerebellar artery--case report.
AB  - A 37-year-old female with toxemia of pregnancy suffered sudden headache and loss
      of consciousness on the day following a cesarean delivery. Computed tomography
      revealed subarachnoid hemorrhage (SAH). Vertebral angiography revealed a fusiform
      dilatation near the origin of the right superior cerebellar artery (SCA) with
      distal luminal narrowing. She underwent surgery within 24 hours of the ictus. A
      SAH clot was carefully removed from the prepontine cistern, and subadventitial
      discoloration was seen in the wall of the right SCA just distal to the aneurysmal
      protuberance (rupture site). The dissecting aneurysm was treated with body
      clipping by directly clipping the rupture site and with additional wrapping of
      the proximal SCA, including the aneurysmal protuberance and discolored site. The
      postoperative clinical course was uneventful. Postoperative angiography revealed
      complete obliteration of the aneurysm and patency of the SCA. Therapeutic
      intervention should be considered for patients with ruptured dissecting aneurysm
      who present with recurrent SAH.

PMID- 10639813
TI  - Aneurysms arising from the cortical segment of the superior cerebellar artery-
      two case reports.
AB  - Two unusual cases of partially thrombosed or fusiform type aneurysm on the
      cortical segment of the superior cerebellar artery (SCA) with subarachnoid
      hemorrhage are described. A 71-year-old female had a partially thrombosed, multi
      lobular aneurysm located at the marginal branch of the SCA. This aneurysm was
      successfully clipped and wrapped via a subtemporal transtentorial approach in the
      acute stage. A 52-year-old female had an atherosclerotic fusiform aneurysm
      located at the distal portion of the hemispheric branch of the SCA. This aneurysm
      was successfully trapped using an infratentorial supracerebellar approach in the
      acute stage. Both patients were discharged without neurological deficits. The
      subtemporal transtentorial or lateral suboccipital approach for the proximal
      cortical segment, and the infratentorial supracerebellar approach for the distal
      cortical segment of the SCA are recommended for surgical treatment of these
      aneurysms.

PMID- 10639814
TI  - Ruptured vertebral artery-posterior inferior cerebellar artery aneurysm
      associated with facial nerve paresis successfully treated with interlocking
      detachable coils--case report.
AB  - An 81-year-old female presented with severe headache. Computed tomography
      revealed subarachnoid hemorrhage. She developed right facial nerve paresis on the
      next day. Angiography revealed a right vertebral artery-posterior inferior
      cerebellar artery aneurysm. The aneurysm was successfully occluded with
      interlocking detachable coils (IDCs) on the 7th day. Magnetic resonance (MR)
      imaging 1 month after IDC placement showed partially thrombosed aneurysm near the
      internal acoustic meatus. Ten months after the ictus, MR imaging revealed marked
      resolution of the intra-aneurysmal thrombus and reduction of the aneurysm size.
      Her facial nerve function gradually recovered during this period. Her facial
      nerve paresis was probably caused by acute stretching of the facial nerve by the
      ruptured aneurysm that was in direct contact with the nerve. Intra-aneurysmal
      thrombosis using coils can reduce aneurysm size and alleviate cranial nerve
      symptoms.

PMID- 10639815
TI  - Bow hunter's stroke associated with an aberrant course of the vertebral artery-
      case report.
AB  - A 53-year-old male presented with repeated vertebrobasilar insufficiency on
      turning the head to the left. Angiography revealed severe stenosis of the
      dominant right vertebral artery at the atlantoaxial level in this position.
      Decompression surgery for the affected vertebral artery at the transverse foramen
      of the atlas was planned. However, surgery revealed an aberrant course of the
      artery, turning at the orifice of the transverse foramen of the atlas and
      perforating the dura at the occipitoatlantal level after passing through the bony
      canal of the atlas. Therefore, decompression was performed at the bony canal,
      which was the contributing site, and the symptoms improved. Bow hunter's stroke
      may be caused by atlantoaxial arterial anomalies, so accurate preoperative
      evaluation of the region is necessary to avoid anatomical confusion at surgery.

PMID- 10639816
TI  - Sellar chondroma--case report.
AB  - A 12-year-old boy presented with right visual disturbance. Skull radiography and
      computed tomography (CT) showed an irregular deformity of the sella turcica,
      hypertrophic change of the dorsum sellae, and an inhomogeneously calcified mass
      in the sella turcica. Magnetic resonance (MR) imaging demonstrated the mass
      lesion filled the hypophyseal fossa, and extended to the dorsum sellae, right
      cavernous sinus, and right suprasellar region. The Dolenc pterional combined
      epidural and subdural approach was carried out. The histological diagnosis was
      chondroma. Sellar chondroma requires relief of the compression to the chiasm or
      optic nerve as soon as possible, so partial resection can still be beneficial.
      However, follow-up MR imaging or CT, visual examination, and control of pituitary
      dysfunction are required after the operation.

PMID- 10639817
TI  - Neurenteric cyst of the craniocervical junction--case report.
AB  - A 60-year-old female presented with occipital headache and limitation of neck
      movement. Neurological examination showed weakness of the right
      sternocleidomastoid muscle. Magnetic resonance imaging revealed a cystic lesion
      at the craniocervical junction and posterior compression of the brain stem. The
      lesion was totally removed through the transcondylar approach. The histological
      diagnosis was neurenteric cyst. The transcondylar approach provides a direct
      operative view of the clivus and anterior craniovertebral junction.

PMID- 10639818
TI  - [International trends in clinical laboratory testing].
AB  - During the 20th century, at least until the 1980s, clinical laboratory practice
      had been rapidly expanded, mainly because of a significant advancement in
      medicine as a whole and also in laboratory technology. However, recent economic
      changes in health care environment worldwide have been influencing greatly future
      trends in clinical laboratory practice. In 1983, the DRG/PPS was introduced in
      the Medicare hospital care in the United States, and it will be introduced also
      in out-patient care after the January of 2000. This payment system has been
      expanded to the HMO, and a drastic change has occurred in clinical laboratory
      practice, particularly since 1988 when the CLIA'88 was implemented. In Japan, the
      DRG/PPS is now in the process of preparing for the future introduction into the
      National Health Insurance System. The clinical laboratory must pursue both
      quality management and adequate utilization of laboratory tests. In near future,
      the ISO standards in clinical laboratory testing will prompt to the
      implementation of quality management in the clinical laboratory. Evidence-based
      laboratory medicine or systematic review in diagnostic testing will be introduced
      in order to improve the utilization of clinical laboratory tests.

PMID- 10639819
TI  - [Department of microbiosensing system using micromachine techniques].
AB  - This paper reviews devices for Point Of Care (POC) testing, especially focusing
      on current and future biosensors and biosensing fields. POC testing involves on
      site diagnosis such as bedside diagnosis and near-patient testing. Biosensors and
      biosensing devices are a key technology to measure all clinically important
      parameters. For many reasons such as historical, simplicity, the high stability
      and activity of the enzyme required, and large demand from diabetics, only
      glucose sensors are commercially available. Various biosensors are waiting for
      commercialization. Not only simple biosensors having a biofunctional membrane on
      a transducer, but more complicated biosensing systems are fabricated on a
      microchip. Micro-Total Analysis System (mu TAS) is a research field to fabricate
      miniaturized sensing devices or systems. In these devices or systems, biochemical
      reactions for detection can be well controlled by running buffers, even though
      the consumption of reagents and sample is very small. Microarray chip technology,
      such as the DNA chip, is now receiving much attention in not only genetic
      research, but other biochemical research and application fields as well.
      Detection apparatus for the DNA chip is currently bench-top size. According to
      recent research, however, the size will be reduced as to a portable-size that is
      suitable for POC testing. Research and development of POC devices are advanced
      not alternative methods of conventional laboratory test, but as complement
      technology with advantages such as mobility, speed, and low-cost.

PMID- 10639820
TI  - [Usefulness of POCT in critical care medicine].
AB  - The need for speedy and accurate test results is becoming increasingly urgent in
      the areas of emergency medicine and ICU. The form of emergency testing is
      changing from conventional testing conducted by laboratory technicians to point
      of-care testing (POCT) performed by the doctor or nurse. Therefore, the skill and
      time of the technician, which used to be expended for emergency testing, is now
      utilized for maintenance and precision control of POCT equipment so that the
      doctors and nurses can conduct POCT with confidence at all times. We also
      attempted point of prehospital care testing (POPCT), comprised of prehospital
      care and POCT. Here, the laboratory technician rides with the doctor to provide
      patient information to the clinicians from the perspective of a laboratory
      technician in the field to support emergency treatment. This has not yet been
      made fully practical, but the usefulness of POCT in critical care medicine seems
      to be essential to the forthcoming advanced emergency medicine, considering its
      usefulness outside the hospital environment.

PMID- 10639821
TI  - [Water metabolism and its disturbances].
AB  - The central and peripheral mechanisms regulate body water balance near an ideal
      set point. Osmosensitive neurons in the organum vasculosum lamina terminalis
      (OVLT) in the anterior hypothalamus play a key role in regulating vasopressin
      release and drinking behaviour. Patients with OVLT lesions are known to have
      osmostat fluctuations. Although the brain water channel is suggested to
      participate in osmoreception, the precise molecular mechanisms of osmoreception
      and thirst appreciation remain to be clarified. Vasopressin gene mutation is
      responsible for hereditary central diabetes insipidus. Mutant vasopressin
      precursors have been reported to impair the secretion of wild-type proteins or
      cause cellular toxicity. Despite the intact production and secretion of
      vasopressin, the kidney is unable to concentrate urine in nephrogenic diabetes
      insipidus (NDI). Most congenital NDI patients have mutations in the G protein
      coupled vasopressin V2 receptor gene. V2 receptor mutants are shown not to reach
      the plasma membrane, not to bind AVP, and not to trigger an intracellular cyclic
      adenosine-monophosphate signal. Congenital NDI with an autosomal recessive
      inheritance has mutations of Aquaporin-2 gene, a vasopressin-sensitive water
      channel in the renal inner medullary collecting duct (IMCD). Aquaporin-2 mutant
      proteins cannot be expressed at the luminal membrane. The corticopapillary
      osmotic gradient is necessary for renal sensitivity to vasopressin. The
      vasopressin-regulated urea transporter in IMCD and the chloride channel (CLC-K1)
      in the ascending loop of the Henle contribute to the formation of the osmotic
      gradient. NDI has been shown in mice lacking the CLC-K1. The pathophysiological
      significance of urea transporter and CLC-K1 has yet to be demonstrated in
      patients with NDI.

PMID- 10639822
TI  - [Renal sodium transport abnormality: Gitelman's syndrome and renal sodium
      transporter].
AB  - Recent studies using molecular biological methods have enabled us to identify the
      genetic abnormality in renal electrolyte metabolism. In renal tubules, diuretic
      sensitive Na transporter systems are present, and key molecules have been cloned.
      Thiazide-sensitive Na-Cl contransporter (TSC) is one of the molecules localized
      in the distal convoluted tubule, whose genetic abnormality causes Gitelman's
      syndrome (a variant of Bartter's syndrome characterized by dehydration,
      hypokalemic metabolic alkalosis, secondary aldosteronism lacking hypertension,
      hypomagnesemia, and hypocalciuria). We identified a mutation in TSC (Leu to Pro
      change at 623 amino acid position, L623P) in familial Gitelman's syndrome, and we
      confirmed the loss of TSC function by this mutation in a functional expression
      system using mammalian cells. This L623P mutation has been found in other
      patients with Gitelman's syndrome living in the northern part of Japan.

PMID- 10639823
TI  - [Metabolism of potassium and its flux in erythrocytes].
AB  - One of the causes of pseudohyperpotassemia is the induction of potassium (K)
      release from blood cells by various factors such as cold-storage of blood
      samples, various drugs including ouabain and so on. We speculated on the effect
      of storage temperature and therapeutic drugs used on the elevation of K levels in
      vitro. Dobutamine was selected for in vitro experiment. The therapeutic dose of
      dobutamine (76 micrograms/l) was mixed with whole blood and incubated at 37
      degrees C. A significant increase in K concentration was observed after
      incubation for 6 hours. These results suggested that many injection drugs used
      clinically induce K release from blood cells in vitro as well as in vivo and the
      administration of such drugs could be one of the causes of pseudohyperpotassemia.
      We developed a simple and practical method to determine the K-flux activity of
      erythrocytes. Employing this method, hemodialysis patients and aged subjects were
      evaluated. These were shown to be reduced compared with those of healthy
      subjects. In 30 hemodialysis patients, K-flux activity and the mean serum K
      concentration expressed as the average of 4 measurements correlated negatively (r
      = -0.482, p < 0.01). The K-flux activity of the erythrocytes collected after
      hemodialysis therapy was increased significantly (p < 0.05) compared with that of
      erythrocytes collected before therapy. We conclude that the K-flux activity of
      erythrocytes might participate partly in the regulation of serum K concentration
      in hemodialysis patients and that the inhibitory factors on K-flux activity might
      be removed by hemodialysis therapy.

PMID- 10639824
TI  - [Approach to examining hypercalcemia in the clinical laboratory].
AB  - The investigation of hypercalcemia is carried out routinely in our laboratory to
      detect primary hyperparathyroidism (PHPT). In a retrospective study, seven
      patients with PHPT and fifty-one patients with non-parathyroid hypercalcemia
      (NPHC) were chosen in a particular year. To obtain a screening index for PHPT,
      discriminant analysis, using a stepwise variable select method, was applied to
      eight biochemical parameters in these patients. A discriminant function (F1) was
      derived from three biochemical parameters and then another discriminant function
      (F2) was also derived from three biochemical parameters in the F1-positive
      patients. In combination of these two functions (F1 and F2), the final
      sensitivity was 100% and specificity was 98% in diagnosing PHPT. This screening
      method was tested prospectively in fifty-six consecutive specimens of
      hypercalcemia (PHPT 4, NPHC 52) over the following six months. The result was
      also satisfactory with a sensitivity of 100% and specificity of 98%. It was
      proven that our screening method using discriminant functions (F1 and F2) was
      very useful for diagnosing patients with PHPT from the survey of hypercalcemia.
      Among these patients with hypercalcemia, the high ratio (54%) of those with
      malignancy was remarkable. This interesting result required us to investigate
      potential hypercalcemia, since the serum calcium concentration was masked by a
      lower level of serum albumin, which was frequently seen in these malignant
      patients. As the next step, we tried to adjust the serum calcium concentration
      based on the serum albumin concentration. A formula for adjusting the calcium
      concentration was derived from a linear structural relationship between calcium
      and albumin in 6,821 specimens within a +/- 2.5 second principal component score
      in 7,021 consecutive specimens in whom both calcium and albumin were measured in
      a particular year; Adjusted Calcium = Calcium - Albumin + 4. After adjustment
      using this formula, the calcium concentrations were elevated above the upper
      limit of the reference interval in 320 of 5,203 specimens (6%) within the
      reference interval and elevated to the reference interval in 1,390 of 1,579
      specimens (88%) below a lower limit of reference interval. A prospective study
      was performed over the following three months. Fifty patients with hypercalcemia
      were screened using this formula. It was a surprise that thirty-one patients
      (62%) showed abnormal values after adjustment. These results suggest that calcium
      adjustment is necessary for interpreting the calcium concentration of patients
      with a reduced albumin concentration such as patients with malignancy.

PMID- 10639825
TI  - [Evaluation of visceral impairments by exercise testing: practice and problems in
      recently-developed exercise testing in disabled patients and an introduction of a
      newly-developed instrument for monitoring cardiopulmonary and postural
      parameters].
AB  - OBJECTIVE: Exercise testing plays a major role in evaluation of visceral
      impairments in disabled patients. We introduced recently-developed exercise
      testing and a newly-developed instrument for monitoring cardiopulmonary and
      postural parameters. We also evaluated the effects of cardiac phase II
      rehabilitation, pulmonary rehabilitation, and lung volume reduction surgery
      (LVRS) in patients with cardiopulmonary diseases. METHODS: 1) The ratio of
      ischemic heart disease in stroke patients was assessed by exercise testing. 2)
      The physical status of the patients with myocardial infarction (MI) was assessed
      before and just after our hospitalized cardiac phase II rehabilitation program,
      and at a 6-month follow-up by cardiopulmonary exercise testing. 3) The physical
      status of the patient with idiopathic interstitial pneumonia was assessed before
      and after pulmonary rehabilitation by a six-minute walking test. 4) The physical
      status of the patients with pulmonary emphysema (PE) was assessed before and 3
      months after LVRS. 5) We introduced a newly-developed instrument for monitoring
      cardiopulmonary and postural parameters (MCPP). RESULTS AND CONCLUSIONS: The
      ratio of ischemic heart disease (IHD) in stroke patients was 18%. Our
      hospitalized phase II cardiac rehabilitation program improved the management of
      cardiac risk factors and the physical status in patients with MI. The physical
      status of the patient with idiopathic interstitial pneumonia was markedly
      improved after pulmonary rehabilitation, and she did not need to undergo lung
      transplantation. The physical status and lung function of PE was significantly
      improved 3 months after LVRS. MCPP was made and used in the field of
      rehabilitation medicine. MCPP shows the picture and cardiopulmonary and postural
      parameters at the same time on a monitor, and is a very useful tool to evaluate
      the activities of daily living of the patients undergoing rehabilitation. MCPP
      may provide useful information to develop more efficient strategies for
      rehabilitation planning and patients' education.

PMID- 10639826
TI  - [Functional evaluation of the hypothalamic-pituitary-adrenal axis].
AB  - The regulation of hypothalamic pituitary-adrenal (HPA) axis is controlled by
      three major factors: stress, circadian rhythm and negative feedback. Hypothalamic
      CRF binds to CRF receptor on ACTH cells and stimulates synthesis and secretion of
      ACTH. However, vasopressin binds to V1b receptor and enhances CRF induced ACTH
      secretion. ACTH stimulate secretion of cortisol and DHEA-S. Cortisol inhibits
      secretion of CRF and ACTH with negative feedback mechanism. To evaluate the
      ability of the hypothalamus to secrete CRF, insulin-induced hypoglycemia and
      metyrapone tests are used. For evaluation of the secretion of pituitary ACTH and
      adrenal cortisol, a CRF test is useful. Autonomic secretion of ACTH and/or
      cortisol is evaluated with a dexamethasone suppression test.

PMID- 10639827
TI  - [Outline of Health Level Seven (HL7) standard].
AB  - Health Level Seven (HL7) is a standard for medical informatics exchange between
      healthcare providers. Its applicable area includes order entry of many kinds,
      test result reporting, prescriptions, Admit/Discharge/Transfer of patient, etc.
      It is one of the most successful medical standards. Merits of HL7 are 1) its
      richness of elements of details for laboratory test orders and results, 2) its
      protocol definitions for HIS-LIS data exchange, 3) its standard body's healthy
      management, and 4) its popularity makes related softwares more available and less
      expensive. Limitations of HL7 are 1) its difficulty of expression of clinical
      findings, signs, and symptoms, which comprise electronic medical records, all
      because of lack of adequate code of these items, and 2) its being a description
      of fixed timing of examination results, not being a sequence of episode of the
      patient. HL7 Japan have been founded in 1998, as the 7th international affiliate
      of HL7. Its secretariat facility is provided by JAHIS (Japan Association of
      Healthcare Information System vendors). Its activities comprise; 1) HL7 seminars
      held more than 3 times each year, 2) Japanese language publication of HL7
      standards and related documents, and 3) submission of requirements from Japanese
      users to HL7 USA for coming versions.

PMID- 10639828
TI  - [Recent progress in laboratory medicine in the field of hematological disorders].

PMID- 10639829
TI  - [Ultrasound-guided fine-needle aspiration cytology for neck lesions].
AB  - In 1997, 240 cases of ultrasound-guided fine-needle aspiration cytology (FNAC)
      were performed for neck lesion at Jichi Medical School Hospital. We compared the
      preoperative cytology findings with postoperative pathologic results for 63 cases
      (56 lesions) from patients who underwent surgery or open biopsy. The sensitivity,
      specificity and accuracy of cytological diagnosis were 93.5%, 100% and 96.2%,
      respectively. There were 2 false negative cases in thyroid gland, which were
      follicular and medullary carcinomas. Insufficient material for cytological
      analysis was obtained in 62 of 240 cases (25.8%). Since FNAC can provide high
      accuracy, we need to reduce insufficient material cases.

PMID- 10639830
TI  - [Relation between human papilloma virus DNA and expressions of p53 and p21
      proteins in cervical lesions].
AB  - Oncogenic types of human papilloma virus (HPV) are known to be closely associated
      with cervical carcinoma. On the other hand, the oncogenic process is associated
      with various abnormalities in the mechanisms of cellular regulation. In this
      study, we detected the expressions of p53 and p21 proteins in cervical lesions by
      immunohistochemical techniques, and examined the relationship with HPV infection
      as well as the clinical usefulness of the results. Cervical biopsy specimens from
      107 cases of cervical lesions were studied. HPV-DNA was detected by the hybrid
      capture method using probe A for low oncogenic types and probe B for high
      oncogenic types. Anti p21, anti-p53 antibodies were used to perform
      immunostaining. Point mutation in the p53 gene was analyzed by the DGGE method.
      High oncogenic HPV types were detected at high frequencies in CIN and SCC. In
      lesions associated with high oncogenic HPV, p53 protein was detected in 33.4% of
      the lesions and p21 protein in 36.3%. The p53 gene was analyzed in all cases, and
      point mutation was not detected. No relation was detected between HPV infection
      and p53/p21 protein expression. Since mutation was not found in the p53 gene, the
      p53 protein expressed was considered to be wild-type, which is suspected to play
      a role in inhibiting disease progression in some cases.

PMID- 10639831
TI  - [An autopsy case of undifferentiated carcinoma of the thyroid with sarcoma-like
      change].
AB  - Although undifferentiated carcinoma of the thyroid is rare, it is often seen in
      aged. Because of rapid growth and frequent remote metastasis, it has poor
      prognosis. We have reported an autopsy case of the undifferentiated carcinoma of
      the thyroid gland, which could be diagnosed in autopsy although it could not be
      diagnosed clinically. In autopsy, multiple tumors were found in the brain, left
      lobe of the thyroid gland involving regional lymph node, lungs, pancreas,
      intestinal mucosa and abdominal soft part. Histologically, the tumor cells showed
      pleomorphism with sarcoma-like change and some of the tumor lesions in the
      thyroid and lungs showed colloid follicles differentiation.
      Immunohistochemically, sarcoma-like tumor cells showed positive for anti-keratin
      staining and the colloid follicle pattern revealed positive for anti
      thyroglobulin staining. And finally, the tumor of this case could be diagnosed as
      the undifferentiated carcinoma of the thyroid with general metastasis.

PMID- 10639832
TI  - Cancer registries in the Caribbean.

PMID- 10639833
TI  - Beyond fibrocystic disease. The evolving concept of pre-malignant breast disease.
AB  - There is a broad spectrum of benign and pre-malignant breast disease that may be
      diagnosed on biopsy. Some of these conditions place affected women at
      significantly increased risk for breast cancer, particularly the atypical
      hyperplasias. All health care workers should be aware of recent developments in
      this important aspect of breast disease. The classification, criteria for
      diagnosis, associated risks for cancer development and various controversies
      related to these benign and borderline breast diseases are discussed.

PMID- 10639834
TI  - Ethics, medicine and society: imperatives for the future.
AB  - Historically, medicine has been a caring profession and social factors have
      directly and indirectly affected clinical practice, yet the social roots of
      disease and suffering in patients and the ethics of patient care have often been
      left out of medical teaching and discussions at medical conferences. As health
      and social problems are inseparable, ethically, medicine and medical teaching
      need to respond to social suffering, and should help to solve the economic
      problems in health care. Further, since all intervention in the lives of human
      beings carries ethical content through the nature of care, ethical competence
      involving ethical analysis, critical thinking, and problem-solving should be
      developed in medical students and doctors simultaneously with clinical judgement
      and expertise.

PMID- 10639835
TI  - Medical research at the Faculty of Medical Sciences, UWI, Mona Campus 1960-1990.
AB  - The objective of this study was to evaluate research output in relation to
      undergraduate teaching output of the Faculty of Medical Sciences, Mona Campus,
      University of the West Indies between 1960 and 1990. The Departmental Reports
      published by the University of the West Indies were examined using a successive
      independent sample design with sentinel years at ten-year intervals for the 30
      year period under review. The numbers of reported peer-reviewed publications for
      each department were disaggregated and analysed. Ten of the fourteen departments
      (10/14, 72%) of the Mona Faculty showed a decline in output of peer-reviewed
      publications of up to 100% between 1960 and 1990 (p < 0.001). The number of
      academic staff had risen from 41 in 1960 to 143 in 1990 (249%) while the
      publication/staff ratio had fallen from 1.73 in 1960 to 0.48 in 1990 (p <
      0.0001). Student/staff ratios had declined significantly over the 30-year period
      (p < 0.005) as had the graduate/staff ratio (p < 0.01). The Faculty reports
      indicated that the research-in-progress reported far exceeded the actual
      publication rate in 1990, whereas the opposite was the case in 1960. There was a
      statistically significant decline in the number of international conference
      abstracts published and an increase in the number of regional conference
      abstracts (p < 0.01) and also a significant decrease in the number of papers
      presented at conferences compared with the number of conferences attended without
      a paper being presented (p < 0.0001). The research publication record and the
      medical graduate/staff ratio of the Mona Faculty had declined significantly over
      the 30 years under review. There was also a significant decline in the
      graduate/staff ratio in the same period. Some of the conventional reasons given
      for this decline such as staff shortages and increased clinical service or
      teaching load are discussed.

PMID- 10639836
TI  - Health research in the commonwealth Caribbean.
AB  - Health research and the dissemination of its findings are important to healthcare
      development. It is therefore useful to monitor the productivity of scientists and
      to examine the difficulties which affect their ability to conduct and publish
      research findings. This study aimed to examine these factors in six Caribbean
      countries. Health researchers publishing two or more papers in referred
      professional journals between 1987 and 1990 were interviewed to determine area of
      research, number of publications and research constraints. In those four years,
      427 first authored articles were published by those interviewed. University of
      the West Indies (UWI) researchers in the three campus territories published most
      of the articles, with little research being done in noncampus territories. Of
      seven priority areas defined by Caribbean Health Ministers, most researchers were
      interested in chronic diseases, maternal and child health, followed by nutrition
      and the acquired immunodeficiency syndrome (AIDS). There was not much research on
      human resource development and strengthening of health care systems. Major
      constraints to research were lack of resources including funding, time, staff and
      equipment. Despite this, only 54% had applied for funding. There were few posts
      for research at the UWI. Notwithstanding these constraints, researchers were
      conducting several projects simultaneously and were involved with more projects
      than would be expected from the number of publications. Many expressed the need
      for experienced advice and assistance in writing protocols and analyzing data. At
      the UWI it might be helpful to appoint a senior person or group in each
      department with specific responsibility for promoting research.

PMID- 10639837
TI  - The challenge of designing a database for auditing surgical in-patients.
AB  - Surgical audit is imperative in modern practice, particularly in the developing
      world where resources are limited and efficient allocation important. The
      structure, process and outcome of surgical care can be determined for quality
      assurance or for research. Improved efficiency and reduction of morbidity and
      mortality are additional goals which may be accomplished. However,
      computerization, medical staff cooperation and the availability of dedicated
      staff are among the hurdles which may be encountered. We report the challenge of
      designing and establishing a database for auditing surgical inpatients in a
      developing country and the difficulties which were encountered.

PMID- 10639838
TI  - The effect of Bromelia pinguin extract on the pregnant rat uterus.
AB  - A non proteinaceous extract of Bromelia pinguin fruit was examined for activity
      on the rat uterus in vivo and in vitro. The in vivo experiments involved pregnant
      rats given the extract intraperitoneally. These rats did not abort nor were any
      foetal deformities observed. The extract inhibited spontaneous activity of the
      pregnant rat uterus in vitro. These results do not support the claimed folklore
      use of the plant as an abortifacient. The extract of Bromelia pinguin fruit may
      have some utero-active compound which inhibits uterine motility.

PMID- 10639839
TI  - Alcohol, cannabis and cocaine usage in patients with trauma injuries.
AB  - Sera from 111 patients with trauma injuries, who presented to the Accident and
      Emergency Unit (A&E), University Hospital of the West Indies, during a 3-month
      period, were screened for blood alcohol. Urine specimens were analysed for
      metabolites of cannabis and cocaine. Sixty-two per cent (62%) of patients were
      positive for at least one substance and 20% for two or more. Positivity rates
      were as follows: cannabis (46%), alcohol (32%) with 71% of these having blood
      alcohol levels (BAC) greater than 80 mg per decilitre; cocaine (6%). Substance
      usage was most prevalent in the third decade of life. The patients who yielded a
      positive result were significantly younger than those who were negative. There
      was no significant difference in age or substance usage between the victims of
      interpersonal violence or road traffic accidents. In the group designated "other
      accidents", patients were significantly older and had a lower incidence of
      substance usage than the other two groups. Cannabis was the most prevalent
      substance in all groups. Fifty per cent (50%) and fifty-five per cent (55%) of
      victims of road accidents and interpersonal violence, respectively, were positive
      for cannabis compared with 43% and 27% for alcohol, respectively. There was no
      significant difference in Hospital Stay or Injury Severity Score between
      substance users and non-users.

PMID- 10639840
TI  - Emotions and psychopathology.
AB  - Few psychological assessment instruments exist for Jamaicans. Studies that
      address the appropriateness of foreign instruments for Jamaicans are sparse and
      empirical focus on psychopathology and its aetiology in Jamaican adults is
      virtually nonexistent. The present study addressed these deficits via
      Confirmatory Factor Analyses (CFA) which revealed that factors on the Toronto
      Alexithymia Scale (TAS-20) and Brief Symptom Inventory (BSI) were not replicated
      for a Jamaican sample (N = 352). Exploratory Factor Analyses (EFA) on the TAS-20
      revealed one factor labelled Unawareness and Confusion Regarding Emotions (UCRE).
      Also, EFA yielded six BSI dimensions labelled Somatic Complaints, Paranoia,
      Hostility, Mild Depression/Dysthymia, Major Depression with Psychotic Features,
      and Agoraphobia with Panic. Regression analyses on the Jamaican-based TAS-20 and
      BSI factors revealed a positive relationship between UCRE and each BSI factor and
      total BSI score. Mild Depression, Agoraphobia with Panic, Paranoia, Hostility,
      Mild Depression and Major Depression were higher for women and younger Jamaicans,
      respectively, but younger Jamaicans with higher UCRE scores had higher scores on
      Paranoia, Major Depression, and total score. The findings suggest that Jamaican
      mental health policy and programmes should focus on the difficulties some
      Jamaicans experience in recognising and expressing their emotions.

PMID- 10639841
TI  - The effects of witnessing domestic violence on behavioural problems and
      depressive symptomatology. A community sample of pupils from St Lucia.
AB  - Behavioural problems and depressive symptomatology were evaluated in a sample of
      60 St Lucian pupils who came from homes where parents were either in violent or
      non-violent marital relationships. Teachers rated pupils using the Revised
      Behaviour Problem Checklist (RBPC) while self rating scores were obtained from
      pupils using either the Reynolds Child Depression Scale (RCDS) or the Reynolds
      Adolescent Depression Scale (RADS), depending on the age of the pupil. The
      results indicated that those pupils whose parents were experiencing violent
      marital discord showed significantly higher levels of both depression and
      behavioural problems than those pupils not exposed to domestic violence. In
      addition, exposed children exhibited more behavioural problems but less
      depressive symptomatology than adolescents. The results from this study are
      consistent with those of more developed countries. The theoretical implications
      of these findings are discussed and methodological refinements are suggested for
      further research.

PMID- 10639842
TI  - Experiences and socialization of Jamaican men with multiple sex partners.
AB  - One of the goals of the Acquired Immunodeficiency Syndrome (AIDS) control
      programme in Jamaica is to encourage persons to have a single sex partner. Before
      this can be achieved in men, it is important to identify the demographic
      characteristics as well as the sexual attitudes and socialization of men who have
      multiple sex partners. A national survey was conducted on sexual decision-making
      in Jamaica in which a random sample of 3,001 persons was selected for study and
      of 2,580 (86%) interviewed 979 were men. The following analyses included the 769
      men who were sexually active. Thirty-four per cent (34%), 95% CI, 30.6-37.4%) of
      these men said that they were currently having sex with more than one woman.
      Although condom use was higher in men with multiple sex partners, 33% of them
      said that they never used condoms. Independent predictors of having multiple sex
      partners were: not being in a stable union; being raised by fathers only; and
      having a secondary school education. There was no significant association with
      church attendance or with occupation. Compared with other males, men who had
      multiple sex partners started having sex at an earlier age and were more likely
      to engage in high-risk sex behaviours such as having sex with prostitutes and
      abusing drugs prior to coitus. They were also more likely to believe in the use
      of sex as a means to control their partners and were less likely to think that
      being married or involved in a long-term relationship was important. These data
      must be taken into consideration by the AIDS control programme in Jamaica when
      formulating policies to promote monogamy. There may also be a need to implement
      parenting support or education programmes for single men who raise their sons.

PMID- 10639843
TI  - Maternal pre-pregnancy weight and placental weight determine birth weight in
      normal Jamaican infants.
AB  - Birth weight is related to neonatal health and long-term risk of chronic disease.
      Since animal studies have shown that birth outcome is related to placental
      function, the present project was designed to explore the relationship between
      birth weight and placental growth and composition with maternal factors during
      pregnancy among normal term pregnancies in 51 primiparous and 40 multiparous
      women delivering at the University Hospital of the West Indies. Both groups were
      followed from 15 weeks of gestation to term. The primiparous group was generally
      younger than the multiparous (mean age 22 +/- 4 versus 31 +/- 5 yr). They were
      significantly lighter (55 +/- 8 versus 61 +/- 9 kg) with a lower body mass index
      (21 +/- 3 versus 23 +/- 4 kg/m2) during early pregnancy, but gained more weight
      during pregnancy, 11 kg compared with 8 kg, respectively. The duration of
      pregnancy was similar for both groups. Although the size of the placenta was not
      significantly different between the two groups, the mean weight of the
      multiparous placentae was more than that of the primiparous placentae. Also, for
      all mothers both placental weight and initial maternal weight related directly to
      birth weight. Placental non collagen protein (NCP), sodium and potassium contents
      were significantly higher for multiparous women and were related to birth weight.
      The primiparous group had babies who were significantly lighter, 3.03 kg compared
      with 3.36 kg, for the multiparous and this could be attributed to differences in
      placental function and maternal weight. When account was taken of the difference
      in maternal weight at the start of pregnancy and the difference in placental
      weight, parity no longer explained any of the differences in birth weight. It is
      concluded that maternal body weight at the time of becoming pregnant and the
      early development of the placenta determine the efficiency with which nutrients
      might be delivered to the foetus and hence foetal growth. The difference in birth
      weight between primiparous and multiparous women can be explained by the
      differences in maternal weight at the time of becoming pregnant.

PMID- 10639844
TI  - Haemoglobin electrophoresis patterns in Barbados.
AB  - Despite the extensive data on haemoglobinopathies and their widespread geographic
      distribution, the number of prospective Caribbean studies which document the
      prevalence of haemoglobinopathies from birth are few. The purpose of this cohort
      study was to document the prevalence of haemoglobinopathies in newborn infants in
      Barbados. One thousand successively collected cord bloods of newborn infants were
      screened for haemoglobinopathies using the Paragon acid electrophoresis
      technique. Seventeen infants were retested at 1 year of age to confirm the
      diagnosis. Three mothers could not be located so their infants' diagnoses could
      not be confirmed. From the 997 blood samples with conclusive results, a
      haemoglobinopathy was found in 72 (7%) samples. Laboratory analysis revealed: 925
      patients (93%) with Hb AA, 41 (4%) with Hb AS, 27 (2.7%) with Hb AC, 2 (0.2%)
      with Hb SS, 1 (0.1%) with Hb CC and 1 (0.1%) with Hb SC. The prevalence of the
      sickle gene and number of cases of Sickle Cell anaemia in the Barbadian
      population is less than has been reported from other regional territories.

PMID- 10639845
TI  - Some clinical factors contributing to the development of the diabetic foot.
AB  - Clinical neurological studies, blood pressure measurements and some
      haematological investigations were performed on a random sample of forty-four
      patients, at the Diabetes Out-Patient Clinic of the University Hospital of the
      West Indies (UHWI), to examine some of the factors that predispose to the
      development of the diabetic foot. Our results revealed that 86% of the patients
      had elevated glycosylated haemoglobin (HbA1 > 9.0%), 82% had clinical signs of
      peripheral sensory neuropathy, 29% had signs of autonomic neuropathy in addition
      to peripheral sensory neuropathy. Sixty-one per cent (61%) of the patients had
      ankle/arm systolic blood pressure ratio less than 1.0 and were diagnosed as
      having peripheral vascular disease (PVD). The group with neuropathy was found to
      have a significantly lower diastolic blood pressure (p < 0.0005) than the group
      without neuropathy. We believe that hyperglycaemia-induced vasodilation
      (indicated by a lower diastolic blood pressure) in a significant number of
      diabetics resulted in compensatory shunting of blood from the deeper tissues,
      including nerves, to the periphery. The resulting endoneural hypoxia could be
      responsible for the unusually high incidence of peripheral sensory neuropathy
      detected in this sample of diabetic patients. Metabolic factors may also play a
      role.

PMID- 10639846
TI  - Inoculation injuries in hospitals in Trinidad and Tobago.
AB  - This paper reviews the frequency of inoculation injuries, which occurred in
      hospitals in Trinidad and Tobago from 1991 to 1997, inclusive. A total of 397
      cases of inoculation injuries were detected. Significantly more of these injuries
      occurred during diagnostic or therapeutic procedures (231, or 58.2%; G = 41.2, df
      9, p < 0.001) than during disposal of needles and other sharps (136, or 34.3%),
      certain situations remote from patient care (21, or 5.2%), and 'rogue incidents'
      related to unsafe disposal with later injury to janitors or others (9, or 2.3%).
      No statistically significant monthly or seasonal variations occurred in the
      incidence of reported inoculation injuries. The two institutions that saw the
      largest number of patients, the Port-of-Spain General and San Fernando General
      Hospitals, accounted for the largest number of cases of inoculation injury, with
      139 (35.0%) and 135 (34.0%), respectively. Interestingly enough, there were 42
      reported inoculation incidents at the St. Ann's Hospital for the Mentally
      Impaired and 23 (52.5%) of these were bites, most of them occurring during
      attempted procedures. Nurses were the main recipients of inoculation injuries
      (287 cases, or > 72%), followed by doctors (9.3%), and ward maids (6.2%). The
      main modes of inoculation were needle sticks (305, or 76.8%). Bites (34, 8.6%),
      injuries with sharps other than needles (29, or 7.3%), and splashes (29, or 7.3%)
      were the other types seen. One recipient was found to be infected with HIV
      following accidental inoculation. The infection control methodologies used in
      hospitals in Trinidad and Tobago are reviewed and recommendations for preventing
      injuries are outlined.

PMID- 10639847
TI  - Ivermectin treatment of mansonellosis in Trinidad.
AB  - This study was conducted to determine the efficacy and long-term effects of an
      intervention programme based on a single dose of Ivermectin (6 mg) administered
      during a double-blind placebo study of 40 persons with Mansonella ozzardi
      infections in Blanchisseuse, Trinidad. After four years, ivermectin reduced
      microfilariae levels by 82.2%. Short- and long-term effectiveness of the drug is
      contingent upon the initial microfilariae levels of the patient. We conclude that
      a single dose of ivermectin reduces microfilariae densities and provides both
      short- and long-term reductions in M ozzardi microfilaraemia.

PMID- 10639848
TI  - Testicular metastases from carcinoma of the prostate.
AB  - Secondary testicular tumours are uncommon and most originate from prostatic
      carcinoma. A retrospective study of the clinico-pathological features of
      prostatic carcinoma metastatic to the testes was conducted in the Department of
      Pathology, University of the West Indies, Jamaica, for the period June 1958 to
      January 1998. Metastatic prostatic carcinoma was seen in 1.4% of the 284
      orchiectomy specimens examined. A brief review of the literature related to this
      entity was undertaken.

PMID- 10639849
TI  - Severe aplastic anaemia--complete response to antilymphocyte globulin and
      cyclosporin.
AB  - Severe aplastic anaemia is uniformly fatal unless treated with immunosuppressive
      therapy or bone marrow transplantation. The latter is curative in 65% of patients
      and is the treatment of choice in children and young adults. Antilymphocyte
      globulin (ALG) and cyclosporin may be used successfully in the absence of an HLA
      matched sibling donor. We report the case of a twelve-year-old boy with severe
      aplastic anaemia who received immunosuppressive treatment with ALG and
      cyclosporin and is alive and well three years and six months post treatment.

PMID- 10639850
TI  - Successful pregnancy by intracytoplasmic sperm injection after radiotherapy
      induced azoospermia.
AB  - A 27-year-old male, who underwent excision and radiotherapy for a pineal gland
      germinoma four years previously, subsequently developed panhypopituitarism and,
      thus, complete azoospermia. Gonadotrophin replacement therapy resulted in the
      production of a small number of motile spermatozoa which were used for
      Intracytoplasmic Sperm Injection (ICSI) into oocytes obtained from his wife.
      After successful fertilization and embryo transfer, a singleton intrauterine
      pregnancy was achieved which resulted in the normal delivery of a morphologically
      normal male live infant at term.

PMID- 10639851
TI  - The prophylaxis of acute rheumatic fever in a pair of monozygotic twins. The
      public health implications.
AB  - Recurrent acute rheumatic fever and rheumatic heart disease can be prevented by
      antibiotic intervention. We report the case of genetically identical twins, one
      of whom had overt rheumatic fever, received penicillin prophylaxis and did not
      have rheumatic heart disease. The other must have had inapparent rheumatic fever,
      received no chemotherapy prophylaxis and proceeded to develop rheumatic heart
      disease. A greater clinical and laboratory vigilance is required for the
      diagnosis of acute rheumatic fever in the asymptomatic identical twin of a
      patient with rheumatic fever. This case provides further evidence of a genetic
      predisposition to rheumatic fever and demonstrates the continued value of
      penicillin in the prophylaxis of acute rheumatic fever. It emphasises the need to
      maintain the integrity of preventive programmes against rheumatic fever
      worldwide. Studies which explore the HLA and other genetic linkages with
      rheumatic fever should be encouraged.

PMID- 10639852
TI  - Female adnexal tumour of probable wolffian origin.
AB  - We report a case of female adnexal tumour of probable wolffian origin, a rare
      tumour of the broad ligament, and discuss aspects of its origin, differential
      diagnosis and behaviour.

PMID- 10639854
TI  - Allergy in the anglophone Caribbean.

PMID- 10639853
TI  - Clinicopathological conference. Nephroblastoma (Wilms tumour) with diffuse
      anaplasia and lymph metastasis.

PMID- 10639855
TI  - The physician as detective.

PMID- 10639856
TI  - Practical solutions for healthcare issues in children should be acted upon.

PMID- 10639857
TI  - Emerging and re-emerging vector-borne diseases in the Caribbean region.

PMID- 10639858
TI  - Positron emission tomography scanning for the early diagnosis of dementia.

PMID- 10639859
TI  - Positron emission tomography for the early diagnosis of dementia.

PMID- 10639860
TI  - The politics and prevention of gun violence.

PMID- 10639861
TI  - Physicians' unions must be able to strike.

PMID- 10639862
TI  - Physicians for responsible negotiations will be heard.

PMID- 10639863
TI  - Aspartame and breast and other cancers.

PMID- 10639864
TI  - Modern obstetrics and female life span.

PMID- 10639865
TI  - Questionnaire survey of California consumers' use and rating of sources of health
      care information including the Internet.
AB  - OBJECTIVE: To understand how Californians use and rate various health information
      sources, including the Internet. RESEARCH DESIGN: Computer-assisted telephone
      interviews through which surveys were conducted in English or Spanish. SUBJECTS:
      A household sample generated by random digit dialing. The sample included 1007
      adults (18+), 407 (40%) of whom had access to the Internet. MAIN OUTCOME
      MEASURES: Past health information sources used, their usefulness and ease of use;
      future health information sources, which are trusted and distrusted; and concerns
      about integrating the Internet into future health information seeking and health
      care behaviors. RESULTS: Physicians and health care providers are more trusted
      for information than any other source, including the Internet. Among those with
      Internet access, a minority use it to obtain health information, and a minority
      is "very likely" to use e-mail to communicate with medical professionals or their
      own doctors and nurses, to refill prescriptions, or to make doctor appointments.
      Also, most of those with Internet access are "unlikely" to make their medical
      records available via the Internet, even if securely protected. CONCLUSIONS: The
      public, including frequent Internet users, has major concerns about the
      confidentiality of electronic medical records. Legislation may not assuage these
      fears and a long-term, open and collaborative process involving consumers and
      organizations from all the health care sectors may be needed for full public
      assurance.

PMID- 10639866
TI  - Rejoice and help patients get the best from the World Wide Web.

PMID- 10639867
TI  - Don't blame the patients.

PMID- 10639868
TI  - Bright light and high-density negative air ionization reduces symptoms of
      seasonal affective disorder.

PMID- 10639869
TI  - Family disadvantages in early life are associated with depression in adulthood.

PMID- 10639870
TI  - Traditional child psychotherapy does not reduce psychopathology when compared
      with academic tutoring.

PMID- 10639871
TI  - Detecting coronary calcification with electron beam computed tomography: its role
      in managing coronary artery disease.

PMID- 10639872
TI  - How much will it cost?

PMID- 10639873
TI  - Topical corticosteroids: back to basics.

PMID- 10639874
TI  - Poison ivy, oak, and sumac dermatitis.

PMID- 10639875
TI  - How accurate is a CT scan in identifying acute strokes?

PMID- 10639876
TI  - A red twisted ankle.

PMID- 10639877
TI  - Building and testing an effective HIV vaccine.

PMID- 10639878
TI  - What about the ethics?

PMID- 10639879
TI  - Training future hospitalists.

PMID- 10639880
TI  - The joys of being a hospitalist.

PMID- 10639881
TI  - The hospitalist and the care of the patient.

PMID- 10639882
TI  - Serving native health needs: merging technology and traditional information
      services.

PMID- 10639883
TI  - Genes and generalists: why we need professionals with added competencies.

PMID- 10639884
TI  - Viagra makes flowers stand up straight.

PMID- 10639885
TI  - In response to MetaStar's comment.

PMID- 10639886
TI  - Who manages care?

PMID- 10639887
TI  - Foundation strives to make difference in women's health.

PMID- 10639889
TI  - Boning up on osteoporosis.
AB  - Osteoporosis may have once been considered just another harbinger of the aging
      process, like liver spots, gray hair and big ears. But few aging Americans today
      will stand for it, literally and figuratively, now that there are various
      treatment alternatives at hand, and more on the way, thanks to medical advances
      in diagnostics and therapeutics. Baby boomers will be not only the largest,
      oldest cohort this nation--perhaps the world--has ever seen, they will also be
      the most active. And, they will be insistent and vocal about receiving medical
      care that allows them to fulfill their elder years with myriad pursuits;
      activities which will require mobility and pain-free living as much as possible.
      "No doubt osteoporosis will become a bigger health care issue," said Dr. Fagan.
      "We still don't think of it in the same category as heart disease and cancer, I
      guess because it is not lethal right away. But we have to recognize that it has
      serious medical implications that can lead to a downward spiral of medical
      problems that can mean the need for extended nursing care or prolonged illness.
      Those who suffer from it acutely can hardly do anything for themselves. People
      with spinal fractures are miserable with pain and a good hip fracture will take
      eight weeks healing time. Preventing these types of fractures by controlling bone
      loss is a basic health issue--a real quality of life issue--that we need to be
      addressing."

PMID- 10639888
TI  - Health care in the US: is there evidence for systematic gender bias?

PMID- 10639890
TI  - Osteoporosis. Patient awareness & choices key to prevention.

PMID- 10639891
TI  - Gender differences in acute myocardial infarction: the University of Wisconsin
      experience.
AB  - OBJECTIVE: To investigate gender differences in baseline characteristics,
      presentation, and treatment of patients with acute myocardial infarction (MI)
      admitted to the University of Wisconsin Hospital Coronary Care Unit (CCU) over a
      1-year period. METHODS: A retrospective review was performed on the charts of all
      patients (n = 293) admitted to the CCU in 1996 with a discharge diagnosis of
      acute MI. In 83 women and 187 men with analyzable data (n = 270), 42 factors
      related to baseline characteristics, presentation, treatment, and outcomes were
      identified and analyzed for gender differences. RESULTS: On average, women were 5
      years older than men (p < .01). By univariate comparison, women were less likely
      than men to be smokers (p < .001); more likely to have underlying hypertension (p
      < .01), diabetes mellitus (p < 0.05), non-Q-wave infarctions (p < .01), and
      congestive heart failure (CHF, p < .05); and more likely to have received
      diuretics (p < .001) and ACE inhibitors (p < .01). While women were less likely
      than men to undergo coronary angiography (p < .05) and more likely to have
      echocardiograms (p < 0.05), rates of coronary artery bypass graft surgery,
      angioplasty, and the use of thrombolytics were similar for men and women.
      Clinical outcomes were similar in both groups. CHF, hypertension, and use of ACE
      inhibitors remained the only significant gender differences when data were
      adjusted for age. CONCLUSION: Comparing men and women with acute MI at UW
      Hospital revealed some differences in clinical characteristics and management.
      Except for CHF, hypertension, and use of ACE inhibitors (all of which may be
      related), these differences disappeared when the data were adjusted for age. This
      is particularly notable for the disappearance of the difference in the use of
      coronary angiography between men and women. The comparable use of beta-blockers,
      aspirin, and nitrates, and the similar clinical outcomes in men and women,
      suggest less gender difference in MI management at UW Hospital than reported in
      other studies.

PMID- 10639892
TI  - Osteoporosis risk assessment by family practice faculty and residents: a chart
      review.
AB  - OBJECTIVE: To assess the frequency of osteoporosis risk assessment of
      postmenopausal women by family practice faculty and residents. METHODS: Review of
      263 charts of women over 50 from 3 residency clinics. Charts were evaluated for
      evidence of osteoporosis risk assessments or discussion of prevention strategies
      during the past 2 years. RESULTS: Overall, 35% of the charts contained
      documentation of some discussion of osteoporosis. Female physicians discussed
      osteoporosis more than their male colleagues (p < 0.05). Documentation of
      osteoporosis discussions decreased as women aged (p < 0.05). There was no
      difference in rates among clinics or between residents and faculty. CONCLUSIONS:
      The documentation of osteoporosis discussions with high risk women was low in
      this sample. Strategies to improve osteoporosis screening are necessary.

PMID- 10639893
TI  - Increasing gap in breast cancer mortality between black and white women.
AB  - Breast cancer mortality rates have declined in the United States and in
      Wisconsin. We examined racial differences in mortality trends among black and
      white women in Wisconsin and the United States from 1979 to 1996. During this
      time period, mortality rates increased 10% among black women and decreased 7%
      among white women in Wisconsin. These trends were similar nationally, with an 18%
      increase among black women and a 3% decrease among white women. The black:white
      gap in mortality increased among women of all ages--especially among women under
      age 55. The increasing racial disparity in breast cancer mortality may result
      from differences in trends in incidence and survival among black women. More
      research is needed to understand the underlying causes of the disparity in breast
      cancer mortality between black and white women.

PMID- 10639894
TI  - Gender differences in hallway ambulation by older adults hospitalized for medical
      illness.
AB  - Bed rest during hospitalization predisposes patients to declines in balance,
      strength, and bone mass, and may contribute to falls and fractures after
      discharge. Periodic ambulation may help prevent these adverse consequences.
      However it is unknown to what extent men and women ambulate during
      hospitalization. We observed hallway ambulation by adults age 55 and over
      hospitalized on 3 medical units of the University of Wisconsin Hospital. Hallways
      were observed during 24 three-hour periods covering the interval from 8 AM to 8
      PM. Prior to each 3-hour observation, nursing staff were asked about
      characteristics of older patients who were able to ambulate in the hallways.
      Results showed that women spent significantly less time ambulating compared to
      men (1.6 versus 4.2 minutes per 3-hour period, p = .047), and were less likely to
      walk independent of hospital staff (10.4% versus 23.5%, p = .049). If these
      findings of gender differences in mobility are validated in other studies, they
      imply that in-hospital rehabilitation programs may need to particularly target
      women.

PMID- 10639895
TI  - Gender disparities in mortality trends, Wisconsin, 1980-1995.
AB  - One of the major goals of Healthy People 2000 is to reduce health disparities
      among Americans. All-cause death counts and mortality rates for Wisconsin by age
      and gender were obtained by accessing the Centers for Disease Control's (CDC)
      mortality information via WONDER, the CDC's web-based link to its databases.
      Mortality trends from 1980 to 1995 were assessed by gender and age overall, and
      for the leading causes of death. Indirect age standardization was used to assess
      changes in the mortality rates. From 1980 to 1995, mortality rates declined for
      males and females and in every age group in Wisconsin, leading to almost 5000
      fewer deaths than expected in 1995. Although mortality rates continue to be
      higher among males in every age group, the rates are declining twice as fast
      among males (13%) than females (7%). There were 3721 fewer deaths among males,
      accounting for about 75% of the decline in deaths. This disparity resulted from
      differences in mortality trends from motor vehicle accidents and HIV among young
      adults and cardiovascular disease and cancer among older adults. Public health
      needs to carefully monitor mortality trends to assure that progress in disease
      prevention is achieved for males and females of all ages.

PMID- 10639896
TI  - Emphysematous cystitis: a case report.

PMID- 10639897
TI  - Hyperhomocysteinemia: an additional cardiovascular risk factor.
AB  - Over the past few years, a substantial body of evidence has accumulated that
      indicates hyperhomocysteinemia as a significant risk factor for cardiovascular
      disease. Hyperhomocysteinemia arises from a lack of key enzymes or vitamins such
      as methylenetetrahydrofolate reductase, vitamin B6, and folate which are involved
      in homocysteine metabolism. Heavy coffee consumption is also known to elevate
      homocysteine levels. The adverse effects associated with hyperhomocysteinemia are
      extensive. It increases risk of myocardial infarction, cardiovascular-related
      morbidity and mortality, peripheral vascular disease, atherosclerosis, coronary
      heart disease, and cerebrovascular disease. Its seriousness as a risk factor has
      been equated to hypercholesterolemia and smoking, two leading causes for
      cardiovascular disease. It also has been shown to produce a multiplicative effect
      with these and other risk factors such as hypertension. Two major hypotheses have
      been proposed to explain how homocysteine induces its harmful effects. It can
      damage endothelial cells lining the vasculature, allowing plaque formation.
      Simultaneously, it interferes with the vasodilatory effect of endothelial derived
      nitric oxide. Also, homocysteine has been found to promote vascular smooth muscle
      cells hypertrophy. Both of these processes induce vessel occlusion. Maintaining a
      normal plasma level of homocysteine as a means to prevent cardiovascular disease
      appears promising. This is achieved through increased intake of folate and
      vitamin B6 through diet or supplementation. Despite the overwhelming evidence
      suggesting homocysteine as a significant risk factor, no long-term prospective
      studies have been completed to demonstrate that folate and vitamin B6 can prevent
      cardiovascular disease related morbidity and mortality in patients with
      hyperhomocysteinemia. Homocysteine is a key metabolite in amino acid synthesis.
      During the process of methylation, S-adenosylmethionine (Ado Met), derived from
      methionine, is converted to S-Adenosylhomocysteine (Figure 1). This product is
      quickly hydrolyzed to form homocysteine and adenosine. Homocysteine can undergo 1
      of 3 reactions depending on the status of the organism. If cysteine levels are
      inadequate, homocysteine utilizes the coenzyme pyridoxal phosphate (vitamin B6)
      to condense with serine, forming the intermediate cystathionine. Subsequent
      reactions with cystathionine lead to the formation of cysteine. When methionine
      levels are low, homocysteine is remethylated in a reaction involving the coenzyme
      N5-methyltetrahydrofolate or betaine. Finally, when both amino acids are in
      adequate supply, homocysteine is cleaved by the enzyme homocysteine desulthydrase
      (cystathionase) to form a-ketobutyrate, ammonia, and H2S. Thus, homocysteine's
      physiological role is to assist in maintaining sulfur-amino acid homeostasis.
      Beyond these metabolic processes, homocysteine is beginning to be recognized as a
      significant risk factor for cardiovascular disease including atherosclerosis,
      coronary artery disease, cerebrovascular disease, and myocardial infarction.

PMID- 10639898
TI  - Wisconsin law banning 'partial-birth' abortion in flux.

PMID- 10639899
TI  - MetaStar set to undertake new quality initiatives.

PMID- 10639900
TI  - Creating much more than a medical school.

PMID- 10639901
TI  - Human morphology and temperature regulation.
AB  - For nearly a century individuals have believed that there is a link between human
      morphology and one's thermoregulatory response in adverse environments. Most
      early research was focussed on the rate of core cooling in a male adult
      population and the role of subcutaneous adipose tissue, surface area and the
      surface-area-to-mass ratio in one's ability to withstand varying degrees of cold
      stress. More recently research has addressed heat tolerance in various
      populations, exploring the role of subcutaneous adipose tissue, surface area and
      the surface-area-to-mass ratio in one's ability to maintain thermal equilibrium
      in warm and hot, dry and humid environments. Since the late 1970s an emphasis has
      been placed on the role of muscle and muscle perfusion in total-body thermal
      insulation. Yet, despite the history of research pertaining to human morphology
      and temperature regulation there is little consensus as to the impact of
      variations in human morphology on thermoregulatory responses. Individuals
      differing in body size, shape and composition appear to respond quantitatively
      differently to variations in both ambient and core temperatures but the
      interrelations between morphological components and temperature regulation are
      complex. It is the purpose of this paper to examine the literature pertaining to
      the impact of variations in muscularity, adipose tissue thickness and patterning,
      surface area and the surface-area-to-mass ratio on thermoregulation and thermal
      stability in response to both heat and cold stress.

PMID- 10639902
TI  - Environmental impacts on offspring survival during the lambing period in central
      Patagonia.
AB  - Weather conditions are the main factors affecting the survival rate of newborn
      lambs. In the windy climate of Patagonia, the influence of weather conditions is
      exacerbated as the wind speed increases noticeably in spring. If the wind
      increases faster than the temperature rises, wind chill conditions worsen
      temporarily. This departure from the predictable improvement in bioclimatic
      conditions as the season moves towards summer may coincide with lambing, if this
      is not adequately regulated. This paper explores bioclimatic conditions during
      the 2-month period in which lambing may take place (i.e. mid-September to mid
      November), and identifies the unfavourable period that occurs in the second
      fortnight of October. Starting from the Mount and Brown (Agric Meteorol 27:241
      255, 1982) model to assess thermal stress in sheep by means of common
      meteorological records, a simpler model was developed employing in long-term
      records. For 2-week averages of temperature (Tf), wind speed (Vf) and total
      precipitation (Pf), the average heat loss in sheep (HLf) was 40.40 - 2.07Tf +
      5.64Vf + 0.04Pf. (r2 = 0.95). A 24-year series of Tf, Vf and Pf data was employed
      in the calculation of HLf, and results showed this parameter was significantly
      higher in the second fortnight in October. HLf values were classified into four
      groups (from "very good" to "very bad" conditions); once again, significant
      differences appeared in the second fortnight in October. Finally, HLf during the
      lambing period was correlated to the percentage of lambs surviving 2 months
      later. Significant differences between the survival of lambs born under "very
      bad" and "very good" conditions were found, but intermediate HLf conditions did
      not show a clear pattern. The survival rate was best correlated to HLf in the
      fortnight preceding lambing (P < 0.05). This suggests that bioclimatic conditions
      during late pregnancy are at least as important as conditions during lambing in
      determining the survival lambs.

PMID- 10639903
TI  - Thermoregulatory responses to acute heat loads in the FOK rat.
AB  - FOK is an inbred rat strain with a genotypic adaptation to hot environments. The
      present study investigated the mechanism of the high heat tolerance of the FOK
      rat. Male FOK and WKAH rats were used. They were loosely restrained and placed
      individually in a direct calorimeter with an ambient temperature of 24 degrees C.
      Their hypothalamic temperature, evaporative and non-evaporative heat loss and
      heat production were measured. After thermal equilibrium had been attained, the
      rats were warmed for 30 min with a chronically implanted intraperitoneal electric
      heater (internal heating). At least 90 min after the heating, the jacket water
      temperature surrounding the calorimeter chamber was gradually raised from 24
      degrees C to 36 degrees C in 80 min (external warming). During the internal
      heating, changes in the thermoregulatory parameters did not differ between the
      groups. During the external warming, the evaporative heat loss of the FOK rat was
      significantly greater than that of the WKAH rat, while changes in nonevaporative
      heat loss and heat production did not differ between the groups. The results
      suggest that in the FOK rat, the improved heat tolerance is attributable to an
      enhanced evaporative heat loss response, but not to a facilitation of
      nonevaporative heat loss or of metabolic depression.

PMID- 10639904
TI  - Deaths from heat-stroke in Japan: 1968-1994.
AB  - Global warming is increasingly recognized as a threat to the survival of human
      beings, because it could cause a serious increase in the occurrence of diseases
      due to environmental heat during intermittent hot weather. To assess the direct
      impact of extremely hot weather on human health, we investigated heat-related
      deaths in Japan from 1968 through 1994, analyzing the data to determine the
      distribution of the deaths by age and their correlation to the incidence of hot
      days in summer. Vital Statistics of Japan, published by the Ministry of Health
      and Welfare of Japan, was the source of the heat-related mortality data employed
      in this study. Meteorological data were obtained from the District Meteorological
      Observatories in Tokyo and Osaka, the two largest cities in Japan. Heat-related
      deaths were most prone to occur on days with a peak daily temperature above 38
      degrees C, and the incidence of these deaths showed an exponential dependence on
      the number of hot days. Thus, even a small rise in atmospheric temperature may
      lead to a considerable increase in heat-related mortality, indicating the
      importance of combating global warming. Furthermore, half (50.1%) of the above
      noted deaths occurred in children (4 years and under) and the elderly (70 years
      and over) irrespective of gender, indicating the vulnerability of these specific
      age groups to heat. Since a warmer climate is predicted in the future, the
      incidence of heat waves will increase, and more comprehensive measures, both
      medical and social, should be adopted for children of 4 years and younger the
      elderly to prevent heat-related deaths in these age groups.

PMID- 10639905
TI  - Ambient ultraviolet radiation levels in public shade settings.
AB  - As people become better informed about the harmful effects of prolonged exposure
      to solar ultraviolet radiation (UVR, 280-400 nm) they will seek the protection of
      shade, particularly in tropical locations such as Townsville (19 degrees south).
      Using broad-band radiation sensors for solar ultraviolet-B (280-315 nm),
      ultraviolet-A (315-400 nm) and daylight (400-800 nm) radiation, the exposure
      levels were measured in both the horizontal (shaded and unshaded) and vertical
      (shaded and unshaded) directions. The measurements were conducted at eight
      locations (shade settings) in Townsville during the period between December 1997
      (summer) and May 1998 (beginning of winter). The quality of protection was
      assessed by the ratio of unshaded to shaded radiation exposure, the UVB/shade
      protection ratio (UVB-SPR). The UVB-SPR varies considerably between the different
      shade settings, with a beach umbrella showing the least protection and dense
      foliage the highest protection. The roof of a house verandah can provide only
      little protection if the verandah catches the afternoon sun. Increasing cloud
      cover decreases the UVB-SPR for all settings because of the increase in the
      diffuse fraction of the radiation. Only one setting provided a UVB-SPR of 15 or
      higher, as suggested for protective shading against solar UVB radiation. Shade
      from direct sunlight alone does not provide enough protection against high levels
      of solar UVR. Apart from the transmission qualities of the shading material, it
      is the construction of the whole shade setting that determines the exposure
      levels underneath. A shade structure with enough overhang is recommended so that
      high levels of scattered radiation do not reach the skin.

PMID- 10639906
TI  - Comparisons of urban and rural bioclimatological conditions in the case of a
      central-European city.
AB  - This paper examines the influence of a medium-sized city (Szeged, Hungary) on the
      bioclimatological conditions of human beings. With the help of suitable indices
      for the available data set, differences in the annual and diurnal variation of
      human bioclimatic characteristics between an urban and rural environment are
      evaluated over a 3-year period. These indices are the thermohygrometric index
      (THI, defined by air temperature and relative humidity), the relative strain
      index (RSI, defined by air temperature and vapour pressure) and the number of
      "beergarden days" (defined by air temperature at 2100 hours). In urban and rural
      areas, "hot" THI conditions characterize 6% and 1% of the year, "comfortable"
      conditions 30% and 20%, "cool" conditions 10% and 12%, and "cold" conditions 54%
      and 66% respectively. Over longer periods (e.g. one, month) RSI remains below the
      threshold value for strong heat stress in the city. The monthly frequencies of
      beergarden days show that these days appears from May until October and the city
      has almost twice as many pleasant evenings as the rural areas. Consequently, the
      city favourably modifies the main climatological elements within the general
      climate of its region; periods likely to be comfortable are therefore found more
      frequently in the city than in rural areas.

PMID- 10639907
TI  - Social support, social stressors at work, and depressive symptoms: testing for
      main and moderating effects with structural equations in a three-wave
      longitudinal study.
AB  - This study investigated the moderating effects of social support by supervisors
      and colleagues relative to social stressors at work and depressive symptoms using
      a structural equations approach in a 3-wave longitudinal study over 1 year. The
      analyses were based on a randomly drawn sample (N = 543) of citizens in the area
      around Dresden in the former East Germany. LISREL analysis with latent moderating
      effects revealed a moderating effect for supervisor support. This applied only if
      the time lag was 8 months, but not for longer or shorter lags. Under low-support
      conditions depressive symptoms were increased by social stressors, whereas,
      contrary to expectations, social stressors reduced subsequent depressive symptoms
      under high-support conditions. No moderating effect for colleague support was
      found. Several mechanisms are discussed that may explain the results.

PMID- 10639908
TI  - Goal commitment and the goal-setting process: conceptual clarification and
      empirical synthesis.
AB  - Goals are central to current treatments of work motivation, and goal commitment
      is a critical construct in understanding the relationship between goals and task
      performance. Despite this importance, there is confusion about the role of goal
      commitment and only recently has this key construct received the empirical
      attention it warrants. This meta-analysis, based on 83 independent samples,
      updates the goal commitment literature by summarizing the accumulated evidence on
      the antecedents and consequences of goal commitment. Using this aggregate
      empirical evidence, the role of goal commitment in the goal-setting process is
      clarified and key areas for future research are identified.

PMID- 10639909
TI  - Unemployed individuals: motives, job-search competencies, and job-search
      constraints as predictors of job seeking and reemployment.
AB  - This study investigated 3 broad classes of individual-differences variables (job
      search motives, competencies, and constraints) as predictors of job-search
      intensity among unemployed job seekers. Also assessed was the relationship
      between job-search intensity and reemployment success in a longitudinal context.
      Results show significant relationships between the predictors employment
      commitment, financial hardship, job-search self-efficacy, and motivation control
      and the outcome job-search intensity. Support was not found for a relationship
      between perceived job-search constraints and job-search intensity. Motivation
      control was highlighted as the only lagged predictor of job-search intensity over
      time for those who were continuously unemployed. Job-search intensity predicted
      Time 2 reemployment status for the sample as a whole, but not reemployment
      quality for those who found jobs over the study's duration.

PMID- 10639910
TI  - Minimizing strain and maximizing learning: the role of job demands, job control,
      and proactive personality.
AB  - Using a sample of 268 production employees, this study extended research on R.
      Karasek's (1979) demands-control model of stress in 2 ways. First, results show
      that R. Karasek's proposed interaction between demands and control when
      predicting strain occurred only for more proactive employees. This 3-way
      interaction helps reconcile previous inconsistent findings about the interaction
      between demands and control when predicting strain. Second, the study extends
      research by investigating the demands-control interaction and the moderating
      influence of proactive personality in relation to learning-oriented outcomes
      (perceived mastery, role breadth self-efficacy, and production ownership). There
      were no 3-way interactions among the variables when predicting these learning
      oriented outcomes, but all were important predictors. These results show (a) that
      demands and control can influence learning as proposed in the dynamic version of
      the demands-control model and (b) that proactive personality plays an important
      moderating role.

PMID- 10639911
TI  - The development, validation, and application of a video-based technique for
      measuring an everyday risk-taking behavior: drivers' speed choice.
AB  - Drivers' choice of speed is an important aspect of everyday risk-taking behavior
      because it has been shown to be one of the most important predictors of road
      accident involvement. This research developed, validated, and applied a measure
      of drivers' speed choice that combined a high degree of experimental control with
      external and ecological validity. In Study 1, a video-simulation measure of
      drivers' speed choice was developed and found to relate specifically to speed
      related accident involvement, implying a degree of external validity. In Study 2,
      the measure was used to investigate the effect of auditory feedback on drivers'
      speed choice. It was found that increasing the level of internal car noise
      decreased drivers' preferred speeds. Further analyses indicated that this was
      likely due to perceptual effects on speed estimation. Results are discussed in
      terms of road safety and the ability of video-based measures to facilitate
      experimental control over tasks involving complex ecological stimuli.

PMID- 10639912
TI  - Collaborative research: the art of negotiation.

PMID- 10639913
TI  - Distraction, imagery, and hypnosis. Techniques for management of children's pain.

PMID- 10639914
TI  - Planning educational services for children who are ventilator assisted.

PMID- 10639915
TI  - Sleep disturbances in children with attention-deficit/hyperactivity disorder.

PMID- 10639916
TI  - Nurses' involvement in interdisciplinary team evaluations: incorporating the
      family perspective into child assessment.

PMID- 10639917
TI  - Instruments for research with families. The Family Environment Scale (FES) and
      Feetham's Family Functioning survey (FFFS).

PMID- 10639918
TI  - Pediatric Web. Professional journals.

PMID- 10639919
TI  - Selecting a graduate program.

PMID- 10639920
TI  - Cost studies/value outcomes.

PMID- 10639921
TI  - USP recommends. Children and adolescents have a right to information and direct
      communications about medicines. U.S. Pharmacopeia.

PMID- 10639922
TI  - The culture of childhood.

PMID- 10639924
TI  - Satisfaction with health care: the adolescent's perspective.

PMID- 10639923
TI  - Culturally competent nursing research: are we there yet?

PMID- 10639925
TI  - Nervous habits and stereotyped behaviors in preschool children.

PMID- 10639926
TI  - Child development, molecular genetics, and what to do with genes once they are
      found.

PMID- 10639927
TI  - Developing reciprocal trust in the caregiving relationship.

PMID- 10639928
TI  - Parents' developmental expectations and child characteristics: longitudinal study
      of children with developmental delays and their families.

PMID- 10639929
TI  - Depression and conduct disorder in Native and non-Native children.

PMID- 10639930
TI  - Validity of DSM-IV attention deficit/hyperactivity disorder for younger children.

PMID- 10639931
TI  - Managed care and children: an overview.

PMID- 10639932
TI  - Writing a good read: strategies for representing qualitative data.

PMID- 10639933
TI  - Graduate student-faculty collaboration in research and publication.

PMID- 10639935
TI  - Professional journals. Pediatric and child health journals: Part 2.

PMID- 10639934
TI  - Watch out! The bogeyman is in the hospital closet. Measurement of children's
      medical fears.

PMID- 10639936
TI  - Patient surveys.
AB  - Clinicians continuously gather patient-related information. Histories and
      physicals, vital signs, lab results, and behavioral descriptions are all part of
      standard care. In recent years it has also proven advantageous to gather
      information regarding patient knowledge and satisfaction with the care they
      receive at our ambulatory and inpatient settings. This article reviews the
      process of conducting patient surveys throughout the continuum of care. Both the
      timing of the survey and the format are described in Table 1.

PMID- 10639937
TI  - When professional issues become personal. Domestic violence strikes close to
      home.

PMID- 10639938
TI  - Society for Adolescent Medicine. Position paper: adolescents and firearms.

PMID- 10639939
TI  - The occupational and environmental nurse in the hospital setting.

PMID- 10639940
TI  - Histology and pathology laboratories. Chemical hazard prevention and
      medical/health surveillance.
AB  - 1. Hospital employees often do not recognize the chemical hazards that exist in
      their work environment. 2. Formaldehyde and xylene are common hazards in
      histology and pathology laboratories. Occupational and environmental health
      nurses need to be familiar with the health effects that may result from exposure
      to these chemicals. 3. Although xylene does not have medical/health surveillance
      requirements set by OSHA, medical evaluation of employees exposed to xylene above
      the action level is effective occupational and environmental health practice. 4.
      Formaldehyde exposed employees require medical/health surveillance. Occupational
      and environmental health nurses need to be familiar with how to implement and
      manage a formaldehyde surveillance program.

PMID- 10639941
TI  - Implementing a latex safe environment in a hospital setting. Case study.
AB  - 1. Change is a difficult process. Using a change model as a guide to implementing
      change can make the process easier. 2. Hospitals work well using the team
      approach to accomplishing change. Representation from all key areas of the
      hospital is essential. 3. It is important to educate resisters regarding the
      benefit and need for change. The strongest opponents can become the strongest
      leaders in the change process. 4. Education cannot be underestimated. It is
      essential to use formal and informal means to educate all personnel.

PMID- 10639942
TI  - Application of the ADA in the workplace. Employment issues.
AB  - 1. Employers have many regulations to follow in relation to ADA compliance. 2.
      Health inquiries are acceptable post-offer and prior to the start of work.
      Inquiries must be the same for all employees in a job category. 3. Health
      inquiries conducted after employment commences have to be based on business
      necessity.

PMID- 10639943
TI  - Hepatitis C. An emerging dilemma.
AB  - 1. Occupational health nurses have the responsibility to educate their clients
      about hepatitis C as a growing public health threat. 2. Occupational health
      nurses have the responsibility to keep their clients up to date on the latest
      treatment modalities. 3. Occupational health nurses practice in a framework from
      which to establish policies and procedures to treat blood and body fluid
      exposures.

PMID- 10639944
TI  - Contracting for occupational health services: Part 2--Contracting tips.

PMID- 10639945
TI  - Health and land go hand in hand.

PMID- 10639946
TI  - Indigenous health in New Zealand: 'by Maori, for Maori'.

PMID- 10639947
TI  - Medicare. We can't afford to lose it.
AB  - With the promise of a federal election in the wind and the commonwealth and
      states battling about the amount of money required for adequate health care, it
      is timely to examine our health system, the politics, the policies on which it is
      based and the values which underpin it.

PMID- 10639948
TI  - Community nursing by horseback. Interview by Susan Hudson.

PMID- 10639950
TI  - RDNS graduate nurse program in community nursing.

PMID- 10639949
TI  - A new adult disability assessment tool.

PMID- 10639951
TI  - Shaping the future of community nursing.

PMID- 10639952
TI  - Part-time diploma offers maximum flexibility.

PMID- 10639953
TI  - Plugging the holes but not fixing the leak.

PMID- 10639954
TI  - The dangers of refusing a blood transfusion.

PMID- 10639955
TI  - Systematic reviews in nursing research.

PMID- 10639956
TI  - Patient assessment: a systematic approach.
AB  - Patient assessment is an important component of any nurse's role. It allows
      patient care to be prioritized in an appropriate manner and it forms the basis of
      nursing care plans both of which impact on patient outcomes.

PMID- 10639957
TI  - A tenacious life. Interview by Susan Hudson.

PMID- 10639958
TI  - The changing face of stroke. Medical management revolution.
AB  - Stroke, the leading cause of adult disability in our society and third most
      common cause of death, costs our community around $1.2 billion per year. As a
      medical condition, stroke conjures negative images in the minds of health care
      providers and the general public as a condition for which little or nothing can
      be done.

PMID- 10639959
TI  - Confusion means chaos for aged care nurses.

PMID- 10639960
TI  - Doctors, not the public, are winners in federal budget.

PMID- 10639961
TI  - Midwives role still undervalued.

PMID- 10639962
TI  - Vietnamese and Australian birth outcomes.

PMID- 10639963
TI  - Launceston Birth Centre.

PMID- 10639964
TI  - Midwives in action.

PMID- 10639965
TI  - Family health research unit leads the way.

PMID- 10639966
TI  - Blood transfusion.
AB  - This Clinical Update considers issues relating to transfusion of blood components
      -erythrocytes, platelets and plasma products--obtained from human donors.

PMID- 10639967
TI  - Toward another country.

PMID- 10639968
TI  - Older, wiser, stronger.

PMID- 10639969
TI  - Care and feeding of the (aging) human body.

PMID- 10639970
TI  - The expanded role nurse in geriatrics.
AB  - The first experience in Halifax with the expanded role nurse (ERN) was in 1993,
      when Victoria General Hospital established an ERN position in the cardiology
      program. A few years later the adult hospitals in the city merged into a new 900
      bed, multi-site facility--the Queen Elizabeth II Health Sciences Centre (QEII).
      In the Geriatrics Department, called the Centre for Health Care of the Elderly
      (CHCE), the director of nursing and the medical director also began to consider
      establishing such a position.

PMID- 10639971
TI  - When seniors relocate.
AB  - Where we will live and die as we age is a dilemma that each of us faces. With the
      population of seniors growing at an unprecedented rate, decisions about where to
      live are evoking considerable attention from families, the health care system and
      the business community. Most seniors hope to live in their own homes as long as
      possible, and many manage to do just that; however, deliberations about
      maintaining or securing affordable, appropriate housing for their elderly members
      remain a necessary part of all families' developmental work. All families have to
      face the if, when and how of housing shifts for their senior members.

PMID- 10639972
TI  - Communicating at life's end.
AB  - With more and more people choosing to die at home, palliative care is an
      increasingly important field. The challenge for those of us working in the field
      is to develop a comprehensive system of care that will provide high quality, in
      home support. Such support involves a large network of formal and informal
      caregivers--family members, caregiving friends, homemakers and a variety of
      health care providers--who collaborate together and with the individual to
      provide holistic care. Thus, co-ordination, collaboration and communication are
      essential if this network is to meet the physical, psychological, social and
      spiritual needs of the dying and their families.

PMID- 10639973
TI  - [Overuse of psychotropic drugs in seniors].
AB  - Seniors take three times as many drugs as the general population and are the
      group most vulnerable to the adverse effects of drug therapy. For this reason, it
      is extremely important that they receive support to help them understand and
      manage their medications. To highlight the major problems in managing medication,
      determine the risk factors and prevent overdosing of psychotropic drugs in
      seniors, the authors carried out a study of 549 senior rural residents living at
      home. The study findings indicate that 19 per cent of people aged 65 or over take
      no drugs at all, while 24 per cent have five prescriptions or more. Two thirds of
      respondents (65.7%) who had only one prescription were well informed about their
      medication, compared with just 14 per cent of those taking five drugs or more.
      One quarter (27%) said they never received information about their prescription,
      while 17.3 per cent reported that the labels on their prescription bottles were
      useless because the print was too small, too pale or because they could not read
      them. Close to half the respondents (42.6%) reported occasionally forgetting
      whether they had taken their medication. The findings also indicate that the
      respondents' sex, their perception of their personal state of health, the
      population density, and the depression index are all major variables that
      significantly relate to use of psychotropic drugs. All of the findings identify
      the specific needs of seniors and suggest a focus for nursing intervention.

PMID- 10639974
TI  - Witnessing wills.
AB  - Nurses are often asked to witness documents. Acting as a witness to someone's
      signature, however, must be carefully thought out, as shown by the fictitious
      scenario described below and follow-up discussion.

PMID- 10639975
TI  - A partner in healthy aging. Interview by Barbara Sibbald.

PMID- 10639976
TI  - JAMU: an Indonesian herbal tradition with a long past, a little known present and
      an uncertain future.
AB  - As this editorial comes in the first issue of the last year of a millennium, it
      may be the time to examine our position in a global context. Our efforts to
      include complementary therapies in nursing and midwifery in the more privileged
      and western world often seem to be a frustrating struggle, tolerated and
      involving a steep learning curve for all those involved. Fifteen years ago, I
      used to say that in 25 years time, there would be a merging and integration and
      fuller acceptance of orthodox and complementary medicine. I am optimistic that my
      current target of 10 years will still hold, as indeed we have seen this happen
      already in the areas of palliative care and some more acute conditions. We can,
      however, become quite despondent with the challenge that remains in front of us
      and wonder if it is worth our time and energy. It is for this reason that I would
      like to present a more global picture, to help us appreciate how relatively easy
      we have it in our organized health systems compared to other more disadvantaged
      countries in the world.

PMID- 10639977
TI  - Across the pond.

PMID- 10639978
TI  - Graphology.
AB  - This paper outlines the history and highlights the uses of graphology in the
      health and educational setting. Graphology can be a useful tool in spotting
      health problems before they become too severe, and is excellent at identifying
      stress in the individual. Valuable insights into people's characters can be
      gained allowing a better understanding of ourselves and others. Examples are
      given in the paper of what to look for generally in assessing health, vitality,
      energy, willpower and originality. Other examples demonstrating specific
      deficiencies, such as physical weakness, poor memory, anxiety, stress, depression
      and lack of confidence are identified. There is growing evidence to suggest that
      graphology can help therapists identify hidden problems, also enabling accurate
      assessment of a person's response to therapy. As the clues pile up, the
      complexities of the writer's character, health and emotional status emerge,
      rather as if you were pulling together a giant jigsaw. Therapy can then be tailor
      made to the individual.

PMID- 10639979
TI  - 'Just the ticket': the findings of a pilot complementary therapy service (Part
      II).
AB  - In part I of this series of articles (Dryden et al. 1998) the authors detailed
      the background to a project offering hand and foot massage incorporating
      reflexology techniques. The following paper reports back on the findings and
      evaluation. Over a 4-month period a total of 61 recorded treatments were given to
      18 in-patients. Each session was to last approximately 30 minutes and included
      recordings of physiological data as well as pre- and post comments from the
      patient. The six practitioners, who were already working within the ward setting
      in various capacities, were asked to record reflective comments after each
      treatment. This paper will conclude by discussing future recommendations. Part
      III of this series (CTNM 5: 2, 1999) will focus on a subgroup of patients within
      the study highlighting the experiences of both practitioners and patients.

PMID- 10639980
TI  - Added value?

PMID- 10639981
TI  - A week in the life.
AB  - Denise Tiran is principal lecturer in complementary therapies and midwifery in
      the School of Health at the University of Greenwich, south London. Here she
      describes a typical week in her busy life.

PMID- 10639982
TI  - Burning the midnight oil.
AB  - A requirement for all trained nurses is that they undertake to follow a
      structured programme of professional development. Unfortunately, the prospect of
      copious amounts of study is the stuff of which bad dreams are made and the
      thought of enrolling for any course, let alone one at degree level, remains a
      very real source of anxiety. Because of my interest in using massage therapy in
      the Trust where I then worked, I enrolled for a part-time course at the
      University of Exeter, a centre well known in nursing circles for its research
      into complementary medicine. The following account of my experience of combining
      study with a full-time job is intended to provide encouragement for anyone who
      may be currently in the process of considering a similar course of action.

PMID- 10639983
TI  - Atrial fibrillation following cardiac surgery.
AB  - Atrial arrhythmias are the most common complication of cardiac surgeries,
      occurring in 30% of patients undergoing coronary revascularization and 60% of
      patients having valvular surgeries. The most frequently occurring atrial
      arrhythmia, atrial fibrillation (AF), not only causes uncomfortable palpitations,
      but has also been shown to increase postoperative hospital length of stay and
      morbidity, including hemodynamic compromise and stroke. Both the frequency and
      the potential consequences of AF make prevention and early intervention important
      aspects in the postoperative care of cardiac surgery patients.

PMID- 10639985
TI  - Angiotensin-converting enzyme inhibitors and left ventricular remodeling:
      implications for nurses.
AB  - Angiotensin-converting enzyme (ACE) inhibitors have been shown to be effective
      agents that improve the sequelae of left ventricular remodeling following a
      myocardial infarction. The critical care nurse can play an active role in
      recognizing those patients who will benefit from ACE inhibitor therapy.

PMID- 10639984
TI  - Candida albicans: an opportunistic threat to critically ill low birth weight
      infants.
AB  - Major advances in the management of critically ill low birth weight (LBW) infants
      have increased their survival. Yet the clinical course of these infants is
      complicated by the emergence of opportunistic microbial pathogens. Most
      importantly, serious infections from opportunistic fungi, such as Candida
      albicans, have produced systemic disease in vulnerable LBW infants. Invasive C.
      albicans infection is generally difficult to manage and is associated with high
      morbidity and mortality. Because the infection has an insidious and rapid course,
      the critical care nurse and advanced practice nurse need to provide key
      prevention and early treatment measures.

PMID- 10639986
TI  - Nurses' attitudes toward organ donation: an Australian perspective.
AB  - Australia's rate of organ donation, which has shown a continuing downward trend,
      is among the lowest in the developed world. Research has demonstrated that
      nurses' attitudes and behaviors are important functions in organ donation,
      particularly retrieval. This study investigated the attitudes and knowledge
      levels about organ donation of paediatric nurses in a large metropolitan
      children's hospital and nurses in two rural hospitals. The results highlight the
      role that critical care nurses and advanced practice nurses need to play in
      improving levels of organ donation.

PMID- 10639987
TI  - Coping strategies of cardiac surgery patients in the perioperative period.
AB  - Clinical nurse specialists, critical care nurses, and advanced practice nurses
      can influence patients' coping before and after cardiac surgery. By understanding
      the patients' experience, clinicians can tailor interventions that maximize
      patient coping. This nursing research study was designed to explore patient
      coping before and after surgery. A repertoire of interventions based on study
      results is provided so critical care and advanced practice clinicians can best
      assist the patient.

PMID- 10639988
TI  - Nursing interventions to reduce perioperative cardiac morbidity and mortality.
AB  - Morbidity and mortality remain high for patients with preexisting cardiac disease
      undergoing noncardiac surgery. These patients use an increasing number of
      intensive care unit, ventilator, and hospital days. This article analyzes
      research on factors influencing morbidity and mortality of noncardiac surgery
      patients and identifies nursing interventions that can improve outcomes for these
      patients.

PMID- 10639989
TI  - Managing sedation in critically ill children.
AB  - Sedating critically ill children presents a challenge for even the most
      experienced critical care nurse. The nurse must differentiate agitation caused by
      pain, fear, hypoxia, or other factors and take appropriate action. This paper
      discusses using an algorithm to assess agitation and sedation needs and presents
      management options for sedation.

PMID- 10639990
TI  - Transsphenoidal resection of pituitary adenoma: using a critical pathway.
AB  - The use of a transsphenoidal critical pathway can be a vital tool for critical
      care nurses in anticipating complications and improving patient outcomes.
      Complications such as diabetes insipidus and cerebrospinal fluid leak associated
      with posttranssphenoidal patients may result in prolonged hospitalization and
      worsened functional outcome. Implementing a transsphenoidal critical pathway for
      these patients can guide their care and alert critical care nurses to potential
      complications and their prevention and/or treatment.

PMID- 10639991
TI  - Identifying compliance with end-of-life care decision protocols.
AB  - For the past decade, end-of-life care decisions, such as advance directives, have
      come to be viewed as an important component in influencing treatment decisions
      for patients with serious illness or loss of competence. However, few studies
      have examined health care providers' compliance with hospital protocols and
      federal regulations on end-of-life decisions. This article describes a hospital
      based standards project to identify the knowledge, beliefs, and practices of
      physicians, nurses, social workers, and pastoral care associates in end-of-life
      care decisions.

PMID- 10639992
TI  - How to assess critical thinking in clinical practice.
AB  - Nursing leaders in critical care face new challenges in assessing their staff's
      critical thinking skills. Specific strategies--such as questioning, clinical
      scenarios, conferences, and context-dependent test items--are needed for this
      assessment. Critical care educators, managers, clinical nurse specialists, acute
      care nurse practitioners, case managers, and nurses in other roles who are
      responsible for orienting staff to critical care and for providing them with
      continued education and development can use these strategies.

PMID- 10639993
TI  - Patients' perceptions of uncertainty and stress during weaning from mechanical
      ventilation.
AB  - Weaning from mechanical ventilation is physiologically and psychologically
      stressful for patients. The critical care nurse is in an optimal position to
      reduce patients' stress during this process. The findings of this exploratory
      study suggest practice changes--based on patients' perspectives--that help reduce
      patients' feelings of uncertainty and stress as they are weaned from mechanical
      ventilation.

PMID- 10639994
TI  - Starting places for Web-surfing critical care nurses.

PMID- 10639995
TI  - A new technology in burn therapy: INTEGRA artificial skin.
AB  - Nurses caring for severely burned patients need to know not only a burn injury's
      multisystem consequences, but also the effects and expected outcomes of burn
      treatment. Excision and grafting remain the primary interventions to promote
      wound healing, but severely burned patients may have little or no skin available
      for autograft harvesting. INTEGRA artificial skin, a commercial dermal
      regeneration template, is a new option for complete physiologic wound closure in
      a variety of clinical situations. This article reviews the physiologic effects,
      complications, and expected outcomes of INTEGRA artificial skin and compares it
      with other methods of closing burn wounds.

PMID- 10639996
TI  - Treating urinary tract infections in the elderly.
AB  - Elderly patients in critical care settings are at increased risk for nosocomial
      infections, especially urinary tract infections (UTIs), the most common type of
      nosocomial infection. Catheter-related UTIs in critically ill elderly patients
      present a particular challenge to the advanced practice nurse and critical care
      nurse in terms of clinical features, diagnosis, and management.

PMID- 10639997
TI  - Lung volume reduction surgery: new hope for emphysema patients.
AB  - Lung volume reduction is a new surgical procedure for patients with severe
      emphysema. The hyperinflated portion of the lung or lungs is removed so the
      patient's chest wall and diaphragm can return to normal positions, easing
      breathing. This article describes the patient criteria, surgical procedure, and
      nursing problems and interventions related to the care of the lung volume
      reduction patient.

PMID- 10639998
TI  - Conscious sedation raises safe staffing concerns.

PMID- 10640000
TI  - Decreasing diagnostic blood loss for patients in critical care units.
AB  - Several studies have investigated the problem of diagnostic blood loss for
      patients in critical care units. This research analysis categorizes these studies
      according to common themes, evaluates their methodologies, and synthesizes the
      findings. The author recommends research-based strategies that nurses can use to
      reduce patients' blood loss and the risk of complications such as nosocomial
      anemia.

PMID- 10639999
TI  - A benchmark project to improve cost and quality outcomes for CABG patients.
AB  - Today's health care environment is forcing health care providers to find ways to
      provide more effective and efficient care. This article describes a collaborative
      benchmark project that examined acute care for coronary artery bypass graft
      surgery patients and reduced costs and improved patient outcomes.

PMID- 10640001
TI  - Getting ready for the challenge of the 21st century.

PMID- 10640003
TI  - Recommendations for managing vital-organ donors.
AB  - This chart describes some clinical problems organ donors may face, how the nurse
      should intervene, and the rationale for the intervention. The recommendations
      were developed by Corrinne Morgan, RN, CCRN, CNRN, for the Delaware Valley, Pa.,
      transplant program, which serves eastern Pennsylvania, southern, New Jersey, and
      Delaware.

PMID- 10640002
TI  - Goodpasture's syndrome: a nursing challenge.
AB  - Goodpasture's syndrome is an uncommon occurring disorder that causes hemorrhage
      in the basement membrane lining of the kidneys and the lungs. By recognizing
      early signs and symptoms of pulmonary-renal syndromes that may lead to a
      diagnosis of Goodpasture's syndrome, critical care and advanced practice nurses
      can play a key role in ensuring successful patient outcomes and preventing
      complications. Expert nursing care and emotional support is essential for the
      patient and family to cope with this usually fatal disease.

PMID- 10640004
TI  - Transplant issues: infections and immunosuppressant drugs.
AB  - Patients who have had organ transplants are at risk for infection and organ
      rejection. Critical care nurses can improve patient outcomes by recognizing and
      treating infection and by familiarizing themselves with the immunosuppressant
      medications used in transplantation.

PMID- 10640005
TI  - Minimally invasive coronary artery bypass grafting: a kinder cut.
AB  - Minimally invasive coronary artery bypass graft (CABG) surgery is a promising
      variation on traditional CABG, avoiding the risks of sternotomy and
      cardiopulmonary bypass. This article describes the procedure, patient-selection
      criteria, and postoperative care.

PMID- 10640006
TI  - Preventing pseudoaneurysms following femoral cannulization.
AB  - Femoral artery pseudoaneurysms following invasive angiographic procedures are an
      increasingly common phenomenon, especially since the advent of thrombolytic
      therapy and the use of larger arterial catheters. This article describes the
      critical care nurse's role in identifying and assessing patients at risk for
      pseudoaneurysms, managing a patient who develops this complication, and assisting
      with treatment. Preventing pseudoaneurysms--and recognizing them promptly if they
      occur--can reduce patient hospitalization and mortality.

PMID- 10640007
TI  - A sedation protocol for preventing patient self-extubation.
AB  - Inadequate sedation management can place critically ill patients in danger of
      self-injury. This article describes the development and use of a protocol for
      managing sedation in intubated patients to prevent injury from self-extubation.
      Critical care nurses can use the protocol to effectively manage agitation in
      intubated patients and prevent self-extubation.

PMID- 10640008
TI  - Web monitor. Exploring the issue of organ donation.

PMID- 10640009
TI  - Patterns of parental stress in PICU emergency admission.
AB  - Emergency admission of a previously healthy child to a pediatric intensive care
      unit for a sudden critical illness or trauma is extremely stressful for the child
      and parents. Although nurses expect parents to be highly anxious, this study
      shows that parental anxiety levels are higher than expected, reaching near-panic
      levels initially. This article suggests ways nurses can adapt their family
      strategies to take into consideration parents' potential difficulties
      concentrating or even asking questions.

PMID- 10640010
TI  - Risk classification, clinical outcomes, and the use of nursing resources for
      cardiac surgery patients.
AB  - Several studies have used risk classification models to examine the effect of
      preoperative risk factors on operative morbidity and mortality. However, previous
      research has not linked risk classification models to factors such as frequency
      of postoperative complications, length of intensive care unit stay, mortality,
      and the use of nursing resources. This article reports on significant differences
      in clinical outcomes and hours of nursing care by risk classifications.

PMID- 10640011
TI  - The priceless gift.

PMID- 10640012
TI  - Successfully weaning the intra-aortic balloon pump patient: an algorithm.
AB  - Guiding a patient safely through the process of weaning from an intra-aortic
      balloon pump (IABP) requires knowledge that goes beyond understanding the
      device's purpose and mechanisms. Critical care nurses are responsible for
      coordinating multidisciplinary care throughout the patient's IABP therapy,
      assessing and supporting the patient throughout the weaning process, and making
      determinations about the rate of--and the patient's response to--weaning. This
      article presents an algorithm for critical care nurses who must make decisions
      before and during the weaning process.

PMID- 10640013
TI  - Using spinal cord stimulation to manage angina pain.
AB  - An implanted electrode that delivers low-voltage electrical current to the spinal
      cord appears to be effective in reducing angina symptoms and improving quality of
      life in patients who are not candidates for bypass surgery. This article
      describes the technology and which patients can benefit from it.

PMID- 10640014
TI  - Reducing the effects of acute pain in critically ill patients.
AB  - Unrelieved pain in critically ill patients can increase mortality, morbidity,
      length of stay, and use of resources. This article reviews the physiologic basis
      of acute pain and the pathophysiologic sequelae that may ensue when critically
      ill patients experience acute pain. The author recommends strategies critical
      care nurses and advanced practice nurses can use to provide effective analgesia
      and potentially improve patient outcomes.

PMID- 10640015
TI  - Meeting the needs of rural families during critical illness: the APN's role.
AB  - Family needs during critical illness have been a major focus of nursing research,
      yet the unique needs of families living in rural America still need to be
      investigated. This study sought to identify the needs of families in rural
      southern Appalachia and compare these findings to those from a study that
      identified the needs of families in a large metropolitan medical center. We found
      13 needs to be significantly different between the rural and urban samples and
      suggest strategies that rural and urban critical care nurses and advanced
      practices nurses can use to care for families of critically ill patients from
      rural areas.

PMID- 10640016
TI  - Web monitor. Some sites for advanced practice nurses.

PMID- 10640018
TI  - Guide to nursing organizations '99.

PMID- 10640017
TI  - Reducing patient restraint use.
AB  - This assessment tool can help nurses identify the reasons a patient may require
      restraint, and find alternative or less-restrictive measures. After using it for
      13 months, the staff from one hospital reduced restraint use by 95%--to less than
      1% of total patient days.

PMID- 10640019
TI  - Pediatric pain management: a research-based clinical pathway.
AB  - Nurses want to provide pain management for pediatric patients, but different
      approaches lead to inconsistent pain management. This article presents a
      pediatric pain management clinical pathways developed as a result of research in
      the pediatric intensive care unit and based on pain management research. Using
      this pathway can help nurses deliver consistent pain management to pediatric
      patients.

PMID- 10640020
TI  - Supervising unlicensed personnel.

PMID- 10640021
TI  - Advanced practice nurses--a growing role in acute care.

PMID- 10640022
TI  - Using ibutilide to convert atrial fibrillation and flutter.
AB  - Ibutilide fumarate injection is the first antiarrhythmic drug approved by the
      Food and Drug Administration for acute conversion of atrial fibrillation and
      flutter of recent onset (up to 90 days). This drug will find its greatest use in
      critical care units and emergency departments. Critical care nurses monitor the
      patients, recognize and assist in treating adverse events, and evaluate patient
      outcomes. Advanced practice nurses will find this information useful for teaching
      patients, colleagues, and new critical care nurses.

PMID- 10640023
TI  - Titanium rib implants: giving children some breathing room.

PMID- 10640024
TI  - When is an albumin infusion needed?
AB  - Albumin infusions can help some critically ill patients, but when to use them is
      controversial. This protocol can help guide the decision.

PMID- 10640025
TI  - Identifying and treating inhalation injuries in fire victims.
AB  - Inhalation injury is the primary cause of fire-related deaths. Although treatment
      of cutaneous burn injuries has greatly improved patient survival, inhalation
      injury remains a clinical challenge. This article reviews the current methods of
      identifying and treating fire-related inhalation injury.

PMID- 10640026
TI  - Magnesium sulfate.

PMID- 10640027
TI  - Acute thoracic aortic dissection: how to defuse a time bomb.
AB  - Acute thoracic aortic dissection is frequently misdiagnosed, and even with
      surgical intervention, the mortality rate is 50%. This article focuses on
      assessment, interventions, and postoperative care of patients with aortic
      dissection.

PMID- 10640028
TI  - A pain management relief plan to improve patient care.
AB  - This article addresses a hospital's initiative to offer responsive pain
      management through the development of a pain management task force. It provides a
      sequential model and guide for nurse-managers to use in their own health care
      environments.

PMID- 10640029
TI  - Patient dumping and ED transfer risks.

PMID- 10640030
TI  - Ensuring competencies of multidisciplinary staff in patient-focused care.
AB  - Faced with rising health care costs and consumer demands, hospitals are finding
      creative ways to streamline the delivery of patient care. One such approach is
      patient-focused care (PFC), in which hospitals bring services to the patient's
      beside and cross-train staff. The success of PFC depends on training and
      measuring staff competence in the new skills. This article describes how to
      implement an educational plan based on competencies for a successful transition
      to PFC.

PMID- 10640031
TI  - Web monitor. Resources for asthma and allergies.

PMID- 10640032
TI  - Meeting cardiac patients' expectations of caring.
AB  - Understanding patients' perceptions of caring is the basis for caring
      interventions. This article describes how nurses can create a caring environment
      for patients by demonstrating nursing competency, teaching patients about their
      illness, and providing humanistic care. Although this study focused on cardiac
      patients, the principles may be applied to all critical care patients.

PMID- 10640033
TI  - Make certification a consumer concern.

PMID- 10640034
TI  - Optimizing care of patients with pulmonary hypertension.
AB  - This article describes the latest strategies for supporting patients with acute
      and chronic forms of this life-threatening condition.

PMID- 10640035
TI  - The role of ST-segment monitoring in assessment of acute myocardial infarction.
AB  - Continuous ST-segment analysis is an accurate and noninvasive tool for monitoring
      coronary artery patency in patients with acute myocardial infarction. This type
      of monitoring also is easy to use and cost-effective. The critical care nurse
      plays a pivotal role in initiating ST-segment monitoring, promptly detecting ST
      segment changes, and rapidly intervening to achieve myocardial reperfusion.

PMID- 10640036
TI  - A guide to pediatric isolation precautions.

PMID- 10640037
TI  - Preventing secondary brain injuries.
AB  - Traumatic brain injury is a leading cause of death from injury in the United
      States. This article reviews nursing interventions to prevent and minimize
      secondary brain injuries and improve patient outcomes.

PMID- 10640038
TI  - Vecuronium.

PMID- 10640039
TI  - A bedside laboratory: point-of-care blood analyzers.
AB  - When are point-of-care testing systems useful? In this article, find out how to
      assess an institution's needs and weigh the advantages of using these portable
      blood analyzers.

PMID- 10640040
TI  - Designing a patient-care 24-hour flow sheet.
AB  - Flow sheets provide a clear understanding of the patient in a timely manner, but
      designing the new charting format can be complex. This guide defines a patient
      care document's purpose, flow sheet strengths, and the evaluation format.

PMID- 10640041
TI  - Nursing's role in Y2K planning.
AB  - Why have more nurses not fulfilled their role in planning for the year 2000?
      Nurses need to apply their skills and expertise to solving often overlooked
      problems such as point-of-service applications, transactions with business
      partners, and contingency planning.

PMID- 10640042
TI  - Spirit at work: supporting patients and colleagues.
AB  - In this article, the authors describe ways to create spirit at work--a sense of
      teamwork and caring for patients, their families, and colleagues. Defining an
      ideal role model and striving to emulate that model are the first steps to
      creating a facility that enriches the lives of patients, families, and health
      care providers.

PMID- 10640043
TI  - Navigating specialty certification.
AB  - Nurses planning to become certified in their specialty or needing to recertify
      can visit these Web sites for test locations and schedules. Some sites also offer
      newsletters.

PMID- 10640045
TI  - Web monitor. Sites to sharpen nursing research.

PMID- 10640044
TI  - Visitor and nurse satisfaction with a visitation policy change in critical care
      units.
AB  - Studies have addressed the visitation needs of visitors and patients and the
      impact of visitation policies on nurses, but few studies compare the level of
      satisfaction between visitors and nurses when visitation policies change. The
      objectives of this study were to investigate whether a more liberal intensive
      care unit visitation policy satisfactorily met the needs and expectations of
      visitors and nurses.

PMID- 10640046
TI  - The importance of nursing research.

PMID- 10640047
TI  - Keeping pace with permanent pacemakers.
AB  - Find out how they work, how to recognize their activity on an ECG,
      troubleshooting tips, and what patients need to know.

PMID- 10640048
TI  - Responding to winter emergencies.
AB  - Nurses need to know how to provide emergency care to victims of wintertime
      injuries and illnesses--and how to survive such circumstances themselves. In this
      article, the author, a ski patrol member, describes cold-weather strategies and
      how to respond to hypothermia, frostbite, winter sports injuries, and avalanches.

PMID- 10640049
TI  - Reteplase.

PMID- 10640050
TI  - Alcohol withdrawal in critical care.
AB  - Alcohol withdrawal syndrome can be fatal if not recognized and treated
      immediately. An estimated 10% to 50% of hospitalized patients abuse alcohol, and
      they may develop withdrawal syndrome during hospitalization. However, nurses can
      successfully treat alcohol withdrawal syndrome, even in critically ill patients,
      with benzodiazepines, the treatment of choice.

PMID- 10640051
TI  - A guide to pediatric critical care medications.

PMID- 10640052
TI  - Applying FOCUS-PDCA to solve clinical problems.
AB  - Many methods have been proposed for solving complex or multifaceted clinical
      problems in a logical, systematic, and accurate way. This article describes one
      method of step-by-step problem solving and how to apply it to a clinical
      situation.

PMID- 10640053
TI  - Role rehearsal: a mock code program.
AB  - This article describes how a hospital implemented a mock code program that
      increased nurses' comfort and skill with increased code arrest duties, improving
      their performance 95%.

PMID- 10640054
TI  - Early discharge with home health care in the coronary artery bypass patient.
AB  - Early hospital discharge after coronary artery bypass graft surgery has been the
      standard of practice throughout the United States. This study compared outcomes,
      readmissions, and costs for patients discharged early with home health care with
      those of patients discharged a day or more later without home health care.
      Discharging open-heart surgery patients on postoperative day 4 with home health
      care was found to be safe and cost-effective.

PMID- 10640055
TI  - Web monitor. Where to find answers on bioethics, cardiology.

PMID- 10640056
TI  - Making your compliance plan work for you.

PMID- 10640057
TI  - Developing practical billing procedures for compliance.
AB  - An effective compliance plan can be a mitigating factor should an agency face
      fraud and abuse charges. The goal of establishing specific procedures to ensure
      accurate and appropriate billing practices not only demonstrates the agency's
      position regarding fraud and abuse, but also eliminates waste and provides better
      quality care to patients. The procedures necessary to ensure that an agency is
      billing only for medically necessary services that have actually been provided in
      accordance with a physician's order encompass most of the agency's clinical and
      financial operations. By concentrating on these areas, the majority of compliance
      issues are addressed while providing the added benefit of the availability of
      more accurate data for analysis and monitoring.

PMID- 10640059
TI  - Making compliance standards realistic.

PMID- 10640058
TI  - Education and training for home care information systems. Part III:
      Implementation issues.

PMID- 10640060
TI  - Home care accreditation: understanding the options.

PMID- 10640061
TI  - The fit of research utilization and evidence-based practice.

PMID- 10640062
TI  - Measurement of affectionate behaviors adolescent mothers display toward their
      infants in neonatal intensive care.
AB  - This paper describes two studies that had three purposes: (a) to modify a parent
      child interaction tool used previously in a neonatal intensive care unit (NICU);
      (b) to demonstrate interrater reliability, Chronbach's Alpha reliability, and
      construct validity of the tool with adolescent mothers, and (c) to determine the
      ability of nurses engaged in usual work duties to observe maternal behaviors. The
      first study tested interrater reliability. Two NICU nurses were trained, observed
      adolescent mothers (n = 20) for the same 15 min, and then separately completed
      the measure. The second study tested internal consistency reliability and
      construct validity with 107 adolescent mothers with infants in a NICU. Nurses in
      the neonatal intensive care unit completed the measure, and data on maternal
      visits were gathered for construct validity. The intraclass correlation
      coefficient for the first study was r = .83. Results of the second study
      demonstrated a Chronbach's Alpha of .85 and a significant correlation between
      ratings of maternal behavior and visits. The instrument obtained acceptably
      reliable and valid estimates of adolescent mothers' affectionate behaviors toward
      their infants. In addition, the studies demonstrated that nurses can observe
      maternal behaviors while performing their usual duties.

PMID- 10640063
TI  - A conceptual framework for studying child adaptation to Type 1 diabetes.
AB  - Understanding the challenges of managing a chronic illness, nurses provide a key
      component of care to patients and families who struggle daily with the demands of
      self-management and the balance of daily life challenges. Even though nurses
      empathize with the issues of chronic illness management, the complexity of
      managing such clients has not been articulated in a theoretical or research base.
      Hence, the nursing process related to facilitating adaptation to childhood
      chronic illness remains in a formative stage. My article presents a conceptual
      framework that can guide the study of children and families coping with children
      with Type 1 diabetes. The framework also may prove useful for other chronic
      illnesses.

PMID- 10640064
TI  - Identification of nurse-family intervention sites to decrease health-related
      family boundary ambiguity in PICU.
AB  - The most common explanation of parental stress associated with hospitalized
      children is based on individual stress theory. Using a family stress and family
      systems approach with an emphasis on examining family integrity, this qualitative
      study selected families in the Pediatric Intensive Care Unit (PICU) with high
      boundary ambiguity in the caregiving environment and identified potential sites
      for nursing actions that impede or assist families in maintaining family
      integrity. Within three days of admission of their child to a major tertiary
      children's hospital PICU, 29 families were recruited and screened with a Health
      Related Family Boundary Ambiguity Scale. High scoring families (n = 11) were
      interviewed using an open-ended method. Data were analyzed using a content
      analysis method, and results were interpreted within a family systems framework.
      The following three potential areas of intervention to encourage family integrity
      during acute illness of a child were identified: fostering family normalcy,
      respecting family rights, and strengthening the family boundary. Implications for
      initiating or improving family centered care in the PICU are discussed.

PMID- 10640065
TI  - Self-care agency and self-care practice of adolescents.
AB  - The purposes of this study were threefold: (a) to describe self-care agency, (b)
      to describe self-care practice, and (c) to describe the relationship between self
      care agency and self-care practice in adolescents. The usefulness of Orem's Self
      Care Deficit Nursing Theory (SCDNT) with adolescents also was evaluated.
      Participants in this study included 173 adolescents, 14 to 19 years of age. Data
      were collected in classroom settings in two diverse high schools. Denyes Self
      Care Agency Instrument-90 and Denyes Self-Care Practice Instrument-90 were
      administered. Results revealed the presence of self-care agency and self-care
      practice. Although self-care practice was lower than self-care agency, a
      significant positive correlation was found between the two concepts. The lower
      self-care practice scores, as compared with the self-care agency scores, suggest
      that characteristic adolescent behaviors may or may not interfere with self-care
      practice. The results of this study support the usefulness of Orem's SCDNT with
      adolescent populations and identify the critical need for further research
      examining self-care in adolescents.

PMID- 10640067
TI  - Preparing staff to deliver age-appropriate nursing care to elderly patients.
AB  - Meeting the Joint Commission on Accreditation of Healthcare Organizations
      accreditation standard for age-appropriate care cannot be accomplished by a once
      a-year inservice educational program. Educational offerings that address the
      specialty of gerontological nursing require deliberate decision-making regarding
      the generic and advanced competencies necessary for care of elderly patients.
      Finding the resources to effectively teach the essential (generic and advanced)
      content is challenging. This article suggests that a staff development department
      may use existing resources and personnel from other organizations to prepare
      nursing staff to deliver age-appropriate care to elderly patients.

PMID- 10640066
TI  - The effects of attrition on implementing and evaluating a mental health
      continuing education program for nursing personnel in long-term care facilities.
AB  - BACKGROUND: The effects of attrition on a continuing education program for
      nursing personnel within long-term care facilities are described. METHODS:
      Allowing flexible participation can enhance the impact of a continuing education
      program designed for paraprofessional staff. Increasing the number of nursing
      staff who experience only a portion of the training has implications for the
      instructional design and the evaluation. Recommendations to improve accommodation
      of staff and enhance dissemination of training are offered as well as appropriate
      evaluation techniques. CONCLUSION: Self-contained short units of instruction
      allow those with minimal time to benefit from the training. Effective evaluation
      requires special sampling and measurement strategies. Cross-sectional methods
      make good use of training resources but usually yield measurable changes only in
      lower-level program objectives.

PMID- 10640068
TI  - Association between continuing education and job satisfaction of nurses employed
      in long-term care facilities.
AB  - BACKGROUND: The purpose of this descriptive, correlational study was to
      investigate the relationship between continuing education and job satisfaction
      among RNs and licensed practical nurses (LPNs) employed in long-term care
      facilities. METHOD: Herzberg's Motivational-Hygiene Theory was used as a
      framework to guide the design of the study. The Professional Educational
      Activities Scale and the McCloskey/Mueller Satisfaction Scale were completed by
      110 nurses employed in long-term care facilities. RESULTS: No difference was
      found between type of employment status (full-time versus part-time) on the level
      of professional educational activities. However, RNs participated in more
      continuing education activities than LPNs. Nurses who reported higher family
      incomes also had greater participation in educational activities. Registered
      nurses reported greater job satisfaction than LPNs. No significant difference was
      found between the degree of job satisfaction for Black and White nurses. The
      results of this study indicated nurses who participated in more continuing
      education activities scored higher on the job satisfaction scale. CONCLUSION: As
      the elderly population increases, a critical need exists for nurses to be
      knowledgeable about current research-based information, including the economic
      and psychosocial effects of illness in later life. To provide the most effective
      care for the elderly population, nurses in long-term care must be knowledgeable
      about the complexity and specific characteristics of chronic illnesses.
      Continuing education activities are an important way to access this information.

PMID- 10640069
TI  - Information resources and knowledge needs of rural nurses regarding Alzheimer's
      disease.
AB  - BACKGROUND: The need for current information on Alzheimer's disease (AD) is
      apparent as medical research, diagnostic, and treatment guidelines are advancing
      at a rapid rate. METHOD: A needs assessment survey determined what educational
      topics related to dementia nurses perceived they most need, would be most likely
      to attend, and what information they likely would solicit in a telephone
      consultation. RESULTS: Nurses in Iowa were interested in continuing education
      programming and teleconferences on major topics regarding AD provided through the
      state's fiberoptic system such as: (a) challenging behaviors over the course of
      illness; (b) family needs such as education, support, respite, referral, and
      safety; (c) case management services for patients and families; (d) long-term
      care services from adult care to hospice; and (e) new developments in AD.
      CONCLUSION: Rural nurses experiencing professional isolation and lack of
      resources can access up-to-date information via continuing education programs
      transmitted by telecommunication strategies.

PMID- 10640070
TI  - Improving aged care education for Australian rural nurses using problem-based
      learning.
AB  - BACKGROUND: A continuing education program in aged care was developed using the
      principles of problem-based learning (PBL) to improve the participating nurses'
      understanding of current government guidelines on aged care, to develop their
      ability to apply this information to their workplace situations, and to give them
      the confidence and strategies to initiate change in their workplaces. The use of
      a guided introduction to PBL and the use of journals were important components in
      the design of this program. METHOD: Both quantitative and qualitative approaches
      were used to evaluate the program, and data collected through observation of the
      participants when working on case scenarios, journal writing, and pre
      questionnaires and post-questionnaires were included. Fifteen nurses participated
      in the program. RESULTS: Participants developed a holistic approach to aged care,
      reflected on their practice in the journals, developed an understanding of the
      current aged care guidelines, and acquired the skills, strategies, and motivation
      to make changes in their workplaces. CONCLUSION: PBL enabled the nurses to link
      theory with practice, not only through the case scenarios considered in the
      program, but also when reflecting on their work practices in their journals. The
      use of journals by participants and the guided introduction to the PBL approach
      were important factors in the Aged Care Program's success.

PMID- 10640071
TI  - Partnership in education: an example of client and educator collaboration.
AB  - This article describes one education strategy designed to assist nursing staff in
      the process of "learning to surrender" the service providers' need to direct
      client decision-making. Using the health promotion principle of "client as
      expert," a nurse educator and a client with advanced multiple sclerosis co
      present an inservice class about the importance of personal empowerment and
      environmental mastery for maintaining physical and psychological well-being in
      the face of a chronic disorder. This collaborative strategy provided the client a
      forum from which to share his personal experience and professional knowledge to
      influence attitudes and provide valuable information to nursing staff in a long
      term care facility. Collaborating with the client to bring information to nursing
      staff is one means to foster a climate of client empowerment, influence staff
      perceptions and communicate the unique experiences of the client.

PMID- 10640072
TI  - Assessment of nurses' attitudes and knowledge regarding pain management.
AB  - BACKGROUND: RNs in North Carolina were surveyed to determine their current
      knowledge and to determine if educational preparation, practice setting, or
      clinical specialty influenced their knowledge levels and attitudes. METHOD: A
      stratified random sample of 1,000 practicing RNs in North Carolina were surveyed
      using the Nurses' Knowledge and Attitudes Survey Instrument developed by
      McCaffery and Ferrell. RESULTS: The mean score was 64.58 based on the percentage
      of correct responses from the 260 subjects who participated. No statistically
      significant difference was found in scores based on educational preparation,
      practice setting, or clinical specialty. CONCLUSION: The findings of this study
      support the concern of inadequate knowledge and inappropriate attitudes regarding
      pain management. It reveals the need for intensive continuing education and staff
      development.

PMID- 10640073
TI  - Genetics 101 essential for all nurses.

PMID- 10640074
TI  - Do needleless intravenous systems increase the risk of infection?
AB  - Since 1995 several studies have addressed whether needleless intravenous systems
      increase patient risk of bloodstream infection (BSI). At this time, conclusive
      evidence is lacking and all studies point to the need for additional research.
      Current studies indicate that there is no evidence that needleless systems
      increase patient risk of BSI when the products are used correctly and in
      conjunction with rigorous aseptic technique. However, these studies also identify
      variables not directly associated with the product or device that may contribute
      to an increased risk of BSI to the patient.

PMID- 10640075
TI  - The benefits and limitations of needle protectors and needleless intravenous
      systems.
AB  - Needleless and needle protector intravenous systems have taken the place of 80%
      of needles used in i.v. therapy. Although these new systems are marketed as safe,
      many have not been widely tested and are not fail-safe. Each of the needleless
      i.v. systems and needle protector systems has limitations and potential benefit
      when applied in the appropriate circumstances. The benefits and limitations of
      these devices in today's healthcare market are discussed.

PMID- 10640076
TI  - Undertransfusion or the prudent, cautious, and wise use of blood?
AB  - Many quality assurance workers have been concerned about undertransfusion since
      acquired immune deficiency syndrome was first shown to be transmitted by blood
      transfusion. Physicians may be reluctant to order transfusions, and patients may
      be hesitant to receive blood therapy, even in situations meeting established
      guidelines for transfusion therapy. Transfusion guidelines are reviewed and
      compared to actual practices in a tertiary care hospital. Clinical cases between
      the limits set by the guidelines are examined and shown not to meet the
      definition of undertransfusion.

PMID- 10640077
TI  - Laboratory sampling. Does the process affect the outcome?
AB  - With the rapidly changing healthcare environment, one of the many increasing
      tasks for the intravenous team is blood sampling. Laboratory test results are
      based on the quality of the patient's blood specimen. The preanalytic phase of
      laboratory testing accounts for 46% of laboratory testing errors, so it needs to
      be managed effectively to eliminate costly, inefficient, and sometimes life
      threatening outcomes to patients. The use of quality blood collection procedures
      and an awareness of preanalytic errors are presented to lead to quality patient
      outcomes.

PMID- 10640078
TI  - Peripherally inserted central catheter placement in swine using magnet detection.
AB  - Positioning a PICC in the lower half of the superior vena cava is a crucial
      aspect of its safety and efficacy. A magnet detection system evaluated in this
      animal study presents a method that allows PICC placements to be performed
      without fluoroscopy. Forty-four localizations were studied in six pigs. The
      detection system located magnet-tagged PICCs with an average error of 0.40 cm and
      a standard deviation of 0.29 cm. The system provided real-time information about
      the path and orientation of the PICC tip during difficult insertions. This study
      demonstrates the accuracy of this magnet location system.

PMID- 10640079
TI  - A prospective study of two intravenous catheter securement techniques in a
      skilled nursing facility.
AB  - A prospective, controlled study was undertaken in a skilled nursing facility to
      determine whether a sterile catheter securement device (StatLock i.v., Venetec
      International, Mission Viejo, CA) would provide better intravenous therapy
      outcomes than a standard securement technique. The StatLock-device resulted in
      significantly longer average catheter dwell times (3.95 days versus 2.45 days)
      and significantly fewer total complications (65 versus 155). In addition, the
      securement device reduced the total time spent managing a vascular access device
      by 13.5 minutes per patient. Thus, the StatLock i.v. device improved overall
      clinical outcomes of i.v. therapy and the quality of care.

PMID- 10640080
TI  - Spelling competence with four Cs in an abilities-based baccalaureate program.

PMID- 10640081
TI  - Experiencing aging: a simulated sensory deprivation experience for students.

PMID- 10640082
TI  - Pupillary response scale made easy.

PMID- 10640083
TI  - Critical thinking in a pathophysiology course.

PMID- 10640084
TI  - Clinical strategies for teaching nursing students to care for the dying client.

PMID- 10640085
TI  - Independent clinical experiences in mental health nursing.

PMID- 10640086
TI  - Professional practice and the NCLEX examination. A bottom-line approach.

PMID- 10640087
TI  - A precepted experience for senior nursing students.
AB  - The author discusses an undergraduate course that provides students with a
      clinical experience focusing on setting priorities, managing time, and organizing
      assignments and responsibilities, with the support of, and under the direction
      of, an experienced RN preceptor. In addition to building confidence and making
      students more competitive during job interviews after graduation, the
      preceptorship course promotes collaboration between academia and service,
      provides students with the opportunity to implement their professional
      practitioner role, and promotes the personal and professional development of the
      preceptors and nursing staff.

PMID- 10640088
TI  - Using small-group instructional diagnosis and collaborative conflict resolution
      to facilitate course changes.
AB  - Small-group instructional diagnosis and collaborative conflict resolution are
      techniques that were successfully employed when course changes aimed at enhancing
      an undergraduate nursing leadership and management course with cultural diversity
      perspectives caused conflict among students and faculty. In this article these
      skills are described in relation to a specific situation; however, they both can
      have wide application. The small-group process can be conducted at midterm in any
      course, and conflict resolution techniques are applicable to most conflict
      situations, whether they occur in classrooms, with colleagues, or out of the
      workplace. Therefore, this article is intended for all faculty members who seek
      knowledge of formative classroom assessment techniques or help in managing
      conflict.

PMID- 10640089
TI  - Opening students' eyes. The process of selecting a research instrument.
AB  - The selection of a research instrument to collect data is crucial to the success
      of a study. This choice can be one of the most time-consuming and challenging
      tasks in the research process. If they have not been involved in conducting a
      research study themselves, nursing students are unaware of the intricacies
      involved in the decision-making process for selection of an instrument. The
      author describes a teaching strategy to help nursing students appreciate the many
      components involved in this critical and challenging step in the research
      process. The example used is from the author's research program on postpartum
      depression, which describes step by step the author's decision-making process for
      selection of an instrument.

PMID- 10640090
TI  - Integrating teaching, research, and practice in a nurse-managed clinic. A
      nonrecursive model.
AB  - An integrated model for teaching, research, and practice within a nurse-managed
      clinic is presented to guide faculty and administration in implementing these
      three roles. The concepts and relationships in the model are described
      theoretically, and a real clinical setting is used to illustrate the practical
      application of the model.

PMID- 10640091
TI  - Development in schools of nursing. Fund-raising to further long-range strategic
      plans.
AB  - Public or private, large or small, research-oriented or teaching- and service
      intensive, every nursing school faces the need to establish a pool of capital to
      enhance financial stability, increase program independence, and fund special
      initiatives in an unknown financial future. A strong development program helps to
      fill such needs. This article addresses several principles of the development
      process so that deans, faculty, and other decision makers can apply them to their
      own situations. The authors note the seven important points on the development
      continuum and then describe the three general gift categories. They discuss
      communication methods employed in development, highlighting the importance of
      recognizing donors and cultivating relationships. Consideration is given to the
      philanthropic potential of women. Finally, the role of the professional
      development officer, should the school have one, is discussed.

PMID- 10640092
TI  - Students' decisions to select HIV services for clinical experiences.
AB  - The ever-growing numbers of persons living with HIV/AIDS emphasizes the need for
      highly trained healthcare professionals to care for this population.
      Understanding why nursing and medical students would choose HIV services for
      clinical rotations, and the impact of those clinical experiences on their future
      professional practice, is key to recruiting healthcare providers to care for this
      population.

PMID- 10640093
TI  - Nursing theories. Creative teaching strategies make this course come alive.
AB  - The author describes creative teaching strategies used to teach a nursing
      theories course. Presentation and term paper assignments encouraged creativity
      and class participation. A final examination question that places students in a
      party setting with all of the theorists in attendance allows students to
      synthesize their knowledge using a creative approach.

PMID- 10640094
TI  - Promoting a positive clinical experience.
AB  - Why are some clinical experiences better than others? Little has been written
      about strategies used in the clinical classroom, yet this setting continues to be
      a major educational component in nursing education. The author explores specific
      actions aimed at promoting a positive clinical experience. Motivational
      principles combined with critical-thinking strategies and total quality
      management techniques together provide a conceptualization of clinical teaching
      and learning. Recommendations are made to integrate the three techniques into the
      clinical classroom.

PMID- 10640095
TI  - Challenges and rewards of educating a profoundly deaf student.
AB  - The faculty and administrators of a college of nursing in a public university
      learned that awareness of the Americans With Disabilities Act of 1990 is very
      different from complying with its mandates in the education of a profoundly deaf
      nursing student. The process began with many challenges and ended with rewards
      beyond the expectations of all involved. Faculty, who initially resisted the
      concept of educating a "deaf nurse," developed creative teaching strategies and
      ultimately gained a new perspective regarding who has the potential to become a
      good nurse. In the final analysis, everyone agreed that this exceptional young
      woman was not only our student, but was also our teacher.

PMID- 10640097
TI  - Practical nursing.

PMID- 10640096
TI  - My cousin Sue, RN.

PMID- 10640098
TI  - Shaping the quality of health care for the elderly: are nursing students
      prepared?
AB  - Today, with few exceptions, a nurse's typical patient is an older adult. People
      65 and over represent 12.8 percent of the American population. Older adults
      account for over 60 percent of ambulatory adult primary care visits, 80 percent
      of home care visits, 48 percent of in-hospital patients, and 85 percent of
      residents in nursing homes.

PMID- 10640099
TI  - The NLN Webcast. Developing and implementing an online conference & business
      meeting.

PMID- 10640100
TI  - Technology in the nursing classroom.

PMID- 10640101
TI  - Competency outcomes for learning and performance assessment. Redesigning a BSN
      curriculum.
AB  - In an atmosphere in which disgruntled students appeal to their legislators for
      intervention and faculty give few unsatisfactory clinical grades, the faculty of
      this state supported school of nursing began a two-step process to strengthen the
      assessment of students. The first step consisted of the appointment of a testing
      committee to provide faculty with ongoing assistance with test construction. The
      next concerned clinical evaluation.

PMID- 10640102
TI  - When students can't write. Solutions through a writing-intensive nursing course.

PMID- 10640103
TI  - Writing for publication in an RN to Baccalaureate program: an exercise in
      critical thinking.
AB  - More than 35,700 registered nurses are currently enrolled in an RN to
      Baccalaureate completion program (I). The demand for these graduates is expected
      to continue, along with an increased demand for community-based educational
      programs. Many of these students have significant clinical experience and
      expertise. Nursing faculty are challenged to develop learning experiences and
      program outcomes that enhance their professional skills and add to their
      expertise.

PMID- 10640104
TI  - Formulating priorities for research in nursing education: a consensus-building
      approach.
AB  - To expand the scientific foundation for nursing education, the National League
      for Nursing is establishing a national agenda for research in nursing education.
      This groundbreaking effort will define research priorities that can serve as a
      rallying point for education researchers across the nation. The goal of this
      consensus-building effort is to focus nursing education research efforts on
      discovering the core of knowledge needed to bridge education and practice as we
      move into the 21st century. This article describes the process being used in this
      historic dialogue.

PMID- 10640106
TI  - Empowering people for better health.

PMID- 10640105
TI  - How does NLNAC handle schemes and scams and inaccurate information?

PMID- 10640107
TI  - Induced hypothermia for head injury.
AB  - Normal and altered pathophysiology of the brain are discussed. Mechanisms of
      cerebral protection by induced hypothermia are outlined. Current research on
      induced hypothermia for brain injury is summarised. Nursing implications for the
      care of these patients are considered including ethical, monitoring and health
      and safety issues.

PMID- 10640108
TI  - Factors known to raise intracranial pressure and the associated implications for
      nursing management.
AB  - Raised intracranial pressure is a major, life-threatening complication addressed
      daily by nurses caring for the neuroscience patient. The primary nursing goal of
      caring for patients with severe head injury is to prevent secondary brain damage
      by controlling increases in intracranial pressure. Nursing management is complex
      and requires structured, specialised care in order to reduce the potential
      adverse effects of raised intracranial pressure associated with common nursing
      procedures.

PMID- 10640109
TI  - Is there a place for parents in the retrieval of critically sick children?
AB  - Retrieval of critically sick children is becoming commonplace within large
      paediatric intensive care centres and has gained much publicity. Only limited
      attention has been paid to the parents of children undergoing emergency
      transportation. Partnership with parents is central to paediatric nursing, yet
      parents are not generally welcome to travel with their child in an emergency.
      This paper argues that it may be possible for parents to be involved with the
      care of their child during retrieval.

PMID- 10640110
TI  - What are the attitudes of coronary care nurses towards the introduction of nurse
      initiated thrombolysis?
AB  - This study explores nurses' attitudes to the introduction of nurse-initiated
      thrombolysis, within a large district coronary care unit. A qualitative survey
      was used to elicit attitudes from all ENB 124 qualified members of staff
      presently employed within the unit. Concerns expressed by the nursing staff,
      prior to introduction of this practice, are described. Four key themes emerging
      from the data are explored; framework for practice; scope for advanced practice;
      decision-making policy; personal attributes. With the increased introduction of
      nurse-initiated thrombolysis, further research within this area is advocated.

PMID- 10640111
TI  - The parameters that cardiothoracic intensive care nurses use to assess the
      progress or deterioration of their patients.
AB  - Intensive care nurses spend approximately 17% of their time recording patient
      observations. There is little published evidence that investigates how nurses
      prioritize their observations within cardiothoracic intensive care. This study
      used a questionnaire to identify which parameters would be used by nurses working
      within a cardiothoracic intensive care unit to monitor the progress or
      deterioration of patients postoperatively. Comparison with two pieces of medical
      research identified a number of parameters which both nursing and medical staff
      saw as important in establishing the status of a patient. These were: arterial
      blood gases, cardiac index, central venous pressure, chest drainage, fluid
      balance total, heart and rhythm, pulmonary artery pressures, pulse oximetry,
      pupil reaction, urea and electrolytes, urine output, and ventilator observations.
      It is suggested that these parameters could be given priority in the development
      of future computerised or paper documentation.

PMID- 10640112
TI  - On the receiving end: experiences of being a relative in critical care. Part 1.
AB  - This is the first of a series of three papers, presenting in her own words the
      experiences of Jane, an intensive care staff nurse, when her husband was admitted
      to her own intensive care unit. In part one, Jane describes her husband's
      admission to the accident and emergency department, the intensive care unit and
      subsequent transfer to a regional neurological unit. Jane gives a powerful and
      often very moving account of her experiences as a relative on the receiving end
      of critical care. There are many aspects of her husband's nursing and medical
      care, with which Jane remains dissatisfied. Some of these issues are discussed
      through professional commentaries, which are offered in the latter part of the
      paper.

PMID- 10640113
TI  - Nurse versus technician: the dilemma of intensive care nursing.
AB  - A definition of technology and technician is offered, relating this to nursing in
      the intensive care unit. It is evident that technicians are focused upon the goal
      of providing care to the machinery. Intensive care nurses possess attributes of
      the technician, but also take into account the wider issues surrounding the
      patient. A conclusion that technology is a means to aid the nurse during his/her
      nursing practice is drawn.

PMID- 10640114
TI  - When things do not turn out the way we expect.

PMID- 10640115
TI  - Using the telephone to improve health behavior and health service delivery.
AB  - The technology for using the telephone to deliver interventions to improve health
      behavior and health care has expanded dramatically and exciting innovations
      continue to emerge. These developments enable the telephone to be used to deliver
      individualized services to a broad cross section of target groups, while
      minimizing logistic and system barriers, and cost. However, as telephone
      delivered interventions have proliferated, a number of questions remain
      concerning the elements that are essential to their effectiveness. We provide a
      broad overview of telephone interventions, published in the past 10 years to
      identify gaps in knowledge about these services, and make recommendations for
      future program development and evaluation.

PMID- 10640116
TI  - A crossover trial evaluating an educational-behavioural joint protection
      programme for people with rheumatoid arthritis.
AB  - Joint protection (JP) is a self-management technique widely taught to people with
      rheumatoid arthritis (RA). JP education aims to enable people with RA to reduce
      pain, inflammation, joint stress and reduce risks of deformity through using
      assistive devices and alternative movement patterns of affected joints to perform
      everyday activities. Previous studies evaluating JP education methods common in
      the UK have identified JP adherence is poor. A group education programme was
      developed using the Health Belief Model and Self-efficacy Theory. Strategies used
      to maximise JP adherence included goal-setting, contracting, modelling, homework
      programmes, motor learning theory, recall enhancing methods and mental practice.
      A crossover trial (n = 35) was conducted. Adherence with JP was measured using an
      objective observational test (the Joint Protection Behaviour Assessment).
      Significant improvements in use of JP were recorded at 12 and 24 weeks post
      education (P < 0.01). No significant changes in measures of pain, functional
      disability, grip strength, self-efficacy or helplessness occurred post-education,
      although this may have been due to the small sample size recruited. In
      conclusion, JP adherence can be facilitated through the use of educational
      behavioural strategies, suggesting this approach should be more widely adopted in
      clinical practice.

PMID- 10640117
TI  - Pain, coping and analgesic medication usage in rheumatoid arthritis patients.
AB  - The major purposes of this study were to describe pain characteristics and coping
      strategies used in rheumatoid arthritis (RA) patients. Further purposes were to
      examine relationships among pain, coping and analgesic medication intake. Sixty
      eight consecutively sampled subjects with RA participated in the study. The Pain
      O-Meter was used to evaluate pain intensity and quality, and the Coping
      Strategies Questionnaire (CSQ) to determine coping strategies. The results showed
      that the patients with RA scored more intense sensory than affective pain
      although they used more affective pain descriptors. The sensory and total pain
      components were related to coping self-statements and increased pain activities.
      There were significant relationships between analgesic medication intake and all
      coping strategies used in the RA patients. The findings' implication for
      education and treatment are discussed.

PMID- 10640118
TI  - Promoting self-care in epilepsy: the views of patients on the advice they had
      received from specialists, family doctors and an epilepsy nurse.
AB  - The aim of the study was to examine patients' satisfaction with information and
      advice on epilepsy and self-care provided by medical specialists, general
      practitioners and a special nurse. We interviewed patients following a trial of
      nurse-run clinics for epilepsy in general practice. 44 patients, two-thirds of
      whom had at least one epilepsy attack in the prior 6 months were seen in their
      homes in the south of England. A recurring theme from interview data was that
      patients perceived the doctors' time as too limited to explain the condition and
      how to manage it, whilst the nurse had the time and expertise to do so. Overall
      the nurse trained in epilepsy care was valued highly for providing advice and
      support, especially in explaining the social aspects of epilepsy. Patients
      expressed the belief that they would have benefited most by seeing a special
      nurse at the time when epilepsy was first diagnosed.

PMID- 10640119
TI  - Knowledge and attitudes of children towards cigarette smoking and its damage.
AB  - The present study reports the results of knowledge and attitudes of 280 children
      (mean age = 6.9 +/- 0.75 years) towards cigarettes and smoking. Subjects were
      divided into two groups: (I) children of parents who smoked (n = 178) and (II)
      children whose parents did not smoke (n = 102). The scoring for knowledge in the
      topics of cigarettes, smoking and the consequences was similar in the two groups
      (6.2 +/- 2.2 vs 6.1 +/- 2) (N.S.). The differences between the two groups were
      obvious and significant (p = 0.001) in their attitude towards smoking and its
      damage; children in group I displayed tolerant attitudes towards smoking even
      though they knew its consequences in comparison with the children of group II
      (6.1 +/- 2.4 vs 7.0 +/- 2.2). Without any exceptions among the children of the
      two groups, 7.4% believe that even at this young age they will begin to smoke one
      day. In addition, 2.1% pointed out that it is possible they will belong one day
      to the smokers' group. Of the population study, 90.2% believe that instruction
      about smoking damage should be included starting from the first grade of
      elementary school, and certainly, it should be at the level which will be
      understandable for them. As the pupils' knowledge about the consequences of
      smoking was lacking, we could add that the important topic of smoking and the
      damage it can inflict should be taught in all schools from the level of the first
      grade and during all subsequent years of study. Pupils should be familiar with
      all aspects of negative consequences caused by cigarette smoking. This knowledge
      may have influence upon their attitude towards smoking and smokers. More studies
      should be done to find what may change the positive attitudes of these pupils
      towards cigarettes and smoking.

PMID- 10640120
TI  - Self medication and health habits in the management of upper gastrointestinal
      symptoms.
AB  - Upper gastrointestinal symptoms are a common complaint among the general
      population but only a small proportion of sufferers seek medical advice. The aim
      of this study was to examine what kind of perceptions persons using self
      medication have about the causes of their gastrointestinal symptoms, whether they
      have made any health-related lifestyle changes, and whether visits to a physician
      are related to lifestyle changes. A pharmacy-based survey was done in 10
      pharmacies in the Helsinki area in 1995. The questionnaire was completed by 292
      customers. The response rate was 53%. Respondents in a population-based health
      interview survey (n = 10,410) were used as a comparison group for poor health
      behavior (consumption of tobacco, alcohol, coffee). The most common perceived
      causes of gastrointestinal symptoms were poor diet, coffee, and stress. Ignorance
      about possible causes of symptoms was especially common among less educated
      respondents and among those persons who had never visited a physician due to
      their symptoms. Respondents were significantly more often smokers and they had
      attempted to reduce their coffee and alcohol consumption more often than the
      general population. Those who had visited a physician during past year, less
      often had poor health-behavior and they had better knowledge about the possible
      causes of their symptoms. They had also made lifestyle changes more often, but
      after adjustment for background characteristics, physician visits were positively
      correlated only with coffee reduction. Counseling about healthy lifestyles,
      especially about smoking, should be increased in physician consultations and in
      pharmacies for all patients and customers having gastrointestinal problems.

PMID- 10640121
TI  - Diabetes care from diagnosis: effects of training in patient-centred care on
      beliefs, attitudes and behaviour of primary care professionals.
AB  - In a randomised trial, general practitioners and nurses in 21 practices were
      trained in patient-centred consulting and use of materials for people with Type 2
      diabetes (GPs 0.5 days; nurses 1.5 days; two optional follow-up half-days).
      Twenty practices formed the comparison group. Professional beliefs, attitudes and
      behaviour were measured (pre-trial, close-of-course and end-of-trial), supported
      by patient reports of nurse behaviour (141 trained: 108 comparison patients, 1
      year after diagnosis). A total of 49 practice nurses responded (29 trained; 20
      comparison). Trained nurses rated relative importance of patient-centred to
      professional-centred care as greater than comparison nurses. Trained nurses
      became less keen on the approach during the trial, and perceived time constraints
      persisted. Patients diagnosed later in the study were less likely to recognise
      intervention materials. Trained nurses rated delivery of important aspects of
      care and satisfaction with style of care as lower than comparison nurses, but
      patients were more positive about delivery of care from trained than comparison
      nurses. Although nurses rated patient-centred care as important, whether or not
      they had been trained as part of the trial, the short, generalizable training
      programme significantly reduced nurse perceptions of their ability to deliver it.
      Nonetheless, patients reported that important aspects of diabetes care were
      delivered more if their nurses had been trained in patient-centred consulting.
      This raises issues concerning measurement scales completed by trained
      professionals.

PMID- 10640122
TI  - A Dutch 'Poststroke Guide': distribution and use.
AB  - Stroke patients and caregivers have a substantial need for information. The Dutch
      'Poststroke Guide' was written in an attempt to meet this need. The study
      investigates the distribution of this guide among stroke patients, caregivers,
      and stroke providers. Stroke patients and caregivers who ordered a copy of the
      first edition received a questionnaire to evaluate the guide and to provide
      information about personal characteristics. Nearly one-third of the guides finds
      its way directly to stroke patients and/or caregivers and more than two-thirds
      goes to providers. Since providers are calling stroke patients' attention to the
      guide to an increasing extent, the information for caregivers ought to be
      improved. Mainly young, slightly disabled male stroke patients with healthy
      caregivers returned the questionnaire. Both stroke patients and caregivers read
      the guide thoroughly; it clearly meets their need for information. In the future,
      distribution will have to be less selective.

PMID- 10640123
TI  - Study circles at the pharmacy--a new model for diabetes education in groups.
AB  - During the past years diabetes education has developed greatly. However, a survey
      of diabetes care in Sweden in 1995 showed that only 40% of the patients examined
      had acceptable HbAlc values. This underlines the need for an effective and low
      cost patient education programme. In this study we tested the feasibility of a 1
      year group education model for patients with type 2 diabetes at Swedish
      pharmacies. In the study circles, led by specially trained pharmacists,
      participants learned how to self-monitor glucose, to interpret the results and to
      act upon them. We conclude that study circles held at pharmacies are a feasible
      way of educating persons with type 2 diabetes. The group setting promoted
      learning through peer help and gave emotional support to participants. Metabolic
      control as measured by HbAlc improved significantly after 6 months, but reverted
      to baseline levels again at 12 months. The reason for this needs further
      investigation.

PMID- 10640124
TI  - Strike?

PMID- 10640125
TI  - Books and the Net.

PMID- 10640126
TI  - Ethics in action. A nurse on a critical care unit has promised her terminally ill
      patient that she will care for him until the end.

PMID- 10640127
TI  - What is the Best Practice Network?

PMID- 10640128
TI  - Critical care close-up.

PMID- 10640129
TI  - What to tell parents about car restraints.

PMID- 10640130
TI  - 1999 earnings survey. What about benefits?

PMID- 10640131
TI  - Iatrogenic injuries: air embolism.

PMID- 10640132
TI  - When the inner ear is out of balance.

PMID- 10640133
TI  - Would you look for this CAD risk factor?

PMID- 10640134
TI  - John needed all I could give.

PMID- 10640135
TI  - Burns. Handle with care.

PMID- 10640136
TI  - Thermometers.

PMID- 10640137
TI  - Good Samaritan laws: protections and limits.

PMID- 10640138
TI  - A new way to treat uterine fibroids.

PMID- 10640139
TI  - Radiation-associated sarcomas are characterized by complex karyotypes with
      frequent rearrangements of chromosome arm 3p.
AB  - Ionizing radiation is a well-known risk factor for sarcoma development. To
      investigate whether radiation-associated sarcomas are characterized by chromosome
      aberrations that distinguish them from de novo sarcomas, we identified those
      patients in our series of more than 500 cytogenetically abnormal sarcomas that
      fulfilled the following criteria: (1) each patient should have been irradiated
      for another malignancy at least 3 years prior to the sarcoma diagnosis, and (2)
      the sarcoma should have developed within the field of radiation. Ten patients
      fulfilling these criteria could be retrieved (median age at sarcoma diagnosis was
      55 years, range 17-79; median latency period between primary tumor and radiation
      associated sarcoma was 9 years, range 4-30). The diagnoses were typical for
      radiation-associated sarcomas: 2 each of malignant fibrous histiocytoma,
      leiomyosarcoma, and pleomorphic sarcoma, and 1 each of osteosarcoma,
      fibrosarcoma, myxofibrosarcoma, and spindle cell sarcoma. All 10 cases had
      relatively complex karyotypes with multiple, mostly unbalanced, structural
      rearrangements, similar to what has been reported in de novo sarcomas of the
      corresponding histologic subtypes. The only cytogenetic features that were
      unusually frequent among the radiation-associated sarcomas were the finding of
      unrelated clones in 3 cases, and loss of material from chromosome arm 3p, in
      particular 3p21-3pter, in 8 cases. Loss of the same chromosome segment has been
      described in 4 of the 8 previously published cases of radiation-associated
      sarcomas that have been analyzed after short-term culturing, which makes this
      imbalance significantly (P < 0.001) more frequent among radiation-associated
      sarcomas (12 of 18 cases) than among unselected cases of the corresponding
      histologic subtypes (74 of 282 cases). In contrast to the cytogenetic results, no
      3p deletions were detected among the 6 cases of the present series that could be
      analyzed by comparative genomic hybridization (CGH). The most frequent imbalance
      detected by CGH was gain of 15cen-q15 (3 cases), followed by loss of chromosome
      13 and gain of 5p, and 7cen-q22, each detected in 2 cases.

PMID- 10640140
TI  - A multicenter investigation with D-FISH BCR/ABL1 probes.
AB  - Twenty-eight laboratories evaluated a new fluorescence in situ hybridization
      (FISH) strategy for chronic myeloid leukemia. In a three-part study, bcr/abl1 D
      FISH probes were used to study bone marrow specimens. First, laboratories
      familiarized themselves with the strategy by applying it to known normal and
      abnormal specimens. Then, collectively the laboratories studied 20 normal and 20
      abnormal specimens blindly and measured workload. Finally, each laboratory and
      two experts studied six serial dilutions with 98-0% abnormal nuclei. Using the
      reported normal cutoff of < 1% abnormal nuclei, participants reported no false
      negative cases and 15 false-positive cases (1-6.6% abnormal nuclei). Results
      provided by participants for serial dilutions approximated the expected
      percentages of abnormal nuclei, but those from the experts exhibited greater
      precision. The clinical sensitivity, precision, nomenclature, workload,
      recommendations for training, and quality assurance in methods using D-FISH in
      clinical practice are discussed.

PMID- 10640141
TI  - Multiplex fluorescence in situ hybridization and cross species color banding of a
      case of chronic myeloid leukemia in blastic crisis with a complex Philadelphia
      translocation.
AB  - Exciting new techniques in molecular cytogenetics--namely, spectral karyotyping,
      multiplex fluorescence in situ hybridization (M-FISH), and cross species color
      banding--have been recently developed. An increasing number of reports
      demonstrate the success of these procedures in providing additional cytogenetic
      information--identifying marker chromosomes and revealing the presence of
      previously undetected chromosomal changes. However, these procedures have their
      limitations, and their absolute sensitivity in the accurate identification of
      subtle chromosomal abnormalities remains to be established. M-FISH and color
      banding have been applied to a case of chronic myeloid leukemia with a complex
      Philadelphia translocation involving chromosomes 9, 17, and 22, which had
      initially been identified from G-banded chromosome analysis. The abnormalities
      were confirmed by chromosome "painting" and specific probes. Although M-FISH and
      color banding revealed no additional cryptic chromosomal changes, this study has
      clearly demonstrated the success of these multiple color FISH approaches in the
      accurate characterization of a complex rearrangement with subtle abnormalities.

PMID- 10640142
TI  - Trisomy 11 and a complex t(11;11;22) in a patient with acute myelomonocytic
      leukemia (AML-M4) following myelodysplasia (MDS): a cytogenetic study of a
      mechanism of leukemogenesis.
AB  - We describe a 73-year-old man diagnosed with acute myelomonocytic leukemia (AML
      M4) following myelodysplasia with trisomy 11 and with a t(11;11;22). This is the
      first case with both abnormalities present in the same cells and with the
      t(11;11;22) involving a chromosome 11 already duplicated at 11q23. This band
      contains the MLL gene that undergoes partial tandem duplication in patients with
      +11, which is "promiscuous," being translocated with a large number of genetic
      partners. Our patient had a complex karyotype that was completely defined by in
      situ hybridization. This technique demonstrated that the t(11;11;22) derivative
      with a duplication of band 11q23 carried from three to four copies of MLL. Two
      copies of the gene were close to each other and centromeric to the break-point
      region. Therefore, a partial tandem duplication of the MLL gene might have
      happened before the occurrence of t(11;11;22). Considering the associated
      chromosome defects, the monosomy for the long arm of chromosome 7, due to an
      unbalanced translocation t(7;17), further underlines the possibility that a
      partial tandem duplication of the MLL gene might have taken place.

PMID- 10640143
TI  - Complex chromosome 9, 20, and 22 rearrangements in acute lymphoblastic leukemia
      with duplication of BCR and ABL sequences.
AB  - Cytogenetic analysis was performed on bone marrow cells from a 28-year-old woman
      who was diagnosed with acute lymphoblastic leukemia (ALL). Her karyotype was:
      46,XX,t(9;22)(q34;q11)[6]/47,
      XX,+8,t(9;22)(q34;q11)[4]/47,XX,+8,t(9;22)(q34;q11),del(20)(q11)[2]/46,
      XX,t(9;22)(q34;q11),del[20](q11)[7]/45,XX,der(9)t(9;22)(q34;q11),-20,-22 ,
      +mar1[8]/45,XX,der(9)t(9;22)(q34;q11),-20,-22,+mar2[3]. Both marker chromosomes
      are dicentric and have the same size and banding pattern but different primary
      constrictions. Fluorescence in situ hybridization (FISH) demonstrated that both
      markers were derived from chromosomes 9, 20, and 22. FISH with the bcr/abl probe
      showed fusion of the BCR gene with the ABL gene; however, this fusion signal was
      present in duplicate on both marker chromosomes. To our knowledge, duplication of
      the BCR/ABL fusion signal on a single chromosome arm has not been reported
      before, except for the extensive amplification of BCR/ABL fusion signals in the
      leukemic cell line K-562. These data demonstrate that the marker chromosomes are
      the result of complex genomic rearrangements. At the molecular level, the BCR/ABL
      fusion gene encodes the p190 fusion protein. Similar findings have never been
      observed in any case of ALL.

PMID- 10640144
TI  - Full cytogenetic characterization of a new neuroblastoma cell line with a complex
      17q translocation.
AB  - Recent studies have shown that structural abnormalities of chromosome 17
      resulting in gain of material are the most frequent genetic changes in
      neuroblastoma. We have established a new neuroblastoma cell line from a patient
      whose disease had evolved from stage 4s to 4, without evidence of deletion of the
      short arm of chromosome 1 and MYCN amplification, which are considered the most
      typical genetic indicators of aggressive disease. The cytogenetic study allowed a
      full characterization of the chromosome changes, and revealed a complex
      translocation of chromosome 17 leading to a derivative marker which may be
      described as follows: der(11)t(11;17)(p15;q12)t(11;17) (q22;q12). This resulted
      in a gain of part of the long arms of chromosome 17, which was recently
      associated with poor prognosis.

PMID- 10640145
TI  - DNA copy number changes and evaluation of MYC, IGF1R, and FES amplification in
      xenografts of pancreatic adenocarcinoma.
AB  - We analyzed eight samples of xenografted human pancreatic tumors and two
      metastases developed in mice by comparative genomic hybridization (CGH). The most
      recurrent changes were: gains on chromosomes 8 (8q24-qter; 7/8 cases), 15 (15q25
      q26; 6/8 cases), 16 (16p in 6/8 cases; 16q in 5/8 cases), 20 (20q; 6/8 cases),
      and 19 (19q; 5/8 cases); and losses on chromosomes 18 (18q21; 6/8 cases), 6 (6q16
      q21 and 6q24-qter; 5/8 cases each), and 9 (9p23-pter; 5/8 cases). The two
      metastases maintained the aberrations of the original pancreatic tumor plus gain
      of 11q12-q13 and 22q. Loss of heterozygosity analysis was carried out for 10p14
      pter, a region that was lost in 3/8 samples. All of them presented allelic
      imbalance for all the informative loci. Fluorescence in situ hybridization and
      Southern analysis were performed to test some candidate oncogenes in 8q24 (MYC)
      and 15q25-qter (IGF1R and FES). Two of seven tumors showed high-level
      amplification of MYC relative to the centromere (> 3-fold), another two tumors
      had low-level amplification (1.5- to 3.0-fold), and one displayed 5.5 MYC
      signals/cell. In relation to the FES gene, low-level amplification was found in
      three tumors. Southern analysis showed five cases with a low-level amplification
      of IGF1R. Our data suggest that either few extra gene copies may be enough for
      cancer progression or other genes located in these regions are responsible for
      the amplifications found by CGH.

PMID- 10640146
TI  - hRAD54 gene and 1p high-resolution deletion-mapping analyses in
      oligodendrogliomas.
AB  - The hRAD54 protein belongs to a superfamily of DNA helicases, and mutations in
      genes with DNA helicase function have been found to be responsible for cancer
      prone syndromes (xeroderma pigmentosum, Bloom syndrome, Werner syndrome). hRAD54
      thus could be a candidate modifier gene in tumors characterized by allelic
      imbalance at 1p32, the chromosome region in which this gene is located. Using a
      panel of 38 1p and five 1q markers, we therefore performed deletion-mapping
      analysis on a series of 35 oligodendrogliomas, which were also studied for
      mutations in the hRAD54 gene. Deletions of the short arm of chromosome 1 were
      evidenced in 26 tumors, mostly involving 1p36-1p13; all thus displayed loss of
      the 1p32 region. We used PCR/SSCP to examine all 18 exons of the hRAD54 gene for
      mutations in 25 tumors, but the mobility shifts detected corresponded to
      previously identified polymorphic changes: T-to-C transition at nucleotide 2865
      (with no amino acid change) and at nucleotide 3008, at the 3' untranslated
      region. We conclude that hRAD54 gene alterations are not required for malignant
      transformation of oligodendrogliomas.

PMID- 10640147
TI  - Fluorescence in situ hybridization identifies inversion 16 masked by
      t(10;16)(q24;q22), t(7;16)(q21;q22), and t(2;16)(q37;q22) in three cases of AML
      M4Eo.
AB  - Bone marrow or peripheral blood from three patients had a t(10;16)(q24;q22),
      t(7;16) (q21;p13.1), and t(2;16)q37;q22), respectively. In all cases,
      fluorescence in situ hybridization confirmed an inv(16) masked by the
      translocation. The three patients were diagnosed with acute myelomonocytic
      leukemia and increased eosinophils. Because inv(16) has a favorable prognosis,
      identification of masked inv(16) will promote improved management of these cases.
      Therefore, all cases that have atypical rearrangement of chromosome 16 should be
      investigated for a possible inversion.

PMID- 10640148
TI  - Translocation (8;13)(q24.2;q33) in a malignant rhabdoid tumor of the liver.
AB  - A case of malignant rhabdoid tumor of the liver associated with hypercalcemia of
      malignancy was studied. The karyotype of the liver primary was
      46,XY,t(8;13)(q24.2;q33)[7]/46,XY[13], and of the brain metastasis
      46,XY,t(8;13)(q24;q33)[5]/46,XY,t(7;13)(p14;q22) [3]/46,XY,t(1;2;3)(q25;q21;p21)
      [2]/46,XY[13], respectively. Band 8q24 was previously reported to be rearranged
      in two malignant rhabdoid tumors, one renal and one hepatic.

PMID- 10640149
TI  - Cellular senescence of a human bladder carcinoma cell line (JTC-32) induced by a
      normal chromosome 11.
AB  - Human chromosome 11 is expected to carry tumor suppressor genes for a variety of
      human cancers, including bladder carcinoma. To examine the functional role of a
      putative tumor suppressor gene(s) on this chromosome in the development of
      bladder carcinoma, we performed microcell-mediated transfer of chromosome 11 into
      the bladder carcinoma cell line, JTC-32. Fifteen of 20 colonies formed by the
      transfer experiment showed a remarkable change in cell morphology. They flattened
      and ceased growing, or senesced, prior to 10 population doublings. The presence
      of transferred chromosome 11-derived fragments in the growth-arrested cells was
      confirmed by PCR-based polymorphism analyses. The remaining 5 microcell hybrid
      clones exhibited a parental cell-like morphology, and presumably escaped from
      senescence, which was accompanied by deletions and/or rearrangements of the
      transferred chromosome 11. On the other hand, a transferred normal chromosome 7
      neither changed the cell morphology nor arrested the cell growth. These results
      support the hypothesis that chromosome 11 contains a gene or genes which restore
      the senescence program lost during the immortalization process of JTC-32 cells.

PMID- 10640150
TI  - Regional fine mapping of HMG17 to chromosomal band 1p35.
AB  - HMG17, a member of the high-mobility group of proteins, is ubiquitously expressed
      in higher eukaryotes. This protein has been shown to enhance transcriptional
      activity of many other genes. Recently, the HMG17 gene has been mapped to
      chromosomal band 1p36.1. Because this region is frequently involved in
      chromosomal aberrations of various human neoplasms, two PAC clones containing an
      HMG17 sequence were isolated. By fluorescence in situ hybridization (FISH) on
      prometaphase spreads, HMG17 was mapped to chromosomal band 1p35.

PMID- 10640151
TI  - Chronic myeloid leukemia with a rare variant Philadelphia translocation:
      t(9;22;21)(q34;q11;q22).
AB  - A case of chronic myeloid leukemia displaying an uncommon t(21;22)(q22;q11) is
      reported. For the first time, this translocation has been characterized by
      fluorescence in situ hybridization (FISH) and the reverse transcriptase
      polymerase chain reaction (RT-PCR). FISH, with the use of whole-chromosome
      painting probes and probes specific for the BCR and ABL genes, showed a three-way
      variant Philadelphia translocation (9;22;21)(q34;q11;q22) with a BCR/ABL fusion
      residing on the der(22). In addition, RT-PCR demonstrated a b2a3 BCR/ABL fusion
      transcript. Underlying mechanisms and prognostic implications are discussed.

PMID- 10640152
TI  - Familial acute myeloid leukemia with monosomy 7: late onset and involvement of a
      multipotential progenitor cell.
AB  - Familial acute myeloid leukemia (AML) with monosomy 7 is a rare syndrome with
      fewer than 10 families reported. The salient features included a young median age
      (8 years) at presentation, equal sex preference, and occurrence of cytopenias and
      myelodysplasia in nonleukemic family members. Owing to its rarity and the fact
      that many cases were reported quite some time ago, detailed clinicopathologic
      features of familial monosomy 7 were not available. We describe a family with
      three siblings affected by AML in whom monosomy 7 was demonstrated. This family
      showed several unique features, including the late onset of AML (at 34 and 37
      years of age in two siblings), and the presence of an antecedent myelodysplastic
      phase before leukemia development. With fluorescence in situ hybridization, the
      monosomy 7 clone was shown to be capable of partial maturation, which was
      consistent with the biologic behavior of myelodysplasia. These observations
      suggest that familial leukemia with monosomy 7 is probably a multistep
      leukemogenic process in which monosomy 7 might be but one of the critical steps.
      Finally, the prognosis in these cases was poor, suggesting that more aggressive
      therapy may be needed to improve treatment outcome.

PMID- 10640153
TI  - Do rosette, heterochromatin, and/or genomic imprinting influence preferential
      translocations in human neoplasia?

PMID- 10640154
TI  - Trisomy 15 in hematological disorders.

PMID- 10640155
TI  - Estimating the efficacy of medical abortion.
AB  - Comparisons of the efficacy of different regimens of medical abortion are
      difficult because of the widely varying protocols (even for testing identical
      regimens), divergent definitions of success and failure, and lack of a standard
      method of analysis. In this article we review the current efficacy literature on
      medical abortion, highlighting some of the most important differences in the way
      that efficacy has been analyzed. We then propose a standard conceptual approach
      and the accompanying statistical methods for analyzing clinical trials of medical
      abortion and to explain how clinical investigators can implement this approach.
      Our review reveals that research on the efficacy of medical abortion has closely
      followed the conceptual model used for analysis of surgical abortion. The
      problem, however, is that, whereas surgical abortion is a discrete event
      occurring in the space of a few minutes or less, medical abortion is a process
      typically lasting from several days to several weeks. In this process, two events
      may occur that are not possible with surgical abortion. First, the woman can opt
      out of the process before a fair determination of efficacy can be made. Second,
      the process of medical abortion allows time for surgical interventions that may
      be convenient for the clinician but not strictly necessary from a medical
      perspective. Another difference from surgical abortions is that, for medical
      abortions, different medical abortion protocols specify different waiting
      periods, giving the drugs less time to work in some studies than in others before
      a determination of efficacy is made. We argue that, when analyzing efficacy of
      medical abortion, researchers should abandon their close reliance on the analogy
      to surgical abortion. In fact, medical abortion is more appropriately analyzed by
      life table procedures developed for the study of another fertility regulation
      technology; contraception. As with medical abortion, a woman initiating use of a
      contraceptive method can change her mind after some period of exposure and opt
      out. Also, as with medical abortion, a contraceptive can fail, usually with the
      risk of failure depending heavily on whether or not the woman follows the
      protocol for that method precisely. Finally, as with medical abortion, medical
      conditions may arise that necessitate discontinuing use of the contraceptive
      method. In both cases, these medical conditions are sometimes open to
      interpretation or subject to the skill, judgment, or experience of the clinician
      involved. The appropriate information to collect for a multiple decrement life
      table analysis of medical abortion includes data on compliance with the protocol,
      timing of the event of interest (abortion) when it is observable, and, because we
      argue that these should be regarded as events of interest, a typology of any
      surgical interventions that are conducted during the woman's participation in the
      study.

PMID- 10640156
TI  - Influence of cycle variability and coital frequency on the risk of pregnancy.
AB  - Researchers have cautioned against generalizing results from contraceptive trials
      because these studies rely on self-selected participants meeting strict selection
      criteria who may differ from typical users. Using information collected on daily
      diaries, we reanalyzed data from the recently completed Reality female condom
      clinical trial to evaluate factors that influence the probability of pregnancy.
      Noncompliant women, women with less variable menstrual cycles (17-43 days), and
      women engaging in intercourse frequently (> or = 11 acts per month) were more
      likely to conceive during this 6-month trial. The adjusted hazard ratios and 95%
      confidence intervals for these three covariates were 6.1 (2.0-18.7), 7.2 (1.0
      54.3), and 2.0 (0.7-5.3), respectively. The strict selection criteria used in
      this study failed to recruit a homogeneous cohort with respect to factors that
      influence the risk of pregnancy. The overall pregnancy rate does not pertain to
      individual study participants, but rather represent average effects for a
      population with the particular mix of characteristics found in this study. In
      particular, we not only confirm the well known importance of compliance and the
      obvious role of frequency of intercourse, but also demonstrate that women with
      cycles outside the range of 17-43 days appear to be at a much lower risk of
      pregnancy.

PMID- 10640157
TI  - A prospective study of pregravid oral contraceptive use and risk of hypertensive
      disorders of pregnancy.
AB  - Oral contraceptive use is associated with hypertension, dyslipidemias, and
      insulin resistance, all of which also characterize hypertensive disorders of
      pregnancy. In this prospective cohort study, the association of oral
      contraceptive use before pregnancy and the risk of gestational hypertension and
      preeclampsia was assessed. Between 1991 and 1995, 3973 nulliparous women who
      reported their first pregnancy lasting > or = 6 months were studied. Pregravid
      exposures were collected by biennial mailed questionnaires, and cases were
      confirmed by medical record review. Recent oral contraceptive use was defined as
      use within 2 years of pregnancy. Proportional hazards analysis was used to adjust
      for potential confounding variables. During the 4 years of follow-up, 133 (3.3%)
      women with gestational hypertension and 62 (1.6%) with preeclampsia were
      identified. Twenty-five percent of women who did not develop these disorders were
      recent users of oral contraceptives, compared with 19% (p = 0.11) of women who
      developed gestational hypertension and 30% (p = 0.38) who developed preeclampsia.
      Mean duration of prior oral contraceptive use was similar for cases and noncases.
      Compared with never and past users, the multivariate relative risk among recent
      users for developing gestational hypertension was 0.7 (95% confidence interval
      (CI), 0.4-1.0) and for preeclampsia was 1.3 (95% CI, 0.8-2.4). Among recent users
      who had used oral contraceptives for > or = 8 years, the relative risk for
      gestational hypertension was 0.6 (95% CI, 0.3-1.2) and for preeclampsia was 2.1
      (95% CI, 1.1-4.2). When the analysis was restricted to women who had never
      smoked, the risk for gestational hypertension was 0.2 (95% CI, 0.1-0.9) and for
      preeclampsia was 4.1 (95% CI, 1.9-8.7). Thus, recent use of oral contraceptives
      was associated with a reduced risk for developing gestational hypertension. In
      contrast, there was a suggestion that recent use was associated with an increased
      risk of developing preeclampsia, but only among women who had used these agents
      for > or = 8 years.

PMID- 10640158
TI  - Endometrial histology during use of a low-dose estrogen-desogestrel oral
      contraceptive with a reduced hormone-free interval.
AB  - The object of the study was to determine the effect of a new low-dose ethinyl
      estradiol-desogestrel oral contraceptive on endometrial histology. The oral
      contraceptive regimen contained fixed doses of ethinyl estradiol (20 micrograms)
      and desogestrel (150 micrograms) for days 1-21, placebo on days 22 and 23, and
      ethinyl estradiol alone (10 micrograms) on days 24-28. Endometrial histology was
      assessed in tissue samples obtained during treatment cycles 13 and 14. All
      endometrial samples were sent to a central laboratory for processing and
      evaluation. No endometrial hyperplasia or metaplasia was found in the endometrial
      biopsy specimens obtained during cycles 13 and 14 in a subset of 12 women
      participating in a multicenter efficacy and safety study. These results suggest
      that this oral contraceptive regimen, which includes 5 days of unopposed ethinyl
      estradiol, is not associated with endometrial hyperplasia or metaplasia. The
      endometrial histologic findings observed in this study were similar to those
      observed during the use of 21-day combination oral contraceptive regimens.

PMID- 10640159
TI  - Analysis of client characteristics that may affect early discontinuation of the
      TCu-380A IUD.
AB  - The purpose of this study was to analyze the reasons for early discontinuation of
      the TCu-380A IUD in women participating in a large multicenter trial. The study
      relates specific characteristics of the women at the time of TCu-380A insertion
      with specific 1-year reasons for discontinuation. A secondary analysis was
      performed on data obtained from 2748 women from sites in Africa, Asia, and Latin
      America. By the end of the year, 321 discontinuations were observed. The gross
      cumulative 12-month life table rates of reasons for discontinuation were 13.3 for
      all reasons and 3.1, 4.5, and 4.3 for expulsion, removals for bleeding/pain, and
      personal reasons, respectively. Study site, age, and religion had a significant
      effect on early discontinuation. Women who had IUD insertions in the African
      centers had significantly higher expulsion rates than women from other centers.
      Women < 20 years old had significantly higher expulsion rates than older women.
      Muslim women had significantly higher rates of removal for bleeding and pain than
      women of other religions. This information may guide the counseling and follow-up
      process of women with such characteristics and result in a more satisfactory use
      and improved continuation rates of the TCu 380A.

PMID- 10640160
TI  - Effects of levonorgestrel-releasing subdermal contraceptive implants on bone
      density and bone metabolism.
AB  - A prospective, randomized clinical trial observed the effects of Norplant long
      term contraceptive implants and domestic implants similar to Norplant on bone
      mineral density and bone metabolism in female acceptors for 1 year. Bone mineral
      density (BMD) and bone mineral content (BMC) of lumbar 2-4 and proximal femur of
      61 normal women of child-bearing age were measured by dual energy x-ray
      absorptiometry (DEXA) before and 12 months after implants insertion in both
      groups. BMD and BMC of lumbar 2-4 in both groups 12 months after implant
      insertion significantly increased (p < 0.01); with an average increase of 2.40%
      and 3.34%, respectively in the Norplant implant group, and 2.75% and 4.47%,
      respectively in the domestic implant group. Urine hydroxyproline and creatinine
      ratio (Hop/Cr) in the domestic implant group significantly decreased (p < 0.01).
      There was no significant differences in the effects on BMD and BMC of lumbar
      spine and femur and on bone metabolism between the two groups of contraceptive
      implants (p > 0.05). Levonorgestrel releasing contraceptive subdermal implants
      were not deleterious to the skeleton in women of child-bearing age. There was no
      significant effect on achieving maximum bone mass in young women.

PMID- 10640161
TI  - Mifepristone-misoprostol medical abortion: home administration of misoprostol in
      Guadeloupe.
AB  - Mifepristone-misoprostol medical abortion promises to revolutionize reproductive
      health-care. Several simplifications of the standard three clinic visit regimen
      may be possible, however. Particularly in developing countries, access to the
      method can be greatly increased by eliminating the longest clinic visit. Indeed,
      shortly after mifepristone's introduction in Guadeloupe, a semi-developed
      Caribbean territory administered by France, in 1991, two of the authors conducted
      a small prospective study of a one treatment-visit regimen. The study regimen was
      subsequently adopted as the standard of care for medical abortion on the island.
      Women (n = 92) with amenorrhea of < or = 49 days received 600 mg mifepristone
      under clinical supervision and were given 400 micrograms oral misoprostol for
      home administration 2 days later, returning 2 weeks later for follow-up. The
      success rate (95.4%) is comparable to rates found when both drugs are
      administered in the clinic and to rates from a similar study conducted recently
      in the United States. Adverse events were also comparable to protocols requiring
      in-clinic administration of misoprostol. Protocol adherence appeared to be
      excellent and loss to follow-up was rare. We suggest that home administration of
      misoprostol can be safe and effective in most nonindustrialized settings.

PMID- 10640162
TI  - Medical treatment of a grossly enlarged adenomyotic uterus with the
      levonorgestrel-releasing intrauterine system.
AB  - Adenomyosis is an important cause of menorrhagia. Besides hysterectomy, the
      treatment options for adenomyosis have been limited. Presented here is the
      successful treatment of adenomyosis in a woman presenting with menorrhagia,
      dysmenorrhea, and an enlarging uterus, for whom conservative therapy initiated
      with mefenamic acid was unsatisfactory. The patient had insertion of the
      levonorgestrel-releasing intrauterine system (LNG-IUS). A marked decrease in
      uterine size occurred within 12 months of insertion accompanied by resolution of
      the menorrhagia and dysmenorrhea. Thus, the LNG-IUS is a viable option and
      represents a real advance in the treatment of adenomyosis.

PMID- 10640163
TI  - Lunelle monthly contraceptive injection (medroxyprogesterone acetate and
      estradiol cypionate injectable suspension): a contraceptive method for women in
      the US and worldwide.

PMID- 10640164
TI  - Comparative safety, efficacy, and cycle control of Lunelle monthly contraceptive
      injection (medroxyprogesterone acetate and estradiol cypionate injectable
      suspension) and Ortho-Novum 7/7/7 oral contraceptive (norethindrone/ethinyl
      estradiol triphasic). Lunelle Study Group.
AB  - An open-label, nonrandomized, parallel, controlled study compared the efficacy,
      safety, and cycle control of a new monthly injectable contraceptive containing 25
      mg of medroxyprogesterone acetate (MPA) and 5 mg of estradiol cypionate (E2C)
      (MPA/E2C) (Lunelle Monthly Contraceptive Injection) with that of a norethindrone
      0.5, 0.75, 1.0 mg/0.035 mg ethinyl estradiol (NET/EE) triphasic oral
      contraceptive (Ortho-Novum 7/7/7). At study enrollment, women chose either the
      injections or the oral contraceptive. A higher proportion of women in the NET/EE
      group (65.1%) than in the MPA/E2C group (48.7%) had used hormonal contraception
      during the month before the study (p < 0.01). Overall, 55.5% (434/782) of MPA/E2C
      users and 67.6% (217/321) of NET/EE users completed the 60-week trial. One-year
      contraceptive efficacy (13 cycles of 28 days) for MPA/E2C and NET/EE was based on
      8008 and 3434 woman-cycles of use, respectively. During the first year, one
      pregnancy occurred in an NET/EE user for a life table rate of 0.3; no pregnancies
      occurred in users of MPA/E2C. One additional pregnancy in the NET/EE group
      occurred during the 15th treatment cycle. After the first treatment cycle, women
      in both groups experienced regular menses, with an average cycle length of 28
      days in MPA/E2C users and 27 days in NET/EE users. Although MPA/E2C users were
      more likely to experience bleeding irregularities, only 2.5% (19/775) cited
      metrorrhagia as a reason for discontinuing treatment. The adverse events reported
      in both treatment groups are consistent with those expected with the use of
      combined hormonal contraceptives. Overall, the results of this first Phase III US
      clinical trial of MPA/E2C confirm this method's high contraceptive efficacy and
      safety, as shown in previous studies by the World Health Organization. These
      results suggest that a monthly combination injectable would represent a welcome
      new contraceptive option for women in the US.

PMID- 10640165
TI  - Lunelle monthly contraceptive injection (medroxyprogesterone acetate and
      estradiol cypionate injectable suspension): assessment of return of ovulation
      after three monthly injections in surgically sterile women.
AB  - The pharmacodynamic effects of medroxyprogesterone acetate (MPA) and estradiol
      cypionate (E2C) (MPA/E2C) (Lunelle Monthly Contraceptive Injection) on ovarian
      function were assessed through changes in serum progesterone concentrations. The
      data described here were obtained simultaneously with pharmacokinetic data
      presented in another article in this issue. Sixteen surgically sterile women with
      regular menstrual cycles were studied for one control cycle, three consecutive
      treatment months, and 3-5 months of follow-up. Suppression, followed by
      resumption of ovulation (the dynamic end point), was assessed by serum
      progesterone levels. Return of ovulation was presumptive based on progesterone
      concentrations > or = 4.7 ng/mL, as ultrasound was not used to determine the
      follicular/ovulatory status of these subjects. Luteal-like serum progesterone
      peaks were observed in all 16 women before drug administration, confirming the
      presence of ovulatory cycles. After the third monthly injection of MPA/E2C,
      progesterone concentrations were measured until demonstration of ovulation. Two
      women discontinued and three were lost to follow-up before this objective was
      achieved. Serum progesterone levels and, consequently, ovulation were suppressed
      beyond the entire dosing interval, indicated by the absence of any luteal-like
      progesterone peaks (serum progesterone concentrations did not exceed 1 ng/mL).
      The first normal ovulatory cycle, based on progesterone concentrations > or = 4.7
      ng/mL, was observed in 11 women between days 63 and 112 after the third
      injection. Select medroxyprogesterone acetate parameters (i.e., area under the
      curve and minimum concentration) were correlated with return of ovulation. The
      correlation coefficients (r) were 0.757 and 0.492 for area under the curve and
      minimum concentration, respectively, indicating that return of ovulation is
      dependent, in part, on area under the curve and on the magnitude of the serum MPA
      trough level. In general, the higher the minimum concentration levels, the longer
      the time to return of ovulation. In conclusion, the return of ovulation, as
      confirmed by serum progesterone concentrations > or = 4.7 ng/mL, was observed as
      early as 63 days after the third and final monthly intramuscular injection of
      MPA/E2C, suggesting that consistent suppression of the hypothalamic-pituitary
      ovarian axis is reversible after discontinuation of dosing.

PMID- 10640166
TI  - Lunelle monthly contraceptive injection (medroxyprogesterone acetate and
      estradiol cypionate injectable suspension): effects of body weight and injection
      sites on pharmacokinetics.
AB  - A new contraceptive option, medroxyprogesterone acetate (MPA) and estradiol
      cypionate (E2C) (MPA/E2C, Lunelle Monthly Contraceptive Injection), will soon be
      available for women in the US. This article reports the results of a US trial
      that assessed the effects of body weight and injection site on the
      pharmacokinetics of MPA, the progestin mediating contraceptive efficacy. This
      assessment was part of a nonrandomized, open-label, multicenter US study in
      healthy women receiving a monthly injection of MPA/E2C for 60 weeks. A total of
      77 women (aged 18-47 years) at four centers participated in the pharmacokinetics
      assessment during the sixth or the seventh injection. For determination of serum
      MPA concentration-time profiles, blood samples were collected before the sixth
      and seventh injections (day 0) and on days 3, 7, 14, 21, and 28 after the sixth
      and seventh monthly administrations. For effects of injection site, MPA
      pharmacokinetics were compared at injection sites of the arm, hip, and leg. The
      pharmacokinetics of MPA, determined at the sixth and seventh injection, were not
      significantly affected by injection sites. The mean area under the curve (AUC0
      28), however, was different between the arm and the leg injection sites; the
      difference was < 20%. More important, the average MPA trough concentrations
      (Cmin) at the fifth and sixth monthly injections were similar (range 0.42-0.51
      ng/mL) for the three injection sites and well above the threshold levels of 0.10
      0.20 ng/mL required to suppress ovulation. For effects of body mass index (BMI)
      on pharmacokinetics, women were stratified into three groups: thin/normal (BMI 18
      28, n = 48), obese (BMI 29-38, n = 23), and highly obese (BMI > 38, n = 6). There
      were no significant differences in the pharmacokinetics of MPA among the three
      BMI categories. The only significant difference (p = 0.0387) was the AUC0-28
      between BMI 18-28 and BMI 29-38. Because of the small sample size in the highly
      obese group, a reanalysis was performed by pooling subjects of the obese and
      highly obese groups. Results of the pooled statistical analysis remained the
      same. In summary, these results suggest that minor differences observed in the
      MPA pharmacokinetics--whether due to injection site or body weight or both--have
      no impact on the contraceptive efficacy of MPA/E2C, as trough concentrations
      (Cmin) are well above the threshold levels required to suppress ovulation. No
      dose adjustment is necessary based on body weight or injection site.

PMID- 10640167
TI  - Lunelle monthly contraceptive injection (medroxyprogesterone acetate and
      estradiol cypionate injectable suspension): steady-state pharmacokinetics of MPA
      and E2 in surgically sterile women.
AB  - The steady-state pharmacokinetics and pharmacodynamics of medroxyprogesterone
      acetate (MPA) and estradiol (E2, released from E2C by esterase enzymes) were
      characterized after administration to surgically sterile women. This report
      describes the pharmacokinetics of this multiple-dose and open-labeled study
      (pharmacodynamics are reported in a subsequent article in this issue). Women with
      regular menstrual cycles were studied for one control cycle, 3 consecutive
      treatment months, and 3-5 months of follow-up. Blood samples were drawn before
      each monthly dose and at specified time points after the third monthly injection.
      A total of 16 women were enrolled, 14 of whom completed the study. These 14 women
      (13 white, one black) ranged in age from 28 to 43.4 years, in body weight from
      47.6 to 68.9 kg, and in height from 150 to 175 cm. Mean serum MPA concentrations
      peaked in the first week after administration of MPA/E2C (Lunelle Monthly
      Contraceptive Injection). The mean MPA Cmax and AUC0-t(last) were 1.25 ng/mL and
      32.13 ng.day/mL, respectively. Serum MPA concentrations declined with a mean
      terminal half-life of 14.7 days, indicating that absorption from the injection
      site is prolonged after administration of MPA/E2C. The time for MPA
      concentrations to fall below the lower limit of quantitation (i.e., < 10 pg/mL)
      after the third injection ranged from 63 to 84 days. The average MPA trough
      (Cmin' day 28) concentrations for the three consecutive monthly injections ranged
      from 0.44 to 0.47 pg/mL, indicating that steady-state conditions were achieved
      after the first injection. The MPA Cmin values were well above threshold levels
      required to suppress ovulation throughout the injection interval. Absorption of
      E2 from the injection site was also prolonged after injection of MPA/E2C. Mean
      concentrations of E2 peaked at approximately 2 days after the third injection,
      and the average Cmax was 247 pg/mL. Serum E2 levels declined with a terminal half
      life of approximately 8 days; E2 levels returned to baseline (typically,
      approximately 100 pg/mL) by 14 days after each injection. The average trough
      (Cmin' day 28) levels for E2 ranged from 40 to 55 pg/mL. The results of this
      study demonstrate that steady-state conditions are achieved after the first
      injection of MPA/E2C; no further MPA or E2 accumulation occurs beyond the first
      injection. Furthermore, the E2 peak observed after injection of MPA/E2C is
      similar to the nontreated preovulatory E2 range and returns to baseline levels by
      approximately 14 days after injection.

PMID- 10640168
TI  - Patient acceptability and satisfaction with Lunelle monthly contraceptive
      injection (medroxyprogesterone acetate and estradiol cypionate injectable
      suspension).
AB  - The results from a User Satisfaction Questionnaire, Treatment Assessment
      Questionnaire, and Global Well-Being Schedule questionnaire administered to women
      participating in an open-labeled, nonrandomized, parallel, controlled study
      comparing a new monthly injectable contraceptive containing 25 mg of
      medroxyprogesterone acetate (MPA) and 5 mg of estradiol cypionate (E2C) (MPA/E2C)
      (Lunelle Monthly Contraceptive Injection) and a triphasic norethindrone (0.5,
      0.75, 1.0 mg)/0.035 mg ethinyl estradiol (NET/EE) oral contraceptive (Ortho-Novum
      7/7/7) are reviewed. Approximately 85% of all 1103 women enrolled in the
      comparative trial completed their initial and final questionnaires. To better
      assess the comparison of a new and extant method of contraception, outcome data
      were divided among MPA/E2C users and new and previous oral contraceptive (OC)
      users. Despite the inherent inequalities in comparing an injectable to an oral
      method of contraception, few treatment assessment and satisfaction outcomes were
      significantly different when comparing MPA/E2C users to new OC (NET/EE) users.
      More women in the MPA/E2C study group reported discomfort with their method than
      women in either NET/EE study group; however, only 19.4% of MPA/E2C users rated
      the administration of their contraceptive to be moderately uncomfortable or
      worse, compared to 11.7% of new NET/EE users and 13.4% of previous OC users.
      Among MPA/E2C users, 86.3% reported no interference with social activities
      compared with 90.4% of new NET/EE users. MPA/E2C and new NET/EE users were also
      similar in their responses recommending their respective contraceptive method to
      friends, with > 90% of both groups stating that they had a very favorable
      experience and would definitely recommend their method to a friend. In general,
      MPA/E2C was well accepted by women in the study group. Their attitudes and
      perceptions are similar to those of women who were starting OCs for the first
      time. These data support the premise that MPA/E2C may become a well accepted,
      first-line contraceptive option for women in the US.

PMID- 10640169
TI  - Emergency contraception in Nairobi, Kenya: knowledge, attitudes and practices
      among policymakers, family planning providers and clients, and university
      students.
AB  - To gauge knowledge, attitudes, and practices about emergency contraception in
      Nairobi, Kenya, we conducted a five-part study. We searched government and
      professional association policy documents, and clinic guidelines and service
      records for references to emergency contraception. We conducted in-depth
      interviews with five key policymakers, and with 93 family planning providers
      randomly selected to represent both the public and private sectors. We also
      surveyed 282 family planning clients attending 10 clinics, again representing
      both sectors. Finally, we conducted four focus groups with university students.
      Although one specially packaged emergency contraceptive (Postinor levonorgestrel
      tablets) is registered in Kenya, the method is scarcely known or used. No extant
      policy or service guidelines address the method specifically, although revisions
      to several documents were planned. Yet policymakers felt that expanding access to
      emergency contraception would require few overt policy changes, as much of the
      guidance for oral contraception is already broad enough to cover this alternative
      use of those same commodities. Participants in all parts of the study generally
      supported expanded access to emergency contraception in Kenya. They did, however,
      want additional, detailed information, particularly about health effects. They
      also differed over exactly who should have access to emergency contraception and
      how it should be provided.

PMID- 10640170
TI  - Emergency contraception in Mexico City: what do health care providers and
      potential users know and think about it?
AB  - Emergency contraception promises to reduce Mexico's high unwanted pregnancy and
      unsafe abortion rates. Because oral contraceptives are sold over-the-counter,
      several emergency contraceptive regimens are already potentially available to
      those women who know about the method. Soon, specially packaged emergency
      contraceptives may also arrive in Mexico. To initiate campaigns promoting
      emergency contraception, we interviewed health care providers and clients at
      health clinics in Mexico City, ascertaining knowledge, attitudes, and practices
      concerning the method. We found limited knowledge, but nevertheless cautious
      support for emergency contraception in Mexico. Health care providers and clients
      greatly overestimated the negative health effects of emergency contraception,
      although clients overwhelmingly reported that they would use or recommend it if
      needed. Although providers typically advocated medically controlled distribution,
      clients believed emergency contraception should be more widely available,
      including in schools and vending machines with information prevalent in the mass
      media and elsewhere.

PMID- 10640171
TI  - The role of matching menstrual data with hormonal measurements in evaluating
      effectiveness of postcoital contraception.
AB  - The effectiveness of postcoital contraception can only be estimated. The most
      commonly used method of calculation compares the expected pregnancy rate in the
      exposed population to the resultant pregnancies after treatment. Estimation of
      the fertile period and the day of ovulation are critical to calculate the
      expected pregnancies. The aim of this study was to improve the accuracy of
      calculations by evaluating the hormonal status on the day of contraceptive
      treatment. A total of 483 consecutive women requesting postcoital contraception
      was included in a prospective observational trial. A blood sample was obtained at
      the moment of consultation to measure serum luteinizing hormone, estradiol, and
      progesterone concentrations. An ethinylestradiol-levonorgestrel combination (100
      micrograms/500 mg for two doses, 12 h apart) was then prescribed. The fertile
      period was estimated according to previous hormonal studies in the normal cycling
      population. Of 483 women, 64 (13.25%) women were excluded because they presented
      irregular menstrual cycles and 37 (7.6%) women were lost to follow-up. Two
      pregnancies occurred in the remaining 382 women. Following Wilcox's and
      Trussell's methods, 21.1 and 17.75 pregnancies should be expected, yielding an
      overall treatment effectiveness of 90.52% (95% confidence interval [CI] 62.58%
      97.6%) and 88.73% (95% CI 55.93%-97.12%), respectively. Hormonal data were
      available in 356 women; 303 of whom presented with regular cycles. Hormonal
      information in this group restricted the number of exposed cases to 88 women. Of
      the women included in Trussell's method of analysis, only 51 (51.5%; p < 0.05)
      were at risk using hormonal data. Fifty-six percent (95% CI 34.9%-75.6%) of women
      with luteinizing hormone levels > 20 IU/L were not between days-1 and +1 of the
      cycle. Hormonal studies suggest that methods based on pregnancy risk calculated
      by cycle day do not faithfully reflect the real exposure.

PMID- 10640172
TI  - Fourteen years' experience in voluntary female sterilization through
      minilaparotomy in Jos, Nigeria.
AB  - Between January 1985 and December 1998, 2913 female sterilizations through
      minilaparotomy were performed. The mean (+/- SD) age was 36.4 +/- 4.2 years and
      68% of the women were between the ages of 30 and 39 years. The mean (+/- SD)
      parity distribution was 8.0 +/- 2.0; 59.5% of the patients were para > or = 8,
      and the mean (+/- SD) number of living children was 6.8 +/- 1.6. Only 32.9% had
      the equivalent > or = 8 number of living children at the time of the procedure.
      Completed desired family size was the indication for the tubal occlusion in 95%
      of the patients. The predominant surgical technique was Pomeroy's method in 97%.
      Tubal ligation as an interval procedure was performed in 93.6% and local
      anesthesia was used in 83.7%. The study showed a yearly increase in the growth of
      voluntary surgical contraception at the institution, made possible by trained
      personnel.

PMID- 10640173
TI  - Is the stroke risk in OC users higher in Europe than in North America?

PMID- 10640174
TI  - Distribution of afferent axons in the bladder of rats.
AB  - The distribution of afferent axons in the bladder of rats was studied by means of
      immunohistochemistry for calcitonin gene-related peptide (CGRP), in frozen
      sections and in wholemount preparations of mucosa and muscle coat. Synaptophysin
      immunofluorescence was used for the general detection of all intramural axons.
      The afferent axons were distributed over four distinct targets: at the base of
      the epithelium, inside the epithelium, on blood vessels (both arteries and veins)
      and along muscle bundles. In the mucosa, all the afferent axons, except the
      perivascular ones, lay either inside the epithelium or in a subepithelial plexus
      very close to the basal surface of the epithelium. The plexus was thickest in the
      neck of the bladder and in the initial portion of the urethra, and it became
      progressively less dense in the adjacent regions; it did not extend beyond the
      equatorial region, and therefore the mucosa of the cranial region of the bladder
      had no afferent axons. Most of the axons in the subepithelial plexus were
      terminal axons and included conspicuous varicosities arranged in very long
      chains; branching points were numerous, usually at right angles and located at
      the level of a varicosity; some axons split and then rejoined, forming closed
      axonal loops. The afferent innervation of the musculature was more diffuse, and
      appeared uniform throughout the bladder. After unilateral surgical denervation
      (by excision of the pelvic ganglion 5-7 days earlier) areas of complete
      denervation were observed, but there were large areas where the innervation was
      only reduced. The results showed that there is a bilateral innervation of many
      regions of the mucosa and the musculature, including individual muscle bundles. A
      substantial number of fibres crossed the midline into the contralateral side of
      the bladder. CGRP-immunofluorescence in mucosal afferent axons is enhanced in the
      surviving axons 5 days after contralateral denervation, a change which is
      interpreted as an early sign of regeneration.

PMID- 10640175
TI  - Membrane-bounded intratubular bodies in rat taste buds.
AB  - The ultrastructural features of membrane-bounded bodies contained in the tubulo
      vesicular system in the outer segment of taste bud cells are described. Each body
      showed a round, fusiform or oval shape, was surrounded by a trilaminar membrane
      and enclosed an electron dense matrix sometimes containing inclusions. These
      bodies were found at all ages studied. Similar structures were also found
      embedded in the material plugging the taste pore. Our findings suggest that these
      bodies could be secreted at the free surface of the cells and be involved in the
      concentration of divalent cations.

PMID- 10640176
TI  - Increased blood-brain barrier permeability and endothelial abnormalities induced
      by vascular endothelial growth factor.
AB  - The early effects of intracerebrally infused vascular endothelial growth factor
      (VEGF) on the blood-brain barrier (BBB) to endogenous albumin were studied using
      a quantitative immunocytochemical procedure. In addition, transmission electron
      microscopy was used to observe morphological changes induced in brain
      vasculature. A solution of VEGF in saline (40 ng/10 microliters) was infused into
      the parieto-occipital cortex of mice, which were killed 10 min, 30 min, and 24 h
      afterwards. Untreated mice and mice that received infusion of saline only were
      used as controls. For immunocytochemical evaluation, ultrathin sections of
      immersion-fixed brain samples embedded in Lowicryl K4M were exposed to anti
      albumin antiserum followed by protein A-gold. Simultaneously, other brain samples
      embedded in Spurr resin were used for ultrastructural examination. Morphometric
      and statistical analysis indicated that as soon as 10 min after infusion of VEGF,
      33% of vascular profiles were leaking albumin, and this value increased at 30 min
      to 92%. This effect of VEGF appears to be of rather short duration because after
      24 h, only 27% of vascular profiles showed signs of leakage. The results of
      ultrastructural observations indicate that VEGF (30 min post-infusion) induces
      several changes in microvascular segments located in the area of intracerebral
      infusion of VEGF. These changes consist of the appearance of interendothelial
      gaps; fragmentation of the endothelium with formation of segmental, fenestrae
      like narrowings; degenerative changes of the vascular basement membrane; and the
      appearance of fibrin gel in the vessel lumen. At 24 h post-infusion, solitary
      diaphragmed fenestrae appeared in attenuated segments of the endothelium in a few
      microvascular profiles. These changes, which are interpreted to be preparatory
      steps for angiogenesis, affect the structural integrity of the vascular segments,
      leading to extravasation of blood plasma proteins, including albumin.

PMID- 10640178
TI  - Regenerated retinal ganglion cell axons form normal numbers of boutons but fail
      to expand their arbors in the superior colliculus.
AB  - Regenerated retinal ganglion cell (RGC) axons can re-form functional synapses
      with target neurons in the superior colliculus (SC). Because preterminal axon
      branching determines the size, shape and density of innervation fields, we
      investigated the branching patterns and bouton formation of individual RGC axons
      that had regrown along peripheral nerve (PN) grafts to the SC. Within the
      superficial layers of the SC, the regenerated axons formed terminal arbors with
      average numbers of terminal boutons that were similar to the controls. However,
      axonal branches were shorter than normal so that the mean area of the regenerated
      arbors was nearly one-tenth that of control arbors and the resulting fields of
      innervation contained greater than normal numbers of synapses concentrated in
      small areas of the target. Our results have delineated a critical defect in the
      reconstitution of retino-collicular circuitry in adult mammals: the failure of
      terminal RGC branches to expand appropriately. Because recent studies have
      documented that brain-derived neurotrophic factor (BDNF) can specifically
      lengthen RGC axonal branches not only during development in the SC but also
      within the adult retina after axotomy, the present quantitative studies should
      facilitate experimental attempts to correct this deficit of the regenerative
      response.

PMID- 10640177
TI  - First continuous human pheochromocytoma cell line: KNA. Biological, cytogenetic
      and molecular characterization of KNA cells.
AB  - Pheochromocytomas are rare tumours, with an incidence of 1-2 per million which
      arise from chromaffin cells of the adrenal medulla. They occur sporadically or as
      part of dominantly inherited cancer syndromes like multiple endocrine neoplasia 2
      (MEN2A and 2B) and others. Continuous cell lines, not available so far, are
      essential tools for studies in these tumours. A continuous cell line (KNA) was
      established from a sporadic pheochromocytoma of the right adrenal gland of a 73
      year-old woman. The KNA cells grow as suspensions of spheroids and show the
      morphological and immunocytochemical characteristics of neuronal chromaffin
      cells, such as neuroendocrine granules, and positive reactions to chromogranin-
      and related peptide-, neuron specific enolase and vasoactive intestinal peptide
      antibodies. Neurite-like processes are formed after addition of nerve growth
      factor. Chromosomal analyses revealed a diploid (46,XX,n = 50) to hypodiploid (43
      45,XX,n = 15) karyotype. In hypodiploid metaphases most frequently #19, #17, #21
      and #22 were missing. Chromosome arms 1p and 4q showed apparently consistent
      interstitial deletions: 6q, 8q, 13q and 22q showed clonal interstitial deletions.
      The cell line shows a heterozygous sequence variant TGC (cysteine) to TGG
      (tryptophan) in codon 611 in exon 10 of the RET proto-oncogene. So far, PC-12, a
      rat adrenal pheochromocytoma, has been the only continuous pheochromocytoma cell
      line available. KNA represents the first report on a human continuous
      pheochromocytoma cell line, the first report of structural chromosome aberrations
      in pheochromocytomas and the first report of a RET mutation TGC to TGG in exon 10
      of the RET proto-oncogene in a sporadic pheochromocytoma.

PMID- 10640179
TI  - Perivascular nerve fibres and endothelial cells of the rat basilar artery: immuno
      gold labelling of antigenic sites for type I and type III nitric oxide synthase.
AB  - Ultrastructural localisation of type I (neuronal) and type III (endothelial)
      isoforms of nitric oxide synthase in perivascular nerve fibres (axons) and
      endothelial cells was studied in the Wistar rat cerebral basilar artery, using
      monoclonal antibodies either to type I or type III nitric oxide synthase and post
      embedding colloidal-gold immunocytochemistry. Labelling signal (gold particles)
      for type I and type III nitric oxide synthase was localised both in axons and
      endothelial cells. In the axon profiles, labelling for either type I or type III
      nitric oxide synthase was localised in the axoplasm and the lumen and/or membrane
      of small agranular synaptic vesicles. In the endothelial cells, labelling for
      either type-I or type-III nitric oxide synthase was predominantly in the
      cytoplasm. The present qualitative data extends our previous study of
      cerebrovascular nerve fibres and endothelial cells employing monoclonal
      antibodies; the localisation of nitric oxide synthase in a subpopulation of
      synaptic vesicles in nitric oxide synthase-positive cerebrovascular nerves
      suggests that vesicular mechanisms may be involved in the production/release of
      nitric oxide.

PMID- 10640180
TI  - Acute osmotic/stress stimuli induce a transient decrease of transcriptional
      activity in the neurosecretory neurons of supraoptic nuclei.
AB  - Administration of hypertonic NaCl solutions by intraperitoneal injection evokes a
      transient expression of immediate-early genes in the hypothalamic magnocellular
      neurons of supraoptic nuclei (SON), which is followed by an upregulation of
      arginine vasopressin synthesis and a general increase in cellular metabolic
      activity. Here we have analysed the changes that occur in the nucleus of SON
      neurons during the period of transient Fos expression after injection of
      hypertonic saline. Within the first 30 minutes after injection, the nuclei become
      significantly smaller, contain more condensed chromatin and incorporate less 3H
      uridine than the controls. By 12 hours these effects are reverting and at 24
      hours the nuclei are already more active than the controls. Additionally, we
      observe an initial decrease in the number of coiled bodies per nucleus within the
      first 2 hours, followed by a 3-fold increase at 24 hours after injection. As
      coiled bodies are transcription-dependent subnuclear 'organelles', these results
      further support the view that injection of hypertonic saline causes a transient
      inhibition of nuclear activity. Our data show that SON neurons respond to acute
      osmotic/stress stimuli first with inhibition and then with activation of gene
      expression. Importantly, inhibition of transcriptional activity occurs
      simultaneously with maximal accumulation of Fos protein in the nucleus, raising
      the possibility that activation of c-fos expression may cause repression of
      target genes.

PMID- 10640181
TI  - Intercellular adhesion molecule-1 (ICAM-1) in the mouse facial motor nucleus
      after axonal injury and during regeneration.
AB  - Intercellular adhesion molecule 1 (ICAM-1, CD54) is a widely expressed
      glycoprotein, which plays an important role in leukocyte extravasation and in the
      interaction of lymphocytes with antigen-presenting cells. In the current study we
      examined the regulation of ICAM-1 in the mouse facial motor nucleus after facial
      nerve transection, using immunohistochemistry, confocal laser microscopy and
      electron microscopy. In the normal facial nucleus ICAM-1 immunoreactivity was
      restricted to vascular endothelium. Transection of the facial nerve led to a
      strong and selective upregulation of ICAM-1 on activated microglia. Quantitation
      of microglial ICAM-1 immunoreactivity revealed a biphasic increase. The first
      peak 1-2 days post operation paralleling the early stage of microglial activation
      was followed by a decline at 4-7 days. The second induction of ICAM-1 occurred at
      day 14 accompanying the period of neuronal cell death and microglial phagocytosis
      of neuronal debris. Immunoelectron microscopy showed strong ICAM-1 reactivity on
      the cell membrane of activated microglia at day 2. During the second peak (day
      14), ICAM-1 was also observed on lymphocytes adhering to phagocytotic microglia
      forming aggregates around neuronal debris. No immunolabelling was observed on
      neurons, astrocytes or oligodendroglia. These data suggest the involvement of
      ICAM-1 in the adhesion of activated microglia, in their phagocytosis of neuronal
      debris, and also in the interaction with infiltrating lymphocytes following this
      injury.

PMID- 10640183
TI  - The ventral motoneurone axon bundle in the CNS--a cordone system?
AB  - In the developing CNS neighbouring structures are commonly separated by transient
      barriers termed cordones, some of which coincide with glial elements. Where
      ventral motoneuron axons cross the spinal white matter as intramedullary bundles
      to reach the CNS-PNS transitional zone they are surrounded from early development
      by a glial sleeve resembling a cordone. This becomes better developed with age
      and, like some cordones, persists into adult life. This could provide a radial
      conduit which might underlie the capacity of central segments of mature ventral
      motoneurone axons to regenerate. It may also provide a pathway for glial
      migration from the central cord to more superficial levels, including the
      transitional zone, where they help form the CNS-PNS barrier. Axons in the
      intramedullary bundle and in the surrounding ventral white column mature at
      different rates. Glial sleeve cells of the intramedullary bundles are apposed to
      both. Morphometric analysis of the axon-glial relationships of the two
      populations indicates that glial development proceeds at a different rate in
      relation to each axon class and that this is influenced by the degree of axonal
      maturation, which may in turn be related to target contact. Furthermore, early
      axon glial relationships differ between the two populations. For ventral
      motoneurone axons these take place in two stages: firstly, glial segregation of
      axons (resembling that in the PNS) and secondly, oligodendrocytic contact and
      ensheathment, which leads on to myelination. Axon-glial relationships in the
      ventral white column begin with the second of these events, as is more typical of
      early CNS myelination in general.

PMID- 10640182
TI  - Transganglionic transport of the lectin soybean agglutinin (Glycine max)
      following injection into the sciatic nerve of the adult rat.
AB  - The lectin soybean agglutinin (SBA) from Glycine max binds to small-sized dorsal
      root ganglion cells and their central terminals in the superficial dorsal horn of
      the spinal cord. Here we investigated the ability of SBA and SBA conjugated to
      horseradish peroxidase (SBA-HRP) to trace thin calibre afferents into the spinal
      cord from a peripheral nerve. Following injection into the sciatic nerve,
      labelled cells in the dorsal root ganglion were predominantly small-sized but
      some medium-sized cells were also labelled. Colocalization studies of transported
      SBA with various neuronal markers showed that all neurons that transported SBA
      HRP showed SBA binding, indicating high uptake specificity for the conjugate. 15%
      were immunoreactive for RT97 indicating that some axons were myelinated, and 54%
      also expressed binding sites for isolectin B4 from Griffonia simplicifolia, a
      selective marker for a subpopulation of unmyelinated afferents. With regard to
      neurotransmitter content, 43% of the SBA cells contained calcitonin gene-related
      peptide, 33% contained substance P and 2.5% somatostatin. In addition, 3%
      contained carbonic anhydrase. Centrally, injection of SBA in the sciatic nerve
      resulted in labelled terminals in somatotopically appropriate regions of laminae
      I-II of the dorsal horn, and in the gracile nucleus. A few neurons in the dorsal
      horn were labelled indicating that some transneuronal transport of SBA had
      occurred. The results show that SBA can be used as a transganglionic tracer to
      label fine calibre primary afferents that project to laminae I-II of the spinal
      cord and the gracile nucleus. It appears to label more afferents than isolectin
      B4, including also a subpopulation of myelinated afferents.

PMID- 10640184
TI  - Axon-myelin sheath relations of oligodendrocyte unit phenotypes in the adult rat
      anterior medullary velum.
AB  - Axon-oligodendrocyte relations of Rip-immunolabelled and dye-injected
      oligodendrocyte units are characterised in the adult rat anterior medullary velum
      (AMV). Each oligodendrocyte unit comprised the oligodendrocyte cell body,
      processes and the internodal myelin segments they support. Oligodendrocyte units
      corresponded to classically described type I/II or type III/IV unit phenotypes
      which respectively myelinated discrete populations of small and large diameter
      axons, delineated by a myelinated fire diameter of 2-4 microns (diameter of the
      axon plus its myelin sheath). Within units, mean fibre diameter was directly
      related to mean internodal length and inversely related to the number of myelin
      sheaths in the unit. The relationship between fibre diameter and internodal
      length was retained in units which myelinated axons of different diameters,
      indicating that axon diameter was an important determinant of the longitudinal
      dimensions of myelin sheaths. We also show that type III/IV units maintained a
      far greater volume of myelin than type I/II units. It was concluded that type
      I/II and III/IV oligodendrocytes represent two functionally and morphologically
      distinct phenotypes whose distribution densities were determined by the diameter
      and spatial dispersion of axons.

PMID- 10640185
TI  - Differential expression of the L- and S-isoforms of myelin associated
      glycoprotein (MAG) in oligodendrocyte unit phenotypes in the adult rat anterior
      medullary velum.
AB  - We have previously demonstrated differences in the expression of carbonic
      anhydrase II (CAII) in oligodendrocyte units myelinating small and large diameter
      fibres in the anterior medullary velum (AMV) of the adult rat (each unit
      comprises the cell body, processes and myelin sheaths). Others have indicated
      that myelin composition may also vary with respect to myelin basic protein (MBP)
      and proteolipid protein (PLP), and the small (S)- and large (L)-isoforms of
      myelin associated glycoprotein (MAG). In this study, we have determined the
      expression of myelin proteins in oligodendrocyte unit phenotypes I-IV, which
      myelinate fibres ranging in diameter from 0.3-12 microns diameter in the AMV, by
      using double immunolabelling for Rip, which labels entire units, and MBP, PLP,
      myelin oligodendrocyte glycoprotein (MOG), L-MAG and S-MAG. We show differences
      in the expression of L- and S-MAG in units which myelinate different diameter
      fibres: (1) type I/II units myelinating small diameter fibres had a L-MAG+/S-MAG
      /CAII+ phenotype; (2) type II/III units myelinating different diameter fibres had
      a L-MAG+/S-MAG+/CAII+ phenotype; (3) type III/IV units myelinated large diameter
      fibres had a L-MAG+/S-MAG+/CAII- phenotype. All units, irrespective of fibre
      diameter, expressed Rip, MBP, PLP and MOG. The results indicate that type I-IV
      units may be variants of a single oligodendrocyte population and that phenotypic
      differences are determined by the diameter of fibres within the unit. The
      possible significance of metabolic and biochemical differences between
      oligodendrocytes myelinating small and large diameter axons are discussed with
      reference to the pathology of demyelination.

PMID- 10640186
TI  - The ultrastructural effects of beta-amyloid peptide on cultured PC12 cells:
      changes in cytoplasmic and intramembranous features.
AB  - The fine structural features of cultured PC12 cells were investigated after
      treatment for 1, 3, or 5 days with different concentrations of the vascular form
      of beta-amyloid 1-40 (beta-AP). PC12 cells treated with beta-AP showed time- and
      concentration-dependent lysosomal system activation and cell toxicity. We
      observed increases in the number and size of cytoplasmic lysosomes as indicated
      by increased acid phosphatase reactivity. Some lysosomes were in the form of
      multivesicular bodies or large residual bodies that appeared to arise by
      autophagia or by endocytotic uptake. Double-sided plasma membrane invaginations
      were observed to give rise to increasingly extensive intracytoplasmic
      vacuolization that was correlated with duration of beta-AP treatment. Freeze
      fracture studies of the intramembranous particle (IMP) population in the plasma
      membrane P-face showed that both control and beta-AP treated cells had two major
      P-face IMP populations, small-diameter (4-8 nm) IMPs, and large-diameter (> or =
      9 nm) IMPs. The larger category of IMPs was found to possess a greater average
      diameter in the beta-AP treated cells than in the control cells. These IMPs could
      represent modifications to existing transmembranous receptors, channels, or
      transducing molecules by the beta-AP. These results demonstrate that beta-AP can
      induce time- and concentration-dependent ultrastructural changes in PC12 cell
      membranes.

PMID- 10640187
TI  - A light and electron microscopic study of GAT-1-positive cells in the cerebral
      cortex of man and monkey.
AB  - Specimens of human cerebral cortex were obtained during neurosurgical operations
      and studied by immunocytochemistry and electron microscopy, using antibodies to
      the GABA transporter GAT-1. Cortical material from macaque monkeys was prepared
      similarly. Large numbers of GAT-1-positive non-pyramidal neurons were observed in
      layers I, II, V, and VI of the cortex. Electron microscopy also showed that the
      GAT-1-positive axon terminals formed symmetrical and not asymmetrical synapses,
      suggesting that they were the terminals of non-pyramidal neurons. Processes of
      cells in the walls of blood vessels were also labelled. We conclude that GAT-1 is
      present in cell bodies and axon terminals of non-pyramidal neurons, and a
      population of mural cells in blood vessels, in the primate cerebral cortex.

PMID- 10640188
TI  - Neuronal nitric oxide synthase in the vasculature of the rat brain: an
      immunocytochemical study using the tyramide signal amplification technique.
AB  - Using the highly sensitive tyramide-signal-amplification technique, we examined
      immunocytochemically the distribution of neuronal nitric oxide synthase (nNOS) in
      blood vessels of the rat brain. In contrast to the endothelial isoform, no clear
      cut immunostaining could be obtained for the nNOS at the light microscopic level.
      An occasional faint immunoreaction at the endothelial lining was difficult to
      interpret. Ultrastructurally, endothelial cells of larger pial vessels, but not
      those of the parenchyma, revealed immunoprecipitates in their cytosol or attached
      to cytoplasmic membranes. Several pial and parenchymal vessels showed nNOS
      positive perivascular nerves. Immunopositive and negative varicosities were
      located along the same fiber. The present study and our previous study reveal a
      clear-cut localization pattern of NOS isoforms in brain endothelium and
      surrounding tissue, whose particular contribution to the regulation of cerebral
      blood flow is still uncertain.

PMID- 10640189
TI  - Ultrastructural localization of immunoglobulin G and complement C9 in the brain
      stem and spinal cord following peripheral nerve injury: an immunoelectron
      microscopic study.
AB  - The ultrastructural localization of immunoreactivity for immunoglobulin G (IgG),
      F(ab')2 and complement C9 was examined with preembedding immunoelectron
      microscopy in the hypoglossal nucleus and gracile nucleus as well as in the L4
      spinal cord dorsal horn 1 week following hypoglossal or sciatic nerve
      transection, respectively. Only a few scattered immunoreactive profiles were
      observed on the unoperated side. On the operated side, IgG and F(ab')2
      immunoreactivity was present in the membranes of all reactive microglial cells
      observed. In addition, the cell membrane of some hypoglossal motoneurons showed
      IgG immunoreactivity. Complement C9 immunoreactivity was present in the cytoplasm
      of all reactive microglial cells examined. In addition, there was diffuse C9
      immunoreactivity in motoneuron perikarya ipsilateral to nerve injury as well as
      in cell membranes in the neuropil, some of which could be identified as neuronal.
      Our interpretation of these findings is (1) that peripheral nerve injury results
      in binding of IgG to reactive microglia, as well as to some axotomized neurons,
      and (2) that C9 is synthesized by reactive microglia in response to axon injury
      and is also associated with axotomized motoneurons. These findings suggest that
      IgG and complement C9 are involved in microglia-neuron interactions after
      peripheral nerve injury.

PMID- 10640190
TI  - Interferon-gamma receptors are expressed at synapses in the rat superficial
      dorsal horn and lateral spinal nucleus.
AB  - Interferon-gamma can facilitate the spinal nociceptive flexor reflex and may
      elicit neuropathic pain-related behavior in rats and mice. Immunoreactivity for
      the interferon-gamma receptor (IFN-gamma R) occurs in the superficial layers of
      the dorsal horn and the lateral spinal nucleus in the rat and mouse spinal cord,
      as well as in subsets of neurons in the dorsal root ganglia. The aim of the
      present study was to examine the cellular localization and origin of the IFN
      gamma R in the spinal cord. As viewed by confocal microscopy, the
      immunopositivity for the IFN-gamma R was co-localized with that of the
      presynaptic marker synaptophysin and with neuronal nitric oxide synthase in the
      lateral spinal nucleus, whereas only a minor overlap with these molecules was
      observed in laminae I and II of the dorsal horn. There was no co-localization of
      the IFN-gamma R with markers for astrocytes and microglial cells.
      Ultrastructurally, the IFN-gamma R was found predominantly in axon terminals in
      the lateral spinal nucleus, but at postsynaptic sites in dendrites in laminae I
      and II. The IFN-gamma R expressed in neurons in dorsal root ganglia was
      transported in axons both centrally and peripherally. Hemisection of the spinal
      cord caused no reduction in immunolabelling of the IFN-gamma R in the dorsal horn
      or the lateral spinal nucleus. Since rhizotomy does not affect the
      immunolabelling in the lateral spinal nucleus, our observation indicates that the
      presynaptic receptors in this nucleus are derived from intrinsic neurons. The
      localization of the IFN-gamma R in the spinal cord differed from that of the AMPA
      glutamate receptor subunits 2 and 3 and the substance P receptor (NK1). Our
      results, showing localization of IFN-gamma R to pre- and postsynaptic sites in
      the dorsal horn and lateral spinal nucleus indicate that IFN-gamma can modulate
      nociception at the spinal cord level.

PMID- 10640191
TI  - The organization of serotonin-, dopamine-, and FMRFamide-containing neuronal
      elements and their possible role in the regulation of spontaneous contraction of
      the gastrointestinal tract in the snail Helix pomatia.
AB  - The distribution of serotonin-, tyrosine hydroxylase-, and FMRFamide
      immunoreactive neuronal elements, as well as the concentrations of serotonin and
      dopamine in the different parts of the gastrointestinal tract, were studied in
      the snail Helix pomatia. The sensitivity of the spontaneous contractions of the
      alimentary tract to serotonin, dopamine, and FMRFamide was also tested. Serotonin
      , tyrosine hydroxylase-, and FMRFamide-immunoreactive elements could be
      demonstrated in each part of the gastrointestinal tract, but they showed
      different innervation patterns. Serotonin- and tyrosine hydroxylase
      immunoreactive elements were dominant in the submucosal layer, whereas FMRFamide
      immunoreactive elements were dominant in both the mucosal and submucosal layers.
      Tyrosine hydroxylase-immunoreactive elements were confined to the longitudinal
      muscle trabeculae of submucosa, whereas serotonin-immunoreactive elements were
      distributed throughout the submucosal layer. No serotonin-immunoreactive cell
      bodies, but only fibers, could be detected in the gastrointestinal tract, and
      therefore they represent extrinsic elements. Tyrosine hydroxylase- and FMRFamide
      immunoreactive cell bodies represent intrinsic elements of the tract. The
      occurrence and density of the serotonin- and tyrosine hydroxylase-immunoreactive
      elements showed significant differences in the different parts of the alimentary
      tract, in accordance with HPLC assays, which revealed a significant frontocaudal
      decrease in both the serotonin (from 2.11 to 1.21 pM/mg) and dopamine (from 3.28
      to 0.52 pM/mg) contents of the different parts of the alimentary tract. Dopamine
      at 10(-5) M concentration proved to be effective only on the longitudinal muscles
      by increasing the tone and frequency of contractions, but was ineffective on the
      circular muscles. Serotonin affected both the longitudinal and circular muscles.
      Serotonin at 10(-5) M concentration decreased the tone and increased the
      frequency of low-amplitude contractions of the longitudinal muscles of the
      esophagus and the gizzard but increased both the tone and frequency of the crop.
      Serotonin at 10(-9) M concentration slightly decreased the tone and blocked the
      contractions of the circular muscles in the crop but at 10(-5) M concentration
      induced contractions of the circular muscles in the gizzard. FMRFamide at 10(-6)
      M concentration decreased the tone and was shown to block the contractions of
      both the longitudinal and circular muscles.

PMID- 10640192
TI  - Inhibition of human gastric and pancreatic lipases by chiral alkylphosphonates. A
      kinetic study with 1,2-didecanoyl-sn-glycerol monolayer.
AB  - Enantiomerically pure alkylphosphonate compounds RR'P(O)PNP (R = CnH2n + 1, R' =
      OY with Y = Cn'H2n' + 1 with n = n' or n not equal to n'; PNP = p-nitrophenoxy)
      noted (RY), mimicking the transition state occurring during the carboxyester
      hydrolysis were synthesized and investigated as potential inhibitors of human
      gastric lipase (HGL) and human pancreatic lipase (HPL). The inhibitory properties
      of each enantiomer have been tested with the monomolecular films technique in
      addition to an enyzme linked immunosorbent assay (ELISA) in order to estimate
      simultaneously the residual enzymatic activity as well as the interfacial lipase
      binding. With both lipases, no obvious correlation between the inhibitor molar
      fraction (alpha 50) leading to half inhibition, and the chain length, R or Y was
      observed. (R11Y16)s were the best inhibitor of HPL and (R10Y11)s were the best
      inhibitors of HGL. We observed a highly enantioselective discrimination, both
      with the pure enantiomeric alkylphosphonate inhibitors as well as a scalemic
      mixture. We also showed, for the first time, that this enantioselective
      recognition can occur either during the catalytic step or during the initial
      interfacial adsorption step of the lipases. These experimental results were
      analyzed with two kinetic models of covalent as well as pseudo-competitive
      inhibition of lipolytic enzymes by two enantiomeric inhibitors.

PMID- 10640193
TI  - Facile syntheses for (5Z,9Z)-5,9-hexadecadienoic acid, (5Z,9Z)-5,9
      nonadecadienoic acid, and (5Z,9Z)-5,9-eicosadienoic acid through a common
      synthetic route.
AB  - The delta 5,9 fatty acids (5Z,9Z)-5,9-hexadecadienoic acid, (5Z,9Z)-5,9
      nonadecadienoic acid, and (5Z,9Z)-5,9-eicosadienoic acid were synthesized for the
      first time in four steps (9-12% overall yield) starting from commercially
      available 2-(2-bromoethyl)-1,3-dioxolane. The synthetic approach provided enough
      material to corroborate the structure and stereochemistry of (5Z,9Z)-5,9
      nonadecadienoic acid which was recently identified in the flowers of Malvaviscus
      arboreus (Malvaceae). The novel phospholipids 1-hexadecanoyl-2-[(5Z,9Z)-5,9
      eicosadienoyl]-sn-glycer o-3-phosphocholine and 1-octadecanoyl-2-[(5Z,9Z)-5,9
      eicosadienoyl]-sn- glycero-3-phosphocholine were also synthesized from
      commercially available L-alpha-phosphatidylcholine (egg yolk) and characterized
      by positive ion electrospray mass spectrometry. These are the first examples of
      unsymmetrical phospholipids with saturated fatty acids at the sn-1 position and
      delta 5,9 fatty acids at the sn-2 position.

PMID- 10640194
TI  - Phase behavior of the monoerucin/water system.
AB  - Monoerucin is a monoacylglycerol incorporating a cis monounsaturated fatty acid,
      22 carbon atoms long, with the double bond at carbon number 13. The original
      temperature-composition phase diagram for the monoerucin/water system,
      constructed on the basis of 'consistency' and light microscopy, includes
      unexpectedly only the lamellar and fluid isotropic phases [Lutton, E.S., 1965. J.
      Am. Oil Chem. Soc. 42:1068-1070]. In separate studies using X-ray diffraction,
      the cubic phase [Larsson et al., 1978. J. Sci. Food Agric. 29:909-914] and the
      inverted hexagonal (HII) phase [Caffrey, M., 1989. Biophys. J. 95:11-21] were
      shown to be the dominant phases. We have resorted to the traditional isoplethal
      diffraction method for constructing the equilibrium phase diagram of monoerucin
      in water with a view to resolving the controversy regarding the thermotropic and
      lyotropic properties of the system. The study confirms the presence of the pure
      HII phase that extends from ca. 10 to 22% (w/w) water and from ca. 35 to 125
      degrees C, and its coexistence with excess water above ca. 24% (w/w) water in the
      same temperature range. The low temperature region of the diagram is dominated by
      the lamellar crystal (Lc) phase, with the existence of the lamellar liquid
      crystal (L alpha) and cubic-Ia3d phases at intermediate temperatures and
      hydration levels. Differential scanning calorimetry and polarizing light
      microscopy were used to confirm the reported equilibrium phase behavior. Full
      structure characterization of the system and how phase microstructure depends on
      sample hydration and temperature are reported.

PMID- 10640195
TI  - Polymorphism in myristoylpalmitoylphosphatidylcholine.
AB  - This study focuses on the mixed-chain lipid myristoylpalmitoylphosphatidylcholine
      (MPPC) near full hydration. The lipid, synthesized according to the procedure of
      (Mason et al., 1981a, has a low degree of acyl chain migration. When MPPC is
      temperature-jumped (T-jumped) from the L alpha phase (T = 38 degrees C) to T = 20
      degrees C or below, a subgel phase forms; this formation takes less than 1 h at a
      temperature below T = 12 degrees C. The subgel remains stable up to T = 29
      degrees C. When MPPC is T-jumped from the L alpha phase to T = 24 degrees C or
      above, a ripple phase forms with coexisting ripple wavelengths of 240 A and 130
      A. In contrast, when MPPC is melted from the subgel phase, the ripple phase is
      characterized by bilayers having a single ripple wavelength of 130 A. In
      agreement with earlier studies (Stumpel et al., 1983; Serrallach et al., 1984.
      Structure and thermotropic properties of mixed-chain phosphatidylcholine bilayer
      membranes. Biochemistry 23:713-720.), no stable gel phase was observed. Instead,
      an ill-defined low-angle X-ray pattern is initially observed, which gradually
      transforms into the subgel phase below 20 degrees C, or into the ripple phase
      above 24 degrees C. In the wide-angle X-ray diffraction, a single peak is
      observed, similar to the ripple phase wide-angle pattern, that either persists
      above 24 degrees C or transforms into a multi-peaked subgel wide-angle pattern
      below 20 degrees C. The absence of a gel phase can be understood
      phenomenologically as the relative dominance of the subgel phase in mixed-chain
      PCs compared to same-chain PCs. The subgel structure and molecular interactions
      responsible for this comparative behavior are interesting open issues.

PMID- 10640196
TI  - Papillary squamous carcinoma: will the real one please stand up?

PMID- 10640197
TI  - Prostate cancer: another piece to the molecular puzzle.

PMID- 10640198
TI  - pT1 urothelial carcinoma of the bladder: criteria for diagnosis, pitfalls, and
      clinical implications.
AB  - One of the challenging areas in genitourinary pathology is the recognition of
      early invasion in urothelial neoplasia. Not uncommon, the patterns of invasion
      into lamina propria are subtle because a desmoplastic response is absent.
      Tangential sectioning due to inability to orient transurethral resection of
      bladder tumor specimens, crush and cautery artifacts further compound this
      problem. This review is presented to familiarize surgical pathologists with the
      criteria and different patterns of lamina propria invasion by urothelial
      carcinoma. Problems and pitfalls associated with the recognition of invasion and
      the clinicopathologic significance of lamina propria invasive urothelial cancer
      are also discussed.

PMID- 10640199
TI  - Recent developments in stereotactic breast biopsy methodologies: an update for
      the surgical pathologist.
AB  - Recently, there have been a number of new devices introduced for stereotactic
      biopsy of nonpalpable, mammographically detected lesions. The vacuum-assisted
      core biopsy (VACB) (Minimal Invasive Breast Biopsy (MIBB), U.S. Surgical,
      Norwalk, CT; Mammotome, Biopsys Medical, Cincinnati, OH) obtains multiple tissue
      cores (11-gauge) in a circumferential manner around the biopsy probe, inserted
      under stereotactic guidance. It provides more complete sampling of mammographic
      lesions than the conventional 14-gauge stereotactic core biopsy, reducing the
      number of unsatisfactory biopsies. The advanced breast biopsy instrumentation
      (ABBI) (United States Surgical Corporation, Norwalk, CT) system utilizes
      stereotactic technique and an oscillating blade-cutting mechanism to obtain a
      single large diameter (5 mm to 20 mm) tissue core, with the aim of obtaining an
      intact lesion in its entirety for histologic assessment. Its potential as a
      treatment option is still under investigation. Suggested protocols for specimen
      handling are presented together with a review of the recent literature. Close
      liaison with radiologists and surgeons performing these biopsies will allow the
      collection of further outcome data to evaluate the strengths and weaknesses of
      each technique.

PMID- 10640200
TI  - Nasopharyngeal angiofibroma: true neoplasm or vascular malformation?
AB  - Nasopharyngeal angiofibromas (NA) are rare tumor-like lesions characterized by
      architecturally irregular vessels set in a fibrous stroma. The unique morphology,
      the strong predilection for male adolescents, and the uncertainty about its
      etiology contributes to significant confusion regarding the classification of NA,
      which still has not been solved today. Based on immunohistochemical and electron
      microscopic examinations, we demonstrate in detail the various unusual vascular
      architectural features of NA. They represent discontinuous vascular basal
      laminae, focal lack of pericytes, and pronounced irregularity of the smooth
      muscle layers. In thick smooth muscle layers and pads, the orientation of muscle
      cells is frequently disturbed, and the individual cells differ in size and shape.
      Occasionally, the muscle layers disperse peripherally into individual cells,
      creating the impression of vessel-independent smooth muscle cells within the
      stroma. The summation of all morphological irregularities demonstrated in this
      paper allows the conclusion that NA represent vascular malformations.

PMID- 10640201
TI  - Benign tumors and tumor-like lesions of the adult kidney. Part II: Benign
      mesenchymal and mixed neoplasms, and tumor-like lesions.
AB  - In this review article the benign tumors and tumor-like lesions of the adult
      kidney are discussed. The incidence of benign renal tumors is low, especially
      when compared to renal cell carcinomas, as most are detected incidentally or at
      autopsy. Some of these tumors, as their names imply, are unique to the kidney,
      e.g., renal adenoma, metanephric adenoma, renal oncocytoma, nephrogenic
      adenofibroma, mesoblastic nephroma, capsuloma, juxtaglomerular cell tumor,
      renomedullary interstitial cell tumor (medullary fibroma), cystic nephroma,
      cystic partially differentiated nephroblastoma, and cystic hamartoma of the renal
      pelvis, while others, such as angiomyolipoma, leiomyoma, hemangioma, lipoma,
      etc., are not unique to the kidney and show similar morphologic features in the
      other sites they affect. Of the tumor-like lesions, xanthogranulomatous
      pyelonephritis, malakoplakia, and renal cysts are the most common. The other
      entities, such as fibroepithelial polyp, are rare, most having been the topic of
      case reports. In Part I of this paper the benign epithelial tumors of the kidney
      were previously discussed. This paper (Part II) is devoted to the benign
      mesenchymal tumors, mixed mesenchymal and epithelial tumors, and the tumor-like
      lesions.

PMID- 10640202
TI  - [Programmed cell death (apoptosis): a sign from the past or the beginning of a
      new millenium?].

PMID- 10640203
TI  - [The influence of coronary flow on atrio-ventricular transmission and ventricular
      contraction in the isolated guinea pig heart].
AB  - It has been demonstrated that coronary flow, through hemodynamic forces,
      stimulates ventricular contraction and atrio-ventricular transmission; however,
      the mechanisms involved in these effects remain unknown. A possibility to explain
      the transduction mechanism, from a mechanical stimulus into a physiological
      response, could be the stretch-activated ion channels. Additionally we explored
      the role of nitric oxide as mediator of these actions. METHODS: We used the
      isolated perfused guinea pig heart according to the method of Langendorff,
      perfused with Krebs solution. We recorded the ventricular contraction by
      development of left ventricular pressure and the atrio-ventricular transmission.
      We studied the effects of the stretch activated ion channel blocker; gadolinium.
      Synthesis of nitric oxide was inhibited by L-NAME and induced with L-arginine.
      RESULTS: Gadolinium inhibited the stimulating effect of flow on atrio-ventricular
      transmission and ventricular contraction. Verapamil, a specific blocker of
      calcium channels, had no effect in the stimulatory effect of flow indicating that
      this type of calcium channel, do not play significant role in the effects of
      flow. L-NAME and L-arginine did not have effects on the effects of flow.
      CONCLUSION: The stimulating effect of coronary flow in these parameters is
      regulated by stretch-activated ionic channels. This effect is independent of
      nitric oxide.

PMID- 10640204
TI  - [Reconstructive surgery of the mitral valve. Experience with 400 cases].
AB  - From january 1980 to december 1992 a total of 400 valvulopathies were subjected
      to conservative mitral procedures: 364 had rheumatic heart disease, 33 were
      congenital abnormalities and 3 probably myxomatous. Functional class and the
      cardiomegaly, were in grade III and IV in most cases. Different procedures were
      done; the most common one was commisurotomy, also subvalvular apparatus opening,
      annuloplasty ring and a newly designed procedure called "Tension Stitch". The
      results were satisfactory, with a reoperation rate of 9.2%, mostly caused by
      fibrosis which in turn caused dysfunction. A second cause were technical
      problems. The mortality rate was 2%, and was not caused by the procedure itself
      but because of bad clinical status of the patients. The follow up period was 13
      years and showed an actuarial survival curve of 98%, with 90.8% free of
      reoperation and a very good post-op quality of life. We present this analysis in
      a effort to bring this procedure to the attention of cardiac surgeons,
      considering it as an alternative to prosthesis placement.

PMID- 10640205
TI  - [Aortic-left ventricular tunnel. Long-term surgical results].
AB  - OBJECTIVE: The aim of this work is to describe the different aspects of diagnosis
      and postoperative follow-up in four patients after surgery for aortic-left
      ventricular tunnel (ALVT). The surgical techniques and results have been
      published, in the literature but there are no reports about the progression of
      aortic regurgitation. METHOD: We reviewed the clinical features of four patients
      operated with ALVT. The clinical information (electrocar-diograms,
      echocardiograms and catheterilution) was studied in the preoperative period.
      Surgical technique and postoperative evolution were analysed. The follow-up
      period ranged between 4.7 and 13 years. RESULTS: In a 14 years period, four
      children (2 boys and 2 girls), were operated for ALVT. The mean age at the time
      of diagnosis was 8.5 years (ranged between 1 month and 14 years). A continuous
      murmurs was present in all cases, associated to cardiac failure in the youngest
      patient (1 month old). The clinical diagnosis was ALVT in the four cases but only
      in two the echocardiographic study showed correctly the anatomic aspects of the
      malformation. The angiohemodynamic study was correct in three patients and the
      differential diagnosis was made in last one with rupture of aortic sinuses of
      Valsalva to the left ventricle. All cases were operated; with direct closure of
      the aortic orifice (two cases), or with dacron patch (two cases). In one case
      aortic valve replacement was also performed. There was not mortality and the mean
      age at the time of surgery was 9 years (1.5 months and 14 years). The mean follow
      up was 8.5 years (ranged between 4.7 and 13 years), three patients showed
      clinically and in the echocardiogram study an aortic valvular regurgitation
      without ALVT deshiscence. All cases are asymptomatic. No patient was reoperated.
      CONCLUSION: The surgical treatment of ALVT must be done as soon as the diagnosis
      is made to prevent left ventricular enlargement, ventriculo-aortic floor
      distortion and aortic valvular lesion. A precise echocardiographic study is
      necessary to avoid catheterization. This study provided a clear knowledge of
      anatomic structure of the ALVT for both clinician and surgeons. This information
      is important in order to obtain an optimal surgical success, particularly to
      prevent the valvar aortic regurgitation.

PMID- 10640206
TI  - [Comparative study of balloon dilatation and stent placement in primary
      angioplasty].
AB  - OBJECTIVE: To communicate our results with primary angioplasty (PA) and stenting
      de novo in acute myocardial infarction. MATERIAL AND METHODS: 163 patients (pts)
      had clinical diagnosis of MI with an average onset time of symptoms of 2.5 hours.
      They were divided in two groups: 100 pts with PA using only balloon (group I) and
      63 pts with primary stenting (group II) (63 pts with 85 stents). A high pressure
      technique (14-16 atm) was used in group II and all pts were on salicylic acid and
      ticlopidine. Both groups were compared. RESULTS: Clinical characteristics,
      infarct location and infarct related-artery were similar, being left anterior
      descending the more frequently vessel involved. Clinical success rate was higher
      in group II (97% vs 87%) and complication rate was threefold higher in group I
      (9% vs 3%). A mean follow up of 57 months in group I showed a 21% clinical and/or
      angiographic restenosis rate, while the 12 months follow up in group II failed to
      show any case of restenosis at all. CONCLUSIONS: The use of stents in PA improves
      the results achieved with balloon procedures. There is a greater success rate,
      less complications and better survival patients who had the procedure while being
      in cardiogenic shock.

PMID- 10640207
TI  - [Comparative analysis of reperfusion time in primary angioplasty vs thrombolysis.
      Success vs time].
AB  - We studied 398 patients with diagnosis of acute myocardial infarction who arrived
      within the first six hours of symptom onset that were treated with thrombolysis
      or primary angioplasty, they were divided in two groups: Group 1 (n = 198), those
      treated with 1.5 million U of streptokinase over 60 min and Group 2 (n = 200),
      those treated with primary angioplasty. In Group 1 the "pain-door" time was 3.7
      +/- 1.7 hs vs 3.8 +/- 2.4 hs in group 2 (p = NS). The "door-needle" time was 48
      +/- 12 min. compared with the "door-balloon" time of 84 +/- 30 min (p < 0.001).
      In Group 1, 154 (77.6%) of the patients had clinical of reperfusion after
      thrombolysis, 58 of them underwent coronary angiography and had an infarct
      related artery (IRA) patency rate of 45.3%. In Group 2 the IRA patency rate was
      85.5% (p < 0.005). CONCLUSION: Thrombolysis was achieved in a lesser period of
      time but our findings showed that primary angioplasty was more effective
      obtaining a TIMI 3 flow.

PMID- 10640208
TI  - [Immediate results of coronary stent implants in octogenarian patients].
AB  - We review our experience and also evaluate the clinical and angiographic results
      of octagenarians patients subjected to percutaneous transluminal angioplasty and
      endovascular prosthesis (stents). In the period between february 1995 and august
      1998, 532 procedures were performed in 400 patients, we describe a subgroup of 51
      patients, who rejected surgical treatment or were considered non appropriate
      candidates for this therapeutic approach. Ages ranged 71 a 85 years mean (74.09
      +/- 3.1). Sex: 37 male and 14 female, their clinical presentation was severe
      angina according to Canadian Society of Cardiology (CSC) in 64%. In 64% previous
      myocardial infarction and multivessel disease in 58.8%. The mean percentage of
      coronary obstruction was 90 +/- 9.2 and ejection fraction 51.6 +/- 8.8, the
      immediate angiographic success was 88.3% six patient (12%) died during 36 to 72
      hours post-procedure from different causes. The follow-up period was 3 to 48
      months, but had angiographic control just eighteen patients (35%). Eighteen cases
      were lost to follow-up for different reasons. Two patients died of non cardiac
      causes. CONCLUSIONS: Stent implantation has an angiographic and clinical success
      with low complications profile. It is a therapeutic option in the management of
      advanced coronary artery disease in this frail group.

PMID- 10640209
TI  - [Double tachyarrhythmia: left anterior fascicular ventricular tachycardia
      associated with atrial flutter and fibrillation. Report of a case].
AB  - A patient with episodes of palpitation in whom the electrocardiogram showed a
      right bundle branch (RBBB) configuration and right axis deviation underwent
      electrophysiologic study and radiofrequency ablation. Left ventricular
      endocardial mapping during ventricular tachycardia (VT) identified the earliest
      ventricular activation in the anterolateral wall of the left ventricle. The fused
      Purkinje potential was recorded at that site, and preceded the QRS complex by 47
      mseg, with pace mapping showing an optimal match between the paced rhythm and the
      clinical VT. The stimulus to QRS time was equal to the Purkinje potential-QRS
      time. Several radiofrequency lesions were applied in this region, one of them
      resulted with termination of the tachycardia. Following delivery of this lesion
      the ventricular tachycardia couldn't be induced either at baseline or during
      isoproterenol infusion. During VT, atrial fibrillation and atrial flutter were
      observed, cardioversion was performed reverting to sinus rhythm.

PMID- 10640210
TI  - [Tumor necrosis factor-alpha: a mediator in the pathogenesis of cardiac
      insufficiency].
AB  - An increasing body of experimental and clinical work suggesting that tumor
      necrosis factor alpha plays a pathogenic role in heart failure continues to
      accumulate. This cytokine is produced in failing but not in normal hearts and
      experimentally, it's expression is induced by hemodynamic conditions of pressure
      or volume overload. Specific receptors for this cytokine are present in the heart
      and dynamic regulation in tumor necrosis factor receptor expression occurs in
      failing myocardium. In addition, tumor necrosis factor alpha may exert major
      cardiac effects that contribute to the development of the failing phenotype:
      induces negative contractil dysfunction, promotes fibrosis, induces
      cardiomyopathy in experimental animals and it is a major mediator of apoptosis in
      vivo and in vitro. The knowledge gained from studying the role of tumor necrosis
      factor alpha in cardiac function draws attention to a series of molecules
      previously unrecognized as potential mediators in the pathogenesis of heart
      failure.

PMID- 10640211
TI  - [The intracellular mechanisms of calcium and insulin in the association of
      arterial hypertension with diabetes].

PMID- 10640212
TI  - [Pharmacological thrombolysis in acute myocardial infarction. Lessons learned
      from ISIS-2 and GUSTO-1. I].

PMID- 10640213
TI  - Diagnosis and classification of erythrocytoses and thrombocytoses.
AB  - An erythrocytosis describes an increased peripheral blood packed cell volume
      (PCV) and is deemed to be absolute or apparent depending on whether or not the
      measured red cell mass (RCM) is above the reference range. This reference range
      must be related to the individual's height and weight to avoid erroneous
      interpretations using ml/kg total body weight expressions in obesity. Absolute
      erythrocytoses are divided into primary, where the erythropoietic compartment is
      intrinsically abnormal, secondary, where the erythropoietic compartment is normal
      but is responding to external pathological events leading to an increased
      erythropoietin drive, and idiopathic, where neither a primary nor a secondary
      erythrocytosis can be established. Both primary and secondary erythrocytoses have
      congenital and acquired forms. The only form of primary acquired erythrocytosis
      that has been defined is the clonal myeloproliferative disorder, polycythaemia
      vera (PV). Modified diagnostic markers for PV are proposed. Thrombocytoses can be
      classified into primary, where megakaryopoiesis is intrinsically abnormal,
      secondary, where megakaryopoiesis is normal but increased platelet production is
      a reaction to some other unrelated pathology, and finally idiopathic. This latter
      new group would be used for patients not satisfying the criteria for primary or
      secondary thrombocytoses, if these were more precise and rigidly used than
      currently is the case. While theoretically congenital and acquired forms of
      primary and secondary thrombocytoses might exist, only one cause of secondary
      congenital thrombocytosis has been established, and primary congenital
      thrombocytosis has not yet been precisely defined. Primary (essential)
      thrombocythaemia (PT) is one of the forms of primary acquired thrombocytoses. The
      diagnostic criteria of PT traditionally involve the exclusion of secondary
      thrombocytoses and other myeloproliferative disorders but marrow histology could
      hold a key positive diagnostic role if objective histological features of PT were
      agreed.

PMID- 10640214
TI  - The histopathology of chronic myeloproliferative diseases.
AB  - This chapter discusses the histopathology of five groups of chronic
      myeloproliferative diseases: chronic myeloid leukaemia, polycythaemia vera,
      essential thrombocythaemia, chronic idiopathic myelofibrosis and unclassifiable
      myeloproliferation. Histological staging of the four haematologically defined
      diseases is performed by grading the three most prominent variables:
      megakaryocytes, fibres and blasts. Histological outcome is correlated to the
      staging of diagnostic bone marrow biopsies; megakaryocytic involvement is
      correlated with the risk of myelofibrosis. An excess of blasts is related to the
      risk of leukaemic transformation. The progression of myelofibrosis depends on the
      grade of fibre increase at diagnosis. These three statements are highly
      significant and valid for all types of chronic myeloproliferative disorders. The
      results of cytogenetics are discussed in relation to the histological
      classification for these patient groups. Changes in bone marrow histology
      following myelosuppressive therapy is presented. Prospective studies under
      standardized protocol therapy are recommended, so that the long-term effects of
      therapy can be assessed.

PMID- 10640216
TI  - Treatment of polycythaemia vera and essential thrombocythaemia.
AB  - The clinical course in both polycythaemia vera (PV) and essential
      thrombocythaemia (ET) is characterized by significant thrombohaemorrhagic
      complications and variable risk of disease transformation into myeloid metaplasia
      with myelofibrosis or acute myeloid leukaemia. Randomized studies have shown that
      the risk of thrombosis was significantly reduced in ET with the use of
      hydroxyurea (HU) and in PV with the use of chlorambucil or 32P. However, the use
      of chlorambucil or 32P has been associated with an increased risk of leukaemic
      transformation. Subsequently, other studies have suggested that both HU and
      pipobroman may be less leukaemogenic and as effective as chlorambucil and 32P for
      preventing thrombosis in PV. However, the results from these prospective studies
      have raised concern that even HU and pipobroman may be associated with excess
      leukaemic events in both ET and PV. The recent introduction of anagrelide as a
      specific platelet-lowering agent, the demonstration of treatment efficacy with
      interferon-alpha, and the revived interest in using low-dose acetylsalicylic acid
      provide the opportunity to initiate prospective randomized studies incorporating
      these treatments.

PMID- 10640215
TI  - Pathogenesis and management of idiopathic myelofibrosis.
AB  - Idiopathic myelofibrosis is the least common and carries the worst prognosis of
      the chronic myeloproliferative disorders. The primary disease process is a clonal
      haematopoietic stem cell disorder which results in a chronic myeloproliferation
      and an atypical megakaryocyte hyperplasia. In contrast, the characteristic
      stromal proliferation is a reactive phenomenon, resulting from the inappropriate
      release of megakaryocyte/platelet-derived growth factors, including PDGF, TGF
      beta bFGF and calmodulin. The median survival is approximately 4 years, although
      individual survival varies greatly. A variety of prognostic schema have been
      developed which enable the identification of high-risk patients, for whom bone
      marrow transplantation should be considered. Management for the majority of
      patients, however, is directed towards the alleviation of symptoms and
      improvement in quality of life. This review summarizes the recent advances in our
      understanding of the disease's pathogenesis and discusses the limited therapeutic
      options available to clinicians.

PMID- 10640217
TI  - Clonality markers in polycythaemia and primary thrombocythaemia.
AB  - Our current understanding of the pathogenesis of the myeloproliferative disorders
      is based on the assumption that they represent a clonal disorder resulting from
      transformation of a haematopoietic stem cell. Clonality assays exploit the fact
      that female cells have only one active X-chromosome. Methods for determining X
      chromosome inactivation have been devised at the protein (G6PD isoenzymes); DNA
      (HUMARA; phosphoglycerate kinase (PGK); hypoxanthine-phosphoribosyl transferase
      (HPRT) and RNA (G6PD; P55; IDS) levels. In this type of RNA assay the product of
      the active X chromosome is quantified by studying polymorphisms present in mRNA.
      The presence of skewed lyonization in normal females is a potential limitation to
      the method, although the use of T cells as a control makes it possible to
      distinguish clonal haematopoiesis from skewed lyonization. However, the
      phenomenon of acquired skewing in normal elderly women means that X-inactivation
      patterns in elderly patients must be interpreted with caution. Clonality studies
      have been conducted in polycythaemia vera (PV) and essential thrombocythaemia
      (ET) patients. They usually demonstrate a clonal X-inactivation pattern in
      granulocytes and/or platelets but a polyclonal pattern in T cells. However, in
      both ET and PV a significant minority of patients exhibit polyclonal
      haematopoiesis with polyclonal patterns in granulocytes/platelets. Female
      patients with polyclonal haematopoiesis differ from those with clonal
      haematopoiesis in terms of age and platelet count and possibly in their
      requirements for treatment. This new technology for the investigation of the MPD
      seems promising for understanding certain clinical aspects of these diseases and
      may be introduced for evaluation of new modalities of treatment.

PMID- 10640218
TI  - Haematopoietic progenitors and signal transduction in polycythaemia vera and
      primary thrombocythaemia.
AB  - While significant progress has been made in understanding the cellular defect and
      molecular basis of polycythaemia vera (PV), elucidation of the primary mutation
      leading to PV remains elusive. While clinically useful, the PV diagnostic
      criteria put forward by the Polycythemia Vera Study Group are not based on the
      pathophysiology of this disorder and in some instances may lead to false
      diagnosis or may not be sufficient to diagnose an early PV. In diagnostically
      unclear situations, clinical and laboratory findings must take into account the
      acquired nature of PV, its clonality, and the presence of endogenous erythroid
      colony formation in serum-containing media. It is likely that other simpler
      assays may be developed based on the rapidly emerging knowledge of the cellular
      pathology of PV. Several intriguing observations of abnormalities pertaining to
      the erythroid signal transduction have been recently reported; these remain to be
      validated in other laboratories and to be proven specific for PV. The clinical
      concept of primary thrombocythaemia (PT) lags behind what we know about PV. While
      the diagnosis of PT is still based on the exclusion of other known causes of
      thrombocytosis, new knowledge is emerging. Recent clonality studies of a large
      number of PT females show that the majority are clonal. It is our belief that
      thrombocythaemic subjects who are not found to be clonal are those with secondary
      thrombocytosis. Multiple in vitro-based assays of megakaryocytic and erythroid
      progenitors have been developed and conflicting data published. It is likely that
      standardized assays of megakaryocytic progenitors will soon become available and
      a reproducible PT specific defect will be found. Such a specific test would be of
      immense diagnostic value in this most elusive of all myeloproliferative
      disorders.

PMID- 10640219
TI  - Molecular genetics and cytogenetics of myeloproliferative disorders.
AB  - The myeloproliferative disorders are believed to represent clonal malignancies
      resulting from transformation of a pluripotent stem cell. X-inactivation patterns
      of peripheral blood cells have been proposed as a useful diagnostic tool but this
      method is limited by the finding of a clonal X-inactivation pattern in a
      significant proportion of normal elderly women. There is no pathognomonic
      chromosomal abnormality associated with the myeloproliferative disorders.
      However, consistent acquired cytogenetic changes include del(20q), del(13q),
      trisomy 8 and 9 and duplication of segments of 1q, all of which have been
      observed at diagnosis or before cytoreductive therapy and therefore represent
      early lesions which contribute to the pathogenesis of these disorders. Although,
      the acquired molecular defects underlying most myeloproliferative disorders have
      not yet been elucidated, translocations associated with the rare 8p11 syndrome
      have permitted identification of a novel fusion protein. The role of a number of
      candidate genes in the other myeloproliferative disorders has also been studied,
      but no mutations have been identified so far. It is likely that a number of genes
      will be involved, given the varied phenotypes of the diseases. Identification of
      causal genes will be of considerable interest to both clinicians, who currently
      lack a specific and sensitive diagnostic test, and scientists interested in
      fundamental issues of stem cell behaviour.

PMID- 10640220
TI  - Familial myeloproliferative disease.
AB  - The occurrence of one or more myeloproliferative disease (MPD) syndromes in 42
      families is described. MPD appeared in a single generation in 10 families, two
      generations in 30 families and three generations in two families. In contrast to
      sparse case reports of familial polycythaemia vera, familial essential
      thrombocythaemia, or familial agnogenic myeloid metaplasia, in which all the
      involved members presented with the same MPD, 21 of the 42 families in the
      present series had members who presented with different MPD variants. The
      occurrence of multiple disease phenotypes in 'MPD families' is entirely
      consistent with the accepted theory of MPD as a disease arising from clonal
      expansion of a pluripotential haematopoietic precursor cell (PHPC) that retains
      its pluripotentiality and produces an array of inter-related syndromes, each
      named for the predominant haematic cell type involved in the proliferation.
      Changes in disease phenotype during the course of MPD and 'hybrid' phenotypes at
      the time of diagnosis are common. This report challenges the previously accepted
      belief that PV and other MPD variants are sporadic and randomly-occurring, and
      that familial occurrence of MPD is rare. The ability to identify 'MPD families'
      by surveying a large population of patients with MPD through the Internet, as was
      done in this study, and heightened awareness of familial occurrence and its
      phenotypic heterogeneity, should facilitate further characterization of the mode
      of inheritance in familial MPD and the nature of the gene mutations responsible
      for the dysregulation of haematopoiesis.

PMID- 10640221
TI  - Fertility, pregnancy and the management of myeloproliferative disorders.
AB  - The management of pregnant patients with chronic myeloproliferative disorders
      (MPD) is a difficult problem. Patients with essential thrombocythaemia (ET), and,
      less frequently, those with chronic myeloid leukaemia (CML) or polycythaemia vera
      (PV), present at a childbearing age. Pregnancy itself does not appear to affect
      adversely the natural course and prognosis of the MPD. However, fertility might
      be reduced, and an adverse outcome of pregnancy due to thrombotic or bleeding
      complications is a matter of concern. It ET, first-trimester abortion is the most
      frequent complication but increased perinatal mortality and premature delivery
      are also observed. Placental infarction due to thrombosis seems to be the most
      consistent event. Maternal thrombotic or haemorrhagic complications are rare but
      are more common than seen in normal pregnancy. The outcome of pregnancy seems to
      be positively influenced by aspirin, at least in some cases. The value of
      cytoreduction and/or heparin prophylaxis has not been established but may have a
      role in selected cases. In CML, the potential adverse effects of
      hyperleukocytosis, and sometimes thrombocytosis, generally make myelosuppressive
      treatment essential. In PV, the number of reported pregnancies is low.
      Maintaining the PCV below 0.45 is of the utmost importance relating to the
      outcome of pregnancy. Although cytoreductive drugs should generally be avoided,
      if possible, until at least after the first trimester of pregnancy, interferon
      alpha seems to be the drug of choice when myelosuppression is indicated. In
      summary, the available information about pregnancy occurring during the course of
      an MPD indicates that successful management of pregnancy is possible. However,
      optimal management of these patients is poorly defined and agreed protocols are
      not available. In view of these problems, it is timely to consider the
      establishment of a national or European registry to monitor prospectively the
      management offered to pregnant women found to have an MPD.

PMID- 10640222
TI  - Childhood myeloproliferative disorders.
AB  - Disorders classified as paediatric myeloproliferative disorders (MPD), such as
      juvenile chronic myeloid leukaemia (JCML), and as paediatric myelodysplastic
      syndrome (MDS), are essentially diseases characterized by abnormal
      myeloproliferation and they share similar genetic events on chromosome 7. As
      such, the abnormalities of increased myeloproliferation in childhood (AIMC)
      should be considered under the same heading. Constitutional and other genetic
      factors play an essential role in children and include the NF1 gene, whereas
      toxic exposure is of greater importance in adults. The most common cytogenetic
      alteration is that of monosomy or deletion of the long arm of chromosome 7.
      Critical regions have been identified and mapped by fluorescence in situ
      hybridization (FISH). It appears that the similar critical regions on chromosome
      7 are involved, and suggests that these regions may contain genes important in
      the pathogenesis of AIMC.

PMID- 10640223
TI  - Sense of control and adjustment to breast cancer: the importance of balancing
      control coping styles.
AB  - The relationship of modes of control and desire for control to psychosocial
      adjustment in women with breast cancer was examined. Fifty-eight women with stage
      I or stage II breast cancer were surveyed shortly after their diagnosis and again
      4 and 8 months later. The authors hypothesized that a control profile in which
      individuals use a positive yielding (i.e., accepting) mode of control in
      conjunction with an assertive mode results in better adjustment than relying
      exclusively or primarily on an assertive mode. Results lend preliminary support
      to this hypothesis. At 8-month follow-up, those women who had a high desire for
      control and were low in positive yielding control showed the poorest adjustment,
      whereas those high in desire and the positive yielding mode showed the best
      psychosocial adjustment. The findings suggest that balanced use of active and
      yielding control efforts may lead to optimal psychosocial adjustment and quality
      of life in the face of life-threatening illnesses.

PMID- 10640224
TI  - Stress and course of disease in multiple sclerosis.
AB  - In this prospective study, 96 healthy controls and 101 multiple sclerosis
      patients were followed up for as many as 6 years, and self-reported stressful
      events and health status were assessed. The authors evaluated (a) whether
      patients reported more stressful life events than healthy controls and (b) the
      bidirectional relationship between stress and functional deterioration among
      patients. Healthy controls reported more life events than patients, Odds ratio
      (OR) = 1.13, p < .0001; and this relationship was attributable to healthy
      controls' reporting more neutral/positive events than patients. A bidirectional
      relationship was confirmed between stress and illness: there was an increased
      risk of disease progression when rate of reported stressful events was higher, OR
      = 1.13, p < .0003, and an increased risk of reported stressful events when rate
      of disease progression was higher, OR = 2.13, p < .0001. There were no
      differences in reported stress by level of baseline disability. The authors
      concluded that multiple sclerosis patients demonstrate a vicious cycle between
      stress and disease progression.

PMID- 10640225
TI  - Psychological adjustment and coping in adults with prosthetic limbs.
AB  - The potential mediating effects of different coping strategies on the adjustment
      to living with a prosthetic limb were investigated in 44 adult amputees.
      Participants completed a questionnaire inquiring about coping, pain, emotional
      well-being, demographics, and disability-related variables. The coping strategy
      adopted and the extent of the adjustment to the prosthetic limb varied with age,
      site of limb loss, and cause of amputation. Furthermore, coping style mediated
      the adjustment to wearing a prosthetic limb. The results are discussed in terms
      of future applications and research.

PMID- 10640226
TI  - Semistarvation-associated eating behaviors among college binge eaters: a
      preliminary description and assessment scale.
AB  - Binge eating is a consequence of semistarvation in victims of war and famine and
      in volunteers in rare semistarvation experiments. These behaviors include bizarre
      mixing of ingredients and adulteration of food; eating inappropriate, soiled, or
      discarded food; secrecy; deception; and defensiveness. Drastic measures to resist
      overeating persist long after the semistarvation experience, even when food is
      plentiful. Binge eating, a central feature of bulimia and sometimes of anorexia
      nervosa, is prevalent in modern society, but the occurrence and frequency of
      semistarvation-related behaviors have not been well identified or quantified. A
      Semistarvation-Associated Behaviors Scale was constructed and administered to 40
      college students. Among binge eaters, reports of bizarre semistarvation-like
      behaviors were common and frequent and were associated with dieting.

PMID- 10640227
TI  - [Unity and opposition of cytogenetic activity of lymphocytes and their antibody
      producing function during recovery processes in organs].

PMID- 10640228
TI  - [Relationship between rat learning in the "shuttle-box" and behavioral entropy in
      the "auto track system"].

PMID- 10640229
TI  - [Effect of semax and its mixture with heparin on the activity of isolated heart
      after total ischemia].

PMID- 10640230
TI  - [Effect of selective vagotomy on the inotropic and chronotropic function of the
      rat heart].

PMID- 10640231
TI  - [Effect of a novel anxiolytic SM-346 on the bioelectric activity of the cerebral
      cortex of MR and MNRA rats].

PMID- 10640232
TI  - [Dynamics of relationship of electrophoretic motility and erythrocyte volume in
      rats during stress].

PMID- 10640233
TI  - [Adaptation to heat activates synthesis of HSP70, limits hyperproduction of
      nitric oxide, and protects organism against acute hypotension during heat shock].

PMID- 10640234
TI  - [C57Bl/6 mice are more resistant to hypoxic hypoxia than BALB/c mice].

PMID- 10640235
TI  - [Effect of native and oxidized LDL on macrophage chemiluminescence].

PMID- 10640236
TI  - [Changes in the level of catecholamines in the brain stem during hypoxia and
      hemorrhage: effect of regulatory peptides].

PMID- 10640237
TI  - [Effect of thymidine and phorbol-12-myristate-13-acetate on the erythroid
      differentiation of K562 cells and their sensitivity to nonspecific lysis by rat
      splenocytes].

PMID- 10640238
TI  - [Bioresonance therapy in rheumatoid arthritis and heat shock proteins].

PMID- 10640239
TI  - [Analysis of pharmacological properties of bromantane].

PMID- 10640240
TI  - [Effect of the neurotoxin MPTP on the behavior and the level of major
      neuromediators in the brain of mice].

PMID- 10640241
TI  - [Neuroprotective activity of angiotensin-converting enzyme inhibitors during
      cerebral ischemia].

PMID- 10640242
TI  - [Effect of D-amphetamine on the extracellular dopamine level and generation of
      hydroxyl radicals in the striatum of free-range rats].

PMID- 10640243
TI  - [reaction of latex-agglutination for express and retrospective diagnosis of
      meningococcal infection].

PMID- 10640244
TI  - [The role of gamma globulin-associated fraction containing carbohydrate component
      in the regulation of human natural killers activity in vitro].

PMID- 10640245
TI  - [Streptococcal IgG Fc-binding proteins--initiation factors of experimental
      glomerulonephritis].

PMID- 10640247
TI  - [The use of allele-specific amplification and analysis of conformational
      polymorphism for detection of rifampicin resistance in clinical isolates of
      Mycobacterium tuberculosis].

PMID- 10640246
TI  - [Immunomodulating activity of beta-heptylglycoside-muramyldipeptide in vivo].

PMID- 10640248
TI  - [Can the neurotransplants of mice with chromosome 16 trisomy be considered as a
      model of pathological changes typical for Alzheimer disease?].

PMID- 10640249
TI  - [Beta-endorphin in the plasma and cerebro-spinal fluid during different types of
      analgesia in early postoperative period and in incurable cancer patients].

PMID- 10640250
TI  - [Changes in the antioxidative activity of tears during experimental eye burns].

PMID- 10640251
TI  - [Catechol estrogen excretion in women receiving estrogen replacement therapy].

PMID- 10640252
TI  - [Functional reserves of the pool of committed bone marrow hematopoietic
      precursors in AKR/JY mice during preleukemic period].

PMID- 10640253
TI  - [Effect of ultraphonophoresis of eplir on the fibrous-sclerotic and adhesive
      changes in uterine adnexa].

PMID- 10640254
TI  - [Effect of adrenals on the hematopoietic microenvironment of the bone marrow].

PMID- 10640255
TI  - [Ultrastructural and biosynthetic reactions in cell populations of kidney
      glomeruli in glomerular pathology].

PMID- 10640256
TI  - [Fluorescent analysis of albumin in aqueous humor and tears].

PMID- 10640257
TI  - The UK migraine patient survey: quality of life and treatment.
AB  - This research confirms that a majority of migraine sufferers in the UK
      acknowledge an incidence, frequency and symptomatology that have a significant
      effect on quality of life (both activity-based and on personal relationships);
      despite this, a significant proportion self-medicate with unsuitable and
      ineffective agents owing to the low level of efficacy and general lack of
      satisfaction with recommended and prescribed therapies. 50,000 migraineurs
      (sample derived from the Consumer Research Bureau) in the UK were invited to self
      complete a questionnaire (during Q2-Q3, 1998). 9770 questionnaires were included
      in the analysis. With the advent of improved diagnosis and medications, the
      present study was undertaken to assess the impact and severity of migraine on the
      normal activities, attitudes and relationships of known migraineurs. The efficacy
      and control achieved by a range of therapeutic interventions were also
      considered. In order to identify the headache characteristics of this self
      selected migraine patient population, diagnosis was confirmed by information
      relating to quality of headache (frequency, duration and symptomatology); the
      extent of restrictions on specific daily activities was also used to provide
      severity characteristics. A majority believed that they could not control their
      migraine and a significant proportion believed that migraine controlled their day
      to-day life. Despite this, sufferers may not consult general practitioners (GPs)
      owing to previous experience, expectations of inadequate therapeutic intervention
      and/or perceived lack of physician empathy. This study is both opinion-based and
      awareness-based, and confirms known statistics while also providing further
      clarification on the overall effect of migraine on associated emotional and
      physical relationships, and on migraineurs' use and opinion of a range of
      available medications.

PMID- 10640258
TI  - A long-term study to maximise migraine relief with zolmitriptan.
AB  - Part 1 of this international study was a randomised, double-blind, placebo
      controlled study of 2.5 mg and 5 mg zolmitriptan (Zomig) in the treatment of
      persistent migraine headache, two hours after an initial dose of 2.5 mg
      zolmitriptan. Part 2 was a non-comparative evaluation of long-term, unrestricted
      zolmitriptan use for treatment of initial, persistent and recurrent migraine
      headaches. In Part 1, following the treatment of moderate or severe persistent
      headache, two-hour headache response rates with 5 mg zolmitriptan (51.6%, n =
      322), 2.5 mg zolmitriptan (49.7%, n = 324) and placebo (51.6%, n = 343) were not
      significantly different. However, the pain-free response rate following the
      treatment of persistent migraine headache of any intensity was significantly
      higher with 5 mg zolmitriptan than with placebo (36.0% vs. 25.5%; p < 0.001).
      This was predominantly due to effects in the subgroup of patients with mild
      headache. Thus, migraine relief in patients whose initial headache shows a
      partial response to 2.5 mg zolmitriptan may be maximised by a second 5 mg dose.
      In Part 2 (involving 2499 evaluable patients), 65.8% of attacks were treated with
      a single dose of zolmitriptan (2.5 mg or 5 mg). Of those migraine attacks
      initially treated with 2.5 mg zolmitriptan, 70.3% required no further dose,
      similarly 62.7% of migraine attacks treated initially with 5 mg zolmitriptan only
      required a single dose. Over the whole attack (i.e. initial and any persistent
      headache), headache response rates to one or two zolmitriptan doses were greater
      than 88.8%. 'Level of pain' was the primary factor influencing the choice of
      dose. Zolmitriptan provided consistent migraine headache relief in the majority
      of patients and was well tolerated.

PMID- 10640259
TI  - Zolmitriptan provides consistent migraine relief when used in the long-term.
AB  - Migraine is a chronic disease that significantly reduces quality of life between,
      as well as during, attacks. Treatments that provide consistent relief may reduce
      the burden of the disease. In the open-label phase of a two-part study, patients
      could choose to treat initial, persistent or recurrent migraine headache of any
      intensity with 2.5 mg or 5 mg zolmitriptan. This novel study design allowed
      patients to manage and maximise their migraine relief. Headache response rates
      and pain-free response rates were assessed within two hours of dosing with
      zolmitriptan, and response rates were compared across migraines with and without
      a history of aura, and associated or not with menses. Consistency of response was
      also assessed in those patients treating at least 20 attacks. Of 49,784 attacks
      treated, 66% (32,737 attacks) were treated with a single dose of zolmitriptan.
      Two-hour headache response rates to an initial dose of 2.5 mg or 5 mg
      zolmitriptan were 85% (median 95%) and 79% (median 88%), respectively, across all
      attacks. Corresponding pain-free response rates were 69% and 59%. Responses were
      independent of gender and age and were similar in patients with and without aura
      and in attacks associated or not associated with menses. Consistent response
      rates were achieved within individual patients; during months 1 to 3, 64% of
      patients reported a headache response in > 75% of their migraine attacks. In
      patients treating at least 20 attacks, 2.5 mg and 5 mg zolmitriptan produced
      consistently high headache response rates (range 84-91% and 76-84%, respectively)
      and pain-free response rates (range 70-76% and 58-65%, respectively) across
      attacks. In the minority of attacks requiring a second dose of zolmitriptan for
      persistent or recurrent headache, response rates to a second dose were also
      consistent across attacks. In conclusion, zolmitriptan 2.5 mg and 5 mg show
      consistent effectiveness in the treatment of multiple migraine attacks in
      individual patients and are unaffected by gender, age and the presence of aura or
      the relationship to menses.

PMID- 10640260
TI  - Zolmitriptan is effective for the treatment of persistent and recurrent migraine
      headache.
AB  - Zolmitriptan is a 5-HT1B/1D receptor agonist for the acute treatment of migraine.
      This study examined the efficacy of a second dose of zolmitriptan for the
      treatment of persistent or recurrent headache. Part 1 was a randomised, placebo
      controlled, double-blind evaluation of 2.5 mg and 5 mg zolmitriptan for the
      treatment of persistent migraine headache, two hours after an initial dose of 2.5
      mg zolmitriptan. In part 2 (open-label), patients treated the first two attacks
      with 2.5 mg zolmitriptan, thereafter patients could treat any initial, persistent
      or recurrent migraine headache with 2.5 mg or 5 mg zolmitriptan. The unique
      design of this trial allowed patients to adjust their treatment to attain maximum
      headache relief and control of their disease. Of 2800 patients treating an
      initial migraine headache in Part 1, 989 patients took a second dose to treat
      persistent headache of moderate or severe intensity. Headache response rates were
      similar across the three treatment groups, but the pain-free response rate was
      significantly higher with 5 mg zolmitriptan than with placebo (p < 0.001). In
      Part 2, 2499 patients treated 49,784 migraine attacks (excluding the first two
      attacks, which had to be treated with 2.5 mg zolmitriptan), of which 66% required
      only a single dose of zolmitriptan. Patients treated 22% of attacks with a second
      dose of zolmitriptan for persistent headache. A headache response was achieved in
      80% and 73% of persistent headaches treated with 2.5 mg or 5 mg zolmitriptan,
      respectively. Corresponding pain-free responses following treatment of persistent
      headaches of any intensity were 64% and 52%. Eight per cent of attacks were
      treated with a second dose of zolmitriptan for moderate or severe recurrent
      headache. A headache response was achieved in 90% and 86% of moderate/severe
      attacks, with a pain-free response in 78% and 70% of attacks of any intensity
      treated with 2.5 mg and 5 mg, respectively. Zolmitriptan was well tolerated. In
      conclusion, 2.5 mg and 5 mg zolmitriptan are highly effective in treating both
      persistent and recurrent migraine headache.

PMID- 10640261
TI  - Maximising the use of HRT: focus on hysterectomised women.
AB  - Hysterectomy is one of the most common gynaecological surgical operations
      performed in the UK. In addition to causing the early onset of the menopause,
      hysterectomy can lead some women to be at increased risk of future CHD and
      osteoporosis owing to declining oestrogen levels. Hysterectomised women are
      therefore an ideal group to receive hormone replacement therapy (HRT). However,
      only small numbers of women receive HRT owing to a number of factors, including
      fear of potential complications and adverse side-effects. Of those women who do
      receive HRT, compliance with therapy is low. In this article, the authors weigh
      the benefits of HRT, in terms of relief of menopausal symptoms, and prevention of
      osteoporosis, Alzheimer's disease and cardiovascular disease, against the known
      risks. The authors suggest that compliance with HRT could be optimised by
      profiling patients in general practice and by educating women on the long-term
      benefits of HRT.

PMID- 10640262
TI  - Metronidazole, its bioactive metabolites and acne.
AB  - Metronidazole's activity has been established in both acneiform rosacea and acne
      vulgaris. Recent research indicating that the breakdown products of several
      antibiotics, including metronidazole, may have considerably greater activity than
      the parent compound, prompted a re-examination of the susceptibility of
      Propionibacterium acnes, the organism involved in the fundamental pathogenesis of
      acne vulgaris. Although the organism was marginally more sensitive to the hydroxy
      derivative, MIC levels were still outside the readily attainable therapeutic
      range. The beneficial effects of metronidazole in acne vulgaris are attributable
      to its anti-inflammatory activities rather than its antibacterial ones.

PMID- 10640263
TI  - Randomised trial of pivampicillin plus pivmecillinam vs. pivampicillin in
      children and young adults with chronic obstructive pulmonary disease and
      infection with Haemophilus influenzae.
AB  - A prospective, randomised, single-blind comparative trial was carried out to
      determine whether double beta-lactam treatment with pivampicillin plus
      pivmecillinam is more effective than pivampicillin alone in the treatment of
      recurrent and chronic lung infections with Haemophilus influenzae in patients
      with chronic obstructive pulmonary disease (COPD) or cystic fibrosis (CF). Fifty
      six children and young adults with COPD or CF were randomised to the clinical
      study. The patients were allocated at random to receive perorally either
      pivmecillinam, 40 mg/kg/day, combined with pivampicillin, 50 mg/kg/day, or
      pivampicillin 50 mg/kg/day alone for 14 days. A cross-over pharmacokinetic study
      using the same drugs was carried out in 10 CF patients to determine the
      antibiotic concentrations in serum and sputum after a single dose of each drug.
      The clinical study showed no significant differences in clinical scoring, lung
      function tests or adverse events after treatment with pivampicillin plus
      pivmecillinam or pivampicillin alone. Follow-up microbiological evaluation 2 and
      6 weeks after the end of treatment showed that the offending pathogen was
      eradicated in 68% of the patients treated with pivampicillin plus pivmecillinam
      and in 67% of the patients treated with pivampicillin alone. Reinfection with
      another biotype was more common in the combination group (50% vs. 21%) than in
      the pivampicillin group. In the pharmacokinetic study the median peak serum
      concentration occurred two hours after intake of tablets. The efficacy of double
      beta lactam treatment in lung infections with H. influenzae appears to be
      equivalent to that of ampicillin on clinical lung symptoms, lung function tests,
      adverse effects and bacteriology.

PMID- 10640264
TI  - Effects of acetate or bicarbonate dialysis solutions on serum HDL and HDL
      subfractions of patients undergoing haemodialysis.
AB  - The aim of this study was to compare the effect of acetate- and bicarbonate
      containing dialysis solutions (buffers) on serum lipid (triglyceride and total
      cholesterol) and lipoprotein (LDL, HDL and its subfractions as HDL2 and HDL3',
      Apolipoprotein A1 and Apolipoprotein B) values in patients undergoing
      haemodialysis. Lipid concentrations in 16 patients on bicarbonate and in 18
      patients on acetate haemodialysis were investigated initially and after four
      weeks of dialysis treatment. Over four weeks of treatment both acetate and
      bicarbonate dialysis treatments had no negative effects on either HDL or HDL
      subfractions, and these buffering systems were indistinguishable from each other.
      We confirm that HDL is the major factor that is changed in the lipid profile in
      haemodialysis patients undergoing acetate or bicarbonate dialysis and suggest
      that the relation between LDL and HDL subfractions may be useful for monitoring
      the lipid changes in haemodialysis patients at risk of atherogenesis.

PMID- 10640265
TI  - Comparison of antioxidant potentials of red wine, white wine, grape juice and
      alcohol.
AB  - Antioxidant potential (AOP) and non-enzymatic superoxide radical scavenger
      activity (NSSA) values of red wine, white wine, grape juice and ethyl alcohol
      were assessed and values were compared. The effects of these beverages on serum
      AOP and NSSA values were also measured in vitro. Red wine, white wine and grape
      juice exert strong antioxidant activity in similar degrees and all produce
      significant effects on serum AOP and NSSA values. However, ethyl alcohol does not
      have either AOP or NSSA, nor does it have an effect on serum AOP or NSSA values.
      AOP values (nmol/ml h) of red wine, white wine and grape juice were 20.8 +/- 4.2,
      23.2 +/- 4.0 and 24.6 +/- 4.8, respectively. NSSA values (U/ml) of red wine,
      white wine and grape juice were 30.4 +/- 6.8, 26.8 +/- 5.6 and 32.6 +/- 5.8,
      respectively. There were no statistically meaningful differences between AOP and
      NSSA values of the groups (p > 0.05 for all). Results suggest that red wine,
      white wine and grape juice all have high antioxidant potential to protect
      cellular structures against peroxidation reaction owing to their rich phenolic
      contents.

PMID- 10640266
TI  - Antitumour immune response and cancer vaccination: the critical role of dendritic
      cells.
AB  - Increasing the capacity of the immune system to mediate tumour regression has
      been a major goal in tumour immunology. Progress towards this goal has been
      recently aided by the identification of immunogenic cancer antigens and by a
      better understanding of the mechanisms of T-cell immune response and tumour
      escape. A rare antigen-presenting cell--the dendritic cell (DC)--appears to be
      the key to these mechanisms. The possibility of generating these cells in vitro
      from blood precursors has initiated a new era in cancer immunotherapy. Using DC
      as a cancer vaccine adjuvant has led to reports of measurable immune responses,
      and, in a few cases, to complete disease responses in patients with B-cell
      lymphoma and melanoma.

PMID- 10640267
TI  - The fourth barrier.
AB  - At the entrance of a new era, clinical xenotransplantation is a valued and
      auspicious option in tackling the problem of donor shortage. Because of ethical
      and anatomical issues, domestic farm animals are considered the most favourable
      species for organ donation, but transplantation of their organs leads to a
      complex process of rejection. Mechanistically, three immunological barriers,
      namely hyperacute rejection, delayed xenograft rejection and a subsequent
      cellular rejection, are distinguished. A fifth (microbiological) barrier is also
      being recognised. This review focuses on problems regarding the fourth barrier,
      i.e. physiology, in possible clinical settings and their corresponding animal
      models. Besides anatomical differences and posture, biochemical differences may
      have a severe impact on recipient survival. Differences in blood components and
      electrolyte and other biochemical concentrations are easily detected throughout
      the species considered for xenotransplantation. Enzymes and hormones have complex
      routes of action, activation and inhibition, and their molecular differences can
      impede function. As infusion or medicine may correct certain imbalances in
      electrolytes and proteins, problems with complex interactions might be difficult
      to retrieve and solve. Experimentally, survival of discordant xenografts show
      promising results, but the first physiological problems have already been
      detected. So, based upon the few experimental data available and the comparison
      of veterinary physiology, one might expect differences between the organs
      grafted, regarding the possible occurrence of physiological problems. Moreover,
      precautions must be taken to extrapolate long-term survival, because of species
      specificity.

PMID- 10640268
TI  - Postoperative pattern of various hormonal and metabolic variables. A pilot study
      in patients without complications following cardiac surgery.
AB  - The use of single predictors for threatening postoperative complications are
      widely accepted. However, a typical pattern of multiple parameters could be more
      helpful than a single predictor. To study this hypothesis, various variables of
      normal postoperative changes in patients without postoperative complications were
      investigated. Secondly, this pattern needs to be compared in the future with
      those findings in patients with postoperative complications. Blood parameters of
      13 patients undergoing cardiovascular surgery without postoperative complications
      for 24 hours were evaluated. Samples were obtained on the afternoon before the
      operation and 1, 3, 6, 12 and 24 hours after the end of surgery. At one hour
      postoperation increased levels of the following parameters were noted: growth
      hormone (p < 0.0001), glucose (p < 0.0001), insulin (p < 0.001), c-peptide (p <
      0.001), lactate (p < 0.002), glutamate (p < 0.0001), aspartate (p < 0.001) and
      total amino acids (p < 0.05), although the concentration of some amino acids
      decreased. Three hours postoperatively free fatty acids (p < 0.05) were
      increased. Total-T3 concentrations were reduced postoperatively. Other parameters
      were not altered. Most of the parameters returned to normal values during the
      period of observation.

PMID- 10640269
TI  - Replication fork pausing and recombination or "gimme a break".

PMID- 10640270
TI  - Role of the rasGAP-associated docking protein p62(dok) in negative regulation of
      B cell receptor-mediated signaling.
AB  - Antigenic stimulation of the B-cell receptor (BCR) is a central event in the
      immune response. In contrast, antigen bound to IgG negatively regulates signals
      from the BCR by cross-linking it to the inhibitory receptor FcgammaRIIB. Here we
      show that upon cross-linking of BCR or BCR with FcgammaRIIB, the rasGAP
      associated protein p62(dok) is prominently tyrosine phosphorylated in a Lyn
      dependent manner. Inactivation of the dok gene by homologous recombination has
      shown that upon BCR cross-linking, p62(dok) suppresses MAP kinase and is
      indispensable for FcgammaRIIB-mediated negative regulation of cell proliferation.
      We propose that p62(dok), a downstream target of many PTKs, plays a negative role
      in various signaling situations.

PMID- 10640271
TI  - Essential role for Max in early embryonic growth and development.
AB  - Loss of Max function in the mouse resulted in generalized developmental arrest of
      both embryonic and extraembryonic tissues at early postimplantation
      (approximately E5.5-6.5), coincident with loss or dilution of maternal Max stores
      in the expanding embryo in vivo and in blastocyst outgrowths in vitro.
      Developmentally arrested embryos were reduced in size and exhibited widespread
      cytological degeneration and feeble BrdU incorporation. Max and, by extension,
      the Myc superfamily, serve essential roles in early mammalian development and a
      maternal reservoir of Max exists in sufficient amount to sustain Myc superfamily
      function through preimplantation stages of development.

PMID- 10640272
TI  - Mcl-1 deficiency results in peri-implantation embryonic lethality.
AB  - We disrupted the Mcl-1 locus in murine ES cells to determine the developmental
      roles of this Bcl-2 family member. Deletion of Mcl-1 resulted in peri
      implantation embryonic lethality. Mcl-1(-/-) embryos do not implant in utero, but
      could be recovered at E3.5-4.0. Null blastocysts failed to hatch or attach in
      vitro, indicating a trophectoderm defect, although the inner cell mass could grow
      in culture. Of note, Mcl-1(-/-) blastocysts showed no evidence of increased
      apoptosis, but exhibited a delay in maturation beyond the precompaction stage.
      This model indicates that Mcl-1 is essential for preimplantation development and
      implantation, and suggests that it has a function beyond regulating apoptosis.

PMID- 10640273
TI  - Identification and disruption of an Arabidopsis zinc finger gene controlling seed
      germination.
AB  - We describe here the Arabidopsis gene DAG1, encoding a zinc finger transcription
      factor of the Dof family, and show that it is involved in the control of seed
      germination. By a reverse genetics approach, we isolated an Arabidopsis mutant
      line with one T-DNA insertion in DAG1. Seeds from homozygous knockout dag1-1
      plants do not develop dormancy and germinate also in the absence of light.
      Segregation analysis indicates that the effect of the mutation is maternal.
      Accordingly, in situ mRNA hybridizations reveal expression of DAG1 in the
      vascular tissue of the flower and maturing fruit but not in the seed.

PMID- 10640274
TI  - Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible
      factor 1alpha.
AB  - The switch to an angiogenic phenotype is a fundamental determinant of neoplastic
      growth and tumor progression. We demonstrate that homozygous deletion of the p53
      tumor suppressor gene via homologous recombination in a human cancer cell line
      promotes the neovascularization and growth of tumor xenografts in nude mice. We
      find that p53 promotes Mdm2-mediated ubiquitination and proteasomal degradation
      of the HIF-1alpha subunit of hypoxia-inducible factor 1 (HIF-1), a heterodimeric
      transcription factor that regulates cellular energy metabolism and angiogenesis
      in response to oxygen deprivation. Loss of p53 in tumor cells enhances HIF-1alpha
      levels and augments HIF-1-dependent transcriptional activation of the vascular
      endothelial growth factor (VEGF) gene in response to hypoxia. Forced expression
      of HIF-1alpha in p53-expressing tumor cells increases hypoxia-induced VEGF
      expression and augments neovascularization and growth of tumor xenografts. These
      results indicate that amplification of normal HIF-1-dependent responses to
      hypoxia via loss of p53 function contributes to the angiogenic switch during
      tumorigenesis.

PMID- 10640275
TI  - Nuclear receptor corepressors partner with class II histone deacetylases in a
      Sin3-independent repression pathway.
AB  - Transcriptional repression mediated by corepressors N-CoR and SMRT is a critical
      function of nuclear hormone receptors, and is dysregulated in human myeloid
      leukemias. At the present time, these corepressors are thought to act exclusively
      through an mSin3/HDAC1 complex. Surprisingly, however, numerous biochemical
      studies have not detected N-CoR or SMRT in mSin3- and HDAC1-containing complexes.
      Each corepressor contains multiple repression domains (RDs), the significance of
      which is unknown. Here we show that these RDs are nonredundant, and that one RD,
      which is conserved in N-CoR and SMRT, represses transcription by interacting
      directly with class II HDAC4 and HDAC5. Endogenous N-CoR and SMRT each associate
      with HDAC4 in a complex that does not contain mSin3A or HDAC1. This is the first
      example of a single corepressor utilizing distinct domains to engage multiple
      HDAC complexes. The alternative HDAC complexes may mediate specific repression
      pathways in normal as well as leukemic cells.

PMID- 10640276
TI  - Isolation of a novel histone deacetylase reveals that class I and class II
      deacetylases promote SMRT-mediated repression.
AB  - The transcriptional corepressor SMRT functions by mediating the repressive effect
      of transcription factors involved in diverse signaling pathways. The mechanism by
      which SMRT represses basal transcription has been proposed to involve the
      indirect recruitment of histone deacetylase HDAC1 via the adaptor mSin3A. In
      contrast to this model, a two-hybrid screen on SMRT-interacting proteins resulted
      in the isolation of the recently described HDAC5 and a new family member termed
      HDAC7. Molecular and biochemical results indicate that this interaction is direct
      and in vivo evidence colocalizes SMRT, mHDAC5, and mHDAC7 to a distinct nuclear
      compartment. Surprisingly, HDAC7 can interact with mSin3A in yeast and in
      mammalian cells, suggesting association of multiple repression complexes. Taken
      together, our results provide the first evidence that SMRT-mediated repression is
      promoted by class I and class II histone deacetylases and that SMRT can recruit
      class II histone deacetylases in a mSin3A-independent fashion.

PMID- 10640277
TI  - A role for neural determination genes in specifying the dorsoventral identity of
      telencephalic neurons.
AB  - Neurogenin1 (Ngn1), Neurogenin2 (Ngn2), and Mash1 encode bHLH transcription
      factors with neuronal determination functions. In the telencephalon, the Ngns and
      Mash1 are expressed at high levels in complementary dorsal and ventral domains,
      respectively. We found that Ngn function is required to maintain these two
      separate expression domains, as Mash1 expression is up-regulated in the dorsal
      telencephalon of Ngn mutant embryos. We have taken advantage of the replacement
      of the Ngns by Mash1 in dorsal progenitors to address the role of the neural
      determination genes in neuronal-type specification in the telencephalon. In Ngn2
      single and Ngn1; Ngn2 double mutants, a population of early born cortical neurons
      lose expression of dorsal-specific markers and ectopically express a subset of
      ventral telencephalic-specific markers. Analysis of Mash1; Ngn2 double mutant
      embryos and of embryos carrying a Ngn2 to Mash1 replacement mutation demonstrated
      that ectopic expression of Mash1 is required and sufficient to confer these
      ventral characteristics to cortical neurons. Our results indicate that in
      addition to acting as neuronal determinants, Mash1 and Ngns play a role in the
      specification of dorsal-ventral neuronal identity, directly linking pathways of
      neurogenesis and regional patterning in the forebrain.

PMID- 10640278
TI  - The yeast Sgs1p helicase acts upstream of Rad53p in the DNA replication
      checkpoint and colocalizes with Rad53p in S-phase-specific foci.
AB  - We have examined the cellular function of Sgs1p, a nonessential yeast DNA
      helicase, homologs of which are implicated in two highly debilitating hereditary
      human diseases (Werner's and Bloom's syndromes). We show that Sgs1p is an
      integral component of the S-phase checkpoint response in yeast, which arrests
      cells due to DNA damage or blocked fork progression during DNA replication. DNA
      polepsilon and Sgs1p are found in the same epistasis group and act upstream of
      Rad53p to signal cell cycle arrest when DNA replication is perturbed. Sgs1p is
      tightly regulated through the cell cycle, accumulates in S phase and colocalizes
      with Rad53p in S-phase-specific foci, even in the absence of fork arrest. The
      association of Rad53p with a chromatin subfraction is Sgs1p dependent, suggesting
      an important role for the helicase in the signal-transducing pathway that
      monitors replication fork progression.

PMID- 10640279
TI  - ATP can be dispensable for prespliceosome formation in yeast.
AB  - The first ATP-dependent step in pre-mRNA splicing involves the stable binding of
      U2 snRNP to form the prespliceosome. We show that a prespliceosome-like complex
      forms in the absence of ATP in yeast extracts lacking the U2 suppressor protein
      CUS2. These complexes display the same pre-mRNA and U snRNA requirements as
      authentic prespliceosomes and can be chased through the splicing pathway,
      indicating that they are a functional intermediate in the spliceosome assembly
      pathway. ATP-independent prespliceosome-like complexes are also observed in
      extracts containing a mutant U2 snRNA. Loss of CUS2 does not bypass the role of
      PRP5, an RNA helicase family member required for ATP-dependent prespliceosome
      formation. Genetic interactions between CUS2 and a heat-sensitive prp5 allele
      parallel those observed between CUS2 and U2, and suggest that CUS2 mediates
      functional interactions between U2 RNA and PRP5. We propose that CUS2 enforces
      ATP dependence during formation of the prespliceosome by brokering an interaction
      between PRP5 and the U2 snRNP that depends on correct U2 RNA structure.

PMID- 10640280
TI  - HAESA, an Arabidopsis leucine-rich repeat receptor kinase, controls floral organ
      abscission.
AB  - Abcission, the natural shedding of leaves, flowers and fruits, is a fundamental
      component of plant development. Abscission is a highly regulated process that
      occurs at distinct zones of cells that undergo enlargement and subsequent
      separation. Although some components of abscission, including accumulation of the
      hormone ethylene and cell wall-degrading enzymes, have been described, the
      regulatory pathways remain largely unknown. In this paper we describe a critical
      component required for floral organ abscission in Arabidopsis thaliana, the
      receptor-like protein kinase HAESA. Histochemical analysis of transgenic plants
      harboring a HAESA promoter:: beta-glucuronidase reporter gene and in situ RNA
      hybridization experiments show HAESA expression in the abscission zones where the
      sepals, petals, and stamens attach to the receptacle, at the base of pedicels,
      and at the base of petioles where leaves attach to the stem. Immunodetection,
      immunoprecipitation, and protein kinase activity assays reveal HAESA is a plasma
      membrane serine/threonine protein kinase. The reduction of function of HAESA in
      transgenic plants harboring an antisense construct results in delayed abscission
      of floral organs, and the severity of the phenotype is directly correlated with
      the level of HAESA protein. These results demonstrate that HAESA functions in
      developmentally regulated floral organ abscission.

PMID- 10640281
TI  - Neuronal nicotinic acetylcholine receptors as novel drug targets.

PMID- 10640282
TI  - Chemically modified oligonucleotides exhibit decreased immune stimulation in
      mice.
AB  - Phosphorothioate oligodeoxynucleotides produce splenomegaly and mononuclear cell
      infiltrates in multiple organs in mice after repeated i.v. administration.
      Several phosphorothioate oligodeoxynucleotides were studied to better understand
      the basis of immunostimulatory properties of these molecules in mice and to study
      the effects of chemically modified oligonucleotides. Chemical modifications
      examined included 5-methyl cytosine and 2'-methoxyethoxy substituents. Male mice
      (six per group) were treated with oligonucleotide concentrations of 0, 2, 10, or
      50 mg/kg by i.v. injection every other day for 14 days. Immune stimulation was
      assessed 24 h after the last dose by measuring spleen weight, or histologic and
      immunohistochemical examination of liver and kidney. Immune stimulation was dose
      dependent for the phosphorothioate oligodeoxynucleotides studied, but potency
      varied as a function of sequence. Results from this study reveal that there is a
      close correlation between the extent of splenomegaly and other evidence of immune
      stimulation, such as the severity of cell infiltrates in liver and kidney in
      mice. Immunohistochemical analysis indicated that cell infiltrates in liver and
      kidney were primarily mononuclear cells associated with increased expression of
      the endothelial-leukocyte cellular adhesion molecule intracellular adhesion
      molecule-1 and the cytokine interleukin-6. Immune stimulation was markedly
      decreased with oligonucleotides containing the 5-methyl cytosine and further
      decreased by 2'-methoxyethoxy modifications. Administration of these modified
      oligonucleotides to mice did not produce splenomegaly even at the 50-mg/kg dose,
      and only produced minimal cell infiltrates despite the presence of comparable or
      greater tissue oligonucleotide concentrations. Thus, chemical modifications
      appeared to increase the tolerability profile for these compounds that are
      representative of the second generation of antisense oligonucleotides.

PMID- 10640283
TI  - Enhanced anti-inflammatory activity of a liposomal intercellular adhesion
      molecule-1 antisense oligodeoxynucleotide in an acute model of contact
      hypersensitivity.
AB  - The anti-inflammatory activity of free and liposome-encapsulated oligonucleotide
      targeted against intercellular adhesion molecule-1 mRNA was investigated in a
      delayed type hypersensitivity model of acute inflammation in mice. Contact
      hypersensitivity reactions to 2, 4-dinitrofluorobenzene were monitored by
      measuring ear thickness and cellular infiltration, both of which were observed to
      be maximal 24 h after ear challenge. A murine-specific phosphorothioate
      oligodeoxynucleotide and various control sequences were each passively
      encapsulated into 100-nm diameter large unilamellar vesicles composed of egg
      phosphatidylcholine and cholesterol. All formulations were administered as a
      single-bolus injection into the tail vein approximately 15 min after initiating
      ear inflammation. Oligodeoxynucleotide dose was varied from 5 to 50 mg/kg and the
      extent of inflammation was assessed 24 h later. Mice treated with free
      oligonucleotide, empty vesicles, or encapsulated control sequences showed no
      measurable effect on ear swelling or cellular infiltration compared with
      untreated controls. However, mice that received the active sequence encapsulated
      in lipid vesicles exhibited near baseline levels of ear thickness and leukocyte
      infiltration, similar to that observed in mice treated with a topical
      corticosteroid. These data demonstrate the utility of liposome-encapsulated
      intercellular adhesion molecule-1 antisense oligonucleotide as a novel anti
      inflammatory therapeutic.

PMID- 10640284
TI  - Phosphorothioate oligodeoxynucleotides distribute similarly in class A scavenger
      receptor knockout and wild-type mice.
AB  - It has been suggested that binding of phosphorothioate oligodeoxynucleotides (P=S
      ODNs) to macrophage scavenger receptors (SR-AI/II) is the primary mechanism of
      P=S ODN uptake into cells in vivo. To address the role of scavenger receptors in
      P=S ODN distribution in vivo, several pharmacokinetic and pharmacological
      parameters were compared in tissues from scavenger receptor knockout mice (SR-A-/
      ) and their wild-type counterparts after i.v. administration of 5- and 20-mg/kg
      doses of P=S ODN. With an antibody that recognizes P=S ODN, no differences in
      cellular distribution or staining intensity in livers, kidneys, lungs, or spleens
      taken from SR-A-/- versus wild-type mice could be detected at the histological
      level. There were no significant differences in P=S ODN concentrations in these
      organs as measured by capillary gel electrophoresis as well, although the
      concentration of P=S ODN in isolated Kupffer cells from livers of SR-A-/- mice
      was 25% lower than that in Kupffer cells from wild-type mice. Furthermore, a P=S
      ODN targeting murine A-raf reduced A-raf RNA levels to a similar extent in livers
      from SRA-/- (92.8%) and wild-type (88.3%) mice. Finally, in vitro P=S ODN uptake
      studies in peritoneal macrophages from SR-A-/- versus wild-type mice indicate
      that other high- and low-affinity uptake mechanisms predominate. Taken as a
      whole, our data suggest that, although there may be some contribution to P=S ODN
      uptake by the SR-AI/II receptor, this mechanism alone cannot account for the bulk
      of P=S ODN distribution into tissues and cells in vivo, including macrophages.

PMID- 10640285
TI  - Interleukin-1beta inhibits gamma-aminobutyric acid type A (GABA(A)) receptor
      current in cultured hippocampal neurons.
AB  - Interleukin-1beta (IL-1beta), a polypeptide immune mediator, is induced within
      the central nervous system in response to a variety of pathological stimuli,
      including systemic infection, hypoxia, brain trauma, and seizure. IL-1beta action
      on the gamma-aminobutyric acid type A (GABA(A)) inhibitory neurotransmitter
      receptor was investigated in whole cell patch-clamped cultured hippocampal
      neurons. Application of IL-1beta at concentrations encountered in
      pathophysiological conditions (1-10 ng/ml; 59-590 pM) irreversibly decreased the
      peak magnitude of current elicited by 30 microM GABA. Current inhibition was IL
      1beta concentration- and time-dependent and was prevented by a specific IL-1beta
      type I receptor antagonist. No significant changes in current kinetics or
      reversal potential were observed. The IL-1beta depression of GABA current was
      inhibited by high concentrations of nonspecific kinase inhibitors staurosporine
      (500 nM) and 1-(5-isoquinolinyl-sulfonyl)-2-methylpiperazine (H-7; 50 microM),
      but not by a protein kinase C selective inhibitor calphostin C (5 microM). We
      conclude that IL-1beta inhibits GABA(A) receptor function in hippocampal neurons
      by the involvement of an unidentified kinase. This blockade of the GABA(A)
      inhibitory neurotransmitter receptor may underlie the central nervous system
      hyperexcitability seen in many pathophysiological conditions.

PMID- 10640286
TI  - Characterization of the transport properties of organic anion transporting
      polypeptide 1 (oatp1) and Na(+)/taurocholate cotransporting polypeptide (Ntcp):
      comparative studies on the inhibitory effect of their possible substrates in
      hepatocytes and cDNA-transfected COS-7 cells.
AB  - In the present study, we compared the inhibitory effects of organic anions
      (including bile acids) on the uptake of taurocholate (TC) and estradiol 17beta-D
      glucuronide (E(2)17betaG), typical substrates for sodium taurocholate
      cotransporting polypeptide (Ntcp) and organic anion transporting polypeptide
      (oatp1), respectively, using primary cultured rat hepatocytes and Ntcp- or oatp1
      transfected COS-7 cells. The Na(+)-dependent uptake of TC was inhibited by nine
      bile acids and five nonbile acid organic anions in a concentration-dependent
      manner, and their inhibitory effects were similar in both primary cultured rat
      hepatocytes and Ntcp-transfected COS-7 cells. BQ-123 (1 microM) and indomethacin
      (10 microM), both of which exhibit no Ntcp-mediated transport, significantly
      inhibited the Na(+)-dependent uptake of TC mediated by Ntcp. In addition, the
      Na(+)-independent uptake of E(2)17betaG was inhibited by 15 organic anions in a
      concentration-dependent manner, and their inhibitory effects were similar between
      primary cultured rat hepatocytes and oatp1-transfected COS-7 cells. BQ-123 (1
      microM), pravastatin (1 microM), and indomethacin (10 microM), all of which do
      not undergo oatp1-mediated transport, significantly inhibited the Na(+)
      independent uptake of E(2)17betaG mediated by oatp1. These results are consistent
      with the hypothesis that the hepatic uptake of TC and E(2)17betaG is
      predominantly mediated by Ntcp and oatp1, respectively. In addition, it was
      clearly demonstrated that we cannot refer to the substrate specificity of
      transporters based on inhibition studies.

PMID- 10640287
TI  - Subthreshold doses of specific phosphodiesterase type 3 and 4 inhibitors enhance
      the pulmonary vasodilatory response to nebulized prostacyclin with improvement in
      gas exchange.
AB  - Aerosolized prostacyclin (PGI(2)) has been suggested for selective pulmonary
      vasodilation, but its effect rapidly levels off after termination of
      nebulization. Stabilization of the second-messenger cAMP by phosphodiesterase
      (PDE) inhibition may offer a new strategy for amplification of the vasodilative
      response to nebulized PGI(2). In perfused rabbit lungs, continuous infusion of
      the thromboxane mimetic U46619 was used to establish stable pulmonary
      hypertension [increase in pulmonary arterial pressure (pPA) from approximately 7
      to approximately 32 mm Hg], which is accompanied by progressive edema formation
      and severe disturbances in gas exchange with a predominance of shunt flow
      (increase from <2 to approximately 58%, as assessed by the multiple inert gas
      elimination technique). In the absence of PGI(2), dose-effect curves for
      intravascular and aerosol administration of the specific PDE3 inhibitor
      motapizone, the PDE4 inhibitor rolipram, and the dual-selective PDE3/4 inhibitor
      tolafentrine on pulmonary hemodynamics were established (potency rank order:
      rolipram > tolafentrine approximately motapizone; highest efficacy on
      coapplication of rolipram and motapizone). Ten-minute aerosolization of PGI(2)
      was chosen to effect a moderate pPA decrease (approximately 4 mm Hg; rapidly
      returning to prenebulization values within 10-15 min) with only a slight
      reduction in shunt flow (approximately 49%). Prior application of subthreshold
      doses of i.v. or inhaled PDE3 or PDE4 inhibitors, which per se did not affect
      pulmonary hemodynamics, caused prolongation of the post-PGI(2) decrease in pPA.
      The most effective approach, rolipram plus motapizone, amplified the maximum pPA
      decrease in response to PGI(2) to approximately 9 to 10 mm Hg, prolonged the post
      PGI(2) vasorelaxation to >60 min, reduced the extent of lung edema formation by
      50%, and decreased the shunt flow to approximately 19% (i.v. rolipram/motapizone)
      and 28% (aerosolized rolipram/motapizone). We conclude that lung PDE3/4
      inhibition, achieved by intravascular or transbronchial administration of
      subthreshold doses of specific PDE inhibitors, synergistically amplifies the
      pulmonary vasodilatory response to inhaled PGI(2), concomitant with an
      improvement in ventilation-perfusion matching and a reduction in lung edema
      formation. The combination of nebulized PGI(2) and PDE3/4 inhibition may thus
      offer a new concept for selective pulmonary vasodilation, with maintenance of gas
      exchange in respiratory failure and pulmonary hypertension.

PMID- 10640288
TI  - Comparative behavioral pharmacology of cocaine and the selective dopamine uptake
      inhibitor RTI-113 in the squirrel monkey.
AB  - The behavioral effects of 3beta-(4-chlorophenyl)tropane-2beta-carboxylic acid
      phenyl ester hydrochloride (RTI-113; 0.03-1.0 mg/kg), a selective dopamine uptake
      inhibitor, were compared with those of cocaine (0.03-3.0 mg/kg) and 1-(2-[bis(4
      fluorophenyl)methoxy]ethyl)-4-(3-phenylpropyl)piperazine dihydrochloride (GBR
      12909; 0.03-3.0 mg/kg) in squirrel monkeys. Intermediate doses of each drug
      produced significant increases in response rate maintained by a fixed-interval
      (FI) 300-s schedule of stimulus termination, but RTI-113 was less effective than
      cocaine or GBR 12909. The order of potency for increasing response rate was RTI
      113 >/= cocaine > GBR 12909. In drug time course determinations, RTI-113 and GBR
      12909 had longer durations of action than cocaine. RTI-113 substituted completely
      for cocaine in subjects trained to discriminate cocaine and saline under a two
      lever drug-discrimination procedure maintained by food delivery. RTI-113 also
      reliably maintained self-administration behavior in subjects trained under a
      second-order FI 900-s schedule of i.v. cocaine delivery. Pretreatment with RTI
      113 significantly decreased responding for cocaine at the highest pretreatment
      dose, but RTI-113 had similar effects on responding maintained by a second-order
      FI 900-s schedule of stimulus termination. The results indicate that the
      behavioral pharmacology of RTI-113 is similar to that of cocaine, further
      implicating a prominent role for dopamine uptake inhibition in the behavioral
      effects of cocaine. Its longer duration of action in conjunction with less
      pronounced behavioral-stimulant effects are desirable properties for a substitute
      pharmacotherapy for cocaine abuse. RTI-113 effectively decreased cocaine self
      administration behavior, although its direct rate-altering effects may have
      contributed to the interactions obtained.

PMID- 10640289
TI  - In vivo antitumor activity and induction of insulin-like growth factor-1
      resistant apoptosis by SC-alphaalphadelta9.
AB  - We previously showed that SC-alphaalphadelta9 (4-(benzyl-(2-[(2, 5-diphenyl
      oxazole-4-carbonyl)-amino]-ethyl)-carbamoyl)-2-decanoylami no butyric acid) is a
      novel antiphosphatase agent that selectively inhibits the growth of transformed
      cells in culture and affects elements of insulin-like growth factor-1 (IGF-1)
      signaling. We now show that SC-alphaalphadelta9 induces IGF-1-resistant apoptosis
      and kills tumor cells in vivo. In cultured murine 32D cells, SC-alphaalphadelta9
      induced concentration-dependent apoptosis that was blocked by ectopic Bcl-2
      expression. No apoptosis was detected in 32D cells treated with the congener SC
      alpha109, which lacks the ability to disrupt IGF-1 signaling. After interleukin-3
      withdrawal or etoposide treatment, exogenous IGF-1 prevented apoptosis and
      elevated levels of Cdc2, a biochemical indicator of a functional IGF-1 receptor
      pathway. In contrast, exogenous IGF-1 did not prevent apoptosis or loss of Cdc2
      expression caused by SC-alphaalphadelta9. Furthermore, IGF-1 receptor
      overexpression failed to protect cells against SC-alphaalphadelta9-induced
      apoptosis. Kinetic analyses demonstrated that Cdc2 down-regulation after SC
      alphaalphadelta9 treatment preceded both apoptosis and loss of the IGF-1
      receptor, indicating that loss of Cdc2 was a direct effect of SC-alphaalphadelta9
      treatment and not secondary to cell death. IGF-1 receptor autophosphorylation
      studies indicated that SC-alphaalphadelta9 did not interact directly with the IGF
      1 receptor nor bind to the growth factor itself, suggesting a site of action
      distal to the IGF-1 receptor. In the SCCVII murine tumor model, a single i.p.
      injection of SC-alphaalphadelta9 caused a dose-dependent decrease in clonogenic
      cell survival. The IC(50) of SC-alphaalphadelta9 was 35 mg/kg, comparable to 25
      mg/kg carboplatin. The ability to induce IGF-1-resistant apoptosis distinguishes
      SC-alphaalphadelta9 from other apoptosis-inducing agents and suggests compounds
      of this class deserve further study as potential anticancer agents.

PMID- 10640290
TI  - Effects of spinal cholecystokinin receptor antagonists on morphine
      antinociception in a model of visceral pain in the rat.
AB  - The objective of the present study was to determine the effects of spinal
      cholecystokinin (CCK) receptor antagonists on morphine antinociception in a model
      of visceral nociception, colorectal distension, in rats with chronic colonic
      inflammation and vehicle-treated controls. Three to five days after intracolonic
      instillation of 2,4,6-trinitrobenzenesulfonic acid (TNBS), an enhanced
      visceromotor response to all pressures of colorectal distension (10-80 mm Hg) was
      evident. The ED(50) of intrathecal morphine (0.93 microgram) in vehicle-treated
      rats produced significantly greater antinociception in TNBS-treated rats.
      Intrathecal proglumide, a nonselective CCK receptor antagonist, dose dependently
      enhanced the antinociceptive effect of morphine in vehicle-treated rats, but not
      in TNBS-treated rats. Similarly, L-365, 260, a specific CCK(B) receptor
      antagonist, dose dependently increased morphine's antinociceptive effects in
      vehicle-treated rats but had no effect in rats with TNBS-induced colonic
      inflammation. L-364,718, a specific CCK(A) receptor antagonist, had no effect on
      morphine antinociception in either vehicle-treated or TNBS-treated rats. These
      data indicate that CCK, acting at the CCK(B) receptor, is involved in modulating
      morphine antinociception following a noxious visceral stimulus. However, CCK
      receptor antagonists no longer enhance morphine antinociception after
      instillation of intracolonic TNBS, suggesting that visceral inflammation may lead
      to a reduction in spinal CCK release.

PMID- 10640291
TI  - Novel uncompetitive N-methyl-D-aspartate (NMDA)-receptor antagonist MRZ 2/579
      suppresses ethanol intake in long-term ethanol-experienced rats and generalizes
      to ethanol cue in drug discrimination procedure.
AB  - Previous findings suggested that drugs modulating glutamatergic neurotransmission
      could be useful in the treatment of alcohol dependence. This study examined the
      effects of chronic and acute treatment with MRZ 2/579 (1-amino-1,3,3,5,5
      pentamethyl-cyclohexane hydrochloride), a novel uncompetitive N-methyl-D
      aspartate receptor antagonist, on voluntary ethanol intake in long-term ethanol
      experienced rats. Rats were implanted with mini-osmotic pumps delivering either
      9.6 mg/day MRZ 2/579 or vehicle, and the effects of treatment on the alcohol
      deprivation effect (ADE) were studied in a four-bottle home cage-drinking
      paradigm. The same rats were tested for a second ADE 3 weeks later in the absence
      of the drug. In a second experiment long-term ethanol-experienced rats trained in
      an operant free-choice ethanol self-administration paradigm with concurrent water
      received acute MRZ 2/579 treatment (0-4 mg/kg i.p.) before a 23-h session either
      during basal drinking or during the ADE. In an additional experiment, MRZ 2/579
      (0.5-4 mg/kg i.p.) was tested for generalization to the ethanol cue in a drug
      discrimination procedure. Chronic MRZ 2/579 treatment selectively abolished the
      increased ethanol intake during the ADE. This effect depended on the presence of
      the drug. Acute MRZ 2/579 treatment (2 and 4 mg/kg) had a short-lasting reductive
      effect on lever pressing for ethanol, but not for water, both during the ADE and
      basal drinking. MRZ 2/579 dose dependently generalized to the ethanol cue in the
      drug discrimination experiment. It is concluded that MRZ 2/579 might exert its
      reducing effect on ethanol intake by substituting for some of the stimulus
      properties of ethanol.

PMID- 10640292
TI  - Potentiation of oxygen-induced lung injury in rats by the mechanism-based
      cytochrome P-450 inhibitor, 1-aminobenzotriazole.
AB  - In this investigation, we tested the hypothesis that the cytochrome P-450 (CYP)
      inhibitor 1-aminobenzotriazole (ABT) alters the susceptibility of rats to
      hyperoxic lung injury. Male Sprague-Dawley rats were treated i.p. with ABT (66
      mg/kg), i.v. with N-benzyl-1-aminobenzotriazole (1 micromol/kg), or the
      respective vehicles, followed by exposure to >95% oxygen for 24, 48, or 60 h.
      Pleural effusion volumes were measured as estimates of hyperoxic lung injury, and
      lung microsomal ethoxyresorufin O-deethylation (EROD) (CYP1A1) activities and
      CYP1A1 apoprotein levels were determined by Western blotting. ABT-pretreated
      animals exposed to hyperoxia died between 48 and 60 h, whereas no deaths were
      observed with up to 60 h of hyperoxia in vehicle-treated animals. In addition,
      three of four ABT-treated rats exposed to hyperoxia for 48 h showed marked
      pleural effusions. Exposure of vehicle-treated rats to hyperoxia led to 6.3-fold
      greater lung EROD activities and greater CYP1A1 apoprotein levels than in air
      breathing controls after 48 h, but both declined to control levels by 60 h. Liver
      CYP1A1/1A2 enzymes displayed responses to hyperoxia and ABT similar to the
      effects on lung CYP1A1. N-Benzyl-1-aminobenzotriazole markedly inhibited lung
      microsomal pentoxyresorufin O-depentylation (principally CYP2B1) activities in
      air-breathing and hyperoxic animals but did not affect lung EROD or liver CYP
      activities. In conclusion, the results suggest that induction of CYP1A enzymes
      may serve as an adaptive response to hyperoxia, and that CYP2B1, the major
      pulmonary CYP isoform, does not contribute significantly to hyperoxic lung
      injury.

PMID- 10640293
TI  - Effects of the T-type Ca(2+) channel blocker mibefradil on repolarization of
      guinea pig, rabbit, dog, monkey, and human cardiac tissue.
AB  - At supratherapeutic doses (2- to 5-fold), the T-type Ca(2+) antagonist mibefradil
      modifies the T/U wave of the human ECG. In this study, we show that this effect
      is observed in conscious monkeys and is duplicated by verapamil or diltiazem. We
      then evaluate the proarrhythmic risk of such alterations of cardiac
      repolarization by examining the actions of mibefradil on cardiac action
      potentials (APs). In isolated cardiomyocytes from guinea pigs or humans,
      mibefradil dose dependently shortens the plateau of the AP; this effect is
      similar to other Ca(2+) antagonists and opposite to drugs having class III
      antiarrhythmic properties. The metabolites of mibefradil, singly or in
      combination, also shorten APs. In isolated rabbit hearts, noncardiodepressant
      concentrations of mibefradil have no effect on monophasic action potentials
      (MAPs), whereas cardiodepressant levels produce a slight nonsignificant
      lengthening. In hearts of open-chest bradycardic dogs, mibefradil has no effect
      on MAP dispersion or on QT interval and shortens MAPs slightly; although high
      doses produce atrioventricular block, likely through Ca(2+) antagonism,
      arrhythmias are never observed. In contrast, d-sotalol lengthens QT interval and
      MAPs, increases dispersion, and produces arrhythmias. Together, these in vitro
      and in vivo results suggest that mibefradil carries no proarrhythmic risk despite
      changes in T/U wave morphology. Although these changes resemble those observed
      with class III compounds, they also are seen with nonproarrhythmic compounds such
      as verapamil and diltiazem. In conclusion, the classical models used in the
      present study could not link the changes in T/U wave morphology produced by
      mibefradil and verapamil to any experimental marker of proarrhythmic liability.

PMID- 10640294
TI  - Differential antinociceptive effects of endomorphin-1 and endomorphin-2 in the
      mouse.
AB  - Two highly selective mu-opioid receptor agonists, endomorphin-1 and endomorphin
      2, have been identified and postulated to be endogenous mu-opioid receptor
      ligands. We determined the antinociceptive effects of these two ligands at the
      supraspinal level in mice with the tail-flick and hot-plate responses. The i.c.v.
      injection of endomorphin-1 and -2 inhibited the tail-flick and hot-plate
      responses in a dose-dependent manner. The endomorphin-1 was found to be 3.3- and
      2.4-fold more potent than endomorphin-2 in inhibiting the tail-flick and hot
      plate responses, respectively. The antinociception induced by endomorphin-1 was
      blocked by i.c.v. pretreatment with the mu-opioid receptor antagonist beta
      funaltrexamine but not by the kappa-opioid receptor antagonist nor
      binaltorphimine, the delta(1)-opioid antagonist 7-benzylidene naltrexamine, or
      the delta(2)-opioid receptor antagonist naltriben. In contrast, the
      antinociception induced by endomorphin-2 was blocked by i.c.v. pretreatment with
      beta-funaltrexamine or nor-binaltorphimine but not by 7-benzylidene naltrexamine
      or naltriben. The inhibition of the tail-flick response induced by endomorphin-2
      was blocked by pretreatment with an antiserum against dynorphin A(1-17) but not
      by antisera against Met-enkephalin, Leu-enkephalin, or beta-endorphin. None of
      these antisera reduced the endomorphin-1-induced tail-flick inhibition. We
      propose that endomorphin-1 produces antinociception by stimulating one type of mu
      opioid receptor, whereas endomorphin-2 initially stimulates different mu-opioid
      receptors, which subsequently induce the release of dynorphins that act on kappa
      opioid receptors to produce antinociception.

PMID- 10640296
TI  - Role of nuclear factor of activated T-cells and activator protein-1 in the
      inhibition of interleukin-2 gene transcription by cannabinol in EL4 T-cells.
AB  - We previously reported that immunosuppressive cannabinoids inhibited interleukin
      (IL)-2 steady-state mRNA expression and secretion by phorbol-12-myristate-13
      acetate plus ionomycin-activated mouse splenocytes and EL4 murine T-cells. Here
      we show that inhibition of IL-2 production by cannabinol, a modest central
      nervous system-active cannabinoid, is mediated through the inhibition of IL-2
      gene transcription. Moreover, electrophoretic mobility shift assays demonstrated
      that cannabinol markedly inhibited the DNA binding activity of nuclear factor of
      activated T-cells (NF-AT) and activator protein-1 (AP-1) in a time- and
      concentration-dependent manner in activated EL4 cells. The inhibitory effects
      produced by cannabinol on AP-1 DNA binding were quite transient, showing partial
      recovery by 240 min after cell activation and no effect on the activity of a
      reporter gene under the control of AP-1. Conversely, cannabinol-mediated
      inhibition of NF-AT was robust and sustained as demonstrated by an NF-AT
      regulated reporter gene. Collectively, these results suggest that decreased IL-2
      production by cannabinol in EL4 cells is due to the inhibition of transcriptional
      activation of the IL-2 gene and is mediated, at least in part, through a
      transient inhibition of AP-1 and a sustained inhibition of NF-AT.

PMID- 10640295
TI  - The preclinical pharmacological profile of WAY-132983, a potent M1 preferring
      agonist.
AB  - Muscarinic M1 preferring agonists may improve cognitive deficits associated with
      Alzheimer's disease. Side effect assessment of the M1 preferring agonist WAY
      132983 showed significant salivation (10 mg/kg i.p. or p.o.) and produced dose
      dependent hypothermia after i. p. or p.o. administration. WAY-132983
      significantly reduced scopolamine (0.3 mg/kg i.p.)-induced hyperswimming in mice.
      Cognitive assessment in rats used pretrained animals in a forced choice, 1-h
      delayed nonmatch-to-sample radial arm maze task. WAY-132983 (0.3 mg/kg i.p)
      significantly reduced scopolamine (0.3 mg/kg s.c.)-induced errors. Oral WAY
      132983 attenuated scopolamine-induced errors; that is, errors produced after
      combining scopolamine and WAY-132983 (to 3 mg/kg p.o.) were not significantly
      increased compared with those of vehicle-treated control animals, whereas errors
      after scopolamine were significantly higher than those of control animals. With
      the use of miniosmotic pumps, 0.03 mg/kg/day (s.c.) WAY-132983 significantly
      reduced AF64A (3 nmol/3 microliter/lateral ventricle)-induced errors.
      Verification of AF64A cholinotoxicity showed significantly lower choline
      acetyltransferase activity in the hippocampi of AF64A-treated animals, with no
      significant changes in the striatal or frontal cortex. Cognitive assessment in
      primates involved the use of pretrained aged animals in a visual delayed match-to
      sample procedure. Oral WAY-132983 significantly increased the number of correct
      responses during short and long delay interval testing. These effects were also
      apparent 24 h after administration. WAY-132983 exhibited cognitive benefit at
      doses lower than those producing undesirable effects; therefore, WAY-132983 is a
      potential candidate for improving the cognitive status of patients with
      Alzheimer's disease.

PMID- 10640297
TI  - Nifedipine and diltiazem but not verapamil up-regulate endothelial nitric-oxide
      synthase expression.
AB  - We have recently shown that felodipine, a long-acting dihydropyridine L-type
      calcium channel blocker (CCB), up-regulates nitric oxide (NO) production and
      endothelial NO synthase (eNOS) expression and activity in cultured endothelial
      cells as well as in animals with chronic renal failure. This study was intended
      to compare the effects of prototypes of the three classes of L-type CCBs on the
      NO system in cultured human coronary artery endothelial cells. Thus, cultured
      endothelial cells were incubated either with nifedipine, diltiazem, or verapamil
      for 24 h at 10(-5) to 10(-7) M concentrations. Cells incubated with inactive
      vehicle served as controls. NO production, as discerned from total nitrate plus
      nitrite recovered in the medium, was significantly increased by nifedipine (P
      <.03) and by diltiazem (P <.05). However, NO production remained unchanged with
      verapamil (P = NS). Similarly, eNOS protein abundance was increased significantly
      by nifedipine (P <.05) and diltiazem (P <.05). In contrast, eNOS expression was
      not changed by verapamil (P = NS). Likewise, NOS activity, as measured from
      [(3)H]L-arginine to [(3)H]L-citrulline conversion, significantly increased with
      nifedipine (P <.01) and diltiazem (P <.01). However, incubation with verapamil
      failed to alter NOS activity of the cultured endothelial cells (P = NS). We
      concluded that prototypes of dihydropyridine and benzothiazepine classes, but not
      phenylalkylamine class of CCBs, up-regulate the NO system. This may, in part,
      account for the different biological properties of these agents.

PMID- 10640298
TI  - The effects of the 5-hydroxytryptamine(1A) agonist 8-hydroxy-2-(di-n
      propylamino)tetralin on spontaneous activity, cocaine-induced hyperactivity and
      behavioral sensitization: a microanalysis of locomotor activity.
AB  - The influence of the 5-hydroxytryptamine(1A) agonist 8-hydroxy-2-(di-n
      propylamino)tetralin (DPAT) on locomotor hyperactivity induced by the acute and
      chronic administration of cocaine was assessed. Horizontal activity was measured
      in the periphery and center of an open field test enclosure equipped with
      photobeams; vertical activity was also recorded. Peripheral hyperactivity induced
      by an acute administration of cocaine (10 or 20 mg/kg) was significantly enhanced
      by 0.2 mg/kg DPAT. In contrast, central and vertical activities were reduced in a
      dose-related manner by DPAT (0.1 and 0.2 mg/kg); DPAT also suppressed central
      (0.2 mg/kg) and vertical (0.1 and 0.2 mg/kg) activities when administered alone.
      Similar observations were made on day 1 of chronic treatment with DPAT (0, 0.1,
      or 0.2 mg/kg) injected 15 min before an injection of cocaine (0, 10, or 15 mg/kg)
      administered twice daily for 7 days. By day 7 of repeated DPAT treatment,
      sensitization of DPAT-evoked peripheral activity developed, which contrasted with
      tolerance to the central and vertical hypoactivity evoked by DPAT. Sensitization
      developed to the repeated treatment with 15 mg/kg cocaine but not 10 mg/kg
      cocaine. Interestingly, enhancements of all activity measures were observed
      between days 1 and 7 in rats cotreated with DPAT plus either dose of cocaine.
      This sensitization to DPAT plus cocaine was expressed on challenge with DPAT and
      cocaine but not with cocaine alone. The present study implies that the
      stimulation of 5-hydroxytryptamine(1A) receptors is capable of modulating the
      hyperactivity evoked by cocaine, possibly via modulation of the mesoaccumbens
      dopamine circuit thought to mediate the behavioral effects of cocaine.

PMID- 10640299
TI  - Midazolam and triazolam biotransformation in mouse and human liver microsomes:
      relative contribution of CYP3A and CYP2C isoforms.
AB  - Midazolam (MDZ) and triazolam (TRZ) hydroxylation, reactions considered to be
      cytochrome P-4503A (CYP3A)-mediated in humans, were examined in mouse and human
      liver microsomes. In both species, alpha- and 4-hydroxy metabolites were the
      principal products. Western blotting with anti-CYP3A1 antibody detected a single
      band of immunoreactive protein in both human and mouse samples: 0.45 +/- 0. 12
      and 2.02 +/- 0.24 pmol/mg protein (mean +/- S.E., n = 3), respectively.
      Ketoconazole potently inhibited MDZ and TRZ metabolite formation in human liver
      microsomes (IC(50) range, 0.038-0.049 microM). Ketoconazole also inhibited the
      formation of both TRZ metabolites and of 4-OH-MDZ formation in mouse liver
      microsomes (IC(50) range, 0.0076-0.025 microM). However, ketoconazole (10 microM)
      did not produce 50% inhibition of alpha-OH-MDZ formation in mouse liver
      microsomes. Anti-CYP3A1 antibodies produced concentration-dependent inhibition of
      MDZ and TRZ metabolite formation in human liver microsomes and of TRZ metabolite
      and 4-OH-MDZ formation in mouse liver microsomes to less than 20% of control
      values but reduced alpha-OH-MDZ formation to only 66% of control values in mouse
      liver microsomes. Anti-CYP2C11 antibodies inhibited alpha-OH-MDZ metabolite
      formation in a concentration-dependent manner to 58% of control values in mouse
      liver microsomes but did not inhibit 4-OH-MDZ formation. Thus, TRZ hydroxylation
      appears to be CYP3A specific in mice and humans. alpha-Hydroxylation of MDZ has a
      major CYP2C component in addition to CYP3A in mice, demonstrating that metabolic
      profiles of drugs in animals cannot be assumed to reflect human metabolic
      patterns, even with closely related substrates.

PMID- 10640300
TI  - The roles of protein kinase C and tyrosine kinases in mediating endothelin-1
      stimulated phospholipase D activity in rat myometrium: differential inhibition by
      ceramides and cyclic AMP.
AB  - The aim of the present study was to investigate the mechanisms that regulate the
      activation of phospholipase D (PLD) by endothelin (ET)-1 in rat myometrium. We
      previously reported that ET-1 exerted part ( approximately 50%) of its effect via
      protein kinase C (PKC) activation. We now show that in addition to ET-1 and 4beta
      phorbol-12,13-dibutyrate (PDBu), pervanadate also stimulated PLD activity.
      Stimulation by pervanadate was not affected by the PKC inhibitor Ro-31-8220 but
      was abolished by protein tyrosine kinase (PTK) inhibitors genistein and
      tyrphostin-47. Genistein partially reduced (52%) ET-1 stimulation, which was
      further attenuated (96%) by Ro-31-8220, indicating that PTKs may account for the
      PKC-independent arm of ET-1-stimulated PLD activity. Cell-permeable ceramides
      reduced ( approximately 50%) the activation of PLD by ET-1 and PDBu but not that
      by pervanadate. Inhibition was also achieved by sphingomyelinase but not with
      sphingosine. Inhibition by genistein and D-erythro-N-hexanoyl-sphingosine was
      additive, whereas inhibition by Ro-31-8220 and D-erythro-N-hexanoyl-sphingosine
      was not, indicating that ceramide affected the PKC-dependent process involved in
      PLD activation by ET-1. Forskolin, as well as dibutyryl-cAMP and iloprost,
      attenuated (approximately 50%) the activation of PLD by ET-1 and pervanadate but
      not that by PDBu. Inhibition by forskolin was prevented by H-89, an inhibitor of
      protein kinase A. Inhibition by forskolin and ceramide was additive, whereas
      inhibition by genistein and forskolin was not, indicating that the cAMP/protein
      kinase A cascade affected the PTK-dependent process involved in PLD activation by
      ET-1. The data illustrate a cross-talk between separate signaling pathways,
      resulting in positive and negative regulation of PLD in rat myometrium.

PMID- 10640301
TI  - Functional and molecular properties of the human recombinant Y4 receptor:
      resistance to agonist-promoted desensitization.
AB  - After stable transfection of Chinese hamster ovary cells with the human Y4
      receptor, clone 29 was isolated and studied for receptor properties. The
      following data were obtained: 1) one class of binding site was identified by
      analysis of (125)I-human pancreatic polypeptide (hPP) binding to cell membranes
      with a K(d) value of 0. 26 nM and a B(max) value of 1.44 pmol/mg protein; 2) the
      K(i) values for inhibition of (125)I-hPP binding by hPP, human peptide YY (hPYY),
      human neuropeptide Y (hNPY), and analogs were hPP (0.7 nM) < rat PP (47 nM) <
      hPYY (94 nM) < h[Leu(31)-Pro(34)]NPY (124 nM) << hNPY = porcine NPY(13-36) = rat
      D-[Trp(32)]NPY (>1 microM); 3) cross-linking experiments using (125)I-hPP
      identified a single M(r) 60,000 glycosylated Y4 receptor; and 4) the natural
      peptides hPP, hPYY, and hNPY inhibited forskolin-stimulated cAMP production in
      clone 29 cells with EC(50) values of 0.56 nM, 218 nM, and >1 microM,
      respectively. The inhibitory effect of hPP was abolished when cells were
      incubated with pertussis toxin, indicating a pertussis toxin-sensitive G(i)
      protein-mediated event. 5) Exposure of cells to 10 nM hPP for 24 h resulted in
      the absence of modification of binding capacity (1.38 versus 1.44 pmol/mg protein
      in control cells) or affinity (0.31 versus 0.26 nM in control cells); there also
      was no modification in the potency and efficacy of hPP in inhibiting forskolin
      stimulated cAMP. Immunofluorescence indicated that the Y4 receptor was not
      internalized within the cells after 24-h treatment with 10 nM hPP. These data
      support that Y4 receptors are resistant to agonist-promoted desensitization and
      internalization. Clone 29 cells provide a valuable tool to further characterize
      the pharmacological aspects of human Y4 receptor.

PMID- 10640302
TI  - Anti-inflammatory activities of a new series of selective phosphodiesterase 4
      inhibitors derived from 9-benzyladenine.
AB  - Adenine derivatives substituted in position 9 have been demonstrated to have
      potent phosphodiesterase (PDE) inhibition properties with high selectivity toward
      PDE4. We compared the effects of various compounds derived from 9-benzyladenine
      with those of the selective PDE4 inhibitor RP 73401 on the inhibition of PDE4
      isolated from bovine aorta, arachidonic acid, and tumor necrosis factor-alpha
      release by mononuclear cells from healthy subjects. The rank order of potency of
      the various compounds for in vitro activities on arachidonic acid release is RP
      73401 > NCS 613 > NCS 630 > NCS 632 > BWA 78U = NCS 631. The most effective
      compounds in vitro (RP 73401 and NCS 613) were further investigated in vivo. Both
      PDE inhibitors dose dependently (1, 10, and 30 mg/kg per os) inhibited the
      recruitment of neutrophils in the bronchoalveolar lavage fluid of mice exposed to
      endotoxin via aerosol. Significant differences were observed with 10 and 30 mg/kg
      RP 73401 and 30 mg/kg NCS 613. In rats, RP 73401, but not NCS 613, significantly
      increased basal acid secretion at 30 mg/kg i.v. and pentagastrin-stimulated acid
      secretion at 0.3, 1, and 10 mg/kg. These results demonstrate that the compounds
      derived from 9-benzyladenine, namely NCS 613, elicit anti-inflammatory
      activities. It is also suggested that their activities have been mediated through
      the inhibition of PDE4 isoenzyme. The fact that NCS 613 did not stimulate the
      gastric acid secretion suggests that this compound may produce fewer
      gastrointestinal side effects than second-generation PDE4 inhibitors, such as RP
      73401.

PMID- 10640303
TI  - Facilitation of constitutive alpha(2A)-adrenoceptor activity by both single amino
      acid mutation (Thr(373)Lys) and g(alphao) protein coexpression: evidence for
      inverse agonism.
AB  - The recombinant human alpha(2A)-adrenoceptor (alpha(2A)-AR, RC 2.1. ADR.A2A) can
      be transformed into a constitutively activated form in CHO-K1 cells by
      coexpression with a rat G(alphao) protein. Constitutive activity could be
      enhanced more by both mutation of Thr(373) of the alpha(2A)-AR to a Lys and
      Cys(351) of the G(alphao) protein by an Ile. The basal [(35)S]GTPgammaS binding
      response displayed a constitutive alpha(2A)-AR activity that amounted to 21% of
      the maximal receptor activation as obtained with 10 microM (-)-adrenaline. UK
      14304, BHT 920, d-medetomidine, oxymetazoline, and clonidine acted as efficacious
      agonists. The enhancement of basal activity was entirely blocked (-50 +/- 3%) by
      ligands that thus appeared to act as inverse agonists (i.e., RX 811059 and its
      (+)-enantiomer, (+)-RX 821002, RS 15385, and yohimbine); the potencies of the
      ligands corresponded with their binding affinities for the alpha(2A)-AR.
      Fluparoxan and WB 4101 displayed partial inverse agonism. Atipamezole and
      dexefaroxan at 10 microM were virtually free of intrinsic activity and thus acted
      as neutral antagonists; idazoxan displayed potent partial agonist properties as
      observed with BRL 44408 and SKF 86466. The inverse agonist activity induced by
      (+)-RX 811059 could be reversed by atipamezole with a pK(B) value (8.73 +/- 0.07)
      that was similar to that required for blockade of the UK 14304-mediated response.
      Constitutive alpha(2A)-AR activation was mainly observed with the G(alphao)
      Cys(351)Ile protein compared with the pertussis toxin-resistant mutants of the
      G(alphai) protein subtypes. The observed spectrum of intrinsic activities for the
      various ligands suggests that pure, neutral antagonists are rather uncommon in
      this specified alpha(2A)-AR system.

PMID- 10640304
TI  - Bidirectional allosteric effects of agonists and GTP at alpha(2A/D)
      adrenoceptors.
AB  - Agonists and GTP exert reciprocal effects on the stability of the G protein
      coupled receptor/G protein complex, implying bidirectional control over the
      receptor/G protein interface. To investigate this relationship, we compared the
      ability of a series of hydroxyl-substituted phenethylamine and imidazoline
      agonists to stimulate [(35)S]guanosine 5'-O-(3-thio)triphosphate
      ([(35)S]GTPgammaS) binding in membranes from alpha(2A/D)-adrenergic receptor
      transfected PC12 cells with the magnitude of the GTP-induced reduction in agonist
      affinity in [(3)H]rauwolscine-binding studies. Agents previously described as
      full and partial agonists in functional studies showed similar relative
      efficacies in promoting GTP binding (r = 0.97) as well as similar relative
      potencies (r = 0.94). Efficacy among agonists for promotion of [(35)S]GTPgammaS
      binding was closely correlated with the relative influence of GTPgammaS on
      agonist binding (r = 0.97), consistent with a bidirectional allosteric influence
      by agonists and GTP on receptor/G protein complexation. In an additional series
      of tolazoline derivatives, a range in efficacy from full agonism to strong
      inverse agonism was observed, depending on the presence or absence of hydroxyl
      substituents. Together these results suggest that agonist-induced repositioning
      of transmembrane helices via their hydroxyl interactions is a critical
      determinant of the stability of the receptor/G protein complex and therefore of
      agonist efficacy.

PMID- 10640305
TI  - Induction of spontaneous tail-flicks in rats by blockade of transmission at N
      methyl-D-aspartate receptors: roles of multiple monoaminergic receptors in
      relation to the actions of antipsychotic agents.
AB  - We examined the involvement of multiple monoaminergic receptors in the induction
      of spontaneous tail-flicks (STFs) by the open channel blocker at N-methyl-D
      aspartate (NMDA) receptors, dizocilpine, and the NMDA recognition site antagonist
      3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP). At doses eliciting a
      maximal STF response, dizocilpine and CPP elevated levels of norepinephrine, but
      not dopamine or serotonin, in dialysates of nucleus accumbens, their known locus
      of action in eliciting STFs. Chemically diverse alpha(2)-adrenergic receptor (AR)
      antagonists atipamezole, L745,743, RX821,002, idazoxan, and desfluparoxan
      abolished induction of STFs by dizocilpine, whereas the preferential alpha(1)-AR
      antagonists prazosin, WB4101, and ARC239 were weakly active: relative potencies
      in blocking STFs correlated significantly with affinity at alpha(2)-ARs. The
      D(1)/D(5) receptor antagonists SCH23390, SCH39166, and NNC756 potently abolished
      STFs, whereas the D(2) antagonist L741,626, the D(3) antagonists GR218,231 and
      S14297, and the D(4) antagonists S18126 and L745,870 were inactive. D(1) and
      alpha(2)-AR antagonists also blocked induction of STFs by CPP. Blockade of
      dizocilpine-induced STFs was specific inasmuch as idazoxan and SCH 23390 did not
      modify induction of ataxia by dizocilpine. Antagonists at multiple 5
      hydroxytryptamine receptors failed to modify induction of STFs. Finally,
      dizocilpine-induced STFs were blocked by clozapine and 11 other antipsychotics,
      the potency of which correlated significantly with affinity at alpha(2)-ARs. In
      conclusion, STFs evoked by interruption of transmission at NMDA receptors are
      dependent on D(1) receptors and alpha(2)-ARs for their expression. Antagonism of
      the alpha(2)-ARs is involved in their blockade by antipsychotics. This model
      should facilitate exploration of interrelationships between glutamatergic and
      monoaminergic mechanisms involved in psychiatric and neurologic disorders.

PMID- 10640306
TI  - 5-Hydroxytryptamine(1A) receptor-stimulated [(35)S]GTPgammaS binding in rat
      brain: absence of regional differences in coupling efficiency.
AB  - In hippocampal membranes, the selective 5-hydroxytryptamine (5-HT(1A)) receptor
      agonists 8-hydroxy-dipropylaminotetralin (8-OH-DPAT) and N,N-dipropyl-5
      carboxamidotryptamine (N,N-DP-5-CT) stimulated guanosine-5'-O-(3
      thio)triphosphate ([(35)S]GTPgammaS) binding by 130 to 140%; binding stimulated
      by nonselective agonists (5-HT and 5-CT) was approximately 30% greater. However,
      the selective 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1
      piperazinyl]ethyl]-N-2-pyridinyl-cyclohex anecarboxamide (WAY100,635) completely
      abolished the increases produced by 8-OH-DPAT and N,N-DP-5-CT but only eliminated
      70% of that elicited by 5-CT. The rank potency order of the tested agonists was
      identical with their rank order of affinity for 5-HT(1A) receptors [5-CT
      congruent with N,N-DP-5-CT > R-(+)-8-OH-DPAT > 5-HT > ipsapirone]. Racemic 8-OH
      DPAT and the partial agonist ipsapirone exhibited lower intrinsic activity than R
      (+)-8-OH-DPAT. R-(+)-8-OH-DPAT also stimulated [(35)S]GTPgammaS binding in
      cortex, but not in striatum, which lacks 5-HT(1A) receptors. Partial irreversible
      inactivation of 5-HT(1A) receptors, in vitro with phenoxybenzamine (0.3 or 1
      microM) or in vivo with N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (1 mg/kg),
      reduced the maximal response produced by R-(+)-8-OH-DPAT but did not alter its
      EC(50). In autoradiographic sections, R-(+)-8-OH-DPAT stimulated [(35)S]GTPgammaS
      binding in 5-HT(1A) receptor-rich regions (dorsal hippocampus, 123%; lateral
      septum, 111%; midhippocampus, 110%; dorsal raphe nucleus, 83%; medial prefrontal
      cortex, approximately 60%). The EC(50) of R-(+)-8-OH-DPAT did not vary
      significantly among brain regions (46-96 nM). Partial irreversible blockade of 5
      HT(1A) receptors in brain sections (phenoxybenzamine, 10 microM) reduced the
      maximal response without altering the EC(50) in both the hippocampus and dorsal
      raphe. Despite prior evidence that dorsal raphe somatodendritic 5-HT(1A)
      autoreceptors exhibit high receptor/effector coupling efficiency (receptor
      reserve) compared with postsynaptic receptors in hippocampus, there was no
      evidence of a difference at the level of receptor/G protein coupling.

PMID- 10640307
TI  - Pharmacological characterization of endogenous acetylcholine release from primary
      septal cultures.
AB  - A detailed investigation of endogenous acetylcholine (ACh) release from primary
      embryonic septal cultures is described in this study. Applications of veratridine
      (25 microM) or increasing extracellular concentrations of K(+) (6-100 mM) induced
      robust increases of endogenous ACh release ( approximately 500-15,000
      fmol/well/10 min). Release stimulated with K(+) (25 mM) was sustainable and did
      not differ significantly over 180 min. ACh release was dependent on extracellular
      choline and decreased proportionally to choline concentrations (0-10 microM). For
      example, after 30 min of stimulation with K(+) (25 mM), release in the absence of
      extracellular choline was approximately 25% of that associated with 10 microM
      choline. The vesicular transport blocker vesamicol (0-5 microM) almost completely
      prevented stimulated and basal ACh release at the highest concentration
      evaluated, which suggests a mostly vesicular mode of release in this model. The
      M(2)-like muscarinic receptor antagonist AF-DX 384 (0-10 microM) enhanced
      stimulated ACh release ( approximately 150% at the highest concentration
      evaluated), whereas the nonspecific muscarinic receptor agonist oxotremorine (0
      10 microM) decreased stimulated release (approximately 60% at the highest
      concentration evaluated), suggesting that functional muscarinic autoreceptors
      exist in primary embryonic septal cultures. Novel findings concerning ACh release
      from primary embryonic septal cultures are reported herein, and the demonstration
      of ACh release gives further credit to the use of these cultures for studying
      cholinergic system functioning and in relation to physiology and pathology.

PMID- 10640308
TI  - Inositol phosphate metabolism and nitric-oxide synthase activity in endothelial
      cells are involved in the vasorelaxant activity of nebivolol.
AB  - Nebivolol is a recently developed beta-blocker provided with vasodilator
      properties. Because the mechanism of the putative endothelium-dependent effect of
      this beta-adrenoceptor blocker has not been completely elucidated, the aim of
      this study was to investigate the effects of nebivolol on an isolated resistance
      vascular bed and on cell messengers and constitutive nitric-oxide synthase
      activity (cNOS) in endothelial cells. Experiments were carried out using the rat
      mesenteric vascular bed and cultured bovine coronary postcapillary venular
      endothelial cells from bovine heart (CVEC). In mesenteric vascular bed
      preconstricted by 30 microM noradrenaline and 0.3 microM U46619, dl-nebivolol
      induced a concentration-dependent relaxing effect at concentrations between 3 and
      30 microM; this effect was changed to a concentration-dependent vasoconstrictor
      response either in endothelium-denuded preparations or in intact preparations
      pretreated with 100 microM N(omega)-nitro-L-arginine methyl ester plus 3 microM
      indomethacin. The vasorelaxant effect of dl-nebivolol in preconstricted
      preparations was completely blocked by pretreatment either with the phospholipase
      C inhibitor U73122 (1 microM) or with the endoplasmic reticulum Ca(2+)-ATPase
      inhibitor thapsigargin (1 microM) for 30 min. The cellular level of the inositol
      trisphosphate metabolite inositol monophosphate in coronary postcapillary venular
      endothelial cells was not affected by dl-nebivolol in the concentration range 100
      nM to 1 microM, but it was concentration dependently increased after exposure for
      15 min to 10 and 30 microM dl-nebivolol. The activity of cNOS was almost doubled
      after a 5-min exposure to 10 microM dl-nebivolol and was significantly impaired
      by thapsigargin and N(omega)-nitro-L-arginine methyl ester treatment, although it
      was unaffected by N(omega)-nitro-D-arginine methyl ester. These findings
      demonstrate that nebivolol, in micromolar concentrations, induces vasorelaxation
      through activation of inositol phosphate metabolism and stimulation of cNOS
      activity in endothelial cells.

PMID- 10640309
TI  - Reversal of morphine-induced apnea in the anesthetized rat by drugs that activate
      5-hydroxytryptamine(1A) receptors.
AB  - The purpose of our study was to test the hypothesis that 5-hydroxytryptamine (5
      HT)(1A) receptor agonists counteract morphine-induced respiratory depression.
      Studies were conducted in anesthetized rats, and respiratory activity was
      monitored with diaphragm electromyography. Morphine was administered i.v. in
      doses that produce apnea. Once apnea was established, i.v. administration of the
      5-HT(1A) receptor agonist drug 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT)
      at 10 or 100 microgram/kg restored normal breathing in each animal (n = 24). This
      antagonistic effect of 8-OH-DPAT on morphine-induced respiratory depression was
      observed in both spontaneously breathing and artificially ventilated animals.
      Results obtained with 8-OH-DPAT were mimicked by buspirone (50 microgram/kg
      i.v.), another 5-HT(1A) receptor agonist drug. Pretreatment with 4-(2'
      methoxyphenyl)-1-[2'[N-(2'-pyridinyl]-p-iodo-benzamido]ethyl]pi perazine, an
      antagonist of 5-HT(1A) receptors, prevented 8-OH-DPAT from counteracting morphine
      induced apnea. These results indicate that activation of central nervous system 5
      HT(1A) receptors is an effective way of reversing morphine-induced respiratory
      depression. Most important, this is the third model of disturbed respiratory
      function in which drugs that stimulate 5-HT(1A) receptors have been shown to
      restore breathing to near-normal levels.

PMID- 10640310
TI  - D(1) dopamine receptor agonists are more effective in alleviating advanced than
      mild parkinsonism in 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine-treated
      monkeys.
AB  - Selective D(1) dopamine receptor agonists exert antiparkinsonian effects in the 1
      methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkey model of Parkinson's
      disease and in human Parkinson's disease. Motor impairment in idiopathic
      Parkinson's disease progresses from mild to severe, but the therapeutic potential
      of D(1) dopamine receptor agonists in early and advanced stages of parkinsonism
      is not known. To compare the effectiveness of D(1) agonists at different levels
      of impairment, we developed a model of mild and advanced parkinsonism in nonhuman
      primates and a rating scale that differentiated the two models. D(1) dopamine
      receptor agonists (SKF 81297, dihydrexidine) and D(2) dopamine receptor agonists
      [quinelorane, (+)-PHNO were administered to monkeys (Macaca fascicularis)
      displaying either mild parkinsonism (two doses of 0.6 mg/kg i.v. MPTP 1 month
      apart) or advanced parkinsonism (three doses of 0.6 mg/kg i.v. MPTP within 10
      days). In normal monkeys (n = 3), SKF 81297 and dihydrexidine did not promote
      increased motor activity. In advanced parkinsonism (n = 4), D(1) and D(2)
      dopamine agonists effectively reversed the motor deficits. In contrast, the
      therapeutic benefits of D(1) agonists SKF 81297 and dihydrexidine were relatively
      limited in mild parkinsonism (n = 4). The D(2) agonists quinelorane and (+)-PHNO
      alleviated some symptoms in mild parkinsonism but also reduced balance and
      induced more dyskinesias than did D(1) agonists. Mild and advanced parkinsonism
      in nonhuman primates can be produced with fixed dosing regimens of MPTP. Based on
      the therapeutic efficacy and side effect profiles derived from these models, D(1)
      agonists are more promising for the treatment of advanced than of mild
      Parkinson's disease.

PMID- 10640311
TI  - Bisprasin, a novel Ca(2+) releaser with caffeine-like properties from a marine
      sponge, Dysidea spp., acts on Ca(2+)-induced Ca(2+) release channels of skeletal
      muscle sarcoplasmic reticulum.
AB  - Bisprasin, a unique bromotyrosine derivative containing a disulfide linkage, was
      isolated from a marine sponge of Dysidea spp. This compound caused a
      concentration-dependent (from 10 to 30 microM) increase in the (45)Ca(2+) release
      from the heavy fraction of skeletal muscle sarcoplasmic reticulum (HSR) of rabbit
      skeletal muscle in the same way as does caffeine. The 50% effective
      concentrations of bisprasin and caffeine were approximately 18 microM and 1.2 mM,
      respectively, indicating that the (45)Ca(2+)-releasing activity of bisprasin was
      approximately 70 times more potent than that of caffeine in HSR. The bell-shaped
      profile of Ca(2+) dependence for bisprasin was almost the same as that for
      caffeine. Typical blockers of Ca(2+)-induced Ca(2+) release channels, such as
      Mg(2+), procaine, and ruthenium red, inhibited markedly bisprasin- and caffeine
      induced (45)Ca(2+) release from HSR. This compound, like caffeine, significantly
      enhanced [(3)H]ryanodine binding to HSR. Scatchard analysis of [(3)H]ryanodine
      binding to HSR revealed that bisprasin and caffeine decreased the K(D) value
      without affecting the B(max) value, suggesting that both the drugs facilitate the
      opening of ryanodine receptor channels. The bisprasin- and caffeine-induced
      increases in [(3)H]ryanodine binding were further enhanced by adenosine-5'-(beta,
      gamma-methylene)triphosphate. These results suggest that the pharmacological
      properties of bisprasin are almost similar to those of caffeine, except for its
      70-fold higher potency. Here, we present the first report on the pharmacological
      properties of bisprasin, which, like caffeine, induces Ca(2+) release from
      skeletal muscle SR mediated through the ryanodine receptor.

PMID- 10640312
TI  - Atypical antipsychotics and dopamine D(1) receptor agonism: an in vivo
      experimental study using core temperature measurements in the rat.
AB  - The study objectives were to examine the effects of the atypical antipsychotic
      drugs olanzapine, risperidone, and quetiapine on core temperature in the rat in
      relation to such effects produced by clozapine and to compare possible in vivo
      intrinsic efficacy of olanzapine, risperidone, and quetiapine at dopamine (DA)
      D(1) receptors with such effects previously shown for clozapine. Core temperature
      measurements were made in adult male Wistar rats maintained under standard
      laboratory conditions using a reversed 12-h daylight cycle. Clozapine (0-32
      micromol/kg s.c.), olanzapine (0-32 micromol/kg s.c.), and risperidone (0-4
      micromol/kg s.c.) all produced a dose-dependent hypothermia. Except for slight
      nondose-dependent hyperthermia, there were no effects of quetiapine (0-16
      micromol/kg s.c. or i.p.) on the core temperature. The hypothermia produced by
      clozapine, but not that produced by equipotent doses of olanzapine or
      risperidone, was fully antagonized by pretreatment with the DA D(1) receptor
      antagonist SCH-23,390 (0.1 micromol/kg s.c.). On the other hand, quinpirole
      induced hypothermia (4 micromol/kg s.c.) was partially antagonized by olanzapine
      (2 micromol/kg s.c.), risperidone (4 micromol/kg s.c.), and quetiapine (16
      micromol/kg s.c.) but not by clozapine (1 micromol/kg s.c.). Clozapine
      preferentially stimulates DA D(1) receptors in comparison with olanzapine and
      risperidone, whereas olanzapine, risperidone, and quetiapine preferentially block
      DA D(2) receptors compared with clozapine. It is suggested that stimulation of DA
      D(1) receptors, presumably in the prefrontal cortex, is a distinguishing feature
      of clozapine responsible for its favorable profile on cognitive functioning in
      schizophrenia.

PMID- 10640313
TI  - Differential sensitivity among nitric oxide donors toward ODQ-mediated inhibition
      of vascular relaxation.
AB  - Nitric oxide (NO) donors are believed to exert their vasodilatory action through
      the activation of soluble guanylate cyclase (sGC), the heme site of which can be
      specifically inhibited by 1H-[1,2, 4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). We
      examined the vascular relaxation of the rat aorta mediated by eight different NO
      donors in the presence of ODQ (0.1, 1, or 10 microM), and demonstrated that these
      NO donors displayed different sensitivities toward ODQ inhibition (ANOVA, P
      <.05). Among the NO donors studied, S-nitrosothiols such as S-nitroso-N
      acetylpenicillamine (SNAP) and S-nitrosoglutathione exhibited partial resistance
      toward ODQ inhibition at 0.1 microM ODQ, whereas nitroglycerin (NTG) showed
      nearly complete inhibition at this concentration of ODQ. Three NO donors
      representing increasing sensitivity toward ODQ inhibition, SNAP < sodium
      nitroprusside (SNP) < NTG, were chosen for additional mechanistic studies. ODQ (1
      microM) inhibition of vascular relaxation by SNAP and SNP, but not that by NTG,
      was partially reversed by a sulfhydryl donor, N-acetylpenicillamine (100 microM),
      and by a phosphodiesterase inhibitor, zaprinast (10 microM), specific for cGMP.
      Our results strongly indicate that the vascular relaxation mechanism(s) of NO
      donors is not identical for each. In the rat aorta, NTG appeared to exhibit its
      vasodilatory effect exclusively through activation of the heme site of sGC. On
      the other hand, in the intact vascular tissue, SNAP and SNP could bring about
      vasodilation through a secondary pathway. These results are consistent with the
      view that SNAP and SNP, but not NTG, can induce vascular relaxation additionally
      through the activation of the sulfhydryl site of sGC.

PMID- 10640314
TI  - Intrathecally administered gabapentin inhibits formalin-evoked nociception and
      the expression of Fos-like immunoreactivity in the spinal cord of the rat.
AB  - In the present study, we investigated the effects of intrathecal gabapentin on
      nociceptive behaviors and the numbers of spinal Fos-like immunoreactive (Fos-LI)
      neurons evoked by injection of 0.25 to 2.5% formalin in the hindpaw of the rat.
      Pretreatment with gabapentin dose dependently decreased flinches and weighted
      pain scores in phase 2, but not phase 1, at each concentration of formalin. The
      highest dose of gabapentin (100 microgram) shifted the EC(50) values of formalin
      for both flinches and weighted pain scores to the right by 2.5-fold, suggesting
      that formalin was perceived to be significantly less noxious. Gabapentin also
      decreased phase 2 behaviors when administered after formalin but was only one
      third as potent. Unlike its inhibition of formalin-evoked nociceptive behaviors,
      the effect of gabapentin on the expression of Fos-like immunoreactivity in the
      spinal cord was highly dependent on the concentration of formalin. Intrathecal
      pretreatment with 100 microgram of gabapentin did not decrease the numbers of Fos
      LI neurons evoked by 0.5% formalin, yet this dose decreased the numbers of Fos-LI
      neurons in laminae I-II and VII-X of rats that received 1.25% formalin and
      uniformly decreased by 50% the numbers of Fos-LI neurons in all laminae of rats
      that received 2.5% formalin. These latter findings suggest that gabapentin
      neither nonselectively decreases the excitability of spinal cord neurons nor
      uniformly inhibits the release of all neurotransmitters from primary afferent
      terminals. Rather, its effects may be preferential for those neurotransmitters
      released by higher, more noxious concentrations of formalin and for conditions in
      which there is a greater induction of central sensitization.

PMID- 10640315
TI  - Diuretic response to adenosine A(1) receptor blockade in normotensive and
      spontaneously hypertensive rats: role of pertussis toxin-sensitive G-proteins.
AB  - Adenosine A(1) receptor antagonists are being developed for use as diuretics in
      the treatment of hypertension, however, there is relatively little data in
      hypertensive animal models regarding the efficacy of these compounds. In
      addition, some controversy exists surrounding the role of pertussis toxin (PT)
      sensitive G-proteins in the signaling pathway for receptors acted on by A(1)
      antagonists. Our objectives for this study were 1) to compare the diuretic,
      natriuretic, and cardiovascular effects of acute A(1) receptor blockade in
      spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto rats (WKY); and 2)
      to determine whether the diuretic effects are mediated through a PT-sensitive
      mechanism. Acute administration of the selective A(1) antagonist 1, 3-dipropyl-8
      cyclopentylxanthine (DPCPX; 10 microgram/kg/min) increased urine output (410 +/-
      116 and 317 +/- 86 microliter/30 min/g kidney) and sodium excretion (90.3 +/-
      25.6 and 76.8 +/- 18.2 micromol/30 min/g kidney) similarly in WKY and SHR,
      respectively. DPCPX significantly decreased mean arterial blood pressure in SHR (
      11.4 +/- 2.7 mm Hg), but not WKY. Prior treatment with PT (30 microgram/kg i.v.)
      abolished the diuretic response to DPCPX in both SHR and WKY. In a subsequent
      experiment in PT-treated Sprague-Dawley rats, DPCPX failed to evoke a diuretic
      response, whereas coinfusion of furosemide with DPCPX induced marked diuresis.
      Our results indicate that acute DPCPX administration produces similar
      natriuretic/diuretic effects in SHR and WKY, with beneficial effects on blood
      pressure in SHR. PT abolishes the response to DPCPX, indicating that the
      natriuretic/diuretic response to DPCPX is mediated via blockade of A(1) receptors
      linked to tubular sodium transport through PT-sensitive G-proteins.

PMID- 10640316
TI  - Predominant contribution of the G protein-mediated mechanism to NaF-induced
      vascular contractions in diabetic rats: association with an increased level of
      G(qalpha) expression.
AB  - The purpose of this study was to determine the mechanism responsible for
      alterations in NaF-induced contractions of blood vessels from streptozotocin
      induced diabetic rats. In the presence of AlCl(3), NaF (>/=7.5 mM) produced
      significantly greater contractions in diabetic aorta and mesenteric artery
      compared with age-matched controls. Pretreatment with 1 microM nifedipine
      eliminated the enhanced contractile responses of diabetic vessels to NaF,
      resulting in no difference in the magnitude of NaF-induced contractions between
      control and diabetic vessels. In the presence of 100 microM deferoxamine, an
      Al(3+) chelator, NaF-induced contractions of diabetic vessels were markedly
      attenuated, whereas only the responses to lower concentrations of NaF were
      reduced in control vessels. No significant difference was found in the peak
      amplitude of transient contractions induced by 10 microM cyclopiazonic acid
      between control and diabetic vessels. The addition of 10 microM okadaic acid
      produced attenuated contractions in diabetic vessels. These findings indicate no
      involvement of the inhibitory effects of NaF on endoplasmic reticular Ca(2+)-pump
      ATPase and protein phosphatases in the genesis of the enhanced responsiveness of
      diabetic vessels to NaF. Western blot analysis showed a 2.5-fold increase in the
      expression of G(qalpha) in diabetic aortic membranes. In contrast, the G(ialpha)
      level was modestly decreased and the G(salpha) and G(betagamma) levels were
      unchanged in diabetes. The present results suggest that enhanced vascular
      contractions to NaF in diabetes is attributed predominantly to a G protein
      mediated Ca(2+) channel activation that results from markedly increased G(qalpha)
      expression in vascular tissues under this pathological state.

PMID- 10640317
TI  - Acute effect of cadmium-metallothionein on glucose and amino acid transport
      across the apical membrane of the rabbit proximal tubule perfused in vitro.
AB  - Acute as well as chronic exposure of cadmium (Cd) leads to proximal tubule
      injury. The exact cellular mechanism of this disorder and whether there is a
      contribution of cadmium-metallothionein (Cd-MT), a binding protein of Cd, remain
      unclear. We perfused isolated S2 segments of rabbit nephron, and the deflections
      of transmural voltage (DeltaV(t)) and apical membrane voltage (DeltaV(a)) on
      elimination of glucose or alanine from the perfusate were measured for the
      parameters of activity of Na(+)-glucose and Na(+)-amino acid cotransporters. The
      effects of Cd-MT or CdCl(2) to either bath or lumen for 10 min on these
      parameters were examined. We also measured the lumen-to-bath [(14)C]glucose flux.
      Addition of Cd-MT to lumen suppressed glucose- or alanine-dependent DeltaV(t) and
      DeltaV(a), as well as baseline V(t) and basolateral membrane voltage (V(b)), at
      approximately 10 min. [(14)C]glucose flux was inhibited by Cd-MT to lumen. The
      effects of Cd-MT to bath and CdCl(2) to either lumen or bath were 100-fold less
      potent than that of Cd-MT to lumen. Luminal Cd-MT immediately suppressed the
      glucose-dependent DeltaV(a), whereas the baseline V(a) and V(t) were unchanged.
      The early effect of luminal Cd-MT was simulated by addition of 10(-4) M
      phloretin. Addition of 10(-4) M ouabain to the bath simulated the later effect of
      Cd-MT. The protection of SH group by dithiothreitol prevented the early effect of
      Cd-MT, but not the later effect. We concluded that Cd-MT initially acts directly
      on Na(+)-glucose and Na(+)-amino acid cotransporters from the lumen by attacking
      SH group, followed by the later inhibition of Na(+)-K(+)-ATPase after entering
      the cell from the apical membrane.

PMID- 10640318
TI  - Stimulation of Cl(-) secretion by chlorzoxazone.
AB  - We previously demonstrated that 1-ethyl-2-benzimidazolone (1-EBIO) directly
      activates basolateral membrane calcium-activated K(+) channels (K(Ca)), thereby
      stimulating Cl(-) secretion across several epithelia. In our pursuit to identify
      potent modulators of Cl(-) secretion that may be useful to overcome the Cl(-)
      secretory defect in cystic fibrosis (CF), we have identified chlorzoxazone [5
      chloro-2(3H)-benzoxazolone], a clinically used centrally acting muscle relaxant,
      as a stimulator of Cl(-) secretion in several epithelial cell types, including
      T84, Calu-3, and human bronchial epithelium. The Cl(-) secretory response induced
      by chlorzoxazone was blocked by charybdotoxin (CTX), a known blocker of K(Ca). In
      nystatin-permeabilized monolayers, chlorzoxazone stimulated a basolateral
      membrane I(K), which was inhibited by CTX and also stimulated an apical I(Cl)
      that was inhibited by glibenclamide, indicating that the G(Cl) responsible for
      this I(Cl) may be cystic fibrosis transmembrane conductance regulator (CFTR). In
      membrane vesicles prepared from T84 cells, chlorzoxazone stimulated (86)Rb(+)
      uptake in a CTX-sensitive manner. In excised, inside-out patches, chlorzoxazone
      activated an inwardly-rectifying K(+) channel, which was inhibited by CTX. 6
      Hydroxychlorzoxazone, the major metabolite of chlorzoxazone, did not activate
      K(Ca), whereas zoxazolamine (2-amino-5-chlorzoxazole) showed a similar response
      profile as chlorzoxazone. In normal human nasal epithelium, chlorzoxazone
      elicited hyperpolarization of the potential difference that was similar in
      magnitude to isoproterenol. However, in the nasal epithelium of CF patients with
      the DeltaF508 mutation of CFTR, there was no detectable Cl(-) secretory response
      to chlorzoxazone. These studies demonstrate that chlorzoxazone stimulates
      transepithelial Cl(-) secretion in normal airway epithelium in vitro and in vivo,
      and suggest that stimulation requires functional CFTR in the epithelia.

PMID- 10640319
TI  - FA-70, a novel selective and irreversible monoamine oxidase-A inhibitor: effect
      on monoamine metabolism in mouse cerebral cortex.
AB  - A series of indolealkylamine derivatives has been previously designed and
      evaluated with the aim of finding the most potent and selective novel monoamine
      oxidase (MAO) inhibitors to be used in the therapy of neurological and affective
      disorders. Among them, FA70, a 5-hydroxy-indolealkylamine derivative, has been
      characterized in vitro as a potent, irreversible, and mechanism-based inhibitor
      of the MAO-A isoform. The comparison with clorgyline, analyzed under the same
      experimental conditions, confirmed FA70 as the most potent MAO-A inhibitor. The
      ex vivo effect of FA70 on MAO activity in mouse cerebral cortex was similar to
      that observed in vitro, showing more efficacy than in peripheral tissues. The ex
      vivo effect of FA70 on amine metabolism also was evaluated after acute and
      chronic treatment, and the results showed that between both MAO isoforms, MAO-A
      is the only one responsible for monoamine metabolism in this region of the brain.
      The ex vivo effect of FA70 on dopamine content was correlated with the activation
      effect on tyrosine hydroxylase activity, the enzyme responsible for the
      regulation of the limiting step in catecholamine synthesis.

PMID- 10640320
TI  - Intrapericardial delivery of fibroblast growth factor-2 induces
      neovascularization in a porcine model of chronic myocardial ischemia.
AB  - Therapeutic angiogenesis is a novel approach to the treatment of myocardial
      ischemia based on the use of proangiogenic growth factors to induce the growth of
      new blood vessels to supply the myocardium at risk. This study was designed to
      assess the safety and efficacy of a single intrapericardial injection of basic
      fibroblast growth factor (FGF-2) in a porcine model of chronic myocardial
      ischemia. Yorkshire pigs underwent ameroid placement around the left circumflex
      coronary artery. At 3 weeks, animals were randomized to receive a single
      intrapericardial injection of either saline (n = 10), 3 mg of heparin (n = 9), 3
      mg of heparin + 30 microgram of FGF-2 (n = 10), 200 microgram of FGF-2 (n = 10),
      or 2 mg of FGF-2 (n = 10). Coronary angiography, microsphere flow, magnetic
      resonance functional, and perfusion imaging were performed before and 4 weeks
      after treatment, at which time histologic analysis was also performed on 3
      animals in each group. In ischemic pigs, FGF-2 treatment resulted in significant
      increases in left-to-left angiographic collaterals and left circumflex coronary
      artery blood flow. These benefits were accompanied by improvements in myocardial
      perfusion and function in the ischemic territory, as well as histologic evidence
      of increased myocardial vascularity without any adverse effects. Not one of these
      benefits was seen in saline- or heparin-treated ischemic animals. A single
      intrapericardial injection of FGF-2 in a porcine model of chronic myocardial
      ischemia results in functionally significant myocardial angiogenesis, without any
      adverse outcomes. This mode of FGF-2 administration may prove to be a useful
      therapeutic strategy for the treatment of patients with ischemic heart disease.

PMID- 10640321
TI  - The antitussive activity of delta-opioid receptor stimulation in guinea pigs.
AB  - In this study, the activity of the delta-opioid receptor subtype-selective
      agonist, SB 227122, was investigated in a guinea pig model of citric acid-induced
      cough. Parenteral administration of selective agonists of the delta-opioid
      receptor (SB 227122), mu-opioid receptor (codeine and hydrocodone), and kappa
      opioid receptor (BRL 52974) produced dose-related inhibition of citric acid
      induced cough with ED(50) values of 7.3, 5.2, 5.1, and 5.3 mg/kg, respectively.
      The nonselective opioid receptor antagonist, naloxone (3 mg/kg, i.m.), attenuated
      the antitussive effects of codeine or SB 227122, indicating that the antitussive
      activity of both compounds is opioid receptor-mediated. The delta-receptor
      antagonist, SB 244525 (10 mg/kg, i.p.), inhibited the antitussive effect of SB
      227122 (20 mg/kg, i.p.). In contrast, combined pretreatment with beta
      funaltrexamine (mu-receptor antagonist; 20 mg/kg, s.c.) and norbinaltorphimine
      (kappa-receptor antagonist; 20 mg/kg, s.c.), at doses that inhibited the
      antitussive activity of mu- and kappa-receptor agonists, respectively, was
      without effect on the antitussive response of SB 227122 (20 mg/kg, i.p.). The
      sigma-receptor antagonist rimcazole (3 mg/kg, i.p.) inhibited the antitussive
      effect of dextromethorphan (30 mg/kg, i.p.), a sigma-receptor agonist, but not
      that of SB 227122. These studies provide compelling evidence that the antitussive
      effects of SB 227122 in this guinea pig cough model are mediated by agonist
      activity at the delta-opioid receptor.

PMID- 10640322
TI  - Pharmacokinetics and pharmacodynamics of a humanized monoclonal antibody to
      factor IX in cynomolgus monkeys.
AB  - The pharmacokinetics and pharmacodynamics (PK/PD) of a humanized anti-Factor IX
      IgG1 monoclonal antibody (SB 249417, FIX mAb) were studied in Cynomolgus monkeys.
      Single i.v. bolus doses of 1, 3, or 10 mg/kg of FIX mAb were administered. The
      total FIX mAb concentration, activated partial thromboplastin time (aPTT), and
      Factor IX activity were monitored for up to 4 weeks after dosing. In the monkey,
      FIX mAb had a plasma clearance of 0.6 ml/h/kg and a steady-state volume of
      distribution of approximately 70 ml/kg. The elimination phase half-life (3.8
      days) was considerably less than other humanized IgG1 mAbs in the monkey, for
      which there is no binding to endogenous antigen. The suppression of Factor IX
      activity and the prolongation of aPTT were rapid and dose dependent. The time for
      aPTT values to return to basal levels (25-170 h) increased with increasing dose.
      A mechanism-based PK/PD model consistent with the stoichiometry of binding (2:1)
      was developed to describe the Factor IX activity and aPTT response time course.
      The model incorporated Factor IX synthesis and degradation rates that were
      interrupted by the sequestration of Factor IX by the antibody. aPTT values were
      related to free Factor IX activity. This model was able to describe the PD
      profiles from the three dose levels simultaneously. The estimated Factor IX half
      life was 11 h and the third-order association rate constant was 3.96 x 10(3)
      microM(-2) h(-1). The PK/PD modeling was useful in summarizing the major
      determinants (endogenous and antibody-ligand binding) controlling FIX mAb-related
      effects.

PMID- 10640323
TI  - Pregnancy induces a modulation of the cAMP phosphodiesterase 4-conformers ratio
      in human myometrium: consequences for the utero-relaxant effect of PDE4-selective
      inhibitors.
AB  - The inhibitory impacts of RP 73401, a phosphodiesterase type 4 (PDE4) selective
      inhibitor of the second generation, versus rolipram, the prototypal PDE4
      inhibitor, were evaluated and compared on cAMP phosphodiesterase (PDE) activity
      and contractility of the myometrium in nonpregnant and pregnant women. In
      enzymatic studies, RP 73401 and rolipram inhibited the cAMP PDE activity with
      significantly greater maximal efficiency in the myometrium of pregnant compared
      with nonpregnant women (75 versus 55%; P <.05). Although myometrial PDE4
      presented a single class of interaction with RP 73401 [pD(2) (-log [IC(50)]) = 
      8.2], it exhibited at least two classes of interaction with rolipram (pD(2) = 
      8.2 and -5.6). In the myometrium of pregnant versus nonpregnant women, rolipram
      is significantly more efficacious in the concentration range >0.01 to 100 microM
      (P <.01), whereas no difference was observed for the concentration range <0.01
      microM. In contractility studies, RP 73401 was equally effective in relaxing
      myometrial strips from both nonpregnant and pregnant women (pD(2) = -8.8).
      Conversely, the ability of rolipram to inhibit contractions of the myometrium in
      pregnant women was significantly lower (pD(2) = -7.2) compared with that in
      nonpregnant women (pD(2) = -8.2; P <.01). Concomitantly, in the myometrium of
      pregnant women, a rise in immunoreactive PDE4B2 signal was detected, whereas the
      PDE4D3 signal was less intense. These results demonstrate that parallel to an
      accumulation of PDE4B2 isoform, a modification in the ratio of PDE4 conformers
      HPDE4 and LPDE4 (conformer that binds rolipram with high and low affinity,
      respectively) occurs in the myometrium of near-term pregnant women with an
      increase of LPDE4 functionally implicated in the contractile process. Such
      modifications provide a strong rationale to propose LPDE4 as potential
      pharmacologic targets for the design of new tocolytic treatments.

PMID- 10640324
TI  - Isolation and characterization of mutants for the vesicular acetylcholine
      transporter gene in Drosophila melanogaster.
AB  - The Drosophila vesicular acetylcholine transporter gene (Vacht) is nested within
      the first intron of the choline acetyltransferase gene (Cha). To isolate Vacht
      mutants, we performed an F(2) genetic screen and identified mutations that failed
      to complement Df(3R)Cha(5), a deletion lacking Cha and the surrounding genes. Of
      these mutations, three mapped to a small genomic region where Cha resides.
      Complementation tests with a Cha mutant allele and rescue experiments using a
      transgenic Vacht minigene have revealed that two of these three mutations are
      nonconditional lethal alleles of Vacht (Vacht(1) and Vacht(2) ). The other is a
      new temperature-sensitive allele of Cha (Cha(ts3) ). Newly isolated Vacht mutants
      were used to reexamine the existing Cha mutations. We found that all deficiencies
      uncovering Cha also lack Vacht function, reflecting the nested organization of
      the two genes. The effective lethal phase for Vacht(1) is the embryonic stage,
      whereas that for Vacht(2) is the larval stage. Viable first-instar larvae
      homozygous for Vacht(2) showed reduced motility. Adult flies heterozygous for
      Vacht mutations were found to have defective responses in the dorsal longitudinal
      muscles following high-frequency brain stimulation. Since cholinergic synapses
      have been shown to be involved in the giant fiber pathway that mediates this
      response, the result suggested that reduction in the Vacht activity to 50% causes
      an abnormality in cholinergic transmission when stressed by a high-frequency
      stimulus.

PMID- 10640325
TI  - Sensitive period for sensorimotor integration during vocal motor learning.
AB  - Sensory experience during sensitive periods in development may direct the
      organization of neural substrates, thereby permanently influencing subsequent
      adult behavior. We report a sensitive period during the imitative motor learning
      phase of sensorimotor integration in birdsong development. By temporarily and
      reversibly blocking efference to the vocal muscles, we disrupted vocal motor
      practice during selected stages of song development. Motor disruption during
      prolonged periods early in development, which allows recovery of vocal control
      prior to the onset of adult song, has no effect on adult song production.
      However, song disruption late in development, during the emergence of adult song,
      results in permanent motor defects in adult song production. These results reveal
      a decreased ability to compensate for interference with motor function when
      disturbances occur during the terminal stage of vocal motor development.
      Temporary disruption of syringeal motor control in adults does not produce
      permanent changes in song production. Permanent vocal aberrations in juveniles
      are evident exclusively in learned song elements rather than nonlearned calls,
      suggesting that the sensitive period is associated with motor learning.

PMID- 10640326
TI  - Intracellular signaling molecules involved in an inhibitory factor-induced
      decrease in fetal-type AChR expression.
AB  - The innervation-induced down-regulation of fetal-type acetylcholine receptor
      (AChR) expression in developing muscle fibers has largely been attributed to
      nerve-evoked muscle activity; however, there is increasing evidence that a neural
      trophic factor also contributes to this receptor down-regulation. Previous
      studies from this laboratory have shown that neural extracts contain a factor
      which decreases fetal-type AChR expression in skeletal muscle cell lines and
      therefore may account for the proposed inhibitory neurotrophic influence. The
      current study investigated possible intracellular signaling molecules involved in
      this receptor down-regulation and demonstrated that activation of protein kinase
      C and p70(S6k) appeared to be important in receptor down-regulation. Decreases in
      AChR density were independent of myogenin. In addition, the receptor down
      regulation was independent of neuregulin, which also induces p70(S6k) activity.
      These studies demonstrate that neural extracts contain an inhibitory factor which
      can down-regulate fetal-type AChR expression independently of nerve-evoked muscle
      activity through intracellular signaling molecules which are known to regulate
      AChR expression.

PMID- 10640327
TI  - Vocal control region sizes of an adult female songbird change seasonally in the
      absence of detectable circulating testosterone concentrations.
AB  - Previous research established that in several species of seasonally breeding
      oscine birds, brain areas [vocal control regions (VCRs)] that control vocal
      behavior learning and expression exhibit seasonal plasticity, being larger during
      than outside the reproductive period. In adult males, this seasonal decrease
      correlates with circulating testosterone (T) concentrations. VCRs contain
      androgen receptors and T plays an important role in neural plasticity and in the
      control of singing behavior. In behaviorally dimorphic species, VCRs are larger
      in males than females and change seasonally also in females, but the dependency
      of these changes on circulating T levels in females has not been established. In
      free-living adult dark-eyed juncos (Junco hyemalis), a species in which females
      do not normally sing, the sizes of three VCRs (high vocal center, robust nucleus
      of the archistriatum, and Area X) were larger in males than females and decreased
      between summer and fall in both sexes. In males, this decrease was associated
      with changes in circulating T concentrations. Females, however, had on average
      undetectable T levels throughout the breeding season. Seasonal changes in VCR
      volumes in adult females may depend on very low (below detection limit)
      circulating T concentrations, on nonandrogenic plasma steroids, on androgen (or
      androgen metabolites) produced in brain tissues, and/or on nonsteroidal factors
      such as photoperiod or social interactions with conspecific birds.

PMID- 10640328
TI  - Guidance of regenerating motor axons in vivo by gradients of diffusible
      peripheral nerve-derived factors.
AB  - During development of the central nervous system, neurons rely on target-derived
      factors to guide their outgrowing processes. Several CNS target-derived
      chemoattractive and repellent factors have been isolated and characterized, and
      their mechanism of action determined. For the peripheral nervous system, the
      results from numerous experiments suggest that during regeneration axons also
      respond to concentration gradients of target-derived factors leading to an
      oriented outgrowth up the gradient to the denervated target in vivo. The results
      from in vitro experiments have shown that diffusible concentration gradients of
      factors released from a length of denervated peripheral nerve, composed
      predominantly of Schwann cells, direct the outgrowth of sensory and motor neuron
      growth cones over distances of several hundred microns. However, a conclusive
      demonstration of a chemoattractive influence of diffusible concentration
      gradients on regenerating adult motor axons in vivo has remained elusive. The
      present experiments show that concentration gradients of denervated peripheral
      nerve-released factors direct the regeneration of adult motor axons in vivo, and
      that these gradients are effective over distances of more than 6.5 mm.
      Nonconditioned medium exerted no influence on the regenerating axons. Thus,
      results from in vivo experiments parallel those from in vitro experiments and
      indicate that isolated peripheral nerve-released factors that are effective in
      vitro will play a similar role on sensory and motor axons in vivo. Finally, the
      results show that diffusible concentration gradients of target-derived factors
      direct axon outgrowth both during both development and regeneration, as well as
      in vivo and in vitro.

PMID- 10640329
TI  - Muscle-dependent and hormone-dependent differentiation of the vocal control
      premotor nucleus robustus archistriatalis and the motornucleus hypoglossus pars
      tracheosyringealis of the zebra finch.
AB  - Sex differences in the vertebrate brain (brain sex) are thought to develop owing
      to the tissue specific action of gonadal hormones similar to the development of
      secondary sex characteristics of the body. Small sex differences in body anatomy
      could, however, retrogradely control the sexual differentiation of the central
      nervous system. This possibility has so far been verified only for motorneuron
      pools, since the connectivity of sex-specific higher brain areas to the sexual
      dimorphic periphery is frequently not well known. Here, we tested whether somatic
      sex differences feed back on higher brain areas by bilateral denervation of the
      syringeal musculature of zebra finches before, during, and after onset of
      estrogen-sensitive sexual differentiation of forebrain vocal nuclei such as RA
      (nucleus robustus archistriatalis). In the zebra finch, the sound-producing
      musculature (the syrinx), the syrinx motornucleus hypoglossus pars
      tracheosyringealis (nXIIts), and the RA are much larger in males compared to
      females. Tract tracing studies revealed that the volume and neuron size
      distribution of the nXIIts was sexually dimorphic in intact but not in animals
      denervated as juveniles. In contrast, the volume of RA and size of RA neurons of
      denervated animals were highly sexually dimorphic. Furthermore, estrogen
      masculinized the RA of denervated females. Thus, sexual differentiation of the RA
      but not of the nXIIts appears independent of somatic sex differences. The syrinx
      muscles are, however, important for the soma size of those RA neurons that
      project to the nXIIts.

PMID- 10640330
TI  - Partial rescue of the ocular retardation phenotype by genetic modifiers.
AB  - The or(J) allele of the murine ocular retardation mutation is caused by a
      premature stop codon in the homeodomain of the Chx10 gene. When expressed on an
      inbred 129/Sv strain, the or(J) phenotype is characterized by microphthalmia and
      a thin, poorly differentiated retina in which the peripheral portion is affected
      to a greater extent than the central portion. Such mutant retinae lack
      differentiated bipolar cells and the optic nerve typically fails to form, leading
      to blindness. Here, we show that progeny from an outcrossed backcross between
      129/Sv-or(J) /or(J) and Mus musculus castaneus produce animals that are
      homozygous for the or(J) mutation and exhibit a much ameliorated eye phenotype.
      Although not of normal size, such modified or(J) eyes are significantly larger
      than those in 129/Sv-or(J) /or(J) mice, and contain a better organized retina
      which includes bipolar cells. Furthermore, optic nerves are frequently present,
      and the eyes show a degree of function as reflected by electroretinogram and
      pupillary response. As in 129/Sv-or(J) /or(J) mice, however, modified or(J) eyes
      show incomplete growth and a lack of cell differentiation in the periphery of the
      retina. The selective, and apparently nonmodifiable, effect of the ocular
      retardation phenotype on the periphery of the retina indicates that Chx10 plays
      an important role in the central-to-peripheral gradient of retinal development.
      These findings demonstrate that the ocular retardation phenotype can be greatly
      modified by the genetic background, and help to define a role for Chx10 in ocular
      development.

PMID- 10640331
TI  - Heterogenous properties of dentate granule neurons in the adult rat.
AB  - Postnatal neurogenesis contributes substantially to the neuronal population of
      the adult dentate gyrus. We report here that the neurons located in the deep
      aspects of the granule cell layer, near the proliferative zone, have different
      properties from those located in the superficial layers. The former group of
      neurons, tentatively designated as young, can be readily identified in a standard
      hippocampal slice preparation by morphological, immunohistochemical, and
      electrophysiological criteria. Electrophysiological recordings and imaging with
      Lucifer yellow from these neurons in the standard hippocampal slice preparation
      showed one or two main dendrites and conically shaped branches possessing
      varicose protrusions. These features are in agreement with the appearance of the
      same population of young neurons immunopositive for TOAD-64, a marker for
      immature neurons. In disinhibited slices, these putative young neurons are
      distinguished from the mature neurons, located in the superficial granule cell
      layer, by showing paired pulse facilitation and having a lower threshold for
      induction of long-term potentiation. The putative young neurons are completely
      unaffected by GABA(A) inhibition and always display robust long-term
      potentiation. In contrast, the mature neurons never produce long-term
      potentiation when the GABA(A) inhibition is intact. We propose that the
      heterogeneity of the functional properties of the granule neurons is related to
      the ongoing neurogenesis in the adult animals.

PMID- 10640332
TI  - Gap junctional coupling between progenitor cells of regenerating retina in the
      adult newt.
AB  - Gap junctional coupling between progenitor cells of regenerating retina in the
      adult newt was examined by a slice-patch technique. Retinal slices at the early
      regeneration stage comprised one to two layers of cells with mitotic activity,
      progenitor cells. These cells were initially voltage-clamped at a holding
      potential of -80 mV, near their resting potentials, and stepped to either
      hyperpolarizing or depolarizing test potentials under suppression of voltage
      gated membrane currents. About half the cells showed passively flowing currents
      that reversed polarity around their resting potentials. The currents often
      exhibited a voltage- and time-dependent decline. As the difference between the
      test potential and resting potential increased, the time until the current
      decreased to the steady-state level became shorter and the amount of steady-state
      current decreased. Thus, the overall current profile was almost symmetrical about
      the current at the resting potential. Input resistance estimated from the initial
      peak of the currents was significantly smaller than that expected in isolated
      progenitor cells. In a high-K(+) solution, which decreased the resting potential
      to around 0 mV, the symmetrical current profile was also obtained, but only when
      the membrane potential was held at 0 mV before the voltage steps. These
      observations suggest that the current was driven and modulated by the junctional
      potential difference between the clamping cell and its neighbors. In addition, we
      examined effects of uncoupling agents on the currents. A gap junction channel
      blocker, halothane, suppressed the currents almost completely, indicating that
      the currents are predominantly gap junctional currents. Furthermore, injection of
      biocytin into the current-recorded cells revealed tracer coupling. These results
      demonstrate that progenitor cells of regenerating retina couple with each other
      via gap junctions, and suggest the presence of their cytoplasmic communication
      during early retinal regeneration.

PMID- 10640334
TI  - History of adolescent medicine in the 20th century: from Hall to Elkind.
AB  - Parents have known since time immemorial, and social scientists have agreed since
      the turn of the last century, that adolescents are "a people unto themselves"-a
      distinct developmental category. Yet it was not until the 1950s that a medical
      subspecialty focusing specifically on teenagers came into being. This article
      examines the interplay between the emergence of adolescent medicine and changes
      in American family relationships, youth culture, popular perceptions about young
      people, and the social experience of adolescence. The author traces the
      development of adolescent medicine from its origins in the works of J. Roswell
      Gallagher at Boston Children's Hospital in the 1950s to its uncertain prospects
      today, when, despite heightened recognition of their specific medical needs, most
      adolescents still receive inadequate health care.

PMID- 10640333
TI  - Pharmacological characterization of ionic currents that regulate the pacemaker
      rhythm in a weakly electric fish.
AB  - Electric organ discharge (EOD) frequency in the brown ghost knifefish
      (Apteronotus leptorhynchus) is sexually dimorphic, steroid-regulated, and
      determined by the discharge rates of neurons in the medullary pacemaker nucleus
      (Pn). We pharmacologically characterized ionic currents that regulate the firing
      frequency of Pn neurons to determine which currents contribute to spontaneous
      oscillations of these neurons and to identify putative targets of steroid action
      in regulating sexually dimorphic EOD frequency. Tetrodotoxin (TTX) initially
      reduced spike frequency, and then reduced spike amplitude and stopped pacemaker
      activity. The sodium channel blocker muO-conotoxin MrVIA also reduced spike
      frequency, but did not affect spike amplitude or production. Two potassium
      channel blockers, 4-aminopyridine (4AP) and kappaA-conotoxin SIVA, increased
      pacemaker firing rates by approximately 20% and then stopped pacemaker firing.
      Other potassium channel blockers (tetraethylammonium, cesium, alpha-dendrotoxin,
      and agitoxin-2) did not affect the pacemaker rhythm. The nonspecific calcium
      channel blockers nickel and cadmium reduced pacemaker firing rates by
      approximately 15-20%. Specific blockers of L-, N-, P-, and Q-type calcium
      currents, however, were ineffective. These results indicate that at least three
      ionic currents-a TTX- and muO-conotoxin MrVIA-sensitive sodium current; a 4AP-
      and kappaA-conotoxin SIVA-sensitive potassium current; and a T- or R-type calcium
      current-contribute to the pacemaker rhythm. The pharmacological profiles of these
      currents are similar to those of currents that are known to regulate firing rates
      in other spontaneously oscillating neural circuits.

PMID- 10640335
TI  - Adolescent medicine: a model for the millennium.
AB  - This article summarizes the past decade of technological development and the past
      century of adolescent development in order to predict the future of adolescent
      medicine. The technology of communication will revolutionize behavior change
      approaches in the 21st century. Health will be seen as an interactive loop of
      connections between patients, physicians, families, institutions, peers, and
      support networks that may be voluntarily navigated and searched. The low-tech of
      counseling will be replaced with the high-tech of the interactive sensor that
      will be developed from our knowledge of human development. The inter
      relationships between social and personal ecology-a basic premise of adolescent
      health care-will take on new importance in the first decade of the 21st century.
      The old will guide the application; the new will define the science. The major
      morbidities of adolescence of the 20th century will now be correctable and
      preventable. Models of care for all age groups will draw heavily on the
      experience of ephebiatrics. With application of the new science, biobehavioral
      issues will surface as the new technology and the practitioners of adolescent
      health care have the potential to lead the way.

PMID- 10640336
TI  - Adolescent sexuality at the dawn of the 21st century.
AB  - Human sexuality can be defined as including the physical characteristics of and
      capacities for specific sex behaviors, together with psychosocial values, norms,
      attitudes, and learning processes that influence these behaviors. It also
      includes a sense of gender identity and related concepts, behaviors, and
      attitudes about the self and others as women or men in the context of one's
      society. At the dawn of the new century, adolescent sexuality remains a topic of
      concern to adults throughout the world. This concern is not unique to this new
      age. In each era of recorded history, adults have been concerned about adolescent
      sexual behavior, particularly sexual intercourse and its consequences. Things
      have not changed all that much in the realm of adolescent sexual behavior. What
      has changed is our ability to prevent the serious consequences of this behavior
      and, hopefully, to help adolescents avoid behaviors that put them at risk for the
      negative consequences of expressing their burgeoning sexuality. This article
      reviews the major influences on adolescents developing' sexuality, the data on
      adolescent sexual activity, some tips on caring for adolescents comprehensively,
      and ends with some predictions of how this issue will be addressed in the new
      century.

PMID- 10640337
TI  - The family and parenting in the 21st century.
AB  - As we enter a new millennium, many are questioning the nature of the family and
      its future in a rapidly changing society. To put these issues in proper
      perspective, this article reviews the changes the family has undergone in the
      past and explores what this suggests about the future. First, a brief historical
      sketch of the American family over the past two centuries is presented. Next, the
      modern concept of the family as a functioning system is explored. Family systems
      not only evolve in structure through history, but each family also develops
      individually through its own family life cycle. These ideas are presented from a
      family therapy perspective in order to give the physician a more practical
      framework within which to view families seen in practice. Finally, some
      implications for the future of families in the next decade are discussed.

PMID- 10640338
TI  - Children, adolescents, and the media in the 21st century.
AB  - American children and adolescents spend an average of 3-5 hours per day with a
      variety of media, including television, radio, videos, videogames, and the
      Internet. Considerable research exists to document concerns about media violence,
      the impact of media on teen sexual attitudes and behavior, the relationship
      between alcohol and cigarette advertising and adolescent drug use, and the impact
      of R-rated films on attitudes about sexual violence. Very little research exists
      concerning adolescents' use of the Internet and the potential behavioral impact,
      but many parents and professionals are concerned. Solutions include: better
      programming, stricter regulation by parents, media education at home and in
      schools, and greater advocacy on the part of health professionals.

PMID- 10640339
TI  - Turning the tide: tobacco and the 21st century.
AB  - Despite efforts by groups as diverse as the federal and state governments, public
      health agencies, and various advocacy groups, tobacco use continued to increase
      among youth during the latter part of the 1990s. This article reviews the history
      of tobacco control in the latter part of the 20th century with special emphasis
      on policy development aimed at controlling use by children and adolescents. New
      trends in prevention and cessation are reviewed along with a discussion of
      tobacco control policies that will extend into this new century.

PMID- 10640340
TI  - Substance abuse: an overview.
AB  - Substance abuse continues to be a major adolescent health risk. Despite
      encouraging trends toward decreased drug use in the late 1980s, an increase in
      use occurred in the early 1990s and only now is beginning to level off. A brief
      update on the status of the most commonly abused substances is provided. A
      discussion of current research is given in support of viewing drug addiction as a
      medical condition, i.e., a "brain disease." Reasons are suggested to explain why
      adolescents use and abuse drugs and why trends occur in their use. Two aspects of
      diagnosis are reviewed: psychiatric and medical comorbidity and drug screening
      and laboratory assessment of the adolescent. Prevention and early intervention
      are presented with an emphasis on drug education, behavioral wellness, family
      communication, doctor-patient discussion and assessment, and referral. Commentary
      is made on the ethics of care; issues of confidentiality and the right to privacy
      with regard to drug testing and sharing of information are explored. A review of
      various policy statements of the American Academy of Pediatrics and other medical
      organizations is presented.

PMID- 10640341
TI  - Adolescent violence: concepts for a new millennium.
AB  - Violence is a form of aggressive behavior that has a debilitating effect on the
      optimal growth and development of our youth. Violence pervades the lives of a
      significant proportion of all adolescents in the U.S., but has a particularly
      devastating impact on males and minority youth. Adolescent males are more likely
      to be victimizers and victims of violence and aggression, except in cases of
      sexual victimization and suicide attempts. For all adolescents, exposure to
      violence at home, school, or in the community is associated with aggression later
      in life, the development of supportive attitudes toward aggression and violence,
      psychological distress, school absenteeism, academic dysfunction, and subsequent
      injury. Violence has historical, cultural, and societal roots in our world. Until
      and unless we begin to understand where violence fits on the continuum of
      aggressive behavior and until we address the politics of violence, we will remain
      conflicted and paralyzed by the dangers our youth face. By understanding the
      social, political, and developmental aspects of violence and understanding the
      nature and characteristics of resilient children, we can better prepare our youth
      for life. We may not be able to protect our adolescents from exposure to
      violence, but we most certainly can help them develop the necessary skills to
      survive such exposure and work to enhance and strengthen their access to
      protective factors so that they can experience a healthy transition from
      adolescence to adulthood in this new millennium.

PMID- 10640342
TI  - Romance with the automobile in the 20th century: implications for adolescents in
      a new millennium.
AB  - Nearly three-fourths of deaths among American adolescents and young adults result
      from only four causes: motor vehicle accidents, other unintentional injuries,
      homicide, and suicide. Thirty percent of those deaths result from motor vehicle
      accidents, the number one cause of death among adolescents. A number of factors
      that influence the morbidity and mortality are associated with driving. Compared
      to other countries, it is easier for American adolescent to obtain a relatively
      inexpensive license and gain access to a car. For the young driver, adolescent
      development and increased risk taking, inexperience, dangerous driving behavior,
      and alcohol-related factors are of special significance. In this article, we
      review recent crash statistics as well as effectiveness of various preventive
      measures, including driver education, graduated licensing, alcohol-related
      measures, and vehicle-related factors. Graduated licensing and alcohol-related
      measures have been the most effective measures so far.

PMID- 10640343
TI  - Sport participation, risk taking, and health risk behaviors.
AB  - Adolescents participate in sports for a variety of reasons. Some seem to enjoy
      participating in what some might consider very-high-risk or "extreme" sports
      activities. For some adolescents risk taking becomes pervasive and can be
      detrimental to normal health and development. The majority of adolescents will do
      well in the context of athletics, and the many positive benefits of regular
      physical activity and sports participation should be appropriately emphasized.
      However, a subset of adolescents may be at greater risk for adverse consequences.
      This article reviews the reasons for participation and attrition from sports, the
      phenomenon of thrill seeking in sports, certain risk-taking behaviors of
      athletes, and studies comparing health risk behaviors in athletes and non
      athletes.

PMID- 10640344
TI  - Protective factors, resiliency and healthy youth development.
AB  - The last decade has been characterized by an increasing focus on the question:
      "What works to promote and protect the health and well-being of adolescents?"
      This question is raised in multiple arenas, from pregnancy prevention to
      substance use and violence prevention, as well as for broad populations of young
      people. An accumulating body of evidence underscores the effectiveness of a dual
      strategy of enhancing protective factors and promoting healthy youth development
      while seeking to reduce risk factors in the lives of youth. Building upon
      research frameworks of the 1970s and 1980s that emphasized the concepts of
      resiliency, risk, vulnerability, and protective factors, this research provides
      insights into best practices when the weight of evidence is sufficiently
      developed, as well as ideas about "best bets" when strategies show particular
      promise. Critical to the ongoing advancement of adolescent health is a powerful,
      evidence-based response to the argument that "nothing can be done" for high-risk
      youth. This perspective must be superseded by practitioners, researchers, and
      advocates who demonstrate, at multiple points of intervention, that the dual
      approach of risk reduction and enhancement of protective factors constitutes an
      effective strategy for adolescent health promotion.

PMID- 10640345
TI  - Financing adolescent health care: the role of Medicaid and CHIP.
AB  - Financing health care for adolescents involves a combination of public and
      private sources of payment and, in the public sector, a combination of insurance
      coverage and categorical programs. In recent years, the importance of health
      insurance coverage has increased along with the potential for insuring more
      adolescents. Medicaid and the new State Children's Health Insurance Program
      (CHIP) offer numerous options for reducing the proportion of uninsured
      adolescents and for increasing adolescents' access to necessary health care. This
      article explores the potential of Medicaid and CHIP for meeting adolescents'
      needs, the extent to which they have done so already, and the gaps or missing
      links that remain. It also reviews issues that cut across funding sources related
      to managed care, consent, and confidentiality.

PMID- 10640346
TI  - Computers and information technology: implications for the 21st century.
AB  - The rapidly changing world of computer and information technology will have
      dramatic changes for adolescent medicine clinicians in the 21st century. This
      article reviews some of this evolving technology, including the electronic
      medical record, the Internet, and telemedicine as well as various advances in
      health screening, assessment, and education. The importance of integrating this
      technology into a total information system is stressed. The article concludes
      with a day in the life of an adolescent medicine clinician in the new century.

PMID- 10640347
TI  - Biosensor analysis of drug-target interactions: direct and competitive binding
      assays for investigation of interactions between thrombin and thrombin
      inhibitors.
AB  - The sensitivity of BIACORE technology is sufficient for detection and
      characterization of binding events involving low-molecular-weight compounds and
      their immobilized protein targets. The technology requires no labeling and
      provides information on the stability of the compound/target complex with a
      single injection of the compound. This is useful for qualifying hits obtained in
      a primary screen and in lead optimization. Although immobilized targets can be
      reused, the surface may slowly deteriorate, solvent effects can distort binding
      levels during injection of compounds, and some compounds may exhibit broad
      protein selectivity rather than target specificity. A reliable direct binding
      assay for compounds binding to immobilized thrombin using a combination of two
      reference surfaces, a dextran surface for subtraction and calibration of solvent
      effects and a protein surface for identification of compounds that tend to bind
      proteins, has been developed. Eleven compounds with known binding specificity to
      thrombin and 159 additional compounds were investigated. All compounds with known
      binding specificity were identified at 1 and 10 microM concentration. One
      additional compound was scored as positive. The direct binding assay compared
      favorably with two competitive assay formats, a surface competitive assay and a
      inhibitor in solution assay, that were examined in parallel.

PMID- 10640348
TI  - Quantitative analysis of a synthetic peptide, NR58-3.14.3, in serum by LC-MS with
      inclusion of a diastereomer as internal standard.
AB  - A method for quantifying an intramolecularly linked all-d-amino acid peptide,
      NR58-3.14.3, in rat serum by LC-MS using selected ion monitoring with inclusion
      of a diastereomer as internal standard was developed. The reproducible
      quantitation of multiply charged compounds by LC-MS using single ion or selective
      reaction monitoring is often a challenge as the intensity ratio of the ions in a
      series of different charge states can vary. Good precision was obtained in the
      selected ion monitoring mode by integrating the summed ion currents of the
      singly, doubly, and triply charged molecular ions. Since stable isotope analogs
      are costly and integration of residual unlabeled material can be of concern, a
      diastereomer of NR58-3.14.3, NR58-3.14.5, was used as internal standard. The
      diastereomers were indistinguishable by electrospray MS, but fully separated by
      reversed-phase LC. Consequently, interference due to isotopic impurities or
      coelution was not encountered. The calibration plot was linear throughout a
      concentration range of 0.2 to 200.0 microg/ml (r(2) = 0.9996). Intraday precision
      of the standards analyzed was less than 12% RSD over the calibration range and
      the accuracy within +/-11% RE. Serum pharmacokinetics were in good agreement with
      the pharmacokinetic profiles of small, ionic, and polar molecules.

PMID- 10640349
TI  - Direct electrochemistry of horseradish peroxidase immobilized on a
      colloid/cysteamine-modified gold electrode.
AB  - Direct electron transfer of immobilized horseradish peroxidase on gold colloid
      and its application as a biosensor were investigated by using electrochemical
      methods. The Au colloids were associated with a cysteamine monolayer on the gold
      electrode surface. A pair of redox peaks attributed to the direct redox reaction
      of horseradish peroxidase (HRP) were observed at the HRP/Au colloid/cysteamine
      modified electrode in 0.1 M phosphate buffer (pH 7.0). The surface coverage of
      HRP immobilized on Au colloid was about 7.6 x 10(-10) mol/cm(2). The sensor
      displayed an excellent electrocatalytic response to the reduction of H(2)O(2)
      without the aid of an electron mediator. The calibration range of H(2)O(2) was 1.
      4 microM to 9.2 mM with good linear relation from 1.4 microM to 2.8 mM. A
      detection limit of 0.58 microM was estimated at a signal-to-noise ratio of 3. The
      sensor showed good reproducibility for the determination of H(2)O(2). The
      variation coefficients were 3. 1 and 3.9% (n = 10) at 46 microM and 2.8 mM
      H(2)O(2), respectively. The response showed a Michaelis-Menten behavior at higher
      H(2)O(2) concentrations. The K(app)(M) value for the H(2)O(2) sensor was found to
      be 2.3 mM.

PMID- 10640350
TI  - Development of a binding assay for p53/HDM2 by using homogeneous time-resolved
      fluorescence.
AB  - The p53 tumor suppressor protein is activated and stabilized in response to DNA
      damage, resulting in cell cycle arrest or apoptosis. HMD2 is a negative regulator
      of p53. Binding of p53 by HDM2 traffics p53 from the nucleus to the cytoplasm
      where it is recognized and targeted for ubiquitin-mediated degradation (D. A.
      Freedman, L. Wu, and A. J. Levine, 1999, Cell. Mol. Life Sci. 55, 96-107).
      Several reports have suggested that disruption of this complex in normal cells
      results in p53 signaling (V. Bottger, A. Bottger, A. Sparks, W.-L. Liu, S. F.
      Howard, and D. P. Lane, 1997, Curr. Biol. 7, 860-869; C. Wasylyk, R. Salvi, M.
      Argentini, C. Dureuil, I. Delumeau, J. Abecassis, L. Debussche, and B. Wasylyk,
      1999, Oncogene 18, 1921-1934). A homogeneous time-resolved fluorescence (HTRF)
      assay has been developed to monitor p53/HDM2 binding. This assay employs a site
      specific biotinylated p53 protein, a GST-fused HDM2 protein, and two fluorophore
      conjugated detection reagents, streptavidin-XL665 and europium cryptate-labeled
      anti-GST antibody ?Eu(K)-anti-GST. Binding of p53 to HDM2 brings the fluorophores
      into close proximity, allowing fluorescence resonance energy transfer to occur.
      Development of this assay and comparison to a traditional ELISA are described in
      this report. The HTRF assay was then utilized to assess the effect of serine
      phosphorylation within the p53 N-terminus on HDM2 binding, and to determine the
      relative affinity of a p73 peptide for HDM2.

PMID- 10640351
TI  - A high-throughput assay to identify compounds that can induce dimerization of the
      erythropoietin receptor.
AB  - Erythropoietin induces dimerization of the erythropoietin receptor on the surface
      of erythroid progenitor cells, promoting the differentiation of these cells into
      mature red blood cells. To facilitate screening of large chemical collections for
      identification of compounds that can dimerize erythropoietin receptor, we have
      developed a novel, high-throughput in vitro assay to detect compounds that can
      cause dimerization of the erythropoietin receptor in solution. To develop this
      assay, amino acid sequences corresponding to the extracellular domain of
      erythropoietin receptor were expressed in Escherichia coli as erythropoietin
      binding protein (rEBP). A modified version of this protein ((33)P-rEBP)
      containing a protein kinase A substrate site incorporated into the rEBP was also
      expressed in E. coli and labeled in vitro using protein kinase A and ?gamma
      (33)PATP. An erythropoietin mimetic peptide (EMP-1), that induces dimerization of
      rEBP in solution was used to demonstrate dimerization of (33)P-rEBP and rEBP in a
      96-well microtiter plate format. EMP-1 induced dimerization of rEBP in this assay
      with an EC(50) of approximately 245 nM and had a maximal effect at 0.5-2 microM
      and required the presence of rEBP immobilized on the plate capable of binding EMP
      1. EMP-1-induced dimerization of (33)P-rEBP and rEBP was reversed by excess
      unlabeled rEBP and was not masked by complex mixtures such as whole cell fungal
      extracts. These data demonstrate the ability of (33)P-rEBP to dimerize with rEBP
      in vitro in a format that is fully compatible with high-throughput screening.

PMID- 10640352
TI  - A positive selection vector combining tetracycline resistance that eliminates the
      need for bacterial plating.
AB  - We describe here the construction of a plasmid that combines positive selection
      with tetracycline resistance. The vector comprises a modified version of the gene
      encoding the cytosine-specific DNA methyltransferase MspI and a modified form of
      the pBR322 tetA(C) gene. The combination of these two genes facilitates the
      selection of recombinant plasmids in broth cultures, thereby eliminating the need
      for bacterial plating.

PMID- 10640353
TI  - Two-dimensional relayed-rotating-frame overhauser spectroscopy (1)H NMR
      experiments for the selective identification of 1,2-glycosidic linkages in
      polysaccharides.
AB  - This communication describes the use of two-dimensional relayed (TOCSY)-ROESY
      experiments for the rapid and selective identification of alpha/beta1,2
      glycosidic linkages in polysaccharides. The method assists in the identification
      of cross-peaks in crowded regions of ROESY spectra by moving them to less
      congested areas. In addition, the appearance of the spectra provides information
      relating the location of the glycosidic linkage within the sequence of the glycan
      under study. Selection of solely the 1,2- linkages is achieved by appropriately
      tuning the duration of the TOCSY mixing period. The method is demonstrated both
      theoretically and experimentally for a variety of test case polysaccharides.

PMID- 10640354
TI  - Protein expression in Drosophila Schneider cells.
AB  - We expressed recombinant secreted, membrane, and cytosolic proteins in stably
      transfected Drosophila Schneider (SL-3) cells. To allow easy cloning of N- and C
      terminal fusion proteins containing epitope- and His-tags for the detection of
      recombinant proteins and purification by affinity chromatography we constructed
      new expression vectors. To exemplify the general applicability of protein
      expression in Schneider cells we characterized the expression system with respect
      to inducibility, localization of the recombinant proteins, yields of purified
      proteins, and presence of posttranslational and cotranslational modifications.
      Secreted proteins became quantitatively N-glycosylated in SL-3 cells and the N
      glycan of a Golgi-resident membrane protein was found to be Endo-H-resistant.
      Myristoylation of AnxXIIIb, a member of the annexin family, could be demonstrated
      and glycosylphosphatidylinositol-anchored proteins containing their lipid anchor
      were expressed efficiently in SL-3 cells. Since generation of stable cell lines
      and mass culture of SL-3 cells is cheap and easy, they provide an attractive
      eukaryotic expression system.

PMID- 10640355
TI  - Enzymatic synthesis and purification of uridine diphospho-beta-l-arabinopyranose,
      a substrate for the biosynthesis of plant polysaccharides.
AB  - Many plant cell wall components such as the polysaccharides xylans and pectins or
      the glycoproteins arabinogalactan proteins and extensins contain arabinosyl
      residues. The arabinosyl substituents are thought to be incorporated into these
      wall polymers by the action of arabinosyltransferases using UDP-l-arabinose as
      the precursor. UDP-l-arabinose is not commercially available and therefore a
      procedure for generating UDP-l-arabinose was developed for use in studies on the
      biosynthesis of the arabinose-containing polymers. In this procedure UDP-d-xylose
      is incubated with an enzyme preparation from wheat germ and the nucleotide sugars
      in the reaction mixture are extracted. High-performance anion-exchange
      chromatography of the extract resolves two major UV-absorbing components: one
      corresponding to UDP-xylose and a second that elutes earlier. TLC analysis of
      collected and hydrolyzed fractions demonstrated the presence of l-arabinose in
      the early eluting fraction. Further analysis by NMR identified the compound as
      UDP-beta-l-arabinopyranose. The procedure reported here provides an efficient
      method for preparing either radioactive UDP-l-[(14)C]arabinose or nonradioactive
      UDP-l-arabinose and can also be used as an assay for UDP-xylose-4-epimerase
      activity.

PMID- 10640356
TI  - Dilution enhancement of COS cell expression cloning.
AB  - To search for an efficient expression cloning method, we mixed plasmid pmDATsv,
      which contains the mouse dopamine transporter (mDAT) cDNA, with a large amount of
      another plasmid prGlyTsv to mimic the situation of a cDNA library and examined
      COS cell expression. Both plasmids have an SV40 replication origin and thus will
      be replicated to high copy numbers in COS cells. After transfecting COS-7 cells
      with pmDATsv/prGlyTsv mixture at 1/1000 ratio, we could not detect any cells
      expressing strong mDAT activity. In contrast, when prGlyTsv was replaced by
      prSERTsk (no SV40 origin) in the transfection mixture, we observed hundreds of
      cells expressing strong mDAT activity. The results suggested that in many cells
      low mDAT expression was not due to the lack of pmDATsv plasmid but due to the
      presence of large numbers of replicable prGlyTsv. Analysis with a mathematical
      model suggests that diluting cDNA libraries with other plasmids without the SV40
      origin should improve the detection of COS cells expressing target cDNAs. We
      tested this conclusion with pmDATsv/prGlyTsv mixture. When the mixture at 1/1000
      ratio was diluted with prSERTsk and used for transfection, we could now easily
      detect cells expressing strong mDAT activity.

PMID- 10640357
TI  - Nitric oxide form of a pyridylphenylurea is a potent inducer of shoot formation
      in plant tissue cultures.

PMID- 10640358
TI  - Refinements of the differential display reverse transcription-polymerase chain
      reaction technique: use of oligo(dT)-based anchored primers with Escherichia coli
      messenger RNA identifies a salt-induced promoter in the dcw gene cluster.

PMID- 10640359
TI  - A scalable protocol for the isolation of large-sized genomic DNA within an hour
      from several bacteria.

PMID- 10640360
TI  - DNA/Calcium phosphate precipitates mixed with medium are stable and maintain high
      transfection efficiency.

PMID- 10640361
TI  - Evolutionary ecology of human life history.
AB  - The human life history is characterized by several unusual features, including
      large babies, late puberty and menopause, and the fact that there is a strong
      cultural influence on reproductive decisions throughout life. In this review I
      examine human life history from an evolutionary ecological perspective. I first
      review the evidence for life history trade-offs between fertility and mortality
      in humans. Patterns of growth, fertility and mortality across the life span are
      then discussed and illustrated with data from a traditional Gambian population.
      After outlining the stages of the human life course, I discuss two phenomena of
      particular interest in evolutionary anthropology, both of which are apparently
      unique to humans and neither yet fully understood. First, I discuss the evolution
      of menopause, the curtailing of female reproduction long before death. The
      evidence that this evolved because investment in existing children's future
      reproductive success is more important than continuing child bearing into old age
      is reviewed, along with data relating to the biological constraints that may be
      operating. Second, I discuss the demographic transition. Declining fertility at a
      time of increasingly abundant resources represents a serious challenge to an
      evolutionary view of human life history and behaviour, and is thus examined in
      detail. Parental investment in children in competition with each other may be key
      to understanding both of these unusual human phenomena. Copyright 2000 The
      Association for the Study of Animal Behaviour.

PMID- 10640362
TI  - Differences in potential reproductive rates of male and female seahorses related
      to courtship roles.
AB  - Dwarf seahorses, Hippocampus zosterae (Syngnathidae), are distinguished by
      extreme morphological specialization for paternal care, the formation of
      monogamous pair bonds and mating repeatedly over the course of a breeding season.
      To determine the potential reproductive rates of male and female dwarf seahorses,
      we measured (1) the maximum number of offspring produced per breeding cycle when
      sexually receptive mates were unlimited, and (2) the relative time each sex was
      unavailable for mating ('time out'). We paired sexually isolated males and
      females with sexually receptive partners and observed them from the day of
      introduction through to copulation, to determine the length of time it takes each
      sex to prepare to mate. We conducted additional experiments to determine the
      length of gestation, which when added to the time needed to prepare to mate and
      copulate gives an estimate of total reproductive cycle duration, T. We estimated
      potential reproductive rate by dividing the mean number of offspring produced per
      breeding cycle by the duration of the breeding cycle (T). We estimated
      reproductive 'time out' by identifying the period of time males and females were
      physiologically capable of mating ('time in', S) and subtracting time S from time
      T. When provided with sexually receptive partners, females took 2 days longer
      than males to complete courtship and copulation, but neither males nor females
      remated during gestation. Therefore, males could potentially produce 17% more
      offspring than females over the course of one breeding season. Females had
      reproductive 'times out' 1.2 times longer than did males, as they were only
      capable of mating during the 4 h directly preceding copulation. Thus, H. zosterae
      males have higher potential reproductive rates and shorter reproductive 'times
      out' compared with H. zosterae females. These results and previous work
      indicating that seahorses display traditional courtship roles support the
      prediction that the sex having the higher potential reproductive rate, or
      equivalently, the shorter 'time out', will compete more intensely for access to
      the opposite sex. Copyright 2000 The Association for the Study of Animal
      Behaviour.

PMID- 10640363
TI  - Song-type matching between neighbouring song sparrows.
AB  - In our study population, neighbouring song sparrows typically share two or more
      of their 6-10 song types. In an earlier experiment, we found that established
      neighbours typically reply to playback of neighbour-shared song with a different
      song they share with that neighbour ('repertoire matching'), rather than with the
      same song ('type matching') or with a nonshared song. In the present experiment,
      we considered the hypothesis that type matching is a threat or warning signal
      (Krebs et al. 1981, Animal Behaviour, 29, 918-923). We tested the specific
      prediction that a bird is more likely to type-match early in the breeding season
      when territory boundaries are new and still unstable, and more likely to
      repertoire-match later in the season, once those boundaries have become well
      established. Birds were played a shared song of a new neighbour once early
      (April) and again late (June) in the breeding season. As predicted, early in the
      season birds usually type-matched the playback (73% of the trials) but late in
      the season they type-matched only rarely (18%); birds never replied (early or
      late) with a nonshared song type. Copyright 2000 The Association for the Study of
      Animal Behaviour.

PMID- 10640364
TI  - Territory tenure in song sparrows is related to song sharing with neighbours, but
      not to repertoire size.
AB  - Song repertoires may be a product of sexual selection and several studies have
      reported correlations of repertoire size and reproductive success in male
      songbirds. This hypothesis and the reported correlations, however, are not
      sufficient to explain the observation that most species have small song
      repertoire sizes (usually fewer than 10, often fewer than five song types). We
      examined a second important aspect of a male's song repertoire, the extent to
      which he shares songs with his neighbours. Song sharing has not been measured in
      previous studies and it may be partially confounded with repertoire size. We
      hypothesized that in song sparrows, Melospiza melodia, song sharing rather than
      repertoire size per se is crucial for male territorial success. Our longitudinal
      study of 45 song sparrows followed from their first year on territory showed that
      the number of songs a bird shares with his neighbourhood group is a better
      predictor of lifetime territory tenure than is his repertoire size. We also found
      that song sharing increases with repertoire size up to but not beyond eight to
      nine song types, which are the most common repertoire sizes in the population
      (range in our sample 5-13). This partial confound of song sharing and repertoire
      size may account for some earlier findings of territory tenure-repertoire size
      correlations in this species and other species having small- or medium-sized
      repertoires. Copyright 2000 The Association for the Study of Animal Behaviour.

PMID- 10640365
TI  - Rearing environment affects behaviour of jumping spiders.
AB  - We tested the effect of rearing conditions on the behaviour of jumping spiders,
      Phidippus audax. Spiders were assigned randomly to either small or large cages
      that either were empty or contained a painted dowel. Laboratory-reared spiders
      were raised from second instar to adult in these environments. Field-caught
      adults also were randomly assigned to these containers and were held for
      approximately 4 months prior to testing. We presented spiders with three tests
      designed to examine a range of behaviours. Field-caught spiders were more likely
      than laboratory-reared spiders to (1) react to videotaped prey, (2) progress
      further on a detour test, and (3) be less stereotactic and more active in an open
      field. Larger cage size and the presence of the dowel also improved performance
      in several tests. Our results suggest that the rearing conditions we used, which
      are commonly employed by behavioural researchers, may profoundly influence the
      behaviour of adult spiders. Copyright 2000 The Association for the Study of
      Animal Behaviour.

PMID- 10640366
TI  - Nest spacing in relation to settlement time in colonial cliff swallows.
AB  - How colonial animals space their nests in relation to conspecifics may provide
      clues as to whether coloniality provides net benefits or occurs only because
      breeding sites are limited. We examined how nearest-neighbour distance varied in
      relation to settlement time in the highly colonial cliff swallow, Petrochelidon
      pyrrhonota, comparing observed nearest-neighbour distances to those expected if
      birds spread out to maximize nest spacing. Cliff swallows generally settled
      closer to each other than required by the available substrate, and clustered
      their nests closer in large colonies than in small ones. The first settlers at a
      colony site spaced themselves further apart than later arrivals but did not
      maximize nearest-neighbour distances. The first arrivals maintained greater nest
      spacing throughout the season than did birds that arrived later. Colony size and
      amount of nesting substrate had no effect on initial settlement distances of the
      first arrivals, but eventual nearest-neighbour distances declined with colony
      size. First arrivals may gain less from nesting with conspecifics and thus are
      less likely to cluster their nests than later arrivals, which may often be young
      or naive birds that gain more from the social benefits of colonial nesting. The
      results are consistent with the presumed social advantages cliff swallows receive
      from coloniality and do not support the hypothesis that colonies result from
      nesting site limitation. Copyright 2000 The Association for the Study of Animal
      Behaviour.

PMID- 10640367
TI  - Avian dependence on sound pressure level as an auditory distance cue.
AB  - Sound pressure level (SPL) has received little attention as a distance cue or
      signal for communication because of the methodological difficulty of determining
      source SPL from free-ranging signallers and because SPL is presumed to be
      unreliable as a distance cue. Eastern towhees, Pipilo erythrophthalmus
      (Emberizidae, Passeriformes), in south-central Florida give a simple call during
      territorial interactions. I obtained measurements of call-source SPL with a
      calibrated microphone positioned 100+/-10 cm from caged male eastern towhees.
      Measurements of source SPL were highly variable, but much of this variation can
      be predicted from measurements of call duration or call frequency variables
      (spectrotemporal variables). Male towhees accurately perceived the distance of a
      speaker after it played synthetic calls that matched the amplitude and structure
      of natural 84-dB and 78-dB call types. Subjects flew further in response to an
      attenuated (-6 or -12 dB) version of an otherwise identical 84-dB call and flew
      shorter in response to an amplified (+6 dB) version of this same call. Towhees
      misjudged speaker distance in approximately half of the trials that included a
      discrepancy (-6, -12 or +6 dB SPL) between playback source SPL and predicted
      spectrotemporal variables. These distance errors suggest that towhees assess
      auditory distance partly from the difference between perceived SPL and source
      SPL, determined from spectrotemporal variables. Copyright 2000 The Association
      for the Study of Animal Behaviour.

PMID- 10640368
TI  - Imprinting and the origin of parasite-host species associations in brood
      parasitic indigobirds, Vidua chalybeata.
AB  - Brood-parasitic village indigobirds, Vidua chalybeata, were bred in captivity and
      foster-reared by their normal host species, the red-billed firefinch,
      Lagonosticta senegala, or by an experimental foster species, the Bengalese finch,
      Lonchura striata. Captive-reared female indigobirds were tested as adults for
      mate choice and for host choice. In tests of mate choice, female indigobirds
      responded preferentially towards mimicry songs of male indigobirds that were
      similar to those of the females' own foster parents. Females reared by Bengalese
      finches responded to male songs that mimicked Bengalese finch song rather than to
      male songs that mimicked their normal host species, the firefinch. In tests of
      host choice, females reared by Bengalese finches laid in the nests of Bengalese
      finches, and females reared by firefinches laid in the nests of firefinches. Wild
      caught females showed the same behaviours as captive-bred females reared by
      firefinches. A female indigobird's social companions (firefinch or Bengalese)
      following her independence of her foster parents had no effect on her sexual
      response to male mimicry song or her choice of a host species in brood
      parasitism. The results support the predictions of a model of imprinting-like
      behaviour development in which young indigobirds focus their attention on their
      foster parents, rather than a model of innate bias for songs and nests of their
      normal host species, or a null model of nonspecific brood parasitism and
      differential survival. The results provide experimental support for the recent
      origin of brood parasite-host associations and the significance of imprinting in
      speciation in these brood parasites. Copyright 2000 The Association for the Study
      of Animal Behaviour.

PMID- 10640369
TI  - An evaluation of video playback using Xiphophorus helleri.
AB  - Video playback is being increasingly used as a technique for behavioural
      research. The importance of critically evaluating the effectiveness of video
      playback is clear, as available video technology is not designed for nonhuman
      visual systems. We discuss several aspects concerning the perception of video
      images that could lead to inconclusive or erroneous results. Researchers should
      verify that behaviour observed in response to video playback is comparable to
      behaviour observed in response to live animals. We conducted such a verification
      using live and video playback methods to measure female response to swords of
      varying lengths in the green swordtail, Xiphophorus helleri. Using both methods,
      female response appeared to be an increasing function of male sword length.
      Females did not differ in their response to live and video versions of
      noncourting, noninteractive males, however, females tended to prefer video
      playbacks of males with longer swords, a result that has also been found in
      experiments using live males. These results suggest that females express the same
      qualitative mating preference, but not necessarily the same quantitative
      preference, for sword length when viewing video stimuli. Several methodological
      factors that may contribute to an apparent difference in the strength of the
      preference are discussed. Despite these differences, both methods produced
      comparable results; female response to sworded males tended to increase as sword
      length increased. These experiments demonstrate that video playback is an
      effective method to measure female preferences accurately in X. helleri and
      provide an example of how video playback can be evaluated in other species.
      Copyright 2000 The Association for the Study of Animal Behaviour.

PMID- 10640370
TI  - Perception of the pollen need by foragers in a honeybee colony.
AB  - Honeybees, Apis mellifera, adjust their pollen foraging activity according to the
      need for pollen within the colony, determined by the amount of stored pollen and
      young brood present in the hive. To clarify how pollen foragers detect the supply
      of pollen, we followed individual honeybees while they were returning with
      pollen. Pollen foragers deposited their loads on the frame where most of the
      unsealed brood was, independent of the position of this frame within the hive.
      They also inspected more cells on that frame and spent most of their time there,
      indicating that pollen foragers may individually evaluate the pollen requirements
      of the colony. In 18 normal-sized colonies we also tested whether olfactory cues
      provided by a frame of hungry young brood or an additional pollen frame covered
      by cages affect foraging activity. These experiments showed that olfactory
      stimulation within the colony is insufficient to increase or decrease the
      foraging effort, but suggest that foragers must have direct contact with the
      brood and pollen area to regulate their foraging activity according to the
      conditions in the colony. The different mechanisms by which foragers may gather
      the information about pollen supply are discussed. Copyright 2000 The Association
      for the Study of Animal Behaviour.

PMID- 10640371
TI  - The influence of queen age and quality during queen replacement in honeybee
      colonies.
AB  - Honeybee, Apis mellifera, colonies replace their queens by constructing many
      queen cells and then eliminating supernumerary queens until only one remains. The
      ages of the queens and the variation in their reproductive potential are
      important factors in the outcome of such events. Selection would favour colonies
      that requeen as quickly as possible to minimize the brood hiatus, therefore
      selecting for queens reared from older larvae. Conversely, reproductive potential
      (queen 'quality') is maximized by rearing queens from younger larvae. This
      potential trade-off was tested during two phases of queen replacement, namely
      queen rearing and polygyny reduction. Our results suggest that queen age is a
      significant element during both queen rearing and polygyny reduction, whereas
      queen quality, at least to the magnitude tested in this experiment, has little
      impact on the outcome of either process. The rate of queen replacement therefore
      appears to be an important factor in the honeybee life cycle, and further
      mechanisms of potential importance during this life history transition are
      discussed. Copyright 2000 The Association for the Study of Animal Behaviour.

PMID- 10640372
TI  - Status signalling, metabolic rate and body mass in the siskin: the cost of being
      a subordinate.
AB  - The higher metabolic rate of dominant individuals, found in different species,
      has been interpreted as the cost that prevents subordinates from cheating by
      adopting large badges of status. However, an alternative prediction for status
      signalling species, in which subordinates may recognize dominants, is that
      subordinates have the higher metabolic rate because of the greater stress of
      locating and actively avoiding aggressive interactions with them. In this study,
      the size of the black bib of the siskin, Carduelis spinus, which is a badge of
      dominance, was negatively correlated with metabolic rate in daylight, even when
      controlling for the bird's activity level in the respirometer chamber and its
      body mass. The size of the black bib, however, was not correlated with metabolic
      rate in darkness. This suggests that the difference between dominance classes is
      not related to intrinsic physiological differences, but that subordinates are
      more susceptible to stressful conditions. When controlling for metabolic rate, a
      positive correlation appeared between dominance status and body mass. This
      stresses the importance of knowing the effects of social status on energy
      requirements for understanding the relationship between body mass and dominance.
      We conclude that maintaining a high social status may be more stressful to
      subordinates than to dominant birds. Copyright 2000 The Association for the Study
      of Animal Behaviour.

PMID- 10640373
TI  - Colour bands, mate choice and paternity in the bluethroat.
AB  - Studies of several bird species have shown that coloured leg bands may affect a
      male's success in mate attraction and/or mating competition. From a colour band
      experiment in the field, we have previously reported that male bluethroats,
      Luscinia s. svecica, with blue and orange bands (BO males) guarded their mates
      less intensely at the peak of female fertility, and spent more time advertising
      for additional mates, than males banded with non-BO colours. These responses
      indicated that BO males experienced less threat to their paternity than did non
      BO males, possibly mediated through an increased attractiveness. Here we present
      paternity analyses of the broods from the field study and test whether there were
      differences between the two male groups in within-pair or extrapair paternity.
      There were no significant differences between the two groups of males in
      paternity, suggesting effective male protection of paternity. However, extrapair
      paternity was infrequent in the 2 years of the field experiment; hence, the power
      in detecting effects on paternity does not allow a definitive conclusion on this
      issue. We also conducted an aviary experiment in which females were given the
      choice between a BO male and a non-BO male, to test whether females had
      preferences for particular colour bands. Females did not associate more with BO
      males, as would have been expected if these males were more attractive in social
      mate choice. Our results suggest that the effects of colour bands on social mate
      choice and paternity are, at best, weak. Copyright 2000 The Association for the
      Study of Animal Behaviour.

PMID- 10640374
TI  - Female mate choice for large males in several species of seaweed fly (Diptera:
      Coelopidae).
AB  - The mating system of the seaweed fly Coelopa frigida involves a vigorous
      premating struggle during which females attempt to dislodge mounted males by
      kicking and shaking from side to side. Additionally females can prevent
      engagement of genitalia by curling their abdomens downwards. Large males gain a
      mating advantage. Male size is partially determined by a chromosomal inversion
      polymorphism which is maintained by strong heterosis. Thus female mate choice on
      the basis of size will affect offspring fitness. We report the occurrence of
      premating struggles and mate choice for large males in five additional species of
      seaweed fly, namely, C. nebularum, C. vanduzeei, C. pilipes, Gluma musgravei and
      G. nitida. Four of these species appear to lack the inversion system, suggesting
      that mate choice for large males can be maintained in its absence and also
      evolved before its establishment. Gluma females had stronger preferences than
      Coelopa females and showed an additional response to mounting, namely, curling
      their abdomens upwards into the male. This may allow assessment of male size.
      Copyright 2000 The Association for the Study of Animal Behaviour.

PMID- 10640375
TI  - Flexible spatial organization of urban foxes, Vulpes vulpes, before and during an
      outbreak of sarcoptic mange.
AB  - The social and spatial organization of urban fox groups prior to and during an
      outbreak of sarcoptic mange was compared with predictions derived from the
      resource dispersion hypothesis (RDH). We investigated the availability of three
      key resources. Neither daytime rest sites nor breeding sites appeared to be
      limited in availability. The availability of food deliberately supplied by local
      householders was examined by questionnaire surveys. The daily and weekly amount
      of food supplied was greatly in excess of the minimum requirements of a pair of
      foxes, but was consistent between territories. The availability of this food
      source increased markedly as a result of more people feeding the foxes. In
      agreement with the RDH, group size prior to the outbreak of mange increased from
      2.25 animals (N=4) to 6.57 animals (N=7). Before the outbreak of mange, two
      territories were divided. Increased scavenge availability on smaller territories
      may have promoted these changes. Excluding these spatial changes, territories
      were very stable between years. After the outbreak of mange, group size declined
      as a direct result of mange-induced mortality. Surviving animals increased their
      ranges only after neighbouring groups had died out. Ranges did not increase in
      size in response to a decline in food availability. Nor were the increases in
      range size associated with the relinquishment of parts of the existing territory.
      These postmange changes are contrary to the RDH. Three factors may have promoted
      these changes: the elimination of interstitial space, the forced dispersal of
      young or future division of the territory. Copyright 2000 The Association for the
      Study of Animal Behaviour.

PMID- 10640376
TI  - Social control of reproduction in banded mongooses.
AB  - Recent theoretical work suggests that the distribution of reproduction, or degree
      of reproductive skew, in animal societies depends crucially on (1) whether
      dominant individuals can fully control subordinate reproduction, and (2) how
      subordinate reproduction affects the fitness of dominants. I investigated these
      two factors in cooperatively breeding banded mongooses, Mungos mungo. Female
      packmates entered oestrus together and were closely guarded by dominant males.
      These males were aggressive to subordinate males who attempted to mate, but
      females still managed to mate with males other than their mate guard. Older
      females were guarded and mated a few days before their younger packmates, yet all
      females usually gave birth on the same day, suggesting that older females may
      have a longer gestation period. Moreover, older females carried more fetuses.
      Overall, ca. 83% of adult females conceived in each breeding attempt and 71%
      carried to term. These results indicate that, among males, dominant individuals
      did not have full control over the mating attempts of subordinates (since they
      could not fully control the mating behaviour of the females they guarded), while
      among females there was little or no attempt to prevent subordinates from
      breeding (at least, prior to parturition). Two within-group infanticides by males
      suggested that some control over reproduction may be exercised postpartum. Per
      capita survivorship of young in the den increased with the number of females who
      gave birth. Thus, dominant females may benefit from subordinate reproduction,
      providing a possible explanation for the lack of reproductive suppression among
      females in this species. Copyright 2000 The Association for the Study of Animal
      Behaviour.

PMID- 10640377
TI  - Analysis of the finescale timing of repeated signals: does shell rapping in
      hermit crabs signal stamina?
AB  - Hermit crabs, Pagurus bernhardus, sometimes exchange shells after a period of
      shell rapping, when the initiating or attacking crab brings its shell rapidly and
      repeatedly into contact with the shell of the noninitiator or defender in a
      series of bouts. Bouts are separated by pauses, and raps within bouts are
      separated by very short periods called 'gaps'. Since within-contest variation is
      missed when signals are studied by averaging performance rates over entire
      contests, we analysed the fine within-bout structure of this repeated, aggressive
      signal. We found that the pattern is consistent with high levels of fatigue in
      initiators. The duration of the gaps between individual raps increased both
      within bouts and from bout to bout, and we conclude that this activity is costly
      to perform. Furthermore, long pauses between bouts is correlated with increased
      vigour of rapping in the subsequent bout, which suggests that the pause allows
      for recovery from fatigue induced by rapping. These between-bout pauses may be
      assessed by noninitiators and provide a signal of stamina. Copyright 2000 The
      Association for the Study of Animal Behaviour.

PMID- 10640378
TI  - The influence of nutritional status on the feeding behaviour of the field slug,
      Deroceras reticulatum (Muller).
AB  - The field slug, Deroceras reticulatum, a common pest of agricultural and
      horticultural crops, is a generalist herbivore with distinct preferences for
      particular food items. However, these preferences are not fixed, but are
      influenced by the recent dietary history of the slugs. In particular, slugs tend
      to select novel food items ('neophilia'). We investigated the basis of such
      influences, using artificial diets in which protein and carbohydrate composition
      could be controlled and non-nutritional ('secondary') chemicals added as
      flavours. The slugs showed no general inclination for neophilia based on taste
      alone. There was a possible learned association between protein content and
      taste, but this was weakly expressed. However, the slugs selected food items,
      when given a choice, containing nutrients that were deficient in earlier diets,
      even though all the food items contained the same familiar secondary taste
      chemicals. Injections of missing nutrients into the haemocoel of slugs inhibited
      such changes in food preference, indicating that slugs' feeding preferences are
      influenced directly by their internal nutritional status. We suggest that
      neophilia in D. reticulatum is a physiological response to a nutritional
      imbalance arising from a suboptimal diet. Copyright 2000 The Association for the
      Study of Animal Behaviour.

PMID- 10640379
TI  - Fluctuating asymmetry, size and mating success in males of Ischnura elegans
      (Vander Linden) (Odonata: Coenagrionidae).
AB  - Fluctuating asymmetry (FA) is thought to be an indicator of developmental
      stability and negatively related to male mating success in many animal taxa. We
      investigated the relationships between mating success of males, body size and FA
      for both wing length and number of setae on the legs in the damselfly Ischnura
      elegans. Males were classified as mated or unmated at the time of sampling.
      Fluctuating asymmetry, expressed as right-left differences, showed normal
      distributions without evidence of directional asymmetry or antisymmetry.
      Univariate analyses showed a significant negative correlation between size and
      mating success, and significant negative correlations between FA and mating
      success for both characters. On the other hand, with a multivariate analysis, new
      to studies on FA, the effect of body size was still significant but FA did not
      reach significance for either character. We conclude that the multivariate
      analysis should be used to assess the role of the different factors affecting
      mating success. Copyright 2000 The Association for the Study of Animal Behaviour.

PMID- 10640380
TI  - Male size does not affect territorial behaviour and life history traits in a
      sphecid wasp.
AB  - The optimum maternal investment per offspring is determined by the relationship
      between the investment per offspring and offspring fitness. In the European
      beewolf, Philanthus triangulum, a solitary mass-provisioning sphecid wasp,
      offspring size correlates with the amount of provisions. We investigated whether
      the reproductive success of adult males depends on body size in a way that would
      influence the allocation of parental investment. Since the mating success of P.
      triangulum males cannot be determined by observation in the field, we assessed
      the influence of male size on characteristics of their territories, territorial
      behaviour and life history traits. Territory size was weakly correlated with male
      size, but a measure of territory quality (number of female nests in the vicinity)
      was independent of male size. Neither the duration of ownership nor the intensity
      of scent marking was correlated with male size. Territory owners were slightly
      smaller than nonterritorial males. The absolute amount of fat was positively
      correlated with size but, owing to allometric relationships, the energetic
      equivalent of the fat store appeared to be independent of size. Life span was not
      significantly influenced by body size under four different conditions (with and
      without food in the laboratory, in an outdoor flight cage and in the field). We
      discuss the discrepancy between these results and other studies that have mostly
      reported advantages to large males. We suggest that in noncontact male-male
      interactions, as seen in the European beewolf, body size might not be the key
      determinant for success in contests. We conclude that there is no evidence for a
      strong size dependence of male reproductive success. Thus the reproductive
      success of male progeny probably does not depend on parental investment in a way
      that would influence the investment allocation of females. Copyright 2000 The
      Association for the Study of Animal Behaviour.

PMID- 10640381
TI  - What, if anything, does visual asymmetry in fallow deer antlers reveal?
AB  - Fluctuating asymmetry (FA), small directionally random deviations from perfect
      bilateral symmetry, is thought to reflect individual quality. Furthermore, it has
      been suggested that FA in secondary sexual characters can be used to assess mate
      or opponent quality during inter- or intrasexual competition. Studies on fallow
      deer, Dama dama, have suggested that FA in antlers reflects individual dominance,
      or the existence of a directional asymmetry (DA) with right antlers being
      consistently more developed than left antlers. To test these conflicting
      hypotheses, we analysed relationships between age, dominance and asymmetry in the
      number of antler points on mature fallow deer males during four rutting seasons
      in a single population. Age and dominance were only weakly correlated. The number
      of antler points displayed a pattern of DA (more points on the right than on the
      left side) that increased with age. Although dominance tended to increase with
      the total number of antler points, there was no relationship between the level of
      DA and dominance. These results failed to support the hypothesis that antler
      asymmetry visually reveals individual quality in fallow deer. Copyright 2000 The
      Association for the Study of Animal Behaviour.

PMID- 10640382
TI  - Female mate guarding: no evidence in a socially monogamous species.
AB  - To understand the behavioural aspects of sperm competition, the costs and
      benefits to both sexes should be considered. However, few studies have addressed
      the costs to females of their social mate engaging in extrapair copulations
      (EPCs). Measures of female mate guarding have concentrated on female solicitation
      and copulation; however, females may also control access to their mate by
      maintaining close proximity, as is common in males. I recorded the maintenance of
      pair proximity behaviour of an urban population of the socially monogamous
      European blackbird, Turdus merula, over three breeding seasons. There was no
      evidence that females guarded their mates to prevent them from engaging in EPCs,
      nor were there any effects of the potential quality indicators of age, body size
      or male bill colour on the intensity of mate guarding between individuals. The
      study adds to a small body of literature suggesting that female mate guarding may
      be found in (facultatively) polygynous species, but not in socially monogamous
      ones. Copyright 2000 The Association for the Study of Animal Behaviour.

PMID- 10640383
TI  - Causal knowledge of predators' behaviour in wild Diana monkeys.
AB  - Wild Diana monkeys, Cercopithecus diana, of Tai forest, Ivory Coast, are preyed
      upon by leopards, Panthera pardus, and chimpanzees, Pan troglodytes. These two
      predators differ in their main hunting tactic and Diana monkeys attempt to avoid
      predation with two distinct antipredator strategies: conspicuous alarm-calling
      behaviour to leopards and silent, cryptic behaviour to chimpanzees. However, the
      Diana monkeys' choice of the appropriate antipredator strategy is complicated by
      the fact that chimpanzees themselves also fall prey to leopards. Chimpanzees give
      loud and conspicuous alarm screams when they detect a leopard. When these
      chimpanzees' leopard alarm calls were played back to different groups of Diana
      monkeys, in about half of the cases recipients switched from a chimp-specific
      cryptic response to a leopard-specific conspicuous response, suggesting that some
      individuals assumed the presence of a leopard. Groups whose home range was in the
      core area of the resident chimpanzee community were more likely to respond this
      way than more peripheral groups, indicating between-group differences in semantic
      knowledge. In a follow-up experiment, the monkeys' understanding of the
      chimpanzee alarm calls was further assessed with a prime-probe technique. Monkeys
      were primed with chimpanzee alarm calls and then, 5 min later, tested with
      leopard growls to see whether they were able to anticipate the presence of a
      leopard. Results were consistent with the hypothesis that monkeys responding
      cryptically to chimpanzee alarm calls did so because they were not able to
      understand the calls' meaning. Data are discussed with respect to three possible
      cognitive mechanisms, associative learning, specialized learning programmes, and
      causal reasoning, that could have led to causal knowledge in some individuals but
      not others. Copyright 2000 The Association for the Study of Animal Behaviour.

PMID- 10640384
TI  - Cheating as a mixed strategy in a simple model of aggressive communication.
AB  - The possibility that frequency-dependent cheating can persist in an
      evolutionarily stable communication system has frequently been proposed. Although
      there is empirical evidence for this idea, however, it has not been investigated
      in terms of game theory. In the present paper I show for a simple symmetric game
      that cheating can be part of a mixed evolutionarily stable strategy (ESS).
      Furthermore, despite the widespread assumption that cheaters must be rare, I show
      that most of the population can be cheaters, while the signalling system remains
      evolutionarily stable. Consequences for signalling theory and experiments to
      detect such mixed ESS are discussed. Copyright 2000 The Association for the Study
      of Animal Behaviour.

PMID- 10640385
TI  - Response to changes in food palatability in tufted capuchin monkeys, Cebus
      apella.
AB  - Palatability of plant foods may change over time in relation to the concentration
      of toxic secondary metabolites. We investigated the behavioural response of
      capuchin monkeys to this type of change and assessed the influence of social
      conditions. Twenty-seven tufted capuchin monkeys were presented in Social or
      Individual conditions with a familiar palatable food (phase 1), with the same
      familiar food to which pepper had been added, making it unpalatable (phase 2),
      and with the same familiar palatable food of phase 1 (phase 3). Five sessions
      were carried out in each phase. The capuchins adapted quickly to the change in
      food palatability by reducing (phase 2) and increasing (phase 3) the amounts of
      food eaten. The unpalatable food prompted an increase in olfactory exploration
      and in food processing. The experimental conditions (Social versus Individual)
      did not influence consumption, or any of the other behaviours. In addition,
      capuchins were more often near subjects with food in phases 2 and 3 in which
      palatability changed than in phase 1. These findings show that capuchins readily
      adjust to changes in flavour and palatability of a familiar food and that sudden
      unpalatability has no carry-over effects. Therefore, capuchins behave differently
      towards a familiar food whose palatability has changed than they do towards novel
      foods. Copyright 2000 The Association for the Study of Animal Behaviour.

PMID- 10640386
TI  - Finding an appropriate order for a hierarchy: a comparison of the I&SI and the
      BBS methods.

PMID- 10640387
TI  - Guidelines for the treatment of animals in behavioural research and teaching.

PMID- 10640388
TI  - Butterfly contests: contradictory but not paradoxical.

PMID- 10640389
TI  - Secretion and purification of recombinant beta1-4 galactosyltransferase from
      insect cells using pFmel-protA, a novel transposition-based baculovirus transfer
      vector.
AB  - The palette of transfer vectors available for generation of recombinant
      baculoviruses based on transposition-mediated recombination has been enlarged by
      constructing the pFmel-protA vector. The pFmel-protA plasmid includes the
      honeybee melittin secretion signal and a Staphylococcus aureus protein A fusion
      protein tag, which allows the secretion and purification of recombinant proteins.
      Using this system, the human beta1-4 galactosyltransferase-I protein was
      expressed in Sf9 insect cells at a level ranging from 22 to 28 U (4.8 to 6.0
      mg)/L. The protein A tag enabled a simple monitoring of recombinant protein
      expression by enzyme-linked immunosorbent assay and Western blotting. Single step
      purification was achieved by immunoglobulin G affinity chromatography achieving a
      recovery yield of 28% and a specific activity of 1.9 U per mg of recombinant
      protein.

PMID- 10640390
TI  - Kinetic analysis of the binding of Ulex europeas agglutinin 1 (UEA 1) to H
      antigenic fucolipid.
AB  - The kinetics and thermodynamics of Ulex europeas agglutinin 1-H-antigenic
      determinant was studied by monitoring the binding of the lectin to H-antigenic
      fucolipid incorporated in liposomes tethered to the sensor surface by surface
      plasmon resonance. The second-order rate constants for the interactions are
      several order of magnitude slower than the diffusion controlled reactions.
      Analyses of activation parameters reveals that these slow second-order rate
      constants are a consequence of an unfavorable activation enthalpy term.

PMID- 10640391
TI  - Specificities of heparin-binding sites from the amino-terminus and type 1 repeats
      of thrombospondin-1.
AB  - Interactions of heparin with intact human thrombospondin-1 (TSP1) and with two
      heparin-binding fragments of TSP1 were characterized using chemically modified
      heparins, a vascular heparan sulfate proteoglycan, and a series of heparin
      oligosaccharides prepared by partial deaminative cleavage. The avidity of TSP1
      binding increased with oligosaccharide size, with plateaus at 4 to 6 and at 8 to
      10 monosaccharide units. The dependence on oligosaccharide size for binding to
      the recombinant amino-terminal heparin-binding domain of TSP1 was the same as
      that of the intact TSP1 molecule but differed from that of a synthetic heparin
      binding peptide from the type 1 repeats, suggesting that the interaction between
      intact TSP1 and heparin is primarily mediated by the amino-terminal domain. Based
      on activities of chemically modified heparins, binding to TSP1 depended primarily
      on 2-N- and 6-O-sulfation of glucosamine and to a lesser degree on 2,3-O
      sulfation and the carboxyl residues of the uronic acids. In contrast, all of
      these modifications were required for binding of heparin to the type 1 repeat
      peptides. Affinity purification of heparin octasaccharides on immobilized TSP1
      type 1 repeat peptides revealed a preference for oligosaccharides containing the
      disaccharide sequence IdoA(2-OSO(3))alpha1-4-GlcNS(6-OSO(3)). Binding of these
      oligosaccharides to the peptide required the Trp residues. These data demonstrate
      that the heparin-binding specificities of intact TSP1 and peptides from the type
      1 repeats overlap with that of basic fibroblast growth factor (FGF2) and are
      consistent with the ability of these TSP1-derived molecules to inhibit FGF2
      stimulated angiogenesis.

PMID- 10640392
TI  - Molecular interactions of neural chondroitin sulfate proteoglycans in the brain
      development.
AB  - Aggrecan family proteoglycans, phosphacan/RPTPzeta/beta, and neuroglycan C (NGC)
      are the major classes of chondroitin sulfate proteoglycan in the developing
      mammalian brain. A multidomain is a common structural feature of these
      proteoglycans which can interact with various molecules including growth factors,
      cell adhesion molecules, and extracellular matrix molecules. Individual
      proteoglycans are distributed in the developing brain in a distinct temporal and
      spatial pattern, suggesting that they are involved in distinct phases of the
      brain development through multiple molecular interactions. This review mainly
      summarizes recent studies on the involvement of these three classes of
      proteoglycan in cell-cell and cell-substratum interactions during the brain
      development. Their expressions and proposed functional roles in injured brains
      are also mentioned. In addition, this review briefly covers potential functions
      of other neural chondroitin sulfate proteoglycans such as decorin, testican, NG2
      proteoglycan, and amyloid precursor protein (APP) in developing and injured
      brains.

PMID- 10640394
TI  - Fucosylated hybrid-type N-glycans on the secreted human epidermal growth factor
      receptor from swainsonine-treated A431 cells.
AB  - N-Glycans linked to the human secreted form of epidermal growth factor receptor
      were isolated from A431 cells after swainsonine treatment. Analysis of the
      oligosaccharides by (1)H NMR spectroscopy and mass spectrometry shows the
      presence of oligomannose- and (alpha2-3)-sialylated hybrid-type glycans. The
      major hybrid-type oligosaccharide chains are fucosylated at the Asn-bound GlcNAc
      residue. Smaller amounts of the hybrid-type structures are also fucosylated at
      peripheral GlcNAc residues, constituting the sialyl-Le(x) antigen. No complex
      type glycans are found, suggesting the absence of alpha-mannosidase III. An assay
      for alpha-mannosidase III on the A431 cells in the absence and presence of 6
      microM swainsonine shows that Man(5)GlcNAc(2) is not converted into
      Man(3)GlcNAc(2), thereby confirming that these cells do not contain alpha
      mannosidase III activity.

PMID- 10640393
TI  - Proteoglycan metabolism during repair of the ruptured medial collateral ligament
      in skeletally mature rabbits.
AB  - The metabolism of the chondroitin/dermatan sulfate (CS/DS) proteoglycans (PGs)
      decorin and biglycan is markedly altered during short-term (3-6 weeks) and long
      term (40 weeks-2 years) repair of surgically ruptured medial collateral ligaments
      from mature rabbits. A PG-rich extracellular matrix accumulates in injury gaps by
      3 weeks postsurgery and extends into tissue regions containing the original
      ligaments, and elevated PG levels remain apparent up to 2 years postinjury. CS/DS
      PGs were prepared from such ligaments and identified after SDS-polyacrylamide gel
      electrophoresis by Alcian blue staining or immunoblotting. In normal ligaments,
      decorin is the most abundant proteoglycan (accounting for approximately 80% of
      the total); the remainder is biglycan and a large PG, possibly versican. In
      repairing ligaments, decorin is barely detected, but instead a large proteoglycan
      and abundant amounts of biglycan accumulate. Biglycan is present in two forms in
      repairing ligaments, and they can be separated on SDS-PAGE into 200- and 140-kDa
      forms. The slower migrating species is absent in normal ligaments and may
      represent a different glycoform (containing either a single or two short
      chondroitin/dermatan sulfate chains) of biglycan. Alteration in PG expression and
      posttranslational processing during medial collateral ligament repair are similar
      to those reported for repair and scar formation of other connective tissues. The
      accumulation of biglycan observed here may interfere with proper collagen network
      remodeling and may lead to persistent inflammatory and matrix turnover processes,
      thus preventing restoration of a long-term functional ligament tissue.

PMID- 10640395
TI  - Cell cycle-dependent regulation of N-acetylglucosaminyltransferase-III in a human
      colon cancer cell line, Colo201.
AB  - The mechanism for cell-cycle-dependent regulation of N
      acetylglucosaminyltransferase III (GnT-III) activity was investigated using
      synchronized culture of Colo201, a human colon cancer cell line. In the
      synchronized culture, it was found that GnT-III activity rapidly increased in the
      M phase and the maximal activity was five times higher than the basal level found
      in the G1 phase. Northern blot and Western blot analyses revealed that the
      increase in the activity is due not to an increase in expression level of its
      mRNA but, rather, to the level of protein. Furthermore, it was shown by a pulse
      chase experiment that the increased protein level of GnT-III is the result of its
      prolonged turnover rate. Lectin blotting with erythroagglutinating
      phytohemagglutinin showed that the content of bisecting N-acetylglucosamine
      structure in glycoproteins was transiently increased during the M phase in
      conjunction with the increased activity of GnT-III. These results suggest that
      GnT-III activity undergoes a cell-cycle-dependent regulation and thereby
      oligosaccharide structures of N-glycans vary specifically during the M phase of
      the cell cycle. Thus, it is possible that the cell-cycle-dependent alteration of
      N-glycans by GnT-III might play a role in biological events, such as the
      progression of cell cycle and cell division.

PMID- 10640396
TI  - Differential effects of interleukin-1 on hyaluronan and proteoglycan metabolism
      in two compartments of the matrix formed by articular chondrocytes maintained in
      alginate.
AB  - Phenotypically stable young adult bovine articular chondrocytes suspended in
      beads of alginate gel were first cultured for 5 days, using daily changes of
      medium containing 10% fetal bovine serum and supplements. The cells in the beads
      were then maintained in culture for a further 3 days in the presence or absence
      of interleukin-1alpha at 1 ng/ml in the daily change of medium. The exposure to
      interleukin-1alpha caused the incorporation of (35)S-sulfate into the predominant
      cartilage proteoglycan, aggrecan, to decrease by approximately 60%. In addition,
      proteoglycans that had accumulated into the cell-associated matrix during the
      first 5 days of culture in the absence of interleukin-1alpha moved into the
      matrix further removed from the cells and from there into the medium. In
      contrast, the exposure to interleukin-1alpha was found to markedly promote the
      rate of synthesis of hyaluronan, especially during the first 24 h. Over the 3
      days of culture in the presence of interleukin-1alpha, a large proportion of the
      newly synthesized hyaluronan molecules, as well as those that had previously
      become residents of the cell-associated matrix, moved out of this compartment and
      appeared to become permanent residents of the further removed matrix. These
      results demonstrate that exposure of young adult articular chondrocytes to
      interleukin-1alpha has profound effects on the metabolism of hyaluronan, a
      molecule that plays a critical role in the retention of proteoglycan molecules in
      the matrix. Importantly, the results suggest that exposure of chondrocytes to
      interleukin-1 in inflamed joints, such as occurs in rheumatoid arthritis, leads
      to the rapid loss of coordination of the synthesis of aggrecan and hyaluronan,
      two of the critical constituents of the proteoglycan aggregate. In addition, we
      present evidence that these interleukin-1-induced effects differentially alter
      the metabolism of hyaluronan in the metabolically active cell-associated matrix
      and the metabolically inactive matrix further removed from the chondrocytes.

PMID- 10640397
TI  - Syndecan-4 binding to the high affinity heparin-binding domain of fibronectin
      drives focal adhesion formation in fibroblasts.
AB  - Cell adhesion to extracellular matrix involves signaling mechanisms which control
      attachment, spreading and the formation of focal adhesions and stress fibers.
      Fibronectin can provide sufficient signals for all three processes, even when
      protein synthesis is prevented by cycloheximide. Primary fibroblasts attach and
      spread following integrin ligation, but do not form focal adhesions unless
      treated with a heparin-binding fragment of fibronectin (HepII), a peptide from
      this domain, or phorbol esters to activate protein kinase C. Syndecan-4 heparan
      sulfate proteoglycan is a transmembrane component present together with integrins
      in focal adhesions. Syndecan-4 binds and activates protein kinase Calpha, whose
      activity is needed for focal adhesion formation. We now report that the
      glycosaminoglycan chains of syndecan-4 bind recombinant HepII and it is
      incorporated into forming focal adhesions.

PMID- 10640398
TI  - Slow-binding inhibition of branching enzyme by the pseudooligosaccharide BAY
      e4609.
AB  - Branching enzyme from Escherichia coli is shown to be inhibited by the
      pseudooligosaccharide BAY e4609. The mechanism of binding is studied in detail by
      kinetics using reduced amylose as substrate. Lineweaver-Burk plots suggest the
      mechanism of a noncompetitive or slow-binding inhibitor. Further studies by
      progress curves and rate of loss of branching activity allows us to conclude BAY
      e4609 as being a slow-binding inhibitor of branching enzyme. We discuss how these
      results parallel the inhibition of alpha-amylase by acarbose and the significance
      of branching enzyme as belonging to the amylolytic family.

PMID- 10640399
TI  - Mannosamine inhibits aggrecanase-mediated changes in the physical properties and
      biochemical composition of articular cartilage.
AB  - The enzymatic processes underlying the degradation of aggrecan in cartilage and
      the corresponding changes in the biomechanical properties of the tissue are an
      important part of the pathophysiology of osteoarthritis. Recent studies have
      demonstrated that the hexosamines glucosamine (GlcN) and mannosamine (ManN) can
      inhibit aggrecanase-mediated cleavage of aggrecan in IL-1-treated cartilage
      cultures. The term aggrecanase describes two or more members of the ADAMTS family
      of metalloproteinases whose glutamyl endopeptidase activity is known to be
      responsible for much of the aggrecan degradation seen in human arthritides. In
      this study we examined the effect of ManN and GlcN on aggrecanase-mediated
      degradation of aggrecan induced by IL-1alpha and the corresponding tissue
      mechanical properties in newborn bovine articular cartilage. After 6 days of
      culture in 10 ng/ml IL-1 plus ManN, mechanical testing of explants in confined
      compression demonstrated that ManN inhibited the IL-1alpha-induced degradation in
      tissue equilibrium modulus, dynamic stiffness, streaming potential, and hydraulic
      permeability, in a dose-dependent fashion, with peak inhibition ( approximately
      75-100% inhibition) reached by a concentration of 1.35 mM. Aggrecan from explants
      cultured in IL-1 was found by Western analysis to be almost entirely processed
      down to the G1-NITEGE(373) end product. Addition of ManN or GlcN was found to
      produce 75-90% inhibition of this cleavage, but the proportion of aggrecan
      remaining in the tissue which was cleaved at aggrecanase sites in the chondroitin
      sulfate (CS)-rich region (Glu(1501) and Glu(1687)) was higher than with IL-1
      alone. This result suggests that the preservation of mechanical properties by
      hexosamines in explants is primarily due to inhibition of cleavage at the
      Glu(373) site in the interglobular domain. While the precise mechanism by which
      hexosamines function in this system is unclear, the present analysis suggests
      that the mechanical properties examined may be predominantly a function of
      electrostatic repulsion due to the charged CS chains in the tightly packed
      repetitive sequences of the CS-1 region.

PMID- 10640400
TI  - Calcium ion-independent recognition of sialyl and nonsialyl N-acetyllactosamine
      and Le(x) structures by boar sperm.
AB  - Recognition of defined carbohydrate structures by boar sperm was studied on the
      basis of oligosaccharide structures of porcine zona pellucida glycoproteins so
      far elucidated. Boar sperm abundantly adhered to fetuin-Sepharose beads,
      moderately to asialofetuin-Sepharose beads, but not at all to galactosidase
      (beta1-4-linkage-specific)-digested asialofetuin-Sepharose beads. The sperm also
      adhered to Le(x) oligosaccharide probe-coupled avidin-Sepharose beads. These
      adhesive activities were retained in the medium containing EDTA instead of
      calcium ion but abolished after induction of acrosome reaction by preincubation
      of sperm with calcium ionophore. Inhibition study of sperm adhesion to the beads
      by soluble ligands demonstrated that boar sperm express at least two kinds of
      carbohydrate recognition molecules, one recognizing both sialyl and nonsialyl N
      acetyllactosamines but not the Le(x) structure and the other recognizing the
      Le(x) structure but not N-acetyllactosamines. Sperm binding to the zona pellucida
      on fixed porcine oocytes was inhibited by N-glycans of fetuin and their asialo
      form but not by the asialo, agalacto-N-glycans. Finally, dextran-based
      multivalent oligosaccharide polymers were prepared and their inhibitory
      activities in sperm-oocyte binding were examined. The result indicated that the
      polymer composed of fetuin N-glycans, its asialo-N-glycans, or lacto-N
      fucopentaose III causes a remarkable inhibition at the oligosaccharide-based
      concentration of 50 microM. Thus, boar sperm are suggested to express multiple
      carbohydrate recognition molecules which may be involved in the sperm-egg
      interaction.

PMID- 10640401
TI  - Soluble fibronectin interaction with cell surface and extracellular matrix is
      mediated by carbohydrate-to-carbohydrate interaction.
AB  - Cell adhesion and spreading on solid phase fibronectin (FN), coated on plate or
      presented in extracellular matrix, are mediated by integrin receptors
      alpha5beta1, alpha4beta1, etc., although binding of "soluble-form FN" to cell
      surface varies extensively depending on glycosylation status of FN per se.
      Deposition or incorporation at the cell surface or pericellular matrix of soluble
      form FN from body fluids or synthesized de novo takes place through a yet-unknown
      (perhaps integrin-independent) mechanism. Here we present evidence that the
      mechanism involves carbohydrate-to-carbohydrate interaction. Binding or
      incorporation of soluble-form placental or hepatoma FN to cell surface or
      pericellular matrix is highly dependent on the specific glycosylation status of
      FN per se and combination with glycosylation status of the cell surface, and is
      greatly promoted by a certain type of coexisting (shedded) glycosphingolipid. A
      few lines of study indicate that the process is mediated by interaction of FN
      carbohydrate with cell surface carbohydrate. The great enhancement of the binding
      process by glycosphingolipid is based on dual interaction of glycosphingolipid
      carbohydrate with FN carbohydrate and with cell surface carbohydrate. Here we
      present an example of promotion of binding of soluble-form FN from placenta or
      from hepatoma cells, having a specific carbohydrate epitope termed "disialyl-I,"
      to K562 or VA13 cell surface in the presence of glycosphingolipid Gg3, which
      interacts specifically with disialyl-I.

PMID- 10640404
TI  - The outlook for TVJ after Y2K. The Veterinary Journal.

PMID- 10640402
TI  - Acquisition of P-selectin binding activity by en bloc transfer of sulfo Le(x)
      trisaccharide to the cell surface: comparison to a sialyl Le(x) tetrasaccharide
      transferred on the cell surface.
AB  - Sialyl Le(x), NeuNAcalpha2 --> 3Galbeta1 --> 4(Fucalpha1 --> 3)GlcNAcbeta --> R,
      is known to be a ligand for E-selectin in various assays. The sulfated
      counterpart of sialyl Le(x), sulfo Le(x), (Sulfo --> 3) Galbeta1 --> 4 (Fucalpha1
      --> 3) GlcNAcbeta --> R, was also shown to be a ligand for E-selectin in solid
      phase assays employing immobilized oligosaccharides. In order to determine
      whether sulfo Le(x) structure on the cell surface also works as E-selectin or P
      selectin ligand, a novel approach for in vitro transfer of oligosaccharides (S.
      Tsuboi, Y. Isogai, N. Hada, J. K. King, O. Hindsgaul, and M. Fukuda (1996) J.
      Biol. Chem. 271, 27213-27216) was utilized. A synthetic GDP-fucose harboring
      sialyl Le(x) or sulfo Le(x) oligosaccharide was enzymatically transferred to
      Chinese hamster ovary (CHO) cells with a milk fucosyltransferase. The resultant
      cells, CHO-sialyl Le(x) and CHO-sulfo Le(x) were tested for adhesion to E
      selectin. IgG or P-selectin. IgG chimeric protein coated on plates. The results
      indicate that CHO-sialyl Le(x) adhered efficiently to E-selectin, while adhesion
      of CHO-sulfo Le(x) was very poor despite the fact that near equal number of the
      ligands had been attached to the cell surface. In contrast, CHO-sulfo Le(x)
      adhered efficiently to P-selectin, while CHO-sialyl Le(x) adhered modestly to P
      selectin. These results demonstrate that sialyl Le(x) and sulfo Le(x) structures
      on the cell surface differ substantially in their ability to adhere to E- and P
      selectin.

PMID- 10640405
TI  - The trouble with transmissible degenerative encephalopathy agents.

PMID- 10640406
TI  - Actinobacillus species in animal disease: A topical subject.

PMID- 10640407
TI  - Clustering of feline coronaviruses in multicat households.

PMID- 10640408
TI  - Inactivation of transmissible degenerative encephalopathy agents: A review.
AB  - The unconventional agents that cause transmissible degenerative encephalopathies,
      such as bovine spongiform encephalopathy, scrapie, and Creutzfeldt-Jakob disease
      (CJD), are relatively resistant to inactivation by standard decontamination
      procedures. The only methods that appear to be completely effective under worst
      case conditions are strong sodium hypochlorite solutions or hot solutions of
      sodium hydroxide. Other procedures that result in significant degrees of
      inactivation are described. The infectivity levels in histologically-fixed tissue
      can be reduced substantially by treatment with concentrated formic acid without
      adversely affecting the microscopic quality of the tissue.

PMID- 10640409
TI  - Actinobacillus species and their role in animal disease.
AB  - Actinobacillus species are Gram-negative bacteria responsible for several quite
      distinct disease conditions of animals. The natural habitat of the organisms is
      primarily the upper respiratory tract and oral cavity. A. lignieresii is the
      cause of actinomycosis (wooden tongue) in cattle: a sporadic, insidiously
      developing granulomatous infection. In sharp contrast is A. pleuropneumoniae
      which is responsible for a rapidly spreading often fatal pneumonia, common among
      intensively reared pigs. Detailed investigation of this organism has provided a
      much clearer picture of the bacterial factors involved in causing disease. A.
      equuli similarly causes a potent septicaemia in the neonatal foal; growing
      apparently unrestricted once infection occurs. Other members of the genus induce
      characteristic pathogenesis in their preferred host, with one, A.
      actinomycetemcomitans, being a cause of human periodontal disease. This article
      reviews recent understanding of the taxonomy and bacteriology of the organisms,
      and the aetiology, pathogenicity, diagnosis and control of animal disease caused
      by Actinobacillus species.

PMID- 10640410
TI  - Epidemiological investigation of the influence of environmental risk factors on
      respiratory diseases in swine--a literature review.
AB  - The influence of environmental and management factors on respiratory diseases in
      pigs is reviewed from an epidemiological point of view. The suitability of
      methods for the investigation of risk factors is discussed including aspects of
      study design, case definition, exposure assessment and data analysis. The results
      of published studies suggest a causal web of factor interaction, the analysis of
      which provides considerable challenges for current epidemiological techniques.
      New approaches to the problem should be further explored in the future in order
      to provide reliable advice to decision makers.

PMID- 10640411
TI  - Comparison of some responses to exercise on the track and the treadmill in French
      trotters: determination of the optimal treadmill incline.
AB  - The purpose of this study was to determine the optimal treadmill slope for
      trotters to produce the same heart rate and blood lactate responses as on the
      track during a standardized exercise test. Nine 2-year-old French trotters
      performed exercise tests on a training track and on a treadmill set at an incline
      of 0, 2 or 4%. For all horses, track testing was performed on day 1 and then on
      the treadmill according to a Latin-square design. The track test utilized three
      steps each of 3 min at speeds of 470, 530, 590 m/min and the same speeds were
      used on the treadmill. Derived physiological variables such as the speed at a HR
      of 200 bpm (V(200)) and the speed inducing blood lactate concentrations of 4
      mmol/L (V(4)) were calculated. There were significant differences for V(200)and
      V(4)(P<0.05) between the track and the treadmill data when the treadmill was set
      at inclines of 0 and 4%, but no significant differences with the treadmill set at
      a 2% incline. The optimal treadmill incline to reproduce similar responses to
      those on the track was determined by regression analysis, and was found to be
      2.4% for the two most often utilized derived physiological variables, V(4)and
      V(200).

PMID- 10640412
TI  - Prevalence and genetic pattern of feline coronaviruses in urban cat populations.
AB  - The prevalence and phylogeny of feline coronaviruses were studied in urban cat
      populations by sampling of 113 clinically healthy cats. Rectal swab samples were
      subjected to a nested reverse-transcription polymerase chain reaction, specific
      for the conservative nucleocapsid region of the virus genome. More than 30% of
      the sampled animals proved positive for the presence of feline coronaviruses. The
      nucleotide sequences of amplified 440 bp products were determined, aligned and
      the phylogenetic analysis revealed noticeable genetic clusters among the
      prevalent feline coronaviruses in the surveyed geographic area. These findings
      will hopefully contribute to the elucidation of the epidemiology of feline
      infectious peritonitis.

PMID- 10640413
TI  - Evaluation of accuracy of pulse oximetry in newborn calves.
AB  - In human medicine, pulse oximetry is widely used to measure non-invasively and
      accurately the percentage of oxygen saturation of arterial haemoglobin (SpO(2)).
      Recently, pulse oximetry has been used in calves, but its accuracy has not been
      evaluated in newborn calves. The purpose of this study was to evaluate the
      accuracy of a pulse oximeter in newborn calves by comparing SpO(2) with arterial
      oxyhaemoglobin saturation (SaO(2)) obtained by use of a blood gas analyser. Fifty
      five newborn calves were investigated from birth to 20 days old. Pulse oximetry
      readings and arterial blood samples were performed 5, 15, 30, 45, 60 min, 2, 3,
      6, 12, 24 h and 1 and 3 weeks after birth. The transmission-type sensors of the
      pulse oximeter were fixed at the recommended site in the bovine species (at the
      base of the calf tail, where the skin had been shaved and was not pigmented) and
      arterial blood samples were withdrawn from the subclavian artery and analysed for
      SaO(2). Five-hundred paired data of SaO(2) and mean SpO(2)(mSpO(2)) were
      collected. Linear regression of the pooled data indicated a highly significant
      correlation of mSpO(2) with SaO(2) (r = 0.87;P< 0.001; mSpO(2) = 15.8 + 0.84
      SaO(2)). The overall data bias value was positive (+2.1%), which indicated that
      the pulse oximeter tended to overestimate the SaO(2). The bias value for each
      SaO(2) category tended to become higher for lower ranges of SaO(2). Precision was
      also lower when SaO(2) values were low. The lower the SaO(2) value, the higher
      the positive bias (overestimation) and the lower the precision. These results
      suggest that pulse oximetry provides a relatively accurate non-invasive,
      immediate and portable method to monitor SaO(2) and to evaluate objectively the
      pulmonary function effectiveness in newborn calves during their adaptation to
      extra-uterine life.

PMID- 10640414
TI  - In vitro and in vivo evaluation of hypericin for photodynamic therapy of equine
      sarcoids.
AB  - The therapeutic potential of the photodynamic compound, hypericin, in the
      treatment of equine sarcoids was evaluated. The in vitro cytotoxicity was
      assessed using three equine cell lines and the observed phototoxic effect was
      comparable to that on different highly sensitive human cell lines and
      significantly influenced by the energy density used although independent of the
      cell type. The in vivo antitumoural action of photodynamic therapy using
      hypericin was evaluated on three equine sarcoids in a donkey. Four intratumoural
      injections were given and the tumours were illuminated daily during 25 days. An
      81% reduction in tumour volume was obtained at the end of therapy and 2 months
      later, a 90% reduction was observed. Further experimental work should be
      performed, but these results suggest that photodynamic therapy using hypericin
      has a potential for the non-invasive treatment of equine sarcoids.

PMID- 10640415
TI  - Ultrasonographic examination of the carpal region in cattle--normal appearance.
AB  - The carpal region was examined ultrasonographically in 18 healthy cattle (14
      cows, 4 bull calves) and five bovine cadavers in order to determine the normal
      appearance of the carpal soft tissues using 7.5 MHz linear transducers. The
      course of the echogenic flexor and extensor tendons over the carpus and the joint
      spaces interposed between the articular bone surfaces were successfully imaged in
      all carpi. The palmar vessels were easily visualized in live animals. The lumina
      of carpal tendon sheaths and the boundaries of the carpal joint pouches could not
      be defined. Small anechoic fluid filled areas were visualized only at the level
      of the joint spaces. After experimental filling, the distended synovial cavities
      were imaged as well demarcated anechoic areas. The cross-sectional diameters of
      the extensor tendons, width of the palmar joint pouches and intraluminal
      diameters of the palmar vessels were measured. The results presented serve as
      reference data for ultrasonographic investigation of disorders of the bovine
      carpus.

PMID- 10640416
TI  - Cytogenetic alterations in feline melanoma.

PMID- 10640417
TI  - SHP-2 can suppress transformation induced by platelet-derived growth factor.
AB  - Signaling by either the type alpha or type beta receptors of platelet-derived
      growth factor occurs by phosphorylation of at least 10 intra-cytoplasmic tyrosine
      residues and their subsequent association of secondary signaling molecules with
      Src homology 2 (SH2) domains. Although the role of several of these secondary
      signaling molecules in mitogenesis has become increasingly clear, their roles in
      morphological transformation are not as well defined. Here we present evidence
      that the SHP-2 phosphatase which associates with Tyr 1009 of the type beta
      receptor and Tyr 720 of the type alpha receptor may suppress transformation
      induced by the PDGF B chain. Cotransfection of a dominant negative mutant of the
      SHP-2 gene and the PDGF B chain gene into mouse fibroblasts that only poorly
      formed foci with the PDGF B chain alone resulted in larger and more prominent
      foci. Furthermore, introduction of a wild-type copy of the SHP-2 gene into a
      tumor cell line, U-87MG, which relies on PDGF expression to form foci in vitro,
      caused a reversion of phenotype.

PMID- 10640418
TI  - Regulation of the lysosome-associated membrane protein in a sucrose model of
      lysosomal storage.
AB  - Lysosomal biogenesis is a complex process requiring the coordinated expression
      and colocalization of numerous soluble and membrane proteins. In storage
      disorders, lysosomal biogenesis is regulated at least partially at, or prior to,
      the level of mRNA. We have used the sucrosome storage model to determine the
      sites of regulation of LAMP-1, a major constituent of the lysosomal membrane. A
      six- to eightfold increase in the level of LAMP-1 mRNA and protein was observed
      in response to sucrose storage. The half-life of LAMP-1 mRNA was not
      significantly different in cells grown in the absence or presence of sucrose,
      implying that the increase observed in mRNA levels reflects an increase in the
      rate of transcription. The sixfold increase in mRNA did not translate into an
      increase in LAMP-1 synthesis, indicating an overall decrease in the translational
      yield in sucrosome cells. The elevation of LAMP-1 protein levels in storage cells
      was due in large part to a threefold increase in the half-life of the protein.
      These results are discussed in view of the current understanding of lysosomal
      biogenesis and how this process is altered during storage.

PMID- 10640419
TI  - Regulation of LPA-promoted myofibroblast contraction: role of Rho, myosin light
      chain kinase, and myosin light chain phosphatase.
AB  - Myofibroblasts generate the contractile force responsible for wound healing and
      pathological tissue contracture. In this paper the stress-relaxed collagen
      lattice model was used to study lysophosphatidic acid (LPA)-promoted
      myofibroblast contraction and the role of the small GTPase Rho and its downstream
      targets Rho kinase and myosin light chain phosphatase (MLCPPase) in regulating
      myofibroblast contraction. In addition, the regulation of myofibroblast
      contraction was compared with that of smooth muscle cells. LPA-promoted
      myofibroblast contraction was inhibited by the myosin light chain kinase (MLCK)
      inhibitors KT5926 and ML-7; however, in contrast to that observed in smooth
      muscle cells, elevation of intracellular calcium alone was not sufficient to
      promote myofibroblast contraction. These results suggest that Ca(2+)-mediated
      activation of MLCK, while necessary, is not sufficient to promote myofibroblast
      contraction. The specific Rho inactivator C3-transferase and the Rho kinase
      inhibitor Y-27632 inhibited LPA-promoted myofibroblast contraction, suggesting
      that contraction depends on activation of the Rho/Rho kinase pathway. Calyculin,
      a type 1 phosphatase inhibitor known to inhibit MLCPPase, could promote
      myofibroblast contraction in the absence of LPA, as well as restore contraction
      in the presence of C3-transferase or Y-27632. Together these results support a
      model whereby Rho/Rho kinase-mediated inhibition of MLCPPase is necessary for LPA
      promoted myofibroblast contraction, in contrast to smooth muscle cells in which
      Ca(2+) activation of MLCK alone is sufficient to promote contraction.

PMID- 10640420
TI  - Adenovirus-mediated transfer of Bcl-X(L) protects neuronal cells from Bax-induced
      apoptosis.
AB  - Bax-mediated apoptosis in neurons is involved in many pathologic conditions
      affecting the central nervous system, including degenerative diseases, stroke,
      and trauma. Two molecules belonging to the Bcl-2 family, Bcl-2 and Bcl-X(L),
      protect cells from Bax-induced apoptosis and show distinct expression patterns in
      adult neurons, with downregulated Bcl-2 and highly upregulated Bcl-X(L)
      expression. To investigate the biological functions of these two molecules in Bax
      mediated apoptosis in neurons, we transduced various levels of Bcl-X(L) or Bcl-2
      via adenoviral vectors into nerve growth factor (NGF)-treated PC12 cells.
      Overexpression of Bax induced drastic apoptosis in NGF-treated PC12 cells. Bcl
      X(L) expressed at a wide range of levels conferred a high level of protection
      against Bax-mediated apoptosis. In contrast, Bcl-2 at various levels conferred
      far less protection against apoptosis. Moreover, Bcl-X(L) protected PC12 cells
      from apoptosis induced by NGF withdrawal. These data indicate that Bcl-X(L)
      mediated protection is the major pathway that suppresses apoptosis in NGF-treated
      PC12 cells and that Bcl-X(L) would be a more relevant target of manipulation in
      future treatment strategies, including gene therapies.

PMID- 10640421
TI  - Lack of cyclooxygenase-2 inhibits growth of teratocarcinomas in mice.
AB  - Two isoforms of cyclooxygenase (COX-1 or COX-2) have been identified in the
      prostanoid biosynthetic pathway. The constitutive form, COX-1, is thought to
      maintain cellular homeostasis and the inducible form, COX-2, is recognized as a
      primary response gene thought to be involved in modulating cell proliferation and
      differentiation. To further characterize the role of the cyclooxygenases in cell
      proliferation, differentiation, and tumorigenicity we developed embryonic stem
      (ES) cell lines which contain homozygous disruptions in either the COX-1 or the
      COX-2 gene. These lines were then examined in terms of their viability,
      proliferation, and in vitro differentiation potential. Our results demonstrate
      that the wild-type ES cells do not express either COX-1 or COX-2 until the cells
      undergo differentiation. And the lack of either cyclooxygenase has no apparent
      effect on ES cell proliferation in vitro. However, the absence of a functional
      COX-2 gene leads to a dramatic reduction in the formation and growth of
      teratocarcinomas that appear when ES cells are injected into syngeneic mice.
      Histological microscopy shows that the few very small tumors that were generated
      from ES cells lacking COX-2 appear more differentiated than tumors emerging from
      COX-1 -/- or wild-type cells by exhibiting greater keratinization in the areas of
      squamous epithelium and the ossification of bone-forming cartilage. We conclude
      that the presence of a functional COX-2 enzyme is necessary for the efficient
      growth of these teratocarcinomas in animals.

PMID- 10640422
TI  - Interconnections between E2-dependent regulation of cell cycle progression and
      apoptosis in MCF-7 tumors growing on nude mice.
AB  - Growth of human breast adenocarcinoma MCF-7 cells as a tumor on nude mice is
      dependent on estrogen. It has been shown that estrogen withdrawal (EW) induces a
      partial regression of the tumor via an inhibition of cell proliferation and an
      induction of apoptosis. We investigated in this in vivo model the underlying
      molecular mechanisms of the hormone-dependent regulation of cell cycle machinery
      and apoptosis. We found that, 2 days after EW, the tumor protein levels of p21
      rose, whereas those of Rb proteins decreased in parallel with the decrease in the
      proportion of tumor cells in S phase and the increase of the tumor apoptotic
      index. Between 3 and 7 days after EW, apoptosis was inhibited and tumor
      proliferation returned to the control value. There was a concomitant decline in
      p21 and an elevation of Rb tumor protein content. Slight variations of cyclin D
      protein level were observed in MCF-7 tumors over the time course following EW
      treatment. Bcl-2 overexpression not only inhibited apoptosis induced by EW but
      also modulated hormone-dependent cell cycle regulation. First, the analysis of
      phosphorylation status of Rb protein and the measurement of the proportion of
      tumor cells in S phase indicated that Bcl-2 overexpression results in a decrease
      of DNA synthesis induced by estradiol. Furthermore, after EW, Bcl-2-induced
      inhibition of hormone-dependent apoptosis was associated with an inhibition of Rb
      protein downregulation, a sustained level of p21 protein, and a prolonged
      inhibition of cell cycle progression. These results suggest that, in human
      hormone-dependent breast cancers, cross-talk exists between the signaling
      pathways which lead to regulation of cell cycle progression and apoptosis.

PMID- 10640423
TI  - The Xenopus XMAP215 and its human homologue TOG proteins interact with cyclin B1
      to target p34cdc2 to microtubules during mitosis.
AB  - Cytoskeleton reorganization, leading to mitotic spindle formation, is an M-phase
      specific event and is controlled by maturation promoting factor (MPF: p34cdc2
      cyclinB1 complex). It has previously been demonstrated that the p34cdc2-cyclin B
      complex associates with mitotic spindle microtubules and that microtubule
      associated proteins (MAPs), in particular MAP4, might be responsible for this
      interaction. In this study, we report that another ubiquitous MAP, TOG in human
      and its homologue in Xenopus XMAP215, associates also with p34cdc2 kinase and
      directs it to the microtubule cytoskeleton. Costaining of Xenopus cells with anti
      TOGp and anti-cyclin B1 antibodies demonstrated colocalization in interphase
      cells and also with microtubules throughout the cell cycle. Cyclin B1,
      TOG/XMAP215, and p34cdc2 proteins were recovered in microtubule pellets isolated
      from Xenopus egg extracts and were eluted with the same ionic strength.
      Cosedimentation of cyclin B1 with in vitro polymerized microtubules was detected
      only in the presence of purified TOG protein. Using a recombinant C-terminal TOG
      fragment containing a Pro-rich region, we showed that this domain is sufficient
      to mediate cosedimentation of cyclin B1 with microtubules. Finally, we
      demonstrated interaction between TOG/XMAP215 and cyclin B1 by co
      immunoprecipitation assays. As XMAP215 was shown to be the only identified
      assembly promoting MAP which increases the rapid turnover of microtubules, the
      TOG/XMAP215-cyclin B1 interaction may be important for regulation of microtubule
      dynamics at mitosis.

PMID- 10640424
TI  - Cell population dynamics (apoptosis, mitosis, and cell-cell communication) during
      disruption of homeostasis.
AB  - The sequence of events involved in maintenance of homeostasis must encompass
      mechanisms within single cells as well as interactions between cells within a
      population. To investigate the interaction among these inter- and intracellular
      mechanisms, disruption of homeostasis by serum deprivation was performed in WB
      F344, a normal diploid epithelial cell line. Changes in cell-cell communication
      (gap junction function) at the population level and in individual cells were
      monitored using the scrape load/dye transfer and fluorescence redistribution
      after photobleaching assays. Apoptosis and mitosis were measured using
      internucleosomal DNA ladder assays and fluorescence-activated cell sorting. The
      results indicate that a common element in early apoptosis and early mitosis is
      sustained gap junction function. As cell life (mitosis) and cell death
      (apoptosis) progressed, a common process of change in gap junction function
      occurred. A transient stimulation of mitosis concomitant with increased apoptosis
      was also observed during serum deprivation. Gap junctions may play a regulatory
      role during initiation of these opposite yet equally important mechanisms of
      maintaining homeostasis. This model system is useful for further studies on the
      relationships among inter- and intracellular mechanisms of homeostasis.

PMID- 10640425
TI  - TGF-alpha differentially regulates GFAP, vimentin, and nestin gene expression in
      U-373 MG glioblastoma cells: correlation with cell shape and motility.
AB  - To begin understanding the regulation and biological significance of changes in
      the expression of intermediate filament proteins in astrocytic tumors, we have
      recently shown that TGF-alpha alters the protein level of glial fibrillary acidic
      protein (GFAP), nestin, and vimentin in U-373 MG glioblastoma cells. Here, we
      have determined the molecular mechanisms regulating these changes. In addition,
      to evaluate the significance of these changes we have examined whether TGF-alpha
      affects various cellular properties related to differentiation. Our results show
      that, in U-373 MG cells treated with TGF-alpha, GFAP gene transcription, mRNA
      level, and specific protein synthesis decrease by approximately 50%. This
      suggests that, in U-373 MG cells, TGF-alpha down-regulates the expression of this
      marker of astrocytic differentiation at the transcriptional level, resulting in
      decreased GFAP mRNA level and specific protein synthesis. In contrast, TGF-alpha
      does not change vimentin gene transcription, but increases by about 50% the
      transcription of the gene for nestin, a marker for undifferentiated astrocytic
      precursors. This differential regulation of GFAP, nestin, and vimentin gene
      expression indicates that TGF-alpha induces further dedifferentiation of U-373 MG
      cells. This notion is also supported by our findings that TGF-alpha increases the
      motility of U-373 MG cells and induces a less stellate morphology.

PMID- 10640426
TI  - Cell cycle arrest induced by the vitamin D(3) analog EB1089 in NCI-H929 myeloma
      cells is associated with induction of the cyclin-dependent kinase inhibitor p27.
AB  - EB1089, a 1,25-dihydroxyvitamin D(3) analog, has been known to have potent
      antiproliferative properties in a variety of malignant cells in vitro and in
      vivo. In the present study, we analyzed the effect of EB1089 on human myeloma
      cell lines. EB1089 inhibited the proliferation of NCI-H929 cells and RPMI8226
      cells in a dose-dependent manner among three myeloma cell lines tested. The
      antiproliferative effect of EB1089 on myeloma cells was related to the expression
      level of vitamin D receptor. To investigate the mechanism of the
      antiproliferative effect of EB1089, cell cycle analysis was attempted in EB1089
      sensitive NCI-H929 cells. EB1089 (1 x 10(-8) M) efficiently induced G(1) arrest
      of the cell cycle. Analysis of G(1) regulatory proteins demonstrated that protein
      levels of CDK2, CDK4, cyclin D1, and cyclin A were decreased in a time-dependent
      manner, but not those of CDK6 and cyclin E, by EB1089. In addition, EB1089 (1 x
      10(-8) M, 72 h) increased the protein level of the CDKI p27 and markedly enhanced
      the binding of p27 with CDK2 compared to EB1089-untreated cells. Furthermore, the
      activity of CDK2-associated cyclin kinase was decreased, which was accompanied by
      the reduction of cyclin-D1-, cyclin-E-, and cyclin-A-associated kinase
      activities, resulting in the hypophosphorylation of Rb protein. These results
      suggest that EB1089 can inhibit the proliferation of human myeloma cells,
      especially NCI-H929 cells, via a G(1) block in association with the induction of
      p27 and the reduction of CDK2 activity.

PMID- 10640427
TI  - Retinoic acid-induced blr1 expression promotes ERK2 activation and cell
      differentiation in HL-60 cells.
AB  - Retinoids are known to induce the differentiation and cell cycle arrest of human
      myeloid leukemia cells in vitro. Differential display was used to identify
      putative early regulatory genes that are differentially expressed in HL-60 human
      promyelocytic leukemia cells treated with retinoic acid. One of the cDNAs cloned
      encodes sequences identifying Burkitt's lymphoma receptor 1 (BLR1), a recently
      described chemokine receptor. Northern blot analysis demonstrates that blr1 mRNA
      expression increases within 9 h of retinoic acid treatment, well before
      functional differentiation or G(1)/G(0) growth arrest at 48 h or onset of
      morphological changes, suggesting a possible regulatory function. The expression
      of blr1 mRNA is transient, peaking at 72 h when cells are differentiated. blr1
      mRNA also is induced by other differentiation-inducing agents, 1alpha,25
      dihydroxyvitamin D(3) and DMSO. Induction of blr1 mRNA by retinoic acid is not
      blocked by the protein synthesis inhibitor cycloheximide. In HL-60 cells stably
      transfected with blr1 cDNA, ectopic expression of blr1 causes an increase in ERK2
      MAPK activation and promotes retinoic acid-induced G(1)/G(0) growth arrest and
      cell differentiation. The early expression of blr1 mRNA during differentiation,
      its ability to increase ERK2 activation, and its enhancement of retinoic acid
      induced differentiation suggest that blr1 expression may be involved in retinoic
      acid-induced HL-60 differentiation.

PMID- 10640428
TI  - Activation of integrin alpha(V)beta(3) regulates cell adhesion and migration to
      bone sialoprotein.
AB  - alpha(V)beta(3), a broadly distributed member of the integrin family of adhesion
      receptors, has been implicated in a variety of physiological and
      pathophysiological events, including control of bone density, angiogenesis,
      apoptosis, tumor growth, and metastasis. Recently, it has been shown that
      activation of alpha(V)beta(3), its transition from a low- to a high
      affinity/avidity state, influences its recognition of certain ligands. Bone
      sialoprotein (BSP) is recognized as an important ligand for alpha(V)beta(3) in
      processes ranging from bone formation to the homing of metastatic tumor cells.
      Here, the influence of alpha(V)beta(3) activation on the adhesion and migration
      of relevant cells to BSP has been examined. Stimulation of lymphoblastoid,
      osteoblastoid, and human umbilical vein endothelial cells (HUVEC) with PMA or
      Mn(2+) markedly enhanced alpha(V)beta(3)-dependent adhesion to BSP.
      alpha(V)beta(3)-mediated migration of HUVEC or osteoblastic cells to BSP was
      substantially enhanced by stimulation, demonstrating that alpha(V)beta(3)
      activation enhances both adhesive and migratory responses. However, adhesion
      and/or migration of certain tumor cell lines, including M21 melanoma and MDA
      MB435 and SKBR3 breast carcinoma cell lines, to BSP was constitutively high and
      was not augmented by alpha(V)beta(3)-activating stimuli. Inhibitors of the
      intracellular signaling molecules, phosphatidylinositol 3-kinase with wortmannin,
      hsp90-dependent kinases with geldanamycin, and calpain with calpeptin, but not
      MAPKK with PD98059, reduced the high spontaneous adhesion and migration of the
      M21 cells to BSP, consistent with the constitutive activation of the receptor on
      these tumor cells. These results indicate that the activation state of
      alpha(V)beta(3) can regulate cell migration and adhesion to BSP and, by
      extension, to other ligands of this receptor. The constitutive activation of
      alpha(V)beta(3) on neoplastic cells may contribute to tumor growth and metastatic
      potential.

PMID- 10640430
TI  - Stability and nuclear distribution of mammalian replication protein A
      heterotrimeric complex.
AB  - Replication protein A (RPA), a stable complex of three polypeptides, is the
      single-stranded DNA-binding protein essential for DNA replication in eukaryotic
      cells. Previous studies of the subcellular distribution and stability of the RPA
      heterotrimer during the mammalian cell cycle have produced conflicting results.
      Here, we present evidence that these inconsistencies can be accounted for by the
      presence of an extractable pool of soluble RPA within the nucleus. Indirect
      immunofluorescence experiments in both CHO and HeLa cells showed that all three
      RPA subunits associated specifically with sites of ongoing DNA synthesis, similar
      to the replication fork protein proliferating cell nuclear antigen. Furthermore,
      we found no evidence for disassembly of the chromatin-bound heterotrimeric RPA
      complex in vivo. Our results are consistent with a role for RPA in the initiation
      and elongation steps of replication, as previously defined in the viral in vitro
      replication systems.

PMID- 10640429
TI  - Intraperoxisomal localization of very-long-chain fatty acyl-CoA synthetase:
      implication in X-adrenoleukodystrophy.
AB  - X-adrenoleukodystrophy (X-ALD) is a demyelinating disorder characterized by the
      accumulation of saturated very-long-chain (VLC) fatty acids (>C(22:0)) due to the
      impaired activity of VLC acyl-CoA synthetase (VLCAS). The gene responsible for X
      ALD was found to code for a peroxisomal integral membrane protein (ALDP) that
      belongs to the ATP binding cassette superfamily of transporters. To understand
      the function of ALDP and how ALDP and VLCAS interrelate in the peroxisomal beta
      oxidation of VLC fatty acids we investigated the peroxisomal topology of VLCAS
      protein. Antibodies raised against a peptide toward the C-terminus of VLCAS as
      well as against the N-terminus were used to define the intraperoxisomal
      localization and orientation of VLCAS in peroxisomes. Indirect immunofluorescent
      and electron microscopic studies show that peroxisomal VLCAS is localized on the
      matrix side. This finding was supported by protease protection assays and Western
      blot analysis of isolated peroxisomes. To further address the membrane topology
      of VLCAS, Western blot analysis of total membranes or integral membranes prepared
      from microsomes and peroxisomes indicates that VLCAS is a peripheral membrane
      associated protein in peroxisomes, but an integral membrane in microsomes.
      Moreover, peroxisomes isolated from cultured skin fibroblasts from X-ALD patients
      with a mutation as well as a deletion in ALDP showed a normal amount of VLCAS.
      The consequence of VLCAS being localized to the luminal side of peroxisomes
      suggests that ALDP may be involved in stabilizing VLCAS activity, possibly
      through protein-protein interactions, and that loss or alterations in these
      interactions may account for the observed loss of peroxisomal VLCAS activity in X
      ALD.

PMID- 10640431
TI  - A mathematical model of tumour angiogenesis incorporating cellular traction and
      viscoelastic effects.
AB  - Angiogenesis is defined as the outgrowth and formation of new vessels from a pre
      existing vascular network (Rakusan, In: Cardiac Growth and Regeneration. Annals
      of the New York Academy of Sciences, 1995), and is of fundamental importance in
      understanding the processes by which a tumour achieves vascularization.
      Diffusible substances, collectively called tumour angiogenesis factors are
      released from the tumour to elicit a variety of responses from the surrounding
      tissues, most importantly the migration of endothelial cells (lining neighbouring
      vessels) towards the tumour. To facilitate locomotion, the cells exert
      appreciable traction forces upon the interstitial extracellular matrix which, in
      turn, influences the resulting direction of their migration. In this paper, we
      examine the role played by cellular traction during cell migration and the
      corresponding viscoelastic effects of the extracellular matrix.

PMID- 10640432
TI  - Modelling the transition of asexual blood stages of Plasmodium falciparum to
      gametocytes.
AB  - In this paper, we investigate the transition of asexual blood stages of P.
      falciparum to gametocytes. The study is based on daily data, collected from 262
      individual courses of parasitaemia. We propose several mathematical models that
      follow biological reasoning. The models are fitted with maximum likelihood and
      are compared with each other. The models differ in the assumptions made about the
      mortality of circulating gametocytes and about the transition rate of the asexual
      parasites. Gametocyte mortality is modelled as being (i) constant over time, (ii)
      linearly increasing over time, (iii) linearly increasing over gametocyte age, and
      (iv) exponentially increasing over gametocyte age, respectively. The transition
      rate is either kept constant per patient or piecewise constant within intervals
      that correspond to waves of asexual parasitaemia which are assumed to be caused
      by different Pf(emp1)-variants. According to likelihood ratio tests, the models
      with age-dependent mortality rate and wave-dependent transition rates are
      superior to the models with constant transition rate and/or constant or time
      dependent mortality rate. The best fits are reached for models with exponentially
      increasing (Gompertz-type) mortality. Furthermore, an impact of high asexual
      parasite densities on the survival of gametocytes, interpreted as a cytokine
      mediated effect, is evident in some cases.

PMID- 10640433
TI  - Physico-chemical constraints connected with the coding properties of the genetic
      system.
AB  - New insights on the origin of the genetic code, based on the analysis of the
      physico-chemical properties of its molecular constituents (RNA and amino acids),
      are reported in this paper. We point out a symmetry in the genetic code table and
      show that it can be explained by the nature of the anticodon-codon interaction.
      The importance of the strength of this interaction is examined and a correlation
      is found between the free-energy change (DeltaG(0)) of anticodon-codon
      association and the volume of the corresponding amino acids. This correlation is
      investigated in conjunction with the well-known one linking the hydrophobicity of
      the anticodons with that of the amino acids. We show that they can be
      considerated separately and that the energy vs. volume correlation may be
      explained by the process implicating the peptide bond formation between two
      successive amino acids during translation. This interpretation is supported by a
      statistical pattern of bases (purines or pyrimidines), observed in present coding
      genes, and by considerations involving the availability of the different kinds of
      amino acids. Finally, we try to explain the hydrophobicity correlation when
      reconstructing the events at the time of the so-called "RNA World". The whole of
      our investigation shows that the genetic code might be sufficiently robust to
      exist without the participation of pre-existing proteins, and that this
      robustness is a consequence of the physico-chemical properties of the four bases
      of the genetic system.

PMID- 10640434
TI  - Accumulation of defective mitochondria through delayed degradation of damaged
      organelles and its possible role in the ageing of post-mitotic and dividing
      cells.
AB  - The mitochondrial theory of ageing proposes that an accumulation of defective
      mitochondria is a major contributor to the cellular deterioration that underlies
      the ageing process. The plausibility of the mitochondrial theory depends
      critically upon the population dynamics of intact and mutant mitochondria in
      different cell types. Earlier work suggested that mutant mitochondria might have
      a replication advantage but failed to account for the fact that mutants
      accumulate faster in post-mitotic than in dividing cells. We describe a new
      mathematical model that allows for damaged mitochondria to replicate more slowly,
      which accommodates experimental evidence of impaired energy generation and a
      reduced proton gradient in defective mitochondria. However, this is compensated
      for by a slower degradation rate of damaged mitochondria than intact ones, as
      suggested by de Grey (1997), which gives damaged mitochondria a selective
      advantage and leads to a clonal expansion of damaged mitochondria. This
      theoretical result is important because it agrees with evidence that, during
      ageing, single muscle fibres are taken over by one or only a few types of mtDNA
      mutants. The model also shows that cell division can rejuvenate and stabilize the
      mitochondrial population, consistent with data that post-mitotic tissues
      accumulate mitochondrial damage faster than mitotically active tissues.

PMID- 10640435
TI  - Prey processing in central place foragers.
AB  - The importance of prey processing as an integral part of foraging behaviour has
      long been acknowledged, but little theoretical consideration has been given to
      the optimization of the processing behaviour itself. Processing renders food down
      to ingestible, palatable portions, and also removes non-essential mass thus
      reducing transport costs. Here, several models of processing are developed for a
      central place forager. When the forager has to make a simple choice between
      processing the prey and not, a critical distance from the central place can be
      calculated, beyond which it is optimal to process prey. If the forager also
      decides on how much of the prey to remove, the optimal amount to be removed can
      also be calculated. Imposing a ceiling on overall metabolic expenditure is shown
      to reduce the distances at which processing becomes the optimal strategy. The
      models are tested using parameters derived for a provisioning merlin, Falco
      columbarius, and alternative explanations as to why observed behaviours should
      differ from the optimal behaviour predicted are discussed.

PMID- 10640436
TI  - Ribosome traffic in E. coli and regulation of gene expression.
AB  - The ribosome traffic during translation of E. coli coding sequences was
      simulated, assuming that the rate of translation of individual codons is limited
      by the cognate tRNA availability. Actual translation rates were taken from
      Solomovici et al. (J. theor. Biol. 185, 511-521, 1997). The mean translation
      rates of the 4271 sequences cover a broad, two-fold range, whereas the local rate
      of translation along messengers varies three-fold on average. The simulation
      allows one to sketch the ribosome traffic on the polysome, in particular by
      providing the extent of mRNA sequences uncovered between consecutive ribosomes
      and the time during which these sequences are exposed. These parameters may
      participate in the control of mRNA stability and transcriptional polarity. By
      averaging the translation rates in a 17-codon window, assumed to be the sequence
      covered by a translating ribosome, and sliding this window along a given coding
      sequence, the addresses KMAX and KMIN, and the times TMAX and TMIN of
      respectively the slowest and the fastest translated window were determined. It is
      shown that under the assumptions made, TMAX sets the number of proteins
      translated from a given mRNA molecule per unit time, in case the delay between
      consecutive translation starts is below TMAX. Both windows display two strong
      biases, one as expected on the usage of codon frequencies, and the other
      surprisingly on the occurrence of amino acids.

PMID- 10640437
TI  - Nitric oxide effects on myocardial function and force-interval relations:
      regulation of twitch duration.
AB  - As the precise role of nitric oxide (NO) as a modulator of myocardial contraction
      and the force-interval relationship remains unclear, the objective of this study
      was to examine the effect of the NO donor S-nitroso-N-acetyl-penicillamine (SNAP)
      on baseline myocardial contraction, and the impact of both SNAP and the NO
      synthase (NOS) inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) on the force
      interval relation. Studies were performed using isolated rat papillary muscles.
      In the presence of baseline NOS blockade, nanomolar to micromolar concentrations
      of SNAP exerted a modest positive inotropic effect with a small but significant
      increase in twitch isometric tension (P<0.007). Nanomolar concentrations of SNAP
      also reduced overall twitch duration (P<0.007). These effects were not seen in
      control experiments using N-acetyl-penicillamine instead of SNAP. The force
      frequency response (FFR) and post-rest contractile potentiation, mechanical
      correlates of sarcoplasmic reticulum (SR) Ca(2+)handling, were also examined.
      Neither L-NAME nor SNAP had any effect on post-rest potentiation following rest
      intervals as long as 6 min, or on the negative FFR at stimulation frequencies
      between 0.3 to 1.7 Hz. However, L-NAME significantly blunted the net reduction in
      twitch duration between 0.3 Hz and 1.7 Hz compared to control (P=0.006), an
      effect reversed by 100 n m SNAP. These results indicate that low concentrations
      of NO can modulate myocardial function by influencing myocardial inotropy and the
      time course of myofilament interaction, but do not impact significantly on the
      force-interval relation and, by inference, SR Ca(2+)handling. Moreover,
      modulation of twitch duration occurs over a range of stimulation frequencies,
      suggesting a mechanistic role for NO in the changes in contraction and relaxation
      time intervals seen during changes in heart rate.

PMID- 10640438
TI  - Pro-inflammatory cytokines stimulate mitogen-activated protein kinase
      subfamilies, increase phosphorylation of c-Jun and ATF2 and upregulate c-Jun
      protein in neonatal rat ventricular myocytes.
AB  - Pro-inflammatory cytokines may be important in the pathophysiological responses
      of the heart. We investigated the activation of the three mitogen-activated
      protein kinase (MAPK) subfamilies ?c-Jun N-terminal kinases (JNKs), p38-MAPKs and
      extracellularly-responsive kinases (ERKs) by interleukin-1 beta (IL-1 beta) or
      tumour necrosis factor alpha (TNF alpha) in primary cultures of myocytes isolated
      from neonatal rat ventricles. Both cytokines stimulated a rapid (maximal within
      10 min) increase in JNK activity. Although activation of JNKs by IL-1 beta was
      transient returning to control values within 1 h, the response to TNF alpha was
      sustained. IL-1 beta and TNF alpha also stimulated p38-MAPK phosphorylation, but
      the response to IL-1 beta was consistently greater than TNF alpha. Both cytokines
      activated ERKs, but to a lesser degree than that induced by phorbol esters. The
      transcription factors, c-Jun and ATF2, are phosphorylated by the MAPKs and are
      implicated in the upregulation of c-Jun. IL-1 beta and TNF alpha stimulated the
      phosphorylation of c-Jun and ATF2. However, IL-1 beta induced a greater increase
      in c-Jun protein. Inhibitors of protein kinase C (PKC) (Ro318220, GF109203X) and
      the ERK cascade (PD98059) attenuated the increase in c-Jun induced by IL-1 beta,
      but LY294002 (an inhibitor of phosphatidylinositol 3' kinase) and SB203580 (an
      inhibitor of p38-MAPK, which also inhibits certain JNK isoforms) had no effect.
      These data illustrate that some of the pathological effects of IL-1 beta and TNF
      alpha may be mediated through the MAPK cascades, and that the ERK cascade, rather
      than JNKs or p38-MAPKs, are implicated in the upregulation of c-Jun by IL-1 beta.

PMID- 10640439
TI  - Induction of lectin-like oxidized LDL receptor by oxidized LDL and
      lysophosphatidylcholine in cultured endothelial cells.
AB  - A functional change in the endothelium induced by oxidized low density
      lipoprotein (OxLDL) and its lipid-constituent, lysophosphatidylcholine (LPC), has
      been implicated in atherogenesis. Recently, we have cloned lectin-like OxLDL
      receptor (LOX-1) from bovine aortic endothelial cells (BAE). It is the major
      binding protein for OxLDL on the surface of BAE and is expressed in atheromatous
      intima of the human carotid artery as well as in intima of normal bovine aorta.
      In the present study, we found that OxLDL induced the expression of LOX-1 in BAE.
      OxLDL upregulated the level of mRNA and protein for LOX-1 in a dose- and time
      dependent manner. This induction was blocked by anti-LOX-1 antibody. OxLDL also
      increased the activity for taking up OxLDL in BAE. Similarly, a major constituent
      of OxLDL, lysophosphatidylcholine (LPC), induced expression of LOX-1 in mRNA,
      protein and activity level, suggesting the OxLDL induced expression of LOX-1, at
      least in part, mediated by LPC. Since LPC did not significantly change the half
      life of LOX-1 mRNA, the upregulation seemed to occur at the transcriptional
      level. These results suggest that LOX-1 is upregulated by the uptake of OxLDL
      through LOX-1 in atheromatous tissues in vivo, which would further enhance the
      uptake and endothelial activation and dysfunction.

PMID- 10640440
TI  - Effect of ionic strength on length-dependent Ca(2+) activation in skinned cardiac
      muscle.
AB  - The length-dependence of myofilament Ca(2+) sensitivity is considered to be an
      important component of the steep force-length relationship in cardiac muscle
      (Frank-Starling relation). Recent studies suggest that Ca(2+) sensitivity is a
      function of the number of strong-binding cross-bridge interactions formed at a
      given sarcomere length. However, the length-dependent step in the thin filament
      activation process is still unknown. This study was designed to test the
      hypothesis that sarcomere length influences the transition of the thin filament
      from the unattached (blocked) state to the weakly bound (closed) state. This
      hypothesis was tested by determining the length-dependence of Ca(2+) sensitivity
      as a function of ionic strength in skinned bovine ventricular muscle. Previous
      studies have shown that reduction in ionic strength below a critical level, in
      the absence of Ca(2+), shifts the thin filament to the closed state. In this
      study normal Ca(2+) regulation was maintained at low ionic strength but the
      length-dependence of Ca(2+) sensitivity and the length-dependence of Ca(2+)
      binding were eliminated. These results are consistent with the hypothesis that
      the transition from the blocked to the closed state is a function of filament
      geometry as well as Ca(2+) and ionic strength.

PMID- 10640441
TI  - Autocrine regulation of TGF beta expression in adult cardiomyocytes.
AB  - As shown before, TGF beta acts in an autocrine manner on the induction of
      hypertrophic responsiveness to beta-adrenoceptor stimulation in cultured
      ventricular cardiomyocytes of adult rat. We now investigated how TGF beta
      expression and activation is regulated in these cultures and how beta
      adrenoceptor stimulation influences TGF beta -mRNA expression. It was found that
      freshly isolated cardiomyocytes secrete latent TGF beta in the culture medium.
      Supplementation of the cultures with 20% FCS resulted in activation of the
      secreted TGF beta to 4.1+/-0.2 ng/ml active TGF beta after 6 days. Presence of
      the protease inhibitor aprotinin (50 microg/ml) reduced TGF beta activity by 44+/
      5% (n=5, P<0.05). In cultures supplemented with 5% FCS, TGF beta was not
      activated. Active TGF beta downregulated its mRNA-expression: after 6 days TGF
      beta(1)-mRNA was reduced to 55.1+/-11.0%, TGF beta(2)-mRNA to 30.1+/-16.5%, and
      TGF beta(3)-mRNA to 0.3+/-0.4% in 20% FCS-cultures as compared to their
      expression in freshly isolated cells (n=4, P<0.05). TGF beta-mRNA expression did
      not change in cultures without active TGF beta. Isoprenaline (1 microm) increased
      TGF beta(1)-mRNA only in cultures which had been pre-exposed to active TGF beta.
      This effect was also seen when hearts from normal mice were compared with hearts
      from transgenic mice overexpressing TGF beta(1): only in hearts from transgenic
      animals perfusion with isoprenaline increased TGF beta(1)-mRNA. In conclusion,
      isolated cardiomyocytes release latent TGF beta, which is activated by external
      proteases. Active TGF beta downregulates its own mRNA expression. Preexposure to
      TGF beta is necessary for a beta-adrenoceptor-mediated increase in TGF beta(1)
      mRNA in cardiomyocytes.

PMID- 10640442
TI  - Characterization of proximal transcription regulatory elements in the rat
      phospholamban promoter.
AB  - Phospholamban is a major regulator of cardiac diastole, with alterations in
      expression associated with modified cardiac relaxation. To study transcriptional
      regulation of phospholamban expression, we made reporter constructs that
      expressed luciferase under control of putative promoter sequences from the rat
      phospholamban gene. When transfected into neonatal rat cardiomyocytes, constructs
      containing at least 159 nucleotides preceding the transcription start site were
      equally active, while truncation to -66/+64 removed all promoter activity.
      Constructs were more active in cardiomyocytes than in HeLa cells (which do not
      express phospholamban), but did not show absolute cell-type specificity of
      expression. Addition of sequences upstream to -4032, all of the intron (7.4 kb),
      or 3'UTR sequences (0. 8 kb) did not enhance cell-specific expression. To focus
      on the basal promoter region (-159/-66), a series of deletion constructs were
      made that identified a novel 35 bp region (-159/-125; Phospholamban Promoter
      Element 1, PPE1) required for promoter activity in cardiomyocytes. Site-specific
      mutations identified nucleotides -150/-133 as containing most of the promoter
      enhancing activity. While the rat PPE1 is highly conserved (>70%) in four other
      mammalian phospholamban genes, it does not contain previously characterized
      regulatory elements. In cardiomyocytes the PPE1 sequence markedly enhanced
      activity of the SV40 early promoter. A conserved CCAAT element (-83/-79) was also
      required for promoter activity in both cardiomyocytes and HeLa cells. Exonuclease
      III footprinting identified protein/DNA interactions in both the extended CCAAT
      box and PPE1 domains. Gel shift studies identified the CCAAT elements as binding
      CBF/NF-Y.

PMID- 10640443
TI  - The green fluorescent protein is an efficient biological marker for cardiac
      myocytes.
AB  - There is a need for a non-toxic marker for cardiac myocytes in studies of cardiac
      development and in experimentally induced pathophysiologic states in adult
      animals. We investigated the possibility of using the enhanced green fluorescent
      protein (EGFP) gene as such a biological marker for cardiac myocytes in both
      whole animal and cell culture systems. Several lines of transgenic mice were
      constructed harboring an EGFP gene directed by a 2.38-kb promoter fragment of the
      hamster beta -myosin heavy chain gene. The transgene was preferentially expressed
      in the cardiac progenitor cells of embryos at E7.5, a developmental stage that
      precedes the formation of the cardiomyotube. It was specifically expressed in the
      cardiomyotube and myotomes along the somites of embryos at E8.5. The EGFP
      transgene expression continued in the heart throughout gestation and became very
      intense at birth. When neonatal cardiac cells were fractionated into myocytes and
      non-myocytes by a differential plating procedure, only myocytes from the
      transgenic mice showed specific green fluorescence of the transgene product that
      can be used as a marker for flow cytometry analysis. Although the expression
      levels were heterogeneous, EGFP expression persisted in the hearts of postnatal
      animals. In addition to the heart, some skeletal and smooth muscles from
      transgenic animals also expressed the transgene. The transgenic mice were healthy
      and had a normal life span, identical to their non-transgenic littermates. These
      results demonstrate that EGFP is an efficient non-toxic biological marker for
      cardiac myocytes.

PMID- 10640444
TI  - Transcription of the SERCA2 gene is decreased in pressure-overloaded hearts: A
      study using in vivo direct gene transfer into living myocardium.
AB  - T. Takizawa, M. Arai, A. Yoguchi, K. Tomaru, M. Kurabayashi and R. Nagai.
      Transcription of the SERCA2 Gene is Decreased in Pressure-overloaded Hearts: A
      Study Using In Vivo Direct Gene Transfer into Living Myocardium. Journal of
      Molecular and Cellular Cardiology (1999) 31, 2167-2174. The sarcoplasmic
      reticulum Ca(2+)-ATPase (SERCA2) controls the myocardial relaxation process.
      Under pressure-overload, the expression of its mRNA decreases, thus controlling
      cardiac function to conform to the load. However, it is not known whether this
      decreased expression is caused by a decrease in the transcription of the SERCA2
      gene. The object of this study was to determine the transcription control
      mechanism of the SERCA2 gene under pressure-overload in vivo, and to identify the
      pressure-overload-sensitive regions of the SERCA2 gene. Ten micrograms of a
      plasmid, containing the 5' upstream (-1810 bp to +350 bp) region of the SERCA2
      gene and a luciferase reporter gene, were introduced into adult rat myocardium by
      in vivo direct gene transfer, and the luciferase activity was measured 5 days
      later. The transcriptional activity under pressure-overload decreased to 27+/-17%
      of the control. Based on this result, we concluded that the decreased mRNA
      expression of SERCA2 in pressure-overload cardiac hypertrophy is due to decreased
      gene transcription. In addition, various deletion fragments of the SERCA2
      promoter region were produced, and tested for luciferase production under
      pressure-overload. Our data suggest that a transcription activation site is
      present between -685 and -284 bp, and two transcription inhibition sites are
      present between -1810 to -1110 bp and -284 to -72 bp. These may be the pressure
      sensitive regions of the SERCA2 gene of in vivo hypertrophied myocardium under
      pressure-overload.

PMID- 10640445
TI  - Altered creatine kinase enzyme kinetics in diabetic cardiomyopathy. A(31)P NMR
      magnetization transfer study of the intact beating rat heart.
AB  - To determine whether the decreased contractile performance in diabetic hearts is
      associated with a reduced energy reserve due to decreased creatine kinase (CK)
      activity, we measured total CK activity (V(max)) in vitro and CK reaction
      velocity in vivo using(31)P NMR spectroscopy in isolated perfused rat hearts
      after 4 and 6 weeks of diabetes. After 4 weeks of diabetes, V(max)decreased by
      22% with a larger decrease of CK MB than of CK MM and mitochondrial-CK
      isoenzymes. There was no further decrease in these parameters after 6 weeks of
      diabetes. Isovolumic contractile performance of 4 and 6 week diabetic hearts,
      estimated as rate-pressure product under identical perfusion and loading
      conditions (EDP set at 6-8 mmHg), was only 50% of that of control. ATP, PCr and
      total creatine concentrations were not different in control and 4 or 6 weeks
      diabetic rat hearts. After 4 weeks of diabetes, CK reaction velocity decreased by
      22%. This was in proportion to the decline of V(max)and therefore predicted by
      the rate equation for the CK reaction. However, the further decline in the CK
      reaction velocity after 6 weeks of diabetes (45%) was greater than that predicted
      from the CK rate equation (17% decrease), and cannot be explained by substrate
      control of the enzyme. When hearts were inotropically stimulated by increasing
      perfusate calcium concentration, CK reaction velocity increased slightly
      (approximately 15%) in both control and diabetic hearts, thereby maintaining a
      constant ATP concentration. We conclude that in the diabetic myocardium, the CK
      reaction velocity decreases but does not limit the availability of high-energy
      phosphates for contraction over the range of workloads studied. We also conclude
      that a mechanism(s) in addition to substrate control regulates CK reaction
      velocity in the 6 week diabetic hearts.

PMID- 10640446
TI  - Clinical L-type Ca(2+) channel blockade prevents ischemic preconditioning of
      human myocardium.
AB  - Although Ca(2+) channel blockers are commonly used to control both blood pressure
      and angina in patients with coronary artery disease, clinical trials have
      associated the use of L-type Ca(2+) channel blockers with increased
      cardiovascular mortality. Recent evidence has implicated Ca(2+) entry through the
      L-type Ca(2+) channel during transient ischemia as a proximal stimulus for
      ischemic preconditioning (IPC) in experimental animals. We therefore hypothesized
      that clinical L-type Ca(2+) channel blockade prevents IPC in human myocardium.
      Human atrial trabeculae were suspended in organ baths, field simulated at 1 Hz,
      and force development was recorded. Following 90 min equilibration, trabeculae
      from control patients and patients taking L-type Ca(2+) channel blockers were
      subjected to simulated ischemia/reperfusion (I/R: 45/120 min) with or without 5
      min of simulated ischemia (IPC stimulus) prior to I/R. IPC increased post
      ischemic developed force in control patients from 14.6+/-2.6 to 43.1+/-3.5%
      baseline developed force (%BDF P<0.05 I/R vs IPC). Whereas IPC failed to increase
      post-ischemic developed force in myocardium from patients taking L-type Ca(2+)
      channel blockers (15. 1+/-1.9 vs 16.6+/-1.7 %BDF, P>0.05 L-type I/R v L-type
      IPC). We conclude that: (1) atrial muscle can be preconditioned by transient
      ischemia; (2) atrial muscle from patients taking L-type Ca(2+) channel blockers
      cannot be preconditioned by transient ischemia; and (3) the increased
      cardiovascular mortality historically associated with the use of Ca(2) channel
      blockers in patients with coronary artery disease may be, in part, due to the
      pharmacological inhibition of ischemic preconditioning.

PMID- 10640447
TI  - Induction of high mobility group I architectural transcription factors in
      proliferating vascular smooth muscle in vivo and in vitro.
AB  - Proliferation of vascular smooth muscle cells (VSMCs) is a hallmark of
      arteriosclerosis. Architectural transcription factors of the high mobility group
      (HMG)-I family have been implicated in the control of cell proliferation and gene
      expression. We studied the pattern of HMG-I mRNA and protein expression in
      proliferating VSMCs. HMG-I(Y) and HMGI-C mRNAs were barely detectable by Northern
      analysis in samples prepared from uninjured rat carotid arteries. In contrast,
      these mRNAs were induced dramatically in carotid arteries 2 and 5-6 days after
      balloon injury. By in situ hybridization at 6 days after injury, the induced
      mRNAs localized to smooth muscle cells of the developing neointima, and
      immunocytochemical analysis showed that HMG-I(Y) protein was expressed in the
      nuclei of these cells. To confirm this association between HMG-I protein
      induction and cell growth, we assessed HMG-I(Y) and HMGI-C mRNA expression in rat
      aortic smooth muscle cells (RASMCs) in primary culture. The HMG-I mRNAs were
      barely detectable in quiescent RASMCs but were induced markedly by serum
      stimulation. This induction of mRNA by serum was time dependent and peaked at 9
      h. Western blot analysis confirmed that HMG-I(Y) protein induction also occurred
      in vitro. To our knowledge, this is the first demonstration of induction of HMG-I
      protein expression in proliferating RASMCs in vivo and in vitro. This
      demonstration suggests that the HMG-I proteins may play an important role in
      smooth muscle cell proliferation.

PMID- 10640448
TI  - Localization of K(+) channels in the tubules of cardiomyocytes as suggested by
      the parallel decay of membrane capacitance, IK(1) and IK(ATP) during culture and
      by delayed IK(1) response to barium.
AB  - Adult ventricular myocytes lose T-tubules over few days in culture, which causes
      the loss of about 60% of the cell membrane capacitance (Cm) (Mitcheson et al.,
      1996). In this study, we have measured, in whole-cell voltage-clamped rabbit
      right ventricular myocytes at 0, 1, 2 and 3-5 days of culture (nine to 20
      myocytes at each age) in a defined Dulbecco's modified Eagle's medium, the value
      of Cm and the magnitudes of the background inward rectifier current (IK(1)) and
      of the 2,4-dinitrophenol-induced ATP-sensitive potassium current (IK(ATP)). Cm,
      IK(1) and IK(ATP) all had decreased significantly by 51, 83 and 88%, respectively
      after 4 days of culture. Analysis using a single exponential decay function of
      time gave time constants of, 2.6+/-0.2, 2.2+/-0.5 and 2.4+/-0.4 days,
      respectively. Linear regressions of IK(1) and IK(ATP) versus Cm had regression
      coefficients of 0.93 and 0. 98, respectively. These observations are consistent
      with a strong link of the decay of IK(1) and IK(ATP) currents to that of Cm.
      Furthermore, the time course of changes in IK(1) when an external blocker (100
      microm BaCl(2)) was applied and washed by local perfusion (95% change in 50 ms)
      agrees with a model including a diffusion time constant of 300 ms. This value is
      consistent with the known kinetics of diffusion of divalent cations in the T
      tubules. Taken together, these results could be explained by the localization of
      a major part of the IK(1) and IK(ATP) currents of ventricular cardiomyocytes in
      the T-tubules. As a consequence, transient accumulation of K(+) ions in cardiac T
      tubules may take place and modulate excitation-contraction coupling.

PMID- 10640449
TI  - Characterization of hepatic iron overload following dietary administration of
      dicyclopentadienyl iron (Ferrocene) to mice: cellular, biochemical, and molecular
      aspects.
AB  - A unique organic form of iron (dicyclopentadienyl iron; ferrocene) has been used
      to further elucidate specific hepatic histopathologic, biochemical, and molecular
      parameters associated with dietary iron overload. Male C57BL/6Ibg mice fed a diet
      containing 0.04-0.2% w/w ferrocene for 115 days displayed severe hepatic
      siderosis of hepatocytes accompanied by a 15-fold induction of nonheme iron
      content compared to control mice receiving a diet with normal amounts of iron.
      The ferrocene treatment led to significant increases in hepatocellular necrosis
      as measured by plasma alanine aminotransferase activity. Histological assessment
      of hepatic fibrosis revealed mild increases in collagen deposition localized with
      accumulations of hemosiderin primarily in centrilobular hepatocytes. Hepatic
      fibrosis was confirmed by measurement of hepatic hydroxyproline content that was
      increased 4-fold in ferrocene-fed animals compared to control animals not
      ingesting ferrocene. Hepatic siderosis was accompanied by significant increases
      in hepatic malondialdehyde content suggesting the ferrocene-induced iron burden
      initiated lipid peroxidation in vivo. Expression of the heavy-chain isoform of
      ferritin mRNA and protein measured in liver after ferrocene feeding was increased
      approximately 8- and 2-fold, respectively, compared to the appropriate controls.
      These results, using an organic form of iron fed to genetically well
      characterized inbred mice, provide new additional insight into the specific
      molecular and biochemical events that occur in association with histopathologic
      changes initiated by iron-induced liver injury. These data support the hypothesis
      that peroxidation of cellular membrane lipids is an important mechanism involved
      in the toxicity of excess hepatic iron and possibly the initiation of liver
      fibrogenesis. The results presented here also provide novel in vivo evidence
      documenting the cellular modulation of ferritin in response to the toxic effects
      of hepatic iron overloading and iron-mediated oxidative stress.

PMID- 10640450
TI  - RAR and RXR expression by Kupffer cells.
AB  - Retinoids are known to modulate macrophage differentiation, proliferation, and
      function including cytokine gene expression. However, signaling of retinoic acid
      (RA), a biologically active metabolite of vitamin A, in Kupffer cells has not
      been characterized. This study reports mRNA expression by rat Kupffer cells of RA
      receptor (RAR) and retinoid X receptor (RXR) subtypes and their binding
      activities to the RA responsive element (RARE) or retinoid X responsive element
      (RXRE). Total RNA and nuclear proteins were extracted from Kupffer cells
      immediately following isolation from livers of normal male Wistar rats.
      Competitive PCR demonstrated relative mRNA expression of RAR and RXR subtypes in
      the order of beta>alpha>gamma for and alpha>beta>gamma, respectively. It also
      demonstrated that the RXR alpha and beta mRNA levels were 5- to 10-fold higher in
      Kupffer cells than in hepatic stellate cells while RAR mRNA expression was shown
      to be similar for all the subtypes in both cell types. Gel mobility shift assays
      of nuclear extracts with labeled RARE and RXRE probes showed distinct binding
      activities for both responsive elements, which were effectively displaced with
      cold probes in excess but not with an unrelated oligonucleotide. A supershift
      assay with an antibody against RARalpha or RXRalpha has confirmed the
      contribution of both receptors to RARE binding and that of the RXRalpha to RXRE
      binding activity. These results represent the first demonstration of RA signaling
      at the nuclear level in Kupffer cells.

PMID- 10640451
TI  - Association of HLA-DQ and -DR alleles with protection from or infection with HIV
      1.
AB  - Infection with human immunodeficiency virus type 1 (HIV-1) and progression to
      acquired immune deficiency syndrome (AIDS) are controlled by both host genetic
      factors and viral factors. The HLA (human leukocyte antigen) region in humans
      controls immune response functions and tissue rejection and influences
      susceptibility to neoplasia, autoimmune diseases, and infectious diseases
      including HIV. Twenty-eight African American and 12 Caucasian patients
      participated in the study. HLA-DQB1 and HLA-DRB1 genotyping was performed using
      PCR and sequence-specific oligonucleotide probe reverse hybridization and
      analyzed with the LiPA Key Typing System and LiPA software. DQB1*0603 was found
      to be positively associated with HIV-1 infection and with HIV-1 infection in
      Caucasians but not African Americans. DQB1*03032 frequencies indicate a positive
      association with protection from HIV-1 infection. It was further found to be
      protective against HIV-1 infection in Caucasians but not in African Amens.
      DQB1*0201 was observed more frequently in HIV(+) African Americans than HIV(-)
      African Americans, suggesting a positive association with HIV-1 infection in this
      ethnic group. HLA-DRB1*04 exhibited a positive association with HIV-1 infection
      in Caucasians. These data show that there are HLA class II alleles associated
      with susceptibility to and protection from HIV-1 infection and that these differ
      between ethnic groups.

PMID- 10640452
TI  - Mechanisms of suppression of experimental autoimmune encephalomyelitis by
      intravenous administration of myelin basic protein: role of regulatory spleen
      cells.
AB  - Experimental allergic encephalomyelitis (EAE) can be downregulated by intravenous
      (iv) administration of myelin basic protein (MBP). In this report we show that
      downregulation of EAE by two 500-microgram doses of MBP administered iv before
      immunization was associated with reduced encephalitogenicity of both spleen and
      lymph node cells (day 12 postimmunization) in adoptive transfer studies. However,
      efficient downregulation of EAE by two 500-microgram iv doses of MBP on days 10
      and 11 after active immunization (at the time of disease onset) was associated
      with no significant change in the encephalitogenicity of lymph node cells, but a
      complete abrogation of the ability of spleen cells (both at day 12
      postimmunization) to transfer EAE compared to controls. Furthermore, coculture of
      spleen cells from rats tolerized by iv MBP on days 10 and 11 after active
      immunization with MBP with MBP-reactive T cells resulted in a decreased ability
      of the spleen T cells to transfer EAE compared to effector cells in monoculture.
      In contrast, coculture of MBP-reactive T cells with spleen cells from rats
      tolerized by iv MBP on days 14 and 7 before active immunization resulted in
      increased disease in recipient rats. These results suggest that reversal of
      clinical EAE by iv injection of MBP at the time of disease onset is due at least
      in part to a T cell control mechanism located in the spleen and suggest the
      presence of splenocyte regulatory cells that can suppress the ability of
      encephalitogenic T cells to induce EAE.

PMID- 10640453
TI  - Facilitation of immune function, healing of pressure ulcers, and nutritional
      status in spinal cord injury patients.
AB  - Multiple communicative pathways among nervous, endocrine, and immune systems
      facilitate physiological immunoregulation. Spinal cord injury (SCI) patients had
      strikingly decreased natural and adaptive immune responses by 2 weeks post
      injury. While NK-cell function was decreased, plasma ACTH and urine-free cortisol
      levels were increased. T cell function and activation were both diminished. With
      rehabilitation therapy, NK and T function increased; without rehabilitation, NK
      levels remained depressed. When rehabilitation ceased, NK function decreased.
      Cervical SCI patients had less NK and T function than thoracic injury patients.
      SCI patients also had reduced levels of cellular adhesion molecules (CAMs) that
      participate in immune function and wound healing. SCI patients with pressure
      ulcers were compared to those without pressure ulcers. LFA-1, VLA-4, and other
      surface markers were decreased on the lymphocytes of all SCI patients. SCI
      patients with pressure ulcers had lower CAM levels than did patients without
      pressure ulcers. Nutritional status was determined by zinc, albumin, and
      prealbumin levels. SCI patients had decreased albumin levels. Those with pressure
      ulcers had decreased prealbumin levels and zinc levels.

PMID- 10640454
TI  - Antibodies to squalene in Gulf War syndrome.
AB  - Gulf War Syndrome (GWS) is a multisystemic illness afflicting many Gulf War-era
      veterans. The molecular pathological basis for GWS has not been established. We
      sought to determine whether the presence of antibodies to squalene correlates
      with the presence of signs and symptoms of GWS. Participants in this blinded
      cohort study were individuals immunized for service in Desert Shield/Desert Storm
      during 1990-1991. They included 144 Gulf War-era veterans or military employees
      (58 in the blinded study), 48 blood donors, 40 systemic lupus erythematosus
      patients, 34 silicone breast implant recipients, and 30 chronic fatigue syndrome
      patients. Serum antibodies to squalene were measured. In our small cohort, the
      substantial majority (95%) of overtly ill deployed GWS patients had antibodies to
      squalene. All (100%) GWS patients immunized for service in Desert Shield/Desert
      Storm who did not deploy, but had the same signs and symptoms as those who did
      deploy, had antibodies to squalene. In contrast, none (0%) of the deployed
      Persian Gulf veterans not showing signs and symptoms of GWS have antibodies to
      squalene. Neither patients with idiopathic autoimmune disease nor healthy
      controls had detectable serum antibodies to squalene. The majority of symptomatic
      GWS patients had serum antibodies to squalene.

PMID- 10640455
TI  - Fluorescent in situ hybridization study of c-myc oncogene copy number in prostate
      cancer.
AB  - We previously conducted a study of 88 cases of prostate cancer in an attempt to
      identify potential prognostic biomarkers that can distinguish aggressive cases
      that must be treated immediately. Prostate cancer is a serious disease affecting
      men worldwide and compromises the quality of life of its patients. Biomarkers
      studied included chromosome 7 trisomy, chromosome 8 trisomy, and HER-2/neu
      oncogene amplification. These biomarkers were initially studied because trisomy 8
      and oncogene amplification of the HER-2/neu gene have been reported in many other
      cancers, including those studied in this laboratory. In view of the fact that HER
      2/neu amplification was not found to play a prominent role in the group of
      prostate cancer specimens that we studied, an exploration of other biomarkers was
      felt to be warranted. Thus, we began a pilot study of c-myc oncogene copy number
      in prostate cancer using the same protocol for fluorescent in situ hybridization
      and a direct-labeled SpectrumOrange LSI c-myc probe (Vysis, Inc., Downers Grove,
      IL) on formalin-fixed, paraffin-embedded tissue. From a total of 36 cases of
      prostate cancers successfully analyzed, we found 11 (31%) tumors exhibiting 3 or
      more positive signals for c-myc in 15% or more of the cells. Of these, only 7
      tumors (19% of the total cases studied) had >/=3 signals in 20% or more of the
      cells. No case had >/=3 signals in 25% or more of the cells. Compared to other
      molecular probes tested, the c-myc signals were more faint and the quality of the
      preparation was less optimal than other tumor specimens that we previously
      studied. Based on the information available thus far, we conclude that an
      increased copy number in c-myc oncogene copy number was not a prominent finding
      in our cohort of prostate cancer patients.

PMID- 10640456
TI  - Hypotetraploidy in a patient with small cell carcinoma.
AB  - While numerical and structural chromosomal abnormalities characterize many
      hematopoietic and nonhematopoietic malignancies, the occurrence of polyploidy is
      by and large rare. We report here an interesting patient with small cell
      carcinoma (SCC) and hypotetraploidy initially referred to us because of a
      question of acute nonlymphocytic leukemia, M3 subtype, with a question of a 15;17
      translocation characteristic of acute promyelocytic leukemia. However, the
      patient did not have a 15;17 translocation and the final hematopathologic
      analysis of the bone marrow aspirates and immunohistochemistry studies
      subsequently revealed the patient to have SCC. Small cell carcinoma is a highly
      malignant and a very aggressive neoplasm. A review of the literature, using
      Medline, Cancerlit, and the Science Citation Index, revealed that in most, if not
      all, reports, the presence of polyploidy is noted as a rare entity. In leukemia,
      reports of polyploidy point to a distinct category of patients with a poor risk
      for which more intensive treatment is needed. Limited information is currently
      available to assess the risk of polyploidy in small cell carcinoma. Our case is
      important not only because of the relative rarity of polyploidy, but also because
      insights gained from the study of this and other similar patients may help shed
      additional light on the mechanism of carcinogenesis, which is not fully known to
      date. As polyploidization is a manifestation of genetic instability and as
      genetic instability has been implicated in the genesis and progression of many
      cancers, it is perhaps not too surprising that polyploidy in our case was
      associated with a poor disease outcome. The patient has since expired.

PMID- 10640503
TI  - Robust assessment of statistical significance in the use of unbound/intrinsic
      pharmacokinetic parameters in quantitative structure-pharmacokinetic
      relationships with lipophilicity.
AB  - The optimization of pharmacokinetic properties remains one of the most
      challenging aspects of drug design. Key parameters, clearance and volume of
      distribution, are multifactorial, which makes deriving structure-pharmacokinetic
      relationships difficult. The correction of clearance and volume of distribution
      for the unbound fraction in plasma is one approach taken that has enabled
      quantitative structure-pharmacokinetic relationships to be derived. Three
      published data-sets where unbound parameters have been correlated with
      lipophilicity have been reanalyzed. The reanalysis has shown that high
      correlation coefficients can be achieved without any true correlation in the data
      and can lead to misinterpretation of the ways in which lipophilicity influences
      pharmacokinetics. Randomization procedures are proposed as a more robust method
      of assessing significance.

PMID- 10640504
TI  - Extensive metabolism of diltiazem and P-glycoprotein-mediated efflux of desacetyl
      diltiazem (M1) by rat jejunum in vitro.
AB  - The objective of this in vitro study was to investigate both the intestinal
      metabolism and transport of diltiazem (DTZ) and its major metabolites in rat
      jejunum. Metabolism experiments were performed with everted sacs, whereas sheets
      mounted in a symmetrical twin chamber system were used in transport studies. DTZ
      was rapidly desacetylated by the rat jejunum to the principle metabolite
      desacetyl-diltiazem (M1). In addition, minor amounts of N-demethyl-diltiazem and
      desacetyl-N-demethyl-diltiazem were formed. Due to the rapid desacetylation, it
      proved difficult to study the transport of DTZ in this model. However, the
      primary metabolite M1 was shown to be subjected to P-glycoprotein (Pgp)-mediated
      efflux. The flux rate of M1 was 6- to 7-fold higher from the serosal to the
      luminal compartment than in the opposite direction. Both coadministration of
      verapamil and Pgp monoclonal antibody dose dependently increased luminal-to
      serosal flux and decreased serosal-to-luminal flux. In conclusion, rat jejunum
      metabolizes DTZ extensively in vitro, and the major primary metabolite M1 is
      subjected to Pgp-mediated efflux.

PMID- 10640505
TI  - Novel metabolic pathway of estrone and 17beta-estradiol catalyzed by cytochrome P
      450.
AB  - We have already reported that the quinol formation from some para-alkylphenols,
      which is a novel metabolic pathway catalyzed by cytochrome P-450, occurs in a rat
      liver microsomal system (). In the present study, we investigated whether estrone
      and 17beta-estadiol, each of which contains a p-alkylphenol moiety, are also
      oxidized into the corresponding quinols by cytochrome P-450. Six recombinant
      human cytochrome P-450 enzymes, CYP1A1, CYP1A2, CYP2B6, CYP2C9, CYP2E1, and
      CYP3A4, were tested. The results show that estrone and 17beta-estadiol were
      converted into the corresponding quinols by CYP1A1, CYP2B6, and CYP2E1.

PMID- 10640506
TI  - Histologic localization of serum constituents, (45)Ca(2+), (36)Cl(-),
      [(14)C]urea, and [(35)S]cysteine in forming hair after systemic administration.
AB  - To further investigate the chemical mechanisms involved in the accumulation of
      drugs or other compounds in hair, we characterized histologically the deposition
      of radiolabeled serum constituents in the hair of BALB/c (albino) and C57
      (pigmented) mice. The extent and location of the incorporation of a normal serum
      cation ((45)Ca(2+)), a serum anion ((36)Cl(-)), a neutral constituent
      ([(14)C]urea), and a structural component of hair ([(35)S]cysteine) were studied
      to provide a comparative framework for the examination of drugs deposited in hair
      from serum. Two mouse strains were used to evaluate the effect of hair
      pigmentation on deposition. Localization of deposition was observed using
      microautoradiography of skin sections from animals given a systemic dose of each
      tracer. The cation, (45)Ca(2+), associated with melanocytes and melanosomes of
      forming C57 hair within 5 min of dosing, but did not associate with the cells of
      forming BALB/c hair. This was consistent with previous results that indicated
      greater concentrations of Ca(2+) in mature C57 mouse hair when compared with
      mature BALB/c hair. Both [(14)C]urea and [(35)S]cysteine associated with all
      cells in the papilla of the forming hair of both C57 and BALB/c mice. This again
      was consistent with previous results that indicated that similar concentrations
      of cysteine and urea were incorporated into mature C57 and BALB/c hair. The
      anion, (36)Cl(-), did not associate with either C57 or BALB/c hair. The lack of
      deposition of (36)Cl(-) may be due to the loss of the tracer during sample
      processing and suggests that Cl(-) could be removed from mature hair. These data
      confirm previous results that suggested that the melanin component of hair was
      capable of ionic interactions and that the protein component was capable of
      neutral, lipophilic interactions. Our findings suggest a multicompartmental model
      of drug deposition in hair.

PMID- 10640507
TI  - Identification of a ubiquitination-Target/Substrate-interaction domain of
      cytochrome P-450 (CYP) 2E1.
AB  - Cytochrome P-450 (CYP) 2E1, the alcohol-inducible form of CYP, metabolizes a wide
      variety of endogenous substrates, therapeutic agents, protoxicants, and
      procarcinogens. CYP2E1 levels are post-transcriptionally elevated in response to
      certain xenobiotic inducers (e.g., pyridine), and proposed mechanisms include
      increased translational efficiency and protection of the enzyme from ubiquitin
      dependent proteolysis. Molecular modeling of a predicted cytosolic domain of
      CYP2E1 resulted in identification of a putative ubiquitination-target/substrate
      interaction structure (residues 317-340). An affinity-purified antibody reactive
      to this domain quenched CYP2E1 ubiquitination in a concentration-dependent manner
      in a rabbit reticulocyte lysate-based ubiquitination assay. The same antibody
      also inhibited rat liver microsomal chlorzoxazone 6-hydroxylase activity, a
      marker of CYP2E1 catalytic activity, in an equivalent concentration-dependent
      manner. These two observations suggest an association between the CYP2E1
      cytosolic domain involved in catalysis and its serving as a target for
      ubiquitination. Thus, these results provide a plausible mechanistic explanation
      for the observation that substrate binding shields the CYP2E1 protein from
      turnover by the ubiquitin-proteasome-dependent machinery.

PMID- 10640508
TI  - Drug interactions with calcium channel blockers: possible involvement of
      metabolite-intermediate complexation with CYP3A.
AB  - The inhibitory effects of six commonly used calcium channel blockers on three
      major cytochrome P-450 activities were examined and characterized in human liver
      microsomes. All six compounds reversibly inhibited CYP2D6 (bufuralol 1'
      hydroxylation) and CYP2C9 (tolbutamide methyl hydroxylation) activities. The
      IC(50) values for the inhibition of CYP2D6 and CYP2C9 for nicardipine were 3 to 9
      microM, whereas those for all others ranged from 14 to >150 microM. Except for
      nifedipine, all calcium channel blockers showed increased inhibitory potency
      toward CYP3A activities (testosterone 6beta-hydroxylation and midazolam 1'
      hydroxylation) after 30-min preincubation with NADPH. IC(50) values for the
      inhibition of testosterone 6beta-hydroxylase obtained in the NADPH-preincubation
      experiment for nicardipine (1 microM), verapamil (2 microM), and diltiazem (5
      microM) were within 10-fold, whereas those for amlodipine (5 microM) and
      felodipine (13 microM) were >200-fold of their respective plasma concentrations
      reported after therapeutic doses. Similar results also were obtained based on
      midazolam 1'-hydroxylase activity. Unlike the observations with mibefradil, a
      potent irreversible inhibitor of CYP3A, the NADPH-dependent inhibition of CYP3A
      activity by nicardipine and verapamil was completely reversible on dialysis,
      whereas that by diltiazem was partially restored (80%). Additional experiments
      revealed that nicardipine, verapamil, and diltiazem formed cytochrome P-450-iron
      (II)-metabolite complex in both human liver microsomes and recombinant CYP3A4.
      Nicardipine yielded a higher extent of complex formation ( approximately 30% at
      100 microM), and was a much faster-acting inhibitor (maximal inhibition rate
      constant approximately 2 min(-1)) as compared with verapamil and diltiazem. These
      present findings that the CYP3A inhibition caused by nicardipine, verapamil, and
      diltiazem is, at least in part, quasi-irreversible provide a rational basis for
      pharmacokinetically significant interactions reported when they were
      coadministered with agents that are cleared primarily by CYP3A-mediated pathways.

PMID- 10640509
TI  - Antisense oligonucleotides targeted to the p53 gene modulate liver regeneration
      in vivo.
AB  - The rapidly proliferating cells of the regenerating liver after partial
      hepatectomy (PH) present a reproducible in vivo model to study the functional
      role of the tumor suppressor gene p53. The present study uses the rat 70% PH
      model along with systemic administration of three different structural types of
      antisense oligonucleotides (ODNs) designed to suppress p53 expression. We tested
      the hypothesis that antisense ODNs can inhibit the expression of p53, resulting
      in the loss of the G(1)-S cell cycle checkpoint and an altered pattern of liver
      regeneration. Intraperitoneal administration of 5 mg/kg/day antisense
      phosphorothioate ODN after 70% PH resulted in reduced expression of the p53
      protein in the regenerating liver. There were concomitant increases in weight
      gain of remnant-regenerating liver and expression of proliferating cell nuclear
      antigen and p21(waf-1) compared with either saline or 5 mg/kg/day mispaired
      phosphorothioate ODN treatment. Flow cytometric analysis of DNA content of
      isolated hepatocytes revealed a reduction in the G(0)/G(1) cell population and
      accumulation of cells with more than 4n DNA in antisense-treated rats. The
      regenerating livers had significantly diminished cytochrome P-450 (CYP) enzyme
      activities. Rats treated with p53 antisense ODNs, but not saline or mispair ODN
      controls, had significantly elevated CYP activities. These observations
      functionally link the expression of p53 with diminished expression of several CYP
      isoforms in the liver regeneration model.

PMID- 10640510
TI  - Tissue- and gender-specific expression of N-acetyltransferase 2 (Nat2*) during
      development of the outbred mouse strain CD-1.
AB  - The human N-acetyltransferase (Nat2) genetic polymorphisms have been modeled in
      mouse strains. We determined the phenotype and genotype of the N
      acetyltransferase 2 (Nat2*) gene among outbred CD-1 mice and found a mixed
      population of heterozygous and rapid and slow homozygous genotypes. Phenotypes
      determined with p-aminobenzoic acid demonstrated complete concordance of slow and
      rapid genotype and phenotype. The kidney p-aminobenzoic acid/Nat2-acetylating
      activity of CD-1 female mice showed a 2.5-fold increase at 80 days of age
      compared with day 1, whereas males showed a 4.3-fold increase at 25 days and a
      5.8-fold increase at 80 days. Immunoblot analysis revealed a 2-fold increase in
      male kidney Nat immunoreactive protein at 80 days of age, whereas no significant
      differences were detected in female mice. Likewise, the Nat2 mRNA levels
      determined by ribonuclease protection assay showed an increase in transcript
      levels in kidney of male mice during postnatal development, whereas they remained
      unchanged in females. Gender-associated differences of Nat2 activity, protein,
      and transcript levels were absent in liver. These observations suggest that the
      increase in Nat2 enzymatic activity in kidney is accomplished by an increase in
      transcript. We propose that the observed increase in Nat2 transcript expression
      in male mice may be a result of androgen regulation during development.

PMID- 10640511
TI  - Metabolism and pharmacokinetics, in the rat, of (R)-N-(2-Heptyl)Methyl
      propargylamine (R-2HMP), a new potent monoamine oxidase inhibitor and
      antiapoptotic agent.
AB  - (R)-N-(2-Heptyl)-N-methylpropargylamine (R-2HMP) is a monoamine oxidase inhibitor
      and putative antiapoptotic agent analogous to (R)-deprenyl. In the rat, the major
      amine metabolites of R-2HMP have been identified as (R)-N-2-heptylmethylamine (R
      2HMA), (R)-N-2-heptylpropargylamine (R-2HPA), and (R)-2-heptylamine (R-2HA).
      After R-2HMP was administered s.c. to male Wistar rats, it was observed that the
      greatest concentration was of the original drug followed in decreasing order by R
      2HMA, R-2HPA, and R-2HA in brain, liver, and plasma at all times after
      administration. The greatest concentrations of the three metabolites were found
      in brain followed by liver and plasma, and the peak concentrations occurred
      between 15 and 30 min after administration. After oral administration, the liver
      contained the greatest concentrations of drug and metabolites, and, again, the
      peak concentrations occurred at about 15 min. In all cases, depropargylation
      appears to occur at a faster rate than demethylation. After s.c. administration,
      R-2HMP and its metabolites exhibited biexponential redistribution and elimination
      losses. Half-lives of the compounds in brain for the redistribution phase were: R
      2HMP, 10 min; R-2HMA, 11 min; R-2HPA, 16 min; and R-2HA, 15 min.

PMID- 10640512
TI  - Pharmacokinetics of the rapid-acting insulin analog, insulin aspart, in rats,
      dogs, and pigs, and pharmacodynamics of insulin aspart in pigs.
AB  - The objective of this study was to compare the pharmacokinetics and
      pharmacodynamics of insulin aspart (IA), a rapidly acting insulin analog, with
      those of human soluble (regular) insulin (HI) in animal models after s.c. and
      i.v. dosing. Single doses of IA and HI were administered i.v. and s.c. to rats
      and dogs at three dose levels, and at one dose level to pigs; rats and dogs also
      underwent repeated s.c. dosing for 1 week. Plasma insulin levels were assessed at
      predetermined time points after dosing; plasma glucose levels were measured in
      pigs only. There were no significant pharmacokinetic differences between IA and
      HI after a single s.c. or i.v. dose in rats or dogs, and no differences were
      observed after repeated s.c. dosing, implying there was no accumulation. In pigs,
      there was a strong trend toward more rapid absorption of IA compared with HI
      after s.c. dosing, whereas there were no differences after i.v. administration.
      After s.c. dosing in pigs, IA produced significantly lower plasma glucose levels
      compared with HI during the period 30 to 75 min after dosing (P <.05). In
      conclusion, IA was more rapidly absorbed than HI after s.c. administration only
      in the pig; this difference was reflected in earlier and more pronounced effects
      on plasma glucose levels.

PMID- 10640513
TI  - Prediction of pharmacokinetic drug/drug interactions from In vitro data:
      interactions of the nonsteroidal anti-inflammatory drug lornoxicam with oral
      anticoagulants.
AB  - CYP2C9 is involved in the metabolism of the oral anticoagulants warfarin,
      phenprocoumon, and acenocoumarol. It is also responsible for the 5'-hydroxylation
      of the nonsteroidal anti-inflammatory drug lornoxicam. Therefore, lornoxicam and
      the oral anticoagulants are potential inhibitors of their metabolism. Their
      inhibitory potency was investigated in microsomes from six human livers. An
      approach to predict pharmacokinetic interactions of lornoxicam from in vitro
      inhibition data was developed. Where possible, the forecasts were verified by
      comparison with data from clinical interaction studies. The following increases
      in steady-state plasma concentrations or areas under the plasma concentration
      time curve of the oral anticoagulants by concomitant lornoxicam medication were
      predicted (values in parentheses are for healthy volunteers): (S)-warfarin, 1. 58
      fold (1.32-fold for racemate); racemic-acenocoumarol, 1.28-fold (1.09-fold); (R)
      acenocoumarol, 1.10-fold (1.0-fold); racemic-phenprocoumon, 1.11-fold (1.18
      fold); and (S)-phenprocoumon, 1.13-fold (1.24-fold). Lornoxicam 5'-hydroxylation
      was competitively inhibited in vitro by both phenprocoumon (K(i) = 1.2 +/- 0.4
      microM) and acenocoumarol (K(i) = 5.5 +/- 3.5 microM). The present results
      indicate that relatively close predictions of the interactions of lornoxicam with
      oral anticoagulants from in vitro data are possible under the assumption that
      hepatic lornoxicam concentrations are similar to its total plasma concentrations.
      The degree of pharmacokinetic interactions exhibited by oral anticoagulants and
      lornoxicam is dependent on the respective contribution of CYP2C9 to their total
      clearance.

PMID- 10640514
TI  - Population-specific polymorphisms of the human FMO3 gene: significance for
      detoxication.
AB  - Flavin-containing monooxygenase form 3 (FMO3) is one of the major enzyme systems
      that protect humans from the potentially toxic properties of drugs and chemicals.
      FMO3 converts nucleophilic heteroatom-containing chemicals and endogenous
      materials to polar metabolites, which facilitates their elimination. For example,
      the tertiary amine trimethylamine is N-oxygenated by human FMO3 to trimethylamine
      N-oxide, and trimethylamine N-oxide is excreted in a detoxication and deoderation
      process. In normal humans, virtually all trimethylamine is metabolized to
      trimethylamine N-oxide. In a few humans, trimethylamine is not efficiently
      metabolized to trimethylamine N-oxide, and those individuals suffer from
      trimethylaminuria, or fishlike odor syndrome. Previously, we identified mutations
      of the FMO3 gene that cause trimethylaminuria. We now report two prevalent
      polymorphisms of this gene (K158E and V257M) that modulate the activity of human
      FMO3. These polymorphisms are widely distributed in Canadian and Australian white
      populations. In vitro analysis of wild-type and variant human FMO3 proteins
      expressed from the cDNA for the two naturally occurring polymorphisms showed
      differences in substrate affinities for nitrogen-containing substrates. Thus, for
      polymorphic forms of human FMO3, lower k(cat)/K(m) values for N-oxygenation of 10
      (N, N-dimethylaminopentyl)-2-(trifluoromethyl) phenothiazine, trimethylamine, and
      tyramine were observed. On the basis of in vitro kinetic parameters, human FMO1
      does not significantly contribute to human metabolism of trimethylamine or
      tyramine. The results imply that prevalent polymorphisms of the human FMO3 gene
      may contribute to low penetrance predispositions to diseases associated with
      adverse environmental exposures to heteroatom-containing chemicals, drugs, and
      endogenous amines.

PMID- 10640515
TI  - Molecular dynamics simulation of metallothionein-drug complexes.
AB  - The intermolecular interactions of metallothionein with nitrogen mustard drugs
      were studied by molecular dynamics simulations. Previous laboratory experiments
      have defined selective alkylation of two cysteine residues, and selective binding
      was proposed to precede alkylation. The present study provides information about
      accessibility to cysteines based on evaluating the intermolecular energies and
      distances in the first few ps of dynamics simulations. A series of dynamics
      simulations was performed with three drug molecules positioned at the eight most
      solvent accessible cysteine residues of the dimeric form of the protein. Sites
      proximal to the sulfhydryl groups of Cys-33 and Cys-48 were found to be the most
      favorable for complexing the aziridinium forms of chlorambucil, melphalan, and
      mechlorethamine. The sites for preferential binding are in qualitative agreement
      with the sites of selective alkylation defined experimentally.

PMID- 10640516
TI  - Metabolism of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in primary
      cultures of rat alveolar type II cells.
AB  - The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
      (NNK) induces primarily lung tumors, which are assumed to derive from malignant
      transformation of alveolar type II (AII) cells within the lung. To elicit its
      carcinogenic effects, NNK requires metabolic activation by cytochrome P-450 (CYP)
      mediated alpha-hydroxylation. Therefore, in this study the metabolism of NNK and
      expression of the NNK-activating CYP isoform CYP2B1 were investigated in primary
      cultures of rat AII cells. Although basal expression of CYP2B1 decreased in a
      time-dependent manner during culture of AII cells, substantial CYP2B1 protein
      expression was observed in AII cell cultures after the first 24 h. When AII cells
      were incubated with 0. 05 microM [5-(3)H]NNK, N-oxidation of NNK, which is
      thought to represent a detoxification pathway, was predominant (42%). alpha
      Hydroxylated metabolites resulting from metabolic activation of NNK amounted to
      35% of all detected metabolites. However, the proportion of alpha-hydroxylated
      metabolites decreased to 17% of all detected metabolites when AII cells were
      incubated with a 100-fold higher concentration of NNK (5 microM). In summary,
      this study indicates a remarkable activity of cultured AII cells to metabolize
      NNK, leading to substantial metabolic activation of NNK, which was more
      pronounced in incubations at low NNK concentration. Because exposure to NNK via
      cigarette smoking is thought to lead to very low plasma NNK concentrations (1-15
      pM), these data suggest that metabolic activation of NNK in cigarette smokers
      might occur to a larger extent than would be expected according to previous
      metabolic studies performed with high (micromolar) NNK concentrations.

PMID- 10640517
TI  - Dexamethasone differentially regulates expression of carboxylesterase genes in
      humans and rats.
AB  - Carboxylesterases play important roles in the metabolism of endogenous and
      foreign compounds, therefore, xenobiotic regulation of carboxylesterase gene
      expression has both physiological and pharmacological significance. We previously
      reported that liver microsomal esterase activity was significantly decreased in
      rats treated with dexamethasone accompanied by a decrease in immunoreactive
      proteins of rat hydrolase A, B, and C. The aim of this study was to determine
      whether the suppressed expression of these enzymes was linked to the change of
      the mRNA levels, and whether cultured hepatocytes responded similar to whole
      animals to this chemical. Northern blotting analyses demonstrated that the levels
      of the corresponding mRNA were markedly decreased in rats treated with
      dexamethasone, suggesting that the suppressed expression is achieved through
      trans-suppression and/or increased degradation of the transcripts. Exposure of
      cultured rat hepatocytes to nanomolar levels of dexamethasone markedly decreased
      the levels of immunoreactive proteins of hydrolase A, B, and C. In contrast,
      exposure of cultured human hepatocytes to dexamethasone caused a slight increase
      in HCE-1 and HCE-2, two major forms of human liver microsomal carboxylesterases.
      The inductive effects in human hepatocytes were observed only when micromolar
      concentrations of dexamethasone were used. These results suggest that a major
      species difference exists regarding the regulation of carboxylesterase gene
      expression by dexamethasone. Both the glucocorticoid receptor and the pregnane X
      receptor are known to mediate dexamethasone action. Differential concentrations
      required suggest that suppression of rat hydrolases is mediated by the
      glucocorticoid receptor, whereas the induction of human carboxylesterases is
      mediated by the pregnane X receptor.

PMID- 10640518
TI  - Disposition of radioactivity in fischer 344 rats after single and multiple
      inhalation exposure to [(14)C]Octamethylcyclotetrasiloxane ([(14)C]D(4)).
AB  - The retention, distribution, metabolism, and excretion of
      [(14)C]octamethylcyclotetrasiloxane (D(4)) were studied in Fischer 344 rats after
      single and multiple exposures to 7, 70, or 700 ppm [(14)C]D(4). Subset groups
      were established for body burden, distribution, and elimination. Retention of
      inhaled D(4) was relatively low (5-6% of inhaled D(4)). Radioactivity derived
      from [(14)C]D(4) inhalation was widely distributed to tissues of the rat. Maximum
      concentrations of radioactivity in plasma and tissues (except fat) occurred at
      the end of exposure and up to 3 h postexposure. Maximum concentrations of
      radioactivity in fat occurred as late as 24 h postexposure. Fat was a depot,
      elimination of radioactivity from this tissue was much slower than from plasma
      and other tissues. With minor exceptions, there were no consistent gender effects
      on the distribution of radioactivity and the concentrations of radioactivity were
      nearly proportional to exposure concentration over the exposure range. Excretion
      of radioactivity was via exhaled breath and urine, and, to a much lesser extent,
      feces. Urinary metabolites included dimethylsilanediol and methylsilanetriol plus
      five minor metabolites. Relative abundance of these metabolites was the same from
      every test group. Elimination was rapid during the first 24 h after exposure and
      was slower thereafter (measured up to 168 h postexposure). In singly-exposed
      female (but not male) rats, small dose-dependent shifts in elimination pathways
      were seen. After multiple exposures, the elimination pathways were dose- and
      gender-independent. These data define possible pathways for metabolism of D(4)
      and allow estimation of the persistence of D(4) and/or its metabolites in rats.

PMID- 10640519
TI  - Pharmacokinetics of all-trans retinoic acid, 13-cis retinoic acid, and
      fenretinide in plasma and brain of Rat.
AB  - We have measured the pharmacokinetics of three retinoids, all-trans retinoic
      acid, 13-cis retinoic acid, and fenretinide in rat blood and rat brain
      [especially white matter (WM) and gray matter (GM)] to help select retinoids for
      treating human malignant glioma. All-trans retinoic acid permeated well into the
      WM, giving peak concentration in WM of 25.7 microg/g, 6 to 7 times higher than
      the peak serum concentration. There was less 13-cis retinoic acid in WM: area
      under the curve (AUC)(0-->infinity) WM/AUC(0-->infinity) serum = 18.00 microg ml(
      1) h/32.67 microg ml(-1) h. The ratio WM/GM was over 1 for these two compounds,
      but the half-lives were short in the serum and cerebral tissue (0.57-1.02 h).
      Fenretinide had different pharmacokinetics: the peak concentrations were in serum
      (1.7 microg/ml) and WM (1.2 microg/ml)-low, but the AUC(0-->infinity) was large
      (25.55 microg ml(-1) in serum and 57.53 microg ml(-1) in WM) due to its long
      elimination half-life (13.78 h in serum and 17.77 h in WM). These findings
      provide information that may be used to select a retinoid and establish
      therapeutic regimens that provide optimal efficacy with minimal toxicity.

PMID- 10640520
TI  - Biliary metabolites of beta-artemether in rats: biotransformations of an
      antimalarial endoperoxide.
AB  - beta-Artemether (AM), the O-methyl ether prodrug of dihydroartemisinin (DHA), is
      an endoperoxide antimalarial. The biliary metabolites of AM in adult male Wistar
      rats were characterized with particular reference to potential antimalarial
      compounds and stable derivatives of free radical intermediates. [13-(14)C]-AM (35
      micromol kg(-1), i.v.) was administered to anesthetized rats. Within 0 to 3 h,
      38.6 +/- 4.8% (mean +/- S.D., n = 6) of the radiolabel was recovered in bile; the
      0- to 5-h recovery was 42.3 +/- 4.3%. The major metabolites (0-3 h) were the
      glucuronides of 9alpha-hydroxyAM (33.4 +/- 6.8% biliary radioactivity) and alpha
      DHA (22.5 +/- 4.4%); four stereochemically unassigned monohydroxyAM glucuronides
      (II, 3.1 +/- 0.9; IV, 4.4 +/- 1.7%; V, 21.4 +/- 3.0%; VI, 3.0 +/- 1.1%) and a
      dihydroxyAM glucuronide (6.0 +/- 2.1%) were also identified. A sixth
      monohydroxyAM glucuronide (VIIa) and desoxyDHA glucuronide were detected in trace
      amounts. The furano acetate isomer of DHA glucuronide, indicative of the
      formation of a radical intermediate, was also found in trace amounts. O-methyl
      substitution of DHA favors ring hydroxylation in vivo. However, the principal
      hydroxylated metabolite, 9alpha-hydroxyAM, is unlikely to possess significant
      antimalarial activity.

PMID- 10640521
TI  - o-hydroxyphenylacetaldehyde is a hepatotoxic metabolite of coumarin.
AB  - o-Hydroxyphenylacetaldehyde (o-HPA), the product of coumarin 3, 4-epoxide, was
      synthesized and its contribution to the hepatotoxic effects of coumarin in the
      rat was determined. The relative toxicity of coumarin and o-HPA were initially
      assessed in Chinese hamster ovary K1 (CHO K1) cells, a cell line that does not
      contain cytochrome P450. In CHO K1 cells, o-HPA-mediated toxicity greatly
      exceeded that of coumarin. CHO K1 cell viability, determined via the reduction of
      3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide (MTT), was
      decreased by 95 and 6% in cultures containing o-HPA and coumarin (4 mM),
      respectively. Coumarin and o-HPA were then incubated in metabolically competent
      primary rat hepatocyte cultures. Cell viability was determined via the reduction
      of MTT, and lactic dehydrogenase (LDH) release was used as a measure of
      cytotoxicity. Concentration-dependent decreases in cell viability and increased
      LDH release were observed using 0.2 to 0.8 mM o-HPA and coumarin, with coumarin
      being consistently less toxic than o-HPA. Cell viability was decreased by 11 and
      50% at 0.5 mM coumarin or o-HPA, respectively. Hepatocyte LDH release increased 5
      fold after a 6-h exposure to 0.8 mM o-HPA, corresponding to a greater than 90%
      loss of cell viability in these cultures. In contrast, 0.8 mM coumarin decreased
      cell viability by 60%, an effect likely due to the conversion of coumarin to
      coumarin epoxide and o-HPA. Furthermore, 3-hydroxycoumarin (0.8 mM), which is not
      a product of coumarin epoxidation, had no effect on cell viability or
      hepatocellular LDH release. These studies demonstrate that metabolically active
      rat hepatocytes convert coumarin into toxic metabolites, and strongly suggest
      that o-HPA and coumarin 3, 4-epoxide mediate the toxicity of coumarin in rodents
      in vivo.

PMID- 10640522
TI  - A new physiologically based, segregated-flow model to explain route-dependent
      intestinal metabolism.
AB  - Processes of intestinal absorption, metabolism, and secretion must be considered
      simultaneously in viewing oral drug bioavailability. Existing models often fail
      to predict route-dependent intestinal metabolism, namely, little metabolism
      occurs after systemic dosing but notable metabolism exists after oral dosing. A
      physiologically based, Segregated-Flow Model (SFM) was developed to examine the
      influence of intestinal transport (absorption and exsorption), metabolism, flow,
      tissue-partitioning characteristics, and elimination in other organs on
      intestinal clearance, intestinal availability, and systemic bioavailability. For
      the SFM, blood flow to intestine was effectively segregated for the perfusion of
      two regions, with 10% reaching an absorptive layer-the enterocytes at the villus
      tips of the mucosa where metabolic enzymes and the P-glycoprotein reside, and the
      remaining 90% supplying the rest of the intestine (serosa and submucosa), a
      nonabsorptive layer. The traditional, physiologically-based model, which regards
      the intestine as a single, homogeneous compartment with all of the intestinal
      blood flow perfusing the tissue, was also examined for comparison. The analytical
      solutions under first order conditions were essentially identical for the SFM and
      traditional model, differing only in the flow rate to the absorptive/removal
      region. The presence of other elimination organs did not affect the intestinal
      clearance and bioavailability estimates, but reduced the percentage of dose
      metabolized by the intestine. For both models, intestinal availability was
      inversely related to the intrinsic clearances for intestinal metabolism and
      exsorption, and was additionally affected by both the rate constant for
      absorption and that denoting luminal loss when drug was exsorbed. However, the
      effect of secretion by P-glycoprotein became attenuated with rapid absorption.
      The difference in flow between models imparted a substantial influence on the
      intestinal clearance of flow-limited substrates, and the SFM predicted markedly
      higher extents of intestinal metabolism for oral over i.v. dosing. Thus, the SFM
      provides a physiological view of the intestine and explains the observation of
      route-dependent, intestinal metabolism.

PMID- 10640523
TI  - Systemic coadministration of chloramphenicol with intravenous but not
      intracerebroventricular morphine markedly increases morphine antinociception and
      delays development of antinociceptive tolerance in rats.
AB  - Chloramphenicol, an in vitro inhibitor of the glucuronidation of morphine to its
      putative antianalgesic metabolite, morphine-3-glucuronide (M3G), was
      coadministered with morphine in adult male Sprague-Dawley rats to determine
      whether it inhibited the in vivo metabolism of morphine to M3G, thereby enhancing
      morphine antinociception and/or delaying the development of antinociceptive
      tolerance. Parenteral chloramphenicol was given acutely (3-h studies) or
      chronically (48-h studies). Morphine was administered by the i.v. or i.c.v.
      route. Control rats received chloramphenicol and/or vehicle. Antinociception was
      quantified using the hotplate latency test. Coadministration of chloramphenicol
      with i.v. but not i.cv. morphine increased the extent and duration of morphine
      antinociception by approximately 5.5-fold relative to rats that received i.v.
      morphine alone. Thus, the mechanism through which chloramphenicol enhances i.v.
      morphine antinociception in the rat does not directly involve supraspinal opioid
      receptors. Acutely, parenteral coadministration of chloramphenicol and morphine
      resulted in an approximately 75% increase in the mean area under the serum
      morphine concentration-time curve but for chronic dosing there was no significant
      change in this curve, indicating that factors other than morphine concentrations
      contribute significantly to antinociception. Antinociceptive tolerance to
      morphine developed more slowly in rats coadministered chloramphenicol, consistent
      with our proposal that in vivo inhibition of M3G formation would result in
      increased antinociception and delayed development of tolerance. However, our data
      also indicate that chloramphenicol inhibited the biliary secretion of M3G.
      Whether chloramphenicol altered the passage of M3G and morphine across the blood
      brain barrier remains to be investigated.

PMID- 10640524
TI  - Analysis of chromosome loss and chromosome segregation in cytokinesis-blocked
      human lymphocytes: non-disjunction is the prevalent mistake in chromosome
      segregation produced by low dose exposure to ionizing radiation.
AB  - The aim of the present work was to examine in human lymphocytes, firstly, whether
      in vitro gamma-rays as compared with X-rays also induce chromatid malsegregation
      and at higher frequencies than chromosome loss and, secondly, whether the
      cytokinesis-blocked micronucleus assay combined with fluorescence in situ
      hybridization might be useful for the biomonitoring of individuals exposed to
      ionizing radiation. After irradiation, the relative frequencies of centromere
      positive micronuclei decreased from 39.2% at 0.1 Gy to 21. 63% at higher doses.
      There was no statistically significant increase in MNCen+ frequencies at doses
      below 1 Gy (0.1, 0.25 and 0.5 Gy), but a statistically significant increase at 1
      (P < 0.05) and 2 Gy (P < 0.001) was observed for all the donors. No significant
      differences in baseline and gamma-ray-induced non-disjunction frequencies for
      chromosomes 1 (P = 0.9) and 17 (P = 0.8) between individuals were detected. For
      radiation-induced non-disjunction, lower doses (0.1, 0. 25 and 0.5 Gy) of gamma
      rays did not induce a statistically significant increase in non-disjunction
      frequencies whereas 1 Gy and above clearly induced a statistically significant
      increase in the total non-disjunction frequencies for all the donors (P < 0.05 at
      1 Gy and P < 0.0001 at 2 Gy). The aneugenic effect of radiation is less clearly
      dose dependent at the lower doses, suggesting an apparent threshold below which
      no change could be demonstrated. At high radiation doses the major mechanism for
      gamma-ray-induced aneuploidy is related to chromosome loss through non
      disjunction, as has been demonstrated using X-rays, and not through the formation
      of micronuclei.

PMID- 10640525
TI  - Induction of aberrant mitosis with PCBs: particular efficiency of 2, 3,3',4,4'
      pentachlorobiphenyl and synergism with triphenyltin.
AB  - The polychlorinated biphenyls 2,2',5,5'- and 3,3',4, 4'-tetrachlorobiphenyl,
      2,3,3',4,4'- and 3,3',4,4', 5-pentachlorobiphenyl and 2,2',4,4',5,5'
      hexachlorobiphenyl were tested for spindle-disturbing activity in V79 Chinese
      hamster cells. Clones lacking endogenous cytochrome P450 activity or expressing
      rat CYP1A1 or CYP2B1 were used. Induction of abnormal chromosomal arrangements in
      mitosis were found to be favoured by o-chlorine substitutions, but not by co
      planarity giving affinity, for example, for the Ah receptor and CYP1A isoenzymes.
      Only 2,2',5, 5'-tetrachloro- and 2,3,3',4,4'-pentachlorobiphenyl gave dose
      response curves similar to many other compounds tested in vitro, showing an
      increase from the background level of 10 to 100% disturbed mitoses with nominal
      concentrations >10(-6) M, i.e. concentrations far above the total PCB
      concentrations found in human blood. Cells transfected with rat CYP2B1 were more
      sensitive to the most active congener, 2,3,3',4,4'-pentachlorobiphenyl, than
      cells lacking P450 activity or expressing CYP1A1. Induction of abnormal mitosis
      by PCB metabolites formed by P450 enzymes cannot be excluded, but does not seem
      likely because of the short treatment time and the reportedly slow metabolism of
      PCBs. 2,3,3',4, 4'-Pentachlorobiphenyl showed synergistic activity with the
      potent spindle poison triphenyltin. Inactive concentrations of both agents (10
      and 50 nM, respectively) caused abnormal configurations when combined. This is an
      important finding since exposure to mixtures of compounds is common and it
      motivates further studies of subthreshold activities of highly lipophilic
      environmental contaminants.

PMID- 10640526
TI  - Trichlorfon induces spindle disturbances in V79 cells and aneuploidy in male
      mouse germ cells.
AB  - In order to assess the effects of trichlorfon on cell division and on aneuploidy
      induction, we conducted an in vitro assay for spindle disturbances using V79
      cells and an in vivo assay for aneuploidy induction in meiosis of male mice using
      multicolour fluorescence in situ hybridization (FISH) with epididymal sperm. In
      the in vitro assay, the chemical caused a concentration-dependent increase in the
      incidence of initial and full c-mitoses in the dose range 40-120 microg/ml
      trichlorfon. The mitotic index (MI) was decreased between 40 and 100 microg/ml
      trichlorfon, whereas at 120 microg/ml the MI was back to the control level,
      coinciding with the dramatic increase in c-mitoses. The results confirm that
      trichlorfon is a potent spindle poison in V79 cells. In the in vivo multicolour
      FISH assay, administration of trichlorfon to male mice at single doses of 200,
      300 and 405 mg/kg caused a dose-dependent increase of the frequencies of disomic
      sperm (0.068, 0.074 and 0.134%, respectively) compared with the corresponding
      controls (0.046, 0.042 and 0.056%, respectively). The prevalence of X-X-8 and Y-Y
      8 sperm suggests that trichlorfon affected chromosome segregation predominantly
      during the second meiotic division. Diploid sperm were not induced by trichlorfon
      treatment, indicating that no meiotic block occurred. It is concluded that
      trichlorfon is a potent spindle poison in V79 cells and induces aneuploidy in
      mouse spermatocytes during meiosis.

PMID- 10640527
TI  - Molecular analysis of 5-azacytidine-induced variants in mammalian cells.
AB  - 5-azacytidine induces 6-thioguanine resistance in AS52 cells. To characterize
      these resistant clones, we isolated 148 of them from 50 independently treated
      flasks. Less than nine (6%) of the 148 variants were spontaneous. PCR
      amplification of the DNA primers flanking the gpt gene produced no product in 15
      clones (10%). Of the 133 remaining clones, 52 showed sequence alterations in the
      gpt structural gene. Of these 52, 34 (65%) were GC-->CG transversions. Only seven
      were located in CpG sequences. Thus, methyltransferase complexes are not major
      contributors to 5-azacytidine-induced point mutations in AS52 cells. The
      remaining 81 clones had no sequence alterations within the coding region of the
      gpt gene. Southern blot analysis of a sample of these variants (37/81) indicated
      that the 6-thioguanine-resistant phenotype was not due to local rearrangements or
      deletions (resolution 50 bp). Sequence analysis of the early promoter region of
      another sample of these variants (24/81) indicated that lesions in the promoter
      could not be responsible for the 6-thioguanine resistance observed. Thus, a
      majority of these variants were formed via a mechanism other than small genomic
      rearrangements, point mutations or deletions of the gpt structural gene or its
      promoter. Neither the mechanisms leading to these variants nor the biological and
      morphological consequences of these variants are known.

PMID- 10640528
TI  - Irradiation of male rats increases the chromosomal sensitivity of progeny to
      genotoxic agents.
AB  - Chromosomal sensitivity to genotoxic agents was studied in the first generation
      progeny of male rats irradiated at a dose of 4.5 Gy X-rays and in the progeny of
      non-exposed animals. The frequency of anaphase chromosome aberrations (bridges
      or/and fragments) in rats exposed to X-rays or treated with cyclophosphamide was
      estimated: in proliferating hepatocytes (2 Gy) as a function of time during liver
      regeneration after partial hepatectomy; in bone marrow cells (2.5 Gy or 25 mg/kg
      body wt); in fetal fibroblasts (3 Gy). The sensitivity of chromosomes to
      genotoxic agents was found to be increased in the progeny of irradiated male rats
      as compared with the progeny of non-exposed animals. This finding provides
      supportive evidence that irradiation of parents is an important factor in
      predisposition of progeny to chromosomal instability.

PMID- 10640529
TI  - A comparison of enzyme activity mutation frequencies in germ cells of mice (Mus
      musculus) and golden hamsters (Mesocricetus auratus) after exposure to 2 + 2 Gy
      gamma-irradiation.
AB  - The radiation-induced germ cell mutation rate has been investigated in two
      species of mammals. Mice and golden hamsters of both sexes were exposed to 2 + 2
      Gy gamma-irradiation with a 24 h fractionation interval and mated to untreated
      partners. In mice, specific locus mutations were examined as positive controls
      and the obtained mutation rates (per locus and gamete x10(-5)) were 51.4, 10.1,
      13.6 and 17.4 for irradiated post-spermatogonia, spermatogonia and 1-7 and >7
      days post-treatment oocytes, respectively. Offspring of mice and golden hamsters
      were screened for activity alterations of 10 erythrocyte enzymes coded by at
      least 14 loci. The observed mutation rates per locus per gamete x10(-5) for
      treated post-spermatogonial stages, spermatogonia and oocytes 1-7 and >7 days
      post-treatment were 6.5, 1.5, 8.8 and 7.0, respectively, for mice and 16.7, 0,
      7.6 and 0, respectively, for golden hamsters. There is a significant difference
      for mutation rates in mouse oocytes 1-7 days post-treatment compared with the
      control. No differences in the frequencies of mutations in the various germ cell
      stages could be observed between mice and golden hamsters. A critical assumption
      for the extrapolation of experimental mutagenesis studies to humans is that no
      species effects exist in sensitivity to mutation induction by irradiation. Our
      results do not contradict this assumption.

PMID- 10640530
TI  - Carboxylesterases, a key factor in evaluating potential genotoxicity of Trinem
      antibiotics.
AB  - Sanfetrinem cilexetil, a hexetil ester of a Trinem antibiotic, does not induce
      micronuclei in rat bone marrow cells or induce DNA repair synthesis in rat
      hepatocytes following oral dosing. However, in vitro chromosome damage and
      mutations are induced in mammalian cells lacking carboxylesterase activity (human
      lymphocytes and mouse lymphoma L5178Y cells). In cells possessing
      carboxylesterase activity (CHL cells), chromosome damage induced by Sanfetrinem
      cilexetil is not observed. Similarly, if induced rat liver preparations or non
      induced preparations from rat or human intestinal cells are present during
      exposure, genotoxic activity is lost, even in those cells lacking
      carboxylesterase enzymes. Thus the lack of demonstrable genotoxicity in vivo, in
      the assays used, is likely to be due to hydrolysis of the parent molecule by non
      specific carboxylesterases present within the intestinal epithelium. In turn this
      data indicates that a genotoxic hazard to humans under therapeutic conditions is
      unlikely.

PMID- 10640531
TI  - p53 intron 7 polymorphisms in urinary bladder cancer patients and controls.
      Stockholm Bladder Cancer Group.
AB  - A C-->T polymorphism in intron 7 of the human tumour suppressor gene p53 was
      studied in 159 urinary bladder cancer patients and 171 non-cancer controls. The
      polymorphism was found in 15% of both patients and controls, suggesting that it
      has no relevance in urinary bladder cancer pathogenesis or aetiology. A second
      polymorphism, a T-->G change located 20 bp downstream of the C-->T change, was
      found in all samples with the C-->T change. Our findings indicate that the C-->T
      and the T-->G changes occur simultaneously and belong to the same allelotype.

PMID- 10640532
TI  - Glutathione and hypotaurine in vitro: effects on human sperm motility, DNA
      integrity and production of reactive oxygen species.
AB  - Sperm DNA integrity is of paramount importance for the accurate conveyance of
      genetic material. DNA damage may be a major contributory factor in male
      infertility as DNA from sperm of infertile men has been found to be more
      susceptible to induced DNA damage in vitro than DNA from fertile men. Reactive
      oxygen species (ROS) are a significant source of DNA damage and human sperm are
      extremely sensitive to ROS attack due to their high content of polyunsaturated
      fatty acids and lack of capacity for DNA repair. Seminal plasma, which contains a
      wealth of antioxidants, provides sperm with crucial protection against oxidative
      insult. However, during preparation for use in assisted conception techniques,
      sperm are separated from seminal plasma and deprived of that essential
      protection. The aim of this study was to determine the effects of supplementation
      with glutathione and hypotaurine during sperm preparation on subsequent sperm
      motility, DNA integrity, induced DNA damage and ROS generation. Semen samples (n
      = 45) were divided into aliquots and prepared by Percoll density centrifugation
      (95.0-47.5%) using medium which had been supplemented with these antioxidants to
      a number of different concentrations all within physiological levels. Control
      aliquots were included which had no glutathione or hypotaurine added. Sperm
      motility was determined using computer-assisted semen analysis. DNA damage was
      induced using H(2)O(2) and DNA integrity was determined using a modified alkaline
      single cell gel electrophoresis (Comet) assay, while ROS generation was measured
      using chemiluminescence. Addition of glutathione and hypotaurine, either singly
      or in combination, to sperm preparation medium had no significant effect on sperm
      progressive motility or baseline DNA integrity. Despite this, sperm were still
      afforded significant protection against H(2)O(2)-induced damage and ROS
      generation.

PMID- 10640533
TI  - Cytogenetic alterations and oxidative stress in thyroid cancer patients after
      iodine-131 therapy.
AB  - This study aimed to assess two end-points of DNA damage, namely chromosomal
      aberrations and micronuclei in peripheral lymphocytes, and their possible
      relationship with oxidative stress (which may be related to DNA damage and
      repair) in thyroid cancer patients receiving therapeutic doses of (131)I.
      Nineteen patients receiving 2590 MBq (70 mCi) were studied. Chromosomal
      aberrations were scored using standard cytogenetic methods and micronuclei scored
      in cytokinesis-blocked lymphocytes. Oxidative stress was assessed by determining
      thiobarbituric acid-reactive substances in blood, total plasma antioxidant status
      and serum uric acid levels. All parameters were assessed before treatment and 1
      and 6 months after (131)I administration. The frequency of micronucleated cells
      per 1000 binucleated cells scored (mean +/- SEM) increased significantly from
      5.21 +/- 0.80 to 9.68 +/- 1.22 1 month after treatment (P < 0.01) and to 8.42 +/-
      1.28 6 months after treatment (P < 0.05). The frequency of cells with chromosomal
      aberrations, excluding gaps, per 100 cells, increased significantly from 1.68 +/-
      0.41 to 3.47 +/- 0. 55 1 month after treatment (P < 0.01) and to 4.05 +/- 0.46 6
      months after treatment (P < 0.01). Oxidative stress parameters showed slight
      modifications over the time period studied, but the differences were not
      significant except for a decrease in thiobarbituric acid-reactive products 6
      months after therapy (P < 0. 05) and in serum uric acid concentration 1 and 6
      months after therapy (P < 0.01). This report demonstrates slight but significant
      and persistent DNA damage in (131)I-treated patients as assessed by cytogenetic
      assays. There was no clear correlation between the cytogenetic findings and
      oxidative stress parameters studied.

PMID- 10640534
TI  - Assessment of the adaptive response induced by quercetin using the MNCB
      peripheral blood human lymphocytes assay.
AB  - Over more than two decades the existence of an adaptive response (AR) has been
      reported in several cell types and extensively studied with low doses of
      radiation. Besides radiation, some chemicals [alkylating compounds, mitomycin C
      (MMC), bleomycin, hydrogen peroxide and metals] may also induce an adaptive
      response. We have recently reported that the food mutagen quercetin can also
      induce an adaptive response in V79 Chinese hamster cells. In this work we have
      studied the effect of low doses of quercetin on the genotoxicity of MMC and
      bleomycin assessed by the formation of micronuclei in cytokinesis-blocked (MNCB)
      human peripheral blood lymphocytes. Our results suggest the existence of an AR
      induced by quercetin in human lymphocytes. Seven of the nine donors studied
      showed in at least one independent experiment a significant decrease in the
      frequency of MNCB induced by MMC. The range of these decreases varied between 31
      and 58%. In addition, we observed an AR induced by quercetin towards challenging
      doses of bleomycin. In accordance with other studies with ionizing radiation in
      which heterogeneity of the AR in the population has been extensively observed,
      the response here reported also showed some degree of variability between the
      different donors studied. In view of the results obtained one cannot rule out a
      possible protective effect of low doses of quercetin leading to adaptation to
      further exposure to mutagens or carcinogens.

PMID- 10640535
TI  - Induction and repair of formaldehyde-induced DNA-protein crosslinks in repair
      deficient human cell lines.
AB  - We have previously shown that the alkaline Comet assay (single cell gel
      electrophoresis) in a modified version is a sensitive test for the detection of
      formaldehyde-induced DNA-protein crosslinks (DPC). Our results also indicated
      that formaldehyde-induced DPC are related to the formation of chromosomal effects
      such as micronuclei and sister chromatid exchanges. To better understand the
      genetic consequences of formaldehyde-induced DPC we have now investigated the
      induction and removal of DPC in relationship to the formation of micronuclei in
      normal and repair-deficient human cell lines. We did not find significant
      differences between normal cells, a xeroderma pigmentosum (XP) cell line and a
      Fanconi anaemia (FA) cell line with respect to the induction and removal of DPC.
      However, the induction of micronuclei was enhanced in both repair-deficient cell
      lines, particularly in XP cells, under the same treatment conditions. Comparative
      investigations with the DNA-DNA crosslinker mitomycin C (MMC) revealed a delayed
      removal of crosslinks and enhanced induction of micronuclei in both repair
      deficient cell lines. FA cells were found to be particularly hypersensitive to
      micronucleus induction by MMC. In contrast to the results with formaldehyde,
      induction of micronuclei by MMC occurred at much lower concentrations than the
      effects in the Comet assay. Our results suggest that more than one repair pathway
      can be involved in the repair of crosslinks and that disturbed excision repair
      has more severe consequences with regard to the formation of chromosomal
      aberrations after formaldehyde treatment than has disturbed crosslink repair.

PMID- 10640536
TI  - Aflatoxin B1-induced mitotic recombination in L5178Y mouse lymphoma cells.
AB  - Aflatoxin B1 is a human hepatocarcinogen. It is also a known point mutagen in
      bacteria and mammalian cells. This mutagenic activity may be at least partly
      responsible for its carcinogenic activity. However, recent studies show that
      aflatoxin B1 induces mitotic recombination in the yeast Saccharomyces cerevisiae.
      Because numerous reports have implicated mitotic recombination in mechanisms
      leading to carcinogenesis and because no one has shown that aflatoxin B1 induces
      recombination in mammalian cells, we decided to examine the ability of aflatoxin
      B1 to induce recombination in a mammalian cell line. We used a combination of
      methods, analysis for loss of heterozygosity and whole chromosome in situ
      hybridization, to identify mechanisms of chromosome mutation, including mitotic
      recombination in the mammalian L5178Y mouse lymphoma cell system. Our experiments
      revealed that mitotic recombination caused approximately 60% or more of the
      aflatoxin B1-induced mutagenic lesions in this cell system. Thus, mitotic
      recombination plays an important role in aflatoxin B1-induced mutagenesis in
      mammalian cells and possibly in chemically induced mutagenesis and
      carcinogenesis. This work suggests that multiple genetic lesions may be involved
      in aflatoxin B1-induced pathology.

PMID- 10640537
TI  - Repression of viral transcription during herpes simplex virus latency.

PMID- 10640538
TI  - Replication of equine herpesvirus type 1 in freshly isolated equine peripheral
      blood mononuclear cells and changes in susceptibility following mitogen
      stimulation.
AB  - In the present study, the outcome of an inoculation of equine peripheral blood
      mononuclear cells (PBMC) with equine herpesvirus type 1 (EHV-1) was studied in
      vitro. Cytoplasmic and plasma membrane expression of viral antigens, intra- and
      extracellular virus titres, and plaque formation in co-culture were determined.
      EHV-1 replicated in monocytes, although in a highly restricted way. Viral
      antigens were found at maximum levels (8.7% of the monocytes) at 12 h post
      infection. The infection was productive in 0.16% of the monocytes. The virus
      yield was 10(0.7) TCID(50) per productive cell. In a population of resting
      lymphocytes, 0.9% of cells were infected and less than 0.05% produced infectious
      virus. After prestimulation with different mitogens, the number of infected
      lymphocytes increased four to twelve times. The susceptible lymphocytes were T
      lymphocytes. In mitogen-stimulated lymphocytes, clear expression of viral
      antigens was found on the plasma membrane.

PMID- 10640539
TI  - Cloning and epitope mapping of a functional partial fusion receptor for human
      cytomegalovirus gH.
AB  - A cDNA clone encoding a partial putative human cytomegalovirus (HCMV) gH fusion
      receptor (CMVFR) was previously identified. In this report, the cDNA sequence of
      CMVFR was determined and the role of this CMVFR in HCMV/cell fusion was confirmed
      by rendering fusion-incompetent MOLT-4 cells susceptible to fusion following
      transfection with receptor cDNA. Blocking experiments using recombinant gH or
      either of two MAbs (against recombinant gH or purified viral gH:gL) provided
      additional evidence for the role of gH binding to this protein in virus fusion.
      An HCMV-binding domain of 12 aa in the middle hydrophilic region of CMVFR was
      identified by fusion blocking studies using synthetic receptor peptides. The 1368
      bp cDNA of CMVFR contained a predicted ORF of 345 aa with two potential membrane
      spanning domains and several possible nuclear localization signals. A search of
      sequence databases indicated that CMVFR is a novel protein. Further
      characterization of this cell membrane protein that confers susceptibility to
      fusion with the viral envelope should provide important information about the
      mechanism by which HCMV infects cells.

PMID- 10640540
TI  - Transactivation activity of the human cytomegalovirus IE2 protein occurs at steps
      subsequent to TATA box-binding protein recruitment.
AB  - The IE2 protein of human cytomegalovirus transactivates viral and cellular
      promoters through a wide variety of cis-elements, but the mechanism of its action
      has not been well characterized. Here, IE2-Sp1 synergy and IE2-TATA box-binding
      protein (TBP) interaction are examined by artificial recruitment of either Sp1 or
      TBP to the promoter. It was found that IE2 could cooperate with DNA-bound Sp1. A
      117 amino acid glutamine-rich fragment of Sp1, which can interact with Drosophila
      TAF(II)110 and human TAF(II)130, was sufficient for the augmentation of IE2
      driven transactivation. In binding assays in vitro, IE2 interacted directly with
      the C-terminal region of Sp1, which contains the zinc finger DNA-binding domain,
      but not with its transactivation domain, suggesting that synergy between IE2 and
      the transactivation domain of Sp1 might be mediated by other proteins such as TAF
      or TBP. It was also found that TBP recruitment to the promoter markedly increased
      IE2-mediated transactivation. Thus, IE2 acts synergistically with DNA-bound Sp1
      and DNA-bound TBP. These results suggest that, in human cytomegalovirus IE2
      transactivation, Sp1 functions at an early step such as recruitment of TBP and
      IE2 acts to accelerate rate-limiting steps after TBP recruitment.

PMID- 10640541
TI  - The vaccinia virus A27L protein is needed for the microtubule-dependent transport
      of intracellular mature virus particles.
AB  - The vaccinia virus (VV) A27L gene encodes a 14 kDa protein that is required for
      the formation of intracellular enveloped virus (IEV) and, consequently, normal
      sized plaques. Data presented here show that A27L plays an additional role in VV
      assembly. When cells were infected with the VV WR32-7/Ind 14K, under conditions
      that repress A27L expression, transport of intracellular mature virus (IMV) from
      virus factories was inhibited and some IMV was found in aberrant association with
      virus crescents. In contrast, other VV mutants (vDeltaB5R and vDeltaF13L) that
      are defective in IEV formation produce IMV particles that are transported out of
      virus factories. This indicated a specific role for A27L in IMV transport.
      Induction of A27L expression at 10 h post-infection promoted the dispersal of
      clustered IMV particles, but only when microtubules were intact. Formation of IEV
      particles was also impaired when cells were infected with WR32-7/14K, a VV strain
      expressing a mutated form of the A27L protein; however, this mutation did not
      inhibit intracellular transport of IMV particles. Collectively, these data define
      two novel aspects of VV morphogenesis. Firstly, A27L is required for both IMV
      transport and the process of envelopment that leads to IEV formation. Secondly,
      movement of IMV particles between the virus factory and the site of IEV formation
      is microtubule-dependent.

PMID- 10640542
TI  - Characterization of the african swine fever virus protein p49: a new late
      structural polypeptide.
AB  - The open reading frame B438L, located within the EcoRI B fragment of the African
      swine fever virus genome, is predicted to encode a protein of 438 amino acids
      with a molecular mass of 49.3 kDa. It presents a cell attachment RGD (Arg-Gly
      Asp) motif but no other significant similarity to protein sequences in databases.
      Northern blot and primer extension analysis showed that B438L is transcribed only
      at late times during virus infection. The B438L gene product has been expressed
      in Escherichia coli, purified and used as an antigen for antibody production. The
      rabbit antiserum specific for pB438L recognized a protein of about 49 kDa in
      virus-infected cell extracts. This protein was synthesized late in infection by
      all the virus strains tested, was located in cytoplasmic virus factories and
      appeared as a structural component of purified virus particles.

PMID- 10640543
TI  - A new genotype of hepatitis B virus: complete genome and phylogenetic
      relatedness.
AB  - The hepatitis B virus (HBV) genotype was determined in a total of 121 plasma
      samples collected in France and the US from patients chronically infected with
      HBV. HBV genotype A was predominant in this collection, appearing in 66 samples
      (54%), while genotypes B, C, D, E and F occurred in 4 (3%), 14 (12%), 23 (19%), 1
      (1%) and 0 (0%) of samples, respectively. However, the genotype of a total of 13
      (11%) samples (2 from France, 11 from the US) could not be determined with the
      methodology used. Sequence analysis, and subsequent phylogenetic analysis of the
      complete genome and the individual open reading frames, showed that the virus
      isolate from these samples was 3248 bp long and, phylogenetically, did not
      cluster with any of the known genotypes. This strain was provisionally called HBV
      genotype G. Virus isolates that were obtained from geographically separated
      regions like France and the US were closely related to each other. All virus
      strains analysed contained some characteristic differences when compared to
      genotype A: a translational stop codon at aa 2 and 28 of the preCore region; a 36
      nt (12 aa) insert in the amino-terminal part of the Core antigen (HBcAg); a 2 aa
      deletion in the carboxy-terminal part of HBcAg; and a 1 aa deletion in the preS1
      open reading frame. The deduced amino acid sequence of HBsAg suggests that this
      newly discovered genotype G strain belongs to serological group adw2.

PMID- 10640544
TI  - Long-term mutation rates in the hepatitis B virus genome.
AB  - Mutations in the hepatitis B virus (HBV) genome have so far been investigated in
      cross-sectional or short-term longitudinal studies. Information about long-term
      changes is lacking due to the difficulty of sampling over long observation
      periods. In this study, a retrospective approach was used that allowed the
      analysis of changes in the viral genome from transmission to late stages of
      infection without the requirement for sampling early during this period. The
      entire viral genome was sequenced from serum samples of three mothers and their
      10 adult children, who presumably had been infected vertically. The emergence of
      mutations between birth and sampling (mean 26.5 years) was assessed by comparing
      the individual sequences with the sequence of the strain assumed to have been
      transmitted. The mean differences from this sequence were 0.02 and 0. 28% in
      seven asymptomatic and one symptomatic hepatitis B e antigen (HBeAg)-positive
      carriers, respectively, and 0.62 % in five HBeAg-negative carriers. Mutations
      occurred throughout the genome and 88% of the mutations caused amino acid
      substitutions spread over all genes. In HBeAg-negative carriers, the number of
      nucleotide and amino acid changes was independent of the severity of liver
      disease and, except the (1762)AGG(1764)-->TGA changes, no specific mutation was
      associated with liver disease. In conclusion, by using a novel method it was
      found that the entire HBV genome is extremely stable over long periods of time
      during the HBeAg-positive phase if the immune response (inflammation) is weak,
      whereas an average of 20 mutations emerged after development of hepatitis and/or
      loss of HBeAg without association with clinical outcome.

PMID- 10640545
TI  - Human immunodeficiency virus type 1 population bottleneck during indinavir
      therapy causes a genetic drift in the env quasispecies.
AB  - The impact of emergence of genetic resistance, soon after the beginning of
      antiretroviral therapy, on the genotype of other viral loci not implicated in the
      development of resistance was studied in four human immunodeficiency type 1 (HIV
      1)-infected patients subjected to indinavir monotherapy. Two patients were chosen
      because they showed no decrease in virus load during the study period and two
      were selected because they showed a rapid decline in plasma viraemia after the
      initiation of therapy and a virus rebound after 12 weeks of treatment. The
      evolution of virus sequences was analysed within the four infected patients by
      examining virus sequences spanning the protease and C2-V3 env genes by RT-PCR of
      plasma samples obtained at the beginning and after 12 weeks of therapy. PCR
      products from the two genomic regions from the two sample points per patient were
      cloned and 10-15 clones from each sample were sequenced. Genotypic indinavir
      resistance was present in the four patients after 12 weeks of therapy. The
      overall protease and C2-V3 env regions quasispecies diversity at time zero was
      higher than that after 12 weeks of therapy, but this difference was more
      significant in the two patients who showed a reduction in virus load soon after
      the initiation of treatment. C2-V3 env sequences indicated that changes during
      emergence of resistance to indinavir were only detected in the two patients who
      showed a drastic reduction in virus load. Thus, a temporal relationship was
      observed between the start of therapy, a drastic reduction in virus load and a
      drift in the HIV-1 env quasispecies.

PMID- 10640547
TI  - A 37 base sequence in the leader region of human T-cell leukaemia virus type I is
      a high affinity dimerization site but is not essential for virus replication.
AB  - Mutagenesis has demonstrated a region in the human T-cell leukaemia virus type I
      (HTLV-I) 5' leader RNA which, when deleted, abolishes stable RNA dimer formation
      in vitro. We have further mapped, using both in vitro transcribed and synthesized
      RNA, this site to a 37 base region, which dimerizes with high affinity. When
      deleted from an HTLV-I Gag-Pol-expressing plasmid which was co-transfected with
      an envelope protein expressor to produce virions capable of single round
      infection, the dimer linkage deletion did not affect viral protein production. In
      addition, virus infectivity was only slightly reduced, to approximately 75-80% of
      the wild-type.

PMID- 10640546
TI  - Virus inactivation in a proportion of human T-cell leukaemia virus type I
      infected T-cell clones arises through naturally occurring mutations.
AB  - Human T-cell leukaemia virus type I (HTLV-I) is the aetiological agent of adult T
      cell leukaemia/lymphoma and tropical spastic paraparesis/HTLV-I-associated
      myelopathy (TSP/HAM). The trans-activating protein (Tax) of HTLV-I is strongly
      implicated in cellular proliferation. We examined the tax gene and 5' long
      terminal repeat (LTR) sequences in eight naturally infected T-cell clones derived
      from TSP/HAM-affected individuals who were either productively (proliferate
      spontaneously) or silently (do not proliferate spontaneously) infected. In two
      silently infected clones point mutations within the proviruses resulted in
      truncation of the Tax protein. One clone harboured both a deleterious tax gene
      mutation and a point mutation in an enhancer element of the 5' LTR. Sequence
      changes, immunological escape mutation, integration site context and host cell
      phenotype may all contribute to the high proportion of latently or silently
      infected T-cells found in vivo in virus carriers.

PMID- 10640548
TI  - In vitro infection of cells of the monocytic/macrophage lineage with bovine
      leukaemia virus.
AB  - The oncogenic retrovirus bovine leukaemia virus (BLV) primarily infects B cells.
      Most infected animals remain asymptomatic for long periods of time before an
      increase in circulating B cells or localized tumours can be observed. This long
      clinical latency period may be explained by cells of the monocyte/macrophage
      lineage (M/M) becoming infected and acting as a reservoir for the virus, as shown
      for other retroviruses (human immunodeficiency virus-1, feline immunodeficiency
      virus). M/M cells in different stages of differentiation (HL-60, THP-1, U-937,
      J774, BGM, PM2, primary macrophages of sheep and cows) were cultured with BLV
      produced by permanently infected donor cells (FLKBLV and BLV-bat(2)). Donor cells
      were inhibited from multiplying by either irradiation or treatment with mitomycin
      C. In other experiments, supernatant from donor cells containing virus was used.
      In co-culture with the donor cells, the less differentiated monocytic cells
      showed severe cellular changes such as differentiation, vacuolization, cell lysis
      and membrane blebbing; apoptosis was a frequent phenomenon. Budding and
      extracellular viruses were also observed. The more differentiated macrophage
      cells, although they showed less signs of infection by microscopy, had a complete
      BLV protein profile, as seen by Western blotting; bands corresponding to p24CA
      (Gag) and its precursors were clearly seen. In addition, gp51SU was identified by
      syncytia formation assays. It is concluded that M/M cells may be infected by BLV,
      the consequences of the infection differing according to the type of cell.

PMID- 10640549
TI  - Mapping of epitopes and structural analysis of antigenic sites in the
      nucleoprotein of rabies virus.
AB  - Linear epitopes on the rabies virus nucleoprotein (N) recognized by six MAbs
      raised against antigenic sites I (MAbs 6-4, 12-2 and 13-27) and IV (MAbs 6-9, 7
      12 and 8-1) were investigated. Based on our previous studies on sites I and IV,
      24 consecutively overlapping octapeptides and N- and C-terminal-deleted mutant N
      proteins were prepared. Results showed that all three site I epitopes studied and
      two site IV epitopes (for MAbs 8-1 and 6-9) mapped to aa 358-367, and that the
      other site IV epitope of MAb 7-12 mapped to aa 375-383. Tests using chimeric and
      truncated proteins showed that MAb 8-1 also requires the N-terminal sequence of
      the N protein to recognize its binding region more efficiently.
      Immunofluorescence studies demonstrated that all three site I-specific MAbs and
      one site IV-specific MAb (7-12) stained the N antigen that was diffusely
      distributed in the whole cytoplasm; the other two site IV-specific MAbs (6-9 and
      8-1) detected only the N antigen in the cytoplasmic inclusion bodies (CIB). An
      antigenic site II-specific MAb (6-17) also detected CIB-associated N antigen
      alone. Furthermore, the level of diffuse N antigens decreased after treatment of
      infected cells with cycloheximide. These results suggest that epitopes at site I
      are expressed on the immature form of the N protein, but epitope structures of
      site IV MAbs 6-9 and 8-1 are created and/or exposed only after maturation of the
      N protein.

PMID- 10640551
TI  - Several protein regions contribute to determine the nuclear and cytoplasmic
      localization of the influenza A virus nucleoprotein.
AB  - A systematic analysis was carried out to identify the amino acid signals that
      regulate the nucleo-cytoplasmic transport of the influenza A virus nucleoprotein
      (NP). The analysis involved determining the intracellular localization of eight
      deleted recombinant NP proteins and 14 chimeric proteins containing the green
      fluorescent protein fused to different NP fragments. In addition, the subcellular
      distribution of NP derivatives that contained specific substitutions at serine-3,
      which is the major phosphorylation site of the A/Victoria/3/75 NP, were analysed.
      From the results obtained, it is concluded that the NP contains three signals
      involved in nuclear accumulation and two regions that cause cytoplasmic
      accumulation of the fusion proteins. One of the karyophilic signals was located
      at the N terminus of the protein, and the data obtained suggest that the
      functionality of this signal can be modified by phosphorylation at serine-3.
      These findings are discussed in the context of the transport of influenza virus
      ribonucleoprotein complexes into and out of the nucleus.

PMID- 10640550
TI  - The bulk of the phosphorylation of human respiratory syncytial virus
      phosphoprotein is not essential but modulates viral RNA transcription and
      replication.
AB  - The ability of variants of the human respiratory syncytial virus (HRSV)
      phosphoprotein (P protein) to support RNA transcription and replication has been
      studied by using HRSV-based subgenomic replicons. The serine residues normally
      phosphorylated in P during HRSV infection have been replaced by other residues.
      The results indicate that the bulk of phosphorylation of P (98%) is not essential
      for viral RNA transcription or replication but that phosphorylation can modulate
      these processes.

PMID- 10640552
TI  - Growth of infectious salmon anaemia virus in CHSE-214 cells and evidence for
      phenotypic differences between virus strains.
AB  - Infectious salmon anaemia virus (ISAV) is a new orthomyxovirus-like virus.
      Thirteen isolates of ISAV (11 from Canada, one from Norway and one from Scotland)
      were studied for their replication in the CHSE-214 cell line compared with that
      in the SHK-1 cell line. All isolates replicated in SHK-1 cells, producing CPE
      between 3 and 12 days post-inoculation (p.i.). Six Canadian isolates also
      replicated in CHSE-214 cells, with production of CPE between 4 and 17 days p.i.
      Analysis of a one-step growth curve of ISAV in CHSE-214 cells showed that progeny
      virions remained predominantly cell-associated, accounting for the focalized
      nature of the CPE in the cell monolayer. One isolate (HKS 36) replicated in CHSE
      214 cells, as shown by positive RT-PCR results of blind passages, but was non
      cytopathic. All of the isolates were analysed for genetic heterogeneity by RT-PCR
      and RFLP with EcoRI and XhoI in a fraction of genome segment 2. The Canadian
      isolates showed a different RFLP profile to those of isolates Glesvaer/2/90 from
      Norway and 390/98 from Scotland. Structural proteins of four isolates, 'Back Bay
      98', RPC/NB-877, RPC/NB-049 and Glesvaer/2/90, were examined further by SDS-PAGE.
      All viruses showed four major polypeptides, designated here as VP1-VP4, in
      Coomassie blue-stained gels. In isolates Glesvaer/2/90 and RPC/NB-877, these
      viral proteins had estimated molecular masses of 74, 53, 46 and 26.5 kDa,
      respectively. Viral proteins in isolates 'Back Bay 98' and RPC/NB-049 were of
      similar sizes, except that VP3 was 43 kDa. Taken together, these results show
      that there are phenotypic differences among strains of ISAV.

PMID- 10640553
TI  - Complete genomic RNA sequence of western equine encephalitis virus and expression
      of the structural genes.
AB  - The complete nucleotide sequence of the 71V-1658 strain of western equine
      encephalitis virus (WEE) was determined (minus 25 nucleotides from the 5' end). A
      5' RACE reaction was used to sequence the 5' terminus from WEE strain CBA87. The
      deduced WEE genome was 11508 nucleotides in length, excluding the 5' cap
      nucleotide and 3' poly(A) tail. The nucleotide composition was 28% A, 25% C, 25%
      G and 22% U. Comparison with partial WEE sequences of strain 5614 (nsP2-nsP3 of
      the nonstructural region) and strain BFS1703 (26S structural region) revealed
      comparatively little variation; a total of 149 nucleotide differences in 8624
      bases (1.7% divergence), of which only 28% (42 nucleotides) altered the encoded
      amino acids. Comparison of deduced nsP1 and nsP4 amino acid sequences from WEE
      with the corresponding proteins from eastern equine encephalitis virus (EEE)
      yielded identities of 84.9 and 83.8%, respectively. Previously uncharacterized
      stem-loop structures were identified in the nontranslated terminal regions. A
      cDNA clone of the 26S region encoding the structural polyprotein of WEE strain
      71V-1658 was placed under the control of a cytomegalovirus promoter and
      transfected into tissue culture cells. The viral envelope proteins were
      functionally expressed in tissue culture, as determined by histochemical staining
      with monoclonal antibodies that recognize WEE antigens, thus, forming the initial
      step in the investigation of subunit vaccines to WEE.

PMID- 10640554
TI  - Linkage of an alphavirus host-range restriction to the carbohydrate-processing
      phenotypes of the host cell.
AB  - The Sindbis virus mutant NE2G216 retains PE2 in place of E2 in its virion
      structure. NE2G216 is a host-range mutant that replicates with near-normal
      kinetics in vertebrate cells, but displays severely restricted growth in cultured
      mosquito cells (C6/36) due to defects in the virus maturation process. In this
      study we tested the hypothesis that the host-range phenotype of NE2G216 was
      linked to the differences in carbohydrate-processing phenotypes between
      vertebrate and arthropod cells. Arthropod cell-derived glycoproteins are
      distinguishable from those synthesized in vertebrate cells by the absence of
      complex- and hybrid-type N-linked oligosaccharides. To test our hypothesis we
      compared the growth of the wild-type virus, TRSB, NE2G216 and three PE2
      containing, C6/36 cell-adapted variants, in vertebrate cells treated with 1
      deoxymannojirimycin (1-dMM). 1-dMM inhibits the Golgi alpha-mannosidase I enzyme
      and limits oligosaccharide processing to high-mannose forms (Man(8-9)GlcNAc(2)).
      The growth of TRSB was not restricted by the action of 1-dMM; however, NE2G216
      was restricted in a dose-dependent manner. In contrast, the growth of each PE2
      containing, C6/36 cell-adapted mutant was enhanced by low concentrations of 1-dMM
      (up to 1500%) and was only slightly affected by the higher concentrations. These
      results demonstrate that virion maturation functions of NE2G216 are sensitive to
      the structure of cis-linked oligosaccharides, and indicate that the carbohydrate
      processing phenotypes of the host cell can influence viral host-range and
      function as a selective pressure in alphavirus evolution.

PMID- 10640555
TI  - Genetic, geographical and temporal variation of porcine reproductive and
      respiratory syndrome virus in Illinois.
AB  - Porcine reproductive and respiratory syndrome virus (PRRSV) ORF5 gene sequences
      were generated by RT-PCR from 55 field isolates collected in Illinois and eastern
      Iowa. Spatial and temporal patterns of genetic variation in the virus were
      examined on a local geographical scale in order to test the hypothesis that the
      genetic similarity of PRRSV isolates (measured as their percentage pairwise ORF5
      nucleotide similarity) was positively correlated with their geographical
      proximity. Levels of genetic variability in the Illinois/eastern Iowa PRRSV
      sample were similar to levels of variability seen across broader geographical
      regions within North America. The genetic similarity of isolates did not
      correlate with their geographical distance. These results imply that the movement
      of PRRSV onto farms does not generally occur via distance-limited processes such
      as wind or wildlife vectors, but more typically occurs via the long-distance
      transport of animals or semen. Genetic distances between PRRSV isolates collected
      from the same farms at different times increased as the time separating the
      collection events increased. This result implies rapid movement of new genetic
      types of PRRSV into and out of farms. PRRSV ORF5 displayed a pattern of third
      codon-position diversity bias that was not evident in a geographically comparable
      sample of pseudorabies virus (a swine alphaherpesvirus) gC gene sequences. This
      result provides evidence that PRRSV ORF5 is experiencing stabilizing selection
      against structural novelty. Despite high genetic variability at all geographical
      levels, PRRSV ORF5 nevertheless contained potentially antigenic regions that were
      invariant at the amino acid level. These regions should make effective vaccine
      targets if they prove to be immunogenic.

PMID- 10640556
TI  - High affinity interaction between nucleocapsid protein and leader/intergenic
      sequence of mouse hepatitis virus RNA.
AB  - The nucleocapsid (N) protein of mouse hepatitis virus (MHV) is the major virion
      structural protein. It associates with both viral genomic RNA and subgenomic
      mRNAs and has structural and non-structural roles in replication including viral
      RNA-dependent RNA transcription, genome replication, encapsidation and
      translation. These processes all involve RNA-protein interactions between the N
      protein and viral RNAs. To better understand the RNA-binding properties of this
      multifunctional protein, the N protein was expressed in Escherichia coli as a
      chimeric protein fused to glutathione-S-transferase (GST). Biochemical analyses
      of RNA-binding properties were performed on full-length and partial N protein
      segments to define the RNA-binding domain. The full-length N protein and the GST
      N protein fusion product had similar binding activities with a dissociation
      constant (K(d)) of 14 nM when the MHV 5'-leader sequence was used as ligand. The
      smallest N protein fragment which retained RNA-binding activity was a 55 aa
      segment containing residues 177-231 which bound viral RNA with a K(d) of 32 nM. A
      consensus viral sequence recognized by the N protein was inferred from these
      studies; AAUCYAAAC was identified to be the potential minimum ligand for the N
      protein. Although the core UCYAA sequence is often tandemly repeated in viral
      genomes, ligands containing one or more repeats of UCYAA showed no difference in
      binding to the N protein. Together these data demonstrate a high-affinity,
      specific interaction between the N protein and a conserved RNA sequence present
      at the 5'-ends of MHV mRNA.

PMID- 10640557
TI  - The entire nucleotide sequence of two hepatitis G virus isolates belonging to a
      novel genotype: isolation in Myanmar and Vietnam.
AB  - A novel genotype of hepatitis G virus (HGV) was recently identified in sera of
      subjects from countries in South-East Asia. These isolates were recovered from
      serum of Myanmarese (designated HGV-MY14) and Vietnamese (designated HGV-VT48)
      subjects, respectively. To characterize the viral genome in more detail, the full
      length nucleotide sequence of the two different HGV isolates belonging to the
      novel genotype was cloned. Both HGV isolates were composed of 9228 nt and had a
      single open reading frame spanning 8529 nt and encoding 2843 aa residues. The
      isolates differed from previously reported HGV/GBV-C isolates types 1 to 3 by 13
      15% (nucleotide sequence) and 4-6% (amino acid sequence). The putative core
      region of both isolates was not clearly identifiable as it consisted of only 16
      aa residues. Based on phylogenetic analysis of full-length genome sequences and
      5'-UTR sequences, HGV-MY14 and HGV-VT48 isolates can be classified as a novel
      genotype, designated type 4.

PMID- 10640558
TI  - Expression and processing of the canine calicivirus capsid precursor.
AB  - The ORF2 product of canine calicivirus (CaCV) was identified and its processing
      in mammalian cells was analysed. Immunoblot analysis revealed the presence of the
      75 kDa capsid precursor in addition to a 57 kDa capsid protein and a 22 kDa N
      terminal polypeptide in CaCV-infected cells treated at an elevated temperature.
      When the CaCV ORF2 was expressed in a transient mammalian expression system, only
      the 75 kDa precursor was detected in immunoblot analysis, suggesting that no post
      translational processing occurred in this system. However, the precursor was
      processed to a 57 kDa protein and a 22 kDa polypeptide by the proteinase of
      feline calicivirus (FCV) when this was co-expressed with ORF2. Processing was
      blocked by site-directed mutagenesis of the putative cleavage site in the capsid
      precursor. The results indicate that the proteinase of FCV can cleave the capsid
      precursor of CaCV to produce the mature capsid protein and that CaCV may have a
      similar proteinase.

PMID- 10640559
TI  - The 2A proteins of three diverse picornaviruses are related to each other and to
      the H-rev107 family of proteins involved in the control of cell proliferation.
AB  - The 2A protein appears to be diverse among picornaviruses, in contrast to the
      other non-structural proteins, which have homologous structures and functions. In
      enteroviruses and rhinoviruses, 2A is a trypsin-like protease involved in protein
      processing and in shut-off of host-cell macromolecular synthesis. The aphthovirus
      and cardiovirus 2A is associated with an unusual processing event at the 2A/2B
      junction. It is shown here that the 2A protein of several diverse picornaviruses,
      the human parechoviruses, Aichi virus and avian encephalomyelitis virus, possess
      previously unrecognized conserved motifs and are likely to have a common
      function. Moreover, these motifs, a conserved histidine and flanking amino acids,
      an asparagine-cysteine dipeptide and a putative transmembrane domain, are
      characteristic of a family of cellular proteins, at least two of which are
      involved in the control of cell growth. These observations have important
      implications for an understanding of picornavirus genome structure and evolution,
      as well as pointing to possible functions of 2A in these viruses.

PMID- 10640560
TI  - Interactions in vivo between the proteins of infectious bursal disease virus:
      capsid protein VP3 interacts with the RNA-dependent RNA polymerase, VP1.
AB  - Little is known about the intermolecular interactions between the viral proteins
      of infectious bursal disease virus (IBDV). By using the yeast two-hybrid system,
      which allows the detection of protein-protein interactions in vivo, all possible
      interactions were tested by fusing the viral proteins to the LexA DNA-binding
      domain and the B42 transactivation domain. A heterologous interaction between VP1
      and VP3, and homologous interactions of pVP2, VP3, VP5 and possibly VP1, were
      found by co-expression of the fusion proteins in Saccharomyces cerevisiae. The
      presence of the VP1-VP3 complex in IBDV-infected cells was confirmed by co
      immunoprecipitation studies. Kinetic analyses showed that the complex of VP1 and
      VP3 is formed in the cytoplasm and eventually is released into the cell-culture
      medium, indicating that VP1-VP3 complexes are present in mature virions. In IBDV
      infected cells, VP1 was present in two forms of 90 and 95 kDa. Whereas VP3
      initially interacted with both the 90 and 95 kDa proteins, later it interacted
      exclusively with the 95 kDa protein both in infected cells and in the culture
      supernatant. These results suggest that the VP1-VP3 complex is involved in
      replication and packaging of the IBDV genome.

PMID- 10640561
TI  - Subcellular distribution analysis of the cucumber mosaic virus 2b protein.
AB  - The cucumoviral 2b protein is a viral counterdefence factor that interferes with
      the establishment of virus-induced gene silencing in plants. Synthetic peptides
      were used to generate an antibody to the 2b protein encoded by the Fny strain of
      cucumber mosaic virus (Fny-CMV). This polyclonal antibody was able to recognize
      the Fny-CMV 2b protein in a 10000 g pellet fraction of infected tobacco. No
      protein of equivalent size was detected in mock-inoculated or tobacco mosaic
      virus-infected samples. This represents the first demonstration of 2b protein
      expression by a subgroup I strain of CMV. Subcellular fractionation experiments
      on CMV-infected tobacco leaf tissue showed that the Fny-CMV 2b protein
      accumulated within a fraction that sedimented at forces of less than 5000 g and
      that the 2b protein was solubilized only by treatment with urea or SDS. These
      results suggested that the 2b protein associates either with the nucleus or
      cytoskeleton of the host cell. Further analysis showed that the 2b protein was
      enriched in a fraction that sedimented through a 2.2 M sucrose cushion. This
      fraction was also enriched in histones, suggesting that the CMV 2b protein
      associates preferentially with the host cell nucleus.

PMID- 10640562
TI  - Phylogenetic analysis of some large double-stranded RNA replicons from plants
      suggests they evolved from a defective single-stranded RNA virus.
AB  - Sequences were recently obtained from four double-stranded (ds) RNAs from
      different plant species. These dsRNAs are not associated with particles and as
      they appeared not to be horizontally transmitted, they were thought to be a kind
      of RNA plasmid. Here we report that the RNA-dependent RNA polymerase (RdRp) and
      helicase domains encoded by these dsRNAs are related to those of viruses of the
      alpha-like virus supergroup. Recent work on the RdRp sequences of alpha-like
      viruses raised doubts about their relatedness, but our analyses confirm that
      almost all the viruses previously assigned to the supergroup are related. Alpha
      like viruses have single-stranded (ss) RNA genomes and produce particles, and
      they are much more diverse than the dsRNAs. This difference in diversity suggests
      the ssRNA alpha-like virus form is older, and we speculate that the
      transformation to a dsRNA form began when an ancestral ssRNA virus lost its
      virion protein gene. The phylogeny of the dsRNAs indicates this transformation
      was not recent and features of the dsRNA genome structure and translation
      strategy suggest it is now irreversible. Our analyses also show some dsRNAs from
      distantly related plants are closely related, indicating they have not strictly
      co-speciated with their hosts. In view of the affinities of the dsRNAs, we
      believe they should be classified as viruses and we suggest they be recognized as
      members of a new virus genus (Endornavirus) and family (Endoviridae).

PMID- 10640563
TI  - A minimum length of N gene sequence in transgenic plants is required for RNA
      mediated tospovirus resistance.
AB  - We showed previously that transgenic plants with the green fluorescent protein
      (GFP) gene fused to segments of the nucleocapsid (N) gene of tomato spotted wilt
      virus (TSWV) displayed post-transcriptional gene silencing of the GFP and N gene
      segments and resistance to TSWV. These results suggested that a chimeric
      transgene composed of viral gene segments might confer multiple virus resistance
      in transgenic plants. To test this hypothesis and to determine the minimum length
      of the N gene that could trans-inactivate the challenging TSWV, transgenic plants
      were developed that contained GFP fused with N gene segments of 24-453 bp.
      Progeny from these plants were challenged with: (i) a chimeric tobacco mosaic
      virus containing the GFP gene, (ii) a chimeric tobacco mosaic virus with GFP plus
      the N gene of TSWV and (iii) TSWV. A number of transgenic plants expressing the
      transgene with GFP fused to N gene segments from 110 to 453 bp in size were
      resistant to these viruses. Resistant plants exhibited post-transcriptional gene
      silencing. In contrast, all transgenic lines with transgenes consisting of GFP
      fused to N gene segments of 24 or 59 bp were susceptible to TSWV, even though the
      transgene was post-transcriptionally silenced. Thus, virus resistance and post
      transcriptional gene silencing were uncoupled when the N gene segment was 59 bp
      or less. These results provide evidence that multiple virus resistance is
      possible through the simple strategy of linking viral gene segments to a silencer
      DNA such as GFP.

PMID- 10640564
TI  - High genetic diversity, distant phylogenetic relationships and intraspecies
      recombination events among natural populations of Yam mosaic virus: a
      contribution to understanding potyvirus evolution.
AB  - To evaluate the genetic diversity and understand the evolution of Yam mosaic
      virus (YMV), a highly destructive pathogen of yam (Dioscorea sp.), sequencing was
      carried out of the C-terminal part of the replicase (NIb), the coat protein (CP)
      and the 3'-untranslated region (3'-UTR) of 27 YMV isolates collected from the
      three main cultivated species (Dioscorea alata, the complex Dioscorea cayenensis
      Dioscorea rotundata and Dioscorea trifida). YMV showed the most variable CP
      relative to eight other potyviruses. This high variability was structured into
      nine distant molecular groups, as revealed by phylogenetic analyses and validated
      by assessment of the molecular evolutionary noise. No correlation was observed
      between the CP and 3'-UTR diversities and phylogenies. The most diversified and
      divergent groups included isolates from Africa. The remaining groups clustered in
      a single clade and a geographical distinction between isolates from the
      Caribbean, South America and Africa was observed. The role of the host in the
      selection of particular isolates was illustrated by the case of a divergent
      cultivar from Burkina Faso. Phylogenetic topological incongruence and
      complementary statistical tests highlighted the fact that recombination events,
      with single and multiple crossover sites, largely contributed to the evolution of
      YMV. We hypothesise an African origin of YMV from the yam complex D. cayenensis
      D. rotundata, followed by independent transfers to D. alata and D. trifida during
      virus evolution.

PMID- 10640565
TI  - The '30K' superfamily of viral movement proteins.
AB  - Relationships among the amino acid sequences of viral movement proteins related
      to the 30 kDa ('30K') movement protein of tobacco mosaic virus - the 30K
      superfamily - were explored. Sequences were grouped into 18 families. A
      comparison of secondary structure predictions for each family revealed a common
      predicted core structure flanked by variable N- and C-terminal domains. The core
      consisted of a series of beta-elements flanked by an alpha-helix on each end.
      Consensus sequences for each of the families were generated and aligned with one
      another. From this alignment an overall secondary structure prediction was
      generated and a consensus sequence that can recognize each family in database
      searches was obtained. The analysis led to criteria that were used to evaluate
      other virus-encoded proteins for possible membership of the 30K superfamily. A
      rhabdoviral and a tenuiviral protein were identified as 30K superfamily members,
      as were plant-encoded phloem proteins. Parsimony analysis grouped tubule-forming
      movement proteins separate from others. Establishment of the alignment of
      residues of diverse families facilitates comparison of mutagenesis experiments
      done on different movement proteins and should serve as a guide for further such
      experiments.

PMID- 10640566
TI  - Virus-like particles assemble in plants and bacteria expressing the coat protein
      gene of Indian peanut clump virus.
AB  - cDNA copies of the coat protein (CP) gene of Indian peanut clump virus (IPCV)-H
      were introduced into cells of Nicotiana benthamiana or Escherichia coli by
      transformation with vectors based on pROKII or pET respectively. In both plant
      and bacterial cells, IPCV CP was expressed and assembled to form virus-like
      particles (VLP). In plant extracts, the smallest preponderant particle length was
      about 50 nm. Other abundant lengths were about 85 and about 120 nm. The commonest
      VLP length in bacterial extracts was about 30 nm. Many of the longer VLP appeared
      to comprise aggregates of shorter particles. The lengths of the supposed
      'monomer' VLP corresponded approximately to those expected for encapsidated CP
      gene transcript RNA. Immunocapture RT-PCR, using primers designed to amplify the
      CP gene, confirmed that the VLP contained RNA encoding IPCV-H CP. The results
      show that encapsidation does not require the presence of the 5'-terminal
      untranslated sequence of the virus RNA and suggest that if there is an 'origin of
      assembly' motif or sequence, it lies within the CP gene. When transgenic plants
      expressing IPCV-H CP were inoculated with IPCV-L, a strain that is serologically
      distinct from IPCV-H, the virus particles that accumulated contained both types
      of CP.

PMID- 10640567
TI  - The complete nucleotide sequence of apple mosaic virus (ApMV) RNA 1 and RNA 2:
      ApMV is more closely related to alfalfa mosaic virus than to other ilarviruses.
AB  - The complete nucleotide sequences of apple mosaic virus RNA 1 and 2 have been
      characterized. Apple mosaic virus RNA 1 is 3476 nucleotides in length and encodes
      a single large open reading frame (ORF), whereas apple mosaic virus RNA 2 is 2979
      nucleotides in length and also encodes a single ORF. The amino acid sequences
      encoded by RNA 1 and 2 show similarity to all of the other ilarviruses for which
      sequence data are available, but both are more closely related to alfalfa mosaic
      virus (AMV) than to other ilarviruses. Points of similarity include the absence
      of ORF 2b, present on the RNA 2 of all previously characterized ilarviruses. The
      close relationship to AMV also occurs in the movement protein, encoded by RNA 3,
      but not with the coat protein. These data suggest that the present taxonomy
      should be revised, and that AMV should be considered an aphid-transmissible
      ilarvirus.

PMID- 10640568
TI  - Expression of a plant virus non-structural protein in Saccharomyces cerevisiae
      causes membrane proliferation and altered mitochondrial morphology.
AB  - Carnation Italian ringspot tombusvirus encodes a protein, referred to as 36K,
      that possesses a mitochondrial targeting signal and two transmembrane segments
      which are thought to anchor this protein to the outer membrane of the
      mitochondrial envelope of infected plant cells. To determine the topology of the
      virus protein inserted in the cell membrane, as well as the sequence requirements
      for targeting and insertion, an in vivo system was set up in which this could be
      analysed in the absence of productive virus infection. The 36K protein was
      expressed in the yeast Saccharomyces cerevisiae in native form or fused to the
      green fluorescent protein. Using a fluorescence microscope, large green
      fluorescing cytoplasmic aggregates were visible which stained red when cells were
      treated with the vital stain MitoTracker, which is specific for mitochondria.
      These aggregates were shown by electron microscopy to be composed of either
      mitochondria or membranes. The latter type was particularly abundant for the
      construct in which the green fluorescent protein was fused at the N terminus of
      the 36K protein. Immunoelectron microscopy demonstrated that the viral protein is
      present in the anomalous aggregates and Western blot analysis of protein extracts
      showed 36K to be resistant to alkaline, urea or salt extraction, a property of
      integral membrane proteins.

PMID- 10640569
TI  - Evidence of synergism between African cassava mosaic virus and a new double
      recombinant geminivirus infecting cassava in Cameroon.
AB  - Stem cuttings were collected in Cameroon from cassava plants displaying cassava
      mosaic disease (CMD) symptoms. The nature of the viruses present was determined
      by using the PCR with primers specific for the coat protein (CP) genes of African
      cassava mosaic virus (ACMV) and East African cassava mosaic virus (EACMV). All
      samples were infected by ACMV and eight of the 50 samples were infected by both
      ACMV and an EACMV-like virus. The complete nucleotide sequences of DNA-A and -B
      of representative ACMV and EACMV-like viruses were determined. The DNA-A
      component of the EACMV-like virus contained evidence of recombination in the AC2
      AC3 region and DNA-B also contained evidence of recombination in BC1. However,
      both components retained gene arrangements typical of bipartite begomoviruses.
      When Nicotiana benthamiana plants were doubly inoculated with these Cameroon
      isolates of ACMV and EACMV (ACMV/CM, EACMV/CM) by using sap from cassava plants
      or infectious clones, the symptoms were more severe than for plants inoculated
      with either virus alone. Southern blot analysis of viral DNAs from infected
      plants showed that there were significantly higher levels of accumulation of both
      ACMV/CM components and, to a lesser extent, of EACMV/CM components in mixed
      infected plants than in singly infected plants. These results strongly suggest
      the occurrence of a synergistic interaction between the two viruses.

PMID- 10640570
TI  - Functional analysis of proteins encoded by banana bunchy top virus DNA-4 to -6.
AB  - Green fluorescent protein (GFP)-tagging was used to determine the intracellular
      localization pattern of the proteins encoded by banana bunchy top virus (BBTV)
      DNA-3, -4 and -6. The protein encoded by BBTV DNA-4, which possesses a
      hydrophobic N terminus, was found to localize exclusively to the cell periphery
      while the proteins encoded by BBTV DNA-3 and -6 were found in both the nucleus
      and the cytoplasm. Co-expression of the DNA-4 protein and the proteins encoded by
      BBTV DNA-3 and -6 revealed that the DNA-4 protein was able to re-locate the DNA-6
      protein, but not the DNA-3 protein, to the cell periphery. The 29 amino acid N
      terminal hydrophobic region of the DNA-4 gene product appeared to be essential
      for specific localization of this protein since deletion of this region abolished
      its ability to localize to the cell periphery. These results indicate that BBTV
      may utilize a system analogous to that of the begomoviruses with the BBTV DNA-6
      protein acting as a nuclear shuttle protein (NSP) while the DNA-4 protein
      transports the NSP-DNA complexes to the cell periphery for intercellular
      transport. The protein encoded by BBTV DNA-5 was found to contain an LXCXE motif
      and yeast two-hybrid analysis revealed that the DNA-5 protein has retinoblastoma
      (Rb)-binding activity. This activity was dependent on an intact LXCXE motif since
      specific mutations to either the C or E residue completely abolished Rb-binding
      activity. These results indicate that the gene product of BBTV DNA-5 is an Rb
      binding-like protein and may play an important role in host-cell cycle
      manipulation.

PMID- 10640571
TI  - Do young children have adult syntactic competence?
AB  - Many developmental psycholinguists assume that young children have adult
      syntactic competence, this assumption being operationalized in the use of adult
      like grammars to describe young children's language. This "continuity assumption"
      has never had strong empirical support, but recently a number of new findings
      have emerged - both from systematic analyses of children's spontaneous speech and
      from controlled experiments - that contradict it directly. In general, the key
      finding is that most of children's early linguistic competence is item based, and
      therefore their language development proceeds in a piecemeal fashion with
      virtually no evidence of any system-wide syntactic categories, schemas, or
      parameters. For a variety of reasons, these findings are not easily explained in
      terms of the development of children's skills of linguistic performance,
      pragmatics, or other "external" factors. The framework of an alternative, usage
      based theory of child language acquisition - relying explicitly on new models
      from Cognitive-Functional Linguistics - is presented.

PMID- 10640572
TI  - Infants' use of featural and experiential information in segregating and
      individuating objects: a reply to Xu, Carey and Welch (2000)

PMID- 10640573
TI  - The emergence of kind concepts: a rejoinder to Needham and Baillargeon (2000).

PMID- 10640574
TI  - Chinese and Americans see opposite apparent motions in a Chinese character.
AB  - The perceived direction of apparent motion can be influenced by both "top-down"
      factors, such as expectation, and by "bottom-up" or stimulus-driven factors, such
      as grouping (Tse, P., Cavanagh, P. & Nakayama, K. (1998). The role of parsing in
      high-level motion processing. In T. Watanabe, High-level motion processing -
      computational, neurobiological and psychophysical perspectives. Cambridge, MA:
      MIT Press). Here we report the results of a single experiment that pitted top
      down cues against bottom-up cues in an apparent motion sequence over the
      successive strokes of a Chinese character. Although each stroke was in fact
      presented all at once, subjects raised in China tended to see apparent motion
      over a single stroke in the direction it would have taken when drawn by hand,
      even though bottom-up cues drive a percept of apparent motion in the opposite
      direction for observers unfamiliar with the Chinese language. There is therefore
      a learned component to motion perception arising from top-down expectations
      capable of overriding bottom-up cues to motion.

PMID- 10640575
TI  - Stability characterization of controlled release coprecipitates and solid
      dispersions.
AB  - The present study was conducted to determine the effects of ageing at exaggerated
      storage conditions on controlled release tablets prepared with indomethacin
      Eudragit((R)) coprecipitates (CPs) and solid dispersions (SDs). CPs and SDs
      compressed as tablets were stored at -20, 4, 37, 45, 55, 37 degrees C/11% RH, 37
      degrees C/51% RH and 37 degrees C/91% RH. The samples were analyzed over a period
      of six months for their dissolution, crystalline reversion and thermal changes.
      Samples stored at extremely low temperatures, higher temperatures and humidity
      conditions exhibited a significant decrease in dissolution rates. However, no
      significant change in the release rates was observed for samples stored at 4
      degrees C. The degree of crystallinity increased over a period of time as
      confirmed by X-ray diffractometry. DSC data demonstrated that indomethacin exists
      in two polymorphic forms, Form I (mp 160-161 degrees C) and Form II (mp 153-154
      degrees C). CPs showed an endotherm of Form I, whereas SDs showed a mixture of
      Form I and II.

PMID- 10640576
TI  - Modulated release of triterpenic compounds from a O/W/O multiple emulsion
      formulated with dimethicones: infrared spectrophotometric and differential
      calorimetric approaches.
AB  - From the use of silicones within O/W/O multiple emulsions, we can expect, two
      principal advantages: (1) the silicones with the lowest molecular weight decrease
      the oily touch; (2) due to the large range of viscosity, this excipient should
      influence the skin distribution of actives after topical application. The purpose
      of our work is to highlight these advantages. Multiple emulsions were formulated
      with several dimethicones and with drug model. Firstly, the effects of different
      dimethicones incorporated within multiple emulsions were studied, through in
      vitro penetration results. Secondly, we investigated the residual film on the
      skin by Differential Scanning Calorimetry (DSC) and by Fourier Transform Infrared
      (FTIR) to determine its structure. Correlations were established between the
      silicone structure and the distribution of drugs in different skin levels or
      between the silicone structure and the percutaneous penetration. The
      incorporation of silicones within O/W/O multiple emulsions seems to be an
      efficient means of modulating the penetration and the distribution of drugs in
      the skin.

PMID- 10640577
TI  - Preparation, characterization and properties of sterically stabilized paclitaxel
      containing liposomes.
AB  - Paclitaxel (Taxol) is a diterpenoid isolated from Taxus brevifolia, approved by
      the FDA for the treatment of ovarian and breast cancers. Due to its low
      solubility in water, it is clinically administered dissolved in Cremophor EL,
      (polyethoxylated castor oil) and ethanol, which cause serious side effects.
      Inclusion of paclitaxel in liposomal formulations has proved to be a good
      approach to eliminating this vehicle and improving the drug's antitumor efficacy.
      We prepared different conventional and PEGylated liposomes containing paclitaxel
      and determined encapsulation efficiency, physical stability and drug leakage in
      human plasma. The best conventional liposome formulation was composed of ePC/PG
      9:1, while for PEGylated liposomes the best composition was ePC/PG/CHOL/PEG(5000)
      DPPE 9:1:2:0.7. PEGylated liposomes were found to be less stable during storage
      than the corresponding conventional liposomes and to have lower drug release in
      human plasma at 37 degrees C. In vitro cytotoxic activities were evaluated on HT
      29 human colon adenocarcinoma and MeWo melanoma cell lines. After 2 and 48 h,
      conventional liposomes had the same cytotoxicity as free paclitaxel, while
      PEGylated liposomes were as active as free drug, only after 48 h.
      Pharmacokinetics and biodistribution were evaluated in Balb/c mice after i.v.
      injection of paclitaxel, formulated in Cremophor EL or in conventional or in
      PEGylated liposomes. Encapsulation of paclitaxel in conventional liposomes
      produced marked differences over the free drug pharmacokinetics. PEGylated
      liposomes were long-circulating liposomes, with an increased t(1/2) beta 48.6 h,
      against t(1/2) beta 9.27 h of conventional liposomes. Biodistribution studies
      showed a considerable decrease in drug uptake in MPS-containing organs (liver and
      spleen) at 0.5 and 3 h after injection with PEGylated compared to conventional
      liposomes.

PMID- 10640578
TI  - Design, optimization and evaluation of domperidone coevaporates.
AB  - Coevaporates of domperidone were prepared using different polymers by solvent
      evaporation technique. Ethyl cellulose and hydroxypropyl methylcellulose
      phthalate were used in preparation of coevaporates. The coevaporates were
      characterized by X-ray diffraction studies, IR spectrophotometry and differential
      scanning calorimetry. The dissolution behavior of coevaporates was studied using
      buffer solution of pH 1.2 for the first 2 h and that of pH 6.8 thereafter up to
      12 h. A two-factor, three-level design was used to quantitate the effect of
      polymers on dissolution profile of domperidone. The drug release rate was found
      to be dependent on the concentration of polymers in the coevaporates. Dissolution
      of drug in a pH 6.8 buffer improved with increasing concentration of
      hydroxypropyl methylcellulose phthalate in coevaporates. Bioavailability studies
      in human volunteers confirmed that domperidone coevaporates sustained drug
      release.

PMID- 10640579
TI  - Determination of threshold energy dose for ultrasound-induced transdermal drug
      transport.
AB  - Low-frequency (20 kHz) ultrasound has been shown to enhance transdermal transport
      of drugs, a phenomenon referred to as sonophoresis. In this paper, we report the
      threshold energy dose for ultrasound-induced transdermal drug transport. The
      threshold was determined by in vitro measurements of the dependence of
      sonophoretic enhancement on ultrasound parameters, including intensity, duty
      cycle, and exposure time. While the enhancement varies linearly with ultrasound
      intensity and exposure times, it is independent of the duty cycle in the range of
      parameters studied. The enhancement is also directly proportional to the
      ultrasound energy density once the threshold value is crossed. For full thickness
      pig skin, the threshold value is about 222 J/cm(2). The overall dependence of
      transport enhancement on ultrasound parameters is similar to that of cavitation
      measured in a model system, pitting of aluminum foil. Specifically, the extent of
      pitting is proportional to ultrasound intensity and exposure time and is
      independent of duty cycle. Furthermore, the extent of pitting is also
      proportional to the ultrasound energy density. The similarity between the
      parametric dependence of transport enhancement and cavitation is consistent with
      previous findings that cavitation plays the dominant role in sonophoresis.

PMID- 10640580
TI  - Biodegradable semi-crystalline comb polyesters influence the microsphere
      production by means of a supercritical fluid extraction technique (ASES).
AB  - The aerosol solvent extraction system (ASES) is a method based on solvent
      extraction using supercritical carbon dioxide for the preparation of
      microspheres. The ASES technology seems to be strongly affected by physico
      chemical properties of biodegradable polymers, leading to incomplete or
      unsuccessful microsphere formation. The number of suitable polymers for ASES,
      such as poly(L-lactide) (L-PLA) and poly(beta-hydroxy-butyric acid) (PHB) is
      rather limited for unknown reasons. Therefore linear and novel branched
      polyesters were synthesized and subjected to the ASES process to explore the
      function property relationship. The properties of these polymers as well as of
      the ASES products were characterized by NMR spectroscopy, differential scanning
      calorimetry, light scattering, wide-angle X-ray scattering and scanning electron
      microscopy. It appears that high degrees of polymer crystallinity are the key
      factor for successful microsphere formation using the ASES process. Under the
      conditions investigated two types of polymers were especially suitable: semi
      crystalline comb polyesters as well as comb polyesters in which crystallinity
      could be induced. These novel polymers are of particular interest for the ASES
      encapsulation technology since they combine beneficial properties both
      controlling drug release due to their three-dimensional architecture and faster
      biodegradability with sufficient mechanical stability to allow particle formation
      using supercritical carbon dioxide.

PMID- 10640581
TI  - Mathematical modeling of diffusion-mediated release from bulk degrading matrices.
AB  - The release of active agent from a bulk degrading matrix is formulated as a
      linear reaction diffusion problem. Two pools of active agent are assumed to
      contribute to the release: a pool of mobile active agent which readily diffuses
      out of the matrix upon immersion in an aqueous medium and a pool of immobilized
      active agent which can diffuse only after matrix degradation. Due to the
      linearity of our model, the dynamics of the two pools of active agent can be
      considered separately, for any mode of bulk degradation kinetics. For
      definiteness, we consider the case of first order degradation kinetics and a
      rectangular parallelepiped shaped matrix. A closed form solution is obtained for
      the release under perfect sink conditions which is then used to describe the in
      vitro release of the PerioChip?trade mark omitted?. This solution can explain the
      bi-phasic release profile characteristic of many hydrolytically degradable
      matrices. The case of mass transfer boundary conditions is solved numerically
      using the finite element method (FEM). This analysis indicates that under
      ordinary mixing conditions the diffusion layer is not rate limiting and the
      release is very well approximated by the analytical result for perfect sink
      conditions.

PMID- 10640582
TI  - Synthesis and conformational studies of poly(L-lysine) based branched
      polypeptides with Ser and Glu/Leu in the side chains.
AB  - In a new group of polypeptides, the branches were composed of DL-Ala
      oligopeptide, L-serine and L-leucine or L-glutamic acid residues. The synthesis
      of eight different side-chain combinations is described. In the first group, Ser
      was attached directly to the epsilon-amino groups of polylysine, and Leu or Glu
      was situated at the side chain end (poly[Lys(X(i)-DL-Ala(m)-Ser(j))]).
      Alternatively, Leu or Glu was positioned next to the polylysine backbone
      (poly[Lys(Ser(j)-DL-Ala(m)-X(i))], where X=L-Leu or L-Glu and m approximately 3
      6, i</=1 and j</=1). The second group of polymers was synthesised by grafting
      oligo(DL-alanine) chains to the epsilon-amino groups of polylysine, followed by
      coupling of Ser and Leu or Glu consecutively to the chain ends, however, in a
      different order, resulting in the polymers (poly[Lys(X(i)-Ser(j)-DL-Ala(m))] and
      poly[Lys(Ser(j)-X(i)-DL-Ala(m))], where X=L-Leu or L-Glu and m approximately 3-6,
      i</=1 and j</=1). The effect of amino-acid composition and sequence of side
      chains in branched polypeptides on solution conformation was studied by CD
      spectroscopy. CD spectra recorded in aqueous solutions of various pH (2-11) and
      ionic strengths (0.02-2.0 M NaCl) suggest that leucine- and serine-containing
      polypeptides have more ordered (alpha-helical) structure than the polymers with
      glutamic acid and serine residues in the same position. The influence of serine
      residues on ordered structure (helical or beta-sheet) formation depends on its
      position in the side chain as well as on the nature of amino acid X (Leu or Glu).
      The incorporation of Ser into the branches resulted in polypeptides possessing
      prolonged shelf stability and high water-solubility. No toxic effect of this new
      class of polymers was observed on mouse spleen cells, even after 4 h of
      incubation.

PMID- 10640583
TI  - Glutaraldehyde crosslinked sodium alginate beads containing liquid pesticide for
      soil application.
AB  - This paper presents experimental results on the successful encapsulation of a
      natural liquid pesticide 'neem (Azadirachta Indica A. Juss.) seed oil' hereafter
      designated as NSO, using sodium alginate (Na-Alg) as a controlled release (CR)
      polymer after crosslinking with glutaraldehyde (GA). The NSO-containing beads
      have been prepared by changing the experimental variables such as the extent of
      crosslinking and the amount of loading in order to optimize the process
      variables. The absence of chemical interactions between active ingredients and
      polymer as well as crosslinking agent was confirmed by FTIR spectral
      measurements. The SEM data indicated that the structure of the walls of the beads
      are smooth and nonporous. The swelling results indicated that swelling of the
      polymeric beads decreases with increasing exposure time to the crosslinking
      agent. However, no significant variation in swelling was observed with different
      amounts of NSO loading. In order to understand the crosslinkability and its
      effect on the NSO release patterns of the beads, an attempt was made to calculate
      the molar mass between crosslinks using the Flory-Rehner equation. The release
      data have been fitted to an empirical equation to estimate the kinetic
      parameters.

PMID- 10640584
TI  - A novel positively thermosensitive controlled-release microcapsule with membrane
      of nano-sized poly(N-isopropylacrylamide) gel dispersed in ethylcellulose matrix.
AB  - A positively thermosensitive drug-release microcapsule (MC) with diameter around
      100 microm was designed and its preparation was carried out by using an air
      suspension coating technique (the Wurster process). The MC had a core layered
      with carbazochrome sodium sulfonate (CCSS, a water-soluble model drug) particles
      and a thermosensitive coat composed of an ethylcellulose matrix containing nano
      sized thermosensitive hydrogels. The hydrogel particles consisted of a newly
      synthesized composite latex with a poly(N-isopropylacrylamide (NIPAAm)) shell
      that could reversibly change the shell thickness in water with response to an
      environmental temperature change. This MC demonstrated a positively
      thermosensitive drug release: the release rate was remarkably enhanced at
      temperatures above a lower gel collapse point (temperature for complete
      deswelling) of 32 degrees C, suggesting that the shrinkage of poly(NIPAAm) shells
      most likely created many voids in the coat and thereby imparted the higher water
      permeability to the coat. Thermosensitivity of drug release highly depended on
      the composite latex particle content in the coat. It became most distinct when
      its content reached 12.5 and 15 wt%. In addition, it was found that the present
      MC membrane made it possible to obtain an 'on-off' pulsatile release, which could
      alter the release rate in the order of a minute, in response to stepwise
      temperature changes between 30 and 50 degrees C.

PMID- 10640585
TI  - Phosphated crosslinked guar for colon-specific drug delivery. I. Preparation and
      physicochemical characterization.
AB  - Guar gum (GG) was crosslinked with increasing amounts of trisodium
      trimetaphosophate (STMP) to reduce its swelling properties for use as a vehicle
      in oral delivery formulations, especially drug delivery systems aimed at
      localizing drugs in the distal portions of the small bowel. Swelling of GG in
      artificial gastrointestinal fluids was reduced from 100 to 120-fold (native GG)
      to 10-35-fold depending on the amount of crosslinker used, showing a bell-shape
      dependency. As a result of the crosslinking procedure GG lost its non-ionic
      nature and became negatively charged. This was demonstrated by methylene blue
      (MB) adsorption studies and swelling studies in sodium chloride solutions with
      increasing concentrations in which the hydrogels' network collapsed. The
      adsorption of MB was also used to characterize the degree of the GG crosslinking,
      from which the effective network density was calculated. In addition, effective
      network density was calculated from elasticity measurements. Both measurements
      showed that the crosslinking density (but not swelling) of the new products was
      linearly dependent on the amount of STMP used in the reaction.

PMID- 10640586
TI  - Phosphated crosslinked guar for colon-specific drug delivery. II. In vitro and in
      vivo evaluation in the rat.
AB  - Targeting of drugs to the colon, following oral administration, can be
      accomplished by the use of modified, biodegradable polysaccharides as vehicles.
      In a previous study, a crosslinked low swelling guar gum (GG) hydrogel was
      synthesized by reacting it with trisodium trimetaphosphate (STMP). In the present
      study the functioning of GG crosslinked products (GGP) as possible colon-specific
      drug carriers was analyzed by studying (a) the release kinetics of pre-loaded
      hydrocortisone from GGP hydrogels into buffer solutions with, or without GG
      degrading enzymes (alpha-galactosidase and beta-mannanase) and (b) direct
      measurements of the polymers' degradation in the cecum of conscious rats. The
      effect of GG diet on alpha-galactosidase and beta-mannanase activity in the cecum
      of the rat and GGP degradation was also measured. It was found that the product
      GGP-0.1 (loosely crosslinked with 0.1 equivalents of STMP) was able to prevent
      the release of 80% of its hydrocortisone load for at least 6 h in PBS, pH=6.4.
      When a mixture of alpha-galactosidase and beta-mannanase was added to the buffer
      solution, an enhanced hydrocortisone release was observed. In-vivo degradation
      studies in the rat cecum showed that despite the chemical modification of GG, it
      retained its enzyme-degrading properties in a crosslinker concentration-dependent
      manner. Eight days of GG diet prior to the study increased alpha-galactosidase
      activity in the cecum of the rat three-fold, compared to its activity without the
      diet. However, this increase in the enzyme activity was unable to improve the
      degradation of the different GGP products. The overall alpha-galactosidase
      activity in the rat cecum was found to be extracellular, while the activity of
      beta-mannanase was found to be bacterial cell-wall associated. It is concluded
      that because CG crosslinked with STMP can be biodegraded enzymatically and is
      able to retard the release of a low water-soluble drug, this polymer could
      potentially be used as a vehicle for colon-specific drug delivery.

PMID- 10640587
TI  - Acyclovir-containing liposomes for potential ocular delivery. Corneal penetration
      and absorption.
AB  - The in vitro corneal penetration and in vivo corneal absorption of acyclovir from
      an acyclovir-containing liposome system were investigated. Results of in vitro
      corneal penetration demonstrated that positively charged liposomes resulted in a
      penetration rate lower than those of negatively charged liposomes and free
      acyclovir in solution. An in vivo study indicated that the extent of acyclovir
      absorption from positively charged liposomes was higher that those from
      negatively charged liposomes and free acyclovir. The acyclovir concentration in
      the cornea after administration of positively charged liposomes showed that an
      acyclovir deposition in the cornea was greater than those of negatively charged
      liposomes and free acyclovir. From morphological observation of the cornea
      surface treated with liposomes, it was suggested that positively charged
      liposomes formed a completely coated layer on the cornea surface. These liposomes
      would bind intimately on the cornea surface, leading to an increase of residence
      time. Therefore, positively charged liposomes resulted in an increase of
      acyclovir (ACV) absorption.

PMID- 10640588
TI  - Preparation, characterization, cytotoxicity and pharmacokinetics of liposomes
      containing water-soluble prodrugs of paclitaxel.
AB  - Paclitaxel (Taxol) is a diterpenoid isolated from Taxus brevifolia, used
      clinically for the treatment of ovarian and breast cancer. Due to its aqueous
      insolubility it is administered dissolved in ethanol and Cremophor EL
      (polyethoxylated castor oil), which has serious side effects. In order to
      eliminate this vehicle, in previous work we entrapped paclitaxel in conventional
      and in polyethylene glycol coated liposomes. However, in neither formulation did
      we obtain satisfactory entrapment efficiency. In this study we increased the
      paclitaxel concentration entrapped in liposomes by incorporating different water
      soluble prodrugs, such as the 2'-succinyl, 2'-methylpyridinium acetate and 2'
      mPEG ester paclitaxel derivatives, in the lipid vesicles. Liposomes containing 2'
      mPEG (5000)-paclitaxel showed the best performance in terms of stability,
      entrapment efficiency and drug concentration (6.5 mgml(-1)). The in vitro
      cytotoxic activity of this liposomal prodrug was similar to that of the parent
      drug. The pharmacokinetic parameters for the free and for the liposomal prodrugs
      fitted a bi-exponential plasma disposition. The most important change in
      pharmacokinetic values of the prodrug vs. the free drug liposomal formulations
      was t(1/2)beta, plasma lifetime, which was longer in liposomes containing 2'-mPEG
      (5000)-paclitaxel.

PMID- 10640589
TI  - Drug release from biodegradable injectable thermosensitive hydrogel of PEG-PLGA
      PEG triblock copolymers.
AB  - An aqueous solution of newly developed low-molecular-weight PEG-PLGA-PEG triblock
      copolymers with a specific composition is a free flowing sol at room temperature
      but becomes a gel at body temperature. Two model drugs, ketoprofen and
      spironolatone, which have different hydrophobicities, were released from the PEG
      PLGA-PEG triblock copolymer hydrogel formed in situ by injecting the solutions
      into a 37 degrees C aqueous environment. Ketoprofen (a model hydrophilic drug)
      was released over 2 weeks with a first-order release profile, while
      spironolactone (a model hydrophobic drug) was released over 2 months with an S
      shaped release profile. The release profiles were simulated by models considering
      degradation and diffusion, and were better described by a model assuming a core
      shell structure of the gel.

PMID- 10640590
TI  - Evaluation of novel soya-lecithin formulations for dermal use containing
      ketoprofen as a model drug.
AB  - In this study soya-lecithin aggregates, prepared by a technique using compressed
      gas, are used to formulate new dermal preparations. Ketoprofen (KP), a
      nonsteroidal anti-inflammatory drug (NSAID) is included as a model drug. The
      technique offers the possibility of incorporating auxiliary agents, such as
      penetration enhancers, anti-irritants and moisturisers together with the drug in
      one process. Apparent partition coefficients for n-octanol-phosphate buffer were
      determined for each of the lecithin aggregates. In general, soya-lecithin
      improves the partition of KP into n-octanol. The resulting products were included
      in widely used hydrophilic and hydrophobic vehicles. After 24 h, the cumulative
      amount of drug released through an artificial membrane was higher from the
      hydrophilic gels (2.6-4.3 mg) and the hydrophobic creams (0.23-0.392 mg) than
      from the control preparations (control hydrogel: 1.3 mg; control hydrophobic
      cream: 0.141 mg). However, the cumulative amount released from the hydrophobic
      vehicles was generally lower than from the hydrophilic matrices. Cumulative
      amounts such as those released from the hydrophilic preparations can also be
      achieved using supersaturated formulations based solely on the drug-loaded
      lecithin aggregates and a suitable oily component (4.07 mg). Results from the
      diffusion studies using artificial membranes were confirmed by permeation studies
      using excised rat skin. The improvement in skin permeation is related to both the
      solubilising effect of the lecithin matrix and the penetration enhancing effect
      of lecithin itself. The novel soya-lecithin aggregates are promising candidates
      for new drug delivery systems in dermatology and cosmetology. Lecithin aggregates
      loaded with drugs are multifunctional carriers that also act as penetration
      enhancers.

PMID- 10640591
TI  - Polyurethane coatings release bioactive antibodies to reduce bacterial adhesion.
AB  - This study describes the formulation of a biomedical grade polyurethane hydrogel
      coating containing solid dispersed bioactive antibodies cast from an organic
      solvent onto a model polymer biomaterial substrate. A prepolymer dispersion in
      anhydrous isopropanol containing a uniformly distributed slurry of 22 microm
      sieved commercial lyophilized polyclonal pooled human immunoglobulin G (IgG)
      solids was coated onto polymer substrates by simple immersion. Maximum antibody
      release was approximately 50 microg/cm(2) from a 15% w/w IgG polymer coating. In
      vitro antimicrobial studies utilized Escherichia coli to compare performance of
      bare uncoated tubing, hydrogel-coated tubing with added aqueous phase antibodies,
      and antibody-dispersed hydrogel-coated tubing. Bacterial adhesion was reduced
      significantly (p<0.05) in the presence of antibodies with the greatest reduction
      seen with the antibody releasing coating. The presence of antibody also
      significantly enhanced the killing of the bacteria in an in vitro
      opsonophagocytic assay using freshly isolated blood neutrophils over 2 h
      indicating that antibody bioactivity is maintained. This controlled release
      polyurethane hydrogel coating imparts infection resistance by exploiting the low
      adhesive properties of the biomedical grade hydrogel and the intrinsic bioactive
      role of the antibodies to reduce bacterial adhesion and promote clearance via
      natural immune mechanisms.

PMID- 10640593
TI  - Effect of formulation and process variables on porosity parameters and release
      rates from a multi unit erosion matrix of a poorly soluble drug.
AB  - The effect of drug loading, water required for granulation and spheronization
      time on porosity parameters (intrusion-extrusion isotherms, pore size
      distribution, total pore surface area, mean pore diameter, shape and morphology
      of pores) and drug release rates from pellets of a poorly soluble drug was
      investigated. Porosity parameters were determined by mercury intrusion
      porosimetry. The drug loading was found to have a profound effect on the porosity
      parameters. Pellets with low drug loading showed increased pore surface area with
      small mean pore diameters and an increased number of total pores. On the other
      hand, pellets with high drug loading had decreased pore surface areas with larger
      mean pore diameters and a reduction in the total number of pores. With high drug
      loading, the drug release rate decreased. Water required for granulation had a
      direct effect on the total porosity of the pellets. Spheronization time from 2 to
      10 min had a pronounced effect on porosity parameters and release rates. No
      changes in porosity parameters and release rates were observed from 10 to 20 min
      of spheronization time. It was shown that each porosity parameter investigated
      was well correlated with drug release rates and thus it is important to study the
      effect of porosity parameters in evaluating the in vitro performance of the multi
      unit erosion matrix for the controlled release of a poorly soluble drug.

PMID- 10640592
TI  - Generation of protective immune responses to plague by mucosal administration of
      microsphere coencapsulated recombinant subunits.
AB  - We have investigated noninvasive immunization to plague. Recombinant subunit
      antigens, F1 and V from Yersinia pestis, were coencapsulated in biodegradable
      poly(L100 LD(50's) inhalational challenge with virulent Y. pestis. These data
      expand on previous findings from our laboratories, providing further insight into
      the mechanics of safeguarding mice from plague through nasal immunization.
      Further, these results demonstrate that in a murine model, solid protection from
      pneumonic plague can be engendered by two intranasal administrations of
      appropriately formulated recombinant proteins.

PMID- 10640594
TI  - Structure-related aspects on water diffusivity in fatty acid-soap and skin lipid
      model systems.
AB  - Simplified skin barrier models are necessary to get a first hand understanding of
      the very complex morphology and physical properties of the human skin barrier. In
      addition, it is of great importance to construct relevant models that will allow
      for rational testing of barrier perturbing/occlusive effects of a large variety
      of substances. The primary objective of this work was to study the effect of
      lipid morphology on water permeation through various lipid mixtures (i.e., partly
      neutralised free fatty acids, as well as a skin lipid model mixture). In
      addition, the effects of incorporating Azone((R)) (1-dodecyl-azacycloheptan-2
      one) into the skin lipid model mixture was studied. Small- and wide-angle X-ray
      diffraction was used for structure determinations. It is concluded that: (a) the
      water flux through a crystalline fatty acid-sodium soap-water mixture (s) is
      statistically significantly higher than the water flux through the corresponding
      lamellar (L(alpha)) and reversed hexagonal (H(II)) liquid crystalline phases,
      which do not differ between themselves; (b) the water flux through mixtures of
      L(alpha)/s decreases statistically significantly with increasing relative amounts
      of lamellar (L(alpha)) liquid crystalline phase; (c) the addition of Azone((R))
      to a skin lipid model system induces a reduction in water flux. However, further
      studies are needed to more closely characterise the structural basis for the
      occlusive effects of Azone((R)) on water flux.

PMID- 10640595
TI  - Genetic variation: molecular mechanisms and impact on microbial evolution.
AB  - On the basis of established knowledge of microbial genetics one can distinguish
      three major natural strategies in the spontaneous generation of genetic
      variations in bacteria. These strategies are: (1) small local changes in the
      nucleotide sequence of the genome, (2) intragenomic reshuffling of segments of
      genomic sequences and (3) the acquisition of DNA sequences from another organism.
      The three general strategies differ in the quality of their contribution to
      microbial evolution. Besides a number of non-genetic factors, various specific
      gene products are involved in the generation of genetic variation and in the
      modulation of the frequency of genetic variation. The underlying genes are called
      evolution genes. They act for the benefit of the biological evolution of
      populations as opposed to the action of housekeeping genes and accessory genes
      which are for the benefit of individuals. Examples of evolution genes acting as
      variation generators are found in the transposition of mobile genetic elements
      and in so-called site-specific recombination systems. DNA repair systems and
      restriction-modification systems are examples of modulators of the frequency of
      genetic variation. The involvement of bacterial viruses and of plasmids in DNA
      reshuffling and in horizontal gene transfer is a hint for their evolutionary
      functions. Evolution genes are thought to undergo biological evolution
      themselves, but natural selection for their functions is indirect, at the level
      of populations, and is called second-order selection. In spite of an involvement
      of gene products in the generation of genetic variations, evolution genes do not
      programmatically direct evolution towards a specific goal. Rather, a steady
      interplay between natural selection and mixed populations of genetic variants
      gives microbial evolution its direction.

PMID- 10640596
TI  - Vaccines, coming of age after 200 years.
AB  - An overview on the short, only 200 years, past history and future expectations in
      the field of vaccines is presented. The focus is on development trends and
      potential rather than individual vaccines. While the first vaccines were a result
      of keen observation, the further development has been tightly dependent on the
      development of microbiology to provide both the knowledge basis and the
      technology for new vaccines for new purposes. The post-genomic era just starting
      therefore promises an exponential increase of vaccine research and new vaccines,
      both improved vaccines with a greater efficacy and less adverse effects to
      replace old ones and vaccines for prevention of diseases for which no vaccines
      exist. Furthermore, fully new applications to prevention or treatment of chronic
      diseases not traditionally associated with infections are expected.

PMID- 10640597
TI  - Secretion and assembly of regular surface structures in Gram-negative bacteria.
AB  - Bacteria synthesize large-sized surface structures through the ordered
      polymerization of protein subunits. This results in planar or tubular regular
      structures that have evolved to accomplish specific functions related to the
      particular environment in which these bacteria are found. Tubular assemblies
      known as flagella are the most complex structures known in bacteria and consist
      of a helical rigid filament, a torsion adapter or hook and a proton-fueled
      rotator known as the basal body. Pili or fimbriae are less complicated helical
      filaments, which consist of a major subunit and 3-5 minor subunits or pilins,
      whose main function is the attachment to specific surfaces. Planar structures
      known as S-layers are the simplest of these regular assemblies and are generally
      made up of a single subunit packed as a bidimensional crystal around the whole
      cell surface. Most of the components of these structures have to be secreted
      through the inner membrane (IM), the periplasm and the outer membrane (OM) before
      reaching their final destination. The so called general secretory pathway (GSP),
      or type II secretion system, appears to be implicated in this process to varying
      degrees, depending on the structure considered. A few S-layers and pili require
      GSP components but also need specific terminal branches, such as the well known
      chaperone-usher pathway. On the other hand, only two of the nearly 40 proteins
      involved in flagellar assembly are dependent on the GSP, while the external
      components are secreted through a specific pathway similar to the type III
      systems identified in some pathogens. Moreover, secretion of subunits of S-layers
      using dedicated type I machinery, without the involvement of any GSP component,
      has also been observed.

PMID- 10640598
TI  - Heterologous protein expression in the methylotrophic yeast Pichia pastoris.
AB  - During the past 15 years, the methylotrophic yeast Pichia pastoris has developed
      into a highly successful system for the production of a variety of heterologous
      proteins. The increasing popularity of this particular expression system can be
      attributed to several factors, most importantly: (1) the simplicity of techniques
      needed for the molecular genetic manipulation of P. pastoris and their similarity
      to those of Saccharomyces cerevisiae, one of the most well-characterized
      experimental systems in modern biology; (2) the ability of P. pastoris to produce
      foreign proteins at high levels, either intracellularly or extracellularly; (3)
      the capability of performing many eukaryotic post-translational modifications,
      such as glycosylation, disulfide bond formation and proteolytic processing; and
      (4) the availability of the expression system as a commercially available kit. In
      this paper, we review the P. pastoris expression system: how it was developed,
      how it works, and what proteins have been produced. We also describe new
      promoters and auxotrophic marker/host strain combinations which extend the
      usefulness of the system.

PMID- 10640599
TI  - The role of ammonia metabolism in nitrogen catabolite repression in Saccharomyces
      cerevisiae.
AB  - Saccharomyces cerevisiae is able to use a wide variety of nitrogen sources for
      growth. Not all nitrogen sources support growth equally well. In order to select
      the best out of a large diversity of available nitrogen sources, the yeast has
      developed molecular mechanisms. These mechanisms consist of a sensing mechanism
      and a regulatory mechanism which includes induction of needed systems, and
      repression of systems that are not beneficial. The first step in use of most
      nitrogen sources is its uptake via more or less specific permeases. Hence the
      first level of regulation is encountered at this level. The next step is the
      degradation of the nitrogen source to useful building blocks via the nitrogen
      metabolic pathways. These pathways can be divided into routes that lead to the
      degradation of the nitrogen source to ammonia and glutamate, and routes that lead
      to the synthesis of nitrogen containing compounds in which glutamate and
      glutamine are used as nitrogen donor. Glutamine is synthesized out of ammonia and
      glutamate. The expression of the specific degradation routes is also regulated
      depending on the availability of a particular nitrogen source. Ammonia plays a
      central role as intermediate between degradative and biosynthetic pathways. It
      not only functions as a metabolite in metabolic reactions but is also involved in
      regulation of metabolic pathways at several levels. This review describes the
      central role of ammonia in nitrogen metabolism. This role is illustrated at the
      level of enzyme activity, translation and transcription.

PMID- 10640600
TI  - Class IIa bacteriocins: biosynthesis, structure and activity.
AB  - In the last decade, a variety of ribosomally synthesized antimicrobial peptides
      or bacteriocins produced by lactic acid bacteria have been identified and
      characterized. As a result of these studies, insight has been gained into
      fundamental aspects of biology and biochemistry such as producer self protection,
      membrane-protein interactions, and protein modification and secretion. Moreover,
      it has become evident that these peptides may be developed into useful
      antimicrobial additives. Class IIa bacteriocins can be considered as the major
      subgroup of bacteriocins from lactic acid bacteria, not only because of their
      large number, but also because of their activities and potential applications.
      They have first attracted particular attention as listericidal compounds and are
      now believed to be the next in line if more bacteriocins are to be approved in
      the future. The present review attempts to provide an insight into general
      knowledge available for class IIa bacteriocins and discusses common features and
      recent findings concerning these substances.

PMID- 10640601
TI  - Target genes for virulence assessment of Escherichia coli isolates from water,
      food and the environment.
AB  - The widespread species Escherichia coli includes a broad variety of different
      types, ranging from highly pathogenic strains causing worldwide outbreaks of
      severe disease to avirulent isolates which are part of the normal intestinal
      flora or which are well characterized and safe laboratory strains. The
      pathogenicity of a given E. coli strain is mainly determined by specific
      virulence factors which include adhesins, invasins, toxins and capsule. They are
      often organized in large genetic blocks either on the chromosome ('pathogenicity
      islands'), on large plasmids or on phages and can be transmitted horizontally
      between strains. In this review we summarize the current knowledge of the
      virulence attributes which determine the pathogenic potential of E. coli strains
      and the methodology available to assess the virulence of E. coli isolates. We
      also focus on a recently developed procedure based on a broad-range detection
      system for E. coli-specific virulence genes that makes it possible to determine
      the potential pathogenicity and its nature in E. coli strains from various
      sources. This makes it possible to determine the pathotype of E. coli strains in
      medical diagnostics, to assess the virulence and health risks of E. coli
      contaminating water, food and the environment and to study potential reservoirs
      of virulence genes which might contribute to the emergence of new forms of
      pathogenic E. coli.

PMID- 10640602
TI  - Frequency of nasal and wound isolates of Staphylococcus aureus associated with
      TSST-1 production in Jordanian population.
AB  - A total of 110 Staphylococcus aureus isolates were obtained from nasal carriers
      and wound infections of Jordanian population. The isolates were identified by
      cultural and biochemical methods. The nasal carrier rate of S. aureus among
      individuals was 22.7%. In comparison with the nasal S. aureus isolates the wound
      isolates did not produce significantly more virulence factors except DNase. Toxic
      shock syndrome toxin-1 production was higher among the S. aureus nasal isolates
      (40%) as compared with the wound isolates (26%) detected by an ELISA method which
      proved to be uniformly more sensitive than the immunodiffusion optimal
      sensitivity plate (OSP) method.

PMID- 10640603
TI  - The dprA gene is required for natural transformation of Helicobacter pylori.
AB  - Genetic recombination in Helicobacter pylori is believed to be involved in host
      adaptation of this gastric pathogen and uptake of DNA by natural transformation
      can result in changes in virulence factors as well as antigenic variation. To
      elucidate the mechanisms involved in natural transformation we tested two genes
      with homology to known competence genes (dprA and traG) for their role in this
      process. Insertion mutants in these genes were constructed in two different H.
      pylori strains and their competence by natural transformation was compared to the
      wild-type. Mutation of the traG homolog did not reduce competence. Mutation of
      the dprA gene, however, severely impaired natural transformation both with
      plasmid and chromosomal DNA. Our data indicate that dprA and comB3 are essential
      parts of a common pathway for chromosomal and plasmid transformation.

PMID- 10640604
TI  - Antigenic cross-reactivity between outer membrane proteins of Neisseria
      meningitidis and commensal Neisseria species.
AB  - Two mouse sera against outer membrane proteins from a pathogenic Neisseria
      meningitidis strain and a commensal N. lactamica strain and two human sera from
      patients recovering from meningococcal meningitis were used to identify antigens
      common to pathogenic and commensal Neisseria species. Two major antigens of 55
      kDa and 32 kDa, present in all N. meningitidis and N. lactamica strains tested,
      were demonstrable with all the sera used; the 55-kDa protein was iron-regulated.
      Demonstration of other common antigens was dependent on the serum used: a 65-kDa
      antigen was visualised with the human and the mouse anti-N. lactamica sera; a 37
      kDa antigen identified as the meningococcal ferric binding protein (FbpA) was
      only detected with the mouse sera, and two antigens of 83 kDa and 15 kDa were
      only shown with the mouse anti-N. meningitidis serum. The results demonstrate the
      existence of several outer membrane antigens common to N. lactamica and N.
      meningitidis strains, in agreement with the hypothesis that natural immunity
      against meningitis is partially acquired through colonisation by commensal
      species, and open new perspectives for the design of vaccine formulations and the
      development of strategies for vaccination against meningitis.

PMID- 10640605
TI  - Protective effect of beta-glucan against systemic Streptococcus pneumoniae
      infection in mice.
AB  - The antimicrobial effect of soluble beta-1,3-D-glucan from Sclerotinia
      sclerotiorum (SSG) was examined in mice experimentally infected intraperitoneally
      (i.p.) with Streptococcus pneumoniae serotypes 4 and 6B. SSG was administered
      i.p. either 3 days before challenge or 3-48 h after challenge. The number of
      bacteria in blood samples and the mouse survival rates were recorded. Pre
      challenge SSG administration protected dose-dependently against both S.
      pneumoniae type 4 and 6B infections. SSG injected 24 h post-challenge had a
      curative effect against type 6B but not type 4 pneumococcal infection. The data
      demonstrate that SSG administered systemically protects against pneumococcal
      infection in mice.

PMID- 10640606
TI  - Characterisation of Candida albicans infections of haematogenous and mucosal
      origin in mice lacking the interferon gamma receptor protein.
AB  - Mice harbouring a null deletion mutation in the IFNgamma receptor gene were used
      to study the role of IFNgamma responsiveness during experimental systemic
      candidiasis of mucosal or haematogenous origin. After intravenous (i.v.) or
      intranasal (i.n.) challenge with Candida albicans the progression of infection
      and concomitant cellular and antibody anti-C. albicans immune responses were
      analysed. During the week following i.v. challenge, the rate of C. albicans
      multiplication in kidneys, liver and spleen was faster in IFNgammaR (-/-) than
      IFNgammaR (+/+) mice. As a result, IFNgammaR (-/-) mice perished earlier than
      IFNgammaR (+/+) mice when challenged with equal numbers of live yeast cells.
      However, the overall susceptibility of the two mouse strains, in terms of
      survival against different C. albicans challenge doses over a 60-day period, was
      similar. No differences were found in the cellular anti-C. albicans response
      generated by i.v. challenge in both mouse strains. In contrast the kinetics and
      strength of the serum anti-C. albicans antibody responses were markedly
      different. Significantly stronger, predominantly IgG2a antibody responses
      accompanied the eventual control of C. albicans infection in IFNgammaR (-/-)
      mice. Following intranasal challenge, there was no difference in the rate of C.
      albicans clearance from the lungs of IFNgammaR (-/-) and IFNgammaR (+/+) mice.
      However, 48 h after challenge, large, conspicuous abscesses appeared in the
      lungs, liver, kidneys and spleen of IFNgammaR (-/-) mice. These abscesses were
      characterised by the presence of C. albicans and abundant neutrophilic
      infiltrates, but very few macrophages. No such abscesses developed in i.n.
      challenged IFNgammaR (+/+) mice. In both mouse strains, i.n. challenge induced
      strong systemic anti-C. albicans cellular responses, but relatively low titre
      systemic antibody responses. Mucosal anti-C. albicans antibody responses were
      detected in IFNgammaR (+/+), but not IFNgammaR (-/-) mice. Splenic adherent
      macrophages obtained from IFNgammaR (-/-) mice exhibited a significantly lower
      candidacidal activity than those of IFNgammaR (+/+) mice, and as expected, were
      not responsive to IFNgamma. In summary, these data suggest that IFNgamma has a
      role in limiting C. albicans multiplication during the early stages of infection,
      as well as in preventing the development of C. albicans-associated abscesses.
      Activation of macrophages by IFNgamma might be pivotal in mediating this role.

PMID- 10640607
TI  - Determination of natural resistance of mice fed dietary lipids to experimental
      infection induced by Listeria monocytogenes.
AB  - Current understanding based on the effect of dietary lipid manipulation upon
      immune system function indicates that fatty acids are involved in the modulation
      of the immune response through different and complex pathways. Reduction of
      several immune parameters by fatty acid action may be applied in the treatment of
      diseases characterised by an overactivation of the immune system. As a
      consequence, a reduction of host resistance against infectious agents has been
      reported in animals fed dietary lipids. The present study confirms the action of
      dietary lipids on the survival of mice infected with the pathogenic bacterium
      Listeria monocytogenes. A significant increase in peritoneal cells from mice fed
      a hydrogenated coconut oil diet was found, while a significant reduction of
      bacterial recovery from spleens of these mice was observed in this group. In
      addition, both eicosanoid and phospholipase inhibitors did not promote any
      modification of lymphocyte proliferation from mice fed olive oil or fish oil.

PMID- 10640608
TI  - Use of the dot-immunogold assay for the rapid diagnosis of acute enteric
      infections.
AB  - A simple method based on an immunodot assay using colloidal gold labels is
      proposed for the rapid diagnosis of a range of acute enteric infections. Owing to
      its rapidity, high sensitivity, and specificity, the method can be recommended
      for routine use in the laboratory diagnosis of enteric infections.

PMID- 10640609
TI  - Effect of erythromycin on Shigella infection of Caco-2 cells.
AB  - Erythromycin (EM), one of the macrolides, shows a dose-dependent effect on
      Shigella flexneri invasion of Caco-2 cells even at concentrations less than the
      minimum inhibitory concentration (subMIC). LS13, a strain of S. flexneri 1b,
      invaded Caco-2 cells in vitro. When the strain was treated with subMIC of EM, the
      invasion efficiency decreased. The carrier rate of the invasion plasmid
      containing virulence genes was reduced by EM treatment, as determined by the
      colony pigmentation test on Congo red agar plates. Presence of the invasion
      plasmid was found to increase susceptibility of the organisms to EM. The growth
      of virulent organisms carrying the invasion plasmid was inhibited at 25 microg
      ml(-1) of EM, whereas the growth of organisms without the plasmid was inhibited
      at 100 microg ml(-1) of EM. This was supported by the finding that the MIC of EM
      for a virulent isolate of S. flexneri 2a YSH6000 (6.25 microg ml(-1)) and for the
      mutant strain del-17 (50 microg ml(-1)), carrying the type III apparatus,
      impaired plasmid. These findings suggested that EM passed through the type III
      apparatus and suppressed the growth of invasive organisms selectively. This
      mechanism may account for the clinical effect of EM on shigellosis.

PMID- 10640610
TI  - Analysis of immunization with DNA encoding Pseudomonas aeruginosa exotoxin A.
AB  - The promising arena of DNA-based vaccines has led us to investigate possible
      candidates for immunization against bacterial pathogens. One such target is the
      opportunistic pathogen Pseudomonas aeruginosa which produces exotoxin A (PE), a
      well-characterized virulence factor encoded by the toxA gene. In its native
      protein form, PE is highly cytotoxic for susceptible eukaryotic cells through ADP
      ribosylation of elongation factor-2 following internalization and processing of
      the toxin. To study the biologic and immunological effects of PE following in
      situ expression, we have constructed eukaryotic plasmid expression vectors
      containing either the wild-type or a mutated, non-cytotoxic toxA gene. In vitro
      analysis by transfection of UM449 cells suggests that expression of the wild-type
      toxA gene is lethal for transfected cells whereas transfection with a mutated
      toxA gene results in the production of inactive PE which can be readily detected
      by immunoblot analysis of cell lysates. To investigate the effects resulting from
      the intracellular expression of potentially cytotoxic gene products in DNA
      vaccine constructs, we immunized mice with both the wild-type and mutant toxA
      plasmid constructs and analyzed the resulting humoral and cellular immune
      responses. Immunization with the mutated toxA gene results in production of
      neutralizing antibodies against native PE and potentiates a T(H)1-type response,
      whereas only a minimal humoral response can be detected in mice immunized with
      wild-type toxA. DNA-based vaccination with the non-cytotoxic toxA(mut) gene
      confers complete protection against challenge with the wild-type PE. Therefore,
      genetic immunization with genes encoding potentially cytotoxic gene products
      raises concern with regard to the selection of feasible gene targets for DNA
      vaccine development.

PMID- 10640611
TI  - Identification of immunodominant epitope of F1 antigen of Yersinia pestis.
AB  - The F1 antigen of Yersinia pestis has been identified as one of the major
      protective antigens of this bacterium. The present study aims to delineate major
      and minor antigenic sites of F1 antigen. Using algorithmic predictions, five
      peptide sequences (P1, P2, P3, P4 and P5) spanning the C-terminal region were
      identified and synthesized. Antibodies were generated in mice against the
      peptides, native F1 protein and polymerized F1 antigen using liposomes as mode of
      immunization. Cross-reactivity between F1 antigen and peptides was tested using
      both solid and solution phase assays. Similar assays were done with rabbit anti
      F1 sera. Competitive inhibition assays using a different combination of antisera
      and competing antigen identified P2 peptide FFVRSIGSKGGKLAAGKYTDAVTV (142-165) as
      the immunodominant sequence. The results indicate that this sequence appears to
      be exposed on the surface of F1 molecule. In a solid phase binding assay, P2
      peptide was recognized even at high F1 antisera dilution. However, when antisera
      raised to different peptides were tested for binding to F1 antigen, antisera to
      P4 peptide showed maximal immunoreactivity. This implies more accessibility of
      this region during immobilization on solid surface. There was consistency in the
      results obtained for different strains of mice as well as for the rabbit
      antisera. Such a sequence of F1 antigen, which is recognized widely in animals of
      different genetic background, would be useful for diagnosis and subunit vaccine.

PMID- 10640612
TI  - Development of an insect model for the in vivo pathogenicity testing of yeasts.
AB  - Conventional in vivo assays to determine the relative pathogenicity of yeast
      isolates rely upon the use of a range of mammalian species. The purpose of the
      work presented here was to investigate the possibility of using an insect
      (Galleria mellonella) as a model system for in vivo pathogenicity testing. The
      haemolymph of G. mellonella larvae was inoculated with PBS containing different
      concentrations of stationary phase yeasts of the genus Candida by injection at
      the last pro-leg. Larvae were incubated at 30 degrees C and monitored over 72
      hours. Results indicate that G. mellonella can be killed by the pathogenic yeast
      Candida albicans and by a range of other Candida species but not to a significant
      extent by the yeast Saccharomyces cerevisiae. The kill kinetics for larvae
      inoculated with clinical and laboratory isolates of C. albicans indicate the
      former class of isolates to be more pathogenic. Differences in the relative
      pathogenicity of a range of Candida species may be distinguished using G.
      mellonella as a model. This work indicates that G. mellonella may be employed to
      give results consistent with data previously obtained using mammals in
      conventional in vivo pathogenicity testing. Larvae of G. mellonella are
      inexpensive to culture, easy to manipulate and their use may reduce the need to
      employ mammals for routine in vivo pathogenicity testing with a concomitant
      reduction in mammalian suffering.

PMID- 10640613
TI  - Altered antigenicity is seen in the lipopolysaccharide profile of non
      serotypeable Actinobacillus actinomycetemcomitans strains.
AB  - Non-serotypeable Actinobacillus actinomycetemcomitans strains may be derived from
      the serotypeable ones. In the present study, we compared the outer membrane
      proteins (OMPs) and lipopolysaccharides (LPSs) of serotypeable and non
      serotypeable A. actinomycetemcomitans strains (n=24) of the same genotype in the
      same subject (n=6) to find out if alterations on the cell-surface contribute to
      the non-serotypeability. Serotypeable and non-serotypeable A.
      actinomycetemcomitans strains showed great similarity in the OMP patterns both
      within and between subjects. Using serotype-specific antisera, clear
      immunoblotting LPS profiles in the O-antigenic region were seen in serotype b and
      c strains but not in non-serotypeable strains from the same subjects. The results
      suggest that changes in LPS lead to the altered antigenicity of non-serotypeable
      A. actinomycetemcomitans strains.

PMID- 10640614
TI  - Intracerebral transportation and cellular localisation of insulin-like growth
      factor-1 following central administration to rats with hypoxic-ischemic brain
      injury.
AB  - Insulin-like growth factor-1 (IGF-1) has been shown to be neuroprotective when
      administered centrally following hypoxic-ischemic (HI) brain injury. However, the
      cerebral distribution and site of action of IGF-1 after intracerebroventricular
      (i.c.v.) administration are not known. A unilateral HI brain injury was induced
      in adult rats by a modified Levine method. Either 3H-IGF-1 alone, or in
      combination with unlabelled IGF-1, was administered into the lateral ventricle 2
      h after injury. The activity of 3H-IGF-1 signal in the potentially injured cortex
      was compared between two treatment groups using image analysis. The regional
      distribution and cellular localisation of 3H-IGF-1 were examined
      autoradiographically in potentially injured hemispheres at 0.5 and 6 h after
      administration. Tritiated IGF-1 was detected predominantly in the pia mater,
      perivascular spaces and subcortical white matter tracts 0.5 h after
      administration and decreased by 6 h (p<0.05). The signals associated with the
      perivascular spaces and pia mater were not blocked by unlabelled IGF-1,
      suggesting non-saturable binding in these brain areas. IGF-1 signal was co
      localised with IGF binding protein (IGFBP)-2 immunostaining in the white matter
      tracts where the signal was blocked by unlabelled IGF-1, suggesting competitive
      association. IGF-1 signal associated with neurons and glia was maximal in the
      cerebral cortex and less in the CA1-2 subregion of the hippocampus which were
      blocked by unlabelled IGF-1 (p<0.05). The signals from cortical neurons did not
      decrease 6 h after administration, suggesting specific and persistent binding to
      these cells. Our results indicate that centrally administered IGF-1 can be
      translocated to neurons and glia via the perivascular circulation and the
      ependymal cell-white matter tract pathways.

PMID- 10640615
TI  - Overexpression of neurotrophin receptor p75 contributes to the excitotoxin
      induced cholinergic neuronal death in rat basal forebrain.
AB  - Both excitotoxicity and altered trophic factor support have been implicated in
      the pathogenesis of Alzheimer's disease. To determine whether stimulation of p75,
      the low-affinity receptor for nerve growth factor, contributes to the excitotoxin
      induced apoptotic death of cholinergic neurons, we examined the effect of
      unilateral kainic acid (KA; PBS vehicle, 1.25, 2.5 and 5.0 nmol) administration
      into rat basal forebrain on neuronal loss and p75 expression. KA (2. 5 nmol)
      destroyed 43% of Nissl-stained neurons and 70% of choline acetyltransferase
      (ChAT)-positive neurons 5 days after injection. Agarose gel electrophoresis
      revealed that KA (2.5 nmol) induced local internucleosomal DNA fragmentation
      after 6-48 h. Immunohistochemical analysis further showed that KA (2.5 nmol)
      augmented p75 immunoreactivity at a time when terminal transferase-mediated
      deoxyuridine trophosphate (d-UTP)-digoxigenin nick end labeling (TUNEL)-positive
      nuclei were increased. Many fragmented nuclei were co-labeled with ChAT antibody.
      The chronic administration of anti-rat p75 or the protein synthesis inhibitor,
      cycloheximide, but not anti-human p75, substantially reduced the KA-induced
      destruction of cholinergic neurons and the induction of internucleosomal DNA
      fragmentation. Anti-rat p75, but not cycloheximide, also reversed the spatial
      memory impairment produced by KA. These findings suggest that overexpression of
      p75 contributes to the excitotoxin-induced death of rat basal forebrain
      cholinergic neurons by an apoptotic-like mechanism.

PMID- 10640616
TI  - Alteration of PACAP distribution and PACAP receptor binding in the rat sensory
      nervous system following sciatic nerve transection.
AB  - Pituitary adenylate cyclase activating polypeptide (PACAP) is a widely expressed
      neuropeptide that has been involved in nerve regeneration, neurone survival and
      nociception. In this study, the distribution of PACAP and PACAP-receptors were
      investigated in rat dorsal root ganglia (DRG), spinal cord and medulla oblongata
      at 3, 7 or 14 days following unilateral sciatic nerve transection using
      immunohistochemistry, 125I-PACAP-binding and in situ hybridisation. In control
      (contralateral side) DRG, about 30% of the nerve cell bodies (92% being small)
      were PACAP-immunoreactive (PACAP-IR). In the spinal cord, PACAP-IR fibres were
      seen in laminae I-II but not in the gracile nuclei. Following sciatic nerve
      transection, PACAP-IR fibres appeared in the gracile nuclei and occasionally in
      the deeper laminae of the dorsal horn consistent with the relative increase in
      larger PACAP-IR DRG neurones. However, the relative number of small PACAR-IR
      neurones was significantly lower on the transected side as compared to the
      control side suggesting a dual reaction for PACAP in the DRG following nerve
      injury. 125I-PACAP-binding was found in laminae I-II, around the central canal
      and in the gracile nuclei but not in the DRG. At 14 days after transection, 125I
      PACAP-binding density was significantly reduced in the ipsilateral dorsal horn.
      PACAP-receptor (PAC(1)) mRNA was detected in neurones of the dorsal and ventral
      horn and in the gracile nuclei with no overt changes observed after transection.
      Very few DRG nerve cell bodies contained PAC(1) mRNA. The findings are consistent
      with a role for PACAP both in nociception and regeneration.

PMID- 10640617
TI  - Immunohistochemical localization and distribution of torsinA in normal human and
      rat brain.
AB  - Dystonia is a disease of basal ganglia function, the pathophysiology of which is
      poorly understood. Primary torsion dystonia is one of the most severe types of
      inherited dystonia and can be transmitted in an autosomal dominant manner.
      Recently, one mutation causing this disorder was localized to a gene on
      chromosome 9q34, designated DYT1, which encodes for a novel protein termed
      torsinA. The role of this protein in cellular function, in either normal or
      dystonic individuals is not known. We have developed a polyclonal antibody to
      torsinA and report its localization and distribution in normal human and rat
      brain. We demonstrate that torsinA is widely expressed in brain and peripheral
      tissues. Immunohistochemical studies of normal human and rat brain reveal the
      presence of torsinA in the dopaminergic neurons of the substantia nigra pars
      compacta (SNc), in addition to many other regions, including neocortex,
      hippocampus, and cerebellum. Labeling is restricted to neurons, as shown by
      double-immunofluorescence microscopy, and is present in both nuclei and
      cytoplasm. An ATP-binding property for torsinA has been suggested by its homology
      to ATP-binding proteins; this was confirmed by enrichment of torsinA in ATP
      agarose affinity-purified fractions from tissue homogenates. An understanding of
      the role of torsinA in cellular function and the impact of the mutation (deletion
      of a glutamic acid at residue 303) is likely to provide insights into the
      etiopathogenesis of primary dystonia.

PMID- 10640618
TI  - Role of the superior colliculus in the motor effects of cannabinoids and
      dopamine.
AB  - We studied the cellular distribution of CB1 cannabinoid receptors in the superior
      colliculus of the rat using an antibody raised against the N-terminal of the
      receptor. The effect of unilateral cannabinoid receptor stimulation in the
      intermediate layers of the superior colliculus on rotational behavior in rats was
      also explored. The antibody against CB1 receptors outlined the crossed descending
      system of the superior colliculus (predorsal bundle output system) as well as the
      collicular commisure. The potent cannabinoid agonist CP55,940 (5 microgram/0.25
      microliter) induced strong contralateral turning when microinjected unilaterally
      into the lateral intermediate layers of the superior colliculus. The levels of
      turning obtained with the intracollicular administration of the cannabinoid were
      comparable to the highest levels obtained with dopamine agonists in the basal
      ganglia. The D(2) dopamine agonist quinpirole or the D(1) dopamine agonist
      SKF82958 reversed this contralateral rotation but failed to affect motor behavior
      on their own. A new motor pathway for cannabinoids is discussed.

PMID- 10640619
TI  - Changes of hippocampal Cu/Zn-superoxide dismutase after kainate treatment in the
      rat.
AB  - In order to evaluate the putative role of Cu,Zn-superoxide dismutase (SOD-1) in
      the antioxidant defense mechanism during the neurodegenerative process, we
      examined the level of mRNA, the specific activity and immunocytochemical
      distribution for SOD-1 in the rat hippocampus after systemic injection of kainic
      acid (KA). Hippocampal SOD-1 mRNA levels were significantly increased by the
      seizure intensity 3 and 7 days after KA. These enhanced mRNA levels for SOD-1
      were consistent with the increased specific activities for SOD-1, suggesting that
      the superoxide radical generated in neurotoxic lesion, induced SOD-1 mRNA. The
      CA1 and CA3 neurons lost their SOD-1-like immunoreactivity, whereas SOD-1
      positive glia-like cells mainly proliferated throughout the CA1 sector and had an
      intense immunoreactivity at 3 and 7 days after KA. This immunocytochemical
      distribution for SOD-1-positive non-neuronal elements was similar to that for
      glial fibrillary acidic protein (GFAP)-positive cells. Each immunoreactivity for
      SOD-1-positive non-neuronal cell or GFAP in the layers of CA1 and CA3 disappeared
      3 and 7 days after a maximal stage 5 seizure. On the other hand, activated
      microglial cells as selectively marked with the lectin occurred in the areas
      affected by KA-induced lesion. Double-labeling immunocytochemical analysis
      demonstrated the co-localization of SOD-1-positive glia-like cells and reactive
      astrocytes as labeled by GFAP or S-100 protein immunoreactivity. This finding
      suggested that the mobilization of astroglial cells for the synthesis of SOD-1
      protein is a response to the KA insult designed to decrease the neurotoxicity
      induced by oxygen-derived free radicals. Therefore, these alterations might
      reflect the regulatory role of SOD-1 against oxygen-derived free radical-induced
      neuronal degeneration after systemic KA administration.

PMID- 10640620
TI  - Survival and mitogenesis of neuroepithelial cells are influenced by noradrenergic
      but not cholinergic innervation in cultured embryonic rat neopallium.
AB  - alpha-Adrenoreceptors are present in the ventricular (VZ) and subventricular
      (SVZ) zones of the mammalian embryonic forebrain, and contribute towards cell
      cycle controls in the germinal neuroepithelium [Pabbathi et al., Brain Res. 760
      (1997) 22-33.]. Since noradrenaline-containing fibres from the locus coeruleus
      (LC) and other brainstem nuclei innervate many parts of the CNS from an early
      stage of embryogenesis, we have used heterochronic cocultures to investigate
      whether noradrenergic innervation may be the source of trophic support. Dorsal
      neopallium from E13 rat embryo was cultured in proximity to E15 rostral pons
      (RP), enabling rapid innervation of the neuroepithelium by differentiated
      noradrenergic neurons of the LC. The projection of interconnecting fibres into
      germinal areas of the cortex was established in vitro by retrograde tracing and
      dopamine beta-hydroxylase (DBH) immunocytochemistry. When functional innervation
      was prevented by transection of axons connecting the explants, the number of
      apoptotic (TUNEL-positive) cells in the neopallium was increased.
      Bromodeoxyuridine (BrdU) double-labelling confirmed that germinal cells were
      amongst those which underwent apoptosis. When cortical explants were innervated
      by a source of non-monoaminergic (cholinergic) axons from the E18 basal forebrain
      diagonal band/septum complex (DS), numbers of apoptotic cells were comparable to
      those in non-innervated cultures. alpha1 and alpha2 adrenoreceptor antagonists
      included in the medium of cortical cocultures innervated by noradrenergic axons
      reversed the survival-promoting effect of innervation. Blockade of alpha1 but not
      of alpha2 receptors also reduced the numbers of S-phase nuclei in the cortex. The
      results provide evidence that local delivery of neurotransmitter from embryonic
      noradrenergic axons terminating in the neocortex can regulate survival and
      proliferation of neuroepithelial cells.

PMID- 10640621
TI  - Influence of neurons on lipopolysaccharide-stimulated production of nitric oxide
      and tumor necrosis factor-alpha by cultured glia.
AB  - Cerebral inflammation often originates in a region where neuronal death occurs
      and thereafter slowly spreads outward. This study aimed to elucidate the roles of
      neurons in modulating the production of inflammatory factors stimulated by the
      bacterial endotoxin lipopolysaccharide (LPS). Culturing neurons with mixed glia
      reduced nitrite and tumor necrosis factor-alpha (TNF-alpha) production compared
      to cultures with only mixed glia, and shifted the dose-response curve to the
      right. The decreased nitrite and TNF-alpha production were not due to the
      cytotoxicity of LPS. Immunocytochemical analysis of glia-neuron co-cultures
      revealed the morphological changes in the activated microglia. Culturing PC12
      cells with rat mixed-glia also reduced nitrite production. The influence of
      neurons on glial inflammation was partly due to the cell-cell contacts between
      neurons and glia via neural cell adhesion molecules (NCAM) because NCAM
      significantly reduced LPS-stimulated nitrite production. These results
      demonstrate that neurons reduce the production of inflammatory factors by glia.
      Since cerebral inflammation is important in many neurological disorders, this
      study might provide insight about the role of glia-neuron interactions in
      inflammatory responses in the brain.

PMID- 10640622
TI  - Distribution of adrenomedullin-like immunoreactivity in the rat central nervous
      system by light and electron microscopy.
AB  - Adrenomedullin is a peptide of marked vasodilator activity first isolated from
      human pheochromocytoma and subsequently demonstrated in other mammalian tissues.
      Using a polyclonal antiserum against human adrenomedullin-(22-52) amide and the
      avidin-biotin peroxidase complex technique, we have demonstrated by light and
      electron microscopy that adrenomedullin-like immunoreactivity is widely
      distributed in the rat central nervous system. Western blotting of extracts of
      different brain regions demonstrated the fully processed peptide as the major
      form in the cerebellum, whereas a 14-kDa molecular species and a small amount of
      the 18-kDa propeptide were present in other brain regions. Immunoreactive neurons
      and processes were found in multipolar neurons and pyramidal cells of layers IV
      VI of the cerebral cortex and their apical processes, as well as in a large
      number of telencephalic, diencephalic, mesencephalic, pontine and medullary
      nuclei. Cerebellar Purkinje cells and mossy terminal nerve fibers as well as
      neurons of the cerebellar nuclei were immunostained, as were neurons in area 9 of
      the anterior horn of the spinal cord. Immunoreactivity was also found in some
      vascular endothelial cells and surrounding processes that probably originated
      from perivascular glial cells. Electron microscopy confirmed the light microscopy
      findings and showed the reaction product in relation to neurofilaments and the
      external membrane of small mitochondria. Immunoreactive terminal boutons were
      occasionally seen. The distribution of adrenomedullin-like immunoreactivity in
      the central nervous system suggests that it has a significant role in neuronal
      function as well as in the regulation of regional blood flow.

PMID- 10640623
TI  - Orphanin FQ-induced outward current in rat hippocampus.
AB  - Orphanin FQ (OFQ) is a heptadecapeptide that structurally resembles opioid
      peptides. It has been demonstrated that the moderate density of binding sites of
      OFQ were localized in the hippocampus and that the expression of OFQ receptor in
      the hippocampus have an important role in learning and memory. This study was
      designed to investigate whether activation of the OFQ receptor could induced
      hyperpolarization in the cultured hippocampus neurons in rats. In the current
      clamp mode, the application of OFQ (10(-8)-10(-5) M) hyperpolarized the membranes
      in cultured hippocampus neurons in a concentration-dependent manner. Moreover, in
      the voltage clamp mode, application of OFQ (10(-6) M) induced outward current in
      hippocampus CA3 pyramidal neurons. In the presence of TTX (3x10(-7) M), the
      average maximal amplitude of the outward current deflection induced by OFQ (10(
      6) M) at -60 mV of a holding potential was 24.7+/-0.54 pA. The OFQ-induced
      current reversed at -99.06+/-3.80 mV (3 mM), which was quite close to the K(+)
      equilibrium potential as calculated by the Nernst equation (E(k)=-96.08 mV, 3 mM)
      for K(+) in our standard solution. This suggests that OFQ-induced current was
      mediated by K(+) ion. It has been demonstrated that [Phe(1)psi(CH(2)
      NH)Gly(2)]Nociceptin(1-13)NH(2)) (a pseudopeptide analog of nociceptin), and
      nocistatin are selective antagonists of OFQ. OFQ (10(-6) M)-induced outward
      current was antagonized by application of [Phe(1)psi(CH(2)-NH)Gly(2)]Nociceptin(1
      13)NH(2) (10(-5) M). In contrast, OFQ-induced outward current was not antagonized
      by application of nocistatin (10(-5) M). These results indicates that there is
      the physiological functioning receptor of OFQ in the hippocampus.

PMID- 10640624
TI  - Duration and distribution of experimental muscle hyperalgesia in humans following
      combined infusions of serotonin and bradykinin.
AB  - The present study examined distribution and duration of muscle hyperalgesia to
      pressure stimuli after intramuscular bolus-infusions of serotonin (5-HT, 20 nmol)
      and bradykinin (BKN, 10 nmol) in 10 volunteers. Infusions were given into the
      tibialis anterior (TA) muscle over 20 s with an inter-infusions interval of 3
      min. Infusions of isotonic saline (NaCl, 0.9%) were given as control. Pain
      intensity was continuously scored on a visual analogue scale (VAS), and subjects
      drew the distribution of the pain areas on an anatomical map. Pressure pain
      thresholds (PPTs) were assessed with an electronic algometer at the injection
      site (10 cm below the patella), 2, 5, and 10 cm distal from the injection site,
      and at the ankle. Control assessments of PPTs were done at the contralateral TA
      and ankle. Skin sensibility was assessed with a Von Frey hair at the same sites.
      All measurements were done before and 5, 20, 40, and 60 min after infusions. The
      VAS-peak after BKN was significantly higher (P<0.05) compared with 5-HT and the
      second infusion of NaCl. The duration of the increase in VAS after 5-HT+BKN was
      significantly longer (P<0.05) compared with the infusions of NaCl. The local pain
      area after infusion of BKN was significantly larger (P<0.05) compared with 5-HT
      and control infusions. Cutaneous sensibility to tactile stimuli was not affected
      by any of the combinations. PPTs at the injection site and 2 cm (5, 20, and 40
      min) were significantly decreased (P<0.05) after 5-HT+BKN compared with baseline
      and isotonic saline. In addition, PPTs were significantly decreased (P<0.05)
      after 5-HT+BKN at 5 cm (5 and 20 min) and 10 cm (5 min). Serotonin may enhance
      the effect of bradykinin in producing experimental muscle pain and muscle
      hyperalgesia to mechanical stimuli. The combination of serotonin and bradykinin
      can produce muscle hyperalgesia, lasted for up to 40 min and located within the
      muscle. No widespread hyperalgesia to the ankle and other leg (tested at 10 cm
      below the patella and ankle) was observed suggesting a predominant peripheral
      origin of the experimentally induced hyperalgesic stage.

PMID- 10640625
TI  - Primary somatosensory cortex is actively involved in pain processing in human.
AB  - We recorded somatosensory evoked magnetic fields (SEFs) by a whole head
      magnetometer to elucidate cortical receptive areas involved in pain processing,
      focusing on the primary somatosensory cortex (SI), following painful CO(2) laser
      stimulation of the dorsum of the left hand in 12 healthy human subjects. In seven
      subjects, three spatially segregated cortical areas (contralateral SI and
      bilateral second (SII) somatosensory cortices) were simultaneously activated at
      around 210 ms after the stimulus, suggesting parallel processing of pain
      information in SI and SII. Equivalent current dipole (ECD) in SI pointed
      anteriorly in three subjects whereas posteriorly in the remaining four. We also
      recorded SEFs following electric stimulation of the left median nerve at wrist in
      three subjects. ECD of CO(2) laser stimulation was located medial-superior to
      that of electric stimulation in all three subjects. In addition, by direct
      recording of somatosensory evoked potentials (SEPs) from peri-Rolandic cortex by
      subdural electrodes in an epilepsy patient, we identified a response to the laser
      stimulation over the contralateral SI with the peak latency of 220 ms. Its
      distribution was similar to, but slightly wider than, that of P25 of electric
      SEPs. Taken together, it is postulated that the pain impulse is received in the
      crown of the postcentral gyrus in human.

PMID- 10640626
TI  - Rats sensitized to morphine are resistant to the behavioral effects of an
      unavoidable stress.
AB  - In agreement with the results of other authors, rats sensitized to morphine and
      challenged with 5 mg/kg of morphine after 7 days of wash-out showed intense
      stereotyped movements, the expression of which was selectively antagonized by SCH
      23390. Sensitized rats were exposed to an unavoidable stress (which consistently
      produces an escape deficit in control animals) after 3, 7 and 21 days of morphine
      wash-out. Twenty-four hours after the unavoidable stress, animals were tested for
      their capacity to escape and their performance was compared to that of control
      stressed and naive rats. Morphine sensitization completely prevented the
      development of escape deficit. This protective effect was similar to that induced
      by a chronic imipramine treatment and, like the effect of imipramine, it was
      antagonized by the administration of SCH 23390 before the unavoidable stress.
      However, it was not affected by the administration of naloxone. Moreover, when
      rats presenting a clear-cut escape deficit, induced by a 10-day treatment with
      SKF 38393, were exposed to the morphine sensitization protocol, a complete
      recovery of their capacity to avoid a noxious stimulus was observed. Finally, the
      down-regulation of both the number of D(1)-dopamine receptors and of the coupled
      adenylyl cyclase activity in the pre-frontal cortex (PFC) produced by long-term
      SKF 38393 administration was reverted by the superimposed morphine sensitization.
      Thus, the condition of morphine sensitization appears to share several common
      effects with chronic imipramine treatment.

PMID- 10640627
TI  - Regulation of phosphorylation of neuronal microtubule-associated proteins MAP1b
      and MAP2 by protein phosphatase-2A and -2B in rat brain.
AB  - The function of the neuronal high molecular weight microtubule-associated
      proteins (MAPs) MAP1b and MAP2 is regulated by the degree of their
      phosphorylation, which in turn is controlled by the activities of protein kinases
      and protein phosphatases (PP). To investigate the role of PP in the regulation of
      the phosphorylation of MAP1b and MAP2, we used okadaic acid and cyclosporin A to
      selectively inhibit PP2A and PP2B activities, respectively, in metabolically
      competent rat brain slices. The alteration of the phosphorylation levels of MAP1b
      and MAP2 was examined by Western blots using several phosphorylation-dependent
      antibodies to these proteins. The inhibition of PP2A, and to a lesser extent of
      PP2B, was found to induce an increased phosphorylation of MAP1b and inhibit its
      microtubule binding activity. Immunocytochemically, a marked increase in neuronal
      staining in inhibitor-treated tissue was observed with antibodies to the
      phosphorylated MAP1b. The inhibition of PP2A but not of PP2B also induced
      phosphorylation of MAP2 at multiple sites and impaired its microtubule binding
      activity. These results suggest that PP2A might be the major PP that participates
      in regulation of the phosphorylation of MAP1b and MAP2 and their biological
      activities.

PMID- 10640628
TI  - Antioxidants protect against dopamine-induced metallothionein-III (GIF) mRNA
      expression in mouse glial cell line (VR-2g).
AB  - Metallothionein (MT)-III, originally discovered as a growth inhibitory factor
      (GIF), is a brain specific isomer of MTs and is markedly reduced in the brain of
      patients with Alzheimer's disease (AD) or other neurodegenerative diseases. We
      analyzed the level and regulation of mRNA expression of MT-III in immortalized
      fetal mouse brain glial cells (VR-2g) by reverse transcriptase-polymerase chain
      reaction (RT-PCR). We have recently reported that dopamine (DA) increases the
      expression of MT-III mRNA in vitro. In this study, we investigated the mechanism
      of such increase by examining the effects of DA agonists (SKF38393 or
      bromocriptine) and DA antagonists (SCH23390 or sulpiride) on the expression of MT
      III mRNA. MT-III mRNA did not change by either agonist and DA-increased MT-III
      mRNA was not inhibited by either antagonist. These results suggested that the
      induction of MT-III mRNA by DA was not mediated by stimulation of DA receptors.
      On the other hand, DA-induced MT-III mRNA expression was strongly inhibited by
      the addition of antioxidants (glutathione, vitamin E or ascorbic acid),
      indicating that DA-enhanced MT-III mRNA was mediated by reactive oxygen species.
      Our results suggest that oxidative stress may be one of the principle factors
      that modulate MT-III mRNA expression.

PMID- 10640629
TI  - Trans-neuronal modification of anterior piriform cortical circuitry in the rat.
AB  - Long-Evans rats received unilateral naris closure on postnatal day 1 (PN1) or
      sham surgery. On PN30, brains were processed for anterograde horseradish
      peroxidase (HRP) labeling of lateral olfactory tract (LOT) fibers in anterior
      piriform cortex (aPCX) Layer Ia, Timm staining of association/commissural fibers
      in aPCX Layer Ib, or Golgi staining for reconstruction of aPCX semilunar cell
      dendrites. The results demonstrate that the width of aPCX Layer Ia was reduced
      ipsilateral to the sealed naris compared to undeprived controls. No significant
      change in Layer Ib was detected. Furthermore, semilunar cell dendrites were
      reduced by unilateral deprivation compared to undeprived controls. The reduction
      in dendritic tree size was localized to distal dendritic segments, roughly
      corresponding to Layer Ia. These results suggest an activity-dependent change in
      both the distribution of cortical afferents and in the dendritic field of their
      target cells. While these results are similar to those reported for other sensory
      systems, the relatively simple architecture and laminated organization of
      bilateral inputs to the aPCX make the olfactory system an ideal model system to
      examine experience-dependent synaptic reorganization and its functional
      consequences.

PMID- 10640630
TI  - Influence of a 1-h immobilization stress on sleep and CLIP (ACTH(18-39)) brain
      contents in adrenalectomized rats.
AB  - Basal sleep amounts in adrenalectomized rats (AdX), as compared to intact
      animals, exhibit a significant increase in slow-wave sleep (SWS), a tendency
      towards an increase in paradoxical sleep (PS), and circadian rhythms (SWS and PS)
      flattened in amplitude. An immobilization stress (IS) of 1 h, imposed on AdX rats
      at the beginning of the dark period, is accompanied by an intense polygraphic
      waking. Just after the IS, SWS amount become significantly higher than in control
      rats (+44%/11 h of darkness) whereas significant increases of PS occur only 5-10
      h after the IS (+24%/11 h of darkness). A specific radioimmunoassay for CLIP
      (corticotropin-like intermediate lobe peptide or ACTH(18-39)) was performed in
      biopsies taken either from the nucleus raphe dorsalis (nRD) or the arcuate
      nucleus (AN). In the nRD, just after the IS, phosphorylated CLIP (Ph-CLIP)
      concentration exhibits a decreasing tendency, but 4 h later, it increases
      significantly (+22%, p<0.05). In the AN, Ph-CLIP concentration remains unchanged
      after the IS as well as 4 h later. These results differ from those previously
      reported in intact animals also submitted to a 1-h IS, that is, a SWS rebound
      less marked (+27%/11 h of darkness), a PS rebound more important starting
      immediately after the IS (+46%/11 h of darkness) and a significant increase in Ph
      CLIP occurring just after the end of the restraint. In conclusion, data obtained
      after a restraint stress either in AdX or in control rats point out the
      dependence of the PS rebound on the nRD Ph-CLIP concentration.

PMID- 10640631
TI  - Stimulus duration-dependent contribution of k(ca) channel activation and cAMP to
      hypoxic cerebrovasodilation.
AB  - Activation of calcium sensitive (K(ca)) K channels and cAMP contribute to pial
      artery dilation observed during a 10-min exposure to hypoxia. Recent studies show
      that pial dilation during a 20- or 40-min hypoxic exposure was less than that
      observed during a 5- or 10-min exposure indicating that stimulus duration
      determines the nature of the vascular response to hypoxia. The present study was
      designed to determine if the stimulus duration modulates the contribution of
      K(ca) channel activation and cAMP-dependent mechanisms to hypoxic pial artery
      dilation in piglets equipped with a closed cranial window. The K(ca) channel
      antagonist iberiotoxin had no influence on pial dilation during 5 min of hypoxia
      (pO(2) approximately 25 mmHg), decremented the dilation during 10- and 20-min
      exposure, but had no effect on the dilation during a 40-min exposure (33+/-1% vs.
      32+/-3%, 33+/-1% vs. 25+/-1%, 23+/-1% vs. 19+/-1%, and 21+/-2% vs. 17+/-2% for 5
      , 10-, 20-, and 40-min hypoxic dilations before and after iberiotoxin). NS1619, a
      K(ca) channel agonist, induced pial dilation during hypoxia that was attenuated
      by 20- and 40-min but not by 5- and 10-min exposure durations. Similarly, the
      cAMP antagonist Rp 8-Bromo cAMPs had no influence on pial dilation during 5 min
      of hypoxia, decremented the dilation during a 10-min exposure, but had no effect
      on the dilation during a 20- or 40-min exposure (36+/-1% vs. 34+/-2%, 34+/-1% vs.
      22+/-1%, 24+/-2% vs. 21+/-2%, and 21+/-2% vs. 19+/-2% for 5-, 10-, 20-, and 40
      min hypoxic dilations before and after Rp 8-Bromo cAMPs). Additionally, CSF cAMP
      was unchanged during 5 min, elevated during 10 min, but such elevations were
      attenuated during 20- and 40-min hypoxic exposure. Pial vasodilation to a cAMP
      analogue during hypoxia was attenuated by 20- and 40-min but not by 5- and 10-min
      hypoxic exposure durations. These data show that K(ca) channel activation and
      cAMP contribute to hypoxic pial artery dilation in a stimulus duration-dependent
      manner. These data suggest that diminished pial artery dilation during longer
      hypoxic exposure results from attenuated K(ca) channel and cAMP-dependent
      mechanisms.

PMID- 10640632
TI  - The effect of PKC activation on the survival of rat retinal ganglion cells in
      culture.
AB  - Natural cell death is a degenerative phenomenon occurring during the development
      of the nervous system. Approximately half the neurons initially generated during
      this period die. The role of trophic molecules produced by target and afferent
      neurons as well as by glial cells controlling this regressive event has been
      extensively demonstrated. The aim of this work was to study the role of activated
      protein kinase C (PKC), an enzyme involved in apoptosis regulation, on the
      survival of retinal ganglion cells kept "in vitro" for 48 h. For this purpose, we
      used the phorbol 12-myristate 13-acetate (PMA), a tumor promoter agent that
      activates PKC. Our results showed that PMA increases the survival of ganglion
      cells. The effect was dose-dependent and PMA concentrations of 10 or 100 ng/ml
      produced the maximal effect (a two-fold increase on ganglion cells survival
      compared with 48 h control). This effect was totally abolished by 1.25 microM
      chelerythrine chloride (an inhibitor of PKC) and 30 microM genistein (an
      inhibitor of tyrosine kinase enzymes). Otherwise, PMA was effective only when it
      was chronically present in the cultures. On the other hand, treatment with 20
      microM 5-fluoro-2'-deoxyuridine, an inhibitor of cell proliferation, or 25 microM
      BAPTA-AM, an intracellular calcium chelator, did not block PMA effect. Our
      results suggest that the survival of retinal ganglion cells "in vitro" may be
      mediated by a mechanism that involves PKC activation.

PMID- 10640633
TI  - Gelsolin inhibits the fibrillization of amyloid beta-protein, and also
      defibrillizes its preformed fibrils.
AB  - Amyloid beta-protein (Abeta) is present in soluble form in the plasma and
      cerebrospinal fluid (CSF) of normal people and patients with Alzheimer's disease
      (AD). However, in AD patients, Abeta gets fibrillized as the main constituent of
      amyloid plaques in the brain. Soluble synthetic Abeta also forms amyloid-like
      fibrils when it is allowed to age. The mechanism that prevents soluble Abeta from
      fibrillization in biological fluids is not clear. We recently reported that
      gelsolin, a secretory protein, binds to Abeta, and that gelsolin/Abeta complex is
      present in the plasma [V.P.S. Chauhan, I. Ray, A. Chauhan, H.M. Wisniewski,
      Biochem. Biophys. Res. Commun. 258 (1999) 241-246.]. We now studied the effect of
      gelsolin on Abeta fibrillization. Congo red staining and electron microscopic
      examination in negative staining of aged samples of Abeta alone and Abeta
      incubated with gelsolin showed that gelsolin inhibits the fibrillization of
      synthetic Abeta 1-40 and Abeta 1-42 at gelsolin to Abeta molar ratio of 1:40. In
      addition, gelsolin also defibrillized the preformed fibrils of Abeta 1-40 and
      Abeta 1-42 in a time-dependent manner. These results suggest that gelsolin
      functions as an anti-amyloidogenic protein in the plasma and CSF, where it
      prevents Abeta from fibrillization, and helps to maintain it in the soluble form.

PMID- 10640634
TI  - Deficits in the coordination of agonist and antagonist muscles in stroke
      patients: implications for normal motor control.
AB  - Movement impairments about a single joint in stroke patients may be related to
      deficits in the central regulation of stretch reflex (SR) thresholds of agonist
      and antagonist muscles. One boundary of the SR threshold range for elbow flexor
      and extensor muscles was measured in hemiparetic subjects by analysing
      electromyographic activity during stretching of relaxed muscles at seven
      different velocities. For each velocity, dynamic SR thresholds were measured as
      angles at which electromyographic activity appeared. These data were used to
      determine the sensitivity of the threshold to velocity and the static SR
      thresholds for flexors and extensors. In contrast to relaxed muscles in healthy
      subjects, static flexor and extensor thresholds lay within the physiological
      range in 11/12 and 4/12 subjects, respectively. This implies that, in the range
      between the static SR threshold and one of the physiological joint limits,
      relaxation of the muscle was impossible. Subjects then made slow movements
      against different loads to determine their ranges of active movement. Maximal
      flexor and extensor torques were lower in hemiparetic subjects throughout the
      angular range. In some subjects, ranges were found in which no active torque
      could be produced in either extensor or both muscle groups. These ranges were
      related to the boundary values of SR thresholds found during passive muscle
      stretch. The range in which reciprocally organized agonist and antagonist muscle
      activity could be generated was limited in all but one subject. When attempting
      to produce torque from positions outside their measured range of movement,
      excessive muscle coactivation occurred, typically producing no or paradoxical
      motion in the opposite direction. Results suggest a relationship between
      spasticity measured at rest and the movement deficit in stroke by demonstrating a
      link between motor deficits and control deficits in the central regulation of
      individual SR thresholds.

PMID- 10640635
TI  - Neuroprotective action of group I metabotropic glutamate receptor agonists
      against oxygen-glucose deprivation-induced neuronal death.
AB  - The metabotropic glutamate receptor (mGluR) non-selective agonist (1S,3R)-1
      aminocycloheptane-trans-1,3-dicarboxylic acid [(1S, 3R)ACPD] and group I
      selective receptor agonist 3, 5-dihydrophenylglycine (DHPG) effectively
      attenuated oxygen-glucose deprivation (OGD)-induced death of the cultured
      cerebellar granule cells. Furthermore, (1S,3R)ACPD (100 microM) reduced the
      number of apoptotic cells. Antiapoptotic action of (1S,3R)ACPD was prevented by
      the group I selective antagonist (RS)-1-aminoindan-1, 5-dicarboxylic acid (AIDA,
      100 microM) and protein kinase C (PKC) inhibitor bisindolylmaleimide (BMI, 1
      microM).

PMID- 10640636
TI  - Immunocytochemical localization of serotonin, monoamine oxidase and assessment of
      monoamine oxidase activity in human dental pulp.
AB  - In the present study serotonin (5-hydroxytryptamine, 5-HT) and monoamine oxidase
      (MAO) were both found localized in the blood vessel walls of human dental pulp.
      Our discovery of MAO activity in human dental pulp suggests a functional
      relationship between serotonin and MAO in this region.

PMID- 10640637
TI  - Human midbrain dopamine neurons express serotonin 2A receptor: an
      immunohistochemical demonstration.
AB  - We demonstrated intense serotonin (5-HT) 2A receptor immunoreactivity in the
      human ventral tegmental area (VTA) using by a recently raised antibody against 5
      HT2A receptor. The substantia nigra (SN) neurons also showed 5-HT2A receptor
      immunoreactivity. Double immunohistochemistry of 5-HT2A receptor and tyrosine
      hydroxylase (TH) revealed many neurons doubly labeled by 5-HT2A receptor and TH
      in the VTA and SN. It is suggested that activity of human midbrain dopaminergic
      neurons might be strongly regulated via 5-HT2A receptors at the level of their
      originating nuclei.

PMID- 10640638
TI  - Plaque-associated alpha-synuclein (NACP) pathology in aged transgenic mice
      expressing amyloid precursor protein.
AB  - Patients with the Lewy body variant (LBV) of Alzheimer's disease (AD) have
      ubiquitinated intraneuronal and neuritic accumulations of alpha-synuclein and
      show less neuron loss and tau pathology than other AD patients. Aged Tg2576
      transgenic mice overexpressing human betaAPP695. KM670/671NL have limited neuron
      loss and tau pathology, but frequent ubiquitin- and alpha-synuclein-positive, tau
      negative neurites resembling those seen in the LBV of AD.

PMID- 10640639
TI  - Targeted disruption of GAP-43 in P19 embryonal carcinoma cells inhibits neuronal
      differentiation. As well as acquisition of the morphological phenotype.
AB  - GAP-43 is expressed in proliferating neuroblasts in vivo and in vitro, but its
      role during early neurogenesis has not been investigated. Here we show that
      neuroectodermal differentiation stimulated by retinoic acid (RA) in the embryonal
      carcinoma (EC) line P19 is accompanied by upregulation of GAP-43 expression in
      neuroepithelial precursor cells. In contrast, when upregulation of GAP-43
      expression was prevented in 3 independent P19 lines because of a targeted
      insertion into the gene, generation of neuroepithelial precursors was inhibited.
      Consequently, neuronal number was significantly decreased, neuronal morphology
      was abnormal and fewer than 20% of all neurons were able to initiate
      neuritogenesis. Extracellular matrix (ECM) was unable to rescue initiation of
      neuritogenesis in the mutant cells, however those neurites that were extended
      responded normally to ECM-stimulated neurite outgrowth-promoting signals. These
      data suggest that GAP-43 function is required for commitment to a neuronal
      phenotype as well as initiation of neurite extension. However, stimulation of
      neurite outgrowth by ECM in P19s occurs independently of GAP-43.

PMID- 10640641
TI  - Biodegradable amphiphilic multiblock copolymers and their implications for
      biomedical applications.
AB  - Alternating multiblock copolymers composed of short blocks of poly(ethylene
      oxide) (PEO) and poly(epsilon-caprolactone) (PCL) or poly(L-lactic acid) (PLLA)
      were synthesized by a coupling reaction. The block copolymers of relatively high
      molecular weights (M(n)20,000) formed a physically crosslinked thermoplastic
      network, while low molecular weight polymers were water-soluble. The block
      copolymers demonstrated solubility in a variety of solvents including acetone,
      tetrahydrofuran, methylene chloride, dioxane, water/acetone mixtures, and
      water/ethanol mixtures. The degree of swelling, optical transparency, and
      mechanical property of the films, prepared by a solvent casting method, were
      affected by the nature of the hydrophobic block used, polymer composition,
      temperature, and thermal history. The crystalline melting temperatures of PCL and
      PLLA in the block copolymers were significantly lowered due to the chemical
      structure of difunctional PCL and PLLA, and partial phase mixing with PEO
      segments. The properties of the block copolymers may be useful for biomedical
      applications as well as controlled drug release formulations. When PEO/PLLA
      multiblock copolymers were applied as a wound healing material loaded with basic
      fibroblast growth factor (bFGF), the feasibility study showed improved wound
      healing when compared to controls of no treatment and the same wound covering
      without bFGF, indicating that a certain degree of the bioactivity of bFGF is
      preserved.

PMID- 10640642
TI  - Effect of degree of quaternization of N-trimethyl chitosan chloride for enhanced
      transport of hydrophilic compounds across intestinal caco-2 cell monolayers.
AB  - N-Trimethyl chitosan chloride (TMC) is a permanently quaternized chitosan
      derivative with improved aqueous solubility compared to native chitosan. TMC is
      able to open the tight junctions of intestinal epithelia at physiological pH
      values, where chitosan is insoluble and therefore ineffective. TMCs with degrees
      of substitution of 40 and 60% were synthesized according to a novel synthesis
      procedure and their effect on the permeability of the tight junctions of the
      intestinal Caco-2 monolayers was studied, measuring the transepithelial
      electrical resistance and the transport of a mainly paracellularly transported
      compound, [14C]-mannitol. Toxicity studies using nucleic stains were done to
      establish the transport as a cause of opening of the tight junctions and not of
      possible cytotoxicity. TMC60 showed higher transport enhancement ratios than
      TMC40 in all concentrations tested (0.05-1. 0%, w/v). Both derivatives did not
      affect the viability of the Caco-2 cell monolayers. These results suggest that
      high charge density is necessary for TMC to substantially improve the
      paracellular permeability of intestinal epithelia. It is expected that TMC40 and
      TMC60 will enhance the intestinal permeation of hydrophilic macromolecular drugs
      such as peptides and proteins.

PMID- 10640643
TI  - Enhanced folate receptor mediated gene therapy using a novel pH-sensitive lipid
      formulation.
AB  - Liposomal gene therapy vectors that penetrate cells by endocytosis must escape an
      endosomal compartment in order to enter the target cell's nucleus. Because such
      endosomal compartments are generally acidic in nature, pH-sensitive liposomes
      have been designed that are stable at extracellular pH ( approximately pH 7.4)
      but fusogenic at endosomal pH values ( approximately pH 5). We report here the
      use of a novel folate-targeted, pH-sensitive, anionic liposomal vector that
      mediates the efficient delivery of DNA into folate receptor-bearing cells and
      discharges the DNA into the cytoplasm. N-Citraconyl
      dioleoylphosphatidylethanolamine (C-DOPE), a derivative of
      dioleylphosphatidylethanolamine (DOPE) that hydrolyzes rapidly at pH 5 to yield
      DOPE, was synthesized and incorporated with DOPE and folate-polyethyleneglycol
      DOPE into liposomes. The resulting liposomes were stable at neutral pH but
      fusogenic at pH 5. Folate-labeled gene transfer vectors were prepared by
      compacting plasmid DNA with polylysine at a 1:0.75 (w/w) ratio and complexing the
      condensed cationic plasmid with the above anionic liposomes. Association of the
      polylysine-DNA with the liposomes was confirmed by sucrose gradient
      centrifugation, where migration of the folate-labeled vectors was midway between
      that of the free liposomes and condensed polylysine-DNA. Transfection of cultured
      cancer cells with the pH-sensitive liposomal vectors was found to be
      significantly more efficient than transfection with DOPE-cholesterol
      hemisuccinate-based vectors, the more commonly used pH-dependent, liposomal
      transfection formulation. Optimization studies revealed that inclusion of only 3%
      C-DOPE and 0.1% folate-derivatized DOPE yielded the highest transfection
      activity. Nearly quantitative competition with free folic acid as well as direct
      correlation of transfection efficiency with folate receptor density for several
      different cell lines further documented that vector uptake was mediated by folate
      receptor endocytosis. Taken together, these data argue that C-DOPE warrants
      further consideration as a pH sensitive component of lipid-based gene delivery
      formulations.

PMID- 10640644
TI  - Gastric retention properties of superporous hydrogel composites.
AB  - In many applications, usefulness of conventional hydrogels is limited by their
      slow swelling. To improve the swelling property of the conventional hydrogels, we
      have synthesized superporous hydrogels (SPHs) which swell fast to equilibrium
      size in minutes due to water uptake by capillary wetting through numerous
      interconnected open pores. The swelling ratio was also large in the range of
      hundreds. The mechanical strength of the highly swollen SPHs was increased by
      adding a composite material during the synthesis. The composite material used in
      the synthesis of SPH composites was Ac-Di-Sol((R)) (croscarmellose sodium). The
      gastric retention property of the prepared SPH composites was tested in dogs both
      in fasted and fed conditions. The SPH composites were placed in a hard gelatin
      capsule (size 000) for oral administration. All dogs tested were fasted for 36 h
      before experiments. Under the fasted condition, the SPH composite remained in the
      stomach for 2-3 h after before breaking into two pieces and being emptied. When
      food was given before the experiment just once following 36 h of fasting, the SPH
      composite remained in the stomach for more than 24 h, even though the fed
      condition was maintained only for the first few hours. Our study indicated that
      SPH composites possessed three properties necessary for gastric retention: fast
      swelling; superswelling; and high mechanical strength. While more improvements
      need to be made, the SPH composites provide the basis for the development of
      effective long-term gastric retention devices.

PMID- 10640645
TI  - New derivatives of polyglutamic acid as drug carrier systems.
AB  - PEG-grafted dextran and PHEG derivatives were synthetized to be used as drug
      carriers. The PEG-containing copolymers showed potential tensioactive properties.
      Dynamic light-scattering measurements and surface tension measurements indicated
      that phase separation of dextran/PHEG and PEG occurs on a molecular level in the
      conjugates and results in the formation of aggregates with a PEG core in which
      free PEG can be trapped. Blood clearance and body distribution studies were
      performed on female BALB/c mice. PEG-modified polymers with a high hydrodynamic
      volume stay longer in the blood stream compared with the non-modified polymers.
      These high molecular weight conjugates stay in the blood for several hours.
      Conjugates with a molecular weight below the renal threshold barrier are cleared
      much faster from the blood and excreted from the body. Concerning the body
      distribution, the PEG conjugates are not excreted very fast and are not taken up
      by any organ in particular. It is notable that PEG substitution prevents dextran
      from liver uptake. Furthermore, a method was developed to link an oligopeptide
      spacer-drug model and PEG to the same polymer. It was shown that PEG substitution
      has only little influence on the enzymatic release of the model drug. The above
      mentioned results showed that the PEG-grafted polymers were promising candidates
      for drug carriers.

PMID- 10640646
TI  - Polymeric drugs based on conjugates of synthetic and natural macromolecules. I.
      Synthesis and physico-chemical characterisation.
AB  - This paper describes the synthesis, physico-chemical characteristics and results
      of selected biological tests of conjugates of antibodies or proteins with
      poly(HPMA) or with poly(HPMA) carriers of anti-cancer drug doxorubicin, designed
      for targeted cancer therapy. Two types of conjugates differing in the method of
      conjugation of polymer with protein were synthesized. In the first, protein is
      attached to the polymer via an oligopeptide sequence in the side chain of the
      polymer backbone and, in the second, the polymer is attached to protein via its
      end-chain functional group. Conjugation of an antibody with poly(HPMA) does not
      influence the binding activity of the antibody for cell surface antigen. The
      physico-chemical characteristics and biological activity of both systems depend
      on the detailed structure of the polymer, the type of antibody or protein moiety
      and the structure of the whole system.

PMID- 10640647
TI  - Matrices for tissue engineering-scaffold structure for a bioartificial liver
      support system.
AB  - This study proposes a new composite scaffold system. A woven
      polyethylenterephtalate (PET) fabric was coated on one side with a biodegradable
      PLGA film, in order to obtain a geometrically polarized scaffold structure for an
      bioartificial liver support system. The composite structure ensures the stability
      of the membrane during degradation of the membrane polymer. The mesh size of the
      composite does not significantly influence the degradation behavior. Hepatocyte
      culturing studies reveal that the formation of aggregates depends on the mesh
      size and on the pretreatment: The largest aggregates could be observed after 48 h
      when PVLA coating, large mesh size and EGF were combined. Thus, the combination
      of a geometrically structured, partially degradable scaffold with receptor
      mediated cell attachment sites offers promising possibilities in liver tissue
      engineering.

PMID- 10640648
TI  - Bioabsorbable polymer scaffolds for tissue engineering capable of sustained
      growth factor delivery.
AB  - Engineering new tissues utilizing cell transplantation on biodegradable polymer
      matrices is an attractive approach to treat patients suffering from the loss or
      dysfunction of a number of tissues and organs. The matrices must maintain
      structural integrity during the process of tissue formation, and promote the
      vascularization of the developing tissue. A number of molecules (angiogenic
      factors) have been identified that promote the formation of new vascular beds
      from endothelial cells present within tissues, and the localized, controlled
      delivery of these factors from a matrix may allow an enhanced vascularization of
      engineered tissues. We have developed a gas foaming polymer processing approach
      that allows the fabrication of three-dimensional porous matrices from
      bioabsorbable materials (e.g., copolymers of lactide and glycolide [PLG]) without
      the use of organic solvents or high temperatures. The effects of several
      processing parameters (e.g., gas type, polymer composition and molecular weight)
      on the process were studied. Several gases (CO(2), N(2), He) were utilized in the
      fabrication process, but only CO(2) resulted in the formation of highly porous,
      structurally intact matrices. Crystalline polymers (polylactide and
      polyglycolide) did not form porous matrices, while amorphous copolymers (50:50,
      75:25, and 85:15 ratio of lactide:glycolide) foamed to yield matrices with
      porosity up to 95%. The mechanical properties of matrices were also regulated by
      the choice of PLG composition and molecular weight. Angiogenic factors (e.g.,
      vascular endothelial growth factor) were subsequently incorporated into matrices
      during the fabrication process, and released in a controlled manner. Importantly,
      the released growth factor retains over 90% of its bioactivity. In summary, a
      promising system for the incorporation and delivery of angiogenic factors from
      three-dimensional, biodegradable polymer matrices has been developed, and the
      fabrication process allows incorporation under mild conditions.

PMID- 10640649
TI  - Improved endothelialization of vascular grafts by local release of growth factor
      from heparinized collagen matrices.
AB  - Endothelial cell seeding, a promising method to improve the performance of small
      diameter vascular grafts, requires a suitable substrate, e.g. crosslinked
      collagen. In addition, the growth of seeded endothelial cells can be improved by
      local release of a heparin-binding protein, basic fibroblast growth factor
      (bFGF). In this study, the influence of immobilization of heparin to collagen,
      crosslinked using N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC) in
      combination with N-hydroxysuccinimide (NHS), on the binding and release of bFGF
      was determined. Heparin was immobilized also using EDC and NHS. Furthermore, the
      effects of the release of bFGF from (heparinized) EDC/NHS-crosslinked collagen on
      the proliferation of seeded endothelial cells was studied in vitro.
      Immobilization of increasing amounts of heparin to EDC/NHS-crosslinked collagen
      (containing 14 free epsilon-amino groups per 1000 amino acid residues, E/N14C)
      resulted in binding of increasing amounts of bFGF to the material. Maximal bFGF
      binding was observed for E/N14C containing 20-30 mg heparin immobilized per gram
      of collagen which was obtained using a molar ratio of EDC to heparin-carboxylic
      acid groups of 0.4 for heparin immobilization (E/N14C-H(0.4)). Up to
      concentrations of 320 ng bFGF/ml, 10% of the added bFGF bound to E/N14C, while
      binding of bFGF to E/N14C-H(0.4) was 22%. The initial release rate of bFGF bound
      to E/N14C was much higher compared to bFGF bound to E/N14C-H(0.4): respectively,
      30 vs. 2% in the first 6 h. After 10 days, the bFGF release from E/N14C and
      E/N14C-H(0.4) amounted to 83 vs. 42%, respectively. Binding of increasing amounts
      of bFGF resulted in increased growth of human umbilical vein endothelial cells
      (HUVECs) seeded on both E/N14C and E/N14C-H(0.4). Nevertheless, after 6 and 10
      days of proliferation cell numbers on E/N14C-H(0.4) where higher than cell
      numbers on E/N14C, irrespective of the bFGF concentration used for loading of the
      matrix. It is concluded that heparinized, EDC/NHS-crosslinked collagen is a good
      synthetic vascular graft coating for in vivo endothelial cell seeding.

PMID- 10640650
TI  - Interactions between red blood cells and a lethal, partly quaternized tertiary
      polyamine.
AB  - Partially quaternized poly[thio-1-(N,N-diethyl-aminomethyl) ethylene]s, Q
      P(TDAE)(x) with x indicating the percentage of quaternized subunits, have been
      proposed as potential carriers for drugs insoluble in water. However these
      cationic polyelectrolytes form emboli upon intravenous administration. In order
      to study the mechanism, Q-P(TDAE)(11) was incubated in vitro with red blood cells
      (RBCs) suspended in various aqueous media such as autologous plasma, autologous
      serum, albumin dissolved in phosphate buffer, plasma-serum mixtures and Tris
      buffer. The deformability of the RBC membrane studied by viscometry was not
      affected by the polycation. Q-P(TDAE)(11)-induced hemagglutination was studied by
      optical microscopy. It depended on the polymer concentration and on the presence
      of plasma proteins. As ghosts were formed in some cases, hemolysis was
      investigated by measuring potassium and hemoglobin released from RBCs. Fibrinogen
      and serum proteins, except albumin, protected RBCs from hemolysis. Moreover the
      order of addition of the suspension components modulated dramatically the Q
      P(TDAE)(11)-induced hemolysis. Addition of Q-P(TDAE)(11) to whole blood caused
      hemolysis whereas addition of the polymer to plasma prior to contact with RBCs
      did not affect the cell integrity. In contrast, addition of the polymer to RBCs
      suspended in albumin solution caused greater hemolysis than the addition to whole
      blood, and the contact between Q-P(TDAE)(11) and albumin prior to RBC addition
      still enhanced cell lysis. Two conclusions can be drawn from these observations:
      (i) Q-P(TDAE)(11) induces both hemagglutination, probably through electrostatic
      interaction, and hemolysis, because Q-P(TDAE)(11) disrupted the RBC lipid
      bilayer; (ii) proteins can decrease or increase the deleterious effects of Q
      P(TDAE)(11) on RBCs.

PMID- 10640651
TI  - Iontophoresis: electrorepulsion and electroosmosis.
AB  - Over the last 10-15 years, the electrical enhancement of drug delivery across the
      skin has undergone intense investigation. During this period, considerable
      amounts of experimental data have been generated, and the successful enhancement
      of a diverse array of molecules has been achieved. Indeed, the commercial
      exploitation of the method can be envisaged within the next few years. Despite
      this progress, however, the mechanistic understanding of iontophoresis remains a
      challenging scientific question that is yet to be fully resolved. The routes of
      permeation under the influence of an applied electrical potential, and the
      molecular interactions of the transporting drug with these pathways, have
      resisted unequivocal and unambiguous identification. Equally, the relative
      contributions of electrorepulsion and electroosmosis to the total iontophoretic
      flux have proven difficult to quantify, due to the difficulty of designing
      appropriate experiments. The situation is further complicated by the fact that it
      has now been established that certain lipophilic cations, in particular, can
      associate strongly with the skin during their iontophoretic delivery, thereby
      altering the electrical properties of the membrane, and changing the mechanism of
      transport. In this short communication, the roles of electrorepulsion and
      electroosmosis have been reconsidered from a simple theoretical point of view,
      and experimental approaches by which their relative importance may be estimated
      have been proposed and subjected to initial evaluation.

PMID- 10640652
TI  - Bone regeneration by transforming growth factor beta1 released from a
      biodegradable hydrogel.
AB  - This paper describes the sustained release of transforming growth factor beta1
      (TGF-beta1) from a biodegradable hydrogel based on polyion complexation for the
      enhancement of bone regeneration activity. Basic TGF-beta1 was adsorbed onto the
      biodegradable hydrogel of acidic gelatin with an isoelectric point of 5.0 by an
      electrostatic interaction. The TGF-beta1 could not be adsorbed onto basic
      gelatin. When acidic gelatin hydrogels incorporating 125I-labeled TGF-beta1 were
      implanted into the back subcutis of mice, the radioactivity decreased with time
      and the in vivo retention of TGF-beta1 was prolonged with a decrease in the water
      content of hydrogels. The higher the water content of hydrogels, the faster their
      biodegradation. The in vivo retention of TGF-beta1 correlated well with that of
      gelatin hydrogels, indicating that TGF-beta1 was released from the gelatin
      hydrogel as a result of hydrogel biodegradation. The ability of TGF-beta1
      incorporated into acidic gelatin hydrogels to induce bone regeneration was
      evaluated in a rabbit calvarial defect model. Eight weeks after treatment, the
      gelatin hydrogels with water contents of 90 and 95 wt% induced significantly high
      bone regeneration compared with those with lower and higher water contents and
      free TGF-beta1. This indicates that the sustained release of TGF-beta1 from the
      hydrogel with suitable in vivo degradability is necessary to effectively enhance
      its osteoinductive function. Rapid hydrogel degradation will result in a
      retention time of TGF-beta1 which is too short to induce bone regeneration. It is
      possible that the slow degradation of the hydrogel physically blocked TGF-beta1
      induced bone regeneration at the skull defect. It can be concluded that the
      gelatin hydrogel is a promising matrix of TGF-beta1 release to induce skull bone
      regeneration.

PMID- 10640653
TI  - Doxorubicin-loaded poly(ethylene glycol)-poly(beta-benzyl-L-aspartate) copolymer
      micelles: their pharmaceutical characteristics and biological significance.
AB  - Doxorubicin (DOX) was physically loaded into micelles prepared from poly(ethylene
      glycol)-poly(beta-benzyl-L-aspartate) block copolymer (PEG-PBLA) by an o/w
      emulsion method with a substantial drug loading level (15 to 20 w/w%). DOX-loaded
      micelles were narrowly distributed in size with diameters of approximately 50-70
      nm. Dimer derivatives of DOX as well as DOX itself were revealed to be entrapped
      in the micelle, the former seems to improve micelle stability due to its low
      water solubility and possible interaction with benzyl residues of PBLA segments
      through pi-pi stacking. Release of DOX compounds from the micelles proceeded in
      two stages: an initial rapid release was followed by a stage of slow and long
      lasting release of DOX. Acceleration of DOX release can be obtained by lowering
      the surrounding pH from 7.4 to 5.0, suggesting a pH-sensitive release of DOX from
      the micelles. A remarkable improvement in blood circulation of DOX was achieved
      by use of PEG-PBLA micelle as a carrier presumably due to the reduced
      reticuloendothelial system uptake of the micelles through a steric stabilization
      mechanism. Finally, DOX loaded in the micelle showed a considerably higher
      antitumor activity compared to free DOX against mouse C26 tumor by i.v.
      injection, indicating a promising feature for PEG-PBLA micelle as a long
      circulating carrier system useful in modulated drug delivery.

PMID- 10640654
TI  - DepoFoam technology: a vehicle for controlled delivery of protein and peptide
      drugs.
AB  - A major challenge in the development of sustained-release formulations for
      protein and peptide drugs is to achieve high drug loading sufficient for
      prolonged therapeutic effect coupled with a high recovery of the protein/peptide.
      This challenge has been successfully met in the formulation of several peptide
      and protein drugs using the DepoFoam, multivesicular lipid-based drug delivery
      system. DepoFoam technology consists of novel multivesicular liposomes
      characterized by their unique structure of multiple non-concentric aqueous
      chambers surrounded by a network of lipid membranes. The objective of this paper
      is to demonstrate that DepoFoam technology can be used to develop sustained
      release formulations of therapeutic proteins and peptides with high loading.
      DepoFoam formulations of a protein such as insulin, and peptides such as
      leuprolide, enkephalin and octreotide have been developed and characterized. The
      data show that these formulations have high drug loading, high encapsulation
      efficiency, low content of free drug in the suspension, little chemical change in
      the drug caused by the formulation process, narrow particle size distribution,
      and spherical particle morphology. Drug release assays conducted in vitro in
      biological suspending media such as human plasma indicate that these formulations
      provide sustained release of encapsulated drug over a period from a few days to
      several weeks, and that the rate of release can be modulated. In vivo
      pharmacodynamic studies in rats also show a sustained therapeutic effect over a
      prolonged period. These results demonstrate that the DepoFoam system is capable
      of efficiently encapsulating therapeutic proteins and peptides and effectively
      providing controlled delivery of these biologically active macromolecules.

PMID- 10640655
TI  - Branched biodegradable polyesters for parenteral drug delivery systems.
AB  - Continuous, 'infusion-like' drug release profiles from biodegradable parenteral
      delivery systems are difficult to achieve for proteins and other hydrophilic
      macromolecular drugs with commonly used linear polyesters from lactic acid (PLA)
      and its random copolymers with glycolic acid (PLG). Drug release rates can be
      modified either by increasing the hydrophilicity of polyesters or by manipulating
      the polymer architecture to adjust polymer degradation rates and thus drug
      release. Therefore, we investigated different branching concepts for
      biodegradable polyesters of PLA and PLG. For one four- and eight-arm
      poly(ethylene oxide)s (PEO) were grafted with shorter polyester chains leading to
      star-branched structures. Secondly we obtained comb-like polyesters using both
      charged and uncharged dextrans or poly(vinyl alcohol)s (PVA) as hydrophilic
      backbones. The star-shaped and brush-like grafted polymers were intensively
      characterized by methods, such as NMR, IR, SEC-SLS, DSC and viscosity
      measurements. Tailor-made properties make these novel biodegradable polyesters
      promising candidates for parenteral protein delivery systems. While the star
      branched polyesters have shown some interesting properties with respect to their
      degradation behavior, retaining the PEO blocks longer than ABA triblock
      copolymers, their release properties need further optimization. Brush-like
      branched polyesters on the other hand seem to possess both degradation and
      release properties meriting further investigations for parenteral protein
      delivery systems.

PMID- 10640656
TI  - Zero-order release of lysozyme from poly(ethylene glycol)/poly(butylene
      terephthalate) matrices.
AB  - Protein release from a series of biodegradable poly(ether ester) multiblock
      copolymers, based on poly(ethylene glycol) (PEG) and poly(butylene terephthalate)
      (PBT) was investigated. Lysozyme-containing PEG/PBT films and microspheres were
      prepared using an emulsion technique. Proteins were effectively encapsulated and
      dense polymer matrices were formed. The swelling in water of PEG/PBT films
      reached equilibrium within 3 days. The degree of swelling increased with
      increasing PEG content and with increasing molecular weight of the PEG segment.
      The release rate of lysozyme from PEG/PBT films could be tailored very precisely
      by controlling the copolymer composition. Release rates increased with increasing
      PEG/PBT weight ratio and increasing molecular weight of the PEG segment. For
      films prepared from block copolymers with PEG blocks of 4000 g/mol, first-order
      lysozyme release was observed. For matrices prepared from polymers with PEG
      segments of 1000 and 600 g/mol, the lysozyme release profile followed near zero
      order kinetics. A mathematical description of the release mechanism was developed
      which takes into account the effect of polymer hydrolytic degradation on solute
      diffusion. The model was found to be consistent with the experimental
      observations. Finally, determination of the activity of released protein showed
      that lysozyme was not damaged during the formulation, storage and release
      periods.

PMID- 10640657
TI  - Copolymers of 2-(dimethylamino)ethyl methacrylate with ethoxytriethylene glycol
      methacrylate or N-vinyl-pyrrolidone as gene transfer agents.
AB  - Random copolymers of 2-(dimethylamino)ethyl methacrylate (DMAEMA) with
      ethoxytriethylene glycol methacrylate (triEGMA) or N-vinylpyrrolidone (NVP) of
      different molecular weights and compositions were synthesized, characterized and
      evaluated as polymeric transfectants in vitro. All synthesized copolymers
      (comonomer fraction up to 66 mol%) were able to bind to DNA, yielding polymer
      plasmid complexes (polyplexes). However, the polymer-plasmid ratio at which small
      complexes (size 0.2-0.3 microm) were formed, increased with increasing mole
      fraction of the comonomer. zeta-Potential measurements revealed that the polymer
      plasmid ratio where charge neutralization of DNA occurred, increased with
      increasing mole fraction of triEGMA. The cytotoxicity of the copolymers, either
      complexed with DNA or in the free form, decreased with increasing mole fraction
      of both comonomers (triEGMA and NVP). This reduction was even more than what
      could be expected based on the DMAEMA mole fraction in the copolymer. The
      copolymers with a molecular weight up to 170? omitted?000 had the same
      transfection capability as a homopolymer of comparable molecular weight. However,
      higher molecular weight copolymers showed a reduced transfection capability
      compared to the homopolymer, which was ascribed to the reduced capability to
      condense the size of plasmid. Transfection efficiency of polyplexes composed of
      copolymers with a low triEGMA content increased with increasing molecular weight.
      Although the copolymers with 50 mol% triEGMA were also better transfectants than
      the homopolymer, the transfection efficiency did not increase further with
      increasing molecular weight. Interestingly, NVP-DMAEMA copolymers synthesized by
      polymerization to high conversion showed both excellent DNA binding and
      condensing characteristics (polyplex size <0.3 microm) and transfection
      capabilities. This is ascribed to a synergistic effect of DMAEMA-rich copolymers
      and NVP-rich copolymers present in this system on the complex formation with
      plasmid DNA.

PMID- 10640658
TI  - Intraarterial protein delivery via intimally-adherent bilayer hydrogels.
AB  - Arterial structure plays an important role in drug delivery from intraarterial
      depots. The internal elastic lamina forms a major diffusive resistance to the
      transport of macromolecular drugs from intimally-adherent hydrogel depots to the
      arterial media. The objectives of this study were to develop an approach by which
      to form a bilayer hydrogel depot with a higher permeability intimally-adherent
      layer, containing the drug, and a lower permeability luminal layer, and to
      evaluate ex vivo whether this luminal layer could enhance the delivery of a
      protein to the arterial media. Sequential interfacial photopolymerization of
      polyethyleneglycol diacrylate precursors (molecular weight 4000 for the luminal
      layer, 10,000 for the intimal layer) with eosin Y and triethanolamine as an
      initiation system was employed to form these bilayer hydrogels. Horseradish
      peroxidase was used as a model protein, and delivery to the arterial media was
      measured in rat carotid arteries ex vivo. The lower permeability luminal layer
      served to enhance delivery of the model protein into the arterial media for
      delivery periods at least up to 72 h. Thus, it was possible to compensate for the
      diffusional resistance of the internal elastic lamina on the one side of the
      hydrogel depot with a second diffusional resistance on the other side of the
      hydrogel.

PMID- 10640659
TI  - A mechanistic analysis of carrier-mediated oral delivery of protein therapeutics.
AB  - This article summarizes the results of a theoretical analysis of protein
      absorption into the systemic circulation from the small intestine, with and
      without molecular 'carriers' designed to enhance absorption. The predictions are
      compared with experimental systemic protein concentrations following
      intraduodenal delivery of insulin, interferon alpha-2b, and human growth hormone.
      The results show that, from the standpoint of improving oral absorption, the
      primary consequence of carrier molecules is to increase epithelial membrane
      permeability, thereby leading to higher bioavailability. Several possible
      mechanisms of this permeability enhancement are discussed.

PMID- 10640660
TI  - The use of bispecific antibodies in tumor cell and tumor vasculature directed
      immunotherapy.
AB  - To overcome dose limiting toxicities and to increase efficacy of immunotherapy of
      cancer, a number of strategies are under development for selectively redirecting
      effector cells/molecules towards tumor cells. Many of these strategies exploit
      the specificity of tumor associated antigen recognition by monoclonal antibodies.
      Using either hybridoma fusion, chemical derivatization or molecular biology
      technology, antibodies with dual specificity can be constructed. These so called
      biospecific antibodies (BsAbs) have been used to redirect the cytolytic activity
      of a variety of immune effector cells such as cytotoxic T lymphocytes, natural
      killer cells, neutrophils and monocytes/macrophages to tumor cells. Local
      administration of BsAbs, either alone or in combination with autologous effector
      cells, is highly effective in eradicating tumor cells. In contrast, systemic
      application of BsAb at present is only suitable for adjuvant treatment of minimal
      residual disease due to poor tumor cell accessibility. As an alternative,
      angiogenesis related determinants on tumor blood vessels can be exploited for the
      selective delivery of effector cells/molecules apart from being used to inhibit
      angiogenesis. Important advantages of this strategy is that the endothelial cell
      associated target epitope(s) are easy accessible. The dependence of tumor growth
      on the tumor's blood supply also renders tumor endothelial cells an attractive
      target for therapy. Although still in its infancy, attacking the tumor's blood
      supply for example by delivering coagulation factors or toxins, or by BsAb
      directed immunotherapies holds great promise for antineoplastic therapy.

PMID- 10640662
TI  - A flexible technology for the linear, pulsatile and delayed release of drugs,
      allowing for easy accommodation of difficult in vitro targets.

PMID- 10640661
TI  - Polymeric drugs based on conjugates of synthetic and natural macromolecules. II.
      Anti-cancer activity of antibody or (Fab')(2)-targeted conjugates and combined
      therapy with immunomodulators.
AB  - We provide data on in vivo targeting of the Thy 1.2 (CDw90) cell surface receptor
      expressed on neoplastic T cells, mouse EL4 T cell lymphoma. The targeting
      antibody and the anticancer drug, doxorubicin (DOX) were conjugated to a water
      soluble copolymer based on N-(2-hydroxypropyl)methacrylamide (HPMA) acting as a
      carrier responsible for controlled intracellular release of the conjugated drug.
      The in vivo therapeutic efficacy of HPMA copolymer-bound DOX targeted with anti
      EL4 antibody, polyclonal anti-thymocyte globulin (ATG), monoclonal anti-Thy 1.2
      antibody or its F(ab')(2) fragment was compared with the efficacy of DOX
      conjugated to HPMA copolymer containing nonspecific IgG or bovine serum albumin
      (BSA). Anti-EL4 antibody-targeted conjugate caused a significant retardation of
      tumor growth and an extension of the life span of treated mice. The effect was
      comparable with that of HPMA copolymer-bound DOX targeted with ATG, anti-Thy 1.2
      antibody or its F(ab')(2) fragment. However, considerable antitumor effect was
      seen also in conjugates targeted instead of specific antibodies with syngeneic
      nonspecific IgG or BSA. Patients with advanced cancer are often immunocompromised
      due to dysfunction of their immune system induced by cancer and cytotoxic drugs.
      A significant decrease of unwanted side-effects of targeted drugs against a
      number of vital organs was already documented. In this study we have compared
      immunotoxic effects of free DOX with those of its antibody-targeted form on NK
      cells and cytolytic T lymphocytes (CTLs) isolated from C57BL/10 mice bearing EL4
      T cell lymphoma. In the same model we have tested the combination therapy with
      immunomodulators (beta-glucan or AM-2) injected together with targeted
      daunomycin. We have observed a significant protective effect of targeted DOX
      against NK cells and CTLs. Moreover, the data revealed that combination therapy
      considerably enhances antitumor efficacy of the targeted anticancer drug.

PMID- 10640663
TI  - Comparative analyses in aquatic microbial ecology: how far do they go?
AB  - Methodological developments in recent years have led to an increase in empirical
      databases on the abundance and functions of aquatic microbes, now allowing
      synthesis studies. Most of these studies have adopted a comparative approach,
      such that comparative analyses are now available for most aspects of aquatic
      microbial food webs (more than 50 papers published in the last 15 years). Some of
      these analyses apparently yield conflicting results, introducing confusion and
      unnecessary disputes in the field. We briefly review the comparative analyses so
      far produced and we highlight generalities, show that some of the perceived
      discrepancies largely derive from partial analyses of a general underlying trend
      and formulate predictions based on these general trends that provide new avenues
      for research.

PMID- 10640664
TI  - A soil microscale study to reveal the heterogeneity of Hg(II) impact on
      indigenous bacteria by quantification of adapted phenotypes and analysis of
      community DNA fingerprints.
AB  - The short term impact of 50 uM Hg(II) on soil bacterial community structure was
      evaluated in different microenvironments of a silt loam soil in order to
      determine the contribution of bacteria located in these microenvironments to the
      overall bacterial response to mercury spiking. Microenvironments and associated
      bacteria, designated as bacterial pools, were obtained by successive soil washes
      to separate the outer fraction, containing loosely associated bacteria, and the
      inner fraction, containing bacteria retained into aggregates, followed by a
      physical fractionation of the inner fraction to separate aggregates according to
      their size (size fractions). Indirect enumerations of viable heterotrophic (VH)
      and resistant (Hg(R)) bacteria were performed before and 30 days after mercury
      spiking. A ribosomal intergenic spacer analysis (RISA), combined with
      multivariate analysis, was used to compare modifications at the community level
      in the unfractionated soil and in the microenvironments. The spatial
      heterogeneity of the mercury impact was revealed by a higher increase of Hg(R)
      numbers in the outer fraction and in the coarse size fractions. Furthermore,
      shifts in RISA patterns of total community DNA indicated changes in the
      composition of the dominant bacterial populations in response to Hg(II) stress in
      the outer and in the clay size fractions. The heterogeneity of metal impact on
      indigenous bacteria, observed at a microscale level, is related to both the
      physical and chemical characteristics of the soil microenvironments governing
      mercury bioavailability and to the bacterial composition present before spiking.

PMID- 10640665
TI  - Fermentation pattern of methanogenic degradation of rice straw in anoxic paddy
      soil.
AB  - The anaerobic degradation of different fractions of rice straw in anoxic paddy
      soil was investigated. Rice straw was divided up into stem, leaf sheath and leaf
      blade. The different straw fractions were mixed with paddy soil and incubated
      under anoxic conditions. Fermentation of straw components started immediately and
      resulted in transient accumulation of acetate, propionate, butyrate, isobutyrate,
      valerate, isovalerate and caproate with much higher concentrations in the
      presence than in the absence of straw. Also some unidentified compounds with UV
      absorption could be detected. The maximum concentrations of these compounds were
      different when using different straw fractions, suggesting differences in the
      degradation pathway of these straw fractions during the early phase of
      incubation, i.e. with Fe(III) and sulfate serving as oxidants. When
      concentrations of the intermediates decreased to background values, CH(4)
      production started. Rates of CH(4)unamended soil. During the methanogenic phase,
      the percentage contribution of fermentation products to CH(4) production was
      determined by inhibition with 2-bromoethanesulfonate (BES). Acetate (48-83%) and
      propionate (18-28%) were found to be the main intermediates of the carbon flow to
      CH(4), irrespective of the fraction of the rice straw or its absence. Mass
      balance calculations showed that 84-89% of CH(4) was formed via acetate in the
      various incubations. Radiotracer experiments showed that 11-27% of CH(4) was
      formed from H(2)/CO(2), thus confirming that acetate contributed 73-89% to
      methanogenesis. Our results show that the addition of rice straw and the fraction
      of the straw affected the fermentation pattern only in the early phase of
      degradation, but had no effect on the degradation pathway during the later
      methanogenic phase.

PMID- 10640666
TI  - Effect of inoculation of a TOL plasmid containing mycorrhizosphere bacterium on
      development of Scots pine seedlings, their mycorrhizosphere and the microbial
      flora in m-toluate-amended soil.
AB  - The purpose of this study was to evaluate the influence of introduced bacteria
      containing a contaminant degrading plasmid on the growth and survival of pine
      seedlings and mycorrhizosphere microbial flora in contaminated soil. The
      Pseudomonas fluorescens strain OS81, originally isolated from fungal hyphae in
      contaminated soil, was supplied with the TOL plasmid pWW0::Km (to generate
      OS81(pWW0::Km)) and inoculated in humus-soil microcosms with and without pine
      seedlings mycorrhized with Suillus bovinus. After 3 months of regular treatment
      with m-toluate (mTA) solutions, the introduced catabolic plasmid was found to be
      disseminated in the indigenous bacterial population of both mycorrhizosphere and
      soil uncolonized by the fungus. Transconjugants were represented by bacteria of
      the genera Pseudomonas and Burkholderia and their number correlated positively
      with the concentration of mTA applied. Indigenous mTA degrading bacteria with low
      similarity to Burkholderia species were also enriched in microcosms. They were
      mostly associated with mycorrhizal soil or fungal structures and virtually absent
      in microcosms without pines. The total number of Tol(+) bacteria was higher in
      mycorrhizospheric soil compared with bulk soil. Inoculation with P. fluorescens
      OS81(pWW0::Km) had a positive effect on the development of roots and fungus in
      contaminated soil. Both inoculation with the P. fluorescens OS81(pWW0::Km) and
      mTA contamination as well as the presence of mycorrhized pine roots and fungal
      hyphae had an effect on the microbial community structure of soil as measured by
      carbon source oxidation patterns. However, the impact of mTA on the microbial
      community was more prominent. The study indicates that an effect on plant and
      fungal development can be obtained by manipulating the mycorrhizosphere. Both
      introduction of the bacterium carrying the degradative plasmid and the plasmid
      itself are likely to have a positive effect not only on the organisms involved,
      but also on bioremediation of contaminated soil, a factor that was not directly
      monitored here.

PMID- 10640667
TI  - Humus bacteria of Norway spruce stands: plant growth promoting properties and
      birch, red fescue and alder colonizing capacity.
AB  - We studied the potential of the humus layer of the Norway spruce stands to supply
      beneficial rhizobacteria to birch (Betula pendula), alder (Alnus incana) and
      fescue grass (Festuca rubra), representatives of pioneer vegetation after clear
      cutting of the coniferous forest. Axenically grown seedlings of these species
      were inoculated with the acid spruce humus, pH 3.7-5.3. Actinorhizal propagules,
      capable of nodulating alder, were present in high density (10(3) g(-1)) in humus
      of long-term limed plots, whereas plots with nitrogen fertilization contained
      almost none (</=10 g(-1)). The genera most frequently found in the humus were
      Bacillus, Paenibacillus, Arthrobacter, Nocardia, Rhodococcus and Pseudomonas,
      independently of prior liming or fertilization of the plots. The taxa found in
      the seedling roots differed from that in humus by the prevalence of the Gram
      negative genera Pseudomonas, Alcaligenes and Comamonas. Enrichment cultures of
      the roots on nitrogen-free media yielded Paenibacillus and Rhodococcus species.
      Nitrogen-fixing R. erythropolis and a novel Paenibacillus, closest by full
      sequence of 16S rDNA to P. durus, represented new classes of nitrogen-fixing
      rhizosphere bacteria. In addition, nitrogen-fixing R. fascians was found in the
      humus. The rhizoflora and humus contained high proportions of bacteria
      antagonistic towards plant pathogenic Rhizoctonia sp., Botrytis cinerea and
      Fusarium culmorum. The antagonistic isolates also commonly produced siderophores
      and/or cell wall degrading enzymes.

PMID- 10640668
TI  - Investigation of 0.2 um filterable bacteria from the Western Mediterranean Sea
      using a molecular approach: dominance of potential starvation forms.
AB  - Although the existence of 0.2 um filterable bacteria has been known since the
      early 80's, they are not taken into consideration when modeling microbial food
      webs, due to an overall lack of information concerning this specific size class.
      According to physiological studies on starvation forms and investigations on
      small bacterial cells in marine ecosystems, a 0.2 um filtrate may consist of
      different phenotypes: starvation forms of typical marine bacteria,
      ultramicrobacteria or bacterial cells, even larger than 0.2 um, but flexible
      enough to pass the nominal filter pore-size. In this pilot study we examined
      three filtered seawater fractions from the Western Mediterranean Sea (Bay of
      Calvi, Corsica/France) - the total bacterial population, the bacterial fraction
      above 0.2 um and the 0.2 um filtrate - to investigate the bacterial community
      structure of each of those fractions by the molecular approach of denaturing
      gradient gel electrophoresis (DGGE) of 16S rDNA fragments. The analysis of the
      resulting DGGE profiles revealed different patterns of dominant bands for the 0.2
      um filterable and the total bacterial populations within the samples.
      Additionally the 0.2 um filterable bacterial compartment exhibited obvious
      differences in band patterns for winter and summer samples, which were not
      observed for the total bacterial fraction. According to the current knowledge
      concerning the status of 0.2 um filterable bacteria, DGGE patterns indicate that
      most of the fragments representing 0.2 um filterable bacteria were rather
      starvation forms of marine bacteria than ultramicrobacteria. The sequencing of
      excised and cloned DNA bands of the DGGE profiles characterized the phylogenetic
      affiliation of the corresponding 0.2 um filterable bacteria, clustering mainly
      with known, typical marine isolates of both alpha-subclass and gamma-subclass of
      the Proteobacteria and the Cytophaga-Flavobacterium-Bacteroides branch.

PMID- 10640669
TI  - Microbial production and consumption of dimethyl sulfide (DMS) in a sea grass
      (Zostera noltii)-dominated marine intertidal sediment ecosystem (Bassin
      d'Arcachon, France).
AB  - The relation between net dimethyl sulfide (DMS) production and changes in near
      surface (0-5 mm) oxygen concentrations in a sea grass (Zostera noltii Hornem)
      covered intertidal sediment ecosystem was examined during a diel cycle. Sediment
      covered with Zostera was found to be more oxygenated than uncovered sediment
      during the period of photosynthesis. This phenomenon was probably caused by
      radial oxygen loss of the Zostera root-rhizome system. The population sizes of
      the three functional groups of microbes mainly responsible for the concentration
      of DMS, the dimethylsulfoniopropionate (DMSP)-demethylating, DMSP-cleaving and
      DMS-oxidizing bacteria, were quantified by most probable number (MPN)
      methodologies. Sediments with Zostera supported substantially higher populations
      of both aerobic (149x10(6) cm(-3) DMSP-utilizing and 0.4x10(6) cm(-3) DMS
      oxidizing) and anaerobic (43x10(6) cm(-3) DMSP-utilizing and 0.4x10(6) cm(-3) DMS
      oxidizing) microorganisms than sediments without Zostera (DMSP-utilizing aerobes
      and anaerobes both 2x10(6) cm(-3) and DMS-oxidizing aerobes and anaerobes both
      0.2x10(6) cm(-3)). Experiments conducted with sediment cores and sediment
      slurries suggested that the net production of DMS in these sediments was
      significantly lower during oxic periods than during anoxic periods. Intact
      sediment cores with and without Zostera produced DMS when incubated under
      anoxic/dark conditions (97.0 and 53.6 nmol DMS m(-2) h(-1), respectively), while
      oxic/light-incubated cores did not produce detectable amounts of DMS. In
      addition, kinetic parameter values (V(max) and K(m)) for DMSP degradation in cell
      suspensions of isolated DMSP-demethylating and DMSP-cleaving bacteria were
      measured and compared to documented values for other strains. Both V(max) and
      K(m) values for DMSP-demethylating organisms were found to be relatively low
      (14.4-20.1 nmol DMSP mg protein(-1) min(-1) and 4.1-15.5 uM, respectively) while
      these parameter values varied widely in the group of the DMSP-cleaving organisms
      (6.7-1000 nmol DMSP mg protein(-1) min(-1) and 2-2000 uM, respectively). It was
      hypothesized that a diel rhythm in DMS emission occurred, with a relatively low
      net production during the day and a high net production during the night.
      Environmental changes which result in increased anoxic conditions in coastal
      sediments, such as an increase in eutrophication, may therefore result in
      increased atmospheric DMS emission rates.

PMID- 10640670
TI  - Bacterial diversity and community composition in the chemocline of the meromictic
      alpine Lake Cadagno as revealed by 16S rDNA analysis.
AB  - Using different techniques of molecular biology we investigated the bacterial
      diversity of the chemocline of the meromictic Lake Cadagno. Cloning of a total
      community 16S rDNA PCR product and subsequent screening with a combination of
      amplified ribosomal DNA restriction analysis and temporal temperature gradient
      gel electrophoresis (TTGE) analysis revealed that 30 of 47 randomly selected
      clones were unique. Partial sequencing and comparative analysis indicated a high
      bacterial diversity dominated by the gamma-Proteobacteria (33.3%). Most of these
      rDNA clone sequences were not closely related to any 16S rDNA sequence in the
      database. In a second approach, the TTGE pattern from an environmental sample was
      compared with the migration of the cloned 16S rDNA fragments. Four clone types
      were identified on the environmental pattern by excising and sequencing
      comigrating bands, three of which were well represented in the library: two
      Chromatiaceae species and one sequence affiliated with the Desulfobulbus
      assemblage. Using the fluorescent in situ hybridization technique we essentially
      confirmed the results of the cloning experiments and the TTGE analysis.

PMID- 10640672
TI  - Localization of the ATP-sensitive potassium channel subunit (Kir6. 1/uK(ATP)-1)
      in rat brain.
AB  - The Kir6.1/uK(ATP)-1, subunit of ATP-sensitive K(+) channels (K(ATP)), was
      localized in adult rat brain by in situ hybridization and immunohistochemistry.
      The mRNA of this subunit was ubiquitously expressed in various neurons and nuclei
      of the adult rat brain. Interestingly, Kir6.1/uK(ATP)-1 mRNA was also expressed
      in glial cells. Kir6.1/uK(ATP)-1 protein staining gave a dispersed array of fine
      dots throughout all neurons and glial cells examined. Under electron microscope,
      the immunoreactive products were specifically restricted to the mitochondria. The
      present study indicates that this K(ATP) subunit is localized in the mitochondria
      and may play a fundamental role in vital brain function.

PMID- 10640671
TI  - 4.5 kb of the rat tyrosine hydroxylase 5' flanking sequence directs tissue
      specific expression during development and contains consensus sites for multiple
      transcription factors.
AB  - To delineate DNA sequences responsible for developmentally correct expression of
      the rat tyrosine hydroxylase (TH) gene, we analyzed a line of transgenic mice
      expressing high levels of human placental alkaline phosphatase (AP) under control
      of 4.5 kb of 5' flanking DNA from the rat TH gene in embryos and adults. Several
      regions, such as the accessory olfactory bulb, which were not thought to
      synthesize TH protein or do so only transiently, were shown to express TH protein
      using an improved method of antigen retrieval for TH immunohistochemistry. Many
      of these regions had been shown to express TH-driven reporter genes in transgenic
      mice. In the central nervous system, AP was detected in essentially all TH
      expressing cell groups throughout development and in adults. In the peripheral
      nervous system, transgene expression paralleled endogenous TH expression in the
      developing adrenal medulla and sympathetic ganglia but not in transiently TH
      positive cells in dorsal root ganglia. Peripheral expression in the adult adrenal
      medulla was very weak and absent in sympathetic ganglia. The specificity with
      which the 4.5 kb region directs transgene expression in embryos is comparable to
      that observed with longer 5' flanking promoter regions, implying that this region
      contains the control elements for appropriate expression during development.
      Sequence analysis of the region demonstrates a GT dinucleotide repeat, an element
      that resembles the neural restrictive silencer element (NRSE), which restricts
      transcription of neuronal genes in non-neuronal cells, and consensus sites for
      three families of transcription factors, Ptx1/3, Nurr1 and Gli1/2, which are
      required for the early differentiation of mesencephalic neurons.

PMID- 10640673
TI  - Exposure of cultured primary rat astrocytes to hypoxia results in intracellular
      glucose depletion and induction of glycolytic enzymes.
AB  - Based on the neurotrophic properties of astrocytes in response to ischemia, the
      current work focuses on the mechanism for cultured astrocytes to adapt to a
      hypoxic environment. Intracellular glucose levels in primary cultured rat
      astrocytes exposed to hypoxia fell by 30% within 24 h, in parallel with a
      decrease in glycogen stores. Glycolytic metabolism was crucial for cell survival
      during hypoxia, as 2-deoxyglucose resulted in rapid ATP depletion and cell death.
      The mechanism for maintaining glucose levels under these conditions appeared to
      be mobilization of glycogen stores, rather than increased extracellular uptake of
      glucose, as gluconolactone (an inhibitor of beta1-4 amyloglucosidase) induced a
      rapid fall in cellular ATP in cultures subjected to hypoxia, whereas cytochalasin
      B was without affect. Addition of cycloheximide diminished the viability of
      astrocytes in hypoxia, suggesting an obligatory role of de-novo gene expression
      to respond to hypoxia. Consistently, the results of differential display
      suggested the induction of glycolytic enzymes, including aldolase A (EC
      4.1.2.13), hexokinase II (ATP: D-hexose 6-phosphotransferase, EC 2.7.1.1), and
      triosephosphate isomerase (EC 5.3.1.1) in the hypoxic culture. Marked induction
      of these glycolytic enzymes in hypoxic astrocytes was confirmed by Northern blot
      analysis. These data provide a theoretical basis to understand the ability of
      astrocytes to tolerate ischemic condition.

PMID- 10640674
TI  - Identification and localization of ataxin-7 in brain and retina of a patient with
      cerebellar ataxia type II using anti-peptide antibody.
AB  - Autosomal dominant cerebellar ataxias (ADCAs) are a complex group of
      neurodegenerative disorders characterized by progressive degeneration of the
      cerebellum, brain stem and spinal cord. The spinocerebellar ataxia type 7 (SCA7)
      is associated with pigmentary macular dystrophy and retinal degeneration leading
      to blindness caused by a CAG/polyglutamine (polyGln) expansion in the coding
      region of the SCA7 gene/protein. The SCA7 gene codes for ataxin-7, a protein of
      unknown function. To investigate its cellular and subcellular localization, we
      have developed a sequence-specific polyclonal antibody against the N-terminal
      part of the protein. Immunohistochemical analysis indicated that ataxin-7
      accumulates as single nuclear inclusion (NI) in the cells of the brain and retina
      of a SCA7 patient but not of controls. The 1C2 antibody, directed against
      expanded polyGln, confirmed the aggregation of mutant ataxin-7 in these NIs.
      Furthermore, ubiquitin was found in these aggregates, suggesting that mutant
      ataxin-7 is a target for ubiquitin-dependent proteolysis, but resistant to
      removal. Electron microscopic studies using immunogold labeling showed that
      ataxin-7 immunoreactive NIs appear as dense aggregates containing a mixture of
      granular and filamentary structures. Together, these data confirm the presence of
      NIs in brain and retina of a SCA7 patient, a common characteristic of disorders
      caused by expanded CAG/polyGln repeats.

PMID- 10640675
TI  - Absence of binding activity of neuron-restrictive silencer factor is necessary,
      but not sufficient for transcription of NMDA receptor subunit type 1 in neuronal
      cells.
AB  - Neuron-restrictive silencer factor (NRSF, also termed REST) has been proposed to
      restrict expression of a set of genes to neurons by blocking their transcription
      in nonneuronal cells. The N-methyl-D-aspartate (NMDA) receptor subunit type I
      (NR1) gene contains a consensus sequence for the NRSF/REST binding site
      (NRSE/RE1). In this study, we evaluated the contribution of NRSF/REST to neuronal
      specificity of the NR1 gene. NR1 mRNA expression correlates with the absence of
      NRSF/REST binding activity, rather than expression of NRSF/REST protein, in
      several cell lines, suggesting that the absence of NRSF/REST-binding activity is
      necessary for the expression of the NR1 gene. HeLa cells, which do not express
      the NR1 gene, have NRSF/REST binding activity to the NR1 NRSE/RE1, resulting in
      inhibition of NR1 promoter activity. However, we also found that two nonneuronal
      cell lines (C6 glioma and P19 embryonal carcinoma) that lack NRSF/REST-binding
      activity, manifest only small amounts of NR1 mRNA compared to neuronal cell lines
      (PC12 pheochromocytoma and neuronally differentiated P19 cells). The enhancement
      of NR1 mRNA levels during neuronal differentiation of P19 cells is accompanied by
      an increase in NR1 promoter activity in an NRSF/REST-binding independent manner.
      Our results suggest therefore that the absence of NRSF/REST-binding activity is
      necessary but not sufficient for robust NR1 transcription in neuronal cells.

PMID- 10640676
TI  - Developmental changes in the expression of Shaker- and Shab-related K(+) channels
      in neurons of the rat trigeminal ganglion.
AB  - We have investigated properties of voltage-gated K(+) channels in neurons of the
      pre- and postnatal rat trigeminal ganglion (TG). To correlate functional data
      with information on gene expression of Shaker- and Shab-related channels in these
      pseudo-unipolar neurons, the patch-clamp technique was combined with the single
      cell reverse transcription-polymerase chain reaction (RT-PCR). A majority (80%)
      of prenatal TG neurons possessed only sustained delayed rectifier currents with
      half-maximal current inactivation at -30 mV. In the postnatal cells, steady-state
      inactivation of sustained currents occurred at more negative voltages (half
      maximal inactivation at -58 mV). About 65% of the postnatal cells displayed a
      transient outward component in addition to the sustained currents. With
      increasing age, the sensitivity of sustained currents to 4-aminopyridine (4-AP)
      decreased significantly. The Shaker channel toxins, alpha-dendrotoxin and
      agitoxin-2 (50 and 10 nM), were much less effective. Discrimination between both
      stages with tetraethylammonium chloride (5 mM) was not possible since the
      currents were reduced generally by about 50%. After recording, the cell content
      was harvested and single-cell RT-PCR was performed to compare K(+) current
      properties and mRNA expression within the same cell. Most cells simultaneously
      expressed several different Shaker- and Shab-like transcripts. At postnatal day
      14, the frequency of cells carrying transcripts encoding Kv1.1 decreased.
      Detailed analysis revealed a higher 4-AP sensitivity of TG neurons expressing
      Kv1.1 transcripts.

PMID- 10640677
TI  - Differential expression of neural cell adhesion molecule isoforms in normal and
      glaucomatous human optic nerve heads.
AB  - Type 1B astrocytes of the human optic nerve head (ONH) constitutively express
      neural cell adhesion molecule (NCAM) in vivo and in vitro. Increased synthesis of
      NCAM has been detected in reactive astrocytes in the glaucomatous ONH of human
      donor eyes. Several NCAM isoforms are generated through alternate RNA splicing in
      tissue- and disease-specific patterns. In this study, we analyzed expression of
      NCAM isoforms in ONH of normal donors at different ages and in glaucoma. Total
      RNA was extracted from ONH of fetal, normal adult and glaucomatous eyes, and
      cultured human ONH astrocytes, fetal brain astrocytes and an astrocytoma cell
      line, for reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. To
      distinguish between NCAM 180 and 140 isoforms, exon-specific primer sets covering
      exons 13-19 were used. Isoform-specific riboprobes were used for in situ
      hybridization (ISH) in glaucomatous and in age-matched ONH. By RT-PCR, NCAM 140
      was the predominant isoform in adult ONH as well as in all cultured cells. NCAM
      180 mRNA was strongly expressed in glaucoma, whereas in normal adult tissues it
      was not detectable. ISH confirmed expression of NCAM in normal adult ONH and
      localized NCAM 140 mRNA to astrocytes. ISH demonstrated expression of NCAM 180
      mRNA in reactive astrocytes in glaucomatous ONH. Our results demonstrate that the
      NCAM 180 isoform is induced in glaucoma. NCAM 180 may play a role in astrocyte
      interaction with extracellular matrix (ECM), vessels, axons and other astrocytes
      and, through its expanded cytoplasmic domain, serve as a signaling molecule for
      reactive astrocytes during remodeling of the ONH in glaucoma.

PMID- 10640678
TI  - Vascular endothelial growth factor upregulation in transient global ischemia
      induced by cardiac arrest and resuscitation in rat brain.
AB  - This study examined vascular endothelial growth factor (VEGF) expression in rat
      brain after reversible global cerebral ischemia produced by cardiac arrest and
      resuscitation. Three alternative splicing forms, VEGF(188), VEGF(164) and
      VEGF(120), were observed in cortex, hippocampus and brainstem by RT-PCR analysis.
      After 24 h of recovery from cardiac arrest, mRNA levels corresponding to
      VEGF(188) and VEGF(164) were significantly increased by about double in all the
      regions analyzed. These mRNA levels remained elevated at 24 and 48 h of recovery
      but returned to basal expression after 7 days of recovery. Changes in VEGF(120)
      expression after cardiac arrest did not reach statistical significance. VEGF
      protein expression measured by Western blot was also increased by about double at
      24 and 48 h of recovery but returned to control levels after 7 days of recovery.
      VEGF immunohistochemistry localized this increased expression mostly associated
      with astrocytes. Considering its biological activity, VEGF induction after
      cardiac arrest and resuscitation may be responsible for the increased vascular
      permeability and the resultant vasogenic edema, found 24-48 h after reversible
      global ischemia.

PMID- 10640679
TI  - Isolation of sex-specific cDNAs from fetal mouse brain using mRNA differential
      display and representational difference analysis.
AB  - Comparing female and male brain structures reveals a variety of sex differences
      in many vertebrates. These differences are manifested throughout the brain, in
      regions such as the hypothalamus, the preoptic area and the amygdala. Some are
      thought to be induced during the fetal period by the effect of steroid hormones
      produced in the gonads. It is well-established that fetal androgens, probably
      through the conversion to estrogen by the enzyme aromatase, masculinize the
      nervous system and set adult mounting behavior in rodents. However, less is known
      about molecular mechanisms involved in gender-specific development of the brain.
      We have taken a broad approach to isolate sex-specific genes from fetal brain.
      mRNAs from 18.5 days post-coitum (dpc) female and male mouse brain were screened
      with the classical and the recently developed signal peptide differential display
      (SPDD) and with representational difference analysis of cDNA (cDNA-RDA). Two sex
      specific cDNAs were isolated, F29 and M17, corresponding to the female-specific
      Xist gene and the male-specific Smcy gene, respectively.

PMID- 10640680
TI  - The nicotinic acetylcholine receptor agonist (+/-)-epibatidine increases FGF-2
      mRNA and protein levels in the rat brain.
AB  - In a previous work, we showed that acute intermittent nicotine treatment up
      regulates the level of fibroblast growth factor-2 (FGF-2) mRNA in brain regions
      of tel- and mesencephalon of rats suggesting that neuroprotective effect of (
      )nicotine may, at least in part, involve an activation of the neuronal FGF-2
      signalling. The present experiments were designed to extend the study on the
      nicotinic receptor mediated up-regulation of FGF-2 mRNA levels to the use of the
      potent nicotinic acetylcholine receptor (nAChR) agonist (+/-)-epibatidine. The
      (+/-)-epibatidine treatment led to a strong and long lasting up-regulation of FGF
      2 mRNA expression in the cerebral cortex, in the hippocampal formation, in the
      striatum and in the substantia nigra. This FGF-2 mRNA induction, already
      statistically significant at 4 h, peaked at 12 h from treatment and was only
      partially returned towards normal levels at 48 h, the last time point examined.
      Using Western blot analysis it was found that the epibatidine-induced
      upregulation of FGF-mRNA is accompaned by an increase of FGF-2 protein level at
      the 20-h time-interval. These (+/-)-epibatidine effects on FGF-2 expression were
      antagonized by the non-competitive nAChR antagonist mecamylamine, indicating an
      involvement of nicotinic receptors. In the same brain areas examined, no changes
      were observed in the fibroblast growth factor receptor-1 (FGFR-1) mRNA levels, in
      brain-derived neurotrophic factor (BDNF) and in glial cell line-derived
      neurotrophic factor (GDNF) mRNA levels. In view of the neurotrophic function of
      FGF-2, these results, together with previous ones, could further help to
      understand the molecular mechanisms mediating the previously observed
      neuroprotective effects of (-)nicotine.

PMID- 10640681
TI  - Water deprivation upregulates the three calmodulin genes in exclusively the
      supraoptic nucleus of the rat brain.
AB  - Calmodulin (CaM), the ubiquitous intracellular calcium-binding protein, is coded
      by three bona fide CaM genes (CaM I, CaM II and CaM III) in mammals. They code
      for the same protein and are transcribed at particularly high levels in the
      brain, where CaM plays an essential role in basic neuronal functions. In this
      study, the expression of the three CaM genes in response to osmotic stimuli by
      water deprivation was investigated in the rat brain, with particular interest as
      concerns the hypothalamic magnocellular nuclei. CaM mRNA levels were determined
      by quantitative in situ hybridization autoradiography with gene-specific
      [35S]cRNA probes. In response to osmotic challenge, it was found that
      upregulation of the three CaM genes participates in the activation of the
      hypothalamo-hypophyseal system in the supraoptic nucleus (SON) (126% to 169%),
      but not in the magnocellular part of the paraventricular hypothalamic nucleus
      (PVN) (-10%). CaM mRNA levels decreased by 10%-15% in the suprachiasmatic nucleus
      (SCh) and many other extrahypothalamic brain areas. The opposite responses of the
      CaM gene expression in the SON and the magnocellular part of the PVN suggest a
      functional difference between them. Moreover, the significantly different
      magnitudes of the changes in the CaM mRNA levels in the SON nucleus (138%, 126%
      and 169% for CaM I, CaM II and CaM III, respectively) exemplify the precise
      differential control of the CaM gene expression in the brain.

PMID- 10640683
TI  - Interaction of PKN with a neuron-specific basic helix-loop-helix transcription
      factor, NDRF/NeuroD2.
AB  - By the yeast two-hybrid screening of a human brain cDNA library with the amino
      terminal regulatory region of PKN as a bait, a clone encoding a neuron-specific
      basic Helix-Loop-Helix (bHLH) transcription factor, NDRF/NeuroD2 was isolated.
      NDRF/NeuroD2 was co-precipitated with PKN from the lysate of COS-7 cells
      transfected with both expression constructs for NDRF/NeuroD2 and PKN. In vitro
      binding studies using the deletion mutants of NDRF/NeuroD2 synthesized in a
      rabbit reticulocyte lysate indicated that the internal region containing the bHLH
      domain of NDRF/NeuroD2 was necessary and sufficient for the interaction with PKN.
      In addition, recombinant NDRF/NeuroD2 purified from Escherichia coli could bind
      PKN, suggesting the direct interaction between NDRF/NeuroD2 and PKN. Transient
      transfection assays using P19 cells revealed that expression of NDRF/NeuroD2
      increased the transactivation of the rat insulin promoter element 3 (RIPE3)
      enhancer up to approximately 12-fold and that co-expression of catalytically
      active form of PKN, but not kinase-deficient derivative, resulted in a further
      threefold increase of NDRF/NeuroD2-mediated transcription. These findings suggest
      that PKN may contribute to transcriptional responses through the post
      translational modification of the NDRF/NeuroD2-dependent transcriptional
      machinery.

PMID- 10640682
TI  - Regulation of NGFI-A (Egr-1) gene expression by the POU domain transcription
      factor Brn-3a.
AB  - NGFI-A is an immediate early gene (IEG) that is transcriptionally induced by
      nerve growth factor (NGF) in PC12 cells and has been implicated in a number of
      cellular responses. Studies have shown that elements within the first 106 base
      pairs of the NGFI-A promoter contribute to its induction by NGF in PC12 cells.
      One element, within the serum response element (SRE) bridge region, bears strong
      homology to a motif previously identified in promoters regulated by the Brn-3a
      POU domain transcription factor. We report here that Brn-3a activates the NGFI-A
      promoter in neurons (both primary and cell lines). Analysis revealed that this
      response requires sequences between positions -49 and -106. Whilst DNA-protein
      interaction studies failed to identify a site bound directly by Brn-3a, the data
      presented here suggest that Brn-3a may cooperate in the regulation of NGFI-A gene
      expression in neurons, possibly during the developmental switch between
      neurotrophin dependency that occurs during neurogenesis.

PMID- 10640684
TI  - Hypothermia abolishes hypoxia-induced hyperpermeability in brain microvessel
      endothelial cells.
AB  - The effect of mild (32 degrees C) and deep (22 degrees C) hypothermia on hypoxia
      induced hyperpermeability was examined using an in vitro model of brain derived
      microvascular endothelial cells (BMEC). It was shown that hypoxia-induced
      hyperpermeability to inulin across the BMEC monolayer was completely abolished at
      32 degrees C and 22 degrees C for up to 24 h of hypoxia. During normoxia, no
      influence of hypothermia on BMEC monolayer permeability was observed. The hypoxia
      induced decrease of the cyclic AMP level after 6 h was abolished at 32 degrees C
      as well as at 22 degrees C of hypoxia. But after 24 h of hypoxia, hypothermia did
      no longer prevent the hypoxia-induced decrease of the cAMP level, which suggests
      that the effect of hypothermia on hypoxia-induced hyperpermeability is not caused
      by maintenance of the cAMP level. Because vascular endothelial growth factor
      (VEGF) has been shown to be the mediator of hypoxia-induced permeability changes
      of BMEC via the release of nitric oxide (NO), the effect of hypothermia on the
      VEGF expression was evaluated. During normoxia, hypothermia did not change the
      VEGF expression significantly but the hypoxia-induced increase in VEGF mRNA and
      protein expression was completely abolished at 32 degrees C and 22 degrees C
      respectively. Accordingly, the hypoxia-induced increase of the cGMP level was
      depressed by hypothermia, which demonstrates that also the amount of NO released
      during hypoxia is decreased at lower temperatures. Results suggest that deep as
      well as mild hypothermia decreased hypoxia-induced hyperpermeability by lowering
      the expression of the permeability-increasing protein VEGF and with it the
      release of NO.

PMID- 10640685
TI  - In situ hybridization analysis of flip/flop splice variants of AMPA-type
      glutamate receptor subunits in the rat parabrachial and Kolliker-Fuse nuclei.
AB  - The aim of the present study was to analyze the occurrence and distribution of
      flip/flop splice variants of AMPA-type glutamate receptors (GluRA-D) in the rat
      parabrachial and Kolliker-Fuse nuclei (PB/KF). We performed in situ hybridization
      experiments on sections through different rostro-caudal levels of the PB/KF and
      analyzed the subunit expression semiquantitatively by means of grain counts for
      each probe in eight PB nuclei and in the KF. Our experiments revealed that the
      splice variants of the AMPA receptor subunit mRNAs are expressed differentially
      in the distinct nuclei of the PB/KF. The flip splice variants were predominantly
      expressed (GluRB-D flip) while the flop splice variants (GluRA flop and C flop)
      were expressed considerably weaker. Within the PB/KF, several nuclei expressed
      transcripts of GluRB flip (superior, central, dorsal, external, and ventral
      lateral PB, waist area, medial PB, KF) and GluRC flip (internal, superior,
      central, dorsal, external, and ventral lateral PB, waist area, KF). GluRB
      transcripts were not found in neurons of the internal lateral PB and in only 50%
      of the neurons in the KF. A more restricted expression in the PB/KF was observed
      for the GluRD flip (internal lateral PB), GluRA flop (medial PB, KF) and GluRC
      flop mRNA (superior lateral PB, KF). The present data demonstrate that the nuclei
      of the PB/KF show a differential expression of AMPA receptor subunits. This
      suggests that the anatomically and functionally distinct nuclei might make use of
      AMPA-type glutamate receptors with different physiological properties and ion
      selectivities.

PMID- 10640686
TI  - The flinders sensitive line rats, a genetic model of depression, show abnormal
      serotonin receptor mRNA expression in the brain that is reversed by 17beta
      estradiol.
AB  - The possible link between estrogen and serotonin (5-HT) in depression was
      investigated using a genetic animal model of depression, the Flinders Sensitive
      Line (FSL) rats, in comparison to control Flinders Resistant Line rats. The mRNA
      levels of the estrogen receptor (ER) alpha and beta subtypes and the 5-HT(1A) and
      5-HT(2A) receptors were analyzed in several limbic-related areas of
      ovariectomized FSL and FRL rats treated with 17beta-estradiol (0.15 microg/g) or
      vehicle. The FSL animals were shown to express significantly lower levels of the
      5-HT(2A) receptor transcripts in the perirhinal cortex, piriform cortex, and
      medial anterodorsal amygdala and higher levels in the CA 2-3 region of the
      hippocampus. The only significant difference between the rat lines in ER mRNA
      expression was found in the medial posterodorsal amygdala, where the FSL rats
      showed lower ERalpha expression levels. Overall, estradiol treatment increased 5
      HT(2A) and decreased 5-HT(1A) receptor mRNA levels in several of the examined
      regions of both lines. Thus, in many areas, estradiol was found to regulate the 5
      HT receptor mRNA expression in the opposite direction to the alterations found in
      the FSL rats. These findings further support the implication of 5-HT receptors,
      in particular the 5-HT(2A) subtype, in the etiology of affective disorders.
      Moreover, the ability of estradiol to regulate the expression of the 5-HT(1A) and
      5-HT(2A) receptor genes might account for the reported influence of gonadal
      hormones in mood and depression.

PMID- 10640687
TI  - Characterization of the 5'-flanking region of the human dopamine transporter
      gene.
AB  - The dopamine transporter (DAT) plays a major role in modulating dopamine (DA)
      neurotransmission by controlling the levels of this neurotransmitter in the
      extracellular space. We have isolated 8.3 kb of the 5'-flanking regulatory region
      of the human DAT (hDAT) gene and identified numerous potential elements involved
      in transcriptional control of the DAT. A series of hDAT-luciferase reporter
      constructs encompassing increasing amounts of 5'-flanking sequence was utilized
      in transient transfection assays assessing basal activity and response to
      selected stimuli. Our results suggest that the proximal hDAT 5'-flanking region
      displays a strong, nonselective promoter activity that is silenced through
      regulatory elements present in the distal portion of the 5'-flanking sequence.
      Although potential cyclic AMP responsive elements (CRE) were identified on the
      sequence, hDAT constructs were unresponsive to cyclic AMP induction. The
      transcription factor nurr1 increases the transcriptional activity of several
      larger hDAT constructs, consistent with the presence of several putative NGFI-B
      response elements (NBRE). The cloning and functional analysis of an extensive
      portion of the 5'-flanking regulatory region of the hDAT gene provides further
      insights into the factors involved in the regulation of this gene.

PMID- 10640688
TI  - Discovery of a putative heme-binding protein family (SOUL/HBP) by two-tissue
      suppression subtractive hybridization and database searches.
AB  - In the domestic chicken, Gallus gallus, the retina and pineal gland contain
      circadian clocks that are directly entrained by environmental light-dark cycles.
      To identify novel genes that are expressed in the retina and pineal gland, we
      performed two-tissue suppression subtractive hybridization (SSH). Two-tissue SSH
      is designed to identify genes expressed in common between two RNA samples while
      at the same time subtracting out abundant transcripts. Using this method, we
      identified a novel chicken gene, named ckSoul, that is strongly expressed in the
      retina and pineal gland. The protein product of ckSoul is similar to a novel heme
      binding protein (p22 HBP) and to an uncharacterized mammalian gene in the
      expressed sequence tag (EST) database. The mouse transcript of this new gene is
      expressed in the retina and may represent the mammalian ortholog of ckSoul.
      Molecular analysis of the mammalian and chicken proteins suggests SOUL and HBP
      are members of a new family of heme-binding proteins.

PMID- 10640690
TI  - Postprandial, seasonal and sexual variations in cholecystokinin gene expression
      in goldfish brain.
AB  - Recently, we described the complete nucleotide sequence of cholecystokinin (CCK)
      mRNA and the deduced amino acid sequence of the precursor on the basis of
      molecular cloning and sequence analysis of cDNA from goldfish brain. In this
      study, we investigated the hypothesis that CCK has a role in feeding behavior by
      examining CCK gene expression in the brain of goldfish using Northern blot. We
      showed that CCK gene is widely but differentially expressed in broad areas of the
      goldfish brain, including the olfactory bulbs, telencephalon and preoptic region,
      hypothalamus, optic tectum-thalamus and posterior brain regions, with highest
      levels in hypothalamus. We found that CCK mRNA levels in goldfish olfactory
      bulbs, telencephalon-preoptic region, optic tectum-thalamus, and posterior brain
      were influenced by sex at least sometime of the seasonal gonadal cycle, with
      female fish having higher levels than males during at least one of the four
      seasonal sampling times. We also observed a transient and acute increase in the
      CCK mRNA levels in the olfactory bulbs, telencephalon-preoptic region,
      hypothalamus, and posterior brain at 120 min after a meal. These widespread
      postprandial changes in CCK gene expression in goldfish brain indicate that CCK
      peptides have multiple roles in regulation of feeding behavior in goldfish. This
      supports the idea that CCK plays a role as a satiety factor in goldfish.

PMID- 10640689
TI  - Sphingosine 1-phosphate induces expression of early growth response-1 and
      fibroblast growth factor-2 through mechanism involving extracellular signal
      regulated kinase in astroglial cells.
AB  - In rat type I astrocytes and C6 glioma cells, sphingosine 1-phosphate (S1P)
      clearly induced the expression of fibroblast growth factor-2 (FGF-2) mRNA to an
      extent comparable to that achieved by platelet-derived growth factor (PDGF) and
      endothelin. In C6 cells, Western blotting showed that S1P also induced expression
      of early growth response-1 (Egr-1), one of the immediate early gene products and
      an essential transcriptional factor for FGF-2 expression. On the other hand,
      sphingosine, a substrate for sphingosine kinase which forms intracellular S1P,
      was a very weak activator for the expression of either FGF-2 or Egr-1. The S1P
      induced Egr-1 expression was partially inhibited by treatment of the cells with
      either calphostin C, an inhibitor of protein kinase C (PKC), or pertussis toxin
      (PTX), and completely inhibited by the combination of these agents. Essentially,
      the same inhibitory pattern by these agents has been observed for S1P-induced
      extracellular signal-regulated kinase (ERK) activation. The S1P-induced
      expression of Egr-1 was also completely inhibited in association with complete
      inhibition of ERK by PD 98059, an ERK kinase inhibitor. Thus, the S1P-induced
      activation of the Egr-1/FGF-2 system may be mediated through ERK activation,
      which may involve at least two signaling pathways, i.e., a PTX-sensitive G
      protein-dependent pathway and a PKC-dependent pathway.

PMID- 10640691
TI  - Transgenic expression of B-50/GAP-43 in mature olfactory neurons triggers
      downregulation of native B-50/GAP-43 expression in immature olfactory neurons.
AB  - The adult mammalian olfactory neuroepithelium is an unusual neural tissue, since
      it maintains its capacity to form new neurons throughout life. Newly formed
      neurons differentiate in the basal layers of the olfactory neuroepithelium and
      express B-50/GAP-43, a protein implicated in neurite outgrowth. During maturation
      these neurons migrate into the upper portion of the epithelium, upregulate
      expression of olfactory marker protein (OMP) and concomitantly downregulate the
      expression of B-50/GAP-43. Transgenic mice that exhibit OMP-promoter directed
      expression of B-50/GAP-43 in mature olfactory neurons display an unexpected
      decrease in the complement of B-50/GAP-43-positive cells in the lower region of
      the olfactory epithelium [A.J.G.D. Holtmaat, P.A. Dijkhuizen, A.B. Oestreicher,
      H. J. Romijn, N.M.T. Van der Lugt, A. Berns, F.L. Margolis, W.H. Gispen, J.
      Verhaagen, Directed expression of the growth-associated protein B-50/GAP-43 to
      olfactory neurons in transgenic mice results in changes in axon morphology and
      extraglomerular growth, J. Neurosci. 15 (1995) 7953-7965]. We have investigated
      whether the decrement in B-50/GAP-43-positive cells in this region was due to a
      dislocation of the immature neurons to other regions of the olfactory epithelium
      or to a downregulation of B-50/GAP-43 synthesis in these immature neurons. In
      eight of nine independent transgenic mouse lines that express the transgene in
      different numbers of olfactory neurons, a decline in the number of B-50/GAP-43
      expressing neurons in the basal portion of the olfactory neuroepithelium was
      observed, both at the protein level and the mRNA level. An alternative marker for
      immature cells, a juvenile form of tubulin, was normally expressed in this
      location, indicating that the olfactory epithelium of OMP-B-50/GAP-43 transgenic
      mice contains a normal complement of immature olfactory neurons and that most of
      these neurons display a downregulation of B-50/GAP-43 expression.

PMID- 10640692
TI  - AP-2beta represses D(1A) dopamine receptor gene transcription in neuro2a cells.
AB  - Expression of the D(1A) dopamine receptor in brain is restricted to specific
      neuronal populations. To investigate the mechanism of this selective expression,
      we localized a silencer upstream of the human D(1A) gene and identified its
      binding transcription factor in the D(1A)-negative neural cell line Neuro2a.
      Using deletion CAT analysis, we narrowed this silencer to the region between
      nucleotides -561 and -532 relative to the CAP site. This 30-bp region, designated
      D1AS1, contains a sequence homologous to the AP-2 binding site and binds to a
      factor that also interacts with the AP-2 consensus sequence. In gel supershift
      assays, this factor is recognized by anti-AP-2beta antibody. Co-transfection of
      Neuro2a cells with an AP-2beta expression vector repressed the basal CAT activity
      of D(1A) promoter-reporter plasmids in a D1AS1-dependent manner. RT-PCR analysis
      indicated that, among AP-2 family members, Neuro2a cells express only AP-2beta.
      Furthermore, co-transfection of these cells with decoy oligonucleotides
      corresponding to the D1AS1 sequence de-repressed the D(1A) gene promoter. Unlike
      in Neuro2a cells, AP-2beta could not repress the D(1A) promoter in the D(1A)
      positive neural cell line, NS20Y. In addition, the expression of AP-2beta in
      different brain regions does not inversely correlate with that of D(1A) dopamine
      receptor. These observations taken together indicate that AP-2beta is a
      repressive transcription factor that acts on the D1AS1 silencer of the D(1A)
      dopamine receptor gene via some cell-specific mechanism(s) in Neuro2a.

PMID- 10640693
TI  - Gene expression of peroxisomal beta-oxidation enzymes in rat brain.
AB  - Despite increasing insight into peroxisomal beta-oxidation, it is still not clear
      which enzymes catalyze very-long-chain fatty acid degradation. Using the northern
      blot and RT-PCR techniques, a brain-specific expression is demonstrated for acyl
      CoA oxidase 3II mRNA, thiolase-A and trans2,3enoyl-CoA hydratase/3-hydroxyacyl
      CoA dehydrogenase multifunctional enzyme type 2.

PMID- 10640694
TI  - Immunocytochemical localization of serotonin and serotonin transporter (SET) in
      taste buds of rat.
AB  - We used an immunocytochemical approach to study the localization of serotonin and
      its termination system, serotonin transporter (SET), in the taste buds of rats
      using specific antibodies against serotonin and SET. Under confocal laser
      scanning microscopy, both serotonin and SET immunoreactivity were detected in the
      taste buds of rat vallate papillae. Serotonin immunoreactivity was seen in the
      spindle-shaped cells with apical processes that seemed to be light (Type II)
      taste cells. SET-immunoreactivity was mainly localized in the periphery or
      interfaces between the taste cells. Double staining studies revealed that all
      serotonin-containing taste cells were immunoreactive for SET, while a subclass of
      SET-positive cells showed serotonin immunoreactivity. These data support the
      hypothesis that serotonin plays a transmitter role in taste receptor cells and
      suggest that the serotonin-induced sensation of taste is terminated by serotonin
      uptake through serotonin transporter.

PMID- 10640695
TI  - Distribution of the receptor EphA7 and its ligands in development of the mouse
      nervous system.
AB  - EphA7 is a receptor tyrosine kinase of the Eph family. We have mapped EphA7
      immunoreactivity and ligand binding in mouse embryo heads and developing brain.
      Immunoreactivity for the full-length receptor is found in all the cell
      populations that express EphA7 mRNA. In particular, it is located on growing
      axons from EphA7-expressing neurons, both in the trigeminal nerve and in
      developing brain. In many cases it persists in terminal fields in adult brain.
      Ligand is detected in a largely complementary distribution in embryos, but is
      surprisingly weak or undetectable in the target regions of many EphA7-positive
      axons postnatally.

PMID- 10640696
TI  - Segregation of the receptor EphA7 from its tyrosine kinase-negative isoform on
      neurons in adult mouse brain.
AB  - The EphA7 gene encodes not only a typical receptor tyrosine kinase (TK+) but also
      an isoform lacking the tyrosine kinase domain (TK-). We have made antibodies to
      localise EphA7 TK+ and TK- isoforms in mouse brain. The TK- isoform was not
      detectable prenatally, despite reported expression of the TK- mRNA in the embryo.
      However, both TK+ and TK- isoforms showed striking distributions in adult brain.
      TK+ receptor immunoreactivity was strong in neuropil throughout most of the
      telencephalon, probably on fine arborisations from neurons which expressed EphA7
      during development (in cerebral cortex, hippocampus, and striatum). In contrast,
      TK- receptor immunoreactivity was conspicuous on cell bodies and proximal
      dendrites of a limited number of neuronal types, some of which carried EphA7 TK+
      receptor on their axons. This suggests that the TK- receptor, acting as a
      dominant negative antagonist, may ensure that the TK+ receptor only responds to
      signals encountered by the growing extremities of axons or dendrites.

PMID- 10640697
TI  - Acute ibogaine injection induces expression of the immediate early genes, egr-1
      and c-fos, in mouse brain.
AB  - The aim of the present study was to evaluate if an acute injection of ibogaine
      (IBO) induces immediate early gene expression in different regions of mouse
      brain. Adult male C57 mice received a single injection of IBO and were perfused
      transcardially with 1% paraformaldehyde 30 min after the drug administration. A
      single injection of IBO produced a significant increase of egr-1 messenger RNA
      induction in nucleus accumbens (NAc), caudate-putamen (CPu), frontal cortex
      (FCx), septum, dentate gyrus (DG) and CA3 region of hippocampus, whereas c-fos
      gene was induced in CPu, FCx, DG, septum and CA1 region of hippocampus. This gene
      expression may be due, in part, to the stimulant properties of IBO, as we found
      with other psychostimulants.

PMID- 10640698
TI  - Mytilus edulis pedal ganglia express mu opiate receptor transcripts exhibiting
      high sequence identity with human neuronal mu1.
AB  - Previous pharmacological and biochemical evidence suggests that mu-subtype opiate
      receptors are expressed in the mollusk Mytilus edulis (Bivalve), including the
      organism's ganglia. In this study, we present molecular evidence of mu opiate
      receptor expression. Using primers derived from the human neuronal mu1 opiate
      receptor, we used reverse transcription-polymerase chain reaction (RT-PCR) to
      detect expression of mu transcripts from Mytilus pedal ganglia. Sequence analysis
      of the RT-PCR products revealed 95% identity with the neuronal human mu1
      receptor. Furthermore, interleukin-1 and morphine exposure to excised pedal
      ganglia resulted in up- and down-regulation of the mu receptor transcripts,
      respectively. This study provides molecular evidence that mu-type opiate
      receptors are expressed in molluscan ganglia, suggesting that they first appear
      in invertebrate organisms and are retained during evolution.

PMID- 10640699
TI  - Membrane-anchorage of Cripto protein by glycosylphosphatidylinositol and its
      distribution during early mouse development.
AB  - cripto is the original member of the family of EGF-CFC genes, recently recognized
      as novel extracellular factors essential for vertebrate development. During the
      early stages of mouse gastrulation, cripto mRNA is detected in mesodermal cells;
      later, cripto mRNA is detected only in the truncus arteriosus of the developing
      heart. Here we describe the in vivo distribution of Cripto protein throughout
      mouse embryo development and show that cripto mRNA and protein colocalize. By
      means of immunofluorescence analysis and biochemical characterization, we show
      that Cripto is a membrane-bound protein anchored to the lipid bilayer by a
      glycosylphosphatidylinositol (GPI) moiety. We suggest that presentation of Cripto
      on the cell surface via a GPI-linkage is important in determining the spatial
      specificity of cell-cell interactions that play a critical role in the early
      patterning of the embryo.

PMID- 10640700
TI  - Expression, regulation and function of the homeobox gene empty spiracles in brain
      and ventral nerve cord development of Drosophila.
AB  - We analyse the role of the empty spiracles (ems) gene in embryonic brain and
      ventral nerve cord development. ems is differentially expressed in the
      neurectoderm of the anterior head versus the trunk region of early embryos. A
      distal enhancer region drives expression in the deutocerebral brain anlage and a
      proximal enhancer region drives expression in the VNC and tritocerebral brain
      anlage. Mutant analysis indicates that in the anterior brain ems is necessary for
      regionalized neurogenesis in the deutocerebral and tritocerebral anlagen. In the
      posterior brain and VNC ems is necessary for correct axonal pathfinding of
      specific interneurons. Rescue experiments indicate that the murine Emx2 gene can
      partially replace the fly ems gene in CNS development.

PMID- 10640701
TI  - Two Pax2/5/8-binding sites in Engrailed2 are required for proper initiation of
      endogenous mid-hindbrain expression.
AB  - During early brain development mouse Engrailed2 (En2) is expressed in a broad
      band across most of the mid-hindbrain region. Evidence from gene expression data,
      promoter analysis in transgenic mice and mutant phenotype analysis in mice and
      zebrafish has suggested that Pax2, 5 and 8 play a critical role in regulating En2
      mid-hindbrain expression. Previously, we identified two Pax2/5/8-binding sites in
      a 1.0 kb En2 enhancer fragment that is sufficient to directed reporter gene
      expression to the early mid-hindbrain region and showed that the two Pax2/5/8
      binding sites are essential for the mid-hindbrain expression in transgenic mice.
      In the present study we have examined the functional requirements of these two
      Pax2/5/8-binding sites in the context of the endogenous En2 gene for directing
      mid-hindbrain expression. The two Pax2/5/8-binding sites were deleted from the
      En2 locus and replaced with the bacterial neo gene by homologous recombination in
      mouse embryonic stem cells. After transmitting the mutation into mice, the neo
      gene was removed by breeding with transgenic mice expressing cre from a CMV
      promoter. Embryos homozygous for this En2 Pax2/5/8-binding site deletion mutation
      had a mild reduction in En2 expression in the presumptive mid-hindbrain region at
      the 5-7 somite stage, when En2 expression is normally initiated. However, from
      embryonic day 9.0 onwards, the mutant embryos showed En2 expression
      indistinguishable from that seen in wild type embryos. Furthermore, the mutants
      did not show the cerebellar defect seen in mice with a null mutation in En2. This
      result demonstrates that the two Pax2/5/8-binding sites that were deleted, while
      being required for mid-hindbrain expression in the context of a 1.0 kb En2
      enhancer, are only required for proper initiation of expression of the endogenous
      En2 gene. Interestingly, a comparison of the lacZ RNA and protein expression
      patterns directed by the 1.0 kb enhancer fragment revealed that lacZ protein was
      acting as a lineage marker in the mid-hindbrain region by persisting longer than
      the mRNA. The transgene expression directed by the 1.0 kb enhancer fragment
      therefore does not mimic the entire broad domain of En2 expression. Taken
      together, these two studies demonstrate that DNA binding sites in addition to the
      two Pax2/5/8-binding sites must be necessary for En2 mid-hindbrain expression.

PMID- 10640702
TI  - Pattern formation and regulation of gene expressions in chick recombinant limbs.
AB  - Recombinant limbs were performed by ensembling dissociated-reaggregated wing bud
      mesoderm inside an ectodermal hull. The zone of polarizing activity was excluded
      from the mesoderm used to perform the recombinant limbs (non-polarized
      recombinants), and grafted when desired (polarized recombinants). Reorganization
      of patterning progressively occurred in the newly formed progress zone under the
      influence of the apical ectodermal ridge (AER), explaining the proximo-distal
      gradient of morphogenesis observed in developed recombinant limbs. The AER,
      without the influence of the polarizing region (ZPA), was sufficient to direct
      outgrowth and appropriate proximo-distal patterning, as observed in the
      expression of the Hoxa-11 and Hoxa-13 genes. The development of the recombinant
      limbs coursed with symmetric AER and downregulation of Bmp expression in the
      mesoderm supporting a negative effect of Bmp signaling upon the apical ridge. The
      recombinant ectoderm maintained previously established compartments of gene
      expressions and organized a correct dorso-ventral patterning in the recombinant
      progress zone. Finally, the ZPA effect was only detected on Bmp expression and
      pattern formation along the antero-posterior axis.

PMID- 10640703
TI  - Requirement for anti-dorsalizing morphogenetic protein in organizer patterning.
AB  - The amphibian Spemann organizer is subdivided in trunk and head organizer and it
      is unclear how this division is regulated. The Xenopus trunk organizer expresses
      anti-dorsalizing morphogenetic protein (ADMP), a potent organizer antagonist. We
      show that ADMP represses head formation during gastrulation and that its
      expression is activated by BMP antagonists. A specifically acting dominant
      negative ADMP anteriorizes embryos and its coexpression with BMP antagonists
      induces secondary embryonic axes with heads as well as expression of head
      inducers. Unlike other BMPs, ADMP is not inhibited by a dominant-negative BMP
      type I receptor, Noggin, Cerberus and Chordin but by Follistatin, suggesting that
      it utilizes a distinct TGF-beta receptor pathway and displays differential
      sensitivity to BMP antagonists. The results indicate that ADMP functions in the
      trunk organizer to antagonize head formation, thereby regulating organizer
      patterning.

PMID- 10640704
TI  - In vivo functional analysis of the daughter of sevenless protein in receptor
      tyrosine kinase signaling.
AB  - One mechanism used by receptor tyrosine kinases to relay a signal to different
      downstream effector molecules is to use adaptor proteins that provide docking
      sites for a variety of proteins. The daughter of sevenless (dos) gene was
      isolated in a genetic screen for components acting downstream of the Sevenless
      (Sev) receptor tyrosine kinase. Dos contains a N-terminally located PH domain and
      several tyrosine residues within consensus binding sites for a number of SH2
      domain containing proteins. The structural features of Dos and experiments
      demonstrating tyrosine phosphorylation of Dos upon Sev activation suggested that
      Dos belongs to the family of multisite adaptor proteins that include the Insulin
      Receptor Substrate (IRS) proteins, Gab1, and Gab2. Here, we studied the
      structural requirements for Dos function in receptor tyrosine kinase mediated
      signaling processes by expressing mutated dos transgenes in the fly. We show that
      mutant Dos proteins lacking the putative binding sites for the SH2 domains of
      Shc, PhospholipaseC-gamma (PLC-gamma) and the regulatory subunit of
      Phosphoinositide 3-kinase (PI3-K) can substitute the loss of endogenous Dos
      function during development. In contrast, tyrosine 801, corresponding to a
      predicted Corkscrew (Csw) tyrosine phosphatase SH2 domain binding site, is
      essential for Dos function. Furthermore, we assayed whether the Pleckstrin
      homology (PH) domain is required for Dos function and localization. Evidence is
      provided that deletion or mutation of the PH domain interferes with the function
      but not with localization of the Dos protein. The Dos PH domain can be replaced
      by the Gab1 PH domain but not by a heterologous membrane anchor, suggesting a
      specific function of the PH domain in regulating signal transduction.

PMID- 10640705
TI  - Embryonic inheritance of the chromatin organisation of the imprinted H19 domain
      in mouse spermatozoa.
AB  - Insulin-like growth factor 2 (Igf 2) and H19 genes are oppositely imprinted and
      as such have been most extensively studied imprinted genes both genetically and
      at the molecular level. Imprints of the H19 gene, being established during
      spermatogenesis, are epigenetically transmitted to the somatic cells of the
      embryo. Current hypotheses attempting to explain the allele-specific silence of
      the H19 gene include DNA methylation and chromatin condensation. In order to
      understand the molecular basis of H19 epigenesis, it is crucial to identify the
      markings in the chromatin organising the imprinted domain in spermatozoa. Using
      Micrococcal nuclease (MNase), DNase I and Methidiumpropyl-EDTA. iron II
      (MPE.Fe(II)) as chromatin probes, we demonstrate that in mouse epididymal
      spermatozoa, at least 4kb DNA upstream of the H19 'cap' site, containing the
      imprinted and differentially methylated domain (DMD), is heterochromatic. The
      cleavage sites in this domain (-2 to -4kb) exhibit approximately 425bp
      periodicity. This structure is maintained in the paternal allele of normal
      embryos and is disrupted at -2.2, -2.65 and at -3.5kb in embryos maternally
      disomic for the distal end of chromosome 7 (MatDp 7). The hypersensitive sites in
      chromatin precisely register the MPE.Fe(II) cleavage sites in chromosomal DNA.
      Therefore, the DNA sequences in the imprinted domain constrain the chromatin
      structure in a way similar to that of 1.688g/cm(3) Drosophila satellite
      chromatin. In addition, we find that condensation of the paternal allele
      correlates with methylation-dependent alteration in the structure of DNA
      sequences in DMD. These results suggest that CpG-methylation induces localised
      changes in DNA conformation and these facilitate consequent remodelling of
      chromatin thereby allowing the paternal and maternal H19 alleles to be
      distinguished.

PMID- 10640706
TI  - A post-mid-blastula transition requirement for TGFbeta signaling in early
      endodermal specification.
AB  - In Xenopus, endodermal cell fate is determined gradually from late blastula to
      early gastrula stages; cell-cell interaction plays an important role in this
      process. Here we use a cell dissociation assay to show that extracellular
      signaling is required continuously before endoderm determination. Activin and
      Vg1, but not BMP2 or basic FGF, rescue the expression of endodermal markers in
      dissociated cells when provided at the mid-blastula transition (MBT, the time in
      which zygotic transcription begins). Removal of exogenously added activin or Vg1
      before MBT results in reduction of endodermal gene expression in dissociated
      vegetal cells. In vivo, endogenous endodermal markers are reduced in vegetal
      explants when activin-like signaling is blocked with dominant negative receptors.
      VegT, a maternal transcription factor shown to be critical for endoderm
      specification, relies on an active TGFbeta pathway to induce endoderm in animal
      caps. These results indicate that TGFbeta signaling may be activated by the
      maternally expressed VegT to participate in endoderm determination. In addition,
      VegT function seems to be required in parallel with the TGFbeta pathway, as
      overexpression of activin does not relieve endoderm repression by a dominant
      negative VegT mutant in vegetal cells. Our data suggest that maternal VegT first
      activates a zygotic TGFbeta signal, then cooperates with this signal to determine
      the endodermal cell fate.

PMID- 10640709
TI  - Expression pattern of mouse sFRP-1 and mWnt-8 gene during heart morphogenesis.
AB  - The Wnt genes encode a large family of secreted proteins that play a key role in
      embryonic development and tissue differentiation in many species (Rijsewijk et
      al., 1987; Nusse and Varmus, 1992). Genetic and biochemical studies have
      suggested that the frizzled proteins are cell surface receptors for Wnts (Vinson
      et al., 1989; Chan et al. , 1992; Bhanot et al., 1996; Wang et al., 1996). In
      parallel, a number of secreted frizzled-like proteins with a conserved N-terminal
      frizzled motif have been identified (Finch et al., 1997; Melkonyan et al., 1997;
      Rattner et al., 1997). One of these proteins, FrzA, the bovine counterpart of the
      murine sFRP-1 (93% identity) is involved in vascular cell growth control, binds
      Wg in vitro and antagonizes Xwnt-8 and hWnt-2 signaling in Xenopus embryos (Xu et
      al. , 1998; Duplaa et al., 1999). In this study, we report that sFRP-1 is
      expressed in the heart and in the visceral yolk sac during mouse development, and
      that sFRP-1 and mWnt-8 display overlapping expression patterns during heart
      morphogenesis. From 8.5 to 12.5 d.p. c., sFRP-1 is expressed in cardiomyocytes
      together with mWnt-8 but neither in the pericardium nor in the endocardium; at
      17.5 d.p.c., they are no longer present in the heart. In mouse adult tissues,
      while sFRP-1 is highly detected in the aortic endothelium and media and in
      cardiomyocytes, mWnt-8 is not detected in these areas. Immunoprecipitation
      experiments demonstrates that FrzA binds to mWnt-8 in cell culture experiments.

PMID- 10640707
TI  - Insights into early vasculogenesis revealed by expression of the ETS-domain
      transcription factor Fli-1 in wild-type and mutant zebrafish embryos.
AB  - Fli-1 is an ETS-domain transcription factor whose locus is disrupted in Ewing's
      Sarcoma and F-MuLV induced erythroleukaemia. To gain a better understanding of
      its normal function, we have isolated the zebrafish homologue. Similarities with
      other vertebrates, in the amino acid sequence and DNA binding properties of Fli-1
      from zebrafish, suggest that its function has been conserved during vertebrate
      evolution. The initial expression of zebrafish fli-1 in the posterior lateral
      mesoderm overlaps with that of gata2 in a potential haemangioblast population
      which likely contains precursors of blood and endothelium. Subsequently, fli-1
      and gata2 expression patterns diverge, with separate fli-1 and gata2 expression
      domains arising in the developing vasculature and in sites of blood formation
      respectively. Elsewhere in the embryo, fli-1 is expressed in sites of
      vasculogenesis. The expression of fli-1 was investigated in a number of zebrafish
      mutants, which affect the circulatory system. In cloche, endothelium is absent
      and blood is drastically reduced. In contrast to the blood and endothelial
      markers that have been studied previously, fli-1 expression was initiated
      normally in cloche embryos, indicating that induction of fli-1 is one of the
      earliest indicators of haemangioblast formation. Furthermore, although fli-1
      expression in the trunk was not maintained, the normal expression pattern in the
      anterior half of the embryo was retained. These anterior cells did not, however,
      condense to form blood vessels. These data indicate that cloche has previously
      unsuspected roles at multiple stages in the formation of the vasculature.
      Analysis of fli-1 expression in midline patterning mutants floating head and
      squint, confirms a requirement for the notochord in the formation of the dorsal
      aorta. The formation of endothelium in one-eyed pinhead, cyclops and squint
      embryos indicates a novel role for the endoderm in the formation of the axial
      vein. The phenotype of sonic-you mutants implies a likely role for Sonic Hedgehog
      in mediating these processes.

PMID- 10640708
TI  - ARNT2 acts as the dimerization partner of SIM1 for the development of the
      hypothalamus.
AB  - One major function of the hypothalamus is to maintain homeostasis by modulating
      the secretion of pituitary hormones. The paraventricular (PVN) and supraoptic
      (SON) nuclei are major integration centers for the output of the hypothalamus to
      the pituitary. The bHLH-PAS transcription factor SIM1 is crucial for the
      development of several neuroendocrine lineages within the PVN and SON. bHLH-PAS
      proteins require heterodimerization for their function. ARNT, ARNT2, and BMAL1
      are the three known general heterodimerization partners for bHLH-PAS proteins.
      Here, we provide evidence that Sim1 and Arnt2 form dimers in vitro, that they are
      co-expressed in the PVN and SON, and that their loss of function affects the
      development of the same sets of neuroendocrine cell types within the PVN and SON.
      Together, these results implicate ARNT2 as the in vivo dimerization partner of
      SIM1 in controlling the development of these neuroendocrine lineages.

PMID- 10640710
TI  - Tissue distribution of PEBBLE RNA and pebble protein during Drosophila embryonic
      development.
AB  - pebble (pbl) is required for cytokinesis during postblastoderm mitoses (Hime, G.,
      Saint, R., 1992. Zygotic expression of the pebble locus is required for
      cytokinesis during the postblastoderm mitoses of Drosophila. Development 114, 165
      171; Lehner, C.F., 1992. The pebble gene is required for cytokinesis in
      Drosophila. J. Cell Sci. 103, 1021-1030) and encodes a putative guanine
      nucleotide exchange factor (RhoGEF) for Rho1 GTPase (Prokopenko, S.N., Brumby,
      A., O'Keefe, L., Prior, L., He, Y., Saint, R., Bellen, H.J., 1999. A putative
      exchange factor for Rho1 GTPase is required for initiation of cytokinesis in
      Drosophila. Genes Dev. 13, 2301-2314). Mutations in pbl result in the absence of
      a contractile ring leading to a failure of cytokinesis and formation of polyploid
      multinucleate cells. Analysis of the subcellular distribution of PBL demonstrated
      that during mitosis, PBL accumulates at the cleavage furrow at the anaphase to
      telophase transition when assembly of a contractile ring is initiated
      (Prokopenko, S.N., Brumby, A., O'Keefe, L., Prior, L., He, Y., Saint, R., Bellen,
      H.J., 1999. A putative exchange factor for Rho1 GTPase is required for initiation
      of cytokinesis in Drosophila. Genes Dev. 13, 2301-2314). In addition, levels of
      PBL protein cycle during each round of cell division with the highest levels of
      PBL found in telophase and interphase nuclei. Here, we report the expression
      pattern of pbl during embryonic development. We show that PEBBLE RNA and PBL
      protein have a similar tissue distribution and are expressed in a highly dynamic
      pattern throughout embryogenesis. We show that PBL is strongly enriched in
      dividing nuclei in syncytial embryos and in pole cells as well as in nuclei of
      dividing cells in postblastoderm embryos. Our expression data correlate well with
      the phenotypes observed in pole cells and, particularly, with the absence of
      cytokinesis after cellular blastoderm formation in pbl mutants.

PMID- 10640711
TI  - Synthesis of hyaluronan of distinctly different chain length is regulated by
      differential expression of Xhas1 and 2 during early development of Xenopus
      laevis.
AB  - The localization of hyaluronan has been determined in tailbud stage embryos of
      Xenopus laevis using a neurocan-alkaline phosphatase fusion protein. This
      polysaccharide was located between the germ layers and enriched in mesenchyme,
      the lumen of the neural tube, the embryonic gut, the hepatic cavity and the
      heart. A full-length cDNA for a hyaluronan synthase, Xhas2 has been cloned. The
      expression pattern of Xhas1 and 2 is closely similar to the distribution of
      hyaluronan in the embryo. Xhas1 produces hyaluronan with a molecular mass of
      around 40-200 kDa, while the product formed by Xhas2 has a molecular mass above 1
      million Da.

PMID- 10640712
TI  - Cloning and expression of the murine sws/NTE gene.
AB  - The Drosophila neurodegeneration gene swiss-cheese encodes a neuronal protein
      apparently involved in glia-neuron interaction and is homologous to human NTE,
      the molecular target of organophosphate-induced neuropathy. The isolated Msws/NTE
      gene is 96% identical to NTE. During development the Msws transcript is expressed
      in the embryonic respiratory system, different epithelial structures and strongly
      in the spinal ganglia. Postnatally, Msws mRNA is expressed in all brain areas,
      with an increasingly restrictive pattern. In adult mice expression is most
      prominent in Purkinje cells, granule cells and pyramidal neurons of the
      hippocampus and some large neurons in the medulla oblongata, nucleus dentatus and
      pons.

PMID- 10640713
TI  - Subcellular and developmental expression of alternatively spliced forms of
      fibroblast growth factor 14.
AB  - Fibroblast growth factors (FGFs) 11-14 comprise a subfamily of FGFs with poorly
      defined biological function. Here we characterize two isoforms of FGF14 (FGF14-1a
      and FGF14-1b) that result from the alternative usage of two different first
      exons. We demonstrate that these isoforms have differential subcellular
      localization and that they are differentially expressed in various adult tissues.
      Using in situ hybridization we show that Fgf14 is widely expressed in brain,
      spinal cord, major arteries and thymus between 12.5 and 14.5 days of mouse
      embryonic development. We also show that during cerebellar development, Fgf14 is
      first observed at postnatal day 1 in post mitotic granule cells, and later in
      development, in migrating and post migratory granule cells. The developmental
      expression pattern of Fgf14 in the cerebellum is complementary to that of Math1,
      a marker for proliferating granule cells in the external germinal layer.

PMID- 10640714
TI  - Expression and cellular localization of the Toucan protein during Drosophila
      oogenesis.
AB  - The toucan (toc) gene is required in the germline for somatic cell patterning
      during Drosophila oogenesis. To better understand the function of toc, we
      performed a detailed analysis of the distribution of the Toucan protein during
      oogenesis. Toc expression is restricted to the germline cells and shows a dynamic
      distribution pattern throughout follicle development. Mislocalization of the Toc
      protein in mutant follicles in which the microtubule network is altered indicates
      that microtubules play a role in Toc localization during oogenesis.

PMID- 10640715
TI  - Expression of Chx10 and Chx10-1 in the developing chicken retina.
AB  - We have isolated full-length cDNAs of chick Chx10 and Chx10-1, two members of the
      paired type homeobox/CVC gene family. A comparison of sequences suggests that
      Chx10 is closely related to Alx/Vsx-2 and Vsx-2 of zebrafish and goldfish,
      respectively; while Chx10-1 is closely related to Vsx-1 of zebrafish and
      goldfish. Chx10 and Chx10-1 are expressed in the early retinal neuroepithelium,
      but not in the pigment epithelium and lens. The expression of Chx10 is present in
      most retinal neuroblasts, while Chx10-1 exhibits a novel pattern along the
      nasotemporal border. In the differentiating retina, both Chx10 and Chx10-1 are
      restricted to bipolar cells and are maintained at a low level in bipolar cells of
      the mature retina.

PMID- 10640716
TI  - Developmental regulation of Tbx5 in zebrafish embryogenesis.
AB  - T-box (tbx) genes constitute a large family of transcriptional regulators
      involved in developmental patterning processes. In tetrapods, tbx5 has been
      implicated in specifying forelimb type identity. Here, we report the cloning of
      the zebrafish tbx5.1 gene and characterise its expression during zebrafish
      embryogenesis and early larval development of wild type and mutant embryos that
      affect pectoral fin patterning. tbx5.1 is expressed during development of the
      heart, the pectoral fins and the eye. Notably, its expression in the lateral
      plate mesoderm defines a single and continuous region of heart and pectoral fin
      precursor cells, and constitutes the earliest specific marker for pectoral fin
      development in the zebrafish.

PMID- 10640717
TI  - Restricted expression and subnuclear localization of the Drosophila gene Dnop5, a
      member of the Nop/Sik family of the conserved rRNA processing factors.
AB  - Members of the conserved nop5/sik1 gene family encode components of small
      nucleolar ribonucleoprotein (snoRNP) complexes, which have an essential function
      in rRNA-processing. We describe a novel Drosophila member of this family, termed
      Dnop5. The gene is expressed in nurse cells during oogenesis and transcripts are
      deposited into the growing oocyte. Maternal transcripts become evenly distributed
      in the egg and remain in a ubiquitous pattern during early embryogenesis. Zygotic
      Dnop5 expression is initiated during the extended germband stage. Transcripts
      accumulate in mesoderm and midgut primordia, and in the developing imaginal discs
      of the larvae. Consistent with a function in rRNA processing, Dnop5 protein
      (DNop5) accumulates in a nuclear substructure, likely to be the nucleolus.
      Maternal protein accumulates in the nucleolus of all cells in the early embryo,
      whereas DNop5 that is derived from zygotic mRNA, is restricted to the nuclei of
      muscles and midgut.

PMID- 10640718
TI  - Localized expression of the Drosophila gene Dxl6, a novel member of the
      serine/arginine rich (SR) family of splicing factors.
AB  - Members of the highly conserved family of serine/arginine rich (SR) splicing
      factors play an essential role in the recognition of the exonic splicing
      enhancers that control the choice of splice sites in primary transcripts. Here,
      we report the cloning and the expression pattern of Dxl6, a novel Drosophila
      member of this protein family. Dxl6 is located on the second chromosome in a
      position next to hrp48 and Dwee1. Its intron contains Dnop5, a small nucleolar
      ribonucleoprotein (snoRNP) which is essential for rRNA-processing. During
      oogenesis, Dxl6 transcripts are expressed in nurse cells. Transcripts are
      transported into the oocyte and maintained in a ubiquitous pattern in the egg and
      early embryo. Zygotic Dxl6 transcripts accumulate in the neuroectodermal region
      of the gastrulating embryo and become highly enriched in the central nervous
      system (CNS) and brain of embryos. During larval stages, Dxl6 transcripts are
      detected in distinct patterns in the developing imaginal discs.

PMID- 10640719
TI  - Developmental expression of the SH3BGR gene, mapping to the Down syndrome heart
      critical region.
AB  - The SH3BGR gene has been recently isolated and mapped to chromosome 21 within the
      Down syndrome (DS) congenital heart disease (CHD) minimal region. As a first step
      to evaluate the possible involvement of SH3BGR in CHD that affect 40% of DS
      patients, we have analyzed by in situ hybridization the expression pattern of the
      mouse homolog gene (Sh3bgr), during development. Our results show that Sh3bgr is
      already expressed at embryonic day 7.75 (E7.75) in the precardiogenic mesoderm
      and that from E8.5 to E10.5 its expression is restricted to the heart. In
      subsequent developmental stages, Sh3bgr transcripts are also detected in skeletal
      muscle and in some visceral smooth muscles including urinary bladder and gut
      wall, but not in vascular smooth muscle. Our results, demonstrating that Sh3bgr
      is expressed in earliest stages of mouse heart development, support a possible
      role of this gene in heart morphogenesis and, consequently, in the pathogenesis
      of CHD in DS.

PMID- 10640720
TI  - Expression of the proteoglycan SPOCK during mouse embryo development.
AB  - SPOCK is a modular proteoglycan, with homology with proteins involved in cell
      adhesion processes and neurogenesis. We have previously shown that SPOCK
      transcripts predominate in the adult mouse brain. Here, we report its expression
      during mouse embryonic development by in situ hybridization, and
      immunocytochemistry. SPOCK is actively expressed at the onset of neurogenesis
      during periods of neuron migration and axonal outgrowth. At a later developmental
      stage, its expression is particularly prevalent within developing synaptic
      fields. In the peripheral nervous system, SPOCK expression is also
      developmentally regulated particularly in dorsal root ganglion neurons.

PMID- 10640721
TI  - The expression pattern of a mouse doublesex-related gene is consistent with a
      role in gonadal differentiation.
AB  - The signal for somatic sex determination in mammals, Caenorhabditis elegans and
      Drosophila melanogaster is chromosomal, but the overall mechanisms do not appear
      to be conserved between the phyla. However it has been found quite recently that
      the C. elegans sex-determining gene Mab-3 contains a domain highly homologous to
      the Drosophila sex-determining gene doublesex (dsx) and shares a similar role.
      These data suggest that at least some aspects of the regulation of sex
      determination might be conserved. In humans, a doublesex-related gene (DMRT1) was
      identified at less than 30 kb from the critical region for sex reversal on
      chromosome 9p24 (TD9). In order to get insights into the role of DMRT1 in sex
      determination/differentiation, we have isolated DMRT1 mouse homologue (Dmrt1) and
      analysed its expression pattern. The gene is expressed in the genital ridges of
      both sexes during the sex-determining switch and it shows male/female dimorphism
      at late stages of sex differentiation.

PMID- 10640722
TI  - Elimination of EVE protein by CALI in the short germ band insect Tribolium
      suggests a conserved pair-rule function for even skipped.
AB  - The question of the degree of evolutionary conservation of the pair-rule
      patterning mechanism known from Drosophila is still contentious. We have employed
      chromophore-assisted laser inactivation (CALI) to inactivate the function of the
      pair-rule gene even skipped (eve) in the short germ embryo of the flour beetle
      Tribolium. We show that it is possible to generate pair-rule type phenocopies
      with defects in alternating segments. Interestingly, we find the defects in odd
      numbered segments and not in even numbered ones as in Drosophila. However, this
      apparent discrepancy can be explained if one takes into account that the primary
      action of eve is at the level of parasegments and that different cuticular
      markers are used for defining the segment borders in the two species. In this
      light, we find that eve appears to be required for the formation of the anterior
      borders of the same odd numbered parasegments in both species. We conclude that
      the primary function of eve as a pair rule gene is conserved between the two
      species.

PMID- 10640723
TI  - Cutting edge: a novel function for the SLAP-130/FYB adapter protein in beta 1
      integrin signaling and T lymphocyte migration.
AB  - The role of integrin-mediated signaling events in T cell function remains
      incompletely characterized. We report here that alpha4beta1 integrin stimulation
      of H9 T cells and normal human T cell blasts results in rapid and transient
      tyrosine phosphorylation of the adapter protein, SH2 domain-containing 76-kDa
      protein (SLP-76)-associated phosphoprotein of 130 kDa (SLAP-130)/FYB at levels
      comparable to those observed following TCR stimulation. Stimulation of T cells
      via the alpha4beta1 integrin enhances the association of tyrosine phosphorylated
      SLAP-130/FYB with the SH2 domain of the src tyrosine kinase p59fyn. Activation of
      normal T cells, but not H9 T cells, via alpha4beta1 leads to tyrosine
      phosphorylation of SLP-76 as well as SLAP-130/FYB. Overexpression of SLAP-130/FYB
      in normal T cells enhances T cell migration through fibronectin-coated filters in
      response to the chemokine stromal cell-derived factor (SDF)-1alpha. These results
      identify SLAP-130/FYB as a new tyrosine phosphorylated substrate in beta1
      integrin signaling and suggest a novel function for SLAP-130/FYB in regulating T
      lymphocyte motility.

PMID- 10640724
TI  - Cutting edge: cytolytic effector function in human circulating CD8+ T cells
      closely correlates with CD56 surface expression.
AB  - Recent data suggest that human effector CD8+ T cells express a distinct CD27
      CD45RAhigh (CD57+CD28-CD11ahigh) phenotype. Here, we propose that CTL effector
      function correlates better with CD56 (neuronal cell adhesion molecule (NCAM))
      surface expression. CD56 was absent on cord blood CD8+ T cells, but was expressed
      by 4-30% of freshly isolated circulating CD8+ T cells from 15 adults. Dramatic
      oligoclonal expansions in 3/3 individuals were confined to the CD56+ subset of
      CD8+ T cells. The CD56+ subset generally contained high amounts of intracellular
      perforin and granzyme B. Finally, direct cytolytic capacity was closely
      restricted to the CD56+(CD45RAhigh) cells, better than to CD27-CD45RAhigh cells
      in 5/5 individuals analyzed. Thus, the phenotype corresponding to the circulating
      effector CD8+ T cell pool may be simplified and more precisely defined by the use
      of just two surface markers: CD8 and CD56.

PMID- 10640725
TI  - Differential Ca2+ influx, KCa channel activity, and Ca2+ clearance distinguish
      Th1 and Th2 lymphocytes.
AB  - In Th1 and Th2 lymphocytes, activation begins with identical stimuli but results
      in the production of different cytokines. The expression of some cytokine genes
      is differentially induced according to the amplitude and pattern of Ca2+
      signaling. Using fura- 2 Ca2+ imaging of murine Th1 and Th2 clones, we observed
      that the Ca2+ rise elicited following store depletion with thapsigargin is
      significantly lower in Th2 cells than in Th1 cells. Maximal Ca2+ influx rates and
      whole-cell Ca2+ currents showed that both Th1 and Th2 cells express
      indistinguishable Ca2+-release-activated Ca2+ channels. Therefore, we
      investigated other mechanisms controlling the concentration of intracellular
      Ca2+, including K+ channels and Ca2+ clearance from the cytosol. Whole-cell
      recording demonstrated that there is no distinction in the amplitudes of voltage
      gated K+ currents in the two cell types. Ca2+-activated K+ (KCa) currents,
      however, were significantly smaller in Th2 cells than in Th1 cells.
      Pharmacological equalization of Ca2+-activated K+ currents in the two cell types
      reduced but did not completely eliminate the difference between Th1 and Th2 Ca2+
      responses, suggesting divergence in an additional Ca2+ regulatory mechanism.
      Therefore, we analyzed Ca2+ clearance from the cytosol of both cell types and
      found that Th2 cells extrude Ca2+ more quickly than Th1 cells. The combination of
      a faster Ca2+ clearance mechanism and smaller Ca2+-activated K+ currents in Th2
      cells accounts for the lower Ca2+ response of Th2 cells compared with Th1 cells.

PMID- 10640726
TI  - Functional consequences of the developmental arrest and follicular exclusion of
      anti-double-stranded DNA B cells.
AB  - Anti-dsDNA B cells are actively tolerized in nonautoimmune BALB/c mice, as
      manifested by their developmental arrest, follicular exclusion, and rapid
      turnover rate. Previously, we have documented changes in the maturation status
      and follicular localization of anti-dsDNA B cells in autoimmune-prone MRL (+/+
      and lpr/lpr) mice. To determine whether these differences in developmental status
      and follicular localization affect the functional capacity of anti-dsDNA B cells,
      we have now compared their in vivo life spans and their responses to in vitro
      stimuli. Our study shows that although anti-dsDNA B cells from both BALB/c and
      MRL-+/+ mice are localized to the T/B interface, only those in BALB/c mice have a
      rapid turnover rate. Therefore, the immature status and not the exclusion from
      the B cell follicle correlates with a shortened life span. Interestingly,
      apoptotic anti-dsDNA B cells were not detected at the T/B interface in BALB/c
      mice, suggesting that they are not dying there. This study also demonstrates that
      anti-dsDNA B cells, regardless of maturation status or follicular localization,
      are able to proliferate and up-regulate the costimulatory molecule B7-2 in
      response to CD40 ligand and IL-4. Therefore, one of the critical in vivo
      differences between anti-dsDNA B cells in BALB/c and MRL-+/+ mice compared with
      MRL-lpr/lpr mice may be the availability of T cell help.

PMID- 10640727
TI  - c-Src mediates mitogenic signals and associates with cytoskeletal proteins upon
      vascular endothelial growth factor stimulation in Kaposi's sarcoma cells.
AB  - Vascular endothelial growth factor (VEGF) appears to be a critical cytokine
      modulating the growth and spread of Kaposi's sarcoma (KS). Furthermore, infection
      with the KS herpes virus results in up-regulation of VEGF and triggering of VEGF
      receptor activation. The molecular mechanisms regulating such cytokine-driven
      proliferation of KS cells are not well characterized. We investigated the role of
      Src-related tyrosine kinases in VEGF-mediated signaling in model KS 38 tumor
      cells. VEGF stimulation specifically activated c-Src kinase activity but not that
      of other related Src kinases such as Lyn, Fyn, or Hck in KS cells.
      Pyrazolopyrimidine, a selective inhibitor of Src family tyrosine kinases,
      significantly blocked the VEGF-induced growth of KS cells. Further studies using
      mutants of c-Src kinase revealed that Src mediates mitogen-activated protein
      kinase activation induced by VEGF. We also observed that VEGF stimulation
      resulted in increased tyrosine phosphorylation of the focal adhesion components
      paxillin and p130cas. Furthermore, VEGF induction enhanced the complex formation
      between Src kinase and paxillin. Src kinase appears to play an important
      functional role in VEGF-induced signaling in KS cells and may act to link
      pathways from the VEGF receptor to mitogen-activated protein kinase and
      cytoskeletal components, thereby effecting tumor proliferation and migration.

PMID- 10640728
TI  - IL-2 unresponsiveness in anergic CD4+ T cells is due to defective signaling
      through the common gamma-chain of the IL-2 receptor.
AB  - Repeated administration of the superantigen staphylococcal enterotoxin A to mice
      transduces a state of anergy in the CD4+ T cell compartment, characterized by
      inhibition of IL-2 production and clonal expansion in vivo. In contrast to what
      has been reported on anergic T cell clones in vitro, culture of in vivo anergized
      CD4+ T cells in the presence of exogenous IL-2 did not overcome the block in
      responsiveness. In this study, we demonstrate that CD4+ T cells from mice
      anergized with staphylococcal enterotoxin A also exhibit a reduced proliferative
      capacity in response to IL-7 and IL-15, cytokines that share a common gamma-chain
      with the IL-2R. Flow-cytometric analysis revealed only modest changes in the
      expression of the different IL-2R chains. In a number of experiments, our results
      also provide evidence that excludes a major role of the IL-2R alpha-chain in this
      system. According to these results, the inability of anergic cells to respond to
      IL-2 is not mainly due to a down-regulation of the high affinity IL-2R, but to a
      perturbation in intracellular signaling. Our study confirmed that the activation
      and tyrosine phosphorylation of Janus-associated kinase 3 and STAT5 were
      considerably weaker after anergy induction. Moreover, anergic CD4+ T cells showed
      significantly reduced DNA-binding ability to STAT5-specific elements. Taken
      together, we suggest that the observed IL-2 unresponsiveness in anergic CD4+ T
      cells could be due to a defect in signaling through the common gamma-chain of the
      IL-2R.

PMID- 10640729
TI  - Analysis of immunomodulatory activities of aqueous humor from eyes of mice with
      experimental autoimmune uveitis.
AB  - Aqueous humor (AqH) contains immunosuppressive factors, especially TGF-beta2,
      that contribute to the immune privileged status of the anterior chamber. However,
      this may not be true when the blood-ocular barrier is compromised by ocular
      inflammation. To determine the immunosuppressive status of AqH from murine eyes
      afflicted with experimental autoimmune uveitis, B10.A mice were immunized with
      interphotoreceptor retinoid-binding protein. AqH was collected from eyes of
      affected mice periodically after immunization and then evaluated for content of
      TGF-beta, proinflammatory cytokines, and the capacity to suppress anti-CD3-driven
      T cell proliferation. mRNA expression of selected cytokines in iris and ciliary
      body from inflamed eyes was analyzed by ribonuclease protection assay. We found
      that TGF-beta levels were significantly increased in AqH from EAU eyes on days
      11, 17, and 28. AqH collected on day 11 (onset of disease) failed to suppress T
      cell proliferation and contained large amounts of locally produced IL-6 that
      antagonized TGF-beta. In contrast, AqH collected at 17 days (when ocular
      inflammation was progressively severe) re-expressed the ability to suppress T
      cell proliferation, in this case due to high levels of blood-derived TGF-beta1
      and eye-derived TGF-beta2 in the absence of IL-6. Thus, during the onset of
      experimental autoimmune uveitis, the ocular microenvironment loses its
      immunosuppressive properties due to local production of IL-6. But as inflammation
      mounts, AqH IL-6 content falls, and the fluid reacquires sufficient TGF-beta
      eventually to suppress immunogenic inflammation. The paradoxical roles of IL-6 in
      antagonizing TGF-beta, while promoting TGF-beta accumulation during ocular
      inflammation, is discussed.

PMID- 10640730
TI  - Blocking the common gamma-chain of cytokine receptors induces T cell apoptosis
      and long-term islet allograft survival.
AB  - The common gammac-chain is an essential signaling component shared by all known T
      cell growth factor (TCGF) receptors (i.e., IL-2, IL-4, IL-7, IL-9, and IL-15). In
      the present study, we have studied the effect of gammac-chain blockade on T cell
      activation and allograft rejection. Treatment of B6AF1 (H-2b/d.k) recipient mice
      with anti-gammac mAbs induced long-term survival of DBA/2 (H-2d) islet allografts
      (>150 days, n = 8), whereas control Ab-treated mice rejected the islet allografts
      within 17 days (n = 6). The state of engraftment induced by the anti-gammac mAbs
      was remarkably stable, as recipient mice bearing the primary islet allografts
      accepted a second DBA/2 islet allograft without further immunosuppression and
      systemic administration of high doses of IL-2Ig fusion protein failed to provoke
      rejection. Blocking the gammac-chain inhibited T cell proliferation and induced T
      cell apoptosis by repressing expression of Bcl-2. Our data suggest that one means
      of inducing T cell apoptosis and stable allograft survival can be achieved via
      gammac-chain blockade.

PMID- 10640731
TI  - Vasoactive intestinal peptide and pituitary adenylate cyclase-activating
      polypeptide inhibit antigen-induced apoptosis of mature T lymphocytes by
      inhibiting Fas ligand expression.
AB  - Apoptosis in T and B lymphocytes is a major element controlling the immune
      response. The Ag-induced cell death (AICD) in T cells is a main mechanism for
      maintaining peripheral tolerance and for limiting an ongoing immune response.
      AICD is initiated by Ag re-engagement of the TCR and is mediated through Fas/Fas
      ligand (FasL) interactions. Vasoactive intestinal peptide (VIP) and the
      structurally related pituitary adenylate cyclase-activating polypeptide (PACAP)
      are two multifunctional neuropeptides present in the lymphoid microenvironment
      that act primarily as anti-inflammatory agents. In the present study we
      investigated whether VIP and PACAP affect AICD in mature peripheral T cells and T
      cell hybridomas. VIP and PACAP reduce in a dose-dependent manner anti-CD3-induced
      apoptosis in Con A/IL-2-preactivated peripheral T cells and the murine T
      hybridomas 2B4.11 and A1.1. A functional study demonstrates that the inhibition
      of AICD is achieved through the inhibition of activation-induced FasL expression
      at protein and mRNA levels. VIP/PACAP-mediated inhibition of both AICD and FasL
      expression is mediated through the specific receptors VPAC1 and VPAC2. Of obvious
      biological significance is the fact that VIP and PACAP prevent Ag-induced clonal
      deletion of CD4+ T cells, but not that of CD8+ T cells. By affecting FasL
      expression, VIP and PACAP may play a physiological role in both the generation of
      memory T cells and the inhibition of FasL-mediated T cell cytotoxicity.

PMID- 10640732
TI  - Protein tyrosine phosphatase activity is required for IL-4 induction of IL-4
      receptor alpha-chain.
AB  - To investigate the role of protein tyrosine phosphatases in IL-4Ralpha-chain
      expression and signaling, we first established that SHP-1, but not SHP-2,
      coimmunoprecipitated with anti-IL-4Ralpha chain Abs in extracts prepared from
      resting lymphocytes. We further observed that the protein tyrosine phosphatase
      inhibitors Na3VO4 and pervanadate blocked the striking induction of IL-4Ralpha
      chain expression that is mediated by IL-4. However, Na3VO4 did not diminish IL-4
      induced Stat6 phosphorylation nor did it block the IL-4-mediated increase in IL
      4Ralpha-chain mRNA. The striking inhibition in total cellular IL-4Ralpha-chain
      and in cell surface IL-4 receptors was associated with an inhibition of
      biosynthetic labeling of IL-4Ralpha-chain after a 30- min pulse with [35S]
      methionine, indicating that reduction of IL-4Ralpha-chain protein resulted from
      either a diminished production of the receptor or a rapid degradation, possibly
      as a result of phosphorylation of the receptor in an early biosynthetic cellular
      compartment. Control of newly synthesized IL-4Ralpha-chain protein expression by
      phosphatase may provide a novel means to regulate IL-4 responsiveness.

PMID- 10640733
TI  - Naive CD8+ T cells do not require costimulation for proliferation and
      differentiation into cytotoxic effector cells.
AB  - Most current models of T cell activation postulate a requirement for two distinct
      signals. One signal is delivered through the TCR by engagement with peptide/MHC
      complexes, and the second is delivered by interaction between costimulatory
      molecules such as CD28 and its ligands CD80 and CD86. Soluble peptide/MHC
      tetramers provide an opportunity to test whether naive CD8+ T cells can be
      activated via the signal generated through the TCR-alphabeta in the absence of
      any potential costimulatory molecules. Using T cells from two different TCR
      transgenic mice in vitro, we find that TCR engagement by peptide/MHC tetramers is
      sufficient for the activation of naive CD8+ T cells. Furthermore, these T cells
      proliferate, produce cytokines, and differentiate into cytolytic effectors. Under
      the conditions where anti-CD28 is able to enhance proliferation of normal B6
      CD4+, CD8+, and TCR transgenic CD8+ T cells with anti-CD3, we see no effect of
      anti-CD28 on proliferation induced by tetramers. The results of this experiment
      argue that given a strong signal delivered through the TCR by an authentic
      ligand, no costimulation is required.

PMID- 10640734
TI  - CD72 negatively regulates signaling through the antigen receptor of B cells.
AB  - The immunoreceptor tyrosine-based inhibition motif (ITIM) is found in various
      membrane molecules such as CD22 and the low-affinity Fc receptor for IgG in B
      cells and the killer cell-inhibitory receptor and Ly-49 in NK cells. Upon
      tyrosine phosphorylation at the ITIMs, these molecules recruit SH2 domain
      containing phosphatases such as SH2-containing tyrosine phosphatase-1 and
      negatively regulate cell activity. The B cell surface molecule CD72 carries an
      ITIM and an ITIM-like sequence. We have previously shown that CD72 is
      phosphorylated and recruits SH2-containing tyrosine phosphatase-1 upon cross
      linking of the Ag receptor of B cells (BCR). However, whether CD72 modulates BCR
      signaling has not yet been elucidated. In this paper we demonstrate that
      expression of CD72 down-modulates both extracellular signal-related kinase (ERK)
      activation and Ca2+ mobilization induced by BCR ligation in the mouse B lymphoma
      line K46micromlambda, whereas BCR-mediated ERK activation was not reduced by the
      ITIM-mutated form of CD72. Moreover, coligation with CD72 with BCR reduces BCR
      mediated ERK activation in spleen B cells of normal mice. These results indicate
      that CD72 negatively regulates BCR signaling. CD72 may play a regulatory role in
      B cell activation, probably by setting a threshold for BCR signaling.

PMID- 10640735
TI  - Induction of CTL responses by simultaneous administration of liposomal peptide
      vaccine with anti-CD40 and anti-CTLA-4 mAb.
AB  - Activation of APC via CD40-CD40 ligand pathway induces up-regulation of
      costimulatory molecules such as B7 and production of IL-12. Interaction between
      B7 on APC and CD28 on naive T cells is necessary for priming the T cells. On the
      other hand, interaction between B7 on APC and CTLA-4 on activated T cells
      transduces a negative regulatory signal to the activated T cells. In the present
      study, we attempted to generate tumor-specific CTL by s.c. administration of
      antigenic peptides encapsulated in multilamellar liposomes (liposomal peptide
      vaccine) with anti-CD40 mAb and/or anti-CTLA-4 mAb. Liposomal OVA257-264 and anti
      CD40 mAb or anti-CTLA-4 mAb were administrated to C57BL/6 mice and the
      splenocytes were cocultured with OVA257-264 for 4 days. The splenic CD8+ T cells
      showed a significant cytotoxicity against EL4 cells transfected with cDNA of OVA.
      In addition, administration of both anti-CD40 and anti-CTLA-4 mAb enhanced the
      CTL responses. Considerable CTL responses were induced in MHC class II deficient
      mice by the same procedure. This finding indicated that CTL responses could be
      generated even in the absence of Th cells. When BALB/c mice were immunized with
      pRL1a peptide that are tumor-associated Ag of RLmale symbol1 leukemia cells using
      the same procedure, significant CTL responses were induced and prolonged survival
      of the BALB/c mice was observed following RLmale symbol1 inoculation. These
      results demonstrate that anti-CD40 mAb and anti-CTLA-4 mAb function as
      immunomodulators and may be applicable to specific cancer immunotherapy with
      antitumor peptide vaccine.

PMID- 10640736
TI  - Phosphorylation of FADD/ MORT1 at serine 194 and association with a 70-kDa cell
      cycle-regulated protein kinase.
AB  - The adapter molecule Fas-associated death domain protein (FADD)/mediator of
      receptor-induced toxicity-1 (MORT1) is essential for signal transduction of the
      apoptosis-inducing receptor CD95 (APO-1/Fas) as it connects the activated
      receptor with the effector caspase-8. FADD also plays a role in embryonic
      development and the cell cycle reentry of T cells. FADD is phosphorylated at
      serine residues. We now show that phosphorylation exclusively occurs at serine
      194. The phosphorylation of FADD was found to correlate with the cell cycle. In
      cells arrested at the G2/M boundary with nocodazole, FADD was quantitatively
      phosphorylated, whereas only nonphosphorylated FADD was found in cells arrested
      in G1/S with hydroxyurea. In this context, we have identified a 70-kDa cell cycle
      regulated kinase that specifically binds to the C-terminal half of FADD. Because
      CD95-mediated apoptosis is independent of the cell cycle, phosphorylation of FADD
      may regulate its apoptosis-independent functions.

PMID- 10640737
TI  - Retrovirally transduced mouse dendritic cells require CD4+ T cell help to elicit
      antitumor immunity: implications for the clinical use of dendritic cells.
AB  - Presentation of MHC class I-restricted peptides by dendritic cells (DCs) can
      elicit vigorous antigen-specific CTL responses in vivo. It is well established,
      however, that T cell help can augment CTL function, raising the question of how
      best to present tumor-associated MHC class I epitopes to induce effective tumor
      immunity. To this end, we have examined the role of MHC class II peptide
      complexes present on the immunizing DCs in a murine melanoma model. To present
      MHC class I- and II-restricted Ags reliably on the same cell, we retrovirally
      transduced bone marrow-derived DCs with the model Ag OVA encoding well-defined
      class I- and II-restricted epitopes. The importance of CD4+ T cells activated by
      the immunizing DCs in this model is demonstrated by the following findings: 1)
      transduced DCs presenting class I and class II epitopes are more efficient than
      class I peptide-pulsed DCs; 2) MHC class II-deficient DCs fail to induce tumor
      protection; 3) CD4+ T cell depletion abolishes induction of tumor protection; and
      4) DCs presenting bovine serum Ags are more effective in establishing tumor
      immunity than DCs cultured in syngeneic serum. When MHC class II-deficient DCs
      were directly activated via their CD40 receptor, we indeed observed a moderate
      elevation of OVA-specific CTL activity. However, this increase in CTL activity
      was not sufficient to induce in vivo tumor rejection. Thus, our results
      demonstrate the potency of genetically modified DCs that express both MHC class I
      and II epitopes, but caution against the use of DCs presenting only the former.

PMID- 10640738
TI  - Non-CD28 costimulatory molecules present in T cell rafts induce T cell
      costimulation by enhancing the association of TCR with rafts.
AB  - While CD28 functions as the major T cell costimulatory receptor, a number of
      other T cell molecules have also been described to induce T cell costimulation.
      Here, we investigated the mechanisms by which costimulatory molecules other than
      CD28 contribute to T cell activation. Non-CD28 costimulatory molecules such as
      CD5, CD9, CD2, and CD44 were present in the detergent-insoluble glycolipid
      enriched (DIG) fraction/raft of the T cell surface, which is rich in TCR
      signaling molecules and generates a TCR signal upon recruitment of the TCR
      complex. Compared with CD3 ligation, coligation of CD3 and CD5 as an example of
      DIG-resident costimulatory molecules led to an enhanced association of CD3 and
      DIG. Such a DIG redistribution markedly up-regulated TCR signaling as observed by
      ZAP-70/LAT activation and Ca2+ influx. Disruption of DIG structure using an agent
      capable of altering cholesterol organization potently diminished Ca2+
      mobilization induced by the coligation of CD3 and CD5. This was associated with
      the inhibition of the redistribution of DIG although the association of CD3 and
      CD5 was not affected. Thus, the DIG-resident costimulatory molecules exert their
      costimulatory effects by contributing to an enhanced association of TCR/CD3 and
      DIG.

PMID- 10640739
TI  - CD5 costimulation up-regulates the signaling to extracellular signal-regulated
      kinase activation in CD4+CD8+ thymocytes and supports their differentiation to
      the CD4 lineage.
AB  - CD5 positively costimulates TCR-stimulated mature T cells, whereas this molecule
      has been suggested to negatively regulate the activation of TCR-triggered
      thymocytes. We investigated the effect of CD5 costimulation on the
      differentiation of CD4+CD8+ thymocytes. Coligation of thymocytes with anti-CD3
      and anti-CD5 induced enhanced tyrosine phosphorylation of LAT (linker for
      activation of T cells) and phospholipase C-gamma (PLC-gamma) compared with
      ligation with anti-CD3 alone. Despite increased phosphorylation of PLC-gamma,
      this treatment down-regulated Ca2+ influx. In contrast, the phosphorylation of
      LAT and enhanced association with Grb2 led to activation of extracellular signal
      regulated kinase (ERK) mitogen-activated protein kinase. When CD3 and CD5 on
      CD4+CD8+ thymocytes in culture were coligated, they lost CD8, down-regulated CD4
      expression, and induced CD69 expression, yielding a CD4+(dull)CD8-CD69+
      population. An ERK inhibitor, PD98059, inhibited the generation of this
      population. The reduction of generation of CD4+CD8- cells resulted from decreased
      survival of these differentiating thymocytes. Consistent with this, PD98059
      inhibited the anti-CD3/CD5-mediated Bcl-2 induction. These results indicate that
      CD5 down-regulates a branch of TCR signaling, whereas this molecule functions to
      support the differentiation of CD4+CD8+ thymocytes by up-regulating another
      branch of TCR signaling that leads to ERK activation.

PMID- 10640740
TI  - Tumors promote altered maturation and early apoptosis of monocyte-derived
      dendritic cells.
AB  - Tumors produce a number of immunosuppressive factors that block the maturation of
      CD34+ stem cells into dendritic cells (DC). We hypothesized that tumors might
      also interfere with the maturation and/or function of human monocyte-derived DC.
      In contrast to stem cells, we found that CD14+ cells responded to tumor culture
      supernatant (TSN) by increasing expression of APC surface markers, up-regulating
      nuclear translocation of RelB, and developing allostimulatory activity. Although
      displaying these characteristics of mature DC, TSN-exposed DC lacked the capacity
      to produce IL-12, did not acquire full allostimulatory activity, and rapidly
      underwent apoptosis. The effects of TSN appeared to be specific for maturing DC,
      and were not reversed by Abs against known DC regulatory factors including IL-10,
      vascular endothelial growth factor, TGF-beta, or PGE2. Supernatants collected
      from nonmalignant cell sources had no effect on DC maturation. The altered
      maturation and early apoptosis of monocyte-derived DC may represent another
      mechanism by which tumors evade immune detection.

PMID- 10640741
TI  - Differential regulation and function of Fas expression on glial cells.
AB  - Fas/Apo-1 is a member of the TNF receptor superfamily that signals apoptotic cell
      death in susceptible target cells. Fas or Fas ligand (FasL)-deficient mice are
      relatively resistant to the induction of experimental allergic encephalomyelitis,
      implying the involvement of Fas/FasL in this disease process. We have examined
      the regulation and function of Fas expression in glial cells (astrocytes and
      microglia). Fas is constitutively expressed by primary murine microglia at a low
      level and significantly up-regulated by TNF-alpha or IFN-gamma stimulation.
      Primary astrocytes express high constitutive levels of Fas, which are not further
      affected by cytokine treatment. In microglia, Fas expression is regulated at the
      level of mRNA expression; TNF-alpha and IFN-gamma induced Fas mRNA by
      approximately 20-fold. STAT-1alpha and NF-kappaB activation are involved in IFN
      gamma- or TNF-alpha-mediated Fas up-regulation in microglia, respectively. The
      cytokine TGF-beta inhibits basal expression of Fas as well as cytokine-mediated
      Fas expression by microglia. Upon incubation of microglial cells with FasL
      expressing cells, approximately 20% of cells underwent Fas-mediated cell death,
      which increased to approximately 60% when cells were pretreated with either TNF
      alpha or IFN-gamma. TGF-beta treatment inhibited Fas-mediated cell death of TNF
      alpha- or IFN-gamma-stimulated microglial cells. In contrast, astrocytes are
      resistant to Fas-mediated cell death, however, ligation of Fas induces expression
      of the chemokines macrophage inflammatory protein-1beta (MIP-1beta), MIP-1alpha,
      and MIP-2. These data demonstrate that Fas transmits different signals in the two
      glial cell populations: a cytotoxic signal in microglia and an inflammatory
      signal in the astrocyte.

PMID- 10640742
TI  - STAT1 affects lymphocyte survival and proliferation partially independent of its
      role downstream of IFN-gamma.
AB  - Lymphocytes derived from mice deficient in STAT1 showed reduced apoptosis and
      enhanced proliferation in vitro. To understand the involvement of STAT1 in the
      observed reduction in apoptosis, we examined the levels of caspase and bcl-2
      family genes that are involved in cell survival and/or apoptosis. The levels of
      caspase 1 and 11, two enzymes involved in both cytokine protein processing and
      induction of apoptosis, were reduced in STAT1-/- cells compared with wild-type.
      However, the levels of bcl-2 genes were comparable in both mice. STAT1-/- cells
      also displayed an enhanced proliferation following TCR stimulation. This
      hyperproliferation could not be ascribed completely to the loss of IFN-gamma
      mediated antiproliferation. First, similar phenotypes were also observed in
      fibroblasts and pre-B cells derived from STAT1-/- mice, which do not produce IFN
      gamma. Second, comparisons with cells lacking the gene for IFN-gamma or with
      cells treated with neutralizing Abs to IFN-gamma only partially mimicked the
      STAT1-/- phenotype. Interestingly, the kinetics of degradation of p27kip1, a CDK
      inhibitor, following TCR ligation were faster, and, concomitantly, the up
      regulation of CDK2 kinase activity and protein levels were increased in
      stimulated T cells of STAT1-/- mice relative to those of wild-type mice.
      Furthermore, STAT1-/- animals were more susceptible to carcinogen-induced thymic
      tumors, a possible consequence of altered T cell growth and/or survival. These
      results demonstrate an essential role for STAT1 for lymphocyte survival and
      proliferation that is only partially dependent on IFN-gamma signaling.

PMID- 10640743
TI  - CCR9A and CCR9B: two receptors for the chemokine CCL25/TECK/Ck beta-15 that
      differ in their sensitivities to ligand.
AB  - We isolated cDNAs for a chemokine receptor-related protein having the database
      designation GPR-9-6. Two classes of cDNAs were identified from mRNAs that arose
      by alternative splicing and that encode receptors that we refer to as CCR9A and
      CCR9B. CCR9A is predicted to contain 12 additional amino acids at its N terminus
      as compared with CCR9B. Cells transfected with cDNAs for CCR9A and CCR9B
      responded to the chemokine CC chemokine ligand 25 (CCL25)/thymus-expressed
      chemokine (TECK)/chemokine beta-15 (CK beta-15) in assays for both calcium flux
      and chemotaxis. No other chemokines tested produced responses specific for the
      cDNA-transfected cells. mRNA for CCR9A/B is expressed predominantly in the
      thymus, coincident with the expression of CCL25, and highest expression for
      CCR9A/B among thymocyte subsets was found in CD4+CD8+ cells. mRNAs encoding the A
      and B forms of the receptor were expressed at a ratio of approximately 10:1 in
      immortalized T cell lines, in PBMC, and in diverse populations of thymocytes. The
      EC50 of CCL25 for CCR9A was lower than that for CCR9B, and CCR9A was desensitized
      by doses of CCL25 that failed to silence CCR9B. CCR9 is the first example of a
      chemokine receptor in which alternative mRNA splicing leads to proteins of
      differing activities, providing a mechanism for extending the range of
      concentrations over which a cell can respond to increments in the concentration
      of ligand. The study of CCR9A and CCR9B should enhance our understanding of the
      role of the chemokine system in T cell biology, particularly during the stages of
      thymocyte development.

PMID- 10640744
TI  - T cells can induce somatic mutation in B cell receptor-engaged BL2 Burkitt's
      lymphoma cells independently of CD40-CD40 ligand interactions.
AB  - The B cell surface trigger(s) and the molecular mechanism(s) of somatic
      hypermutation remain unknown, partly because of the lack of amendable in vitro
      models. Recently, however, we reported that upon B cell receptor cross-linking
      and coculture with activated T cells, the Burkitt's lymphoma cell line BL2
      introduces mutations in its IgVH gene in vitro. We now confirm the relevance of
      our culture model by establishing that the entire spectrum of somatic mutations
      observed in vivo, including insertions and deletions, could be found in the DNA
      of BL2 cells. Additionally, we show that among four human B cell lines, only two
      with a centroblast-like phenotype can be induced to mutate. Triggering of somatic
      mutations in BL2 cells requires intimate T-B cell contacts and is independent of
      CD40-CD40-ligand (CD40L) interactions as shown by 1) the lack of effect of anti
      CD40 and/or anti-CD40L blocking Abs on somatic mutation and 2) the ability of a
      CD40L-deficient T cell clone (isolated from an X-linked hyper-IgM syndrome
      patient) to induce somatic mutation in B cell receptor-engaged BL2 cells. Thus,
      our in vitro model reveals that T-B cell membrane interactions through surface
      molecules different from CD40-CD40L can trigger somatic hypermutation.

PMID- 10640745
TI  - Oral administration of chitin down-regulates serum IgE levels and lung
      eosinophilia in the allergic mouse.
AB  - Previous studies showed that local macrophages phagocytose nonantigenic chitin
      particles (1-10 micrometer polymers of N-acetyl-<cmd SC>d<cmd /SC> -glucosamine)
      through mannose receptors and produce IL-12, IL-18, and TNF-alpha. These
      cytokines lead to the production of IFN-gamma by NK cells. To determine whether
      chitin could down-regulate Th2 responses, chitin was given orally (8 mg/day for 3
      days before and 13 days during ragweed allergen immunization) in BALB/c and
      C57BL/6 mice. These ragweed-immunized mice were given ragweed intratracheally on
      day 11. Three days after the challenge, the immunized mice with saline (controls)
      showed increases in serum IgE levels and lung eosinophil numbers. The chitin
      treatment resulted in decreases of these events in both strains. To dissect the
      inhibitory mechanisms of Th2 responses, spleen cells (4 x 106 cells/ml) isolated
      from the ragweed-immunized mice (controls) were cultured in the presence of
      ragweed and/or chitin for 3 days (recall responses). Ragweed alone stimulated the
      production of IL-4 (0.6 ng/ml), IL-5 (20 U/ml), and IL-10 (3.2 ng/ml), but not
      IFN-gamma. Ragweed/chitin stimulation resulted in significant decreases of IL-4,
      IL-5, and IL-10 levels and the production of IFN-gamma (48 U/ml). Moreover,
      spleen cells isolated from the chitin-treated mice showed ragweed-stimulated IFN
      gamma production (15 U/ml) and significantly lower levels of the Th2 cytokines,
      suggesting that the immune responses were redirected toward a Th1 response.
      Collectively, these results indicate that chitin-induced innate immune responses
      down-regulate Th2-facilitated IgE production and lung eosinophilia in the
      allergic mouse.

PMID- 10640746
TI  - Annexin V binds to viable B cells and colocalizes with a marker of lipid rafts
      upon B cell receptor activation.
AB  - Recombinant annexin V (rAnV) has been used to identify apoptotic cells based on
      its ability to bind phosphatidylserine (PS), a lipid normally restricted to the
      cytoplasmic face of the plasma membrane, but externalized early during apoptosis.
      However, this association of rAnV binding and apoptosis is not an obligatory one.
      We demonstrate that rAnV binds to a large fraction of murine B cells bearing
      selectable Ag receptors despite the fact that these cells are not apoptotic.
      Phosphatidylserine, which is uniformly distributed on resting B cells, is
      mobilized to co-cap with IgM on anti-IgM-treated B cells and to colocalize with
      GM1, a marker of lipid rafts. Cross-linking PS before anti-IgM treatment
      sequesters this lipid and alters signaling through IgM. Thus, PS exposed on the
      majority of B cells in vivo does not reflect early apoptosis, but, instead, plays
      a role in receptor-mediated signaling events.

PMID- 10640747
TI  - Neuronal fractalkine expression in HIV-1 encephalitis: roles for macrophage
      recruitment and neuroprotection in the central nervous system.
AB  - HIV-1 infection of the brain results in chronic inflammation, contributing to the
      neuropathogenesis of HIV-1 associated neurologic disease. HIV-1-infected
      mononuclear phagocytes (MP) present in inflammatory infiltrates produce
      neurotoxins that mediate inflammation, dysfunction, and neuronal apoptosis.
      Neurologic disease is correlated with the relative number of MP in and around
      inflammatory infiltrates and not viral burden. It is unclear whether these cells
      also play a neuroprotective role. We show that the chemokine, fractalkine (FKN),
      is markedly up-regulated in neurons and neuropil in brain tissue from pediatric
      patients with HIV-1 encephalitis (HIVE) compared with those without HIVE, or that
      were HIV-1 seronegative. FKN receptors are expressed on both neurons and
      microglia in patients with HIVE. These receptors are localized to cytoplasmic
      structures which are characterized by a vesicular appearance in neurons which may
      be in cell-to-cell contact with MPs. FKN colocalizes with glutamate in these
      neurons. Similar findings are observed in brain tissue from an adult patient with
      HIVE. FKN is able to potently induce the migration of primary human monocytes
      across an endothelial cell/primary human fetal astrocyte trans-well bilayer, and
      is neuroprotective to cultured neurons when coadministered with either the HIV-1
      neurotoxin platelet activating factor (PAF) or the regulatory HIV-1 gene product
      Tat. Thus focal inflammation in brain tissue with HIVE may up-regulate neuronal
      FKN levels, which in turn may be a neuroimmune modulator recruiting peripheral
      macrophages into the brain, and in a paracrine fashion protecting glutamatergic
      neurons.

PMID- 10640748
TI  - Cell-mediated DNA transport between distant inflammatory sites following
      intradermal DNA immunization in the presence of adjuvant.
AB  - After intradermal genetic immunization, naked DNA is transported from the site of
      injection to regional lymph nodes. Little is known on how inflammation influences
      this process and whether DNA is transported beyond local lymph nodes. In the
      experiments herein reported, we injected naked DNA in the presence of adjuvant to
      address questions related to 1) the fate of naked DNA in the presence of
      inflammation; 2) the generation of immune responses to the encoded protein during
      inflammation; and, more in general, 3) the fate of ingested molecules beyond
      regional lymph nodes during inflammation. Two sites of inflammation were induced
      in vivo in mice. Naked DNA was injected in the nape together with adjuvant, and
      adjuvant only was injected at a distant peritoneal site. Injected DNA, uptaken at
      the primary dermal site of inflammation, was transported beyond regional lymph
      nodes to distant organs such as the spleen and to the distant peritoneal site of
      inflammation. This transport, mediated by CD11b+ cells, was cumulative during
      chronic inflammation. These results indicate a novel route of transport of DNA
      beyond regional lymph nodes and may have specific implications for DNA-based
      immune modulation.

PMID- 10640749
TI  - Effects of liver-derived dendritic cell progenitors on Th1- and Th2-like cytokine
      responses in vitro and in vivo.
AB  - There is evidence that donor-derived dendritic cells (DC), particularly those at
      a precursor/immature stage, may play a role in the immune privilege of liver
      allografts. Underlying mechanisms are poorly understood. We have examined the
      influence of in vitro generated mouse liver-derived DC progenitors (DCp) on
      proliferative, cytotoxic, and Th1/Th2 cytokine responses induced in allogeneic T
      cells. Liver DCp, propagated in GM-CSF from C57B10 mice (H2b), induced only
      minimal proliferation, and weak cytotoxic responses in allogeneic (C3H; H2k) T
      cells compared with mature bone marrow (BM)-derived DC. Flow-cytometric analysis
      of intracellular cytokine staining revealed that mature BM DC, but not liver DCp,
      elicited CD4+ T cell production of IFN-gamma. Intracellular expression of IL-10
      was very low in both BM DC- and liver DCp-stimulated CD4+ T cells. Only
      stimulation by liver DCp was associated with IL-10 secretion in primary MLR.
      Notably, these liver DCp cocultured with allogeneic T cells stained strongly for
      IL-10. Following local (s.c. ) injection in allogeneic recipients, both BM DC and
      liver DCp homed to T cell areas of draining lymph nodes and spleen, where they
      were readily detected by immunohistochemistry up to 2 wk postinjection. Liver DCp
      induced clusters of IL-10- and IL-4-secreting mononuclear cells, whereas Th2
      cytokine-secreting cells were not detected in mice injected with mature BM DC. By
      contrast, comparatively high numbers of IFN-gamma+ cells were induced by BM DC.
      Modulation of Th2 cytokine production by donor-derived DCp may contribute to the
      comparative immune privilege of hepatic allografts.

PMID- 10640750
TI  - Phosphatidylinositol 3-kinase as a mediator of TNF-induced NF-kappa B activation.
AB  - The activation of transcription factor NF-kappa B by TNF involves the stimulation
      of a novel signaling cascade. In this paper we show that phosphatidylinositol 3
      kinase (PI 3-kinase) may play a pivotal role in TNF-mediated activation of NF
      kappa B-dependent genes. Consistent with its involvement in TNF signaling, PI 3
      kinase activities in HepG2 and U937 cells can be stimulated by TNF in a rapid but
      transient manner through a mechanism that may involve its association with the
      insulin receptor substrate-1. A dominant-negative mutant of the p85 regulatory
      subunit of PI 3-kinase, which is a potent inhibitor of PI 3-kinase signaling,
      effectively blocked the TNF-induced expression of an NF-kappa B-dependent
      reporter gene. Although PI 3-kinase may be required for NF-kappa B activation,
      overexpression of its p110 catalytic subunit alone was unable to induce an NF
      kappa B/chloramphenicol acetyltransferase (CAT) reporter gene. However, when TNF
      was added to p110-overexpressing cells, there was a synergistic activation of the
      NF-kappa B/CAT reporter, suggesting that other TNF-inducible signals may
      cooperate with PI 3-kinase to activate NF-kappa B. Consistent with its role in NF
      kappa B activation, inhibition of PI 3-kinase activity by wortmannin or LY294002
      greatly potentiated TNF-induced apoptosis. This TNF/wortmannin-induced apoptosis
      was markedly prevented in cells overexpressing Rel A. Taken together, our results
      indicate that a PI 3-kinase-regulated step in TNF-signaling is critical for the
      expression of NF-kappa B-dependent genes.

PMID- 10640752
TI  - Identification of a functional NF-kappa B site in the platelet endothelial cell
      adhesion molecule-1 promoter.
AB  - Platelet endothelial cell adhesion molecule-1 (PECAM-1) is a type I transmembrane
      adhesion protein of 130 kDa that belongs to a subgroup of the Ig gene
      superfamily, characterized by the presence of immunoreceptor tyrosine-based
      inhibitory motifs. PECAM-1 is expressed in circulating platelets, monocytes,
      neutrophils, a selective subgroup of T cells, and in endothelial cells, where it
      is preferentially located at intercellular junctions and participates in
      leukocyte transmigratory processes. The identification of two consensus NF-kappa
      B sites within the PECAM-1 promoter led us to analyze their possible involvement
      in the PECAM-1 expression regulated by inflammatory stimuli. We found that
      surface expression and promoter activity of PECAM-1 in myeloid cells are
      regulated by modulators of NF-kappa B, including TNF-alpha, PMA, and pyrrolidine
      dithiocarbamate. Mobility shifts assays identified a specific NF-kappa B-binding
      element at +110/+120, whose mutation abolished the basal promoter activity of
      PECAM-1 and decreased NF-kappa B-dependent responses of the PECAM-1 gene
      promoter. Furthermore, cotransfection experiments with an expression vector
      encoding the p65 subunit of NF-kappa B showed transactivation of the PECAM-1
      promoter. These results demonstrate that NF-kappa B can regulate the
      transcriptional activity of PECAM-1.

PMID- 10640751
TI  - The nuclear receptor PPAR gamma and immunoregulation: PPAR gamma mediates
      inhibition of helper T cell responses.
AB  - The peroxisome proliferator-activated receptors (PPARs) are a family of
      transcription factors belonging to the nuclear receptor superfamily. Until
      recently, the genes regulated by PPARs were those believed to be predominantly
      associated with lipid metabolism. Recently, an immunomodulatory role for PPAR
      gamma has been described in cells critical to the innate immune system, the
      monocyte/macrophage. In addition, evidence for an antiinflammatory role of the
      PPAR gamma ligand, 15-deoxy-Delta 12,14-PGJ2 (15d-PGJ2) has been found. In the
      present studies, we demonstrate, for the first time, that murine helper T cell
      clones and freshly isolated splenocytes express PPAR gamma 1. The PPAR gamma
      expressed is of functional significance in that two ligands for PPAR gamma, 15d
      PGJ2 and a thiazolidinedione, ciglitazone, mediate significant inhibition of
      proliferative responses of both the T cell clones and the freshly isolated
      splenocytes. This inhibition is mediated directly at the level of the T cell and
      not at the level of the macrophage/APC. Finally, we demonstrate that the two
      ligands for PPAR gamma mediate inhibition of IL-2 secretion by the T cell clones
      while not inhibiting IL-2-induced proliferation of such clones. The demonstration
      of the expression and function of PPAR gamma in T cells reveals a new level of
      immunoregulatory control for PPARs and significantly increases the role and
      importance of PPAR gamma in immunoregulation.

PMID- 10640753
TI  - Functional role of the noncatalytic subunit of complement C5 convertase.
AB  - The C5 convertase is a serine protease that consists of two subunits: a catalytic
      subunit which is bound in a Mg2+-dependent complex to a noncatalytic subunit. To
      understand the functional role of the noncatalytic subunit, we have determined
      the C5-cleaving properties of the cobra venom factor-dependent C5 convertase
      (CVF, Bb) made with CVF purified from the venom of Naja naja (CVFn) and Naja haje
      (CVFh) and compared them to those for two C3b-dependent C5 convertases (ZymC3b,Bb
      and C3b,Bb). A comparison of the kinetic parameters indicated that although the
      four C5 convertases (CVFn,Bb, ZymC3b,Bb, CVFh,Bb, and C3b,Bb) had similar
      catalytic rate constants (kcat = 0.004-0.012 s-1) they differed 700-fold in their
      affinity for the substrate as indicated by the Km values (CVFn,Bb = 0.036 microM,
      ZymC3b,Bb = 1.24 microM, CVFh,Bb = 14.0 microM, and C3b,Bb = 24 microM). Analysis
      of binding interactions between C5 and the noncatalytic subunits (CVFh or C3b, or
      CVFn) using the BIAcore, revealed dissociation binding constants (Kd) that were
      similar to the Km values of the respective enzymes. The kinetic and binding data
      demonstrate that the binding site for C5 resides in the noncatalytic subunit of
      the enzyme, the affinity for the substrate is solely determined by the
      noncatalytic subunit and the catalytic efficiency of the enzyme appears not to be
      influenced by the nature of this subunit.

PMID- 10640754
TI  - Mamu-I: a novel primate MHC class I B-related locus with unusually low
      variability.
AB  - The rhesus macaque is an important animal model for several human diseases and
      organ transplantation. Therefore, definition of the MHC of this species is
      crucial to the development of these models. Unfortunately, unlike humans,
      lymphocytes from a single rhesus macaque express up to 12 different MHC class I
      cDNAs. From which locus these various alleles are derived is unclear. In our
      attempts to define the MHC class I loci of the rhesus macaque, we have identified
      an unusual MHC class I locus, Mamu-I. We isolated 26 I locus alleles from three
      different macaque species but not from three other Cercopithecine genera,
      suggesting that the I locus is the result of a recent duplication of the B locus
      occurring after the divergence of macaques from the ancestor of the other extant
      Cercopithecine genera. Mamu-I mRNA transcripts were detected in all tissues
      examined and Mamu-I protein was produced in rhesus B lymphoblastoid cell lines.
      Furthermore, Mamu-I protein was detected by flow cytometry on the surface of
      human 721.221 cells transfected with Mamu-I. In contrast to the polymorphism
      present at this locus, there is unusually low sequence variability, with the mean
      number of nucleotide differences between alleles being only 3.6 nt. Therefore,
      Mamu-I is less variable than any other polymorphic MHC class I locus described to
      date. Additionally, no evidence for positive selection on the peptide binding
      region was observed. Together, these results suggest that Mamu-I is an MHC class
      I locus in primates that has features of both classical and nonclassical loci.

PMID- 10640755
TI  - Mucosa-specific targets for regulation of IFN-gamma expression: lamina propria T
      cells use different cis-elements than peripheral blood T cells to regulate
      transactivation of IFN-gamma expression.
AB  - Activation of lamina propria (LP) T cells via the CD2 pathway enhances IFN-gamma
      (IFN-gamma) secretion with further enhancement after CD28 coligation. The
      molecular mechanisms regulating IFN-gamma expression in LP T cells remain
      unknown. Previous studies in PBL and T cell lines identified cis- and trans
      regulatory elements in TCR-mediated expression of IFN-gamma. This study examines
      CD2 and PMA/ionophore-responsive IFN-gamma promoter elements. Activation of LPMC
      via CD2-induced IFN-gamma secretion and a parallel up-regulation of mRNA
      expression. CD28 coligation enhanced mRNA stability without up-regulating
      transcription as measured by nuclear run-on. Transfection of a -2.7-kb IFN-gamma
      promoter-reporter construct into PBL and LP mononuclear cells (LPMC) revealed
      significant promoter activity after CD2 activation, with additional
      transactivation after CD2/CD28 costimulation in PBL, but not in LPMC. Functional
      analysis using truncated promoter fragments identified distinct cis-regulatory
      regions selectively transactivating IFN-gamma expression in PBL compared with
      LPMC. In PBL, CD2 activation elements reside within the -108- to +64-bp region.
      However, in LPMC the upstream region between -204 and -108 bp was essential.
      Transfection of the proximal and distal AP-1-binding elements, as well as TRE/AP
      1 constructs, revealed functional activation of AP-1 subsequent to CD2 signaling,
      with activation critical in PBL but diminished in LPMC. Electromobility shift
      analysis using oligonucleotides encompassing the proximal, distal, and BED/AP-1
      binding regions failed to demonstrate selective transactivation after CD2
      signaling of LPMC. This report provides evidence that activation of LPMC results
      in transactivation of multiple promoter elements regulating IFN-gamma expression
      distinct from those in PBL.

PMID- 10640756
TI  - Differences among HIV-1 variants in their ability to elicit secretion of TNF
      alpha.
AB  - HIV-1 infection of human PBMC has been shown to elicit secretion of several
      different cytokines. TNF-alpha secretion induced by this virus has been of
      particular interest because it has been associated with the development of HIV-1
      dementia and because TNF-alpha increases viral replication by enhancing NF-kappaB
      interaction with the viral promoter, the HIV-1 long terminal repeat. Thus, an
      autocrine pathway is potentially created in which HIV-1 stimulates its own
      replication. Conflicting reports exist, however, on the ability of HIV-1 to
      induce TNF-alpha secretion in vitro or in vivo. Using experimental protocols that
      controlled for potential bacterial endotoxin-induced TNF-alpha secretion, the
      current study demonstrates significant differences in TNF-alpha-eliciting
      properties among primary and laboratory obtained HIV-1. The relative TNF-alpha
      inducing ability of different variants is conserved when tested using PBMC from
      different individuals. Elicitation of TNF-alpha secretion was not blocked by
      exposure of cells to zidovudine, indicating that viral integration was not
      required to induce secretion. Rather, the interaction between the virus and cell
      surface is critical for TNF-alpha induction, as Abs against CD4 or CCR5 blocked
      the induction of TNF-alpha synthesis by PBMC when added before virus exposure.
      Furthermore, the ability to induce TNF-alpha secretion mapped to a region of the
      HIV-1 env gene that includes the third hypervariable domain. Differences in the
      ability of different HIV-1 variants to elicit TNF-alpha may account for
      individual differences in HIV-1 disease course.

PMID- 10640757
TI  - Analyses of TCRB rearrangements substantiate a profound deficit in recombination
      signal sequence joining in SCID foals: implications for the role of DNA-dependent
      protein kinase in V(D)J recombination.
AB  - We reported previously that the genetic SCID disease observed in Arabian foals is
      explained by a defect in V(D)J recombination that profoundly affects both coding
      and signal end joining. As in C.B-17 SCID mice, the molecular defect in SCID
      foals is in the catalytic subunit of the DNA-dependent protein kinase (DNA-PKCS);
      however, in SCID mice, signal end resolution remains relatively intact. Moreover,
      recent reports indicate that mice that completely lack DNA-PKCS also generate
      signal joints at levels that are indistinguishable from those observed in C.B-17
      SCID mice, eliminating the possibility that a partially active version of DNA
      PKCS facilitates signal end resolution in SCID mice. We have analyzed TCRB
      rearrangements and find that signal joints are reduced by approximately 4 logs in
      equine SCID thymocytes as compared with normal horse thymocytes. A potential
      explanation for the differences between SCID mice and foals is that the mutant
      DNA-PKCS allele in SCID foals inhibits signal end resolution. We tested this
      hypothesis using DNA-PKCS expression vectors; in sum, we find no evidence of a
      dominant-negative effect by the mutant protein. These and other recent data are
      consistent with an emerging consensus: that in normal cells, DNA-PKCS
      participates in both coding and signal end resolution, but in the absence of DNA
      PKCS an undefined end joining pathway (which is variably expressed in different
      species and cell types) can facilitate imperfect signal and coding end joining.

PMID- 10640758
TI  - A bactericidal monoclonal antibody elicits a change in its antigen, OspB of
      Borrelia burgdorferi, that can be detected by limited proteolysis.
AB  - mAb CB2, directed against outer surface protein B (OspB), causes bacteriolysis of
      Borrelia burgdorferi in the absence of complement. How this happens is unknown.
      We examined the effect of mAb binding on OspB tertiary structure by using limited
      proteolysis to probe changes in protein conformation. Truncated OspB (tOspB) that
      lacked N-terminal lipid was cleaved by four enzymes: trypsin, endoproteinase Arg
      C, endoproteinase Asp-N, and endoproteinase Glu-C. CB2 affected the cleavage by
      trypsin and Arg-C, but not by AspN or Glu-C. None of the enzymes cleaved CB2
      under these conditions. Both trypsin and Arg-C cleaved tOspB near the N-terminus;
      CB2 slowed the rate of cleavage, but did not affect the identity of the sites
      cleaved. Irrelevant mAb had no effect, indicating that the effect was specific.
      CB2 was active against tOspB of strain B31, but not against tOspB of strain BEP4,
      to which it does not bind, suggesting that binding was required to elicit the
      effect on cleavage. With trypsin, CB2 showed a maximal effect at 8 mol of tOspB
      to 1 mol of mAb. At this ratio, not enough CB2 was present to bind all the tOspB;
      therefore, either CB2 shows turnover or CB2 acts by binding tOspB and effecting a
      change in this tOspB such that it, in turn, propagates the effect in other
      molecules of tOspB. Regardless of the mechanism, these data show that CB2 elicits
      a change in tOspB that can be measured by its reduced susceptibility to protease
      cleavage.

PMID- 10640759
TI  - Structural correlates of an anticarcinoma antibody: identification of specificity
      determining residues (SDRs) and development of a minimally immunogenic antibody
      variant by retention of SDRs only.
AB  - Clinical utility of murine mAbs is limited because many elicit Abs to murine Ig
      constant and variable regions in patients. An Ab humanized by the current
      procedure of grafting all the complementarity determining regions (CDRs) of a
      murine Ab onto the human Ab frameworks is likely to be less immunogenic, except
      that its murine CDRs could still evoke an anti-variable region response. Previous
      studies with anticarcinoma mAb CC49 showed that light chain LCDR1 and LCDR2 of
      humanized CC49 could be replaced with the corresponding CDRs of a human Ab with
      minimal loss of Ag-binding activity. The studies reported in this paper were
      undertaken to dissect the CC49 Ag-binding site to identify 1) specificity
      determining residues (SDRs), the residues of the hypervariable region that are
      most critical in Ag-Ab interaction, and 2) those residues that contribute to the
      idiotopes that are potential targets of patients' immune responses. A panel of
      variants generated by genetic manipulation of the murine CC49 hypervariable
      regions were evaluated for their relative Ag-binding affinity and reactivity to
      sera from several patients who had been immunized with murine CC49. One variant,
      designated HuCC49V10, retained only the SDRs of CC49 and does not react with the
      anti-variable region Abs of the sera from the murine CC49-treated patients. These
      studies thus demonstrate that the genetic manipulation of Ab variable regions can
      be accomplished by grafting only the SDRs of a xenogeneic Ab onto human Ab
      frameworks. This approach may reduce the immunogenicity of Abs to a minimum.

PMID- 10640760
TI  - Porcine lung surfactant protein D: complementary DNA cloning, chromosomal
      localization, and tissue distribution.
AB  - Porcine organs and lung surfactant have medically important applications in both
      xenotransplantation and therapy. We have started to characterize porcine lung
      surfactant by cloning the cDNA of porcine surfactant protein D (SP-D). SP-D and
      SP-A are important mediators in innate immune defense for the lung and possibly
      other mucosal surfaces. Porcine SP-D will also be an important reagent for use in
      existing porcine animal models for human lung infections. The complete cDNA
      sequence of porcine SP-D, including the 5' and 3' untranslated regions, was
      determined from two overlapping bacteriophage clones and by PCR cloning. Three
      unique features were revealed from the porcine sequence in comparison to SP-D
      from other previously characterized species, making porcine SP-D an intriguing
      species addition to the SP-D/collectin family. The collagen region contains an
      extra cysteine residue, which may have important structural consequences. The
      other two differences, a potential glycosylation site and an insertion of three
      amino acids, lie in the loop regions of the carbohydrate recognition domain,
      close to the carbohydrate binding region and thus may have functional
      implications. These variations were ruled out as polymorphisms or mutations by
      confirming the sequence at the genomic level in four different pig breeds.
      Porcine SP-D was shown to localize primarily to the lung and with less abundance
      to the duodenum, jejunum, and ileum. The genes for SP-D and SP-A were also shown
      to colocalize to a region of porcine chromosome 14 that is syntenic with the
      human and murine collectin loci.

PMID- 10640761
TI  - Normal isotype switching in B cells lacking the I mu exon splice donor site:
      evidence for multiple I mu-like germline transcripts.
AB  - Ig class switch recombination (CSR) in activated B cells is preceded by the
      generation of "switch" transcripts from the heavy chain constant region (CH)
      genes targeted for rearrangement. Switch transcripts include a sterile "I" exon
      spliced onto the first CH exon. Targeted mutations disrupting the expression or
      splicing of I exons severely hamper CSR to all tested CH loci, except mu.
      However, all mu switch transcript mutations tested so far have left the I mu exon
      splice donor site intact. To test the possibility that the residual CSR activity
      in I mu mutants could be due to splicing of a truncated I mu exon, we generated
      new mutants specifically lacking the I mu splice donor site. Surprisingly, normal
      CSR was observed in the I mu splice donor mutants even in the absence of
      detectable spliced I mu transcripts. In a search for potential alternative
      sources of switch-like transcripts in the mu locus, we identified two novel exons
      which map just upstream of the Smu region and splice onto the C mu 1 exon. Their
      expression is detectable from early B cell developmental stages, and, at least in
      hybridomas, it does not require the Emu enhancer. These studies highlight a
      unique structure for the mu locus I exon region, with multiple nested switch
      transcript-like exons mapping upstream of Smu. We propose that all of these
      transcripts directly contribute to mu class switching activity.

PMID- 10640762
TI  - IL-13 is a susceptibility factor for Leishmania major infection.
AB  - Leishmania major infection is useful as an experimental model to define factors
      responsible for the development and maintenance of Th cell immune responses.
      Studies using inbred mouse strains have identified that the Th1 response
      characteristic of C57BL/6 mice results in healing, whereas BALB/c mice fail to
      control the infection due to the generation of an inappropriate Th2 response. We
      now demonstrate that IL-13 is a key factor in determining susceptibility to L.
      major infection. Overexpression of IL-13 in transgenic mice makes the normally
      resistant C57BL/6 mouse strain susceptible to L. major infection even in the
      absence of IL-4 expression. This susceptibility correlates with a suppression of
      IL-12 and IFN-gamma expression. Furthermore, using BALB/c mice deficient in the
      expression of IL-4, IL-13, or both IL-13 and IL-4, we demonstrate that IL-13
      deficient mice are resistant to infection and that there is an additive effect of
      deleting both IL-4 and IL-13.

PMID- 10640764
TI  - The neuronal apoptosis inhibitory protein (Naip) is expressed in macrophages and
      is modulated after phagocytosis and during intracellular infection with
      Legionella pneumophila.
AB  - Legionella pneumophila is an intracellular pathogen that causes Legionnaires'
      disease in humans. Inbred mouse strains are uniformly resistant to L. pneumophila
      infection with the notable exception of A/J, where the chromosome 13 locus Lgn1
      renders A/J macrophages permissive to L. pneumophila replication. The mouse Lgn1
      region is syntenic with the spinal muscular atrophy (SMA) locus on human
      chromosome 5 and includes several copies of the neuronal apoptosis inhibitory
      protein (Naip) gene. We have analyzed a possible link among Lgn1, Naip, and
      macrophage function. RNA expression studies show that Naip (mostly copy 2) mRNA
      transcripts are expressed in macrophage-rich tissues, such as spleen, lung, and
      liver and are abundant in primary macrophages. Immunoblotting and
      immunoprecipitation analyses identify Naip protein expression in mouse
      macrophages and in macrophage cell lines RAW 264.7 and J774A. Interestingly,
      macrophages from permissive A/J mice express significantly less Naip protein than
      their nonpermissive C57BL/6J counterpart. Naip protein expression is increased
      after phagocytic events. Naip protein levels during infection with either
      virulent or avirulent strains of L. pneumophila increase during the first 6 h
      postinfection and remain elevated during the 48-h observation period. This
      enhanced expression is also observed in macrophages infected with Salmonella
      typhimurium. Likewise, an increase in Naip protein levels in macrophages is
      observed 24 h after phagocytosis of Latex beads. The cosegregation of Lgn1 and
      Naip together with the detected Naip protein expression in host macrophages as
      well as its modulation after phagocytic events and during intracellular infection
      make it an attractive candidate for the Lgn1 locus.

PMID- 10640763
TI  - Liver CD4-CD8- NK1.1+ TCR alpha beta intermediate cells increase during
      experimental malaria infection and are able to exhibit inhibitory activity
      against the parasite liver stage in vitro.
AB  - Experimental infection of C57BL/6 mice by Plasmodium yoelii sporozoites induced
      an increase of CD4-CD8- NK1.1+ TCR alpha beta int cells and a down-regulation of
      CD4+ NK1.1+ TCR alpha beta int cells in the liver during the acute phase of the
      infection. These cells showed an activated CD69+, CD122+, CD44high, and CD62Lhigh
      surface phenotype. Analysis of the expressed TCRV beta segment repertoire
      revealed that most of the expanded CD4-CD8- (double-negative) T cells presented a
      skewed TCRV beta repertoire and preferentially used V beta 2 and V beta 7 rather
      than V beta 8. To get an insight into the function of expanded NK1.1+ T cells,
      experiments were designed in vitro to study their activity against P. yoelii
      liver stage development. P. yoelii-primed CD3+ NK1.1+ intrahepatic lymphocytes
      inhibited parasite growth within the hepatocyte. The antiplasmodial effector
      function of the parasite-induced NK1.1+ liver T cells was almost totally reversed
      with an anti-CD3 Ab. Moreover, IFN-gamma was in part involved in this
      antiparasite activity. These results suggest that up-regulation of CD4-CD8-
      NK1.1+ alpha beta T cells and down-regulation of CD4+ NK1.1+ TCR alpha beta int
      cells may contribute to the early immune response induced by the Plasmodium
      during the prime infection.

PMID- 10640765
TI  - Nitric oxide production by human intestinal epithelial cells and competition for
      arginine as potential determinants of host defense against the lumen-dwelling
      pathogen Giardia lamblia.
AB  - Giardia lamblia infection of the human small intestine is a common protozoan
      cause of diarrheal disease worldwide. Although infection is luminal and generally
      self-limiting, and secretory Abs are thought to be important in host defense,
      other defense mechanisms probably affect the duration of infection and the
      severity of symptoms. Because intestinal epithelial cells produce NO, and its
      stable end products, nitrite and nitrate, are detectable mainly on the apical
      side, we tested the hypothesis that NO production may constitute a host defense
      against G. lamblia. Several NO donors, but not their control compounds, inhibited
      giardial growth without affecting viability, suggesting that NO is cytostatic
      rather than cytotoxic for G. lamblia. NO donors also inhibited giardial
      differentiation induced by modeling crucial environmental factors, i. e.,
      encystation induced by bile and alkaline pH, and excystation in response to
      gastric pH followed by alkaline pH and protease. Despite the potent antigiardial
      activity of NO, G. lamblia is not simply a passive target for host-produced NO,
      but has strategies to evade this potential host defense. Thus, in models of human
      intestinal epithelium, G. lamblia inhibited epithelial NO production by consuming
      arginine, the crucial substrate used by epithelial NO synthase to form NO. These
      studies define NO and arginine as central components in a novel cross-talk
      between a luminal pathogen and host intestinal epithelium.

PMID- 10640766
TI  - C-C chemokine receptor 3 antagonism by the beta-chemokine macrophage inflammatory
      protein 4, a property strongly enhanced by an amino-terminal alanine-methionine
      swap.
AB  - Allergic reactions are characterized by the infiltration of tissues by activated
      eosinophils, Th2 lymphocytes, and basophils. The beta-chemokine receptor CCR3,
      which recognizes the ligands eotaxin, eotaxin-2, monocyte chemotactic protein
      (MCP) 3, MCP4, and RANTES, plays a central role in this process, and antagonists
      to this receptor could have potential therapeutic use in the treatment of
      allergy. We describe here a potent and specific CCR3 antagonist, called Met
      chemokine beta 7 (Ckbeta7), that prevents signaling through this receptor and, at
      concentrations as low as 1 nM, can block eosinophil chemotaxis induced by the
      most potent CCR3 ligands. Met-Ckbeta7 is a more potent CCR3 antagonist than Met-
      and aminooxypentane (AOP)-RANTES and, unlike these proteins, exhibits no partial
      agonist activity and is highly specific for CCR3. Thus, this antagonist may be of
      use in ameliorating leukocyte infiltration associated with allergic inflammation.
      Met-Ckbeta7 is a modified form of the beta-chemokine macrophage inflammatory
      protein (MIP) 4 (alternatively called pulmonary and activation-regulated
      chemokine (PARC), alternative macrophage activation-associated C-C chemokine
      (AMAC) 1, or dendritic cell-derived C-C chemokine (DCCK) 1). Surprisingly, the
      unmodified MIP4 protein, which is known to act as a T cell chemoattractant, also
      exhibits this CCR3 antagonistic activity, although to a lesser extent than Met
      Ckbeta7, but to a level that may be of physiological relevance. MIP4 may
      therefore use chemokine receptor agonism and antagonism to control leukocyte
      movement in vivo. The enhanced activity of Met-Ckbeta7 is due to the alteration
      of the extreme N-terminal residue from an alanine to a methionine.

PMID- 10640767
TI  - Inhibition of mesangial cell nitric oxide in MRL/lpr mice by prostaglandin J2 and
      proliferator activation receptor-gamma agonists.
AB  - MRL/Mp-lpr/lpr (MRL/lpr) mice develop immune complex glomerulonephritis similar
      to human lupus. Glomerular mesangial cells are key modulators of the inflammatory
      response in lupus nephritis. When activated, these cells secrete inflammatory
      mediators including NO and products of cyclooxygenase perpetuating the local
      inflammatory response. PGJ2, a product of cyclooxygenase, is a potent in vitro
      inhibitor of macrophage inflammatory functions and is postulated to function as
      an in vivo inhibitor of macrophage-mediated inflammatory responses. We
      hypothesized that in lupus, a defect in PGJ2 production allows the inflammatory
      response to continue unchecked. To test this hypothesis, mesangial cells were
      isolated from MRL/lpr and BALB/c mice and stimulated with IL-1beta or LPS plus
      IFN-gamma. In contrast to the 2- to 3-fold increase in PGJ2 production by
      stimulated BALB/c mesangial cells, supernatant PGJ2 did not increase in MRL/lpr
      mesangial cell cultures. NO production in stimulated MRL/lpr and BALB/c mesangial
      cells, was blocked by PGJ2 and pioglitazone. These studies suggest that
      abnormalities in PGJ2 production are present in MRL/lpr mice and may be linked to
      the heightened activation state of mesangial cells in these mice.

PMID- 10640768
TI  - A soluble recombinant multimeric anti-Rh(D) single-chain Fv/CR1 molecule restores
      the immune complex binding ability of CR1-deficient erythrocytes.
AB  - CR1 (CD35, the C3b/C4b receptor) is a widely distributed membrane glycoprotein
      with a unique cluster conformation on the surface of erythrocytes (E). CR1 on E
      is responsible for the transport of immune complexes (IC) to liver and spleen. As
      a cofactor of the C3b cleavage by factor I, CR1 is also a potent inhibitor of C
      activation and inflammation. In some diseases (systemic lupus erythematosus,
      hemolytic anemia, AIDS, etc.) an acquired low level of CR1 on E has been
      observed, leading to an impaired clearance of IC. The aim of this study was to
      design a heterofunctional molecule that will bind to E and restore a normal or a
      supranormal CR1 density on E that could mimic the unique distribution pattern of
      CR1 on normal E. For that purpose a new multimerizing system based on the
      properties of the C-terminal part of the alpha-chain of the C4 binding protein
      (C4bp) was used. We first produced a multimeric soluble CR1 that proved to be a
      better inhibitor of in vitro C activation than the monomeric form of CR1, then a
      heteromultimeric molecule made of CR1 and single-chain Fv anti-Rh(D) valences
      able to attach E and providing E with as much as a 10-fold increase in CR1
      density with the same CR1 distribution pattern as native E. CR1/single-chain Fv
      anti-Rh(D)-treated E were able in vitro to attach as many opsonized IC as native
      E. These data open the way for future use of multimeric and heteromultimeric
      forms of soluble recombinant CR1 as therapy of IC diseases.

PMID- 10640769
TI  - C-reactive protein binding to murine leukocytes requires Fc gamma receptors.
AB  - Human C-reactive protein (CRP) is an acute phase protein that binds to receptors
      on human and mouse leukocytes. We have recently determined that the high and low
      affinity receptors for CRP on human leukocytes are Fc gamma RIIa and Fc gamma RI,
      respectively. Previous work by others suggested that CRP receptors on mouse
      macrophages are distinct from Fc gamma R. We have taken advantage of the
      availability of mice deficient in one or more Fc gamma R to reexamine the role of
      Fc gamma R in CRP binding to mouse leukocytes. Three strains of Fc gamma R
      deficient mice were examined: gamma-chain-deficient mice that lack Fc gamma RI
      and Fc gamma RIII, Fc gamma RII-deficient mice, and mice deficient in both gamma
      chain and Fc gamma RII that lack all Fc gamma R. No binding of CRP was detected
      to leukocytes from double-deficient mice, indicating that Fc gamma R are required
      for CRP binding. CRP binding to leukocytes from gamma-chain-deficient and Fc
      gamma RII-deficient mice was reduced compared with binding to leukocytes from
      wild-type mice. Further analysis of CRP binding to macrophages, neutrophils, and
      lymphocytes provides direct evidence that Fc gamma RIIb1, Fc gamma RIIb2, and Fc
      gamma RI are the receptors for CRP on mouse leukocytes. These findings may have
      important implications in understanding the physiological function of CRP.

PMID- 10640770
TI  - Positive regulation of c-Jun N-terminal kinase and TNF-alpha production but not
      histamine release by SHP-1 in RBL-2H3 mast cells.
AB  - The SH2-containing protein tyrosine phosphatase1 (SHP-1) is important for
      signaling from immune receptors. To investigate the role of SHP-1 in mast cells
      we overexpressed the wild-type and the phosphatase-inactive forms of SHP-1 in rat
      basophilic leukemia 2H3 (RBL-2H3) mast cell line. The phosphatase-inactive SHP-1
      (C453S or D419A) retains its ability to bind tyrosine phosphorylated substrates
      and thereby competes with the endogenous wild-type enzyme. Overexpression of wild
      type SHP-1 decreased the FcepsilonRI aggregation-induced tyrosine phosphorylation
      of the beta and gamma subunits of the receptor whereas the dominant negative SHP
      1 enhanced phosphorylation. There were also similar changes in the tyrosine
      phosphorylation of Syk. However, receptor-induced histamine release in the cells
      expressing either wild-type or dominant negative SHP-1 was similar to that in the
      parental control cells. In contrast, compared with the parental RBL-2H3 cells,
      FcepsilonRI-induced c-Jun N-terminal kinase phosphorylation and the level of TNF
      alpha mRNA was increased in the cells overexpressing wild-type SHP-1 whereas the
      dominant negative SHP-1 had the opposite effect. The substrate-trapping mutant
      SHP1/D419A identified pp25 and pp30 as two major potential substrates of SHP-1 in
      RBL-2H3 cells. Therefore, SHP-1 may play a role in allergy and inflammation by
      regulating mast cell cytokine production.

PMID- 10640771
TI  - Multispecific CD4+ T cell response to a single 12-mer epitope of the
      immunodominant heat-shock protein 60 of Yersinia enterocolitica in Yersinia
      triggered reactive arthritis: overlap with the B27-restricted CD8 epitope,
      functional properties, and epitope presentation by multiple DR alleles.
AB  - Yersinia heat-shock protein 60 (Ye-hsp60) has recently been found to be a
      dominant CD4 and CD8 T cell Ag in Yersinia-triggered reactive arthritis. The
      nature of this response with respect to the epitopes recognized and functional
      characteristics of the T cells is largely unknown. CD4+ T cell clones specific
      for Ye-hsp60 were raised from synovial fluid mononuclear cells from a patient
      with Yersinia-triggered reactive arthritis. and their specificity was determined
      using three recombinant Ye-hsp60 fragments, overlapping 18-mer synthetic peptides
      as well as truncated peptides. Functional characteristics were assessed by
      cytokine secretion analysis in culture supernatants after specific antigenic
      stimulation. Amino acid positions relevant for T cell activation were detected by
      single alanine substitutions within the epitopes. Fragment II comprising amino
      acid sequence 182-371 was recognized by the majority of clones. All these clones
      were specific for peptide 319-342. Th1 clones and IL-10-secreting clones occurred
      in parallel, sometimes with the same fine specificity. The 12-mer core epitope
      322-333 is a degenerate MHC binder and is presented to some T cell clones in a
      "promiscuous" manner. This epitope is almost identical with a B27-restricted CTL
      epitope of Ye-hsp60. Cross-reactivity of Ye-hsp60-specific T cell clones with
      self-hsp60 was not observed. In conclusion, an interesting Ye-hsp60 T cell
      epitope has been identified and characterized. It remains to be determined
      whether this epitope is also relevant in other reactive arthritis patients.

PMID- 10640772
TI  - Evidence for local eosinophil differentiation within allergic nasal mucosa:
      inhibition with soluble IL-5 receptor.
AB  - Eosinophil differentiation occurs within the bone marrow in response to
      eosinopoietic cytokines, particularly IL-5. Recently, however, eosinophil
      precursors (CD34/IL-5Ralpha+ cells) and IL-5 mRNA+ cells have been identified
      within the lungs of asthmatics, indicating that a population of eosinophils may
      differentiate in situ. In this report, we examined the presence of eosinophil
      precursors within allergic nasal mucosa and examined whether they undergo local
      differentiation following ex vivo stimulation. We cultured human nasal mucosa
      obtained from individuals with seasonal allergic rhinitis with either specific
      allergen, recombinant human IL-5 (rhIL-5), or allergen + soluble IL-5Ralpha (sIL
      5Ralpha), shown to antagonize IL-5 function. Simultaneous immunocytochemistry and
      in situ hybridization demonstrated that there were fewer cells coexpressing CD34
      immunoreactivity and IL-5Ralpha mRNA following culture with allergen or rhIL-5,
      compared with medium alone. Immunostaining revealed that the number of major
      basic protein (MBP) immunoreactive cells (eosinophils) was higher within tissue
      stimulated with allergen or rhIL-5, compared with unstimulated tissue. In situ
      hybridization detected an increase in IL-5 mRNA+ cells in sections from tissue
      cultured with allergen, compared with medium alone. These effects were not
      observed in tissue cultured with a combination of allergen and sIL-5Ralpha.
      Colocalization analysis indicated this expression to be mainly, but not
      exclusively, T cell (44%) and eosinophil (10%) derived. Our findings suggest that
      a subset of eosinophils may differentiate locally within allergic nasal mucosa,
      in what appears to be a highly IL-5-dependent fashion, and imply that this
      process might be regulated in vivo by endogenous production of sIL-5Ralpha.

PMID- 10640774
TI  - Highly altered V beta repertoire of T cells infiltrating long-term rejected
      kidney allografts.
AB  - Chronic rejection represents a major cause of long-term kidney graft loss. T
      cells that are predominant in long-term rejected kidney allografts (35 +/- 10% of
      area infiltrate) may thus be instrumental in this phenomenon, which is likely to
      be dependent on the indirect pathway of allorecognition only. We have analyzed
      the variations in T cell repertoire usage of the V beta chain at the
      complementary determining region 3 (CDR3) level in 18 human kidney grafts lost
      due to chronic rejection. We observed a strongly biased intragraft TCR V beta
      usage for the majority of V beta families and also a very high percentage (55%)
      of V beta families exhibiting common and oligoclonal V beta-C beta rearrangements
      in the grafts of patients with chronic rejection associated with superimposed
      histologically acute lesions. Furthermore, V beta 8 and V beta 23 families
      exhibited common and oligoclonal V beta-J beta rearrangements in 4 of 18 patients
      (22%). Several CDR3 amino acid sequences were found for the common and
      oligoclonal V beta 8-J beta 1.4 rearrangement. Quantitative PCR showed that
      biased V beta transcripts were also overexpressed in chronically rejected kidneys
      with superimposed acute lesions. In contrast, T lymphocytes infiltrating rejected
      allografts with chronic rejection only showed an unaltered Gaussian-type CDR3
      length distribution. This pattern suggests that late graft failure associated
      with histological lesions restricted to Banff-defined chronic rejection does not
      involve T cell-mediated injury. Thus, our observation suggests that a limited
      number of determinants stimulates the recipient immune system in long-term
      allograft failure. The possibility of a local response against viral or
      parenchymatous cell-derived determinants is discussed.

PMID- 10640773
TI  - Oxidative stress causes mucin synthesis via transactivation of epidermal growth
      factor receptor: role of neutrophils.
AB  - Oxidative stress has been implicated in the pathogenesis of inflammatory diseases
      of airways. Here we show that oxidative stress causes ligand-independent
      activation of epidermal growth factor receptors (EGFR) and subsequent activation
      of mitogen-activated protein kinase kinase (MEK)-p44/42 mitogen-activated protein
      kinase (p44/42mapk), resulting in mucin synthesis in NCI-H292 cells. Exogenous
      hydrogen peroxide and neutrophils activated by IL-8, FMLP, or TNF-alpha increased
      EGFR tyrosine phosphorylation and subsequent activation of p44/42mapk and up
      regulated the expression of MUC5AC at both mRNA and protein levels in NCI-H292
      cells. These effects were blocked by selective EGFR tyrosine kinase inhibitors
      (AG1478, BIBX1522) and by a selective MEK inhibitor (PD98059), whereas a
      selective platelet-derived growth factor receptor tyrosine kinase inhibitor
      (AG1295), a selective p38 MAPK inhibitor (SB203580), and a negative compound of
      tyrosine kinase inhibitors (A1) were without effect. Neutrophil supernatant
      induced EGFR tyrosine phosphorylation, activation of p44/42mapk, and MUC5AC
      synthesis were inhibited by antioxidants (N-acetyl-cysteine, DMSO, dimethyl
      thiourea, or superoxide dismutase); neutralizing Abs to EGFR ligands (EGF and TGF
      alpha) were without effect, and no TGF-alpha protein was found in the neutrophil
      supernatant. In contrast, the EGFR ligand, TGF-alpha, increased EGFR tyrosine
      phosphorylation, activation of p44/42mapk, and subsequent MUC5AC synthesis, but
      these effects were not inhibited by antioxidants. These results implicate
      oxidative stress in stimulating mucin synthesis in airways and provide new
      therapeutic approaches in airway hypersecretory diseases.

PMID- 10640775
TI  - Evidence for common autoimmune disease genes controlling onset, severity, and
      chronicity based on experimental models for multiple sclerosis and rheumatoid
      arthritis.
AB  - The pathogenicity of multiple sclerosis is still poorly understood, but
      identification of susceptibility genes using the animal model experimental
      allergic encephalomyelitis (EAE) could provide leads. Certain genes may be shared
      between different autoimmune diseases, and identification of such genes is of
      obvious importance. To locate gene regions involved in the control of EAE and to
      compare the findings with the susceptibility loci recently identified in a model
      for rheumatoid arthritis (pristane-induced arthritis), we made crosses between
      the encephalomyelitis- and arthritis-susceptible rat strain DA and the resistant
      E3 strain. Genetic analysis of animals produced in a F2 intercross identified 11
      loci associated with specific EAE-associated traits. Interestingly, five of these
      loci were situated at the same position as major loci controlling pristane
      induced arthritis and showed similarities in inheritance pattern and subphenotype
      associations. Our results show that different phases of EAE are controlled by
      different sets of genes and that common genes are likely to be involved in
      different autoimmune diseases.

PMID- 10640776
TI  - NZB mice exhibit a primary T cell defect in fetal thymic organ culture.
AB  - Defects in T cell development have been suggested to be a factor in the
      development of systemic autoimmunity in NZB mice. However, the suggestion of a
      primary T cell defect has often been by extrapolation, and few direct
      observations of T cell precursors in NZB mice have been performed. Moreover, the
      capacity of NZB bone marrow T cell precursors to colonize the thymus and the
      ability of the NZB thymic microenvironment to support T lymphopoiesis have not
      been analyzed. To address this important issue, we employed the fetal thymic
      organ culture system to examine NZB T cell development. Our data demonstrated
      that NZB bone marrow cells were less efficient at colonizing fetal thymic lobes
      than those of control BALB/c or C57BL/6 mice. In addition, NZB bone marrow cells
      did not differentiate into mature T cells as efficiently as bone marrow cells
      from BALB/c or C57BL/6 mice. Further analysis revealed that this defect resulted
      from an intrinsic deficiency in the NZB Lin-Sca-1+c-kit+ bone marrow stem cell
      pool to differentiate into T cells in fetal thymic organ culture. Taken together,
      the data document heretofore unappreciated deficiencies in T cell development
      that may contribute to the development of the autoimmune phenotype in NZB mice.

PMID- 10640778
TI  - Retrovirally mediated IFN-beta transduction of macrophages induces resistance to
      HIV, correlated with up-regulation of RANTES production and down-regulation of C
      C chemokine receptor-5 expression.
AB  - Constitutive expression of IFN-beta by HIV target cells may be an alternative or
      complementary therapeutic approach for the treatment of AIDS. We show that
      macrophages derived from CD34+ cells from umbilical cord blood can be efficiently
      transduced by a retroviral vector carrying the IFN-beta coding sequence. This
      results in resistance to infection by a macrophage-tropic HIV type 1, as shown by
      the drastic reduction in the HIV DNA copy number per cell and in p24 release.
      Moreover, IFN-beta transduction totally blocked secretion of proinflammatory
      cytokines after HIV infection. The constitutive IFN-beta production also resulted
      in an increased production of IL-12 and IFN-gamma Th1-type cytokines and of the
      beta-chemokines macrophage-inflammatory protein-1alpha, macrophage-inflammatory
      protein-1beta, and RANTES. RANTES was found to be involved in the HIV resistance
      observed, and this was correlated with a down-regulation of the CCR-5 HIV entry
      coreceptor. These results demonstrate the feasibility and the efficacy of such
      IFN-beta-mediated gene therapy. In addition to inhibiting HIV replication, IFN
      beta transduction could have beneficial immune effects in HIV-infected patients
      by favoring cellular immune responses.

PMID- 10640777
TI  - Viral IL-10 and soluble TNF receptor act synergistically to inhibit collagen
      induced arthritis following adenovirus-mediated gene transfer.
AB  - Viral IL-10 (vIL-10) and soluble TNF receptor (sTNFR) are anti-inflammatory
      proteins that can suppress collagen-induced arthritis (CIA). These and related
      proteins have shown efficacy in the treatment of human rheumatoid arthritis;
      however, neither alone is able to completely suppress disease. Furthermore, they
      have short half-lives, necessitating frequent administration. To determine the
      ability of these proteins to act synergistically following gene transfer,
      arthritis was induced in DBA/1 male mice by immunization with type II collagen on
      days 0 and 21. Mice were injected i.v. either before disease onset (day 20) or
      after disease onset (day 28) with 1010 particles of adenovirus encoding vIL-10, a
      soluble TNF receptor-IgG1 fusion protein (sTNFR-Ig), a combination of both
      vectors, or a control vector lacking a transgene. Significant synergism was
      observed with the combination of vIL-10 and sTNFR-Ig, with a substantial
      reduction in both the incidence and severity of disease as well as inhibition of
      progression of established disease. sTNFR-Ig alone had no effect on CIA. vIL-10
      alone inhibited disease when given before disease onset, but had minimal effect
      on established disease. Both proteins inhibited spleen cell proliferation and IFN
      gamma secretion in response to stimulation with type II collagen, but only vIL-10
      reduced the synovial mRNA levels of the proinflammatory cytokines IL-1beta, TNF
      alpha, and IL-6. These findings demonstrate that vIL-10 and sTNFR-Ig act
      synergistically in suppressing CIA and suggest that gene transfer offers a
      potential therapeutic modality for the treatment of arthritis.

PMID- 10640779
TI  - NF-kappa B modulates TNF-alpha production by alveolar macrophages in asymptomatic
      HIV-seropositive individuals.
AB  - Local TNF-alpha production in different organs may affect HIV replication and
      pathogenesis. Alveolar macrophages (AMs) obtained by bronchoalveolar lavage from
      asymptomatic HIV-seropositive and HIV-seronegative individuals did not
      spontaneously release TNF-alpha, but LPS stimulation of these cells significantly
      increased TNF-alpha production. We tested whether NF-kappa B affects TNF-alpha
      production by AMs using N-tosyl-<cmd SC>l<cmd /SC> -phenylalanine
      chloromethylketone (TPCK) or N-benzoyl-<cmd SC>l<cmd /SC> -tyrosine ethyl ester
      (BTEE), which inhibit the degradation of I kappa B, or tricyclodecan-9-yl
      xanthogenate-potassium (D609), which inhibits phospholipase C. Alveolar
      macrophages were exposed to LPS alone and with the chemical protease inhibitors
      TPCK, BTEE, and D609. NF-kappa B DNA binding induced by LPS treatment of AMs was
      inhibited by TPCK, BTEE, and D609. These agents also inhibited TNF-alpha mRNA and
      TNF-alpha protein production. After 24 h, the levels of TNF-alpha mRNA reached
      equilibrium, as assessed by RT-PCR. The levels of NF-kappa B mRNA remained
      constant under all conditions. The levels of I kappa B-alpha mRNA were similar
      after 30, 60, and 180 min, but the I kappa B-beta mRNA concentration was
      initially low and increased over time under all conditions. I kappa B-alpha and I
      kappa B-beta protein production was not affected by the chemical protease
      inhibitors. Our data show that TNF-alpha production by LPS-stimulated AMs from
      asymptomatic HIV-seropositive and -seronegative individuals is regulated via the
      phospholipase C pathway and by NF-kappa B DNA binding activity without obvious
      changes in I kappa B-alpha or I kappa B-beta protein concentrations.

PMID- 10640780
TI  - Characteristics of human IgA and IgM genes used by plasma cells in the salivary
      gland resemble those used in duodenum but not those used in the spleen.
AB  - Immunologically, the parotid salivary gland is an effector site that secretes
      large quantities of polyspecific Abs into the saliva, mainly of the IgA isotype.
      It is considered to be part of the common mucosal immune system but the inductive
      site for the Ab-producing cells of the salivary gland has not yet been clearly
      identified. The origin and diversity of cells of B lineage can be investigated by
      analyzing their Ig heavy chain genes (IgH). We have obtained sequences of IgM and
      IgA VH4-34 genes from plasma cells in human salivary gland, duodenal lamina
      propria, and splenic red pulp. Related sequences were found in different areas
      sampled within each tissue studied, indicating that the plasma cells carrying
      these genes are widespread with limited diversity. Examples of related IgH genes
      that are isotype switched were also seen in the salivary gland. The genes from
      plasma cells of the salivary gland were highly mutated, as were duodenal plasma
      cell sequences. The level of mutation was significantly higher than that seen in
      splenic plasma cell sequences. Analysis of CDR3 regions showed that the sequences
      from salivary gland had significantly smaller CDR3 regions than sequences from
      spleen, due to differences in number and type of DH regions used. Sequences from
      duodenum also had smaller CDR3 regions. Therefore, plasma cells from human
      duodenum and salivary gland showed characteristics that differed from those of
      human splenic plasma cells.

PMID- 10640781
TI  - HIV-1-specific mucosal CD8+ lymphocyte responses in the cervix of HIV-1-resistant
      prostitutes in Nairobi.
AB  - Understanding how individuals with a high degree of HIV exposure avoid persistent
      infection is paramount to HIV vaccine design. Evidence suggests that mucosal
      immunity, particularly virus-specific CTL, could be critically important in
      protection against sexually acquired HIV infection. Therefore, we have looked for
      the presence of HIV-specific CD8+ T cells in cervical mononuclear cells from a
      subgroup of highly HIV-exposed but persistently seronegative female sex workers
      in Nairobi. An enzyme-linked immunospot assay was used to measure IFN-gamma
      release in response to known class I HLA-restricted CTL epitope peptides using
      effector cells from the blood and cervix of HIV-1-resistant and -infected sex
      workers and from lower-risk uninfected controls. Eleven of 16 resistant sex
      workers had HIV-specific CD8+ T cells in the cervix, and a similar number had
      detectable responses in blood. Where both blood and cervical responses were
      detected in the same individual, the specificity of the responses was similar.
      Neither cervical nor blood responses were detected in lower-risk control donors.
      HIV-specific CD8+ T cell frequencies in the cervix of HIV-resistant sex workers
      were slightly higher than in blood, while in HIV-infected donor cervical response
      frequencies were markedly lower than blood, so that there was relative enrichment
      of cervical responses in HIV-resistant compared with HIV-infected donors. HIV
      specific CD8+ T cell responses in the absence of detectable HIV infection in the
      genital mucosa of HIV-1-resistant sex workers may be playing an important part in
      protective immunity against heterosexual HIV-1 transmission.

PMID- 10640782
TI  - Atopic dermatitis is associated with a functional mutation in the promoter of the
      C-C chemokine RANTES.
AB  - Up-regulation of C-C chemokine expression characterizes allergic inflammation and
      atopic diseases. A functional mutation in the proximal promoter of the RANTES
      gene has been identified, which results in a new consensus binding site for the
      GATA transcription factor family. A higher frequency of this allele was observed
      in individuals of African descent compared with Caucasian subjects (p < 0.00001).
      The mutant allele was associated with atopic dermatitis in children of the German
      Multicenter Allergy Study (MAS-90; p < 0.037), but not with asthma. Transient
      transfections of the human mast cell line HMC-1 and the T cell line Jurkat with
      reporter vectors driven by either the mutant or wild-type RANTES promoter showed
      an up to 8-fold higher constitutive transcriptional activity of the mutant
      promoter. This is the first report to our knowledge of a functional mutation in a
      chemokine gene promoter. Our findings suggest that the mutation contributes to
      the development of atopic dermatitis. Its potential role in other inflammatory
      and infectious disorders, particularly among individuals of African ancestry,
      remains to be determined.

PMID- 10640783
TI  - Delineation of a CpG phosphorothioate oligodeoxynucleotide for activating primate
      immune responses in vitro and in vivo.
AB  - Oligodeoxynucleotides (ODN) containing unmethylated CpG dinucleotides within
      specific sequence contexts (CpG motifs) are detected, like bacterial or viral
      DNA, as a danger signal by the vertebrate immune system. CpG ODN synthesized with
      a nuclease-resistant phosphorothioate backbone have been shown to be potent Th1
      directed adjuvants in mice, but these motifs have been relatively inactive on
      primate leukocytes in vitro. Moreover, in vitro assays that predict in vivo
      adjuvant activity for primates have not been reported. In the present study we
      tested a panel of CpG ODN for their in vitro and in vivo immune effects in mice
      and identified in vitro activation of B and NK cells as excellent predictors of
      in vivo adjuvant activity. Therefore, we tested >250 phosphorothioate ODN for
      their capacity to stimulate proliferation and CD86 expression of human B cells
      and to induce lytic activity and CD69 expression of human NK cells. These studies
      revealed that the sequence, number, and spacing of individual CpG motifs
      contribute to the immunostimulatory activity of a CpG phosphorothioate ODN. An
      ODN with a TpC dinucleotide at the 5' end followed by three 6 mer CpG motifs (5'
      GTCGTT-3') separated by TpT dinucleotides consistently showed the highest
      activity for human, chimpanzee, and rhesus monkey leukocytes. Chimpanzees or
      monkeys vaccinated once against hepatitis B with this CpG ODN adjuvant developed
      15 times higher anti-hepatitis B Ab titers than those receiving vaccine alone. In
      conclusion, we report an optimal human CpG motif for phosphorothioate ODN that is
      a candidate human vaccine adjuvant.

PMID- 10640784
TI  - Linear PADRE T helper epitope and carbohydrate B cell epitope conjugates induce
      specific high titer IgG antibody responses.
AB  - Linear carbohydrate-peptide constructs based on the 13 amino acid nonnatural pan
      DR epitope (PADRE) and carbohydrate B cell epitopes are demonstrated to be potent
      immunogens. These data support our belief that PADRE should be considered as an
      alternative to more complex carriers for use in prophylaxis and therapeutic
      vaccines. Two model carbohydrate-PADRE glycoconjugates were used to demonstrate
      that PADRE could effectively provide T cell help for carbohydrate-specific Ab
      responses. Conjugates of PADRE covalently linked to the human milk
      oligosaccharide, lacto-N-fucopentose II or a dodecasaccharide derived from
      Salmonella typhimurium O-Ag induced high titer IgG Ab responses in mice, which
      were comparable to glycoconjugates employing human serum albumin (HSA) as the
      carrier protein. Different adjuvants, in combination with PADRE conjugates,
      allowed for the modulation of the isotype profile with alum supporting an IgG1
      profile; QS-21 an IgG2a, 2b profile, while an alum/QS-21 mixture generated a
      balanced IgG1/IgG2b isotype profile. As defined by binding to synthetic
      glycoconjugates, dodecasaccharide-specific Abs exhibited fine specificity similar
      to protective polyclonal Ab responses previously reported for dodecasaccharide
      protein conjugates. The same Abs bound to intact S. typhimurium cells, suggesting
      that biologically relevant specificities were produced. The affinity of the
      dodecasaccharide-specific Abs was further shown to be comparable to that of a
      well-characterized, high affinity monoclonal anti-carbohydrate Ab recognizing the
      same epitope.

PMID- 10640785
TI  - Responses of movement-sensitive visual interneurons to prey-like stimuli in the
      praying mantis Sphodromantis lineola (Burmeister).
AB  - Previous behavioral work using both mechanical and computer-generated visual
      stimuli has demonstrated that mantids use a computational algorithm to recognize
      prey similar to that used by some amphibian predators: A stimulus elicits prey
      capture behavior if it falls within a perceptual envelope defined by five
      fundamental stimulus parameters: (1) overall size, (2) length of the leading
      edge, (3) contrast to the background, (4) location in the visual field, and (5)
      apparent speed. In this study, we recorded simultaneously from both cervical
      nerve cords of monocular Sphodromantis lineola while they viewed the same visual
      stimuli successfully used in the behavioral studies. Extracellular recordings
      showed three consistently proportioned amplitude classes of movement-elicited
      spikes in each cord and these were repeatedly and reliably identifiable across
      mantids. Overall, the movement-elicited activity in both cords was dominated by
      very large spikes suggesting the existence of several large, descending movement
      sensitive interneurons projecting both ipsilaterally and contralaterally from the
      optic lobes. However, only the largest contralateral spikes occurred
      preferentially to prey-like stimuli, mirrored the behavioral response curves
      generated by S. lineola to the same visual stimuli, and displayed activity peaks
      that were correlated with the times at which the mantid emitted predatory
      strikes.

PMID- 10640786
TI  - Short-term effects of fights for social dominance and the establishment of
      dominant-subordinate relationships on brain monoamines and cortisol in rainbow
      trout.
AB  - We report changes in brain serotonergic, noradrenergic and dopaminergic activity,
      along with plasma cortisol concentrations, occurring during the initial 24-h
      period following the establishment of dominant-subordinate relationships in pairs
      of rainbow trout. Immediately (within 5 min) after the termination of staged
      fights for social dominance, a large increase in blood plasma cortisol was
      observed in both fight losers (future subordinate fish) and winners (future
      dominant fish). In dominant fish, cortisol decreased rapidly (within 3 h) to the
      level of unstressed controls, while continuing to increase in subordinate fish.
      At 3 h following fights, the brain serotonergic system was activated in both
      dominant fish and subordinate fish, at least in some brain regions
      (telencephalon). This effect was reversed in dominant individuals within 24 h of
      social interaction, whereas in subordinate fish a substantial activation of the
      serotonergic system was manifest in all brain regions by 24 h. Similarly, a
      strong increase in brain catecholaminergic activation was indicated after 24 h of
      social interaction in subordinate fish, but not in dominant fish. Relationships
      between plasma cortisol and brain serotonergic and noradrenergic activity in the
      various experimental groups suggest that these systems influence cortisol
      secretion under normal conditions and during moderate or short-term stress.

PMID- 10640787
TI  - Immunohistochemical localization of NMDA- and AMPA-type glutamate receptor
      subunits in the basal ganglia of red-eared turtles.
AB  - Corticostriatal and thalamostriatal projection systems have been shown to utilize
      glutamate as a neurotransmitter in mammals and birds. Although corticostriatal
      and thalamostriatal projection systems have been demonstrated in turtles, it is
      uncertain whether they too use glutamate as their neurotransmitter.
      Immunohistochemical localization of glutamate and of NMDA- and AMPA-type
      ionotropic glutamate receptor subunits (NMDAR2A/B, GluR1, GluR2/3, and GluR4)
      were used to address this issue. Numerous medium-sized neurons that were rich in
      NMDAR2A/B and GluR2/3 were observed in the striatal part of the basal ganglia of
      red-eared turtles. Smaller numbers of medium-sized neurons and some large neurons
      rich in the GluR1 and GluR4 subunits were also observed in the striatum. The
      striatal neuropil was notably rich in GluR1, GluR2/3 and NMDAR2A/B subunits. The
      pallidal region was specifically rich in large neurons possessing GluR4 subunits.
      Consistent with the glutamate receptors on striatal and pallidal neurons, sources
      of input to the striatum and pallidum in turtle such as the dorsomedial and
      dorsolateral thalamic nuclei (which appear to correspond to intralaminar thalamic
      nuclei), telencephalic pallial cell groups, and the apparent subthalamic nucleus
      homologue were rich in glutamatergic neurons. The results show that the
      thalamostriatal, corticostriatal and subthalamo-pallidal projection systems of
      turtles are glutamatergic and that similar basal ganglia cell types in turtles
      and mammals have largely similar glutamate receptor characteristics.

PMID- 10640788
TI  - A morphological study of the cochlear nuclei of the pigeon (Columba livia).
AB  - The pigeon cochlear nucleus angularis (NA) and nucleus magnocellularis (NM) were
      analyzed with Golgi and Nissl techniques. NA was divided into a medial NAm and NA
      proper, which could be subdivided further into an intermediate NAi and lateral
      NAl. NAm contained a mostly homogeneous population of a unique multipolar cell
      type with very short dendrites and large somatic spines. NA proper contained four
      cell types: large, medium, and small multipolars, and medium bipolar. The medium
      multipolar cells were most common, and resembled the multipolar cells of the
      mammalian ventral cochlear nucleus. NM presented a homogenous appearance with a
      mediolateral gradient of cell size and shape. Medially located higher best
      frequency NM principal cells had round cell bodies with small somatic spines and
      few dendrites. By comparison, laterally located low best frequency NM stellate
      cells had more dendrites and spindle shaped cell bodies. The similarities between
      the cell types of NA and the cell types in the cochlear nuclei of other amniote
      vertebrates may be due to homology or convergent evolution.

PMID- 10640789
TI  - Angina pectoris in severe aortic stenosis.
AB  - We studied the value of angina pectoris as a predictor of significant coronary
      artery disease (CAD) in very elderly patients with severe aortic stenosis (AS).
      The study population consisted of patients with age at least 70 years who were
      referred for balloon aortic valvuloplasty (n = 90 patients). Routine coronary
      angiography was performed before the valvular intervention. Patients were grouped
      according to the presence or absence of angina pectoris. Of the patients with
      angina pectoris, 78% had obstructive (>50% diameter stenosis) CAD on coronary
      angiogram, while only 17% of patients without angina pectoris had obstructive CAD
      (p < 0.01). Angina pectoris had a sensitivity of 78% and a specificity of 82% for
      prediction of obstructive CAD. This suggests that in elderly patients with severe
      AS, the presence of angina pectoris is a strong determinant of CAD, and the
      absence of angina strongly suggests absence of obstructive CAD. In a very elderly
      population, appropriate decision-making with respect to AS management should not
      await diagnostic coronary angiography.

PMID- 10640790
TI  - Fixed subaortic stenosis revisited. congenital abnormalities in 72 new cases and
      review of the literature.
AB  - Seventy-two patients aged 2-65 years (mean 20.2) with fixed subaortic stenosis
      (FSS) are reported. All patients underwent echocardiography and angiography prior
      to surgical intervention. Sixty-four (89%) had discrete subaortic stenosis (DSS)
      and 8 (11%) tunnel type stenosis (TSS). Patients with DSS aged 2-65 years (mean
      29) while patients with TSS aged 10-34 years (mean 19) and had a distinct female
      preponderance (7:1). Twenty-five patients (39%) with DSS had other congenital
      abnormalities of which aortic stenosis associated with bicuspid aortic valve was
      slightly more common than ventricular septal defect (7:6). Five patients with TSS
      had a small aortic annulus and hypoplastic aorta. Our data and those in the
      literature indicate that TSS although related to DSS has certain features that
      may set it apart as a distinct entity. In addition DSS appears to be associated
      with aortic stenosis and bicuspid aortic valve as frequently as with ventricular
      septal defect.

PMID- 10640791
TI  - CD40L activation in circulating platelets in patients with acute coronary
      syndrome.
AB  - The CD40-CD40L interaction, which was initially shown to have important roles in
      the T cell-mediated activation of B cells during humoral immune responses, is now
      known to have roles in activation of endothelial cells, smooth muscle cells, and
      macrophages within atherosclerotic plaques. Recently, CD40L expression was found
      in activated platelets in the thrombus in vivo and CD40L was reported to be
      responsible for the platelet-mediated activation of endothelial cells in vitro.
      To investigate the activation status of platelets in coronary artery disease
      patients, we tested expression levels of CD40L, and platelet-endothelial cell
      adhesion molecule-1 (PECAM-1/CD31) in platelets isolated from peripheral blood,
      using flow cytometric analysis. Twenty-nine patients with acute coronary syndrome
      (10 acute myocardial infarction and 19 unstable angina patients) were compared
      with 14 normal subjects or 14 stable angina patients. In platelets isolated from
      normal subjects, the expression of CD40L was not detected in all subjects. In the
      patients with acute coronary syndrome, the average level of CD40L showed a
      significant increase (p = 0.0028), while stable angina patients did not have any
      increase when compared to normal subjects. Patients with more complex lesions or
      vessel occlusion tended to have a high platelet CD40L level compared to patients
      who do not. The expression levels of CD31 were increased in a small portion of
      the ACS patients. These data indicate that the rupture of plaque and subsequent
      formation of thrombus may lead to the activation of CD40L expression in
      circulating platelets of ACS patients.

PMID- 10640792
TI  - The fractal dimension of atrial fibrillation: a new method to predict left atrial
      dimension from the surface electrocardiogram.
AB  - BACKGROUND: Previous studies have shown inconsistent relationships between left
      atrial size and various characteristics of atrial fibrillation seen on the
      surface electrocardiogram. The purpose of this study was to determine if the
      fractal dimension of atrial fibrillation derived from the ECG would be useful in
      predicting left atrial size. METHODS: The fractal dimension (D) was calculated
      using resting 12-lead ECGs from 53 patients (age 48-90) in chronic atrial
      fibrillation (greater than one year duration). D is the slope of the log/log plot
      of total length of a strip of atrial fibrillation against progressively
      decreasing lengths of measurement, plus one. Left atrial size was determined by
      standard M-mode echocardiography. RESULTS: When D was large (greater than 1.14),
      all patients had a left atrial size of 4.6 cm or greater. When D was small (less
      than 1. 09), all patients had a left atrial size of 4.6 cm or smaller. Values of
      D between 1.09 and 1.14 showed no relationship to atrial size. Larger values of D
      were associated with a higher degree of irregularity, roughness, and complexity
      in the surface ECG rhythm strips. CONCLUSIONS: In patients with chronic atrial
      fibrillation, the fractal dimension D derived from the surface ECG may be useful
      in predicting left atrial size.

PMID- 10640793
TI  - Cholesterol paradox in patients with paroxysmal atrial fibrillation.
AB  - Hypercholesterolemia is a major risk factor for coronary heart disease (CHD), but
      the associations among lipids, lipoproteins and paroxysmal atrial fibrillation
      (PAF) have not yet been reported. The associations among lipids, lipoproteins and
      PAF were examined in a case-control study, in which cases and controls were
      defined as those with/without definite ECG-detectable PAF, respectively. CHD
      patients were excluded from the study. The mean values of serum total cholesterol
      (TC), triglyceride (TG) and high density lipoprotein-cholesterol (HDL-C), after
      adjusting for age and gender, in patients with PAF were lower than those in
      patients without PAF (175 +/- 4 mg/dl vs. 190 +/- 3 mg/dl, 104 +/- 7 mg/dl vs.
      123 +/- 6 mg/dl, 46.0 +/- 1.7 mg/dl vs. 51.8 +/- 1.4 mg/dl, respectively), as
      assessed by an analysis of covariance. After controlling for age and gender, TC,
      TG and HDL-C (all in quartiles) were inversely and linearly (p < 0.05) associated
      with the percentage of patients with PAF, as assessed by a multiple logistic
      regression analysis. The associations between TC or TG and PAF varied with the
      HDL-C level: significant when HDL-C was low (p < 0.05), but not when HDL-C was
      high. The odds ratio (relative risk of PAF) for patients with both low TC or TG
      and low HDL-C was 4.08 (95% CI: 1.81-9.57) times or 9. 40 (3.25-32.0) times
      higher (p < 0.01) than that for patients with high TC or TG and high HDL-C,
      respectively. In conclusion, low serum levels of TC and TG were found in PAF
      patients, while reduced HDL-C may cause PAF. Hypolipoproteinemia including low
      HDL-C may affect atrial vulnerability and cause atrial fibrillation.

PMID- 10640794
TI  - Ventricular premature beats in triathletes: still a physiological phenomenon?
AB  - Sudden death is a tragic fact, unexpectedly arising in all age groups.
      Ventricular arrhythmias are the main cause. At the end of a maximal exercise test
      more ventricular premature beats were noted in a group of well trained
      triathletes compared with a similar control group. The etiology is
      multifactorial. When these ventricular premature beats are associated with
      specific structural and functional heart adaptations, echocardiographically and
      electrocardiographically well-documented, then those 'banal' ventricular
      premature beats cannot longer be considered as a physiological phenomenon. In
      these circumstances the involved subject is a candidate for dangerous arrhythmias
      and 'sudden cardiac death'. PURPOSE: The principal cause of 'Sudden cardiac
      death' is ventricular arrhythmias. We explore the incidence of ventricular
      premature beats (VPB) in triathletes, who engage in enforced endurance sports.
      METHODS: Fifty-two triathletes were compared with twenty-two control subjects
      with comparable anthropometric parameters in function of structural and
      functional cardiac adaptations. Maximal exercise tests were conducted on a
      stationary bicycle and a treadmill. During the last two minutes of each test, the
      VPB were registered. RESULTS: Statistically significant differences emerged in
      the cardiac structure and function between the triathletes and the controls.
      There were signs of cardiac hypertrophy and arguments for a supernormally
      diastolic left ventricular function in the triathletes. The performance capacity
      was also significantly higher in the triathletes. The maximal heart rate was
      significantly higher in the control group. The number of VPB was significantly
      higher in the triathletes. The increased risk of VPB in the triathlon group is
      caused by several factors: the degree of cardiac hypertrophy, the increased
      diastolic reserve, the duration of the exercise, the existence of an aortic
      insufficiency jet and some specific electrocardiographic findings. CONCLUSIONS:
      The triathlete has an increased risk of VPB during maximal efforts. We doubt the
      traditionally accepted view of the physiological nature of those VPB and suspect
      that the limit of physiological cardiac adaptations to sport efforts is exceeded
      with the appearance of VPB. The triathlete with VPB and with specific
      electrocardiographic and echocardiographic findings is a candidate for 'sudden
      cardiac death'.

PMID- 10640795
TI  - Reversal of left ventricular hypertrophy following once daily administration of
      felodipine for two years to elderly subjects with isolated systolic hypertension.
AB  - Left ventricular mass sometimes decreases during the treatment of hypertension.
      In a two-year open study, we investigated the ability of extended release (ER)
      felodipine (5 or 10 mg), plus chlorthalidone (25 mg), given once daily, to reduce
      left ventricular mass in 84 elderly patients with isolated systolic hypertension.
      Drug dosage was determined in an initial stepped-care titration phase lasting six
      weeks. Mean systolic blood pressure decreased after two years of treatment with 5
      or 10 mg of felodipine (p < 0. 001) and the left ventricular mass index decreased
      too (p < 0.0001). One or two weeks after withdrawal of therapies, blood pressure
      returned to pretreatment values. We concluded that left ventricular mass can be
      reduced in elderly patients with isolated systolic hypertension and ventricular
      hypertrophy who receive felodipine 5-10 mg once daily. This treatment was
      generally well tolerated.

PMID- 10640796
TI  - Volume measurement of the left ventricle in children with congenital heart
      defects: 3-dimensional echocardiography versus angiocardiography.
AB  - BACKGROUND: Volume measurement of the left ventricle is currently done by 2
      dimensional echocardiography or angiocardiography. However, for the calculation
      of volumes by these methods, geometrical assumptions must be made. For a precise
      ventricular volumetry, independent of mathematical assumptions, imaging
      techniques as the 3-dimensional echocardiography (3D-echo) are required, which
      permit the imaging of the real ventricular shape. The aim of the study was
      therefore to detect, whether 3D-echocardiography is suitable for left ventricular
      volumetry in children with congenital heart disease and whether the 3D
      echocadiographically measured volumes correlate sufficiently well with
      angiocardiographically measured left ventricular volumes. METHODS: 102 children
      with congenital heart disease were investigated. For angiocardiographic left
      ventricular volume measurement Simpson's rule was used. Results were corrected
      with Lange's correction factors. The 3D-echo data sets were registered with a
      rotating transthoracic transducer. Ventricular volumes were calculated after
      manual planimetry by summation of the volumes of the single slices. RESULTS: The
      left ventricular volume could be calculated by 3D-echo in 83% of patients of all
      ages. In comparison to angiocardiography, the measured volumes were 0.6 +/- 3. 3
      ml (0.9 +/- 25.8%) or 7.1 +/- 28.4 ml (7.4 +/- 12.1%) smaller during systole or
      diastole, respectively. The correlation coefficients r(2) were 0.89 for systolic
      and 0.93 for diastolic measurements after logarithmic transformation. Pressure or
      volume overload did not influence significantly the difference between the two
      methods. CONCLUSION: Transthoracic 3D-echocardiography with a rotating
      transmitter is feasible for volumetry of the left ventricle in most children. The
      volumes measured by 3D-echo were significantly smaller than those calculated from
      the angiocardiography by Simpson's rule. The measurements were not influenced by
      the kind of load of the ventricle. The correlation between the two methods is
      good.

PMID- 10640797
TI  - Failure of thrombin generation markers to triage patients presenting with chest
      pain.
AB  - Thrombin generation (TG) is an important pathogenic factor in acute coronary
      syndromes including acute myocardial infarction (AMI). Since the diagnostic
      utility of TG remains uncertain we sought to determine whether markers of TG may
      triage patients presenting to the Emergency Department with chest pain. Soluble
      plasma levels of prothrombin fragment 1+2 (F(1+2)), and thrombin/antithrombin III
      complexes (TAT) were determined by ELISA in 80 patients presenting with chest
      pain to the Emergency Department and compared with 20 controls. There were no
      differences in TG markers between patients with non-cardiac chest pain and
      healthy controls. Patients with unstable angina (UA), and congestive heart
      failure (CHF) did not differ from controls with respect to F(1+2), and TAT was
      elevated in UA patients (6.05 +/- 1.15 ng/ml, p = 0.033) when compared with
      controls (3.34 +/- 0.20 ng/ml). Contrary to expectations, TAT levels at
      presentation with AMI were well below the concentrations observed in patiens with
      UA and CHF. Moreover, plasma F(1+2) levels were significantly lower than in
      healthy controls (0.84 +/- 0.10 ng/ml versus 1.22 +/- 0.11, p = 0.026). At the
      time of presentation to the Emergency Department, F(1+2) and TAT failed to
      suitably triage patients with chest pain. The surprisingly low levels of TG
      markers in AMI patients before applying intensive therapy and reperfusion
      strategies deserves further investigation.

PMID- 10640798
TI  - Effect of age, heart rate and tricuspid regurgitation on the Doppler
      echocardiographic evaluation of right ventricular diastolic function.
AB  - Pulsed-wave Doppler analysis of tricuspid inflow and hepatic venous flow allows
      the determination of multiple parameters of right-ventricular (RV) diastolic
      function. This study sought to evaluate the influence of heart rate, age and
      tricuspid regurgitation on Doppler parameters of RV diastolic performance. We
      studied 80 subjects (20 normal and 60 with RV pathology) with Doppler recordings
      of the tricuspid inflow and hepatic vein. All tricuspid Doppler parameters were
      dependent on heart rate, age or regurgitation severity as were the hepatic vein S
      wave, S/D ratio and systolic filling fraction. The atrial reversal velocity in
      the hepatic vein Doppler tracing was not affected by age, heart rate or
      regurgitation. In addition, the inspiratory increase in this parameter was
      significantly elevated in RV pathologic states. This study demonstrates that most
      Doppler echocardiographic parameters of RV diastolic performance are dependent on
      age, tricuspid regurgitation or heart rate.

PMID- 10640799
TI  - Asymptomatic intracardiac thrombi and primary antiphospholipid syndrome.
AB  - Intracardiac thrombi have rarely been reported in patients with the
      antiphospholipid syndrome. We describe a new case revealed by systematic
      echocardiography in an asymptomatic woman who consulted for mild
      thrombocytopenia. Our case is characterized by a past history of migraine, fetal
      loss and psychiatric disturbances and by a high level of antiphospholipid
      antibodies (anticardiolipin, anti-beta(2)-glycoprotein I and lupus
      anticoagulant). Echography, in the absence of any cardiovascular symptom, showed
      bulky right intra-atrial thrombi requiring surgical excision. Histopathological
      analysis revealed the fibrino-cruoric nature of the lesion without myxoma. This
      case shows that, when faced with a mild thrombocytopenia associated with
      antiphospholipid antibodies, echocardiography may reveal a life-threatening and
      completely asymptomatic intracardiac thrombosis.

PMID- 10640800
TI  - Early-onset familial dilatation of the ascending aorta.
AB  - A mother and her two children with idiopathic ascending aortic dilatation are
      reported. This provides further evidence that genetic factors are involved in the
      etiology of aortic aneurysms and calls for screening first-degree family members,
      including children, of young adult patients diagnosed with this condition.

PMID- 10640801
TI  - Is it safe to administer thrombolytic therapy to myocardial infarction patients
      soon after laparoscopic cholecystectomy?
AB  - Thrombolytic therapy is usually contraindicated after abdominal surgery because
      of the risk of bleeding. We report a case of a 73-year-old woman who was admitted
      because of anterior wall acute myocardial infarction (AMI) two weeks after
      laparoscopic cholecystectomy. She was treated with streptokinase, aspirin and
      heparin and subsequently developed a hematoma at the site of the removed
      gallbladder. Our observation suggests that thrombolytic therapy for anterior AMI,
      two weeks after laparoscopic cholecystectomy, should be considered as a relative
      contraindication and an optional treatment in this life-threatening situation.

PMID- 10640802
TI  - Assignment of fibulin-5 (FBLN5) to human chromosome 14q31 by in situ
      hybridization and radiation hybrid mapping.

PMID- 10640803
TI  - Zoo-FISH analysis of dog chromosome 5: identification of conserved synteny with
      human and cat chromosomes.
AB  - Conserved segments of synteny between the human genome and chromosome 5 (CFA 5)
      of the domestic dog (Canis familiaris) have been identified by reciprocal
      chromosome painting analysis. A CFA 5 paint probe was applied to human metaphase
      spreads, revealing distinct hybridisation sites on human (HSA) chromosomes 1, 11,
      16, and 17. Paint probes for these human chromosomes were then hybridised to dog
      metaphase spreads, identifying the regions of CFA 5 with which homology is shared
      with the corresponding human chromosome. Application of the CFA 5 paint probe to
      metaphase spreads of the domestic cat (Felis catus, FCA) demonstrated
      hybridisation to cat chromosomes C1, D1, E1, and E2. Dog PCR primers for type 1
      markers known to lie in the corresponding regions of HSA 11, 16, and 17 were used
      to isolate dog BAC clones representing four genes. Fluorescence in situ
      hybridisation analysis confirmed their localisation to CFA 5 and suggested that
      two of the conserved segments lie in opposing orientations on CFA 5, compared to
      the human chromosome concerned. A third segment appears to lie in the same
      orientation on both human and dog chromosomes. No suitable gene markers were
      available for analysis of the fourth segment. The significance of these findings
      is discussed with reference to current and future dog genome mapping efforts.

PMID- 10640804
TI  - Lack of tumor suppression but induced loss of copies of indigenous chromosome 10
      in vitro following microcell-mediated transfer of a deleted human der(9)t(X;9)
      chromosome to Syrian hamster BHK-191-5C cells.
AB  - We have previously shown that microcell-mediated transfer of a der(9)t(X;9)
      chromosome, containing an almost complete human chromosome (HSA) 9 derived from
      the human fibroblast strain GM0705, into the Syrian hamster (Mesocricetus
      auratus) cell line BHK-191-5C suppressed the anchorage independence and
      tumorigenicity of the hybrids. Transfer of a normal HSA X did not have any effect
      on these phenotypes. Although the recipient cell line contained a 1:1 ratio of
      near-diploid and near-tetraploid cells, all hybrids retaining the der(9)
      chromosome were near-tetraploid, in contrast to hybrids retaining a normal X
      chromosome. In the present study, we have generated microcell hybrids by
      transferring another der(9)t(X;9) chromosome derived from the human fibroblast
      strain GM01429. This derivative chromosome contained a deletion on the short arm
      of HSA 9 and was also missing the distal part of the long arm of HSA 9 due to the
      involvement in a reciprocal (constitutive) translocation of this chromosome with
      HSA X. Cytogenetic analysis showed that all hybrid clones were near-tetraploid,
      confirming our previous finding. We also observed that the introduction of the
      deleted der(9) chromosome forced the hybrids to lose Syrian hamster chromosome
      10. A soft agar test and nude mice assay indicated that none of the hybrids was
      suppressed for either anchorage independent growth or tumor formation. These data
      suggest that there is an antagonistic relationship between growth-promoting genes
      and antiproliferative genes. The observed dosage effects of both growth-promoting
      and growth-suppressing genes indicate that cellular growth may be a quantitative
      trait.

PMID- 10640805
TI  - cDNA cloning of human muskelin and localisation of the muskelin (MKLN1) gene to
      human chromosome 7q32 and mouse chromosome 6 B1/B2 by physical mapping and FISH.
AB  - Muskelin is a novel intracellular protein, identified in mouse cells, that acts
      as a mediator of cell spreading and cytoskeletal responses to the extracellular
      matrix component thrombospondin-1. We report that human muskelin is 98% identical
      with mouse muskelin at the amino acid level. The human muskelin gene is located
      at 7q32. The mouse muskelin gene maps syntenically at chromosome 6 B1/B2.

PMID- 10640806
TI  - Comparative FISH mapping on Z chromosomes of chicken and Japanese quail.
AB  - Using direct R-banding fluorescence in situ hybridization, we assigned five
      functional genes-growth hormone receptor (GHR), prolactin receptor (PRLR), spleen
      tyrosine kinase (SYK), aldolase B (ALDOB), and muscle skeletal receptor tyrosine
      kinase (MUSK)-to the chicken Z chromosome. SYK and MUSK were newly localized to
      the chicken Z chromosome in this study. GHR and PRLR were situated close to each
      other on the short arm of the chicken Z chromosome, as are their counterparts on
      human chromosome 5. SYK, MUSK, and ALDOB, which have been mapped to human
      chromosome 9, were localized to the long arm of the chicken Z chromosome. Thus,
      the present results indicate the presence of conserved synteny between the
      chicken Z chromosome and human chromosomes 5 and 9. Using the same method, four
      of the genes (GHR, PRLR, ALDOB, and MUSK) were assigned to the Japanese quail Z
      chromosome. The locations of these four Z-linked genes were conserved between
      chicken and Japanese quail. The results support the notion that the avian Z
      chromosome and the mammalian X chromosome did not evolve from a common ancestral
      linkage group.

PMID- 10640807
TI  - A potential model for early stages of chromosomal evolution via concentric
      Robertsonian fans: a large area of polymorphism in southern short-tailed shrews
      (Blarina carolinensis).
AB  - Western Tennessee contains unusually highly polymorphic populations of southern
      short-tailed shrews (Blarina carolinensis). We previously documented eight
      Robertsonian translocations (ROBs) accounting for a variation in diploid number
      from 46 in most of this species' range to 34-40 in western Tennessee. We have now
      expanded our study to include data from adjacent areas in Tennessee and
      Mississippi, 10 localities in all. The new data show a variation in diploid
      number ranging from 31 to 41, four new ROBs (for a total of 12), and the novel
      finding of monobrachial translocations in this group. All animals collected from
      this large area (extending over 12, 000 km(2)) had some level of ROBs, and none
      represented the 2n = 46 form seen in other parts of the range of this species.
      Because other species of shrews (genus Sorex) are not affected in the same area,
      the factors and/or selective forces causing this extensive polymorphism in B.
      carolinensis must be unique to this species and to this geographic area. Some
      ROBs were found throughout this large area of over 12,000 km(2). Other
      translocations (including those with monobrachial homology) were located in one
      or two localities in this large area, and still other translocations were
      intermediate in their distribution. There was a concentric pattern to the
      evolution and presumed spreading of the ROBs. This allowed us to expand the
      concept of a Robertsonian "fan," introduced by Matthey (1970), to that of
      concentric evolution of multiple fusion fans: ROBs likely arose independently,
      separated temporally and geographically, and radiated into surrounding
      populations to create this complex zone of polymorphism. This is an active
      process in its infancy, and it is not as mature as that seen in European studies
      of Mus and Sorex.

PMID- 10640808
TI  - Cytogenetic mapping of 31 functional genes on chicken chromosomes by direct R
      banding FISH.
AB  - Using direct R-banding fluorescence in situ hybridization, we determined the
      location of 31 functional genes on chicken chromosomes. Replication R-banded
      chromosomes were obtained by synchronizing splenocyte cultures with excessive
      thymidine, followed by BrdU treatment. Thirty-one functional genes were directly
      localized to banded chicken chromosomes using genomic DNA and cDNA fragments as
      probes. The possibility of conserved linkage homology between chicken and human
      chromosomes was demonstrated for seven chicken chromosome regions (1p, 1q, 2q,
      4p, 4q, and 5q).

PMID- 10640809
TI  - Preferential occurrence of chromosome 21 malsegregation in peripheral blood
      lymphocytes of Alzheimer disease patients.
AB  - To further investigate our finding of high levels of spontaneous aneuploidy in
      somatic cells of Alzheimer's disease (AD) patients (Migliore et al. 1997), we
      studied the molecular cytogenetics of eight patients with sporadic AD and six
      healthy controls of similar age. Cytochalasin B-blocked binucleated peripheral
      blood lymphocytes from the AD patients and unaffected controls were used to
      measure micronucleus induction or other aneuploidy events, such as the presence
      of malsegregation in interphase nuclei (representing chromosome loss and gain).
      Dual-color fluorescence in situ hybridization (FISH) with differential labeled
      DNA probes was applied. We used a probe specific for the centromeres of
      chromosomes 13 and 21 combined with a single cosmid for the Down's syndrome
      region (21q22.2) to obtain information on spontaneous chromosome loss and gain
      frequencies for both chromosomes (13 and 21). FISH data showed that AD
      lymphocytes had higher frequencies of chromosome loss (evaluated as fluorescently
      labeled micronuclei) for both chromosomes, as well as higher frequencies of
      aneuploid interphase nuclei, again involving both chromosomes, compared to
      control lymphocytes. However, aneuploidy for chromosome 21 was more frequent than
      for chromosome 13 in AD patients. This preferential occurrence of chromosome 21
      in malsegregation in somatic cells of AD patients raises the hypothesis that
      mosaicism for trisomy of chromosome 21 could underlie the dementia phenotype in
      AD patients, as well as in elderly Down's syndrome patients.

PMID- 10640810
TI  - ULS: a versatile method of labeling nucleic acids for FISH based on a
      monofunctional reaction of cisplatin derivatives with guanine moieties.
AB  - The broad extension of an existing chemical DNA labeling technique for molecular
      cytogenetics is described. Called the Universal Linkage System (ULS(TM)), it is
      based on the capability of monoreactive cisplatin derivatives to react at the N7
      position of guanine moieties in DNA. Simple repetitive probes, cosmids, PACs, and
      chromosome-specific painting probes were labeled by ULS and used in a series of
      multicolor fluorescence in situ hybridization experiments on interphase and
      metaphase cells. It is demonstrated that ULS-labeled probes, in general, perform
      as well as the more conventional enzymatically labeled probes. The advantage of
      ULS labeling over enzymatic labeling techniques is that it is a fast and simple
      procedure, and that the labeling can easily be scaled up for bulk probe
      synthesis. In addition, with ULS labeling it is possible to label degraded DNA, a
      situation in which enzymatic labeling is known to perform unsatisfactorily.

PMID- 10640811
TI  - Genomic structure and chromosome mapping of the genes encoding clathrin
      associated adaptor medium chains mu1A (Ap1m1) and mu1B (Ap1m2).
AB  - The protein mu1B is a member of the medium chain family of the clathrin
      associated adaptor complex and is expressed exclusively in epithelial cells. We
      determined the genomic structure of previously cloned murine genes for mu1B
      (Ap1m2) and its closely related homolog, mu1A (Ap1m1). Comparison of their
      genomic structures revealed that the positions of introns are identical between
      these two genes, except for the insertion of an additional intron in Ap1m1
      (intron 4). By contrast, these structures are different from that of the more
      distantly related Ap2m1 gene encoding mu2. Taken together with the similarity of
      amino acid sequences among these genes, the data presented in this study suggest
      that Ap1m1/2 and Ap2m1 diverged long before the separation of Ap1m1 and Ap1m2,
      which most likely resulted from a relatively recent gene duplication. We also
      mapped AP1M2 to human chromosome 19p13.2 and Ap1m2 to the proximal region of
      mouse chromosome 9. The results are consistent with the fact that these regions
      are syntenic.

PMID- 10640812
TI  - Physical assignment of microsatellite- containing BACs to bovine chromosomes.
AB  - Here we report the physical assignment of 40 microsatellite markers by
      fluorescence in situ hybridization to 13 different bovine chromosomes. This
      information will be valuable in providing physically anchored landmarks for the
      construction of contigs throughout the bovine genome. It also is useful for the
      purpose of integrating the linkage maps of these chromosomes to their physical
      maps and determining the physical coverage of these linkage groups.

PMID- 10640813
TI  - Equal induction and persistence of chromosome aberrations involving chromosomes
      with heterogeneous lengths and gene densities.
AB  - Little is known about the factors modulating the initial induction and
      persistence of chromosome aberrations. Chromosome length and gene density have
      been proposed to play a significant role. We have therefore analyzed the
      induction and persistence of gamma-ray-induced aberrations involving four human
      chromosomes (1, 4, 18, and 19) with highly heterogeneous lengths and gene
      densities. Multicolor FISH was performed on a wild-type lymphoblastoid cell line
      1, 3, 7, 14, 28, 42, and 56 d after gamma-irradiation. The frequency of induced
      chromosomal aberrations was proportional to the length of the chromosomes.
      Complex aberrations, dicentrics, and fragments were highly unstable and
      disappeared during the first week after treatment and with similar kinetics for
      all four chromosomes. The frequency of translocations decreased with time and
      followed an exponential decline. Thirty percent of the gamma-ray-induced
      translocations were stable over the entire study period, irrespective of the
      length and the gene density of the chromosome involved. Accordingly, we concluded
      that the induction of chromosome aberrations is proportional to the length of the
      chromosome, that gene density makes no measurable contribution to induction, and
      that neither length nor gene density influences the persistence of chromosome
      aberrations.

PMID- 10640814
TI  - Comparative chromosome analysis (R- and C-bands) of two South African murid
      species, Lemniscomys rosalia and Rhabdomys pumilio (Rodentia, murinae).
AB  - We carried out a comparative chromosome analysis (R- and C-bands) on two South
      African murid rodent species, Lemniscomys rosalia and Rhabdomys pumilio, whose
      banded karyotypes are reported here for the first time. The study revealed that,
      in spite of minor differences in diploid number and the number of autosomal arms
      (48 vs. 46 and 58 vs. 60, respectively), these species differ by at least 10
      structural rearrangements, comprising seven Robertsonian translocations (two of
      which share monobrachial homology), two tandem translocations, and one
      pericentric inversion. Despite the high level of chromosomal differentiation
      observed, almost complete homologous banding patterns were detected between the
      two species. The present study therefore strengthens the hypothesis about the
      close phylogenetic affinities between L. rosalia and R. pumilio and their
      belonging to a set of genera referred to as "arvicanthine" rodents.

PMID- 10640815
TI  - Characterization and chromosome location of the mouse link protein gene (Crtl1).
AB  - Link protein (LP) plays an essential role in endochondral bone formation by
      stabilizing the supramolecular assemblies of aggrecan and hyaluronan. We have
      isolated and characterized the mouse link protein gene (Crtl1). It is longer than
      40 kb and transcribed from two alternative promoters, leading to heterogenous
      mRNAs between 5.3 and 1.3 kb in size. Apart from the coding sequence, the 5'
      flanking region is also highly conserved in mammals. Immunostaining revealed high
      levels of LP expression in the cartilaginous primordia of skeletal elements and
      low levels in other tissues. Using single-strand conformation polymorphism
      analysis, Crtl1 was assigned to mouse chromosome 13, tightly linked to Dhfr.

PMID- 10640817
TI  - Cloning, expression, and mapping of PDCD9, the human homolog of Gallus gallus pro
      apoptotic protein p52.
AB  - We report the sequence, tissue distribution, and chromosome location of a novel
      gene, PDCD9 (programmed cell death 9). PDCD9 is the mammalian counterpart of the
      Gallus gallus pro-apoptotic protein p52. The human cDNA has an open reading frame
      of 1,314 nucleotides and was predicted to encode a protein of 438 amino acids
      with a calculated mass of 50 kDa. The protein sequences of chicken, mouse, and
      human PDCD9 are remarkably conserved. PDCD9 mRNA is expressed ubiquitously in
      adult tissues, displaying a stronger signal in heart, skeletal muscle, kidney,
      and liver. PDCD9 was mapped to chromosome 5q11.

PMID- 10640816
TI  - Identification, characterization, and mapping of a mouse homolog of the gene
      mutated in Nijmegen breakage syndrome.
AB  - The rare autosomal recessive disorder Nijmegen breakage syndrome (NBS) results
      from mutations in the NBS1 gene on human chromosome 8q21. A mouse homolog of the
      NBS1 gene was isolated and its nucleotide sequence determined. Somatic cell
      hybrid analysis and fluorescence in situ hybridization were used to map this
      gene, Nbn, to mouse chromosome band 4A. Northern blotting revealed comparable
      levels of Nbn transcripts in most tissues in the mouse. However, transcripts were
      elevated 10-20 fold in the testes, consistent with a possible role for the
      product of the Nbn gene in meiotic recombination.

PMID- 10640818
TI  - Assignment of the ectodermal-neural cortex 1 gene (ENC1) to human chromosome band
      5q13 by in situ hybridization.

PMID- 10640819
TI  - Mouse mitotic spindle checkpoint Bub3 gene maps to the distal region of
      chromosome 7 by interspecific backcross analysis.

PMID- 10640820
TI  - The assignment of the human insulin receptor-related receptor gene (INSRR) to
      chromosome 1q21-->q23 by the use of radiation hybrid mapping.

PMID- 10640821
TI  - The murine urea transporter genes Slc14a1 and Slc14a2 occur in tandem on
      chromosome 18.

PMID- 10640822
TI  - Assignment of the genes for membrane-type-4 matrix metalloproteinase (Mmp17,
      MMP17) to mouse chromosome 5, human chromosome band 12q24.3 and membrane-type-5
      matrix metalloproteinase (Mmp24, MMP24) to mouse chromosome 2 and human
      chromosome band 20q11.2-->q12, respectively, by radiation hybrid and in situ
      hybridization.

PMID- 10640823
TI  - cDNA cloning and chromosome mapping of the mouse casein kinase I epsilon gene
      (Csnk1e).

PMID- 10640824
TI  - Assignment of the protein kinase homolog of YAK1 (HIPK3) to human chromosome band
      11p13 by in situ hybridization.

PMID- 10640825
TI  - Assignment of the rat phospholipase C-gamma1 gene Plcg1 to rat chromosome band
      3q42 by fluorescence in situ hybridization.

PMID- 10640826
TI  - Localization of the rat genes encoding the RNA binding protein TIAR (Tial1) and
      the integrin beta1 subunit (Itgb1): evidence for multiple homology relationships
      between the rat chromosome 19q12 region and the human genome.

PMID- 10640827
TI  - Structure and chromosome mapping of the human SIX4 and murine Six4 genes.
AB  - Six4, a member of the homeobox gene subfamily (Six), is expressed in a
      developmentally regulated fashion, and supposed to be involved in embryogenesis.
      We cloned the human SIX4 and murine Six4 genomic DNAs and determined their
      structures. The structure, including the 5' upstream region of both genes, was
      well conserved suggesting the conserved function and regulation of these genes.
      Human SIX4 was mapped to chromosome 14q23.

PMID- 10640828
TI  - Assignment of the programmed cell death 4 gene (PDCD4) to human chromosome band
      10q24 by in situ hybridization.

PMID- 10640829
TI  - Assignment of the human FAN protein gene (NSMAF) to human chromosome region 8q12-
      >q13 by in situ hybridization.

PMID- 10640830
TI  - Assignment of human desert hedgehog gene (DHH) to chromosome band 12q13.1 by in
      situ hybridization.

PMID- 10640831
TI  - Genomic structure, alternative transcripts and chromosome location of the human
      LIM domain binding protein 1 gene LDB1.
AB  - By protein interaction screening using a radioactive LMO2 protein probe we have
      isolated a LIM domain binding protein. The gene shows high homology to
      independently isolated genes from mouse, Xenopus and Drosophila called
      Ldb1/Nli/Clim-2, Xldb1 and Chip, respectively. The human and mouse genes differ
      by only two amino acids, suggesting that the gene that we have isolated is the
      human homologue. Here we describe the genomic organization, alternative
      transcript forms and the chromosome mapping of the human gene LDB1 (alias NLI).
      The gene is spread over at least 12 kb and has 11 exons. Preceding the described
      ATG initiation site in the mouse a highly conserved region between mouse, chicken
      and human was detected with a second possible in frame initiation site coding for
      further 36 amino acids. An alternative splice site adding six nucleotides
      corresponding to the addition of two amino acids at the end of exon 10 was found.
      The gene was mapped to chromosome 10q24-->q25 by in situ hybridization, a region
      frequently deleted in many types of cancer. Fine mapping with a radiation hybrid
      panel localized the gene in the interval between the markers D10S603 and D10S540.

PMID- 10640832
TI  - The human gene for the poly(A)-specific ribonuclease (PARN) maps to 16p13 and has
      a truncated copy in the Prader-Willi/Angelman syndrome region on 15q11-->q13.
AB  - The deadenylation nuclease or poly(A)-specific ribonuclease (PARN) is a 3'
      exonuclease, which degrades the poly(A)-tail of eukaryotic mRNA molecules. By DNA
      sequence analysis of cDNA and genomic clones, fluorescence in situ hybridization,
      and reverse transcriptase-PCR, we have determined that the active human PARN gene
      is located in 16p13 and that a truncated copy lacking the 5' end is located in
      15q11. The truncated gene maps close to a copy of the D15F37 gene family at the
      proximal Prader-Willi/Angelman (PWS/AS) deletion breakpoint region. Other copies
      of the F37 gene family are located at the distal PWS/AS deletion breakpoint
      region and on 16p11.2. Although PARN and F37 gene sequences are present on 15q
      and 16p, our data suggest that the synteny of these loci is the result of
      independent genetic events.

PMID- 10640833
TI  - Assignment of human MFNG, manic fringe Drosophila homolog, to 22q13.1 using
      tyramide fluorescence in situ hybridization (T-FISH).

PMID- 10640834
TI  - Standard G-, Q-, and R-banded ideograms of the domestic sheep (Ovis aries):
      homology with cattle (Bos taurus). Report of the committee for the
      standardization of the sheep karyotype.
AB  - Revised G-, Q- and R-banded karyotypes and ideograms for sheep chromosomes at the
      420-band level of resolution are presented. The positions of landmark bands on
      the sheep chromosomes are defined by their distance relative to the centromere to
      facilitate comparison with equivalent cattle chromosomes. Chromosome-specific
      (reference) molecular markers that have been mapped to sheep chromosomes and
      their equivalent cattle chromosomes are proposed. Reference markers will
      facilitate genome comparisons between sheep and cattle and minimise confusion due
      to chromosome nomenclature. Numbering of the Robertsonian translocation
      chromosomes remains as previously reported.

PMID- 10640835
TI  - Collagen uses in dermatology - an update.
AB  - Collagen-derived materials have been used in medicine for many decades. Sutures,
      hemostatic devices and matrices which stimulate cell growth and soft tissue
      augmentation are the major applications. In this update, we discuss the two major
      applications for collagen in dermatology: tissue augmentation and wound healing.

PMID- 10640836
TI  - Receptor tyrosine kinase and p16/CDKN2 expression in a case of tripe palms
      associated with non-small-cell lung cancer.
AB  - BACKGROUND: Tripe palms is a descriptive term for a cutaneous paraneoplastic
      keratoderma. Tripe palms are frequently associated with gastric and pulmonary
      carcinoma. The pathogenetic mechanism remains unknown. OBJECTIVE: To determine
      the influence of receptor tyrosine kinases, which are both expressed in pulmonary
      carcinomas and in human skin, we performed expression studies on epidermal growth
      factor receptor (EGFR), HER2, HER3 in a skin sample of tripe palms obtained from
      a patient with non-small-cell lung cancer with lymph node involvement. Two months
      after diagnosis, the patient had developed palmoplantar 'tripe palms'.
      Additionally, the expression of SRC, c-myc and p16/ CDKN2 were studied. METHOD:
      Conventional reverse-transcription polymerase chain reaction was performed on a
      tissue sample of tripe palms. RESULTS: Weak expression of HER2 and of p16/CDKN2
      was found. EGFR, HER3, c-myc and SRC were not expressed. CONCLUSION: Receptor
      tyrosine kinases of subclass I, the tyrosine kinase SRC and the oncogene c-myc
      play no major role in the pathogenesis of this case of tripe palms.

PMID- 10640837
TI  - Interleukin 11 reduces apoptosis in UVB-irradiated mouse skin.
AB  - BACKGROUND: UVB radiation, the major cause of skin cancer, causes apoptosis in
      the skin, characterized by the appearance of 'sunburn cells'. Interleukin 11 (IL
      11) has been shown to protect cells in the gastrointestinal system from
      chemotherapy and radiation-induced death. OBJECTIVE: To determine whether
      exogenous IL-11 has any effect on the UVB-induced apoptosis of cutaneous tissues.
      METHODS: Mice were injected with IL-11 or vehicle control prior to irradiation,
      and TUNEL assays were performed on paraffin-embedded tissue sections at various
      times after irradiation. RESULTS: Exogenous IL-11 protects epidermal
      keratinocytes, epithelial cells of the hair follicles inflammatory cells and
      fibroblasts in the dermis from UVB-induced apoptotic death. CONCLUSION: These
      findings suggest that IL-11 may play a role in the general homeostasis of the
      skin.

PMID- 10640838
TI  - Retinol and retinyl ester epidermal pools are not identically sensitive to UVB
      irradiation and anti-oxidant protective effect.
AB  - BACKGROUND: UV irradiation can deplete epidermal vitamin A, thus the hypothesis
      that UV-induced depletion of vitamin A in sun-exposed skin is involved in the
      pathogenesis of skin cancers and skin ageing. OBJECTIVES: In this study we
      addressed two questions: (1) Are retinol (ROL) and retinyl esters (RE) - the two
      predominant forms of vitamin A - equally sensitive to the action of UVB, and (2)
      could the depletion be prevented by anti-oxidants? METHODS: Hairless mice were
      irradiated with a single UVB dose, corresponding to the maximum of ROL and RE
      absorption. Retinoid content, enzyme activities catalysing the esterification of
      ROL (ARAT and LRAT) and the hydrolysis of RE (REH), as well as retinol-binding
      protein (CRBP-1) expression were determined in the epidermis. RESULTS: A single
      UVB dose induced a rapid, dose-dependent decrease in both ROL and RE in the
      epidermis of hairless mice, with partial replenishment after 24 h. The dose
      response curve for ROL showed a high sensitivity to UV at doses not exceeding 200
      mJ/cm(2), followed by a plateau, whereas RE underwent a continuous dose-dependent
      decrease at UVB doses up to 1 J/cm(2). A topical anti-oxidant mixture containing
      0.5% ascorbate, 0.25% tocopherol and 0.25% melatonin failed to protect epidermal
      RE from UVB-induced depletion, whereas it did prevent ROL depletion. ARAT and
      REH, as well as CRBP-1, were not affected by UVB in these conditions. CONCLUSION:
      Vitamin A storage in the epidermis comprises two forms, ROL and RE, that do not
      show similar sensitivity to acute UVB exposure. ROL stores comprise a UVB
      resistant (possibly by CRBP) portion and a UVB-sensitive portion that can be
      protected by anti-oxidants. RE stores do not show such a pattern.

PMID- 10640839
TI  - Successful treatment of chronic hand eczema with oral 9-cis-retinoic acid.
AB  - BACKGROUND: 9-cis-Retinoic acid (9-cis-RA) has a particular pattern of binding
      and activating retinoid receptors. Treatment of chronic hand eczema is often
      refractory to conventional treatment. OBJECTIVE: Evaluation of oral 9-cis-RA
      therapy in chronic hand eczema in a pilot study. METHODS: Thirty-eight patients
      with refractory chronic hand eczema were treated in an exploratory open-label
      study with oral 9-cis-RA. RESULTS: Twenty-one (55%) showed a very good response,
      13 (34%) a good response, 2 (5.5%) a moderate response and 2 (5.5%) no response.
      Side effects were mild. CONCLUSION: 9-cis-RA is a valuable drug when given at low
      doses to patients with chronic hand eczema.

PMID- 10640840
TI  - Dystrophic psoriatic fingernails treated with 1% 5-fluorouracil in a nail
      penetration-enhancing vehicle: a double-blind study.
AB  - BACKGROUND: Topically applied nail therapeutics need to permeate the nail plate
      to reach the nail bed or nail matrix and exert their potential beneficial effect
      at these locations to obtain a therapeutic benefit. So far only topically applied
      5-fluorouracil on affected nails of psoriatic patients has been shown to produce
      a notable clearance. Vehicle formulations enhancing nail permeation processes are
      thought to increase the concentration of the active agent and therefore
      therapeutic efficacy, possibly enabling the use of a low concentration of the
      active agent thereby lowering the incidence of adverse effects. OBJECTIVE: This
      study was designed to verify whether a recently developed nail penetration
      enhancer in a lotion formulation, Belanyx((R)) (urea, propylene glycol), improves
      the efficacy of a low concentration of 5-fluorouracil (1%) in psoriatic
      fingernail lesions. METHODS: In a randomised, double-blind, left-right study the
      efficacy of 1% 5-fluorouracil in the Belanyx vehicle was compared to the vehicle
      preparation Belanyx in dystrophic fingernails of 57 psoriatic patients. Both
      preparations were applied in a once daily regimen for 12 weeks. Responses and
      adverse effects of one selected target nail were recorded at screening, at
      baseline and at weeks 2, 4, 8 and 12 of treatment with a final assessment at week
      16: 4 weeks after the end of treatment. As parameter of efficacy was chosen the
      total nail area severity (NAS) score, consisting of the separate parameters nail
      pitting area, number of nail pits, subungual keratosis, onycholysis, oil spots
      and the various scores of overall improvement. RESULTS: The efficacy of 1% 5
      fluorouracil in lotion and that of the vehicle in suppressing the parameters of
      dystrophy were shown to be similar at the end of treatment (p = 0.063) or follow
      up (p = 0.130). Both preparations produced statistically significant improvements
      (p </= 0.05) for almost all assessed parameters after 12 weeks of treatment and
      after the 4 weeks of follow-up. For Belanyx lotion this applied to the nail
      pitting area, the number of nail pits, subungual keratosis, onycholysis and oil
      spots. The investigators' and patients' opinion of overall improvement of
      severity as well as the total NAS score of one target nail likewise showed a
      statistically significant improvement at the end of treatment and at the end of
      the observation period (p </= 0.05). With the 1% 5-fluorouracil lotion the same
      statistically significant improvements were obtained in all of the assessed
      symptoms with the exception of the number of pits and onycholysis at week 12 and
      week 16. Possible treatment-related adverse effects were established in 6
      patients showing inflammation and infection (3 patients) or discoloration (5
      patients); 3 patients on 5-fluorouracil lotion showed onycholysis. CONCLUSION:
      Addition of 1% 5-fluorouracil to the nail permeation enhancer Belanyx does not
      increase the efficacy of the active agent in psoriatic nail dystrophy of this
      study population. The obtained results also suggest that Belanyx lotion can be
      used in this indication since it has shown a favourable efficacy-safety ratio.

PMID- 10640841
TI  - Efficacy of topical application of eosin compared with zinc oxide paste and
      corticosteroid cream for diaper dermatitis.
AB  - BACKGROUND: Corticosteroids, zinc paste and eosin 2% are well-known topical
      agents for the treatment of moderate to severe diaper dermatitis. Among these
      treatments, the aqueous solution of eosin 2% is extensively used in several
      European countries, but not in the USA or Israel. OBJECTIVE: To assess the
      therapeutic efficacy of eosin 2% solution compared to the other treatment
      modalities for diaper dermatitis. METHODS: Fifty-four infants with diaper
      dermatitis, recruited from hospital wards and community clinics, were randomly
      assigned to three treatment groups: zinc oxide paste (containing allantoin 0.5%,
      cod liver oil 17% and zinc oxide 47epercnt;); clobetasone butyrate 0.05%, and
      aqueous solution of eosin 2%. The severity of the disorder was graded on a 6
      point scale by observation and quantitative measurement of the lesions. The
      groups were compared for rates and time to heal. Due to the red color of eosin, a
      double-blind controlled study was impossible. RESULTS: Following 5 days of
      treatment, the rate of complete healing in the group treated with eosin (61%) was
      significantly higher (p = 0.0479) than that in the zinc oxide paste and
      corticosteroid groups (22 and 33%, respectively). Furthermore, in cases of
      partial healing, the degree of improvement was higher in the eosin group than the
      other two (p = 0.0205). The fastest improvement was observed in the group treated
      with corticosteroid cream. CONCLUSION: Considering the potential hazards of
      topical corticosteroids and the greater overall efficacy of eosin 2% solution, we
      suggest that eosin is the preferred treatment for diaper dermatitis.

PMID- 10640842
TI  - Clobetasol under hydrocolloid occlusion in psoriasis results in a complete block
      of proliferation and in a rebound of lesions following discontinuation.
AB  - BACKGROUND: It is a well-established fact that very potent corticosteroids are
      highly effective in the treatment of psoriatic plaques, and that the addition of
      a hydrocolloid occlusive dressing (HCD) enhances its efficacy. It is known that
      topical steroids induce normal differentiation and diminish hyperproliferation
      during treatment of psoriatic plaques. These changes are reflected by an increase
      in keratin 10 (K10) and a decrease in keratin 6 (K6), respectively. However, the
      influence of class IV corticosteroids under HCD on K10 and K6 subpopulations has
      never been studied. OBJECTIVE: The present study was performed to study
      quantitatively the influence of a class IV topical steroid under HCD on the
      dynamics of K10 and K6 subpopulations. METHODS: In the present study, we treated
      moderately severe stable psoriatic plaques with clobetasol-17-propionate under
      HCD until clearance was achieved. We took biopsies prior to treatment, after
      clearance and at relapse. Using flow cytometry, we studied the dynamics of K10
      and K6 subpopulations. RESULTS: Prior to treatment, 41.8% of all cells expressed
      K6. After treatment-induced clearance, this proportion decreased to 1.2%, which
      is below the normal range. At relapse, pre-treatment levels were observed again.
      A trend to an increasing number of basal cells and an increase in the
      proliferative activity of these basal cells at relapse compared to the stable
      situation prior to treatment was observed. CONCLUSION: We conclude that
      clobetasol under hydrocolloid occlusion induces virtually a total block of
      proliferation of the basal cell population and decreases hyperproliferation
      associated keratins dramatically. Furthermore, based upon epidermal cell
      characteristics, we conclude that a rebound phenomenon occurs following
      discontinuation of therapy with clobetasol under hydrocolloid occlusion.

PMID- 10640843
TI  - Bullous and pruritic variant of disseminated superficial actinic porokeratosis:
      successful treatment with grenz rays.
AB  - We describe a case of intensively pruritic and partially bullous disseminated
      superficial actinic prorokeratosis, with acute flare-ups. Histopathological
      examination showed the characteristic cornoid lamella and subepidermal blister
      formation in one biopsy. Grenz ray treatment resulted in a marked regression of
      the skin lesions and pruritus.

PMID- 10640844
TI  - Two cases of cutaneous apocrine ductal carcinoma of the axilla. Case report and
      review of the literature.
AB  - We report 2 cases of cutaneous apocrine ductal carcinoma (CADC) of the axilla in
      a 64- and a 54-year-old male. Histological examination revealed 2 solid, ductal
      and glandular tumors with decapitation secretion. Tumor cells showed cellular and
      nuclear atypism, and infiltrative growth of tumor cell nests was also observed.
      Although there were no characteristic features of extramammary Paget's disease on
      the overlying skin, case 1 exhibited a typical Paget's phenomenon. We concluded
      that the Paget's phenomenon of case 1 was a result of upward extension of the
      tumor in the dermis. The neoplastic cells of both cases were
      immunohistochemically positive for gross cystic disease fluid protein, lysozyme,
      CD15 and carcinoembryonic antigen but negative for S-100 protein. Based on these
      findings, we concluded that these tumors were cutaneous apocrine ductal
      carcinomas. There was no evidence of tumor remnants in the axilla, and the
      patients have shown no signs of local recurrence or metastasis. We also reviewed
      the literature and summarize here the clinical features of CADC.

PMID- 10640845
TI  - Two cases of pilomatrixoma in Turner's syndrome.
AB  - Multiple and familial cases of pilomatrixomas have been reported in myotonic
      dystrophy. We report 2 cases of pilomatrixoma in Turner's syndrome. Between 5 and
      19 years of age, 1 patient developed 6 pilomatrixomas including atypical
      occurrences on the chest and the posterior aspect of the leg. This is the first
      report of multiple pilomatrixomas in Turner's syndrome.

PMID- 10640846
TI  - Bacterial interdigital scaly erythema (Kitamura): a possible new clinical entity.
AB  - Four patients with scaly erythema on their finger webs and sides of their fingers
      during summer are described. These patients were working in either butcher's
      shops or a sushi bar, where they handled raw meat, chicken or fish for many
      hours. The eruptions first appeared as scaly erythema, sometimes accompanied by
      small pustules, on the second, third and fourth finger webs, and later the
      erythema extended to the sides of the fingers and palms. Maceration and/or
      shallow erosion sometimes appeared on the finger webs. Symptoms were usually
      mild; the patients complained of slight itching, irritation or pain. Direct
      examination of specimens stained with Parker blue-black ink containing KOH
      revealed scales containing bacterial granules or filaments. Several species of
      bacteria were cultured including Corynebacterium sp. Fungus was not detected in
      either KOH specimens or in cultures. The lesions responded rapidly to topical or
      oral antibiotics; however, they recurred frequently during hot and humid weather.
      Hitherto a similar condition has not been described and is possibly a new
      clinical entity.

PMID- 10640847
TI  - Vaginal ulcers as initial presentation of subacute myelomonocytic leukemia.
AB  - Cutaneous disorders can allow the detection of severe systemic disease. We report
      the case of a woman with vaginal ulcerations. The lesions persisted despite oral
      antibiotics, antifungal therapy and local care. Biopsy showed an inflammatory
      ulcerating process with discrete vasculitis. Peripheral blood count showed
      thrombocytopenia and monocytosis, and bone marrow smears revealed as subacute
      myelomonocytic leukemia. A review of the literature indicates that genital
      ulcerations are not known in association with subacute myelomonocytic leukemia.
      In our case, the persistent vaginal ulcerations were the initial symptom of the
      subacute myelomonocytic leukemia.

PMID- 10640848
TI  - Acute monocytic leukemia presenting as cutaneous involvement.
AB  - Specific cutaneous lesions appearing during acute monocytic leukemia (AMoL) are
      more frequent than those associated with other types of leukemia. However, skin
      involvement preceding the presence of leukemic cells in the peripheral blood is
      quite rare. In this paper, we describe a case where a 25-year-old male had
      multiple infiltrative erythemas and nodules on his arms. Histologically, the
      nodules were formed by masses of tumor cells in the dermis. Peripheral-blood
      tests revealed no abnormalities, but bone marrow aspiration from the sternum led
      to a diagnosis of AMoL. The diagnosis of specific cutaneous lesions of AMoL was
      confirmed by the results of cytochemical studies of bone marrow smears, and
      cutaneous nodules of cutaneous biopsy specimens led to early diagnosis. Complete
      remission was achieved with combination chemotherapy and peripheral blood stem
      cell transplantation.

PMID- 10640849
TI  - Paederus dermatitis: a report of 46 cases in Aydin, Turkey.
AB  - Paederus dermatitis is a specific form of acute irritant contact dermatitis
      caused by pederin, a secretion of insects of the genus Paederus. The disease is
      characterized by vesicles, bullae and sometimes small pustules on an erythematous
      base with sudden onset of a stinging, burning sensation. The dermatitis is most
      frequently seen in regions with a hot, tropical climate. We present 46 cases from
      Aydin, Turkey, a province well known for its long hot summers. These are the
      first cases reported from this region. We would like to point out the possibility
      of Paederus dermatitis in regions with a similar climate and suggest that 'night
      burn' be included among other differential diagnoses of a grouped vesicular
      and/or pustular lesion on an erythematous base.

PMID- 10640850
TI  - Atopic dermatitis and HTLV-1-associated myelopathy: associated or coincidental
      disorders?
AB  - Reports from Jamaica have indicated that some patients with infective dermatitis
      or atopic dermatitis (AD) are seropositive for antibodies to human T-lymphotropic
      virus type 1 (HTLV-1). We describe a 32-year-old Israeli woman with long-term AD
      and paresthesia in the distal parts of the extremities. Neurological examination
      revealed a positive Babinski's sign. HLA typing demonstrated that this patient
      has the common HTLV-1-associated myelopathy/tropical spastic paraparesis
      (HAM/TSP) and infective dermatitis haplotype for DRB1* DQB1*. The presence of
      HTLV-1 was demonstrated with polymerase chain reaction; HTLV-1-antibodies were
      detected by the Western blot method and by inoculation of the patient's
      peripheral blood mononuclear cells into F344 rats. This study confirms the
      presence of HTLV-1 antibodies and proviral genome in a patient with AD which
      later evolved into HAM/TSP. We cannot yet conclude whether these two diseases are
      associated or coincidental disorders.

PMID- 10640851
TI  - Simultaneous reactivation of herpes simplex virus and varicella-zoster virus in a
      patient with idiopathic thrombocytopenic purpura.
AB  - Simultaneous reactivation of distinct Herpesviridae with development of clinical
      manifestations is exceptional. We report a 48-year-old woman suffering from
      idiopathic thrombocytopenic purpura. As the disease remained refractory to
      corticosteroids, immunoglobulins and splenectomy, a cure of vinblastine was
      administered. An atypical stomatitis developed few days later.
      Immunohistochemistry on a Tzanck smear and a biopsy evidenced a Herpes simplex
      virus type 1 (HSV-1) infection. The patient presented simultaneously a single
      necrotic lesion on the abdomen. Immunohistochemistry on a skin biopsy revealed
      the presence of the varicella-zoster virus (VZV) gE, gB and IE63 proteins.
      Intravenous aciclovir was initiated. The present case of simultaneous clinical
      infections by HSV-I and VZV underlines the importance of complementary viral
      identification testing in the event of unusual clinical presentations.

PMID- 10640852
TI  - A case of acral Darier's disease.
AB  - A sporadic case of acral Darier's disease in a 20-year-old woman is reported. The
      disease was diagnosed on the basis of clinical, histological and ultrastructural
      data. Only few cases of exclusively acral clinical manifestations of Darier's
      disease have been described in the literature.

PMID- 10640853
TI  - Congenital alopecia areata: another case.

PMID- 10640854
TI  - Single-hair transplant: a novel technique.

PMID- 10640855
TI  - Myopathy, destructive arthropathy and peripheral neuropathy in a patient with
      reticular erythematous mucinosis and monoclonal gammopathy.

PMID- 10640856
TI  - Reversible ascending motor neuropathy as a side effect of systemic treatment with
      ciclosporine for nodular prurigo.

PMID- 10640857
TI  - Cutaneous lupus erythematosus following the lines of Blaschko.

PMID- 10640858
TI  - The 'Doughnut Sign' revisited.

PMID- 10640859
TI  - Prolonged cytosolic calcium elevations in growth cones contacting muscle.
AB  - Encounters by growth cones or neurites of motor neurons with target muscle cells
      evoke prolonged elevations in the concentrations of neuronal cytosolic free
      calcium ([Ca(2+)](c)). These calcium elevations are initiated at the point of
      contact and spread throughout the neuron over a period of tens of minutes. In
      this study, we addressed how target muscle cells initiate this unique presynaptic
      response. Primary questions regarding the nature of the muscle signal are whether
      it is diffusible and whether it must first be induced by a growth cone as part of
      reciprocal interaction. We addressed whether the signal was strictly target
      contact dependent by fixing C2 mouse myotubes with formaldehyde, rinsing
      extensively and then allowing processes of chick ciliary ganglion neurons to
      interact with them. We observed frequent sustained elevations in [Ca(2+)](c) in
      ciliary ganglion processes contacting the fixed myotubes. As a control, ciliary
      neurons were allowed to interact with fixed myotubes of the S27 variant line. S27
      cells were isolated from the parent C2 line on the basis of a defect in
      glycosaminoglycan biosynthesis and previously shown to be defective in supporting
      synaptic vesicle localization in contacting neurites. Few elevations in
      [Ca(2+)](c) were detected in encounters between ciliary processes and fixed S27
      cells. In addition, neuron-neuron encounters never elicited prolonged increases
      in [Ca(2+)](c). These observations demonstrate contact dependence in the neuronal
      response and rule out reciprocal cellular interactions, diffusible factors or
      electrical activity in the muscle. The defect in carbohydrate biosynthesis in S27
      cells further suggests that cell surface carbohydrates are essential to the
      signal on the myotube surface that triggers the presynaptic elevation in
      [Ca(2+)](c). We conclude that growth cone contact with preexisting cell surface
      structures on target muscle cells induces changes in presynaptic [Ca(2+)](c) that
      are associated with retrograde signaling, and that proper carbohydrate
      biosynthesis is required for this signal.

PMID- 10640860
TI  - Evidence for regulation of myelin protein synthesis by contact between adjacent
      Schwann cell plasma membranes.
AB  - The spontaneously immortalized S16 Schwann cell line expresses higher levels of
      myelin-associated glycoprotein (MAG) and PO glycoprotein and their messenger RNAs
      when grown at high density than at low density [Sasagasako et al: J Neurochem
      1996;66:1432-1439]. This up-regulation of myelin protein expression at high
      density is not associated with decreased cellular proliferation and may be caused
      by direct cell-to-cell contact. To investigate the hypothesis that increased mRNA
      levels for myelin proteins are caused by contact between Schwann cells, sparse
      S16 cell cultures were treated for 48 h with plasma-membrane-enriched fractions
      isolated from dense S16 cells. The treatment had no effect on the proliferation
      of the cells, but MAG and PO mRNAs were elevated 2- and 1.3-fold, respectively,
      in comparison to untreated cells. These effects on levels of myelin protein mRNAs
      were eliminated by pretreatment of the membrane fraction with heat or trypsin and
      were not caused by plasma membrane fractions from NIH 3T3 cells. These data
      support the hypothesis that homotypic contact between Schwann cells up-regulates
      expression of myelin proteins and suggest the possibility of autotypic contact
      mediated regulation of myelinogenesis by adjacent spiraled membranes of
      individual Schwann cells.

PMID- 10640861
TI  - Monoclonal antibody against a neuronal antigen impairs formation of the axon
      scaffold in grasshopper central nervous system.
AB  - The pathway a growing axon follows is determined by a number of cues, including
      differential adhesion to surface molecules on axons and the matrix of the
      fascicles along which they grow. We have characterized the differential
      expression of an extracellular antigen and the effects of a monoclonal antibody
      against this molecule on the development of the grasshopper central nervous
      system (CNS). The 5C1 monoclonal antibody was generated against ganglion chains
      of grasshopper embryos; it labels cell bodies of newly differentiated neurons and
      their axons as they extend. Electron microscopy of embryos at 42% of development
      reveals that 5C1 labels neuronal filopodia, axons and somata, and areas of glial
      membrane in apposition to neurite fascicles. After 70% of development, labeling
      is lost from axon bundles, but remains on cell bodies. 5C1 also cross-reacts with
      an epitope expressed in Drosophila CNS during embryonic development. Enzymatic
      digestion suggests that the antigen recognized by the antibody is likely to be a
      glycolipid. In embryos exposed to 5C1 during early stages of development of the
      CNS, at the time when the first axons begin to extend, the formation of axon
      pathways is blocked or greatly delayed. Our results suggest that the 5C1 antigen
      participates in the formation of the axon scaffold and may play a functional role
      in the initiation and maintenance of axon outgrowth during early development of
      the CNS.

PMID- 10640862
TI  - A mechanism for acetylcholine receptor clustering distinct from agrin signaling.
AB  - Acetylcholine receptors (AChRs) and other postsynaptic molecules cluster
      spontaneously on cultured C2 myotubes. The frequency of clustering is enhanced by
      neural agrin, neuraminidase, or calcium through a signaling pathway which
      includes tyrosine phosphorylation of a muscle-specific kinase (MuSK) and the AChR
      beta-subunit. Vicia villosa agglutinin (VVA) lectin, previously shown to
      potentiate agrin-induced clustering on C2 myotubes, is shown here to also
      potentiate neuraminidase- and calcium-induced clustering of AChRs, while having
      no effect on the level of tyrosine phosphorylation of MuSK or the AChR beta
      subunit. We propose that VVA lectin increases the frequency of AChR clustering
      through a mechanism that is distinct from agrin signaling, and that may involve
      alpha-dystroglycan.

PMID- 10640863
TI  - Prenatal ethanol exposure reduces spinal cord motoneuron number in the fetal rat
      but does not affect GDNF target tissue protein.
AB  - Fetal rats were exposed throughout gestation to one of three diets: an ethanol
      containing liquid diet, a liquid diet with the isocaloric substitution of sucrose
      for ethanol or a laboratory chow control diet. At postnatal day 1 (P1), the
      spinal cords were taken for analyses of motoneuron number and size. These
      analyses revealed a significant loss of motoneurons and a reduction of motoneuron
      size in the ethanol-exposed animals, compared to both sucrose and chow controls.
      Spinal cord length and ventral horn volume were not altered as a result of
      ethanol treatment, so the change in motoneuron number cannot be attributed to
      volumetric changes. The content of the motoneuron survival factor glial cell-line
      derived neurotrophic factor (GDNF) was also assessed in the P1 limb motoneuron
      target tissue. This analysis was undertaken because GDNF is a potent survival
      factor for developing motoneurons and has been shown to protect this population
      from ethanol neurotoxicity. Thus, its depletion could contribute to motoneuron
      loss. These analyses, using the ELISA assay, did not detect reductions in GDNF in
      the ethanol-exposed animals. Therefore, alterations in other neurotrophic factors
      or ethanol neurotoxicity by other means appear to be responsible for the
      motoneuron loss. These results are consistent with earlier studies in the chick
      embryo, which also found reduced motoneuron numbers as a function of
      developmental ethanol exposure, and point again to the general lethality of
      ethanol to the developing nervous system.

PMID- 10640864
TI  - Developmental regulation of the distribution of aromatase- and estrogen-receptor-
      mRNA-expressing cells in the zebra finch brain.
AB  - Strong evidence exists for the masculinizing effects of estrogen on the neural
      network that controls song learning and behavior in zebra finches. However, the
      mechanisms by which estrogen acts to influence the development of this circuitry
      are not well understood. In this study, we used in situ hybridization to detect
      the distribution of cells expressing mRNAs for AROM and ERalpha at postnatal days
      5-25 (P5-25). Our findings revealed developmental regulation of both mRNAs in the
      neostriatum, archistriatum, hippocampus, diencephalon and midbrain. Within the
      vocal control circuitry, cells expressing ERalpha mRNA were found in the medial
      HVC (P10-25), archistriatum lateral to the RA (Ad; P25), in the ICo (P5-25), and
      along the fiber tract containing efferents from the RA. High levels of AROM mRNA
      were found in the neostriatum, including both the lateral and mMAN and along
      their projections to the RA and HVC, respectively, (P5-25), in the archistriatum
      (P18-25) and around RA (P18). Codistribution of the two mRNAs occurred along the
      border of the HVC suggesting that in this region, local synthesis of estrogen may
      be acting through its nuclear receptor to regulate gene transcription. Taken
      together, our findings show that the neural circuitry controlling song may be
      exposed to the effects of estrogen during early postnatal development. However,
      in most of the song control regions, these mRNAs were not expressed together
      either temporally or spatially, indicating that AROM may have a role in the
      development of the song system independent of ERalpha.

PMID- 10640865
TI  - Evidence that CNS hypomyelination does not cause death of jimpy-msd mutant mice.
AB  - Mice expressing three of the proteolipid protein (Plp) mutations in the mouse
      (jimpy, jimpy-msd, and jimpy-4J) all have a severe deficiency of CNS myelin and
      oligodendrocytes (OLs), and die sometime in their 4th postnatal week. The
      prevailing view has been that the animals' shortened life span and lack of myelin
      are causally related. Here we describe the survival of jimpy-msd males for as
      long as postnatal day (P) 210. Although these spontaneously occurring longer
      lived jimpy-msd males show a 2- to 8-fold increase in numbers of myelinated axons
      in many CNS regions, this does not protect them from a later but still premature
      death. Investigating the cause of premature death may reveal previously
      undiscovered properties of the myelin genes or the cells that express them, or
      perhaps additional unsuspected cellular responses that contribute to the disease.
      This study identifies small accumulations of inflammatory cells in the brain
      parenchyma of jimpy-msd mice as young as P14 and as old as P60, suggesting that
      the pathology of the disease produced by at least this Plp mutation may be far
      more complex than has been previously recognized.

PMID- 10640866
TI  - Quaking*shiverer double-mutant mice survive for at least 100 days with no CNS
      myelin.
AB  - Mice expressing mutations that produce CNS hypomyelination often die prematurely:
      the more severe the hypomyelination, the shorter the life span. However, we have
      previously described jimpy-msd mice that survive twice as long as usual; although
      they acquire significantly increased amounts of myelin, they still succumb long
      before their unaffected littermates. This result contradicts any postulated
      causal relationship between extent of CNS hypomyelination and premature death of
      the animal. Here we have addressed this question in another way, by using an
      animal model that does not involve a proteolipid protein (Plp) gene mutation. We
      demonstrate that quaking*shiverer double-mutant mice can survive for at least 100
      days without any CNS myelin whatsoever. Therefore, at least for a mouse, absence
      of CNS myelin is not lethal per se.

PMID- 10640867
TI  - Activation of microglia during developmentally regulated cell death in the
      cerebral cortex.
AB  - Neuronal elimination in the developing CNS is accomplished by an orderly type of
      cellular suicide called programmed cell death. The principal non-neuronal cells
      implicated in regulating programmed cell death and subsequent phagocytosis of
      dying neurons are the brain's macrophage population, the microglia. Little is
      known about the signaling between microglia and neurons during programmed cell
      death. However, macrophages in non-neural tissues express receptors for
      immunoglobulin (IgG) and complement, and these molecules help regulate
      phagocytosis of dying cells and foreign organisms. Since many of the neurons
      generated early in CNS development are transient cell types that are
      immunoreactive for IgG [Upender et al.: J Comp Neurol 1997; 384:271-282], we
      hypothesized that IgG might alter the phagocytic properties of microglia within
      the developing nervous system and potentiate engulfment of dying cells. To begin
      to address this hypothesis, we first asked whether cortical neurons
      immunoreactive for IgG or calbindin-D28k exhibit morphological evidence of
      programmed cell death in the cerebral cortex of neonatal rat pups. Secondly, we
      quantified the incidence of contacts made by microglia on IgG- vs. calbindin
      immunoreactive neurons. Thirdly, perturbation experiments were performed to
      elevate intracortical levels of IgG and the incidence of microglia:neuron
      contacts were determined. We found that although the nuclei of some IgG
      immunoreactive neurons exhibited condensation and fragmentation characteristic of
      programmed cell death, we did not observe pyknotic calbindin-immunoreactive
      neurons. IgG-immunoreactive neurons were also more likely to be contacted by
      microglia than calbindin-immunoreactive neurons. Elevating intracortical levels
      of IgG experimentally led to a dramatic increase in the expression of microglia
      complement receptors throughout the cerebral cortex. Taken together, these
      results suggest that IgG normally present within neuronal subsets in the
      developing cerebral cortex could serve to locally regulate the expression of
      complement receptors on microglia.

PMID- 10640868
TI  - Prenatal orogastric gene delivery results in transduction of the small bowel in
      the fetal rabbit.
AB  - BACKGROUND: Gene therapy for meconium ileus, or other genetic diseases involving
      the gastrointestinal epithelium, may be possible with prenatal delivery of the
      CFTR gene to the gastrointestinal tract. Although minimally invasive techniques
      will probably be used for any future therapy of gastrointestinal disease, it is
      important to first test this strategy with a reliable animal model. METHODS: The
      technique of orogastric fetal gene delivery was assessed using 7 pregnant rabbits
      (22 days' gestation n = 1, 25 days' gestation n = 4, 28 days' gestation n = 2).
      Four fetuses from each litter were given an adenoviral vector carrying a marker
      gene by instilling it into the posterior pharynx with an animal feeding needle (1
      x 10(10) particles of ADV/RSV/LacZ suspended in 0.3 ml of saline), with the
      untreated fetuses serving as control animals. RESULTS: There were no recoverable
      fetuses from the does that had surgery at 22 and 28 days (n = 3) due to maternal
      death (n = 2) and premature delivery (n = 1). Among the 4 does that underwent
      hysterotomy at 25 days of gestation, 1 underwent cesarean section 2 days after
      fetal gene delivery and 3 delivered at term, 5 (n = 1) or 6 (n = 2) days
      following gene delivery. Eleven of the 16 experimental pups and 7 untreated
      control animals were collected alive, and were sacrificed at delivery for study.
      Nine of the 11 experimental pups (82%) showed positive blue (LacZ+) nuclei in the
      small intestine by X-gal staining. No positive cells were found in 7/7 control
      animals. The presence of the reporter gene LacZ was confirmed in 8/11 (73%) virus
      treated pups by PCR with 5/5 control animals negative for LacZ by PCR.
      CONCLUSIONS: There was significant maternal and fetal loss related to anesthetic
      and husbandry issues when surgery was performed at 22 or 28 days of gestation.
      Based on these preliminary results, we conclude that orogastric gene delivery in
      the rabbit fetus at 25 days' gestation is an encouraging animal model to study
      fetal delivery to the gastrointestinal tract.

PMID- 10640869
TI  - Hemangioma of the umbilical cord: stenotic change of the umbilical vessels.
AB  - We report a rare case of an umbilical cord hemangioma diagnosed by ultrasound at
      16 weeks of gestation. The umbilical cord consisted of a hemangioma nodule and
      pseudocysts near the placental insertion, a large gelatin-like swelling adjacent
      to the nodule on its fetal side, and a short normal part extending to the navel.
      At 17 weeks of gestation, this condition resulted in the intrauterine death of
      the fetus. Microscopically, there were communications between the capillary of
      the hemangioma and the umbilical vessels, verifying the origin of the tumor.
      Moreover, the umbilical vein and one of the arteries changed stenotically due to
      the intravascular proliferation of the hemangioma. These findings indicate the
      possibility of a pathological association between the umbilical cord hemangioma
      and fetal demise due to impaired umbilical circulation.

PMID- 10640870
TI  - Course of maternal serum magnesium levels in low-risk gestations and in preterm
      labor and delivery.
AB  - OBJECTIVES: To describe the course of total and ionized magnesium and total
      calcium levels in maternal serum during low-risk pregnancies and to compare women
      who developed preterm labor and delivery with those who delivered at term.
      METHODS: 209 women with low-risk pregnancies were enrolled in a prospective trial
      before the 18th week of gestation. No woman received oral magnesium
      supplementation. The ionized and total magnesium and total calcium levels in
      maternal serum were measured every 4-6 weeks. The data were grouped into 3
      gestational periods (</=18, 19-27 and >/=28 weeks of gestation) for overall
      comparison and analyzed with the general linear model for repeated measurements
      and ANOVA. p values of < 0.05 were considered statistically significant. RESULTS:
      145 gestations were available for analysis. 27 women were hospitalized for
      preterm labor and in 16 of these preterm delivery occurred. Ionized and total
      magnesium and calcium levels were significantly lower after the 18th week of
      gestation than before. The cation levels in women with preterm labor and delivery
      did not differ from those with term delivery. CONCLUSION: Ionized and total
      magnesium and calcium levels decrease with increasing gestational age. Preterm
      labor and delivery do not seem to be related to changes in serum cation levels.

PMID- 10640871
TI  - Failure of amniotic septostomy in the management of 3 subsequent cases of severe
      previable twin-twin transfusion syndrome.
AB  - INTRODUCTION: Amniotic septostomy has been described as a method to treat twin
      twin transfusion syndrome. A case report of 3 patients treated in this way is
      described. CASE REPORT: Three subsequent patients, who presented with twin-twin
      transfusion syndrome, were treated by amniotic septostomy. All 3 showed initial
      improvement in the amniotic fluid volume and mobility of the donor fetus.
      However, all three pregnancies were lost within 5 days of the amniotic septostomy
      due to ruptured membranes and premature labour. CONCLUSION: In our experience,
      amniotic septostomy did not improve the pregnancy outcome in twin-twin
      transfusion syndrome. Possible reasons for this are discussed.

PMID- 10640872
TI  - Serum enzyme activities in premature infants with bronchopulmonary dysplasia.
AB  - Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma
      glutamyltranspeptidase (gamma-GT) and lactate dehydrogenase (LDH) activities were
      measured in 26 premature infants with bronchopulmonary dysplasia (BPD) (group 1),
      and in 24 premature controls, matched for gestational age and birth weight (group
      2). Blood samples were taken serially on 3, 10, 20, 30 and 60 postpartum days.
      Group 1 and group 2 premature infants showed statistically higher LDH activities
      on the 3rd postpartum day. These differences disappeared later and LDH activities
      progressively decreased with time in both premature groups. Mean AST values of
      group 1 and group 2 premature infants were also significantly higher on the 3rd
      postpartum day. Subsequently, in all groups, AST showed a postpartal decrease,
      and a stabilization from the 10th day of life until the 2nd postnatal month. Mean
      ALT values were instead, comparable on the 3rd postnatal day and subsequently
      increased, although not significantly. Like the AST, gamma-GT of group 1 and
      group 2 premature infants were slightly more elevated on the 3rd postpartum day.
      The subsequent decrease was however transitory, and at 1 and 2 postnatal months a
      noticeable, significant progressive increase in mean values was found. It is
      concluded that serum ALT, AST, LDH and gamma-GT measurement of sick premature
      infants within the first 2 months of life are not significantly altered by the
      occurrence of BPD.

PMID- 10640873
TI  - Significance of echogenic foci in the left ventricle of the fetal heart in a low
      risk population.
AB  - OBJECTIVE: To determine if there exists a significant association between
      prenatally detected left ventricular echogenic foci and chromosomal
      abnormalities. METHODS: Over a 10-month period the presence of intracardiac
      echogenic foci was recorded on all low-risk patients referred for anatomical
      assessment. The study group consisted of 113 singleton fetuses and was compared
      to a control group with no foci. RESULTS: Among the study group with echogenic
      foci, 5 chromosomal abnormalities (three trisomies) were detected. In the control
      group only one chromosomal abnormality was diagnosed. CONCLUSION: An association
      exists between the finding of intracardiac echogenic foci in the fetus and the
      presence of chromosomal abnormalities.

PMID- 10640874
TI  - Are bilateral fetal lung masses double trouble?
AB  - OBJECTIVES: To examine the perinatal natural history of bilateral fetal cystic
      lung masses. METHODS: The records of a tertiary medical center over a 3-year
      period were reviewed for cases of fetal bilateral pulmonary masses. RESULTS:
      Three of 98 fetuses referred for evaluation over a 3-year period from September
      of 1995 to August of 1998 had bilateral lung lesions. Two of these cases resulted
      in live births, while one, associated with hydrops, resulted in death after
      preterm delivery. CONCLUSIONS: Similar to prenatally diagnosed unilateral lung
      lesions, hydropic fetuses with bilateral cystic lung lesions have a poor
      prognosis. Nonhydropic fetuses, however, may be asymptomatic despite persistent
      lesions on postnatal CT scan. These observation may prove helpful for prenatal
      counseling for these rare lesions.

PMID- 10640875
TI  - Amniotic band syndrome in triplet pregnancy.
AB  - We present a case of amniotic band syndrome leading to encephalocele in one
      triplet. In this case, discordance in fetal growth was observed at 9 weeks'
      gestation, and the amniotic membrane was not recognized in the sac of the
      smallest fetus. Thus, significant first-trimester growth discordance in
      multifetal pregnancies suggests congenital anomalies, and examinations
      considering amniotic band syndrome should be performed. Absence of the amniotic
      membrane in the gestational sac may be a useful marker of amniotic band syndrome.

PMID- 10640877
TI  - Multifetal pregnancy reduction and selective termination: the Canadian
      experience.
AB  - OBJECTIVE: To describe the experience of two Canadian referral centres with
      multifetal pregnancy reduction (MFPR) and selective termination (ST). METHODS:
      Retrospective chart review of all MFPR and ST procedures during the periods from
      January 1, 1990, to December 31, 1997 (Vancouver), and from September 1, 1995, to
      December 31, 1997 (Toronto). Outstanding outcome data were obtained by telephone.
      All women were managed according to standard protocols. Non-parametric analysis
      of continuous variables and Fisher's exact test for categorical variables were
      used. RESULTS: 61 women underwent transabdominal MFPR (n = 44) or ST (n = 17).
      Median maternal age: MFPR and ST 33.0 years; gestational age at reduction: MFPR
      11.4, ST 20.2 weeks; procedure duration: MFPR 4, ST 10 min. 89% MFPR and 12% ST
      cases followed assisted reproduction. 7% MFPR and 18% ST pregnancies lost <24
      weeks (n.s.). 97% MFPR and 83% ST non-reduced fetuses delivered alive. Median
      delivery gestational age: MFPR and ST 37 weeks. CONCLUSIONS: The results are
      similar to published series. This procedure has increased options for Canadian
      couples, offering the procedure 'close to home', reducing costs and, more
      importantly, the significant psychological morbidity following these procedures.

PMID- 10640876
TI  - Continuous observation of nitric oxide production in the fetal rat brain during
      uteroplacental ischemia.
AB  - OBJECTIVES: To demonstrate real-time changes in nitric oxide (NO) production
      within fetal rat brain during uteroplacental ischemia and subsequent reperfusion.
      METHODS: Using a selective microsensor for NO, changes in NO electrocurrent in
      the brains of 10 fetal rats at gestational day 20 were observed during and after
      30 min occlusion of uterine vessels in anesthetized pregnant rats. RESULTS: The
      NO electrocurrent reached 397 +/- 71.0% of the control level 30 min after
      occlusion and increased throughout the observation (p < 0.05) until placental
      administration of 1 M of L-NAME. In contrast, no significant changes in NO
      electrocurrent were found in 7 sham operated rats. CONCLUSION: An NO-specific
      microelectric sensor detected excessive NO production by fetal rat brains in
      response to uteroplacental ischemia.

PMID- 10640878
TI  - Cerebellar hypoplasia: could it be a sonographic finding of abnormal fetal
      karyotype in early pregnancy?
AB  - OBJECTIVE: To evaluate the screening utility of early transvaginal measurement of
      transverse cerebellar diameter for the identification of fetuses with abnormal
      karyotype. METHODS: We retrospectively analyzed the transverse cerebellar
      diameters of 56 fetuses with abnormal karyotypes (study group) and 1,892 euploid
      fetuses (control group) at 11-16 weeks of gestation. A nomogram with confidence
      intervals (10th and 90th percentile) was established for transverse cerebellar
      diameters versus gestational age in the control fetuses and individual values for
      chromosomally abnormal fetuses were plotted. A regression equation of expected
      transverse cerebellar diameter for each gestational age was calculated from 100
      euploid fetuses chosen randomly and applied to the remaining control fetuses and
      to the study group fetuses. The ratio of observed to expected cerebellar
      diameters was calculated in the control group and compared with those obtained in
      single chromosome anomalies. RESULTS: The measurements obtained in aneuploid
      fetuses are within the normal range for gestational age. Only in 2 of the 37 Down
      syndrome fetuses and in 2 of the 4 fetuses with trisomy 13 was the observed to
      expected measurement ratio below the 5th percentile for gestational age.
      CONCLUSION: In our experience, the measurement of transverse cerebellar diameter
      cannot be considered as a useful tool in the detection of aneuploidy in early
      pregnancy. The data concerning trisomy 13 are too small, so that caution should
      be exercised when supposing an association between cerebellar hypoplasia
      detectable by early transvaginal scan and risk of this aneuploidy.

PMID- 10640879
TI  - Initiating extradural analgesia during labour: comparison of three different
      bupivacaine concentrations used as the loading dose.
AB  - OBJECTIVE: Potential effects of extradural analgesia on the progress of labour
      and obstetric outcome are still a matter of concern and the focus of ongoing
      debates. Despite this, little attention is paid to the initiation of extradural
      labour analgesia. The objective of this prospective, randomized, double-blind
      trial was to identify the optimal of three concentrations of bupivacaine used as
      a loading bolus for initiating extradural analgesia during labour. METHODS: Sixty
      seven full-term parturients requesting extradural analgesia received either
      bupivacaine 0.25% (group A), 0.125% (group B) or 0. 0625% (group C). Bupivacaine
      administration was titrated to achieve a pain score </=1.5 on a 10-cm visual
      analogue scale (VAS) and was limited to a maximum of 20 ml of the study drug. We
      recorded the time to achieve a VAS </=1.5, the total amount of local anaesthetic
      used, sensory level, maternal and foetal as well as neonatal side effects.
      RESULTS: The probability of obtaining a VAS pain score </=1. 5 was significantly
      lower in group C. Although mean times to reach a VAS pain score </=1.5 were not
      statistically different, survival curves show a significantly lower probability
      for reaching this score. Significantly more parturients in group A developed a
      motor block >/=1 based on using a modified Bromage scoring scale. There were no
      differences in incidence of maternal hypotension, ephedrine requirements, foetal
      heart rate abnormalities, mode of delivery and neonatal outcome. CONCLUSIONS: Of
      the three concentrations used in this clinical setting, 0.125% was the most
      suitable concentration of plain bupivacaine to initiate extradural analgesia in
      labour. Using 0.25% bupivacaine increased the incidence of motor block, whereas
      for 0.0625% plain bupivacaine the probability to achieve adequate analgesia was
      unacceptably low.

PMID- 10640881
TI  - Locomotion and posture in Lagothrix lagotricha.
AB  - This long-term study of woolly monkey (Lagothrix) locomotor and postural
      behaviour employs methods identical to those used during a previous study of the
      locomotion and posture of two species of Ateles, allowing a detailed comparison
      between the two genera, which are strong competitors in extensive parts of the
      Amazon basin and northern Andes. As in Ateles, Lagothrix locomotion can be
      divided into five patterns, based on limb usage: quadrupedal walking and running,
      suspensory locomotion, climbing, bipedalism (very rare in wild woolly monkeys)
      and leaping. Lagothrix differs from Ateles primarily in its greater reliance on
      quadrupedal locomotion during both travel and feeding and on its de-emphasis of
      the use of suspensory locomotion as compared to Ateles, while the use of climbing
      and leaping is roughly equal in the two genera. Lagothrix exhibits more
      generalised (primitive) locomotive behaviour in accordance with its morphology,
      in comparison to the more specialised Ateles. The generic differences reflect
      differences in habitat use and particularly foraging ecology.

PMID- 10640880
TI  - A longitudinal study of the growth pattern of the maxillary sinus in the pig
      tailed macaque (Macaca nemestrina).
AB  - The ontogeny of sexual dimorphism in maxillary sinus size in a nonhuman primate
      was studied longitudinally for a period of 8 years in 25 female and 25 male
      Macaca nemestrina via lateral cephalograms. The maxillary sinus was traced and
      its area digitized. The growth of female maxillary sinuses was described with a
      Gompertz model; the best fit to the male data was obtained by the logistic model.
      Growth curves and confidence intervals revealed that the sinuses grew in a
      similar fashion for 3-4 years in both sexes. After this, female sinuses achieved
      a plateau in their development while male sinuses continued to grow. Confidence
      intervals suggested that size dimorphism appeared at the age of 6.3 years. Lowess
      regression indicated growth spurts in both sexes. Females experienced an earlier
      and smaller spurt than males. Sexual dimorphism in maxillary sinus size seems to
      represent a combination of differences in velocity and length of growth. This
      study indicates that growth of the maxillary sinus follows closely the growth in
      body size. Nevertheless, due to the variation in sinus size in Macaca, it is
      questionable if body size is the main determinant of maxillary sinus size. It is
      suggested that Macaca, with its wide geographic range and different environments,
      is an especially appropriate genus to use to test hypotheses about the evolution
      of skull pneumatization in primates.

PMID- 10640882
TI  - Preliminary vocal repertoire and vocal communication of wild bonobos (Pan
      paniscus) at Lilungu (Democratic Republic of Congo).
AB  - Vocal communication in bonobos, Pan paniscus, has been studied mainly in captive
      groups. The few studies carried out in the wild are on only specific aspects of
      their behaviour. The aim of this study is to give a preliminary description of
      the vocal repertoire and a qualitative account of the contextual use of the
      vocalizations described. Observations were carried out on three wild communities,
      with a total of 68 individuals, for 685 h. No artificial feeding was used at any
      stage of the study. The vocal repertoire is composed of 15 vocal units and 19
      sequences. There is great variability both in the sequences and in the vocal
      units, and the categories are not always completely discrete. The repertoire is
      compared to that of captive bonobos described by De Waal. Most sequences are used
      in various contexts, and for each behaviour there is a complete array of
      sequences and their variation. The behaviour patterns observed and the sequences
      uttered by the animals in each context are discussed.

PMID- 10640883
TI  - Female dominance in captive red ruffed lemurs, Varecia variegata rubra (Primates,
      lemuridae).

PMID- 10640884
TI  - Predation on a wild slow loris (Nycticebus coucang) by a reticulated python
      (Python reticulatus).

PMID- 10640885
TI  - Habituation of bonobos (Pan paniscus): first reactions to the presence of
      observers and the evolution of response over time.

PMID- 10640886
TI  - Maldescendus testis.
AB  - Maldescendus testis is a common congenital abnormality occurring in 2-5% of full
      term boys at birth in the Western countries. By 3 months of age, the incidence
      rate spontaneously reduces to 1-2% in this group. The etiology of the disorder is
      not known, but normal hypothalamo-pituitary-gonadal axis is usually a
      prerequisite for normal descent of the testes. Abnormal sexual differentiation is
      associated with maldescent. However, the majority of boys with maldescended
      testes show no endocrine abnormalities after birth. Several defects in
      developmental genes, such as homeobox genes and Insl3, have been described to
      cause cryptorchidism in mice, and disturbances in the regulation of these genes
      or their mutations may explain etiology of a large part of human testicular
      maldescent in the future. Increased degeneration of germ cells can be observed in
      undescended testes after the first year, and therefore early treatment is
      recommended. Surgical treatment is the most effective and reliable method to
      bring testes into the scrotum, but hormone treatment with either hCG or GnRH
      analogues can be considered, particularly in cases where testes can be palpated
      in high scrotal position. The efficacy of hormone treatment is less than 20% and
      depends on the initial location of the testis. Nonpalpable testes rarely descend
      with hormone treatment. Both surgery and hormone treatment can have untoward
      effects. Treatment with hCG has been associated with an inflammation-like
      reaction in the testes and an increased rate of apoptosis of germ cells leading
      to a reduced adult size of the testes. Vascular complications can occur during
      surgery, particularly in staged orchidopexies. Men with a history of undescended
      testis have an increased risk of testicular cancer. Impaired fertility is another
      long-term risk associated to maldescended testes. Fertility potential may be
      improved by early treatment. Although our knowledge on cryptorchidism has
      increased considerably during the last decades, many questions remain to be
      answered: Is the incidence rate increasing? What is causing maldescent? Do
      hormones have any role in the treatment?

PMID- 10640887
TI  - Auxological and biochemical evaluation of pubertal suppression with the GnRH
      agonist leuprolide acetate in early and precocious puberty.
AB  - We studied the auxological effects of treatment with the GnRH agonist leuprolide
      acetate (Lucrin((R))) at 3.75 mg/ 28 days in 38 children with early or precocious
      puberty. We present our newly developed scoring system, the Puberty Suppression
      Score (PSS), in which clinical and biochemical parameters determine whether
      suppression was effective. Leuprolide acetate suppressed pubertal development in
      the majority of cases. During treatment there was a significant correlation
      between the number of times that PSS was >0 and gain in predicted adult height
      (PAH) compared to initial prediction at the start of treatment. After 6 months of
      treatment, ineffective suppression measured by PSS was associated with the
      magnitude of gain in PAH. We conclude that a leuprolide acetate dosage of 3.75 mg
      every 28 days effectively suppresses puberty. PSS is helpful in monitoring the
      suppressive capacity of a GnRH agonist. We recommend to start with leuprolide
      acetate at 3.75 mg/28 days and to increase the injection frequency or dose in
      case PSS is >0 after 6 months of treatment.

PMID- 10640888
TI  - Comparison of bone metabolic markers between maternal and cord blood.
AB  - We studied 41 normal pregnant women and their neonates in order to compare bone
      metabolism between them. We examined more specific bone formation markers (intact
      osteocalcin, bone-specific alkaline phosphatase) and a recently developed and
      more sensitive bone resorption marker (C-telopeptide of type I collagen; CTX)
      than previously available in maternal and umbilical cord venous blood taken at
      delivery. The concentrations of all markers of bone turnover, including CTX, in
      cord serum were significantly higher than those in maternal serum. There was no
      significant correlation between maternal and cord serum levels for any marker.
      These results indicate that fetal bone turnover is markedly enhanced compared
      with maternal bone turnover and is independent of maternal bone metabolism in
      late pregnancy.

PMID- 10640889
TI  - Effect of vitamin D(3) treatment in the neonatal or adolescent age (hormonal
      imprinting) on the thymic glucocorticoid receptor of the adult male rat.
AB  - Single neonatal treatment with 25 microg vitamin D(3) significantly decreased the
      thymic glucocorticoid receptor density (B(max)) of 6-week-old male rats. In
      females, a similar treatment did not cause any changes. Single vitamin D(3)
      treatment (50 microg) during adolescence (i.e. 6-week-old animals) significantly
      increased the glucocorticoid receptor density in adult (10-week-old) males. No
      significant changes in receptor affinity (K(d)) could be observed. Considering
      that in earlier experiments similar neonatal treatments influenced bone mineral
      mass and sexual behavior, the hormonal imprinting effect of vitamin D(3) and its
      harmful effect on the development of other members of the steroid receptor
      superfamily, seems to be unquestionable.

PMID- 10640890
TI  - Diagnosis of growth hormone (GH) deficiency and the use of GH in children with
      growth disorders.

PMID- 10640891
TI  - The ethical dilemma of growth hormone treatment of short stature: a scientific
      theoretical approach.

PMID- 10640892
TI  - Immunological models of type 1 diabetes.
AB  - Type 1 diabetes mellitus is a serious health problem that affects several million
      new people each year. Although it is recognized that type 1 diabetes results from
      an autoimmune destruction of the insulin-producing beta-cells in the pancreatic
      islets of Langerhans, its etiopathogenesis is still not well understood. A
      certain genetic phenotype seems to be required, but it is not sufficient per se
      to trigger diabetes development. Numerous studies have pointed to the role of
      infectious agents as important environmental factors in breaking 'self'-tolerance
      and triggering activation of autoreactive T cells. Activated T cells, in turn,
      destroy target cells harboring the corresponding tissue-specific self-antigen,
      causing organ damage and loss of function. Several theories have been proposed to
      explain how environmental factors can initiate and/or perpetuate autoimmunity
      towards pancreatic beta-cells.

PMID- 10640893
TI  - Management of males with 45,X/46,XY gonadal dysgenesis.
AB  - Males with the 45,X/46,XY karyotype and malformations of the external genitalia
      carry an increased risk of developing germ cell neoplasia of the gonads. We have
      studied gonadal tissue from 10 individuals, 0.3-17 years of age, with a male
      phenotype and either hypospadias and/or cryptorchidism. Four patients, 0.3-15
      years of age, had carcinoma in situ, 1 boy had Sertoli-cell-only pattern and the
      remainder prepubertal histology. Gonadoblastoma or invasive carcinoma was not
      found. On the basis of our current knowledge we propose a strategy for management
      and follow-up of these boys in order to detect possible premalignant histological
      changes early and prevent development of a gonadal tumour.

PMID- 10640894
TI  - Solitary thyroid nodules in 93 children and adolescents. a 35-years experience.
AB  - Over a period of 35 years from 1963 to 1998, 93 patients under the age of 18
      years, 74 girls and 19 boys, were seen for evaluation of a solitary nodule of the
      thyroid gland. All patients had preoperative scintiscans of the thyroid gland and
      had their solitary nodule excised. Seventy-seven of the patients had a cold
      nodule on scintiscanning. The most common cause of solitary thyroid nodules was
      follicuar adenoma (68.9%). Fifteen of the 77 cold nodules were malignant (19.9%).
      The frequency of carcinoma in males was 26.3%, while in females it was 13.5%. Our
      experience suggests that the incidence of thyroid carcinoma may be decreasing in
      pediatric patients not exposed to known risk factors. Available diagnostic
      methods for attempting differentiation of benign from malignant solitary nodules
      are reviewed and recommendations to the clinical management are presented.

PMID- 10640895
TI  - Power Doppler improves the diagnostic accuracy of color Doppler ultrasonography
      in cold thyroid nodules: follow-up results.
AB  - The usefulness of a recent color Doppler (CD) ultrasonography technique, named
      power Doppler (PD), was evaluated in the diagnosis of thyroid nodules showing low
      or absent uptake of (99m)Tc-pertechnetate, in order to investigate the
      possibility to improve the diagnostic accuracy of ultrasonography. The rationale
      was the evidence that at PD the color map displays the total integrated Doppler
      power in color, while CD generally displays an estimate of the mean Doppler
      shift. The vascular patterns recorded at PD and CD evaluation of 322 thyroid
      nodules were compared to the results of cytology and/or histology, when surgery
      was performed. In respect to the results of cytology, PD has a higher sensitivity
      (100 vs. 91%) and specificity (95.1 vs. 86.2%) than CD. A similar result was
      found when PD and CD were compared to the results of histology, sensitivity being
      100 vs. 89% and specificity 98.1 vs. 93.7%, respectively. During the follow-up
      the 2 nodules considered false positive at PD resulted to be tumoral lesions. On
      this basis, the final specificity of PD in our series was 100%. In conclusion, in
      the current series including 322 thyroid nodules characterized by a low or absent
      uptake of (99m)Tc-pertechnetate, PD seems to provide a better characterization of
      thyroid nodules, possibly allowing a more accurate selection of the patients to
      subject to fine-needle biopsy.

PMID- 10640896
TI  - Ontogenetic diurnal variation of adrenal responsiveness to ACTH and stress in
      rats.
AB  - We performed studies in 8-, 16-, 24-, 30 and 35-day-old Wistar rats at 8.00 h
      (AM) and 20.00 h (PM) to investigate the relationship between the diurnal
      variations of basal plasma corticosterone (compound B, CB) and its responses to
      ACTH and ether stress during the postnatal period. Basal plasma CB levels
      increased at PM from 8 to 35 days of age and an AM-PM difference was observed at
      16 days. Although an AM-PM difference in CB responsiveness to ACTH was detected
      only at 24 and 35 days, ACTH induced an increasingly higher CB response at PM
      than at AM from 8 to 35 days. A stress-induced CB response was observed starting
      at 8 days of age and presented an age-dependent increase; however, no AM-PM
      difference was observed at any age. The stress-induced CB levels were higher than
      ACTH-induced CB values at all ages tested except at PM in 8-day old rats. These
      data demonstrate that the basal CB levels and adrenal sensitivity to ACTH rise
      during the evening as a function of neonatal development.

PMID- 10640897
TI  - Dominant expression of progesterone receptor form B mRNA in ovarian
      endometriosis.
AB  - This study was designed to examine the biological implications of progesterone
      receptor form A (PR-A) and B (PR-B) mRNA expressions in human ovarian
      endometriosis (ectopic endometrium). A high ratio of PR-B to PR-AB (PR-A+PR-B)
      mRNA expression was found in 8 of 14 cases of endometriosis, compared with the
      ratio in eutopic endometrium. The mean ratio in ectopic endometria was
      significantly (p < 0.01) higher than in eutopic endometria. The ratio in eutopic
      and ectopic endometria showed no significant change during the menstrual cycle.
      The mean ratio in ectopic endometria in the proliferative and secretory phases of
      the endometrium was significantly (p < 0.01) higher than in eutopic endometria.
      In conclusion, PR-B mRNA was relatively highly expressed in some endometriomas,
      which might lead to aberrations in the control of progestational effects
      involving responsiveness to sex steroidal growth regulation.

PMID- 10640898
TI  - Panhypopituitarism associated with diabetes insipidus in a girl with a
      suprasellar arachnoid cyst.
AB  - We report on a female patient with a large suprasellar arachnoid cyst (3.5 x 2.5
      cm) combined with right optic nerve hypoplasia. She developed growth hormone
      deficiency and hypothyroidism at the age of 8.5 years, adrenal insufficiency at
      the age of 11 years, diabetes insipidus and hypogonadotropic hypogonadism at the
      age of 15 years. When last seen at the age of 19 years she was extremely obese
      (+5.9 BMI SDS). The endocrine picture suggests that arachnoid cysts might be
      involved in far more complex hypothalamic-pituitary disturbances than previously
      thought.

PMID- 10640899
TI  - Pituitary adenoma showing intermittent secretion of high molecular weight
      adrenocorticotropin without evidence of Cushing's disease.
AB  - A 29-year-old woman was admitted in March 1998 due to high plasma ACTH levels,
      amenorrhea and uncontrolled diabetes mellitus (DM) which had persisted since
      1991. Plasma ACTH levels showed a wide range of changes: they were usually high
      (59-240 pg/ml), intermittently very high (336-942 pg/ml), and sometimes normal or
      low. Plasma cortisol levels were usually normal but were sometimes high when the
      ACTH levels were very high. However, even when the plasma ACTH levels were very
      high, she did not show any cushingoid features. DM was diagnosed as non-insulin
      dependent DM. Plasma ACTH showed an excessive response to CRH, while cortisol
      showed a delayed response. Plasma cortisol showed a poor response to ACTH-(1-24).
      ACTH receptor gene analysis revealed no mutations in the ACTH receptor-coding
      region. MRI showed a nonenhancing mass on the left side of the pituitary.
      Cavernous sinus sampling showed a very high plasma ACTH level in the left
      cavernous sinus compared with the levels in the right cavernous sinus and
      peripheral blood. Sephadex G-75 gel filtration of plasma ACTH immunoreactivity in
      plasma obtained by cavernous sinus sampling showed mainly high molecular forms of
      ACTH, probably proopiomelanocortin and ACTH-beta-lipotropin. This case is a very
      rare form of pituitary adenoma showing intermittent secretion of high molecular
      ACTH unaccompanied by cushingoid features.

PMID- 10640900
TI  - Giant prolactinoma presented as unilateral exophthalmos in a prepubertal boy:
      response to cabergoline.
AB  - We report the case of a giant prolactinoma in a 7-year-old boy, which was
      complicated by unilateral exophthalmos. The initial levels of prolactin (PRL)
      were about 80,000 microU/ml. Treatment with cabergoline (CAB) resulted in rapid
      normalization of serum PRL (6 weeks after initiation of treatment) and reduction
      of tumor size. In particular, magnetic resonance imaging (MRI), which was done
      2.5 months after the patient was put on CAB, revealed tremendous improvement with
      a decrease in the size of the tumor which now showed no extrasellar extension.
      Subsequent MRI studies demonstrated further improvement. Exophthalmos, anisocoria
      and visual fields improved. In summary, this patient represents the first report
      of the therapeutic use of CAB as the primary mode of treatment in a 7-year-old
      boy with infiltrative giant prolactinoma complicated by unilateral exophthalmos.
      It is a noninvasive treatment that can preserve and restore vision, as well as
      pituitary function, and is preferable to surgery or radiation in the treatment of
      prolactin-secreting macroadenoma in childhood and adolescence.

PMID- 10640901
TI  - Revised guidelines for neonatal screening programmes for primary congenital
      hypothyroidism. Working Group on Neonatal Screening of the European Society for
      Paediatric Endocrinology.

PMID- 10640902
TI  - Invasive potential and substrate dependence of attachment in the dunning R-3327
      rat prostate adenocarcinoma model.
AB  - Cancer cell attachment to and invasion of the extracellular matrix has been
      associated with the metastatic potential of cell lines of the Dunning R-3327 rat
      prostatic adenocarcinoma model. We investigated the cell-matrix interactions of
      prostate tumor cells by comparing the invasive ability through reconstructed
      extracellular matrix and attachment upon EHS NATRIX (natural extracellular
      matrix), fibronectin, laminin, and collagen Type IV. We observed a correlation
      between metastatic potential and substrate dependence of attachment in prostate
      cancer cells. Nonmetastatic AT-1 cells possessed a higher adhesive potential to
      extracellular matrix components than the highly metastatic cells (ML, MLL and AT
      3). It was also found that the invasive potential of the three highly metastatic
      cell lines was significantly higher than that of the nonmetastatic cell line.
      Here, it is reported that the ability to traverse a matrigel matrix correlates
      with their metastatic potential. These observations suggest that the
      extracellular matrix components are highly involved in influencing prostate
      cancer cell activities. In addition, we investigated the effects of two
      differentiation agents, retinoic acid (RA) and difluoromethylornithine (DFMO), on
      the adhesive and invasive profiles of the tumor cells. After treatment with both
      agents, adhesion was increased to levels not different from nonmetastatic cells.
      Furthermore, the ability of highly metastatic cells to traverse a matrigel
      barrier was significantly reduced after treatment with both differentiation
      agents. These results suggest that RA and DFMO are capable in reversing the
      metastatic potential of prostate cancer cells in vitro and may give a possible
      insight into their role as potential therapeutic agents in vivo.

PMID- 10640904
TI  - Distribution of non-diploid flow-cytometric DNA indices and their relation to the
      nodal metastasis in squamous cell carcinomas of the head and neck.
AB  - Squamous cell carcinomas of the head and neck (HNSCC) evolve from diploid
      epithelial cells of the mucosa. At the time of diagnosis about two thirds of
      clinically diagnosed HNSCC are non-diploid according to flow-cytometric (FCM)
      analysis, indicating that during tumour progression there must be an acquisition
      and accumulation of chromosomal aberrations. At diagnosis one third to one half
      of HNSCC have clinically positive neck nodes. The objective of the present study
      was to see whether the progression to a metastatic phenotype is reflected in the
      distribution of FCM DNA ploidy in node-negative and node-positive HNSCC. The
      series comprised 200 patients with HNSCC. Tumour samples were obtained from
      diagnostic biopsies or primary surgery. A multistep preparation method and
      propidium iodide staining of nuclear DNA content was used for FCM. One hundred
      and forty one (71%) of the tumours were non-diploid. Only two tumours were
      hypodiploid (DNA index 0.73 and 0.93, respectively). Ten of the tumours exhibited
      two non-diploid stem cell lines. The frequency of non-diploidy in node-negative
      tumours was 65% and in node-positive ones about 80%. The frequency distribution
      of non-diploid DNA indices clustered in the hypotetraploid region (with a modal
      value of 1.71-1.74) and did not differ between node-negative and node-positive
      tumours. The hypothesis that the disposition to metastasis is reflected in the
      frequency distribution of non-diploid DNA indices could thus not be verified.

PMID- 10640903
TI  - Effects of EGF and TGF-alpha on invasion and proteinase expression of uterine
      cervical adenocarcinoma OMC-4 cells.
AB  - Uterine cervical adenocarcinoma typically is an aggressive neoplasm with a
      propensity for early invasion and dissemination; however, the regulatory
      mechanism of invasive activity of cervical adenocarcinoma cells has not been
      fully understood. In this study, biological effects of epidermal growth factor
      (EGF) and transforming growth factor (TGF)-alpha on invasion and proteinase
      expression of human cervical adenocarcinoma OMC-4 cells were investigated. Tumor
      cell migration along a gradient of substratum-bound fibronectin and invasion into
      the reconstituted basement membrane were stimulated by 0.1-10 nM EGF and TGF
      alpha in a concentration-dependent manner. Their effects on tumor cell migration
      were also confirmed by wound assay. The zymography of tumor-conditioned medium
      showed that the treatment of OMC-4 cells with EGF and TGF-alpha resulted in the
      increase of matrix metalloproteinase (MMP)-2 and urokinase-type plasminogen
      activator (uPA). Matrilysin (MMP-7), also secreted by OMC-4 cells, was not
      affected by these growth factors. These results suggest that EGF and TGF-alpha
      act as positive regulators on the invasion of cervical adenocarcinoma cells,
      which may be associated with their stimulatory effects on tumor cell motility and
      the induction of type IV collagenase and uPA secreted by tumor cells.

PMID- 10640905
TI  - A model system to quantitate tumor burden in locoregional lymph nodes during
      cancer spread.
AB  - In order to quantitate the metastatic burden of secondary tumor deposits in
      locoregional lymph nodes, we produced a green fluorescent protein (GFP)
      expressing murine cell line (B16F1) metastatic to lymph nodes in immunocompetent
      mice. When implanted into the hindleg of mice, all animals developed paraaortic
      lymph node metastases. Fluorescence microscopy, immunohistochemistry, and RT-PCR
      confirmed the presence of metastatic cells in lymph nodes. Tumoral deposits
      occurred preferentially in marginal sinuses and spread superficially to the
      subcortical area. Western blot analysis showed that the local tumor burden could
      be quantitated in individual lymph nodes. This model system should be useful for
      quantitating metastatic invasion particularly of micrometastases and aid in the
      development of lymphotropic drugs to detect and/or treat lymph node metastases in
      advanced cancers.

PMID- 10640906
TI  - A new bioassay using transient transfection for invasion-related gene analysis.
AB  - To understand the mechanisms of tumor invasion and metastasis, model systems are
      required that isolate the individual steps of these complicated, multifaceted
      processes. We propose a new procedure to identify genes involved in cell invasion
      and/or motility that features the combined advantages of transient gene
      transfection and Matrigel invasion assays. Cancer cells were transiently
      cotransfected with two vectors expressing the gene of interest and luciferase, as
      a marker of transfected cells, and then assayed for Matrigel invasion. Luciferase
      cotransfection appeared to be a sensitive semiquantitative assay for transfected
      cells and was maximal throughout the invasion assay. The proposed transfection
      procedure, using calcium phosphate precipitation, did not affect cell
      invasiveness and allowed cellular coexpression of both genes. When applying this
      method, we found that transient expression of the unliganded and liganded human
      estrogen receptor alpha prevented invasiveness of MDA-MB-231 breast cancer cells.
      In conclusion, we propose rapid and versatile in vitro procedure for studying the
      effects of individual cloned genes on cellular processes, such as invasion and
      motility.

PMID- 10640907
TI  - UCN-01, a protein kinase C inhibitor, inhibits endothelial cell proliferation and
      angiogenic hypoxic response.
AB  - Angiogenesis is required for tumor formation and growth; inhibition of
      angiogenesis is a promising new approach in cancer therapy. UCN-01, a protein
      kinase C (PKC) inhibitor, induces growth arrest and apoptosis in cancer cells and
      was recently introduced in a phase I clinical trial. We demonstrate that UCN-01,
      at concentrations lower than those necessary to inhibit cancer cell growth,
      inhibit proliferation of human endothelial cells in vitro. Moreover, UCN-01, at
      concentrations as low as 32 nM, prevent microvessel outgrowth from explant
      cultures of rat aortic rings. Since hypoxia activates hypoxia-inducible factor
      (HIF-1)-dependent transcription in cancer cells that, in a paracrine fashion,
      drive tumor angiogenesis, we investigated the effects of UCN-01 on HIF-1
      responsive promoter constructs. We report that, in addition to direct inhibitory
      effects on endothelial cell growth, UCN-01 abrogates hypoxia-mediated
      transactivation of HIF-1-responsive promoters in a prostate cancer cell line. We
      conclude that UCN-01, at clinically relevant concentrations, exerts an anti
      neovascularization effect by blocking two important steps in vessel formation:
      (1) the response of cancer cells to hypoxia, and (2) endothelial cell
      proliferation.

PMID- 10640908
TI  - Important animal allergens are lipocalin proteins: why are they allergenic?
AB  - Major respiratory allergens of dogs, mice, rats, horses and cows belong to the
      lipocalin group of proteins. The sequence identity of lipocalins is often less
      than 20%, but they contain between one and three structurally conserved regions
      and their three-dimensional structures are similar. Lipocalins share common
      biological functions, predominantly related to the transport of small hydrophobic
      molecules, such as vitamins and pheromones. Immune reactivity to lipocalin
      allergens is not well known. In Bos d 5, the IgE-binding epitopes are spread
      along the molecule, whereas in Bos d 2, the C terminus appears to contain the
      human B cell epitopes. Bos d 5 contains several murine T cell epitopes. No
      information is available on human T cell epitopes. The maximal number of epitopes
      an allergic patient's T cells could recognize in Bos d 2 was five. Three of the
      epitopes were colocalized in the structurally conserved regions of lipocalins.
      Interestingly, one of the epitopes was recognized by the T cells of all patients
      and the computer predictions suggested that there would be an epitope in the
      corresponding parts of human endogenous lipocalins. The proliferative responses
      of peripheral blood mononuclear cells of Bos d 2-allergic subjects to Bos d 2
      were weak. The T cell response was Th2-dominated. To explain these observations,
      we have proposed that the allergenicity of lipocalins may be a consequence of
      molecular mimicry between lipocalin allergens and endogenous lipocalins at the T
      cell level.

PMID- 10640909
TI  - Allergy to mammalian proteins: at the borderline between foreign and self?
AB  - Atopic individuals are characterized by their genetically determined tendency to
      mount IgE antibody responses against otherwise harmless antigens. Many of the
      environmental allergens (e. g., plant-, insect-, mould-derived allergens) are
      recognized as foreign intruders by the immune system. However, a substantial
      proportion of atopic individuals mount IgE responses to allergens of mammalian
      origin and, as recently reported, certain of them even react with human proteins
      (i. e., autoallergens). Through the application of molecular biological
      techniques for allergen characterization, the molecular nature and biological
      function of an increasing number of mammalian allergens have been revealed. This
      review provides a summary of well characterized mammalian allergens derived from
      hair/dander, saliva, serum and urine of animals (cat, dog, rodents, cow, horse)
      as well as of some recently characterized autoallergens. In addition, mammalian
      allergens were grouped in protein families with similar sequences and/or
      biological functions. The importance of cross-reactivities is exemplified for
      albumins which represent abundant mammalian serum proteins and highly cross
      reactive allergens. Finally, possible advantages of using recombinant animal
      allergens for novel forms of component-resolved diagnosis and treatment of
      allergies to mammalian proteins are described.

PMID- 10640910
TI  - Purified and recombinant latex proteins stimulate peripheral blood lymphocytes of
      latex allergic patients.
AB  - BACKGROUND: Natural rubber latex proteins have been implicated in severe allergy
      in individuals exposed to latex products, particularly health care workers. Until
      recently, only crude antigens were available to study the immune response in
      these patients. In recent years a number of relevant allergens have been
      purified, but few have been used in lymphocyte studies. Hence, to better
      understand the immunological mechanisms involved in latex allergy, we
      investigated the response of peripheral blood mononuclear cells (PBMCs) to
      various purified natural rubber latex allergens. METHODS: Using conventional
      protein purification methods and gene cloning, we have obtained 6 natural rubber
      latex proteins. We studied allergen-specific IgE levels and PBMC responses to
      these allergens along with 3 crude latex antigen preparations. RESULTS: Of the 28
      latex-allergic health care workers studied, 16 reacted to one or more of the
      allergens studied, but PBMCs from controls failed to respond to these antigens.
      Serum IgE to the antigens was detected in 11-90% of the patients. CONCLUSION:
      Fifty-seven percent of the latex-allergic patients demonstrated PBMC responses to
      at least one of the latex allergens tested, but there was no direct correlation
      between serum IgE levels and PBMC responses. However, since none of the control
      subjects showed any PBMC stimulation, this may prove useful in determining
      sensitization to latex. Among the allergens studied, the predominant mononuclear
      cell responses were directed against Hev b 2, while serum IgE against rHev b 6
      was demonstrable in the greatest number of patients. The crude latex allergens
      were toxic to PBMCs and hence, the purified allergens may be of greater value in
      demonstrating sensitization of patients to latex allergens.

PMID- 10640911
TI  - The recognition pattern of sequential B cell epitopes of beta-lactoglobulin does
      not vary with the clinical manifestations of cow's milk allergy.
AB  - BACKGROUND: beta-Lactoglobulin (BLG) represents one of the major allergens
      causing cow's milk allergy (CMA) - a disease with a wide spectrum of clinical
      symptoms. The aim of this study was to evaluate sequential B cell epitopes of BLG
      by the Pin-ELISA method. Furthermore, we wanted to investigate a possible
      association of the IgE recognition patterns in sera of patients with BLG
      sensitization and the type of clinical reactions following contact with cow's
      milk. METHODS: Overlapping sequential decapeptides corresponding to the amino
      acid sequence of BLG were used in Pin-ELISAs specific for human IgE. Tested sera
      were from 14 individuals with CMA, 8 of them with a history of immediate systemic
      reactions and 6 with delayed skin reactions following contact with cow's milk.
      All of them showed specific IgE antibodies to BLG in the CAP-RAST. Control sera
      were from 5 healthy nonallergic individuals. RESULTS: All sera from BLG
      sensitized individuals showed IgE binding with one region of BLG corresponding to
      amino acids 95-113. Furthermore, individual sera showed reactions with two
      further regions, 12-27 and 124-135. Inhibition of IgE binding to BLG with one
      soluble synthetic peptide confirmed the major epitope. No differences were found
      in the B cell epitope recognition pattern to BLG in the two groups of patients
      with CMA, characterized by acute systemic or delayed skin reactions. CONCLUSIONS:
      Using IgE Pin-ELISAs we were able to confirm previously described sequential B
      cell epitopes of BLG. However, the recognition pattern of one of the major cow's
      milk allergens is not predictive of the clinical type of reaction.

PMID- 10640912
TI  - Immunogold electron microscopic localization of the cross-reactive two-EF-hand
      calcium-binding birch pollen allergen Bet v 4 in dry and rehydrated birch pollen.
AB  - BACKGROUND: Recently, a novel family of low-molecular-weight (8-9 kD), two-EF
      hand calcium-binding proteins has been described as allergens in plant pollens.
      Approximately 10% of pollen-allergic patients have IgE antibodies which cross
      react with the two-EF-hand allergens in tree, grass and weed pollens. The aim of
      the present study was to localize Bet v 4, the two-EF-hand allergen from birch,
      in mature, dry pollen and to study the release of this allergen after hydration
      of the pollen by immunogold electron microscopy. METHODS: Using completely
      anhydrous fixation techniques in combination with immunogold electron microscopy,
      we localized Bet v 4 and, for control purposes, the major birch pollen allergen
      Bet v 1, in dry birch pollen as well as in pollen grains after different periods
      of hydration. Parallel with these morphological studies, we monitored the release
      of Bet v 4 and Bet v 1 into aqueous supernatants of hydrated birch pollen grains
      by immunoblotting. RESULTS: Bet v 4 was found in the electron-dense cytosol, in
      particular between the vesicles and cisternae of the endoplasmic reticulum,
      inside mitochondria and in the vegetative as well as in the generative nucleus.
      Bet v 1 was localized in similar cellular compartments except for the
      mitochondria. After 30 s to 1 min of hydration, Bet v 4 migrated into the pollen
      exine and into the aqueous supernatants. Bet v 1 also moved out of the pollen
      grain, though not as quickly as Bet v 4. CONCLUSION: Bet v 4 represents an
      intracellular pollen protein which, following hydration of pollen grains, rapidly
      migrates to the pollen surface (exine) and is washed out. This behavior explains
      how Bet v 4, being primarily an intracellular pollen protein, becomes available
      to sensitize patients.

PMID- 10640913
TI  - Interaction of human IgE with Fc epsilon RI alpha exposes hidden epitopes on IgE.
AB  - BACKGROUND: Binding of human IgE via the heavy-chain constant region domain 3
      (Cepsilon3) to the alpha-chain of its high affinity receptor (FcepsilonRIalpha)
      is a key event in mediating allergic reactions. We wanted to identify epitopes
      within Cepsilon3 that are stable to denaturation and to evaluate whether such
      structures are involved in receptor binding. The existence of stable epitopes
      would facilitate the generation of compounds that inhibit the IgE
      FcepsilonRIalpha interaction. METHODS: Monoclonal anti-human IgE-antibodies
      against recombinant bacterially synthesized Cepsilon3, which is known to be
      partly misfolded, were raised in mice. These antibodies were probed for binding
      to native, immobilized and receptor-bound IgE, respectively, providing tools for
      the identification of the indicated stable epitopes. RESULTS: Two of the
      generated antibodies (8E7, 3G9) discriminate between IgE in solution and IgE
      attached to FcepsilonRIalpha, pointing towards a steric rearrangement within
      Cepsilon3 induced upon receptor binding. The described antibodies represent tools
      for studying the mechanism of the Fcepsilon-FcepsilonRIalpha interaction and may
      be of diagnostic value since serum IgE from various human donors was differently
      recognized by 8E7, which is indicative for naturally occurring IgE molecules with
      different steric conformation. CONCLUSION: The presented data support the
      hypothesis of a conformational change within IgE Cepsilon3 upon receptor binding
      by showing that monoclonal antibodies raised against recombinant Cepsilon3
      differently recognize soluble and receptor-bound IgE. The presence of an IgE
      portion in sera of human donors that is recognized by 8E7 indicates the existence
      of IgE molecules in different steric conformations in human blood, which may be
      related to pathologic parameters.

PMID- 10640914
TI  - Expression of mast cell proteases in rat lung during helminth infection: mast
      cells express both rat mast cell protease II and tryptase in helminth infected
      lung.
AB  - BACKGROUND: The phenotype of proliferated mast cells in Nippostrongylus
      brasiliensis-infected rat lung has been identified as mucosal mast cells (MMC)
      but not connective tissue mast cells (CTMC). However, a previous study of ours
      showed that the expression of rat mast cell tryptase (RMCT) mRNA, which has been
      reported to be confined to CTMC, significantly increased in rat lung 14 days
      after infection. METHODS: The expression of four mast cell proteases in rat lung
      during the course of infection with N. brasiliensis was examined by RNA blot
      analysis. Immunohistochemical analysis of RMCT and rat mast cell protease (RMCP)
      II, which has been reported to be confined to MMC was also performed. RESULTS:
      The number of lung mast cells did not change until 7 days after infection, then
      gradually increased until 21 days after infection. The expression of the RMCP II
      gene had increased 14 and 21 days after infection. In addition, the expression of
      the RMCP I and RMCT genes had also increased at the same time points, but RMCP
      III had not. By immunohistochemistry, most of the mast cells in infected lung
      were identified as RMCP II+/RMCT- (MMC), but both RMCP II+ and RMCT+ mast cells
      were also observed. CONCLUSIONS: The present results suggest that mast cell
      phenotype alteration or a distinct mast cell subset might be present in N.
      brasiliensis-infected rat lung, and therefore N. brasiliensis-infected rat lung
      may be a useful tool for studying the differentiation mechanism of mast cells.

PMID- 10640915
TI  - Heparin, derived from the mast cells of human lungs is responsible for the
      generation of kinins in allergic reactions due to the activation of the contact
      system.
AB  - BACKGROUND: In a recent study mast cell heparin proteoglycan (HepPG) of a cell
      line derived from a mouse mastocytoma was isolated. Glycosaminoglycans proved to
      be an initiating surface for starting contact activation and could explain kinin
      generation present in allergic reactions. It is the aim of the present study to
      prove that HepPG or glycosaminoglycan derived from human mast cells is also
      capable of acting as a physiologic macromolecule and to induce contact
      activation. METHODS: HepPG molecules were isolated by anionic column
      chromatography. Their ability to accelerate reciprocal activation of factor XII
      was investigated by spectrophotometry. The anticoagulant effect was demonstrated
      by an increase in partial thromboplastin time. HPLC was performed to correlate
      these effects with molecular weight (MW). RESULTS: The isolated heparin showed
      high contact-activating and anticoagulant potency. Both actions were suppressed
      by incubation with heparinase I. The maximum contact activation peak appeared at
      a lower MW than the anticoagulant effect. CONCLUSION: These in vitro results
      explain the results of in vivo allergen challenge studies where a high degree of
      kinin generation occurs. Heparin derived from human mast cells therefore seems to
      represent the physiological macromolecule capable of activating the contact
      system and could be a missing link between cellular and humoral responses in
      allergic reactions.

PMID- 10640916
TI  - Administration of SIN-1 induces guinea pig airway hyperresponsiveness through
      inactivation of airway neutral endopeptidase.
AB  - BACKGROUND: Peroxynitrite plays an important role in the pathogenesis of airway
      inflammation. We have already found that peroxynitrite may contribute to
      decreased beta(2)-adrenoceptor responses in airway smooth muscle. However, it is
      not known whether peroxynitrite can alter neutral endopeptidase (EC 3.4.24.11;
      NEP) activity in the airways. This study was designed to determine whether
      peroxynitrite induces airway hyperresponsiveness to substance P (SP) and
      endothelin-1 (ET-1) through the inactivation of airway NEP. METHODS: We examined
      whether the administration of S-morpholinosydnonimine (SIN-1), a compound that
      releases peroxynitrite, increased bronchoconstrictor responses to SP and ET-1 in
      anesthetized guinea pigs. In addition, we assayed NEP activity in the airways of
      SIN-1-exposed guinea pigs. RESULTS: Though SIN-1 (10(-7) M) alone had no effect
      on pulmonary resistance, pretreatment with SIN-1 significantly enhanced SP- and
      ET-1-induced bronchoconstriction. Pretreatment with phosphoramidon, an NEP
      inhibitor, also enhanced SP- and ET-1-induced bronchoconstriction. However,
      simultaneous administration of phosphoramidon and SIN-1 had no additive effect on
      SP- and ET-1-induced bronchoconstriction. Peroxynitrite formation by SIN-1 was
      completely inhibited by N-acetylcysteine (NAC) and glutathione (GSH) in vitro,
      and pretreatment with NAC and GSH significantly reversed the potentiation by SIN
      1 of SP-induced bronchoconstriction. In addition, the NEP activity of the trachea
      after SIN-1 exposure was significantly reduced compared to the level in control
      guinea pigs (solvent for SIN-1: 30.0+/-4.2 fmol.min(-1).mg tissue(-1); 10(-7) M
      SIN-1; 15.5+/-4.5 fmol.min(-1).mg tissue(-1), p<0.05). CONCLUSIONS: These
      findings suggest that peroxynitrite induces airway hyperresponsiveness to SP and
      ET-1 through the inactivation of airway NEP, and that peroxynitrite is an
      important mediator of the alterations in airway functions.

PMID- 10640917
TI  - Utilization of impedance measurements in pallidotomy using a monopolar electrode.
AB  - OBJECT: This study was performed to evaluate the reliability and utility of using
      monopolar impedance monitoring for estimation of the location of the thermocouple
      electrode during a pallidotomy procedure. METHODS: In 26 patients, impedance
      profiles were measured at 2-mm intervals and anatomical boundaries were marked on
      postoperative MRI studies in 19 patients. The pattern of change in impedance as
      the electrode was towards the target coordinates in the globus pallidus was
      studied empirically in relation to MRI-defined anatomy and by electrical
      stimulations. The pattern of impedance change was of greater reliability than
      absolute impedance values. A drop in impedance was noted in 10 cases where the
      electrode entered the putamen or globus pallidus upon exiting the internal
      capsule, and in 9 of these this drop was measured before or at the distal
      boundary of the internal capsule. A variable pattern in the region of the base of
      the globus pallidus was observed, with 10 of 19 cases demonstrating a decrease
      and 8 cases an increase, consistent with the proximity of a CSF cistern in the
      former and the ansa lenticularis and optic tract in the latter. Simulations
      showed that the monopolar electrode was more sensitive to the approach of a
      boundary than the bipolar electrode. CONCLUSION: Our measurements and simulations
      suggest that a monopolar electrode could predict a nearby region of high or low
      impedance before penetrating it and a trend of decreasing impedance as the distal
      edge of the globus pallidus is approached.

PMID- 10640918
TI  - Temperature distribution produced in brain tissue and other media by a
      radiofrequency hyperthermia generator.
AB  - The temperature distribution produced in living brain tissue by a radiofrequency,
      Neuro N-50, hyperthermia probe was measured as a function of probe temperature,
      heating duration, and distance from the heating probe by a sensor containing five
      thermocouples for durations up to 2 min. Brain sections were examined to
      determine the effects of heating at various temperatures. It was found that a
      simple theoretical conductive heat transfer model predicted the steady-state
      temperature distributions quite well. At distances up to 7.4 mm from the heating
      probe, a heating time of 20 s was sufficient to produce about 90% of the
      temperature rise measured at 120 s. The equilibrium temperature at any distance
      from the center of the probe was a linear function of the reciprocal of this
      distance. The time constant for heating was approximately 3 s at 0. 95 mm from
      the heating probe and about 10 s at 7.4 mm for brain tissue, while these values
      are about 5-20 s in egg white. For a given probe size, higher probe temperatures
      increased the size of the region of cell death. According to the heat transfer
      model, the diameter of the region of tissue that attains a given temperature is
      proportional to the diameter of the probe. The use of probe temperatures up to 90
      degrees C would enable an increase in the volume of the region of cell death, or
      the use of a smaller diameter probe to produce a lesion of a given size.

PMID- 10640919
TI  - Accuracy of magnetic resonance imaging stereotactic coordinates with the cosman
      roberts-wells frame.
AB  - Quality assessment on the accuracy of a Cosman-Roberts-Wells (CRW) magnetic
      resonance imaging (MRI) stereotactic ring which had nonferrous stainless steel
      screws and positioning posts and a localizer with petroleum jelly in the
      fiducials, purchased in 1994, revealed errors of greater than 4 mm with targets
      in phantoms. Image fusion of objects within the phantom indicated the central
      area was accurately depicted by CT or MRI. We then tested a newer CRW- MRI ring
      (MRIA-IHR with titanium screws and posts) and localizer (MRIA-2-LF with fiducials
      filled with copper sulfate) and found that the MRI stereotactically calculated
      target coordinates matched both the known position of these targets in the
      phantom as well as the CT stereotactically calculated coordinates within
      approximately 1 mm. We also describe excellent superimposition of CT and MRI
      stereotactically determined surfaces in a recent clinical case using the new
      hardware. This shows that recent modifications to the CRW-MRI stereotactic system
      can make it accurate for small targets, but we emphasize that all systems need to
      undergo ongoing local quality assessment to ensure acceptable accuracy in
      practice.

PMID- 10640920
TI  - Deep brain stimulation of the ventral intermediate nucleus of the thalamus for
      control of tremors in Parkinson's disease and essential tremor.
AB  - The beneficial effects of ventral intermediate nucleus (VIM) stimulation were
      evaluated in 20 patients with tremor refractory to medical therapy. Thalamic
      stimulation is a non-ablative procedure which has the advantage of a reversible,
      non-destructive lesion. Eleven patients [7 with Parkinson's disease (PD) and 4
      with essential tremor (ET)] received unilateral VIM implantation, while 9
      patients had staged bilateral VIM implantation (4 with PD, 5 with ET). PD
      patients showed a significant improvement in contralateral arm and leg rest
      tremor and ipsilateral leg rest tremor (p < 0.02) at a mean follow-up period of
      16.2 +/- 7.0 months. Patients with PD did not demonstrate any significant
      decrease in medication use at follow-up. ET patients demonstrated significant
      improvement in postural and action tremor in the contralateral arm (p < 0.001),
      but no significant improvement in the contralateral leg tremor at follow-up.
      Significant improvements were also seen in ET patients in the Clinical Rating
      Scale for Tremor (p < 0.001) with respect to several activities of daily living
      at a mean follow-up of 14.9 +/- 8. 1 months. Deep brain stimulation is a safe and
      effective treatment for severe tremor refractory to medications. It is a highly
      effective, reversible, adaptable, and predictable procedure which avoids the
      complication of cognitive deficit seen in patients with bilateral thalamotomies.

PMID- 10640921
TI  - Treatment of symptomatic intracranial arachnoid cysts by stereotactic cyst
      ventricular shunting.
AB  - BACKGROUND: The optimal treatment of symptomatic intracranial arachnoid cysts is
      controversial and different surgical approaches have been described. The aim of
      the treatment is to reduce the intracystic pressure. To accomplish this goal,
      many techniques have been proposed, each with specific limitations or failures.
      METHODS: Nine patients with symptomatic arachnoid cysts were treated by
      stereotactic cyst-ventricular shunting. One patient with suprasellar arachnoid
      cyst showed signs related to intracranial pressure, the remaining 8 patients
      complained of headache and/or drug-resistant epilepsy. All the intracranial cysts
      were supratentorial. The surgical procedure was performed under general
      anesthesia in 6 cases and local anesthesia in 3 cases. The CRW Stereotactic
      System (Radionics) was used. The acquisition of both target points (cyst and
      ventricle) was always realized by means of CT scan slices. A right precoronal
      burr hole was made and a silicon catheter was stereotactically inserted into the
      lateral ventricle. Another burr hole was subsequently performed close to the
      cyst; a silicon catheter was placed in the middle of the cavity in the shortest
      intracerebral crossing. Then both catheters were connected to a subcutaneous burr
      hole Ommaya reservoir. RESULTS: All patients tolerated the procedure well and the
      preoperative clinical signs progressively disappeared or improved. The CT scan at
      1, 3, 6 and over 12 months showed progressive reduction in size of the cysts. No
      clinical recurrence was found at the follow-up (14-73 months). CONCLUSIONS: The
      successful outcome of the above cases suggests that, in carefully selected
      symptomatic intracranial arachnoid cysts, stereotactic cyst-ventricular shunting
      is likely to prove an effective operative method.

PMID- 10640922
TI  - A subepidermal bullous eruption associated with IgG autoantibodies to a 200 kd
      dermal antigen: the first case report from the United States.
AB  - We describe an 81-year-old white man in whom a subepidermal bullous eruption
      developed that clinically resembled bullous pemphigoid. The eruption promptly
      responded to oral tetracycline and niacinamide and topical clobetasol. Histologic
      examination of perilesional skin revealed neutrophilic infiltration with
      formation of papillary microabscesses and subepidermal cleavage. Direct
      immunofluorescence showed linear deposition of IgG and C3 along the basement
      membrane zone. By indirect immunofluorescence, circulating IgG autoantibodies
      bound exclusively to the dermal side of salt-split normal human skin. Immunoblot
      analysis demonstrated that the patient's autoantibodies reacted with a 200 kd
      dermal protein that was different from type VII collagen, the epidermolysis
      bullosa acquisita autoantigen. This patient represents the first confirmed case
      from the United States with a recently reported novel autoimmune subepidermal
      bullous disease associated with IgG autoantibodies to a 200 kd dermal antigen.

PMID- 10640923
TI  - Drug-induced linear IgA bullous dermatosis after vancomycin discontinuance in a
      patient with renal insufficiency.
AB  - Linear IgA bullous dermatosis (LABD) is an autoimmune, subepidermal,
      vesiculobullous disease that has been commonly associated with the use of
      vancomycin hydrochloride. Lesions typically appear during vancomycin therapy, 24
      hours to 15 days after the first dose. A 65-year-old white man with renal
      insufficiency developed pruritic, tense bullae on the right chest, right medial
      arm, right flank, abdomen, and right upper thigh 14 days after his last dose of
      vancomycin. Histopathologic examination and immunofluorescence studies were
      diagnostic of LABD. Vancomycin-related LABD may appear as long as 2 weeks after
      the drug is discontinued.

PMID- 10640924
TI  - Invisible mycosis fungoides: A diagnostic challenge.
AB  - We describe a 76-year-old woman who presented persistent generalized pruritus as
      the only cutaneous manifestation of a cutaneous T-cell lymphoma (mycosis
      fungoides). No cutaneous lesions were observed throughout the patient's course.
      Skin biopsies obtained from normal-looking pruritic skin revealed a discrete
      perivascular lymphocytic infiltrate in the upper dermis and focal intraepidermal
      clusters of atypical lymphoid cells (Pautrier's microabscesses). PCR analysis of
      TCR-gamma gene disclosed a monoclonal T-cell rearrangement. Sequencing of the PCR
      monoclonal product identified the J(8)V(2)C(2) TCR gene rearrangement. This
      observation illustrates the existence of a peculiar and exceedingly rare form of
      mycosis fungoides characterized only by persistent pruritus unresponsive to
      several therapeutic approaches. The diagnostic difficulties of this rare variant
      are stressed.

PMID- 10640925
TI  - Pustular psoriasis with a striking linear pattern.
AB  - Pustular psoriasis has different clinicomorphologic forms such as generalized,
      localized (mainly palmoplantar or acral), and annular. There are also few cases
      with a linear distribution pattern. We report a case of pustular psoriasis with a
      striking linear distribution probably related to Blaschko's lines. We suggest
      that linear pattern should also be considered among the morphologic variants of
      pustular psoriasis.

PMID- 10640926
TI  - Sweet's syndrome presenting as palmoplantar pustulosis.
AB  - Sweet's syndrome was initially described as a reactive dermatosis characterized
      by sudden onset of fever, leucocytosis, and raised erythematous plaques
      infiltrated with neutrophils, and therefore called acute febrile neutrophilic
      dermatosis. However, later it became obvious that fever and neutrophilia are
      variable features, and a number of other characteristics have been described.
      Although the dorsa of the hands are frequently affected, the palmoplantar
      involvement mimicking pustulosis observed in our case appears to be unusual.

PMID- 10640927
TI  - Anetoderma secondary to generalized granuloma annulare.
AB  - Anetoderma is a rare disorder of cutaneous atrophy with loss of dermal elastic
      tissue. Secondary anetoderma is seen after a variety of dermatoses. We describe a
      33-year-old woman with secondary anetoderma after generalized granuloma annulare
      lesions that were most pronounced on sun-exposed areas.

PMID- 10640928
TI  - Myeloma-associated systemic amyloidosis presenting as chronic paronychia and
      palmodigital erythematous swelling and induration of the hands.
AB  - Mucocutaneous involvement occurs predominantly in primary systemic amyloidosis as
      well as in myeloma-associated systemic amyloidosis. It is rarely observed in
      other types of amyloidoses. Signs of such involvement may aid in the early
      diagnosis of the disease process. Herein, we describe a 64-year-old white male
      patient with myeloma-associated systemic amyloidosis in whom the disease
      presented with unique cutaneous lesions consisting of chronic paronychia and
      palmodigital erythematous swelling and induration of the hands. Following weekly
      regimens with prednisone (20 mg/day) and melphalan (2 mg/day) administered every
      16 weeks, almost complete resolution of the cutaneous lesions was observed after
      1 year of therapy. Also, in response to chemotherapy, modest regression of the
      myelomatous bone lesions and complete resolution of the underlying gammopathy
      occurred.

PMID- 10640929
TI  - Management of cutaneous verruciform xanthoma.
AB  - Verruciform xanthoma is an uncommon mucocutaneous condition of uncertain cause
      that only occasionally affects the skin. The histopathology is distinctive for
      the presence of foamy histiocytes present within elongated dermal papillae.
      Although simple excision of intraoral lesions is reportedly curative, treatment
      of cutaneous lesions has not been previously reported. We describe a 62-year-old
      man with a large lesion of verruciform xanthoma affecting both inguinal folds.
      Immunohistochemical staining, reverse transcriptase polymerase chain reaction for
      human papilloma virus, and ultrastructural analysis were performed to investigate
      the pathogenesis of this lesion. The results of these studies support the theory
      that the source of lipid in dermal histiocytes is degenerating keratinocytes.
      Initial treatment with wire loop electrosection, pulsed dye (585 nm) laser, and x
      ray therapy of this patient proved unsuccessful. Preliminary success has been
      achieved using wide surgical excision with primary closure.

PMID- 10640930
TI  - An overlap of Cowden's disease and Bannayan-Riley-Ruvalcaba syndrome in the same
      family.
AB  - We describe a family with the unusual association of Cowden's disease and
      Bannayan-Riley-Ruvalcaba syndrome. The father has characteristic mucocutaneous
      features that are palmoplantar keratoses, multiple facial papules, oral
      papillomatoses, lipomas, and vitiligo with involvement of the thyroid and
      digestive tract. The son presents with pigmented macules of the penis,
      macrocephaly, and a lipoma that are typical for Bannaya-Riley-Ruvalcaba syndrome.
      Recent studies have demonstrated that these 2 diseases are allelic disorders at
      the PTEN locus on chromosome 10q.

PMID- 10640931
TI  - Cutaneous acanthamoebiasis in AIDS.
AB  - Acanthamoeba is a recognized pathogen in the immunocompromised patient, commonly
      presenting as chronic or subacute encephalitis. However, cutaneous disease in the
      absence of CNS involvement is increasingly recognized, especially in the setting
      of chronic, nonhealing skin lesions in the patient with AIDS. We describe a
      patient with AIDS and cutaneous acanthamoebiasis and review our experience with
      treatment and diagnosis.

PMID- 10640932
TI  - Peristomal allergic contact dermatitis due to Gantrez in Stomahesive paste.
AB  - We report a case of severe peristomal dermatitis that was refractory to
      conventional treatments. Patch testing revealed positive allergies to myroxylon
      perulase (balsam of Peru), propylene glycol, Stomahesive paste, and Gantrez. This
      is the second reported case of patch-test-positive peristomal allergy to Gantrez.

PMID- 10640933
TI  - Coexistence of acanthosis nigricans and the sign of Leser-Trelat in a patient
      with gastric adenocarcinoma: a case report and literature review.
AB  - The association of acanthosis nigricans (AN) with the sign of Leser-Trelat (LT)
      and gastric carcinoma is rare. Our patient was a 69-year-old man, who presented
      with hematemesis; a stage-IV poorly differentiated, diffuse-type, adenocarcinoma
      of the gastric antrum was diagnosed. The AN was striking, with florid cutaneous
      papillomatosis that also involved the mucous membranes of the mouth and eyelids,
      and keratoderma. AN and the sign of LT predated tumor detection by 6 months and
      regressed after chemotherapy in parallel with reduction of the tumor load,
      demonstrating the dermatoses as paraneoplastic phenomena. The patient died 7
      months after completion of chemotherapy. The coexistence of AN and the sign of LT
      should prompt a search for underlying malignancy. The pathogenesis of both
      dermatoses is discussed.

PMID- 10640934
TI  - Subcutaneous abscesses in a patient with ulcerative colitis.
AB  - Ulcerative colitis (UC) is a clinical form of inflammatory bowel disease. The
      association of pyoderma gangrenosum or erythema nodosum with UC is well known. In
      addition, pustular eruption has been reported in UC. We describe a patient with
      UC who exhibited subcutaneous abscesses, as well as pustular eruption with a
      clinical course paralleling that of UC exacerbation.

PMID- 10640935
TI  - Unusual presentation of a Merkel cell carcinoma.
AB  - Merkel cell carcinoma (MCC) is an uncommon, potentially lethal, cutaneous tumor
      that mainly occurs in sun-exposed skin of the head and neck area of the elderly.
      We report a case of MCC presenting as a 2-mm crusted erosion on the nose of an
      elderly patient, the smallest MCC reported thus far in the literature. The
      optimal management of MCC has not been clearly established. In view of its high
      local recurrence rate, predilection to metastasis, and significant mortality,
      aggressive treatment has been advocated. Identification of this tumor at such a
      small size posed a management dilemma because of lack of prospective treatment
      data involving biologic markers of prognostic significance for MCC.

PMID- 10640937
TI  - An unusually aggressive trichoblastoma.
AB  - Trichogenic tumors are neoplasms of the hair germ cell that usually exhibit
      benign behavior. We describe a case of a large invasive trichoblastoma requiring
      Mohs micrographic surgery for its removal. Immunohistochemical studies performed
      demonstrate overlapping features of this trichogenic tumor with basal cell
      carcinoma.

PMID- 10640936
TI  - Pediatric cutaneous malignant fibrous histiocytoma.
AB  - Malignant fibrous histiocytoma (MFH) is an aggressive soft-tissue sarcoma that
      most commonly occurs in the skeletal muscle of the extremities or retroperitoneum
      of adults. Although the majority of MFH is located beneath the fascia, the tumor
      occasionally occurs in the subcutaneous tissue. MFH rarely occurs in children and
      the disease course, prognosis, and outcome in younger patients has not been well
      described. We report a case of cutaneous MFH presenting on the thigh of a 12-year
      old boy.

PMID- 10640938
TI  - Nodular tertiary syphilis mimicking granuloma annulare.
AB  - We describe a 47-year-old man with annular plaques on the arms and torso that
      were treated as granuloma annulare, based on clinical and histopathologic
      findings. Exacerbation of the lesions during treatment with topical
      corticosteroids prompted a search for an infectious cause, which proved to be
      syphilis in the tertiary stage. The clinician should maintain a high index of
      suspicion for syphilis in the differential diagnosis of unusual annular skin
      lesions in a patient with noncaseating granulomas seen on skin biopsy.

PMID- 10640939
TI  - Relapsing Henoch-Schonlein purpura associated with Pseudomonas aeruginosa
      pyelonephritis.
AB  - Henoch-Schonlein purpura is a systemic vasculitis of unknown cause. It is
      frequently triggered by a streptococcal upper respiratory tract infection. Other
      bacteria have been implicated as triggering agents. We report a recurring case of
      Henoch-Schonlein purpura in a patient with Pseudomonas pyelonephritis. The Henoch
      Schonlein purpura remitted only when the infection was eradicated. Pseudomonas
      infection should be added to the list of bacteria that can trigger Henoch
      Schonlein purpura.

PMID- 10640940
TI  - Angioma serpiginosum with extensive cutaneous involvement.
AB  - Angioma serpiginosum is a rare condition that involves both the proliferation and
      dilatation of superficial blood vessels in the skin. It classically begins in
      childhood, is more common in females, and is asymptomatic. Typical lesions appear
      on the extremities and are often asymmetric. We report a case of angioma
      serpiginosum involving extensive areas of the extremities and the trunk to
      emphasize that extensive cutaneous involvement must be included in the clinical
      spectrum of this condition.

PMID- 10640941
TI  - Melanoma in situ of the penis.
AB  - Melanoma of the penis is rare and the prognosis is very poor. We report a case of
      melanoma in situ localized on the penile shaft. Melanoma in situ of the penis is
      extremely rare. We emphasize that early diagnosis of melanoma in situ will
      improve the prognosis of melanoma of the penis.

PMID- 10640942
TI  - A view on the science: physical anthropology at the millennium.
AB  - EDITOR's NOTE The year 2000 marks the onset of the 21rst century. Physical
      anthropologists will provide brief reflections on our discipline, including what
      attracted them to it, and their views on the directions our discipline may pursue
      as we enter, in January 2001, the third millennium.

PMID- 10640943
TI  - From a dry bone to a genetic portrait: a case study of sickle cell anemia.
AB  - The potential and reliability of DNA analysis for the identification of human
      remains are demonstrated by the study of a recent bone sample, which represented
      a documented case of sickle cell anemia. beta-globin gene sequences obtained from
      the specimen revealed homozygosity for the sickle cell mutation, proving the
      authenticity of the retrieved residual DNA. Further investigation of
      mitochondrial and Y chromosome DNA polymorphic markers indicated that this sample
      came from a male of maternal West African (possibly Yoruban) and paternal Bantu
      lineages. The medical record, which became available after the DNA analyses had
      been completed, revealed that it belonged to a Jamaican black male. These
      findings are consistent with this individual being a descendent of Africans
      brought to Jamaica during the trans-Atlantic slave trade. This study exemplifies
      how a "reverse population genetics" approach can be applied to reconstruct a
      genetic profile from a bone specimen of an unknown individual.

PMID- 10640944
TI  - Hematological and pulmonary responses to high altitude in Quechuas: a
      multivariate approach.
AB  - This study investigates the relationships among hematological variables,
      pulmonary function, and age in a sample of high-altitude natives. The following
      anthropometric and physiological variables were examined in 77 adult Quechua
      males from the Peruvian Central Andes (Huancavelica, 3,680 m): height, weight,
      sitting height, chest diameters, chest and abdominal circumferences, forced vital
      capacity (FVC), forced expiratory volume at 1 sec (FEV1), peak expiratory flow
      (PEF), hemoglobin concentration (Hb), red blood cells (RBC), hematocrit (Htc),
      diastolic and systolic blood pressure, body temperature, pulmonary rate, and
      pulse rate. The means of these variables for the Huancavelica sample fall within
      the range of variability previously observed in Andean populations. Principal
      components analysis and canonical correlation analysis suggest that in this
      native Andean population: 1) aging decreases lung function but does not affect
      hematological features, and 2) there is a negative age-independent correlation
      between lung function (FVC, FEV1, PEF) and hematological traits (Hb, RBC, Htc).

PMID- 10640945
TI  - Analysis of the vertical facial form in patients with severe hypodontia.
AB  - We examined the lateral cephalograms of Russian patients in the following
      categories: control with acceptable occlusions (group 1); severe hypodontia with
      absence of six or more teeth (group 2); and severe hypodontia associated with
      hypohidrotic ectodermal dysplasia (HED) (group 3). Analysis was in a cross
      sectional manner, comparing dimensions at the start of the mixed dentition phase
      (age 6-10) and in the permanent dentition (age 12-18). The groups were matched
      for age and sex. Thirty-one hard- and soft-tissue landmarks were traced, and 35
      linear, 19 angular, and 7 ratioed measurements were taken and compared, using
      analysis of variance to compare the means of each group. A reduced anterior face
      height was found in groups 2 and 3 as a consequence of a reduced anterior lower
      face height. In group 2 in the mixed dentition, the posterior face height was
      also reduced. The inclination of the mandible (<Se S Go Gn) was significantly
      reduced to 28.22 degrees +/- 0.71 degrees in group 2 and to 24.07 degrees +/-
      0.97 degrees in group 3. The facial profile appeared flat or concave (<se pn pg
      was increased up to 8.42 degrees +/- 1.56 degrees in children and 16.81 degrees
      +/- 2.18 degrees in adolescents). The subnasion point was behind the aesthetic
      line (EL), and in group 2 patients the naso-labial angle was obtuse when compared
      to nonaffected patients. In group 3 patients, the naso-labial angle became acute
      and lips were protuberant and everted as a consequence of the reduced vertical
      height. Groups 2 and 3 have the typical facial characteristics unique to
      hypodontia, with reduced vertical dimensions as a consequence of limited alveolar
      bone growth. However, group 3 patients have a unique abnormal craniofacial
      development.

PMID- 10640946
TI  - Population variation in osteological aging criteria: an example from the pubic
      symphysis.
AB  - A fundamental assumption made by skeletal biologists is that both the pattern and
      rate of age-related morphological changes observed in modern reference
      populations are not significantly different than in past populations. In this
      brief exploration, the composition of a single reference and two independent,
      known-age, target samples are evaluated for the pubic symphysis. Differences in
      the timing of age-progressive changes between the reference and target samples
      are observed, and in particular, females demonstrated a pattern that was
      fundamentally different from the reference sample. These results serve as a
      cautionary note for the use of osteological aging criteria and issues of
      representativeness for modern standards.

PMID- 10640947
TI  - Biocultural analysis of sex differences in mortality profiles and stress levels
      in the late medieval population from Nova Raca, Croatia.
AB  - Human skeletal remains of 104 individuals from the late medieval (14th-18th
      century) Nova Raca cemetery, in continental Croatia, are described. Historic data
      from the parish Book of the Dead, relevant to a period in the early 19th century,
      suggest that females may have been under greater stress than males. To test this
      hypothesis, the skeletal material is analyzed for the presence and distribution
      of enamel hypoplasias and cribra orbitalia. Observations are also made on the
      presence and pattern of dental disease, skeletal infection, trauma,
      osteoarthritis, vertebral degenerative changes, and Schmorl's depression
      frequencies. The mortuary sample, consisting of 36 subadults and 68 adults,
      exhibits underrepresentation of subadults, and differential adult male/female
      mortality profiles. Peak female mortality is between 21-25 years, compared to
      peak male mortality between 31-35 years. Average adult female age at death is
      29.9 years, compared to 34.1 years in adult males. Significant sex differences
      are present in the frequencies of enamel hypoplasia. Adult females have higher
      frequencies of hypoplastic teeth, and a larger number of defects in the teeth
      affected than in males. Subadults in the series also exhibit higher frequencies
      of hypoplastic teeth, and a larger number of defects in the teeth affected than
      in adults, documenting a relationship between enamel hypoplasia-causing stress
      events and reduced life expectancy. Significant sex differences are also present
      in dental pathology frequencies, possibly reflecting differences in resource
      access. Sex differences in vertebral osteoarthritis and Schmorl's depression
      frequencies may reflect differential activity patterns.

PMID- 10640948
TI  - Analysis of bacterial DNA in skin and muscle of the Tyrolean iceman offers new
      insight into the mummification process.
AB  - About 80 sequences (16s ribosomal RNA gene) of bacterial DNA in samples of skin
      and muscle taken directly from the Tyrolean iceman (3350-3100 years B.C.) or
      recovered during the 1992 archaeological expedition at the Alpine site were
      analyzed to obtain clues to the natural mummification process that allowed the
      corpse of the Neolithic shepherd/hunter to be preserved for more than 5,000
      years. The investigation was made more complex by the fact that the surface of
      the mummy had been swabbed with phenol soon after the discovery (September 19,
      1991). Our results show that no trace of microbial DNA is left on the actual
      surface of the body, while the untreated skin still bears the remains of large
      numbers of bacteria belonging to the genera Sphingomonas, Afipia, Curtobacterium,
      Microbacterium, Agromyces, and others. Compared to the untreated skin, the
      iceman's muscle is also very rich in bacterial DNA. However, this DNA comes, with
      few exceptions, from the species Clostridium algidicarnis. The sharp difference
      in the bacterial DNA composition of skin and muscle suggests that the remains of
      the original cadaveric microflora of the latter have not disappeared during the
      iceman's taphonomic history. On the other hand, the massive presence of C.
      algidicarnis, a cold-adapted sporigenous, the DNA of which was previously (Ubaldi
      et al. [1998] Am. J. Phys. Anthropol. 107:285-295) found in the soft tissue of a
      naturally desiccated Andean mummy, indicates that the hypothesis that the
      iceman's corpse underwent rapid dehydration by the effect of a warm wind (fohn)
      is no longer plausible. The results best fit with the hypothesis (Bereuter et al.
      [1997] Chem. Eur. J. 7:1032-1038) that the body was first covered by snow and
      ice, and then underwent thawing and, finally, desiccation.

PMID- 10640949
TI  - Taxonomic and functional aspects of the patterning of enamel thickness
      distribution in extant large-bodied hominoids.
AB  - One of the few uncontested viewpoints in studies of enamel thickness is that the
      molars of the African apes, Pan and Gorilla, possess "thin" enamel, while Pongo
      and modern humans possess varying degrees of "thick" enamel, even when
      interspecific differences in overall body or tooth size are taken into account.
      Such studies focus primarily on estimates of the total volume of enamel relative
      to tooth size (i.e., "relative" enamel thickness), as this is thought to bear
      directly on questions concerning dietary proclivities and phylogenetic
      relationships. Only recently have studies shifted focus to examining differences
      in the distribution of enamel across the tooth crown, i.e., the patterning of
      enamel thickness, as this may contribute to more refined models of tooth function
      and dietary adaptations in extant hominoids. Additionally, this feature has been
      suggested to be a reliable indicator of taxonomic affinity in early hominins,
      though no study has specifically addressed whether species-specific patterns
      exist among known phena. The aims of this paper were to test more explicitly
      whether enamel thickness patterning provides valuable taxonomic, functional,
      and/or phylogenetic information for maxillary molars of large-bodied extant
      hominoids. A series of seven linear enamel thickness measurements was recorded in
      the plane of the mesial cusps in cross sections of a total of 62 maxillary molars
      of P. troglodytes, G. gorilla, P. pygmaeus, and H. sapiens to estimate the
      patterning of enamel thickness distribution. Results from a discriminant function
      analysis reveal that, overall, this trait reclassifies extant hominoid maxillary
      molars with 90% accuracy: 100% of extant Homo, 75. 0% of Pongo, 83.3% of Pan, and
      66.7% of Gorilla are reclassified correctly, indicating that this feature
      possesses a strong taxonomic signal. Furthermore, differences in the structure of
      the enamel cap are evident among hominoids: modern humans differ from Pongo in
      possessing proportionally thicker enamel in areas of the crown associated with
      shearing activity; Pan molars are better designed than those of Gorilla for
      generating a greater component of crushing/grinding loads. Thus, African ape
      molars are structurally dissimilar, even though they are both considered to
      belong to a morphologically homogeneous "thin-enameled" group. Simple
      developmental mechanisms can be invoked to explain the sometimes subtle
      differences in the achievement of adult morphology. For instance, human and
      orangutan molar cusps possess a similar degree of enamel thickness, but the
      possibility exists that despite similarities in morphology, each species follows
      a different sequence of secretory activity of enamel to achieve the final, albeit
      similar, degree of enamel thickness. Such a finding would suggest that the shared
      possession of "thick" or "thin" enamel among species may be phylogenetically
      uninformative, as it would not represent a developmental synapomorphy.

PMID- 10640950
TI  - Cineradiographic study of forelimb movements during quadrupedal walking in the
      brown lemur (Eulemur fulvus, Primates: Lemuridae).
AB  - Movements of forelimb joints and segments during walking in the brown lemur
      (Eulemur fulvus) were analyzed using cineradiography (150 frames/sec). Metric
      gait parameters, forelimb kinematics, and intralimb coordination are described.
      Calculation of contribution of segment displacements to stance propulsion shows
      that scapular retroversion in a fulcrum near the vertebral border causes more
      than 60% of propulsion. The contribution by the shoulder joint is 30%, elbow
      joint 5%, and wrist joint 1%. Correlation analysis was applied to reveal the
      interdependency between metric and kinematic parameters. Only the effective
      angular movement of the elbow joint during stance is speed-dependent. Movements
      of all other forelimb joints and segments are independent of speed and influence,
      mainly, linear gait parameters (stride length, stance length). Perhaps the most
      important result is the hitherto unknown and unexpected degree of scapular
      mobility. Scapular movements consist of ante-/retroversion, adduction/abduction,
      and scapular rotation about the longitudinal axis. Inside rotation of the scapula
      (60 degrees -70 degrees ), together with flexion in the shoulder joint, mediates
      abduction of the humerus, which is not achieved in the shoulder joint, and is
      therefore strikingly different from humeral abduction in man. Movements of the
      shoulder joint are restricted to flexion and extension. At touch down, the
      shoulder joint of the brown lemur is more extended compared to that of other
      small mammals. The relatively long humerus and forearm, characteristic for
      primates, are thus effectively converted into stride length. Observed asymmetries
      in metric and kinematic behavior of the left and right forelimb are caused by an
      unequal lateral bending of the spinal column.

PMID- 10640951
TI  - New fossil materials of the earliest new world monkey, Branisella boliviana, and
      the problem of platyrrhine origins.
AB  - Branisella boliviana, from the Late Oligocene of Salla, Bolivia, is the oldest
      fossil platyrrhine monkey discovered. To date, several fossil specimens of
      Branisella have been obtained, but most of them are fragmentary dentitions, so
      the animals craniodental morphology is still obscure. During the 1996 field
      season a pair of upper and lower jaw fragments and another nearly complete
      mandible were recovered. These new fossil materials reveal the following
      morphological features in Branisella: 1) P(2) is much smaller than P(3,4),
      whereas P(2) is relatively small but probably sexually dimorphic; 2) the
      zygomatic arch protrudes smoothly posterolaterally from the maxillary bone, as in
      extant Callicebus; 3) the mandibular arcade is nearly V-shaped and the symphysial
      angle, which is formed by the horizontal plane and the anterior face of
      mandibular symphysis, is about 40 degrees, i.e., it neither leans as far
      anteriorly as in callitrichines nor does it stand as vertically as Cebus; 4)
      upper and lower molars wore down rapidly in life, suggesting a herbivorous diet
      and the possibility of terrestriality; and 5) dental eruptive sequence is the
      same as in extant Aotus. As a whole, the dentition of Branisella is very similar
      to that of Proteopithecus from the Late Eocene of Fayum, Egypt, except in the
      lower canine morphology, suggesting a close phyletic relationship between them.
      The origin and early diversification of platyrrhine monkeys might have occurred
      on the African continent before crossing the Atlantic Ocean.

PMID- 10640952
TI  - Testing type II error rates in biological anthropology.
AB  - This paper presents a look at the underused procedure of testing for Type II
      errors when "negative" results are encountered during research. It recommends
      setting a statistical alternative hypothesis based on anthropologically derived
      information and calculating the probability of committing this type of error. In
      this manner, the process is similar to that used for testing Type I errors, which
      is clarified by examples from the literature. It is hoped that researchers will
      use the information presented here as a means of attaching levels of probability
      to acceptance of null hypotheses.

PMID- 10640953
TI  - Immunohistochemical study of MUC1 mucin in premalignant oral lesions and oral
      squamous cell carcinoma: association with disease progression, mode of invasion,
      and lymph node metastasis.
AB  - BACKGROUND: MUC1 mucin is a transmembrane, mucin-like glycoprotein encoded by the
      MUC1 gene. Although MUC1 expression has been identified in a variety of
      neoplastic tissues, to the authors' knowledge, few studies have examined MUC1
      expression in premalignant and malignant oral lesions. METHODS: A total of 36
      specimens of oral epithelial dysplasia, 12 carcinoma in situ (CIS) specimens and
      77 specimens of oral squamous cell carcinoma (OSCC), were examined by both light
      and electron microscopy using immunohistochemical staining of MUC1 mucin.
      Relations between staining patterns and clinicopathologic findings also were
      examined. RESULTS: Distinct membrane MUC1 mucin staining patterns were identified
      in epithelial dysplasia (33.0%), CIS (50.0%), and OSCC (59.7%) cases. A
      predominantly cytoplasmic staining pattern was detected in epithelial dysplasia
      (5.6%), CIS (41.7%), and OSCC (32.5%) cases. Significant positive correlations
      were found between MUC1 mucin membranous immunoreactivity and disease progression
      from epithelial dysplasia to OSCC (P < 0.01), mode of tumor invasion (P < 0.02),
      and lymph node metastasis (P < 0.01). Furthermore, the malignant transformation
      of oral epithelium, tumor invasion, and tumor metastasis were associated with
      higher MUC1 mucin expression in the cytoplasm (P < 0.01). In addition to the
      usual cell surface expression, cytoplasmic expression of MUC1 mucin was confirmed
      by colloidal gold labeling with transmission electron microscopy. CONCLUSIONS:
      The results of the current study suggest that determination of MUC1 mucin
      expression may be a parameter in the diagnosis of premalignant and malignant
      lesions arising in the oral cavity and that this expression may affect the
      malignant behavior of OSCC. MUC1 mucin expression may be a useful diagnostic
      marker for prediction of the invasive/metastatic potential of OSCC.

PMID- 10640954
TI  - Elevation of serum vascular endothelial growth factor in male patients with
      metastatic nasopharyngeal carcinoma.
AB  - BACKGROUND: Angiogenesis is essential for tumor growth and metastasis. Vascular
      endothelial growth factor (VEGF) is the most potent angiogenic factor identified
      to date. The authors investigated the correlation between the levels of serum
      VEGF (S-VEGF) in patients with nasopharyngeal carcinoma (NPC) and disease
      progression. METHODS: The sera from 65 male patients with nonmetastatic NPC, 22
      male patients with metastatic NPC, and 27 healthy male volunteers were obtained.
      A quantitative enzyme-linked immunosorbent assay was performed to measure the
      concentrations of S-VEGF in the sera. RESULTS: The mean S-VEGF levels were 371.0
      pg/mL(-1) (range, 128.5-691.1 pg/mL(-1)) for healthy controls, 375.6 pg/mL(-1)
      (range, 72.9-1202.5 pg/mL(-1)) for patients with nonmetastatic NPC, and 958.6
      pg/mL(-1) (range, 264.4-3744.9 pg/mL(-1)) for patients with metastatic NPC. The
      mean S-VEGF level in patients with metastatic NPC was significantly higher than
      in either patients with nonmetastatic NPC (P < 0.001) or healthy controls (P <
      0.001). However, there was no statistical difference between these results for
      healthy controls and patients with nonmetastatic NPC. At the level of 900 pg/mL(
      1), S-VEGF indicated distant dissemination of NPC with a specificity of 95.4%, a
      sensitivity of 31.8%, a positive predictive value of 70.0%, and a negative
      predictive value of 80.5%. No significant differences in the levels of S-VEGF
      were found among various T classifications, N classifications, and clinical
      stages of nonmetastatic NPC. CONCLUSIONS: The levels of S-VEGF were significantly
      elevated in male patients with metastatic NPC. These levels did not correlate
      with locoregional progression of NPC. The usefulness of detecting S-VEGF in the
      early diagnosis of NPC appears to be limited.

PMID- 10640955
TI  - Small cell carcinoma of the esophagus: the University of Texas M. D. Anderson
      Cancer Center experience and literature review.
AB  - BACKGROUND: Small cell carcinoma of the esophagus is a rare disease with
      aggressive behavior and poor prognosis. Multidrug chemotherapy remains the
      treatment of choice given the systemic nature of the disease. Radiotherapy has
      been used concurrently with chemotherapy to enhance local control. The role of
      surgery in patients with limited disease is controversial. Limited data exist
      regarding the pathologic response of the tumor to chemoradiotherapy. The goal of
      the current study was to analyze the outcome of 8 patients treated at the M. D.
      Anderson Cancer Center, with particular focus on the histologic findings of the
      resected specimens. METHODS: Patient records were reviewed for demographics,
      presenting symptoms, diagnostic modalities, disease stage, treatment, and
      outcome. RESULTS: Two of eight patients had metastatic disease at the time of
      diagnosis and received combination chemotherapy. Six patients had limited stage
      disease. Four received combined modality treatment including esophagectomy, and
      two received radiotherapy only. All four patients who underwent esophagectomy had
      pure small cell carcinoma histology at diagnosis and received preoperative
      combination chemotherapy with or without radiotherapy. None of the four patients
      achieved a pathologic complete remission. Two patients had residual small cell
      carcinoma; one patient had squamous cell carcinoma and one adenocarcinoma. The
      median overall survival for the group of patients was 12.5 months (range, 5-57
      months). CONCLUSIONS: In selected patients with limited stage disease, surgery
      with curative intent should be considered as part of multimodality treatment.

PMID- 10640956
TI  - Gains of 8q23-qter and 20q and loss of 11q22-qter in esophageal squamous cell
      carcinoma associated with lymph node metastasis.
AB  - BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is associated with poor
      prognosis and lymph node metastasis is one of the critical prognostic factors.
      Although it is important to elucidate the genetic aberrations underlying its
      lymph node metastasis, to the authors' knowledge little is known regarding
      alterations in the primary ESCC that are linked with ESCC metastasis to the lymph
      nodes. METHODS: To elucidate genetic aberrations involved in the lymph node
      metastasis of ESCC, comparative genomic hybridization analysis was applied to 36
      ESCC specimens, from 12 cases with no lymph node metastasis and 24 cases with
      lymph node metastasis. RESULTS: Copy number gains frequently were detected at 3q
      (75%), 8q23-qter (50%), 11q13 (44%), 5p14-pter (25%), 20q (25%), 7q (22%), 2p
      (19%), 12p (17%), and 20p (17%) and losses were detected at 18q (58%), 3p (50%),
      9p (44%), 5q14-23 (39%), 4q (33%), 13q (22%), and 11q22-qter (19%). DNA
      amplifications were detected at four loci: 11q13, 2q12, 7q21, and 20q11.2 It is
      interesting to note that the gains of 8q23-qter (P < 0.0005) and 20q (P < 0.02)
      and loss of 11q22-qter (P < 0.05) were observed in tumors metastatic to the lymph
      nodes. The gains of 3q and 11q13 and losses of 18q, 3p, 9p, 5q14-23, and 4q were
      detected in both early and advanced stage ESCCs. CONCLUSIONS: These observations
      suggest that gains of 8q23-qter and 20q and loss of 11q22-qter allow the
      prediction of lymph node metastasis, and that gains of 3q and 11q13 and losses of
      18q, 3p, 9p, 5q14-23, and 4q are associated with the development of ESCC.

PMID- 10640957
TI  - Individual and joint contribution of family history and Helicobacter pylori
      infection to the risk of gastric carcinoma.
AB  - BACKGROUND: Helicobacter pylori infection and a positive family history of
      gastric carcinoma have been identified as risk factors for the disease. It is
      unclear, however, to what degree their impact on the risk of gastric carcinoma is
      independent, because H. pylori also clusters within families. METHODS: The
      authors carried out a population-based, statewide case-control study in Saarland,
      Germany, to assess the individual and joint contributions of family history and
      H. pylori infection to the risk of gastric carcinoma. Cases included 68 patients
      with histologically verified gastric carcinoma. Controls included 239 patients
      with colorectal carcinoma who were matched to the cases by age and gender.
      Information on family history (defined as gastric carcinoma in at least one first
      degree relative) and potential confounders was collected by standardized
      interviews. Immunoglobulin G antibodies against H. pylori were measured by enzyme
      linked immunosorbent assay. In addition, antibodies against the CagA antigen were
      determined by Western blot analysis. RESULTS: H. pylori infection and family
      history were positively related, and both risk factors were more common among
      cases than among controls. Although the association between family history and
      gastric carcinoma was somewhat reduced by control for H. pylori infection, both
      risk factors still showed strong independent relations with gastric carcinoma
      after control for each other. Compared with uninfected subjects who had no family
      history, subjects with both a positive family history and infection with a CagA
      positive H. pylori strain had a more than 8-fold total risk of gastric carcinoma
      (adjusted odds ratio [OR], 8.2; 95% confidence interval [CI], 2.2-30.4) and a 16
      fold risk of noncardia gastric carcinoma (OR, 16.0; 95% CI, 3.9-66.4).
      CONCLUSIONS: Infection with CagA positive H. pylori strains and a positive family
      history appear to be strong independent risk factors for gastric carcinoma. They
      may be useful markers for identifying subjects at high risk for the disease and
      for targeting efforts of prevention and early detection.

PMID- 10640958
TI  - Detection of circulating gastric carcinoma-associated antigen MG7-Ag in human
      sera using an established single determinant immuno-polymerase chain reaction
      technique.
AB  - BACKGROUND: In 1994, a novel sensitive method termed immuno-polymerase chain
      reaction (PCR) for the detection of the gastric carcinoma-associated antigen MG7
      Ag in the gastric carcinoma cell line KATO III was reported. Compared with the
      enzyme-linked immunoadsorbent assay, the single determinant immuno-PCR technique
      could allow for as few as 20 cells to be detected and was found to show an
      approximately 10,000-fold enhancement in sensitivity of the detection limit. The
      current study clinically evaluated the significance of serum MG7-Ag detection in
      gastric carcinoma patients. METHODS: The sera of patients were immobilized on
      wells and a specific DNA molecule, which could be amplified by PCR, was employed
      as a marker. The biotinylated monoclonal antibody against gastric carcinoma was
      added to bind the antigen immobilized on the wells. After the biotinylated
      antibody was bound to the antigen, free avidin was used to attach a biotinylated
      monoclonal antibody and biotinylated DNA molecule. The biotinylated DNA complexed
      with antigen-antibody-avidin was amplified by PCR and the PCR products were
      analyzed by agarose gel electrophoresis. In the current study this method was
      used to detect circulating MG7-Ag in the sera of patients with gastric carcinoma
      and other various malignancies. For comparison, carcinoembryonic antigen, CA 50,
      CA 19-9, and TAG-72 were quantitated by radioimmunoassay and immunoradiometric
      assay using the relevant commercial kits in the same sera samples from 86
      patients with pathologically confirmed gastric carcinoma and 83 patients with
      relevant benign diseases of the stomach. In addition, the semiquantitative
      analysis of PCR products among gastric carcinoma patients with or without
      metastasis was performed to compare the intensity of DNA band amplification.
      RESULTS: Using the immuno-PCR assay, positive results were obtained in 164 of 198
      patients with gastric carcinoma (82.8%). The rates of positivity in other
      malignancies were 17.4% for esophageal carcinoma (15 of 86 patients), 44.4% for
      colonic carcinoma (40 of 90 patients), 0% for liver carcinoma (none of 84
      patients), 2.2% for ovarian carcinoma (1 of 45 patients), 0% for uterine
      carcinoma (none of 27 patients), and 6.1% for lung carcinoma (4 of 66 patients).
      The positive results obtained from those patients with benign diseases were: 7.7%
      for peptic ulcer (6 of 78 patients), 5.9% for chronic gastritis (7 of 118
      patients), 3.3% for chronic colitis (2 of 60 patients), and 0.8% for healthy
      blood donors (2 of 236 patients). In addition, the semiquantitative analysis of
      PCR products showed that the intensity of DNA band amplified from the PCR
      products of those patients with metastasis was much higher than that of patients
      without metastasis or those with early stage tumors (1.94 +/- 0.03 vs. 1.28 +/-
      0.02). In comparative studies of immuno-PCR and commercial assays for tumor
      associated antigens the sensitivity of immuno-PCR was 81.4% and pseudopositivity
      was lower (8.4% vs. 7.2-12.0% with radioimmunoassay or immunoradiometric assay).
      CONCLUSIONS: The results of the current study demonstrate that introducing PCR
      into the indirect determination of tumor-associated antigen in the serum can
      improve the sensitivity of detection greatly. This novel assay also might be used
      to monitor the circulating amount of tumor-associated antigen after gastrectomy
      and provide information regarding recurrence or metastasis, as well as for
      screening elderly patients who have no indications for endoscopy and those with
      precancerous conditions. The application of immuno-PCR in the serologic diagnosis
      of carcinoma has significant advantages including ready application in the
      clinical setting as well as use as a potential screening tool in mass surveys of
      high risk populations with gastric carcinoma. (c) 2000 American Cancer Society.

PMID- 10640959
TI  - A clinicopathologic study of primary small intestine lymphoma: prognostic
      significance of mucosa-associated lymphoid tissue-derived lymphoma.
AB  - BACKGROUND: It remains unclear whether the presence of mucosa-associated lymphoid
      tissue (MALT) lymphoma has prognostic implications for patients with primary
      small intestine lymphoma. METHODS: The clinicopathologic features of 80 patients
      with primary small intestine lymphoma were examined retrospectively in relation
      to the presence of MALT lymphoma. Survival was compared univariately and
      multivariately among the groups divided by clinicopathologic findings. RESULTS:
      Twenty-one cases (26%) were diagnosed as low grade B-cell lymphoma (15 marginal
      zone B-cell lymphoma of MALT type, 2 mantle cell lymphoma, and 4 follicle center
      lymphoma), 46 cases (58%) were diagnosed as high grade B-cell lymphoma (19
      secondary large cell lymphoma with a low grade MALT component, 17 diffuse large
      cell lymphoma without MALT features, 7 Burkitt lymphoma, and 3 lymphoblastic
      lymphoma), and 13 cases (16%) were diagnosed as T-cell lymphoma. A significantly
      better survival was noted for patients without colorectal and/or gastric
      involvement, diffuse infiltration under macroscopy, high grade histology, and
      perforation. Those patients with MALT type tumors, less advanced stage of
      disease, B-cell phenotype, benign lymphoid follicular hyperplasia, and radical
      tumor resectability appeared to have a better survival rate. Based on Cox
      multivariate analysis, early stage disease and MALT-derived tumors were
      determined to be independent prognostic factors (P < 0.05). CONCLUSIONS: The
      presence of MALT-derived lymphoma appears to have a favorable prognosis among
      patients with primary small intestinal lymphoma.

PMID- 10640960
TI  - Tissue factor expression in human colorectal carcinoma: correlation with hepatic
      metastasis and impact on prognosis.
AB  - BACKGROUND: It has been suggested that tissue factor (TF) plays an important role
      in tumor metastasis. Its expression in sarcoma cells was reported to up-regulate
      the vascular endothelial growth factor (VEGF) gene and thereby enhance tumor
      angiogenesis, which is essential to tumor metastasis. Although many malignant
      tumors have been reported to express this protein constitutively, recent clinical
      studies have focused mainly on the correlations among TF expression, tumor
      progression, and histologic grade. Therefore, to address the role of TF and the
      underlying mechanism of hematogenous metastasis of colorectal carcinoma, the
      authors analyzed the correlations among TF expression, hepatic metastasis, and
      VEGF gene expression in surgical specimens. Furthermore, they analyzed the
      prognostic significance of TF expression with respect to overall patient
      survival. METHODS: Expression of TF and VEGF genes in 67 advanced colorectal
      carcinoma specimens was studied by immunohistochemistry and Northern blot
      analysis, respectively. The correlations among TF expression, hepatic metastasis,
      and other factors were analyzed with univariate and multivariate statistics.
      Survival rates were calculated using the Kaplan-Meier method. RESULTS: Univariate
      and multivariate analyses showed TF expression to be a significant (P = 0.0001)
      and independent risk factor for hepatic metastasis, whereas a weak but
      insignificant correlation was observed between TF and VEGF gene expression. The
      outcomes in the TF positive group were significantly worse in all cases (P =
      0.0001) and in the cases without synchronous hepatic metastasis (P = 0.0156).
      CONCLUSIONS: Although the precise mechanisms are unknown, TF expression is a
      suitable indicator of both hepatic metastasis and prognosis for colorectal
      carcinoma patients.

PMID- 10640961
TI  - Percutaneous microwave coagulation therapy for patients with primary and
      metastatic hepatic tumors during interruption of hepatic blood flow.
AB  - BACKGROUND: Although percutaneous microwave coagulation is relatively noninvasive
      therapy for patients with hepatic tumors, coagulation of tumors is sometimes
      incomplete and local recurrence occurs. The authors hypothesized that the cause
      of incomplete coagulation was a cooling effect in surrounding hepatic blood flow.
      To prove this hypothesis and to improve the efficacy of this therapy, they
      interrupted hepatic blood flow during the treatment and measured the amount of
      tumor tissue coagulated by microwave. METHODS: The authors first performed an
      animal experiment on pigs. After laparotomy, the liver of an anesthetized pig was
      coagulated by microwave with or without interruption of hepatic blood flow; the
      interruption was achieved by squeezing hepatic blood vessels. Next, the authors
      applied the microwave coagulation percutaneously to 25 human patients with
      primary or metastatic carcinoma in the liver with or without intraoperative
      temporary interruption of hepatic blood flow; the interruption was achieved by
      inflating balloon catheters inserted in the hepatic blood vessels through femoral
      vessels. RESULTS: The greatest dimension of area of normal liver tissue
      coagulated by microwave with blood flow interruption was significantly (P <
      0.001) larger (18.8 +/- 1.0 mm, n = 4) than without it (9.8 +/- 1.7 mm, n = 4) in
      the experiment with pigs. In human hepatic tumors, the greatest dimension of the
      area coagulated by microwave with blood flow interruption was also significantly
      (P < 0.001) larger (41.1 +/- 9.3 mm, n = 14) than without it (26.9 +/- 8.5 mm, n
      = 11). The local recurrence rate of the tumor during a period of 6 months after
      the treatment was lower (P < 0.05) with blood flow interruption (7%) than without
      it (45%). CONCLUSIONS: Intraoperative interruption of hepatic blood flow
      increases the areas of primary and metastatic hepatic tumors coagulated by
      microwave. It is expected to increase the efficacy of percutaneous microwave
      coagulation therapy for patients with hepatic tumors.

PMID- 10640962
TI  - Precancerous hepatic nodules had significant levels of telomerase activity
      determined by sensitive quantitation using a hybridization protection assay.
AB  - BACKGROUND: Telomeric repeat amplification protocol using internal telomerase
      assay standard (ITAS) (conventional TRAP) has detected telomerase activity in
      various malignant tumors. With conventional TRAP, it is difficult to
      differentiate quantitatively low levels of telomerase activity between well
      differentiated hepatocellular carcinomas (HCCs) and dysplastic nodules because of
      quantitative limitation. To apply a telomerase assay for differential diagnosis,
      we used a hybridization protection assay combined with TRAP (TRAP/HPA). This
      combination had better sensitivity and wider linearity than conventional TRAP.
      METHODS: TRAP/HPA was applied for quantitative measurement of telomerase activity
      in various hepatic tissues. Telomerase activity was evaluated in 10 precancerous
      hepatic nodules, 17 well-differentiated HCCs, 19 moderately differentiated HCCs,
      5 poorly differentiated HCCs, 22 nontumorous chronic hepatic disease samples, and
      2 normal liver tissues. RESULTS: Telomerase activity in HCCs tended to increase
      according to the malignant transformation. The average relative telomerase
      activity in 0.6 microg protein, which was expressed as cell equivalent activity
      of MKN-1, a gastric carcinoma cell line, was 8.5 in precancerous hepatic nodules,
      87 in well-differentiated HCCs, 265 in moderately differentiated HCCs, 447 in
      poorly differentiated HCCs, and 0.4 in nontumorous hepatic tissues, including
      chronic liver diseases. CONCLUSIONS: TRAP/HPA was sensitive enough to distinguish
      the telomerase activity in precancerous hepatic nodules from that in other
      lesions. Telomerase activity in precancerous hepatic nodules was higher than that
      in nontumorous hepatic tissues. However, the activity in precancerous hepatic
      nodules was lower than that in well-differentiated HCCs, although statistically
      not significant. The authors suggest that precancerous hepatic nodules with
      telomerase activity above the diagnostic cutoff level (twice the highest activity
      in nontumorous hepatic tissues, or the 2 cell equivalent activity of MKN-1)
      should be treated as malignancy.

PMID- 10640963
TI  - UFT plus cisplatin combination chemotherapy in the treatment of patients with
      advanced nonsmall cell lung carcinoma: a multiinstitutional phase II trial. For
      the Japan UFT Lung Cancer Study Group.
AB  - BACKGROUND: Combination chemotherapy comprised of oral UFT (a combination of
      tegafur and uracil) and cisplatin was shown to be an effective regimen for the
      treatment of advanced nonsmall cell lung carcinoma and to be associated with a
      low incidence rate of toxicity in a previous, single institution, Phase II trial
      on a small patient sample. Therefore, the current multiinstitutional Phase II
      trial was conducted to confirm the earlier results. METHODS: Eligible patients
      had histologically or cytologically confirmed Stage IIIB or IV nonsmall cell lung
      carcinoma and good performance status. Patients who had received prior treatment
      were excluded. All had measurable disease. UFT (400 mg/m(2)) was administered
      orally on Days 1-14, and cisplatin (80 mg/m(2)) was injected intravenously on Day
      8. Treatment was repeated every 3-4 weeks. RESULTS: Approximately 70% of the 108
      eligible patients had systemic metastatic disease. All 108 patients were
      assessable for toxicity and survival, and 103 were assessable for response. Among
      these 103 patients there was 1 complete response and 29 partial responses, for an
      overall response rate of 29.1% (95% confidence limits [CL], 20.4-37.9%). The
      median survival time was 40 weeks and the 1-year survival rate was 39% (95% CL,
      30-49%). The median progression free survival time was 28 weeks. Eastern
      Cooperative Oncology Group Grade 3 leukopenia and thrombocytopenia were observed
      in only 1 patient (0.9%) and 3 patients (2.8%), respectively. Grade 3/4
      nonhematologic toxicities included elevated bilirubin (6.5%) and emesis (7.4%).
      One patient who had a past history of duodenal ulcer died of ulcer perforation 15
      days after completing the first treatment cycle. CONCLUSIONS: Oral UFT plus
      cisplatin is a moderately active regimen with an extremely low rate of incidence
      of myelosuppression as an adverse event, and warrants comparison with other
      cisplatin-based regimens in a prospective randomized trial.

PMID- 10640964
TI  - Osteosarcomas of flat bones in adolescents and adults.
AB  - BACKGROUND: Osteosarcomas typically are long bone tumors and rarely affect the
      flat bones of the axial or appendicular skeleton. METHODS: The authors examined
      cases of high grade osteosarcoma of flat bones diagnosed at La Timone Adults
      University Hospital during a 16-year period. RESULTS: Sixteen patients with flat
      bone osteosarcomas were treated between 1980-1997. The median age of the patients
      was 25 years, with a male-to-female ratio of 14:2. Common presenting symptoms
      were swelling, pain, or both. Primary therapy included resection (n = 11
      patients: alone in 8 patients and with radiation therapy in 3 patients),
      radiation therapy (n = 2 patients), or no local treatment (n = 3 patients). All
      patients received polychemotherapy, 7 preoperatively and postoperatively and 9 in
      the adjuvant setting. The overall 5-year survival rate was 47.7%; the overall
      median survival was 39 months (range, 4-211 months). The adequate local control
      rate was 68.7%. The local recurrence rate in patients who benefited from local
      treatment was 54%. Significant adverse prognostic factors on survival included
      the presence of synchronous metastases (three patients), metastases at any time
      during the course of the disease (eight patients), and inadequate local control
      (five patients). The overriding predictor of survival appeared to be the presence
      of metastases. Local recurrence appeared to have no influence on survival. No
      patient with metastases was alive at 3 years, whereas patients without recurrence
      or with local recurrence alone had a 5-year survival rate of 100%. Because the
      majority of patients with flat bone osteosarcomas ultimately die of metastatic
      disease, intensive systematic polychemotherapy should be an important component
      of treating these tumors. CONCLUSIONS: Based on the very encouraging results
      observed in the treatment of long bone osteosarcomas, the therapy for flat bone
      osteosarcomas should combine radical surgery with preoperative and postoperative
      adjuvant chemotherapy.

PMID- 10640965
TI  - Plasma FLT3-L levels predict bone marrow recovery from myelosuppressive therapy.
AB  - BACKGROUND: During the recovery period after anticancer myelosuppressive therapy,
      hematopoietic progenitor cells become mitotically active in order to replenish
      the bone marrow compartment and remain hyperproliferative even after
      normalization of peripheral white blood cells and platelets. At this stage, the
      progenitors are more radiosensitive and chemosensitive. Dosing patients with
      additional cytotoxic therapy during this phase will likely result in more severe
      toxicity. For example, the authors have noted that the red bone marrow (RM) dose
      resulting from radioantibody therapy does not correlate with observed bone marrow
      toxicity. Several patients given similar RM doses had Grade 3 or 4 toxicity,
      whereas others had Grade 0-2 toxicity even though their white blood cell (WBC)
      and (PLT) counts were normal at the time of dosing. The goal of these studies was
      to establish a noninvasive predictive marker of bone marrow activity that could
      determine stem cell and progenitor cell recovery from previous myelosuppressive
      therapy. METHODS: A retrospective study was conducted to quantitate plasma levels
      of 5 cytokines regulating hematopoiesis, namely, 2 stimulatory fms-like tyrosine
      kinase (FLT3-L) and stem cell factor (SCF) and 3 inhibitory growth factors tumor
      necrosis factor-alpha (TNFalpha), tumor growth factor-beta, and macrophage
      inflammatory protein (MIP-1alpha), by immunoassay in 43 patients enrolled in
      clinical trials at Garden State Cancer Center in Belleville, New Jersey. All
      patients had had previous chemotherapy with a duration of 1-24 months. The serum
      cytokine values were correlated with the magnitude of leukopenia or
      thrombocytopenia following a single dose of radioantibody as the cytotoxic
      therapy. RESULTS: Plasma FLT3-L levels predicted excess platelet toxicity in 13
      of 16 patients (mean = 225 +/- 106 pg/mL) and resulted in a false-positive in
      only 3 of 27 other patients (mean = 80 +/- 41 pg/mL). Plasma FLT3-L > 135 pg/mL
      resulted in 81% sensitivity and 89% and 86% specificity and accuracy,
      respectively, for predicting excess toxicity caused by additional cytotoxic
      therapy. The positive likelihood ratio was 7.5 (95% confidence interval, 2.5
      22.5) and the negative likelihood ratio was 0.19 (95% confidence interval, 0.05
      0.67). CONCLUSIONS: Elevated plasma FLT3-L in patients who previously received
      chemotherapy is a predictive measure of the stage of recovery of the bone marrow
      compartment. FLT3-L seems to identify the likelihood that the patient will
      experience Grade > or = 3 thrombocytopenia if additional cytotoxic therapy is
      administered. Knowledge of bone marrow activity should permit therapy that is
      more aggressive by establishing the earliest possible time for dosing with any
      cytotoxic agent for which myelosuppression is the dose-limiting toxicity.

PMID- 10640966
TI  - Derivation of a new hematopoietic cell line with endothelial features from a
      patient with transformed myeloproliferative syndrome: a case report.
AB  - BACKGROUND: During embryonal development primitive hematopoiesis can be observed
      first in the yolk sac, in which both hematopoietic and endothelial cells are
      derived from a common precursor, the hemangioblast. Whether cells with this dual
      differentiation potential persist during postnatal life is unknown. METHODS: A
      cell line was derived from a patient with secondary acute leukemia. Because of
      its ability to grow in soft agar and in SCID mice, this cell line was analyzed
      for expression of differentiation antigens by fluorescence-activated cell sorter
      analysis, immunocytochemistry, fluorescent in situ hybridization (FISH) analysis
      with simultaneous cell surface staining, and polymerase chain reaction (PCR).
      RESULTS: A new cell line was established from a patient with essential
      thrombocytosis that transformed into acute leukemia. The patient's initial
      clinical presentation included skin and lymph node infiltrations that were taken
      for an angiosarcoma due to positivity for CD34, CD31, and von Willebrand factor
      on immunohistology. In addition to hematopoietic markers, leukemic cells
      expressed endothelial antigens such as CD62E, CD105, and bound Ulex europaeus
      lectin-1. Immunocytochemistry revealed positive staining for vascular endothelial
      growth factor receptor type 2 (KDR), Tie-2/Tek, the angiopoietin receptor, and
      vascular endothelial cadherin. These results were confirmed by PCR analysis.
      Simultaneous staining for CD62E and FISH analysis showed that cells with
      endothelial characteristics belonged to the leukemia. FISH analysis of histologic
      sections of the lymph node infiltration confirmed this manifestation as part of
      the leukemic process. The derived cell line, UKE-1, forms colonies in soft agar
      and is tumorigenic in SCID mice. CONCLUSIONS: This new cell line, UKE-1, appears
      to combine hematopoietic and endothelial features, indicating the close ontogenic
      relation of both lineages.

PMID- 10640967
TI  - Deoxycoformycin in the treatment of patients with hairy cell leukemia: results of
      a Spanish collaborative study of 80 patients.
AB  - BACKGROUND: Deoxycoformycin (DCF) has been reported to produce high response
      rates in patients with hairy cell leukemia (HCL), but to the authors' knowledge
      data regarding experience with such therapy in a large HCL series are scarce.
      METHODS: Between 1988-1997, DCF (4 mg/m(2)/day, every 2 weeks) was administered
      to 80 HCL patients in 32 Spanish institutions. In 35 of 78 evaluable patients DCF
      was the first-line therapy; the remaining 43 patients had received other
      therapies. Pretreatment variables influencing the achievement of complete
      remission (CR) and event free survival were identified by multivariate analyses.
      RESULTS: The median number of cycles administered was 7 (range, 1-22 cycles). A
      CR was obtained in 56 patients (72%) and a partial remission was obtained in 13
      patients, for an overall response rate of 88%. In the multivariate analysis
      previous splenectomy and an Eastern Cooperative Oncology Group (ECOG) performance
      status > or = 2 were the parameters adversely influencing CR achievement. With a
      median follow-up of 31.2 months (range, 0.4-126.5 months), disease recurrence was
      observed in 11 of the CR patients, 5 of whom showed a further response to DCF. An
      ECOG performance status > or = 2 was the only pretreatment variable associated
      with a shorter event free survival. Seven patients died, four during the
      treatment period. The actuarial median event free survival was 46 months (95%
      confidence interval, 22.5-69.5 months), and 48.7% of the 56 patients who achieved
      a CR were expected to be alive and disease free at 5 years. Hematologic toxicity
      (marked neutropenia [22 cases], anemia [6 cases], and thrombocytopenia [1 case])
      was the main side effect, followed by nausea and emesis (5 cases); 14 patients
      required hospitalization. CONCLUSIONS: The results of the current study confirm
      the effectiveness and acceptable toxicity of DCF in the treatment of patients
      with HCL.

PMID- 10640968
TI  - Peritoneal carcinomatosis from non-gynecologic malignancies: results of the
      EVOCAPE 1 multicentric prospective study.
AB  - BACKGROUND: Peritoneal carcinomatosis (PC) is a common evolution of digestive
      cancer, associated with a poor prognosis. Yet it is poorly documented in the
      literature. METHODS: Three hundred seventy patients with PC from non-gynecologic
      malignancies were followed prospectively: the PC was of gastric origin in 125
      cases, of colorectal origin in 118 cases, of pancreatic origin in 58 cases, of
      unknown origin in 43 cases, and of miscellaneous origins in 26 cases. A
      previously reported PC staging system was used to classify these 370 patients.
      RESULTS: Mean and median overall survival periods were 6.0 and 3.1 months,
      respectively. Survival rates were mainly affected by the initial PC stage (9.8
      months for Stage I with malignant peritoneal granulations less than 5 mm in
      greatest dimension, versus 3.7 months for Stage IV with large, malignant
      peritoneal masses more than 2 cm in greatest dimension). The presence of ascites
      was associated with poor survival of patients with gastric or pancreatic
      carcinoma. Differentiation of the primary tumor did not influence the prognoses
      of patients with PC. CONCLUSIONS: A better knowledge of the natural history of PC
      is needed, in view of the many Phase I, II, and III trials currently being
      conducted to evaluate aggressive multimodal therapeutic approaches to treating
      patients with PC from non-gynecologic malignancies.

PMID- 10640969
TI  - Metastases to the retroperitoneum in patients with extremity soft tissue sarcoma:
      an unusual metastatic pattern.
AB  - BACKGROUND: Extremity soft tissue sarcoma (STS) metastasizes preferentially to
      the lungs via the hematogenous route. Metastases in extrapulmonary sites such as
      bone, brain, and subcutaneous tissues are observed less frequently. To the
      authors' knowledge, limb STS primarily metastasizing to the retroperitoneum has
      not been described to date. The current study reviews the clinical course,
      management, and patient prognosis in such a pattern of metastasis. METHODS:
      Records of patients with retroperitoneal metastases originating from an extremity
      STS between 1994-1998 were reviewed. Patient demographics, primary tumor site,
      other tumor sites, local recurrence, distant metastasis, treatment, and survival
      were analyzed. RESULTS: Ten patients were included in the study. All had primary
      STS of different histologic types and high histologic grade confined to a lower
      limb. The retroperitoneal metastases were diagnosed between 6-120 months (mean,
      45 months) after diagnosis of the primary sarcoma. At that time, one patient had
      evidence of local recurrence of the primary tumor site, two patients had lung
      metastases, and one patient had diffuse bone metastases. Eight patients were
      eligible for surgery. In six of these patients the metastases were excised
      completely. The median follow up was 12 months. Of the six patients who underwent
      complete resection, 3 were alive at last follow-up with no evidence of disease
      after 12 months, 14 months, and 24 months, respectively. Two patients with
      recurrent retroperitoneal disease and one patient with retroperitoneal and lung
      metastases died despite systemic chemotherapy. CONCLUSIONS: Extremity STS can
      metastasize hematogenously to the retroperitoneum, a fact that mandates a high
      index of suspicion and abdominal imaging studies during the follow-up of such
      patients. Retroperitoneal metastases necessitate aggressive surgical resection to
      enable prolongation of survival.

PMID- 10640970
TI  - Age-related variation in the treatment and outcomes of patients with breast
      carcinoma.
AB  - BACKGROUND: There is controversy regarding the effect of age on breast carcinoma,
      and previous analyses have often excluded the most elderly patients as well as
      those with advanced cancers. This study assessed treatment variations and outcome
      in relation to age for a complete series of patients who presented with breast
      carcinoma within a defined geographic district. METHODS: Data were collected
      prospectively for all 784 patients who presented with breast carcinoma in North
      Bedfordshire, United Kingdom, from 1990 to 1996. Stage of disease, treatment, and
      outcome were compared for different age groups. RESULTS: Older patients had more
      advanced cancers: 14% of lymph node negative patients age > or = 60 years had T3
      or T4 tumors compared with 4% of younger lymph node negative patients (P < 0.
      0001). Treatment varied with age: 94% of lymph node negative patients age > or =
      60 years received tamoxifen compared with 73% of younger lymph node negative
      patients (P < 0.0001). For lymph node positive patients, outcome was unaffected
      by age; however, for lymph node negative patients, outcome was best for patients
      ages 60-69 years: disease free survival was 91% compared with 78% for other ages
      at 3 years (P = 0.008), and the locoregional recurrence rate was 2% compared with
      7% at 3 years (P = 0.04). The improvement in the locoregional recurrence rate
      applied to all lymph node negative patients age > or = 60 years: the recurrence
      rate was 2% compared with 9% for younger patients at 3 years (P = 0.04).
      CONCLUSIONS: These data support the theory that breast carcinomas are more
      aggressive in younger patients. The high prescription rate of tamoxifen for older
      lymph node negative women may have contributed to the low locoregional recurrence
      rate for this group.

PMID- 10640971
TI  - A phase II trial of high dose epirubicin in patients with advanced breast
      carcinoma.
AB  - BACKGROUND: Anthracyclines are among the most active drugs in the treatment of
      breast carcinoma and exhibit a steep dose-response curve in vitro. This trial was
      performed to determine the efficacy and toxicity of epirubicin in the treatment
      of patients with advanced breast carcinoma when administered as a single agent in
      maximal doses. METHODS: Patients with chemotherapy-naive American Joint Committee
      on Cancer/International Union Against Cancer Stage IIIB or IV breast carcinoma
      received epirubicin, 180 mg/m(2), intravenously every 3 weeks for a maximum of 8
      cycles of therapy. Hematopoietic growth factors and cardioprotective agents were
      not used routinely. RESULTS: Twenty-seven patients were entered in the study.
      Although NCI/CTC criteria Grade 4 neutropenia occurred in 96% of patients,
      epirubicin was administered at 83.1% of the planned dose intensity. The median
      fall in left ventricular ejection fraction was 10%; clinical cardiac toxicity was
      observed in 3 patients. Objective responses were observed in 21 patients,
      including 6 complete responses. CONCLUSIONS: High dose epirubicin was found to
      result in substantial hematologic toxicity but was highly active in the treatment
      of patients with advanced breast carcinoma.

PMID- 10640972
TI  - Antitumor activity of a novel glyco-nitric oxide conjugate in ovarian carcinoma.
AB  - BACKGROUND: Several studies have shown that nitric oxide (NO)-releasing agents
      can kill tumor cells. Unfortunately, currently available NO delivery molecules do
      not target tumor cells preferentially. To exploit the overexpression of glucose
      transport proteins and the high level of glucose transport characteristics of
      tumor cells, glucose was conjugated to S-nitroso-N-acetyl-penicillamine (2
      gluSNAP) and evaluated for cytotoxicity in human ovarian carcinoma cells.
      METHODS: The cytotoxicity of 2-gluSNAP and SNAP was assessed by clonogenic cell
      survival assays performed in A2780S (cisplatin sensitive) and A2780cP (cisplatin
      resistant) ovarian carcinoma cells in vitro. Immunoblotting and
      immunohistochemistry were used to assess the expression of Glut-1 hexose
      transport protein in the cell lines as well as in paraffin blocks from 28
      surgical specimens of epithelial ovarian carcinoma. Apoptosis was assessed by an
      end-labeling assay. RESULTS: The ovarian carcinoma cell lines consistently were
      more sensitive to 2-gluSNAP than SNAP alone. The median effective doses (MEDs)
      for 2-gluSNAP and SNAP in the A2780s cell line were 0.0042 microM and 20.4
      microM, respectively. Therefore, 2-GluSNAP was nearly 5000-fold more potent than
      the NO-donating moiety (SNAP) alone. In the A2780cP cells, the MED for 2-gluSNAP
      (0.38 microM) was 250-fold lower than that for SNAP alone (100 microM).
      Immunoblotting and immunohistochemistry studies showed overexpression of Glut-1
      in the cell lines and in 23 of 28 epithelial ovarian carcinoma specimens.
      CONCLUSIONS: The novel glyco-NO conjugate 2-gluSNAP exhibits a much greater
      cytotoxicity than the parent NO donor without the hexose moiety. These agents
      have the potential to target tumor cells preferentially, that overexpress Glut-1.
      This transporter is expressed highly in epithelial ovarian carcinoma.

PMID- 10640973
TI  - Primary cytoreductive surgery with rectosigmoid colon resection for patients with
      advanced epithelial ovarian carcinoma.
AB  - BACKGROUND: The impact of radical bowel resection with multiple organ resection
      on the survival if patients with advanced ovarian carcinoma has not been well
      defined. The authors investigated whether primary cytoreductive surgery including
      rectosigmoid colon resection would affect the recurrence free interval and
      survival of these patients. METHODS: Between April 1990 and April 1997, 66
      previously untreated Stage IIIC-IV ovarian carcinoma patients with macroscopic
      involvement of the rectosigmoid colon were enrolled. All patients underwent
      cytoreductive surgery with rectosigmoid colon resection to remove residual tumor
      less than 2 cm in greatest dimension and received 6 cycles of cisplatin-based
      postoperative chemotherapy. RESULTS: The median follow-up was 26 months (range, 7
      104 months). In multivariate analysis, residual disease and depth of tumor
      infiltration of the bowel wall were independently associated with overall
      survival and recurrence free interval. Disease stage was independently associated
      only with overall survival. Residual tumor was the most strongly predictive
      factor for recurrence or death. The 2-year estimated survival rates according to
      the amount of residual tumor were 100% for 24 patients with no macroscopic
      residual disease and 77.3% for 28 patients with residual disease less than 1 cm.
      None of the 14 patients with residual disease larger than 1 cm were alive 2-years
      after operation. Overall, 48 patients (72.7%) developed disease recurrence: 43
      (65.1%) in the abdomen, 19 (29.8%) in the liver, and 3 (4.5%) in the pelvis.
      CONCLUSIONS: The current findings suggest that cytoreductive surgery with
      rectosigmoid colon resection should be considered for ovarian carcinoma patients
      with bulky pelvic disease to help ensure that they are left with no residual
      disease after debulking surgery.

PMID- 10640974
TI  - Second malignancies in prostate carcinoma patients after radiotherapy compared
      with surgery.
AB  - BACKGROUND: In the treatment of prostate carcinoma, radiotherapy and surgery are
      common choices of comparable efficacy; thus a realistic comparison of the
      potential long term sequelae, such as the risk of second malignancy, may be of
      relevance to treatment choice. METHODS: Data regarding the rate of incidence from
      the Surveillance, Epidemiology, and End Results Program cancer registry (1973
      1993) were used to compare directly second malignancy risks in 51,584 men with
      prostate carcinoma who received radiotherapy (3549 of whom developed second
      malignancies) with 70,539 men who underwent surgery without radiotherapy (5055 of
      whom developed second malignancies). Data were stratified by latency period, age
      at diagnosis, and site of the second malignancy. Directly comparing the risks in
      the radiotherapy group with those in the surgery group largely avoids problems
      associated with underreporting second malignancies. RESULTS: Radiotherapy for
      prostate carcinoma was associated with a small, statistically significant
      increase in the risk of solid tumors (6%; P = 0.02) relative to treatment with
      surgery. Among patients who survived for >/= 5 years, the increased relative risk
      reached 15%, and was 34% for patients surviving >/= 10 years. The most
      significant contributors to the increased risk in the irradiated group were
      carcinomas of the bladder, rectum, and lung, and sarcomas within the treatment
      field. No significant increase in rates of leukemia was noted. CONCLUSIONS:
      Radiotherapy for prostate carcinoma was associated with a statistically
      significant, although fairly small, enhancement in the risk of second solid
      tumors, particularly for long term survivors. The pattern of excess second
      malignancies among men treated with radiotherapy was consistent with
      radiobiologic principles in terms of site, dose, and latency. In absolute terms,
      the estimated risk of developing a radiation-associated second malignancy was 1
      in 290 for all prostate carcinoma patients treated with radiotherapy, increasing
      to 1 in 70 for long term survivors (>/= 10 years). Improvements in
      radiotherapeutic techniques, along with diagnosis at younger ages and earlier
      stages, are resulting in longer survival times for patients with prostate
      carcinoma. Because of the long latency period for radiation-induced tumors, this
      may result in radiation-related second malignancy risk becoming a more
      significant issue.

PMID- 10640975
TI  - Short term neoadjuvant androgen deprivation therapy does not affect prostate
      specific membrane antigen expression in prostate tissues.
AB  - BACKGROUND: Prostate specific membrane antigen (PSMA) is a transmembrane
      glycoprotein highly expressed in benign prostate secretory-acinar epithelium and
      prostate carcinoma. The results of several studies suggest that PSMA expression
      is increased in prostate carcinoma cell lines subjected to androgen deprivation
      and in androgen-independent tumors. The authors studied the effects of short term
      (3-month) androgen deprivation on PSMA expression in prostate carcinoma specimens
      using two anti-PSMA monoclonal antibodies (mAbs), 7E11 and PM2J004.5. METHODS:
      The study included patients with clinically localized prostate carcinoma who were
      prospectively randomized into 1 of 2 treatment groups: 3 months of neoadjuvant
      androgen deprivation therapy followed by radical prostatectomy (ADT/RP), or
      radical prostatectomy (RP) alone. Representative formalin fixed, paraffin
      embedded prostate sections were immunostained with the anti-PSMA mAbs 7E11 and
      PM2J004.5 by the streptavidin-biotin method. The authors recorded the staining
      intensity and the percentage of positive cells stained in benign epithelium, high
      grade prostatic intraepithelial neoplasia (PIN), and prostate carcinoma. They
      compared the results of 7E11 with those of PM2J004.5 in benign epithelium, high
      grade prostate, and carcinoma and also compared the results between the two
      treatment groups (ADT/RP vs. RP alone). RESULTS: Both anti-PSMA mAbs stained
      benign secretory-acinar epithelium, high grade PIN, and prostate carcinoma. In
      both treatment groups, PM2J004.5 reacted with a significantly greater percentage
      of cells (P < 0.001) and with significantly greater intensity (P < 0.001)
      compared with 7E11 in benign epithelium and prostate carcinoma. With both anti
      PSMA mAbs, the percentage of cells stained and the intensity of staining in high
      grade PIN was similar to that in prostate carcinoma. In the group that received
      RP alone, the percentage of cells stained and the intensity of staining with 7E11
      were significantly greater in high grade PIN and prostate carcinoma compared with
      benign epithelium (P < 0.001), and the intensity of staining with the PM2J004.5
      was significantly greater in high grade PIN and prostate carcinoma compared with
      benign epithelium (P < 0.001). In the ADT/RP group, the percentage of cells
      stained and the intensity of staining with 7E11 and PM2J004.5 were significantly
      greater in prostate carcinoma compared with benign epithelium (P < 0.006). PSMA
      staining did not correlate with either Gleason score (in the group that received
      RP alone) or pathologic stage (in both the RP-alone and ADT/RP groups) and did
      not differ between the two treatment groups. CONCLUSIONS: Short term neoadjuvant
      ADT does not affect PSMA expression in benign prostate secretory-acinar
      epithelium, high grade PIN, or prostate carcinoma. Prostate carcinoma and high
      grade PIN express significantly higher levels of PSMA than benign prostate
      secretory-acinar epithelium. Compared with 7E11, the PM2J004.5 anti-PSMA mAb is a
      more sensitive immunohistochemical marker of prostate carcinoma in formalin
      fixed, paraffin embedded tissue.

PMID- 10640976
TI  - Prognostic significance of p16 and CDK4 proteins in localized prostate carcinoma.
AB  - BACKGROUND: In prostate carcinoma, a very low frequency of point mutations of the
      tumor suppressor gene CDKN2/MTS1 (p16(INK4) ) has been reported, but deletions of
      9p21 and inactivation by promoter methylation are observed more frequently. In
      the current study the authors evaluated the expression of p16 and CDK4 proteins
      and their prognostic significance in patients with clinically localized prostate
      carcinoma. METHODS: The levels of p16 and CDK4 proteins were quantitated by
      immunofluorescence flow cytometry, using paraffin embedded material, in 104
      adenocarcinomas of the prostate after radical prostatectomy. These levels then
      were compared with 25 cases of benign prostate hyperplasia (BPH). RESULTS: In
      prostatic carcinoma specimens, p16 protein was elevated significantly compared
      with BPH, with a median fluorescence index (FI) of 15.4 versus 10.7, respectively
      (P = 0.010). This was not the case for CDK4 protein, although p16 protein
      expression correlated significantly with CDK4 protein expression in BPH (Spearman
      rank correlation [R(S)] = 0.63) and carcinoma (R(S) = 0.78). In univariate
      survival analysis of the first 5 years, high levels of p16 protein expression (FI
      > 11.7) (P = 0.005), tumor greatest dimension, World Health Organization (WHO)
      histologic grade, capsular penetration, seminal vesicle invasion, positive
      surgical margins, lymph node involvement, and preoperative serum prostate
      specific antigen > 20 ng/mL all were significant predictors of biochemical
      failure. In multivariate survival analysis, high p16 protein expression (P =
      0.015), age, WHO histologic grade, capsular penetration, and seminal vesicle
      involvement remained as independent predictors of biochemical failure.
      CONCLUSIONS: These data suggest that increased expression of p16 protein, but not
      CDK4 protein, may be involved in the development of prostate carcinoma and may
      represent an independent predictor of biochemical failure after radical
      prostatectomy.

PMID- 10640977
TI  - A comparison of external beam radiation therapy versus radical prostatectomy for
      patients with low risk prostate carcinoma diagnosed, staged, and treated at a
      single institution.
AB  - BACKGROUND: The authors retrospectively reviewed their institution's long term
      experience treating a group of comparably staged low risk prostate carcinoma
      patients with either radical prostatectomy or external beam radiation therapy
      (RT) to determine whether the method of treatment resulted in significant
      differences in biochemical control and/or survival. METHODS: From January of 1987
      through December of 1994, 382 patients (157 who underwent radical prostatectomy
      and 225 who received external beam RT) were treated with curative intent for
      localized prostate carcinoma at William Beaumont Hospital. All patients had a
      pretreatment serum prostate specific antigen (PSA) level < or =10.0 ng/mL and a
      biopsy Gleason score </=6. Patients treated with RT received a median dose of
      66.6 gray (Gy) (range, 59.2-70.2 Gy) to the prostate. Patients treated surgically
      underwent radical retropubic prostatectomy with a pelvic lymph node dissection.
      For surgical patients, biochemical failure was defined as a detectable PSA level
      > or =0.2 ng/mL at any time after prostatectomy. For RT patients, biochemical
      failure was defined according to the American Society for Therapeutic Radiology
      and Oncology Consensus Panel definition. Pretreatment PSA levels and Gleason
      scores were not significantly different between patients treated with radical
      prostatectomy or RT. The median follow-up in each treatment group was 5.5 years.
      RESULTS: The 7-year actuarial rates of biochemical control and cause specific
      survival were not significantly different between patients treated either with
      radical prostatectomy or RT (67% vs. 69% for biochemical control and 99% vs. 97%
      for cause specific survival, respectively). A number of clinical, pathologic, and
      treatment-related factors were analyzed for an association with biochemical
      failure (i.e., age, pretreatment PSA, Gleason score, and treatment modality).
      Only pretreatment PSA and Gleason score were significantly related to outcome in
      both univariate and multivariate analyses. CONCLUSIONS: Low risk prostate
      carcinoma patients with similar pretreatment PSA levels and biopsy Gleason scores
      treated at the same institution with either radical prostatectomy or RT achieved
      similar 7-year rates of biochemical control and cause specific survival,
      regardless of treatment technique. These findings suggest that for patients with
      pretreatment PSA levels </=10 ng/mL and Gleason scores </=6, conventional doses
      of external beam RT and radical retropubic prostatectomy can be expected to
      produce comparable treatment results unaffected by age at diagnosis.

PMID- 10640978
TI  - Predominance of brain tumors in an extended Li-Fraumeni (SBLA) kindred, including
      a case of Sturge-Weber syndrome.
AB  - BACKGROUND: Li-Fraumeni syndrome (LFS) is characterized by a plethora of cancers,
      most prominent of which is carcinoma of the breast followed by sarcomas, brain
      tumors, leukemia, lymphoma, lung carcinoma, and adrenocortical carcinoma
      (therefore, also referred to by the acronym SBLA syndrome). METHODS: The family
      reported herein was first described 2 decades ago. Now extensive follow-up has
      shown the predictable occurrence of these tumor types, in addition to an excess
      of brain tumors and the finding of Sturge-Weber syndrome (SWS) in an LFS-affected
      family member. RESULTS: A possible new feature of the disorder, suggestive of
      SWS, was identified in a patient in the direct genetic lineage. This patient had
      a rhabdomyosarcoma of the eyelid at age 29 months and at age 14 years was
      diagnosed with lymphoblastic lymphoma/acute lymphoblastic leukemia. A remarkable
      excess of brain tumors was identified in this family through this current update.
      The p53 germ-line mutation was not identified in any affected member of this
      family. CONCLUSIONS: To the authors' knowledge, this is the first example of SWS
      in the context of LFS. Brain tumors appear to be an important component of the
      tumor spectrum of LFS, as evidenced in this family.

PMID- 10640979
TI  - A role for telomeric and centromeric instability in the progression of chromosome
      aberrations in meningioma patients.
AB  - BACKGROUND: The primary chromosome aberration in meningiomas is monosomy or
      deletion of chromosome 22. Common secondary aberrations include losses or
      deletions of chromosomes 1p, 14q, and 10q and unstable chromosome aberrations
      including rings, dicentrics, and telomeric associations. Despite the analysis of
      several hundred tumors by cytogenetic and molecular techniques, the mechanisms
      involved in the progression of chromosome aberrations in meningioma remain poorly
      understood. METHODS: Sixty-seven meningiomas were cultured successfully using a
      short term in situ technique and harvested incorporating a high resolution G
      banding technique with ethidium bromide. RESULTS: Twenty-six tumors (39%) showed
      normal karyotypes, whereas 41 tumors (61%) showed clonal chromosome aberrations.
      The most frequently observed aberration was the loss of chromosome 22 or
      structural aberrations involving 22q12, which occurred in 30 tumors (45%). The
      second most common aberrations were whole arm translocations involving the
      centromeric breakpoint at 1q10, resulting in the loss of the entire 1p chromosome
      in 12 tumors (18%). Two tumors showed a new, recurring, unbalanced, whole arm
      translocation der(1;2)(q10;q10). A third aberration, telomeric associations, were
      observed in 16 tumors (24%), occurring transiently in 11 tumors and recurring
      clonally in 5 tumors. Dicentric chromosome 22 was found in 7 tumors (10%), with
      the progressive loss of chromosome 22q material being found in 2 tumors.
      CONCLUSIONS: The chromosome instability demonstrated in the current series of
      tumors suggests that the progression of chromosome aberrations in meningioma is
      mediated in some respects by both telomeric and centromeric instability. These
      two types of instability may be early events in the progression of chromosome
      aberrations in meningioma and each can account for at least some of the loss of
      heterozygosity of chromosomes 22q and 1p detected by molecular analysis.

PMID- 10640980
TI  - Short term treatment with Escherichia coli recombinant human granulocyte
      macrophage-colony stimulating factor prior to chemotherapy for Hodgkin disease.
AB  - BACKGROUND: Granulocyte-macrophage-colony stimulating factor (GM-CSF)
      administration stimulates the proliferation of hemopoietic progenitors. Shortly
      (48-96 hours) after its discontinuation, feedback phenomena occur and the
      progenitor proliferation rate drops below baseline levels. As the quiescence of
      hyperplastic bone marrow suggests that hemopoietic cells may be refractory to the
      toxic effects of cytostatic drugs, the decision was made to test the hypothesis
      that GM-CSF given before chemotherapy may be myeloprotective. METHODS: Fifty-six
      patients with newly diagnosed Stage II-IV Hodgkin disease, ages 18-77 years, were
      randomized to receive GM-CSF (5 microg/kg subcutaneously) or placebo from Day 7
      to Day 4 before each chemotherapy administration (6 cycles of a hybrid of
      mechlorethamine, vincristine, procarbazine, and prednisone with doxorubicin,
      bleomycin, vinblastine, and dacarbazine). The treatment was considered a success
      if the delivery rate of chemotherapy was >90% after 3 cycles and >80% after 6
      cycles. RESULTS: Thirty patients received GM-CSF and 26 placebo. The dose
      intensity (85.2% vs. 79.6%) and the overall success in terms of delivery rate
      (56.7% vs. 50%) were higher in the GM-CSF group, although these differences were
      not statistically significant. The neutrophil nadirs were higher in the GM-CSF
      group during the first three cycles and subsequently similar in both groups.
      CONCLUSIONS: No significant differences in terms of myelotoxicity or drug
      delivery were observed between the two treatment arms. Although the
      myeloprotective effect of the prechemotherapy administration of GM-CSF seems to
      be minimal, the data indicate a safe timing between GM-CSF discontinuation and
      further chemotherapy. Because cumulative myelotoxicity has been observed with
      other growth factors, given in the interval between the chemotherapy cycles, this
      may be relevant to the planning of rapid cycling.

PMID- 10640981
TI  - The tumor-associated shift in immunoglobulin G1/G2 is expressed at the messenger
      RNA level of peripheral blood B lymphocytes in patients with gynecologic
      malignancies.
AB  - BACKGROUND: Previously, it could be demonstrated that human patients with
      malignant diseases of various tissues exhibited characteristic and highly
      significant changes in the serum patterns of immunoglobulin (Ig)G subclasses,
      consisting of a decrease in IgG1 and an increase in IgG2 relative to total IgG.
      The aim of the current study was to determine whether this phenomenon was
      detectable at the level of IgG-producing B lymphocytes. METHODS: Using a
      competitive reverse transcriptase polymerase chain reaction specific to IgG1 and
      IgG2, the gene expression of these 2 IgG subclasses in peripheral B cells from 10
      patients with carcinomas of various sites within the female reproductive tract
      and 10 healthy controls was quantitatively determined, in parallel with the
      concentrations of the respective serum proteins. RESULTS: Absolute levels of IgG
      subclass messenger ribonucleic acid (mRNA) showed a slight but not significant
      decrease in IgG1 and an increase in IgG2 in patients with gynecologic
      malignancies. However, the ratio of IgG1 to IgG2 expression showed a highly
      significant (P < 0.001) decrease in tumor patients compared with healthy
      controls, and corresponded to the change in the ratio of IgG1 to IgG2 serum
      proteins. CONCLUSIONS: These data suggest that the shifts in the serum patterns
      of IgG1 and IgG2 observed in patients with gynecologic malignancies are due to
      irregular biosynthesis of these IgG subclasses at the B-cell level.

PMID- 10640982
TI  - Orthotopic human lung carcinoma xenografts in BALB/c mice immunosuppressed with
      anti-CD4 monoclonal antibodies and chronic alcohol consumption.
AB  - BACKGROUND: The role of the immune system in the surveillance of the body for
      cancer cells is well established. Human tumor cells do not survive in mice with
      intact immune systems, but they propagate in athymic nude mice. Presumably, the
      lack of a thymus gland and consequent loss of T lymphocytes results in a
      seriously compromised immune system without adequate cell-mediated immunity and
      tumor surveillance. In patients infected with the human immunodeficiency virus
      (HIV), a progressive loss of cell-mediated immunity is associated with the
      development of malignancies and opportunistic infections. This effect may be
      exacerbated in patients who chronically consume alcohol. METHODS: Normal and
      alcoholic BALB/c mice were treated with a monoclonal antibody to deplete CD4(+)
      lymphocytes before orthotopic implantation of human lung adenocarcinoma
      xenografts. Tumor volume and weight were measured and compared between groups.
      RESULTS: The authors' data show that a single treatment of anti-CD4 antibody
      causes almost complete depletion of CD4(+) lymphocytes and permits the formation
      of large intrapulmonary human nonsmall lung carcinoma xenografts in 100% of
      treated mice. All control animals injected with heat-denatured antibody failed to
      produce tumors. Chronic alcohol consumption by CD4-depleted mice resulted in
      larger tumors, compared with mice that did not receive ethanol in their diet (P =
      0.05). CONCLUSIONS: Depletion of CD4(+) lymphocytes allows for the orthotopic
      growth of human lung adenocarcinoma xenografts in BALB/c mice. Furthermore, the
      consumption of alcohol reduces the ability of the impaired immune system to
      reject tumors.

PMID- 10640983
TI  - Splenic rupture in children with hematologic malignancies.
AB  - BACKGROUND: Splenic rupture is an uncommon but life-threatening complication of
      leukemias and lymphomas, and is reported mostly in adults. The authors
      investigated the frequency with which splenic rupture is diagnosed in pediatric
      patients with hematologic malignancies and reviewed its clinical profile and
      outcome. METHODS: The data base of St. Jude Children's Research Hospital was
      searched for cases coded as splenic laceration or rupture, splenic infarction, or
      splenectomy in patients diagnosed with lymphoma or leukemia between January 1962
      and December 1997. The medical records of patients with histopathologic or
      radiologic evidence of splenic rupture were reviewed. The time spanned by the
      study was divided into early (1962-1990) and recent (1991-1997) eras to reflect
      the availability of modern diagnostic imaging techniques. RESULTS: Seven children
      experienced splenic rupture. They were between ages 5-17 years. There were four
      males and three females. Primary diagnoses included acute myeloid leukemia (four
      patients), acute lymphoblastic leukemia (two patients), and Hodgkin lymphoma (one
      patient). Five patients were diagnosed in the recent era and two in the early
      era. Four patients had radiologic or bacteriologic evidence of fungal infection
      concomitant with the splenic event. Of five deaths, only two were related
      causally to splenic rupture; these occurred in the early era. All seven acute
      episodes of splenic rupture were managed conservatively without surgery.
      CONCLUSIONS: The overall frequency with which splenic rupture was detected in
      children with hematologic malignancy at the study institution was 0.18%. In the
      recent era, the frequency of detection was 9-fold higher (0.55%) than that of the
      early era (0.06%). Improved imaging techniques and increased utilization of
      imaging studies may account for the increased incidental detection of
      "preclinical" splenic rupture. Adolescent age group, acute myeloid leukemia
      (especially acute promyelocytic leukemia), a high leukocyte count,
      thrombocytopenia, and coagulopathy may predispose children with leukemia to
      pathologic splenic rupture. Fungal infection frequently was associated with
      splenic rupture and may play a role in its pathogenesis.

PMID- 10640984
TI  - Into 2000: the journal of pathology on the web
AB  - The Journal of Pathology is now available to institutional and member subscribers
      in both PDF and HTML formats. The use of HTML offers the possibility of various
      enhancements to the Journal's content, including the creation of hot links to
      cited articles, which will greatly ease the access to relevant literature.
      Articles will shortly be made available online before the print issues, allowing
      for early dissemination. The Journal will also soon be able to publish
      supplementary material in electronic format only. A personalized e-mail alerting
      service could be provided to subscribers with defined areas of special interest.
      Authors and readers are encouraged to express their views on these and other
      potential developments, by communicating with the Editor-in-Chief (e-mail:
      j.pathology@qub.ac.uk). Copyright 2000 John Wiley & Sons, Ltd.

PMID- 10640985
TI  - Adhesion molecule expression in breast cancer: the phoenix in tumour metastasis?
AB  - Adhesion molecules have a number of diverse roles, amongst which is the control
      of tissue architecture and the maintenance of tissue integrity. Most tumours have
      an abnormal architecture and loss of tissue integrity is thought to be an
      important step in the development of local invasion. Thus, alterations in
      adhesion molecules may have a role in both tumour development and tumour
      invasion. The role of these molecules in the establishment of tumour metastases
      is much less certain. The tumour cells in a metastatic deposit are in a different
      environment and are faced with a different set of selection pressures, which may
      drive tumour evolution in a new direction. Metastatic deposits often resemble the
      tumour of origin and not infrequently show better differentiation. Together with
      evidence from experimental maintenance systems which shows that maintenance of
      intercellular contact may prevent apoptosis, this implies a role for adhesion
      molecules in tumour metastasis.

PMID- 10640986
TI  - Molecular detection of low-level disease in patients with cancer.
AB  - The accurate detection of low-level disease in patients with cancer is essential
      to improve the staging of disease and consequently to define appropriate
      treatment strategies. Most methods currently used for staging are based on
      imaging studies and histological and immunocytochemical analysis of tissues such
      as bone marrow aspirates, or antibody assays for marker proteins secreted into
      the circulation. These methods have limited sensitivity. However, assays for
      nucleic acid-based markers may be valuable tools for the sensitive detection,
      assessment, and monitoring of disease status in asymptomatic cancer patients.
      Application of these methods may allow the early detection of cancer, when the
      tumour burden is smaller and the disease potentially more curable. The last
      decade has seen the application of polymerase chain reaction (PCR)-based methods
      to the detection of tumour in a wide variety of compartments, including
      peripheral blood, bone marrow, lymph nodes, urine, sputum, faeces, pancreatic
      juice, and more recently plasma. Molecular detection of disease by PCR has
      targeted DNA and RNA markers, including mutations, microsatellites, and tissue
      specific gene expression. It is likely that these molecular methods will provide
      important clinical information, though their current clinical utility remains
      unclear. The current status of nucleic acid-based assays for the detection and
      assessment of disease status in the management of patients with solid tumours is
      reviewed.

PMID- 10640987
TI  - Re-expression of E-cadherin, alpha-catenin and beta-catenin, but not of gamma
      catenin, in metastatic tissue from breast cancer patients [seecomments].
AB  - Tumour cell invasion and metastasis are the processes which kill most cancer
      patients. Tumour cells with the greatest invasive and metastatic capacity may be
      those with the highest number of genetic aberrations. The present study has
      analysed the expression of several tumour-related proteins in both primary
      tumours and metastatic lesions from 34 breast cancer patients. Protein expression
      of p53, bcl-2, p21, cyclin D1, E-cadherin, alpha-catenin, beta-catenin, and gamma
      catenin was investigated by immunohistochemistry (IHC) using monoclonal
      antibodies. Metastatic tissue showed a different expression profile from the
      primary tumour in most patients. The most significant finding was the re
      expression of E-cadherin, alpha-catenin, and beta-catenin, and increased down
      regulation of gamma-catenin, in metastatic lesions. These results demonstrate
      that tumour cells, when released from the primary site and after regrowth
      elsewhere, are capable of re-expression of adhesion molecules. gamma-catenin may
      play a different role in metastatic lesions than in primary tumours, since it is
      selectively down-regulated in tumour tissue at the metastatic site.

PMID- 10640988
TI  - Fas ligand is expressed in normal breast epithelial cells and is frequently up
      regulated in breast cancer.
AB  - Fas (CD95/Apo-1) is a cell membrane receptor that upon binding by its ligand
      (FasL), triggers a signal resulting in apoptotic cell death. Fas is produced by
      breast epithelial cells, but its contribution to breast tissue homeostasis is
      unknown. This study investigated whether FasL is synthesized in the breast. By
      reverse transcription-polymerase chain reaction (RT-PCR), western blotting, and
      immunohistochemistry, FasL expression was analysed in normal and malignant human
      breast epithelial cell lines, normal breast tissue, benign breast disease
      (fibrocystic changes, fibroadenoma), and breast cancer (ductal carcinoma in situ;
      invasive ductal, lobular, mucinous and medullary carcinomas). The results
      demonstrate expression of FasL by normal breast epithelial cells and show a
      marked increase of FasL protein in the majority of breast carcinomas, compared
      with normal breast tissue and benign breast disease. By western blot analysis,
      soluble FasL was detected in culture supernatants of one of three normal breast
      epithelial cell lines and in all four breast cancer cell lines tested. The
      expression of Fas protein was more heterogeneous in benign and malignant breast
      tissue, with expression levels ranging from weak to strong, but breast cancer
      cells frequently exhibited a weaker Fas expression than surrounding residual
      normal breast epithelial cells. In vitro, two out of three normal breast
      epithelial cell lines were sensitive to cell death induction by an agonistic anti
      Fas antibody. Co-treatment with cycloheximide, an inhibitor of protein
      translation, rendered the resistant cell line sensitive. In contrast, two out of
      four breast cancer cell lines were resistant to the anti-Fas antibody and this
      resistance could not be reversed by cycloheximide. These results suggest that
      increased expression of FasL may confer an advantage on breast cancer cells,
      possibly by eliminating tumour-infiltrating immune cells, and/or by facilitating
      tissue destruction during invasion.

PMID- 10640989
TI  - Cytogenetic characterization of peripheral nerve sheath tumours: a report of the
      CHAMP study group.
AB  - The findings of characteristic, sometimes pathognomonic, chromosome aberrations
      in several types of soft tissue tumours have not only added to our understanding
      of the mechanisms behind the genesis of these tumours, but have also revealed the
      importance of cytogenetic analysis as a diagnostic tool. For many soft tissue
      tumours, including peripheral nerve sheath tumours, the number of analysed cases
      is, however, still very low, precluding evaluations of the clinical or biological
      significance of different chromosomal patterns. As part of an ongoing project
      aiming at identifying clinical-histopathological-cytogenetic correlations among
      soft tissue tumours, a series of 46 benign, the vast majority of which were
      located in the extremities, and 20 malignant peripheral nerve sheath tumours
      (BPNSTs and MPNSTs, respectively) that had been successfully analysed by
      chromosome banding techniques were evaluated with regard to clinical,
      morphological, and cytogenetic features. Clonal chromosome aberrations were found
      in 20 BPNSTs, with abnormal karyotypes being significantly more frequent among
      Schwannomas than among neurofibromas. Recurrent aberrations, all of which were
      confined to the Schwannoma subtypes, included loss of 22q material, loss of a sex
      chromosome, and trisomy 7. The results show that the cytogenetic features of
      Schwannomas are not dependent on the site of origin. The MPNSTs, all of which had
      clonal chromosome aberrations, displayed complex karyotypes with numerous
      structural and numerical changes, except in two cases showing +7 and -22,
      respectively, as the sole changes. None of the recurrent imbalances was
      restricted to either NF1-associated or sporadic MPNST, nor was any of the
      imbalances significantly associated with clinical outcome. The presence of a
      triploid or tetraploid clone was, however, associated with grade 3 tumours and a
      poor prognosis. The cytogenetic findings in peripheral nerve sheath tumours show
      that the karyotype is a good discriminator between BPNSTs and MPNSTs, and that
      the pattern of aberrations among the latter may add prognostic information.

PMID- 10640990
TI  - Transcriptional activation of tyrosinase and TRP-1 by p53 links UV irradiation to
      the protective tanning response.
AB  - We are exposed constantly to potentially harmful compounds and radiations.
      Complex adaptive protective responses have evolved to prevent such agents causing
      cellular damage, including potentially oncogenic mutation. The p53 tumour
      suppressor appears to have a role in co-ordinating such responses: it is
      activated by diverse insults and it acts as a transcriptional regulator of
      downstream genes that facilitate cellular adaptation. Ultraviolet (UV) light is a
      particularly potent inducer of p53 expression. In addition, UV light induces the
      production of melanin as a protection against further irradiation-induced damage.
      This study shows that the promoters of the genes coding for the enzymes crucial
      in melanin biosynthesis, namely tyrosinase and tyrosinase-related protein-1 (TRP
      1), are activated by wild-type p53. Both promoters have p53-responsive elements
      and are activated in vivo in a dose-dependent manner by wild-type p53, as well as
      by the p53 homologues p73alpha and p63alpha.

PMID- 10640991
TI  - Distinct B-cell clonal bands in Helicobacter pylori gastritis with lymphoid
      hyperplasia.
AB  - Helicobacter pylori (Hp)-associated gastritis is a risk factor for gastric mucosa
      associated lymphoid tissue (MALT) lymphoma. Clonal B-cell populations are present
      in both reactive and neoplastic MALT tissue, thus limiting their usefulness in
      the evaluation of gastric lymphoid infiltrates in endoscopic biopsy specimens.
      The aim of this study was to identify the presence of clonal B-cell populations
      in Hp-gastritis with MALT and to assess their usefulness in distinguishing
      reactive from malignant infiltrates. Routinely fixed paraffin-embedded blocks
      from 20 patients with Hp-gastritis with lymphoid hyperplasia were analysed for B
      cell clonality by a semi-nested polymerase chain reaction (PCR) using FRIII/LJH
      and FRIII/VLJH primers for amplification of the VDJ region of the immunoglobulin
      heavy chain gene. The histopathological findings were evaluated according to a
      previously published scoring system. Immunohistochemistry was performed by the
      labelled streptavidin-biotin technique using the following primary antibodies:
      CD45, CD45RO, CD3, CD20, and cytokeratin. The histopathological findings were
      diagnostic of Hp-chronic active gastritis (grade 2, n=17; grade 3, n=3).
      Scattered intraepithelial B-cells were present in all cases and non-destructive
      lymphoepithelial lesions in one grade 3 case. Amplifiable DNA was obtained from
      all samples. Clonal bands were observed in ten (7/17 grade 2 and 3/3 grade 3
      lesions) and polyclonal smears in ten cases (all grade 2). The clonal bands were
      often (n=6) associated with a background polyclonal smear and were not
      reproducible from deeper sections (n=10) or another paraffin block (n=1), while
      the clonal bands in control low-grade MALT lymphomas were not associated with a
      background smear and were reproducible from deeper sections. None of the patients
      has developed lymphoma to date (follow-up 21-44 months). In conclusion, B-cell
      clonal bands are common in H. pylori-gastritis with lymphoid hyperplasia. The
      irreproducibility of these bands is a useful feature in favouring a reactive
      process.

PMID- 10640992
TI  - Specificity of PCR-based clonality analysis of immunoglobulin heavy chain gene
      rearrangements for the detection of bone marrow involvement by low-grade B-cell
      lymphomas.
AB  - A study was performed to investigate the utility of polymerase chain reaction
      (PCR)-based analysis of immunoglobulin heavy chain (IgH) gene rearrangements for
      the diagnosis of low-grade malignant B-cell lymphomas on formalin-fixed, EDTA
      decalcified, and paraffin-embedded bone marrow trephine biopsies. On amplifying
      two DNA samples per biopsy, no reproducible monoclonal PCR result was found in 32
      patients with reactive lymphoid hyperplasias. In contrast, 5/14 patients with
      known low-grade B-cell lymphomas, but histomorphologically and
      immunohistochemically lymphoma-free bone marrow, showed a reproducible monoclonal
      IgH gene rearrangement. In three of these cases, sequence analysis revealed
      completely different amplification products on comparing bone marrow and lymph
      node infiltrations, while in the other two cases the products were identical. In
      one of the latter biopsies, an unequivocal lymphoma infiltrate was found after
      step sectioning of the biopsy, while the other case remained lymphoma-free
      according to conventional criteria. A third group of three patients with known
      lymphomas and bone marrow findings that were suggestive but not diagnostic of
      bone marrow involvement showed monoclonal PCR results in all three cases, with
      identical sequences in bone marrow and extramedullary lymphoma infiltrates. These
      data suggest that a reproducible monoclonal IgH gene rearrangement is highly
      specific for the presence of malignant B-cells in bone marrow. In staging
      procedures for low-grade B-cell lymphomas, PCR yields no additional information
      in cases that are morphologically and immunohistochemically lymphoma-free after
      evaluation of representative sections. PCR may be useful in equivocal cases,
      provided that IgH gene rearrangements of extramedullary lymphoma and bone marrow
      are sequenced and compared.

PMID- 10640993
TI  - Expression of the imprinted tumour-suppressor gene H19 is tightly regulated
      during normal haematopoiesis and is reduced in haematopoietic precursors of
      patients with the myeloproliferative disease polycythaemia vera.
AB  - cDNA subtraction was employed to uncover differences in gene expression between
      myeloproliferative polycythaemia vera (PV) and normal haematopoietic precursors.
      Following cDNA subtraction using mRNAs isolated from PV and normal CD34+/CD33-
      bone-marrow cells, expression of the tumour suppressor H19 was found to be low or
      absent in the PV sample. Low levels of H19 expression in PV patients were
      confirmed by in situ hybridization. Using semi-quantitative reverse transcriptase
      polymerase chain reaction (RT-PCR) to examine expression in the pluripotent
      haematopoietic cell line FDCP-mix and single bone-marrow precursors, unambiguous
      IGF2 and H19 expression was demonstrated in normal haematopoietic precursors.
      Examination of individual bone-marrow precursors revealed that all IGF2
      expressing haematopoietic precursors also co-expressed H19, indicating that H19
      and IGF2 may be co-ordinately regulated during haematopoiesis. Analysis of FDCP
      mix undergoing differentiation and single pluripotent and committed bone-marrow
      precursors revealed that the pattern of H19 expression coincided with the
      commitment to a single lineage. Taken together, these observations demonstrate
      that H19 and IGF2 are specifically expressed during haematopoiesis and that low
      levels of H19 expression are associated with PV and may contribute to the
      pathology of the disease.

PMID- 10640994
TI  - Facilitated detection of oncogene mutations from exfoliated tissue material by a
      PNA-mediated 'enriched PCR' protocol.
AB  - An 'enriched polymerase chain reaction (PCR)' protocol has been established for
      the sensitive detection of oncogene mutations in body fluid samples from cancer
      patients. This two-step protocol combines an allele-specific PCR clamping step
      followed by a PCR-RFLP (restriction fragment length polymorphism) confirmatory
      step. The method thus resembles a nested PCR technique starting directly from
      genomic DNA material and, in no more than 54 PCR cycles, allows the sensitive
      detection of one mutant allele in 10(3) normal alleles. This protocol was tested
      on bronchial cytology samples and sputum taken from lung cancer patients and
      point mutations could be detected both in codon 12 of K-ras and in three codons
      (248, 249, and 273) of the p53 gene. Comparing this protocol with a different
      'enriched PCR' method based on repetitive PCR-RFLP steps, a high concordance was
      noted between the two methods. Although the present protocol seems to be less
      sensitive by approximately one order of magnitude, it is much easier to perform
      and thus could be applied to the rapid but sensitive detection of allelic
      subfractions in a population of cells derived from exfoliative material.

PMID- 10640995
TI  - Clonality analysis of multifocal carcinoid tumours of the small intestine by X
      chromosome inactivation analysis.
AB  - The clonality of intestinal carcinoids and the relationship between different
      tumour deposits of multiple intestinal carcinoids were investigated in this
      study. Six cases of multiple ileal carcinoids were selected for analysis and
      three independent carcinoid lesions from each case were microdissected. Clonality
      of the lesions was determined by polymerase chain reaction (PCR)-based X
      chromosome inactivation of the human androgen receptor gene. Four out of six
      cases were heterozygous for microsatellite repeats within the androgen receptor
      gene and thus informative for the study. The results showed that all 12 lesions
      analysed had non-random X-chromosome inactivation (monoclonal) patterns, compared
      with the background normal intestinal mucosal tissues. This finding proves for
      the first time the monoclonal origin of human intestinal carcinoids, by X
      chromosome inactivation analysis. More interestingly, identical X-chromosome
      inactivation patterns were found in different carcinoid lesions from each
      individual case. This evidence strongly indicates that multiple carcinoids of the
      small intestine were generated by metastasis of a primary tumour to different
      locations in the intestine, rather than being of multiple origin. This study
      provides an important insight into the carcinogenesis of intestinal carcinoids.

PMID- 10640996
TI  - Expression profile of telomerase subunits in human pleural mesothelioma.
AB  - Using the TRAP assay, telomerase activity was previously detected in over 90% of
      human pleural mesotheliomas (MMs), but not in mesothelial cell cultures (MCCs),
      suggesting that telomerase re-activation occurs during multi-step mesothelioma
      carcinogenesis. The present study determined the expression of the telomerase RNA
      template (hTERC), the telomerase-associated protein (hTEP1), and the telomerase
      catalytic sub-unit (hTERT), in 16 pleural MMs and 4 MM-derived cell lines, in two
      pleural solitary fibrous tumours and in six MCCs. Reverse transcription
      polymerase chain reaction analysis revealed that hTERT mRNA expression parallels
      the activity status documented by the TRAP assay, whereas hTERC and hTEP1 mRNA
      are commonly expressed in all malignant and non-malignant serosal cells and
      tissues. Three alternatively spliced hTERT transcripts were detected in all
      telomerase-positive samples, whereas neither variant could be detected in the
      MCCs. Detection of the hTERT protein with a commercially available antibody was
      not successful. These results indicate that hTERT expression is rate-limiting for
      human telomerase activity and that re-activation, rather than up-regulation, of
      hTERT expression can play a critical role in MM carcinogenesis. While waiting
      suitable anti-hTERT antibodies, these results provide information for the design
      of hTERT mRNA-specific in situ probes to study telomerase in archived pre
      malignant serosal lesions.

PMID- 10640997
TI  - Mesothelial regeneration is not dependent on subserosal cells.
AB  - It has been proposed that after mesothelial injury, resident cells within the
      subserosal connective tissue proliferate, differentiate, and migrate to the
      serosal surface. The aim of this study was to examine the temporal and spatial
      changes of proliferating cells in a murine model of testicular mesothelial
      healing and assess the potential of submesothelial cells to reconstitute the
      damaged mesothelium. Histology and autoradiography were employed to determine the
      number of cells within the submesothelial connective tissue, as well as the
      proportion of cells undergoing DNA synthesis on and beneath the injured serosa.
      Mesothelial cells surrounding the wound demonstrated maximal DNA synthesis 48 h
      after injury (27. 82+/-5.64% SEM, compared with 0.17+/-0.16% (3)H-TdR labelled
      cells for resting mesothelium), whereas a significant increase in proliferating
      submesothelial cells was not seen until day 4 post-injury (7.79+/-3.31% compared
      with 0.85+/-0.64% (3)H-TdR labelled cells at day 2). Furthermore, this small
      number of dividing submesothelial cells must include cells other than the
      proposed mesothelial precursors, indicating a very low proportion of precursor
      cells in the submesothelial cell population. As large numbers of mesothelial
      cells were seen at the wound centre by 3-4 days after injury, it is unlikely that
      submesothelial cells contributed significantly to the repopulation of the injured
      mesothelium. It is hypothesized that regenerating mesothelium is more likely to
      originate from the surrounding uninjured mesothelial cell population.

PMID- 10640998
TI  - Immunohistochemical analysis of cell-matrix adhesion molecules and their ligands
      in the portal tracts of primary biliary cirrhosis.
AB  - Intraepithelial migration of lymphoid cells (epitheliotropism) through the
      basement membrane of the bile duct is a key event in the development of chronic
      non-suppurative destructive cholangitis (CNSDC) and eventual immune-mediated bile
      duct loss in primary biliary cirrhosis (PBC). Cell-to-cell and cell-to
      extracellular matrix proteins may play an important role in the development of
      CNSDC. To address the events of epitheliotropism in CNSDC, the expression of cell
      matrix adhesion molecules such as integrins alpha1, alpha3, alpha4, alpha5, and
      alpha6 and the distribution of fibronectin, laminin, and collagen type IV were
      studied immunohistochemically, with emphasis on both infiltrating lymphocytes and
      the bile ducts, in frozen sections from 15 PBC cases and 34 controls (chronic
      viral hepatitis, extrahepatic biliary obstruction, and normal liver). In PBC and
      chronic viral hepatitis, most of the infiltrating lymphoid cells expressed
      integrin alpha4, while such expression was less common in extrahepatic biliary
      obstruction and normal liver. A biliary basement membrane-like structure was
      delineated by immunostaining of collagen type IV and laminin in PBC and controls.
      On the basement membrane of CNSDC, fibronectin, a ligand of integrin alpha4, was
      strongly and frequently expressed in PBC, while such expression on the biliary
      basement membrane was rare in other controls. These results suggest that
      increased fibronectin expression on the biliary basement membrane and integrin
      alpha4-fibronectin interaction facilitate adhesion and the penetration of
      infiltrating alpha4-expressing lymphocytes into the biliary epithelial layer in
      PBC.

PMID- 10640999
TI  - Mast cell involvement in normal human skin wound healing: expression of monocyte
      chemoattractant protein-1 is correlated with recruitment of mast cells which
      synthesize interleukin-4 in vivo.
AB  - Mast cells (MCs) are known as key cells of immediate type hypersensitivity
      reactions. It has recently been shown that MCs regulate fibroblast proliferation
      by heterotypic cell-cell contact and secretion of interleukin-4 (IL-4) in vitro.
      It was therefore hypothesized that MCs may contribute to wound repair in vivo.
      Using immunohistology and in situ hybridization, the time course of mast cell
      recruitment and the expression of MC-attractant chemokines were analysed in a
      human skin wound-healing model, and the production of IL-4 by MCs in vivo was
      investigated. The data obtained indicate that the five-fold increase of the
      tryptase+ MCs at the fibrotic border of the wound within the first 10 days is the
      result of increased recruitment/survival of MCs or MC precursors, but not of
      increased local proliferation. Recruitment of MCs is paralleled by the expression
      of monocyte chemoattractant protein-1 (MCP-1), but not by other chemokines such
      as RANTES (regulated on activation, normal T cell expressed and secreted) and/or
      MIP (macrophage inflammatory protein)-1alpha/beta. Notably, 60-70% of MCs
      exhibited strong and selective IL-4 immunoreactivity, whereas other resident and
      passenger cells were rather quiescent. The data suggest that MC contribute
      significantly to the cytokine network of wound repair via MC-derived IL-4 and
      stimulation of fibroblast proliferation.

PMID- 10641000
TI  - Proliferative populations in intestinal metaplasia: evidence of deregulation in
      Paneth and goblet cells, but not endocrine cells.
AB  - In the small intestinal mucosa, four principal epithelial cell lineages are found
      - the Paneth, goblet, enterocytic, and endocrine cell lineages. These cell
      lineages are terminally differentiated, non-proliferative, and derive from
      multipotent stem cells near the bases of the crypts of Lieberkuhn. Intestinal
      metaplasia of the stomach is considered to be a premalignant condition. Since
      proliferative populations in this condition are not well studied, this feature
      was examined using double-labelling immunohistochemical and histochemical
      methods; 20 paraffin blocks of small intestinal mucosa and 24 paraffin blocks of
      intestinal metaplasia of the human stomach were studied. Double-staining was
      carried out with MIB-1 as a proliferation marker, with Alcian blue for goblet
      cells, anti-chromogranin A for endocrine cells, and p-dimethylaminobenzaldehyde
      nitrite for Paneth cells. Double-labelling showed that numerous Paneth cells and
      goblet cells in intestinal metaplasia were in the cell cycle, but endocrine cells
      appeared non-proliferative. Double-labelled Paneth or endocrine cells were not
      seen in the control small intestinal mucosa but scanty double-labelled goblet
      cells were observed in normal intestinal mucosa. In intestinal metaplasia of the
      stomach, there is evidence of cell-cycle deregulation in the goblet and Paneth
      cell lineages. These observations have considerable implications for the biology
      and histogenesis of Paneth cells, goblet cells, and endocrine cells, and the
      nature of intestinal metaplasia in the gastric mucosa.

PMID- 10641001
TI  - Distribution of sonographically detected tendon abnormalities in patients with a
      clinical diagnosis of chronic achilles tendinosis.
AB  - PURPOSE: We conducted a retrospective study of the distribution of
      sonographically detected abnormalities in the heels of patients who had a
      clinical diagnosis of Achilles tendinosis. METHODS: One hundred eighteen
      symptomatic heels in 73 patients who had a clinical diagnosis of chronic Achilles
      tendinosis were examined over a 12-month period by the same experienced
      sonologist. The distribution of altered tendon architecture and features
      suggesting retrocalcaneal bursitis or Achilles paratendinosis were evaluated.
      RESULTS: Sonograms of 118 symptomatic heels demonstrated that 96 (81%) had
      abnormalities confined to the proximal two thirds of the Achilles tendon, 9 (8%)
      had abnormalities in the distal third alone, and 13 (11%) had abnormalities at
      both sites. Of the 109 heels with proximal two-third Achilles tendon disease, 99
      (91%) had medial tendon involvement; 22 of the 99 showed diffuse tendon changes.
      Lateral tendon segment changes were seen in 22 (19%) of the 118 symptomatic
      heels. No lateral tendon segment was involved in isolation. Of the 22 heels with
      distal third abnormalities, 14 (64%) had sonographic evidence of Achilles
      paratendinitis, and 13 (59%) had sonographic evidence of Achilles tendinosis.
      Eighteen of the 22 had sonographic evidence of retrocalcaneal bursitis. In all
      cases of distal third tendinosis, the deep surface of the tendon was primarily
      involved. In the heels with both proximal and distal changes, superficial segment
      involvement of the mid-Achilles tendon was present. CONCLUSIONS: Sonography
      provides information that helps to accurately diagnose clinical Achilles
      tendinopathy and may help to determine the biomechanical processes involved in
      the injury.

PMID- 10641002
TI  - Gray-scale and power doppler sonographic appearances of acute inflammatory
      diseases of the scrotum.
AB  - PURPOSE: We describe the spectrum of gray-scale and power Doppler sonographic
      appearances in inflammatory scrotal diseases. METHODS: Twenty-five patients
      ranging in age from 3 to 69 years underwent gray-scale and power Doppler
      sonography with multifrequency transducers of 7-9 MHz or 10-13 MHz. In addition,
      color Doppler and power Doppler findings were compared in 7 cases. RESULTS: In
      all 5 prepubertal patients, power Doppler imaging demonstrated hyperemia
      associated with epididymitis and, in some cases, orchitis. Among the 20 pubertal
      and adult patients, power Doppler imaging revealed increased vascularity
      associated with spermatic cord involvement, epididymitis, orchiepididymitis, or
      orchitis. Enlargement and heterogeneity of the epididymis and/or testis were seen
      in 11 patients, with vas efferens ectasia in 3 patients. Abscess formation and
      testicular infarction were easily depicted by power Doppler imaging. In 5 cases
      total, hyperemia was the only sonographic finding of inflammation. In the
      comparison between color and power Doppler imaging, a subjective increase in the
      number and length of vessels was seen with power Doppler imaging. CONCLUSIONS:
      Power Doppler imaging is an easy and fast Doppler modality for evaluating
      inflammatory conditions of the scrotum and proved especially useful in cases with
      no gray-scale sonographic anomalies, in prepubertal patients, and in patients
      with abscesses or ischemic lesions.

PMID- 10641003
TI  - Renal histomorphometry and resistance index in children with renal disease.
AB  - PURPOSE: The aim of this study was to examine the relationships between the renal
      resistance index (RI) and histomorphometric variables measured in children with
      glomerular or nonglomerular renal disease. Patients and Methods The medical
      records, sonography reports, and biopsy specimens of 30 children with glomerular
      or nonglomerular renal disease (mean age, 11.0 +/- 4.7 years; range, 2. 5-17
      years) who underwent sonographic evaluation and biopsy of the right kidney were
      retrospectively studied. Biopsy specimens were evaluated for glomerular surface
      density, number of glomeruli in the stroma, capillary surface density, number of
      capillaries within the glomeruli, and the diameters of the afferent arterioles.
      RESULTS: The RI was negatively correlated with age in patients 2.5-4.0 years old
      (rho = -1.0, p < 0.001). The RI was positively correlated with serum creatinine
      levels (rho = 0.63, p < 0.001), and the RI differed significantly between
      patients with abnormally high and age-appropriate serum creatinine levels (0.8 +/
      0.1 and 0.6 +/- 0.1, respectively; p = 0.002). No differences in age,
      histomorphometric variables, RI, or arteriolar diameter were found between
      patients who had interstitial fibrosis and those who did not, and the RI was not
      correlated with histomorphometric variables in either group. However, the mean RI
      was significantly higher in patients with severe fibrosis than in those with mild
      fibrosis. In those with severe fibrosis, the RI was negatively correlated with
      number of glomeruli in the stroma (rho = -0.975, p < 0.01), glomerular surface
      density (rho = -0.931, p < 0.05), number of capillaries within the glomeruli (rho
      = -0.989, p < 0.01), and arteriolar diameter (rho = -1.00, p < 0.01).
      CONCLUSIONS: The RI was correlated with histomorphometric variables in patients
      with severe interstitial fibrosis and could be useful in the follow-up of these
      patients.

PMID- 10641004
TI  - Longitudinal doppler sonographic measurements of vascular impedance in the
      central and peripheral spiral arteries throughout pregnancy.
AB  - PURPOSE: We assessed vascular impedance in the spiral arteries in the central and
      peripheral placental bed throughout uncomplicated pregnancies. METHODS:
      Transabdominal color Doppler sonography was used to measure the pulsatility index
      (PI), resistance index (RI), and peak systolic velocity in the central and
      peripheral spiral arteries in 94 women with uncomplicated singleton pregnancies.
      Sonographic examinations took place approximately every 5 weeks from 10 to 40
      weeks' menstrual age. RESULTS: PI, RI, and peak systolic velocity were not
      different in the central versus the peripheral segments of the spiral arteries.
      The PI and RI values of central spiral arteries after 25 weeks' menstrual age.
      The PI and RI values of peripheral arteries decreased after 20 weeks' menstrual
      age. CONCLUSIONS: Additional subjects are needed to clarify changes in the
      impedance of central and peripheral spiral arteries over the course of normal and
      complicated pregnancies.

PMID- 10641005
TI  - Changes in portal venous hemodynamics in patients with severe acute hepatitis
      over one year.
AB  - PURPOSE: A wide range of portal vein blood flow velocity (PVV) values can be
      found in acute hepatitis. We studied course and medical significance of PVV
      changes in patients with severe acute hepatitis over a 1-year period. METHODS:
      Portal venous hemodynamics were studied by Doppler sonography in 90 patients at
      study enrollment and 3, 6, and 12 months following an episode of severe acute
      hepatitis. RESULTS: Forty-one survivors who had a maximum PVV at enrollment
      greater than or equal to the value measured at the third month were classified as
      the "declining PVV" group. Thirty-six survivors who had a maximum PVV at
      enrollment less than the value measured at the third month were classified as the
      "rising PVV" group. Thirteen patients died of acute hepatic failure and were
      classified as the fatality group. The fatality group had significantly lower
      maximum PVV, worse liver biochemical test results, and a higher prevalence of
      ascites at enrollment. In contrast, the declining PVV group showed significantly
      better liver biochemical test results and a lower prevalence of ascites. There
      was no significant difference in portal vein blood flow between the rising and
      declining PVV groups since portal vein diameter increased while PVV decreased.
      CONCLUSIONS: An initially decreased PVV can be found in some patients with severe
      acute hepatitis and is inversely correlated with the severity of liver damage.

PMID- 10641006
TI  - Granular cell tumor of the breast: definitive diagnosis by sonographically guided
      percutaneous biopsy.
AB  - Granular cell tumor is a rare, benign breast neoplasm that may mimic malignancy
      both clinically and radiologically. We present 2 cases in which granular cell
      tumor was initially diagnosed by sonographically guided percutaneous biopsies.
      Sonographic guidance confirmed needle placement during multiple passes and
      thereby decreased the likelihood of sampling error. A diagnosis of granular cell
      tumor prior to definitive resection enables optimal therapeutic planning and
      allows radical surgery to be avoided.

PMID- 10641007
TI  - Sonographic diagnosis of recurrent ulcer penetrating the anterior abdominal wall.
AB  - Penetration of a recurrent ulcer into the anterior abdominal wall after surgical
      treatment of peptic ulcer disease is a rare surgical emergency. Early diagnosis
      is essential, but there are no specific radiographic or endoscopic features. We
      report 2 cases of recurrent ulcer penetration into the anterior abdominal wall
      diagnosed preoperatively with transabdominal sonography. The ulcers appeared as
      cavity lesions, with hyperechoic bases that had destroyed the continuity of the
      stomach wall. Associated findings were a minimal amount of fluid around the ulcer
      cavity and a hypoechoic area considered secondary to inflammation or edema. The
      diagnoses were confirmed at laparotomy.

PMID- 10641008
TI  - Prenatal sonographic diagnosis of Holt-Oram syndrome.
AB  - Holt-Oram syndrome is an autosomal dominant disorder characterized by heart
      defects in combination with characteristic upper-limb abnormalities. A woman with
      no family history of genetic diseases underwent prenatal sonography at 25 weeks'
      menstrual age to screen for fetal anomalies. Sonography revealed abnormalities in
      the upper limbs and heart. The limb abnormalities included bilateral absence of
      radii and thumbs: the left hand had no carpal or metacarpal bones, and each of
      the 4 fingers on that hand had only 1 phalangeal bone. Cardiac malformations
      included an atrial septal defect and Ebstein's anomaly. Other structures were
      normal. Prenatal cytogenetic analysis by cordocentesis revealed a normal 46,XY
      karyotype. Spontaneous labor and delivery at 34 weeks' menstrual age produced a
      1,960-g male infant who died of cardiac insufficiency shortly after birth. The
      postnatal appearance and autopsy findings confirmed the prenatal findings. In
      this case, Holt-Oram syndrome was readily diagnosed by prenatal sonography.

PMID- 10641009
TI  - Sonographic discovery of a pharyngocele.
AB  - Cervical sonography was performed in a 25-year-old man who was referred to our
      department because of the recent appearance of a left anterolateral cervical
      mass. This mass had the sonographic properties of air; it communicated with and
      extended the piriform sinus as well as deformed the left lamina of the thyroid
      cartilage. A preliminary diagnosis of left pharyngocele was confirmed by CT. To
      our knowledge, this is the first sonographic description of such an abnormality.

PMID- 10641010
TI  - Sonographic diagnosis of a pseudoaneurysm in an intravenous drug abuser.
AB  - We report a case of a traumatic pseudoaneurysm and arteriovenous fistula in the
      groin of a drug abuser. Gray-scale and Doppler sonography were used to establish
      the diagnosis. Gray-scale sonography revealed an anechoic, ovoid, 7 x 4 cm mass
      posterior to the right superficial femoral artery, which was displaced
      anteriorly, with limited visualization of the deep femoral artery. Power Doppler
      sonography showed complete color filling of the mass, and turbulence was seen on
      conventional color Doppler sonography. The turbulence was confirmed with pulsed
      Doppler sonography of the mass. Pulsed Doppler imaging of the right external
      iliac vein also showed an arterialized spectral flow pattern.

PMID- 10641011
TI  - Identification of the 1-cyano-3,4-epithiobutane-derived urinary mercapturic acid
      N-acetyl-S-(4-cyano-2-thio-1-butyl)-cysteine in male Fischer 344 rats.
AB  - 1-Cyano-3,4-epithiobutane (CEB), a naturally occurring nitrile derived from
      cruciferous plants, causes nephrotoxicity in male Fischer 344 rats.
      Nephrotoxicity induced by CEB is dependent on glutathione (GSH) conjugation and
      bioactivation. Conjugation with GSH and subsequent metabolism leads to the
      formation of specific urinary metabolites. The objectives of the present study
      were to identify CEB-derived urinary metabolites and quantify urinary non-protein
      thiols and thioethers in male Fischer 344 rats. Animals received 125 mg kg(-1) of
      CEB alone or following pretreatment with one of three selective inhibitors of GSH
      metabolism: acivicin, probenecid or aminooxyacetic acid. Total non-protein
      urinary thiol and urinary thioether concentrations were elevated in all treated
      groups at 12 and 24 h; however, elevations in non-protein thiols were not
      significantly greater in rats administered CEB alone as compared to negative
      controls. A single predominant urinary metabolite was identified as the CEB
      derived mercapturic acid N-acetyl-S-(4-cyano-thio-1-butyl)-cysteine. Evidence for
      other CEB-derived metabolites was also demonstrated. These findings represent the
      identification of a unique compound and provide further evidence for the
      importance of GSH conjugation as a significant pathway in CEB metabolism.

PMID- 10641012
TI  - Derivation of temporary emergency exposure limits (TEELs).
AB  - Short-term chemical concentration limits are used in a variety of applications,
      including emergency planning and response, hazard assessment and safety analysis.
      Development of emergency response planning guidelines (ERPGs) and acute exposure
      guidance levels (AEGLs) are predicated on this need. Unfortunately, the
      development of peer-reviewed community exposure limits for emergency planning
      cannot be done rapidly (relatively few ERPGs or AEGLs are published each year).
      To be protective of Department of Energy (DOE) workers, on-site personnel and the
      adjacent general public, the DOE Subcommittee on Consequence Assessment and
      Protective Actions (SCAPA) has developed a methodology for deriving temporary
      emergency exposure limits (TEELs) to serve as temporary guidance until ERPGs or
      AEGLs can be developed. These TEELs are approximations to ERPGs to be used until
      peer-reviewed toxicology-based ERPGs, AEGL or equivalents can be developed.
      Originally, the TEEL method used only hierarchies of published concentration
      limits (e.g. PEL- or TLV-TWAs, -STELs or -Cs, and IDLHs) to provide estimated
      values approximating ERPGs. Published toxicity data (e.g. lc(50), lc(LO), ld(50)
      and ld(LO) for TEEL-3, and tc(LO) and td(LO) for TEEL-2) are included in the
      expanded method for deriving TEELs presented in this paper. The addition here of
      published toxicity data (in addition to the exposure limit hierarchy) enables
      TEELs to be developed for a much wider range of chemicals than before. Hierarchy
      based values take precedence over toxicity-based values, and human toxicity data
      are used in preference to animal toxicity data. Subsequently, default assumptions
      based on statistical correlations of ERPGs at different levels (e.g. ratios of
      ERPG-3s to ERPG-2s) are used to calculate TEELs where there are gaps in the data.
      Most required input data are available in the literature and on CD ROMs, so the
      required TEELs for a new chemical can be developed quickly. The new TEEL
      hierarchy/toxicity methodology has been used to develop community exposure limits
      for over 1200 chemicals to date. The new TEEL methodology enables emergency
      planners to develop useful approximations to peer-reviewed community exposure
      limits (such as the ERPGs) with a high degree of confidence. For definitions and
      acronyms, see Appendix.

PMID- 10641013
TI  - In vitro effects of melatonin on cell proliferation in a colon adenocarcinoma
      line.
AB  - The effect of melatonin on inhibition of cell growth was studied in CT-26, a
      murine colon carcinoma-derived cell line. Cells growing in exponential phase were
      exposed to low (10(-7)-10(-10) M) and high doses (1, 2 and 3 x 10(-3) M) of
      melatonin during 24 h. Synthesis of DNA was measured by 5-bromo-2'-deoxyuridine
      incorporation. There was no effect at low doses, but a statistically significant
      correlation was found between the decrease in DNA synthesis and the dose of
      melatonin used (r = -0.52, P < 0.001). This implied the following percentages of
      inhibition: 1 mM, 22%; 2 mM, 25%; 3 mM, 47%. Potential cell membrane damage by
      high doses of melatonin was investigated by lactate dehydrogenase measurement and
      no significant levels were observed. Analysis with a single saturation technique
      showed no detectable oestradiol receptors in this cell type; therefore, we can
      assume that the effects occurring with the addition of melatonin were not
      mediated by modulation of this hormone on oestrogen receptors. The decreases in
      cell growth were attributed to a moderate, but significant antiproliferative
      action of melatonin on this non-hormone-dependent cell line.

PMID- 10641014
TI  - Effects of phenylhydrazine or phlebotomy on peripheral blood, bone marrow and
      erythropoietin in Wistar rats.
AB  - This study was conducted to characterize better the response of rats to blood
      loss and hemolysis and to incorporate automated methods into the routine
      evaluations of those responses. Serial phlebotomies of 1.5-2.0 ml of blood per
      day for 5 days, or intraperitoneal injection of 50 mg kg(-1) phenylhydrazine
      (PHZ) for 3 days, were used to cause anemia associated with blood loss or
      hemolysis, respectively. Maximum decreases in red blood counts were observed on
      Day 3 in PHZ-treated animals (68%) and Day 4 in blood-loss animals (35%). In the
      routine complete blood count (CBC), hemoglobin, hematocrit/hemoglobin ratio and
      erythrocyte indices could be used to discriminate between the two treatments.
      Free plasma hemoglobin in PHZ-treated animals resulted in marked elevations of
      mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration
      (MCHC) with a 2:1 hematocrit/hemoglobin ratio rather than the anticipated 3:1
      ratio. Although both groups of animals had elevated white blood cell counts, PHZ
      treated animals also had monocytosis and basophilia. Reticulocyte counts were
      more sensitive than erythropoietin (EPO) concentrations in predicting erythroid
      changes. Maximum mean reticulocyte values were ca. 24% in serially phlebotomized
      animals and >99% in PHZ-treated rats. Plasma EPO levels were 4-10-fold higher
      than EPO levels in urine, kidney or liver. Flow cytometric differentials of rat
      bone marrow using 2, 7-dichlorofluorescin successfully predicted erythroid
      hyperplasia in both experimental groups. Erythrocyte indices returned to normal
      within 14 days and the remaining CBC parameters were normal within 28 days for
      both treatment groups. Reticulocyte counts remained slightly elevated on Day 28,
      but were normal when assessed at Day 56 in blood-loss and PHZ-treated animals.

PMID- 10641015
TI  - The peripubertal male rat assay as an alternative to the Hershberger castrated
      male rat assay for the detection of anti-androgens, oestrogens and metabolic
      modulators.
AB  - A range of chemicals with various levels of activity as actual or potential
      endocrine disrupters have been evaluated for activity in the peripubertal male
      rat assay. The chemicals studied included anti-androgens (vinclozolin),
      cyproterone acetate, flutamide, 2, 2-bis(4-chlorophenyl)-1,1-dichloroethylene
      (DDE), metabolic modulators (anastrazole, finasteride, ketoconazole) and
      oestrogens (butyl benzyl phthalate (BBP), methoxychlor, bisphenol A (BPA),
      diethylstilboestrol (DES)), the suspected anti-androgen dibutyl phthalate (DBP)
      and the non-oestrogen fenitrothion. Dosing extended over postnatal days (pnd) 22
      35, 36-50, 36-55 and 22-35, with recovery to pnd 55 or 22-55. The endpoints
      studied were changes in the weights of testes, epididymides, seminal vesicles and
      prostate. Changes in body weight and the weights of the liver and kidney were
      also monitored. In some experiments changes in the day of prepuce separation
      (PPS) were also determined. Only BBP and BPA were inactive in all the assays
      conducted. Changes in the weight of reproductive tissues provided a sensitive
      indicator of activity for the remaining chemicals with the exception of DDE, for
      which higher dose levels could have been used. However, none of the curtailed
      periods of exposure were able to detect all of the agents. Diethyl stilboestrol,
      and to a lesser extent DBP and DDE, delayed PPS when exposure occurred over the
      period pnd 22-55. A complex dependence of the day of PPS on the period of
      exposure and the body weight of the test animals was observed, and caution is
      recommended when assessing this endpoint in the presence of reductions in body
      weight. It is concluded that reproductive tissue weight changes in the
      peripubertal male have shown sensitivity to a range of biochemical modulators,
      oestrogens and anti-androgens, and that as such the assay warrants further
      evaluation. Measurement of delays in PPS may be of value in cases of large
      delays, but delays of 1-2 days will be difficult to interpret with confidence.
      The present results are discussed within the context of the sexually mature male
      rat assay described by O'Connor and the castrated male rat assay described by
      Hershberger, both of which are the subject of current international study. It is
      concluded that a decision on the usefulness of the peripubertal male rat assay
      must await the generation of further data on each of these three assays. There is
      an urgent need for international agreement on a list of reference endocrine
      disrupters and their active dose levels, with which to validate individual
      endocrine disruption assays and batteries of assays.

PMID- 10641016
TI  - Pulmonary and intraperitoneal inflammation induced by cellulose fibres.
AB  - The inflammatory effects of respirable cellulose fibres were studied in two short
      term animal models: intraperitoneal injection in mice, and inhalation in rats.
      The mouse peritoneal cavity is particularly sensitive to fibrous compared to non
      fibrous particles. Both cellulose fibres and the positive control fibre,
      crocidolite asbestos, were administered in doses ranging from 10(4) to 10(8)
      fibres and caused marked, dose-dependent recruitment of inflammatory cells to the
      mouse peritoneal cavity, which was highest 1 day following injection. Crocidolite
      was much more active than cellulose, despite the mass dose of cellulose being 66
      times greater for an equivalent number of fibres. Crocidolite at the higher doses
      caused inflammation to persist through 7 days. For the inhalation study, rats
      were exposed daily, 5 days per week, to aerosols of cellulose dust for ca. 3
      weeks at a concentration of 1000 fibres ml(-1). Inhalation exposure induced an
      early inflammatory response in rat lungs, as determined by bronchoalveolar
      lavage, which peaked at 1 day following the start of inhalation and thereafter
      declined, despite a further 13 days of exposure over a period of 18 calendar
      days. In vitro production of the pro-inflammatory cytokine tumour necrosis factor
      alpha (TNF-alpha) by lavaged alveolar macrophages was markedly depressed by the
      end of the exposure period in cellulose-exposed animals, compared to sham-exposed
      controls, and this effect was still present in rats that had been allowed to
      recover for 28 days beyond the end of exposure. We conclude that the cellulose
      material studied is less inflammogenic than crocidolite and that the extent of
      the inflammatory response within the lung appears to reduce with continued
      exposure over a 14-day period.

PMID- 10641017
TI  - Disorders of male rat reproductive tract under the influence of atrazine.
AB  - The effects of atrazine exposure on testicular sperm number, epididymal sperm
      number and motility and alpha-glucosidase activity in the epididymis were studied
      in Fischer rats. Histological changes in the testicular tissue were followed by
      light and electron microscopy. Groups of adult animals were treated i.p. with 60
      and 120 mg atrazine kg(-1) body wt. twice a week over 60 days. The results
      indicate a decrease in the body weight and relative weights of pituitary and
      ventral prostate vs control, measured on the last day of treatment in both
      treated groups. Testicular sperm number (expressed as number of sperm per 500
      Sertoli cells) in atrazine-treated groups increased with the treatment time due
      to the reduced sperm motility. Therefore atrazine treatment provoked a
      significant decrease in sperm number and motility in epididymis, measured after
      the last day of treatment. alpha-Glucosidase activity in the epididymis, after
      the last day of treatment, showed a decrease in both treated groups vs control
      values. Histological analysis of testicular tissue from treated rats showed the
      cell disorganization and cell clusters together with spermatocytes. Electron
      microscopy presented differently vacuolated cytoplasm, collagen fibre was
      reduced, Leydig cells were of irregular shape with unequal form and cisternae of
      rough endoplasmic reticulum were accentuated and softly widened. In Sertoli cell
      cytoplasm, atrazine treatment provoked degenerative changes. According to the
      results obtained, it is evident that atrazine exerted morphological changes and a
      toxic effect on sperm and their motility.

PMID- 10641018
TI  - Results of the L5178Y mouse lymphoma assay and the Balb/3t3 cell in vitro
      transformation assay for eight phthalate esters.
AB  - Eight phthalate esters, with alcohol chain lengths of 1-11 carbon atoms and with
      various degrees of branching, were tested in vitro in the L5178Y mouse lymphoma
      mammalian cell mutation assay and in the Balb/3T3 cell transformation assay. The
      tests were performed as part of a voluntary testing agreement between the
      Chemical Manufacturers Association's Phthalate Esters Panel and the United States
      Environmental Protection Agency (US EPA). The esters tested were: dimethyl
      phthalate (DMP), di-n-butyl phthalate (DBP), butyl benzyl phthalate (BBP), di-?n
      hexyl, n-octyl, n-decyl? phthalate (610P), di-isononyl phthalate (DINP), di
      ?heptyl, nonyl, undecyl? phthalate (711P), di-isodecyl phthalate (DIDP) and di
      undecyl phthalate (DUP). Both DMP and DBP were found to produce significant
      increases in the mutant frequency in the mouse lymphoma assay in the presence but
      not in the absence of an Aroclor-induced rat liver activation system (S-9). Ester
      610P gave equivocal results in the mouse lymphoma assay in the presence and
      absence of rat liver S-9. There was no indication of mutagenic potential for any
      of the other test materials in the mouse lymphoma assay, and none of the test
      materials increased transformation frequency in the Balb/3T3 cell transformation
      assay. Aldehyde metabolites of the de-esterified alcohols are postulated to play
      a role in the positive results for DMP and DBP.

PMID- 10641021
TI  - Prognostic models based on literature and individual patient data in logistic
      regression analysis.
AB  - Prognostic models can be developed with multiple regression analysis of a data
      set containing individual patient data. Often this data set is relatively small,
      while previously published studies present results for larger numbers of
      patients. We describe a method to combine univariable regression results from the
      medical literature with univariable and multivariable results from the data set
      containing individual patient data. This 'adaptation method' exploits the
      generally strong correlation between univariable and multivariable regression
      coefficients. The method is illustrated with several logistic regression models
      to predict 30-day mortality in patients with acute myocardial infarction. The
      regression coefficients showed considerably less variability when estimated with
      the adaptation method, compared to standard maximum likelihood estimates. Also,
      model performance, as distinguished in calibration and discrimination, improved
      clearly when compared to models including shrunk or penalized estimates. We
      conclude that prognostic models may benefit substantially from explicit
      incorporation of literature data.

PMID- 10641019
TI  - Reproductive effects of hexachlorobenzene in female rats.
AB  - Hexachlorobenzene (HCB) is a polyhalogenated aromatic hydrocarbon widely
      distributed in the environment. In animal testing, HCB has been shown to be a
      reproductive toxin. Previous investigations of the effects of HCB on ovarian
      function have yielded equivocal results. Thus, the effects of chronic
      administration of HCB (1 g kg(-1) body wt.) on the ovary and pituitary hormone
      levels, hepatic and uterine oestradiol receptors, ovarian histopathological
      changes and oestrus cycle characteristics were investigated in spontaneously
      cycling rats. Our data demonstrate that HCB treatment, under the conditions of
      the present study, reduced circulating levels of oestradiol and prolactin without
      differences in serum concentrations of progesterone. Follicle-stimulating hormone
      serum levels were elevated. Hexachlorobenzene treatment resulted in irregularity
      of cycles, characterized mainly as prolonged periods of oestrus with a reduced
      number of ova recovered. In addition, HCB administration resulted in
      significantly decreased uterine nuclear oestrogen receptor levels.
      Histopathological examination revealed degenerative changes of the ovarian
      follicles and germinal epithelium and increased numbers of atresic follicles.

PMID- 10641022
TI  - Using AIDS mortality data to reconstruct HIV/AIDS epidemics.
AB  - The back-calculation methods used to reconstruct HIV epidemics and to predict
      future AIDS cases use data on the number of AIDS reported cases and information
      about the time from HIV infection to AIDS diagnosis. In this paper we modify a
      back-calculation method, presented in Verdecchia and Mariotto, to estimate HIV
      incidence from AIDS mortality data rather than the AIDS registered cases. In this
      application the AIDS incubation time is replaced by the time from HIV infection
      to AIDS death. Since AIDS is an irreversible condition leading to death within a
      few years, mortality data is expected to be approximately as informative as AIDS
      data. The main application of this method would be in countries where an AIDS
      registry is not available or where the registration of AIDS cases is not
      consistent, for example, due to changes in the definition of AIDS. Application to
      the Italian AIDS mortality data shows that the number of AIDS cases reconstructed
      from this method is very close to the registered number of cases. Also, the two
      estimates of HIV incidence and prevalence obtained from back-calculation on both
      AIDS mortality data and the number of AIDS reported cases were very similar,
      although there was more variability in the estimates obtained from mortality
      data.

PMID- 10641023
TI  - Uncertainty of AIDS incubation time and its effects on back-calculation
      estimates.
AB  - Incubation time is the period from the onset of HIV infection to AIDS. The
      distribution of the incubation time is one of the main parameters of the back
      calculation method for the estimation of incidence of HIV infection. Because of
      the long and variable incubation time, the assessment of its distribution is
      uncertain and this uncertainty spreads through the back-calculation method and
      affects the estimation of the precision of incidence of HIV infection. We propose
      a method to investigate the sensitivity of the estimates to variations of the
      incubation times, with particular regard to the covariate AGE in the modelling of
      the incubation period, making use of the parametric bootstrap. An application to
      the HIV epidemic in Italy is presented. The amplification of the uncertainty of
      the HIV incidence estimates resulting from the implementation of our proposed
      method tends to concentrate around the earlier periods of the epidemic,
      corresponding to the right tail of the incubation time distribution, which is
      very sensitive to small perturbations.

PMID- 10641024
TI  - A test for spatial disease clustering adjusted for multiple testing.
AB  - Tango (1995) proposed a test statistic C for detecting spatial disease clusters.
      However, like most other methods, it requires a value of the scale parameter
      which adjusts for the size of cluster to be detected in advance of its use. When
      an appropriate size of cluster cannot be predicted and many clustered areas are
      expected, we usually repeat the procedure by changing the size parameter, but
      this practice clearly faces a multiple testing problem. In this paper, to
      ameliorate this problem, we propose an extended test statistic which searches the
      minimum of the profile P-value of C for the parameter on cluster size which
      varies continuously from a small value near zero upwards until it reaches to
      about half the size of the whole study area. Monte Carlo simulation study shows
      that the power of the proposed method is shown to be reasonably high compared
      with the best power attained by C unadjusted for multiple testing in all the
      cluster models considered. The proposed procedure is illustrated with some
      disease maps simulated in the Tokyo Metropolitan Area.

PMID- 10641025
TI  - Sample size calculation for planning group sequential longitudinal trials.
AB  - Procedures are developed in this paper for sample size calculations for planning
      a group sequential longitudinal trial with various correlation structures, using
      a test statistic based on generalized estimating equations (Lee, Kim and Tsiatis)
      and group sequential boundaries based on type I error spending functions (Lan and
      DeMets).

PMID- 10641026
TI  - Bayesian accelerated failure time analysis with application to veterinary
      epidemiology.
AB  - Standard methods for analysing survival data with covariates rely on asymptotic
      inferences. Bayesian methods can be performed using simple computations and are
      applicable for any sample size. We propose a practical method for making prior
      specifications and discuss a complete Bayesian analysis for parametric
      accelerated failure time regression models. We emphasize inferences for the
      survival curve rather than regression coefficients. A key feature of the Bayesian
      framework is that model comparisons for various choices of baseline distribution
      are easily handled by the calculation of Bayes factors. Such comparisons between
      non-nested models are difficult in the frequentist setting. We illustrate
      diagnostic tools and examine the sensitivity of the Bayesian methods.

PMID- 10641027
TI  - Smoking during pregnancy: foetal growth retardation and other risks for the
      newborn.
AB  - In spite of the well-known effect of tobacco on embryo growth retardation, of the
      higher perinatal mortality of the offspring of smoking mothers, and of the
      dependence of perinatal mortality risk on small birth weight, it has consistently
      been found that small infants of smoking mothers have lower mortality rates than
      small infants of non-smoking mothers. This problem was studied on the perinatal
      database of a hospital, using adverse outcomes (death or Apgar score <7 at the
      10th minute of life) as endpoints rather than perinatal or foetal mortality. A
      stochastic model constructed to account for cause-effect relations demonstrated
      that tobacco influences weight and mortality by independent pathways.
      Furthermore, this model shed some light on the non-tobacco determinants of small
      birth weight and neonatal morbidity. The method undertaken, based on the use of
      latent variables, had the advantage of analysing the prevalence, consequences and
      interactions of some risk factors without identifying them.

PMID- 10641028
TI  - Total deviation index for measuring individual agreement with applications in
      laboratory performance and bioequivalence.
AB  - In areas of inter-laboratory quality control, method comparisons, assay
      validation and individual bioequivalence, etc., the agreement between
      observations and target (reference) values is of interest. The mean of the
      squared difference between observations and target values (MSD) is a good measure
      of the total deviation. A new user-friendly statistic, the total deviation index
      (TDI(1-p)), is introduced that translates the MSD into an index that can be
      directly compared to a predetermined criterion. The TDI(1-p) describes a boundary
      such that a majority, 100(1-p) per cent, of the observations are within the
      boundary (measurement unit and/or per cent) from their target values. Statistical
      inference using the sample counter part (estimate) is presented. A Monte Carlo
      experiment with 5000 runs was performed to confirm the estimate's validity.
      Applications in laboratory performance and validation, as well as individual
      bioequivalence, are presented.

PMID- 10641029
TI  - R(2): a useful measure of model performance when predicting a dichotomous
      outcome.

PMID- 10641030
TI  - Cytogenetics and molecular genetics of childhood leukemia.
AB  - Childhood leukemia is the commonest form of childhood cancer and represents
      clonal proliferation of transformed hemopoietic cells as a result of genetic
      changes. Molecular characterization of these changes, in particular chromosomal
      translocations, has yielded a wealth of information on the mechanisms of
      leukemogenesis. These findings have also allowed the development of sensitive
      assays for the identification of underlying molecular defects, which is
      applicable to disease diagnosis and to monitor response to treatment. Genetic
      alterations in childhood leukemia are powerful prognostic indicators. TEL-AML1
      fusion and hyperdiploidy >50 chromosomes are associated with a good prognosis in
      childhood acute lymphoblastic leukemia, whereas BCR-ABL fusion and MLL
      rearrangements are associated with a poor prognosis. Hence cytogenetic and
      molecular genetic classification of childhood leukemia will significantly improve
      the ability of clinicians to predict therapeutic response and prognosis, which
      paves the way for risk stratification based on clinical and genetic features.
      Finally, deciphering of genetic lesions in leukemia has allowed elucidation of
      the molecular basis of current treatment, as typified by the success of all-trans
      retinoic treatment in acute promyelocytic leukemia, and has identified targets
      for novel therapeutic approaches. It is envisaged that efforts in
      characterization of molecular defects in childhood leukemia will ultimately be
      translated into better clinical outcome for patients.

PMID- 10641031
TI  - Positive serology for Lyme disease borrelias in primary cutaneous B-cell
      lymphoma: a study in 22 patients; is it a fortuitous finding?
AB  - BACKGROUND: The historical association of acrodermatitis chronica atrophicans
      (ACA), now known to be a late manifestation of Lyme disease caused by Borrelia
      afzelii, with cutaneous lymphoma, and several small series of PCBCL with positive
      Lyme disease borrelial serology initiated a study of this association. Material
      and methods In the last 9 years, 30 patients with PCBCL have been observed and
      followed, 22 of them were tested for borrelial serology. The control group
      consisted of 85 patients with NHL (10 cutaneous T-cell, 25 extranodal B-cell non
      PCBCL, 50 nodal B-cell), 30 patients with breast cancer and 60 blood donors. The
      screening tests were two different ELISA tests for B. burgdorferi sensu lato and
      sensu stricto, and reactive sera were further tested with the ELISA test for B.
      garinii, a Western blot (WB) test for Swiss Borrelia strains and a WB test for
      Bavarian Borrelia strains, since an immunoblot made with local strains was not
      available. Studies with a differential WB test for B. burgdorferi sensu stricto,
      B. garinii and B. afzelii was performed afterwards, as well as serological
      studies ruling out cross-reactions with Leptospiras and Treponema. RESULTS:
      Fifteen of 22 patients with PCBCL were positive on the screening tests, three of
      them falsely. Thus, the incidence of positive borrelial serology was 12/22 (55
      per cent) in the PCBCL group. No positives were detected in the cutaneous T-cell
      lymphoma group; 2/25 patients (8 per cent) were positive in the extranodal B-cell
      NHL group (the localizations being vestibulum nasi and oral cavity), 2/50 (4 per
      cent) were positive in the nodal B-cell NHL group, 2/30 (7 per cent) in the
      breast cancer group and 2/60 (3 per cent) in the blood donor group. The
      cumulative incidence in the control groups was 8/175 (4,6 per cent). The
      incidence was significantly higher in PCBCL patients as compared to each of the
      control groups, p value ranging from 0.004 to <0.0001. Two positive patients had
      ACA, one arthritis. Borrelia afzelii was most often implied for positive serology
      in the differential WB. No cross-reactions with Treponema and the Leptospiras
      were documented. CONCLUSION: In conclusion there appears to be a clustering of
      positive serology for Lyme disease Borrelias in PCBCL patients possibly related
      to an ethiopathogenic relationship. Mechanisms of Borrelia escape from
      immunosurveillance mechanisms, persistence of both their mitogenic and antigenic
      stimuli for B-cells, and SALT formation may be involved in the pathogenesis of a
      subset of PCBCL.

PMID- 10641032
TI  - Preferential type 1-1 cytokine gene expressions in peripheral T-cell lymphomas.
AB  - In this study, we have investigated whether a pattern of cytokine gene expression
      can be found in non-Hodgkin's peripheral T-cell lymphoma (PTCL). By using RNase
      protection assays and RT-PCR, we have systematically studied IL1alpha, IL1beta,
      IL1-Ra, IL2, IL4, IL5, IL6, IL9, IL10, IL12p35, IL12p40, IL13, IL14, IL15,
      IFNgamma, IFNbeta, TNFalpha, TNFbeta, LTbeta, and TGFbeta1, TGFbeta2 and
      TGFbeta3. Twenty-two cases of PTCL inclusive of three nasal NK-cell lymphomas
      were selected for the study; three cases of reactive lymphoproliferation were
      included for comparison. Results show that IFNgamma gene expression (key Type 1
      cytokine) was frequently detected [18/22 (82 per cent)]. In contrast, IL4 (key
      Type 2 cytokine) was only detected in 4/22 (18 per cent) of cases (weaker than
      IFNgamma in three cases). This distinction was also found at the protein level by
      immunohistochemistry. In addition, TNFbeta and TNFalpha (strongly expressed by
      Type 1 cells) were almost complimentarily detected [4/19 (21 per cent)] and 12/19
      (63 per cent), respectively). In contrast, neither IL5 nor IL13 (strongly
      expressed by Type 2 cells) were detected at all. However, 14/22 cases expressed
      IL10, another Type 2 cytokine, which suggests that the autoregulatory feedback
      loop is stimulated. Compared to the tumour types, the cytokine profiles in the
      reactive lymphoproliferative types also resembled a Type 1-like pattern but was
      less striking. The overall result suggested a preferential expression of certain
      cytokines, and these cytokines may play an important role in pathophysiologic
      progression in these T-cell disorders.

PMID- 10641033
TI  - A mannose-binding protein from the cell surface of flocculent Saccharomyces
      cerevisiae (NCIM 3528): its role in flocculation.
AB  - A cell surface lectin was isolated and purified to homogeneity from the cell
      walls of a highly flocculent strain of Saccharomyces cerevisiae (NCIM 3528) by
      chromatography on DEAE-cellulose, phenyl Sepharose and Sephacryl S-300. It showed
      a molecular mass of 40 kDa on SDS-PAGE. It is an acidic protein with a pI of 4.0
      and contains 44% hydrophobic amino acids. The N-terminal sequence up to 10 amino
      acid residues showed at least 70% homology with the predicted N-terminal sequence
      of the putative FLO1 as well as FLO5 gene products. The mannose-binding nature of
      the lectin was indicated by its high affinity and specificity towards the
      branched trisaccharide of mannose, a ligand which also inhibits the flocculation
      of yeast cells. Immunofluorescence studies confirmed the presence of lectin on
      the yeast cell surface and lectin-specific IgGs prevented flocculation of the
      cells. This cell surface mannose-specific lectin probably plays an important role
      in flocculation, with the branched trimannoside on the cell wall being the
      apparent carbohydrate receptor. The N-terminal sequence data gives a primary
      indication that the lectin could be a product of one of the FLO genes.

PMID- 10641034
TI  - Calorimetric characterization of critical targets for killing and acquired
      thermotolerance in yeast.
AB  - We characterized thermal behaviours of cellular components by differential
      scanning calorimetry (DSC) in order to investigate how Saccharomyces cerevisiae
      cells acquire thermotolerance after heat shock or in stationary phase. Whole-cell
      DSC profiles consisted of at least five endothermic components over the range 45
      75 degrees C for exponentially growing, heat-shocked and stationary-phase cells.
      In these profiles, we attempted to localize the endothermic profiles due to
      denaturation of the two critical targets which were predicted by using the
      Arrhenius parameters of hyperthermic killing of the cells (Obuchi et al., 1998).
      This prediction indicated that (a) the heat shock stabilized one family of
      targets and destabilized the other, while (b) arrest in stationary phase
      stabilized both targets. Therefore, the heat-shock response does not stabilize
      all cellular components, and arrest in stationary phase appears to stabilize
      cellular components in a different manner from the heat-shock response. It was
      not possible unambiguously to resolve the profiles of the critical targets in the
      DSC scans of whole cells. Components I (T(m)=49.7 degrees C) and II (T(m)=56.1
      degrees C) may both include denaturations of critical targets 1 (T(m)=55.4
      degrees C) and 2 (T(m)=53.0 degrees C) in exponential cells. Components I and II
      were both stabilized (T(m)=53.5 and 57.2 degrees C, respectively) in heat-shocked
      cells. Sub-cellular fractions suspended in 1.2 M trehalose solution, which mimics
      the cytosol in tolerant cells, were more stable than those in 0.6 M KCl, which
      mimics the cytosol in sensitive cells. The microsomal fractions in KCl and
      trehalose had endothermic profiles in similar temperature ranges to those
      predicted for sensitive and tolerant cells, respectively. This agreement suggests
      that the microsomal fraction may contain critical targets, and that trehalose
      accumulation in the heat-shocked and in the stationary phase yeast cells is a
      stabilizer of cellular components.

PMID- 10641035
TI  - The level of cAMP-dependent protein kinase A activity strongly affects
      osmotolerance and osmo-instigated gene expression changes in Saccharomyces
      cerevisiae.
AB  - The influence of cAMP-dependent protein kinase (PKA) on protein expression during
      exponential growth under osmotic stress was studied by two-dimensional
      polyacrylamide gel electrophoresis (2D-PAGE). The responses of isogenic strains
      (tpk2Deltatpk3Delta) with either constitutively low (tpk1(w1)), regulated (TPK1)
      or constitutively high (TPK1bcy1Delta) PKA activity were compared. The activity
      of cAMP-dependent protein kinase (PKA) was shown to be a major determinant of
      osmotic shock tolerance. Proteins with increased expression during growth under
      sodium chloride stress could be grouped into three classes with respect to PKA
      activity, with the glycerol metabolic proteins GPD1, GPP2 and DAK1 standing out
      as independent of PKA. The other osmotically induced proteins displayed a
      variable dependence on PKA activity; fully PKA-dependent genes were TPS1 and
      GCY1, partly PKA-dependent genes were ENO1, TDH1, ALD3 and CTT1. The proteins
      repressed by osmotic stress also fell into distinct classes of PKA-dependency.
      Ymr116c was PKA-independent, while Pgi1p, Sam1p, Gdh1p and Vma1p were fully PKA
      dependent. Hxk2p, Pdc1p, Ssb1p, Met6p, Atp2p and Hsp60p displayed a partially PKA
      dependent repression. The promotors of all induced PKA-dependent genes have STRE
      sites in their promotors suggestive of a mechanism acting via Msn2/4p. The
      mechanisms governing the expression of the other classes are unknown. From the
      protein expression data we conclude that a low PKA activity causes a protein
      expression resembling that of osmotically stressed cells, and furthermore makes
      cells tolerant to this type of stress.

PMID- 10641036
TI  - Stress response and expression patterns in wine fermentations of yeast genes
      induced at the diauxic shift.
AB  - During wine fermentation yeasts quickly reach a stationary phase, where cells are
      metabolically active by consuming sugars present in grape must. It is,
      consequently, of great interest at this stage to identify suitable gene promoters
      that may be used to induce the expression of genes with enological applications.
      With this aim, we have studied a group of genes showing an induction peak at the
      diauxic shift, and possessing stress response elements (STRE) at their promoters.
      We have determined their induction levels under individualized stress conditions,
      such as carbon source starvation or high salt concentrations. In all the cases
      studied, the activation and/or basal transcription are dependent on the
      transcriptional factors Msn2p and Msn4p. We have analysed the expression patterns
      and mRNA levels during wine fermentation, and have found that they are all
      activated at the stationary phase. Finally, we have identified SPI1, a new highly
      expressed yeast gene which is specifically induced at the stationary phase of
      both microvinification and laboratory growth conditions.

PMID- 10641037
TI  - A fission yeast kinesin affects Golgi membrane recycling.
AB  - We report here an in vivo study of kinesin heavy chain (KHC) functions in yeast.
      We have identified in Schizosaccharomyces pombe a kinesin motor gene, klp3(+),
      which has the highest homology to the Neurospora crassa KHC. Using indirect
      immunofluorescence, HA epitope-tagged Klp3 protein is cytoplasmic and appears as
      one to a few distinct patches that are coincident with microtubules. The klp3
      null allele is viable. In klp3 deleted cells, ER, Golgi and mitochondrial
      distribution appear normal. Mitochondrial distribution in S. pombe is known to be
      microtubule-associated. We show that latrunculin A does not cause mitochondria to
      aggregate, suggesting that mitochondrial distribution in fission yeast, unlike
      budding yeast, is not dependent upon actin-based processes. Neither latrunculin A
      nor thiabendazole affects ER or Golgi distribution. We also used the vital dye
      FM4-64 to visualize the internalization of the dye and its transport to vacuoles
      in fission yeast in the presence and absence of Klp3. We observed no significant
      difference between the wild-type and Klp3 null cells in either the dynamics of
      endocytosis or the distribution and fusion of vacuoles. The drug brefeldin A
      causes Golgi-to-ER recycling in wild-type fission yeast cells. Although recycling
      of Golgi to ER after brefeldin A treatment occurs in klp3 null cells, recycling
      is defective and the distribution pattern we see is different from that observed
      in the wild-type strain. We conclude that Klp3 plays a role in BFA-induced
      membrane transport. The nucleotide sequence of S. pombe klp3(+) was submitted to
      GenBank under Accession No. AF154055.

PMID- 10641039
TI  - A web site for the computational analysis of yeast regulatory sequences.
AB  - A series of computer programs were developed for the analysis of regulatory
      sequences, with a special focus on yeast. These tools are publicly available on
      the web (http://copan.cifn.unam. mx/Computational_Biology/yeast-tools or
      http://www.ucmb.ulb.ac. be/bioinformatics/rsa-tools/). Basically, three classical
      problems can be addressed: (a) search for known regulatory patterns in the
      upstream regions of known genes; (b) discovery of unknown regulatory patterns
      within a set of upstream regions known to be co-regulated; (c) search for unknown
      genes potentially regulated by a known transcription factor. Each of these tasks
      can be performed on basis of a simple (string) or more refined (matrix)
      description of the regulatory patterns. A feature-map program automatically
      generates visual representations of the positions at which patterns were found.
      The site also provides a series of general utilities, such as generation of
      random sequence, automatic drawing of XY graphs, interconversions between
      sequence formats, etc. Several tools are linked together to allow their
      sequential utilization (piping), but each one can also be used independently by
      filling the web form with external data. This widens the scope of the site to the
      analysis of non-regulatory and/or non-yeast sequences.

PMID- 10641038
TI  - Glycine metabolism in Candida albicans: characterization of the serine
      hydroxymethyltransferase (SHM1, SHM2) and threonine aldolase (GLY1) genes.
AB  - Genes encoding the mitochondrial (SHM1) and cytosolic (SHM2) serine
      hydroxymethyltransferases, and the L-threonine aldolase gene (GLY1) from Candida
      albicans were cloned and sequenced. All three genes are involved in glycine
      metabolism. The C. albicans Shm1 protein is 82% identical to that from
      Saccharomyces cerevisiae and 56% identical to that from Homo sapiens. The
      corresponding identities for the Shm2 proteins are 68% and 53%. The Gly1 protein
      shares significant identity with the S. cerevisiae L-threonine aldolase (55%) and
      also with threonine aldolases from Aeromonas jandiae (36%) and Escherichia coli
      (36%). Genetic ablation experiments show that GLY1 is a non-essential gene in C.
      albicans and that L-threonine aldolase plays a lesser role in glycine metabolism
      than it does in S. cerevisiae. GenBank Accession Nos of the C. albicans SHM1 and
      SHM2 are AF009965 and AF009966, respectively. Accession No. for C. albicans GLY1
      is AF009967.

PMID- 10641040
TI  - The chemistry and biological activity of herbs used in Flor-Essence herbal tonic
      and Essiac.
AB  - The herbal mixtures, Essiac and Flor-Essence, are sold as nutritional supplements
      and used by patients to treat chronic conditions, particularly cancer. Evidence
      of anticancer activity for the herbal teas is limited to anecdotal reports
      recorded for some 40 years in Canada. Individual case reports suggest that the
      tea improves quality of life, alleviates pain, and in some cases, impacts cancer
      progression among cancer patients. Experimental studies with individual herbs
      have shown evidence of biological activity including antioxidant,
      antioestrogenic, immunostimulant, antitumour, and antiocholeretic actions.
      However, research that demonstrates these positive effects in the experimental
      setting has not been translated to the clinical arena. Currently, no clinical
      studies of Essiac or Flor-essence are published, but a clinical study is being
      planned at the British Columbia Cancer Agency by the University of Texas-Center
      for Alternative Medicine (UT-CAM) and Tzu-Chi Institute for Complementary and
      Alternative Medicine.

PMID- 10641041
TI  - Chemical, pathological and toxicological studies of the effects of RICOM-1013-J
      of Ricinus communis var minor on women volunteers and rodents.
AB  - RICOM-1013-J (Ricinus communis var minor) administered orally once to each of 12
      women volunteers at a dose of 2.5-2.7 g per 8 months, protected against pregnancy
      over a period of 7-8 months of study. A study of the effect of a contraceptive
      dose (20 mg/kg) on metabolic parameters in rat (food and water in-take, urine and
      faecal output and body weight) over a period of 4 months showed a slight decrease
      in all the parameters in the first 1-8 weeks. This effect was reversible
      attaining pretreatment levels from week 16. The LD(50) in an acute toxicity test
      in mice was 63.1 +/- 16.0 g/kg s.c. Determination of blood urea, sodium (Na(+)),
      potassium (K(+)), chloride (Cl(-)) and bicarbonate (HCO$_?3? ?-?$)as a measure of
      renal function and alkaline phosphatase (ALP), transaminases (GPT and GOT) and
      transpeptidases (GGT) as a measure of liver function showed that liver function
      profiles in pretreated rats were not significantly different from control (p <
      0.05) on day 21 to day 150. However, serum levels of ALP and GGT at day 120 to
      day 150 were moderately but significantly elevated (p > 0.05) compared with the
      control. There were no significant changes in renal function profiles in
      pretreated rats (p < 0.05) compared with the control. The results of the liver
      and renal function profiles in women volunteers showed that there were no
      significant (p < 0.05) changes in renal functions on day 206 following RICOM-1013
      J administration. However, serum levels of ALP and GGT showed a slight rise in
      about 70% of volunteers, whereas bilirubin and transaminases levels were normal.
      The present results indicate a very high efficacy and margin of safety of RICOM
      1013-J in women volunteers. The increase in ALP and GGT in both animal and women
      volunteers suggest mild intrahepatic cholestatic changes which may be attributed
      to an oestrogenic effect of RICOM-1013-J.

PMID- 10641042
TI  - Effects of peppermint oil and caraway oil on gastroduodenal motility.
AB  - The effect of enteric-coated (Enteroplant) and non-enteric-coated preparations
      containing a peppermint-caraway oil combination with 90 mg peppermint oil and 50
      mg caraway oil was studied on gastroduodenal motility with stationary manometry
      in six healthy volunteers. The results showed that: (1) both enteric-coated and
      non-enteric-coated preparations have effects on the migrating motor complex
      (MMC); (2) mainly a decrease in the number of contractions and contraction
      amplitudes is seen during the various phases of the MMC; (3) non-enteric-coated
      preparations have their effects mainly during the first MMC after administration;
      (4) enteric-coated preparations have their effects temporally delayed during the
      second MMC after administration. In conclusion, enteric-coated and non-enteric
      coated peppermint-caraway oil combinations are safe preparations, acting locally
      to cause smooth muscle relaxation.

PMID- 10641043
TI  - Ethnomedicinally selected plants as sources of potential analgesic compounds:
      indication of in vitro biological activity in receptor binding assays.
AB  - A number of plant species used in traditional medicine for the relief of pain
      have been selected from the medicinal and scientific literature of China, South
      America, Asia and West Africa. Extracts were prepared and tested in three in
      vitro receptor radioligand binding assays to determine whether there was an
      indication of biological activity, in particular their selectivity to a single
      receptor implicated in the mediation of pain. The three neuropeptide receptors
      chosen were Bradykinin (BK II), expressed in Chinese hamster ovary cells (CHO),
      neurokinin 1 (NK 1) expressed in astrocytoma cells, and calcitonin gene related
      peptide (CGRP) which were all implicated in the mediation of acute pain in the
      mammaliancentral nervous system. The plant species chosen to investigate were
      Ageratum conyzoides, Barringtonia edulis, Croton tiglium, Ipomea pes-caprae,
      Panax ginseng, Physostigma venenosum, Sinomenium acutum, Solidago virgaurea,
      Symplocos leptophylla and Typhonium giganteum. The results showed that there was
      a strong indication of biological activity for some of the plants which are used
      ethnomedicinally to treat pain, in the three in vitro receptor binding assays
      used, and particular plant extracts exhibited selective action to a single
      receptor.

PMID- 10641044
TI  - The influence of active components of Eleutherococcus senticosus on cellular
      defence and physical fitness in man.
AB  - The influence of active components of Eleutherococcus senticosus, contained in
      Taiga Wurzel preparation, were studied on cellular defence and physical fitness
      in man. 50 healthy volunteers of both sexes were selected, and basic clinical
      examination and laboratory tests were performed in all subjects. All were
      randomly subdivided into two study groups: group A with 35 subjects receiving
      Taiga Wurzel and group B with 15 subjects receiving Echinacea. 20 healthy males
      were randomly selected from both groups and underwent an ergospirometric study.
      The preparations were administered for 30 days as follows: Taiga Wurzel 25 drops
      three times daily, Echinacea 40 drops three times daily. After 1 month blood was
      drawn for control tests. Changes in the following blood parameters were observed
      in comparison to initial values in group A: total and LDL cholesterol,
      triglycerides and glucose. No alterations were seen in group B. The
      ergospirometric test revealed a higher oxygen plateau in group A (Taiga Wurzel).
      On the basis of the present study the following conclusions were drawn: active
      components in Eleutherococcus senticosus contained in Taiga Wurzel preparation
      affect cellular defence and physical fitness, as well as lipid metabolism.

PMID- 10641045
TI  - Pharmacological activity of Elaeocarpus sphaericus.
AB  - Elaeocarpus sphaericus fruits are used in Ayurveda for mental diseases, epilepsy,
      asthma, hypertension, arthritis and liver diseases. Sequential petroleum ether
      (PE), benzene (BE), chloroform (CE), acetone (AE) and ethanol (EE) extracts (50
      200 or 200 mg/kg, ip, or 200 mg/kg, po) of dried Elaeocarpus sphaericus fruits,
      pretreatment time 30-45 min, showed significant antiinflammatory action against
      both acute and sub-acute models, analgesic, barbiturate-hypnosis potentiation and
      antiulcerogenic activities in rats. All the extracts, except PE and EE decreased
      swim stress immobility in mice indicating some degree of antidepressant activity.
      All the extracts protected guinea-pigs against bronchospasm induced by histamine
      and acetylcholine aerosols. Chemically, the extracts showed the presence of
      glycosides, steroids, alkaloids and flavonoids.

PMID- 10641047
TI  - The in vitro effect of dandelions antioxidants on microsomal lipid peroxidation.
AB  - Dandelions have long been used in herbal medicine for their choleretic, diuretic,
      antiinflammatory, appetite-stimulating and laxative properties. An antioxidant
      property can be supposed as a basis of their-therapeutic effects. To understand
      the mechanism of the drug's action, the effects of natural extracts on a
      microsomal fraction of rat liver were examined. The extracts diminished the
      enzymatically induced-lipid peroxidation and reduced the cytochrome c with and
      without NADPH in a concentration dependent manner.

PMID- 10641046
TI  - Preliminary clinical investigation of the contraceptive efficacy and chemical
      pathological effects of RICOM-1013-J of Ricinus communis var minor on women
      volunteers.
AB  - The seeds of Ricinus communis Linn, RICOM-1013-J, administered as a single oral
      dose of 2.3-2.5 g once per 12 months protected against pregnancy in 50 women
      volunteers for a period of one year. The antifertility and contraceptive efficacy
      of the seed was demonstrated in this study. Clinical observation revealed very
      minimal side effects. Some of the side effects investigated included headache,
      nausea, vomiting, weight gain, loss of appetite, raised blood pressure and
      dysmenorrhoea. Furthermore, both the renal and liver functions were not affected
      as revealed by urea, electrolyte and creatinine values as well as total
      bilirubin, conjugated bilirubin, serum albumin, total protein and transaminases
      values when compared with control values. In addition cholesterol and
      phospholipids were not significantly altered. When all these results are
      considered together, it seems unlikely that the antifertility and contraceptive
      efficacy of RICOM-1013-J is due to hormonal mechanisms alone since side effects,
      renal and liver function, and cholesterol effects attributable to oestrogen
      and/or progesterone were minimal in the volunteers.

PMID- 10641048
TI  - Antimalarial activity of four plants used in traditional medicine in Mali.
AB  - Mitragyna inermis (De Willd.) O. Kuntze Rubiaceae, Nauclea latifolia (Sm.)
      Rubiaceae, Glinus oppositofolius (Linn) Molluginaceae and Trichilia roka (Forsk.)
      Chiv. Meliaceae were investigated for their in vitro antimalarial activity.
      Leaves, roots and stem barks were submitted to aqueous, hydromethano and
      chloroform extractions and antimalarial activity was evaluated by microscopic and
      flow cytometric analysis. The results present evidence that the alkaloids
      contained in chloroform extracts and ursolic acid, purified from the
      hydromethanol extract of M. inermis induced a significant decrease of parasite
      proliferation. However, aqueous extracts, traditionally used for medication did
      not show high antimalarial activity. Statistical comparison between microscopic
      and cytometric analysis demonstrated the validity of this new technique for the
      screening of active antimalarial compounds isolated from plants.

PMID- 10641049
TI  - Brine shrimp bioassay of ethanol extracts of Sesuvium verrucosum, Salsola
      baryosma and Zygophyllum quatarense medicinal plants from Bahrain.
AB  - Ethanol whole plant extracts of three halophytic plants from Bahrain Sesuvium
      verrucosum, Salsola baryosma, Zygophyllum quatarense have been tested for their
      cytotoxic activity by the brine shrimp method. Only S. verrucosum showed a marked
      significant activity (LC(50) = 102.7 microg/mL)

PMID- 10641050
TI  - Inhibition of nitric oxide release by an aqueous extract of Tinospora
      tuberculata.
AB  - An aqueous extract of Tinospora tuberculata stems was found to scavenge nitric
      oxide (NO) in vitro in both cell and cell-free systems. When the aqueous extract
      was added to lipopolysaccharide-stimulated murine macrophages, it inhibited NO
      release dose-dependently, and similar activity was found in a cell-free system
      using sodium nitroprusside as a NO donor. These findings may help to explain, in
      part, certain pharmacological activities of Tinospora tuberculata.

PMID- 10641051
TI  - Testosterone 5alpha-reductase inhibitor bisnaphthoquinone derivative from
      Impatiens balsamina.
AB  - The 35% EtOH extract of aerial parts of Impatiens balsamina L. has been
      investigated for activity against testosterone 5alpha-reductase. Activity-guided
      fractionation led to the identification of the bisnaphthquione derivative named
      impatienol (1), 3-hydroxy-2-?[3-hydroxy-1,4-dioxo (2-naphthyl)] ethyl?
      naphthalene-1, 4-dione, which exhibited significant testosterone 5alpha-reductase
      inhibitory activity. This 5alpha-reductase inhibitory compound has been
      previously synthesized, but this is the first report of its isolation from a
      natural source.

PMID- 10641052
TI  - Depressant and anticonvulsant properties of the root decoction of Afrormosia
      laxiflora (Leguminosae).
AB  - The lyophilized root decoction of Afrormosia laxiflora (Leguminosae), claimed to
      be beneficial in epilepsy and psychosis, was screened for depressant and
      anticonvulsant activities using in vivo models. The root decoction, 150-300
      mg/kg, showed significant inhibition of motor activity in mice, indicating
      depressant actions. Similarly, doses of 150-300 mg/kg of this extract
      significantly diminished the duration of convulsive symptoms, and increased the
      seizure latency, in both picrotoxin- and electroshock-induced seizures when
      compared with controls. The results suggest possible beneficial effects of the
      plant's root and also offer a rational explanation for its folklore usage in
      epilepsy and related disorders.

PMID- 10641053
TI  - The antimicrobial activity of roots of Jatropha podagrica (Hook).
AB  - Hexane, chloroform and methanol extracts of the rootwood and rootbarks of
      Jatropha podagrica were studied for their antimicrobial activity against 18
      organisms. All the extracts exhibited some broad spectrum antibacterial activity,
      at a concentration of 20 mg/mL. The hexane extracts were generally more active
      than the chloroform and methanol extracts. The hexane extract of the yellow
      rootbark was the most active of all the extracts and its activity was comparable
      to that of gentamycin but better with regard to the control of S. aureus and B.
      cereus. Three of the extracts, hexane extract of the yellow rootbark and hexane
      and methanol extracts of the rootwood showed moderate antifungal activity against
      the yeast fungus, Candida albicans.

PMID- 10641054
TI  - Exploration of antifilarial potential and possible mechanism of action of the
      root extracts of Saxifraga stracheyion on cattle filarial parasite Setaria cervi.
AB  - The effect of aqueous and alcohol extracts of the roots of Saxifraga stracheyi
      Engl. On the spontaneous movements of both the whole worm and the nerve muscle
      preparation of Setaria cervi and on the survival of microfilariae in vitro was
      studied. Both extracts caused the inhibition of spontaneous movements of the
      whole worm and the nerve-muscle preparation of S. cervi, characterized by an
      increase in the amplitude and a decrease in the rate of contractions, while the
      tone of the contractions remained visibly unaffected. The concentration required
      to inhibit the movements of the whole worm preparation was 140 microg/ml for the
      aqueous and 250 microg/ml for the alcohol extract. The concentration of S.
      stracheyi extracts required to produce an equivalent effect on the nerve-muscle
      preparation was 30 microg/ml for aqueous, and 20 microg/ml for the alcohol
      extract, suggesting a cuticular permeability barrier.

PMID- 10641055
TI  - Patents alert

PMID- 10641056
TI  - Selected bibliography

PMID- 10641057
TI  - The privatized water industry and dental public health: water fluoridation?

PMID- 10641058
TI  - Special care dentistry: moving towards a specialty. A view from the executive of
      the BASCD Section in Clinical Community Dentistry. British Association for the
      Study of Community Dentistry.

PMID- 10641060
TI  - The reliability of two methods of utility assessment in dentistry.
AB  - OBJECTIVE: The objective of this study was to investigate the modification of two
      utility assessment techniques (visual analogue scale and daily time trade-off)
      used in medicine to the dental setting, with a focus on their test-retest
      reliability and ease of use. BASIC RESEARCH DESIGN: The study involved a postal
      questionnaire survey which incorporated a dental visual analogue scale (DVAS) to
      assess utility values for 12 specified tooth states, and a specifically designed
      instrument, the dental freetime trade-off (DFTO) to assess utility of the
      participants' current dental health state. PARTICIPANTS: A total of 582 regularly
      attending adolescent dental patients were sent the questionnaire. A further 100
      of those who fully completed the relevant sections of the questionnaire were sent
      a repeat questionnaire to facilitate assessment of test-retest reliability.
      RESULTS: A final response rate of 74.7% was achieved with the mean age of
      respondents being 17 years. Fifty per cent of those sent a repeat questionnaire
      for the purposes of reliability assessment returned the questionnaire. Test
      retest reliability of both utility assessment techniques appeared acceptable.
      Spearman correlation coefficients for the dental freetime trade-off (DFTO) and
      the dental visual analogue scale (DVAS) were (0.67 and 0.83 respectively.
      Promising results, in terms of utility values, were elicited from the DVAS whilst
      utility values elicited using the DFTO were highly skewed. CONCLUSIONS: The newly
      developed modification to the daily time trade-off technique, the DFTO, showed a
      good level of test-retest reliability and ease of completion although the highly
      skewed utility results produced may indicate a design flaw. The DVAS however,
      appears to show promise, in terms of test-retest reliability, ease of completion
      and resultant utility values.

PMID- 10641059
TI  - Sugar, drinks, deprivation and dental caries in 14-year-old children in the north
      west of England in 1995.
AB  - OBJECTIVES: To examine associations between dental caries and reported drink
      consumption. DESIGN: A cross-sectional caries prevalence study including reported
      drink consumption. SETTING: Secondary schools across the former North Western
      Region of England. SUBJECTS: A random sample of 6,014, 14-year-old children.
      RESULTS: The mean DMFT of the sample was 2.74. The reported mean weekly
      consumption of cans of carbonated drinks was 5.66, with a range of zero to 42.
      There was a significant gender difference in drink consumption and a significant
      correlation between the reported weekly consumption of cans of carbonated drinks
      and DMFT. Logistic regression analysis showed tea drinkers had a significantly
      lower DMFT than coffee drinkers and that this effect was independent of the
      addition of sugar and the number of cans of drink consumed. Reported use of sugar
      free carbonated drinks was not associated with better dental health. CONCLUSIONS:
      Reported consumption of sugared drinks and carbonated drinks was associated with
      significantly higher levels of dental caries. Drinking tea was associated with
      lower levels of caries. Sugar-free drinks were not associated with better dental
      health.

PMID- 10641062
TI  - A model framework comparing resources required for activities in the Community
      Dental Service validated using the Delphi technique.
AB  - OBJECTIVE: To validate a model framework comparing resources required for
      activities in the Community Dental Service. The framework consisted of five
      levels of care of increasing complexity for six groups of patients. The patient
      groups were: children with behavioural problems, mentally disabled patients,
      anxious adults, paedodontic patients, medically compromised and physically
      disabled patients. DESIGN: Delphi study using two sequential questionnaires.
      Participants were asked to rate the difficulty of 29 different treatments on a
      scale from 1 to 100. PARTICIPANTS: Six clinical directors and eleven senior
      dental officers working in the Community Dental Service in the North West of
      England. RESULTS: Seventeen of the 29 treatments were rated at the level of care
      predicted by the model. Nine were rated lower and three higher. Within the
      patient groups the order of increasing complexity, predicted by the model, was
      verified with only one exception. CONCLUSIONS: The research confirmed that it is
      possible to measure CDS activity in a rational way. Consensus was reached on a
      suitable framework which was simpler than the original model in having only four
      levels of care. The use of the modified model is now being tested in the
      Community Dental Service.

PMID- 10641061
TI  - Caries experience, dental health behaviour and social status--three comparative
      surveys among Danish military recruits in 1972, 1982 and 1993.
AB  - OBJECTIVE: To compare caries experience among young Danish men in 1972, 1982 and
      1993; and on the same occasions to describe relationship between their
      utilisation of regular dental care and social status, as well as the relationship
      between their caries experience, utilisation of dental services and social
      status. DESIGN: During their routine health examinations in 1972, 1982 and 1993
      all recruits enlisted in the Danish Air Force were subjected to an additional
      oral examination combined with a structured socio-dental questionnaire. Identical
      methods were applied in each of the three surveys. SETTING: Dental clinics at air
      bases in Denmark. SUBJECTS: 4,103 male military recruits, aged 18 to 25 years.
      OUTCOME MEASURES: Caries was registered in accordance with the WHO Basic Methods
      1971. The questionnaire provided information on age, place of residence during
      childhood, social origin, and patterns of utilisation of dental services.
      RESULTS: The findings indicated a considerable decrease in average caries
      experience from 16.6 DMFT in 1972 to 11.8 in 1982 and 6.2 in 1993. The results
      further documented markedly increased availability of public school dental health
      services, the coverage rising from 33% in 1972 to 65% in 1982 and 100% in 1993,
      as well as moderately increased utilisation of regular dental care with private
      practitioners, rising from 71% in 1972 to 86% in 1982 and 84% in 1993. In 1993 as
      in 1982 and 1972, recruits who used the public school dental health services and
      also received regular dental care after their school leaving age showed the
      lowest average caries experience. CONCLUSIONS: The findings indicate a marked
      decrease in average caries experience and an increased utilisation of dental
      services among Danish young men from 1972 to 1993. However, in 1993 the least
      privileged social group continued to maintain the highest average caries
      experience and the lowest rate of utilisation of regular dental care.

PMID- 10641064
TI  - The sequential modular curriculum for oral health personnel: an evaluation of the
      Fijian experience after five years.
AB  - In 1993 a new sequential modular curriculum was introduced for the training and
      education of oral health personnel in Pacific Island countries. The five-year
      model provided a multi-stage course with the opportunity to exist at the level of
      dental hygienist after two years, dental therapist or dental technologist after
      three years and dental surgeon after five years. After five years' experience the
      principles involved in the introduction of such a curriculum have been confirmed
      as educationally sound. The model may also be useful for introduction in other
      countries providing its structure and the details of individual modules are
      tailored to local social, cultural and demographic needs.

PMID- 10641063
TI  - Use of the generalised linear model with Poisson distribution to compare caries
      indices.
AB  - In dental epidemiological studies, an analysis of variance assuming a normal
      distribution is commonly used to compare caries indices, which are often not
      normally distributed. As these indices represent discontinuous data, it would be
      preferable to use the negative binomial or the Poisson distribution. In this
      study, in order to compare the DMFS indices of adults working in the
      confectionery manufacturing industry in France, the results of the generalised
      linear model obtained using the normal and the Poisson distribution with identity
      or log built-in link function were compared. The negative binomial distribution
      was not used because it is very often unavailable in the most used statistical
      software. Analysis of the caries indices showed that the use of the normal
      distribution could lead to an incorrect interpretation of the data. Therefore it
      is concluded that the generalised linear model with Poisson distribution and over
      dispersion is to be preferred when comparing caries levels.

PMID- 10641065
TI  - An oral health programme for schoolchildren in Kuwait 1986-97.
AB  - OBJECTIVES: To assess whether it was possible to implement an oral health
      programme in Kuwait which followed guidelines underlying the public Danish Child
      Oral Health Service, and thereby improve the oral health of Kuwaiti children.
      DESIGN: Successive cross-sectional surveys were carried out in one governorate in
      Kuwait (Al-Ahmadi) during the period 1986-97 interrupted by the Gulf War. Data
      were collected by clinical examinations. SETTING: The programme was initiated by
      the Ministry of Health in Kuwait in order to improve the community services
      through a school-based oral health care programme. PARTICIPANTS: The study
      population comprised incrementally all children in the four primary school
      classes in the governorate. INTERVENTIONS: The children received bi-weekly tooth
      brushing instructions with fluoridated toothpaste and fluoride rinsing, fissure
      sealing, oral health education, and restorative treatment of dental caries.
      OUTCOME MEASURES: The children were clinically examined each year before the
      start of the treatment. Dental caries was scored at surface level in accordance
      with the Danish registration system, using the WHO criteria for dental caries.
      RESULTS: The average participation rate was 94%. The percentage of caries-free
      children, exemplified by second class, increased from 64% in 1987 to 78% in 1990,
      dropped to 71% in 1992 and increased again to 79% in 1997. CONCLUSION: It is
      concluded that it has been possible to adapt the principles from the Danish Child
      Oral Health Service programme to Kuwait, that parents and teachers accepted the
      principle of treating the children during school hours, and that the oral health
      of the children improved. Whether the improvement in the oral health is due to
      the programme or to changes in the society is discussed.

PMID- 10641066
TI  - Determinants of caries prevalence and severity in higher SES Indian children.
AB  - OBJECTIVES: Recent epidemiological studies in the economically developing
      countries show that the prevalence and severity of dental caries has increased
      with industrialization and exposure of these populations to western diets. The
      aim of this study was to quantify the caries experience, and identify
      determinants associated with caries, in a population which has a higher socio
      economic status (SES), and is the most westernized in India. BASIC RESEARCH
      DESIGN: The study site was Goa, a former Portuguese colony, which became part of
      India in 1961. Data came from a cross-sectional survey of 1,189 seventh grade
      children in private schools, consisting of a clinical dental examination and a
      self-administered questionnaire to their parents. MAIN OUTCOME MEASURES: The
      study used the cavitated/non-cavitated criteria to score for caries, the TF index
      for fluorosis, and the Silness and Loe index for plaque. RESULTS: The mean age of
      the children was 12.2 years. The proportion of children caries-free in the
      permanent dentition was 22.2%. The mean DMFT and DMFS in the study group were
      2.78 and 4.20, respectively. The decayed component accounted for over 87% of the
      DMFT, DMFS, dft, and dfs. Results of the crude, stratified, and multivariate
      regression analyses showed that poor oral hygiene, mother's highest level of
      education, use of fluoride toothpaste before the age of six years, and higher
      frequency of tooth brushing were risk indicators of caries prevalence and
      severity. CONCLUSION: The findings suggest that risk indicators of caries in this
      study population were similar to those in developed countries.

PMID- 10641067
TI  - Dental caries status and treatment needs of 12-13-year-old children in Sichuan
      Province, southwestern China.
AB  - OBJECTIVE: To update information on the dental caries status of children living
      in the Southwestern part of China for planning appropriate dental care services
      and to obtain information on caries level in rural areas. METHOD: All first year
      students studying in seven secondary schools (two in urban, two in peri-urban and
      three in rural areas) in Sichuan Province were surveyed. The students were
      clinically examined in their schools using procedures and diagnostic criteria
      recommended by the World Health Organization. RESULTS: A total of 1,542 children,
      12-13 years of age, were examined of which 660, 519 and 363 were from the urban,
      peri-urban and rural schools respectively. The prevalence of caries experience
      was highest in urban children (30%), followed by peri-urban children (21%) and
      lowest in rural children (13%). The respective DMFT index scores for the urban,
      peri-urban and rural children were 0.62, 0.38 and 0.18. The differences were
      statistically significant (P < 0.001). The major component of the DMFT index was
      untreated decay (DT) in all three areas. CONCLUSION: There was a clear trend of
      increasing prevalence and severity of dental caries in children as the survey
      sites moved from rural, through peri-urban to urban areas. Thus, estimates of
      dental caries in Chinese child populations of this age based on surveys conducted
      in urban areas will probably lead to gross over-estimation as over 80% of the
      people live in rural areas.

PMID- 10641068
TI  - Improving oral health: public or private funding?

PMID- 10641069
TI  - 'Get brighter now'.

PMID- 10641070
TI  - Development and evaluation of a sugar-free medicines campaign in north east
      England: analysis of findings from questionnaires.
AB  - OBJECTIVE: To develop a strategy for a campaign aimed at general medical
      practitioners (GPs) and pharmacists and to evaluate the effectiveness of the
      campaign on (a) awareness of the role of liquid oral medicines containing sugar
      in dental disease and (b) changing prescribing and dispensing of sugar-containing
      medicines. DESIGN: Pre- and post-campaign questionnaires were sent to community
      pharmacists and GPs and following a series of qualitative interviews with them, a
      campaign was developed. Following post campaign questionnaires, changes due to
      the effects of the campaign were evaluated. SETTING: The test area was Newcastle
      and North Tyneside Health Authority area with Sunderland and South Tyneside
      Health Authority areas as control. INTERVENTIONS: An information pack followed up
      by a personal contact was the main form of intervention. The pack comprised a
      Smile for Sugar-Free Medicines leaflet used in the north west campaign, abstracts
      from professional journals illustrating the benefits of sugar-free medicines,
      local dental health information and computing information which could be used to
      adapt computer terminals in surgeries to display sugar-free options more
      prominently. MAIN OUTCOME MEASURES: Changes in the knowledge and awareness of
      both pharmacists and GPs to liquid oral medicines containing sugar as assessed by
      questionnaires. RESULTS: Increased knowledge and awareness of both pharmacists
      and GPs to the role of liquid oral medicines containing sugar and the use of
      sugar-free medicines had taken place but these were not statistically
      significant. CONCLUSION: The campaign created awareness amongst GPs and
      pharmacists about dental issues and it is hoped that this awareness can be built
      upon in future oral health promotion campaigns. However, it is likely that
      facilitation of sugar-free medicines use will occur only if sustained and
      constant reinforcement is available. The methodology used presented several
      difficulties in evaluating change.

PMID- 10641071
TI  - Evaluation of a sugar-free medicines campaign in north east England: quantitative
      analysis of medicines use.
AB  - OBJECTIVE: The aim of the study was to evaluate the effectiveness of a sugar-free
      medicines campaign using suitable prescribing and purchasing indicators. BASIC
      RESEARCH DESIGN: Quantitative analysis of sugar-free medicine use, before (1995)
      and after (1996) the campaign. CLINICAL SETTING: Two test and two control
      districts in north east England. PARTICIPANTS: General medical practitioners
      (GPs) and community pharmacists. INTERVENTION: A 12-month campaign involving
      development and distribution of information packs designed to increase the
      proportion of prescriptions dispensed sugar-free for paediatric use. MAIN OUTCOME
      MEASURES: Changes in the proportion of the following which were sugar-free: (a)
      for target prescribed medicines (i) number of prescriptions dispensed. (ii)
      number of prescribed daily amounts (PDA); (b) for target over the counter (OTC)
      medicines, (i) number of bottles sold, (ii) number of standard daily amounts
      (SDA) sold. RESULTS: Quantitative analysis of prescriptions and OTC sales showed
      statistically highly significant changes towards sugar-free prescribing and
      dispensing of prescribed medicines but only small increases in the proportion of
      some sugar-free OTC sales. CONCLUSIONS: The impact of the campaign was shown to
      be greatest in changing prescribing habits of GPs with less effect on OTC
      medicine use. The outcome measures used were suitable for quantitative evaluation
      of the campaign. POST-CAMPAIGN DEVELOPMENT: Sustainable changes in GPs'
      prescribing behaviour can be facilitated by software suppliers' modifications to
      computing software used for prescription writing.

PMID- 10641072
TI  - Changing trends in South Wales fluoride prescription dispensing (1993-7).
AB  - OBJECTIVE: To observe patterns of fluoride preparation dispensing by primary care
      practitioners in a health authority. DESIGN: Observational study. SETTING: The
      Prescription Pricing Agency of the Welsh Health Common Services Authority
      (WHCSA). SUBJECTS: Individuals who had exchanged a prescription for a fluoride
      preparation at a pharmacy in Bro Taf Health Authority in the six months from 1
      January 1997 to 30 June 1997. METHOD: Information from each prescription
      including a fluoride preparation, passed to WHCSA from pharmacists during the
      study, was entered onto a database, including the prescriber's postcode and
      profession, the recipient's postcode and product information. Numbers of dental
      prescriptions were correlated to local levels of NHS primary dental care
      provision and caries prevalence data. Comparisons were made with a similar study
      undertaken in 1993. RESULTS: 415 dentists' prescriptions were dispensed within
      the area, of which 38.8% originated from five dentists. At least one prescription
      had been made by 89 of the 253 local primary dental care providers (35%). Within
      the area monitored in both 1993 and 1997, dental prescribing rates had almost
      halved. Of the 122 doctors' prescriptions that were dispensed over the six-month
      period, 98 were mouthwash preparations for adult patients and four were for
      children. CONCLUSION: NHS provision of fluoride supplementation was low and
      remained related to prescribing patterns of individuals rather than to evidence
      on local variations in dental caries prevalence.

PMID- 10641073
TI  - Dental health, population size and the distribution of general dental
      practitioners in England.
AB  - OBJECTIVE: To assess the distribution of general dental practitioners (GDPs) in
      England in relation to the distribution of various indicators of dental health in
      the population. RESEARCH DESIGN: Simple graphical and statistical analyses using
      Lorenz curves and Gini coefficients linking Department of Health data on numbers
      of GDPs by health authority and previously undertaken survey data on dental
      health levels by health authority area. MAIN OUTCOME MEASURES: Lorenz curves and
      Gini coefficients of GDPs in relation to population and dental health. RESULTS:
      The distribution of GDPs in relation to dental health levels of children and
      adults was found to be far more inequitable than implied by looking at population
      levels alone. CONCLUSIONS: The results raise serious questions for all those
      concerned with reducing inequalities in dental health in England, and strengthens
      the case for an active manpower policy.

PMID- 10641074
TI  - Better oral health, more inequality--empirical analysis among young adults.
AB  - OBJECTIVE: The purpose of the study was to examine the development of the
      distribution of oral health according to socio-economic status in young adults
      from 1983 to 1994. PARTICIPANTS: Study material consisted of 23-24 year old
      adults randomly selected from municipalities in Trondelag in 1983 and 1994 (n =
      796, n = 454). RESULTS: The results showed that while overall oral health had
      improved (reduction in mean DFS of 54% from 1983 to 1994), inequality in DFS
      between socio-economic groups had increased from 1983 to 1994. The widening
      disparity appeared to be mainly due to a greater decrease in DFS among the group
      of individuals with high education. None of the comparable variables, gender,
      residence, time since last dental visit nor type of clinic could explain the
      widening gap in DFS. For 1994, differences in oral health according to socio
      economic status seemed not to be associated with the use of dental services but
      rather with the comprehensiveness of treatment. Smoking was more prevalent in the
      low socio-economic group and associated with a higher mean DFS. CONCLUSION: The
      target set by the WHO that by the year 2000 the actual differences in health
      status between groups should be reduced by at least 25% (WHO, 1988) seems to be
      unattainable among young adults in Norway.

PMID- 10641075
TI  - Distribution of caries in 12-year-old children in Sweden. Social and oral health
      related behavioural patterns.
AB  - OBJECTIVE: To describe the distribution of caries in 12-year-old children in
      Sweden according to socio-demographic and oral health related behaviour.
      PARTICIPANTS: The study group consisted of 3,373 12-year-old children residing in
      catchments of 26 different public dental health clinics in Sweden, geographically
      well represented. METHOD: The clinical examination for dental caries was
      performed by 28 calibrated dentists. A questionnaire on lifestyle was distributed
      to the children with questions on ethnicity, socio-economic level and oral health
      as well as overall health attitudes. RESULTS: The proportion of 12-year-old
      children with no experience of dentine caries was 47% and 35% were completely
      free from all caries. Intraoral distribution of caries showed most lesions on the
      first molar mesial surface, with 80% enamel and 20% dentine caries. Almost all
      children brushed their teeth twice a day and a third of the children had an extra
      intake of fluoride. Decayed surfaces including enamel caries (DeS) was chosen as
      a measure of ongoing caries and used when dividing children into three caries
      groups; caries free (50%), 1-3 lesions (40%) and the high caries group (10%) with
      more than 3 lesions. These groups showed distribution differences. More non
      Swedish children, children from workers' homes, and children who brushed their
      teeth less than twice a day were found in the high caries group. More children
      from workers' homes living in big cities and snacking more than once a week were
      also found in the high caries group. This could not be shown for other social
      groups. Also children who had an extra intake of fluoride were classified in the
      high caries group.

PMID- 10641076
TI  - Dental caries in Danish children and adolescents 1988-1997.
AB  - OBJECTIVE: To describe the occurrence of dental caries in Danish children and
      adolescents from 1988 to 1997. DESIGN: Cross-sectional data collected by the
      Danish National Board of Health. RESULTS: The earlier trend of a marked annual
      decline in caries now appears to have halted, especially in respect of the
      permanent dentition of 7-year-old children. The distributions show marked
      positive skewness for all age groups, which may give rise to considerations of
      implementing high risk strategies in order to obtain further reductions in DMFS
      in the population. CONCLUSION: Calculations indicate, that the effect of a
      hypothetical high risk strategy on the occurrence of caries at the population
      level will be limited.

PMID- 10641077
TI  - Dental care of six-year-old high-caries patients in relation to their
      cooperation.
AB  - OBJECTIVE: To evaluate caries occurrence in, and dental care given to, 6-year-old
      high-caries patients in relation to their cooperation as judged by the dentist.
      DESIGN: Retrospective evaluation study. SETTING: Children selected on the basis
      of their high number of decayed teeth (dt + DT). Data from personal oral health
      records. PARTICIPANTS: High-caries children aged 6 years (n = 97) clinically
      examined and treated in public dental clinics in Helsinki, Finland, with mean dt
      + DT = 8.7, range 4-18. OUTCOME MEASURES: Data covering ages 3 to 7 years:
      utilization of dental services, operative and preventive treatment by visit.
      RESULTS: Treatment strategy for the 6-year-old high-caries patients was not
      preventive-oriented. High-caries patients had three to four times as many visits
      as all 6-year-old children on average, but the visits had mostly served for
      operative treatment. Dentists had judged 34% of the high-caries patients to be
      non-cooperative. These patients had more past and present caries in their
      deciduous teeth (P < 0.01), more dental visits (P < 0.01), and received more
      demanding treatment (P < 0.001) than the cooperative high-caries patients. Caries
      preventive treatment given to all high-caries patients was rare, number of
      preventive interventions per patient and per visit (intensity) tended to
      correlate negatively with patients' cooperation (r = -0.12 and r = -0.23).
      Treatment courses were completed in 39% among the non-cooperative and in 63 per
      cent among the cooperative high-caries patients (P < 0.05). CONCLUSION: Dentists
      should be encouraged to integrate preventive interventions more closely into the
      treatment of non-cooperative high-caries children.

PMID- 10641079
TI  - Presidential address. British Association for the Study of Community Dentistry,
      Chester, April 1999.

PMID- 10641080
TI  - [The arterial irrigation of the optic chiasma].
AB  - The purpose of this study was to determine the distribution of the arterial
      branches that are supplying the optic chiasma. This study was carried out on 40
      cerebral hemispheres fixed in formaldehid and dissected under a surgical
      microscope; 12 of them were at first injected with colored nitrolac. It was
      observed the origin, traject and distribution of the arterial branches which
      supply the optic chiasma. The arteries are branches from the anterior cerebral
      artery (100%); internal carotid artery (90%); anterior communicating artery
      (70%); posterior communicating artery (40%); anterior choroidal artery (5%). Some
      of this branches pass directly into the chiasma, others form a superficial, pial
      network, well represented on the inferior surface and posterior border of the
      optic chiasma. The data obtained add new aspects to a systematic description of
      the arterial branches distributed to the chiasma. The knowledge of the blood
      supply of the optic chiasma, in relationship with the somatopy of the optic
      fibers allow to understand some hemianopic visual field defects in different
      neuro-ophthalmologic syndromes.

PMID- 10641078
TI  - The impact of tooth loss in a denture wearing population: an assessment using the
      Oral Health Impact Profile.
AB  - OBJECTIVES: To assess the impact of tooth loss in complete denture wearers using
      the Oral Health Impact Profile (OHIP), and to compare the validity of 49 and 14
      item versions of OHIP in a denture wearing population. DESIGN: In this cross
      sectional study, data were collected at Newcastle Dental Hospital, UK. Two groups
      were involved: (1) subjects edentulous in one or both jaws seeking dental
      implants to retain their intra-oral prostheses (n = 48); (2) an edentulous
      control group of the same age and gender distribution requesting conventional,
      complete dentures (n = 35). All participants in the study completed a 49 item
      OHIP (OHIP-49) and a validated denture satisfaction questionnaire prior to active
      treatment. OHIP data were computed using the weighted standardised and simple
      count methods. Non-parametric statistical tests were used to compare the
      responses of implant and control subjects. RESULTS: Both groups were dissatisfied
      with their conventional dentures and had relatively similar levels of
      dissatisfaction. There were statistically significant differences between the
      groups for all seven OHIP-49 sub-scale scores. Differences between OHIP-14 sub
      scale scores were also significant, with presence of teeth influencing the impact
      on psychological discomfort. CONCLUSION: Subjects in the implant group were
      significantly more impaired, disabled and handicapped by tooth loss than subjects
      seeking conventional dentures. The results suggested that OHIP-49 and OHIP-14 had
      a similar ability to discriminate between the groups. This indicates that OHIP-14
      may be a useful aid in a clinical setting.

PMID- 10641081
TI  - [Photodynamic therapy in ophthalmology].
AB  - This work presents the ophthalmic applications of photodynamic therapy (PDT).
      Very good results of PDT were observed in the treatment of neovascularization and
      tumors.

PMID- 10641082
TI  - [The ocular manifestations in rheumatoid polyarthritis].
AB  - Systemic diseases as rheumatoid arthritis and ankylosing spondylitis have unknown
      etiologies, unclear pathogenic mechanisms and multiorgan involvements. Ocular
      involvement is variable and may effect several levels: sclera, cornea, uvea and
      conjunctiva. Because an ocular event signify an enhancement of inflammatory
      immune reactions, the patient may undergo a complete investigation and general
      therapy must complete local treatment. The paper showing the ocular manifestation
      in patients with rheumatic arthritis through a ten-years period.

PMID- 10641083
TI  - [The ocular changes in patients on chronic dialysis].
AB  - The paper propose the study of lacrimal secretion alterations, the lacrimal level
      of the urea and the fundus optic alterations at the patients with chronic renal
      failure, during the hemodialysis. For the study we used the general
      ophthalmologic examination, the fundus optic examination before and after the
      hemodialysis, the lacrimal secretion examination by Schirmer l-test and the
      measure of lacrimal urea by the Berthelot modified method. The study was done on
      a member of 30 patients, with chronic renal failure, having a age of the dialysis
      between one and 80 months. The results of the study showed lacrimal
      hyposecretion, the urea lacrimal level being lower than the urea blood level and
      a concordance between the lacrymal and sanguine clearance of the urea. The fundus
      optic examination during the hemodialysis showed a pale aspect of the fundus the
      pallidity being more pronounced before the dialysis with filiforme arterioles,
      apparently without content, significant for decreasing of the circulatory debit.

PMID- 10641084
TI  - [The effects of the drug Mirtilene Sifi on retinal sensitivity in healthy
      subjects].
AB  - Our study involve 15 normal ophthalmological subjects, when take 4 doses a day of
      Mirtelene Sifi for 15 days. The assessment of the efficiency of this drug on
      visual performances was made by comparison of the results (before and after the
      administration) obtained by testing the retinal sensibility (threshold central 30
      2, Humphrey visual field analyzer) and the adaptation ability to dark of the
      retina. The results show the real efficiency of the drug on both the parameters.

PMID- 10641085
TI  - [The ocular hypotensive effect of the combination of latanoprost with
      dorzolamide].
AB  - OBJECTIVE: To analyze the hypotensive effect and ocular tolerance produced by the
      association of a topic carbonic anhidraze inhibitor (dorzolamide--Trusopt) and a
      prostaglandin derivative (latanoprost--Xalatan) in the treatment of the
      hypertensive glaucomas. MATERIAL AND METHOD: The study includes two steps: STEP
      I: A double-blind randomized prospective study which includes 32 eyes with
      primary open angle glaucoma, divided in two groups: group A, in which Trusopt is
      administrated for 7 days and then Xalatan is associated for another 7 days and
      group B, in which the order is reversed: for the first 7 days only Xalatan is
      administrated and then for another 7 days, Trusopt is associated in the
      treatment. The intraocular pressure and the secondary effects were assessed
      daily. STEP II: An open clinical trial that includes 47 eyes with different types
      of glaucomas in which the combination Trusopt + Xalatan was used for 90 days. The
      intraocular pressure and the secondary effects were assessed weekly. RESULTS: In
      the first study (step I) the combination Trusopt + Xalatan induces an additive
      type of ocular hypotensive effect which is not depend by the order of the two
      drugs used in the beginning of the treatment (37.49% for group A and 39.16% for
      group B); In the clinical trial for medium term (step II), the combination
      Trusopt + Xalatan results in a decrease of IOP, which varies between 27.94% and
      37.02% and was stable on the whole period of the study; We observed the following
      secondary effects: conjunctival hyperemia (6 cases), burning sensation (3 cases),
      foreign body sensation (1 case), itching (2 cases) and hazing (1 case).
      CONCLUSIONS: The association Trusopt + Xalatan results in an additive ocular
      hypotensive effect which was stable on the whole period of the study (medium
      term); The ocular tolerance of this combination is good and was not followed by
      the interruption of the treatment.

PMID- 10641086
TI  - [YAG laser capsulotomy in secondary cataract].
AB  - The purpose of the study is to evaluate the modern possibilities of performed by
      laser YAG in secondary cataract. MATERIAL AND METHOD: We performed a study on 200
      eyes with secondary cataract operated in the University Eye Hospital from Cluj
      Napoca during 1991-1997. RESULTS: We had 95 male and 105 female, with age between
      30-90 years old. The capsular fibrosis was present in 86% of the cases. Secondary
      cataract was present in 13.33% of the cases with PC-IOL. Functional results
      showed a visual acuity between 0.7-1 in cases from the 50 cases review after 1
      week after YAG Laser. CONCLUSIONS: 1. Secondary cataract is the most frequent
      complications of PC-IOL which influence the visual acuity. 2. YAG laser
      capsulotomy is a modem, efficient and non-invasive method to solve the secondary
      cataract.

PMID- 10641087
TI  - [Treatment with acyclovir combined with a new Romanian product from plants].
AB  - The paper presents a study of the associated effect of acyclovir and a plant
      extract from Calendula officinalis, Actium lappa and Geranium robertianum. We
      studied a number of 52 patients suffering of herpetic keratitis. Better results
      in resolving complains and faster healing of ulceration were obtained using the
      associated treatment then the usual acyclovir treatment only.

PMID- 10641088
TI  - [Functional recuperation in aphakia with contact lenses].

PMID- 10641090
TI  - [Iridoschisis and glaucoma].
AB  - Three patients with unilateral iridoschisis and glaucoma (1 with bilateral open
      angle glaucoma, 1 with unilateral glaucoma) were observed for 3 to 15 years. In
      none of these patients did iridoschisis progress and a good control of the
      glaucoma was achieved. The mechanism of this rare condition is yet not clear.

PMID- 10641089
TI  - [Drug therapy regimens in diabetic retinopathy].
AB  - Diabetes mellitus constitutes the fourth cause of general mortality and diabetic
      retinopathy, one of the most important cause of blindness. The paper shows the
      necessity and the possibilities of the most precocious treatment of diabetic
      retinopathy, depending of the complex pathogenesis of the disease, as well as the
      necessity of the new clinical and pharmacological trials for certify its effects.

PMID- 10641091
TI  - [Current therapeutic management in retinoblastoma with invasion of the optic
      nerve--a case report].
AB  - INTRODUCTION: Retinoblastoma is the most frequent primitive intraocular tumour in
      children. The extension of retinoblastoma at the optic nerve level gives a dark
      prognosis implying a complex treatment and a long period of supervision.
      OBSERVATION: An eleven-months-old child, female, is taken in the hospital with
      the suspicion of retinoblastoma left eye. The diagnosis was suspected when the
      child was six months old within another ophthalmologic department, but the
      treatment was postponed. Surgical treatment consisted of enucleation with at
      least a 10 mm resection of the optic nerve. The anatomo-pathologic examination
      shows a retinoblastoma with the optic nerve invasion (stage II b 2--after
      Grabowski's classification). Because of the early age of the patient, we are
      obliged to give up applying radiotherapy (technical reasons) and systemic
      chemotherapy is recommended, in six cycles, under very severe clinic and
      paraclinic control. CONCLUSIONS: The extension of retinoblastoma at the optic
      nerve level indicates a severe prognosis with high lethal risk. The correct
      treatment during thus phase implies the association of radiotherapy (40-45 Gy)
      and chemotherapy. After 24 months from the finishing of the treatment the patient
      is in total remission (clinic and paraclinic), but the supervision is going on
      for at least another 3 years. The early enucleation as well as its appliance with
      the removal of a large part of the optic nerve represents a therapeutical manner
      and leads to an important prognosis.

PMID- 10641092
TI  - [Methods for resolving facial carcinomatosis].
AB  - This study presents the case of a patient of 57 years old, hospitalized in the
      Dept. Ophthalm. of the City Hospital of Arad, presenting a face carcinomas with
      the following locations: the inferior left eyelid, the area between the eyebrows,
      the nose pyramid, the right nasogenian area, the right preauricular area. The
      surgical intervention was made in one step the had oncologic free borders, and
      the recovery of the skin and of the mucous membranes were performed through
      plastic surgeries. After one year from the intervention, the patient did not
      present recurrence.

PMID- 10641093
TI  - [Edematous maculopathy-- a too broad diagnostic "umbrella"?].
AB  - In the beginning, the paper presents some theoretical concepts about the
      pathological anatomy and the psychopathology of the macular oedema. The next part
      realizes a systematization of the most important ocular diseases associated with
      macular oedema, sustained by ophthalmoscopical and fluorescein angiography
      images. The final part contains the conclusions.

PMID- 10641094
TI  - [Indirect diode laser treatment and cryotherapy in retinopathy of prematurity].
AB  - Retinopathy of prematurity (ROP) is a major cause of blindness in babies. To
      explore the incidence, treatment and short-term outcome of the disease in
      Romania, a small scale study on 24 preterm infants with gestational age < 32
      weeks and birthweight < 1500 g was undertaken. Gestational age was < 28 weeks in
      66.6% and birthweight was < 1000 g in 70.8% of the children. The average age at
      the first examination with the indirect ophthalmoscope was 31.8 weeks, only two
      children having been seen at less than 6 weeks of age. 66.6% of the babies had
      ROP in various stages with 93.8% of these having bilateral (symmetrical or
      asymmetrical) abnormalities. 37.5% of the babies with ROP were in stage 5. 12.5%
      (2 patients) had bilateral threshold disease: one infant was treated with diode
      laser delivered with the laser indirect ophthalmoscope and the other with
      cryotherapy. In three eyes of these two infants the disease regressed. No major
      short term complications were noted and no second session of treatment was
      necessary. In our patients, the well-recognised correlation between the incidence
      and severity of the disease and gestational age and, to a lesser extent,
      birthweight was confirmed. Lack of equipment was the main reason for the delay in
      diagnosis. The extent of the disease in our patients, in a country where the
      number of surviving preterm babies is expected to increase in the coming years,
      warrants the initiation of a national screening programme for retinopathy of
      prematurity in Romania.

PMID- 10641095
TI  - [The art of teaching].

PMID- 10641096
TI  - [Artificial drainage devices in glaucoma].
AB  - During the last two decades, glaucoma drainage devices (GDD) have been
      increasingly applied to the treatment of complicated glaucoma in which standard
      surgical therapy has failed. Most GDD's consist of a segment of silicone rubber
      attached to a rigid plastic or flexible rubber explant and evolved from the
      Molteno glaucoma implant, on which clinical studies first appeared in 1969. GDD's
      should be reserved for the most difficult cases because of the difficulty of the
      surgical procedure and the complications that can attend their use.

PMID- 10641097
TI  - [Ocular cicatricial pemphigoid].
AB  - The scarry ocular pemphigoid, is an autoimmune disease, belonging to the category
      of the acquired oculo-muco-cutaneous bullous dermatosis. The ocular symptoms,
      during the acute stage are conjunctival bullae, which evolve quickly into
      ulcerous lesions. During the chronic stage, the disease consists of a chronic
      scarry conjunctivitis, accompanied by corneal lesions, ocular dryness syndrome,
      disturbances of the palpebral statics and dynamics. The immunopathological
      mechanism, is represented by a type II hypersensitiveness reaction, in which the
      antigen-antibody-complement interaction, takes place at the level of the
      conjunctival epithelium basement membrane. We have reviewed the structures with
      antigenic potential: the antigen of the bullous pemphigoid-2, 5-6 laminin, beta 4
      integrin. The participation of the immunoregulating cells (eosinocytes, mast
      cells, neutrocytes, macrophages) during the acute stage of the disease, is
      displayed. The key role of the activated fibroblasts, in producing the
      subepithelial fibrosis, during the chronic stage of the scarry ocular pemphigoid,
      is also underlined.

PMID- 10641098
TI  - [The exacerbating role of the vascular factor in the evolution of open-angle
      glaucoma].
AB  - The paper proposes to study the ophthalmic and carotid circulation of patients
      with primary open-angle glaucoma in varied stages of evolution. MATERIAL AND
      METHOD: The lot is formed by 8 patients with primary open-angle glaucoma,
      selected such that one eye to be absolute or quasiabsolute and the congener eye
      in incipient stage. The average (medium) age is 64 years, the patients having
      blood pressure within normal limits. The study of ophthalmic and carotid
      circulation was made by echo-Doppler and the calcul of velocimetric indices.
      RESULTS: The resistance index is increased in concordance with the stage of
      glaucoma. The diastolic flux is the most serious affected. There is no
      parallelism between the blood pressure value and the grade affectation of
      velocimetric indices. CONCLUSIONS: The local vascular diseases, ophthalmic and
      carotid, influence unsatisfactory the evolution of primary open-angle glaucoma.

PMID- 10641099
TI  - [Alpha-2 adrenergic agonists in the treatment of glaucoma].
AB  - The study represent an up-to-date of the role and place of alpha 2-adrenergic
      agonists in glaucoma treatment. The first available alpha 2-agonist, clonidine is
      of historical importance today. Apraclonidine decrease the aqueous humor
      secretion and episcleral venous pressure. It is employed to prevent or blunt the
      acute intraocular pressure rise after ocular laser therapy. It is not recommended
      as long term therapy due to its high incidence of local adverse reactions and
      tachyphylaxis. Brimonidine became the alpha 2-agonist of choice in glaucoma
      chronic treatment, acting by decreasing aqueous humor secretion and increasing
      uveoscleral outflow. It has a lower incidence of the ocular adverse effects
      because of greater alpha 2 selectivity. Brimonidine has neuroprotective effect,
      which is an important feature in the new contexts of glaucoma pathogenesis.
      Brimonidine has hypotensor effect similar with timolol but with a greater
      incidence of adverse local reactions. It has been no effects on cardiopulmonary
      function. Brimonidine would be of value as first-line therapy in patients who
      have contraindications to beta-blockers.

PMID- 10641100
TI  - [The value of the cytological exam in the diagnosis of allergic conjunctivitis].
AB  - Cytologic investigations was performed in four groups of patients: central group
      (10 cares), without pathologic lesions; 12 patients were admitted with allergic
      conjunctivitis (with positive allergy tests, atopic state or clinical manifest
      allergic diseases), 20 cases with bacterial conjunctivitis; 8 cases with mix
      allergic and bacterial conjunctivitis (that hardly respond to therapy). Smears
      from the conjunctivae secretion were air-dried and stained with blue
      polycrometanin Dragan method. Cytologic lesions characteristic for each group of
      patients are described. Our results suggest that cytology from the conjunctivae
      secretion is helpful in the diagnosis of the allergic etiology; also, it
      accurately the allergic components mix conjunctivitis.

PMID- 10641102
TI  - Seven years experience with LASIK for myopia.
AB  - PURPOSE: This paper presents the results of the last seven years with LASIK for
      the treatment of myopia. METHODS: 4170 eyes of 3163 patients with a mean
      preoperative spherical equivalent--9.66 diopters were submitted to LASIK. The
      eyes were divided in three groups according to the preoperative refraction: Group
      A (-5 to 10D), group B (-10 to 16D) and group C (over -16 D). RESULTS: At one
      year the percentage of eyes within +/- 1D of emmetropia was the following: group
      A: 84.4%, group B: 70.8%, and group C: 42.8%. CONCLUSIONS: The method is safe,
      effective, and predictable especially in the range of myopia between -5 and -15 D
      of myopia. Predictability could be further improved by secondary procedures.

PMID- 10641101
TI  - [The cytodiagnosis of eyelid and conjunctival tumors; the cytohistological
      correlations].
AB  - There were studied 24 patients with tumour diseases of palpebral and conjunctival
      type. There were taken samples of conjunctival secretion and touch samples, fixed
      by drying and coloured with the quick blue polychrom tannin BPT-Dragan method.
      Nuclear and cytoplasmatic alterations were highly suggestive for malignity in 21
      of 24 cases (88%). Cytologic results were compared to histopathologic ones. The
      touch samples made intra-surgical after the excision of the tumour, indicate the
      maintaining of the oncological safety borders in 22 of 24 cases through the
      absence of malignancy cells (91.7%). Our results are in the favour of the routine
      application of the cytological method in the early diagnosis, during the
      operation and surveillance follow-up of the patient with malignant conjunctival
      and palpebral tumour.

PMID- 10641103
TI  - [The clinico-evolutionary neuro-ophthalmological aspects in multiple sclerosis].
AB  - The paper presents the dynamic of the more important neuro-ophthalmologic signs
      in 112 patients with multiple sclerosis from the first attack to the second one
      using an interdisciplinary methodology. The existence of ocular signs at the
      first attack as well as the fortuitous association of the signs of the disease
      make doubtfully the utility of defining a neuro-ophthalmologic clinical form of
      the disease. The more significant dominance of the ocular signs at the first
      attack points out the importance of the ophthalmologic examination for the early
      diagnosis of the multiple sclerosis.

PMID- 10641104
TI  - [The posterior chamber artificial crystalline lens implant in the diabetic
      patient].
AB  - The purpose of this study is to display the influence of diabetes on the course
      of the operation, postoperative complications and functional results in operated
      primary cataract. MATERIAL AND METHODS: We performed a study on 72 eyes with
      cataract and diabetes operated in the University Eye Hospital from Cluj-Napoca
      during 1992-1997. RESULTS: From the 72 cases, 58 had diabetes noninsuline
      dependent. Background diabetic retinopathy was present in only 18 cases. In 71
      cases it was performed EEC + IOL-CP and 1 case with open angle glaucoma we made
      the triple procedure (EEC + CP-IOL + trabeculectomy). In 43 cases it was striate
      keratitis, in 30 eyes pigmentary migration and in 4 cases uveitis. As late
      postoperative complication we had 10 secondary cataract and i retinal detachment.
      Functional results were in majority cases between 0.1-0.3. CONCLUSIONS: Diabetes
      do not influence the course of planned extracapsular extraction with PC-IOL,
      which is the best choice for the patients with cataract and diabetes. Functional
      results depends on the presence of diabetic retinopathy.

PMID- 10641105
TI  - [Emergency keratoplasty].
AB  - In some ocular diseases may occur the corneal perforation. This condition
      requires an emergency penetrating keratoplasty. We show in this paper the
      conditions, surgical techniques and the complications in this kind of surgical
      intervention, with examples from our clinical cases.

PMID- 10641106
TI  - [Argon laser trabeculoplasty--the possibility for antiglaucoma treatment].
AB  - The current role of argon laser trabeculoplasty in the treatment of open angle
      glaucoma is still open discussion. To evaluate the effectiveness of ALT we
      performed a study on 36 patients followed for 2 years. We noted a success rate of
      61.11% after 2 years and noticed that the success rate decreased in time. ALT
      should be considered as an intermediate therapy in the management of open angle
      glaucoma, after drug therapy has failed and before filtering surgery is
      performed.

PMID- 10641107
TI  - [Cataract surgery in diabetic patients].
AB  - PURPOSE: Analysis of functional results, per- and postoperative complications
      after cataract surgery in diabetic patients. MATERIAL AND METHOD: Retrospective
      study including 100 non-diabetic patients and 50 patients with type II diabetes,
      with extracapsular extraction and IOL implantation in the postoperator chamber
      followed for 10.3-7.3 months postoperative complications. RESULTS: Postoperative
      visual acuity was lower in diabetic patients (0.317 +/- 0.24) versus non-diabetic
      patients (0.634 +/- 0.30); postoperative visual acuity was lower in diabetic
      patients without retinopathy (0.437 +/- 0.26) versus diabetic patients with non
      proliferative retinopathy (0.348 +/- 0.26) or diabetic proliferative retinopathy
      (0.116 +/- 0.11); the incidence of per- and postoperative complications (early
      and late) is higher in diabetic patients compared with the control group.
      CONCLUSIONS: Cataract surgery in diabetic patients is followed by higher rate of
      per- and postoperative complications. The postoperative functional result is
      dependent, in principal, on the retinal status of the diabetic patient and,
      secondary, on the per- and postoperative complications.

PMID- 10641108
TI  - [Erosive marginal keratitis due to pilocarpine allergy].
AB  - In 3 patients under local pilocarpine medication, corneal marginal infiltration
      and limbic ulcerations were noted that were typical for allergic marginal
      keratitis. A classical allergic conjunctivitis was present in every case. They
      healed after pilocarpine instillations were suspended and local corticosteroids
      together with oral antihistaminic drugs were applied. Marginal allergic erosions
      of the cornea is another form of secondary complication in patients using
      pilocarpine.

PMID- 10641109
TI  - [Difficulties in the diagnosis of glaucoma; the therapeutic implications].
AB  - The glaucomatous disease has, the most of time, an insidious beginning; the
      diagnosis is occasioned by some refraction problems or by a systematic
      ophthalmological examination or a request coming from another physician. As a
      consequence, the diagnosis of glaucoma is not always very easy thing, because, in
      the early stages, the diagnostic criteria rises special problems. Under these
      conditions, the therapeutical attitude will be differentiated from a case to
      another. After these general considerations, the authors will discuss some
      clinical cases, knowing that the diagnosis and the initiation of treatment will
      give rise to some contradictory discussions.

PMID- 10641110
TI  - [The use of antimetabolites in the treatment of glaucoma].
AB  - Many adjunctive therapies have been proposed to increase the success and prevent
      or reduce the incidence of complications associated with filtering surgery.
      Intraoperative or postoperative use of an antimetabolite has found a place as
      adjunctive therapy for eyes with otherwise pour prognosis following glaucoma
      filtering surgery.

PMID- 10641111
TI  - [Immunoglobulins in the tear secretion in cases of herpetic keratitis].
AB  - The goal of this study is to analyse the immunoglobulins of patients with
      herpetic keratitis. Tears have been collected from 36 patients with herpetic
      keratitis (study group) and 20 healthy volunteers (control group). Quantitative
      determination of A, G, M immunoglobulins and secretor IgA has been performed by
      Mancini radial immunodiffusion method. Our study has revealed the following
      results: a decrease in IgM and IgA levels compared with control group (p < 0.01)
      and an increase in secretory IgA compared with fellow eye (p < 0.05) in patients
      with herpetic keratitis of the first manifestation; eyes with recidivant herpetic
      keratitis showed higher level of IgA than the control group (p < 0.01) and a
      higher level of IgG than the first disease manifestation group (p < 0.05); the
      IgA level in the healthy eye of the patients with herpetic keratitis appeared
      significantly lower than in the control group (p < 0.001).

PMID- 10641112
TI  - [Phlyctenular keratoconjunctivitis and lymph node tuberculosis].
AB  - It is presented 28 cases of tuberculous keratoconjunctivitis from which 13 cases
      appears between 4-13 years at children with primary tuberculosis. All patients
      have a positive tuberculin skin test, a family or personal history of
      tuberculosis. Many of them have perihilar or cervical adenopathy and radiological
      evidence of a healed pulmonary tuberculous lesion. We report a case of
      tuberculous adenopathy with histopathological examine and tuberculous adenopathy
      with histopathological examine and tuberculous keratoconjunctivitis. Anti
      tuberculous treatment was with isoniazid, pyrazinamide, rifampicin in cases with
      primary tuberculosis. The rest of patients was treated with topical medicine.

PMID- 10641113
TI  - [Graves' ophthalmopathy--a prospective clinical study].
AB  - Graves' disease is an autoimmune disorder, progressive and with a variable
      evolution. In 10-25% of cases, thyroid ophthalmopathy (or dysthyroid
      ophthalmopathy) occurs in the absence of both clinical and biochemical evidence
      of thyroid dysfunction. In patients with Graves' disease, ocular modification may
      precede, coincide with or follow of Graves' disease. Dysthyroid ophthalmopathy
      has in 85% of cases bilateral proptosis more than a half in unilateral proptosis.

PMID- 10641114
TI  - [Cytological changes in patients with diabetes mellitus and corneal ulcer].
AB  - There were studied 11 diabetic patients, insulin dependents, from 4 were with
      juvenile diabetes mellitus. These were hospitalized in the Dept. Ophthalm. of the
      City Hospital of Arad, during 1996-1998, admitted with the diagnosis of corneal
      ulcer. There were made samples of the gathered secretion from the level of
      conjunctiva and of the grataj material, gathered at the level of the edges of the
      corneal ulcer. All samples were stained with the BPT-Dragan method. There are
      described cytologic alterations, insisting on details that indicate the severity
      of the corneal disease. There are taken into consideration cytologic aspects in
      relationship with the clinical outcome of the disease, pointing out the cellular
      alterations which announce a nonfavourable prognosis. Cytologic results can
      improve the diagnosis and they are involved in therapeutic schedule.

PMID- 10641115
TI  - [The epidemiology of diabetic retinopathy].
AB  - The paper presents a statistic study of the incidence of the diabetic retinopathy
      in patients who have been recently taken into evidence in the Antidiabetic Centre
      Timisoara. These patients were diagnosed between 1994 and 1997. The incidence of
      the diabetic retinopathy in Romania is more significant than in other countries
      like USA, France, UK, Finland. The prevalence of the diabetic retinopathy is
      significant too being placed around the value of 0.02-0.03%. When diabetes
      mellitus was found, the incidence of nonproliferative diabetic retinopathy was
      placed around 8% while the incidence of proliferative diabetic retinopathy was
      placed around 1%. The diabetic retinopathy is more often diagnosed in patients
      insulin dependent. After 20 years of diabetes mellitus evolution, 80% of the
      insulin dependent patients and 60% of the noninsulin dependent patients present
      diabetic retinopathy with a more or less important impact on the visual function.

PMID- 10641116
TI  - [Surgical treatment in strabismus with a vertical component].
AB  - In the paper we studied 87 patients with vertical or combined deviations treated
      in Eye Clinic from Cluj-Napoca between 1994-1998. The most patients show vertical
      deviation due to inferior muscle overaction (70 patients). 17 patients had a
      vertical deviation due to another causes (superior oblique paresis, III-nerve
      paresis and dissociated vertical deviations). We treated vertical deviation due
      to superior oblique muscle overaction only when was an important deviation in the
      primary position of gate. In superior muscle paresis we did a superior oblique
      muscle resection or weaken of inferior oblique muscle secondary overacting. In
      III-nerve paresis with contralateral superior rectus muscle overaction we did
      recession of this muscle. The results are favourable: the deviation disappear in
      the primary position of the gaze and decrease or disappear in the lateral gaze.

PMID- 10641117
TI  - Intraoperative complications in vitreoretinal surgery.
AB  - Pars plana vitrectomy is a well developed and widespread used surgical technique
      with several instruments and special tools for selected vitreoretinal cases.
      Knowledge of complications during the various steps of the surgical procedure
      make easier to avoid them. Most important is first to collect experiences with
      simple cases and to get accustomed to the otherwise special surgical technique
      that needs good cooperation of the surgeons two hands, two feet and needs steady
      attention on the tips of the intraocular instruments. However, after certain
      experience complications will occur because of the complicated cases of
      proliferative diabetic retinopathy or other vitreoretinal diseases.

PMID- 10641118
TI  - [Difficulties in the treatment of secondary cataracts with the YAG-Nd laser].
AB  - The paper presents a clinical study performed about 402 patients with secondary
      cataract treated between 1989-1994 with YAG-Nd Laser capsulotomy in the
      University Eye Hospital from Tg. Mures. We described the technique used, taking
      into consideration the recovery obtained, the early and belated complications and
      the secondary effects.

PMID- 10641119
TI  - [Progressive lenses--a new possibility in sight for presbyopes].
AB  - Technological advances in the manufacture of the progressive lenses have made an
      effective and comfortable alternative in presbyopic correction. Nevertheless the
      small percentage of those patients are knowing and wearing them. The paper shown
      our clinical experience about prescribe Varilux progressive lenses at the 40
      presbyopic patients. At the same time we try demonstrate the visual problems due
      that lenses, the difficult adaptation to this kind of spectacles and the degree
      of satisfaction of the subjects.

PMID- 10641120
TI  - [The specialist contribution--cataract].
AB  - The degenerative processes of the lens, combined with the deficiency lacrimal
      secretion syndrome duct to the old age and high sensitivity, often need the use
      of drops containing potassium and iodum, drops Known as anticataractogen drugs.
      Independent of the patient psychological balance status the decrease of visual
      acuity caused by the decrease of visual acuity caused by the senile cataracts,
      could be late with a time factor of 1.8-2.5 studied on a selected group of
      patients. We can conclusion that some forms of senile cataracts are associated
      with the deficiency of lacrimal substances which are essential in the lens
      metabolism. With the progression of time there isn't important improvement
      neither in congenital cataract nor in the traumatic cataract which progresses
      fast to opacification caused by direct or indirect lesion of the lens. The
      patients presenting senile cataracts at incipient stage or advanced are good
      responsive at the anticataractogen drugs. For a therapeutic successful is
      important to begin the treatment as early is possible, and to do this with
      regularity.

PMID- 10641121
TI  - [The diode laser and diabetic maculopathy].
AB  - PURPOSE: Revealing the diode laser therapy's results in the diabetic macular
      edema. METHOD: The diabetic retinopathies in which macular photocoagulation has
      been performed (between Sept. 1996-Sept. 1998) are analyzed. The cases were
      selected according the ophthalmoscopy appearance: clinical significant macular
      edema. The technical features and the clinical and functional parameters'
      evolution after the treatment are described. RESULTS: Visual acuity's evolution
      has been stationary in 80% of cases. No complication during or after the macular
      photocoagulation with the diode laser has occurred.

PMID- 10641122
TI  - [An extensive left subperiosteal frontotemporal orbital abscess and left
      suppurative pansinusitis with an odontogenic origin].
AB  - A 28-years-old patient with pansinusitis and orbital abscesses to odontogenic
      infection origin were present. Treatment, complication and evolution are
      discussed.

PMID- 10641123
TI  - [Painful ophthalmoplegia--a clinical case].
AB  - We present the case of the patient S.M., female, 32 years old, who came in our
      eye clinic for left painful ophthalmoplegia. The onset of the clinical
      manifestations was a year and half ago, with the decrease of visual acuity at
      left eye, left partial ophthalmoplegia (partial lesion of the left oculomotor
      nerve) and secondary left trigeminal neuralgia. The paraclinical investigations
      excluded the systemic and locoregional diseases. CT exams, the left internal
      carotid angiography and the surgical intervention at the Neurosurgery Clinic in
      Timisoara revealed a left juxtasella tumor at the base skull, located extradural,
      which capsule invade the left nerve oculomotor. We conclusion that the painful
      ophthalmoplegia are complex clinical syndromes, with a different etiopathogenesis
      (inflammatory, tumoral, vascular malformations: aneurysm etc.) and their
      diagnosis and treatment need a good interdisciplinary collaboration:
      ophthalmologist-neurologist-neurosurgeon-endocrinologist-paraclinical exams.

PMID- 10641124
TI  - [Recurrent unilateral inflammatory exophthalmos].
AB  - The issue discusses the diagnosis difficulties concerning the case of 58-years
      old woman who was watched for a recurrent exophthalmos after a mild conjunctival
      trauma. The debut was orbital cellulite appearance, complicated by a nonaxial
      exophthalmos due to a dacryoadenitis. The exophthalmos is axial in the other two
      recurrences. All exophthalmic episodes progressed with inflammatory features
      associated with optic neuritis and oculomotor nerves implication without any
      neurological signs. The paraclinical tests (ECHO, orbital radiography, CAT) find
      inflammation of orbital elements: extrinsic muscles and lacrimal gland.
      Biochemical tests showed minimal inflammatory changes without be able to provide
      the positive diagnosis. Initial combined therapy (antibiotics and steroids), then
      steroid monotherapy had favorable response.

PMID- 10641125
TI  - [Ocular manifestations in Recklinghausen's disease].
AB  - Four cases of Recklinghausen disease are presented with different clinical
      manifestations. The diagnosis in each case was established on NIH Consensus
      Statement criteria. The last case is a controversial one concerning the type of
      neurofibromatosis.

PMID- 10641126
TI  - [Hypotony after trabeculectomy in a case of pigmentary glaucoma].
AB  - In the following we present the evolution of a case of pigmentary glaucoma and
      the efficient solution of rare complication in the filtering surgery--hypotonia.
      We also made some modern pathogenetic considerations about the appearance of
      ocular hypertension.

PMID- 10641127
TI  - [The use of excimer lasers in ophthalmology--an update and the outlook].
AB  - This article presents the actual therapy with excimer lasers. These lasers help
      the ophthalmologist in the healing of some little imperfections of the nature, as
      refractive errors. Also we can observe the great potential of the excimer lasers.

PMID- 10641128
TI  - Role of nutrition in toxic injury.
AB  - The importance of nutrition in protecting the living organism against the
      potentially lethal effects of reactive oxygen species and toxic environmental
      chemicals has recently been realized. This new perspective has prompted re
      evaluation of the food constituents of human diet from the point of view of their
      nutritional adequacy, deficiency and toxicity. The biological antioxidant defense
      system is an integrated array of enzymes, antioxidants and free radical
      scavengers. These include glutathione reductase, glutathione-s-transferase,
      glutathione peroxidase, phospholipid hydroperoxide glutathione peroxidase,
      superoxide dismutase (SOD) and catalase, together with the antioxidant vitamins
      C, E and A. The individual components of this system get utilized in various
      physiological process and for chemoprotection and therefore require replenishment
      from the diet. Other components of the diet like carbohydrates, proteins and
      lipids are important for maintaining the levels of various enzymes required in
      body's defense system providing protection against carcinogens. However, the
      emerging newer concepts focus on the role of trace elements and other dietary
      components in antioxidant defense and detoxification mechanisms. Trace elements
      like Iron, zinc magnesium, selenium, copper, and manganese are some of the
      elements involved in antioxidant defense mechanisms. Inadequate intake of these
      nutrients has been associated with ischemic heart disease, arthritis, stroke and
      cancer, where pathogenic role of free radicals is suggested. Further the
      importance of diet in the prevention of chemical induced toxicity can not be
      undetermined. Recent reports on the role of bioflavonoids as antioxidents and
      their potential use to reduce the risks of coronary heart disease and cancer in
      human beings have opened a new arena for future research. Induction of the
      cytochrome P450 isoenzymes by food pyrolysis, mutagens, alcohol and fasting, on
      the other hand is reported to contribute to chemical toxicity and
      carcinogenecity. Certain chemicals moieties in the food are mutagenic and
      carcinogenic.

PMID- 10641129
TI  - Experimental methods for evaluation of psychotropic agents in rodents: II
      Antidepressants.
AB  - Rodent models of clinical depression are extensively used for the evaluation of
      putative antidepressants. In the present review, the available experimental
      methods which can be utilized by most laboratories involved in preclinical
      screening of antidepressants, have been discussed. The methods have been
      categorized on the basis of induction of the depressive state or on the
      assumption that monoamine deficiency leads to depression. These methods have been
      critically validated in terms of efficacy of standard antidepressants in these
      tests and, in some cases, by the neurochemical basis of depression, namely, the
      deficient monoaminergic theory of clinical depression.

PMID- 10641130
TI  - Pharmacology of rosemary (Rosmarinus officinalis Linn.) and its therapeutic
      potentials.
AB  - The use of plants is as old as the mankind. Natural products are cheap and
      claimed to be safe. They are also suitable raw material for production of new
      synthetic agents. Rosemary (Rosmarinus officinalis Linn.) is a common household
      plant grown in many parts of the world. It is used for flavouring food, a
      beverage drink, as well as in cosmetics; in folk.medicine it is used as an
      antispasmodic in renal colic and dysmenorrhoea, in relieving respiratory
      disorders and to stimulate growth of hair. Extract of rosemary relaxes smooth
      muscles of trachea and intestine, and has choleretic, hepatoprotective and
      antitumerogenic activity. The most important constituents of rosemary are caffeic
      acid and its derivatives such as rosmarinic acid. These compounds have
      antioxidant effect. The phenolic compound, rosmarinic acid, obtains one of its
      phenolic rings from phenylalanine via caffeic acid and the other from tyrosine
      via dihydroxyphenyl-lactic acid. Relatively large-scale production of rosmarinic
      acid can be obtained from the cell culture of Coleus blumei Benth when supplied
      exogenously with phenylalanine and tyrosine. Rosmarinic acid is well absorbed
      from gastrointestinal tract and from the skin. It increases the production of
      prostaglandin E2 and reduces the production of leukotriene B4 in human
      polymorphonuclear leucocytes, and inhibits the complement system. It is concluded
      that rosemary and its constituents especially caffeic acid derivatives such as
      rosmarinic acid have a therapeutic potential in treatment or prevention of
      bronchial asthma, spasmogenic disorders, peptic ulcer, inflammatory diseases,
      hepatotoxicity, atherosclerosis, ischaemic heart disease, cataract, cancer and
      poor sperm motility.

PMID- 10641131
TI  - Cardioprotective effect of magnesium chloride in experimental acute myocardial
      infarction.
AB  - Cardioprotective role of intravenous administration of magnesium chloride was
      evaluated in rabbits by biochemical and histopathological parameters. Myocardial
      damage was induced by injecting (i.v.) isoprenaline 1, 2.5, 5 and 7.5 mg/kg body
      weight of animal. There was a dose dependent increase in the activity of cardiac
      enzyme creatinine kinase CK (C Max). Maximal elevation of CK (C Max) was observed
      with 2.5 mg isoprenaline. The mean T-max (mean of the time duration in hr at
      which maximum creatinine kinase activity of individual rabbit was observed in a
      group) shifted early, significantly with 2.5, 5 and 7.5 mg isoprenaline compared
      to control group. Histopathologically, myocardial damage was quite significant in
      2.5 mg isoprenaline subgroup of animals. A mortality of 29% was observed in
      animals injected with 5 and 7.5 mg isoprenaline, whereas all animals subjected
      with 1 and 2.5 mg isoprenaline were alive for 72 hr. Considering the data on
      serial determination of cardiac enzyme CK and histopathological changes, 2.5 mg
      isoprenaline was chosen as standard dose to study efficacy of cardioprotection by
      gold standard verapamil and magnesium chloride. Verapamil (5 microM) injected
      prior to 2.5 mg isoprenaline administration revealed significant reduction of CK
      (C Max) activity (P < 0.05) compared to animals infused with isoprenaline alone.
      T-max value did not show any alteration in both the groups. Histopathological
      findings showed no areas of necrosis and cellular infiltrates in animals primed
      with 2.5 mg isoprenaline following verapamil. Highly significant reduction in CK
      (C-max) activity was observed in animals administered with 40 mg magnesium
      chloride prior to isoprenaline compared to animals treated with isoprenaline
      alone (P < 0.001). In addition to this, significant delay in T-max of CK activity
      was observed in group treated with 40 mg magnesium chloride and isoprenaline
      compared to group treated with only isoprenaline (P < 0.01). The study clearly
      highlighted and confirmed the valuable role of magnesium chloride as
      cardioprotective agent.

PMID- 10641132
TI  - Effect of insulin-like growth factor-1 on steroidogenesis in cultured carp
      ovarian follicles: interactions with estradiol.
AB  - The biological action of insulin like growth factor-1 (IGF-1) on follicular
      steroidogenesis during follicular development in common carp was examined.
      Studies were carried out by culturing small (1-2 mm diam.) and large (> 2 mm
      diam.) follicles. IGF-1 (0.3-100 ng/ml) had no effect on progesterone
      accumulation or aromatase activity during 48 hr culture of small follicles.
      Progesterone accumulation by large follicles was also unaffected by IGF-1 over
      the same period, although aromatase activity was stimulated in a dose dependent
      manner (8-fold increase over basal levels with a maximum stimulatory dose of 30
      ng IGF-1/ml). In contrast, small and large follicles responded to IGF-1 in terms
      of both progesterone accumulation and aromatase activity after longer periods of
      culture (4 days for progesterone and 6 days for aromatase). Concurrent treatment
      of small follicles with estradiol (10(-7) M) enhanced the action of IGF-1 on both
      indices of steroidogenesis and advanced the time at which IGF-1 stimulated
      activity was first detectable. The effect of estradiol on follicular IGF-1
      responsiveness were independent of cell number. In summary, these results
      demonstrate varied actions of IGF-1 carp ovarian follicular steroidogenesis in
      vitro. The results indicate that carp follicles acquire responsiveness to IGF-1
      in terms of aromatase activity during follicular development in vivo and that
      estradiol can induce the response in vitro. The results also suggest that
      estrogen and progesterone biosynthesis by cultured carp ovarian follicles is
      differentially regulated by IGF-1. Together, these results provide new insights
      into the biological actions of IGF-1 in fish ovary.

PMID- 10641133
TI  - CNS activity of Vitex negundo Linn. in mice.
AB  - Methanolic extract (ME) of the leaves of V. negundo potentiated significantly the
      sleeping time induced by pentobarbitone sodium, diazepam and chlorpromazine in
      mice. ME possesses analgesic properties and potentiated analgesia induced by
      morphine and pethidine. ME also showed significant protection against strychnine
      and leptazole induced convulsions. The results suggest that ME exhibits CNS
      depressant activity in a dose dependent manner.

PMID- 10641134
TI  - Hepatic fibrogenesis using chronic arsenic ingestion: studies in a murine model.
AB  - Chronic oral arsenic (As) ingestion has been alleged to cause hepatic fibrosis,
      non-cirrhotic portal fibrosis and cirrhosis of the liver. The present study was
      aimed to investigate if hepatic fibrogenesis and non-cirrhotic portal fibrosis
      (NCPF) is caused by arsenic. A significant increase in the hepatic protein and
      collagen was seen compared with controls; hepatic 4-hydroxyproline levels,
      indicative of fibrogenesis, were increased 4-14 folds with different dosages of
      arsenic compared to the controls. Hepatocellular necrosis and inflammation were
      negligible to mild in all the groups. None of the animals developed significant
      splenomegaly or features of non-cirrhotic portal hypertension. The results
      suggest that (i) prolonged oral arsenic ingestion in mice leads to significant
      hepatic fibrogenesis and collagen synthesis with minimal hepato-cellular injury;
      (ii) arsenic ingestion alone is unlikely to cause non-cirrhotic portal fibrosis
      or cirrhosis of liver. This murine model of arsenic feeding could be used for the
      evaluation of new antifibrotic agents for the liver.

PMID- 10641135
TI  - Phenylalanine transport in Aspergillus nidulans: demonstration of role of
      phenylalanine binding proteins.
AB  - Crude shock proteins extracted by two stage osmotic shock were further purified
      by affinity chromatography to obtain ligand (phenylalanine) specific binding
      protein (phebip) a component of phenylalanine (phe) transport system from wild
      type and a phe transport mutant fpaD11 of Aspergillus nidulans. A new eluent 0.1
      M Tris-HCl containing 1.5 N NaCl and 0.5 N Na2CO3, pH 8 was used during the
      investigation. The elution profile of mutant phebip exhibited one simple and two
      compound peaks instead of three simple ones as exhibited by the wild type phebip.
      SDS-PAGE profile of mutant phebip showed faster electrophoretic mobility than
      that of wild type one. It is therefore evident that the mutant phebip has reduced
      molecular mass (M(r)) due to deletion of a segment that somehow has bearing on
      the binding capacity of the active site of phebip. The resultant erosion in the
      binding capacity of the mutant phebip is in turn responsible for its incapability
      to stimulate transport of ligand across the plasma membrane.

PMID- 10641136
TI  - Comparative evaluation of sensitivity of RNA-polyacrylamide gel electrophoresis
      and dot immunobinding assay for detection of bluetongue virus in cell culture.
AB  - Bluetongue virus serotype 1 (Avikanagar isolate) was grown in BHK-21 cell line
      and titrated. The titre of the virus in BHK-21 cell line was 10(6) TCID50/ml. RNA
      polyacrylamide gel electrophoresis (RNA-PAGE) and dot immunobinding assay (DIA)
      were performed on 10-fold serial dilutions of the sonicated cell culture
      material. The results indicated that the minimum limit of detection of the virus
      by RNA-PAGE and DIA was 10(5) TCID50/ml.

PMID- 10641137
TI  - Spindle damaging effect of salbutamol sulphate on bone marrow cells of mice.
AB  - In vivo assessment and identification of aneuploidy are important phases of
      genotoxicity evaluation. Considerable effort has been devoted to assess the
      utility of the existing bioassays and to develop simpler techniques for
      identifying environmental aneugens. Salbutamol sulphate--an antiasthmatic drug
      was tested for its spindle damaging effects in bone marrow cells of mice using an
      in vivo technique, for the evaluation of mitotic index, C-mitotic effects,
      anaphase reduction and hyperdiploidy. Doses of 0.12, 0.24, 1.2, 2.4, mg/kg body
      weight were dissolved in bidistilled water and administered intraperitoneally to
      the mice. Colchicine was taken as positive control for its known aneuploidy
      inducing effects. The drug showed positive C-mitotic effects accompanied with
      increases of mitotic index and decreased frequencies of anaphase in higher doses.
      Significant levels of hypodiploidy also noted at higher doses. The preliminary
      results indicated that Salbutamol is capable of inducing C-mitotic effects in
      mouse bone marrow cells, which is suggestive of possible induction of aneuploidy.

PMID- 10641138
TI  - Cytotoxic effect of 2,3-disubstituted chromanones in human cancer cell lines.
AB  - Four different synthetic compounds [3-aryl-2-(3-pyridyl)chromanones] were
      prepared and screened for cytotoxicity against a panel of 29 human cancer cell
      lines in five different concentrations separately. All compounds displayed
      cytotoxicity against cancer cell lines and one of them possessed cell type
      selectivity also.

PMID- 10641139
TI  - Effect of methyl parathion formulation on estrous cycle and reproductive
      performance in albino rats.
AB  - The animals were injected intraperitoneally with graded doses of methyl parathion
      at 1.5 to 3 mg/kg body weight for 15 days from the day of estrus. Results
      indicated that the methyl parathion treatment showed irregular estrous cycles,
      affect the duration of each estrous cycle, proestrus and diestrus were
      significantly changed in 2.5 and 3 mg treatment groups. But there was no
      significant change in the number and duration of each estrous cycle, duration of
      proestrus and diestrus in 1.5 and 2 mg methyl parathion treatment groups.
      However, there was a significant decrease in the duration of estrus, while there
      was no significant change in the duration of metestrus in all methyl parathion
      treatment rats when compared with those of the corresponding parameters of the
      control. There was no significant effect on number of live pups on day 1 and 5
      except in 3 mg methyl parathion treatment group where it was significantly
      decreased. There was no significant change in reproductive indices like
      pregnancy, parturition, live birth and viability in all the methyl parathion
      treatment rats except the viability index in the highest dose.

PMID- 10641140
TI  - Influence of gonadotropins on adrenalectomy induced changes in the testis of
      albino mouse.
AB  - Effects of adrenalectomy and administration of gonadotropins on cell counts of
      different cell types of spermatogenesis and morphology of the Leydig cells were
      studied in 30 day old mice. Adrenalectomy (duration, 12 days; age at autopsy 42
      days) caused a significant decrease in the diameters of seminiferous tubules and
      Leydig cell nucleus and, cell counts of intermediate spermatogonia, round and
      elongated spermatids. Administration of FSH (75 micrograms/0.1 ml saline) + LH
      (25 micrograms/0.1 ml saline) everyday for 12 days to adrenalectomized mice
      restored testicular activity as revealed by significant increases in mean
      diameter of the Leydig cell nuclei and cell counts of intermediate spermatogonia
      and elongated spermatids over those of adrenalectomized mice. The results
      indicate that (i) testis of adrenalectomized mouse responds to gonadotropin
      treatment and (ii) impairment in gonadotropin secretion is possibly a major
      factor in inducing testicular regression following adrenalectomy.

PMID- 10641141
TI  - Superoxide dismutase, catalase and glutathione peroxidase activities in the brain
      of streptozotocin induced diabetic rats.
AB  - Brain antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT) and
      glutathione peroxidase (GPX) levels were studied in the brains of early diabetic
      (72 hr) and long term diabetic (one month) rats. Diabetes was induced by
      injecting streptozotocin (50 mg/kg, i.p.) in citrate buffer. One group of
      diabetic rats was treated with insulin (1U/day/animal). The results indicate that
      early diabetic rats exhibit increased SOD and CAT activities with no alteration
      in the GPX activity. On the contrary, increased CAT decreased GPX activities with
      no alteration in the SOD activity, was noted in the long-term Diabetic rats.
      Insulin treatment reversed these alterations in both the groups. It can be
      concluded that, in diabetic condition antioxidant enzyme levels are elevated and
      insulin treatment attenuated these changes. Hence, diabetes mellitus, if left
      untreated, may initiate degenerative processes and other CNS complications due to
      accumulation of oxidative free radicals.

PMID- 10641142
TI  - Effect of graded doses of nicotine on ovarian and uterine activities in albino
      rats.
AB  - Nicotine (2 and 4 mg/kg body weight, i.p.) administered to albino rats for 20
      days decreased the number of healthy follicles and increased the number of
      regressing follicles in the ovary. Uterine weight, its diameter, thickness of
      myometrium and endometrium and height of epithelium were reduced. Increase in the
      ovarian cholesterol level and decrease in glycogen content in nicotine treated
      rats indicate the inhibition brought in the steroidogenesis which is dependent on
      pituitary gonadotrophins. Decreased protein content of the ovary and uterus may
      be due to their retarded growth. Reduced number of estrous cycle with prolonged
      metaestrus and diestrus also supports the decreased estrogen synthesis
      responsible for cornification of vaginal smear in nicotine treated rats.

PMID- 10641143
TI  - Effect of helium-neon laser on wound healing.
AB  - To estimate the biostimulatory effects of low intensity laser radiation on
      healing of skin wounds, two linear skin wounds were produced on either side of
      dorsal midline in rats and immediately sutured. Wounds on the left side were
      irradiated daily with helium neon laser at 4 Joules/sq.cm for 5 min., while those
      on right side were not exposed and served as controls. The mean time required for
      complete closure in control group was 7 days while irradiated test wounds took
      only 5 days to heal (P < 0.01). The mean breaking strength, as measured by the
      ability of the wound to resist rupture against force, was found to be
      significantly increased in the test group. Early epithelization, increased
      fibroblastic reaction, leucocytic infiltration and neovascularization were seen
      in the laser irradiated wounds. The results establish the biostimulatory effects
      of low intensity laser radiation on healing of skin wounds.

PMID- 10641144
TI  - Release of iron from haemoglobin--a possible source of free radicals in diabetes
      mellitus.
AB  - Increased blood glucose in diabetes mellitus stimulates nonenzymatic
      glycosylation of several proteins, including haemoglobin. Although iron is
      tightly bound to haemoglobin, it is liberated under specific circumstances
      yielding free reactive iron. Studies with purified haemoglobin from normal
      individuals and diabetic patients revealed that concentration of free iron was
      significantly higher in the latter cases and increased progressively with extent
      of the disease. In vitro glycosylation of haemoglobin also led to increase in
      release of iron from protein. This increase in free iron, acting as a Fenton
      reagent, might produce free radicals, which, in turn might be causing oxidative
      stress in diabetes.

PMID- 10641145
TI  - Effect of antidiabetic compounds on glyoxalase I activity in experimental
      diabetic rat liver.
AB  - The activity of glyoxalase I from the soluble fraction of diabetic rat liver was
      found to decrease as compared to the control. Sodium orthovanadate in drinking
      water and Trigonella foenum graecum seed powder when administered to these
      diabetic animals were found to reverse the activity of glyoxalase I to control
      values. A combination of the above two antidiabetic compounds showed a better
      reversal. Vanadate and Trigonella seed powder treatment separately to diabetic
      rats also normalized hyperglycemia together with glyoxalase I activity. A
      combination of vanadate and Trigonella seed powder also restored the other
      general parameters of the diabetic animals.

PMID- 10641146
TI  - Modulation of some gluconeogenic enzyme activities in diabetic rat liver and
      kidney: effect of antidiabetic compounds.
AB  - The effects of insulin, sodium orthovanadate and a hypoglycemic plant material,
      Trigonella foenum graecum (fenugreek) seed powder were studied on the activities
      of glucose-6-phosphatase and fructose-1,6-bisphosphatase in diabetic liver and
      kidney. The significantly increased activities of the two enzymes during diabetes
      in liver and kidney were found to be lowered to almost control values by the use
      of the antidiabetic compounds. Diabetic liver exhibited a much greater increase
      in the activities of the two enzymes than diabetic kidney. The highest percentage
      of reversal to normal values was seen using the combination of vanadate and
      Trigonella seed powder. The lowered rate of growth of the animals as well as the
      increased blood sugar were reversed almost to the control levels by the
      Trigonella seed powder and vanadate treatment. The inclusion of the Trigonella
      seed powder overcame the toxicity of vanadium encountered when it was given alone
      as insulin mimetic agent. Much lower levels of vanadate were needed when it was
      given in combination with Trigonella seed powder. Their combined effects were
      better at restoring the above parameters than those induced by insulin
      administration.

PMID- 10641147
TI  - Effects of vanadate, insulin and fenugreek (Trigonella foenum graecum) on
      creatine kinase levels in tissues of diabetic rat.
AB  - The in vivo effects of insulin, and other insulino mimetic agents like vanadate
      and fenugreek (T. foenum graecum) were followed on the changes in the activities
      of creatine kinase in heart, skeletal muscle and liver of experimental diabetic
      rats. As compared to control rats, creatine kinase activities were found to
      decrease significantly in the tissues during experimental diabetes. All the
      antidiabetic compounds used namely, insulin, vanadate and Fenugreek seed powder
      normalised the decreased activities to almost control values. The effects of
      insulin and vanadate were comparable in restoring normoglycemia and the creatine
      kinase activities.

PMID- 10641148
TI  - Immunization of cattle against Hyalomma anatolicum anatolicum using larval
      antigens.
AB  - Development of immunity in cross-bred (Bos taurus x Bos indicus) calves against
      Hyalomma anatolicum anatolicum, vector of bovine tropical theileriosis, was
      studied using larval antigen (LS) in Freund's complete adjuvant (FCA). Calves
      immunized with LS + FCA showed significant rejection of larvae (57.25 +/- 6.8)
      and nymphs (45.75 +/- 5.16). Abnormally fed larvae (11.4 +/- 0.8) and nymphs
      (8.25 +/- 1.2) were also recovered from immunized calves. This abnormal feeding
      may possibly be attributed to their inability to gain access to the blood vessels
      owing to the host immunological reactions. Consequently, feeding of extravascular
      fluid leads to white colour of fed ticks. Sera from all immunized calves after a
      week of immunization were positive for anti-LS antibodies in ELISA. The
      investigation indicates that LS in FCA enhanced anti-tick immunity.

PMID- 10641149
TI  - Immunohistochemical co-expression of c-erbb-2/Neu oncoprotein, altered tumour
      suppressor (p53) protein, EGF-R and EMA in histological subtypes of infiltrating
      duct carcinoma of the breast.
AB  - Carcinoma of the breast has an unpredictable biological behaviour. Several
      oncogenes have been implicated in the progression of breast cancer.
      Immunohistochemical staining of c-erbB-2 (Neu) oncoprotein and mutant p53 protein
      on 45 cases of infiltrating duct carcinoma (IDC) of the breast revealed 33%
      membrane positivity of c-erbB-2 oncoprotein, 46% nuclear positivity of mutated
      p53 protein, 33% and 84% membrane positivity of EGF-R and EMA respectively.
      Staining profile of c-erb-B2 oncoprotein in various histological subtypes of IDC
      of the breast indicated a high positivity rate in comedo followed by NOS and
      cibriform subtype. Similarly, high incidence of immunopositivity of mutated p53
      protein was observed in comedo and cibriform subtypes while papillary carcinoma
      were found exclusively positive for mutated p53 protein. Interestingly, tubular
      subtype of IDC was not positive for c-erbB-2 oncoprotein as well as p53 mutant
      protein. Further, comedo and cibriform subtypes of IDC revealed 'high grade'
      histological features of tumour of the breast with high mitotic count, presence
      of marked pleomorphism and multinucleation thus, reflecting a positive
      relationship with overexpression of c-erbB-2 (Neu) oncoprotein as well as mutant
      p53 protein. The results on immunoexpression of c-erbB-2 oncoprotein and mutated
      p53 protein in various histological subtypes of IDC of the breast demonstrated c
      erbB-2 status as an important predictor and also indicated that oncogene product
      may be involved in growth factor response pathway.

PMID- 10641150
TI  - Effect of sodium valproate and flunarizine administered alone and in combination
      on pentylenetetrazole model of absence seizures in rat.
AB  - Sodium valproate (VPA) and flunarizine (FLU) administered individually and
      together were examined for their effects on behavioural, and EEG changes in the
      pentylenetetrazole (PTZ) induced rat model of absence seizures. PTZ, 20 mg/kg,
      i.p., produced behavioural staring and immobility with concomitant, repetitive 7
      to 9 Hz spike/wave discharges (SWDs) in EEG, monitored continuously for 1 hr and
      thereafter, intermittently for 4 hr, post-vehicle/drug. The number and duration
      (sec) of SWDs/hr were the parameters used for evaluation of vehicle vs. drug
      effects in normal as well as rats made epileptogenic by repeated cortical
      stimulation. VPA, 200 mg/kg, i.p., produced a significant reduction in the number
      and duration of SWDs at 20 min only in epileptogenic rats, declining to non
      significant levels at 60 min, whereas FLU, 10 mg/kg i.p. had no effect on either
      parameter. The combination of VPA and FLU produced a highly significant reduction
      of the number and duration of SWDs/h for 60 min in normal and epileptogenic rats.
      The results provide evidence for a synergistic effect of VPA and FLU in
      experimental absence seizures and possible potential benefit in pharmaco
      resistant seizures.

PMID- 10641151
TI  - Involvement of dopamine D2 and 5-HT1A receptors in roxindole-induced
      antinociception.
AB  - Roxindole, a DA D2 receptor agonist (2-16 mg/kg) produced dose-dependent increase
      in percentage antinociception. The effect which was blocked by DA D2 antagonist (
      )sulpiride (50 mg/kg) and 5-HT1A receptor antagonist (-) pindolol (5 mg/kg).
      Roxindole (4 and 8 mg/kg) reversed both naloxone (20 mg/kg)-induced hyperalgesia
      and reserpine (2 mg/kg)-induced hyperalgesia. This reversal was sensitive to
      blockade by both (-)sulpiride (50 mg/kg) and (-) pindolol (5 mg/kg). The present
      study suggests that roxindole-induced antinociception is mediated by postsynaptic
      DA D2 and 5-HT1A receptors.

PMID- 10641152
TI  - Anti-oxidant effects of cinnamon (Cinnamomum verum) bark and greater cardamom
      (Amomum subulatum) seeds in rats fed high fat diet.
AB  - In order to gain insight into the antioxidant effect of cinnamon (Cinnamomum
      verum; Lauraceae) and cardamom (Amomum subulatum; Zingiberaceae) hepatic and
      cardiac antioxidant enzymes, glutathione (GSH) content and lipid conjugated
      dienes were studied in rats fed high fat diet along with cinnamon or cardamom.
      The antioxidant enzyme activities were found to be significantly enhanced whereas
      GSH content was markedly restored in rats fed a fat diet with spices. In
      addition, these spices partially counteracted increase in lipid conjugated dienes
      and hydroperoxides, the primary products of lipid peroxidation. Thus, it appears
      that these spices exert antioxidant protection through their ability to activate
      the antioxidant enzymes.

PMID- 10641153
TI  - Biochemical effects of garlic protein on lipid metabolism in alcohol fed rats.
AB  - Garlic protein is a very good hypolipidemic agent. In the present study the water
      soluble protein fraction of garlic was investigated for its effect on
      hyperlipidemia induced by alcohol (3.76 g/kg. body wt./day). The hypolipidemic
      action is mainly due to an increase in cholesterol degradation to bile acids and
      neutral sterols and mobilization of triacyl glycerols in treated rats. Garlic
      protein (500 mg./kg body wt./day) showed significant hypolipidemic action
      comparable with a standard dose of gugu-lipid (50 mg./kg. body wt./day).

PMID- 10641154
TI  - Mechanism of action of antiinflammatory effect of fixed oil of Ocimum basilicum
      Linn.
AB  - Fixed oil of O. basilicum was found to possess significant antiinflammatory
      activity against carrageenan and different other mediator-induced paw edema in
      rats. Significant inhibitory effect was also observed in castor oil-induced
      diarrhoea in rats. It also inhibited arachidonic acid- and leukotriene-induced
      paw edema. The results of antiinflammatory activity of O. basilicum support the
      dual inhibition of arachidonate metabolism as indicated by its activity in
      inflammation models that are insensitive to selective cyclooxygenase inhibitors.
      On the basis of these findings, it possible to conclude that O. basilicum may be
      a useful antiinflammatory agent which block both cyclooxygenase and lipoxygenase
      pathways of arachidonic acid metabolism.

PMID- 10641155
TI  - Evaluation of gastric anti-ulcer activity of fixed oil of Ocimum basilicum Linn.
      and its possible mechanism of action.
AB  - Fixed oil of O. basilicum was found to possess significant antiulcer activity
      against aspirin, indomethacin, alcohol, histamine, reserpine, serotonin and
      stress-induced ulceration in experimental animal models. Significant inhibition
      was also observed in aspirin-induced gastric ulceration and secretion in pylorus
      ligated rats. The lipoxygenase inhibiting, histamine antagonistic and
      antisecretory effects of the oil could probably contribute towards antiulcer
      activity. O. basilicum fixed oil may be considered to be a drug of natural origin
      which possesses both antiinflammatory and anti-ulcer activity.

PMID- 10641156
TI  - Mast cell stabilizing and lipoxygenase inhibitory activity of Cedrus deodara
      (Roxb.) Loud. wood oil.
AB  - Volatile oil of C. deodara, administered orally at the doses of 50, 100 and 200
      mg/kg body weight, significantly inhibited the pedal edema induced by compound
      48/80 in rats. The oil significantly inhibited compound 48/80 induced
      degranulation of isolated rat peritoneal mast cells at concentrations ranging
      from 25-200 micrograms/ml. C. deodara wood oil also significantly inhibited the
      enzyme lipoxygenase at a concentration of 200 micrograms/ml. Thus, the anti
      inflammatory activity of C. deodara wood oil could be attributed to its mast cell
      stabilizing activity and the inhibition of leukotriene synthesis.

PMID- 10641157
TI  - Modulation of glutathione and antioxidant enzymes by Ocimum sanctum and its role
      in protection against radiation injury.
AB  - Aqueous extract (OE) of the leaves of Ocimum sanctum, the Indian holy basil, has
      been found to protect mouse against radiation lethality and chromosome damage and
      to possess significant antioxidant activity in vitro. Therefore a study was
      conducted to see if OE protects against radiation induced lipid peroxidation in
      liver and to determine the role, if any, of the inherent antioxidant system in
      radioprotection by OE. Adult Swiss mice were injected intraperitoneally (i.p.)
      with 10 mg/kg of OE for 5 consecutive days and exposed to 4.5 Gy of gamma
      radiation 30 min after the last injection. Glutathione (GSH) and the antioxidant
      enzymes glutathione transferase (GST), reductase (GSRx), peroxidase (GSPx) and
      superoxide dismutase (SOD), as well as lipid peroxide (LPx) activity were
      estimated in the liver at 15 min, 30 min, 1, 2, 4 and 8 hr post-treatment. LPx
      was also studied after treatment with a single dose of 50 mg/kg of OE
      with/without irradiation. OE itself increased the GSH and enzymes significantly
      above normal levels whereas radiation significantly reduced all the values. The
      maximum decline was at 30-60 min for GSH and related enzymes and at 2 hr for SOD.
      Pretreatment with the extract checked the radiation induced depletion of GSH and
      all the enzymes and maintained their levels within or above the control range.
      Radiation significantly increased the lipid peroxidation rate, reaching a maximum
      value at 2 hr after exposure (approximately 3.5 times that of control). OE
      pretreatment significantly (P < 0.0001) reduced the lipid peroxidation and
      accelerated recovery to normal levels. The results indicate that Ocimum extract
      protects against radiation induced lipid peroxidation and that GSH and the
      antioxidant enzymes appear to have an important role in the protection.

PMID- 10641158
TI  - Effect of support materials on cephamycin C production by immobilized
      Streptomyces clavuligerus.
AB  - In order to know the effect of supports on cephamycin C production, under similar
      experimental conditions, S. clavuligerus cells were immobilized with--sponge, 2%
      agar, 2% and 4% alginate support materials. An experimental set of free cell was
      also maintained as control. Cephamycin C production by these immobilized and free
      cells was estimated at 48, 96 and 120 hr of fermentation. In all the cases
      cephamycin C production was found to be high at 120 hr of fermentation. Sponge
      was found to be a better support material than other supports used for
      immobilization.

PMID- 10641159
TI  - Suppressor cell activity of intestinal mucosal leucocytes from buffalo (Bubalus
      bubalis arni).
AB  - Suppressor activity of buffalo intestinal intraepithelial leucocytes and lamina
      propria leucocytes was induced by Concanavalin A, and was assayed against the
      mitogenic response of autologous and allogenic leucocytes to mitogens.
      Appreciable suppression was observed with 25 micrograms ConA/ml on the
      proliferative activity of the responder cells cocultured at a ratio of < 2:1
      (suppressor:responder cell). Mitomycin C treatment of intestinal leucocytes did
      not totally vanish the viability and functionality of leucocytes.

PMID- 10641160
TI  - Immunomodulation of macrophages by radio-detoxified lipopolysaccharide of
      Salmonella typhimurium.
AB  - Lipopolysaccharide (LPS) and ratio-detoxified LPS (Rd-LPS) from Salmonella
      typhimurium were analysed for their ability to stimulate murine peritoneal
      exudate cells (PEC) and macrophages. Rd-LPS induced much more inflammatory
      response as compared to LPS. PEC numbers/mouse obtained were significantly higher
      (3-fold) in response to Rd-LPS than LPS. The haemorrhage was induced in mice by
      LPS but not by Rd-LPS. Activation of macrophages in vivo by Rd-LPS was
      significantly higher as compared to LPS. This was evident from the increase
      levels of their lysosomal enzymes and cytokines. Rd-LPS induced 10-fold increase
      in acid phosphatase contents of macrophages as compared to controls while only 7
      fold increase was obtained with LPS. Arylsulfatase and beta-glucuronidase
      increased by about 2-fold by Rd-LPS and LPS. Macrophages incubated with Rd-LPS in
      vitro showed 16-fold and 20-fold increase in the cell associated levels of
      arylsulfatase and beta-glucuronidase respectively as compared to unstimulated
      cells. On the other hand, only 6-fold increase was observed in response to LPS in
      the levels of both the enzymes. TNF-[symbol: see text] and IL-1 secreted by
      macrophages increased considerably in response to Rd-LPS as compared to those
      released by LPS. Rd-LPS, thus seems to be a better immunomodulator than untreated
      LPS.

PMID- 10641161
TI  - Olfactory bulbectomy-induced changes in the reproductive behaviour of the south
      Indian gerbil, Tatera indica cuvieri.
AB  - Male South Indian gerbils (T. indica cuvieri), both adults and weanlings, were
      olfactory bulbectomized (OBX) and changes in male reproductive behaviour were
      assessed. Consequent to OBX, majority of the adult males failed to ejaculate, and
      courtship behaviour has also been considerably reduced. All OBX weanlings were
      rendered incapable of ejaculation. However, maturational parameters, and organ
      weights (testes, epididymis and seminal vesicle) remained unchanged in OBX males.

PMID- 10641162
TI  - Biodegradable dental implants of ciprofloxacin beta-cyclodextrin inclusion
      complex in the treatment of periodontitis.
AB  - Dental implants of ciprofloxacin beta-cyclodextrin inclusion complex were
      formulated using poly (epsilon-caprolactone), a biodegradable polymer and
      evaluated. Clinical evaluation was carried out in ten patients with acute
      peridontitis. Various clinical parameters, viz. gingival index, plaque score,
      attachment gain, reduction in pocket depth were evaluated at 10, 20, 30, 40 days
      of treatment and compared with placebo as control. A significant (P < 0.0001)
      improvement in the healing of periodontal pockets treated with ciprofloxacin beta
      cyclodextrin implant was observed in most of the clinical parameters. Estimation
      of gingival crevicular fluids (GCF) for the drug content revealed that drug
      levels above the minimum inhibitory concentration (10.2 micrograms/mg) for many
      of the periodontal pathogens were maintained throughout the period of study (40
      days). This confirms the clinical efficacy of the dose and the duration of the
      study. It was found that biodegradable carrier was better accepted than the non
      biodegradable carriers reported earlier.

PMID- 10641163
TI  - Circulating immune complex in murine autoimmune hepatitis.
AB  - High level of circulating immune complexes (CIC) in the serum has been reported
      in different forms of hepatitis particularly in complicated cases of viral
      hepatitis due to hepatitis B virus (HBV) infection. In this study CIC level in
      experimental autoimmune hepatitis were assessed by detection of polyethylene
      glycol (PEG) index. The sera of mice with established autoimmune hepatitis (EAH)
      confirmed by histopathological study showed higher PEG index (C57BL/6 mice: 34.56
      +/- 6.28 and C3H mice: 31.95 +/- 28.99). The control healthy mice showed lower
      PEG index (C57BL/6 mice: 19.48 +/- 6.85 and C3H mice: 21.27 +/- 6.1). The high
      level of PEG index in EAH was found statistically significant. The role of CIC in
      the development of autoimmune hepatitis is discussed.

PMID- 10641164
TI  - Effect of catecholamines on bursa of fabricius in chicken.
AB  - Effect of catecholamines are studied on the bursa of fabricius of chicken. It is
      found that in epinephrine (E) treated chicken, the lymph follicles are slightly
      decreased in size. Some amount of nuclear pycnosis is visible in E and
      norepinephrine (NE) treated chicken. There is no change in the bursa weight and
      histology in NE treated groups. No deviation is observed in the level of DNA,
      RNA, total protein and sialic acid content of catecholamine treated birds.

PMID- 10641165
TI  - Influence of the stage of the cycle on olfactory sensitivity in laboratory mice.
AB  - Females in estrus showed maximum olfactory sensitivity as judged by their ability
      in locating the buried bait. The results suggest that olfactory sensitivity in
      females varies during the stages of the estrous cycle. The findings further
      indicate that gonadal steroids play an important role in the expression of
      olfactory sensitivity in females.

PMID- 10641166
TI  - Light has no role in spermatogenesis in the frog Rana cyanophlyctis (Schneider).
AB  - The effect of 3 months exposure to short day length (L:D, 9:15) on
      spermatogenesis in R. cyanophlyctis was studied. There was no difference in the
      qualitative and quantitative aspect of spermatogenesis between control frogs
      exposed to ambient photoperiod (L:D, 12.16:11.44) and frogs exposed to short day
      light. The present findings indicate that light has no role in spermatogenesis in
      the frog.

PMID- 10641167
TI  - Integrin cell adhesion molecules in endometrium of fertile and infertile women
      throughout menstrual cycle.
AB  - Integrins (ITGs) are ubiquitous cell adhesion molecules that undergo dynamic
      alterations during the normal menstrual cycle in human endometrium. The
      distribution of four different subunits, viz. alpha 4, alpha 6, beta 3 and beta 4
      in human endometrial tissue at different stages of the menstrual cycle was
      studied using immunohistochemical, enzyme immunoassay and SDS-PAGE/Western blot
      techniques. The specificity of each mAb to their respective ligands viz., laminin
      (Ln), fibronectin (Fn) and vitronectin (Vn) was done by cell adhesion assays.
      Both alpha 6 and beta 4 subunits (Ln receptors) expressed primarily on the
      glandular epithelium, while glandular, stromal and luminal cells expressed
      predominantly alpha 4 (Fn receptor) and beta 3 (Vn receptor). The appearance of
      alpha 4 and beta 3 ITG subunits was found to be cell and cycle specific. The
      levels of both alpha 6 and beta 4 increased throughout the menstrual cycle, while
      beta 3 subunit appeared abruptly on cycle day 19/20. The immunostaining for alpha
      4 and beta 3 was absent in 90% of infertile women. The timing of expression of
      alpha 4 and beta 3, the two cycle--dependent ITGs framed the putative window of
      implantation and suggests a role in the diagnosis of infertility. In conclusion,
      the absence of alpha 4 and beta 3 ITG expression in the endometrium of
      infertility subjects during mid luteal phase may be associated with defects in
      uterine function. The defective uterine receptivity may be an unrecognised cause
      of infertility in these group of women.

PMID- 10641168
TI  - Anticonvulsant profile of nimodipine and nitrendipine against pentylenetetrazole
      induced seizures in rats.
AB  - The activity of nimodipine and nitrendipine against pentylenetetrazole (PTZ)
      induced seizures in Albino rats was studied alone and in combination with
      valproate. The median effective dose [ED50] of valproate, nimodipine and
      nitrendipine were initially determined. All the 3 drugs were injected i.p. 30 min
      before the induction of seizures. Seizures were induced by PTZ 85 mg/kg i.p., and
      subsequently the effect of combining ED50 doses of nimodipine and nitrendipine
      with ED50 dose of valproate was evaluated. ED50 of valproate and nitrendipine
      were 129 and 2.5 mg/kg respectively. ED50 of nimodipine could not be established
      since a dose-response relationship was not obtained. Hence, for the purpose of
      combination studies, 4 mg/kg of nimodipine was used. Both nimodipine (4 mg/kg)
      and nitrendipine (2.5 mg/kg) decreased the ED50 of valproate from 129 to 40
      mg/kg. Both nimodipine and nitrendipine potentiate the activity of valproate
      against PTZ induced seizures and can be considered as potential adjuvant
      anticonvulsants which merit further study.

PMID- 10641169
TI  - Induction of stress proteins in response to hypoxia.
AB  - Hypoxia is a severe stress factor to which man and most other mammalian species
      are capable of adapting. However, the cellular mechanism which enable cells to
      adapt are still unknown. Effect of hypoxia was studied on the synthesis of
      hypoxia induced proteins in rat kidney and in vero cell line (monkey kidney).
      These were exposed to hypoxia at 240 mmHg pressure for 1 hr. The induction of
      stress protein was determined by probing with monoclonal antibodies against 65
      kDa heat shock protein (hsp65). The induction of a 65 kDa protein was 3.6 fold
      higher to the total cellular protein, both in cell lines and kidney of rats. In
      vivo response was predominantly observed in renal cortical region particularly in
      glomeruli. The induction of stress proteins during hypoxia suggests their
      importance in the maintenance of cellular integrity under hypoxia.

PMID- 10641170
TI  - Adrenergic influence of uterine muscle contractions stimulated by a glycoside
      from the root of Dalbergia saxatilis.
AB  - The mechanism of uterine muscle contraction stimulated by a triterpenoid
      glycoside (dalsaxin) isolated from the root of D. saxatilis was investigated by
      in vitro methods in the rat. Dalsaxin caused a dose-related increase in uterine
      muscle contraction. The contraction was single and transient and was abolished by
      moderate doses of isoprenaline (1.80 nmol-0.40 mumol) and salbutamol (0.13-25
      mumol). Adrenaline (9.10 nmol) also caused a reversible decrease (92.6%; P <
      0.01) in myometrial contraction stimulated by this glycoside (0.24 mg/ml).
      Uterine muscle responses to dalsaxin (0.24 mg/ml) were enhanced by the beta
      adrenergic receptor antagonist, propranolol, in a dose related manner.
      Atipamezole (1.50 ng/ml) but not prazosin (7.72 nmol-15.60 nmol) substantially
      reduced (80%; P < 0.01) myometrial contractions induced by this uterine
      spasmogen. The results suggest that dalsaxin enhances uterine muscle contraction
      by stimulating post junctional alpha 2-adrenergic receptors, presumably by
      inhibiting plasma membrane adenylate cyclase system and its associated increase
      in intracellular cAMP content.

PMID- 10641171
TI  - Diethylhydroxylamine given in vivo inhibits lipid peroxidation and lipofuscin
      formation in the nervous tissues of rat.
AB  - In vivo effects of diethylhydroxylamine (DEHA) on lipid peroxidation and
      lipofuscin formation in the nervous tissues of rat have been investigated. Rats
      were fed DEHA for 30, 60 and 90 days and lipid peroxidation levels and lipofuscin
      concentration measured in cerebellum, brain stem and spinal cord. Lipofuscin
      contents were also assessed histochemically. The results showed that the drug
      caused a significant reduction in lipid peroxidation level and lipofuscin
      concentration related to ageing.

PMID- 10641172
TI  - Bottleneck effect on intra- and interspecific competition in Drosophila
      malerkotliana.
AB  - Intra and interspecific competition experiments involving control and bottleneck
      lines of monomorphic and polymorphic populations of D.malerkotliana with D.nasuta
      nasuta have been carried out. Productivity and population size were evaluated in
      these lines. The results show that control line had higher relative fitness and
      adaptedness (productivity and population size) under both intra and interspecific
      competition than their respective bottleneck lines and D.nasuta nasuta. This
      indicates that bottlenecks have an effect on competition in D.malerkotliana. The
      consequence of such competition studies using control and bottleneck lines of
      D.malerkotliana and D.nasuta nasuta is discussed.

PMID- 10641173
TI  - Gastric mucosal cellular changes induced by indomethacin (NSAID) in male albino
      rats.
AB  - Indomethacin (2 mg/100 g body weight), induces haemorrhagic gastric ulcers in
      albino rats. The incidence and severity of ulceration increased with starvation
      period. Indomethacin caused little or no effect on the cellular and the nuclear
      diameter of parietal and chief cells while reduction was observed in mucus and
      endocrine cells. The effect was enhanced with increased duration of starvation.
      Both mucous and endocrine cells decreased in their number after 72 hr of
      starvation. Thus prolonged starvation enhanced the gastric mucosal damage induced
      by indomethacin.

PMID- 10641174
TI  - Inhibitory activity in buffalo follicular fluid and its elution pattern during
      different season.
AB  - Two pools of whole buffalo follicular fluid collected in winter (December,
      January) and spring (March, April) season were fractionated by Sephadex G-200
      column chromatography. Follicular fluid collected in winter and spring eluted
      into different pattern resulted into four and three peaks respectively. Both the
      pools of follicular fluid were salted out with 18.5% ammonium sulphate. The
      salted out fraction of winter and spring season follicular fluid was again
      subjected to sephadex column chromatography which eluted into two and single peak
      respectively. Whole follicular fluid (0.6 ml) was administered into
      ovariectomized mice to see its inhibitory effect. The percentage of compensatory
      ovarian hypertrophy was 16.3 +/- 4.4 which was significantly different (P < 0.01)
      as compared to control. 200 micrograms material from peak 1 and peak 2 obtained
      after fractionation of salted out winter follicular fluid also had inhibitory
      effect on compensatory ovarian hypertrophy as compared to control group. It was
      35.6 +/- 9.3 and 15.9 +/- 4.3% respectively. Thus, the variation in nature of
      buffalo follicular fluid and its inhibitory effect in ovariectomised mice have
      significant relation with anoestrus condition in summer and humid months in this
      species.

PMID- 10641175
TI  - Effect of ammonium and nitrate ratio on glucose oxidase activity during gluconic
      acid fermentation by a mutant strain of Aspergillus niger.
AB  - Of the factors tested, the source and concentration of carbon and nitrogen in the
      medium exerted maximum effect on growth and acid production. Glucose (15%) and
      urea (0.14%) induced glucose oxidase synthesis and optimum yield of calcium
      gluconate. Potassium dihydrogen phosphate (0.2%) and magnesium sulphate (0.06%)
      stimulated glucose oxidase activity and calcium gluconate production. Borax at a
      concentration of 1.5 g/L induced maximum glucose oxidase and calcium gluconate
      production with increased glucose utilization.

PMID- 10641176
TI  - Effect of mild hyperlipidaemia on testicular cell population dynamics in albino
      rats.
AB  - Mild hyperlipidaemia induced by cholesterol feeding to male rats altered
      testicular histology. The sperm motility and density were significantly reduced
      in cauda epididymides and testes in mild hyperlipidaemic rats. The testicular
      cell population i.e. spermatocytes (primary and secondary) and spermatids were
      significantly reduced (P < or = 0.01 to 0.001). However, the number of
      degenerating Leydig cells (interstitial cells) were increased significantly (P <
      or = 0.001). Serum biochemistry reveals significant rise in cholesterol and
      triglycerides. It is concluded that cholesterol feeding caused inhibition of
      spermato genesis.

PMID- 10641177
TI  - Effect of betacarotene on protein glycosylation in alloxan induced diabetic rats.
AB  - Free radicals are increasingly formed in diabetes mellitus by the auto oxidation
      of glucose and glycosylated proteins. Oxidative stress and proteinglycosylation
      are closely related processes and have been shown to contribute to the
      development of complications in diabetes mellitus. The extent of protein
      glycosylation was assessed in alloxan induced diabetic rats after being treated
      with 50 mg of betacarotene for 40 days. The level of fructosamine and
      glycosylated haemoglobin was comparison with non treated diabetic rats. The
      results indicate the beneficial role of betacarotene in reducing diabetic
      complications like glycosylation in experimental diabetic rats.

PMID- 10641178
TI  - Progesterone potentiating effect of Dipsacus mitis D. Don for its contraceptive
      action in hamster.
AB  - A pure compound, isolated from ethyl acetate extract (root) of D. mitis D. Don,
      prevented pregnancy by 100% in adult female hamster but partially in rat when
      administered orally on Days 1-7 and 1-10 post-coitum respectively. The effective
      dose in both species was 150 mg/kg. Using uterine wet weight in ovariectomized
      immature rat as bioassay method, the compound was found to be devoid of
      estrogenic and antiestrogenic property. On examination for progestational and
      antiprogestational activity, using trauma-induced deciduoma formation in immature
      rat uterus as end points, the compound (per se) did not show the former activity
      but in a conjoint treatment with progesterone it augmented the action of latter.
      The compound was assumed to act by potentiating progesterone biosynthesis, the
      excess of which might be the cause for interruption of pregnancy in hamster. This
      is the first study to report contraceptive efficacy and mode of its action at the
      uterine level.

PMID- 10641179
TI  - Does TAME induced contraction involve an endothelium dependent nitric oxide
      cyclic GMP mediated pathway?
AB  - Two enzyme inhibitors namely L-NAME, a nitric oxide synthase (NOS) inhibitor and
      methylene blue, a guanylate cyclase inhibitor, were used to elucidate whether N
      alpha-tosyl L-arginine methyl ester (TAME)-induced contractions in toad
      intestinal rings in vitro are mediated through a nitric oxide (NO)- cyclic GMP (c
      GMP) pathway. Moreover, a NO precursor, L-arginine was also used to investigate
      its effect on TAME-induced contractions. Our findings provide evidence that TAME
      induced contractions have both an endothelium-dependent and an endothelium
      independent component. Based on our findings we now propose that TAME induced
      contraction involves an endothelium-dependent component mediated through NO and c
      GMP.

PMID- 10641180
TI  - Anti-cholestatic activity of HD-03, a herbal formulation in thioacetamide (TAA)
      induced experimental cholestasis.
AB  - In the present study HD-03, a herbal formulation was investigated for its anti
      cholestatic activity in TAA-induced cholestasis in anaesthetized guinea pigs.
      Administration of TAA at a dose of 100 mg/kg body wt significantly reduced the
      bile flow, bile acid and bile salt excretion. Pretreatment with HD-03 at a dose
      of 750 mg/kg body wt per orally for 15 days in guinea pigs significantly
      prevented thioacetamide-induced changes in bile flow, bile acids and bile salts
      excretion. Thus, HD-03 can serve as a potent choleretic and anti-cholestatic
      agent.

PMID- 10641181
TI  - Antipyretic activity of Cardiospermum halicacabum.
AB  - Cardiospermum halicacabum extracts have been evaluated for their antipyretic
      activity against yeast-induced pyrexia in rats. The ethanol as well as n-hexane
      extracts (400 mg/kg) of the whole plant powder showed potent antipyretic
      activity. The water extract was devoid of significant activity. The antipyretic
      activity of the ethanol extract was concentration dependent.

PMID- 10641182
TI  - Inhibitory effect of piceatannol, a protein tyrosine kinase inhibitor, on asexual
      maturation of Plasmodium falciparum.
AB  - This report describes the effect of piceatannol (3,4,3',5'-tetrahydroxy trans
      stilbene), a plant secondary natural product, on protein tyrosine kinase (PTK)
      activity in different stages of P. falciparum grown in vitro. Piceatannol
      inhibited PTK activity in trophozoites and schizonts suggesting that PTK may be
      important in the initial asexual maturation of the parasite. Inhibition of PTK
      activity by piceatannol may thus provide new insights into more specific tools
      for chemotherapeutic interventions for P. falciparum.

PMID- 10641183
TI  - Gene HI1472 of Haemophilus influenzae Rd is a novel gene involved in DNA repair.
AB  - A chimeric plasmid, pJPuvr4, consists of a 16.7 kbp Haemophilus influenzae Rd
      chromosomal DNA insert at the EcoRI site of vector pJ1-8. This plasmid
      complements the UV and gamma ray sensitivity of the mutant strain MBH4. This
      plasmid carries the wild type allele of gene uvr4 which was localised to a 3.8
      kbp DraI fragment, with an internal EcoRI site. Partial sequencing of the gene
      and its alignment with the published genome sequence of H. influenzae Rd revealed
      uvr4 to be HI1472. HI1472 is a putatively identified open reading frame (ORF),
      which has been assigned no function so far. The partial sequence did show nt
      database match with 3D exon of N cadherin gene of homosepians and moaA gene of H.
      influenzae. Cadherins are involved in cell adhesion, cell to cell contact and
      morphogenesis in homosepians and moaA gene codes for molybdenum biosynthesis
      subunitA. This report implicates HI1472 of Haemophilus influenzae Rd in DNA
      repair. Nucleotide sequence obtained for the gene uvr4 was compared with the
      published sequence of gene HI1472. A wild type strain variation was observed at
      the 592nd nucleotide position corresponding to a change from aspartic acid to
      threonine.

PMID- 10641184
TI  - Comparative studies on immunoreactivity of truncated recombinant proteins of foot
      and mouth disease virus (FMDV) produced in E.coli and insect cells.
AB  - For effective FMD control programme, India needs large quantities of cheaper
      diagnostics in addition to vaccine. Diagnostic reagents produced through
      conventional methods may not be able to meet such requirements. Alternatively,
      rDNA technology using suitable heterologous systems that permit production of
      recombinant antigens to the most native form may be exploited. Studies conducted
      in our laboratory have led us to select carboxy terminal part of VP1 for
      expression and evaluation. The protein, which was purified from E.coli under
      denaturing conditions, was renatured and its reactivity was compared with the
      protein expressed in insect cells through recombinant baculovirus. The expressed
      protein in the insect cell whole lysate reacted more efficiently with antibodies
      raised against whole virus than the purified and renatured protein produced in
      E.coli. But for its lower reactivity, protein produced from E.coli was found to
      be suitable in type detection. In addition, the size of the protein is small (16
      kD) and production and purification of it from E.coli may be cost effective.
      Hence, it may be exploited for FMDV typing.

PMID- 10641185
TI  - Comparative pulmonary toxicity of cadmium and nickel: histopathological and
      bronchoalveolar lavage analysis.
AB  - Pulmonary toxicity of cadmium and nickel was evaluated in rat lungs following
      intratracheal instillation of their chlorides. Concentration of both the metals
      varied from 0.2-5 mM. Both the metals increased total number of cells, number of
      polymorphonuclear neutrophils, total protein, sialic acid and the activity of
      lactate dehydrogenase and beta-glucuronidase in bronchoalveolar lavage 3 days
      after exposure. Increase in the levels of the selected parameters was more
      following Cd exposure than in Ni exposed rats. Histologically there was an
      inflammatory response and interstitial fibroblastic proliferation in the lungs of
      Cd exposed animals. These changes were mild in Ni-exposed animals and higher
      concentrations of Ni were needed to produce changes similar to those produced by
      smaller concentrations of Cd.

PMID- 10641186
TI  - Biochemical alterations induced by a new phosphorothionate (RPR-II) in tissues of
      male and female rats.
AB  - This study was conducted to investigate the effect of a new phosphorothionate,
      the methyl ester of 2-butenoic acid-3-diethoxy phosphinothioyl (RPR-II) on
      membrane bound target enzymes aspartate amino transferase (ASAT), alanine amino
      transferase (ALAT) and RBC acetylcholinesterase (AChE) in different tissues of
      male and female albino wistar rats when treated orally with 0.014 (low), 0.028
      (medium) and 0.042 (high) mg/kg daily for a period of 90 days. Repeated
      administration of RPR-II caused significant increase of ASAT and ALAT enzymes in
      serum, liver and kidney and significant decrease was recorded in lung in both
      male and female rats when measured after 45 and 90 days of treatment. This
      compound also caused significant inhibition of RBC AChE indicating its effect on
      nerve synapsis. Females were more susceptible than males with regard to ASAT and
      ALAT levels in serum and liver and also in kidney ASAT, whereas reverse trend was
      recorded in lung ALAT, suggesting sexual dimorphism in the treated rats. These
      studies also indicated that the levels of these affected enzymes were recovered
      to normal conditions after 28 days of post treatment (withdrawal study). Positive
      correlation was observed with regard to these enzymes between serum, liver and
      kidney, whereas in case of serum and lung a negative correlation was recorded.
      These enzymes profile elucidates lung necrosis whereas in other tissues the level
      of enzymes increased showing an adaptive mechanism due to the chemical stress.

PMID- 10641187
TI  - Assessment of toxicological effects of mancozeb in male rats after chronic
      exposure.
AB  - Mancozeb, an ethylenebisdithiocarbamate fungicide was administered orally to male
      rats at doses 0, 500, 1000 and 1500 mg/kg/day for 90, 180 and 360 days produced
      dose dependent signs of poisoning, loss in body weight gain and mortality.
      However the signs of toxicity and mortality were more pronounced initially at 0
      90 days as compared to 90-360 days of treatment period. A significant increase in
      the relative weight of liver and slight decrease in the kidney weight were
      observed in animals exposed to mancozeb (1000 and 1500 mg/kg/day) for 180 and 360
      days associated with pathomorphological changes in liver, brain and kidney.
      Mancozeb has produced significant enzymatic changes in the activities of
      aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), alkaline
      phosphatase (ALP), lactate dehydrogenase (LDH) and acetylcholinesterase (AChE)
      throughout the period of study in a dose dependent manner. The alterations in the
      activity of enzymes associated with pathomorphological changes suggest that the
      chronic exposure of mancozeb produced significant toxicological effects in rats.

PMID- 10641188
TI  - Changes in embryonic protein profile and economic characters of Bombyx mori
      (Lepidoptera:Bombycidae) following UV irradiation.
AB  - Eggs of B. mori were irradiated with UV (254.4 nm wavelength) for different
      durations. Increase in the time of exposure to UV decreased the percentage
      hatchability of the eggs, cocoon and pupal weights. The shell weight remained
      unaltered proving the stability of silk gland DNA. Irradiation of eggs also
      delayed the degradation/utilization of the embryonic proteins, viz. vitellin
      (heavy and light subunits), egg-specific protein and 30K protein.

PMID- 10641189
TI  - Role of alcoholic extract of shoot of Hypericum perforatum Linn on lipid
      peroxidation and various species of free radicals in rats.
AB  - The alcoholic extract of the shoot of H. perforatum shows strong antioxidant
      property. It possesses the iron chelation property with more affinity to the
      ferrous form. It has scavenging property for both superoxide and for hydroxyl
      radicals but the response is more towards the superoxide radicals. Thus in
      addition to the anti-depressant property it has strong antioxidant property also.

PMID- 10641190
TI  - Effect of cerebellar modulation on rat gastric secretion and enterochromaffin
      like cell.
AB  - Effect of cerebellar lesion and vestibular stimulation (VS) on the activity and
      alternation of ECL-cells along with changes in gastric volume and acid secretion
      was studied. The results suggest that cerebellar lesion caused increased gastric
      volume and acid secretion and tended to decrease ECL-cell density. On the other
      hand VS of nodular lesioned rats resulted in decrease of above parameter which
      became marked only after 21 days of nodular lesion.

PMID- 10641191
TI  - Changes of gastroduodenal peroxidase activity of rats by cerebellar modulation.
AB  - The effect of vestibulo-cerebellar lesion and its stimulation by rotation on
      gastric and duodenal peroxidase activity of rats was studied. Vestibulocerebellar
      lesion by kainic acid produced gastroduodenal ulceration and peroxidase activity
      of these tissues were decreased. Mucosal thickness of gastric and duodenal tissue
      were also decreased. It was observed that when vestibulo-cerebellar lesioned rats
      were subjected to vestibular stimulation, the peroxidase activity was increased
      together with increased mucosal thickness of gastric and duodenal tissue. At the
      same time, it was noted that the severity of ulceration was decreased. We
      conclude that the study of peroxidase activity is a sensitive and potentially
      useful estimate of gastric and duodenal injury produced by cerebellar lesion that
      can be valuable in assessing ulcerogenesis and healing.

PMID- 10641192
TI  - Mating activity and fitness of a few wild type strains of Drosophila ananassae.
AB  - Courtship time, duration of copulation and fertility were tested in six wild type
      strains of D. ananassae originating from different geographical localities. The
      results indicate that there is significant variation among the strains tested
      with respect to courtship time, duration of copulation and fertility. The strains
      showing a longer duration of copulation produce more progeny. These findings
      suggest that there is a positive correlation between duration of copulation and
      fertility in D. ananassae.

PMID- 10641193
TI  - Evaluation of hematological and hepatorenal functions of methanolic extract of
      Moringa oleifera Lam. root treated mice.
AB  - Methanolic extract of M. oleifera root was found to contain some alkaloids (total
      alkaloid 0.2%). Effects of multiple weekly (35, 46, 70 mg/kg) and daily
      therapeutic (3.5, 4.6, 7.0 mg/kg) i.p. doses of the crude extract (CE) on liver
      and kidney functions and hematological parameters in mice were studied. No
      alteration in hematological and biochemical parameters at low and moderate dose
      level of daily and low dose level of weekly treatment of the extract was
      observed. However, the extract at moderate dose level in weekly treatment changed
      serum aminotransferase and plasma cholesterol levels significantly. High dose in
      addition to the above parameters changed total bilirubin, non protein nitrogen,
      blood urea and plasma protein. High dose of daily treatment and moderate and high
      dose of weekly treatment of CE increased WBC count and decreased clotting time
      significantly. The results indicate that the weekly moderate and high dose (> 46
      mg/kg body wt.) and daily/therapeutic high dose (7 mg/kg) of CE affects liver and
      kidney functions and hematological parameters whereas the weekly dose (3.5 mg/kg)
      and low and moderate daily/therapeutic dose (3.5 and 4.6 mg/kg) did not produce
      adverse effects on liver and kidney functions.

PMID- 10641194
TI  - Effects of selenium toxicity on oestrous cyclicity, ovarian follicles, ovulation
      and foetal survival in rats.
AB  - Effects of intraperitoneal injections of sodium selenite (2.0 and 4.0 mg/kg body
      weight) to normally cycling female albino Wistar rats daily for 30 days, and of
      single injection either during proestrous or oestrous and at each stage of the 4
      day oestrous cycle were determined on oestrous cyclicity, ovarian follicles,
      ovulation, implantation and pregnancy outcome on day 14 of gestation.
      Administration of selenite for 30 days had no effect on the duration of first two
      oestrous cycles but afterwards the rats remained at the dioestrus stage. Their
      ovaries developed cystic follicles. Selenite treatments during the oestrous cycle
      preceding mating affects the implantation and pregnancy outcome in a dose-related
      manner. Its single dose containing 2.0 mg/kg body weight administered either at
      proestrous or oestrous, though had no effect on different reproductive parameters
      investigated in this study but its daily dose during the 4 day oestrous cycle
      reduced the number of corpora lutea and implantations as compared to saline
      injected control female rats. Similar effects of a single dose of selenite (4.0
      mg/kg body weight) when injected at proestrous were recorded. Higher dose of
      selenite at oestrous or throughout the cycle decreased the number of
      implantations, but in addition, also increased the resorption rate/litter on day
      14 of gestation. The present studies clearly show that high selenium levels in
      the body during the oestrous cycle preceding mating affects the number of
      ovulations, implantations and live embryos depending upon its dose and stage of
      administration.

PMID- 10641195
TI  - Newer methodologies in immunohistochemistry and diagnosis.

PMID- 10641196
TI  - Ultrasound and ultrasound biomicroscopy as a diagnostic tool.

PMID- 10641197
TI  - Lessons to be learned from experimental uveitis.

PMID- 10641198
TI  - Lymphocyte surface antigens in uveitis patients.

PMID- 10641199
TI  - The role of cytokines and chemokines in uveitis.

PMID- 10641200
TI  - Oral tolerance in autoimmune uveitis.

PMID- 10641201
TI  - Immunogenetics and uveitis.

PMID- 10641202
TI  - Essential laboratory tests in uveitis.

PMID- 10641203
TI  - Clinical aspects and diagnostic guidelines of ocular Behcet's disease.

PMID- 10641204
TI  - Medical management of Behcet's syndrome.

PMID- 10641205
TI  - The use of immunosuppressive drugs in uveitis.

PMID- 10641206
TI  - Prediction of treatment outcome in uveitis.

PMID- 10641207
TI  - Surgery of cataract in patients with uveitis.

PMID- 10641208
TI  - Postsurgery intraocular inflammation.

PMID- 10641209
TI  - Management of ocular manifestations in patients with acquired immunodeficiency
      syndrome.

PMID- 10641211
TI  - Antifungal agents

PMID- 10641212
TI  - Periocular fungal infections

PMID- 10641210
TI  - Mycosis of the eye and its adnexa.

PMID- 10641213
TI  - Mycoses of the anterior segment of the eye

PMID- 10641214
TI  - Fungal endophthalmitis

PMID- 10641215
TI  - Histoplasmosis

PMID- 10641216
TI  - Experimental findings in the eye

PMID- 10641217
TI  - Recent progress in anti-influenza chemotherapy.
AB  - Influenza virus infections in high risk individuals, such as infants, the
      elderly, and patients with cardiopulmonary disorders or immunocompromised states,
      cause severe manifestations which often result in fatalities. The emergence of a
      new antigen type of influenza A virus (H5N1) in Hong Kong during 1997 and 1998
      threatened a possible pandemic of a new influenza infection. The investigation
      for anti-influenza chemotherapies has progressed in the last decade whereas
      clinical trials of new compounds have been limited to amantadine, rimantadine and
      ribavirin. Fusion inhibitors which directly inhibit conformational change of
      haemagglutinin (HA), protease inhibitors which inhibit cleavage of HA to HA1 and
      HA2, RNA transcription inhibitors which inhibit cap formation of mRNA and
      antisense oligonucleotides targeted at mRNA of PB2 (a part of viral RNA
      polymerase) have been reported, in their development phases. Recently, 2
      neuraminidase (NA) inhibitors, zanamivir and oseltamivir (GS 4104), were used in
      clinical trials for the treatment of patients with influenza. Both agents showed
      promising results. A polyoxometalate, PM-523, inhibits fusion between the virus
      envelope and cell membrane and inhibits the penetration of the virus into cells.
      This compound has shown potent anti-influenza activity and synergistic inhibitory
      activity in combination with ribavirin or zanamivir in vitro and in vivo.
      Resistant strains for zanamivir, oseltamivir or PM-523 have been isolated. The
      analysis of mutation points of these strains have contributed to the
      investigation of the antiviral mechanisms of action of these compounds and the
      mechanism of resistance of the mutants to these compounds.

PMID- 10641218
TI  - New chemotherapeutic agents for influenza virus infections. Summary and table.

PMID- 10641219
TI  - Arbidol.

PMID- 10641220
TI  - Oseltamivir. EN 241104, GS 4104, RO 640796, Tamiflu.

PMID- 10641221
TI  - Zanamivir. 4-guanidino Neu5Ac2en, GG 167, GR 121167, GR 121167X, Relenza.

PMID- 10641222
TI  - Prophylactic anti-infective vaccines in clinical development. Summary and table.

PMID- 10641223
TI  - Cholera vaccine inactivated oral.

PMID- 10641224
TI  - DTaP-hepatitis B-poliovirus vaccine (SmithKline Beecham). InfanrixDTPa-HepB-IPV.

PMID- 10641225
TI  - Haemorrhagic fever vaccine.

PMID- 10641226
TI  - Hepatitis B vaccine recombinant (bio-technology general). BioHepB, Sci-B-Vac.

PMID- 10641227
TI  - Hepatitis B vaccine recombinant (Janssen/Medeva). Hepagene.

PMID- 10641228
TI  - Hib-DTaP vaccine (Wyeth-Lederle). Hib-DTP-acellular vaccine--Wyeth-Lederle,
      Tetracel.

PMID- 10641229
TI  - Influenza virus vaccine live intranasal (Aviron). FluMist, influenza vaccine live
      intranasal.

PMID- 10641230
TI  - Leishmaniasis vaccine.

PMID- 10641231
TI  - Lyme disease vaccine (Pasteur Merieux Connaught). ImuLyme.

PMID- 10641232
TI  - Meningococcal vaccine group C conjugate (Wyeth-Lederle).

PMID- 10641233
TI  - Pneumococcal vaccine conjugate (Wyeth-Lederle). PNCRM5, PNCRM7, PNCRM9.

PMID- 10641234
TI  - Rotavirus W179-9 vaccine (Merck and Co).

PMID- 10641235
TI  - Shigella Sonnei vaccine.

PMID- 10641236
TI  - Brain chips: postpone the debate.

PMID- 10641238
TI  - The dead donor rule.

PMID- 10641237
TI  - Organ wars.

PMID- 10641239
TI  - When is "dead"?

PMID- 10641240
TI  - A xenotransplantation protocol.

PMID- 10641241
TI  - Surfing for studies. Clinical trials on the Internet.

PMID- 10641242
TI  - Organ swapping.

PMID- 10641243
TI  - The fallacy of the "gift of life".

PMID- 10641244
TI  - Tough priorities. Organ triage and the legacy of apartheid.

PMID- 10641245
TI  - [72nd Meeting of the Society of Ophthalmologists of the Rhein-Main Region. 6
      November 1999, Homburg (Saar)].

PMID- 10641246
TI  - [3rd Glaucoma Symposium 1999. 17 November 1999 in Aachen].

PMID- 10641247
TI  - [Annual Meeting of the Bavarian Society of Ophthalmology. Erlangen, 26-27
      November 1999].

PMID- 10641248
TI  - [The Berlin-Brandenburg Ophthalmologic Society, 11-12 December 1999,
      Charite/Virchov Clinic, Humboldt University, Berlin].

PMID- 10641250
TI  - A function-based treatment for school refusal behavior using shaping and fading.
AB  - A function-based behavioral treatment package was developed for an 18-year-old
      male with mild mental retardation admitted to a specialized inpatient unit for
      treatment of severe destructive behaviors associated with school refusal
      behavior. Teacher and school attendance reports, parent interview, and
      unstructured observations led to the hypothesis that the subject's school refusal
      behavior was maintained by positive reinforcement. The treatment goals included
      increasing the subject's compliance with a morning hygiene routine and attending
      school (shaping), increasing the involvement of the subject's parents in managing
      the subject's problem behaviors (fading), and generalizing treatment from the
      hospital to the home. All three treatment goals were achieved in a relatively
      brief period of time and follow-up data indicated that the treatment effects were
      durable. The authors concluded that function-based assessment and treatment can
      be successfully utilized to treat school refusal behavior in children with
      developmental disabilities.

PMID- 10641249
TI  - A reliability study of measures assessing the impact of deinstitutionalization.
AB  - This study examined the reliability of several scales and indices used to measure
      outcome variables (independence, integration, productivity, and satisfaction)
      among people with developmental disabilities. A stratified random sample of 112
      people was interviewed twice in a two-week period and included equal numbers of
      verbal and nonverbal consumers, of parent versus other caregivers, and consumers
      with diagnosed level of retardation being dichotomized into high and low. In
      addition, half of the interviews were test-retest and half were interrater. After
      stratifying on these four variables, the sample was chosen randomly within
      subgroups from the total database of 3,700 individuals who receive services
      through the Developmental Disabilities Services Division of the Oklahoma
      Department of Human Services. Correlation and proportion agreement analyses were
      performed on the pre- and post-tests and comparisons made on each scale for each
      stratification to examine variations in reliability. Acceptable correlations and
      matched agreements of at least 0.70 for all measures were found, with the
      Adaptive Development Scale having particularly strong correlations. In addition,
      responses from people with developmental disabilities on items of the Consumer
      Satisfaction scale were acceptably reliable.

PMID- 10641251
TI  - Noncontingent reinforcement: effects of satiation versus choice responding.
AB  - Recent research findings suggest that the initial reductive effects of
      noncontingent reinforcement (NCR) schedules on destructive behavior result from
      the establishing effects of an antecedent stimulus (i.e., the availability of
      "free" reinforcement) rather than extinction. A number of authors have suggested
      that these antecedent effects result primarily from reinforcer satiation, but an
      alternative hypothesis is that the individual attempts to access contingent
      reinforcement primarily when noncontingent reinforcement is unavailable, but
      chooses not to access contingent reinforcement when noncontingent reinforcement
      is available. If the satiation hypothesis is more accurate, then the reductive
      effects of NCR should increase over the course of a session, especially for
      denser schedules of NCR, and should occur during both NCR delivery and the NCR
      inter-reinforcement interval (NCR IRI). If the choice hypothesis is more
      accurate, then the reductive effects of NCR should be relatively constant over
      the course of a session for both denser and leaner schedules of NCR and should
      occur almost exclusively during the NCR interval (rather than the NCR IRI). To
      evaluate these hypotheses, we examined within-session trends of destructive
      behavior with denser and leaner schedules of NCR (without extinction), and also
      measured responding in the NCR interval separate from responding in the NCR IRI.
      Reductions in destructive behavior were mostly due to the participants choosing
      not to access contingent reinforcement when NCR was being delivered and only
      minimally due to reinforcer satiation.

PMID- 10641252
TI  - Use of self-operated auditory prompts to decrease aberrant behaviors in students
      with moderate mental retardation.
AB  - We examined the effectiveness of self-operated auditory prompts when used to
      decrease the off-task and aberrant behaviors of two students with moderate mental
      retardation. Its purpose was to determine if self-operated auditory prompts could
      be effectively used by these individuals to decrease their off-task and aberrant
      behaviors in work settings and during transitional times between settings. A
      multiple-probe across settings design with a reversal and replication was used to
      evaluate the effectiveness of the self-operated auditory prompting system on
      aberrant student behaviors in school and community settings. Previous findings
      were replicated in this study that demonstrate that stimulus control can be
      achieved through the use of self-operated auditory prompts, and demonstrates that
      these prompts can serve to occasion a decrease in aberrant behaviors when used by
      individuals with moderate mental retardation in school and community settings.

PMID- 10641254
TI  - [Ivan Petrovich Pavlov--his greatness as a scientist and a citizen].

PMID- 10641253
TI  - The relationship of self-injurious behavior and aggression to social skills in
      persons with severe and profound learning disability.
AB  - In this study, we investigated differences in social skills among four groups of
      individuals with severe and profound learning disabilities. The comparison groups
      were composed of individuals engaging in self-injurious behavior, aggression,
      both behaviors, or neither of the behaviors. We measured social skills using the
      Matson Evaluation of Social Skills for Individuals with Severe Retardation, a
      standardized assessment of social skills in persons with severe or profound
      learning disability. The results indicated that individuals displaying
      maladaptive behaviors exhibited a restricted range of social behaviors compared
      to controls. Also, group membership based on self-injury and aggression was
      predicted based on profiles of scores on the Matson Evaluation of Social Skills
      for Individuals with Severe Retardation. These findings are consistent with
      reports in other studies that note social skills deficits in aggressive and self
      injurious persons with learning disabilities. However, in this case a
      standardized assessment of these deficits was possible and specific skills
      problems were identified. Implications of the findings for identification and
      treatment of self-injury and aggression are discussed.

PMID- 10641255
TI  - [Development of the I. P. Pavlov's idea of the goal reflex in studies of
      mechanism of the biological motivation].
AB  - An ingestional behaviour was shown to be constructed by a domineering motivation
      in the systemic organisation of behavioural acts. The paper uncovers the
      mechanisms determining the energy of biological motivations as well as their
      controlling component: the of action acceptor. The role of reinforcement is shown
      in the mechanisms of forming the behaviour molecular engrams on the action of
      result acceptor.

PMID- 10641256
TI  - [Neuronal correlates of the integrative activity in the monkey striatum].
AB  - The unit activity was studied in monkeys during various behavioural activities.
      The striatum unit responses revealed no functional specifics. Separate units
      reflected the character of activity in their firing rate as well as in different
      interrelationships between excitatory and inhibitory responses. The putamen units
      were shown to discriminate experimental alternatives mainly when the money
      arrived at a decision, and successful solving of the problem was shown to depend
      on the level of the discrimination. Specific corticofugal signals from different
      and dispersed cortical areas seem to converge while interacting at the striatum.

PMID- 10641257
TI  - [Evolutionary aspects of development of the integrative activity in the human
      brain].

PMID- 10641258
TI  - [Conditioning studies in the Pavlov's laboratory during 75 years of its existence
      (on the 150th birthday of Ivan Petrovich Pavlov)].
AB  - The paper reviews experimental and clinical data obtained on physiology and
      pathology of the higher nervous system by the Laboratory founded by I. P. Pavlov
      during 75 years of its existence: the principle of systemic organisation of the
      brain structures activity, the role of separate subcortical structures in
      organisation of behaviour, theoretical development of experimental pathology
      problems, inner inhibition, the role of sympathetic nervous system in
      conditioning, possible neurophysiological and neurochemical mechanisms of
      conditioning.

PMID- 10641259
TI  - [Basal ganglia and behavior].
AB  - A comparative analysis of the most well known hypotheses of basal ganglia
      participation in organisation and control of behavioural functions, is presented.

PMID- 10641260
TI  - [The cognitive set and problems of the human higher nervous activity].
AB  - Two kinds of cognitive sets for verbal and non-verbal stimuli were revealed in
      healthy subjects: an "intellectual blindness" and a distortion of perception and
      assessment of the stimuli size. Analysis of the response time to a probe stimulus
      and a spectral analysis of the cortical EEG revealed a participation of these
      sets in cortical functions: a stable set organizes and improves the stimuli
      perception and assessment but impedes this process in a modified situation. An
      optimal balance between the two sets seems to be necessary for effective
      cognitive activity.

PMID- 10641261
TI  - [Cytokine neurobiology: behavior and adaptive responses].
AB  - Reactions of the brain to systemic LPS or IL-1 beta treatment were shown to have
      different thresholds, be mediated by different neurotransmitter systems, and have
      different mechanisms of realisation. Changes in behaviour and neurotransmitter
      systems activity of the hypothalamus induced by a systemic IL-1 beta treatment
      were shown to be mediated by its receptors in the brain. Expression of mRNA of
      the tumour necrosis factor was revealed in the rabbit brain following
      administration of high pyrogenic doses of the LPS. The data obtained corroborate
      the concept of the cytokines role in maintenance of the defence responses in
      activation of the immune system, as well as their probable role in normal
      mechanisms of physiological functions control.

PMID- 10641262
TI  - [Systemic hemodynamics].

PMID- 10641263
TI  - [Mechanogenic regulation of the tonus and reactivity of blood vessels].
AB  - In acute experiments on cats and rats, as well as on isolated segments of the rat
      mesenteric and tail arteries, the parameters of myogenic and endothelium
      dependent regulation of the blood vessels were studied. An important role of
      mechanical stimulation of the endothelium in development of vasodilatation in the
      skeletal muscles along with the increase of the pressure pulse amplitude, was
      revealed. A diminution of endothelium-dependent vasodilatation was shown in
      spontaneously hypertensive rats in an increase of the pulse pressure.

PMID- 10641264
TI  - [Integrative mechanisms of the formation of the small intestine motor effects].
AB  - Contractile responses of the small intestine to serotonine and histamine are
      mediated by cholinergic neurones, while the inhibitory responses of the
      substances--by nonadrenergic inhibitory neurones of the enterometasympathetic
      nervous system. An inhibitory response of the small intestine to met-enkephalin
      results from its depressing action on the effector cholinergic neurones.
      Catecholamines activate enteric cholinergic neurones via presynaptic beta
      adrenoceptors and inhibit them via pre- and postsynaptic alpha-adrenoceptors. The
      cholinergic neurones of the enterometasympathetic nervous system seem to be under
      a double adrenergic control, and a mechanisms seems to exist in the small
      intestine for adrenergic activation of its contractile apparatus.

PMID- 10641265
TI  - [I. P. Pavlov's style of thinking as an experimenter in studies of the physiology
      of digestion].

PMID- 10641266
TI  - [Various responses to the "Pavlov" stimulus].

PMID- 10641267
TI  - [Pavlov and Skinner. Two lives in the science (A foreword to B. F. Skinner's
      paper: Various responses to the "Pavlov" stimulus)].

PMID- 10641268
TI  - [New documents on interrelations between the scientist and the state].

PMID- 10641269
TI  - [I. P. Pavlov's student years at the St. Petersburg Emperor's University].

PMID- 10641270
TI  - [At the origins of psychophysiology].

PMID- 10641271
TI  - [Ivan Petrovich Pavlov in the archives of the Russian Federation's Ministry of
      Defense Museum of military medicine (on the 150th birthday)].

PMID- 10641272
TI  - [Current approaches to the evaluation of genetically modified food products.
      Soybean 40-3-2 data].
AB  - Different methodological approaches were elaborated to evaluate quality and
      safety of genetically modified food products. The new engineering is proposed to
      rate medical, biological, genetic and technological advantage of these products.
      Using the same engineering, a complete analysis of the genetically modified
      soybean 40-3-2 ("Monsanto Co", USA) has been performed.

PMID- 10641273
TI  - [Medical and biological evaluation of safety of protein concentrate from
      genetically-modified soybeans. Biochemical studies].
AB  - The rats were fed with albuminous concentrate from the genetically modified
      soybean 40-3-2 ("Monsanto Co", USA) 1.25 g/rat/day for 5 months. Their blood,
      urea and liver were investigated to measure total protein and glucose levels,
      aminotransferase and alkaline phosphatase activities, pH, relative density and
      creatinine level in the urea, as well as hepatic enzyme activity of the I and II
      phases of xenobiotic metabolism, and the whole and non-sedimentated lysosomal
      enzyme activities. The lasting albuminous concentrate supplementation from the
      genetically modified soybean to the rat's diet has been shown to modify
      hepatocyte membrane function and enzymatic activity within physiological
      standards. It was not harmful to the adaptation systems.

PMID- 10641274
TI  - [Model of nutritional iron deficiency anemia in rats].
AB  - Model of alimentary iron deficiency anemia (AIDA) in rats has been created by the
      use of iron elimination from all diet components as much as possible. It was
      established that the time of AIDA development depended on iron content in diet.
      The model can be used for estimation of efficiency of new food products and food
      supplements enriched with iron.

PMID- 10641275
TI  - [Analysis of the nutritional status of space crews].
AB  - Presented are the results of nutrition status analysis of the orbital "MIR"
      station crews. Investigations carried out both on the basis of subjective
      information concerning the state of crews members appetite, quantity of consumed
      food etc. as well as on the subjectives results of biochemical blood analysis
      reflecting the status of metabolic processes in human in zero-gravity conditions.
      The obtained data prove that jointly developed Russian-American food rations
      sustained the satisfactory level of working ability and health of cosmonauts and
      astronauts.

PMID- 10641276
TI  - [Seasonal variations of vitamin sufficiency in pregnant women (Mzensk City)].
AB  - The investigation of sufficiency of vitamin C, A, E, B2, B6, carotenoids and iron
      dietary intake has been carried out in 61 pregnant women in spring and early
      autumn 1998. There were no women adequately supplied with all vitamins
      irrespective of season and residence. Most of them (70-80 per cent) had combined
      deficiency of 3-5 vitamins in spring. About 50 per cent of women had combined
      insufficiency of vitamins and iron. Intake of vitamins improved in autumn
      especially due to vitamins C, A, E and carotenoids. The frequency of 3-5 vitamins
      deficit decreased while occurrence of combined deficiency of vitamin B6 and
      carotenoids still often took place. Thus, normalization of vitamin status of
      pregnant women is necessary all year round.

PMID- 10641277
TI  - [Antacid and sorption properties of mushroom powder made of dried solids
      (Pleurotus ostreatus)].
AB  - It was established in the experiments determining the influence of the mushroom
      powder on acidity of the HCl solution by means of ionometrical method that in 15
      minutes after introduction 3 gram of the powder pH of the solution increases from
      1.62 up to 2.64. The stable meaning of the solution pH (without fall) can be
      (held) the same in the presence of the powder more than 23 hours. The mushroom
      powder reduces the high content of the ions Pb2+ and Cu2+ in the solution from
      8.8 x 10(-6) up to 3.3 x 10(-6) and from 11.8 x 10(-6) up to 8.6 x 10(-6) mole/ml
      correspondingly. The trustworthy reduction (fall) of the concentration of the
      ions Zn2+ and Cd2+ in the filtrate was not discovered (found out). To determine
      the content of metal in the solution the method of flaming atomic adsorption.

PMID- 10641278
TI  - [Evaluation of the effects of fish and vegetable omega-3 PUFA complex on the
      erythrocyte fatty acid composition in patients with ischemic heart disease and
      impaired glucose tolerance].
AB  - Anti-atherogenic diet supplemented with "Eicolen" (30% linseed oil, and 70% cod
      liver oil, 9 grams per day) has been analyzed in 10 cases of ischemic heart
      disease, and in 11 cases of ischemic heart disease complicated by impaired
      glucose tolerance. The fish and vegetable PUFA omega-3 from "Eicolen" have been
      found to improve clinical condition as well as to modify erythrocyte membrane
      fatty acid composition. The ratio omega-6/omega-3 decreased in both groups in
      different grade.

PMID- 10641279
TI  - [Possibility of correction of erythrocyte fatty acid composition in men with
      anamnesis of hereditary ischemic heart disease].
AB  - The results of 4-year monitoring of men with hereditary history of ischemic heart
      disease are presented. The examinees were divided into two groups: a group of
      diet correction with alimentary omega-3 polyunsaturated fatty acid (PUFA)
      extracted from Far Eastern sardine oil and a control group which did not take
      part in the preventive treatment. The composition of fatty acids of erythrocytes
      of men from the study and control groups was analyzed in the course of
      preventative treatment, 3, 6 months and 4 years after it. It has been proved that
      the progress of disorder in composition of fatty acids in men can be stopped by
      using alimentary omega-3 PUFA.

PMID- 10641280
TI  - [Effects of vitamin D metabolites on indicators of protein, phosphorus and
      calcium metabolism in children with chronic renal failure].
AB  - Amino acid analysis and investigation of nitrogen, calcium and phosphorus balance
      were done in two groups of patients with renal failure and osteodystrophy on
      vitamin D metabolites and analogues treatment. The results of the investigation
      confirm vitamin D metabolites influence on free amino acid metabolism and on
      nitrogen, calcium, phosphorus balance. We observed significant decreases of blood
      amino acids and good influence on renal osteodystrophy in patients treated with
      vitamin D metabolites. Vitamin D metabolites didn't influence retention, urinary
      and fecal excretion of endogenous nitrogen in patients with renal failure.

PMID- 10641281
TI  - The tert-butylammonium perchlorate complex of 2,3-naphtho-18-crown-6 at 115 K.
AB  - In the title complex, tert-butylammonium perchlorate-2,5,8,11,14,17
      hexaoxatricyclo[16.8.0.0(20,25]hexac osa- 1(26),18,20(25),21,23-pentaene-ethyl
      acetate-dichloromethane (4/4/1/1), C4H12N+.C20H26O6.ClO4-.0.25C4-H8O2.0.25CH2Cl2
      , the tert-butylammonium cation binds to the macrocyclic host (Chemical Abstracts
      name: 2,3,5,6,8,9,11,12,14,15-decahydro-1,4,7,10,13,16-hexaoxanaphtho [2,3-
      b]cyclooctadecin) in the expected tripod arrangement, while the perchlorate anion
      links naphthyl groups in the crystal through C-H...O-Cl-O...H-C interactions.
      Thermal motion analysis indicates that the tert-butylammonium group and the
      perchlorate anion each librate with respect to the host, with amplitudes of 6.2
      (4) and 11.4 (2) degrees, respectively.

PMID- 10641282
TI  - The biologically active iron chelators 2-pyridylcarboxaldehyde
      isonicotinoylhydrazone, 2-pyridylcarboxaldehyde benzoylhydrazone monohydrate and
      2-furaldehyde isonicotinoylhydrazone.
AB  - In the crystal structures of the respective title compounds, C12H10N4O,
      C13H11N3O.H2O and C11H9N3O2, variations in the torsion angles of the aromatic
      pyridyl and benzoyl groups are observed, and the disposition of the heterocyclic
      aldehyde is shown to be influenced by the ring size of this group.

PMID- 10641283
TI  - Inhibitor of HIV-1 reverse transcriptase: N'-(5-bromo-2-pyridyl)-N-[2-(2,5
      dimethoxyphenyl)ethyl]thiourea.
AB  - The crystal structure of the title compound, C16H18Br-N3O2S (HI-236), a potent
      non-nucleoside inhibitor of HIV-1 reverse transcriptase, revealed an
      intramolecular hydrogen bond between a thiourea N atom and the pyridyl-N atom [N
      H...N = 2.671 (3) A, graph-set motif S1(1)(6)] that imparts a more rigid
      conformation to the molecule. A second hydrogen bond between a thiourea N atom
      and the thiocarbonyl-S atom [N-H2...S = 3.403 (2) A, graph-set motif R2(2)(8)]
      was observed between inversion-related molecules of HI-236. The first-level
      hydrogen-bond graph-set notation for HI-236 was determined to be
      S1(1)(6)R2(2)(8).

PMID- 10641284
TI  - Taraxerol acetate at 100 K.
AB  - The title triterpene, D-friedoolean-14-en-3 beta-yl acetate, C32H52O2, was
      isolated from dichloromethane extracts of the roots of common ragweed Ambrosia
      artemisiifolia. The skeleton contains five fused six-membered rings with an
      average Csp3-Csp3 bond distance of 1.549 (6) A and one double bond of length
      1.348 (6) A. The D and E rings are cis-fused. The compound also contains a beta
      oriented acetate group with a C-O distance 1.461 (5) A.

PMID- 10641285
TI  - Network of C-H...O interactions in 4-benzyloxy-3-methoxybenzaldehyde (vanillin
      benzyl ether).
AB  - The title aldehyde, C15H14O3, crystallized in the centrosymmetric space group
      P2(1)/c with one molecule in the asymmetric unit. Six significant intermolecular
      C-H...O interactions have C...O distances ranging from 3.405 (2) to 3.802 (2) A
      and C-H...O angles ranging from 121 to 162 degrees. These six intermolecular
      interactions link a molecule directly to six neighbors and form a three
      dimensional network. The dihedral angle between the best-fit planes of the
      benzene rings within a molecule is 78.1 (1) degrees. The dihedral angle between
      the carboxaldehyde-group plane and the best-fit plane of the ring to which it is
      attached is 3 (1) degrees.

PMID- 10641286
TI  - Hydrogen bonding and C-H...O interactions in bis(4-carboxyquinolinium) sulfate
      monohydrate.
AB  - The title substance, 2C10H8NO2+.SO4(2-).H2O, crystallized in the centrosymmetric
      space group P1 with two organic cations, one sulfate ion and one water molecule
      in the asymmetric unit. Seven leading intermolecular hydrogen bonds are formed in
      this structure: two N-H...O bonds have N...O distances of 2.592 (3) and 2.650 (3)
      A, while five O-H...O bonds have O...O distances ranging from 2.493 (2) to 3.072
      (3) A. All of the potential donors are involved in these bonds, but three of the
      potential nine acceptors are not. The H and O atoms in all these hydrogen bonds
      are ordered. The hydrogen bonds form a three-dimensional network. In addition,
      there are nine significant C-H...O interactions for which the H...O distances are
      less than the corresponding van der Waals radii sum. The dihedral angle between
      the best-fit quinoline core plane and the carboxyl group plane is 35.2 (3)
      degrees for one of the organic cations and 6.4 (4) degrees for the other.

PMID- 10641287
TI  - Surface plasmon resonance (SPR) analysis of coagulation in whole blood with
      application in prothrombin time assay.
AB  - It is previously shown that surface plasmon resonance (SPR) can be used to study
      blood plasma coagulation. This work explores the use of this technique for the
      analysis of tissue factor induced coagulation, i.e. prothrombin time (PT)
      analysis, of whole blood and plasma. The reference method was nephelometry. The
      prothrombin time analysis by SPR was performed by mixing two volumes of
      blood/plasma, one volume of thromboplastin, and one volume of CaCl2 solution
      directly on a sensor surface. The measurements show good agreement between
      nephelometry and SPR plasma analysis and also between SPR plasma and whole blood
      analysis. The effect of anticoagulant treatment on the clotting times was
      significant both quantitatively and qualitatively. The impact on the SPR signal
      of different physiological events in the coagulation process is discussed, and
      tentative interpretations of the sensorgram features are given. The major
      advantage of the SPR method compared to nephelometry is the possibility to
      perform analysis on whole blood instead of plasma. In conclusion, SPR is a
      promising method for whole blood coagulation analysis.

PMID- 10641288
TI  - Study of erythrocyte sedimentation behavior by piezoelectric crystal impedance
      sensor.
AB  - Based on the impedance characteristic of erythrocytes at high frequency, the
      response of piezoelectric crystal impedance (PCI) sensor in the erythrocyte
      suspension was derived and verified experimentally. A method of using PCI sensor
      to investigate erythrocyte aggregation-sedimentation phenomenon was proposed.
      From the frequency response of the PCI sensor, the erythrocyte aggregation time
      and sedimentation rate could be obtained during erythrocyte aggregation and
      sedimentation. With the present method, the effects of the erythrocyte
      deformability, the osmotic pressure and the coexisting macromolecules on the
      erythrocyte sedimentation rate were studied. The results show that the PCI sensor
      possesses some advantages, such as good sensitivity, simplicity of use and no
      thermal effect for the impedance study of erythrocyte aggregation and
      sedimentation.

PMID- 10641289
TI  - Sensitive amperometric biosensor for the determination of biogenic and synthetic
      amines using pea seedlings amine oxidase: a novel approach for enzyme
      immobilisation.
AB  - We prepared a new inorganic sorbent based on modified triazine (2-[4,6-bis
      (aminoethylamine)-1,3,5-triazine]-Silasorb; BAT-Silasorb) which binds pea
      seedlings amine oxidase (PSAO) very tightly without loss of its catalytic
      activity. This unique feature as well as the wide substrate specificity of PSAO
      was successfully utilised in the construction of an amperometric biosensor based
      on a carbon paste electrode for the fast and sensitive detection of various
      amines at a formal potential 0 mV versus Ag/AgCl reference electrode. The
      reaction layer of the biosensor is created by the direct immobilisation of PSAO
      at the electrode surface via affinity carrier BAT-Silasorb. Used arrangement
      facilitates a simple restoration of the inactive biosensor. An amperometric
      signal results from horseradish peroxidase catalysed reduction of H2O2, a
      secondary product of the oxidative deamination of amines, catalysed by PSAO. The
      sensor was used for the basic characterisation of 55 biogenic and synthetic
      amines, from numerous mono-, di- and polyamines to various hydroxy-, thio-,
      benzyl- and aromatic derivatives in order to establish its suitability as a
      postcolumn detector. Its high sensitivity to putrescine 20.0 +/- 0.64 mA l-1 per
      mol (636.9 +/- 2.03 mA l-1 per mol per cm2), a limit of detection of 10 nmol l-1
      (determined with respect to a signal-to-noise ratio 3:1), a linear range of
      current response to 0.01-100 mumol l-1 concentration of substrate and good
      reproducibility all indicate that the sensor could be applied to future
      industrial and clinical analyses.

PMID- 10641290
TI  - Development of sensors for direct detection of organophosphates. Part I:
      Immobilization, characterization and stabilization of acetylcholinesterase and
      organophosphate hydrolase on silica supports.
AB  - Biosensors for organophosphates in solution may be constructed by monitoring the
      activity of acetylcholinesterase (AChE) or organophosphate hydrolase (OPH)
      immobilized to a variety of microsensor platforms. The area available for enzyme
      immobilization is small (< 1 mm2) for microsensors. In order to construct
      microsensors with increased surface area for enzyme immobilization, we used a sol
      gel process to create highly porous and stable silica matrices. Surface porosity
      of sol-gel coated surfaces was characterized using scanning electron microscopy;
      pore structure was found to be very similar to that of commercially available
      porous silica supports. Based upon this analysis, porous and non-porous silica
      beads were used as model substrates of sol-gel coated and uncoated sensor
      surfaces. Two different covalent chemistries were used to immobilize AChE and OPH
      to these porous and non-porous silica beads. The first chemistry used amine
      silanization of silica followed by enzyme attachment using the homobifunctional
      linker glutaraldehyde. The second chemistry used sulfhydryl-silanization followed
      by enzyme attachment using the heterobifunctional linker N-gamma
      maleimidobutyryloxy succinimide ester (GMBS). Surfaces were characterized in
      terms of total enzyme immobilized, total and specific enzyme activity, and long
      term stability of enzyme activity. Amine derivitization followed by
      glutaraldehyde linking yielded supports with greater amounts of immobilized
      enzyme and activity. Use of porous supports not only yielded greater amounts of
      immobilized enzyme and activity, but also significantly improved long term
      stability of enzyme activity. Enzyme was also immobilized to sol-gel coated glass
      slides. The mass of immobilized enzyme increased linearly with thickness of
      coating. However, immobilized enzyme activity saturated at a porous silica
      thickness of approximately 800 nm.

PMID- 10641291
TI  - A microbial biosensor based on Yarrowia lipolytica for the off-line determination
      of middle-chain alkanes.
AB  - A microbial biosensor based on immobilised psychrotrophic yeast Yarrowia
      lipolytica integrated to FIA for the determination of middle chain alkanes was
      developed. The system responded very well to middle chain alkanes even at low
      operational temperatures down to +5 degrees C. The maximum sensitivity was
      obtained at 15 degrees C. A linear relationship was observed between the sensor
      response and dodecane concentration up to 100 microM.

PMID- 10641292
TI  - Comparative electrochemical behaviour of biotin hydrazide and photobiotin.
      Importance in the development of biosensors.
AB  - The cyclic voltammetric behaviour of biotin hydrazide and photobiotin on carbon
      paste electrodes has been studied. Biotin hydrazide presents an anodic and
      irreversible process, meanwhile photobiotin presents two, adsorptive in nature.
      This characteristic makes photobiotin desirable for following the interaction
      between biotin and streptavidin, being possible to detect a streptavidin
      concentration of 10(-12) M. The evidence of this reaction has been shown either
      directly in solution or on the electrode surface. Photobiotin as the molecule
      portable of analytical information and carbon paste as the solid support could be
      applied to the development of sensors based on the oxidation of this molecule.

PMID- 10641293
TI  - A glucose biosensor operating under non-isothermal conditions: the dynamic
      response.
AB  - The results obtained with a glucose biosensor operating under non-isothermal
      conditions are presented and discussed. Glucose oxidase, immobilized onto Nylon
      membranes, was used as biological element. An amperometric two electrodes system
      was employed to measure the anodic current produced by oxidation of hydrogen
      peroxide. Non-isothermal conditions were characterised in terms of the
      temperature difference, delta T = Tw - Tc, and of the average temperature of the
      system, Tav = (Tw + Tc)/2, Tw and Tc being the temperature in the warm and cold
      half-cells constituting the biosensor. Comparison between the functioning of the
      biosensor under isothermal and non-isothermal conditions was performed. It was
      found that, under non-isothermal conditions, the dynamic response and sensitivity
      increased, while the response times and the detection limit decreased, if
      comparison was done with the same parameters measured under isothermal
      conditions. The increase of the dynamic response was found to be proportional to
      the applied temperature gradient.

PMID- 10641294
TI  - Interaction between impaired and unimpaired speakers: inter-subjectivity and the
      interplay of culturally shared and situation specific knowledge.
AB  - The part played by culturally shared knowledge in interaction is generally
      recognised. However, the details of how it may be manifested in interaction are
      largely undocumented. This study explores this issue in the context of
      interactions between impaired and unimpaired speakers, using a conversation
      analytic approach in combination with a communication task commonly employed in
      experimental social psychology. Three exemplary cases are analysed. Results show
      that when the task interaction is co-constructed, the interaction is
      collaboratively enacted, participants' actions are in alignment, and the task
      outcome is relatively accurate. When the unimpaired speaker proceeds on the basis
      of culturally shared knowledge, and thereby 'unilaterally' manages the
      interaction, two courses of action are available to the impaired speaker. The
      impaired speaker may make attempts to provide situation specific details. In this
      case, because each participant is drawing on different resources to construct the
      interaction, their actions are out of alignment, and the task outcome is less
      accurate. Alternatively, the impaired speaker may concur with the culturally
      shared knowledge drawn on by the unimpaired speaker, in which case the
      participants' actions are in alignment, but the task outcome is highly
      inaccurate. The authors conclude that by combining a conversation analytic
      approach with a communication task which reflects participants' everyday
      experiences, orientations to different interaction resources can be drawn out.
      This can have relevance for, and help to elicit, practices in everyday
      interaction.

PMID- 10641295
TI  - Towards a relational self: social engagement during pregnancy and psychological
      preparation for motherhood.
AB  - This study works towards a theoretical model of the relational self derived from
      the intensive examination of a small number of case studies of women going
      through their first pregnancy. The study is idiographic, grounded in the women's
      own accounts of the experience, and it is primarily qualitative. It employs
      interviews, diaries, repertory grids and interpretative phenomenological
      analysis. The theory argues that pregnancy can accentuate the symbiotic relation
      of one's perception of self and others, and that this aids psychological
      preparation for mothering. Increasing contact with key others can be
      psychologically informative: the woman may perceive herself as becoming more like
      key other(s); close involvement with existing family can facilitate the woman's
      preparation for taking on the new role of mother. The model is explicated with
      illustrations from the women's accounts. It is then discussed in relation to the
      existing literature.

PMID- 10641296
TI  - Building your own lifeboat: working-class male offenders talk about economic
      crime.
AB  - This study examines the ways in which a group of working-class men serving
      custodial sentences and probation orders for money-related crimes talk about
      criminal activity and the implications of this talk for their gender identity.
      Using a critical social-psychological approach, we carried out nine semi
      structured group discussions in probation centres and one open prison and then
      analyzed the transcripts using a combination of grounded theory and discourse
      analytic methods. The men critiqued dominant constructions of crime and argued
      that their criminal activity was justified in two related ways. First, they drew
      on a discourse of male breadwinning to argue that they were expected to provide
      for their families. Second, they argued that those now suffering under the broken
      promises made by the State should not be expected to conform to its rules. For
      the majority of men, earning through crime was talked about as a last resort and
      the parameters of 'what they did to whom' were informed by a Robin Hood-type
      cultural narrative. Finally, the study contextualizes and critically explores
      these patterns of discourse and their rhetorical use from a historical and
      structural perspective.

PMID- 10641297
TI  - Garnering the interest of others: mediating the effects among physical
      attractiveness, self-worth and dominance.
AB  - OBJECTIVES: Evolutionary psychologists emphasize that self-worth and well-being
      are largely determined by the degree to which individuals garner and hold the
      interest of others. Personal attributes, such as physical attractiveness, are
      viewed as resources which serve as signals to others to pay attention to us.
      DESIGN AND METHOD: This study examined (a) the degree to which participant
      appraisals (N = 75) of self-worth were related to appraisals of how interested
      others were in them; and (b) the extent to which interest ratings account for the
      relation among self-worth, dominance and attractiveness ratings. RESULTS: The
      main findings of the present study showed (a) that the degree to which
      individuals derive self-worth from various attributes was strongly related to the
      degree to which individuals believed others were interested in them; and (b) that
      the amount of interest one believes others show in them mediated the relation
      between physical attractiveness and social self-worth. CONCLUSION: Results have a
      number of implications concerning the nature of self-worth and the utility of
      psychological theories that emphasize evolutionary principles.

PMID- 10641298
TI  - Analysis of activity preferences as a function of differential consequences.
AB  - Individuals who do not possess the verbal skills to express meaningful choice in
      the absence of its consequences may have difficulty indicating their preference
      for protracted activities that are unavailable until some time in the future
      (e.g., taking a walk, riding a bike). When we examined the preferences of 4
      individuals with developmental disabilities by showing them pictorial
      representations of various activities, their initial choices showed no clear
      preferences. In a subsequent condition, selecting a photograph resulted in brief
      access to the depicted activity. When selections produced differential
      consequences (i.e., access to the activity), clear preferences emerged. In
      addition, 3 individuals' preferences were later shifted to an initially less
      preferred but more socially desirable option by superimposing additional
      reinforcement contingencies for engaging in the less preferred activity. Results
      are discussed in terms of the conditions under which choice functions as an
      indicator of preference and how those conditions may be altered to improve the
      quality of choice making without limiting access to preferred options.

PMID- 10641299
TI  - An evaluation of the properties of attention as reinforcement for destructive and
      appropriate behavior.
AB  - The analogue functional analysis described by Iwata, Dorsey, Slifer, Bauman, and
      Richman (1982/1994) identifies broad classes of variables (e.g., positive
      reinforcement) that maintain destructive behavior (Fisher, Ninness, Piazza, &
      Owen-DeSchryver, 1996). However, it is likely that some types of stimuli may be
      more effective reinforcers than others. In the current investigation, we
      identified 2 participants whose destructive behavior was maintained by attention.
      We used concurrent schedules of reinforcement to evaluate how different types of
      attention affected both destructive and appropriate behavior. We showed that for
      1 participant praise was not an effective reinforcer when verbal reprimands were
      available; however, praise was an effective reinforcer when verbal reprimands
      were unavailable. For the 2nd participant, we identified a type of attention that
      effectively competed with verbal reprimands as reinforcement. We then used the
      information obtained from the assessments to develop effective treatments to
      reduce destructive behavior and increase an alternative communicative response.

PMID- 10641300
TI  - Evaluating self-control and impulsivity in children with severe behavior
      disorders.
AB  - Impulsivity and self-control involve a choice between a smaller, more immediate
      reinforcer and a larger, more delayed reinforcer. Impulsive behavior occurs when
      responding produces the more immediate, relatively smaller reinforcers at the
      expense of delayed larger reinforcers. Self-control occurs when responding
      produces delayed larger reinforcers at the expense of immediate smaller
      reinforcers. Recently, researchers in applied behavior analysis have suggested
      that evaluations of self-control and impulsivity are relevant to socially
      important behaviors. Further, common behavioral treatments such as differential
      reinforcement may be influenced by variables such as reinforcer delay. In this
      study, we showed that aggression, reinforced by access to food, could be
      maintained as impulsive behavior. The participants were 2 young boys with severe
      developmental disabilities. For both participants, descriptive observations, care
      provider report, and functional analyses suggested that aggression was reinforced
      by food access (and television access for 1 participant). Next, we introduced a
      differential reinforcement procedure in which appropriate mands were reinforced.
      After various manipulations, we showed that aggression occurred when it produced
      immediate but small reinforcers even though mands produced larger, more delayed
      reinforcers. However, both participants displayed self-control when the delay to
      reinforcement was signaled (with a hand gesture or a timer).

PMID- 10641301
TI  - A systematic evaluation of preferences identified through person-centered
      planning for people with profound multiple disabilities.
AB  - Person-centered planning is becoming a popular means of designing supports for
      people with disabilities. However, very little research evaluating person
      centered planning exists. We evaluated the degree to which items and activities
      reported to be preferred in person-centered plans represented accurate
      preferences based on how individuals responded when presented with the items and
      activities. Person-centered planning meetings were conducted with 4 individuals
      with profound multiple disabilities to develop preference maps and to identify
      leisure-related preferences. A sample of the reported preferences in the plans
      was then systematically assessed by observing each participant's approach and
      avoidance responses to the items and activities. Of the sampled items and
      activities reported to be preferred in the plans, 42% represented moderate
      preferences based on the latter assessment process and 33% represented strong
      preferences. With 2 participants, several preferences identified in the plans
      were nonpreferred items and activities based on the preference assessments, and
      some were frequently avoided. These results suggested that although person
      centered plans may identify some accurate preferences for people with profound
      multiple disabilities, this approach should be used cautiously. Results also
      suggested that such plans should be supplemented with systematic preference
      assessments to ensure the accuracy of identified preferences. Future research
      areas focus on evaluating other aspects of person-centered planning.

PMID- 10641302
TI  - Relative versus absolute reinforcement effects: implications for preference
      assessments.
AB  - We compared results obtained in two previous studies on reinforcer identification
      (Fisher et al., 1992; Pace, Ivancic, Edwards, Iwata, & Page, 1985) by combining
      methodologies from both studies. Eight individuals with mental retardation
      participated. During Phase 1, two preference assessments were conducted, one in
      which stimuli were presented singly (SS method) and one in which stimuli were
      presented in pairs (PS method). Based on these results, two types of stimuli were
      identified for each participant: High-preference (HP) stimuli were those selected
      on 75% or more trials during both preference assessments; low-preference (LP)
      stimuli were those selected on 100% of the SS trials but on 25% or fewer of the
      PS trials. During Phase 2, the reinforcing effects of HP and LP stimuli were
      evaluated in reversal designs under two test conditions: concurrent and single
      schedules of continuous reinforcement. Two response options were available under
      the concurrent-schedule condition: One response produced access to the HP
      stimulus; the other produced access to the LP stimulus. Only one response option
      was available under the single-schedule condition, and that response produced
      access only to the LP stimulus. Results indicated that 7 of the 8 participants
      consistently showed preference for the HP stimulus under the concurrent schedule.
      However, when only the LP stimulus was available during the single-schedule
      condition, response rates for 6 of the 7 participants were as high as those
      observed for the HP stimulus during the concurrent-schedule condition (1
      participant showed no reinforcement effect). These results indicate that,
      although the concurrent-schedule procedure is well suited to the assessment of
      relative reinforcement effects (preference for one reinforcer over another),
      absolute reinforcement effects associated with a given stimulus may be best
      examined under single-schedule conditions.

PMID- 10641303
TI  - Evaluation of antecedent stimulus parameters for the treatment of escape
      maintained aberrant behavior.
AB  - We evaluated a methodology for identifying the range of stimulus features of
      antecedent stimuli associated with aberrant behavior in demand contexts in
      natural settings. For each participant, an experimental analysis of antecedents
      (Phase 1) was conducted to confirm the hypothesis that task instructions
      occasioned increases in aberrant behavior. During Phase 2, specific stimulus
      features associated with the presentation of task instructions were assessed by
      evaluating the child's behavior across two distinct settings, therapists, and
      types of tasks in a sequential fashion. Aberrant behavior occurred immediately
      across settings and therapists, presumably because the presence of a
      discriminative stimulus for escape-maintained behavior (the delivery of a task
      instruction) occasioned aberrant behavior. However, aberrant behavior decreased
      initially across tasks, suggesting that familiarity with the task might be a
      variable. During Phase 3, an experimental (functional) analysis of consequences
      was conducted with 2 participants to verify that aberrant behavior was maintained
      by negative reinforcement. During Phase 4, a treatment package that interspersed
      play with task instructions was conducted to disrupt the ongoing occurrence of
      aberrant behavior. Immediate and durable treatment effects occurred for 2 of the
      3 participants.

PMID- 10641304
TI  - On the displacement of leisure items by food during multiple-stimulus preference
      assessments.
AB  - Previous studies have demonstrated that when food and leisure stimuli are
      combined in multiple-stimulus preference assessments, individuals typically
      select food more often, although the leisure stimuli also have known reinforcing
      properties. The purpose of the current study was to replicate this effect and
      determine its durability by examining the effect after mealtimes. Four adults who
      had been diagnosed with severe mental retardation were given three initial
      multiple-stimulus (without replacement) preference assessments (i.e., food,
      leisure stimuli, and combined). All participants selected food items as the most
      preferred stimuli in the combined assessments. Combined assessments were then
      administered immediately before and after the evening meal for each participant
      for 1 week. The results showed similar data both before and after mealtimes.

PMID- 10641305
TI  - The use of symmetrical "do" and "don't" requests to interrupt ongoing activities.
AB  - The results of a modified functional analysis demonstrated that aggression,
      displayed by a 27-year-old man, was occasioned by the use of "don't" requests to
      interrupt the client's ongoing and often inappropriate activities (e.g., lying on
      the floor, pica, inappropriate touching of others). Subsequent analyses
      demonstrated that aggression was lower when ongoing activities were interrupted
      with symmetrical "do" requests than with "don't" requests. An intervention
      utilizing symmetrical "do" requests (i.e., prompting an individual to engage in
      an incompatible behavior) to interrupt such activities resulted in reduced levels
      of aggression.

PMID- 10641307
TI  - Further evaluation of reinforcer magnitude effects in noncontingent schedules.
AB  - We closely replicated the procedures of a previous study that showed a positive
      relationship between reinforcer magnitude and the response-rate-reducing effects
      of noncontingent schedules (NCS). NCS reduced response rates, as expected, but
      the NCS-magnitude effect was not reproduced, illuminating possible weaknesses of
      current arbitrary-response procedures and suggesting avenues for future research.

PMID- 10641306
TI  - Rapid assessment of the effects of restraint on self-injury and adaptive
      behavior.
AB  - We evaluated the effects of restraint on occurrences of self-injurious behavior
      (SIB) and adaptive responses exhibited by 2 individuals across eight response
      effort conditions: baseline (no restraints); restraint sleeves without stays;
      restraints with 5, 10, 15, 20, or 25 thin metal stays; and restraints with five
      thick metal stays. From this analysis, we identified a restraint level for each
      participant that reduced SIB but did not inhibit adaptive responding.

PMID- 10641308
TI  - Behavior modification: what it is and how to do it: a review of Martin and Pear's
      6th edition

PMID- 10641309
TI  - Dynamic instability of visuospatial images.
AB  - Five experiments using a visuospatial task were conducted to study memory
      accuracy and variability and to identify the origin of variations in steady
      states. This research was conducted from a dynamical perspective, that is, by
      analyzing the temporal course of discrepancies between the perceptual
      configuration and its memory (accuracy) and the temporal course of discrepancies
      between 2 successive memories (variability). In Experiment 1 the stimulus (12
      black dots randomly disposed) was presented repeatedly to assess the general
      evolution of accuracy and variability. In Experiments 2 and 3 memory accuracy and
      memory variability were separated to identify their relationship. In Experiments
      4 and 5 memory variability was studied to determinate the origin of steady state
      variations. Results show that memory accuracy and memory variability evolved
      independently and that memory variability reached a threshold that was subject
      dependent. The dynamic properties of image construction and stability are
      discussed.

PMID- 10641311
TI  - Perceiving spatially inseparable objects: evidence for feature-based object
      selection not mediated by location.
AB  - In 4 experiments, stimulus elements were arranged into an LED-like array, and
      letters were defined within the array by feature similarity between the elements
      with respect to color and form. These stimuli allowed the display of a target and
      a distractor letter simultaneously at the same location. They were spatially
      inseparable but could be separated in feature space. Participants had to identify
      the letter on a prespecified feature dimension (color or form). As a result, the
      distractors produced specific compatibility effects. This showed that nontarget
      features could not be ignored at an early stage (i.e., that color and form were
      processed automatically and in parallel up to a high stage). The target was
      selected from the resulting objects according to the prespecified feature
      dimension. Results demonstrate that object selection is possible without
      selecting absolute spatial arrays.

PMID- 10641310
TI  - The temporal dynamics of visual search: evidence for parallel processing in
      feature and conjunction searches.
AB  - Feature and conjunction searches have been argued to delineate parallel and
      serial operations in visual processing. The authors evaluated this claim by
      examining the temporal dynamics of the detection of features and conjunctions.
      The 1st experiment used a reaction time (RT) task to replicate standard mean RT
      patterns and to examine the shapes of the RT distributions. The 2nd experiment
      used the response-signal speed-accuracy trade-off (SAT) procedure to measure
      discrimination (asymptotic detection accuracy) and detection speed (processing
      dynamics). Set size affected discrimination in both feature and conjunction
      searches but affected detection speed only in the latter. Fits of models to the
      SAT data that included a serial component overpredicted the magnitude of the
      observed dynamics differences. The authors concluded that both features and
      conjunctions are detected in parallel. Implications for the role of attention in
      visual processing are discussed.

PMID- 10641312
TI  - Influence of attentional capture on oculomotor control.
AB  - Previous research has shown that when searching for a color singleton, top-down
      control cannot prevent attentional capture by an abrupt visual onset. The present
      research addressed whether a task-irrelevant abrupt onset would affect eye
      movement behavior when searching for a color singleton. Results show that in many
      instances the eye moved in the direction of the task-irrelevant abrupt onset.
      There was evidence that top-down control could neither entirely prevent
      attentional capture by visual onsets nor prevent the eye from starting to move in
      the direction of the onset. Results suggest parallel programming of 2 saccades: 1
      voluntary goal-directed eye movement toward the color singleton target and 1
      stimulus-driven eye movement reflexively elicited by the abrupt onset. A
      neurophysiologically plausible model that can account for the current findings is
      discussed.

PMID- 10641313
TI  - Do equiluminant object onsets capture visual attention?
AB  - S. Yantis and A. P. Hillstrom (1994) have claimed that abrupt onset of a new
      visual object captures attention even when the new object is equiluminant with
      its background, implying that attention is captured at the level of object
      descriptions rather than at the level of luminance change detection. S. Yantis
      and A. P. Hillstrom's experiments contained potential flaws that call their
      conclusion into question. The present article reports 5 experiments investigating
      these and related issues. The results suggest that for abruptly onsetting visual
      objects to capture attention, detection of change in a dimension of sensory
      stimulation is a necessary, but perhaps not a sufficient, requirement. Evidence
      is also presented against the view that attentional priority for new objects
      arises as a result of visual masking of old objects in the same displays.

PMID- 10641314
TI  - Comparing effects of the horizontal-vertical illusion on grip scaling and
      judgment: relative versus absolute, not perception versus action.
AB  - The discovery that the prehension component of an open-loop, two-fingered reach
      is largely immune to certain salient pictorial illusions has been used to suggest
      that humans possess 2 distinct visual systems, 1 that subserves perceptual
      judgment and 1 that mediates visually controlled action. In this article, the
      authors present evidence that suggests that the critical distinction is not that
      of reaching and judgment but of relative and absolute perception. Experiment 1
      extends the findings of S. Aglioti, J. F. X. DeSouza, and M. A. Goodale (1995)
      and suggests that the manual prehension component of open-loop reaching is
      affected by the horizontal-vertical illusion to a much smaller degree than
      perceptual size judgments. In Experiments 2 and 3, however, when perceptual size
      judgment is directed at a single element of the display, this difference
      vanishes. Experiment 4 demonstrates that grip scaling is strongly affected by the
      illusion when a single reach is scaled to both the horizontal and vertical
      components of a triangular figure.

PMID- 10641315
TI  - Action for perception: a motor-visual attentional effect.
AB  - Five experiments investigated whether preparation of a grasping movement affects
      detection and discrimination of visual stimuli. Normal human participants were
      required to prepare to grasp a bar and then to grasp it as fast as possible on
      presentation of a visual stimulus. On the basis of the degree of sharing of their
      intrinsic properties with those of the to-be-grasped bar, visual stimuli were
      categorized as "congruent" or "incongruent." Results showed that grasping
      reaction times to congruent visual stimuli were faster than reaction times to
      incongruent ones. These data indicate that preparation to act on an object
      produces faster processing of stimuli congruent with that object. The same
      facilitation was present also when, after the preparation of hand grasping,
      participants were suddenly instructed to inhibit the prepared grasping movement
      and to respond with a different motor effector. The authors suggest that these
      findings could represent an extension of the premotor theory of attention, from
      orienting of attention to spatial locations to orienting of attention to
      graspable objects.

PMID- 10641316
TI  - Perceptual organization of complex auditory sequences: effect of number of
      simultaneous subsequences and frequency separation.
AB  - Previous findings on streaming are generalized to sequences composed of more than
      2 subsequences. A new paradigm identified whether listeners perceive complex
      sequences as a single unit (integrative listening) or segregate them into 2 (or
      more) perceptual units (stream segregation). Listeners heard 2 complex sequences,
      each composed of 1, 2, 3, or 4 subsequences. Their task was to detect a temporal
      irregularity within 1 subsequence. In Experiment 1, the smallest frequency
      separation under which listeners were able to focus on 1 subsequence was
      unaffected by the number of co-occurring subsequences; nonfocused sounds were not
      perceptually organized into streams. In Experiment 2, detection improved
      progressively, not abruptly, as the frequency separation between subsequences
      increased from 0.25 to 6 auditory filters. The authors propose a model of
      perceptual organization of complex auditory sequences.

PMID- 10641317
TI  - The attentional blink reflects retrieval competition among multiple rapid serial
      visual presentation items: tests of an interference model.
AB  - When people respond to a target (T1) in a rapid serial visual presentation
      stream, their perception of a subsequent target (T2) is impaired if the
      intertarget stimulus onset asynchrony is between about 100 and 500 ms. Three
      experiments supported the interference model's (K. L. Shapiro, J. E. Raymond, &
      K. M. Arnell, 1994) claim that this attentional blink reflects competition for
      retrieval among multiple items in visual short-term memory. Experiments 1 and 2
      revealed that items appearing during the blink are named as T2 on an above-chance
      proportion of trials when T2 must be identified. Experiment 3 demonstrated that
      both the size of the blink and sensitivity to T2 reflected the number of items
      competing for retrieval as T2; such competition, moreover, occurred at a
      conceptual or categorical level rather than at a purely visual one. The
      relationship between the interference and alternative models of the attentional
      blink is discussed.

PMID- 10641318
TI  - 2-D center-surround effects on 3-D structure-from-motion.
AB  - This study investigates how mechanisms for amplifying 2-D motion contrast
      influence the assignment of 3-D depth values. The authors found that the
      direction of movement of a random-dot conveyor belt strongly inclined observers
      to report that the front surface of a superimposed, transparent, rotating, random
      dot sphere moved in a direction opposite to the belt. This motion-contrast effect
      was direction selective and demonstrated substantial spatial integration. Varying
      the stereo depth of the belt did not compromise the main effect, precluding a
      mechanical interpretation (sphere rolling on belt). Varying the speed of the
      surfaces of the sphere also did not greatly affect the interpretation of rotation
      direction. These results suggest that 2-D center-surround interactions influence
      3-D depth assignment by differentially modulating the strength of response to the
      moving surfaces of an object (their prominence) without affecting featural
      specificity.

PMID- 10641319
TI  - Repetition blindness for locations: evidence for automatic spatial coding in an
      RSVP task.
AB  - The authors report a new phenomenon called repetition blindness (RB) for
      locations: When 3 or 4 letters are presented rapidly and sequentially at random
      locations within a spatial array, experimental participants have difficulty
      reporting pairs of letters appearing in the same location within 250 ms of each
      other. This deficit occurs both during report of letter identities and during
      report of the locations in which the letters appear; it can also be found using a
      partial report task. During letter report, the deficit is found for 4-location
      arrays but not for 8-location arrays. In contrast, letter RB is not found during
      location report even when the letters are always chosen from a set of 4. These
      results indicate that a small number of locations--but not letters--can be
      encoded automatically even when they are not explicitly reported. The authors
      argue that RB for locations results from a difficulty individuating 2 tokens at
      the same spatial location.

PMID- 10641320
TI  - Children's haptic and cross-modal recognition with familiar and unfamiliar
      objects.
AB  - Five-year-old children explored multidimensional objects either haptically or
      visually and then were tested for recognition with target and distractor items in
      either the same or the alternative modality. In Experiments 1 and 2, haptic,
      visual, and cross-modal recognition were all nearly with familiar objects; haptic
      and visual recognition were also excellent with unfamiliar objects, but cross
      modal recognition was less accurate. In Experiment 3, cross-modal recognition was
      also less accurate than within-mode recognition with familiar objects that were
      members of the same basic-level category. The results indicate that children's
      haptic recognition is remarkably good, that cross-modal recognition is otherwise
      constrained, and that cross-modal recognition may be accomplished differently for
      familiar and unfamiliar objects.

PMID- 10641321
TI  - Oligomeric and biogenetic combinatorial libraries.

PMID- 10641322
TI  - Biosynthesis of marine natural products: microorganisms and macroalgae.

PMID- 10641323
TI  - Quinoline, quinazoline and acridone alkaloids.

PMID- 10641324
TI  - The hemithigh microvascular transfer (combined anterolateral thigh flap and
      tensor fasciae latae flap) for a full thickness abdominal wall reconstruction: a
      case report.
AB  - In large, full thickness upper abdominal wall defects a free microvascular tissue
      transfer is the only option which will enable reconstruction of the structural
      integrity of the abdominal wall as well as give a good aesthetic appearance. We
      present a case in which such a defect was reconstructed by a 29 x 19 cm hemithigh
      free flap, combining the adjacent vascular territories of the anterolateral thigh
      flap and the tensor fasciae latae flap based on the lateral circumflex femoral
      artery.

PMID- 10641325
TI  - Importance of the short saphenous vein as a vein graft.

PMID- 10641326
TI  - Tumor implantation at the flap donor site: a case report.
AB  - The genesis of cancer and its variable patterns of spread have been theorized and
      debated upon for decades. Recurrences, both local and metastatic, are dreaded by
      both the patient as well as the surgeon. An interesting case of tumor
      implantation at the flap donor site was noted in a patient who underwent a
      primary flap reconstruction for cancer of the cheek. The details of the case and
      theories regarding tumor implantation have been enumerated in this report.

PMID- 10641327
TI  - Our experience with the use of the temporal muscle in facial surgery.
AB  - The authors present their experience with the use of the temporal muscle in
      reconstruction of defects after exenteration of the orbit, palate, filling of the
      spaces after extirpation of extensive tumours in the infratemporal area and area
      of the anterior cranial fossa. They operated a total of 25 patients where they
      used part of the temporal muscle or the whole muscle. None of the operated
      patients, although two had a ligature of the external carotid artery, developed
      necrosis or inflammatory complications during incorporation of the transferred
      muscle. The procedure can be considered a reliable method in the reconstruction
      of the face and cranial base.

PMID- 10641328
TI  - Reconstruction of elbow flexion by transposition of pedicled long head of triceps
      brachii muscle.
AB  - A new technique of restored flexion in the elbow joint in an inveterate injury of
      the brachial plexus is described. The insertion of the long head of the triceps
      brachii muscle was transferred with an intact nervous and vascular supply to the
      anterior brachial region and sutured above the radial tuberosity with the
      insertion tendon of the biceps brachii muscle. The muscle strength three months
      after surgery according to the muscle test was 4-. Flexion in the elbow joint was
      possible up to 85 degrees. Extension in the elbow joint was preserved, the muscle
      strength was 3. Anatomical investigation revealed that the mean length of the
      nerve of the long head of the triceps was 5.5 cm, the number of terminal branches
      was 3-4, 70% of the vascular supply was from the brachial artery, the length of
      the vascular bundle was 3.6 cm. In 33% there was an additional neurovascular
      hilus which was 2-3 cm distally from the main hilus. The investigation confirms
      that the neurovascular pedicle of the long head of the triceps brachii muscle is
      sufficiently mobile and damage by traction during transposition of the insertion
      tendon is therefore not likely. Transfer of the long head of the triceps brachii
      muscle in inveterate injuries of the brachial plexus is a suitable alternative
      for reconstruction of nerves or transfer of other muscles to restore flexion in
      the elbow joint.

PMID- 10641329
TI  - Time trends in incidence of hypertrophic scarring in children treated for burns.
AB  - Control of burn-scar hypertrophy remains a priority program in the care of burned
      children. We analysed data from 779 clinical notes of children aged from 0 to 15
      years who were hospitalised at the Burn Centre in Brno between 1991 and 1996. The
      occurrence of hypertrophic scarring in burn-injured children was studied by
      monitoring two periods separately, the first period from 1991 to 1993 and the
      second period with better clinical advantages from 1994 to 1996 using
      outpatients' records. The incidence of scar hypertrophy was at least 32% in both
      periods. However, the occurrence of hypertrophic scarring in these two periods
      did not appear to have been influenced by changes in clinical practice.

PMID- 10641330
TI  - Burn injury resulting in mutilation in childhood.
AB  - We present 3 cases of boys aged 5, 11 and 12 years who sustained very deep burn
      injury of their extremities. Their future lives were extremely limited. All the 3
      boys had a strong emotional reaction to the injury. Two of them sustained
      amputation of upper extremities as a result from electrical injury, the youngest
      boy survived without the feet and with mutilated fingers on his hands. To
      encourage their survival and sense of life we admitted their mothers. Our aim was
      not only to secure psychological support to the patients but also to prepare the
      family to accept the sequelae of the injury. This accompaniment in the ward was
      very useful for both. The mothers were able to watch the progress in the
      treatment. In this way they were involved in the future care and they coped with
      the problems from a realistic point of view. The mothers helped the boys with
      physiotherapy under supervision. All the families were well prepared for
      discharge of their boys from the hospital without any fear of the following care.
      The significance of the family member influence upon the patient's
      resocialization we saw in early acceptance of the child to the society.

PMID- 10641331
TI  - Diagnostic radiology of pet and wild birds: a review II. Indications of
      radiological examination and radiographs of pathological lesions.
AB  - The second part of the review dealing with the diagnostic radiology of pet and
      wild birds discusses the indications of radiological examination, the
      interpretation of radiographs taken of pathological lesions, and the differential
      diagnosis of such lesions. Radiology has paramount importance in the diagnosis of
      diseases affecting the skeletal, digestive, respiratory, urogenital and
      cardiovascular systems. Certain diseases (shortage of grits, ovarian cysts)
      cannot be recognized without radiography. Other conditions (e.g. Macaw Wasting
      Disease, renal tumours, egg retention) require this complementary diagnostic
      method for confirmation of a suspicion based upon the clinical signs.
      Radiographic examination is also indicated for follow-up of the surgical
      management of bone fractures and for facilitating the implantation of
      transponders aimed at individual identification of the birds.

PMID- 10641332
TI  - Use of protected methionine (Mepron M 85) in cattle.
AB  - The ruminal stability of Mepron M 85 and the effect of supplementation with
      Mepron M 85 on free methionine level of blood were studied in rumen-fistulated
      cows and rumen- and duodenum-fistulated growing bulls. In five rumen-fistulated
      cows in situ 69.5% and 64.6% of the methionine content of Mepron M 85 was found
      after ruminal incubation of 16 h and 24 h, respectively. Daily rations of the
      rumen-fistulated cows were supplemented with 15.0 g DL-methionine and 17.7 g
      Mepron M 85, which increased the free methionine level of blood from 13.64
      mumol/L to 15.35 and 20.46 mumol/L, respectively, three hours after feeding. In
      the four rumen- and duodenum-fistulated growing bulls, supplementation with 15.0
      g DL-methionine and 17.7 g Mepron M 85 increased the total methionine getting
      into the duodenum during 24 h from 14.99 g to 16.84 and 20.84 g, respectively.
      The influence of Mepron M 85 on milk production was studied in 35 pairs of
      Hungarian Fleckvieh x Holstein-Friesian cows. The animals were coupled on the
      basis of the number of finished lactations, milk production in the previous
      lactation, and the date of calving. Daily supplementation of 18.0 g Mepron M 85
      increased daily milk production significantly (p < 0.05), by 1.24 litres. Milk
      fat content also increased significantly (from 3.10% to 3.19%, p < 0.05) in the
      experimental group. The supplementation did not influence milk protein content.

PMID- 10641333
TI  - Myxobolus infection of the gills of common bream (Abramis brama L.) in Lake
      Balaton and in the Kis-Balaton reservoir, Hungary.
AB  - During a five-year survey including studies on the parasite fauna of bream
      (Abramis brama), four gill-parasitic Myxobolus species (M. bramae, M. hungaricus,
      M. impressus and M. macrocapsularis) were recorded in a total of 313 breams from
      Lake Balaton. The commonest species, M. bramae showed a prevalence of 33%, while
      the other species occurred sporadically. Myxobolus bramae and M. macrocapsularis
      infected the tips of the gill filaments and caused both intralamellar and
      interlamellar infection. Intralamellar plasmodia of small size developed in the
      capillary network of the gill lamellae whereas the much larger interlamellar
      plasmodia were formed in the arteria afferens. The intralamellar plasmodia of M.
      hungaricus always infected the basal or central part of the gill filaments. In
      contrast to the above species developing in the blood vessels, M. impressus
      proved to be an epithelial parasite, as its plasmodia always developed in the
      adjacent gill filaments of two opposite haemibranchia, in the stratified
      epithelium between the respiratory plates, causing changes of the haemibranchium
      which were well visible even by the naked eye.

PMID- 10641334
TI  - Mortality of fish fry as a result of specific and aspecific cercarial invasion
      under experimental conditions.
AB  - Although the effect exerted on fish by fluke cercariae developing in fish as
      intermediate hosts is fairly well known, cercariae of flukes requiring
      intermediate hosts other than fish occur in fish ponds in much higher numbers. To
      study the effect of these latter cercariae on fish fry, a few days old common
      carp fry (Cyprinus carpio) were exposed to cohorts of xiphidiocercariae or
      echinocercariae shed by one or two snails acting as intermediate hosts. The
      observed pathogenicity of these cercariae was compared to the well-known
      pathogenic effect of Diplostomum cercariae. Although Diplostomum cercariae proved
      to be the most pathogenic, occasionally also the other two types of cercariae
      could kill the common carp fry by invading their body. Xiphidiocercariae ingested
      by the fish penetrated the intestinal wall and developed into metacercariae
      within the body of the fry. They could also get into the musculature through the
      skin. The much larger echinocercariae invaded the gill cavity where they became
      encapsulated, thus hampering gill function and leading to fish mortality due to
      oxygen deficiency. Diplostomum cercariae were more pathogenic than the cercariae
      of the other two flukes in that they were shed by the intermediate host in very
      large numbers. Although much less xiphidiocercariae and echinocercariae emerged
      from the intermediate host snails than Diplostomum cercariae, the former could
      kill the fish fry already in lower numbers. These findings prove that fluke
      cercariae nonspecific to fish may exert pathogenic effects on fish, and
      presumably contribute to the early mortality of young fry placed out into fish
      ponds.

PMID- 10641335
TI  - The effects of cyclophosphamide and its uroprotective agents, mesna and
      hyperbaric oxygen, on urinary bladder motility in guinea pigs.
AB  - The aim of this research was to observe the effects of cyclophosphamide and its
      uroprotective agents, mesna and hyperbaric oxygen (HBO), on the motility of
      urinary bladder muscle in guinea pigs. In the experimental groups, mesna and
      cyclophosphamide were intraperitoneally injected at a dose of 21.5 mg/kg and 68.1
      mg/kg, respectively. For the combination of mesna and cyclophosphamide, one dose
      of mesna was injected 20 min before cyclophosphamide administration and three
      additional injections of mesna were repeated every three hours. A total of 8 HBO
      exposures were performed at 2.8 ATA for 90 min twice daily for another
      experimental group. In the HBO and cyclophosphamide combined group 5 HBO
      exposures were given prophylactically before cyclophosphamide. The combination of
      mesna, HBO and cyclophosphamide was administered by the same procedure. The
      contractions obtained in response to acetylcholine (ACh, 10(-4) M) in the control
      group were reduced using cyclophosphamide and HBO individually, but not by mesna.
      However, the contractions belonging to the various combinations of these three
      agents were not different from those seen in the control group. On the other
      hand, the combinations of cyclophosphamide, mesna and HBO showed higher responses
      to ACh than the groups in which cyclophosphamide and HBO were used individually,
      while the responses elicited by the cyclophosphamide and HBO combination were
      greater than those seen in the group treated with HBO only.

PMID- 10641336
TI  - Pregnancy associated glycoproteins in ruminants: inactive members of the aspartic
      proteinase family.
AB  - The Pregnancy Associated Glycoproteins (PAGs) presented in this paper are largely
      expressed in the ruminant placenta. These proteins are classified as probably
      inactive members of the aspartic proteinase family. Pepsinogen, renin, cathepsin
      E & D and chymosine are typical members of this family, characterised by the
      presence of aspartic acids boarding the recognition sites. Secreted in the
      peripheral blood of the pregnant female from early pregnancy, these proteins can
      be used in serological tests for establishing different diagnoses. In the
      veterinary practice, these diagnoses are useful for both pregnancy confirmation
      and follow-up of trophoblastic function. The first aspect can help breeders in
      the management of reproduction, while the second one more specifically concerns
      clinicians and researchers wishing to establish a differential diagnosis of
      pathologic conditions affecting pregnancy.

PMID- 10641337
TI  - Observations on the quasispecies composition of three animal pathogenic RNA
      viruses.
AB  - The quasispecies nature of three animal pathogenic RNA viruses of field origin
      was examined by testing variants of classical swine fever virus (CSFV)
      originating from geographically different areas, feline coronavirus (FCoV)
      detected from the same animal by successive sampling, and rabbit haemorrhagic
      disease virus (RHDV) originating from successive outbreaks in the same geographic
      area. Clinical samples were investigated using reverse transcriptase polymerase
      chain reaction (RT-PCR) and ensuing single strand conformational polymorphism
      (SSCP) assay. By the combination of these methods even subtle differences could
      be detected among the amplified fragments of the same virus species of different
      origin. FCoV proved to comprise the most and CSFV the less heterogeneous virus
      quasispecies. The results show that the combination of RT-PCR and SSCP provides
      novel and highly sensitive means for the characterisation of RNA viruses, with
      special regard to genome composition, evolution, features of pathogenicity and
      molecular epizootiology.

PMID- 10641338
TI  - Induction of protective immunity in chickens immunised with plasmid DNA encoding
      infectious bursal disease virus antigens.
AB  - Direct DNA inoculations were used to determine the efficacy of gene immunisation
      of chickens to elicit protective immune responses against infectious bursal
      disease virus (IBDV). The vp2 gene of IBDV strains GP40 and D78, and the vp2-vp4
      vp3 encoding segment of strain D78 were cloned in an expression vector which
      consisted of human cytomegalovirus (HCMV) immediate early enhancer and promoter,
      adenovirus tripartite leader sequences and SV40 polyadenylation signal. For
      purification of vaccine-quality plasmid DNA from E. coli, an effective method was
      developed. Chickens were vaccinated by inoculation of DNA by two routes
      (intramuscular and intraperitoneal). Two weeks later, chickens were boosted with
      DNA, and at 2 weeks post-boost, they were challenged with virulent IBDV strain.
      Low to undetectable levels of IBDV-specific antibodies and no protection were
      observed with DNA encoding VP2. However, plasmids encoding VP2-VP4-VP3 induced
      IBDV-specific antibodies and protection in the chickens. DNA immunisation opens a
      new approach to the development of gene vaccines for chickens against infectious
      diseases.

PMID- 10641339
TI  - Detection of adenovirus hexon sequence in a cat by polymerase chain reaction
      (short communication).
AB  - Adenoviral nucleic acid was detected by polymerase chain reaction (PCR) in
      pharyngeal and rectal swab samples of a cat seropositive for adenovirus and
      suffering from transient hepatic failure. The samples were taken at a one-year
      interval, and both faecal samples as well as the second pharyngeal sample were
      positive in PCR performed with general adenovirus primers. The size of the
      amplified products corresponded to that of the positive control. The identity of
      the amplicons was also confirmed by DNA sequencing. The 301 bp long hexon gene
      fragment was very similar to but distinguishable from the corresponding hexon
      sequence of human adenovirus type 2. This result suggests the possibility of
      persistent carrier status and shedding of adenovirus in cats.

PMID- 10641340
TI  - Denver American Indian mental health needs survey.
AB  - American Indians are at higher risk for mental health problems than other ethnic
      groups in the United States (Nelson, McCoy, Stetter, & Vanderwagen, 1992). Little
      attention has been directed towards assessing mental health problems among urban
      American Indians. In response to an Indian Health Service (IHS) call for
      proposals, this survey addressed the mental health needs of Denver urban American
      Indians. The purpose of the survey was to gather data from Denver American Indian
      adults and adolescents as well as service providers in the Denver area who work,
      to one degree or the other, with members of the American Indian community. These
      data were to provide a general idea of the breadth of mental health and other
      associated problems among the Denver American Indian population.

PMID- 10641341
TI  - North American Indian Alliance mental health needs assessment report.
AB  - The North American Indian Alliance (NAIA), located in Butte, Montana, conducted a
      mental health needs assessment from December, 1991 to June, 1992. The goals of
      this assessment were to identify unmet health needs, obtain input regarding the
      need for additional services, and identify barriers to providing and accessing
      services. Surveys of mental health service providers (n = 30) and consumers of
      NAIA services (n = 74) were conducted. The results of these surveys and their
      implications for service provision are explored.

PMID- 10641342
TI  - Mental health needs assessment of off-reservation American Indian people in
      northern Arizona.
AB  - Native Americans For Community Action, Inc. (NACA) implemented a community-wide
      mental health needs assessment in Northern Arizona using bilingual interviewers
      recruited from the local community. A total of 235 people: 156 adults, 28
      adolescents, and parents of 51 children were interviewed. File data from the NACA
      Family Health Center was also analyzed. Thirty-eight percent (38%) of adults
      reported problems with depression, 27% reported completed or attempted suicide
      among family members, 31% had problems with drugs or alcohol, and 25% reported
      problems with physical abuse. Sixty-five percent (65%) of those surveyed never
      sought professional help. A majority of respondents said that mental health
      services were needed in their community.

PMID- 10641343
TI  - Mental health needs assessment of Tucson's urban Native American population.
AB  - This report presents the design, implementation, and results of a 1992 mental
      health needs assessment of Tucson's urban American Indians. The study was
      conducted under the auspices of the Traditional Indian Alliance (TIA) of Greater
      Tucson, Inc. TIA is a community-based, non-profit corporation committed to
      addressing the health and social welfare issues of Tucson's American Indians. As
      a result of having provided health and social services since 1974, TIA recognized
      that there were many unmet needs for culturally sensitive American Indian mental
      health programs. The organization established a goal of assessing the mental
      health needs of Tucson's urban American Indians in order to obtain the
      information needed to enhance program development and the provision of services.
      This survey was conducted in order for Traditional Indian Alliance to enhance its
      mental health program development and improve the provision of mental health
      services to Tucson's urban American Indians. The specific objectives of this
      study on Tucson's urban American Indian population included documentation of (a)
      the nature of socioeconomic problems that might have a psychological effect, (b)
      the existence of psychological distress, and (c) the types of available support
      systems and their utilization.

PMID- 10641344
TI  - Medicare: where have we been? Where are we going?

PMID- 10641345
TI  - Social integration and mortality in Australia.
AB  - OBJECTIVE: To investigate the relationship between social integration and
      mortality at the aggregate level of analysis. METHOD: The data were compiled from
      several Australian Bureau of Statistics documents. The unit of analysis was State
      (Territory)-year. The multivariate regression analysis included data from all
      States and the Australian Capital Territory for 1990-96. Five indicators of
      social integration--percentage of people living alone; divorce rate; unemployment
      rate; proportion of people who are discouraged job seekers; and unionization rate
      -were used as predictors of nine measures of mortality. RESULTS: Higher levels of
      social integration, as measured by all indicators except unionization, were
      associated with lower mortality rates. In the case of unionization, higher levels
      were associated with increased mortality rates. CONCLUSION: Studies concerning
      the relationship between social integration and health should investigate the
      'type' and 'level' of social integration that is conducive to better health.
      IMPLICATIONS: To help reduce disparities in health and mortality across
      communities, public health researchers and policy makers need to closely monitor
      geographic and temporal trends in social integration measures. Social policies
      that emphasise investment in social integration or social capital through job
      creation and training, provision of gainful employment and social services for
      discouraged and marginalized workers, improved work conditions and social support
      may lower mortality directly or through their beneficial effects on health
      promoting behaviours such as reduced levels of smoking, drinking and physical
      inactivity.

PMID- 10641346
TI  - Prevalence and socio-demographic predictors of dietary goal attainment in an
      older population.
AB  - OBJECTIVE: To describe the measured dietary intakes and anthropometry of a large,
      free-living population of middle-aged and older Australians who participated in
      the Australian Blue Mountains Eye Study (BMES), and to identify the socio
      demographic characteristics associated with attainment or non-attainment of
      dietary goals. METHOD: Anthropometry and dietary intakes were compared with
      current population dietary goals and Recommended Dietary Intakes for 2,873 people
      (79% of eligible residents) aged > or = 49 years who participated in the BMES.
      Nutrient intakes were measured by a validated food frequency questionnaire.
      RESULTS: Nutrients for which mean intakes deviated most from nutrition goals
      included: percentages of energy from total and saturated fat, carbohydrate and
      alcohol (men), as well as absolute intakes of calcium, zinc and fibre. More than
      half the men (60%) and women (54%) were overweight or obese. Several micro
      nutrient goals were more likely to be met in households where the respondents
      and/or their spouses were independent. Married men were more likely to meet goals
      for fibre and iron, but less likely to meet the goal for cholesterol. Several
      goals were more likely to be met by men and women who had qualifications after
      leaving school, those with higher job status and non-pensioners, suggesting an
      socio-economic status dimension. CONCLUSIONS AND IMPLICATIONS: These results
      indicate that over- rather than under-nutrition is more prevalent among community
      dwelling older people, although under-nutrition should not be overlooked.
      Particular sub-groups that are less likely to meet some dietary goals may require
      targeting in community nutrition interventions.

PMID- 10641347
TI  - Health and well-being of women family carers: a comparative study with a generic
      focus.
AB  - OBJECTIVE: To examine differences between women family carers of people with
      chronic illnesses or disabilities and a group of women 'non-carers' in self
      reported physical health, psychological well-being, life satisfaction, social
      support and feelings of overload. METHOD: Using a computer-assisted telephone
      interviewing system, a random survey of more than 26,000 households was conducted
      in Victoria to identify and then interview a representative sample of family
      carers of people with disabilities or chronic illnesses. The women in the sample
      (n = 857) were then compared with a sample of women with 'usual family
      responsibilities' (n = 219) in terms of physical and emotional states. RESULTS:
      We found higher rates of self-reported ill-health and use of medication, more
      negative effect, and less life satisfaction and perceived social support, among
      carers than among women in the comparison group. Even though the latter were more
      likely to be caring for one or more children, compared with the carers they
      reported less overload. Irrespective of carers status, women without partners
      expressed less life satisfaction, and more social isolation and negative effect.
      CONCLUSIONS AND IMPLICATIONS: The poorer health status and emotional well-being
      of carers compared with non-carers among women, and associations between
      overload, social isolation, negative effect and health problems within carers,
      point to a number of practical interventions such as promoting an awareness in
      GPs and other health professionals of the impact of caregiving on the health of
      their patients; informing them about relevant community services; and encouraging
      appropriate referrals.

PMID- 10641348
TI  - Asthma induced by alcoholic drinks: a new food allergy questionnaire.
AB  - OBJECTIVE: Asthmatic reactions to foods and drinks are a significant health
      problem in the community, however, the true extent of this problem is unclear. In
      this study, a new food allergy questionnaire (FAQ) was designed to specifically
      investigate the prevalence and characteristics of asthmatic reactions triggered
      by alcoholic drinks, as well as other foods and chemicals. The questionnaire's
      validity and reliability were assessed by comparing respondents' answers with
      data from clinical interview and repeat application. METHODS: Twenty consecutive
      outpatients attending a Hospital Asthma Clinic completed the FAQ and subsequently
      were interviewed independently by their respiratory physician. The FAQ's ability
      to classify the asthma severity and atopic status of respondents, and to identify
      those asthmatics sensitive to alcoholic drinks, sulphite-containing foods and
      aspirin was assessed by comparison with clinical interview. The questionnaire's
      reliability was assessed in a separate and diverse community group of 20
      asthmatic volunteers using the test-retest method. RESULTS: Responses to the FAQ
      were found to correlate highly with assessment by clinical interview for all of
      the parameters assessed. Specifically, the FAQ identified reactions to alcoholic
      drinks with a coefficient of agreement of 88.9%, a sensitivity of 100%, and a
      specificity of 83.3%. Responses to the FAQ were also found to be reproducible for
      all of the parameters assessed. CONCLUSION AND IMPLICATIONS: The FAQ is a useful
      and reliable tool for assessing the sensitivity of asthmatics to alcoholic drinks
      and various foods and chemicals, and provides a means to collect data relating to
      the prevalence and characteristics of these responses in community-based
      populations.

PMID- 10641349
TI  - Risk factors for asthma deaths: a population-based, case-control study.
AB  - OBJECTIVES: To investigate risk factors for death from asthma using a case
      control study design with two control groups. METHODS: Cases (n = 42) comprised
      subjects aged 10-59 years who died from asthma. Two control groups were selected:
      a random sample of asthmatics from the community (n = 132) and age and sex
      matched patients recently admitted to hospital for asthma (n = 89). We obtained
      information from proxies of cases and controls, and their general practitioners,
      by a structured telephone survey. Matched and unmatched logistic regression
      analyses were used to determine odds ratios for risk factors for asthma deaths.
      RESULTS: Compared to community controls, important risk factors for asthma deaths
      included indicators of asthma severity, use of three or more groups of asthma
      medications, more extensive use of health services for asthma, poor compliance
      with asthma medications and regularly missing hospital and general practitioner
      appointments for asthma. Compared to hospital controls, risk factors for asthma
      deaths were previous visits to emergency department for asthma, knowledge about
      asthma medications and regularly missing general practitioner appointments.
      CONCLUSIONS: In this study, severity of asthma, increased health service
      utilisation and suboptimal asthma self-management were associated with increased
      risks for asthma death. IMPLICATIONS: People with severe asthma or poorly
      controlled asthma have a greater risk of dying from their asthma. Both clinicians
      and non-clinicians managing asthma should regularly assess the appropriateness of
      management to prevent deaths.

PMID- 10641350
TI  - Long-term benefits for Maori of an asthma self-management program in a Maori
      community which takes a partnership approach.
AB  - BACKGROUND: In 1991, an intervention trial of the efficacy of an asthma self
      management plan was carried out in partnership with a rural Maori community. The
      program relied on Maori community health workers and other health professionals
      working in partnership, was delivered through clinics in traditional Maori
      community centres and Maori processes were followed throughout. The plan was
      shown to be effective in reducing asthma morbidity. OBJECTIVE: To assess whether
      the long-term benefits of the program extent beyond reduced asthma morbidity and
      the extent to which any additional benefits may be related to the partnership
      approach employed by the program. METHOD: Forty-seven (68%) of the original
      program participants were surveyed in August 1997. Participants were questioned
      on the program's impact in areas such as cultural development, health service
      access and lifestyle. RESULTS: In addition to the improvements in asthma
      morbidity, the program was found to have four key benefits: cultural affirmation;
      improved access to other health services; a greater sense of control for
      participants; and positive impacts on the extended family. CONCLUSIONS: The
      program's benefits extended beyond reduced asthma morbidity and were not due
      simply to the introduction of the asthma self-management plan but also to the
      partnership approach employed by the program. IMPLICATIONS: The study provides
      support for providing public health services for indigenous communities that take
      a partnership approach, utilise community expertise and are delivered in a way
      that is consistent with each community's cultural processes.

PMID- 10641351
TI  - Food service in long day care centres--an opportunity for public health
      intervention.
AB  - OBJECTIVE: To determine the characteristics of long day care centre operations,
      food service management practices, and nutrition resources use and needs. METHOD:
      In October 1996, all 330 long day care centres in Western Australia were surveyed
      by telephone to gather information to help develop strategies for food service
      improvement. RESULTS: The response rate was 85%. An accreditation committee
      directed operations in 76% of centres. Most centres employed a cook with limited
      or no cooking training. Coordinators identified training needs for cooks that are
      specific to the National Childcare Accreditation Council's Quality Improvement
      and Accreditation System (QIAS) guidelines: food hygiene; nutritional and food
      requirements of children; menu planning; and multicultural cooking. CONCLUSIONS:
      National standards for the quantification of foods to meet children's nutritional
      requirements in long day care would allow for consistency in educating child care
      workers, training cooks, and establishing and assessing government regulations
      and the QIAS guidelines. Nine recommendations for strategies to improve food
      service in long day care are presented. IMPLICATIONS: There are two main messages
      for public health practitioners working to improve the quality of food served to
      children in long day care: the strong influence of the QIAS guidelines, and the
      need for specific nutrition recommendations.

PMID- 10641352
TI  - Cost effectiveness of rotavirus vaccination in Australia.
AB  - OBJECTIVE: Rotavirus gastroenteritis causes substantial morbidity, including
      hospital admission, in young children. In the context of recent vaccine
      developments, this study aimed to estimate the cost-effectiveness of a rotavirus
      vaccination program in Australia. METHOD: Standard methods of health economic
      evaluation were used to assess the total cost of rotavirus immunisation (as the
      difference between estimated vaccination program costs and the cost of disease
      that would be avoided by immunisation) and relate this to the number of cases of
      disease that would be prevented. Estimates were made from both societal and
      health care systems perspectives. RESULTS: Based on Australian data on disease
      incidence and cost of hospitalisation, the current annual cost of rotavirus
      disease is about $26.0 million. Using conservative vaccine efficacy estimates,
      current immunization uptake rates and a cost of $30 per dose of vaccine,
      rotavirus immunisation would incur a net societal cost of $2.9 million ($11 per
      child), at a gross program cost of $21.6 million. These estimates are sensitive
      to two sources of uncertainty in the estimation of program delivery costs:
      vaccine price and whether separate immunization visits would be required.
      CONCLUSION: A rotavirus immunisation program would be cost-neutral to Australian
      society at a vaccine price of $26 per dose (or $19 when health care system costs
      only are considered). IMPLICATIONS: Rotavirus immunization may be cost-effective
      in Australia, but considerable uncertainty remains. Policy decisions will depend
      heavily on pricing of the vaccine and may also need to consider intangible costs
      not accounted for in this analysis.

PMID- 10641353
TI  - Satisfaction with the process of lead remediation in an urban Australian
      community.
AB  - OBJECTIVE: To assess householders' satisfaction with the process of residential
      lead abatement in an urban Australian population. METHOD: The study area
      consisted of suburbs immediately surrounding a lead-related industry on
      Australia's east coast. Nineteen of 20 remediated households in the study area
      agreed to participate in the survey. One trained interviewer conducted semi
      structured qualitative interviews with one 'key' person from each remediated
      household. Participants were asked for their personal views as well as general
      household views about the rationale for, process and results of lead remediation.
      RESULTS: The 19 households varied from three to seven people and contained 1-5
      children (16 years or under). The opinions of residents of remediated households
      were polarised, with the majority being either greatly satisfied or greatly
      dissatisfied with the process. Level of satisfaction was clearly linked to
      perceived quality of the remediation works. CONCLUSIONS: Satisfaction with
      household lead remediation could be improved by ensuring effective communication
      between all parties; providing clear, simple, but detailed information about the
      remediation works to be undertaken on each household; providing timely support
      for householders when problems arise; and ensuring that all contractors are
      skilled, reputable and have acceptable communication skills.

PMID- 10641354
TI  - Risk factors for hepatitis C transmission in the Victorian population: a
      telephone survey.
AB  - OBJECTIVE: To measure knowledge and prevalences of risk factors for hepatitis C
      infection in the Victorian community. METHOD: Telephone survey of 757 Victorian
      householders aged 15+ years, March 1996. RESULTS: An estimated 2.2% of Victorians
      have injected illicit drugs; 4.8% have tattoos and 49.6% have skin piercings;
      11.4% received a blood transfusion before screening for HCV was introduced; 10.9%
      have had a test for HCV antibody. A majority of respondents perceived sexual
      contact and receipt of a transfusion to be risks for HCV transmission.
      CONCLUSIONS: Risk factors associated with the spread of HCV are widespread in the
      Victorian community; however, the most important risk factor--injecting drug use-
      has low prevalence. Considerable uncertainty exists about risk factors for
      hepatitis C. IMPLICATIONS: A very small percentage of Victorians are injecting
      drug users and therefore at highest risk of hepatitis C infection, therefore
      transmission control programs can be efficiently focused on this group. The
      Victorian community needs to be better educated about risk factors for hepatitis
      C, in particular that transfusions and blood donations are safe.

PMID- 10641355
TI  - Random digit dialling and Electronic White Pages samples compared: demographic
      profiles and health estimates.
AB  - OBJECTIVE: To compare the methodologies of and health estimates derived from two
      telephone household survey methods. In particular, to establish if White Pages
      telephone listings provide a relatively unbiased sampling frame for population
      health surveys. METHOD: In South Australia in 1998, a health survey questionnaire
      was administered by telephone to two randomly selected population samples. The
      first method used EWP (Electronic White Pages, n = 6,012), which contains all
      listed residential telephone numbers as the sampling frame. The results were
      compared to a RDD (random digit dialling, n = 3,080) sample where all listed and
      unlisted telephone numbers were included in the sampling frame. Demographic
      variables and health estimates were compared between the surveys, and then
      compared to a 'gold standard' door-to-door household survey conducted
      concurrently. RESULTS: The response rate for EWP (83.8%) exceeded that of RDD
      (65.4%). More than four times as many calls were required per completed interview
      in RDD. Demographic profiles and health estimates were substantially similar.
      CONCLUSIONS: EWP requires fewer telephone calls and enables approach letters
      establishing the bona fides of the survey to be sent to each selected address
      before calling, increasing the response rate. RDD is a more inclusive sampling
      frame but also includes non-connected and business numbers, and offers no
      significant advantages in providing health estimates. IMPLICATIONS: There are
      substantial methodological and cost advantages in using EWP over RDD as the
      sampling, frame for population health surveys, without introducing significant
      bias into health estimates.

PMID- 10641356
TI  - Factors associated with participation in resident action groups in metropolitan
      Sydney: a cross-sectional survey.
AB  - OBJECTIVE: To explore the characteristics of participants in resident action
      groups in metropolitan Sydney. METHODS: A stratified random sample of
      participants in 50 groups registered with local councils were surveyed in 1997.
      Demographic, social/psychological, cost/benefit, group process and group potency
      variables and four measures of amount of participation were examined. RESULTS: An
      increase in the hours of participation per month was associated with a decrease
      in the self-reported costs of participation, an increase in the self-reported
      benefits of participation and an increase in group potency. Involvement in a
      greater number of activities was associated with a decrease in the self-reported
      costs and an increase in the self-reported benefits associated with
      participation, increased satisfaction with group processes, a decrease in group
      potency and an increase in the number of members known prior to group membership.
      Length of group membership was positively associated with age and more positive
      expectations of the group's future success. An increase in the proportion of
      meetings attended was associated with self-reported satisfaction with group
      processes. CONCLUSIONS AND IMPLICATIONS: An important principle of public health
      is community participation. The results of this study indicate that the greatest
      potential for increasing individual participation may be in efforts to reduce the
      costs associated with participation, increase the benefits associated with
      participation and increase the satisfaction of group members with group
      processes.

PMID- 10641357
TI  - Variation in dental service provision among adult migrant public-funded patients.
AB  - OBJECTIVE: To examine type of care, oral health status and service patterns by
      country of birth and language. METHODS: A random sample of public-funded patients
      (n = 6, 109) was surveyed in 1995-96. RESULTS: Emergency care was highest among
      overseas-born patients who spoke a non-English language at home; edentulism was
      highest among Australian-born/English only patients; while a higher percentage of
      Australian-born persons were in the periodontal health category (chi 2; p <
      0.05). Differences in caries experience were generally small (ANOVA; p < 0.05).
      Service provision varied by country of birth/language after controlling for socio
      demographic characteristics, type of care, and oral health status in six service
      areas (logistic regression; p < 0.05). CONCLUSIONS: Service patterns may reflect
      behavioural and cultural factors of patients or providers operating independently
      of socio-demographic and oral health status variables. IMPLICATIONS: Variation
      and potential inequality in service patterns related to cultural factors existed
      within a group of disadvantaged patients.

PMID- 10641358
TI  - Same-sex attraction, drug injection and binge drinking among Australian
      adolescents.
AB  - OBJECTIVE: To document the prevalence of same-sex attraction among students in
      years 10 and 12 in Australian Government high schools and to assess the
      association between same-sex attraction, binge drinking and drug injection.
      METHOD: Cross-section survey by anonymous, self-administered questionnaire of
      3,387 students in Years 10 and 12 of the Government school system in Australia.
      RESULTS: Approximately 6% of respondents reported being currently attracted to
      members of their own sex. Being attracted to members of the same-sex was
      associated with more frequent binge drinking among boys and girls, and a three-
      to four-fold increase in the likelihood of reporting injecting drug use both over
      the lifetime and within the previous 12 months. CONCLUSIONS: Adolescents
      attracted to members of the same-sex report engaging in elevated levels of health
      limiting behaviours. There is an urgent need for further research to document the
      reasons for this. It is recommended that health promotion activities directed at
      moderating young people's drug and alcohol practices explicitly acknowledge the
      over-representation of same-sex attracted young people in their target audience.

PMID- 10641359
TI  - Food ads on TV: a health hazard for children?
AB  - OBJECTIVE: To examine the nutritional quality of food in television food
      advertisements that are targeted at children. METHOD: We videotaped 42 hours of
      children's programs and analysed the food advertisements' content and nutrient
      composition using the New Zealand Food Composition Database. RESULTS: Of 269 food
      advertisements, 63% were for foods 'high in fat and/or sugar'. Children who ate
      only the advertised foods would eat a diet too high in fat, saturated fat,
      protein, free sugars and sodium. Furthermore, their diets would have suboptimal
      levels of fibre and suboptimal intakes of a number of important micronutrients
      (depending on age), including magnesium, selenium and vitamin E. The food
      products advertised on this channel rarely included nutritious low-cost foods
      that are necessary for food security in low-income groups. There were also no
      food advertisements that included any of the healthy foods consumed by Maori and
      Pacific peoples. CONCLUSIONS: Food advertisements targeted at children generally
      reflect the dietary pattern associated with an increased risk of obesity and
      dental caries in childhood; and cardiovascular disease, diabetes and cancers in
      adulthood.

PMID- 10641360
TI  - The Northern Territory's cask wine levy: health and taxation policy implications.
AB  - OBJECTIVE: To examine the effect of the application, and removal, in the Northern
      Territory of a levy on the sale of cask wine--a beverage shown to contribute
      disproportionately to alcohol-related harm. METHOD: Using data on licensee
      purchases of alcoholic beverages and ABS population data, estimates were made of
      per capita consumption of pure alcohol by beverage type. Time series variables
      were analysed using multiple linear regression analysis. RESULTS: Prior to the
      introduction of the levy, quarterly per capita consumption of cask wine among
      persons aged > or = 15 years was 0.73 litres. During the levy period, this fell
      to 0.49 litres and following removal of the levy rose to 0.58 litres. Imposition
      of the levy had no significant effect on the consumption of other beverages.
      CONCLUSIONS: Taxation is an effective means of reducing excessive alcohol
      consumption and related harm. IMPLICATIONS: In the interests of public health,
      support should be given to the introduction of a tiered tax based on alcohol
      content.

PMID- 10641361
TI  - How accurate is in-patient smoking status data collected by hospital admissions
      staff?
AB  - OBJECTIVE: To determine the validity of self-reported in-patient smoking status
      data collected by admissions staff. METHOD: Smoking status of new inpatients was
      recorded on to the computer registration screen. Urine samples collected from the
      patients (n = 167) were analysed for the presence of cotinine. RESULTS: Only 63%
      (95% CI 46%-81%) of the patients classified as smokers on the basis of urinary
      cotinine levels were recorded as smokers on the computerised record created by
      hospital admissions staff. CONCLUSIONS: Admissions staff do not obtain reliable
      data on smoking status. However, most patients entered as non-smokers by
      admissions staff but registering high cotinine levels were subsequently recorded
      as smokers by their doctor in their medical record. IMPLICATIONS: This study
      suggests that inpatients are more likely to report their smoking status
      accurately to their doctor than an admissions clerk, but about two-thirds of
      smokers will be correctly identified at admission and so could be targeted in
      computer-driven smoking-cessation interventions.

PMID- 10641362
TI  - Industry, air quality, cigarette smoke and rates of respiratory illness in Port
      Adelaide.
AB  - OBJECTIVES: To examine the prevalence of self-reported asthma,
      bronchitis/emphysema, wheezing, night cough and smoking in Port Adelaide; to
      explore the relationship of the disorders to the presence of industry, tobacco
      smoke, indoor appliances and air quality. METHODS: Prevalence data from a 1995
      survey of Port Adelaide residents were compared with data from the 1995 National
      Health Survey and the 1995 South Australian Health Omnibus Survey. These data
      were then compared across three geographic areas in Port Adelaide, one being
      highly industrialised. Their relation to tobacco smoke and the presence of
      unflued gas appliances were examined. Finally, outdoor gaseous air pollutants
      were examined across the three areas. RESULTS: Males in Port Adelaide had higher
      rates of asthma and bronchitis/emphysema than nationally. Asthma was
      significantly higher for children aged 5-14 years and for adults aged 25-44
      years. Bronchitis/emphysema was significantly higher for males aged 25-64. The
      highly industrial area had a higher rate of asthma (OR 1.85, 95% CI 1.07-3.22) in
      males that appeared unrelated to smoking or ambient gaseous pollutants. Smoking
      in Port Adelaide was significantly higher than in the general population, and was
      significantly associated with wheeze, night cough and bronchitis/emphysema. The
      presence of unflued gas heaters at home was significantly associated with asthma
      prevalence in males (OR 3.27, 95% CI 1.40-7.64). CONCLUSIONS: Respiratory disease
      appeared to be independently related to an area of high industry, smoking and
      presence of unflued gas appliances in Port Adelaide.

PMID- 10641363
TI  - 'Pharmacist only' medicines.
AB  - While there is a global trend to switch medicines from prescription to non
      prescription status, Australia has created a unique schedule of 'pharmacist only
      medicines' (POM). Such medicines may provide consumers with greater choice and
      control of health care decisions. However, the impact of these actions has not
      been evaluated. Public health concerns including the appropriate use of
      medicines, awareness and equity of access to POM, and access to information on
      POM are discussed using antifungal vaginal products as an example. The National
      Medicines Policy advocates a partnership approach to achieve improved health
      outcomes by the quality use of medicines, however currently no data on POM are
      available. Recommendations include changes to legislation, public health data
      collection and the provision of quality information including pharmaceutical and
      non-pharmaceutical interventions.

PMID- 10641364
TI  - A positive view of biomedical advances.

PMID- 10641365
TI  - Facilitating tolerance of delayed reinforcement during functional communication
      training.
AB  - Few clinical investigations have addressed the problem of delayed reinforcement.
      In this investigation, three individuals whose destructive behavior was
      maintained by positive reinforcement were treated using functional communication
      training (FCT) with extinction (EXT). Next, procedures used in the basic
      literature on delayed reinforcement and self-control (reinforcer delay fading,
      punishment of impulsive responding, and provision of an alternative activity
      during reinforcer delay) were used to teach participants to tolerate delayed
      reinforcement. With the first case, reinforcer delay fading alone was effective
      at maintaining low rates of destructive behavior while introducing delayed
      reinforcement. In the second case, the addition of a punishment component reduced
      destructive behavior to near-zero levels and facilitated reinforcer delay fading.
      With the third case, reinforcer delay fading was associated with increases in
      masturbation and head rolling, but prompting and praising the individual for
      completing work during the delay interval reduced all problem behaviors and
      facilitated reinforcer delay fading.

PMID- 10641366
TI  - Thinking about self-efficacy.
AB  - People's perceptions of their capabilities for performance, or self-efficacy
      perceptions, are a cognitive mechanism underlying behavioral change. This article
      addresses three questions in the study of perceived self-efficacy: Do self
      efficacy perceptions generalize across situations? Do affective states influence
      perceived self-efficacy? Do people have a singular level of perceived self
      efficacy in any domain, or are there multiple aspects to self-efficacy
      perception? These questions are answered by analyzing the cognitive processes
      through which people appraise their efficacy for performance. The research
      reviewed indicates that (a) self-efficacy perceptions generalize across
      idiosyncratic sets of situations relating to schematic personal attributes; (b)
      induced negative mood does not reliably influence perceived self-efficacy but
      does raise performance standards, creating efficacy-standards discrepancies; (c)
      distinct aspects of self-efficacy appraisal can be organized by distinguishing
      between perceived self-efficacy for executing strategies and for attaining goals.

PMID- 10641367
TI  - Changes in levels of dental anxiety as a function of dental experience.
AB  - From the literature, it is increasingly apparent that dentally anxious
      individuals are not a homogeneous group and that the development and maintenance
      of dental anxiety are complex phenomena. In this study, individuals who had
      avoided dental treatment in the past due to fear but were no longer fearful were
      compared with others who had avoided and were still fearful on a number of
      demographic, experiential, and attitudinal variables under the assumption that
      avoidance is likely to prevent the emotional processing of dental anxiety. The
      groups differed markedly in their experience of dentistry; anxious avoiders were
      more likely to have experienced more invasive and less noninvasive dental
      treatment; they feared pain more and were more negative about dentistry than
      those whose anxiety had remitted. In addition, the remitted avoiders were less
      likely to claim frightening or embarrassing dental experiences as well as being
      less reactive to these experiences than the others.

PMID- 10641368
TI  - Attention, automaticity, and affective disorder.
AB  - This article reviews possible mechanisms for attentional bias in affective
      disorders and anxiety. Attentional bias is sometimes conceptualized as automatic
      in nature. However, there are methodological difficulties with studies purporting
      to demonstrate automaticity, and empirical and simulation evidence suggest that
      bias may be predominantly strategic. Bias in the voluntary control of attention
      may be driven by coping strategies, which in turn depend on appraisal of external
      demands, metacognitions of mental function, access of self-relevant knowledge in
      long-term memory, and self-focus of attention. The Self-Regulatory Executive
      Function (S-REF) model of emotion and attention specifies how these processes
      interact to influence attentional control. Clinical disorder is associated with
      loss of dynamic adaptability and a syndrome of perseverative rumination and worry
      that directs attention toward monitoring for threat and away from restructuring
      of maladaptive self-knowledge. Implications of the S-REF model for therapeutic
      interventions directed toward attentional control are discussed.

PMID- 10641369
TI  - Differential reinforcement of other behavior (DRO) to reduce aggressive behavior
      following traumatic brain injury.
AB  - Severe brain injury can result in significant neurobehavioral and social
      functioning impairment. In rehabilitation settings, behavioral problems of
      aggression and nonadherence to therapeutic activities can pose barriers to
      maximal recovery of function. Behavioral interventions seem to be effective in
      reducing problem behavior among individuals recovering from severe brain trauma,
      but well-controlled studies examining the efficacy of such interventions are
      sparse. This article presents a single-case, multiple-baseline study of a
      differential reinforcement of other behavior (DRO) procedure in a 28-year-old,
      brain-injured male with aggressive behavior problems. The procedure successfully
      reduced the frequency of problem behavior by up to 74%, maintained at 1-month
      follow-up. Implications of this intervention for individuals with brain injury
      are discussed, and testing of this procedure using a between-group design seems
      indicated.

PMID- 10641370
TI  - The origins of social phobia.
AB  - A greater understanding of the origins of social phobia is much needed. The
      research to date is limited by the relatively small number of studies that sample
      clinical populations of individuals with social phobia. There is, however,
      research derived from related areas such as shyness, social anxiety, self
      consciousness, peer neglect, and social withdrawal that contributes to a richer
      understanding of the etiology of social fears. Combining these areas of research,
      this review addresses four main factors that may be important to the origins of
      social phobia: (a) genetic factors; (b) family factors; (c) other environmental
      factors; and (d) developmental factors.

PMID- 10641371
TI  - Are deluded people unusually prone to illusory correlation?
AB  - This study reexamines the possibility that paranoid individuals are unusually
      prone to perceive illusory correlations. The authors use emotionally neutral word
      pairs to examine the illusory correlation phenomenon in three diagnostic groups:
      nonparanoid schizophrenia (n = 10), paranoid schizophrenia or delusional disorder
      (n = 9), and depression (n = 10). A one-way analysis of variance shows that the
      three groups do not differ in their tendency to make illusory correlations. Three
      separate t tests that compare the data from each of the clinical groups in this
      study with normative data again reveal no significant difference. The clinical
      implications of these findings are discussed.

PMID- 10641372
TI  - The promotion of evidence-based occupational therapy practice in Canada.
AB  - Occupational therapists must utilize evidence in decision making in order to
      define approaches for occupational therapy service which attain optimal client
      outcomes, promote consistency, continuity and cost containment, and validate the
      role of occupational therapy to clients, payers and other health professionals.
      CAOT has undertaken many initiatives to teach the skills, provide the tools and
      facilitate the generation and dissemination of evidence required for evidence
      based occupational therapy. CAOT recognizes the importance of working in
      partnership with other stakeholders involved in occupational therapy practice in
      Canada in order to successfully break down barriers to the integration of
      evidence in occupational therapy practice.

PMID- 10641373
TI  - 1999 Muriel Driver Lectureship. Risk taking: an antidote to diffidence.

PMID- 10641374
TI  - Knowledge about pain among newly graduated occupational therapists: relevance for
      curriculum development.
AB  - In recent years there has been a growing awareness amongst health professionals
      of the need to prepare undergraduate students more adequately for practice with
      clients who have pain. Occupational therapists have a central role in enabling
      such clients to have productive lives despite pain. In this study, an examination
      was made of the adequacy of preparation for pain practice in graduates from one
      Australian occupational therapy curriculum. Recent occupational therapy graduates
      from the University of Queensland, Australia, who responded to a postal survey,
      obtained an overall 53% correct response rate to a 69-item pain knowledge and
      attitudes questionnaire. Results indicated the need for further education in this
      area, especially in the areas of pharmacological management, and pain assessment
      and measurement. These results were comparable to those obtained from final year
      occupational therapy students at Dalhousie University in Halifax, Nova Scotia
      prior to undertaking an elective course about pain. Follow-up interviews with a
      number of new graduates supported the inclusion of an elective pain course in the
      undergraduate occupational therapy curriculum at the University of Queensland in
      Australia.

PMID- 10641375
TI  - Practices of recycling assistive technology in Quebec.
AB  - The aim of this study was to document professional factors to be considered in
      implementing a provincial policy of recycling assistive technology in Quebec. A
      qualitative study was conducted with 22 experts from various sectors: health
      professionals (including occupational therapists), industry and community. They
      were interviewed using a semi-structured questionnaire. Data collection also
      involved observing recycling practices and analyzing working documents.
      Implementation strategies were considered from the perspectives of health
      professionals, the commercial sector, users of assistive technology and
      government administrators. Factors that contribute to tension between
      occupational therapists and other players are discussed. It is recommended that
      occupational therapists take a united position on this issue such that their
      voices may have more weight in intersectoral collaborations.

PMID- 10641376
TI  - Promoting independence for teens and young adults with physical disabilities.
AB  - The transition to adult roles and responsibilities poses unique challenges for
      young people with physical disabilities. The Independence Programme (TIP) assists
      youths to meet these challenges. TIP is client-centred and addresses each
      participant's occupational performance problems. Participants live in a student
      residence located near shops, restaurants and other businesses for 20 consecutive
      days during TIP. This paper describes TIP and results from the evaluation of one
      summer's programme. Ten youths with physical disabilities, such as cerebral
      palsy, participated. The programme was evaluated using interviews with each
      participant at the beginning and end of the programme, and at a four month follow
      up with the Canadian Occupational Performance Measure (COPM) (Law et al., 1994a).
      Participants made clinically important changes in performance and satisfaction of
      their identified occupations. They rated this programme as the best experience of
      the summer. Participants valued the opportunities to learn about and access
      environmental supports, to assume greater independence, and to develop
      connectedness with peers.

PMID- 10641377
TI  - Physical housing environment: development of a self-assessment instrument.
AB  - The aims of this study were to construct and develop a self-administered
      assessment instrument, useful for studying clients' own perception of
      accessibility and usability in their housing environment, and to test the
      instrument for reliability. It was developed for use in combination with an
      objective, norm-based assessment of the physical housing environment, the Enabler
      instrument. The instrument developed in this study contains 31 questions about
      different aspects of the physical housing environment. Answers are given on a 7
      point rating scale. Content validity was established by the use of an expert
      panel and pilot testing, followed by a test-retest study. Internal consistency of
      the instrument was good (Cronbach's alpha 0.96), and very good to moderate
      agreement between the two ratings was found on all items (mean weighted kappa, Kw
      0.71) indicating good reliability. However, the removal of three items from the
      standardized part of the instrument is suggested. The instrument has a client
      centred approach and is a valid and reliable tool, useful for occupational
      therapy practice and research.

PMID- 10641378
TI  - [The topographic patterns in the synchronism of the shifts in the intensity of
      the alpha activity in the human EEG].

PMID- 10641379
TI  - [The desynchronization and synchronization of the adolescent EEG evoked by
      stimuli triggering or suppressing a sensorimotor reaction. I. The effect of the
      modality of the stimuli].

PMID- 10641381
TI  - [The age-related dynamics of the reaction time to visual stimuli].

PMID- 10641380
TI  - [The interhemispheric relationships in patients with a partial corpus
      callosotomy: an analysis of EEG coherence and of voluntary movements].

PMID- 10641382
TI  - [The evaluation of human perception of the rate and acceleration in the approach
      and withdrawal of a sound source].

PMID- 10641383
TI  - [The alpha rhythm dynamics at different stages of pregnancy with normal and
      complicated courses].

PMID- 10641384
TI  - [The effect of dolphin-assisted therapy sessions on the functional status of
      children with psychoneurological disease symptoms].

PMID- 10641385
TI  - [Evoked bioelectrical activity of the somatosensory cortex in orthopedic patients
      undergoing lengthening of the upper extremities].

PMID- 10641386
TI  - [The reaction of the cerebral circulation to light physical loads].

PMID- 10641387
TI  - [The effect of stimulation of the low-threshold ulnar nerve fibers on the firing
      motoneurons of the ulnar flexor muscle of the human wrist].

PMID- 10641388
TI  - [The mechanics of cough].

PMID- 10641390
TI  - [The biochemical indices during extreme air hypothermia].

PMID- 10641389
TI  - [The circadian rhythms of human mineralotropic hormones during prolonged
      antiorthostatic hypokinesia].

PMID- 10641391
TI  - [Trends in the trials of histochemical dyes as potential agents for "laser
      histochemical surgery"].

PMID- 10641392
TI  - [Criteria for regulating the amount of thermal load in using a sauna].

PMID- 10641394
TI  - [The electrophoretic characteristics and volume of the erythrocytes in newborn
      infants with a history of acute hypoxia].

PMID- 10641393
TI  - [Intraerythrocytic metabolism and hemoglobin oxygen affinity in athletes of
      different qualifications exposed to intensive physical loads].

PMID- 10641395
TI  - [The determination of the degree of body thiamine allowance].

PMID- 10641396
TI  - [Coronary, carotid and iliac femoral atherothrombotic lesions. Similarities and
      differences].

PMID- 10641397
TI  - [Diagnostic methods of polydistributed arteriothrombosis].

PMID- 10641399
TI  - [Arteriothrombosis as a polyvascular disease. Common therapeutic aspects of
      different localizations].

PMID- 10641398
TI  - [Carotid arteriosclerosis as a predictor of major cardiovascular events].

PMID- 10641400
TI  - [The prevention of venous thromboembolism in the oncologic patient].

PMID- 10641401
TI  - Heterogeneity of endothelial function.

PMID- 10641402
TI  - [Evaluation of the functional state of the claudication patient].

PMID- 10641403
TI  - Protocols on clinical research and therapeutical applications of angiogenic
      therapy.

PMID- 10641404
TI  - [Protocols for clinical and instrumental control in reconstructive surgery of the
      limbs].

PMID- 10641405
TI  - [Follow-up of distal bypass. Results as a function of surgical technique].

PMID- 10641406
TI  - [Below-the-knee surgery for limb salvage: results according to age].

PMID- 10641407
TI  - Functional assessment of the claudicant importance of treatment and follow-up
      strategies.

PMID- 10641408
TI  - Can we predict neointima development after carotid endarterectomy? Insights from
      the Carotid Atherosclerosis and Restenosis Study.

PMID- 10641409
TI  - [Prevention of cardiovascular events with antiplatelet drugs: aspirin (and
      others)?].

PMID- 10641410
TI  - [New metabolic risk factors. Genetic basis].

PMID- 10641411
TI  - [Genetic polymorphism of coagulation factors as a cardiovascular risk factor].

PMID- 10641412
TI  - [Blood homocysteine as a cardiovascular risk factors].

PMID- 10641413
TI  - [Flow-mediated vasoactivity. Physiopathologial aspects, risk factor correlation
      and possible correction].

PMID- 10641414
TI  - [Plasma and cell hemorrheologic factors in atherothrombotic physiopathology].

PMID- 10641415
TI  - [Deep vein thrombosis: present and future drugs].

PMID- 10641416
TI  - [Deep vein thrombosis. Pharmacologic and mechanical thrombolysis].

PMID- 10641417
TI  - [Surgical approaches to post-thrombotic syndrome].

PMID- 10641418
TI  - [New epidemiological and therapeutic data on chronic critical leg ischemia].

PMID- 10641419
TI  - [Clinical experience with the treatment of gingival hyperplasia induced by
      calcium channel blocking agents].
AB  - The prevalence of the nifedipine-induced gingival hyperplasia is ranging from 0.5
      83% in the dental literature. The pathomechanism of the nifedipine-induced
      gingival hyperplasia is not clearly understood. Evaluating the dental history and
      the course of disease of 34 patients treated and followed up at the Department of
      Periodontology the following answers were raised: What sort of local and systemic
      factors are enhancing the recurrence of the gingival overgrowth and how this can
      be anticipated in patients on continuous Ca channel blocking medication. Eight
      out of the 34 patients participating in the clinical trial did not remember the
      onset of their gingival overgrowth. 10 cases developed three years and three
      cases after less then one year of the onset of the drug administrations. 27 out
      of the 34 cases required gingival surgery and seven showed good clinical
      improvement after the hygienic phase of the comprehensive periodontal treatment.
      70% of the gingival hyperplasia cases presented no clinical sign of recurrence
      one year after the completion of the active phase of the treatment. A positive
      correlation was found between the oral hygiene and the recurrence rate of
      gingival overgrowth. Oral hygiene seems to play a decisive role in the
      development of gingival enlargement. The present findings and substantial
      evidences from the dental literature indicate that the gingival enlargement can
      be successfully controlled even under the continuous nifedipine administration by
      meticulous professional and individual oral hygiene.

PMID- 10641420
TI  - [Comparative study of the analgesic effect of Apranax and Cataflam after oral
      surgical procedures].
AB  - After oral- and maxillo-facial surgical interventions both Apranax and Cataflam
      proved to be satisfying against pain. Though there is no difference in the
      kinetics of the effect, we found Apranax more effective to relieve postoperative
      pain. Besides the fast elimination of pain the medicine significantly mitigate
      the symptoms of inflammation.

PMID- 10641421
TI  - [Analysis of activated cells in apical granuloma].
AB  - The ratio and in situ distribution of CD3+ T-lymphocytes, CD4+ and CD8+ subsets,
      CD14+ macrophages, CD56+ natural killer cells and CD25+ activated T-lymphocytes
      and CD68+ activated macrophages were determined in 20 chronic peripical
      granulomas by immunohistochemical method using monoclonal antibodies. CD3+ T
      lymphocytes made up about 50% of the mononuclear cells. CD14+ macrophages were
      distributed all over the area but their proportion was much less that that of the
      T-lymphocytes. CD56+ natural killer cells made up a small proportion of the
      cells. The major proportion of the T-lymphocytes and macrophages were in
      activated stage within the lesion.

PMID- 10641422
TI  - [Patient care personnel, patients and illnesses at the Geneva General Hospital at
      the beginning of the 17th century].
AB  - During the early decades of the seventeenth century, the city of Calvin, as well
      as most of Europe, experienced a severe economic depression, worsened by wars and
      recurring outbreaks of plague. This sad era is characterized by poverty coupled
      with illness, the formidable yokes of the poor and the feeble. Sustained by the
      city government, the Hopital General of Geneva was the hub of social and medical
      assistance during those "years of darkness". The aim of this article is to shed
      new light upon the medical techniques of that era by focusing on the caregivers
      and their patients, on health, disease, and suffering.

PMID- 10641423
TI  - [The behavioral code of "savoir faire" as a cover for physician helplessness? A
      contribution to the physician-patient relationship of the 18th century].
AB  - Eighteenth century literature contains critiques of physicians' behavior, as for
      example in Goethe's Faust. These critiques aim at the physicians' therapeutical
      incapacity which they try to compensate with a behavioral code called "savoir
      faire". This paper compares the critiques with the advices of medical authors
      given to their younger colleagues in the "savoir faire" literature. These sources
      often discuss, how to hide doubts, how to maintain the authority over the
      patients or to prevent complaints of malpractice. Obviously, physicians often
      didn't trust in their therapeutical proficiency and tried to bind their patients
      by inspiring a behavior of confidence, independent of the question of the real
      effectiveness of their treatments.

PMID- 10641424
TI  - [Crisis and decline of bath houses].
AB  - For centuries bath-houses and barber-surgeons formed such an integral part of
      public life that one is mystified by their vanishing from modern view with hardly
      any trace left. Previous authors have offered a variety of reasons for this
      disappearance: the bath-houses' notorious reputation, developing fuel-shortage,
      the "new" fashion of taking the waters and the outbreak of previously unknown
      contagious diseases are among those mentioned most frequently. While these
      factors may be valid reasons for a crisis afflicting the "hot-houses" they would
      hardly explain why fate overtook the barber-surgeons' entire trade. Judging from
      the sources available one cannot help but feel that the philosophers of the
      Enlightenment were largely responsible for such a dramatic change of society.
      Sceptical philosophy discarded the wisdom of the ancient medical authorities
      replacing traditional steam-bathing with "modern" cold-bathing. Society itself
      was subject to equally revolutionary changes: the local masters of the trade had
      to make room for surgeons educated at medical schools setting the stage for a new
      reality which has become "normal" to us.

PMID- 10641425
TI  - [Herman Lundborg and French eugenicists].
AB  - Herman Lundborg, the director of the Institute of Racial Biology in Uppsala,
      corresponded with some prominent French eugenicists in the 1920s and 1930s. The
      historical context of this correspondence is analyzed, and the importance of the
      national differences as well as of the international eugenic organization's
      efforts are emphasized.

PMID- 10641426
TI  - [Medical history of trauma].
AB  - 'Trauma' tends to exceed human understanding. It disrespects boundaries,
      interrupts all kinds of units and makes them blend, it disturbs bodily and
      psychic organisms and upsets social and historical organization. Some
      characteristics of the history of trauma have their origin in this situation. One
      of them is the gradual extension for instance of the notion of 'trauma' which
      makes the surgical 'wound' (greek: trauma) evolve into a bio-psycho-social
      phenomenon. Other characteristics of the history of trauma are its association
      with questions of endogenous versus exogenous causes of suffering and with the
      issue of guilt and its recurrent falling into oblivion. The paper traces the
      history of traumatogenic illness from the simple wound to forensically important
      damages like the 'railway-injuries' entitling to claims for damages, to
      'traumatic-' and 'war-neuroses' and finally to the more or less endemic
      'posttraumatic stress syndrome' of present time.

PMID- 10641428
TI  - Genetics: the future of medicine.

PMID- 10641427
TI  - [John F. Fulton (1899-1960). On the 100th birthday of the physiologist and
      medical historian].

PMID- 10641429
TI  - Hypnotizability and the use of traditional dhami-jhankri healing in Nepal.
AB  - This study examined the role of hypnotic responsiveness in the practice of a
      dhami-jhankri, a traditional Nepali healer. The hypnotic capacity of 248 male
      patients was measured in an allopathic (Western) clinic, an Ayurvedic (ancient
      Hindu healing art) clinic, and a dhami-jhankri's practice. Hypnotizability was
      assessed using the Hypnotic Induction Profile (HIP). The Induction scores of the
      HIP were significantly higher among the dhami-jhankri's patients than among
      either the Ayurvedic or allopathic patients. Furthermore, patients who returned
      to the dhami-jhankri were more highly hypnotizable than first-time dhami-jhankri
      patients. In addition, treatment satisfaction as reported by dhami-jhankri
      patients was positively correlated with HIP scores. The authors conclude that
      hypnotic phenomena as measured in the West might be an important component of the
      dhami-jhankri's treatment in the East.

PMID- 10641430
TI  - Cardiovascular reactivity during hypnosis and hypnotic susceptibility: three
      studies of heart rate variability.
AB  - This paper was designed to examine the relationship between hypnotic
      susceptibility and cardiovascular measures, especially parasympathetic activity,
      in 3 separate studies. In these studies, neither heart rate nor heart rate
      variability differed between the high and low hypnotically susceptible
      individuals at the initial baseline. Furthermore, in the first study,
      experimental tasks designed to elicit differential sympathetic and
      parasympathetic cardiac responses demonstrated no interaction with hypnotic
      susceptibility. Overall, these 3 studies suggest that hypnotic susceptibility in
      itself is not associated with parasympathetic aspects of either basal cardiac
      states or cardiac responses. In addition, a hypnotic induction itself did not
      differentially influence parasympathetic activity for the high versus low
      susceptible individuals.

PMID- 10641431
TI  - Suggestion difficulty as a hypothesized moderator of the relation between
      absorption and suggestibility: a new spectral analysis.
AB  - Measures of hypnotic suggestibility and absorption were administered to 146
      participants in the guise of different experiments. A spectral analysis was
      performed by correlating the difficulty of individual hypnotic suggestions with
      the magnitude of the association between suggestions and absorption. Contrary to
      the two-component model, absorption was not more highly correlated with passing
      difficult suggestions than easier suggestions. This was confirmed by a meta
      analysis of this and other spectral analysis studies. In addition, cross-study
      correlations revealed that the magnitude of the association between absorption
      and individual suggestions is highly variable, rendering the two-component model
      very difficult to test. These findings indicate that discrepant results in
      previous spectral analyses may have been due to low reliability of associations
      with individual scale items, as well as the relatively small number of
      correlations that constitute the raw data of these analyses.

PMID- 10641432
TI  - Italian norms for the Harvard Group Scale of Hypnotic Susceptibility, Form A.
AB  - Norms for an Italian translation of the Harvard Group Scale of Hypnotic
      Susceptibility, Form A (HGSHS:A) by Shor and Orne (1962) are presented. Subjects
      recruited from 1986 to 1989 were pooled, resulting in a sample of 376
      participants (297 women and 79 men). The normative data were generally congruent
      with earlier normative studies in score distribution, item difficulty levels, and
      reliability. Women had significantly higher hypnotizability scores and item pass
      rates than men. The reliability scores of the Italian adaptation of the HGSHS:A
      were the same as a previously reported Danish sample and higher than a German
      sample, but lower than those of the Australian, Canadian, and original American
      samples. These results suggest that the Italian version of the HGSHS:A is an
      efficient tool for initial hypnotizability screening in an Italian context.

PMID- 10641433
TI  - Reflections on the hypnotic relationship: projective identification, containment,
      and attunement.

PMID- 10641434
TI  - The long and winding road from concept to practice: the intersubjective shaping
      of psychoanalytically informed technique in contemporary hypnosis--a commentary
      upon and extension of Baker's "reflections on the hypnotic relationship".

PMID- 10641435
TI  - Stochastic model revisited.
AB  - Micromanipulation of murine and human hematopoietic progenitors has demonstrated
      various combinations of lineages in multilineage colonies, a finding consistent
      with the stochastic model of stem cell differentiation. Debate continued,
      however, on the mechanisms of stem cell differentiation, partly because some
      studies of cell lines suggested a deterministic model. Recently, transfection of
      primary hematopoietic progenitors with natural or chimeric cytokine receptors
      demonstrated that forced expression of cytokine receptors does not change the
      intrinsic differentiation potential of the primary progenitors. Studies also have
      demonstrated remarkable absence of specificity of signaling pathways in the
      primary progenitors. These studies are consistent with the stochastic model of
      stem cell differentiation in which cytokines play permissive and not instructive
      roles. This review summarizes some of the pertinent literature and discusses the
      cellular and molecular mechanisms of stem cell differentiation.

PMID- 10641436
TI  - The Tec family protein-tyrosine kinases: a subset of kinases for a subset of
      signalings.
AB  - The Tec family has emerged recently as a subfamily among nonreceptor type protein
      tyrosine kinases, consisting of Tec, Btk, Itk/Tsk/Emt, Bmx, and Txk/Rlk. Because
      many members of this family have been shown to be activated in response to growth
      and differentiation stimuli in hematopoietic tissues, they are presumed to
      function in vivo as important signaling mediators. Although that hypothesis was
      further strengthened by the knowledge that mutations in Btk cause
      agammaglobulinemia in humans, we have only limited information concerning the
      molecular interaction through which Tec kinases exert their effects. One
      characteristic feature of Tec family members is the presence of a pleckstrin
      homology domain in their protein structure, suggesting a physical and functional
      interaction with the phospholipid-dependent signaling pathways. Recent data have
      revealed that Tec kinases regulate phospholipase C isoforms. This review
      summarizes current knowledge concerning the in vivo roles of the Tec family
      proteins.

PMID- 10641437
TI  - Sharing of receptor subunits and signal transduction pathway between the IL-4 and
      IL-13 receptor system.
AB  - In this review, we summarize the subunit structure of the interleukin (IL)-4 and
      IL-13 receptor system and the molecular mechanism of signals through the cytokine
      receptor systems. We have demonstrated that two different forms of IL-4R exist,
      classical and alternative. Classical IL-4R is predominantly expressed in
      hematopoietic cells and consists of IL-4R p140 (beta) and IL-2R gamma (gamma c)
      chains. The alternative form of IL-4R is predominantly expressed in
      nonhematopoietic cells and consists of IL-4R beta and IL-13R alpha' chains.
      Moreover, the alternative form of IL-4R is also used as a functional component in
      the IL-13R complex. For signal transduction through IL-4R and IL-13R, we have
      demonstrated that in nonhematopoietic cells, Janus protein tyrosine kinase (JAK)
      2 is phosphorylated and activated instead of JAK3 tyrosine kinase. While JAK3 is
      required for signal transducer and activator of transcription-6 (STAT6)
      activation in hematopoietic cells, we recently demonstrated that in
      nonhematopoietic cells JAK2 is required for STAT6 activation for the alternative
      form of IL-4R. Thus, a major difference exists between hematopoietic and
      nonhematopoietic cells with regard to structure and signal transduction through
      the IL-4R and IL-13R systems.

PMID- 10641438
TI  - Clonal hematopoiesis in acquired aplastic anemia revealed by rearrangement of the
      immunoglobulin heavy chain gene-JH region.
AB  - We report on a female patient with acquired aplastic anemia whose bone marrow
      cells showed DNA rearrangement of the immunoglobulin-JH region that disappeared
      after 1 month with recovery of hematopoiesis through treatment with granulocyte
      colony-stimulating factor (G-CSF) and immunosuppressive drugs. The patient is now
      2 years and 6 months from onset, and her hematopoiesis is almost within normal
      limits without medication. This finding provides new data supporting clonal
      hematopoiesis in acquired aplastic anemia but does not imply that the disease is
      resistant to immunosuppressive therapy.

PMID- 10641439
TI  - Successful therapy of myelodysplastic syndrome with menatetrenone, a vitamin K2
      analog.
AB  - Although vitamin K2 is an inducer of the in vitro differentiation of myeloid
      leukemic cell lines, its clinical efficacy in the treatment of myelodysplastic
      syndrome (MDS) is unclear. We administered a vitamin K2 analog, menatetrenone, at
      45 mg daily to an 80-year-old woman with MDS (refractory anemia) heavily
      dependent on red-cell transfusions. The patient's pancytopenia gradually
      improved, and she became transfusion-independent after 14 months. Pancytopenia
      recurred when menatetrenone was discontinued but recovered again with
      readministration. Administration of menatetrenone at a dose effective in
      improving osteoporosis may also be useful in restoring hematopoiesis in MDS
      patients, possibly by way of inducing differentiation.

PMID- 10641441
TI  - Analysis of circulating hematopoietic progenitor cells after peripheral blood
      stem cell transplantation.
AB  - We investigated the kinetics of posttransplant circulating progenitor cells
      (PTCPC) in the early phase after autologous (auto-) and allogeneic (allo-)
      peripheral blood stem cell transplantation (PBSCT). We analyzed the number of
      myeloid progenitor cells (CFU-GM) per 10 ml of peripheral blood (PB) on days 0
      (just prior to transplantation), 1 (12-15 hours after completion of first
      transplantation), 2, 3, 5, 7, 10, 14, 17, 21 and 28 (after auto-PBSCT), and also
      additionally on day 35 after allo-PBSCT. A standard methylcellulose colony assay
      was used for analysing the number of CFU-GGM and BFU-E on all of the days. In
      addition, high proliferative potential-colony forming cells (HPP-CFC) of the
      harvested PBSC from donors and day 1 PB from recipients were assayed in 5 allo
      PBSCT patients. Furthermore, a proportion of CD38- cells among CD34+ cells in the
      harvested PBSC and day 1 PB was evaluated by two-color flow cytometric analysis
      in 5 allo-PBSCT patients. The number of CFU-GM on day 1 ranged from 7 to 119 per
      10 ml PB after auto-PBSCT, and from 15 to 61 per 10 ml PB after allo-PBSCT. After
      these transient increases, PTCPC diminished rapidly. Then, PTCPC emerged again on
      day 7 after auto-PBSCT and on day 10 or 14 after allo-PBSCT along with neutrophil
      recovery. A proportion of HPP-CFC among myeloid colonies from day 1 PB of
      recipients was significantly higher than that from the harvested PBSC from donors
      (65.6 +/- 12.7% vs. 17.4 +/- 13.0%, respectively, n = 5, P = 0.0013). In
      addition, two-color flow cytometric analysis revealed that the proportion of
      CD34+CD38- cells was significantly higher in day 1 PB of recipients than in the
      harvested PBSC from donors (57.5 +/- 17.6% vs. 11.7 +/- 4.9%, n = 5, P = 0.005).
      These observations suggest that both primitive and committed transplanted myeloid
      progenitor cells may circulate in the very early period following PBSCT.

PMID- 10641440
TI  - A new marrow T cell depletion method using anti-CD6 monoclonal antibody
      conjugated magnetic beads and its clinical application for prevention of acute
      graft-vs.-host disease in allogeneic bone marrow transplantation: results of a
      phase I-II trial.
AB  - We established a simple method of T cell depletion using anti-CD6 monoclonal
      antibody-conjugated immunomagnetic beads. Preliminary experiments using this
      method demonstrated that CD3+ T cells could be partially depleted without
      depleting CD56+ NK cells. A phase I-II clinical study was performed to assess the
      safety and efficacy of this partial T cell depletion method for the prevention of
      acute graft-vs.-host disease (GVHD) in 10 leukemia patients at high risk for GVHD
      (defined as 1) unrelated transplant from MLC-positive or HLA-DRB1 mismatched
      donor or 2) related transplant from serologically HLA-A, -B, or -DR one-locus
      mismatched donor). Cyclosporine (CSP) and methotrexate (MTX) were used for
      additional prophylaxis against GVHD in all cases. Sustained engraftment occurred
      in 9 of the 10 patients. Although acute GVHD developed in 6 of the 9 evaluable
      patients, none developed more than grade III severe acute GVHD. Five patients
      were alive in remission at a median follow-up of 32 months after bone marrow
      transplantation, and no relapse of leukemia was observed. We conclude from this
      pilot study that selective T cell depletion with anti-CD6 monoclonal antibody
      coupled with CSP and MTX posttransplant immunosuppressive therapy is safe.
      Further analysis of the phase II-III study is needed to confirm the effectiveness
      of this protocol.

PMID- 10641442
TI  - Genotype frequency of plasminogen activator inhibitor-1 (PAI-1) 4G/5G
      polymorphism in healthy Japanese males and its relation to PAI-1 levels.
AB  - Plasminogen activator inhibitor-1 (PAI-1) plays an inhibitory role in the
      fibrinolytic enzyme system and is associated with thrombotic diseases. The gene
      for PAI-1 has an insertion/deletion polymorphism at the promoter region, the
      4G/5G polymorphism, which is related to differences in transcription activity in
      vitro. Association of the 4G/5G polymorphism with plasma PAI-1 levels, however,
      has not been uniformly reported. We evaluated the relationship between the 4G/5G
      polymorphism and plasma PAI-1 antigen levels in 104 Japanese males not taking
      lipid-lowering drugs and without non-insulin-dependent (type 2) diabetes mellitus
      or coronary artery disease. The genotype frequency was 37.5%, 50.0%, and 12.5%
      for 4G/4G, 4G/5G, and 5G/5G genotypes, respectively, which differs from that
      reported for healthy Caucasian males (P < 0.01), with the 4G allele more
      frequently found in the Japanese population. No association was found between the
      4G/5G polymorphism and plasma PAI-1 antigen levels. Multiple regression analysis
      revealed a significant (P < 0.01) contribution of triglyceride (TG) levels to
      variations in plasma PAI-1 antigen levels. The correlation between TG levels and
      plasma PAI-1 antigen levels was not 4G/5G genotype-specific. These findings
      suggest that PAI-1 4G/5G polymorphism is not associated with plasma PAI-1 antigen
      levels among healthy Japanese males and that TG levels correlate to plasma PAI-1
      antigen levels in all PAI-1 4G/5G genotypes.

PMID- 10641443
TI  - Shear-dependent functions of the interaction between soluble von Willebrand
      factor and platelet glycoprotein Ib in mural thrombus formation on a collagen
      surface.
AB  - Recent flow studies have clearly established the function of von Willebrand
      factor (vWF) in initial platelet adhesion, in which the interaction of surface
      immobilized vWF with platelet glycoprotein (GP) Ib, particularly at high shear
      rates, leads to the transient capture of flowing platelets onto the surface. This
      interaction is thought to trigger activation of platelet GP IIb/IIIa, leading to
      irreversible platelet adhesion and subsequent mural thrombus growth. The role of
      vWF-GP Ib interaction in secondary thrombus growth remains to be clarified,
      however. In this study, time-course images of the thrombus formation process were
      obtained using a whole blood flow system that allows real-time visualization of
      fluorescence-labeled platelet thrombus formation. The system employs a collagen
      coated surface in a parallel plate flow chamber mounted on an epifluorescence
      microscope, which is then subjected to computer-assisted image analysis. In
      perfusion of blood preincubated with anti-vWF antibody NMC-4, which blocks the
      vWF-GP Ib interaction in solution, neither primary platelet adhesion nor
      subsequent thrombus growth on a collagen surface was detected at high shear rates
      (> or = 1210/s). In addition, even under experimental conditions in which initial
      platelet adhesion normally occurred, NMC-4-treated blood perfusion showed an
      apparent defect of secondary thrombus growth at the same high shear rates. The
      overall process of thrombus formation at low shear rates (< or = 340/s) was not
      affected by specific blockers of the vWF-GP Ib interaction. These findings
      indicate that, in addition to the interaction of surface-immobilized vWF with GP
      Ib in platelet adhesion, the interaction of soluble vWF with GP Ib is required
      for secondary thrombus growth selectively at high shear rates.

PMID- 10641444
TI  - Low prevalence of a polymorphism of platelet membrane glycoprotein Ib beta
      associated with neonatal alloimmune thrombocytopenic purpura in Asian
      populations.
AB  - Iy alloantigen system is the first polymorphism of platelet glycoprotein Ib beta
      reported to cause neonatal alloimmune thrombocytopenic purpura. We investigated
      the allelic frequency of Iy alloantigen among Japanese and Korean populations by
      polymerase chain reaction-restriction fragment length method to determine the
      possibility of alloimmunization against Iy. Two hundred and nine Japanese and 97
      Korean subjects were examined. All 306 individuals were homozygous for glycine at
      amino acid position 15 and negative for Iy. The allelic frequency of Iy in these
      populations was calculated to be less than 0.0016. Alloimmunization associated
      with Iy antigen in Asian populations seems unlikely from these results.

PMID- 10641445
TI  - Anaphylactoid reaction to cyclophosphamide in a patient with T cell lymphoma and
      hemophagocytic syndrome.

PMID- 10641446
TI  - Eosinophilia-preceded myelodysplastic syndrome associated with deletion of
      chromosome 20q and isochromosome 17q.

PMID- 10641447
TI  - Posttransfusion hepatitis B infection after revised screening for hepatitis B.

PMID- 10641448
TI  - Prevalence of allergic diseases in children in Beirut: comparison to worldwide
      data.
AB  - OBJECTIVE: To report on the prevalence of allergic rhinitis and atopic eczema in
      school children in Beirut, Lebanon, and compare the prevalence rates of allergic
      diseases in Beirut to the rest of the world. SUBJECTS AND METHODS: A random
      sample of school children aged 13-14 years completed the ISAAC written and video
      questionnaires. Data was entered using a special program prepared by ISAAC and
      analyzed using SPSS version 6.0. RESULTS: The prevalence rates of allergic
      rhinitis and rhinoconjunctivitis were 25.5% and 15.9% respectively. Atopic eczema
      was more common among males, with a total prevalence rate of 11%. CONCLUSION: The
      prevalence rates of allergic diseases in childhood was along the 50th percentile
      worldwide. The prevalence rates of uncontrolled asthma was very high while that
      of allergic rhinitis was low as compared to the rest of the world.

PMID- 10641449
TI  - Osteoporosis: an overview of practice guidelines for bone density measurements
      and osteoporosis treatment strategies.

PMID- 10641450
TI  - [Allergic eczema caused by food hypersensitivity].

PMID- 10641451
TI  - Pharmacologic treatment of type 2 diabetes mellitus: realities and perspectives.

PMID- 10641452
TI  - [Gastroesophageal reflux in the adult: "diagnosis and treatment". French National
      Society of Gastroenterology. Belgium Royal Society of Gastroenterology].

PMID- 10641453
TI  - Hydatid disease.

PMID- 10641454
TI  - [Recurrent cerebrovascular accident: unusual and isolated manifestation of myxoma
      of the left atrium].
AB  - The authors report an unusual case of left atrial myxoma in a 30-year-old woman,
      discovered after a recurrent stroke. This tumor was misdiagnosed earlier because
      of an exclusive neurologic symptomatology, a normal cardiac exam without any sign
      of mitral obstruction (unusual high implantation of the myxoma within the roof of
      the left atrium), and the lack of doing an echocardiography which should be
      systematically done after an ischemic stroke, even if its etiology seems to be
      evident. Surgical resection of the tumor led to prevent further myxomatous
      emboli, but unfortunately, the patient keeps severe neurological sequelae.

PMID- 10641455
TI  - Acute rupture of a left ventricular false aneurysm.
AB  - Left ventricular aneurysm develop when rupture of the free ventricular wall is
      contained by the inflammatory surrounding tissues. These false aneurysms rupture
      secondarily and should be treated soon after diagnosis. The diagnosis is
      suggested by echocardiography and confirmed by cardiac catheterization. Immediate
      surgery is recommended, with good survival in most reports. The patient presented
      in this report had ruptured his left ventricular false aneurysm before diagnosis.
      He was operated and had a good initial postoperative course. He died later from a
      severe pulmonary infection.

PMID- 10641456
TI  - Transfusion associated graft versus host disease in immunocompetent patients.
      Report of two cases.
AB  - Transfusion graft versus host disease (TGVHD) in immunocompetent patients is a
      recently recognized disease, reported mainly after open heart surgery, and almost
      always fatal. We report two cases of TGVHD in immunocompetent patients after open
      heart surgery. The disease is characterized by the occurrence of fever, skin
      rash, liver failure and pancytopenia. Preventive measures include exclusion of
      first- and second-degree relatives as blood donors, and/or irradiation of blood
      to be transfused.

PMID- 10641457
TI  - [Unusual presentation of typhoid fever. Apropos of 3 cases].
AB  - Typhoid fever is still an endemic disease in Lebanon with a risk of mortality
      especially in the immunosuppressed patients. We report 3 atypical observations
      and discuss cardiopulmonary, neurological, hematologic and urinary manifestations
      of this disease.

PMID- 10641458
TI  - Metastases to the ureter. Review of the world literature, and three new case
      reports.
AB  - The rarity of metastases to the ureter justifies the reporting of three new
      personal cases. In two cases the primary was in the bladder, and in one case, the
      primary was in the prostate. In two cases there were more than one primary tumor;
      and in two cases the diagnosis was made at autopsy. A total of 342 cases of
      metastases to the ureter (including our three new cases) have been collected from
      the world literature and subjected to study and review.

PMID- 10641459
TI  - The ethics of selective termination cases. Opening the door to abortion
      extortion.

PMID- 10641460
TI  - 1998 LeTourneau Award. The legal implications of noncompetition agreements in
      physician contracts.

PMID- 10641461
TI  - Physician peer review. Serving the patient or the physician?

PMID- 10641462
TI  - Chronic hiccups following chemotherapy.

PMID- 10641463
TI  - Lessons learned from a snapshot pain survey.

PMID- 10641464
TI  - Prospective study of home morphine infusion in 62 terminally ill patients.
AB  - The project "Infusion Therapy at Home" studied the practice of parenteral
      infusion therapy at home. Among the treatment modalities was the administration
      of morphine infusions to terminally ill patients. With infusion of morphine,
      patients were pain-free on 73% of the treatment days. Quality of care, quality of
      life, and costs were acceptable.

PMID- 10641465
TI  - Pursuit of assisted dying: a pilot study of inquiries made to a national consumer
      based organization.
AB  - Legal developments in assisted dying have focused on assisted suicide for
      mentally competent, terminally ill adults. Requests for assisted dying are likely
      to represent broader concerns, but studies have been limited to surveys of
      specific patient groups or recollections of physicians. To describe the nature of
      inquiries by a broad range of persons seeking assisted dying, a retrospective
      review was performed of confidential client memoranda summarizing telephone
      inquiries regarding assisted dying to a counseling service of a national, not-for
      profit, consumer-based organization. The review evaluated the underlying medical
      condition prompting the inquiry, evidence of patient's decisional capacity, and
      relationship of caller to the patient. Of 125 assisted suicide calls, 111 with
      medical illness were analyzed. Among 111 inquiries, 71 (64%) were made by someone
      other than the person suffering from the illness ("the patient"); 52 (47%) of
      these were family members, 14 (13%) were friends, and 5 (7%) were professionals.
      Cancer accounted for 25% of cases, HIV/AIDS and amyotrophic lateral sclerosis
      (ALS) for 10 and 9%, respectively, other neurological diseases for 23%, and
      chronic or other medical conditions for approximately 17%. In an additional 10
      cases, there was no medical illness. Within the group of callers inquiring on
      behalf of others, 18 (25%) stated the patient lacked ability to communicate his
      or her wishes and 7 (10%) stated there was uncertainty. Inquiries about assisted
      dying represent a broader range of concerns than represented by legal
      initiatives. More study is needed to determine if enhanced knowledge about
      alternatives, such as palliative care, reduces requests for assisted dying.

PMID- 10641466
TI  - Reproducing a cancer patient's pain on physical examination: bedside provocative
      maneuvers.
AB  - While various aspects of the physical examination in pain patients have been
      validated, the value of screening maneuvers that reproduce a cancer patient's
      pain on physical examination has been less well defined. The purpose of this
      prospective case series is to better characterize the role of bedside provocative
      maneuvers as part of the comprehensive evaluation of cancer pain patients. Fifty
      consecutive patients referred to an ambulatory cancer pain clinic were evaluated;
      they described a total of 89 discrete pains. All or much of the pain that brought
      each patient to medical attention was reproduced by a provocative maneuver in 47
      (94%) patients; 79 of 89 (89%) pains were elicited at the bedside. Pains that
      were not reproducible with any provocative maneuver included paroxysmal spells of
      pain, neuropathic pain, and steady headache. On the basis of the history,
      physical examination, and both positive and negative provocative maneuvers, all
      pains were characterizable as somatic, visceral, neuropathic, or mixed, and a
      pathophysiological basis for the pain was inferred in 85 of 89 (95%) pains. On
      the basis of this preliminary report, we conclude that provocative bedside
      maneuvers are usually able to reproduce a cancer patient's pain. They help to
      better characterize the pain and identify the pain sensitive structure, and
      should be a routine part of the comprehensive assessment of cancer pain patients.
      Further research is needed to validate the diagnostic role of standardized pain
      provoking maneuvers in a variety of clinical situations.

PMID- 10641467
TI  - Assessment and treatment of discomfort for people with late-stage dementia.
AB  - People with dementia have often been excluded from pain studies. However, there
      is evidence supporting that people with dementia experience frequent pain, often
      poorly assessed and undertreated, and that the etiology for pain descriptions is
      poorly documented. The Assessment of Discomfort in Dementia (ADD) Protocol is
      designed to: a) more accurately assess discomfort in people with dementia who can
      no longer verbally describe physical pain or affective discomfort; b) more
      accurately and thoroughly treat physical pain and affective discomfort; and c)
      decrease inappropriate use of psychotropic medication. The use of the ADD
      Protocol was studies with a convenience sample of 104 residents of long-term care
      with end-stage dementia. Use of the ADD Protocol was associated with a
      significant decrease in discomfort (t = 6.56, p = 0.000). The most frequently
      seen behavioral symptoms associated with discomfort were tense body language, sad
      facial expression, fidgeting, perseverant verbalizations, and verbal outburts.
      The ADD Protocol was also associated with a significant increase in the use of
      scheduled analgesics and non-pharmacological comfort interventions. The protocol
      was not associated with an increase in the use of prn analgesics or with prn or
      scheduled psychotropics. This study has provided some support for the notion that
      the needs of people with significant dementia can be discerned and treated.

PMID- 10641468
TI  - Do physical and sexual abuse differentially affect chronic pain states in women?
AB  - To evaluate the role of physical and/or sexual abuse on chronic pain symptoms and
      health care utilization in women, 104 consecutive female patients presenting to a
      multidisciplinary pain center for management of chronic pain were surveyed.
      Outcomes included a measure of sexual or physical abuse history (Drossman Sexual
      Physical Abuse Survey), and measures of anxiety, health care utilization,
      substance abuse, and somatic symptoms. Forty-eight percent of the sample reported
      a history of physical abuse (PA) or sexual abuse (SA). Forty percent of the
      abused patients reported both PA and SA and the remainder reported SA (37%) or PA
      (23%) alone. The women who reported abuse had increased pain, physical symptoms,
      anxiety symptoms, and mental health care utilization compared to nonabused women.
      The women who reported abuse were also more likely to smoke and abuse street
      drugs. Women who reported both PA and SA were more likely to report head pain
      when compared to those who reported only PA or SA. Given the impact of abuse,
      particularly SA, on the presentation of chronic pain, queries regarding abuse
      should become a routine component of the patient interview. Abused patients
      should be referred to mental health care practitioners as a component of
      successful pain management if unresolved issues persist.

PMID- 10641469
TI  - Reporting of adverse effects in clinical trials should be improved: lessons from
      acute postoperative pain.
AB  - We assessed the quality of assessment and reporting of adverse effects in
      randomized, double-blind clinical trials of single-dose acetaminophen or
      ibuprofen compared with placebo in moderate to severe postoperative pain. Reports
      were identified by systematic searching of a number of bibliographic databases
      (e.g., MEDLINE). Information on adverse effect assessment, severity and
      reporting, patient withdrawals, and anesthetic used was extracted. Compliance
      with former guidelines for adverse effect reporting was noted. Fifty-two studies
      were included; two made no mention of adverse effects. No method of assessment
      was given in 19 studies. Twenty trials failed to report the type of anesthetic
      used, eight made no mention of patient withdrawals, and nine did not state the
      severity of reported adverse effects. Only two studies described the method of
      assessment of adverse effect severity. When all adverse effect data were pooled,
      significantly more adverse effects were reported with active treatment than with
      placebo. For individual adverse effects, there was no difference between active
      (acetaminophen 1000 mg or ibuprofen 400 mg) and placebo; the exception was
      significantly more somnolence/drowsiness with ibuprofen 400 mg. Ninety percent of
      trials reporting somnolence/drowsiness with ibuprofen 400 mg were in dental pain.
      All studies published after 1994 complied with former guidelines for adverse
      effect reporting. Different methods of assessing adverse effects produce
      different reported incidence: patient diaries yielded significantly more adverse
      effects than other forms of assessment. We recommend guidelines for reporting
      adverse effect information in clinical trials.

PMID- 10641470
TI  - A descriptive study of the use of visual analogue scales and verbal rating scales
      for the assessment of postoperative pain in orthopedic patients.
AB  - Visual analogue scales (VAS) and verbal rating scales (VRS) are widely used to
      assess pain. This paper presents a secondary analysis of a subsection of data
      collected as part of an evaluation of an intervention to improve nighttime pain.
      The aims were to describe the relationship between the VAS and VRS; to compare
      characteristics of the noncompliant groups in terms of age, gender, type of
      surgery, and analgesics; to explore the reasons for noncompletion of the VAS or
      VRS; and to determine the noncompliance rates with each assessment scale. Worst
      and average pain scores were obtained for the second postoperative night for 417
      patients. Fifty-nine patients (14.2%) did not complete the VAS. In contrast, two
      patients did not complete the VRS (0.5%). The scores generated from the VAS and
      VRS correlated well, although the range of VAS scores corresponding to each VRS
      category was wide. We conclude that the VRS was more suitable for use in this
      clinical setting.

PMID- 10641471
TI  - Case presentation: end-of-life care and mental illness: the case of Ms. W.

PMID- 10641472
TI  - Commentary: promoting end-of-life planning for patients with all diagnoses.

PMID- 10641473
TI  - Commentary: the risks and benefits of competence assessment.

PMID- 10641474
TI  - The nurse executive. Slicing and dicing nursing.

PMID- 10641475
TI  - Professional practice. Faculty practice--the scholarship of application.

PMID- 10641476
TI  - Public policy. Nursing and Medicare.

PMID- 10641477
TI  - Research. Electronic theses and dissertations--the wave of the future.

PMID- 10641479
TI  - Making sense of a new nursing role: a phenomenological study of an organizational
      change.
AB  - Although health care organizational change is a constant phenomenon, little is
      understood as to how staff experience this change. Unsuccessful change efforts
      have suggested the possible important relationship between understanding staff's
      experience and improved results. The purpose of this phenomenological study was
      to describe what staff on a medical-surgical unit experience during the initial
      phase of the implementation of a nursing care coordinator position, a first step
      in a broad organizational change. A purposeful sample of 11 nursing and non
      nursing staff, considered unit experts, were interviewed using broad, open-ended
      questions designed to solicit their experience. Additionally, observations and
      document abstraction were used to add depth and clarification to the interviews.
      Analysis of data was conducted using a combination of Giorgi's and Colaizzi's
      procedures. Contextual elements framing staff's experiences included introduction
      of a new role with no organizational history into an increasingly demanding
      environment that staff perceived as constantly changing. Major themes of
      "experiencing the effect" and "struggling to make sense" were revealed. These
      findings suggest that the introduction of a new role can create turmoil and job
      insecurity in the current health care environment. Recommendations to support
      staff's efforts to "make sense" are provided.

PMID- 10641478
TI  - Teaching qualitative research through participatory coursework and mentorship.
AB  - Many doctoral programs in nursing now offer at least one course in qualitative
      research. Yet it remains a challenge to adequately prepare new qualitative
      researchers due to lack of faculty expertise and mentorship, student
      unfamiliarity with qualitative research when entering the doctoral program, and
      uncertainty as to appropriate teaching methods. The authors describe how they
      addressed these issues historically and in their current two-course qualitative
      research sequence. Accompanying reports of four studies conducted by students who
      completed the two-course sequence during academic year 1996 to 1997 provide
      evidence of the viability of the authors' approach and serve as the basis for
      recommendations to others who use a similar strategy for teaching qualitative
      research.

PMID- 10641480
TI  - Implementation of a case coordinator role: a focused ethnographic study.
AB  - This study was a focused ethnography of a 21-bed, inpatient psychiatric unit.
      Patient care was provided by a multidisciplinary team, and a case coordinator
      role was developed to coordinate the team's efforts. The purpose of the study was
      to describe perceptions of the implementation of the case coordinator role. Data
      collection methods included document review, participant and nonparticipant
      observation, and personal interviews of key informants. Field notes and
      transcriptions were analyzed throughout data collection. Three themes were
      identified: role development, role confusion, and role expectation. Role
      development was defined as the process of recognizing the need for and
      instituting the position of case coordinator. Role confusion was defined as the
      lack of a clear distinction between the role of the case coordinator and the role
      of the staff nurse. Role expectation was defined as the process of directing the
      development of the role based on individuals' perceptions of the role. Although
      the role as implemented had not met initial expectations, team members were
      confident the role would evolve to fulfill the unit's needs.

PMID- 10641481
TI  - Implementation of the care coordinator role: a grounded theory approach.
AB  - The purpose of this study was to explore the process of implementing a new care
      coordinator role on a medical-surgical unit. Qualitative data were collected from
      employees and patients during a 3-month period; data analysis occurred
      concurrently. Using the constant comparative method, a grounded theory was
      developed to explain the initial process of implementation of the clinical nurse
      III (CNIII) role. The basic social psychological problem associated with
      implementation was role ambiguity. The basic social psychological process used to
      resolve this problem was "making the role of the CNIII". Making the role involves
      the following four strategies, which may occur simultaneously: communicating the
      vision, gaining new knowledge, accessing resources, and defining boundaries.
      Communicating the vision refers to efforts to articulate the role before and
      during the implementation process. Gaining new knowledge includes participating
      in educational workshops and acquiring new skills. Accessing resources refers to
      development of new relationships and acquisition of office space and equipment.
      Defining boundaries includes determining the scope of responsibilities and
      differentiating the role from other roles. This theory may be useful to
      researchers, educators, and administrators interested in role implementation.

PMID- 10641482
TI  - An ethnographic study of differentiated practice in an operating room.
AB  - An ethnographic study was conducted to investigate implementation of the clinical
      nurse III or team leader (TL) role as part of a newly executed nursing
      differentiated practice model. The six TLs studied were employed in the operating
      room (OR). Through participant observation, interviews, and document analysis,
      the TL role--as well as perceptions of the role by the TLs and OR staff--were
      studied. Problems related to performance of the role and its evolutionary process
      were delineated. Data analysis involved identifying categories and subcategories
      of data and developing a coding system to identify themes. Salient themes were
      related to the culture of the OR. Because of the OR's highly technical
      environment, the TLs defined their roles in relation to the organizational and
      technical needs of their surgical service. Refinement of surgeon "preference
      cards" and "instrument count sheets" was considered the initial priority for the
      TLs. Various controllable and uncontrollable factors were identified that
      affected implementation of the new TL role. Findings suggest that introduction of
      the role requires insight into setting and an emphasis on staging and orientation
      of employees to the new role.

PMID- 10641483
TI  - Defining scholarship for the discipline of nursing. American Association of
      Colleges of Nursing.
AB  - Although the mission of institutions of higher learning is unique in each
      setting, the commitment to scholarly approaches to education, practice, and
      research creates common bonds across the academic nursing community. This
      document is intended to clarify, extend, and enhance the scholarly work of
      nursing in academic settings. The application of the standards proposed in this
      document will differ by institution, yet the standards themselves will provide a
      framework for the advancement of nursing knowledge, which ultimately will improve
      the health of all people.

PMID- 10641484
TI  - Radiological states around the Kraton-4 underground nuclear explosion site in
      Sakha.
AB  - A radiological survey around the site of Kraton-4, an underground nuclear
      explosion (Yield of 20 kt, depth of 560 m, 1978) in Sakha was carried out in
      March 1998. Gamma survey and in-situ spectroscopy on the ground exhibited quite
      normal levels: a dose rate of 0.022 microSv/h and Cs-137 surface contamination of
      less than 1.1 kBq/m2 around the hypocenter. The results suggested no remarkable
      leakage of radioactivity from the epicenter to the ground surface at least not
      for non-rare gas elements as of 1998.

PMID- 10641485
TI  - Dose-response relationship for induction of solid tumors in female B6C3F1 mice
      irradiated neonatally with a single dose of gamma rays.
AB  - Our previous studies showed that mice during infancy are highly susceptible to
      the induction of several types of solid tumors. The present study was designed to
      elucidate the dose-response relationships for induction of solid tumors after
      exposure to 0.48-5.70 Gy of 137Cs gamma rays in the neonatal period in female
      mice. A total of 2988 mice were allowed to live out their life span under a
      specific pathogen free condition and lifetime incidences of liver, pituitary,
      ovarian, lung and bone tumors were recorded. The dose-response curves for liver,
      pituitary, ovarian and lung tumors were convex upward in the dose range examined,
      and were composed of three parts: an initial rapid increase of incidence at doses
      below 1 Gy, a gradual increase to the highest incidence, and a decrease in
      incidence with increasing dose in the higher dose range. The dose which induces
      neoplasm at the highest incidence seemed to be different for each type of solid
      tumor. The shape of the dose-response curve for induction of bone tumors was
      quite different from that for other solid tumors; the initial slope of the curve
      was concave upward. Dose-response relationships were analyzed using a model that
      allows for tumorigenic effect, inactivation of potentially tumorigenic cells and
      competing risks. The results showed that the tumorigenic effect was proportional
      to the dose of gamma rays for induction of liver, pituitary, ovarian and lung
      tumors; whereas the tumorigenic effect for bone tumors was proportional to the
      square of the dose. A significant increase in incidence was also found for
      gastrointestinal tumors, kidney tumors, adrenal tumors and hemangiomas of spleen,
      although dose-response relationships could not be analyzed.

PMID- 10641486
TI  - In vitro determination of oxidation of atmospheric tritium gas in vegetation and
      soil in Ibaraki and Gifu, Japan.
AB  - To quantify the rate of oxidation of tritium gas (referred to as HT) to tritiated
      water in the environment, various woody and herbaceous plant leaves and roots,
      mosses and lichens taken from a forest and fields in Ibaraki prefecture, and a
      forest in Toki, Gifu prefecture, were investigated as to their ability to oxidize
      atmospheric HT in in vitro experiments. The HT oxidation activity in vegetation
      was compared with that in the surrounding surface soil (0-5 cm in depth). The
      rate of oxidation of HT in woody plant leaves including pine needles was
      extremely low, only about 1/10000-1/1000 that in the surface soil, as well as in
      herbaceous plant leaves with some exceptions (Phalaris arundinacea and Vaccinium
      smallii), whereas the rate in mosses and lichens was 50-500 times that in pine
      needles. The HT oxidation activity in roots of several plants including Phalaris
      arundinacea, Pieris japonica and Lespedeza homoloba was quite high and comparable
      to that in the surrounding surface soil. These results suggest that mosses,
      lichens and the leaves or roots of particular plants with high HT oxidation
      activity can be used to monitor the accidental release of HT into the
      environment.

PMID- 10641487
TI  - Contribution of inflammatory cytokine release to activation of resident
      peritoneal macrophages after in vivo low-dose gamma-irradiation.
AB  - The activation mechanism of resident peritoneal macrophages by in vivo gamma
      irradiation was investigated. The function of macrophages as accessory cells in
      concanavalin A-induced proliferation of spleno-lymphocytes (accessory function)
      was enhanced 4 h after a low-dose irradiation (4 cGy) in vivo, but not in vitro,
      indicating that low-dose irradiation acts indirectly on the activation of
      macrophages. Because we expected that macrophages were activated by the
      recognition of substances damaged by in vivo irradiation, we co-cultured
      macrophages with oxidized erythrocyte-ghosts. No change was found in their
      accessory function. The production of inflammatory cytokines, interleukin-1 beta
      (IL-1 beta) and interferon-gamma (IFN-gamma), in the supernatant of cocultures of
      spleno-lymphocytes and macrophages was determined by an ELISA. Production of both
      increased in the presence of in vivo irradiated macrophages. Furthermore, IL-1
      beta production from in vivo-irradiated macrophages treated with recombinant IFN
      gamma also was enhanced. The mRNA expression of the cytokines released from
      macrophages and lymphocytes was determined by RT-PCR. Increases in IL-1 beta mRNA
      expression were found in both in vivo- and in vitro-irradiated macrophages. In
      vivo irradiation also enhanced the expression of IFN-gamma mRNA in lymphocytes,
      whereas there was no change after in vitro irradiation. On the basis of these
      observations, we propose that the activation of macrophages is caused by
      interaction with neighboring cells, such as lymphocytes, and by paracrine
      induction of certain cytokines which is initiated by the small amount of IL-1
      beta released by irradiated macrophages.

PMID- 10641488
TI  - Apoptosis of human tumor cells by chemotherapeutic anthracyclines is enhanced by
      Bax overexpression.
AB  - One of the major factors for efficacy of a chemotherapeutic drug is its activity
      to induce apoptosis of tumor cells. Doxorubicin and daunorubicin, radiomimetic
      anthracycline-group drugs, have been used for chemotherapy for about 30 years.
      Here we established the colorectal tumor and osteosarcoma cells in which Bax
      expression can be induced by the treatment of isopropyl-beta-D
      thiogalactopyranoside, and examined the effect of the Bax overexpression on the
      cell death caused by these drugs. While the Bax overexpression neither affected
      growth nor morphology of the undamaged cells, it enhanced the cell death caused
      by these drugs. Increase in cellular nucleus fragmentation and DNA ladder
      formation indicates that the Bax-enhanced cell death is due to enhanced apoptosis
      of the drug-treated cells. The enhanced cell death was not observed when the
      cells were irradiated with X-ray or treated with other chemotherapeutic agents we
      examined. These results indicate that Bax may have a specific role to enhance the
      efficacy of chemotherapy with anthracycline-group agents.

PMID- 10641489
TI  - Radiation augments a sequential program of differentiation in PKC inhibitor-
      pretreated mouse epidermal cells.
AB  - The aim of this study was to determine whether gamma-rays affect differentiation
      in mouse epidermal cells. After a pre-treatment with the PKC inhibitor
      staurosporin (STS) or 1-(5-isoquinolinesulfomyl)-2-methylpiperazine (H7), gamma
      rays were irradiated with or without an elevation of 0.12 mM Ca2+ and expressions
      of differentiation markers and each PKC isozyme were examined in normal primary
      and v-rasHa transformed mouse keratinocytes. Gamma-rays induced the expressions
      of differentiation markers of keratin 1 and 10 (K1 and 10), filaggrin, loricrin
      and SPR-1 in normal keratinocytes when the Ca2+ concentration was increased, and
      these phenomena were augmented in H7 pretreated cells. Similar results were
      obtained in STS pretreated cells; in this case, gamma-rays enhanced the
      expressions of the differentiation markers even without an elevated Ca2+
      concentration. In v-rasHa transformed cells, gamma-rays induced the expression of
      differentiation markers not only at 0.05 mM Ca2+, but in 0.12 mM Ca(2+)-shifted
      cells, and in H7 pretreated cells, these phenomena were augmented. The
      translocation of PKC alpha to the particulate fraction was seen in H7 pretreated
      normal keratinocytes. Radiation also induced PKC alpha expression in STS
      pretreated cells, independent of Ca(2+)-shift, as well as altered expressions of
      PKC delta and -eta, while expressions of PKC alpha, -delta, -epsilon, and -eta
      were enhanced in v-rasHa transformed cells. In conclusion, gamma-rays augmented
      the expressions of both spinous and granular differentiation markers in normal
      and v-rasHa transformed keratinocytes and this effect was augmented when PKC
      inhibitors were used, which may be mediated by the cellular redistribution of PKC
      isozymes.

PMID- 10641490
TI  - Prepare the 'total' osteopathic physician for rural healthcare and public health
      roles.

PMID- 10641491
TI  - Make patients' immunizations Y2K compliant.

PMID- 10641492
TI  - Multiple sclerosis--Part 2. Treatment strategies.
AB  - Because it is a chronic, relapsing or progressive disease, multiple sclerosis has
      an unpredictable clinical course generally spanning 10 to 20 years. During that
      time, neurologic disability is cumulative. Therefore, it is difficult to evaluate
      the efficacy of a given mode of treatment in an individual patient. This second
      part of a two-part series reviews current and emerging modes of therapy for
      multiple sclerosis. Future treatment directions in multiple sclerosis will
      require a better understanding of the pathophysiology of the disease. Future
      therapeutic modalities will also rely on more accurate clinical markers, such as
      improved magnetic resonance imaging techniques or specific immune markers to
      follow the disease progression. Part 1 of this series appearing in the November
      1999 issue of JAOA included several sections on multiple sclerosis, including an
      overview, pathophysiology, diagnostic evaluation, and clinical parameters.

PMID- 10641493
TI  - Family cluster of atrial septal defect.
AB  - Atrial septal defect is one of the most common congenital cardiac defects,
      occurring in 9% to 15% of live births. This defect has been reported to have a
      genetic etiology in some cases, although the full extent of genetic involvement
      in atrial septal defect is not known. Because symptoms are often lacking in
      childhood and manifest primarily in adulthood and because physical findings may
      be lacking, it is important to take a family history in patients in whom the
      defect is suspected. When evaluating children, a family history of atrial septal
      defect should raise suspicion of increased risk so that early diagnosis and
      treatment can be made. The author reports a cluster of 11 diagnosed atrial septal
      defects within one 32-member family group, 6 of whom required surgery to repair
      the defects. It is significant that most of the individuals were lacking in
      objective findings on physical examination, notably a murmur, as well as in
      subjective complaints. Diagnoses were made by use of two-dimensional
      echocardiography with color-enhanced Doppler ultrasonography in all but two cases
      -one diagnosed with transesophageal echocardiography and one, serendipitously,
      during cardiac catheterization. Echocardiography also revealed mitral valve
      prolapse, thin atrial septal wall, with aneurysm in some cases, and regurgitation
      of mitral or tricuspid valves in several individuals. Cardiac enlargement,
      usually of the right atrium, was seen in most of the individuals.

PMID- 10641494
TI  - Vertex hemangioma mimicking an encephalocele.
AB  - Most extracranial masses detected prenatally by use of ultrasonography are either
      encephaloceles or meningoceles. This article describes an extracranial mass
      detected prenatally that was initially thought to be an encephalocele, but was
      subsequently found to be a large hemangioma.

PMID- 10641495
TI  - Spread of anti-affirmative action is threatening the future of America's minority
      medical community.

PMID- 10641497
TI  - In vivo production of type 1 cytokines in healthy sickle cell disease patients.
AB  - Interleukins (IL)-1, 2, 12, and interferon (IFN)-gamma, along with soluble IL-2
      receptor (sIL-2R) were measured from sera obtained from healthy sickle cell
      disease (SCD) patients and comparable healthy control subjects. The cytokines
      were assessed by enzyme-linked immunosorbent assay (ELISA) in 60 SCD patients and
      58 controls. No significant detectable levels of IL-1 or IL-12 were found in the
      sera of either group of patients. Significantly elevated levels of IFN-gamma were
      measured in 20 (33%) of 60 SCD patients and 21 (36%) of 58 controls. A large
      subset of 18 (41%) of 43 healthy controls and a smaller subset of 12 (21%) of 58
      SCD demonstrated detectable levels of IL-2. The sIL-2R levels of the SCD group
      (4465 +/- 552 pg/mL) were significantly higher (P < .0001) than that of controls
      (3473 +/- 411 pg/mL). The results revealed comparable circulating levels of all
      type 1 cytokines in both healthy SCD and normal control subjects, with the
      exception of in vivo sIL-2R production. Elevated serum levels of both IL-6 and
      tumor necrosis factor (TNF)-alpha have been reported previously in a significant
      percentage of SCD steady-state subjects. These two cytokines are known to
      increase sIL-2R expression and may help explain the difference between the
      patient populations. Immune activation markers such as sIL-2R are produced by
      cells that mediate host responses to infection or inflammatory stimuli. The
      implication of higher levels of sIL-2R in SCD is not clear, but chronic
      parvovirus B19 infection, chronic polyclonal activation of B cells or defective
      regulation of antibodies are possible explanations for the elevated levels in
      SCD.

PMID- 10641498
TI  - Delirium episodes during the course of clinically diagnosed Alzheimer's disease.
AB  - A retrospective review was conducted of 122 charts of patients with clinically
      diagnosed Alzheimer's disease (CDAD) who had participated in a longitudinal
      dementia study at the Mayo Clinic from 1965 to 1970. DSM-III-R diagnoses were
      assigned based on the longitudinal description of symptoms detailed in the Mayo
      Clinic medical records of the hospitalizations; clinic, home, and nursing home
      visits; and state hospital admissions. Thirty patients (25%) were found to have a
      delirium episode during their course of CDAD that occurred during inpatient
      admissions; 50% (15 of 30) of the delirium episode occurred in patients ages 80
      to 89. Among patients with a delirium episode, 50% died within one year of the
      delirium episode and 64% died within two years. Of 13 patients, 10 (77%) had
      multiple delirium episodes within two years. Admitting diagnoses were mainly
      primary degenerative dementia of the Alzheimer's type (PDDAT) or PDDAT with
      delirium. Only 3 (10%) demented patients experienced delirium episodes during a
      medical admission. No deaths occurred during hospitalization for the years
      covered by this study. A psychiatric consultation was requested in only 17 (14%)
      patients; 88% of these patients received diagnoses involving PDDAT, late onset.
      An additional diagnosis included depressive disorders. Psychopharmacology was the
      major management strategy (82% of patients with a delirium episode received
      medication) with a resolution of symptoms within 48 hours. At discharge, only 2
      (7%) patients failed to clear the increased degree of confusion.

PMID- 10641496
TI  - Psychiatric diagnosis of African Americans: diagnostic divergence in clinician
      structured and semistructured interviewing conditions.
AB  - This study is a primary data collection that varied patient race and diagnosis
      and used two diagnostic interviewing conditions: one clinician-structured (phase
      one) and the other a semi-structured diagnostic instrument (phase two). Four
      basic research questions are addressed: What is the relationship between race and
      the hospital diagnosis? How is race related to diagnosis in both research
      interviewing conditions? Why does diagnostic concordance between the hospital
      diagnosis and the research diagnosis vary by research interviewing condition? Is
      diagnostic concordance between the hospital and research diagnosis influenced by
      patient race? A total of 291 patients completed an interview during phase one,
      while 665 patients completed an interview during phase two. Blacks were more
      likely to receive a hospital diagnosis of schizophrenia and less likely to be
      diagnosed with mood disorder. Patient race was similarly related to the research
      diagnoses produced in the clinician-structured research condition (phase one).
      Although less pronounced, a higher percentage of African Americans than whites
      received a diagnosis of schizophrenia using the semi-structured DSM-III-R Symptom
      Checklist (phase two). The black-white distribution for mood disorders showed
      that whites were more likely than blacks to be diagnosed with mood disorder.

PMID- 10641499
TI  - Early colorectal cancer in a flat adenoma.
AB  - A 56-year-old man presented with intermittent rectal bleeding of six months'
      duration. Colonoscopy revealed three left colon polyps, one of which harbored
      adenocarcinoma. Endoscopic mucosal resection (band-assisted colonoscopic
      polypectomy) was successful. Endoscopic ultrasonography did not demonstrate any
      local or regional spread; however, abdominal computed tomography (CT) scan raised
      suspicion of an isolated metastasis to the liver. The patient's mother had
      recently died from metastatic colorectal cancer. When presented with the options
      of no surgery, postendoscopic mucosal resection, and CT-directed needle biopsy of
      the suspected isolated metastasis to the liver versus segmental resection of the
      flat adenoma site and wedge resection of the liver lesion for the maximum chance
      of a surgical cure, the patient opted for the surgical approach. Histopathology
      revealed no evidence of malignancy in the rectosigmoid colon, pericolonic lymph,
      or liver specimen. Awareness of increased risk of early cancer in flat adenomas
      with central depression is important because prompt recognition can lead to
      curative therapy.

PMID- 10641500
TI  - Lamivudine for chronic hepatitis B: uses and abuses.

PMID- 10641501
TI  - The Redbridge Stroke Unit--experience gained from a one year study.
AB  - OBJECTIVE: To assess the impact of stroke unit on overall management of stroke
      illness within the district. SETTING: A multidisciplinary stroke unit. METHODS:
      Study was made of the mortality, durations of stay and discharge destinations of
      76 patients with stroke selected for stroke unit rehabilitation from a total of
      164 stroke patients admitted to the Redbridge Hospitals during a 12 month period.
      These were compared with the outcomes of stroke patients admitted during the year
      prior to the Unit opening. RESULTS: There was no difference in mortality, 16% in
      each group. The durations of admissions of patients treated in the Stroke Unit
      were longer than the control group, although there was no increase in the mean
      duration of hospital stay of the total number of stroke patients. When patients
      treated in the stroke unit were compared with a selected control group taken from
      the stroke patients admitted during the previous year, 27% more patients were
      discharged back into the community, 4% less patients required long stay elderly
      care and 20% less patients required further rehabilitation outside the district.
      When all stroke admissions were considered, 29% more patients were discharged
      home, 10% less patients required long stay care and 15% less patients required
      further specialized rehabilitation. CONCLUSION: Treatment in the stroke unit
      substantially improved patient outcome.

PMID- 10641502
TI  - Prevalence and risk factors of symptoms of pelvic inflammatory disease in a rural
      community of Jamshoro, Sindh, Pakistan.
AB  - OBJECTIVES: (1). To estimate the prevalence of symptoms of pelvic inflammatory
      disease (PID) in rural Jamshoro, Sindh, (2). To assess specific social and
      biological risk factors of symptoms of PID. METHODOLOGY: Trained females
      conducted the interviews using a pre-tested Sindhi questionnaire during a cross
      sectional survey carried out in 8 villages of rural Jamshoro, Sindh. Women
      reporting either lower abdominal pain or vaginal discharge with continuous or
      intermittent fever during the 6 months prior to interview, were classified as
      having PID symptoms. RESULTS: We approached 753 ever-married women and
      successfully interviewed 738 (98%) from July-September 1997. Sixty-five women
      (9%) had symptoms consistent with PID, and 156 (24%) reported ever using a modern
      contraceptive. Symptomatic women were 3.6 times more likely to have ever used
      IUCD/tubal ligation (95% CI, 1.9-6.9), 1.8 times more likely to have married at
      earlier age (< 15) (95% CI, 1.1-3), and 3 times more likely to be housewives by
      occupation (95% CI, 10-8.4) as compared to women who did not have PID symptoms.
      CONCLUSION: Symptoms of PID among tubal ligation/IUCD users may reflect existence
      of unhygienic conditions during application of procedure, delay in replacement of
      IUCD and mismatching in the size of IUCD with uterus. The quality of life is
      affected in women with PID symptoms and may have serious consequences like
      infertility. These symptoms need thorough evaluation/investigation to gauge the
      magnitude and nature of the problem and to guide intervention, effective
      promotion of women's socio-economic status, health education regarding
      counselling for delaying age at marriage and hygienic/safe use of family planning
      methods.

PMID- 10641503
TI  - Bone and renal stone disease in patients operated for primary hyperparathyroidism
      in Pakistan: is the pattern of disease different from the west?
AB  - OBJECTIVE: To document the clinical presentation of primary hyperparathyroidism
      (PHPT) in a developing country and note differences from the West. SETTING: A
      tertiary care teaching hospital. METHOD: The records of 37 patients operated for
      PHPT between January 1986 and December 1997 were reviewed. Symptoms, laboratory
      parameters and histopathology results were analyzed. RESULTS: Surgery for PHPT
      accounted for 0.055% of 67,566 operative procedures performed in the Department
      of Surgery during the 12 year period. The mean age of our patients was 38.4 +/-
      13.2 years (range 17 to 73 years). Ninety percent of patients were less than 60
      years old and 51% less than 40 years. At presentation, the mean serum parathyroid
      hormone (sPTH) level was 618 +/- 741% above the upper limit of normal (range 0
      2900% using a variety of assays). A solitary adenoma was present in 86.5%,
      hyperplasia in 5.4% and carcinoma in 5.4% of patients. There was one (2.7%)
      negative exploration. Thirty-five percent of patients had renal stone disease
      (StD), 32.4% had bone disease alone (BD) and 27% had both bone abnormality and
      stones (BStD). There were neither bone disease nor stones in 5.4% of patients. BD
      was associated with a statistically non-significantly (p = 0.08) higher alkaline
      phosphatase level (sALP) as compared to the StD and BStD groups. The mean urinary
      calcium (Ca) was higher in the BD group (482 +/- 340 mg/24 hours) as compared to
      StD group (265 +/- 89 mg/24 hours) (p = 0.013). The post-operative hospital stay
      was longer in the BD group (14.4 +/- 16 days) as compared to the StD group (6.7
      +/- 3.7 days) (p = 0.001). CONCLUSION: As compared to reports from the Western
      world, PHPT is less commonly diagnosed in our country and occurs at a younger
      age. In the absence of a screening programme, symptomatic disease and bone
      involvement occur more frequently. The high levels of PTH may indicate long
      standing disease in our population, which may account for higher proportion of
      patients with symptoms. Unexpectedly, patients with bone disease had higher
      levels of urinary calcium than patients with stone disease.

PMID- 10641504
TI  - Demographic aspects of hepatitis C in northern Pakistan.
AB  - OBJECTIVE: To find out the prevalence of hepatitis C in various, age, sex and
      ethnic groups in Pakistan. SETTING: Specimens obtained from military/civil
      hospitals and General Practitioners of Rawalpindi Islamabad, region and other
      areas of Northern Pakistan, in vicinity. SUBJECTS: Serum of 1710 patients of
      hepatitis C, diagnosed at Armed Forces Institute of Pathology (AFIP), Rawalpindi
      between 1st July 1996 and Dec 31, 1997, tested for Anti HCV by 3rd generation
      Murex Elisa. Required information was collected on a proforma filled for each
      patient. RESULTS AND CONCLUSION: The majority of the cases were between 30-60
      years of age. There was male preponderance. The infection was more common in Urdu
      speaking fraction of the patients as compared with others.

PMID- 10641505
TI  - Facial nerve palsy unusual complication of percutaneous angiography and
      embolization for juvenile angiofibroma.

PMID- 10641506
TI  - Classification and criteria for diagnosis of diabetes mellitus: recent proposal.

PMID- 10641507
TI  - [Problems of clinical evaluation of hemodynamics at rest and during exercise in
      chronic heart disease. Value of cardiac catheterization and problems of clinical
      classification].
AB  - BACKGROUND: NYHA classification is mostly used for graduation of clinical
      limitation due to cardiac failure. Right heart catheterization is not generally
      used to evaluate hemodynamics and to define the effects of drugs in patients with
      chronic cardiac failure. Clinical data and results from echocardiography, stress
      tests or nuclear cardiology seem to be sufficient. Our aim was to demonstrate
      subjectivity of a classification system (NYHA) comparing the graduation done by
      physicians and by patients and to represent the difficulty to prognosticate
      hemodynamic data of patients with heart failure. PATIENTS AND METHODS: Limitation
      of 53 patients with heart diseases was classified by physicians and patients
      using NYHA classification. Pulmonary capillary wedge pressure (PCWP), stroke
      volume (SV) and cardiac output were predicted by physicians; they were allowed to
      utilize all examination data they could get. Predicted hemodynamic data were
      compared with the results of measurement at rest and during exercise. RESULTS:
      Patients classified themselves significantly worse than physicians did: 2.68 +/-
      0.64 vs. 2.23 +/- 0.74 (p = 0.0012). Similarity in NYHA classification was found
      in 29/53 cases. Correlation of predicted and measured hemodynamic data was low:
      PCWP (at rest) r = 0.346; PCWP (during exercise) r = 0.232; SV (at rest) r =
      0.476; SV (during exercise) r = 0.445; HMV (at rest) r = 0.412; HMV (during
      exercise) r = 0.538. CONCLUSION: Clinical classification systems like NYHA are
      subjective, classification by physicians differs significantly from
      classification by patients. Prediction of hemodynamics is not possible despite
      all examination data had been available. Right heart catheterization is necessary
      to define hemodynamics at rest and during exercise.

PMID- 10641508
TI  - [Common effect measures in medical and health economics studies? Results of an
      exploratory survey of physicians].
AB  - BACKGROUND: In economic evaluation studies quality-adjusted life years (QALYs)
      are often used as measure of effects. QALYs are calculated by weighting survival
      time with a valuation of health-related quality of life (HRQoL). The results may
      support clinical decisions for patient groups provided that physicians consider
      QALYs acceptable and clinically relevant. This study investigates whether
      physicians accept the various methodological steps of the calculation of QALYs
      and whether effect measures that result from these steps are useful in clinical
      studies, too. METHODS: In summer 1998, 41 physicians (21 principal investigators
      of clinical studies in oncology, 12 surgeons, 8 primary care physicians)
      completed a questionnaire. RESULTS: 90% of the physicians considered HRQoL a
      relevant measure of clinical effectiveness but only 54% were familiar with the
      concept of HRQoL. 80% accepted the creation of an index of HRQoL, 68% accepted
      the integration of HRQoL and survival time into a single effect measure, but only
      44% accepted the multiplicative way of calculating QALYs. According to most
      physicians, HRQoL should be valued either by study patients or health care
      professionals rather than general population samples. 92% of the physicians
      considered identical effect measures in clinical and economic studies necessary
      or desirable. CONCLUSIONS: QALYs are not generally rejected by the responding
      physicians. The integration of HRQoL is largely accepted. The multiplicative way
      of combining survival time and HRQoL values is rejected by many physicians. The
      findings can be used to define a starting point for the development of common
      effect measures in medicine and health economics.

PMID- 10641509
TI  - [Rheumatoid arthritis: new molecular and cellular aspects].
AB  - BACKGROUND: Rheumatoid arthritis is a chronic systemic disorder of unknown
      etiology, that is characterized by inflammation, synovial hyperplasia and
      destruction of the affected joints. Novel molecular biology techniques have
      identified important cellular and molecular pathways in the pathogenesis of
      rheumatoid arthritis during the last years. RESULTS: The cellular activation of
      aggressively growing, matrix-degrading synovial fibroblasts is a key event in the
      pathogenesis of rheumatoid arthritis. The cellular activation results in an
      altered expression of apoptosis regulating molecules (for example CD 95 and
      Sentrin) as well as of protooncogenes (for example RAS and MYC). Important
      extracellular stimuli such as the pro-inflammatory cytokines interleukin-1 and
      TNF-alpha are overexpressed in the rheumatoid arthritis synovium. First clinical
      trials with cytokine inhibiting molecules (interleukin-1 receptor antagonist,
      recombinant soluble TNF-alpha receptor/Etanercept and monoclonal TNF-alpha
      antibodies/Remicade) revealed promising results. Etanercept is now available for
      the treatment of rheumatoid arthritis in the USA. In addition, gene transfer
      methods could help to overcome the problem of a continuous expression of
      therapeutic molecules in the affected joints; gene delivery of the interleukin-1
      receptor antagonist is currently tested in a human trial. Finally, the inhibition
      of matrix degrading enzymes such as matrix metalloproteinases, that mediate the
      joint destructive features of the activated synovial fibroblasts, could be
      another therapeutic approach. CONCLUSIONS: The elucidation of important molecular
      and cellular pathways in the pathogenesis resulted in novel concepts in the
      therapy of rheumatoid arthritis. Gene transfer methods are of importance in
      studying the pathogenesis of the disease, however, their clinical safety and
      usefulness have to be proven in additional studies.

PMID- 10641510
TI  - [Diagnostic and therapeutic management of the superior vena cava syndrome].
AB  - BACKGROUND: Superior vena cava syndrome (SVCS) is the clinical expression of
      obstruction of blood flow through the superior caval vein. In more than 80% of
      patients this complication is due to a malignant tumor, and in 60% of cases the
      first symptom of this tumor. DIAGNOSIS AND TREATMENT: If the clinical course of
      SVCS represents an absolute emergency, irradiation may have to be started
      immediately, even before the histologic diagnosis is established. Alternatively,
      expandable metallic stents have been used with considerable success for treatment
      of vena caval obstruction since patients respond immediately after stent
      implantation. For diagnosis, a chest X-ray and a CT scan should be performed.
      Chemotherapy is the treatment of choice for high-grade lymphomas, germ cell
      tumors and small-cell lung cancer since this modality is more effective than
      radiotherapy (response rate: 80%). For less chemotherapy responsive tumors
      radiotherapy is the primary treatment. Successful experience with thrombolytic
      agents is limited to treatment of catheter-induced SVCS, in contrast, only 20% of
      patients respond to thrombolytic therapy in the absence of a central catheter.
      Surgical resection of SVCS associated tumors has not improved survival rates and
      should be avoided.

PMID- 10641511
TI  - [Familial Mediterranean fever. New aspects with respect to molecular genetics and
      pathogenesis revealed in three case reports].
AB  - HISTORY AND CLINICAL PRESENTATION: Three young Turkish males were admitted
      because of acute abdominal pain and fever. All 3 patients had recurrent attacks
      of these symptoms every few weeks since years with each attack lasting 2 to 3
      days. One patient developed a renal amyloidosis with an end-stage renal failure.
      DIAGNOSTICS AND CLINICAL COURSE: All patients presented with local abdominal
      tenderness and an elevation of inflammatory parameters (WBC, ESR, CRP and
      fibrinogen). X-ray studies, ultrasound and upper endoscopy were normal. In 1
      patient histology yielded amyloid fibrils in the antrum of the stomach. In a
      molecular genetic analysis 2 patients were compound heterozygous for 2 common
      mutations of the gene responsible for the familial Mediterranean fever (FMF). In
      all patients the symptoms vanished spontaneously according to an acute attack of
      FMF. After symptomatic treatment a prophylaxis with colchicine was started.
      CONCLUSION: Cloning of the FMF gene and its mutations and identification of the
      gene product "pyrin" reveals new aspects on genetics and pathophysiology. The
      improved diagnostic procedure enables an early start of colchicine treatment,
      especially to prevent renal amyloidosis.

PMID- 10641512
TI  - [Rapidly progressing renal insufficiency as the primary manifestation of systemic
      sarcoidosis].
AB  - CASE REPORT: We report the history of a 67-year-old patient who was admitted to
      hospital because of rapidly progressive renal insufficiency. The renal biopsy
      revealed granulomatous interstitial nephritis. The diagnosis of systemic
      sarcoidosis was confirmed by typical findings of bronchoalveolar lavage and of
      transbronchial, liver and bone marrow biopsy. Indications for sarcoidosis-related
      nephrocalcinosis/nephrolithiasis or glomerulonephritis were absent.
      Simultaneously a monoclonal gammopathy of unknown significance (MGUS) was
      diagnosed. While the patient having been uremic at the time of diagnosis, the
      administration of prednisolone effectively improved renal function. CONCLUSIONS:
      As a rare manifestation of sarcoidosis granulomatous interstitial nephritis can
      cause rapidly progressive renal insufficiency, which can effectively be treated
      by steroids, if distinct interstitial fibrosis is absent.

PMID- 10641513
TI  - [Bilateral emphysematous pyelonephritis, a rare cause of acute renal failure].
AB  - BACKGROUND: The emphysematous pyelonephritis is a life-threatening complication
      of a bacterial interstitial nephritis, and it occurs mainly in diabetics. The
      infection with optional anaerobic microorganisms, which are able to produce gas,
      is supported by a reduced state of resistance, a high glucose level in the tissue
      in diabetic derailment and ischemia in the infected organ, for example by a
      kidney infarction or by an obstructive uropathy. Mostly the inflammation occurs
      unilateral, only in 10% of all cases both kidneys are affected. Computer
      tomography allows a fast diagnosis by demonstrating gas accumulation in the
      kidney. Surgical measures and antibiotic therapy are the principal therapeutic
      methods. CASE REPORT: The example of a 55-year-old diabetic man with bilateral
      emphysematous pyelonephritis demonstrates the diagnostic and therapeutic
      possibilities. After a fast diagnostic procedure, immediate hemodialysis in
      uremia and bilateral nephrectomy let the patient survive in a stable clinical
      condition dependent on regular dialysis treatment.

PMID- 10641514
TI  - [Mitral valve stenosis caused by a left atrial myxoma].

PMID- 10641515
TI  - [Performance and production-oriented allocation of personnel and operational
      budgets on basis of intrafaculty and external evaluations. Models at German
      medical faculties and a general proposal].

PMID- 10641517
TI  - [Monitoring of clinical trials. Methodology, interim analyses, and end results].
AB  - BACKGROUND: Clinical trials play an important role in developing and establishing
      new therapeutic and diagnostic procedures. In the planning and execution of these
      trials procedures and measures which allow for continual observation, description
      and evaluation of the study progress are to be taken into account. This is due to
      ethical, scientific and economic considerations. Together these procedures and
      measures are termed "monitoring". Repeated evaluation of the main study question
      is one particular monitoring measure. Results from this sequential procedure may
      lead to an early termination of patient recruitment. In the last 3 decades
      methods for interim analyses were developed which take into account the increased
      chance of errors when evaluating repeatedly the same question. By adjustment they
      guarantee a prespecified level of significance in the end result of the trial.
      Even though statistical significance may be evident in an interim analysis, this
      has not always to result in early termination of the trial. The decision to end a
      trial early must include other considerations than the mere evaluation of the
      main study question. In particular, consequences of the decision such as
      credibility and transferability of the trial result to subsequent therapeutic
      routine application are to be discussed.

PMID- 10641516
TI  - [A hairy case].

PMID- 10641518
TI  - Powers of attorney and medical records.

PMID- 10641519
TI  - The next frontier in end-of-life care. The hospital.

PMID- 10641520
TI  - Leading physicians into the new millennium. MSMS introduces new services to meet
      members changing needs.
AB  - The challenges in the practice of medicine change every day. Physicians are
      looking for ways to meet those challenges with effective, cost-efficient, and
      high quality resources that improve their practices, yet protect their
      relationships with their patients. MSMS has responded to physicians' needs with
      an array of cutting edge.

PMID- 10641521
TI  - Births and deaths: preliminary data for 1998.
AB  - OBJECTIVES: This report presents preliminary data for 1998 on births and deaths
      in the United States. U.S. data on births are shown by age, race, and Hispanic
      origin of mother. Natality data on marital status, prenatal care, cesarean
      delivery, and low birthweight are also presented. Mortality data presented
      include life expectancy, leading causes of death, and infant mortality. METHODS:
      Data in this report are based on more than a 99-percent sample of births and on
      more than an 85-percent sample of deaths in the United States for 1998. The
      records are weighted to independent control counts of births, infant deaths, and
      deaths 1 year and over received in State vital statistics offices in 1998.
      Comparisons are made with 1997 final data. RESULTS: The birth rate for teenagers
      continued to decline, dropping another 2 percent for 1997-98. The rate for young
      teens aged 15-17 years fell 5 percent, and the rate for teens aged 18-19 years
      declined 2 percent. Since 1991 rates have fallen 21 percent for teens aged 15-17
      years and 13 percent for teens aged 18-19 years. Birth rates for women aged 20-29
      years rose slightly. Among women in their thirties, birth rates rose 3 to 4
      percent to the highest levels observed in three decades. The birth rate for women
      aged 40-44 years was the highest level reported since 1970. The birth rate for
      unmarried women was 44.3 per 1,000, 1 percent higher than 1997, but below the
      peak level reported for 1994 (46.9). The rate of prenatal care utilization
      continued to improve. The total cesarean rate increased to 21.2 percent. The low
      birthweight rate rose from 7.5 to 7.6 percent. In 1998 the age-adjusted death
      rate reached a record low, 2 percent below the rate for 1997. Human
      immunodeficiency virus infection (HIV infection) moved off the list of the 15
      leading causes of death for the first time since 1987. Declines in age-adjusted
      rates occurred for Homicide and legal intervention (homicide) (14 percent) and
      Atherosclerosis (10 percent), while rates for Septicemia and Pneumonia and
      influenza increased 5 percent. Mortality also decreased for drug-induced deaths,
      deaths from injury by firearms, and alcohol-induced deaths. The infant mortality
      rate was unchanged. Life expectancy reached a record high of 76.7 in 1998.

PMID- 10641523
TI  - Public health nutrition and food safety, 1900-1999.

PMID- 10641522
TI  - Nutrition and Alzheimer's disease.
AB  - Alzheimer's disease begins with cognitive deficiencies that gradually become
      worse with the extension of cerebral lesions. Other troubles arise such as loss
      of independence, orientation impairments, disordered eating behavior, and weight
      loss. This weight loss increases the risk of infections, skin ulcers, and falls
      and consequently decreases quality of life in Alzheimer's patients. Various
      hypotheses (increased energy expenditure, mesial temporal cortex atrophy) were
      suggested to explain weight loss. We set up a Health Promotion Program that aims
      to prevent weight loss in patients with Alzheimer's disease. This program uses
      various tools (nutrition calendar, Mini Nutritional Assessment, nutrition
      education sessions) described in this article.

PMID- 10641524
TI  - Take. II: Hearings continue on scope of practice measures.

PMID- 10641525
TI  - Diabetes Quality Improvement Project.

PMID- 10641526
TI  - Connecting medical students to organized medicine.

PMID- 10641527
TI  - Low-molecular-weight heparin: an anticoagulation therapy option.

PMID- 10641528
TI  - Hepatitis C prevalence in persons with mental retardation.
AB  - BACKGROUND: Hepatitis C virus (HCV) was identified in 1989 and has since been
      found in most of the world. Due to the lack of information about the prevalence
      of HCV in institutions for the mentally retarded it was decided to conduct a
      study in this population in Israel. METHODS: The Division for the Mentally
      Retarded in Israel provides service to 6,022 persons in 53 institutions. Four
      institutions in the central part of the country were selected for this pilot
      study. In connection with routine blood examinations a blood specimen was drawn
      to detect serologic markers for hepatitis C by microparticle enzyme immunoassay
      (MEIA). RESULTS: Of the 251 subjects tested (56% male), 10% had mild, 30%
      moderate, 29% severe, and 31% profound mental retardation. 4% were aged 11-18
      years, 61% aged 19-45, 30% 46-60, and 5% over 61 years. In the four institutions,
      two subjects (0.8%) with antibodies to HCV were found. CONCLUSION: The prevalence
      of HCV in institutions for the mentally retarded (0.8%) does not differ
      appreciably from the general population in Israel (0.5%). This study, together
      with studies from the United States, Canada, England, Spain, Denmark, and Italy,
      appears to indicate that HCV is not a major public health problem in institutions
      for the mentally retarded.

PMID- 10641529
TI  - Infective endocarditis in a tertiary-care hospital in southern Israel.
AB  - During the years 1980-1994, 84 patients were treated in our institution due to
      suspected infective endocarditis (IE). Seventy-one of these episodes occurring in
      71 patients, classified definite or possible according to the Duke criteria, were
      retrospectively analyzed in this study. There were 52 cases of native valve
      endocarditis, 7 cases of early prosthetic valve endocarditis, and 12 cases of
      late prosthetic valve endocarditis. The incidence of IE did not change
      significantly during the study period. The overall mortality rate was 15%. Only
      one case of drug addiction appeared in our series despite its growing frequency
      in Israel. Rheumatic heart disease remained the main underlying cardiac condition
      and Streptococcus viridans remained the most common pathogen. Streptococcus bovis
      was found to be a significant pathogen causing IE in our patient population,
      while Staphylococcus aureus appeared to be less frequent. The Duke criteria
      significantly classified a greater proportion of cases as definitive, as opposed
      to the von Reyn criteria. Fewer cases were rejected by the Duke criteria,
      especially culture-negative cases, and those without histopathological
      confirmation. Application of the Duke criteria permits a more consistent approach
      to the diagnosis of IE, even in a non-drug-addict patient population.

PMID- 10641530
TI  - The capability to resist smoking relapse.
AB  - BACKGROUND: Remaining in the maintenance stage and preventing a relapse of
      smoking is the main problem in the smoking cessation process. The objectives of
      this study were to compare characteristics of successful quitters with those who
      relapsed, to examine characteristics of the maintenance stage, and reasons for
      not resuming smoking. METHODS: Prospective face-to-face interviews with 1094
      subjects registered with a family practice. Those who had relapsed or stopped
      smoking permanently comprised the study group. RESULTS: Of all subjects studied,
      10.1% stated that they had stopped smoking and 10.8%, that they had relapsed.
      Quitters were older than relapsers, less educated, smoked significantly more
      cigarettes per day, and made fewer attempts to quit smoking. No significant
      difference was found between quitters and relapsers in marital status, country of
      origin, age of starting to smoke, duration of smoking, and method used to stop
      smoking. Age and the number of cigarettes smoked per day were associated with the
      maintenance stage, which was longer when smoking > or = 25 cigarettes/day. No
      significant association was found between the maintenance stage and marital
      status, country of origin, education, age of starting to smoke, and duration of
      smoking. Eighty-three (74.8%) of the quitters stated that the reasons for
      remaining in the maintenance stage were having the capability to overcome smoking
      and a strong resistance to temptation for relapse, 16 (14.4%) noted that they had
      no interest in cigarettes, 8 (7.2%) reported that cigarettes had a bad taste and
      deterred them from smoking, 4 (3.6%) stated that they were afraid of illness. The
      main factors associated with remaining in the maintenance stage were the
      quitters' age, heavy smoking before smoking cessation, and quitters' strong
      character and ability to overcome relapse and temptations to re-start smoking.

PMID- 10641531
TI  - [Chronology of asthma medications].

PMID- 10641532
TI  - [Medical history: diagnostic tool for allergic rhinitis].
AB  - AIMS: To determine the diagnostic value of the medical history in the allergic
      rhinitis. MATERIAL AND METHOD: This study included 112 subjects, sex indistinct,
      between 2 and 31 years old, mean. We made 2 groups, one of the cases and another
      of control. Data were obtained by medical history, laboratory test and X-Ray of
      the upper respiratory tract. The gold standard of the diagnosis was the skin
      testing. We assessment, sensitivity (S), specificity (E), predictive value
      positive (VP+), and predictive value negative (VP-) RESULTS: From total subjects,
      53.57% were female, the evolution mean time was 4 years, with 5 monthly acute
      crisis. In 80% of the cases was perennial the presentation. 57.14% had family
      history of allergy (S = 57%, E = 100%, p = 0.0001). Clinical dates obtained were:
      sneezing 75% of the cases (S = 75%, E = 100%, p = 0.0001), nasal congestion 50%
      (S = 50%, E = 100%, p = 0.0001). 30.35% had risen above the upper level of
      circulating eosinophils (S = 30.35%, E = 91%, p = 0.0049), 26.78% had high levels
      of IgE (S = 26%, E = 87.5% p = 0.0002), in 78.57% were found nasal mucous
      eosinophils (S = 39.28%, E = 89.28%, p = 0.0009) and in 10.34% were identified
      intestinal parasitosis (P = NS). CONCLUSION: In accordance with this work, it is
      necessary to promote a change in attitude, utilizing the medical history as a
      diagnostic instrument and do not restrict prevention and opportunity in treatment
      to laboratory results.

PMID- 10641533
TI  - [Recurrent upper respiratory tract obstruction in children].
AB  - BACKGROUND: The systematic approach of the pediatric patient with recurrent upper
      airway obstruction (RUAO) must be based on a through clinical history, physical
      examination, and the adequate use of the laboratory and diagnostic procedures,
      which must complement the correct identification of the causes of UAO and its
      interrelation with comorbid conditions as allergic rhinitis, rhinosinusitis and
      adenoiditis, with or without significant hypertrophy. OBJECTIVE: this work, is to
      propose the study protocol of the patient with recurrent upper airway obstruction
      used in our own Instituto Privado de Alergia, Inmunologia y Vias Respiratorias.
      MATERIAL AND METHODS: We studied in a prospective fashion, a cohort of 117
      pediatric patients, 12 years old and under, with clinical complaints of RUAO. 2/3
      of these patients had a suggestive cytology pattern of nasal allergy and
      infection at the same time, following the method proposed by Dr. Alfredo
      Jalowayski from UC San Diego. RESULTS: The use of conventional radiology (lateral
      neck x ray) in the diagnosis of hypertrophy/hyperplasia of adenoidal tissue is
      useful and give us an orientation regarding the adenoidal size in 75% of the
      patients; nevertheless, it should not be considered as the most sensible
      diagnostic procedure to decide the best therapeutic option. If this study shows a
      decrease in diameter of the airway between the hard palate and the adenoidal
      shadow of 20% or more, we should proceeded with a flexible rhinopharyngoscopy to
      evaluate not only the real size of the adenoidal tissue, its mucosal appearance
      and its relation within the posterior pharynx with the Eustaquian tube (oto
      pharyngeal tube-OPT). The endoscopic procedure is easy to perform, even in small
      children and showed us that almost half of the patients with abnormal lateral X
      ray, have at least some degree of OFT obstruction. Aside from these results, the
      nasopharyngoscope give us useful information about comorbid and or existing
      conditions such as allergic rhintis, nasal polyposis, status of the osteomeatal
      complex, presence of bullae, anatomic variations, septal deviations and status of
      the olfactory epithelium. CONCLUSIONS: The use and feasibility to perform the
      nasal cytology test using the rhinoprobe technique, allow us to know the
      predominant cellular pattern of the nasal mucous, differentiate the allergic or
      non allergic rhintis, eosinophilic, basophilic, infectious or non infectious
      process.

PMID- 10641534
TI  - [Exhaled nitric oxide as marker of inflammation in children with asthma].
AB  - The nitric oxide is a reactive gas that is produced of endogenous way by enzymes
      nitric oxide sintetase. Exist a great nitric oxide production induced by the
      isoforms of the enzyme nitric oxide sintetase, that gives as a result the
      products training citotoxic, they are important mediating of the defence
      mechanisms and of normal inflammatory response. The nitric oxide can be detected
      in the air exhaled in human, their concentrations are increased in patient with
      asthma, and after the exposition to allergens. The measurement of the exhaled
      nitric oxide is effected by simple methods, not invasive, to value the degree of
      inflammation of the air route and response to the treatment with steroids in
      pediatric patients.

PMID- 10641535
TI  - [Wheezing in infants].
AB  - The wheeze are a common symptom in nursing, especially when suffer infections of
      the respiratory tract. They are common in 75 to 85% of the children, who have
      wheezes during some stage of their development between 2 to 5 years old. They can
      be related to smoking motherly during the pregnancy, exposition to the smoke of
      the tobacco to the subsequent stage to the birth, exposition to environmental and
      certain factor infections veers them. The wheezes in patient with atopy maybe
      they are related to a IgE two standard deviations up above of what is normal and
      persist as asthma in late stages. The wheeze is an affection syndromatic
      therefore it is obligatory to seek the factor unfetter you to arrive to a
      definitive diagnosis.

PMID- 10641536
TI  - Risk of inducing autoimmune disease by using Klebsiella pneumoniae
      immunostimulants.

PMID- 10641537
TI  - [The characteristics of the hypotensive effect of combined cryo- and interference
      therapy in arterial hypertension patients].
AB  - Cryotherapy was combined with interference currents in the treatment of 93
      patients with mild and moderate hypertension. Compared to single use of these
      factors, their combination potentiates hypotensive effect, i.e. lowers systolic
      and diastolic pressure already after the first procedure, stabilizes it after 3-4
      procedures.

PMID- 10641538
TI  - [The effect of radon baths on the physical work capacity and extrasystole in
      patients with ischemic heart disease and stable stenocardia].
AB  - Balneotherapy was given to 113 patients with ischemic heart disease (IHD) with
      stable angina (functional class I and II). 40 patients and 43 patients took radon
      baths (40 nCi/l and 120 nCi/l, respectively), 30 patients took the course of
      fresh-water baths. Treatment results were assessed at spiroveloergometry and
      ambulatory Holter monitoring. Radon baths had a training effect in IHD with extra
      systole. It manifests in higher physical performance and coronary heart reserve.
      Antiarrhythmic effect of the radon baths was different: a significant reduction
      in the average number of 24-h ventricular extrasystoles by 78.1, supraventricular
      extrasystoles by 92.3%, and by 79.9 and 94.7% for the 40 nCi/l baths and 120
      nCi/l baths, respectively.

PMID- 10641539
TI  - [A trial of using psychotherapy in the sanatorium on servicemen with
      psychosomatic pathology of the cardiac system].
AB  - Administration of rehabilitation psychotherapy, including pathogenetic and
      symptomatic psychotherapy, raises efficacy of combined sanatorium treatment of
      early stages of such cardiological diseases as ischemic heart disease, angina of
      effort class I, essential hypertension stage I. Psychotherapy also promotes
      relief of psychoemotional stress, anxiety, frustration, rigidity, aggression,
      alexithymia, asthenia being primary and secondary prophylaxis of psychosomatic
      disorders.

PMID- 10641540
TI  - [The effect of sanatorium-health resort treatment using foot baths on bronchial
      patency in children with chronic nonspecific diseases of the respiratory organs].
AB  - 174 children aged 7-14 years in remission of recurrent asthmatic bronchitis and
      bronchial asthma took feet baths in addition to standard course of sanatorium
      treatment. Measurements of bronchial permeability and reactivity have
      demonstrated that foot baths have no negative effects on bronchial permeability
      in all the disease forms and maintain tolerance of the respiratory system to both
      cold and exercise.

PMID- 10641541
TI  - [The effect of EHF puncture on the immune status of patients with gastric peptic
      ulcer].
AB  - Microwave puncture (MP) effects were compared to effects of 4-component basic
      medication in 63 patients with gastric ulcer. The study was made of nonspecific
      defense factors, serum levels of IgA, IgM, IgG, gastric juice levels of IgA, pool
      structure of circulating lymphocytes (DR+, CD3+, CD22+, CD4+, CD8+), spontaneous
      and LPS-stimulated Ig-synthetic function of B-lymphocytes. Mean time of the ulcer
      healing in MP usage made up 14.6 +/- 1.6 days, in standard therapy--27.2 +/- 3.1
      days (P < 0.001). Immunomodulating effect shown by MP consisted in activation of
      nonspecific defense factors and activation of immunoglobulin-synthetizing
      function of B-lymphocytes.

PMID- 10641542
TI  - [Changes in tissue insulin sensitivity under the action of potable mineral waters
      (clinico-experimental research)].
AB  - The trial included 43 Wistar rats with alloxan diabetes, 80 patients with
      impaired carbohydrate tolerance, 80 patients with non-insulin-dependent diabetes
      mellitus (NIDDM). 22 healthy volunteers and 60 intact rats served control.
      Glucose levels were measured 10, 20, 30, 45, 60, 90 and 120 minutes after insulin
      administration (3.7 U/m2). It was found that insulin resistance in impaired
      carbohydrate tolerance was higher than in diabetes. Mineral water intake improves
      recovery of sensitivity to insulin. This improvement was more evident in intact
      rats. Therefore, mineral water is a good prophylactic modality.

PMID- 10641543
TI  - [The effect of thermal-vibration massage on the function of the hepatobiliary
      system in patients with chronic cholecystitis and opisthorchiasis].
AB  - The study made by the authors has proved that thermovibration massage of
      infrasound frequency (10 Hz) used as an adjuvant in combined treatment of chronic
      cholecystitis and opisthorchiasis promotes normalization of motor-evacuatory
      function of the biliary system and intrahepatic hemodynamics, improves
      biochemical structure of the bile. This improves overall efficacy of the
      treatment measures.

PMID- 10641544
TI  - [The combined therapy of patients with chronic nonspecific pyelonephritis using
      interference currents and and radon procedures].
AB  - The exposure of the lumbar region to interference currents in combination with
      radon baths conducted in 37 patients with chronic pyelonephritis inhibited
      activity of the inflammation, hypercalciuria and hyperoxaluria, improved function
      of the kidneys. The same clinical effects were achieved in 32 patients who had
      received interference therapy in combination with intake of radon water.

PMID- 10641545
TI  - [Chronic inflammation of the adnexa uteri: new possibilities for the
      electrotherapeutic correction of the hemodynamic disorders].

PMID- 10641546
TI  - [Multilevel magnetic and electrical stimulation in the combined treatment of
      neurosurgical patients].
AB  - The program of rehabilitation of neurosurgical patients with effective physical
      methods (multilayer magnetic and electric stimulation, scanning laser therapy,
      QHF therapy) has been used in 265 patients with functional disorders because of
      nervous affection. The program reduced the treatment duration and improved the
      quality of treatment of neurosurgical patients.

PMID- 10641547
TI  - [Therapeutic exercises in the rehabilitative treatment of patients with
      diaphyseal fractures of the leg bones].
AB  - The results of exercise therapy were compared in patients with diaphysial leg
      fractures operated by standard technique and those operated by the technique of
      closed blocking intramedullary osteosynthesis (CBIO). After CBIO rehabilitation
      was more successful and required less time. This arises from the fact that in
      blocking osteosynthesis soft tissues of the damaged segment are not cut while
      intraosseous blocking screws exclude shortening of the leg and rotation
      instability of the fragments. That's why it is not necessary to fix the leg with
      a circular gypsum bandage which allows early intensification of exercise load.

PMID- 10641548
TI  - [The effect of hypokinesia on the development of allergic reactions in an
      experiment].
AB  - 434 mature and immature guinea pigs were divided into two groups. Test animals
      were kept under hypokinesia for 72 days. Control animals were not exposed to
      hypokinesia. Sensitization was made on day 60 in both the groups. On
      sensitization day 10, blood count was made, on day 12 anaphylactic shock was
      induced in all the animals. Allergological and immunological tests have shown
      that hypokinesia contributes to development of immediate allergy in animals of
      different age and therefore can be considered as a risk factor of allergy of
      immediate type.

PMID- 10641549
TI  - [Extracts of sulfide sludge and the validation of their use in clinical
      practice].

PMID- 10641550
TI  - [A new deposit of carbonate mineral waters in the Far East].

PMID- 10641551
TI  - [Transcutaneous electrostimulation of the respiratory musculature in the
      treatment of patients with chronic obstructive lung diseases].

PMID- 10641552
TI  - [The use of the preparation MIGI-K and ultrasound in patients with
      osteochondrosis of the lumbosacral spine].

PMID- 10641553
TI  - [The treatment of the metabolic syndrome in patients with non-insulin-dependent
      diabetes mellitus by acupuncture reflexotherapy].

PMID- 10641554
TI  - [The initial forms of cerebral vascular lesions: the prevention of their
      progression by using physical therapy methods].

PMID- 10641555
TI  - [The physio- and balneotherapy of diabetes mellitus].

PMID- 10641556
TI  - [Physical factors in the rehabilitative treatment of patients with benign
      prostatic hyperplasia].

PMID- 10641557
TI  - Defining asthma in genetic studies.
AB  - Genetic studies have been hampered by the lack of a gold standard to diagnose
      asthma. The complex nature of asthma makes it more difficult to identify asthma
      genes. Therefore, approaches to define phenotypes, which have been successful in
      other genetically complex diseases, may be applied to define asthma in genetic
      studies. These approaches include narrowing of the disease definition and use of
      intermediate phenotypes of asthma. Future studies are required to apply these
      approaches in genetic studies of asthma and, most likely, this will facilitate
      the search for genes for asthma.

PMID- 10641558
TI  - Specific IgE--one gene fits all? German Asthma Genetics Group.
AB  - Specific immunoglobulin E (IgE) production is increased in allergic diseases.
      Research into the main factors of IgE responsiveness are complicated by different
      steps in the antibody production from somatic recombination to isotype switching
      and more general amplification loops. We have therefore started a positional
      cloning approach to identify relevant genes. Ninety-seven families, each with two
      children with asthma, were examined. Of these, 415 persons were analysed for 13
      specific IgE against major allergens and genotyped for 351 microsatellite markers
      distributed in equal distances over the genome. Of the initial set of allergens,
      four major groups were identified where the most frequent allergen was analysed
      consecutively: birch for the tree group, mixed grass for grass pollen,
      Dermatophagoides pteronyssinus for dust mites and cat for the pet group. Parental
      sensitization with the same allergen seemed to be a weak risk factor for the
      children. Also several environmental exposure variables showed only moderate
      effects on the prevalence of IgE antibodies in children. A quantitative linkage
      analysis of the specific IgE values gave evidence for one or two linked regions
      but was different for each allergen. From this initial observation it is likely
      that the factors for genetic upregulation of IgE responsiveness cannot be
      described by the action of a single major gene. Genes seem to be more likely to
      influence general IgE responsiveness at the amplification level rather than at
      the level of differentiation into fine specificity of antibodies.

PMID- 10641559
TI  - Genome-wide screen for atopy susceptibility alleles in the Hutterites.
AB  - A genome-wide screen for loci influencing positive skin prick tests (SPT) to
      airborne allergens was conducted in the Hutterites, a founder population of
      European ancestry. Positive SPT to 14 standardized allergens was measured in 370
      subjects in our primary sample and 324 subjects in a replication sample. Evidence
      for linkage to positive SPT was assessed using the transmission disequilibrium
      test (TDT) with 337 autosomal markers (average spacing 9.13 cM, SD = 7.8 cM).
      Three loci showed the strongest overall evidence of linkage to atopy, with at
      least one allele-specific and a locus-specific p< 1 x 10(-4). This study provides
      evidence for at least three atopy-susceptibility loci in the Hutterites on
      chromosomes 1, 6 and 16.

PMID- 10641560
TI  - EGEA (Epidemiological study on the Genetics and Environment of Asthma, bronchial
      hyperresponsiveness and atopy)-- descriptive characteristics.
AB  - The Epidemiological study on the Genetics and Environment of Asthma (EGEA) was
      planned to assess genetic, environmental risk factors and their interactions for
      asthma and for the two related traits of bronchial hyperresponsiveness and atopy.
      The population examined includes 348 nuclear families ascertained by one
      asthmatic (213 adult and 135 paediatric probands) and 416 controls, totalling
      1,847 subjects (EGEA I). Prevalences of asthma, skin prick test response, high
      IgE and bronchial hyperresponsiveness were for parents, siblings, and offspring
      of cases intermediate between cases and spouses or controls, both in adults and
      children, confirming the familial resemblance for asthma and related traits. With
      an additional sample of 40 families ascertained by two asthmatic siblings (EGEA
      II), a total of 119 families with two asthmatic siblings has been ascertained for
      a genome screening.

PMID- 10641561
TI  - Genetic markers of atopy in infancy: results from the German Multicenter Allergy
      Study.
AB  - Genetic studies of atopy-associated traits require unambiguous phenotypes to
      avoid both type 1 and 2 errors. The German Multicenter Allergy Study has provided
      a birth cohort with longitudinally well defined and stable phenotypes. We
      summarize data on candidate gene studies on chromosomes 12q, 5q, and 13q using
      high total IgE and atopic dermatitis (AD) as the most common atopy associated
      phenotypes in early childhood. We also present data on a functional RANTES
      promoter polymorphism that we recently identified. A significantly higher
      frequency of the mutant allele was seen in individuals of African descent
      compared to Caucasian subjects. In addition, an association of the polymorphism
      with AD could be demonstrated in the MAS cohort. Although the statistical
      approaches are limited, the MAS cohort has provided a valuable population for
      candidate gene studies in atopy.

PMID- 10641563
TI  - Genome screen and candidate gene studies in parasitized populations.
AB  - The immunoglobulin E (IgE) antibody system is important in the genesis of asthma,
      but it appears to have originally evolved for defence against parasite infection.
      In order to study how IgE contributes to asthma, there are advantages in studying
      parasitized populations. Firstly, the IgE system can be studied when it is
      operating in a more natural state, and this could allow new insight into basic
      immune function. Secondly, the genetic susceptibility to produce high levels of
      IgE is more likely to be expressed, as the most intense IgE responses in nature
      are those found in the presence of parasitic infection. These more intense IgE
      responses should facilitate finding new 'asthma genes', assist in investigating
      how the DNA variations in candidate genes affect gene function and provide the
      possibility of developing new approaches to the treatment of asthma.

PMID- 10641562
TI  - Candidate genes and a genome-wide search in Italian families with atopic
      asthmatic children.
AB  - To identify genetic factors for susceptibility to atopy and asthma in childhood,
      1,083 subjects were identified, mainly from the Veneto region and Bolzano
      province in North-east Italy, of whom 817 were from 172 families with at least
      two affected people, 189 were sporadic cases, and 77 unrelated controls. All the
      subjects were characterized for clinical asthma (asthma), total serum IgE (IgE),
      skin prick test (SPT) reactivity to common aeroallergens and bronchial
      hyperresponsiveness (BHR) to methacoline test. Atopy was defined as SPT
      positivity and/or increased IgE levels. Several candidate genes were
      investigated, and genome-wide linkage analysis was been initiated. The high
      affinity IgE receptor beta chain (FcepsilonRIbeta) locus showed significant
      allele sharing in affected sib-pairs for BHR and for SPT positivity. Lymphotoxin
      alpha (Ltalpha) gene Ncol mutation showed a suggestive linkage with atopy, and
      the LTalphaNcol 2/2 genotype was found to be associated with increased total IgE
      levels in all females. No evidence for linkage or association of any phenotype to
      the tumour necrosis factor alpha (TNFalpha) - 308 mutation or to the interleukin
      4 receptor alpha (IL-4Ralpha) Q576R mutation was found. BHR, asthma and increased
      IgE were found to be linked to X and Y long arm pseudoautosomal region (PAR2)
      markers. Initial data were also collected from linkage analysis with chromosome
      12, 14, and 19, DNA markers. Non-parametric multipoint analysis provides
      preliminary evidence for linkage of asthma with D12S390, of atopy with D19S601,
      and of BHR with D14S617. These results suggest that several genetic factors
      contribute to different allergic asthma phenotypes in the population
      investigated.

PMID- 10641564
TI  - HLA class II genotype, HLA-DR B cell surface expression and allergen specific IgE
      production in atopic and non-atopic members of asthmatic family pedigrees.
AB  - HLA class II polymorphism is variably associated with sensitization to specific
      allergens, but few convincing HLA associations with asthma or the general state
      of atopy have been demonstrated. In this study we investigated HLA class II
      genotype associations with asthma, atopy and specific IgE (sIgE) production to
      six allergen extracts and six purified major allergens (Der p 1, Der p 2, Fel d
      1, Can f 1, Alt a 1 and Phl p 5) in 176 individuals from 20 asthmatic family
      pedigrees. In selected individuals, cell surface HLA-DR peripheral B-cell
      expression was correlated with HLA-DRB1 genotype and atopic status. Results
      showed that HLA-DRB1*08 was negatively associated with asthma (2% vs 17%; Pc =
      0.02; OR = 0.08) and atopy (0% vs 16%; Pc = 0.04; OR = 0.1), while DRB1*15 was
      positively associated with asthma (36% vs 13%; Pc = 0.02; OR = 3.6). Analysis of
      DRB1 sequences showed that only 29% of individuals with GAG TAC TCT ACG at codons
      9-12 in one or both alleles were atopic, compared with 53% of individuals without
      this sequence (P = 0.002; OR = 0.36). DPA1*0201 was negatively associated with
      sIgE to both grass pollen mix and Phl p 5 (0% vs 23%; Pc = 0.02; OR = 0.14). A
      non-significant trend towards higher HLA-DR B-cell expression was seen in both
      non-atopic and DRB1*08 individuals. In conclusion, this single centre study has
      demonstrated a number of HLA class II genotype associations with asthma, atopy
      and sIgE to grass pollen mix and Phl p 5, including hitherto unreported DRB1*08,
      DRB1 codon 9-12 and DPA1*0201 associations. No significant associations between
      HLA-DR expression and DRB1 genotype or atopy were demonstrated, although a trend
      towards higher expression was seen in non-atopic individuals and individuals of
      DRB1*08 genotype.

PMID- 10641565
TI  - Neuronal NO synthase (NOS1) is a major candidate gene for asthma.
AB  - Asthma is a common, but heterogeneous disease, characterized by reversible airway
      obstruction, bronchial hyperresponsiveness (BHR); and is commonly associated with
      atopy. The messenger molecule nitric oxide (NO), that is formed by neuronal NO
      synthase (NOS1), is known to have a key role in bronchomotor control in animals.
      In humans the gene for NOS1 is located on chromosome 12q24, in a region that had
      been shown in family studies to be linked to the diagnosis of asthma. We
      identified variants of the NOS1 gene, and assessed whether there was a genetic
      association between these variants of NOS1 and the diagnosis asthma. A total of
      410 Caucasian asthma patients and 228 Caucasian controls were screened for three
      bi-allelic polymorphisms in the NOS1 gene that had been detected by single
      stranded conformational polymorphism (SSCP) analysis and confirmed by sequencing.
      Allele frequencies of a polymorphism in exon 29 of the NOS1 gene were
      significantly different between asthmatics and controls (P<0.05). These findings
      suggest that variants of the NOS1 gene may be one source of genetic risk for
      asthma.

PMID- 10641567
TI  - Gene-environment and gene-gene interaction studies in the molecular genetic
      analysis of asthma and atopy.
AB  - Asthma is a complex trait for which genetic predisposition is fundamental in
      disease aetiology, but poorly understood. Unravelling the genetic aetiology is
      complicated by the tremendous influence of the environment over disease
      expression. For this reason, asthma is multifactorial, in that disease expression
      is influenced by interactions between multiple major and minor genes, and
      modulated by interacting non-genetic factors (e.g. environment). 'Parent of
      origin' effects may be both genetic and environmental in aetiology, and have been
      observed in a number of population studies on asthma. The primary focus of this
      review is to evaluate the current approaches used in identifying the
      interrelationship between (1) certain environmental factors (e.g. allergen
      exposure, maternal inheritance) and genetic susceptibility to asthma and its
      associated phenotypes; and (2) candidate genes in chromosomal regions that have
      been linked to asthma and atopy in ongoing, molecular genetics studies.

PMID- 10641566
TI  - Coding block and 5 leader cistron polymorphisms of the beta2-adrenergic receptor.
AB  - The gene encoding the beta2-adrenergic receptor (beta2AR) is highly polymorphic
      in the human population. Common polymorphisms in the receptor coding block (amino
      acids 16 and 27) affect agonist-promoted downregulation. Another common
      polymorphism in the 5' leader cistron of the beta2AR gene also regulates receptor
      expression, but does so through a mechanism that is independent of agonist
      exposure. None of these polymorphisms appears to be causative factor for asthma.
      However, data from several studies now indicate that the asthmatic phenotype and
      therapeutic response may be modified by the different polymorphic variants. This
      modifying effect is not likely due to a single dominant polymorphic locus, but
      rather the result of interaction among multiple polymorphic loci that regulate
      receptor expression through different mechanisms.

PMID- 10641568
TI  - Mapping disease genes using the Malecot model for allelic association and the
      beta model for linkage.
AB  - Although there are a number of alternative methods for mapping oligogenes the
      beta model implemented in the program BETA has been shown to be amongst the more
      powerful. The model has been applied to a sample of 240 asthma and atopy families
      typed for markers on chromosome 12 and the results suggest at least one asthma
      determinant may be present. The Malecot model implemented in the program ALLASS
      has yet to be applied to oligogenes but has been effective in the localization of
      major genes by exploiting the relationship between linkage disequilibrium and
      distance from the gene. Extension to oligogenes would seem to be a profitable way
      forward.

PMID- 10641569
TI  - Meta-analysis and retrospective collaboration: two methods to map oligogenes for
      atopy and asthma.
AB  - Combination of evidence over samples, each of which is too small to be
      conclusive, is the central problem in complex inheritance. There are three
      approaches: meta-analysis, prospective collaboration, and retrospective
      collaboration. Our experience with the first and last, which are the most cost
      effective, is discussed.

PMID- 10641570
TI  - The effects of GM-CSF, steel factor and MIP-1alpha on the expression and
      activation of Cdc25A phosphatase in Mo7e cells.
AB  - Active cyclin-dependent kinases (CDKs) are required for progression through the
      G1 phase of the cell cycle and entry into S phase. Activity of G1 CDKs is
      controlled by mechanisms including phosphorylation of Thr14 and Tyr15 residues.
      Removal of inhibitory phosphates on these amino acid residues is required for G1
      CDK activation, and is mediated by the Cdc25A phosphatase. Regulation of active
      Cdc25A phosphatase levels may be important for the proliferation of hematopoietic
      progenitor cells, effects assessed in the human growth-factor-dependent cell line
      Mo7e. Constitutive Cdc25A protein levels were enhanced with granulocyte
      macrophage colony-stimulating factor (GM-CSF) plus steel factor (SF). Cdc25A is
      thought to exert its activity in the nucleus, and nuclear protein levels of
      Cdc25A were also enhanced with GM-CSF and SF. GM-CSF plus SF promote synergistic
      growth of Mo7e cells. Pretreatment with macrophage inflammatory protein (MIP
      1alpha) inhibited GM-CSF- plus SF-induced growth and upregulation of Cdc25A
      protein levels. Stimulation with GM-CSF and SF also rapidly increased Cdc25A
      phosphatase activity, an effect suppressed by MIP-1alpha. A concomitant
      inhibition of increased CDK4 kinase activity correlated with increased
      phosphotyrosine levels on CDK4 when cells were pretreated with MIP-1alpha prior
      to GM-CSF and SF. These data suggest that Cdc25A expression and activity are
      regulated during proliferation of Mo7e cells.

PMID- 10641571
TI  - Intradermal injection of granulocyte-macrophage colony-stimulating factor (GM
      CSF) in patients with metastatic melanoma recruits dendritic cells.
AB  - Dendritic cells (DCs) are the main antigen-presenting cells in the skin. We
      hypothesized that intradermal (i.d.) injection of granulocyte-macrophage colony
      stimulating factor (GM-CSF) would recruit DCs into melanoma skin metastases and
      enhance autologous melanoma antigen presentation to host T cells. Sixteen
      patients with cutaneous or subcutaneous melanoma metastases were treated with GM
      CSF injected i.d. into a single dermal metastasis and into a normal skin site for
      10 consecutive days at one of four dose levels (10, 20, 40, or 80
      microg/injection). Pretreatment and post-treatment skin and tumor biopsies were
      stained for a panel of T-cell, B-cell, macrophage, and DC immunohistochemical
      markers. Positive cells were quantitated in a blinded fashion. There was a
      significant increase in the number of DCs (HLA-DR+, S100+, factor XIIIa+) and
      CD45R0+ T cells in the skin and in the tumors Injected with GM-CSF at all dose
      levels. Uninjected control tumors showed no increase in HLA-DR+ cells or T-cell
      infiltrate, but did show an Increase in S100+ and factor XIIIa+ cells, suggesting
      a non-DC population. ID GM-CSF administered in this manner recruited DCs into
      melanoma tumors and normal skin. Although no antitumor effects were seen, this
      represents a potential method of preparing skin sites for vaccine delivery.

PMID- 10641572
TI  - Allogeneic cell therapy in murine B-cell leukemia (BCL1): 1. Alloimmune-mediated
      graft-versus-leukemia (GVL) effects induced by unmodified and in vitro rIL-2
      activated bone marrow and lymphocytes from different lymphoid compartments.
AB  - We have investigated the efficacy of graft-versus-leukemia (GVL) effects induced
      by cells obtained from different syngeneic and allogeneic lymphoid compartments,
      by comparing the response to cell therapy with syngeneic (BALB/c x C57BL/6)F1 (H
      2d/b) (F1) or allogeneic C57BL/6 (H-2b) (B6) lymphocytes in F1 recipients
      inoculated with B-cell leukemia (BCL1) of BALB/c (H-2d) origin. Eradication of
      BCL1 was confirmed in vivo by adoptive transfer of 10(5) spleen cells obtained
      from treated mice into syngeneic BALB/c recipients. Immunotherapy induced by
      allogeneic but not syngeneic spleen and lymph node lymphocytes was
      therapeutically more effective than thymocytes and bone marrow cells (BMC).
      Alloreactive cells could be further activated in vivo with recombinant human
      interleukin-2 (rIL-2). The GVL effect of allogeneic lymphocytes was cell-dose
      dependent; a heavy leukemia load was more efficiently eradicated after three
      doses than after a single dose of allogeneic spleen cells (100% versus 23%
      disease-free survival rate of secondary adoptive recipients respectively). The
      GVL effect induced by allogeneic spleen cells was preserved after ex vivo
      exposure of cells to 250 cGy, but not 500 cGy or more. Interestingly, GVL was
      preserved following administration of ex vivo irradiated (500 cGy) spleen cells
      when rIL-2 was administered in vivo (p < 0.05). Syngeneic effector cells did not
      induce GVL, regardless of in vitro and in vivo activation with rIL-2. Our data
      suggest that allogeneic but not syngeneic (in analogy to autologous) cell therapy
      may be an effective tool to control residual leukemia following high-dose chemo
      radiotherapy. The feasibility of augmenting GVL by successive doses of activated
      allogeneic donor lymphocytes, partly inactivated in vitro by low-dose ionizing
      irradiation to prevent severe graft-versus-host disease (GVHD), may lead to safer
      therapeutic approaches that can be used to reduce the incidence of relapse while
      avoiding the risk of uncontrolled GVHD.

PMID- 10641573
TI  - Allogeneic cell therapy in murine B-cell leukemia (BCL1): 2. The role of non
      activated and rIL-2-activated CD4+ and CD8+ T cells in immunotherapy for
      leukemia.
AB  - Graft-versus-leukemia (GVL) effects play a key role in the elimination of
      residual leukemia cells in the course of allogeneic bone marrow transplantation
      (alloBMT). GVL effects can also be induced by donor lymphocyte infusion following
      alloBMT. We have investigated the role of CD4+ and CD8+ T cells in the
      development of GVL in mice with B-cell leukemia/lymphoma (BCL1) following
      allogeneic cell therapy. Sublethally irradiated (C57BL/6 x BALB/c)F1 mice were
      intravenously inoculated with 10(5) BCL1 cells and given untreated or recombinant
      human Interleukin-2 (rIL-2)-activated C57BL/6 spleen cells. Effective elimination
      of clonogenic BCL1 cells was confirmed by adoptive transfer of spleen cells
      obtained from treated mice into secondary BALB/c recipients. GVL effects were
      maintained after inactivation of CD4+ cells with monoclonal anti-CD4 antibodies
      in the inoculum, while inactivation of CD8+ cells with monoclonal anti-CD8
      antibodies resulted in complete loss of GVL effects induced both by resting and
      rIL-2-activated allogeneic spleen lymphocytes. These results indicate that Thy-1
      cells play the major role in the induction of GVL effects, mediated by C57BL/6
      effector T cells in this model. Since the number of natural killer (NK) cells
      also increased during in vitro culture with rIL-2, their contribution, especially
      that of CD8+ NK cells, in GVL effects mediated by rIL-2-activated CD8+ cells
      cannot be ruled out.

PMID- 10641574
TI  - The incidence of chromosome 9p21 abnormalities and deletions of tumor suppressor
      genes p15(INK4b)/p16(INK4a)/p14(ARF) in patients with acute lymphoblastic
      leukemia.
AB  - Cytogenetic changes are of pivotal prognostic significance in patients with de
      novo acute lymphoblastic leukemia (ALL). However, in some cases leukemic blasts
      can harbor gene lesions on a submicroscopic level without evidence of a
      corresponding abnormality by conventional cytogenetic studies. This can result in
      failure to recognize chromosomal abnormalities and inappropriate evaluation with
      respect to therapy assignments. To study the discrepancy in the detection of
      deletions of the short arm of chromosome 9 and deletions of tumor suppressor
      genes p15/p16/p14 on chromosome 9p21, we analyzed bone marrow samples from 92
      patients with ALL both by cytogenetic analysis and by Southern blot. In 41
      patients (45%), we found deletions of p15/p16/p14, which were homozygous in 27
      and hemizygous in 14. Cytogenetic analysis demonstrated abnormalities of the
      short arm of chromosome 9 in the form of 9p- or del(9p21-22) in only 5 of the 41
      patients (12%). Only 2 of 51 patients without gene deletions as detected by
      Southern blot revealed a 9p- abnormality, which was found only in a subpopulation
      of the cells. We demonstrate that deletions of the p15/p16/p14 genes on
      chromosome 9p21 are more frequent than indicated by cytogenetic analysis.
      Molecular techniques in addition to cytogenetic studies are necessary to detect
      otherwise-unrecognized genetic lesions of the short arm of chromosome 9.

PMID- 10641575
TI  - TNF-alpha secretion and apoptosis of lymphocytes mediated by gene transfer.
AB  - Efficient gene transfer of lymphocytes is extremely difficult. Apoptosis may play
      a role in this gene transfer resistance of lymphocytes. Here we show that
      transfection of lymphocytes via non-viral vectors leads to induction of apoptosis
      in a significant proportion of cells. Since apoptosis may be mediated via tumor
      necrosis factor d (TNF-alpha) and the TNF-alpha receptor pathway, we studied the
      amount of TNF-alpha secreted by lymphocytes transfected without gene insert. TNF
      alpha secretion was dependent on the gene transfer method used. High amounts were
      detected using receptor-mediated gene transfer and lipofection. In contrast, only
      low amounts of TNF-alpha were detected after electroporation and retroviral gene
      transfer. In receptor-mediated gene transfer, TNF-alpha secretion was due to the
      use of anti-CD3 antibody. Transfection of lymphocytes led to selective decrease
      in CD120b/TNF-alpha receptor II (TNFR-2)-positive cells. Induction of apoptosis
      and necrosis mediated by TNF-alpha via TNFR-2 (p80) was partially blocked using a
      neutralizing anti-TNF-alpha antibody. Blockage of apoptosis and necrosis could be
      further increased by adding anti-Fas-ligand (FasL) antibody, suggesting that
      induction of apoptosis via FasL and Fas receptor (Apo-1/CD95) may also play a
      role. This blockage led to a significant increase in the proliferation rate of
      lymphocytes transfected with cytokine genes. In conclusion, various gene transfer
      techniques led to TNF-alpha secretion, apoptosis and necrosis of lymphocytes.
      Apoptosis and necrosis could be partially blocked using a neutralizing anti-TNF
      alpha antibody.

PMID- 10641576
TI  - Filgrastim (r-metHuG-CSF) and its potential use in the reduction of radiation
      induced oropharyngeal mucositis: an interim look at a randomized, double-blind,
      placebo-controlled trial.
AB  - We wished to determine if filgrastim administration to chemotherapy/radiation
      therapy-naive patients receiving external-beam irradiation for head-and-neck
      malignancies would reduce the incidence and severity of oral/oropharyngeal
      mucositis. Patients were randomized to receive subcutaneous injections of either
      filgrastim or placebo beginning on day 1 of radiation and continuing daily
      throughout treatment. Study medication was titrated to keep the neutrophil count
      between 10 x 10(9) and 30 x 10(9)/l. The left and right buccal mucosa, hard
      palate, and posterior pharyngeal wall were scored weekly, by a blinded evaluator
      using two different scales, and the most severe score per week was used in data
      analysis. Fourteen of a planned 54 patients were randomized (8 filgrastim, 6
      placebo), and were evaluable for a planned interim analysis. No statistically
      significant between-group differences were seen in mean worst scores across time
      using repeated measures analysis of variance (Hickey, p = 0.231; WHO, p= 0.288).
      At almost all timepoints, however, the worst mean scores were lower in patients
      treated with filgrastim compared with those in patients treated with placebo, and
      the number of severe (i.e., grade 3) mucositis scores was significantly lower in
      the filgrastim-treated group. Filgrastim may decrease the severity of radiation
      induced oral/oropharyngeal mucositis.

PMID- 10641578
TI  - Morphological asymmetry in anterior limb of human internal capsule revealed by
      confocal laser and polarized light microscopy.
AB  - The fiber structure in the anterior limb of the internal capsule was investigated
      in a region where stereotactic lesions (anterior capsulotomy) result in
      successful treatment of obsessive-compulsive disorder (OCD). Eight human
      hemispheres were sectioned in comparable planes parallel to the ACPC plane.
      Microscopic slices were labeled with DiI and analyzed with confocal laser and
      polarized light microscopy. Three distinct systems of fibers were detected.
      Single fibers run from the caudate nucleus to the lentiform nucleus. The anterior
      thalamic peduncle connects the mediodorsal and partially the anterior thalamic
      nucleus with the frontal lobe. The frontopontine tract system connects the
      frontal lobe with the pons. This fiber tract occupies 38% of the anterior limb
      and is arranged in small bands. Right-left comparison of morphometric parameters
      of these bundles demonstrated that more and smaller bundles were located on the
      left-hand side than on the right-hand side. Tendencies for this configuration
      were noticeable in all brains investigated, with statistical significance in one
      brain. These morphological differences correlate with functional differences, as
      it was possible to demonstrate right hemispheric dysfunctions in cases of OCD.
      The benefit of anterior capsulotomy in OCD is generally seen in the interruption
      of fronto-basal ganglia-thalamic loops by disconnecting the anterior thalamic
      peduncle. In addition, the frontopontine fiber tract is disconnected in this
      stereotactic procedure.

PMID- 10641577
TI  - Brain metabolic changes in major depressive disorder from pre- to post-treatment
      with paroxetine.
AB  - Functional brain imaging studies of subjects with Major Depressive Disorder (MDD)
      have suggested that decreased dorsolateral (DLPFC) and increased ventrolateral
      (VLPFC) prefrontal cortical activity mediate the depressed state. Pre- to post
      treatment studies indicate that these abnormalities normalize with successful
      treatment. We performed [18F]fluorodeoxyglucose positron emission tomography (FDG
      PET) scans on 16 outpatients with MDD before and after treatment with paroxetine
      (target dose = 40 mg/day). Regions of interest (ROIs) for this analysis were
      drawn by a rater blind to subject identity on the magnetic resonance image of
      each subject and transferred onto their coregistered PET scans. We hypothesized
      that DLPFC metabolism would increase, while ventral frontal metabolism [in the
      VLPFC, the orbitofrontal cortex (OFC), and the inferior frontal gyrus (IFG)]
      would decrease with successful treatment. Treatment response was defined as a
      decrease in the Hamilton Depression Rating Scale of > 50% and a Clinical Global
      Improvement Scale rating of 'much' or 'very much' improved. By these criteria,
      nine of the subjects were classified as treatment responders. These responders
      had significantly greater decreases in normalized VLPFC and OFC metabolism than
      did non-responders. There were no significant effects of treatment response on
      change in the DLPFC or IFG in this sample. However, there was a positive
      correlation between change in HAM-D scores and change in normalized IFG and VLPFC
      metabolism. There were no significant interactions with laterality. On pre
      treatment scans, lower metabolism in the left ventral anterior cingulate gyrus
      was associated with better treatment response. These findings implicate ventral
      prefrontal-subcortical brain circuitry in the mediation of response to serotonin
      reuptake inhibitors in MDD.

PMID- 10641579
TI  - A magnetic resonance imaging study of thalamic area in adolescent patients with
      either schizophrenia or bipolar disorder as compared to healthy controls.
AB  - The purpose of this study was to compare thalamic size in adolescent patients
      with either schizophrenia or bipolar disorder and healthy controls. T2-weighted
      axial magnetic resonance images were used to manually define the area of the
      thalamus for 20 schizophrenia patients, 15 bipolar patients and 16 normal control
      subjects, all of whom were adolescents. Two orthogonal planned contrasts were
      tested: Contrast 1, patients with schizophrenia vs. patients with bipolar
      disorder; and Contrast 2, both patient groups taken as a single group compared to
      controls. Contrast 1 was not statistically significant for right or left thalamic
      area. Contrast 2 was statistically significant and indicated reductions in
      thalamic area in the patients as compared to controls. The same pattern of
      results emerged after adjustment for total brain volume. Our results indicate
      that thalamic abnormalities reported in adult schizophrenic and bipolar patients
      are also observed in adolescent patients. Our findings also add to the evidence
      implicating the thalamus in the pathophysiology of schizophrenia and bipolar
      disorder.

PMID- 10641580
TI  - [123I]Iomazenil SPECT benzodiazepine receptor imaging in schizophrenia.
AB  - Deficient inhibitory neurotransmission of gamma-aminobutyric acid (GABA) has been
      implicated in the pathophysiology of schizophrenia based on postmortem studies.
      However, in vivo studies have shown predominantly negative or conflicting
      results. The goal of this study was to better characterize possible changes of
      the regional GABA(A)-benzodiazepine receptor distribution volume (BZR V3-p) in
      schizophrenia in vivo, using a larger sample size than previous studies. Single
      photon emission computed tomography (SPECT) with [123I]iomazenil was used with a
      constant infusion paradigm to measure the BZR V3-p under sustained radiotracer
      equilibrium conditions. Twenty-five patients with schizophrenia and 24 matched
      healthy control subjects were studied. Positive and Negative Syndrome Scale
      (PANSS) ratings were done in all subjects. Statistical parametric mapping (SPM)
      96 was used to compare patients and control subjects as well as to study the
      relationship between SPECT results and composite PANSS scores based on two
      factorial models: the pentagonal model (positive, negative, dysphoric mood,
      activation, and autistic preoccupation factors) and the taxometric model
      (disorganized dimension). On the basis of 'absolute' values of V3-p with no
      normalization for total brain uptake, the schizophrenic patients showed no
      significant differences in BZR levels compared to the healthy control subjects.
      With a global normalization procedure, which is more sensitive to relative
      regional differences in activity, BZR V3-p was significantly decreased in the
      patients in the left precentral gyrus (BA 6). The relative BZR V3-p showed a
      significant positive correlation with duration of illness in the superior
      occipital gyri (BA 19). No significant correlations were observed between either
      absolute or relative BZR V3-p and either age or any of the composite PANSS scores
      based on any of the two factorial models in either patients or control subjects.
      No significant differences were observed between cigarette smoking vs. non
      smoking patients, nor between the patients on atypical antipsychotics vs. on
      typical antipsychotics vs. not on any antipsychotics. In general, no significant
      differences in BZR V3-p were observed between patients and control subjects,
      except for a decrease in relative BZR V3-p in the left precentral gyrus. Grey
      matter atrophy is unlikely to be the cause for this decrease. However, we could
      not exclude that possibility. The positive correlation with duration of illness
      might reflect the relative preservation of neurons expressing BZR in the superior
      occipital gyri as compared to other cortical brain regions in schizophrenia.

PMID- 10641581
TI  - 'Simple schizophrenia': a controlled MRI and clinical/neuropsychological study.
AB  - The present study explored the frequency of neuromorphological, neurological and
      neuropsychological abnormalities in 13 patients with an ICD-8/9 diagnosis of
      simple schizophrenia, also fulfilling DSM-IV criteria for 'simple deteriorative
      disorder', and in 13 matched patients with an ICD-8/9 diagnosis of a subtype of
      schizophrenia other than simple schizophrenia, fulfilling DSM-IV criteria for
      schizophrenia. The frequency of neuromorphological abnormalities in the two
      patient groups was also compared with that observed in 13 neurological control
      subjects. Both patients with simple schizophrenia and those with other
      schizophrenia subtypes showed a higher frequency of brain developmental
      abnormalities and greater ventricular and subarachnoid space volumes than
      controls. There was no significant difference between the two groups of patients
      with respect to neuromorphological variables. Two patients with simple
      schizophrenia (vs. none of those with other schizophrenia subtypes) had gross
      brain abnormalities; they were the most deteriorated subjects in the whole
      sample. Patients with simple schizophrenia, as compared to those with other
      schizophrenia subtypes, presented a higher frequency of soft neurological signs
      and a greater impairment of social relationships.

PMID- 10641582
TI  - Age- and dose-dependent glucose-induced increases in memory and attention in
      schizophrenia.
AB  - Glucose is the principal energy substrate for the brain, and alterations in
      glucose availability can alter neuronal function, including cognitive
      performance. Investigators have previously demonstrated glucose-induced memory
      and attentional improvements in humans, including a previous report from this
      group in subjects with schizophrenia. However, the age- and dose-dependence of
      this effect in schizophrenia has not been addressed. This within-subjects, double
      blind experiment evaluated the cognitive effects of placebo-controlled, multiple
      fixed-dose oral glucose administration (0 g, 25 g, 50 g, 75 g) in younger and
      older patients with schizophrenia (n = 20) and healthy age-matched controls (n =
      20). Each dose condition was administered on a different morning after a 9-h
      fast, with cognitive testing and plasma sampling following dose administration on
      each day. Older patients demonstrated dose-dependent improvements in recall
      performance on a spatial delayed response task and reaction time on a delayed
      match to sample task, while younger patients had decreases in attentional
      performance at the 75-g dose compared to placebo. As in previous reports,
      patients demonstrated higher plasma glucose and insulin concentrations than
      controls in response to fixed glucose dosing. The results provide further
      evidence that glucose and/or insulin can regulate brain functions relevant to
      memory and attention, and suggest that systemic changes in glucose regulation in
      schizophrenia deserve further study.

PMID- 10641584
TI  - Electrodermal activation in first-episode psychotic patients and their first
      degree relatives.
AB  - We hypothesized that electrodermal deviations evident in patients with
      schizophrenia would also be present in their biological relatives and examined
      the specificity of abnormal EDA to schizophrenia patients and their families. One
      hundred and thirty-five first-episode psychotic patients with either
      schizophrenia or other psychotic disorders; 104 non-psychiatric comparison
      subjects; 178 relatives of these subjects; and a comparison group of 61 patients
      with chronic schizophrenia had their EDA monitored while they listened to
      auditory stimuli. Electrodermal non-responding, regardless of the nature of the
      stimulus, was common to all patient groups and tended to run in families.
      However, non-responding did not differentiate the relatives of the psychotic
      patients from those of non-psychiatric subjects. Responders in both the chronic
      and first-episode schizophrenia patients showed an excessively high rate of non
      specific fluctuations (NSFs), as did the first-degree relatives of the first
      episode patients. Patients with major depression had more NSFs than normal, but
      significantly so only during one of the tone series. Their relatives, however,
      had a high NSF rate in both tone series. The results indicate that a high NSF
      rate may represent a psychophysiological marker of risk for schizophrenia and
      psychotic depression. Electrodermal non-responding is not specific to
      schizophrenia and is not likely to be useful as an indicator of genetic risk.

PMID- 10641583
TI  - Opposite links of positive and negative symptomatology with memory errors in
      schizophrenia.
AB  - We wished to confirm and extend a previous correlational study of our group,
      suggesting that positive symptoms in schizophrenia were linked to an increase in
      certain types of memory errors, and negative symptoms to a decrease in other
      types of errors. A post-hoc analysis was conducted in 33 schizophrenic patients
      and 40 normal control subjects on memory errors collected in a free recall task
      and two types of recognition tasks. The memory errors were intrusions and list
      errors in free recall, and decision bias towards false alarms in recognition, all
      assumed to reflect a source-monitoring failure. In a first analysis, the patient
      sample was split along the median for positive symptoms as rated by the Scale for
      the Assessment of Positive Symptoms (SAPS). In a second analysis, it was split
      along the median for negative symptoms as rated by the Scale for the Assessment
      of Negative Symptoms (SANS). Patients with high ratings of positive symptoms made
      more memory errors (intrusions, list errors, false alarms) than those with low
      ratings, supporting the hypothesis of a link between positive symptomatology and
      source-monitoring failure. On the other hand, patients with high ratings of
      negative symptoms made fewer of these errors than the other patients. Fewer
      errors were specifically associated with more affective flattening, alogia and
      anhedonia, whereas avolition was entirely unrelated to them.

PMID- 10641585
TI  - The orienting response in schizophrenia and mania.
AB  - We examined skin conductance (SCR) and finger pulse amplitude response (PULSE) in
      53 schizophrenic, 30 manic, and 28 control subjects to provide information on
      orienting response (OR) dysfunction in severe psychiatric disorders. SCR and
      PULSE to neutral and task-relevant tones were measured in acutely ill inpatients
      and normal control subjects on two occasions separated by a 3-week interval.
      There were no significant group differences in proportions of SCR and PULSE non
      responders to neutral tones. PULSE frequency to task-relevant tones in both the
      schizophrenic and manic patients was lower than that for the control subjects in
      both OR sessions, but did not differ significantly between patient groups.
      Although PULSE frequency was inversely related to neuroleptic dose in the
      schizophrenia sample, reanalysis of unmedicated patients did not change our
      results. OR frequency to task-relevant but not to neutral tones exhibited test
      retest reliability. Certain aspects of OR dysfunction may overlap in
      schizophrenia and bipolar disorder. Our failure to demonstrate excessive OR non
      responding to neutral tones in schizophrenia patients is inconsistent with many
      previous studies but may be due to a high proportion of OR non-responders among
      the control subjects.

PMID- 10641586
TI  - Mania: gender, transmitter function, and response to treatment.
AB  - Noradrenergic and GABA systems may be involved in mania, but there is little
      information about relationships between the function of these systems and
      response to specific antimanic treatments. We investigated relationships between
      indices of catecholamine or GABA system function, pretreatment mania severity and
      antimanic response to divalproex, lithium, or placebo. Plasma GABA and urinary
      excretion of catecholamine metabolites were measured before randomization to
      lithium, divalproex or placebo in patients hospitalized for manic episodes.
      Severity of mania was evaluated using the Manic Syndrome, Behavior and Ideation
      and Mania Rating Scale scores from the SADS-C. Multiple regression analysis
      showed that pretreatment plasma GABA was related to severity of manic symptoms.
      This relationship seemed stronger in women. Multiple regression analysis showed
      that pretreatment levels of urinary MHPG correlated with improvement in manic
      syndrome scores. These data suggest that GABA and norepinephrine may be related
      to different aspects of the manic state and to its pharmacologic sensitivity.

PMID- 10641587
TI  - Derivation of the SPAN, a brief diagnostic screening test for post-traumatic
      stress disorder.
AB  - The Davidson Trauma Scale (DTS) is a validated 17-item self-rating scale used in
      the diagnosis of post-traumatic stress disorder (PTSD), which is sensitive to the
      effects of treatment. It was felt that a shorter version of the scale might
      provide a better diagnostic screening tool. Subjects were drawn from a sample of
      243 patients obtained from multiple cohorts that included a group of survivors of
      various forms of trauma, including natural disaster, rape and combat. All
      subjects had diagnostic assessments for PTSD with a clinical interview and
      completed the DTS. The data were randomly divided between two subsamples, and
      frequency and severity scores were calculated for the DTS. A four-item scale, the
      SPAN (named for its top four items: Startle, Physiological arousal, Anger, and
      Numbness), was developed. It demonstrated an efficiency of 0.88, sensitivity of
      0.84, specificity of 0.91 and positive likelihood ratio of 9.1. In a replication
      sample, values were slightly lower but still acceptable (efficiency = 0.80). A
      subgroup of PTSD patients received either fluoxetine or placebo in a clinical
      trial, and a significant SPAN score improvement was observed on fluoxetine. The
      SPAN, which correlated significantly with the Impact of Events Scale, the Sheehan
      Disability Scale, and the Structured Interview of PTSD, was found to have a
      diagnostic accuracy of 88%.

PMID- 10641588
TI  - Childhood predictors of adult obesity: a systematic review.
AB  - OBJECTIVE: To identify factors in childhood which might influence the development
      of obesity in adulthood. BACKGROUND: The prevalence of obesity is increasing in
      the UK and other developed countries, in adults and children. The adverse health
      consequences of adult obesity are well documented, but are less certain for
      childhood obesity. An association between fatness in adolescence and undesirable
      socio-economic consequences, such as lower educational attainment and income, has
      been observed, particularly for women. Childhood factors implicated in the
      development of adult obesity therefore have far-reaching implications for costs
      to the health-services and economy. SEARCH STRATEGY: In order to identify
      relevant studies, electronic databases--Medline, Embase, CAB abstracts, Psyclit
      and Sport Discus-were searched from the start date of the database to Spring
      1998. The general search structure for electronic databases was (childhood or
      synonyms) AND (fatness or synonyms) AND (longitudinal or synonyms). Further
      studies were identified by citations in retrieved papers and by consultation with
      experts. INCLUSION CRITERIA: Longitudinal observational studies of healthy
      children which included measurement of a risk factor in childhood (<18 y), and
      outcome measure at least 1 y later. Any measure of fatness, leanness or change in
      fatness or leanness was accepted. Measures of fat distribution were not included.
      Only studies with participants from an industrialized country were considered,
      and those concerning minority or special groups, e.g. Pima Indians or children
      born preterm, were excluded. FINDINGS: Risk factors for obesity included parental
      fatness, social factors, birth weight, timing or rate of maturation, physical
      activity, dietary factors and other behavioural or psychological factors.
      Offspring of obese parent(s) were consistently seen to be at increased risk of
      fatness, although few studies have looked at this relationship over longer
      periods of childhood and into adulthood. The relative contributions of genes and
      inherited lifestyle factors to the parent-child fatness association remain
      largely unknown. No clear relationship is reported between socio-economic status
      (SES) in early life and childhood fatness. However, a strong consistent
      relationship is observed between low SES in early life and increased fatness in
      adulthood. Studies investigating SES were generally large but very few considered
      confounding by parental fatness. Women who change social class (social mobility)
      show the prevalence of obesity of the class they join, an association which is
      not present in men. The influence of other social factors such as family size,
      number of parents at home and childcare have been little researched. There is
      good evidence from large and reasonably long-term studies for an apparently clear
      relationship for increased fatness with higher birth weight, but in studies which
      attempted to address potential confounding by gestational age, parental fatness,
      or social group, the relationship was less consistent. The relationship between
      earlier maturation and greater subsequent fatness was investigated in
      predominantly smaller, but also a few large studies. Again, this relationship
      appeared to be consistent, but in general, the studies had not investigated
      whether there was confounding by other factors, including parental fatness, SES,
      earlier fatness in childhood, or dietary or activity behaviours. Studies
      investigating the role of diet or activity were generally small, and included
      diverse methods of risk factor measurement. There was almost no evidence for an
      influence of activity in infancy on later fatness, and inconsistent but
      suggestive evidence for a protective effect of activity in childhood on later
      fatness. No clear evidence for an effect of infant feeding on later fatness
      emerged, but follow-up to adulthood was rare, with only one study measuring
      fatness after 7y. Studies investigating diet in childhood were limited and inconc

PMID- 10641589
TI  - The SOCS-1 story.
AB  - SOCS-1 is an intracellular protein able to block the differentiation of leukemic
      M1 cells inducible by interferon gamma (IFN-gamma) or regulators using the gp130
      receptor. Its transient production is readily inducible by cytokine stimulation,
      and SOCS-1 appears to be a negative feedback molecule, modulating or suppressing
      receptor signaling activated by at least eight cytokines. Mice lacking SOCS-1
      develop a lethal neonatal syndrome including liver damage, depletion of T and B
      lymphocytes, and granulocyte-macrophage infiltration of the liver, lungs,
      pancreas, heart, and skin. These and the associated hematologic abnormalities in
      SOCS-1-/- mice can all be mimicked by the neonatal injection of high doses of IFN
      gamma. The lethal neonatal disease in SOCS-1-/- mice is preventable by injection
      of antibodies to IFN-gamma or by crossing SOCS-1-/- mice with IFN-gamma-/- mice,
      identifying IFN-gamma as being essential for the initiation of the neonatal
      disease and death. IFN-gamma appears not to be overproduced in SOCS-1-/- mice,
      and the lethal disease may arise from hyperresponsiveness of -/- cells to normal
      levels of IFN-gamma. SOCS-1-/- mice allowed to survive the neonatal period by
      cross-mating with IFN-gamma-/- mice may well ultimately develop other disease
      states, because loss of SOCS-1 potentially renders them hyperresponsive to other
      cytokine signaling.

PMID- 10641590
TI  - A new form of Filgrastim with sustained duration in vivo and enhanced ability to
      mobilize PBPC in both mice and humans.
AB  - Granulocyte colony-stimulating factor (G-CSF) has proven effective in the
      prophylaxis of chemotherapy-induced neutropenia and as a mobilizer of peripheral
      blood progenitor cells. The longevity of G-CSF action is limited by its removal
      from the body by two mechanisms. The first is thought to be mediated via
      receptors (receptor mediated clearance [RMC]) predominantly on neutrophils, the
      second process is likely the result of renal clearance. With the intention of
      developing a novel form of Filgrastim (r-met HuG-CSF) with a sustained duration
      of action in vivo, a new derivative named SD/01 has been made by association of
      Filgrastim with poly(ethylene glycol). The desired properties of this new agent
      would include a prolonged duration of action sufficient to cover a complete
      single course of chemotherapy. SD/01 is shown here to sustain significantly
      elevated neutrophil counts in hematopoietically normal mice for 5 days. In
      neutropenic mice effects were noted for at least 9 days, accompanying a
      significant reduction in the duration of chemotherapy induced neutropenia. Normal
      human volunteers showed higher than baseline ANC for around 9 to 10 days after a
      single injection of SD/01. Data from these normal volunteers also indicate that
      mobilization of CD34+ cells and progenitors may occur in a more timely manner and
      to around the same absolute numbers as with repeated daily injections of
      unmodified Filgrastim. These data indicate that SD/01 represents an efficacious
      novel form of Filgrastim with actions sustained for between one and two weeks
      from a single injection.

PMID- 10641591
TI  - Granulocyte macrophage colony-stimulating factor and interleukin-3 regulate
      chemokine and chemokine receptor expression in bone marrow macrophages.
AB  - The beta-chemokine macrophage inflammatory protein-1 alpha (MIP-1alpha) and its
      associated receptors are involved in the regulation of pro-inflammatory and
      haemopoietic processes. This study was designed to investigate regulation of
      expression MIP-1alpha and its receptors by other haemopoietic cytokines. Murine
      bone marrow macrophages (BMM) were treated with or without GM-CSF or IL-3 and
      expression of MIP-1alpha, other chemokines and their receptors examined by
      Northern blotting. Receptor levels were also examined using Scatchard analysis
      and functional tests. Treatment of BMM with GM-CSF revealed a striking increase
      in MIP-1alpha mRNA levels, relative to untreated cells with a corresponding
      increase in MIP-1alpha protein. A similar increase in mRNA levels was found when
      BMM were treated with IL-3. An increase in the expression of three other beta
      chemokines namely MIP-1beta, MCP-1 and MCP-3, was also found following treatment
      with GM-CSF or IL-3. We have additionally examined the expression of the known
      beta-chemokine receptors in BMM and observed an increase in CCR1 mRNA levels
      following treatment with GM-CSF and IL-3, but no change was seen in the level of
      CCR5 expression. The increase in CCR1 expression was reflected in an increase in
      the number of cell surface receptors for MIP-1alpha on the GM-CSF treated BMM and
      in an enhanced response of the GM-CSF treated BMM to CCR1 ligands. These data
      suggest that GM-CSF and IL-3 may be involved in mechanisms regulating expression
      levels of MIP-1alpha and its receptors.

PMID- 10641592
TI  - Use of combinatorial mutagenesis to select for multiply substituted human
      interleukin-3 variants with improved pharmacologic properties.
AB  - A combinatorial mutagenesis strategy was used to create a collection of nearly
      500 variants of human interleukin 3 (IL-3), each with four to nine amino acid
      substitutions clustered within four linear, nonoverlapping regions of the
      polypeptide. The variants were secreted into the periplasm of Escherichia coli
      and supernatants were assayed for IL-3 receptor-dependent cell proliferation
      activity. Sixteen percent of the variants, containing "region-restricted"
      substitutions, retained substantial proliferative activity through two rounds of
      screening. A subset of these was combined to yield variants with substitutions
      distributed through approximately half of the polypeptide. With one exception,
      "half-substituted" variants exhibited proliferative activity within 3.5-fold of
      native IL-3. A subset of the "half-substituted" variants was combined to yield
      "fully substituted" IL-3 variants having 27 or more substitutions. The
      combination of the substitutions resulted in a set of polypeptides, some of which
      exhibit increased proliferative activity relative to native IL-3. The elevated
      hematopoietic potency was confirmed in a methylcellulose colony-forming unit
      assay using freshly isolated human bone marrow cells. A subset of the multiply
      substituted proteins exhibited only a modest increase in inflammatory mediator
      (leukotriene C4) release. The molecules also exhibited 40- to 100-fold greater
      affinity for the alpha subunit of the IL-3 receptor and demonstrated a 10-fold
      faster association rate with the alpha-receptor subunit. The multiply substituted
      IL-3 variants described in this study provide a unique collection of molecules
      from which candidates for clinical evaluation may be defined and selected.

PMID- 10641593
TI  - Ehrlich tumor stimulates extramedullar hematopoiesis in mice without secreting
      identifiable colony-stimulating factors and without engagement of host T cells.
AB  - Tumor growth is associated with neutrophilia, thrombocytosis, and extramedullar
      hematopoiesis. The mechanism(s) accounting for these phenomena is unclear,
      although granulocyte-macrophage colony-stimulating factor (GM-CSF) and/or
      granulocyte colony-stimulating factor (G-CSF) released by tumor cells have been
      involved. We studied whether CSF released by Ehrlich tumor (ET) may play a role.
      A comparative study was performed with two cell variants (ET and ET/0) growing in
      euthymic, nude, and SCID mice. Extramedullar hematopoiesis was assessed in the
      spleen by scoring organ enlargement, wheat germ agglutinin ve+ cells, and
      interleukin 3-dependent granulocyte-macrophage colony-forming unit (GM-CFU). Both
      cell lines showed the same cytokine profile by reverse transcriptase polymerase
      chain reaction, including GM-CSF, G-CSF, and macrophage colony-stimulating factor
      (M-CSF); yet, only ET cells produced detectable colony-stimulating activity in
      vitro, mainly due to GM-CSF. No differences in tumorigenicity were noted between
      ET and ET/0 cells inoculated to normal or immunodeficient mice. An increase in
      extramedullar hematopoiesis, accompanied by neutrophilia and thrombocytosis, was
      associated with tumor progression irrespective of the cell line. A strong
      correlation was obtained between the increase in splenic GM-CFU and tumor mass (r
      = 0.96, p < 0.0001) that was independent on the tumor cell line, strain of mice,
      or stage of tumor development. The results point against CSF released by tumor
      cells and/or reactive host T cells as the only factors involved in the
      extramedullar hematopoiesis in this tumor model. The remarkable correlation
      between splenic GM-CFU and the tumor mass still suggests that a factor(s) of
      tumor origin may play a critical role.

PMID- 10641594
TI  - Characterization of germinal center dendritic cells in follicular lymphoma.
AB  - A subset of dendritic cells called germinal center dendritic cells (GCDC) has
      recently been described inside germinal center from reactive lymphoid organs. We
      investigated this newly recognized population in follicular lymphoma (FL), which
      is considered to be the pathologic counterpart of germinal center B cells.
      Immunohistochemistry analysis with a panel of antibodies demonstrated the
      presence of a cell population with the peculiar GCDC phenotype in FL biopsies and
      a similar localization of these cells inside tumoral and reactive follicles.
      Therefore, we analyzed the relationships between GCDC and the other cell subsets
      of the tumor follicles. Some of CD4+ and CD8+ T lymphocytes present inside the
      follicle were found to be in close association with GCDC, suggesting a potential
      implication of GCDC in their activation. In addition, the distribution of GCDC
      inside FL and reactive follicles did not appear disrupted, in contrast to
      follicular dendritic cells, the other follicle dendritic cell type. Finally, we
      demonstrated that GCDC could be detected from FL lymph node cell suspension by
      flow cytometry. Taken together, these results indicate that FL development is not
      associated with a disappearance of GCDC or with a lack of physical interactions
      between GCDC and T cells inside the follicles. In addition, the fact that GCDC
      can be observed in FL samples by flow cytometry should allow their purification
      to further study their putative role in FL development and maintenance.

PMID- 10641595
TI  - PEG-rHuMGDF promotes multilineage hematopoietic recovery in myelosuppressed mice.
AB  - PEG-rHuMGDF administered to normal mice is a lineage-specific growth factor for
      megakaryocytes and platelets as judged by morphologic examination of hematologic
      cells in marrow and peripheral blood smears. The purpose of this study was to
      document that PEG-rHuMGDF in myelosuppressed mice promotes multilineage
      hematopoietic recovery. High-dose 5-fluorouracil (5-FU) in mice results in
      profound myelosuppression and 0-30% survival. Mice receiving a single dose of PEG
      rHuMGDF (1000 microg/kg) 1 day after 5-FU (225 mg/kg) demonstrate an increased
      survival (76% vs 27% in control mice at 14 days). Compared to surviving controls,
      PEG-rHuMGDF-treated mice not only show the expected higher platelet counts, but
      also increased marrow colony-forming unit granulocyte-macrophage, increased
      multilineage marrow cellularity, and increased neutrophil, monocyte, and
      lymphocyte counts in peripheral blood. PEG-rHuMGDF- and vehicle-treated mice both
      develop hepatic abscesses after 5-FU treatment, but the abscesses in the PEG
      rHuMGDF-treated mice contain more neutrophils, suggesting that myeloid
      reconstitution contributes to their survival. Furthermore, survival in 5-FU
      treated mice is significantly improved by granulocyte colony-stimulating factor
      and antibiotics, suggesting that infection rather than thrombocytopenia is the
      predominant cause of death. PEG-rHuMGDF after 5-FU promotes survival accompanied
      by accelerated lymphohematopoietic repopulation, suggesting that PEG-rHuMGDF, a
      lineage-specific thrombopoietic factor in normal mice, promotes multilineage
      hematopoietic recovery in myelosuppressed mice.

PMID- 10641596
TI  - Vascular smooth muscle differentiation of murine stroma: a sequential model.
AB  - Previous studies by our group showed that stromal cells from human long-term
      marrow cultures were mesenchymal cells following a vascular smooth muscle
      pathway. The present study using 58 immortalized stromal lines from different
      hematopoietic sites was conducted to verify whether this hypothesis also held
      true for murine stroma. Principal components analysis performed using
      cytoskeletal and extracellular matrix proteins allowed the segregation of five
      factors explaining more than 70% of the variance. Factor I, including osteopontin
      and vimentin, and factor II, laminins and fibronectins, were representative of
      the mesenchyme. The remaining three factors were representative of vascular
      smooth muscle: factor III, including alphaSM actin, SM alpha actinin, SM22alpha,
      EDa+ fibronectin, and thrombospondin-1; factor IV, metavinculin and h-caldesmon;
      and factor V, smooth muscle myosin SM1 and desmin. All lines expressed factors I
      and II; 53 lines expressed factor III, 35 lines expressed factor IV; and 11 lines
      expressed factor V. A second principal components analysis including membrane
      antigens indicated the cosegregration of vascular cell adhesion molecule-1 with
      osteopontin and that of Ly6A/E with vimentin, whereas CD34 and Thy-1 appeared to
      be independent factors. The heterogeneity of vascular smooth muscle markers
      expression suggests that harmonious maintenance of hematopoiesis depends on the
      cooperation between different stromal cell clones.

PMID- 10641597
TI  - The tyrosine kinase NPM-ALK, associated with anaplastic large cell lymphoma,
      binds the intracellular domain of the surface receptor CD30 but is not activated
      by CD30 stimulation.
AB  - The heterogenous group of anaplastic large cell lymphomas (ALCLs) is
      characterized by expression of the Ki-1/CD30 antigen, a member of the tumor
      necrosis factor receptor superfamily. About 40 to 50% of cases diagnosed as ALCL
      contain a specific chromosomal rearrangement, t(2;5)(p23;q35), resulting in
      expression of the chimeric tyrosine kinase NPM-ALK. As NPM-ALK-positive lymphomas
      define a distinct subtype within the group of ALCL, the chimeric protein might be
      responsible for certain pathogenetic and clinicopathologic characteristics. To
      better elucidate the function of NPM-ALK, we investigated a possible mechanism
      for regulation of its activity. We demonstrate that NPM-ALK specifically binds to
      the intracellular domain of the cytokine receptor CD30. In vitro binding assays
      revealed that the ALK portion of NPM-ALK mediates interaction of the two
      proteins. Stimulation of the CD30 receptor by cross-linking with immobilized anti
      CD30 antibody results in complete growth inhibition of Karpas 299, an NPM-ALK
      positive ALCL cell line, but does not alter proliferation of HDLM-2, a Hodgkin's
      lymphoma-derived cell line lacking t(2;5). Western blot analysis of
      coimmunoprecipitated CD30 and NPM-ALK proteins from stimulated Karpas 299 cells
      showed that the interaction of the proteins is not modified by stimulation.
      Activation of CD30 neither enhanced NPM-ALK activity measured by
      autophosphorylation of the chimeric tyrosine kinase nor phosphorylation of
      phospholipase C-gamma, an NPM-ALK substrate. We conclude that NPM-ALK is not
      stimulated by CD30 activation, but exists as a constitutively hyperactivated
      protein. Interaction with CD30 may extend the subcellular localization of NPM-ALK
      to the microenvironment of membrane-associated proteins.

PMID- 10641598
TI  - Increased migration of cord blood-derived CD34+ cells, as compared to bone marrow
      and mobilized peripheral blood CD34+ cells across uncoated or fibronectin-coated
      filters.
AB  - Hematopoietic progenitor cells (CD34+ cells) migrate to the bone marrow after
      reinfusion into peripheral veins. Stromal cell-derived factor-1 (SDF-1) is a
      chemokine produced by bone marrow stromal cells that induces migration of CD34+
      cells. In this study we compared spontaneous and SDF-1-induced migration of CD34+
      cells from bone marrow (BM), peripheral blood (PB), and cord blood (CB) across
      Transwell filters. Under all circumstances, CB CD34+ cells showed significantly
      more migration than did BM or PB CD34+ cells. SDF-1 induced migration of BM CD34+
      cells was higher than that of PB CD34+ cells, possibly due to differences in
      sensitivity towards SDF-1. Indeed, PB CD34+ cells showed a significantly lower
      expression of the receptor for SDF-1 (CXCR-4) than did BM and CB CD34+ cells. The
      sensitivity to SDF-1, as measured by migration towards different concentrations
      of SDF-1, was identical for BM and CB-derived CD34+ cells and correlated with
      their equal CXCR-4 receptor expression. Coating of the filters with the
      extracellular matrix protein fibronectin (FN) strongly enhanced the SDF-1-induced
      migration of PB CD34+ cells (2.5 times) and of BM CD34+ cells (1.5 times). SDF-1
      induced migration of PB CD34+ cells over FN-coated filters was blocked by
      antibodies against beta1 integrins. Subsequently, analysis was performed to
      determine whether SDF-1 preferentially promoted migration of subsets of CD34+
      cells. Actively cycling CD34+ cells, which were present in BM (14%) but hardly in
      PB (2.2%) or CB (1.2%), were found to migrate preferentially towards SDF-1. In
      the input, 14%+/-2.5% of the BM CD34+ cells were in G2/M and S phase, whereas in
      the migrated fraction 20%+/-5.7% of the cells were actively cycling (p < 0.05).
      We did not observe preferential migration of phenotypically recognizable
      primitive CD34+ subsets, despite the fact that CB CD34+ cells are thought to
      contain a higher percentage of immature subsets. In conclusion, the relatively
      lower migration of PB CD34+ cells seems to be due to a lower sensitivity towards
      SDF-1, and the higher migrational capacity of CB CD34+ cells, in comparison to BM
      and PB CD34+ cells, seems to have an as yet unknown intrinsic cause. The
      increased migration of CB CD34+ cells may favor homing of these cells to the bone
      marrow, which might reduce the number of cells required for hematological
      reconstitution after transplantation.

PMID- 10641599
TI  - An in vivo model of human skin acute graft-versus-host disease: transplantation
      of cultured human epidermal cells and dermal fibroblasts with human lymphocytes
      into SCID mice.
AB  - The ability of mixed epidermal cell-lymphocyte reactions to detect allogeneic
      reactivities in an in vivo model was investigated by developing an in vivo model
      of acute graft-versus-host disease (GVHD), using SCID mice with a C.B-17
      background in which human skin structures were generated by transplantation of
      cultured human epidermal cells (HEC) with dermal fibroblasts (HDFC). Suspensions
      containing cultured HEC and HDFC from a single donor were mixed with autologous
      peripheral blood mononuclear cells (PBMNC) or with PBMNC from unrelated
      individuals, and were injected into the flanks of C.B-17-SCID mice. Ten and 21
      days after injection, subcutaneous nodules generated in the mice were examined
      histologically and immunohistochemically. Cystic structures developing after
      injection of HEC and HDFC without human PBMNC showed normal epidermislike tissue.
      Human skin generated in SCID mice injected with HEC and HDFC with auto-PBMNC
      showed no graft-versus-host reaction (GVHR) histologically, whereas those mice
      injected with PBMNC from siblings that shared an HLA haplotype showed mild GVHR.
      Human skin in SCID mice injected with HEC and HDFC with histoincompatible
      unrelated PBMNC showed moderate to severe GVHR. The severity of GVHR paralleled
      the dose of unrelated PBMNC, and GVHR was prevented by peroral treatment with
      cyclosporine A. Immunohistochemically, inflammatory cells infiltrating human
      cutaneous tissue formed in the SCID mice were stained by an anti-human CD45RO
      antibody that reacts with human T cells but not with murine lymphocytes, and most
      T cells were stained by an anti-human CD8 antibody recognizing HLA class I
      antigens. These findings are similar to those in clinical skin graft-versus host
      disease (GVHD) observed in patients undergoing allogeneic bone marrow
      transplantation. This experimental system should be useful as an in vivo model of
      human skin GVHD.

PMID- 10641600
TI  - Importance of marrow dose on posttransplant outcome in acute leukemia: models
      derived from patients autografted with mafosfamide-purged marrow at a single
      institution.
AB  - Several prospective randomized trials in acute myelocytic leukemia (AML)
      documented a lower relapse rate with autologous bone marrow transplantation
      (ABMT) than with conventional chemotherapy. However, they also identified some
      transplant difficulties, such as failure to collect sufficient numbers of stem
      cells, slow kinetics of engraftment, and a high transplant-related mortality that
      diminished or negated positive impact on overall survival. Data for ABMT are
      inconclusive in acute lymphocytic leukemia (ALL) in adults. We retrospectively
      analyzed patients with acute leukemia autografted with marrow purged with
      mafosfamide after January 1983 in our institution. The population comprised 229
      consecutive patients; 165 with AML [123 in first remission (CR1), 32 in second
      remission (CR2)]; 61 with ALL (46 in CR1, 4 in CR2); and 3 with undifferentiated
      acute leukemia. All patients were autografted with marrow purged with
      mafosfamide. Mafosfamide was given at a constant dose of 50 microg/mL in 103 and
      adjusted individually to produce a CFU-GM LD 95 (5% residual CFU-GM post purging)
      in 126. The outcome was analyzed for correlation with patient characteristics,
      the disease including cytogenetics, and the graft itself. Prognostic factors
      identified by multivariate analysis were used to derive a prognostic
      classification. Patients receiving higher doses of marrow submitted to purging
      (>5.46 x 10(4) CFU-GM/kg) experienced a lower treatment-related mortality (RR =
      0.11, p = 0.005) and a higher leukemia-free (RR = 0.5, p = 0.005) and overall
      survival (RR = 0.4, p = 0.001). Patients receiving <0.004% CFU-GM of marrow
      actually infused post purging had a lower relapse rate (RR = 0.51, p = 0.003).
      Modeling of prognostic groups identified good-, intermediate-, and poor-risk
      categories. Patients receiving a stem cell dose evaluated before purging of >5.46
      x 10(4) CFU-GM/kg and doses actually infused post purging of < or =0.02 x
      10(4)/kg had a treatment-related mortality of only 2+/-2%, a leukemia-free
      survival of 70%, and an overall survival of 77+/-7% at 10 years. In this study of
      autotransplantation for acute leukemia using mafosfamide-purged marrow, the stem
      cell dose used for purging and the intensity of purging were the most important
      factors predicting outcome.

PMID- 10641601
TI  - Electroencephalography in infants with periventricular leukomalacia: prognostic
      features at preterm and term age.
AB  - Cystic periventricular leukomalacia represents the most severe white-matter
      lesion in preterm infants and its occurrence accounts for most cases of
      neurologic impairment in these subjects. Electroencephalographic (EEG) findings
      and their prognostic value in relation to motor and cognitive outcome were
      investigated in a group of preterm infants affected by different degrees of
      cystic periventricular leukomalacia. EEG recordings were carried out in the early
      postnatal period (first 2 weeks of life) on 24 infants and at term age on 29. In
      the early postnatal period, background EEG abnormalities ("dysmaturity") were
      significantly more apparent in affected infants than in a control group, and,
      among infants with cystic periventricular leukomalacia, this parameter related to
      the occurrence of cerebral palsy; moreover, at the same age, the incidence of
      abnormal EEG transients seemed to show a correlation with cognitive outcome. At
      term age, these latter abnormalities were significantly more apparent in neonates
      with cystic periventricular leukomalacia than in control subjects, but they did
      not show any prognostic value. In conclusion, these data indicate that, during
      the early postnatal period, the EEG is a useful diagnostic and prognostic tool
      for preterm infants with white-matter lesions, whereas at term age, the role of
      EEG tracings appears secondary.

PMID- 10641602
TI  - Disability evaluation in children with hemidecorticectomy: use of the activity
      scales for kids and the pediatric evaluation disability inventory.
AB  - The purpose of this study is to investigate the level of disability of children
      who are either candidates for or have undergone a hemidecorticectomy. The
      Activity Scales for Kids and the Pediatric Evaluation Disability Inventory were
      demonstrated to be useful measurement tools yielding comparative results between
      subgroups. Overall, children with congenital disease seemed less autonomous
      postoperatively than were preoperative patients or children with acquired
      disease. Age at surgery and the interval between seizure onset and surgery are
      potentially important predictors of disability. This could reflect the importance
      of timing of surgery, development, environment, and possibly brain plasticity
      processes in this population.

PMID- 10641603
TI  - Paroxysmal tonic upgaze: physiopathological considerations in three additional
      cases.
AB  - Paroxysmal tonic upgaze of childhood has been described as a benign distinctive
      syndrome of abnormal ocular movement, with or without concomitant ataxia. After
      the first observation of four children, a further 29 patients have been reported
      with a wide spectrum of neurologic abnormalities such as ataxia, unsteady of
      gait, learning disabilities and mental retardation at follow-up.
      Electroencephalograms were normal in all the subjects and magnetic resonance
      imaging showed deficient myelination in only one patient. Recently it has been
      suggested that paroxysmal tonic upgaze could be a heterogeneous syndrome, ranging
      from a simply age-dependent manifestation to a clinical appearance of a variety
      of disorders affecting the corticomesencephalic loop of vertical eye movement.
      Moreover, it also could be an early sign of more widespread neurologic
      dysfunction. We describe three patients who presented paroxysmal tonic upgaze; in
      one, ataxia was present; in the second child, ataxia and language disorder also
      were observed; and in the third patient paroxysmal tonic upgaze was associated
      with loss of muscle tone (drop-attack-like events). On magnetic resonance
      imaging, a pinealoma compressing the dorsal mesencephalic region was detected. On
      the basis of our observations, we suggest that any insult with periaqueductal
      mesencephalic gray-matter involvement could be considered the basic condition for
      this peculiar clinical manifestation.

PMID- 10641604
TI  - Neurotrophin-3 levels in cerebrospinal fluid from children with bacterial
      meningitis, viral meningitis, or encephalitis.
AB  - Neurotrophin-3 levels were measured in the cerebrospinal fluid of 35 patients
      with bacterial meningitis, viral meningitis, or encephalitis by two-site enzyme
      immunoassay. Elevated cerebrospinal fluid levels of neurotrophin-3 were
      demonstrated in 8 of 18 patients with bacterial meningitis. Follow-up examination
      of the eight patients at the convalescent stage showed diminished cerebrospinal
      fluid levels of neurotrophin-3. In contrast, none of the 17 patients with viral
      meningitis or encephalitis showed an elevation of neurotrophin-3 levels in
      cerebrospinal fluid. No relationships were observed between neurotrophin-3 levels
      and cerebrospinal fluid cell numbers, cerebrospinal fluid protein levels, serum C
      reactive protein concentrations, or outcome in bacterial meningitis. Since
      neurotrophin-3 is involved in the survival of neurons and the modulation of the
      immune system, neurotrophin-3 could play a neuroprotective or immunomodulatory
      role in bacterial meningitis.

PMID- 10641605
TI  - Childhood head tremor.
AB  - We report here four children (three girls, one boy) with head tremor followed
      longitudinally, ages 15 months to 11 years, with follow-up over 1 to 8 years.
      Each demonstrated onset of head tremor between the ages of 5 and 10 months. In
      each case head tremor was characterized by a predominant "yes-yes" or "no-no"
      movement of the head. In two of the children the movement was slightly skewed
      with chin movement toward the shoulder. Oscillations were at a frequency of about
      1 to 2 Hz. They were accentuated when sitting upright without head support,
      increased at times of movement, and dissipated while lying flat or sleeping. The
      children were unable to voluntarily suppress the action and did not experience
      any sensation of movement. Three of the children had shuddering spells prior to
      onset of head tremor. Two children have developed mild dystonic posturing of the
      legs when intently concentrating. Their general and neurologic examinations were
      normal. Normal investigations included brain magnetic resonance imaging and
      computed tomography, urine amino acids and organic acids screening, serum
      lactate, erythrocyte sedimentation rate, antinuclear antibodies, and
      ceruloplasmin and copper levels. A family history of tremor was present in two
      children, maternal epilepsy in one child, and infantile shuddering occurred in
      the father of one child. Therapy included trials of selective and nonselective
      beta-adrenergic blockers, alpha-adrenergic agonists, anticholinergics,
      anticonvulsants, and amantadine. One child responded well to both timolol and
      trihexyphenidyl. A second child responded moderately to primidone. Two have not
      been treated. Two have had head tremor spontaneously remit. We conclude from this
      small series of children with head tremor that it can evolve from a prior history
      of shuddering spells, occurs in the context of a positive family history of
      tremor, and can be accompanied by the development of a mild dystonia. Therapeutic
      response is variable to multiple agents. Spontaneous remission occurs, suggesting
      a benign course.

PMID- 10641606
TI  - The value of partial sleep deprivation as a routine measure in pediatric
      electroencephalography.
AB  - For more than 50 years it has been known that in patients with epilepsy, sleep
      markedly increases the diagnostic yield of the electroencephalogram (EEG). Sleep
      deprivation could have an additional activating role. Many laboratories do not
      use these methods routinely but reserve them for a second EEG if equivocal or
      negative findings are present in the initial EEG. We studied a regime of routine
      partial sleep deprivation without the use of hypnotic agents in 396 children
      younger than age 17 years who were referred for EEG with a diagnosis of epilepsy
      or suspected epilepsy. Sleep was achieved for the EEG in 77% (96% in the 1 month
      to 2 year age group, 78% in the 2 to 8 year age group, and in 64% of those more
      than 8 years old). In a comparison group of 72 children who had not been sleep
      deprived, sleep was achieved in 44% (69% of those less than 2 years old, 27% of
      those between 2 and 8 years of age, and 33% of those older than 8 years). The
      differences were highly significant. The regime was well tolerated. Routine
      partial sleep deprivation is a practical and effective method of obtaining sleep
      and thus maximizing the information obtained from a single EEG.

PMID- 10641607
TI  - Hallervorden-Spatz disease: two new early childhood onset cases.
AB  - Hallervorden-Spatz disease is a rare, autosomal-recessive hereditary condition
      characterized by early onset of progressive movement alterations such as
      dystonia, rigidity, and choreoathetosis, which is usually associated with
      pyramidal signs and mental deterioration. The authors report two cases for which
      diagnosis of Hallervorden-Spatz disease was based on clinical manifestations that
      appeared during the first year of life, illness progression, and late-stage
      magnetic resonance imaging findings. The possibility that these two cases, along
      with other previously described rare instances with similar clinical features, be
      considered as a variant of subtype of the early-onset type of Hallervorden-Spatz
      disease is suggested. The need to differentiate these cases from cases of static
      encephalopathy with mental retardation and motor impairment is also stressed.

PMID- 10641608
TI  - Brainstem auditory evoked response in newborns and infants.
AB  - Brainstem auditory evoked response studies were carried out on 105 neonates, with
      gestational ages ranging from 26 to 43 weeks. The mean chronologic and
      postconception ages of the subjects were 6.5 weeks and 40.6 weeks, respectively.
      Statistically significant relationships between brainstem auditory evoked
      response and gestational age, postconception age (gestational age plus
      chronologic age), and the 5-minute Apgar score, were demonstrated. Shortening of
      brainstem auditory evoked response as related to postconception age was
      demonstrated and this trend was statistically significant. However, of these
      factors a statistically significant shortening (maturation) of evoked response
      was demonstrated only in relation to postconception age.

PMID- 10641609
TI  - The influence of premorbid language skills and behavior on language recovery in
      children with verbal auditory agnosia.
AB  - Previous studies of children with Landau-Kleffner syndrome and related language
      epilepsy syndromes have focused on the relationship of seizure control to
      language recovery. We examined the effect of premorbid language skills and
      behavior, as well as some characteristics of clinical seizures and
      electroencephalograms, on language recovery in a retrospective study of 67
      children with the severe receptive and expressive language disorder, verbal
      auditory agnosia. Fifty-eight percent of these children had seizures, 76% were
      autistic, and 24% had a history of language regression after showing previously
      normal language skills. The duration of language loss was not influenced by the
      persistence of clinical seizures. Premorbid language and behavior were more
      predictive of language recovery in these children. Most children with normal
      early language (acquired verbal auditory agnosia) had onset of language loss
      after age 3 years, in contrast to those with abnormal early language. Children
      with acquired verbal auditory agnosia were more likely to show fluctuations in
      language skills than those in other groups. Autistic children were more likely to
      begin having seizures before age 3 years, and had a longer duration of language
      loss and lower educational placement at time of last follow-up than those with
      normal behavior. This study emphasizes the importance of assessing premorbid
      language and behavior in predicting recovery of language skills in children with
      language-epilepsy syndromes.

PMID- 10641610
TI  - Neurologic presentations of mitochondrial disorders.
AB  - This article describes the neurologic presentations of children with
      mitochondrial disorders. The charts of 42 children with highly suspect
      mitochondrial disorders were reviewed. Thirty-seven children were diagnosed as
      having definite mitochondrial disorders based on a suggestive clinical
      presentation and at least one accepted criteria, while in five patients the
      diagnosis remained probable. All patients had nervous system involvement, but it
      was the presenting symptom in 28 of 42. Eighteen children had normal intelligence
      and 24 had mental retardation or developmental delay at the onset of their
      disease. Twenty-five patients had either an acute regression or a progressive
      encephalopathy. The most frequent neurologic manifestations were abnormal tone,
      seizures, extrapyramidal movements, and autonomic dysfunction. The eyes were
      involved in 11 children. Nerve deafness was found in seven patients. Myopathy was
      found in only six patients. In conclusion, a complex neurologic picture,
      especially with other organ involvement, warrants a full mitochondrial
      evaluation.

PMID- 10641611
TI  - Long-term computer-assisted outpatient electroencephalogram monitoring in
      children and adolescents.
AB  - The aims of this study were (1) to define the role of long-term computer-assisted
      outpatient electroencephalographic monitoring (COEEG) in children and adolescents
      with known or suspected epilepsy, and (2) to compare COEEG data with routine
      interictal electroencephalograms (EEG). We performed 18-channel COEEG in 84
      children and adolescents with diagnosed (group 1, n = 49) or suspected (group 2,
      n = 35) epilepsy. Mean recording time was 1.4 days. Overall, COEEG was useful in
      87% of patients. In group 1, events were recorded in 73% of patients and were
      electrographic seizures in 45%. In group 2, events were detected in 86% of
      patients and were electrographic seizures in 17%. Nocturnal and partial seizures
      predominated. Seizure diagnosis and classification by COEEG was concordant with
      interictal EEG findings in 19% and discordant in 63% of patients. COEEG is a
      useful technique for the diagnosis of epileptic and nonepileptic events among
      selected children and adolescents. When compared to routine interictal EEG, COEEG
      could offer additional accuracy in the classification of seizures in pediatric
      patients.

PMID- 10641612
TI  - Single photon emission computed tomographic evaluation of brainstem release
      phenomenon and seizure in neonates.
AB  - We report the ictal brain single photon emission computed tomographic (SPECT)
      findings in two neonates. One neonate had hypoxic-ischemic encephalopathy, a
      disorganized discontinuous electroencephalogram (EEG) background, lethargy,
      seizures, and brainstem release phenomena. A brain SPECT was performed during a
      brainstem release phenomenon characterized by a 34-second sustained tonic posture
      of the right arm and chewing. It did not reveal focal cerebral hemisphere
      hyperfusion. The second neonate had hemimegalencephaly, low-voltage irregular EEG
      background, and seizures. A brain SPECT was performed during a seizure
      characterized by a 32-second sustained tonic posture of the right arm. It
      revealed focal hyperperfusion in the posterior region of the left hemisphere. The
      brain SPECT findings in these patients indicate that despite clinically similar
      events, brainstem release phenomena and seizures have different perfusion
      characteristics, and refute the theory that brainstem release phenomena are due
      to epileptic foci in the cerebral hemispheres undetectable by EEG.

PMID- 10641613
TI  - Syncope as a first sign of seizure disorder.
AB  - We studied the long-term follow-up of patients with the diagnosis of "syncope of
      unknown origin," and their progression to epilepsy to gain a better understanding
      of the relationship between syncope and epilepsy, and to determine whether
      findings of the first syncopal attack have prognostic significance in
      relationship to the onset of epilepsy or not. Eighteen patients with the
      diagnosis of syncope of unknown origin were evaluated for the possibility of
      becoming epileptic during a 4-year period, and four patients showed
      characteristic seizure disorder. There were no clinical or laboratory features
      that differentiated them from the nonepileptic group, except that they were all
      girls. The interval between the first syncopal attack and the typical epileptic
      seizure ranged between 7 and 19 months. Syncope of unknown origin could be the
      first sign of an epileptic disorder, especially in girls. Long-term follow-up
      extending up to 1 year is necessary to disclose the risk of becoming epileptic.

PMID- 10641614
TI  - Syndrome of microcephaly, mental retardation, and tracheoesophageal fistula
      associated with features of Rett syndrome.
AB  - We report a 12-year-old girl with features of the syndrome of microcephaly,
      mesobrachydactyly, and tracheoesophageal fistula, who also developed distinctive
      features of Rett syndrome including regression of milestones with repetitive
      actions, autistic-like behavior, stereotypic hand movements, and seizures. This
      unique combination of clinical manifestations appears to constitute a "new
      syndrome." We speculate that this association may represent a contiguous gene
      syndrome.

PMID- 10641615
TI  - Acute quadriplegic myopathy in a 17-month-old boy.
AB  - Acute quadriplegic myopathy is a rare condition associated with the use of
      nondepolarizing muscle-blocking agents and corticosteroids in the course of
      severe systemic illness. A 17-month-old boy underwent liver transplantation for
      fulminant hepatitis. He was intubated for 24 days and treated with vecuronium
      bromide and high-dose methylprednisolone. The child was weaned from the
      ventilator and presented extreme weakness in the upper limbs and total paralysis
      of the lower limbs. Serum creatine kinase level was normal and electromyography
      showed myopathic abnormalities. Muscle biopsy showed severe type-1 fiber atrophy
      and selective loss of myosin thick filaments was seen on electron microscopy.
      Scattered regenerating fetal myosin-positive fibers were present, mu calpain was
      absent, while m calpain was diffusely expressed. Physical therapy was immediately
      started and the child recovered even though corticosteroids were not
      discontinued. The pathogenesis of acute quadriplegic myopathy is still unknown.
      We suggest that it could be due to abnormal protein turnover in the muscle.
      Several independent factors, such as corticosteroid treatment, immobilization, or
      cytokines, could take part in a cascade of events that leads to an excessive yet
      selective degradation of proteins involving myosin thick filaments and possibly
      components of sarcolemma, causing muscle inexcitability.

PMID- 10641616
TI  - Encephalopathy as the presenting symptom of Hashimoto's thyroiditis.
AB  - In recent years, encephalopathy has increasingly been recognized as a
      complication of Hashimoto's thyroiditis. It can begin abruptly as a stroke-like
      event, acute seizures, or confusion, or as an insidious decline in cognitive
      function. Most reported cases have been on adult patients, although this
      encephalopathy does affect children as well. This form of encephalopathy should
      be considered in the differential diagnosis of children and adults with
      unexplained neurologic deterioration. We describe the case of a child in whom
      acute encephalopathy was the presenting symptom of Hashimoto's thyroiditis.

PMID- 10641617
TI  - A time domain rough surface scattering model based on wedge diffraction:
      application to low-frequency backscattering from two-dimensional sea surfaces
AB  - A time domain method for calculating the acoustic impulse response of
      impenetrable, rough, two-dimensional (2D) surfaces is presented. The method is
      based on an extension of the wedge assemblage (WA) method to 2D surfaces and
      objects. Like the WA method for one-dimensional (1D) surfaces, the approach for
      2D surfaces uses Biot's and Tolstoy's exact solution for the impulse response of
      an infinite impenetrable wedge [J. Acoust. Soc. Am. 29, 381-391 (1957)] as its
      fundamental building block. The validity of the WA method for backscattering from
      2D sea surfaces is assessed through comparisons with calculations based on
      Milder's operator expansion (OE) method [J. Acoust. Soc. Am. 89, 529-541 (1991)].
      Average intensities for backscattering from 2D fully developed seas (20 m/s wind
      speed) were computed by the WA and OE methods using 50 surface realizations and
      compared at 11 frequencies between 100 and 200 Hz. A single, moderately low
      grazing angle of incidence (20 degrees) and several scattered grazing angles (90
      degrees, 45 degrees, 20 degrees , and 10 ) were considered. Excellent overall
      agreement between the two models was obtained. The utility of the WA method as a
      tool to describe the physics of the scattering process is also discussed.

PMID- 10641618
TI  - Stop-pass behavior of acoustic waves in a 1D fractured system
AB  - This study examines the dispersion and the stop-pass band behavior of acoustic
      waves propagating across periodically spaced and non periodically spaced parallel
      fractures. Laboratory ultrasonic wave measurements performed on a stack of
      synthetic fractures (identical steel plates with roughened interfaces) and
      numerical propagator matrix simulations show spectra with distinct stop-pass band
      structures that develop with decreasing fracture stiffness. To understand the
      physics behind these observations, an exact dispersion equation for wave
      propagation through an infinite series of equally spaced fractures is derived
      using displacement-discontinuity boundary conditions to model the constitutive
      behavior of the fractures and Floquet's (Bloch's) theory for the periodic
      boundary conditions. Both the measured and numerically simulated stop-pass band
      structures show good agreement with the theoretical predictions. Furthermore, the
      theory reveals that the left boundary of the stop-bands contains information
      about the fracture stiffness, suggesting the possibility of determining the
      stiffness of the parallel fractures from seismic waves. This paper also discusses
      the effects of fractured systems with random distributions of fracture spacings
      and stiffnesses on the stop-pass band structures of seismic waves in fractured
      rock.

PMID- 10641619
TI  - The reconstruction of a spatially incoherent two-dimensional source in an
      acoustically rigid rectangular cavity
AB  - This paper applies Green's function modal expansion techniques to inverse source
      problems within an acoustically rigid rectangular cavity. In particular,
      solutions are developed for the reconstruction of a random spatially incoherent
      distributed source and a deterministic point source by using pressure-field
      measurements on adjacent walls. Such problems have seemingly not been addressed
      previously. Several example problems are studied in this paper. As is
      characteristic of inverse problems in general, numerical instabilities are
      encountered in the example problems addressed in this paper. These are linked to
      the notion of compactness in the forward operator, and dealt with using magnitude
      regularization and projections onto convex sets. The behavior of the example
      problems studied in this paper greatly deteriorates at frequencies near cavity
      resonances, particularly low frequency resonances (i.e., with ka < or = 2pi,
      where a is the smallest cavity dimension). Other results concerning the example
      problems are also given. A proof of compactness of an infinite rank version of
      the type of operator used in this paper is given in the Appendix. This proof
      implies that the convergence of the Green's function modal expansion in the
      kernel of the forward problem is related to the instability of the inverse
      problem. This implies that, if it suffices to know an integral of the source
      profile rather than the actual profile, the problem becomes more stable.

PMID- 10641620
TI  - Acoustic X-wave reflection and transmission at a planar interface: spectral
      analysis
AB  - The spectral structure of a three-dimensional X-wave pulse incident on a planar
      surface of discontinuity is examined. Introducing a novel superposition of
      azimuthally dependent pulsed plane waves, it is shown for oblique incidence that
      the reflected pulse has a localized wave structure. On the other hand, the
      transmitted field maintains its localization up to a certain distance from the
      interface, beyond which it starts disintegrating. An estimate of the localization
      range of the transmitted pulse is established; also, the parameters affecting the
      localization range are identified. The reflected and transmitted fields are
      deduced for X-waves incident from either a slower medium or a faster one. For the
      former case the evanescent fields in the second medium are calculated and their
      explicit time dependence is deduced for a normally incident X-wave. Furthermore,
      at near-critical incidence the transmitted pulse exhibits significant pulse
      compression and focusing.

PMID- 10641621
TI  - Modeling of lamb waves generated by integrated transducers in composite plates
      using a coupled finite element-normal modes expansion method
AB  - Thin piezoelectric transducers attached to or embedded within composite
      structures could be used for in situ structural health monitoring. For plate
      shaped structures, the useful ultrasonic vibration modes are Lamb waves.
      Preliminary testing has already demonstrated the suitability and practical
      feasibility of such integrated transducers, but better control of the generation
      of Lamb modes seems to be necessary. Therefore, an original modeling approach has
      been developed, which can be used to design and optimize these "sensitive
      materials." This modeling technique allows the determination of the amplitude of
      each Lamb mode excited in a composite plate with surface-bonded or bulk-embedded
      piezoelectric elements. The method consists of a coupling of the finite element
      method (FEM) and the normal modes expansion method. The limited finite element
      mesh of the transducer and its vicinity enables the computation of the mechanical
      field created by the transducer, which is then introduced as a forcing function
      into the normal modes equations. The adequacy and accuracy of this modeling
      method have been numerically and experimentally verified.

PMID- 10641622
TI  - Sound scattering by bubble clouds near the sea surface
AB  - The classical exact formulation required to evaluate the form function (or the
      scattering cross-section, SCS) of a single, ideal, air bubble in a boundless
      liquid is briefly recalled. It is then immediately generalized to the case of a
      round cloud of many possibly interacting such bubbles of known volume
      concentration, contained within the same boundless medium. This is further
      generalized to the case when the bubble cloud is near a free surface. The
      presence of the nearby pressure release surface, assumed flat, substantially
      alters the cloud's scattering cross-section relative to its value in the absence
      of boundaries. We then use an earlier technique of ours [i.e., see I.E.E.E. J.
      Ocean. Eng. 20, 285-293 (1995)] based on the method of images that uses the
      addition theorem for the spherical wave functions, to relate all the scattered
      sound fields to a common origin and thus obtain the (modified) SCS of the cloud
      now near the boundary. This formulation accounts for all orders of multiple
      scattering and yields an infinite set of coupled algebraic equations for the
      coupling coefficients. This set is then solved for the coupling coefficients in
      terms of infinite sums of products of pairs of Wigner 3-j symbols, which are then
      used to construct and evaluate the form function. We display numerical results in
      four cases that correspond to geographical sites in which the bubble
      concentrations within the cloud have been measured along a couple of oblique
      upward directions, or have been assumed to have increasing (and in a few
      instances, purposely unrealistically high) values. In all cases considered here
      the bubble clouds are only a few meters beneath the sea surface and consist of
      ideal bubbles. The results are also compared to those found in the absence of a
      boundary in all the cases considered.

PMID- 10641623
TI  - Edge wave on axis behind an aperture or disk having a ragged edge
AB  - Diffraction by a circular aperture or disk having a ragged edge is investigated.
      Theory and measurements are reported. The ragged edge is modeled as N arcs, of
      differing radii a(i), each of which contributes a scattered signal to the edge
      wave on axis behind the aperture or disk. The amplitude of each scattered signal
      is proportional to the angle of the arc, and the corresponding time delay is
      square root of [(ai)2 + (s0)2/c0], where s0 is the axial distance from the
      aperture plane and c0 is the sound speed. Kirchhoff theory is used to make the
      calculation. A formula is derived for the rms pressure of the edge wave in terms
      of the rms pressure and autocorrelation function of the incident wave. The
      formula can be evaluated for incident waves that are sinusoidal, random (e.g.,
      noise), or transient. Predictions agree reasonably well with underwater
      measurements made with a spark-generated pulse incident on various apertures. The
      main result is that making the edge ragged reduces the rms pressure of the edge
      wave. Indeed, an edge profile is presented that, for a given frequency and axial
      observation point, eliminates the edge wave completely.

PMID- 10641624
TI  - Backscattering enhancements from Rayleigh waves on the flat face of a tilted
      solid cylinder in water
AB  - When the face of a finite solid elastic cylinder is ensonified by an acoustic
      wave, a variety of backscattering contributions associated with acoustic wave
      coupling into elastic waves are observed. A significant backscattering
      enhancement is observed for tilts such that the acoustic wave is incident on the
      face of the cylinder in the vicinity of the coupling angle for launching Rayleigh
      waves across the face. The observed backscattering indicates that the Rayleigh
      waves are reflected at the edge of the face and subsequently radiate acoustic
      waves in the backscattering direction. The measured backscattering is compared to
      an approximate theoretical prediction. Approximating the focusing of the Rayleigh
      wave after reflection at the (circular) edge by a Gaussian beam pressure
      distribution on the cylinder's face yields simple expressions for the amplitude
      which are consistent with the measurements. In the vicinity of end-on incidence,
      other backscattering contributions due to the reflection of waves traveling down
      the length of the cylinder are observed. There is also evidence of a face
      traversing longitudinal wave for slightly tilted cylinders.

PMID- 10641625
TI  - Radiated noise characteristics of a modern cargo ship
AB  - Extensive measurements were made of the radiated noise of M/V OVERSEAS HARRIETTE,
      a bulk cargo ship (length 173 m, displacement 25 515 tons) powered by a direct
      drive low-speed diesel engine-a design representative of many modern merchant
      ships. The radiated noise data show high-level tonal frequencies from the ship's
      service diesel generator, main engine firing rate, and blade rate harmonics due
      to propeller cavitation. Radiated noise directionality measurements indicate that
      the radiation is generally dipole in form at lower frequencies, as expected.
      There are some departures from this pattern that may indicate hull interactions.
      Blade rate source level (174 dB re 1 microPa/m at 9 Hz, 16 knots) agrees
      reasonably well with a model of fundamental blade rate radiation previously
      reported by Gray and Greeley, but agreement for blade rate harmonics is not as
      good. Noise from merchant ships elevates the natural ambient by 20-30 dB in many
      areas; the effects of this noise on the biological environment have not been
      widely investigated.

PMID- 10641626
TI  - The Rayleigh-like collapse of a conical bubble
AB  - Key to the dynamics of the type of bubble collapse which is associated with such
      phenomena as sonoluminescence and the emission of strong rebound pressures into
      the liquid is the role of the liquid inertia. Following the initial formulation
      of the collapse of an empty spherical cavity, such collapses have been termed
      "Rayleigh-like." Today this type of cavitation is termed "inertial," reflecting
      the dominant role of the liquid inertia in the early stages of the collapse.
      While the inertia in models of spherical bubble collapses depends primarily on
      the liquid, experimental control of the liquid inertia has not readily been
      achievable without changing the liquid density and, consequently, changing other
      liquid properties. In this paper, novel experimental apparatus is described
      whereby the inertia at the early stages of the collapse of a conical bubble can
      easily be controlled. The collapse is capable of producing luminescence. The
      similarity between the collapses of spherical and conical bubbles is investigated
      analytically, and compared with experimental measurements of the gas pressures
      generated by the collapse, the bubble wall speeds, and the collapse times.

PMID- 10641627
TI  - Mean force on a small sphere in a sound field in a viscous fluid
AB  - A mean force exerted on a small rigid sphere by a sound wave in a viscous fluid
      is calculated. The force is expressed as a sum of drag force coming from the
      external steady flow existing in the absence of the sphere and contributions that
      are cross products of velocity and velocity derivatives of the incident field.
      Because of the drag force and an acoustic streaming generated near the sphere,
      the mean force does not coincide with the acoustic radiation pressure, i.e., the
      mean momentum flux carried by the sound field through any surface enclosing the
      sphere. If the sphere radius R is considerably smaller than the viscous wave
      penetration depth delta, the drag force can give the leading-order contribution
      (in powers of delta/R) to the mean force and the latter can then be directed
      against the radiation pressure. In another limit, delta< or =R, the drag force
      and acoustic streaming play a minor role, and the mean force reduces to the
      radiation pressure, which can be expressed through source strengths of the
      scattered sound field. The effect of viscosity can then be significant only if
      the incident wave is locally plane traveling.

PMID- 10641628
TI  - Study of horizontal multipaths and ray chaos due to ocean mesoscale structure
AB  - Long-range ocean acoustic propagation in the presence of idealized mesoscale
      structure is studied by first deriving a two-dimensional horizontal-plane
      parabolic wave equation that follows from the adiabatic mode approximation. In
      the geometric limit, a nonautonomous Hamiltonian dynamical system having one
      degree of freedom is derived. A stochastic formalism is developed to analyze this
      nonintegrable dynamical system. The main result is that on average two rays that
      are initially separated by an infinitesimal amount diverge exponentially at a
      rate given by the Lyapunov exponent that has been calculated theoretically and
      compared to numerical experiments with agreement to two decimal places. The
      practical implication of this result is that tomographic inversions based on
      assumed pointwise accurate ray predictions might not be possible beyond the
      "predictability horizon" of many thousands of kilometers, due to horizontal-plane
      multipaths induced by naturally occurring mesoscale activity.

PMID- 10641629
TI  - An acoustic study of soils that model seabed sediments containing gas bubbles
AB  - The acoustic response of gassy seabed sediment is unique. It is a dispersive and
      extraordinarily attenuative natural material at frequencies which cause gas
      bubble resonance. It conceals the structure of the seabed from seismic profiling
      and it dampens acoustic signals that, for example, trigger acoustic mines. In the
      past, theoretical studies have formulated the probable cause of this response and
      crude experimental work has partially corroborated theory. This study measures
      compressional wave velocity and attenuation in a laboratory soil simulating
      natural gassy soil, and it investigates the structural properties that cause the
      unique acoustic response. It was confirmed that below the frequencies which cause
      resonance the soil behaves as a compressible material (containing gas), and above
      as a relatively incompressible material (containing no gas). Over the frequency
      range producing bubble resonance it is suggested that the soil should be modeled
      as a biphasic material of gas and a relatively incompressible saturated soil
      matrix (particles and fluid). Velocities for gassy soil were found to be as low
      as 220 m/s at frequencies below resonance and 1500 m/s above resonance;
      attenuations were found to be as high as 60 dB/cm for moderately gassy soil and
      as low as 1 dB/cm for soil with almost no gas.

PMID- 10641630
TI  - A model for the horizontal directionality of breaking wave noise in the surf zone
AB  - A model is presented for the horizontal directionality of the noise generated by
      individual breaking waves in the surf zone. The model is based on the interaction
      between sound radiated by ringing bubbles created in a breaking wave crest and
      the population of acoustically quiescent bubbles left on the seaward side of the
      wave in the shallow water waveguide. The effect of the quiescent bubbles is to
      absorb sound from all but the very ends of the breaking crest, resulting in the
      formation of "acoustic hot-spots." The model calculations are in good agreement
      with observations of the horizontal directionality of noise from individual
      breaking waves in the surf zone.

PMID- 10641631
TI  - Multifrequency acoustical volume backscattering patterns in the Arabian Sea--265
      kHz to 3 MHz
AB  - High-frequency acoustical volume backscattering was examined during three periods
      of the annual cycle of winds in the Arabian Sea-the Winter Northeast (NE)
      Monsoon, the Summer Southwest (SW) Monsoon, and the Fall Intermonsoon-using a
      multifrequency acoustic profiling system deployed on an undulating towed body.
      This system measured acoustical volume backscattering strengths at six
      frequencies ranging from 265 kHz to 3.0 MHz. Measurements were made from near the
      surface to 250 m depth along a ship track that paralleled the coast of Oman, then
      proceeded away from the coast towards the middle of the Arabian Sea. At all
      frequencies, volume backscattering strength was highest near the surface,
      decreasing with increasing depth. Contrary to expectation, backscattering was
      generally lower during the Summer SW Monsoon than during the Winter NE Monsoon.
      Also contrary to expectation, backscattering was not appreciably higher near the
      coast than it was offshore during the Summer SW Monsoon, although it was higher
      near the coast during the Winter NE Monsoon. Generally speaking, regional and
      seasonal differences were smaller than expected, and much smaller than the fine
      scale spatial and temporal variability, particularly at frequencies below 1 MHz.
      There was a daily pattern of increased nighttime backscattering in the upper 100
      m at 265 and 420 kHz. This pattern was less evident at 1.1 MHz and above.

PMID- 10641632
TI  - Acoustic normal mode fluctuation statistics in the 1995 SWARM internal wave
      scattering experiment
AB  - In order to understand the fluctuations imposed upon low frequency (50 to 500 Hz)
      acoustic signals due to coastal internal waves, a large multilaboratory,
      multidisciplinary experiment was performed in the Mid-Atlantic Bight in the
      summer of 1995. This experiment featured the most complete set of environmental
      measurements (especially physical oceanography and geology) made to date in
      support of a coastal acoustics study. This support enabled the correlation of
      acoustic fluctuations to clearly observed ocean processes, especially those
      associated with the internal wave field. More specifically, a 16 element WHOI
      vertical line array (WVLA) was moored in 70 m of water off the New Jersey coast.
      Tomography sources of 224 Hz and 400 Hz were moored 32 km directly shoreward of
      this array, such that an acoustic path was constructed that was anti-parallel to
      the primary, onshore propagation direction for shelf generated internal wave
      solitons. These nonlinear internal waves, produced in packets as the tide shifts
      from ebb to flood, produce strong semidiurnal effects on the acoustic signals at
      our measurement location. Specifically, the internal waves in the acoustic
      waveguide cause significant coupling of energy between the propagating acoustic
      modes, resulting in broadband fluctuations in modal intensity, travel-time, and
      temporal coherence. The strong correlations between the environmental parameters
      and the internal wave field include an interesting sensitivity of the spread of
      an acoustic pulse to solitons near the receiver.

PMID- 10641633
TI  - Modeling mode arrivals in the 1995 SWARM experiment acoustic transmissions
AB  - As part of the Shallow Water Acoustics in a Random Medium (SWARM) experiment, a
      16 element WHOI vertical line array (WVLA) was moored in 70 m of water off the
      New Jersey coast. A 400-Hz acoustic tomography source was moored some 32-km
      shoreward of this array, such that an acoustic path was created that was anti
      parallel to the primary propagation direction for shelf-generated internal wave
      solitons. The presence of these soliton internal waves in the acoustic waveguide
      causes significant coupling of energy between propagating acoustic modes,
      creating fluctuations in modal intensities and modal peak arrival times, as well
      as time spreading of the pulses. Two methods by which acoustic propagation and
      scattering in soliton-filled waveguides can be modeled are presented here in
      order to understand and explain the scattering observed in the SWARM field data.
      The first method utilizes the Preisig and Duda [IEEE J. Ocean. Eng. 22, 256-269
      (1997)] Sudden Interface Approximation (SIA) to represent the solitons. The
      second method, which is computationally slower, uses a finely meshed,
      "propagated" thermistor record to simulate the solitons in the SWARM experiment
      waveguide. Both numerical methods are found to generate scattering
      characteristics that are similar to the SWARM field data.

PMID- 10641634
TI  - Reverberation at the Mid-Atlantic Ridge during the 1993 ARSRP experiment seen by
      R/V Alliance from 200-1400 Hz and some modeling inferences
AB  - In July 1993 SACLANTCEN participated in an experiment for the Acoustic
      Reverberation Special Research Program (ARSRP). The primary objective was to take
      high resolution measurements to shed light on the detailed physical processes
      dominating the low frequency scattering from rough topographic features and from
      deep sediment pond areas. A very detailed set of monostatic and bistatic
      scattering experiments were conducted just west of the Mid-Atlantic Ridge near 26
      degrees N, 47 degrees W. Results from SACLANTCEN's R/V ALLIANCE are presented
      which show monostatic and bistatic scattering from selected bathymetric features
      using pulsed sources from 200-1400 Hz and SUS charges. Area water depths ranged
      from 3300 to greater than 5200 m. The receivers were a horizontal array of 128
      elements spaced at 0.5, 1, and 2 m. Source depths varied from 120 to 1200 m and
      receiver depths ranged from 400 to 500 m. Received reverberation levels are
      presented as functions of the estimated scatterer position on area bathymetry
      maps. Results show the same high scattering areas from one seamount were observed
      in three distinct frequency bands centered at 227, 350, and 700 Hz. Even at 1350
      Hz the correlation of scattering highlights with nearby bathymetric features is
      quite good. Comparisons of measured reverberation and modeled reverberation are
      presented which suggest that the dominant longer range scattering from the large
      features is driven by the steep slopes present above the critical depth but that
      small scale roughness is also essential for strong backscatter.

PMID- 10641635
TI  - Wave scattering on a fractal surface
AB  - A generalized Von Koch surface was constructed. On the basis of Freedman' s
      formulation for wave scattering and by applications of the Lipchitz transform
      under Holder conditions in fractals, a demonstration was given that the Hausdorff
      dimension of the solid-angle discontinuity on the scattering surface is the same
      as the one of the surface itself, and an expression of the scattering strength of
      the fractal surface has been given. A comparison with the Schulkin-Shaffer
      empirical formula for the sound scattering from sea surface proposes that, in
      this situation, the generalized (continuous) Koch surface seems to degenerate
      into the (discrete) four-two Cantor sets, only the latter make a contribution to
      the backscattering.

PMID- 10641636
TI  - Modeling of subcritical penetration into sediments due to interface roughness
AB  - Recent experimental results reveal acoustic penetration into sandy sediments at
      grazing angles below the critical angle. A mechanism for this subcritical
      penetration is described based on scattering at a rough water-sediment interface.
      Using perturbation theory, a numerically tractable three-dimensional model is
      used for simulating experiments. The rough interface scattering has been treated
      using formally averaged methods as well as with single rough surface
      realizations. Data-model comparisons show that scattering by interface roughness
      is a viable hypothesis for the observed subcritical penetration.

PMID- 10641638
TI  - On analytic design of loudspeaker arrays with uniform radiation characteristics
AB  - Some notes on analytical derived loudspeaker arrays with uniform radiation
      characteristics are presented. The array coefficients are derived via analytical
      means and compared with so-called maximal flat sequences known from
      telecommunications and information theory. It appears that the newly derived
      array, i.e., the quadratic phase array, has a higher efficiency than the Bessel
      array and a flatter response than the Barker array. The method discussed admits
      generalization to the design of arrays with desired nonuniform radiating
      characteristics.

PMID- 10641637
TI  - Localization using Bartlett matched-field processor sidelobes
AB  - Ambiguity surface sidelobes generated by the Bartlett matched-field processor
      (MFP) shift location with frequency. This sidelobe shift can be viewed as a
      continuous trajectory in a range-frequency plane at a fixed depth, where the
      trajectories converge to the correct source range for a perfectly matched
      surface. In isovelocity or bottom-interacting environments the sidelobe
      trajectories are straight lines that converge to the true range at zero
      frequency, while environments with upward-refracting sound-speed profiles have
      trajectories that asymptotically converge as the frequency approaches infinity.
      This behavior can be explained by the theory of waveguide invariants, which
      predict the local behavior of interference maxima/minima of acoustic intensity in
      the frequency-range plane. As the ambiguity surface of the Bartlett matched-field
      processor has a physical interpretation in terms of a time-reversed acoustic
      field, with the sidelobes analogous to local interference maxima, these invariant
      concepts can be reformulated for application to MFP. These interference
      trajectories are demonstrated to exist in simulations, broadband source tows, and
      a type A blue whale vocalization. Sidelobe trajectories also exist in the range
      depth plane, but they contain no information about the correct source depth. An
      appendix demonstrates how these sidelobe properties can be exploited when
      combining ambiguity surfaces through use of gradient and Radon transform
      information. The resulting range estimators demonstrate better peak-to-sidelobe
      ratios than a simple incoherent average.

PMID- 10641639
TI  - Plane harmonic waves in orthorhombic thermoelastic materials
AB  - Keeping in view the increased usage of orthorhombic materials in the development
      of advanced engineering materials such as fibers and composites and other
      multilayered media, the aim of the present paper is to give a detailed account of
      the plane harmonic generalized thermoelastic waves in orthorhombic materials.
      According to the frequency equation, the four waves, a quasi-longitudinal, two
      quasi-transverse, and a quasi-thermal wave, can propagate in an orthorhombic
      crystal. When plane waves propagate along the axis of an orthorhombic solid, then
      only the longitudinal and thermal waves are coupled, whereas the transverse waves
      get decoupled from the rest of the motion. For plane waves propagating in one
      plane of the solid, only the SH wave in that plane remains purely transverse and
      gets decoupled from the rest of the motion and vice versa. The other three waves
      are coupled and get modified due to thermal variations and relaxation time. The
      particle paths and stability of the waves have been discussed and the results
      verified numerically. These have been represented graphically for single crystals
      of solid helium and cobalt material.

PMID- 10641640
TI  - The influence of backward wave transmission on quantitative ultrasonic evaluation
      using Lamb wave propagation
AB  - In view of the various novel quantitative ultrasonic evaluation techniques
      developed using Lamb wave propagation, the influence of an important related
      phenomenon, backward transmission, is investigated in this paper. Using the
      discrete layer theory and a multiple integral transform method, the surface
      displacement and velocity responses of isotropic plates and cross-ply laminated
      composite plates due to the Lamb waves excited by parabolic- and piston-type
      transmitting transducers are evaluated. Analytical expressions for the surface
      displacement and velocity frequency response functions are developed. Based on
      this a large volume of calculations is carried out. Through examining the
      characteristics of the surface displacement and velocity frequency response
      functions and, especially, the different propagation modes' contributions to
      them, the influence of the backward wave transmission related to quantitative
      ultrasonic nondestructive evaluation applications is discussed and some important
      conclusions are drawn.

PMID- 10641641
TI  - Development of an on-line diagnosis system for rotor vibration via model-based
      intelligent inference
AB  - An on-line fault detection and isolation technique is proposed for the diagnosis
      of rotating machinery. The architecture of the system consists of a feature
      generation module and a fault inference module. Lateral vibration data are used
      for calculating the system features. Both continuous-time and discrete-time
      parameter estimation algorithms are employed for generating the features. A
      neural fuzzy network is exploited for intelligent inference of faults based on
      the extracted features. The proposed method is implemented on a digital signal
      processor. Experiments carried out for a rotor kit and a centrifugal fan indicate
      the potential of the proposed techniques in predictive maintenance.

PMID- 10641642
TI  - Active control of the plate energy transmission in a semi-infinite ribbed plate
AB  - Active control of the plate flexural wave transmission through the beam in a semi
      infinite beam-reinforced plate is analytically investigated. The ribbed plate is
      modeled as a continuous system, using equations of motion to describe the plate
      in flexure and the beam in both flexure and torsion. The maximum transmission of
      the plate flexural waves through the reinforcing beam is found to occur at
      resonance frequencies corresponding to the optimal coupling between the plate
      flexural waves and the flexural and torsional waves in the beam. A single control
      force is applied to the beam, and a cost function is developed to attenuate the
      far-field flexural energy transmission. It can be observed that the transmission
      peaks corresponding to the flexural resonances in the beam are reduced.
      Similarly, the transmission peaks corresponding to the torsional resonance
      conditions in the beam can be attenuated using a single control moment applied to
      the beam. Significant attenuation of all the resonance peaks in the flexural wave
      transmission can also be achieved with the application of a single force and a
      single moment collocated on the beam. In this paper, the feasibility of
      attenuating the flexural wave transmission due to both the flexural and torsional
      resonance conditions by using a single point force and point moment collocated on
      the beam is demonstrated.

PMID- 10641643
TI  - Radiation modal expansion: application to active structural acoustic control
AB  - This paper demonstrates active structural acoustic control using multiple
      input/output adaptive sensoriactuators combined with radiation filters and a
      feedback control paradigm. A new method of reduced order modeling/design of
      radiation filters termed radiation modal expansion (RME) is presented. For the
      experiments detailed in this paper, the RME technique reduced the modeling of the
      radiation matrix from 400 transfer functions to 6 transfer functions (multiplied
      by a constant transformation matrix). Experimental results demonstrate reductions
      of radiated sound power on the order of 5 dB over the bandwidth of 0-800 Hz.

PMID- 10641644
TI  - Acoustical design of the Tokyo Opera City (TOC) concert hall, Japan
AB  - The Tokyo Opera City concert hall seats 1632, volume 15 300 m3, and reverberation
      time, with audience and orchestra, 1.95 s. As part of the design process,
      measurements on CAD computer and 1:10 wooden models of the hall and full-sized
      materials samples were conducted over a 5-yr. period. The hall in plan is
      rectangular. The ceiling is a distorted pyramid, with its peak 28 m above the
      main floor and nearer the stage than the rear of the hall. This unique shape was
      analyzed on the models so that all interior surfaces combine to distribute
      sources on the stage uniformly over the seating areas and to yield optimum values
      for reverberation time (RT), early decay time (EDT), interaural cross-correlation
      coefficient (IACCE3), bass ratio (BR), initial-time-delay gap (ITDG), strength
      (G), and sound diffusion index (SDI) [for definitions see L. Beranek, Concert and
      Opera Halls: How They Sound (Acoustical Society of America, Woodbury, NY, 1996)].
      On the long ceiling facing the stage, Schroeder QRD diffusers provide diffusion,
      eliminate a possible echo, and strengthen lateral reflections. Performers and
      critics judge the acoustics excellent.

PMID- 10641645
TI  - Acoustical design of the opera house of the New National Theatre, Tokyo, Japan
AB  - Architect Takahiko Yanagisawa's preface explains his approach to the design. The
      NNT opera house seats 1810, its volume is 14500 m3, and its reverberation time,
      with audience, is 1.5 s (proscenium curtain open). Measurements on CAD computer
      and 1:10 wooden models and full-sized materials samples were conducted over a 7
      yr. period. The main floor is almost rectangular, the three balconies have modest
      fan shape in plan, although the balcony facia at each level create a rectangular
      shape. The unique design has a large curved reflector in front of and above the
      proscenium and six curved reflecting surfaces at the front ends of the three side
      balconies to form, in combination, an "acoustic trumpet." These surfaces, along
      with the balcony faces and the shaped ceiling, distribute the singers' voices
      uniformly over the seating areas from a large portion of the large stage at sound
      levels that easily override the orchestra in the pit.

PMID- 10641646
TI  - Objective and subjective evaluations of twenty-three opera houses in Europe,
      Japan, and the Americas
AB  - The room acoustical parameters, reverberation time RT, early decay time EDT,
      clarity factor C80, bass ratio BR, strength G, interaural cross-correlation
      coefficient IACC, and initial-time-delay gap ITDG [definitions in Hidaka et al.,
      J. Acoust. Soc. Am. 107, 340-354 (2000) and Beranek, Concert and Opera Halls: How
      They Sound (Acoustical Society of America, New York, 1996)], were measured in 23
      major opera houses under unoccupied conditions in 11 countries: Argentina,
      Austria, Czech, France, England, Germany, Hungary, Italy, Japan, The Netherlands,
      and the USA. Questionnaires containing rating scales on the acoustical quality of
      24 opera houses were mailed to 67 conductors, 22 of whom responded. The objective
      measurements were analyzed for reliability and orthogonality, and were related to
      the subjective responses. Presented are (a) the rankings of 21 opera houses each
      rated by at least 6 conductors for acoustical quality as heard by them both in
      the audience areas and in the pit; (b) relations between objective room
      acoustical parameters and subjective ratings; (c) findings of the most important
      of the parameters for determining acoustical quality: RT (or EDT), G(M), ITDG, [1
      - IACC(E3)], texture (appearance of reflectrograms in the first 80-100 ms after
      arrival of the direct sound), a lower limiting value for BR, and major concern
      for diffusion and avoidance of destructive characteristics (noise, vibration,
      echoes, focusing, etc.); (d) the differences between average audience levels with
      and without enclosed stage sets; and (e) the differences between average levels
      in audience areas for sounds from the stage and from the pit.

PMID- 10641647
TI  - Adaptive eigenvalue decomposition algorithm for passive acoustic source
      localization
AB  - To find the position of an acoustic source in a room, the relative delay between
      two (or more) microphone signals for the direct sound must be determined. The
      generalized cross-correlation method is the most popular technique to do so and
      is well explained in a landmark paper by Knapp and Carter. In this paper, a new
      approach is proposed that is based on eigenvalue decomposition. Indeed, the
      eigenvector corresponding to the minimum eigenvalue of the covariance matrix of
      the microphone signals contains the impulse responses between the source and the
      microphone signals (and therefore all the information we need for time delay
      estimation). In experiments, the proposed algorithm performs well and is very
      accurate.

PMID- 10641648
TI  - Nearfield broadband array design using a radially invariant modal expansion
AB  - This paper introduces an efficient parameterization for the nearfield broadband
      beamforming problem with a single parameter to focus the beamformer to a desired
      operating radius and another set of parameters to control the actual broadband
      beampattern shape. The parameterization is based on an orthogonal basis set of
      elementary beampatterns by which an arbitrary beampattern can be constructed. A
      set of elementary beamformers are then designed for each elementary beampattern
      and the desired beamformer is constructed by summing the elementary beamformers
      with frequency and source-array distance dependent weights. An important
      consequence of our result is that the beamformer can be factored into three
      levels of filtering: (i) beampattern independent elementary beamformers; (ii)
      beampattern shape dependent filters; and (iii) radial focusing filters where a
      single parameter can be adjusted to focus the array to a desired radial distance
      from the array origin. As an illustration the method is applied to the problem of
      producing a practical array design that achieves a frequency invariant
      beampattern over the frequency range of 1:10 (which is suitable for speech
      acquisition using a microphone array), and with the array focused either to
      farfield or nearfield where at the lowest frequency the radial distance to the
      source is only three wavelengths.

PMID- 10641649
TI  - Inverse problem of the wave equation and the Schwinger approximation
AB  - A new method of profile inversion for acoustic waves propagating in a medium with
      spherical inhomogeneity based on the Schwinger variational method is presented.
      The wave equation of interest is transformed into a Schrodinger equation, so that
      the Born approximation and the new method could also be applied at high
      frequencies. It is shown that the new method is stable and is more accurate than
      the Born approximation. To illustrate the method, an exactly solvable analytical
      example is presented. Also numerical examples using synthetic data, with and
      without additive noise, are given and the corresponding inversion results and the
      stability of the method are studied.

PMID- 10641650
TI  - Correlated cortical populations can enhance sound localization performance.
AB  - Neurons within cortical populations often evidence some degree of response
      correlation. Correlation has generally been regarded as detrimental to the
      decoding performance of a theoretical vector-averaging observer making inferences
      about the physical world-for example, an observer estimating the location of a
      sound source. However, if an alternative decoder is considered, in this case a
      Maximum Likelihood estimator, performance can improve when responses in the
      population are correlated. Improvement in sound localization performance is
      demonstrated analytically using Fisher information, and is also shown using Monte
      Carlo simulations based on recordings from single neurons in cat primary auditory
      cortex.

PMID- 10641651
TI  - Vibration characteristics of bone conducted sound in vitro.
AB  - A dry skull added with damping material was used to investigate the vibratory
      pattern of bone conducted sound. Three orthogonal vibration responses of the
      cochleae were measured, by means of miniature accelerometers, in the frequency
      range 0.1-10 kHz. The exciter was attached to the temporal, parietal, and frontal
      bones, one at the time. In the transmission response to the ipsilateral cochlea,
      a profound low frequency antiresonance (attenuation) was found, verified psycho
      acoustically, and shown to yield a distinct lateralization effect. It was also
      shown that, for the ipsilateral side, the direction of excitation coincides with
      that of maximum response. At the contralateral cochlea, no such dominating
      response direction was found for frequencies above the first skull resonance. An
      overall higher response level was achieved, for the total energy transmission in
      general and specifically for the direction of excitation, at the ipsilateral
      cochlea when the transducer was attached to the excitation point closest to the
      cochlea. The transranial attenuation was found to be frequency dependent, with
      values from -5 to 10 dB for the energy transmission and -30 to 40 dB for
      measurements in a single direction, with a tendency toward higher attenuation at
      the higher frequencies.

PMID- 10641652
TI  - A performance adequate computational model for auditory localization.
AB  - A computational model of auditory localization resulting in performance similar
      to humans is reported. The model incorporates both the monaural and binaural cues
      available to a human for sound localization. Essential elements used in the
      simulation of the processes of auditory cue generation and encoding by the
      nervous system include measured head-related transfer functions (HRTFs), minimum
      audible field (MAF), and the Patterson-Holdsworth cochlear model. A two-layer
      feed-forward back-propagation artificial neural network (ANN) was trained to
      transform the localization cues to a two-dimensional map that gives the direction
      of the sound source. The model results were compared with (i) the localization
      performance of the human listener who provided the HRTFs for the model and (ii)
      the localization performance of a group of 19 other human listeners. The
      localization accuracy and front-back confusion error rates exhibited by the model
      were similar to both the single listener and the group results. This suggests
      that the simulation of the cue generation and extraction processes as well as the
      model parameters were reasonable approximations to the overall biological
      processes. The amplitude resolution of the monaural spectral cues was varied and
      the influence on the model's performance was determined. The model with 128
      cochlear channels required an amplitude resolution of approximately 20 discrete
      levels for encoding the spectral cue to deliver similar localization performance
      to the group of human listeners.

PMID- 10641653
TI  - Distortion product otoacoustic emission (2f1-f2) amplitude growth in human adults
      and neonates.
AB  - Distortion product otoacoustic emissions (DPOAEs) are thought to be by-products
      of an active amplification process in the cochlea and thus serve as a metric for
      evaluating the integrity of this process. Because the cochlear amplifier
      functions in a level-dependent fashion, DPOAEs recorded as a function of stimulus
      level (i.e., a DPOAE growth function) may provide important information about the
      range and operational characteristics of the cochlear amplifier. The DPOAE growth
      functions recorded in human adults and neonates may provide information about the
      maturation of these active cochlear processes. Two experiments were conducted.
      Experiment I included normal-hearing adults and term-born neonates. The 2f1-f2
      DPOAE growth functions were recorded for both age groups at three f2 frequencies.
      Experiment II was an extension of the first experiment but added a subject group
      of premature neonates. The results of these studies indicate that DPOAE growth
      functions most often show amplitude saturation and nonmonotonic growth for all
      age groups. However, premature neonates show monotonic growth and the absence of
      amplitude saturation more often than adults. Those premature neonates who do show
      saturation also show an elevated threshold for amplitude saturation relative to
      adults. In contrast, term neonates are adultlike for most measures except that
      they show a larger percentage of nonsaturating growth functions than adults.
      These results may indicate immaturity in cochlear amplifier function prior to
      term birth in humans. Outer hair cell function and/or efferent regulation of
      outer hair cell function are hypothesized sources of this immaturity, although
      some contribution from the immature middle ear cannot be ruled out.

PMID- 10641654
TI  - Indications of different distortion product otoacoustic emission mechanisms from
      a detailed f1,f2 area study.
AB  - The primary site of generation on the basilar membrane for the 2f1-f2 distortion
      product (DP) is generally considered to be near where the higher-frequency
      stimulus tone peaks. This site has also been shown to be a source of DP
      otoacoustic emission (DPOAE) in the ear canal, but a second source of emission is
      known to exist in the region of the DP frequency place. The DPOAE phase versus
      frequency gradient provides a means of investigating the emission mechanisms.
      "Wave-fixed" and "place-fixed" mechanisms have been proposed to account for the
      very different phase gradients found depending on whether the 2f1-f2 DPOAE is
      evoked by a small or large stimulus-frequency ratio. DPOAE phase versus frequency
      gradients can be investigated either by sweeping f1,f2 or by sweeping both
      frequencies maintaining a constant frequency ratio. Each manipulation gives only
      a partial description of DP behavior. In this study, the place-fixed/ wave-fixed
      dichotomy is analyzed using extensive 2f1-f2 and 2f2-f1 DP stimulus-frequency
      sweep data presented on matrices of f1 vs f2 and f2/f1 ratio versus DP frequency.
      These show how the DPs are related and provide a more complete picture of 2 f1-f2
      and 2f2-f1 DPOAE phase and amplitude versus frequency behavior. The phase data
      contain evidence for a systematic variation in the proportions of wave- and place
      fixed emission. The results suggest that 2f1-f2 DPOAEs with a wide stimulus
      frequency ratio are wave fixed, while all other DPOAEs are place fixed. A
      transition occurs within the 2 f1-f2 DP data region at a frequency ratio of about
      f2/f1 = 1.1. The 2f1-f2 DP and 2 f2-f1 DP phase behavior is continuous across the
      f2/f1 = 1 boundary. As the 2 f2-f1 DP generation region must be strongly
      influenced by the DP frequency place, the results imply that the place-fixed
      component of the 2 f1-f2 DP is also linked to its frequency place. A similar
      pattern was obtained with the 3f1-2f2 and 3f2-2f1 DPs. The results support the
      following model: For the limited set of stimulus conditions that gives rise to 2
      f1-f2 wave-fixed emissions, DP energy is largely generated in the f2 region and
      is emitted directly. All other DPOAEs are place-fixed emissions, and while
      nonlinearity within the f2 stimulus envelope remains the generator, the DP is not
      directly emitted but travels apically until it is re-emitted basally via a
      separate reflection mechanism in the region of the DP place.

PMID- 10641655
TI  - Three-dimensional numerical modeling for global cochlear dynamics.
AB  - A hybrid analytical-numerical model using Galerkin approximation to variational
      equations has been developed for predicting global cochlear responses. The
      formulation provides a flexible framework capable of incorporating
      morphologically based mechanical models of the cochlear partition and realistic
      geometry. The framework is applied for a simplified model with an emphasis on
      application of hybrid methods for three-dimensional modeling. The resulting
      formulation is modular, where matrices representing fluid and cochlear partition
      are constructed independently. Computational cost is reduced using two methods, a
      modal-finite-element method and a boundary element-finite-element method. The
      first uses a cross-mode expansion of fluid pressure (2.5D model) and the second
      uses a waveguide Green's-function-based boundary element method (BEM). A novel
      wave number approach to the boundary element formulation for interior problem
      results in efficient computation of the finite-element matrix. For the two
      methods a convergence study is undertaken using a simplified passive structural
      model of cochlear partition. It is shown that basilar membrane velocity close to
      best place is influenced by fluid and structural discretization. Cochlear duct
      pressure fields are also shown demonstrating the 3D nature of pressure near best
      place.

PMID- 10641656
TI  - Neural responses to the onset of voicing are unrelated to other measures of
      temporal resolution.
AB  - Voice onset time (VOT) is a temporal cue that can distinguish consonants such as
      /d/ from /t/. It has previously been shown that neurons' responses to the onset
      of voicing are strongly dependent on their static spectral sensitivity. This
      study examined the relation between temporal resolution, determined from
      responses to sinusoidally amplitude-modulated (SAM) tones, and responses to
      syllables with different VOTs. Responses to syllables and SAM tones were obtained
      from low-frequency neurons in the inferior colliculus (IC) of the chinchilla. VOT
      and modulation period varied from 10 to 70 ms in 10-ms steps, and discharge rates
      elicited by stimuli whose amplitude envelopes were modulated over the same
      temporal interval were compared. Neurons that respond preferentially to syllables
      with particular VOTs might be expected to respond best to the SAM tones with
      comparable modulation periods. However, no consistent agreement between responses
      to VOT syllables and to SAM tones was obtained. These results confirm the
      previous suggestion that IC neurons' selectivity for VOT is determined by
      spectral rather than temporal sensitivity.

PMID- 10641657
TI  - Vestibular responses to loud dance music: a physiological basis of the "rock and
      roll threshold"?
AB  - In this paper new evidence is provided to indicate that vestibular responses may
      be obtained from loud dance music for intensities above 90 dB(A) SPL (Impulse
      weighted). In a sample of ten subjects acoustically evoked EMG were obtained from
      the sternocleidomastoid muscle in response to a sample of techno music typical of
      that which may be experienced in a dance club. Previous research has shown that
      this response is vestibularly mediated since it can be obtained in subjects with
      loss of cochlear function, but is absent in subjects with loss of vestibular
      function (Colebatch et al. [J. Neurol. Neurosurg. Psychiatr. 57, 190-197 (1994)].
      Given that pleasurable sensations of self-motion are widely sought after by more
      normal means of vestibular stimulation, it is suggested that acoustically evoked
      sensations of self-motion may account for the compulsion to exposure to loud
      music. Given further the similarity between the thresholds found, and the
      intensities and frequency distributions that are typical in rock concerts and
      dance clubs, it is also suggested that this response may be a physiological basis
      for the minimum loudness necessary for rock and dance music to work-the "rock and
      roll threshold".

PMID- 10641658
TI  - Basilar-membrane nonlinearity estimated by pulsation threshold.
AB  - The pulsation threshold technique was used to estimate the basilar-membrane (BM)
      response to a tone at characteristic frequency (CF). A pure-tone signal was
      alternated with a pure-tone masker. The frequency of the masker was 0.6 times
      that of the signal. For signal levels from around 20 dB above absolute threshold
      to 85 dB SPL, the masker level was varied to find the level at which a transition
      occurred between the signal being perceived as "pulsed" or "continuous" (the
      pulsation threshold). The transition is assumed to occur when the masker
      excitation is somewhat greater than the signal excitation at the place on the BM
      tuned to the signal. If it is assumed further that the response at this place to
      the lower-frequency masker is linear, then the shape of the masking function
      provides an estimate of the BM response to the signal. Signal frequencies of
      0.25, 0.5, 1, 2, 4, and 8 kHz were tested. The mean slopes of the masking
      functions for signal levels between 50 and 80 dB SPL were 0.76, 0.50, 0.34, 0.32,
      0.35, and 0.41, respectively. The results suggest that compression on the BM
      increases between CFs of 0.25 and 1 kHz and is roughly constant for frequencies
      of 1 kHz and above. Despite requiring a subjective criterion, the pulsation
      threshold measurements had a reasonably low variability. However, the estimated
      compression was less than in an earlier study using forward masking. The smaller
      amount of compression observed here may be due to the effects of off-frequency
      listening.

PMID- 10641659
TI  - Perceptual salience of individually distinctive features in the calls of adult
      king penguins.
AB  - In the king penguin, Aptenodytes patagonicus, incubation and brooding duties are
      undertaken alternately by both partners of a pair. Birds returning from foraging
      at sea find their mate in the crowded colony using acoustic signals. Acoustic
      recognition of the mate maintains and strengthens the mate's fidelity and favors
      synchronization in the different stages of reproduction. In this study it was
      found that the king penguin vocalizes in response to the mate's playback calls,
      but not to those of neighbors or unfamiliar conspecific individuals. To study
      individual features used by the birds for individual recognition of mates,
      various experimental signals consisting of synthesized modifications of the mate'
      s call were played back to the incubating bird. Results indicated that birds
      attend to the FM profile of the call, in particular its initial inflexion. The
      frequency modulation shape of the syllable can be assimilated to a vocal
      signature repeated though the different syllables of the call. King penguins pay
      little attention to the call' s AM envelope or its absolute frequency.

PMID- 10641660
TI  - Binaural sluggishness in the perception of tone sequences and speech in noise.
AB  - The binaural system is well-known for its sluggish response to changes in the
      interaural parameters to which it is sensitive. Theories of binaural unmasking
      have suggested that detection of signals in noise is mediated by detection of
      differences in interaural correlation. If these theories are correct,
      improvements in the intelligibility of speech in favorable binaural conditions is
      most likely mediated by spectro-temporal variations in interaural correlation of
      the stimulus which mirror the spectro-temporal amplitude modulations of the
      speech. However, binaural sluggishness should limit the temporal resolution of
      the representation of speech recovered by this means. The present study tested
      this prediction in two ways. First, listeners' masked discrimination thresholds
      for ascending vs descending pure-tone arpeggios were measured as a function of
      rate of frequency change in the NoSo and NoSpi binaural configurations. Three
      tone arpeggios were presented repeatedly and continuously for 1.6 s, masked by a
      1.6-s burst of noise. In a two-interval task, listeners determined the interval
      in which the arpeggios were ascending. The results showed a binaural advantage of
      12-14 dB for NoSpi at 3.3 arpeggios per s (arp/s), which reduced to 3-5 dB at
      10.4 arp/s. This outcome confirmed that the discrimination of spectro-temporal
      patterns in noise is susceptible to the effects of binaural sluggishness. Second,
      listeners' masked speech-reception thresholds were measured in speech-shaped
      noise using speech which was 1, 1.5, and 2 times the original articulation rate.
      The articulation rate was increased using a phase-vocoder technique which
      increased all the modulation frequencies in the speech without altering its
      pitch. Speech-reception thresholds were, on average, 5.2 dB lower for the NoSpi
      than for the NoSo configuration, at the original articulation rate. This binaural
      masking release was reduced to 2.8 dB when the articulation rate was doubled, but
      the most notable effect was a 6-8 dB increase in thresholds with articulation
      rate for both configurations. These results suggest that higher modulation
      frequencies in masked signals cannot be temporally resolved by the binaural
      system, but that the useful modulation frequencies in speech are sufficiently low
      (<5 Hz) that they are invulnerable to the effects of binaural sluggishness, even
      at elevated articulation rates.

PMID- 10641661
TI  - Fidelity of three-dimensional-sound reproduction using a virtual auditory
      display.
AB  - The fidelity of reproducing free-field sounds using a virtual auditory display
      was investigated in two experiments. In the first experiment, listeners directly
      compared stimuli from an actual loudspeaker in the free field with those from
      small headphones placed in front of the ears. Headphone stimuli were filtered
      using head-related transfer functions (HRTFs), recorded while listeners were
      wearing the headphones, in order to reproduce the pressure signatures of the free
      field sounds at the eardrum. Discriminability was investigated for six sound
      source positions using broadband noise as a stimulus. The results show that the
      acoustic percepts of real and virtual sounds were identical. In the second
      experiment, discrimination between virtual sounds generated with measured and
      interpolated HRTFs was investigated. Interpolation was performed using HRTFs
      measured for loudspeaker positions with different spatial resolutions. Broadband
      noise bursts with flat and scrambled spectra were used as stimuli. The results
      indicate that, for a spatial resolution of about 6 degrees, the interpolation
      does not introduce audible cues. For resolutions of 20 degrees or more, the
      interpolation introduces audible cues related to timbre and position. For
      intermediate resolutions (10 degrees - 15 degrees) the data suggest that only
      timbre cues were used.

PMID- 10641662
TI  - Use of context by young and aged adults with normal hearing.
AB  - Word recognition in sentences with and without context was measured in young and
      aged subjects with normal but not identical audiograms. Benefit derived from
      context by older adults has been obscured, in part, by the confounding effect of
      even mildly elevated thresholds, especially as listening conditions vary in
      difficulty. This problem was addressed here by precisely controlling signal-to
      noise ratio across conditions and by accounting for individual differences in
      signal-to-noise ratio. Pure-tone thresholds and word recognition were measured in
      quiet and threshold-shaped maskers that shifted quiet thresholds by 20 and 40 dB.
      Word recognition was measured at several speech levels in each condition.
      Threshold was defined as the speech level (or signal-to-noise ratio)
      corresponding to the 50 rau point on the psychometric function. As expected,
      thresholds and slopes of psychometric functions were different for sentences with
      context compared to those for sentences without context. These differences were
      equivalent for young and aged subjects. Individual differences in word
      recognition among all subjects, young and aged, were accounted for by individual
      differences in signal-to-noise ratio. With signal-to-noise ratio held constant,
      word recognition for all subjects remained constant or decreased only slightly as
      speech and noise levels increased. These results suggest that, given equivalent
      speech audibility, older and younger listeners derive equivalent benefit from
      context.

PMID- 10641663
TI  - Pitch estimation by early-deafened subjects using a multiple-electrode cochlear
      implant.
AB  - Numerical estimates of pitch for stimulation of electrodes along the 22-electrode
      array of the Cochlear Limited cochlear implant were obtained from 18 subjects who
      became deaf very early in life. Examined were the relationships between subject
      differences in pitch estimation, subject variables related to auditory
      deprivation and experience, and speech-perception scores for closed-set
      monosyllabic words and open-set Bamford-Kowal-Bench (BKB) sentences. Reliability
      in the estimation procedure was examined by comparing subject performance in
      pitch estimation with that for loudness estimation for current levels between
      hearing threshold and comfortable listening level. For 56% of subjects, a
      tonotopic order of pitch percepts for electrodes on the array was found. A
      deviant but reliable order of pitch percepts was found for 22% of subjects, and
      essentially no pitch order was found for the remaining 22% of subjects. Subject
      differences in pitch estimation were significantly related to the duration of
      auditory deprivation prior to implantation, with the poorest performance for
      subjects who had a longer duration of deafness and a later age at implantation.
      Subjects with no tonotopic order of pitch percepts had the lowest scores for the
      BKB sentence test, but there were no differences across subjects for monosyllabic
      words. Performance in pitch estimation for electrodes did not appear to be
      related to performance in the estimation procedure, as all subjects were
      successful in loudness estimation for current level.

PMID- 10641664
TI  - Effects of pitch-shift velocity on voice Fo responses.
AB  - Previous studies have shown that voice fundamental frequency (F0) is modified by
      changes in the pitch of vocal feedback and have demonstrated that the audio-vocal
      control system has both open- and closed-loop control properties. However, the
      extent to which this system operates in closed-loop fashion may have been
      underestimated in previous work. Because the step-type stimuli used were very
      rapid, and people are physically unable to change their voice F0 as rapidly as
      the stimuli, feedback responses might have been reduced or suppressed. In the
      present study, pitch-shift stimuli, consisting of a disparity between voice F0
      and feedback pitch of varying ramp onset velocities, were presented to subjects
      vocalizing a steady /ah/ sound to examine the effect of stimulus onset on voice
      F0 responses. Results showed that response velocity covaried with stimulus
      velocity. Response latency and time of the peak response decreased with increases
      in stimulus velocity, while response magnitude decreased. A simple feedback model
      reproduced most features of these responses. These results strongly support
      previous suggestions that the audio-vocal system monitors auditory feedback and,
      through closed-loop negative feedback, adjusts voice F0 so as to cancel low-level
      fluctuations in F0.

PMID- 10641665
TI  - Viscoelastic shear properties of human vocal fold mucosa: theoretical
      characterization based on constitutive modeling.
AB  - The viscoelastic shear properties of human vocal fold mucosa (cover) were
      previously measured as a function of frequency [Chan and Titze, J. Acoust. Soc.
      Am. 106, 2008-2021 (1999)], but data were obtained only in a frequency range of
      0.01-15 Hz, an order of magnitude below typical frequencies of vocal fold
      oscillation (on the order of 100 Hz). This study represents an attempt to
      extrapolate the data to higher frequencies based on two viscoelastic theories,
      (1) a quasilinear viscoelastic theory widely used for the constitutive modeling
      of the viscoelastic properties of biological tissues [Fung, Biomechanics
      (Springer-Verlag, New York, 1993), pp. 277-292], and (2) a molecular (statistical
      network) theory commonly used for the rheological modeling of polymeric materials
      [Zhu et al., J. Biomech. 24, 1007-1018 (1991)]. Analytical expressions of elastic
      and viscous shear moduli, dynamic viscosity, and damping ratio based on the two
      theories with specific model parameters were applied to curve-fit the empirical
      data. Results showed that the theoretical predictions matched the empirical data
      reasonably well, allowing for parametric descriptions of the data and their
      extrapolations to frequencies of phonation.

PMID- 10641666
TI  - Comparison between electroglottography and electromagnetic glottography.
AB  - Newly developed glottographic sensors, utilizing high-frequency propagating
      electromagnetic waves, were compared to a well-established electroglottographic
      device. The comparison was made on four male subjects under different phonation
      conditions, including three levels of vocal fold adduction (normal, breathy, and
      pressed), three different registers (falsetto, chest, and fry), and two different
      pitches. Agreement between the sensors was always found for the glottal closure
      event, but for the general wave shape the agreement was better for falsetto and
      breathy voice than for pressed voice and vocal fry. Differences are attributed to
      the field patterns of the devices. Whereas the electroglottographic device can
      operate only in a conduction mode, the electromagnetic device can operate in
      either the forward scattering (diffraction) mode or in the backward scattering
      (reflection) mode. Results of our tests favor the diffraction mode because a more
      favorable angle imposed on receiving the scattered (reflected) signal did not
      improve the signal strength. Several observations are made on the uses of the
      electromagnetic sensors for operation without skin contact and possibly in an
      array configuration for improved spatial resolution within the glottis.

PMID- 10641667
TI  - Effect of stimulation rate on phoneme recognition by nucleus-22 cochlear implant
      listeners.
AB  - This study investigated the effect of pulsatile stimulation rate on medial vowel
      and consonant recognition in cochlear implant listeners. Experiment 1 measured
      phoneme recognition as a function of stimulation rate in six Nucleus-22 cochlear
      implant listeners using an experimental four-channel continuous interleaved
      sampler (CIS) speech processing strategy. Results showed that all stimulation
      rates from 150 to 500 pulses/s/electrode produced equally good performance, while
      stimulation rates lower than 150 pulses/s/electrode produced significantly poorer
      performance. Experiment 2 measured phoneme recognition by implant listeners and
      normal-hearing listeners as a function of the low-pass cutoff frequency for
      envelope information. Results from both acoustic and electric hearing showed no
      significant difference in performance for all cutoff frequencies higher than 20
      Hz. Both vowel and consonant scores dropped significantly when the cutoff
      frequency was reduced from 20 Hz to 2 Hz. The results of these two experiments
      suggest that temporal envelope information can be conveyed by relatively low
      stimulation rates. The pattern of results for both electrical and acoustic
      hearing is consistent with a simple model of temporal integration with an
      equivalent rectangular duration (ERD) of the temporal integrator of about 7 ms.

PMID- 10641668
TI  - The time-frequency characteristics of violin vibrato: modal distribution analysis
      and synthesis
AB  - A high-resolution time-frequency distribution, the modal distribution, is applied
      to the study of violin vibrato. The analysis indicates that the frequency
      modulation induced by the motion of the stopped finger on the string is
      accompanied by a significant amplitude variation in each partial of that note.
      Amplitude and frequency estimates for each partial are extracted from the modal
      distribution of ten pitches that span the range of the violin instrument. The
      frequency modulation is well-represented by a single sinusoid with a mean rate of
      5.9 Hz and a mean excursion of +/- 15.2 cents. A spectral decomposition of the
      amplitude envelopes of the partials shows that the peaks lie primarily at integer
      multiples of the vibrato rate. These amplitude and frequency estimates are used
      in an additive synthesis model to generate synthetic replicates of violin
      vibrato. Simple approximations to these estimates are created, and synthesized
      sounds using these are evaluated perceptually by seven subjects using
      discrimination, nonmetric multidimensional scaling (MDS), and sound quality
      scoring tasks. It is found that the absence of frequency modulation has little
      effect on the perceptual response to violin vibrato, while the absence of
      amplitude modulation causes marked changes in both sound quality and MDS results.
      Low-order spectral decompositions of the amplitude and frequency estimates also
      occupy the same perceptual space as the original recording for a subset of the
      pitches studied.

PMID- 10641669
TI  - The extracellular matrix is an important source of ultrasound backscatter from
      myocardium.
AB  - Ultrasound tissue characterization with measurement of backscatter has been
      employed in numerous experimental and clinical studies of cardiac pathology, yet
      the cellular components responsible for scattering from cardiac tissues have not
      been unequivocally identified. This laboratory has proposed a mathematical model
      for myocardial backscatter that postulates the fibrous extracellular matrix (ECM)
      as a significant determinant of backscatter. To demonstrate the importance of
      ECM, this group sought to determine whether measurements of backscatter from the
      isolated ECM could reproduce the known directional dependence, or anisotropy of
      backscatter, from intact cardiac tissues in vitro. Segments of left ventricular
      free wall from ten formalin fixed porcine hearts were insonified at 50 MHz,
      traversing the heart wall from endo- to epicardium to measure the anisotropy of
      myocardial backscatter, defined as the difference between peak (perpendicular to
      fibers) and trough (parallel to fibers) backscatter amplitude. The tissue
      segments were then treated with 10% NaOH to dissolve all of the cellular
      components, leaving only the intact ECM. Scanning electron micrographs (SEM) were
      obtained of tissue sections to reveal complete digestion of the cellular
      elements. The dimensions of the residual voids resulting from cell digestion were
      approximately the diameter of the intact myocytes (10-30 microm). These samples
      were reinsonified after seven days of treatment to compare the anisotropy of
      integrated backscatter. The magnitude of anisotropy of backscatter changed from
      15.4 +/- 0.8 to 12.6 +/- 1.1dB for intact as compared with digested specimens.
      Because digestion of the myocardium leaves only extracellular sources of
      ultrasonic scattering, and because the isolated ECM exhibits similar ultrasonic
      anisotropy as does the intact myocardium, it is concluded that there is a direct
      association between the ECM and the anisotropy of backscatter within intact
      tissue. Thus, it is suggested that ultrasonic tissue characterization represents
      a potentially clinically applicable method for delineating the structure and
      function of the ECM.

PMID- 10641670
TI  - Difference thresholds for intensity perception of whole-body vertical vibration:
      effect of frequency and magnitude.
AB  - Difference thresholds for seated subjects exposed to whole-body vertical
      sinusoidal vibration have been determined at two vibration magnitudes [0.1 and
      0.5 ms(-2) root mean square (r.m.s.)] and at two frequencies (5 and 20 Hz). For
      12 subjects, difference thresholds were determined using the up-and-down
      transformed response method based on two-interval forced-choice tracking. At both
      frequencies, the difference thresholds increased by a factor of five when the
      magnitude of the vibration increased from 0.1 to 0.5 ms(-2) r.m.s. The median
      relative difference thresholds, Weber fractions (deltaI/I), expressed as
      percentages, were about 10% and did not differ significantly between the two
      vibration magnitudes or the two frequencies. It is concluded that for the
      conditions investigated the difference thresholds for whole-body vibration are
      approximately consistent with Weber's Law. A vibration magnitude will need to be
      reduced by more than about 10% for the change to be detectable by human subjects;
      vibration measurements will be required to detect reductions of less than 10%.

PMID- 10641671
TI  - Range discrimination by big brown bats (Eptesicus fuscus) using altered model
      echoes: implications for signal processing.
AB  - The sonar emissions of two big brown bats (Eptesicus fuscus) were modeled to
      create a "normal" echolocation signal for each bat which was then used as an
      artificial echo to synthesize a phantom target. The bat's task was to indicate
      which of two phantom targets (presented singly) was the "near" target and which
      the "far" target. Threshold range discrimination at a nominal target distance of
      80 cm was about 0.6 cm for both bats. The normal signal was then modified to
      change the relative energy in each harmonic, the signal duration, the curvature
      of the frequency sweep, the absolute frequency, the phase of the second and third
      harmonics relative to the first, or the Doppler shift of the signal. To determine
      which modifications affected ranging performance, the altered models were used in
      tests of range discrimination that were interleaved on a day-to-day basis with
      tests using the normal model. Of the 12 modifications tested, only those changing
      the curvature of the frequency sweep affected performance. This result appears
      not to be predicted by current models of echo processing in FM bats. Eptesicus
      may be able to compensate for certain types of distortions of a returning echo,
      an ability possibly related to Doppler tolerance or to the characteristics of the
      natural variation in a bat's emissions.

PMID- 10641672
TI  - Sperm whale clicks: directionality and source level revisited.
AB  - In sperm whales (Physeter catodon L. 1758) the nose is vastly hypertrophied,
      accounting for about one-third of the length or weight of an adult male. Norris
      and Harvey [in Animal Orientation and Navigation, NASA SP-262 (1972), pp. 397
      417] ascribed a sound-generating function to this organ complex. A sound
      generator weighing upward of 10 tons and with a cross-section of 1 m is expected
      to generate high-intensity, directional sounds. This prediction from the Norris
      and Harvey theory is not supported by published data for sperm whale clicks
      (source levels of 180 dB re 1 microPa and little, if any, directionality). Either
      the theory is not borne out or the data is not representative for the
      capabilities of the sound-generating mechanism. To increase the amount of
      relevant data, a five-hydrophone array, suspended from three platforms separated
      by 1 km and linked by radio, was deployed at the slope of the continental shelf
      off Andenes, Norway, in the summers of 1997 and 1998. With this system, source
      levels up to 223 dB re 1 microPa peRMS were recorded. Also, source level
      differences of 35 dB for the same click at different directions were seen, which
      are interpreted as evidence for high directionality. This implicates sonar as a
      possible function of the clicks. Thus, previously published properties of sperm
      whale clicks underestimate the capabilities of the sound generator and therefore
      cannot falsify the Norris and Harvey theory.

PMID- 10641673
TI  - Source levels and estimated yellowfin tuna (Thunnus albacares) detection ranges
      for dolphin jaw pops, breaches, and tail slaps.
AB  - Tuna fishers in the eastern Pacific Ocean often exploit an association between a
      few genus of dolphin (Stenella and Delphinus) and yellowfin tuna (Thunnus
      albacares) to locate and capture the tuna. Identification of a mechanism which
      facilitates the tuna/dolphin bond may provide a means of exploiting the bond and
      capturing tuna without catching dolphin. To investigate if tuna may be attracted
      to low-frequency sounds produced by dolphins, source levels of bottlenose dolphin
      (Tursiops truncatus) jaw pops, breaches, and tail slaps were experimentally
      measured and used to estimate the maximum range at which yellowfin could detect
      similar sounds produced by pelagic species. The effective acoustic stimulus to
      the tuna was defined as the maximum one-third-octave level between 200 and 800
      Hz, the frequency range where T. albacares is most sensitive. Spherical spreading
      was assumed to predict transmission loss with range. Breaches and jaw pops
      produced maximum one-third-octave source levels between 200 and 800 Hz of 153 (+/
      4) and 163 (+/-2) dB re: 1 microPa-m, respectively, which resulted in estimated
      detection ranges of 340-840 and 660-1040 m, respectively. Tail slaps had lower
      source levels [max. 141 (+/-3) dB re: 1 microPa-m] and a maximum detection range
      of approximately 90-180 m.

PMID- 10641674
TI  - Localized vibration modes in free anisotropic wedges.
AB  - Propagation of flexural localized vibration modes along edges of anisotropic
      wedges is considered in the framework of the geometrical-acoustics approach. Its
      application allows for straightforward evaluation of the wedge-mode velocities in
      the general case of arbitrary elastic anisotropy. The velocities depend on the
      wedge apex angle and on the mode number in the same way as in the isotropic case,
      but there appears to be additional dependence on elastic coefficients. The
      velocities in tetragonal wedges (with the midplane orthogonal to the four-fold
      axis) and in "weakly" monoclinic wedges are explicitly calculated and analyzed.
      Bounds of the wedge-wave velocity variation in tetragonal materials are
      established.

PMID- 10641675
TI  - Displacement of droplets and deformation of thin liquid layers using flexural
      vibrations of structures. Influence of acoustic radiation pressure.
AB  - In this paper observations concerning some effects of vibrating structures on
      fluids are presented, followed by a tentative theoretical analysis. First, a
      brief description of a caterpillar-like structure is made. This structure is
      almost equivalent to an infinite beam which allows the choice of positions of the
      nodal lines of a vibrating mode. Displacement of liquid droplets using switching
      between two modes of this structure is then presented. This phenomenon is
      supposed to be induced by acoustic radiation pressure. Possible extensions of
      this principle are then discussed. After this, results are reported concerning
      deformations of thin liquid layers.

PMID- 10641676
TI  - A principle of least complexity for musical scales.
AB  - The following properties of equally tempered scales are demonstrated in this
      Letter: For N semitones and M notes, each distinct scale (interval) structure can
      be represented by an associated multiplet of N scales. These scales allow
      themselves to be labeled by a set of integers ?c?. Each label c is the difference
      between the number of sharps and flats in a given scale. The equivalence classes
      [c] modulo N form a commutative ring with unity. When the ratio N/M cannot be
      simplified further, then each member of a given multiplet will have a unique
      label (modulo N), different from the other members of the same multiplet. Because
      this labeling depends not on the interval structure of the multiplet but only on
      N and M, different multiplets with the same N and M values will have members
      carrying the same respective labels. Each equally tempered scale (interval)
      structure possesses a property which will be referred to as complexity. This
      Letter proposes a quantitative measure for complexity which distinguishes between
      different scale (interval) structures. For the particular case where N= 12 and
      M=7, out of 462 possible different equally tempered scale structures, those with
      minimum complexity are the major scale and the modes, which suggests a minimum
      principle in music based on equally tempered scales. This simplicity of structure
      allows the practical use of key signatures in music.

PMID- 10641677
TI  - Sperm whales (Physeter catodon L. 1758) do not react to sounds from detonators.
AB  - A number of observations show that sperm whales (Physeter catodon L. 1758) react
      to various man-made pulses with moderate source levels. The behavioral responses
      are described to vary from silence to fear. Click rates of five submerged male
      sperm whales were measured during the discharge of eight detonators off Andenes,
      northern Norway. In addition, the behavioral response of a surfaced specimen was
      observed. Click rates of the submerged whales and the behavior of the surfaced
      specimen did not change during the discharges with received sound levels of some
      180 dB re 1 microPa peRMS. The apparent lack of response to the discharges could
      be due to similarity between sperm whale clicks and detonations. Accordingly, it
      can be speculated that the discharges may have been perceived as isolated clicks
      from conspecifics.

PMID- 10641678
TI  - Scaling of turbulent wall pressure fluctuations downstream of a rearward facing
      step.
AB  - The turbulent boundary layer that forms downstream of a surface discontinuity is
      locally inhomogeneous. Here, we consider the boundary layer that occurs
      downstream of a rearward facing step discontinuity on a flat plate that is
      exposed to a zero incidence, uniform subsonic flow. The wall pressure "point"
      spectra are measured by small, flush-mounted pressure transducers located at
      various locations downstream of the step. A new form of the non-dimensional point
      wall pressure auto-frequency spectrum is proposed that includes the statistical
      variations of the reattachment location. This form is shown to collapse quite
      well all of the spectra measured slightly upstream, within, and downstream of the
      flow reattachment location.

PMID- 10641679
TI  - Publication of abstracts submitted to the annual meeting of the Pediatric
      Orthopaedic Society of North America.
AB  - A computerized MEDLINE search was performed to determine the publication pattern
      of the abstracts submitted for podium presentation at the 1991-1994 annual
      meetings of the Pediatric Orthopaedic Society of North America (POSNA). The
      publication percentage for all papers submitted to the POSNA meetings from 1991
      through 1994 was 45%. Fifty-three percent of papers accepted for podium
      presentation were ultimately published in comparison with 38% of those not
      accepted for presentation (p < 0.001). The mean time to publication was 29 months
      and did not differ significantly for the two groups. The majority of papers (65%)
      were published in either Journal of Pediatric Orthopaedics (48%) or The Journal
      of Bone and Joint Surgery (American) (17%). The frequency of ultimate publication
      of abstracts submitted to the annual POSNA meetings compares favorably with the
      rates for other medical subspecialties.

PMID- 10641680
TI  - Fractures of the proximal radial head and neck in children with emphasis on those
      that involve the articular cartilage.
AB  - This is a review of 116 children who had a fracture of the proximal radial head
      or neck over a 15-year period. Of 33 teenagers with closed physes, 17 (52%) had
      intraarticular involvement. Of 83 younger children with an open proximal radial
      physis, six (7%) had an intraarticular fracture (Salter-Harris type III or IV).
      Of the 17 patients with closed physes and intraarticular fracture, 13 had
      adequate follow-up. There were eight excellent, three good, one fair, and one
      poor results. Of the six children with open physes and intraarticular fracture,
      there were one good and five poor results. This study confirms that
      intraarticular fracture of the radial head is much more common if the proximal
      radial physis is closed. In addition, this review indicates that the prognosis is
      extremely poor for children who have a radial head intraarticular fracture that
      also involves an open physis (Salter-Harris types III and IV), particularly when
      the fracture is treated initially nonoperatively. Displaced proximal radial
      fractures that involve both physeal and articular cartilage may be occult, and as
      with all physeal and intraarticular fractures, anatomic reduction (open if
      necessary) is mandatory.

PMID- 10641681
TI  - Avascular necrosis of the radial head in children.
AB  - Avascular necrosis of the radial head is uncommon. A 20-year review of records at
      a Pediatric Trauma Center revealed eight cases of avascular necrosis of the
      radial head in children with an average of 10 years (range, 7-16 years). Symptoms
      of pain or restriction of elbow motion began at an average of 23 months after
      trauma in seven cases, and in one case, there was no history of trauma. Of the
      seven secondary to trauma, six resulted from a fall, and one from a torsional
      injury. The types of injuries associated with avascular necrosis of the radial
      head were two supracondylar fractures, a fracture of the lateral condyle, two
      fractures of the radius, a radial head dislocation that underwent a proximal
      radial osteotomy, and one with only an elbow contusion. The long-term results of
      radial head necrosis were poor, with three ultimately requiring radial head
      resection, and the remainder having considerable limitation of elbow motion. Loss
      of vascularity to the radial head is very analogous to avascular necrosis of the
      femoral head, with the late onset of incongruity, osteoarthritis, and hypertrophy
      of the head. It should be considered in any child with late-onset loss of elbow
      motion after trauma.

PMID- 10641682
TI  - Effect of delay of surgical treatment on rate of infection in open fractures in
      children.
AB  - This study reviews all open fractures treated at a tertiary children's hospital
      from 1990 to 1995 to determine whether delaying surgical debridement influences
      the rate of infection in the pediatric population. One hundred four open
      fractures were followed until both clinical and radiographic union was evident. A
      1.0% rate of infection requiring surgical drainage, and a 1.0% rate of soft
      tissue infection managed with oral antibiotics alone was found. Infection rates
      for fractures treated within 6 h of injury was 2.5%, and for fractures treated
      with >6 h delay was 1.6%. No significant statistical difference in infection rate
      with delay in surgical debridement was found (p = 0.77). Delays of 5 and 16 h
      were found in the two fractures complicated by infection, compared with an
      average delay of 12 h for those that healed uneventfully. Our findings suggest
      that in children given early parenteral antibiotics, operative irrigation and
      debridement may be delayed >6 h without an increased risk of infection. As this
      series contains only 18 patients with grade III open fractures and nine patients
      whose surgery was delayed >24 h, conclusions should not be made in these groups.

PMID- 10641683
TI  - Flexible stable intramedullary pinning technique in the treatment of pediatric
      fractures.
AB  - We report our 12 years' experience with the treatment of 308 fractures of the
      long bones in children using the flexible stable intramedullary pinning technique
      (FSIMP). This technique is a simple, rapid, and reliable procedure with minimal
      complications. It assures correct reposition and sufficient stable fixation of
      fragments, needs only small incisions, and most of all, allowed early
      mobilization of a child, thus avoiding long hospitalization and permitting his
      rapid normal activity and return to the school. The results are very encouraging
      for children up to age 5 years. The age limit is caused by the volume of the
      intramedullary space.

PMID- 10641684
TI  - Quantitative assessment with SPECT imaging of stress injuries of the pars
      interarticularis and response to bracing.
AB  - The evaluation and management of acute spondylolysis remains unclear in part
      because of outcome data that are primarily subjective. The aim of this study was
      to evaluate and monitor these patients objectively using quantitative single
      photon emission computed tomography (SPECT). Thirty-four patients were so
      observed clinically between 1987 and 1996 and were studied with an initial and at
      least one follow-up SPECT scintigram. Initial radiographs and planar bone scans
      failed to demonstrate the pars lesion in 53 and 19% of the patients,
      respectively. The average SPECT ratio before brace treatment was 1.45. After
      treatment, this ratio significantly decreased to 1.27 (p = 0.03). A subset of
      patients remained symptomatic at follow-up. Their reduction in SPECT ratio
      averaged only 2.8% as compared with 13% for the remainder of the patients (p =
      0.01). Patients diagnosed and braced in the early, more active stage of the
      condition (with greater intensity on SPECT) had more predictable symptom relief.
      An initial SPECT ratio of >1.5 was associated with complete symptom resolution
      after brace treatment. Patients treated with activity restriction only (>3
      months) before bracing were more likely to have persistent symptoms and more
      modest improvement on SPECT (p = 0.01). These data, which use SPECT scintigraphy,
      support prompt treatment with brace immobilization for acute spondylolysis in
      children and adolescents.

PMID- 10641685
TI  - Pediatric hand injuries due to home exercycles.
AB  - The clinical presentation and management of 19 children who sustained injuries by
      stationary exercise bicycles were reviewed retrospectively. These injuries
      represented 32 traumatized digits with a minimum of 2-year follow-up. The index
      and long fingers were most commonly involved. Wheel-spoke injuries typically
      produced repairable nerve and tendon lacerations, and full functional recovery in
      these cases was common. The chain/sprocket injury involved a crushing mechanism
      and frequently produced severe injury including amputations that were not
      salvageable. Stationary exercise bicycles represented a predictable source of
      severe hand injury in children between the ages of 18 months and 5 years. Adult
      supervision was not reliable in preventing contact between an operating exercycle
      and a child's hand. We recommend that children not be allowed access to any
      stationary exercycle machinery, whether it is in use or not. Safety design
      considerations should focus on not only shielding the wheel spokes, but also (and
      perhaps even more important) on enclosing the entire chain axis and gear
      interface. In addition to these design considerations, public education will be
      critical in reducing the incidence of injury.

PMID- 10641686
TI  - The incidence of joint involvement with adjacent osteomyelitis in pediatric
      patients.
AB  - Sixty-six patients admitted to our institution over an 8-year period with the
      diagnosis of osteomyelitis were analyzed to determine the incidence of adjacent
      joint involvement. Patients with osteomyelitis of the hand, foot, spine, and
      extraarticular pelvis were excluded from this study. The average age was 5.8
      years (range, 1 month to 17 years). Forty-two percent of our patients who had
      osteomyelitis had evidence of adjacent joint involvement (either septic or
      nonseptic). One third of our patients had evidence of septic joint involvement.
      The most commonly involved joint was the knee. There was no difference in the
      incidence of adjacent joint involvement in those patients who were younger than
      18 months compared with the incidence in older children. Our study suggests that
      the incidence of adjacent joint involvement in children who have osteomyelitis is
      higher than that suggested in the literature. We believe that careful evaluation
      of the adjacent joint should be an important part of the evaluation of any child
      who has osteomyelitis.

PMID- 10641687
TI  - A shortened course of parenteral antibiotic therapy in the management of acute
      septic arthritis of the hip.
AB  - We reviewed 20 consecutive patients with a culture-proven acute septic arthritis
      of the hip who were treated with a shortened course of parenteral antibiotic
      therapy after a surgical drainage. Patients were switched over to an oral
      antibiotic when they showed clinical improvement. Sixteen of the 20 patients had
      parenteral antibiotic therapy of <10 days, whereas nine of these patients
      received <7 days of parenteral therapy (mean, 8.2 days). No recurrence of
      infection, readmission, or osteomyelitis was observed after the discharge. At the
      follow-up interview (mean, 32 months), 18 patients were completely asymptomatic,
      and two patients had occasional hip pain with activity but no physical
      limitations. All 20 patients had normal hip range of motion and gait. Their
      latest radiographs (mean, 26 months) revealed 11 patients with normal findings,
      six patients with mild coxa magna, and three patients with a smaller ossific
      nucleus compared with the unaffected side. We conclude that a community-acquired,
      acute gram-positive septic arthritis of the hip can be managed safely with a
      surgical drainage and a shortened course of parenteral antibiotic therapy, which
      can be switched over to an oral therapy based on the patient's response to the
      therapy.

PMID- 10641688
TI  - Cervical spine in diastrophic dysplasia: an MRI analysis.
AB  - In this cross-sectional study, we evaluated the cervical spine in patients with
      diastrophic dysplasia (DD) by using magnetic resonance imaging (MRI). From 90 (57
      female, 33 male) patients of different ages (0.3-56.0 years), T1- and T2-weighted
      images were obtained. The craniocervical junction and status of the medulla were
      examined, and the transverse areas of dural tube and medulla were measured.
      Alignment of the cervical spine, vertebral abnormalities, and disc changes also
      were evaluated. The cervical spinal canal was moderately narrowed, particularly
      in adults. The transverse areas of the medulla and especially of the dural tube
      were smaller compared with a normal population (p < 0.0001). There was no
      stenosis of the foramen magnum in patients with DD, but the spinal canal was
      narrowed. Degenerative changes were common. In all age groups, intervertebral
      discs were dark and disc heights were narrowed. Three (3%) patients (two
      children, one adult) had cervical kyphosis. Compression of the medulla was noted
      in association with severe cervical kyphosis in one child and one adult. Typical
      findings of the cervical spine in DD were exceptionally wide foramen magnum,
      narrowed spinal canal and early degenerative changes, and in older age groups,
      especially midcervically narrowed spinal canal. Severe cervical kyphosis caused
      medullar compression. The intervertebral discs developed abnormally. Abnormal
      disc structure may be one etiologic factor in the development of cervical
      kyphosis. Early and rapid progression of the degenerative changes is a normal
      finding in patients with DD, regardless of their age, and this also explains the
      stiffness of the cervical spine in clinical examination.

PMID- 10641689
TI  - Variability in three-dimensional measurements of back contour with raster
      stereography in normal subjects.
AB  - Forty normal children with a mean age of 9.1 years were investigated by using a
      Quantec Spinal Image System (QSIS). The QSIS uses computerized raster
      stereography technology to acquire three-dimensional measurements of back
      contour. Within a 95-percentile confidence interval (a) coronal-plane QSIS angles
      ranged from 0.05 to 2.36 degrees; (b) transverse-plane QSIS angles ranged from
      0.03 to 1.96 degrees; and (c) sagittal-plane QSIS angles ranged from 36.8 to 44.8
      degrees. Trunk-alignment deviation ranged from 3.51 to 7.45 mm within a 95
      percentile confidence interval. An intraobserver standard deviation of +/-4.2
      degrees was noted across all angular metrics. Normal ranges of QSIS-determined
      values for a population of 40 children without clinical evidence of pathology are
      reported.

PMID- 10641690
TI  - Occult intraspinal anomalies in congenital scoliosis.
AB  - Thirty consecutive patients with congenital spinal deformity underwent magnetic
      resonance imaging (MRI) to determine the incidence of occult intraspinal anomaly.
      These congenital spinal deformities included 29 cases of congenital scoliosis and
      one case of congenital kyphosis. Physical examination findings and plain
      radiographs were reviewed in an attempt to correlate these findings with
      subsequent intraspinal pathology. Nine patients had intraspinal anomalies
      identified on MRI consisting of five with tethered cord, four with syringomyelia,
      three with lipoma, and one with diastematomyelia. One patient required surgery
      for diastematomyelia; another underwent release of his tethered cord. Only one
      patient, with diastematomyelia associated with a syrinx and bifocal tethering,
      had his anomaly suggested by physical examination and plain radiographs. Two
      other patients had findings on plain radiographs previously associated with high
      prevalence of occult intraspinal anomalies; one patient with congenital kyphosis
      had a tethered cord, and one patient with a unilateral hemivertebrae associated
      with a contralateral bar had a tethered cord. Two of nine patients with occult
      intraspinal anomalies required surgery for their anomaly. In patients with a
      congenital spinal deformity, we found nine (30%) of 30 to have an associated
      anomaly within the spinal canal. Only three of these nine had plain radiographs
      and physical examination findings suggestive of their subsequent MRI findings.
      Given the poor correlation between findings on physical examination, plain
      radiographs, and subsequent occult intraspinal anomalies on MRI, we believe that
      MRI is helpful in evaluating patients with congenital spinal anomalies.

PMID- 10641691
TI  - A modified wake-up test for use in very young children undergoing spinal surgery.
AB  - In a consecutive series of five very young children undergoing hemivertebrectomy
      and fusion, a modified intraoperative wake-up test was used to confirm neurologic
      integrity. Standard leads attached to a nerve stimulator and positioned over the
      plantar aspect of each foot were used to apply tetanic electrical stimulation at
      the time of intraoperative wake-up. Four children responded vigorously with
      flexion and extension of the knees and ankles after only minimal delay. One
      neurologically intact child did not respond because of technical issues. This
      report describes our favorable preliminary experience with this technique.

PMID- 10641692
TI  - Intraobserver reproducibility and interobserver reliability of cervical spine
      measurements.
AB  - Lateral flexion-extension radiographs of 72 patients with Down syndrome were used
      to assess the interobserver reliability and intraobserver reproducibility of the
      atlanto-dens interval, Wiesel-Rothman measurement, occiput atlas angle, and
      Power's ratio in flexion and extension. The radiographs were reviewed by three
      blinded observers on three different occasions with at least a 1-month interval
      between assessments. The intraclass correlation coefficient was used to measure
      the reproducibility of the measurements from a given observer and the reliability
      between different observers. With the exception of observer one, the atlanto-dens
      interval had a statistically significant intraobserver agreement compared with
      any of the other measurements (p < 0.05). The atlanto-dens interval and the
      Wiesel-Rothman measurements tended to have better correlation between observers,
      although there was only fair agreement. The agreement, however, was statistically
      significant (p < 0.05) compared with Power's ratio. The degree of intraobserver
      reproducibility and interobserver reliability may make it difficult to base
      treatment protocols on these measurements.

PMID- 10641693
TI  - Bone mineral density and fractures in boys with Duchenne muscular dystrophy.
AB  - The relationships between bone density, mobility, and fractures were assessed in
      41 boys with Duchenne muscular dystrophy. Bone density in the lumbar spine was
      only slightly decreased while the boys were ambulatory (mean z-score, -0.8), but
      significantly decreased with loss of ambulation (mean z-score, -1.7). In
      contrast, bone density in the proximal femur was profoundly diminished even when
      gait was minimally affected (mean z-score, -1.6), and then progressively
      decreased to nearly 4 standard deviations below age-matched normals (mean z
      score, -3.9). These are consistent with the findings that 18 (44%) of the boys
      sustained a fracture, 66% of these fractures involved the lower extremities, and
      there were no spinal compression fractures. Furthermore, four (44%) of nine boys
      who were walking with aids or support at the time of fracture never resumed
      walking after the fracture. Osteoporosis is most profound in the lower
      extremities of boys with Duchenne muscular dystrophy, and begins to develop early
      while still ambulating. Frequent fractures that may result in loss of ambulation
      are the clinical consequences.

PMID- 10641694
TI  - Reliability and validity of the Gillette Functional Assessment Questionnaire as
      an outcome measure in children with walking disabilities.
AB  - A 10-level, parent-report walking scale encompassing a range of walking abilities
      from nonambulatory to ambulatory in all community settings and terrains was
      developed at Gillette Children's Specialty Healthcare (GCSH) as part of the
      Gillette Functional Assessment Questionnaire (FAQ). The reliability and validity
      of the walking-scale portion of the FAQ were tested on a group of individuals
      seen in the Motion Analysis Laboratory at GCSH between May 1996 and January 1997.
      A complete data set on 41 individuals with neuromuscular conditions represented
      the community ambulation levels (6-10) of the walking scale. Good test-retest
      reliability among parents and good interrater reliability between parents and
      community caregivers was demonstrated. Content and concurrent validity were also
      high, as assessed by correlation to standardized functional outcome measures,
      energy expenditure, and gait-analysis information. A reliable and valid scale
      specific to the task of walking such as the FAQ can assist clinicians in
      documenting functional change in children with chronic neuromuscular conditions.

PMID- 10641695
TI  - Charcot arthropathy in spina bifida.
AB  - This multicenter study was undertaken to identify the prevalence of Charcot
      arthropathy in the spina bifida population; to evaluate the relationship of
      neurosegmental level, ambulatory level, and distribution of joint involvement;
      and to assess treatment results and make treatment recommendations. Sixteen
      patients were identified with Charcot arthropathy based on clinical and
      radiographic criteria ranging in age from 9 to 42 years. There were 15 ankles,
      seven knees, and four hips identified with Charcot arthropathy. Six patients
      underwent surgery and modification of orthoses, eight had a modification of
      orthoses only, one had no modification, and one was lost to follow-up. Mean
      follow-up was 4 years and 9 months (with four good, 17 fair, and five poor
      results). The best results were seen in 13 compliant patients with a brace
      modification, whereas poor results were seen in three patients with poor brace
      compliance. Based on our study, we have noted the prevalence of Charcot
      arthropathy in spina bifida to be one in 100 cases.

PMID- 10641696
TI  - Abnormalities in the uninvolved lower limb in children with spastic hemiplegia:
      the effect of actual and functional leg-length discrepancy.
AB  - We assessed the pattern of gait in children with spastic hemiplegia and a leg
      length discrepancy, particularly in relation to the uninvolved limb. The
      kinematics of the uninvolved limbs were compared with the pattern in normal
      children. The uninvolved limbs in children with hemiplegia and a significant leg
      length discrepancy were compared with the uninvolved limb in those children who
      did not have a leg-length discrepancy. We found that the involved and uninvolved
      legs in patients with hemiplegia had characteristic patterns that were
      significantly different from normal. The kinematics of the involved leg were not
      affected by the presence of a leg-length discrepancy. The abnormal pattern in the
      uninvolved limb was more exaggerated in children with a leg-length discrepancy.
      The abnormal sagittal plane kinematics in the uninvolved lower limb in hemiplegic
      children appears to be related to the presence of an actual or functional leg
      length discrepancy and have not previously been described. Our findings suggest
      that attention be paid to the functional and actual leg-length discrepancy that
      exists in these children, and early consideration be given to epiphysiodesis of
      the uninvolved limb.

PMID- 10641697
TI  - One-stage correction of the dysplastic hip in cerebral palsy with the San Diego
      acetabuloplasty: results and complications in 104 hips.
AB  - Ninety-two patients with cerebral palsy underwent a special type of pericapsular
      acetabuloplasty designed to correct the hip dysplasia that occurs in cerebral
      palsy. The osteotomy was performed as part of a combined procedure (including
      femoral osteotomy and soft-tissue releases). Retrospective analysis was performed
      on 75 of the children (104 hips from 1982 through 1995) with a mean follow-up of
      6.9 years. Ninety-nine (95%) of the 104 hips remained well reduced at follow-up.
      There were no redislocations. If the preoperative migration percentage was >70%
      (severe subluxation), improved results were noted in hips that had an open
      reduction with capsulorrhaphy. There were 13 complications including
      intraarticular extension of the acetabuloplasty (one) and avascular necrosis of
      the femoral head (eight hips, 8%). Indications for addition of a pericapsular
      acetabuloplasty include an open triradiate cartilage, acetabular dysplasia
      (acetabular index >25 degrees), and subluxation or dislocation with a migration
      percentage of >40%. Even hips with relative incongruity and some deformity of the
      femoral head can be successfully treated with this combined approach.

PMID- 10641698
TI  - The risk of spinal deformity after selective dorsal rhizotomy.
AB  - To define the risk of spinal deformity after selective dorsal rhizotomy (SDR) for
      the treatment of spasticity due to cerebral palsy, 43 patients were reviewed
      before and after the procedure. The average length of follow-up was 5.3 years
      with a range of 2-9 years. Scoliosis was present in three patients before
      rhizotomy. One patient had a thoracic hyperkyphosis, and another, a lumbar
      hyperlordosis deformity preoperatively. Wide laminectomies were performed in 46
      patients, and none had laminoplasties. Twenty-eight significant spinal
      deformities developed in 19 patients; 15 cases of scoliosis, seven instances of
      lumbar hyperlordosis, five thoracic hyperkyphosis, and one L4-5
      spondylolisthesis. Five patients were placed in braces, and three patients went
      on to have surgical stabilization of their deformities. For the entire group, the
      risk of developing a structural spinal deformity was 36%, with 6% requiring
      stabilization at an average of 4.9 years after SDR. Older age, more severe
      neurologic impairment, and preexisting spinal deformity seems to increase this
      risk.

PMID- 10641699
TI  - Botulinum toxin type A neuromuscular blockade in the treatment of lower extremity
      spasticity in cerebral palsy: a randomized, double-blind, placebo-controlled
      trial. BOTOX Study Group.
AB  - Increased gastrocnemius/soleus muscle tone in children with cerebral palsy may
      cause an equinus of the ankle. Botulinum toxin type A (BTX), a neuromuscular
      blocking agent, reduces muscle tone in various neuromuscular disorders. The
      safety and short-term efficacy of BTX injections were evaluated in a prospective,
      3-month, double-blind, randomized clinical trial involving 114 children with
      cerebral palsy and dynamic equinus foot deformity. Outcome was determined by
      observational gait analysis, ankle range-of-motion measurements, and
      quantification of muscle denervation by nerve conduction. Patients in the BTX
      group demonstrated improved gait function and partial denervation of the injected
      muscle. No serious adverse events were reported.

PMID- 10641701
TI  - Slotted acetabular augmentation: is a hip spica necessary?
AB  - Between 1988 and 1996, 16 patients who underwent a total of 18 slotted acetabular
      augmentation procedures were managed postoperatively without a spica cast, by
      using instead a protocol of limited weight bearing and restriction of hip range
      of motion. Postoperatively, no patients experienced hip stiffness. No patients
      exhibited any migration or change of position of their bone graft. Radiographic
      examination revealed the following: center-edge angle (CEA) averaged 3 degrees
      preoperatively and 54 degrees postoperatively. Acetabular index averaged 35
      degrees preoperatively and 18 degrees postoperatively. No patients experienced
      any deleterious effects by not using a spica cast. We believe that by obviating
      the spica cast, we may ease the postoperative recovery for patients, avoid
      postoperative hip stiffness, and thereby expand the applications of this safe and
      reliable method of acetabular reconstruction in selected patients.

PMID- 10641700
TI  - Pre- and postoperative three-dimensional computed tomography analysis of triple
      innominate osteotomy for hip dysplasia.
AB  - Traditional methods of analysis and surgical techniques for hip dysplasia
      concentrate on frontal-plane analysis of the hip. More recent studies on imaging
      and operative correction of hip dysplasia recommend three-dimensional (3D)
      analysis, and some have mentioned but not emphasized the importance of transverse
      plane acetabular anatomy (anteversion/retroversion). In this study we found that
      failure to analyze and understand transverse-plane acetabular anatomy can
      contribute to complications after triple innominate osteotomy (TIO). A subset of
      seven patients (eight hips) who were treated with TIO for deficient acetabular
      coverage resulting from hip dysplasia or Legg-Calve-Perthes disease had both pre-
      and postoperative 3D computed tomography (CT) studies. Most of the postoperative
      studies were obtained to analyze complications (external limb rotation,
      nonunion). Analysis of the 3D CT studies showed a change in the position of the
      acetabular fragment after osteotomy into greater adduction, anterior rotation
      (extension), and external rotation, improving femoral head coverage. All of the
      hips had increased external rotation of the acetabulum after TIO. Excessive
      external rotation (>10 degrees) was noted in five hips, and these included two
      hips with pubic osteotomy nonunion, two with ischial nonunion, and one with
      marked external rotation of the lower limb. External rotation of the acetabular
      fragment during redirectional pelvic osteotomy can result in (a) excessive
      external rotation of the lower limb, (b) decreased posterior coverage, (c)
      increased gaps at the pubic and/or ischial osteotomy sites with resultant higher
      rates of nonunion, and (d) lateralization of the joint center. The surgical
      technique for TIO should be designed to avoid excessive external rotation of the
      acetabular fragment.

PMID- 10641702
TI  - Legg-Calve-Perthes disease, protein C deficiency, and beta-thalassemia major:
      report of two cases.
AB  - Legg-Calve-Perthes disease is an idiopathic osteonecrosis or avascular necrosis
      of the capital femoral epiphysis and the associated complications thereof
      occurring in an immature growing child. The association between osteonecrosis of
      the femoral head and thrombophilia was postulated by Glueck in 1994. We describe
      Legg-Calve-Perthes disease associated with protein C deficiency and beta
      thalassemia major in two children among a cohort of 79 beta-thalassemia patients
      treated in our clinic. The association of thrombophilia, aseptic necrosis of the
      femoral head, and beta-thalassemia has not been previously described in the
      literature.

PMID- 10641703
TI  - Oxidative stress status: OSS, BOSS, and "Wild Bill" Donovan.

PMID- 10641704
TI  - Novel HPLC analysis of tocopherols, tocotrienols, and cholesterol in tissue.
AB  - Tocopherols and tocotrienols are being increasingly recognized to have an
      important role in the prevention of atherosclerosis. It has been reported that
      they protect low-density lipoprotein (LDL) and tissues from oxidative stress and
      that tocotrienols can reduce plasma cholesterol levels. Two isocratic high
      performance liquid chromatography (HPLC) methods for simultaneous analysis of
      tocopherols, tocotrienols, and cholesterol in muscle tissue were developed.
      Method A involves basic saponification of the sample, but causes losses of the
      gamma- and delta-homologs of vitamin E. Method B does not involve saponification,
      thereby protecting the more sensitive homologs. Both permit rapid analysis of
      multiple samples and neither requires specialized equipment. These methods may
      provide techniques useful in simultaneous assessment of oxidative stress status
      (OSS) and cholesterol levels.

PMID- 10641705
TI  - Baseline diene conjugation in LDL lipids: an indicator of circulating oxidized
      LDL.
AB  - The wide acceptance of the diene conjugation-method in monitoring low-density
      lipoprotein (LDL) oxidation ex vivo has led to development of an assay, which
      measures the amount of baseline diene conjugation (BDC) in circulating LDL, and
      is an indicator of oxidized LDL in vivo. The LDL-BDC assay is based on
      precipitation of serum LDL with buffered heparin, and spectrophotometric
      determination of baseline level of conjugated dienes in lipids extracted from
      LDL. Compared to existing methods for oxidized LDL, LDL-BDC is fast and simple to
      perform. Chemical studies by HPLC and NMR have verified that LDL-BDC is a
      specific indicator of circulating mildly oxidized LDL. Validity of the assay is
      further indicated by strong correlation with the titer of autoantibodies against
      oxidized LDL. Clinical studies have shown that LDL-BDC is closely related to
      coronary, carotid, and brachial atherosclerosis. Moreover, several independent
      studies have demonstrated surprisingly strong associations between LDL-BDC and
      known atherosclerosis risk factors (obesity, physical inactivity, hypertension,
      diabetes, and arterial functions). Indeed, these studies seem to indicate that as
      an indicator of the risk of atherosclerosis LDL-BDC clearly exceeds sensitivity
      and specificity of the common lipid markers of atherosclerosis. It is concluded
      that LDL-BDC is a promising candidate in search for methods for the evaluation of
      in vivo LDL oxidation and the risk of atherosclerosis.

PMID- 10641706
TI  - Stable markers of oxidant damage to proteins and their application in the study
      of human disease.
AB  - The mechanisms of formation and the nature of the altered amino acid side chains
      formed on proteins subjected to oxidant attack are reviewed. The use of stable
      products of protein side chain oxidation as potential markers for assessing
      oxidative damage in vivo in humans is discussed. The methods developed in the
      authors laboratories are outlined, and the advantages and disadvantages of these
      techniques compared with other methodologies for assessing oxidative damage to
      proteins and other macromolecules. Evidence is presented to show that protein
      oxidation products are sensitive markers of oxidative damage, that the pattern of
      products detected may yield information as to the nature of the original
      oxidative insult, and that the levels of oxidized side-chains can, in certain
      circumstances, be much higher than those of other markers of oxidation such as
      lipid hydroperoxides.

PMID- 10641707
TI  - Measurement of oxidant-induced signal transduction proteins using cell imaging.
AB  - In addition to their capacity to damage macromolecules, oxidants play important
      roles in initiation of a number of signal transduction pathways. These include
      phosphorylation and dephosphorylation of members of the extracellular-regulated
      kinase (ERK) family of the mitogen-activated protein kinase (MAPK) cascade and
      events leading to activation of the transcription factor nuclear factor-kappaB
      (NF-kappaB). These cascades are key to transcriptional upregulation of genes
      important for cell survival, apoptosis, proliferation, transformation, and
      inflammation. To complement biochemical assays, cell-imaging approaches are
      necessary to detect the phosphorylated proteins of these cascades and their
      nuclear translocation, i.e., activation in cells. Protocols for these studies are
      presented, and the advantages of in situ microscopy-based techniques to detect
      oxidant-induced signaling pathways are discussed.

PMID- 10641708
TI  - In vivo total antioxidant capacity: comparison of different analytical methods.
AB  - Several methods have been developed to measure the total antioxidant capacity of
      a biological sample. The use of peroxyl or hydroxyl radicals as pro-oxidants in
      the oxygen radical absorbance capacity (ORAC) assay makes it different and unique
      from the assays that involve oxidants that are not necessarily pro-oxidants. An
      improvement in quantitation is achieved in the ORAC assay by taking the reaction
      between substrate and free radicals to completion and using an area-under-curve
      technique for quantitation compared to the assays that measure a lag phase. The
      interpretation of the changes in plasma or serum antioxidant capacity becomes
      complicated by the different methods used in detecting these changes. The
      interpretation also depends upon the conditions under which the antioxidant
      capacity is determined because the measurement reflects outcomes in a dynamic
      system. An increased antioxidant capacity in plasma or serum may not necessarily
      be a desirable condition if it reflects a response to increased oxidative stress.
      Similarly, a decrease in plasma or serum antioxidant capacity may not necessarily
      be an undesirable condition if the measurement reflects decreased production of
      reactive species. Because of these complications, no single measurement of
      antioxidant status is going to be sufficient, but a "battery" of measurements,
      many of which will be described in Forum articles, will be necessary to
      adequately assess oxidative stress in biological systems.

PMID- 10641709
TI  - Clinical application of breath biomarkers of oxidative stress status.
AB  - Isolation and quantification of volatile breath biomarkers indicative of relevant
      alterations in clinical status has required development of new techniques and
      applications of existing analytical chemical methods. The most significant
      obstacles to successful application of this type of sample have been reduction in
      required sample volume permitting replicate analysis (an absolute requirement for
      all clinical studies), separation of the analyte(s) of interest from background
      molecules, water vapor and other molecules with similar physical properties,
      introduction of automation in analysis and the use of selective detection systems
      (electron impact mass spectrometry, flame photometric, thermionic detectors), and
      automated sample collection from the human subject. Advances in adsorption
      technology and trace gas analysis have permitted rapid progress in this area of
      clinical chemistry.

PMID- 10641710
TI  - Analysis of oxidized heme proteins and its application to multiple antioxidant
      protection.
AB  - Oxidation in tissues and homogenates can be determined by the analysis of
      oxidized heme proteins. Oxidation of heme proteins can be measured by spectral
      changes and the deconvolution of the spectra of mixtures of heme proteins by a
      spreadsheet heme spectra analysis program (HSAP), incorporating the spectra of
      the individual pure heme proteins. HSAP also is used to analyze the spectra of
      mixtures of heme proteins found in the literature. HSAP is applied in measuring
      the protective effects in rats of multiple antioxidants suitable for use in
      humans for protection against diseases.

PMID- 10641711
TI  - H2O2 is required for UVB-induced EGF receptor and downstream signaling pathway
      activation.
AB  - Ultraviolet radiation (UVR)-induced receptor phosphorylation is increasingly
      recognized as a widely occurring phenomenon. However, the mechanisms, mediators,
      and sequence of events involved in this process remain ill-defined. We have
      recently shown that exposure of human keratinocytes to physiologic doses of
      ultraviolet B radiation (UVB) activates epidermal growth factor receptor
      (EGFR)/extracellular-regulated kinase 1 and 2 (ERK1/2), and p38 signaling
      pathways via reactive oxygen species. Here we demonstrate that UVB exposure
      increased intra- and extracellular H2O2 production rapidly in a time-dependent
      manner. An EGFR-specific monoclonal antibody abrogated EGFR autophosphorylation
      and markedly decreased the phosphorylation of ERK1/2 whereas p38 activation was
      unaffected. Overexpression of catalase strongly inhibited UVB-induced EGFR/ERK1/2
      pathway activation. These findings establish the sequence of events after UVB
      irradiation: (i) H2O2 generation, (ii) EGFR phosphorylation, and (iii) ERK
      activation. Our results identify UVB-induced H2O2 as a second messenger that is
      required for EGFR and dependent downstream signaling pathways activation.

PMID- 10641712
TI  - Harmful singlet oxygen can be helpful.
AB  - Highly reactive harmful singlet oxygen O2(1delta(g)) can be helpful while
      relaxing to its triplet ground state O2(3sigma(g)-). The energy emitted during
      this relaxation from the excited energy state is discernable at 634 nm. We report
      here on the effect of this energy as photon illumination and as energy transfer
      in air on the production of reactive oxygen species (ROS) by human monocytes,
      measured as isoluminol-enhanced chemiluminescence. We demonstrate up to 60%
      decrease in the secretion of ROS after 2-min illumination of the monocytes
      stimulated with phorbol myristate acetate (PMA). The results provide in vitro
      documentation of the utility of singlet oxygen energy in modifying cellular
      behaviour.

PMID- 10641713
TI  - Glutathione redox potential in response to differentiation and enzyme inducers.
AB  - The reduced glutathione (GSH)/oxidized glutathione (GSSG) redox state is thought
      to function in signaling of detoxification gene expression, but also appears to
      be tightly regulated in cells under normal conditions. Thus it is not clear that
      the magnitude of change in response to physiologic stimuli is sufficient for a
      role in redox signaling under nontoxicologic conditions. The purpose of this
      study was to determine the change in 2GSH/GSSG redox during signaling of
      differentiation and increased detoxification enzyme activity in HT29 cells. We
      measured GSH, GSSG, cell volume, and cell pH, and we used the Nernst equation to
      determine the changes in redox potential Eh of the 2GSH/GSSG pool in response to
      the differentiating agent, sodium butyrate, and the detoxification enzyme
      inducer, benzyl isothiocyanate. Sodium butyrate caused a 60-mV oxidation (from 
      260 to -200 mV), an oxidation sufficient for a 100-fold change in protein
      dithiols:disulfide ratio. Benzyl isothiocyanate caused a 16-mV oxidation in
      control cells but a 40-mV oxidation (to -160 mV) in differentiated cells. Changes
      in GSH and mRNA for glutamate:cysteine ligase did not correlate with Eh; however,
      correlations were seen between Eh and glutathione S-transferase (GST) and
      nicotinamide adenine dinucleotide phosphate (NADPH):quinone reductase activities
      (N:QR). These results show that 2GSH/GSSG redox changes in response to
      physiologic stimuli such as differentiation and enzyme inducers are of a
      sufficient magnitude to control the activity of redox-sensitive proteins. This
      suggests that physiologic modulation of the 2GSH/GSSG redox poise could provide a
      fundamental parameter for the control of cell phenotype.

PMID- 10641714
TI  - Yeast superoxide dismutase mutants reveal a pro-oxidant action of weak organic
      acid food preservatives.
AB  - Saccharomyces cerevisiae could provide a simple experimental system for testing
      the antioxidant or pro-oxidant actions of chemicals, because it has the capacity
      for aerobic and anaerobic growth and can readily lose its mitochondrial electron
      transport chain (the major endogenous source of reactive oxygen species [ROS]).
      This study showed that yeast superoxide dismutase mutants, in a simple petri dish
      test, readily distinguish a compound that enhances the detrimental effects of
      endogenous ROS production by the mitochondrial respiratory chain from another
      chemical that generates oxidative stress by redox cycling. Using this system,
      weak organic acid food preservatives are shown to exert a strong pro-oxidant
      action on aerobic yeast cells. In addition these acids are mutagenic toward the
      yeast mitochondrial genome, even at levels that are subinhibitory to growth. This
      raises the concern that the large-scale consumption of these preservatives in the
      human diet may generate oxidative stress within the epithelia of the
      gastrointestinal tract.

PMID- 10641715
TI  - Lysosomal release of cathepsin D precedes relocation of cytochrome c and loss of
      mitochondrial transmembrane potential during apoptosis induced by oxidative
      stress.
AB  - Apoptosis was induced in human foreskin fibroblasts by the redox-cycling quinone
      naphthazarin (5,8-dihydroxy-1,4-naphthoquinone). Most of the cells displayed
      ultrastructure typical of apoptosis after 8 h of exposure to naphthazarin.
      Apoptosis was inhibited in fibroblasts pretreated with the cathepsin D inhibitor
      pepstatin A. Immunofluorescence analysis of the intracellular distribution of
      cathepsin D revealed a distinct granular pattern in control cells, whereas cells
      treated with naphthazarin for 30 min exhibited more diffuse staining that
      corresponded to release of the enzyme from lysosomes to the cytosol. After 2 h,
      release of cytochrome c from mitochondria to the cytosol was indicated by
      immunofluorescence. The membrane-potential-sensitive probe JC-1 and flow
      cytometry did not detect a permanent decrease in mitochondrial transmembrane
      potential (delta psi(m)) until after 5 h of naphthazarin treatment. Our findings
      show that, during naphthazarin-induced apoptosis, lysosomal destabilization
      (measured as release of cathepsin D) precedes release of cytochrome c, loss of
      delta psi(m), and morphologic alterations. Moreover, apoptosis could be inhibited
      by pretreatment with pepstatin A.

PMID- 10641716
TI  - Effects of ischemia and H2O2 on the cold stress protein CIRP expression in rat
      neuronal cells.
AB  - Expression of CIRP (cold-inducible RNA-binding protein) is inducible at 32
      degrees C in cultured fibroblasts. Because ischemia is known to induce expression
      of heat shock proteins, its effect on the CIRP expression was examined using the
      rat transient forebrain ischemia model. The isolated rat CIRP cDNA encoded amino
      acids 100% identical in its sequence to mouse CIRP. Northern blot analysis
      revealed that the CIRP transcripts were ubiquitously expressed in various
      tissues. In situ hybridization histochemistry of normal rat brain revealed the
      expression of CIRP in neurons in the hippocampus and the cerebral cortex among
      others. In the hippocampus of postischemic rats, CIRP mRNA level decreased from 3
      6 h after the onset of reperfusion, while it did not change in the cerebral
      cortex. When PC12 pheochromocytoma cells were cultured at 32 degrees C, the CIRP
      mRNA level was increased. The presence of H2O2 in the culture media inhibited
      dose dependently this induction as well as constitutive expression, suggesting
      that the effect of brain ischemia on CIRP expression is related to generation of
      reactive oxygen species. Further studies are necessary to clarify the roles
      played by cold shock proteins in the hypothermic therapy of brain damages.

PMID- 10641717
TI  - Damage to the cytoplasmic membrane of Escherichia coli by catechin-copper (II)
      complexes.
AB  - In the presence of a nonlethal concentration of Cu(II), washed Escherichia coli
      ATCC11775 cells were killed by (-)-epigallocatechin (EGC) and (-)-epicatechin
      (EC). Cell killing was accompanied by a depletion in both the ATP and potassium
      pools of the cells, but the DNA double strand was not broken, indicating that the
      bactericidal activity of catechins in the presence of Cu(II) results from damage
      to the cytoplasmic membrane. Induction of endogenous catalase in E. coli cells
      increased their resistance to being killed by the combination of catechins and
      Cu(II). In all cases studied, EGC and EC with Cu(II) were found to generate
      hydrogen peroxide, but its concentration was too low to account for the
      bactericidal activity. The bactericidal activity of EGC in the presence of Cu(II)
      was completely suppressed by ethylenediaminetetraacetate, bathocuproine,
      catalase, superoxide disumutase (SOD), heated catalase, and heated SOD, but not
      by dimethyl sulfoxide. When catalase, either heated or unheated, was added to the
      cells incubated with EGC in the presence of Cu(II), it completely inhibited
      further killing of the cells. These findings suggest that recycling redox
      reactions between Cu(II) and Cu(I), involving catechins and hydrogen peroxide on
      the cell surface, must be important in the mechanism of the killing.

PMID- 10641718
TI  - 8-Hydroxyguanosine formed in human lung tissues and the association with diesel
      exhaust particles.
AB  - Diesel exhaust particles consist of various organic chemicals, heavy metals, and
      carbon particles. Knowledge of the fate of organic chemicals and carbon particles
      in the lungs is important to determine the mechanisms responsible for lung
      tumors. In the present study, diesel particle extracts were found to show
      mutagenicity for YG3003, a sensitive strain to some oxidative mutagens, as well
      as other mutant strains, and those of lung tissues obtained from lung cancer
      patients exhibited potent mutagenicity. Formation of 8-hydroxyguanosine (8-OHdG)
      as a biomarker of oxidative damage was analyzed with in vitro and in vivo assay
      systems. The 8-OHdG was detected in all 22 cases of lung tissues with carcinomas
      tested and their levels increased with the increasing age of the patients,
      suggesting a correlation between age and the presence of carbon particles in lung
      tissues. Therefore, the formation of 8-OHdG due to diesel exhaust particles was
      investigated via intratracheal injections into mice. 8-OHdG formation was
      elevated when carboneceous particles, after removal of organic chemicals with
      various solvents, were administered to mice, but it was not elevated when
      polyaromatic compounds such as benzo[a]pyrene, 1,8-dinitropyrene, and 1
      nitropyrene were used in the same procedure in mice. The carboneceous particles
      were formed from a giant particle that was aggregated by micro-particles with
      diameters of 1.47 +/- 1.34 to 1.05 +/- 0.83 microm. These results suggest that
      carboneceous particles, but not mutagens and carcinogens, promote the formation
      of 8-OHdG, and that as a mechanism, alveolar macrophages may be involved in
      oxidative damage. The oxidative damage may be due to the fact that the mutation
      is involved with the generation of a hydroxyl radical during phagocytosis, and
      the hydroxyl radical leads to hydroxylation at the C-8 position of the
      deoxyguanosine residue in the DNA.

PMID- 10641719
TI  - Comparison of the bioavailability of quercetin and catechin in rats.
AB  - Quercetin and catechin are present in noticeable amounts in human diet and these
      polyphenolic compounds are supposed to exert beneficial effects on human health.
      However, their metabolic fates in the organism have never been compared. In the
      present study, rats were fed a 0.25% quercetin or a 0.25% catechin diet.
      Quercetin and catechin metabolites were analyzed in plasma and liver samples by
      high-performance liquid chromatography coupled to an ultraviolet or a
      multielectrode coulometric detection. All plasma metabolites were present as
      conjugated forms, but catechin metabolites were mainly constituted by
      glucuronidated derivatives, whereas quercetin metabolites were sulfo- and
      glucurono-sulfo conjugates. Quercetin was more intensively methylated than
      catechin in plasma. The plasma quercetin metabolites are well maintained during
      the postabsorptive period (approximately 50 microM), whereas the concentration of
      catechin metabolites dropped dramatically between 12- and 24-h after an
      experimental meal (from 38.0 to 4.5 microM). In the liver, the concentrations of
      quercetin and catechin derivatives were lower than in plasma, and no accumulation
      was observed when the rats were adapted for 14 d to the supplemented diets. The
      hepatic metabolites were intensively methylated (90-95%), but in contrast to
      plasma, some free aglycones could be detected. Thus, it clearly appears that
      studies dealing with the biological impact of these polyphenols should take into
      account the feature of their bioavailability, particularly the fact that their
      circulating metabolites are conjugated derivatives.

PMID- 10641720
TI  - Metabolism-dependent stimulation of reactive oxygen species and DNA synthesis by
      cyclosporin A in rat smooth muscle cells.
AB  - The clinical use of the immunosuppressive drug cyclosporin A (CsA) is limited by
      its side effects, namely hypertension and nephrotoxicity. It has been proposed
      that reactive oxygen species (ROS) could be involved as mediators of the toxic
      effects of CsA. Here, we have studied the possible interrelationship between CsA
      metabolism and production of ROS. Using cultures of rat aortic smooth muscle
      cells (RASMC), CsA (1 microM) produced a rapid (within 10 min) increase in
      reactive oxygen species, detected by oxidation of the fluorescent probes 2,7
      dichlorofluorescin and dihydrorhodamine-123. DNA synthesis was increased in the
      presence of CsA as assessed by [3H]thymidine incorporation. The superoxide
      dismutase inhibitor diethyldithiocarbamate (1 mM) and the iron chelator desferal
      (5 microM), as well as ketoconazole (1 microM) and troleandomycin (10 microM),
      inhibitors of the cytochrome P-450 3A, were able to block both effects. High
      performance liquid chromatography analysis revealed that RASMC were capable to
      metabolize CsA to its primary metabolites (AM1, AM9 and AM4N), and that their
      formation was inhibited by ketoconazole and troleandomycin. Furthermore, mRNAs
      encoding cytochrome P-450 3A1 and 3A2 were detected in RASMC by reverse
      transcriptase-polymerase chain reaction. Our data suggest that CsA is metabolized
      by cytochrome P-450 3A in RASMC producing reactive oxygen species, most likely
      superoxide and the hydroxyl radical, known to damage lipids and DNA.

PMID- 10641721
TI  - Redox-regulation of intrinsic prion expression in multicellular prostate tumor
      spheroids.
AB  - The cellular function of the intrinsic prion protein (PrPc) remains largely
      unknown. In the present study PrPc expression was investigated in multicellular
      prostate tumor spheroids and was correlated to the intracellular redox state as
      evaluated using the fluorescent dye 2'7'-dichlorodihydrofluorescein diacetate
      (H2DCFDA). In small tumor spheroids (diameter 100 +/- 20 microm) reactive oxygen
      species (ROS) levels were increased as compared with large (diameter 250 +/- 50
      microm) spheroids. ROS generation was mediated by the mitochondrial respiratory
      chain and a NADPH oxidaselike enzyme, because carbonylcyanide-m
      chlorophenylhydrazone (CCCP), rotenone, and diphenylene iodonium chloride (DPI)
      significantly reduced ROS levels. The elevated ROS were correlated to an
      increased expression of PrPc, Cu/Zn superoxide dismutase (SOD-1), and catalase in
      small as compared with large spheroids. In large tumor spheroids, PrPc was
      predominantly expressed in the peripheral cell layers and colocalized with SOD-1
      and catalase. Raising intracellular ROS in large tumor spheroids by hydrogen
      peroxide, menadione, buthionine sulfoximine (BSO), and incubation in glutamine
      reduced medium increased PrPc expression. In small spheroids PrPc was
      downregulated after incubation with the radical scavengers dehydroascorbate (DHA)
      and vitamin E. Our data indicate that PrPc expression in tumor spheroids is
      related to the intracellular redox state and may participate in antioxidative
      defense.

PMID- 10641722
TI  - Oxidative DNA damage in circulating leukocytes occurs as an early event in
      chronic HCV infection.
AB  - Chronic hepatitis C virus (HCV) infection is associated with an increased
      production of reactive oxygen species within the liver that are responsible for
      the oxidation of intracellular macromolecules. To ascertain whether the increased
      risk of hepatocellular carcinoma in individuals with chronic HCV infection is
      related to an accumulation of oxidative DNA damage, the 8-hydroxydeoxyguanosine
      (8-OHdG) content in the DNA of liver tissue and leukocytes of 87 individuals with
      HCV- or HBV-related liver disease and of 10 healthy controls was measured. Serum
      levels of thiobarbituric acid reactive substances (TBARS) were also assessed as
      an index of lipid peroxidation. RESULTS: The 8-OHdG content in the circulating
      leukocytes correlated with that of liver tissue (r = 0.618, p < .0004). HCV
      patients had the highest median 8-OHdG levels (p < .0004). 8-OHdG leukocyte
      levels in HCV patients were higher than in HBV patients (p < .04) and they
      significantly correlated with the clinical diagnosis (p < .025), the serum
      ferritin levels (p < .05), and the amount of liver steatosis (p < .001). No
      correlation was found with age, gender, history of drinking or smoking, ALT or
      GGT levels, ESR, alpha-1, or gamma-globulin level and Ishak score. TBARS levels
      were significantly higher in cirrhotics than in noncirrhotics (p < .01).
      CONCLUSIONS: The 8-OHdG level in circulating leukocytes is a reliable marker of
      oxidative stress occurring in the liver of individuals with chronic HCV
      infection. DNA oxidative damage appears to be an early and unique event in the
      natural history of HCV-related hepatitis. This injury increases the risk of
      genomic damage and may be one of the important factors involved in the
      carcinogenic process in cases of HCV-related chronic liver disease.

PMID- 10641723
TI  - The role of glutathione, membrane sphingomyelin, and its metabolites in oxidative
      stress-induced calcium "dysregulation" in PC12 cells.
AB  - Previous research showed that increasing membrane sphingomyelin (SPH) levels in
      rat pheochromocytoma (PC12) cells to the same extent as that seen in some brain
      regions with aging dramatically increases the vulnerability to oxidative stress
      (OS). These increases in vulnerability were determined by assessing deficits in
      the ability of these cells to extrude and/or sequester Ca2+ following 30 mM KCl
      induced depolarization (recovery). The purpose of the present experiments was to
      discern whether increasing the levels of particular SPH metabolite(s), i.e.,
      ceramide (Cer), sphingosine (Ssine), or sphingosine-1-phosphate (SPP), or
      indirectly increasing the concentrations of these metabolites with
      sphingomylinase (Sase), would interact with the cell's sensitivity to OS induced
      by low (5 microM) or high (nonlethal, 300 microM) H2O2. In addition, the OS
      vulnerability was examined as above under decreased SPH levels by exposing the
      cells to L-cycloserine (Lcc), which prevents SPH synthesis. Both Sase and SPP
      significantly decreased Ca2+ recovery of PC12 cells after H2O2 exposure.
      Conversely, Lcc-treated cells showed no further OS-induced decrements in recovery
      below those seen in controls. SPP significantly decreased glutathione levels
      (GSH) in the absence of OS. Repletion of GSH with 20 mM N-acetylcysteine
      significantly attenuated the effect of 5 microM H2O2 on recovery in SPP-treated
      cells and decreased sensitivity of SPP-treated cells to low doses of OS. Overall,
      our results suggest a critical role for GSH and SPP in the regulation of OS
      vulnerability, especially as it relates to Ca2+ homeostasis.

PMID- 10641724
TI  - Body nitrosation potential measured by a novel 15N breath test.
AB  - Oxygenated nitrogen species, for example, the protonated form of nitrous acid
      (H2ONO+), dinitrogentrioxide (N2O3), dinitrogentetroxide (N2O4), or peroxynitrite
      (ONOO-), can react with amines to form molecular nitrogen. These reactions can
      occur spontaneously with primary aliphatic amines or via cytochrome P450
      catalysed reactions with secondary amines. In principle measurements of the
      excretion of the molecular nitrogen generated by these reactions could be used as
      an index of the levels of oxygenated nitrogen compounds acting as nitrosating
      agents. To test this idea, [15N2]urea (3 mmol) was administered orally to five
      patients infected with Helicobacter pylori (as diagnosed by the [13C]urea breath
      test) and to four healthy volunteers. All participants ingested 3-mmol sodium
      nitrate as a precursor for NA 5 min before the ingestion of the nitrogen tracer.
      During the test the participants breathed 100% oxygen to increase the sensitivity
      of detection of endogenous molecular nitrogen. After the administration of
      [15N2]urea, the patients with H. pylori showed significantly increased 15N
      enrichments of exhaled N2, expressed as delta value (per 1000), compared with
      healthy volunteers (patients: 3.5 +/- 0.9 vs. volunteers: 1.3 +/- 0.4; p < .05).
      We speculate that the endogenous production of molecular nitrogen is a protective
      process controlling the body NO and nitrite levels. The 15N breath technique
      allows the noninvasive estimation of the body nitrosation and could indicate the
      health risk, possibly the oxidative stress status, caused by highly reactive
      oxygenated nitrogen species and carbenium ion intermediates.

PMID- 10641725
TI  - Electron spin resonance study of free radicals formed from a procyanidin-rich
      pine (Pinus maritima) bark extract, pycnogenol.
AB  - The free radical generated from the oxidation of a French maritima pine bark
      extract Pycnogenol (PYC), by the horseradish peroxidase (HRP)-hydrogen peroxide
      (H2O2) system at pH 7.4-10.0 was studied using electron spin resonance (ESR)
      spectrometer. The formation rate of the PYC radical (aH = 0.92 G; g = 2.0055) was
      dependent on the PYC and HRP concentrations and pH; the lifetime of the radical
      was up to 90 min. Furthermore, it was found that the PYC radical was mainly
      composed of the secondary radical formed from procyanidin B3, one of major
      procyanidins in PYC. The primary radical signal of procyanidin B3 with hyperfine
      splitting constants aH = 3.67 G (1H), aH = 0.92 G (3H), and g = 2.0055 was
      transient and disappeared quickly, whereas its secondary radical signal appeared
      and increased with time. The secondary radical from dimer procyanidin B3 showed
      quite high stability, differing from the radical from monomer (+)-catechin that
      could not be observed possibly because of its instability. These results provide
      evidence to support the idea that the intramolecular hydrogen bond between the O*
      at the 4' position in one B ring and an OH group in the other B ring of
      procyanidin B3 is formed during its oxidation in the presence of HRP and H2O2.

PMID- 10641726
TI  - Anti- and pro-oxidative effects of flavonoids on metal-induced lipid
      hydroperoxide-dependent lipid peroxidation in cultured hepatocytes loaded with
      alpha-linolenic acid.
AB  - Lipid hydroperoxide (LOOH)-dependent lipid peroxidation was induced in alpha
      linolenic acid (LNA)-loaded hepatocytes by adding Fe, Cu, V, or Cd ions at
      concentrations from 20 to 500 microM. The effects of structurally related
      flavonoids at concentrations from 10 to 500 microM on the lipid peroxidation were
      examined. The results with regard to each flavonoid subclass are as follows: (i)
      Flavonols such as myricetin, quercetin, fisetin, and kaempferol, but not morin,
      showed dose-dependent antioxidative activity against metal-induced lipid
      peroxidation at all metal concentrations. Myricetin, quercetin, and fisetin were
      the most effective antioxidants, although their efficacies depended on the metal
      ion. Kaempferol and morin had antioxidative activity equal to the other flavonols
      in the presence of Cu ions, but were much less effective for the other three
      metal ions. (ii) Flavones, luteolin, apigenin, and chrysin were antioxidative at
      low Fe concentrations, but were pro-oxidative at high Fe concentrations. Luteolin
      exhibited antioxidative activity similar to that of catechol-containing flavonols
      in the presence of the other three metal ions. Apigenin and chrysin also acted as
      pro-oxidants with V or with all metal ions, respectively. (iii) Taxifolin, a
      flavanone, also showed both anti- and prooxidative activity, depending on Fe
      concentrations, but with other metal showed only antioxidative activity ions.
      (iv) Epigallocatechin, a flavanol, was antioxidative with all metal ions, and its
      activity was similar to that of catechol-containing flavonols. The various
      effects of flavonoids on metal-induced lipid peroxidation in LNA-loaded
      hepatocytes is discussed with regard to the change in redox potential of
      flavonoid-metal complexes.

PMID- 10641727
TI  - Low-dose gamma-ray irradiation reduces oxidative damage induced by CCl4 in mouse
      liver.
AB  - We examined the effects of irradiation (50 cGy of gamma-ray) reducing the
      oxidative damage in carbon tetrachloride (CCl4)-hepatopathy mice. We made
      pathological examinations and analyzed transaminase activity (glutamic
      oxaloacetic transaminase and glutamic pyruvic transaminase), lipid peroxide level
      and the activities of endogenous antioxidants in the mouse. The irradiation was
      found to accelerate the recovery. Based on pathological examination as well as
      changes in each transaminase activity and lipid peroxide levels, it was shown
      that hepatopathy improved 3 d after the irradiation. The activities of
      glutathione reductase and glutathione peroxidase rapidly elevated after
      irradiation, and the total glutathione content gradually increased in the
      irradiation group. Both activities of gamma-glutamylcysteine synthetase and
      catalase were higher than normal at all times after the irradiation and gradually
      increased. In addition, the gamma-glutamylcysteine synthetase activity changed in
      a similar fashion to the total glutathione content. However, superoxide dismutase
      activity in both groups decreased and that of the irradiation group was
      significantly lower than that of the sham-irradiation group. These findings
      suggest that low-dose radiation relieved functional disorder at least in the
      liver of mice with active oxygen diseases.

PMID- 10641728
TI  - Expression of superoxide dismutases, catalase, and glutathione peroxidase in
      glioma cells.
AB  - Four primary antioxidant enzymes were measured in both human and rat glioma
      cells. Both manganese-containing superoxide dismutase (MnSOD) and copper-zinc
      containing superoxide dismutase (CuZnSOD) activities varied greatly among the
      different glioma cell lines. MnSOD was generally higher in human glioma cells
      than in rat glioma cells and relatively higher than in other tumor types. High
      levels of MnSOD in human glioma cells were due to the high levels of expression
      of MnSOD mRNA and protein. Heterogeneous expression of MnSOD was present in
      individual glioma cell lines and may be due to subpopulations or cells at
      different differentiation stages. Less difference in CuZnSOD, catalase, or
      glutathione peroxide was found between human and rat glioma cells. The human
      glioma cell lines showed large differences in sensitivity to the glutathione
      modulating drugs 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) and buthionine
      sulfoximine (BSO). A good correlation was found between sensitivity to BCNU and
      the activities of catalase in these cell lines. Only one cell line was sensitive
      to BSO and this line had low CuZnSOD activity.

PMID- 10641729
TI  - Gamma-glutamylcysteine synthetase activity in human lung epithelial (A549) cells:
      factors influencing its measurement.
AB  - Despite the central role of gamma-glutamylcysteine synthetase (gammaGCS) in lung
      antioxidant defenses, the limited studies of the activity of this enzyme in
      respiratory cells have produced variable results. This study has examined the
      factors, which may influence the measurement of gammaGCS activity in cultured
      human lung epithelial cells (A549). Although a source of potential error,
      gammaGCS activity in A549 cell extracts did not vary significantly when
      appropriately assayed by three different methods or after removal of the
      endogenous inhibitor, glutathione (GSH). However, gammaGCS activity did increase
      significantly during the early stages of cell proliferation (3.50 +/- 0.31 vs.
      2.35 +/- 0.16 nmol/min/10(6) cells for baseline, p < .001) and thereafter
      returned to baseline levels during the later stages of cell growth. Variations in
      initial plating density also significantly altered gammaGCS activity (3.11 +/-
      0.14 vs. 4.04 +/- 0.50 nmol/min/10(6) cells, at 0.25 x 10(5) and 0.58 x 10(5)
      cells/cm2, respectively, p < .001) and GSH content (45.43 +/- 4.43 vs. 63.64 +/-
      3.28 nmol/10(6) cells at 0.25 x 10(5) and 0.58 x 10(5) cells/cm2, respectively, p
      < .001) during the early stages of cell proliferation. In addition, gammaGCS
      activity and GSH content were highest in A549 cells grown in medium containing
      cystine as the predominant sulfur-containing amino acid. These results suggest
      that gammaGCS activity of A549 cells is strongly dependent on initial plating
      density, stage of cell growth and sulfur amino acid content of the medium and may
      account for some of the variation in values reported by different investigators.
      Whether gammaGCS has an important role in the early phase of cell proliferation
      needs further investigation.

PMID- 10641730
TI  - Cellular antioxidant and pro-oxidant actions of nitric oxide.
AB  - We describe a biphasic action of nitric oxide (NO) in its effects on oxidative
      killing of isolated cells: low concentrations protect against oxidative killing,
      while higher doses enhance killing, and these two effects occur by distinct
      mechanisms. While low doses of NO (from (Z)-1-[N-(3-ammonio propyl)-N-(n-propyl)
      amino]-diazen-1-ium-1,2(2) diolate [PAPA/NO] or S-nitroso-N-acetyl-L
      penicillamine [SNAP] prevent killing of rat hepatocytes by t-butylhydroperoxide
      (tBH), further increasing doses result in increased killing. Similar effects
      occur with rat hepatoma cells treated with PAPA/NO and tBH or H2O2. Increased
      killing with higher concentrations of NO donor is due to both NO and tBH, because
      NO donor alone is without effect. Glutathione (GSH) is not involved in either of
      these actions. Based on measurements of thiobarbituric acid-reactive substances
      (TBARS) and effects of lipid radical scavenger (DPPD) and deferoxamine, the
      protective effect, but not the enhancing effect, involves peroxidative chemistry.
      Fructose has no effect on tBH killing alone but provides substantial protection
      against killing by higher concentrations of NO plus tBH, suggesting that the
      enhancing effect involves mitochondrial dysfunction. Hepatocytes, when stimulated
      to produce NO endogenously, become resistant to tBH killing, indicative of the
      presence of an NO-triggered antioxidant defensive mechanism. The finding that the
      protective effects of low concentrations of NO and the harmful effects of high
      concentrations of NO are fundamentally different in nature suggest that
      therapeutic interventions could be designed, which selectively prevent its pro
      oxidant activity at high concentrations, thus converting NO from a "Janus-faced"
      modulator of oxidant injury into a "pure" protectant.

PMID- 10641731
TI  - DNA damage induced by catecholestrogens in the presence of copper (II):
      generation of reactive oxygen species and enhancement by NADH.
AB  - Certain estrogen metabolites are involved in carcinogenesis and the development
      of resistance to methotrexate (MTX). In this study, we determined whether these
      well-established biological effects correlate with the relative efficiency of
      several estrogen metabolites to induce DNA strand breaks in the presence of
      copper, and investigated the potential enhancing effect of reduced nicotinamide
      adenine dinucleotide (NADH). DNA strand breaks induced by estradiol metabolites
      were measured by the conversion of supercoiled phage phiX-174 RF1 DNA to open
      circular and linear forms. The most active catecholestrogens were the 4-hydroxy
      derivatives, which produced about 2.5 times more DNA double strand breaks than
      the 2-hydroxy derivatives, while estradiol and 16alpha-hydroxyestrone were
      inactive. In addition, our results show that 4-hydroxyestradiol (4-OHE2) at
      physiological concentrations was capable of exhibiting DNA cleaving activity. The
      formation of these catecholestrogen-induced DNA strand breaks was associated with
      the utilization of oxygen and the generation of H2O2, because catalase inhibited
      the DNA cleaving activity of 4-OHE2. Interestingly, we also observed that NADH
      enhanced the induction of DNA strands breaks by 4-OHE2/Cu(II), probably by
      perpetuating the redox cycle between the quinone and the semiquinone forms of the
      catecholestrogen. In conclusion, this study demonstrated that the relative
      efficiency of 2-, and 4-hydroxyestrogen in carcinogenesis and for the enhancement
      of MTX resistance correlates with their relative capability to induce DNA strand
      breaks. In order to inhibit these estrogen-mediated biological effects, it may be
      important to develop different strategies to block the production of reactive
      oxygen species by the catecholestrogen-redox cycle.

PMID- 10641732
TI  - Differential mechanisms for structural and functional alterations of trypsin by
      heparin, evidence for a specific, radical-generating mechanism at low heparin
      concentrations.
AB  - The oxidative mechanism whereby heparin may interact with various proteins was
      investigated in detail in this work by addressing the role of doses of heparin on
      the nature and effects of its binding to bovine trypsin, taken as reference
      protein. Unfractionated heparin was used at concentrations ranging from 6 to 400
      microg/ml with a fixed trypsin concentration (250 microg/ml). At concentrations
      of up to 60 microg/ml, equivalent to trypsin/heparin molar ratios of between 30
      and 3, increasing inhibition of amidolytic activity and radical-dependent peptide
      bond cleavage of the enzyme was observed, with the appearance in the
      electrophoretic pattern of new bands of trypsin fragments to which heparin was
      demonstrated to be bound specifically. Structural modifications were also
      revealed by increases in fluorescence emission spectra. On the whole, however,
      the alterations induced by these heparin concentrations only involved a limited
      number of trypsin molecules. At concentrations from 120 to 400 microg/ml
      (equivalent trypsin/heparin molar ratios of 1.5-0.46), heparin binding to trypsin
      appeared to cause more profound and generalized alterations of enzyme structure
      and function, with dose-dependent quenching of fluorescence emission and almost
      complete loss of amidolytic activity, although evidence of radical production was
      lacking. Collectively, the results stress the crucial role of heparin dose on
      both the nature and effects of its binding to trypsin. The change in heparin
      effects which reflects distinct underlying molecular mechanisms occurs
      dramatically at a critical concentration threshold. While a specific, radical
      generating mechanism operates at low concentrations, less specific ionic
      linkages, apparently independent of radical production, best explain the effects
      of high heparin concentrations.

PMID- 10641733
TI  - Peroxynitrite irreversibly decreases diastolic and systolic function in cardiac
      muscle.
AB  - Much of the damaging action of nitric oxide in heart may be due to its diffusion
      limited reaction with superoxide to form peroxynitrite. Direct infusion of
      peroxynitrite into isolated perfused hearts fails to model the effects of in situ
      formation because the bulk of peroxynitrite decomposes before reaching the
      myocytes. To examine the direct effects of peroxynitrite on the contractile
      apparatus of the heart, we exposed intact and skinned rat papillary muscles to a
      steady state concentration of 4-microM peroxynitrite for 5 min, followed by a 30
      min recovery period to monitor irreversible effects. In intact muscles developed
      force fell immediately to 26% of initial force, recovering to 43% by 30 min.
      Resting tension increased by 600% immediately, and was still elevated 500% by 30
      min. Nitrotyrosine immunochemistry showed that peroxynitrite can induce tyrosine
      nitration at low concentrations and is capable of penetrating 200-380 microm into
      the papillary muscle after a 5-min infusion. Decomposed peroxynitrite had no
      effect on either intact or skinned muscle developed force or resting tension. Our
      results show that peroxynitrite directly damages both developed force and resting
      tension of isolated heart muscle, which can be extrapolated to systolic and
      diastolic injury in intact hearts.

PMID- 10641734
TI  - Differential effect of dopamine catabolism and uptake inhibition on dopamine
      induced calcium dysregulation and viability loss.
AB  - The present study was aimed at evaluating of the effects of dopamine (DA)
      toxicity on PC12 cells' calcium homeostasis, cellular viability, and free radical
      levels. Moreover, the effect of receptor inhibition, and DA metabolism and
      reuptake antagonism on all parameters was also evaluated. Acute treatment with DA
      impaired the ability of PC12 cells to buffer excess calcium after K+
      depolarization, decreased cellular viability by approximately 35%, and increased
      free radical levels by about 10% in a dose dependent manner. Pretreatment with
      both active and inactive pargyl monoamine oxidase inhibitors (MAOi) protected
      PC12 cells from DA toxicity on cellular viability and free radical levels,
      regardless of the presence or absence of their target enzymes in PC12 cells.
      These results suggest a lack of specific involvement of DA metabolism by MAO in
      dopamine's effects on cellular viability and production of free radicals.
      However, DA-induced dysregulation of calcium homeostasis seems to be more
      specifically mediated by DA metabolism by MAO. Results indicate that, in order
      for toxicity to occur the DA must be taken up into the cells. DA receptors do not
      mediate dopamine cytoxicity, and the D2 receptor plays a modest role in DA
      induced calcium dysregulation and generation of free radicals. Moreover, DA
      induced cell viability loss is not mediated by calcium, nor by caspase-3 enzyme,
      but is prevented by inhibition of mitochondrial permeability transition pores.

PMID- 10641735
TI  - Stimulation of reactive oxygen, but not reactive nitrogen species, in vascular
      endothelial cells exposed to low levels of arsenite.
AB  - Elevated levels of arsenite, the trivalent form of arsenic, in drinking water
      correlates with increased vascular disease and vessel remodeling. Previous
      studies from this laboratory demonstrated that environmentally relevant
      concentrations of arsenite caused oxidant-dependent increases in nuclear
      transcription factor levels in cultured porcine vascular endothelial cells. The
      current studies characterized the reactive species generated in these cells
      exposed to levels of arsenite that initiate cell signaling. These exposures did
      not deplete 5'-triphosphate, nor did they affect basal or bradykinin-stimulated
      intracellular free Ca2+ levels, indicating that they were not lethal. Electron
      paramagnetic resonance (EPR) spectroscopy, including spin trapping with carboxy
      PTIO (cPTIO), demonstrated that 5 microM or less of arsenite did not increase *NO
      levels over a 30-min period relative to *NO release stimulated by bradykinin.
      However, these same levels of arsenite rapidly increased both oxygen consumption
      and superoxide formation, as measured by EPR oximetry and spin trapping with 5,5
      dimethyl-1-pyrroline N-oxide (DMPO), respectively. Pretreatment of the cells with
      DPI, apocynin, or superoxide dismutase abolished arsenite-stimulated DMPO-OH
      adduct formation. Finally arsenite increased extracellular accumulation of H2O2,
      measured as oxidation of homovanillic acid, with the same time and dose
      dependence, as seen for superoxide formation. These data suggest that superoxide
      and H2O2 are the predominant reactive species produced by endothelial cells after
      arsenite exposures that stimulate cell signaling and activate transcription
      factors.

PMID- 10641736
TI  - Antioxidant capacity of flavanols and gallate esters: pulse radiolysis studies.
AB  - Reactivities of several proanthocyanidins (monomers of condensed tannins) and
      gallate esters (representing hydrolyzable tannins) with hydroxyl radicals, azide
      radicals, and superoxide anions were investigated using pulse radiolysis combined
      with kinetic spectroscopy. We determined the scavenging rate constants and the
      decay kinetics of the aroxyl radicals both at the wavelength of the semiquinone
      absorption (275 nm) and the absorption band of the gallate ester ketyl radical
      (400-420 nm). For most compounds second-order decay kinetics were observed, which
      reflect disproportionation of the semiquinones. In the case of the oligomeric
      hydrolysable tannins, pentagalloyl glucose and tannic acid, the decay kinetics
      were more complex involving sequential first-order and second-order reactions,
      which could only be resolved by kinetic modeling. A correlation of the reaction
      rates with hydroxyl radicals (k*OH) with the number of adjacent aromatic hydroxyl
      groups (i.e., representing catechol and/or pyrogallol structures) was obtained
      for both condensed and hydrolyzable tannins. Similar correlation for the
      reactions with azide radicals and superoxide anions are less obvious, but exist
      as well. We consider proanthocyanidins superior radical scavenging agents as
      compared with the monomeric flavonols and flavones and propose that these
      substances rather than the flavonoids proper represent the antioxidative
      principle in red wine and green tea.

PMID- 10641737
TI  - TEAC antioxidant activity of 4-hydroxybenzoates.
AB  - The influence of pH, intrinsic electron donating capacity, and intrinsic hydrogen
      atom donating capacity on the antioxidant potential of series of hydroxy and
      fluorine substituted 4-hydroxybenzoates was investigated experimentally and also
      on the basis of computer calculations. The pH-dependent behavior of the compounds
      in the TEAC assay revealed different antioxidant behavior of the nondissociated
      monoanionic form and the deprotonated dianionic form of the 4-hydroxybenzoates.
      Upon deprotonation the radical scavenging ability of the 4-hydroxybenzoates
      increases significantly. For mechanistic comparison a series of fluorobenzoates
      was synthesized and included in the studies. The fluorine substituents were shown
      to affect the proton and electron donating abilities of 4-hydroxybenzoate in the
      same way as hydroxyl substituents. In contrast, the fluorine substituents
      influenced the TEAC value and the hydrogen atom donating capacity of 4
      hydroxybenzoate in a way different from the hydroxyl moieties. Comparison of
      these experimental data to computer-calculated characteristics indicates that the
      antioxidant behavior of the monoanionic forms of the 4-hydroxybenzoates is not
      determined by the tendency of the molecule to donate an electron, but by its
      ability to donate a hydrogen atom. Altogether, the results explain qualitatively
      and quantitatively how the number and position of OH moieties affect the
      antioxidant behavior of 4-hydroxybenzoates.

PMID- 10641738
TI  - Aging and high concentrations of glucose potentiate injury to mitochondrial DNA.
AB  - Deletions of mitochondrial DNA (mtDNA) are associated with aging and several
      chronic diseases. We have reported heterogeneous mutations between base pair 8468
      and 13446 in mtDNA, the region known as the "common" deletion, in muscle of older
      humans with impaired glucose tolerance or diabetes mellitus. To further
      characterize potential effects of age and glycemia on mtDNA integrity, we studied
      corpulent JCR:LA-cp rats that are characterized by insulin resistance,
      hyperinsulinemia, and hyperlipidemia, factors strongly associated with both aging
      and cardiovascular disease. In addition to skeletal muscle, we isolated vascular
      smooth muscle cells (VSMC) from aortas of 6-, 12-, and 17-month-old rats and
      exposed them to 5-, 25-, 62-, and 100-mM glucose or a combination of hypoxanthine
      (100 microM) and xanthine oxidase (0.025 U/ml) to generate reactive oxygen
      species in separate cultures. Long- and short-fragment and nested polymerase
      chain reaction was used to detect mutations in the common deletion region. The
      data demonstrate that aging and the cp genotype confer susceptibility to mtDNA
      deletions in vivo and that high glucose concentrations can induce mtDNA mutations
      in vitro. Accordingly, aging and glucose-related oxidative stress and possibly
      hyperinsulinemia may contribute to alterations in mitochondrial gene integrity
      and the cp genotype appears to increase the susceptibility of muscle to the age
      related accumulation of mtDNA mutations.

PMID- 10641739
TI  - On the role of bicarbonate in peroxidations catalyzed by Cu,Zn superoxide
      dismutase.
AB  - The interaction of Cu,ZnSOD with H2O2 generates an oxidant at the active site
      that can then cause either the inactivation of this enzyme or the oxidation of a
      variety of exogenous substrates. We show that the rate of inactivation, imposed
      by 10-mM H2O2 at 25 degrees C and pH 7.2, is not influenced by 10-mM HCO3-;
      whereas the oxidation of 2,2'-azino-bis-[3-ethylbenzothiazoline sulfonate]
      (ABTS=) is virtually completely dependent upon HCO3-. The reduction of the active
      site Cu(II) by H2O2, which precedes inactivation of the enzyme, occurred at the
      same rate in phosphate buffer with or without bicarbonate added. These results
      indicate that HCO3- does not play a role in facilitating the interaction of H2O2
      with the active site copper, but they can be accommodated by the proposal that
      HCO3- is oxidized to HCO3*, which then diffuses from that site and causes the
      oxidation of substrates, such as ABTS=, that are too large to traverse the
      solvent access channel to the Cu(II).

PMID- 10641740
TI  - Ozone-induced inflammation assessed in sputum and bronchial lavage fluid from
      asthmatics: a new noninvasive tool in epidemiologic studies on air pollution and
      asthma.
AB  - We investigated correlations between ozone-induced increases in inflammatory
      markers in induced sputum and in bronchial lavage fluid. Sixteen volunteers with
      intermittent asthma participated in a placebo-controlled parallel study with two
      exposures. Six days before and 16 h after the first exposure to ozone (0.4 ppm
      during 2 h) sputum was induced with hypertonic saline. This resulted in a
      significant increase in the sputum levels of eosinophil cationic protein (ECP;
      1.8-fold; p = .03), neutrophil elastase (5.0-fold; p = .005) and the total cell
      number (1.6-fold; p = .02). After 4 weeks, a second exposure was randomized for
      air or ozone. Six days before and 16 h after the second exposure a bronchial
      lavage was performed. ECP values in sputum and in bronchial lavage fluid obtained
      after ozone correlated significantly (Rs = .79; p = .04), as did interleukin-8
      (IL-8) values (Rs = .86; p = .01), and the percentage eosinophils (Rs = .89; p =
      .007). Moreover, the ozone-induced changes in percentage eosinophils observed in
      sputum and lavage fluid were highly correlated (Rs = .93; p = .003). In
      conclusion, changes in eosinophils, IL-8, and ECP markers induced by ozone and
      measured in sputum reflect the inflammatory responses in the lower airways of
      asthmatics, and may provide a noninvasive tool in epidemiologic studies on air
      pollution and asthma.

PMID- 10641741
TI  - Role of an oxidative stress in the macrophage dysfunction caused by
      erythrophagocytosis.
AB  - A phagocytic challenge with immunoglobulin G (IgG)-coated erythrocytes (EIgGs)
      has been shown to cause a subsequent depression of macrophage respiratory burst
      capacity and phagocytic function. The present study evaluated the hypothesis that
      this macrophage dysfunction is caused by an oxidative stress. An oxidative stress
      induced by ferric ammonium citrate (FAC) plus cumene hydroperoxide (CHP) caused a
      depression of macrophage function that was attenuated by antioxidants and iron
      chelators. In contrast, the same antioxidants and iron chelators did not alter
      changes caused by a challenge with EIgGs. EIgG challenge caused an increase in
      lipid peroxidation but failed to deplete glutathione (GSH) or decrease the
      activity of glyceraldehyde-3-phosphate dehydrogenase (GA-3-PD), suggesting that
      there was only a slight oxidative stress. Inhibition of the Fc gamma receptor (Fc
      gammaR) stimulated respiratory burst by removing calcium during the challenge did
      not attenuate the changes caused by an EIgG challenge. A phagocytic challenge
      with nonerythrocyte particles, IgG-coated beads (BIgGs), did not depress the
      respiratory burst capacity but did depress phagocytic function. Fc gammaR
      expression was depressed following a phagocytic challenge but not an oxidative
      stress. Thus, an oxidative stress can depress macrophage function, but the
      dysfunction caused by a phagocytic challenge with EIgGs involves Fc gammaR
      depletion and the erythrocyte contents rather than an oxidative stress.

PMID- 10641742
TI  - The use of phenylalanine to detect hydroxyl radical production in vivo: a
      cautionary note.

PMID- 10641743
TI  - The role of protein kinase C in the regulation of cell growth and in signalling
      to the cell nucleus.
AB  - The protein kinase C (PKC) family of serine/threonine kinases consists of at
      least 11 mammalian isoforms, which show slight differences in their molecular
      structure and enzymatic properties. PKC isoforms are involved in a wide variety
      of intracellular signalling events and play an important role in tumour promotion
      and cell growth control in general. Studies of expression levels in cancer cells
      and studies using overexpression of single isoforms or expression of dominant
      negative isoforms reveal that, depending on the cellular background, PKC isoforms
      can either promote or inhibit cell growth. To understand the role of PKC isoforms
      in growth control, it is essential to understand how PKC functions in the
      intracellular signalling cascades towards the cell nucleus. Recent work has shown
      that PKC isoforms can act either in the cytoplasm, and cause nuclear effects
      indirectly by triggering signalling pathways directed towards the cell nucleus,
      or, after translocation and activation, can themselves act in the cell nucleus.

PMID- 10641744
TI  - Evaluation of Epstein-Barr virus infection in sinonasal small round cell tumors.
AB  - Sinonasal undifferentiated carcinoma, olfactory neuroblastoma and malignant
      melanoma of the sinonasal regions are included within the category of small round
      cell tumors of the sinonasal region. It is difficult to diagnose these tumors on
      the basis of light-microscopic features alone, but, in some instances,
      immunohistochemical staining evaluating cytokeratin and S-100 protein, for
      example, is of value. On the other hand, the sinonasal region is a significant
      site for Epstein-Barr-virus (EBV)-related tumors, including sinonasal
      undifferentiated carcinoma or malignant lymphoma. Twenty-three sinonasal small
      round cell tumors (SSRCT) comprising 5 sinonasal undifferentiated carcinomas, 9
      olfactory neuroblastomas and 9 malignant melanomas were evaluated for the
      presence of EBV infection by in situ hybridization for EBV-encoded RNA, combined
      with immunostaining for EBV-related proteins (LMP-1 and EBNA2). Furthermore, 55
      SSRCT comprising 37 sinonasal undifferentiated carcinomas, 9 olfactory
      neuroblastomas, and 9 malignant melanomas were examined for the presence of
      cytokeratins (AE1/ AE3 and CAM5.2), S-100 protein and p53 protein using
      immunohistochemical staining. According to in situ hybridization for detecting
      EBV-encoded RNA 1 (EBER1), all of the sinonasal undifferentiated carcinomas
      showed clear, intense hybridization signals localized over the nuclei of the
      tumor cells and, in 3 out of 9 (33.3%) malignant melanomas, hybridization signals
      were also recognized. However, none of the olfactory neuroblastomas revealed
      hybridization signals. Immunohistochemically, 4 out of 5 (80%) sinonasal
      undifferentiated carcinomas were positive for LMP-1, whereas only 2 out 9 (22.2%)
      malignant melanomas and no olfactory neuroblastomas were positive. With regard to
      EBNA2, sinonasal undifferentiated carcinomas, malignant melanomas and olfactory
      neuroblastomas were all negative. Out of 37 sinonasal undifferentiated carcinomas
      35 (94.6%) showed a diffuse positive immunoreaction for AE1/AE3, whereas neither
      olfactory neuroblastoma nor malignant melanoma revealed a positive reaction. All
      9 malignant melanomas and 6 out of 9 olfactory neuroblastomas (75%) were positive
      for S-100 protein, whereas only 6 cases of sinonasal undifferentiated carcinomas
      (19.4%) were positive. As for p53 protein, 16 of 37 sinonasal undifferentiated
      carcinomas (43.2%) were positive, whereas neither olfactory neuroblastoma nor
      malignant melanoma revealed any positive reaction. The above results suggest that
      EBV infection is closely associated with sinonasal undifferentiated carcinomas,
      and that some malignant melanomas may also have a relationship with its
      infection. For the differential diagnosis of SSRCT, it is important to evaluate
      EBV infection along with immunohistochemical staining for cytokeratins and S-100
      protein. The overexpression of p53 protein was found to be related to the
      oncogenesis of sinonasal undifferentiated carcinoma; however, there was no
      association between its overexpression and malignant melanoma or olfactory
      neuroblastoma.

PMID- 10641745
TI  - alpha-Chemokine growth factors for adenocarcinomas; a synthetic peptide inhibitor
      for alpha-chemokines inhibits the growth of adenocarcinoma cell lines.
AB  - PURPOSE: The experiments aimed to determine if alpha-chemokine inhibitors are
      effective suppressors of the growth of adenocarcinomas, a neoplasm with a high
      mortality rate. METHODS: Expression of growth-related oncogene (GROalpha) and
      interleukin-8 (IL-8) was determined by enzyme-linked immunosorbent assay.
      Inhibition of alpha-chemokine binding to tumor cells was assessed in the presence
      and absence of the hexapeptide, antileukinate. 3-(4,5-Dimethylthiazol-2-yl)-2,5
      diphenyltetrazolium bromide assays were performed to determine the effect of
      alpha-chemokines, monoclonal antibodies (mAb), and antileukinate on cell
      proliferation. Finally, antileukinate inhibition of human, lung adenocarcinoma
      tumor growth, was determined in BALB/c nude mice. RESULTS: All of the
      adenocarcinomas tested produced either GROalpha or IL-8 or both. Proliferation of
      lung, stomach and colon adenocarcinoma cells was inhibited by anti-GROalpha mAb
      and/or anti-IL-8 mAb while recombinant human GROalpha stimulated the
      proliferation of lung and stomach adenocarcinomas. Antileukinate inhibited
      GROalpha binding to specific receptors on adenocarcinoma cells and inhibited the
      proliferation of all adenocarcinomas tested. Colon-derived adenocarcinomas
      specifically bound IL-8 and this binding was also inhibited by antileukinate.
      Administration of antileukinate in vivo inhibited the tumor growth of
      adenocarcinoma A549. CONCLUSIONS: GROalpha and IL-8 are necessary for the growth
      of lung, stomach and colon adenocarcinomas, and can be inhibited by the
      hexapeptide, antileukinate. The findings suggest the possibility of using alpha
      chemokine receptor inhibitors in the treatment of adenocarcinoma.

PMID- 10641746
TI  - Myocardial enzyme activities in plasma after whole-heart irradiation in rats.
AB  - Plasma levels of myocardial enzymes present after local heart irradiation were
      studied in a rat model. The purpose was to investigate whether, within days after
      irradiation, these enzyme levels change to such an extent that they may be
      helpful in assessing the severity of cardiac damage after radiotherapy.
      Therefore, activities of creatine kinase (CK), lactate dehydrogenase (LDH),
      aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alpha
      hydroxybutyrate dehydrogenase (alpha-HBDH) were determined in the plasma and left
      ventricular myocardium of rats following local heart irradiation with a single
      dose of 20 Gy. A dose of 20 Gy is known to cause irreversible cardiac damage and
      to reduce survival times of the animals. Cardiac enzyme assays were performed
      directly after and twice daily for up to 2 weeks after radiation. Plasma CK, LDH,
      AST and alpha-HBDH levels were increased between 2 h and 24 h after irradiation.
      Plasma ALT levels remained unchanged. Myocardial enzyme levels, measured between
      24 h and 16 days after radiation, did not differ between irradiated and control
      animals, although acute (first 12 h) reductions were observed in the irradiated
      group. The elevated enzyme levels in plasma appeared to correlate with the
      acutely reduced myocardial enzyme levels. Although irradiation with a dose of 20
      Gy induced acute rises of cardiac enzyme levels in plasma, it is doubtful that
      fractionated radiation, as applied clinically for treatment of solid tumors, will
      induce plasma enzyme elevations that are large enough to indicate the extent of
      cardiac damage occurring acutely or chronically.

PMID- 10641747
TI  - Enhanced migration of the acute promyelocytic leukemia cell line NB4 under in
      vitro conditions during short-term all-trans-retinoic acid treatment.
AB  - All-trans-retinoic acid (RA) is a potent differentiating agent that is very
      effective in the treatment of patients with acute promyelocytic leukemia (APL).
      Since clinical response can be accompanied by extramedullary manifestations, we
      have investigated the influence of RA on cell adhesion to and migration through
      reconstituted basement membranes (Matrigel) in the APL cell line NB4. No apparent
      cellular differentiation was observed during a 24-h incubation with 1 microM RA,
      as indicated by the nitroblue tetrazolium reduction test. However, exposure to RA
      significantly enhanced NB4 cell adhesion to Matrigel and consecutive migration
      through Matrigel barriers in a dose-dependent manner. Several integrin molecules
      potentially involved in this process, i.e., CD29, CD18, CD11a, CD11b and CD11c,
      were therefore studied by fluorescence-activated cell sorting analysis. The
      expression of the beta subunit of the beta2 integrins (CD18), but not that of
      beta1 integrins (CD29), was increased during 24-h RA treatment. Among the beta2
      integrins, the expression of LFA-1 (CD11a) and of Mac-1 (CD11b), but not of
      p150,95 (CD11c), was induced by RA. When monoclonal antibodies that specifically
      block the interaction of these integrins with their ligands were used, we
      observed that CD29 is only involved in adhesion and CD11b only in migration,
      whereas CD11a participates in both processes. NB4 cells constitutively secreted
      the matrix metalloproteinases MMP-9 and MMP-2, which are known to promote
      cellular invasion processes by degradation of the extracellular matrix. RA
      treatment had no influence on the quantity of secreted MMP-9 or MMP-2 in these
      cells as determined by zymography. Addition of Batimastat (BB-94), a synthetic
      inhibitor of matrix metalloproteinases, blocked RA-induced cell migration without
      affecting cellular adhesion to Matrigel. These findings indicate that adhesion
      molecules as well as matrix metalloproteinases are involved in RA-stimulated
      migration of NB4 cells through Matrigel, possibly providing some explanation of
      tissue infiltration by leukemic cells as observed during treatment of APL
      patients with RA.

PMID- 10641749
TI  - p21WAF1 protein expression determined by quantitative immunoassay in relation to
      non-small-cell lung cancer aggressiveness.
AB  - PURPOSE: p21WAF1, a cyclin-dependent kinase inhibitor, is an important mediator
      of the cell-cycle arrest and tumor suppression induced by the protein p53.
      Although alterations of the p53 gene and its overexpression are frequent in most
      malignancies, including non-small-cell lung cancer (NSCLC), and may be associated
      with poor patient prognosis, the clinical utility of p21WAF1 expression in NSCLC
      has not been established. METHODS: We have used a commercial enzyme-linked
      immunosorbent assay (ELISA) kit for p21WAF1 to test soluble extracts of 54 NSCLC
      specimens with known clinicopathological properties. RESULTS: There was no
      correlation between p21WAF1 and p53 concentrations, the latter being determined
      by a time-resolved immunofluorometric assay developed in-house. Furthermore,
      p21WAF1 levels were not associated with patient age, tumor/node/metastasis (TNM)
      stage, lymph node metastasis, histological grade or type, or smoking history, in
      Mann-Whitney analysis. chi2-tests, based on cutoffs equal to the 25th, 50th, or
      75th percentiles of the p21WAF1 distribution, similarly did not reveal any
      statistically significant associations between p21WAF1 and other
      clinicopathological variables. Because of the small number of patients and the
      median follow-up of only 18 months, a meaningful survival analysis could not be
      performed. CONCLUSION: In summary, this preliminary study suggests that ELISA
      quantified p21WAF1 levels in NSCLC extracts are weaker than p53 in terms of
      prognostic value and do not contribute to the further subclassification of
      patients.

PMID- 10641748
TI  - Repeated administration of short infusions of bendamustine: a phase I study in
      patients with advanced progressive solid tumours.
AB  - PURPOSE: The cytotoxic agent bendamustine combines a purine-like benzimidazol and
      bifunctionally alkylating nitrogen mustard group. The drug has clinical
      antitumour activity in lymphoma, myeloma and breast cancer. In earlier dose
      finding studies, the clinically tolerated dose for single-bolus bendamustine was
      215 mg/m2; for fractionated therapy on 4 consecutive days it was 85 mg/m2.
      Anticholinergic symptoms, myelosuppression and cardiac dysrhythmia were dose
      limiting. Our trial was designed to define the maximum tolerated dose of a short
      infusion schedule and to establish a recommended dose for ongoing and future
      clinical studies. METHODS: Patients with refractory malignant tumours qualified
      for the trial after written informed consent had been obtained. Bendamustine was
      given as a 30-min iv. infusion on days 1 and 8 of a 4 week cycle, with a starting
      dose of 100 mg/m2 and an increment per group of 20 mg/m2. RESULTS: Nineteen
      patients (13 male, 6 female; median age 57 years, range 37-74 years) were treated
      for one to two cycles with up to 180 mg/m2 bendamustine. At 160 mg/m2, fatigue
      grade 3 (NCI Common Toxicity Criteria) and dryness of the mouth grade 3 occurred
      in 2 patients, diarrhoea grade 3 in 1 patient; another patient with a history of
      myocardial infarction and arrhythmia developed a reversible total
      atrioventricular block after the first administration of 160 mg/m2 bendamustine.
      Other events, such as nausea/vomiting, loss of appetite, fever or chills, were
      not dose-limiting. Haematological toxicity was mild, except for sudden and long
      lasting grade 3-4 lymphocytopenia, which occurred in all treatment cycles.
      Opportunistic infections were not observed. CONCLUSIONS: The maximum tolerated
      dose of a days-1 and -8 schedule of bendamustine, given as a 30-min i.v.
      infusion, is 160 mg/ m2; mouth dryness and fatigue are dose-limiting. The
      recommended dose for future trials is 140 mg/m2.

PMID- 10641750
TI  - Determination of the cellular retinoic-acid-binding protein in dysplastic
      epithelia of the cervix uteri, differentiated into apo and holo forms.
AB  - PURPOSE: The appearance of the cervical mucosa is regulated by different factors
      including retinoic acid. Hormone-dependent alteration of the cervix uteri mucosa
      is accompanied by a decrease or increase of cytoplasmatic retinoic-acid-binding
      protein (CRABP). To elucidate whether this hormone-dependent alteration of CRABP
      is preserved in the case of neoplasms of the cervix uteri, we measured the level
      of total and apo-CRABP in normal and neoplastically transformed cervical cells.
      METHODS: In a prospective pilot study, standardised biopsies of normal epithelium
      and cervical intra-epithelial neoplasm grade 3 (CIN III) were taken from 24
      patients. A newly developed method was used to determine the intra-epithelial
      level of apo- and total CRABP. RESULTS: The concentration of total CRABP in
      normal squamous epithelium compared with that in intra-epithelial neoplasm grade
      3 is very significantly lower in the CIN III areas (normal: 3.66 +/- 1.46 pmol/
      mg wet weight +/- SD; CIN III 1.43 +/- 0.59 pmol/mg P < 0.01). In addition CRABP
      in the apo form is lower in normal than in neoplastic epithelium (Wilcoxon test
      for paired non-parametric values: P < 0.05; mean for all patients: normal: 1.65 +
      0.82 pmol/mg; CIN III: 1.14 +/- 0.23 pmol/mg). CONCLUSION: From our results we
      conclude that, in neoplastically transformed cells, the hormone-dependent CRABP
      cycle is interrupted. Whether this has consequences for the further development
      of the neoplastic cells has to be elucidated.

PMID- 10641751
TI  - Expression of platelet-derived endothelial cell growth factor and vascular
      endothelial growth factor in hepatocellular carcinoma and portal vein tumor
      thrombus.
AB  - PURPOSE: Both platelet-derived endothelial cell growth factor (PD-ECGF) and
      vascular endothelial growth factor (VEGF) are known to promote the development of
      new blood vessels, which are fundamental to tumor growth and metastasis. We aimed
      at evaluating the gene expression of PD-ECGF and VEGF in hepatocellular carcinoma
      (HCC) and portal vein tumor thrombus (PVTT). PATIENTS AND METHODS: Surgical
      specimens (28 HCC, 28 nontumorous liver tissues and 18 PVTT) were studied by
      Northern blot analysis. The levels of PD-ECGF mRNA and VEGF mRNA expression were
      measured by densitometric scanning of the autoradiographs, and they were
      normalized to the level of expression of an internal control
      (glyceraldehydephosphate dehydrogenase) mRNA. RESULTS: The expression rates of PD
      ECGF mRNA in PVTT, HCC and nontumorous liver tissues were 77.8% (14/18), 67.9%
      (19/28) and 35.7% (10/28), being 88.9% (16/18), 75.0% (21/28) and 17.9% (5/28)
      respectively for VEGF mRNA. The expressions of PD-ECGF mRNA and VEGF mRNA were
      higher in HCC with PVTT than when PVTT was absent (P < 0.05). The PVTT was more
      often seen in patients with positive expression of both PD-ECGF mRNA and VEGF
      mRNA in HCC than in patients who were positive for only one of these factors or
      negative for both (P < 0.05). CONCLUSION: Both PD-ECGF and VEGF correlated well
      with the formation of PVTT of HCC.

PMID- 10641752
TI  - Mutant p53 protein, Bcl-2/Bax ratios and apoptosis in paediatric acute
      lymphoblastic leukaemia.
AB  - PURPOSE: The Bcl-2 family of proteins regulates a late step in the apoptosis
      pathway. Bcl-2 protein is believed to be involved in imparting resistance to
      programmed cell death or apoptosis induced by chemotherapeutic agents and
      radiation. The anti-apoptotic function of the Bcl-2 protein appears to be
      modulated by its ability to heterodimerize with other members of the gene family,
      predominantly Bax, a protein favouring induction of apoptosis. Susceptibility to
      undergoing apoptosis may, therefore, be dependent on the ratio between Bcl-2 and
      Bax. Both Bax and Bcl-2 are regulated by the tumour-suppressor protein p53. The
      present study therefore aims to study the significance of the Bcl-2:Bax ratio,
      p53 expression and apoptosis in paediatric acute lymphoblastic leukaemia (ALL).
      METHODS: Expression of Bax, Bcl-2 and p53 was determined by immunocytochemistry,
      and apoptosis was evaluated by an enzymatic end-labelling technique using biotin
      dUTP and further confirmed by annexin binding. The presence of mutant p53 was
      determined using a mutant-p53-specific enzyme-linked immunosorbent assay (ELISA).
      RESULTS: A total of 32 cases and 20 controls were evaluated. Bcl-2 was found to
      be expressed in 22/32 of the ALL cases. Pretreatment (spontaneous) apoptosis was
      observed in 23/32 cases. The mean pretreatment apoptotic index was 11.34 +/-
      2.04% with a median value of 7.5%. CONCLUSIONS: There was a positive correlation
      between apoptosis and Bax expression (r = 0.5044; P = 0.0038). There was good
      correlation between the immunoreactivity of p53 and detection of mutant p53 by
      ELISA (r = 0.4605; P = 0.0079). The apoptosis index showed a negative borderline
      correlation to the expression of Bcl-2 protein (r = -0.3181; P = 0.076). There
      was an inverse correlation between extent of apoptosis and the presence of mutant
      p53 protein (r = -0.4732; P = 0.006). p53 protein expression also showed a
      correlation with both Bcl-2 (r = 0.4647; P = 0.007) and Bax (r = 0.4128; P =
      0.018). The Bcl-2/Bax ratio, however, showed no significant correlation with
      apoptosis (r = -0.3131; P = 0.08) or with p53 expression. No significant
      association was evident between clinical and laboratory parameters with the Bcl
      2/Bax protein expression except lymphadenopathy (r = 0.5774; P = 0.03). However,
      Bax expression showed a borderline correlation with the immediate tumour response
      to chemotherapy (r = -0.338; P = 0.0628). These patients are being followed-up to
      look for any association between clinical outcome, Bcl-2/Bax ratio and apoptosis.

PMID- 10641753
TI  - Neonatal aspiration lesions of the hippocampal formation impair visual
      recognition memory when assessed by paired-comparison task but not by delayed
      nonmatching-to-sample task.
AB  - Previous experiments showed that neonatal aspiration lesions of the hippocampal
      formation in monkeys yield no visual recognition loss at delays up to 10 min,
      when recognition memory was assessed by a trial-unique delayed nonmatching-to
      sample (DNMS) task. The present study examined whether neonatal hippocampal
      lesions also have no effect on visual recognition when assessed by a visual
      paired-comparison (VPC) task. In the VPC task, animals are looking at visual
      stimuli and their preference for viewing new stimuli is measured. Normal adult
      monkeys showed strong preference for looking at the novel stimuli at all delays
      tested. By contrast, adult monkeys with neonatal hippocampal lesions, which
      included the dentate gyrus, cornus ammon (CA) fields, subicular complex, and
      portions of parahippocampal areas TH/TF, showed preference for novelty at short
      delays of 10 s but not at longer delays of 30 s to 24 h. This visual recognition
      loss contrasts with the normal performance of the same operated animals when
      tested in the DNMS task. The discrepancy between the results obtained in the two
      recognition tasks suggests that, to perform normally on the DNMS task, the
      operated monkeys may have used behavioral strategies that do not depend on the
      integrity of the hippocampal formation. In this respect, VPC appears to be a more
      sensitive task than DNMS to detect damage to the hippocampal region in primates.

PMID- 10641754
TI  - N-methyl-D-aspartate receptor antagonists are less effective in blocking long
      term potentiation at apical than basal dendrites in hippocampal CA1 of awake
      rats.
AB  - Long-term potentiation (LTP) of field excitatory postsynaptic potentials (fEPSPs)
      at the apical or basal dendrites of CA1 pyramidal cells was induced by
      stimulation with a 1-s train of 200-Hz pulses in awake rats, with or without the
      presence of various doses of an N-methyl-D-aspartate (NMDA) receptor antagonist.
      Apical LTP was blocked by an intracerebroventricular (i.c.v.) dose of 40 microg D
      2-amino-5-phosphonopentanoic acid (D-AP5) or 20 mg/kg i.p. D-2-amino-4-methyl-5
      phosphono-3-pentanoic acid (CGP-40116), whereas basal LTP was blocked by half the
      dose of D-AP5 or CGP-40116. The noncompetitive antagonist MK-801 (< or =1 mg/kg
      i.p.) had no significant effect on apical LTP. Apical LTP was not blocked by
      i.c.v. nifedipine. The effect of an NMDA receptor antagonist alone on apical and
      basal fEPSPs was also evaluated, to assess the net effect of the NMDA receptor
      antagonist in blocking LTP. MK-801 (0.5-1 mg/kg i.p.) or CGP-40116 (10-20 mg/kg
      i.p.) but not D-AP5 suppressed apical fEPSPs for several hours and confounded the
      expression of apical LTP during this time. We concluded that hippocampal LTP at
      different synapses has different sensitivity to NMDA receptor antagonists and
      that a general blockade of hippocampal NMDA receptor functions cannot be inferred
      by a single hippocampal LTP measure.

PMID- 10641755
TI  - Synaptogenesis of mossy fibers induced by spatial water maze overtraining.
AB  - Synaptic plasticity has been proposed as a mechanism underlying learning and
      memory. Synaptic reorganization of hippocampal mossy fibers has been observed
      after experimentally induced epilepsy, and after brief high-frequency activation
      inducing long-term potentiation. Furthermore, it has been suggested that synaptic
      changes in the hippocampus may occur after spatial learning. In this study, by
      using a zinc-detecting histologic technique (Timm), we demonstrate a significant
      increase of mossy fiber terminals in the CA3 stratum oriens region induced by
      training rats during 3 days in a spatial Morris water maze. In contrast, animals
      trained for only 1 day and animals that were just allowed to swim or were
      overtrained in a stress-motivated inhibitory avoidance task did not show
      increments of mossy fiber terminals in the stratum oriens. Electron microscopy
      confirmed that synaptic density of mossy fiber terminals in the stratum oriens
      increases significantly in water maze overtrained animals compared with the
      swimming control animals. Taken together, these results suggest that overtraining
      in a spatial learning task induces mossy fiber synaptogenesis that could be
      involved in the mechanisms underlying long-term memory storage. Hippocampus
      1999;9:631-636.

PMID- 10641756
TI  - Parametric fMRI analysis of visual encoding in the human medial temporal lobe.
AB  - A number of functional brain imaging studies indicate that the medial temporal
      lobe system is crucially involved in encoding new information into memory.
      However, most studies were based on differences in brain activity between
      encoding of familiar vs. novel stimuli. To further study the underlying cognitive
      processes, we applied a parametric design of encoding. Seven healthy subjects
      were instructed to encode complex color pictures into memory. Stimuli were
      presented in a parametric fashion at different rates, thus representing different
      loads of encoding. Functional magnetic resonance imaging (fMRI) was used to
      assess changes in brain activation. To determine the number of pictures
      successfully stored into memory, recognition scores were determined afterwards.
      During encoding, brain activation occurred in the medial temporal lobe,
      comparable to the results obtained by others. Increasing the encoding load
      resulted in an increase in the number of successfully stored items. This was
      reflected in a significant increase in brain activation in the left lingual
      gyrus, in the left and right parahippocampal gyrus, and in the right inferior
      frontal gyrus. This study shows that fMRI can detect changes in brain activation
      during variation of one aspect of higher cognitive tasks. Further, it strongly
      supports the notion that the human medial temporal lobe is involved in encoding
      novel visual information into memory.

PMID- 10641757
TI  - Proteome map of the human hippocampus.
AB  - The proteins expressed by a genome have been termed the proteome. By comparing
      the proteome of a disease-affected tissue with the proteome of an unaffected
      tissue it is possible to identify proteins that play a role in a disease process.
      The hippocampus is involved in the processing of short-term memory and is
      affected in Alzheimer's disease. Any comparative proteome analysis that can
      identify proteins important in a disease affecting the hippocampus requires the
      characterization of the normal hippocampal proteome. Therefore, we homogenised
      normal hippocampal tissue and separated the proteins by two-dimensional
      polyacrylamide gel electrophoresis (2DE). Seventy-two unique protein spots were
      collected from Coomassie blue-stained 2DE gels and subjected to in-gel digestion
      with trypsin, reversed-phase high-pressure liquid chromatography peptide
      separation, and N-terminal protein sequencing. Sufficient protein sequence was
      obtained to successfully characterize 66 of the 72 protein spots chosen (92%).
      Three of the 66 proteins were not present in any database (4.5%). The
      characterized proteins comprised two dominant functional groups, i.e., enzymes
      involved in intermediary cellular metabolism (40%), and proteins associated with
      the cytoskeleton (15%). The identity, molecular mass, isoelectric point, and
      relative concentration of the characterized proteins are described and constitute
      a partial proteome map of the normal human hippocampus.

PMID- 10641758
TI  - Neonatal stress alters LTP in freely moving male and female adult rats.
AB  - We previously reported that neonatal isolation stress significantly changes
      measures of hippocampal long-term potentiation (LTP) in male and female juvenile
      rats, i.e., at 30 days of age. The changes in dentate granule population
      measures, i.e., excitatory postsynaptic potential (EPSP) and population spike
      amplitude (PSA), evoked by tetanization of the medial perforant pathway,
      indicated that juvenile rats exposed to neonatal isolation exhibit different
      enhancement profiles with respect to both the magnitude and duration of LTP in a
      sex-specific manner. Isolated males showed a significantly greater enhancement of
      LTP, while female "isolates" showed significantly longer LTP duration when
      compared to all other groups. The present study was designed to determine whether
      the effects of the neonatal isolation stress paradigm endures into adulthood.
      Rats isolated from their mothers for 1 h per day during postnatal days 2-9 were
      surgically prepared at 70-90 days of age, with stimulating and recording
      electrodes placed in the medial perforant pathway and the hippocampal dentate
      gyrus, respectively. Prior to tetanization, no significant effect of sex or
      treatment was obtained for baseline measures of EPSP slope or PSA. In order to
      rule out baseline differences in hippocampal cell excitability in female adult
      rats, we measured the response of dentate granule cells for one estrus cycle and
      found no pretetanization enhancement in the evoked response in either controls or
      previously stressed rats. Following tetanization, there was a significant
      treatment and sex effect. During the induction of LTP, PSA values were
      significantly enhanced in both isolated males and females and had significantly
      longer LTP duration when compared to the unhandled control group. Additionally,
      we observed that females took longer to reach baseline levels than males. Taken
      together, these results indicate that repeated infant isolation stress enhances
      LTP induction and duration in both males and females. These results indicate that
      infant stress alters hippocampal neuroplasticity in such a way that its effect
      endures into adulthood.

PMID- 10641759
TI  - Calibrating space: exploration is important for allothetic and idiothetic
      navigation.
AB  - Allothetic and idiothetic navigation strategies rely on very different cues and
      computational procedures. Allothetic navigation uses the relationships between
      external cues (visual, auditory, and olfactory) and mapping or geometrical
      calculations to locate places. Idiothetic navigation relies on cues generated by
      self-movement (proprioceptive cues or cues from optic, auditory, and olfactory
      flow, or efference copy of motor commands) and path integration to locate a
      present location and/or a starting point. Whereas it is theorized that
      exploratory behavior is used by animals to create a central representation of
      allothetic cues, it is unclear whether exploration plays a role in idiothetic
      navigation. Computational models suggest that either a reference frame,
      calibrated by exploration, or vector addition, without reference to exploration,
      could support path integration. The present study evaluated the contribution of
      exploration in these navigation strategies by comparing its contribution to the
      solution of both allothetic and idiothetic navigation problems. In two
      experiments, rats were trained to forage on an open table for large food pellets,
      which they then carried to a refuge to eat. Once trained, they were given probe
      trials from novel locations in either normal light, which permits the use of
      allothetic cues, or in infrared light, which requires the use of idiothetic cues.
      When faced with a new problem in either lighting condition, the rats first
      explored the foraging table before navigating directly home with the food. That
      exploration is equally important for allothetic and idiothetic navigation,
      suggests that both navigation strategies require a calibrated representation of
      the environment.

PMID- 10641760
TI  - Dentate gyrus-selective colchicine lesion and disruption of performance in
      spatial tasks: difficulties in "place strategy" because of a lack of flexibility
      in the use of environmental cues?
AB  - The effects of intradentate colchicine injections on the performance of tasks
      requiring spatial working and reference memory are controversial. Multiple-site
      colchicine injections (7 microg/microl; via a drawn micropipette) throughout the
      dentate gyrus (DG) of rats (nine sites in each hemisphere, 0.06 microl at each
      site) selectively destroy about 90% of the DG granule cells, as revealed by
      quantitative stereological estimates; stereology also revealed minor neuronal
      losses in the CA4 (33%) and CA1 (23%) subfields, but lack of damage to the CA3
      hippocampal subfield. Spatial reference and working memory were assessed in
      Morris' water maze; in the reference memory task, the rats were required to learn
      a single, fixed location for the platform over several days of training; in the
      working memory task, animals were required to learn a new platform location every
      day, in a matching-to-place procedure. Compared to sham-operated controls,
      lesioned rats showed significant disruption in acquisition of the reference
      memory water maze task; however, the data reveal that these rats did acquire
      relevant information about the task, probably based on guidance and orientation
      strategies. In a subsequent probe test, with the platform removed, lesioned rats
      showed disruption in precise indexes of spatial memory (e.g., driving search
      towards the surroundings of the former platform location), but not in less
      precise indexes of spatial location. Finally, the lesioned rats showed no
      improvement in the match-to-place procedure, suggesting that their working memory
      for places was disrupted. Thus, although capable of acquiring relevant
      information about the task, possibly through guidance and/or orientation
      strategies, DG-lesioned rats exhibit a marked difficulty in place strategies.
      This is particularly evident when these rats are required to deal with one-trial
      place learning in a familiar environment, such as in the working memory version
      of the water maze task, which requires flexibility in the use of previously
      acquired information.

PMID- 10641761
TI  - Of mice and memory.

PMID- 10641762
TI  - Silent synapses in neural plasticity: current evidence.
AB  - Silent synapses, defined as structural specializations for neurotransmission that
      do not produce a physiological response in the receiving cell, may occur
      frequently in neural circuits. Their recruitment to physiological effectiveness
      may be an important component of circuit modification. In several nervous
      systems, evidence from electrophysiological and optophysiological measurements
      has established a strong case for the existence of silent synapses and for their
      emergence as active synapses with appropriate stimulation. During normal
      development and aging, synapses of individual neurons change in number, and many
      of these may be functionally silent at certain stages of their developmental
      trajectory. Changes in their status may contribute to shaping the properties of
      neural pathways during development, often in response to neural activity. In
      general, it is often difficult to distinguish physiological emergence of pre
      established silent synapses from developmental maturation or de novo formation of
      new synapses. Several possible mechanisms for silent synapses and their
      recruitment are reviewed. These include incompletely assembled synapses that lack
      structural components, insufficient availability of key presynaptic proteins, and
      nonfunctional postsynaptic receptors, or presence of receptors that do not
      mediate a postsynaptic response except under specific conditions (conditionally
      silent synapses). The available silent synapses can often be rapidly activated,
      and conversely, active synapses appear to be rapidly silenced in many instances.
      These properties enable silent synapses to participate in short-term facilitation
      and depression. In addition, they may contribute to long-term facilitation and
      potentiation, especially during development.

PMID- 10641763
TI  - Dissociation between the effects of damage to perirhinal cortex and area TE.
AB  - Perirhinal cortex and area TE are immediately adjacent to each other in the
      temporal lobe and reciprocally interconnected. These areas are thought to lie at
      the interface between visual perception and visual memory, but it has been
      unclear what their separate contributions might be. In three experiments, monkeys
      with bilateral lesions of the perirhinal cortex exhibited a different pattern of
      impairment than monkeys with bilateral lesions of area TE. In experiment 1,
      lesions of the perirhinal cortex produced a multimodal deficit in recognition
      memory (delayed nonmatching to sample), whereas lesions of area TE impaired
      performance only in the visual modality. In experiment 2, on a test of visual
      recognition memory (the visual paired comparison task) lesions of the perirhinal
      cortex impaired performance at long delays but spared performance at a very short
      delay. In contrast, lesions of area TE impaired performance even at the short
      delay. In experiment 3, lesions of the perirhinal cortex and lesions of area TE
      produced an opposite pattern of impairment on two visual discrimination tasks,
      simple object discrimination learning (impaired only by perirhinal lesions), and
      concurrent discrimination learning (impaired only by TE lesions). Taken together,
      the findings suggest that the perirhinal cortex, like other medial temporal lobe
      structures, is important for the formation of memory, whereas area TE is
      important for visual perceptual processing.

PMID- 10641764
TI  - Two time windows of anisomycin-induced amnesia for inhibitory avoidance training
      in rats: protection from amnesia by pretraining but not pre-exposure to the task
      apparatus.
AB  - We have studied the effect of training conditions on hippocampal protein
      synthesis-dependent processes in consolidation of the inhibitory avoidance task.
      Adult male Wistar rats were trained and tested in a step-down inhibitory
      avoidance task (0.4 mA foot shock, 24 hr training-test interval). Fifteen minutes
      before or 0, 3, or 6 hr after training, animals received a 0.8-microl
      intrahippocampal infusion of the protein-synthesis inhibitor anisomycin (80
      microg) or vehicle (PBS, pH 7.4). The infusion of anisomycin impaired retention
      test performance in animals injected 15 min before and 3 hr after the training
      session, but not at 0 or 6 h post-training. Pretraining with a low foot shock
      intensity (0.2 mA) 24 hr before training, prevented the amnestic effect of
      anisomycin injected at 15 min before or 3 hr after training. However, simple pre
      exposure to the inhibitory avoidance apparatus did not alter the amestic effects
      of anisomycin. The results suggest that hippocampal protein synthesis is critical
      in two periods, around the time of, and 3 hr after training. A prior weak
      training session, however, which does not itself alter step-down latencies, is
      sufficient to prevent the amnestic effect of anisomycin, suggesting that even if
      not behaviorally detectable, weak training must be sufficient to produce some
      lasting cellular expression of the experience.

PMID- 10641765
TI  - pCREB in the neonate rat olfactory bulb is selectively and transiently increased
      by odor preference-conditioned training.
AB  - Early olfactory preference learning in rat pups occurs when novel odors are
      paired with tactile stimulation, for example stroking. cAMP-triggered
      phosphorylation of cAMP response element binding protein (pCREB) has been
      implicated as a mediator of learning and memory changes in various animals (Frank
      and Greenberg 1994). In the present study we investigate whether CREB is
      phosphorylated in response to conditioned olfactory training as might be
      predicted given the proposed role of the phosphorylated protein in learning. On
      postnatal day 6, pups were trained for 10 min using a standard conditioned
      olfactory learning paradigm in which a conditioned stimulus, Odor, was either
      used alone or paired with an unconditioned stimulus, Stroking (using a fine brush
      to stroke the pup). In some instances stroking only was used. The pups were
      sacrificed at 0, 10, 30, or 60 min after the training. Using Western blot
      analysis, we observed that the majority of olfactory bulbs in conditioned pups
      (Odor + Stroking) had a greater increase in pCREB activation at 10 min after
      training than pups given nonlearning training (Odor only or Stroking only). The
      phosphorylated protein levels were low at 0 min and at 60 min after training.
      This is in keeping with the slightly delayed and short-lived activation period
      for this protein. The localization of pCREB increases within the olfactory bulb
      as seen by immunocytochemistry. Naive pups were not exposed to odor or training.
      There was a significantly higher level of label in mitral cell nuclei within the
      dorsolateral quadrant of the bulb of pups undergoing odor-stroke pairing. No
      significant differences were observed among nonlearning groups (Naive, Odor only,
      or Stroking only) or among any training groups in the granule or periglomerular
      cells of the dorsolateral region. The localized changes in the nuclear protein
      are consistent with studies showing localized changes in the bulb in response to
      a learned familiar odor. The present study demonstrates that selective increases
      in pCREB occur as an early step following pairing procedures that normally lead
      to the development of long-term olfactory memories in rat pups. These results
      support the hypothesized link between pCREB and memory formation.

PMID- 10641766
TI  - A nitric oxide-independent and beta-adrenergic receptor-sensitive form of
      metaplasticity limits theta-frequency stimulation-induced LTP in the hippocampal
      CA1 region.
AB  - The induction of long-term potentiation (LTP) and long-term depression (LTD) at
      excitatory synapses in the hippocampus can be strongly modulated by patterns of
      synaptic stimulation that otherwise have no direct effect on synaptic strength.
      Likewise, patterns of synaptic stimulation that induce LTP or LTD not only modify
      synaptic strength but can also induce lasting changes that regulate how synapses
      will respond to subsequent trains of stimulation. Collectively known as
      metaplasticity, these activity-dependent processes that regulate LTP and LTD
      induction allow the recent history of synaptic activity to influence the
      induction of activity-dependent changes in synaptic strength and may thus have an
      important role in information storage during memory formation. To explore the
      cellular and molecular mechanisms underlying metaplasticity, we investigated the
      role of metaplasticity in the induction of LTP by theta-frequency (5-Hz) synaptic
      stimulation in the hippocampal CA1 region. Our results show that brief trains of
      theta-frequency stimulation not only induce LTP but also activate a process that
      inhibits the induction of additional LTP at potentiated synapses. Unlike other
      forms of metaplasticity, the inhibition of LTP induction at potentiated synapses
      does not appear to arise from activity-dependent changes in NMDA receptor
      function, does not require nitric oxide signaling, and is strongly modulated by
      beta-adrenergic receptor activation. Together with previous findings, our results
      indicate that mechanistically distinct forms of metaplasticity regulate LTP
      induction and suggest that one way modulatory transmitters may act to regulate
      synaptic plasticity is by modulating metaplasticity.

PMID- 10641768
TI  - One year later.

PMID- 10641769
TI  - Use of the peritoneal cavity for therapeutic delivery.

PMID- 10641767
TI  - Plasma membrane ordering agent pluronic F-68 (PF-68) reduces neurotransmitter
      uptake and release and produces learning and memory deficits in rats.
AB  - A substantial body of evidence indicates that aged-related changes in the
      fluidity and lipid composition of the plasma membrane contribute to cellular
      dysfunction in humans and other mammalian species. In the CNS, reductions in
      neuronal plasma membrane order (PMO) (i.e., increased plasma membrane fluidity)
      have been attributed to age as well as the presence of the beta-amyloid peptide
      25-35, known to play an important role in the neuropathology of Alzheimer's
      disease (AD). These PMO increases may influence neurotransmitter synthesis,
      receptor binding, and second messenger systems as well as signal transduction
      pathways. The effects of neuronal PMO on learning and memory processes have not
      been adequately investigated, however. Based on the hypothesis that an increase
      in PMO may alter a number of aspects of synaptic transmission, we investigated
      several neurochemical and behavioral effects of the membrane ordering agent, PF
      68. In cell culture, PF-68 (nmoles/mg SDS extractable protein) reduced
      [3H]norepinephrine (NE) uptake into differentiated PC-12 cells as well as reduced
      nicotine stimulated [3H]NE release. The compound (800-2400 microg/kg, i.p.,
      resulting in nmoles/mg SDS extractable protein in the brain) decreased step
      through latencies and increased the frequencies of crossing into the unsafe side
      of the chamber in inhibitory avoidance training. In the Morris water maze, PF-68
      increased the latencies and swim distances required to locate a hidden platform
      and reduced the time spent and distance swam in the previous target quadrant
      during transfer (probe) trials. PF-68 did not impair performance of a well
      learned working memory task, the rat delayed stimulus discrimination task (DSDT),
      however. Studies with 14C-labeled PF-68 indicated that significant (pmoles/mg wet
      tissue) levels of the compound entered the brain from peripheral (i.p.)
      injection. No PF-68 related changes were observed in swim speeds or in visual
      acuity tests in water maze experiments, rotorod performance, or in tests of
      general locomotor activity. Furthermore, latencies to select a lever in the DSDT
      were not affected. These results suggest that PF-68 induced deficits in learning
      and memory without confounding peripheral motor, sensory, or motivational effects
      at the tested doses. Furthermore, none of the doses induced a conditioned taste
      aversion to a novel 0.1% saccharin solution indicating a lack of nausea or
      gastrointestinal malaise induced by the compound. The data indicate that
      increases in neuronal plasma membrane order may have significant effects on
      neurotransmitter function as well as learning and memory processes. Furthermore,
      compounds such as PF-68 may also offer novel tools for studying the role of
      neuronal PMO in mnemonic processes and changes in PMO resulting from age-related
      disorders such as AD.

PMID- 10641770
TI  - Y2K and the peritoneal dialysis patient.

PMID- 10641771
TI  - Vascular and interstitial changes in the peritoneum of CAPD patients with
      peritoneal sclerosis.
AB  - OBJECTIVE: To analyze morphological changes in the peritoneum of peritoneal
      sclerosis (PS) patients. Emphasis was put on vascular abnormalities, because the
      continuous exposure to glucose-based dialysis solutions could cause diabetiform
      changes and because longitudinal transport studies suggested the development of a
      large peritoneal vascular surface area. DESIGN: Peritoneal biopsies from
      continuous ambulatory peritoneal dialysis (CAPD) patients were investigated in
      two studies. Diabetic patients were excluded. In study 1, 11 PS biopsies were
      compared to three control groups varying in duration of CAPD treatment: 0 months
      (n = 15), 2 - 25 months (n = 7), and > 25 months CAPD (n = 7). The second study
      was a case-control study, comparing six biopsies from the long-term control group
      to six PS biopsies, matched for age and duration of CAPD. All biopsies were
      scored for presence and type of fibrosis [Picro Sirius red, type IV collagen,
      alpha-smooth muscle actin (alphaSMA)] and for neoangiogenesis (factor VIII).
      Thickening of vascular walls by type IV collagen and vasodilation of capillaries
      were measured by computer-aided planimetry. RESULTS: In study 1 the presence of
      sclerosing fibrosis, deposition of interstitial type IV collagen, and the number
      of myofibroblasts (alphaSMA-positive cells) was greater in the PS biopsies than
      biopsies from all control groups (p < 0.002). Moreover, the number of vessels per
      field was higher in PS biopsies (p < 0.01). Vascular wall thickening of small
      arteries (p < 0.008) and vasodilation of capillaries were found in PS biopsies
      compared to all control groups (p < 0.007). The second study revealed differences
      in the presence of sclerosis but not in the extent of fibrosis between PS
      biopsies and their controls. The number of vessels per field in PS biopsies was
      higher compared to controls (p = 0.04). Also, thickening of the vascular wall was
      more marked in PS biopsies (p = 0.03). Vasodilation of capillaries was greater in
      PS biopsies than in controls (p = 0.07). CONCLUSION: Fibrosis of the peritoneum
      may precede peritoneal sclerosis. The deposition of type IV collagen and the
      presence of myofibroblasts in the interstitial layer could be part of a
      pathologic process similar to the scarring in diabetic nephropathy.
      Neoangiogenesis and thickening of the vascular wall by type IV collagen are
      consistent with glucose-induced microangiopathy.These abnormalities and the
      vasodilation of the capillaries can explain the high dialysate-to-plasma ratios
      or mass transfer area coefficients of low molecular weight solutes that can be
      found in long-term CAPD patients.

PMID- 10641772
TI  - A prospective, randomized multicenter study comparing APD and CAPD treatment.
AB  - OBJECTIVE: The goals for maintenance dialysis treatment are to improve patient
      survival, reduce patient morbidity, and improve patient quality of life. This is
      the first randomized prospective study comparing automated peritoneal dialysis
      (APD) and continuous ambulatory peritoneal dialysis (CAPD) treatment with respect
      to quality of life and clinical outcomes in relation to therapy costs. DESIGN: A
      prospective, randomized multicenter study. SETTING: Three Danish CAPD units.
      PATIENTS: Thirty-four adequately dialyzed patients with high or high-average
      peritoneal transport characteristics were included in the study.Twenty-five
      patients completed the study. INTERVENTIONS: After randomization, 17 patients
      were allocated to APD treatment and 17 patients to CAPD treatment for a period of
      6 months. Medical and biochemical parameters were evaluated at monthly controls
      in the CAPD units. Quality-of-life parameters were assessed at baseline and after
      6 months by the self-administered short-form SF-36 generic health survey
      questionnaire supplemented with disease- and treatment-specific questions.
      Therapy costs were compared by evaluating dialysis-related expenses. MAIN OUTCOME
      MEASURES: Quality-of-life parameters, dialysis-related complications, dialysis
      related expenses. RESULTS: The quality-of-life studies showed that significantly
      more time for work, family, and social activities was available to patients on
      APD compared to those on CAPD (p < 0.001). Although the difference was not
      significant, there was a tendency for less physical and emotional discomfort
      caused by dialysis fluid in the APD group. Sleep problems, on the other hand,
      tended to be more marked in the APD group. Any positive effect of APD compared to
      CAPD on dialysis-related hospital days or complication rates could not be
      confirmed. With larger patient samples, it is possible, however, that a
      significant difference might have been achieved. The running costs for APD
      treatment were US $75 per day and for CAPD treatment US $61 per day. CONCLUSION:
      If APD treatment can help to keep selected patients vocationally or socially
      active, paying the extra cost seems reasonable.

PMID- 10641773
TI  - Small and middle molecular weight solute clearance in nocturnal intermittent
      peritoneal dialysis.
AB  - OBJECTIVES: To determine the dialysate-to-plasma (D/P) concentration ratios and
      peritoneal dialytic clearance (CI(D)) of substances with a wide range of
      molecular weights in subjects receiving a simulated nocturnal intermittent
      peritoneal dialysis (NIPD) session. DESIGN: Open-label single-dose study.
      SUBJECTS: Six end-stage renal disease patients undergoing peritoneal dialysis
      (PD). SETTING: Clinical research center of a university-affiliated hospital.
      INTERVENTIONS: Subjects received intravenous gentamicin and vancomycin on the
      first day of the study. Subjects received no PD until their return on the
      following day, when subjects underwent a simulated NIPD session utilizing four 2-
      to 2.5-L peritoneal dialysate dwells of 2 hours. Blood and dialysate samples were
      collected immediately before the session and after each dialysate dwell for
      determination of urea, creatinine, gentamicin, vancomycin, and beta2
      microglobulin (beta2M) concentrations. Each solute's D/P concentration ratio and
      peritoneal CI(D) were calculated. MEASUREMENTS AND MAIN RESULTS: The (mean +/-
      SD) 2-hour D/P concentration ratios were 0.78 +/- 0.05 (urea), 0.49 +/- 0.11
      (creatinine), 0.38 +/- 0.08 (gentamicin), 0.11 +/- 0.06 (vancomycin), and 0.07 +/
      0.03 (beta2M). Peritoneal CI(D) values (mL/min of dialysis) were 19.0 +/- 2.8
      (urea), 12.1 +/- 3.5 (creatinine), 8.4 +/- 2.8 (gentamicin), 2.7 +/- 1.5
      (vancomycin), and 1.7 +/- 0.8 (beta2M). The D/P concentration ratios and
      peritoneal CI(D) values for urea, creatinine, and gentamicin were significantly
      different from vancomycin and beta2M (repeated measures ANOVA, p < 0.05). Beta2
      microglobulin peritoneal CI(D) was strongly related to gentamicin peritoneal
      CI(D) (r = 0.96, p < 0.05). CONCLUSION: Small molecular weight solutes have
      significantly greater D/P and peritoneal CI(D) than middle molecular weight
      solutes in NIPD. In NIPD, daily peritoneal CI(D) of beta2M is lower than that
      reported in continuous ambulatory PD. NIPD also results in lower drug CI(D) than
      that reported in continuous ambulatory PD studies.

PMID- 10641774
TI  - The self-locating catheter: clinical evaluation and comparison with the Tenckhoff
      catheter.
AB  - BACKGROUND: Peritoneal catheter displacement appears to be related to various
      causes including omental attachment, bowel contractions, peritoneal adhesions,
      and the catheter floating in the dialysis fluid. In order to prevent this
      complication, which can impair peritoneal dialysis efficacy, Di Paolo et al.
      designed a "self-locating catheter" (SLC) that is similar to the Tenckhoff
      catheter (TC) and includes a small tungsten cylinder (weight 12 g) at the distal
      end (Di Paolo N, et al. The self positioning catheter. Proceedings of the VII
      Italian Congress on Peritoneal Dialysis. Milan: Wichtig Editore, 1993:539-42).
      The weight of the tip prevents the catheter from floating and migrating by
      gravitation toward the Douglas cavity. OBJECTIVE: Starting in 1996, we implanted
      SLC in 15 continuous ambulatory peritoneal dialysis patients. The aim of our
      study was to compare the ratio of migration and other catheter-related
      complications between patients with SLC (196 patient-months) and 13 patients with
      conventional straight TC (295 patient-months). RESULTS: Peritonitis ratio,
      catheter complication rate, dialysate inflow and outflow, and weekly creatinine
      clearance were similar in the two groups of patients. The incidence of catheter
      displacement was significantly higher (p = 0.0349) in theTC group than in the SLC
      group (4 vs 0). CONCLUSION: In our experience, the SLC seems to be useful in
      preventing catheter migration by continuous gravitation of its extremity toward
      the pelvic cavity.

PMID- 10641775
TI  - Fluoroscopically-guided manipulation of malfunctioning peritoneal dialysis
      catheters.
AB  - OBJECTIVE: To review our experience with fluoroscopic evaluation and manipulation
      of malpositioned, malfunctioning, peritoneal dialysis (PD) catheters. MATERIALS
      AND METHODS: Thirty-one patients, over a 5-year period (1 May 1992 to 30 April
      1997) with malfunctioning PD catheters, who had fluoroscopically-guided
      manipulation were reviewed. Catheters were manipulated using a malleable aluminum
      bar and, if necessary, guide wires or other stiffeners. Technical success was
      assessed on the basis of adequate, fluoroscopically verified, catheter placement
      at the time of the procedure and improved flows. A functional PD catheter at 30
      days post manipulation was considered to be a clinically successful manipulation.
      RESULTS: There were 41 manipulations [33 initial (IM) and 8 remanipulations (RM)]
      for malpositioned or kinked catheters. In 31 (19 male, 12 female) patients
      ranging in age from 31 to 76 years (mean age 60 years), the initial technical
      success rate was 85% for IM (n = 28/33) and 63% (n = 5/8) for RM. The overall
      clinical success rate, or 30-day primary patency, was 55% for IM (n = 18/33) and
      63% for RM. Catheter function (combined IM and RM) continued for a median 869
      days (95% CI: 118, 1620). No early complications were noted. CONCLUSIONS:
      Fluoroscopic manipulation, including attempts at remanipulation, of PD catheters
      is a safe procedure. The technique is a simple, inexpensive, and effective way of
      prolonging PD catheter life, thereby reducing the number of surgical
      interventions.

PMID- 10641776
TI  - Recurrent infection and catheter loss in patients on continuous ambulatory
      peritoneal dialysis.
AB  - OBJECTIVE: To elucidate the factors leading to catheter loss from recurrent
      infection in patients on continuous ambulatory peritoneal dialysis (CAPD).
      DESIGN: All catheters removed from patients were prospectively examined for
      infection. SETTING: CAPD unit in large tertiary-care general hospital. PATIENTS:
      Sixty-five consecutive patients undergoing catheter removal for whatever cause;
      20 catheters rejected because of desiccation or contamination in transit.
      INTERVENTIONS: None. MAIN OUTCOME MEASURES: Micro-organisms linked to catheter
      removal; their locations on removed catheters. RESULTS: Of 45 catheters removed
      between January 1994 and August 1995, 26 were infected: 13/26 infections were
      caused by Staphylococcus aureus and 7/26 by Pseudomonas aeruginosa. In only one
      case was S. epidermidis associated with catheter removal. The most striking
      finding was that the inner cuff harbored large numbers of the infecting
      organisms, even when antibiotics had eradicated them from the peritoneal cavity
      and exit site, where present, and the catheter lumen. CONCLUSION: The importance
      of S. aureus and Ps. aeruginosa rather than S. epidermidis in catheter loss due
      to relapsing infection is confirmed. Persistence of the causative organisms in
      the inner cuff is a likely explanation for relapse after treatment, and might be
      due to the predominantly intraperitoneal administration of antibiotics. A
      clinical trial of the effect on catheter retention of empirical use of systemic
      or oral agents that give high tissue levels and are active against intracellular
      micro-organisms, along with recommended intraperitoneal regimens, is indicated.

PMID- 10641777
TI  - A multinational clinical validation study of PD ADEQUEST 2.0. PD ADEQUEST
      International Study Group.
AB  - OBJECTIVE: To clinically validate the use of the newly released kinetic modeling
      program, PD ADEQUEST 2.0 for Windows (Baxter Healthcare Corporation, Deerfield,
      IL, U.S.A.), by assessing the level of agreement between measured and modeled
      values of urea and creatinine clearances (CCr), glucose absorption, total drain
      volumes, and net ultrafiltration for all forms of peritoneal dialysis. DESIGN: A
      nonrandomized, multinational, prospective longitudinal study. PATIENTS: The study
      involved 104 adult patients [41 on continuous ambulatory peritoneal dialysis
      (CAPD), 63 on automated peritoneal dialysis (APD)] from 16 centers in 7
      countries. All patients underwent a 4-hour peritoneal equilibration test (PET)
      but with varying percentage dextrose concentrations (1.5% or 2.5% dextrose) and
      varying fill volumes (range 1.5 - 2.5 L). Patients with a residual renal function
      greater than 10 mL/min were excluded, as were patients who had peritonitis within
      6 weeks prior to baseline. MAIN OUTCOME MEASURES: Correlation coefficients and
      Bland-Altman limits of agreement were used to assess the level of agreement
      between measured and modeled values of weekly peritoneal urea Kt/V (pKt/V) and
      total Kt/V, weekly peritoneal creatinine clearance (pCCr, L/week/1.73 m2) and
      total CCr (L/week/1.73 m2), daily drain volume (L/day), net ultrafiltration (UF,
      L/day), daily peritoneal urea and creatinine mass removal (g/day), and daily
      peritoneal glucose absorption (g/day). Measured values were obtained from three
      repeat 24-hour urine and dialysate collections per patient, while modeled values
      were calculated using the Baxter PD ADEQUEST 2.0 program in conjunction with
      kinetic parameters estimated from a 4-hour PET and long-dwell exchange
      independent of the 24-hour collections. RESULTS: The results show there is
      excellent agreement between measured and modeled urea Kt/V and CCr with
      concordance correlation coefficients ranging from 0.83 to 0.97 among CAPD and APD
      patients. There was also excellent agreement between measured and modeled values
      of glucose absorption and total drain volumes (concordance correlations of 0.90
      and 0.98, respectively). This level of agreement was further supported by a Bland
      Altman analysis of individual differences, including differences between measured
      and modeled net UF (coefficient of clinical agreement ranged from 0.66 to 0.92).
      CONCLUSIONS: Data from a carefully performed PET and overnight exchange can, in
      combination with a scientifically and clinically validated kinetic model, provide
      clinicians with a powerful mathematical tool for use in CAPD and APD prescription
      management. Although not intended to replace actual measurements, kinetic
      modeling can prove useful as a means for quickly estimating approximate levels of
      clearance for a wide variety of alternative prescriptions. This, in turn, should
      speed up the process by which a physician can optimize the dose of dialysis
      suitable for a given patient and his/her lifestyle.

PMID- 10641778
TI  - Follow-up study of peritoneal fluid kinetics in infants and children on
      peritoneal dialysis.
AB  - OBJECTIVES: To study longitudinal changes in transcapillary ultrafiltration
      (TCUF) and marker clearance (MC), as a reflection of lymphatic absorption, in
      children on peritoneal dialysis (PD). To present data on fluid kinetics in
      infants younger than 2.5 years, using an intraperitoneal volume of 1200 mL/m2
      body surface area (BSA). DESIGN: The study involved a 4-hour dwell of 1200 mL/m2
      BSA of dialysis fluid containing 3.86% glucose with Dextran 70 as volume marker.
      Cumulative TCUF and cumulative MC were measured. SETTING: A tertiary-care
      university hospital. PATIENTS: A follow-up period of 33 months of serial (1 - 4)
      peritoneal equilibration tests (PETs) was studied in 20 children with a median
      age of 6.4 years (range 2.1 - 15.4 years). Fluid kinetics in 5 additional infants
      with a median age of 1.4 years (range 0.5 - 2.5 years) was measured. RESULTS:
      Cumulative TCUF was 1041 mL/1.73 m2 at 1 - 3 months after start of PD, 1026
      mL/1.73 m2 at 7 - 9 months, 1021 mL/1.73 m2 at 11 - 13 months, and 756 mL/1.73 m2
      at 26 - 33 months (NS). Cumulative MC was 235 mL/1.73 m2 at 1 - 3 months after
      start of PD, 311 mL/1.73 m2 at 7 - 9 months, 395 mL/1.73 m2 at 11 - 13 months,
      and 509 mL/1.73 m2 at 26 - 33 months (NS). In infants, cumulative TCUF was 755 +/
      237 mL/1.73 m2; cumulative MC was 400 +/- 214 mL/1.73 m2. CONCLUSIONS:
      Transcapillary ultrafiltration and marker clearance do not change in children >
      2.5 years during the period studied. Fluid kinetics does not differ between
      infants < 2.5 years and older children when intraperitoneal volumes of 1200 mL/m2
      BSA are used.

PMID- 10641780
TI  - Pain due to peritonitis.

PMID- 10641779
TI  - Comparison of intraperitoneal and subcutaneous epoetin alfa in peritoneal
      dialysis patients.
AB  - OBJECTIVE: To compare the efficacy of intraperitoneal (i.p.) and subcutaneous
      (s.c.) administration of epoetin alfa in patients receiving peritoneal dialysis
      (PD). DESIGN: A 32-week prospective, randomized, cross-over experimental design.
      SETTING: Two university-based outpatient PD centers. PATIENTS: Twenty adult PD
      patients receiving stable doses of s.c. epoetin alfa enrolled in the study.
      Thirteen patients completed 32 weeks of follow-up. INTERVENTION: Patients were
      randomly assigned to receive either s.c. or i.p. epoetin alfa at the start of the
      study. Dose adjustments were made to maintain baseline hematocrit +/- 3
      percentage points. Following 16 weeks of treatment, patients crossed over to the
      other route of administration for an additional 16 weeks. Intraperitoneal epoetin
      alfa was administered into an empty peritoneal cavity for approximately 8 hours
      before resuming dialysis. End-of-study i.p. epoetin alfa doses required to
      maintain target hematocrit were given twice weekly (n = 1), once weekly (n = 11),
      or once every other week (n = 1). All patients received iron supplements to
      maintain or exceed prestudy iron parameters. MAIN OUTCOME MEASURE: Prior to the
      study, the primary outcome measure was defined as the difference in epoetin alfa
      dose between i.p. and s.c. administration. RESULTS: Thirteen patients completed
      the study. The area under the dosing-requirement curve for i.p. epoetin alfa was
      larger than for s.c. administration (p = 0.0029), and the slope of the 16-week
      dose-requirement curve was greater for i.p. administration (p = 0.017),
      suggesting greater dose stability for s.c. administration. Paired analysis
      indicated greater i.p. intrapatient dose requirements (p < 0.0001). The mean
      difference in s.c. versus i.p. doses was 5000 +/- 1510 units per week. Some
      patients required escalating i.p. doses to maintain target hematocrit values.
      Iron administration and iron stores were similar in both groups. CONCLUSION:
      Intraperitoneal epoetin alfa may be a suitable alternative for some patients for
      whom s.c. dosing is undesirable. Large i.p. versus s.c. dosing differences noted
      in a few patients are unexplained, but may result from interpatient variability
      in i.p. epoetin alfa absorption. Intraperitoneal dosing into an empty peritoneum
      can be done safely and effectively.

PMID- 10641781
TI  - Psychosexual function in CAPD and hemodialysis patients.

PMID- 10641782
TI  - Kt/V in children on CAPD: how much is enough?

PMID- 10641783
TI  - A case for selective treatment of protein calorie malnutrition with amino acid
      peritoneal dialysis.

PMID- 10641784
TI  - Mycobacterium fortuitum peritonitis associated with CAPD: diagnosis by a
      molecular biology technique.

PMID- 10641786
TI  - Usefulness of pericardiostomy with guidance of transesophageal echocardiography
      in a CAPD patient with pericardial tamponade.

PMID- 10641785
TI  - Bloody discoloration of peritoneal dialysate bags.

PMID- 10641787
TI  - Everything I ever wanted to know about peritoneal dialysis. Nursing application:
      PD at a United States center.

PMID- 10641788
TI  - Literature. November-December 1999.

PMID- 10641789
TI  - HGF: a multifunctional growth factor controlling cell scattering.
AB  - Hepatocyte Growth Factor, also known as Scatter Factor, is a polypeptide that
      shows structural homology with enzymes of the blood coagulation cascade. It is a
      biologically inactive single chain precursor that is then cleaved by specific
      serine proteases to a fully active alphabeta heterodimer. All the biological
      responses induced by HGF/SF are elicited by binding to its receptor, a
      transmembrane tyrosine kinase encoded by the MET proto-oncogene. The signaling
      cascade triggered by HGF begins with the autophosphorylation of the receptor and
      is mediated by concomitant activation of different cytoplasmic effectors that
      bind to the same multifunctional docking site. During development, HGF function
      is essential: knock-out mice for both ligand and receptor show an embryonic
      lethal phenotype. HGF/SF displays a unique feature in inducing "branching
      morphogenesis", a complex program of proliferation and motogenesis in a number of
      different cell types. Moreover, HGF is involved in the invasive behaviour of
      several tumor cells both in vivo and in vitro. The role of HGF as putative
      therapeutical agent in pathologies characterized by massive cell loss or
      deregulated cell proliferation is under investigation.

PMID- 10641790
TI  - SPARC (osteonectin/BM-40).
AB  - SPARC (Secreted ProteinAcidic and Rich in Cysteine) is a prototype of a family of
      biologically active glycoproteins that bind to cells and to extracellular matrix
      (ECM) components. It is expressed spatially and temporally during embryogenesis,
      tissue remodeling and repair. SPARC is a modular protein (34 kDa) comprised of
      three structural domains, one or more of which are implicated in the regulation
      of cell adhesion, proliferation, matrix synthesis/turnover. Rapid proteolysis of
      SPARC by extracellular proteases accounts for its transient detection in the
      extracellular environment. The proposed roles of SPARC in the development of
      cataracts and the regulation of angiogenesis during wound healing and tumor
      growth account for the recent attention it has received from the biomedical
      community.

PMID- 10641791
TI  - The transcription factor Evi-1.
AB  - Evi-1 is a transcription factor with two sets of zinc finger domains. The
      temporally and spatially restricted pattern of Evi-1 expression in embryonic
      tissues suggests a role of Evi-1 in organogenesis and morphogenesis in mouse
      development. Mice lacking Evi-1, which die within the first few weeks of life
      with multiple defects in embryonic development, suggest that Evi-1 is essential
      for developmental cell proliferation, vascularization, and cell-specific
      signaling at midgestation. In hematopoietic cells, Evi-1 expression is restricted
      at a transient stage of myeloid cell differentiation. Constitutive expression of
      Evi-1 in hematopoietic cells, which is caused by retroviral insertions or
      chromosomal translocations and inversions, is closely associated with myelogenous
      leukemias and myelodysplastic syndromes in mice and humans. In the aspect of
      potential therapeutic approaches, some pharmaceutical drugs or antisense
      oligonucleotides that repress Evi-1 expression would be useful for the treatment
      of Evi-1-induced neoplastic tumors.

PMID- 10641792
TI  - Apoptosis of skeletal muscles during development and disease.
AB  - Cells from multicellular organisms self-destroy when no longer needed or when
      damaged. They do this by activating genetically controlled machineries that lead
      to apoptosis. Skeletal muscles in adult animals are fully differentiated
      syncytial cells. Apoptosis has been described in developing and, recently, in
      adult skeletal muscle. The cellular and molecular aspects of myoblast and
      myofibre apoptosis and their role in disease are analysed in this review.
      Alterations in the pathways that regulate myoblasts proliferation/differentiation
      lead to induction of apoptosis during myogenesis both in vivo and in vitro. In
      adult muscle myofibres apoptosis seems to start from segmental areas of myofibres
      often producing loss of a single myonucleus. The bcl2/bax system is active in
      muscle when apoptosis occurs. On the other hand conflicting results are reported
      on the role played by FasL/Fas system. These findings are confirmed by in vitro
      results on myotubes and on their susceptibility to apoptosis. Though apoptosis
      has been shown to occur in the skeletal muscle, the role played in diseases and
      the pattern followed in myogenic cells are far from being clear.

PMID- 10641793
TI  - Inversion of selectivity of N-substituted propargylamine monoamine oxidase
      inhibitors following structural modifications to quaternary salts.
AB  - A number of N-substituted-propargylamines are well known mechanism-based MAO
      inhibitors. Clorgyline and deprenyl in fact represent archetypal MAO-A and MAO-B
      inhibitors respectively. In the present study several ring-substituted deprenyl
      structural analogues were synthesized and alterations of selectivity and potency
      towards MAO-A and MAO-B activities were found. When deprenyl and its structural
      analogues were further modified to their corresponding quaternary ammonium salts.
      i.e. by attaching either an extra propargyl or a methyl group to the nitrogen
      atom, the potency of inhibition of MAO-B activity was drastically reduced and
      inhibition of MAO-A activity substantially increased. Such a complete inversion
      of selectivity may be related to a hydrophilic and electrophilic region seemingly
      present only in the MAO-A but not in the MAO-B molecule. The results also suggest
      that at least three sites are required for the selectivity and mechanism-based
      action of an inhibitor towards MAO.

PMID- 10641794
TI  - Emergence of the active site of spleen exonuclease upon association of the two
      basic monomers of the tetrameric enzyme.
AB  - The 5'-->3' exonuclease from beef spleen is a 160-kDa tetramer consisting of four
      subunits of two types. Partial reduction of the tetramer led to one stable
      intermediate state of the enzyme with Mr = 80 kDa. The aim of this paper was to
      attribute the exonucleolytic activity to one of the two monomers, to the dimer or
      to the tetramer. The different forms of the exonuclease were separated by SDS
      polyacrylamide gel electrophoresis, transferred on an Immobilon-P membrane and
      subsequently renaturated. Antibodies monospecific against each of the two
      monomers as well as against the dimer were isolated and their inhibitory effect
      on the holoenzyme determined. It was found that after renaturation the two
      monomers did not possess any exonuclease activity while the 80-kDa dimer showed a
      lower recovery of the specific activity of the enzyme (20.8+/-0.23 nkat/nmol, (n
      = 5)) in comparison with the 160-kDa tetramer (64.8+/-0.75 nkat/nmol (n = 5)). It
      was demonstrated that the antibodies monospecific against the dimer caused 53%
      maximum inhibition of the 160-kDa exonuclease. The antibodies monospecific
      against 25- and 55-kDa monomers did not inhibit the activity of the holoenzyme.
      No single-strand endonuclease activity of the spleen exonuclease was observed
      when using supercoiled Bluescript KS+ plasmid DNA as a substrate. This data
      suggest the emergence of an 80 kDa active form of beef spleen exonuclease upon
      association of two monomers of the tetrameric enzyme.

PMID- 10641795
TI  - Human apo-lipoprotein B from normal plasma contains oxidised peptides.
AB  - Oxidation of low density lipoprotein (LDL) may be atherogenic, but radical
      initiated oxidation of its apoprotein B-100 (apoB) has been little studied.
      Transition metal ions iron and copper are candidates for mediating radical
      oxidation of LDL in vivo. Therefore, we studied the copper-ion-induced oxidation
      of apoB in human LDL. Using HPLC methods developed in our recent work, we studied
      the destruction of native and the generation of six oxidised amino acids; we also
      assessed the release of peptides from the LDL particle by FPLC. We observed time
      dependent losses of apoB histidine, lysine and glycine. Long-lived reactive
      species, the reductant DOPA, and the oxidant hydroperoxides of valine and leucine
      (measured as hydroxides after reduction), were generated. Their relative
      abundance (mol/mol of parent amino acid) was DOPA > o- and m-tyrosine >
      dityrosine, valine-hydroxides, leucine hydroxides. Low molecular weight fragments
      were also released from the LDL in a time-dependent manner, contained
      hydroperoxides sensitive to GSH peroxidase, and generated radicals on reaction
      with iron-EDTA. The fragments contained peptides active in the quinone redox
      cycling procedure, comprising 0.25% of the supplied LDL amino acids.
      Characteristic peptides were present in each FPLC fraction containing the
      fragments, as judged by further HPLC fractionation. Some fragments were present
      in the unoxidised LDL preparations, and when these were largely removed by FPLC,
      copper oxidation could still generate fragments, suggesting that those present in
      the starting material might indicate prior oxidation. Concordantly, we found that
      fresh plasma LDL apoB contained 43% of total plasma protein-bound oxidised amino
      acids, and with the same relative abundance. We conclude that plasma proteins
      including apoB are subject to physiological oxidation, similar to that inflicted
      by copper ions; the latter may contribute to intimal LDL oxidation, which could
      be the source of oxidised plasma apoB.

PMID- 10641796
TI  - Variable accumulation of insulin-like growth factor II in mouse tissues deficient
      in insulin-like growth factor II receptor.
AB  - The insulin-like growth factor II receptor mediates endocytosis of insulin-like
      growth factor II, resulting in growth factor degradation in lysosomes. This
      degradation is an important regulator of growth factor activity in vivo, as shown
      by the phenotype of receptor deficient mice. Recent evidence suggests that the
      insulin-like growth factor II receptor functions as a tumour suppressor in
      humans, and that loss of receptor function leads to increased levels of the
      growth factor in tumours. It is difficult to establish such a causal relationship
      in human tumours however, since most tumours have undergone several genetic
      changes by the time they are examined. Using mouse embryos deficient in receptor
      expression, and an insulin-like growth factor II-specific radioimmunoassay, we
      tested the hypothesis that lack of receptor function leads to local accumulation
      of insulin-like growth factor II. We found that mutant blood and skeletal muscle
      had excess insulin-like growth factor II, but that mutant lungs and liver had no
      accumulation. Mutant hearts had less growth factor than wild-type hearts, an
      unexpected observation, since the normal embryonic heart expresses very high
      levels of insulin-like growth factor II receptor, and mutant mice apparently die
      of congestive heart failure. The placentas of mutant mice were larger than those
      of wild-type, but this did not correlate with an excess of placental insulin-like
      growth factor II. These results indicate that lack of insulin-like growth factor
      II receptor can lead to local excess of the growth factor but that such excess is
      not a necessary consequence of receptor-deficiency.

PMID- 10641797
TI  - Use of a 49-peptide library for a qualitative and quantitative determination of
      pseudomonal serralysin specificity.
AB  - The Pseudomonas aeruginosa serralysin (E.C. 3.4.24.40.), which is a zinc
      dependent metalloprotease from the metzincin superfamily, has quite a broad
      specificity, which has not yet been clearly identified. We have studied it with
      an original approach, using a 49-peptide library of the type Z-AXXA (amide) (X =
      A, L, V, F, S, R, E). The library was analyzed by LC-MS before and after
      enzymatic hydrolysis. A great number of hydrolyzed peptides were screened and the
      preferential hydrolysis was the X-X peptide bond, even if in some cases, A-X and
      X-A bond could be hydrolyzed. No amino acids with a ionized side chain could be
      found in the P1' position. The results obtained suggest that the specificity in
      the P1' position, where an hydrophobic residue was preferentially found, seems
      more selective that in the Pn position. The P1 position was not very specific,
      but, on a quantitative point of view, the enzymatic activity was particularly
      increased when R, F or A were in this position. The results allow us to define
      the P1' and P1 residues for an optimal substrate of pseudomonal serralysin and
      usable for the design and the synthesis of a specific inhibitor.

PMID- 10641798
TI  - HIV-1 reverse transcriptase is phosphorylated in vitro and in a cellular system.
AB  - Phosphorylation modulates the activity of many proteins that interact with
      nucleic acids including DNA and RNA polymerases. The HIV-1 reverse transcriptase
      (RT) is essential during the replicative cycle of the HIV-1 virus. HIV-1 RT has
      several potential sites for phosphorylation that could regulate its activities.
      In this work, the phosphorylation of HIV-1 RT is examined in vitro and in vivo,
      to evaluate any role for this modification in regulating RT metabolism.
      Recombinant unphosphorylated HIV-1 RT heterodimer expressed in bacteria can be
      phosphorylated in vitro by several purified mammalian protein kinases. Seven
      kinases were tested, and five of these enzymes phosphorylated HIV-1 RT. Using an
      insect baculovirus expression system, the 66 kDa HIV-1 RT was also phosphorylated
      in vivo. However, HIV-1 RT immunoprecipitated from H9-lymphoma cells infected
      with HIV-1 showed negligible phosphorylation. Our results indicate that purified
      HIV-1 RT can be phosphorylated by several mammalian protein kinases in vitro and
      during expression in baculovirus infected insect cells.

PMID- 10641799
TI  - Health geography: style and paradigms.

PMID- 10641801
TI  - Selling sex in the time of AIDS: the psycho-social context of condom use by sex
      workers on a Southern African mine.
AB  - This paper provides a detailed account of the social organisation of commercial
      sex work in a squatter camp in a South African gold mining community. On the
      basis of in-depth interviews with 21 women, living in conditions of poverty and
      violence, the paper examines factors which might serve to help or hinder a newly
      implemented community-based peer education and condom distribution project aimed
      at vulnerable single women. Attention is given to the way in which the routine
      organisation of sex workers' everyday working and living conditions, as well as
      the strategies they use to construct positive social identities despite working
      in the most stigmatised of professions, serve to undermine their confidence in
      their ability to insist on condom use in sexual encounters with reluctant
      clients. However, even amongst this disadvantaged group of women, the interviews
      suggest that the tendency to speak of women's 'powerlessness' (as is the case in
      many studies of African women in the context of the HIV epidemic) is unduly
      simplistic and fails to take account of the range of coping strategies and social
      support networks that women have constructed to deal with their day to day life
      challenges. These strategies and networks could serve as potentially strong
      resources for community-based sexual health promotion programmes.

PMID- 10641800
TI  - The intersections of HIV and violence: directions for future research and
      interventions.
AB  - The purpose of this paper is to review the available literature on the
      intersections between HIV and violence and present an agenda for future research
      to guide policy and programs. This paper aims to answer four questions: (1) How
      does forced sex affect women's risk for HIV infection? (2) How do violence and
      threats of violence affect women's ability to negotiate condom use? (3) Is the
      risk of violence greater for women living with HIV infection than for noninfected
      women? (4) What are the implications of the existing evidence for the direction
      of future research and interventions? Together this collection of 29 studies from
      the US and from sub-Saharan Africa provides evidence for several different links
      between the epidemics of HIV and violence. However, there are a number of
      methodological limitations that can be overcome with future studies. First,
      additional prospective studies are needed to describe the ways which violence
      victimization may increase women's risk for HIV and how being HIV positive
      affects violence risk. Future studies need to describe men's perspective on both
      HIV risk and violence in order to develop effective interventions targeting men
      and women. The definitions and tools for measurement of concepts such as physical
      violence, forced sex, HIV risk, and serostatus disclosure need to be harmonized
      in the future. Finally, combining qualitative and quantitative research methods
      will help to describe the context and scope of the problem. The service
      implications of these studies are significant. HIV counseling and testing
      programs offer a unique opportunity to identify and assist women at risk for
      violence and to identify women who may be at high risk for HIV as a result of
      their history of assault. In addition, violence prevention programs, in settings
      where such programs exist, also offer opportunities to counsel women about their
      risks for sexually transmitted diseases and HIV.

PMID- 10641802
TI  - A critical review of the concept of patient motivation in the literature on
      physical rehabilitation.
AB  - Rehabilitation professionals have long suspected that a patient's motivation
      plays an important role in determining the outcome of therapy, despite the lack
      of a clear definition of the phenomenon. The fact that such a subjective concept
      is commonly used by clinicians prompted this investigation into the range and
      nature of professional understandings of patient motivation. The literature
      dealing with physical rehabilitation and motivation was reviewed and was found to
      fall into three broad groups. One group of mainly clinical articles conceives of
      motivation as an internal 'personality trait' of the individual patient, and
      explains the nature and causes of motivation purely in terms of internal
      dispositions. Another body of literature considers motivation to be a quality
      which is affected by social factors, and stresses the importance of awareness of
      such factors in explaining motivation. The third approach considers social
      factors in combination with personality or clinical characteristics. It is argued
      that the personality-based approach facilitates moralising in the therapeutic
      encounter, a problem which is both highlighted and critiqued by the methodology
      which emphasises the importance of social factors. The practical implications of
      the relative merits of these different theories of motivation are considered.

PMID- 10641803
TI  - The production of health and the valuation of medical inputs in wage-amenity
      models.
AB  - Using a hedonic wage-amenity model, this paper examines the valuation of medical
      inputs into the production of health. The data used in this study include the
      incomes, demographics and measures of human capital for households in eastern
      North Carolina with county level medical input supply. These data allow an
      estimate of the marginal value of medical care inputs such as the physician to
      population ratio and the availability of specialized services in an area of the
      country where the lack of available medical care has been of particular concern
      to policy makers. Our results indicate that while health care inputs are not a
      significant determinant of earnings overall, they are important in counties that
      have been designated as medically underserved. In underserved counties each
      additional physician per 10,000 individuals in the county decreases earnings by
      about 11.6%. This suggests that physicians act as an amenity and workers are
      willing to accept lower wages to locate in counties with a higher physician to
      population ratio.

PMID- 10641804
TI  - Over the limit: the association among health, race and debt.
AB  - This research responds to the call for more research on the conceptualization and
      measurement of socio-economic status that moves beyond merely considering
      education, occupation and income variables. Credit card usage and credit card
      debt is a growing phenomenon in developed countries. Using data from a 1997
      representative sample of more than 900 adults in Ohio, we explored how credit
      card debt and stress regarding debt is associated with health. We found that both
      credit card debt and stress regarding debt are associated with health. In
      addition, health behaviors and risks explain part of this association.

PMID- 10641805
TI  - Gender, family structure and cardiovascular activity during the working day and
      evening.
AB  - This study applied psychophysiological methods to the investigation of social
      roles and well-being, using cardiovascular function over a working day and
      evening as an index of physiological activation. One hundred and sixty-two full
      time school teachers (102 women and 60 men) were assessed using automated
      ambulatory blood pressure monitoring apparatus, with readings every 20 min
      through the working day (9.00 am-5.40 pm), and every 30 min in the evening (6.00
      10.30 pm). The influence of gender, marital status and parenthood (defined as
      having at least one child living at home) on blood pressure during the working
      day and on day-evening differences was examined. There were no differences in
      blood pressure and heart rate across the working day in relation to marital roles
      or family structure. However, the decrease in blood pressure between working day
      and evening was greatest in parents, intermediate in married non-parents, and
      smallest in single participants without children. Differences in systolic
      pressure adjusted for age and body mass index averaged -4.46, -1.76 and +0.22
      mmHg in the three groups, respectively. A similar pattern was observed for
      diastolic pressure but not heart rate. We also found that the day-evening fall in
      systolic pressure was moderated by social support, with the greatest change (mean
      adjusted difference -6.76 mmHg) in parents who reported high levels of social
      support. These blood pressure responses did not differ between men and women, and
      there was no indication of multiple role strain for full-time working mothers.
      The results were independent of concomitant physical activity, location during
      measurement, or reported job strain. We argue that findings are consistent with
      an enhancement model of multiple social roles, and with lower allostatic load on
      individuals who are working, married and parents. Psychophysiological studies of
      daily life can complement epidemiological and sociological investigations of
      social roles and health.

PMID- 10641806
TI  - Cadaveric donotransplantation: nurses' attitudes, knowledge and behaviour.
AB  - Human organ transplantation is an important treatment for certain medical
      conditions, and for irreversible organ failure. There is a shortfall in the
      number of organs required for transplantation. The close and continuous proximity
      of nurses to potential donors and their families make them critical links in the
      organ donation process. Therefore, success in organ procurement may depend on
      nurses' awareness and integration of knowledge about donotransplantation (the
      process of organ/tissue donation and transplantation). Postal questionnaires were
      distributed throughout the United Kingdom (UK) to 2465 registered nurses, to
      assess their personal attitudes, knowledge and behaviour regarding cadaveric
      donotransplantation. One thousand, three hundred and thirty-three questionnaires
      were returned, a response rate of 54%. Overall, nurses held positive attitudes to
      donotransplantation, with 78% agreeing with organ donation and only 10% clearly
      being opposed. However, nurses were found to share ambivalent attitudes of
      altruism and fear which appear to surround decisions about donation. Factor
      analysis was used to further explore nurses' attitude structure. Six factors were
      confirmed providing a non-significant likelihood ratio fit (P = 0.468) and a well
      reproduced correlation matrix. The factors related to: (1) the value and
      contribution made by donotransplantation; (2) the unique idea of having another's
      tissue in one's own body; (3) the importance of organ donation; (4) the
      individual's moral, and nurses' professional rejection of the responsibility for
      organ/tissue donation; (5) the post-mortem mutilation of the body; and, (6) the
      potential distress donation may cause a bereaved family. Comparisons were made
      between certain of nurses' specialist groups and significant differences were
      found. Comparisons of factor scores between certain specialist groups or other
      strata were assessed by analysis of variance. Nurses working in renal units were
      significantly more in favour of donotransplantation than any other group of
      nurses.

PMID- 10641807
TI  - The Medical Interaction Process System (MIPS): an instrument for analysing
      interviews of oncologists and patients with cancer.
AB  - The increase in communication skills training for doctors has led to the need for
      more effective means of evaluation. Analysis of video and audiotaped
      consultations using systems of interaction analysis can provide the trainee with
      in-depth feedback about their communication skills. Most interaction process
      systems were designed for use in primary care and recent research has questioned
      the applicability of these systems in medical specialties such as oncology. We
      describe the development of a new instrument, the Medical Interaction Process
      System (MIPS) for use in teaching communication skills and empirical research in
      medical encounters, particularly, between doctors and patients with cancer. A
      comparison of the MIPS and comparable behaviour categories of another widely used
      system (the Roter Interaction Analysis System) was made to test convergent
      validity. Pearson correlation coefficients suggested a good level of concurrence
      between the two systems. Intercoder reliability tests were carried out between
      two coders at two separate time periods. Both of these indicated good reliability
      for the majority of categories. The two major advantages of the MIPS over other
      coding systems are: (1) the system allows for sequential and parallel coding,
      thus avoiding major coding conflicts and (2) the design of the coding sheet
      results in a multidimensional view of the consultation without data loss. We
      believe that the MIPS yields useful information for teaching doctors
      communication skills and also provides an objective method for evaluating the
      effectiveness of communication skills courses.

PMID- 10641808
TI  - Continuity and change in women's weight orientations and lifestyle practices
      through pregnancy and the postpartum period: the influence of life course
      trajectories and transitional events.
AB  - The life course perspective offers a framework for understanding continuity and
      change in health and health practices. Body weight, and the diet and physical
      activity strategies used to manage weight in pregnancy and the postpartum period,
      are a focus of much study because of an association between parity and body
      weight. The motherhood transition offers an opportunity to study weight concerns
      and weight management strategies during a period of weight fluctuation that is
      part of a life transition for many women. Our aim was to develop an in-depth
      understanding of women's experiences of pregnancy and postpartum weight changes,
      the strategies that women used to deal with weight changes, and patterns in their
      attitudes and strategies across pregnancy and the postpartum period. A
      longitudinal design, using multiple, in-depth, qualitative interviews with 36
      women from pregnancy through the postpartum period, was chosen for data
      collection. Prepregnancy orientations towards body weight emerged as the primary
      influence on women's pregnancy and postpartum attitudes towards weight, on
      patterns of physical activity and diet, and on postpartum weight outcomes among
      most study participants. Four different trajectories ("relaxed maintenance",
      "exercise", "determined", and "unhurried"), characterized by differences in
      women's orientations towards their body weight and their diet and physical
      activity patterns across pregnancy and the postpartum period, emerged from the
      data. Only a few women diverged from prepregnancy trajectories in weight
      orientation and diet and physical activity patterns postpartum. Delayed
      resumption of prepregnancy physical activity and dietary patterns contributed to
      postpartum weight retention for a subset of "exercisers". Stress and age- or role
      related changes in perspective interrupted the continuity of weight orientations
      and behavioral patterns for three other women. These findings highlight the
      direction and momentum provided by trajectories in health attitudes and
      strategies as processes shaping responses to a life transition.

PMID- 10641809
TI  - Sense of coherence and health: evidence from two cross-lagged longitudinal
      samples.
AB  - We explored the stability of sense of coherence (SOC) and the relationship
      between SOC and health in two cross-lagged longitudinal samples by using
      structural equation modeling. In Study 1, comprising 577 municipal male and
      female employees, SOC was found to be stable in both sexes. In women, SOC
      significantly predicted sickness absences in the 4-year follow-up period. A low
      SOC, but not a high SOC, was associated with health prospects. Surprisingly, SOC
      did not influence sickness absences among men. Study 2 further tested the
      relationship between SOC and health in 320 male technical designers. Although SOC
      was cross-sectionally associated with psychological and somatic health
      complaints, it did not predict later health complaints in a 5-year follow-up.
      Thus, the present study supports the dispositional character of SOC in both sexes
      and its predictive validity among women. No support was found to the salutogenic
      status of SOC and an unexpected gender difference was revealed.

PMID- 10641810
TI  - Primordial prevention: the path from Victoria to Catalonia.
AB  - Primordial prevention seeks to prevent future disease by influencing its social
      determinants. Henry Blackburn's writings are prime portrayals of social factors
      causing premature cardiovascular disease (CVD). His classic paper, Diet and Mass
      Hyperlipidemia, identified changes needed in professional attitudes, medical
      economics, food production, food labeling, and food advertising. The 1982 WHO
      report, Coronary Heart Disease (Blackburn, rapporteur), introduced the term
      "primordial prevention," starting a cycle of initiatives, all with considerable
      influence worldwide. He participated in the now widely disseminated Victoria
      Declaration on Heart Health (1992), which contained 64 policy recommendations,
      many focussing on broad social forces that influence modern CVD epidemics. The
      path he initiated led to the Catalonia Declaration: Investing in Heart Health
      (1996), which echoed many of his pleas for resources necessary to influence CVD
      rates. Some roots of CVD's recent decline in many countries are thus clearly
      attributable to Blackburn's prescient wisdom and visionary scholarship.

PMID- 10641811
TI  - Understanding the coronary disease process and the potential for prevention: a
      summary.
AB  - This presentation describes the atherothrombotic processes leading to acute
      coronary syndromes based on the recent studies of vascular biology. It outlines
      the mechanism of action and the evolving impact of lipid-lowering therapy in
      stabilization and secondary prevention of such processes. The present
      understanding of the pathogenesis of each phase of progression and of the various
      lesions preceding myocardial infarction emphasizes the physical, structural,
      cellular, and chemical properties of "vulnerable or unstable plaques" prone to
      disruption.

PMID- 10641812
TI  - The development and prevention of cardiovascular disease risk factors:
      socioenvironmental influences.
AB  - In Third World countries, coronary heart disease is more frequent in the upper
      classes. In industrial countries such as the United States, Canada, and the
      United Kingdom, there has been a widening social class difference in the opposite
      direction. Yet the social class differences have been largely ignored in the
      development of public health programs to prevent cardiovascular disease. This
      paper presents specific recommendations to correct this glaring defect, including
      giving priority to the reduction of risk factor prevalence among low-income blue
      collar and white collar workers, strengthening regulatory, taxation, and other
      measures that directly impact all classes of the population, reversing the
      declining living standards of large segments of the U.S. population which result
      from current economic and political policy, and greatly expanding the resources
      available for public health programs from their grossly inadequate level at the
      present time.

PMID- 10641813
TI  - Diet as primordial prevention in Seventh-Day Adventists.
AB  - Epidemiologic studies of Seventh-Day Adventists have clearly shown that dietary
      habits are associated with risk of coronary heart disease (CHD) and other chronic
      diseases. However, a few surprising results emerge. Meat consumption is clearly
      hazardous for Adventist men by raising CHD mortality. However, no such effect was
      seen in women. Possible reasons are discussed. Our data, and that of others,
      strongly support the role of a fatty food, specifically nuts, as protective for
      CHD. The possible implications of this result for fat intake as a risk factor for
      CHD are discussed. In particular, it may be that consumption of modest quantities
      of certain fats is beneficial, rather than hazardous. The lower risk of CHD in
      Adventists probably has a complicated explanation and certainly cannot be
      entirely explained by their nonsmoking status or a superior serum lipid profile.
      Adventists are unique in that the majority of this group have adopted a dietary
      habit that is either vegetarian or tending in this direction. The power of
      incorporating health into a system of religious belief is discussed. Possibly
      others can also implement such a model to their advantage.

PMID- 10641814
TI  - The psychology of social influence and healthy public policy.
AB  - Social-psychological research has led to effective health interventions based on
      social influence processes. For example, school-based substance abuse prevention
      programs using the social influences model consistently produce better results
      than programs emphasizing only health information. Other areas of application
      have been prevention of AIDS, marketing social action programs, community-wide
      health promotion, anti-prejudice intervention, aggression control, crime and
      injury prevention, and resource conservation. Yet another area for application is
      the emerging field of health promotion, which seeks to cross traditional
      boundaries to build healthy public policies in all sectors of society. A
      comprehensive social influences approach is needed because education alone is not
      likely to change fundamental ideas about where the responsibility for health
      rests. Current assignment of responsibility to the health sector and victim
      blaming will be difficult to defeat. Positive changes at the required levels will
      depend on better understanding of how to instill health promotion values in
      policy arenas beyond the health care sector and better understanding of the
      dynamics of policy-making behaviors and related social influence processes.
      Social psychologists can and should assist the health promotion field to meet
      these challenges by conducting descriptive and intervention research on the
      psychology of social influence processes in public policy-making arenas.

PMID- 10641815
TI  - Socioeconomic considerations in the primordial prevention of cardiovascular
      disease.
AB  - Economic policy is an important determinant of population health; it is part of
      health policy. True primordial prevention of cardiovascular disease (CVD) may
      require regulation of the domestic and international market forces which produce
      and distribute CVD risk factors and their determinants. Because the market does
      not bear the cost of the legacy of poor health that it generates, primordial
      prevention of CVD may need to concern itself with societal mechanisms for holding
      these market forces accountable. Indeed, this approach is now an important part
      of the public health lexicon for preventing smoking. No program of primordial
      prevention of smoking could possibly ignore the national and international
      economic interests of the tobacco industry. We need to start thinking about
      primordial prevention of CVD risk factors such as low physical activity, high-fat
      diet, and psychosocial stress in the same way.

PMID- 10641816
TI  - The influence of socioeconomic factors on cardiovascular disease risk factor
      development.
AB  - In the industrialized, urban United States, there is an increasingly strong
      inverse association of socioeconomic status (SES) and cardiovascular disease
      (CVD) risk and mortality. The large difference in levels and trends in CVD risk
      associated with SES indicates a major potential for primordial prevention if
      carried out at both individual and community levels and with broader
      socioeconomic improvements.

PMID- 10641817
TI  - Primordial prevention of cardiovascular disease through applied genetics.
AB  - Primordial prevention might be considered prevention of the development of
      disease at its earliest stages or early intervention on risk factors to eliminate
      increased risk in the first place. In this review we consider how knowledge of
      genetic causes of early cardiovascular disease can lead to directed screening and
      better treatment of high risk individuals. While gene therapy would be the most
      "primordial" approach to prevention of some diseases such as familial
      hypercholesterolemia, its practical application remains on the horizon.
      Nevertheless, there is much we can do now to prevent early deaths in genetically
      high risk patients. Here we consider epidemiology as the parent discipline for
      applied genetics and as integral to primordial prevention. With new knowledge of
      special susceptibility and new understanding of the interaction of genetics and
      exposures, prevention of individual high-risk in the first place is realizable.
      We summarize here the known and candidate genes influencing atherosclerosis,
      hypertension, and thrombosis; their diagnosis; and some useful preventive
      approaches. MEDPED, an international scheme for detection of risk in medical
      pedigrees, is described, along with the cost and social implications of its
      application as a preventive strategy.

PMID- 10641818
TI  - Mass media, secular trends, and the future of cardiovascular disease health
      promotion: an interpretive analysis.
AB  - Mass media roles in promoting cardiovascular health in the context of lessons
      learned from major U.S. community studies, changing media technology, and
      emergent models of media-community partnerships are discussed. Three principal
      issues are explored: (1) implications of the current expansion, convergence, and
      harmonization of mass media technology;(2) recent trends in media coverage of
      heart disease and population practices; and (3) implications for the future
      relationship between the media and public health in cardiovascular health
      promotion. It is concluded that classic campaign models focusing on individual
      level change have evolved to recognize environmental-level influences on
      behavior. Emergent public health campaign models have moved toward "agenda
      building," in which the focus is on a more unified approach to influencing public
      and community agendas for social, behavioral, and policy change. Recent
      developments among the commercial mass media may offer new opportunities for
      public health partnerships to promote cardiovascular health.

PMID- 10641819
TI  - The role of the health care system in primordial prevention.
AB  - The health care system has the resources to assume an important role in
      primordial prevention. The extent to which it does so will be determined largely
      by the financial and economic forces that are transforming the health care
      system. There is reason to be optimistic about the effectiveness of a partnership
      between community-based organizations and medical centers in addressing the
      challenges of primordial prevention in the 21st century.

PMID- 10641820
TI  - How the health care system can influence cardiovascular disease risk factors.
AB  - Only a small fraction of the health-care dollar is directed toward lifestyle
      changes that would reduce the social burden from cardiovascular diseases (CVD).
      Here we discuss the challenge, opportunity, methods, and potential for managed
      care to implement risk reduction strategies and preventive care. A systematic
      team approach involving nurses, nutritionists, exercise physiologists, and
      behavioral experts has been shown to be effective, along with physicians, in
      reducing CVD risk. This approach is increasingly accepted by and practiced in the
      CVD community and the managed care industry.

PMID- 10641821
TI  - Prevention of cardiovascular risk factors in the first place.
AB  - Cardiovascular disease (CVD) prevention can address the major risk factors-blood
      lipids, blood pressure, and smoking-and their determinants throughout the
      lifespan, with approaches varying according to age and risk. The Task Force on
      Research in Epidemiology and Prevention of Cardiovascular Diseases gave new
      impetus to the concept of early intervention: Their highest priority in CVD
      prevention was "to prevent the development of CVD risk in the first place." Six
      issues follow: (1) the relation between "primordial prevention" of CVD and
      "prevention of the risk factors in the first place"; (2) the place of youth in
      context with older and younger age groups; (3) the importance of bridging
      institutional gaps between youth and adulthood; (4) the need to strengthen the
      scientific base linking the major risk factors (e.g., blood cholesterol
      concentration) with their determinants; (5) the value of rate of change in risk
      factors with age, and not only incidence of "treatable" levels of risk factors,
      as an outcome in assessing interventions; and (6) the role and appropriate design
      strategies for both observational and intervention studies. It is time for a
      radical expansion of our investment in preventing the risk factors in the first
      place.

PMID- 10641822
TI  - Cardiovascular disease prevention among youth: visioning the future.
AB  - Health behaviors among youth are interrelated and appear likely to extend into
      adult years. Thus cardiovascular disease prevention among youth will continue to
      be needed and may be critical to the prevention of high risk in the first place.
      These prevention efforts should be guided by behavioral models and etiological
      research. Healthy environments are important for the maintenance of healthy
      behaviors among young people and we need to know better how to change them.
      Moreover, successful prevention strategies among youth need to be disseminated
      globally as rapidly as they are found.

PMID- 10641823
TI  - Primordial prevention of cardiovascular disease among African-Americans: a social
      epidemiological perspective.
AB  - BACKGROUND: The primordial prevention of cardiovascular disease (CVD) among
      African-Americans represents a formidable challenge for public health. This paper
      discusses the nature of this challenge, highlighting the role that economic and
      cultural factors play in shaping the distributions of major CVD risk factors
      among African-Americans. The paper concludes with specific suggestions for
      research. METHODS: Data from recent national health surveys on black/white
      differences in major CVD risk factors like hypertension, obesity, cholesterol,
      cigarette smoking, and physical inactivity were reviewed for the purpose of
      identifying promising avenues for primordial prevention research among African
      Americans. RESULTS: Cigarette smoking has a delayed onset among African-Americans
      compared to whites. Black/white differences in "vigorous" leisure-time physical
      activity (e.g., social dancing and team sports) are not apparent until around age
      40. These findings have relevance for primordial prevention work in black
      communities since they suggest the existence of broad-based, health-relevant
      cultural norms which could support primordial prevention programs, such as
      regular physical activity, across the life cycle. CONCLUSIONS: CVD primordial
      prevention programs among African-Americans must be grounded in an understanding
      of how cultural values as well as economic conditions shape CVD risk factor
      distributions in this population. Ultimate success will depend on the strength of
      the partnerships that public health researchers, primary care providers, and
      community residents are able to build.

PMID- 10641824
TI  - Do Mexican Americans really have low rates of cardiovascular disease?
AB  - In this article we challenge the conclusion made from vital statistics that
      Hispanic Americans have lower all-cause and cardiovascular disease (CVD)
      mortality than non-Hispanic whites. There is reason to believe that vital
      statistics underascertain minority, and in particular Hispanic, deaths. Cohort
      studies minimize many of these limitations. In the San Antonio Heart Study risk
      factor distributions predicted higher all-cause and CVD mortality among Mexican
      Americans than among non-Hispanic whites. Follow-up of the cohort confirmed a
      mortality ratio of 1.38 for all-cause and 1.30 for CVD mortality for Mexican
      Americans vs non-Hispanic whites. This excess risk was confined to U.S.-born
      Mexican Americans, since immigrants from Mexico had very low mortality despite
      low socioeconomic status. We attribute this latter finding to a "healthy migrant
      effect."

PMID- 10641825
TI  - Issues for cardiovascular disease risk factor development in Europe.
AB  - A review of U.S. and European clinical trials and cardiovascular prevention
      studies indicates a strong relation among cardiovascular disease risk factors and
      between metabolic factors and health behaviors established in youth. Social and
      behavioral determinants of risk are best modified by strategies applied in
      schools, families, and whole communities to provide a firm base for primordial
      prevention of risk factor development. This is illustrated with results from a
      European intervention trial and from observational studies in the young.

PMID- 10641826
TI  - Trends of cardiovascular risk factors and diseases in Japan: implications for
      primordial prevention.
AB  - We have documented a 70% fall in stroke mortality and a 20% decline in coronary
      disease (CHD) mortality over the past 30 years in Japan. This parallels a change
      away from the traditional Japanese eating pattern, with less salt and more meat
      and dairy products, and decreased rates of smoking. A recent increase in CHD
      rates among urban Japanese men raises the need for vigorous primordial prevention
      efforts to avoid elevated blood lipids in modern Japanese populations, while
      primary prevention efforts must continue for the prevention of hypertension and
      smoking.

PMID- 10641827
TI  - Primordial prevention of cardiovascular disease risk in The Netherlands.
AB  - Developments about cardiovascular disease (CVD) risk factors in The Netherlands
      since the 1970s are described in relation to health policy. The prevalence of
      hypercholesterolemia, hypertension, and obesity changed little in the 1970s and
      1980s. In recent years, however, the prevalence of hypercholesterolemia tended to
      decrease and that of obesity to increase. The prevalence of hypertension remained
      stable but the percentage of treated hypertensives declined since 1987. Between
      1958 and 1993 the percentage of male smokers decreased from 90% to about 40%. In
      women the percentage of smokers decreased from about 40% in 1975 to about 30% in
      1993. Between 1987 and 1992 the intake of saturated fat decreased from 16.5 to
      14.1% of energy. But during that period the intake of vegetables also decreased
      from 144 to 128 g/day and that of fruits from 125 to 114 g/day. Recent surveys
      show that up to age 65, approximately 25% of the Dutch population is physically
      inactive. This percentage increases sharply after age 65. Health policy for
      primordial prevention of CVD in The Netherlands is aimed at reduction of smoking
      prevalence, improvement of dietary habits, and promotion of physical activity.

PMID- 10641828
TI  - Cardiovascular risk factors in Italy.
AB  - In the 1950s the Italian population was known for its low mean levels of major
      cardiovascular risk factors and serum cholesterol in particular. A definite
      increase of those mean levels was associated, in the next 2 decades, with
      increasing death rates from cardiovascular diseases and coronary heart disease.
      Between the late 1970s and early 1990s cardiovascular death rates declined by
      over 40%. Large population surveys showed, between 1978 and 1987, small decreases
      in the mean levels of blood pressure (in both sexes), of smoking habits (in men),
      and of body weight (in women), while serum cholesterol remained stable. These
      changes mathematically explained about two-thirds of the observed decline in
      cardiovascular mortality among middle-aged people. In the late 1980s and early
      1990s scattered population studies suggested a decline in mean population levels
      of serum cholesterol, at least in some areas of the country. More coordinated or
      systematic preventive campaigns were organized by the public health authorities.
      On the other hand activities of many small private organizations dealing with
      heart health likely explain the spread of knowledge, attitude, and practice in
      the prevention of cardiovascular diseases. Food industry started to produce low
      fat products and to label foods with nutrition facts. Changes in food consumption
      in the beneficial direction started to be recorded in the late 1980s. The spread
      of antihypertensive treatment was partly favored by the National Health Service
      offering anti-hypertensive drugs at relatively low cost. Government regulations
      have more and more restricted the public areas where smoking is allowed. An
      increasing interest for prevention on the part of physicians is a recent issue,
      mainly bound to the success of some major controlled trials of
      hypocholesterolemic drugs.

PMID- 10641829
TI  - Primordial prevention of coronary heart disease in India: challenges and
      opportunities.
AB  - Demographic shifts, lifestyle changes, and adverse effects of childhood nutrition
      portend an epidemic of coronary heart disease in the Indian subcontinent, which
      is currently experiencing health transition. Indian susceptibility includes
      atherogenic blood lipid levels and a metabolic complex of central obesity,
      glucose intolerance, hyperinsulinemia, and dyslipidemia due to insulin
      resistance. These characteristics are demonstrated dramatically in urban Indians
      and in Indian migrants to the west. Prime targets for effective strategies of
      primordial prevention include children and families in lower socio-economic
      classes now in transition. There is the greatest urgency in India for medical,
      political, and social action to prevent high risk in the first place, combating
      the tobacco trade, enlisting food and agriculture agencies, and promoting
      physical activity in the population. An empowered community with an enlightened
      policy can prevent the threatened epidemic.

PMID- 10641830
TI  - Cardiovascular diseases and risk factors in Finland.
AB  - We summarize here the evidence from the 1960s and 1970s of exceptionally high
      risk of cardiovascular disease (CVD) in Finland. In parallel with voluntary and
      governmental prevention programs, the level of risk factors and CVD attack rates
      have shown dramatic improvement in the past 25 years, but the decline has slowed
      in recent years. This experience strongly supports population-wide strategies for
      primary prevention, and it also highlights the continued need for primordial
      prevention directed toward youth in high-risk societies.

PMID- 10641831
TI  - Primordial prevention of cardiovascular disease risk factors: panel summary.

PMID- 10641832
TI  - Enhancement of the point-spread function for imaging in scattering media by use
      of polarization-difference imaging.
AB  - Polarization-difference (PD) imaging techniques have been demonstrated to improve
      the detectability of target features that are embedded in scattering media. The
      improved detectability occurs for both passive imaging in moderately scattering
      media (<5 optical depths) and active imaging in more highly scattering media.
      These improvements are relative to what is possible with equivalent polarization
      blind, polarization-sum (PS) imaging under the same conditions. In this
      investigation, the point-spread functions (PSF's) for passive PS and PD imaging
      in single-scattering media are studied analytically, and Monte Carlo simulations
      are used to study the PSF's in single- and moderately multiple-scattering media.
      The results indicate that the PD PSF can be significantly narrower than the
      corresponding PS PSF, implying that better images of target features with high
      spatial-frequency information can be obtained by using differential polarimetry
      in scattering media. Although the analysis was performed for passive imaging at
      moderate optical depths, the results lend insight into experiments that have been
      performed in more highly scattering media with active imaging methods to help
      mitigate the effects of multiple scattering.

PMID- 10641833
TI  - Three-dimensional tomographic reconstruction of an absorptive perturbation with
      diffuse photon density waves.
AB  - A three-dimensional tomographic reconstruction algorithm for an absorptive
      perturbation in tissue is derived. The input consists of multiple two-dimensional
      projected views of tissue that is backilluminated with diffuse photon density
      waves. The algorithm is based on a generalization of the projection-slice theorem
      and consists of depth estimation, image deconvolution, filtering, and
      backprojection. The formalism provides estimates of the number of views necessary
      to achieve a given spatial resolution in the reconstruction. The algorithm is
      demonstrated with data simulated to mimic the absorption of a contrast agent in
      human tissue. The effects of noise and uncertainties in the depth estimate are
      explored.

PMID- 10641834
TI  - Interferometric data analysis based on Markov nonlinear filtering methodology.
AB  - For data processing in conventional phase shifting interferometry, Fourier
      transform, and least-squares-fitting techniques, a whole interferometric data
      series is required. We propose a new interferometric data processing methodology
      based on a recurrent nonlinear procedure. The signal value is predicted from the
      previous step to the next step, and the prediction error is used for nonlinear
      correction of an a priori estimate of the parameters phase, visibility, or
      frequency of interference fringes. Such a recurrent procedure is correct on the
      condition that the noise component be a Markov stochastic process realization.
      The accuracy and stability of the recurrent Markov nonlinear filtering algorithm
      were verified by computer simulations. It was discovered that the main advantages
      of the proposed methodology are dynamic data processing, phase error
      minimization, and high noise immunity against the influence of non-Gaussian noise
      correlated with the signal and the automatic solution of the phase unwrapping
      problem.

PMID- 10641835
TI  - Large-scale failures of f(-alpha) scaling in natural image spectra.
AB  - Several studies have demonstrated that the power spectra of natural image
      ensembles scale as f(-alpha). A stronger claim that has been made is that the
      power spectra of single natural images typically also scale as f(-alpha). Results
      are presented that challenge this latter claim. The results are based on a method
      for estimating large-scale structure in single images that compares aliasing
      artifacts produced by image windows of different shape. Failures of f(-alpha)
      scaling are found at large scales in many natural images. These failures cannot
      be accounted for by f(-alpha) scaling models such as a linear superposition model
      or a model based on two-dimensional occlusions in the image plane. The results
      imply that claims about f(-alpha) scaling in single natural images have been
      exaggerated. The results also offer insight into why such failures of f(-alpha)
      scaling occur.

PMID- 10641836
TI  - Inverse source problem and minimum-energy sources.
AB  - We present a new linear inversion formalism for the scalar inverse source problem
      in three-dimensional and one-dimensional (1D) spaces, from which a number of
      previously unknown results on minimum-energy (ME) sources and their fields
      readily follow. ME sources, of specified support, are shown to obey a homogeneous
      Helmholtz equation in the interior of that support. As a consequence of that
      result, the fields produced by ME sources are shown to obey an iterated
      homogeneous Helmholtz equation. By solving the latter equation, we arrive at a
      new Green-function representation of the field produced by a ME source. It is
      also shown that any square-integrable (L2), compactly supported source that
      possesses a continuous normal derivative on the boundary of its support must
      possess a nonradiating (NR) component. A procedure based on our results on the
      inverse source problem and ME sources is described to uniquely decompose an L2
      source of specified support and its field into the sum of a radiating and a NR
      part. The general theory that is developed is illustrated for the special cases
      of a homogeneous source in 1D space and a spherically symmetric source.

PMID- 10641837
TI  - Phase reconstruction from undersampled intensity patterns.
AB  - We demonstrate the uniqueness and convergence of phase recovery from high-spatial
      frequency and undersampled intensity data. Furthermore, this is accomplished
      without the ambiguities that arise in phase unwrapping and without the need to
      employ a priori information. The method incorporates the technique of line
      integration of the phase gradient to find the first approximation to the phase
      and the algorithm of synthetic interferograms to find the unknown phase with high
      accuracy. The method may be used with any experimental method that at a certain
      data processing step obtains generalized sine and cosine intensity functions.

PMID- 10641838
TI  - Branch-point reconstruction in laser beam projection through turbulence with
      finite-degree-of-freedom phase-only wave-front correction.
AB  - Wave-front sensing and deformable mirror control algorithms in adaptive optics
      systems are designed on the premise that a continuous phase function exists in
      the telescope pupil that can be conjugated with a deformable mirror for the
      purpose of projecting a laser beam. However, recent studies of coherent wave
      propagation through turbulence have shown that under conditions where
      scintillation is not negligible, a truly continuous phase function does not in
      general exist as a result of the presence of branch points in the complex optical
      field. Because of branch points and the associated branch cuts, least-squares
      wave-front reconstruction paradigms can have large errors. We study the
      improvement that can be obtained by implementing wave-front reconstructors that
      can sense the presence of branch points and reconstruct a discontinuous phase
      function in the context of a laser beam projection system. This study was
      conducted by fitting a finite-degree-of-freedom deformable mirror to branch-point
      and least-squares reconstructions of the phase of the beacon field, propagating
      the corrected field to the beacon plane, and evaluating performance in the beacon
      plane. We find that the value of implementing branch-point reconstructors with a
      finite-degree-of-freedom deformable mirror is significant for optical paths that
      cause saturated log-amplitude fluctuations.

PMID- 10641839
TI  - Diffractive variable beam splitter: optimal design.
AB  - The analytical expression of the phase profile of the optimum diffractive beam
      splitter with an arbitrary power ratio between the two output beams is derived.
      The phase function is obtained by an analytical optimization procedure such that
      the diffraction efficiency of the resulting optical element is the highest for an
      actual device. Comparisons are presented with the efficiency of a diffractive
      beam splitter specified by a sawtooth phase function and with the pertinent
      theoretical upper bound for this type of element.

PMID- 10641840
TI  - Confined wave packets in the domain of Rayleigh-Wood anomalies.
AB  - It is known that near grating anomalies of the resonance type a beam may undergo
      a lateral shift of the order of the beam width, and a pulse may be delayed by a
      time of the order of the pulse duration. These numerical investigations are
      extended to Rayleigh anomalies that occur when, upon variation of the wavelength
      or the angle of incidence, an additional propagating diffraction order emerges.
      It is shown that delays and displacements are 1 order of magnitude smaller than
      in the resonance case. However, with increasing beam width (or pulse duration),
      the lateral displacement (or the temporal delay) can become large.

PMID- 10641841
TI  - Terahertz pulse propagation in the near field and the far field.
AB  - We present a detailed investigation of the propagation properties of beams of
      ultrashort terahertz (THz) pulses emitted from large-aperture (LA) antennas. The
      large area of the emitter is demonstrated to have substantial influence on the
      temporal pulse profile in both the near field and the far field. We perform a
      numerical analysis based on scalar and vectorial broadband diffraction theory and
      are able to distinguish between near-field and far-field contributions to the
      total THz signal. We find that the THz beam from a LA antenna propagates like a
      Gaussian beam and that the temporal profile of the THz pulse, measured in the
      near field, contains information about the temporal and spatial field
      distribution on the emitter surface, which is intrinsically connected to the
      carrier dynamics of the antenna substrate. As a result of pulse reshaping,
      focusing of the THz beam leads to a reduced relative pulse momentum, with
      implications in THz field-ionization experiments.

PMID- 10641842
TI  - Effect of holes and vortices on beam quality.
AB  - The effect of a vortex on the invariant quality factors of a light beam is
      studied. It is shown that a vortex degrades beam quality. The beam intensity at
      the eye of the vortex necessarily vanishes, creating a hole in the intensity
      distribution. The degradation in the beam quality is shown to be due partly to
      the vortex phase and partly to the hole. The results are illustrated graphically.
      An important inequality to be obeyed by the beam-quality parameters is exhibited.

PMID- 10641843
TI  - Evolution of the polarization state for radiation propagating in a nonuniform,
      birefringent, optically active, and dichroic medium: the case of a magnetized
      plasma.
AB  - First, the analytic expressions are derived that describe some properties of the
      Poincare sphere that are related to the coherent sum of two waves having
      different polarizations. Then these expressions are used to obtain the
      differential equation that describes the evolution of the state of polarization
      of radiation propagating in a medium that is nonuniform, birefringent, optically
      active, and dichroic. Finally, an important example is presented: that of a
      magnetized plasma in which particle collisions are not negligible, such as the
      earth's ionosphere or certain laboratory plasmas. The evolution equation is the
      basis of plasma polarimetry.

PMID- 10641844
TI  - Computational study of diffraction patterns for near-field Fresnel and Gabor zone
      plates.
AB  - Near-field designs of Fresnel and Gabor zone plates are computationally analyzed
      by using versions that allow the foci to be brought closer to the plate than in
      the usual far-field applications. It is found that the Fresnel plate has a
      dominant primary conjugate pair of foci well inside the far-field region and a
      more intense primary focus and smaller off-focal-plane sidelobes than the near
      field Gabor systems, thus yielding a superior imaging performance.

PMID- 10641845
TI  - Speckle photography with different pupils in a multiple-exposure scheme.
AB  - The use of different multiple-aperture pupils for recording each image in speckle
      photography is proposed. The introduction of suitable spatial frequency carriers,
      by internally modulating imaged speckles, allows one to selectively isolate or
      combine the spectral content of different images into spatially separated regions
      in the Fourier plane. Theoretical and experimental results extend the speckle
      photography technique to the depiction of several specklegrams of multiple
      uniform in-plane displacements. In this case, because different pupils are
      considered for recording, the cross-correlation functions for the amplitudes and
      intensities in the image plane are calculated on the basis of the statistical
      properties of the object. Also, the ensemble-average intensity in the Fourier
      plane is analytically derived, and fringe visibility is investigated.

PMID- 10641846
TI  - Analysis of light noise sources in a recycled Michelson interferometer with Fabry
      Perot arms.
AB  - We present a method by which the effect of laser field variations on the signal
      output of an interferometric gravitational wave detector is rigorously
      determined. Using the Laser Interferometer Gravitational Wave Observatory (LIGO)
      optical configuration of a power recycled Michelson interferometer with Fabry
      Perot arm cavities as an example, we calculate the excess noise after the input
      filter cavity (mode cleaner) and the dependence of the detector strain
      sensitivity on laser frequency and amplitude noise, radio frequency oscillator
      noise, and scattered-light phase noise. We find that noise on the radio frequency
      sidebands generally limits the detector's sensitivity.

PMID- 10641847
TI  - Genetic algorithm for ellipsometric data inversion of absorbing layers.
AB  - A new data reduction method is presented for single-wavelength ellipsometry. A
      genetic algorithm is applied to ellipsometric data to find the best fit. The
      sample consists of a single absorbing layer on a semi-infinite substrate. The
      genetic algorithm has good convergence and is applicable to many different
      problems, including those with different independent measurements and situations
      with more than two angles of incidence. Results are similar to those obtained by
      other inversion techniques.

PMID- 10641848
TI  - Ellipsomicroscopy for surface imaging: contrast mechanism, enhancement, and
      application to CO oxidation on Pt(110).
AB  - Ellipsomicroscopy for surface imaging (EMSI) is a powerful new tool for studying
      spatiotemporal adsorbate pattern formation on catalyst surfaces. It is a surface
      sensitive technique that is able to measure submonolayer coverage of adsorbates.
      The imaging of the sample's surface achieves a spatial sensitivity, making it
      possible to measure nonuniformity of adsorbate coverage. The image contrast,
      however, depends strongly on the setup of the instrument. The optimum setup can
      be calculated from the ellipsometric properties of the catalyst/adsorbate system
      and the intrinsic parameters of the EMSI instrument. Optimizing the setup of the
      EMSI instrument permitted enhancement of the image contrast over the previous
      setup. As a result, new features in CO oxidation on Pt(110) were discovered.

PMID- 10641849
TI  - Asymmetrical properties of the optical reflection response of the Fabry-Perot
      interferometer.
AB  - It may be shown that, even when a Fabry-Perot interferometer is used with plane
      waves propagating at normal incidence, the variations of the intensity reflected
      by it with respect to the phase difference (induced by the distance between the
      two mirrors) are generally not symmetrical around its extrema. We study this
      problem and express the necessary and general conditions for obtaining a
      symmetrical optical response in the reflection mode. We analyze the simple case
      of a Fabry-Perot interferometer the first mirror of which is constituted by a
      thin layer of metal.

PMID- 10641850
TI  - Anisotropy and multiple scattering in thick mammalian tissues.
AB  - A dual-channel Mach-Zehnder interferometer using heterodyne detection allowed us
      to measure simultaneously parallel and perpendicular polarization components
      through various mammalian tissues at a wavelength of lambda = 633 nm. By contrast
      with liver tissue, squeletic muscles of a few millimeters thickness exhibit
      strong anisotropic properties that change the direction of the linear
      polarization of the light. This rotation of the initial plane of polarization is
      to be distinguished from the depolarization that is due to the multiple light
      scattering that goes along with large temporal fluctuations. Complementary photos
      under linearly polarized light illustrate the behavior difference between liver
      (isotropic medium) and muscle (anisotropic medium).

PMID- 10641851
TI  - Generalized algorithm for the unified analysis and simultaneous evaluation of
      geometrical spin-redirection phase and Pancharatnam phase in a complex
      interferometric system.
AB  - To permit unified analysis and simultaneous evaluation of geometrical spin
      redirection phase and Pancharatnam phase, the conventional 2 x 2 Jones matrix
      calculation is generalized and a new scheme of 3 x 3 matrix calculation is
      proposed. With the proposed algorithm one can trace the polarization state
      changes and the geometric phase shifts caused by beam propagation along an
      arbitrary optical path that involves both reflection and refraction at surfaces
      with Fresnel shift and birefringence.

PMID- 10641852
TI  - Reflectivity properties of an abruptly ended asymmetrical slab waveguide for the
      case of transverse magnetic modes.
AB  - We deal with the scattering phenomenon from an abruptly terminated asymmetrical
      slab waveguide for the case of transverse magnetic (TM) modes. The analysis uses
      both the integral equation method and the variational technique. The reflection
      coefficient of the dominant TM guided mode and the far-field radiation pattern
      are computed, and the discontinuity of the electric field distribution on the
      core-clad interface is exhibited. Numerical results are presented for several
      cases of abruptly ended waveguides, including the three-layer slab guide and the
      structure with variable profile of the refractive index.

PMID- 10641853
TI  - Polaritons in uniaxial materials propagating in hollow cylinders.
AB  - The properties of polaritons propagating in hollow dielectric and magnetic
      cylinders embedded in an optically inert medium are studied. We pay special
      attention to those solutions of Maxwell's equations that give the behavior of the
      nonradiative modes (confined and localized) propagating in an optically active
      cylindrical medium. The dispersion relation of surface (localized) modes is
      obtained. Numerical results are presented for cylinders constituted by magnetic
      and dielectric materials, such as the uniaxial Heisenberg antiferromagnet MnF2
      and the dielectric TiO2.

PMID- 10641854
TI  - Implant sequence effects in intact male Holstein veal calves: live and slaughter
      traits.
AB  - Seven sequences of growth promotant implants were used in special-fed intact male
      Holstein veal calves (n = 443). Calves received implants 4 d after arrival at the
      veal barn, 42, and 84. The following implants were used: placebo (0), Z (36 mg
      zeranol), ET (20 mg estradiol, 200 mg testosterone), EP/2 (10 mg estradiol, 100
      mg progesterone), EP (20 mg estradiol, 200 mg progesterone), and EBA (24 mg
      estradiol, 120 mg trenbolone acetate). The following sequences were compared: 0-0
      0 (negative control), 0-ET-ET, Z-ET-ET, 0-EP-EP, Z-EP-EP, 0-EP/2-EBA, and Z-0
      EBA. From 0 to 42 d, Z implants increased (P<.05) ADG by 3.4% compared to
      placebo. However, implant schemes without an initial Z implant (0-ET-ET and 0-EP
      EP) had higher (P<.05) mean ADG for the period from d 42 to 84. From 84 d to the
      end of the experiment, only the 0-EP/2-EBA treatment increased (P<.05) ADG
      compared to 0-0-0. Over the entire trial 0-ET-ET, 0-EP-EP, Z-EP-EP, and 0-EP/2
      EBA implant sequences increased (P<.05) ADG by 3.2, 3.2, 2.4, and 4.7%,
      respectively, compared to the 0-0-0 sequence. Blood traits measured within 2 wk
      before slaughter were not affected by implant sequence, except that sequences
      with EP had higher (P<.05) leukocyte counts than were observed for the other
      sequences. Testicular weight was less (P<.01) for all of the implant sequences
      than for the negative control and less (P<.05) for Z-ET-ET than for 0-ET-ET, 0-EP
      EP, 0-EP/2-EBA, and Z-0-EBA. The type and frequency of medical treatments did not
      differ among implant sequences for any of the 42-d phases, or over the entire
      trial. Generally, the growth promotant implants currently approved for beef
      cattle resulted in approximately 50% of the increase in growth rate in Holstein
      intact bull calves, as has been observed in beef-type steers or heifers.

PMID- 10641856
TI  - Influence of frame size and body condition score on performance of Brahman
      cattle.
AB  - The effects of frame size (FS) and body condition score (BCS) on performance of
      Brahman cows were evaluated using records collected from 1984 to 1994 at the
      Subtropical Agricultural Research Station, Brooksville, Florida. Age at puberty
      (AP), calving rate (CR), calving date (CD), survival rate (SR), weaning rate
      (WR), birth weight (BWT), weaning weight (WWT), preweaning ADG, and kilograms of
      calf produced per cow exposed (PPC) were obtained from first- (n = 215), second-
      (n = 130), and third or greater-parity (n = 267) dams. Based on hip height at 18
      mo of age, heifers were assigned to three FS groups: small (115 to 126 cm),
      medium (127 to 133 cm), or large (134 to 145 cm). Small and medium FS heifers
      attained puberty at younger (P<.05) ages (633.2+/-12.3 and 626.4+/-12.0 d) than
      large FS heifers (672.3+/-17.1 d). Calving rate in large FS second-parity dams
      was 27% less (P<.05) than in small and medium FS dams. In third or greater-parity
      dams, CR was greater (P<.05) for small FS cows than for medium and large FS cows.
      Across the three parity groups, CR improved with increasing BCS. Except for the
      first-parity dams, animals with better fall BCS calved earlier (P<.05). In first
      parity dams, SR was less (P<.01) in large (47.9+/-11.0%) than in small (80.7 +/
      5.2%) and medium (83.4+/-4.7%) FS groups. Weaning rates of large FS first- and
      second-parity dams were less (P<.05) than those of small and medium FS dams.
      Second-parity dams with BCS 3 had lower (P<.05) WR than dams with BCS 4 and 5.
      Within first- and third or greater-parity dams, BWT of calves born to small FS
      cows were the lightest, and those born to large FS dams were the heaviest; those
      born to medium FS dams were intermediate (P<.05). In second-parity dams, BWT of
      calves of large FS dams were greater (P<.05) than those of small and medium FS
      dams. In first-parity dams, calves weaned by small FS cows had lower (P<.05) WWT
      than those weaned by higher FS cows. In the third or greater-parity group, large
      FS dams weaned heavier calves (P<.05) than other dams. In all parity groups of
      dams, calves out of large FS cows had greater ADG (P<.05) than those from small
      and medium FS cows. In first-parity dams, PPC was comparable between small and
      medium FS dams, but both tended to be greater (P<.10) than PPC of large FS dams.
      Small and medium FS females reached puberty at an earlier age, calved earlier,
      and had greater calving, survival, and weaning rates, as well as greater
      kilograms of calf produced per cow exposed than the large FS females. As the
      large FS cows matured, they seemed to have overcome the negative effects imposed
      by FS that were observed at younger ages. Their performance traits were generally
      all comparable to those of smaller cows once they had reached maturity.

PMID- 10641855
TI  - Implant sequence effects in intact male Holstein veal calves: carcass
      characteristics.
AB  - Seven sequences of growth promotant implants were used in intact male Holstein
      veal calves (n = 443). Implants were administered on d 0 (within 4 d after
      arrival at the veal barn), 42, and 84. The implants used were placebo (0), Z (36
      mg zeranol), ET (20 mg estradiol, 200 mg testosterone), EP/2 (10 mg estradiol,
      100 mg progesterone), EP (20 mg estradiol, 200 mg progesterone), and EBA (24 mg
      estradiol, 120 mg trenbolone acetate). The following sequences were compared: 0-0
      0 (negative control), 0-ET-ET, Z-ET-ET, 0-EP-EP, Z-EP-EP, 0-EP/2-EBA, and Z-0
      EBA. Sequences 0-EP-EP, Z-EP-EP, and 0-EP/2-EBA increased (P<.05) carcass weight
      from 3.3 to 3.9% compared to nonimplanted controls. There were no differences
      (P>.05) in percentage of carcass weight accounted for by the fore vs. rear halves
      of carcasses, suggesting there was no difference in the distribution of weight.
      Although there were differences in longissimus area, the results were not
      consistent, except that there was a trend for longissimus area to be increased by
      the use of estrogenic-androgenic implants (ET and EBA). There were no differences
      among implant sequences for carcass conformation, fat cover, muscle texture,
      marbling/ feathering, muscle color, or muscle chemical composition. Of four
      implant sequences (0-0-0, 0-ET-ET, 0-EP-EP, and 0-EP/2-EBA) tested for
      differences in Warner-Bratzler shear force tenderness, the latter two sequences
      averaged higher (P<.05) for shear force than did the negative control. These
      results suggest that aggressive implant strategies in young, intact Holstein bull
      calves (raised as veal) have minimal effects on carcass characteristics.

PMID- 10641857
TI  - Lactation curves in captive Iberian red deer (Cervus elaphus hispanicus).
AB  - This study examines milk production and the effect of milk production and sex of
      calf on body weights and gains of red deer calves and hinds of the Iberian
      subspecies (Cervus elaphus hispanicus). Milk production was assessed in 14 hinds
      by weighing calves before and after suckling and by adjusting these values to the
      Gamma function. Gamma estimates of total milk production up to d 105 were similar
      to the amounts computed directly from double weighing. Hinds showed two types of
      lactation curve: 1) the standard mammal lactation curve, with an asymmetrical
      peak at wk 2 to 4 (Type I) and 2) decreasing curves with no peak (Type II).
      Although there was great interindividual variability, hinds with Type I curves
      showed a trend to produce more milk than those with Type II. The type of curve
      did not seem to affect weight variables of the calf or those of the dam. Calves
      that gained more weight consumed greater amounts of milk (P<.05). Males were
      heavier than females at birth (P<.05), but males did not differ from females in
      their weight at 105 d, milk consumption, and gain. Gender did not affect hind
      weight, but dams of male calves showed a trend to be lighter (P = .063) at d 105
      than dams of female calves. Our results suggest that suckling differences found
      in other studies between male and female calves may not involve differences in
      milk production, although other rearing costs seem to affect hind weight losses.
      They also suggest that the curve type may not depend only, as reported, on the
      nutrition plane.

PMID- 10641858
TI  - Impacts of increasing amounts of supplemental soybean meal on intake and
      digestion by beef steers and performance by beef cows consuming low-quality
      tallgrass-prairie forage.
AB  - Two experiments were conducted to evaluate the impacts of increasing levels of
      supplemental soybean meal (SBM) on intake, digestion, and performance of beef
      cattle consuming low-quality prairie forage. In Exp. 1, ruminally fistulated beef
      steers (n = 20; 369 kg) were assigned to one of five treatments: control (forage
      only) and .08, .16, .33, and .50% BW/d of supplemental SBM (DM basis). Prairie
      hay (5.3% CP; 49% DIP) was offered for ad libitum consumption. Forage OM intake
      (FOMI) and total OM intake (TOMI) were increased (cubic, P = .01) by level of
      supplemental SBM, but FOMI reached a plateau when the daily level of SBM
      supplementation reached .16% BW. The concomitant rises in TOMI and OM
      digestibility (quadratic, P = .02) resulted in an increase (cubic, P = .03) in
      total digestible OM intake (TDOMI). In Exp. 2, spring-calving Hereford x Angus
      cows (n = 120; BW = 518 kg; body condition [BC] = 5.3) grazing low-quality, tall
      grass-prairie forage were assigned to one of three pastures and one of eight
      treatments. The supplemental SBM (DM basis) was fed at .08, .12, .16, .20, .24,
      .32, .40, and .48% BW/d from December 2, 1996, until February 10, 1997 (beginning
      of the calving season). Performance seemed to reach a plateau when cows received
      SBM at approximately .30% BW/d. Below this level, cows lost approximately .5 unit
      of BC for every .1% BW decrease in the amount of supplemental SBM fed. Providing
      supplemental SBM is an effective means of improving forage intake, digestion, and
      performance of beef cattle consuming low-quality forages.

PMID- 10641859
TI  - Influence of equine chorionic gonadotropin on weaning-to-estrus interval and
      estrus duration in early-weaned, primiparous, female swine.
AB  - The weaning-to-estrus interval (WEI) influences the total nonproductive days
      (NPD) accumulated by the breeding herd and affects herd productivity. Short
      lactation lengths (LL) are commonly followed by prolonged WEI, which are also
      associated with short estrus duration (ED). Equine chorionic gonadotropin
      treatment is a tool that has been used to reduce WEI, especially for low-parity
      females. The objectives for this study were to evaluate the effect of LL on the
      association between WEI and ED and to estimate the effects of postweaning eCG
      administration on WEI and ED for early-weaned females. Two treatments (TREAT)
      consisting of 750 IU of eCG (n = 96) or control (n = 77) were applied 1 d after
      weaning to first-parity, weaned females. The study was conducted on a commercial
      farm having a target LL of 18 d. Estrus detection was conducted three times
      daily, and estrus duration was determined as the interval between the first and
      the last positive response to back pressure. Analyses of variance were conducted
      to estimate the effects of LL and TREAT on WEI and the effects of TREAT and WEI
      on estrus duration. Mean LL was 17.9+/-1.7 d, mean WEI was 106.6+/-29.2 h, and
      mean estrus duration was 55.9+/-15.5 h. Even though the frequency of short WEI
      tended to increase with longer LL, mean WEI was shortest for females weaned after
      18 d and longest for those weaned after 20 d (P<.05). The WEI for females
      receiving eCG (98.7+/-2.7 h) was shorter (P = .0001) than that for control
      females (121.5+/-3.3 h). The WEI was also affected by a LL x TREAT interaction (P
      = .0014), indicating that the interval was longer (P<.05) for control females
      weaned after 17 and 20+ d than for other females. The LL and TREAT did not affect
      estrus duration (P = .20 and P = .157, respectively). However, estrus duration
      was reduced as the WEI increased (P = .0001), and it was also influenced by a WEI
      x TREAT interaction (P = .024). A linear regression model estimated that the
      association between WEI and estrus duration was stronger in the eCG group than in
      the control group (R2 = .51 and .15, respectively; both P<.001). In conclusion,
      the use of eCG postweaning was associated with more precise prediction of estrus
      duration as a function of the WEI and allows optimization of breeding management
      in early-weaned, primiparous females.

PMID- 10641860
TI  - Health of finishing steers: effects on performance, carcass traits, and meat
      tenderness.
AB  - The impact of respiratory disease during a 150-d feedlot finishing period on
      daily gain, carcass traits, and longissimus tenderness was measured using 204
      steer calves. Feedlot health status was monitored in two ways. First, clinical
      signs of respiratory infection were evaluated each day; treatment with antibiotic
      was based on degree of fever (if rectal temperature exceeded 40 degrees C then
      calves were treated). Steers that were treated (n = 102) had lower (P<.05) final
      live weights, ADG, hot carcass weights (HCW), less external and internal fat, and
      more desirable yield grades. Steers that were treated had a higher prevalence of
      carcasses that graded U.S. Standard than steers that were never treated. Second,
      as an alternative index of health status, lungs of all steers were evaluated at
      the processing plant using a respiratory tract lesion classification system; this
      health index included presence or absence of preexisting pneumonic lesions in the
      anterioventral lobes plus activity of the bronchial lymph nodes (inactive vs
      active). Lung lesions were present in 33% of all lungs and were distributed
      almost equally between treated (37%) and untreated cattle (29%). Steers with
      lesions (n = 87) had lower (P<.05) daily gains, lighter HCW, less internal fat,
      and lower marbling scores than steers without lesions. Compared to steers with
      lesions but inactive bronchial lymph nodes (n = 78), steers with lung lesions
      plus active lymph nodes had lower (P<.01) ADG and dressing percentage.
      Longissimus shear force values for steaks aged 7 d were lower (P = .05) from
      steers without lung lesions than those for steaks from steers with lung lesions.
      Overall, morbidity suppressed daily gains and increased the percentage of U.S.
      Standard carcasses. Compared to health assessment by clinical appraisal (based on
      elevated body temperature), classification based on respiratory tract lesions at
      slaughter proved more reliable statistically and, thereby, more predictive of
      adverse effects of morbidity on production and meat tenderness.

PMID- 10641861
TI  - Comparison of models to estimate genetic effects of weaning weight of Angus
      cattle.
AB  - Weaning weights from nine sets of Angus field data from three regions of the
      United States were analyzed. Six animal models were used to compare two
      approaches to account for an environmental dam-offspring covariance and to
      investigate the effects of sire x herd-year interaction on the genetic
      parameters. Model 1 included random direct and maternal genetic, maternal
      permanent environmental, and residual effects. Age at weaning was a covariate.
      Other fixed effects were age of dam and a herd-year-management-sex combination.
      Possible influence of a dam's phenotype on her daughter's maternal ability was
      modeled by including a regression on maternal phenotype (fm) (Model 3) or by
      fitting grandmaternal genetic and grandmaternal permanent environmental effects
      (Model 5). Models 2, 4, and 6 were based on Models 1, 3, and 5, respectively, and
      additionally included sire x herd-year (SH) interaction effects. With Model 3,
      estimates of fm ranged from -.003 to .014, and (co)variance estimates were
      similar to those from Model 1. With Model 5, grandmaternal heritability estimates
      ranged from .02 to .07. Estimates of maternal heritability and direct-maternal
      correlation (r(am)) increased compared with Model 1. With models including SH,
      estimates of the fraction of phenotypic variance due to SH interaction effects
      were from .02 to .10. Estimates of direct and maternal heritability were smaller
      and estimates of r(am) were greater than with models without SH interaction
      effects. Likelihood values showed that SH interaction effects were more important
      than fm and grandmaternal effects. The comparisons of models suggest that r(am)
      may be biased downward if SH interaction and(or) grandmaternal effects are not
      included in models for weaning weight.

PMID- 10641862
TI  - Preference for flavored wheat straw by lambs conditioned with intraruminal
      infusions of starch administered at different times after straw ingestion.
AB  - We hypothesized that the development and extinction of preferences for flavored
      foods paired with infusions of starch depends on the delay between food ingestion
      and starch administration and on the frequency of starch administration. To test
      this hypothesis, we divided 24 lambs into three groups of 8 lambs/group. On even
      days, half of the lambs were offered chopped wheat straw flavored with a
      distinctive flavor, whereas the other half received straw with a different
      flavor. Starch (12% of the daily DE required by the lambs) was infused into the
      rumen immediately after lambs began to eat straw in Group 1 (150 g starch),
      immediately after lambs began to eat straw (75 g) and 30 min later (75 g) in
      Group 2, and when straw refusals were collected 1 h after lambs began to eat
      straw in Group 3 (150 g). On odd days, the flavors were switched and infusions of
      starch were replaced with water. After 8 d of conditioning, starch infusions were
      suspended, and lambs were offered a choice of wheat straw with the two
      distinctive flavors. All lambs acquired strong preferences for flavored straw
      paired with starch (P< .001), but the delay between straw ingestion and starch
      infusion affected preferences (P<.05). Lambs that received starch 1 h after
      beginning to eat straw (Group 3) had lower preferences than lambs that received
      starch immediately after beginning to eat straw (Groups 1 and 2). Lambs that
      received two starch infusions (Group 2) did not show higher preferences for
      flavored straw than lambs that received only one starch infusion immediately
      after beginning to eat (Group 1). Lambs in our study retained preferences for at
      least 17 d when eating straw was no longer reinforced with starch (P<.001).
      However, preferences were less persistent for lambs that received starch
      immediately after beginning to eat straw (Group 1) than for lambs that received
      starch in two pulses (Group 2) or lambs that received starch 1 h after beginning
      to eat straw (Group 3). Collectively, our results support the hypothesis that the
      delay between food ingestion and starch administration affects food preferences
      of lambs. These findings suggest that manipulating the chemical characteristics
      of foods, which affects the kinetics of forage degradation in the rumen, can
      increase food preferences in ruminants.

PMID- 10641863
TI  - Effect of segregated early weaning on postweaning small intestinal development in
      pigs.
AB  - The effect of segregated early weaning (SEW) on postweaning small intestinal
      development was investigated in SEW and control (CON) pigs. Small intestines were
      collected from a total of 15 pigs killed at 11 (preweaning), 15 (3 d
      postweaning), and 34 d of age. At 3 d postweaning, the SEW and CON pigs had
      shorter villi (P<.01), deeper crypts (P<.01), and reduced (P<.01) ratios of
      villus height:crypt depth (V:C) compared with preweaning. Weaning also reduced
      specific activities of lactase (P<.01) in duodenum and ileum and alkaline
      phosphatase (ALP) (P<.05) in duodenum and jejunum. Sucrase activity in the three
      regions of the small intestine marginally decreased in both groups at 3 d
      postweaning. The mucosal protein:DNA ratio in duodenum and jejunum increased
      (P<.05) in SEW and CON pigs at 3 d postweaning compared with preweaning pigs. The
      SEW and CON treatments resulted in differences in postweaning gut development. At
      15 d of age in SEW pigs, the mucosal protein:DNA ratio in duodenum and jejunum
      were 20 and 25.5% (P<.05) less, respectively, than those in CON pigs. However, at
      34 d, these ratios in duodenum, jejunum, and ileum were 43.5 (P<.05), 24.3, and
      32.9% (P<.05) greater, respectively, in SEW pigs than in CON pigs. Longer villi,
      shorter crypts (P<.01), and higher V:C ratios (P<.01) in jejunum and ileum were
      observed in SEW pigs vs CON pigs at 34 d of age. The specific activities of
      lactase in duodenum (P<.01) and jejunum (P<.05) and of ALP in duodenum (P<.01)
      were higher in SEW pigs. Sucrase activity in duodenum, jejunum, and ileum was
      21.7, 46.3 (P<.05), and 11.2% greater in SEW pigs at 34 d of age. These results
      demonstrate differences in postweaning gut development between SEW and CON pigs.
      Furthermore, the number of intraepithelial lymphocytes in jejunum was greater
      (P<.001) in 34-d-old SEW pigs compared with CON pigs. Microscopy revealed a thick
      mucus coating over epithelial cells in the ileum of 34-d-old CON pigs that was
      not apparent in the SEW pigs. These observations are consistent with reduced
      pathogen exposure associated with SEW. We suggest that segregated early weaning
      advances postweaning gut maturation, which is consistent with improved growth and
      feed efficiency observed in SEW pigs.

PMID- 10641864
TI  - Regulation of porcine adipocyte metabolism by insulin and adenosine.
AB  - The acute effects of insulin and adenosine on rates of lipolysis and lipogenesis
      in pig adipocytes were investigated to determine what limits the expression of
      the insulin response in vitro. Adenosine and insulin independently inhibited
      isoproterenol-stimulated lipolysis. Adenosine, acting through the pertussis toxin
      sensitive G-protein Gi, was more effective than insulin and could completely
      inhibit lipolysis. Fatty acid synthesis from glucose was increased by both
      adenosine and insulin. Neutralization of endogenous adenosine with adenosine
      deaminase decreased basal rates of lipogenesis and increased the insulin response
      from 30 to 60% above basal. Neutralization of Gi with pertussis toxin further
      decreased the basal rate and increased the insulin response to 160% above basal.
      These data indicate that Gi, and the ligands that signal through Gi, stimulate
      glucose incorporation into fatty acids and can attenuate the insulin response. It
      seems likely that an exaggerated rate of glucose metabolism in the absence of
      insulin contributes to the inconsistent insulin responses exhibited in pig
      adipose tissue in vitro. These data also demonstrate that insulin and adenosine
      have major roles in regulating pig adipose tissue metabolism.

PMID- 10641865
TI  - Effect of feed intake on antimicrobially induced increases in porcine serum
      insulin-like growth factor I.
AB  - This study was conducted to determine whether an antimicrobially induced (ASP
      250) increase in serum IGF-I was the result of differences in feed intake. Serum
      IGF-I concentrations were measured in crossbred pigs that were fed a control diet
      or a diet supplemented with ASP-250 either for ad libitum consumption or limited
      to 85% of the control pigs' consumption. The pigs that consumed either diet ad
      libitum, control or ASP-250, consumed similar quantities of feed. The ASP-250 ad
      libitum-intake pigs had serum IGF-I concentrations that were greater (P<.01) than
      those of their ad libitum-intake control littermates. Similarly, the ASP-250
      limit-fed pigs had serum IGF-I concentrations that were greater (P<.01) than
      those of the controls. Although the serum IGF-I concentrations of pigs fed the
      ASP-250-supplemented diet for ad libitum intake were greater than the serum IGF-I
      concentrations of the pigs limit-fed the ASP-250-supplemented diet, the
      differences were not significant (P<.08). The ASP-250-fed pigs had higher serum
      IGF binding protein (BP)-3 concentrations than did their control littermates
      (P<.003). A time course of antimicrobially induced alterations in serum IGF-I
      concentrations revealed that the effect of increased serum IGF-I levels in ASP
      250-supplemented pigs (P<.02) was observed within 4 d and was maintained
      throughout the 4-wk study. These findings show that feed intake is not
      responsible for the increase in serum IGF-I observed with ASP-250
      supplementation. Additionally, the antimicrobially induced increase in serum IGF
      I concentrations occurs within a few days after initiation of the treatment.

PMID- 10641866
TI  - Effect of breed-type and feeding regimen on goat carcass traits.
AB  - Meat-type (Boer x Spanish and Spanish) goats from two feeding regimens (feedlot
      and range) were slaughtered and live and carcass weights were obtained. At 24 h
      after death, various yield and quality measurements were collected. One side from
      each carcass was fabricated into major wholesale cuts for dissection into major
      carcass components. Feedlot goats had heavier (P<.05) live and carcass weights
      and carcasses that yielded more (P<.05) dissectible fat and lean and less (P<.05)
      bone, as a percentage of carcass weight, than did the carcasses of range goats.
      In the feedlot environment, Boer x Spanish goats had greater (P<.05) live
      weights, carcass weights, actual and adjusted fat thicknesses, carcass
      conformation scores, and leg circumference scores than did Spanish goats of
      similar age. The only breed-type differences that were significant after
      adjusting for live weight using analysis of covariance were that Boer x Spanish
      goats in the feedlot treatment had greater (P<.05) actual and adjusted fat
      thickness and carcass conformation than Spanish goats on the feedlot treatment.
      The Boer x Spanish goat carcass trait advantage could mainly be attributed to
      their larger size and enhanced capacity for growth.

PMID- 10641867
TI  - Trained sensory panel and consumer evaluation of the effects of gamma irradiation
      on palatability of vacuum-packaged frozen ground beef patties.
AB  - The objectives for this experiment were to determine the effects of gamma
      irradiation on 1) the palatability of vacuum-packaged frozen ground beef patties
      by trained sensory panel and 2) consumer evaluation of the taste of hamburgers
      made with those patties. Boxes (4.5 kg) of frozen (-28 degrees C) ground beef
      patties (113.4 g/patty, 19% fat) from a commercial supplier were irradiated at a
      commercial gamma irradiation facility at one of three levels (0, 3.0, or 4.5
      kGy). All boxes were stored at 28 degrees C for 27 to 29 d after irradiation
      before evaluation by a trained descriptive attribute sensory panel and for 62 to
      104 d after irradiation before consumer evaluation. The trained panel evaluated
      grilled patties for ground beef aroma intensity, off-aroma, and off-flavor on 4
      point scales (4 = intense, none, and none; 1 = none, intense, and intense,
      respectively) and ground beef flavor intensity, tenderness, and juiciness on 8
      point scales (8 = extremely intense, tender, or juicy; 1 = extremely bland,
      tough, or dry). Control patties had more intense (P<.05) ground beef aroma (3.1
      vs 2.6), less off-aroma (3.3 vs 2.6), and more intense ground beef flavor (4.9
      vs. 4.3) than irradiated patties. However, there were no differences (P>.05) in
      any sensory trait between frozen ground beef patties treated with 3.0 or 4.5 kGy
      of gamma irradiation. There were no differences (P>.05) among treatments for
      tenderness (6.3, 6.6, and 6.7) or juiciness ratings (5.7, 5.9, and 5.9),
      respectively, for 0, 3.0, and 4.5 kGy. The consumers evaluated taste of a
      hamburger that included their choice of condiments on a 10-point scale (10 =
      excellent; 1 = terrible). Hamburgers made with patties treated with 4.5 kGy were
      rated lower (P<.05) in taste than hamburgers made with either control patties or
      those treated with 3.0 kGy (6.5, 6.6, and 6.2, respectively, for 0, 3.0, and 4.5
      kGy); however, all doses were rated at some level of "fair." These results imply
      that hamburgers made from ground beef patties irradiated under the conditions of
      this experiment would encounter little, if any, consumer acceptance problems at
      the 3.0 kGy dose and only slightly greater problems at the 4.5 kGy dose.

PMID- 10641868
TI  - Technical note: a rapid method for quantification of calpain and calpastatin
      activities in muscle.
AB  - Stepwise and continuous gradient ion-exchange chromatography were compared for
      yield of calpains and calpastatin from ovine muscle in a study designed to
      quantify their activities for comparative purposes. In Exp. 1, a continuous (25
      to 400 mM NaCl) gradient and a two-step gradient method (200 mM NaCl to coelute
      mu-calpain and calpastatin together and then 400 mM NaCl to elute mu-calpain)
      were compared. For the two-step method, mu-calpain activities were determined by
      subtracting calpastatin activities before and after heat inactivation of mu
      calpain. Both the two-step and the continuous gradient method yielded similar
      results over a broad range of activities. The stepwise gradient method does not
      require the use of fraction collectors and pumps, and it can be completed in a
      fraction of the time required for the continuous gradient method. In Exp. 2, the
      two-step method was compared with a three-step method (100 mM NaCl to elute
      calpastatin, then 200 mM NaCl to elute mu-calpain, and then 400 mM NaCl to elute
      m-calpain). Unlike the continuous gradient method, calpastatin and mu-calpain
      could not be completely separated using the three-step chromatography method.
      Thus, the three-step gradient method should not be used to quantify the
      components of the calpain proteolytic system. The present results indicate that
      the two-step gradient method is a fast and inexpensive method to determine
      calpain and calpastatin activities in studies designed to quantify the components
      of the calpain proteolytic system in skeletal muscle.

PMID- 10641869
TI  - Calcium-activated tenderization of strip loin, top sirloin, and top round steaks
      in diverse genotypes of cattle.
AB  - Steers of known percentage Brahman (B) and Angus (A) breeding (100% A, n = 6; F1
      B x A, n = 6; and 100% B, n = 6) were used to determine the effect of calcium
      chloride injection on the calpain proteinase system and meat tenderness. The
      steers were slaughtered in six replications (at either 9 or 14 mm of backfat,
      determined ultrasonically), with each breed type represented. Calpains and
      calpastatin activities were measured on fresh, prerigor longissimus muscle
      samples. Carcass data were collected after a 24-h chill, and the short loin (IMPS
      #180), top sirloin (IMPS #184), and top round (IMPS #168) were removed from both
      sides of each carcass. The cuts from the right side were then injected at 5%
      (wt/wt) with CaCl2 solution (2.2%). Longissimus muscle calpain and calpastatin
      activities were also measured at 48 h postmortem from the injected and control
      sides of each carcass. Warner-Bratzler shear force was measured on steaks from
      the three subprimals aged 1, 2, 5, 15, or 31 d. Marbling scores and USDA quality
      grades were higher (P<.05) in A than in F1 B x A and B carcasses. Calpastatin
      activity was higher (P<.05) in muscle from B than in muscle from A and F1 B x A
      steers, and postmortem storage (O vs 48 h) and CaCl2 injection reduced (P<.05)
      the activity of the calpains and calpastatin. Strip loin and top sirloin steaks
      from A and F1 B x A steers were more tender (P<.05) than steaks from B steers;
      however, top round steak tenderness did not differ (P>.05) across breed type.
      Calcium injection improved strip loin and top sirloin steak tenderness, but it
      did not affect top round steak tenderness. Collectively, these data show that
      CaC12 injection can be used to improve meat tenderness, with similar responses
      shown in cattle containing 0, 50, and 100% B inheritance. However, even with
      CaCl2 injection, B steaks are less tender than their A and F1 B x A counterparts.

PMID- 10641870
TI  - The effect of excess protein on growth performance and protein metabolism of
      finishing barrows and gilts.
AB  - Two experiments were conducted to evaluate the effect of excess protein on growth
      performance, carcass characteristics, organ weights, plasma urea concentration,
      and liver arginase activity of finishing barrows and gilts. In Exp. 1, 35 barrows
      and 35 gilts with an initial BW of 51 kg were used. Five pigs of each sex were
      slaughtered at the start of the study to determine initial body composition. The
      remaining 60 pigs were allotted to a randomized complete block (RCB) experiment
      with a 2x5 factorial arrangement of treatments (two sexes x five protein levels:
      13, 16, 19, 22, and 25% CP). The experiment continued until the average BW was
      115 kg, at which time three blocks of pigs (30 total) were selected randomly and
      slaughtered. Feed intake decreased with increasing protein concentration (linear,
      P<.05), and the reduction was greater in gilts than in barrows (P<.05). There was
      a trend toward a linear negative effect of dietary protein on ADG (P<.10) and
      also a quadratic effect of protein on protein accretion (P<.10). Fat accretion
      decreased linearly as protein level increased (P<.05). Increased protein
      concentrations increased liver, kidney, and pancreas weights (linear, P<.05).
      Plasma urea concentration increased with each protein concentration, with the
      exception of the 25 vs. 22% CP treatment in gilts. In Exp. 2, 18 barrows and 18
      gilts (BW 63 kg) were allotted to an RCB design consisting of a 2x2 factorial
      arrangement of treatments with two sexes and two dietary protein concentrations
      (16 and 25% CP). The experiment was terminated when the average BW of pigs
      reached 105 kg. Average daily feed intake was greater (P<.10) in barrows than in
      gilts. Average daily gain was reduced by 18% in gilts when dietary protein was
      increased from 16 to 25% but was only reduced 3% in barrows (sex x protein,
      P<.10). Barrows had lighter livers (P<.005), greater arginase activities (P<.05),
      and greater plasma urea concentrations (P<.005) than did gilts. Increasing
      dietary protein concentration from 16 to 25% increased liver weight, arginase
      activity, and plasma urea concentration (P<.005). These data suggest that gilts
      are more sensitive than barrows to excessive intakes of protein. The more
      negative effects in gilts may be related to liver metabolic capacity and activity
      of urea cycle enzymes.

PMID- 10641871
TI  - The effect of infusion of urea into the vena cava on feed intake of finishing
      gilts.
AB  - Three experiments were conducted to evaluate the relationship between feed intake
      and plasma urea concentration. In Exp. 1, six gilts (BW 53 kg) with catheters in
      their venae cavae were used in a 5x5+1 Latin square design to determine the
      amount of infused urea needed to mimic the plasma urea concentration of pigs fed
      a 25% CP diet. Five gilts were fed a 16% CP corn-soybean meal diet and were
      infused continuously with either saline or one of four doses of urea (6, 12, 18,
      and 24 g/d) during each of five periods (12 h/period). Between periods, infusions
      were stopped for 36 h. The sixth pig was fed a 25% CP diet and infused with
      saline during each of the experimental periods. Venous blood samples were
      obtained at 1-h intervals starting 1 h before infusion. As expected, plasma urea
      concentration increased with increasing amount of urea infused. A daily infusion
      of 24 g of urea resulted in a plasma urea concentration similar to that of the
      pig fed the 25% CP diet with saline infusion. In Exp. 2, 12 gilts (BW 60 kg) were
      used in a crossover design. Pigs received a 16% CP diet and a different treatment
      (saline or 24 or 30 g/d of urea) in each of three infusion periods. Each infusion
      period lasted 2 wk. Infusions were stopped for 2 d between periods. Blood samples
      were obtained before infusion and daily after infusions started. Feeders were
      weighed daily to determine ADFI. Experiment 3 was similar to Exp. 2, except that
      only two treatments (saline and 30 g/d of urea) were used. Data from Exp. 2 and 3
      were combined for statistical analysis. Plasma urea concentration increased
      linearly (P<.001) with increasing amount of urea infused. Overall, there was a
      trend (P<.10) for urea infusion to decrease ADFI, and pigs infused with 30 g/d
      consumed less (P<.05) feed than pigs infused with saline. Therefore, plasma urea
      concentration may play a role in regulating feed intake in gilts consuming excess
      protein.

PMID- 10641872
TI  - The effects of feed intake and body fatness on progesterone metabolism in
      ovariectomized gilts.
AB  - We studied the effects of feed intake and fatness on metabolic clearance rate
      (MCR) and half-life of progesterone in 40 ovariectomized gilts (10x4
      littermates). One gilt from each litter was randomly allocated to each of four
      treatments in a randomized block design. Gilts were reared to be either lean
      (Ln), 113 kg BW and 10 mm backfat measured 65 mm from the midline at the level of
      the last rib (P2), or fat (F), 124 kg BW and 20 mm P2 backfat. They were
      ovariectomized and fitted with bilateral jugular catheters. Fat and Ln gilts were
      then fed either low (1.15 x maintenance energy, L), or high (2.30 x maintenance
      energy, H) feed intakes. Gilts received an i.m. injection of 130 mg of
      progesterone on two consecutive days (d1 and 2). From d 3, progesterone was
      infused at 5.4 mg/h (130 mg/d) for 60 h. Blood samples for progesterone analysis
      were taken during the last 24 h of infusion and for a further 72 h. Gilts were
      then slaughtered, and livers were sampled for microsomal studies. Fatness did not
      affect any aspect of progesterone metabolism measured. Postprandial MCR was
      greater in H than in L gilts, 103.0 vs. 76.1 mL x min(-1) x kg BW(-1) (P<.01),
      respectively. Feed intake did not affect the disappearance rate constant of
      progesterone (mean -.019), and the estimated half-life of progesterone was 36.5
      h. High-intake gilts had larger proportional liver size (P<.001) than L gilts.
      Microsomal metabolism of progesterone and P450 enzyme concentration were similar
      across treatments. We conclude that increasing feed intake increases MCR of
      progesterone and could be used to manipulate progesterone concentration in sows.

PMID- 10641873
TI  - Variability among sources and laboratories in nutrient analyses of corn and
      soybean meal. NCR-42 Committee on Swine Nutrition. North Central Regional-42.
AB  - A cooperative research study involving members of a regional committee (North
      Central Regional Committee on Swine Nutrition [NCR-42]) was conducted to assess
      the variability in nutrient composition (DM, CP, Ca, P, Se, and amino acids) of
      corn and soybean meal from 16 sources (15 states, mostly in the Midwest) and to
      assess the analytical variability in nutrient assays among 22 laboratories (labs;
      16 experiment station labs and six commercial labs). Corn samples were obtained
      from each participating station's feed mill during a 3-yr period (1989, 1990, and
      1992), as were soybean meal samples during a 2-yr period (1989 and 1990). Both
      regular soybean meal (with hulls) and dehulled soybean meal were represented in
      the study. Samples were analyzed for DM and CP by all 22 labs, for Ca and P by 15
      labs, for amino acids by 10 labs, and for Se by 6 labs. Each lab used its own
      analytical procedures. Samples of corn and soybean meal varied in their nutrient
      composition depending on the area of origin. The greatest variation among sources
      was in Se concentration, ranging from .02 to .29 mg/kg in corn and .08 to .95
      mg/kg in soybean meal. Crude protein and lysine in corn were positively
      correlated, but the regression coefficient was low (r2 = .49). The relationship
      between CP and lysine for the two soybean meals combined was considerably
      stronger (r2 = .81). Lysine in corn increased by .018 percentage point and lysine
      in soybean meal (regular and dehulled combined) increased by .063 percentage
      point for each 1 percentage point increase in CP. Except for CP and Se, the
      analytical variability among labs was as great as, and in some cases greater
      than, the variability in nutrient composition among sources of corn and soybean
      meal. Within-lab analytical variability tended to be less than among-lab
      variability. Some labs performed certain analyses with considerably less
      variability and more accuracy than others.

PMID- 10641874
TI  - Changes in energy metabolism in relation to physical activity due to fermentable
      carbohydrates in group-housed growing pigs.
AB  - Fermentable nonstarch polysaccharides (dietary fiber) affect energy retention in
      group-housed growing pigs by reducing physical activity. This study assessed the
      effects of fermentation and bulkiness of dietary carbohydrates on physical
      activity in relation to energy metabolism. Eight clusters of 14 pigs were fed one
      of four diets in a 2x2 factorial arrangement. Factors included 1)
      gastrointestinal fermentation and 2) dietary bulkiness. Contrasts in fermentation
      were created by exchanging gelatinized maize starch with raw potato starch on a
      volume basis. Bulkiness was altered by adding 15% milled wheat straw to the
      diets. Apart from these differences, amounts of other dietary ingredients fed to
      the pigs were similar. Pigs were housed in groups. Nitrogen and energy balances
      were measured per cluster during a 14-d period. Dietary bulkiness did not affect
      ME intake, heat production, or energy retention. Metabolizability decreased when
      maize starch was replaced with raw potato starch (P< .01), resulting in a lower
      energy retention on the potato starch diets (P<.01). However, the lower ME intake
      on the potato diets was partially compensated by a reduced energy expenditure on
      physical activity (P< .01), which was 17.6% lower than that of pigs fed the maize
      starch diets. Dietary bulkiness did not affect physical activity. The effect of
      fiber-rich diets (nonstarch polysaccharides) on activity in growing group-housed
      pigs seems to be related to fermentation in the gastrointestinal tract, and not
      to bulkiness (volume).

PMID- 10641875
TI  - Effects of body weight and feed intake level on basal ileal endogenous losses in
      growing pigs.
AB  - An experiment was carried out to determine the effects of feeding level, body
      weight, and time after surgery on basal ileal endogenous amino acid (AA) and N
      losses in growing pigs. Three pairs of littermate pigs were surgically prepared
      with ileo-rectal anastomoses. One pig in each pair was anastomosed at 38 kg BW,
      and the remaining pigs were anastomosed at 67 kg BW. Each pig received at
      different periods 50, 70, or 90 g of dry matter per kilogram of BW.75 of a
      protein-free diet according to a Latin square design involving three pigs
      starting at 45 kg BW and involving six pigs starting at 77 kg BW. For most AA,
      the time after surgery x feeding level interaction was significant. The basal
      endogenous losses (in g/d) increased linearly with feeding level at both BW. At
      the higher BW, the basal endogenous losses (in g/kg DMI) were constant regardless
      of feeding level, whereas at the lower BW they responded quadratically. At the
      low feeding level, the endogenous losses were higher than at the medium or high
      feeding level. We concluded that the basal endogenous losses are proportional to
      DMI when the feeding level is higher than 70 g/kg BW.75. The AA profile was not
      influenced by these three variables, but there was a large animal effect. These
      results suggest that, in digestibility trials, an assessment of the basal ileal
      endogenous AA losses must be performed on each pig to correct the apparent ileal
      AA digestibility data.

PMID- 10641876
TI  - Effects of L-carnitine fed during gestation and lactation on sow and litter
      performance.
AB  - Multiparous sows (n = 307) were used to evaluate the effects of added dietary L
      carnitine, 100 mg/d during gestation and 50 ppm during lactation, on sow and
      litter performance. Treatments were arranged as a 2 (gestation or lactation) x2
      (with or without L-carnitine) factorial. Control sows were fed 1.81 kg/d of a
      gestation diet containing .65% total lysine. Treated sows were fed 1.59 kg/d of
      the control diet with a .23 kg/d topdressing of the control diet that provided
      100 mg/d of added L-carnitine. Lactation diets were formulated to contain 1.0%
      total lysine with or without 50 ppm of added L-carnitine. Sows fed 100 mg/d of
      added L-carnitine had increased IGF-I concentration on d 60 (71.3 vs. 38.0 ng/mL,
      P<.01) and 90 of gestation (33.0 vs. 25.0 ng/mL, P = .04). Sows fed added L
      carnitine had increased BW gain (55.3 vs 46.3 kg; P<.01) and last rib fat depth
      gain (2.6 vs. 1.6 mm; P = .04) during gestation. Feeding 100 mg/d of added L
      carnitine in gestation increased both total litter (15.5 vs. 14.6 kg; P = .04)
      and pig (1.53 vs 1.49 kg; P<.01) birth weight. No differences were observed in
      pig birth weight variation. Added L-carnitine fed during gestation increased
      litter weaning weight (45.0 vs. 41.3 kg, P = .02); however, no effect of feeding
      L-carnitine during lactation was observed. No differences were observed in
      subsequent days to estrus or farrowing rate. Compared to the control diet,
      feeding added L-carnitine in either gestation, lactation, or both, increased
      (P<.05) the subsequent number of pigs born alive, but not total born. In
      conclusion, feeding L-carnitine throughout gestation increased sow body weight
      and last rib fat depth gain and increased litter weights at birth and weaning.

PMID- 10641877
TI  - Effects of L-carnitine fed during lactation on sow and litter performance.
AB  - Sows of differing parities and genetics were used at different locations to
      determine the effects of feeding added L-carnitine during lactation on sow and
      litter performance. In Exp. 1, sows (n = 50 PIC C15) were fed a lactation diet
      (1.0% total lysine, .9% Ca, and .8% P) with or without 50 ppm of added L
      carnitine from d 108 of gestation until weaning (d 21). No differences in litter
      weaning weight, survivability, sow ADFI, or sow weight and last rib fat depth
      change were observed. Number of pigs born alive in the subsequent farrowing were
      not different (P>.10). In Exp. 2, parity-three and -four sows (n = 115 Large
      White cross) were used to determine the effect of feeding 0, 50, 100, or 200 ppm
      of added L-carnitine during lactation (diet containing .9% total lysine, 1.0% Ca,
      and .8% P) on sow and litter performance. No improvements in the number of pigs
      or litter weights at weaning were observed (P>.10). Sows fed added L-carnitine
      had increased weight loss (linear; P<.04), but no differences (P>.10) were
      observed in last rib fat depth change or subsequent reproductive performance. In
      Exp. 3, first-parity sows (n = 107 PIC C15) were fed a diet with or without 50
      ppm of added L-carnitine during lactation (diet containing 1.0% total lysine).
      Sows fed added L-carnitine tended (P<.10) to have fewer stillborn and mummified
      pigs than controls (.42 vs .81 pigs). No differences were observed for litter
      weaning weight, survivability, or subsequent farrowing performance. Feeding 50 to
      200 ppm of added L-carnitine during lactation had little effect on sow and litter
      performance.

PMID- 10641878
TI  - Effect of nutrient intake on mammary gland growth in lactating sows.
AB  - Sixty-one primiparous sows were used to determine the response of mammary gland
      growth to different energy and protein intakes during lactation. After birth,
      litter size was set to 9 or 10 pigs. Sows were slaughtered at selected times up
      to 30 d of lactation. Individual sows were fed one of four diets that were
      combinations of different amounts of energy and protein (3.0 Mcal ME and 8.0 g
      lysine/kg diet; 3.0 Mcal ME and 16.2 g lysine/kg diet; 3.5 Mcal ME and 6.4 g
      lysine/kg diet; or 3.5 Mcal ME and 13.0 g lysine/kg diet). Mammary glands were
      collected at slaughter and trimmed of skin and the extraneous fat pad. Each gland
      was weighed, cut in half to measure cross-sectional area, ground, and stored at 
      20 degrees C for chemical analysis. Frozen, ground tissue was used to determine
      dry matter, dry fat-free tissue (DFFT), total tissue protein, ash, and DNA
      content. Only glands known to have been suckled were included in this data set.
      Response surface regression was used for statistical analysis. The percentage of
      protein, fat, ash, and DNA in each suckled mammary gland was affected only by
      total energy intake (P<.05). The percentage of dry tissue and fat decreased as
      the total energy consumed during lactation increased, whereas the percentage of
      protein and DFFT increased as total energy intake increased. There were quadratic
      effects (P<.05) of both total energy and protein intake on wet weight, dry
      weight, protein amount, DFFT amount, and DNA amount of each suckled mammary gland
      during lactation. This study shows that mammary gland growth is affected by
      nutrient intake during lactation. The weight of suckled mammary glands and the
      amount of mammary tissue protein, DFFT, and total DNA were maximal on d 27.5 of
      lactation when sows had consumed an average of 16.9 Mcal of ME and 55 g of lysine
      per day during lactation. Provision of adequate amounts of nutrients to sows
      during lactation is important for achieving maximal growth of mammary glands and
      maximal milk production.

PMID- 10641879
TI  - Mammary gland growth as influenced by litter size in lactating sows: impact on
      lysine requirement.
AB  - Twenty-eight primiparous sows were used to determine the effect of litter size on
      the growth of mammary glands and nursing pigs during lactation. Litter size was
      set to 6, 7, 8, 9, 10, 11, or 12 pigs by cross-fostering immediately after birth.
      Four sows were allotted to each litter-size group. Sows were allowed to consume a
      daily maximum of 13.6 Mcal ME and 46.3 g of lysine during lactation. Sows were
      slaughtered on d 21 (20.6+/-1.1) of lactation. Mammary glands were collected at
      slaughter and trimmed of skin and the extraneous fat pad. Each gland was
      separated, weighed, and ground for chemical analysis. Dry matter, dry fat-free
      tissue (DFFT), crude protein, ash, and DNA contents were measured. Only glands
      known to have been nursed were included in the data set. Wet and dry weights and
      the amounts of DFFT, protein, DNA, ash, and fat in individual nursed mammary
      glands linearly decreased (P<.05) as litter size increased. Percentages of DFFT,
      protein, and DNA were quadratically affected (P<.05) by litter size on d 21 of
      lactation. Total mammary wet and dry weights and total DFFT, protein, DNA, fat,
      and ash amount of all nursed mammary glands of each sow were increased as litter
      size increased (P<.05). Changing litter size from 6 to 12 pigs resulted in 2,098,
      432, 253, 227, 4.4, 178, and 20 g increases in the amounts of total mammary wet
      weight, dry weight, DFFT, protein, DNA, fat, and ash, respectively, on d 21 of
      lactation. Litter weight gain was 18.1 kg greater in sows with 12 pigs than in
      sows with 6 pigs. Sows with a larger litter size had a greater increase in total
      mass of mammary gland tissue and litter weight but had lower growth of individual
      nursed mammary glands and individual pigs than sows with the smaller litter size.
      The need for nutrients to support additional mammary gland and litter growth as
      litter size increases should be considered when estimating nutrient requirements
      for lactating sows. Sows need an additional .96 g lysine per day to account for
      mammary gland growth for each pig added to a litter.

PMID- 10641880
TI  - The partial substitution of digestible protein with gelatinized starch as an
      energy source reduces susceptibility to lipid oxidation in rainbow trout
      (Oncorhynchus mykiss) and sea bass (Dicentrarchus labrax) muscle.
AB  - We evaluated the influence of dietary gelatinized starch and protein on the fatty
      acid composition of muscle in rainbow trout and European sea bass and on the
      susceptibility of flesh to lipid peroxidation. The possibility that flesh
      peroxidation could be accounted for by lipogenesis and the deposition of fat was
      also explored. The inclusion of gelatinized starch in the diet of rainbow trout
      improved growth with respect to that observed in fish fed crude starch (P<.001).
      This was especially noticeable at the lowest concentration of dietary protein
      tested (P = .037); suggesting that gelatinized starch may partially replace
      protein in the production of energy without inducing a negative effect on growth.
      However, in European sea bass, the gelatinization of starch and dietary protein
      concentration showed no significant effect on final body weight. The
      intramuscular neutral lipid concentration of the sea bass was reduced by the
      gelatinization of dietary starch (P = .034). The highest dietary protein
      concentration increased the proportion of saturated fatty acids in the neutral (P
      = .0742) and polar (P = .0033) lipid fractions. The dietary inclusion of high
      levels of protein in rainbow trout led to a lower concentration of total (n-3) (P
      = .0457) and (n-6) (P = .0522) fatty acids and a higher concentration of total
      monounsaturated fatty acids (P = .0006). The inclusion of gelatinized starch led
      to a lower concentration of (n-3) fatty acids (P = .0034) and a higher
      concentration of saturated fatty acids (P = .0007). The polar fraction was hardly
      affected by the same treatment. A significantly lower susceptibility of the
      dorsal muscle to oxidation was observed in groups of European sea bass fed
      gelatinized starch (P<.01). A similar trend was observed in rainbow trout,
      although differences were not significant. The findings suggest that the
      digestible protein concentration of nutrient-dense diets for rainbow trout and
      European sea bass can be reduced with a beneficial effect on tissue lipid
      oxidation and no negative effects on growth and muscle composition.

PMID- 10641881
TI  - Dietary carbohydrates and fat influence radiographic bone mineral content of
      growing foals.
AB  - Hydrolyzable carbohydrate intake in horse diets may become excessive when rapidly
      growing pastures are supplemented with grain-based concentrates. The substitution
      of fat and fiber for hydrolyzable carbohydrate in concentrates has been explored
      in exercising horses but not in young, growing horses. Our objective was to
      compare bone development in foals that were fed pasture and concentrates rich in
      sugar and starch (corn, molasses) or fat and fiber (corn oil, beet pulp, soybean
      hulls, oat straw). Forty foals were examined, 20 each in 1994 and 1995. In each
      year, 10 mares and their foals were fed a corn and molasses supplement (SS) and
      10 others were fed a corn oil and fiber supplement (FF). The concentrates were
      formulated to be isocaloric and isonitrogenous, and mineral content was balanced
      to complement the pastures and meet or exceed NRC requirements. Dorsopalmar
      radiographs were taken of the left third metacarpal monthly from birth to weaning
      and then every other month until 1 yr of age. Bone density was estimated using
      imaging software and an aluminum stepwedge. Radiographic examination indicated
      differences in medial, lateral, and central bone mineral content of the
      metacarpal III. Bone mineral content increased with age, and a plateau was
      observed during winter. Bone mineral content was lower in weanlings and yearlings
      fed the FF supplement than in those fed SS. Subjective clinical leg evaluations
      indicated differences in physitis, joint effusion, and angular and flexural limb
      deformities in response to age, and possibly to season. Regression analysis
      indicated positive relationships between bone mineral content and body weight,
      age, and body measurements. Nutrient and chemical interactions, such as the
      binding of calcium by fat and fiber, may alter the availability of elements
      necessary for bone development.

PMID- 10641882
TI  - Hormonal and behavioral correlates of emotional states in sexually trained boars.
AB  - Physiological and behavioral traits of sexually mature boars were compared
      between episodes of copulation and sexual frustration in order to determine
      reliable indicators of the differences in emotional states. Ten boars,
      approximately 6 mo of age, were trained to mount a stationary artificial sow
      (ArtSow) and to ejaculate when digital pressure was applied to the extended
      penis. This method of semen collection is the typical procedure of the industry.
      All 10 boars used in this study were fully trained to this procedure before the
      onset of the study. Each boar was subjected to trials in which one of the
      following two treatments was applied. In the control (CTRL) treatment, boars were
      treated the same as during their training (i.e., allowed to complete
      ejaculation). In the frustration (FRUS) treatment, boars were allowed to mount
      the ArtSow, but because no manual pressure was applied to the extended penis,
      ejaculation never occurred. Blood was collected via indwelling catheters before
      onset of the trial, during exposure to the ArtSow, and after returning to their
      home pen. Concentrations of testosterone, cortisol, and beta-endorphin were
      quantified. Behavior of the boars was recorded during exposure to the ArtSow and
      for 30 min after return to their home pen. Relative to preexposure levels, serum
      cortisol increased (P<.05) during CTRL exposure and after exposure to both
      treatments (CTRL; P<.04 and FRUS; P<.06). Serum testosterone did not change
      during and after either treatment. Serum concentrations of beta-endorphin did not
      change during or after CTRL trials, but serum beta-endorphin was greater (P<.05)
      during FRUS than during CTRL trials. Behavioral analysis revealed that boars
      spent less time lying down and more time moving about their home pen (P<.05)
      after a FRUS than after a CTRL trial. In summary, serum cortisol did not allow us
      to distinguish between the excitement of copulation and the negative affect
      associated with sexual frustration, whereas increases in serum beta-endorphin and
      motor activity seemed to be indicators of the negative emotional state of sexual
      frustration in trained boars.

PMID- 10641883
TI  - In vitro production of sexed embryos for gender preselection: high-speed sorting
      of X-chromosome-bearing sperm to produce pigs after embryo transfer.
AB  - The objectives for the present experiments were to apply sperm sexing technology
      to an in vitro production system with porcine oocytes obtained from
      slaughterhouse material. On six experimental days, ovaries were obtained from an
      abattoir, and cumulus-oocyte-complexes were matured in vitro. Semen was collected
      from mature boars of proven fertility and was sorted for X-chromosome-bearing
      sperm, using the Beltsville Sperm Sexing Technology incorporating the use of high
      speed sorting. A total of 5,378 oocytes were submitted for in vitro fertilization
      (IVF). Of these, 559 ova were stained for cytogenetic analysis 18 h after IVF.
      From the remaining 4,819 ova, 1,595 cleaved, and 1,300 of the cleaved embryos
      were transferred into 26 synchronized recipients (5 control gilts for unsorted
      sperm, 21 gilts for X-sorted sperm). In a test of two fertilization media (FERT-A
      vs FERT-B) higher cleavage rates (P<.05) were obtained when FERT-B was used as a
      fertilization medium for unsorted (43.4+/-5.1%) and sorted sperm (43.1+/-1.1%;),
      whereas in FERT-A unsorted sperm gave a cleavage rate of 17.9+/-4.4% and sorted
      sperm gave 30.4+/-1.4%. Additionally, cleavage rates were higher (P<.05) after
      fertilization with sorted sperm vs unsorted sperm, independent of fertilization
      medium. Cytogenetic analysis of ova revealed that more oocytes with unsorted than
      with sorted sperm remained in Metaphase 2 arrest (P<.05). This was also
      independent of the fertilization medium. Monospermic fertilization rates were the
      same for IVF with unsorted or sorted sperm, independent of the fertilization
      system, except FERT-A with unsorted sperm (P<.05). Polyspermic fertilization
      rates were highest in FERT-B (37.6+/-6.6). A total of 57 pigs were born from nine
      litters. Six litters from sexed sperm (X-sorted) produced 33 females (97%) and
      one male. Three litters from control transfers produced 23 pigs, 11 of which were
      female (48%). The sex ratio of the offspring was predicted based on the sort
      reanalysis of the sorted sperm for DNA content.

PMID- 10641884
TI  - The effect of supplemental energy, nitrogen, and protein on feed intake,
      digestibility, and nitrogen flux across the gut and liver in sheep fed low
      quality forage.
AB  - Our objective was to determine the impact of supplemental energy, N, and protein
      on feed intake and N metabolism in sheep fed low-quality forage. Six Texel x
      Dorset wethers (16 mo, 63+/-3.1 kg) fitted with mesenteric, portal, and hepatic
      venous catheters were used in a Latin square design with five sampling periods.
      Lambs were fed chopped bromegrass hay (4.3% CP) to appetite, and a mineral
      mixture was given. Treatments were 1) control (no supplement), 2) energy
      (cornstarch, molasses, and soybean oil), 3) energy plus urea, 4) energy plus
      soybean meal (SBM), and 5) energy plus ruminally undegraded protein (RUP; 50:50
      mixture of blood and feather meals). Supplements were fed once daily (.3% BW).
      Forage DMI did not differ (P = .13), but intake of total DM, N, and energy
      differed (P<.01) among treatments. Apparent digestibilities of DM, OM, and energy
      were less (P<.01) for control than for other treatments. Apparent N digestibility
      was least for control and energy and greatest for urea treatments (P<.05). As a
      result, digested DM, OM, and energy ranked from least to greatest were control,
      energy, urea, SBM, and RUP, respectively. Apparently digested N was 2.44, 2.24,
      11.39, 9.80, and 11.25 g/d for control, energy, urea, SBM, and RUP (P<.01; SE =
      .10). Hour of sampling x treatment was a significant source of variation for
      blood concentrations of ammonia N and urea N, net ammonia N release from portal
      drained viscera (PDV) and liver, and urea N release from splanchnic tissues.
      These results were primarily because patterns through time for the urea treatment
      differed from the other treatments. Net PDV release of alpha-amino N did not
      differ (P>.05) between control and energy treatments. Values for those treatments
      were about one-half of values for urea, SBM, and RUP treatments, which did not
      differ (P>.05). Hepatic net uptake (negative release) of alpha-amino N for
      control was 53% of values for the other treatments, which did not differ (P>.05).
      Net release of alpha-amino N from splanchnic tissues did not differ among
      treatments (P = .34) and did not differ from zero. The data indicate that
      arterial alpha-amino N concentration, hepatic alpha-amino N uptake, PDV release
      and hepatic uptake of ammonia N, and hepatic release of urea N were greater in
      energy than in control treatments. We also found that hepatic uptake of alpha
      amino N was 187% of PDV release in energy-supplemented lambs. These results
      suggest that energy supplementation of a protein-limiting diet stimulated
      mobilization of body protein.

PMID- 10641885
TI  - Effect of selenate as a feed supplement to dairy cows in comparison to selenite
      and selenium yeast.
AB  - The main aim of this trial was to define the possible differences between
      selenite and selenate in their ability to increase the selenium (Se)
      concentration of milk, in comparison with organic Se. Dairy cows (n = 42) were
      fed a basal diet containing .10 to .12 mg Se/kg DM for 5 mo and were then divided
      into four groups of 10 or 11, as similar as possible in age and stage of
      lactation. During the next 84 d, the cows in three of the groups were
      supplemented with 3 mg of Se daily, whereas the cows in one control group
      remained unsupplemented. The Se supplement was given as sodium selenite, sodium
      selenate, or a Se yeast product. The total Se concentration of the diets varied
      with the cows' stage of lactation and was for the supplemented groups .24 to .31
      mg/kg DM, but remained between .10 and .12 mg/kg in the control group. At the end
      of the trial, the mean whole blood Se concentrations in the selenite, selenate,
      yeast, and control groups were 138, 141, 165, and 104 microg/L, respectively. The
      Se concentration in plasma apparently reached a plateau level within 4 wk, at
      approximately 75 microg/L in the selenite group, 80 microg/L in the selenate
      group, and 90 microg/L in the yeast group. In the control group the mean
      concentration in plasma remained at approximately 50 microg/L. The increase of
      the activity of glutathione peroxidase (GSH-Px) in the erythrocytes was
      significantly higher in the supplemented groups than in the control group. The
      mean concentrations of Se in milk in the selenite, selenate, and yeast groups
      were 16.4, 16.4, and 31.2 microg/L, respectively, whereas the concentration
      remained at approximately 14 microg/L in the control group. The milk Se
      concentration reached a plateau within 1 wk after the start of Se
      supplementation. Dietary supplementation with selenite and selenate, thus, had
      only a limited effect on the Se concentration in milk, and there was no
      significant difference between the two inorganic compounds in any variable
      measured. Organic Se was much more effective than inorganic Se in increasing the
      concentration of Se in milk.

PMID- 10641886
TI  - The influence of dietary selenium as selenium yeast or sodium selenite on the
      concentration of selenium in the milk of Suckler cows and on the selenium status
      of their calves.
AB  - The aim of this trial was to determine whether the selenium status of suckling
      calves could be improved by supplementing their dams' diet with organic Se
      instead of sodium selenite. A herd of 103 Hereford cows, which were on grass
      paddocks all year round, was divided into two groups. Both groups had free access
      to a mineral supplement that contained 30 mg of Se/kg; for one group the source
      of the Se was a Se yeast product, and for the other group the source was sodium
      selenite. The basal feed contained .02 mg of Se/kg DM. During the trial, the mean
      daily consumption of the mineral supplement was approximately 110 g/cow. The
      calving season started in the middle of March and ended in the middle of May.
      Blood samples were taken from 11 cows and their calves in the yeast group and
      from nine in the selenite group at the end of April and again at the beginning of
      June, and milk samples were taken at the same times. At both samplings, the
      concentration of Se in whole blood and the activity of glutathione peroxidase
      (GSH-Px) in the erythrocytes of the cows and calves in the yeast group were
      higher than in the samples from the animals in the selenite group. The same
      pattern was seen for plasma, except for the cows at the first sampling. The mean
      concentrations of Se in whole blood from calves in the yeast and selenite groups
      were 130 and 84 microg/L, respectively, and plasma concentrations were 48 and 34
      microg/ L, respectively. Mean Se concentration in the milk from the yeast group
      (17.3 microg/L) was higher than that in milk from the selenite group (12.7
      microg/L). There were significant correlations (r = .59 to .68) between the
      concentrations of Se in the cow's milk or cow's whole blood compared with Se
      concentrations in the calves whole blood and plasma or with the erythrocyte GSH
      Px activity of the calves. The Se status of the calves in the selenite group was
      considered to be marginal, but the status of the calves in the yeast group was
      considered to be adequate. Supplementation of the suckler cows' diet with organic
      Se in the form of Se yeast rather than sodium selenite improved the Se status of
      their calves when the Se was mixed into a mineral supplement containing 30 mg of
      Se/kg. In practice, such supplementation would probably eliminate the risk of
      nutritional muscular degeneration in suckling calves.

PMID- 10641887
TI  - Effects of different levels of methionine and ruminally undegradable protein on
      the amino acid profile of effluent from continuous culture fermenters.
AB  - Eight dual-flow continuous culture fermenters were used to study the effects of
      feeding different levels of methionine and ruminally undegradable protein (RUP)
      on the amino acid (AA) profile of protein residue after microbial fermentation.
      Four isocaloric (1.76 Mcal/kg of NE(l)) and isonitrogenous (17.7% CP) diets were
      formulated based on NRC recommendations for a 630-kg cow producing 42 kg/d of
      milk. Two dietary treatments, diets HmLr (high methionine, low RUP) and HmHr
      (high methionine, high RUP), were formulated to meet, but not exceed, more than
      140% of each estimated individual AA requirement for milk production. Diets LmLr
      (low methionine, low RUP) and LmHr (low methionine, high RUP) were formulated to
      meet the estimated individual AA requirement except for methionine. Diets HmLr
      and LmLr contained 35% RUP, and diets HmHr and LmHr contained 43% RUP. Digestion
      of DM, OM, and NDF was not affected (P>.05) by treatments. Tyrosine, cystine, and
      threonine ranked as the most resistant AA to microbial fermentation, whereas
      methionine and lysine ranked among the most degradable. In general, microbial
      degradation of individual AA followed the same pattern as CP degradation, being
      higher in diets HmLr and LmLr and lower in diets HmHr and LmHr. Because true
      microbial digestion of methionine, cystine, tyrosine, and isoleucine was reduced
      in the presence of high levels of methionine, we concluded that supplementation
      of dietary methionine could increase flows of these amino acids to the duodenum.

PMID- 10641888
TI  - Correcting the calculation of extent of degradation to account for particulate
      matter loss at zero time when applying the polyester bag method.
AB  - The established calculation of ruminal extent of degradation using the polyester
      bag method overestimates extent. The wash fraction, at least in part, is subject
      to losses from the rumen due to passage. Four formulae are proposed to minimize
      this risk of overestimation. Four options are considered: 1) passage losses for
      particulate matter escaping from the bag at zero time are according to the
      particulate fractional passage rate, 2) the liquid rate, and 3) the average of
      the two, and additionally 4) there is no instantly degradable fraction. The
      established and proposed formulae were examined using polyester bag data for six
      forages: grass silage, fresh ryegrass, fresh white clover, alfalfa hay, mixed
      grasses hay, and hay from a permanent mountain meadow. The established formula
      gave appreciably higher estimates of extent of degradation in all cases.
      Overestimation was at least 6.9, 4.9, 2.9, 2.1, 2.4, and 4.5%, respectively, for
      the six forages.

PMID- 10641889
TI  - Effects of a return chewing gum/packaging material mixture on in situ
      disappearance and on feed intake, nutrient digestibility, and ruminal
      characteristics of growing steers.
AB  - In situ and in vivo digestibility experiments were conducted to determine the
      acceptability, digestibility, and safety of a return chewing gum/packaging (G/P)
      material mixture when fed to steers. In the in situ experiment, both ruminal and
      intestinal disappearances were measured. Two ruminally and duodenally cannulated
      steers, which were given free access to alfalfa hay (AH), were used in this
      study. Duplicate Dacron bags containing the G/P were incubated in the rumen for
      0, 3, 6, 12, 24, and 48 h. After ruminal incubation, the 12-, 24-, and 48-h bags
      were placed in the duodenum and collected in the feces to determine intestinal
      disappearance. In situ ruminal DM disappearance was greater than 70% for all
      substrates tested at 0 h, indicating high solubility of the substrates in water,
      and began to reach a plateau after 12 h of incubation. Intestinal in situ
      disappearance was not different (P>.25) from zero. In the digestion trial, four
      ruminally cannulated steers (337+/-21.3 kg BW; mean +/- SD) were used in a 4x4
      Latin square design with the following treatments: 0) 50% corn (C), 50% AH; 10)
      45% C, 45% AH, 10% G/P; 20) 40% C, 40% AH, 20% G/P; 30) 35% C, 35% AH, 30% G/P.
      Steers fed G/P-containing diets had greater (P<.01) DMI than the control steers.
      Increasing the G/P resulted in a linear (P<.05) increase in DMI. Apparent DM
      digestibility tended to be higher (P<.10) for the G/P-containing diets than for
      the control. A quadratic effect (P<.05) on digestible DMI was observed, with
      greater (P<.01) digestible DMI values for G/P-containing diets (4.8 vs. 5.8
      kg/d). Digestible organic matter and total nonstructural carbohydrate intakes
      followed trends similar to those of DM. Apparent aluminum digestibility of G/P
      containing diets was not different (P>.13) from zero. The level of G/P in the
      diet had no effect (P>.2) on total VFA concentration or ruminal pH. There was a
      linear decrease (P<.01) in the molar percentage of isobutyrate and isovalerate in
      addition to a linear increase (P<.01) in butyrate and valerate with increasing
      levels of G/P. There was a quadratic effect (P<.01) on molar proportions of
      acetate and propionate and on the acetate:propionate ratio. Results of both
      experiments suggest that G/P may be fed to safely replace up to 30% of corn
      alfalfa hay diets for growing steers with advantages in improving DMI and
      digestibility.

PMID- 10641890
TI  - Rapid communication: nucleotide sequence of chamois, alpine ibex, and red deer
      tRNA(Lys) and ATPase8 mitochondrial genes.

PMID- 10641891
TI  - Rapid communication: a PCR-RFLP in the coding region of the bovine tumor necrosis
      factor-alpha locus.

PMID- 10641892
TI  - Extraocular muscles: relationship of structure and function to disease.

PMID- 10641893
TI  - Two pioneer Queensland ophthalmologists.

PMID- 10641894
TI  - Current treatment and outcome in orbital cellulitis.
AB  - BACKGROUND: Bacterial orbital cellulitis is an uncommon condition previously
      associated with severe complications. The purpose of this paper is to describe
      current investigations and treatment in orbital cellulitis, establish their
      effectiveness and to describe the incidence of complications and surgical
      intervention. METHODS: A chart review of all patients admitted to the Royal
      Victorian Eye and Ear Hospital and the Royal Children's Hospital, Melbourne with
      a diagnosis of orbital cellulitis for the period July 1993 to July 1997. RESULTS:
      A total of 52 patients fulfilling the diagnostic criteria for orbital cellulitis
      were identified. Paranasal sinus disease was the commonest predisposing cause,
      especially in the paediatric age group. Diagnosis was made clinically with
      radiological confirmation in all cases. Microbiological investigation and results
      varied. The commonest species isolated were Staphylococci and Streptococci. Three
      cases of mixed anaerobes and one of Clostridium were seen. Cultures from abscess
      cavities and infected sinuses gave the highest positive yield (50-100%). Blood
      cultures were taken in 26% of adults and in 56% of children; none was positive.
      Treatment was either by intravenous broad-spectrum antibiotics alone or with
      surgery to drain orbital abscesses, usually n conjunction with sinus surgery. No
      patient suffered permanent visual impairment other than one case of enucleation
      for endophthalmitis that had caused orbital cellulitis. There was one case of
      permanent ocular motility impairment, and one of meningitis. CONCLUSIONS: Despite
      its past history of severe morbidity and even mortality, adequately treated
      orbital cellulitis rarely has significant morbidity today. Paranasal sinus
      disease remains the commonest cause. Culture of infected paranasal sinuses or pus
      from abscesses is most likely to yield significantly positive results in this
      study. Blood cultures were not helpful.

PMID- 10641895
TI  - Clinical aspects of ocular leptospirosis in New Caledonia (South Pacific).
AB  - PURPOSE: The incidence of leptospirosis is very high in New Caledonia (average
      annual incidence rate: 180/100 000 of the population). To investigate the role of
      pathogenic leptospires as an aetiological agent of ocular diseases, we report the
      results of a 5-year survey in New Caledonia. METHODS: We reviewed 13 patients
      (corresponding to 17 investigated pathologic eyes) retrospectively. The selection
      of patients was based on epidemiological data, initial clinical examination,
      biological confirmation of leptospirosis according to reference procedures and a
      specific polymerase chain reaction assay. The anatomic criteria of uveitis and
      the criteria describing the evolution of the disease were those recommended by
      the International Uveitis Study Group. RESULTS: Consequent rates of optic
      neuritis (65%), posterior uveitis (35%), secluded pupil (24%), interstitial
      keratitis (18%) and pars planitis (12%) were found. Our rates of recurrence (46%)
      and of ophthalmic complications (82%) were substantial; some symptoms indicated
      brain involvement.The final visual damage was severe in 35% of eyes. CONCLUSIONS:
      Microagglutination and polymerase chain reaction hybridization are complementary
      tests for the diagnosis of Leptospira-induced ophthalmic lesions. Before deciding
      on treatment, one must consider the ability of virulent leptospires to persist in
      immunologically privileged sites such as aqueous humor, cerebrospinal fluid and
      eukaryotic cells. Polymerase chain reaction is a useful tool for the diagnosis of
      Leptospira-induced ocular complications, which are probably misdiagnosed if based
      only on routine laboratory tests. It enables early diagnosis and early specific
      treatment that now consists of quinolone and cyclines.

PMID- 10641896
TI  - Evaluating photoscreeners II: MTI and fortune videorefractor.
AB  - BACKGROUND: Amblyopia is a public health problem, usually amenable to treatment
      if detected early. Photoscreeners are camera-based instruments which can detect
      risk factors for amblyopia such as squint, refractive errors and media opacities.
      OBJECTIVE: To evaluate two commercially available photoscreeners, namely the MTI
      photoscreener (Medical Technology, Iowa City, IA, USA) and the Fortune Optical
      VRB-100 (Fortune Optical, Padova, Italy) videophotorefractor, in a selected
      childhood population, having a high prevalence of amblyopia, before undertaking a
      full-scale trial in the general population. SUBJECTS AND METHODS: The study
      design was a double-masked study. One-hundred and five children aged between 12
      and 44 months with either normal vision or known visual disorders were
      photoscreened without cycloplegia using the Fortune and the MTI photoscreeners.
      Each child had a full ophthalmic examination either on the day of screening or in
      the preceding 6 months. Risk factors were: any manifest strabismus (squint),
      hypermetropia >3.5 D, anisometropia > or =1 D sphere, myopia > or =2 D sphere,
      astigmatism > or =2 D, media opacity or fundus abnormality affecting vision. The
      prevalence of risk factors for amblyopia was 60%. Photoscreen images were
      reviewed by two independent masked observers for indicators of amblyopiogenic
      risk factors and compared to the full ophthalmological examination to determine
      sensitivity and specificity for each instrument. RESULTS: Sensitivities and
      specificities for the detection of risk factors for amblyopia were as follows.
      Fortune photoscreener: reader 1, sensitivity 60%, specificity 75%; reader 2,
      sensitivity 68% specificity 86%. MTI photoscreener: reader 1, sensitivity 56%,
      specificity 79%; reader 2, sensitivity 61%, sensitivity 86%. The results for
      reader 1 and 2 showed no significant differences for either instrument.
      CONCLUSION: Both instruments performed unsatisfactorily in a study population
      aged 1-4 years with a high prevalence of amblyopiogenic risk factors.
      Accordingly, we do not believe that either instrument can be recommended to
      screen for eye disorders in children between the ages of 1 and 4 years because
      the low prevalence of amblyopia in this population demands very high sensitivity
      and specificity in order to avoid inappropriate over- or under-referral.

PMID- 10641897
TI  - Relationship of the eye to the bony orbit, with clinical correlations.
AB  - PURPOSE: To examine normal anatomic relationship of the globe to the bony orbit,
      and relate variations in this relationship to clinical parameters. METHODS:
      Seventy-nine axial and sagittal magnetic resonance imaging (MRI) scans of the
      globe and orbit were studied. Any patients with pathology, as reported by the
      radiologists' findings, were excluded. Measurements were made on the images to
      determine the position of the globe relative to the bony orbit and to describe
      the configuration of the anterior face of the maxillary sinus. Clinical
      measurements were performed on photographs of 36 patients who underwent MRI
      scans. An independent observer rated these photographs for two clinical findings:
      inferior scleral show and tear trough deformity. RESULTS: Correlations were found
      in the following sets of variables. (i) Corneal projection from infraorbital rim
      and corneal projection from lateral rim; (ii) corneal projection from
      supraorbital rim and corneal projection from lateral rim; (iii) scleral show and
      corneal projection from lateral orbital rim; and (iv) tear trough deformity
      rating and angle of anterior face of maxillary sinus. There were no significant
      correlations found in the other data variables. CONCLUSIONS: The data show that
      abnormal relationships between the globe and the bony orbit can have clinical
      consequences. Inferior scleral show is shown to be related to relative globe
      prominence, measured from either the lateral or the inferior orbital rims. The
      tear trough deformity is correlated with a sloping maxillary face. The results
      provide a rational basis for surgeries designed to normalize these relationships.

PMID- 10641898
TI  - Management of diabetic retinopathy by Australian optometrists. Working Group on
      Evaluation of NHMRC Retinopathy Guideline Distribution. National Health and
      Medical Research Council.
AB  - PURPOSE: To describe current practices related to the management of diabetic
      retinopathy by Australian optometrists. SETTING AND METHODS: A two-page self
      administered questionnaire was mailed to a random sample of 504 Australian
      optometrists. The survey included questions about the practice (such as size and
      location); current practice with regard to management of patients with diabetic
      retinopathy; barriers to use of dilating drops; and a number of patient scenarios
      related to screening, follow-up and treatment of diabetic retinopathy. RESULTS:
      Completed questionnaires were returned by 407 of the 473 eligible optometrists
      (86%). They had been practising optometry between 1 and 50 years (median 14). Of
      the 243 optometrists who provided details about the location of their practices,
      145 (37%) had at least one of their practices in a rural area. The estimated
      percentage of patients with diagnosed diabetes ranged from 0.5 to 40% (median =
      5.0%). Three-hundred and twenty-two optometrists (79%) reported that they would
      often or almost always ask new patients over the age of 40 whether they have
      diabetes. The majority of optometrists (n = 387, 95%) would often or almost
      always ask their new patients with diabetes about their control of blood glucose
      levels and the majority of optometrists (n = 330, 81%) would often or almost
      always tell their patients with diabetes about the importance of strict glucose
      control in delaying retinopathy. The most common barrier to dilated
      ophthalmoscopy was patients not wanting to be dilated, with 38.1% of optometrists
      reporting this to be a moderate or major barrier. The next most common barrier
      was fear of precipitating angle closure glaucoma; 17.1% of optometrists reported
      this to be a moderate or major barrier CONCLUSION: The National Health and
      Medical Research Council (NHMRC) guidelines for the management of diabetic
      retinopathy are timely in relation to the expressed desire of Australian
      optometrists to learn more about management of diabetic retinopathy These data
      will be used prospectively to assess changes in management of patients with
      diabetic retinopathy as a result of the release of the NHMRC guidelines.

PMID- 10641899
TI  - Baseline ophthalmic findings in the vitamin E, cataract and age-related
      maculopathy (VECAT) study.
AB  - PURPOSE: To describe the methodology of eye examination and the baseline eye
      characteristics of the Vitamin E, Cataract and Age-Related Maculopathy (VECAT)
      study participants. METHODS: A sample of volunteers from an urban area of
      Melbourne, Australia, were recruited to participate in a randomized, controlled
      trial investigating the effect of vitamin E on the development of cataract and
      age-related maculopathy Standardized eye examinations involved clinical
      assessment, which included Wilmer grading of the lens, digital photography of the
      lens with Nidek EAS-1000 lens camera and stereo photography of the macular area
      with the Nidek 3-DX fundus camera. All cases of ophthalmic findings were
      determined on the basis of pathology in the worse eye. RESULTS: Most eyes were
      free from abnormalities. The most frequent findings were cataract and age-related
      macular changes. Nuclear cataract (nuclear opacity grade >2) was present in 4.5%,
      cortical cataract (cortical opacity grade >2) in 14.3% and posterior subcapsular
      cataract in 3.0% of participants; in addition, coronary cataract was observed in
      13.6%. Soft drusen larger than 125 pm were found in 11.4%, retinal pigment
      epithelium changes in 9.5%, epiretinal membrane in 6.6% and age-related macular
      degeneration in 0.5% of participants. SUMMARY: Due to the selection criteria, the
      majority of participants had clear or minor lens changes and/or minor retinal age
      related changes. Precise instrumental documentation will allow an accurate
      assessment of the incidence and dynamics of these changes throughout 4 years of
      observation.

PMID- 10641900
TI  - Comparative evaluation of plate haptic lenses with smaller and larger positioning
      holes.
AB  - PURPOSE: To evaluate the visual outcome, intraoperative problems and
      postoperative complications of plate haptic intraocular lenses with smaller foot
      plate positioning holes and larger holes. METHODS: Fifty eyes of 50 patients
      underwent clear corneal phacoemulsification with implantation of either small
      hole plate haptics (25 eyes) or large hole plate haptic lenses (25 eyes). The
      intraoperative complications were noted and the postoperative parameters were
      evaluated on the first day, 1 week, 1 month, 3 months, 6 months and 12 months.
      These included the best corrected visual acuities, intraocular lens (IOL)
      decentring, diameter of anterior capsulorhexis and posterior capsule
      opacification. RESULTS: The mean duration of follow-up was 14.8+/-2.1 months in
      the group with the small foot plate positioning holes (Chiron C10UB) lens and
      15.6+/-3.2 months in the group with the large feet plate positioning holes
      (Chiron C11UB) lens. The was no significant difference in the visual acuities of
      the two groups. The mean IOL decentring was 0.42+/-0.28 mm in the C10UB lenses
      and 0.24+/-0.10 mm in the C11UB lenses (P = 0.05). The mean diameter of the
      anterior capsulorhexis was 4.68+/-0.23 mm in the former, while it was 4.21+/-0.68
      mm in the latter (P = 0.0027). The posterior capsule opacification was
      significantly increased in the C11UB group (P = 0.0298). Neodymium : yttrium
      aluminium garnet (Nd: YAG) laser capsulotomy was required in 8% of the C10UB
      group, compared to 28% in the C11UB group. CONCLUSION: Results are similar with
      the two types of plate haptic lenses. The lenses with larger holes have a
      significantly higher posterior capsule opacification and more anterior
      capsulorhexis contracture, although the IOL decentring is less with these lenses.

PMID- 10641901
TI  - Changes as the result of ageing in extraocular muscles: a post-mortem study.
AB  - BACKGROUND: Extraocular muscles differ from typical skeletal muscle in many
      respects such as smaller fibre size, high mitochondrial content, unusual
      contractile/innervation patterns and highly developed microvascular bed. Changes
      in typical skeletal muscle with ageing have been well documented yet the reports
      on ageing changes in extraocular muscles is limited. The aim of this study was to
      examine these changes. METHODS: The right inferior and medial rectus muscles were
      removed at post-mortem from patients with no history of prior ocular or
      neuromuscular disease. These included 25 patients aged between 23 and 88 years
      (14 male, 11 female). The median age of the patients was 69 years and 72% of
      patients were aged older than 66 years. The median post-mortem interval was 28 h,
      RESULTS: In young adults between 20 and 30 years of age, the muscle fibres were
      regular, of fairly uniform size with minimal endomysial connective tissue and no
      lipofuscin was detected in fibres. In adults between 40 and 50 years of age, a
      small amount of subsarcolemmal lipofuscin was detected. Between 50 and 60 years
      of age, a few fibres with reduced density of myofibrils were noted. All patients
      over 65 years had definite changes of ageing and those between 70 and 80 years of
      age showed similar features to those between 60 and 80 years of age. These
      changes included variation in fibre size, increased endomysial fibrous tissue and
      increased endomysial adipose tissue, and loss of myofibrils with some fibres
      devoid of fibrils and comprising 'bags' of mitochondria. There was increased
      lipofuscin in a number of fibres, increased 'degenerative' changes such as
      vacuolation of fibres, scattered 'eosinophilic intracytoplasmic bodies' and
      increased numbers of 'ringbinden'.

PMID- 10641902
TI  - In vitro potency and stability of fortified ophthalmic antibiotics.
AB  - PURPOSE: This study evaluates the in vitro potency, stability and contamination
      of the fortified ophthalmic antibiotic preparations of cefazolin, vancomycin,
      gentamicin and tobramycin stored for 4 weeks. The effects of the different
      solvents and storage temperatures on the antimicrobial potency and stability were
      also examined. METHODS: The fortified stock solution of cefazolin and vancomycin
      were prepared by reconstituting with 0.9% sodium chloride and with artificial
      tears. Gentamicin and tobramycin were prepared by adding parenteral forms into
      their commercial ophthalmic solutions. The antimicrobial potency was measured by
      the minimum bactericidal concentration for cefazolin (33.3 mg/mL) and vancomycin
      (31 mg/mL) against Staphylococcus aureus, and for tobramycin (13.5 mg/mL) and
      gentamicin (13.5 mg/mL) against Pseudomonas aeruginosa. The stability of solution
      was evaluated by measuring absorbance spectra and pH. During the study period the
      levels of contamination of the stock solutions were examined by culturing on
      blood and on Sabouraud-dextrose media. RESULTS: There were no differences in the
      antimicrobial potency of the cefazolin, vancomycin and tobramycin within the 4
      week period; however, the potency of gentamicin was decreased at both
      temperatures after 21 days. It was found that different solvents or storage
      temperatures had no effect on the potency. Throughout the 4-week period, no
      change was found in the absorbance spectra of gentamicin and tobramycin, whereas
      the absorbance spectra of cefazolin and vancomycin stored at 24 degrees C
      increased in both of the solvents used (P<0.05). In all of the antibiotics, pH
      changed at 24 degrees C after 7-10 days; however, at 4 degrees C, only the pH of
      tobramycin exhibited changes after 14 days (P<0.05). No contamination was
      detected in the stock solutions during the study period. CONCLUSION: Topical
      fortified antibiotic solutions used for longer than 7 days should be stored at <
      or =4 degrees C, those stored at 24 degrees C should be discarded after 7 days.

PMID- 10641903
TI  - Intravitreal triamcinolone and elevated intraocular pressure.
AB  - PURPOSE: To ascertain whether intravitreal triamcinolone given for subretinal
      neovascularization is associated with an ocular pressure rise. METHODS: A total
      of 113 patients with angiographically proven subretinal neovascularization were
      enrolled into a prospective study of the effects of intravitrea triamcinolone.
      Intraocular pressure was one of the parameters studied. RESULTS: Approximately
      30% of the study group developed a significant rise (> or =5 mm Hg) in
      intraocular pressure above baseline during the first 3 months. CONCLUSIONS:
      Patients considering this form of treatment should be fully informed of the known
      risks of intraocular injections of steroids.

PMID- 10641904
TI  - Spontaneous suprachoroidal haemorrhage in a patient receiving low-molecular
      weight heparin (fraxiparine) therapy.
AB  - Spontaneous suprachoroidal bleeding is a rare event. Of the six previously
      reported cases, five had identifiable mechanisms for the development of choroidal
      bleeding in addition to concurrent systemic anticoagulation/thrombolytic therapy.
      We report a case of spontaneous suprachoroidal haemorrhage in a patient who
      received subcutaneous low-molecular-weight heparin therapy but without any
      identifiable ocular condition predisposing to choroidal bleeding.

PMID- 10641905
TI  - Preretinal haemorrhages: an unusual manifestation of intravitreal amikacin
      toxicity.
AB  - PURPOSE: To report a case with multiple preretinal haemorrhages after
      intravitreal amikacin. METHOD: A 58-year-old patient developed postoperative
      endophthalmitis following a routine extracapsular cataract extraction in his left
      eye. He received two intravitreal injections of cephazoline (2.25 mg) and
      amikacin (0.4 mg), given 48 h apart. RESULTS: The patient presented to us with
      large preretinal haemorrhages at the posterior pole. Multiple large areas of
      blocked fluorescence were seen on fundus fluorescein angiography. CONCLUSION:
      Widespread posterior pole preretinal haemorrhages may be an unusual manifestation
      of intravitreal amikacin toxicity.

PMID- 10641906
TI  - Lamellar corneal autograft for corneal perforation.
AB  - BACKGROUND: Corneal perforation secondary to exteriorization of the haptic foot
      of the anterior chamber intraocular lens (IOL) is a rare complication in IOL
      surgery. CASE REPORT: A superior penetrating corneal defect developed in the
      right eye of a 74-year-old woman associated with exteriorization of the superior
      haptic of an anterior chamber IOL. METHODS: We describe the technique of
      repositioning and successful patching of the defect using a lamellar cornea
      sclera rotational autograft. CONCLUSIONS: This technique is useful for small
      perforations when cornea donor tissue is not available.

PMID- 10641907
TI  - Ring keratitis from topical anaesthetic misuse.
AB  - BACKGROUND: Topical anaesthetic abuse is now an established differential
      diagnosis of ring keratitis. Published evidence suggests that this condition
      often has a poor prognosis, with the eyes sometimes requiring penetrating
      keratoplasty or the patient becoming blind. METHOD: A case of topical anaesthetic
      abuse and its subsequent management is presented. Ocular examination including
      pachymetry and specular microscopy is reported. RESULTS: The cornea made an
      excellent recovery, allowing a visual acuity of 6/6. Pachymetry showed corneal
      thickening and specular microscopy demonstrated a decreased cell count in the
      affected eye. CONCLUSIONS: With prompt recognition and appropriate treatment the
      prognosis for these cases can be excellent. However, there is evidence to suggest
      permanent cellular damage to the endothelium.

PMID- 10641909
TI  - Bowen's disease of the eyelid in a renal transplant recipient on
      immunosuppressants.

PMID- 10641908
TI  - Linear IgA disease.
AB  - PURPOSE: A case of linear IgA disease is reported to alert ophthalmologists and
      physicians to this unusual cause of chronic cicatrizing conjunctivitis. METHODS:
      Clinical records of a patient suffering from linear IgA disease were reviewed.
      RESULTS: A 65-year-old woman with a complicated medical history experienced
      rapidly progressive chronic cicatrizing conjunctivitis leading to corneal
      perforation. Undiagnosed gingivitis and palatal ulceration had been present for 5
      years prior to the onset of ocular symptoms and vitamin C deficiency had followed
      the consequent dietary restrictions. A diagnosis of linear IgA disease was made
      on conjunctival biopsy, which demonstrated linear deposits of IgA along the
      epithelial basement membrane. The perforation was managed successfully with a
      conjunctival pediculate flap. Control of the inflammation was achieved with
      systemic prednisolone and cyclophosphamide but at the expense of serious systemic
      side-effects. CONCLUSIONS: Linear IgA disease causes progressive conjunctival
      cicatrization in many affected individuals. Although dapsone generally controls
      the inflammation, heavier systemic immunosuppression was required in this case.
      Involvement of skin or other mucosal surfaces may become symptomatic before the
      conjunctivitis, and physicians must be educated to refer patients for
      ophthalmological review on diagnosis. Conversely, ophthalmologists encountering
      ocular linear IgA disease should be aware of the possibility of other mucosal
      involvement requiring physician intervention.

PMID- 10641910
TI  - Thomas a'Beckett Travers, 1902-1999.

PMID- 10641911
TI  - Status of alcohol absorption in drinking drivers killed in traffic accidents.
AB  - One issue which constantly confronts the forensic toxicologist in drinking driver
      cases is the relationship between the breath or blood alcohol concentration (AC)
      of the driver at the time of an event such as a traffic stop or an accident and
      the AC measured at a time subsequent to the event. In theory, the AC can be
      rising, on a plateau or declining at the time of the event. Several studies have
      indicated that the overwhelming majority of drinking drivers are on a plateau or
      are post-absorptive at the time of the event. In this study, driver fatality
      cases investigated by the Office of the Chief Medical Examiner, State of Maryland
      during a three-year period were reviewed. Included in this study were cases
      positive for alcohol in the blood at a cutoff of 0.01 g/dL and death occurring
      within 15 min of the accident. In fact, many of these deaths were instantaneous
      or near instantaneous based on the injuries documented by the medical examiner at
      autopsy. The blood and urine were analyzed for alcohol by head-space gas
      chromatography and urine AC to blood AC ratios were calculated. A total of 129
      cases were included in this study. Eleven of the 129 cases (8.5%) had urine to
      blood AC ratio less than 1.0. It is likely that these individuals were in the
      absorptive phase at the time that the accident occurred. Thirty-two cases had a
      urine to blood AC ratio between 1.0 and 1.2 inclusive. In these cases, the
      subject could be viewed as in the plateau phase of the blood AC versus time
      curve. The remaining 86 cases had a urine to blood AC ratio greater than 1.2.
      This suggests that these individuals were in the post-absorptive state at the
      time of the accident. The information acquired from this study provides
      additional evidence to support the notion that the vast majority of individuals
      are not in the absorptive phase at the time of a traffic stop or an accident.

PMID- 10641912
TI  - Among fatal poisonings dextropropoxyphene predominates in younger people,
      antidepressants in the middle aged and sedatives in the elderly.
AB  - To compare the characteristics of dextropropoxyphene (DXP) poisoning victims with
      those of victims of poisonings by antidepressants and sedatives, we examined all
      fatal poisonings due to DXP, antidepressants or sedatives among autopsies
      performed at one department of forensic medicine in Sweden during the six-year
      period from 1992 to 1997. In 202 cases, death was classified as fatal poisonings
      by DXP, antidepressants or sedatives. DXP caused death in 78 cases (39%),
      antidepressants in 49 (24%), and sedatives in 75 (37%). DXP as a single
      preparation was predominant in causing death. The second compound, flunitrazepam,
      caused death in 30 cases (15%). The victims of poisonings by DXP,
      antidepressants, or sedatives shared a similar history of alcohol/drug abuse,
      depression and somatic illness. They were mostly living alone at the time of
      death (>60%), the majority died at home (81%), and suicide was the most frequent
      manner of death (73%). Age seemed to be an important characteristic regarding the
      choice of drug. Younger people predominantly died of DXP (mean age 43 years, 95%
      confidence interval, CI 39-47), and elderly people of sedatives (mean age 59
      years, CI 55-63). Antidepressants were found mainly in middle-aged victims (mean
      age 51 years, CI 48-54). The predominance of sedatives among the elderly might be
      explained by a very high prescription rate of such drugs in older age groups, but
      prescription rate could not explain the DXP predominance among younger people. We
      hypothesize that younger people are more prone to abuse therapeutic drugs for
      euphoric reasons than elderly people, and that because of its high toxicity, DXP
      leads to accidental deaths more often than sedatives.

PMID- 10641913
TI  - Postmortem investigation of lamotrigine concentrations.
AB  - Lamotrigine is a relatively new anticonvulsant. Therapeutic plasma concentrations
      generally range from 1 to 4 mg/L, although several studies have shown that good
      control of epilepsy has been achieved with concentrations reaching 10 mg/L
      generally, with little toxicity. In overdose, however, the drug has been linked
      to ECG changes that may suggest a possible arrythmogenic effect and hence cardiac
      toxicity. Lamotrigine has also been shown to cause encephalopathy and thus
      neurotoxicity. There is no information concerning postmortem lamotrigine
      concentrations and their interpretation. We describe lamotrigine concentrations
      in postmortem specimens including blood, liver, bile, vitreous humour, and urine
      from eight cases. A high performance liquid chromatography (HPLC) method is
      described with extraction procedures for the various tissues. Two possible groups
      were identified. The first being the "broader therapeutic" group with blood
      concentrations ranging from 0.9 to 7.2 mg/L and corresponding liver
      concentrations ranging from 16 to 36 mg/kg. The second being a "supratherapeutic"
      group with blood concentrations ranging from 20 to 39 mg/L and corresponding
      liver concentrations ranging from 53 to 350 mg/kg. Although none of the eight
      cases described were attributed to overdose by lamotrigine alone, the cause of
      death for one of the three cases in the "supratherapeutic" group was given as
      mixed drug toxicity. Cause of death for the remaining two cases in this group was
      reported as epilepsy. However, both these cases showed elevated concentrations of
      lamotrigine and both were co-medicated with valproic acid. Such co-administration
      has been shown in the literature to lead to elevated lamotrigine concentrations
      and a reduction in lamotrigine dose has been recommended. With such data, we
      highlight the importance of monitoring lamotrigine concentrations in cases co
      medicated, particularly with valproic acid.

PMID- 10641914
TI  - Cause and manner of death among users of anabolic androgenic steroids.
AB  - Medicolegally investigated deaths among 34 male users of anabolic androgenic
      steroids (AAS) are described. Nine persons were victims of homicide, 11 had
      committed suicide, 12 deaths were judged as accidental and 2 as indeterminate. In
      two cases of accidental poisoning, the levels of pharmaceuticals and illicit
      drugs were considered too low to be the sole cause of death and AAS was
      considered part of the lethal polypharmacia. Chronic cardiac changes were
      observed in 12 cases. In two cases of accidental poisonous deaths, these changes
      were regarded as contributory cause of death. Homicides, suicides, and poisonings
      determined accidental or indeterminate in manner were related to impulsive,
      disinhibited behavior characterized by violent rages, mood swings, and/or
      uncontrolled drug intake. The observations in the present study indicate an
      increased risk of violent death from impulsive, aggressive behavior, or
      depressive symptoms associated with use of AAS. There are also data to support
      earlier reports of possible lethal cardiovascular complications from use of AAS.
      Furthermore, a contributing role of AAS in lethal polypharmacia is suggested.
      Finally, the observations indicate that use of AAS may be the gateway of approach
      to abuse of other psychotropic drugs.

PMID- 10641915
TI  - Potency trends of delta9-THC and other cannabinoids in confiscated marijuana from
      1980-1997.
AB  - The analysis of 35,312 cannabis preparations confiscated in the USA over a period
      of 18 years for delta-9-tetrahydrocannabinol (delta9-THC) and other major
      cannabinoids is reported. Samples were identified as cannabis, hashish, or hash
      oil. Cannabis samples were further subdivided into marijuana (loose material,
      kilobricks and buds), sinsemilla, Thai sticks and ditchweed. The data showed that
      more than 82% of all confiscated samples were in the marijuana category for every
      year except 1980 (61%) and 1981 (75%). The potency (concentration of delta9-THC)
      of marijuana samples rose from less than 1.5% in 1980 to approximately 3.3% in
      1983 and 1984, then fluctuated around 3% till 1992. Since 1992, the potency of
      confiscated marijuana samples has continuously risen, going from 3.1% in 1992 to
      4.2% in 1997. The average concentration of delta9-THC in all cannabis samples
      showed a gradual rise from 3% in 1991 to 4.47% in 1997. Hashish and hash oil, on
      the other hand, showed no specific potency trends. Other major cannabinoids
      [cannabidiol (CBD), cannabinol (CBN), and cannabichromene (CBC)] showed no
      significant change in their concentration over the years.

PMID- 10641916
TI  - Neck injuries caused by being run over by a motor vehicle.
AB  - We report a homicide involving the use of a motor vehicle and simulating a
      traffic accident. This observation was the reason for a retrospective analysis of
      neck injuries in victims of traffic accidents, in which a person has been run
      over (RO) by a motor vehicle. The autopsy material of two institutes from 1990
      1996 was used. The following findings were obtained in 63 victims: laryngohyoid
      fractures (LH-fx): 10 cases (16%) with a clear difference between the institutes
      (22% versus 7%). This resulted from examination with special regard to such
      injuries in many cases at one of the institutes, whereas only autopsy reports
      were taken retrospectively from the other institute. Five of these cases had
      suffered only minor LH-fx (as seen frequently in strangulation), although
      extensive run over (RO) injuries of the other cervical tissues were present. All
      LH-fx were caused by direct compression of the neck; in eight of the cases they
      were combined with mandibular fractures. Petechial hemorrhages (petH) at the eye
      lids/conjunctivae were seen in 19 cases (30%); 16 of these were related to thorax
      RO injuries, three to abdominal RO only. Four cases involved LH-fx, petH as well
      as cervical skin lesions and additional cervical soft tissue hemorrhages.
      Interpretation can be extremely difficult with this combination of findings if
      the character of the event cannot be established as accidental beyond doubt on
      the basis of the circumstances.

PMID- 10641917
TI  - Spectroscopic determination of skin viability. A predictor of postmortem
      interval.
AB  - We have demonstrated that skin viability decreases at a measurable rate following
      death in an animal model. The decreased skin viability was measured by
      fluorescein diacetate and ethidium bromide using fluorescence emission
      spectroscopy. There is significant decrease of the fluorescence intensity of the
      fluorescein diacetate assay between the 1-4 h, the 6-24 h, and the >40 h time
      points postmortem. For times between 6-24 h and >40 h postmortem the ethidium
      bromide assay showed consistent and significant increases in signal. The
      fluorescence measurements in this study showed that under the experimental
      conditions the time of death could be determined for <4, 6-24, and >40
      hapotmotrem. The application of these assays in the field will require further
      study of the environmental factors.

PMID- 10641918
TI  - Heroin body packing: three fatal cases of intestinal perforation.
AB  - Death from heroin body packing has been well described in the forensic
      literature. Most fatalities are due to drug leakage and consequent acute heroin
      toxicity. Recently, drug traffickers have become more sophisticated in their
      packaging, and the risk of rupture of drug packets is more remote. Though
      intestinal obstruction is a recognized risk of body packing, rarely has this
      resulted in death. We describe four cases of heroin body packing presenting to
      the Regional Medical Examiner Office in New Jersey. Death in three of these cases
      was due to intestinal obstruction, with resultant intestinal rupture and
      peritonitis. Toxicologic evaluation in these three cases was negative for opiates
      or other drugs of abuse. In one case, death was due to acute heroin toxicity,
      validated by toxicologic analysis. We briefly discuss the differing drug
      packaging found in these four cases and the ramifications of packaging as it
      relates to intestinal obstruction.

PMID- 10641919
TI  - In vivo facial tissue depth measurements for children and adults.
AB  - This study reports results of a facial tissue depth measurements project
      conducted over a two-year period on a modern sample of children and adults of
      both sexes and varying ages and races. The purpose of this research was to
      increase available tissue depth data for children and update facial tissue depth
      measurements for American adults. Most volunteers for this project were patients
      or visitors to the pediatric clinic at the Louisiana State University Medical
      Center, School of Dentistry, in New Orleans. Using state of-the-art ultrasound
      technology, we scanned 551 children and 256 adults at 19 points across the face.
      Thirteen of the scanned points were traditional landmarks while six others were
      areas not measured by previous researchers or were points for which very little
      data exist for both children and adults. For this presentation, we analyzed data
      for 515 children and 197 adults. Results of Pearson's correlations, analysis of
      variance, and paired t-tests indicate that age, sex, and race are significant
      factors when considering tissue depth means for different measurement locations
      across the human face. These new standards are compared to the work of other
      researchers. Our results provide valuable assistance in both two-dimensional and
      three-dimensional facial reproductions and superimpositions.

PMID- 10641920
TI  - The rhomboid fossa of the clavicle as a sex and age estimator.
AB  - The costoclavicular (rhomboid) ligament connects the first rib to the clavicle,
      stabilizing the pectoral girdle. It produces skeletal traits that may be
      tubercles, roughened impressions, shallow groove-like fossae, deep fossae, or
      leave no trace. A pit or depression at this site is often called a "rhomboid
      fossa." While these markings may appear pathological, they are normal variants of
      the clavicle. Using a large contemporary sample (N = 344:113 females, 231 males),
      we evaluated the presence of a rhomboid fossa as a sex and age indicator for
      unidentified skeletal remains. Logistic regression found significant
      relationships between the presence of a rhomboid fossa and sex and between
      presence of a rhomboid fossa and age. Fossae were more common in males (36% left,
      31% right) than in females (3% left, 8% right). Posterior probabilities suggest
      that a fossa on the right clavicle is indicative of a male with 81.7%
      probability; a fossa on the left is indicative of a male with 92.2% probability.
      Younger individuals more commonly exhibited rhomboid fossae than older
      individuals, and the largest fossae were most common in males 20-30 years of age.
      However, the age effect was not conclusive and must be corroborated by other
      methods. A test of the sex estimation method on an independent sample (26 males,
      23 females) found nine males and only one female with fossae present on the left
      clavicle. When the costoclavicular attachment exhibits an impression, a tubercle,
      or leaves no trace, this method cannot be used for sex estimation. When a
      clavicle exhibits a rhomboid fossa, it is likely from a male. The greater
      difference in fossa expression between the sexes on the left clavicle makes use
      of the left bone preferable. This technique can corroborate other sex estimates
      or provide an estimate for unknown individuals in the absence of other skeletal
      indicators.

PMID- 10641921
TI  - Ground penetrating radar surveys to locate 1918 Spanish flu victims in
      permafrost.
AB  - The "Spanish Flu" killed over 40 million people worldwide in 1918. Archival
      records helped us identify seven men who died of influenza in 1918 and were
      interred in Longyearbyen, Svalbard, Norway, 1,300 km from the North Pole. Ground
      Penetrating Radar (GPR) was used successfully, in a high-resolution field survey
      mode, to locate a large excavation with seven coffins, near the existing seven
      grave markers. The GPR indicated that the ground was disturbed to 2 m depth and
      was frozen below 1 m. Subsequent excavation showed that: a) the GPR located the
      position of the graves accurately, b) the coffins were buried less than 1 m deep,
      and c) that the frozen ground was 1.2 m deep where the coffins were located. The
      GPR assisted in planning the exhumation, safely and economically, under the high
      degree of containment required. Virologic and bacteriologic investigations on
      recovered tissues may give us an opportunity to isolate and identify the micro
      organisms involved in the 1918 influenza and expand our knowledge on the
      pathogenesis of influenza.

PMID- 10641922
TI  - Stalking behavior in delusional jealousy.
AB  - Stalking behavior has been associated with several mental disorders, both
      psychotic and non-psychotic. The most frequently associated condition appears to
      be an individual with primitive personality psychopathology regardless of co
      occurring psychotic symptomatology. Among the psychotic symptoms, erotomanic, and
      jealousy delusions may be the most clinically and torensically relevant. However,
      delusional jealousy has not been well appreciated in the psychiatric literature
      as an important contributor to stalking behavior. In this article, we explore the
      psychiatric, psychosocial, and forensic aspects of stalking in the context of
      delusional jealousy. We use a case example to highlight important issues in this
      area.

PMID- 10641923
TI  - Rapid search and quantitative analysis of gunshot residue particles in the SEM.
AB  - Automated scanning electron microscopy coupled with image analysis and X-ray
      micro analysis was used to characterize a variety of gunshot residue (GSR)
      samples. More than 500 rounds of commercially available ammunition and six
      different types of hand gulls were used in the study of 17 GSR and 19 reference
      specimens. The individual particle X-ray composition was determined for 12
      different elements. Elemental composition of GSR particles was highly variable
      but consistent with compounds mixed into or associated with a barium oxide
      matrix. When present in a specimen, GSR could be adequately characterized with
      automated procedures in less than an hour by restricting analyses to features
      larger than 2 microm. In "clean" samples, a higher resolution particle search was
      required to avoid reporting false negatives. Careful control of the back
      scattered electron signal strength threshold, by reference to a standard, was
      needed to ensure both time-efficient and accurate analyses. Samples collected
      from non-shooting subjects. active in a physical environment which contained
      firearms discharge residue were seen to be easily contaminated by sub-micron GSR
      particles.

PMID- 10641924
TI  - Analysis of pressure sensitive adhesive tape: I. Evaluation of infrared ATR
      accessory advances
AB  - Attenuated total reflection (ATR), also known as internal reflection spectroscopy
      (IRS), is a forensically accepted method for infrared (IR) analysis of pressure
      sensitive adhesive tapes. Advancements of ATR accessories in the last decade have
      provided the forensic examiner several ATR methods to choose from. These
      accessories offer a variety of ATR crystal choices with a variety of prices and
      capabilities. Four different types of pressure sensitive adhesive tapes including
      duct tape, electrical tape, packaging tape and office tape have been used to
      compare six different ATR methods. Each of the methods tested offers both
      benefits and limitaltions which must be considered for the type of sample to be
      analyze. The intent of this paper is to assist the reader in better understanding
      ATR techniques, the many differences among currently available ATR accessories
      and how the method is applied to the analysis of pressure sensitive adhesive
      tape.

PMID- 10641925
TI  - Tracing the source of illicit drugs through plastic packaging--a database
AB  - Common plastic drug packaging material available in Australia and in Asia was
      analyzed using a standard protocol including optical examination, UV-visible and
      Fourier transform infrared spectrometry. The aims were to determine whether there
      are significant differences between different sources, to establish the
      evidential value of these examinations, and to build a database of common
      packaging material. Visual examination was the most effective means for
      discriminating samples. Thickness and weight measurements provided useful
      information. Visualization of machining marks using crossed polarized light was
      found to be useful in the comparison process. UV-visible spectrophotometry has
      some value for distinguishing samples. Fourier transform infrared analysis was a
      good technique for determination of the polymer composition of the packaging.
      Significant differences were observed between Australian and overseas samples.
      The "Australian Database of Drug Packaging Materials" was created to
      systematically collate all of the collected data for application on personal
      computers. It is concluded that the properties of plastic packaging materials can
      be excellent indicators for identifying the specfic brand or origin of the
      packaging.

PMID- 10641926
TI  - Medical examination of sexually abused children: medico-legal value.
AB  - The Department of Forensic Medicine (forensic pathology and clinical forensic
      medicine), Aarhus, Jutland, Denmark, performs examinations of children suspected
      to have been sexually abused when reported to and requested by the police in
      Jutland, Denmark. Jutland covers an area of 210,000 km2 with about 300,000
      inhabitants in Aarhus. A colposcope initially equipped with an Olympus camera,
      but now with a video camera attached has been used since 1994. Since 1994 the
      department has performed more than 100 examinations of children suspected of
      having been sexually abused. A preliminary study was taken to evaluate all cases
      from 1995 including the legal outcome. RESULTS: The material included 34 cases
      with three boys, mean age 11 years, and 31 girls, mean age 8 years, at the time
      of the examination. The sexual abuse events were fondling including penetration
      of the vagina, vaginal (14), anal (7), and oral (5) intercourse as well as
      cunnilingus and nontouching abuses. The medical examination was most often
      performed more than a week after the abuse. The examination revealed normal
      findings in 23 cases, nonspecific findings including erytherma in 13 cases, and
      in only one child was a traumatic lesion with rupture of the hymen seen. The
      perpetrators were above 25 years of ane and were family members or someone known
      to the child. Nine perpetrators were convicted at court, of whom three admitted
      having abused the child. CONCLUSION: A medical examination in cases of sexual
      child abuse seldom provides a legal proof of sexual abuse. The most important is
      the story told by the child. Therefore, the examination is a supplement which may
      support or remain neutral to the story told by the child.

PMID- 10641928
TI  - A replication study of obsessional followers and offenders with mental disorders.
AB  - The purpose of this study was to compare certain demographic, clinical, and
      criminal variables within subgroups of obsessional followers, and compare them to
      a group of offenders with mental disorders to attempt to replicate earlier
      findings. A static group archival design utilized a non-random group of
      convenience and a randomly selected comparison group. Sixty-five obsessional
      followers and 65 offenders with mental disorders were evaluated by psychiatrists
      and psychologists for court ordered reasons during their criminal proceedings.
      Both groups were evaluated during the same period, in the same court diagnostic
      clinic, and generally for sentencing determinations. The obsessional followers
      were measured on demographic, diagnostic, pursuit, victim, threat, violence,
      emotional, motivational, and defense variables. Inferential comparisons that used
      parametric and nonparametric statistics were done within and between groups on
      select variables. The obsessional followers had significantly greater estimated
      IQ than the offenders with mental disorders, but were neither older nor better
      educated. There were no significant differences in the high prevalence of both
      DSM-IV Axis I and II diagnoses. Obsessional followers who stalked prior sexual
      intimates were significantly more likely to have a substance abuse or dependence
      diagnosis. Obsessional followers who stalked strangers or acquaintances were more
      likely to be delusional. The majority of the obsessional followers, primarily
      motivated by anger, both threatened and were violent toward person or property.
      The modal obsessional follower is an average or above IQ, unemployed, unmarried
      male in his fourth decade of life. chronically pursuing a prior sexually intimate
      female. He is diagnosed with substance abuse or dependence and a personality
      disorder NOS, and has a prior psychiatric, criminal and substance abuse history.
      He is angry, likely to threaten her, and assault her person or property without
      causing serious injury.

PMID- 10641927
TI  - World population data for the HLA-DQA1, PM and D1S80 loci with least and most
      common profile frequencies for combinations of loci estimated following NRC II
      guidelines.
AB  - All published and unpublished gene frequency data for the PCR-based loci HLA
      DQA1, LDLR, GYPA, HBGG, D7S8, GC, and D1S80 that could be located are presented
      in summary tables. These gene frequencies provide the data necessary for
      estimating probabilities of chance match according to NRC II guidelines for any
      DNA profile that includes any combination of these loci for any of the
      populations. To illustrate the range of polymorphism for combined locus profiles,
      least and most common profile frequencies were estimated following NRC II
      guidelines for: the PM loci for all populations for which PM data were available;
      and for combinations of HLA-DQA1/PM, HLA-DQA1/D1S80, PM/D1S80, and HLA-DQA1/
      PM/D1S80 for populations for which data were available for the relevant
      combinations. The profile frequencies were calculated at theta values of zero and
      0.01. Minimum allele frequencies (MAF) were calculated, and are shown, for each
      data set for which the MAF was greater than the lowest observed allele frequency.
      Least common profile frequencies were calculated using MAF in those cases to
      illustrate a conservative estimate. The effect of using MAF versus lowest
      observed allele frequency in estimating least common profile frequencies is
      briefly illustrated as well. We finally show that aggregate U.S. gene frequency
      data for the classical MN and GC polymorphisms for both Caucasian and African
      American populations is fully in accord with the DNA-based gene frequency data
      obtained from PM reverse dot-blot strips for GYPA and GC, respectively.

PMID- 10641929
TI  - Determining the time and day of photography.
AB  - Photographs taken by crime victims and perpetrators are at times important
      evidence. Their time of photography may also affect their value as such. Three
      methods of determining when a picture was taken by using the content of the
      picture are presented. The methods utilize solar direction-measured from shadows
      in the photograph, identifying flowering wild plants and correlating cloudiness
      with meteorological observations. Solar direction is the most accurate and
      involved method and therefore is the main part of this paper. A case using all
      three methods is described.

PMID- 10641930
TI  - An evaluation of the relevance of routine DNA typing of fingernail clippings for
      forensic casework.
AB  - DNA extracted from fingernail clippings of victims in forensic cases is a
      possible source of DNA from the perpetrator in cases where victims struggled or
      defended themselves. The source of this DNA on a victim's fingernails could
      possibly originate from contact with the suspect's blood, saliva, semen or
      scratched skin. In this technical note we evaluate the relevance of routine DNA
      typing of fingernail clippings in the forensic biology laboratory when, in real
      casework, normally only small quantities of nail material is sent. This was
      carried out by extracting DNA from fingernail clippings from a number of
      volunteers, before and after aggressively scratching other volunteers. No blood
      was drawn from the scratching, but skin flakes were observed under the nails
      before cutting and subsequent DNA typing. The DNA extracted was then typed using
      the STR systems: HUMTHO1, HUMTPOX and HUMCSF1PO (CTT triplex) and the system of
      D1S80. These profiles were compared with profiles achieved by similar typing of
      buccal swabs as a reference from each volunteer. In this study, the profile
      detected from each volunteer's clippings was the same before and after
      scratching, and matched the profile of the corresponding volunteer as defined by
      typing each volunteer's reference buccal swab. Fingernail clippings that are sent
      to our lab in actual casework are usually so small that additional treatment by
      swabbing or removing debris from below the clipping is not possible. For this
      reason, in this simulation the entire clippings were used for DNA extraction, to
      maximize the possibility of finding an additional profile. In conclusion, the
      findings from this study show that although the profiles obtained when typing
      fingernail clippings are those of the donors themselves, we suggest that typing
      of fingernail clippings should be carried out in forensic cases only when
      relevant. We would suggest that fingernail clippings not be routinely sent to the
      biology laboratory as items of evidence to be tested.

PMID- 10641931
TI  - Determination of amphetamine by HPLC after acetylation.
AB  - An analytical procedure has been developed for the HPLC determination of
      amphetamine by off-line pre-column derivatization. The proposed procedure
      consists of sample preparation by acetylation of amphetamine with acetic
      anhydride and a subsequent reversed-phase HPLC separation on an octadecyl silica
      stationary phase with salt-free mobile phase (tetrahydrofuran, acetonitrile, 0.1%
      triethylamine in water, 15:15:70 v/v) applying UV-detection. The applicability of
      the elaborated procedure is demonstrated with results obtained by analysis of
      real samples seized in the Hungarian black market.

PMID- 10641932
TI  - Allelic frequencies for the HLA-DQA1, D1S80, HUMTHO1, HUMTPOX, HUMCSF1PO and
      HUMVWA loci in Cantabria (middle north Spain).
AB  - Allele frequencies for six DNA polymorphisms have been studied in a population
      sample from Cantabria (middle north Spain) using the polymerase chain reaction.
      The HLA-DQA1 locus was analyzed by the reverse dot-blot technique and the other
      five by polyacrylamide gel electrophoresis followed by silver staining. Six
      alleles were found for HLA-DQA1. 15 alleles for D1S80, 6 alleles for HUMTHO1 and
      HUMCSF1PO, 7 for HUMTPOX and 8 alleles for HUMVWA. The 21 repeat allele in HUMVWA
      had not previously been reported in a Spanish population. The genotype
      distributions met Hardy-Weinberg expectations for all the systems and some
      statistical parameters of forensic interest were calculated. Comparisons with
      other populations revealed significant differences for HLA-DQA1, HUMVWA and
      HUMTHO1, with interracial differences being more pronounced than between Spanish
      populations. The HUMVWA system showed the highest forensic efficiency of the six
      polymorphisms studied.

PMID- 10641933
TI  - Doping control for beta-adrenergic compounds through hair analysis.
AB  - An original procedure was developed to simultaneously test beta2-agonists
      (salbutamol and clenbuterol) and beta-blockers (atenolol, acebutolol, pindolol,
      betaxolol, propranolol, timolol, sotalol, metoprolol, tertatolol, bisoprolol,
      labetalol and oxprenolol) in both human and animal hair. After decontamination
      with methylene chloride (2 times, 2 min), a 200 mg hair strand is pulverized in a
      ball mill. Then, a 100 mg portion is incubated overnight in 2 mL 0.1 N HCl, at 56
      degrees C, in the presence of carteolol, which was used as an internal standard.
      After neutralization of the acid phase with 0.1 N NaOH, a 2 mL bicarbonate buffer
      (pH 8.6) is added to the preparation, which is then purified by solid-phase
      extraction with Isolute C18 columns. Drugs are derivatized using a mixture of
      trimethylboroxine-ethyl acetate for 15 min at 80 degrees C to form
      methaneboronate derivatives. Drugs are detected using GC/MS on an HP 6890-5973
      system. A 4 microL portion of the derivatized extract is injected using a pulsed
      mode in a 30 m HP5 MS capillary column. Linearity was observed for all compounds
      in the range 25 pg/mg to 10 ng/mg. Limits of detection were in the range 2 to 10
      pg/mg. At 1 ng/mg, recoveries were in the range from 37 to 100%, with a within
      run precision of 5.9 to 14.1% (n = 8). The application of the method can be
      documented by the following examples: (1) Hair from asthmatic patients (n - 11),
      including two cases of asthma deaths, tested positive for salbutamol in the range
      of 27 to 210 pg/mg. (2) A 24-year-old swimmer who tested positive in urine for
      salbutamnol denied the results. Hair analysis confirmed salbutamol exposure, with
      a concentration of 71 pg/mg. (3) A shooting specialist was assumed to chronically
      use metoprolol (100 mg/daily during some periods). Hair concentration of
      metoprolol was 8.41 ng/mg. (4) An archery specialist was assumed to chronically
      use sotalol (80 mg/daily, during some periods). Hair concentration of sotalol was
      261 pg/mg. (5) Hair from two calves revealed chronic exposure to clenbuterol,
      which was used to increase the mass of the animals at a concentration of 30 and
      48 pg/mg.

PMID- 10641934
TI  - When is 100% inspection not enough? An analysis of three pickup truck front wheel
      assembly failures
AB  - The loss of a cotter pin in the front wheel assembly of cars and trucks has been
      a problem for several years. This is shown by the fact that the automobile
      manufacturers have been committed to a 100% inspection of the process for
      installing them on cars and trucks. In this paper, three accident cases are
      presented, along with a method by which the forensic engineer can determine if a
      cotter pin has ever been installed on the front wheel assembly. Testing was done
      to show what the spindle would look like if the cotter pin had been installed
      properly and forcibly removed. Photographs show both the accident and test
      spindle for comparison.

PMID- 10641935
TI  - Superfecundation and dual paternity in a twin pregnancy ending with placental
      abruption.
AB  - A case of superfecundation and dual paternity in a twin pregnancy is presented.
      Placental abruption developed at week 33 of gestation and the two boys had to be
      saved by emergency cesarean section. As they shared one placenta, had almost
      identical weight and had the same sex, they were assumed to be monozygotic.
      However, a subsequent paternity suit led to the conclusion, based on DNA
      analysis, that the twin brothers had been fathered by two different men.
      Obstetrical implications are discussed.

PMID- 10641936
TI  - Use of fecal material to associate a suspect with a crime scene: report of two
      cases.
AB  - Fecal matter analyses were applied to two cases: a homicide and a robbery.
      Scrapings of fecal matter removed from samples of clothing obtained from a
      homicide suspect were examined for their plant cell and cell fragment content and
      compared with fecal matter from a rape-homicide victim and scrapings from her
      clothing. Scrapings were hydrated and examined microscopically. Types of food
      plants were identified from the observed cells by comparison with known food
      plants. A similar analysis was conducted on the clothing of a robbery suspect and
      compared with fecal material left at the crime scene. The results showed that,
      respectively in the two cases, the reference samples were remarkably similar, if
      not identical, to those from the suspects' clothing.

PMID- 10641937
TI  - A case of Cotard's syndrome associated with self-starvation.
AB  - Cotard's syndrome is a psychotic condition often associated with nihilistic
      delusions. This syndrome can be associated with destructive behaviors directed at
      the self and/or others. In this report we highlight the psychiatric-legal issues
      involving a case of Cotard's syndrome associated with self-starvation.

PMID- 10641938
TI  - Diagnostic values of polysomnography in forensic medicine.
AB  - A man accused of a first-degree murder of a two-year-old girl claimed that he had
      not been conscious during the time of the alleged murder. The possibility that he
      may have committed the crime while "sleepwalking" was raised. The forensic
      psychiatrist looked to the sleep disorders facility to conduct polysomnographic
      investigation of the accused in order to investigate the possibility that he had
      a parasomnia. Overnight sleep recordings with video surveillance carried out for
      two consecutive nights showed no evidence of parasomnia. On the basis of the full
      assessment, the final report of the forensic psychiatrist did not support a legal
      defense of non-insane automatism and "sleepwalking" was withdrawn as a possible
      defense by the lawyer of the accused.

PMID- 10641939
TI  - A descriptive study of child and adolescent obsessional followers.
AB  - This study is a preliminary descriptive investigation of the phenomenon of
      stalking in children and adolescents. Data on offender characteristics, victim
      characteristics, and stalking patterns were examined in a sample of 13
      obsessional followers ranging in age from 9 to 18. Many research findings from
      investigations on adults who stalk were replicated in this study, including the
      fact that most stalking offenders are male, most victims are female, and about
      half of stalking cases involve threats made toward the victim. In addition, the
      rate of violence was 31% in this sample of juvenile stalking offenders and the
      most common methods of stalking were physical approach, telephone calls, and
      letter writing. Some interesting trends in the data emerged which require further
      study and suggest some differences may exist between juvenile and adult stalking
      offenders. The results are preliminary and suggest directions for future
      research.

PMID- 10641940
TI  - Familicide, depression and catathymic process.
AB  - A case of familicide by a 36-year-old male is reported. After years of stable
      marriage, exemplary military service, and steady employment, the subject
      developed his first episode of depression triggered, in part, by his inability to
      solve a problem associated with completion of a home improvement project. As the
      depression intensified, and dormant conflicts regarding his competency and self
      esteem were rekindled, he experienced pronounced feelings of failure. After an
      extended period of agonizing about his problem, the idea suddenly emerged that
      his only recourse was to kill his family and himself, in order to spare everyone
      the humiliation of his perceived inadequacy. Such a fixed idea, along with a
      mounting pressure to act, is characteristic of the (chronic) catathymic process,
      in which a subject, without apparent motive, resorts to extreme violence directed
      at someone close to him. A detailed discussion of this case within the framework
      of catathymic process adds to our knowledge of family mass murder and refines the
      profile of potentially familicidal men.

PMID- 10641941
TI  - Hydrocephalus: a fatal late consequence of mumps encephalitis.
AB  - Common and usually self-limited diseases may occasionally have fatal
      consequences. Hydrocephalus is a very rare complication of mumps, with just a few
      cases reported in the literature. Here we report a fatal case of hydrocephalus
      presenting 19 years after mumps encephalitis. The long latency period between
      encephalitis and hydrocephalus-associated symptoms makes this case particularly
      interesting.

PMID- 10641942
TI  - Suicide using a hand grenade.
AB  - The authors describe an unusual case of suicide that required particular
      attention to establish whether the victim was murdered, was preparing a terrorist
      attack or had committed suicide. Examination of the corpse and the crime scene,
      as well as testimonies, led the authors to determine the real cause of death,
      namely, an unusual method of suicide.

PMID- 10641943
TI  - Fatal fall of an aircraft stowaway: a demonstration of the importance of death
      scene investigation.
AB  - Scene investigation is of paramount importance in forensic pathology. Many
      medical and coroner systems wisely and routinely evaluate the scene in homicides
      but do not routinely investigate traffic fatality scenes. This case originally
      was thought to be a pedestrian-automobile event, but, due to proper and prompt
      scene investigation, it was determined that the decedent was actually a wheel
      well stowaway who fell from a commercial aircraft.

PMID- 10641944
TI  - Suicide by electrocution with low-voltage current.
AB  - Three cases of suicide by electrocution with low-voltage current were observed in
      five years (1994-1998) by medical clinical forensic examiners of an Emergency
      Forensic Unit of the Paris suburb among 2,000 external death examinations. The
      cases involved one woman, aged 72 and two men, aged 38 and 41. In the last two
      cases, electric burns were retrieved under bared electric wires, placed on the
      arms or fingers in order to realize a hand-to-hand electric circuit involving the
      heart muscle. In the other case, the electric circuit between mouth and foot also
      involved the heart muscle. Household low-voltage current delivered (220 V in
      France) had a sufficient strength to induce local muscular paralysis and heart
      fibrillation. In the three cases, blood samples taken have retrieved very high
      levels of muscular enzymes (CPK, LDH) correlated to the mechanism of electric
      death. The rareness of suicide by electrocution and its forensic characteristics
      are detailed in order to help the clinical forensic examiners, prosecutors, and
      police officers concerned by such death examinations.

PMID- 10641945
TI  - Death due to inhalation of ethyl chloride.
AB  - A 30-year-old white male was found dead in a locked apartment with a rag held
      loosely in his mouth. Four cans (3 empty, 1 partially empty) containing ethyl
      chloride and labeled as VCR head cleaner were found next to the body.
      Phenylpropanolamine and low therapeutic levels of diazepam (64 microg/L) and
      nordiazepam (126 microg/L) were detected during toxicological analysis. An
      unidentified peak was observed when performing ethanol analysis by headspace gas
      chromatography. The peak was identified as ethyl chloride and the concentrations
      in the blood, urine, vitreous, brain, and lungs of the deceased were 423 mg/L, 35
      mg/L, 12 mg/L, 858 mg/kg, and 86 mg/kg, respectively. The results were compared
      with previously reported levels of ethyl chloride in blood and vitreous and,
      based on a literature search, we believe that this is the first report of ethyl
      chloride levels in tissue.

PMID- 10641946
TI  - Fatal intoxication following self-administration of a massive dose of
      buprenorphine.
AB  - Several drug packages, including Subutex (high-dose buprenorphine, as sublingual
      tablets) boxes, were found near the corpse of a 25-year-old male drug addict, who
      apparently had committed suicide. The autopsy revealed a fatal respiratory
      depression. The toxicological investigations concluded that death resulted from
      massive burpienorphine intoxication. The determination of buprenorphine (BU) and
      norbuprenorphine (NBU) in all biological specimens was performed by liquid
      chromatography-electrospray mass spectrometry (LC-ES-MS) after hydrolysis (for
      solid tissues), deproteinization of the matrices, and solid-phase extraction of
      the compounds. Exceptionally high concentrations of BU and NBU were found in
      blood (3.3 and 0.4 mg/L, respectively), urine (3.4 and 0.6 mg/L), bile (2035 and
      536 mg/L and brain (6.4 a nd 3.9 microg/g). The high concentration of BU (899
      mg/L) and the absence of NBU in gastric liquid suggested oral intake. High
      concentrations of amino-7-flunitra/epam, the main metabolite of flunitra/epam,
      were also found in blood, urine and gastric liquid. This benzodiazepine may have
      been a co-factor in the toxic effects of BU.

PMID- 10641947
TI  - DNA extraction from stamps and envelope flaps using QIAamp and QIAshredder.
AB  - The use of Qiagen QIAamp and QIAshredder for extracting DNA from envelope flaps
      and stamps is reported. The stamps or flaps can be added directly to extraction
      solutions and the DNA is bound to a spin column containing a silicon membrane for
      washing prior to elution. DNA extracted from four stamps and four envelope flaps
      was amplified and analyzed using a multiplex PCR system. Complete DNA profiles
      were obtained from five samples.

PMID- 10641948
TI  - Population data on the X chromosome short tandem repeat locus HumHPRTB in two
      regions of Germany.
AB  - This report contains the results of two population studies on the X chromosome
      STR HumHPRTB carried out in a Northern and a Southern region of Germany. The
      numbers of unrelated individuals were 443 and 335, respectively. Eight alleles
      (alleles 9 to 16) were found. In female individuals 29 different genotypes were
      encountered. In German populations the HumHPRTB STR was characterized by the
      following data: PIC = 0.750; HET = 0.769: MEC = 0.556. Allele distribution met
      the Hardy-Weinberg expectations. The Northern and Southern populations did not
      show any significant differences.

PMID- 10641949
TI  - Interferences with semen detection by an immunoassay for a seminal vesicle
      specific antigen.
AB  - A commercial enzyme-linked immunosorbent assay (ELISA), the SEMA assay, for a
      seminal vesicle-specific antigen (SVSA) provides highly sensitive detection of
      semen. Here we show marked interference of proteins such as albumin, serum
      proteins, or mucin with the assay. This would substantially decrease the
      sensitivity for detecting semen mixed with other biological fluids such as blood
      or vaginal secretions.

PMID- 10641950
TI  - Distribution of HLA-DQA1 and amplitype PM locus alleles in a Saudi Arabian
      population sample.

PMID- 10641951
TI  - Minimal standards for the performance and interpretation of toxicology test in
      legal proceedings.

PMID- 10641952
TI  - The Heart and Estrogen/Progestin Replacement Study: what have we learned and what
      questions remain?
AB  - The Heart and Estrogen/Progestin Replacement Study (HERS) was the first
      randomised, double-blind, placebo-controlled study to evaluate the outcome of
      hormone replacement therapy (HRT) on subsequent cardiac events in postmenopausal
      women with established coronary heart disease (CHD). Of the 2763 women enrolled,
      1380 were randomised to receive 0.625mg of conjugated equine estrogens plus 2.5mg
      of medroxyprogesterone daily (Prempro) and 1383 were randomised to receive a
      placebo. The results were surprising: 179 women in the hormone group and 182
      women in the placebo group experienced either a nonfatal myocardial infarction or
      CHD death (relative hazard 0.99, 95% confidence interval 0.81 to 1.22). This
      occurred despite a net 11% reduction in low density lipoprotein (LDL) and a net
      10% increase in high density lipoprotein (HDL) after 1 year of follow-up (p <
      0.001 for LDL and HDL). Also, there were no differences between the 2 treatment
      groups in any secondary cardiovascular outcomes. The overall null effect may have
      been the result of an unexpected early adverse effect of the HRT regimen that
      offset a later reduction in risk. Clearly, the use of HRT for secondary
      prevention of heart disease is more complex than was initially believed. More
      data are needed from other clinical trials concerning the risks and benefits of
      HRT to confirm or refute the puzzling HERS results. HERS also underscores the
      need for trials with clinical end-points to evaluate both the safety and efficacy
      of drug therapy. Although observational studies are useful, they cannot provide
      definitive answers regarding treatment recommendations. Until further data are
      available, clinicians should not use estrogen plus medroxyprogesterone for the
      sole purpose of secondary prevention of CHD.

PMID- 10641953
TI  - Herbal medications for common ailments in the elderly.
AB  - The popularity of herbal medicine is at an all time peak. This article provides
      an overview of systematic reviews of herbal treatments for conditions common in
      elderly individuals. According to this evidence, there is little doubt that
      Hypericum perforatum (St John's Wort) is well tolerated and effective for mild to
      moderate depression. Although widely used, Valeriana officinalis (valerian) has
      not been shown beyond reasonable doubt to be effective for insomnia. There is
      relatively compelling evidence that Ginkgo biloba (ginkgo) is effective in
      delaying the clinical course of dementias. It has been well documented that
      Aesculus hippocastanum (horse chestnut) seed extracts alleviate the subjective
      symptoms and reduce the objective signs of chronic venous insufficiency. Serenoa
      repens (saw palmetto) is effective in improving the symptoms of benign prostatic
      hyperplasia. Finally, yohimbine has been shown to be effective forerectile
      dysfunction. It is concluded that several plant-based medicines can be useful
      additions to our therapeutic repertoire for treating common conditions in the
      elderly. However, several uncertainties remain and, at present, prevent
      unreserved recommendations.

PMID- 10641954
TI  - Treatment of nocturia in the elderly.
AB  - The aging process, behavioural habits and a multitude of pathological conditions
      are the main contributors to the development of nocturia in the elderly. Age
      related physiological changes can alter the regular pattern of urine excretion
      and lead to increased nocturnal frequency of voiding. In addition, aging is
      associated with anatomical and physiological changes of the urinary tract itself
      that predispose to increased urinary frequency without affecting urine volume.
      Several urinary and extra-urinary tract conditions may have nocturia as a
      prominent symptom. These conditions can be grouped as those associated with
      bladder overactivity, bladder outlet obstruction, bladder hypotonicity and an
      increased urine volume. A detailed assessment that gathers clues from the medical
      history, physical examination and laboratory is of utmost importance in
      identifying the specific causes. Overactive bladder can be idiopathic or
      associated with different triggers such as UTI, bladder stones, bladder tumours
      and CNS diseases that disrupt the normal inhibitory signals to the bladder. It
      may be cured by the successful elimination of the trigger conditions. Therapeutic
      modalities include behavioural therapies with scheduled voiding, anticholinergic
      drugs and in women the use of transvaginal electrical stimulation. Benign
      prostatic hyperplasia is the most common cause of bladder outlet obstruction in
      men. Different drug classes (e.g. peripheral alpha-adrenoceptor blockers and 5
      alpha-reductase inhibitors) are now available for the treatment of mild to
      moderate symptoms. Surgery is reserved for patients with severe symptoms or with
      complications, with new and less invasive surgical techniques being preferred.
      Bladder hypotonicity is usually caused by peripheral neuropathies, spinal cord
      lesions and the indiscriminate use of drugs with anticholinergic actions.
      Treatment involves discontinuation of implicated drugs, short term use of
      cholinergic drugs and urinary catheterisation. Increased urine volumes and
      nocturia are frequently seen in hyperosmolar and oedematous states. Excessive
      ingestion of fluids, caffeinated or alcoholic beverages are habits that commonly
      produce nocturia. Although more definitive studies are awaited, low dose loop
      diuretics given a few hours prior to bedtime and desmopressin nasal spray or
      tablets may be useful alternatives for the control of nocturic symptoms in
      elderly patients with nocturnal polyuria syndrome. Whenever nocturia is present,
      clinicians should try to identify its causes by means of a thorough history,
      physical examination and pertinent complimentary tests. Once the specific cause
      or causes are found, most cases can be satisfactorily managed with behavioural,
      pharmacological or surgical therapies.

PMID- 10641956
TI  - Colony-stimulating factors in the treatment of older patients with acute
      myelogenous leukaemia.
AB  - The treatment of acute myelogenous leukaemia (AML) in the elderly is a difficult
      and increasing problem. The elderly are generally less able to tolerate the
      intensive chemotherapy required to achieve a sustained remission, and there is an
      increased incidence of resistant disease in this age group. Granulocyte- and
      granulocyte-macrophage colony-stimulating factors have been demonstrated to
      shorten the duration of severe neutropenia following chemotherapy for solid
      tumours and after bone marrow/peripheral blood stem cell transplantation, and the
      effect of these growth factors in the treatment of AML has been investigated in a
      number of trials using 2 distinct strategies. Growth factors may be administered
      following chemotherapy in an attempt to accelerate neutrophil recovery, and they
      may be given before and during chemotherapy with the aim to increase the number
      of leukaemic blast cells in cell cycle and enhance their responsiveness to
      chemotherapy. Both of these approaches have proved safe despite initial
      theoretical concerns regarding the expression of receptors for these growth
      factors on leukaemic cells. The results of trials using these growth factors in
      the treatment of AML in the elderly generally show a significant reduction in the
      duration of neutropenia following induction chemotherapy. However, consistent
      benefits with respect to morbidity and early mortality together with improvements
      in long term disease outcome have not been observed. The 'priming' approach using
      growth factors before and during induction chemotherapy has proved equally
      disappointing in failing to improve response rates or survival. The routine use
      of these growth factors in the treatment of AML in the elderly population as a
      whole would, therefore, not seem to be cost effective.

PMID- 10641955
TI  - Corticosteroids and glaucoma risk.
AB  - Corticosteroids (glucocorticoids), used frequently as potent anti-inflammatory
      agents, increase the risk of glaucoma by raising the intraocular pressure (IOP)
      when administered exogenously (topically, periocularly or systemically) and in
      certain conditions of increased endogenous production (e.g. Cushing's syndrome).
      Approximately 18 to 36% of the general population are corticosteroid responders.
      This response is increased to 46 to 92% in patients with primary open-angle
      glaucoma (POAG). Patients over 40 years of age and with certain systemic diseases
      (e.g. diabetes mellitus, high myopia) as well as relatives of patients with POAG
      are more vulnerable to corticosteroid-induced glaucoma. The association of
      corticosteroid-induced ocular hypertension in other conditions which are
      considered as risk factors for glaucoma (racial origins, hypertension, migraine,
      vasospasm) is likely but not fully established. The proposed mechanism of
      corticosteroid-induced glaucoma includes morphological and functional changes in
      the trabecular meshwork system and is similar to the pathogenesis of POAG.
      Trabecular cells exposed to corticosteroids in vitro show endoreplication of
      nuclei, an increase in cell size and excessive production of an approximately
      56kD glycoprotein, identified as myocilin and transcribed by the GLC1A gene.
      Induction of ocular hypertension after corticosteroid administration depends on
      the specific drug, the dose, the frequency of administration and the
      corticosteroid responsiveness of the patient. The risk of corticosteroid-induced
      glaucoma can be minimised with judicious use of corticosteroids, as well as
      education of patients and medical practitioners. New treatment modalities include
      modified steroids and nonsteroidal anti-inflammatory agents that will have less
      effect on the elevation of IOP.

PMID- 10641957
TI  - Calcium antagonists in the post-myocardial infarction setting.
AB  - At present, the use of calcium antagonists for the secondary prevention of
      cardiac events following an acute myocardial infarction (MI) is not recommended.
      This advice is based on several large mortality studies using short-acting
      calcium antagonists in the absence of coronary reperfusion therapy. Even in these
      studies, discrepancies between the different pharmacological classes of calcium
      antagonists were recognised. When separated from the dihydropyridine calcium
      antagonists, the rate-lowering calcium antagonists, verapamil and diltiazem, do
      appear to provide some benefit in reduction of recurrent MI. Three large trials
      using verapamil post-MI demonstrated a significant reduction in reinfarction with
      a favourable trend towards reducing death as well. Similarly, the effects of
      diltiazem post-MI have been evaluated in 3 large trials. In 2 earlier trials,
      diltiazem lessened cardiac events in patients with nonQ-wave infarctions and
      those without pulmonary congestion upon presentation. Overall, there was a
      significant benefit in lessening reinfarction with no effect on mortality. The
      recently completed Incomplete Infarction Trial of European Research Collaborators
      Evaluating Prognosis Post-Infarction (INTERCEPT) trial found that sustained
      release diltiazem given after thrombolytic therapy for acute MI lessened cardiac
      events by 23% (a nonsignificant difference) without worsening congestive
      symptoms. Overall, there is adequate data to support the use of heart-rate
      lowering calcium antagonists for secondary prevention post-MI provided the
      patient is intolerant of beta-blocker therapy. These trials are reviewed in
      detail, and suggestions for clinical practice are provided in this article.

PMID- 10641958
TI  - The use of sulphonylureas in the elderly.
AB  - Type 2 diabetes mellitus is a heterogeneous disorder characterised by defects in
      insulin secretion as well as reduced insulin action. During aging, glucose
      intolerance will gradually develop, and this is manifested primarily by an
      increase in the postprandial blood glucose response while fasting blood glucose
      levels are often less elevated. Abnormal beta-cell secretion of insulin is a main
      feature of this. Treatment of elderly patients with type 2 diabetes mellitus
      focuses on reduction of (hyperglycaemic) complaints and prevention of the
      development or progression of secondary complications. Although regular physical
      activity and dietary measures, aiming at bodyweight normalisation, are the
      cornerstones of therapy, pharmacological treatment with oral blood glucose
      lowering-agents often proves necessary to control the hyperglycaemia. In the
      United Kingdom Prospective Diabetes Study (UKPDS) it was clearly shown that
      patients with type 2 diabetes mellitus who were intensively treated with oral
      blood glucose-lowering agents or insulin developed less microvascular
      complications. The question whether achievement of strict metabolic control is
      also of benefit in elderly patients, is still unanswered. Sulphonylureas are
      drugs which stimulate insulin secretion by enhancing the release of insulin from
      the pancreatic beta-cells without an effect on insulin synthesis. They are
      frequently used in the treatment of type 2 diabetes mellitus, and several
      preparations are available. In general, there are no major differences in
      effectiveness between the various sulphonylureas. Long term treatment with
      sulphonylureas will decrease fasting and postprandial plasma glucose levels by 3
      to 5 mmol/L, and glycosylated haemoglobin by 20%. However, after its initial
      decline, plasma glucose level will often go up slightly during the following
      months to years. Sulphonylureas are usually well tolerated. Hypoglycaemia is the
      most frequently occurring adverse effect, which may be very serious and damaging
      in the elderly. It has been associated primarily with long-acting sulphonylureas,
      like chlorpropamide and glibenclamide (glyburide). Hypoglycaemic episodes may
      trigger serious events like myocardial infarction or stroke. Therefore, shorter
      acting compounds like tolbutamide and gliclazide have been relatively well
      tolerated and appear to be the best choice to treat elderly patients. It is
      advisable to start with a low dose and increase the dose, when needed, in small
      steps. The efficacy of sulphonylureas is much greater when they are taken before
      a meal. Because of the fact that type 2 diabetes mellitus is a progressive
      disease, and residual beta-cell function decreases with time, insulin therapy may
      ultimately be warranted in a significant number of patients.

PMID- 10641960
TI  - Virtual congresses.
AB  - A new form of scientific medical meeting has emerged in the last few years--the
      virtual congress. This article describes the general role of computer
      technologies and the Internet in the development of this new means of scientific
      communication, by reviewing the history of "cyber sessions" in medical education
      and the rationale, methods, and initial results of the First Virtual Congress of
      Cardiology. Instructions on how to participate in this virtual congress, either
      actively or as an observer, are included. Current advantages and disadvantages of
      virtual congresses, their impact on the scientific community at large, and future
      developments and possibilities in this area are discussed.

PMID- 10641959
TI  - An object-oriented taxonomy of medical data presentations.
AB  - A variety of methods have been proposed for presenting medical data visually on
      computers. Discussion of and comparison among these methods have been hindered by
      a lack of consistent terminology. A taxonomy of medical data presentations based
      on object-oriented user interface principles is presented. Presentations are
      divided into five major classes-list, table, graph, icon, and generated text.
      These are subdivided into eight subclasses with simple inheritance and four
      subclasses with multiple inheritance. The various subclasses are reviewed and
      examples are provided. Issues critical to the development and evaluation of
      presentations are also discussed.

PMID- 10641961
TI  - The immune system as a model for pattern recognition and classification.
AB  - OBJECTIVE: To design a pattern recognition engine based on concepts derived from
      mammalian immune systems. DESIGN: A supervised learning system (Immunos-81) was
      created using software abstractions of T cells, B cells, antibodies, and their
      interactions. Artificial T cells control the creation of B-cell populations
      (clones), which compete for recognition of "unknowns." The B-cell clone with the
      "simple highest avidity" (SHA) or "relative highest avidity" (RHA) is considered
      to have successfully classified the unknown. MEASUREMENT: Two standard machine
      learning data sets, consisting of eight nominal and six continuous variables,
      were used to test the recognition capabilities of Immunos-81. The first set
      (Cleveland), consisting of 303 cases of patients with suspected coronary artery
      disease, was used to perform a ten-way cross-validation. After completing the
      validation runs, the Cleveland data set was used as a training set prior to
      presentation of the second data set, consisting of 200 unknown cases. RESULTS:
      For cross-validation runs, correct recognition using SHA ranged from a high of 96
      percent to a low of 63.2 percent. The average correct classification for all runs
      was 83.2 percent. Using the RHA metric, 11.2 percent were labeled "too close to
      determine" and no further attempt was made to classify them. Of the remaining
      cases, 85.5 percent were correctly classified. When the second data set was
      presented, correct classification occurred in 73.5 percent of cases when SHA was
      used and in 80.3 percent of cases when RHA was used. CONCLUSIONS: The immune
      system offers a viable paradigm for the design of pattern recognition systems.
      Additional research is required to fully exploit the nuances of immune
      computation.

PMID- 10641962
TI  - Exploring the degree of concordance of coded and textual data in answering
      clinical queries from a clinical data repository.
AB  - OBJECTIVE: To query a clinical data repository (CDR) for answers to clinical
      questions to determine whether different types of fields (coded and free text)
      would yield confirmatory, complementary, or conflicting information and to
      discuss the issues involved in producing the discrepancies between the fields.
      METHODS: The appropriate data fields in a subset of a CDR (5,135 patient records)
      were searched for the answers to three questions related to surgical procedures.
      Each search included at least one coded data field and at least one free-text
      field. The identified free-text records were then searched manually to ensure
      correct interpretation. The fields were then compared to determine whether they
      agreed with each other, were supportive of each other, contained no entry
      (absence of data), or were contradictory. RESULTS: The degree of concordance
      varied greatly according to the field and the question asked. Some fields were
      not granular enough to answer the question. The free-text fields often gave an
      answer that was not definitive. Absence of data was most logically interpreted in
      some cases as lack of completion of data and in others as a negative answer. Even
      with a question as specific as which side a hernia was on, contradictory data
      were found in 5 to 8 percent of the records. CONCLUSIONS: Using the data in the
      CDR to answer clinical questions can yield significantly disparate results
      depending on the question and which data fields are searched. A database cannot
      just be queried in automated fashion and the results reported. Both coded and
      textual fields must be searched to obtain the fullest assessment. This can be
      expected to result in information that may be confirmatory, complementary, or
      conflicting. To yield the most accurate information possible, final answers to
      questions require human judgment and may require the gathering of additional
      information.

PMID- 10641963
TI  - Assessing the quality of clinical data in a computer-based record for calculating
      the pneumonia severity index.
AB  - OBJECTIVE: This study examined whether clinical data routinely available in a
      computerized patient record (CPR) can be used to drive a complex guideline that
      supports physicians in real time and at the point of care in assessing the risk
      of mortality for patients with community-acquired pneumonia. SETTING: Emergency
      department of a tertiary-care hospital. DESIGN: Retrospective analysis with
      medical chart review. PATIENTS: All 241 inpatients during a 17-month period (Jun
      1995 to Nov 1996) who presented to the emergency department and had a primary
      discharge diagnosis of community-acquired pneumonia. METHODS/MAIN OUTCOME
      MEASURES: The 20 guideline variables were extracted from the CPR (HELP System)
      and the paper chart. The risk score and the risk class of the Pneumonia Severity
      Index were computed using data from the CPR alone and from a reference standard
      of all data available in the paper chart and the CPR at the time of the emergency
      department encounters. Availability and concordance were quantified to determine
      data quality. The type and cause of errors were analyzed depending on the source
      and format of the clinical variables. RESULTS: Of the 20 guideline variables, 12
      variables were required to be present for every computer-charted emergency
      department patient, seven variables were required for selected patients only, and
      one variable was not typically available in the HELP System during a patient's
      encounter. The risk class was identical for 86.7 percent of the patients. The
      majority of patients with different risk classes were assigned too low a risk
      class. The risk scores were identical for 72.1 percent of the patients. The
      average availability was 0.99 for the data elements that were required to be
      present and 0.79 for the data elements that were not required to be present. The
      average concordance was 0.98 when all a patient's variables were taken into
      account. The cause of error was attributed to the nurse charting in 77 percent of
      the cases and to the computerized evaluation in 23 percent. The type of error
      originated from the free-text fields in 64 percent, from coded fields in 21
      percent, from vital signs in 14 percent, and from laboratory results in 1
      percent. CONCLUSION: From a clinical perspective, the current level of data
      quality in the HELP System supports the automation and the prospective evaluation
      of the Pneumonia Severity Index as a computerized decision support tool.

PMID- 10641964
TI  - Representing the UMLS as an object-oriented database: modeling issues and
      advantages.
AB  - OBJECTIVE: The Unified Medical Language System (UMLS) combines many well
      established authoritative medical informatics terminologies in one knowledge
      representation system. Such a resource is very valuable to the health care
      community and industry. However, the UMLS is very large and complex and poses
      serious comprehension problems for users and maintenance personnel. The authors
      present a representation to support the user's comprehension and navigation of
      the UMLS. DESIGN: An object-oriented database (OODB) representation is used to
      represent the two major components of the UMLS-the Metathesaurus and the Semantic
      Network-as a unified system. The semantic types of the Semantic Network are
      modeled as semantic type classes. Intersection classes are defined to model
      concepts of multiple semantic types, which are removed from the semantic type
      classes. RESULTS: The authors provide examples of how the intersection classes
      help expose omissions of concepts, highlight errors of semantic type
      classification, and uncover ambiguities of concepts in the UMLS. The resulting
      UMLS OODB schema is deeper and more refined than the Semantic Network, since
      intersection classes are introduced. The Metathesaurus is classified into more
      mutually exclusive, uniform sets of concepts. The schema improves the user's
      comprehension and navigation of the Metathesaurus. CONCLUSIONS: The UMLS OODB
      schema supports the user's comprehension and navigation of the Metathesaurus. It
      also helps expose and resolve modeling problems in the UMLS.

PMID- 10641965
TI  - Representing nursing activities within a concept-oriented terminological system:
      evaluation of a type definition.
AB  - OBJECTIVE: A type definition, as a component of the categorical structures of a
      concept-oriented terminology, must support nonambiguous concept representations
      and, consequently, comparisons of data that are represented using different
      terminologies. The purpose of the study was to evaluate the adequacy and utility
      of a proposed type definition for nursing activity concepts. DESIGN: Nursing
      activity terms (n = 1039) from patient charts and intervention terms from two
      nursing terminologies (Home Health Care Classification and Omaha System) were
      decomposed into the attributes of the proposed type definition-Delivery Mode,
      Activity Focus, and Recipient. MEASUREMENTS: Attributes of the type definition
      were coded as present or absent for each term by multiple raters. In addition,
      Delivery Mode was rated as Explicit or Implicit and Recipient was rated as
      Explicit, Implicit, or Ambiguous. The data were summarized using descriptive
      statistics. Inter-rater reliabilities were calculated for each attribute of the
      type definition. RESULTS: All attributes of the type definition were present in
      73.9 percent of the chart terms, 91.3 percent of Home Health Care Classification
      intervention terms, and 63.5 percent of Omaha System intervention terms. While
      Delivery Mode and Activity Focus were almost universally present, Recipient was
      problematic. It was rated as ambiguous in 4.8 percent of the chart terms, 8.7
      percent of Home Health Care Classification intervention terms, and 36.5 percent
      of Omaha System intervention terms. CONCLUSIONS: The study findings supported the
      adequacy and utility of the type definition. Further research is needed to refine
      the type definition and its use for representing nursing activity concepts within
      a concept-oriented terminological system.

PMID- 10641966
TI  - Use of the equity implementation model to review clinical system implementation
      efforts: a case report.
AB  - This paper presents the equity implementation model (EIM) in the context of a
      case that describes the implementation of a medical scheduling system. The model
      is based on equity theory, a well-established theory in the social sciences that
      has been tested in hundreds of experimental and field studies. The predictions of
      equity theory have been supported in organizational, societal, family, and other
      social settings. Thus, the EIM helps provide a theory-based understanding for
      collecting and reviewing users' reactions to, and acceptance or rejection of, a
      new technology or system. The case study (implementation of a patient scheduling
      and appointment setting system in a large health maintenance organization)
      illustrates how the EIM can be used to examine users' reactions to the
      implementation of a new system.

PMID- 10641967
TI  - The use of electronic mail in biomedical communication.
AB  - OBJECTIVES: To determine whether there are statistically significant differences
      in the content of electronic mail (e-mail) and conventional mail sent to authors
      of papers published in medical journals. DESIGN: Prospective study by postal
      questionnaire. Over two one-month periods, corresponding authors of papers
      published in medical journals were asked to record details of the correspondence
      prompted by their publications. MEASUREMENTS: Conventional and e-mail
      correspondence received. Reprint requests. Content of correspondence. Quality of
      correspondence. RESULTS: Eighty-two of 96 authors replied. Fifty received e-mail
      (mean, 5.7+/-8.8 e-mails per author) and 72 received conventional mail (15.5+/
      32.8 letters per author) (p < 0.05). Seventy percent of e-mails and only 53% of
      correspondence sent by conventional mail (p < 0.05) referred to the content of
      the paper. CONCLUSIONS: Publication in general medical journals stimulates more
      conventional than electronic mail. However, the content of e-mail may be of
      greater scientific relevance. Electronic mail can be encouraged without fear of
      diminishing the quality of the communications received.

PMID- 10641968
TI  - Assessing data quality: from concordance, through correctness and completeness,
      to valid manipulatable representations.

PMID- 10641969
TI  - A standard metadata scheme for health resources.

PMID- 10641970
TI  - Informatics at NIH.

PMID- 10641971
TI  - Rivastigmine, a new-generation cholinesterase inhibitor for the treatment of
      Alzheimer's disease.
AB  - Rivastigmine is a cholinesterase inhibitor (ChEI) with a structural formula
      different from that of currently available ChEIs. Tacrine and donepezil are
      classified as short-acting or reversible agents since binding to
      acetylcholinesterase enzyme (AChE) is hydrolyzed within minutes. Rivastigmine is
      classified as an intermediate-acting or pseudo-irreversible agent due to its long
      inhibition on AChE of up to 10 hours. Preclinical biochemical studies indicated
      that rivastigmine has central nervous system selectivity over peripheral
      inhibition. It ameliorated memory impairment in rats with forebrain lesions. The
      drug is rapidly absorbed orally, with a bioavailability of 0.355 and low protein
      binding (40%). Its elimination half-life is less than 2 hours, and it is
      converted to an inactive metabolite at the site of action, bypassing hepatic
      metabolic pathways. Its disposition essentially is unaltered in patients with
      renal or hepatic impairment. It also has dose-dependent effects on AChE
      inhibition. In the two large multicenter clinical trials (total 1324 patients)
      that used a forced-dosage titration scheme, rivastigmine 6-12 mg/day was superior
      to placebo on three cognitive and functioning scales (p<0.001). Gastrointestinal
      symptoms are the most frequently reported adverse events. They occurred mostly
      during the dosage titration phase and decreased during the maintenance phase.
      Rivastigmine offers clinicians another therapeutic agent to treat Alzheimer's
      disease.

PMID- 10641972
TI  - HIV-associated lipodystrophy syndrome.
AB  - Highly active antiretroviral therapy (HAART) for human immunodeficiency virus-1
      (HIV-1) and prophylactic therapy for opportunistic infections have increased
      survival. Adverse effects of HAART include lipid profile alterations, diabetes
      mellitus, and fat redistribution. These metabolic and physical changes are called
      the HIV-associated lipodystrophy syndrome. A link to protease inhibitors has been
      suggested, and more recently to nucleoside reverse transcriptase inhibitors and
      factors related to duration of HIV-1 infection itself.

PMID- 10641973
TI  - Antipsychotic agents in patients with dementia.
AB  - We conducted a MEDLINE search to obtain data on various antipsychotics
      administered to patients with dementia and psychosis or behavioral symptoms.
      Additional unpublished data from conference proceedings and unpublished clinical
      trials were provided by Janssen Pharmaceutica, Eli Lilly and Company, and Zeneca
      Pharmaceuticals. All clinical trials that evaluated traditional typical or
      atypical antipsychotics in patients with dementia were reviewed for efficacy and
      safety data. Consensus guidelines published in 1994 or later were considered.
      After reviewing clinical trials and expert opinions, we devised an algorithm for
      optimal treatment of these patients. Although data are limited and do not
      conclusively show superiority of one agent over another, based on clinical
      experience and side effect profiles, risperidone is considered to be the drug of
      choice for treating patients with dementia and psychosis. Alternative treatment
      options in an algorithmic format also are recommended.

PMID- 10641974
TI  - Osteoporosis: a new challenge in cystic fibrosis.
AB  - The increased life expectancy of patients with cystic fibrosis (CF) may lead to
      medical complications such as osteoporosis. Based on data collected through a
      MEDLINE search (1985-May 1999) and review of references for additional relevant
      articles, nutrition status, weight, and disease severity are factors most highly
      correlated with osteopenia. Links also were noted with calcium and vitamin D
      intake, hypogonadism, chronic inflammation, and age, but findings in these areas
      are not consistent from one report to the next. Increased fracture rates and
      kyphosis are consequences of osteoporosis. Simple measures such as compliance
      with recommended nutrition guidelines and restrictions in corticosteroid therapy
      could be considered first-line management options. Further studies must be
      conducted to clarify factors involved in the etiology of osteoporosis in patients
      with CF and to identify the best treatment and prevention methods.

PMID- 10641975
TI  - Helicobacter pylori, Chlamydia pneumoniae, and cytomegalovirus: chronic
      infections and coronary heart disease.
AB  - We conducted a MEDLINE search of the English-language literature from 1966-1999
      on the association of chronic infections with Helicobacter pylori, Chlamydia
      pneumoniae, and cytomegalovirus (CMV) with coronary heart disease (CHD);
      additional literature was retrieved from references of selected articles. All
      human studies were included. Abstracts were excluded because of limited data.
      Chronic infections in CHD are speculated to be due to serum antibody
      concentrations of one or more of the three organisms. Data for H. pylori and CMV
      are difficult to interpret due to the confounding factor of childhood poverty and
      studies conducted in transplant recipients, respectively. Chlamydia pneumoniae
      data appear stronger with elevated IgG antibody titers (> or = 64) as a risk
      factor. Larger prospective studies are warranted to determine an association with
      CHD before universal prophylaxis or treatment of these chronic infections.

PMID- 10641977
TI  - Frequency, severity, and treatment of agitation in young versus elderly patients
      in the ICU.
AB  - STUDY OBJECTIVE: To study the frequency, duration, severity, and treatment of
      agitation in patients in the intensive care unit (ICU) to determine if the
      elderly represent a distinct population. DESIGN: Prospective cohort study
      SETTING: Tertiary care, 10-bed, multidisciplinary ICU. PATIENTS: All patients
      older than 18 years of age admitted for longer than 24 hours during a 4-month
      period. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: One hundred thirty
      patients were studied for 916 patient-days; 63 (48%) were elderly (> 65 yrs).
      Nurses and physicians described agitated behavior in 92 patients (70.8%) during
      534 (58.3%) patient-days, and it was severe or dangerous in 60 patients (46.1%)
      during 273 (30%) patient-days. There were no age-related differences in
      frequency, severity, and duration of agitation. Opiates, benzodiazepines, and
      haloperidol were administered during 72%, 62%, and 29% of agitated patient-days,
      respectively. Haloperidol was administered more often to elderly patients
      (p=0.015); otherwise no between-group differences were noted. Daily dosing
      requirements were less in the elderly for intermittent intravenous lorazepam,
      haloperidol, and morphine but not for midazolam (p=0.15). When these dosages were
      corrected for body mass, no statistical differences between young and old were
      found. CONCLUSION: In the ICU, the elderly are not a distinct population for
      agitation.

PMID- 10641976
TI  - Induction of interleukin-8 release by lung epithelium with cystic fibrosis
      epithelial lining fluid is marginally affected by inhibitors of interleukin
      1beta.
AB  - Interleukin-1beta (IL-1beta) and neutrophil elastase (NE) are present in the
      epithelial lining fluid (ELF) of patients with cystic fibrosis (CF). Both factors
      activate surrounding cells including lung epithelial cells, causing release of IL
      8, a potent chemoattractant for neutrophils. Previous studies showed up
      regulation of IL-8 release by lung epithelial cells as a function of NE in CF;
      however, few studies addressed the relationship between IL-1beta and activation
      of lung epithelial cells in CF lungs. Confluent layers of A549 cells, a type II
      like human lung epithelial cell line, were incubated overnight with IL-1beta (0-5
      ng/ml) or NE (100 nM), and supernatants were analyzed for IL-8 by enzyme-linked
      immunosorbent assay (ELISA). Both IL-1beta and NE led to a significant increase
      in IL-8: 12.8 +/- 2.8 ng/ml and 0.8 +/- 0.3 ng/ml, respectively. Next,
      bronchoalveolar lavage (BAL) samples were obtained from one healthy adult
      volunteer and six patients with CF and measured for IL-8 and IL-1beta
      concentrations by ELISA. Both IL-8 (range 169.00 +/- 56.57 to 1742.04 +/- 338.98
      pg/ml) and IL-1beta (range 0-24.26 +/- 0.52 pg/ml) were detected in CF specimens,
      whereas neither was detected in the volunteer's specimen. Normal and CF BALs then
      were incubated overnight at a 1:10 dilution with confluent A549 cells. Analysis
      by ELISA of cell-free supernatants revealed increased IL-8 production from cells
      stimulated with CF BALs only. Similar experiments were performed with BAL
      supernatants that had been incubated with soluble IL-1 type II receptor, soluble
      IL-1 receptor antagonist, or a peptide inhibitor of NE. Addition of IL-1
      inhibitors had a marginal effect on the amount of IL-8 release after incubation
      with CF BAL samples, whereas inhibition of NE had no effect. Our results indicate
      that other factors present in ELF in CF account for IL-8 release from lung
      epithelial cells.

PMID- 10641978
TI  - Assessment of patients' perceptions and beliefs regarding herbal therapies.
AB  - We evaluated the demographics and beliefs regarding safety and efficacy of herbal
      therapy among individuals in Iowa and assessed the willingness to discuss the use
      of these products with health care providers. We distributed 1300 surveys to two
      random samples: patients attending eight clinics, and residents of the state
      (mailing). Data were categorized according to herb use and compared between users
      and nonusers. The response rate was 61% (794 people), with 41.6% of respondents
      reporting herb use. They were predominately white women and were likely to have
      had education beyond high school (p<0.05). Their use of prescription drugs was
      high (p<0.05). Although users rated safety and efficacy of herbs higher than
      nonusers (p<0.05), both groups believed that health care providers should be
      aware of use and would provide this information.

PMID- 10641979
TI  - Intravenous valproate in neuropsychiatry.
AB  - Valproic acid (VPA) is administered for a variety of indications in neurology and
      psychiatry. The intravenous form of VPA, valproate, has been used extensively by
      neurologists since the 1980s for patients with status epilepticus, as serum
      levels can be achieved rapidly and telemetry is not required during
      administration. Psychiatrists have less experience with intravenous valproate,
      and little is documented in the literature regarding its nonepileptic
      indications. Patients who are unable or unwilling to take drugs orally, or for
      whom rapid treatment is clinically indicated, may benefit from VPA. Neuroleptics
      and benzodiazepines often are given parenterally; however, they may be
      accompanied by side effects. Intravenous valproate was administered successfully
      to three patients with neuropsychiatric disorders. It is hoped that this report
      will increase clinicians' awareness of this important and well-tolerated
      treatment option.

PMID- 10641980
TI  - Decreased methadone effect after ritonavir initiation.
AB  - Combination antiretroviral therapy including protease inhibitors such as
      ritonavir has added significant potency to therapy for human immunodeficiency
      viral (HIV) infection as well as substantial drug-drug interactions. Methadone
      metabolism is affected by cytochrome P450 (CYP) 3A4 inhibitors or inducers.
      Because ritonavir can induce CYP3A, it can decrease methadone plasma levels. An
      HIV-infected patient receiving methadone maintenance experienced withdrawal
      symptoms after ritonavir, saquinavir, and stavudine were added to his regimen;
      the most likely cause was ritonavir.

PMID- 10641981
TI  - Possible drug-associated pancreatitis after paclitaxel-cremophor administration.
AB  - Paclitaxel, a relatively new antineoplastic agent, is associated with numerous
      side effects, including two reported cases of pancreatitis. Our patient also
      developed paclitaxel-associated pancreatitis. Several companion drugs, including
      steroids, diphenhydramine, histamine2 blockers, serotonin type 3 antagonists, and
      other chemotherapeutic agents administered with paclitaxel, must be considered as
      possible causes of pancreatitis. In addition, paclitaxel is a hydrophobic agent
      that requires a vehicle, cremophor (CrEL), for solubility. Intravenous
      cyclosporine also requires CrEL and has been associated with pancreatitis. In the
      cerulein-induced pancreatitis rat model, paclitaxel with dimethyl sulfoxide as a
      vehicle prevents pancreatitis, suggesting that another causal agent is
      responsible. Animal studies of CrEL as a single agent may be required to settle
      this question, but for now, awareness that paclitaxel may be associated with
      pancreatitis may lead to earlier treatment of this potentially fatal
      complication.

PMID- 10641982
TI  - Potentiation of warfarin's hypoprothrombinemic effect with miconazole vaginal
      suppositories.
AB  - A 53-year-old woman being treated for a vaginal yeast infection experienced
      ecchymosis. Laboratory evaluation revealed a prolonged prothrombin time. It is
      possible that the bleeding was due to an interaction between warfarin and
      miconazole. Health care professionals should be aware of the potential for drug
      interactions with vaginally administered miconazole, especially in women
      receiving anticoagulation therapy.

PMID- 10641983
TI  - Anaphylactoid reaction to muromonab-CD3 in a pediatric renal transplant
      recipient.
AB  - Muromonab-CD3 (OKT3), a murine IgG2a antibody directed against the T3 (CD3)
      complex on mature lymphocytes, triggers adverse immune reactions. Anaphylactic
      reactions have occurred in patients exposed to OKT3 and are mediated by anti-OKT3
      IgE antibodies. The reactions are not antibody mediated and can occur within
      seconds of administration of a mast cell secretogogue. A renal transplant
      recipient became hypotensive and hypoxic immediately after receiving her first
      dose of OKT3 and required advanced life support. Serum antibody tests were
      negative for anti-OKT3 IgG, IgE, and antimouse protein antibodies. To our
      knowledge, this is the first published report of a patient with an anaphylactoid
      reaction to the initial infusion of OKT3.

PMID- 10641984
TI  - Acute mental status changes and hyperchloremic metabolic acidosis with long-term
      topiramate therapy.
AB  - Mental status changes and metabolic acidosis may occur with topiramate therapy.
      These adverse events were reported during dosage titration and with high dosages
      of the drug. A 20-year-old man receiving topiramate, valproic acid, and phenytoin
      experienced acute-onset mental status changes with hyperchloremic metabolic
      acidosis. He had been receiving a modest dose of topiramate for 9 months. He was
      weaned off topiramate over 5 days, and his mental status returned to baseline
      within 48 hours of discontinuing the agent. This case illustrates the need for
      close evaluation of patients who experience acute-onset mental status changes
      during topiramate therapy.

PMID- 10641986
TI  - The challenge of managing mild Parkinson's disease.
AB  - Clinicians have a number of options when diagnosing and managing Parkinson's
      disease. The decision to start pharmacotherapy often depends on the particular
      needs of the patient and careful weighing of possible benefits, cost, and adverse
      outcomes. Even mild parkinsonism may require the input of a specialist to obtain
      the best results.

PMID- 10641985
TI  - Duration of penicillin prophylaxis in sickle cell anemia: issues and
      controversies.
AB  - Functional asplenia occurs in 94% of patients with homozygous sickle cell anemia
      by 5 years of age and may result in fatal septicemia due to encapsulated
      microorganisms such as Streptococcus pneumoniae. Penicillin prophylaxis in these
      patients significantly reduces the risk of septicemia; however, continuation of
      prophylaxis beyond 5 years of age is controversial, since the risk of developing
      septicemia is reduced after this age and prolonged prophylaxis may lead to
      emergence of penicillin resistance. Although reports of penicillin-resistant
      pneumococci in patients receiving penicillin prophylaxis are conflicting, the
      prevalence of these organisms in the general population in North America
      increased from 5% in 1989 to more than 35% in 1997. Discontinuation of
      prophylaxis after age 5 years may be recommended because of lack of benefit,
      difficulty maintaining compliance, reduced risk of developing pneumococcal
      bacteremia after that age, and increase in prevalence of penicillin-resistant
      pneumococci worldwide.

PMID- 10641987
TI  - Pharmacotherapy for advanced Parkinson's disease.
AB  - Medical management of Parkinson's disease consists of two strategies. A
      presynaptic strategy attempts to maintain physiologic synaptic concentrations of
      dopamine, usually by individualizing delivery of levodopa (or exogenous dopamine)
      by varying the rate of gastrointestinal absorption or blood-brain barrier
      passage. A postsynaptic strategy bypasses degenerating nigrostriatal neurons by
      stimulating striatal neurons directly with dopamine agonists. With advancing
      disease, motor fluctuations appear, related to physiologic changes that narrow
      the window of levodopa concentration in which symptoms are under control. Then it
      becomes necessary to add dopamine agonists to therapy.

PMID- 10641989
TI  - New drugs for the treatment of Parkinson's disease.
AB  - Since the introduction of levodopa to treat Parkinson's disease (PD), several new
      therapies have been directed at improving symptom control, which can decline
      after a few years of levodopa therapy. Dopaminergic agents can serve as adjuncts
      or as alternatives to levodopa. In addition, a new class of drugs, catechol-O
      methyltransferase inhibitors, can extend the duration of levodopa action.
      Although surgical options such as pallidotomy offer improvement of parkinsonism
      beyond the realm of pharmacologic treatment, judicious administration of drugs in
      combination can generally solve most problems of PD.

PMID- 10641990
TI  - Maximizing the benefit of pharmacotherapy in Parkinson's disease.
AB  - Levodopa is one of the principal agents administered to treat patients with
      Parkinson's disease (PD). Several pharmacologic strategies can limit its side
      effects and enhance its activity. Although certain exceptions apply, dosage
      adjustments and drug changes should be instituted slowly. Levodopa is typically
      introduced in the form of carbidopa-levodopa, with upward dosage titration weekly
      until symptoms improve. A dopamine agonist may be added when the dosage of
      levodopa reaches 300-500 mg/day Dopamine agonists are used to control symptoms of
      PD, decrease or delay motor fluctuations, and allow lower dosages of levodopa to
      be administered. These agents are also being prescribed early in treatment before
      carbidopa-levodopa therapy is begun. Addition of a catechol-O-methyltransferase
      inhibitor can increase the duration of levodopa's effect and may prove especially
      valuable for patients who experience early wearing off of levodopa. Patients with
      PD require close monitoring for drug toxicity. Because most of them are treated
      with several agents to provide maximum improvement and also receive treatment for
      comorbid conditions, drug-drug interactions are possible. Frequently, clinically
      significant interactions are associated with agents that block D2 receptors or
      deplete dopamine stores in the brain.

PMID- 10641988
TI  - Clinical pharmacology of dopamine agonists.
AB  - With the availability of newer dopamine agonists selective for dopamine (D2)
      receptor subtypes, medical management of Parkinson's disease has progressed
      substantially. These agents can decrease the frequency of ergot-related side
      effects and dyskinesias. Also, when given as adjunctive therapy with levodopa,
      they can allow the levodopa maintenance dosage to be reduced without loss of
      symptom control. Based on early clinical experience, dopamine agonists can also
      be prescribed as initial monotherapy and can delay therapy with levodopa. Their
      therapeutic roles will be defined further by long-term studies.

PMID- 10641991
TI  - Developmental changes that regulate the activity of locus coeruleus neurons.

PMID- 10641992
TI  - The use of sevoflurane anesthesia during early pregnancy.
AB  - Sevoflurane has favorable pharmacodynamic properties such as a rapid, smooth
      induction and emergence from anesthesia. However, there is only one report of
      sevoflurane anesthesia during early pregnancy. We report the use of sevoflurane
      for maintenance of general anesthesia in a pregnant patient undergoing non
      obstetric surgery. A 25-year-old, female patient, at 13 weeks gestation, was
      diagnosed as having a strangulated ileus. General anesthesia was performed and
      maintained with oxygen, nitrous oxide, and sevoflurane. Six months later a
      healthy infant without abnormalities was delivered.

PMID- 10641993
TI  - EMG responses in lower leg muscles elicited by head-taps.
AB  - Forehead-taps elicited short-latency motor responses in the lower leg muscle
      which, together with vestibulocollic reflexes, might contribute to multisensory
      control of posture. We tested this paradigm in human subjects standing upright in
      order to determine if the responses differed depending on whether the taps were
      to the forehead or temporal bone. Forehead-taps elicited short-latency inhibitory
      EMG responses in both gastrocnemius muscles with a mean latency of 48 to 99 ms.
      The right or left temporal bone-taps elicited short-latency inhibitory EMG
      responses in the ipsilateral gastrocnemius muscle of 47 to 77 ms, short-latency
      excitatory EMG responses in the contralateral gastrocnemius muscle of 46 to 78
      ms, and short-latency excitatory EMG responses in the contralateral tibialis
      anterior muscle of 48 to 78 ms. The temporal bone-taps elicited short-latency
      inhibitory EMG responses in the ipsilateral gastrocnemius muscle and excitatory
      EMG responses in the contralateral gastrocnemius muscle, which were thought to be
      generated by vestibular afferents and convergent with vestibular input for the
      multisensory control of posture.

PMID- 10641995
TI  - Development of a "Type C" inventory: cross-cultural applications.
AB  - The authors are preparing for cross-cultural studies of immunosuppressive
      behaviors and emotions, commonly called "Type C," in both healthy persons and in
      patients with cancer. To this end, validity and reliability of a Type C
      Personality Inventory were assessed in a sample of 128 healthy volunteers.
      Reliability of the instrument was supported by moderate to high Cronbach alpha
      coefficients. Acceptable validity was evident by relatively high correlations of
      the instrument's subscales with other, standardized, psychological tests.

PMID- 10641994
TI  - The impact of HLA-A matching in corneal transplantation.
AB  - Previously, we have reported the results of our retrospective study on the effect
      of HLA class II allele matching on the outcome of corneal transplant. Here, we
      demonstrate our findings of the study for HLA class I allele matching in the same
      study subjects. Eighty transplant recipients were typed for HLA-A, and 79
      transplant recipients were typed for HLA-B alleles, by PCR-SSOP. The association
      between HLA class I allele matching and 1-year rejection-free graft survival was
      evaluated. When a total of 79 transplant recipients were subdivided into groups
      with matching (one to four alleles matched) and without matching (no allele
      matched) for HLA class I (HLA-A and -B), a significantly higher rate of 1-year
      rejection-free graft survival was detected in transplant recipients with
      matching, compared with those without matching (p=0.0258). We have found that
      matching for at least one HLA class I allele was more beneficial especially in
      high-risk transplant recipients (p=0.0076). Also, an analysis of matching for
      each locus separately, detected that, HLA-A matching was significantly associated
      with a higher rate of 1-year rejection-free graft survival. Transplant recipients
      with HLA-A matching (one or two-alleles matched) had significantly higher
      rejection-free graft survival compared with those without matching (no allele
      matched), when high- and low-risk groups were analyzed together (p=0.0099).
      Furthermore, matching for HLA-A allele was significantly beneficial compared with
      no matching in high-risk transplant recipients (p=0.0154). Nevertheless, no
      significant effect of HLA-B matching was detected. We conclude that HLA class I,
      especially HLA-A matching has a beneficial effect for corneal transplant outcome.

PMID- 10641996
TI  - Immunohistochemical studies in canine prostatic hyperplasia--effect of
      antiandrogen.
AB  - To investigated spontaneous benign prostatic hyperplasia (BPH) in dog the effect
      of a synthetic steroidal antiandrogen, chlormadinone acetate (CMA) was studied.
      Old male beagle dogs (5-8 years old) were divided into following experimental
      groups: group 1 consisted of BPH controls; group 2 received CMA 0.3mg/kg/day
      p.o., for 6 months. In group 1 animals, glandular hyperplasia of the prostate was
      clearly detected. The glandular epithelial cells showed uniformly intense
      immunostaining for nuclear androgen receptors (AR). AR was also localized in the
      nuclei of the fibro-muscular cells. Immunoreactivity of 5alpha-reductase type I
      was positive in most glandular epithelial cells. The staining was positive in the
      cytoplasm but not in the nuclei. No fibro-muscular cells were stained. In
      contrast, CMA produced marked atrophy of the glandular epithelium. The
      interacinar fibro-muscular stroma was prominent. Furthermore, immunostaining of
      nuclear AR of both epithelial and stroma cells was remarkably decreased. The
      intensity of staining for 5alpha-reductase type I in most glandular epithelial
      cells also decreased. Interestingly, some basal cells exhibited positive staining
      for 5alpha-reductase type I. These results indicate that the uptake of
      testosterone and/or its androgenic effect on the prostate may be suppressed by
      CMA. We further speculate that the basal cells produce sufficient
      dihydrotestosterone to maintain themselves even in the presence of low
      testosterone levels.

PMID- 10641997
TI  - Arthroplasty in the rheumatoid upper extremity: a plea for earlier referral.

PMID- 10641998
TI  - Cortical strut grafting for enigmatic thigh pain following total hip
      arthroplasty.
AB  - Enigmatic thigh pain remains a difficult problem to treat after total hip
      arthroplasty. This article reports on the use of strut cortical allografting for
      the treatment of recalcitrant enigmatic thigh pain following total hip
      arthroplasty in patients with a well-fixed cemented or cementless femoral
      component.

PMID- 10641999
TI  - Skin blood flow level and stump healing in ischemic amputations.
AB  - Skin blood flow was measured with xenon 133-histamine mixture in 20 lower
      extremities of 18 patients before performing amputations. The amputation levels
      were chosen according to clinical criteria; 13 below-knee, 3 distal femoral, 1
      midfemoral, 2 transmetatarsal, and 1 Syme's amputations were performed. Fourteen
      stumps had normal healing, 2 had delayed healing, and 3 had necrosis. All of the
      stumps with normal healing had a skin blood flow >1.76 ml/100 g tissue/minute.
      Bleeding from the skin also was a good predictor of healing. Skin blood flow
      measurement may be helpful for level selection in ischemic amputations.

PMID- 10642000
TI  - A comparison of plate and pin fixation for arthrodesis of the rheumatoid wrist.
AB  - This retrospective study compared plate fixation versus pin fixation in 57
      patients with rheumatoid arthritis who underwent wrist arthrodesis. Fixation was
      achieved by using plates in 32 patients and longitudinal pins in 25 patients.
      Clinical follow-up averaged 29 months (range: 12-57 months) and radiographic
      follow-up averaged 16 months (range 12-39 months). Union occurred in 97% of the
      wrists fixed with plates and in 96% of the wrists fixed with pins. There were 6
      (19%) complications in the plate group and 7 (28%) complications in the pin
      group. Three (12%) wrists fixed with pins moved from the immediate postoperative
      position to a position of relative volar flexion, while radiographs showed no
      changes in wrist position in the plate group. With both methods, successful
      arthrodesis stabilized the wrist in a high percentage of patients. Plate fixation
      offers an excellent alternative method for arthrodesis of the rheumatoid wrist.

PMID- 10642001
TI  - Influence of anteroposterior and mediolateral instability on range of motion
      after total knee arthroplasty: an ultrasonographic study.
AB  - Ultrasonographically, the femoral component and the tibial plate of total knee
      prostheses are strongly echogenic, while the high-density polyethylene insert is
      hypoechoic. This study evaluated the influence of mediolateral and
      anteroposterior stability after total knee arthroplasty (TKA) on range of motion
      using real-time monitoring with ultrasound. Mediolateral stress translation,
      which is increased by horizontal resection of more bone at the ends of the femur
      or tibia for easy prosthesis implantation, was examined on coronal scans at the
      level of the collateral ligaments. Anteroposterior drawer was examined on
      sagittal scans at the level of the patellar tendon. Mediolateral translation (0
      10 mm; mean 2.24 mm) did not correlate with range of motion, while
      anteroposterior drawer (2-10 mm, mean 5.05 mm) correlated well with range of
      motion. These ultrasonographic findings suggest that horizontal over-resection of
      the ends of the femur and tibia contributed to joint laxity, which would not
      result in better ROM. Rollback and sliding of the femoral component on the tibia,
      which is believed to be correlated with anteroposterior drawer, may be important
      in achieving better range of motion and obtaining excellent results in TKA.

PMID- 10642002
TI  - Fracture of the lateral process of the talus.

PMID- 10642003
TI  - Clinicopathologic features, diagnosis, and treatment of malignant fibrous
      histiocytoma of bone.

PMID- 10642004
TI  - Dislocation of total hip prosthesis by false aneurysm of the medial circumflex
      femoral artery.

PMID- 10642005
TI  - Arthroscopic replacement of a dislodged DePuy AMK locking post.

PMID- 10642006
TI  - Radiologic case study. Bone marrow transplant and multiple sites of
      osteonecrosis.

PMID- 10642007
TI  - Processing of syntactic information monitored by brain surface current density
      mapping based on MEG.
AB  - The cortical network subserving language processing is likely to exhibit a high
      spatial and temporal complexity. Studies using brain imaging methods, like fMRI
      or PET, succeeded in identifying a number of brain structures that seem to
      contribute to the processing of syntactic structures, while their dynamic
      interaction remains unclear due to the low temporal resolution of the methods. On
      the other hand, ERP studies have revealed a great deal of the temporal dimension
      of language processing without being able to provide more than very coarse
      information on the localisation of the underlying generators. MEG has a temporal
      resolution similar to EEG combined with a better spatial resolution. In this
      paper, Brain Surface Current Density (BSCD) mapping in a standard brain model was
      used to identify statistically significant differences between the activity of
      certain brain regions due to syntactically correct and incorrect auditory
      language input. The results show that the activity in the first 600 ms after
      violation onset is mainly concentrated in the temporal cortex and the adjacent
      frontal and parietal areas of both hemispheres. The statistical analysis reveals
      significantly different activity mainly in both frontal and temporal cortices.
      For longer latencies above 250 ms, the differential activity is more prominent in
      the right hemisphere. These findings confirm other recent results that suggest
      right hemisphere involvement in auditory language processing. One interpretation
      might be that right hemisphere regions play an important role in repair and re
      analysis processes in order to free the specialised left hemisphere language
      areas for processing further input.

PMID- 10642008
TI  - Lateralization of cerebral activation in auditory verbal and non-verbal memory
      tasks using magnetoencephalography.
AB  - The magnetic flux normal to the scalp surface was measured with a whole-head
      neuromagnetometer while right-handed subjects (N = 15) were engaged in either an
      auditory word- or a tone-recognition task. Sources of the recorded magnetic
      fields were modeled as equivalent current dipoles at 4 ms intervals and the
      number of sources in the later portion of the magnetic response was used as an
      index of the degree of brain activation. Significantly more sources were found in
      the left as compared to the right hemisphere in the word but not the tone task on
      a group basis. On an individual basis, 13/15 subjects had more sources in the
      left as compared to the right hemisphere during the word task, while in the tone
      task 3/10 subjects showed this pattern. Sources of activity were found in the
      left superior and middle temporal gyri in all subjects with available MRI scans.
      Sources were also found in the supramarginal gyrus and in medial temporal areas,
      including the hippocampus, in the majority of cases. MEG appears to be a
      promising tool for detecting activity in cerebral areas specialized for language
      and memory function.

PMID- 10642009
TI  - EEG correlates of cerebral engagement in reading tasks.
AB  - This study evaluated the utility of electroencephalographic (EEG) measures as
      indices of regional cerebral engagement activation during reading in
      neurologically intact adult volunteers. EEG was recorded from 16 scalp locations
      as participants performed four visual detection tasks designed to tap into
      increasingly more complex operations regularly involved in reading, namely visual
      spatial, orthographic, phonological, and semantic. EEG records were quantified
      using power spectrum measures in four frequency bands (delta, theta, alpha,
      beta1, and beta2), in addition to a non-linear estimate of signal complexity
      (prediction error). Results showed that (1) changes in spectral power between
      pairs of reading tasks, and (2) regional variations in EEG measures for each
      task, were restricted to signals recorded over the left hemisphere. These
      findings are in agreement with knowledge regarding left hemisphere involvement in
      higher level component processes of reading.

PMID- 10642010
TI  - Spatially fixed patterns account for the spike and wave features in absence
      seizures.
AB  - Despite genetic, morphological and experimental in vivo, data implying fixed
      abnormalities in patients with absence seizures, attempts to find highly
      consistent features in the 3-Hz spike-and-wave pattern recorded during sequential
      seizures from the same subject have been largely unsuccessful. We used a new data
      decomposition technique called Independent Component Analysis (ICA) to separate
      multiple spike-and-wave episodes in the EEG recorded from five subjects with
      absence seizures into multiple consistent components. Each component corresponded
      to a temporally-independent waveform and a fixed spatial distribution. Almost all
      components separated by the ICA algorithm had overlapping, largely frontal
      spatial distributions. The analysis unmasked 5-8 components from each subject
      that were consistently activated across all seizures, with no components detected
      that were selectively activated by one seizure and not another. The "spike" and
      "wave" features noted in the EEG of every subject were each separated by the ICA
      algorithm into two or more components. Other components were active only at the
      beginning of each seizure or were related to ongoing brain activity not directly
      related to the 3Hz spike-and-wave pattern. By contrast randomly selected spatial
      patterns used for data decomposition resulted in components that were
      uninformative, similar to simply changing the montage for viewing the EEG. Our
      results suggest that despite previously described variability in the raw EEG,
      certain highly specific spatial distributions of activation are reproducible
      across seizures. These may reflect ictal and non-ictal brain activity
      consistently activating the same group of neurons.

PMID- 10642011
TI  - High resolution DC-EEG of the Bereitschaftspotential preceding anatomically
      congruent versus spatially congruent bimanual finger movements.
AB  - The purpose of the present study was to observe how the supplementary, cingulate
      and primary motor areas (SCMA, MI) participate in the spatiotemporal coordination
      of bimanual index finger movement and what role the SCMA plays. The
      Bereitschaftspotential (BP) was recorded using 64 channel direct current EEG (DC
      EEG) to compare the anatomically congruent movements (abduction, adduction) with
      spatially congruent movements (both fingers to the right or left) in 16 normal
      volunteers. Subjects were required to move their two index fingers simultaneously
      in the horizontal plane (1) away from the midline (abduction), (2) toward the
      midline (adduction), (3) both index fingers to the right or (4) both fingers to
      the left. The results showed that there were significant differences (p<0.001)
      among the four tasks, across the 56 electrodes, and within the 20 different time
      points of the 3.5 s analysis epoch. BP amplitudes of the spatially congruent
      movements were significantly higher (p<0.05) than the ones of the anatomically
      congruent movements, and they were higher over the mesial wall motor areas SCMA
      than they were over the MIs. However, the significant differences differed
      between the left and right hemisphere in their amount and onset. The values of
      the difference ratio statistics between the SCMA and the MI indicated that the
      left hemisphere was more active than the right in our right-handed subjects for
      all tasks, particularly in the early (BP1) as compared to the late (BP2)
      component. Current source density mappings revealed that BP1 had its earliest
      onset in SCMA (6aalpha and 6abeta) for all four tasks. The onset times of BP2
      were earlier and BP densities were higher in the spatially congruent tasks 3 and
      4 as compared to the anatomically congruent tasks 1 and 2. Also, preparation
      (early component BP1) tended to start earlier and BP amplitudes tended to be
      higher for the spatially congruent tasks as compared to the anatomically
      congruent tasks.

PMID- 10642012
TI  - High temporal resolution dynamic mapping of instantaneous EEG amplitude
      modulation after tone-burst auditory stimulation.
AB  - A new method of instantaneous EEG analysis based on amplitude modulation (AM-EEG)
      was applied to analyze the AM-EEG changes in the alpha frequency band (8.20-12.89
      Hz) for successive 5 ms epochs. Repeated auditory tone-burst stimuli (of 220 ms
      duration) were presented at fixed 2.56 second intervals to 12 attending right
      handed young female volunteers, who were EEG-recorded over 19 EEG channels at 200
      Hz sampling frequency. The time-course of functional activation was characterized
      in terms of percent decrease in instantaneous amplitude modulation, as compared
      to baseline, in analogy with the classical event-related desynchronization
      paradigm. A dynamic sequence of the successive 122 AM-EEG maps obtained for the
      610 ms from beginning of tone-burst was stored and later animated on PC
      microcomputer. Topological changes among successive maps were extracted into 40
      specific AM-EEG maps. Early left temporal and centro-temporal activation was
      observed, followed first by strong bilateral frontal, and then by left temporal
      activation. These changes induced by a warning tone-burst are discussed in terms
      of functional neurophysiology. The present method therefore allows an improved
      time-resolution for functional brain activation paradigms.

PMID- 10642014
TI  - Interdisciplinary geriatric primary care evaluation and management: two-year
      outcomes.
AB  - BACKGROUND: The long-term efficacy of interdisciplinary outpatient primary care
      Geriatric Evaluation and Management (GEM) has not been proven. This article
      focuses on results obtained during the 2 years of the study. METHODS: In this 2
      year randomized clinical trial, at the Veterans Affairs Medical Center, Memphis,
      TN, 128 veterans, age 65 years and older, were randomized to outpatient GEM or
      usual care (UC). Two-year follow-up analyses are based on the 98 surviving
      individuals. Study outcome measurements included health status, function, and
      quality of life including affect, cognition, and mortality. RESULTS: At 2 years,
      there were positive intervention effects for eight of 1 outcome measures, five of
      which had attained significance at 1 year. GEM subjects, compared with UC
      subjects, had significantly greater improvement in health perception (P = .001),
      smaller increases in numbers of clinic visits (P = .019) and instrumental
      activities of daily living (IADL) impairments (P = .006), improved social
      activity (P<.001), greater improvement in Center for Epidemiologic Studies
      Depression (CES-D) scores (P = .003), general well-being (P = .001), life
      satisfaction (P<.001), and Mini-Mental State Exam (MMSE) scores (P = .025). There
      were no significant treatment effects in activities of daily living (ADL) scores
      (P = .386), number of hospitalizations (P = .377), or mortality (P = .155).
      CONCLUSIONS: These findings suggest that a primary care approach that combines an
      initial interdisciplinary comprehensive assessment with long-term,
      interdisciplinary outpatient management may improve outcomes for targeted older
      adults significantly. Findings suggest further that outcomes may continue to
      improve over time and that the GEM care model provides an effective way to manage
      health care of older adults.

PMID- 10642013
TI  - The effect of a multifaceted physician office-based intervention on older women's
      mammography use.
AB  - BACKGROUND: In response to identified low mammography use among older women in
      three geographic areas in Connecticut, a physician office-based mammography
      intervention was initiated under the Health Care Financing Administration's
      Health Care Quality Improvement Program. OBJECTIVE: To evaluate the
      intervention's impact on older women's mammography use. DESIGN: A quasi
      experimental design comparing mammography rates for women in the intervention
      program with a randomly selected control sample. SETTING: Community-based
      physician offices. PATIENTS: Female Medicare beneficiaries aged 65 to 74 years
      seen by participating and control physicians for at least one primary care visit
      in 1995 (baseline) and 1996 (follow-up). In the baseline period, 1720 women in
      the intervention sample and 2761 women in the control sample were included in the
      study. INTERVENTION: The recruitment strategies included the use of physician
      opinion leaders and modified academic detailing. The multifaceted intervention
      incorporated patient education, physician reminders, and audit-with-feedback
      MEASUREMENTS: Biennial mammography rates. Patient adherence to physician
      mammography referral was evaluated in a restricted cohort of women selected from
      the intervention sample. RESULTS: The mammography rate for the intervention
      sample increased from 62.7% (baseline) to 73.1% (follow-up), (P<.001), whereas
      the control sample's rate remained essentially unchanged (68.3 to 69.5%), (P =
      .34). The intervention patients were 48% more likely than controls to experience
      an increase in biennial mammography use (OR = 1.48; 95% CI, 1.22-1.79) after
      adjustment for patient race and income and physician gender, specialty, and age.
      The proportion of women who adhered to their physicians' mammography referral was
      70.6%. CONCLUSIONS: These data demonstrate the effectiveness of a multifaceted
      intervention program administered in the setting of community physician
      practices. The relatively low rate of patients' acceptance of their physicians'
      mammography recommendations has identified the need to address more effectively
      older women's concerns about mammography screening.

PMID- 10642015
TI  - Knowledge, attitudes, and practices of geriatricians regarding patients with
      dementia who are potentially dangerous automobile drivers: a national survey.
AB  - OBJECTIVES: To determine geriatrician knowledge regarding how to prevent a
      patient with dementia who is a potentially dangerous driver from driving and to
      determine their willingness to recommend license revocation against the wishes of
      both the patient and the patient's family. Included is a comparison of responses
      from geriatricians in California, where related legislation has existed for a
      decade, with responses from geriatricians from all other US states combined.
      DESIGN: Survey sample. SETTING: Geriatric practices. PARTICIPANTS: Probability
      sample of 467 geriatricians. MAIN OUTCOME MEASURES: Survey responses. RESULTS:
      More than 28% of all geriatricians (95% CI, 24.3%-32.7%) do not know how to
      report patients with dementia who are potentially dangerous drivers. A 22%
      difference (95% CI, 13.9%-30.8%) exists between California geriatricians and
      those in all other US states. More than 75% (95%, CI, 71.5%-79.5%) of all
      geriatricians agreed that physicians are responsible for reporting patients. More
      than 86% (95% CI, 83.2%-89.6%) of all geriatricians would contact state
      authorities despite the objections of the patient, and 72.9% (95% CI, 68.7%
      77.1%) would contact authorities despite the objections of the patient's family.
      CONCLUSIONS: Although most geriatricians will act to protect the public from
      patients with dementia who are potentially dangerous drivers, many do not know
      how to report these drivers. Legislation can improve a physician's ability to
      report patients with dementia who are potentially dangerous drivers.

PMID- 10642016
TI  - Characteristics of motor vehicle crashes of drivers with dementia of the
      Alzheimer type.
AB  - OBJECTIVE: To determine whether there is a difference in crash rates and
      characteristics between drivers with dementia of the Alzheimer type (DAT) and
      nondemented older persons who were controls. DESIGN: A pilot study using a 5-year
      retrospective analysis of state-recorded crash data and crash characteristics
      followed by patient enrollment into a study on road test skills. SETTING:
      Alzheimer's Disease Research Center at Washington University in St. Louis,
      Missouri. Subjects were enrolled as volunteers in a longitudinal study of aging
      and DAT. PARTICIPANTS: One hundred twenty-one subjects (58 nondemented, older
      drivers and 63 drivers with DAT) with a mean age of 77 years met the inclusion
      criteria for this study. DAT was diagnosed using validated clinical diagnostic
      criteria and was staged by the Clinical Dementia Rating (CDR) Scale. All subjects
      with DAT were in the very mild (CDR = 0.5) or mild (CDR = 1) stages. MAIN OUTCOME
      MEASURE: State-recorded traffic crashes. Also, a daily driving diary was
      completed by each subject and used to estimate miles traveled per year. RESULTS:
      Subjects diagnosed with mild DAT (CDR = 1) reported less roadway exposure
      (average number of miles driven per year) than did drivers with very mild DAT
      (CDR = 0.5) or controls. Crashes in both groups were infrequent, with 0.07 state
      recorded crashes per driver per year in the nondemented group (CDR = 0), 0.06 in
      the very mild DAT group (CDR = 0.5), and 0.04 in the mild DAT group (CDR = 1).
      There was no statistical difference in the crash frequency between groups, even
      when adjusting for exposure. Drivers with DAT had trends toward more at-fault
      crashes, crashes with injuries, and crashes in which the officer on the scene
      cited failure to yield. CONCLUSIONS: In our sample, individuals with very mild or
      mild DAT who continued to drive seemed to have crash rates similar to those of
      the controls. There may be significant differences between the causes and the
      consequences of crashes involving drivers with DAT when compared with cognitively
      intact age-matched controls, but none were found in this pilot study. Further
      research on crash characteristics is needed in larger samples of community-based
      drivers with DAT across wider ranges of dementia severity to address issues such
      as driving competency and public safety.

PMID- 10642017
TI  - Completed suicide among older patients in primary care practices: a controlled
      study.
AB  - OBJECTIVE: To determine whether physical and psychiatric illness, functional
      status, and treatment history distinguish older primary care patients who
      committed suicide from those who did not. DESIGN: A case-control study using data
      collected by psychological autopsies of suicides and prospective patient
      interviews for controls. SETTING: Primary care practices in Monroe County, NY.
      PARTICIPANTS: Forty-two suicides aged 60 years and older who visited a primary
      care provider within 30 days of death and 196 patients aged 60 years and older
      from a group practice of general internal medicine (n = 115) or family medicine
      (n = 81). MEASUREMENTS: Psychiatric diagnosis; depressive symptom severity;
      physical health and function; psychiatric treatment history. RESULTS: Completed
      suicides had more depressive illness (P = .001), physical illness burden (P =
      .0002), and functional limitations (P = .0001) than controls and were more likely
      to be prescribed antidepressants (P = .004), anxiolytic agents (P = .0001), and
      narcotic analgesics (P = .022). Among depressed subjects, affective symptom
      severity (P< .0001) and emotional dysfunction (P<.0001) distinguished suicide
      completers. However, physical health, overall function, and treatments received
      did not differ between groups. CONCLUSIONS: The primary care setting is an
      important venue for late life suicide prevention. Primary care providers should
      be well prepared to diagnose and treat depression in their older patients.
      Additional research is needed concerning the interactions of physical health,
      functional status, and depressive symptoms in determining suicide risk.

PMID- 10642018
TI  - The influence of patient age on primary care resident physician-patient
      interaction.
AB  - OBJECTIVES: To explore resident physician-patient interaction in primary care to
      address issues relevant to quality of care for older people. DESIGN: A sample of
      509 new, adult, nonpregnant patients was assigned to the care of second- and
      third-year residents in primary care clinics. Care was compared for three
      subgroups of patients: older patients (65 years or older; n = 45), those aged 18
      to 44 years (n = 320), and those aged 45 to 64 years (n = 144). SETTING:
      Observations were made at the family medicine and general internal medicine
      clinics at the University of California, Davis. MEASUREMENTS: Self-report by
      means of the Medical Outcomes Study Short Form-36 (MOS SF-36) was used to
      determine patient demographics and patient health status. Two measures of
      satisfaction were obtained gauging reaction to medical care in general and to the
      videotaped visit specifically. Videotapes were coded for content using the Davis
      Observation Code. RESULTS: Self-reported health status of older persons was
      poorer than that of younger groups as measured by the MOS SF-36. Differences in
      demographics were explored and then controlled, along with physical health status
      in subsequent analyses. Supporting prior studies, this study found that older
      patients had more return visits and reported higher levels of satisfaction than
      did younger comparison groups. Contrary to prior literature, older patients were
      found to have longer visits than did younger cohorts. The physician-patient
      interaction was significantly different in many areas between these three groups.
      Whereas older patients experienced more chatting in their visits, they were given
      less counseling, asked fewer questions, had less discussion about their families
      and their use of substances, were asked to change their health behavior habits
      less often, and were given less health education. For older patients, more of
      each visit was spent checking on compliance with earlier treatment and developing
      treatment plans. CONCLUSIONS: These results provide a new and more detailed view
      of how resident physician-patient interaction differs between older and younger
      groups and raise important issues on whether quality of care needs for this
      population are being adequately addressed, particularly regarding mental health
      issues.

PMID- 10642019
TI  - Acute stroke in very old people: clinical features and predictors of in-hospital
      mortality.
AB  - OBJECTIVES: To examine demographic characteristics, clinical features,
      neuroimaging data, and outcome of all acute stroke events occurring in
      individuals aged 85 years or older. DESIGN: Collection of data from a prospective
      hospital-based stroke registry. SETTING: Between January 1986 and December 1995,
      the data was collected of 2,000 stroke patients admitted consecutively to the
      department of neurology ( having 25 beds and an acute stroke unit) of Sagrat Cor
      L'Alianza Hospital of Barcelona (an acute care, 350-bed teaching hospital serving
      a population of approximately 250,000). PARTICIPANTS AND MEASUREMENTS: For the
      purpose of this study, very old patients (aged 85 years or older) were selected
      (n = 262). The data of very old stroke patients were compared with the data of
      patients younger than 85 years of age (n = 1738). Predictors of in-hospital
      mortality based on clinical and neuroimaging variables were recorded within 48
      hours of stroke onset, and outcome variables (medical complications that
      developed during hospitalization) were assessed by multiple regression analysis.
      RESULTS: The very old patients showed a significantly greater frequency of
      atherothrombotic (27.5% vs. 21.9%, P<.05) and cardioembolic infarctions (24.4%
      vs. 26.3%, P<.001) and a lesser frequency of stroke of unusual cause. Acute
      stroke in the very old patients was more severe than in patients younger than 85
      years of age, with greater rates of in-hospital mortality (27% vs. 13.5%,
      P<.001), longer duration of hospital stay (22.03+/-29.6 vs. 17.5+/-21.5 days,
      P<.001), and lesser frequency of absence of neurologic deficit at the time of
      hospital discharge (21.4% vs. 33.1%, P<.001). Altered consciousness, limb
      weakness, sensory symptoms, involvement of the parietal lobe and temporal lobe,
      involvement of the internal capsule (with a protective effect), intraventricular
      hemorrhage, cardiac events, and respiratory events were selected as independent
      predictors of in-hospital mortality in the multivariate analysis. CONCLUSIONS:
      Very old patients with acute stroke showed a differential clinical profile,
      different frequency of stroke subtypes, and a poorer outcome compared with stroke
      patients who were younger than 85 years of age. Clinical and neuroimaging factors
      that are indicative of the severity of stroke and that were available at the time
      of the initial diagnosis and at the time of the development of cardiac and
      respiratory complications showed a predominant influence on in-hospital mortality
      and may help clinicians to establish prognosis more accurately.

PMID- 10642020
TI  - Measures of postural stability are not predictors of recovery from large postural
      disturbances in healthy older adults.
AB  - OBJECTIVES: To determine, in healthy older adults, the relationship between
      postural steadiness, stability limits, and the ability to recover balance from
      three postural disturbances requiring anteriorly directed stepping responses.
      DESIGN: Analysis of multiple motor tasks in a cross-sectional sample of healthy
      older adults. SETTING: A biomechanics research laboratory. PARTICIPANTS: Fifty
      women and 29 men aged 65 or older, all healthy, living in the community,
      participated in this study. Subjects were examined by a geriatrician to identify
      the presence of exclusionary factors. MEASUREMENTS: Anterior-posterior and medial
      lateral excursion distances of the center of pressure during quiet standing
      (postural steadiness), static leaning (static stability limits), and dynamic
      swaying (dynamic stability limits) were determined from ground reaction forces
      measured by a strain gauge forceplate. Within the same group of subjects, the
      maximum angle of forward lean from which a subject could recover with a single
      step, the ability to recover balance in response to an accelerated support
      surface, and the ability to recover balance after being tripped were determined.
      RESULTS: Recovery from the three types of postural disturbances were found to be
      statistically independent. The postural steadiness and the stability limit
      variables were only weakly correlated. Postural steadiness and stability limits
      were not related to the maximum recoverable angle of lean. The average medial
      lateral center of pressure speed during the postural steadiness test was
      significantly slower for those who failed to recover after tripping than for the
      subjects who recovered successfully. However, a logistic regression model failed
      to achieve statistical significance, suggesting that the difference may not be
      functionally important. The anterior-posterior static stability limits were
      significantly larger for subjects who recovered successfully than for those who
      failed to recover during the accelerated support surface test. Although logistic
      regression suggested that a reduced anterior-posterior stability limit represents
      a risk factor for failure to recover during this task, only nine of 28 failures
      could be properly classified, thus diminishing the functional importance of this
      finding. CONCLUSIONS: Because recovery following postural disturbances could not
      generally be predicted from measures of postural stability, these findings
      suggest that these measures of postural stability are of limited utility in
      identifying potential anteriorly directed fallers in healthy older adults.

PMID- 10642021
TI  - Aging-related decline of gonadal function in healthy men: correlation with body
      composition and lipoproteins.
AB  - OBJECTIVE: To assess if androgen decline in physiological aging contributes to
      the concomitant changes in body composition and lipoprotein levels. DESIGN: Cross
      sectional, observational study. SETTING: A university-based outpatient center.
      SUBJECTS: The study comprised 206 healthy volunteers (aged 18-95 years).
      MEASUREMENTS: Blood samples were drawn after an overnight fast for the assay of
      hormones (free testosterone (FT), estradiol (E2), and sex hormone-binding
      globulin (SHBG)) and lipids (total cholesterol, triglycerides, high-density
      lipoprotein cholesterol, and lipoprotein Lp(a)). At the same time, body
      composition was assessed by both anthropometry (fat mass percentage (FM%)
      estimated from four measures of skinfold thickness using the Durnin and Womersley
      equation and the Siri equation) and by bioimpedance analysis (FM% estimated using
      the Segal or Deurenberg equations, respectively, for subjects younger or older
      than 62 years). RESULTS: A significant age-related decline was found for FT and
      E2 concentrations, whereas SHBG levels were related positively with age. No
      significant association was apparent between hormonal changes and the concomitant
      modifications of body composition and lipoproteins. Only SHBG showed a
      significant inverse association between FM% and the waist-to-hip ratio,
      independent of age. The comparison between older hypogonadal (with FT levels
      below the lower limit of the normality range assessed in younger subjects) and
      eugonadal men did not show any significant differences in body composition or
      lipid profile. CONCLUSIONS: This study suggests that, in men, androgen decline
      caused by normal aging does not significantly affect some targets of testosterone
      action, such as body composition and lipid metabolism. Therefore, androgen
      supplementation in hypogonadal older men cannot be expected to influence
      nutritional status and body composition to the same extent that it does other
      main targets of testosterone action, such as sexual activity and muscle strength.
      However, we cannot exclude that selected subsets of older patients with low
      testosterone levels, especially if affected by catabolic disease, could benefit
      from the effects of androgen administration on nutritional status.

PMID- 10642022
TI  - Are we improving the quality of nursing home care: the case of pressure ulcers.
AB  - BACKGROUND: There are widespread concerns regarding the quality of nursing home
      care and whether care is improving. We evaluated a large provider of nursing home
      care to determine whether risk-adjusted rates of pressure ulcer development have
      changed. METHODS: We used the Minimum Data Set to study National HealthCare
      Corporation nursing homes from 1991 through 1995. Rates of pressure ulcer
      development were calculated for successive 6-month periods by determining the
      proportion of residents initially ulcer-free having a stage 2 or larger pressure
      ulcer on subsequent assessments. Rates were risk-adjusted for patient
      characteristics. The proportion of new ulcers that were deep (stages 3 or 4) were
      also calculated. RESULTS: We examined risk-adjusted rates of pressure ulcer
      development based on 144,379 observations of 30,510 residents at 107 nursing
      homes. The number of observations per 6-month period ranged from 11,041 to
      15,805. Between 1991 and 1995, there was a significant (P<.05) rate decline of
      more than 25%. Additionally, the proportion of new ulcers that were stages 3 or 4
      declined from 30 to 22% (P<.01). CONCLUSIONS: Nursing homes showed significant
      improvement in the quality of pressure ulcer preventive care from 1991 to 1995.

PMID- 10642023
TI  - Comparison of rectal and infrared ear temperatures in older hospital inpatients.
AB  - OBJECTIVES: To assess the agreement between infrared emission detection (IRED)
      ear and rectal temperatures and to determine the validity of IRED ear thermometry
      in detecting rectal fever. DESIGN: Prospective, convenience sample, unblinded
      study. SETTING: An acute geriatric unit (teaching hospital) and a
      multidisciplinary intensive care unit. PARTICIPANTS: The study included 45
      inpatients (26 women and 19 men), aged 78.3+/-6.9 years, admitted over a 4-month
      period. Twelve of the patients were definitely infected. MEASUREMENTS: Sequential
      rectal (RT) and ear temperature (ET) measurements were performed using mercury-in
      glass and IRED ear thermometers, respectively. IRED ear temperatures were
      measured at both ears (unadjusted mode), with the highest of six ear temperatures
      considered the true value. RESULTS: Mean RT (37.39 degrees C +/- 0.52 degrees C)
      was significantly (P<.001) higher than mean ET (36.89 degrees C +/-0.59 degrees
      C). A highly significant positive correlation was found between RT and ET (slope
      = 0.69; 95% CI, 0.52-0.86; P<.001; r = 0.78). The mean bias (mean of the
      differences) between RT and ET was 0.50 degrees C +/-0.37 degrees C (95% CI, 0.41
      degrees C-0.59 degrees C), and the 95% limits of agreement -0.22 degrees C and
      1.23 degrees C (95% CI, -0.38 degrees C to 1.39 degrees C). According to the
      standard criterion (RT > or =37.6 degrees C), 14 patients were febrile. Using an
      optimum IRED ear fever threshold (37.2 degrees C), the sensitivity and
      specificity of IRED ear thermometry for predicting rectal fever were 86% and 89%,
      respectively (positive predictive value, 80%; negative predictive value, 93%).
      CONCLUSIONS: The degree of agreement between rectal temperature and the highest
      of six IRED ear temperatures was acceptable. Using an optimal IRED ear fever
      threshold of 37.2 degrees C (99 degrees F), IRED ear thermometry had acceptable
      sensitivity and specificity for predicting rectal fever.

PMID- 10642024
TI  - Health care for older persons: a country profile--Spain.

PMID- 10642025
TI  - A series of cases of dementia presenting with PTSD symptoms in World War II
      combat veterans.

PMID- 10642026
TI  - The increasing medical malpractice risk related to pressure ulcers in the United
      States.

PMID- 10642027
TI  - Treatment guideline for nursing home-acquired pneumonia based on community
      practice.
AB  - OBJECTIVES: To describe the findings of a retrospective study of the treatment of
      nursing home-acquired pneumonia (NHAP) in 11 nursing homes in one community and
      the development of a treatment guideline for NHAP using data from the
      retrospective study. DESIGN: A retrospective chart review of 239 episodes of NHAP
      occurring between November 1, 1997, and April 30, 1998, was performed. Data
      regarding antibiotic treatment of NHAP were used to revise a treatment guideline
      developed by the authors. Further refinements of the guideline were made based on
      small group discussions with physicians and nurse practitioners caring for the
      study population. SETTING: Residents with NHAP were identified among the
      populations of 11 nursing homes in the metropolitan Buffalo, New York area (Erie
      county). These 11 nursing homes had a total of 2375 beds, comprising nearly one
      third of all nursing home beds in the county. PARTICIPANTS: Nursing home
      residents with chest X-rays showing infiltrates and signs and symptoms of
      pneumonia. MEASUREMENTS: Antibiotic treatment (drug used, route of
      administration, and duration of treatment), location of initial treatment
      (nursing home or hospital), and status (alive or dead) of each resident were
      recorded 30 days after diagnosis of NHAP. RESULTS: Of the 239 episodes of NHAP,
      171 (72%) were initially treated in nursing homes. Of these 171 patients, 105
      (61%) were treated only with an oral regimen, whereas 66 (39%) were treated
      initially with an intramuscular antibiotic and subsequently with an oral regimen.
      There was no significant difference in 30-day mortality rates between those
      initially treated in nursing homes (22%) and those initially treated in hospitals
      (31%; P = .15) or between those initially treated with an oral regimen in nursing
      homes (21%) and those initially treated with an intramuscular antibiotic in
      nursing homes (25%; P = .56). There was no consistency in how physicians made the
      choice to use intramuscular antibiotics in nursing homes, and a logistic model
      for predicting this approach could explain very little. The frequency of the
      prescription of various antibiotic agents in nursing homes and in hospitals was
      tabulated as well as the duration of treatment; specific attention was paid to
      the timing of the switch to an oral agent among episodes initially treated with a
      parenteral agent. These data were used in the guideline to make specific
      recommendations regarding which agent to prescribe, the duration of parenteral
      therapy, the timing of the switch to an oral regimen, and the duration of
      treatment. In the setting of informal small groups, the guideline was discussed
      with physicians who cared for residents with NHAP in the study nursing homes.
      Revisions made to the guideline were based on these discussions. CONCLUSIONS: A
      treatment guideline for NHAP was developed primarily on the basis of the
      practices of geriatricians in one community. These treatment practices were
      similar to those reported in the literature in terms of the proportion of
      patients treated in nursing homes and the antibiotics prescribed. The guideline
      also provided specific recommendations for timing of the switch to an oral agent
      after parenteral therapy and for duration of treatment. Studies are in progress
      to determine if use of this guideline will reduce some of the variation observed
      in the treatment of NHAP.

PMID- 10642028
TI  - In the steps of giants: the early geriatrics texts.
AB  - This article briefly reviews some of the major early geriatric textbooks of the
      last two centuries. Among the more important are books by George Day, Charcot,
      Nascher, Worcester, and Cowdry. Lord Amulree's book Adding Life to Years has
      become a watchword of modern geriatrics. It is of interest that during this time
      period the basic plea for high touch care of older patients and the lament that
      physicians have little knowledge of the needs of older patients has remained
      remarkably constant.

PMID- 10642029
TI  - Management of nursing home-acquired pneumonia: unresolved issues and priorities
      for future investigation.

PMID- 10642030
TI  - Increasing liability risks among nursing homes: therapeutic consequences, costs,
      and alternatives.

PMID- 10642031
TI  - New laws or better information and communication?

PMID- 10642032
TI  - Medication for chronic pain in older persons.

PMID- 10642033
TI  - Guidance to surveyors--long-term care facilities: angry comments from one down in
      the trenches.

PMID- 10642034
TI  - Relationship between physical and cognitive function in healthy older men: a role
      for aerobic power?

PMID- 10642035
TI  - Innovative intergenerational prevention programming for older adults and
      adolescents.

PMID- 10642036
TI  - Renal effects of ibuprofen during sodium restriction in the aged.

PMID- 10642037
TI  - Single-enhancing CT lesions in Indian patients with seizures: a review.
AB  - Single enhancing CT lesions are the commonest radiological abnormality in Indian
      patients with new-onset partial seizures. In few patients the lesions may be
      'tuberculoma' (especially in presence of evidence of tuberculosis elsewhere).
      However, histopathological studies have proved that neurocysticercosis is the
      most frequent cause for these lesions. Acute inflammation in and around the
      cerebral lesions of cysticercosis manifests as acute seizure disorder. These
      cysticercal granulomas represent 'colloidal' and 'nodular-granular' stages of
      Escobar's pathological classification of natural evolution of a parenchymal
      cysticercus cyst. In 8-12 weeks time majority of these lesions spontaneously
      disappear, few may calcify. As albendazole therapy is of controversial value,
      these patients, possibly, need to be treated only with antiepileptic drugs.
      Associated seizure disorder is also benign in nature and remit in majority within
      6-8 months, recurrences are usually infrequent. Antiepileptic drug may be
      withdrawn once follow-up CT scan shows resolution of the lesion. If seizures
      recur after resolution of the lesion, CT lesion persists or CT lesion calcified,
      a long-term (2-3 years) antiepileptic therapy may be required. The single
      enhancing CT lesions which persist despite anticysticercal or antituberculous
      therapy may need histopathological evaluation to establish the correct diagnosis.

PMID- 10642038
TI  - A ketogenic diet has different effects upon seizures induced by maximal
      electroshock and by pentylenetetrazole infusion.
AB  - The purpose of these experiments was to determine whether a ketogenic diet
      previously shown to elevate seizure threshold also reduced seizure severity.
      Seizure threshold was tested by intravenous infusion of pentylenetetrazole (PTZ)
      whereas seizure severity was determined from measuring the hindlimb extension to
      flexion (E/F) ratio after seizures were evoked by maximal electroshock
      stimulation (MES). Surprisingly, seizures evoked by MES were more severe in
      animals fed a calorie-restricted ketogenic diet. Controls fed an isocaloric,
      calorie-restricted normal diet also exhibited more severe seizures than did
      animals fed the same diet ad libitum. When seizure threshold was evaluated in the
      same animals, those animals fed a calorie-restricted ketogenic diet exhibited a
      significant increase in seizure resistance compared to animals fed a ketogenic
      diet ad libitum, a calorie-restricted normal diet or a normal diet ad libitum.
      These findings suggest that both the amount and type of food affect seizures in
      rats and show that diet-related seizure protection depends upon the method by
      which seizures are provoked.

PMID- 10642039
TI  - Hippocampal kindled seizures impair spatial cognition in the Morris water maze.
AB  - We investigated the effects of hippocampally kindled seizures on spatial
      performance of rats in the Morris water maze (MWM). Seizures were elicited with
      stimulation of field CA1 of dorsal hippocampus 25-45 min prior to daily testing
      in the water maze. One group of rats was naive to the MWM (acquisition groups),
      while another group received pretraining in the MWM (retention groups). These
      groups were further subdivided into rats that experienced non-convulsive seizures
      prior to daily testing and rats that experienced fully generalized convulsive
      seizures prior to daily testing. We found that CA1 seizures significantly
      disrupted water maze performance during both acquisition and retention, and the
      effects were similar when either non-convulsive or fully generalized convulsive
      seizures were evoked. Our findings are consistent with previous reports
      suggesting that epileptiform activity in the hippocampus acutely impairs
      performance in tasks sensitive to spatial learning and memory deficits and
      suggest that both new learning and demonstration of an established place response
      are susceptible to such disruption.

PMID- 10642040
TI  - Familial temporal lobe epilepsy autosomal dominant inheritance in a large
      pedigree from southern Italy.
AB  - To further elucidate the inheritance pattern and range of phenotypic
      manifestations of benign familial temporal lobe epilepsy (FTLE), we report a
      large family recently identified in southern Italy. There were 8 patients (4
      men), ranging in age from 31 to 68 years in three generations. One affected
      patient was deceased at the time of the study. Genealogical study strongly
      supported autosomal dominant inheritance with incomplete penetrance, as three
      unaffected individuals transmitted the disease. Clinical anticipation could not
      be assessed because of the ascertainment method. Male to male transmission
      occurred. Identifiable antecedents for seizures were present in only two
      patients, who had a simple febrile convulsion and a closed head trauma,
      respectively. Migraine was overrepresented in this family. Onset of seizures
      ranged from 17 to 52 years (mean: 27 years). All patients had weekly simple
      partial seizures suggestive of temporal origin with vegetative or experiential
      phenomena. Very rare partial complex seizures occurred in 6/7 patients. One had
      two generalized nocturnal seizures as well. Two had previously been misdiagnosed
      as having gastritis or panic attacks, and one had not been diagnosed. Interictal
      anteromesiotemporal spiking was seen in 5/7 patients, and occurred mostly during
      NREM sleep. Neurological examination, brain CT or MR scans were normal.
      Antiepileptic medication always controlled the seizures.

PMID- 10642041
TI  - Absence of simple partial seizure in temporal lobe epilepsy: its diagnostic and
      prognostic significance.
AB  - The diagnostic and prognostic significance of the absence of simple partial
      seizures (SPS) immediately preceding complex partial seizures (CPS) was examined
      in patients with temporal lobe epilepsy. The status of self-reported SPS in 193
      patients with temporal lobe epilepsy who had surgical therapy more than 2 years
      ago was reviewed. Before surgery, 37 patients never experienced SPS before CPS
      (Group A), 156 patients either always or occasionally had SPS before CPS (Group
      B). The frequency of mesial temporal sclerosis (MTS) was lower and the age at
      onset of epilepsy was higher in Group A. The seizure focus was in the language
      dominant temporal lobe in 73% of the cases in Group A, compared with 40% in Group
      B. The surgical outcome did not differ between the two groups. The findings
      suggest that temporal lobe seizures without preceding SPS tend to originate in
      the language-dominant temporal lobe that contains a pathologic etiology other
      than MTS, especially in the lateral temporal lobe. The surgical outcome in
      patients without SPS is similar to that in patients with SPS.

PMID- 10642042
TI  - Temporal lobe epilepsy with sensory aura: interictal glucose hypometabolism.
AB  - Patients with mesial temporal lobe epilepsy (mTLE) exhibit marked depressions of
      the regional cerebral glucose metabolism (rCMRGlu) in the mesiotemporal region.
      We hypothesised that patients with temporal lobe epilepsy (TLE) who have a
      bilateral somatosensory or acoustic ( = temporolateral/SII-) aura can be
      differentiated from mTLE by rCMRGlu depressions primarily involving temporo
      perisylvian locations. We therefore used this ictal semiology as a clinical
      criterion to define a subgroup of such patients and measured the rCMRGlu in 16
      patients with TLE as evident from interictal and ictal EEG-video monitoring.
      Clinically, they presented with medically refractory complex partial seizures and
      were subjected to presurgical evaluation. The pattern of the interictal rCMRGlu
      in the TLE patients was different from that observed in patients with mTLE and
      showed significant depressions ipsilateral to the epileptic focus in mesial
      temporal and lateral temporal regions but spared the thalamus. The neocortical
      metabolic depressions were spatially more extended in right than in left TLE
      patients. Magnetic resonance images (MRI) were either normal (n = 5) or revealed
      unilateral or bilateral hippocampal atrophy/sclerosis (n = 7), or temporal or
      extratemporal focal cortical dysplasia (n = 4). The selected TLE patients
      presented here comprise a heterogeneous group showing most pronounced metabolic
      depressions in the lateral temporal cortex. Thus, our data suggest that non
      invasive metabolic imaging can assist in identifying the neocortical
      symptomatogenic zone in putative temporo-perisylvian lobe epilepsy.

PMID- 10642043
TI  - Mental and behavioural outcome of infantile epilepsy treated by vigabatrin in
      tuberous sclerosis patients.
AB  - Vigabatrin (VGB) has demonstrated high efficacy in infantile spasms (IS) due to
      tuberous sclerosis. Our first objective was to evaluate the cognitive long term
      effect outcome of children whose refractory spasms definitely disappeared when
      VGB was given as an add on drug. Our second objective was to determine the
      response of generalized epilepsy (infantile spasms) compared to partial epilepsy
      on cognitive impairment. A non selected series of 13 children underwent
      psychometric and behavioural evaluation before VGB initiation at a mean of 3
      years on VGB treatment. Eight of them could perform detailed neuropsychological
      tests at follow-up. Seven had infantile spasms (Group I), they all were spasm
      free before 2 years of age and five remained with rare partial seizures (mean
      age, 5.5 years). Six others had partial epilepsy without spasms (Group II) and
      five remained with rare seizures (mean age, 7.5 years). Patients of Group I
      experienced dramatic changes. Developmental quotient (DQ) significantly rose in
      six out of seven by ten to more than 45 points (P = 0.03) and autistic behaviour
      disappeared in five out of the six who presented with. The four tested children
      had normal verbal level after 5 years and could integrate at school but they
      remained with marked visuospatial disabilities. By contrast, patients of Group II
      remained with an unchanged DQ of about 60 so that both groups had similar DQ
      levels on follow-up. The cessation of spasms with VGB is therefore associated
      with significant improvement of cognition and behaviour in children with tuberous
      sclerosis. Controlling secondary generalization induced by infantile spasms seems
      to be a key factor for mental development.

PMID- 10642044
TI  - Epileptiform activity of veratridine model in rat brain slices: effects of
      antiepileptic drugs.
AB  - The effects of the antiepileptic drugs valproic acid (VPA), phenytoin (PHT), and
      ethosuximide (ESM) on evoked and spontaneous seizure-like (epileptiform) activity
      were studied in the veratridine epileptiform model in rat brain slices, using
      conventional electrophysiological intracellular recording techniques. The
      veratridine model is generated by treatment of brain slices with a low
      concentration (0.3 microM) of the alkaloid veratridine. The drug modifies sodium
      channel function so that a brief current injection in hippocampal CA1 pyramidal
      neurons evokes bursts of epileptiform activity. Therapeutic concentrations of VAP
      (50-200 microM) inhibited both evoked and spontaneous bursting in a voltage
      dependent manner without affecting membrane resting potential or input
      resistance. Similarly, therapeutic concentrations of PHT (4-15 microM) inhibited
      both evoked and spontaneous bursting in a voltage-dependent fashion with no
      apparent change in the membrane resting potential. However, PHT increased the
      membrane input resistance and elevated the firing threshold of neurons. The
      antiepileptic drug ESM failed to inhibit evoked or spontaneous bursting even at
      high concentrations. The results suggest that the veratridine model of
      epileptiform activity is sensitive only to antiepileptic drugs that primarily
      affect the sodium channels.

PMID- 10642045
TI  - Seizure suppression by systemic epinephrine is mediated by the vagus nerve.
AB  - The present study investigated the seizure-suppressing effects of systemic
      epinephrine. Rats were injected with epinephrine, and seizures induced with
      pentylenetetrazol. Seizure severities were significantly reduced 15 min after 1
      mg/kg of epinephrine. Severing the subdiaphragmatic vagus nerves abolished this
      effect, demonstrating that epinephrine-induced seizure suppression is mediated by
      subdiaphragmatic vagal afferents. The development of novel anti-epileptic drugs
      that exploit this peripheral pathway may yield new seizure treatments.

PMID- 10642046
TI  - A new model of chronic temporal lobe epilepsy induced by electrical stimulation
      of the amygdala in rat.
AB  - Spontaneous seizures are the hallmark of human epilepsy but they do not occur in
      most of the epilepsy models that are used to investigate the mechanisms of
      epilepsy or to test new antiepileptic compounds. This study was designed to
      develop a new focal epilepsy model that mimics different aspects of human
      temporal lobe epilepsy (TLE), including the occurrence of spontaneous seizures.
      Self-sustained status epilepticus (SSSE) lasting for 6-20 h was induced by a 20
      30 min stimulation of the lateral nucleus of the amygdala (100 ms train of 1 ms,
      60 Hz bipolar pulses, 400 microA, every 0.5 s). Stimulated rats (n = 16) were
      monitored with a video-EEG recording system every other day (24 h/day) for 6
      months, and every other video-EEG recording was analyzed. Spontaneous epileptic
      seizures (total number 3698) were detected in 13 of the 15 animals (88%) after a
      latency period of 6 to 85 days (median 33 days). Four animals (31%) had frequent
      (697-1317) seizures and 9 animals (69%) had occasional seizures (1-107) during
      the 6-months follow-up period. Fifty-seven percent of the seizures occurred
      during daytime (lights on 07:00-19:00 h). At the end of the follow-up period,
      epileptic animals demonstrated impaired spatial memory in the Morris water-maze.
      Histologic analysis indicated neuronal loss in the amygdala, hippocampus, and
      surrounding cortical areas, and mossy fiber sprouting in the dentate gyrus. The
      present data indicate that focal stimulation of the amygdala initiates a cascade
      of events that lead to the development of spontaneous seizures in rats. This
      model provides a new tool to better mimic different aspects of human TLE for
      investigation of the pathogenesis of TLE or the effects of new antiepileptic
      compounds on status epilepticus, epileptogenesis, and spontaneous seizures.

PMID- 10642047
TI  - Seizure precipitants and perceived self-control of seizures in adults with poorly
      controlled epilepsy.
AB  - This study was set up in order to investigate the prevalence and nature of
      seizure precipitants and self-control behaviours in adults with intractable
      seizures. A semi-structured interview was conducted with 100 patients attending
      neurology or neuropsychiatry epilepsy out-patient clinics. The interview included
      six questions regarding seizure precipitants, the extent to which the patients
      seek and avoid precipitants, and their ability to induce or abort seizures. The
      study revealed that over 90% of the participants could identify at least one
      seizure precipitant. Stress, depression, tiredness and the menstrual cycle were
      the most common precipitants reported. In addition, 65% of the participants could
      identify at least one 'low-risk' situation in which seizures were unlikely to
      occur. Fifteen percent reported they could induce a seizure, 52% said that they
      consciously try to avoid seizure precipitants and 47% said they could sometimes
      stop their seizures from happening. These results indicate that the majority of
      the sample could identify factors which trigger their seizures, and that some of
      the participants engage in attempts to reduce their seizure frequency by avoiding
      these factors and by controlling the onset of their seizures. The possible
      mechanisms involved in the relationship between precipitants and seizure genesis
      are discussed.

PMID- 10642048
TI  - Early magnetic field changes preceding the intracortical penicillin induced
      spikes.
AB  - Events preceding interictal activity were studied using a combination of
      magnetoencephalography (MEG), electrocorticography (ECoG), and intracortical
      field potential recordings in rabbits. We measured MEG signals simultaneously
      with ECoG before and during interictal discharges induced by penicillin injected
      in the cortex (group 1: n = 12, medial cortex, regio retrosplenialis granularis;
      group 2: n = 4, cortical convexity, regio retrosplenialis agranularis; control
      group: n = 5); in group 3 (n = 12) a 16-channel depth electrode array was used to
      calculate the current source density in the cortical area exhibiting interictal
      epileptiform discharges. The modified Z-parameter as a lumped measure of magnetic
      field pattern changes and the global field power as a lumped measure of changes
      of field amplitude differences were calculated. In almost all recordings of both
      group 1 and 2, the Z-parameter of intra-individual MEG data became significantly
      larger than the control condition before the earliest change of the interictal
      spike recorded at the penicillin injection site (20-310 ms earlier, median: 91
      ms, n = 151). The increase in Z-parameter in averaged MEG data of group 1 was
      significantly correlated with time as early as 790 ms before the spike (Pearson
      correlation coefficient, P < 0.05). After the start of the early increase of the
      Z-parameter, the global field power also began to increase before the ECoG spike.
      These results suggest a prespike field recruitment nearly 1 s before an
      interictal spike.

PMID- 10642049
TI  - The role of technical, biological, and pharmacological factors in the laboratory
      evaluation of anticonvulsant drugs. VII. Seasonal influences on anticonvulsant
      drug actions in mouse models of generalized seizures.
AB  - Seasonal or circannual rhythms have been reported in various physiologic,
      biochemical, pharmacological, and toxicological studies in mice and rats despite
      laboratory conditions with standardized and controlled light cycle, temperature,
      humidity, and food. This may either be explained by the existence of innate, free
      running circannual rhythms or by the existence of seasonally varying
      environmental factors ('zeitgeber') which are detected by the animals despite
      controlled laboratory conditions. In the present study, it was evaluated whether
      circannual rhythms affect the anticonvulsant activity of phenobarbital,
      carbamazepine, or valproate in two mouse models of generalized seizures, i.e. the
      threshold for generalized tonic seizures in the maximal electroshock seizure
      (MES) test and the threshold for different types of generalized seizures induced
      by the chemical convulsant pentylenetetrazol (PTZ). A study protocol was used
      with data sampling in separate groups of mice per month (using each group only
      once) over a period of 13 months beginning and ending in late summer (September),
      so that data collected in the other seasons could be compared with summer values
      of 2 subsequent years. With all three anticonvulsants, marked seasonal variation
      was observed in both seizure models with lowest anticonvulsant efficacy and
      potency in March and April, i.e. in late winter and early spring. The most marked
      loss of anticonvulsant activity in this period of the year was observed with
      valproate. Analysis of drug levels in plasma and brain indicated that the
      seasonal variation in phenobarbital's and carbamazepine's anticonvulsant effect
      was predominantly due to alterations in drug metabolism leading to reduced brain
      levels in March and April, while the seasonal rhythm in valproate's activity
      appeared to be mainly related to altered pharmacodynamic activity. These findings
      indicate that the time of the year is an important variable in the experimental
      evaluation of anticonvulsant drugs. Furthermore, the present data add to the
      accumulating evidence that endogenous circannual rhythms should be considered
      during animal experiments under controlled laboratory conditions.

PMID- 10642050
TI  - Can a generalized kindling seizure induce a reward state?
AB  - The postictal behavioral depression (PBD), characterized by behavioral immobility
      and unresponsiveness to environmental stimuli, observed after a stage 5 kindling
      seizure is opioid dependent. Morphine injection prolongs while naloxone and
      naltrexone (opioid antagonists) reduce or eliminate PBD. Opioids have clear
      rewarding actions that can be easily detected by place preference conditioning
      (PPC). In the present study, we evaluated if the opioid release after a stage 5
      kindling seizure that produces PBD could induce PPC. Male rats were kindled in
      the medial preoptic area (MPOA), the amygdala (AMG) or insular cortex (IC). After
      kindling was established their initial preference in a three-compartment chamber
      was determined. During conditioning, subjects received a standard kindling
      stimuli that evoked a stage 5 seizure. At the end of the after discharge and
      during the PBD the animals were placed in the non-preferred chamber for 30 min.
      On alternate days they were placed without stimulation in the preferred chamber.
      At the end of conditioning the kindled groups showed a clear change of
      preference. This change of preference was completely blocked by injection of
      naloxone. These results suggest that opioid release after a stage 5 kindling
      seizure can induce a positive affect of sufficient intensity and duration to
      induce conditioning.

PMID- 10642051
TI  - Mastocytosis with skin manifestations: current status.
AB  - AIM: To review our present knowledge about mastocyte origin, mastocytosis
      classification and management. METHODS: Literature review. RESULTS: Mastocytoses
      are chronic and recurrent disorders with symptoms which might either be limited
      only to the skin or to internal organs as well. The mastocytes, coming from bone
      marrow progenitor cells, migrate to tissues where they participate in
      inflammation and in cellular immunity as well as in the metabolism of connective
      and osseous tissues. Their proliferation causes the appearance of mastocytoses.
      The classification of the clinical manifestations of the mastocytoses into
      cutaneous, reactive (under the influence of the degranulator factors) and
      systemic disease, facilitates dialog among clinicians. Determination of prognosis
      and appropriate therapeutic regimens depend on individual features. CONCLUSIONS:
      Mastocytosis diagnosis is verified by histological study of skin lesion biopsy
      material. Management is symptomatic and unfortunately does not eradicate the
      disease.

PMID- 10642052
TI  - Reducing AIDS risk among inner-city women: a review of the Collectivist
      Empowerment AIDS Prevention (CE-AP) Program.
AB  - We discuss the process underlying our HIV-prevention project for young inner-city
      women. Health interventions are almost uniformly based on individualistic models
      of health and behavior. In contrast, AIDS and AIDS prevention, by their very
      social nature, may require more collectivist principles of disease, health, and
      intervention. We conducted a behavioral intervention, the Collectivist
      Empowerment AIDS Prevention (CE-AP) Program, with young, inner-city women to deal
      with this critical health issue. Our primary intervention goal was to promote
      women's sense of owning and making healthy choices about their bodies. We
      attempted to accomplish this by emphasizing the concepts of empowerment,
      collectivism (as opposed to individualism), and culturally sensitive skill
      building. Collectivism is emphasized to encourage women to involve others in
      their behavioral health decisions and to gain power through social joining and
      coalition building. A woman's behavioral decisions affect many others in her
      life. Thus, involving others in decision making emphasizes the connection between
      an individual's actions and their impact on interpersonal relationships. CE-AP
      was found to be effective in changing safer-sex behavior and we review our
      findings and future directions.

PMID- 10642053
TI  - Malignant fibrous histiocytoma of the scalp. Multidisciplinary treatment.
AB  - BACKGROUND: Malignant fibrous histiocytomas (MFH) are uncommon in the skin, and
      even less frequent on the scalp. On the scalp they are often very difficult to
      excise and it is even more difficult to close the resulting wound. OBJECTIVE: To
      review all malignant fibrous histiocytomas diagnosed and treated in our
      Department during the past 6 years, and to describe the multidisciplinary
      procedure employed to treat one special case of aggressive malignant fibrous
      histiocytoma on the scalp that recurred twice. RESULT: Malignant fibrous
      histiocytomas represent 0.01% of malignant cutaneous tumors in our area. The
      immediate results after a multidisciplinary treatment performed on a recurrent
      malignant fibrous histiocytoma located on the scalp were excellent, but
      recurrence was observed 6 months later. Two years later we have also treated
      another case of MFH on the scalp. The same surgical technique was performed, but
      the patient received high-dose-methotrexate-based neoadjuvant chemotherapy (HD
      MTX). One year later, this patient is still alive and no signs of recurrence have
      been detected. CONCLUSION: When malignant fibrous histiocytoma occurs on the
      scalp it must be treated immediately by means of an excision with a large
      peripheral edge of 2 cm from the visual or CAT limits of the lesion, since the
      first treatment must be definitive.

PMID- 10642054
TI  - Comparative chemical evaluation of two commercially available derivatives of
      hyaluronic acid (hylaform from rooster combs and restylane from streptococcus)
      used for soft tissue augmentation.
AB  - Hyaluronic acid (HA) derivatives have been developed to try to enhance
      rheological properties of this molecule to make it suitable for various medical
      applications. The main dermatological application of HA derivatives is the
      augmentation of soft tissues, via injection into the dermis. HA derivatives are
      indicated for the correction of cutaneous contour deficiencies of the skin,
      particularly in cases of ageing or degenerative lesions or to increase lips. Two
      HA derivatives have been evaluated: Hylaform Viscoelastic Gel (Hylan B), derived
      from rooster combs and subjected to cross-linking, and Restylane, produced
      through bacterial fermentation (streptococci) and stabilized, as declared by the
      producer. In both cases the purpose is to improve HA theological characteristics
      and slow down its degradation once it is in contact with biological structures.
      Distribution of particle dimensions, pH, protein concentration and rheological
      properties have been investigated in order to evaluate their reliability as
      fillers for soft tissue augmentation. The results of the analyses showed that
      there are differences between Restylane and Hylaform. Especially as far as
      rheological characteristics are concerned, the results outline different
      structures of the products: Hylaform behaves as a strong hydrogel, Restylane as a
      weak hydrogel; rheologically Hylaform is clearly superior to Restylane. Hylaform
      contains a definitely minor quantity (about a quarter) of cross-linked hyaluronic
      acid than Restylane. Furthermore, although not declared by the manufacturer,
      Restylane contains protein, resulting from bacterial fermentation or added to
      enable cross-linking reaction; the quantity of proteins contained by Restylane
      can be as much as four times the quantity contained by Hylaform, for the same
      volume (1 ml). It is evident that Hylaform offers higher safety margin than
      Restylane. Furthermore, wide literature and 20 years of clinical experience on
      hyaluronan derived from rooster combs confirm the reliability of this derivative
      while we did not find evidence regarding about the safety of HA obtained from
      streptococcus.

PMID- 10642055
TI  - Simultaneous occurrence of multiple melanoma in situ on sun-damaged skin (lentigo
      maligna), solar lentigo and labial melanosis: the value of dermoscopy in
      diagnosis.
AB  - We report on a patient developing simultaneous occurrence of lentigo maligna
      lesions, solar lentigines and an extensive melanosis of the oral mucosa.
      Diagnostically, epiluminescence microscopy had a relevant role in the
      preoperative assessment and selection of suspicious pigmented lesions, as the
      lesions histologically labelled as lentigo maligna and solar lentigo were
      clinically indistinguishable. We review the clinical, dermoscopic and
      histopathologic differential diagnosis of solar lentigo, malignant lentigo and
      mucosal melanosis with other melanocytic and keratinocytic lesions and discuss
      the possible relationship between these entities.

PMID- 10642056
TI  - Squamous cell carcinoma secondary to recessive dystrophic epidermolysis bullosa:
      report of eight tumours in four patients.
AB  - BACKGROUND: The development of squamous cell carcinomas is the main cause of
      death of patients with Dystrophic epidermolysis bullosa. We think it is of
      interest to know their clinical characteristics and the treatment difficulties
      they cause. METHODS: We followed the clinical evolutions and carried out
      histopathological studies of eight primary cutaneous squamous cell carcinomas on
      three males and one female with recessive dystrophic epidermolysis bullosa.
      Patient ages ranged from 16 to 34 years (mean 27). RESULTS: Two patients had two
      tumours and one three, all were in characteristically scarred skin; four on upper
      limbs; four on lower. Maximum tumour dimensions ranged from 2 to 28 cm (mean 13),
      and represented 6 or more months of evolution. In three cases the affected limb
      must be amputated. Five tumours were well differentiated, three were moderately
      differentiated. CONCLUSIONS: The patients consulted too late and their large
      lesions needed aggressive treatment. Appropriate information and regular
      examination of patients with RDEB helps early diagnosis of tumours and may avoid
      disabling operations.

PMID- 10642057
TI  - L-carnitine supplementation in patients with cystic acne on isotretinoin therapy.
AB  - BACKGROUND: Patients with cystic acne (CA) on Isotretinoin (Iso) therapy might
      present muscular symptoms as side effect of the drug. Myalgia, weakness,
      hypotension are also some of the main characteristics of carnitine (car)
      deficiency. METHODS: Two hundred and thirty (N = 230) patients with CA were
      treated with Isotretinoin (0.5 mg/kg per 24 h). All the patients were requested
      to visit our out-patient department at the onset of muscular symptoms. Laboratory
      tests including car (total, free, acylcarnitine) were determined in blood and
      urine before treatment, at the onset of muscular symptoms and after the end of a
      45 day study. Fifty percent of the patients with muscular involvement received L
      carnitine (100 mg/kg per 24 h per os) (group C) and 50% placebo (group P).
      RESULTS: Their laboratory tests showed the well known increases of their liver
      enzymes and lipids, whereas car blood levels were remarkably decreased at the
      onset of their muscular symptoms and or at the end of the study. Their
      supplementation with L-car, in patients of group C (N = 20) without Iso
      discontinuation or reduction, resulted in the disappearance of their muscular
      symptoms within 5-6 days and normalisation not only of the increased levels of
      their liver enzymes but also those of car, at the 45 day of their therapy.
      Additionally, the patients who received placebo (group P, N = 20) continued
      complaining for mualgias. The rest of the patients (group A, N = 190) did not
      experience any muscular symptoms, their laboratory tests showed elevation of
      liver enzymes and lipids and a decrease in car levels in the blood whereas a
      remarkable increase of car excretion was determined in their urine. CONCLUSIONS:
      Iso therapy decreases car blood levels in patients with CA. L-car supplementation
      might treat liver and muscular side effects of the drug. These hopeful
      preliminary results need further investigation.

PMID- 10642058
TI  - Congenital non-familial unilateral basaloid follicular hamartoma.
AB  - Basaloid follicular hamartoma is not a well-recognized clinical entity and has
      often been diagnosed as trichoepithelioma or basal cell carcinoma. It is a unique
      benign follicular tumour which comprises a variety of clinical manifestations. We
      present the case of a 24-year-old male with unilateral basaloid follicular
      hamartoma present at birth and later misdiagnosed as basal cell carcinoma.
      Histological features of basaloid follicular hamartoma are not always diagnostic
      and clinico-pathological correlation is particularly important to distinguish
      this benign hamartoma from other basaloid tumours including basal cell carcinoma.
      Continuous follow-up of our patient did not reveal any clinical or histological
      malignant transformation.

PMID- 10642059
TI  - Treatment of cutaneous leishmaniasis with 20% paromomycin ointment.
AB  - Cutaneous leishmaniasis is an infectious disease caused by flagellate protozoa of
      the genus Leishmania. In Mediterranean countries, the most common causative
      agents are Leishmania (L.) major, L. infantum and L. tropica. In Croatia,
      cutaneous leishmaniasis is a rare disease, the last case being reported in 1988.
      Our patient was a 5-year-old boy with a left cheek skin lesion in the form of
      papule with central exulceration, hyperkeratotic crust and erythema of a 6-month
      duration. The diagnosis of cutaneous leishmaniasis was based on history data
      (stay in the southernmost region of Croatia and multiple mosquito bites), light
      microscopic histology (dense infiltrates of large histiocytes with extracellular
      bodies), and positive Montenegro (leishmanin) test. A new therapy with
      aminosidine (paromomycin), an aminoglycoside antibiotic, in the form of ointment
      at a concentration of 20%, was for the first time used in Croatia. Four-week
      therapy resulted in complete regression of the skin lesions with residual
      hyperpigmentation. During therapy, no local or systemic side effects were
      observed. Thus, topical therapy with paromomycin could be considered an efficient
      therapeutic alternative in the management of cutaneous leishmaniasis.

PMID- 10642060
TI  - Nevoid hyperkeratosis of the nipple and areola: treatment with topical retinoic
      acid.
AB  - Nevoid hyperkeratosis of the nipple and areola is a rare dermatosis with unknown
      etiology, (Perez-Izquierdo JM, Vilata JJ, Sanchez JL, et al. Retinoic acid
      treatment of nipple hyperkeratosis. Arch Dermatol 1990;126:687-688). Only 40
      cases have been reported until 1997 (Alpsoy E, Yilmaz E, Aykol A. Hyperkeratosis
      of the nipple: report of two cases. J Dermatol 1997;24:43-45). The disease has a
      benign course and may only be a cosmetic problem. Different modalities have been
      used in the treatment of NHNA. In our case treatment with topical retinoic acid
      induced an acceptable response.

PMID- 10642061
TI  - Atypical herpes simplex can mimic a flare of disease activity in patients with
      pemphigus vulgaris.
AB  - We present a 69-year-old white woman with pemphigus vulgaris limited to the oral
      mucosa who presented with oral pain and difficulty swallowing of 2 days duration,
      followed by multiple irregular ulcers arising from normal mucosa with no grouping
      of individual lesions--herpes simplex should be considered in the differential
      diagnosis of lesions that appear suddenly in patients with PV, particularly if
      the lesions fail to respond to an increased dose of corticosteroids.

PMID- 10642062
TI  - Metastatic ulcerative penile Crohn's disease.
AB  - Metastatic Crohn's disease (MCD) is a cutaneous granulomatous reaction which
      affects patients with bowel disease in areas of the skin distant from the
      affected bowel. Penile involvement is a very uncommon observation. We report a
      case of penile ulcerative MCD in a 37-year-old man, which requested surgical
      management. The lesion developed during reactivation of the bowel disease.

PMID- 10642063
TI  - Gabapentin treatment for brachioradial pruritus.

PMID- 10642064
TI  - Allergic contact dermititis from a wet suit.

PMID- 10642065
TI  - Mediterranean spotted fever: a case report.

PMID- 10642066
TI  - Spirometric indices and the risk of pulmonary barotrauma in submarine escape
      training.
AB  - Between 1975 and 1997, a total of 115,090 ascents, from depths of between 9 and
      28 m, have been made by trainees at the submarine escape training tank HMS
      Dolphin. During this 22-yr period, 53 incidents have occurred in which, after an
      ascent, the trainee required hospital or recompression therapy or both. Scrutiny
      of the incident records revealed unequivocal evidence of pulmonary barotrauma in
      six incidents with an additional four in which, despite a negligible gas burden,
      a confident diagnosis of acute neurologic decompression illness with short
      latency could be made. No causative mechanism other than arterial gas embolism
      following pulmonary barotrauma can be implicated in these four cases despite the
      absence of clinical or radiographic evidence of lung injury. In all 10 cases the
      forced vital capacity (FVC) of the trainees was less than the predicted value for
      their age and height, revealing a statistically significant (P< 0.01) association
      between values of FVC below predicted and pulmonary barotrauma. The median FEV1
      for the 10 cases was also significantly (P < 0.05) less than the predicted value
      after allowing for age and height. No such association was found for the FEV1:FVC
      ratio. FVC would thus seem to be the measure of lung function most closely
      associated with increased risk of pulmonary barotrauma. Possible reasons for this
      finding are discussed. It is concluded that although the association between low
      FVC and pulmonary barotrauma is statistically significant, it is insufficiently
      specific for low FVC to serve as an exclusion criterion for submarine escape
      training.

PMID- 10642067
TI  - Effects of hyperbaric oxygen on aerobic performance in a normobaric environment.
AB  - The purpose was to examine the acute effects of a hyperbaric oxygen (HBO2)
      treatment on a) recovery following prolonged exercise and b) aerobic performance
      in a trained population. Subjects were six male and six female, trained runners
      with mean Vo2max values of 64.6 +/- 5.6 and 51.9 +/- 6.6 ml x kg(-1) x min(-1),
      respectively. Subjects performed four exercise-HBO2 conditions in random order:
      a) control, b) exercise-no HBO2, c) no exercise-HBO2; and d) exercise-HBO2.
      Exercise was a 90-min run at 75-80% of Vo2max x HBO2 treatments consisted of
      breathing 95% O2 at 2.5 atm abs for 90 min. At the end of each condition, aerobic
      performance was assessed with a VO2max test and by the oxygen cost of running on
      a treadmill at three submaximal velocities. Recovery was not enhanced following a
      single HBO2 treatment at 2.5 atm abs for 90 min, nor did it alter submaximal or
      maximal running performance.

PMID- 10642068
TI  - Hyperbaric oxygen treatment and pulmonary function.
AB  - Hyperbaric oxygen (HBO2) treatment exposes the lungs to the potentially toxic
      effect of free oxygen radicals and may lead to impairment of pulmonary function.
      HBO2 significantly improves wound healing in patients with osteoradionecrosis of
      the mandible following radiation therapy for intraoral cancer. In 18 consecutive
      patients with osteoradionecrosis of the mandible, pulmonary function was assessed
      during 6 wk of HBO2 treatment, applied daily in a monoplace chamber for 90 min
      and at a partial oxygen pressure of 2.4 atm abs. Pretreatment forced vital
      capacity (FVC) was 104 +/- 14% (mean +/- SD) of a reference population, the 1 s
      forced expiratory volume (FEV1) 95 +/- 20%, total lung capacity (TLC) 100 +/-
      13%, and the carbon monoxide diffusing capacity (DL(CO)) 81 +/- 17% (P < 0.05,
      compared to reference population). These parameters remained unchanged throughout
      the treatment period (after 6 wk and expressed relative to the percentage of the
      expected value at baseline): deltaFVC: +4 +/- 8%; deltaFEV1: -2 +/- 4%; deltaTLC:
      +2 +/- 5%; deltaDL(CO): 0 +/- 9%; deltaRV 0 +/- 11%. It is concluded that
      intermittent HBO2 treatment in a monoplace chamber has no persistent effect on
      pulmonary function and can be offered even to patients with a reduced diffusing
      capacity.

PMID- 10642069
TI  - Voluntary breath holding affects spontaneous brain activity measured by
      magnetoencephalography.
AB  - Spontaneous brain activity was measured by multichannel magnetoencephalography
      (MEG) during voluntary breath holds. Significant changes in the activity are
      limited to the alpha rhythm: 0.25 Hz frequency increase and narrowing of the
      peak. The area of alpha activity shifts slightly toward (fronto-) temporal. The
      topography of other rhythms is unaffected by breath holding.
      Electroencephalographic (EEG; 36 channels maximal) recordings generally made
      simultaneously with the MEG recordings show similar effects. However, EEG was
      inadequate to reveal the small topographic differences. Systemic hypercapnia
      caused by a long breath hold is unlikely to play an important role in producing
      the observed effects.

PMID- 10642070
TI  - Effects of hyperbaric oxygen therapy on children with spastic diplegic cerebral
      palsy: a pilot project.
AB  - Hyperbaric oxygen (HBO2) therapy for children with cerebral palsy (CP) is not
      new. Research documenting the effects in this population has been anecdotal. We
      evaluated the effects of HBO2 therapy for 25 children (X = 5.6 +/- 1.6 yr) with a
      functional diagnosis of spastic diplegic CP. Pre- and post-HBO2 evaluations
      consisted of the following measures: gross motor function measure (GMFM), fine
      motor function (Jebsen test for hand function), spasticity (modified Ashworth
      scale), video analysis, and parental questionnaire. The protocol for HBO2 therapy
      was 20 treatments of 95% oxygen at 1.75 atm abs for 60 min. The Wilcoxon matched
      pairs signed-rank test for non-parametric measures was used to compare pre- and
      post-treatment data. Results showed improved gross motor function in three of the
      five items in the GMFM test, improved fine motor function in three of the six
      hand tests, reduced spasticity in three of four muscle groups when assessed by a
      physician specializing in CP, and improvements for four of nine questions posed
      to parents.

PMID- 10642071
TI  - Risk factors for symptomatic otic and sinus barotrauma in a multiplace hyperbaric
      chamber.
AB  - This retrospective study examines the relationship of multiplace chamber
      compression rates and the influence of several predisposing factors on the risk
      of symptomatic barotrauma. Data were reviewed from a 3-yr period for 111 patients
      who received 2,394 routine hyperbaric oxygen treatments. A total of 35 patients
      reported symptoms of barotrauma, with an overall rate of 3.05 cases per 100
      treatments. Most symptoms occurred during a patient's initial three treatments
      and with minimal increased pressure. The most frequently affected area was the
      ears (95%) with objective findings noted in 18% of patients reporting fullness
      compared to 39% of patients reporting pain. Referral diagnosis was not related to
      the incidence of barotrauma. Although the overall risk of symptomatic barotrauma
      increased as the compression rate increased, it was not significant (RR = 1.57,
      CI0.95 = 0.65, 3.80). Female patients were at significantly increased risk (RR =
      2.14, CI0.95 = 1.37, 3.34) compared to males, and patients less than age 40 were
      at higher risk than those age 40 and older (RR = 3.00, CI0.95 = 1.80, 5.03). Well
      designed prospective studies are needed to more clearly define risk factors and
      identify compression rates with the least risk of barotrauma.

PMID- 10642072
TI  - Effect of anti-C5a antibody on blood-lung and blood-brain barrier in rabbits
      after decompression.
AB  - The complement activation product C5a may be an important mediator of tissue
      injury after decompression stress. This study investigated whether the
      administration of anti-C5a antibody may reduce changes after decompression in the
      lung and in the brain. Two groups of rabbits were used; one receiving anti-C5a
      monoclonal antibody (n = 7) and the other receiving a sham antibody as control (n
      = 7) before pressure exposure. Five rabbits (4 in the anti-C5a group and 1 in the
      control group) died during the 2-h observation period postdive due to massive
      bubbling. Polymorphonuclear leukocyte (PMN) infiltration of lung tissue and
      pulmonary edema was observed, but this accumulation was unaffected by anti-C5a
      pretreatment. However, a significant positive correlation was observed between
      PMN accumulation and survival time postdive. Brain-specific gravity was lower for
      the group treated with anti-C5a antibody compared to the control group. Further,
      it was lower for those rabbits that died early compared to the ones that survived
      the 2-h period. This study was unable to prove a protective effect on the blood
      brain and blood-lung barrier by injecting anti-C5a antibody. A possible
      beneficial effect of anti-C5a antibody may be masked by the mechanical damage
      caused by the gas bubbles.

PMID- 10642073
TI  - Infraorbital hypesthesia after maxillary sinus barotrauma.
AB  - We report a case of a diver who suffered an episode of maxillary sinus barotrauma
      that presented with decreased sensation over the cutaneous distribution of the
      infraorbital nerve after an ascent which produced facial pain and crepitus. This
      case illustrates a potential confusion between a decompression sickness etiology
      and a barotraumatic etiology for the observed sensory deficit. The clinical
      features of this case were most consistent with a barotraumatic etiology for the
      findings noted. The anatomy of the trigeminal nerve and previous reports of
      cranial nerve deficits following barotrauma are reviewed.

PMID- 10642074
TI  - Noise-induced neurologic disturbances in divers exposed to intense water-borne
      sound: two case reports.
AB  - Divers may be exposed to intense noise underwater. Two cases of neurologic
      disturbances during experimental exposures to 15 min of continuous underwater
      sound are described. Sound exposure in the first case consisted of a warble tone
      with center frequency of 240 Hz and a sound pressure level of 160 dB re 1
      microPa. Symptoms during exposure consisted of somnolence, lightheadedness, and
      an inability to concentrate. No apparent effect on hearing was noted. In the
      second case, a center frequency of 1,000 Hz at 181 dB was used. Lightheadedness,
      inability to concentrate, agitation, and head vibrations were noted during the
      exposure. The diver also exhibited a temporary auditory threshold shift of 19.2
      dB. In both cases, overt symptoms resolved within 30 min after exposure, but both
      divers reported recurrent symptoms days to weeks after the exposures. Medical
      histories and examinations, assessment of dive profiles, and breathing gas
      analysis failed to support a source other than the sound exposures to account for
      the symptoms observed. Potential mechanisms for the described symptoms are
      discussed.

PMID- 10642075
TI  - Hyperbaric oxygen: a plea for uniform nomenclature.

PMID- 10642076
TI  - Perioperative nutrition.

PMID- 10642077
TI  - Total parenteral nutrition and enteral nutrition in diabetes.
AB  - A quarter or more of critically ill patients are likely to have carbohydrate
      intolerance or frank diabetes, either pre-existing or secondary to the stress of
      illness. Those patients who require parenteral nutrition should be treated using
      regimens similar to those used in nondiabetic patients, along with sufficient
      insulin (given by separate infusion) to maintain near-normal glycaemia. The role
      of novel substrates in diabetes remains to be established. In patients who
      require enteral nutrition, there is accumulating evidence that high-fat (as
      monounsaturated fatty acid) formulations achieve better overall metabolic control
      than conventional high-carbohydrate preparations. In view of the fact that
      macrovascular disease is the major cause of morbidity and mortality in type 2
      diabetes in particular, and the fact that the risk of macrovascular complications
      is relatively unaffected by glycaemic control, the improved lipid and haemostatic
      profile achieved with preparations that are high in monounsaturated fatty acids
      is of particular importance in patients on long-term nutritional support.

PMID- 10642078
TI  - Enteral nutrition in the patient with diabetes mellitus.
AB  - Diabetes mellitus is a serious and fairly common metabolic disorder that affects
      carbohydrate, protein and fat metabolism. Indications for nutritional support are
      no different for patients with diabetes than in any other patient group. The
      setting may be recovery from surgery or trauma and transition to solid food is
      anticipated, or, as a result of permanent injury or stroke, enteral feeding may
      be the permanent manner of nutrition delivery. Attention must be given to the
      selection of a macronutrient intake that will optimize blood glucose and lipid
      control. It is vital that blood glucose concentration be carefully monitored and
      that over- and underfeeding be avoided.

PMID- 10642079
TI  - Nutritional and metabolic aspects of pancreatic cancer.
AB  - Most patients with pancreatic cancer suffer from a variety of severe metabolic
      and nutritional disturbances. Despite this fact, the role of perioperative
      nutritional support for these patients remains controversial. This review
      highlights the results of randomized prospective clinical trials, and meta
      analyses that have addressed this issue. The 'current opinion' put forth in this
      discussion is based on these reviews, and on personal observations in treating
      more than 500 patients.

PMID- 10642080
TI  - Ethical and legal considerations in the provision of nutritional support to the
      perioperative patient.
AB  - Despite the extensive current literature on ethics, very few publications have
      specifically addressed the ethical issues surrounding the provision of nutrition
      to perioperative patients. Four publications are particularly relevant and highly
      recommended [1-4]. This review is an attempt to draw attention to those ethical
      issues that are relevant to the use of nutritional support in the perioperative
      patient and offer guidance on appropriate action by clinicians. Emphasis is on
      adult patients rather than children and not on the issues that surround the
      terminally ill patient. General principles are discussed first and then the
      application of these principles.

PMID- 10642081
TI  - New concepts on nutritional management of severe malnutrition: the role of
      protein.
AB  - Current guidelines for the management of severe malnutrition are mainly based on
      new concepts regarding the causes of malnutrition and on advances in our
      knowledge of the physiological roles of micronutrients. In contrast to the early
      'protein dogma', there is a growing body of evidence that severely malnourished
      children are unable to tolerate large amounts of dietary protein during the
      initial phase of treatment. Similarly, great caution must be exercised to avoid
      excessive supply of iron and sodium in the diet, while keeping energy intake at
      maintenance levels during early treatment. Because severely malnourished children
      require special micronutrients, a mineral-vitamin mix is added to the milk-based
      formula diets, which are specially designed for the initial treatment and the
      rehabilitation phase. To further improve nutritional rehabilitation and reduce
      cases of relapse, 'ready-to-use therapeutic food' and 'ready-to-eat nutritious
      supplements' with relatively low protein (10% protein calories) and high fat
      content (54-59% lipidic calories) have been developed. Although current dietary
      recommendations do not differentiate between oedematous and nonoedematous forms
      of malnutrition or between adults and children, there are indications that
      further clarification is still needed for applying dietary measures for specific
      target groups.

PMID- 10642082
TI  - The effect of age on protein metabolism.
AB  - The mechanisms of senescence remain to be fully defined. This review focuses on
      recent advances in our understanding of body protein turnover, which is essential
      for the remodeling of tissues and production of specific proteins in time of
      need. Recent advances in technology make it possible to measure the synthesis
      rate of muscle myosin heavy chain, mitochondrial proteins and sarcoplasmic
      proteins, providing insight into the mechanisms of the sarcopenia of aging. A
      reduced synthesis rate of myosin heavy chain and mitochondrial protein may
      explain muscle weakness and fatiguability that occurs with aging. Aging also
      seems to affect selected liver proteins such as fibrinogen. The potential roles
      of exercise and hormone replacement in slowing the age-related decline in protein
      turnover is discussed.

PMID- 10642083
TI  - Protein metabolism and the gut.
AB  - This paper reviews the recent literature concerning the importance of the gut in
      extraintestinal protein metabolism. A growing body of evidence suggests that the
      gut modulates amino acid flux and inter-organ relationships in various metabolic
      states. This may be particularly true during the absorptive period, when the gut:
      (1) controls amino acid absorption; (2) may modulate catabolism and uptake for
      synthesis of absorbed amino acid; and (3) consequently influences the
      availability of liver and extrasplanchnic amino acids, as well as their pattern
      and kinetics through portal flow delivery.

PMID- 10642084
TI  - Interorgan amino acid exchange.
AB  - This review is concerned with the status of our current research related to the
      exchange of amino acids across organs. Accumulation of knowledge regarding how
      amino acid pools are maintained within the body remains a work in progress. In
      recent years, the use of organ balance measurement techniques in combination with
      isotopic tracers has much increased our understanding of the role of the kidney
      and splanchnic organs in amino acid metabolism, and in kidney and liver
      gluconeogenesis from amino acids. An interorgan cooperation between the kidney
      and splanchnic organs for leucine-ketoisocaproate metabolism has also been
      demonstrated.

PMID- 10642085
TI  - Arginine nutrition in development, health and disease.
AB  - As a precursor of nitric oxide, polyamines and other molecules with enormous
      biologic importance, L-arginine plays versatile key roles in nutrition and
      metabolism. Arginine is an essential amino acid in the fetus and neonate, and is
      conditionally an essential nutrient for adults, particularly in certain disease
      conditions. L-Arginine administration is beneficial in improving reproductive,
      cardiovascular, pulmonary, renal, gastrointestinal, liver and immune functions,
      and in facilitating wound healing. The effect of L-arginine in treating many
      common health problems is unique among amino acids, and offers great promise for
      improved health and well-being in the future.

PMID- 10642087
TI  - Bibliography. Current world literature. Perioperative nutrition.

PMID- 10642088
TI  - Bibliography. Current world literature. Protein metabolism and therapy.

PMID- 10642086
TI  - Effects of insulin on muscle tissue.
AB  - The anabolic nature of insulin on muscle protein has been recognized since the
      initial clinical use of insulin therapy in type 1 diabetes about sixty years ago,
      but the exact mechanism whereby insulin effects muscle protein metabolism in
      human subjects remains unclear. In particular, the effect of insulin on muscle
      protein synthesis has been debated. In vitro studies document a stimulatory
      effect of insulin on muscle protein synthesis, but in vivo results are
      conflicting. Everything from decreased muscle protein synthesis to increased
      muscle protein synthesis in response to insulin has been reported. A recent
      publication suggests that the response of muscle protein synthesis to insulin is
      dose dependent, and that only supraphysiological dose of insulin stimulate muscle
      protein synthesis. On the other hand, some studies show a stimulatory effect of
      insulin in low doses. It is possible to form a more coherent picture of the
      effect of insulin if the results from various experiments are expressed in the
      context of the availability of amino acids. In general, insulin stimulated muscle
      protein synthesis in studies in which intramuscular amino acid availability was
      maintained or increased regardless of the dose of insulin. In contrast, insulin
      was ineffective in stimulating muscle protein synthesis when amino acid
      availability was allowed to drop, irrespective of the dose of insulin. Thus,
      whereas insulin has a potential stimulatory effect on human muscle protein
      synthesis, an adequate availability of amino acids is required for that potential
      to be expressed in an actual increase in the synthetic rate.

PMID- 10642089
TI  - Neurotrophin-3 reverses nerve conduction velocity deficits in streptozotocin
      diabetic rats.
AB  - The ability of neurotrophin-3 (NT-3) to reverse established nerve disorders was
      investigated in the peripheral neuraxis of streptozotocin-diabetic rats. Sciatic
      sensory and motor nerve conduction velocity deficits established after 2 months
      of diabetes were completely normalized by one further month of treatment with
      either NT-3 or insulin. None of these conduction velocity changes were associated
      with altered mean axonal caliber in the sciatic nerve. In the dorsal and ventral
      roots, mean axonal caliber was significantly decreased after 8 weeks of diabetes
      (both P < 0.05). Subsequently, one month of insulin, but not NT-3, treatment
      increased mean axonal caliber to age-matched control values. NT-3 treatment was
      also without effect on the significant (both P < 0.05) decrease in phosphorylated
      heavy neurofilament (NFH) subunits seen in dorsal and ventral roots of 12 week
      diabetic rats. In the sural nerve, diabetes attenuated a maturation-associated
      increase in mean axonal caliber over the first 8 weeks of diabetes, and induced
      atrophy between weeks 8 and 12 that was ameliorated by both NT-3 and insulin
      treatment. Reductions in sural nerve axonal caliber were associated with a
      tendency for elevation of both phosphorylated NFH levels in large fibers and the
      ratio of phosphorylated to nonphosphorylated NFH that was attenuated by NT-3.
      These data demonstrate that NT-3 corrects established sciatic nerve conduction
      deficits in diabetic rats in a manner independent of changes in axonal caliber in
      this nerve. Further, although NT-3 was without effect on decreases in axonal
      caliber and NFH subunit phosphorylation in the spinal roots, reversal of axonal
      caliber deficits in peripheral nerves of sensory fibers may involve NT-3-mediated
      normalization of aberrant neurofilament phosphorylation.

PMID- 10642090
TI  - Rat dorsal root ganglia express m1-m4 muscarinic receptor proteins.
AB  - The distribution of m1-m4 muscarinic acetylcholine receptors was investigated by
      immunolight and electron microscopy in rat dorsal root ganglia, by using subtype
      specific antibodies. The light microscopic observations show that both the
      intensity and the localisation of immunolabeling of the four muscarinic subtypes
      are different. The m2 receptor is the most represented; m2 and m4 receptor
      proteins are principally expressed in the small-medium type neurones, while m1
      and m3 receptor proteins are more homogeneously distributed among the neuronal
      population of the ganglion. On the contrary, there are no relevant differences in
      the subcellular distribution. Ultrastructural analysis shows that immunolabeling
      is associated with the Nissl bodies, budding Golgi cisterns, and as far as the m2
      receptor is concerned, just beneath the plasmalemma with discrete loci along the
      neuronal plasma membrane. Unmyelinated nerve fibres are always immunopositive for
      all muscarinic receptor subtypes, suggesting an active transport for all
      subtypes. Occasionally perineuronal satellite cells surrounding large neurones
      are immunopositive for the m2 receptor, while both myelinating and non
      myelinating Schwann cells faintly express all muscarinic receptor subtypes. These
      observations, together with previous data concerning pharmacological and
      functional characterisation of muscarinic acetylcholine receptors in dorsal root
      ganglion, suggest that sensory neurones are able to respond to acetylcholine. The
      presence of m2 and m4 immunoreactivity in the small type neurones and in their
      fibres involved in nociceptive response, suggest that these receptors may
      participate in the modulation of transduction of noxious stimuli from the
      periphery to the spinal cord. m1 and m3 receptors, having a more homogeneously
      distribution, may be involved in transduction of different kinds of stimuli.

PMID- 10642091
TI  - Classification of teased nerve fibers for multicenter clinical trials.
AB  - Teased nerve fibers are used widely in both clinical and experimental
      neuropathology, but anecdotal evidence indicates that even experienced readers
      find little agreement on categories for teased fiber classification. To develop a
      classification scheme that could be used and understood by both experienced and
      naive readers, specific criteria were developed for normal fibers and those
      exhibiting Wallerian degeneration, demyelination, hypomyelination, remyelination,
      and abnormal paranodal myelination. Twenty fibers teased from human sural nerve
      biopsies were selected as examples of one or more of these categories. Ten
      readers, including seven having no previous experience with teased fibers, were
      given a set of instructions and asked to score each fiber for all matching
      categories. These readers averaged high rates of true positive (56-85%)
      classifications, while average false positive (3-18%) rates were much lower.
      Among the three experienced readers, true positive agreements averaged between 75
      and 100% across the fiber classifications. False positives were correspondingly
      low, ranging between 0 and 8%. These results suggest that it is possible to
      design an easily learned, meaningful scheme for classifying teased nerve fibers.

PMID- 10642092
TI  - Lumbar transplant of neurons genetically modified to secrete galanin reverse pain
      like behaviors after partial sciatic nerve injury.
AB  - The use of cell lines as biologic "minipumps" to chronically deliver
      antinociceptive molecules such as the peptide galanin near the pain processing
      centers of the spinal cord after nerve injury is a newly developing technology
      for the treatment of neuropathic pain. The neuronal rat cell line, RN33B, derived
      from E13 brainstem raphe and immortalized with the SV40 temperature-sensitive
      allele of large T antigen (tsTag), was transfected with rat preprogalanin (GAL)
      cDNA and the galanin-synthesizing and -secreting cell line, 33GAL.19, was
      isolated [1]. The 33GAL.19 cells transfected with the GAL gene expressed
      immunoreactivity (ir) for the GAL protein and synthesized low levels of GAL-ir at
      permissive temperature (33 degrees C), when the cells were proliferating, and
      increased GAL-ir during terminal differentiation at non-permissive temperature
      (39 degrees C) in vitro. A control cell line, 33V.1, RN33B cells transfected with
      the pCEP4 vector alone and similarly isolated by subcloning, contained no
      detectible GAL-ir at either temperature in vitro. These cell lines were used as
      grafts in a model of chronic neuropathic pain induced by unilateral chronic
      constriction injury (CCI) of the sciatic nerve. Pain-related behaviors, including
      cold and tactile allodynia and thermal and mechanical hyperalgesia, were
      evaluated in the affected hindpaw after CCI and transplants. The 33GAL.19 and
      33V.1 cells transplanted in the lumbar subarachnoid space near the spinal cord
      one week after CCI, survived at least seven weeks on the pial surface around the
      spinal cord and only the 33GAL.19 cells expressed GAL-ir in vivo after
      transplant. Furthermore, the tactile and cold allodynia and tactile and thermal
      hyperalgesia induced by CCI was significantly reduced or eliminated during the
      two to seven week period after grafts of 33GAL.19 cells. The maximal effect on
      chronic pain behaviors with the GAL grafts occurred one to three weeks after
      transplantation. Transplants of 33V.1 control cells had no effect on the
      allodynia and hyperalgesia induced by CCI. These data suggest that a chronically
      applied, low local dose of galanin supplied by transplanted cells near the lumbar
      spinal dorsal horn was able to reverse the development of chronic neuropathic
      pain following CCI. The use of transplants of genetically modified neural cell
      lines that are able to deliver antinociceptive molecules, such as galanin, offers
      a safe and novel approach to pain management.

PMID- 10642093
TI  - A comparison of assessments of functional recovery in the rat.
AB  - Assessment of functional recovery following any peripheral nerve manipulation is
      critical. While quantitative neurobehavioral testing has been developed in the
      anesthesia literature for the assessment of neural function, the surgical
      literature relies mainly on walking track analysis for evaluation of motor
      recovery. The latter method is both cumbersome to perform and difficult to
      quantify. We compared standard walking track analysis with the quantitative
      neurobehavioral tests recently developed for anesthetic testing. We found a close
      correlation between the recovery predicted by walking track analysis and that
      suggested by neurobehavioral testing. In addition, the neurobehavioral test
      battery offered information regarding the rate of return of pure motor function,
      complex integrated function, proprioceptive function, and sensation. The tests
      are easier to perform and less susceptible to interpretative error.
      Neurobehavioral testing may be an effective substitute for walking track analysis
      in the assessment of functional recovery following manipulation of the rat
      sciatic nerve.

PMID- 10642094
TI  - Glycemic control and not protein kinase C inhibition prevents the early decrease
      of glutathione peroxidase activity in peripheral nerve of diabetic mice.
AB  - Experimental diabetes promotes changes in biochemical activities of peripheral
      nervous tissue. Glutathione peroxidase activity decreases in sciatic nerve of
      diabetic mice very early after onset of experimental diabetes. Effective glycemic
      control with insulin restores the early lost glutathione peroxidase activity in
      peripheral nerve of diabetic mice to control values. Data are also presented
      demonstrating that glutathione peroxidase activity in diabetic mouse peripheral
      nerve is not modified by the constant delivery of calphostin C, a protein kinase
      C inhibitor, therefore this decrease seems to be independent on a protein kinase
      C mediated mechanism. Thus, the early glutathione peroxidase activity decrease in
      peripheral nerve of diabetic mice is closely related to hyperglycemia, and a
      tight glycemic control is rather effective in restoring the control levels of
      this enzymatic activity. The results herein do not rule out the benefits of
      antioxidant adjuvant therapies in diabetes to help recover the overall decrease
      in antioxidant defense in peripheral nerve elicited by the decrease of
      glutathione peroxidase activity.

PMID- 10642095
TI  - Neurokinin-1 receptor expression in dorsal root ganglion neurons of young rats.
AB  - The expression of neurokinin-1 receptors was studied in the fourth lumbar dorsal
      root ganglia of young rats using immunohistochemical and electrophysiological
      techniques. Use of a specific immunoserum raised against the C-terminal fragment
      of rat neurokinin-1 receptor revealed immunoreactivity in 32 +/- 1.5% of dorsal
      root ganglion neurons. The diameter of the majority of the neurokinin-1 receptor
      immunostained neurons was smaller than 30 microm. Double immunohistochemical
      labelling using neurokinin-1 receptor and substance P antibodies revealed that
      about 1/3 of the neurokinin-1 receptor expressing neuron contains substance P.
      Likewise, about 1/3 of the substance P producing DRG cells expressed the
      neurokinin-1 receptor. Superfusion of substance P (1 microM) to an in vitro
      preparation of the fourth lumbar dorsal root ganglion induced a reversible long
      lasting depolarization as measured by extracellular suction electrodes attached
      to the dorsal roots. This response to substance P was only partially antagonized
      by the selective neurokinin-1 receptor antagonist RP 67580 (1 microM).
      Intracellular recordings distinguished between Aalpha/beta-, Adelta- and C-sub
      types of ganglion neurons. Superfusion of substance P (1 microM) evoked
      excitatory responses in Adelta- and C-type neurons. These results demonstrate the
      expression of functional neurokinin-1 receptors on a subpopulation of Adelta- and
      C-type sensory ganglion neurons. Our data suggest the possible physiological
      importance of peripheral neurokinin-1 receptors located on dorsal root ganglion
      neurons.

PMID- 10642096
TI  - Report of the 8th annual symposium of the European Charcot-Marie-Tooth
      Consortium, Antwerpen, Belgium, July 2-4, 1999.

PMID- 10642097
TI  - Quantitative perfusion imaging in carotid artery stenosis using dynamic
      susceptibility contrast-enhanced magnetic resonance imaging.
AB  - Quantitative, multislice dynamic susceptibility contrast-enhanced MRI perfusion
      measurements were used to determine the patterns of cerebral blood flow (CBF),
      cerebral blood volume (CBV), mean transit time (MTT), and normalized first moment
      of the tissue deltaR2-time curve (N) in 11 subjects with carotid artery occlusion
      or stenosis. MTT correlated with degree of carotid stenosis, whereas a range of
      alterations in CBF and CBV were found presumably reflecting variables degrees of
      collateral flow. There was no significant correlation between MRI and SPET flow
      perfusion measurements, with increasing disparity between the two techniques at
      higher inter-hemispheric flow ratios. The effect of obtaining the arterial input
      function (AIF) from the middle cerebral artery (MCA) ipsilateral or contralateral
      to the stenosis was determined. Despite the use of an AIF from the MCA, which is
      distal to the circle of Willis, and hence the major sources of collateral supply,
      there was still some extra dispersion of the contrast agent bolus due to
      differences in arrival time.

PMID- 10642098
TI  - Vessel diameter measurements in gadolinium contrast-enhanced three-dimensional
      MRA of peripheral arteries.
AB  - In this study, the possibilities for quantification of vessel diameters of
      peripheral arteries in gadolinium contrast-enhanced magnetic resonance
      angiography (Gd CE MRA) were evaluated. Absolute vessel diameter measurements
      were assessed objectively and semi-automatically in maximum intensity projections
      (MIPs) of contrast-enhanced T1-weighted 3D spoiled gradient-echo datasets,
      studied with digital subtraction techniques. In vivo, the complete peripheral
      arterial bed of six patients was studied, from the aorto-iliac bifurcation down
      to the distal run-off. By measuring the signal intensity (SI) over the lumen of a
      vessel in the MIP, an SI-plot was obtained. Next, the vessel boundaries were
      determined using a threshold algorithm; from these boundary points individual
      diameter values could be obtained along the trajectory of the vessel. In an in
      vitro study, an optimal threshold value of 30% of the range of SI-values between
      the background and the maximal SI in the vessel was obtained for accurate
      diameter measurement in Gd CE MRA (i.e., full-width 30%-maximum). Furthermore,
      the relationship between the accuracy of these measurements and the scan
      resolution was investigated. Accuracy was found to be acceptable (i.e., less than
      10% over/underestimation) for vessel sizes covering at least 3 pixels. In six
      patients, diameters were measured in MIPs of the total datasets (i.e., D(T)) as
      well as in selective MIPs of the clipped datasets (i.e., D(S)) (n = 209). D(T)
      and D(S) were statistically significantly correlated (p < 0.01) with a Pearson
      correlation coefficient rP = 0.98. Measurements in the total MIPs yielded
      statistically significant (p < 0.01) smaller diameter values compared with
      measurements in selective MIPs, with a mean difference of 0.15 mm. Diameter
      values from the selective MIPs of the aorto-iliac arteries were also compared
      with diameter values measured at corresponding anatomic positions in X-ray
      angiograms of these patients (i.e., D(x)) (n = 70). D(X) and D(S) were
      statistically significantly correlated (p < 0.01) with a Pearson correlation
      coefficient rP = 0.92. Diameters measured in the selective MIPs were smaller than
      those measured in the X-ray angiograms (mean difference 0.49 mm) and this
      difference was statistically significant (p < 0.01). In conclusion, diameter
      values can be evaluated accurately in MIPs of vessels with at least 3 pixels in
      diameter, using the full-width 30%-maximum criterion.

PMID- 10642099
TI  - An amplitude optimized single-shot hybrid QUEST technique.
AB  - Rapid MR imaging techniques either deposit high amounts of radio frequency power
      or require powerful gradient systems with high slew rates, which might not be
      available on conventional scanners. QUEST provides a fast imaging method with
      scan times of the order of hundreds of milliseconds and avoids these problems at
      the cost of low signal-to-noise ratios (SNR). In this work, QUEST was optimized
      with regard to image quality and measuring time. With the use of a Hybrid QUEST
      technique, that refocuses the image echoes several times, a spatial resolution of
      1.9 mm x 1.6 mm x 5 mm was achieved. By acquiring both the necessary correction
      data and the image information in a single echo train, the Hybrid QUEST technique
      was implemented as a true single-shot measurement with a total scan time of 190
      ms. Optimization of the excitation flip angles and the amplitude and phase
      correction methods for image reconstruction resulted in an improved SNR of 53.7
      in the white matter of the human head for a 10 mm slice thickness at 1.5 T. In
      contrast to echo planar imaging techniques, no image distortions were observed
      with Hybrid QUEST in anatomic regions with many tissue interfaces.

PMID- 10642100
TI  - Relationship between cancellous bone induced magnetic field and ultrastructure in
      a rat ovariectomy model.
AB  - The site-dependent variations in trabecular bone morphology were studied in the
      rat tibia by magnitude and phase difference three-dimensional nuclear magnetic
      resonance microscopy and image processing, and the implications of ovariectomy
      were evaluated. Specimens excised from the proximal tibial metaphysis in
      ovariectomized (n = 7) and intact control (n = 4) rats were imaged at 9.4T with
      their anatomic axes parallel to the direction of the magnetic field. An echo
      offset 3D rapid spin-echo excitation pulse sequence was used to generate phase
      difference maps, from which the standard deviation of the phase difference,
      sigma(delta psi), was calculated. In addition, a fictitious rate constant, R2',
      was calculated from the slope of the exponential portion of the Fourier transform
      of the phase difference histogram. Trabecular bone volume fraction was also
      determined in the same volume of interest. The results show strong correlations
      between bone volume fraction and both sigma(delta psi) and R2', suggesting that
      these parameters could be useful for nondestructive assessment of trabecular bone
      volume.

PMID- 10642101
TI  - Measurement of the extracellular volume of human melanoma xenografts by contrast
      enhanced magnetic resonance imaging.
AB  - The magnitude of the extracellular volume fraction (ECV) of tumors is of
      importance for the transport of macromolecular therapeutic agents from the vessel
      wall to the tumor cells. The aim of this study was to develop a method for
      measurement of tumor ECV by contrast enhanced MRI. Tumors of two human amelanotic
      melanoma xenograft lines (A-07 and R-18) grown intradermally in Balb/c nu/nu mice
      were used as model system, and muscle tissue was used as control. The renal
      arteries of the mice were ligated prior to i.v. administration of Gd-DTPA, and an
      MRI protocol for calculating Gd-DTPA concentration in tissue was followed. ECV
      was calculated from the Gd-DTPA concentrations in the tissue and in a plasma
      sample. In muscle tissue, the concentration reached a constant level after 1 min
      and the ECV was calculated to be 0.12 (+/- 0.01), consistent with values reported
      in the literature. Individual tumors showed large differences in the uptake of Gd
      DTPA. The Gd-DTPA concentration in the tissue at 40 min after the Gd-DTPA
      administration was used to calculate tumor ECV. The ECV was found to differ
      significantly among regions of individual tumors and among individual tumors. The
      ECV ranged from 0.075 to 0.33 for A-07 tumors and from 0.016 to 0.097 for R-18
      tumors. The intra- and intertumor heterogeneity in ECV was confirmed by
      histologic findings, showing that contrast enhanced MRI is suitable for non
      invasive studies of the ECV in experimental tumors without necrosis.

PMID- 10642102
TI  - Dealing with the subvoxel vessel position relative to the reconstruction voxel
      grid in 2D MR quantitative flow measurements.
AB  - A method is introduced that quantifies the error in 2D MR Quantitative Flow
      measurements induced by the position of the vessel relative to the reconstruction
      voxel grid, called the subvoxel vessel position. In this method, the vessel area
      and the volume flow rate are determined for all possible subvoxel vessel
      positions resulting in a mean value with standard deviation. Since the subvoxel
      vessel position in standard MR image reconstruction is completely arbitrary, the
      standard deviation can be considered as a measure of its random error
      contribution. Simulation studies and in vivo measurements show that our method
      can be used to quantify and subsequently eliminate this random error. It is
      further quantitatively shown that, for low noise levels, Fourier interpolation to
      a higher reconstruction matrix also decreases the random error. We conclude that
      the precision of a 2D MR Quantitative Flow measurement is improved either by
      using our method or by reconstruction to a higher matrix.

PMID- 10642103
TI  - Complex denoising of MR data via wavelet analysis: application for functional
      MRI.
AB  - A fast post-processing method for noise reduction of MR images, termed complex
      denoising, is presented. The method is based on shrinking noisy discrete wavelet
      transform coefficients via thresholding, and it can be used for any MRI data-set
      with no need for high power computers. Unlike previous wavelet application to MR
      images, the denoising algorithm is applied, separately, to the two orthogonal
      sets of the complex MR image. The norm of the combined data are used to construct
      the image. With this method, signal-noise decoupling and Gaussian white noise
      assumptions used in the wavelet noise suppression scheme, are better fulfilled.
      The performance of the method is tested by carrying out a qualitative and
      quantitative comparison of a single-average image, complex-denoised image,
      multiple-average images, and a magnitude-denoised image, of a standard phantom.
      The comparison shows that the complex-denoising scheme improves the signal-to
      noise and contrast-to-noise ratios more than the magnitude-denoising scheme,
      particularly in low SNR regions. To demonstrate the method strength, it is
      applied to fMRI data of somatosensory rat stimulation. It is shown that the
      activation area in a cross-correlation analysis is approximately 63% larger in
      the complex-denoised versus original data sets when equal threshold value is
      used. Application of the method of Principal Component Analysis to the complex
      denoised, magnitude-denoised, and original data sets results in a similar but
      higher variance of the first few principal components obtained from the former
      data set as compared to those obtained from the later two sets.

PMID- 10642104
TI  - MRI phase mapping of temperature distributions induced in food by microwave
      heating.
AB  - A range of temperature-sensitive MRI parameters of water (T2, T1, diffusion
      coefficient, and chemical shift) were evaluated to map in three dimensions the
      non-uniform temperature distributions induced by microwave heating in both model
      and real food systems. Phase mapping was found to be the most robust method, and
      evaluations of possible experimental errors were based on semi-quantitative
      studies of homogeneous and heterogeneous systems. The MRI protocol provides
      complementary phase and magnitude data, which are related to the sample
      temperature and structural heterogeneity, respectively. Used together, they
      relate the temperature changes to the differential thermal properties of the
      various components within a heterogeneous sample. The potential applications of
      this technique to microwave and other forms of heating is discussed.

PMID- 10642105
TI  - Breathhold cine MRI of left ventricular function in patients with obstructive
      sleep apnea: work-in-progress.
AB  - Obstructive sleep apnea (OSA) is a sleep-related breathing disorder that can
      cause left ventricular (LV) dysfunction. In patients with OSA, the LV dysfunction
      is usually evaluated by echocardiography. The purpose of this study was to
      evaluate whether the use of breathhold cine MRI for the study of LV dysfunction
      would be feasible and well tolerated by patients with OSA. Six volunteers and
      five patients underwent a breathhold cine MRI study of the LV using a 1.5 Tesla
      MR imager. Cine MRI was performed using a breathhold k-space segmented TurboFLASH
      technique during end-expiration. Systolic thickening of the LV septal wall was
      49% +/- 16% in normals vs. 25% +/- 10.5% in patients (p < 0.05). Systolic
      thickening of the LV free wall was 42% +/- 12% in normals vs. 22% +/- 9% in
      patients (p < 0.05). There was a significant difference in end-diastolic wall
      thickness between the two groups. All patients tolerated the procedure well. The
      total duration of each study was relatively short (less than 11 min). Breathhold
      MRI techniques can be used to study LV dysfunction in patients with respiratory
      disability such as OSA.

PMID- 10642106
TI  - Comparison of two exploratory data analysis methods for fMRI: fuzzy clustering
      vs. principal component analysis.
AB  - Exploratory data-driven methods such as Fuzzy clustering analysis (FCA) and
      Principal component analysis (PCA) may be considered as hypothesis-generating
      procedures that are complementary to the hypothesis-led statistical inferential
      methods in functional magnetic resonance imaging (fMRI). Here, a comparison
      between FCA and PCA is presented in a systematic fMRI study, with MR data
      acquired under the null condition, i.e., no activation, with different noise
      contributions and simulated, varying "activation." The contrast-to-noise (CNR)
      ratio ranged between 1-10. We found that if fMRI data are corrupted by scanner
      noise only, FCA and PCA show comparable performance. In the presence of other
      sources of signal variation (e.g., physiological noise), FCA outperforms PCA in
      the entire CNR range of interest in fMRI, particularly for low CNR values. The
      comparison method that we introduced may be used to assess other exploratory
      approaches such as independent component analysis or neural network-based
      techniques.

PMID- 10642107
TI  - Detection of dimethyl sulfone in the human brain by in vivo proton magnetic
      resonance spectroscopy.
AB  - We wish to report the detection of dimethyl sulfone (methylsulfonylmethane,
      C2H6O2S) in the brain of a normal 62-year-old male using in vivo proton magnetic
      resonance spectroscopy. The presence of this exogenous metabolite resulted from
      ingestion of a dietary supplement containing dimethyl sulfone. The concentration
      of this compound in the brain was measured to be 2.4 mmol, with a washout "half
      life" of approximately 7.5 days. The in vivo T1 and T2 relaxation times of
      dimethyl sulfone were measured to be 2180 ms and 385 ms, respectively. The
      concentration of major brain metabolites, namely N-acetylaspartate, total
      Creatine and Choline, and myo-Inositol were within normal limits.

PMID- 10642108
TI  - Rhombencephalosynapsis diagnosed in childhood: clinical and MRI findings.
AB  - Rhombencephalosynapsis is an unfrequent malformation of the posterior fossa
      essentially characterized by vermian agenesis or hypogenesis, fusion of the
      cerebellar hemispheres and fusion of the dentate nuclei. Supratentorial
      abnormalities are usually associated. No specific clinical syndrome can be
      described in relation with this disorder. We report a case diagnosed by MRI in a
      living patient.

PMID- 10642109
TI  - Prenatal cocaine raises mu-opioid receptor density in piglet cardiorespiratory
      medulla.
AB  - Repeated prenatal exposure to cocaine attenuates arousal and cardiorespiratory
      functions in neonates. This study explored the possible role of brainstem mu- and
      delta-opioid systems in these effects. Medullary sections were obtained from 6 to
      7 (young) and 20 to 21-day-old (older) piglets either unexposed or exposed
      prenatally to a 2-mg/kg intravenous cocaine hydrochloride dose, injected to the
      pregnant sow four times a day during the last third of gestation. Mu- and delta
      opioid receptor binding was assessed by quantitative autoradiography using,
      respectively, 125I-DAMGO (Tyr-D-Ala-Gly-N-Me-Phe-Gly-ol) and 125I-DPDPE (Tyr-D
      Pen-Gly-pCl-Phe-D-Pen). At control, delta-, but not mu-opioid, receptor density
      increased with postnatal age. In contrast, cocaine-induced mu-, but not delta
      opioid, receptor density increased 1) in the dorsal motor vagal (dmnX) and facial
      (nF) nuclei, and, at borderline significance level, in the cardiorespiratory
      related gigantocellular reticular nucleus (nRG) of the young, and 2) in the
      spinal trigeminal nucleus and tract (nSp5), and in the cardiorespiratory-related
      medial solitary tract (nTSm) and lateral reticular (nRL) nuclei of both age
      groups. These findings support a possible participation of the mu-opioid system
      in the attenuation of arousal and cardiorespiration after repeated prenatal
      exposure to cocaine.

PMID- 10642110
TI  - Visuoperceptual functioning differs in 9- to 12-year olds prenatally exposed to
      cigarettes and marihuana.
AB  - Visuoperceptual performance was examined in 146 9- to 12-year old children for
      whom prenatal exposure to marihuana and cigarettes had been ascertained. The
      subjects, participants in an ongoing longitudinal study, were from a low-risk,
      predominantly middle class sample. The tasks ranged in complexity from those that
      required basic visuoperceptual skills to those that required considerable
      integration and cognitive manipulation of such skills. Trend analysis revealed a
      dose dependent negative association between prenatal cigarette exposure and an
      overall score reflecting basic visuoperceptual functioning. This association
      remained after consideration of potential prenatal confounds, pre- and postnatal
      secondhand smoke exposure, and the nonperceptual demands of the tasks. This
      poorer performance in the basic visuoperceptual domain underlay a poorer
      performance in more complex visuoperceptual tasks among the offspring of
      cigarette smokers. In contrast, prenatal marihuana exposure was not associated
      with basic visuoperceptual functioning but was negatively associated with
      performance in visual problem solving situations. The interpretation of the
      marihuana findings is discussed in relation to a "top-down" integrative ability
      associated with executive function, the extant prefrontal literature, and earlier
      observations of this sample.

PMID- 10642111
TI  - Prenatal PCB exposure and neonatal behavioral assessment scale (NBAS)
      performance.
AB  - We examined the relationship between prenatal (cord blood) polychlorinated
      biphenyls (PCBs) and Neonatal Behavioral Assessment Scale (NBAS) performance in
      babies born to women who consumed contaminated Lake Ontario fish. Cord blood
      PCBs, DDE, HCB, Mirex, lead, and hair mercury levels were determined for 152
      women who reported never consuming Lake Ontario fish and 141 women who reported
      consuming at least 40 PCB-equivalent lbs. of Lake Ontario fish over their
      lifetime. Earlier work demonstrated that the newborns of fish eaters are exposed
      to a more heavily chlorinated distribution of PCB congeners, and that highly
      chlorinated PCBs (hepta-, octa-, and nonachlorinated biphenyls) are most strongly
      correlated with breast milk levels, perhaps providing the best index of PCB
      exposure in the Oswego cohort. Given the above, one would predict that these PCBs
      would be related to impaired performance on those NBAS clusters associated with
      fish consumption: namely Habituation, Autonomic, and Reflex clusters of the NBAS.
      Excepting the Relex cluster, these predictions were confirmed. Results revealed
      significant linear relationships between the most heavily chlorinated PCBs and
      performance impairments on the Habituation and Autonomic clusters of the NBAS at
      25-48 h after birth. Additionally, higher prenatal PCB exposure was associated
      with a nonspecific performance impairment on the NBAS as evidenced by a
      significantly greater proportion of NBAS scales in which poor performance was
      exhibited (more than 1 standard deviation below the mean) in the most highly
      exposed neonates. Moreover, PCBs of lighter chlorination were unrelated to NBAS
      performance, as were DDE, Mirex, HCB, lead, and mercury. These results
      corroborate our earlier findings linking Lake Ontario fish consumption to the
      most heavily chlorinated PCB congeners, and suggest that the chlorination and
      persistence of PCBs may be an important factor both for exposure assessment and
      for determining relationships with neurobehavioral functions.

PMID- 10642112
TI  - Adaptation of a primate operant test battery to the rat: effects of
      chlorpromazine.
AB  - The National Center for Toxicological Research (NCTR) Operant Test Battery (OTB)
      has been used extensively in rhesus monkeys to characterize the effects of drugs
      and toxicants on the performance of tasks designed to model several cognitive
      functions. Recently, the majority of the OTB tasks have been adapted for use in
      rats. The current study is the first to examine the effects of a prototypic
      pharmacological agent previously assessed in monkeys on rat OTB performance. The
      effects of the dopamine antagonist chlorpromazine (0.56-5.6 mg/kg, i.p.) were
      assessed in rats performing tasks designed to model auditory-visual-position
      discrimination, learning, time estimation, and appetitive motivation. All four
      tasks were equally sensitive to the behavioral effects of chlorpromazine. This
      pattern of sensitivity was very similar to that obtained when chlorpromazine was
      tested in monkeys performing the OTB. These data thus suggest that operant tasks
      designed to model cognitive functions in monkeys can also be used in rats, and
      that the effects of chlorpromazine on the performance of these tasks may be
      predictive of results obtained with monkeys. Further characterization of the rat
      OTB using prototypic pharmacological agents will further determine the extent to
      which drug effects on rat OTB performance can be generalized to primates.

PMID- 10642113
TI  - Intrahippocampal cholinergic-rich transplants restore lead-induced deficits: a
      preliminary study in rats.
AB  - In the present study restorative potential of fetal cholinergic rich cell
      suspensions in ameliorating cognitive deficits in rats perinatally exposed to
      lead was studied. Lactating dams with 1-day old litters were given 0.2% (w/v)
      lead acetate in drinking water throughout lactation from postnatal day (PND) 1 to
      PND21 at the end of which the treatment was stopped and the animals were weaned.
      On PND42 lead exposed rats were given bilateral, intrahippocampal, cholinergic
      rich fetal neural transplants (approximately 60,000 cells per site) and
      subsequently assessed 3 and 6 months posttransplantation. Control animals (Sham
      operated and transplanted) were also run in parallel. Lead exposed rats exhibited
      a decreased learning ability and locomotor activity. A significant decrease in
      the levels of acetylcholinesterase and sodium potassium ATPase Na+,K+-ATPase
      activity was observed in hippocampal region of lead exposed rats. The levels of
      lead were increased by fivefold in the hippocampal region of lead exposed rats.
      Transplantation showed marginal improvement in the above impairments at 3 months
      which were more marked at 6 months. Lead levels at 6 months were not
      significantly higher in lead exposed rats as compared with the control. Results
      confirm previous findings that fetal neural transplants help in restoring the
      lost functional deficits and demonstrate their restorative potential in case of
      lead induced deficits.

PMID- 10642114
TI  - Effects of chronic low-level oral lead exposure on prepulse inhibition of
      acoustic startle in the rat.
AB  - Previous work has suggested that the behavioral effects of chronic low-level lead
      exposure on fixed interval (FI) operant behavior result from enhanced
      dopaminergic neurotransmission in the nucleus accumbens (Cory-Slechta et al., J
      Pharmacol Exp Ther 286: 794-805, 1998). The present studies were designed to
      further characterize the effects of chronic low-level oral lead exposure on
      another behavior that is modulated by dopaminergic neurotransmission in the
      nucleus accumbens. In these studies acoustic startle and the prepulse inhibition
      (PPI) of startle were studied in rats following chronic low-level oral lead
      exposure. Weanling male rats were treated for 5-6 weeks with lead via drinking
      water (250 ppm lead acetate; controls drank 250 ppm sodium acetate). Acoustic
      startle reactivity (95, 105, and 115 dB noise bursts) and PPI (prepulses of 1-8
      dB over the 70-dB background) of startle were tested following lead exposure.
      Lead exposure did not affect body weight. Lead exposure also did not
      significantly affect baseline [i.e., no prepulse inhibition (NO-PPI)] acoustic
      startle as measured by 1) startle amplitude on the first startle trial (105 dB),
      2) the average startle amplitude for the first ten trials (105 dB), or 3) the
      average startle amplitude for the NO-PPI trials during PPI testing (95, 105, and
      115 dB). Lead exposure also did not affect the latency to onset for the startle
      response. In contrast, for both the 105 dB and 115 dB acoustic startle stimuli,
      chronic low-level oral lead exposure significantly attenuated the capacity of an
      acoustic prepulse to reduce the startle response. This effect was present whether
      the data were presented and analyzed as raw change from baseline or as the
      percentage of baseline startle. Given the strong link between the modulation of
      PPI and dopaminergic neurotransmission in the nucleus accumbens, the present data
      support the hypothesis that chronic low-level oral lead exposure facilitates
      dopamine neurotransmission in the nucleus accumbens.

PMID- 10642115
TI  - Early postnatal cocaine exposure causes sequential, dose-dependent, enduring but
      reversible supersensitivity in 5-HT2A receptor-mediated function during
      development in male mice.
AB  - This report investigated whether postnatal exposure to cocaine affects the index
      of 5-HT2A receptor function during development by utilizing the ability of the 5
      HT2A/C agonist DOI to induce the head-twitch response (HTR) in mice. Thus,
      several groups of mice litters were treated with varying doses of cocaine (0,
      0.5, 1, 5, and 10 mg/kg, IP) twice daily from postnatal days 5 to 14. Then,
      different groups of cocaine-exposed male mice pups along with their corresponding
      age-matched vehicle-exposed control groups were HTR tested once during
      development on the following postnatal test days: 15, 16, 18, 20, 30, 45, and 60.
      The HTR testing involved administration of DOI (0.5 mg/kg, IP) and counting the
      frequency of the behavior for the next 20 min. Cocaine exposure caused bell
      shaped, dose-dependent, enduring but reversible increase in DOI-induced HTR
      frequency (mean +/- SEM) during development. The developing pups were most
      sensitive to low and intermediate doses of cocaine (0.5-5 mg/kg). The greatest
      degree of increase in HTR frequency in response to DOI challenge occurred in the
      1 mg/kg cocaine-exposure group on most test days. The onset of HTR
      supersensitivity varied from 48 h (5 mg/kg) to 144 h (0.5 mg/kg) following the
      termination of chronic cocaine exposure. Moreover, maximal supersensitivity for
      the latter doses of cocaine occurred 96 and 384 h postcocaine treatment,
      respectively. Other cocaine exposure groups attained their maxima sometime
      between the latter time periods. The duration of persistence of 5-HT2A receptor
      supersensitivity varied with different doses of cocaine: the 10-mg/kg group was
      supersensitive up to 384 h postcocaine treatment, the 1- and 5-mg/kg groups up to
      744 h; and the 0.5-mg/kg group up to 1104 h. Although developmentally cocaine
      exposed pups exhibit some similarities (i.e., exquisite sensitivity and bell
      shaped dose-response) in 5-HT2A receptor adaptation to mature adult mice exposed
      to cocaine, they also differ from mature adult cocaine-exposed mice in the onset
      of appearance as well as the enduring persistence of the induced
      supersensitivity.

PMID- 10642116
TI  - Fertility and developmental neurotoxicity effects of inhaled hydrogen sulfide in
      Sprague-Dawley rats.
AB  - In this study, we examined whether perinatal exposure by inhalation to hydrogen
      sulfide (H2S) had an adverse impact on pregnancy outcomes, offspring prenatal and
      postnatal development, or offspring behavior. Virgin male and female Sprague
      Dawley rats (12 rats/sex/concentration) were exposed (0, 10, 30, or 80 ppm H2S; 6
      h/day, 7 days/week) for 2 weeks prior to breeding. Exposures continued during a 2
      week mating period (evidence of copulation = gestation day 0 = GD 0) and then
      from GD 0 through GD 19. Exposure of dams and their pups (eight rats/litter after
      culling) resumed between postnatal day (PND) 5 and 18. Adult male rats were
      exposed for 70 consecutive days. Offspring were evaluated using motor activity
      (PND 13, 17, 21, and 60+/-2), passive avoidance (PND 22+/-1 and 62+/-3),
      functional observation battery (PND 60+/-2), acoustic startle response (PND 21
      and 62+/-3), and neuropathology (PND 23+/-2 and 61+/-2). There were no deaths and
      no adverse physical signs observed in F0 male or female rats during the study. A
      statistically significant decrease in feed consumption was observed in F0 male
      rats from the 80-ppm H2S exposure group during the first week of exposure. There
      were no statistically significant effects on the reproductive performance of the
      F0 rats as assessed by the number of females with live pups, litter size, average
      length of gestation, and the average number of implants per pregnant female.
      Exposure to H2S did not affect pup growth, development, or performance on any of
      the behavioral tests. The results of our study suggest that H2S is neither a
      reproductive toxicant nor a behavioral developmental neurotoxicant in the rat at
      occupationally relevant exposure concentrations (< or =10 ppm).

PMID- 10642117
TI  - Environmental factors: modulators of development. Papers from a symposium
      sponsored by the Neurobehavioral Teratology Society.

PMID- 10642118
TI  - Psychosocial stressors and mammary tumor growth: an animal model.
AB  - Stressful life events and the ability to cope with stress may play a role in the
      progression of breast cancer; however, the complex relationship between stressors
      and tumor growth is difficult to investigate in humans. Our studies have utilized
      the androgen-responsive Shionogi mouse mammary carcinoma (AR SC115) in male mice
      to investigate the effects of social housing condition on tumor growth rates and
      responses to chemotherapy. We demonstrate that, depending on social housing
      condition, mammary tumor growth and response to chemotherapy can both increase
      and decrease. We have examined the possible role(s) of 1) psychosocial variables,
      2) testosterone and corticosterone, hormones altered by stress and known to
      stimulate SC115 cells in vivo and in vitro, 3) NK cells, one of the body's first
      lines of defense against tumor cells, 4) stress proteins, in mediating the
      differential tumor growth rates observed in our model. This review discusses the
      investigations we have undertaken to elucidate the mechanisms through which a
      psychosocial stressor, social housing condition, can alter tumor growth rate.

PMID- 10642119
TI  - Amelioration of fetal alcohol-related neurodevelopmental disorders in rats:
      exploring pharmacological and environmental treatments.
AB  - Fetal alcohol syndrome (FAS) and alcohol-related neurodevelopmental disorders
      (ARNDs) in children are characterized by life-long compromises in learning,
      memory, and adaptive responses. Until the advent of effective prevention
      measures, it will remain necessary to seek ways to treat the life-long
      neurobehavioral consequences of prenatal alcohol exposure. To date, there are no
      clinical remedies to recommend for either specific or global fetal alcohol
      effects. This article reviews our basic research in animal models that assesses
      the potential of global environmental manipulations or specific
      psychopharmacological treatments to ameliorate the neurobehavioral effects of
      prenatal exposure to alcohol. Postweaning environmental enrichment can improve
      behavioral performance and ameliorate or even eliminate deficits in prenatal
      alcohol-exposed rats, although there is persistent impairment in neuronal
      plasticity, as indicated by the failure of hippocampal pyramidal cells to
      increase dendrite spine density. Behavioral and neural responses to CNS
      stimulants differ in rats exposed prenatally to alcohol, although it is not clear
      that these shifts in dose-response curves would predict benefit to children.
      Although the present results may sound a note of optimism for the development of
      effective treatment strategies for children with FAS or ARNDs, it is important to
      consider that application of these findings in rodents may not be
      straightforward. We also need to know the critical features of specific
      environments that influence brain development, and the limits of pharmacotherapy,
      as well as critical periods of exposure. Continued study of the beneficial,
      ameliorative effects of environmental enrichment, rehabilitative training, and of
      pharmacological therapies in animal models, will remain a valuable source of
      information for eventually devising treatments specific for children with FAS and
      ARNDs.

PMID- 10642120
TI  - Preweaning experience as a modifier of prenatal drug effects in rats and mice--a
      review.
AB  - The effects of preweaning experience in rats and mice on neuroendocrine and
      behavioral end points and their implications for prenatal drug effects are
      reviewed. The hypothalamo-pituitary-adrenal axis and the dopaminergic system were
      shown to be affected. Behavior related to hippocampal, adrenocortical functions
      and to the benzodiazepine receptor system was also modified. Other paradigms
      (nociception, conditioned taste aversion) exhibited susceptibility to such
      preweaning manipulations also. The effects of these early experiences seem to be
      mediated through complex factors including neuroendocrine responses of the pup to
      hypothermia and a permanent alteration of mother-infant interactions, with
      subsequent effects on neuroendocrine functions that are important for postnatal
      brain organization. Studies of interactions between prenatal drug effects and
      preweaning manipulations have been performed only with ethanol. When extending
      this work to other compounds, the systems and functions described above may
      provide some guidance in looking for possible interactions. In most cases the
      preweaning manipulations alleviated the effects of prenatal ethanol exposure.
      These findings may have important implications regarding the controversy about
      environmental influences affecting the outcome of exposure to neurobehavioral
      teratogens.

PMID- 10642121
TI  - Therapeutic motor training ameliorates cerebellar effects of postnatal binge
      alcohol.
AB  - We have used training on complex motor tasks to ameliorate effect of neonatal
      alcohol exposure. On postnatal days 4-9, alcohol-exposed (AE) rats were given 4.5
      g/kg/day of alcohol by artificial rearing; gastrostomy control (GC) rats were
      given an isocaloric mixture of maltose/dextrin; suckling control (SC) rats were
      suckled normally. At 6 months of age, animals from the three groups underwent
      either rehabilitation training on a series of complex motor tasks, motor
      conditioning on a flat runway, or an inactive home cage condition. Subsequently,
      animals were either tested on three tests of balance and coordination, or were
      used for cerebellar morphology. After rehabilitation, but not after motor
      conditioning, male and female AE rats exhibited significant improvement in
      independent tests of motor skills. Using unbiased stereological morphological
      techniques, rehabilitated SC and AE animals were found to exhibit significantly
      more parallel fiber synapses per Purkinje cell in the paramedian lobule.

PMID- 10642122
TI  - Effect modification in epidemiologic studies of low-level neurotoxicant exposures
      and health outcomes.
AB  - Little attention has been invested in exploring the possibility that the nature
      or magnitude of a neurotoxicant's health impact on children depends on host
      characteristics (e.g., sex, age) or contextual factors (e.g., socioeconomic
      status, other chemical exposures). Such effect modification is a property of a
      true association, and should be distinguished from confounding. In epidemiologic
      studies of children, most efforts to identify effect modification have been
      unsystematic, pursued as part of data analysis rather than of study design. As a
      result, most samples have insufficient statistical power to characterize effect
      modification with adequate precision. This may contribute to an inconsistency in
      results across studies. Failure to assess effect modification adequately may also
      lead to invalid inferences. If the magnitude of an association between a
      neurotoxicant exposure and a particular end point varies across strata of a third
      factor, an estimate that summarizes the association across strata of this factor
      will be inappropriate, overestimating the association in a stratum in which the
      association is absent, and underestimating it in a stratum in which it is
      present. Until such dependencies are identified, our understanding of the
      mechanism(s) of a compound's neurotoxicity will remain incomplete, as will the
      knowledge base required to formulate public policy that adequately protects the
      most sensitive subgroups of the population.

PMID- 10642123
TI  - Cardiac pacing and electrophysiology at millennium's end: historical notes and
      observations.

PMID- 10642124
TI  - Arrhythmia vulnerability assessment using magnetic field maps and body surface
      potential maps.
AB  - Magnetic field maps and body surface potential maps can be used to measure
      cardiac activity. The ability of magnetic and potential body surface maps to
      identify patients' vulnerable to recurrent sustained ventricular arrhythmia (VA)
      were compared. Magnetic field maps (MFM) and body surface potential mapping
      (BSPM) were obtained from 76 normal (N) subjects, 15 myocardial infarct (MI)
      patients, and 15 VA patients. QRST integral maps were calculated for each subject
      and nondipolar content was determined using Karhunen-Loeve transform eigen-maps.
      Although differences in nondipolar content were significant between the normal
      and patient groups (P = 2.4 x 10(-5) for BSPM and P = 6.0 x 10(-8) for MFM),
      differences in nondipolar content between MI and VA patients using QRST integral
      BSPM and MFM maps were not significant. The trajectory of the location of the
      maxima and minima on the map area during the QRS and ST-T intervals were also
      constructed. Discrimination between MI and VA patients was based on intergroup
      differences in the amount of fragmentation of the trajectory plots. The ST-T
      trajectory plots were significantly more fragmented (P < 0.0001 and P < 0.05 for
      MFM and BSPM, respectively) for VA than for MI patients. The ST-T interval MFM
      and BSPM trajectory plots enabled separation of MI and VA patients with
      accuracies of 83% and 73%, respectively. These results suggest that
      repolarization MFM and BSPM extrema trajectory plots can be used effectively as a
      means of identifying patients at risk for VA.

PMID- 10642125
TI  - Increase in heart rate precedes episodes of ventricular tachycardia and
      ventricular fibrillation in patients with implantable cardioverter
      defibrillators: analysis of spontaneous ventricular tachycardia database.
AB  - Patients with heart disease and decreased heart rate variability (HRV) have an
      increased risk of all-cause mortality as well as arrhythmic death. The question
      of acute changes in HRV immediately preceding arrhythmic events remains
      unanswered. We analyzed data from patients with implantable cardioverter
      defibrillators who had ventricular tachycardia (VT) or ventricular fibrillation
      (VF) detected by the device. The device stores 1,000 consecutive RR intervals
      preceding the arrhythmic event detection and before device interrogation.
      Compared to this control segment, the mean heart rate (HR) increased prior to the
      arrhythmic event for both VT (88.5 vs 72.7 beats/min, P < 0.0005) and VF (85.4 vs
      73.3 beats/min, P < 0.05) patients. No difference in HRV (as analyzed by a time
      domain, frequency-domain [fast Fourier transform], and a nonlinear technique) has
      been detected. We estimated the amount of ectopic beats from the number of RR
      intervals that differed from the preceding RR interval by > 10%. The frequency of
      such beats was significantly higher in the prearrhythmic data segments than in
      the control segments for VT (10.7 vs 6.6/50 beats, P < 0.05) although not for VF
      (9.8 vs 6.1/50 beats, NS). We conclude that the HR and frequency of ectopic beats
      are higher prior to onset of the arrhythmic events, although HRV does not change
      markedly. These results are consistent with sympathetic activation being the
      predominant autonomic change prior to VT/VF onset in this patient population.

PMID- 10642126
TI  - Electrophysiological properties of the left atrium evaluated by coronary sinus
      pacing in patients with atrial fibrillation.
AB  - Repetitive atrial firing (RAF), marked fragmentation of atrial activity (FAA),
      and interatrial conduction delay (CD) have been shown to be electrophysiological
      features of the atrium in patients with atrial fibrillation (AF). Moreover, it
      has been observed that atrial extrastimuli are more likely to induce AF when
      delivered from the right atrial appendage (RAA) than from the distal coronary
      sinus (CSd). We examined the electrophysiological properties of the atrial muscle
      by CS and RAA stimulation in patients with paroxysmal AF. Patients were divided
      into two groups: group I, consisting of 18 patients with clinical paroxysmal AF;
      and group II, consisting of 22 patients with various cardiac arrhythmias in which
      the substrate does not exist in the atrium. In group I, the following values of
      electrophysiological parameters of the atrium indicated that AF was more likely
      to be induced during RAA pacing than CSd pacing: atrial effective refractory
      period (RAA vs CSd: 201 +/- 28 ms vs 240 +/- 35 ms, P < 0.001), RAF zone (16 +/-
      25 ms vs 0 +/- 0 ms, P < 0.03), FAA zone (38 +/- 37 ms vs 5 +/- 19 ms, P < 0.01),
      maximum interatrial conduction time (144 +/- 19 ms vs 93 +/- 19 ms, P < 0.0001)
      and CD zone (53 +/- 21 ms vs 9 +/- 18 ms, P < 0.0001). The values of the
      electrophysiological parameters of the atrium evaluated by CSd pacing in group I
      patients were not significantly different from those in group II patients. In
      conclusion, when coronary sinus stimulation is performed, electrophysiological
      properties of the atrium in patients with AF show a significant decrease in
      atrial vulnerability compared to stimulation from RAA and also show similar
      values to those in patients without AF. It might be suggested that the left
      posterior or posterolateral atrium is electrophysiologically stable even in
      patients with paroxysmal AF.

PMID- 10642127
TI  - Reliability of single-lead VDD atrial sensing and pacing during exercise.
AB  - If atrial sensing ability of a single-lead VDD pacemaker is well accepted at
      rest, the detection quality by atrial floating electrodes remains less recognized
      during exercise. The aim of this study was to verify, during treadmill test and a
      continous telemetry, the atrial tracking performance using four different leads
      technologies. From November 1994 to July 1997, 21 patients (71.3 +/- 6.3 years
      old, 7 female, cardiopathy: 57%) were paced for isolated high degree (permanent:
      13, paroxystic: 8) AV block. The implanted devices were the Vitatron
      Saphir/Brillant lead (13 patients), Intermedics Unity/425/04-13 lead (5
      patients), Pacesetter Addvent (2 patients), and Biotronik Eikos (1 patient). The
      acute atrial signal amplitude was 1.66 +/- 0.75 mV. The treadmill test used the
      chronotropic assessment exercise protocol after pacemaker reprogramming to detect
      atrial undersensing (AV delay < or = 120 ms, no hysteresis, no flywheel, upper
      rate increase). The mean delay was 31.1 weeks (range 1-100). The testing duration
      was 6.1 +/- 2.3 minutes, the number of steps was 3.3 +/- 1.3 per patient, and the
      peak exercise rate was 135 +/- 19 beats/min. At rest, complete atrial tracking
      was complete in 90% of the patients, and during testing in only 23.8% of the
      patients, while AV synchronization > 95% was present in 57.1%, > 90% in 71.4%,
      and > 85% in 90.4% of patients (Vitatron 13/13, Intermedics 3/5, Biotronik 1/1,
      and Pacesetter 1/2). During the recovery period synchronization was always > 95%.
      The mean P wave amplitude at rest was 1.1 +/- 0.5 mV; during the first step, 1.04
      +/- 0.61 mV; second step, 0.94 +/- 0.53 mV; third step, 0.82 +/- 0.58 mV; fourth
      step, 0.67 +/- 0.39 mV; and during recovery, 1.13 +/- 0.67 mV. The mean P wave
      decrease signal at peak of exercise is 0.21 mV (from -1.31 to +0.5). In fact, P
      wave variations have several patterns: a decrease was measured in 7 patients, an
      increase in 2 patients, and no significant change in 7 patients. Single-lead VDD
      P wave identification during exercise was almost accurate. However, often there
      was progressive lowering of atrial sensing with transient loss of AV synchrony.

PMID- 10642128
TI  - Improved efficacy of anodal biphasic defibrillation shocks following a failed
      defibrillation attempt.
AB  - Although it is generally assumed that defibrillation becomes more difficult when
      the duration of VF is prolonged, after a failed defibrillation attempt, there is
      little information on the defibrillation efficacy of multiple shocks delivered at
      the same energy. The purpose of this study was to systematically examine the
      efficacy of a second shock delivered at the same or reversed polarity after a
      failed first shock. Defibrillation was attempted after 10 seconds of VF in 12
      pigs (30-56 kg) using biphasic waveforms and a nonthoracotomy lead system. Shock
      energy was held constant for the first and second shocks at 50%-90% of the DFT.
      The second shock was delivered 10 seconds after a failed first shock. First and
      second shock polarity (first phase) was randomized to (+, +), (+, -), (-, -), (-,
      +). The incidence of successful defibrillation (for all polarities) was 12.3% for
      first and 49.1% for second shocks (P < 0.0001). Anodal first shocks had a 17.2%
      incidence of success as opposed to a 7.4% incidence of success with cathodal
      first shocks (P = 0.001). Anodal second shocks had a 55.5% incidence of success
      compared to a 42.7% incidence of success with cathodal second shocks (P = 0.008).
      There was no significant benefit from polarity reversal after a failed first
      shock (P = 0.29). In conclusion, less energy is required for successful
      defibrillation by a second shock after a failed first. The optimal configuration
      for first and second shocks is with the RV as anode. Polarity reversal of a
      second shock after a failed first does not affect the probability of second shock
      success.

PMID- 10642129
TI  - Localization of precise origin of idiopathic ventricular tachycardia from the
      right ventricular outflow tract by a 12-lead ECG: a study of pace mapping using a
      multielectrode "basket" catheter.
AB  - Radiofrequency catheter ablation guided by pace-mapping techniques has proven
      effective in eliminating idiopathic ventricular tachycardia (VT) originating from
      the right ventricular outflow tract (RVOT). A method for rapidly identifying the
      origin of VT from 12-lead electrocardiogram (ECG) findings would be helpful for
      the catheter ablation procedure. The purpose of this study is to precisely
      localize the origin of idiopathic VT from the RVOT by a 12-lead ECG from a study
      of multipoint pace mapping. In one patient with premature ventricular complex
      (PVC) and 3 with VT, a "basket" catheter was deployed in the RVOT for bipolar
      pacing from 56 sites in the endocardium of RVOT. Under fluoroscopy the pacing
      sites were classified into the septum and free wall. We investigated the QRS
      morphology in leads, I, II, and III; the depth of the QS wave in leads aVR and
      aVL; and the height of the initial r wave in leads V1 and V2. Pacing was captured
      in 30-47 of 56 sites (54%-84%). As the pacing sites changed from the anterior to
      posterior of the septum, the QS notch (-) type in lead I shifted through rs to R,
      while a shift from R type to rR' or Rr' was noted in leads II and III. As the
      pacing sites changed from the anterior to posterior of the free wall, lead I
      showed a shift from the QS notch (+) type to R, while a shift from rR' to Rr' (or
      rR' unchanged) was found in leads II and III. The depth of the QS wave in leads
      aVR and aVL showed a tendency for aVR to be deeper than aVL toward the
      posterolateral attachment of both the septum and free wall, whereas aVL tended to
      be deeper than aVR toward the anterior attachment. The initial r waves in V1 and
      V2 became greater as the pacing site was positioned at a higher or more posterior
      location. These findings may provide more precise and clinically useful
      diagnostic information on the site of the origin of idiopathic VT originating
      from the RVOT by a 12-lead ECG.

PMID- 10642130
TI  - Multicenter evaluation of implantable cardioverter defibrillator testing after
      implant: the Post Implant Testing Study (PITS).
AB  - To reassess the function of the implantable cardioverter defibrillator (ICD) many
      electrophysiology centers perform a second test after the initial test at
      implant. A prospective multicenter study evaluated the necessity and yield of
      routine postimplant defibrillator testing. The results of 843 postimplant
      defibrillator tests were collected from 31 centers. The 764 routine tests in
      which ventricular fibrillation was successfully induced were analyzed. Variables
      examined included patient age, presenting arrhythmia, underlying heart disease,
      left ventricular ejection fraction, defibrillator age, make and model of ICD,
      electrode system, defibrillation threshold, polarity, and waveform. The overall
      failure rate was 3.1% (24/764). Units tested later than 365 days after implant
      tended to have a higher failure rate than those tested within the first month or
      the next eleven months (6.5%, 3.0%, 2.3%, respectively, P = 0.374). The failure
      rate was higher in patients with left ventricular ejection fraction < 40% than
      those with higher ejection fractions (3.8% vs 2.0%, P = 0.167). These trends did
      not reach statistical significance. No other baseline characteristic was
      associated with higher failure rates. Routine testing of ICDs reveals an overall
      failure rate of 3.1%. While the rate was low, defibrillator failure places the
      patient at high risk for sudden cardiac death. As any failure in this population
      is associated with a high risk of sudden cardiac death, routine defibrillator
      testing may be justified.

PMID- 10642131
TI  - Effects of proximal ventricular septal pacing on hemodynamics and ventricular
      activation.
AB  - Recently the use of alternate site pacing to improve cardiac function in patients
      with bradyarrhythmias has increased. In the present study, hemodynamics of right
      ventricular septal pacing were studied in seven dogs. A bipolar screw-in lead and
      endocardial lead were placed in the proximal right ventricular septum and right
      ventricular apex, respectively. The right ventricle was paced from each site. A
      conductance catheter and Millar catheter were inserted into the left ventricle to
      determine the left ventricular pressure and the pressure-volume loop. Cardiac
      output was measured using the thermodilution method. In five of the seven dogs,
      ventricular activation was documented by isochronal epicardial activation mapping
      during each pacing mode. Mean arterial pressure and cardiac output during septal
      pacing were significantly higher than during apical pacing (110 +/- 17 mmHg vs
      100 +/- 18 mmHg; 1.00 +/- 0.39 L/min vs 0.89 +/- 0.33 L/min). The positive dp/dt
      during septal pacing was significantly higher than during apical pacing (2137 +/-
      535 mmHg/s vs 1911 +/- 404 mmHg/s). End-systolic elastance during septal pacing
      was significantly higher compared to apical pacing (13.1 +/- 0.3 mmHg/mL vs 8.9
      +/- 4.0 mmHg/mL). The ventricular activation time during septal pacing was
      significantly shorter than during apical pacing. The epicardial maps generated
      during septal pacing were similar to those from atrial pacing. We conclude that
      hemodynamics and interventricular conduction are less disturbed by proximal right
      ventricular septal pacing than apical pacing in dogs with normal hearts.

PMID- 10642132
TI  - Influence of the pacing rate on the atrioventricular conduction time during
      aerobic and anaerobic exercise: basic concepts for a dromotropically controlled
      rate responsive pacemaker.
AB  - The dromotropic pacemaker concept needs a rate responsive algorithm in which the
      pacing rate is controlled by the atrioventricular conduction time (AVCT). To
      develop basic concepts for such a rate responsive algorithm, the influence of the
      pacing rate on the AVCT was investigated. Seven patients (62 +/- 7.8 years) with
      sick sinus syndrome and intact atrioventricular conduction underwent two
      cardiopulmonary exercise tests (CPX) on a treadmill. According to the
      determination of the anaerobic threshold (AT) and the patients maximum capacity
      in the first incremental CPX the work rate for two exercise levels below and
      above the AT were chosen for the second constant workload CPX. The calculation of
      the optimal pacing rate (HRopt) was based on the oxygen uptake (VO2) during
      exercise after reaching steady-state conditions. According to the increase of the
      VO2 from 14.8 +/- 2.3 mL/min per kilogram during aerobic work (38.3 +/- 16.0 W)
      to 19.4 +/- 4.7 mL/min per kilogram during anaerobic work (80.6 +/- 32.3 W), the
      HRopt was calculated to be 98.6 +/- 6.9 beats/min and 116.4 +/- 4.7 beats/min.
      Starting from HRopt, the pacing rate was increased (overpacing) and decreased
      (underpacing) by about 5 beats/min every minute. At optimal pacing rate the AVCT
      decreased significantly from 233.0 +/- 30.5 ms during aerobic work and to 226.4
      +/- 27.3 ms during anaerobic work (P < 0.05). Whereas overpacing induced a
      significant prolongation of the AVCT during aerobic work (4.17 +/- 1.78 ms per 10
      beats/min) and anaerobic work (3.84 +/- 1.60 ms per 10 beats/min), underpacing
      yielded a significant shortening of the AVCT by about 4.49 +/- 2.64 ms per 10
      beats/min during aerobic work and 4.75 +/- 1.87 ms per 10 beats/min during
      anaerobic work (P < 0.01). The slopes of the regression lines of the relationship
      between AVCT and pacing rate were not significantly. different. Based on the
      reciprocal relationship of heart rate (HR) and AVCT, basic concepts may be
      established for a dromotropic rate responsive algorithm.

PMID- 10642134
TI  - Transvenous cardioverter defibrillator lead malfunction due to terminal connector
      damage in pectoral implants.
AB  - Lead failure places patients with implantable cardioverter defibrillators (ICD)
      at risk for sudden cardiac death or results in delivery of inappropriate shocks.
      This study describes a mechanism of lead malfunction occurring at the junction of
      the terminal ring with the conductor coil of the rate sensing terminal connector
      in one specific model of a transvenous ICD lead. We detected the problem in a
      population of 179 patients with a mean age of 61 +/- 10 years and a mean lead
      implant duration of 16 +/- 11 months. All patients underwent pectoral ICD
      implantation using a submuscular approach. The implanting physician chose to
      place the ICD on the left side in 155 patients (87%) and on the right side in 24
      patients (13%). Cephalic vein cutdown provided central venous access in 147
      patients (82%), and subclavian vein puncture provided access in 32 patients
      (18%). Follow-up examination detected lead failure in six patients (3.5% over 31
      months) due to insulation damage with or without conductor coil fracture at the
      junction of the terminal ring and conductor coil of the IS-1 rate sense terminal.
      We detected lead disruption 17 +/- 9 months (range 5-31 months) after
      implantation. Multiple nonsustained arrhythmia episodes exhibiting nonphysiologic
      intervals associated with noisy rate sensing electrograms during pocket
      manipulation led to discovery in three patients. The other three patients
      presented with inappropriate device discharges confirmed by stored high-energy
      lead electrograms showing normal rhythm. Pacing lead impedance abnormally dropped
      in two patients. Impedance remained stable in the other four patients. In
      conclusion, the generator pocket represents an important site of ICD transvenous
      lead vulnerability. Lead failure may result from conductor coil and/or insulation
      disruption at the interface with the rate sensing terminal connector.

PMID- 10642133
TI  - Interaction between autonomic tone and the negative chronotropic effect of
      adenosine in humans.
AB  - Prior studies have demonstrated that sympathetic tone may influence the effects
      of adenosine on His-Purkinje automaticity, and that enhanced vagal tone may
      influence its effects on the sinus node. However, the interaction between
      autonomic tone and the effects of adenosine on the sinus node in humans remains
      unknown. Therefore, this study was designed to investigate the interaction
      between different states of autonomic tone and the bradycardiac response of the
      sinus node to adenosine. In 11 patients without structural heart disease who
      underwent a clinically indicated electrophysiology procedure, the sinus cycle
      length was measured before and after a 12-mg bolus of adenosine in the baseline
      state, during an infusion of 2 mcg/min of isoproterenol, after the administration
      of 0.2 mg/kg of propranolol, and again after the administration of 0.04 mg/kg of
      atropine. Adenosine significantly lengthened the sinus cycle length in the
      baseline state (760 +/- 165 vs 909 +/- 188 ms, P < 0.05), during isoproterenol
      infusion (516 +/- 67 vs 766 +/- 146 ms, P < 0.05), after propranolol (850 +/- 153
      vs 914 +/- 143 ms, P < 0.05) and after the combination of propranolol and
      atropine (662 +/- 76 vs 801 +/- 121 ms, P < 0.05). The degree of lengthening in
      sinus cycle length was significantly greater (P < 0.05) during isoproterenol
      infusion (253 +/- 157 ms, or 51% +/- 40%) than in the baseline state (149 +/- 85
      ms, or 20% +/- 12%), after propranolol (68 +/- 53 ms, or 8% +/- 8%), and after
      propranolol and atropine (140 +/- 110 ms, or 21% +/- 18%). The negative
      chronotropic effect of adenosine is influenced by autonomic tone. The effect of
      adenosine on the sinus node is accentuated by beta-adrenergic stimulation and
      unaffected by beta-adrenergic blockade or combined beta-adrenergic and
      cholinergic blockade.

PMID- 10642135
TI  - Adjustable atrial and ventricular temporary electrode for low-energy termination
      of tachyarrhythmias early after cardiac surgery.
AB  - Supraventricular and ventricular tachycardias are common and serious
      postoperative complications early after cardiac surgery. We introduce a
      completely removable temporary adjustable defibrillation electrode (TADE) for low
      energy cardioversion/defibrillation of postoperative atrial and ventricular
      tachyarrhythmias. The electrode consists of three loops of steel wires connected
      to one steel wire, which are movable within an isolation sheet for adjusting the
      active surface to the individual size of the heart chambers. Evaluation of the
      electrode was performed in 10 open-chest beagles with a mean weight of 25.5 kg.
      The electrodes were first positioned on the left and right atrium. Atrial
      fibrillation (AF) was induced via a bipolar temporary heart wire. Atrial
      defibrillation thresholds (DFTs) were measured according to a step-down shock
      protocol (5-0.4 J). Thereafter, the electrodes were adjusted and positioned on
      the right and left ventricle. Ventricular fibrillation (VF) was induced and DFTs
      were recorded the same way. Aortic flow and pressure and left ventricular
      pressure were continuously monitored throughout the experiment. For termination
      of AF, mean DFTs were 0.4 +/- 0 J (lowest possible shock level) with a mean shock
      impedance of 70 +/- 7.6 ohms. VF was terminated with a mean DFT of 3 +/- 1.1 J
      with a mean impedance 56.1 +/- 7.9 ohms. Complete transcutaneous removal of the
      electrodes was possible in all animals without any complications. In conclusion,
      successful low energy termination of AF and VF is possible with the tested
      temporary adjustable electrode. A clinical study is planned for further
      evaluation.

PMID- 10642136
TI  - Impact of chronic DDD pacing on time-domain indexes of heart rate variability in
      patients with hypertrophic obstructive cardiomyopathy.
AB  - The aim of this study was to examine whether DDD pacing affects time-domain
      indexes of heart rate variability (HRV) in patients with hypertrophic obstructive
      cardiomyopathy (HOCM). We studied 11 patients (7 men, age 52 +/- 8 years) with
      HOCM refractory to drugs. In all patients a DDD pacemaker was implanted and the
      atrioventricular delay was programmed to ensure a full ventricular activation
      sequence. Time-domain indexes of HRV (mean NN, SDANN, SDNN, SD, rMSSD, pNN50)
      were determined from 24-hour Holter recordings 3 days before and 1 year after
      pacemaker implantation. The pacemaker was turned off during the second
      recordings. The same indexes were determined in ten healthy controls at the same
      time points. The controls showed no significant differences in any of the
      measured parameters between the two time points. The HOCM patients showed an
      increase in SD (from 27 +/- 13 to 41 +/- 13 ms, P < 0.001), rMSSD (from 18 +/- 5
      to 32 +/- 8 ms, P < 0.001), and pNN50 (from 1.03 +/- 1.06 to 8.52 +/- 4.84%, P <
      0.0001). As a result, the values of these three parameters, which were lower in
      the HOCM patients than in the controls before pacing, were restored to normal
      levels by the end of the study. In conclusion, our findings indicate that long
      term pacing in HOCM patients restores the sympathovagal balance in the heart by
      increasing vagal activity.

PMID- 10642137
TI  - Patients over 100 years of age with implanted cardiac pacemakers.
AB  - Ten patients of the authors' practice who have survived to be 100 years of age or
      more have had an implanted pacemaker for an average of 11.4 years. As the life
      expectancy of the country (Uruguay) is 75 years, their survival is considered to
      be unusual, confirming the statistical conclusion that patient survival with an
      implanted pacemaker may be expected to be as good or better than those who do not
      require a pacemaker implant.

PMID- 10642138
TI  - Percutaneous transcatheter repositioning of displaced permanent pacemaker lead.
AB  - In three patients, two with a pacemaker and one with an implantable cardioverter
      defibrillator, hospitalized for dislodgement of a passive fixation J-shaped
      atrial lead, a percutaneous transcatheter repositioning was successfully
      attempted thus avoiding surgical revision. This procedure, performed through the
      femoral vein, is easy and safe. The stability of the lead position and of the
      pacing and sensing parameters was confirmed 1 and 6 months after the
      transcatheter repositioning.

PMID- 10642139
TI  - Analysis of charges and complications of permanent pacemaker implantation in the
      cardiac catheterization laboratory versus the operating room.
AB  - During the last two decades, an increasing number of permanent pacemakers have
      been implanted outside of the operating room (OR) by nonsurgeons. Previous
      investigators have demonstrated that pacemakers can be safely implanted in the
      cardiac catheterization laboratory with no increase in complications or
      infections. This is the first study of its kind to simultaneously evaluate cost,
      length of hospitalization, and complications between pacemakers implanted in the
      OR by surgeons with those implanted in the catheterization laboratory by an
      electrophysiologist. A total of 254 consecutive pacemaker implants were analyzed
      over a 2-year period. The OR group consisted of 122 patients with a mean age of
      64 +/- 21 years versus 132 patients in the catheterization laboratory group with
      a mean age of 65 +/- 17 years. The indication and type of pacemaker implanted
      were similar among both groups with 78% of OR patients and 73% of catheterization
      laboratory patients receiving dual chamber devices. The average cost for
      pacemaker implantation in our study was significantly higher in the OR group
      $5,464 +/- $1,670 versus $2,682 +/- $8 for the catheterization laboratory group
      (P < 0.001). There was a reduction in preimplant days in the catheterization
      laboratory group 3.16 +/- 12.40 days versus 5.65 +/- 9.54 days in the OR group (P
      < 0.05). Complications were minimal and there were no significant differences
      between the two groups. This study confirms that pacemakers can be safely
      implanted in the catheterization laboratory by nonsurgeons with no increase in
      complications and a significant reduction in hospital costs.

PMID- 10642140
TI  - A case of atrial flutter or fibrillation?

PMID- 10642141
TI  - Intrapulmonary artery and intrabronchial migration and extraction of a fragment
      of J-shaped atrial pacing catheter.
AB  - A fragment of a fractured Telectronics Atrial Accufix 330-801 lead
      asymptomatically perforated the adjacent bronchus and was detected on routine
      chest X-ray. The metallic fragment was located by chest CT scan and bronchial
      fluoroscopy to lie between the right lobar bronchus and the pulmonary artery,
      confirming bronchial perforation. The foreign body was removed without
      complication by direct visualisation with rigid bronchoscopy.

PMID- 10642142
TI  - Affective distress and implantable cardioverter defibrillators: cases for
      psychological and behavioral interventions.
AB  - The implantable cardioverter defibrillator (ICD) may be associated with some
      degree of psychological maladjustment, especially in patients experiencing high
      rates of discharge. This article reviews the psychological literature related to
      ICDs and presents two case examples illustrating common psychological
      complications related to multiple discharges. A brief, psychological intervention
      can be implemented to improve patient adjustment. To explain possible processes
      by which psychological complications may develop in ICD patients, two well
      established psychological theories of learning and behavior, classical
      conditioning and learned helplessness, are reviewed. Multidisciplinary teams that
      include consultation with clinical psychologists are suggested for the routine
      care of ICD patients.

PMID- 10642143
TI  - Atrioventricular dissociation as a cause of syncope determined by head-up tilt
      test.
AB  - This report describes a patient with syncopal attacks in a sitting position on a
      reclining seat, in whom atrioventricular dissociation due to accelerated
      ventricular rhythm was determined to be the cause by recording of the
      electrocardiogram, blood pressure, and mitral and aortic Doppler flow during a 60
      degree head-up tilt test.

PMID- 10642144
TI  - Variability of atrial sensing during exercise in a patient with a dual chamber
      ICD caused inappropriate ICD discharges.
AB  - We present the case of a patient with a dual chamber implantable cardioverter
      defibrillator (ICD) who experienced inappropriate ICD discharges during exercise.
      Interrogation of the ICD revealed intermittent atrial undersensing during
      exercise that was responsible for the erroneous classification by the ICD of
      sinus tachycardia as ventricular tachycardia. Monitoring of the intracardiac
      electrograms and Marker Channels during an exercise test confirmed a marked
      decrease in P wave amplitude during exercise. By increasing the atrial
      sensitivity setting the problem was resolved.

PMID- 10642145
TI  - Failure of left-sided implantable cardioverter defibrillator implantation due to
      absence of left brachiocephalic vein.
AB  - Implantation of an implantable cardioverter defibrillator by the transvenous
      approach was impossible from the left side in a patient with on absence of the
      left brachiocephalic vein; the left subclavian vein was connected by a large left
      superior intercostal vein to the accessory hemiazygos vein that joined the azygos
      vein; then the blood flowed into the superior vena cava. Implantation was
      successfully attempted using the right-sided venous access.

PMID- 10642146
TI  - Evaluation of appropriate pacing with myocardial perfusion and cardiac function
      as a treatment of end-stage idiopathic dilated cardiomyopathy.
AB  - We sought to determine an appropriate pacing mode on the basis of myocardial
      perfusion and cardiac function as assessed by nitrogen-13 ammonia positron
      emission tomography in a patient with end-stage idiopathic dilated
      cardiomyopathy.

PMID- 10642147
TI  - Pacing lead adhesions after long-term ventricular pacing via the coronary sinus.
AB  - Left ventricular pacing via the coronary sinus is being increasingly used. There
      is little data to guide possible lead extractions that might be required in the
      future. Significant adhesions to the coronary veins were found 12 years after
      placing a pacing lead in the posterolateral coronary vein in a man with double
      inlet left ventricle and severe subpulmonary stenosis who had undergone a Fontan
      operation. The appearances suggest that percutaneous extraction from the proximal
      coronary sinus may be feasible but that difficulty may be encountered if the lead
      tip is placed into the distal coronary veins.

PMID- 10642148
TI  - Optimized pulse durations minimize the effect of polarity reversal on
      defibrillation efficacy with biphasic shocks.

PMID- 10642149
TI  - Relatively simple techniques that may facilitate the more widespread utilization
      of the cephalic vein implant method.

PMID- 10642150
TI  - Septal/right ventricular outflow tract (RVOT) lead placement.

PMID- 10642151
TI  - STIMAREC report.

PMID- 10642173
TI  - Affinity of Src family kinase SH3 domains for HIV Nef in vitro does not predict
      kinase activation by Nef in vivo.
AB  - Nef is an HIV accessory protein required for high-titer viral replication and
      AIDS progression. Previous studies have shown that the SH3 domains of Hck and Lyn
      bind to Nef via proline-rich sequences in vitro, identifying these Src-related
      kinases as potential targets for Nef in vivo. Association of Nef with Hck causes
      displacement of the intramolecular interaction between the SH3 domain and the SH2
      kinase linker, leading to kinase activation both in vitro and in vivo. In this
      study, we investigated whether interaction with Nef induces activation of other
      Src family kinases (Lyn, Fyn, Src, and Lck) following coexpression with Nef in
      Rat-2 fibroblasts. Coexpression with Nef induced Hck kinase activation and
      fibroblast transformation, consistent with previous results. In contrast,
      coexpression of Nef with Lyn was without effect, despite equivalent binding of
      Nef to full-length Lyn and Hck. Furthermore, Nef was found to suppress the kinase
      and transforming activities of Fyn, the SH3 domain of which exhibits low affinity
      for Nef. Coexpression with Nef did not alter c-Src or Lck tyrosine kinase or
      transforming activity in this system. Differential modulation of Src family
      members by Nef may produce unique downstream signals depending on the profile of
      Src kinases expressed in a given cell type.

PMID- 10642174
TI  - Secondary structure, orientation, oligomerization, and lipid interactions of the
      transmembrane domain of influenza hemagglutinin.
AB  - Influenza virus hemagglutinin (HA), the viral envelope glycoprotein that mediates
      fusion between the viral and cellular membranes, is a homotrimer of three
      subunits, each containing two disulfide-linked polypeptide chains, HA(1) and
      HA(2). Each HA(2) chain spans the viral membrane with a single putative
      transmembrane alpha-helix near its C-terminus. Fusion experiments with
      recombinant HAs suggest that this sequence is required for a late step of
      membrane fusion, as a glycosylphosphatidylinositol-anchored analogue of HA only
      mediates "hemifusion" of membranes, i.e., the merging of the proximal, but not
      distal, leaflets of the two juxtaposed lipid bilayers [Kemble et al. (1994) Cell
      76, 383-391]. To find a structural explanation for the function of the
      transmembrane domain of HA(2) in membrane fusion, we have studied the secondary
      structure, orientation, oligomerization, and lipid interactions of a synthetic
      peptide representing the transmembrane segment of X:31 HA (TMX31) by circular
      dichroism and attenuated total reflection Fourier transform infrared spectroscopy
      and by gel electrophoresis. The peptide was predominantly alpha-helical in
      detergent micelles and in phospholipid bilayers. The helicity was increased in
      lipid bilayers composed of acidic lipids compared to pure phosphatidylcholine
      bilayers. In planar lipid bilayers, the helices were oriented close to the
      membrane normal. TMX31 aggregated into small heat-resistant oligomers composed of
      two to five subunits in SDS micelles. Amide hydrogen exchange experiments
      indicated that a large fraction of the helical residues were accessible to water,
      suggesting the possibility that TMX31 forms pores in lipid bilayers. Finally, the
      peptide increased the acyl chain order in lipid bilayers, which may be related to
      the preferential association of HA with lipid "rafts" in the cell surface and
      which may be an important prerequisite for complete membrane fusion.

PMID- 10642175
TI  - Plasminogen-independent initiation of the pro-urokinase activation cascade in
      vivo. Activation of pro-urokinase by glandular kallikrein (mGK-6) in plasminogen
      deficient mice.
AB  - The plasminogen activation (PA) system is involved in the degradation of fibrin
      and various extracellular matrix proteins, taking part in a number of
      physiological and pathological tissue remodeling processes including cancer
      invasion. This system is organized as a classical proteolytic cascade, and as for
      other cascade systems, understanding the physiological initiation mechanism is of
      central importance. The attempts to identify initiation routes for activation of
      the proform of the key enzyme urokinase-type plasminogen activator (pro-uPA) in
      vivo have been hampered by the strong activator potency of the plasmin, that is
      generated during the progress of the cascade. Using gene-targeted mice deficient
      in plasminogen (Plg -/- mice) [Bugge, T. H., Flick, M. J., Daugherty, C. C., and
      Degen, J. L. (1995) Genes Dev. 9, 794-807], we have now demonstrated and
      identified a component capable of initiating the cascade by activating pro-uPA.
      The urine from Plg -/- mice contained active two-chain uPA as well as a
      proteinase capable of activating exogenously added pro-uPA. The active component
      was purified and identified by mass spectrometry-based peptide mapping as mouse
      glandular kallikrein mGK-6 (true tissue kallikrein). The pro-uPA converting
      activity of the mGK-6 enzyme, as well as its ability to cleave a synthetic
      substrate for glandular kallikrein, was inhibited by the serine proteinase
      inhibitor leupeptin but not by other serine proteinase inhibitors such as
      aprotinin, antithrombin III, or alpha(1)-antitrypsin. We suggest that mouse
      glandular kallikrein mGK-6 is an activator of pro-uPA in the mouse urinary tract
      in vivo. Since this kallikrein is expressed in a number of tissues and also
      occurs in plasma, it can also be considered a candidate for a physiological pro
      uPA activator in other locations.

PMID- 10642176
TI  - Mechanism of 8-amino-7-oxononanoate synthase: spectroscopic, kinetic, and
      crystallographic studies.
AB  - 8-Amino-7-oxononanoate synthase (also known as 7-keto-8-aminopelargonate
      synthase, EC 2.3.1.47) is a pyridoxal 5'-phosphate-dependent enzyme which
      catalyzes the decarboxylative condensation of L-alanine with pimeloyl-CoA in a
      stereospecific manner to form 8(S)-amino-7-oxononanoate. This is the first
      committed step in biotin biosynthesis. The mechanism of Escherichia coli AONS has
      been investigated by spectroscopic, kinetic, and crystallographic techniques. The
      X-ray structure of the holoenzyme has been refined at a resolution of 1.7 A (R =
      18.6%, R(free) = 21. 2%) and shows that the plane of the imine bond of the
      internal aldimine deviates from the pyridine plane. The structure of the enzyme
      product external aldimine complex has been refined at a resolution of 2.0 A (R =
      21.2%, R(free) = 27.8%) and shows a rotation of the pyridine ring with respect to
      that in the internal aldimine, together with a significant conformational change
      of the C-terminal domain and subtle rearrangement of the active site hydrogen
      bonding. The first step in the reaction, L-alanine external aldimine formation,
      is rapid (k(1) = 2 x 10(4) M(-)(1) s(-)(1)). Formation of an external aldimine
      with D-alanine, which is not a substrate, is significantly slower (k(1) = 125 M(
      )(1) s(-)(1)). Binding of D-alanine to AONS is enhanced approximately 2-fold in
      the presence of pimeloyl-CoA. Significant substrate quinonoid formation only
      occurs upon addition of pimeloyl-CoA to the preformed L-alanine external aldimine
      complex and is preceded by a distinct lag phase ( approximately 30 ms) which
      suggests that binding of the pimeloyl-CoA causes a conformational transition of
      the enzyme external aldimine complex. This transition, which is inferred by
      modeling to require a rotation around the Calpha-N bond of the external aldimine
      complex, promotes abstraction of the Calpha proton by Lys236. These results have
      been combined to form a detailed mechanistic pathway for AONS catalysis which may
      be applied to the other members of the alpha-oxoamine synthase subfamily.

PMID- 10642177
TI  - Collagenolytic activity of cathepsin K is specifically modulated by cartilage
      resident chondroitin sulfates.
AB  - Cathepsin K is the predominant cysteine protease in osteoclast-mediated bone
      remodeling, and the protease is thought to be involved in the pathogenesis of
      diseases with excessive bone and cartilage resorption. Osteoclastic matrix
      degradation occurs in the extracellular resorption lacuna and upon phagocytosis
      within the cell's lysosomal-endosomal compartment. Since glycosaminoglycans
      (GAGs) are abundant in extracellular matrixes of cartilage and growing bone, we
      have analyzed the effect of GAGs on the activity of bone and cartilage-resident
      cathepsins K and L and MMP-1. GAGs, in particular chondroitin sulfates,
      specifically and selectively increased the stability of cathepsin K but had no
      effect on cathepsin L and MMP-1. GAGs strongly enhanced the stability and, to a
      lesser extent, the catalytic activity of cathepsin K. To combine the activity and
      stability parameters, we defined a novel kinetic term, named cumulative activity
      (CA), which reflects the total substrate turnover during the life span of the
      enzyme. In the presence of chondroitin-4-sulfate (C-4S), the CA value increased
      200-fold for cathepsin K but only 25-fold with chondroitin-6-sulfate (C-6S). C-4S
      dramatically increased the hydrolysis of soluble as well insoluble type I and II
      collagens, whereas the effects of C-6S and hyaluronic acid were less pronounced.
      C-4S acts in a concentration-dependent manner but reaches saturation at
      approximately 0.1%, a concentration similar to that found in the synovial fluid
      of arthritis patients. C-4S increased the cathepsin K-mediated release of
      hydroxyproline from insoluble type I collagen 10-fold but had only a less than 2
      fold enhancing effect on the hydrolysis of intact cartilage. The relatively small
      increase in the hydrolysis of cartilage by C-4S was attributed to the endogenous
      chondroitin sulfate content present in the cartilage. Although C-4S increased the
      pH stability at neutral pH, a significant increase in the collagenolytic activity
      of cathepsin K at this pH was not observed, thus suggesting that the unique
      collagenolytic activity of cathepsin K at acidic pH is mechanistically determined
      and not by the enzyme's instability at neutral pH. The selective and significant
      stabilization and activation of cathepsin K activity by C-4S may provide a
      rationale for a novel mechanism to regulate the enzyme's activity during bone
      growth and aging, two processes known for significant changes in the GAG content.

PMID- 10642178
TI  - Protein-directed DNA structure. I. Raman spectroscopy of a high-mobility-group
      box with application to human sex reversal.
AB  - Protein-directed reorganization of DNA underlies mechanisms of transcription,
      replication, and recombination. A molecular model for DNA reorganization in the
      regulation of gene expression is provided by the sequence-specific high-mobility
      group (HMG) box. Structures of HMG-box complexes with DNA are characterized by
      expansion of the minor groove, sharp bending toward the major groove, and local
      unwinding of the double helix. The Raman vibrational signature of such DNA
      reorganization has been identified in a study of the SRY HMG box, encoded by the
      human male-determining region of the Y chromosome. We observe in the human SRY
      HMG:DNA complex extraordinarily large perturbations to Raman bands associated
      with vibrational modes of the DNA backbone and accompanying large increases in
      intensities of Raman bands attributable to base unstacking. In contrast, DNA
      major-groove binding, as occurs for the bZIP protein GCN4 [Benevides, J. M., Li,
      T., Lu, X.-J., Srinivasan, A. R., Olson, W. K., Weiss, M. A., and Thomas, G. J.,
      Jr. (2000) Biochemistry 39, 548-556], perturbs the Raman signature of DNA only
      marginally. Raman markers of minor-groove recognition in the human SRY-HMG:DNA
      complex are due primarily to perturbation of specific vibrational modes of
      deoxyribose moieties and presumably reflect desolvation at the nonpolar interface
      of protein and DNA. These Raman markers may be diagnostic of protein-induced DNA
      bending and are proposed as a baseline for comparative analysis of mutations in
      SRY that cause human sex reversal.

PMID- 10642179
TI  - Protein-directed DNA structure II. Raman spectroscopy of a leucine zipper bZIP
      complex.
AB  - Mechanisms of transcription may involve protein-directed changes in DNA structure
      and DNA-directed changes in protein structure. We have employed Raman
      spectroscopy to characterize vibrational signatures associated with such induced
      molecular fitting for two classes of transcription factors-the basic leucine
      zipper (bZIP) motif and the high-mobility-group (HMG) box-each with a DNA target
      site. Results for bZIP are described here; findings for the HMG-box are reported
      in the preceding paper in this issue [Benevides, J. M., Chan, G., Lu, X.-J.,
      Olson, W. K., Weiss, M. A., and Thomas, G. J., Jr. (2000) Biochemistry 39, 537
      547]. The yeast activator GCN4 provides a well-studied example of bZIP
      recognition, wherein B-DNA serves essentially as a template for protein folding.
      Analysis of Raman spectra of the 57-residue GCN4 bZIP domain, its AP-1 binding
      site, and their specific complex confirms a DNA-induced increase in alpha
      helicity, attributable to folding of GCN4 basic arms with virtually no change in
      B-DNA structure, consistent with previous X-ray and NMR structure determinations.
      The absence of DNA perturbations in the bZIP model contrasts sharply with the HMG
      box, where DNA structure perturbations predominate. The bZIP and HMG-box models
      represent two opposing extremes in a range of induced fits identifiable by Raman
      spectroscopy. Previously characterized lambda repressor/operator complexes
      [Benevides, J. M., Weiss, M. A., and Thomas, G. J. (1994) J. Biol. Chem. 269,
      10869-10878] occupy an intermediate position within this range. A comprehensive
      tabulation of Raman markers proposed as diagnostic of different protein/DNA
      recognition motifs is presented. The results are analyzed in terms of available
      DNA crystal structures (Nucleic Acid Database) to identify details of DNA
      conformation that correlate with specific Raman recognition markers.

PMID- 10642180
TI  - Ultraviolet damage and nucleosome folding of the 5S ribosomal RNA gene.
AB  - The Xenopus borealis somatic 5S ribosomal RNA gene was used as a model system to
      determine the mutual effects of nucleosome folding and formation of ultraviolet
      (UV) photoproducts (primarily cis-syn cyclobutane pyrimidine dimers, or CPDs) in
      chromatin. We analyzed the preferred rotational and translational settings of 5S
      rDNA on the histone octamer surface after induction of up to 0.8 CPD/nucleosome
      core (2.5 kJ/m(2) UV dose). DNase I and hydroxyl radical footprints indicate that
      UV damage at these levels does not affect the average rotational setting of the
      5S rDNA molecules. Moreover, a combination of nuclease trimming and restriction
      enzyme digestion indicates the preferred translational positions of the histone
      octamer are not affected by this level of UV damage. We also did not observe
      differences in the UV damage patterns of irradiated 5S rDNA before or after
      nucleosome formation, indicating there is little difference in the inhibition of
      nucleosome folding by specific CPD sites in the 5S rRNA gene. Conversely,
      nucleosome folding significantly restricts CPD formation at all sites in the
      three helical turns of the nontranscribed strand located in the dyad axis region
      of the nucleosome, where DNA is bound exclusively by the histone H3-H4 tetramer.
      Finally, modulation of the CPD distribution in a 14 nt long pyrimidine tract
      correlates with its rotational setting on the histone surface, when the strong
      sequence bias for CPD formation in this tract is minimized by normalization.
      These results help establish the mutual roles of histone binding and UV
      photoproducts on their formation in chromatin.

PMID- 10642181
TI  - An accessory DNA binding motif in the zinc finger protein Adr1 assists stable
      binding to DNA and can be replaced by a third finger.
AB  - The DNA binding domain of Adr1, the protein derived from alcohol dehydrogenase
      regulatory gene 1, is unusual for zinc finger proteins in that it consists of two
      classical Cys2His2 zinc fingers and an amino-terminal proximal accessory region
      termed PAR. PAR is unstructured in the free protein and becomes structured in the
      DNA-bound form. We investigated the role of PAR in DNA binding using molecular
      and biochemical approaches, and its importance for activation in vivo, using Adr1
      dependent reporter genes. PAR was unimportant for DNA binding when a third finger
      was added to Adr1, and its importance was diminished but not eliminated by
      mutations in finger two that increased DNA binding affinity. The kinetic rate
      constants for three Adr1 proteins containing or lacking PAR were determined by
      surface plasmon resonance. PAR increased the on rate and decreased the off rate
      for specific DNA sites for Adr1 containing wild-type fingers one and two.
      Surprisingly, PAR had no significant effect on the kinetic rate constants when a
      third finger was present, or when single-stranded DNA was used as the substrate
      for DNA binding. A mutant form of Adr1-F1F2 in which finger 2 makes three base
      specific contacts with DNA had a higher affinity for DNA than Adr1 containing
      three fingers, yet the mutant protein still depended on PAR for optimal binding
      affinity. The ability to activate transcription in vivo was correlated with a low
      dissociation rate, suggesting that stabilizing an activator at the promoter might
      be rate-limiting for transcription in vivo. PAR may have evolved to lend
      additional stability to DNA-Adr1 complexes encompassing short binding sites. In
      addition, PAR may have a role in transcription at a step after DNA binding since
      deletion of PAR from Adr1 with three fingers decreased activation in vivo but had
      no effect on DNA binding kinetics.

PMID- 10642182
TI  - Aggregation events occur prior to stable intermediate formation during refolding
      of interleukin 1beta.
AB  - A point mutation, lysine 97 --> isoleucine (K97I), in a surface loop in the beta
      sheet protein interleukin 1beta (IL-1beta), exhibits increased levels of
      inclusion body (IB) formation relative to the wild-type protein (WT) when
      expressed in Escherichia coli. Despite the common observation that less stable
      proteins are often found in IBs, K97I is more stable than WT. We examined the
      folding pathway of the mutant and wild-type proteins at pH 6.5 and 25 degrees C
      with manual-mixing and stopped-flow optical spectroscopy to determine whether
      changes in the properties of transiently populated species in vitro correlate
      with the observation of increased aggregation in vivo. The refolding reactions of
      the WT and K97I proteins are both described by three exponential processes. Two
      exponential processes characterize fast events (0.1-1.0 s) in folding while the
      third exponential process correlates with a slow (70 s) single pathway to and
      from the native state. The K97I replacement affects the earlier steps in the
      refolding pathway. Aggregation, absent in the WT refolding reaction, occurs in
      K97I above a critical protein concentration of 18 microM. This observation is
      consistent with an initial nucleation step mediating protein aggregation. Stopped
      flow kinetic studies of the K97I aggregation process demonstrate that K97I
      aggregates most rapidly during the earliest refolding times, when unfolded
      protein conformers remain highly populated and the concentration of folding
      intermediates is low. Folding and aggregation studies together support a model in
      which the formation of stable folding intermediates afford protection against
      further K97I aggregation.

PMID- 10642183
TI  - Electron spin-echo envelope modulation study of multicrystalline Cu(2+)-insulin:
      effects of Cd(2+) on the nuclear quadrupole interaction of the Cu(2+)-coordinated
      imidazole remote nitrogen.
AB  - A comparison of electron spin-echo envelope modulation (ESEEM) spectra from multi
      crystalline Cu(2+)-insulin with and without additional Cd(2+) show a dramatic
      change in the quadrupole coupling parameters of the remote nitrogens of the two
      histidine imidazoles that ligate to copper. Without Cd(2+), the quadrupole
      parameters are like those observed in blue copper proteins and in copper
      substituted lactoferrin. With Cd(2+) soaked into the Cu(2+)-insulin crystals, the
      quadrupole parameters are similar to those found in galactose oxidase.
      Theoretical simulations of ESEEM spectra guided by structure modeling suggest
      that these changes originate from differences in the hydrogen bonding
      environments of the imidazole remote nitrogen. In addition, a compilation of
      results from previous ESEEM studies of copper proteins reveals that the asymmetry
      parameter, eta, may be an indicator of type of hydrogen bond the imidazole remote
      nitrogen makes. When eta > or = 0.9, the nitrogen hydrogen bonds to water,
      whereas when eta < 0.9, the nitrogen hydrogen bonds to the protein.

PMID- 10642184
TI  - Crystal structure of the complex of brugia malayi cyclophilin and cyclosporin A.
AB  - The resistance of the human parasite Brugia malayi to the antiparasitic activity
      of cyclosporin A (CsA) may arise from the presence of cyclophilins with
      relatively low affinity for the drug. The structure of the complex of B. malayi
      cyclophilin (BmCYP-1) and CsA, with eight independent copies in the asymmetric
      unit, has been determined at a resolution of 2.7 A. The low affinity of BmCYP-1
      for CsA arises from incomplete preorganization of the binding site so that the
      formation of a hydrogen bond between His132 of BmCYP-1 and N-methylleucine 9 of
      CsA is associated with a shift in the backbone of approximately 1 A in this
      region.

PMID- 10642185
TI  - pH dependence of photolysis intermediates in the photoactivation of rhodopsin
      mutant E113Q.
AB  - Glutamic acid at position 113 in bovine rhodopsin ionizes to form the counterion
      to the protonated Schiff base (PSB), which links the 11-cis-retinylidene
      chromophore to opsin. Photoactivation of rhodopsin requires both Schiff base
      deprotonation and neutralization of Glu-113. To better understand the role of
      electrostatic interactions in receptor photoactivation, absorbance difference
      spectra were collected at time delays from 30 ns to 690 ms after photolysis of
      rhodopsin mutant E113Q solubilized in dodecyl maltoside at different pH values at
      20 degrees C. The PSB form (pH 5. 5, lambda(max) = 496 nm) and the unprotonated
      Schiff base form (pH 8. 2, lambda(max) = 384 nm) of E113Q rhodopsin were excited
      using 477 nm or 355 nm light, respectively. Early photointermediates of both
      forms of E113Q were qualitatively similar to those of wild-type rhodopsin. In
      particular, early photoproducts with spectral shifts to longer wavelengths
      analogous to wild-type bathorhodopsin were seen. In the case of the basic form of
      E113Q, the absorption maximum of this intermediate was at 408 nm. These results
      suggest that steric interaction between the retinylidene chromophore and opsin,
      rather than charge separation, plays the dominant role in energy storage in
      bathorhodopsin. After lumirhodopsin, instead of deprotonating to form
      metarhodopsin I(380) on the submillisecond time scale as is the case for wild
      type, the acidic form of E113Q produced metarhodopsin I(480), which decayed very
      slowly (exponential lifetime = 12 ms). These results show that Glu-113 must be
      present for efficient deprotonation of the Schiff base and rapid visual
      transduction in vertebrate visual pigments.

PMID- 10642186
TI  - Imino proton exchange in DNA catalyzed by ammonia and trimethylamine: evidence
      for a secondary long-lived open state of the base pair.
AB  - The base-pair opening kinetics of the self-complementary oligomer
      d(CGCGAATTCGCG)(2) has been derived from NMR measurements of the imino proton
      exchange. In general, it has previously been found that imino proton exchange in
      duplex DNA is limited by the proton-transfer step from the open state and that
      the dependence of the exchange times on the inverse concentration of an added
      exchange catalyst is linear. In the present study, a curvature is observed for,
      in particular, the innermost AT base pair with both ammonia and trimethylamine
      (TMA) as exchange catalysts. The two catalysts act on the same open states, but
      the accessibility of TMA is reduced by a factor of 2-3 compared to ammonia.
      Assuming that ammonia accesses the imino proton equally in the open state of the
      base pair and in the mononucleoside, the curvature is consistent with 7-9% of the
      openings ending in open states with lifetimes of about 1 micros while the bulk of
      open-state lifetimes fall in the nanosecond range. A curvature is also found for
      the exchange times of the imino protons in the A-tract sequence
      CGCA(8)CGC/GCGT(8)GCG. This curvature becomes increasingly pronounced from the 5'
      end toward the center of the tract and hereby seems to be correlated with the
      contraction of the minor groove. Thus, while the base-pair lifetimes deduced from
      the present study are in accordance with previous measurements, a substantial
      fraction of the open states formed by the central AT-base pairs in the two
      oligomers exhibits microsecond lifetimes in contrast to previous estimates in the
      nanosecond range. These findings may be of relevance for the way sequence
      specific recognition is accomplished by proteins and ligands.

PMID- 10642188
TI  - Hammerhead ribozyme mechanism: A ribonucleotide 5' to the substrate cleavage site
      is not essential

PMID- 10642187
TI  - Equilibrium studies of a fluorescent paclitaxel derivative binding to
      microtubules.
AB  - A fluorescent derivative of paclitaxel, 3'-N-m-aminobenzamido-3'-N
      debenzamidopaclitaxel (N-AB-PT), has been prepared in order to probe paclitaxel
      microtubule interactions. Fluorescence spectroscopy was used to quantitatively
      assess the association of N-AB-PT with microtubules. N-AB-PT was found equipotent
      with paclitaxel in promoting microtubule polymerization. Paclitaxel and N-AB-PT
      underwent rapid exchange with each other on microtubules assembled from GTP-, GDP
      , and GMPCPP-tubulin. The equilibrium binding parameters for N-AB-PT to
      microtubules assembled from GTP-tubulin were derived through fluorescence
      titration. N-AB-PT bound to two types of sites on microtubules (K(d1) = 61 +/-
      7.0 nM and K(d2) = 3.3 +/- 0.54 microM). The stoichiometry of each site was less
      than one ligand per tubulin dimer in the microtubule (n(1) = 0.81 +/- 0.03 and
      n(2) = 0.44 +/- 0.02). The binding experiments were repeated after exchanging the
      GTP for GDP or for GMPCPP. It was found that N-AB-PT bound to a single site on
      microtubules assembled from GDP-tubulin with a dissociation constant of 2.5 +/-
      0.29 microM, and that N-AB-PT bound to a single site on microtubules assembled
      from GMPCPP-tubulin with a dissociation constant of 15 +/- 4.0 nM. It therefore
      appears that microtubules contain two types of binding sites for paclitaxel and
      that the binding site affinity for paclitaxel depends on the nucleotide content
      of tubulin. It has been established that paclitaxel binding does not inhibit GTP
      hydrolysis and microtubules assembled from GTP-tubulin in the presence of
      paclitaxel contain almost exclusively GDP at the E-site. We propose that although
      all the subunits of the microtubule at steady state are the same "GDP-tubulin
      paclitaxel", they are formed through two paths: paclitaxel binding to a tubulin
      subunit before its E-site GTP hydrolysis is of high affinity, and paclitaxel
      binding to a tubulin subunit containing hydrolyzed GDP at its E-site is of low
      affinity.

PMID- 10642189
TI  - Redox cycles in trimethylamine dehydrogenase and mechanism of substrate
      inhibition

PMID- 10642190
TI  - Modulation of the redox potential of the

PMID- 10642191
TI  - Statistics of Dark Matter Halos from Gravitational Lensing.
AB  - We present a new approach to measure the mass function of dark matter halos and
      to discriminate models with differing values of Omega through weak gravitational
      lensing. We measure the distribution of peaks from simulated lensing surveys and
      show that the lensing signal due to dark matter halos can be detected for a wide
      range of peak heights. Even when the signal-to-noise ratio is well below the
      limit for detection of individual halos, projected halo statistics can be
      constrained for halo masses spanning galactic to cluster halos. The use of peak
      statistics relies on an analytical model of the noise due to the intrinsic
      ellipticities of source galaxies. The noise model has been shown to accurately
      describe simulated data for a variety of input ellipticity distributions. We show
      that the measured peak distribution has distinct signatures of gravitational
      lensing, and its non-Gaussian shape can be used to distinguish models with
      different values of Omega. The use of peak statistics is complementary to the
      measurement of field statistics, such as the ellipticity correlation function,
      and is possibly not susceptible to the same systematic errors.

PMID- 10642192
TI  - Has Blending Compromised Cepheid-based Determinations of the Extragalactic
      Distance Scale?
AB  - We examine the suggestion that half of the galaxies observed by the Hubble Space
      Telescope Key Project and the Type Ia Supernova Calibration Team have had their
      distances systematically underestimated, by 0.1-0.3 mag in the distance modulus,
      because of the underappreciated influence of stellar profile blending on the Wide
      Field Camera chips. The signature of such an effect would be a systematic trend
      in (1) the Type Ia supernova-corrected peak luminosity and (2) the Tully-Fisher
      residuals, with increasing calibrator distance, and (3) a differential offset
      between Planetary Camera and Wide Field Camera distance moduli, within the same
      galaxy. The absence of a trend would be expected if blending were negligible (as
      has been inherently assumed in the analyses of the aforementioned teams). We
      adopt a functional form for the predicted influence of blending that is
      consistent with the models of Mochejska et al. and Stanek & Udalski, and we
      demonstrate that the expected correlation with distance predicted by these
      studies is not supported by the data. We conclude that the Cepheid-based
      extragalactic distance scale has not been severely compromised by the neglect of
      blending.

PMID- 10642193
TI  - Environment of the Gamma-Ray Burst GRB 971214: A Giant H ii Region Surrounded by
      a Galactic Supershell.
AB  - Among a number of gamma-ray bursts whose host galaxies are known, GRB 971214
      stands out for its high redshift (z>/=3) and the Lyalpha emission line having a P
      Cygni-type profile, which is interpreted to be a direct consequence of the
      expanding supershell. From a profile-fitting analysis, we estimate the expansion
      velocity of the supershell (vexp=1500 km s-1) and the neutral column density
      (NHi=1020 cm -2). The redshift z=3.418 of the host galaxy proposed by Kulkarni et
      al. in 1998 has been revised to be z=3.425 from our profile analysis. The
      observed Lyalpha profile is fitted well by a Gaussian curve, which yields the
      Lyalpha luminosity LLyalpha=&parl0;1.8+/-0.8&parr0;x1042 ergs s-1. Assuming that
      the photon source is a giant H ii region, we deduce the electron number density
      in the H ii region ne=&parl0;40+/
      10&parr0;&parl0;L/LLyalpha&parr0;0.5&parl0;R/100 pc&parr0;-1.5 cm-3, which
      corresponds to the illumination by about 104 O5 stars. We estimate the star
      formation rate to be RSF=7+/-3 M middle dot in circle yr-1 with the internal and
      the Galactic extinction corrected. The theory on the evolution of supernova
      remnants is used to propose that the supershell is at the adiabatic phase, with
      its radius R=18E1&solm0;253 pc, its age t=4.7x103E1&solm0;253 yr, and the density
      of the ambient medium n1=5.4E-1&solm0;253 cm-3, where E53=E&solm0;1053 ergs; we
      estimate the kinetic energy of the supershell to be Ek=7.3x1052E53 ergs. These
      values are consistent with the hypothesis that the supershell is the remnant of a
      gamma-ray burst. We note similarities between supershells found in nearby
      galaxies and remote primeval galaxies and propose that the gamma-ray burst may
      have occurred in a giant H ii region whose environment is similar to that in star
      forming galaxies.

PMID- 10642194
TI  - Hubble Space Telescope and Very Large Array Observations of the H2O Gigamaser
      Galaxy TXS 2226-184.
AB  - We present Hubble Space Telescope/Wide-Field and Planetary Camera 2 images in
      Halpha + [N ii] lambdalambda6548, 6583 lines and continuum radiation and a VLA
      map at 8 GHz of the H2O gigamaser galaxy TXS 2226-184. This galaxy has the most
      luminous H2O maser emission known to date. Our red continuum images reveal a
      highly elongated galaxy with a dust lane crossing the nucleus. The surface
      brightness profile is best fitted by a bulge plus exponential disk model,
      favoring classification as a highly inclined spiral galaxy (i=70&j0;). The color
      map confirms that the dust lane is aligned with the galaxy major axis and is
      crossing the putative nucleus. The Halpha + [N ii] map exhibits a gaseous,
      jetlike structure perpendicular to the nuclear dust lane and the galaxy major
      axis. The radio map shows compact, steep spectrum emission that is elongated in
      the same direction as the Halpha + [N ii] emission. By analogy with Seyfert
      galaxies, we therefore suspect that this alignment reflects an interaction
      between the radio jet and the interstellar medium. The axes of the nuclear dust
      disk, the radio emission, and the optical line emission apparently define the
      axis of the active galactic nucleus. The observations suggest that in this galaxy
      the nuclear accretion disk, obscuring torus, and large-scale molecular gas layer
      are roughly coplanar. Our classification of the host galaxy strengthens the trend
      for megamasers to be found preferentially in highly inclined spiral galaxies.

PMID- 10642195
TI  - The Dwarf Irregular Galaxy UGC 7636 Exposed: Stripping at Work in the Virgo
      Cluster.
AB  - We present the results of optical spectroscopy of a newly discovered H ii region
      residing in the H i gas cloud located between the dwarf irregular galaxy UGC 7636
      and the giant elliptical galaxy NGC 4472 in the Virgo Cluster. By comparing UGC
      7636 with dwarf irregular galaxies in the field, we show that the H i cloud must
      have originated from UGC 7636 because (1) the oxygen abundance of the cloud
      agrees with that expected for a galaxy with the blue luminosity of UGC 7636 and
      (2) MHi&solm0;LB for UGC 7636 becomes consistent with the measured oxygen
      abundance of the cloud if the H i mass of the cloud is added back into UGC 7636.
      It is likely that tides from NGC 4472 first loosened the H i gas, after which ram
      pressure stripping removed the gas from UGC 7636.

PMID- 10642196
TI  - Ultracompact X-Ray Binaries in Globular Clusters: Variability of the Optical
      Counterpart of X1832-330 in NGC 6652.
AB  - Evidence is emerging that the luminous X-ray sources in the cores of globular
      clusters may often consist of, or perhaps even as a class be dominated by,
      ultracompact (P less, similar1 hr) binary stars. To the two such systems already
      known, in NGC 6624 and NGC 6712, we now add evidence for two more. We detect
      large-amplitude variability in the candidate optical counterpart for the X-ray
      source in the core of NGC 6652. Although the available observations are
      relatively brief, the existing Hubble Space Telescope data indicate a strong 43.6
      minute periodic modulation of the visible flux of semiamplitude 30%. Further,
      although the orbital period of the source in NGC 1851 is not yet explicitly
      measured, we demonstrate that previous correlations of optical luminosity with X
      ray luminosity and accretion disk size, strengthened by recent data, strongly
      imply that the period of that system is also less than 1 hr. Thus, currently
      there is evidence that four of the seven globular cluster X-ray sources with
      constrained periods are ultracompact, a fraction far greater than that found in X
      ray binaries the field.

PMID- 10642197
TI  - The Evolutionary Status of SS 433.
AB  - We consider possible evolutionary models for SS 433. We assume that common
      envelope evolution is avoided if radiation pressure is able to expel most of a
      super-Eddington accretion flow from a region smaller than the accretor's Roche
      lobe. This condition is satisfied, at least initially, for largely radiative
      donors with masses in the range 4-12 M middle dot in circle. For donors more
      massive than about 5 M middle dot in circle, moderate mass ratios q=M2&solm0;M1
      greater, similar1 are indicated, thus tending to favor black hole accretors. For
      lower mass donors, evolutionary considerations do not distinguish between a
      neutron star or black hole accretor. In all cases the mass transfer (and mass
      loss) rates M&d2;tr approximately 7x10-6 to 4x10-4 M middle dot in circle yr-1
      are much larger than the likely mass-loss rate M&d2;jet approximately 10-6 M
      middle dot in circle yr-1 in the precessing jets. Almost all of the transferred
      mass is expelled at radii considerably larger than the jet acceleration region,
      producing the "stationary" Halpha line and the infrared luminosity and accounting
      for the low X-ray luminosity.

PMID- 10642198
TI  - Discovery of Circularly Polarized Radio Emission from SS 433.
AB  - We report the discovery of circularly polarized radio emission from the radio-jet
      X-ray binary SS 433 with the Australia Telescope Compact Array. The flux density
      spectrum of the circular polarization, clearly detected at four frequencies
      between 1 and 9 GHz, is of the form V~nu-0.9+/-0.1. Multiple components in the
      source and a lack of very high spatial resolution do not allow a unique
      determination of the origin of the circular polarization or of the spectrum of
      fractional polarization. However, we argue that the emission is likely to arise
      in the inner regions of the binary, possibly via propagation-induced conversion
      of linear to circular polarization, and the fractional circular polarization of
      these regions may be as high as 10%. Observations such as these have the
      potential to help us investigate the composition, whether pairs or baryonic, of
      the ejecta from X-ray binaries.

PMID- 10642199
TI  - The Orbital Period of the Be/Neutron Star Binary RX J0812.4-3114.
AB  - We present the results of Rossi X-Ray Timing Explorer (RXTE) observations of the
      Be star X-ray binary system RX J0812.4-3114. A light curve obtained with the RXTE
      All-Sky Monitor (ASM) shows that the source is currently in an active state with
      outbursts occurring at approximately 80 day intervals. The source underwent a
      transition from an inactive state to this regular outburst state early in 1998.
      An observation of RX J0812.4-3114 was obtained with the RXTE Proportional Counter
      Array (PCA) close to the time of a predicted maximum in 1999 March, and strong
      pulsations were detected at a period of 31.88 s. This confirms the result of an
      earlier PCA observation by Reig & Roche that was also obtained serendipitously
      near the predicted maximum flux of the 80 day period and also near the start of
      the current active state. We interpret the periodicity in the ASM light curve as
      indicating the orbital period of RX J0812.4-3114 with outbursts occurring around
      periastron passage.

PMID- 10642200
TI  - The Temperature and Cooling Age of the White Dwarf Companion to the Millisecond
      Pulsar PSR B1855+09.
AB  - We report on Keck and Hubble Space Telescope observations of the binary
      millisecond pulsar PSR B1855+09. We detect its white dwarf companion and measure
      mF555W=25.90+/-0.12 and mF814W=24.19+/-0.11 (Vega system). From the reddening
      corrected color, (mF555W-mF814W&parr0;0=1.06+/-0.21, we infer a temperature
      Teff=4800+/-800 K. The white dwarf mass is known accurately from measurements of
      the Shapiro delay of the pulsar signal, MC=0.258+0.028-0.016 M middle dot in
      circle. Hence, given a cooling model, one can use the measured temperature to
      determine the cooling age. The main uncertainty in the cooling models for such
      low-mass white dwarfs is the amount of residual nuclear burning, which is set by
      the thickness of the hydrogen layer surrounding the helium core. From the
      properties of similar systems, it has been inferred that helium white dwarfs form
      with thick hydrogen layers, with mass greater, similar3x10-3 M middle dot in
      circle, which leads to significant additional heating. This is consistent with
      expectations from simple evolutionary models of the preceding binary evolution.
      For PSR B1855+09, though, such models lead to a cooling age of approximately 10
      Gyr, which is twice the spin-down age of the pulsar. It could be that the spin
      down age were incorrect, which would call the standard vacuum dipole braking
      model into question. For two other pulsar companions, however, ages well over 10
      Gyr are inferred, indicating that the problem may lie with the cooling models.
      There is no age discrepancy for models in which the white dwarfs are formed with
      thinner hydrogen layers ( less, similar3x10-4 M middle dot in circle).

PMID- 10642201
TI  - RR Lyrae Stars in NGC 6388 and NGC 6441: A New Oosterhoff Group?
AB  - NGC 6388 and NGC 6441 are anomalies among Galactic globular clusters in that they
      cannot be readily placed into either Oosterhoff group I or Oosterhoff group II
      despite their significant numbers of RR Lyrae variables. The mean pulsation
      periods, &angl0;Pab&angr0;, of their RRab variables, at 0.71 and 0.76 days,
      respectively, are even larger than for Oosterhoff II clusters. Moreover,
      Oosterhoff II clusters are very metal poor, whereas NGC 6388 and NGC 6441 are the
      most metal-rich globular clusters known to contain RR Lyrae stars. The location
      of the NGC 6388 and NGC 6441 RRab variables in the period-amplitude diagram
      implies that the RR Lyrae stars in those two clusters are brighter than expected
      for their metallicities. Our results therefore indicate that a universal
      relationship may not exist between the luminosity and the metallicity of RR Lyrae
      variables.

PMID- 10642202
TI  - Evolutionary Model and Oscillation Frequencies for alpha Ursae Majoris: A
      Comparison with Observations.
AB  - Inspired by the observations of low-amplitude oscillations of alpha Ursae Majoris
      A by Buzasi et al. using the WIRE satellite, a grid of stellar evolutionary
      tracks has been constructed to derive physically consistent interior models for
      the nearby red giant. The pulsation properties of these models were then
      calculated and compared with the observations. It is found that, by adopting the
      correct metallicity and for a normal helium abundance, only models in the mass
      range of 4.0-4.5 M middle dot in circle fall within the observational error box
      for alpha UMa A. This mass range is compatible, within the uncertainties, with
      the mass derived from the astrometric mass function. Analysis of the pulsation
      spectra of the models indicates that the observed alpha UMa oscillations can be
      most simply interpreted as radial (i.e., l=0) p-mode oscillations of low radial
      order n. The lowest frequencies observed by Buzasi et al. are compatible, within
      the observational errors, with model frequencies of radial orders n=0, 1, and 2
      for models in the mass range of 4.0-4.5 M middle dot in circle. The higher
      frequencies observed can also be tentatively interpreted as higher n-valued
      radial p-modes, if we allow that some n-values are not presently observed. The
      theoretical l=1, 2, and 3 modes in the observed frequency range are g-modes with
      a mixed mode character, that is, with p-mode-like characteristics near the
      surface and g-mode-like characteristics in the interior. The calculated radial p
      mode frequencies are nearly equally spaced, separated by 2-3 uHz. The nonradial
      modes are very densely packed throughout the observed frequency range and, even
      if excited to significant amplitudes at the surface, are unlikely to be resolved
      by the present observations.

PMID- 10642203
TI  - Broad Halpha Wing Formation in the Planetary Nebula IC 4997.
AB  - The young and compact planetary nebula IC 4997 is known to exhibit very broad
      wings with a width exceeding 5000 km s-1 around Halpha. We propose that the broad
      wings are formed through Rayleigh-Raman scattering that involves atomic hydrogen,
      by which Lybeta photons with a velocity width of a few 102 km s-1 are converted
      to optical photons and fill the Halpha broad wing region. The conversion
      efficiency reaches 0.6 near the line center, where the scattering optical depth
      is much larger than 1, and rapidly decreases in the far wings. Assuming that
      close to the central star there exists an unresolved inner compact core of high
      density, nH approximately 109-1010 cm-3, we use the photoionization code "CLOUDY"
      to show that sufficient Lybeta photons for scattering are produced. Using a top
      hat-incident profile for the Lybeta flux and a scattering region with a H i
      column density NHi=2x1020 cm-2 and a substantial covering factor, we perform a
      profile-fitting analysis in order to obtain a satisfactory fit to the observed
      flux. We briefly discuss the astrophysical implications of the Rayleigh-Raman
      processes in planetary nebulae and other emission objects.

PMID- 10642204
TI  - Paying for the NHS. First decide how much we are willing to pay, then think about
      how to collect it.

PMID- 10642205
TI  - Improving cancer outcomes through radiotherapy. Lack of UK radiotherapy resources
      prejudices cancer outcomes.

PMID- 10642206
TI  - The rise in bacterial resistance is partly because there have been no new classes
      of antibiotics since the 1960s.

PMID- 10642207
TI  - Why can't GPs follow guidelines on depression? We must question the basis of the
      guidelines themselves.

PMID- 10642208
TI  - Private health care: modernisation stops here. The government has missed an
      opportunity to regulate--and integrate--the private sector properly.

PMID- 10642209
TI  - US health spending accelerated in 1998.

PMID- 10642211
TI  - Pinochet's opponents call for medical evidence to be made public

PMID- 10642210
TI  - Patients with cancer asked to sign waivers on dangers of delays.

PMID- 10642213
TI  - In brief

PMID- 10642212
TI  - Scientists make rats' torn nerves regenerate

PMID- 10642215
TI  - Lord winston attacks Labour's health policy

PMID- 10642214
TI  - Blair promises to raise spending on NHS to european average

PMID- 10642216
TI  - UK nurses and doctors receive pay boost.

PMID- 10642217
TI  - US company claims to have 90% of human genome on its database.

PMID- 10642218
TI  - EU law makes netherlands reconsider its health system

PMID- 10642219
TI  - EU law makes Netherlands reconsider its health system.

PMID- 10642221
TI  - US relaxes its guidelines on herbal supplements.

PMID- 10642222
TI  - Drug companies seek MS patients to lobby for new products.

PMID- 10642223
TI  - European commission proposes a European food authority.

PMID- 10642224
TI  - Mental health experts should offer training to GPs, report says.

PMID- 10642225
TI  - Non-compliance often the cause when AIDS drugs "fail"

PMID- 10642226
TI  - A systematic review of treatments for settling problems and night waking in young
      children.
AB  - OBJECTIVES: To assess the efficacy of treatments for settling problems and night
      waking in young children. DESIGN: A systematic review of randomised controlled
      trials of interventions for settling problems and night waking in young children.
      SETTING: Electronic bibliographic databases and references on identified papers,
      hand searches, and personal contact with specialists. SUBJECTS: Children aged 5
      years or less who had established settling problems or night waking.
      INTERVENTIONS: Interventions had to be described and a placebo, waiting list, or
      another intervention needed to have been used as a comparison. Interventions
      comprised drug trials or non-drug trials. MAIN OUTCOME MEASURES: Number of wakes
      at night, time to settle, or number of nights in which these problems occurred.
      RESULTS: Drugs seemed to be effective in treating night waking in the short term,
      but long term efficacy was questionable. In contrast, specific behavioural
      interventions showed both short term efficacy and possible longer term effects
      for dealing with settling problems and night waking. CONCLUSIONS: Given the
      prevalence and persistence of childhood sleep problems and the effects they can
      have on children and families, treatments that offer long lasting benefits are
      appealing and these are likely to be behavioural interventions.

PMID- 10642228
TI  - Disability is in the mind of the beholder

PMID- 10642227
TI  - Bacteraemia and antibiotic resistance of its pathogens reported in England and
      Wales between 1990 and 1998: trend analysis.
AB  - OBJECTIVES: Determination of causes, trends, and antibiotic resistance in reports
      of bacterial pathogens isolated from blood in England and Wales from 1990 to
      1998. DESIGN: Description of bacterial isolates from blood, judged to be
      clinically significant by microbiology staff, reported to the Communicable
      Disease Surveillance Centre. SETTING: Microbiology laboratories in England and
      Wales. SUBJECTS: Patients yielding clinically significant isolates from blood.
      MAIN OUTCOME MEASURES: Frequency and Poisson regression analyses for trend of
      reported causes of bacteraemia and proportions of antibiotic resistant isolates.
      RESULTS: There was an upward trend in total numbers of reports of bacteraemia.
      The five most cited organisms accounted for over 60% of reports each year. There
      was a substantial increase in the proportion of reports of Staphylococcus aureus
      resistant to methicillin, Streptococcus pneumoniae resistance to penicillin and
      erythromycin, and Enterococcus faecalis and Enterococcus faecium resistance to
      vancomycin. No increase was seen in resistance of Escherichia coli to gentamicin.
      CONCLUSIONS: Reports from laboratories provide valuable information on trends and
      antibiotic resistance in bacteraemia and show a worrying increase in resistance
      to important antibiotics.

PMID- 10642229
TI  - Response to diphtheria booster vaccination in healthy adults: vaccine trial.

PMID- 10642230
TI  - "I don't like Mondays"-day of the week of coronary heart disease deaths in
      Scotland: study of routinely collected data.

PMID- 10642231
TI  - Systemic granulomatous disease after intravesical BCG instillation.

PMID- 10642232
TI  - Risk assessment of left ventricular systolic dysfunction in primary care: cross
      sectional study evaluating a range of diagnostic tests.
AB  - OBJECTIVES: To assess the probability of left ventricular systolic dysfunction
      without echocardiography in patients from general practice. DESIGN: Cross
      sectional study using multivariate regression models to examine the relation
      between clinical variables and left ventricular systolic dysfunction as
      determined by echocardiography. SETTING: Three general practices in Copenhagen.
      SUBJECTS: 2158 patients aged >40 years were screened by questionnaires and case
      record reviews; 357 patients with past or present signs or symptoms of heart
      disease were identified, of whom 126 were eligible for and consented to
      examination. MAIN OUTCOME MEASURES: Clinical variables that were significantly
      (P<0.05) related to ejection fraction </=0.45 and their predictive value for left
      ventricular systolic dysfunction. RESULTS: 15 patients (12%) had left ventricular
      systolic dysfunction. The prevalence was significantly related to three
      questions: does the electrocardiogram have Q waves, left bundle branch block, or
      ST-T segment changes? (P=0.012); is resting supine heart rate greater than the
      simultaneous diastolic blood pressure? (P=0.002); and is plasma N-terminal atrial
      natriuretic peptide>0.8 nmol/l? (P=0.040)? Only one of 60 patients with a normal
      electrocardiogram had systolic dysfunction (2%, 95% confidence interval 0% to 9%)
      regardless of response to the other two questions. The risk of dysfunction was
      appreciable in patients with a yes answer to two or three questions (50%, 27% to
      73%). CONCLUSIONS: A normal electrocardiogram implies a low risk of left
      ventricular systolic dysfunction. Patients can be identified for echocardiography
      on the basis of an abnormal electrocardiogram combined with increased natriuretic
      peptide concentration or a heart rate greater than diastolic blood pressure, or
      both.

PMID- 10642234
TI  - National enthusiasm and alcohol

PMID- 10642233
TI  - Evaluation of the effectiveness of an educational intervention for general
      practitioners in adolescent health care: randomised controlled trial.
AB  - OBJECTIVE: To evaluate the effectiveness of an educational intervention in
      adolescent health designed for general practitioners in accordance with evidence
      based practice in continuing medical education. DESIGN: Randomised controlled
      trial with baseline testing and follow up at seven and 13 months. SETTING: Local
      communities in metropolitan Melbourne, Australia. PARTICIPANTS: 108 self selected
      general practitioners. INTERVENTION: A multifaceted educational programme for 2.5
      hours a week over six weeks on the principles of adolescent health care followed
      six weeks later by a two hour session of case discussion and debriefing. OUTCOME
      MEASURES: Objective ratings of consultations with standardised adolescent
      patients recorded on videotape. Questionnaires completed by the general
      practitioners were used to measure their knowledge, skill, and self perceived
      competency, satisfaction with the programme, and self reported change in
      practice. RESULTS: 103 of 108 (95%) doctors completed all phases of the
      intervention and evaluation protocol. The intervention group showed significantly
      greater improvements in all outcomes than the control group at the seven month
      follow up except for the rapport and satisfaction rating by the standardised
      patients. 104 (96%) participants found the programme appropriate and relevant. At
      the 13 month follow up most improvements were sustained, the confidentiality
      rating by the standardised patients decreased slightly, and the objective
      assessment of competence further improved. 106 (98%) participants reported a
      change in practice attributable to the intervention. CONCLUSIONS: General
      practitioners were willing to complete continuing medical education in adolescent
      health care and its evaluation. The design of the intervention using evidence
      based educational strategies proved an effective and quick way to achieve
      sustainable and large improvements in knowledge, skill, and self perceived
      competency.

PMID- 10642236
TI  - Lesson of the week. Warming milk-a preventable cause of scalds in children.

PMID- 10642235
TI  - Science, medicine, and the future. Allergic disorders.

PMID- 10642237
TI  - ABC of heart failure. Clinical features and complications.

PMID- 10642238
TI  - Concerns about immunisation.

PMID- 10642240
TI  - Smoking: a hateful custom

PMID- 10642239
TI  - Not thinking of things

PMID- 10642241
TI  - Clinical trial safety committees: the devil's spoon.

PMID- 10642242
TI  - Using cost effectiveness information.

PMID- 10642243
TI  - Meningococcal disease in healthcare workers. Vaccine is available in Latin
      America.

PMID- 10642244
TI  - Guided self management of asthma. More information is needed on what patients
      think about such management.

PMID- 10642245
TI  - Why mortality from heart disease is low in France. Rates of coronary events are
      similar in France and Southern Europe.

PMID- 10642246
TI  - Private finance initiative. Partnership between private and NHS is not
      necessarily wrong.

PMID- 10642247
TI  - Medical advice columns give both good and bad counsel.

PMID- 10642248
TI  - Patient partnership is just one aspect of treating patients.

PMID- 10642249
TI  - Composite indicators may not be helpful in comparing health authorities.

PMID- 10642250
TI  - Obituaries

PMID- 10642251
TI  - GPs given advice on primary care trusts

PMID- 10642252
TI  - Auscultation skills: breath and heart sounds

PMID- 10642253
TI  - What a blessing she had chloroform

PMID- 10642254
TI  - Wit

PMID- 10642255
TI  - The flu news epidemic

PMID- 10642256
TI  - Competing interests

PMID- 10642258
TI  - Changes

PMID- 10642257
TI  - Surfacing after burnout

PMID- 10642260
TI  - Behavioural treatment may help solve childhood sleep problems

PMID- 10642259
TI  - Getting a prime minister to turn: roast slowly and then turn up the heat suddenly

PMID- 10642261
TI  - Reporting of blood cultures shows worrying increase in antibiotic resistance in
      england and wales

PMID- 10642262
TI  - Single booster dose does not protect adults from diphtheria

PMID- 10642264
TI  - Simple tests help identify systolic dysfunction in primary care

PMID- 10642263
TI  - More deaths from heart disease in scotland on mondays may relate to binge
      drinking

PMID- 10642265
TI  - Evidence based education in adolescent health seems to work

PMID- 10642267
TI  - Impact of different partition values on prevalences of left ventricular
      hypertrophy and concentric geometry in a large hypertensive population : the LIFE
      study.
AB  - Left ventricular (LV) hypertrophy and concentric remodeling have been defined by
      using a variety of indexation methods and partition values (PVs) for LV mass and
      relative wall thickness (RWT). The effects of these methods on the distribution
      of LV geometric patterns in hypertensive subjects remain unclear. Echocardiograms
      were obtained in 941 patients with stage I to III hypertension and LV hypertrophy
      by ECG. LV mass was calculated by using different methods of indexation for body
      size and different PVs to identify hypertrophy: LV mass/body surface area
      (g/m(2)) PV for men/women 116/104, 125/110, or 125/125; LV mass/height (g/m) PV
      143/102 or 126/105; and LV mass/height(2.7) (g/m(2.7)) PV 51/51 or 49.2/46.7. RWT
      was calculated by either 2xend-diastolic posterior wall thickness (PWT)/end
      diastolic LV internal dimension (LVID) or end-diastolic interventricular septum
      dimension+end-diastolic PWT/end-diastolic LVID. LV hypertrophy or remodeling was
      present in 63% to 86% of subjects, and LV hypertrophy was present in 42% to 77%.
      By any index, eccentric hypertrophy was the common LV geometric pattern. Use of
      interventricular septum dimension+PWT/LVID to calculate RWT slightly increased
      the prevalence of normal geometry and eccentric hypertrophy compared with the use
      of 2xPWT/LVID. Subjects with LV hypertrophy identified by only LV
      mass/height(2.7) PV 49.2/46.7 were more obese, whereas those identified by only
      LV mass/body surface area PV 116/104 were taller and thinner than those in the 2
      concordant groups with or without LV hypertrophy by both criteria. By either
      criterion, there were no significant differences between different LV geometric
      patterns in clinical cardiovascular disease. Hypertensive patients with LV
      hypertrophy by ECG have a high prevalence of geometric abnormalities, especially
      eccentric hypertrophy, irrespective of method of indexation or PV. LV mass
      indexation by body surface area or height(2.7) identifies lean and obese
      subjects, respectively. We found no difference in prevalent cardiovascular
      disease in subjects identified by either criterion, suggesting a similar high
      risk.

PMID- 10642268
TI  - Effect of obesity on electrocardiographic left ventricular hypertrophy in
      hypertensive patients : the losartan intervention for endpoint (LIFE) reduction
      in hypertension study.
AB  - Obesity may limit sensitivity of ECG voltage criteria for left ventricular
      hypertrophy (LVH) because of the attenuating effects of increased body mass on
      precordial voltages. However, obesity is associated with an increased prevalence
      of anatomic LVH, making more accurate ECG criteria in obese patients a clinical
      priority. ECG LVH by Cornell voltage-duration product and/or Sokolow-Lyon voltage
      criteria was used to select patients for the Losartan Intervention For Endpoint
      (LIFE) Reduction in Hypertension Study. Clinical and ECG data were available in
      8417 patients (54% women; mean age, 67+/-7 years); 2519 were overweight and 1573
      were obese by gender-specific body mass index criteria. Increased body mass index
      had significant but directionally opposite effects on ECG LVH by these 2
      criteria. Compared with normal-weight patients, obese and overweight patients had
      lower Sokolow-Lyon voltage and a lower prevalence of ECG LVH by Sokolow-Lyon
      criteria (10.9% versus 16.2% versus 31.4%; P<0.001). In contrast, obese and
      overweight patients had higher mean values of the Cornell product and higher
      prevalences of ECG LVH by this criterion (75.1% versus 69.9% versus 60.7%; P<0.
      001). After adjustment for age, gender, race, myocardial infarction, and
      diastolic and pulse pressure with the use of logistic regression analysis,
      increased body mass remained highly predictive of the presence of ECG LVH.
      Compared with normal-weight patients, obese patients had a >2-fold higher risk of
      ECG LVH by the Cornell product but a 4-fold lower risk of ECG LVH by Sokolow-Lyon
      voltage; overweight status was associated with intermediate risks, with a 151%
      greater likelihood of ECG LVH by the Cornell product but only 44% of the risk of
      LVH by Sokolow-Lyon voltage criteria compared with normal-weight individuals.
      Thus, Sokolow-Lyon voltage criteria underestimate the prevalence of anatomic LVH
      in the presence of obesity, whereas Cornell product criteria for ECG LVH appear
      to provide a more accurate measure of LVH in obese and overweight patients.

PMID- 10642269
TI  - Inhibitory regulation of hypertrophy by endogenous atrial natriuretic peptide in
      cultured cardiac myocytes.
AB  - Atrial natriuretic peptide (ANP) may function as an endogenous regulator of
      cardiac hypertrophy, because the natriuretic peptide receptor has been found in
      the heart and because mice lacking its receptor have been shown to have a
      markedly elevated ventricular mass. We examined the role of endogenous ANP in
      cardiac hypertrophy in vitro. The effects of the blockade of endogenous ANP by
      its receptor antagonist, HS-142-1, on cell hypertrophy were investigated with the
      use of cultured neonatal rat ventricular myocytes. HS-142-1 increased the basal
      and phenylephrine (PE, 10(-5) mol/L)-stimulated protein syntheses in a
      concentration-dependent manner (1 to 300 microg/mL). A significant increase in
      the cell size of myocytes was also induced by this antagonist. In addition, the
      expression levels of skeletal alpha-actin, beta-myosin heavy chain, and ANP
      genes, markers of hypertrophy, were partially elevated by treatment with HS-142-1
      (100 microg/mL) under nonstimulated or PE-stimulated conditions. A cGMP-specific
      phosphodiesterase inhibitor, zaprinast (5x10(-4) mol/L), and a cGMP analogue (10(
      4) mol/L) suppressed the basal and PE-stimulated protein syntheses. Our
      observations suggest that endogenous ANP inhibits cardiac myocyte hypertrophy
      under basal and PE-stimulated conditions, probably through a cGMP-dependent
      process. ANP may play a role as an autocrine factor in the regulation of cardiac
      myocyte growth.

PMID- 10642270
TI  - Kallikrein gene delivery attenuates myocardial infarction and apoptosis after
      myocardial ischemia and reperfusion.
AB  - The tissue kallikrein-kinin system is present in the heart, and kinin has been
      shown to have cardioprotective effects. In this study, we investigated the
      potential role of tissue kallikrein in myocardial ischemia/reperfusion injury
      through adenovirus-mediated human kallikrein gene delivery. One week after gene
      delivery, the rats were subjected to a 30-minute coronary occlusion followed by a
      2-hour reperfusion. Kallikrein gene delivery caused significant decreases in the
      ratio of infarct size to ischemic area at risk (from 69.6% to 44.5%, n=10 and 8,
      P<0.01) and in the incidence of ventricular fibrillation (from 64.3% to 16.7%,
      n=14 and 24, P<0.01) compared with the group injected with control adenovirus.
      Kallikrein gene delivery also attenuated programmed cell death in the ischemic
      area compared with the control area as assessed with the terminal
      deoxynucleotidyl transferase-mediated nick end labeling assay (n=6, P<0.01).
      Icatibant, a specific bradykinin B(2) receptor antagonist, abolished these
      kallikrein-mediated beneficial effects. The expression of human tissue kallikrein
      mRNA was identified in rat heart, kidney, lung, liver, and adrenal gland. After
      kallikrein gene delivery, cardiac kinin and cGMP levels were significantly
      elevated compared with the control (29.6+/-12.7 versus 6.1+/-2.1 pg/mg protein,
      n=7, P<0.01; 1.30+/-0.06 versus 0.86+/-0.09 pmol/mg protein, n=5, P<0.05). These
      results indicate that kallikrein gene delivery protects against myocardial
      infarction, ventricular arrhythmias, and apoptosis in ischemia/reperfusion injury
      via kinin-cGMP signal pathway. The successful application of this technology may
      have potential therapeutic value in the treatment of coronary artery diseases.

PMID- 10642271
TI  - Potentiation of the vascular response to kinins by inhibition of myocardial
      kininases.
AB  - Inhibitors of angiotensin I-converting enzyme (ACE) are very efficacious in the
      potentiation of the actions of bradykinin (BK) and are able to provoke a B(2)
      receptor-mediated vasodilation even after desensitization of this receptor.
      Because this activity cannot be easily explained only by an inhibition of kinin
      degradation, direct interactions of ACE inhibitors with the B(2) receptor or its
      signal transduction have been hypothesized. To clarify the significance of
      degradation-independent potentiation, we studied the vasodilatory effects of BK
      and 2 degradation-resistant B(2) receptor agonists in the isolated rat heart, a
      model in which ACE and aminopeptidase P (APP) contribute equally to the
      degradation of BK. Coronary vasodilation to BK and to a peptidic (B6014) and a
      nonpeptidic (FR190997) degradation-resistant B(2) agonist was assessed in the
      presence or absence of the ACE inhibitor ramiprilat, the APP inhibitor
      mercaptoethanol, or both. Ramiprilat or mercaptoethanol induced leftward shifts
      in the BK dose-response curve (EC(50)=3.4 nmol/L) by a factor of 4.6 or 4.9,
      respectively. Combined inhibition of ACE and APP reduced the EC(50) of BK to 0.18
      nmol/L (ie, by a factor of 19) but potentiated the activity of B6014 (EC(50)=1.9
      nmol/L) only weakly without altering that of FR190997 (EC(50)=0.34 nmol/L).
      Desensitization of B(2) receptors was induced by the administration of BK (0.2
      micromol/L) or FR190997 (0.1 micromol/L) for 30 minutes; the vascular reactivity
      to ramiprilat or increasing doses of BK was tested thereafter. After
      desensitization with BK, but not FR190997, an additional application of
      ramiprilat provoked a B(2) receptor-mediated vasodilation. High BK concentrations
      were still effective at the desensitized receptor. The process of desensitization
      was not altered by ramiprilat. These results show that in this model, all
      potentiating actions of ACE inhibitors on kinin-induced vasodilation are
      exclusively related to the reduction in BK breakdown and are equivalently
      provoked by APP inhibition. The desensitization of B(2) receptors is overcome by
      increasing BK concentrations, either directly or through the inhibition of ACE.
      These observations do not suggest any direct interactions of ACE inhibitors with
      the B(2) receptor or its signal transduction but point to a very high activity of
      BK degradation in the vicinity of the B(2) receptor in combination with a
      stimulation-dependent reduction in receptor affinity.

PMID- 10642272
TI  - G-Protein-coupled receptor kinase activity in hypertension : increased vascular
      and lymphocyte G-protein receptor kinase-2 protein expression.
AB  - Impaired receptor-stimulated adenylyl cyclase activation has been observed in
      lymphocytes from hypertensive subjects and has been linked to an increase in
      lymphocyte G-protein receptor kinase-2 (GRK-2) protein expression. However,
      whether the increase in lymphocyte GRK-2 reflected an increase in vascular GRK-2
      was unknown. Therefore, we compared GRK-2 protein expression in lymphocytes and
      aortas obtained from normotensive Wistar rats, Wistar-Kyoto rats (WKY), and
      spontaneously hypertensive rats (SHR) and from aortas of Dahl rats. Impaired beta
      adrenergic responsiveness was observed in lymphocytes and vascular tissues
      obtained from hypertensive SHR (10 and 15 weeks old) but not in those obtained
      from prehypertensive SHR (5 weeks old). Immunodetectable lymphocyte GRK-2 protein
      expression was increased in 10-week-old SHR (143+/-10% of the expression in 10
      week-old Wistar rats and 131+/-11% of the expression in 10-week-old WKY, n=5 in
      each group). Immunodetectable vascular smooth muscle cell GRK-2 was comparably
      increased (169+/-14% of the expression in Wistar rats and 138+/-7% of the
      expression in WKY, n=5 in each group). Also, in hypertensive Dahl salt-sensitive
      rats, vascular GRK-2 protein expression was increased (185+/-14% of the
      expression in Dahl salt-resistant rats, n=5 in each group) compared with Dahl
      salt-resistant controls. These studies support a generalized defect in vascular
      GRK-2 protein expression in hypertension, which could be an important factor in
      the impairment of beta-adrenergic-mediated vasodilation, characteristic of the
      hypertensive state.

PMID- 10642273
TI  - Aging and chronic hypertension decrease expression of rat aortic soluble guanylyl
      cyclase.
AB  - We analyzed the influence of aging and genetic hypertension on the function and
      expression of soluble guanylyl cyclase (sGC) in the aortas of prehypertensive and
      old spontaneously hypertensive rats (SHR) as well as in age-matched normotensive
      Wistar-Kyoto rats (WKY). The expression of heterodimeric sGC (alpha(1) and
      beta(1)) was assessed at the mRNA and protein level, and its function was
      assessed by the relaxant responses of phenylephrine-contracted endothelium
      denuded aortic rings to the nitric oxide (NO) donor sodium nitroprusside. The
      vasodilator potency of sodium nitroprusside was significantly reduced (P<0.05)
      with age (3- to 6-fold increase in the EC(50) in old WKY and SHR compared with
      their young counterparts) as well as with hypertension (3-fold increase in old
      SHR compared with age-matched WKY), whereas the vasodilator potency of sodium
      nitroprusside did not differ between young SHR and WKY. A similar influence of
      aging and hypertension on NO-stimulated GC activity was revealed at the GC
      expression level: Whereas the beta(1) protein content was similar in young rats
      of both strains, old WKY exhibited 60% lower and old SHR exhibited 80% lower
      beta(1) subunit protein compared with young rats (P<0.05). Moreover, the
      abundance of alpha(1) and beta(1) mRNA (assessed by reverse transcriptase
      polymerase chain reaction) was similar in young rats but was 2.5-fold (alpha(1))
      and 4.3-fold (beta(1)) lower in old SHR compared with old WKY. In conclusion, our
      findings show that both aging and hypertension decrease sGC expression and its NO
      dependent activation in aortic tissue. Downregulation of sGC may therefore
      contribute to arterial dysfunction in senescence and chronic hypertension.

PMID- 10642274
TI  - Microalbuminuria and pulse pressure in hypertensive and atherosclerotic men.
AB  - To identify the biological covariates of microalbuminuria (albuminuria >/=15
      microg/min) in nondiabetic subjects, brachial blood pressure, echocardiographic
      left ventricular mass, and other cardiovascular and metabolic parameters were
      evaluated in 211 untreated males (38 normal controls, 109 uncomplicated stage 1
      to 3 essential hypertensives, and 64 patients with clinically stable
      atherosclerotic peripheral vascular disease either with [n=44] or without [n=20]
      essential hypertension) with normal cardiac and renal function. Compared with
      normoalbuminuric subjects, microalbuminuric subjects (n=67) were characterized by
      higher systolic blood pressure, comparable diastolic blood pressure, and,
      therefore, wider pulse pressure. Greater prevalence of hypertension, peripheral
      vascular disease, left ventricular hypertrophy, and reduced HDL cholesterol
      values further distinguished microalbuminuric from normoalbuminuric subjects in
      univariate comparisons. The risk of microalbuminuria increased by ascending pulse
      pressure quintiles in age-corrected logistic regression models, in which pulse
      pressure was more predictive than systolic pressure and was independent of mean
      pressure. When microalbuminuric status was regressed against a series of
      dichotomous (vascular and active smoker status) and continuous (age, pulse and
      mean pressure, left ventricular mass index, and HDL and LDL cholesterol)
      variables, only pulse pressure, left ventricular mass index, and smoking status
      were independent predictors. The association of increased albuminuria with wider
      pulse pressure, a correlate of the pulsatile hemodynamic load and conduit vessel
      stiffness as well as an important cardiovascular risk factor, may explain why
      microalbuminuria predicts cardiovascular events in nondiabetic subjects. The
      independence from concomitant vascular disease also suggests that wider pulse
      pressure, rather than representing a simple marker for atherosclerotic disease,
      influences albuminuria directly.

PMID- 10642275
TI  - Increased chymase activity in internal thoracic artery of patients with
      hypercholesterolemia.
AB  - Apart from ACE, various angiotensin II (Ang II)-forming serine proteinases (eg,
      chymase, kallikrein, and cathepsin G) are known to exist in human tissues, but
      their clinical significance or the regulatory mechanisms that control their
      activities are not well established. A recent clinical study has shown that
      chymase activity was significantly increased in human atherosclerotic or
      aneurysmal aorta. The association between vascular Ang II-forming activities
      (AIIFAs) in the human internal thoracic artery (ITA) and various clinical
      parameters was studied with the use of ITAs obtained from 32 patients who
      underwent coronary artery bypass graft surgery. Total and ACE- and chymase
      dependent AIIFAs in homogenates of ITAs were determined. Total AIIFA was 8.67+/
      0.86 (nmol Ang II formed. min(-1). mg protein(-1) [U]), and approximately 95% of
      the activities were due to chymase. Serum total cholesterol level, but no other
      risk factors, significantly correlated with chymase- (r=0. 60, P<0.001) and ACE-
      (r=0.35, P<0.05) dependent AIIFAs, respectively. LDL cholesterol level was also
      correlated with chymase-dependent AIIFAs (r=0.47, P<0.05). Mast cells identified
      through the use of toluidine blue or immunohistochemical staining appeared in the
      adventitia but not in the intima or media of ITAs. Our results suggest that an
      increased plasma LDL cholesterol level may induce increased arterial chymase and
      ACE activity.

PMID- 10642276
TI  - Extracellular signal-regulated kinase pathway is involved in basic fibroblast
      growth factor effect on angiotensin II-induced Ca(2+) transient in vascular
      smooth muscle cell from Wistar-Kyoto and spontaneously hypertensive rats.
AB  - We studied the effect of basic fibroblast growth factor (b-FGF) on different
      Ca(2+) mechanisms elicited by angiotensin II (Ang II) in normotensive Wistar
      Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). Intracellular Ca(2+)
      (Ca(2+)(i)) variations were studied in cultured vascular smooth muscle cells
      (VSMCs) isolated from the aorta of 5- to 6-week-old WKY rats and SHR. Ca(2+)(i)
      was assessed in Fura-2-loaded cells with fluorescent imaging microscopy. Ang II
      subtype 1 receptor activation by Ang II (1 micromol/L) induced a transient
      increase in Ca(2+)(i) that was partially attenuated by genistein, a tyrosine
      kinase inhibitor. Pretreatment of VSMCs with b-FGF for 24 hours markedly
      stimulated the Ang II-induced Ca(2+)(i) release from the internal stores in WKY
      rats, whereas it was without effect in SHR. This was not consequent to a change
      in the affinity of Ang II subtype 1 receptors or an increase in their density.
      Inhibition of mitogen-activated protein kinase with PD 98059 reduced this
      stimulatory effect of the cytokine in the WKY rats. On the other hand, b-FGF
      stimulated the Ang II-induced Ca(2+) influx in both strains. Similar results were
      observed when Ca(2+) influx was induced with thapsigargin. Genistein and PD 98059
      abolished the effect of b-FGF. These results show for the first time that b-FGF
      regulates Ca(2+) mechanisms induced by Ang II and that this regulation is
      different in SHR than in normotensive control animals. The extracellular signal
      regulated kinase cascade is implicated in this cross-regulation with G protein
      signaling pathway at 2 levels and possibly more: 1 at the tyrosine kinases and
      the other downstream of the extracellular signal-regulated kinase family. These
      results may prove useful in understanding the interaction between these 2
      pathways and their implication in genetic hypertension.

PMID- 10642277
TI  - Induction of cyclooxygenase-2 by angiotensin II in cultured rat vascular smooth
      muscle cells.
AB  - Angiotensin II (Ang II) stimulates the release of prostaglandins (PGs) in various
      cells and tissues. Recently, cyclooxygenase-2 (COX-2) emerged as a new key
      regulator for PG synthesis. In the present study, we investigated whether Ang II
      regulates COX-2 expression in cultured rat vascular smooth muscle cells (VSMCs).
      Ang II markedly increased the expression of COX-2 mRNA in a time- and dose
      dependent manner. This effect was completely blocked by the Ang II type 1
      receptor antagonist losartan but not by the Ang II type 2 receptor antagonist
      PD123319. The p42/44 mitogen-activated protein kinase (MAPK) kinase-1 inhibitor
      PD98059 and the p38 MAPK inhibitor SB203580 significantly suppressed Ang II
      induced COX-2 mRNA and protein expression. Ang II did not increase transcription
      of the COX-2 gene, as examined with a COX-2 promoter/luciferase chimeric plasmid
      construct. Instead, it suppressed the degradation of COX-2 mRNA. PD98059 and
      SB203580 markedly enhanced the decay of COX-2 mRNA induced by Ang II, implying
      that p42/44 and p38 MAPK activated by Ang II play a role in the regulation of COX
      2 through stabilization of its mRNA. The COX-2-specific inhibitor NS-398
      attenuated Ang II-stimulated DNA and protein synthesis, as well as PGE(2)
      production by VSMCs. These results suggest that Ang II regulates COX-2 expression
      and PG production and modulates cell proliferation through MAPK-mediated
      signaling pathways in rat VSMCs.

PMID- 10642278
TI  - Dissociation between neural and vascular responses to sympathetic stimulation :
      contribution of local adrenergic receptor function.
AB  - Sympathetic activation produced by various stimuli, eg, mental stress or
      handgrip, evokes regional vascular responses that are often nonhomogeneous. This
      phenomenon is believed to be the consequence of the recruitment of differential
      central neural pathways or of a sympathetically mediated vasodilation. The
      purpose of this study was to determine whether a similar heterogeneous response
      occurs with cold pressor stimulation and to test the hypothesis that local
      differences in adrenergic receptor function could be in part responsible for this
      diversity. In 8 healthy subjects, local norepinephrine spillover and blood flow
      were measured in arms and legs at baseline and during sympathetic stimulation
      induced by baroreflex mechanisms (nitroprusside infusion) or cold pressor
      stimulation. At baseline, legs had higher vascular resistance (27+/-5 versus 17+/
      2 U, P=0.05) despite lower norepinephrine spillover (0.28+/-0.04 versus 0.4+/
      0.05 mg. min(-1). dL(-1), P=0.03). Norepinephrine spillover increased similarly
      in both arms and legs during nitroprusside infusion and cold pressor stimulation.
      On the other hand, during cold stimulation, vascular resistance increased in arms
      but not in legs (20+/-9% versus -7+/-4%, P=0.03). Increasing doses of
      isoproterenol and phenylephrine were infused intra-arterially in arms and legs to
      estimate beta-mediated vasodilation and alpha-induced vasoconstriction,
      respectively. beta-Mediated vasodilation was significantly lower in legs compared
      with arms. Thus, we report a dissociation between norepinephrine spillover and
      vascular responses to cold stress in lower limbs characterized by a paradoxical
      decrease in local resistance despite increases in sympathetic activity. The
      differences observed in adrenergic receptor responses cannot explain this
      phenomenon.

PMID- 10642279
TI  - Pranidipine enhances the action of nitric oxide released from endothelial cells.
AB  - Nitric oxide (NO) synthesis in vascular endothelium of patients with hypertension
      is altered. Calcium antagonists have been shown to improve endothelial function
      in hypertensive patients. Here we report that pranidipine, one of the latest long
      acting calcium antagonists in the dihydropyridine group, enhances the actions of
      NO released from endothelial cells (ECs). Pranidipine significantly enhanced cGMP
      accumulation in vascular smooth muscle cells cocultured with ECs, whereas
      amlodipine and nifedipine had no significant effects. In addition, pranidipine
      also suppressed basal and thrombin-stimulated endothelin-1 production from ECs.
      Pranidipine also enhanced cGMP accumulation in rat aortic segments with
      endothelium but not in endothelium-denuded vessels. In contrast, pranidipine had
      no effect in the presence of N(G)-monomethyl-L-arginine, an inhibitor of NO
      synthesis. Pranidipine did not affect the basal expression of endothelial NO
      synthase in ECs. However, pranidipine upregulated the activity of superoxide
      dismutase in ECs. These findings suggest that pranidipine enhances NO action
      through inhibition of superoxide-induced NO decomposition in the vessel wall.
      Thus, pranidipine may be useful in the treatment of impaired endothelial function
      in patients with hypertension.

PMID- 10642280
TI  - Role of transforming growth factor-beta1 in cardiovascular inflammatory changes
      induced by chronic inhibition of nitric oxide synthesis.
AB  - We previously reported that chronic inhibition of nitric oxide (NO) synthesis
      with N(omega)-nitro-L-arginine methyl ester (L-NAME) induces inflammatory changes
      (monocyte infiltration, myofibroblast formation, and monocyte chemoattractant
      protein-1 [MCP-1] and transforming growth factor-beta1 [TGF-beta1] expression) in
      the rat heart and vessel. There is debate regarding whether TGF-beta1 exhibits
      proinflammatory or anti-inflammatory activities. We used the rat model to
      investigate the role of TGF-beta in the pathogenesis of such inflammatory
      changes. We show here that infiltrating monocytes and myofibroblasts in the
      inflammatory lesions produced TGF-beta1 on the third day of L-NAME
      administration. Cotreatment with a monoclonal antibody against TGF-beta1, but not
      with control IgG, prevented the L-NAME-induced cardiac inflammation. The antibody
      also significantly inhibited the gene expression of MCP-1, P-selectin, and
      intercellular adhesion molecule-1. In summary, the antibody against TGF-beta1
      prevented inflammatory changes in rat heart and vessel induced by chronic
      inhibition of NO synthesis, suggesting that increased production of TGF-beta1 is
      involved in the inflammatory changes in this model.

PMID- 10642281
TI  - Platelet Ca(2+)ATPases : a plural, species-specific, and multiple hypertension
      regulated expression system.
AB  - Gaining insight into nonmuscle Ca(2+) signaling requires basic knowledge of the
      major structures involved. We investigated the expression of platelet
      Ca(2+)ATPases in normal and hypertension-associated abnormal Ca(2+) signaling.
      First, overall identification of normotensive Wistar-Kyoto rat Ca(2+)ATPases was
      attempted by looking for newly described human platelet 3'-end alternatively
      spliced sarco/endoplasmic reticulum Ca(2+)ATPases (SERCA) 3b mRNA and plasma
      membrane Ca(2+)ATPase (PMCA) 1b and 4b proteins, in addition to SERCA2b and
      SERCA3a isoforms. For SERCAs, comparative analyses of human and Wistar-Kyoto rat
      SERCA3 platelet mRNA by reverse transcription-polymerase chain reaction (RT-PCR)
      followed by sequencing established that human platelets coexpressed SERCA3b and a
      third SERCA3c, while rat cells were devoid of them but expressed a still unknown
      splice variant that we termed rSERCA3b/3c. Its identification using 3'-end SERCA3
      gene and rapid amplification of cDNA ends (RACE)-PCR studies showed that it
      results from an additional SERCA3 alternative splicing process, which uses a
      second alternative polyadenylation site located in the last intron. For PMCAs,
      with the use of gene-specific RT-PCR followed by sequencing and Western blotting
      using 5F10 monoclonal antibody, expression of human and rat platelet PMCA1b and
      PMCA4b was similar. Second, comparative analysis of these newly identified
      Ca(2+)ATPases and SERCA3a in age-matched spontaneously hypertensive rat platelets
      demonstrated (1) a marked downregulation of rSERCA3b/3c, which became null, and a
      1.71-fold increase in SERCA3a and (2) an opposite regulation of the 2 PMCAs,
      namely, a 3.3-fold decrease in PMCA1b mRNA and a 3.7-fold increase in PMCA4b
      mRNA. Hence, platelets coexpress multiple, diverse, and species-specific
      Ca(2+)ATPases, including a novel fourth SERCA3. Moreover, expression of PMCA (1b
      and 4b), SERCA3a, and rSERCA3b/3c was modulated in rat hypertension. Hence,
      Ca(2+)ATPases should be regarded as constituting a new rational basis for the
      understanding of nonmuscle cell Ca(2+) signaling.

PMID- 10642282
TI  - Tyrosine phosphorylation of human platelet plasma membrane Ca(2+)-ATPase in
      hypertension.
AB  - Intracellular Ca(2+) is increased in the platelets of hypertensive individuals.
      Previously, we demonstrated that platelet plasma membrane Ca(2+)-ATPase (PMCA)
      activity inversely correlates with diastolic blood pressure and that inhibition
      of this Ca(2+) pump could explain the elevation of cytosolic Ca(2+) in
      hypertension. More recently, we discovered that PMCA is phosphorylated on
      tyrosine residues during thrombin-stimulated platelet aggregation and that this
      phosphorylation causes inhibition of PMCA activity. In the present work, we
      tested the hypothesis that tyrosine phosphorylation of PMCA in hypertensive
      patients could account for the observed inhibition of the Ca(2+) pump. Platelets
      were obtained from untreated hypertensive and normotensive volunteers. PMCA was
      immunoprecipitated from solubilized platelets, and tyrosine phosphorylation was
      quantified by chemiluminescence of immunoblots treated with anti-phosphotyrosine.
      PMCA content was measured on the same immunoblots by stripping and reprobing with
      anti-PMCA. Phosphorylation was reported as normalized phosphotyrosine
      chemiluminescence per nanogram PMCA (mean+/-SE). The average PMCA tyrosine
      phosphorylation for 15 normotensive subjects was 0.53+/-0. 09, whereas the
      average for 8 hypertensive individuals was 1.82+/-0. 25 (P<0.0005, Mann-Whitney U
      test). Age, gender, and systolic blood pressure did not correlate with PMCA
      phosphorylation. These results suggest that PMCA in platelets of hypertensive
      individuals is inhibited because of tyrosine phosphorylation, resulting in
      increased platelet intracellular Ca(2+), hyperactive platelets, and increased
      risk of heart attack and stroke.

PMID- 10642283
TI  - Metformin improves vascular function in insulin-resistant rats.
AB  - This study assessed the effect of metformin treatment on insulin, mean arterial
      pressure (MAP), and endothelial function in insulin-resistant (IR) rats. In
      addition, we assessed the direct effect of metformin in vitro. Sprague-Dawley
      rats were randomized to control (n=28) or IR (n=28) groups. Rats were further
      randomized to receive metformin (300 mg/kg) or placebo for 2 weeks. MAP and
      insulin were measured. Subsequently, a third-order branch of the superior
      mesenteric artery was isolated, and endothelial function was assessed.
      Specifically, dose-response experiments of acetylcholine (ACh) with or without N
      nitro-L-arginine (LNNA) were performed. For in vitro experiments, mesenteric
      arteries were removed from untreated control and IR rats and treated with
      metformin (100 micromol/L) before ACh+/-LNNA. MAP and insulin levels were
      improved in IR-metformin compared with IR-placebo rats. Maximal relaxation
      (E(max)) to ACh was enhanced in IR-metformin (92+/-2%) compared with IR-placebo
      rats (44+/-4%) (P<0.05). Relaxation in response to ACh+LNNA was greater in IR
      metformin (33+/-4%) than in IR-placebo rats (12+/-4%) but remained depressed
      compared with control rats (E(max)=68+/-5%). The control group was not affected
      by metformin. In vitro treatment of arteries with metformin in response to ACh
      produced results similar to those in the experiments with metformin-treated rats.
      Although metformin improves metabolic abnormality in IR rats, this action does
      not appear to mediate its effect on vascular function. Both in vivo and in vitro
      metformin improved ACh-induced relaxation in IR rats to control levels,
      apparently through nitric oxide-dependent relaxation. These data suggest that
      metformin improves vascular function through a direct mechanism rather than by
      improving metabolic abnormalities.

PMID- 10642284
TI  - Intralymphocyte free magnesium in patients with primary aldosteronism:
      aldosterone and lymphocyte magnesium homeostasis.
AB  - It is known that hyperaldosteronism has been associated with magnesium
      deficiency, yet there are no data on the intracellular concentration of ionized
      magnesium ([Mg(2+)(i)]) in subjects with primary aldosteronism (PA). We measured
      intralymphocyte free magnesium ([Mg(2+)(i)]) and intralymphocyte free calcium
      ([Ca(2+)(i)]) in 16 patients with PA and 26 normotensive control subjects (NCs).
      [Mg(2+)(i)] and [Ca(2+)(i)] were also measured in blood lymphocytes incubated in
      vitro with aldosterone, according to a fluorimetric method. In subjects with PA,
      [Mg(2+)(i)] was significantly lower than that in NCs (mean+/-SD; PA 203+/-56
      micromol/L, NCs 291+/-43 micromol/L, 95% confidence interval 57 to 119, P=0.001).
      In the patients, [Ca(2+)(i)] did not prove to be statistically different from
      that of NCs (mean+/-SD; PA 47.2+/-10.6 nmol/L, NCs 53.2+/-11 nmol/L). The
      lymphocytes exposed to the action of aldosterone showed a significant reduction
      in [Mg(2+)(i)] (n=15, NCs 271+/-28 micromol/L, aldosterone treatment 188+/-39
      micromol/L, P=0.001, 95% confidence interval 57 to 108). The dose-effect curve of
      aldosterone on [Mg(2+)(i)] showed an EC(50) value of approximately 0.5 to 1
      nmol/L aldosterone. The reduction in [Mg(2+)(i)] mediated by aldosterone is
      antagonized by the receptor inhibitor of aldosterone; it is inhibited by
      inhibitors of protein synthesis and is not measurable when the lymphocytes are
      incubated in an Na(+)-free medium. The data are consistent with the hypothesis
      that aldosterone affects the cellular homeostasis of magnesium, probably through
      modification of the activity of the Na(+)-Mg(2+) antiporter.

PMID- 10642285
TI  - Reproducibility of the hyperbaric index as a measure of blood pressure excess.
AB  - The approach of establishing a time-specified tolerance limit reflecting the
      circadian variability in blood pressure and then determining the hyperbaric
      index, the area of blood pressure excess above the upper limit of the tolerance
      interval, has been proposed for diagnosing hypertension as well as for evaluating
      the patient's response to treatment. The retrospective evaluation of this test
      provided high sensitivity and specificity in the diagnosis of hypertension, with
      a threshold value for the hyperbaric index of 15 mm Hg. h. To evaluate the
      stability and reproducibility of this tolerance-hyperbaric test, we studied 332
      previously untreated subjects (218 men) who underwent sequential 48-hour
      ambulatory blood pressure monitoring for 2 years, providing a total of 1337 blood
      pressure profiles. Diagnosis of hypertension was established for each subject on
      the restricted basis of presenting at least 1 blood pressure profile with a
      hyperbaric index above the previously defined threshold. Sensitivity of this
      tolerance-hyperbaric test was 98.6%, with a negative predictive value of 99.7%.
      For the same subjects, the blood pressure load (percentage of values >140/110/90
      mm Hg for systolic/mean arterial/diastolic blood pressure during activity or
      >120/95/80 mm Hg during resting hours) had a sensitivity of 49% and specificity
      of 25%. The 24-hour mean, still the most common approach for diagnosing
      hypertension on the basis of ambulatory monitoring, had sensitivities of 40% and
      31% for systolic and diastolic blood pressure, respectively. Despite the
      limitations of ambulatory blood pressure monitoring, the tolerance-hyperbaric
      test represents a reproducible, noninvasive, and high-sensitivity test for the
      identification of subjects in need of prophylactic or therapeutic intervention.

PMID- 10642286
TI  - Restraint stress : differential cardiovascular responses in Wistar-Kyoto and
      spontaneously hypertensive rats.
AB  - With the use of a restraint stress paradigm, both normotensive Wistar-Kyoto (WKY
      ) rats and spontaneously hypertensive rats (SHR) underwent acute (1-hour
      restraint in a Perspex tube), chronic (1-hour restraint for 10 consecutive days),
      or no-restraint (control) stress. Rats experiencing chronic restraint were
      previously implanted with telemetric probes to measure heart rate and blood
      pressure. Basal (prestress session) cardiovascular variables did not change
      during the course of the study (SHR: mean arterial pressure 129+/-1 mm Hg, heart
      rate 288+/-4 bpm; WKY rats: mean arterial pressure 103+/-1 mm Hg, heart rate
      285+/-3 bpm). Restraint caused tachycardia and pressor responses in the WKY rats
      and SHR, but these effects were greater in the hypertensive strain. The duration
      of restraint-induced tachycardia did not change in the WKY rats between acute and
      chronic stress; however, a graded reduction in the duration of restraint-induced
      tachycardia occurred in the SHR, decreasing to WKY rat levels by day 7 of the 10
      day regimen. These data indicate that although the WKY rats can effectively
      "cope" within a single period of restraint, the coping mechanism is apparently
      impaired in the SHR compared with the WKY rats. A reduced capacity to cope with
      processive stressors may thus have an affect on cardiovascular regulation and
      represent an additional risk factor in hypertension.

PMID- 10642287
TI  - Angiotensin III depressor action in the conscious rabbit is blocked by losartan
      but not PD 123319.
AB  - Vasodilator and vasodepressor properties of angiotensins have been reported, and
      mediation by prostaglandins or nitric oxide has been proposed. Other studies
      indicate that angiotensin AT(2) receptors might mediate a depressor action, and
      the present study was designed to delineate and explore this possibility in a
      conscious rabbit model. Large intravenous boluses of angiotensin III (15 nmol/kg)
      produced a predictable pressor peak (82+/-4 mm Hg) followed by a depressor phase
      (20+/-3 mm Hg), whereas equipressor doses of angiotensin II were less effective
      at producing depressor responses. Angiotensin-(1-7) did not exert a depressor
      action, and the reduced potency of angiotensin IV (relative to angiotensin III)
      was similar for both the pressor and depressor phases ( approximately 100-fold).
      It is clear that specific angiotensin IV or angiotensin-(1-7) receptors do not
      mediate depressor effects in this model. The AT(1) antagonist losartan (1 mg/kg)
      blocked both the pressor and depressor components of the angiotensin III
      response, whereas the AT(2) antagonist PD 123319 (35 mg/kg) had no effect on
      either element of the response. The data obtained with the angiotensin receptor
      subtype-selective compounds, losartan and PD 123319, suggest that the depressor
      action is an AT(1)-mediated effect and give no indication that AT(2) receptors
      could be involved. Paradoxically, the greater potency of angiotensin III as a
      vasodepressor belies the conclusion that the response is AT(1)-mediated, because
      AT(1) receptors have a greater affinity for angiotensin II versus angiotensin
      III.

PMID- 10642288
TI  - Human Na+/H+ exchanger genes : identification of polymorphisms by radiation
      hybrid mapping and analysis of linkage in end-stage renal disease.
AB  - The Na+/H+ exchangers (NHEs) are membrane-bound transporters that catalyze the
      electro-neutral movement of extracellular Na+ for intracellular H+. NHE genes
      play a critical role in pH homeostasis and cellular volume regulation and can be
      considered candidate genes for essential hypertension and renal disease. This
      study was performed to determine whether the NHE genes contributed to genetic
      susceptibility in end-stage renal disease (ESRD). To date, 5 isoforms of NHE have
      been cloned in mammals (NHE1 to NHE5). The complementary DNA (cDNA) sequences of
      NHE1 to NHE3 and NHE5 are known in humans. Because the chromosomal structure of
      the NHE genes is unknown, we used cDNA sequences to design polymerase chain
      reaction primers for use in radiation hybrid mapping. Radiation hybrid mapping of
      NHE genes identified nearby polymorphic markers for NHE1 to NHE3 (NHE1: D1S197,
      D1S2677; NHE2: D2S373, D2S1789; and NHE3: D5S678, D5S2005). We used these
      markers, and other previously identified polymorphic markers for NHE5, in linkage
      and association analyses of ESRD. The NHE1 to NHE3 and NHE5 loci did not
      demonstrate evidence for linkage to ESRD. However, NHE5 showed significant
      evidence for association (P</=1.0x10(-4)). The strongest evidence for association
      was observed with allele 6 of NHE5 (P</=0.001 to 0. 01). Allele 6 appeared to
      have a renoprotective effect, with a frequency of 0.15 in the control population
      and 0.06 to 0.09 in patients with ESRD. The combined approach of designing
      primers from cDNA and radiation hybrid mapping has proven successful in
      identifying polymorphisms for human genes of which only cDNA sequences were
      previously available. The NHE primers and associated polymorphic loci identified
      in this study can be used in genomic, linkage, and association analysis of NHE
      genes in future genetic studies of hypertension and renal failure. Given the
      allelic association, further evaluation of the role of NHE5 in ESRD
      susceptibility appears warranted.

PMID- 10642289
TI  - Effect of continuous positive airway pressure on blood pressure : a placebo
      trial.
AB  - This study examined the effect of continuous positive airway pressure (CPAP)
      treatment on blood pressure in patients with obstructive sleep apnea. Thirty-nine
      patients with sleep apnea were studied. Ambulatory blood pressure monitoring was
      obtained before and after patients were randomized to receive either 1 week of
      CPAP or placebo CPAP (CPAP administered at ineffective pressure). Blood pressure
      was examined over daytime hours (6 AM to 10 PM) and during nighttime hours (10 PM
      to 6 AM). Daytime mean arterial blood pressure decreased significantly but
      equally in both the active treatment group and the placebo treatment group
      (P=0.001). Nighttime mean arterial pressure levels decreased to a much greater
      extent over time in the patients who received active CPAP treatment (P=0. 032).
      CPAP does appear to decrease nighttime blood pressure. However, the decrease in
      daytime blood pressure may reflect a nonspecific response (ie, placebo), since
      both the active treatment group and the placebo treatment group developed
      comparable decreases in blood pressure.

PMID- 10642290
TI  - Proceedings of the council for high blood pressure research, 1999

PMID- 10642291
TI  - Implications of species difference for clinical investigation: studies on the
      renin-angiotensin system.
AB  - The justification for clinical investigation has its roots in the fact that
      physiological mechanisms and disease pathogenesis in animal models replicate
      mechanisms and pathogenesis in humans only in part. In the case of the renin
      angiotensin system, there is species variation in the anatomic distribution of
      the renin-angiotensin system, in the active site of the renin enzyme, and in the
      structure of angiotensin and the AT(1) receptor. The conversion of angiotensin I
      (Ang I) to angiotensin II (Ang II) may prove to be the most important aspect of
      species variation. In plasma, all the conversion occurs through a single enzyme,
      angiotensin-converting enzyme (ACE), and species variation in structure and
      function have not been reported. Non-ACE-dependent pathways, which occur only at
      the tissue level, show unambiguous, striking species variation. Specifically,
      chymase, the most important enzyme responsible for non-ACE conversion of Ang I to
      Ang II, shows striking species variation. In humans and a number of species,
      including the hamster, quantitatively important chymase-independent Ang II
      formation from Ang I occurs in the heart, arteries, and kidney. In rats and
      rabbits, on the other hand, chymase differs, is not active in the conversion of
      Ang I to Ang II, and indeed is involved in Ang II degradation. Consequently, one
      would anticipate that blockade of the system at the ACE step would be equivalent
      to that at the Ang II receptor in the rat. This has been widely reported. In
      humans, on the other hand, one would anticipate that the AT(1) receptor blockers
      will be more effective than ACE inhibitors. Again, preliminary evidence favors
      this possibility. The implications for therapeutics are clear.

PMID- 10642292
TI  - Role of the angiotensin type 2 receptor in the regulation of blood pressure and
      renal function.
AB  - The renin-angiotensin system is a major physiological regulator of body fluid
      volume, electrolyte balance, and arterial pressure. Virtually all of the
      biological actions of the principle effector peptide angiotensin II (ANG II) have
      been attributed to an action at the type 1 (AT(1)) ANG receptor. Until recently,
      the functional role of the type 2 (AT(2)) receptor, if any, has been unknown,
      possibly because the AT(2) receptor has a low degree of expression compared with
      that of the AT(1) receptor. Evidence has now accumulated that the AT(2) receptor
      opposes functions mediated by the AT(1) receptor. Whereas the AT(1) receptor
      stimulates cell proliferation, the AT(2) receptor inhibits proliferation and
      promotes cell differentiation. These differences in growth responses have been
      ascribed to different cell signaling pathways in which the AT(1) receptor
      stimulates protein phosphorylation and the AT(2) receptor dephosphorylation.
      During the past 5 years, studies have demonstrated that the AT(2) receptor is
      responsible for vasodilation and natriuresis, thus opposing the vasoconstrictor
      and antinatriuretic effects of ANG II mediated through the AT(1) receptor. Work
      from our laboratory and others indicates that the AT(2) receptor stimulates
      vasodilation and natriuresis by an autocrine cascade including bradykinin, nitric
      oxide, and cyclic GMP. The AT(2) receptor also has been found to control
      vasodilator prostaglandins, which have a role in blood pressure regulation. The
      AT(2) receptor appears to play a counterregulatory protective role in the
      regulation of blood pressure and sodium excretion that opposes the AT(1)
      receptor.

PMID- 10642293
TI  - Genes and hypertension: from gene mapping in experimental models to vascular gene
      transfer strategies.
AB  - Human essential hypertension is a complex, multifactorial, quantitative trait
      under a polygenic control. Several strategies have been developed over the last
      decade to dissect genetic determinants of hypertension. Of these, the most
      successful have been studies that identified rare mendelian syndromes in which a
      single gene mutation causes high blood pressure. The attempts to identify
      multiple genes, each with a small contribution to the common polygenic form of
      hypertension, have been less successful. Several laboratories focused their
      attention on rat models of genetic hypertension, which can be considered as a
      reductionist paradigm for human disease. Using numerous crosses between
      hypertensive and normotensive strains, investigators identified several
      quantitative trait loci (QTL) for blood pressure subphenotypes and for
      cardiovascular complications such as left ventricular hypertrophy, kidney
      failure, stroke, and insulin resistance. Furthermore, congenic strains have been
      produced to confirm the existence of some of these QTL and to narrow down the
      chromosomal regions of interest. A number of interesting strategies have been
      developed, including a "speed" congenic strategy perfected by our group in
      Glasgow. However, the limit of congenic strategy is estimated at 1 cM, which
      corresponds to 2x10(6) base pairs of DNA and approximately 50 candidate genes. It
      is envisaged that gene expression profiling with cDNA microarrays might allow a
      quick progression toward the gene identification within cardiovascular QTL. In
      parallel experimental effort, several laboratories have been developing gene
      transfer/therapy strategies with adenoviral or adeno-associated viral vectors
      used, for example, to overexpress protective vascular genes such as vascular
      endothelial growth factor or endothelial nitric oxide synthase. It is anticipated
      that further developments in positional cloning of susceptibility and severity
      genes in hypertension and its complications will lead to a direct transfer of
      these discoveries to essential hypertension in humans and will ultimately produce
      novel targets for local and systemic gene therapy in cardiovascular disease.

PMID- 10642295
TI  - Applicability of a "speed" congenic strategy to dissect blood pressure
      quantitative trait loci on rat chromosome 2.
AB  - The identification of any quantitative trait locus (QTL) via a genome scan is
      only the first step toward the ultimate goal of gene identification. The next
      step is the production of congenic strains by which the existence of a QTL may be
      verified and the implicated chromosomal region be reduced to a size applicable to
      positional cloning of the causal gene. We used a speed congenic breeding protocol
      previously verified in mice for 2 blood pressure QTLs on rat chromosome 2. Four
      congenic strains were produced through introgression of various segments of
      chromosome 2 from Wistar-Kyoto rats from Glasgow colonies [WKY((Gla)) rats] into
      the recipient stroke-prone spontaneously hypertensive rats from Glasgow colonies
      [SHRSP((Gla))], and vice versa. The number of backcross generations required for
      each strain to achieve complete homozygosity at 83 background genetic markers in
      a "best" male varied between 3 and 4. Transfer of the region of rat chromosome 2
      containing both QTLs from WKY((Gla)) into an SHRSP((Gla)) genetic background
      lowered both baseline and salt-loaded systolic blood pressure by approximately 20
      and approximately 40 mm Hg in male congenic rats compared with the SHRSP parental
      strain (F=53.4, P<0.005; F=28.0, P< 0.0005, respectively). In contrast, control
      animals for stowaway heterozygosity presented no deviation from the blood
      pressure values recorded for the SHRSP((Gla)), indicating that if such
      heterozygosity exists, its effect on blood pressure is negligible. A reciprocal
      strategy in which 1 or both QTLs on rat chromosome 2 were transferred from
      SHRSP((Gla)) into a WKY((Gla)) genetic background resulted in statistically
      significant but smaller blood pressure increases for 1 of these QTLs. These
      results confirm the existence of blood pressure QTLs on rat chromosome 2 and
      demonstrate the applicability of a speed congenic strategy in the rat and
      emphasize the important role of the genetic background.

PMID- 10642294
TI  - Ion channels and vascular tone.
AB  - Ion channels in the plasma membrane of vascular muscle cells that form the walls
      of resistance arteries and arterioles play a central role in the regulation of
      vascular tone. Current evidence indicates that vascular smooth muscle cells
      express at least 4 different types of K(+) channels, 1 to 2 types of voltage
      gated Ca(2+) channels, >/=2 types of Cl(-) channels, store-operated Ca(+) (SOC)
      channels, and stretch-activated cation (SAC) channels in their plasma membranes,
      all of which may be involved in the regulation of vascular tone. Calcium influx
      through voltage-gated Ca(2+), SOC, and SAC channels provides a major source of
      activator Ca(2+) used by resistance arteries and arterioles. In addition, K(+)
      and Cl(-) channels and the Ca(2+) channels mentioned previously all are involved
      in the determination of the membrane potential of these cells. Membrane potential
      is a key variable that not only regulates Ca(+2) influx through voltage-gated
      Ca(2+) channels, but also influences release of Ca(2+) from internal stores and
      Ca(2+)- sensitivity of the contractile apparatus. By controlling Ca(2+) delivery
      and membrane potential, ion channels are involved in all aspects of the
      generation and regulation of vascular tone.

PMID- 10642296
TI  - Endothelin-dependent and -independent components of strain-activated brain
      natriuretic peptide gene transcription require extracellular signal regulated
      kinase and p38 mitogen-activated protein kinase.
AB  - The application of mechanical strain to cultured cardiac myocytes in vitro leads
      to activation of the brain natriuretic peptide (BNP) gene promoter, a marker of
      cardiac hypertrophy. We have previously shown that this activation results from
      both a direct mechanostimulatory event and an indirect autocrine/paracrine
      stimulation involving the sequential production of angiotensin II and endothelin
      (ET). In the present study, we examined the role of p38 mitogen-activated protein
      kinase (MAPK) and extracellular signal regulated kinase (ERK) in signaling the
      increase in promoter activity trafficking through each of these pathways. ET was
      shown to stimulate both p38 MAPK and ERK activity in these cultures and to
      activate human BNP (hBNP) promoter activity. Activation of the promoter was
      inhibited approximately 45% by SB-203580, a p38 MAPK inhibitor, and approximately
      70% by PD98059, an inhibitor of the ERK-activating kinase MAPK kinase. The ET
      independent (ie, direct) stimulation of the hBNP promoter by mechanical strain
      was inhibited approximately 70% by SB-203580 and approximately 60% by PD98059,
      implying that similar signaling circuitry is used, albeit to different degrees,
      by the direct and indirect pathways. The p38 MAPK component of both the ET
      dependent and the ET-independent responses to strain appears to operate through a
      series of nuclear factor-kappaB binding, shear stress response element-like
      structures in the hBNP gene promoter. Collectively, these data suggest that
      activation of the BNP promoter by hypertrophic stimuli involves the participation
      of several independent signaling pathways. Such redundancy would help to
      guarantee generation of the full hypertrophic phenotype independently of the
      nature of the hypertrophic stimulus.

PMID- 10642297
TI  - NF-kappaB inhibition ameliorates angiotensin II-induced inflammatory damage in
      rats.
AB  - We recently reported that the activation of nuclear factor-kappaB (NF-kappaB)
      promotes inflammation in rats harboring both human renin and angiotensinogen
      genes (double-transgenic rats [dTGR]). We tested the hypothesis that the
      antioxidant pyrrolidine dithiocarbamate (PDTC) inhibits NF-kappaB and ameliorates
      renal and cardiac end-organ damage. dTGR feature hypertension, severe renal and
      cardiac damage, and a 40% mortality rate at 7 weeks. Electrophoretic mobility
      shift assay showed increased NF-kappaB DNA binding activity in hearts and kidneys
      of dTGR. Chronic PDTC (200 mg/kg SC) treatment decreased blood pressure (162+/-8
      versus 190+/-7 mm Hg; P=0.02) in dTGR compared with dTGR controls. The cardiac
      hypertrophy index was also significantly reduced (4.90+/-0.1 versus 5.77+/-0.1
      mg/g; P<0. 001). PDTC reduced 24-hour albuminuria by >95% (2.5+/-0.8 versus 57.
      1+/-8.7 mg/d; P<0.001) and prevented death. Vascular injury was ameliorated in
      small renal and cardiac vessels. Electrophoretic mobility shift assay showed that
      PDTC inhibited NF-kappaB binding activity in heart and kidney, whereas AP-1
      activity in the kidney was not decreased. dTGR exhibited increased left
      ventricular c-fos and c-jun mRNA expression. PDTC treatment reduced c-fos but not
      c-jun mRNA. Immunohistochemistry showed increased p65 NF-kappaB subunit
      expression in the endothelium and smooth muscle cells of damaged small vessels,
      as well as infiltrating cells in glomeruli, tubules, and collecting ducts of
      dTGR. PDTC markedly reduced the immunoreactivity of p65. PDTC also prevented the
      NF-kappaB-dependent transactivation of the intercellular adhesion molecule ICAM-1
      and inducible nitric oxide synthase. Monocyte infiltration was markedly increased
      in dTGR kidneys and hearts. Chronic treatment reduced monocyte/macrophage
      infiltration by 72% and 64%, respectively. Thus, these results demonstrate that
      PDTC inhibits NF-kappaB activity, ameliorates inflammation, and protects against
      angiotensin II-induced end-organ damage.

PMID- 10642298
TI  - Angiotensin I-converting enzyme antisense gene therapy causes permanent
      antihypertensive effects in the SHR.
AB  - The renin-angiotensin system plays a critical role in the control of blood
      pressure (BP), and its hyperactivity is associated with the development and
      maintenance of hypertension. Although traditional pharmacological therapies
      targeted toward the inhibition of the renin-angiotensin system are effective in
      the control of this disease, they pose significant limitations. We used an
      antisense gene delivery strategy to circumvent these limitations and established
      that a single intracardiac administration of angiotensin type 1 receptor
      antisense (AT(1)R-AS) causes permanent prevention of hypertension in the
      spontaneously hypertensive rat (SHR), an animal model of primary human
      hypertension. Our objectives in this study were 2-fold: to determine (1) whether
      the targeting of angiotensin I-converting enzyme (ACE) mRNA by a similar
      antisense strategy would prevent the SHR from developing hypertension and (2)
      whether the antihypertensive phenotype is transmitted to the offspring from the
      antisense-treated parents. Administration of a retroviral vector containing ACE
      antisense (LNSV-ACE-AS) caused a modest yet significant attenuation of high BP (
      approximately 15+/-2 mm Hg) exclusively in the SHR. This was associated with a
      complete prevention of cardiac and renovascular pathophysiological alterations
      that are characteristic of hypertension. Like their parents, the F(1) generation
      offspring of the LNSV-ACE-AS-treated SHR expressed lower BP, decreased cardiac
      hypertrophy, and normalization of renal arterial excitation-coupling compared
      with offspring derived from the LNSV-ACE-tS (truncated sense)-treated SHR. In
      addition, the endothelial dysfunction commonly observed in the SHR renal
      arterioles was significantly prevented in both parents and offspring of the LNSV
      ACE-AS-treated SHR. Polymerase chain reaction followed by Southern analysis
      revealed that the ACE-AS was integrated into the SHR genome and transmitted to
      the offspring. These observations suggest that transmission of ACE-AS by
      retroviral vector may be responsible for the transference of normotensive
      phenotypes in the SHR offspring.

PMID- 10642299
TI  - Angiotensin I-converting enzyme antisense prevents altered renal vascular
      reactivity, but not high blood pressure, in spontaneously hypertensive rats.
AB  - The renin-angiotensin system plays a critical role in the control of blood
      pressure, and its hyperactivity is associated with the development of human
      primary hypertension. Because low-dose angiotensin I-converting enzyme (ACE)
      inhibitors cause small reductions in blood pressure that are associated with the
      complete reversal of altered vascular pathophysiology, our objective in this
      study was to determine whether ACE antisense (ACE-AS) gene delivery prevents
      alterations in renal vascular physiology in the parents and F(1) offspring of AS
      treated spontaneously hypertensive rats (SHR). A single bolus intracardiac
      injection of ACE-AS (2x10(8) colony-forming units) in SHR neonates caused a
      modest (18+/-3 mm Hg, n=7 to 9) lowering of blood pressure, which was maintained
      in the F(1) generation offspring (n=7 to 9). Alterations in renal vascular
      reactivity, electrophysiology, and [Ca(2+)](i) homeostasis are underlying
      mechanisms associated with the development and establishment of hypertension.
      Renal resistance arterioles from truncated ACE sense-treated SHR showed a
      significantly enhanced contractile response to KCl and phenylephrine (n=24 rings
      from 6 animals, P<0.01) and significantly attenuated acetylcholine-induced
      relaxations (n=24 rings from 6 animals, P<0.01) compared with arterioles from ACE
      AS-treated SHR. In addition, compared with cells dissociated from arterioles of
      ACE-AS-treated SHR, cells from truncated ACE sense-treated animal vessels had a
      resting membrane potential that was 22+/-4 mV more depolarized (n=38, P<0.01), an
      enhanced L-type Ca(2+) current density (2.2+/-0.3 versus 1.2+/-0.2 pA/pF, n=23,
      P<0.01), a decreased Kv current density (16.2+/-1.3 versus 5.4+/-2.2 pA/pF, n=34,
      P<0.01), and increased Ang II-dependent changes in [Ca(2+)](i) (n=142, P<0.01).
      Similar effects of ACE-AS treatment were observed in the F(1) offspring. These
      results demonstrate that ACE-AS permanently prevents alterations in renal
      vascular pathophysiology in spite of the modest effect that ACE-AS had on high
      blood pressure in SHR.

PMID- 10642300
TI  - G-Protein beta(3) subunit gene variant and left ventricular hypertrophy in
      essential hypertension.
AB  - A functional genetic variant consisting of a C825T substitution in the GNB3 gene,
      encoding for the G-protein beta(3) subunit, has been associated with enhanced G
      protein activation and cell growth. The aim of the study was to investigate the
      association of this polymorphism with left ventricular hypertrophy (LVH) in a
      sample of patients with essential hypertension. Left ventricular mass was
      assessed by 2-mode echocardiography in 86 patients with essential hypertension,
      and GNB3 C825T genotype was determined by polymerase chain reaction and
      restriction digestion. Thirty-seven (0.43) patients were homozygous for the C
      allele (CC), 40 (0.47) were heterozygous (CT), and 9 (0.10) were homozygous for
      the T allele (TT). The genotype distribution among the patients was in Hardy
      Weinberg equilibrium. Values of left ventricular end-diastolic diameter (52.0+/
      0.7 versus 48.9+/-0.9 mm, P=0.007), posterior wall thickness (11.3+/-0.2 versus
      10.6+/-0.2 mm, P=0.042), and left ventricular mass index (152.7+/-4.4 versus
      135.2+/-6.4 g/m(2), P=0. 023) were significantly higher in patients with CT and
      TT genotypes considered together (CT+TT) than in CC patients. The distribution of
      the genotypes was significantly different when comparing patients with LVH: 20
      (0.33) CC and 40 (0.67) CT+TT patients had this complication, and 17 (0.65) CC
      and 9 (0.35) CT+TT patients did not (P<0.01). The frequency of the T allele was
      significantly different among patients with (0.40) and without (0.20) LVH
      (P<0.01). A logistic regression analysis showed that the association between the
      T allele and LVH was independent of age, mean blood pressure, body mass index,
      and alcohol consumption. The relative risk of LVH in patients bearing the T
      allele (CT+TT group) compared with CC hypertensive patients was 3.03 (95% CI 1.14
      to 8.05). The findings suggest an association between LVH and the 825T allele in
      hypertensive patients.

PMID- 10642301
TI  - New beta-blocker: prolonged reduction in high blood pressure with beta(1)
      antisense oligodeoxynucleotides.
AB  - beta-Blockers are widely used for hypertension treatment but must be taken daily.
      We have developed a novel beta-blocker by targeting beta(1)-adrenergic receptor
      (beta(1)-AR) mRNA with antisense oligodeoxynucleotides (beta(1)-AS-ODN). A single
      intravenous injection of beta(1)-AS-ODN significantly reduced cardiac
      contractility and blood pressure (38+/-5 mm Hg, P<0.05) in spontaneously
      hypertensive rats for 3 weeks. In the present study, we improved the
      antihypertensive effect of beta(1)-AS-ODN by delivery with the cationic liposomes
      DOTAP/DOPE and studied its impact on the peripheral renin-angiotensin system.
      Five charge ratios (+/-) of liposome/ODN from 0 to 3.5 were tested to deliver 0.
      5 mg/kg beta(1)-AS-ODN intravenously in spontaneously hypertensive rats (n=30).
      On the basis of the magnitude and duration of hypotension, 2.5 was determined to
      be the optimal charge ratio, which decreased blood pressure by up to 35 mm Hg for
      20 to 33 days (P<0.05). The effects were specific for beta(1)-AR, because
      radioligand binding assay and quantitative autoradiography showed a 35% reduction
      in beta(1)-AR levels in kidney but no change in beta(2)-AR. beta(1)-AS-ODN
      diminished the preprorenin mRNA levels in renal cortex by 37% 4 days after
      administration. This transient effect was followed by a delayed yet marked
      diminution of plasma renin activity and plasma angiotensin II levels on days 10
      and 17 (P<0.01). The results show that beta(1)-AS-ODN has an effective long-term
      antihypertensive effect up to 33 days with a single intravenous injection. The
      mechanism appears to be through reduced beta(1)-AR number specifically and
      reduced cardiac contractility. The inhibition of the renin-angiotensin system is
      probably a second mechanism to produce the sustained antihypertensive effect of
      beta(1)-AS-ODN.

PMID- 10642302
TI  - Genetic analysis of rat chromosome 1 and the Sa gene in spontaneous hypertension.
AB  - Linkage studies in segregating populations derived from the spontaneously
      hypertensive rat (SHR) indicate that a blood pressure quantitative trait locus
      exists on rat chromosome 1 in the vicinity of the Sa gene. On the basis of these
      findings and the observation of increased renal expression of the Sa gene in SHR
      versus normotensive rats, the Sa gene has been proposed as a candidate gene for
      spontaneous hypertension. In SHR congenic strains, we and others have found that
      replacement of a segment of SHR chromosome 1 that contains the Sa gene with the
      corresponding chromosome segment from a normotensive Brown Norway (BN) rat or
      Wistar-Kyoto rat can reduce blood pressure. To test whether the Sa gene is
      necessary for the effect of this region of chromosome 1 on blood pressure, we
      studied a new SHR congenic subline that harbors a smaller segment of BN
      chromosome 1 that does not include the Sa gene. Transfer of this subregion of
      chromosome 1 from the BN rat onto the SHR background was associated with
      significant reductions in blood pressure comparable to those previously observed
      on transfer of a larger region of chromosome 1 that included the Sa gene. Thus,
      in the SHR-BN model of hypertension, the results of these mapping studies (1)
      demonstrate that molecular variation in the Sa gene is not required for the
      effect of this region of chromosome 1 on blood pressure and (2) should direct
      attention toward other candidate genes within the differential chromosome segment
      of the new congenic subline.

PMID- 10642303
TI  - Increased nitrovasodilator sensitivity in endothelial nitric oxide synthase
      knockout mice: role of soluble guanylyl cyclase.
AB  - Endogenously produced nitric oxide (NO) modulates nitrovasodilator-induced
      relaxation. We investigated the underlying mechanism in wild-type (WT) mice and
      endothelial NO synthase knockout (eNOS(-/-)) mice to determine whether a chronic
      lack of endothelial NO alters the soluble guanylyl cyclase (sGC) pathway. In
      aortic segments from eNOS(-/-) mice, the vasodilator sensitivity to sodium
      nitroprusside (SNP) was significantly greater than that in WT mice. There was no
      difference in sensitivity to the G-kinase I activator 8-para-chlorophenylthio
      cGMP or to cromakalim. N(omega)-Nitro-L-arginine had no effect on the SNP-induced
      relaxation in eNOS(-/-) but increased the sensitivity in WT mice so it was no
      longer different than that of eNOS(-/-). Basal cGMP levels in aortic rings were
      significantly lower in eNOS(-/-) mice than in WT mice. SNP (300 nmol/L) induced a
      significantly greater cGMP accumulation in eNOS(-/-) mice than in WT mice. The
      maximal SNP-induced (10 micromol/L) increase in cGMP was similar in both strains.
      SNP-stimulated sGC activity was significantly greater in eNOS(-/-) mice than in
      WT mice. Incubation of aortic segments from WT mice with N(omega)-nitro-L
      arginine increased sGC activity, an effect prevented by coincubation with SNP (10
      micromol/L). The aortic expressions of the sGC alpha1 and beta1 subunits in WT
      and eNOS(-/-) mice were identical as determined with Western blot analysis. These
      data suggest that chronic exposure to endothelium-derived NO, as well as acute
      exposure to nitrovasodilator-derived NO, desensitizes sGC to activation by NO but
      does not alter sGC expression. Both the acute cessation of endothelial NO
      formation in WT mice and the chronic deficiency of NO in eNOS(-/-) mice restore
      the NO sensitivity of sGC and enhance vascular smooth muscle relaxation in
      response to nitrovasodilator agents.

PMID- 10642304
TI  - Cyclic AMP inhibited proliferation of human aortic vascular smooth muscle cells,
      accompanied by induction of p53 and p21.
AB  - Although cAMP is an important second messenger that plays a pivotal role in the
      regulation of platelet aggregation and dilatation of blood vessels, little is
      known about the action of cAMP on the growth of vascular smooth muscle cells
      (VSMCs). Thus, we initially studied the effects of cAMP accumulation by using
      various cAMP stimulants, including a phosphodiesterase type 3 inhibitor
      (cilostazol) on human aortic VSMC growth. Accumulation of cAMP inhibited the
      platelet-derived growth factor (PDGF)-stimulated VSMC growth in a dose-dependent
      manner (P<0.01), whereas PDGF significantly stimulated the growth of human VSMCs.
      Thus, we focused on the role of cell cycle regulatory genes, especially on a
      negative regulator, an anti-oncogene, p53. The protein of p53 was potentiated by
      cilostazol as well as forskolin and 8-bromo-cAMP, whereas PDGF decreased p53
      expression. Upregulation of p53 protein by cAMP was further confirmed by the
      observation that the decrease in p21, a p53-inducible protein, by PDGF was
      significantly attenuated by cilostazol in a dose-dependent manner (P<0.01). These
      results revealed that accumulation of cAMP inhibited VSMC proliferation, which
      was at least in part due to an increase in p53-p21 expression. Because p53 and
      p21 have been reported to induce apoptosis, we examined apoptotic cells for cAMP
      accumulation. Incubation of VSMCs with cilostazol resulted in a significant
      increase in apoptotic cells in a dose-dependent manner compared with vehicle
      treatment as assessed by nuclear chromatic morphology (P<0.01); forskolin also
      stimulated apoptotic cells. Consistent with nuclear staining, DNA fragmentation
      in VSMCs treated with forskolin as well as 8-bromo-cAMP and cilostazol was
      significantly increased compared with DNA fragmentation in VSMCs treated with
      vehicle, whereas PDGF significantly decreased the rate of DNA fragmentation
      (P<0.01). Overall, these results demonstrated that cAMP inhibited the
      proliferation of human aortic VSMCs, accompanied by p53-p21-mediated apoptosis.
      Analogues of cAMP that have direct inhibitory effects on VSMC proliferation can
      be considered as potential antiproliferative drugs against VSMC growth.

PMID- 10642305
TI  - 5-Hydroxytryptamine-induced potentiation of endothelin-1- and norepinephrine
      induced contraction is mitogen-activated protein kinase pathway dependent.
AB  - 5-Hydroxytryptamine (5-HT)-induced arterial contraction depends on activation of
      the tyrosine kinase-dependent extracellular signal-regulated mitogen-activated
      protein kinase (Erk MAPK) pathway. The importance of 5-HT in the control of
      peripheral resistance has been questioned because circulating free levels of 5-HT
      are low (in the nanomolar range). We tested the hypothesis that physiologically
      relevant concentrations of 5-HT potentiate arterial contraction in response to
      agonists proved to have importance in blood pressure maintenance (norepinephrine
      [NE] and endothelin-1 [ET-1]) in a tyrosine kinase- and an Erk MAPK-dependent
      manner. Strips of endothelium-denuded rat tail artery were used for the
      measurement of isometric force. The general tyrosine kinase inhibitor genistein
      (5 micromol/L) and the inhibitor of MAPK/Erk kinase activation PD098059 (10
      micromol/L) shifted concentration-response curves to 5-HT (1x10(-9) to 3x10(-4)
      mol/L) rightward but did not shift concentration-response curves to NE or ET-1.
      In separate experiments, 5-HT (10 nmol/L) potentiated contraction in response to
      NE (20 nmol/L) by approximately 200% to 300% and to ET-1 (0.3 and 1 nmol/L) by
      640% and 180%, respectively. Genistein and PD098059 significantly (66% to 100%)
      reduced 5-HT-induced potentiation of both NE (20 nmol/L)- and ET-1 (0.3 and 1
      nmol/L)-induced contraction. Thus, these data support the ability of low
      physiological concentrations of 5-HT to amplify arterial responses to hormones
      with bona fide effects on blood pressure in the novel manner of depending on a
      tyrosine kinase/Erk MAPK pathway. Although these findings were generated in large
      arteries, we speculate that they may be applicable to vascular functioning in the
      deoxycorticosterone acetate salt model of hypertension in which all 3 hormones, 5
      HT, NE, and ET-1, have been implicated as causal factors.

PMID- 10642306
TI  - Role of Ca(2+)-independent phospholipase A(2) in the regulation of inducible
      nitric oxide synthase in cardiac myocytes.
AB  - We have previously shown that the regulation by interleukin-1beta (IL-1beta) of
      inducible nitric oxide synthase (iNOS) involves phospholipase A(2) (PLA(2))
      metabolites in neonatal ventricular myocytes. Based on studies in which ONO-RS
      082 is used to inhibit secretory PLA(2) and methyl arachidonyl fluorophosphonate
      is used to inhibit cytosolic PLA(2), our data suggest that a secretory PLA(2)
      metabolite was involved in the regulation by IL-1beta of iNOS. In addition, a
      third PLA(2) isoform, which is Ca(2+) independent (iPLA(2)), has also been
      detected in cardiac myocytes and shown to be regulated by cytokines. We tested
      whether iPLA(2) metabolites are involved in the regulation by IL-1beta of iNOS
      with the use of bromoenol lactone (BEL), a specific and irreversible inhibitor of
      iPLA(2). For this, we measured IL-1beta-stimulated nitrite (NOx) production with
      use of the Griess reagent, prostaglandin E(2) (PGE(2)) production with use of an
      enzyme immunoassay, and arachidonic acid release in the presence and absence of
      BEL. We also detected iNOS and iPLA(2) proteins by Western blotting. Treatment
      with IL-1beta (5 ng/mL) for 24 hours stimulated NOx production by 8-fold and iNOS
      protein levels by at least 10-fold. In addition, arachidonic acid release was
      increased by 1.6-fold and PGE(2) production was increased by 300-fold. When
      neonatal ventricular myocytes were treated with 10 micromol/L BEL, both IL-1beta
      stimulated PGE(2) production and arachidonic acid release were inhibited. BEL
      inhibited IL-1beta-stimulated NOx production and iNOS protein by 88% and 93%,
      respectively. Lysophosphatidic acid, but not arachidonic acid or
      lysophosphatidylcholine, stimulated iNOS expression. Our results indicate that an
      iPLA(2) metabolite, perhaps lysophosphatidic acid, may be involved in the IL
      1beta-signaling pathway, regulating the synthesis of iNOS.

PMID- 10642307
TI  - Angiotensin II and PDGF-BB stimulate beta(1)-integrin-mediated adhesion and
      spreading in human VSMCs.
AB  - beta(1)-Integrins play an important role for adhesion and spreading of human
      smooth muscle cells. In the present study we examined the influence of
      angiotensin II and platelet-derived growth factor (PDGF)-BB on beta(1)-integrin
      dependent functions of human smooth muscle cells obtained from iliac arteries.
      Treatment of these cells with PDGF-BB (20 ng/mL) and Angiotensin II (1
      micromol/L) did not change beta(1)-integrin expression up to 48 hours as analyzed
      by flow cytometry and reverse transcription polymerase chain reaction. beta(1)
      integrins predominantly mediated adhesion of human smooth muscle cells to
      collagen I (79.7+/-4.4%, P<0.01) and fibronectin (66. 6+/-2.4%, P<0.01).
      Treatment of smooth muscle cells with Angiotensin II (1 micromol/L) and PDGF-BB
      (20 ng/mL) significantly increased the adhesion to collagen I by 56.5% and 44.3%,
      respectively, and to fibronectin by 49.6% and 36.4%, respectively (all P<0.05).
      Angiotensin II-induced effects were mediated by the AT(1) receptor. The PDGF-BB
      mediated increase of adhesion was inhibited in the presence of genestein, a
      tyrosine-kinase inhibitor and by protein kinase C downregulation with phorbol 12
      myristate 13-acetate. Spreading of smooth muscle cells also was beta(1)-integrin
      dependent on collagen I and alpha(5)beta(1)-integrin dependent on fibronectin.
      Angiotensin II and PDGF-BB increased cell spreading on fibronectin up to 276% and
      318%, respectively, and on collagen I up to 133% and 138% (all P<0.05). These
      increases were significantly inhibited by blocking antibodies against beta(1)
      integrin, alpha(5)-integrin on fibronectin, the AT(1) receptor blocker
      irbesartan, and genestein. The present data demonstrate that angiotensin II and
      as well PDGF-BB enhance beta(1)-integrin-dependent adhesion and spreading of
      human vascular smooth muscle cells. Furthermore, the experiments with PDGF
      suggest an involvement of protein kinase C activation leading to these enhanced
      effects.

PMID- 10642308
TI  - Estradiol inhibits smooth muscle cell growth in part by activating the cAMP
      adenosine pathway.
AB  - Estradiol inhibits smooth muscle cell growth; however, the mechanisms involved
      remain unclear. Because estradiol stimulates cAMP synthesis and adenosine
      inhibits cell growth, we hypothesized that the conversion of cAMP to adenosine
      (ie, the cAMP-adenosine pathway) mediates in part the inhibitory effects of
      estradiol on vascular smooth muscle cell growth. To test this hypothesis, we
      examined the effects of estradiol (0.001 to 1 micromol/L) on serum-induced DNA,
      collagen, and total protein synthesis and cell number in the absence and presence
      of 1, 3-dipropyl-8-p-sulfophenylxanthine (10 nmol/L; A(1)/A(2) adenosine receptor
      antagonist), KF17837 (10 nmol/L; selective A(2) adenosine receptor antagonist), 8
      cyclopentyl-1,3-dipropylxanthine (10 nmol/L; selective A(1) adenosine receptor
      antagonist), and 2', 5'-dideoxyadenosine (10 micromol/L; adenylyl cyclase
      inhibitor). Estradiol inhibited all measures of cell growth, and the
      concentration-dependent inhibitory curves for estradiol were shifted to the right
      (P<0.05) by 1,3-dipropyl-8-p-sulfophenylxanthine, KF17837, and 2',5'
      dideoxyadenosine but not by 8-cyclopentyl-1, 3-dipropylxanthine. Moreover, the
      inhibitory effects of estradiol were enhanced by stimulation of adenylyl cyclase
      with forskolin and by inhibition of adenosine metabolism with erythro-9-(2
      hydroxy-3-nonyl)adenine plus iodotubericidin (adenosine deaminase and kinase
      inhibitors, respectively). Estradiol also increased levels of cAMP and adenosine,
      and these effects were blocked by 2',5'-dideoxyadenosine (P<0.05). Our results
      support the hypothesis that estradiol stimulates cAMP synthesis and cAMP-derived
      adenosine regulates smooth muscle cell growth via A(2) adenosine receptors. Thus,
      the cAMP-adenosine pathway may contribute importantly to the antivasooclusive
      effects of estradiol.

PMID- 10642309
TI  - A(2B) receptors mediate antimitogenesis in vascular smooth muscle cells.
AB  - Adenosine inhibits growth of vascular smooth muscle cells. The goals of this
      study were to determine which adenosine receptor subtype mediates the
      antimitogenic effects of adenosine and to investigate the signal transduction
      mechanisms involved. In rat aortic vascular smooth muscle cells, platelet-derived
      growth factor-BB (PDGF-BB) (25 ng/mL) stimulated DNA synthesis ([(3)H]thymidine
      incorporation), cellular proliferation (cell number), collagen synthesis
      ([(3)H]proline incorporation), total protein synthesis ([(3)H]leucine
      incorporation), and mitogen-activated protein (MAP) kinase activity. The
      adenosine receptor agonists 2-chloroadenosine and 5'-N
      methylcarboxamidoadenosine, but not N(6)-cyclopentyladenosine or CGS21680,
      inhibited the growth effects of PDGF-BB, an agonist profile consistent with an
      A(2B) receptor-mediated effect. The adenosine receptor antagonists KF17837 and
      1,3-dipropyl-8-p-sulfophenylxanthine, but not 8-cyclopentyl-1, 3
      dipropylxanthine, blocked the growth-inhibitory effects of 2-chloroadenosine and
      5'-N-methylcarboxamidoadenosine, an antagonist profile consistent with an A(2)
      receptor-mediated effect. Antisense, but not sense or scrambled, oligonucleotides
      to the A(2B) receptor stimulated basal and PDGF-induced DNA synthesis, cell
      proliferation, and MAP kinase activity. Moreover, the growth-inhibitory effects
      of 2-chloroadenosine, 5'-N-methylcarboxamidoadenosine, and erythro-9-(2-hydroxy-3
      nonyl) adenine plus iodotubericidin (inhibitors of adenosine deaminase and
      adenosine kinase, respectively) were abolished by antisense, but not scrambled or
      sense, oligonucleotides to the A(2B) receptor. Our findings strongly support the
      hypothesis that adenosine causes inhibition of vascular smooth muscle cell growth
      by activating A(2B) receptors coupled to inhibition of MAP kinase activity.
      Pharmacological or molecular biological activation of A(2B) receptors may prevent
      vascular remodeling associated with hypertension, atherosclerosis, and restenosis
      following balloon angioplasty.

PMID- 10642310
TI  - Angiotensin II enhances integrin and alpha-actinin expression in adult rat
      cardiac fibroblasts.
AB  - Angiotensin II (Ang II) plays an important role in cardiac remodeling through
      stimulation of proliferation and extracellular matrix (ECM) production in cardiac
      fibroblasts. Integrins are a family of transmembrane receptors that mediate the
      attachment of cells to ECM. We hypothesized that Ang II regulation of integrins
      further contributes to its role in cardiac remodeling. We cultured adult rat
      cardiac fibroblasts with and without Ang II (100 nmol/L) to determine the effects
      on mRNA and protein levels of integrins, as well as alpha-actinin and other
      cytoskeletal proteins that link to integrins at the site of focal adhesions. Ang
      II was also added in the presence of irbesartan (10 micromol/L), a specific Ang
      II type 1 (AT(1)) receptor antagonist, or PD 123319 (10 micromol/L), a specific
      Ang II type 2 receptor antagonist. To investigate the function of these
      integrins, we determined the effects of blocking antibodies on Ang II-induced
      adhesion to ECM. We also treated spontaneously hypertensive rats (SHR) with an
      AT(1) receptor blocker, losartan, or with hydralazine to investigate integrin and
      alpha-actinin expression in treated and untreated SHR. Ang II enhanced alpha(v),
      beta(1), beta(3), and beta(5) integrins; osteopontin; and alpha-actinin mRNA and
      protein levels in cardiac fibroblasts. All of these effects were inhibited by
      irbesartan but not by PD 123319. Pretreatment of cardiac fibroblasts with Ang II
      enhanced cell attachment to ECM proteins and induced focal adhesion kinase
      phosphorylation. Blocking antibodies to beta(3) and alpha(v)beta(5) attenuated
      Ang II-induced adhesion. In SHR, ventricular alpha(v) and beta(5) integrin
      expression and alpha-actinin were increased compared with those in Wistar-Kyoto
      rats. Although both losartan and hydralazine lowered mean arterial pressure and
      decreased peripheral vascular resistance, only losartan attenuated the increased
      integrin, alpha-actinin, fibronectin laminin, and osteopontin expression and the
      increased left ventricular mass (as determined with echocardiography). Hydralzine
      had none of these effects. Although both agents attenuated beta-myosin heavy
      chain expression, a marker of hypertrophy, losartan had a greater effect. These
      results suggest that integrins and alpha-actinin are upregulated by Ang II and in
      left ventricular hypertrophy and that the block of expression of these proteins
      through inhibition of the AT(1) receptor is associated with attenuation of the
      hypertrophic response. Ang II induces integrin and alpha-actinin expression in
      cardiac fibroblasts that is associated with adhesion and left ventricular
      hypertrophy and blocked through inhibition of the AT(1) receptor.

PMID- 10642311
TI  - Endothelin-mediated calcium signaling in preglomerular smooth muscle cells.
AB  - This study was performed to test the hypothesis that endothelin peptides
      differentially influence intracellular calcium concentration ([Ca(2+)](i)) in
      preglomerular microvascular smooth muscle cells (MVSMC), in part through
      activation of endothelin (ET)(A) receptors. Experiments were performed in vitro
      with the use of single MVSMC freshly isolated from rat preglomerular
      microvessels. The effect of ET-1, ET-2, and ET-3 on [Ca(2+)](i) was measured with
      the use of the calcium-sensitive dye, fura 2, and standard fluorescence
      microscopy techniques. Baseline [Ca(2+)](i) averaged 84+/-3 nmol/L (n=141 cells
      from 23 dispersions). ET-1 concentrations of 1, 10, and 100 nmol/L evoked peak
      increases in [Ca(2+)](i) of 48+/-16, 930+/-125, and 810+/-130 nmol/L,
      respectively. The time course of the [Ca(2+)](i) response was biphasic, beginning
      with a rapid initial increase followed by a sustained plateau phase or a period
      during which [Ca(2+)](i) oscillated sharply. Similar responses were observed
      after ET-2 administration. In contrast, ET-3 stimulated monophasic increases in
      [Ca(2+)](i) of only 14+/-5, 33+/-16, and 44+/-19 nmol/L at peptide concentrations
      of 1, 10, and 100 nmol/L, respectively. These responses are significantly smaller
      than responses to ET-1 or ET-2, respectively. The relative contributions of
      calcium mobilization and calcium influx in the response to ET-1 were also
      evaluated. Removal of calcium from the bathing medium did not significantly alter
      the peak response to 10 nmol/L ET-1 but abolished the late phase elevation of
      [Ca(2+)](i). These data demonstrate that endothelin peptides increase [Ca(2+)](i)
      in preglomerular MVSMC. The concentration-response profiles are consistent with
      the response involving activation of ET(A) receptors. Furthermore, these results
      suggest that ET-1 increases [Ca(2+)](i) by stimulating both the release of
      intracellular calcium and the influx of calcium from the extracellular medium.

PMID- 10642312
TI  - Endothelin-1 attenuates omega3 fatty acid-induced apoptosis by inhibition of
      caspase 3.
AB  - Endothelin-1 (ET-1) may be involved in the induction of vascular hypertrophy in
      hypertension. ET-1 may also modulate vascular growth through the exertion of
      antiapoptotic effects. The omega3 fatty acids (omega3 FAs), which have
      antiproliferative effects in various cell types, may have a beneficial role in
      hypertension. We tested the hypothesis that ET-1 could act as a survival factor
      against omega3 FA-induced apoptosis and attempted to elucidate possible molecular
      mechanisms underlying the protective action of ET-1 on docosahexaenoic acid (DHA)
      induced apoptosis. Mesenteric vascular smooth muscle cells were stimulated with
      DHA, a representative omega3 FA. Dose-response curves of DHA at different
      apoptotic stages were assessed with the use of flow cytometry: (1) very early:
      plasma membrane phosphatidylserine (PS) translocation; (2) early: change in
      mitochondrial transmembrane potential (DeltaPsim); and (3) late: cell cycle
      analysis. Expression of the proapoptotic protein bax and the antiapoptotic
      protein bcl-2 was determined with Western blot assay. The activity and the
      expression of caspase 3, which is a critical proteolytic enzyme involved in the
      death-signaling pathway, were evaluated with a fluorometric immunosorbent enzyme
      assay and Western blot analysis, respectively. Apoptosis, which was detected with
      PS translocation, DeltaPsim disruption, and cell cycle analysis, was increased
      dose dependently by DHA. DHA-induced apoptosis was attenuated through exposure to
      ET-1 for 1 hour before DHA in cell cycle analysis. The interference of ET-1 with
      DHA-induced apoptosis, as detected with cell cycle analysis, was not apparent at
      the membrane (PS translocation) or the mitochondrial (DeltaPsim) level. The
      increase in bax/bcl-2 ratio in DHA-stimulated cells was not affected by ET-1.
      However, DHA increased both caspase 3 activity and the active forms of caspase 3
      (20 and 17 kDa), resulting in enhanced DNA fragmentation as shown through Hoechst
      staining and fluorescence microscopy, which were attenuated by ET-1 pretreatment.
      In conclusion, DHA, an omega3 FA, induced apoptosis in vascular smooth muscle
      cells in a dose-dependent manner. ET-1 exerted important protective effects
      through the attenuation of DHA-induced caspase 3 activation and subsequent DNA
      fragmentation in the late stages of apoptosis.

PMID- 10642313
TI  - Interleukin-1beta regulates the human brain natriuretic peptide promoter via
      Ca(2+)-dependent protein kinase pathways.
AB  - We have shown that interleukin-1beta (IL-1beta) activates the human brain
      natriuretic peptide (hBNP) promoter via a transcriptional mechanism. Others have
      reported that changes in intracellular calcium (Ca(2+)) mediate the action of IL
      1beta. We questioned whether Ca(2+) and Ca(2+)-dependent pathways mediate IL
      1beta regulation of the hBNP promoter in cardiac myocytes. The hBNP promoter (
      1818 to +100) coupled to a luciferase cDNA reporter gene was transferred into
      neonatal cardiac myocytes. Cells were then treated with agents that modify Ca(2+)
      levels or inhibit Ca(2+)-dependent kinases, and luciferase activity was measured
      as an index of hBNP promoter activity. The Ca(2+) ionophore A23187 increased hBNP
      promoter activity; however, neither EGTA nor nifedipine reduced IL-1beta
      stimulated promoter activity. Long-term treatment with thapsigargin, which
      depletes intracellular Ca(2+) stores, decreased basal promoter activity and
      blocked the effect of IL-1beta. Inhibition of protein kinase C completely blocked
      IL-1beta-stimulated hBNP promoter activity, whereas inhibition of
      Ca(2+)/calmodulin-dependent kinase II decreased promoter activity by 40%. In
      contrast, inhibition of the Ca(2+)-regulated phosphatase calcineurin by
      cyclosporin A had no effect. These data suggest that (1) Ca(2+) activates the
      hBNP promoter; (2) release of Ca(2+) from intracellular stores is important to IL
      1beta regulation of the hBNP promoter, but transport via voltage-sensitive Ca(2+)
      channels is not; (3) protein kinase C and Ca(2+)/calmodulin-dependent kinase II
      mediate the action of IL-1beta; and (4) the phosphatase calcineurin is not
      involved in IL-1beta regulation of the hBNP promoter. Thus, Ca(2+) and Ca(2+)
      dependent pathways are critical to IL-1beta regulation of the hBNP promoter.

PMID- 10642314
TI  - Downregulation of angiotensin II type 1 receptor by all-trans retinoic acid in
      vascular smooth muscle cells.
AB  - All-trans retinoic acid (atRA) is a biologically active metabolite of vitamin A
      that plays an important role in cell differentiation and proliferation. Although
      neointimal formation after balloon injury of rat carotid artery is inhibited by
      atRA, the mechanisms are not clearly understood. Because the renin-angiotensin
      system is one of the crucial components of atherosclerosis, we examined the
      effects of atRA on the expression of angiotensin II type 1 receptor (AT(1)-R) in
      vascular smooth muscle cells. atRA (1 micromol/L) decreased the AT(1)-R mRNA
      level by 50% after 24 hours; AT(1)-R number was also reduced to the same extent
      after 48 hours. atRA markedly suppressed promoter activity of the AT(1)-R
      promoter-luciferase construct, but AT(1)-R mRNA stability was not affected.
      Cycloheximide blocked the atRA-induced decrease in AT(1)-R mRNA expression,
      suggesting that this process requires de novo protein synthesis. Simultaneous
      treatment with an agonist (Ro40-6055) specific for retinoic acid receptor (RAR)
      and an agonist (Ro25-7836) specific for retinoid X receptor (RXR) suppressed the
      AT(1)-R mRNA expression comparable to that with treatment with atRA, suggesting
      that the RAR/RXR heterodimer mediates the effect of atRA in AT(1)-R
      downregulation. These results suggest that atRA suppressed AT(1)-R mRNA
      transcription through new protein synthesis induced by RAR/RXR-dependent
      transcription. This study provides novel insight into a role of atRA as an
      important molecule that regulates AT(1)-R gene expression and provides possible
      mechanisms for the suppression of neointimal formation by atRA.

PMID- 10642315
TI  - Insulin inhibits migration of vascular smooth muscle cells with inducible nitric
      oxide synthase.
AB  - Vascular smooth muscle cell (VSMC) migration participates in atherosclerosis and
      arterial restenosis after balloon angioplasty. Because these processes are
      enhanced in insulin-resistant states, our goal was to determine whether insulin
      affects VSMC migration and, if so, how. The migration of primary cultured VSMCs
      from canine femoral artery was measured with the use of a wound migration assay
      and related to cGMP levels. Insulin (1 nmol/L) did not affect migration or cGMP
      production in control cells. When inducible nitric oxide synthase (iNOS) was
      induced by 24-hour preincubation with lipopolysaccharide and interleuken-1beta,
      basal migration decreased, cGMP production increased, and insulin inhibited
      migration by >90% and stimulated cGMP production by 3-fold. The nitric oxide
      synthase inhibitor N(G)-monomethyl-L-arginine blocked the affect of insulin on
      the migration of VSMCs with iNOS. 8-Bromo-cGMP inhibited VSMC migration in
      control cells, and 1-H-1[1,2,4]oxadiazolo-[4, 3a]quinoxolin-1-one, a selective
      inhibitor of guanylate cyclase, blocked the inhibition by insulin of migration of
      cells with iNOS. We conclude that insulin does not normally affect cGMP
      production or the migration of these VSMCs. However, after the induction of iNOS,
      insulin stimulates cGMP production and inhibits migration via an NOS-and a cGMP
      dependent mechanism.

PMID- 10642316
TI  - Cytochrome P450 and cyclooxygenase metabolites contribute to the endothelin-1
      afferent arteriolar vasoconstrictor and calcium responses.
AB  - Arachidonic acid metabolites contribute to the endothelin-1 (ET-1)-induced
      decrease in renal blood flow, but the vascular sites of action are unknown.
      Experiments performed in vitro used the rat juxtamedullary nephron preparation
      combined with videomicroscopy. The response of afferent arterioles to ET-1 was
      determined before and after cytochrome P450 (CYP450) or cyclooxygenase (COX)
      inhibition. Afferent arteriolar diameter averaged 20+/-1 microm (n=17) at a renal
      perfusion pressure of 100 mm Hg. Superfusion with 0.001 to 10 nmol/L ET-1 caused
      a graded decrease in diameter of the afferent arteriole. Vessel diameter
      decreased by 30+/-2% and 41+/-2% in response to 1 and 10 nmol/L ET-1,
      respectively. The afferent arteriolar response to ET-1 was significantly
      attenuated during administration of the CYP450 hydroxylase inhibitor N
      methylsulfonyl-12,12-dibromododec-11-enamide (DDMS), such that afferent
      arteriolar diameter decreased by 19+/-3% and 22+/-3% in response to 1 and 10
      nmol/L ET-1, respectively. COX inhibition also greatly attenuated the
      vasoconstriction elicited by ET-1, whereas the CYP450 epoxygenase inhibitor N
      methylsulfonyl-6-(2-proparglyoxyphenyl) hexanamide enhanced the ET-1-mediated
      vascular response. Additional studies were performed using freshly isolated
      smooth muscle cells prepared from preglomerular microvessels. Renal microvascular
      smooth muscle cells were loaded with the calcium-sensitive dye fura 2 and studied
      by use of single-cell fluorescence microscopy. Basal renal microvascular smooth
      muscle cell [Ca(2+)](i) averaged 95+/-3 nmol/L (n=42). ET-1 (10 nmol/L) increased
      microvascular smooth muscle cell [Ca(2+)](i) to a peak value of 731+/-75 nmol/L
      before stabilizing at 136+/-8 nmol/L. Administration of DDMS or the COX inhibitor
      indomethacin significantly attenuated the renal microvascular smooth muscle cell
      calcium response to ET-1. These data demonstrate that CYP450 hydroxylase and COX
      arachidonic acid metabolites contribute importantly to the afferent arteriolar
      diameter and renal microvascular smooth muscle cell calcium responses elicited by
      ET-1.

PMID- 10642317
TI  - Involvement of Rho-kinase in angiotensin II-induced hypertrophy of rat vascular
      smooth muscle cells.
AB  - Angiotensin II (Ang II) is now believed to play a critical role in the
      pathogenesis of hypertrophy and/or hyperplasia of vascular smooth muscle cells
      (VSMCs). Several G(i)- and G(q)-coupled receptors, including the Ang II type 1
      (AT(1)) receptor, activate Rho and Rho-associated kinase in Swiss 3T3 cells and
      cardiac myocytes. However, little is known about the role of Rho-kinase in Ang II
      induced vascular hypertrophy in VSMCs. In the present study, we explored the role
      of Rho and Rho-kinase in Ang II-induced protein synthesis in VSMCs. In
      unstimulated cells, RhoA was observed predominantly in the cytosolic fraction,
      but it was translocated in part to the particulate fraction in response to Ang II
      (100 nmol/L). This effect was completely blocked by the AT(1) receptor blocker
      candesartan but not by the Ang II type 2 (AT(2)) receptor antagonist PD123319.
      Botulinum C(3) exoenzyme, which inactivated RhoA, attenuated Ang II-induced
      [(3)H]leucine incorporation. The specific Rho-kinase inhibitor, Y-27632, dose
      dependently abolished Ang II-induced protein synthesis and also suppressed Ang II
      induced c-fos mRNA expression. On the other hand, Y-27632 had no effect on Ang II
      stimulated phosphorylation of p70 S6 kinase and extracellular signal-regulated
      kinase 1/2, which are reported to be involved in Ang II-induced protein
      synthesis, nor had it any effect on the Ang II-induced phosphorylation of PHAS-I,
      a heat- and acid-stable eIF-4E-binding protein. The phosphorylation of PHAS-I is
      regulating for translation initiation. These observations suggest that the Rho,
      Rho-kinase, and c-fos pathways may play a role in Ang II-induced hypertrophic
      changes of VSMCs through a novel pathway.

PMID- 10642318
TI  - eNOS mediates L-arginine-induced inhibition of thick ascending limb chloride
      flux.
AB  - We recently reported that the rat thick ascending limb (THAL) possesses an active
      isoform of nitric oxide synthase (NOS) that is substrate-limited in vitro. NO
      produced by THAL NOS inhibits chloride flux. Protein and transcript for each of
      the primary NOS isoforms-endothelial (eNOS), inducible (iNOS), and neuronal
      (nNOS)-have been demonstrated in THALs. However, the NOS isoform that mediates NO
      induced inhibition of chloride flux is unknown. We hypothesized that NO produced
      from eNOS in the THAL inhibits NaCl transport. THALs from male eNOS, iNOS, and
      nNOS knockout mice and C57BL/6J wild-type controls were perfused in vitro and the
      response of transepithelial chloride flux (J(Cl)) to L-arginine (L-Arg), the
      substrate for NOS, and spermine NONOate (SPM), an NO donor was measured. We first
      tested whether isolated mouse THALs could synthesize NO and whether this NO
      inhibits transport. Addition of 0. 5 mmol/L L-Arg to the bath decreased J(Cl)
      from 105.8+/-17.5 to 79. 2+/-15.8 pmol/mm per minute (P<0.01) in C57BL/6J wild
      type mice, whereas addition of D-Arginine had no effects on J(Cl.) In contrast,
      addition of 0.5 mmol/L L-Arg to the bath did not alter J(Cl) of THALs from eNOS
      knockout mice. When 10 micromol/L SPM was added to the bath of eNOS knockout
      THALs, J(Cl) decreased from 89.1+/-8.6 to 74.8+/-7.5 pmol/mm/min (P<0.05). Thus
      the lack of responsiveness of eNOS knockout THALs to L-Arg was not due to an
      inability to respond to NO. We next evaluated the role of iNOS and nNOS in the
      response to L-Arg. Addition of 0.5 mmol/L L-Arg to the bath decreased J(Cl) in
      THALs from iNOS and nNOS knockout mice by 37.7+/-6.4% (P<0.05) and 31.8+/-8.3%
      (P<0.01), respectively. We conclude that eNOS is the active isoform of NOS in the
      THAL under basal conditions. Mouse THAL eNOS responds to exogenous L-Arg by
      increasing NO production, which, in turn, inhibits J(Cl).

PMID- 10642319
TI  - Inhibition of adrenal cell aldosterone synthesis by endogenous nitric oxide
      release.
AB  - Adrenal zona glomerulosa (ZG) cells do not contain nitric oxide (NO) synthase
      (NOS). We conferred endothelial NOS activity onto adrenal ZG cells through
      transduction with a recombinant adenovirus encoding the endothelial NOS gene
      (AdeNOS) to determine the effect of endogenous NO on aldosterone synthesis. A 135
      kDa protein band immunoreactive to anti-endothelial NOS antibody was observed in
      Western blots of AdeNOS-transduced ZG cells but not in control cells or cells
      transduced with adenovirus encoding the beta-galactosidase gene (AdbetaGal).
      Nitrate/nitrite production in AdeNOS-transduced ZG cells increased from 0.15+/
      0.01 to 0.27+/-0.01 micromol/L after stimulation with 1 nmol/L angiotensin II.
      The treatment of AdeNOS-transduced cells with 30 micromol/L L-nitro-arginine
      decreased angiotensin II-stimulated nitrite production from 0.27+/-0. 01 to
      0.17+/-0.01 micromol/L. Basal and angiotensin II-stimulated nitrite production
      was not increased in AdbetaGal-transduced or control cells. AdeNOS-transduced
      cells demonstrated diaminofluorescein-2 diacetate fluorescence, which was blocked
      by pretreatment with L-nitro-arginine. Angiotensin II-stimulated aldosterone
      synthesis decreased from 5123+/-177 pg/mL in AdbetaGal-transduced ZG cells to
      72+/-27 pg/mL in AdeNOS-transduced cells. Treatment with the NOS inhibitor
      thiocitrulline (30 micromol/L) increased angiotensin II-stimulated aldosterone
      synthesis to 2158+/-45 pg/mL after AdeNOS transduction. These data demonstrate
      that adenovirus-mediated gene transfer of eNOS in ZG cells results in the
      expression of active endothelial NOS enzyme and that this endogenous NO
      production by ZG cells decreases aldosterone synthesis.

PMID- 10642321
TI  - Nitric oxide synthase activity and isoforms in rat renal vasculature.
AB  - Experiments were performed to quantify nitric oxide synthase (NOS) activity and
      identify the NOS isoforms present in the Sprague-Dawley rat renal vasculature.
      NOS enzymatic activity was measured by adding [(3)H]arginine to microdissected
      renal blood vessels and quantifying the conversion to [(3)H]citrulline by reverse
      phase high-performance liquid chromatography. Total NOS activity was greatest in
      microdissected vasa recta (123+/-41 pmol. mg(-1). h(-1), n=5) and significantly
      less in glomeruli (46+/-9 pmol. mg(-1). h(-1), n=6) and afferent arterioles (42+/
      10 pmol. mg(-1). h(-1), n=6) and averaged <5 pmol. mg(-1). h(-1) in arcuate (n=8)
      and interlobular (n=9) arteries. Addition of 1.0 mmol/L EDTA to the reaction
      decreased NOS activity to <5 pmol. mg(-1). h(-1) in afferent arterioles,
      glomeruli, and vasa recta (n=5 each), indicating that the NOS enzymatic activity
      in these segments is primarily a result of constitutive NOS. Both neuronal and
      endothelial NOS mRNA were identified in each vascular segment by reverse
      transcription-polymerase chain reaction, but inducible NOS mRNA was detected only
      in microdissected arcuate arteries. The present experiments indicate that the
      vasa recta, glomeruli, and afferent arterioles contain large amounts of calcium
      dependent NOS enzymatic activity and that neuronal NOS and endothelial NOS mRNA
      are present in these segments.

PMID- 10642320
TI  - Obesity is associated with tissue-specific activation of renal angiotensin
      converting enzyme in vivo: evidence for a regulatory role of endothelin.
AB  - In the C57BL/6J mice model, we investigated whether obesity affects the function
      or expression of components of the tissue renin-angiotensin system and whether
      endothelin (ET)-1 contributes to these changes. ACE activity (nmol. L His-Leu. mg
      protein(-1)) was measured in lung, kidney, and liver in control (receiving
      standard chow) and obese animals treated for 30 weeks with a high-fat, low
      cholesterol diet alone or in combination with LU135252, an orally active ET(A)
      receptor antagonist. ACE mRNA expression was measured in the kidney, and the
      effects of LU135252 on purified human ACE were determined. Aortic and renal
      tissue ET-1 protein content was measured, and the vascular contractility to
      angiotensin II was assessed. Obesity was associated with a tissue-specific
      increase in ACE activity in the kidney (55+/-4 versus 33+/-3 nmol/L) but not in
      the lung (34+/-2 versus 32+/-2 nmol/L). Long-term LU135252 treatment completely
      prevented this activation (13.3+/-0.3 versus 55+/-4 nmol/L, P<0.05) independent
      of ACE mRNA expression, body weight, or renal ET-1 protein but did not affect
      pulmonary or hepatic ACE activity. Obesity potentiated contractions in response
      to angiotensin II in the aorta (from 6+/-2% to 33+/-5% KCl) but not in the
      carotid artery (4+/-1% to 3.6+/-1% KCl), an effect that was completely prevented
      with LU135252 treatment (6+/-0.4% versus 33+/-5% KCl). No effect of LU135252 on
      purified ACE was observed. Thus, obesity is associated with the activation of
      renal ACE in vivo independent of its mRNA expression and enhanced vascular
      contractility to angiotensin II. These effects are regulated by ET in an organ
      specific manner, providing novel mechanisms by which ET antagonists may exert
      organ protection.

PMID- 10642322
TI  - Expression and actions of heme oxygenase in the renal medulla of rats.
AB  - Recent studies have shown that the heme oxygenase (HO) product, carbon monoxide
      (CO), induces vasodilation and that inhibition of HO produces a sustained
      hypertension in rats. Given the importance of renal medullary blood flow (MBF) in
      the long-term control of arterial blood pressure, we hypothesized that the HO/CO
      system may play an important role in maintaining the constancy of blood flow to
      the renal medulla, which in turn contributes to the antihypertensive effects of
      the renal medulla. To test this hypothesis, we first determined the expression of
      2 isoforms of HO (HO-1 and HO-2) in the different kidney regions. By Northern
      blot analyses, the abundance of both isozyme mRNAs was found highest in the renal
      inner medulla and lowest in the renal cortex. The transcripts for HO-1 in the
      renal outer medulla and inner medulla were 2.5 and 3.7 times that expressed in
      the renal cortex and those for HO-2 in the outer medulla and inner medulla were
      1.3 and 1.6 times that expressed in the renal cortex, respectively. Western blot
      analyses of both enzymes showed the same expression pattern in these kidney
      regions as the mRNAs. To determine the role that HO plays in the control of renal
      MBF, we examined the effect of the HO inhibitor zinc deuteroporphyrin 2,4-bis
      glycol (ZnDPBG) on cortical blood flow and MBF in anesthetized rats. ZnDPBG was
      given by renal medullary interstitial infusion, and cortical blood flow and MBF
      were measured by laser Doppler flowmetry. Renal medullary interstitial infusion
      of ZnDPBG at a dose of 60 nmol/kg per minute produced a 31% decrease in MBF over
      a period of 60 minutes as measured by laser Doppler flow signal (0.62+/-0.02 vs
      0.43+/-0.04 V in control vs ZnDPBG). With the use of an in vivo microdialysis
      technique, ZnDPBG was found to significantly reduce renal medullary cGMP
      concentrations when infused into the renal medullary interstitial space. These
      results suggest that both HO-1 and HO-2 are highly expressed in the renal
      medulla, that HO and its products play an important role in maintaining the
      constancy of blood flow to the renal medulla, and that cGMP may mediate the
      vasodilator effect of HO products in the renal medullary circulation.

PMID- 10642323
TI  - Release of angiotensin-(1-7) from the rat hindlimb: influence of angiotensin
      converting enzyme inhibition.
AB  - The results of recent studies have demonstrated that angiotensin (Ang)-(1-7)
      contributes to the antihypertensive actions of either combined ACE/Ang II type 1
      receptor blockade or ACE inhibition alone. The vasculature is a key site of
      action for either drug regimen, and evidence favors a local Ang system within
      these tissues. Because ACE may degrade Ang-(1-7), we determined whether ACE
      inhibition alters Ang-(1-7) release from the rat hindlimb perfused with Krebs
      Ringer buffer containing Ficoll. Ang-(1-7) release averaged 36+/-13 fmol (period
      1, 15-minute collection) and 44+/-11 fmol (period 2) in the control buffer. The
      addition of the ACE inhibitor lisinopril to the perfusion buffer augmented levels
      of Ang-(1-7) in periods 3 (144+/-39 fmol) and 4 (163+/-35 fmol; P<0.05 versus 1
      or 2, n=8). HPLC and radioimmunoassay of effluent from control or lisinopril
      treatment demonstrated a single immunoreactive peak with a retention time
      identical to that of Ang-(1-7). The addition of the neprilysin inhibitor SCH
      39370 reduced Ang-(1-7) release in the lisinopril buffer from 177+/-32 (period 1)
      and 173+/-39 (period 2) fmol to 112+/-24 (period 3) and 87+/-23 fmol (period 4;
      P<0.05 versus 1 or 2, n=6). Ang I metabolism in the collected perfusate revealed
      the formation of Ang-(1-7) that was sensitive only to thimet oligopeptidase
      inhibition; Ang II generation was not detected. The present study demonstrates
      the recovery of endogenous Ang-(1-7) from the perfused hindlimb. The release of
      Ang-(1-7) is significantly influenced by inhibition of ACE, which may reflect
      both increased substrate (Ang I) levels and reduced metabolism of the peptide.
      Neprilysin inhibition reduced but did not abolish Ang-(1-7) release, which
      suggests that other endopeptidases may contribute to the release of the peptide.

PMID- 10642324
TI  - Angiotensin-converting enzyme expression in human carotid artery atherosclerosis.
AB  - Angiotensin-converting enzyme (ACE) inhibitors reduce the progression of
      atherosclerosis in animal models and reinfarction rates after myocardial
      infarction in humans. Although expression of components of the renin-angiotensin
      system has been reported in human coronary arteries, no data regarding their
      presence in carotid arteries, a frequent site for the occurrence of
      atherosclerosis plaques, are available. The following study sought to determine
      whether ACE mRNA and protein can be detected in human carotid atheromatous
      lesions. Twenty-four intact endarterectomy specimens were obtained from patients
      with severe carotid occlusive disease (17 males and 7 females, aged 68+/-1 years)
      and fixed within 30 minutes. Carotid artery specimens contained advanced Stary
      type V and VI lesions, and human ACE mRNA expression and protein were localized
      in cross sections by the combination of in situ hybridization and
      immunohistochemistry. Cell type-specific antibodies were used to colocalize ACE
      to smooth muscle cells, endothelial cells, macrophages, or lymphocytes. ACE
      protein was localized in the intima, whereas the overlying media was largely free
      of ACE staining. In less complicated lesions, ACE staining was modest and could
      be visualized in scattered clusters of macrophages and on the luminal side of
      carotid artery vascular endothelium. Smooth muscle cells were largely negative.
      ACE staining increased as lesions became more complex and was most prominent in
      macrophage-rich regions. The shoulder regions of plaques contained numerous ACE
      positive macrophage foam cells and lymphocytes. In these areas, microvessels were
      positive for endothelial cell and smooth muscle cell ACE expression. However,
      microvessels in plaques free of inflammatory cells were stained only faintly for
      ACE expression. Labeling for ACE mRNA mirrored the pattern of protein expression,
      localizing ACE mRNA to macrophages and microvessels within the intima. In
      conclusion, atherosclerosis alters carotid artery ACE production, increasing
      transcription and translation within regions of plaque inflammation. These data
      provide another important mechanism by which inflammation associated with
      increased ACE expression may contribute to the progression of atherosclerosis.

PMID- 10642326
TI  - Decreased endothelium-dependent vascular relaxation during reduction of uterine
      perfusion pressure in pregnant rat.
AB  - Reduction in uterine perfusion and the ensuing placental ischemia during late
      pregnancy have been proposed to trigger increases in systemic vascular resistance
      and pregnancy-induced hypertension; however, the intermediary mechanisms involved
      are unclear. The purpose of the present study was to test the hypothesis that
      reduced uterine perfusion pressure during late pregnancy is associated with
      impaired endothelium-dependent vascular relaxation and, consequently, enhanced
      systemic vascular reactivity. Active stress was measured in aortic strips
      isolated from late pregnant Sprague-Dawley rats and a hypertensive pregnant rat
      model produced through the long-term reduction in uterine perfusion pressure
      (RUPP). Phenylephrine (Phe, 10(-5) mol/L) caused an increase in active stress to
      4.5+/-0.4x10(3) N/m(2) in normal pregnant rats and a larger increase to 9.4+/-0.
      7x10(3) N/m(2) in RUPP rats. Removal of the endothelium significantly enhanced
      Phe-induced stress in pregnant (6.4+/-0. 6x10(3) N/m(2)) but not RUPP (9.95+/
      0.95x10(3) N/m(2)) rats. In endothelium-intact strips, acetylcholine (ACh) was
      more potent in inducing relaxation of Phe contraction in pregnant (ED(50) 0.
      1x10(-6) mol/L) than in RUPP (ED(50) 1.2x10(-6) mol/L) rats. Pretreatment of
      endothelium-intact strips with N(G)-nitro-L-arginine methyl ester(100
      micromol/L), to inhibit nitric oxide (NO) synthase, significantly inhibited ACh
      induced relaxation and enhanced Phe-induced stress in pregnant (6.2+/-0.5x10(3)
      N/m(2)) but not RUPP (9.5+/-0.85x10(3) N/m(2)) rats. Pretreatment of endothelium
      intact strips with methylene blue (10 micromol/L), to inhibit cGMP production in
      smooth muscle, also inhibited ACh-induced relaxation and enhanced Phe-induced
      stress in pregnant (6.9+/-0.65x10(3) N/m(2)) but not RUPP (9.3+/-0.7x10(3)
      N/m(2)) rats. In endothelium-denuded strips, relaxation of Phe contraction with
      the exogenous NO donor sodium nitroprusside was not significantly different
      between pregnant and RUPP rats. These results suggest that an endothelium
      dependent relaxation pathway involving the release of NO from endothelial cells
      and increased cGMP production in smooth muscle is inhibited in systemic vessels
      of late pregnant rats with reduced uterine perfusion pressure and may in part
      explain the increased vascular resistance in pregnancy-induced hypertension.

PMID- 10642325
TI  - Cyclosporin A protects against angiotensin II-induced end-organ damage in double
      transgenic rats harboring human renin and angiotensinogen genes.
AB  - Leukocyte infiltration and adhesion molecule activation play a central role in
      the pathogenesis of angiotensin II (Ang II)-induced end-organ damage in double
      transgenic rats (dTGR) harboring human renin and angiotensinogen genes. We tested
      the hypothesis that the immunosuppressive agent cyclosporine (CsA) protects
      against the Ang II-induced myocardial and renal damage in dTGR. Furthermore, we
      investigated the influence of CsA on interleukin-6 (IL-6) and inducible nitric
      oxide synthase (iNOS) expression and the DNA binding activity of transcription
      factor necrosis factor-kappaB (NF-kappaB). The 4-week-old rats were divided into
      4 groups: (1) control dTGR (n=20), (2) dTGR plus CsA (5 mg/kg SC for 3 weeks,
      n=15), (3) normotensive Sprague-Dawley (SD) rats (n=10), and (4) SD rats plus CsA
      (n=8). In dTGR, CsA completely prevented cardiovascular death (0 of 15 versus 9
      of 20), decreased 24-hour albuminuria by 90% and systolic blood pressure by 35 mm
      Hg, and protected against the development of cardiac hypertrophy. Whole blood CsA
      concentrations 24 hours after the last drug treatment were 850+/-15 ng/mL.
      Semiquantitative ED-1 and Ki-67 (a nuclear cell proliferation-associated antigen)
      scoring showed that CsA prevented perivascular monocyte/macrophage infiltration
      and prevented cell proliferation in the kidneys and hearts of dTGR, respectively.
      The beneficial effects of CsA were, at least in part, mediated by the suppression
      of IL-6 and iNOS expression. Electrophoretic mobility shift assay revealed that
      CsA regulated inflammatory response in part through the NF-kappaB transcriptional
      pathway. In contrast to dTGR, CsA increased blood pressure in normotensive SD
      rats by 10 mm Hg and had no effect on cardiac mass or 24-hour urinary albumin
      excretion. Perivascular monocyte/macrophage infiltration, IL-6, and iNOS
      expression or cell proliferation were not affected by CsA in SD rats. Our
      findings indicate that CsA protects against Ang II-induced end-organ damage and
      underscore the central role of vascular inflammatory response in the pathogenesis
      of myocardial and renal damage in dTGR. The beneficial effects of CsA in the
      kidney and heart are mediated, at least in part, by suppression of IL-6 and iNOS
      expression via NF-kappaB transcriptional pathway.

PMID- 10642327
TI  - Cyclooxygenase-2 involved in stimulation of renal mechanosensitive neurons.
AB  - Stretching of the renal pelvic wall activates renal mechanosensitive neurons,
      resulting in an increase in afferent renal nerve activity (ARNA). Prostaglandin
      (PG)E(2) plays a crucial role in the activation of renal mechanosensitive neurons
      through facilitation of the release of substance P from the sensory neurons in
      the renal pelvic wall. Because wall stretch may induce cyclooxygenase-2 activity,
      we examined whether cyclooxygenase-2 was expressed in the renal pelvic wall and
      whether activation of cyclooxygenase-2 contributed to the ARNA response produced
      through increased renal pelvic pressure. In situ hybridization showed a strong
      cyclooxygenase-2 mRNA signal in the papilla and subepithelial layer of the renal
      pelvic wall from time control kidneys and from kidneys exposed to 15 minutes of
      increased renal pelvic pressure in anesthetized surgically operated rats. In
      anesthetized rats, an increase in renal pelvic pressure increased ARNA by 40+/-2%
      and increased renal pelvic release of PGE(2) from 289+/-46 to 1379+/-182 pg/min
      (P<0.01). Renal pelvic perfusion with the cyclooxygenase-2 inhibitor etodolac
      reduced the increases in ARNA and PGE(2) by 66+/-7% and 55+/-13%, respectively
      (P<0.01). Likewise, the cyclooxygenase-2 inhibitor 5, 5-dimethyl-3-(3
      fluorophenyl)-4-(4-methylsulfonyl)phenyl-2(5H)-furanone reduced the increases in
      ARNA and PGE(2) by 43+/-5% and 47+/-8%, respectively. We conclude that
      cyclooxygenase-2 is expressed in the renal pelvic wall and that the activation of
      cyclooxygenase-2 contributes to the stimulation of renal mechanosensitive neurons
      in the pelvic wall.

PMID- 10642328
TI  - Sympathetic control of arterial membrane potential by ATP-sensitive K(+)
      channels.
AB  - Stimulation of perivascular nerve terminals leads to a release of various
      neurotransmitters such as norepinephrine, epinephrine, acetylcholine, nitric
      oxide, and calcitonin gene-related peptide (CGRP). Because some of these
      substances have been shown to cause smooth muscle hyperpolarization by direct or
      endothelium-dependent mechanisms, we hypothesized that the liberation of 1 or
      more of these transmitters may lead to neurogenic hyperpolarization in arterial
      muscle cells. The present study was designed to determine the presence or absence
      of neurogenic hyperpolarization and, if present, its underlying mechanisms in
      isolated rat mesenteric resistance arteries, through the use of conventional
      microelectrode techniques. The experiments were performed under the combined
      blockade of alpha-adrenoceptors and purinoceptors with phentolamine and suramin
      to eliminate depolarizing responses to nerve stimulation. Under these conditions,
      perivascular nerve stimulation (5 Hz, 30 seconds) evoked smooth muscle
      hyperpolarization (-3.3+/-0.3 mV, n=15), which was abolished by tetrodotoxin,
      indicating the neurogenic origin of the response. This neurogenic
      hyperpolarization was resistant to atropine, nitro-L-arginine, or CGRP8-37, a
      CGRP antagonist, but was abolished by guanethidine and beta-blocker propranolol.
      This hyperpolarization was also abolished by glibenclamide, an ATP-sensitive K(+)
      channel (K(ATP)) blocker, but was unaffected by apamin, a Ca(2+)-activated K(+)
      channel blocker. In separate experiments, exogenous norepinephrine caused
      glibenclamide-sensitive hyperpolarization in the presence of phentolamine. On the
      other hand, norepinephrine-induced depolarization in the absence of phentolamine
      was enhanced by propranolol. These findings suggest that neurally released
      catecholamines cause membrane hyperpolarization through the activation of K(ATP)
      by beta-adrenoceptors. Such hyperpolarization may play an important role in the
      control of arterial membrane potential by opposing alpha-adrenergic
      depolarization.

PMID- 10642330
TI  - Angiotensin II type 1 receptor blockade prevents cardiac remodeling in bradykinin
      B(2) receptor knockout mice.
AB  - Knockout mice (B(2)(-/-)) lacking the bradykinin (BK) B(2) receptor gene develop
      mild hypertension, cardiac hypertrophy, and myocardial damage. We hypothesized
      that these effects are due to the hypertrophying and damaging actions of
      angiotensin II (Ang II) in the absence of the balancing protection of BK. To
      verify this hypothesis, B(2)(-/-) or wild-type mice (B(2)(+/+)) were administered
      a nonpeptide antagonist of Ang II type 1 (AT(1)) receptors (A81988) from
      conception through 180 days of age. Untreated B(2)(+/+) and B(2)(-/-) served as
      controls. Blood pressure (BP) and heart rate were monitored with the use of tail
      cuff plethysmography at regular intervals. Ventricular weights, diameters, wall
      thickness, chamber volume, and myocardial fibrosis were measured at 40 and 180
      days. No differences were observed in BP, heart rate, and cardiac weight and
      dimensions between treated and untreated B(2)(+/+). The BP of AT(1) antagonist
      treated B(2)(-/-) was reduced until 70 days; then, it increased to the levels
      found in untreated B(2)(-/-). AT(1) receptor blockade resulted in a reduction in
      left ventricular mass, chamber volume, and wall thickness and abrogated
      myocardial fibrosis in B(2)(-/-). These results indicate that Ang II is the major
      factor responsible for ventricular remodeling and myocardial damage in mice with
      disruption of BK B(2) receptor signaling. The interaction of Ang II and BK
      appears to be essential for the development of a normal heart.

PMID- 10642329
TI  - Endothelin enhances and inhibits adrenal catecholamine release in
      deoxycorticosterone acetate-salt hypertensive rats.
AB  - Endothelin (ET) and the sympathoadrenal system contribute to the development and
      maintenance of deoxycorticosterone acetate (DOCA)-salt hypertension. ET can act
      directly on the adrenal medulla to enhance the release of catecholamines. In
      addition, the level of ET peptide is increased in the adrenal glands of DOCA-salt
      hypertensive rats. Therefore, we tested the hypothesis that ET enhances adrenal
      medullary catecholamine release during DOCA-salt hypertension. The infusion of
      exogenous ET-1 into an isolated, perfused adrenal gland preparation resulted in
      an increase in the basal release of norepinephrine (NE) and epinephrine (EPI) in
      control and DOCA-salt hypertensive rats. Nerve-stimulated (0.3 Hz) release of NE
      was significantly inhibited during ET-1 infusion in the DOCA-salt hypertensive
      rats but not in the control rats. The role of endogenous ET on basal and nerve
      stimulated NE and EPI release was also examined. An infusion of either BQ-123
      (10(-7) mol/L), an ET(A) receptor antagonist, or BQ-788 (10(-7) mol/L), an ET(B)
      receptor antagonist, did not alter basal NE or EPI release in either control or
      DOCA-salt hypertensive rats. BQ-788 did not alter nerve-stimulated release of NE
      and EPI. In contrast, the nerve-stimulated release of EPI, but not NE, was
      enhanced during BQ-123 infusion in DOCA-salt hypertensive rats. Nerve-stimulated
      NE and EPI release was unaffected by BQ-123 in the control rats. These data
      suggest that ET can stimulate adrenal medullary catecholamine release in
      normotensive and DOCA-salt hypertensive rats. However, ET also inhibits adrenal
      medullary catecholamine release in DOCA-salt hypertensive rats.

PMID- 10642331
TI  - Inhibition of cADP-ribose formation produces vasodilation in bovine coronary
      arteries.
AB  - cADP-ribose (cADPR) induces the release of Ca(2+) from the intracellular stores
      of coronary artery smooth muscle cells. However, little is known about the role
      of cADPR-mediated intracellular Ca(2+) release in the control of vascular tone.
      The present study examined the effects of nicotinamide, a specific inhibitor of
      ADP-ribosylcyclase, on the vascular tone of bovine coronary arteries. A bovine
      coronary artery homogenate stimulated the conversion of nicotinamide guanine
      dinucleotide into cGDP-ribose, which is a measure of ADP-ribosylcyclase activity.
      Nicotinamide significantly inhibited the formation of cGDP-ribose in a
      concentration-dependent manner: at a concentration of 10 mmol/L, it reduced the
      conversion rate from 3.34+/-0.11 nmol. min(-1). mg(-1) of protein in control
      cells to 1.42+/-0.11 nmol. min(-1). mg(-1) of protein in treated cells, a 58%
      reduction. In U46619-precontracted coronary artery rings, nicotinamide produced
      concentration-dependent relaxation. Complete relaxation with nicotinamide
      occurred at a dose of 8 mmol/L; the median inhibitory concentration (IC(50)) was
      1.7 mmol/L. In the presence of a cell membrane-permeant cADPR antagonist, 8-bromo
      cADPR, nicotinamide-induced vasorelaxation was markedly attenuated. Pretreatment
      of the arterial rings with ryanodine (50 micromol/L) significantly blunted the
      vasorelaxation response to nicotinamide. However, iloprost- and adenosine-induced
      vasorelaxation was not altered by 8-bromo-cADPR. Moreover, nicotinamide
      significantly attenuated KCl- or Bay K8644-induced vasoconstriction by 60% and
      70%, respectively. These results suggest that the inhibition of cADPR formation
      by nicotinamide produces vasorelaxation and blunts KCl- and Bay K8644-induced
      vasoconstriction in coronary arteries and that the cADPR-mediated Ca(2+)
      signaling pathway plays a role in the control of vascular tone in coronary
      circulation.

PMID- 10642332
TI  - Elevated sympathetic activity contributes to hypertension and salt sensitivity in
      diabetic obese Zucker rats.
AB  - Zucker rats are a useful model in which to define the mechanisms that link
      obesity to diabetes and associated cardiovascular disease. The present study
      tests the hypothesis that diabetic obese (compared with nondiabetic lean) Zucker
      rats are hypertensive and display a further increase in arterial pressure when
      fed a high salt diet. Male, nondiabetic lean and diabetic obese Zucker rats were
      chronically instrumented with telemetry probes and fed a basal salt diet for 3
      weeks followed by exposure to a high salt diet for 11 days. On the basal diet,
      obese (vs lean) rats had significantly higher arterial pressures ( approximately
      13 mm Hg), and the high salt diet significantly elevated mean arterial pressure
      (MAP) in obese (but not lean) Zucker rats ( approximately 12 mm Hg). Blockade of
      the sympathetic nervous system with hexamethonium caused a significantly larger
      decrease in MAP in obese (vs lean) Zucker rats fed the basal diet (51 vs 33 mm
      Hg), but the high salt diet did not increase the hexamethonium-induced reduction
      in arterial pressure in obese rats. Acute blockade of angiotensin receptors with
      losartan resulted in similar decreases in MAP in both groups on either diet.
      Acetylcholine-induced vasodilatory capacity of the carotid artery was
      significantly less in the obese (vs lean) Zucker rats. Together these data
      indicate that increased sympathetic nervous system activity and decreased
      vascular reactivity may contribute to elevated arterial pressure in type 2
      diabetic, obese Zucker rats, but the sympathetic nervous system does not appear
      to contribute to the dietary salt-sensitive hypertension in this model.

PMID- 10642333
TI  - The brain renin-angiotensin system modulates angiotensin II-induced hypertension
      and cardiac hypertrophy.
AB  - The potential involvement of the brain renin-angiotensin system in the
      hypertension induced by subpressor doses of angiotensin II was tested by the use
      of newly developed transgenic rats with permanent inhibition of brain
      angiotensinogen synthesis [TGR(ASrAOGEN)]. Basal systolic blood pressure
      monitored by telemetry was significantly lower in TGR(ASrAOGEN) than in Sprague
      Dawley rats (parent strain) (122.5+/-1.5 versus 128.9+/-1.9 mm Hg, respectively;
      P<0.05). The increase in systolic blood pressure induced by 7 days of chronic
      angiotensin II infusion was significantly attenuated in TGR(ASrAOGEN) in
      comparison with control rats (29.8+/-4.2 versus 46. 3+/-2.5 mm Hg, respectively;
      P<0.005). Moreover, an increase in heart/body weight ratio was evident only in
      Sprague-Dawley (11.1%) but not in TGR(ASrAOGEN) rats (2.8%). In contrast, mRNA
      levels of atrial natriuretic peptide (ANP) and collagen III in the left ventricle
      measured by ribonuclease protection assay were similarly increased in both
      TGR(ASrAOGEN) (ANP, x2.5; collagen III, x1.8) and Sprague-Dawley rats (ANP, x2.4;
      collagen III, x2) as a consequence of angiotensin II infusion. Thus, the
      expression of these genes in the left ventricle seems to be directly stimulated
      by angiotensin II. However, the hypertensive and hypertrophic effects of
      subpressor angiotensin II are at least in part mediated by the brain renin
      angiotensin system.

PMID- 10642334
TI  - Excitatory amino acids in the rostral ventrolateral medulla support blood
      pressure in spontaneously hypertensive rats.
AB  - Injection of the excitatory amino acid (EAA) antagonist kynurenic acid (KYN) into
      the rostral ventrolateral medulla (RVLM) of anesthetized rats has no effect on
      arterial pressure. However, we recently reported that after inhibition of the
      caudal ventrolateral medulla, injection of KYN into the RVLM decreased arterial
      pressure to the same level as produced by complete inhibition of the RVLM. We
      have suggested that these results reflect tonically active EAA-mediated inputs to
      the RVLM producing both direct excitation of RVLM vasomotor neurons and indirect
      inhibition of these neurons. On the basis of this model, we hypothesize that the
      balance between these EAA-driven direct excitatory and indirect inhibitory
      influences on the RVLM may be altered in models of experimental hypertension. To
      begin to test this hypothesis, the effects of injecting KYN into the RVLM of
      spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) were compared.
      In chloralose-anesthetized WKY, bilateral injection of KYN into the RVLM did not
      alter arterial pressure, whereas similar injections in SHR reduced mean arterial
      pressure by approximately 40 mm Hg. After inhibition of the caudal ventrolateral
      medulla, which similarly increased arterial pressure in both strains, injection
      of KYN into the RVLM reduced mean arterial pressure to the same level as produced
      by autonomic blockade. These results suggest that the balance of excitatory and
      inhibitory influences on RVLM vasomotor neurons driven by tonically active EAA
      mediated inputs to the RVLM is disrupted in SHR and may contribute to the
      hypertension in SHR.

PMID- 10642335
TI  - Increase in renal medullary nitric oxide synthase activity protects from
      norepinephrine-induced hypertension.
AB  - Studies were performed in conscious Sprague-Dawley rats to determine the role of
      the alpha(2)-adrenergic receptor-mediated increase in the renal medullary nitric
      oxide synthase (NOS) activity as a counterregulatory mechanism of blood pressure
      control in response to increased renal adrenergic stimulation. A subpressor dose
      of norepinephrine (NE, 8 microg. kg(-1). h(-1)) was infused intravenously, and
      NOS activity was determined with arginine-citrulline conversion by high
      performance liquid chromatography in renal cortical and outer and inner medullary
      tissues. It was found that after 7 days of intravenous NE infusion, NOS activity
      was significantly higher in both the outer and inner medullary tissues (158+/-45
      versus 30+/-24 pmol. mg(-1). h(-1) [outer medulla] and 5.1+/-0.7 versus 2.0+/-0.5
      nmol. mg(-1). h(-1) [inner medulla] for NE-treated versus control rats,
      respectively). To determine whether the increase of NOS activity was mediated
      through renal medullary alpha(2)-receptors, the receptor antagonist rauwolscine
      (RAU, 1 microg. kg(-1). min(-1)) was infused via an implanted renal medullary
      interstitial catheter, and the consequences of intravenous NE administration were
      evaluated. NOS activity was significantly lower in the RAU-infused animals and
      did not increase with infusion of NE. To determine the systemic effects of the
      renal medullary alpha(2)-receptors, studies were performed to determine the
      consequences of chronic intravenous infusion of subpressor amounts of NE in the
      presence and absence of renal medullary alpha(2)-receptor inhibition. Under
      conditions in which RAU was continuously infused into the renal medulla, the same
      subpressor dose of NE caused sustained and reversible hypertension (mean arterial
      pressure increased from 120+/-3 to 131+/-3 mm Hg). Chronic blunting of the renal
      medullary NOS activity with N(G)-nitro-L-arginine methyl ester (75 microg. kg(
      1). h(-1)) also enabled NE to produce a significant rise in mean arterial
      pressure (from 117+/-2 to 134+/-4 mm Hg). We conclude that the hypertensive
      effects of moderate elevations of renal adrenergic activity were chronically
      buffered by the alpha(2)-receptor-mediated increase in NOS activity within the
      renal medulla.

PMID- 10642336
TI  - High- or low-salt diet from weaning to adulthood: effect on insulin sensitivity
      in Wistar rats.
AB  - Because of conflicting results in the literature, further studies are needed to
      confirm an association between the degree of salt consumption and insulin
      sensitivity. The aim of this study was to measure insulin sensitivity in rats fed
      from weaning to adulthood with a low (LSD), normal (NSD), or high (HSD) salt
      diet. Body weight, carcass lipid content, blood glucose, nonesterified fatty
      acids, plasma insulin, plasma renin activity, and a glucose transporter (GLUT4)
      were measured. A euglycemic hyperinsulinemic clamp was used in 52 anesthetized
      rats. Body weight was higher in rats on LSD than in those on NSD (P<0.05) or HSD
      (P<0.001). Percentage fat carcass content was higher (P<0.05) in rats on LSD than
      in those on NSD. Basal plasma insulin and glucose levels were not altered
      (P>0.05) by salt consumption. Nonesterified fatty acids were lower in rats on HSD
      than in those on LSD (P<0.05) or NSD (P<0.01). Glucose uptake was lower in rats
      on LSD than in those on NSD (P<0.05) or HSD (P<0. 001). When a euglycemic
      hyperinsulinemic clamp was used on pair-weight rats, similar results were
      obtained, which suggests that the effect of LSD on insulin sensitivity was not
      due to higher body weight. GLUT4 in insulin-sensitive tissues was increased in
      rats on HSD except in the cardiac muscle. Captopril treatment partially reversed
      low insulin sensitivity in LSD rats, whereas losartan did not change it, which
      indicates that the effect of LSD on insulin sensitivity is angiotensin
      independent. In conclusion, the present results demonstrate that chronic dietary
      salt restriction induces a decrease in insulin sensitivity not associated with
      renin-angiotensin system activity or body weight changes.

PMID- 10642337
TI  - Integration of aortic nerve inputs in hypertensive rats.
AB  - The integration of arterial baroreceptor afferent inputs was studied in renal
      wrap hypertensive (HT) and normotensive (NT) rats. In anesthetized and paralyzed
      rats, aortic nerve (AN)-evoked depressor responses were reduced in HT compared
      with NT rats (P<0.05). We tested the hypothesis that the attenuated baroreflex
      was associated with altered integration of baroreceptor inputs within the nucleus
      of the solitary tract. Based on onset latency and the ability of monosynaptic
      neurons (MSNs) to respond to each of 2 AN stimuli separated by 5 ms, cells in HT
      and NT rats were divided into 3 groups: short-latency MSNs (SLMSNs), long-latency
      MSNs (LLMSNs), and polysynaptic neurons (PSNs). A higher percentage of PSNs (73%
      versus 61%) and a lower percentage of SLMSNs (20% versus 27%) or LLMSNs (7%
      versus 12%) were found in HT rats (P<0.05). In addition, in HT compared with NT
      rats, the AN onset latency was greater in PSNs (29. 9+/-1.1 versus 26.7+/-0.8 ms)
      but not in SLMSNs (5.0+/-0.5 versus 5. 0+/-0.3 ms) or LLMSNs (22.9+/-1.2 versus
      24.1+/-0.7 ms) (P<0.05). Finally, in HT compared with NT rats, the number of PSNs
      responding to a single AN stimulus with multiple action potentials was increased
      (40% versus 19%) (P<0.05). This was not observed in SLMSNs (26% versus 13%) or
      LLMSNs (12% versus 18%). The results indicate that renal wrap hypertension is
      associated with reduced AN-evoked depressor responses. There also were
      alterations in the integration of AN afferent inputs within the nucleus of the
      solitary tract, and these alterations were most marked in the PSN population.

PMID- 10642338
TI  - A nonpeptide mimic of bradykinin blunts the development of hypertension in young
      spontaneously hypertensive rats.
AB  - We tested whether FR190997, a nonpeptide B(2) agonist, prevented the development
      of hypertension in young spontaneously hypertensive rats (SHR), which secrete
      less kallikrein into the urine than do Wistar-Kyoto rats. An intra-arterial (IA)
      injection of FR190997 (0.3 to 30 nmol/kg) caused dose-dependent hypotension in
      conscious Sprague-Dawley rats. Although the maximum hypotensive potency of
      FR190997 equaled that of bradykinin, its action lasted approximately 10 times as
      long. Hoe140 (100 nmol/kg IA) significantly blocked the hypotensive response
      induced by FR190997 (10 nmol/kg). Atropine (100 nmol/kg IA) did not affect this
      response. A selective infusion of FR190997 into the renal artery induced
      natriuresis and diuresis in anesthetized rabbits. A continuous infusion (2 nmol.
      10 mL(-1). h(-1) per rat) of FR190997 into the abdominal aorta of young SHR (6
      weeks old, n=6) for 6 days significantly (P<0.05) reduced mean blood pressure to
      114+/-6 (day 2) and 110+/-6 (day 5) mm Hg, from 149+/-7 and 162+/-6 mm Hg,
      respectively, in vehicle-infused rats (n=6). At 8 days after continuous infusion
      (day 14), mean blood pressure (148+/-5 mm Hg) in FR190997-infused rats remained
      significantly (P<0. 05) lower than that in vehicle-infused rats (190+/-6 mm Hg),
      almost the peak value. The mesenteric artery isolated from FR190997-treated rats
      (day 14) had lower contractile sensitivity to norepinephrine than that from
      vehicle-treated rats. These results suggested that the continuous infusion of a
      nonpeptide B(2) agonist may prevent hypertension if performed in the critical
      phase.

PMID- 10642339
TI  - Role of FMRFamide-activated brain sodium channel in salt-sensitive hypertension.
AB  - FMRFamide, a cardioexcitatory neuropeptide, directly activates a newly cloned
      amiloride-sensitive sodium channel that is expressed specifically in the brain
      and blocked by benzamil hydrochloride. In the present study, we investigated the
      effects of short- and long-term intracerebroventricular infusion of FMRFamide on
      arterial pressure, sympathetic activity, vasopressin release, and brain renin
      angiotensin system genes in rats and studied the role of FMRFamide-activated
      brain sodium channels in salt-sensitive hypertension. The intracerebroventricular
      preinjection of FMRFamide and subsequent intracerebroventricular infusion of 0.15
      mol/L NaCl increased mean arterial pressure (FMRFamide: 30 nmol/kg +13+/-2.6 mm
      Hg, P<0.01; 100 nmol/kg +21+/-1.8 mm Hg, P<0.01), heart rate, abdominal
      sympathetic activity, and plasma vasopressin concentration compared with vehicle.
      The intracerebroventricular copreinjection with either benzamil or CV-11974
      abolished these increases. In rats administered a high-salt diet (8% NaCl), the
      continuous intracerebroventricular infusion of FMRFamide (50 and 200 nmol. kg(
      1). d(-1)) for 5 days increased mean arterial pressure, heart rate, urinary
      excretion of vasopressin and norepinephrine, and mRNAs of renin, angiotensin I
      converting enzyme, and angiotensin II type 1 receptor in hypothalamus and brain
      stem compared with vehicle. These increases were abolished by
      intracerebroventricular coinfusion of benzamil. In rats administered a low-salt
      diet (0.3% NaCl), however, increases in these variables were smaller than those
      in rats receiving a high-salt diet. Together, these findings suggest that brain
      FMRFamide-activated sodium channels may be involved in the mechanism of salt
      sensitive hypertension through regulation of the brain renin-angiotensin system.

PMID- 10642340
TI  - Inhibition of nitric oxide synthesis potentiates hypertension during chronic
      glucose infusion in rats.
AB  - Endothelial dysfunction has been proposed to contribute to impaired blood flow
      control or hypertension in many conditions characterized by hyperinsulinemia or
      hyperglycemia. However, most studies have focused on whether endothelial
      dysfunction is present in the established phases of these various hypertensive
      states, and there is little known concerning the role of the endothelium in the
      initial stages. This study tested whether nitric oxide production, before
      endothelial dysfunction develops, plays an important role in counteracting the
      hypertensive response to chronic glucose infusion. Glucose was infused (18.6
      mg/kg per minute IV) for 7 days in 8 normal rats (G) and in 9 rats with a long
      term background intravenous infusion of N(G)-nitro-L-arginine methyl ester (L
      NAME) at 10 microg/kg per minute (G+L). Mean arterial pressure (MAP), measured 24
      hours per day, increased an average of approximately 11 mm Hg in the G rats. L
      NAME treatment increased MAP an average of 28+/-2 mm Hg in the G+L rats, and
      glucose infusion raised MAP >30 mm Hg above that, averaging 155+/-8 mm Hg by day
      6. In addition, heart rate increased from an average of 389+/-8 bpm to 441+/-16
      bpm by day 6, whereas there was no significant change in the G rats. Glomerular
      filtration rate decreased significantly with L-NAME treatment and decreased in
      both groups by day 3 of glucose infusion, reaching lower levels in the G+L rats.
      These results show that NO is required to minimize the increase in MAP during
      glucose infusion and suggest that renal and neural mechanisms may be important in
      mediating that effect.

PMID- 10642341
TI  - Contribution of Ras GTPase/MAP kinase and cytochrome P450 metabolites to
      deoxycorticosterone-salt-induced hypertension.
AB  - We recently reported that norepinephrine and angiotensin II activate the
      Ras/mitogen-activated protein (MAP) kinase pathway through generation of a
      cytochrome P450 (CYP450) and lipoxygenase metabolites. The purpose of this study
      was to determine the contribution of Ras/MAP kinase to deoxycorticosterone
      acetate (DOCA)-salt-induced hypertension in rats. Administration of DOCA and 1%
      saline drinking water to uninephrectomized rats for 6 weeks significantly
      elevated mean arterial blood pressure (MABP) (166+/-5 mm Hg, n=19) compared with
      that of normotensive controls (95+/-5 mm Hg, n=7) (P<0.05). The activity of Ras
      and MAP kinase measured in the heart was increased in DOCA-salt hypertensive
      rats. Infusion of the Ras farnesyl transferase inhibitors FPT III (138 ng/min)
      and BMS-191563 (694 ng/min) significantly (P<0.05) attenuated MABP to 139+/-4 mm
      Hg (n=14) and 126+/-1 mm Hg (n=4), respectively. Moreover, infusion of MAP kinase
      kinase inhibitor PD-98059 (694 ng/min) also reduced MABP in hypertensive rats.
      Morphological studies of the kidney showed that treatment of rats with FPT III,
      which reduced Ras activity, minimized the hyperplastic occlusive arteriosclerosis
      and fibrinoid vasculitis observed in untreated hypertensive rats. In addition,
      the rise in CYP450 activity and MABP in hypertensive rats was prevented by the
      CYP450 inhibitor aminobenzotriazole (50 mg/kg) and was associated with a decrease
      in Ras and MAP kinase activity in the heart. These data suggest that the Ras/MAP
      kinase pathway contributes to DOCA-salt-induced hypertension and associated
      vascular pathology consequent to activation of CYP450.

PMID- 10642342
TI  - Mechanisms of increased venous smooth muscle tone in desoxycorticosterone acetate
      salt hypertension.
AB  - The purpose of the present study was to identify mechanisms that contribute to
      increased venous smooth muscle tone in desoxycorticosterone acetate (DOCA)-salt
      hypertension in rats. Male Sprague-Dawley rats were uninephrectomized, received
      subcutaneous implants of DOCA, and drank 1% sodium chloride/0.2% potassium
      chloride solutions. Sham-operated rats received only uninephrectomy and drank tap
      water. Three to 4 weeks later, arterial and venous catheters were implanted for
      measurements of arterial and central venous pressures, respectively, and a
      silicone balloon catheter was permanently fixed in the right atrium to produce
      brief circulatory arrest. Venous smooth muscle activity was estimated on the
      basis of repeated measurements of mean circulatory filling pressure in conscious
      rats resting in their home cages. DOCA-salt-treated rats were hypertensive and
      had elevated mean circulatory filling pressure compared with normotensive sham
      operated rats. Blockade of the endothelin subtype A receptor with 1 mg/kg ABT-627
      IV decreased arterial blood pressure and mean circulatory filling pressure
      significantly more in hypertensive rats than in normotensive rats. Ganglionic
      blockade with 30 mg/kg hexamethonium IV also decreased arterial blood pressure
      and mean circulatory filling pressure more in hypertensive than in normotensive
      rats. Pretreatment with ABT-627 did not affect subsequent hemodynamic responses
      to ganglionic blockade. We conclude that venous smooth muscle tone is increased
      in DOCA-salt hypertension through the independent actions of both endogenous
      endothelin-1 acting on subtype A receptors and sympathetically mediated
      venoconstrictor activity.

PMID- 10642343
TI  - Increased blood pressure in alpha-calcitonin gene-related peptide/calcitonin gene
      knockout mice.
AB  - Nerves that contain calcitonin gene-related peptide (CGRP) are components of the
      sensory nervous system. Although these afferent nerves have traditionally been
      thought to sense stimuli in the periphery and transmit the information centrally,
      they also have an efferent vasodilator function. Acute administration of a CGRP
      receptor antagonist increases the blood pressure (BP) in several models of
      hypertension, which indicates that this potent vasodilator plays a
      counterregulatory role to attenuate the BP increase in these settings. To
      determine the role of this peptide in the long-term regulation of cardiovascular
      function, including hypertension, we obtained mice that have a deletion of the
      alpha-calcitonin gene-related peptide (alpha-CGRP) gene. Although the beta
      calcitonin gene-related peptide (beta-CGRP) gene is intact in these mice, alpha
      CGRP is by far the predominant species of CGRP produced in dorsal root ganglia
      (DRG) sensory neurons. Initially, we examined the effect of deletion of the alpha
      CGRP on baseline BP and beta-CGRP and substance P mRNA expression. Systolic BP
      was significantly higher in the knockout mice (n=7) compared with wild-type in
      both male (160+/-6.1 vs 125+/-4.8 mm Hg) and female (163+/-4.8 vs 135+/-33 mm Hg)
      mice. Next, groups (n=7) of knockout and wild-type mice had catheters surgically
      placed in the right carotid artery for mean arterial pressure recording. With the
      animals fully awake and unrestrained, the knockout mice displayed an elevated
      mean arterial pressure compared with wild-type in both male (139+/-4.9 vs 118+/
      4.9 mm Hg) and female (121+/-3.4 vs 107+/-3.1 mm Hg) mice. Northern blot analysis
      of DRG RNA samples confirmed the absence of alpha-CGRP mRNA in the knockout mice.
      Substance P mRNA content in DRG was unchanged between the 2 groups; however, beta
      CGRP mRNA levels were reduced 2-fold in the knockout mice. These results indicate
      for the first time that alpha-CGRP may be involved in the long-term regulation of
      resting BP and suggest that these mice are particularly sensitive to challenges
      to BP homeostasis because of the loss of a compensatory vasodilator mechanism.

PMID- 10642344
TI  - Subpressor doses of angiotensin II increase plasma F(2)-isoprostanes in rats.
AB  - The present study was performed to determine whether physiologically relevant
      doses of angiotensin II (Ang II), which do not affect renal hemodynamics but do
      cause slow response hypertension, result in oxidative stress as measured by
      production of vasoconstrictor F(2)-isoprostane, a prostaglandin-like non
      cyclooxygenase-produced arachidonic acid metabolite that is the end product of
      lipid peroxidation. Rats were instrumented with abdominal aortic and left femoral
      venous catheters, and before and throughout Ang II (or saline) infusion, all rats
      received enalapril (250 mg/L). Four days after the initiation of enalapril, rats
      were infused with Ang II (10 ng. kg(-1). min(-1), n=6) or saline (n=6) for 14
      days. Mean arterial pressure was measured 24 hours per day, and on day 12,
      glomerular filtration rate and renal plasma flow were measured. Mean arterial
      pressure in control rats averaged 85+/-1 mm Hg, and with Ang II infusion, mean
      arterial pressure increased slowly and reached a plateau on day 3, averaging
      117+/-2 mm Hg (P<0.0001 compared with enalapril alone). Glomerular filtration
      rate and renal plasma flow were not affected by Ang II. Free F(2)-isoprostanes in
      plasma increased by 54% with Ang II (P<0.01), and the production of F(2)
      isoprostanes esterified in plasma lipids tended to be higher with Ang II also but
      did not reach significance (P=0.1). These studies suggest that low doses of Ang
      II are capable of producing oxidative stress in animals. Whether oxidative stress
      plays a causative role in Ang II-mediated slow-response hypertension or is
      secondary to the hypertension is not clear from these data and will require
      further study.

PMID- 10642345
TI  - Gender differences in development of hypertension in spontaneously hypertensive
      rats: role of the renin-angiotensin system.
AB  - Previous data strongly support a role for androgens in promoting the gender
      difference in hypertension in the spontaneously hypertensive rat(s) (SHR), but
      the mechanism is not clear. Because males develop higher blood pressures than do
      females, we hypothesize that androgens may affect the renin-angiotensin system to
      promote the development of hypertension in male SHR. The present study was
      performed to determine the effect of converting enzyme inhibition (CEI) on the
      development of hypertension in SHR. Male, female, castrated male, and
      ovariectomized (ovx) female SHR (n=10 per gender per treatment group) received
      enalapril (250 mg/L) in drinking water for 8 to 10 weeks. Some ovx females were
      also given testosterone chronically. At 17 to 19 weeks of age, 24-hour protein
      excretion and mean arterial pressure were measured. By 13 weeks of age, male rats
      had higher systolic blood pressures by tail plethysmography than did the other
      rats, and CEI reduced blood pressures to similar levels in all groups. At 17 to
      19 weeks, the same trend was found by direct measurement of mean arterial
      pressure. The ovx females treated with testosterone had serum testosterone and
      blood pressure levels similar to those found in males. CEI reduced mean arterial
      pressure to similar levels in all gender groups. Untreated males and ovx females
      given testosterone had significantly higher levels of urinary protein excretion
      than did the other groups, and CEI had no effect on proteinuria in any of the
      rats. These data suggest that the development of hypertension in SHR regardless
      of sex steroids is mediated by the renin-angiotensin system. However, the data
      further suggest that androgens promote the exacerbation of hypertension in male
      SHR via a mechanism involving the renin-angiotensin system.

PMID- 10642346
TI  - Role of female sex hormones in the development and reversal of dahl hypertension.
AB  - Female sex hormones protect against the development of Dahl hypertension mediated
      by increases in dietary sodium. The role of female sex hormones in the reversal
      of Dahl hypertension mediated by decreases in dietary sodium is unknown. The goal
      of this study was to identify sex differences in the reversal of Dahl
      hypertension and the associated changes in water and electrolyte homeostasis.
      Male (M, n=8), female (F, n=8), and ovariectomized female (OVX, n=9) Dahl salt
      sensitive rats were instrumented with an abdominal radiotelemetry device for 24
      hour monitoring of blood pressure (BP) and heart rate. Daily measurements of food
      intake, water intake, and urine output were recorded as diet was changed from a
      low-sodium diet (0.15% NaCl) to a diet containing 8% NaCl. The diet was then
      changed back to 0.15% NaCl. The responses to changes in the salt diet were
      compared with responses observed in rats (M, n=4; F, n=4; OVX, n=4) that were
      maintained on 0.15% NaCl during the experiment. Sex differences in BP were
      observed when M, F, and OVX rats were fed 8% NaCl diet for 2 weeks (152+/-4,
      141+/-3, and 154+/-5 mm Hg, respectively). BP was significantly greater (P<0.05)
      in M and OVX rats than in F rats. Fluid balance (water intake minus urine volume)
      and sodium balance (sodium intake minus sodium excretion) were similar in all
      groups on the 8% NaCl diet. BP in time-control M, F, and OVX rats was 121+/-3,
      130+/-4, and 162+/-11 mm Hg, respectively. Compared with time-control groups,
      differences in BP while rats were eating the 8% NaCl diet were observed in M and
      F rats but not OVX rats. Reinstatement of an NaCl-deficient diet reversed the
      hypertension in M and F but not OVX rats (124+/-4, 124+/-2, and 145+/-5 mm Hg,
      respectively). The changes in dietary sodium caused similar changes in renal
      handling of sodium and water in all groups of rats; therefore, the effect on
      blood pressure was independent of renal excretory function. The inability to
      reverse the hypertension by decreasing sodium intake in OVX rats and the
      development of spontaneous hypertension in OVX females maintained on a low-sodium
      diet indicates that removal of the female sex hormones predisposes the animal to
      the development of hypertension that is sodium independent. We conclude that
      female sex hormones protect Dahl S rats against the development of sodium
      dependent and -independent hypertension.

PMID- 10642347
TI  - Influence of the I/D polymorphism of the angiotensin-converting enzyme gene on
      the outcome of microalbuminuria in essential hypertension.
AB  - The objective of the present study was to analyze the influence of the I/D
      polymorphism of the ACE gene on the outcome of microalbuminuria in essential
      hypertensive patients who were receiving antihypertensive treatment. One hundred
      thirty-six essential hypertensive patients who were <50 years old and had never
      previously received treatment with antihypertensive drugs were included in the
      study. During a 3-year period, patients received nonpharmacological treatment
      consisting of moderate salt restriction and a low-calorie diet they were obese,
      with or without a regimen of antihypertensive drugs based on beta-blockers or ACE
      inhibitors. Hydrochlorothiazide was added when necessary to maintain the blood
      pressure goal of <135/85 mm Hg. At the beginning of the study and at yearly
      intervals, systolic and diastolic blood pressures (SBP and DBP, respectively), 24
      hour urinary albumin excretion (UAE), renal function, and biochemical profile
      measurements were made. The insertion/deletion (I/D) polymorphism of the ACE gene
      was determined through the use of polymerase chain reaction. The variables used
      in the statistical analysis were the measurements at the start of the study and
      the increase or decrease detected during the follow-up, estimated as individual
      specific regression line slope values. At baseline, no differences in blood
      pressure or UAE values were observed among genotypes. Likewise, the genotype or
      allele frequency was not significantly different between normoalbuminurics and
      microalbuminurics. After the 3 treatment years, significant reductions in SBP,
      DBP, and UAE were found (SBP 151.6+/-17.3 reduced to 137.2+/-14.3 mm Hg, P<0.001;
      DBP 96.6+/-8.9 reduced to 84.5+/-9.8 mm Hg, P<0.001; UAE 36.7+/-71.5 reduced to
      28.3+/-78.6 mg/24 h, P<0. 05). The slopes of these parameters over time did not
      differ significantly among genotypes. The slope of SBP was the main factor
      related to the slope of logUAE (P<0.003). A significant positive correlation
      coefficient between the SBP and logUAE slopes was observed for the DD patients
      (r=0.57, P<0.0001) but was absent in patients carrying the I allele (II r=-0.03,
      P=NS; I/D r=0.01, P=NS). Follow-up studies should be used to achieve a better
      understanding of the impact of candidate gene polymorphisms on the development of
      hypertension-induced organ damage. Assessment of the I/D polymorphism of the ACE
      gene may identify subjects who require a greatly lowered blood pressure to
      prevent organ damage and to reduce hypertension-associated complications and
      death.

PMID- 10642348
TI  - Socioeconomic status and blood pressure reactivity in healthy black adolescents.
AB  - Adolescents in low-socioeconomic-status environments are more susceptible to
      illnesses, such as hypertension and cardiovascular diseases. This study examined
      the influence of both neighborhood- and family-level socioeconomic status (SES)
      on blood pressure (BP) reactivity in a healthy sample of 76 black adolescents. It
      was hypothesized that a higher level of parental education and/or income would
      reduce the elevated BP reactivity associated with living in poorer neighborhoods.
      Census-derived data were obtained using each participant's address. Neighborhood
      level of SES was based on percentage of households below the poverty line, female
      headed households, owner-occupied housing, percentage vacant housing, and average
      number of persons per household. Family level of SES was based on self-reported
      level of parental education and annual family income. Adolescents participated in
      a competitive video game to establish their BP reactivity scores. As predicted,
      adolescents who lived in poorer neighborhoods had lower diastolic BPs if their
      parents were more (versus less) educated (P<0.05; 7+/-8 versus 13+/-6 mm Hg).
      Adolescents who lived in poorer neighborhoods also had significantly lower
      diastolic BP reactivity (P<0.05) if their family had a higher (versus lower)
      annual income (7+/-7 versus 12+/-8 mm Hg). These data are the first to
      demonstrate the buffering effect of family SES on the negative health
      consequences of living in low-SES neighborhoods in healthy black adolescents.

PMID- 10642349
TI  - Effect of the angiotensin II type 1 receptor blocker candesartan on endothelial
      function in patients with essential hypertension.
AB  - Patients with essential hypertension are characterized by impaired basal and
      agonist-evoked nitric oxide release and increased endogenous endothelin (ET)-1
      induced vasoconstriction. To assess whether candesartan, an angiotensin II type 1
      receptor blocker, can improve endothelial function, we studied the changes in
      forearm blood flow (FBF) induced in 15 hypertensive patients and in 15 control
      subjects by the intrabrachial infusion of N(G)-monomethyl-L-arginine (L-NMMA),
      norepinephrine, the ET A/B receptor antagonist TAK 044, sodium nitroprusside, and
      acetylcholine. In hypertensive patients, the FBF study was repeated 2 and 12
      months after the start of treatment with candesartan cilexetil (8 to 16 mg
      daily). Compared with controls (maximal FBF decrease, -46+/-11%), hypertensive
      patients showed a reduced (P<0.001) vasoconstrictor response to L-NMMA (maximal
      FBF decrease, -28+/-7%); the response to norepinephrine was only slightly
      impaired, and the response to sodium nitroprusside was similar to that of
      controls. Finally, TAK-044 caused greater vasodilation in hypertensive patients
      (maximal FBF increase, 77+/-9%) than in controls (maximal FBF increase, 17+/
      10%). In hypertensive patients, candesartan cilexetil significantly enhanced
      vasoconstriction to L-NMMA after 2 and 12 months (maximal FBF decrease, 37+/-2%
      [P<0.05] and 42+/-2% [P<0.001], respectively). The responses to norepinephrine,
      acetylcholine, and sodium nitroprusside were not modified after 2 months. After
      12 months, the responses to acetylcholine and sodium nitroprusside were
      significantly (P<0.05) enhanced at the highest rates. Vasodilation to TAK-044 was
      abolished after treatment with candesartan cilexetil; this effect is associated
      with a reduced plasma ET-1 concentration. This study demonstrated that the
      angiotensin II receptor blocker candesartan improves tonic nitric oxide release
      and reduces vasoconstriction to endogenous ET-1 in the forearm of hypertensive
      patients.

PMID- 10642350
TI  - Insulin action is associated with endothelial function in hypertension and type 2
      diabetes.
AB  - A primary defect in the vascular action of insulin may be a key intermediate
      mechanism that links endothelial dysfunction with reduced insulin-mediated
      cellular glucose uptake in metabolic and cardiovascular disorders. The present
      study was designed to characterize more fully the relations between insulin
      action and endothelial function in male patients with essential hypertension (H,
      n=9) or type 2 diabetes (D, n=9) along with healthy control subjects (C) matched
      for age, body mass index, and lipid profile. They attended for measurement of
      whole-body insulin sensitivity (MCR) by the hyperinsulinemic clamp technique (day
      1) and forearm vasoreactivity in response to intra-arterial infusions of
      insulin/glucose (day 2) and N(G)-monomethyl-L-arginine (L-NMMA) and
      norepinephrine (day 3) by bilateral venous-occlusion plethysmography. Results
      expressed as mean+/-SE MCR (mL/kg per minute) were 7.22+/-0. 99 (C), 6.32+/-0.78
      (H), and 5.06+/-0.53 (D). Insulin/glucose-mediated vasodilation (IGMV) was 17.1+/
      5.6% (C), 17. 2+/-5.5% (H), and 12.3+/-6.4% (D). L-NMMA vasoconstriction (LNV)
      was 37.9+/-5.1% (C), 37.5+/-2.3% (H), and 33.6+/-2.8% (D). There were no
      significant differences among groups for these parameters. Pooled correlation
      analyses revealed associations between MCR and IGMV (r=0. 46, P<0.05), MCR and
      LNV (r=0.44, P<0.05), and IGMV and LNV (r=0.52, P<0.01). This study supports
      functional coupling between insulin action (both metabolic and vascular) and
      basal endothelial nitric oxide production in humans.

PMID- 10642351
TI  - Renin-angiotensin system genetic polymorphisms and salt sensitivity in essential
      hypertension.
AB  - We evaluated the association between salt-sensitive hypertension and 3 different
      genetic polymorphisms of the renin-angiotensin system. Fifty patients with
      essential hypertension were classified as salt sensitive or salt resistant,
      depending on the presence or absence of a significant increase (P<0.05) in 24
      hour ambulatory mean blood pressure (BP) after high salt intake. The
      insertion/deletion (I/D) angiotensin-converting enzyme (ACE) gene, the M235T
      angiotensinogen (AGT) gene, and the A1166C angiotensin II type 1 (AT1) receptor
      gene polymorphisms were determined with the use of standard polymerase chain
      reaction methods. Twenty-four (48%) patients with significantly increased
      (P<0.05) 24-hour mean BP with high salt intake (from 107.3+/-9.4 to 114.8+/-10.6
      mm Hg) were classified as salt sensitive. In the remaining 26 patients (52%),
      high salt intake did not significantly modify 24-hour mean BP (from 107.6+/-10 to
      107. 8+/-9 mm Hg), and they were classified as having salt-resistant
      hypertension. We did not find any significant association between either M235T
      AGT or A1166C AT1 receptor genotypes and the BP response to high salt intake.
      However, patients with essential hypertension homozygous for the insertion allele
      of the ACE gene (II) had a significantly higher BP increase with high salt intake
      (9. 8+/-8.1 mm Hg for systolic BP and 5.2+/-4.2 mm Hg for diastolic BP) than that
      observed in patients homozygous for the deletion allele (DD) (1.2+/-5.9 mm Hg for
      systolic BP; P=0.0118 and -0.2+/-4.2 mm Hg for diastolic BP; P=0.0274).
      Heterozygous patients (ID) exhibited an intermediate response. The prevalence of
      salt-sensitive hypertension also was significantly higher (P=0.012) in II (67%)
      and DI patients (62%) compared with DD hypertensives (19%). We conclude that a
      significant association exists between the I/D polymorphism of the ACE gene and
      salt-sensitive hypertension. Patients with II and DI genotypes have significantly
      higher prevalence of salt sensitivity than DD hypertensives.

PMID- 10642353
TI  - Hoechst marion roussel hypertension research clinical fellowship award 1999

PMID- 10642352
TI  - Endothelin-A blockade attenuates systemic and renal hemodynamic effects of L-NAME
      in humans.
AB  - Eight Na-repleted volunteers underwent 3 separate 90-minute infusions of either
      N(G)-nitro-L-arginine methyl ester (L-NAME) 3.0 mg. kg(-1). min(-1) or endothelin
      A receptor (ET-A) blocker BQ-123 (BQ) 0.125 nmol. kg(-1). min(-1) or both. Mean
      arterial pressure (MAP), glomerular filtration rate (GFR), renal blood flow
      (RBF), renal vascular resistances (RVR), and sodium excretion rate (UNaV) were
      measured at baseline (b) and from 0 to 45 minutes (period 1) and 45 to 90 minutes
      (period 2) of infusion. BQ alone had no effect. GFR declined by 4.9% (P<0.001
      versus b) in period 1, to 9.9% (P<0. 001) in period 2 with L-NAME, and by 3.3%
      (P<0.01) to 6.6% (P<0.001) with L-NAME plus BQ (P=NS between L-NAME and L-NAME
      plus BQ). UNaV fell equally with L-NAME or L-NAME plus BQ. MAP rose significantly
      in period 2 with L-NAME (6.9%; P<0.001) but not with coinfused BQ (2. 1%; P=NA
      versus b, P=0.005 versus L-NAME alone). RBF declined by 12. 2% (P<0.001) to 18.3%
      (P<0.001) with L-NAME and by 4.6% (P<0.005) to 8.2% (P<0.001) with L-NAME plus
      BQ. These changes were smaller with L-NAME plus BQ (P<0.05 in period 1 and P<0.02
      in period 2). Blunted changes were also seen for RVR (P<0.005 in period 1 and
      P<0.001 in period 2 between L-NAME alone and L-NAME plus BQ). These findings show
      that systemic and renal vasoconstriction due to L-NAME are attenuated by BQ,
      which suggests that an interaction between endogenous nitric oxide production and
      ET-A activity participates in the maintenance of baseline systemic and renal
      vascular tone in humans.

PMID- 10642354
TI  - New thematic series

PMID- 10642356
TI  - Effects of intratracheal instillation of TNF-alpha on surfactant metabolism.
AB  - Tumor necrosis factor-alpha (TNF-alpha) has been shown to play an integral role
      in the pathogenesis of the acute respiratory distress syndrome. This disorder is
      characterized by a deficiency of alveolar surfactant, a surface-active material
      that is composed of key hydrophobic proteins and the major lipid disaturated
      phosphatidylcholine (DSPC). We investigated how TNF-alpha might alter DSPC
      content in rat lungs by instilling the cytokine (2.5 microg) intratracheally for
      10 min and then assaying parameters of DSPC synthesis and degradation in alveolar
      type II epithelial cells, which produce surfactant. Cells isolated from rats
      given TNF-alpha had 26% lower levels of phosphatidylcholine compared with
      control. TNF-alpha treatment also decreased the ability of these cells to
      incorporate [(3)H]choline into DSPC by 45% compared with control isolates. There
      were no significant differences in the levels of choline substrate or choline
      transport between the groups. However, TNF-alpha produced a 64% decrease in the
      activity of cytidylyltransferase, the rate-regulatory enzyme required for DSPC
      synthesis. TNF-alpha administration in vivo also tended to stimulate
      phospholipase A(2) activity, but it did not alter other parameters for DSPC
      degradation such as activities for phosphatidylcholine-specific phospholipase C
      or phospholipase D. These observations indicate that TNF-alpha decreases the
      levels of surfactant lipid by decreasing the activity of a key enzyme involved in
      surfactant lipid synthesis. The results do not exclude stimulatory effects of the
      cytokine on phosphatidylcholine breakdown.

PMID- 10642355
TI  - Ventilatory decline after hypoxia and hypercapnia is not different between
      healthy young men and women.
AB  - The gradual decay in ventilation after removal of a respiratory stimulus has been
      proposed to protect against cyclic breathing disorders such as obstructive sleep
      apnea (OSA). The male predominance of OSA, and the increased incidence of OSA in
      women after menopause, indicates that the respiratory-stimulating effect of
      progesterone may provide protection against OSA by altering the rate of
      poststimulus ventilatory decline (PSVD). It was therefore hypothesized that PSVD
      is longer in premenopausal women than in men and is longer in the luteal
      menstrual phase compared with the follicular phase. PSVD was measured in 12 men
      and in 11 women at both their luteal and follicular phases, after cessation of
      isocapnic hypoxia and normoxic hypercapnia. PSVD was compared between genders and
      between women in the luteal and follicular phases by repeated-measures ANOVA.
      There were no significant differences in PSVD between any of the groups after
      either respiratory stimulus. This suggests that the higher occurrence of OSA in
      men does not reflect an underlying gender difference in PSVD and implies the
      increased prevalence of OSA in women after menopause is not representative of an
      effect of progesterone on PSVD.

PMID- 10642357
TI  - Altered reactivity of pulmonary vessels in postobstructive pulmonary
      vasculopathy.
AB  - Chronic ligation of one pulmonary artery results in pulmonary vascular remodeling
      and bronchial angiogenesis, collectively known as postobstructive pulmonary
      vasculopathy (POPV). To investigate pulmonary vascular reactivity in POPV, we
      ligated the left main pulmonary artery of guinea pigs and, after 1-10 mo,
      prepared explants by inflating lungs with agarose and sectioning them into
      approximately 1-mm-thick slices; we measured areas of pulmonary vessels and
      determined contractile responses to histamine and serotonin (5-HT) and relaxant
      responses to ACh and sodium nitroprusside. We found maximal contractions of
      arteries to 5-HT (24. 4 +/- 2.6%) and of veins to histamine (53.9 +/- 4.7%) were
      significantly increased in POPV of 3-mo duration compared with those of controls
      (16.8 +/- 1.5 and 40.8 +/- 5.0%, respectively). Relaxation of arteries with ACh
      was enhanced at 10 mo but not at 1 mo after ligation. Relaxation with sodium
      nitroprusside was increased in veins at 1 mo after ligation but was not altered
      in arteries. Morphometry revealed reduced diameters of arteries and veins without
      increased medial thickness. Our data suggest that the enhanced contractile
      responses of pulmonary vessels to histamine and 5-HT in POPV were not a result of
      endothelial dysfunction or of structural alterations but might be caused by as
      yet-undiscovered mechanisms.

PMID- 10642359
TI  - Effects of high-frequency initial pulses and posttetanic potentiation on power
      output of skeletal muscle.
AB  - The effects of high-frequency initial pulses (HFIP) and posttetanic potentiation
      on mechanical power output during concentric contractions were examined in the in
      situ medial gastrocnemius of the rat with an intact origin on the femur and blood
      supply. Stimulation of the muscle was performed via the severed sciatic nerve. In
      the experiments, HFIP or the potentiating tetanus was followed by a stimulation
      of 80, 120, or 200 Hz. The results showed that both HFIP and the tetanus
      increased power output at high contraction velocities (>75 mm/s) when followed by
      a train of 80 or 120 Hz (200 Hz resulted in no effects). Mechanical power output
      was increased maximally by HFIP to 120 and 168% by the tetanus. Furthermore, when
      HFIP or the tetanus were followed by a train of 80 Hz, the peak power in the
      power-velocity curve tended to be shifted to a higher velocity.

PMID- 10642358
TI  - Nandrolone decanoate does not enhance training effects but increases IGF-I mRNA
      in rat diaphragm.
AB  - To examine whether concomitant anabolic steroid treatment combined with training
      might enhance previously observed training effects (A. Bisschop, G. Gayan
      Ramirez, H. Rollier, R. Gosselink, R. Dom, V. de Bock, and M. Decramer. Am. J.
      Respir. Crit. Care Med. 155: 1583-1589, 1997) and whether insulin-like growth
      factor I (IGF-I) was involved in these changes, male and female rats were
      submitted to inspiratory muscle training (IMT) for 8 wk (30 min/day, 5 times/wk)
      and were compared with untrained controls. During the last 5 wk of training,
      trained rats were divided to receive weekly either low-dose (LD; 1.5 mg/kg) or
      high-dose (HD; 7.5 mg/kg) nandrolone decanoate or saline for the IMT and control
      rats. In both sexes, diaphragm muscle mass and contractile properties were
      unchanged with treatment. In males, HD resulted in decreased diaphragm type I
      cross-sectional area (-15%; P < 0.05, HD vs. IMT), whereas no changes were
      observed in females. Finally, an increase in IGF-I mRNA levels was present in HD
      male (+73%; P < 0.05, HD vs. IMT) and female treated rats [LD (+58%) and HD
      (+96%) vs. IMT; P < 0.001]. We conclude that administration of nandrolone
      decanoate did not enhance the previously observed training effects in rat
      diaphragm, although it increased the IGF-I mRNA expression levels.

PMID- 10642360
TI  - Intense exercise stimulates albumin synthesis in the upright posture.
AB  - We tested the hypothesis that an elevation in albumin synthetic rate contributes
      to increased plasma albumin content during exercise-induced hypervolemia. Albumin
      synthetic rate was measured in seven healthy subjects at 1-5 and 21-22 h after 72
      min of intense (85% peak oxygen consumption rate) intermittent exercise and after
      5 h recovery in either upright (Up) or supine (Sup) postures. Deuterated
      phenylalanine (d(5)-Phe) was administrated by a primed-constant infusion method,
      and fractional synthetic rate (FSR) and absolute synthetic rate (ASR) of albumin
      were calculated from the enrichment of d(5)-Phe in plasma albumin, determined by
      gas chromatography-mass spectrometry. FSR of albumin in Up increased
      significantly (P < 0.05) from 4.9 +/- 0.9%/day at control to 7.3 +/- 0.9%/day at
      22 h of recovery. ASR of albumin increased from 87.9 +/- 17.0 to 141.1 +/- 16.6
      mg albumin. kg body wt(-1). day(-1). In contrast, FSR and ASR of albumin were
      unchanged in Sup (3.9 +/- 0.4 to 4.0 +/- 1.4%/day and 74.2 +/- 8.9 to 85.3 +/-
      23.9 mg albumin. kg body wt(-1). day(-1) at control and 22 h of recovery,
      respectively). Increased albumin synthesis after upright intense exercise
      contributes to the expansion of greater albumin content and its maintenance. We
      conclude that stimuli related to posture are critical in modulating the drive for
      albumin synthesis after intense exercise.

PMID- 10642361
TI  - Effect of delivery temperature on endocrine stimulation of thermoregulation in
      lambs born by cesarean section.
AB  - We examined the hypothesis that exogenous stimulation with physiological doses of
      3,5,3'-triiodothyronine (T(3)) and/or norepinephrine at birth can improve
      thermoregulation in near-term lambs delivered by cesarean section. This was
      achieved by investigating the effect of delivery temperature [i.e., warm (30(
      degrees )C) vs. cool (15( degrees )C) ambient temperatures] on hormonal
      stimulation on uncoupling protein-1 (UCP1) abundance in brown adipose tissue. In
      vivo measurements of temperature control (i. e., colonic temperature, oxygen
      consumption, and incidence of shivering) were made over the first 2.5 h after
      birth. Each lamb was injected with saline with or without T(3), norepinephrine,
      or T(3) plus norepinephrine. Irrespective of delivery temperature, abundance of
      UCP1 increased and incidence of shivering decreased by all hormonal treatments,
      but this only reduced the rate of decline in colonic temperature of cool
      delivered lambs. Oxygen consumption was higher in cool-delivered lambs that were
      able to fully restore body temperature, an adaptation not observed in controls or
      any warm-delivered groups. Exogenous administration of endocrine stimulatory
      factors can enhance the abundance of UCP1 in cesarean-section-delivered lambs
      with the magnitude of thermoregulatory response being greater at cool than warm
      delivery temperatures.

PMID- 10642362
TI  - Twitch transdiaphragmatic pressure depends critically on thoracoabdominal
      configuration.
AB  - We measured the effect of thoracoabdominal configuration on twitch
      transdiaphragmatic pressure (Pdi, t) in response to supramaximal, transcutaneous,
      bilateral phrenic nerve shocks in three thin normal men. Pdi, t was measured as a
      function of lung volume (VL) in the relaxation configuration, at functional
      residual capacity (FRC), and at the same end-tidal VL 1) during relaxation; 2)
      with the abdomen (Ab) expanded and the rib cage (RC) in its relaxed FRC
      configuration; 3) with RC expanded and Ab in its relaxed FRC configuration; and
      4) in configuration 3 with an active transdiaphragmatic pressure similar to that
      required to produce configuration 2. In increasing VL from FRC to configuration
      1, Pdi, t decreased by 3.6 cmH(2)O; to configuration 2 by 14.8 cmH(2)O; to
      configuration 3 by 3.7 cmH(2)O; and to configuration 4 by 2.7 cmH(2)O. We argue
      that changes in velocity of shortening and radius of curvature are unlikely to
      account for these effects and suggest that changes in diaphragmatic fiber length
      (L(di)) are primarily responsible. If so, equivolume displacements of Ab and RC
      change L(di) in a ratio of approximately 4:1. We conclude that Pdi, t is
      exquisitely sensitive to abdominal displacements that must be rigorously
      controlled if Pdi, t is to be used to assess diaphragmatic contractility.

PMID- 10642363
TI  - Rapid increase in plasma growth hormone after low-intensity resistance exercise
      with vascular occlusion.
AB  - Hormonal and inflammatory responses to low-intensity resistance exercise with
      vascular occlusion were studied. Subjects (n = 6) performed bilateral leg
      extension exercise in the seated position, with the proximal end of their thigh
      compressed at 214 +/- 7.7 (SE) mmHg throughout the session of exercise by means
      of a pressure tourniquet. Mean intensity and quantity of the exercise were 20% of
      1 repetition maximum and 14 repetitions x 5 sets, respectively. In each set, the
      subjects repeated the movement until exhaustion. Plasma concentrations of growth
      hormone (GH), norepinephrine (NE), lacate (La), lipid peroxide (LP), interleukin
      6 (IL-6), and activity of creatine phosphokinase (CPK) were measured before and
      after the exercise was finished and the tourniquet was released. Concentrations
      of GH, NE, and La consistently showed marked, transient increases after the
      exercise with occlusion, whereas they did not change a great deal after the
      exercise without occlusion (control) done at the same intensity and quantity.
      Notably, concentration of GH reached a level approximately 290 times as high as
      that of the resting level 15 min after the exercise. IL-6 concentration showed a
      much more gradual increase and was maintained at a slightly higher level than in
      the control even 24 h after exercise. Concentrations of LP and CPK showed no
      significant change. The results suggest that extremely light resistance exercise
      combined with occlusion greatly stimulates the secretion of GH through regional
      accumulation of metabolites without considerable tissue damage.

PMID- 10642364
TI  - Myosin heavy chains in fibers of TTX-paralyzed rat soleus and medial
      gastrocnemius muscles.
AB  - The expression of five myosin heavy chain (MHC) isoforms was analyzed in the rat
      soleus (Sol) and the deep and superficial medial gastrocnemius (dGM, sGM) muscle
      after 2 and 4 wk of TTX paralysis by using immunohistochemical techniques. In
      Sol, after 4 wk of paralysis, fibers containing type I MHC were either pure type
      I (14%) or also contained developmental (D; 76%), IIa (26%), or IIx (18%) MHC.
      Values for corresponding fibers in dGM were 8.5, 65, 38, and 22%. Also, by 4 wk
      an increase was seen in the proportions of fibers expressing IIa MHC in Sol (from
      16 to 38%) and dGM (from 24 to 74%). In a region of sGM in control muscles
      containing pure IIb fibers, a major proportion (86%) remained pure after 4 wk of
      paralysis, with the remainder coexpressing IIb and IIx. The results indicate that
      TTX-induced muscle paralysis results in an increase in fibers containing multiple
      MHC isoforms and that the D isoform appears in a major proportion of these hybrid
      fibers.

PMID- 10642365
TI  - Cocaine and exercise: alpha-1 receptor blockade does not alter muscle
      glycogenolysis or blood lactacidosis.
AB  - In our previous work, we routinely observed that a combined cocaine-exercise
      challenge results in an abnormally rapid muscle glycogen depletion and excessive
      blood lactacidosis. These phenomena occur simultaneously with a rapid rise in
      norepinephrine and in the absence of any rise in epinephrine. We postulated that
      norepinephrine may cause vasoconstriction of the muscle vasculature through
      activation of alpha-1 receptors during cocaine-exercise, thus inducing hypoxia
      and a concomitant rise in glycogenolysis and lactate accumulation. To test this
      hypothesis, rats were pretreated with the selective alpha-1-receptor antagonist
      prazosin (P) (0.1 mg/kg iv) or saline (S). Ten minutes later, the animals were
      treated with cocaine (-C) (5 mg/kg iv) or saline (-S) and run for 4 or 15 min at
      22 m/min at 10% grade. In the S-S group, glycogen content of the white vastus
      lateralis muscle was unaffected by exercise at both time intervals, whereas in S
      C rats glycogen was reduced by 47%. This effect of cocaine-exercise challenge was
      not attenuated by P. Similarly, blood lactate concentration in S-C rats was
      threefold higher than that of S-S after exercise, a response also not altered by
      pretreatment with P. On the basis of these observations, we conclude that the
      excessive glycogenolysis and lactacidosis observed during cocaine-exercise
      challenge is not the result of vasoconstriction secondary to norepinephrine
      activation of alpha-1 receptors.

PMID- 10642366
TI  - Hemodynamic and metabolic responses to moderate asphyxia in brain and skeletal
      muscle of late-gestation fetal sheep.
AB  - The purpose of this study was to investigate metabolic and hemodynamic responses
      in two fetal tissues, hindlimb muscle and brain, to an episode of acute moderate
      asphyxia. Near-infrared spectroscopy was used to measure changes in total
      hemoglobin concentration ([tHb]) and the redox state of cytochrome oxidase (COX)
      simultaneously in the brain and hindlimb of near-term unanesthetized fetal sheep
      in utero. Oxygen delivery (DO(2)) to, and consumption (VO(2)) by, each tissue was
      derived from the arteriovenous difference in oxygen content and blood flow,
      measured by implanted flow probes. One hour of moderate asphyxia (n = 11), caused
      by occlusion of the maternal common internal iliac artery, led to a significant
      fall in DO(2) to both tissues and to a significant drop in VO(2) by the head.
      This was associated with an initial fall in redox state COX in the leg but an
      increase in the brain. [tHb], and therefore blood volume, fell in the leg and
      increased in the brain. These data suggest the presence of a fetal metabolic
      response to hypoxia, which, in the brain, occurs rapidly and could be
      neuroprotective.

PMID- 10642367
TI  - Stretch-activated ion channels contribute to membrane depolarization after
      eccentric contractions.
AB  - We tested the hypothesis that eccentric contractions activate mechanosensitive or
      stretch-activated ion channels (SAC) in skeletal muscles, producing increased
      cation conductance. Resting membrane potentials and contractile function were
      measured in rat tibialis anterior muscles after single or multiple exposures to a
      series of eccentric contractions. Each exposure produced a significant and
      prolonged (>24 h) membrane depolarization in exercised muscle fibers. The
      magnitude and duration of the depolarization were related to the number of
      contractions. Membrane depolarization was due primarily to an increase in Na(+)
      influx, because the estimated Na(+)-to-K(+) permeability ratio was increased in
      exercised muscles and resting membrane potentials could be partially repolarized
      by substituting an impermeant cation for extracellular Na(+) concentration.
      Neither the Na(+)/H(+) antiport inhibitor amiloride nor the fast Na(+) channel
      blocker TTX had a significant effect on the depolarization. In contrast, addition
      of either of two nonselective SAC inhibitors, streptomycin or Gd(3+), produced
      significant membrane repolarization. The results suggest that muscle fibers
      experience prolonged depolarization after eccentric contractions due,
      principally, to the activation of Na(+)-selective SAC.

PMID- 10642368
TI  - Severe diabetes prohibits elevations in muscle protein synthesis after acute
      resistance exercise in rats.
AB  - This study determined whether rates of protein synthesis increase after acute
      resistance exercise in skeletal muscle from severely diabetic rats. Previous
      studies consistently show that postexercise rates of protein synthesis are
      elevated in nondiabetic and moderately diabetic rats. Severely diabetic rats
      performed acute resistance exercise (n = 8) or remained sedentary (n = 8). A
      group of nondiabetic age-matched rats served as controls (n = 9). Rates of
      protein synthesis were measured 16 h after exercise. Plasma glucose
      concentrations were >500 mg/dl in the diabetic rats. Rates of protein synthesis
      (nmol phenylalanine incorporated. g muscle(-1). h(-1), means +/- SE) were not
      different between exercised (117 +/- 7) and sedentary (106 +/- 9) diabetic rats
      but were significantly (P < 0.05) lower than in sedentary nondiabetic rats (162
      +/- 9) and in exercised nondiabetic rats (197 +/- 7). Circulating insulin
      concentrations were 442 +/- 65 pM in nondiabetic rats and 53 +/- 11 and 72 +/- 19
      pM in sedentary and exercised diabetic rats, respectively. Plasma insulin-like
      growth factor I concentrations were reduced by 33% in diabetic rats compared with
      nondiabetic rats, and there was no difference between exercised and sedentary
      diabetic rats. Muscle insulin-like growth factor I was not affected by resistance
      exercise in diabetic rats. The results show that there is a critical
      concentration of insulin below which rates of protein synthesis begin to decline
      in vivo. In contrast to previous studies using less diabetic rats, severely
      diabetic rats cannot increase rates of protein synthesis after acute resistance
      exercise.

PMID- 10642370
TI  - Effect of carbohydrate or carbohydrate plus medium-chain triglyceride ingestion
      on cycling time trial performance.
AB  - This study examined the effectiveness of ingesting a carbohydrate or carbohydrate
      + medium-chain triglycerides (MCT) on metabolism and cycling performance. Eight
      endurance-trained men [peak O(2) uptake = 4.71 +/- 0.09 (SE) l/min] completed 35
      kJ/kg as quickly as possible [time trial (TT)] while consuming 250 ml/15 min of
      either a 6% (wt/vol) carbohydrate solution (C), a 6% carbohydrate + 4.2% MCT
      solution (C+M), or a sweet placebo (P). Time to complete the set amount of work
      was reduced in both C and C+M compared with P by 7 and 5%, respectively (C: 166
      +/- 7 min; C+M: 169 +/- 7 min; P: 178 +/- 11 min; P < 0.01). Plasma glucose
      concentration was maintained at or above resting values throughout both C and C+M
      trials but decreased (P < 0.05) below resting values in P at the completion of
      the TT. The estimated rate of carbohydrate oxidation was not different during the
      first 90 min of exercise but thereafter was reduced (P < 0.05) in P and was
      maintained in both C and C+M. These data demonstrate that carbohydrate ingestion
      during exercise improves 100-km TT performance compared with a sweet placebo, but
      the addition of MCT does not provide any further performance enhancement.

PMID- 10642369
TI  - Effect of creatine loading on neuromuscular fatigue threshold.
AB  - The purpose of this investigation was to determine the effect of creatine (Cr)
      loading on the onset of neuromuscular fatigue by monitoring electromyographic
      fatigue curves from the vastus lateralis muscle using the physical working
      capacity at the fatigue threshold (PWC(FT)) test. Using a double-blind random
      design, 15 women athletes [mean age 19.0 +/- 2.0 (SD) yr] from the university
      crew team received a placebo (n = 8; 20 g glucose) or Cr (n = 7; 5 g Cr
      monohydrate + 20 g glucose) four times per day for 5 consecutive days. Analysis
      of covariance was used to analyze the data (covaried for presupplementation
      PWC(FT) values). The adjusted mean postsupplementation PWC(FT) value for the Cr
      group (mean = 186 W) was significantly (P < 0.05) higher than that of the placebo
      group (mean = 155 W). These findings suggest that Cr loading may delay the onset
      of neuromuscular fatigue.

PMID- 10642371
TI  - Effect of zonal conditions and posture on pulmonary blood flow distribution to
      subpleural and interior lung.
AB  - Observations made on vessels seen directly beneath the pleura may not accurately
      reflect what occurs in vessels located deeper in the interior of the lung. We
      quantified flow to subpleural and deeper, interior regions under zone 1 or 2
      conditions in excised (n = 5) and in vivo (n = 6) rabbit lungs, in the head-up or
      inverted position. After infusion of radiolabeled microspheres, lungs were dried
      at alveolar pressure of 25 cmH(2)O and sliced in 1-cm sections along the
      gravitational plane and in three planes in the dorsal-ventral axis. Regions
      located <1 mm from the pleural surface were dissected away from the remaining
      tissue. In both zonal conditions, 1) weight-normalized flow to the interior
      exceeded that found in subpleural regions; and 2) flow followed the gravitational
      gradient, with the correlation varying with the scale of measurement. We conclude
      that flow through subpleural vessels is less than that which occurs deeper in the
      interior, but the regional distributions of flow and the effects of zonal
      conditions are similar in the two regions.

PMID- 10642372
TI  - Magnetic stimulation of the human motor cortex evokes skin sympathetic nerve
      activity.
AB  - Single-pulse magnetic coil stimulation (Cadwell MES 10) over the cranium induces
      without pain an electric pulse in the underlying cerebral cortex. Stimulation
      over the motor cortex can elicit a muscle twitch. In 10 subjects, we tested
      whether motor cortical stimulation could also elicit skin sympathetic nerve
      activity (SSNA; n = 8) and muscle sympathetic nerve activity (MSNA; n = 5) in the
      peroneal nerve. Focal motor cortical stimulation predictably elicited bursts of
      SSNA but not MSNA; with successive stimuli, the SSNA responses did not readily
      extinguish (94% of discharges to the motor cortex evoked SSNA responses) and had
      predictable latencies [739 +/- 33 (SE) to 895 +/- 13 ms]. The SSNA responses were
      similar after stimulation of dominant and nondominant sides. Focal stimulation
      posterior to the motor cortex elicited extinguishable SSNA responses. In three of
      six subjects, anterior cortical stimulation evoked SSNA responses similar to
      those seen with motor cortex stimulation but without detectable movement; in the
      other subjects, anterior stimulation evoked less SSNA discharge than that seen
      with motor cortex stimulation. Contrasting with motor cortical stimulation,
      evoked SSNA responses were more readily extinguished with 1) peripheral
      stimulation that directly elicited forearm muscle activation accompanied by
      electromyograms similar to those with motor cortical stimulation; 2) auditory
      stimulation by the click of the energized coil when off the head; and 3) in
      preliminary experiments, finger afferent stimulation sufficient to cause
      tingling. Our findings are consistent with the hypothesis that motor cortex
      stimulation can cause activation of both alpha-motoneurons and SSNA.

PMID- 10642373
TI  - Influence of tension time on muscle fiber sarcolemmal injury in rat diaphragm.
AB  - We hypothesized that the amount of sarcolemmal injury is directly related to the
      total tension time (TT(tot)), calculated as mean tension x total stimulation
      time. Diaphragm strips from Sprague-Dawley rats were superfused at optimal muscle
      length with Krebs containing procion orange to identify sarcolemmal injury.
      TT(tot) was induced by stimulation with 100 Hz for 3 min at duty cycles of 0.02,
      0.15, 0.3, and 0.6, or with continuous contractions at 0.2, 0.4, 0.6, and 1.0 of
      maximal tension. A significant positive correlation between TT(tot) and the
      percentage of fibers with injured sarcolemma (r(2) = 0.63, P < 0.05) is seen.
      Stimulation (at 100 Hz, duty cycle = 1) resulted in fast fatigue with low injury,
      likely caused by altered membrane conductivity. Stimulations inducing the largest
      injury are those showing progressive force loss and high TT(tot), where injury
      may be due to activation of membrane degradative enzymes. The maximal tension
      measured at 20 min poststimulation was inversely related to the number of fibers
      injured, suggesting loss of force is caused by cellular injury.

PMID- 10642374
TI  - Afferent input from rat slow skeletal muscle inhibits bioassayable growth hormone
      release.
AB  - The release of a bioassayable form of growth hormone (BGH), distinct from growth
      hormone as measured by immunoassay (IGH), from the rat pituitary into the blood
      is differentially regulated by afferent input from fast and slow skeletal
      muscles. Specifically, activation of low-threshold fast muscle afferents for 15
      min increased plasma BGH by 217 and 295% and decreased pituitary BGH by 68 and
      45% in male and female rats, respectively. In contrast, activation of slow muscle
      afferents inhibited BGH release, decreasing plasma BGH by approximately 60% and
      increasing pituitary BGH by 30-50% in male rats. Female rats from which food had
      been withheld for approximately 12 h had elevated basal plasma BGH levels, which
      then were decreased by 81% after slow muscle nerve stimulation. Plasma IGH
      concentrations were unchanged after any nerve stimulation condition. These
      results demonstrate that regulation of BGH release can be differentially mediated
      through low-threshold afferent inputs from fast or slow skeletal muscle.
      Furthermore, the results indicate that BGH responses are independent of gender or
      feeding status.

PMID- 10642375
TI  - Plasma acid-base regulation above and below ventilatory threshold in late
      gestation.
AB  - Stewart's physicochemical approach was used to study the effects of pregnancy on
      acid-base regulation in arterialized blood. Responses of 15 healthy pregnant
      women (PG; gestational age, 37.1 +/- 0.2 wk) were compared with those of 15
      nonpregnant controls (CG) at rest and during cycling at 70 and 110% of the
      ventilatory threshold (T(vent)). Hydrogen ion concentration ([H(+)]) was lower in
      the PG vs. CG at rest and during exercise (P < 0.05 at rest and 70% T(vent)).
      Exercise-induced changes in [H(+)] were similar between groups. Lower resting
      [H(+)] values in the PG vs. CG resulted from lower values for arterialized PCO(2)
      (Pa(CO(2))) and total weak acid ([A](tot)), which were partly offset by a lower
      strong-ion difference ([SID]). Reductions in [A](tot) and [SID] at rest were
      primarily the result of reductions in albumin [Alb] and sodium [Na(+)],
      respectively. In the transition from rest to 70% T(vent), small increases in
      Pa(CO(2)) and [A](tot) contributed to moderate increases in [H(+)] in both
      groups, however [SID] increased in the PG and decreased in the CG (P < 0.05
      between groups). In the transition from rest to 110% T(vent), decreases in [SID]
      made a significantly greater contribution to changes in [H(+)] in the CG vs. PG.
      Exercise-induced increases in [H(+)] are similar in the pregnant vs. nonpregnant
      state, but there is a reduced contribution of [SID] both above and below T(vent)
      during pregnancy.

PMID- 10642376
TI  - Unloading of juvenile muscle results in a reduced muscle size 9 wk after
      reloading.
AB  - The role of satellite cells and DNA unit size in determining muscle size was
      examined by inhibiting postnatal skeletal muscle development by using hindlimb
      suspension. Satellite cell mitotic activity and DNA unit size were determined in
      the soleus muscles from hindlimb-suspended and age-matched weight-bearing rats
      before the initiation of hindlimb suspension, at the conclusion of a 28-day
      hindlimb-suspension period, 2 wk after reloading, and 9 wk after reloading. The
      body weights of hindlimb-suspended rats were significantly (P < 0.05) less than
      those of weight-bearing rats at the conclusion of hindlimb suspension, but they
      were the same (P > 0. 05) as those of weight-bearing rats 9 wk after reloading.
      The soleus muscle weight, soleus muscle weight-to-body weight ratio, myofiber
      diameter, nuclei per millimeter, and DNA unit size for the hindlimb-suspended
      rats were significantly (P < 0.05) smaller than for the weight-bearing rats at
      all recovery times. Satellite cell mitotic activity was significantly (P < 0.05)
      higher in the soleus muscles from hindlimb-suspended rats 2 wk after reloading,
      but it was the same (P > 0.05) as in weight-bearing rats 9 wk after reloading.
      Juvenile soleus muscles failed to achieve normal muscle size 9 wk after reloading
      because there was incomplete compensation for the hindlimb-suspension-induced
      interruptions in myonuclear accretion and DNA unit size expansion.

PMID- 10642377
TI  - Effect of acute postexercise ethanol intoxication on the neuroendocrine response
      to resistance exercise.
AB  - This investigation was conducted to determine the effect of postexercise ethanol
      intoxication (21.97 +/- 1.09 mmol/l blood) on the response of selected aspects of
      the neuroendocrine system to a resistance exercise (Ex) session. Nine resistance
      trained men (25.0 +/- 1.4 yr, 179.4 +/- 3.4 cm, 79.7 +/- 3.3 kg) were used to
      compare three 3-day treatments: control, Ex, and ethanol after exercise (ExEt).
      Blood was collected serially from an antecubital vein before exercise,
      immediately after exercise, and for pooled analysis at 20-40 (2 samples), 60-120
      (4 samples), and 140-300 (9 samples) min after exercise on day 1 and in the
      morning (2 samples each) on days 2 and 3. Ethanol did not increase circulating
      epinephrine, norepinephrine, or cortisol concentration (Cort) above Ex
      elevations. At 60-120 min, only ExEt Cort was greater than control Cort.
      Concentrations of testosterone, luteinizing hormone, and corticotropin were not
      affected by either treatment. It is concluded that, although this blood ethanol
      concentration is insufficient to acutely increase Cort above that caused by Ex
      alone, it appears that ethanol may have a prolonged effect beyond the Ex
      response. This blood ethanol concentration does not further stimulate the
      sympathoadrenal system during the postexercise response.

PMID- 10642378
TI  - IL-10 reduces grain dust-induced airway inflammation and airway hyperreactivity.
AB  - To determine whether interleukin-10 (IL-10) could alter the development of grain
      dust-induced airway disease, we pretreated mice with either saline or IL-10
      intravenously, exposed the mice to an inhalation challenge with corn dust extract
      (CDE), and measured inflammation and the development of airway hyperreactivity.
      Pretreatment with IL-10, in comparison to saline, reduced the concentration and
      percentage of polymorphonuclear cells in the lavage fluid 30 min after the
      inhalation challenge with CDE (P < 0. 05). In comparison to saline-treated mice,
      IL-10 did not significantly alter the degree of airway hyperreactivity 30 min
      after the exposure to CDE. IL-10-treated mice lavaged 18 h after challenge with
      CDE also exhibited a lower percentage of polymorphonuclear cells in the lavage
      fluid (P < 0.05) and had significantly less airway hyperreactivity than did mice
      pretreated with the saline placebo (P < 0.05). These findings indicate that
      exogenous IL-10 is effective in reducing airway inflammation and airway
      hyperreactivity due to the inhalation of CDE.

PMID- 10642379
TI  - Ca(2+) measurements in skinned cardiac fibers: effects of Mg(2+) on Ca(2+)
      activation of force and fiber ATPase.
AB  - In contrast to previous studies, a new fluorescent method was used to accurately
      determine the Ca(2+) concentration in test solutions used to activate skinned rat
      cardiac cells. This method used the calcium green-2 fluorescent indicator, which
      is shown to change its fluorescence over the Ca(2+) range responsible for Ca(2+)
      activation of force and ATPase. The dissociation constant (K(d)) of calcium green
      2 for Ca(2+) was determined for three different Mg(2+) concentrations in
      solutions similar to those used in the experiment. Increasing Mg(2+)
      concentration from 1.0 to 8.0 mM had no significant effect on the Ca(2+)
      sensitivity of either force or actomyosin ATPase activity, in contrast to
      previous reported studies on force. The ATPase activity was activated at lower
      Ca(2+) concentration than the force. The ratio (ATPase/force) is proportional to
      the dissociation rate of force-generating myosin cross bridges and decreased
      during Ca(2+) activation. These findings are consistent with the hypothesis that
      cardiac muscle contraction is activated by a single Ca(2+)-specific binding site
      on troponin C.

PMID- 10642380
TI  - Respiratory muscle blood flows during physiological and chemical hyperpnea in the
      rat.
AB  - Whether the diaphragm retains a vasodilator reserve at maximal exercise is
      controversial. To address this issue, we measured respiratory and hindlimb muscle
      blood flows and vascular conductances using radiolabeled microspheres in rats
      running at their maximal attainable treadmill speed (96 +/- 5 m/min; range 71-116
      m/min) and at rest while breathing either room air or 10% O(2)-8% CO(2) (balance
      N(2)). All hindlimb and respiratory muscle blood flows measured increased during
      exercise (P < 0.001), whereas increases in blood flow while breathing 10% O(2)-8%
      CO(2) were restricted to the diaphragm only. During exercise, muscle blood flow
      increased up to 18-fold above rest values, with the greatest mass specific flows
      (in ml. min(-1). 100 g(-1)) found in the vastus intermedius (680 +/- 44), red
      vastus lateralis (536 +/- 18), red gastrocnemius (565 +/- 47), and red tibialis
      anterior (602 +/- 44). During exercise, blood flow was higher (P < 0.05) in the
      costal diaphragm (395 +/- 31 ml. min(-1). 100 g(-1)) than in the crural diaphragm
      (286 +/- 17 ml. min(-1). 100 g(-1)). During hypoxia+hypercapnia, blood flows in
      both the costal and crural diaphragms (550 +/- 70 and 423 +/- 53 ml. min(-1). 100
      g(-1), respectively) were elevated (P < 0.05) above those found during maximal
      exercise. These data demonstrate that there is a substantial functional
      vasodilator reserve in the rat diaphragm at maximal exercise and that hypoxia +
      hypercapnia-induced hyperpnea is necessary to elevate diaphragm blood flow to a
      level commensurate with its high oxidative capacity.

PMID- 10642381
TI  - Involvement of substance P in neutral endopeptidase modulation of carotid body
      sensory responses to hypoxia.
AB  - Previously, we showed that carotid bodies express neutral endopeptidase (NEP)
      like enzyme activity and that phosphoramidon, a potent inhibitor of NEP,
      potentiates the chemosensory response of the carotid body to hypoxia in vivo. NEP
      has been shown to hydrolyze methionine enkephalin (Met-Enk) and substance P (SP)
      in neuronal tissues. The purpose of the present study is to determine whether NEP
      hydrolyzes Met-Enk and SP in the carotid body and if so whether these peptides
      contribute to phosphoramidon-induced potentiation of the sensory response to
      hypoxia. Experiments were performed on carotid bodies excised from anesthetized
      adult cats (n = 72 carotid bodies). The hydrolysis of Met-Enk and SP was analyzed
      by HPLC. The results showed that both SP and Met-Enk were hydrolyzed by the
      carotid body, but the rate of Met-Enk hydrolysis was approximately fourfold
      higher than that of SP. Phosphoramidon (400 microM) markedly inhibited SP
      hydrolysis ( approximately 90%) but had only a marginal effect on Met-Enk
      hydrolysis ( approximately 15% inhibition). Hypoxia (PO(2), 68 +/- 6 Torr) as
      well as exogenous administration of SP (10 and 20 nmol) increased the sensory
      discharge of the carotid body in vitro. Sensory responses to hypoxia and SP (10
      nmol) were potentiated by approximately 80 and approximately 275%, respectively
      (P < 0.01), in the presence of phosphoramidon. SP-receptor antagonists Spantide
      (peptidyl) and CP-96345 (nonpeptidyl) either abolished or markedly attenuated the
      phosphoramidon-induced potentiation of the sensory response of the carotid body
      to hypoxia as well as to SP. These results demonstrate that SP is a preferred
      substrate for NEP in the carotid body and that SP is involved in the potentiation
      of the hypoxic response of the carotid body by phosphoramidon.

PMID- 10642382
TI  - Mechanical strain increases type I collagen expression in pulmonary fibroblasts
      in vitro.
AB  - Tissue remodeling is an adaptive response to mechanical tension in the lung.
      However, the role of pulmonary fibroblasts in this response has not been well
      characterized. This study investigates the influence of extracellular matrix on
      the response of fibroblasts to mechanical strain. Cells were cultured on flexible
      bottom surfaces coated with fibronectin, laminin, or elastin and exposed to
      strain. Under these conditions, fibroblasts align perpendicular to the force
      vector. This stimulus results in an increase in alpha(1)(I) procollagen mRNA in
      cells cultured on laminin or elastin but not fibronectin. Increased alpha(1)(I)
      procollagen mRNA was detected 6 h after exposure to strain and reached control
      levels by 72 h. [(3)H]proline incorporation into newly synthesized procollagen
      reflects changes in mRNA levels. Strained fibroblasts cultured on laminin or
      elastin incorporated 190 and 114%, respectively, more [(3)H]proline into
      procollagen than did unstrained cells. No difference was detected in strained
      fibroblasts cultured on fibronectin. These results suggest that fibroblasts
      respond to mechanical strain in vitro, and this response is signaled by cell
      extracellular matrix interactions.

PMID- 10642383
TI  - Pulmonary vasoregulation by endothelin in conscious dogs after left lung
      transplantation.
AB  - We tested the hypothesis that regulation of the pulmonary circulation by
      endogenous endothelin (ET) during normoxia and hypoxia was altered in conscious
      dogs 1 mo after left lung autotransplantation (LLA). Sham-operated control and
      post-LLA dogs were chronically instrumented to measure the left pulmonary
      vascular pressure-flow (LP-Q) relationship. LP-Q plots were generated on separate
      days during normoxia and hypoxia (arterial PO(2) approximately 50 Torr) in the
      intact condition, after selective ET(A)-receptor inhibition (BQ-485), and after
      combined ET(A+B)-receptor inhibition (bosentan). Although LLA resulted in a
      chronic increase in pulmonary vascular resistance, the ET-receptor antagonists
      had no effect on the LP-Q relationship during normoxia in either group. The
      magnitude of hypoxic pulmonary vasoconstriction (HPV) was flow dependent in both
      groups, and the HPV response was potentiated post-LLA compared with control.
      ET(A)-receptor inhibition attenuated the HPV response to the same extent in both
      groups. ET(A+B)-receptor inhibition attenuated the HPV response to a greater
      extent than did ET(A)-receptor inhibition alone, and this effect was greater post
      LLA compared with control. Plasma ET-1 concentration only increased during
      hypoxia in the LLA group. These results indicate that ET does not regulate the
      baseline LP-Q relationship in either group. Both ET(A)- and ET(B)-receptor
      activation mediate a component of HPV in conscious dogs, and the vasoconstrictor
      influence of ET(B)-receptor activation is enhanced post-LLA.

PMID- 10642384
TI  - Preexercise medium-chain triglyceride ingestion does not alter muscle glycogen
      use during exercise.
AB  - This investigation determined whether ingestion of a tolerable amount of medium
      chain triglycerides (MCT; approximately 25 g) reduces the rate of muscle glycogen
      use during high-intensity exercise. On two occasions, seven well-trained men
      cycled for 30 min at 84% maximal O(2) uptake. Exactly 1 h before exercise, they
      ingested either 1) carbohydrate (CHO; 0.72 g sucrose/kg) or 2) MCT+CHO [0.36 g
      tricaprin (C10:0)/kg plus 0.72 g sucrose/kg]. The change in glycogen
      concentration was measured in biopsies taken from the vastus lateralis before and
      after exercise. Additionally, glycogen oxidation was calculated as the difference
      between total carbohydrate oxidation and the rate of glucose disappearance from
      plasma (R(d) glucose), as measured by stable isotope dilution techniques. The
      change in muscle glycogen concentration was not different during MCT+CHO and CHO
      (42.0 +/- 4.6 vs. 38.8 +/- 4.0 micromol glucosyl units/g wet wt). Furthermore,
      calculated glycogen oxidation was also similar (331 +/- 18 vs. 329 +/- 15
      micromol. kg(-1). min(-1)). The coingestion of MCT+CHO did increase (P < 0.05)
      R(d) glucose at rest compared with CHO (26.9 +/- 1.5 vs. 20.7 +/- 0. 7
      micromol.kg(-1). min(-1)), yet during exercise R(d) glucose was not different
      during the two trials. Therefore, the addition of a small amount of MCT to a
      preexercise CHO meal did not reduce muscle glycogen oxidation during high
      intensity exercise, but it did increase glucose uptake at rest.

PMID- 10642385
TI  - Effects of exercise on muscle transverse relaxation determined by MR imaging and
      in vivo relaxometry.
AB  - The purpose of this study was to determine the effects of intense exercise on the
      proton transverse (T(2)) relaxation of human skeletal muscle. The flexor
      digitorium profundus muscles of 12 male subjects were studied by using magnetic
      resonance imaging (MRI; 6 echoes, 18-ms echo time) and in vivo magnetic resonance
      relaxometry (1,000 echoes, 1.2-ms echo time), before and after an intense
      handgrip exercise. MRI of resting muscle produced a single T(2) value of 32 ms
      that increased by 19% (P < 0.05) with exercise. In vivo relaxometry showed at
      least three T(2) components (>5 ms) for all subjects with mean values of 21, 40,
      and 137 ms and respective magnitudes of 34, 49, and 14% of the total magnetic
      resonance signal. These component magnitudes changed with exercise by -44% (P <
      0.05), +52% (P < 0.05), and +23% (P < 0.05), respectively. These results
      demonstrate that intense exercise has a profound effect on the multicomponent
      T(2) relaxation of muscle. Changes in the magnitudes of all the T(2) components
      synergistically increase MRI T(2), but changes in the two shortest T(2)
      components predominate.

PMID- 10642386
TI  - Evolution of inspiratory and expiratory muscle pressures during endurance
      exercise.
AB  - We investigated the relationship between minute ventilation (VE) and net
      respiratory muscle pressure (Pmus) throughout the breathing cycle [Total Pmus =
      mean Pmus, I (inspiratory) + mean Pmus, E (expiratory)] in six normal subjects
      performing constant-work heavy exercise (CWHE, at approximately 80% maximum) to
      exhaustion on a cycle ergometer. Pmus was calculated as the sum of chest wall
      pressure (elastic + resistive) and pleural pressure, and all mean Pmus variables
      were averaged over the total breath duration. Pmus, I was also expressed as a
      fraction of volume-matched, flow-corrected dynamic capacity of the inspiratory
      muscles (P(cap, I)). VE increased significantly from 3 min to the end of CWHE and
      was the result of a significantly linear increase in Total Pmus (Delta = 43 +/-
      9% from 3 min to end exercise, P < 0.005) in all subjects (r = 0. 81-0.99).
      Although mean Pmus, I during inspiratory flow increased significantly (Delta = 35
      +/- 10%), postinspiratory Pmus, I fell (Delta = -54 +/- 10%) and postexpiratory
      expiratory activity was negligible or absent throughout CWHE. There was a greater
      increase in mean Pmus, E (Delta = 168 +/- 48%), which served to increase VE
      throughout CWHE. In five of six subjects, there were significant linear
      relationships between VE and mean Pmus, I (r = 0.50-0.97) and mean Pmus, E (r =
      0.82-0.93) during CWHE. The subjects generated a wide range of Pmus, I/P(cap, I)
      values (25-80%), and mean Pmus, I/P(cap, I) increased significantly (Delta = 42
      +/- 16%) and in a linear fashion (r = 0.69-0.99) with VE throughout CWHE. The
      progressive increase in VE during CWHE is due to 1) a linear increase in Total
      Pmus, 2) a linear increase in inspiratory muscle load, and 3) a progressive fall
      in postinspiratory inspiratory activity. We conclude that the relationship
      between respiratory muscle pressure and VE during exercise is linear and not
      curvilinear.

PMID- 10642387
TI  - Women at altitude: carbohydrate utilization during exercise at 4,300 m.
AB  - To evaluate the hypothesis that exposure to high altitude would reduce blood
      glucose and total carbohydrate utilization relative to sea level (SL), 16 young
      women were studied over four 12-day periods: at 50% of peak O(2) consumption in
      different menstrual cycle phases (SL-50), at 65% of peak O(2) consumption at SL
      (SL-65), and at 4,300 m (HA). After 10 days in each condition, blood glucose rate
      of disappearance (R(d)) and respiratory exchange ratio were measured at rest and
      during 45 min of exercise. Glucose R(d) during exercise at HA (4.71 +/- 0.30 mg.
      kg(-1). min(-1)) was not different from SL exercise at the same absolute
      intensity (SL-50 = 5.03 mg. kg(-1). min(-1)) but was lower at the same relative
      intensity (SL-65 = 6.22 mg. kg(-1). min(-1), P < 0.01). There were no
      differences, however, when glucose R(d) was corrected for energy expended
      (kcal/min) during exercise. Respiratory exchange ratios followed the same
      pattern, except carbohydrate oxidation remained lower (-23.2%, P < 0.01) at HA
      than at SL when corrected for energy expended. In women, unlike in men,
      carbohydrate utilization decreased at HA. Relative abundance of estrogen and
      progesterone in women may partially explain the sex differences in fuel
      utilization at HA, but subtle differences between menstrual cycle phases at SL
      had no physiologically relevant effects.

PMID- 10642388
TI  - CO(2) homeostasis during periodic breathing in obstructive sleep apnea.
AB  - The contribution of apnea to chronic hypercapnia in obstructive sleep apnea (OSA)
      has not been clarified. Using a model (D. M. Rapoport, R. G. Norman, and R. M.
      Goldring. J. Appl. Physiol. 75: 2302-2309, 1993), we previously illustrated
      failure of CO(2) homeostasis during periodic breathing resulting from temporal
      dissociation between ventilation and perfusion ("temporal V/Q mismatch"). This
      study measures acute kinetics of CO(2) during periodic breathing and addresses
      interapnea ventilatory compensation for maintenance of CO(2) homeostasis in 11
      patients with OSA during daytime sleep (37-171 min). Ventilation and expiratory
      CO(2) and O(2) fractions were measured on a breath-by-breath basis by means of a
      tight-fitting full facemask. Calculations included CO(2) excretion, metabolic
      CO(2) production, and CO(2) balance (metabolic CO(2) production - exhaled CO(2)).
      CO(2) balance was tabulated for each apnea/hypopnea event-interevent cycle and as
      a cumulative value during sleep. Cumulative CO(2) balance varied (-3,570 to
      +1,388 ml). Positive cumulative CO(2) balance occurred in the absence of overall
      hypoventilation during sleep. For each cycle, positive CO(2) balance occurred
      despite increased interevent ventilation to rates as high as 45 l/min. This
      failure of CO(2) homeostasis was dependent on the event-to-interevent duration
      ratio. The results demonstrate that 1) periodic breathing provides a mechanism
      for acute hypercapnia in OSA, 2) acute hypercapnia during periodic breathing may
      occur without a decrease in average minute ventilation, supporting the presence
      of temporal V/Q mismatch, as predicted from our model, and 3) compensation for
      CO(2) accumulation during apnea/hypopnea may be limited by the duration of the
      interevent interval. The relationship of this acute hypercapnia to sustained
      chronic hypercapnia in OSA remains to be further explored.

PMID- 10642389
TI  - Food restriction suppresses muscle growth and augments osteopenia in
      ovariectomized rats.
AB  - We examined effects of 4 wk of food restriction on ovariectomy-related changes in
      muscle, bone, and plasma insulin-like growth factor I (IGF-I). Female Sprague
      Dawley rats (7 mo old) were assigned to freely eating groups: sham-operated
      (Sham), ovariectomized (Ovx-AL), and estrogen (estradiol)-replaced Ovx
      (Ovx+E(2)). Ovx rats were also pair fed with Sham (Ovx-PF) or weight matched with
      Sham by food restriction (Ovx-FR). Ovx-AL and Ovx-PF rats had similar estrogen
      status and body weight; therefore, the groups were combined (group: Ovx). After
      treatment, body weight was approximately 10% greater in Ovx than in Sham rats (P
      < 0.05), and muscle weight-to-body weight ratios were comparable among all
      groups. Bone mineral contents of whole tibiae in Ovx-FR and Ovx were
      approximately 15% (P < 0.05) and approximately 6% lower than in Sham rats (P <
      0.05), respectively. Plasma IGF-I was approximately 30% higher in Ovx than in
      Sham (P < 0.05) but was similar between Sham and Ovx-FR. IGF-I was highly
      correlated with body weight and muscle mass. Within non-estrogen-replaced Ovx
      rats, IGF-I explained approximately 19% of variance in bone mineral content after
      accounting for variance attributable to body weight. Findings suggest that
      estrogen acts indirectly on skeletal muscle and bone in rats through regulation
      of body growth by factors such as IGF-I.

PMID- 10642391
TI  - Global field power helps separate respiratory-related evoked potentials from EMG
      contamination.
AB  - Respiratory-related evoked potentials (RREPs) were stimulated by brief (200-ms)
      oral pressure pulses (-10 cmH(2)O) applied at the onset of inspiration in 12
      subjects. Scalp potentials were measured at 30 sites on a rectangular grid that
      encompassed the right side of the scalp overlying the somatosensory cortex (SSC).
      Concurrent and significant masseter EMG (mEMG) activity was evoked by the
      pressure pulse, and we found correlational evidence for contamination of the RREP
      by the mEMG. The global field power (GFP) was used to provide a robust, reference
      independent measure of SSC activation that provided partial insulation from mEMG
      contamination. The mean GFP from all subjects, reflective of afferent information
      from respiratory mechanoreceptors, showed a latency to onset of significant
      afferent SSC activity of approximately 25 ms. Scalp GFP activity during control
      experiments (absence of applied pressure) was significant and may reflect ongoing
      afferent activity from inspiration.

PMID- 10642390
TI  - Women at altitude: energy requirement at 4,300 m.
AB  - To test the hypotheses that prolonged exposure to moderately high altitude
      increases the energy requirement of adequately fed women and that the sole cause
      of the increase is an elevation in basal metabolic rate (BMR), we studied 16
      healthy women [21.7 +/- 0.5 (SD) yr; 167.4 +/- 1.1 cm; 62.2 +/- 1.0 kg]. Studies
      were conducted over 12 days at sea level (SL) and at 4,300 m [high altitude
      (HA)]. To test that menstrual cycle phase has an effect on energetics at HA, we
      monitored menstrual cycle in all women, and most women (n = 11) were studied in
      the same phase at SL and HA. Daily energy intake at HA was increased to respond
      to increases in BMR and to maintain body weight and body composition. Mean BMR
      for the group rose 6.9% above SL by day 3 at HA and fell to SL values by day 6.
      Total energy requirement remained elevated 6% at HA [ approximately 670 kJ/day
      (160 kcal/day) above that at SL], but the small and transient increase in BMR
      could not explain all of this increase, giving rise to an apparent "energy
      requirement excess." The transient nature of the rise in BMR may have been due to
      the fitness level of the subjects. The response to altitude was not affected by
      menstrual cycle phase. The energy requirement excess is at present unexplained.

PMID- 10642392
TI  - Contribution of supraglottal mechanoreceptor afferents to respiratory-related
      evoked potentials in humans.
AB  - We used the global field power (GFP) to estimate the magnitude and timing of
      activation of the somatosensory cortex by respiratory mechanoreceptor afferents
      in normal humans in response to brief, negative oral pressure pulses applied at
      the onset of inspiration. We compared responses before (test) and after insertion
      of a laryngeal mask airway (LMA) that prevented supraglottal airway receptors
      from sensing the applied stimulus. Evoked potential responses without
      supraglottic stimulation were smaller, with delayed or missing features, than
      those with all receptors stimulated. Supraglottic receptors contribute about one
      half of the GFP summed over the 100 ms poststimulus, and subglottal receptors,
      including those in the larynx, provide a GFP response approximately 38% above
      baseline. The most obvious difference between test and LMA responses occurred at
      55 ms on average, when the LMA GFP lacked activation features seen in the test
      condition. We conclude that mechanoreceptors above the larynx are responsible for
      a major portion of the midlatency afferent information arriving at the
      somatosensory cortex in response to applied pressure pulses.

PMID- 10642393
TI  - Human cardiovascular and humoral responses to moderate muscle activation during
      dynamic exercise.
AB  - We examined the hypothesis that activation of the muscle metaboreflex during
      dynamic exercise would augment influences tending to cause a rise in arginine
      vasopressin, plasma renin activity, and catecholamines during dynamic exercise in
      humans. Ten healthy adults performed 30 min of supine cycle ergometer exercise at
      approximately 50% of peak oxygen consumption with or without moderate muscle
      metaboreflex activation by application of 35 mmHg lower body positive pressure
      (LBPP). Application of LBPP during the first 15 or last 15 min of exercise
      increased mean arterial blood pressure, plasma lactate concentration, and minute
      ventilation, indicating an activation of the muscle metaboreflex. These changes
      were rapidly reversed when LBPP was removed. During exercise at this intensity,
      LBPP augmented the release of arginine vasopressin and catecholamines but not of
      plasma renin activity. These results suggest that, although in humans hormonal
      responses are induced by moderate activation of the muscle metaboreflex during
      dynamic exercise, the thresholds for these responses may not be uniform among the
      various glands and hormones.

PMID- 10642394
TI  - Versatile, high-speed force transducer using a laser diode beam as an optical
      lever.
AB  - A force transducer with variable sensitivity and speed is described. Its moving
      element is a cantilever beam that projects vertically into a muscle bath. A brace
      constrains bending of the beam to a short, proximal "hinge." Rotation of the beam
      about the hinge is amplified 30-fold by an optical lever consisting of a laser
      diode beam reflected from a mirror on the cantilever to a photodiode pair. This
      design places the electrical components at a distance from the damp environment
      of the muscle bath. Large changes in sensitivity and speed can be obtained by
      substituting different cantilevers. Smaller changes can be made by varying the
      length of the hinge. A transducer with a 6-mm cantilever optimized for the study
      of single, skinned skeletal muscle fibers is described in detail. This device had
      a resonant frequency of 22 kHz and sensitivity such that the total root-mean
      square noise in the circuit was more than 500-fold smaller than the expected
      maximum force. Variations of this device with orders of magnitude different
      sensitivities are also described.

PMID- 10642395
TI  - A modular NIRS system for clinical measurement of impaired skeletal muscle
      oxygenation.
AB  - Near-infrared spectrometry (NIRS) is a well-known method used to measure in vivo
      tissue oxygenation and hemodynamics. This method is used to derive relative
      measures of hemoglobin (Hb) + myoglobin (Mb) oxygenation and total Hb (tHb)
      accumulation from measurements of optical attenuation at discrete wavelengths. We
      present the design and validation of a new NIRS oxygenation analyzer for the
      measurement of muscle oxygenation kinetics. This design optimizes optical
      sensitivity and detector wavelength flexibility while minimizing component and
      construction costs. Using in vitro validations, we demonstrate 1) general optical
      linearity, 2) system stability, and 3) measurement accuracy for isolated Hb.
      Using in vivo validations, we demonstrate 1) expected oxygenation changes during
      ischemia and reactive hyperemia, 2) expected oxygenation changes during muscle
      exercise, 3) a close correlation between changes in oxyhemoglobin and
      oxymyoglobin and changes in deoxyhemoglobin and deoxymyoglobin and limb volume by
      venous occlusion plethysmography, and 4) a minimal contribution from movement
      artifact on the detected signals. We also demonstrate the ability of this system
      to detect abnormal patterns of tissue oxygenation in a well-characterized patient
      with a deficiency of skeletal muscle coenzyme Q(10). We conclude that this is a
      valid system design for the precise, accurate, and sensitive detection of changes
      in bulk skeletal muscle oxygenation, can be constructed economically, and can be
      used diagnostically in patients with disorders of skeletal muscle energy
      metabolism.

PMID- 10642396
TI  - Perspective on historical perspectives

PMID- 10642397
TI  - Skeletal muscle adaptation to exercise: a century of progress.
AB  - Skeletal muscle physiology and biochemistry is an established field with Nobel
      Prize-winning scientists, dating back to the 1920s. Not until the mid to late
      1960s did there appear a major focus on physiological and biochemical training
      adaptations in skeletal muscle. The study of adaptations to exercise training
      reveals a wide range of integrative approaches, from the systemic to the
      molecular level. Advances in our understanding of training adaptations have come
      in waves caused by the introduction of new experimental approaches. Research has
      revealed that exercise can be effective at preventing and/or treating some of the
      most common chronic diseases of the latter half of the 20th century. Endurance
      trained muscle is more effective at clearing plasma triglyceride, glucose, and
      free fatty acids. However, at the present time, most of the mechanisms underlying
      the adaptation of human skeletal muscle to exercise still remain to be
      discovered. Little is known about the regulatory factors (e.g., trans-acting
      proteins or signaling pathways) directly modulating the expression of exercise
      responsive genes. Because so many potential physiological and biochemical signals
      change during exercise, it will be an important challenge in the next century to
      move beyond "correlational studies" and to identify responsible mechanisms.
      Skeletal muscle metabolic adaptations may prove to be a critical component to
      preventing diseases such as coronary heart disease, type 2 diabetes, and obesity.
      Therefore, training studies have had an impact on setting the stage for a
      potential "preventive medicine reformation" in a society needing a return to a
      naturally active lifestyle of our ancestors.

PMID- 10642398
TI  - Research in the exercise sciences: where do we go from here?
AB  - The goal of this article is to provide a perspective on how research involving
      the acute and chronic effects of exercise (referred to as "exercise sciences") on
      the structure and function of organs systems will evolve in the next century.
      Within the last 30 years, exercise-related research has rapidly transitioned from
      an organ to a subcellular/molecular focus. Thus future research will continue to
      be heavily influenced by molecular biology tools, fueled by both emerging
      technologies (e.g., "gene-chip microarrays") designed to dissect gene function on
      a macro scale as well as by the completion of the human genome project in which
      the approximately 80,000 genes comprising humans will be completely sequenced.
      These successes will drive the emerging fields of functional genomics (the
      dissecting of a gene's identity and function) and proteomics (the study of the
      properties of proteins). Funding levels at the National Institutes of Health will
      likely increase in order to expand these emerging fields as well as provide
      avenues for translating fundamental knowledge into solving the complexities of a
      number of degenerative diseases influenced heavily by activity/inactivity factors
      such as cardiopulmonary disease, diabetes, obesity, and the debilitating
      disorders associated with aging. Thus there are many challenges facing future
      exercise scientists who must harness the new technologies and take an aggressive
      stance in bringing this important field to the forefront.

PMID- 10642399
TI  - Integrin signaling's potential for mediating gene expression in hypertrophying
      skeletal muscle.
AB  - Overloaded skeletal muscle undergoes dramatic shifts in gene expression, which
      alter both the phenotype and mass. Molecular biology techniques employing both in
      vivo and in vitro hypertrophy models have demonstrated that mechanical forces can
      alter skeletal muscle gene regulation. This review's purpose is to support
      integrin-mediated signaling as a candidate for mechanical load-induced
      hypertrophy. Research quantifying components of the integrin-signaling pathway in
      overloaded skeletal muscle have been integrated with knowledge regarding
      integrins role during development and cardiac hypertrophy, with the hope of
      demonstrating the pathway's importance. The role of integrin signaling as an
      integrator of mechanical forces and growth factor signaling during hypertrophy is
      discussed. Specific components of integrin signaling, including focal adhesion
      kinase and low-molecular-weight GTPase Rho are mentioned as downstream targets of
      this signaling pathway. There is a need for additional mechanistic studies
      capable of providing a stronger linkage between integrin-mediated signaling and
      skeletal muscle hypertrophy; however, there appears to be abundant justification
      for this type of research.

PMID- 10642400
TI  - The Na(+)-K(+)-ATPase alpha2 gene and trainability of cardiorespiratory
      endurance: the HERITAGE family study.
AB  - The Na(+)-K(+)-ATPase plays an important role in the maintenance of electrolyte
      balance in the working muscle and thus may contribute to endurance performance.
      This study aimed to investigate the associations between genetic variants at the
      Na(+)-K(+)-ATPase alpha2 locus and the response (Delta) of maximal oxygen
      consumption (VO(2 max)) and maximal power output (W(max)) to 20 wk of endurance
      training in 472 sedentary Caucasian subjects from 99 families. VO(2 max) and
      W(max) were measured during two maximal cycle ergometer exercise tests before and
      again after the training program, and restriction fragment length polymorphisms
      at the Na(+)-K(+)-ATPase alpha2 (exons 1 and 21-22 with Bgl II) gene were typed.
      Sibling-pair linkage analysis revealed marginal evidence for linkage between the
      alpha2 haplotype and DeltaVO(2 max) (P = 0.054) and stronger linkages between the
      alpha2 exon 21-22 marker (P = 0.005) and alpha2 haplotype (P = 0.003) and
      DeltaW(max). In the whole cohort, DeltaVO(2 max) in the 3.3-kb homozygotes of the
      exon 1 marker (n = 5) was 41% lower than in the 8.0/3.3-kb heterozygotes (n = 87)
      and 48% lower than in the 8.0-kb homozygotes (n = 380; P = 0.018, adjusted for
      age, gender, baseline VO(2 max), and body weight). Among offspring, 10.5/10.5-kb
      homozygotes (n = 14) of the exon 21-22 marker showed a 571 +/- 56 (SE) ml
      O(2)/min increase in VO(2 max), whereas the increases in the 10.5/4.3-kb (n = 93)
      and 4.3/4.3-kb (n = 187) genotypes were 442 +/- 22 and 410 +/- 15 ml O(2)/min,
      respectively (P = 0.017). These data suggest that genetic variation at the Na(+)
      K(+)-ATPase alpha2 locus influences the trainability of VO(2 max) in sedentary
      Caucasian subjects.

PMID- 10642401
TI  - Skeletal muscle Ca(2+)-independent kinase activity increases during either
      hypertrophy or running.
AB  - Spikes in free Ca(2+) initiate contractions in skeletal muscle cells, but whether
      and how they might signal to transcription factors in skeletal muscles of living
      animals is unknown. Since previous studies in non-muscle cells have shown that
      serum response factor (SRF) protein, a transcription factor, is phosphorylated
      rapidly by Ca(2+)/calmodulin (CaM)-dependent protein kinase after rises in
      intracellular Ca(2+), we measured enzymatic activity that phosphorylates SRF
      (designated SRF kinase activity). Homogenates from 7-day-hypertrophied anterior
      latissimus dorsi muscles of roosters had more Ca(2+)-independent SRF kinase
      activity than their respective control muscles. However, no differences were
      noted in Ca(2+)/CaM-dependent SRF kinase activity between control and trained
      muscles. To determine whether the Ca(2+)-independent and Ca(2+)/CaM-dependent
      forms of Ca(2+)/CaM-dependent protein kinase II (CaMKII) might contribute to some
      of the SRF kinase activity, autocamtide-3, a synthetic substrate that is specific
      for CaMKII, was employed. While the Ca(2+)-independent form of CaMKII was
      increased, like the Ca(2+)-independent form of SRF kinase, no alteration in
      CaMKII occurred at 7 days of stretch overload. These observations suggest that
      some of SRF phosphorylation by skeletal muscle extracts could be due to CaMKII.
      To determine whether this adaptation was specific to the exercise type (i.e.,
      hypertrophy), similar measurements were made in the white vastus lateralis muscle
      of rats that had completed 2 wk of voluntary running. Although Ca(2+)-independent
      SRF kinase was increased, no alteration occurred in Ca(2+)/CaM-dependent SRF
      kinase activity. Thus any role of Ca(2+)-independent SRF kinase signaling has
      downstream modulators specific to the exercise phenotype.

PMID- 10642402
TI  - Heat stress attenuates skeletal muscle atrophy in hindlimb-unweighted rats.
AB  - This study tested the hypothesis that elevation of heat stress proteins by whole
      body hyperthermia is associated with a decrease in skeletal muscle atrophy
      induced by reduced contractile activity (i.e. , hindlimb unweighting). Female
      adult rats (6 mo old) were assigned to one of four experimental groups (n =
      10/group): 1) sedentary control (Con), 2) heat stress (Heat), 3) hindlimb
      unweighting (HLU), or 4) heat stress before hindlimb unweighting (Heat+HLU).
      Animals in the Heat and Heat+HLU groups were exposed to 60 min of hyperthermia
      (colonic temperature approximately 41.6 degrees C). Six hours after heat stress,
      both the HLU and Heat+HLU groups were subjected to hindlimb unweighting for 8
      days. After hindlimb unweighting, the animals were anesthetized, and the soleus
      muscles were removed, weighed, and analyzed for protein content and the relative
      levels of heat shock protein 72 (HSP72). Compared with control and HLU animals,
      the relative content of HSP72 in the soleus muscle was significantly elevated (P
      < 0.05) in both the Heat and Heat+HLU animals. Although hindlimb unweighting
      resulted in muscle atrophy in both the HLU and Heat+HLU animals, the loss of
      muscle weight and protein content was significantly less (P < 0.05) in the
      Heat+HLU animals. These data demonstrate that heat stress before hindlimb
      unweighting can reduce the rate of disuse muscle atrophy. We postulate that HSP70
      and/or other stress proteins play a role in the control of muscle atrophy induced
      by reduced contractile activity.

PMID- 10642404
TI  - Changes for Trauma Nursing.

PMID- 10642403
TI  - Public health advisory: infections from endoscopes inadequately reprocessed.

PMID- 10642405
TI  - Caught up in the symphony.

PMID- 10642406
TI  - New partnerships that inspire synergy in nursing.

PMID- 10642407
TI  - Case report: a nursing challenge, the unstable pelvic fracture.
AB  - A case report is presented that describes the initial care of a severely injured
      patient who was hemodynamically unstable. The discussion highlights the process
      used to recognize life-threatening injuries, to differentiate internal sources of
      hemorrhage, to provide damage-control surgery, and to stop further bleeding with
      an interventional radiologic examination. The emergency nursing care of a patient
      with unstable pelvic trauma is included.

PMID- 10642408
TI  - Resuscitation considerations to prevent pressure ulcers in trauma patients.
AB  - The success of a trauma resuscitation is often measured in short-term patient
      outcomes. To be a true success, the patient should also be protected from long
      term problems that are easily preventable. Skin pressure ulcers are a real threat
      to trauma patients who are immobilized. Nurses involved in the initial care of
      these patients should be aware of the common causes of skin breakdown and how to
      prevent it.

PMID- 10642410
TI  - Assessing Your Knowledge of Childhood and Adolescent Injuries.

PMID- 10642409
TI  - Pulmonary artery rupture: serious complication associated with pulmonary artery
      catheters.
AB  - An analysis of the Manufacturer and User Facility Device Experience database of
      the Food and Drug Administration was conducted to identify adverse event reports
      associated with pulmonary artery catheter use between 1993 and 1999. Of 714
      adverse event reports, there were 48 deaths of which 42 (88%) were related to
      pulmonary artery rupture. A further analysis of risk factors was conducted and
      found "postmenopausal female" was a most significant finding. Further study is
      recommended to establish a causal relationship.

PMID- 10642411
TI  - Diagnosing acute venous thrombosis.

PMID- 10642412
TI  - To be a nurse.

PMID- 10642413
TI  - Not-so-simple silicosis: a case for public health action.

PMID- 10642414
TI  - Is silicosis required for silica-associated lung cancer?
AB  - BACKGROUND: Abundant epidemiologic and experimental evidence supports the 1997
      International Agency for Research on Cancer classification of crystalline silica
      as a human lung carcinogen. Nonetheless, there remains uncertainty about whether
      excessive lung cancer occurs exclusively among workers with silicosis. METHODS: A
      review was performed of published occupational epidemiologic literature directly
      pertinent to the interrelations among silica exposure, silicosis, and lung
      cancer. RESULTS: The association between silica and lung cancer is generally, but
      not uniformly, stronger among silicotics than nonsilicotics. However, the
      existing literature is ambiguous due to incomplete or biased ascertainment of
      silicosis, inadequate exposure assessment, and the inherently strong correlation
      between silica exposure and silicosis which hinders efforts to disentangle unique
      contributions to lung cancer risk. CONCLUSIONS: Until more conclusive
      epidemiologic findings become available, population-based or individually-based
      risk assessments should treat silicosis and lung cancer as distinct entities
      whose cause/effect relations are not necessarily linked.

PMID- 10642415
TI  - Mixed dust fibrosis and tuberculosis in comparison with silicosis and macular
      pneumoconiosis.
AB  - BACKGROUND: To assess the relationship between mixed dust fibrosis (MDF) and
      tuberculosis. METHODS: We performed a comparative analysis with MDF, silicosis,
      and macular pneumoconiosis (Mac), using autopsy records from 1975 to 1994.
      RESULTS: Prevalences of having tuberculosis among MDF, silicosis, and Mac were
      not significantly different, albeit a tendency of higher prevalence in silicosis.
      Cure rates of tuberculosis were, in order, silicosis < MDF < Mac (P=0. 085).
      Death rates associated with tuberculosis were, in order, silicosis > MDF=Mac
      (P=0.911). With respect to the two types of association with tuberculosis, i.e.,
      combined type (tuberculopneumoconiosis) and complicated one (pneumoconiosis with
      tuberculosis); the former was significantly dominant in silicosis, the latter was
      significantly dominant in Mac, and intermediate in MDF. As a whole, the
      complicated type had a tendency of a higher cure rate than the combined type
      (P=0.071). Although the differences of profiles between the combined and
      complicated types were not statistically significant, the combined type had a
      tendency to have longer duration of exposure to dusts, earlier registration for
      treatment, higher profusion score, and earlier death compared with the
      complicated type. CONCLUSIONS: From our findings, MDF takes an intermediate
      position between silicosis and Mac regarding the relationship with tuberculosis.
      The type of association with tuberculosis rather than the kind of background
      pneumoconiosis seemed to be more important in light of responsiveness to the
      treatment.

PMID- 10642416
TI  - Qualitative assessment of isocyanate skin exposure in auto body shops: a pilot
      study.
AB  - BACKGROUND: Little is known about the extent of human isocyanate skin exposure in
      auto body shops and the effectiveness of personal protective equipment. Animal
      studies have suggested that skin exposure to isocyanates may be an important risk
      factor for respiratory sensitization leading to asthma. This study provides
      initial data on hexamethylene diisocyanate skin exposure in three auto body
      shops. METHODS: Three auto body shops of different size which use different paint
      systems were examined for the presence of aliphatic isocyanates on environmental
      surfaces and workers' skin and for breakthrough of personal protective equipment.
      Qualitative detection of contamination by isocyanates was conducted using a wipe
      sampling technique. Assessment focused on the painters and their tasks, although
      other auto body repairers were also evaluated. RESULTS: Environmental surfaces
      such as painters' workbenches, spray equipment, and cleaning tools were found
      contaminated with isocyanates. Painters had frequent contact with contaminated
      surfaces, often without wearing gloves. Moderate to heavy contamination of some
      skin surfaces was found with painters from two of the three auto body shops.
      Latex gloves used for skin protection showed significant penetrations by
      isocyanates even after a single painting session. CONCLUSIONS: Contaminated
      environmental surfaces and skin exposure to isocyanates were documented in
      several auto body shops. Latex gloves were not adequate protection for workers
      using isocyanate paints. Further research which would better quantify skin
      exposure, and its potential relationship to respiratory sensitization and asthma
      is warranted.

PMID- 10642417
TI  - Mesothelioma and lung tumors attributable to asbestos among petroleum workers.
AB  - BACKGROUND: Asbestos exposure has been definitively found to be associated with
      both mesothelioma and lung cancer. Nevertheless, in the overall population of oil
      refinery workers potentially exposed to asbestos, many studies clearly show a
      definitely increased risk of mesothelioma, but no proven excess of lung cancer
      after comparison to the general population. Through the presentation of new data
      and the re-appraisal of two recent and independent epidemiological studies
      conducted in Liguria, Italy, and Ontario, Canada, we attempt to shed light on
      this apparently paradoxical finding. METHODS: Lung cancer mortality was studied
      among maintenance workers exposed to asbestos, and among two other subgroups of
      refinery employees: blue collar and white collar workers. The comparison with
      blue collar workers was performed in order to take into account the role of
      healthy worker effect, smoking habit, and the socioeconomic level. The comparison
      with white collar workers was performed to control for other occupational lung
      carcinogens. RESULTS AND CONCLUSIONS: Results reveal a consistency between the
      two studies and show that 96-100% of the mesotheliomas and 42-49% of the lung
      tumors arising among maintenance workers were attributable to asbestos exposure.
      Our new analysis, estimating two cases of asbestos-related lung cancer for each
      case of mesothelioma, confirms published findings on the magnitude of asbestos
      related tumors in oil refineries.

PMID- 10642418
TI  - Are current biomarkers suitable for the assessment of manganese exposure in
      individual workers?
AB  - BACKGROUND: Whole blood and urinary manganese have been measured in occupational
      and environmental studies for the assessment of exposure. The aim of this study
      was to assess the relationship between the airborne concentrations of manganese
      and these biological indicators. METHODS: Environmental and biological monitoring
      was performed in a group of 94 employees in a ferroalloy production, who were
      exposed to manganese (Mn) oxides (MnO(2) and Mn(3)O(4)). The results were
      compared with those from a control group of 87 subjects not exposed to Mn.
      RESULTS: Mn exposure levels ranged between 5 and 740 micrograms/m(3), with
      arithmetic and geometric mean and median values being 202.6, 97.6, and 150
      micrograms/m(3), respectively. Arithmetic and geometric means for Mn in total
      blood (MnB) were, respectively, 10.3+/-3.8 and 9.7 micrograms/L in the exposed
      and 5.9+/-1.7 and 5.7 micrograms/L in the controls. For urinary Mn (MnU),
      arithmetic and geometric means were, respectively, 4.9+/-3.6 and 3. 8
      micrograms/L in the exposed and 1.2+/-1.4 and 0.7 micrograms/L in the controls.
      On a group comparison, a significant relationship was found between high and low
      exposed subgroups, identified according to Mn atmospheric concentrations (MnA),
      for both MnB (F value=38.0, P > 0.0001) and MnU (F value=36.1, P > 0.0001). On a
      linear relationship, a correlation was observed between MnA and MnB (r=0. 34;
      r(2)=0.112; P=0.001), whereas no association was found between MnA and MnU. A
      significant relationship emerged also between MnB and MnU (r=0.48, r(2)=0.23, P <
      0.0001). No association was observed between an index of cumulative exposure and
      the biological indicators of exposure. CONCLUSIONS: These results confirm that
      MnB and MnU can discriminate groups of occupationally exposed workers from groups
      of nonexposed subjects. MnB is also related to the intensity of external exposure
      on a linear relationship, but given a high variability, it is not suitable for
      individual biological monitoring. Therefore, further research should focus on
      more accurate biomarkers of Mn exposure.

PMID- 10642419
TI  - The prevalence of pleural plaques and/or pulmonary changes among construction
      workers in Okayama, Japan.
AB  - BACKGROUND: Since asbestos has been widely used in Japanese building materials
      since 1960s, a large number of Japanese construction workers may be exposed to
      asbestos occupationally. METHODS: Among 2951 construction workers in Okayama,
      Japan, the prevalence of asbestos-induced pleural or pulmonary changes was
      examined by screening chest x-rays; these findings were confirmed by computed
      tomography (CT) scanning of the chest. RESULTS: Among 2951 construction workers,
      168 (5.7%) were found to have significant findings for pleural plaque or
      pulmonary changes on chest x-ray. Seventy-four had both pleural plaque and
      asbestosis, 85 pleural plaques alone, and 9 asbestosis alone. In 11 subjects,
      pleural plaques were suggested by chest x-ray, but neither pleural plaque nor
      asbestosis was demonstrated by chest CT. Honeycombing as one of the
      characteristic findings of asbestosis was found in 29 subjects. Others showed
      subpleural spots or curvilinear shadow, which suggested the early stage of
      asbestosis. The occupations of these workers were carpenters (64), plasterers
      (27), and concrete board cutters (14). About 30% of the workers with these
      findings were aware that they were handling asbestos in activities such as
      installation of asbestos boards, and/or asbestos spraying. CONCLUSIONS: As the
      incidence of malignant mesothelioma and primary lung cancer associated with
      asbestos exposure are high, screening by chest CT is necessary for detecting
      asbestos-induced pulmonary and/or pleural lesions. Education for protection such
      as telling about the presence of asbestos in building materials is also
      necessary.

PMID- 10642420
TI  - Is a reduction in residual volume a sub-clinical manifestation of hydrogen
      sulfide intoxication?
AB  - BACKGROUND: A number of employees at an aircraft factory were accidentally
      exposed to hydrogen sulfide. Because of concern that this may have resulted in
      lung injury, forty-seven workers were referred for clinical and physiological
      evaluation. METHODS: Comprehensive pulmonary function tests were performed
      including spirometry, flow volume curves, static lung volumes, and diffusion
      capacity for carbon monoxide. RESULTS: The results obtained indicated that ten
      people (23%) had an isolated reduction in residual volume. This was an unexpected
      finding as other physiological indices of lung function were within normal
      limits. Clinical examination was also normal, therefore, radiological
      investigations were considered inappropriate. CONCLUSIONS: It is suggested that
      the decrement in residual volume, in the presence of other normal indices of lung
      function, could represent a sub-acute manifestation of hydrogen sulfide
      intoxication.

PMID- 10642421
TI  - Social and occupational differences in chronic obstructive lung disease in
      Denmark 1981-1993.
AB  - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a common crippling
      disorder related to exposure to noxious dust and fumes. The purpose of this study
      was to estimate relative rates of COPD in socioeconomic groups and in 'classic'
      high-risk industries. METHODS: Cohorts of all gainfully employed 20-59 year old
      Danes in the years 1981, 1986, and 1991 were formed, to compare standardized
      hospitalization ratios (SHR) and time trends (1981-93). RESULTS: The risk ratio
      (RR) between unskilled workers and senior salaried staff was 2.31, (95% CI 2.13
      2.51) for men and 1.62 (1.38-1.92) for women. Among classic high-risk occupations
      we found a decreasing SHR in farmers and an increasing SHR in the hotel and
      restaurant industry and for taxi and bus drivers. The study confirmed earlier
      reports on high risks in the metal, rubber, and bakery industries. CONCLUSIONS:
      Apart from the reduced SHR among farmers there were no signs of decreasing
      differences in COPD risk.

PMID- 10642422
TI  - Migrant farmworkers and green tobacco sickness: new issues for an understudied
      disease.
AB  - BACKGROUND: The transition from family tobacco production to dependence on hired
      labor has placed migrant and seasonal farmworkers (MSF) at risk for green tobacco
      sickness (GTS). No previous studies of GTS have focused on MSF. METHODS: One
      hundred and forty-four Hispanic MSF working in tobacco production in North
      Carolina were surveyed to obtain self-reports of GTS, preventive behaviors, and
      treatments. RESULTS: Forty-one percent reported having GTS at least once during
      the summer. Most had taken no precautions to prevent GTS. Ninety-six percent of
      those with GTS had tried to treat it. Antinausea medications were the most common
      treatments. Only 9% sought medical treatment; 7% lost work time. CONCLUSIONS: The
      incidence of GTS obtained by interviewing MSF is much higher than that in other
      studies, which have relied on rates of medical treatment or farmers' reports for
      their workers. MSF constitute a population at risk for GTS who have little
      control over work conditions to prevent GTS or seek treatment.

PMID- 10642423
TI  - Beyond the workplace: an exploratory study of the impact of neurotoxic workplace
      exposure on marital relations.
AB  - BACKGROUND: The impact on family life and social relations that may result from
      symptoms associated with exposure to neurotoxic substances has never been
      addressed. This exploratory study assessed the associations between exposure to
      neurotoxic agents in the workplace, mental health, and marital difficulties.
      METHODS: Fifty-five (55) male workers and their spouses completed standardized
      measures of mental health and marital difficulties. Workers' exposure to
      neurotoxic substances was evaluated by questionnaire and interview, using a
      semiquantitative classification system. RESULTS: A positive relation was observed
      between exposure level and measures of workers' psychological symptoms and
      marital stress; no relation was observed between workers' exposure level and
      wives' psychological symptoms. More severe exposure to neurotoxic substances was
      associated with wives' reports of more severe marital conflicts, and this
      association was mediated by husbands' psychological symptoms. As compared to low
      exposure husbands, high exposure husbands reported higher degrees of stress
      surrounding marital discussions, more consistent incidence of minor physical
      assaults by wives, and stronger associations between their levels of stress, the
      verbal aggressions of wives, and the number of marital conflicts. CONCLUSIONS:
      The results of this study confirm that neurotoxic exposure is a risk factor for
      mental health and suggest how this may influence marital relations. Because of
      the importance of these findings for the well-being of workers and their
      families, these associations should be further studied.

PMID- 10642424
TI  - Two-stage global search designs for linkage analysis I: use of the mean statistic
      for affected sib pairs.
AB  - Two-stage global search designs for linkage analysis using pairs of affected
      relatives were shown by Elston et al. [1996] to typically halve the cost of a
      study compared to a one-stage design. The statistic used for testing linkage in
      that study was based on the proportion of pairs sharing no marker alleles
      identical by descent (IBD). However, it has been established that the mean
      statistic often has the greatest power for full sib pairs [Blackwelder and
      Elston, 1985; Schaid and Nick, 1990; Knapp et al. 1994]. In this paper, we study
      optimal two-stage global search designs, in the case of affected full sib pairs,
      when using the mean test statistic to test for linkage. When dominant genetic
      variance is present, using the mean statistic is usually more cost efficient than
      using the proportion of pairs sharing no maker alleles IBD; in the case when
      there is no dominant genetic variance, the mean statistic leads to a better
      design, in the sense of being more cost-saving, provided that the relative risk
      ratio for first-degree relatives is small. The effect of heterogeneity and
      markers' informativeness is also investigated, the latter using the Linkage
      Information Content value for sibs.

PMID- 10642425
TI  - Two-stage global search designs for linkage analysis II: including discordant
      relative pairs in the study.
AB  - The optimal two-stage designs proposed by Elston [1992, 1994] for a global search
      of the genome to locate disease genes by linkage analysis typically halve the
      cost of a study compared to one-stage designs [Elston et al., 1996]. These
      designs were based on sampling affected pairs of relatives. Usually, using
      affected relative pairs is more powerful than using discordant relative pairs
      [Blackwelder and Elston, 1985; Risch 1990b]. However, in certain situations
      discordant relative pairs can be as powerful as, or even more powerful than,
      affected relative pairs. In addition, combining discordant pairs with affected
      pairs provides a control study. In this paper, we investigate optimal two-stage
      designs when: 1) using only discordant relative pairs, and 2) combining
      discordant with affected relative pairs. We show that including discordant
      relatives pairs into the study not only provides a control, but is also cost
      effective.

PMID- 10642426
TI  - Segregation analysis of IgE levels in 335 French families (EGEA) using different
      strategies to correct for the ascertainment through a correlated trait (asthma).
AB  - The main objective of this study was to search for a major gene controlling total
      serum immunoglobulin E (IgE) levels, an intermediate phenotype for asthma and
      allergy. We studied 335 French nuclear families of the EGEA study
      (Epidemiological study of the Genetics and Environment of Asthma), ascertained
      through asthmatic probands (123 are parents in the family, 212 children).
      Segregation analyses were performed by regressive models, which can take into
      account a major gene effect, various sources of familial covariation (genetic
      and/or environmental) as well as measured risk factors (i.e. , age, sex, smoking
      habits). Different strategies were considered to account for the mode of
      ascertainment of the families through a correlated trait (asthma): the
      ascertainment mode was either ignored (strategy A) or taken into account by
      adjusting IgE levels for the position in the family, i.e., probands, blood
      relatives, spouses (strategy B) or excluding the asthmatic children-probands and
      computing the likelihood of each family conditionally on parents' IgE levels
      (strategy C). Whereas a major gene effect could not be detected with strategy A,
      strategies B and C showed evidence for the transmission of a dominant major gene
      for high IgE levels, which was more significant with strategy B. This gene does
      not interact with any of the covariates and is responsible for approximately 15%
      of IgE variation (the allele frequency is 0.65).

PMID- 10642427
TI  - Effect of allelic heterogeneity on the power of the transmission disequilibrium
      test.
AB  - Due in part to an influential paper by Risch and Merikangas [(1996) Science
      273:1516-1517], which suggested that disequilibrium tests would have greater
      power to detect genes of small effect than would linkage tests, interest in the
      use of the Transmission Disequilibrium Test (TDT) as an analysis tool for
      genomewide studies is steadily growing. However, the paper by Risch and
      Merikangas made several simplifying assumptions. One such assumption was that the
      underlying gene showed allelic homogeneity, and another was that the allele being
      measured was the actual susceptibility allele. Here we investigate the effect of
      allelic heterogeneity on the power of the TDT using multiplicative, additive,
      dominant, and recessive modes of inheritances in the context of a genomewide
      study. We further distinguish two cases: first, that the marker alleles are the
      actual susceptibility alleles, and second, that alleles are measured at a marker
      linked to the disease gene with zero recombination. We consider two family
      structures, either a single affected offspring (SAO) and two parents, or an
      affected sib-pair (ASP) and two parents. We find that, as expected, the power of
      the TDT declines as the number of susceptibility alleles at the locus being
      tested increases and the effect on power can be substantial. When a linked marker
      is measured rather than a susceptibility allele itself, sample sizes reach
      unattainable levels when as few as two susceptibility alleles are present. Across
      all the models we consider, the required number of families for a TDT with ASP
      sampling varies from 19 to over a million families. Thus, the TDT may not be an
      optimal test in the context of genomic screens under more biologically realistic
      assumptions.

PMID- 10642428
TI  - Bootstrap confidence intervals for relative risk parameters in affected-sib-pair
      data.
AB  - In affected-sib-pair (ASP) studies, parameters such as the locus-specific sibling
      relative risk, lambda(s), may be estimated and used to decide whether or not to
      continue the search for susceptibility genes. Typically, a maximum likelihood
      point estimate of lambda(s) is given, but since this estimate may have
      substantial variability, it is of interest to obtain confidence limits for the
      true value of lambda(s). While a variety of methods for doing this exist, there
      is considerable uncertainty over their reliability. This is because the discrete
      nature of ASP data and the imposition of genetic "possible triangle" constraints
      during the likelihood maximization mean that asymptotic results may not apply. In
      this paper, we use simulation to evaluate the reliability of various asymptotic
      and simulation-based confidence intervals, the latter being based on a
      resampling, or bootstrap approach. We seek to identify, from the large pool of
      methods available, those methods that yield short intervals with accurate
      coverage probabilities for ASP data. Our results show that many of the most
      popular bootstrap confidence interval methods perform poorly for ASP data, giving
      coverage probabilities much lower than claimed. The test-inversion, profile
      likelihood, and asymptotic methods, however, perform well, although some care is
      needed in choice of nuisance parameter. Overall, in simulations under a variety
      of different genetic hypotheses, we find that the asymptotic methods of
      confidence interval evaluation are the most reliable, even in small samples. We
      illustrate our results with a practical application to a real data set, obtaining
      confidence intervals for the sibling relative risks associated with several loci
      involved in type 1 diabetes.

PMID- 10642429
TI  - Risk models for familial ovarian and breast cancer.
AB  - We investigated risk models for the inherited susceptibility of breast and
      ovarian cancer, using data from both high-risk families and a population based
      series of ovarian cancer. The first data set consisted of 112 families containing
      two or more relatives with epithelial ovarian cancer. BRCA1 and BRCA2 germline
      mutations were detected in 50% of these families. The second study involved 374
      ovarian cancer cases, unselected for family history, who had DNA samples analyzed
      for BRCA1 mutations. Twelve women were found to be carriers. We constructed
      genetic models for ovarian and breast cancer using the computer program MENDEL.
      In the first study, we modeled the effects of BRCA1 and BRCA2 simultaneously and
      allowed for a third gene predisposing to ovarian cancer. None of the models
      fitted gave significant evidence for a third gene. Population frequencies of
      BRCA1 and BRCA2 mutations were estimated to be 0. 00128 and 0.00172,
      respectively. Our results suggest that BRCA1 and BRCA2 may be sufficient to
      explain the majority of familial ovarian cancer and that families without
      mutations can be explained by sensitivity of mutation testing and chance clusters
      of sporadic cases. Using data on the families of the 12 mutation carriers in the
      second study, we estimated age-specific ovarian and breast cancer risks for BRCA1
      mutation carriers. Under the best-fitting model, the cumulative ovarian cancer
      risk was 66% by age 70, and the corresponding breast cancer risk was 45%. The
      high penetrance estimate for ovarian cancer, compared with other studies,
      suggests that modifying genetic or environmental factors may be important
      determinants of risk.

PMID- 10642430
TI  - Twelfth international conference on carcinogenesis and risk assessment gene
      environment interactions: emerging issues, technologies, and biological paradigms

PMID- 10642431
TI  - Apolipoprotein E genetic polymorphism, serum lipoproteins, and breast cancer
      risk.
AB  - Apolipoprotein E (apoE) is a polymorphic gene involved in lipid metabolism with
      three common variant alleles (epsilon2, epsilon3, and epsilon4). The epsilon4
      allele has been associated with elevated levels of cholesterol as well as greater
      risk of coronary heart disease and Alzheimer's disease. In this case-control
      study we examined whether apoE genotype affected the association between serum
      lipids and breast cancer risk. In a subset of a study in western New York, 260
      women with incident, primary breast cancer and 332 community controls were
      interviewed and provided blood samples. Polymerase chain reaction-restriction
      fragment length polymorphism analyses of the apoE polymorphism were performed.
      Participants were classified as apoE2 (epsilon2, epsilon2 or epsilon2, epsilon3),
      apoE3 (epsilon3, epsilon3), or apoE4 (epsilon4, epsilon4 or epsilon4, epsilon3).
      No unconditional logistic regression was used to compute adjusted odds ratios
      (ORs) and 95% confidence intervals (CI). Compared with women with the apoE3
      genotype, there were no associations with risk for women with the apoE2 (OR=1.0;
      95% CI=0. 91-1.64) or apoE4 genotype (OR=0.97; 95% CI=0.63-1.54). Higher serum
      levels of total cholesterol, HDL cholesterol, and LDL cholesterol were not
      associated with risk, either in the total sample or among subgroups of women
      defined by apoE genotype. Women with the highest serum triglyceride levels had an
      increase in risk (OR=1.63; 95% CI=1. 03-2.59) compared to women with the lowest
      levels. This effect was not apparent among women with the apoE2 or apoE3
      genotype, but much stronger among women with the apoE4 genotype (OR=4.69; 95%
      CI=1. 49-14.7). These data suggest that the apoE4 genotype may modify the
      association between serum triglycerides and breast cancer risk.

PMID- 10642432
TI  - The insulin-like growth factor-1 elevates urokinase-type plasminogen activator-1
      in human breast cancer cells: a new avenue for breast cancer therapy.
AB  - Tumor recurrence is a common problem in the treatment of breast cancer. In breast
      cancer, the expression of high protein levels of the insulin-like growth factor-1
      receptor (IGF-1R) and urokinase-type plasminogen activator-1 (uPA) is strongly
      associated with breast cancer recurrence and decreased survival. The expression
      of uPA by tumors is thought to not only stimulate tumor invasion but also
      facilitate angiogenesis. In this study, our goal was to address whether IGF-1R
      could influence the expression of the extracell ular matrix proteases, matrix
      metalloproteinase (MMP), or uPA thus allowing a selective advantage for tumor
      invasion and concomitant neovascularization. Initially, we determined whether or
      not insulin-like growth factor (IGF)-1 regulated the production MMP or uPA in the
      human breast cancer MDA-MB-231 cells. There was no increase in MMP activity when
      the cells were treated with IGF-1 (10 ng/mL) for 24 h. In contrast, uPA mRNA and
      protein were induced in a time-dependent manner. Furthermore, clones expressi ng
      a dominant negative inhibitor of IGF-1R termed 486stop had less uPA mRNA, and the
      clones were less invasive through Matrigel. Taken together, these data illustrate
      that IGF-1R stimulates uPA production. Hence, these two prognostic indicators may
      be interrelated, suggesting they may function in a synergistic manner to
      facilitate local tumor invasion as well as angiogenesis. Our data suggest that
      disruption of IGF-1 signaling in breast cancer may lead to breast cancer
      prevention and intervention by decreasing uPA expression.

PMID- 10642433
TI  - Vitamin D receptor polymorphisms and prostate cancer.
AB  - Prostate cancer is a common disease, yet determinants of prostate cancer risk
      remain largely unidentified. Low circulating levels of 1, 25-dihydroxy vitamin D
      (1,25-D) have been implicated as a risk factor for prostate cancer. In addition,
      1,25-D exhibits significant antineoplastic properties both in vitro and in vivo,
      and these antiproliferative effects appear to be mediated through the vitamin D
      receptor (VDR). The VDR has a number of common polymorphisms, including a TaqI
      restriction fragment length polymorphism in exon 9 and a poly(A) length
      polymorphism in the 3'-untranslated region. Previous studies have found an
      association between the TaqI T allele or poly(A) L allele and prostate cancer. To
      further investigate the putative link between VDR polymorphisms and prostate
      cancer, we conducted a case-control study of prostate cancer patients from the
      Piedmont region of North Carolina. Using polymerase chain reaction-based
      techniques on DNA extracted from peripheral blood, we genotyped 77 cases (70
      white, seven black) and 183 controls (169 white, 14 black) for the TaqI and
      poly(A) alleles. We report here an overall lack of association between either the
      TaqI or poly(A) genotype and prostate cancer odds ratio (OR)=1.4, 95% confidence
      interval (CI)=0.7-2.8; and OR=1.2, 95% CI=0.6-2.5, respectively). Using a case
      case analysis, we tested whether these polymorphisms might be associated with
      more advanced disease but found no statistically significant association for the
      TaqI T or poly(A) L allele (OR=2.5, 95% CI=0.3-21.7; OR=2.8, 95% CI=0.3-23.8,
      respectively). We report strong evidence of linkage disequilibrium between the
      TaqI and poly(A) polymorphisms (P < 0.0001), with whites demonstrating stronger
      linkage disequilibrium than blacks (D=0.24 vs. D=0.18).

PMID- 10642434
TI  - A farnesyl transferase inhibitor suppresses TPA-mediated skin tumor development
      without altering hyperplasia in the ras transgenic Tg.AC mouse.
AB  - The Tg.AC mouse carries an activated v-Ha-ras oncogene fused to an embryonic zeta
      globin promoter and develops cutaneous papillomas in response to specific
      chemicals, full thickness wounding, and ultraviolet radiation. Papilloma
      development in these mice has been suggested to be dependent upon activation of
      ras transgene expression, thus providing a potential model for studying ras
      inhibitory compounds. Farnesyl transferase inhibitors (FTIs) prevent a critical
      posttranslational modification step necessary for activation of ras proteins. Our
      studies demonstrated that a tricyclic FTI (SCH 56582) applied directly to the
      skin of homozygous Tg.AC mice 1 h prior to administration of the tumor promoter
      TPA decreased tumor multiplicity compared to TPA-only controls. In addition, a
      reduction of TPA-induced tumor development was seen in similarly treated
      hemizygous Tg.AC mice either on an FVB/N strain background or 50% C57BL/6.
      Histological examination of skin from Tg. AC(+/-):FVB/N mice revealed no
      differences with respect to 12-O-tetradecamoylpharbol-13-acetate (TPA)-mediated
      hyperplasia. Keratinocytes isolated from treated and control skin were assayed
      for ras transgene expression by reverse transcription-polymerase chain reaction,
      and expression was detected in both TPA- and FTI+TPA-treated tissue, although the
      appearance of transgene positive pre-papillomas was observed only in histological
      sections taken 21 d after the first treatment. In summary, we have used a regimen
      of topical application of an FTI (SCH 56582) to suppress TPA-mediated
      papillomagenesis in v-Ha-ras transgenic Tg.AC mice. These studies demonstrate
      that TPA-induced epidermal hyperplasia is a ras-independent process, while
      papilloma development in response to TPA treatment requires the function of
      activated ras.

PMID- 10642435
TI  - Analysis of aromatic DNA adducts and 7,8-dihydro-8-oxo- 2'-deoxyguanosine in
      lymphocyte DNA from a case-control study of lung cancer involving minority
      populations.
AB  - The purpose of this study was to examine the level of smoking-related aromatic
      DNA adducts and oxidative DNA damage in current smokers from a lung cancer case
      control study in African Americans and Mexican Americans. In addition, mutagen
      sensitivity (bleomycin-induced chromatid breaks), a marker of genetic
      susceptibility, was assessed in these patients and correlated with the level of
      DNA damage. Lymphocyte DNA from cases and age-, sex-, and ethnicity-matched
      controls was analyzed for aromatic DNA adducts (43 cases and 47 controls) and the
      level of 7, 8-dihydro-8-oxo-2'-deoxyguanosine (8-oxo-dG) was determined in 46
      cases and 48 controls using (32)P-postlabeling. Overall, lung cancer cases had
      significantly (P < 0.05) higher levels of aromatic DNA adducts and 8-oxo-dG
      (mean+/-SEM; 6.03+/-1.16/10(8) nucleotides and 5.82+/-0.77/10(5) nucleotides,
      respectively) compared to the controls (2.80+/-0.36/10(8) nucleotides and 3.65+/
      0.56/10(5) nucleotides, respectively). The case-control differences for these two
      biomarkers were especially evident in current smokers. Both male and female lung
      cancer cases had higher levels of aromatic DNA adducts compared to the
      corresponding controls but only in men was the difference statistically
      significant (P=0.002). Cases who started smoking at earliest age had highest
      levels of aromatic DNA adducts and 8-oxo-dG. The level of aromatic DNA adducts in
      lung cancer cases, but not controls, was positively correlated with bleomycin
      induced chromatid breaks (P=0.011). In contrast, the level of 8-oxo-dG was not
      correlated with mutagen sensitivity in either cases or controls or with the level
      of aromatic DNA adducts. The data suggest that levels of both aromatic DNA
      adducts and 8-oxo-dG may be useful in predicting risk of lung cancer in these
      minority populations. The correlation between aromatic DNA adducts and mutagen
      sensitivity in lung cancer cases and the trend for higher levels of DNA damage in
      cancer cases who started smoking earliest are particularly interesting and merit
      further study.

PMID- 10642436
TI  - A locus that influences susceptibility to 1, 2-dimethylhydrazine-induced colon
      tumors maps to the distal end of mouse chromosome 3.
AB  - While inheritance of mutated alleles of highly penetrant tumor suppressor genes
      such as retinoblastoma or p53 predisposes individuals to a greatly increased risk
      of developing cancer, epidemiological data indicate that the majority of sporadic
      tumors in humans result from interactions of environmental and host genetic
      factors. The host genetic factors are poorly penetrant tumor susceptibility genes
      that determine the likelihood that a cancer will arise from carcinogen exposure.
      The majority of colon tumors in humans are sporadic in nature. 1,2
      dimethylhydrazine (DMH)-induced colon tumors in mice provide a useful animal
      model to identify genes that influence susceptibility to carcinogen-induced colon
      tumors in humans. A genome-wide scan of genetic crosses of relatively sensitive
      C57BL/6J with relatively resistant CBA mice treated with DMH revealed a linkage
      of DMH susceptibility with the distal end of mouse chromosome 3, suggesting that
      one or more tumor susceptibility genes may map to this region.

PMID- 10642437
TI  - CRIM1, a novel gene encoding a cysteine-rich repeat protein, is developmentally
      regulated and implicated in vertebrate CNS development and organogenesis.
AB  - Development of the vertebrate central nervous system is thought to be controlled
      by intricate cell-cell interactions and spatio-temporally regulated gene
      expressions. The details of these processes are still not fully understood. We
      have isolated a novel vertebrate gene, CRIM1/Crim1, in human and mouse. Human
      CRIM1 maps to chromosome 2p21 close to the Spastic Paraplegia 4 locus. Crim1 is
      expressed in the notochord, somites, floor plate, early motor neurons and
      interneuron subpopulations within the developing spinal cord. CRIM1 appears to be
      evolutionarily conserved and encodes a putative transmembrane protein containing
      an IGF-binding protein motif and multiple cysteine-rich repeats similar to those
      in the BMP-associating chordin and sog proteins. Our results suggest a role for
      CRIM1/Crim1 in CNS development possibly via growth factor binding.

PMID- 10642438
TI  - Identification of the pancreatic endocrine cells of Pseudemys scripta elegans by
      immunogold labeling.
AB  - The endocrine pancreatic cells of Pseudemys scripta elegans were investigated
      immunocytochemically by light and electron microscopy. Insulin-, somatostatin
      (SST)-1, SST-28 (1-12)-, salmon (s)SST-25-, glucagon-, pancreatic polypeptide
      (PP)-, peptide tyrosine tyrosine (PYY)-, and neuropeptide tyrosine (NPY)-like
      immunoreactivities were observed. Insulin cells were immunogold labeled with
      bonito insulin antiserum and secretory granules were characterized by a wide halo
      and a dense core of varying shape. Consecutive PAP-immunostained sections showed
      that SST-28 (1-12), SST-14, and sSST-25 immunoreactivities occurred in the same
      cells. However, preabsorption tests demonstrated that anti-sSST-25 serum detected
      the invariant SST-14 molecule. The SST-28 (1-12)/SST-14-immunogold-labeled cells
      mainly had round or ovoid medium electron-dense granules. Glucagon-IR cells were
      characterized by round secretory granules with an electron-dense core, with or
      without a narrow clear halo. There were PP, PYY, and NPY (NPY-like)
      immunoreactivities in a population of glucagon-IR cells in the pancreatic
      duodenal region (glucagon/NPY cells). Most of the secretory granules of these
      glucagon/NPY-like cells had an electron-dense content and were round, although
      there were also pyriform or ovoid secretory granules which were smaller than
      those of glucagon-IR cells. Preabsorption tests proved that the NPY-like peptides
      detected in the endocrine pancreas of P. scripta elegans were more similar to NPY
      or PYY than to PP.

PMID- 10642439
TI  - Expression of calcium-sensing receptor gene by avian parathyroid gland in vivo:
      relationship to plasma calcium.
AB  - Calcium-sensing receptor (CaR) gene expression and parathyroid hormone (PTH)
      content were evaluated in situ in chicken parathyroid glands (PG) in relation to
      changes in plasma calcium. The CaR gene is expressed by the parathyroid chief
      cells, the same cells that store and secrete PTH. An increase in plasma calcium,
      achieved by repletion of vitamin D-deficient chicks with a normal diet, by PTH
      injection, or during eggshell formation, increased the expression of the CaR
      gene. Low plasma calcium concentration in vitamin D-deficient chicks or in
      layers, before or after eggshell formation, was associated with decrease in CaR
      gene expression in the PG. The level of CaR gene expression was inversely
      correlated with the PTH content of the PG. The results of this study demonstrate
      for the first time that, in contrast to mammals, the CaR gene expression in the
      PG of the chicken is inversely associated with changes in plasma calcium.

PMID- 10642440
TI  - Changes in parathyroid hormone-related peptide receptor binding in the shell
      gland of laying hens (Gallus domesticus) during the oviposition cycle.
AB  - In this study, parathyroid hormone (PTH) receptor binding was examined in the
      membrane fraction of the endometrium of the shell gland of laying and nonlaying
      hens by the use of (125)I-PTH-related peptide (PTHrP) binding assays. Specific
      (125)I-PTHrP binding was found in the endometrium of the shell gland and
      increased during the first 1 h of incubation and then reached a plateau. Specific
      (125)I-PTHrP binding increased in line with an increase in protein concentration
      from 10 to 80 microg. The membrane fraction had specific binding to (125)I-PTHrP.
      The Scatchard plot analysis revealed a linear profile that indicated the presence
      of one type of receptor. The equilibrium dissociation constant (K(d)) and the
      maximum binding capacity (B(max)) in the shell gland decreased 19 h before
      oviposition in egg-laying hens and remained low for about 20 h during the period
      of calcification. In contrast, the K(d) and the B(max) in nonlaying hens were
      constant throughout a 24-h period. These results suggest that PTH acts on the
      endometrium of the shell gland during the eggshell calcification.

PMID- 10642441
TI  - Seasonal changes in plasma glucocorticosteroids of free-living female yellow-pine
      chipmunks: effects of reproduction and capture and handling.
AB  - We measured plasma levels of cortisol and corticosterone in female yellow-pine
      chipmunks (Tamias amoenus) while observing seasonal reproductive and life-history
      events by live-trapping a natural population during the active (nonhibernating)
      season. Both glucocorticosteroids (GCs) varied significantly from March through
      September, starting with minimal values at the time of mating (cortisol
      approximately 900 ng/ml, corticosterone approximately 50 ng/ml), rising to a peak
      by late lactation (cortisol approximately 1600 ng/ml, corticosterone
      approximately 175 ng/ml), and then declining prior to hibernation. Following
      their emergence from natal burrows, young of the year had GC levels
      indistinguishable from those of adults. Body mass also varied significantly over
      the season, increasing after mating and again after parturition to a peak in
      lactation, after which it declined steadily until hibernation. In addition to the
      use of standard trapping to describe seasonal hormonal patterns, we also trapped
      chipmunks using a special protocol to examine the effects of capture and handling
      on GCs; we obtained an initial (basal) blood sample immediately, within 1-3 min
      of observing a capture, and then a second sample 30 min after holding the animal
      in the trap. Chipmunks consistently increased GCs above the initial (basal) level
      during the 30 min after capture and initial handling; these significant increases
      in GCs ranged approximately 70-130% for cortisol and 50-190% for corticosterone,
      depending on season and reproductive state. GC levels at 30 min after capture and
      handling were similar to those obtained from samples drawn from our standard
      trapping and blood sampling. We conclude that although capture and handling
      increase the absolute level of plasma GC hormones, that effect does not obscure
      natural patterns of seasonal variation in GCs. Overall, our observations suggest
      an important role of adrenocortical activity in the energy balance of these free
      living rodents in two different contexts: (1) the seasonal regulation of
      physiological state, including body mass, energy reserves, and reproductive
      function, and (2) an acute response to stimulatory events, encompassing
      physiological stress, as represented here by capture and handling.

PMID- 10642442
TI  - Rainbow trout androgen receptor-alpha fails to distinguish between any of the
      natural androgens tested in transactivation assay, not just 11-ketotestosterone
      and testosterone.
AB  - We have recently isolated two androgen receptor cDNA clones from the rainbow
      trout testis. To investigate the functions of the rainbow trout androgen receptor
      alpha (rtAR-alpha), we investigated the ligand binding ability and
      transcriptional activity of rtAR-alpha. Interestingly, in ligand-competition
      experiments, testosterone (T) (IC(50) 3 x 10(-9) M) competed with
      [(3)H]mibolerone binding for rtAR-alpha slightly more potently than the teleost
      fish-specific natural androgen 11-ketotestosterone (11KT) (IC(50) 8 x 10(-9) M),
      which is thought to be the functional spermatogenesis inducer. In contrast, T
      (EC(50) 5 x 10(-9) M) and 11KT (EC(50) 6 x 10(-9) M) showed similar efficiency
      upon cotransfection into EPC cells with a rtAR-alpha expression vector and an
      androgen-responsive element-based reporter gene. These results indicated that
      activation of rtAR-alpha does not distinguish between 11KT and T and suggested
      that a specific system, which is mediated only by 11KT, may exist in the rainbow
      trout.

PMID- 10642444
TI  - Concentrations of progesterone in milk from bottlenose dolphins during different
      reproductive states.
AB  - There are few published reports of an alternative, less invasive method than
      blood sampling to obtain reproductive hormone concentrations from captive
      dolphins. The aims of this study were to: (1) validate milk as an effective
      alternative to blood plasma for determining progesterone concentrations; and (2)
      utilize milk samples collected frequently to obtain progesterone concentration
      profiles and determine reproductive status. During the course of this study 16
      plasma/milk sample pairs were collected from four adult bottlenose dolphins to
      correlate plasma and milk concentrations of progesterone. Milk samples were also
      collected approximately weekly for 4-5 months during three independent
      lactational periods. Additionally, milk samples were collected daily for
      approximately 1 year during three other independent lactational periods. A highly
      significant correlation was found between progesterone concentrations in plasma
      and milk (r(2) = 0.91, P < 0. 01). Progesterone contained in milk whey, fat, and
      solids were 3.95 +/- 1.3, 8.5 +/- 1.1, and 52.0 +/- 0.6%, respectively.
      Progesterone profiles from milk samples collected from two dolphins during 1995
      indicated pregnancies (with progesterone concentrations between 8 and 46.5 ng/ml)
      which resulted in parturition. High progesterone concentrations in a third
      dolphin that did not give birth indicated a possible pseudopregnancy or fetal
      resorption. A possible ovulation not resulting in pregnancy was evident in one
      female in 1998, follicular activity in another female in 1998, and a year-long
      anestrous period in the third animal studied in 1998. It is confirmed that
      dolphins can become pregnant while lactating and that the approximate time of
      conception is identifiable in milk profiles, illustrating the potential
      application of this method in pregnancy detection and reproductive monitoring.

PMID- 10642443
TI  - Effect of restricted food intake on production, catabolism, and effects of IGF-I
      and cyclic nucleotides in cultured ovarian tissue of domestic nutria (Myocastor
      coypus).
AB  - The aims of these in vitro experiments were to examine the effects of short-term
      food restriction on ovarian secretory activity and the role of IGF-I and cAMP-
      and cGMP-dependent intracellular mechanisms in the control of ovarian function in
      domestic nutria. Slices of ovary from sexually mature animals kept under
      conditions of normal and restricted ((1/2) of standard ration) feeding were
      cultured with or without IGF-I (50 ng/ml), cAMP analogues (dbcAMP and Rp-cAMPS),
      and cGMP analogues (8-pCPT-cGMP and Rp-8-Br-PET-cGMPS; all at 100 nM). In
      nonovarian cells dbcAMP activates and Rp-cAMPS inhibits protein kinase A, while 8
      p-CPT-cGMP activates and RP-8-Br-PET-cGMPS inhibits protein kinase G and cGMP
      gated ion channels. IGF-I release and catabolism, as well as the release of
      progesterone (P), estradiol (E), and cAMP by the cultures, were evaluated using
      RIA. IGF-I did not affect cAMP release, while each of the cAMP and cGMP analogues
      inhibited IGF-I release in both control and experimental groups. Fasting did not
      affect cAMP or IGF-I release. It partially prevented the effect of Rp-cAMPS, but
      not of other cyclic nucleotides, on IGF-I release and inhibited IGF-I catabolism.
      The Rp-cAMPS and Rp-8-Br-PET-cGMPS also inhibited IGF-I catabolism and the
      effects were greater with tissue from food-restricted than control animals.
      Ovaries from the underfed nutria secreted significantly more P and less E than
      those from normally fed animals. IGF-I and both cAMP analogues, given alone, did
      not affect P release whereas a combination of IGF-I and Rp-cAMPS increased P
      output in control, but not in the experimental group. The 8-pCPT-cGMP had no
      effect P release. Rp-8-Br-PET-cGMPS, given alone or in combination with IGF-I,
      dramatically increased P secretion by tissue from control but not underfed
      animals. Estradiol secretion by tissue from underfed animals was stimulated by
      IGF-I, dbcAMP, Rp-cAMPS, 8-pCPT-cGMP, and Rp-8-Br-PET-cGMPS as well as by
      combinations of IGF-I and Rp-cAMPS or Rp-8-Br-PET-cGMPS; these effects were not
      seen with control tissue. The results demonstrate that: (1) ovaries of domestic
      nutria secrete IGF-I, P, E, and cAMP; (2) cAMP and cGMP can influence IGF-I
      release and catabolism; (3) the cyclic nucleotides may have an IGF-I-mediated
      effect on P and E output; (4) IGF-I and cyclic nucleotides can prevent the effect
      of undernutrition on E, but not on P release; (5) effects of cAMP and cGMP on P
      and E are probably not mediated by protein kinase A, protein kinase G, or cGMP
      gated ion channels; and (6) food restriction can influence ovarian IGF-I
      catabolism, P, and E release and modulate the effects of cyclic nucleotides and
      IGF-I on steroidogenesis. It is concluded that ovarian secretory activity may be
      regulated separately by nutrition and the cyclic nucleotide-IGF-I system, and
      there may be functional interrelationships between these mechanisms.

PMID- 10642445
TI  - Evidence that acute stress inhibits ovarian steroidogenesis in rainbow trout in
      vivo, through the action of cortisol.
AB  - Sexually mature (preovulatory) rainbow trout exposed to confinement stress showed
      a transitory increase in plasma cortisol levels that was accompanied by a
      similarly brief depression in plasma testosterone (T) levels. Plasma levels of
      maturational gonadotropin (GtH) and 17beta-estradiol (E(2)) were unaffected by
      stress. A similar pattern was displayed by fish exposed to stress in
      midvitellogenesis. Treatment of vitellogenic fish with exogenous cortisol
      resulted in significant increases in plasma cortisol at 1 and 3 h postinjection
      (p.i.). This was associated with significant depression of plasma T levels at 1
      and 3 h p.i. and plasma E(2) levels at 3 and 6 h p.i. Plasma levels of GtH were
      unaffected by treatment with cortisol. Treatment of fish at an earlier stage of
      vitellogenesis with two different doses of cortisol resulted in very high
      elevations of plasma cortisol, but no effect on plasma levels of E(2) or GtH. In
      contrast, plasma T levels showed a stepwise decline over time. These results
      suggest that the inhibitory effects of stress on reproduction are mediated by
      cortisol and that the effect does not involve inhibition of GtH secretion and
      possibly acts at the level of GtH signal-transduction.

PMID- 10642446
TI  - Metamorphosis in the summer flounder, Paralichthys dentatus: thyroidal status
      influences gill mitochondria-rich cells.
AB  - Metamorphosis in the summer flounder (Paralichthys dentatus) is mediated by
      thyroid hormones (TH) and is accompanied by changes in gill mitochondria-rich
      cells (MRCs) and in salinity tolerance. Altered thyroid status during larval
      development and metamorphosis in this species influences salinity tolerance,
      though the influence of any hormone on MRCs of larval marine teleosts is not
      known. This study characterized the effect of altered thyroid status on MRC
      intracellular membranes, mitochondria size and ultrastructure, immunoreactive
      (ir)-Na(+),K(+)-ATPase, and cell size and density during metamorphosis in summer
      flounder. Inhibition of metamorphosis with thiourea (30 ppm) (TU, an inhibitor of
      TH synthesis) inhibited changes in MRCs, producing large "larval" type MRCs with
      weak reactivity to osmium; large, electron-lucent mitochondria; and weak ir
      Na(+),K(+)-ATPase. Replacement of TH with TU + thyroxine-Na salt (100 ppb)
      rescued the fish from developmental inhibition, producing smaller "juvenile" type
      MRCs with strong reactivity to osmium; smaller, electron-opaque mitochondria; and
      strong ir-Na(+), K(+)-ATPase. The findings suggest that TH are necessary for MRCs
      to change from larval to juvenile form during metamorphosis.

PMID- 10642447
TI  - Isolation, cDNA cloning, and growth promoting activity of rabbitfish (Siganus
      guttatus) growth hormone.
AB  - We report the isolation, cDNA cloning, and growth promoting activity of
      rabbitfish (Siganus guttatus; Teleostei; Perciformes; Siganidae) growth hormone
      (GH). Rabbitfish GH was extracted from pituitary glands under alkaline
      conditions, fractionated by gel filtration chromatography on Sephadex G-100, and
      purified by high-performance liquid chromatography. The fractions containing GH
      were identified by immunoblotting with bonito GH antiserum. Under nonreducing
      conditions, the molecular weight of rabbitfish GH is about 19 kDa as estimated by
      SDS-PAGE. The purified hormone was potent in promoting growth in rabbitfish fry.
      Weekly intraperitoneal injections of the hormone significantly accelerated
      growth. This was evident 3 weeks after the start of the treatment, and its effect
      was still significant 2 weeks after the treatment was terminated. Rabbitfish GH
      cDNA was cloned to determine its nucleotide sequence. Excluding the poly (A)
      tail, rabbitfish GH cDNA is 860 base pairs (bp) long. It contained untranslated
      regions of 94 and 175 bp in the 5' and 3' ends, respectively. It has an open
      reading frame of 588 bp coding for a signal peptide of 18 amino acids and a
      mature protein of 178 amino acid residues. Rabbitfish GH has 4 cysteine residues.
      On the amino acid level, rabbitfish GH shows high identity (71-74%) with GHs of
      other perciforms, such as tuna, sea bass, yellow tail, bonito, and tilapia, and
      less (47-49%) identity with salmonid and carp GHs.

PMID- 10642448
TI  - Evidence for an involvement of vitellogenin in the steroidogenic activity of
      rainbow trout (Oncorhynchus mykiss) vitellogenic oocytes.
AB  - In vivo and in vitro the concentration of vitellogenin (VTG) inside the oocyte
      can alter VTG production by the liver, modulating the synthesis of 17beta
      estradiol (E(2)) by the ovary. To gain a greater insight into this mechanism, the
      in vitro production of free and conjugated testosterone (T), E(2), and
      androstenedione (A) by rainbow trout oocytes from the early and middle
      vitellogenic stage was measured by radioimmunoassay. There was a decreased E(2)
      production that was greater in September (40%) than October (30%), by the oocytes
      incubated with the vitellogenic fraction. The production of E(2) conjugated as
      glucuronide was lower than sulfate (P < 0.05), but similar in control and VTG
      incubated oocytes. Levels of free T increased from September to October, and
      conjugates were both produced at low levels, and no differences were detected
      between control and incubated VTG oocytes. The decreased synthesis of E(2) by
      oocytes incubated with VTG was not followed by an increase in the amount of T or
      conjugated E(2), because there were no differences under the two circumstances.
      However, there was a reduced synthesis of A with oocytes producing low levels of
      E(2). These results suggest that the presence of high levels of VTG in the oocyte
      suppresses the synthesis of A and E(2), affecting the activities of the enzymes
      C17,20 lyase and aromatase and probably interfering with the heme protein
      cytochrome P450 which in the ovary catalyses C 17,20 lyase (P450 c17) and
      aromatase (P450 arom).

PMID- 10642449
TI  - Circulating C-21 steroids in relation to reproductive condition of a viviparous
      marine teleost, Sebastes rastrelliger (grass rockfish).
AB  - Plasma concentrations of free, glucuronidated, and sulfated steroids were
      measured in grass rockfish (Sebastes rastrelliger) at identified stages of
      ovarian development and pregnancy using radioimmunoassays validated for the
      detection of individual steroids or compounds with a particular configuration.
      Changes in reproductive status were most clearly reflected in concentrations of
      free C-21 steroids. Previtellogenic, vitellogenic, and postspawn fish exhibited
      uniformly low concentrations of circulating C-21 steroids while pregnant fish
      showed a pronounced and significant increase in a series of free 17,20beta
      dihydroxylated steroids together with 17,20alpha-P. Among individual steroids,
      the compound exhibiting the greatest fluctuation in relation to reproductive
      condition was 17,20beta-P-5beta, which during pregnancy showed a 22-fold increase
      from basal concentrations. Smaller relative increases in association with
      pregnancy were also seen in 17, 20beta-P, 17,20beta,21-P, and 17,20alpha-P (3.5-,
      3.5-, and 5.5-fold increases, respectively). Fish in the final stages of
      pregnancy or which had recently spawned exhibited uniformly low concentrations of
      the C-21 steroids, indicating a drop in circulating amounts of these compounds
      around the time of parturition. The hormone profiles established during the
      annual reproductive cycle of the grass rockfish suggest that C-21 steroids may
      contribute to the endocrine mechanisms which regulate viviparity in this highly
      fecund marine teleost. The C-21 steroids characterized in this study may provide
      appropriate reference compounds in the future evaluation of this concept.

PMID- 10642450
TI  - Sexual dimorphism in numbers of vasotocin-immunoreactive neurons in brain areas
      associated with reproductive behaviors in the roughskin newt.
AB  - Vasotocin (VT) and vasopressin control many endocrine and neuroendocrine
      functions, including the regulation of reproductive behaviors. In the roughskin
      newt (Taricha granulosa), VT administration can enhance courtship behaviors in
      males and egg-laying behaviors in females. This study used immunohistochemistry
      to investigate whether there are sex differences in VT in specific brain areas,
      and whether these differences persist in nonbreeding animals. Numbers of VT
      immunoreactive (ir) cell bodies were counted in males and females collected in
      February, April, June, and August. Radioimmunoassay of plasma samples confirmed
      that testosterone and 5alpha-dihydrotestosterone concentrations were higher in
      males than females, and that 17beta-estradiol concentrations were higher in
      females than males. In 11 brain areas, no sexual or seasonal differences in the
      number of VTir cells were found. But in 3 brain regions-the bed nucleus of the
      stria terminalis (BNST), the nucleus amygdalae dorsolateralis (AMYG), and the
      anterior preoptic area (aPOA)-there were significantly greater numbers of VTir
      cells in males than in females, and these differences did not change seasonally.
      In the aPOA, an area important to male sex behaviors, the sexual dimorphism in
      VTir was particularly pronounced. In four brain regions, there were significantly
      greater numbers of VTir cells in females than males, but only in specific
      seasons. In April-collected (breeding) animals, more VTir cells were found in
      females than in males in the populations of VT cells within the pars dorsalis
      hypothalami and ventromedial hypothalamus, brain regions frequently associated
      with stress responses and female mating behaviors. In August-collected
      (nonbreeding) animals, more VTir cells were found in females than in males, in
      the region of the bed nucleus of the decussation of the fasciculus lateralis
      telencephali and in the nucleus visceralis superior, nucleus isthmi region.
      Significantly greater numbers of VTir cells were observed in the magnocellular
      preoptic area of males and females collected in February. These results indicate
      that the functional interactions between gonadal steroid hormones and VT are
      complex and appear to involve site-, sex-, and season-specific regulatory
      mechanisms. Furthermore, it seems likely that populations of VT neurons in the
      BNST, AMYG, and aPOA are involved in regulating male-specific behaviors, and that
      the VT neurons in the pars dorsalis hypothalami/ventromedial hypothalamus may be
      involved in female-specific behaviors.

PMID- 10642451
TI  - Seasonal changes in sex and adrenal steroid hormones of gopher tortoises
      (Gopherus polyphemus).
AB  - We sampled a population of gopher tortoises (Gopherus polyphemus) from May to
      October 1997 to determine seasonal cycles of steroid hormones (testosterone, T;
      17beta-estradiol, E; and progesterone, P) and related them to observations of
      mating behavior. In males, plasma T levels peaked in July and August and remained
      elevated through October. This coincides with the reported time of peak mating
      and spermatogenesis, indicating that males display an associated pattern of
      reproduction. In females, E levels were high in September and October. Plasma T
      levels in females were elevated in May, decreased to basal levels in June and
      July, and rose again in August and September. Elevated E and T levels correspond
      to the reported time of peak vitellogenic activity, indicating that females also
      display an associated cycle. Plasma P in females remained basal throughout the
      active season, suggesting that ovulation occurs in late winter. We also
      determined levels of corticosterone (B) to assess the influence of capture stress
      on tortoises and correlated B levels with tortoise activity patterns and sex
      steroid levels. We found no seasonal variation in levels of B in males or
      females. Plasma B levels were not correlated with levels of T or E, but were
      positively correlated with female P levels. Further, we found no relationship
      between plasma B levels in males and mean distance moved, mean number of burrows
      used, or mean home range size. However, there was a significant negative
      correlation between plasma B levels and male body size. In females, there was no
      relationship between B levels and mean distance moved, but B levels were
      significantly negatively correlated with the number of burrows females occupied.
      Lastly, there was no relationship between levels of B and the number of minutes
      required to obtain blood from an animal. However, B levels increased with the
      length of time that a tortoise spent in a trap, suggesting that trapped tortoises
      do exhibit capture stress.

PMID- 10642453
TI  - Preventive medicine in the year 2000

PMID- 10642454
TI  - Page for patients

PMID- 10642452
TI  - Cloning and characterization of cDNA encoding cdc2 kinase, a component of
      maturation-promoting factor, in Rana dybowskii.
AB  - In order to understand the mechanism of oocyte maturation in seasonal-breeding
      wild frogs, we have cloned and sequenced a cDNA encoding Cdc2 kinase, a component
      of the maturation-promoting factor (MPF) in Rana dybowskii. About 1.2-kb cDNA was
      isolated by reverse transcription coupled to polymerase chain reaction (RT-PCR)
      and cDNA library screening. The cloned Rana Cdc2 cDNA encodes a complete open
      reading frame with 302 amino acid residues, which deduce a 34-kDa protein.
      Homology of more than 80% was found between the deduced amino acid sequence of
      Rana Cdc2 and that of five phylogenetically distant organisms, and 94% identity
      was found between Rana and Xenopus. More importantly, the Thr14, Tyr15, and
      Thr161 residues, the phosphorylation sites for the activation of the enzyme, are
      highly conserved. In vitro-translated Rana Cdc2 cross-reacted with Xenopus
      p34(cdc2) antibody as shown by Western blot. Northern blot analysis showed that a
      1.7-kb transcript was highly expressed in the gonads compared to other tissues,
      indicating the important role of Cdc2 kinase in gonads as a component of MPF. The
      cloned Rana Cdc2 cDNA also exhibited histone H1 kinase activity when expressed in
      CV-1 cells. In the present study, therefore, we have characterized the Rana Cdc2
      kinase in amphibian, which will be helpful in understanding the process of oocyte
      maturation related to the reproduction cycle of wild frogs.

PMID- 10642455
TI  - Historical reflections on current preventive practice.
AB  - BACKGROUND: Preventive care in medicine and public health has evolved through
      historical stages. Recently, developments within the contemporary health care
      environment have pressured primary care physicians to deliver more preventive
      care, but little was known about the actual delivery of such services. The Direct
      Observation of Primary Care study investigated the delivery of preventive
      services. METHODS: In the study's qualitative portion, research nurses observed
      138 family physicians in northeast Ohio, dictating observational fieldnotes.
      After transcription, the fieldnotes were content analyzed to identify patterns
      and themes. Further consideration led to a secondary historical analysis of ideas
      influencing medicine and public health. Fieldnotes were then re-analyzed from a
      historical perspective. RESULTS: The primary analysis showed variations among
      physician's philosophies and styles of practice that influenced the delivery of
      preventive services. The secondary analysis highlighted competing historical
      ideas that have shaped medicine and public health. The authors argue that
      contemporary physician's philosophies and styles of practice have parallels in
      the history of ideas informing medical and public health practice. CONCLUSIONS:
      The implications of these findings, particularly a lost appreciation of ideas
      that continue to be operational in practice, may be important if there is to be
      improvement in the delivery of preventive services.

PMID- 10642456
TI  - Physical exercise and psychological well-being: a population study in Finland.
AB  - BACKGROUND: Regular physical exercise has been characterized as a positive health
      behavior having physiological benefits. It may also yield psychological benefits.
      The purpose of the present study was therefore to explore the association between
      physical exercise frequency and a number of measures of psychological well-being
      in a large population-based sample. METHODS: A total of 3403 participants (1856
      women and 1547 men) of the Finnish cardiovascular risk factor survey, ranging in
      age between 25 and 64, completed questionnaires. Besides answering questions
      concerning their exercise habits and perceived health and fitness, the
      participants also completed the Beck Depression Inventory, the State-Trait Anger
      Scale, the Cynical Distrust Scale, and the Sense of Coherence inventory. RESULTS:
      The results of this cross-sectional study suggest that individuals who exercised
      at least two to three times a week experienced significantly less depression,
      anger, cynical distrust, and stress than those exercising less frequently or not
      at all. Furthermore, regular exercisers perceived their health and fitness to be
      better than less frequent exercisers did. Finally, those who exercised at least
      twice a week reported higher levels of sense of coherence and a stronger feeling
      of social integration than their less frequently exercising counterparts.
      CONCLUSIONS: The results indicate a consistent association between enhanced
      psychological well-being, as measured using a variety of psychological
      inventories, and regular physical exercise.

PMID- 10642457
TI  - The effect of age, sex, and education on food consumption of a middle-aged
      English cohort-EPIC in East Anglia.
AB  - BACKGROUND: Different dietary patterns are associated with differing risks of
      chronic disease. Yet independent relationships between diet and demographic
      variables, such as age, sex, and education, are poorly described. METHODS: The
      first 1968 subjects enrolled to the European Prospective Investigation of Cancer
      (EPIC) cohort from general practices in East Anglia, UK, provided food frequency
      and demographic data. RESULTS: Men ate meat, eggs, milk, and sugary foods more
      frequently, but fruit and vegetables less frequently than women. Older subjects
      ate red meats and saturated bread spreads more frequently but consumed less
      poultry and drank less coffee than younger subjects. Better educated subjects ate
      less meat, more salads, and fewer cakes and sweet foods than those less educated.
      Five clusters representing different dietary patterns were readily identified.
      These were (a) younger well-educated, probably containing many vegetarians; (b)
      "low calorie," two-thirds female; (c) high alcohol, nuts, meat, largely male; (d)
      preferring fruits, vegetables, unsaturated fats, poultry, and fish, 71% female;
      (e) preferring meat, potatoes, sweet foods, saturated fats, less well-educated
      older men. CONCLUSIONS: The reported consumption of many foods varies by age,
      gender, and education. A pattern of eating that is generally considered less
      healthful was particularly seen in older men, placing them at increased risk of
      chronic disease.

PMID- 10642458
TI  - Attendance to cervical cancer screening in family practices in The Netherlands.
AB  - BACKGROUND: The effectiveness of three different organizational approaches to
      cervical cancer screening (community based, family practice based, and a
      combination) was evaluated in nationally representative family practices. METHOD:
      We selected 122 family practices with a computerized sex-age register from a
      database of 1, 251 family practices, representative of all 4,758 family practices
      in The Netherlands. Approximately 40 practices were linked with each approach. We
      measured the attendance, the reasons for nonattendance, and the influence of a
      reminder on the attendance of women invited for cervical screening in September,
      October, and November 1996. The patients were grouped according to age. A cross
      sectional design was used for the study. RESULTS: For younger women, the total
      attendance rate, coverage (percentage of women "protected" against cervical
      cancer), and control rate (percentage of women with medical reasons for
      nonattendance or postponement of the smear) were highest in practices using the
      family practice-based approach (68, 77, and 90%, respectively) and lowest in
      practices with the community-based approach (53, 62, and 68%, respectively). For
      older women, the family practice-based approach and the combination approach were
      associated with attendance rates significantly higher than those for the
      community-based approach (approximately 60, 80, and 80% vs 47, 67, and 70%,
      respectively). A reminder sent by the family physician to women not responding to
      an initial invitation increased the attendance rate by 7 to 11% in both age
      categories, depending on who had sent the first invitation. CONCLUSION: A family
      practice-based cervical screening approach appeared to be the most effective at a
      national level, achieving the highest attendance rate, coverage, and control
      rate.

PMID- 10642459
TI  - Descriptive epidemiology of physical activity in African-American women.
AB  - OBJECTIVES: We assessed walking for exercise and moderate and strenuous physical
      activity in relation to both demographic and health-related characteristics among
      African-American women from various parts of the United States who participate in
      the Black Women's Health Study. METHODS: The data were collected in 1995 by mail
      questionnaire from 64,524 U.S. black women aged 21 to 69 years. The 64,101 women
      who provided data on physical activity are the subjects of the present report.
      RESULTS: The present study revealed low levels of physical activity among the
      African-American women: 57% reported an hour or less per week walking for
      exercise, 18% reported moderate activity, and 61% reported strenuous physical
      activity. Strenuous physical activity increased with education. Higher levels of
      walking for exercise and moderate and strenuous activity were associated with
      higher levels of participation in strenuous exercise in high school. CONCLUSION:
      Physical activity levels are low in African-American women. Based on the findings
      of the present study it may be suggested that educational efforts to increase
      levels of physical activity should start at an early age.

PMID- 10642460
TI  - Evaluation of a workplace brief intervention for excessive alcohol consumption:
      the workscreen project.
AB  - BACKGROUND: The workplace provides a useful setting for early identification and
      intervention with individuals who have unhealthy lifestyles. The objective was to
      evaluate the effects of a workplace-based lifestyle intervention (Workscreen) to
      reduce excessive drinking. METHOD: There were eight Australia Post networks
      randomly allocated to experimental and control conditions, comprising 67
      worksites and 1206 employees. The experimental condition involved a broad
      spectrum lifestyle campaign, incorporating support from management, employee
      awareness of health, and brief interventions for high-risk behaviors, including
      excessive alcohol use. Focus groups identified relevant cultural factors. Changes
      in workplace culture and employee behavior were assessed 10 months after
      baseline. Males and females were analyzed separately. RESULTS: Over half of APOST
      employees participated at each screening point. In the experimental condition 61%
      of employees overall and 58% of those identified as excessive drinkers in Phase 1
      responded to the lifestyle campaign by attending health assessments. Analyses
      focusing on the organization as a whole did not reveal significant reductions in
      excessive alcohol consumption among men or women. However, a significant
      reduction in number of drinks was observed in the experimental condition among
      women for whom completion of baseline and follow-up could be confirmed (P <
      0.001). CONCLUSIONS: The present study indicates that a workplace-based lifestyle
      campaign can assist self-selected employees in reducing their alcohol
      consumption. There was a moderately high level of participation among those
      identified as drinking excessively, which supports our approach of embedding a
      low-intensity alcohol program within the context of a broader health promotion
      campaign.

PMID- 10642461
TI  - Incremental cost-effectiveness of two zidovudine regimens to prevent perinatal
      HIV transmission in the United States.
AB  - BACKGROUND: Recently concluded clinical trials in Thailand have demonstrated that
      a short course of zidovudine therapy administered to human immunodeficiency virus
      infected women during late pregnancy and labor can substantially reduce the
      likelihood of perinatal transmission of HIV. This regimen is both less expensive
      and less effective than the full course of therapy recommended for use in the
      United States by the U.S. Public Health Service (PHS). The objective of the
      current study is to estimate the incremental cost-effectiveness of the full
      course zidovudine regimen in comparison to the short-course regimen that was
      tested in Thailand and to determine conditions under which the PHS-recommended
      regimen produces a net savings in societal resource utilization, relative to the
      shorter regimen. METHODS: We used standard methods of incremental cost
      effectiveness analysis and derived cost and effectiveness estimates from
      published studies. The main outcome measure is the incremental cost-effectiveness
      ratio, which is the additional cost per additional case of perinatal HIV
      infection averted by the full course of therapy. RESULTS: Full-course zidovudine
      therapy costs an additional $21,337 per additional case of HIV infection averted,
      relative to the shorter regimen; this is much less than the cost of treating a
      case of pediatric HIV infection. CONCLUSIONS: Economic and clinical findings both
      favor full-course zidovudine therapy over short-course therapy to prevent
      perinatal transmission of HIV in the United States.

PMID- 10642462
TI  - Leisure-time physical activity in school environments: an observational study
      using SOPLAY.
AB  - BACKGROUND: Schools provide settings for physical activity (PA), but objective
      tools for measuring PA are lacking. We assessed an instrument to directly observe
      group PA and measured the leisure-time PA of adolescents throughout the school
      day. METHODS: Leisure-time PA was studied by direct observation in 24 middle
      schools in Southern California using SOPLAY (System for Observing Play and
      Leisure Activity in Youth). SOPLAY uses momentary time sampling to record the
      activity of each individual as sedentary, walking, or very active. RESULTS: The
      largest proportion of students visited activity areas at lunch time (19.5%),
      followed by before (4. 1%) and after school (2.1%). More boys than girls visited
      activity areas before school (33.4 vs 7.7) and at lunch time (148.8 vs 36.7).
      Boys in areas engaged in more moderate to vigorous PA than girls before school
      (59.6 vs 40%) and at lunch time (67.7 vs 51.7%). CONCLUSIONS: Few students use
      opportunities to be physically active during lesiure time at school. Policies and
      environmental manipulations (e.g., supervision, equipment, structured programs)
      are needed to attract more adolescents, especially girls, to existing activity
      areas. The feasibility of SOPLAY for measuring group PA was established.

PMID- 10642463
TI  - The validity of self-reported prostrate cancer screening history.

PMID- 10642464
TI  - Reply

PMID- 10642465
TI  - Why a journal of hand surgery?

PMID- 10642466
TI  - Why a journal of hand Surgery? II

PMID- 10642467
TI  - History of the journal of hand surgery: 1976-1999
AB  - This paper is a brief history of The Journal of Hand Surgery from its founding in
      July 1976 through the third issue published in July 1999. An analysis of the
      3,713 scientific articles published is done relative to type, content, and
      country of origin. The persons responsible for the journal are named and other
      features of the Journal are discussed. (J Hand Surg 2000; 25A:5-13. Copyright
      2000 by the American Society for Surgery of the Hand.).

PMID- 10642468
TI  - Classic papers in hand surgery.
AB  - Throughout the development of hand surgery as a specialty thousands of papers
      have been published. This paper identifies the classic papers in 13 categories
      covering the field of hand surgery. To be named a classic paper, it must meet
      three criteria: (1) it must establish or refine a technique or concept; (2) the
      technique must survive the passage of time; and (3) it must change the course of
      treatment. (J Hand Surg 2000; 25A:14-18.

PMID- 10642469
TI  - Outcome following nonoperative treatment of displaced distal radius fractures in
      low-demand patients older than 60 years.
AB  - Twenty-five sedentary, low-demand patients older than 60 years were
      retrospectively evaluated for function and radiographic results following
      nonoperative treatment of displaced distal radius fractures. The mean age was 72
      years and the average follow-up period was 34 months. All patients had
      radiographic and functional evaluations. The radiographic assessment included a
      scoring system based on measurements of the final dorsal angle, loss of radial
      length, and the final radial inclination. The development of radiocarpal and
      distal radioulnar joint arthrosis was also investigated. The functional
      assessment included subjective and objective criteria. Overall satisfaction,
      ability to return to previous activity level or occupation, concern over wrist
      appearance, and a functional task questionnaire were part of the subjective
      assessment. Objective assessment included neuromuscular evaluation and
      measurements of range of motion and grip strength. The final radiographic scores
      revealed that 6 patients (24%) had excellent results, 11 (44%) had good results,
      2 (8%) had fair results, and 6 (24%) had poor results. Six of 10 patients with
      intra-articular fractures developed progressive wrist arthrosis. Two of 6
      patients with radiographic arthrosis had unsatisfactory functional outcome. Five
      of 8 patients with intra-articular fractures that healed with a residual stepoff
      >/=2 mm had satisfactory functional outcome; 3 of these 8 patients had
      unsatisfactory functional outcome. The functional assessment revealed that 22
      patients (88%) had excellent or good results and 3 (12%) had fair or poor
      results. The radiographic outcome did not correlate with the functional outcome.
      Twenty-three of 25 patients (92%) were satisfied with the overall outcome of the
      treatment and 22 (88%) were able to return to their previous activity level or
      occupation. Despite an obvious clinical deformity in over half of the patients,
      none were unhappy with the clinical appearance of the wrist. According to the
      functional task questionnaire, jar opening was by far the most difficult task to
      perform after fracture healing. Functional outcome was satisfactory in most
      cases; a high level of personal satisfaction and return to previous activity
      level was observed, regardless of the radiographic result. Nonoperative treatment
      of distal radius fractures yields satisfactory outcome, especially in those with
      low functional demands. It also is indicated in poor operative candidates. (J
      Hand Surg 2000; 25A:19-28.

PMID- 10642470
TI  - Comparison of three different plating techniques for the dorsum of the distal
      radius: a biomechanical study.
AB  - Three different plating techniques were used on experimentally produced dorsally
      displaced distal radius fractures in cadavers and were tested in 4-point bending:
      a AO 3.5-mm T plate (group 1), two 2. 0-mm titanium plates 60 degrees to each
      other (group 2), and the AO pi plate (group 3). A metaphyseal defect was
      simulated by a dorsally open wedge osteotomy. The tests show that the 2-mm double
      plating technique has superior stiffness and statistically equivalent bending and
      bone gap to failure compared with the AO 3.5-mm T plate or the pi plate when
      applied to the unstable distal radius fracture model. (J Hand Surg 2000; 25A:29
      33.

PMID- 10642471
TI  - Experimental carpal reverse-flow pedicle vascularized bone grafts. Part I: the
      anatomical basis of vascularized pedicle bone grafts based on the canine distal
      radius and ulna.
AB  - We investigated the detailed extraosseous and intraosseous vascular anatomy of
      the distal radius and ulna in 55 pairs of canine forelimbs. Ten specimens were
      used for compartment identification. One hundred specimens were investigated
      after intra-arterial injection with red latex or Batson's compound. The
      extraosseous vascular network, including the nutrient artery location, was
      studied by delicate dissection and soft tissue digestion. Two superficial and 4
      deep arteries were found on the dorsal aspect, with constant relationships to the
      retinaculum. On the palmar aspect, bony nutrient vessels rose from the branches
      of the radial artery (descriptive anatomy). The vascular supply of the canine
      distal forelimb was very consistent and enabled the design of 5 vascularized
      pedicle bone grafts similar to those described in humans (applied anatomy). These
      reverse-flow pedicle grafts may be placed in the carpus, allowing the canine
      forelimb to serve as an experimental model for the study of vascularized carpal
      bone grafting. (J Hand Surg 2000; 25A:34-45.

PMID- 10642472
TI  - Experimental carpal reverse-flow pedicle vascularized bone grafts. Part II: bone
      blood flow measurement by radioactive-labeled microspheres in a canine model.
AB  - Reverse-flow pedicle vascularized bone grafts (VBGs) from the radius, commonly
      used for carpal nonunion and avascular necrosis, provide superior clinical
      results. In this experimental study bone blood flow in canine distal radius VBGs
      was measured to determine the status of the bone circulation immediately after
      elevation (group 1) and 2 weeks later (group 2). Immediate VBG flow (group 1) was
      substantial, but significantly less than the contralateral undisturbed distal
      radius (8.42 mL/min/100 g and 16.53 mL/min/100 g, respectively). At 2 weeks after
      surgery (group 2) VBG flow was compared with nonvascularized control grafts.
      Vascularized bone graft flow was significantly higher than group 1 (mean, 33.72
      mL/min/100 g). Minimal flow was seen in the conventional graft control (0.62
      mL/min/100 g). This study demonstrates that reverse-flow pedicle radius VBG
      maintain enhanced bone circulation long-term. Given the similarity of human and
      canine distal radius vascular anatomy, these data support the clinical use of
      reverse-flow VBG for carpal pathology. (J Hand Surg 2000; 25A:46-54.

PMID- 10642473
TI  - Comparison of ulnar shortening osteotomy and the wafer resection procedure as
      treatment for ulnar impaction syndrome.
AB  - A retrospective review was performed that compared the results of 2 different
      surgical treatments for ulnar impaction syndrome in 22 patients over a 6-year
      period. Ulnar shortening osteotomy and wafer distal ulna resection (wafer
      resection procedure) were each performed in 11 patients based on the preference
      of 3 individual hand surgeons. All patients presented with ulnar wrist pain and
      positive ulnar variance on either neutral rotation or pronated-grip x-rays and
      each failed conservative management. At a minimum follow-up time of 18 months, 9
      patients had good to excellent results following ulnar shortening osteotomy
      compared with 8 following the wafer resection procedure. This difference was not
      statistically significant. All patients regained functional wrist motion and 21
      of the 22 patients had satisfactory pain relief. There was 1 poor result in the
      wafer group that required revision to complete resection of the distal ulna. Five
      secondary procedures were required in the osteotomy group to remove painful
      hardware and union was delayed in 2 patients. Although ulnar shortening osteotomy
      provides effective treatment for ulnar impaction syndrome, the wafer resection
      procedure provides favorable pain relief and restoration of function but without
      the potential for nonunion or hardware removal. (J Hand Surg 2000; 25A:55-60.

PMID- 10642474
TI  - Thumb trapeziometacarpal joint arthritis: partial trapeziectomy with ligament
      reconstruction and interposition costochondral allograft.
AB  - Qualitative and quantitative outcomes were assessed clinically and
      radiographically in 41 patients (46 thumbs) with thumb basal joint arthritis
      limited to the trapeziometacarpal joint treated with hemiresection arthroplasty
      of the trapezium, flexor carpi radialis ligament reconstruction, and allograft
      costochondral interposition graft. Results of the validated Disability of Arm,
      Shoulder, and Hand questionnaire at a mean follow-up time of 42 months (range, 24
      48 months) revealed that 90% of the patients had a high level of function with
      minimal symptoms. Important improvements in web space with increased palmar and
      radial abduction and grip and pinch strength measurements were observed. The
      trapeziometacarpal space had decreased 21% after surgery while trapeziometacarpal
      subluxation was 16% compared with 21% before surgery. There was an inverse
      correlation between the loss of trapezial height and subluxation and clinical
      outcome. The results of this study demonstrate that although the preoperative
      trapezial height was not maintained, the reconstructed thumbs remained stable,
      with little subluxation and improved clinical outcomes. (J Hand Surg 2000; 25A:61
      76.

PMID- 10642475
TI  - Treatment of ununited fracture of the hook of hamate by low-intensity pulsed
      ultrasound: a case report.
AB  - A patient presented 4 months after sustaining a fracture of the hook of hamate. X
      rays and computed tomography scanning of the carpal tunnel confirmed the presence
      of an ununited fracture. Low-intensity ultrasound was applied to the fracture
      site. After 4.5 months of exposure to ultrasound, union was confirmed by both x
      rays and computed tomography scanning of the carpal tunnel. (J Hand Surg 2000;
      25A:77-79.

PMID- 10642476
TI  - Factors influencing use of digital prostheses in workers' compensation
      recipients.
AB  - The purposes of this study were to retrospectively identify factors associated
      with decreased use of digital prostheses in workers' compensation recipients 6
      months after fitting and to identify characteristics of those individuals who
      requested and received a second set of prostheses after demonstrating consistent
      use of the first set. One hundred seventy-eight patients fitted with 281 digital
      prostheses completed a questionnaire 6 months after fitting. Forty-nine patients
      (28%) stated they never or occasionally used their prosthesis (low utilization)
      and 42 (24%) stated they used them more than 4 hours per day (high utilization).
      One hundred ten patients (62%) reported stump problems; 37 (21%) stated that the
      problem interfered with the use of the prosthesis. High utilization was
      associated with nonmanual employment after the injury. Low utilization was
      associated with male gender, stump problems, and a distal amputation level. Ring
      finger prostheses were least likely to be used; small finger prostheses, most
      likely. The country of origin of the patient was not associated with frequency of
      use. One hundred sixty-one patients had received the prostheses at least 3 years
      before the end of the study; 45% of these patients had requested and received a
      second set of prostheses. Women were more likely to request and receive a second
      set than men. We could not accurately predict future use of digital prostheses.
      Each case must be evaluated on an individual basis. (J Hand Surg 2000; 25A:80-85.

PMID- 10642477
TI  - Osseointegrated finger prosthesis: An alternative method for finger
      reconstruction.
AB  - Three patients had traumatic amputation of the index and middle fingers at the
      base of the proximal phalanx. A 2-stage reconstruction procedure with
      osseointegrated titanium implants was performed in each patient to fix a finger
      prosthesis to the proximal phalanx. The first stage included implantation of the
      titanium fixture into the medullary canal of the proximal phalanx. After a 3
      month rest period to allow the fixture to firmly osseointegrate with the proximal
      phalanx, a skin-penetrating abutment was placed on top of the fixture, to which
      the prosthesis was firmly attached. The follow-up period ranged from 16 to 24
      months. There were minimal skin problems. Some tactile sensibility, better motor
      function, and good cosmetic results were achieved. (J Hand Surg 2000; 25A:86-92.

PMID- 10642479
TI  - Identification of myelinated motor and sensory axons in a regenerating mixed
      nerve.
AB  - The common peroneal nerves of Wistar rats were transected and repaired to compare
      the sequential changes in the numbers of regenerating motor and sensory
      myelinated axons in a single mixed nerve. At sequential intervals (2, 4, and 12
      weeks) after nerve repair, 3 kinds of staining were performed: cholinesterase
      staining (Karnovsky's staining) for motor axons, carbonic anhydrase staining for
      sensory axons, and antineurofilament immunohistochemical staining for all axons.
      At 2 weeks there was a large number of carbonic anhydrase-positive axons (600 +/-
      98; mean +/- SD) and cholinesterase-positive axons were occasionally seen.
      Subsequently, there was a striking increase of cholinesterase-positive myelinated
      axons, reaching to 302 +/- 50 at 12 weeks. The results suggest that the
      myelinated sensory axons regenerate faster in the early stage of nerve
      regeneration and that regeneration of the myelinated motor axons is prominent in
      the subsequent stage. (J Hand Surg 2000; 25A:104-111.

PMID- 10642478
TI  - The effect of wrapping scarred nerves with autogenous vein graft to treat
      recurrent chronic nerve compression.
AB  - The purpose of this study was to determine the efficacy of vein wrapping of
      scarred nerves in a chronic nerve compression model in rats. The ultimate goal
      was to provide experimental evidence for application of the technique of vein
      wrapping of nerves for the treatment of recurrent compressive neuropathy. The
      chronic nerve compression model was created in 100 rats. After 8 months the
      nerves were decompressed. In 50 rats the nerves were wrapped with an opened
      femoral vein graft; the remaining 50 animals served as controls. The sciatic
      nerves of both groups were evaluated at 4, 8, 12, 24, and 48 weeks after surgery.
      Functionally, the sciatic nerves in the vein-wrapped group showed greater
      improvement than those in the non-vein-wrapped group. For electrophysiologic
      testing the latency was significantly shorter in the vein-wrapped group.
      Histologic evaluation showed marked nerve degeneration and scar tissue formation
      around the nerves in the non-vein-wrapped group but not in the vein-wrapped
      group. The results indicate that the vein graft could improve the recovery of
      nerve function by protecting the nerve from surrounding scar and is an effective
      and feasible technique for the surgical treatment of recurrent compressive
      neuropathy. (J Hand Surg 2000; 25A:93-103.

PMID- 10642480
TI  - Changes in digital flexor tendon mechanics after endoscopic and open carpal
      tunnel releases in cadaver wrists.
AB  - Digital flexor tendon excursion due to isolated wrist motion was measured in 5
      cadaver wrists. Five sequential experimental conditions were tested: (1) intact
      wrists, (2) after single-incision endoscopic carpal tunnel release, (3) after
      addition of a distal endoscopic portal, (4) after conversion to an open palm
      incision, and (5) after suturing of the palm incision. Combined tendon excursion
      increased 27.8% after 1-incision and 29.7% after 2-incision endoscopic release;
      both increases were significant. A further increase in combined excursion to
      43.4% over the value in intact wrists was measured after conversion to an open
      palm incision. Combined flexor tendon excursion after open release was
      significantly greater than excursion after either type of endoscopic release.
      Increases in excursion were also significant when flexor digitorum superficialis
      and flexor digitorum profundus tendons were considered separately. Excursion did
      not change significantly after skin suturing. These findings suggest that digital
      flexor tendon mechanics are closer to normal after endoscopic carpal tunnel
      release than after open release. It remains to be shown whether the difference is
      an advantage of endoscopic release over open release in the clinical setting. (J
      Hand Surg 2000; 25A:112-119.

PMID- 10642481
TI  - A systematic review of the clinical diagnostic tests for carpal tunnel syndrome.
AB  - The purpose of this report was to critically review studies of the clinical
      diagnostic tests for carpal tunnel syndrome. The reports were located through
      Medline, Current Contents, related readings, and the reference lists of the
      articles. They all explored the use of clinical diagnostic tests for carpal
      tunnel syndrome compared with the results of NCS. Criteria for systematically
      reviewing the studies were developed, tested for reliability, and applied to the
      studies. Many studies did not have sufficient detail to allow repetition of the
      protocol by other researchers. The sensitivities and specificities reported for
      each can be compared with the quality criteria ratings they each received. The
      literature supports the use of the wrist flexion and carpal compression test and
      suggests that 2-point discrimination has low sensitivity for diagnosing carpal
      tunnel syndrome. Many reports do not include methodology, which makes the results
      difficult to reproduce and to apply to other populations. (J Hand Surg 2000;
      25A:120-127.

PMID- 10642482
TI  - Innervation of the metacarpophalangeal and interphalangeal joints: a
      microanatomic and histologic study of the nerve endings.
AB  - Six pairs of fresh human cadaver hands were dissected under the surgical
      microscope at x28 to x32 and selectively silver stained. In addition, 18 proximal
      interphalangeal and metacarpophalangeal joints of fresh cadaver hands were
      processed with protein gene product 9.5 for measurement and analysis of nerve
      endings in those joints. The results demonstrated that the proximal
      interphalangeal joints are innervated by 2 palmar articular nerves (mean
      diameter, 0.21-0.53 mm). Each metacarpophalangeal joint of the second through
      fifth fingers is predominantly supplied by 1 palmar articular nerve (mean
      diameter, 0.41-0.59 mm), which comes from the deep branches of the ulnar nerve,
      as well as by 2 dorsal articular nerves (mean diameter, 0.11-0.24 mm). The
      metacarpophalangeal joint of the thumb also had 2 dorsal articular nerves (mean
      diameter, 0.18-0.24 mm) and 2 palmar joint nerves (mean diameter, 0.29-0.31 mm).
      The mean densities of the type IV free nerve endings and the mean numbers of the
      encapsulated endings in the palmar capsules were consistently much greater than
      in the dorsal or lateral capsules. The majority of encapsulated endings were
      pacinian corpuscles. The anatomic and histologic information may help the surgeon
      avoid damaging these small joint nerves during operative procedures and to
      reconstruct or de-innervate them if necessary. (J Hand Surg 2000; 25A:128-133.

PMID- 10642483
TI  - Multiple constrictions of the radial nerve without external compression.
AB  - We report a patient with multiple constrictions within the main trunk of the
      radial nerve that was found after epineurectomy and speculate that the etiology
      is an inflammatory response. (J Hand Surg 2000; 25A:134-137.

PMID- 10642484
TI  - Effect of muscle tension during tendon transfer on sarcomerogenesis in a rabbit
      model.
AB  - Sarcomere number change was investigated in an animal model of tendon transfer.
      In 9 adult New Zealand white rabbits, the flexor digitorum longus muscle was cut
      distally and transferred and woven into the tibialis anterior tendon. Ankles were
      then immobilized for 3 weeks in 75 degrees flexion. Transferred flexor digitorum
      longus muscles were harvested and complete architectural analysis was performed.
      Sarcomere lengths were measured using laser diffraction. Serial sarcomere number
      in transferred flexor digitorum longus fibers was a strong function of the
      sarcomere length at the time of transfer. A highly significant negative
      correlation between these 2 parameters was approximated by a linear relationship.
      Based on this finding, we conclude that serial sarcomere number is significantly
      affected by the degree of stretch during the transfer itself. This could easily
      compromise the purpose of surgical tendon transfer by reducing the procedure to
      little more than a tenodesis. (J Hand Surg 2000; 25A:138-143.

PMID- 10642485
TI  - Protection of the deltoid to triceps tendon transfer repair sites.
AB  - The posterior deltoid muscle was used to replace lost elbow extension in 11
      patients with C5 or C6 level tetraplegia. During surgery stainless steel sutures
      were inserted into the donor muscle, graft, and tendon insertion sites. Over the
      succeeding time periods (1 month to 2 years) the distances between the various
      markers were measured. Significant tendon elongation of 23.1 +/- 4.8 mm (mean +/-
      SEM; n = 6) was observed in patients receiving traditional postoperative care. To
      reduce the tendon elongation observed, a specially designed armrest was developed
      and applied the first postoperative day. The armrest was designed to maintain the
      elbow in 20 degrees flexion and to prevent shoulder adduction. The addition of
      this armrest to the traditional postoperative protocol resulted in a dramatic
      decrease of tendon elongation to only 8.4 +/- 3.0 mm (n = 5). Elongation occurred
      within the first 6 postoperative weeks in the armrest group; in the nonprotected
      group, elongation continued for several additional months. The majority of the
      elongation in both groups occurred in the proximal portion of the tendon-graft
      tendon unit. Although this study did not explicitly measure strength, we conclude
      that preventing excessive muscle length change is required to protect repair
      sites in posterior deltoid to triceps transfer. (J Hand Surg 2000; 25A:144-149.

PMID- 10642486
TI  - Basement membrane chondroitin sulfate proteoglycan and vascularization of the
      developing mammalian limb bud.
AB  - We used immunocytochemistry to study the basement membrane-chondroitin sulfate
      proteoglycan (BM-CSPG) distribution in mammalian limb bud and its relationship to
      and possible role in limb development. Anti-BM-CSPG immunostaining was examined
      in the developing limb buds of 24 Sprague-Dawley rats at embryonic days 12 to 14
      and 19. BM-CSPG immunostaining was present in 3 regions. The first region was
      located peripherally in the limb bud ectodermal basement membrane (BM) that
      separates ectoderm from mesoderm and was present at all embryonic stages
      examined. The second region was in the mesenchymal extracellular matrix
      independent of the vascular system. This staining pattern was diffuse, granular,
      and often homogeneous, except for clustering adjacent to developing vessels, and
      was observed distally in the limb bud. In the mesenchymal extracellular matrix
      adjacent to the distal BM this staining pattern formed fibrils that were
      perpendicular and connected to the limb bud BM and extended into the underlying
      mesenchyme. The third region was localized to the BM of developing blood vessels
      of the limb bud. Blood vessel staining allowed analysis of limb bud vessel
      formation. The early developing blood vessels at the proximal limb bud were
      organized differently from those located distally. Large central vessels were
      present proximally, whereas a rich plexus of smaller vascular channels was
      present at the distal margin. A subectodermal avascular zone was observed at the
      margin of the limb bud, except beneath the apical ectodermal ridge where
      immunostained blood vessels extended from the distal vascular plexus toward the
      apical ectodermal ridge. The formation of central larger vessels occurs
      proximally, whereas formation of peripheral smaller vessels seems to take place
      locally and distally under the influence of the apical ectodermal ridge. BM-CSPG
      plays an important role in blood vessel formation and mammalian limb bud
      development. (J Hand Surg 2000; 25A:150-158.

PMID- 10642487
TI  - Hyperbaric oxygen: a means of decreasing ischemic epiphyseal damage in a
      pediatric rabbit model.
AB  - The effect of hyperbaric oxygen on epiphyseal ischemia was evaluated using a
      pediatric rabbit model. Forty-five animals were compared in this study: 23 from a
      control pilot study and 22 hyperbaric exposed animals. In each animal the right
      distal femoral and proximal tibial epiphyses were isolated on a popliteal
      vascular pedicle. The left leg acted as the control. The growth difference
      between the rabbit's hindlimbs was the means of comparison throughout the groups
      established. Warm ischemia was induced by applying a vascular clamp to the right
      popliteal artery for 12 hours (20 animals) and 7 hours (17 animals). The
      remaining 8 animals underwent a sham operation without interruption of epiphyseal
      perfusion. On completion of the ischemic period hyperbaric oxygen therapy (HBOT)
      was performed on 12 12-hour (12h-HBOT) and 10 7-hour (7h-HBOT) animals at 2
      atmospheres for 90 minutes twice per day for 4 postoperative days. The animals
      were killed on either postoperative day 14 or 90. Measurement of longitudinal
      bone growth was performed on the 90-day animals from serial radiographs at the
      time of surgery and then at 1 month, 2 months, and 3 months after surgery. There
      was no significant difference in longitudinal bone growth between the sham
      operated and the 7h-HBOT animals at 1, 2, and 3 months. There was a statistically
      significant difference, however, between the normal growth of the 7h-HBOT group
      compared with the abnormal growth of the 7-hour, 12-hour, and 12h-HBOT animals.
      Histology was consistent, with the bone growth data demonstrating relative
      normalcy of the 7h-HBOT group epiphyseal plates versus severe architectural
      aberrance and necrosis of the 12h-HBOT group epiphyses. Our experimental data
      indicate that a clinical trial should be instituted using HBO for pediatric
      replantation patients when warm ischemia exceeds 7 hours. (J Hand Surg 2000;
      25A:159-165.

PMID- 10642488
TI  - Irreducible palmar metacarpophalangeal joint dislocation due to junctura tendinum
      interposition: a case report and review of the literature.
AB  - Three different anatomic structures have been reported to prevent reduction of a
      palmar dislocation of metacarpophalangeal joint: dorsal capsule, palmar plate,
      and a ruptured collateral ligament. In our case, extensor digitorum communis of
      the fifth finger and extensor digiti minimi subluxated on the ulnar side of the
      fifth metacarpal neck. Extensor digitorum communis of the fourth finger remained
      in its anatomic location. The junctura tendinum connecting the fourth and fifth
      extensor digitorum communis tendons slipped distal and then palmar to the
      metacarpal head, where it was trapped between the metacarpal neck and the base of
      the proximal phalanx. It was easily pulled out and the joint promptly reduced.
      Residual subluxation persisted due to rupture of the radial collateral ligament
      and the dorsal capsule. Repair restored joint reduction and stability. (J Hand
      Surg 2000; 25A:166-172.

PMID- 10642489
TI  - Methicillin-resistant Staphylococcus aureus in a finger felon.
AB  - Methicillin-resistant Staphylococcus aureus is an increasingly prevalent
      nosocomial pathogen that presents therapeutic challenges. We report an incidence
      of methicillin-resistant S aureus in a felon. The biochemical and clinical
      characteristics of methicillin-resistant S aureus are reviewed. The alarming
      increase of this organism in various types of infections demands the attention of
      all surgeons and emphasizes the importance of early surgical drainage and culture
      of pus in all cases of infection. (J Hand Surg 2000; 25A:173-175.

PMID- 10642490
TI  - The wire interlock technique for harvesting a partial-width distally attached
      tendon graft.
AB  - A wire interlock technique useful for harvesting a partial-width tendon graft
      with an intact insertion for local reconstructive procedures is described. This
      technique is rapid and reliable for procuring attached tendon grafts with minimal
      exposure. The technique was used to harvest a flexor carpi radialis tendon graft
      for basal joint interposition arthroplasty in 12 patients. This method also may
      be readily applicable for other procedures requiring local ligament
      reconstruction with a partial-width tendon graft. (J Hand Surg 2000; 25A:176-182.

PMID- 10642491
TI  - Diagnostic testing in carpal tunnel syndrome.

PMID- 10642492
TI  - Diagnostic testing in carpal tunnel syndrome

PMID- 10642493
TI  - Complications of endoscopic and open carpal tunnel release.

PMID- 10642494
TI  - Complications of endoscopic and open carpal tunnel release

PMID- 10642496
TI  - Cytoplasmic STAT proteins associate prior to activation.
AB  - The commonly accepted model of STAT factor activation at the cytoplasmic part of
      the receptor assumes that signal transducers and activators of transcription
      (STATs) are recruited from a cytoplasmic pool of monomeric STAT proteins. Based
      on a previous observation that non-phosphorylated STAT3-Src homology 2 domains
      dimerize in vitro, we investigated whether the observed dimerization is of
      physiological relevance within the cellular context. We show that STAT1 and STAT3
      are pre-associated in non-stimulated cells. Apparently, these complexes are not
      able to translocate into the nucleus. We provide evidence that the event of STAT
      activation is more complex than previously assumed.

PMID- 10642497
TI  - Mitochondrial aspartate aminotransferase: direction of a single protein with two
      distinct functions to two subcellular sites does not require alternative splicing
      of the mRNA.
AB  - During differentiation of mouse 3T3-L1 fibroblasts to an adipocyte phenotype, the
      mitochondrial isoform of aspartate aminotransferase accumulates on the plasma
      membrane. The determination of whether this reflects translation of an
      alternatively spliced message lacking the mitochondrial leader sequence required
      cloning of the enzyme's uncommon a allele, for which these cells are homozygous.
      The 1.4-kb cDNA sequence of the a allele was obtained from oligo-dT-primed
      reverse-transcriptase PCR products amplified from FVB mouse RNA. It differed from
      the b allele at only 2 bp and one amino acid. By contrast, gene-specific primers
      generated an additional 1.4-kb fragment that differed from the b allele by
      approximately 1% of nucleotides, encoding four amino acid substitutions. This
      sequence proved to represent a recently diverged processed pseudogene. The
      presence of such pseudogenes can complicate interpretation of expressed-sequence
      tag data and single-nucleotide-polymorphism genotyping studies. Using probes
      derived from the a allele, RNase protection analyses indicated that only a single
      message for the enzyme was present in 3T3-L1 fibroblasts and adipocytes, despite
      differences in subcellular protein distribution.

PMID- 10642498
TI  - Preliminary evidence for the existence of specific functional assemblies between
      enzymes of the beta-oxidation pathway and the respiratory chain.
AB  - The electron-transferring flavoprotein (ETF) has been detected in two large
      soluble-protein complexes partially purified from sonicated porcine liver
      mitochondria. Size-exclusion chromatography and sucrose-density
      ultracentrifugation suggested molecular masses in the region of 390 to 420 kDa
      for the two complexes. Activities of medium-chain acyl-CoA dehydrogenase,
      sarcosine dehydrogenase and ETF:ubiquinone oxidoreductase were also detected. No
      evidence of oxidative-phosphorylation properties was obtained. Treatment with
      antimycin A inhibited the activity of both complexes. Pyridine haemochromogens,
      prepared from the partially purified species, show the presence of cytochrome
      proteins. The possible composition of these complexes and their relationship to
      the electron transport chain are discussed.

PMID- 10642495
TI  - Phospholipase D: molecular and cell biology of a novel gene family.
AB  - Interaction of extracellular-signal molecules with cell-surface receptors often
      activates a phospholipase D (PLD)-mediated hydrolysis of phosphatidylcholine and
      other phospholipids, generating phosphatidic acid. The activation of PLD is
      believed to play an important role in the regulation of cell function and cell
      fate. Multiple PLD activities were characterized in eukaryotic cells, and, more
      recently, several PLD genes have been cloned. A PLD gene superfamily, defined by
      a number of structural domains and sequence motifs, also includes
      phosphatidyltransferases and certain phosphodiesterases. Among the eukaryotic PLD
      genes are those from mammals, nematodes, fungi and plants. The present review
      focuses on the structure, localization, regulation and possible functions of
      cloned mammalian and yeast PLDs. In addition, an overview of plant PLD genes, and
      of several distinct PLD activities that have not yet been cloned, is provided.
      Emerging evidence from recent work employing new molecular tools indicates that
      different PLD isoforms are localized in distinct cellular organelles, where they
      are likely to serve diverse functions in signal transduction, membrane vesicle
      trafficking and cytoskeletal dynamics.

PMID- 10642499
TI  - The regulation of AMP-activated protein kinase by phosphorylation.
AB  - The AMP-activated protein kinase (AMPK) cascade is activated by an increase in
      the AMP/ATP ratio within the cell. AMPK is regulated allosterically by AMP and by
      reversible phosphorylation. Threonine-172 within the catalytic subunit (alpha) of
      AMPK (Thr(172)) was identified as the major site phosphorylated by the AMP
      activated protein kinase kinase (AMPKK) in vitro. We have used site-directed
      mutagenesis to study the role of phosphorylation of Thr(172) on AMPK activity.
      Mutation of Thr(172) to an aspartic acid residue (T172D) in either alpha1 or
      alpha2 resulted in a kinase complex with approx. 50% the activity of the
      corresponding wild-type complex. The activity of wild-type AMPK decreased by
      greater than 90% following treatment with protein phosphatases, whereas the
      activity of the T172D mutant complex fell by only 10-15%. Mutation of Thr(172) to
      an alanine residue (T172A) almost completely abolished kinase activity. These
      results indicate that phosphorylation of Thr(172) accounts for most of the
      activation by AMPKK, but that other sites are involved. In support of this we
      have shown that AMPKK phosphorylates at least two other sites on the alpha
      subunit and one site on the beta subunit. Furthermore, we provide evidence that
      phosphorylation of Thr(172) may be involved in the sensitivity of the AMPK
      complex to AMP.

PMID- 10642500
TI  - Four isoforms of serum response factor that increase or inhibit smooth-muscle
      specific promoter activity.
AB  - Serum response factor (SRF) is a key transcriptional activator of the c-fos gene
      and of muscle-specific gene expression. We have identified four forms of the SRF
      coding sequence, SRF-L (the previously identified form), SRF-M, SRF-S and SRF-I,
      that are produced by alternative splicing. The new forms of SRF lack regions of
      the C-terminal transactivation domain by splicing out of exon 5 (SRF-M), exons 4
      and 5 (SRF-S) and exons 3, 4 and 5 (SRF-I). SRF-M is expressed at similar levels
      to SRF-L in differentiated vascular smooth-muscle cells and skeletal-muscle
      cells, whereas SRF-L is the predominant form in many other tissues. SRF-S
      expression is restricted to vascular smooth muscle and SRF-I expression is
      restricted to the embryo. Transfection of SRF-L and SRF-M into C(2)C(12) cells
      showed that both forms are transactivators of the promoter of the smooth-muscle
      specific gene SM22alpha, whereas SRF-I acted as a dominant negative form of SRF.

PMID- 10642501
TI  - Analysis of free and protein-bound nitrotyrosine in human plasma by a gas
      chromatography/mass spectrometry method that avoids nitration artifacts.
AB  - Measurement of nitrotyrosine in biological fluids and tissues is increasingly
      being used to monitor the production of reactive nitrogen species in vivo. The
      detection of nitrotyrosine in vivo has been reported with the use of a variety of
      methods including immunoassay, HPLC and GLC/MS. The validity of HPLC and
      immunoassays have been questioned with regard to their selectivity and
      sensitivity limits. In principle, the measurement of nitrotyrosine by GLC/MS
      permits a highly specific, highly sensitive and fully quantitative assay. The
      nitration of tyrosine under acidic conditions in the presence of nitrite is well
      documented. Derivatization for the full quantification of nitrotyrosine by using
      GLC/MS can lead to the artifactual nitration of tyrosine if performed under
      acidic conditions in the presence of nitrite. We describe a novel alkaline method
      for the hydrolysis and derivatization of nitrotyrosine and tyrosine, and
      demonstrate its applicability to the measurement of plasma concentrations of both
      free and protein-bound nitrotyrosine and tyrosine. A detection limit of 1 pg for
      nitrotyrosine and 100 pg for tyrosine has been achieved. Our method allows, for
      the first time, the analysis of free and protein-bound nitrotyrosine and tyrosine
      in biological samples. The plasma concentrations (means+/-S.E.M.) of free
      tyrosine and nitrotyrosine in eight normal subjects were 12+/-0.6 microg/ml and
      14+/-0.7 ng/ml respectively. Plasma proteins contained tyrosine and nitrotyrosine
      at 60.7+/-1.7 microg/mg and 2.7+/-0.4 ng/mg respectively.

PMID- 10642502
TI  - Glucose persistence on high-mannose oligosaccharides selectively inhibits the
      macroautophagic sequestration of N-linked glycoproteins.
AB  - The macroautophagic-lysosomal pathway is a bulk degradative process for cytosolic
      proteins and organelles including the endoplasmic reticulum (ER). We have
      previously shown that the human colonic carcinoma HT-29 cell population is
      characterized by a high rate of autophagic degradation of N-linked glycoproteins
      substituted with ER-type glycans. In the present work we demonstrate that
      glucosidase inhibitors [castanospermine (CST) and deoxynojirimycin] have a
      stabilizing effect on newly synthesized glucosylated N-linked glycoproteins and
      impaired their lysosomal delivery as shown by subcellular fractionation on
      Percoll gradients. The inhibition of macroautophagy was restricted to N-linked
      glycoproteins because macroautophagic parameters such as the rate of
      sequestration of cytosolic markers and the fractional volume occupied by
      autophagic vacuoles were not affected in CST-treated cells. The protection of
      glucosylated glycoproteins from autophagic sequestration was also observed in
      inhibitor-treated Chinese hamster ovary (CHO) cells and in Lec23 cells (a CHO
      mutant deficient in glucosidase I activity). The interaction of glucosylated
      glycoproteins with the ER chaperone binding protein (BiP) was prolonged in
      inhibitor-treated cells in comparison with untreated CHO cells. These results
      show that the removal of glucose from N-glycans of glycoproteins is a key event
      for their delivery to the autophagic pathway and that interaction with BiP could
      prevent or delay newly synthesized glucosylated N-linked glycoproteins from being
      sequestered by the autophagic pathway.

PMID- 10642503
TI  - alpha-crystallin assists the renaturation of glyceraldehyde-3-phosphate
      dehydrogenase.
AB  - alpha-Crystallin, a major lens protein, has many of the properties of a molecular
      chaperone, but its ability to assist refolding of proteins has been less certain.
      In the present work it was shown that alpha-crystallin specifically increased the
      reactivation of guanidine-denatured glyceraldehyde-3-phosphate dehydrogenase with
      most of the activity being recovered. In the incubation mixture the recovered
      enzyme activity was partly free but mostly it appeared in a protective complex
      with alpha-crystallin. The aggregation of the denatured enzyme on dilution from
      the guanidine solution was prevented. Thus alpha-crystallin not only protects
      against aggregation and inactivation of enzymes during denaturation, but can also
      prevent aggregation and assist recovery of the native structure during
      renaturation.

PMID- 10642504
TI  - Collagen fragments in urine derived from bone resorption are highly racemized and
      isomerized: a biological clock of protein aging with clinical potential.
AB  - Fragments of the alpha1 C-terminal telopeptide of type I collagen containing the
      sequence AHDGGR(1209-1214) (CTx) can be measured in urine as an index of bone
      resorption. We report here that these molecules undergo racemization and
      isomerization of Asp(1211) in vitro and in vivo, generating a mixture of four
      isomers: the native peptide form (alphaL), an isomerized form containing a beta
      Asp bond (betaL), a racemized form containing a D-Asp residue (alphaD) and an
      isomerized/racemized form (betaD). To study these reactions at this specific site
      in collagen, we have employed four immunoassays, each specific for one of the
      isoforms, and developed HPLC methods for their separation. The kinetics of these
      reactions were studied in vitro under physiological conditions by incubation of
      synthetic AHDGGR hexapeptide or mineralized bone collagen. Reactions were found
      to be strongly shifted towards the beta-Asp forms and slightly in favour of the D
      enantiomeric forms. CTx isomers were measured in human urine and in enzymic
      digests of bovine bone collagen. The results indicated that the extent of
      racemization and isomerization were correlated with the age and turnover of
      collagen. The ratios between the native and age-related forms of CTx were
      elevated in urine from patients with Paget's disease or osteoporosis as compared
      with that from healthy adults. The alphaL/alphaD CTx ratio had the highest
      discriminatory power (T-score=23.2; P<0.0001 and T-score=1. 5; P<0.0001 for
      Paget's disease and osteoporosis respectively). In conclusion, these findings
      indicate that an assessment of CTx ratios in urine may provide an estimate of
      bone turnover, aiding in the diagnosis of metabolic bone diseases.

PMID- 10642505
TI  - Racemization and isomerization of type I collagen C-telopeptides in human bone
      and soft tissues: assessment of tissue turnover.
AB  - Urinary excretion of the type I collagen C-telopeptide (CTx) has been shown to be
      a sensitive index of the rate of bone resorption. The human type I collagen
      sequence A(1209)HDGGR(1214) of CTx can undergo racemization of the aspartic acid
      residue Asp(1211) and isomerization of the bond between this residue and
      Gly(1212). These spontaneous non-enzymic chemical reactions takes place in vivo
      in bone, and the degree of racemization and isomerization of CTx molecules may be
      an index of the biological age and the remodelling of bone. The aim of the
      present study was to investigate the degree of racemization and isomerization of
      type I collagen in human connective soft tissues, in order to estimate the rate
      of collagen turnover in adult tissues and compare it with that of bone. We also
      performed a systematic evaluation of the pyridinium cross-link content in adult
      human tissues. Using antibodies raised against the different CTx forms, we found
      that bone and dermis are the tissues that show most racemization and
      isomerization. The type I collagen of arteries, lung, intestine, kidney, skeletal
      muscle and heart shows significantly less racemization and isomerization than
      that of bone, suggesting that these soft tissues have a faster turnover than
      bone. We also found that pyridinoline and, to a lesser degree, deoxypyridinoline
      are distributed throughout the different tissues investigated. Because bone type
      I collagen is characterized by a high degree of both racemization/isomerization
      and deoxypyridinoline cross-linking, the concomitant assessment of these two post
      translational modifications is likely to result in a highly specific marker of
      bone resorption.

PMID- 10642506
TI  - L-Pipecolic acid oxidase, a human enzyme essential for the degradation of L
      pipecolic acid, is most similar to the monomeric sarcosine oxidases.
AB  - L-Pipecolic acid oxidase activity is deficient in patients with peroxisome
      biogenesis disorders (PBDs). Because its role, if any, in these disorders is
      unknown, we cloned the associated human gene and expressed its protein product.
      The cDNA was cloned with the use of a reverse genetics approach based on the
      amino acid sequence obtained from purified L-pipecolic acid oxidase from monkey.
      The complete cDNA, obtained by conventional library screening and 5' rapid
      amplification of cDNA ends, encompassed an open reading frame of 1170 bases,
      translating to a 390-residue protein. The translated protein terminated with the
      sequence AHL, a peroxisomal targeting signal 1. Indirect immunofluorescence
      studies showed that the protein product was expressed in human fibroblasts in a
      punctate pattern that co-localized with the peroxisomal enzyme catalase. A BLAST
      search with the amino acid sequence showed 31% identity and 53% similarity with
      Bacillus sp. NS-129 monomeric sarcosine oxidase, as well as similarity to all
      sarcosine oxidases and dehydrogenases. No similarity was found to the peroxisomal
      D-amino acid oxidases. The recombinant enzyme oxidized both L-pipecolic acid and
      sarcosine. However, PBD patients who lack the enzyme activity accumulate only L
      pipecolic acid, suggesting that in humans in vivo, this enzyme is involved mainly
      in the degradation of L-pipecolic acid.

PMID- 10642507
TI  - Evidence that the inhibition of cartilage proteoglycan breakdown by mannosamine
      is not mediated via inhibition of glycosylphosphatidylinositol anchor formation.
AB  - The effect of mannosamine, an inhibitor of glycosylphosphatidylinositol (GPI)
      anchor formation, on chondrocyte-mediated cartilage proteoglycan breakdown was
      investigated using cartilage explant cultures. Mannosamine inhibited interleukin
      1alpha-, tumour necrosis factor alpha- and retinoic acid-stimulated proteoglycan
      release from bovine nasal and articular cartilage, and retinoic acid-stimulated
      proteoglycan release from human cartilage. Its effects on two GPI-anchored
      proteins [the urokinase receptor, which binds urokinase-type plasminogen
      activator (uPA) to cell surfaces, and alkaline phosphatase] were also studied
      using bovine chondrocytes. Enzyme histochemistry and zymography demonstrated cell
      associated uPA-like serine proteinase activity and PA activity respectively which
      was not reduced by treatment of chondrocytes with mannosamine at concentrations
      effective at inhibiting cartilage proteoglycan breakdown. Similarly, the activity
      of cell-associated alkaline phosphatase was not reduced, except at mannosamine
      concentrations much higher than those used to inhibit proteoglycan breakdown.
      These results demonstrate that inhibition of proteoglycan breakdown by
      mannosamine is too potent to be explained by an effect on GPI-anchor formation.

PMID- 10642508
TI  - Human Nedd4 interacts with the human epithelial Na+ channel: WW3 but not WW1
      binds to Na+-channel subunits.
AB  - The epithelial Na(+) channel (ENaC) regulates Na(+) absorption in epithelial
      tissues including the lung, colon and sweat gland, and in the distal nephrons of
      the kidney. When Na(+)-channel function is disrupted, salt and water homoeostasis
      is affected. The cytoplasmic regions of the Na(+)-channel subunits provide
      binding sites for other proteins to interact with and potentially regulate Na(+)
      channel activity. Previously we showed that a proline-rich region of the alpha
      subunit of the Na(+) channel bound to a protein of 116 kDa from human lung cells.
      Here we report the identification of this protein as human Nedd4, a ubiquitin
      protein ligase that binds to the Na(+)-channel subunits via its WW domains.
      Further, we show that WW domains 2, 3 and 4 of human Nedd4 bind to the alpha,
      beta and gamma Na(+)-channel subunits but not to a mutated beta subunit. In
      addition, when co-expressed in Xenopus oocytes, human Nedd4 down-regulates Na(+)
      channel activity.

PMID- 10642509
TI  - Analysis of tissue inhibitor of metalloproteinases-2 effect on pro-matrix
      metalloproteinase-2 activation by membrane-type 1 matrix metalloproteinase using
      baculovirus/insect-cell expression system.
AB  - Membrane-type 1 matrix metalloproteinase (MT1-MMP; MMP14) is known to activate
      pro-matrix metalloproteinase-2 (pro-MMP-2; progelatinase A) on the cell surface.
      To analyse the tissue inhibitor of metalloproteinases-2 (TIMP-2) effect on
      activation of pro-MMP-2 by MT1-MMP, we have expressed the full-size MT1-MMP (fMT1
      MMP) and a transmembrane (TM)-domain-deleted soluble MT1-MMP (sMT1-MMP) in the
      baculovirus/Sf9 (Spodoptera frugiperda 9) insect-cell system, where neither
      endogenous gelatinolytic MMPs nor TIMP-2 are expressed. Both fMT1-MMP and sMT1
      MMP expressed in the expression system were found not to contain the pro-domain
      and were able to activate the TIMP-2-free pro-MMP-2. Both in the insect cells and
      in vitro, activation of pro-MMP-2 by fMT1-MMP was enhanced at low concentrations
      of TIMP-2 and inhibited by its higher concentrations. The maximal enhancing
      effect was detected at 0.05 molar fraction of TIMP-2/fMT1-MMP. In contrast,
      activation of pro-MMP-2 by sMT1-MMP was dose-dependently inhibited by TIMP-2.
      These results demonstrate that the TM domain of MT1-MMP is not required for the
      ability to activate pro-MMP-2, but is required for the enhancing effect of TIMP-2
      on pro-MMP-2 activation by recruiting pro-MMP-2 to the MT1-MMP-TIMP-2 complex as
      a cell-surface pro-MMP-2 receptor. Moreover, our data strongly suggest that the
      pro-domain of MT1-MMP is not required for the TIMP-2-mediated enhancing effect on
      pro-MMP-2 activation. In addition, the pro-MMP-2 in the MT1-MMP-TIMP-2-pro-MMP-2
      ternary complex was not activated without external activator, but readily by
      addition of sMT1-MMP. This result demonstrates that MT1-MMP free of TIMP-2 would
      be the enzyme responsible for activation of the pro-MMP-2 in the ternary complex
      under physiological conditions.

PMID- 10642510
TI  - The gene for human TATA-binding-protein-associated factor (TAFII) 170: structure,
      promoter and chromosomal localization.
AB  - The TATA-binding protein (TBP) plays a central role in eukaryotic transcription
      and forms protein complexes with TBP-associated factors (TAFs). The genes
      encoding TAF(II) proteins frequently map to chromosomal regions altered in human
      neoplasias. TAF(II)170 of B-TFIID is a member of the SF2 superfamily of putative
      helicases. Members of this superfamily have also been implicated in several human
      genetic disorders. In this study we have isolated human genomic clones encoding
      TAF(II)170 and we show that the gene contains 37 introns. Ribonuclease-protection
      experiments revealed that TAF(II)170 has multiple transcription start sites,
      consistent with the observation that the promoter lacks a canonical TATA box and
      initiator element. Deletion analysis of the promoter region showed that a
      fragment of 264 bp is sufficient to direct transcription. In addition, we
      determined the chromosomal localization by two independent methods which mapped
      the gene to human chromosome 10q22-q23 between the markers D10S185 and WI-1183.
      The region surrounding these markers has been implicated in several human
      disorders.

PMID- 10642511
TI  - Mouse BTEB3, a new member of the basic transcription element binding protein
      (BTEB) family, activates expression from GC-rich minimal promoter regions.
AB  - Members of the three-zinc-finger family of transcription factors play an
      important role in determining basal transcription. We have cloned mouse BTEB3
      (mBTEB3), a new member of the basic transcription element binding protein (BTEB)
      family, which is expressed in a wide variety of tissues. mBTEB3 activates
      transcription of the simian virus 40 early promoter (4-fold) and of the tissue
      specific SM22alpha promoter (100-fold), suggesting that, like BTEB1 and Sp1,
      mBTEB3 is a basal transcription factor.

PMID- 10642512
TI  - Induction of Myc-intron-binding polypeptides MIBP1 and RFX1 during retinoic acid
      mediated differentiation of haemopoietic cells.
AB  - Retinoic acid-mediated differentiation of HL60 cells is associated with an
      alteration of chromatin structure that maps to protein-binding sequences within
      intron I of the c-myc gene and with down-regulation of c-myc expression. By using
      HeLa cell extracts, we previously identified two polypeptides, designated MIBP1
      (for Myc-intron-binding peptide) and RFX1, that interact in vivo and bind to the
      intron I element; we showed that tandem repeats of an MIBP1/RFX1-binding site can
      exhibit silencer activity on a heterologous promoter. Here we demonstrate that
      p160 MIBP1 and p130 RFX1 are absent from undifferentiated HL60 cells. In
      addition, we show that treatment with retinoic acid induces both MIBP1 and RFX1
      protein, as well as their DNA-binding activity, upon granulocytic differentiation
      of HL60 cells, with a gel mobility pattern identical to that of HeLa cells. In
      the absence of p160 MIBP1 and p130 RFX1, we observed that the altered gel
      mobility-shift pattern detected in undifferentiated HL60 cells reflects the
      binding of two novel polypeptides, p30 and p97, that can be cross-linked to the
      same recognition intron sequence. We also show that the time course of MIBP1 and
      RFX1 induction is inversely correlated with the down-regulation of c-myc levels
      during the treatment of HL60 cells with retinoic acid.

PMID- 10642513
TI  - Gi-mediated translocation of GLUT4 is independent of p85/p110alpha and p110gamma
      phosphoinositide 3-kinases but might involve the activation of Akt kinase.
AB  - Activation of phosphoinositide 3-kinase (PI-3K) is essential for insulin
      stimulated translocation of GLUT4 and glucose transport in insulin target
      tissues. A novel p110gamma PI-3K was reported to be activated by G(i)-coupled
      receptors via Gbetagamma subunits. We asked whether the stimulation of G(i)
      coupled receptors would trigger GLUT4 translocation and glucose uptake by the
      activation of Gbetagamma-dependent p110gamma PI-3K. We find that this
      translocation and glucose uptake can be induced by the ligand stimulation of G(i)
      coupled alpha(2A) adrenergic receptor and fMet-Leu-Phe receptor in cells stably
      expressing these receptors. The noradrenaline ('noradrenaline')- and fMet-Leu-Phe
      stimulated GLUT4 translocations were abolished by pretreatment with pertussis
      toxin. Pretreatment with wortmannin or genistein also inhibited the G(i)-mediated
      GLUT4 translocation. On ligand stimulation of these two kinds of G(i)-coupled
      receptor, although there was a slight increase in PtdIns(3,4,5)P(3) production,
      activation of either the p85/p110alpha PI-3K or Gbetagamma-dependent p110gamma PI
      3K was not observed even in Chinese hamster ovary cells stably overexpressing
      exogenous p101/p110gamma. The G(i)-mediated GLUT4 translocation was accompanied
      by activation of the serine-threonine kinase Akt; the inhibitory effects of
      pertussis toxin, wortmannin and genistein on G(i)-mediated GLUT4 translocation
      paralleled their inhibitory effects on Akt activation. In contrast, the
      activation of some other G(i)-coupled receptors, such as prostaglandin EP3alpha
      receptor and platelet-activating factor receptor, did not cause either pertussis
      toxin-sensitive translocation of GLUT4myc or activation of Akt kinase. These
      results indicate that the ligand stimulation of some G(i)-coupled receptors
      triggers GLUT4 translocation that occurs independently of p85/p110alpha-type and
      p110gamma-type PI-3Ks but might involve the activation of Akt kinase.

PMID- 10642514
TI  - The recombinant N-terminal region of human salivary mucin MG2 (MUC7) contains a
      binding domain for oral Streptococci and exhibits candidacidal activity.
AB  - MG2 (the MUC7 gene product) is a low-molecular-mass mucin found in human
      submandibular/sublingual secretions. This mucin is believed to agglutinate a
      variety of microbes and thus is considered an important component of the non
      immune host defence system in the oral cavity. We have shown that MUC7 can bind
      to cariogenic strains of Streptococcus mutans and that this binding requires a
      structural determinant in the N-terminal region. In the present study an
      expression construct, pNMuc7, encoding the N-terminal 144 amino acids of MUC7 was
      generated, and the recombinant protein rNMUC7 was expressed in Escherichia coli.
      Purified rNMUC7 was characterized and the binding of this protein to oral
      bacteria was investigated in an established assay. The results showed that the
      recombinant protein bound to S. mutans ATCC 25175 and ATCC 33402, and that
      alkylation of the two cysteine residues (Cys(45) and Cys(50)) resulted in the
      complete loss of bacterial binding. This suggests that binding of MUC7 to S.
      mutans occurs between the N-terminal region of the mucin molecule and the
      bacterial surface, and that this interaction is dependent on a cysteine
      containing domain within this region of MUC7. In addition, the killing activity
      of rNMUC7 was compared with that of the candidacidal salivary protein histatin 5
      in an established Candida albicans (ATCC 44505) blastoconidia killing assay. It
      was found that the LD(50) values of rNMUC7 and histatin 5 were comparable, and
      that the recombinant protein displayed significant killing activity at the
      physiological concentration range of MUC7 in whole saliva. This study is the
      first to show that the N-terminal region of MUC7 contains a structural
      determinant for bacterial binding and that this region exhibits candidacidal
      activity.

PMID- 10642515
TI  - Evidence that serine 304 is not a key ligand-binding residue in the active site
      of cytochrome P450 2D6.
AB  - Homology models of cytochrome P450 2D6 (CYP2D6) have identified serine 304 as an
      active-site residue and implicated a putative role for this residue in substrate
      enantioselectivity and the differential inhibition of enzyme activity by the
      diastereoisomers quinine and quinidine. The role of serine 304 in selectivity is
      thought to be achieved through a preferential hydrogen-bond interaction between
      the hydroxyl group of the residue and one of the stereoisomers of each ligand. We
      have tested this hypothesis by substituting serine 304 with alanine, a non
      hydrogen-bonding residue, and compared the properties of the wild-type and mutant
      enzymes in microsomes prepared from yeast cells expressing the appropriate cDNA
      derived enzyme. The Ser(304)Ala substitution did not alter the enantioselective
      oxidation of metoprolol; the O-demethylation reaction remained R-(+)
      enantioselective (wild-type, R/S, 1.7; mutant, R/S, 1.6), whereas alpha
      hydroxylation remained S-(-)-enantioselective (wild-type and mutant, R/S, 0.7).
      Similarly, the selective oxidation of the R-(+) and S-(-) enantiomers of
      propranolol to the major 4-hydroxy metabolite was identical with both wild-type
      and mutant forms of the enzyme (R/S 0.9), although the formation of minor
      metabolites (5-hydroxy and deisopropylpropranolol) did show some slight
      alteration in enantioselectivity. The differential inhibition of enzyme activity
      by quinine and quinidine was also identical with both forms of CYP2D6, the IC(50)
      values for each enzyme being approx. 10 microM and 0.1 microM for quinine and
      quinidine, respectively. The kinetics of formation of alpha-hydroxymetoprolol and
      4-hydroxydebrisoquine by wild-type and the Ser(304)Ala mutant was also very
      similar. However, modest changes in the regioselective oxidation of metoprolol
      and debrisoquine were observed with the Ser(304)Ala mutant. The regio- and
      enantioselective oxidation of an analogue of metoprolol, in which the hydroxyl
      group attached to the chiral carbon was replaced by a methyl moiety, was again
      identical with both wild-type and Ser(304)Ala mutant. However, the observed
      selectivity was the reverse of that observed with metoprolol. Collectively, these
      data indicate that Ser(304) is unlikely to be a key ligand-binding residue,
      although the residue may indeed be located in the active-site cavity. The
      reversal of selectivity with the methyl analogue of metoprolol indicates that the
      hydroxyl group attached to the chiral centre of ligands, such as metoprolol, is
      important in defining the enzyme's selective properties, and that a hydrogen
      bonding residue, other than Ser(304), may be involved in this interaction.
      Current homology models of the active site of CYP2D6 that predict a hydrogen-bond
      interaction between Ser(304) and specific ligands will need to be re-evaluated,
      and other candidate residues capable of such an interaction nominated and tested
      by site-directed mutagenesis studies.

PMID- 10642516
TI  - Disulphide-bond pattern and molecular modelling of the dimeric disintegrin EMF
      10, a potent and selective integrin alpha5beta1 antagonist from Eristocophis
      macmahoni venom.
AB  - The disulphide-bond pattern of the heterodimeric disintegrin EMF-10, a potent and
      selective integrin alpha(5)beta(1) antagonist from Eristocophis macmahoni venom,
      was established by combination of amino-acid analysis, N-terminal sequencing and
      collision-induced dissociation by nanoelectrospray ionization quadrupole ion-trap
      MS of fragments isolated by reversed-phase HPLC after degradation of EMF-10 with
      oxalic acid. Each EMF-10 subunit contains four intrachain disulphide bonds. Two
      interchain cystine residues join the EMF-10 polypeptides. The intrachain linkages
      are conserved in monomeric disintegrins. A molecular model of EMF-10 was built
      using averaged NMR co-ordinates of flavoridin as a template. The active hairpin
      loops of the EMF-10 subunits occupy opposite locations at the ends of an
      elongated disulphide-bond ladder. In the EMF-10 model the N-terminal polypeptide
      of EMF-10B is close to the RGD-loop of the EMF-10A subunit, suggesting that the N
      terminal region of the B-subunit could potentially influence the biological
      activity of the A-subunit.

PMID- 10642517
TI  - Purification and characterization of a novel human acidic nuclease/intra
      cyclobutyl-pyrimidine-dimer-DNA phosphodiesterase.
AB  - A novel N-glycosylated, mannose-rich protein has been purified approx. 4000-fold
      from human liver in a seven-step procedure including ion-exchange chromatography
      and fractionation on concanavalin A-Sepharose, Sephadex G-75 and oligo(dT)
      cellulose matrices. The molecular mass of the protein is 46 kDa when measured by
      gel filtration (i.e. under non-denaturing conditions) and 60 kDa by SDS/PAGE
      (i.e. under denaturing conditions). The protein possesses two DNA backbone
      incising activities, namely, the random introduction of single-strand breaks in
      native DNA and the rupture of the phosphodiester linkage internal to cyclobutyl
      pyrimidine dimers, the major class of DNA lesions induced by solar UV rays. Both
      activities are optimal at pH 5.0 in vitro, although the non-specific nuclease
      displays appreciable activity at neutral pH, depending on the buffer composition.
      The protein has been named acidic nuclease/intra-cyclobutyl-pyrimidine-dimer-DNA
      phosphodiesterase (AN/IDP). As a nuclease, the protein 'prefers' a linear DNA
      structure over a covalently closed circular molecule and is more proficient at
      digesting single-stranded than double-stranded DNA. The polynucleotide cleavage
      products of the nuclease contain 5'-OH and 3'-PO(4) termini, which are refractory
      to direct rejoining by DNA ligases. Depending on the substrate, the nuclease
      activity exhibits a temperature optimum of 50 degrees C or greater, and is
      neither stimulated by Mg(2+) or Ca(2+) nor inhibited by Zn(2+). AN/IDP is present
      in human liver and in cultured human cells of both fibroblastic and lymphocytic
      origins. Intracellularly, the protein can be readily detected in both the
      cytosolic and nuclear fractions, although much more (approx. 3-fold) is found in
      the latter fraction. We propose that this bifunctional enzyme may be involved in
      both apoptotic DNA digestion and metabolism of cyclobutyl pyrimidine dimers in UV
      irradiated human cells.

PMID- 10642518
TI  - Neuroserpin is expressed in the pituitary and adrenal glands and induces the
      extension of neurite-like processes in AtT-20 cells.
AB  - Two cDNAs encoding the serine protease inhibitor (serpin) neuroserpin were cloned
      from a rat pituitary cDNA library (rNS-1, 2922 bp; rNS-2, 1599 bp). In situ
      hybridization histochemistry showed neuroserpin transcripts in the intermediate,
      anterior and posterior lobes of the pituitary gland and medullary cells in the
      adrenal gland. Expression of rNS-1 mRNA was restricted to selected cells in the
      pituitary gland. Analysis of purified secretory-granule fractions from pituitary
      and adrenal tissues indicated that neuroserpin was found in dense-cored secretory
      granules. This result suggested that endocrine neuroserpin may regulate
      intragranular proteases or inhibit enzymes following regulated secretion. To
      investigate the function of neuroserpin in endocrine tissues we established
      stable anterior pituitary AtT-20 cell lines expressing neuroserpin. Cells with
      increased levels of neuroserpin responded by extending neurite-like processes.
      Extracellular proteolysis by serine protease plasminogen activators has been
      suggested to regulate neurite outgrowth. As neuroserpin inhibits tissue
      plasminogen activator (tPA) in vitro, we measured plasminogen-activator levels.
      Zymographic analysis indicated that AtT-20 cells synthesized and secreted a
      plasminogen activator identical in size to tPA. A higher-molecular-mass tPA
      neuroserpin complex was also observed in AtT-20-cell conditioned culture medium.
      tPA levels were similar in parent AtT-20 cells and a stable cell line with
      increased levels of neuroserpin. There was no accumulation of a tPA-neuroserpin
      complex. Together these results identify endocrine cells as an important source
      of neuroserpin. Moreover they suggest that neuroserpin is released from dense
      cored secretory granules to regulate cell-extracellular matrix interactions
      through a mechanism that may not directly involve tPA.

PMID- 10642519
TI  - Lipid metabolic changes caused by short-chain ceramides and the connection with
      apoptosis.
AB  - The effects of the short-chain ceramides D-erythro-N-acetylsphingosine (C(2)
      ceramide), 6-[N-(7-nitrobenz-2-oxa-1, 3-diazole-4-yl)amino]hexanoyl-D-erythro
      sphingosine(NBD-ceramide) and N-[4,4-difluoro-5,7-dimethyl-4-bora-3a, 4a-diaza-s
      indacene-3-pentanoyl]-D-erythro-sphingosine (DMB-ceramide) on the incorporation
      of [(14)C]acetate into baby-hamster kidney (BHK) fibroblasts have been examined.
      C(2)-ceramide at concentrations up to 20 microM caused an inhibition of synthesis
      of phosphatidylcholine (PtdCho), sphingolipids and cholesterol within 2 h.
      Similar effects in BHK cells were seen using other radioactive tracers
      ([(3)H]water, [(3)H]palmitate and [(3)H]choline) and using HL60 cells labelled
      with [(14)C]acetate. The inhibition of PtdCho synthesis corresponded to an
      accumulation of label in diacylglycerol and triacylglycerol, probably as a
      consequence of cytidylyltransferase blockade. With [(3)H]choline label, the
      decrease in sphingomyelin synthesis could be partly accounted for by accumulation
      of a slow-moving lipid, likely to be C(2)-sphingomyelin. NBD-ceramide also
      reduced sphingomyelin and cholesterol biosynthesis, but had much less effect on
      PtdCho and acylglycerols. In contrast, the only apparent effect of DMB-ceramide
      was to inhibit synthesis of sphingomyelin, with a reciprocal increase in DMB
      sphingomyelin synthesis. However, all of these short-chain ceramides caused
      massive apoptosis after 18 h, whereas addition of N-acetyldihydrosphingosine or
      elevation of natural ceramide by treatment of cells with sphingomyelinase had
      little effect on lipid synthesis or apoptosis. The present findings suggest that
      the apoptotic effect of short-chain ceramides is sometimes associated with
      inhibition of cytidylyltransferase, but is more closely correlated with a
      competitive inhibition of normal sphingomyelin biosynthesis.

PMID- 10642520
TI  - A bone sialoprotein-binding protein from Staphylococcus aureus: a member of the
      staphylococcal Sdr family.
AB  - Staphylococcus aureus bacteria, isolated from bone and joint infections,
      specifically interact with bone sialoprotein (BSP), a glycoprotein of bone and
      dentine extracellular matrix, via a cell-surface protein of M(r) 97000 [Yacoub,
      Lindahl, Rubin, Wendel, Heinegard and Ryden, (1994) Eur. J. Biochem. 222, 919
      925]. Amino acid sequences of seven trypsin fragments from the 97000-M(r) BSP
      binding protein were determined. A gene encoding a protein encompassing all seven
      peptide sequences was identified from chromosomal DNA isolated from S. aureus
      strain O24. This gene encodes a protein with 1171 amino acids, called BSP-binding
      protein (Bbp), which displays similarity to recently described proteins of the
      Sdr family from S. aureus. SdrC, SdrD and SdrE encode putative cell-surface
      proteins with no described ligand specificity. Bbp also shows similarity to a
      fibrinogen-binding protein from S. epidermidis called Fbe. A serine-aspartic acid
      repeat sequence was found close to the cell-wall-anchoring Leu-Pro-Xaa-Thr-Gly
      sequence in the C-terminal end of the protein. Escherichia coli cells were
      transformed with an expression vector containing a major part of the bbp gene
      fused to the gene for glutathione S-transferase. The affinity-purified fusion
      protein bound radiolabelled native BSP, and inhibited the binding of
      radiolabelled BSP to staphylococcal cells. Serum from patients suffering from
      bone and joint infection contained antibodies that reacted with the fusion
      protein of the BSP-binding protein, indicating that the protein is expressed
      during an infection and is immunogenic. The S. aureus Bbp protein may be
      important in the localization of bacteria to bone tissue, and thus might be of
      relevance in the pathogenicity of osteomyelitis.

PMID- 10642521
TI  - Leukotriene A4 hydrolase: a critical role of glutamic acid-296 for the binding of
      bestatin.
AB  - Leukotriene A(4) hydrolase is a bifunctional Zn(2+)-containing enzyme catalysing
      the formation of the potent chemotaxin leukotriene B(4). From an analysis of
      three mutants of Glu-296 we have found that this catalytic residue is critical
      for the binding of bestatin, a classical aminopeptidase inhibitor. For bestatin,
      but not for three other tight-binding inhibitors, the IC(50) values for
      inhibition of the epoxide hydrolase activity decreased in the mutants to 0.7
      0.003% of the control. Hence Glu-296 is an important structural determinant for
      binding of bestatin to leukotriene A(4) hydrolase; this conclusion might also
      apply to other members of the M1 family of metallopeptidases.

PMID- 10642522
TI  - Quantitative assessment of complex formation of nuclear-receptor accessory
      proteins.
AB  - Like other nuclear receptors, steroid hormone receptors form large protein hetero
      complexes in their inactive, ligand-friendly state. Several heat-shock proteins,
      immunophilins and others have been identified as members of these highly dynamic
      complexes. The interaction kinetics and dynamics of hsp90, hsp70, p60 (Hop),
      FKBP52, FKBP51, p48 (Hip) and p23 have been assessed by a biosensor approach
      measuring the complex formation in real time. A core chaperone complex has been
      reconstituted from p60, hsp90 and hsp70. p60 forms a molecular bridge between
      hsp90 and hsp70 with an affinity in the range of 10(5) M(-1). Dynamics of hsp90
      p60 complex formation is modulated by ATP through changes in the co-operativity
      of interaction. At low protein concentrations ATP stabilizes the complex. Binding
      of p23 to hsp90 did not change the affinity of the hsp90-p60 complex and the
      stabilizing effect of ATP. Saturation of the p48-hsp70 interaction could not be
      achieved, suggesting multiple binding sites. A picture of the protein complex,
      including stoichiometric coefficients, co-operativity of interaction and
      equilibrium-binding constants, has been formed.

PMID- 10642523
TI  - pgaA and pgaB encode two constitutively expressed endopolygalacturonases of
      Aspergillus niger.
AB  - The nucleotide sequence data for pgaA and pgaB have been deposited with the EMBL,
      GenBank and DDBJ Databases under accession numbers Y18804 and Y18805
      respectively. pgaA and pgaB, two genes encoding endopolygalacturonases (PGs, EC
      3.2.1.15) A and B, were isolated from a phage genomic library of Aspergillus
      niger N400. The 1167 bp protein coding region of the pgaA gene is interrupted by
      one intron, whereas the 1234 bp coding region of the pgaB gene contains two
      introns. The corresponding proteins, PGA and PGB, consist of 370 and 362 amino
      acid residues respectively. Northern-blot analysis revealed that pgaA- and pgaB
      specific mRNA accumulate in mycelia grown on sucrose. mRNAs are also present upon
      transfer to media containing D-galacturonic acid and pectin. Recombinant PGA and
      PGB were characterized with respect to pH optimum, activity on polygalacturonic
      acid, and mode of action and kinetics on oligogalacturonates of different chain
      length (n=3-7). At their pH optimum the specific activities in a standard assay
      for PGA (pH 4.2) and PGB (pH 5.0) were 16.5 mu+kat.mg(-1) and 8.3 mu+kat.mg(-1)
      respectively. Product progression analysis, using polygalacturonate as a
      substrate, revealed a random cleavage pattern for both enzymes and indicated
      processive behaviour for PGA. This result was confirmed by analysis of the mode
      of action using oligogalacturonates. Processivity was observed when the degree of
      polymerization of the substrate exceeded 6. Using pectins of various degrees of
      methyl esterification, it was shown that PGA and PGB both preferred partially
      methylated substrates.

PMID- 10642524
TI  - Heat shock cognate protein 70 chaperone-binding site in the co-chaperone murine
      stress-inducible protein 1 maps to within three consecutive tetratricopeptide
      repeat motifs.
AB  - Murine stress-inducible protein 1 (mSTI1) is a co-chaperone homologous with the
      human heat shock cognate protein 70 (hsc70)/heat shock protein 90 (hsp90)
      organizing protein (Hop). The concomitant interaction of mSTI1 with hsp70 and
      hsp90 at its N- and C-termini respectively is mediated by the tetratricopeptide
      repeat (TPR) motifs in these regions. With the use of co-precipitation assays, we
      show here that the N-terminal TPR domain of mSTI1 without extensive flanking
      regions is both necessary and sufficient to mediate a specific interaction with
      hsc70. In contrast, other TPR-containing co-chaperones require TPR flanking
      regions for target substrate recognition, suggesting different mechanisms of TPR
      mediated chaperone-co-chaperone interactions. Furthermore, the interaction
      between mSTI1 and hsc70 was analysed to ascertain the effect of replacing or
      deleting conserved amino acid residues and sequences within the three TPR motifs
      constituting the N-terminal TPR domain of full-length mSTI1. Replacement of a
      bulky hydrophobic residue in TPR1 disrupted the interaction of mSTI1 with hsc70.
      A highly conserved sequence in TPR2 was altered by deletion or single amino acid
      replacement. These derivatives retained a specific interaction with hsc70. These
      results are consistent with a model in which conserved residues within the N
      terminal TPR region of mSTI1 contribute differentially to the interaction with
      hsc70, and in which TPR1 has a significant role in targeting mSTI1 to hsc70. The
      contribution of the TPR domain mutations and deletions are discussed with respect
      to their effect on target substrate interactions.

PMID- 10642526
TI  - Dehydroascorbic acid uptake in a human keratinocyte cell line (HaCaT) is
      glutathione-independent.
AB  - Vitamin C plays an important role in neutralizing toxic free radicals formed
      during oxidative metabolism or UV exposure of human skin. This study was
      performed to investigate the mechanisms that regulate the homoeostasis of vitamin
      C in HaCaT cells by identifying the events involved in the transport and in the
      reduction of dehydroascorbic acid. Dehydroascorbic acid accumulated to a greater
      extent and faster compared with ascorbic acid; its transport appeared to be
      mediated by hexose transporters and was entirely distinct from ascorbic acid
      transport. Dehydroascorbate reductase activity was unaffected by glutathione
      depletion, although it was sensitive to thiol protein reagents. These
      observations, as well as the subcellular distribution of this enzymic activity
      and the cofactor specificity, indicate that thioredoxin reductase and lipoamide
      dehydrogenase play an important role in this reduction process. HaCaT cells were
      able to enhance their dehydroascorbic acid reductase activity in response to
      oxidative stress.

PMID- 10642525
TI  - Androctonin, a hydrophilic disulphide-bridged non-haemolytic anti-microbial
      peptide: a plausible mode of action.
AB  - Androctonin is a 25-residue non-haemolytic anti-microbial peptide isolated from
      the scorpion Androctonus australis and contains two disulphide bridges.
      Androctonin is different from known native anti-microbial peptides, being a
      relatively hydrophilic and non-amphipathic molecule. This raises the possibility
      that the target of androctonin might not be the bacterial membrane, shown to be a
      target for most amphipathic lytic peptides. To shed light on its mode of action
      on bacteria and its non-haemolytic activity, we synthesized androctonin, its
      fluorescent derivatives and its all-D-amino acid enantiomer. The enantiomer
      preserved high activity, suggesting a lipid-peptide interaction between
      androctonin and bacterial membranes. In Gram-positive and (at higher
      concentrations) Gram-negative bacteria, androctonin induced an immediate
      perturbation of the permeability properties of the cytoplasmic membrane of the
      bacterial energetic state, concomitant with perturbation of the morphology of the
      cell envelope as revealed by electron microscopy. Androctonin binds only to
      negatively charged lipid vesicles and induces the leakage of markers at high
      concentrations and with a slow kinetics, in contrast with amphipathic alpha
      helical anti-microbial peptides that bind and permeate negatively charged
      vesicles, and to a smaller extent also zwitterionic ones. This might explain the
      selective lytic activity of androctonin towards bacteria but not red blood cells.
      Polarized attenuated total reflection-Fourier transform infrared spectroscopy
      revealed that androctonin adopts a beta-sheet structure in membranes and did not
      affect the lipid acyl chain order, which supports a detergent-like effect. The
      small size of androctonin, its hydrophilic character and its physicochemical
      properties are favourable features for its potential application as a replacement
      for commercially available antibiotics to which bacteria have developed
      resistance.

PMID- 10642527
TI  - LKB1, a novel serine/threonine protein kinase and potential tumour suppressor, is
      phosphorylated by cAMP-dependent protein kinase (PKA) and prenylated in vivo.
AB  - Peutz-Jeghers syndrome (PJS) is an autosomal dominant disease characterized by
      melanocytic macules, hamartomatous polyps and an increased risk for numerous
      cancers. The human LKB1 (hLKB1) gene encodes a serine/threonine protein kinase
      that is deficient in the majority of patients with PJS. The murine LKB1 (mLKB1)
      cDNA was isolated, sequenced and shown to produce a 2.4-kb transcript encoding a
      436 amino acid protein with 90% identity with hLKB1. RNA blot and RNase
      protection analysis revealed that mLKB1 mRNA is expressed in all tissues and cell
      lines examined. The widespread expression of LKB1 transcripts is consistent with
      the elevated risk of multiple cancer types in PJS patients. The predicted LKB1
      protein sequence terminates with a conserved prenylation motif (Cys(433)-Lys-Gln
      Gln(436)) directly downstream from a consensus cAMP-dependent protein kinase
      (PKA) phosphorylation site (Arg(428)-Arg-Leu-Ser(431)). The expression of
      enhanced green fluorescent protein (EGFP)-mLKB1 chimaeras demonstrated that LKB1
      possesses a functional prenylation motif that is capable of targeting EGFP to
      cellular membranes. Mutation of Cys(433) to an alanine residue, but not
      phosphorylation by PKA, blocked membrane localization. These findings suggest
      that PKA does phosphorylate LKB1, although this phosphorylation does not alter
      the cellular localization of LKB1.

PMID- 10642528
TI  - Cellular adaptation to down-regulated iron transport into lymphoid leukaemic
      cells: effects on the expression of the gene for ribonucleotide reductase.
AB  - Ribonucleotide reductase is an iron-containing enzyme that is essential for DNA
      synthesis. Whereas previous studies have used various iron chelators to examine
      the relationship between cellular iron metabolism and ribonucleotide reductase
      activity in cells, they have not elucidated the relationship between iron
      transport into cells and the expression of the gene for ribonucleotide reductase.
      To investigate this, we examined ribonucleotide reductase mRNA, protein and
      enzyme activity in a novel line of CCRF-CEM cells (DFe-T cells) that display an
      approx. 60% decrease in their uptake of iron compared with the parental wild-type
      cell line. We found that DFe-T cells displayed an approx. 40% decrease in
      ribonucleotide reductase specific enzyme activity relative to wild-type cells
      without a change in their proliferation. Kinetic analysis of CDP reductase
      activity revealed an approx. 60% decrease in V(max) in DFe-T cells without a
      change in K(m). Despite the decrease in enzyme activity, the mRNA and protein for
      the R1 and R2 subunits of ribonucleotide reductase in DFe-T cells were similar to
      those of wild-type cells. ESR spectroscopy studies revealed that DFe-T cells had
      a 22% decrease in the tyrosyl free radical of the R2 subunit, suggesting that a
      larger amount of R2 protein was present as functionally inactive apo-R2 in these
      cells. Our studies indicate that ribonucleotide reductase activity in CCRF-CEM
      cells can be down-regulated by more than 50% in response to down-regulated iron
      transport without an adverse effect on cell proliferation. Furthermore, our
      studies suggest a regulatory link between ribonucleotide reductase activity and
      iron transport into these cells.

PMID- 10642529
TI  - Mechanistic studies of morphine dehydrogenase and stabilization against covalent
      inactivation.
AB  - Morphine dehydrogenase (MDH) of Pseudomonas putida M10 catalyses the NADP(+)
      dependent oxidation of morphine and codeine to morphinone and codeinone. This
      enzyme forms the basis of a sensitive detection and assay method for heroin
      metabolites and a biotransformation process for production of hydromorphone and
      hydrocodone. To improve these processes we have undertaken a thorough examination
      of the kinetic mechanism of MDH. Sequence comparisons indicated that MDH belongs
      within the aldose reductase enzyme family. MDH was shown to be specific for the
      pro-R hydrogen of NADPH. In steady-state kinetic studies, product inhibition
      patterns suggested that MDH follows a Theorell-Chance mechanism for codeinone
      reduction at pH 7, and a non-Theorell-Chance sequential ordered mechanism for
      codeine oxidation at pH 9.5. Residues corresponding to the catalytically
      important Tyr-48, Lys-77 and Asp-43 of aldose reductase were modified by site
      directed mutagenesis, resulting in substantial loss of activity consistent with a
      catalytic role for these residues. Loss of activity of MDH in the presence of the
      reaction product morphinone was found to be due to the formation of a covalent
      adduct with Cys-80; alteration of Cys-80 to serine resulted in an enzyme with
      greatly enhanced stability.

PMID- 10642530
TI  - Isolation and characterization of glycosylphosphatidylinositol-anchored, mucin
      like surface glycoproteins from bloodstream forms of the freshwater-fish parasite
      Trypanosoma carassii.
AB  - Wild and farmed freshwater fishes are widely and heavily parasitized by the
      haemoflagellate Trypanosoma carassii. In contrast, common carp, a natural host,
      can effectively control experimental infections by the production of specific
      anti-parasite antibodies. In this study we have identified and partially
      characterized mucin-like glycoproteins which are expressed in high abundance [(6.
      0+/-1.7)x10(6) molecules.cell(-1)] at the surface of the bloodstream
      trypomastigote stage of the parasite. The polypeptide backbone of these
      glycoproteins is dominated by threonine, glycine, serine, alanine, valine and
      proline residues, and is modified at its C-terminus by a
      glycosylphosphatidylinositol membrane anchor. On average, each polypeptide
      carries carbohydrate chains composed of about 200 monosaccharide units
      (galactose, N-acetylglucosamine, xylose, sialic acid, fucose, mannose and
      arabinose), which are most probably O-linked to hydroxy amino acids. The mucin
      like molecules are the target of the fish's humoral immune response, but do not
      undergo antigenic variation akin to that observed for the variant surface
      glycoprotein in salivarian trypanosomes. The results are discussed with reference
      to the differences between natural and experimental infections, and in relation
      to the recently delineated molecular phylogeny of trypanosomes.

PMID- 10642531
TI  - Differential recognition of snake venom proteins expressing specific Arg-Gly-Asp
      (RGD) sequence motifs by wild-type and variant integrin alphaIIbbeta3: further
      evidence for distinct sites of RGD ligand recognition exhibiting negative
      allostery.
AB  - Several studies have demonstrated that the amino acid residues flanking the Arg
      Gly-Asp (RGD) sequence of high-affinity ligands modulate their specificity of
      interaction with integrin complexes. Because of the absence of structural data
      for integrin complexes with bound ligand, the molecular basis for this
      specificity modulation remains obscure. In a previous paper [Rahman, Lu, Kakkar
      and Authi (1995) Biochem. J. 312, 223-232] we demonstrated that two genetically
      distinct venom-derived RGD proteins, kistrin and dendroaspin (both containing the
      sequence PRGDMP), were simple competitors, indicating the recognition of an
      identical binding site on the alpha(IIb)beta(3) complex. Furthermore, both
      kistrin and dendroaspin inhibited the binding of the disintegrin elegantin
      (containing the sequence ARGDNP) via a non-competitive mechanism, suggesting that
      the binding of elegantin to the alpha(IIb)beta(3) complex was at a remote site
      and down-regulated via an allosteric mechanism. Here we present further evidence
      for distinct RGD ligand recognition sites on the alpha(IIb)beta(3) complex that
      exhibit a negative allosteric relationship. A panel of well-characterized
      recombinant dendroaspin and elegantin derivatives were employed for this study.
      These recombinant molecules were constructed as glutathione S-transferase fusion
      proteins with either an Ala or Pro residue N-terminal to the RGD sequence in
      combination with either a Met or an Asn residue immediately C-terminal.
      Equilibrium competition experiments showed that elegantin binding to ADP-treated
      platelets was inhibited by derivatives Eleg. AM (ARGDMP) and Eleg. PM (PRGDMP)
      via an allosteric competitive mechanism, providing direct evidence that
      modulation of the RGD motif can alter competitive behaviour. In addition,
      recombinant kistrin and dendroaspin both inhibited elegantin binding via a non
      competitive mechanism, confirming our previous observations. Further evidence for
      distinct binding sites employing an independent approach was obtained by
      analysing the binding of the panel of venom proteins to the functionally
      defective heterodimer alpha(IIb)beta(3) Ser(123)-->Ala expressed on Chinese
      hamster ovary cells. These studies demonstrated that simple competitors kistrin
      and dendroaspin bound with high affinity to the variant integrin complex. In
      contrast, the binding of elegantin and most significantly, recombinant Dendro. PN
      (PRGDNP) and Dendro. AN (ARGDNP) were abolished. These observations, taken
      together, are consistent with a model depicting the presence of distinct sites of
      RGD ligand recognition on the alpha(IIb)beta(3) complex that show the
      preferential recognition of specific RGD motifs. Competition experiments
      demonstrate a negative allosteric relationship between these RGD recognition
      sites.

PMID- 10642532
TI  - A possible origin of differences between calorimetric and equilibrium estimates
      of stability parameters of proteins.
AB  - To test the validity of thermodynamic parameters from the equilibrium method, we
      have studied the reversible heat-induced denaturations of lysozyme, ribonuclease
      A, cytochrome c and myoglobin at various pH values, using absorption spectral
      measurements. For each protein, if a linear temperature-dependence of the pre-
      and post-transition baselines is assumed for the analysis of the conformational
      transition curve, the estimate of DeltaH (the enthalpy change on denaturation at
      T(m), the midpoint of denaturation) is significantly less than DeltaH, the value
      obtained by the calorimetric measurements. If the analysis of thermal
      denaturation curves assumes that the temperature-dependence of pre- and post
      transition baselines is described by a parabolic function, there exists an
      excellent agreement between DeltaH(m) values of all proteins obtained from
      equilibrium and calorimetric methods. The latter analysis is supported by the
      studies on model compounds, for measurements of absorption properties of
      tyrosine, tryptophan and haem as a function of temperature suggested that the
      temperature-dependencies of the optical properties are indeed non-linear. We have
      observed that for each protein the constant-pressure heat-capacity change on
      denaturation (DeltaC(p)) determined from the plots of DeltaH versus T(m) is not
      only independent of the method of analysis of the transition curve, but it is
      also in excellent agreement with calorimetric DeltaC(p). An important conclusion
      of this study is that for these proteins that exhibit two-state character, all
      stability parameters are measured with the same error as that observed with a
      calorimeter.

PMID- 10642533
TI  - Signalling via ADP-ribosylation factor 6 lies downstream of phosphatidylinositide
      3-kinase.
AB  - ADP-ribosylation factor (ARF) 6 regulates plasma membrane trafficking and
      cortical actin formation by cycling between inactive GDP and active GTP-bound
      conformations. Here we show that agonist stimulation of phosphatidylinositide 3
      kinase (PI 3-kinase) activates a pathway that leads to ARF6 activation. We also
      describe experiments that propose a central role in this pathway for the PI 3
      kinase-dependent plasma membrane recruitment of the cytohesin-1 family of
      PtdIns(3,4,5)P(3)-binding ARF-exchange factors.

PMID- 10642534
TI  - Characterization of a second member of the subfamily of calcium-binding
      mitochondrial carriers expressed in human non-excitable tissues.
AB  - We have recently identified a subfamily of mitochondrial carriers that bind
      calcium, and cloned ARALAR1, a member of this subfamily expressed in human muscle
      and brain. We have now cloned a second human ARALAR gene (ARALAR2) coding for a
      protein 78.3% identical to Aralar1, but expressed in liver and non-excitable
      tissues. Aralar2 is identical to citrin, the product of the gene mutated in type
      II citrullinaemia [Kobayashi, Sinasac, Iijima, Boright, Begum, Lee, Yasuda,
      Ikeda, Hirano, Terazono et al. (1999) Nat. Genet. 22, 159-163]. A related
      protein, DmAralar, 69% identical to Aralar1, was found in Drosophila
      melanogaster, the DMARALAR locus lying on the right arm of the third chromosome,
      band 99F. The N-terminal half of Aralar2/citrin is able to bind calcium and this
      requires the presence of the two most distal EF-hands. The localization of
      Aralar2/citrin expressed in human cell lines is mitochondrial, the C-terminal
      half containing sufficient information for import and assembly into mitochondria.
      The C-terminal half of Aralar proteins is related to the yeast YPR020c gene, with
      a very high sequence conservation (54.3% identity), suggesting that these
      proteins play an important role. Thus Aralar proteins are probably expressed in
      all tissues in an isoform-specific fashion, where they function as calcium
      regulated metabolite (possibly anionic) carriers.

PMID- 10642535
TI  - Direct and reversed amino acid sequence pattern analysis: structural reasons for
      activity of reversed sequence sites and results of kinase site mutagenesis.
AB  - During studies of kinase phosphorylation, not all functional kinase
      phosphorylation may be found using consensus sequence patterns. This type of
      phosphorylation is termed 'non-consensus' or 'cryptic' phosphorylation. Results
      presented here based on molecular dynamics of short peptides show that protein
      kinases may phosphorylate not only established consensus sequences (reading a
      sequence from N-terminus to C-terminus) but also reversed consensus sequences
      (reading from C- to N-terminus). Several protein sequences were analysed and
      corresponding biochemical data were presented. Similarity of molecular shapes of
      direct and reversed consensus peptides, and sequence conservation in the regions
      of reversed sites in the analysed proteins, indicate that at least part of the
      phosphorylation sites considered as 'cryptic' may be explained in terms of
      reversed consensus pattern occurrences.

PMID- 10642536
TI  - 14-3-3zeta interacts with the alpha-chain of human interleukin 9 receptor.
AB  - Interleukin 9 (IL-9) exerts its pleiotropic effects through the IL-9 receptor (IL
      9R) complex, which consists of the IL-9R alpha-chain, which determines the
      cytokine specificity, and the IL-2 receptor gamma-chain. In the present study we
      used a modified yeast two-hybrid system to isolate cDNA species encoding proteins
      that interacted with the intracellular domain of the human IL-9R alpha-chain (hIL
      9Ralpha). We have identified 14-3-3zeta as an hIL-9Ralpha-interacting protein. We
      also mapped residues 518-522 (Arg-Ser(519)-Trp-Thr(521)-Phe) in hIL-9Ralpha and
      helix I of 14-3-3zeta as being important for interaction. Moreover, peptide
      competition experi-ments suggested that interaction between hIL-9Ralpha and 14-3
      3zeta requires the phosphorylation of Ser(519) or Thr(521). This is the first
      demonstration that 14-3-3 can interact with a non-tyrosine kinase receptor. The
      interaction between 14-3-3 and IL-9Ralpha but not IL-4Ralpha also suggests a
      potential role for 14-3-3 in determining cytokine specificity.

PMID- 10642537
TI  - Characterization and gene structure of a novel retinoblastoma-protein-associated
      protein similar to the transcription regulator TFII-I.
AB  - Retinoblastoma protein (Rb) is an important regulator of vertebrate cell cycle
      and development. It functions through a direct interaction with protein factors
      involved in cell cycle progression and differentiation. In the present study we
      characterized a novel Rb-associated protein, Cream1, which bound to Rb
      specifically through a C-terminal region. Cream1 contained 959 amino acid
      residues and migrated as a protein of approx. 120 kDa on SDS/PAGE. It was a
      widely expressed nuclear protein with a nuclear localization signal resembling
      that of the large T antigen of simian virus 40. Its primary sequence was
      characteristic of five direct repeats that were similar to, but distinct from,
      those of TFII-I, a multifunctional transcription regulator. Three additional
      regions were also highly conserved in both proteins. Cream1 exhibited an
      activation activity that was attributed to its N-terminal portion when assayed in
      yeast. Its relationship with the muscle-enhancer-binding protein MusTRD1 further
      suggests a role in regulating gene expression. The structural gene, CREAM1,
      contained 27 exons and spanned more than 150 kb. It was located at human
      chromosome 7q11.23 in a region deleted for Williams' syndrome, a
      neurodevelopmental disease with multisystem abnormalities, implying its
      involvement in certain disorders. Taken together, our results suggest that Cream1
      might serve as a positive transcription regulator under the control of Rb.

PMID- 10642539
TI  - Emerging infectious diseases of wildlife--threats to biodiversity and human
      health.
AB  - Emerging infectious diseases (EIDs) of free-living wild animals can be classified
      into three major groups on the basis of key epizootiological criteria: (i) EIDs
      associated with "spill-over" from domestic animals to wildlife populations living
      in proximity; (ii) EIDs related directly to human intervention, via host or
      parasite translocations; and (iii) EIDs with no overt human or domestic animal
      involvement. These phenomena have two major biological implications: first, many
      wildlife species are reservoirs of pathogens that threaten domestic animal and
      human health; second, wildlife EIDs pose a substantial threat to the conservation
      of global biodiversity.

PMID- 10642538
TI  - Platelet-derived growth factor (PDGF)-induced activation of signal transducer and
      activator of transcription (Stat) 5 is mediated by PDGF beta-receptor and is not
      dependent on c-src, fyn, jak1 or jak2 kinases.
AB  - Several growth factors activate signal transducers and activators of
      transcription (Stats) but the mechanism of Stat activation in receptor tyrosine
      kinase signalling has remained elusive. In the present study we have analysed the
      roles of different platelet-derived growth factor (PDGF)-induced tyrosine kinases
      in the activation of Stat5. Co-expression experiments in insect and mammalian
      cells demonstrated that both PDGF beta-receptor (PDGF beta-R) and Jak1, but not c
      Src, induced the activation of Stat5. Furthermore, immune-complex-purified PDGF
      beta-R was able to phosphorylate Stat5 directly. The role of the cytoplasmic
      tyrosine kinases in the PDGF-induced activation of Stat5 was further investigated
      by overexpressing kinase-negative (KN) and wild-type Jak and c-Src kinases. Jak1
      KN or Jak2-KN had no effect but both Src-KN and wild-type c-Src similarly
      decreased the PDGF-beta-R-induced activation of Stat5. The activation of both Src
      and Stat5 is dependent on the same tyrosine residues Tyr(579) and Tyr(581) in
      PDGF beta-R; thus the observed inhibition by Src might result from competition
      for binding of Stat5 to the receptor. Finally, fibroblasts derived from Src(-/-)
      and Fyn(-/-) mice showed normal pattern of PDGF-induced tyrosine phosphorylation
      of Stat5. Taken together, these results indicate that Stat5 is a direct substrate
      for PDGF beta-R and that the activation does not require Jak1, Jak2, c-Src or Fyn
      tyrosine kinases.

PMID- 10642540
TI  - Late cretaceous polar wander of the pacific plate: evidence of a rapid true polar
      wander event
AB  - We reexamined the Late Cretaceous-early Tertiary apparent polar wander path for
      the Pacific plate using 27 paleomagnetic poles from seamounts dated by
      (40)Ar/(39)Ar geochronology. The path shows little motion from 120 to 90 million
      years ago (Ma), northward motion from 79 to 39 Ma, and two groups of poles
      separated by 16 to 21 degrees with indistinguishable mean ages of 84 +/- 2 Ma.
      The latter phenomenon may represent a rapid polar wander episode (3 to 10 degrees
      per million years) whose timing is not adequately resolved with existing data.
      Similar features in other polar wander paths imply that the event was a rapid
      shift of the spin axis relative to the mantle (true polar wander), which may have
      been related to global changes in plate motion, large igneous province eruptions,
      and a shift in magnetic field polarity state.

PMID- 10642541
TI  - Neutral, single-component nickel (II) polyolefin catalysts that tolerate
      heteroatoms
AB  - More than half of the 170 million metric tons of polymers produced each year are
      polyolefins. Current technology uses highly active cationic catalysts, which
      suffer from an inability to tolerate heteroatoms such as oxygen, nitrogen, and
      sulfur. These systems require scrupulously clean starting materials and
      activating cocatalysts. A family of catalysts has been developed whose members
      are tolerant of both heteroatoms and less pure starting materials. These
      heteroatom-tolerant neutral late transition metal complexes are in fact highly
      active systems that produce high-molecular-weight polyethylene, polymerize
      functionalized olefins, and require no cocatalyst.

PMID- 10642542
TI  - Information storage and retrieval through quantum phase
AB  - Information was stored as quantum phase in an N-state Rydberg atom data register.
      One or more flipped states stored in an eight-state atomic wave packet could be
      retrieved in a single operation, in agreement with a recent proposal by Grover.

PMID- 10642543
TI  - Mirrorless lasing from mesostructured waveguides patterned by soft lithography
AB  - Mesostructured silica waveguide arrays were fabricated with a combination of
      acidic sol-gel block copolymer templating chemistry and soft lithography.
      Waveguiding was enabled by the use of a low-refractive index (1.15) mesoporous
      silica thin film support. When the mesostructure was doped with the laser dye
      rhodamine 6G, amplified spontaneous emission was observed with a low pumping
      threshold of 10 kilowatts per square centimeter, attributed to the
      mesostructure's ability to prevent aggregation of the dye molecules even at
      relatively high loadings within the organized high-surface area mesochannels of
      the waveguides. These highly processible, self-assembling mesostructured host
      media and claddings may have potential for the fabrication of integrated optical
      circuits.

PMID- 10642544
TI  - Detection of molecular alignment in confined films
AB  - Optical second harmonic generation was used to study the in-plane alignment of
      self-assembled silane monolayers attached to a glass surface under mechanical
      loading. The measurements allow correlation of the macroscopic forces acting on
      the monolayer with the average orientation and the azimuthal molecular alignment
      of the terminal molecular entity. Compression and shear forces lead to an
      alignment of the initially randomly oriented molecules on a macroscopic length
      scale. The change in azimuthal alignment of molecules under mechanical stress was
      found to be irreversible on the time scale of 12 hours, whereas changes of the
      molecular tilt angle were reversible.

PMID- 10642545
TI  - Ultrafast mid-infrared response of YBa(2)Cu(3)O(7-delta)
AB  - Optical spectra of high-transition-temperature superconductors in the mid
      infrared display a gap of in-plane conductivity whose role for superconductivity
      remains unresolved. Femtosecond measurements of the mid-infrared reflectivity of
      YBa(2)Cu(3)O(7-delta) after nonequilibrium optical excitation are used to
      demonstrate the ultrafast fill-in of this gap and reveal two gap constituents: a
      picosecond recovery of the superconducting condensate in underdoped and optimally
      doped material and, in underdoped YBa(2)Cu(3)O(7-delta), an additional
      subpicosecond component related to pseudogap correlations. The temperature
      dependent amplitudes of both contributions correlate with the antiferromagnetic
      41-millielectronvolt peak in neutron scattering, supporting the coupling between
      charges and spin excitations.

PMID- 10642546
TI  - All-optical magnetic resonance in semiconductors
AB  - A scheme is proposed wherein nuclear magnetic resonance (NMR) can be induced and
      monitored using only optical fields. In analogy to radio-frequency fields used in
      traditional NMR, circularly polarized light creates electron spins in
      semiconductors whose hyperfine coupling could tip nuclear moments. Time-resolved
      Faraday rotation experiments were performed in which the frequency of electron
      Larmor precession was used as a magnetometer of local magnetic fields experienced
      by electrons in n-type gallium arsenide. Electron spin excitation by a periodic
      optical pulse train appears not only to prepare a hyperpolarized nuclear moment
      but also to destroy it resonantly at magnetic fields proportional to the pulse
      frequency. This resonant behavior is in many ways supportive of a simple model of
      optically induced NMR, but a curious discrepancy between one of the observed
      frequencies and classic NMR values suggests that this phenomenon is more complex.

PMID- 10642547
TI  - Trienoic fatty acids and plant tolerance of high temperature.
AB  - The chloroplast membrane of higher plants contains an unusually high
      concentration of trienoic fatty acids. Plants grown in colder temperatures have a
      higher content of trienoic fatty acids. Transgenic tobacco plants in which the
      gene encoding chloroplast omega-3 fatty acid desaturase, which synthesizes
      trienoic fatty acids, was silenced contained a lower level of trienoic fatty
      acids than wild-type plants and were better able to acclimate to higher
      temperatures.

PMID- 10642548
TI  - One polypeptide with two aminoacyl-tRNA synthetase activities.
AB  - The genome sequences of certain archaea do not contain recognizable cysteinyl
      transfer RNA (tRNA) synthetases, which are essential for messenger RNA-encoded
      protein synthesis. However, a single cysteinyl-tRNA synthetase activity was
      detected and purified from one such organism, Methanococcus jannaschii. The amino
      terminal sequence of this protein corresponded to the predicted sequence of
      prolyl-tRNA synthetase. Biochemical and genetic analyses indicated that this
      archaeal form of prolyl-tRNA synthetase can synthesize both cysteinyl-tRNA(Cys)
      and prolyl-tRNA(Pro). The ability of one enzyme to provide two aminoacyl-tRNAs
      for protein synthesis raises questions about concepts of substrate specificity in
      protein synthesis and may provide insights into the evolutionary origins of this
      process.

PMID- 10642549
TI  - A H+-gated urea channel: the link between Helicobacter pylori urease and gastric
      colonization.
AB  - Acidic media trigger cytoplasmic urease activity of the unique human gastric
      pathogen Helicobacter pylori. Deletion of ureI prevents this activation of
      cytoplasmic urease that is essential for bacterial acid resistance. UreI is an
      inner membrane protein with six transmembrane segments as shown by in vitro
      transcription/translation and membrane separation. Expression of UreI in Xenopus
      oocytes results in acid-stimulated urea uptake, with a pH profile similar to
      activation of cytoplasmic urease. Mutation of periplasmic histidine 123 abolishes
      stimulation. UreI-mediated transport is urea specific, passive, nonsaturable,
      nonelectrogenic, and temperature independent. UreI functions as a H+-gated urea
      channel regulating cytoplasmic urease that is essential for gastric survival and
      colonization.

PMID- 10642550
TI  - Transmission of vesicular stomatitis virus from infected to noninfected black
      flies co-feeding on nonviremic deer mice.
AB  - Vesicular stomatitis is an economically important arboviral disease of livestock.
      Viremia is absent in infected mammalian hosts, and the mechanism by which insects
      become infected with the causative agents, vesicular stomatitis viruses, remains
      unknown. Because infected and noninfected insects potentially feed on the same
      host in nature, infected and noninfected black flies were allowed to feed on the
      same host. Viremia was not detected in the host after infection by a black fly
      bite, but because noninfected black flies acquired the virus while co-feeding on
      the same host with infected black flies, it is concluded that a viremic host is
      not necessary for an insect to be infected with the virus. Thus co-feeding is a
      mechanism of infection for an insect-transmitted virus.

PMID- 10642551
TI  - Transgenic mouse model of stunned myocardium.
AB  - Stunned myocardium is a syndrome of reversible contractile failure that
      frequently complicates coronary artery disease. Cardiac excitation is uncoupled
      from contraction at the level of the myofilaments. Selective proteolysis of the
      thin filament protein troponin I has been correlated with stunned myocardium.
      Here, transgenic mice expressing the major degradation product of troponin I
      (TnI1-193) in the heart were found to develop ventricular dilatation, diminished
      contractility, and reduced myofilament calcium responsiveness, recapitulating the
      phenotype of stunned myocardium. Proteolysis of troponin I also occurs in
      ischemic human cardiac muscle. Thus, troponin I proteolysis underlies the
      pathogenesis of a common acquired form of heart failure.

PMID- 10642552
TI  - Role of the enteric nervous system in the fluid and electrolyte secretion of
      rotavirus diarrhea.
AB  - The mechanism underlying the intestinal fluid loss in rotavirus diarrhea, which
      often afflicts children in developing countries, is not known. One hypothesis is
      that the rotavirus evokes intestinal fluid and electrolyte secretion by
      activation of the nervous system in the intestinal wall, the enteric nervous
      system (ENS). Four different drugs that inhibit ENS functions were used to obtain
      experimental evidence for this hypothesis in mice in vitro and in vivo. The
      involvement of the ENS in rotavirus diarrhea indicates potential sites of action
      for drugs in the treatment of the disease.

PMID- 10642553
TI  - A role for histone acetylation in the developmental regulation of VDJ
      recombination.
AB  - VDJ recombination is developmentally regulated in vivo by enhancer-dependent
      changes in the accessibility of chromosomal recombination signal sequences to the
      recombinase, but the molecular nature of these changes is unknown. Here histone
      H3 acetylation was measured along versions of a transgenic VDJ recombination
      reporter and the endogenous T cell receptor alpha/delta locus. Enhancer activity
      was shown to impart long-range, developmentally regulated changes in H3
      acetylation, and H3 acetylation status was tightly linked to VDJ recombination.
      H3 hyperacetylation is proposed as a molecular mechanism coupling enhancer
      activity to accessibility for VDJ recombination.

PMID- 10642554
TI  - A critical role for murine complement regulator crry in fetomaternal tolerance.
AB  - Complement is a component of natural immunity. Its regulation is needed to
      protect tissues from inflammation, but mice with a disrupted gene for the
      complement regulator decay accelerating factor were normal. Mice that were
      deficient in another murine complement regulator, Crry, were generated to
      investigate its role in vivo. Survival of Crry-/- embryos was compromised because
      of complement deposition and concomitant placenta inflammation. Complement
      activation at the fetomaternal interface caused the fetal loss because breeding
      to C3-/- mice rescued Crry-/- mice from lethality. Thus, the regulation of
      complement is critical in fetal control of maternal processes that mediate tissue
      damage.

PMID- 10642555
TI  - Rad6-dependent ubiquitination of histone H2B in yeast.
AB  - Although ubiquitinated histones are present in substantial levels in vertebrate
      cells, the roles they play in specific biological processes and the cellular
      factors that regulate this modification are not well characterized. Ubiquitinated
      H2B (uH2B) has been identified in the yeast Saccharomyces cerevisiae, and
      mutation of the conserved ubiquitination site is shown to confer defects in
      mitotic cell growth and meiosis. uH2B was not detected in rad6 mutants, which are
      defective for the ubiquitin-conjugating enzyme Ubc2, thus identifying Rad6 as the
      major cellular activity that ubiquitinates H2B in yeast.

PMID- 10642556
TI  - Mouse oviduct-specific glycoprotein gene: genomic organization and structure of
      the 5'-flanking regulatory region.
AB  - A member of the chitinase protein family, oviduct-specific glycoprotein (OGP),
      can directly associate with gametes or with the early embryo in the oviduct.
      Although the glycoprotein is widely distributed among mammalian species and there
      is indirect evidence concerning the involvement of the molecule in the
      fertilization process, its physiological functions are far from completely
      understood. To understand the fundamental mechanisms that direct gene expression
      as well as to know the physiological significance of OGP, we have isolated and
      characterized a mouse OGP gene (mogp-1). The gene was found to span 13.4
      kilobases (kb) including 11 exons and 10 introns. The genomic organization of
      mogp-1 is well conserved compared to the other members of the chitinase family.
      Two transcription initiation sites were found at positions 18 and 14 upstream
      from the first ATG codon. Fluorescence in situ hybridization analysis
      demonstrated that the mogp-1 was located on the R-positive F3 band of mouse
      chromosome 3. Although the putative promoter region of mogp-1 lacked typical
      TATA, CAAT, or GC box sequences, the region contained several motif sequences of
      transcription factor binding sites including 10 half-palindromic estrogen
      responsive elements (ERE) and an imperfect ERE. Transient transfection
      experiments demonstrated that promoter activity could be modulated by various
      sequences within the 2.2 kb of the 5'-flanking region, and that the mogp-1
      promoter was transactivated in an estrogen receptor-positive cell line, MCF-7, by
      the addition of estradiol-17beta (E(2)). In addition, relevant promoter activity
      for E(2) responsiveness resides within the first 270 base pairs upstream of the
      mogp-1. These findings should facilitate our understanding of the regulation of
      OGP gene expression, and they may be helpful for designing experiments to unravel
      the role of OGP in the process of mammalian fertilization.

PMID- 10642557
TI  - Effects of diets containing gossypol on reproductive capacity of rainbow trout
      (Oncorhynchus mykiss).
AB  - We evaluated five practical diets in which 0%, 25%, 50%, 75%, and 100% (dietary
      treatments 1-5) of fish meal protein was replaced by solvent-extracted cottonseed
      meal protein. Adult rainbow trout (initial average weight 247 +/- 8 g) were fed
      the diets over a period of 131 days during which a general 2-fold body weight
      increase occurred. The total diet gossypol concentration (free and protein-bound)
      showed a gradual increase with increased cottonseed meal substitution. Blood
      samples were collected on Days 0, 64, 112, and 131 for hematological and steroid
      hormone determination in plasma of males and females. Hemoglobin content was
      significantly reduced in fish from treatment 5 (7.9 +/- 0.3 g/dl) in comparison
      to treatments 1-3 (10.3-10.9 g/dl). After 112 and 131 days of feeding, testis
      weights, concentrations of testosterone, and 11-ketotestosterone were elevated in
      fish from dietary treatments 2 and 3 in comparison to control and diets 4 and 5.
      On Day 71, sperm were collected from 6 fish per dietary treatment to assess sperm
      quality. No significant differences in sperm concentrations (7.2-9.8 x 10(9)/ml),
      motility (78-89%), and standardized (300 x 10(5) sperm/egg) fertilizing ability
      (18.9-22.6% hatched embryos) were found. Total gossypol concentrations in blood
      plasma differed significantly among treatments, and the levels were among the
      highest ever recorded in animals fed cottonseed-supplemented diets (2.9 +/- 0.2,
      11.7 +/- 4.1, 21.7 +/- 1.4, and 29.9 +/- 3.9 microg/ml, for treatments 2-5,
      respectively). The major portion of gossypol in blood plasma was protein-bound
      (81-93%). This was in contrast to minute amounts of gossypol present in seminal
      plasma, mostly in free form (0.02-0.18 microg/ml), which indicates the presence
      of a barrier between general circulation and the testis with respect to gossypol
      distribution in lower vertebrates. Thus, the reproductive parameters of male
      rainbow trout examined in this study were not significantly affected by feeding
      cottonseed meal for 131 days.

PMID- 10642558
TI  - Bovine blastocyst-derived trophectoderm and endoderm cell cultures: interferon
      tau and transferrin expression as respective in vitro markers.
AB  - Continuous cultures of bovine trophectoderm (CT-1 and CT-5) and bovine endoderm
      (CE-1 and CE-2) were initiated and maintained on STO feeder cells. CT-1 and CT-5
      were derived from the culture of intact, 10- to 11-day in vitro-produced
      blastocysts. CE-1 and CE-2 were derived from the culture of immunodissected inner
      cell masses of 7- to 8-day in vitro-produced blastocysts. The cultures were
      routinely passaged by physical dissociation. Although morphologically distinct,
      the trophectoderm and endoderm both grew as cell sheets of polarized epithelium
      (dome formations) composed of approximately cuboidal cells. Both cell types,
      particularly the endoderm, grew on top of the feeder cells for the most part.
      Trophectoderm cultures grew faster, relative to endoderm, in large, rapidly
      extending colonies of initially flat cells with little or no visible lipid. The
      endoderm, in contrast, grew more slowly as tightly knit colonies with numerous
      lipid vacuoles in the cells at the colony centers. Ultrastructure analysis
      revealed that both cell types were connected by desmosomes and tight junctional
      areas, although these were more extensive in the trophectoderm. Endoderm was
      particularly rich in rough endoplasmic reticulum and Golgi apparatus indicative
      of cells engaged in high protein production and secretion. Interferon tau
      expression was specific to trophectoderm cultures, as demonstrated by reverse
      transcription-polymerase chain reaction, Western blot, and antiviral activity;
      and this property may act as a marker for this cell type. Serum protein
      production specific to endoderm cultures was demonstrated by Western blot; this
      attribute may be a useful marker for this cell type. This simple coculture method
      for the in vitro propagation of bovine trophectoderm and endoderm provides a
      system for assessing their biology in vitro.

PMID- 10642559
TI  - Culture of in vitro-produced bovine embryos with vitamin E improves development
      in vitro and after transfer to recipients.
AB  - Detrimental effects of oxygen-derived free radicals on embryos during culture
      have been demonstrated in several species. Vitamin E occurs naturally in cell
      membranes and protects cells from oxidative stress. Under some conditions,
      vitamin C acts synergistically to enhance the antioxidant effects of vitamin E, a
      benefit that may be further enhanced by EDTA. The present experiments concerned
      culture of bovine embryos derived from in vitro-matured, fertilized oocytes with
      vitamin E, vitamin C, and EDTA in a chemically defined culture medium + 0.2% BSA
      at 5% O(2), 5% CO(2), and 90% N(2). In the first experiment, more zygotes
      developed to expanded blastocysts (17%, n = 224, P < 0.05) when culture medium
      contained 100 microM vitamin E than in control medium (11%, n = 234). Development
      to early, expanded, and hatched blastocysts was lower with vitamins E and C
      combined than with vitamin E alone (15%, 9%, and 2% vs. 24%, 17%, and 5%,
      respectively; P < 0.05), as was the mean number of cells per blastocyst (56 vs.
      84, P < 0.05). Addition of EDTA (3 microM) failed to improve development over
      that in culture with vitamin E + vitamin C. In experiment 2, in vitro-produced
      embryos cultured 5.5 days in medium with or without 100 microM vitamin E were
      transferred nonsurgically to recipient cows and heifers and then collected
      nonsurgically 7 days later. Embryos cultured with vitamin E (n = 37) were
      approximately 63% larger in surface area than controls (1.16 mm(2) vs. 0.71 mm(2)
      surface area; n = 27, P < 0.04).

PMID- 10642560
TI  - In vitro maturation and ultrastructural observation of cryopreserved minke whale
      (Balaenoptera acutorostrata) follicular oocytes.
AB  - Minke whale (Balaenoptera acutorostrata) follicular oocytes were cryopreserved by
      a slow-step freezing procedure using ethylene glycol. The morphologically viable
      proportion of postthawed minke whale follicular oocytes was 39.7%. The maturity
      of the animals (immature and mature whales) or the presence or absence of cumulus
      cells (CC) did not affect the proportion of morphologically viable oocytes.
      Postthawed oocytes were examined for nuclear status after in vitro maturation.
      The presence of CC (29.1%) significantly enhanced (P < 0.05) the proportion of
      oocytes at metaphase I/anaphase I/telophase I stages compared to results with the
      absence of CC (13.5%). A total of 4 of 194 postthawed oocytes matured to the
      second metaphase stage after culture for 5.5 days with or without CC. The
      cryopreserved immature oocytes obtained from immature and mature whales were
      processed to examine the ultrastructure by transmission electron microscopy.
      Varying ultrastructural damage to the cytoplasm was observed as a result of the
      cryopreservation procedures. These results show that 20-30% of cryopreserved
      minke whale follicular oocytes can resume meiosis in vitro, but damage induced by
      the freezing and thawing procedures was observed.

PMID- 10642561
TI  - Participation of the mouse implanting trophoblast in nitric oxide production
      during pregnancy.
AB  - While considerable progress has been made in elucidating nitric oxide (NO)
      regulatory mechanisms in the later stages of gestation, much less is known about
      its synthesis and role during embryo implantation. Thus, to evaluate the
      participation of the trophoblast in the production of NO during this phase, this
      study focused on NADPH-diaphorase activity and the distribution of NO synthase
      isoforms (NOS) using immunohistochemistry in pre- and postimplantation mouse
      embryos in situ and in vitro, as well as on NO production itself, measured as
      total nitrite, in trophoblast culture supernatants (Griess reaction). No NADPH
      diaphorase activity was found in preimplanting embryos except after culturing for
      at least 48 h, when a few trophoblastic giant cells were positive. Conversely,
      postimplantation trophoblast cells either lodged into the implantation chamber
      (in situ) or after culturing (in vitro) showed intense NADPH-diaphorase activity.
      Also in the postimplantation trophoblast, the endothelial and inducible NOS (eNOS
      and iNOS) isoforms were immunodetected, under both in situ and in vitro
      conditions, although in different patterns. Extracts of ectoplacental cone also
      revealed bands of 135 and 130 kDa on SDS-PAGE that reacted with anti-eNOS and
      anti-iNOS, respectively, on Western blot. Analysis of the culture supernatant
      demonstrated that the nitrite concentration was 1) proportional to the number of
      cultured trophoblast cells, 2) almost completely abolished in the presence of
      N(omega)-nitro-L-arginine methyl ester, and 3) increased 2-fold in cultures
      stimulated with gamma-interferon. These results strongly suggest the production
      of NO from constitutive and inducible isoforms of NOS by the implanting mouse
      trophoblast. They also emphasize the possibility of the participation of these
      cells in vasodilatation and angiogenesis, and in cytotoxic mechanisms involved in
      the intense phagocytosis of injured maternal cells, which occur during the
      implantation process.

PMID- 10642563
TI  - Expression of carbohydrate antigens in the goat uterus during early pregnancy and
      on steroid-treated polarized uterine epithelial cells in vitro.
AB  - Our objectives were to determine whether specific fucosylated carbohydrate
      antigens, associated with uterine receptivity in rodents, are expressed in
      pregnant caprine uterine tissues and polarized uterine luminal epithelial (ULE)
      cells in culture. Immunofluorescence microscopy on frozen endometrium revealed
      that expression of the H-type 1 antigen, confined to epithelial cells, was
      regulated during early pregnancy. Staining was high on Day 5 and low on Days 11
      and 13. Strong, uniform apical staining was characteristic of ULE cells between
      Days 15 and 19 but declined markedly by Day 25. Immunofluorescence analysis of
      the apical surface of polarized ULE cells cultured in steroid-free medium
      revealed weak and diffuse staining for the H-type 1 antigen, while progesterone
      (P(4)) treatment resulted in the formation of aggregates of punctate staining
      along the apical surface. Domain-specific biotinylation of polarized ULE cells,
      coupled with streptavidin precipitation and Western blotting, revealed that six
      apical surface proteins (31, 33, 42, 55, 60, and 70 kDa) carry the H-type 1
      antigen. Therefore, H-type 1 antigen expression is up-regulated in vivo during
      the periimplantation period, stimulated by P(4) on polarized ULE cells in
      culture, and may be a useful marker for uterine receptivity in this species.

PMID- 10642562
TI  - Decreased progesterone levels and progesterone receptor antagonists promote
      apoptotic cell death in bovine luteal cells.
AB  - We tested the hypothesis that progesterone (P(4)) acts at a local level to
      inhibit luteal apoptosis. Initial experiments employed aminoglutethimide, a P450
      cholesterol side-chain cleavage inhibitor, to inhibit steroid synthesis. Cultured
      bovine luteal cells were treated with aminoglutethimide (0.15 mM) +/- P(4) (500
      ng/ml) for 48 h. Luteal cells were recovered and snap frozen for isolation and
      analysis of oligonucleosomal DNA fragmentation or fixed for morphological
      analysis. Medium was collected for analysis of P(4) levels by RIA.
      Aminoglutethimide inhibited P(4) synthesis by > 95% and increased the level of
      apoptosis as evidenced by (32)P-labeled oligonucleosomal DNA fragmentation (>
      40%). P(4) supplementation inhibited the onset of apoptosis that was induced by
      aminoglutethimide. These data were further supported by morphological assessment
      of apoptotic cells utilizing a Hoechst staining technique and together strongly
      suggest that P(4) has anti-apoptotic capacity. Using reverse transcription
      polymerase chain reaction, we were able to isolate a 380-base pair cDNA from the
      bovine corpus luteum (CL) that was 100% homologous to the progesterone receptor
      (PR) previously found in bovine oviductal tissue. Furthermore, PR transcripts
      were present in large and small luteal cells. Immunohistochemistry also revealed
      that PR protein was present in both large and small luteal cells. To determine
      whether the anti-apoptotic effect of P(4) was regulated at the receptor level,
      luteal cells were cultured in the presence of PR antagonists, RU-486 and
      onapristone, for 48 h. Both antagonists caused approximately a 40% increase in
      (32)P-labeled oligonucleosomal DNA fragmentation. Interestingly, there was no
      difference (P >/= 0.05) in P(4) levels after treatment with PR antagonists. These
      observations support the concept that P(4) represses the onset of apoptosis in
      the CL by a PR-dependent mechanism.

PMID- 10642564
TI  - A longitudinal study of leptin during development in the male rhesus monkey: the
      effect of body composition and season on circulating leptin levels.
AB  - The objective of this study was to examine longitudinal changes in serum leptin
      concentrations during development and to correlate those changes with sexual
      development in male rhesus monkeys housed under natural environmental conditions.
      Blood samples were drawn from 8 control animals approximately every other month
      from 10 to 30 mo of age and thereafter monthly through 80 mo of age. Leptin
      levels declined through the juvenile period until the onset of puberty and were
      negatively correlated with body weight. Seven of the eight animals became
      sexually mature during the breeding season of their fourth year of life. Puberty
      was delayed in the other animal until the subsequent breeding season. There were
      no significant fluctuations in leptin levels prior to or in association with the
      pubertal rise in LH and testosterone (T) secretion. During the peripubertal
      period, levels of leptin varied between 2 and 3 ng/ml. The animal that exhibited
      delayed puberty had the lowest body weight and highest leptin levels during this
      period. With the achievement of sexual maturity, leptin levels varied seasonally,
      with peak levels in the late winter (Jan-Mar) and a nadir in the late summer (Aug
      Sept). A late winter rise in leptin was also evident in most of the animals
      during Years 2 and 3, but not during Year 4. In the fall of Years 5 and 6, the
      seasonal rise in leptin concentrations lagged 3-4 mo behind the seasonal increase
      in LH and T. In the fall of Year 5, but not thereafter, leptin levels were
      positively related to percent body fat and negatively correlated with lean body
      mass. The data do not support the hypothesis that increasing leptin
      concentrations trigger the onset of puberty in the male rhesus monkey. During the
      juvenile period and after sexual maturation, but not during the peripubertal
      period, leptin secretion varied with season in the animals; but the environmental
      factors that cue or drive this rhythm remain to be determined.

PMID- 10642565
TI  - Butyrolactone I reversibly inhibits meiotic maturation of bovine oocytes,Without
      influencing chromosome condensation activity.
AB  - In this study, butyrolactone I (BL I), a potent and specific inhibitor of cyclin
      dependent kinases, was shown to block germinal vesicle (GV) breakdown (GVBD) in
      bovine oocytes in a concentration-dependent manner; GVBD was almost totally
      inhibited over the course of 24-48 h of culture when 100 microM BL I was included
      in tissue culture medium 199 containing either polyvinyl alcohol or BSA.
      Correlated with this inhibition was the failure of either p34(cdc2) kinase or
      mitogen-activated protein (MAP) kinase to become activated, and it was unlikely
      that BL I directly inhibited MAP kinase, since 100 microM BL I did not inhibit
      MAP kinase activity present in extracts obtained from metaphase II-arrested
      bovine eggs that possess high levels of MAP kinase activity. Nevertheless, the
      formation of highly condensed bivalents was observed in 78% of the BL I-treated
      GV-intact oocytes. This result suggests that chromosome condensation during first
      meiosis in bovine oocytes does not require the activity of either p34(cdc2)
      kinase or MAP kinase. Treatment of BL I-arrested oocytes with okadaic acid (OA)
      did not result in either the activation of p34(cdc2) kinase or MAP kinase, or
      inducement of GVBD. The BL I-induced block of GVBD for 24 h was reversible, and a
      subsequent 24-h culture resulted in 90% of oocytes reaching metaphase II with
      emission of the first polar body. Correlated with the progression to and arrest
      at metaphase II was the full activation of both p34(cdc2) and MAP kinases. The
      reversibility after 48 h of culture in BL I was partially decreased when compared
      to that achieved after an initial 24-h culture. Fertilization in vitro of these
      eggs resulted in a high incidence of both sperm penetration and pronucleus
      formation (88% and 70%, respectively).

PMID- 10642566
TI  - Sperm mobility: phenotype in roosters (Gallus domesticus) determinedby
      concentration of motile sperm and straight line velocity.
AB  - Previous research demonstrated that sperm mobility, i.e., the net movement of a
      sperm population, is a quantitative trait of the domestic fowl. However, the
      cellular basis for this trait was unknown. In the present work, individual motile
      sperm were evaluated with a Hobson SpermTracker in order to identify one or more
      properties of motile sperm that could account for variation in sperm mobility
      observed among males. A method was validated for assessing sperm motion over an
      erythrocyte monolayer at body temperature. A small-scale experiment with roosters
      from the tails and center of a normal distribution of sperm mobility phenotypes
      (n = 33 roosters) demonstrated that straight line velocity (VSL) and motile
      concentration were critical to expression of phenotype. The importance of these
      variables was confirmed with a large-scale experiment using a representative
      subpopulation (n = 100 roosters). VSL of individual sperm at 41 degrees C ranged
      between 5 and 100 microm/sec. VSL averaged 32, 39, and 40 microm/sec for low,
      average, and high sperm mobility phenotypes. Sperm were diluted to 1.2 x 10(6)/ml
      for motion analysis. Mean motile concentrations were 0.52, 0.84, and 0.95 x
      10(6)/ml for low, average, and high sperm mobility phenotypes. Motile
      concentration was correlated with sperm mobility (r = 0.71). VSL appeared to have
      an additive effect as it was correlated with straightness of sperm cell
      trajectory (r = 0.79).

PMID- 10642567
TI  - Expression of estrogen receptor beta is developmentally regulated in reproductive
      tissues of male and female mice.
AB  - By the use of ribonuclease protection assay (RPA) combined with
      immunohistochemical techniques, the expression of estrogen receptor (ER) alpha
      and ERbeta was mapped in the developing gonads and reproductive tracts of male
      and female mice from fetal day 14 to postnatal day 26 (PND 26). This study was
      designed to determine the pattern of expression of both ER subtypes in specific
      tissue compartments during development. In ovaries, ERalpha mRNA was detected at
      all ages examined; ERbeta mRNA was seen as early as PND 1, and its expression
      increased with age. Immunolocalization showed ERbeta in differentiating granulosa
      cells of the ovary, whereas ERalpha was predominantly seen in interstitial cells.
      The remainder of the female reproductive tract showed ERalpha mRNA at all ages
      examined with little or no significant levels of ERbeta, except on PND 1 when a
      low level of message appeared. In males, ERalpha and ERbeta mRNA were detected in
      the fetal testis; however, ERbeta gradually increased until PND 5 and
      subsequently diminished to undetectable levels by PND 26. Immunolocalization
      showed ERalpha in the interstitial compartment of the testis, whereas ERbeta was
      seen predominantly in developing spermatogonia. The remainder of the male
      reproductive tract showed varying amounts of both receptors by RPA and
      immunostaining throughout development. These studies provide information useful
      in studying the role of both ER subtypes in normal differentiation, and they
      provide indications of differential tissue expression during development.

PMID- 10642568
TI  - Identification of human sperm peptide sequence involved in egg binding for
      immunocontraception.
AB  - Development of a vaccine based on sperm antigens represents a promising approach
      to contraception. The sperm-zona pellucida (ZP) interaction constitutes the most
      important event in the fertilization process, and the molecular sequences
      involved at this site may provide the most attractive candidates for
      immunocontraception. In the present study, using the phase peptide display
      technique, a novel dodecamer sequence, designated as YLP(12), was identified that
      is involved in sperm-ZP recognition/binding. The synthetic 12-mer peptide based
      on this sequence and its monovalent Fab' antibodies specifically and
      significantly (P < 0.05) inhibited human sperm-ZP binding. In Western blot and
      immunoprecipitation procedures, the YLP(12) peptide recognized the ZP3 component
      of solubilized human ZP proteins. In the Western blot procedure involving 10
      different human tissue extracts, the anti-YLP(12) Fab' antibodies recognized a
      protein band of approximately 72 +/- 2 kDa only in the testis lane. The peptide
      sequence was localized on the acrosomal region of the human sperm cell. These
      findings indicate that the novel testis-specific 12-mer YLP(12) that is present
      in the acrosomal region and is involved in human sperm-ZP interaction may find
      applications in contraceptive vaccine development, as well as in diagnosis and
      treatment of male infertility mediated through sperm dysfunction.

PMID- 10642569
TI  - A role of insulin-like growth factor I for follicle-stimulating hormone receptor
      expression in rat granulosa cells.
AB  - The present study was undertaken to identify the mechanisms underlying the effect
      of insulin-like growth factor I (IGF-I) on FSH receptor (FSHR) in rat granulosa
      cells. Treatment with FSH produced a substantial increase in FSHR mRNA level, as
      was expected, while concurrent treatment with increasing concentrations of IGF-I
      brought about dose-dependent increases in FSH-induced FSHR mRNA, with a maximal
      response 2.8-fold greater than that induced by FSH alone. IGF-I, either alone or
      in combination with FSH, did not affect intracellular cAMP levels, whereas it
      enhanced the effect of 8-bromo (Br)-cAMP on FSHR mRNA production. Taken together,
      these findings suggest that the ability of IGF-I to enhance FSH action concerning
      the induction of FSHR is exerted at sites distal to cAMP generation. We then
      investigated whether the effect of IGF-I and FSH on FSHR mRNA levels was the
      result of increased transcription and/or altered mRNA stability. The rates of
      FSHR mRNA gene transcription, assessed by nuclear run-on transcription assay,
      were not increased by the addition of IGF-I. On the other hand, the decay curves
      for the 2. 4-kilobase (kb) FSHR mRNA transcript in primary granulosa cells
      significantly altered the slope of the FSHR mRNA decay curve in the presence of
      IGF-I and increased the half-life of the FSHR mRNA transcript. These data suggest
      a possible role for changes in FSHR mRNA stability in the IGF-I-induced
      regulation of FSHR in rat granulosa cells. Treatment with activin produced a
      substantial increase in FSHR mRNA level, as was expected, and concurrent
      treatment with IGF-I did not affect activin-induced FSHR mRNA. Our data suggest
      that the IGF-I effect on FSHR expression is related to cAMP production induced by
      FSH and may maintain FSHR mRNA level because of prolonged FSHR mRNA stability.

PMID- 10642570
TI  - Expression of parathyroid hormone-related peptide (PTH-rp) and its receptorin the
      porcine ovary: regulation by transforming growth factor-beta and possible
      paracrine effects of granulosa cell PTH-rp secretion on theca cells.
AB  - Parathyroid hormone-related peptide (PTH-rp) and the PTH-rp receptor are
      expressed in certain cancers as well as in many normal tissues. To evaluate the
      expression of this Ca(2+)-regulating hormone and its receptor in porcine ovary,
      we isolated partial cDNAs encoding homologous PTH-rp and PTH-rp receptor using
      reverse transcription-polymerase chain reaction (RT-PCR). The cDNA encoding PTH
      rp (419 base pairs [bp]) was 92% and 87% homologous to human and rat sequences,
      respectively, while the PTH-rp receptor clone (167 bp) was 94% and 91% identical
      to the human and rat genes. Qualitative estimates of PTH-rp mRNA by RT-PCR
      indicated that the PTH-rp gene is expressed at high levels in the corpus luteum
      but is undetectable in granulosa and theca cells isolated from small (1-5 mm) and
      medium-sized (5-8 mm) antral follicles. In contrast, PTH-rp receptor transcripts
      were most abundant in corpora lutea and theca cells, and least abundant (albeit
      detectable) in granulosa cells. Regulation of PTH-rp protein production was
      assessed in serum-free monolayer cultures of porcine granulosa cells.
      Transforming growth factor (TGF)-beta1 (100 ng/ml) increased PTH-rp
      concentrations (assayed by two-site immunoradiometric assay of culture media) as
      well as corresponding PTH-rp mRNA accumulation (assessed by RT-PCR) in a time
      dependent manner, with maximal responses of 3- to 5-fold at 96 h. TGF-beta1 dose
      response studies revealed an ED(50) of 0. 24-0.38 ng/ml with a maximal effect at
      30 ng/ml. Other growth factors and hormones, including insulin, insulin-like
      growth factor (type I), epidermal growth factor, FSH, estradiol, and interleukin
      1, failed to alter PTH-rp secretion. Biological effects of PTH-rp were evident in
      purified porcine theca cells. Using the Ca(2+)-sensitive fluorescent indicator
      dye, fura-2, and digital imaging videomicroscopy, we found that PTH-rp (1 microM)
      stimulated intracellular free calcium ion concentrations ([Ca(2+)](i)) in single
      porcine theca cells. The [Ca(2+)](i) elevation was characterized by a slow and
      prolonged rise. After PTH-rp stimulation, theca cells maintained responsiveness
      to hormone stimulation by LH, which elicited a typical theca cell [Ca(2+)](i)
      response. Our results allow a hypothesis of a paracrine intrafollicular signaling
      system involving interaction between theca cell-derived TGF-beta and granulosa
      cell-derived PTH-rp, with feedback by PTH-rp on theca cells. Alternatively,
      expression of mRNAs encoding PTH-rp and its receptor in corpora lutea suggests
      that this peptide may play a role in luteal cell function. The precise role of
      this intraovarian PTH-rp system will require further study.

PMID- 10642571
TI  - Identification and characterization of a bovine sperm protein that binds
      specifically to single-stranded telomeric deoxyribonucleic acid.
AB  - Telomere DNA at the physical termini of chromosomes forms a single-stranded 3'
      overhang. In lower eukaryotes, e.g., ciliated protozoa, this DNA extension is
      capped by specific proteins that have been structurally and functionally
      characterized. Much less is known about single-stranded telomere DNA-binding
      proteins in vertebrates. Here we describe a new protein from bovine sperm
      designated bsSSTBP that specifically interacts with single-stranded (TTAGGG)(N)
      DNA. The bsSSTBP was extracted from nuclei by 0.6 M KCl. The native size of this
      protein, estimated by gel filtration, was 20-40 kDa. SDS-PAGE of the UV cross
      linked complex between bsSSTBP and telomere DNA indicated that several
      polypeptides are involved in complex formation. Bovine sSSTB had high specificity
      toward nucleotide sequence, since single nucleotide substitutions in the
      (TTAGGG)(4) substrate suppressed binding. The minimal number of (TTAGGG) repeats
      required for binding of bsSSTBP was 3, and the protein recognized linear but not
      folded DNA structures. We propose that the bsSSTBP participates in telomere
      telomere interactions and the telomere membrane localization observed in mature
      sperm. In mammals, somatic telomere-binding proteins are apparently substituted
      by sperm-specific ones that may lead to a structural reorganization of telomere
      domains to fulfill functions important during meiosis and fertilization.

PMID- 10642572
TI  - Testicular regression in response to food restriction and short photoperiod in
      white-footed mice (Peromyscus leucopus) is mediated by apoptosis.
AB  - Short day lengths or reduced food availability are salient cues for small mammals
      that breed seasonally. Photoperiod-mediated gonadal regression in white-footed
      mice (Peromyscus leucopus) is a slow, orderly process that involves testicular
      apoptosis. Testicular regression in response to restricted caloric intake is
      relatively rapid, and it is generally reversed quickly by ad libitum (ad lib)
      feeding. To determine the contribution of apoptotic cell death during food
      restriction, and to examine possible interactions with photoperiod, mice housed
      in long (16L:8D) or short (8L:16D) photoperiods were fed either ad lib or 70% of
      their average ad lib intake. Testes were removed at 2, 4, 6, or 8 wk of
      experimental treatment. Apoptotic activity was determined by in situ TUNEL
      labeling and assessment of DNA laddering. Significant (P < 0.05) gonadal
      regression in response to short days was first detected at 8 weeks in mice fed ad
      lib. Food-restricted, long-day mice also showed significant testicular regression
      at 8 wk. Combined exposure to short day lengths and food restriction resulted in
      significant testicular regression at 6 wk (P < 0.05). TUNEL labeling was
      slightly, though significantly, elevated in germ cells at 2 and 4 wk in long-day
      food-restricted mice (P < 0.05). TUNEL labeling was also elevated in short-day
      food-restricted males at these early times but then increased nearly 5-fold at 6
      and 8 wk in these mice (P < 0.001). DNA laddering confirmed elevated apoptosis.
      Overall apoptotic activity negatively correlated with paired testis mass, plasma
      testosterone, and spermatogenic index measurements in both ad lib and food
      restricted males. Few histological markers of necrotic cell death were observed
      in any group. Taken together, these results suggest that testicular regression in
      response to limited caloric intake or short days is mediated by apoptosis.

PMID- 10642573
TI  - Impact of bovine oocyte maturation media on oocyte transcript levels, blastocyst
      development, cell number, and apoptosis.
AB  - The objectives were 1) to investigate the effects of oocyte maturation in serum
      free and amino acid-supplemented defined media on oocyte transcript levels,
      blastocyst cell number, and apoptosis; 2) to investigate the influence of oocyte
      maturation culture atmosphere on blastocyst development, total cell number, and
      apoptosis; and 3) to examine the influence of epidermal growth factor (EGF)
      during oocyte maturation on blastocyst cell number and apoptosis. The results
      demonstrate that blastocysts derived from in vitro maturation, fertilization, and
      embryo culture protocols undergo apoptosis but that apoptotic levels are not
      greatly influenced by the oocyte maturation environment. Amino acid
      supplementation of oocyte maturation media was associated with enhanced
      developmental frequencies, increased blastocyst cell number, and elevated oocyte
      maternal mRNA levels. Oocyte maturation with supplemented synthetic oviduct fluid
      medium (cSOFMaa) resulted in blastocyst cell numbers comparable to those observed
      with Tissue Culture Medium 199 + newborn calf serum. Blastocyst development was
      reduced following oocyte maturation under a 5% CO(2), 7% O(2), 88% N(2) culture
      atmosphere. EGF supplementation of oocyte maturation medium resulted in a
      concentration-dependent increase in blastocyst development but did not influence
      blastocyst total cell number or apoptosis. Our findings indicate that cSOFMaa
      medium is an effective base medium for bovine oocyte maturation.

PMID- 10642574
TI  - Effects of progesterone and estradiol on uterine secretion of prostaglandin
      f(2alpha)in response to oxytocin in ovariectomized sows.
AB  - Thirty ovariectomized sows were used in an experiment designed to determine
      whether the ability of the porcine uterus to release prostaglandin (PG) F(2alpha)
      in response to oxytocin is regulated by progesterone (P(4)) and estradiol (E(2)).
      Sows were assigned to one of four treatment groups: 1) no steroids
      (ovariectomized controls; n = 8), 2) E(2) (n = 8), 3) P(4) (n = 7), or 4) E(2) +
      P(4) (n = 7). P(4) and E(2) were administered so as to mimic the normal temporal
      changes that occur in these hormones during the estrous cycle. A group of intact
      sows (n = 9) was included for comparison. All sows received an injection of
      oxytocin (30 IU, i.v.) on Days 12, 15, and 18 postestrus. Jugular venous blood
      samples were collected from 60 min before through 120 min after injection of
      oxytocin for quantification of 13,14-dihydro-15-keto-PGF(2alpha) (PGFM).
      Preinjection baseline concentrations of PGFM, the magnitude of the PGFM response
      above baseline, and area under the PGFM response curve (AUC) were calculated for
      each sow on each day and compared among treatment groups by ANOVA. Among the
      ovariectomized sows receiving steroid replacement, baseline concentrations of
      PGFM were low on Day 12 postestrus in all four groups. On Days 15 and 18,
      baseline concentrations remained low in the two groups that did not receive P(4)
      but increased in those that did. Both the magnitude of the response to oxytocin
      and AUC were small on Day 12 postestrus in all 4 groups. By Day 15, the magnitude
      of the response and AUC increased in the group that received both P(4) and E(2)
      but remained low in the other three groups. By Day 18, responses to oxytocin were
      greater in both groups that received P(4) than in those that did not. Baseline
      concentrations were similar in intact sows and in those that received both P(4)
      and E(2) on all three days examined. The magnitude of the response and the AUC
      were greater in the ovariectomized sows receiving P(4) and E(2) replacement than
      in the intact control sows on Days 15 and 18 postestrus. From these results, we
      conclude that P(4) and E(2) interact to control the time when the uterus begins
      to secrete PGF(2alpha) in response to oxytocin and the amount of PGF(2alpha)
      secreted.

PMID- 10642575
TI  - Growth differentiation factor-9 stimulates proliferation but suppresses the
      follicle-stimulating hormone-induced differentiation of cultured granulosa cells
      from small antral and preovulatory rat follicles.
AB  - In addition to pituitary gonadotropins and paracrine factors, ovarian follicle
      development is also modulated by oocyte factors capable of stimulating granulosa
      cell proliferation but suppressing their differentiation. The nature of these
      oocyte factors is unclear. Because growth differentiation factor-9 (GDF-9)
      enhanced preantral follicle growth and was detected in the oocytes of early
      antral and preovulatory follicles, we hypothesized that this oocyte hormone could
      regulate the proliferation and differentiation of granulosa cells from these
      advanced follicles. Treatment with recombinant GDF-9, but not FSH, stimulated
      thymidine incorporation into cultured granulosa cells from both early antral and
      preovulatory follicles, accompanied by increases in granulosa cell number.
      Although GDF-9 treatment alone stimulated basal steroidogenesis in granulosa
      cells, cotreatment with GDF-9 suppressed FSH-stimulated progesterone and
      estradiol production. In addition, GDF-9 cotreatment attentuated FSH-induced LH
      receptor formation. The inhibitory effects of GDF-9 on FSH-induced granulosa cell
      differentiation were accompanied by decreases in the FSH-induced cAMP production.
      These data suggested that GDF-9 is a proliferation factor for granulosa cells
      from early antral and preovulatory follicles but suppresses FSH-induced
      differentiation of the same cells. Thus, oocyte-derived GDF-9 could account, at
      least partially, for the oocyte factor(s) previously reported to control cumulus
      and granulosa cell differentiation.

PMID- 10642576
TI  - Cholesterol efflux promotes acrosome reaction in goat spermatozoa.
AB  - Cholesterol efflux and membrane destabilization play an important role in sperm
      capacitation and membrane fusion in the acrosome reaction (AR). In this study we
      establish the effect of cholesterol removal from spermatozoa on acrosomal
      responsiveness. Mature goat spermatozoa were incubated in BSA-free medium in the
      presence of beta-cyclodextrin (betaCD) as cholesterol acceptor. After incubation
      with 8 mM betaCD, 50-60% of cholesterol was released from sperm membranes with no
      loss in the phospholipid content, and 35% of AR was induced. However, when 30% of
      cholesterol was lost, this moderate cholesterol decrease was unable to initiate
      AR. Cholesterol desorption was very rapid, following an exponential kinetics with
      a half-time of around 10 min, which is in contrast with the slow sigmoidal
      kinetics of acrosomal responsiveness: around 2 h was required for maximal AR. Our
      results suggest that cholesterol efflux has a direct influence on the onset of
      the AR, that is, merely removing cholesterol would trigger the AR.

PMID- 10642577
TI  - In vitro production of embryos alters levels of insulin-like growth factor-II
      messenger ribonucleic acid in bovine fetuses 63 days after transfer.
AB  - The objective of this study was to determine the effect of embryo production
      systems on the expression of insulin-like growth factor (IGF)-II mRNA in fetal
      bovine tissues at Day 70 of gestation (63 days after transfer). Oocytes aspirated
      from ovaries of Holstein cows were matured and fertilized in vitro. Zygotes were
      cultured in either tissue culture medium (TCM)-199 + 10% estrous cow serum (ECS;
      in vitro-produced with serum [IVPS]) or TCM-199 + 1% BSA (in vitro-produced with
      serum restriction [IVPSR]). At 72 h postinsemination, IVPSR embryos were
      transferred into fresh TCM-199 + 10% ECS whereas IVPS embryos had fresh medium
      replaced. All embryos were cultured for an additional 96 h. In vivo-produced
      embryos were harvested from superovulated Holstein cows (multiple ovulations
      [MO]). Grade 1 blastocysts from all groups were transferred singly into Angus
      heifers. At Day 70 of gestation, fetuses (n = 14, 13, and 11 for MO, IVPS, and
      IVPSR, respectively) were collected; liver and skeletal muscle samples were snap
      frozen, and whole-cell RNA (wcRNA) was extracted. Levels of IGF-II mRNA were
      determined by RNase protection assay and quantified relative to 18S rRNA (mean
      arbitrary units +/- SEM). WcRNA from adult and Day 90 fetal bovine liver were
      used as controls. Adult liver contained 9-fold less IGF-II mRNA than liver from
      Day 90 fetuses (P < 0.05). Fetal livers of males originating from IVPS and IVPSR
      groups possessed approximately 2-fold greater levels of mRNA for IGF-II than
      those from MO males (0.25 +/- 0.07, 0.33 +/- 0.04, and 0.14 +/- 0.03,
      respectively; P < 0.05). Levels of mRNA for IGF-II tended to be lower (P = 0.07)
      in skeletal muscle of fetuses originating from the IVPSR group (0.043 +/- 0.005)
      compared to MO controls (0.070 +/- 0.008). In conclusion, at Day 70 of gestation,
      fetuses originating from in vitro production systems possessed altered levels of
      IGF-II mRNA in both liver and skeletal muscle.

PMID- 10642578
TI  - Characterization of ovarian carbonyl reductase gene expression during ovulation
      in the gonadotropin-primed immature Rat.
AB  - In this differential-display polymerase chain reaction-based study, four
      different primer sets generated cDNA fragments of ovarian carbonyl reductase
      genes that were uniquely expressed during the ovulatory process in eCG-primed
      immature rats. The temporal pattern of expression of this aldo-keto reductase
      gene was delineated by extracting ovarian RNA at 0, 2, 4, 8, 12, and 24 h after
      induction of ovulation via injection of the primed animals with hCG. The results
      showed that at least four homologous forms of this gene were transcribed during
      ovulation. Northern blot analyses indicated a 14-fold increase in ovarian mRNA
      for carbonyl reductase, with expression reaching a peak at 8 h after hCG
      treatment and then declining to negligible levels during the next 16 h. In situ
      hybridization revealed that most of the transcription was in the thecal
      connective tissue of the ovary and was absent from the granulosa layer of ovarian
      follicles. Treatment of the animals with ovulation-blocking doses of epostane (an
      inhibitor of progesterone synthesis) or indomethacin (an inhibitor of prostanoid
      synthesis) did not reduce the expression of ovarian carbonyl reductase.
      Nevertheless, the temporal pattern of expression of carbonyl reductase after the
      induction of ovulation suggests that this enzyme activity is at least indirectly
      associated with the ovulatory process.

PMID- 10642579
TI  - Rescue of the corpus luteum and an increase in luteal superoxide dismutase
      expression induced by placental luteotropins in the rat: action of testosterone
      without conversion to estrogen.
AB  - The superoxide radical and its scavenger, superoxide dismutase (SOD), play
      important roles in the regulation of corpus luteum function. The present study
      was undertaken to investigate whether SOD is related to pregnancy-induced
      maintenance of corpus luteum function. Placentae obtained from rats on Day 12 of
      pregnancy were incubated for 24 h, and the supernatant was used as placental
      luteotropins. Pseudopregnant rats were given the placental incubation medium from
      Day 9 to Day 12 of pseudopregnancy. The treatment significantly increased serum
      progesterone concentrations on Day 12 of pseudopregnancy. Both activities and
      mRNA levels of copper-zinc SOD (Cu,Zn-SOD) and manganese SOD (Mn-SOD) in the
      corpus luteum were also increased on Day 12 of pseudopregnancy. Treating the
      placental incubation medium with charcoal significantly eliminated the
      stimulatory effects of placental incubation medium on serum progesterone
      concentrations and luteal Mn-SOD expression, but not on Cu,Zn-SOD expression. The
      inhibitory effect of the charcoal treatment on luteal Mn-SOD expression was
      reversed by supplementation with testosterone or dihydrotestosterone (DHT), but
      serum progesterone concentrations were recovered only by DHT. Testosterone or DHT
      alone had no effect on serum progesterone concentrations and luteal SOD
      expression. In conclusion, placental luteotropins increased SOD expression in the
      corpus luteum and stimulated progesterone production, suggesting that SOD is
      involved in the maintenance of the corpus luteum function by placental
      luteotropins. In addition, androgen, with other placental luteotropins, acted to
      stimulate progesterone production and Mn-SOD expression in pseudopregnant rats.

PMID- 10642580
TI  - Expression of the chemokine eotaxin and its receptor, CCR3, in human endometrium.
AB  - Eosinophils are present in human endometrium only immediately before and during
      menstruation, suggesting a role in that process. The expression of the eosinophil
      chemoattractant, eotaxin, and its receptor, CCR3, within the human endometrium
      were investigated by immunohistochemical analysis of tissue sections spanning the
      entire menstrual cycle. Eotaxin was localized to perivascular cells in the late
      secretory phase, and it was also identified in eosinophils. However, the highest
      levels of this chemokine were present in both luminal and glandular epithelial
      cells during the proliferative and secretory phases of the cycle. Treatment of
      endometrial tissue with monensin, which blocks protein secretion, increased
      epithelial immunoreactive eotaxin, substantiating synthesis in these cells.
      Although the CCR3 receptor was expressed by eosinophils, it was also strongly
      expressed by endometrial epithelial cells. The CCR3 receptor on purified,
      cultured endometrial epithelial cells was functional, as assessed by a transient
      Ca(2+) flux in response to eotaxin. These analyses demonstrate that eotaxin is
      expressed by endometrial cells and may therefore be involved in the recruitment
      of eosinophils into this tissue premenstrually. However, the observation that
      this chemokine and the CCR3 molecule are strongly expressed by epithelial cells
      throughout the cycle suggests that these proteins may have additional important
      functions within the endometrium.

PMID- 10642581
TI  - Cell cycle synchronization of porcine fetal fibroblasts: effects of serum
      deprivation and reversible cell cycle inhibitors.
AB  - The success of somatic nuclear transfer critically depends on the cell cycle
      stage of the donor nucleus and the recipient cytoplast. In this study we tested
      serum deprivation as well as two reversible cell cycle inhibitors, aphidicolin
      and butyrolactone I, for their ability to synchronize porcine fetal fibroblasts
      at either G0 stage or G1/S or G2/M transition. The synchronization efficiency of
      the various protocols was determined by fluorescence-activated cell sorting
      (FACS), cell proliferation assays, and semiquantitative multiplex reverse
      transcription-polymerase chain reaction detection of the cell cycle-regulated
      porcine Polo-like kinase mRNA (Plk-p). FACS measurements revealed that 66.6-73.3%
      of the porcine fetal fibroblasts were in G0/G1 stage (2C DNA content) in serum
      supplemented medium. Short periods of 24-72 h of serum deprivation significantly
      increased the proportion of cells at G0/G1 phase to 77.9-80.2%, and mitotic
      activity had already terminated after 48 h. Prolonged culture in serum-deprived
      medium induced massive DNA fragmentation. Aphidicolin treatment led to an
      accumulation of 81.9 +/- 4.9% of cells at the G1/S transition. Butyrolactone I
      arrested 81.0 +/- 5.8% of the cells at the end of G1 stage and 37.0 +/- 6.8% at
      the G2/M transition. The effects of both chemical inhibitors were fully
      reversible, and their removal led to a rapid progression in the cell cycle. The
      measurement of Plk-p expression allowed discrimination between the presumptive G0
      phase induced by serum deprivation and the G1/S transition arrest achieved by
      chemical inhibitors. These data indicate that porcine fetal fibroblasts can be
      effectively synchronized at various cell cycle stages without compromising their
      proliferation capacity.

PMID- 10642583
TI  - Oxytocin receptors in guinea pig myometrium near term and during labor.
AB  - Oxytocin receptors in myometrium of women, rats, and rabbits rise markedly before
      the onset of labor, suggesting a role in the initiation of labor. In guinea pigs,
      a previous study reported no such rise by one-point determination of oxytocin
      binding. The purpose of this study was to use a more rigorous method to determine
      whether the binding characteristics of myometrial oxytocin receptors change in
      relation to labor in guinea pigs. Competitive binding studies were carried out in
      microsomes from inner and outer myometrium between 42 days of gestation and
      labor. Binding to analogs was also tested. Data were analyzed with affinity
      spectra and LIGAND. Oxytocin bound to one site with a dissociation constant of
      6.3 +/- 0.65 x 10(-9) M. Binding capacity was 1.0 +/- 0.1 x 10(-12) mol/mg
      protein. The Hill coefficient was near unity. No significant changes occurred
      with gestation or labor in dissociation constant, binding capacity, or Hill
      coefficient (all P >/= 0.2, nested ANOVA). Binding capacity was higher in the
      outer than in the inner layer (1.2 +/- 0.2 vs. 0.8 +/- 0.1 x 10(-12) mol/mg
      protein, P = 0.02), but the dissociation constants were similar. Differences
      existed in the dissociation constants of the analogs tested. The main conclusion
      is that oxytocin receptors are unlikely to have a regulatory role in the
      initiation of labor in guinea pigs.

PMID- 10642582
TI  - A tumor necrosis factor decoy receptor homologue is up-regulated in the brook
      trout (Salvelinus fontinalis) ovary at the completion of ovulation.
AB  - An up-regulated cDNA fragment was obtained from differential-display polymerase
      chain reaction of brook trout ovarian tissue stimulated by phorbol-12-myristate
      13-acetate (PMA) and calcium ionophore A23187. Using this cDNA as a probe, a full
      length cDNA of 2267 base pairs was obtained by screening a library of PMA/A23187
      stimulated ovarian cDNA. The mRNA obtained presumably encodes for a 302-amino
      acid protein showing similarities with several members of the tumor necrosis
      factor (TNF) receptor superfamily. The protein contains several cysteine-rich
      domains characteristic of mammalian TNF receptor members and is most similar to
      human decoy receptor 3 and osteoprotegerin, two soluble decoy TNF receptors.
      Consequently, this TNF receptor homologue was tentatively named a trout decoy
      receptor (TDcR). On Northern blots of ovarian tissue, TDcR hybridized with a 2.2
      kilobase transcript that was strongly up-regulated under phorbol ester
      stimulation. TDcR mRNA was localized in granulosa cells and was detected in the
      ovary during and after natural ovulation. Its expression was up-regulated at the
      end of ovulation and progressively down-regulated after 48 h postovulation. Among
      other trout tissues tested, the transcript was present only in the testis. To our
      knowledge this is the first description of a member of the TNF receptor family
      from a lower vertebrate and the first report of a decoy-like TNF receptor in the
      vertebrate ovary.

PMID- 10642584
TI  - Role of the pituitary gland in the development of photorefractoriness and
      generation of long-term changes in prolactin secretion in rams.
AB  - Hypothalamo-pituitary disconnected Soay rams were exposed to two photoperiodic
      treatments: 1) constant long days (16L:8D) for 48 wk after pretreatment under
      short days (LD group), and 2) constant short days (8L:16D) for 48 wk after
      pretreatment under long days (SD group). In the LD group, plasma prolactin (PRL)
      concentrations increased from 0 to 8 wk (maximum: 143.3 +/- 8.4 microg/l; 8.8 +/-
      1. 2 wk), decreased from 9 to 34 wk (minimum: 15.6 +/- 1.6 microg/l; 34. 5 +/-
      1.5 wk), and finally increased again under the constant conditions, with a
      similar cyclical pattern for all individuals. In the SD group, PRL concentrations
      showed an inverse pattern (minimum: 8.6 +/- 2.6 microg/l; 17.1 +/- 2.0 wk;
      maximum: 46.4 +/- 5.5 microg/l; 30.2 +/- 3.2 wk), with more variability. Plasma
      concentrations of FSH were basal in both groups. The duration of the daily
      nocturnal melatonin peak (measured at 10, 24, and 44 wk) remained close to 8 h
      under long days (high-fidelity melatonin signal) but decreased significantly
      (13.8 h to 9.3 h) under short days (low-fidelity melatonin signal). The results
      support the conclusion that the melatonin signal encoding photoperiod acts within
      the pituitary gland to induce both acute (inductive) and chronic (refractory)
      effects photoperiod on PRL secretion.

PMID- 10642585
TI  - Expression of vascular endothelial growth factor receptors in the human
      endometrium: modulation during the menstrual cycle.
AB  - Angiogenesis is fundamental for human endometrial development and differentiation
      necessary for implantation. These vascular changes are thought to be mediated by
      the vascular endothelial growth factor (VEGF), whose specific receptors have not
      been examined in detail thus far. We conducted the present study to determine, by
      immunocytochemistry and computerized image analysis of the functionalis, the
      expression and modulation of the receptors Flk-1/KDR and Flt-1, which mediate
      VEGF effects on endothelial mitogenicity, chemotaxis, and capillary permeability.
      VEGF receptors are expressed mainly in endometrial endothelial cells, with
      variations of intensity and number of stained capillaries related to the phase of
      the cycle. The number of capillaries immunostained for Flk-1/KDR was maximal in
      the proliferative phase (ratio Flk-1/CD34: 1), twice as high as the number of Flt
      1-expressing capillaries (ratio Flt-1/CD34: 0.47). The staining intensity for Flk
      1 decreased during the late proliferative and early secretory phases, to increase
      again in the midsecretory period. The number of Flt-1-labeled capillaries was
      about 2-fold higher in the secretory than in the proliferative phase; however,
      the proportion of Flt-1-positive cells did not change, owing to the associated
      increase in vascular density that characterizes progression of the functionalis
      from the proliferative to the secretory stage. The staining intensity for Flt-1
      was higher during the late proliferative and secretory phases (especially in the
      midsecretory phase) and the premenstrual period. In contrast, the proportion of
      capillaries expressing Flk-1/KDR decreased in the secretory phase (ratio Flk
      1/Von Willebrand factor: 0.55). Enhanced expression of Flk-1/KDR, and of Flt-1,
      on narrow capillary strands at the beginning of and during the proliferative
      phase may account for the rapid capillary growth associated with endometrial
      regeneration following menstrual shedding. The high coexpression of Flk-1/KDR and
      Flt-1 observed on capillaries during the midsecretory period correlates with an
      increase of endometrial microvascular density and of permeability characteristic
      of this phase of the cycle, which is a prerequisite for implantation. Finally,
      strong expression of Flt-1, but not Flk-1/KDR, was observed on dilated
      capillaries during the premenstrual period and the late proliferative phase,
      suggesting preferential association of Flt-1 with nonproliferating capillaries at
      those times; activation of this receptor by VEGF could be involved in
      premenstrual vascular hyperpermeability, edema, and extravasation of leukocytes.
      In addition to the endothelial localization, we found that epithelial cells
      expressed Flt-1 and Flk-1/KDR. We conclude that Flt-1 and Flk-1/KDR in the
      functionalis are modulated in parallel or independently according to the phase of
      the cycle, and that these changes are responsible for VEGF actions on endometrial
      vascular growth and permeability. The molecular mechanisms concerning these
      regulations will require further investigation.

PMID- 10642586
TI  - Ovine uterine gland knock-out model: effects of gland ablation on the estrous
      cycle.
AB  - Ovine endometrial gland development is a postnatal event that can be inhibited
      epigenetically by chronic exposure of ewe lambs to a synthetic progestin from
      birth to puberty. As adults, these neonatally progestin-treated ewes lack
      endometrial glands and display a uterine gland knockout (UGKO) phenotype that is
      useful as a model for study of endometrial function. Here, objectives were to
      determine: 1) length of progestin exposure necessary from birth to produce the
      UGKO phenotype in ewes; 2) if UGKO ewes display normal estrous cycles; and 3) if
      UGKO ewes could establish and/or maintain pregnancy. Ewe lambs (n = 22) received
      a Norgestomet (Nor) implant at birth and every two weeks thereafter for 8 (Group
      I), 16 (Group II), or 32 (Groups III and IV) weeks. Control ewe lambs (n = 13)
      received no Nor treatment (Groups V and VI). Ewes in Groups I, II, III, and VI
      were hemihysterectomized (Hhx) at 16 weeks of age. After puberty, the remaining
      uterine horn in Hhx ewes was removed on either Day 9 or 15 of the estrous cycle
      (Day 0 = estrus). Histological analyses of uteri indicated that progestin
      exposure for 8, 16, or 32 weeks prevented endometrial adenogenesis and produced
      the UGKO phenotype in adult ewes. Three endometrial phenotypes were consistently
      observed in Nor-treated ewes: 1) no glands, 2) slight glandular invaginations
      into the stroma, and 3) limited numbers of cyst- or gland-like structures in the
      stroma. Overall patterns of uterine progesterone, estrogen, and oxytocin receptor
      expression were not different in uteri from adult cyclic control and UGKO ewes.
      However, receptor expression was variegated in the ruffled luminal epithelium of
      uteri from UGKO ewes. Intact UGKO ewes displayed altered estrous cycles with
      interestrous intervals of 17 to 43 days, and they responded to exogenous
      prostaglandin F(2 approximately ) (PGF) with luteolysis and behavioral estrus.
      During the estrous cycle, plasma concentrations of progesterone in intact control
      and UGKO ewes were not different during metestrus and diestrus, but levels did
      not decline in many UGKO ewes during late diestrus. Peak peripheral plasma
      concentrations of PGF metabolite, in response to an oxytocin challenge on Day 15,
      were threefold lower in UGKO compared to control ewes. Intact UGKO ewes bred
      repeatedly to intact rams did not display evidence of pregnancy based on results
      of ultrasound. Collectively, results indicate that 1) transient, progestin
      induced disruption of ovine uterine development from birth alters both structural
      and functional integrity of the adult endometrium; 2) normal adult endometrial
      integrity, including uterine glands, is required to insure a luteolytic pattern
      of PGF production; and 3) the UGKO phenotype, characterized by the absence of
      endometrial glands and a compact, disorganized endometrial stroma, limits or
      inhibits the capacity of uterine tissues to support the establishment and/or
      maintenance of pregnancy.

PMID- 10642587
TI  - Genetic control of fertility and embryonic waste in the mouse: A rolefor
      angiotensinogen.
AB  - The purpose of this study was to evaluate the impact of angiotensinogen gene
      (Agt) deficiency on reproductive fitness in a rodent model. Mice with 0 (Agt(-/
      )), 1 (Agt(-/+)), and 2 (Agt(+/+)) copies of Agt were bred according to the
      following schemes: 1) Agt(-/-) x Agt(-/-), 2) Agt(-/+) x Agt(-/+), 3) Agt(+/+) x
      Agt(+/+), and 4) Agt(+/+) female symbol x Agt(-/+) male symbol. There were 4
      breeding pairs per scheme. Breedings were time mated. Mice and litters were
      weighed daily. Southern blotting was used for genotyping. We found that Agt(-/-)
      breeding pairs had fewer litters (2 [range 1-2] vs. 4 [range 3-5]; P = 0.01),
      fewer pups per litter (4 [range 1-7] vs. 6 [range 1-10]; P = 0.006), and longer
      interpregnancy intervals (43 days [range 31-44] vs. 35.5 days [range 22-58]; P =
      0.04) compared to wild-type controls. The ratio of postcoital plugs to subsequent
      litters was 4.0 and 1.2 for Agt(-/-) and Agt(+/+) breedings, respectively (P =
      0.03). Median maternal weights during all trimesters of pregnancy were
      significantly lower for Agt-deficient mice compared to wild-type controls. Among
      Agt(-/+) x Agt(-/+) breedings, the proportions of Agt(+/+) (n = 17), Agt(-/+) (n
      = 38), and Agt(-/-) (n = 4) offspring differed significantly from the expected
      1:2:1 Mendelian inheritance pattern (P = 0.03). Neonatal survival among the
      offspring derived from the Agt(-/-) x Agt(-/-) breeding scheme was significantly
      reduced (P = 0. 001). We conclude that Agt deficiency is associated with an in
      utero lethal effect, decreased fertility, and impaired neonatal survival.

PMID- 10642588
TI  - Structural aspects of the zona pellucida of in vitro-produced bovine embryos: a
      scanning electron and confocal laser scanning microscopic study.
AB  - Structural aspects of the bovine zona pellucida (ZP) of in vitro-matured (IVM)
      oocytes and in vitro-produced (IVP) embryos were studied in two experiments to
      find a tentative explanation for the zona's barrier function against viral
      infection. In Experiment 1, the ultrastructure of the outer ZP surface was
      studied. The diameter (nm) and the number of the outer pores within an area of
      5000 microm(2) of 10 IVM oocytes, 10 zygotes, 10 8-cell-stage embryos, and 10
      morulae were evaluated by scanning electron microscopy. In oocytes and morulae,
      the ZP surface showed a rough and spongy appearance with numerous pores. In
      zygotes, the ZP surface was found to have a smooth, melted appearance with only a
      few pores. In 8-cell-stage embryos, both surface patterns were found. The mean
      number (per 5000 microm(2)) and the mean diameter of the outer pores were
      different between the four stages of development (P < 0.001): 1511 pores in
      oocytes, 1187 in zygotes, 1658 in 8-cell-stage embryos, and 3259 in morulae, with
      mean diameters of 182, 223, 203, and 155 nm, respectively. In Experiment 2, the
      continuity of the meshes (network of pores) towards the embryonic cells was
      examined by confocal laser scanning microscopy. Therefore, the passage through
      and the location in the ZP of fluorescent microspheres, with similar dimensions
      as bovine viral diarrhea virus (BVDV, 40-50 nm) and bovine herpesvirus-1 (BHV-1;
      180-200 nm), were evaluated. For all stages, the smallest beads were detected
      halfway through the thickness of the ZP, whereas the beads with a size of 200 nm
      were found only within the outer-fourth part of the ZP. It can be concluded that
      the intact ZP of bovine IVM oocytes and IVP embryos are constructed in such a way
      that BVDV and BHV-1 should not be able to traverse the ZP and reach the embryonic
      cells. However, the risk exists that viral particles can be trapped in the outer
      layers of the ZP.

PMID- 10642589
TI  - Production of live calves derived from embryonic stem-like cells aggregated with
      tetraploid embryos.
AB  - To date, cloned farm animals have been produced by nuclear transfer from
      embryonic, fetal, and adult cell types. However, mice completely derived from
      embryonic stem (ES) cells have been produced by aggregation with tetraploid
      embryos. The objective of the present study was to generate offspring completely
      derived from bovine ES-like cells. ES-like cells isolated from the inner cell
      mass of in vitro-produced embryos were aggregated with tetraploid bovine embryos
      generated by electrofusion at the 2-cell stage. A total of 77 embryo aggregates
      produced by coculture of two 8-cell-stage tetraploid embryos and a clump of ES
      like cells were cultured in vitro. Twenty-eight of the aggregates developed to
      the blastocyst stage, and 12 of these were transferred to recipient cows. Six
      calves representing 2 singletons and 2 sets of twins were produced from the
      transfer of the chimeric embryos. Microsatellite analysis for the 6 calves
      demonstrated that one calf was chimeric in the hair roots and the another was
      chimeric in the liver. However, unfortunately, both of these calves died shortly
      after birth. Two of the placentae from the remaining pregnancies were also
      chimeric. These results indicate that the bovine ES-like cells used in these
      studies were able to contribute to development.

PMID- 10642590
TI  - Congenital disorders of glycosylation caused by defects in mannose addition
      during N-linked oligosaccharide assembly.

PMID- 10642591
TI  - Matrix metalloproteinase-3-dependent generation of a macrophage chemoattractant
      in a model of herniated disc resorption.
AB  - Herniated disc (HD) is a common health problem that is resolved by surgery unless
      spontaneous resorption occurs. HD tissue contains abundant macrophage
      infiltration and high levels of matrix metalloproteinases (MMPs) MMP-3 and MMP-7.
      We developed a model system in which disc tissue or isolated chondrocytes from
      wild-type or MMP-null mice were cocultured with peritoneal macrophages and used
      this system to investigate the role of MMPs and chondrocyte/macrophage
      interactions in disc resorption. We observed a marked enhancement of MMP-3
      protein and mRNA in chondrocytes after exposure to macrophages. Chondrocytic MMP
      3, but not MMP-7, was required for disc resorption, as determined by assaying for
      a reduction in wet weight and proteoglycan content after 3 days of coculture.
      Surprisingly, chondrocyte MMP-3 was required for the generation of a macrophage
      chemoattractant and the subsequent infiltration of the disc tissue by
      proteolytically active macrophages. We conclude that macrophage induction of
      chondrocyte MMP-3 plays a major role in disc resorption by mechanisms that
      include the generation of a bioactive macrophage chemoattractant.

PMID- 10642592
TI  - Matrix metalloproteinase-7-dependent release of tumor necrosis factor-alpha in a
      model of herniated disc resorption.
AB  - Herniated disc (HD), one of the major causes of low back pain, is often resolved
      spontaneously without surgical intervention. Resorption is associated with a
      marked increase in infiltrating macrophages, and the matrix metalloproteinases
      (MMP) MMP-3 and MMP-7 have been implicated in this phenomenon. We developed a
      murine organ culture model in which intact intervertebral discs were cocultured
      with peritoneal macrophages to investigate the role of MMPs in HD resorption.
      Using macrophages isolated from MMP-null mice, we report that macrophage-produced
      MMP-7 was required for proteoglycan degradation, loss of wet weight, and
      macrophage infiltration of cocultured discs. The inability of MMP-7-deficient
      macrophages to infiltrate discs could not be attributed to a defect in macrophage
      migration. MMP-7 was required for the release of the cytokine TNF-alpha from
      peritoneal macrophages. The generation of soluble TNF-alpha was essential for the
      induction of MMP-3 in disc cocultures, which in turn is required for the
      generation of a macrophage chemoattractant and subsequent macrophage
      infiltration. TNF-alpha release from macrophages was necessary but insufficient
      for disc resorption, which required macrophage infiltration. We conclude that
      there is extensive communication between macrophages and chondrocytes in HD
      resorption and that an essential component of this communication is the
      requirement for MMPs to release soluble bioactive factors.

PMID- 10642593
TI  - Defective HDL particle uptake in ob/ob hepatocytes causes decreased recycling,
      degradation, and selective lipid uptake.
AB  - Levels of plasma HDL are determined in part by catabolism in the liver. However,
      it is unclear how the hepatic catabolism of holo-HDL is regulated or mediated.
      Recently, we found that ob/ob mice have defective liver catabolism of HDL
      apoproteins in vivo that can be reversed by low-dose leptin treatment. Here we
      examined HDL catabolism and trafficking at the cellular level using isolated
      hepatocytes. We demonstrate that ob/ob hepatocytes have reduced binding,
      association, degradation, and resecretion of HDL apoproteins and 50% less
      selective lipid uptake relative to wild-type hepatocytes. In addition, HDL
      apoproteins were found to colocalize with transferrin in the general endosomal
      recycling compartment (ERC) in wild-type hepatocytes. However, the localization
      to the ERC was markedly reduced in ob/ob hepatocytes. Filipin staining of
      cellular cholesterol revealed decreased cholesterol in the ERC in ob/ob
      hepatocytes. Defects in HDL cell association and cholesterol distribution were
      reversed by leptin administration. The findings show a major defect in HDL uptake
      and recycling in ob/ob hepatocytes and suggest that HDL recycling through the ERC
      plays a role in the determination of plasma HDL protein and cholesterol levels.

PMID- 10642594
TI  - Wnt-1 regulation of connexin43 in cardiac myocytes.
AB  - Gap junction channels composed of connexin43 (Cx43) are essential for normal
      heart formation and function. We studied the potential role of the Wnt family of
      secreted polypeptides as regulators of Cx43 expression and gap junction channel
      function in dissociated myocytes and intact hearts. Neonatal rat cardiomyocytes
      responded to Li(+), which mimics Wnt signaling, by accumulating the effector
      protein beta-catenin and by inducing Cx43 mRNA and protein markedly. Induction of
      Cx43 expression was also observed in cardiomyocytes cocultured with Rat-2
      fibroblasts or N2A neuroblastoma cells programmed to secrete bioactive Wnt-1. By
      transfecting a Cx43 promoter-reporter gene construct into cardiomyocytes, we
      demonstrated that the inductive effect of Wnt signaling was transcriptionally
      mediated. Enhanced expression of Cx43 increased cardiomyocyte cell coupling, as
      determined by Lucifer Yellow dye transfer and by calcium wave propagation.
      Conversely, in a transgenic cardiomyopathic mouse model that exhibits ventricular
      arrhythmias and gap junctional remodeling, beta-catenin and Cx43 expression were
      downregulated concordantly. In response to Wnt signaling, the accumulating Cx43
      colocalized with beta-catenin in the junctional membrane; moreover, forced
      expression of Cx43 in cardiomyocytes reduced the transactivation potential of
      beta-catenin. These findings demonstrate that Wnt signaling is an important
      modulator of Cx43-dependent intercellular coupling in the heart, and they support
      the hypothesis that dysregulated signaling contributes to altered impulse
      propagation and arrhythmia in the myopathic heart.

PMID- 10642595
TI  - Stable mixed chimerism and tolerance using a nonmyeloablative preparative regimen
      in a large-animal model.
AB  - Bone marrow transplantation (BMT) has considerable potential for the treatment of
      malignancies, hemoglobinopathies, and autoimmune diseases, as well as the
      induction of transplantation allograft tolerance. Toxicities associated with
      standard preparative regimens for bone marrow transplantation, however, make this
      approach unacceptable for all but the most severe of these clinical situations.
      Here, we demonstrate that stable mixed hematopoietic cell chimerism and donor
      specific tolerance can be established in miniature swine, using a relatively
      mild, non-myeloablative preparative regimen. We conditioned recipient swine with
      whole-body and thymic irradiation, and we depleted their T-cells by CD3
      immunotoxin-treatment. Infusion of either bone marrow cells or cytokine-mobilized
      peripheral blood stem cells from leukocyte antigen-matched animals resulted in
      stable mixed chimerism, as detected by flow cytometry in the peripheral blood,
      thymus, and bone marrow, without any clinical evidence of graft-versus-host
      disease (GvHD). Long-term acceptance of donor skin and consistent rejection of
      third-party skin indicated that the recipients had developed donor-specific
      tolerance.

PMID- 10642596
TI  - The high-affinity IgE receptor (FcepsilonRI) blocks apoptosis in normal human
      monocytes.
AB  - Monocytes have a limited life span, and their homeostasis is regulated by
      apoptosis in vivo. When cultured in the absence of appropriate exogenous stimuli,
      they undergo apoptosis, but under the influence of survival signals, these cells
      differentiate into macrophages or dendritic cells. Here we show that ligation of
      the high-affinity IgE receptor (FcepsilonRI) on human monocytes from nonatopic
      individuals markedly reduces apoptosis induced by serum deprivation or by
      CD95/Fas ligation. Aggregation of FcepsilonRI reduces its own expression but
      fails to modulate CD95/Fas expression. In contrast, FcepsilonRI ligation enhances
      the expression of the antiapoptotic molecules Bcl-2 and Bcl-xL, but not Mcl-1, in
      monocytes. Incubation of unstimulated cells with culture supernatants of
      FcepsilonRI-activated monocytes prolongs their life span, whereas CD95/Fas
      expression remains unaffected. The incidence of apoptosis is restored
      considerably when the supernatant is depleted of TNF-alpha, whereas elimination
      of IL-1beta, GM-CSF, or IL-12 has no effect. These results indicate that
      FcepsilonRI mediates signals preventing monocyte apoptosis directly by increasing
      the levels of Bcl-2 and Bcl-xL, and indirectly by means of TNF-alpha in an
      autocrine and paracrine fashion. This process may contribute to the establishment
      of chronic allergic disorders such as atopic dermatitis.

PMID- 10642597
TI  - Dolichol phosphate mannose synthase (DPM1) mutations define congenital disorder
      of glycosylation Ie (CDG-Ie)
AB  - Congenital disorders of glycosylation (CDGs) are metabolic deficiencies in
      glycoprotein biosynthesis that usually cause severe mental and psychomotor
      retardation. Different forms of CDGs can be recognized by altered isoelectric
      focusing (IEF) patterns of serum transferrin (Tf). Two patients with these
      symptoms and similar abnormal Tf IEF patterns were analyzed by metabolic labeling
      of fibroblasts with ?2-(3)Hmannose. The patients produced a truncated dolichol
      linked precursor oligosaccharide with 5 mannose residues, instead of the normal
      precursor with 9 mannose residues. Addition of 250 microM mannose to the culture
      medium corrected the size of the truncated oligosaccharide. Microsomes from
      fibroblasts of these patients were approximately 95% deficient in dolichol
      phosphate-mannose (Dol-P-Man) synthase activity, with an apparent K(m) for GDP
      Man approximately 6-fold higher than normal. DPM1, the gene coding for the
      catalytic subunit of Dol-P-Man synthase, was altered in both patients. One
      patient had a point mutation, C(274)G, causing an R(92)G change in the coding
      sequence. The other patient also had the C(274)G mutation and a 13-bp deletion
      that presumably resulted in an unstable transcript. Defects in DPM1 define a new
      glycosylation disorder, CDG-Ie.

PMID- 10642598
TI  - Tissue-specific insulin resistance in mice with mutations in the insulin
      receptor, IRS-1, and IRS-2.
AB  - Type 2 diabetes is characterized by abnormalities of insulin action in muscle,
      adipose tissue, and liver and by altered beta-cell function. To analyze the role
      of the insulin signaling pathway in these processes, we have generated mice with
      combined heterozygous null mutations in insulin receptor (ir), insulin receptor
      substrate (irs-1), and/or irs-2. Diabetes developed in 40% of ir/irs-1/irs-2(+/
      ), 20% of ir/irs-1(+/-), 17% of ir/irs-2(+/-), and 5% of ir(+/-) mice. Although
      combined heterozygosity for ir/irs-1(+/-) and ir/irs-2(+/-) results in a similar
      number of diabetic mice, there are significant differences in the underlying
      metabolic abnormalities. ir/irs-1(+/-) mice develop severe insulin resistance in
      skeletal muscle and liver, with compensatory beta-cell hyperplasia. In contrast,
      ir/irs-2(+/-) mice develop severe insulin resistance in liver, mild insulin
      resistance in skeletal muscle, and modest beta-cell hyperplasia. Triple
      heterozygotes develop severe insulin resistance in skeletal muscle and liver and
      marked beta-cell hyperplasia. These data indicate tissue-specific differences in
      the roles of IRSs to mediate insulin action, with irs-1 playing a prominent role
      in skeletal muscle and irs-2 in liver. They also provide a practical
      demonstration of the polygenic and genetically heterogeneous interactions
      underlying the inheritance of type 2 diabetes.

PMID- 10642599
TI  - Desmoglein-1-specific T lymphocytes from patients with endemic pemphigus
      foliaceus (fogo selvagem).
AB  - Fogo selvagem (FS), the endemic form of pemphigus foliaceus, is a cutaneous
      autoimmune disease characterized by subcorneal blistering of the epidermis and
      the production of autoantibodies against the desmosomal antigen desmoglein-1
      (Dsg1). Previously, we showed that mice injected with autoantibodies from FS
      patients develop a skin disease that reproduces the clinical, histological, and
      immunological features of FS, indicating that autoantibodies play an essential
      role in the development of this disease. The purpose of this study was to
      characterize the autoimmune T-cell response associated with FS. We provide here
      the first evidence, to our knowledge, that the great majority of FS patients have
      circulating T lymphocytes that specifically proliferate in response to the
      extracellular domain of Dsg1. Long-term T cells developed from these patients
      also responded to Dsg1, and this antigen-specific response was shown to be
      restricted to HLA-DR molecules. These Dsg1-reactive FS T cells exhibited a CD4
      positive memory T-cell phenotype and produced a T helper 2-like cytokine profile.
      These findings represent the initial steps in defining the role of T cells in FS
      autoimmunity.

PMID- 10642600
TI  - Requirement of aquaporin-1 for NaCl-driven water transport across descending vasa
      recta.
AB  - Deletion of AQP1 in mice results in diminished urinary concentrating ability,
      possibly related to reduced NaCl- and urea gradient-driven water transport across
      the outer medullary descending vasa recta (OMDVR). To quantify the role of AQP1
      in OMDVR water transport, we measured osmotically driven water permeability in
      vitro in microperfused OMDVR from wild-type, AQP1 heterozygous, and AQP1 knockout
      mice. OMDVR diameters in AQP1(-/-) mice were 1.9-fold greater than in AQP1(+/+)
      mice. Osmotic water permeability (P(f)) in response to a 200 mM NaCl gradient
      (bath > lumen) was reduced about 2-fold in AQP1(+/-) mice and by more than 50
      fold in AQP1(-/-) mice. P(f) increased from 1015 to 2527 microm/s in AQP1(+/+)
      mice and from 22 to 1104 microm/s in AQP1(-/-) mice when a raffinose rather than
      an NaCl gradient was used. This information, together with p
      chloromercuribenzenesulfonate inhibition measurements, suggests that nearly all
      NaCl-driven water transport occurs by a transcellular route through AQP1, whereas
      raffinose-driven water transport also involves a parallel, AQP1-independent,
      mercurial-insensitive pathway. Interestingly, urea was also able to drive water
      movement across the AQP1-independent pathway. Diffusional permeabilities to small
      hydrophilic solutes were comparable in AQP1(+/+) and AQP1(-/-) mice but higher
      than those previously measured in rats. In a mathematical model of the medullary
      microcirculation, deletion of AQP1 resulted in diminished concentrating ability
      due to enhancement of medullary blood flow, partially accounting for the observed
      urine-concentrating defect.

PMID- 10642601
TI  - Fas-mediated apoptosis in clinical remissions of relapsing experimental
      autoimmune encephalomyelitis.
AB  - PLP139-51-induced experimental autoimmune encephalomyelitis (R-EAE) displays a
      relapsing-remitting paralytic course in female SJL mice. We investigated the role
      of apoptosis/activation-induced cell death (AICD) in the spontaneous recovery
      from acute disease. Clinical EAE was significantly enhanced in Fas (CD95/APO-1)
      deficient SJL lpr/lpr mice, which displayed significantly increased mean peak
      clinical scores, reduced remission rates, and increased mortality when compared
      with their SJL +/lpr littermates. PLP139-151-specific proliferative responses
      were fairly equivalent in the 2 groups, but draining lymph node T cells from SJL
      lpr/lpr mice produced dramatically increased levels of IFN-gamma. Central nervous
      system (CNS) Fas and FasL mRNA levels in wild-type SJL (H-2(s)) mice peaked just
      before spontaneous disease remission and gradually declined as disease remitted.
      We applied the terminal deoxynucleotidyl transferase-mediated dUTP nick-end
      labeling (TUNEL) assay to detect apoptosis in situ in spinal cords of mice at
      various clinical stages of EAE. Most TUNEL(+) cells were found during active
      periods of inflammation: the acute, peak, and relapse time points. Significantly
      fewer apoptotic cells were observed at preclinical and remission time points.
      Collectively, these findings indicate that Fas-mediated apoptosis/AICD plays a
      major role in the spontaneous remission after the initial acute inflammatory
      episode and represents an important intrinsic mechanism in regulation of
      autoimmune responses.

PMID- 10642603
TI  - Characterization of high affinity monoclonal antibodies specific for chlamydial
      lipopolysaccharide.
AB  - Pathogens belonging to the genus Chlamydia contain lipopolysaccharide with a 3
      deoxy-D- manno- oct-2-ulosonic acid (Kdo) trisaccharide of the sequence alpha-Kdo
      (2-->8)-alpha-Kdo-(2-->4)-alpha-Kdo. This lipopolysaccharide is recognized in a
      genus-specific pattern by murine monoclonal antibodies (mAbs), S25-23 and S25-2
      (both IgG1kappa), which bind as the minimal structures the trisaccharide and the
      terminal Kdo-disaccharide, respectively. The variable domains of these mAbs were
      reverse transcribed from mRNA which was isolated from hybridomas and cloned as
      single-chain variable fragments (scFvs) in E.coli TG1. The kinetics of binding of
      whole antibodies, Fab fragments and scFvs to natural and synthetically modified
      ligands were determined by surface plasmon resonance (SPR) using synthetic
      neoglycoconjugates. As examples of an antibody-carbohydrate interaction involving
      anionic carboxyl groups on the ligand, we report that the affinities of these
      antibodies are higher than usually observed in carbo-hydrate-protein interactions
      (K(D)of 10(-3)to 10(-5)M). SPR analy-ses of monovalent Fab and scFv binding to
      the natural trisaccharide epitope gave dissociation constants of 770 nM for S25-2
      and 350 nM for S25-23, as determined by global fitting (simultaneous fitting of
      several measurements at different antibody concentrations) of sensorgram data to
      a one-to-one interaction model. Local fitting (separate fitting of individual
      sensorgram data at different antibody concentrations) and Scatchard analysis of
      the data gave kinetic and affinity constants that were in good agreement with
      those obtained by global fitting. The SPR data also showed that while S25-2 bound
      well to several Kdo disaccharides and carboxyl-reduced Kdo ligands, S25-23 did
      not. Identification of amino acids in the complementarity determining regions
      revealed the presence of a large number of positively charged amino acids which
      were located towards the center of the combining site, thus suggesting a
      different recognition mechanism than that observed for neutral ligands. The
      latter mainly involves aromatic amino acids for hydrophobic stacking inter
      actions and hydrogen bonds.

PMID- 10642602
TI  - Deficiency of dolichol-phosphate-mannose synthase-1 causes congenital disorder of
      glycosylation type Ie.
AB  - Congenital disorders of glycosylation (CDG), formerly known as carbohydrate
      deficient glycoprotein syndromes, lead to diseases with variable clinical
      pictures. We report the delineation of a novel type of CDG identified in 2
      children presenting with severe developmental delay, seizures, and dysmorphic
      features. We detected hypoglycosylation on serum transferrin and cerebrospinal
      fluid beta-trace protein. Lipid-linked oligosaccharides in the endoplasmic
      reticulum of patient fibroblasts showed an accumulation of the dolichyl
      pyrophosphate Man(5)GlcNAc(2) structure, compatible with the reduced dolichol
      phosphate-mannose synthase (DolP-Man synthase) activity detected in these
      patients. Accordingly, 2 mutant alleles of the DolP-Man synthase DPM1 gene, 1
      with a 274C>G transversion, the other with a 628delC deletion, were detected in
      both siblings. Complementation analysis using DPM1-null murine Thy1-deficient
      cells confirmed the detrimental effect of both mutations on the enzymatic
      activity. Furthermore, mannose supplementation failed to improve the
      glycosylation status of DPM1-deficient fibroblast cells, thus precluding a
      possible therapeutic application of mannose in the patients. Because DPM1
      deficiency, like other subtypes of CDG-I, impairs the assembly of N-glycans, this
      novel glycosylation defect was named CDG-Ie.

PMID- 10642604
TI  - Involvement of CD2 and CD3 in galectin-1 induced signaling in human Jurkat T
      cells.
AB  - Galectin-1 (gal-1) a member of the mammalian beta-galactoside-binding proteins
      recognizes preferentially Galbeta1-4GlcNAc sequences of oligosaccharides
      associated with several cell surface glycoconjugates. In the present work, gal-1
      has been identified to be a ligand for the CD3-complex as well as for CD2 as
      detected by affinity chromatography of Jurkat T-cell lysates on gal-1 agarose and
      by binding of the biotinylated lectin to CD3 and CD2 immunoprecipitates on blots.
      In CD45(+)Jurkat E6.1 cells, the lectin stimulates a sustained increase in the
      intracytoplasmic calcium concentration ([Ca(2+)](i)) consisting of both the
      release of calcium from intracellular stores and the calcium influx from the
      extracellular space. This effect of gal-1 on [Ca(2+)](i)is completely inhibited
      by lactose at 10 mM and was absent in CD45(-)Jurkat J45.01 cells. Preincubation
      of Jurkat E6.1 cells with cholera toxin or with the protein tyrosine kinase
      inhibitor herbimycin A reduced the gal-1 induced calcium response whereas the
      increase in [Ca(2+)](i)stimulated by CD2 or CD3 monoclonal antibodies (mAbs) was
      completely inhibited. Depolarization of E6.1 cells in a high-potassium buffer, a
      standard method to activate voltage-operated calcium channels, was without effect
      on [Ca(2+)](i). Membrane depolarization with gramicidin or by a high-potassium
      buffer was without effects on the lectin-mediated calcium release from
      intracellular stores but inhibited the gal-1 induced receptor-operated calcium
      influx. In Jurkat E6.1 cells the lectin stimulates the transient generation of
      inositol-1,4,5-trisphosphate and the tyrosine phosphorylation of phospholipase
      Cgamma1. The results suggest that the ligation of CD2 and CD3 by gal-1 induces
      early events in T-cell activation comparable with that elicited by CD2 or CD3
      mAbs.

PMID- 10642605
TI  - Xenotransplantation: in vitro analysis of synthetic alpha-galactosyl inhibitors
      of human anti-Galalpha1-->3Gal IgM and IgG antibodies.
AB  - Pig-to-human xenotransplantation might be an option to overcome the increasing
      shortage of human donor organs. However, naturally occurring antibodies in human
      blood against the Galalpha1-->3Gal antigen on pig endothelial cells lead to
      hyperacute or, if prevented, acute or delayed vascular rejection of the pig
      graft. The purpose of this study was therefore to evaluate synthetic
      oligosaccharides with terminal Galalpha1-->3Gal to inhibit antigen-binding and
      cytotoxicity of anti-alphaGal antibodies against pig cells. Different
      oligosaccharides were synthesized chemically and by a combined chemico-enzymatic
      approach. These included monomeric di-, tri-, and pentasaccharides, a
      polyacrylamide-conjugate (PAA-Bdi), as well as di-, tetra-, and octamers of
      Galalpha1-->3Gal. All were tested for inhibitory activity by anti-alphaGal ELISA
      and complement-dependent cytotoxicity tests. PAA-Bdi was the best inhibitor of
      binding as well as cytotoxicity of anti-alphaGal antibodies. Monomeric
      oligosaccharides efficiently prevented binding of anti-alphaGal IgG, but less
      well that of anti-alphaGal IgM, with tri- and pentasaccharides showing a better
      efficacy than the disaccharide. The two trisaccharides Galalpha1-->3Galbeta1-
      >4GlcNAc and Galalpha1-->3Galbeta1-->3GlcNAc were equally effective. Oligomers of
      Galalpha1-->3Gal were more effective than monomers in blocking the binding of
      anti-alphaGal IgG. However, they could not block IgM binding, nor could they
      match the efficacy of PAA-Bdi. We conclude that oligosaccharides with terminal
      Galalpha1-->3Gal, most effectively as PAA-conjugates, can prevent binding and
      cytotoxicity of human anti-alphaGal in vitro. The PAA-Bdi conjugate might be most
      suited for use as a Sepharose-bound immunoabsorption material.

PMID- 10642606
TI  - Mucous granule exocytosis and CFTR expression in gallbladder epithelium.
AB  - A mechanistic model of mucous granule exocytosis by columnar epithelial cells
      must take into account the unique physical-chemical properties of mucin
      glycoproteins and the resultant mucus gel. In particular, any model must explain
      the intracellular packaging and the kinetics of release of these large, heavily
      charged species. We studied mucous granule exocytosis in gallbladder epithelium,
      a model system for mucus secretion by columnar epithelial cells. Mucous granules
      released mucus by merocrine exocytosis in mouse gallbladder epithelium when
      examined by transmission electron microscopy. Spherules of secreted mucus larger
      than intracellular granules were noted on scanning electron microscopy. Electron
      probe microanalysis demonstrated increased calcium concentrations within mucous
      granules. Immunofluorescence microscopic studies revealed intracellular
      colocalization of mucins and the cystic fibrosis transmembrane conductance
      regulator (CFTR). Confocal laser immunofluorescence microscopy confirmed
      colocalization. These observations suggest that calcium in mucous secretory
      granules provides cationic shielding to keep mucus tightly packed. The data also
      suggests CFTR chloride channels are present in granule membranes. These
      observations support a model in which influx of chloride ions into the granule
      disrupts cationic shielding, leading to rapid swelling, exocytosis and hydration
      of mucus. Such a model explains the physical-chemical mechanisms involved in
      mucous granule exocytosis.

PMID- 10642607
TI  - Biosynthesis of heparin/heparan sulfate: kinetic studies of the glucuronyl C5
      epimerase with N-sulfated derivatives of the Escherichia coli K5 capsular
      polysaccharide as substrates.
AB  - The D-glucuronyl C5-epimerase involved in the biosynthesis of heparin and heparan
      sulfate was investigated with focus on its substrate specificity, its kinetic
      properties, and a comparison of epimerase preparations from the Furth mastocytoma
      and bovine liver, which synthesize heparin and heparan sulfate, respectively. New
      substrates for the epimerase were prepared from the capsular polysaccharide of
      Escherichia coli K5, which had been labeled at C5 of its D-glucuronic and N
      acetyl-D-glucosamine moieties by growing the bacteria in the presence of D-[5
      (3)H]glucose. Following complete or partial ( approximately 50%) N-deacetylation
      of the polysaccharide by hydrazinolysis, the free amino groups were sulfated by
      treatment with trimethylamine.SO(3)complex, which yielded products that were
      recognized as substrates by the epimerase and released tritium from C5 of the D
      glucuronyl residues upon incubation with the enzyme. Comparison of the kinetic
      properties of the two substrates showed that the fully N-sulfated derivative was
      the best substrate in terms of its K(m)value, which was significantly lower than
      that of its partially N-acetylated counterpart. The V(max)values for the E.coli
      polysaccharide derivatives were essentially the same but were both lower than
      that of the O-desulfated [(3)H]heparin used in our previous studies.
      Surprisingly, the apparent K(m)values for all three substrates increased with
      increasing enzyme concentration. The reason for this phenomenon is not entirely
      clear at present. Partially purified C5-epimerase preparations from the Furth
      mastocytoma and bovine liver, respectively, behaved similarly in terms of their
      reactivity towards the various substrates, but the variation in apparent
      K(m)values with enzyme concentration precluded a detailed comparison of their
      kinetic properties.

PMID- 10642608
TI  - Glycotyping of prostate specific antigen.
AB  - Measurement of serum levels of the prostate specific antigen (PSA) is now widely
      used for the diagnosis of prostate cancer and benign prostate hyperplasia. This
      serum marker is of value since it is derived only from the tissue of interest,
      but increased levels of PSA in serum do not allow a completely clear cut
      diagnosis of benign versus malignant changes. Since PSA is a glycoprotein with
      one asparagine linked oligosaccharide, and since malignant transformation often
      leads to an increased branching of such oligosaccharides, we initially studied
      the asparagine linked structures on PSA made by a cell line derived from
      malignant metastatic prostate tissue. We observed that unlike normal PSA, which
      bears only biantennary oligosaccharides, PSA from the metastatic cell line has a
      mixture of biantennary and triantennary oligosaccharides. Further experiments
      will reveal carbohydrate differences derived from the PSA from sera or, prostate
      tissue of normal versus prostate cancer patients, and of the utility of such
      carbo-hydrate differences as a possible diagnostic marker for prostate cancer.

PMID- 10642609
TI  - An early step of glycosylphosphatidyl-inositol anchor biosynthesis is abolished
      in lepidopteran insect cells following baculovirus infection.
AB  - The expression of recombinant proteins in their native state has become a
      prerequisite for a variety of functional and structural studies, as well as
      vaccine development. Many biochemical properties and functions of proteins are
      dependent on or reside in posttranslational modifications, such as glycosylation.
      The baculovirus system has increasingly become the system of choice due to it
      capabilities of performing posttranslational modifications and usually high
      yields of recombinant proteins. The Toxoplasma gondii surface antigen SAG1 was
      used as a model for a glycosylphosphatidyl-inositol (GPI)-anchored protein and
      expressed in insect cells using the baculovirus system. We show that the T.
      gondii SAG1 surface antigen expressed in this system was not modified by a GPI
      anchor. In vitro and in vivo studies demonstrate that uninfected insect cells are
      able to produce GPI-precursors and to transfer a mature GPI-anchor to nascent
      proteins. These cells however are not capable to produce GPI-precursors following
      infection. We also show that the biosynthesis of the early GPI intermediate
      GlcNH(2)-PI is blocked in baculovirus-infected H5 cells, thus preventing the
      subsequent mannosylation steps for the synthesis of the conserved GPI-core
      glycan. We therefore conclude that the baculovirus system is not appropriate for
      the expression of GPI-anchored proteins.

PMID- 10642610
TI  - Urinary excretion of glycosaminoglycans and albumin in experimental diabetes
      mellitus.
AB  - Diabetes mellitus was induced in one group of rats by a single injection of
      streptozotocin. The glycemia, the body weight, and the blood systolic pressure
      were measured every week, and the 24 h urine volume and urinary excretions of
      creatinine, albumin and glycosaminoglycans were measured every 2 weeks. At the
      end of the experiment (12 weeks) the weight and the glycosaminoglycan composition
      of the kidneys were determined. All the diabetic animals were hyperglycemic,
      hypertense, and did not gain weight during all the experimental period.
      Albuminuria appeared from the second week on. Rat urine was shown to contain
      heparan sulfate, chondroitin sulfate, and dermatan sulfate, and the
      glycosaminoglycan excretion decreased in all diabetic animals. The onset of the
      change in glyco-samino-glycan excretion rate was a very early event, appearing in
      the second week after diabetes induction. The main glycosaminoglycan found in
      normal rat kidney was heparan sulfate and, in contrast to the urine, the total
      kidney glycosaminoglycans increased in diabetic kidney, due to chondroitin
      sulfate and dermatan sulfate accumulation. The heparan sulfate concentration (per
      tissue dry weight) did not change. Our results suggest that quantification of
      urinary glycosaminoglycans may be a useful tool for the early diagnosis of
      diabetic nephropathy.

PMID- 10642611
TI  - Preparation of oligomeric beta-glycosides from cellulose and hemicellulosic
      polysaccharides via the glycosyl transferase activity of a trichoderma reesei
      cellulase.
AB  - Oligoglycosyl (allyl, 2,3-dihydroxypropyl, ethyl, 2-hydroxyethyl, and methyl)
      beta-glycosides were generated by endo -transglycosylation reactions catalyzed by
      commercially available Trichoderma reesei cellulase. A polymeric donor substrate
      (xyloglucan or cellulose) was incubated with the enzyme in an aqueous solution
      containing 20% of the acceptor alcohol (allyl alcohol, glycerol, ethanol,
      ethylene glycol, and methanol, respectively). The products of these reactions
      included oligomeric alkyl beta-glycosides and reducing oligosaccharides. The high
      yield of alkyl beta-glycosides may be explained by the resistance of the
      xyloglucan beta-glycosides to cellulase-mediated hydrolysis. The resistance of
      the oligoxyloglucan beta-glycosides to endo glucanase catalyzed hydrolysis
      supports the hypothesis that productive binding of the glycan substrate depends
      on its interaction with enzyme subsites on both sides of the cleavage point,
      leading to distortion of the ring geometry of the residue whose glycosidic bond
      is cleaved. Oligoxyloglucan beta-glycosides were purified by a combination of gel
      permeation and reversed-phase HPLC and were structurally characterized by MS and
      NMR spectroscopy. These results demonstrate that novel oligosaccharide beta
      glycosides can be efficiently produced by enzyme-catalyzed
      fragmentation/transglycosylation reactions starting with a polysaccharide donor
      substrate. This class of reactions may represent a convenient source of beta
      glycosides to be used as synthons for the rapid synthesis of complex glycans.

PMID- 10642612
TI  - Sulfation of sialyl N-acetyllactosamine oligosaccharides and fetuin
      oligosaccharides by keratan sulfate Gal-6-sulfotransferase.
AB  - We have previously cloned keratan sulfate Gal-6-sulfotransferase (KSGal6ST),
      which transfers sulfate from 3'-phosphoadenosine 5'-phosphosulfate to position 6
      of Gal residue of keratan sulfate. In this study, we examined whether KSGal6ST
      could transfer sulfate to sialyl N -acetyllactosamine oligosaccharides or fetuin
      oligo-saccharides. KSGal6ST expressed in COS-7 cells catalyzed transfer of
      sulfate to NeuAcalpha2-3Galbeta1-4GlcNAc (3'SLN), NeuAcalpha2-3Galbeta1
      4GlcNAcbeta1-3Galbeta1-4Gl cNAc (SL1L1), NeuAcalpha2-3Galbeta1-4(6
      sulfo)GlcNAcbeta1-3(6-sulfo) Galbeta1-4(6-su lfo)GlcNAc (SL2L4), and their
      desialylated derivatives except for Galbeta1-4GlcNAc, but not to NeuAcalpha2
      3Galbeta1-4(Fucalpha1-3)GlcNAc (SLex). When the sulfated product formed from
      3'SLN was degraded with neuraminidase and reduced with NaBH(4), the resulting
      sulfated disaccharide alditol showed the same retention time in SAX-HPLC as that
      of [(3)H]Gal(6SO(4))beta1-4GlcNAc-ol. KSGal6ST also catalyzed sulfation of
      fetuin. When the sulfated oligosaccharides released from the sulfated fetuin
      after sequential digestion with proteinase and neuraminidase were subjected to a
      reaction sequence of hydrazin-olysis, deaminative cleavage and NaBH(4)reduction,
      the major product was co-eluted with [(3)H]Gal(6SO(4))beta1-4anhydromannitol in
      SAX-HPLC. These observations show that KSGal6ST is able to sulfate position 6 of
      Gal residue of 3'SLN and fetuin oligosaccharides. The relative rates of the
      sulfation of SL2L4 was much higher than the rate of the sulfation of keratan
      sulfate. These results suggest that KSGal6ST may function in the sulfation of
      sialyl N -acetyllactosamine oligosaccharide chains attached to glycoproteins.

PMID- 10642613
TI  - Trans-sialidase from Trypanosoma cruzi catalyzes sialoside hydrolysis with
      retention of configuration.
AB  - The trans -sialidase from Trypanosoma cruzi is a member of the sialidase
      superfamily that functions as a sialidase in the absence of a carbohydrate
      acceptor. We have used(1)H nuclear magnetic resonance (NMR) spectroscopy to
      investigate the stereospecificity of the hydrolysis of two substrates, namely, 4
      methyl-umbelliferyl- N -acetylneur-aminic acid and alpha(2-3)-sialyllactose,
      catalyzed by a recombinant T.cruzi trans -sialidase. We demonstrate that, in
      aqueous solution, the thermodynamically less stable alpha-form of N 
      acetylneuraminic acid is the initial product of the hydrolysis; subsequent
      mutarotation leads eventually to an equilibrium mixture of the alpha and beta
      forms, in molar ratio 8:92. In a mixed water/methanol solution, the hydrolysis
      reaction produces also the alpha-methyl sialoside but not its beta-methyl
      counterpart. We also show that 4-methyl-umbelliferyl- N -acetylneuraminic acid is
      a significantly better substrate for the sialidase than alpha(2-3)-sialyllactose.
      Prolonged incubation of alpha(2-3)-sialyllactose with an excess of trans 
      sialidase produced a trace of 2-deoxy-2,3-didehydro- N -acetylneuraminic acid, as
      identified by NMR spectroscopy and by gas liquid chromatography/mass spectro
      metry. In conclusion, this study shows that the stereo-selectivity of the
      sialidase activity of T.cruzi trans -sialidase is identical to that of bacterial,
      viral, and mammalian sialidases, suggesting a similar active-site architecture.

PMID- 10642614
TI  - Structural characterization of the N-glycans of Dictyocaulus viviparus: discovery
      of the Lewis(x) structure in a nematode.
AB  - This paper reports the first rigorous evidence for the existence of N-linked
      oligosaccharides in Dictyocaulus viviparus, an economically important nematode
      that parasitises cattle. Structural strategies based upon fast atom bombardment
      mass spectrometry were employed to examine detergent extracts of homogenised
      adult D.viviparus for their N-glycan content. These revealed that detergent
      soluble material is rich in high mannose, truncated and complex-type families of
      N-linked oligosaccharides. Importantly, the most abundant antennae in the complex
      type structures were shown to carry the Lewis(x)epitope (Galbeta1-4(Fucalpha1
      3)GlcNAc). Although the Lewis(x)moiety occurs in other helminths such as
      schistosomes, nematodes have previously been thought to lack this epitope. The
      Lewis(x)epitopes in D.viviparus are carried on bi-, tri-, and tetraantennary
      glycans and are therefore candidates for recognition events requiring multivalent
      ligands. There is compelling evidence from schistosome research that
      glycoconjugates containing Lewis(x)structures are immunomodulators. We propose
      that the Lewis(x)-rich glycans identified in this study might similarly be
      involved in D.viviparus host interactions.

PMID- 10642615
TI  - [Three hundred years ago, Racine died of liver disease].

PMID- 10642616
TI  - [Increased incidence of hepatocellular carcinoma in western countries: the
      reasons and the consequences].

PMID- 10642617
TI  - [Do general practitioners want to manage chronic hepatitis C and take part in
      hepatitis C health networks? A national survey].
AB  - OBJECTIVES: To assess information that general practitioners had on hepatitis C
      and on the hepatitis C network in hospitals and private practice. METHODOLOGY: A
      national telephone survey of 604 general practitioners was conducted between
      March 18 and 23, 1998. RESULTS: Screening and management of hepatitis C was
      important for 89% and 97% of general practitioners. Screening was performed in
      relation to the relative risk (IV drug users 89%, blood transfusion before 1991
      88%). General practitioners wanted more information on treatment (54%), patient
      counselling (42%) and the potential risks of the disease (42%). Of 604 general
      practitioners, 6% were involved in a hepatitis C network, while 21% were involved
      in another network (drug users 9%, AIDS 8%). Of the 94% general practitioners who
      were not part of the network, 33% were willing to join a hepatitis C network.
      Only 56% were aware of a hepatitis C network (press article 30%, mailing 17% or
      local meeting 12%). The difficulties for the involvement of general practitioners
      were: lack of time, topics not adapted to daily practice and geographic
      constraints (74%), too few patients in their practice (52%), no need (38%), the
      idea itself of a network and lack of information (28%). CONCLUSION: General
      practitioners screen patients at risk of hepatitis C. They want to be better
      informed about treatment, patient counselling, and the potential risks of
      hepatitis C. They are less involved in hepatitis C networks than in other
      networks (drug, AIDS). However, one third of general practitioners would like to
      be involved in a hepatitis C network. These results could be useful for
      implementing post-graduate courses and general practitioner training.

PMID- 10642618
TI  - [Measurement of the quality of life in chronic hepatitis C: validation of a
      general index and specific index. First French results].
AB  - OBJECTIVES: To report the validation of 2 questionnaires of quality of life in
      chronic hepatitis C and the first results in 100 patients. METHODS: The
      questionnaire included 118 items and took 30 to 45 minutes to answer. It included
      a general index, the Nottingham Health Profile, with 38 items in 6 themes
      (physical mobility, social isolation, emotional reactions, pain, sleep and
      energy) and a specific index, the Montpellier Specific Index, with 80 items in 7
      themes: symptoms, food, alcohol and tobacco, work, relations with other people,
      perception of disease. RESULTS: The questionnaires were self-administered to the
      100 first patients with chronic hepatitis C without cirrhosis before treatment;
      55 men, 45 women, average age 40 year-old, median Knodell's score 8 and median
      METAVIR score A2 F1. Reduction in the quality of life was frequent and was not
      highly correlated with biological, virological and histological parameters; it
      was associated with psychological disorders, reduced sexuality and apprehension
      of the future. CONCLUSION: This study showed the feasibility, validation,
      sensitivity and agreement of a quality of life questionnaire, which included a
      general index and a specific index of chronic hepatitis C in France. These
      initial results must be confirmed in studies during antiviral treatment of
      patients.

PMID- 10642619
TI  - [Drug-induced liver injury. Twelfth updated edition of the bibliographic database
      of liver injuries and related drugs].

PMID- 10642620
TI  - [Quality of surgical excision in cancer of the rectum: an important prognostic
      factor].

PMID- 10642621
TI  - [Reporting of resected colonic carcinomas. Assessment of practices in 8 French
      counties in 1995].
AB  - OBJECTIVES: The objective of this work was to study the reporting of resected
      colonic carcinomas and to compare them with Consensus Guidelines published in
      January 1998. METHODS: The study included 535 colonic carcinomas collected in 8
      French registries in 1995, and chosen by drawing lots. For each report, the
      presence of the information requested by the Guidelines was looked for. Three
      synthetic variables were built: 2 scores and one qualitative at 2 classes. The
      influence of patients, tumour and health care system's characteristics was
      analysed on the 3 dependent variables. RESULTS: Some important variations were
      observed for information's percents in reporting. In monovariate analysis, scores
      were significantly influenced by cancer's sub-location, area of patient's
      residence, surgical center, type of laboratories and pathologist case volume. In
      multivariate analysis, significant heterogeneity in practices remained between
      geographical areas. Types of laboratories and pathologist case volume affected
      differently dependent variables. CONCLUSION: This study shows the necessity to
      assess the practices before consensus because of the impact of pathological forms
      in therapeutic decisions and variations observed.

PMID- 10642622
TI  - [Natural history of non alcoholic and non familial chronic pancreatitis. Results
      of a multicentre study].
AB  - The natural history and complications of non alcoholic chronic pancreatitis
      (NACP) is poorly understood compared to that of alcoholic chronic pancreatitis
      (ACP). PATIENTS AND METHODS: From April 1993 to April 1996, 77 patients with NACP
      were prospectively evaluated in 17 French centres. This population was compared
      to a cohort of 417 patients with ACP. RESULTS: No significant difference was
      observed with respect to mean age between NACP and ACP (43 +/- 20 vs 44 +/- 11
      years, respectively). The median patient follow-up time was also comparable: 7
      years (1-28) and 6 years (1-34) respectively for NACP and ACP. There were
      significantly more males in the ACP group (9/1 in ACP group and 1.3/1 in NACP
      group; P<10(- 7) ). Patients with NACP were less likely to have calcifications
      (58% vs 77%; P=0.01), pseudocysts (19 vs 47%, P<0.001), portal vein thrombosis (5
      vs 16%, P<0.02). Importantly, patients with NACP required less surgical
      procedures than those with ACP (26% vs 44%, P=0.004). The actuarial death rate at
      15 years was 0% in the NACP group compared to 20.5% in those with ACP (no CP
      related death). CONCLUSION: NACP has a less severe disease progression, fewer
      complications and requires less surgical interventions than ACP. The lower
      actuarial survival rate in patients with ACP correlates with the extra-pancreatic
      complications encountered in patients with alcohol related diseases and not with
      the evolution of CP itself.

PMID- 10642623
TI  - [Frequency and prognostic value of epithelioid granuloma in inflammatory bowel
      disease].

PMID- 10642624
TI  - [Left branch portal vein thrombosis associated with hyperhomocysteinemia].
AB  - A 34 year-old man, who was a smoker, was hospitalised because of severe
      epigastric and right upper quadrant pain. An isolated left branch portal vein
      thrombosis was diagnosed using ultrasonography and arteriography. Two
      thrombogenic pathologies were found: i) a latent myeloproliferative syndrome with
      spontaneous presence of erythroid colony forming unit (CFU-E) in bone marrow
      culture, normal blood cell count, platelet count and medullogram; ii) a
      hyperhomocysteinemia associated with low serum folate levels and a methyl
      tetrahydrofolate reductase mutation. The association of these two factors
      probably resulted in portal vein thrombosis. This is the first adult case of a
      portal vein thrombosis associated with hyperhomocysteinemia. Increased
      homocysteine serum levels could be a previously unrecognized factor for portal
      vein thrombosis. Homocysteinemia should be systematically investigated in
      patients with idiopathic portal vein thrombosis since folate supplements could
      prevent deleterious vascular effects of hyperhomocysteinemia.

PMID- 10642625
TI  - [Herpetic esophagitis in human immunodeficiency virus non infected patients].
AB  - We report five cases of herpetic esophagitis in human immunodeficiency virus non
      infected patients. Herpetic esophagitis is a frequent infection in
      immunocompromised patients. However, sixty four cases of herpetic esophagitis
      have been reported in immunocompetent patients. The infection presents non
      specific esophageal symptoms. Diagnosis relies on esophageal histology and viral
      cultures. Treatment by acyclovir is recommended to prevent severe complications.
      This infection is probably underestimated in immunocompetent hosts but seems to
      be more frequent in patients with severe illness that can be responsible for
      transitory immunodeficiency. Biopsies of esophageal lesions should be
      systematically performed in these patients.

PMID- 10642626
TI  - [Hepatitis C screening in an anonymous and free screening center in Rouen].

PMID- 10642627
TI  - [Acarbose-induced acute hepatitis].

PMID- 10642628
TI  - [Acute severe fibrosing hepatitis associated with ciprofibrate treatment].

PMID- 10642629
TI  - [Severe chronic interstitial nephritis associated with Crohn's disease, but not
      with mesalazine?].

PMID- 10642630
TI  - [Duodenal metastasis revealing primary lung carcinoma].

PMID- 10642631
TI  - [Bullous hemorrhagic colitis revealing type AL amyloidosis].

PMID- 10642632
TI  - [Metal stents for the endoscopic palliative treatment of pyloro-duodenal
      stenosis].

PMID- 10642634
TI  - [Extensive digestive localization in a case of chronic lymphocytic leukemia:
      efficacy of radiotherapy].

PMID- 10642633
TI  - [Hemangioma of the small bowel manifesting as gastrointestinal bleeding,
      diagnosed by pushed enteroscopy].

PMID- 10642635
TI  - [Do hospitals need to be ranked?].

PMID- 10642636
TI  - [A controversial survey revisited].

PMID- 10642637
TI  - [Management of multiple trauma in the emergency room].
AB  - The management of multiple trauma patient in the emergency room is paradoxical
      because the treatment must be performed as soon as possible, but the precise
      diagnosis using imaging is time consuming. Multiple trauma might be classified
      into 3 classes. Patient in class 1 is severely injured with serious neurological,
      respiratory and/or hemodynamic distress. Imaging procedures only consist on chest
      x-ray, abdominal ultrasonography and echocardiography if needed, while saving
      treatments are immediately required such as tracheal intubation and mechanical
      ventilation in case of severe brain trauma or acute respiratory failure, chest
      tubing in case of massive pleural effusion, surgery for hemostasis. Class 2 is
      represented by a patient who is seriously injured but quite stabilized by
      intensive care such as massive vascular loading. The aim of clinical examination
      is to choose specific imaging to detect and to treat potential lethal injuries
      such as abdominal US, chest x-ray (4 views), angiography for embolisation, brain
      CT scan. Class 3 patient is stabilized because of medical management on the field
      by MICU (SAMU/SMUR). The best management is to first perform total body CT scan
      to obtain quick and precise diagnosis of injury and to organize specific imaging
      procedure or specific surgery. In conclusion, the best management of multiple
      trauma implies trained medical and paramedical staff including emergency
      physicians and anesthesiologists in the hospital but also in the fields,
      efficient medical dispatching to transport the patient in the hospital able to
      immediately manage the patient, surgeons of several specialties, radiologist.
      Indeed, the aim is not to transport as quick as possible the patient in the
      nearest center, but to have a logical strategy in order to have the quickest
      discharge with the least sequellae as possible.

PMID- 10642638
TI  - [Surgical management of acute abdominal pain in children].
AB  - Acute abdominal pain is one of the most frequent causes of admission to an
      emergency department of a children's hospital. It continues to be a clinical
      challenge and the diagnosis viewed with the most apprehension is acute
      appendicitis. The clinical examination must be meticulous and repeated in order
      to assess the evolution of the abdominal syndrome and to adapt the paraclinic
      examinations. All the abdominal pains are not surgical but justify an admission
      for observation in pediatric surgical department.

PMID- 10642639
TI  - [Hepatic segment resection: technique of segment IV resection].

PMID- 10642640
TI  - [Video-endoscopic excision of a parathyroid adenoma: surgical technique].

PMID- 10642641
TI  - [Colo-epiploic dissection].

PMID- 10642642
TI  - [Colo-colonic invagination disclosing a giant diverticulum of the cecum].

PMID- 10642643
TI  - [Pretherapeutic endosonography in rectal adenocarcinoma].
AB  - The advent of transrectal ultrasonography has contributed to improving
      therapeutic management of cancer of the rectum. The 7.5 MHz transrectal probe
      evidences five tissue layers in the rectal wall. The 10-12.5 MHz probe can
      visualize seven layers. Transrectal ultrasonography can also be used to explore
      the perirectal environment and detect possible nodes. Echographically, the tumor
      is seen as an hypoechogenic mass invading the rectal wall outwardly,
      disorganizing the wall structures. Parietal recurrence is seen as a hypoechogenic
      heterogeneous thickening. Ultrasonographic surveillance can be proposed for
      operable patients with a high risk of recurrence. Cautious interpretation is
      required due to the known limitations of transrectal ultrasonography. Truly
      invaded nodes may not be seen due to their small size (less than 2-3 mm) or their
      localization far from the probe (false negatives). Transrectal ultrasonography
      provides important information for therapeutic decision making in terms of
      surgical access and/or indications for possible adjuvant therapy. Transanal
      resection may also be ruled out if there are perirectal nodes. Patients may also
      be selected for preoperative radiotherapy, possibly associated with chemotherapy.

PMID- 10642644
TI  - [Surgical treatment of hepatocellular carcinoma].
AB  - There are two principal aspects to surgical treatment of hepatocellular
      carcinoma, hepatectomy and transplantation. Transplantation is a treatment of the
      tumor and the underlying liver disease. When discovered in a <<healthy>> liver,
      hepatocellular carcinoma is often seen as a large tumor. Resection is indicated
      if there is no bilobar diffusion or metastasis. If the liver is <<diseased>>,
      liver resection is contraindicated in case of liver failure or atrophy. In
      patients with no liver failure (Child-Pugh A), bi-segmentary resection can be
      proposed. In the long run, the causes of mortality after resection for
      hepatocellular carcinoma are mainly subsequent to tumor recurrence.
      Transplantation is a priori the best possible treatment for small sized
      hepatocellular carcinoma developing on a chronically ill liver. For several
      reasons, this option cannot however be proposed for all patients: limited number
      of liver grafts available, high operative mortality around 10%. In addition, the
      risk of recurrence of the causal liver disease, particularly in case of hepatitis
      B and C infections, is high. Finally, even if the initial tumor is a unique small
      sized lesion, the risk of recurrence is favored by the immunosuppression required
      for tolerance after liver transplantation.

PMID- 10642645
TI  - [A 35-year-old man with chronic pancreatitis].

PMID- 10642646
TI  - [Treatment of intimal hyperplasia by gene therapy: an update].
AB  - Injury to the vessel wall leads to smooth muscle cell (SMC) activation followed
      by intimal hyperplasia (IH). This process contributes to restenosis following
      balloon angioplasty--particularly with stenting--occlusion of vascular bypasses,
      and transplant arteriopathy. Genetic interventions affecting the cell cycle or
      early postinjury events have been successful in limiting SMC proliferation in
      vitro and in animal models. Gene therapy strategies have included the use of
      antisense oligonucleotides that block protein synthesis, transduced "suicide"
      genes that cause cytotoxicity, and cells engineered genetically to reduce the
      response to injury. The clinical application of gene therapy in vascular diseases
      should become a reality with the development of new delivery systems permitting
      efficient gene transfer to the injured vascular wall (J Mal Vasc 1999; 24: 349
      355).

PMID- 10642647
TI  - [Capillaroscopy and vascular acrosyndromes].
AB  - Periungual capillaroscopy is a simple noninvasive exploration contributing to the
      clinical examination. It is highly contributive to the etiological diagnosis of
      Raynaud's phenomenon and is the simplest means of detecting scleroderma early.
      Capillaroscopy has also largely contributed to better understanding of the
      pathogenesis of vascular disorders encountered in acrosyndromes. Experience has
      shown however that clinical indications should be more precise and results
      interpreted with more scientific rigor (J Mal Vasc 1999; 24: 357-362).

PMID- 10642648
TI  - [Glomus tumor of the extremities].
AB  - Glomus tumor is a neuro-myo-arterial benign tumor accounting for 1 to 5% of hand
      tumors which occurs principally in young adult females. It may be unique or
      multiple. Acute, focalized, pain is the main sign, the pressure of a small
      trigger zone induces a syncopal pain and immediate hand withdrawal. Differential
      diagnoses includes neurinoma, melanoma, hematoma, osteoid osteoma, fibrokeratoma,
      mucoid cyst, angioma, and exostosis. The diagnosis is suspected on clinical
      grounds, and X rays exhibits a bone erosion in one third of the cases. Magnetic
      resonance angiography is now the first line non invasive tool for both diagnosis
      and precise localization. Treatment consists in complete surgical tumor resection
      (J Mal Vasc 1999; 24: 364-367).

PMID- 10642649
TI  - [Severe and distal ischemia of the upper limb. Results of a surgical follow-up of
      11 years in 34 patients].
AB  - The aim of this retrospective study was to evaluate etiology, frequency and
      prognosis of the distal and severe arterial diseases of the upper limb treated in
      a vascular surgical unit. Between Jan. 1986 and Jan.1997, 34 patients, 22 males
      and 12 females, mean age 56 years (range 30 to 87 years) were followed in the
      vascular and thoracic surgical unit in Angers. Follow-up was 100% complete. Each
      patient was explored by selective angiography of the upper limb due to the
      critical characteristic of ischemia.19 patients (56%) had tissue loss. Among
      multiple etiologies, arteriosclerosis was found in 32% of the cases. When medical
      treatment was unsuccessful, a thoracic sympathectomy was attempted in 50% of the
      cases, and 21% of the patients had direct arterial surgery. Nine deaths, due to
      initial pathology, occurred during follow-up. Eight digitalis amputations were
      carried out whose two directly because serious necrosis. Severe arterial diseases
      of the upper limb represented 6, 4% of critical limb ischemia treated during this
      same period. At time, this study showed arteriosclerosis preponderance over
      systemic diseases, and the seriousness of cases referred to a vascular surgical
      center after unsuccessful medical treatment (J Mal Vasc 1999; 24: 368-372).

PMID- 10642650
TI  - Association between Takayasu's arteritis and Crohn's disease in two young women:
      case reports.
AB  - Among 34 patients under observation, two young women, aged 23 and 24, developed
      Takayasu's disease (Takayasu's arteritis) associated with Crohn's disease. The
      typical vascular symptoms of Takayasu's arteritis developed late during a
      quiescent phase of Crohn's disease. We discuss the usefulness of diagnostic
      methods, particularly the contribution of duplex Doppler. Currently, this method
      appears to provide effective diagnosis of Takayasu's arteritis although clinical
      data, including hyposphygmy of the radial arteries and carotidynia (pain
      appearing along the carotid course) are still fundamental. The possible
      etiopathogenic relations between these two diseases and correlation of results
      with those in the literature are discussed (J Mal Vasc 1999; 24: 373-376).

PMID- 10642651
TI  - [Arterial fibromuscular dysplasia unveiled by a traumatic false aneurysm: a case
      report].
AB  - An inadvertent puncture of the brachio-cubital artery during an intravenous
      perfusion provoked a false aneurysm in a 59-year-old woman. The angiographic
      check-up disclosed a "pile of dishes" pattern on the humeral artery. Pathological
      examination of the resected false aneurysm confirmed the presence of an extensive
      medial fibromuscular dysplasia distant from the rupture area. This clinical case
      underlines the importance of a systematic study of all traumatic vascular
      specimens in order to find any possible occult disease responsible for the
      weakening of the vessel (J Mal Vasc 1999; 24: 377-380).

PMID- 10642652
TI  - [Acute complication of a composite graft replacement of the aortic root].
AB  - A 78-year old man operated for an acute aortic dissection 8 years ago was
      hospitalized for an unusual clinical presentation with acute cor pulmonale and
      superior vena caval syndrome. He had poorly controlled high blood pressure, and
      coronary artery disease with aorto-coronary by-pass 10 years ago. He underwent
      Bentall procedure 2 years later for type I acute aortic dissection, with vein
      graft reimplantation on the valvular conduit. A pseudoaneurysm was noted in the
      post-operative period, which remained stable at 45 mm during the follow-up.
      Thoracic CT-scan highlighted a 14.5 cm diameter pseudoaneurysm compressing the
      superior vena cava and right pulmonary artery. Detached right aorto-coronary by
      pass, suspected on transesophageal echocardiography, was confirmed peri
      operatively; the aortic anastomosis blood in the peri-prosthetic space,
      explaining the acute clinical picture. The severity of the lesions did not permit
      surgical repair and the patient died during operation. This observation evidences
      the complications observed after aortic root replacement and favors echographic
      and radiological follow-ups (J Mal Vasc 1999; 24: 381-383).

PMID- 10642653
TI  - [Therapeutic nicotinic replacement and list of approved drugs].

PMID- 10642654
TI  - [Imaging and oncology: necessarily associated].

PMID- 10642655
TI  - [Neurocysticercosis].
AB  - The neurocysticercosis is an infestation of the central nervous system by larvae
      of Taenia solium. The disease is endemic in a few countries of Latin America,
      Asia, and Africa and is becoming increasingly prevalent in the United States and
      Europe. The immigration of individuals from endemic areas and the tourism in
      these areas require a good knowledge of this disease. A retrospective study
      evaluating the neurocysticercosis lesions with MR and CT is proposed.
      Parenchymal, subarachnoid and intraventricular cysts are evaluated. We were able
      to recognise four CT and MR stages. MR was useful in detecting the cysts of
      neurocycticercosis in the first stage but was inferior in the detection of
      parenchymal calcifications.

PMID- 10642656
TI  - [From accreditation to certification. Quality management in a radiology
      department].
AB  - The leaders of a radiology department started a quality process based on ISO 9001
      certification and the total quality management program. The purpose of this work
      is to match the conformity of this quality system to ANAES recommendations. If
      the concordance is obvious, the advantages of using quality insurance to get an
      accreditation are important. In conclusion, a quality process is proposed, it
      includes a quality insurance manual of ISO 9001 norm, the total quality
      management in the first point of the norm and the ANAES recommendations spread
      over the 20 points of the norm.

PMID- 10642657
TI  - [Analysis of the acetabulum anterior cover].
AB  - PURPOSE: The false profile X-Ray view as described by Lequesne, allowing the
      measurement of the anterior cover of the acetabulum, is a slantwise view obtained
      by a 65 degrees inclination of the pelvis on the radiographic plate. The errors
      introduced by this radiological measurement of the anterior cover are evaluated.
      MATERIALS AND METHODS: An anatomical and radiological analysis is conducted on 20
      acetabula. The anterior cover is measured on the bone and the A point, the
      anterior extremity of the acetabular roof, is plumbed. Each pelvis is imaged
      following the Lequesne method. The VCA angle is measured with the radiological
      point A described by Lequesne and with the metallic point A as reference.
      RESULTS: The difference between the anatomical and radiological values of the
      anterior cover is an average by 11 degrees and undervalues the anatomical value.
      The deviation is reduced by the application of a trigonometrical formula. A
      difference between the radiological localisation of A point described by Lequesne
      and the metallic marker is pointed out. This difference increases when the
      acetabulum becomes dysplasic. CONCLUSION: The acetabular anterior cover measured
      with the radiological incidence described by Lequesne undervalues the real value.
      Moreover, the error increases when the acetabulum is dysplasic.

PMID- 10642658
TI  - [Analysis of inter-hospital teleradiology consultation in Aquitaine: a 2 year
      follow-up study in Mont-de-Marsan's Emergency Department].
AB  - PURPOSE: This paper relates a technical and functional study of teleradiology
      network after two years of duty in Mont-de-Marsan's general hospital. MATERIALS
      AND METHODS: We studied from november 1995 to november 1997, the following items:
      the number of transmitted files, the medical departments involved, the degree of
      emergency, the purpose of the transmission, the number and type of images, if
      patient's transfer is wished or not, and the way the answer is given. RESULTS:
      During this 2-year period, 94 files were transmitted mainly to the University
      Hospital. The radiology department was the main user (36%), followed by the
      emergency department (29%). A notion of emergency occurred in 63% of the cases.
      Most of the cases where for radiodiagnosis (48%), and therapeutic advice (42%),
      mainly in neurosurgery. Each file consisted of 3 to 4 images of which 77% were CT
      Scan. The patient transfer was wished for in 13 files. Answer was given by
      computerised methods in 43% of the cases, and otherwise by telephone. CONCLUSION:
      Despite a better medical management of patients, this network is underused. The
      main reasons being the lack of information, the lack of time and the fact the
      network has not yet found its place in our professional environment.

PMID- 10642660
TI  - [MR cholangiopancreatography in choledochal cysts].
AB  - PURPOSE: To assess the value of MR cholangiopancreatography (MRCP) in the
      diagnosis and preoperative evaluation of choledochal cysts. MATERIAL AND METHODS:
      Five patients (aged between 6 days and 28 years) were investigated by MRCP,
      referred for ultrasonographic detection of a bile duct dilatation or a cystic
      structure, of antenatal diagnosis (1 case), for jaundice or abdominal pain (3
      cases) or in late follow-up of a choledochal cyst surgery. Two endoscopic
      ultrasonographic studies were performed. The five patients underwent surgery
      without preoperative biliary cholangiography. MRCP was performed using a HASTE
      sequence in frontal, oblique, axial planes (1,5 Tesla MR unit). RESULTS: MRCP
      allowed to confirm choledochal cyst, helps to specify the anatomical type (2 type
      I, 3 type II), detects choledocholithiasis (3 cases). Anatomic correlation was
      perfect. MRCP allowed to exclude gastrointestinal duplication. Anomalous junction
      of the pancreaticobiliary duct was found in one case. CONCLUSION: MRCP diagnoses
      choledochal cysts, specifies type, helps surgery and can avoid endoscopic
      retrograde cholangiography or endoscopic sonographic examinations especially for
      children. It may find an anomalous junction of the pancreaticobiliary duct.

PMID- 10642659
TI  - [Determination of the best diagnostic criteria of sacroiliitis with MRI].
AB  - AIM: To determine which signs are the most accurate in the diagnosis of
      sacroiliitis with MRI. MATERIAL AND METHODS: 40 consecutive patients with
      inflammatory low back pain underwent MRI at 1.5 T with FSE T2 and SE T1 weighted
      images before and after Gadolinium-DOTA injection. 22 patients were suffering
      from spondylarthropathy while the other 18 patients constituted the control
      group. Each examination was interpreted by two independent observers who analysed
      11 different signs. RESULTS: Intra and inter observer reproducibility were high
      (respectively 76% and 70%). Inter observer reproducibility was excellent for bone
      marrow edema (89%) but low for bone productions (38%). Three lesions displayed a
      high positive predictive value: ligamentous contrast enhancement (86%), bone
      marrow edema (80%) and bone erosions (70%). Intra articular enhancement of the
      sacro-iliac joint was a less sensitive sign than bone marrow edema. CONCLUSION:
      This study confirms the excellent positive predictive value of MRI for an early
      diagnosis of active sacroiliitis. Bone marrow edema seems to be a more pertinent
      sign than intra articular enhancement.

PMID- 10642661
TI  - [Colonic tubular adenoma following ureterosigmoidostomy: CT features].
AB  - We report a case of benign colonic tubular adenoma arising in a 36-year-old
      female at the site of ureterosigmoidostomy performed 25 years before. The tumor
      was revealed by recurrent episodes of pyelonephritis; hydronephrosis was present.
      On colonic enema, the tumor appeared lobulated, 4 cm in diameter. CT scan showed
      a multiloculated mass, which enhanced after injection. Pathology revealed a
      tubular adenoma of the colon with cystic dilatation of glandular structures. The
      role of imaging studies in the follow-up of patients after ureterosigmoidostomy
      is discussed.

PMID- 10642662
TI  - [Fibrous splenic hamartoma: imaging features].
AB  - Splenoma or splenic hamartoma is a rare primary splenic tumor most often
      incidentally discovered. The authors report the case of a splenic hamartoma,
      developed in an asymptomatic man and imaged by US, CT and MRI. This tumor which
      measured 7 cm in diameter, was hypoechoic with posterior hardening of the
      ultrasound beam, and not much vascularized as demonstrated by Duplex and color
      Doppler examination. The tumor MR imaging showed hyperintensity on T1-weighted
      and hypointensity on T2-weighted. The final diagnosis was not established until
      the histologic examination of the splenectomy specimen was performed.
      Histopathologically, the tumor corresponded to a fibrous type of splenic
      hamartoma. The atypical imaging features which led to splenectomy were probably
      related to the fibrous component of the hamartoma.

PMID- 10642663
TI  - [Radiological diagnosis of renal sarcoidosis].
AB  - We report a case of renal sarcoidosis revealed by a malignant hypertension
      associated with renal insufficiency. Ultrasonographic and CT findings are
      described. The lesions showed multifocal hypoechogenic areas within the renal
      parenchyma. The disease was pathologically proved after US guided biopsy.

PMID- 10642664
TI  - [CT imaging and fourth branchial pouch fistula in adults].
AB  - We report two cases of fourth branchial pouch in adult. This rare and little
      known pathology is indeed responsible for suppurative thyroiditis and left lower
      cervical abscess recurring in spite of antibiotic treatment and incision
      drainage. CT scan using, iv contrast, air as a agent contrast with Valsalva test,
      shows air in the thyroid and perithyroid soft tissue infection, proving
      communication between the pyriform fossa and the thyroid. Bubble of air behind
      the left thyroid alar in the sinus track is the best argument for diagnosis.
      Hypopharyngoscopy shows the mucous opening of the bottom at the pyriform sinus.

PMID- 10642665
TI  - [Quid? What do you think ? Diagnosis: radio-cubital post-traumatic proximal
      translocation].

PMID- 10642666
TI  - [Questions about appendiceal CT].

PMID- 10642667
TI  - [Is informed consent always necessary for randomized controlled trials?].

PMID- 10642668
TI  - A practical guide for serologic evaluation of autoimmune connective tissue
      diseases.
AB  - Serologic testing is important in the evaluation of patients with autoimmune
      connective tissue diseases (CTD). There are many techniques. Each of the tests
      has different sensitivity and specificity with varying diagnostic value. These
      serologic tests detect antibodies to numerous cellular components. The diagnostic
      significance and specificity of each antibody vary. Choosing the appropriate test
      and understanding its clinical utility is an important aspect in the diagnostic
      evaluation of patients with CTD. (J Am Acad Dermatol 2000;42:159-74.) LEARNING
      OBJECTIVE: At the conclusion of this learning activity, participants should be
      familiar with the various serologic tests for CTD, should understand the
      associations of specific antibodies with individual CTD, and should identify the
      factors that influence the predictive value of these serologic tests.

PMID- 10642670
TI  - Relevant contact sensitivities in patients with the diagnosis of oral lichen
      planus.
AB  - BACKGROUND: The concept of contact allergy aggravating or inducing oral lichenoid
      mucositis diagnosed as oral lichen planus (OLP) is well recognized but somewhat
      controversial. OBJECTIVE: We sought to identify clinically relevant contact
      allergens that may be important in the management of patients with OLP. METHODS:
      We retrospectively reviewed patients with OLP who had patch tests performed at
      Mayo Clinic Rochester and Mayo Clinic Scottsdale from 1994 to 1997 and 1988 to
      1997, respectively. RESULTS: Patch tests were performed on 46 patients with a
      clinical and histopathologic diagnosis of OLP. Of these, 25 (54%) had positive
      patch test results. Eighteen (72%) of the patients with positive results had
      clinically relevant reactions. Of the patients with positive metal reactions, 5
      had improvement after removal of the metal prosthesis or restoration. Six others
      noted that their most troublesome areas were adjacent to metal dental
      restorations. Six patients with reactions to flavorings and one patient with an
      acrylate dental retainer sensitivity had improvement after avoiding these
      allergens. CONCLUSION: Our findings support the concept that contact allergy to
      metals, flavorings, and plastics can be important in the pathogenesis and
      management of patients with oral lichenoid mucositis diagnosed as OLP.

PMID- 10642671
TI  - Photopatch testing: the 12-year experience of the German, Austrian, and Swiss
      photopatch test group.
AB  - BACKGROUND: In 1984, the German, Austrian, and Swiss Photopatch Test Group was
      founded to standardize the photopatch test procedure and to investigate
      photoallergic reactions, as well as the epidemiology of photoallergy, in central
      Europe. Therefore in a first test period from 1985-1990, 32 test substances were
      applied on the backs of patients suspected to be photosensitive. After evaluation
      of these data, some substances were dismissed, and others were additionally
      integrated into the test tray. Thus a modified test tray comprising 26 test
      substances was used for the second test period (1991-1997). OBJECTIVE: According
      to the standard photopatch test procedure defined in the first test period, the
      aim of this multicenter study was to apply compounds from the modified second
      test tray to a large group of photosensitive patients. After evaluation of the
      second test period (1991-1997), the outcome was compared with the results of the
      first period. On the basis of these results and influenced by concurrently
      published case reports, a third modified photopatch test tray has been
      established. METHODS: After the application of a duplicate test tray for 24
      hours, one test site was irradiated with 10 J/cm(2) UVA, and the other test site
      served as the control area. Readings were performed immediately and 24, 48, and
      72 hours after irradiation. Test reactions were qualitatively graded according to
      a 4-point scale and classified by the investigators of the participating centers.
      In 49 participating clinics 1261 photopatch tests were performed. All data were
      subjected to computer-assisted analysis by using a specially developed software
      to classify all positive test reactions as plain contact or photoinduced
      reactions (nonspecific, toxic, or allergic photoreactions) and to define
      substance-specific reaction patterns. RESULTS: In test period 1 data of 1129
      patients were evaluated. From 2859 positive test reactions, 28.6% were excluded
      as plain contact reactions, 71.4% were found to be photoinduced reactions, and
      3.8% were classified as photoallergic. In test period 2 data of 1261 patients
      were evaluated. One thousand four hundred fifteen positive test reactions were
      observed, and of these, 28.7% were excluded as plain contact reactions, 71.3%
      were classified as photoinduced reactions, and 8.1% were classified as
      photoallergic reactions. In both test periods nonsteroidal anti-inflammatory
      drugs, disinfectants, and phenothiazines represented the leading photoallergens
      in the evaluated central European region. By using computer-assisted reaction
      pattern analysis, substance-specific reaction patterns could be distinguished.
      These substance-specific reaction patterns comprised 4 main categories: the well
      known decrescendo (phototoxic) and crescendo (photoallergic) reaction patterns,
      as well as a combined and a plateau pattern. CONCLUSION: The test modification
      after the first test period led to a notably reduced number of positive (mainly
      nonphotoallergic and thus nonrelevant) test reactions per patient in the second
      test period (from 2.6 to 1.1). In contrast, the percentage of photoallergic
      reactions increased significantly from 3.8% to 8.1% of all positive test
      reactions. Test modifications after the first test period led to a remarkably
      improved specificity of the photopatch test. Furthermore, substance-specific
      reaction patterns observed in test period 1 were confirmed in test period 2.

PMID- 10642672
TI  - HIV-1 protease inhibitor-associated partial lipodystrophy: clinicopathologic
      review of 14 cases.
AB  - BACKGROUND: A novel type of acquired partial lipodystrophy resulting from chronic
      treatment with HIV-1 protease inhibitor drugs has recently been described.
      OBJECTIVE: We studied the clinical and histopathologic features of a series of
      patients with HIV-1 protease inhibitor-associated lipodystrophy to evaluate the
      frequency of associated abnormalities. METHODS: The study group consisted of 14
      consecutive HIV-infected patients receiving treatment with HIV-1 protease
      inhibitors, who experienced partial lipodystrophy. Clinical (including
      anthropometric data) and histopathologic findings, as well as biochemical and
      virologic data, were evaluated. RESULTS: A significant loss of fat in the face
      and extremities was associated with fat deposition on the abdomen, breast, and
      dorsocervical fat pad. Central obesity was frequently present. Histopathologic
      features disclosed a peculiar type of involutional lipodystrophy.
      Hypertriglyceridemia was detected in 78.5% of patients. Low serum levels of
      cholesterol-high-density lipoprotein and high cholesterol-very-low-density
      lipoprotein were noted. Hyperglycemia, hypercholesterolemia, or hyperinsulinemia
      were occasionally detected. CONCLUSION: HIV-1 protease inhibitor-associated
      lipodystrophy represents a new entity with peculiar clinical and histopathologic
      features. Metabolic associated abnormalities may imply a risk of future
      atherogenic complications.

PMID- 10642673
TI  - Polymorphous light eruption: A clinical, photobiologic, and follow-up study of
      110 patients.
AB  - BACKGROUND: Polymorphous light eruption is a common chronic idiopathic
      photodermatosis. The action spectrum and therapy are under debate. OBJECTIVE: The
      aim of the study was to analyze the clinical aspects of this dermatosis, the
      photodiagnostic tests, and the results of therapy in an academic center. METHODS:
      To obtain a reasonable follow-up period, we examined all available data of the
      patients who underwent diagnostic phototests in the period 1985 through 1991. Our
      procedure of phototesting included determination of minimal erythema doses,
      photoprovocation tests, and photopatch tests. The evaluation of the effect of the
      therapy was based on the patients' experiences, time spent outdoors, and amount
      of sun exposure. RESULTS: Our collection included data on 35 men and 75 women.
      The age at onset differed significantly between men and women (averages 46 and 28
      years, respectively; P <.01). The minimal erythema doses for UVB were lowered in
      43% of the men and in 4% of the women (P <.01); the minimal erythema doses for
      UVA were lowered in 37% of the men and in 11% of the women (P <.01). The
      photoprovocation tests showed a pathologic reaction to both UVB and UVA in 88% of
      the men and in 52% of the women (P <.01). In the remaining patients we found
      pathologic reactions to UVB alone (for men 9%, for women 24%; P >.05) or UVA
      alone (for men 3%, for women 24%; P <.01). The abnormal reactions to visible
      light were almost exclusively observed in those patients who reacted
      pathologically to both UVB and UVA (43% of the male patients, 11% of the female
      patients; P <.01). The photopatch tests showed a large number of positive test
      results, mainly to skin care products or sunscreens (75% of all patients). The 70
      most sensitive patients (64%) were treated with prophylactic UVB therapy 2 or 3
      times a week at home or initially in the outpatient department. This treatment
      was normally done from February to June, but in severe cases throughout the whole
      year. CONCLUSION: Phototests revealed abnormal reactions to UVB as well as UVA
      and to some extent also to visible light. Prophylactic UVB therapy is a
      successful treatment for polymorphous light eruption.

PMID- 10642674
TI  - Hydroa vacciniforme: A clinical and follow-up study of 17 cases.
AB  - BACKGROUND: Hydroa vacciniforme (HV) is a rare, sporadic, idiopathic
      photodermatosis characterized by vesicles and crust formation after sunlight
      exposure. The lesions typically heal with vacciniform scarring. OBJECTIVE: We
      identify and review the clinical features and follow-up data of Scottish patients
      with HV and report on the prevalence of this condition. This is the largest
      recent study of HV patients from a single center. METHODS: In this retrospective
      study, patients with HV were identified by means of the diagnostic database from
      the Photobiology Unit, Dundee. Patients were contacted and details of clinical
      features, duration of disease, results of investigations, and treatment were
      recorded. At review, disease progress was assessed. RESULTS: Between 1973 and
      1997, 17 patients (9 males and 8 females) with a diagnosis of HV were
      investigated. Data from 15 patients showed a mean age at onset of 7.9 years
      (range, 1 to 16 years), with females (mean, 6.7 years; range, 2 to 12 years)
      having an earlier onset than males (mean, 8.7 years; range, 1 to 16 years). A
      bimodal age distribution was also identified with onsets between the ages of 1
      and 7 years and 12 and 16 years. At review, spontaneous clearing had occurred in
      9 patients (60%) with mean duration of disease being 9 years (range, 4 to 17
      years). Males had longer disease duration (mean, 11 years; range, 5 to 17 years)
      than females (mean, 5 years; range, 4 to 7 years). Eight patients (53%) were
      sensitive in the UVA wave-band on monochromator phototesting, and 6 (40%)
      experienced papulovesicular lesions on repetitive broad-spectrum UVA irradiation.
      All patients received broad-spectrum sunscreens with variable results. Of the 5
      patients treated with narrow-band UVB (TL-01) phototherapy, 3 reported beneficial
      results with an increase in tolerance to sunlight exposure and associated
      reduction in disease severity. CONCLUSION: The estimated prevalence of HV was at
      least 0.34 cases per 100,000 with an approximately equal sex ratio. Males had a
      later onset and longer duration of disease than females. Phototesting showed
      abnormal responses in the UVA wavebands in 53% of cases, whereas 60% of patients
      treated with prophylactic TL-01 phototherapy found it beneficial.

PMID- 10642675
TI  - Confirmation of onychomycosis by in vivo confocal microscopy.
AB  - Onychomycosis is common in adults and constitutes 20% of all nail disease. Widely
      used methods to confirm a clinical diagnosis of onychomycosis often yield
      negative results (ie, potassium hydroxide [KOH] preparation) or are slow (ie,
      dermatophyte cultures). We report a case of onychomycosis in which we used in
      vivo confocal microscopy to diagnose the disease; we also correlated our findings
      with results from routine KOH preparations. On the basis of our findings, we
      hypothesize that in vivo confocal microscopy may be faster and more accurate than
      the conventional microscope used in KOH preparations in the diagnosis of
      onychomycosis.

PMID- 10642676
TI  - Onychomycosis caused by nondermatophytic molds: clinical features and response to
      treatment of 59 cases.
AB  - BACKGROUND: Nail invasion by nondermatophytic molds (NDM) is considered uncommon
      with prevalence rates ranging from 1.45% to 17. 6%. OBJECTIVE: We report the
      clinical features and response to treatment of onychomycosis caused by these
      molds. METHODS: From 1995 through 1998 we performed a mycologic study on 1548
      patients affected by nail disorders, and we diagnosed 431 cases of onychomycosis
      including 59 cases of onychomycosis caused by molds. These include 17 patients
      with onychomycosis caused by Scopulariopsis brevicaulis, 26 patients with
      onychomycosis caused by Fusarium sp, 9 patients with onychomycosis caused by
      Acremonium sp, and 7 patients with onychomycosis caused by Aspergillus sp.
      RESULTS: Onychomycosis caused by S brevicaulis, Fusarium sp, and Aspergillus sp
      may often be suspected by clinical examination. In fact 38 of 50 patients with
      onychomycosis resulting from these molds were affected by proximal subungual
      onychomycosis associated with inflammation of the proximal nailfold. In our
      experience mold onychomycosis is not significantly associated with systemic
      diseases or immunodepression. NDM are difficult to eradicate; by using and
      combining different treatments (systemic itraconazole, systemic terbinafine,
      topical terbinafine after nail plate avulsion, and ciclopirox nail lacquer) we
      were able to cure only 69.2% of patients with S brevicaulis onychomycosis, 71.4%
      of patients with Acremonium onychomycosis, and 40% of patients with Fusarium
      onychomycosis. Aspergillus onychomycosis, on the other hand, responded very well
      to therapy and all our patients were cured after systemic or topical treatment.
      Eradication of the mold produced a complete cure of the nail abnormalities in all
      the patients who responded to treatment. CONCLUSION: Clinical examination usually
      suggests diagnosis of onychomycosis resulting from NDM. Topical treatment can be
      more successful than systemic therapy to cure onychomycosis caused by S
      brevicaulis, Fusarium sp, and Acremonium sp.

PMID- 10642677
TI  - Residual lesions after Kasabach-Merritt phenomenon in 41 patients.
AB  - BACKGROUND: Kasabach-Merritt phenomenon (KMP) is the association of a vascular
      tumor and thrombocytopenic coagulopathy. Vascular tumors are either kaposiform
      hemangioendothelioma or tufted angioma but not "true" common hemangioma of
      infancy. There is a conspicuous absence in the literature regarding the late
      outcome and possible residual lesions after apparent clinical cure of KMP.
      OBJECTIVE: The purpose of the study was to analyze these residua in a large
      number of patients. METHODS: Clinical data on 41 patients who had KMP were
      accrued in an international cooperative study. The emphasis was on the residual
      lesions after resolution of the thrombocytopenia and other coagulation
      abnormalities. Imaging studies (follow-up magnetic resonance imaging studies
      available for 10 patients) and histologic specimens (30 specimens available for
      26 patients, 18 biopsies done during the KMP and 12 concerning the sequelae) were
      reviewed. RESULTS: Residual lesions after "cure" of KMP were common. They
      exhibited 3 clinical patterns: type I lesions (n = 28) showed a cutaneous red
      stain, with or without associated red papules. The stain might overlap a minor
      fibrotic infiltration or a significant poorly delineated diffuse fibrotic
      infiltration. These cutaneous vascular lesions varied in size and appearance over
      time and were occasionally painful. Type II lesions were telangiectatic streaks
      and swelling (n = 5), and type III lesions showed a minor, firm, irregular,
      subcutaneous mass assessed by palpation or deep infiltration evidenced by
      computed tomography or magnetic resonance imaging (n = 8). A fourth feature was
      sequelae in muscles and/or joints. Histologically, tufted angioma was more common
      in the specimens from residual lesions, whereas kaposiform hemangioendothelioma
      was more common during the active phase of KMP. Imaging findings were remarkably
      reproducible and revealed a persistent vascular tumor. CONCLUSION: Residua of
      tumors associated with KMP are common after the resolution of thrombocytopenia
      and coagulopathy. They are (more or less) prominent dormant vascular tumors, not
      "scars" and, clinically as well as histologically, they differ markedly from
      involuted hemangioma.

PMID- 10642678
TI  - A comparative study of oral ivermectin and topical permethrin cream in the
      treatment of scabies.
AB  - BACKGROUND: The conventional antiscabietics have poor compliance. Ivermectin, an
      oral antiparasitic drug, has been shown to be an effective scabicide and could be
      a useful substitute. OBJECTIVE: This study compares the efficacy of oral
      ivermectin with topical permethrin cream in the treatment of scabies. METHODS:
      Eighty-five consecutive patients were randomized into 2 groups. Forty patients
      and their family contacts received 200 microg/kg body weight of ivermectin, and
      another 45 patients and their family contacts received a single overnight topical
      application of 5% permethrin cream. Patients were followed up at intervals of 1,
      2, 4, and 8 weeks. RESULTS: A single dose of ivermectin provided a cure rate of
      70%, which increased to 95% with 2 doses at a 2-week interval. A single
      application of permethrin was effective in 97.8% of patients. One (2.2%) patient
      responded to 2 applications at a 2-week interval. Permethrin-treated patients
      recovered earlier. CONCLUSION: A single application of permethrin is superior to
      a single dose of ivermectin. Two doses of ivermectin is as effective as a single
      application of permethrin. The temporal dissociation in clinical response
      suggests that ivermectin may not be effective against all the stages in the life
      cycle of the parasite.

PMID- 10642679
TI  - Erythromycin in pityriasis rosea: A double-blind, placebo-controlled clinical
      trial.
AB  - BACKGROUND: The study stemmed from an incidental observation of improvement in 2
      patients with pityriasis rosea while receiving erythromycin. OBJECTIVE: The
      purpose of the study was to evaluate the efficacy of erythromycin in patients
      with pityriasis rosea. METHODS: A double-blind, placebo-controlled clinical study
      was performed in an outpatient setting in a major hospital. Ninety patients over
      a period of 2 years were alternatively assigned to treatment group or placebo
      group. Patients in the treatment group received erythromycin in divided doses for
      14 days. The response was categorized as complete response, partial response, or
      no response. All patients were followed up for 6 weeks. RESULTS: Both groups were
      comparable with regard to age at presentation, sex, and average duration of
      disease at the time of reporting to the clinic. Upper respiratory tract infection
      before the appearance of skin lesions was reported in 68.8% of all patients.
      Complete response was observed in 33 patients (73.33%) in the treatment group and
      none in the placebo group (P <.0001). CONCLUSION: Oral erythromycin was effective
      in treating patients with pityriasis rosea.

PMID- 10642680
TI  - Treatment of generalized vitiligo in children with narrow-band (TL-01) UVB
      radiation therapy.
AB  - BACKGROUND: Only a few clinical trials have been performed on the treatment of
      generalized vitiligo in children. Recently, narrow-band UVB therapy has been
      reported to be an effective and safe therapeutic option in adult patients with
      vitiligo. OBJECTIVE: We studied the efficacy and safety of UVB (311 nm) therapy
      in children with generalized vitiligo and evaluated the effect of the therapy on
      the quality of life in these children. METHODS: In an open trial, 51 children (20
      males, 31 females) with generalized vitiligo were treated twice weekly with
      narrow-band UVB radiation therapy for the maximum period of 1 year. The
      Children's Dermatology Life Quality Index (CDLQI) was used to evaluate the
      psychosocial impact of disease and treatment and was scored before and after
      therapy. RESULTS: The treatment resulted in more than 75% overall repigmentation
      in 53% of patients and in stabilization of the disease in 80%. Responsiveness to
      therapy was positively correlated with localization of the lesions and the
      patients' compliance. Adverse events were limited and transient. The better the
      repigmentation grade, the better the CDLQI scores had improved. CONCLUSION:
      Narrow-band UVB therapy is effective and safe in childhood vitiligo; it also may
      significantly improve the quality of life.

PMID- 10642681
TI  - Long-term efficacy of medium-dose UVA1 phototherapy in atopic dermatitis.
AB  - BACKGROUND: UVA1 (340-400 nm) therapy proved to be highly effective in patients
      with severe atopic dermatitis. The optimal dose regarding therapeutic efficacy
      and possible side effects is still to be evaluated. In vitro cell culture as well
      as in vivo animal studies recently indicated that a correlation between UVA
      irradiation and photoaging, skin carcinogenesis, or melanoma induction may exist.
      Therefore it seems appropriate to focus research activities on reducing the UVA1
      dose applied during phototherapeutic regimens minimizing nonbeneficial side
      effects. OBJECTIVE: The present study was performed to evaluate the therapeutic
      effectiveness and long-term efficacy of medium-dose UVA1 irradiation in patients
      treated for acute exacerbated atopic dermatitis. METHODS: Thirty-two patients
      underwent a medium-dose UVA1 therapy consisting of 15 treatments applied from
      Monday to Friday for a period of 3 weeks. The applied dose per treatment was 50
      J/cm(2) resulting in a cumulative dose of 750 J/cm(2). Clinical severity was
      assessed according to the SCORAD index before and after irradiation as well as in
      monthly intervals up to 3 months after cessation of phototherapy. RESULTS: Medium
      dose UVA1 phototherapy is effective for alleviating acute exacerbated atopic
      dermatitis as shown by a significant reduction of SCORAD ratings (P <.001) at the
      end of the active UV treatment period. A significant skin improvement was still
      present 1 month later (P <.001). However, at the end of the 3-month posttreatment
      observation period the skin condition had reached the pretreatment level.
      CONCLUSION: According to our data, medium-dose UVA1 phototherapy is a highly
      effective, nonsteroidal, therapeutic alternative for treatment of acute
      exacerbated atopic dermatitis. However, effectiveness is merely short term,
      limited, and is followed by recurrence of symptoms within a 3-month observation
      interval.

PMID- 10642682
TI  - Topical dinitrochlorobenzene therapy in the treatment of refractory atopic
      dermatitis: systemic immunotherapy.
AB  - BACKGROUND: Repeated dinitrochlorobenzene (DNCB) application has been proposed as
      a systemic immunotherapy on the basis of its ability to stimulate T helper 1
      (T(H)1) responses, such as those for systemic lupus erythematosus and HIV
      infection. OBJECTIVE: We report the effect of topical DNCB therapy in an open
      trial in patients with refractory atopic dermatitis (AD). METHODS: Eight patients
      with refractory AD received weekly application of 0.2% to 1% DNCB to a 2. 5-cm(2)
      area on the upper arm after sensitization with 5% DNCB; the position was rotated
      at each application. Disease activity was monitored by pruritus score, percentage
      of body involvement, clinical severity score, eosinophil counts, serum IgE
      levels, and serum soluble interleukin 2 receptor levels. RESULTS: Six of 8
      patients (patients 1-6) showed apparent improvement both on clinical scores and
      laboratory data until 16 weeks after DNCB therapy (week 16). The clinical
      severity scores of patients 1 to 6 were significantly correlated with eosinophil
      counts, IgE levels, and serum soluble interleukin 2 receptor levels. One patient
      did not show clear improvement, and another (patient 8) showed deterioration.
      DNCB therapy was discontinued at week 12 for patient 8. CONCLUSION: Topical DNCB
      may systemically stimulate T(H)1 cell responses of patients with AD, resulting in
      restoration of the T(H)1/T(H)2 imbalance and possible clinical improvement. These
      results, however, should be interpreted with caution until additional
      documentation is obtained.

PMID- 10642683
TI  - Tumors arising in nevus sebaceus: A study of 596 cases.
AB  - BACKGROUND: Prophylactic surgical excision of nevus sebaceus (NS) during
      childhood is often recommended because various neoplasms can occur on NS. The
      proportion of malignant tumors occurring on NS is highly variable among the
      published series, and there are controversies on the nature of these neoplasms
      because many of the previously described basal cell carcinomas could actually be
      trichoblastomas, which are benign follicular tumors. OBJECTIVE: We
      retrospectively analyzed all cases of NS of our collection, excised during the
      period from 1932 through 1998, and recorded all associated epithelial and
      nonepithelial changes. We especially differentiated basal cell carcinomas from
      trichoblastomas by silhouette analysis and examination of the stroma. These
      findings were analyzed according to gender, age, and localization. METHODS:
      Microscopic analysis of NS by two examiners was performed independently of
      clinical data. RESULTS: A total of 596 cases were included from 290 females and
      306 males, mean age 25.4 years (range, 1 month to 87 years); 232 were excised in
      children younger than 16 years. NSs were located on the scalp in 49.8% of cases.
      Basal cell carcinomas were found in 5 cases (0.8%, mean age 39.3 years) and
      benign tumors in 81 cases (13.6%, mean age 46.3 years). Syringocystadenoma
      papilliferum (n = 30, 15 males, 15 females) and trichoblastoma (n = 28, 7 males,
      21 females) were the most frequent benign tumors. NS with associated tumors were
      located on the scalp in 79% of cases. Only 4 benign tumors (1.7%) and 2 warts
      were observed in patients younger than 16 years. Various types of epithelial
      hyperplasia were noted that could not be considered neoplasms, as well as
      epidermal and apocrine cysts. CONCLUSION: The rate of malignant tumors arising on
      NS was very low and we did not observe such cases in children, who had associated
      benign tumors in only 1.7% of cases. Benign neoplasms were common and most of
      them occurred on the scalp; this was not a bias resulting from a longer duration
      before surgery. Trichoblastoma and not basal cell carcinoma was the most frequent
      follicular tumor associated with NS and showed a striking female predominance.
      Most trichoblastomas had previously been misdiagnosed but could actually be
      easily recognized by typical histologic features. Because most tumors occurred in
      adults older than 40 years, our study suggests that prophylactic surgery in young
      children is of uncertain benefit. Clinical follow-up is probably sufficient, and
      even those cases with clinical changes often proved to be benign tumors or warts.

PMID- 10642684
TI  - The ABC rule for clinical detection of subungual melanoma.
AB  - BACKGROUND: Subungual melanoma is a relatively rare disease with reported
      incidence between 0.7% to 3.5% of all melanoma cases in the general population.
      Unlike the significant improvement in the diagnosis of cutaneous melanoma, the
      diagnosis of subungual melanoma has shown little, if any, improvement over the
      years. The widespread adoption of the ABCDs of cutaneous melanoma has helped
      increase public and physician awareness, and thus helped increase the early
      detection of cutaneous melanoma; the same criteria cannot be applied to the
      examination of the nail pigmentation. OBJECTIVE: We reviewed the world literature
      on subungual melanoma and arranged the available information into a system for
      the identification of subungual melanoma. This system has to be thorough, easy to
      remember, and easy to apply by both physician and lay public. A case to
      illustrate the delayed diagnosis often encountered in the current evaluation of
      nail melanoma is presented. METHODS: A thorough review of the world literature on
      subungual melanoma was undertaken. The important findings of various studies and
      case reports were compared among themselves and the salient features were
      summarized. The information was then categorized under the easily recalled
      letters of the alphabet, ABCD, that have already become associated with melanoma.
      RESULTS: The most salient features of subungual melanoma can be summarized
      according to the newly devised criteria that may be categorized under the first
      letters of the alphabet, namely ABCDEF of subungual melanoma. In this system A
      stands for a ge (peak incidence being in the 5th to 7th decades of life and
      African Americans, Asians, and native Americans in whom subungual melanoma
      accounts for up to one third of all melanoma cases. B stands for brown to black b
      and with breadth of 3 mm or more and variegated borders. C stands for change in
      the nail band or lack of change in the nail morphology despite, presumably,
      adequate treatment. D stands for the digit most commonly involved; E stands for
      extension of the pigment onto the proximal and/or lateral nailfold (ie,
      Hutchinson's sign); and F stands for family or personal history of dysplastic
      nevus or melanoma. CONCLUSION: Although each letter of the alphabet of subungual
      melanoma is important, one must use all the letters together to improve early
      detection and thus survival of subungual melanoma. Still, as with cutaneous
      melanoma, the absolute diagnosis of subungual melanoma is made by means of a
      biopsy.

PMID- 10642685
TI  - Vascular tumors and vascular malformations: evidence for an association.
AB  - BACKGROUND: The International Society for the Study of Vascular Anomalies
      classification is an updated biologic classification that distinguishes vascular
      tumors from vascular malformations on the basis of clinical and histologic
      characteristics and biologic behavior. OBJECTIVE: We propose that in a minority
      of cases there is an association between vascular tumors and vascular
      malformations. METHODS: We retrospectively identified clinical cases in our
      medical centers and others reported in the medical literature that demonstrate an
      association between vascular tumors and vascular malformation clinically or
      histologically. RESULTS: We identified several clinical or histologic settings in
      which vascular tumors and vascular malformations were associated: (1) coexistence
      of hemangioma and vascular malformation at the same anatomic site or in close
      proximity; (2) pyogenic granuloma arising within a vascular malformation; (3)
      hemangioma associated with developmental vascular anomalies; (4) spindle-cell
      hemangioendothelioma and venous malformation; (5) kaposiform hemangioendothelioma
      and lymphatic malformation. CONCLUSION: The biologic classification of vascular
      birthmarks distinguishing vascular tumors from vascular malformations is
      clinically useful and forms the framework for our understanding of vascular
      anomalies. These examples suggest that in a small minority of patients there is
      an association between vascular tumors and vascular malformations.

PMID- 10642686
TI  - Surgical pearl: high-pressure channeled postoperative wound cleansing.

PMID- 10642687
TI  - Unilesional cutaneous T-cell lymphoma: clinical features, therapy, and follow-up
      of 10 patients with a treatment-responsive mycosis fungoides variant.
AB  - Ten patients, mean age 61 years, who presented with unilesional cutaneous T-cell
      lymphoma (CTCL) were studied. Lesional structure and distribution were similar to
      disseminated CTCL. Ablative therapy was successful in all patients. The
      relatively benign behavior of unilesional CTCL may reflect the prognostic
      importance of minimal tumor burden. Locally ablative therapy in the management of
      localized CTCL appears effective.

PMID- 10642688
TI  - Subacute cutaneous lupus erythematosus presenting with generalized poikiloderma.
AB  - A 64-year-old woman experienced progressive generalized poikiloderma after an
      episode of sunburn 4 years earlier. The diagnosis of subacute cutaneous lupus
      erythematosus (SCLE) was confirmed by the presence of anti-Ro/SS-A and
      antinuclear antibodies, the histology, and the direct immunofluorescent findings
      (ie, positive lupus band test and "dust-like" epidermal IgG staining pattern).
      Poikiloderma has not been previously reported in the spectrum of SCLE. As a major
      pathomechanism of SCLE, photosensitivity might explain this uncommon clinical
      manifestation of the disease.

PMID- 10642689
TI  - Spontaneous bullae over laser resurfaced skin.
AB  - We report 2 cases of facial bullae occurring subsequent to full-face carbon
      dioxide laser skin resurfacing. Although the cause is unknown, both responded to
      potent topical corticosteroid treatment. Laser resurfacing is a relatively new
      procedure, and physicians should be aware of this complication.

PMID- 10642690
TI  - Retiform hemangioendothelioma: another tumor associated with human herpesvirus
      type 8?
AB  - Retiform hemangioendothelioma is a rare low-grade angiosarcoma of the skin. It
      shares some clinical characteristics with Kaposi's sarcoma, a tumor with known
      human herpesvirus 8 (HHV-8) association. We report a case of retiform
      hemangioendothelioma in which we detected HHV-8 DNA sequences.

PMID- 10642691
TI  - Subcutaneous oleomas induced by self-injection of sesame seed oil for muscle
      augmentation.
AB  - This case presentation describes a 48-year-old man who experienced subcutaneous
      nodules 9 months after self-injection of sesame seed oil into the pectoral area
      for muscle augmentation. This procedure was reported by our patient to be
      frequently performed in the body-building and fitness scene. Ultrasound imaging
      showed multiple, low reflecting round nodular areas of up to 1 cm diameter in
      both breasts. Excision of a representative nodule revealed a cyst filled with
      oily material, surrounded by granulomatous tissue. This case report demonstrates
      an unusual side effect of augmentation measures in body-builders.

PMID- 10642692
TI  - Pyoderma gangrenosum and Chlamydia pneumoniae infection in a diabetic man:
      pathogenic role or coincidence?
AB  - Chlamydia Pneumoniae is not a known cause of skin infections, but unusual
      pathogens cause chronic infections in diabetic patients. Multiple idiopathic
      pyoderma gangrenosum-like (PG-like) lesions were refractory to multiple
      therapeutic agents in a diabetic patient who had C pneumoniae identified by
      serologic tests and polymerase chain reaction. Based on complete resolution by
      prolonged anti-chlamydial antibiotic therapy and concomitant decrease in
      serologic and titers determined by polymerase chain reactions, the PG-like
      lesions were presumed to be due to C pneumoniae.

PMID- 10642693
TI  - Pemphigus vulgaris induced by D-penicillamine therapy in a patient with systemic
      sclerosis.
AB  - D: -Penicillamine-induced pemphigus occurs infrequently, typically in patients
      with rheumatoid arthritis. We describe a patient with systemic sclerosis who
      experienced this complication 3 months after starting D -penicillamine therapy.
      Nikolsky's sign, histopathologic findings, and direct immunofluorescence all
      confirmed the diagnosis. Termination of disease progression required intravenous
      pulse glucocorticoids, azathioprine, and 3 courses of plasmapheresis. The
      presentation, treatment, and etiology of D -penicillamine-induced pemphigus are
      reviewed, and the incidence of this complication in scleroderma patients is
      examined.

PMID- 10642694
TI  - Bacillary angiomatosis by Bartonella quintana in an HIV-infected patient.
AB  - Bacillary angiomatosis and bacillary peliosis are opportunistic infections caused
      by Bartonella henselae and Bartonella quintana, which occur in patients with late
      stage infection. We report a case of bacillary angiomatosis in an HIV-infected
      patient with skin, bone, and probably liver involvement, The identification of
      the agent (B quintana ) was done by polymerase chain reaction in the skin
      specimen. The patient had complete regression of all lesions after a 6-month
      regimen of oral erythromycin.

PMID- 10642695
TI  - Topical tacrolimus (FK 506) is effective in the treatment of pyoderma
      gangrenosum.

PMID- 10642697
TI  - Second case of ranitidine-related toxic epidermal necrolysis in a patient with
      idiopathic thrombocytopenic purpura.

PMID- 10642698
TI  - Eosinophils in fibrous tracts and near hair bulbs: A helpful diagnostic feature
      of alopecia areata.

PMID- 10642700
TI  - Skin cancer in kidney and heart transplant recipients and different long-term
      immunosuppressive therapy regimens.

PMID- 10642701
TI  - Lipodermatosclerosis and compression stockings.

PMID- 10642703
TI  - Presidential address: a team for the 21st century: the vascular center.

PMID- 10642704
TI  - Surgical reconstruction of the extracranial vertebral artery: management and
      outcome.
AB  - PURPOSE: The purpose of this study was to identify the risk and outcome of
      reconstruction of the extracranial vertebral artery (ECVA). METHOD: The study was
      conducted as a retrospective review of 369 consecutive ECVA reconstructions.
      RESULTS: The clinical presentations consisted of hemispheric symptoms alone in 4%
      of the cases, hemispheric and vertebrobasilar symptoms in 30%, and
      vertebrobasilar symptoms alone in 60%. The cause of the lesion was
      atherosclerosis (n = 300), extrinsic compression (n = 42), dissection (n = 7),
      radiation arteritis (n = 5), intimal hyperplasia (n = 3), fibromuscular dysplasia
      (n = 2), previous surgical ligation (n = 3), aneurysm (n = 2), and other (n = 5).
      All the patients underwent preoperative arteriography. There were 252 proximal
      ECVA reconstructions (218 transpositions, 42 bypass grafting procedures, and two
      other) and 117 distal ECVA reconstructions (85 bypass grafting procedures, 25
      transpositions, and seven other). In 83 patients, the ECVA operation was
      performed concomitant with a carotid or supraaortic trunk reconstruction. This
      series was analyzed in two separate sets: before 1991 (n = 215), when changes in
      indications and management were occurring; and after 1991 (n = 154), when we
      acquired a dedicated anesthesia team and digital arteriography in the operating
      room and established uniform protocols for the management of ECVA disease. The
      stroke, death, and stroke/death rates for the period before 1991 were,
      respectively, 4. 1%, 3.2% and 5.1%. The stroke, death, and stroke/death rates for
      the period after 1991 were, respectively, 1.9%, 0.6% and 1.9%. The patency rate
      at 5 years was 80%. The survival rate at 5 years was 70%. Most of the deaths
      during the follow-up period were caused by cardiac disease. Among the survivors,
      the protection rate from stroke was 97%. CONCLUSION: The changes in operative
      selection and management have improved the results of ECVA reconstruction. The
      data reported for ECVA reconstruction in patients who underwent operation since
      1991 reflect the outcome of ECVA reconstruction today. In our experience, a
      reconstruction of the ECVA is less risky than a carotid reconstruction.

PMID- 10642705
TI  - Eversion versus conventional carotid endarterectomy: late results of a
      prospective multicenter randomized trial.
AB  - OBJECTIVE: The durability of carotid endarterectomy (CEA) may be affected by
      carotid restenosis. The data from randomized trials show that the highest
      incidence of restenosis after CEA occurs from 12 to 18 months after surgery. The
      optimal CEA technique to reduce perioperative complications and restenosis rates
      is still undefined. This study examines the long-term clinical outcome and
      incidence of recurrent stenosis in patients who undergo eversion CEA. Previously
      published perioperative results of this study did not show statistically
      significant differences in study endpoints between the eversion and standard
      techniques. METHODS: From October 1994 to March 1997, 1353 patients with surgical
      indications for carotid stenosis were randomly assigned to undergo eversion (n =
      678) or standard CEA (n = 675; primary closure, 419; patch, 256). Withdrawal from
      the assigned treatment occurred in 1.6% of the patients (in 13 assigned to
      eversion CEA, and in nine assigned to standard CEA). The clinical and duplex scan
      follow-up examination was 99% complete, and the mean follow-up interval was 33
      months (range, 12 to 55 months). The primary outcomes were perioperative and late
      major stroke and death, carotid restenosis (stenosis >/= 50% of the lumen
      diameter detected at duplex scanning), and carotid occlusion. The primary
      evaluation of study outcomes was conducted on the basis of an intention-to-treat
      analysis. RESULTS: Restenosis was found at duplex scanning in 56 patients (19 in
      the eversion group, and 37 in the standard group). Within the standard group, the
      restenosis rates were 7.9% in the primary closure population and 1.5% in the
      patched population. Of the patients with restenosis, 36% underwent cerebral
      angiography that confirmed restenosis in all cases. The cumulative restenosis
      risk at 4 years was significantly lower in the group that underwent treatment
      with eversion CEA as compared with the standard group (3.6% vs 9.2%; P =.01),
      with an absolute risk reduction of 5. 6% and a relative risk reduction of 62%.
      Eighteen patients would have had to undergo treatment with eversion CEA to
      prevent one restenosis during the 4-year period. The incidence rate of
      ipsilateral stroke was 3.3% in the eversion population and 2.2% in the standard
      group. There were no significant differences in the cumulative risks of
      ipsilateral stroke (3.9% for eversion, and 2.2% for standard; P =.2) and death
      (13.1% for eversion, and 12.7% for standard; P =.7)) in the two groups. Of the 18
      variables that were examined for their influence on restenosis, eversion CEA
      (hazard ratio, 0.3; 95% confidence interval, 0.2 to 0.6; P =.0004) and patch CEA
      (hazard ratio, 0.2; 95% confidence interval, 0.07 to 0.6; P =. 002) were negative
      independent predictors of restenosis with multivariate Cox proportional hazards
      regression analysis. CONCLUSION: The EVEREST (EVERsion carotid Endarterectomy
      versus Standard Trial) showed that eversion CEA is safe, effective, and durable.
      No statistically significant differences were found in late outcome between the
      eversion and standard techniques at the available follow-up examination.

PMID- 10642706
TI  - Etiologic factors in progression of carotid stenosis: a 10-year study in 905
      patients.
AB  - PURPOSE: The purpose of this study was to determine the etiologic factors in the
      progression of carotid stenosis. METHODS: We performed prospective serial duplex
      scan surveillance of 1470 carotid arteries in 905 asymptomatic patients during a
      10-year period, with an average follow-up interval of 29 months and an average of
      3.0 scans per carotid artery. Vascular laboratory and hospital records were used
      to collect risk factor information. The data were analyzed with proportional
      hazards modeling. RESULTS: We examined several demographic, clinical, and
      laboratory risk factors that were chosen because of their potential relevance to
      atherosclerotic disease. These factors were analyzed with univariate proportional
      hazards modeling, in which time to progression of stenosis was the outcome
      variable. The six significant predictors (P <.05) were age, sex, systolic
      pressure, pulse pressure (systolic pressure - diastolic pressure), total
      cholesterol, and high-density lipoprotein (HDL). All, except HDL, were positive
      predictors of time to disease progression. With multivariate modeling, only pulse
      pressure and HDL remained as significant independent predictors of stenosis
      progression. The risk ratio for a 10-mm Hg rise in pulse pressure was 1.12, and
      the risk ratio for a 10-mg/dL decrease in HDL was 1.20. CONCLUSION: In this large
      cohort of patients who were followed prospectively for carotid stenosis, pulse
      pressure and HDL were found to be the key risk factors for carotid stenosis
      progression. The fact that pulse pressure superseded systolic pressure in
      multivariate modeling may shed light on the biology of carotid plaque
      progression. Further, our identification of these modifiable risk factors may
      help in the design of therapeutic trials for the prevention of progression of
      carotid atherosclerosis.

PMID- 10642707
TI  - Hemispheric symptoms and carotid plaque echomorphology.
AB  - PURPOSE: In patients with carotid bifurcation disease, the risk of stroke mainly
      depends on the severity of the stenosis, the presenting hemispheric symptom, and,
      as recently suggested, on plaque echodensity. We tested the hypothesis that
      asymptomatic carotid plaques and plaques of patients who present with different
      hemispheric symptoms are related to different plaque structure in terms of
      echodensity and the degree of stenosis. METHODS: Two hundred sixty-four patients
      with 295 carotid bifurcation plaques (146 symptomatic, 149 asymptomatic) causing
      more than 50% stenosis were examined with duplex scanning. Thirty-six plaques
      were associated with amaurosis fugax (AF), 68 plaques were associated with
      transient ischemic attacks (TIAs), and 42 plaques were associated with stroke. B
      mode images were digitized and normalized using linear scaling and two reference
      points, blood and adventitia. The gray scale median (GSM) of blood was set to 0,
      and the GSM of the adventitia was set to 190 (gray scale range, black = 0; white
      = 255). The GSM of the plaque in the normalized image was used as the objective
      measurement of echodensity. RESULTS: The mean GSM and the mean degree of
      stenosis, with 95% confidence intervals, for plaques associated with hemispheric
      symptoms were 13.3 (10.6 to 16) and 80.5 (78.3 to 82.7), respectively; and for
      asymptomatic plaques, the mean GSM and the mean degree of stenosis were 30.5
      (26.2 to 34.7) and 72. 2 (69.8 to 74.5), respectively. Furthermore, in plaques
      related to AF, the mean GSM and the mean degree of stenosis were 7.4 (1.9 to 12.
      9) and 85.6 (82 to 89.2), respectively; in those related to TIA, the mean GSM and
      the mean degree of stenosis were 14.9 (11.2 to 18.6) and 79.3 (76.1 to 82.4),
      respectively; and in those related to stroke, the mean GSM and the mean degree of
      stenosis were 15.8 (10.2 to 21.3) and 78.1 (73.4 to 82.8), respectively.
      CONCLUSION: Plaques associated with hemispheric symptoms are more hypoechoic and
      more stenotic than those associated with no symptoms. Plaques associated with AF
      are more hypoechoic and more stenotic than those associated with TIA or stroke or
      those without symptoms. Plaques causing TIA and stroke have the same echodensity
      and the same degree of stenosis. These findings confirm previous suggestions that
      hypoechoic plaques are more likely to be symptomatic than hyperechoic ones. They
      support the hypothesis that the pathophysiologic mechanism for AF is different
      from that for TIA and stroke.

PMID- 10642708
TI  - The use of arm vein in lower-extremity revascularization: results of 520
      procedures performed in eight years.
AB  - PURPOSE: The absence of an adequate ipsilateral saphenous vein in patients
      requiring lower-extremity revascularization poses a difficult clinical dilemma.
      This study examined the results of the use of autogenous arm vein bypass grafts
      in these patients. METHODS: Five hundred twenty lower-extremity revascularization
      procedures performed between 1990 and 1998 were followed prospectively with a
      computerized vascular registry. The arm vein conduit was prepared by using
      intraoperative angioscopy for valve lysis and identification of luminal
      abnormalities in 44.8% of cases. RESULTS: Seventy-two (13. 8%) femoropopliteal,
      174 (33.5%) femorotibial, 29 (5.6%) femoropedal, 101 (19.4%) popliteo
      tibial/pedal, and 144 (27.7%) extension "jump" graft bypass procedures were
      performed for limb salvage (98.2%) or disabling claudication (1.8%). The average
      age of patients was 68.5 years (range, 32 to 91 years); 63.1% of patients were
      men, and 36.9% of patients were women. Eighty-five percent of patients had
      diabetes mellitus, and 77% of patients had a recent history of smoking. The
      grafts were composed of a single arm vein segment in 363 cases (69. 8%) and of
      spliced composite vein with venovenostomy in 157 cases (30.2%). The mean follow
      up period was 24.9 months (range, 1 month to 7.4 years). Overall patency and limb
      salvage rates for all graft types were: primary patency, 30-day = 97.0% +/- 0.7%,
      1-year = 80.2% +/- 2.1%, 3-year = 68.9% +/- 3.6%, 5-year = 54.5% +/- 6.6%;
      secondary patency, 30-day = 97.0% +/- 0.7%, 1-year = 80.7% +/- 2.1%, 3-year =
      70.3% +/- 3.4%, 5-year = 57.5% +/- 6.2%; limb salvage, 30-day = 97.6% +/- 0.7%, 1
      year = 89.8% +/- 1.7%, 3-year = 82.1% +/- 3.3%, 5-year = 71.5% +/- 6.9%.
      Secondary patency and limb salvage rates were greatest at 5 years for
      femoropopliteal grafts (69.8% +/- 12.8%, 80.7% +/- 11.8%), as compared with
      femorotibial (59.6% +/- 10. 3%, 72.7% +/- 10.5%), femoropedal (54.9% +/- 25.7%,
      56.8% +/- 26.9%, ) and popliteo-tibial/pedal grafts (39.0% +/- 7.3%, 47.6% +/-
      15.4%). The patency rate of composite vein grafts was equal to that of single
      vein conduits. The overall survival rate was 54% at 4 years. CONCLUSION:
      Autogenous arm vein has been used successfully in a wide variety of lower
      extremity revascularization procedures and has achieved excellent long- and short
      term patency and limb salvage rates, higher than those generally reported for
      prosthetic or cryopreserved grafts. Its durability and easy accessibility make it
      an alternative conduit of choice when an adequate saphenous vein is not
      available.

PMID- 10642709
TI  - Endovascular-assisted versus conventional in situ saphenous vein bypass grafting:
      cumulative patency, limb salvage, and cost results in a 39-month multicenter
      study.
AB  - OBJECTIVE: In this retrospective multicenter study, the results of a minimally
      invasive method of endovascular-assisted in situ bypass grafting (EISB) versus
      "open" conventional in situ bypass grafting (CISB) were evaluated with a
      comparison of primary and secondary patency, limb salvage, and cost. METHODS:
      Enrolled in this study were 273 patients: 117 underwent CISB (42 femoropopliteal,
      75 femorocrural) and 156 underwent EISB (41 femoropopliteal, 115 femorocrural).
      EISB was performed with an angioscopic Side Branch Occlusion system and an
      angioscopically guided valvulotome. All the patients underwent follow-up
      examination with serial color-flow ultrasound scanning. RESULTS: Both groups had
      similar comorbid risk factors for diabetes mellitus, coronary artery heart
      disease, hypertension, and cigarette smoking. The primary patency rates (CISB,
      78.2% +/- 5% [SE]; EISB, 70.5% +/- 5%; P =.156), the secondary patency rates
      (CISB, 84.1% +/- 4%; EISB, 82.9% +/- 5%; P =.26), and the limb salvage rates
      (CISB, 85.8%; EISB, 88.4%; P =.127) were statistically similar, with a follow-up
      period that extended to 39 months (mean, 16.6 months; range, 1 to 40 months). In
      veins that were less than 2.5 to 3.0 mm in diameter, the EISB grafts fared
      poorly, with an increased incidence of early (12-month) graft thromboses (CISB,
      10 grafts, 8.5%; EISB, 24 grafts, 15.3%). However, wound complications (CISB,
      23%; EISB, 4%; P =.003), mean hospital length of stay (CISB, 6.5 days +/- 4.83;
      EISB, 3.2 days +/- 3.19; P =.001), and mean hospital charges (CISB, $25,349 +/-
      $19,476; EISB, $18,096 +/- $14,573; P =.001) were all significantly reduced in
      the EISB group. CONCLUSION: The CISB and EISB midterm primary and secondary
      patency and limb salvage rates were statistically similar. In smaller veins (<
      2.5 to 3.0 mm in diameter), however, EISB is not appropriate because overly
      aggressive instrumentation may cause intimal trauma, with resultant early graft
      failure. With the avoidance of a long leg incision in the EISB group, wound
      complications and hospital length of stay were significantly reduced, which
      lowered hospital charges and justified the additional cost of the endovascular
      instruments. When in situ bypass grafting is contemplated, EISB in appropriate
      patients is a safe, minimally invasive, and cost-effective alternative to CISB.

PMID- 10642710
TI  - Vein interposition cuffs decrease the intimal hyperplastic response of
      polytetrafluoroethylene bypass grafts.
AB  - PURPOSE: The modification of the distal anastomosis of polytetrafluoroethylene
      (PTFE) bypass grafts with vein interposition cuffs (VCs) has been reported to
      increase graft patency. However, the mechanisms that are responsible for this
      improved patency are unclear. Because intimal hyperplasia (IH) is a primary cause
      of prosthetic graft failure, we hypothesized that VCs affect the distal
      anastomosis by decreasing the IH response of the outflow artery. METHODS: Twenty
      three female domestic Yorkshire pigs (mean weight, 35 kg) underwent 42 femoral
      PTFE bypass grafting procedures. The PTFE bypass grafts were separated into the
      following three groups according to distal anastomotic configuration: end-to-side
      anastomoses (ES), VCs, and cuffs constructed with PTFE (PCs). Four femoral
      arteries from two pigs served as healthy controls. At sacrifice, the grafts were
      perfusion fixed, and the distal anastomoses harvested at 1 and 4 weeks. The
      specimens were hemisected and serially sectioned to identify the heel, toe, and
      mid-anastomotic regions. The sections were cut into 5-microm segments and
      analyzed for intima and media thickness and area, intima/media area ratio, and
      the distribution of IH in the vein cuff. The roles of transforming growth factor
      beta1 and platelet-derived growth factor-BB in IH development were assessed with
      immunohistochemistry. RESULTS: IH development was significantly lower at all
      areas of the anastomosis, with VCs compared with ES and PCs at 4 weeks (P
      </=.001). IH decreased in VCs from 1 to 4 weeks in all areas of the anastomosis
      (P </=.001). PCs showed pronounced IH at the mid-anastomosis as compared with VCs
      and ES (P </=.001). IH was most pronounced at the toe with ES and PCs (P
      </=.001). Qualitatively, VCs altered the site of IH development, sparing the
      recipient artery with preferential thickening of the vein cuff and formation of a
      pseudointima at the vein-PTFE interface. Immunohistochemistry results showed
      positive staining for transforming growth factor-beta1, platelet-derived growth
      factor-BB, and smooth muscle alpha-actin in the hyperplastic intima. CONCLUSION:
      PTFE bypass grafts with VCs had less IH develop than did grafts with ES and PC
      anastomoses. IH regression in VCs at 4 weeks suggests compensatory vessel wall
      remodeling mediated by the presence of the VC. Furthermore, VCs caused a
      redistribution of hyperplasia to the vein-PTFE interface, delaying IH-induced
      outflow obstruction in the recipient artery. The marked increase in IH with PCs,
      despite a similar geometric configuration to VCs, suggests that the biologic
      properties of autogenous tissue dissipate IH development. Similarly, the flow
      patterns in PCs and VCs should be identical, which suggests a less important role
      of hemodynamic forces in VC-mediated protection.

PMID- 10642711
TI  - Changes in the practice of angioaccess surgery: impact of dialysis outcome and
      quality initiative recommendations.
AB  - PURPOSE: Recommendations recently published by the National Kidney Foundation
      Dialysis Outcome and Quality Initiative (DOQI) included an appeal for increased
      use of native arteriovenous fistulas (NAVFs) to improve overall patency and
      contain angioaccess costs. We evaluated the impact of the DOQI recommendations on
      angioaccess surgery and its outcome at our institution. METHODS: From June 1996
      to April 1999, 483 angioaccess procedures were performed on 247 patients. There
      were 133 men and 114 women, with an average age ranging from 28 to 95 years (mean
      age, 69 +/- 0.59 years). Risk factors included smoking in 143 patients (58%),
      diabetes mellitus in 135 patients (55%), hypertension in 150 patients (61%), and
      coronary artery disease in 98 patients (40%). The patients were divided in two
      groups. Group I (pre-DOQI) included patients who had angioaccess procedures
      between June 1996 and November 1997, and group II (post-DOQI) included patients
      who had angioaccess procedures between December 1997 and April 1999. The types of
      procedures performed included placement of arteriovenous grafts (AVGs) in 122
      patients (25%), creation of NAVFs in 99 patients (20%), revision of AVGs in 123
      patients (25%), and temporary access procedures in 135 patients (28%). Forty
      seven of the NAVF procedures were radial-cephalic fistulas (47%), 22 were
      brachial-cephalic fistulas (23%), and 30 were brachial-basilic fistulas (30%).
      Patients underwent serial ultrasonography scanning and physical examinations; the
      mean follow-up period was 9 months. Choice of angioaccess procedures and patency
      rates before and after implementation of the DOQI recommendations were compared.
      RESULTS: There was a significant increase in the use of NAVFs after implementing
      DOQI recommendations (5% vs 68%, P <.001). The 1-year primary patency rate of
      AVGs was less than that of arteriovenous fistulas (54% vs 85%, P <.001). During
      the study period, the percentage of AVGs placed at our institution that required
      revision (59%; 72 of 123) was higher than that of NAVFs that required revision
      (4%; 4 of 99; P <.001). There was no significant difference in the maturation
      rates of radial-cephalic fistulas (75%), brachial-cephalic fistulas (91%), and
      brachial-basilic fistulas (87%). CONCLUSION: By adopting the DOQI
      recommendations, we used NAVFs more often. This resulted in superior patency
      rates, compared with synthetic grafts. The liberal use of preoperative duplex
      venous mapping further increased NAVF use, surpassing the DOQI expectations for
      primary arteriovenous fistulas. Additionally, fewer revisions were required.

PMID- 10642712
TI  - Functional status and walking ability after lower extremity bypass grafting or
      angioplasty for intermittent claudication: results from a prospective outcomes
      study.
AB  - OBJECTIVE: The purpose of this study was the prospective comparison of functional
      outcomes after lower extremity bypass grafting surgery, angioplasty, or medical
      management of intermittent claudication. METHODS: The study was designed as a
      prospective cohort study to compare functional outcomes for patients with
      interventional management to medical management, including a matched (younger,
      with more disability) subgroup, followed for a mean of 19 months. Sixteen Chicago
      area vascular surgery clinics participated in the study. The subjects were
      consecutively enrolled patients with an abnormal ankle-brachial blood pressure
      index (ABI), without signs of rest pain, ulcer, or gangrene, and without prior
      lower extremity revascularization procedures. The main outcome measures were
      changes in physical functioning, community walking distance, bodily pain, leg
      symptoms, and ABI. RESULTS: Of the 526 study patients, 20% underwent
      revascularization procedures (60 surgical bypass grafting and 44 angioplasty
      only). The mean ABI improved significantly for the patients who underwent bypass
      grafting surgery (0.20; P <.001) and modestly for the patients who underwent
      angioplasty (0.09; P <. 05). Patients undergoing bypass grafting and angioplasty
      maintained highly significant (P <.001) improvements in mean physical
      functioning, (17%, 14%), bodily pain (18%, 13%), and walking distance (28%, 27%)
      scores and reported greater leg symptom improvement. The results were far
      superior for the patients with greater improvement in ABI. The conditions of the
      277 unmatched patients who underwent medical management declined on all outcome
      measures, and the conditions of the 145 matched patients who underwent medical
      management improved 5% (P <.001) on walking distance score. Eighteen percent of
      the study patients failed to complete the full study follow-up period.
      CONCLUSION: Most of the functional improvement achieved by patients who underwent
      interventional management appears to be related to improved patency rather than
      to selection bias or placebo effects. The functional gains were approximately
      half those often reported for patients for hip arthroplasty and similar to
      patients who undergo elective coronary angioplasty.

PMID- 10642714
TI  - Expansion rates and outcomes for iliac artery aneurysms.
AB  - PURPOSE: The expansion rates and outcomes of iliac artery aneurysms (IAAs) were
      determined. METHODS: A retrospective chart review was conducted to identify
      patients in whom IAAs had been diagnosed between June 1990 and March 1999 in a
      vascular surgery service at a large university-affiliated Veterans Affairs
      medical center. The patients were veterans, 187 men and two women, in whom the
      diagnosis of an IAA was made, as defined by the Ad Hoc Committee on Reporting
      Standards of The Society for Vascular Surgery and International Society for
      Cardiovascular Surgery, North American Chapter (IAA >/= 1.5 cm). Expansion rates
      relative to the size of IAAs and clinical outcomes were noted for all patients.
      RESULTS: One hundred eighty-nine patients (mean age, 72.3 +/- 0.5 years) with 323
      IAAs (mean size, 2.34 +/- 0.7 cm) were found. The mean follow-up (96% of patients
      with B mode ultrasound scanning) period was 31.4 months, with each patient
      undergoing a mean of 4.2 studies. The 4-year life-table survival rate was 78.2%,
      with no patient deaths related to their IAAs. Symptoms were noted in six of 189
      patients (3.1%; two ruptures, four chronic pain), who all had IAAs larger than 4
      cm. IAAs were repaired in 34 of 189 patients (18%), in 25 of the 34 patients
      because of their associated abdominal aortic aneurysms and in nine of 34 patients
      because of their IAAs alone. All nine patients requiring operative treatment of
      indications related to the IAA had an IAA larger than 4 cm. Expansion rates were
      slow for IAAs smaller than 3 cm (0.11 +/- 0.02 cm/year) and significantly greater
      (P <.003) for IAAs 3 to 5 cm (0.26 +/- 0.1 cm/year). The correlation between B
      mode ultrasound scanning and computed tomography scanning was excellent. The size
      of the IAAs was underestimated by 0.03 +/- 0. 06 cm by means of B mode ultrasound
      scanning. CONCLUSION: The IAAs followed up by this contemporary Veterans Affairs
      vascular surgery service were small, rarely caused symptoms or rupture, and
      expanded at a slow rate. IAAs smaller than 3 cm could be followed up safely on an
      annual basis with B mode ultrasound scanning. IAAs that are 3 cm or larger and
      smaller than 3.5 cm should be carefully followed with B mode ultrasound scanning
      at 6-month intervals, whereas elective repair should be considered for IAAs 3.5
      cm or larger in good-risk patients. Based on this report and currently available
      evidence and recommendations, asymptomatic IAAs that are 4 cm or larger and all
      other symptomatic IAAs should be considered for operative repair. Also, the
      reported high rupture rate of IAAs that are 5 cm or larger mandates prompt
      operative repair.

PMID- 10642713
TI  - Hypothenar hammer syndrome: proposed etiology.
AB  - PURPOSE: Finger ischemia caused by embolic occlusion of digital arteries
      originating from the palmar ulnar artery in a person repetitively striking
      objects with the heel of the hand has been termed hypothenar hammer syndrome
      (HHS). Previous reports have attributed the arterial pathology to traumatic
      injury to normal vessels. A large experience leads us to hypothesize that HHS
      results from trauma to intrinsically abnormal arteries. METHODS: We reviewed the
      arteriography, histology, and clinical outcome of all patients treated for HHS in
      a university clinical research center study of hand ischemia, which prospectively
      enrolled more than 1300 subjects from 1971 to 1998. RESULTS: Twenty-one men had
      HHS. All had occupational (mechanic, carpenter, etc) or avocational (woodworker)
      exposure to repetitive palmar trauma. All patients underwent upper-extremity and
      hand arteriography, unilateral in eight patients (38%) and bilateral in 13
      patients (62%). By means of arteriogram, multiple digital artery occlusions were
      shown in the symptomatic hand, with either segmental ulnar artery occlusion in
      the palm or characteristic "corkscrew" elongation, with alternating stenoses and
      ectasia. Similar changes in the contralateral asymptomatic (and less traumatized)
      hand were shown by means of 12 of 13 bilateral arteriograms (92%). Twenty-one
      operations, consisting of segmental ulnar artery excision in the palm and vein
      grafting, were performed on 19 patients. Histology was compatible with
      fibromuscular dysplasia with superimposed trauma. Patency of arterial repairs at
      2 years was 84%. One patient (5%) required amputative debridement of necrotic
      finger tips. No other tissue loss occurred. There have been no recurrences of
      ischemia in patients with patent bypass grafts. CONCLUSION: To our knowledge,
      this is the largest reported group of HHS patients. The characteristic
      angiographic appearance, histologic findings, and striking incidence of bilateral
      abnormalities in patients with unilateral symptoms lead us to conclude that HHS
      occurs when persons with preexisting palmar ulnar artery fibrodysplasia
      experience repetitive palmar trauma. This revised theory for the etiology of HHS
      explains why HHS does not develop in most patients with repetitive palmar trauma.

PMID- 10642715
TI  - Endovascular aneurysm repair in high-risk patients.
AB  - PURPOSE: The purpose of this study was to evaluate the role of endovascular
      aneurysm repair in high-risk patients. METHODS: The elective endovascular repair
      of infrarenal aortic aneurysm was performed in 116 high-risk patients with either
      custom-made or commercial stent grafts. The routine follow-up examination
      included contrast-enhanced computed tomography (CT) before discharge, at 3, 6,
      and 12 months, and annually thereafter. Patients with endoleak on the initial CT
      underwent re-evaluation at 2 weeks. Those patients with positive CT results at 2
      weeks underwent endovascular treatment. RESULTS: Endovascular repair was
      considered feasible in 67% of the patients. The mean age was 75 years, and the
      mean aneurysm diameter was 6.3 cm. The American Society of Anesthesiologists
      grade was II in 3.4%, III in 65.5%, IV in 30.1%, and V in 0.9%. There were no
      conversions to open repair. Custom-made aortomonoiliac stent grafts were
      implanted in 77.6% of the cases, custom-made aortoaotic stent grafts in 11.2%,
      and commercial bifurcated stent grafts in 11.2%. The 30-day rates of mortality,
      major morbidity, and minor morbidity were 3.4%, 20.7%, and 12%, respectively, in
      the first 58 patients and 0%, 3.4%, and 3.4%, respectively, in the last 58. The
      late complications included five cases of stent graft kinking, two cases of
      femorofemoral graft occlusion, and three cases of proximal stent migration, one
      of which led to aneurysm rupture. At 2 weeks after repair, endoleak was present
      in 10.3% of the cases. All the type I (direct perigraft) endoleaks underwent
      successful endovascular treatment, whereas only one type II (collateral) endoleak
      responded to treatment. The technical success rate at 2 weeks was 86.2%, and the
      clinical success rate was 96.6%. The continuing success rate was 87.9%. Seventeen
      patients died late, unrelated deaths. CONCLUSION: Endovascular aneurysm repair is
      safe and effective in patients at high risk, for whom it may be the preferred
      method of treatment.

PMID- 10642716
TI  - Early complications and endoleaks after endovascular abdominal aortic aneurysm
      repair: report of a multicenter study.
AB  - OBJECTIVE: The aim of this study was the identification of risk factors for
      adverse events and the assessment of the early success rate in 1554 patients with
      abdominal aortic aneurysms (AAAs) who underwent treatment with endovascular
      technique between January 1994 and March 1999. For this purpose, the clinical and
      procedural data were correlated with observed complications and endoleaks.
      METHODS: The data were collected from 56 European centers and submitted to a
      central registry. Patient characteristics, aortoiliac anatomic features,
      operative technical details, types of devices used, and experience of the teams
      of physicians were correlated with the occurrence of complications and endoleaks.
      The technical success rate was assessed according to the Society for Vascular
      Surgery/International Society for Cardiovascular Surgery, North American Chapter,
      guidelines. For the assessment of correlations between risk factors and adverse
      events, a multivariate logistic regression analysis was used. RESULTS: The
      operative complications were grouped into three categories: failure to complete
      the procedure (39 patients, of which 27 underwent a conversion to an open AAA
      repair; 2.5%); device-related or procedure-related complications (149 patients;
      10%); and arterial complications (51 patients; 3%). The most important risk
      factors for failure to complete the procedure included an aneurysm diameter of 60
      mm or more and the need for adjuvant procedures. The factors that predicted
      device-related and arterial complications were the experience of the team with
      endovascular AAA treatment and the need for adjuvant procedures. Forty patients
      (2.6%) died within 30 days after operation. American Society of Anesthesiologists
      III and IV operative risk classification results predicted higher mortality rates
      than did American Society of Anesthesiologists operative risk classification I
      and II results. The patients who underwent operation in 1994, the first year
      documented in this registry, and those who required adjuvant procedures also had
      an increased risk of perioperative death. The incidence rate of systemic
      complications within the first 30 days (279 patients; 18%) was higher in patients
      aged 75 years or more, in patients with an impaired cardiac status, and in
      patients considered unfit for an open procedure. An endoleak was detected at the
      completion of the procedure in 16% of the cases and was still present after 1
      month in 9%. The risk factors for primary endoleaks were female gender and age of
      75 years and older. The observed technical success rate in this patient series
      was 72%. CONCLUSION: The learning curve of the doctors and the need for adjuvant
      procedures were independent risk factors of operative device-related and arterial
      complications. The importance of proper instruction during an institution's
      initial phase with this treatment is emphasized by these observations. Although
      the endovascular management of AAAs is less stressful than open surgery, systemic
      complications were still the most common adverse events during the first
      postoperative month. These complications were associated with several patient
      related factors, including advanced age, impaired cardiac status, and poor
      general medical condition. These observations may be a guide for improved patient
      selection for endovascular AAA repair.

PMID- 10642717
TI  - Endovascular repair of descending thoracic aortic aneurysms: an early experience
      with intermediate-term follow-up.
AB  - PURPOSE: The purpose of this study was to report an initial experience with the
      endovascular repair of descending thoracic aortic aneurysm. Complications and
      intermediate-term morphologic changes were identified with the intent of altering
      patient selection and device design. METHODS: Endografts were placed into 25
      patients at high-risk for conventional surgical repair over a 3(1/2)-year period.
      Devices were customized on the basis of preoperative imaging information. Follow
      up computed tomography scans were obtained at 1, 3, 6, and 12 months and yearly
      thereafter. Additional interventions occurred in the setting of endoleaks,
      migration, and aneurysm growth. RESULTS: The overall 30-day mortality rate was
      20% (12.5% for elective cases; 33% for emergent cases). There were 3 conversions
      to open repair. Neurologic deficits developed in 3 patients; 1 insult resulted in
      permanent paraplegia. Neurologic deficits were associated with longer endografts
      (P =.019). Three endoleaks required treatment, and 1 fatal rupture of the
      thoracic aneurysm treated occurred 6 months after the initial repair. Migrations
      were detected in 4 patients. The maximal aneurysm size decreased yearly by 9.15%
      (P =.01) or by 13.5% (P =.0005) if patients with endoleaks (n = 3 patients) were
      excluded. Both the proximal and distal neck dilated slightly over the course of
      follow-up (P =.019 and P =.001, respectively). The length of the proximal neck
      was a significant predictor of the risk for endoleakage (P =.02). CONCLUSION: The
      treatment of descending thoracic aortic aneurysms with an endovascular approach
      is feasible and may, in some patients, offer the best means of therapy. Early
      complications were primarily related to device design and patient selection. All
      aneurysms without endoleaks decreased in size after treatment. Late complications
      were associated with changing aneurysm morphologic features and device migration.
      The morphologic changes remain somewhat unpredictable; however, alterations in
      device design may result in improved fixation and more durable aneurysm
      exclusion.

PMID- 10642718
TI  - Can knitting structure affect dilation of polyester bifurcated prostheses? A
      randomized study with the use of helical computed tomography scanning.
AB  - PURPOSE: The aim of this study was to prospectively evaluate the postoperative
      dilation of two types of knitted polyester arterial prostheses with the use of
      helical computed tomographic scanning. METHODS: Thirty-four patients who
      underwent aortoiliac or aortofemoral bifurcation grafting were randomized to
      receive a collagen-sealed warp-knitted polyester graft (n = 16 patients) or a
      gelatin-sealed Koper-knitted polyester graft (n = 18 patients). Alterations in
      size of all parts of the grafts were evaluated by helical computed tomographic
      scanning at postoperative day 8, at 3 months, and at 6 months. RESULTS: On
      postoperative day 8, the mean dilation of the Koper-knitted grafts was 18% +/- 8%
      for the stem and 15% +/- 12% for the limbs. At the same time period, the mean
      dilation of warp-knitted grafts was 27% +/- 13% for the stem and 33% +/- 18% for
      the limbs. No increase in graft dilation was observed at 3 and 6 months. Despite
      the wide range of values among patients with the same graft type, at each time
      interval, the Koper-knitted grafts dilated significantly less than the warp
      knitted grafts (P <. 05). CONCLUSION: In this randomized study, helical computed
      tomographic scanning was an accurate technique with which to assess graft
      dilation. For a 6-month follow-up interval, the Koper-knitted polyester structure
      dilated less than the warp-knitted structure. Longer-term serial scans should
      allow a better understanding of the clinical significance of graft dilation.

PMID- 10642719
TI  - Influence of segmental spinal cord perfusion on intrathecal oxygen tension during
      experimental thoracic aortic crossclamping.
AB  - PURPOSE: The purpose of this study was to evaluate the possibility of identifying
      alterations in blood supply to the spinal cord during thoracic aortic
      crossclamping. METHODS: In 17 pigs, a multiparameter PO(2), PCO(2,) and pH sensor
      was introduced into the intrathecal space for continuous monitoring of
      cerebrospinal fluid (CSF) oxygenation during aortic crossclamping. An epidural
      laser Doppler probe was used to measure spinal cord flux. After insertion of an
      aortic shunt from the left subclavian to the left iliac artery and interruption
      of the right subclavian and lumbar arteries (L2-L5), the thoracic aorta just
      distal to the left subclavian artery was clamped for 60 minutes. By placement of
      the distal aortic crossclamping below the level of L1 in group A (n = 9 animals),
      perfusion of only the abdominal visceral arteries was maintained. In group B (n =
      8 animals), the distal aortic crossclamping was above the level of T12, and thus
      some spinal cord perfusion was maintained through the aortic shunt. RESULTS: The
      significant decrease in CSF PO(2) was observed within 3 minutes after the
      placement of the proximal aortic crossclamping and was normalized in all animals
      after establishment of the shunt flow. In group A, distal aortic crossclamping
      caused a decrease in CSF PO(2) with at least 50% of the preclamping values within
      3 minutes. The mean CSF PO(2) of 2.99 +/- 0.70 kPa at 60 minutes of distal aortic
      crossclamping in group B was significantly higher than in group A (0.11 +/- 0.11
      kPa; P <. 001). In group A, PCO(2) measurements showed no significant changes in
      3 minutes after distal aortic crossclamping but revealed significantly higher
      values at 30 and 60 minutes compared with group B. Spinal cord flux values showed
      similar changes as CSF PO(2) during the whole experiment in both groups.
      CONCLUSION: In this experimental model of aortic crossclamping, continuous CSF
      oxygen tension monitoring allows rapid detection of alterations in spinal cord
      circulation.

PMID- 10642720
TI  - Mechanism of dacron-activated monocytic cell oxidation of low density
      lipoprotein.
AB  - PURPOSE: Oxidized lipids are believed to contribute to atherogenesis and may play
      a role in the development of anastomotic intimal hyperplasia in prosthetic
      vascular grafts. This study examines the hypothesis that clinically relevant
      graft material activates monocytes to oxidize low density lipoprotein (LDL).
      METHODS: LDL and Dacron or expanded polytetrafluoroethylene (ePTFE) graft
      material were incubated in the presence of U937 cells, a monocytic cell line. LDL
      oxidation was measured by conjugated dienes, lipid peroxides, thiobarbituric acid
      reacting substances, and electrophoretic mobility. Cell production of superoxide
      was measured by ferricytochrome c reduction. Metal ion requirement was assessed
      with the metal chelators, ethylenediaminetetra-acidic acid, deferoxamine, and
      bathocuproinedisulfonic acid. To determine whether human monocytes were capable
      of being activated by Dacron graft material to oxidize LDL, freshly isolated
      peripheral blood monocytes were also studied. RESULTS: Incubation of LDL with
      U937 cells and Dacron increased LDL oxidation by 5- to 20-fold. LDL incubated
      with ePTFE or U937 cells alone resulted in minimal oxidation. Dacron graft
      increased U937 cell production of superoxide by 4-fold, whereas ePTFE had no
      effect. Superoxide dismutase inhibited Dacron-activated U937 cell oxidation of
      LDL by greater than 50%, which indicates a role for superoxide.
      Ethylenediaminetetra-acidic acid, deferoxamine, and bathocuproinedisulfonic acid
      each inhibited Dacron-activated U937 cell oxidation of LDL. Human peripheral
      blood monocytes were activated by Dacron graft material to oxidize LDL;
      superoxide dismutase inhibited Dacron-activated human monocytic oxidation of LDL,
      which suggests a role for superoxide. CONCLUSION: These results suggest that
      Dacron graft material activates monocytes to oxidize LDL by a mechanism that
      involves superoxide and requires iron and copper ions. Our work suggests a
      mechanism by which lipids that have been deposited within implanted vascular
      grafts may become oxidized. Oxidized lipids may contribute to the cellular
      dysfunction that results in anastomotic intimal hyperplasia and graft failure.

PMID- 10642721
TI  - Isolation of endothelial cells and their progenitor cells from human peripheral
      blood.
AB  - PURPOSE: We have developed techniques to isolate endothelial cell (EC)
      progenitors from human peripheral and umbilical cord blood. METHODS: Human adult
      peripheral and umbilical cord blood monocytes were isolated by centrifugation,
      and progenitor cells were separated with the use of magnetic polystyrene beads
      that were coated with a monoclonal antibody specific for the CD34 cell-membrane
      antigen. Cells were propagated in selective media, and developing cultures were
      immunostained for CD31, CD34, factor VIII, and vascular endothelial growth factor
      cell receptors. ECs that developed were transfected with a gene for prourokinase
      and used to line ePTFE grafts, which were evaluated in vitro in a pulsatile flow
      system. RESULTS: Umbilical cord monocyte cultures demonstrated colonies that
      resembled ECs at approximately 2 weeks, with growth being best supported by EC
      growth media plus 20% calf serum with iron. Immunostaining of colonies was
      positive for CD31 and factor VIII. After 18 days in culture, CD34(+) cells from
      adult peripheral blood were noted, which had the typical cobblestone appearance
      of ECs and immunostained positively for CD31 and factor VIII-related antigens.
      Cultures of umbilical cord-derived cells and adult peripheral blood-derived cells
      developed complex line formations within 1 week in culture that stained
      positively for vascular endothelial growth factor receptor-2. Urokinase
      transfected ECs were shown to overexpress urokinase. Prosthetic grafts lined with
      transfected cells showed 87.33% +/- 4.97% cell adherence after 2 hours in a
      pulsatile flow system at clinically relevant shear stress. CONCLUSION: We
      conclude that endothelial progenitor cells can be isolated from human adult
      peripheral and umbilical cord blood and developed into EC cultures as a source of
      cells for vascular graft seeding and gene therapy.

PMID- 10642722
TI  - Aortoduodenal fistula after endovascular stent-graft of an abdominal aortic
      aneurysm.
AB  - Despite satisfying short- and middle-term effectiveness and feasibility,
      endovascular stent-grafting for abdominal aortic aneurysm is still under
      evaluation. We report a case of an aortoduodenal fistula after the use of this
      technique. Enlargement of the upper aneurysmal neck was followed by caudal
      migration of the major portion of the stent-graft, which resulted in kinking of
      the device in the aneurysmal sac. Ulcerations were found on adjacent portions of
      both the aneurysmal sac and the adjacent duodenum. Only the textile portion of
      the prosthetic contralateral limb separated the aortic lumen from the
      corresponding duodenal lumen. Early detection of complications after stent
      grafting is essential to allow successful treatment, either surgical or
      endoluminal.

PMID- 10642723
TI  - Delayed onset of ascending paralysis after thoracic aortic stent graft
      deployment.
AB  - Delayed spinal cord ischemia after thoracic aortic aneurysm repair is an
      infrequent but devastating complication. The use of stent grafts to exclude
      aortic aneurysms is thought to decrease the incidence of the neurologic deficit
      because there is no period of significant aortic occlusion. We report a case of
      paraplegia that progressed to quadriplegia occurring 48 hours after the
      apparently successful deployment of a thoracic aortic stent graft.

PMID- 10642724
TI  - Minimally invasive approach for aortic arch branch vessel reconstruction.
AB  - Minimally invasive aortic arch branch vessel reconstruction was successfully
      accomplished in four patients over the past 3 years. There were no operative
      complications. Three patients had an uneventful hospital course, ranging from 3
      to 5 days. The fourth patient with multiple medical problems and severe
      peripheral vascular disease had a prolonged hospital course for reasons unrelated
      to the surgical procedure. This minimally invasive surgical exposure can be used
      to effectively and safely repair innominate and left common carotid artery
      lesions.

PMID- 10642725
TI  - Simultaneous evaluation of the effects of RF hyperthermia on the intra- and
      extracellular tumor pH.
AB  - 31P-magnetic resonance spectroscopy (MRS) and a fiberoptic pH meter were used
      simultaneously to follow the changes in intra- (pHi) and extracellular pH (pHe),
      respectively, of murine RIF-1 tumors with hyperthermia. Hyperthermia was induced
      at 34 MHz using the same coil used for MR. The study was carried out until 3.5 hr
      after hyperthermia. In untreated tumors (n = 29), pHi was always higher than pHe.
      pHi was reduced after hyperthermia (30 min) at both 42 degrees C and 45 degrees
      C. pHe registered an increase after 42 degrees C and a decrease after 45 degrees
      C. The reduction in pHi was larger than the initial differential between pHi and
      pHe, and the change in pHe was relatively small. Hyperthermia changed the acidity
      of the intra- and extracellular compartments, such that pHe became more alkaline
      than pHi by 0.15 +/- 0.13 units after 42 degrees C [pHe (7.20 +/- 0.12) and pHi
      (7.03 +/- 0.05)], and by 0.12 +/- 0.14 units after 45 degrees C [pHe (6.84 +/-
      0.24) and pHi (6.72 +/- 0.19)]. Simultaneous measurements of pH from the intra-
      and extracellular compartments demonstrated reversal in the pH gradient after
      hyperthermic treatment.

PMID- 10642726
TI  - Elastic matching of dynamic MR mammographic images.
AB  - Dynamic magnetic resonance imaging (MRI) carried out with paramagnetic contrast
      media has been proven to increase sensitivity and specificity in the detection of
      breast cancer. Due to movements of the patients and changes in the shape of the
      breasts during the measurement period, a coregistration (matching) of the
      acquired data volumes is necessary to obtain higher accuracy for the localization
      of lesions. In this study, an algorithm for the elastic matching of dynamic MRI
      volume data is presented. The approach includes automatic feature extraction
      along with the analysis of corresponding features between the data sets. The
      matching is actually slice-oriented, even though information on displacement
      vectors in adjacent slices is taken into account. An extension of the procedure
      to fully three-dimensionally (3D) matching is straight forward. Up until now, the
      approach has been applied to 20 dynamic MRI studies. The matching time for two
      image data sets with 256 x 256 x 15 voxels each was about 4 min using a PC
      (Pentium Pro, 200MHz).

PMID- 10642727
TI  - Clinical application of BASING and spectral/spatial water and lipid suppression
      pulses for prostate cancer staging and localization by in vivo 3D 1H magnetic
      resonance spectroscopic imaging.
AB  - In previous in situ point-resolved spectroscopy (PRESS) three-dimensional (3D) 1H
      magnetic resonance (MR) spectroscopic imaging studies, it has been demonstrated
      that the ratio of prostatic metabolites can noninvasively discriminate prostate
      cancer from surrounding normal tissue. However, in these studies, conventional
      chemical shift selective suppression (CHESS) and short-time inversion recovery
      (STIR) techniques often resulted in inadequate water and lipid suppression. To
      improve suppression and spatial coverage, the newly developed T1 insensitive dual
      band selective inversion with gradient dephasing (BASING) Bandstop Filter and
      dual phase-compensating spectral/spatial spin-echo pulses have been implemented
      in a clinical setting. In phantom studies, no change in metabolic profiles was
      observed with application of either BASING or spectral/spatial pulses. In a study
      of 17 prostate cancer patients, the use of either BASING or spectral/spatial
      pulses allowed for suppression of water (BASING 99.80 +/- 0.14% and
      spectral/spatial 99.73 +/- 0.47%) and lipid (BASING 98.56 +/- 1.03% and
      spectral/spatial 98.44 +/- 1.90%) without a significant difference in the
      prostatic metabolite ratios. Spectral/spatial suppression has the added advantage
      of reducing the chemical shift dependence of the PRESS volume, but optimal
      performance requires high-speed gradients with negligible eddy current effects.
      BASING suppression is less reliant on accurate pulse and gradient timings and can
      be implemented easily with no loss in performance on clinical MR scanners with
      conventional gradients.

PMID- 10642728
TI  - Very selective suppression pulses for clinical MRSI studies of brain and prostate
      cancer.
AB  - Focal three-dimensional magnetic resonance spectroscopic imaging (3D MRSI)
      methods based on conventional point resolved spectroscopy (PRESS) localization
      are compromised by the geometric restrictions in volume prescription and by
      chemical shift registration errors. Outer volume saturation (OVS) pulses have
      been applied to address the geometric limits, but conventional OVS pulses do
      little to overcome chemical shift registration error, are not particularly
      selective, and often leave substantial signals that can degrade the spectra of
      interest. In this paper, an optimized sequence of quadratic phase pulses is
      introduced to provide very selective spatial suppression with improved B1 and T1
      insensitivity. This method was then validated in volunteer studies and in
      clinical 3D MRSI exams of brain tumors and prostate cancer.

PMID- 10642729
TI  - A model of unloaded human intervertebral disk based on NMR relaxation.
AB  - NMR relaxation rates were related to the composition of the nucleus pulposus from
      11 and anulus fibrosus from six human intervertebral disks. Tissue water was
      proportional to glycosaminoglycan (GAG) and residue, the noncollagen, non-GAG
      portion of the dry weight (R2 = 0.74). The solid signal fraction depended on
      collagen and residue protons (R2 = 0.89). 1/T1 was proportional to collagen and
      residue (R2 = 0.97). T2 showed 2-4 components labeled A, B, C, and D, with means
      +/- standard deviations of 3.1 +/- 1.6, 17.5 +/- 9.5, 64 +/- 22, and 347 +/- 162
      msec. Signal fractions of A and B depended on the collagen-associated water
      protons (R2 = 0.94 and 0.85), C on residue-associated water protons (R2 = 0.82),
      and D on GAG-associated water protons (R2 = 0.74). The data led to a model of
      disk architecture in which the collagen and residue were largely solid, forming
      distinct water compartments; the remaining water was present in a proteoglycan
      gel.

PMID- 10642730
TI  - Cocaine administration decreases functional connectivity in human primary visual
      and motor cortex as detected by functional MRI.
AB  - Functional magnetic resonance imaging (fMRI) was conducted to observe the effects
      of cocaine administration on the physiological fluctuations of fMRI signal in two
      brain regions. Seven long-term cocaine users with an average age of 32 years and
      8 years of cocaine use history were recruited for the study. A T2*-weighted fast
      echo-planar imaging (EPI) pulse sequence was employed at 1.5 T to acquire three
      sets of brain images for each subject under three conditions (at rest, after
      saline injection, and after cocaine injection [0.57 mg/kg]). Cross-correlation
      maps were constructed using the synchronous, low frequency signal from voxel time
      courses after filtering respiratory, cardiac, and other physiological noise. A
      quantitative evaluation of the changes in functional connectivity was made using
      spatial correlation coefficient (SCC) analysis. A marked 50% reduction in SCC
      values in the region of primary visual cortex and 43% reduction in SCC values in
      the region of primary motor cortex were observed after cocaine administration.
      This significant reduction in SCC values in these cortical regions is a
      reflection of changes in neuronal activity. It is suggested that the observed
      changes in low frequency components after acute cocaine administration during a
      resting, no-task situation may be used as a baseline reference source when
      assessing the effects of cocaine on task-driven activation or on mesolimbic
      dopamine pathways.

PMID- 10642731
TI  - Histogram-based characterization of healthy and ischemic brain tissues using
      multiparametric MR imaging including apparent diffusion coefficient maps and
      relaxometry.
AB  - Decreased, renormalized, or increased values of the calculated apparent diffusion
      coefficient (ADC) are observed in stroke models. A quantitative description of
      corresponding tissue states using ADC values may be extended to include true
      relaxation times. A histogram-based segmentation is well suited for
      characterizing tissues according to specific parameter combinations irrespective
      of the heterogeneity found for human healthy and ischemic brain tissues. In a new
      approach, navigated diffusion-weighted images and ADC maps were incorporated into
      voxel-based parameter sets of relaxation times (T1, T2), and T1- or T2-weighted
      images, followed by a supervised histogram-based analysis. Healthy tissues were
      segmented by incorporating T1 relaxation into the data set, ischemic regions by
      combining T2- or diffusion-weighted images with ADC maps. Mean values of healthy
      and pathologic tissues were determined, spatial distributions of the parameter
      vectors were visualized using color-encoded overlays. One to six days after
      stroke, ischemic regions exhibited reduced relative mean ADC values.

PMID- 10642732
TI  - Proton-resonance frequency shift MR thermometry is affected by changes in the
      electrical conductivity of tissue.
AB  - The proton-resonance frequency (PRF) shift method of MR thermometry provides an
      easy and practical means of quantitatively monitoring in vivo temperatures for MR
      image-guided thermal-coagulation therapy. However, reported discrepancies in the
      numerical value of the PRF-thermal coefficient persist, when measured in a
      variety of experimental conditions and in different tissue types, both ex vivo
      and in vivo. In this report, a potential source of variation in the PRF-shift
      method of thermometry is identified that manifests as a constant incremental
      phase shift per unit change in temperature that is independent of the echo-time
      setting, when constructing temperature-sensitive phase images from a gradient
      echo pulse sequence. It is proposed that this confounding phase-shift offset
      arises from thermally induced changes in the electrical conductivity of the
      material. To this end, it is demonstrated that the MR-derived temperature changes
      could be in error by as much as 28%, as measured from a simple calibration
      experiment on freshly excised cow liver. A simple method of overcoming this phase
      shift offset is described.

PMID- 10642733
TI  - Dynamic models in fMRI.
AB  - Most statistical methods for assessing activated voxels in fMRI experiments are
      based on correlation or regression analysis. In this context, the main
      assumptions are that the baseline can be described by a few known basis functions
      or variables and that the effect of the stimulus, i.e., the activation, stays
      constant over time. As these assumptions are in many cases neither necessary nor
      correct, a new dynamic approach that does not depend on those assumptions will be
      presented. This allows for simultaneous nonparametric estimation of the baseline
      and, as an important feature, of time-varying effects of stimulation. This method
      of estimating the stimulus related areas of the brain furthermore provides the
      possibility to analyze the temporal and spatial evolution of the activation
      within an fMRI experiment.

PMID- 10642734
TI  - Linear combination steady-state free precession MRI.
AB  - A new, fast, spectrally selective steady-state free precession (SSFP) imaging
      method is presented. Combining k-space data from SSFP sequences with certain
      phase schedules of radiofrequency excitation pulses permits manipulation of the
      spectral selectivity of the image. For example, lipid and water can be resolved.
      The contrast of each image depends on both T1 and T2, and the relative
      contribution of the two relaxation mechanisms to image contrast can be controlled
      by adjusting the flip angle. Several potential applications of the technique,
      referred to as linear combination steady-state free precession (LCSSFP), are
      demonstrated: fast musculoskeletal, abdominal, angiographic, and brain imaging.

PMID- 10642735
TI  - Undersampled projection reconstruction applied to MR angiography.
AB  - Undersampled projection reconstruction (PR) is investigated as an alternative
      method for MRA (MR angiography). In conventional 3D Fourier transform (FT) MRA,
      resolution in the phase-encoding direction is proportional to acquisition time.
      Since the PR resolution in all directions is determined by the readout
      resolution, independent of the number of projections (Np), high resolution can be
      generated rapidly. However, artifacts increase for reduced Np. In X-ray CT,
      undersampling artifacts from bright objects like bone can dominate other tissue.
      In MRA, where bright, contrast-filled vessels dominate, artifacts are often
      acceptable and the greater resolution per unit time provided by undersampled PR
      can be realized. The resolution increase is limited by SNR reduction associated
      with reduced voxel size. The hybrid 3D sequence acquires fractional echo
      projections in the k(x)-k(y) plane and phase encodings in k(z). PR resolution and
      artifact characteristics are demonstrated in a phantom and in contrast-enhanced
      volunteer studies.

PMID- 10642736
TI  - Regression analysis of metabolite concentrations estimated from localized proton
      MR spectra of active and chronic multiple sclerosis lesions.
AB  - Localized short echo time magnetic resonance (MR) spectra were obtained from
      patients with multiple sclerosis of relapsing-remitting or secondary chronic
      progressive course and from healthy controls. Automated analysis using model
      spectra, sensitivity correction, and subtraction of partial ventricular volume
      yielded tissue concentrations of metabolites that were in line with findings of
      previous studies. Additional findings were increased creatine in chronic lesions
      and increased myo-inositol in normal-appearing white matter. Regression analysis
      was performed to reveal concomitant changes of metabolite concentrations.
      Differences in the correlations between cholines and myo-inositol suggest
      increased expression of myo-inositol in chronic lesions or of cholines in active,
      contrast-enhanced lesions. A correlation between N-acetyl-aspartate and creatine,
      which is probably due to extracellular edema, was observed in active but not in
      chronic lesions. Creatine and cholines correlated in chronic lesions, which may
      be the result of gliosis. The consequences of these findings for the
      interpretation of absolute concentrations and creatine ratios are discussed.

PMID- 10642737
TI  - MR imaging of shear waves generated by focused ultrasound.
AB  - This study has shown that magnetic resonance elastography (MRE) can detect shear
      waves excited by focused ultrasound (FUS) in both gel phantoms and ex vivo
      muscle. Good agreement was shown between the shear modulus measured from MRE
      images generated using FUS and that using previously reported MRE techniques. The
      shear wave displacement amplitude at the FUS focus was studied and found to be
      proportional with both FUS ultrasonic pulse intensity and the FUS modulation
      pulse period over the range tested.

PMID- 10642738
TI  - Validation of MR-based polymer gel dosimetry as a preclinical three-dimensional
      verification tool in conformal radiotherapy.
AB  - The aim of this work was to investigate MR-based polymer gel dosimetry as a three
      dimensional (3D) dosimetry technique in conformal radiotherapy. A cylindrical
      container filled with polymer gel was placed in a water-filled torso phantom to
      verify a treatment plan for the conformal irradiation of a mediastinal tumor
      located near the esophagus. Magnetic resonance spin-spin relaxation rate images
      were acquired and, after calibration, converted to absorbed dose distributions.
      The dose maps were compared with dose distributions measured using radiographic
      film. The average root-mean-square structural deviation, for the complete dose
      distribution, amounted to less than 3% between gel and film dose maps. It may be
      expected that MR gel dosimetry will become a valuable tool in the verification of
      3D dose distributions. The influence of imaging artifacts arising from eddy
      currents, temperature drift during scanning, and B1 field inhomogeneity on the
      dose maps was taken into account and minimized.

PMID- 10642739
TI  - Diurnal variation in the femoral articular cartilage of the knee in young adult
      humans.
AB  - Our objective was to test the hypothesis that diurnal changes occur in thickness
      or volume of the femoral articular cartilage of the knee in asymptomatic young
      adults. Fat-suppressed three-dimensional (3D) spoiled gradient-echo magnetic
      resonance imaging (MRI) was employed. Six volunteers each were scanned early in
      the morning and at the end of a working day spent mainly standing. This protocol
      was repeated on 3 successive weeks. Femoral cartilage volumes were obtained via
      semiautomatic segmentation that employed a seeding algorithm. These segmentations
      then were regridded onto a 500-pixel template, and differences in the resulting
      thickness maps were assessed. Analysis of variance showed no significant diurnal
      variation in overall volume or thickness. The reproducibility for volume (test
      retest coefficient of variation) was 1.6%. There were, however, statistically
      significant diurnal changes in the thickness maps. Cartilage thickness decreased
      by up to 0.6 mm during the day in each of the following three specific locations:
      the patellofemoral compartment, the lateral tibiofemoral compartment, and the
      medial tibiofemoral compartment. Elsewhere, cartilage thickness was unchanged or
      increased by up to 0.5 mm. We conclude that, in asymptomatic young adults,
      cartilage volume does not change during the day; however, the cartilage does
      become thinner in locations that encounter the greatest biomechanical force.

PMID- 10642740
TI  - Diffusion imaging of the spinal cord in vivo: estimation of the principal
      diffusivities and application to multiple sclerosis.
AB  - Magnetic resonance (MR) diffusion imaging is a useful technique with which to
      increase our understanding of pathologic damage to the central nervous system. To
      fully quantitate diffusion and anisotropy in the spinal cord, as in other
      tissues, it is necessary to determine the diffusion tensor. If spinal cord
      diffusion is assumed to be cylindrically symmetric and the orientation of the
      cord in the gradient frame is known, then it is shown that full quantification is
      possible from only three images, two of which are diffusion-weighted. Mean
      diffusivity and volume ratio were determined in the normal cord of four healthy
      volunteers and in seven cord lesions of three patients with clinically definite
      multiple sclerosis (MS) who had locomotor disability suggesting the presence of
      spinal pathology. MS cord lesions exhibited increased mean diffusivity reflecting
      structural damage to the cord white matter. Quantification of diffusion and
      anisotropy using spinal cord diffusion imaging provides new structural
      information in relation to spinal cord pathology in vivo.

PMID- 10642741
TI  - A shielded Overhauser marker for MR tracking of interventional devices.
AB  - Improvements to an active MR tracking technique are described. Real-time position
      monitoring of interventional procedures can be realized by incorporating a small
      marker that emits an NMR signal into the tip of an interventional device, and the
      marker's emitted NMR signal is enhanced by use of the Overhauser phenomenon. A
      significant advance over prior designs has achieved by making the marker have a
      cylindrical shape and by confining the saturation energy to the marker's
      interior. The performance of the improved active marker was verified in the
      laboratory and in vitro. The experiments demonstrated that the marker was visible
      in MR images when inserted in different excised tissues, and even in air, with
      positive contrast and with various imaging sequences. The tissue magnetization
      was minimally perturbed, and the marker emitted a variable but enhanced signal in
      all orientations in the magnetic field. The marker can potentially be used to
      mark locations on the body for frameless stereotaxy or to identify inserted
      devices.

PMID- 10642742
TI  - Absolute measurements of water content using magnetic resonance imaging:
      preliminary findings in an in vivo focal ischemic rat model.
AB  - Using a magnetic resonance (MR) imaging method, absolute measurements of in vivo
      brain water content were obtained in 15 male Long Evans rats that underwent a 90
      min focal cerebral ischemia. A strong linear relationship (r = 0.80) with a slope
      of 1 was observed when correlating MR-measured water content to that obtained
      with the ex vivo wet/dry measurements. This effective spin-density-based method
      is the first-reported in vivo absolute quantification of brain tissue water
      content associated with a pathophysiological state and preliminary findings
      suggest that a noninvasive measurement of brain water content can be obtained
      with MRI.

PMID- 10642743
TI  - Automatic field map generation and off-resonance correction for projection
      reconstruction imaging.
AB  - A new projection reconstruction technique utilizes the oversampling of low
      spatial frequencies to estimate and correct for off-resonance effects.
      Interleaved spokes are acquired at one of two different echo times. From
      separated early-TE and late-TE raw data, two one-quarter resolution images are
      reconstructed and a one-quarter resolution field map is computed. Multifrequency
      reconstruction with all the data is then used to simultaneously correct for off
      resonance and compensate for the difference in echo times. Resulting images
      obtained on phantoms and in vivo demonstrate significantly reduced off-resonance
      artifact without the acquisition of a separate field map.

PMID- 10642744
TI  - In vivo fMRI demonstration of hypothalamic function following intraperitoneal
      glucose administration in a rat model.
AB  - The hypothalamic functional MRI (fMRI) response in an animal model was studied
      following energy intake. Six fasted (12 h) Sprague-Dawley (SD) rats were
      administered an intraperitoneal injection of glucose (0.72 grams/kg body weight),
      while a mid-sagittal slice through the hypothalamus was continuously imaged for
      60 min using a conventional T2*-weighted gradient-echo sequence. All rats
      demonstrated a significant acute transient decrease in the fMRI signal intensity
      (mean: 3.4%) in the hypothalamic region within 12-16 min after intraperitoneal
      glucose injection. The SD rat may be a suitable model for future fMRI studies of
      the hypothalamus involving the administration of exogenous nutrients and
      medications.

PMID- 10642745
TI  - k-Space partition diagrams: a graphical tool for analysis of MRI pulse sequences.
AB  - A new type of graphical tool for explaining and analyzing magnetic resonance
      imaging pulse sequences is developed and illustrated. This tool combines the
      partition diagram, which shows the evolution of multiple echoes with the
      application of multiple RF pulses, and k-space graphs, which show the evolution
      of the transverse magnetization as gradients are applied. The strength of the new
      tool lies in its ability to depict clearly the progression of complex imaging
      pulse sequences. Several complicated excitation sequences are used to illustrate
      this method.

PMID- 10642747
TI  - Cultured astrocyte proliferation induced by extracellular guanosine involves
      endogenous adenosine and is raised by the co-presence of microglia.
AB  - Extracellular adenosine (Ado) and ATP stimulate astrocyte proliferation through
      activation of P(1) and P(2) purinoceptors. Extracellular GTP and guanosine (Guo),
      however, that do not bind strongly to these receptors, are more effective
      mitogens than ATP and Ado. Exogenous Guo, like GTP and 5'-guanosine-betagamma
      imidotriphosphate (GMP-PNP), dose-dependently stimulated proliferation of rat
      cultured astrocytes; potency order GMP-PNP > GTP > or = Guo. The mitogenic effect
      of Guo was independent of the extracellular breakdown of GTP to Guo, because GMP
      PNP, a GTP analogue resistant to hydrolysis, was the most mitogenic. In addition
      to a direct effect on astrocytes, Guo exerts its proliferative activity involving
      Ado. Exogenous Guo, indeed, enhanced the extracellular levels of endogenous Ado
      assayed by HPLC in the medium of cultured astrocytes. Culture pretreatment with
      Ado deaminase (ADA), that converts Ado into inosine, reduced but did not abolish
      Guo-induced astrocyte proliferation whereas erythro-9-(2-hydroxy-3-nonyl)adenine
      (EHNA), that inhibits ADA activity, amplified Guo effect. Moreover, the mitogenic
      activity of Guo was partly inhibited by 8-cyclopentyl-1,3-dipropylxanthine and
      alloxazine, antagonists of Ado A(1) and A(2B) receptors, respectively. Also
      microglia seem to be a target for the action of Guo. Indeed, the mitogenic effect
      of Guo on astrocytes was: i) increased proportionally to the number of microglial
      cells present in the astrocyte cultures; ii) amplified when purified cultures of
      astrocytes were supplemented with conditioned medium deriving from Guo-pretreated
      microglial cultures. These data indicate that the mitogenic effects exerted by
      exogenous Guo on rat astrocytes are mediated via complex mechanisms involving
      extracellular Ado and microglia-derived soluble factors.

PMID- 10642746
TI  - Effects of ATP and derivatives on neuropile glial cells of the leech central
      nervous system.
AB  - We investigated the effects of ATP (adenosine 5'-triphosphate) and derivatives on
      leech neuropile glial cells, focusing on exposed glial cells. ATP dose
      dependently depolarized or hyperpolarized neuropile glial cells in situ as well
      as exposed neuropile glial cells. These potential shifts varied among cells and
      repetitive ATP application did not change their amplitude, duration or direction.
      In exposed neuropile glial cells, ATP most frequently induced a Na(+)-dependent
      depolarization and decreased the input resistance. The agonist potency ATP > ADP
      (adenosine 5'-diphosphate) > AMP (adenosine 5'-monophosphate) > adenosine
      indicates that P2 purinoceptors mediate this depolarization. The P2Y agonist 2
      methylthio-ATP mimicked the ATP-induced depolarization, whereas the P2Y
      antagonist PPADS (pyridoxal-phosphate-6-azophenyl-2', 4'-disulphonic acid)
      reduced it. P2X agonists were without effect. Because the P1 antagonist 8-SPT (8
      (p-sulphophenyl)-theophylline) also depressed ATP-induced depolarizations and
      some ATP-insensitive glial cells responded to adenosine, we suggest coexpression
      of metabotropic P2Y and P1 purinoceptors. The ATP-induced depolarization requires
      activation of Na(+) channels or nonselective cation channels, whereas the ATP
      induced hyperpolarization indicates activation of K(+) channels. ATP also
      increased the intracellular Ca(2+) concentration ([Ca(2+)](i)), that is
      independent of Ca(2+) influx but reflects intracellular Ca(2+) release possibly
      triggered by IP(3) formation. ADP and AMP also increased [Ca(2+)](i), but were
      less efficient than ATP; adenosine and 2-methylthio-ATP did not affect
      [Ca(2+)](i). In view of the mobilization of intracellular Ca(2+), ATP is clearly
      different from other leech neurotransmitters, because it enables intracellular
      Ca(2+) signaling without causing prominent changes in glial membrane potential.
      Thus disturbance of the extracellular microenvironment and the demand for
      metabolic energy are minimized.

PMID- 10642748
TI  - Glucocorticoids up-regulate the expression of glial fibrillary acidic protein in
      the rat suprachiasmatic nucleus.
AB  - Immunoreactivity against glial fibrillary acidic protein (GFAP) was used as a
      dynamic index in adrenalectomized rats subjected or not to corticosterone
      replacement to investigate whether glucocorticoids may interact with astrocytes
      in the suprachiasmatic nucleus (SCN), the master component of the central
      circadian clock. GFAP staining in the SCN was significantly higher in rats having
      received implants that restored physiological plasma levels of corticosterone
      within diurnal or nocturnal limits than in non-normalized rats. The effects of
      corticosterone were similar in the parvocellular portion of the paraventricular
      nucleus but were opposite in the hippocampus, another major site of negative feed
      back regulation of the hypothalamic-pituitary-adrenal axis, where a decreased
      GFAP staining was observed in discrete regions of the dentate gyrus. This
      indicates that glucocorticoids may positively or negatively regulate GFAP,
      depending on the target brain structure. In the SCN, that contains only few if
      any glucocorticoid receptors, indirect mechanisms that may involve serotoninergic
      neurons are probably responsible for the effects of corticosterone level. It is
      proposed that the corticosterone-induced increase in GFAP staining in that
      nucleus accounts for dynamic changes in neurone-astrocyte interactions that might
      occur in relation with natural fluctuations of glucocorticoids over the 24 h
      period.

PMID- 10642749
TI  - Characterization of striatal lesions produced by glutamate uptake alteration:
      cell death, reactive gliosis, and changes in GLT1 and GADD45 mRNA expression.
AB  - This study investigated the time course of the striatal lesions produced by
      continuous local injection of the glutamate uptake inhibitor, L-trans-pyrrolidine
      2,4-dicarboxylate (PDC) at the rate of 25 nmol/h in rats. The extent of the
      neurodegeneration area (defined as the lesion area) did not significantly vary
      with the duration of the PDC treatment between 3 and 14 days, but was markedly
      reduced 3 months after cessation of the 14-day treatment, probably reflecting
      striatal atrophy. After the 3-day treatment, the lesion zone showed calcium
      precipitates and marked microglial reaction contrasting with the reduction of
      astroglial labeling and loss of the glutamate transporter GLT1 mRNA expression;
      however reactive astrocytes were observed around the lesion. After the 14-day
      treatment, the lesion zone presented reactive astrocytes and microglia without
      calcification, and a partial recovery of GLT1 mRNA expression. Interestingly, the
      growth arrest DNA damage-inducible GADD45 mRNA expression was induced around the
      lesion after 3 days but inside the lesion after 14 days of treatment. Three
      months after the 14-day treatment, the astroglial reactivity persisted within the
      lesion whereas most of the other markers examined tended to normalize. These data
      suggest that defective glutamate transport induces primary death of neurons and
      dysfunction of astrocytes. They strongly implicate reactive astrocytes with GLT1
      and GADD45 transcripts in preventing secondary neuronal death.

PMID- 10642750
TI  - Novel microtubule-associated protein-2 isoform is expressed early in human
      oligodendrocyte maturation.
AB  - We have identified a developmentally regulated, oligodendrocyte-specific protein,
      designated microtubule-associated protein-2 expressing exon 13 (MAP-2+13), in the
      human central nervous system (CNS). Monoclonal antibodies directed against MAP
      2+13 labeled oligodendrocytes in the white matter of human fetal spinal cord.
      Double-label immunofluorescence and confocal microscopy, and immunoelectron
      microscopy localized MAP-2+13 to the soma and extending processes of fetal
      oligodendrocytes, but not to the myelin sheath. The immunoreactivity was
      throughout the perikarya. Ultrastructural examination of the fetal myelin sheaths
      showed them to be thin and not fully compacted, indicating that myelination was
      in progress. There was no overlap in staining of GFAP+ astrocytes and MAP-2+13+
      oligodendrocytes. MAP-2+13 was also expressed in intermediate filament-negative
      "radial glia" extending from the central canal to the subpial surface. In the
      mature CNS, MAP-2+13 also marked cells of oligodendroglial morphology, but these
      cells were rare. These finding demonstrate that in the human CNS, MAP-2+13 is a
      novel protein transiently expressed in cells of oligodendroglial lineage.

PMID- 10642751
TI  - Formation of intranuclear crystalloids and proliferation of the smooth
      endoplasmic reticulum in schwann cells induced by tellurium treatment:
      association with overexpression of HMG CoA reductase and HMG CoA synthase mRNA.
AB  - Administration of tellurium (Te) in weaning rats causes a well-established
      demyelinating neuropathy induced by the inhibition in myelinating Schwann cells
      (SC) of the synthesis of cholesterol, a major component of the myelin sheath, at
      the level of squalene epoxidase. We have used this experimental model of Te
      neuropathy to study the biogenesis and reorganization of the endomembranes of the
      nuclear envelope and endoplasmic reticulum (ER) in response to Te treatment by
      ultrastructural analysis and in situ hybridization for the detection of HMG CoA
      reductase and synthase mRNA, which encode key enzymes in cholesterol synthesis.
      The adaptive response of myelinating SC to cholesterol depletion includes cell
      hypertrophy, the formation of tubular invaginations of proliferating nuclear
      membranes giving rise to peculiar nuclear inclusions termed crystalloids, and, at
      the cytoplasmic level, the formation of lamellar bodies of rough ER,
      proliferation of the smooth ER, and overexpression of HMG CoA reductase and
      synthase mRNAs. The changes revert after withdrawal of Te treatment. Our results
      show that the biogenesis and structural organization of both endomembrane systems
      change dynamically upon Te-induced cholesterol depletion, indicating that this
      constituent plays a critical role in the organization of nuclear envelope and ER
      compartments in SC. The results also suggest that the HMG CoA reductase, an
      integral membrane protein of ER, provides the signal for the extensive membrane
      assembly. While the physiological meaning of crystalloid remains to be clarified,
      the hypertrophy of the smooth ER may represent a cytoprotective mechanism
      involved in detoxification of the neurotoxic agent or its metabolic derivates.

PMID- 10642752
TI  - Contribution of heparan sulfate to the non-permissive role of the midline glia to
      the growth of midbrain neurites.
AB  - Radial glial cells and astrocytes are heterogeneous with respect to morphology,
      cytoskeletal- and membrane-associated molecules and intercellular interactions.
      Astrocytes derived from lateral (L) and medial (M) midbrain sectors differ in
      their abilities to support neuritic growth of midbrain neurons in coculture
      (Garcia-Abreu et al. J Neurosci Res 40:471, 1995). There is a correlation between
      these abilities and the differential patterns of laminin (LN) organization that
      is fibrillar in growth-permissive L astrocytes and punctate in the non-permissive
      M astroglia (Garcia-Abreu et al. NeuroReport 6:761, 1995). There are also
      differences in the production of glycosaminoglycans (GAGs) by L and M midbrain
      astrocytes (Garcia-Abreu et al. Glia 17:339, 1996). We show that the relative
      amounts of the glycoproteins laminin LN, fibronectin (FN) and tenascin (TN) are
      virtually identical in L and M glia, thus, confirming that an abundant content of
      LN is not sufficient to promote neurite growth. To further analyze the role of
      GAGs in the properties of M and L glia, we employed enzymatic degradation of the
      GAGs chondroitin sulfate (CS) and heparan sulfate (HS). Treatment with
      chondroitinase has little effect on the non-permissive properties of M glia but
      reduces the growth-supporting ability of L glia. By contrast, heparitinase I
      produces no significant changes on L glia but leads to neurite growth promotion
      by M glia. Taken together, these results suggest that glial CS helps to promote
      neurite growth and, more importantly, they indicate that a HS proteoglycan is, at
      least, partially responsible for the non-permissive role of the midline glia to
      the growth of midbrain neurites.

PMID- 10642754
TI  - Spontaneous neuronal activity in organotypic cultures of mouse dorsal root
      ganglion leads to upregulation of calcium channel expression on remote Schwann
      cells.
AB  - It is well established that neurons regulate the properties of both central and
      peripheral glial cells. Some of these neuro-glial interactions are modulated by
      the pattern of neuronal electrical activity. In the present work, we asked
      whether blocking the electrical activity of dorsal root ganglion (DRG) neurons in
      vitro by a chronic treatment with tetrodotoxin (TTX) would modulate the
      expression of the T-type Ca(2+) channel by mouse Schwann cells. When recorded in
      their culture medium, about one-half of the DRG neurons spontaneously fired
      action potentials (APs). Treatment for 4 days with 1 microM TTX abolished both
      spontaneous and evoked APs in DRG neurons and in parallel significantly reduced
      the percentage of Schwann cells expressing Ca(2+) channel currents. On the
      fraction of Schwann cells still expressing Ca(2+) channel currents, these
      currents had electrophysiological parameters (mean amplitude, mean inactivation
      time constant, steady-state inactivation curve) similar to those of control
      cultures. Co-treatment for 4 days with 1 microM TTX and 2 mM CPT-cAMP, a cAMP
      analogue that induces the expression de novo of Ca(2+) channel currents in
      Schwann cells deprived of neurons, maintained the percentage of Schwann cells
      expressing Ca(2+) channel currents, showing that TTX does not directly affect the
      expression of Ca(2+) channel currents by Schwann cell. We conclude that blocking
      spontaneous activity of DRG neurons in vitro downregulates Ca(2+) channel
      expression by Schwann cells. These results strongly suggest that DRG neurons
      upregulate Ca(2+) channel expression by Schwann cells via the release of a
      diffusible factor whose secretion is dependent on electrical activity.

PMID- 10642753
TI  - Differential induction of chemokines in human microglia by type I and II
      interferons.
AB  - Chemokines are secreted proteins that function as chemoattractants, mediating the
      recruitment of specific subsets of leukocytes to sites of tissue damage and
      immunological reactions. Chemokines may also function as antiviral agents, since
      viruses such as human immunodeficiency virus type 1 (HIV-1) use chemokine
      receptors as co-receptors for viral entry. This study examines whether virus
      induced interferon, IFNbeta, or immune-related interferon, IFNgamma, affects the
      production of beta-chemokines by CNS microglia and peripheral monocytes. When
      IFNbeta was used as the stimulus, induction of MIP-1alpha, MIP-1beta, MCP-1, and
      RANTES mRNA and protein was observed within 12 h of stimulation in microglia. By
      contrast, when IFNgamma was used as the stimulus, only MCP-1 was induced. IFNbeta
      stimulation of blood monocytes resulted in upregulation of MIP-1alpha, MIP-1beta,
      and MCP-1. Thus, type I and II interferons differentially regulate beta
      chemokines in human fetal microglia and peripheral blood monocytes. These
      observations may have relevance for the therapeutic activity of IFNbeta in
      multiple sclerosis and for the antiviral effects of IFNbeta for HIV-1 infection
      of monocytes and microglia.

PMID- 10642755
TI  - Directed spatial potassium redistribution in rat neocortex.
AB  - The functional role of the glial network as a draining system for extracellular
      potassium (spatial buffer) was investigated in rat neocortical brain slices.
      After electrical stimulation, extracellular space volume decreased in the middle
      cortical layers and increased in the upper cortical layers, confirming
      predictions for a spatial buffer. The widening of extracellular space was
      associated with an increase in extracellular potassium. The data suggested a
      delayed redistribution of potassium from middle to superficial cortical layers.
      Interruption of gap junctions abolished the widening of extracellular space. The
      data show that a multicellular directed network connected by gap junctions
      participates in maintaining potassium homeostasis in brain.

PMID- 10642756
TI  - Acute and late outcome after use of 2.5-mm intracoronary stents in small (< 2.5
      mm) coronary arteries.
AB  - We describe the high-pressure deployment of 2.5-mm stents in small (< 2.5 mm)
      coronary vessels. Forty-three lesions in 40 patients were treated. The mean
      reference vessel diameter was 2.3 +/- 0.2 mm. The mean % luminal stenosis was 90
      +/- 9. The mean lesion length was 11. 7 +/- 9.1 mm. Sixteen lesions were
      pretreated with rotational atherectomy, and the remainder with PTCA. The rate of
      successful stent deployment was 41/43 (95%). The mean postintervention % stenosis
      was -1 +/- 10. There were no in-hospital deaths or procedure-related Q-wave MI.
      The patients were followed for a mean of 18 months. Eight patients (or 21%)
      developed recurrent chest pain and/or angiographically proven restenosis. One
      patient (3%) developed intermediate restenosis. Twenty-nine patients (or 76%)
      either remain symptom-free or have patent target sites on repeat angiography. It
      appears that reasonable acute and long-term results can be achieved with 2.5-mm
      stents in small coronary arteries using high-pressure deployment techniques.
      Cathet. Cardiovasc. Intervent. 49:121-126, 2000.

PMID- 10642757
TI  - Resurrection or benevolent epitaph?

PMID- 10642758
TI  - Ad hoc coronary intervention.
AB  - Ad hoc coronary intervention is a percutaneous revascularization procedure
      performed at the same sitting as diagnostic cardiac catheterization. While this
      appears to be an efficient strategy, the safety and cost of ad hoc coronary
      intervention compared with delayed coronary intervention have not been clearly
      documented. Special preparation and precautions are necessary for patients in
      whom ad hoc coronary intervention is anticipated. Ad hoc coronary intervention is
      not appropriate if informed consent has not been previously obtained or if it
      would pose greater risks than delayed intervention. While ad hoc coronary
      intervention is often efficient and effective, its use should be individualized.
      Cathet. Cardiovasc. Intervent. 49:130-134, 2000.

PMID- 10642759
TI  - One-year clinical outcomes and relative costs of primary infarct artery stenting
      versus angioplasty following systemic thrombolysis for acute myocardial
      infarction.
AB  - We investigated the clinical effectiveness and relative cost of two different
      infarct artery revascularization strategies in patients following systemic
      thrombolysis for acute myocardial infarction. The clinical efficacy and relative
      cost of stenting and angioplasty have not been investigated in patients requiring
      infarct artery revascularization after systemic thrombolysis for myocardial
      infarction. We prospectively enrolled 220 consecutive patients who received
      thrombolytic therapy for acute myocardial infarction and were subsequently
      treated with either angioplasty or primary stenting of the infarct artery. In
      hospital and 1-year clinical outcomes, including death, myocardial infarction,
      and repeat revascularization, and total hospital costs over the 1-year study
      period were assessed. Compared to angioplasty, primary stenting resulted in lower
      in-hospital mortality (4% vs. 0%; P = 0.01) and reduced rates of repeat
      percutaneous or surgical revascularization (7% vs. 0%; P = 0.0009). At 1-year
      follow-up, stenting was associated with a lower death rate (6.25% vs. 0%; P =
      0.002) and reduced repeat infarct artery revascularization (11% vs. 27%; P = 0.
      001). Initial hospitalization costs were higher in the stent group ($11,818 +/-
      $3,377 vs. $9,723 +/- $8,661; P = 0.014) due primarily to catheterization
      laboratory-related expenditures ($7,346 +/- $2, 395 vs. $3,567 +/- $1,212; P =
      0.0001). However, the cumulative 1-year medical cost difference between the two
      groups was not significant ($13,938 +/- $5,939 vs. $12,914 +/- $9,308; P = 0.33).
      Following thrombolytic therapy, primary infarct artery stenting reduced in
      hospital and 1-year mortality and revascularization rates compared to
      angioplasty. Stenting was associated with higher initial hospital costs, which
      were off-set by lower revascularization rates, resulting in comparable total
      hospitalization costs after 1 year. These findings have important clinical and
      economic implications in an increasingly cost-conscious health care environment.
      Cathet. Cardiovasc. Intervent. 49:135-141, 2000.

PMID- 10642760
TI  - Interventional therapy of vascular complications caused by the hemostatic
      puncture closure device angio-seal.
AB  - The hemostatic puncture closure device Angio-Seal is a quick, safe, and easy-to
      use system, allowing rapid sealing of the vascular access site following coronary
      angiography and interventional procedures. It is advantageous for patients in
      whom early mobilization is desired and may therefore decrease hospital costs.
      Despite the documented low complication rate, there are some specific problems.
      Reporting on five cases, we describe problems in diagnosis and possible
      interventional therapy of Angio-Seal-associated complications such as stenosis,
      occlusion, or peripheral embolism. Our experience led to the concept of precise
      diagnosis in any patient with leg symptoms and early interventional treatment
      with the aim of complete removal of the intra-arterial parts of the Angio-Seal
      device. Any delay in diagnosis and treatment increases the risk of additional
      thrombotic occlusion. Spontaneous dissolution of the Angio-Seal sponge limits
      interventional possibilities of complete removal. Cathet. Cardiovasc. Intervent.
      49:142-147, 2000.

PMID- 10642761
TI  - Percutaneous arterial access closure: now do we have the be all and end all? not
      yet!

PMID- 10642762
TI  - Transradial coronary stenting: comparison with femoral access closed with an
      arterial suture device.
AB  - The purpose of this study was to determine if closure of the femoral artery
      access site using a percutaneous arterial suture device (Perclose, Menlo Park,
      CA) in patients undergoing coronary stenting can result in the same benefits as
      seen with radial artery access. A total of 218 consecutive patients underwent
      coronary stenting (109 femoral, 109 radial) by investigators experienced with
      each technique. The two groups were matched in terms of sex, age, clinical
      presentation (50% acute), number of vessels and lesions stented, and lesion
      morphology. The relative costs of the femoral and radial procedures were examined
      using a decision analytic model and sensitivity analysis. The suture device was
      not used in 20/109 patients (18%) for anatomic reasons and failed to obtain
      hemostasis in 9/89 patients (10%). One radial patient had an occluded radial
      artery postprocedure, but this was recanalized at follow-up a month later.
      Primary success, procedural complications, postprocedure length of stay, and the
      percentage of patients discharged the same day were the same in both groups.
      Because of the added time to deploy Perclose, total procedure time was
      significantly longer in the femoral group (57 +/- 22 min femoral vs. 44 +/- 22
      min radial, P < 0.01). Access site complications occurred only in the femoral
      group. More patients were ambulatory the same day of the procedure in the radial
      group (95% radial vs. 56% femoral, P < 0.01). The cost of the radial approach was
      substantially less than the femoral approach because of lower supply costs and
      fewer access complications. The transradial approach is a dominant strategy for
      coronary stenting, offering better outcomes at lower cost. Cathet. Cardiovasc.
      Intervent. 49:150-156, 2000.

PMID- 10642763
TI  - Transradial coronary stenting: ready for prime time?

PMID- 10642764
TI  - Aortic laceration secondary to palmaz stent placement for treatment of superior
      vena cava syndrome.
AB  - Aortic laceration secondary to Palmaz Stent placement for treatment of superior
      vena cava syndrome is reported. This potentially life-threatening complication
      should be considered when rigid balloon expandable stents are used to treat
      superior vena cava syndrome of benign origin. Cathet. Cardiovasc. Intervent.
      49:160-162, 2000.

PMID- 10642765
TI  - A tragedy during palmaz stent implant for SVC syndrome: was it the stent or was
      it the balloon delivery system?

PMID- 10642766
TI  - Transcatheter closure of single muscular ventricular septal defects using the
      amplatzer muscular VSD occluder: initial results and technical considerations.
AB  - Surgical closure of multiple muscular ventricular septal defects (MVSDs) is
      associated with mortality and morbidity; therefore, both surgeons and
      cardiologists welcome a nonsurgical safe approach. We report our initial results
      of catheter closure of MVSD using the new Amplatzer muscular VSD occluder
      delivered via the venous or arterial routes. Eight patients with MVSD underwent
      closure of their VSDs using the Amplatzer VSD occluder under general endotracheal
      anesthesia. The mean +/- SD of age was 5.4 +/- 3.1 years (2-10 years) and mean
      weight was 18.4 +/- 6.5 kg (11.5-29 kg). All patients had left ventricular volume
      overload with mean Qp/Qs ratio of 1.7 +/- 0.6 (1.4-3). The location of the VSD
      was mid muscular in four, anterior in two, apical in one, and posterior in one.
      The systolic pulmonary artery pressure ranged from 25 to 85 mm Hg (mean, 39.9 +/-
      18.8 mm Hg). The device was implanted successfully in all eight patients. In five
      patients (four mid muscular and one apical), the deployment of the device was
      anterograde from the right internal jugular vein and in three patients (two
      anterior and one posterior VSD), the initial attempt at anterograde deployment
      was unsuccessful due to kinking in the delivery sheath; therefore, retrograde
      deployment was attempted successfully. The size of the device used ranged from 6
      to 14 mm (the size of the connecting waist). In patients with elevated pulmonary
      artery pressure, repeat measurements immediately after closure revealed
      normalization in all. There was immediate complete closure of the defect in two
      patients and six patients had trivial residual shunt (foaming through the
      device), which disappeared completely within 24 hr in five and at 6-month follow
      up in the sixth patient. The mean fluoroscopy time was 37.1 +/- 13 min (11.7-55
      min). Complications encountered included transient junctional rhythm in one
      patient. No blood transfusion was required. On follow-up evaluation, there has
      been no episode of endocarditis, thromboembolism, hemolysis, or wire disruption.
      we conclude that the Amplatzer MVSD occluder is a safe and effective device for
      closure of MVSDs up to 12 mm in diameter. Further clinical trials with this
      device are underway. Cathet. Cardiovasc. Intervent. 49:167-172, 2000.

PMID- 10642767
TI  - Transcatheter closure of apical ventricular muscular septal defect combined with
      arterial switch operation in a newborn infant.
AB  - This report describes a case of transposition of the great arteries and apical
      muscular ventricular septal defect in a newborn infant successfully treated by
      transcatheter closure of the septal defect with the Amplatzer duct occluder
      device followed by an arterial-switch operation within the first 2 weeks of life.
      Cathet. Cardiovasc. Intervent. 49:173-176, 2000.

PMID- 10642768
TI  - Fatal cerebral hemorrhage and severe thrombocytopenia during abciximab treatment.
AB  - We describe the case of a fatal cerebral hemorrhage associated with a severe
      thrombocytopenia (4.0 x 10(9)/l), occurring only 90 min after starting treatment
      with abciximab, in a patient undergoing primary percutaneous transluminal
      coronary angioplasty (PTCA) for an acute myocardial infarction. Cathet.
      Cardiovasc. Intervent. 49:177-180, 2000.

PMID- 10642769
TI  - Diffuse alveolar hemorrhage following administration of tirofiban or abciximab: a
      nemesis of platelet glycoprotein IIb/IIIa inhibitors.
AB  - We describe three patients who developed severe pulmonary hemorrhage following
      administration of tirofiban (one patient) and abciximab (two patients). Pulmonary
      hemorrhage associated with abciximab use has been described, but to the best of
      our knowledge there has been no previous reports of this complication with
      tirofiban. Cathet. Cardiovasc. Intervent. 49:181-184, 2000.

PMID- 10642770
TI  - Cerebral arterial air embolism treated by a vertical head-down maneuver.
AB  - A case of cerebral arterial air embolism (CAAE) occurring from inadvertent
      injection of air during aortic root angiography is presented. Prompt treatment by
      suspending the patient briefly in a vertical head-down position beside the
      catheterization table appeared to be life-saving and resulted in complete
      neurological recovery. This approach may offer the first immediate therapy for
      CAAE. Cathet. Cardiovasc. Intervent. 49:185-187, 2000.

PMID- 10642771
TI  - Spontaneous and diffuse coronary artery spasm unresponsive to conventional
      intracoronary pharmacological therapy: a case report.

PMID- 10642772
TI  - Guiding catheter thrombectomy during percutaneous coronary interventions for
      acute coronary syndromes.
AB  - Despite the advancements in the pharmacological and mechanical treatment of acute
      coronary syndromes, intracoronary thrombus and distal embolization remain among
      the major limitations of percutaneous transluminal coronary interventions. We
      describe three cases in which intragraft or intracoronary thrombus was completely
      aspirated during PTCI using the guiding catheter. In the first case, a 4-cm-long
      unfragmented embolized thrombus was effectively and completely aspirated from a
      saphenous vein graft, with immediate restoration of normal flow. In the second
      case, multiple fragments of embolized thrombus were aspirated from a large right
      coronary artery, while in the third case, intragraft thrombus was electively
      aspirated. In each case, the index lesions were then successfully stented without
      complications. Cathet. Cardiovasc. Intervent. 49:192-196, 2000.

PMID- 10642774
TI  - Successful inoue balloon mitral commissurotomy in double-orifice mitral stenosis.
AB  - We report a rare case of stenotic double-orifice mitral valve of incomplete
      bridge type in a 40-year-old male. The fibrous bridge tissue between the leaflets
      was successfully split with a 24-mm Inoue balloon catheter using the stepwise
      dilation technique. Cathet. Cardiovasc. Intervent. 49:200-203, 2000.

PMID- 10642773
TI  - Successful percutaneous stenting of a right gastroepiploic coronary bypass graft
      using monorail delivery system: a case report.
AB  - The right gastroepiploic artery (RGEA) is being successfully used as an arterial
      conduit in a selected group of patients undergoing coronary artery bypass graft
      surgery. However, myocardial ischemia may result due to spasm, occlusion, and
      stenosis of this graft. The anastamosis site at distal right coronary artery
      (RCA) or posterior descending artery (PDA) is the most common location for
      stenosis of an in situ gastroepiploic coronary bypass graft. Balloon angioplasty
      of such stenoses has been reported with optimal short-term results. Stent
      deployment would decrease the restenosis rate, so that repeat procedures could be
      minimized for these technically challenging lesions. We describe a case of
      successful deployment of a stent with monorail delivery system at the anastamotic
      site stenosis of an in situ gastroepiploic right coronary artery bypass graft.
      This percutaneous coronary intervention could prevent redo coronary artery bypass
      graft surgery. Cathet. Cardiovasc. Intervent. 49:197-199, 2000.

PMID- 10642775
TI  - Mobile right atrial hydatid cyst with multiorgan involvement.
AB  - A 25-year-old woman who had hydatid cysts in her lung was referred to our clinic
      for the hydatid cyst in her cardiac localization. Multiple hydatid cysts of
      different cardiac localizations were diagnosed by two-dimensional
      echocardiography, confirmed by computed tomography and magnetic resonance
      imaging, supported by enzyme-linked immunosorbent assay (ELISA) for
      echinococcosis. Surgical resection was performed for the right atrial cyst and
      pathology confirmed the diagnosis. Oral albendazole treatment was given
      postoperatively. Cathet. Cardiovasc. Intervent. 49:204-207, 2000.

PMID- 10642776
TI  - Cardiac Kaposi's sarcoma following heart transplantation.
AB  - Kaposi's sarcoma (KS) is a tumor seen with increased frequency in organ
      transplant recipients. We present a case of disseminated KS in a heart transplant
      recipient of Mediterranean origin in whom myocardial involvement was suspected on
      the basis of coronary angiographic and magnetic resonance imaging (MRI) findings.
      KS in the transplant population and cardiac KS are reviewed. Cathet. Cardiovasc.
      Intervent. 49:208-212, 2000.

PMID- 10642777
TI  - Myocardial waffling: a sign of previous infarction.

PMID- 10642778
TI  - Gelfoam embolization of a distal coronary artery guidewire perforation.
AB  - A guidewire-induced distal coronary artery perforation presenting with cardiac
      tamponade was occluded by distal Gelfoam embolization via an infusion catheter.
      This extends the treatment options for this rare complication of coronary
      interventional procedures. Cathet. Cardiovasc. Intervent. 49:214-217, 2000.

PMID- 10642779
TI  - New long-tip guiding catheters designed for right transradial coronary
      intervention.
AB  - New long-tip catheters, one for the left and the other for the right coronary
      artery, were designed specifically for right transradial intervention. We
      utilized the overbending principle to achieve more precise control of the
      catheters. We also analyzed principal factors involved to determine guiding
      catheter support considering the anatomy of the innominate artery, ascending
      aorta, left and right coronary arteries. Catheter shapes were designed to exploit
      favorable factors to compensate for mechanically disadvantageous anatomy. The
      catheter for the left coronary artery has an initial loop to make use of the
      angle between the innominate artery and the ascending aorta to introduce the
      catheter to the correct position to provide strong backup support. The catheter
      for the right coronary artery has a unique three-dimensional curve that provides
      sufficient backup support and compensates for the angles between the innominate
      artery and the proximal portion of right coronary artery to achieve coaxial
      engagement. The distal portions of these catheters include long tips aiming to
      minimize the loss of transmitted force. The performance of these catheters was
      studied in 143 patients with 161 lesions. Successful engagement was achieved in
      138 patients with 156 lesions (97%) and coronary intervention was successful in
      136 patients with 154 lesions (99%). No major complications or coronary artery
      dissection occurred due to use of these catheters. This study showed the present
      long-tip catheters to be safe and highly effective for right transradial coronary
      intervention. Cathet. Cardiovasc. Intervent. 49:218-224, 2000.

PMID- 10642781
TI  - Acute occlusion of the left main coronary artery following intracoronary
      ultrasound examination.

PMID- 10642780
TI  - Acute animal studies of the STARFlex system: a new self-centering cardioSEAL
      septal occluder.
AB  - The STARFlex system is a modified CardioSEAL device with a flexible self
      centering mechanism comprised of nitinol springs strung between opposing arms, a
      connecting ball (sleeve joint that allows the device to pivot prerelease), and a
      front-loading delivery system. It was designed to allow a smaller device/defect
      sizing ratio and delivery profile, provide centering capability, and improve
      closure rates. To test this system, 13 devices (23, 28, and 33 mm) were deployed
      in six sheep within created atrial septal defects (12- to 22-mm diameter; n =
      10), in the left atrium (n = 2), and in inferior vena cava (n = 1). All
      implantations in atrial septal defects were successful, with device/defect ratio
      ranging from 1.3 to 1.9 (median, 1.3), with no residual leak by angiography or
      echocardiography in seven (3/10 had </= small immediate leaks). The STARFlex
      system was effective in closing created atrial septal defects using a 10 Fr
      delivery sheath and low device/defect sizing ratios, comparing favorably with the
      standard CardioSEAL. Cathet. Cardiovasc. Intervent. 49:225-233, 2000.

PMID- 10642782
TI  - Practice guideline for the treatment of patients with eating disorders
      (revision). American Psychiatric Association Work Group on Eating Disorders.

PMID- 10642783
TI  - Regulation of cell-fate determination in Dictyostelium.
AB  - A key step in the development of all multicellular organisms is the
      differentiation of specialized cell types. The eukaryotic microorganism
      Dictyostelium discoideum provides a unique experimental system for studying cell
      type determination and spatial patterning in a developing multicellular organism.
      Unlike metazoans, which become multicellular by undergoing many rounds of cell
      division after fertilization of an egg, the social amoeba Dictyostelium achieves
      multicellularity by the aggregation of approximately 10(5) cells in response to
      nutrient depletion. Following aggregation, cell-type differentiation and
      morphogenesis result in a multicellular organism with only a few cell types that
      exhibit a defined patterning along the anterior-posterior axis of the organism.
      Analysis of the mechanisms that control these processes is facilitated by the
      relative simplicity of Dictyostelium development and the availability of
      molecular, genetic, and cell biological tools. Interestingly, analysis has shown
      that many molecules that play integral roles in the development of higher
      eukaryotes, such as PKA, STATs, and GSK-3, are also essential for cell-type
      differentiation and patterning in Dictyostelium. The role of these and other
      signaling pathways in the induction, maintenance, and patterning of cell types
      during Dictyostelium development is discussed.

PMID- 10642784
TI  - DNA-binding specificity and embryological function of Xom (Xvent-2).
AB  - Xom (also known as Xvent-2) is a homeobox-containing gene expressed throughout
      the early gastrula of the Xenopus embryo with the exception of the organizer.
      Activation of Xom is an immediate-early response to BMP signaling, and
      overexpression of Xom, like overexpression of BMP family members, causes
      ventralization of the embryo. In this paper we first show that Xom is a
      transcriptional repressor and we then define its preferred DNA-binding site.
      Overexpression of wild-type Xom and a dominant-negative form suggests that Xom
      functions by repressing transcription of goosecoid, and analysis of the goosecoid
      promoter reveals a site which is required for Xom-mediated repression of
      goosecoid promoter reporter constructs. Together, these results suggest that Xom
      causes down-regulation of goosecoid in a direct fashion and that this accounts,
      at least in part, for the ability of Xom to cause ventralization of the Xenopus
      embryo.

PMID- 10642785
TI  - A three-dimensional model of the mouse at embryonic day 9.
AB  - This paper describes a digital, three-dimensional model of the mouse embryo at
      E9. The model was made by reconstruction from images of serial histological
      sections digitally warped to remove distortions and has a resolution of
      approximately 9 microns. The model can be digitally resectioned in any plane to
      provide images which resemble conventional histological sections. The main
      tissues have been identified and delineated by digital painting so that the
      anatomical components can be visualized and manipulated in 3-D surface- and
      volume-rendered views. This provides a three-dimensional definition of anatomy
      that will provide a useful tool for interpreting and understanding spatial data
      in mouse embryos. The anatomy of the model is discussed where it provides
      landmarks for interpretation and navigation or where it is unexpected in light of
      existing descriptions of the E9 mouse embryo. The complete anatomy is not
      presented in this paper but will be available on CD-ROM. A detailed description
      of the technical aspects of the construction of the model is included in an
      appendix. The model is the first of a series that will form the basis for an
      atlas/database of mouse development. This reconstruction and its associated
      anatomy are available in a variety of data formats with some supporting software
      from http:@genex.hgu.mrc.ac.uk/.

PMID- 10642786
TI  - Control of muscle cell-type specification in the zebrafish embryo by Hedgehog
      signalling.
AB  - The specification of different muscle cell types in the zebrafish embryo requires
      signals that emanate from the axial mesoderm. In previous studies we and others
      have shown that overexpression of different members of the Hedgehog protein
      family can induce the differentiation of two types of slow-twitch muscles, the
      superficially located slow-twitch fibres and the medially located muscle pioneer
      cells. Here we have investigated the requirement for Hedgehog signalling in the
      specification of these distinct muscle cell types in two ways: first, by
      characterising the effects on target gene expression and muscle cell
      differentiation of the u-type mutants, members of a phenotypic group previously
      implicated in Hedgehog signalling, and second, by analysing the effects of
      overexpression of the Patched1 protein, a negative regulator of Hedgehog
      signalling. Our results support the idea that most u-type genes are required for
      Hedgehog signalling and indicate that while such signalling is essential for slow
      myocyte differentiation, the loss of activity of one signal, Sonic hedgehog, can
      be partially compensated for by other Hedgehog family proteins.

PMID- 10642787
TI  - Activation of Stat3 by cytokine receptor gp130 ventralizes Xenopus embryos
      independent of BMP-4.
AB  - Stat3 is one of the main signaling components of cytokine receptors, including
      gp130. Here we show that activation of cytokine receptor gp130 resulted in a
      dramatic ventralization of Xenopus embryos and that the ventralization correlated
      well with Stat3 activation potential of the receptor. This finding led to
      identification of Xenopus Stat3 (Xstat3), which showed a 95% homology to its
      murine and human counterparts, at the amino acid level, and was expressed from
      the one-cell stage throughout development. The mechanism of gp130/XStat3-mediated
      ventralization proved to be independent of BMP-4. gp130/Xstat3 stimulation
      inhibited Smad2-induced ectopic axis formation in embryos and Smad2-dependent
      luciferase activity. A dominant-negative Stat3, in contrast, dorsalized Xenopus
      embryos, resulting in ectopic axis formation. We propose that Stat3-mediated
      signaling has the capacity to modify dorsoventral patterning in the early
      development of Xenopus.

PMID- 10642788
TI  - Expression of the cytoplasmic domain of E-cadherin induces precocious mammary
      epithelial alveolar formation and affects cell polarity and cell-matrix
      integrity.
AB  - Cadherins are cell adhesion molecules involved in cell-cell adhesion, signalling,
      and cellular proliferation and differentiation. E-cadherin is required for the
      formation of epithelium in vivo. We investigated the contribution of the
      cytoplasmic domain of E-cadherin to adhesion, signalling, and differentiation
      during murine mammary gland development, by in vivo expression of a gene encoding
      a truncated form of E-cadherin lacking the extracellular domain. The expression
      of this gene in mammary epithelial cells during pregnancy induced precocious
      lobular epithelial morphogenesis associated with morphological differentiation
      and the early synthesis of various molecules (advanced milk fat globule
      appearance and milk protein production). After delivery, when a fully
      differentiated and secretory epithelium is required for lactation, the
      cytoplasmic domain of E-cadherin had a dominant-negative effect on cell-cell
      adhesion and affected the structure and function of the epithelium. This also led
      to the partial loss of epithelial polarisation and changes in the basement
      membrane, both important in malignancy. Thus, the cytoplasmic domain of E
      cadherin induces epithelial morphogenesis, but also alters the cohesiveness of
      the fully differentiated epithelium.

PMID- 10642789
TI  - Plasticity of axial identity among somites: cranial somites can generate
      vertebrae without expressing Hox genes appropriate to the trunk.
AB  - Classic studies have shown that the presomitic mesoderm is already committed to a
      specific morphological fate, for example, the ability to generate a rib. Hox gene
      expression in the paraxial mesoderm has also been shown to be fixed early and not
      susceptible to modulation by an ectopic environment. This is in contrast to the
      plasticity of Hox expression in neuroectodermal derivatives. We reexamine here
      the potential of somites for morphological plasticity by transplanting the
      cranial (occipital) somites 1-4, that normally produce small contributions to the
      skull, to the trunk of avian embryos. Surprisingly, the transposed cranial
      somites are able to form reasonably normal vertebral anlage. In addition, the
      cranial somitic mesoderm produces intervertebral disks, structures not normally
      found in the skull. These somites are however unable to generate some elements of
      the vertebrae, such as the costal process. In contrast to the morphogenetic
      plasticity of the occipital somites, their characteristic inability to support
      survival of dorsal root ganglia was not significantly modified by posterior
      transplantation. Dorsal root ganglia initially developed and then degenerated
      with the same morphological stages as normally observed. In striking contrast to
      the plasticity of morphology, we found that all four members of the of the fourth
      paralogous group of Hox genes that are expressed endogenously at the level of the
      graft are not upregulated in the caudad-transposed cranial mesoderm. It therefore
      appears that genes other than those of the Hox family normally expressed at this
      axial level control the position-specific morphogenesis of ectopic vertebrae
      formed from cranial somites. In evolutionary terms, the present results imply
      that occipital somites that were incorporated into the "New Head" retain the
      ability to develop according to their original morphogenetic fate, into
      vertebrae.

PMID- 10642790
TI  - Cusp patterning defect in Tabby mouse teeth and its partial rescue by FGF.
AB  - Tabby is a mouse mutant characterized by deficient development of the ectodermal
      organs: teeth, hair, and a subset of glands. Ectodysplasin, the protein encoded
      by the Tabby gene, was recently identified as a novel TNF-like transmembrane
      protein but little is known about its function. We have examined the Tabby tooth
      phenotype in detail by analysis of the adult and embryonic teeth. Tabby first
      molars had an obvious defect in cusp patterning as the number of cusps was
      reduced and the buccal and lingual cusps were joined. The disturbance in
      development was first visible morphologically in the bud stage molar. The primary
      enamel knot in a cap stage Tabby tooth expressed all enamel knot markers analyzed
      but was smaller than wild type and the first pair of developing secondary enamel
      knots was fused. We propose that the Tabby tooth phenotype is due to growth
      retardation during early stages of development which leads to reduced signaling
      from the primary enamel knot, followed by deficient growth of the dental
      epithelium and lack of formation of the last developing secondary enamel knots.
      The ectodysplasin transcripts were expressed in the outer enamel epithelium and
      dental lamina. When cultured in vitro Tabby bud/cap stage molars formed fewer
      cusps than wild-type controls. This phenotype was not rescued by exogenously
      added EGF despite the previously proposed link between Tabby and EGF. Instead FGF
      10 partially restored morphogenesis and stimulated the development of additional
      tooth cusps in cultured Tabby molars.

PMID- 10642791
TI  - Neural induction and patterning in the mouse in the absence of the node and its
      derivatives.
AB  - The signals which induce vertebrate neural tissue and pattern it along the
      anterior-posterior (A-P) axis have been proposed to emanate from Spemann's
      organizer, which in mammals is a structure termed the node. However, mouse
      embryos mutant for HNF3 beta lack a morphological node and node derivatives yet
      undergo neural induction. Gene expression domains occur at their normal A-P axial
      positions along the mutant neural tubes in an apparently normal temporal manner,
      including the most anterior and posterior markers. This neural patterning occurs
      in the absence of expression of known organizer genes, including the neural
      inducers chordin and noggin. Other potential signaling centers in gastrulating
      mutant embryos appear to express their normal constellation of putative secreted
      factors, consistent with the possibility that neural-inducing and -patterning
      signals emanate from elsewhere or at an earlier time. Nevertheless, we find that
      the node and the anterior primitive streak, from which the node derives, are
      direct sources of neural-inducing signals, as judged by expression of the early
      midbrain marker Engrailed, in explant-recombination experiments. Similar
      experiments showed the neural-inducing activity in HNF3 beta mutants to be
      diffusely distributed. Our results indicate that the mammalian organizer is
      capable of neural induction and patterning of the neural plate, but that
      maintenance of an organizer-like signaling center is not necessary for either
      process.

PMID- 10642792
TI  - Ventral cell rearrangements contribute to anterior-posterior axis lengthening
      between neurula and tailbud stages in Xenopus laevis.
AB  - Studies of morphogenesis in early Xenopus embryos have focused primarily on
      gastrulation and neurulation. Immediately following these stages is another
      period of intense morphogenetic activity, the neurula-to-tailbud transition.
      During this period the embryo is transformed from the spherical shape of the
      early stages into the long, thin shape of the tailbud stages. While gastrulation
      and neurulation depend largely on active cell rearrangement and cell shape
      changes in dorsal tissues, we find that the neurula-to-tailbud transition depends
      in part on activities of ventral cells. Ventral explants of neurula lengthen
      autonomously as much as the ventral sides of intact embryos, while dorsal
      explants lengthen less than the dorsal sides of intact embryos. Analyses of cell
      division, cell shapes, and cell rearrangement by transplantation of labeled cells
      and by time lapse recordings in live intact embryos concur that cell
      rearrangements in ventral mesoderm and ectoderm contribute to the autonomous
      anterior-posterior axis lengthening of ventral explants between neurula and
      tailbud stages.

PMID- 10642793
TI  - FGF signaling and the anterior neural induction in Xenopus.
AB  - We previously showed that FGF was capable of inducing Xenopus gastrula ectoderm
      cells in culture to express position-specific neural markers along the
      anteroposterior axis in a dose-dependent manner. However, conflicting results
      have been obtained concerning involvement of FGF signaling in the anterior neural
      induction in vivo using the same dominant-negative construct of Xenopus FGF
      receptor type-1 (delta XFGFR-1 or XFD). We explored this issue by employing a
      similar construct of receptor type-4a (XFGFR-4a) in addition, since expression of
      XFGFR-4a was seen to peak between gastrula and neurula stages, when the neural
      induction and patterning take place, whereas expression of XFGFR-1 had not a
      distinct peak during that period. Further, these two FGFRs are most distantly
      related in amino acid sequence in the Xenopus FGFR family. When we injected mRNA
      of a dominant-negative version of XFGFR-4a (delta XFGFR-4a) into eight animal
      pole blastomeres at 32-cell stage, anterior defects including loss of normal
      structure in telencephalon and eye regions became prominent as examined
      morphologically or by in situ hybridization. Overexpression of delta XFGFR-1
      appeared far less effective than that of delta XFGFR-4a. Requirement of FGF
      signaling in ectoderm for anterior neural development was further confirmed in
      culture: when ectoderm cells that were overexpressing delta XFGFR-4a were
      cocultured with intact organizer cells from either early or late gastrula
      embryos, expression of anterior and posterior neural markers was inhibited,
      respectively. We also showed that autonomous neuralization of the anterior-type
      observed in ectoderm cells that were subjected to prolonged dissociation was
      strongly suppressed by delta XFGFR-4a, but not as much by delta XFGFR-1. It is
      thus indicated that FGF signaling in ectoderm, mainly through XFGFR-4, is
      required for the anterior neural induction by organizer. We may reconcile our
      data to the current "neural default model," which features the central roles of
      BMP4 signaling in ectoderm and BMP4 antagonists from organizer, simply
      postulating that the neural default pathway in ectoderm includes constitutive FGF
      signaling step.

PMID- 10642794
TI  - The homeobox gene Otx of the jellyfish Podocoryne carnea: role of a head gene in
      striated muscle and evolution.
AB  - In many bilaterian animals members of the Otx gene family are expressed in head
      or brain structures. Cnidarians, however, have no clearly homologous head and no
      distinct brain; but an Otx homolog from the jellyfish Podocoryne carnea is highly
      conserved in sequence and domain structure. Sequence similarities extend well
      beyond the homeodomain and Podocoryne Otx can be aligned over its entire length
      to human OTX1, OTX2, and CRX. The overall structure of Otx is better conserved
      from Podocoryne to deuterostomes while protostomes appear to be more derived. In
      contrast, functions seem to be conserved from protostomes to vertebrates but not
      in Podocoryne or echinoderms. Podocoryne Otx is expressed only during medusa bud
      formation and becomes restricted to the striated muscle of medusae. Cnidaria are
      the most basal animals with striated muscle. Podocoryne polyps have no striated
      muscle and no Otx expression; both appear only during the asexual medusa budding
      process. The common ancestor of all animals that gave rise to cnidarians,
      protostomes, and deuterostomes already had an Otx gene more similar to today's
      Podocoryne and human homologs than to Drosophila otd, while the head-specific
      function appears to have evolved only later.

PMID- 10642795
TI  - Targeted disruption of Hoxd9 and Hoxd10 alters locomotor behavior, vertebral
      identity, and peripheral nervous system development.
AB  - The five most 5' HoxD genes, which are related to the Drosophila Abd-B gene, play
      an important role in patterning axial and appendicular skeletal elements and the
      nervous system of developing vertebrate embryos. Three of these genes, Hoxd11,
      Hoxd12, and Hoxd13, act synergistically to pattern the hindlimb autopod. In this
      study, we examine the combined effects of two additional 5' HoxD genes, Hoxd9 and
      Hoxd10. Both of these genes are expressed posteriorly in overlapping domains in
      the developing neural tube and axial mesoderm as well as in developing limbs.
      Locomotor behavior in animals carrying a double mutation in these two genes was
      altered; these alterations included changes in gait, mobility, and adduction.
      Morphological analysis showed alterations in axial and appendicular skeletal
      structure, hindlimb peripheral nerve organization and projection, and distal
      hindlimb musculature. These morphological alterations are likely to provide the
      substrate for the observed alterations in locomotor behavior. The alterations
      observed in double-mutant mice are distinct from the phenotypes observed in mice
      carrying single mutations in either gene, but exhibit most of the features of
      both individual phenotypes. This suggests that the combined activity of two
      adjacent Hox genes provides more patterning information than activity of each
      gene alone. These observations support the idea that adjacent Hox genes with
      overlapping expression patterns may interact functionally to provide patterning
      information to the same regions of developing mouse embryos.

PMID- 10642796
TI  - The spatial-temporal gradient of naturally occurring motoneuron death reflects
      the time of prior exit from the cell cycle and position within the lateral motor
      column.
AB  - Embryonic lumbar spinal motoneurons (MNs) are characterized by a period of
      programmed cell death (PCD) that spans several days and occurs in a rostrocaudal
      gradient. The generation of these MNs also takes place in a temporal-spatial
      gradient, such that MNs within rostral lumbar segments exit the cell cycle
      earlier and MNs within progressively caudal regions are born later. In vitro
      studies have shown that the latest born spinal MNs, presumably through the
      possession of endogenous "survival properties," are also the last to acquire
      their trophic dependence. If the birth date and therefore spinal cord location of
      lumbar spinal MNs influence the spatial-temporal pattern of PCD, then earlier
      born MNs should die sooner and be located more rostrally than those generated
      later. Alternatively, if the time at which MNs die during development is
      unrelated to their prior exit from the cell cycle, those born at various phases
      should die throughout the period of PCD. We report here that lumbar MNs generated
      during the earliest part (embryonic day 2-3) of the proliferative period in the
      developing chick spinal cord tend to die during the earliest stages of the PCD
      period and that MNs born in successive 12-h intervals die at correspondingly
      later periods during PCD. Furthermore, the spatial progression of PCD of these
      subpopulations of MNs occurs in a rostrocaudal gradient. Finally, while MNs do
      appear to die in a mediolateral gradient during the period of MN PCD, this
      pattern is only partly accounted for by MNs born in consecutive intervals. These
      data support the notion that the timing and rostrocaudal location of MNs
      undergoing PCD reflect their time of exit from the cell cycle.

PMID- 10642797
TI  - Neurogenesis and neuronal migration in the neonatal rat forebrain anterior
      subventricular zone do not require GFAP-positive astrocytes.
AB  - A prolific neuronal progenitor cell population in the anterior portion of the
      neonatal rat forebrain subventricular zone, the SVZa, is specialized for the
      production of olfactory bulb interneurons. At all ages, SVZa-derived cells
      traverse a tangential migratory pathway, the rostral migratory stream (RMS),
      while en route to the olfactory bulb. Unlike other neuronal progenitor cells of
      the forebrain, migrating progeny of SVZa progenitors express neuronal-specific
      proteins and continue to divide into adulthood. Recent studies indicate that in
      the adult, migrating SVZa-derived cells are ensheathed by astrocytes, although
      the function of these astrocytes has not been determined. To explore the possible
      role(s) of astrocytes in the rat SVZa and RMS, we examined the expression of
      astroglial-specific genes in the postnatal SVZa and RMS using RT-PCR, in situ
      hybridization, and immunohistochemistry during (Postnatal Days 1-10) and after
      the period of peak olfactory bulb interneuron generation. We also examined the
      expression of neuronal-specific genes throughout the rostral-caudal extent of the
      postnatal subventricular zone to determine if differential cell type-specific
      gene expression could distinguish the neurogenic SVZa as a region distinct from
      the remainder of the SVZ. We found little to no astrocyte-specific gene
      expression in the P0-P7 SVZa, although the neuron-specific isoforms of tubulin (T
      alpha 1 and beta-III tubulin) were expressed abundantly in the SVZa and RMS. In
      contrast, astrocyte-specific genes were strongly expressed in the SVZ posterior
      to the SVZa. GFAP expressions begins to appear in some restricted areas of the
      rostral migratory stream after the first postnatal week. These data suggest that
      astroglia are not involved in the generation or migration of most olfactory bulb
      interneurons. Moreover, the scarcity of glial markers in the neonatal SVZa
      indicates that the forebrain subventricular zone includes a distinct neurogenic
      anterior region containing predominantly committed neuronal progenitor cells.

PMID- 10642798
TI  - MEIG1 localizes to the nucleus and binds to meiotic chromosomes of spermatocytes
      as they initiate meiosis.
AB  - Meiosis, the fundamental evolutionarily conserved differentiative process by
      which haploid gametes are produced, is a complex and tightly regulated nuclear
      process. The murine Meig1 gene was previously shown to have a germ cell-specific
      transcript which is abundantly expressed during meiosis, in both males and
      females, suggesting that it is involved in meiotic processes. Protein analysis
      revealed that MEIG1 appears in multiple phosphorylated forms, including two
      dimeric forms of M(r) 31,000 and 32,000, which exhibit a developmentally
      regulated switch in their relative abundance. The tyrosine-phosphorylated M(r)
      31,000 form becomes the dominant form once the cells enter meiosis. In this study
      we show that the M(r) 31,000 dimeric form appears in the nuclear fraction of
      testicular protein extract, whereas the M(r) 32,000 dimeric form and the
      monomeric forms of MEIG1 remain cytoplasmic. The appearance in the nuclear
      fraction is developmentally regulated, coinciding with progression of the first
      spermatogenic wave through meiotic prophase I. Utilizing immunocytochemistry we
      show that nuclear localization is apparent in primary spermatocytes through their
      maturation into elongated spermatozoa, but not in either somatic cells or germ
      cells from early postnatal pups. We also show that MEIG1 associates specifically
      with meiotic chromosomes in vivo. These results indicate that in germ cells, the
      M(r) 31,000 dimeric form enters the nucleus during the first meiotic prophase and
      binds to the meiotic chromatin. Possible nuclear functions, as well as possible
      modes of nuclear localization, are discussed.

PMID- 10642799
TI  - Clonal analysis of epidermal patterning during maize leaf development.
AB  - In plants, specialized epidermal cells are arranged in semiordered patterns. In
      grasses such as maize, stomata and other specialized cell types differentiate in
      linear patterns within the leaf epidermis. A variety of mechanisms have been
      proposed to direct patterns of epidermal cell differentiation. One class of
      models proposes that patterns of cellular differentiation depend on the lineage
      relationships among epidermal cells. Another class of models proposes that
      epidermal patterning depends on positional information rather than lineage
      relationships. In the dicot epidermis, cell lineage is an important factor in the
      patterning of stomata, but not trichomes. In this study, the role of cell lineage
      in the linear patterning of stomata and bulliform cells in the maize leaf
      epidermis is investigated. Clones of epidermal cells in juvenile leaves were
      marked by excision of dSpm from gl15-m and in adult leaves by excision of Ds2
      from bz2-m. These clones were analyzed in relation to patterns of stomata and
      bulliform cells, testing specific predictions of clonal origin hypotheses for the
      patterning of these cell types. We found that the great majority of clones
      analyzed failed to satisfy these predictions. Our results clearly show that
      lineage does not account for the linear patterning of stomata and bulliform
      cells, implying that positional information must direct the differentiation
      patterns of these cell types in maize.

PMID- 10642800
TI  - An intrinsic timer that controls cell-cycle withdrawal in cultured cardiac
      myocytes.
AB  - Developing cardiac myocytes divide a limited number of times before they stop and
      terminally differentiate, but the mechanism that stops their division is unknown.
      To help study the stopping mechanism, we defined conditions under which embryonic
      rat cardiac myocytes cultured in serum-free medium proliferate and exit the cell
      cycle on a schedule that closely resembles that seen in vivo. The culture medium
      contains FGF-1 and FGF-2, which stimulate cell proliferation, and thyroid
      hormone, which seems to be necessary for stable cell-cycle exit. Time-lapse video
      recording shows that the cells within a clone tend to divide a similar number of
      times before they stop, whereas cells in different clones divide a variable
      number of times before they stop. Cells cultured at 33 degrees C divide more
      slowly but stop dividing at around the same time as cells cultured at 37 degrees
      C, having undergone fewer divisions. Together, these findings suggest that an
      intrinsic timer helps control when cardiac myocytes withdraw from the cell cycle
      and that the timer does not operate by simply counting cell divisions. We provide
      evidence that the cyclin-dependent kinase inhibitors p18 and p27 may be part of
      the timer and that thyroid hormone may help developing cardiac myocytes stably
      withdraw from the cell cycle.

PMID- 10642801
TI  - The lin-4 regulatory RNA controls developmental timing in Caenorhabditis elegans
      by blocking LIN-14 protein synthesis after the initiation of translation.
AB  - lin-4 encodes a small RNA that is complementary to sequences in the 3'
      untranslated region (UTR) of lin-14 mRNA and that acts to developmentally repress
      the accumulation of LIN-14 protein. This repression is essential for the proper
      timing of numerous events of Caenorhabditis elegans larval development. We have
      investigated the mechanism of lin-4 RNA action by examining the fate of lin-14
      mRNA in vivo during the time that lin-4 RNA is expressed. Our results indicate
      that the rate of synthesis of lin-14 mRNA, its state of polyadenylation, its
      abundance in the cytoplasmic fraction, and its polysomal sedimentation profile do
      not change in response to the accumulation of lin-4 RNA. Our results indicate
      that association of lin-4 RNA with the 3' UTR of lin-14 mRNA permits normal
      biogenesis of lin-14 mRNA, and normal translational initiation, but inhibits
      step(s) thereafter, such as translational elongation and/or the release of stable
      LIN-14 protein.

PMID- 10642802
TI  - High-dose busulfan/melphalan as conditioning for autologous PBPC transplantation
      in pediatric patients with solid tumors.
AB  - We conducted a prospective pilot study to assess the feasibility and safety of
      high-dose busulfan/melphalan as conditioning therapy prior to autologous PBPC
      transplantation in pediatric patients with high-risk solid tumors. From January
      1995 to January 1999, 30 patients aged 2-21 years (median 8) were entered into
      the study. There were 14 females and 16 males. Diagnoses included neuroblastoma
      in 10 patients; Ewing's sarcoma and peripheral neuroectodermal tumor (PNET) in 15
      patients and rhabdomyosarcoma in five patients. Treatment consisted of busulfan
      16 mg/kg, orally over 4 days (from days -5 to -2) in 6 hourly divided doses, and
      melphalan at a dose of 140 mg/m2 given by intravenous infusion over 5 min on day 
      1. G-CSF mobilized PBPC were used as autologous stem-cell rescue. One patient
      developed a single generalized convulsion during busulfan therapy. The most
      relevant non-hematologic toxicity was gastrointestinal, manifesting as grade 2-3
      mucositis and diarrhea in 12 patients. Two patients died of procedure-related
      complications, one from veno-occlusive disease of liver and multiorgan failure
      and the other from adult respiratory distress syndrome. Probability of treatment
      related mortality was 6.6 +/- 4.5%. With a median follow-up of 18 months (range,
      1-48), 19 patients are alive and disease-free, the actuarial EFS at 4 years being
      55 +/- 12% for the whole group. We conclude that high-dose busulfan/melphalan for
      autologous transplantation in children with solid tumors is feasible even in
      small patients. It is well-tolerated, with an acceptable transplant-related
      mortality and has proven antitumor activity.

PMID- 10642803
TI  - Characterisation of CTL directed towards non-inherited maternal alloantigens in
      human cord blood.
AB  - Allogeneic cord blood transplantation (CBT), especially from unrelated donors, is
      being increasingly used for treating paediatric patients with both malignant and
      non-malignant disorders. Recent clinical and experimental evidence suggests that
      human cord blood mononuclear cells (CBMC) may acquire in utero a state of
      tolerance towards non-inherited maternal antigens (NIMA). In order to better
      define this phenomenon, we measured, by means of a limiting dilution assay (LDA),
      the frequency of NIMA-specific CTL precursors (CTLp) in cord blood samples
      obtained from 13 healthy neonates. The immunophenotype of the effector cells
      recovered from LDA was also analysed. Data concerning both CTLp frequency and
      phenotype of effector cells were compared with those obtained stimulating CBMC
      with cells of paternal origin (NIPA) and adult PBMC with allogeneic targets.
      Results showed that cytotoxic cells directed towards cells of maternal origin
      could be detected in all cord blood samples tested. Phenotype analysis
      demonstrated that NIPA elicit the expansion of CD3+/CD8bright T cells, a
      phenotype associated with alloreactive CTL. By contrast, NIMA preferentially
      stimulated the expansion of CD3-/CD8dim+ cells, a phenotype associated with NK
      cells, which are known to be able, in certain clinical conditions, to kill
      allogeneic haematopoietic cells without causing GVHD. Thus, our results indicate
      that, when evaluated in a limiting dilution condition, NIMA-reactive cord blood
      cells are detectable and a preferential expansion of NK cells is observed.

PMID- 10642804
TI  - The number and generative capacity of human B lymphocyte progenitors, measured in
      vitro and in vivo, is higher in umbilical cord blood than in adult or pediatric
      bone marrow.
AB  - The lack of human B lymphocyte development in beige/nude/XID (bnx) mice is in
      sharp contrast to the robust development observed in another immune deficient
      strain, the NOD/SCID mouse. The ability to generate human B lymphocytes in the
      NOD/SCID, but not bnx mouse has been hypothesized to be caused by differences in
      the microenvironments or systemic cytokine concentrations. In the current studies
      we report that the differences in development can be primarily attributed to the
      source of the progenitors transplanted into the mice. The prior studies in bnx
      mice used cultured pediatric or adult bone marrow (BM) as the source of the CD34+
      cells, whereas the NOD/SCID studies have predominantly used fresh or cultured
      umbilical cord blood (UCB). We have analyzed BM and UCB for the number of human
      CD34+/CD38- cells capable of in vitro B lymphocyte development, and have found a
      lower frequency of B lymphocyte generation in BM. The individual B lymphocyte
      clones that developed from bone marrow produced 100-fold fewer cells than the UCB
      derived clones. In agreement with the in vitro studies, human B lymphocytes
      developed in bnx mice from both CD34+ and CD34+/CD38- cells isolated from human
      umbilical cord blood, but not from equivalent numbers of CD34+ and CD34+/CD38-
      progenitors from bone marrow. Therefore, the lower generative capacity, and
      frequency of B lymphocyte precursors in human marrow may be responsible for the
      previous results that showed a lack of B lymphocyte development in bnx mice.

PMID- 10642805
TI  - Allogeneic blood stem cell and bone marrow transplantation for acute myelogenous
      leukemia and myelodysplasia: influence of stem cell source on outcome.
AB  - We have compared the outcomes of 87 patients with acute myelogenous leukemia
      (AML) and myelodysplasia (MDS) receiving matched sibling transplants with stem
      cells from peripheral blood (blood cell transplant, BCT) or bone marrow (BMT). In
      good risk patients (AML in CR1) granulocytes recovered to 0.5 x 10(9)/l a median
      of 14 days after BCT compared with 19 days after BMT (P < 0.0001). For patients
      with poor risk disease (AML beyond CR1 and MDS) corresponding figures were 16 vs
      26 days (P < 0.0001). Platelet recovery to 20 x 10(9)/l was also faster after BCT
      (good risk 12 vs 20 days, P < 0.0001; poor risk 17 vs 22 days, P = 0.04). Red
      cell transfusions were unaffected by cell source, but BCT recipients required
      less platelet transfusions (good risk 1 vs 5, P = 0.002; poor risk 5 vs 11, P =
      0.004). Blood cell transplants resulted in more chronic GVHD (86% vs 48%, P =
      0.005) and a significantly higher proportion of recipients with KPS of 80% or
      less (48% vs 5%, P = 0.004). Disease-free survival at 4 years was 23% for both
      groups of poor risk patients but outcome in good risk patients was better after
      BCT (93% vs 62%, P = 0.047) related mainly to less relapse. While disease-free
      survival may be better after BCT than BMT for AML in CR1, quality of life may be
      relatively impaired.

PMID- 10642806
TI  - Feasibility and response to budesonide as topical corticosteroid therapy for
      acute intestinal GVHD.
AB  - Therapy of acute intestinal GVHD is still one of the main challenges after
      allogeneic transplantation. Increasing systemic immunosuppression (IS) is the
      first choice and includes corticosteroids and lymphocyte antibodies, often
      associated with severe side-effects. In inflammatory bowel diseases such as
      Crohn's disease and ulcerative colitis, topical steroid therapy is used very
      successfully. Because of the similarity between these and acute intestinal GVHD
      we conducted a trial with oral budesonide (Budenofalk), a new topically active
      glucocorticoid, to treat patients with acute GVHD > or = grade II. After a
      diagnosis of aGVHD > or = grade II, 22 patients received increased IS, mainly
      systemic corticosteroids, and additionally budesonide 9 mg/day divided into three
      doses. Improvement in aGVHD, infectious side-effects, reduction of systemic IS
      and outcome were documented. Results were compared with the results of 19 control
      patients, who were treated only by increasing IS dose. In 17/22 patients (70%),
      treated with budesonide, the acute intestinal GVHD resolved and no relapse
      occurred after decreasing the systemic IS, while continuing budesonide. In only
      8/19 patients in the control group did the acute intestinal GVHD resolve and 2/8
      patients had a relapse of intestinal GVHD after decreasing IS, with an overall
      response of 33%. No severe intestinal infections occurred. We conclude that
      budesonide may be effective in acute intestinal GVHD as a topical corticosteroid
      and prospective, randomized studies should demonstrate its efficacy in allowing
      reduction of systemic immunosuppressive therapy, and its side-effects.

PMID- 10642807
TI  - Characterization of autotransplant-related thrombocytopenia by evaluation of
      glycocalicin and reticulated platelets.
AB  - Thrombocytopoiesis of 21 multiple myeloma patients undergoing single or double
      transplant regimen was characterized by measuring the level of reticulated
      platelets and plasma glycocalicin. Since reticulated platelets are an index of
      thrombopoietic activity and glycocalicin plasma values are related to platelet
      damage and turnover, it may be possible to perform a novel type of analysis of
      the thrombopoietic compartment during the mobilizing regimen and during
      transplant-related chemotherapy. Patients underwent mobilizing therapy and first
      transplant. Some randomized patients also underwent a second transplant with
      mobilized peripheral blood stem cells. The results show that the percentage of
      reticulated platelets decreased after therapy and then gradually increased in the
      recovery phase either during first or second transplant. By contrast, the
      percentage of reticulated platelets increased until day +8 and then gradually
      decreased during the mobilizing regimen. The glycocalicin index (glycocalicin
      plasma value normalized for the individual platelet count) increased
      significantly both during the course of mobilization and after transplant-related
      chemotherapy when the platelet number was at its nadir. However, the glycocalicin
      index was more elevated after transplant-related chemotherapy than after the
      mobilizing regimen. Our findings suggest that chemotherapy-related
      thrombocytopenia may be due to a dual mechanism: thrombocytopenia results from
      decreased platelet production in addition to increased platelet damage and
      possible destruction.

PMID- 10642808
TI  - Diagnostic yield of bronchoscopy in histologically proven invasive pulmonary
      aspergillosis.
AB  - Invasive pulmonary aspergillosis (IPA) is a life-threatening infectious
      complication in neutropenic patients after high-dose chemotherapy or
      hematopoietic stem cell transplantation. Its diagnosis is mainly based on
      clinical symptoms, and radiological signs on thoracic CT scan. The value of
      bronchoscopy is controversial. We analyzed the diagnostic yield of bronchoscopy
      in 23 consecutive patients with histologically proven invasive pulmonary
      aspergillosis. In seven patients (30%) bronchoscopically obtained specimens were
      diagnostic for pulmonary fungal infection. Typical hyphae were detected by
      cytology in six patients and fungal cultures were positive in four cases.
      Patients with a positive bronchoscopic result presented more often with multiple
      changes on thoracic CT scan (71%; 5/7), but had received a lower median
      cumulative dose of amphotericine B (300 mg; 168-3010 mg) compared to patients
      with non-diagnostic bronchoscopy (25% multiple lesions (4/16); amphotericine dose
      1100 mg, 260-2860 mg). The diagnostic yield of bronchoscopy was not associated
      with clinical symptoms or duration of neutropenia. Bronchoscopy allows the
      diagnosis of IPA in about one third of patients. Fungal cultures and cytological
      examination of intrabronchial specimens obtained during bronchoscopy have a high
      specificity, but its sensitivity is low. It is advisable to perform diagnostic
      bronchoscopy before starting antifungal therapy. Better diagnostic tools are
      urgently needed.

PMID- 10642809
TI  - Human herpesvirus 6 infection inhibits specific lymphocyte proliferation
      responses and is related to lymphocytopenia after allogeneic stem cell
      transplantation.
AB  - Human herpesvirus 6 (HHV-6) infection and the HHV-6-specific lymphocyte
      proliferation response were studied longitudinally in 24 patients in the first 3
      months after allogeneic stem cell transplantation (allo-SCT). HHV-6 DNAemia was
      analyzed by a nested PCR method, and the HHV-6-specific lymphocyte proliferation
      responses were evaluated with a standard lymphocyte proliferation assay. All
      patients who responded to HHV-6 GS (variant A) antigen also responded to HHV-6
      Z29 (variant B) antigen, and a response to HHV-6 Z29 antigen was detected more
      often than to HHV-6 GS antigen after allo-SCT (P = 0.048). HHV-6 DNA was detected
      in more patients after than before transplantation (P = 0.01) and in more
      patients with acute GVHD grades II-IV than those without (P = 0.009). An HHV-6
      specific proliferative response was more often detected in patients without, than
      in those with persistent HHV-6 infection (three consecutively positive PBL
      samples; P < 0.001). Patients with persistent HHV-6 infection had lower
      lymphocyte counts from the 8th week after transplantation than those without (P =
      0.03). No HHV-6-specific proliferation responses were detected in the three
      patients who developed HHV-6 disease. HHV-6 infection was associated with
      persistent lymphocytopenia and might thereby inhibit immune function.

PMID- 10642810
TI  - Oral ciprofloxacin as antibacterial prophylaxis after allogeneic bone marrow
      transplantation: a reappraisal.
AB  - The efficacy of ciprofloxacin as antibacterial prophylaxis for allogeneic bone
      marrow transplantation has been well documented, and it virtually eliminated
      bacteremias caused by gram-negative pathogens in early reports. Ciprofloxacin was
      therefore incorporated into the prophylactic antibiotic regimen during allogeneic
      bone marrow or peripheral blood stem cell transplantation at Veterans General
      Hospital, Kaohsiung from February 1997. In 12 consecutive patients receiving
      allogeneic bone marrow or peripheral blood stem cell transplantation,
      ciprofloxacin-resistant Escherichia coli bacteremia developed in three (25%). In
      addition to our data, increasing evidence suggests that the widespread use of a
      fluoroquinolone is associated with the emergence of resistant isolates as well as
      documented infections caused by these resistant strains. The incidence of
      Escherichia coli bacteremia in our transplant patients was 25%, which was similar
      to that in patients not receiving preventive therapy or in those receiving
      trimethoprim-sulfamethoxazole prophylaxis. The prophylactic efficacy of
      ciprofloxacin in allogeneic bone marrow transplant or peripheral blood stem cell
      transplant recipients should therefore be reassessed.

PMID- 10642812
TI  - The course of anxiety and depression during the first year after allogeneic or
      autologous stem cell transplantation.
AB  - Psychological distress is frequently reported in transplant survivors. We
      prospectively assessed anxiety and depression before transplant, in the isolation
      period and during a follow-up period of 1 year. The Hospital Anxiety and
      Depression Scale (HADS) was administered to 131 cancer patients treated with high
      dose chemotherapy followed by allogeneic (SCT) or autologous (ASCT) stem cell
      transplantation, and a concurrent group of 123 lymphoma patients receiving
      standard chemotherapy (CT) who served as a reference group. Relatively low levels
      of anxiety and depression were found. The level of anxiety slightly declined from
      baseline during follow-up (mean scores SCT: from 5.3 to 3.6, CT: from 6.0 to 4.2)
      or remained fairly stable (ASCT: from 5.4 to 4.8). The level of depression peaked
      when the transplant patients were in protective isolation or shortly thereafter
      (SCT: 6.1, ASCT: 6.4), but stabilized at baseline levels after 4 months. The
      highest level of depression in the CT group was reported 4 months after start of
      chemotherapy (3.4). Elevated levels of anxiety and depression at baseline
      predicted more anxiety and depression at the later assessments (P values <
      0.0001). The ASCT group had higher levels of anxiety after 1 year (mean 4.8) than
      those found in the other two groups (SCT: 3.6, CT: 4.2), although they were not
      statistically significant. This study revealed lower than expected levels of
      anxiety and depression after intensive chemotherapy followed by SCT or ASCT.
      There was a decline in psychological distress during the 1-year follow-up period.

PMID- 10642811
TI  - Infections in patients managed at home during autologous stem cell
      transplantation for lymphoma and multiple myeloma.
AB  - A group of 51 patients with multiple myeloma, non-Hodgkin's lymphoma or Hodgkin's
      disease receiving high-dose chemotherapy and autologous peripheral blood stem
      cell rescue received chemotherapy and clinical care in the peritransplant period
      at home. This group was compared with 88 cases with the same diagnoses, receiving
      the peripheral stem cell transplant over the same time period as an inpatient in
      a high efficiency particulate air filtered bone marrow transplant unit. Patients
      were treated at home based on choice, geographic accessibility, availability of
      an educated care giver and a clean home environment, and comprehension of the
      concepts of infection and aseptic techniques. Febrile neutropenia and sepsis were
      not increased in the home group and no episodes of septic shock were seen in this
      group. Patients at home received prophylactic oral ciprofloxacin and
      roxithromycin during the phase when the absolute neutrophil count was < 1 x
      10(9)/l. Fewer gram-negative infections, but no diminution in gram-positive
      infections or in the rate of fever were seen in patients at home. Empiric therapy
      with a third generation cephalosporin, teicoplanin and tobramycin was instituted
      in 31 patients who developed a fever greater than 38.5 degrees C. Of this group
      of 31, 18 required admission to hospital, 12 because of febrile neutropenia which
      persisted or was considered unsuitable for management at home due to sepsis. The
      remaining 13 with febrile neutropenia remained at home throughout, as did the 20
      cases not developing neutropenic fever. This study demonstrates the feasibility
      of managing carefully selected patients in their home environment when at risk
      from febrile neutropenia or other septic complications following autologous
      peripheral stem cell support.

PMID- 10642813
TI  - Umbilical cord blood T lymphocytes are induced to apoptosis after being allo
      primed in vitro.
AB  - In this study, the immunity of umbilical cord blood (UCB) T lymphocytes against
      allo-antigens was investigated by a standard MLC. No significant difference,
      between the UCB T cells or peripheral blood (PB) mature T cells, was observed in
      the primary responses (stimulation index (SI), 51.8 +/- 14.8 and 46.5 +/- 15.0,
      respectively). In contrast, in the secondary response, the SI obtained with the
      CD4 T cells from UCB decreased dramatically (16.3 +/- 6.4), while it increased
      with the CD4 T cells from PB (118.5 +/- 21.7). UCB (CD4 and CD8) T cells
      separately showed much higher frequencies of apoptosis after a primary allo
      priming, compared with PB CD4 and CD8 T cells (CD4, UCB 30.5% vs PB 0.8%; CD8,
      UCB 32% vs PB 1.3%). The higher apoptotic level of the UCB CD4 T cells was
      confirmed by a second, ELISA-based, Tunel assay (OD values, UCB CD4 1.93 +/- 0.31
      vs PB CD4 0.59 0.9; P < 0.01). Those apoptotic steps were not attributed to the
      amount of cytokine (IL-2, 4 and IFN-gamma) production, which was found to be
      similar in both cases. In conclusion, UCB lymphocytes are much more likely to be
      induced to apoptosis by allo-priming than adult lymphocytes. This supports their
      possible, successful engraftment across barriers of HLA incompatibility.

PMID- 10642814
TI  - Enhanced assessment of allogeneic bone marrow transplant engraftment using
      automated fluorescent-based typing.
AB  - Traditional qualitative gel electrophoresis approaches lack accurate' and
      quantitative assessment of mixed chimerism in BMT patients. The likelihood of
      informative markers is greatly increased using simultaneous amplification of 10
      highly polymorphic loci with fluorescent-labeled primers in an automated DNA
      sequencer. This allows for more precise interpretation of mixed chimerism with a
      detection level approximating 1%. To evaluate this approach to quantitative
      assessment of chimeric populations we mixed varying proportions of samples from
      two unrelated donors, by either mixing aliquots of DNA isolated from whole blood,
      or by first counting the white blood cells and mixing varying proportions of
      cells together prior to DNA isolation. The allelic-peak area ratios were
      identical to allelic-peak height ratios and corresponded to the proportion of
      mixed DNA, regardless of the method used to create the mixture. Formulas to
      provide routine, consistent and quantitative interpretation of mixed chimerism
      are presented. We analyzed 14 allograft recipients and one autologous BMT patient
      with transfusion-induced GVHD. In all cases, at least four out of nine markers
      were informative. Inter-laboratory concordance of results was also obtained with
      an eight marker panel using an automated Alf-Express. In conclusion, the
      automated DNA fluorescent-labeled primer approach using an eight to 10 marker
      panel is quantitative and informative in assessing chimerism.

PMID- 10642816
TI  - Successful treatment of human herpesvirus-6 encephalitis after bone marrow
      transplantation.
AB  - We report two cases of human herpesvirus-6 (HHV-6)-associated encephalitis in
      patients after BMT. Both patients reported distinct neurological symptoms with
      disorientation, sleepiness and loss of short-term memory. Diagnosis was based on
      PCR analysis of the cerebrospinal fluid (CSF) positive for HHV-6 variant B-DNA.
      After institution of therapy with foscarnet in both cases, neurological symptoms
      improved and in one patient clearance of HHV-6-DNA from CSF was demonstrated.
      These cases show that HHV-6 infection has to be considered in patients with
      neurological symptoms following BMT and effective treatment of HHV-6 encephalitis
      is possible if instituted early.

PMID- 10642815
TI  - Acute hepatitis B after autologous stem cell transplantation in a man previously
      infected by hepatitis B virus.
AB  - We report a case of acute hepatitis B after autologous stem cell transplantation
      (ASCT) in a patient with low-grade non-Hodgkin's lymphoma. At diagnosis of the
      hematological disease, the patient had the characteristic serology of a previous
      hepatitis B infection, being Ag HBs negative, hepatitis B virus core antibody
      positive (anti-HBC) and hepatitis B virus surface antibody weakly positive. He
      developed fatal hepatitis B after autologous stem cell transplantation,
      suggesting reactivation consequent to immunosuppression.

PMID- 10642817
TI  - Hepatopulmonary syndrome after allogeneic bone marrow transplantation.
AB  - A 10-year-old girl with aplastic anemia received an allogeneic bone marrow
      transplantation (BMT). Three years after an uneventful course apart from chronic
      graft-versus-host disease (GVHD) she presented with chronic hypoxemia, reduced
      diffusion capacity of the lungs, normal spirometric lung function and increased
      bilirubin and liver enzymes. Intrapulmonary vascular dilatations were
      demonstrated. Pulmonary complications after BMT may include a hepatopulmonary
      syndrome (liver disease, hypoxemia, intrapulmonary vascular dilatations).

PMID- 10642818
TI  - Use of rituximab and irradiated donor-derived lymphocytes to control Epstein-Barr
      virus-associated lymphoproliferation in patients undergoing related haplo
      identical stem cell transplantation.
AB  - Epstein-Barr virus-associated lymphoproliferative disorder (EBV-LPD) is an
      uncommon but potentially fatal complication of allogeneic stem cell
      transplantation. We report here two patients who underwent T cell-depleted
      mismatched-related stem cell transplantation for hematologic malignancies and
      required aggressive post-transplant immunosuppression for graft-versus host
      disease (GVHD). Both patients subsequently developed markedly elevated EBV-DNA
      titers in association with monoclonal, light chain-restricted B cell populations
      in the blood. Although immunosuppressive medications were rapidly tapered,
      neither patient could receive potentially curative therapy with unmanipulated
      donor-derived lymphocyte infusions (DLI) because of the substantial risk of
      severe GVHD. Therefore, both patients received repeated courses of rituximab, an
      anti-CD20 monoclonal antibody, in combination with irradiated DLI. This
      therapeutic strategy resulted in normalization of the elevated EBV-DNA titers and
      disappearance of the monoclonal B cell populations. Our results suggest that
      rituximab and possibly irradiated DLI played an important role in controlling
      early EBV-LPD in these two patients and may be an effective alternative
      therapeutic strategy for patients who develop EBV-LPD post transplant and are
      unable to receive unmanipulated DLI.

PMID- 10642819
TI  - Intravesicular instillation of E-aminocaproic acid for patients with adenovirus
      induced hemorrhagic cystitis.
AB  - Hemorrhagic cystitis (HC) is a known complication of allogenic BMT. We report a
      case of a 28-year-old female with CML in chronic phase, which was treated with a
      matched unrelated donor (MUD) transplant, complicated by hemorrhagic cystitis on
      day +42 after the transplant. Adenovirus was isolated from the urine and she was
      treated with ribavirin, 1 g twice a day for 8 days. We report the use of Amicar
      (E-aminocaproic acid), 2.5 g solution as bladder instillation to treat the
      intractable hematuria.

PMID- 10642820
TI  - Matched unrelated donor bone marrow transplantation in leukocyte adhesion
      deficiency.
AB  - The severe phenotype of leukocyte adhesion deficiency is a rare, congenital
      disorder of leukocyte function that is usually fatal in the first few years of
      life. Allogeneic hematopoietic stem cell transplantation currently offers the
      only curative approach for this disease. We describe the first successful matched
      unrelated donor bone marrow transplant in an infant with leukocyte adhesion
      deficiency.

PMID- 10642821
TI  - Next century's academic clinical research development in blood and marrow
      transplants requires continental organizational development.

PMID- 10642822
TI  - Ascorbate and glutathione regulation in hibernating ground squirrels.
AB  - Ground squirrels withstand up to 90% reductions in cerebral blood flow during
      hibernation as well as rapid reperfusion upon periodic arousals from torpor.
      Metabolic suppression likely plays a primary adaptive role which allows
      hibernating species to tolerate such phenomena. However, several other aspects of
      hibernation physiology are also consistent with tolerance to dramatic
      fluctuations in cerebral blood flow, suggesting that multiple neuroprotective
      adaptations may work in concert during hibernation. The purpose of the present
      work was to study the dynamics of the low molecular weight antioxidants,
      ascorbate and glutathione (GSH), during hibernation. Alterations in
      concentrations of ascorbate during hibernation and arousal in two species of
      hibernating ground squirrels suggest that it could play a protective role during
      hibernation or arousal. Samples were collected during the hibernation season from
      arctic ground squirrels (AGS; Spermophilus parryii) and 13-lined ground squirrels
      (TLS; S. tridecemlineatus) during prolonged torpor and in squirrels that did not
      hibernate or had not been hibernating for several weeks. We determined
      antioxidant levels in plasma, cerebrospinal fluid (CSF), and in frontal cortex,
      hippocampus and cerebellum using high-performance liquid chromatography (HPLC).
      Plasma ascorbate concentrations increased dramatically (3-4-fold) in both species
      during hibernation and rapidly returned to prehibernation levels upon arousal. By
      contrast, plasma GSH concentrations fell slightly or remained stable during
      hibernation. Ascorbate levels in the CSF doubled in hibernating AGS (not
      determined in TLS), while brain ascorbate content fell slightly (10-15%) in both
      species. Substantial increases in plasma and CSF ascorbate concentrations suggest
      that this antioxidant could play a protective role during hibernation and
      reperfusion upon arousal from hibernation.

PMID- 10642823
TI  - Adolescent nicotine exposure causes persistent upregulation of nicotinic
      cholinergic receptors in rat brain regions.
AB  - Whereas numerous studies have explored the consequences of fetal or adult
      nicotine exposure, little or no basic research has been conducted for nicotine
      exposure during adolescence, the developmental period in which regular cigarette
      use typically begins. We administered nicotine to adolescent rats on postnatal
      days 30-47 via continuous infusion with implanted osmotic minipumps, using a dose
      rate (3-6 mg kg-1 day-1) set to achieve plasma nicotine levels found in smokers;
      results were compared to exposure of adult rats. During and after exposure, we
      assessed nicotinic cholinergic receptor binding in the midbrain, cerebral cortex,
      and hippocampus, using [3H]cytisine. Robust receptor upregulation was observed
      with both adolescent and adult nicotine exposure but there were major differences
      in the regional specificity and persistence of effect. In adolescents,
      upregulation was uniform across all regions during the infusion period, whereas
      in adults, there was a distinct regional hierarchy: midbrain < cerebral cortex <
      hippocampus; accordingly, receptors in the adolescent midbrain were upregulated
      far more than with adult exposure. In addition, adolescent nicotine treatment
      produced long-lasting effects on the receptors, with significant increases still
      apparent in male rats 1 month after the termination of drug exposure. We also
      obtained evidence for hippocampal cell damage in adolescent female rats exposed
      to nicotine, characterized by increases in total membrane protein concentration
      indicative of a decrease in overall cell size. Adolescent nicotine exposure thus
      elicits region- and gender-selective effects that differ substantially from those
      in adults, effects that may contribute to increased addictive properties and
      lasting deficits in behavioral performance.

PMID- 10642825
TI  - Site- and modality-specific modulation of experimental muscle pain in humans.
AB  - The neurophysiological mechanisms involved in diffuse noxious inhibitory controls
      (DNIC) have been investigated extensively, but information is lacking about the
      effect of different stimulus modalities and somatic locations on the
      effectiveness of DNIC. This study is the first to examine the hypoalgesic effects
      on a deep, tonic and painful test stimulus (TS) of both painful and non-painful
      conditioning stimuli (CS) applied to different sites of the body. Two separate
      experiments were performed using painful electrical stimulation of the left
      anterior tibialis muscle as the TS. In the first experiment (n = 9), injection of
      5% hypertonic saline was used as a painful CS into one of four muscles: anterior
      tibialis of each leg and brachioradialis of each arm. In the second experiment (n
      = 5), a non-painful vibratory stimulus was used as the CS at the same four sites.
      Compared with TS alone, the perceived pain intensity of the TS increased (4.5 +/-
      1.8%; P = 0.019) in combination with the painful CS applied to the same muscle
      (ipsilateral homotopic site), but decreased (-25.3 +/- 1.4%; P < 0.001) in
      combination with non-painful CS at the same site. Both painful and non-painful CS
      applied at the three heterotopic sites caused significant and site-dependent
      decreases in the perceived pain intensity of the TS (range 15%-37%; P < 0.05). We
      conclude that a hypoalgesic DNIC-like effect on muscle pain is not produced
      exclusively by painful stimuli, and that the valence and magnitude of the
      modulation depend on the nature of the CS and its location relative to the
      applied TS.

PMID- 10642824
TI  - In vitro status epilepticus causes sustained elevation of intracellular calcium
      levels in hippocampal neurons.
AB  - Calcium ions and calcium-dependent systems have been implicated in the
      pathophysiology of status epilepticus (SE). However, the dynamics of
      intracellular calcium ([Ca2+]i) levels during SE has not yet been studied. We
      have employed the hippocampal neuronal culture (HNC) model of in vitro SE that
      produces continuous epileptiform discharges to study spatial and dynamic changes
      in [Ca2+]i levels utilizing confocal laser scanning microscopy and the calcium
      binding dye, indo-1. During SE, the average [Ca2+]i levels increased from control
      levels of 150-200 nM to levels of 450-600 nM. This increased [Ca2+]i was
      maintained for the duration of SE. Following SE, [Ca2+]i levels gradually
      returned to basal values. The duration of SE was shown to affect the ability of
      the neuron to restore resting [Ca2+]i levels. Both N-methyl-D-aspartate (NMDA)
      receptor-gated and voltage-gated Ca2+ channels (VGCCs) contributed to the
      increased calcium entry during SE. Moreover, this elevation in [Ca2+]i occurred
      in both the nucleus and cytosol. These results provide the first dynamic
      measurement of [Ca2+]i during prolonged electrographic seizure discharges in an
      in vitro SE model and suggest that prolonged epileptiform discharges give rise to
      abnormal sustained increases in [Ca2+]i levels that may play a role in the
      neuronal cell damage and long-term plasticity changes associated with SE.

PMID- 10642826
TI  - Muscarinic regulation of Ca2+ oscillation frequency in GH3 cells.
AB  - The GH3 anterior pituitary cell line has been used as a model to investigate
      diverse aspects of pituitary cell physiology including Ca2+ homeostasis and
      secretion. These cells possess muscarinic receptors which, by activating K+
      channels and inhibiting Ca2+ channels, should decrease electrical excitability.
      We measured the effect of carbachol (10 microM) on the frequency of Ca2+
      oscillations caused by Ca2+ action potentials in the plasma membrane. Carbachol
      reduced oscillation frequency by approximately 85% (p < 0.001). This inhibition
      was reversed by atropine (1 microM), and was prevented by pre-incubation with
      pertussis toxin (200 ng/ml, 24 h). Since many anterior pituitary cell types
      secrete acetylcholine, the presence of muscarinic receptors coupled to cell
      excitability in these cells suggest that ACh could exert a paracrine- or
      autocrine-like action in GH3 cell cultures. In experiments designed to test this
      idea, perfusion with 1 microM atropine caused a small but significant increase (p
      < 0.05) in oscillation frequency when the cells had previously been incubated for
      30 min without perfusion. However, this effect was not blocked by either pre
      treatment with pertussis toxin or by including atropine during the entire
      experiment (including the 30-min incubation without perfusion). We conclude that
      these cells respond to muscarinic agonists by decreasing oscillation frequency
      but find no evidence for feedback control by endogenous ACh under these
      conditions.

PMID- 10642827
TI  - Differential expression of hepatocyte growth factor and its receptor, c-Met in
      the rat retina during development.
AB  - Hepatocyte growth factor (HGF) is a pleiotrophic factor with mitogenic,
      motogenic, and morphogenic activities. Recent evidence has suggested that HGF
      plays an important role in the development and maintenance of the nervous system.
      In this study, we examined spatial and temporal expression of HGF and its
      receptor, c-Met, during retinal development at RNA or protein levels. Competitive
      RT-PCR revealed that HGF and c-met mRNA expressions were up-regulated during the
      development and sustained at high levels in adulthood. By immunohistochemical
      analysis, we demonstrated that c-Met-immunoreactivity (IR) was present in the
      major classes of retinal neurons after their differentiation. In the adult, c-Met
      IR was predominantly present in the photoreceptors. In contrast, HGF-IR was
      observed from P7 and thereafter in ganglion cells and the inner nuclear layer,
      but not in other layers. Differential or co-localization of HGF and c-Met
      indicates the autocrine or paracrine action of HGF depending on the cell types
      and developmental stages. Moreover, dynamic regulation of HGF and c-Met
      implicates their multiple roles in the development, maintenance and modification
      of retinal system.

PMID- 10642828
TI  - Long-lasting decrease in neuronal Ca2+/calmodulin-dependent protein kinase II
      activity in a hippocampal neuronal culture model of spontaneous recurrent
      seizures.
AB  - Ca2+/calmodulin-dependent protein kinase II (CaM Kinase II) activity was
      evaluated in a well-characterized in vitro model of epileptiform activity. Long
      lasting spontaneous recurrent seizure (SRS) activity was induced in hippocampal
      neuronal cultures by exposure to low Mg2+ media for 3 h. Analysis of endogenous
      Ca2+/calmodulin-dependent phosphorylation revealed a significant long-lasting
      decrease in 32P incorporation into the alpha (50 kDa) and beta (60 kDa) subunits
      of CaM kinase II in association with the induction of SRS activity in this
      preparation. Ca2+/calmodulin-dependent substrate phosphorylation of the synthetic
      peptides, Autocamtide-2 and Syntide II, was also significantly reduced following
      the induction of SRSs and persisted for the life of the neurons in culture. The
      decrement in CaM kinase II activity associated with low Mg2+ treatment remained
      significantly decreased when values were corrected for changes in levels of alpha
      subunit immunoreactivity and neuronal cell loss. Addition of the protein
      phosphatase inhibitors, okadaic acid and cyclosporin A, to the phosphorylation
      reaction did not block the SRS-associated decrease in substrate phosphorylation,
      indicating that enhanced phosphatase activity was not a contributing factor to
      the observed decrease in phosphate incorporation. The findings of this study
      demonstrate that CaM kinase II activity is decreased in association with
      epileptogenesis observed in these hippocampal cultures and may contribute to the
      production and maintenance of SRSs in this model.

PMID- 10642829
TI  - The paraventricular nucleus of the thalamus alters rhythms in core temperature
      and energy balance in a state-dependent manner.
AB  - Exposure to chronic stress facilitates activity within the hypothalamic-pituitary
      adrenal (HPA) axis and is associated with enhanced neuronal activity in a
      discreet set of brain regions, including the posterior division of the
      paraventricular nucleus of the thalamus (pPVTh). Because HPA function is
      intimately associated with systems that regulate metabolism, including core
      temperature and energy balance, we examined the effects of chronic stress on
      circadian rhythms in temperature, locomotor activity, body weight gain and food
      intake and adipose depot weights in rats. We also examined the potential role of
      the pPVTh in mediating these functions using ibotenate lesions of this nucleus.
      Chronic stress lowered the amplitude of core temperature rhythms, and lesions of
      the pPVTh blocked this effect in chronically stressed animals, but did not affect
      the amplitude of temperature rhythms in unstressed controls. In addition, lesions
      of the pPVTh increased cumulative food intake and overall body weight gain in
      controls but they increased subcutaneous white adipose depot weight in
      chronically stressed animals. Thus, the functional paraventricular nucleus of the
      thalamus appears to inhibit both temperature rhythms and specific white adipose
      depots only in chronically stressed animals. Together with our previous results,
      we show that the PVTh affects rhythms in food intake and body weight and is a
      nexus that differentially regulates core temperature rhythms/HPA
      activity/specific white adipose depots depending on the stress state of the
      animal.

PMID- 10642830
TI  - Protection of methamphetamine nigrostriatal toxicity by dietary selenium.
AB  - Multiple dose administration of methamphetamine (MA) results in long-lasting
      toxic effects in the nigrostriatal dopaminergic system. These effects are
      considered to be primarily due to oxidative damage mediated by increased
      production of hydrogen peroxide or other reactive oxygen species in the
      dopaminergic system. The present study was designed to determine the protective
      effects of dietary antioxidant selenium on MA-induced neurotoxicity in the
      nigrostriatal dopaminergic system. Male C57BL/6J mice were fed either selenium
      deficient (< 0.01 ppm Se) or selenium-replete (0.2 ppm Se) diets for 90 days. MA
      treatment decreased the dopamine (DA) levels in the striatum and substantia nigra
      (SN) of both Se-replete and Se-deficient animals. However, in Se-replete animals,
      this DA depletion was significantly attenuated in both the striatum and SN. A
      novel observation is that MA administration resulted in increased activity of
      Cu,Zn-SOD in the brains of both Se-deficient and Se-replete animals. However, MA
      administration to Se-deficient animals exhibited a higher Cu,Zn-SOD activity in
      the nigrostriatal system than the control animals. Elevated malondialdehyde (MDA)
      levels in the striatum and SN were also observed in Se-deficient MA-treated
      animals. Se repletion significantly increased the glutathione peroxidase (GPx)
      activity and the ratio of reduced glutathione (GSH)/oxidized glutathione (GSSG)
      in the MA-treated animals. In conclusion, we have shown that dietary Se
      attenuated methamphetamine neurotoxicity and that this protection involves GPx
      mediated antioxidant mechanisms. Even though Cu,Zn-SOD activity was significantly
      elevated by MA treatment, the role of this enzyme in MA-mediated neurotoxicity is
      not yet clear.

PMID- 10642831
TI  - Neuropeptide Y induced inhibition of noradrenaline release in rat hypothalamus:
      role of receptor subtype and nitric oxide.
AB  - We aimed at characterizing the receptor subtype and the signaling pathway
      involved in the inhibitory effect of neuropeptide Y on the release of endogenous
      noradrenaline from rat hypothalamus. Slices of hypothalamus were stimulated with
      two trains of electrical pulses, and the release of noradrenaline and nitric
      oxide was measured. The electrical stimulation of hypothalamic slices induced a
      consistent release of both endogenous noradrenaline and NO. Neuropeptide Y
      inhibited concentration dependently the stimulated noradrenaline release.
      Similarly, agonists for neuropeptide Y Y1, Y2 and Y5 receptors inhibited
      noradrenaline release, albeit with a potency lower than neuropeptide Y. GW1229, a
      selective neuropeptide Y Y1 receptor antagonist counteracted the effect of
      neuropeptide Y, but not that of PYY-(3-36), an agonist active at neuropeptide Y
      Y5 and Y2 receptors. These results indicate that the inhibitory effect of
      neuropeptide Y is likely mediated by several receptor subtypes, including
      neuropeptide Y Y1, Y5 and possibly Y2 receptors. One microM NPY significantly
      enhanced NO release induced by the electrical stimulation. NG-monomethyl-L
      arginine, an inhibitor of nitric oxide synthase, abolished NO release and blocked
      the inhibitory effect of neuropeptide Y on noradrenaline release. We conclude
      that nitric oxide participates in the signaling pathway of neuropeptide Y in the
      rat hypothalamus.

PMID- 10642832
TI  - Tumor necrosis factor-a attenuates N-methyl-D-aspartate-mediated neurotoxicity in
      neonatal rat hippocampus.
AB  - Tumor necrosis factor-a TNFa. has been implicated in the pathophysiology of acute
      neonatal brain injury. We hypothesized that acute brain injury would induce TNFa
      expression and that exogenous TNFa would influence the severity of N-methyl-D
      aspartate-induced tissue damage. We performed two complementary groups of
      experiments to evaluate the potential role s. of TNFa in a neonatal rodent model
      of excitotoxic injury, elicited by intracerebral injection of N-methyl-D
      aspartate. We used immunohistochemistry and ELISA to evaluate N-methyl-D
      aspartate-induced changes in TNFa expression, and we co-injected TNFa with N
      methyl-D-aspartate, to evaluate the effect of this cytokine on the severity of
      tissue injury. Both intra-hippocampal and intra-striatal injection of N-methyl-D
      aspartate 5 nmol. stimulated TNFa expression. Increased TNFa expression was
      detected 3-12 h after lesioning; TNFa was localized both in glial cells in the
      corpus callosum, and in cells with the morphology of interneurons in the
      ipsilateral hippocampus, striatum, cortex and thalamus. Intra-hippocampal or
      intra-striatal administration of TNFa 50 ng. alone did not elicit neuropathologic
      damage. In the hippocampus, when co-injected with N-methyl-D-aspartate 5 or 10
      nmol., TNFa 50 ng. attenuated excitotoxic injury by 35%-57%, compared to controls
      co-injected with heat-treated TNFa. In contrast, in the striatum, co-injection of
      TNFa with N-methyl-D-aspartate had no effect on the severity of the ensuing
      damage. The data indicate that TNFa is rapidly produced in glial cells and
      neurons after an excitotoxic insult in the neonatal rat brain, and that
      administration of exogenous TNFa results in region-specific attenuation of
      excitotoxic damage. We speculate that endogenous TNFa may modulate the tissue
      response to excitotoxic injury in the developing brain.

PMID- 10642833
TI  - Distribution of vasoactive intestinal peptide-like immunoreactivity in the brain
      and pituitary of the frog (Rana esculenta) during development.
AB  - The localization of vasoactive intestinal peptide (VIP)-like immunoreactive (ir)
      elements was investigated in the brain of the anuran amphibian, Rana esculenta,
      during development. Using an antiserum raised against the porcine VIP, ir cell
      bodies and fibers were observed in the forebrain of tadpoles a few days after
      hatching. During early premetamorphosis, ir perikarya were distributed in the
      ventral infundibular nucleus of the hypothalamus and in the posterocentral
      nucleus of the thalamus. Labeled fibers were detected in the olfactory bulbs and
      in the hypothalamus. In these larvae, furthermore, several VIP-ir cells were
      found in the pars distalis of the pituitary and there were ir fibers in the pars
      nervosa. In tadpoles at stages VIII-IX, a new group of VIP-labeled neurons was
      observed in the dorsal part of the infundibular nucleus. In other brain regions,
      the distribution of the immunoreactivity was similar to that described in the
      earliest stages, i.e., IV-VII. During mid-premetamorphosis, stages X-XII of
      development, an additional set of ir perikarya appeared in the ventrolateral area
      of the thalamus. During late premetamorphosis, stages XIII-XVIII, the
      organization of VIP-like immunoreactivity was more complex and its distribution
      more widespread. Two new groups of ir cell bodies appeared, one in the preoptic
      nucleus and another in the anteroventral area of the thalamus, and for the first
      time, VIP immunoreactivity was observed in the median eminence. This distribution
      pattern persisted through to the prometamorphic, four-limb stage. Strikingly, no
      VIP-ir elements were observed anywhere in the mid- and hindbrain. The present
      results indicate that a VIP-like ir peptide may be involved in the processing of
      olfactory information or may act as a neurohormone, hypophysiotropic factor, and
      neuromodulator in the brain of R. esculenta during development.

PMID- 10642834
TI  - Extracellular calcium-sensing receptor induces cellular proliferation and
      activation of a nonselective cation channel in U373 human astrocytoma cells.
AB  - A receptor for extracellular calcium ions (Ca2+o), cloned from parathyroid gland,
      serves a critical function in Ca2+o homeostasis by regulating PTH release via
      "sensing" of its physiological agonist, Ca2+o. Its cloning from rat striatum
      revealed that the extracellular calcium-sensing receptor (CaR) could be involved
      in sensing ambient Ca2+o within the brain, where Ca2+ plays key roles in
      virtually all aspects of central nervous system (CNS) function. The CaR is
      expressed in neurons, oligodendrocytes, microglia and the human astrocytoma cell
      line, U87 where its functions include control of cellular proliferation and
      modulation of ion channels, such as outward K+ channels and nonselective cation
      channels (NCC). In this report, we have shown that the CaR is expressed in U373
      cells as assessed by RT-PCR using CaR-specific primers followed by sequencing of
      the amplified products, by Northern blot analysis using a CaR-specific probe as
      well as by Western analysis utilizing a specific polyclonal anti-CaR antiserum.
      Furthermore, agents known to activate the cloned CaR induce increases in cellular
      proliferation and the open probability of an NCC. Thus our study strongly
      suggests that elevated levels of Ca2+o, acting via the CaR, activate an NCC that
      could contribute to the associated CaR-induced stimulation of proliferation.

PMID- 10642835
TI  - A selective group of dopaminergic neurons express Nurr1 in the adult mouse brain.
AB  - Nurr1, an orphan receptor of the nuclear receptor superfamily, is widely
      expressed in the central nervous system (CNS) including brain regions where
      dopaminergic neurons are abundant. Recent analyses of Nurr1 null mutant mice have
      shown that Nurr1 is essential for the development and survival of midbrain
      dopaminergic neurons. However, other dopaminergic neuronal populations do not
      seem to be affected by ablation of the Nurr1 gene. The purpose of the present
      study was to investigate the degree of co-existence of Nurr1 mRNA and tyrosine
      hydroxylase (TH) immunoreactivity in the brain of adult mice to better
      characterize the selective effects of Nurr1 on catecholaminergic neurons. Our
      results indicate that the majority of TH-immunoreactive neurons in the substantia
      nigra (SN; 96%), ventral tegmental area (VTA; 95%), retrorubral field (91%),
      olfactory bulb (85%), linear nucleus raphe (91%) and central grey (61%) express
      Nurr1. In contrast, dopaminergic cells of the paraventricular and periventricular
      hypothalamic nucleus showed only a few Nurr1/TH double labeled neurons, while TH
      immunoreactive neurons in the arcuate nucleus and zona incerta did not express
      Nurr1 mRNA. Nurr1 expression was also excluded from (nor)adrenergic neurons of
      the brainstem. In conclusion, Nurr1 transcripts were not found in all CNS
      catecholaminergic neurons. Nurr1 expression was confined to periglomerular and
      midbrain dopaminergic neurons. These results suggest that within the adult mouse
      brain, Nurr1 may participate in dopaminergic functions of the olfactory bulb and
      midbrain.

PMID- 10642836
TI  - Role of nitric oxide in the cerebral circulation during hypotension after
      hemorrhage, ganglionic blockade and diazoxide in awake goats.
AB  - The role of nitric oxide in cerebrovascular response to hypotension was analyzed
      by evaluating the changes in cerebrovascular resistance after inhibition of
      nitric oxide synthesis with Nw-nitro-L-arginine methyl ester (L-NAME) during
      three types of hypotension in conscious goats. Blood flow to one brain hemisphere
      was electromagnetically measured, hypotension was induced by controlled bleeding,
      and by i.v. administration of hexametonium (ganglionic blocker) or of diazoxide
      (vasodilator drug), and L-NAME was injected by i.v. route (35 mg kg-1). Under
      control conditions (13 goats), L-NAME increased arterial pressure from 98 +/- 3
      to 123 +/- 4 mmHg and decreased cerebral blood flow from 65 +/- 3 to 40 +/- 3 ml
      min-1 (all P < 0.001); cerebrovascular resistance increased from 1.52 +/- 0.04 to
      3.09 +/- 0.013 mmHg ml-1 min-1 (P < 0.01) (delta = 1.59 +/- 0.12 mmHg ml-1 min
      1). After bleeding (five goats), mean arterial pressure decreased to 60 +/- 4
      mmHg and cerebral blood flow decreased to 37 +/- 4 ml min-1 (all P < 0.01);
      cerebrovascular resistance did not change (1.56 +/- 0.14 vs. 1.54 +/- 0.12 mmHg
      ml-1 min-1, P > 0.05). During this hypotension, L-NAME increased arterial
      pressure to reach the normotensive values an did not affect the hypotensive
      values for cerebral blood flow; cerebrovascular resistance increased from the
      hypotensive values to 2.91 +/- 0.19 mmHg ml-1 min-1 (P < 0.01) (delta = 1.37 +/-
      0.16 mmHg ml-1 min-1), and this increment is comparable to that under control
      conditions (P > 0.05). Ganglionic blockade (six goats) decreased arterial
      pressure to 67 +/- 2 mmHg) and did not affect significantly cerebral blood flow;
      cerebrovascular resistance decreased from 1.71 +/- 0.11 to 1.05 +/- 0.09 mmHg ml
      1 min-1 (P < 0.01). During this hypotension, L-NAME increased arterial pressure
      to 103 +/- 6 mmHg (P < 0.001), and did not affect cerebral blood flow;
      cerebrovascular resistance increased from the hypotensive values to 1.68 +/- 0.18
      mmHg ml-1 min-1 (P < 0.01) (delta = 0.63 +/- 0.10 mmHg ml-1 min-1), and this
      increment was lower than under control conditions (P < 0.01). Diazoxide (six
      goats) decreased arterial pressure to 69 +/- 5 mmHg (P < 0.01) without changing
      cerebral blood flow; cerebrovascular resistance decreased from 1.89 +/- 0.11 to
      1.16 +/- 0.14 mmHg ml-1 min-1 (P < 0.01). During this hypotension, L-NAME
      increased arterial pressure to 87 +/- 6 mmHg (P < 0.05) and did not affect the
      hypotensive values for cerebral blood flow (P > 0.05); cerebrovascular resistance
      increased from the hypotensive values to 1.53 +/- 0.13 mmHg ml-1 min-1 (P < 0.05)
      (delta = 0.36 +/- 0.06 mmHg-1 ml-1 min-1), and this increment was lower than
      under control conditions (P < 0.01). Therefore, the role of nitric oxide in
      cerebrovascular response to hypotension may differ in each type of hypotension,
      as this role during hemorrhagic hypotension may not change and during hypotension
      by ganglionic blockade or diazoxide may decrease. These differences may be
      related to changes in nitric oxide release as stimuli on the endothelium (shear
      stress and sympathetic activity) may vary in each type of hypotension.

PMID- 10642837
TI  - Peripheral benzodiazepine receptors in cerebral cortex, but not in internal
      organs, are increased following inescapable stress and subsequent
      avoidance/escape shuttle-box testing.
AB  - Stress-induced alterations in peripheral benzodiazepine receptor (PBR) density
      have been reported in humans and in rats. However, the PBR response is highly
      specific, and its function remains largely unexplained. The aim of the present
      study was to investigate the relationship between behavior in the two-way active
      avoidance paradigm (2WAA) and post-test PBR densities in adrenal, testis, kidney,
      and cerebral cortex. Adult male Wistar rats were tested in the 2WAA either in the
      naive state (AA) or 24 h following shock preexposure (PE), known to interfere
      with avoidance/escape response acquisition, and decapitated immediately after
      testing. Control subjects were decapitated without experimental experience. The
      stressful characteristic of the experiment was validated by significantly
      increased post-test corticosterone levels in AA and PE subjects compared with
      controls, with a trend towards higher corticosterone levels in PE relative to AA
      rats. Similarly, PE compared with AA subjects tended to show retarded acquisition
      of the escape/avoidance response. PBR densities in adrenal, kidney, and testis
      and central benzodiazepine receptors (CBR) in the cerebral cortex remained
      unaffected by avoidance testing. Cerebral cortex PBR density was significantly
      increased in PE subjects. These findings suggest that avoidance testing, although
      stressful to the animals, led to changes confined to cerebral cortex PBR,
      indicating that the hypothalamic-pituitary-adrenal (HPA) response occurs
      independently of the PBR response in peripheral organs, and also suggest that the
      opportunity for coping alters the impact of the stressor on the subject and
      prevents the expression of PBR response in peripheral organs.

PMID- 10642838
TI  - Primed-bursts induced long-term potentiation in rat visual cortex: effects of
      dark-rearing.
AB  - Theta burst stimulation (TBS) and primed bursts (PBs) stimulation are among the
      effective tetanic stimulations for induction of long-term potentiation (LTP) in
      the hippocampus. Recent studies have indicated that TBS is effective in LTP
      induction of layer III synapses of neocortex, only if applied to layer IV.
      However, the possibility of neocortical LTP induction using PBs has not been
      investigated yet. Sensory deprivation greatly influences the development of
      neocortex. According to the effect of sensory deprivation on synaptic plasticity
      of developing neocortex, we studied the induction of LTP by PBs in visual
      cortical slices of control and dark-reared rats. The results showed that
      application of PBs to layer IV could effectively induce LTP of layer II/III field
      potentials. These potentials are consisted of two components: pEPSP1, (population
      excitatory postsynaptic potential 1) and pEPSP2. In control slices PBs led to
      selective potentiation of pEPSP2. Visual deprivation increased the incidence of
      LTP of pEPSP1 and decreased the amount of LTP of pEPSP2. These findings showed
      that PBs could be used as an effective tetanic stimulation to study the synaptic
      plasticity in neocortex. The effects of visual deprivation on PBs-induced LTP are
      consistent with its role in the development of excitatory system in neocortex.

PMID- 10642839
TI  - Elevated transglutaminase-induced bonds in PHF tau in Alzheimer's disease.
AB  - Transglutaminase-induced epsilon-(gamma-glutamyl)lysine bonds covalently cross
      link and polymerize peptides into insoluble high molecular weight protein
      aggregates resistant to degradation and proteolytic digestion. We investigated
      the hypothesis that excessive deposition of epsilon-(gamma-glutamyl)lysine bonds
      is a neuropathological mechanism which induces the polymerization of tau protein
      into stable aggregates leading to the formation of paired helical filaments
      (PHFs) which deposit into neurofibrillary tangles in Alzheimer's disease (AD)
      brain. We demonstrate a significant (45%) elevation in epsilon-(gamma
      glutamyl)lysine cross-links in AD cortex as compared to control cortex. In vivo,
      PHF tau, and high and medium molecular weight neurofilament proteins have
      significantly greater cross-linking by epsilon-(gamma-glutamyl)lysine bonds in AD
      brains as compared to controls. The cross-linking of PHF tau occurs both intra
      molecularly and inter-molecularly. The inter-molecular cross-linking of tau could
      account for the formation of high molecular weight tau polymers. These results
      suggest that transglutaminase-induced cross-linking of tau protein could play a
      role in the formation and stabilization of neurofibrillary tangles. Inhibition of
      transglutaminase-induced cross-linking may therefore, provide a novel strategy
      for the treatment of AD.

PMID- 10642840
TI  - Responses of neurons in the lateral thalamus of the cat to stimulation of urinary
      bladder, colon, esophagus, and skin.
AB  - In seven female alpha-chloralose-anesthetized cats, 52 lateral thalamic neurons
      were tested with noxious distension of the urinary bladder, the distal colon and
      the lower esophagus. In addition, the neurons were characterized with innocuous
      and noxious mechanical stimulation of the skin and deep structures. Of the 52
      neurons tested, 32 (62%) were visceroceptive. Of these visceroceptive neurons, 20
      (63%) were located in the periphery of the ventral posterolateral nucleus (VPLp),
      10 (31%) in the adjacent posterior complex (PO), and two (6%) in the
      ventrolateral nucleus (VL). No differences were found with respect to location
      between neurons responsive or unresponsive to visceral stimulation. Ten neurons
      (31%) received input from more than one viscus and, therefore, showed
      viscerovisceral convergence. Excitatory or "inhibitory" responses were elicited
      by stimulation of the esophagus in 21 neurons, of the colon in 13, and of the
      urinary bladder in 11 neurons. No indications were found for a segregation of
      neurons responsive to a certain viscus and their location in VPLp or PO. Of 51
      neurons, for which a somatic receptive field was determined, 44 (86%) exhibited
      low threshold type (LT), and seven (14%) wide dynamic range type (WDR) responses.
      The data indicate that there might exist a somatovisceral coregistration, because
      many neurons (69%) had homosegmental receptive fields, and bladder stimulation
      was the most successful stimulus. It is concluded that VPLp and the adjacent PO
      in the cat play a role in the perception and localization of painful events
      originating from thoracic and pelvic organs.

PMID- 10642841
TI  - Prenatal cocaine produces signs of neurodegeneration in the lateral habenula.
AB  - The lateral habenula is a nucleus in the dorsal thalamus that innervates midbrain
      dopaminergic and serotonergic nuclei via projections through its major efferent
      pathway, the fasciculus retroflexus (FR). It was previously demonstrated that
      cocaine administered continuously to adult rats over several days produces
      neurodegeneration in the lateral habenula and FR. Because exposure to cocaine
      during pregnancy reportedly can cause neurobehavioral deficits, we examined
      whether rat fetuses exposed to continuous cocaine during the last week of
      gestation would similarly demonstrate selective neurodegeneration in the lateral
      habenula. On day 17 of gestation, dams were implanted with two silicone pellets,
      each containing either vehicle or one of 2 doses of cocaine (80 mg or 55 mg per
      pellet). Degenerating neurons containing silver deposits were counted in lateral
      habenula and in the striatum. Cocaine-exposed pups had significantly more silver
      stained cells in the lateral habenula than vehicle-treated pups, but similar
      numbers of silver-stained cells were present in the striatum of all three groups.
      When similarly treated vehicle- and cocaine-exposed animals were tested
      behaviorally at 60 days of age, they did not differ on measures of open field
      activity, open arm avoidance on the elevated plus-maze or conditioned place
      preference for cocaine, although a linear trend analysis indicated some
      hyperactivity of the cocaine-pretreated pups during the place preference test.
      These results indicate that continuous cocaine exposure has selective neurotoxic
      effects on the habenula of the developing fetus similar to cocaine's effects in
      the adult.

PMID- 10642842
TI  - [3H]tiagabine binding to GABA uptake sites in human brain.
AB  - The binding of [3H]tiagabine ((RS-1-(4,4-(3-methyl-2-thienyl)-3-butenyl)-3
      piperidine carboxylic acid) to homogenates of frozen post-mortem human brain has
      been characterized. Inhibition experiments with gamma-aminobutyric acid (GABA),
      GABA uptake inhibitors, ligands active at postsynaptic GABA receptors and
      receptors for other neurotransmitters, suggest that [3H]tiagabine binds with high
      affinity to GABA uptake sites. Inhibition and kinetic experiments suggests that
      70%-80% of the binding is to a high affinity site. Saturation experiments showed
      that the binding was saturable. Bmax was 3.4 pmol/mg protein and Kd 16 nM in
      frontal cortex. The dissociation constants (Kd) measured in kinetic and
      equilibrium experiments were in the same range (16-56 nM). The regional
      distribution was studied in nine brain regions and the binding was heterogenous,
      with the highest binding in frontal cortex and parietal cortex and the lowest
      binding in nucleus caudatus and putamen. This is, to our knowledge, the first
      study on [3H]tiagabine binding in human tissue. It is concluded that
      [3H]tiagabine binding can be used as a specific marker for the GABA transporter
      GAT-1 in homogenates of human brain.

PMID- 10642843
TI  - Low external NaCl concentration and low osmolarity enhance voltage-gated Ca
      currents but depress K currents in freshly isolated rat hippocampal neurons.
AB  - In previous experiments, reducing bath osmolarity (pi o) or external NaCl
      concentration ([NaCl]o) caused an increase in synaptic currents recorded in whole
      cell configuration from pyramidal cells of CA1 region of hippocampal slices. Slow
      inward current surges, assumed to be calcium currents, were also enhanced. This
      contrasted with the strong, reversible, generalized depression of voltage
      dependent ion currents in isolated neurons, caused by sudden, brief exposure to
      very low pi o. I have now recorded voltage-dependent whole-cell Na-, K- and Ca
      currents from freshly isolated hippocampal CA1 pyramidal neurons during more
      gradual lowering of pi o or [NaCl]o. Changes in cell size were determined from
      image areas and changes in intracellular Ca2+ activity were measured as the ratio
      of the fluorescences of fluo-3/fura-red by confocal microscopy. Iso-osmotic
      substitution of 40 or 60 mM NaCl by mannitol or sucrose for 5-7 min, or reducing
      pi o by deleting NaCl from the bath (osmolarity decreased by 69 or 108 mosM/kg)
      depressed K currents. Na currents were also strongly depressed, but this is in
      part attributable to reduced driving potential and ionic conductance. The
      depression of IK varied widely and it was inversely correlated with the degree of
      hypotonic swelling, suggesting that reduced ion channel conductance also reduces
      permeability to water. Reducing [NaCl]o by 60 mM, or pi o by 105 mosM/kg
      consistently and reversibly increased Ca currents. Intracellular Ca2+ level also
      increased, but the changes of [Ca2+]i and ICa were not correlated. Facilitation
      of the Ca influx into presynaptic terminals could explain the increase of
      synaptic currents. Depression of outward currents could also contribute to the
      irritability of the central nervous system typical of clinical hyponatremia.

PMID- 10642844
TI  - Resistance to diet-induced obesity is associated with increased
      proopiomelanocortin mRNA and decreased neuropeptide Y mRNA in the hypothalamus.
AB  - Mechanisms mediating genetic susceptibility to diet-induced obesity have not been
      completely elucidated. Elevated hypothalamic neuropeptide Y (NPY) and decreased
      hypothalamic proopiomelanocortin (POMC) are thought to promote the development
      and maintenance of obesity. To assess the potential role of hypothalamic
      neuropeptide gene expression in diet-induced obesity, the present study examined
      effects of a high-fat diet on hypothalamic NPY and POMC mRNA in three strains of
      mice that differ in susceptibility to develop diet-induced obesity. C57BL/6J,
      CBA, and A/J mice were fed either normal rodent chow or a high-fat diet for 14
      weeks after which hypothalamic gene expression was measured. On the high-fat
      diet, C57BL/6J mice gained the most weight, whereas A/J mice gained the least
      weight. On the high-fat diet, NPY mRNA significantly decreased as body weight
      increased in CBA and A/J mice, but not in C57BL/6J mice. In addition, POMC mRNA
      significantly increased as body weight increased in A/J mice, but not in CBA and
      C57BL/6J mice. Since decreased NPY mRNA and increased POMC mRNA would presumably
      attenuate weight gain, these results suggest that a high-fat diet produces
      compensatory changes in hypothalamic gene expression in mice resistant to diet
      induced obesity but not in mice susceptible to diet-induced obesity.

PMID- 10642845
TI  - Effects of mineralocorticoid and glucocorticoid receptors on long-term
      potentiation in the CA3 hippocampal field.
AB  - We have previously shown that the two types of adrenal steroid receptors,
      mineralocorticoid MR. and glucocorticoid GR. produce opposite effects on long
      term potentiation LTP. in the dentate gyrus in vivo. and CA1 hippocampal field in
      vitro. More specifically, MR activation enhanced and prolonged LTP, whereas GR
      activation suppressed LTP in these areas and also produced a long-term depression
      LTD. of the synaptic response. In the present experiment we investigated acute
      effects of MR and GR activation on LTP induction in the mossy fiber and
      commissural associational input to the CA3 hippocampal field, since the
      mechanisms underlying LTP induction in these two pathways differ, the former
      being N-methyl-D-aspartate receptor NMDAR. independent while the latter being
      NMDAR-dependent. Rats were either adrenalectomized ADX or adrenally intact. ADX
      animals were acutely injected with either the specific MR agonist, aldosterone,
      the specific GR agonist RU 28362 or vehicle. One hour following the injection,
      the animals were prepared for electrophysiological recording stimulation. Field
      potential recordings were performed in the radiatum or laconosum moleculare
      layers of the CA3 field, with stimulation of either the mossy fibers or the
      commissural associational input from the contralateral hemisphere. We also
      replicated our previous findings by recording in the dentate gyrus with
      stimulation of the medial perforant pathway, in the same animals. As observed in
      our previous study in the dentate gyrus, we found an enhancement and a
      suppression of LTP with MR and GR activation, respectively. Similarly, for the
      commissural associational input to CA3, MR activation enhanced LTP, while GR
      activation reduced it. In contrast, for the mossy fiber input to CA3, neither MR
      nor GR activation significantly affected LTP induction. These results indicate
      that adrenal steroids may modulate LTP induction in the hippocampus via an
      interaction with glutamatergic NMDAR.

PMID- 10642846
TI  - Brain endothelial cell production of a neuroprotective cytokine, interleukin-6,
      in response to noxious stimuli.
AB  - Brain endothelial cells (BECs), specialized cells of the blood-brain barrier
      (BBB), are ideally positioned to monitor and respond to events in the periphery.
      The present study examined their potential role in transducing immune signals to
      the brain and in responding to noxious stimuli. BECs were isolated from rhesus
      monkeys at 3 age points (fetal/neonatal, adult, and very old animals). Cells were
      then challenged in vitro with either an immune stimulus (interleukin-1 beta (IL-1
      beta), or lipopolysaccharide (LPS)) or an oxidative challenge (hypoxia). BECs
      released interleukin-6 (IL-6), which is known to have neurotrophic and
      neuroprotective functions. Furthermore, higher amounts of IL-6 were released in
      both baseline and stimulated conditions by BECs derived from aged animals. This
      research indicates a pathway whereby immune signals may be communicated to the
      CNS and has revealed one way that the BBB may protect neuronal survival under
      challenge conditions.

PMID- 10642847
TI  - Glial cell line derived neurotrophic factor promotes the recovery of dopamine
      neurons damaged by 6-hydroxydopamine in vitro.
AB  - Glial cell line derived neurotrophic factor (GDNF) has been shown to be a potent
      neurotrophic factor for dopamine neurons in culture and to prevent the loss of
      substantia nigra dopamine neurons following in vivo lesions with 6
      hydroxydopamine (6-OHDA). In this study we used mesencephalic cultures containing
      both neurons and glia to examine whether GDNF protects dopamine neurons from 6
      OHDA toxicity in vitro. Our data show that GDNF does not prevent the loss of
      dopamine neurons caused by treatment with 6-OHDA in vitro. However, continuous
      exposure to GDNF increases the high affinity dopamine uptake in cultures treated
      with 6-OHDA, suggesting that it enhances the growth of damaged dopamine neurons.
      We also show that in vitro treatment with 6-OHDA causes widespread cell death in
      mesencephalic cultures, which is not restricted to dopamine neurons. The lack of
      selectivity of 6-OHDA toxicity when applied in vitro may explain the inability of
      GDNF to prevent the loss of dopamine neurons in mesencephalic cultures. The
      stimulation of the growth of 6-OHDA damaged dopamine neurons by GDNF, observed in
      our study, suggests that it may prove beneficial in the treatment of injured
      dopamine neurons.

PMID- 10642848
TI  - Adenosine modulates synaptic plasticity in hippocampal slices from aged rats.
AB  - Adenosine is known to modulate synaptic plasticity in the hippocampus of young
      animals through activation of adenosine A1 receptors. The objective of the
      present study is to investigate whether the modulatory role of adenosine on
      phenomena of synaptic plasticity is maintained or modified in the hippocampus of
      aged animals. We compared the effects of the selective adenosine A1 receptor
      antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, 50 nM), on paired-pulse
      facilitation (PPF), long-term depression (LTD), long-term potentiation (LTP) and
      depotentiation elicited in hippocampal slices taken from young adult (5-6 weeks)
      and old (2 years old) male Wistar rats. DPCPX attenuated PPF both in young (1.64
      +/- 0.05 vs. 1.76 +/- 0.05%, n = 6) and in old rats (1.33 +/- 0.05 vs. 1.55 +/-
      0.1%, n = 6). LTD was only observed in the presence of DPCPX in both young (21.3
      +/- 0.6%, n = 4) and old rats (14.4 +/- 0.9%, n = 6). LTP induced by high
      frequency stimulation (HFS) was not significantly different in young and old
      animals, in the presence or in the absence of DPCPX. A larger depotentiation was
      observed in the presence of DPCPX in young rats (27.6 +/- 4.4% vs. 16.8 +/- 4.7%,
      n = 7) as well as in old rats (41.3 +/- 5.1% vs. 16.1 +/- 2.7%, n = 6). LTP
      induced by theta-burst stimulation was observed only in the presence of DPCPX
      (53.9 +/- 4.9%, n = 5) in young rats, but could be obtained either in the control
      solution (81.8 +/- 17.9%, n = 7) or in the presence of DPCPX (98.5 +/- 24.2%, n =
      7) in old rats. The modulatory role of endogenous adenosine on synaptic
      plasticity is generally maintained in aged animals. Drugs interfering with
      adenosine A1 receptor effects could then be used in old animals to modify
      synaptic plasticity with relevant behavioural consequences.

PMID- 10642850
TI  - D-fenfluramine activates rat oxytocinergic and vasopressinergic neurons through
      different mechanisms.
AB  - Activation of serotonin neurotransmission produces increase of plasma oxytocin,
      prolactin, vasopressin and ACTH levels. Using dual-immunocytochemistry, the
      number of oxytocinergic neurons in the hypothalamic magnocellular nuclei co
      storing Fos after administration of D-fenfluramine was found to be 15-fold higher
      compared to vehicle, comprising about 30% of the total number of these neurons.
      Vasopressinergic neurons were virtually not affected. These results show that
      serotonergic neurotransmission induces Fos transcription in oxytocinergic neurons
      that may lead to a release of oxytocin to the general circulation, whereas
      vasopressinergic neurons are activated through another mechanism.

PMID- 10642849
TI  - Progressive degeneration of dopamine system functions after transient cerebral
      oligemia in rats.
AB  - A reduction in cerebral blood flow to oligemic levels was achieved in
      pentobarbital-anesthetized adult rats by clamping both carotid arteries (BCCA)
      for 60 min. To assess the extent to which the animals' dopaminergic system was
      affected over an increasing time span, their spontaneous locomotor activity in an
      unfamiliar environment and in response to the subcutaneous administration of
      apomorphine was tested at various times after either BCCA or sham operation.
      Eight to 14 days after the operation, it was possible to observe a diminished
      locomotor activity in response to apomorphine injection in BCCA as compared with
      sham-operated animals, while oral stereotypical behavior such as licking was
      increased. At 3 months, there was only a subtle decrease in apomorphine-induced
      locomotor activity, and stereotypical behavior was similar in both groups. At 7
      months, the BCCA rats covered shorter distances than sham-operated controls
      during the habituation phase; after apomorphine injection, more stereotypic
      movements, such as, e.g., sniffing, were observed, and less running. Twelve
      months after surgery, no further differences could be observed between the two
      groups during the habituation phase, but the injection of apomorphine led to
      increased stereotypic sniffing movements, rearing and locomotor activity in BCCA
      animals to a greater extent than in the controls. At 12 months, sensorimotor
      disturbances elicited by the rota rod test, which were only transiently observed
      at 11 weeks and 7 months, did not appear any different from the normal age
      related motor decline of the sham-operated controls. The animals' motor co
      ordination in the chimney test was not significantly disturbed during the time
      between 7 and 12 months after surgery. At 15 months, nocturnal locomotor
      activities in BCCA rats were significantly decreased. In situ hybridization (ISH)
      histochemistry revealed decreased D1 receptor mRNA (D1RmRNA) in striatal neurons
      19 months after surgery, while D2 receptor mRNA (D2RmRNA) and the neuronal number
      remained the same. The present results show that just as is already known for the
      immature rat brain, the adult rat brain, too, reacts to a transient decrease in
      its blood supply by appearance of long-lasting alterations in function, and that
      even a single oligemic episode is capable of inducing progressive dopaminergic
      dysfunctions and ultimately the partial loss of striatal D1RmRNA.

PMID- 10642851
TI  - Electrical stimulation of the medial frontal lobe elicits a pattern of body
      movements in sheep.
AB  - Acute experiments were conducted in sheep anaesthetized with sodium pentobarbital
      to identify regions in the brain where electrical stimulation would elicit
      movements of body parts. Stimulating the dorsal frontal cortex 2 mm from midline
      from the front of the brain backward for 30 mm caused movements, in order, of the
      lower jaw, face in general, neck, shoulder and front and back legs.

PMID- 10642852
TI  - Methamphetamine administration causes overexpression of nNOS in the mouse
      striatum.
AB  - The accumulated evidence suggests that the overproduction of nitric oxide (NO) is
      involved in methamphetamine (METH)-induced neurotoxicity. Using NADPH-diaphorase
      histochemistry, neuronal nitric oxide synthase (nNOS) and inducible nitric oxide
      synthase (iNOS) antibody immunohistochemistry, the possible overexpression of
      nNOS and iNOS was investigated in the brains of mice treated with METH. The
      number of positive cells or the density of positive fibers was assessed at 1 h,
      24 h and 1 week after METH injections. There were no clear positive iNOS cells
      and fibers demonstrated in the brains of mice after METH treatment. In contrast,
      METH caused marked increases in nNOS in the striatum and hippocampus at 1 and 24
      h post-treatment. The nNOS expression normalized by 1 week. There were no
      statistical changes in nNOS expression in the frontal cortex, the cerebellar
      cortex, nor in the substantia nigra. These results provide further support for
      the idea that NO is involved in the neurotoxic effects of METH.

PMID- 10642853
TI  - A role of glucocorticoid receptors in the guinea pig vestibular system.
AB  - To investigate glucocorticoid receptor (GR) function in the vestibular periphery,
      GR antagonist RU38486 was administered to the guinea pig inner ear by osmotic
      pump, and we observed post-rotatory nystagmus (PRN) changes as a marker of
      vestibular function. Ten days after treatment, RU38486 (1 mM) resulted in
      ipsilateral vestibule hyperexcitability in response to rotation stimulation. This
      effect was dose-dependent. These data indicate that steroid hormones may play an
      important role in maintaining vestibular function.

PMID- 10642854
TI  - Differential subcellular distribution of neurolysin (EC 3.4.24.16) and thimet
      oligopeptidase (EC 3.4.24.15) in the rat brain.
AB  - Immunohistochemistry was used to analyze the rat brain distribution of thimet
      oligopeptidase and neurolysin. Both enzymes appear ubiquitously distributed
      within the entire rat brain. However, neuronal perikarya and processes stained
      for neurolysin, while intense nuclear labeling was only observed for thimet
      oligopeptidase. These data suggest that neurolysin and thimet oligopeptidase,
      endopeptidases sharing several functional and structural similarities, are
      present in distinctive intracellular compartments in neuronal cells.

PMID- 10642855
TI  - Glutamic acid decarboxylase mRNA in the suprachiasmatic nucleus of rats housed in
      constant darkness.
AB  - This study demonstrates that the levels of the mRNAs encoding the two isoforms of
      glutamic acid decarboxylase (GAD) (i.e., GAD65 and GAD67) do not differ over the
      circadian activity cycle in the suprachiasmatic nucleus (SCN) of rats housed in
      constant darkness. These data indicate that the rhythmic expression of GAD56 mRNA
      previously observed in animals housed in a light:dark cycle [K.L. Huhman, A.C.
      Hennessey, H.E. Albers, Rhythms of glutamic acid decarboxylase mRNA in the
      suprachiasmatic nucleus, J. Biol. Rhythms 11 (1996) 311-316.] is the result of
      the activity of retinal afferents.

PMID- 10642856
TI  - Subcellular immunolocalization of NMDA receptor subunit NR-1 in the chinchilla
      vestibular periphery.
AB  - The immunohistochemical localization of N-methyl-D-aspartate (NMDA) glutamate
      receptor subunit, NR-1 was investigated in the chinchilla cristae ampullaris and
      utricular maculae at the light and electron microscopy level with the use of
      specific antipeptide antibodies. The afferent calyces that innervate type I hair
      cell, and the basolateral type I vestibular hair cell is NR-1 immunoreactive. The
      afferent boutons innervating type II hair cells and the basal portion of type II
      hair cell are NR-1 non-immunoreactive. These findings are consistent with NMDA
      receptor mediation of afferent excitatory neurotransmission from type I, but not
      type II hair cells to the primary afferent vestibular nerve. The NMDA receptors
      on the type I hair cell are located in areas of synaptic specialization, and may
      play a role in autoregulation. The localization of the NMDA receptor subunit in
      type I but not type II hair cells is intriguing.

PMID- 10642858
TI  - C-fos expression in the spinal cord of rats exhibiting allodynia following
      contusive spinal cord injury.
AB  - Contusive spinal cord injury (SCI) may result in central neuropathic pain marked
      by allodynia-like features in the dermatomes close to the level of injury. The
      aim of this study was to compare the laminar distribution of activated neurons
      (as determined by c-fos immediate early gene expression) in the spinal cord
      immediately above the level of a SCI in rats with or without allodynia-like
      features. Non-noxious mechanical stimulation was applied to half the animals in
      the dermatomes corresponding to the level of injury prior to perfusion.
      Stimulation resulted in a significant increase in c-fos labelling in all laminae
      of the spinal dorsal horn in the segment immediately above the level of injury
      only in allodynia animals. Animals that had allodynia also demonstrated a
      significant increase in the level of c-fos labelling in lamina III, IV and V of
      the dorsal horn without stimulation. Thus, allodynia following SCI is associated
      with significant increases in basal and evoked c-fos expression ("neuronal
      activity") in response to non-noxious mechanical stimulation. The data also
      suggest that allodynia-like behaviour following SCI cannot be accounted for
      solely by changes occurring at a spinal level.

PMID- 10642857
TI  - Amitriptyline increases GABA-stimulated 36Cl- influx by recombinant (alpha 1
      gamma 2) GABAA receptors.
AB  - WSS-1 cells expressing (alpha 1 gamma 2)GABAA receptors show an augmented 36Cl-
      response to GABA in the presence of amitriptyline that is increased by
      flumazenil, unlike augmentation by diazepam which is blocked by flumazenil. This
      amitriptyline effect is opposite to the inhibition of GABA-stimulated 36Cl influx
      manifested in membrane vesicles prepared from drug-naive rats or submissive rats
      (a model of depression) but is similar to that seen in tissue from amitriptyline
      treated rats or dominant rats. The results suggest a novel mechanism of
      antidepressant drug action having a delayed onset.

PMID- 10642859
TI  - Saffron extract prevents acetaldehyde-induced inhibition of long-term
      potentiation in the rat dentate gyrus in vivo.
AB  - We have previously found that alcohol extract of Crocus sativus L. (CSE),
      commonly known as saffron, prevents ethanol-induced inhibition of hippocampal
      long-term potentiation (LTP). In the present study, CSE (250 mg/kg, p.o.) was
      also effective in preventing acetaldehyde-induced inhibition of LTP in the
      dentate gyrus of anesthetized rats. These results suggest that CSE can prevent
      aversive effects induced by ethanol and its metabolite acetaldehyde.

PMID- 10642860
TI  - Suppression of morphine withdrawal by electroacupuncture in rats: dynorphin and
      kappa-opioid receptor implicated.
AB  - Our previous work has demonstrated that 100-Hz electroacupuncture (EA) or 100-Hz
      transcutaneous electrical nerve stimulation (TENS) was very effective in
      ameliorating the morphine withdrawal syndrome in rats and humans. The mechanism
      was obscure. (1) Rats were made dependent on morphine by repeated morphine
      injections (5-140 mg/kg, s.c., twice a day) for eight days. They were then given
      100-Hz EA for 30 min 24 h after the last injection of morphine. A marked increase
      in tail flick latency (TFL) was observed. This effect of 100-Hz EA could be
      blocked by naloxone (NX) at 20 mg/kg, but not at 1 mg/kg, suggesting that 100-Hz
      EA-induced analgesia observed in morphine-dependent rats is mediated by kappa
      opioid receptors. (2) A significant decrease of the concentration of dynorphin A
      (1-17) immunoreactivity (-ir) was observed in the spinal perfusate in morphine
      dependent rats, that could be brought back to normal level by 100-Hz EA. (3) 100
      Hz EA was very effective in suppressing NX-precipitated morphine withdrawal
      syndrome. This effect of EA could be prevented by intrathecal administration of
      nor-BNI (2.5 micrograms/20 microliters), a kappa-opioid receptor antagonist, or
      dynorphin A (1-13) antibodies (25 micrograms/20 microliters) administered 10 min
      prior to EA. In conclusion, while the steady-state spinal dynorphin release is
      low in morphine-dependent rats, it can be activated by 100-Hz EA stimulation,
      which may be responsible for eliciting an analgesic effect and ameliorating
      morphine withdrawal syndrome, most probably via interacting with kappa-opioid
      receptor at spinal level.

PMID- 10642861
TI  - The planning and implementation of the Canadian Joint Replacement Registry.

PMID- 10642862
TI  - The Swedish Knee Arthroplasty Register. 25 years experience.

PMID- 10642863
TI  - The Norwegian Joint Registry.
AB  - The Norwegian Orthopaedic Association established The Norwegian Arthroplasty
      Register in 1987, first as a hip prosthesis register, but from January 1994 it
      was extended to include all artificial joints. The main aim has been to survey
      the results of joint replacement surgery. The orthopaedic surgeons in all
      hospitals in the country of Norway have agreed to participate. More than 60,000
      total hip replacements have been registered so far. Both primary operations and
      revisions are reported, and by using the patients' national identification
      numbers, we can link the revisions to the primary operation and perform survival
      analysis of the implants, with adjustment for potential confounding by factors
      such as age, gender, and diagnosis. As the prosthesis components are registered
      on an individual basis, survival of components such as the cup or the stem can be
      calculated separately, with revision used as an end-point. The reason for
      revision is registered, and we can assess the rate of revision due to aseptic
      loosening of the stem or cup, infection, dislocation, wear, osteolysis, or other
      reasons. For the safety of the surgeons, and to obtain a complete reporting of
      failures, we do not register the name of the surgeons and we keep the individual
      hospitals' results confidential. The operating costs of register are covered by
      the state and the register is not dependent on grants from the industry. The cost
      per registered implant is approximately $18 (US). With this system we have been
      able to detect inferior results of implants as early as after three years of use.
      Several brands of uncemented prostheses and two brands of cement have been
      withdrawn from the market mainly based on our findings.

PMID- 10642864
TI  - Development of the New Zealand Joint Register.
AB  - In 1997, to mark 30 years of joint arthroplasty in New Zealand, the New Zealand
      Orthopaedic Association agreed to establish a national hip and knee register, to
      be based in the Department of Orthopaedic Surgery at Christchurch Hospital. This
      paper details the steps in the development of the Register, the problems
      encountered and their solutions, and the trial process involved before the
      national implementation of the data collection process in 42 hospitals throughout
      New Zealand in April of 1999. The whole process took seventeen months and the
      special features are the enthusiastic and voluntary involvement of nursing staff
      and the inclusion of patient generated outcomes data. However, it will be at
      least five years before there is sufficient data for any meaningful analysis.

PMID- 10642865
TI  - Clinical outcomes in orthopaedic surgery. The collaborative efforts of
      orthopaedic surgeons with industry.

PMID- 10642866
TI  - Veterinary homeopathy--a rebuttal.

PMID- 10642867
TI  - An ethicist's commentary on the case of a proposed farm tour while cattle are
      infected with Salmonella.

PMID- 10642868
TI  - Facing the demographic challenge.

PMID- 10642869
TI  - Revaccination guidelines revisited.

PMID- 10642870
TI  - The impact of the human/companion animal/veterinarian bond on the future of the
      veterinary profession.

PMID- 10642871
TI  - Bovine respiratory disease: commercial vaccines currently available in Canada.
AB  - Bovine respiratory disease (BRD) remains a significant cost to both the beef and
      dairy industries. In the United States, an estimated 640 million dollars is lost
      annually due to BRD. Losses are largely a result of pneumonic pasteurellosis
      ("shipping fever"), enzootic pneumonia of calves, and atypical interstitial
      pneumonia. In Canada, over 80% of the biologics licensed for use in cattle are
      against agents associated with BRD. The objectives of this paper were (a) to
      summarize information available concerning commercial vaccines currently used in
      Canada for protection against BRD, and (b) to provide an easily accessible
      resource for veterinary practitioners and researchers. Information from the most
      recent Compendium of Veterinary Products has been tabulated for each vaccine by
      trade name, according to vaccine type, and the pathogens against which they are
      designed to protect. Additional information from published articles (peer
      reviewed and other) has been provided and referenced.

PMID- 10642872
TI  - Anesthesia of wood bison with medetomidine-zolazepam/tiletamine and xylazine
      zolazepam/tiletamine combinations.
AB  - This study was designed to evaluate 2 combinations for immobilization of bison.
      Seven wood bison received 1.5 mg/kg body weight (BW) of xylazine HCl + 1.5 mg/kg
      BW of zolazepam HCl and 1.5 mg/kg BW of tiletamine HCl on one occasion. The bison
      received 60 micrograms/kg BW of medetomidine HCl + 0.6 mg/kg BW of zolazepam HCl
      and 0.6 mg/kg BW of tiletamine HCL on another occasion. Xylazine was antagonized
      with 3 mg/kg BW of tolazoline HCl and medetomidine HCl was antagonized with 180
      micrograms/kg (BW) of atipamezole HCl. Temporal characteristics of immobilization
      and physiological effects (acid-base status, thermoregulatory, cardiovascular,
      and respiratory effects) of the drug combinations were compared. Induction was
      significantly faster with xylazine HCl-zolazepam HCl/tiletamine HCl. Recovery
      following antagonist administration was significantly faster with medetomidine
      HCl-zolazepam HCl/tiletamine HCl. The average drug volumes required were 7.00 mL
      of xylazine HCl-zolazepam HCl/tiletamine HCL and 2.78 mL of medetomidine HCl
      zolazepam HCl/tiletamine HCl. Hypoxemia, hypercarbia, and rumenal tympany were
      the major adverse effects with both drug combinations.

PMID- 10642873
TI  - Salmonellosis in songbirds in the Canadian Atlantic provinces during winter
      summer 1997-98.
AB  - From winter 1997 to summer 1998, an epizootic of salmonellosis affected several
      species of songbirds over a large area of the eastern North American continent.
      This article describes the details of this epizootic in the Canadian Atlantic
      provinces, based on laboratory examination of dead affected birds and on
      suspected but unconfirmed cases of salmonellosis reported by members of the
      public. The common redpoll (Carduelis flammea) was the species most often
      affected, followed by pine siskins (C. pinus), purple finches (Carpodacus
      purpureus), evening grosbeaks (Coccothraustes vespertinus), and American
      goldfinches (Carduelis tristis). A poor body condition and necrotizing and
      fibrinopurulent esophagitis and ingluvitis were the most common gross lesions in
      these birds. Thirty-four of 35 isolates of Salmonella recovered from these birds
      were identified as phage type 40. Despite the magnitude of this and previous
      epizootics of salmonellosis among North American songbirds, the sources of these
      epizootics and the precise influence of environmental factors on their occurrence
      remain poorly understood.

PMID- 10642874
TI  - Emphysematous cholecystitis in a Siberian husky.
AB  - A 6-year-old, intact male Siberian husky was evaluated for a 24-hour history of
      vomiting and lethargy. Diagnosis of emphysematous cholecystitis was achieved
      based on survey abdominal radiographs, a barium contrast gastrointestinal series,
      and abdominal ultrasound. Diagnosis and medical and surgical management of the
      condition are discussed.

PMID- 10642875
TI  - Primary sarcoma of the ribs in a large, mixed breed dog.
AB  - A 9-year-old, 30-kg, neutered male, mixed breed dog was referred for en bloc
      resection of a tentatively diagnosed costal chondrosarcoma. Light microscopic
      examination of the excised mass confirmed osteosarcoma. Adjuvant chemotherapy
      with 4 treatments with carboplatin was initiated. There have been no signs of
      metastases 5 months postsurgery.

PMID- 10642876
TI  - Multiple protein sequence alignment using double-dynamic programming.
AB  - A method of multiple sequence alignment is described based on the double dynamic
      programming (DDP) algorithm previously used for treating structural constraints
      encountered in structure comparison and threading. Following these applications,
      the inconsistencies that emerge when trying to combine pair-wise alignments into
      a multiple alignment are reconciled by summing all the, possibly inconsistent,
      paths (low-level alignments) into a matrix which is then used to provide a final
      (high-level) alignment. This process is applied to all sequence pairs and the
      pair-wise results combined in a simple multiple sequence alignment program. From
      this alignment, further constraints are selected to bias the low-level alignments
      in the DDP algorithm and the process iterated. The results, however, showed that
      this overall iteration was not needed and one-pass gave results at least as good
      as the 'standard' progressive method of multiple sequence alignment. Further
      applications of the method are discussed.

PMID- 10642877
TI  - Estimating local backbone structural deviation in homology models.
AB  - After the atomic coordinates themselves, the most important data in a homology
      model are the spatial reliability estimates associated with each of the atoms
      (atom annotation). Recent blind homology modeling predictions have demonstrated
      that principally correct sequence-structure alignments are achievable to sequence
      identities as low as 25% [Martin, A.C., MacArthur, M.W., Thornton, J.M., 1997.
      Assessment of comparative modeling in CASP2. Proteins Suppl(1), 14-28]. The
      locations and extent of spatial deviations in the backbone between correctly
      aligned homologous protein structures remained very poorly estimated however, and
      these errors were the cause of errant loop predictions [Abagyan, R., Batalov, S.,
      Cardozo, T., Totrov, M., Webber, J., Zhou, Y., 1997. Homology modeling with
      internal coordinate mechanics: deformation zone mapping and improvements of
      models via conformational search. Proteins Suppl(1), 29-37]. In order to derive
      accurate measures for local backbone deviations, we made a systematic study of
      static local backbone deviations between homologous pairs of protein structures.
      We found that 'through space' proximity to gaps and chain termini, local three
      dimensional 'density', three-dimensional environment conservation, and B-factor
      of the template contribute to local deviations in the backbone in addition to
      local sequence identity. Based on these finding, we have identified the
      meaningful ranges of values within which each of these parameters correlates with
      static local backbone deviation and produced a combined scoring function to
      greatly improve the estimation of local backbone deviations. The optimized
      function has more than twice the accuracy of local sequence identity or B-factor
      alone and was validated in a recent blind structure prediction experiment. This
      method may be used to evaluate the utility of a preliminary homology model for a
      particular biological investigation (e.g. drug design) or to provide an improved
      starting point for molecular mechanics loop prediction methods.

PMID- 10642878
TI  - A theory of information with special application to search problems.
AB  - Classical information theory concerns itself with communication through a noisy
      channel and how much one can infer about the channel input from a knowledge of
      the channel output. Because the channel is noisy the input and output are only
      related statistically and the rate of information transmission is a statistical
      concept with little meaning for the individual symbol used in transmission. Here
      we develop a more intuitive notion of information that is concerned with asking
      the right questions--that is, with finding those questions whose answer conveys
      the most information. We call this confirmatory information. In the first part of
      the paper we develop the general theory, show how it relates to classical
      information theory, and how in the special case of search problems it allows us
      to quantify the efficacy of information transmission regarding individual events.
      That is, confirmatory information measures how well a search for items having
      certain observable properties retrieves items having some unobserved property of
      interest. Thus confirmatory information facilitates a useful analysis of search
      problems and contrasts with classical information theory, which quantifies the
      efficiency of information transmission but is indifferent to the nature of the
      particular information being transmitted. The last part of the paper presents
      several examples where confirmatory information is used to quantify protein
      structural properties in a search setting.

PMID- 10642879
TI  - Sequence complexity for biological sequence analysis.
AB  - A new statistical model for DNA considers a sequence to be a mixture of regions
      with little structure and regions that are approximate repeats of other
      subsequences, i.e. instances of repeats do not need to match each other exactly.
      Both forward- and reverse-complementary repeats are allowed. The model has a
      small number of parameters which are fitted to the data. In general there are
      many explanations for a given sequence and how to compute the total probability
      of the data given the model is shown. Computer algorithms are described for these
      tasks. The model can be used to compute the information content of a sequence,
      either in total or base by base. This amounts to looking at sequences from a data
      compression point of view and it is argued that this is a good way to tackle
      intelligent sequence analysis in general.

PMID- 10642880
TI  - Detecting localized repeats in genomic sequences: a new strategy and its
      application to Bacillus subtilis and Arabidopsis thaliana sequences.
AB  - A new method for the search of local repeats in long DNA sequences, such as
      complete genomes, is presented. It detects a large variety of repeats varying in
      length from one to several hundred bases, which may contain many mutations. By
      mutations we mean substitutions, insertions or deletions of one or more bases.
      The method is based on counting occurrences of short words (3-12 bases) in
      sequence fragments called windows. A score is computed for each window, based on
      calculating exact word occurrence probabilities for all the words of a given
      length in the window. The probabilities are defined using a Bernoulli model
      (independent letters) for the sequence, using the actual letter frequencies from
      each window. A plot of the probabilities along the sequence for high-scoring
      windows facilitates the identification of the repeated patterns. We applied the
      method to the 1.87 Mb sequence of chromosome 4 of Arabidopsis thaliana and to the
      complete genome of Bacillus subtilis (4.2 Mb). The repeats that we found were
      classified according to their size, number of occurrences, distance between
      occurrences, and location with respect to genes. The method proves particularly
      useful in detecting long, inexact repeats that are local, but not necessarily
      tandem. The method is implemented as a C program called EXCEP, which is available
      on request from the authors.

PMID- 10642881
TI  - A global compositional complexity measure for biological sequences: AT-rich and
      GC-rich genomes encode less complex proteins.
AB  - Different local regions of natural amino acid or nucleotide sequences show
      remarkable heterogeneity in residue composition, reflecting diversity in
      evolutionary history and physiochemical constraints. Compositional complexity
      measures are helpful for describing and understanding this variegation. Motivated
      by some open problems in comparative genomics and protein folding, we have
      developed a new 'global' compositional complexity measure, G1, which overcomes a
      crucial limitation of earlier methods. The 'local' measures used in previous
      research resemble entropy functions and are inherently dependent on an underlying
      probability distribution. Local measures cannot rigorously compare complexity
      across sequences of substantially different size, because real sequences show
      very irregular heterogeneity and do not have the necessary ergodicity in scaling
      and asymptotic properties. G1 is a member of a new class of scale-independent,
      distribution-independent complexity functions. For a sequence S of length L on an
      N-letter alphabet, G1 is derived from ratios in the integer partition lattice,
      P?L,N? of L with N parts, where the elements of P?L,N? are the state vectors of
      S, (n1, n2,..., nN), ranked by an order principle. We present theorems and proofs
      relating to the metric properties of G1 and its relationship to other state
      vector-dependent compositional complexity functions, together with a fully
      efficient O(L) algorithm to compute G1. The distributions of G1 were calculated
      for the entire sets of translated proteins encoded by extensively sequenced
      genomes. The results establish the existence of a clear evolutionary principle,
      common to bacteria, archaea and eukaryotes, that the proteins encoded by more
      extreme AT-rich and GC-rich genomes have generally lower compositional complexity
      than those of more typical organisms.

PMID- 10642882
TI  - The homeodomain: an ancient evolutionary motif in animals and plants.
AB  - The homeodomain is a DNA-binding motif within transcription factor proteins.
      These transcription factors may be involved in cell differentiation and control
      of cell growth, as well as patterning of diverse organisms. Given their strong
      evolutionary conservation, it has been suggested that homeodomain proteins have
      been fundamental to the evolution of animal species. We have previously shown
      that the major classes of animal homeodomains originated early in the evolution
      of metazoans. Here, I investigate the evolutionary relationships of homeodomain
      sequences in plants. Using distance matrix approaches with unweighted or weighted
      character state transitions, the overall results support the same conclusion: in
      plants, as in animals, multiple independent classes of divergent homeodomains can
      be distinguished, again suggesting an early evolutionary origin. These studies
      advance the hypothesis that the homeodomain represents a fundamental motif of
      gene regulation in multicellular organisms.

PMID- 10642883
TI  - Origin of life on earth and Shannon's theory of communication.
AB  - The genetic information system is segregated, linear and digital. It is
      astonishing that the technology of information theory and coding theory has been
      in place in biology for at least 3.850 billion years (Mojzsis, S.J.,
      Kishnamurthy, Arrhenius, G., 1998. Before RNA and after: geological and
      geochemical constraints on molecular evolution 1-47. In: Gesteland, R.F. (Ed.),
      The RNA World: The Nature of Modern RNA Suggests a Prebiotic RNA, second ed. Cold
      Spring Harbor Laboratory Press, Boca Raton, FL). The genetic code performs a
      mapping between the sequences of the four nucleotides in mRNA to the sequences of
      the 20 amino acids in protein. It is highly relevant to the origin of life that
      the genetic code is constructed to confront and solve the problems of
      communication and recording by the same principles found both in the genetic
      information system and in modern computer and communication codes. There is
      nothing in the physico-chemical world that remotely resembles reactions being
      determined by a sequence and codes between sequences. The existence of a genome
      and the genetic code divides living organisms from non-living matter. If the
      historic process of the origin and evolution of life could be followed, it would
      prove to be a purely chemical process (Wachtershauser, G., 1997. The origin of
      life and its methodological challenge. J. Theor. Biol. 187, 483-694). The
      question is whether this historic process or any reasonable part of it is
      available to human experiment and reasoning; there is no requirement that
      Nature's laws be plausible or even known to mankind. Bohr (Bohr, N., 1933. Light
      and life. Nature 308, 421-423, 456-459) argued that life is consistent with but
      undecidable by human reasoning from physics and chemistry. Perhaps scientists
      will come closer and closer to the riddle of how life emerged on Earth, but, like
      Zeno's Achilles, never achieve a complete solution.

PMID- 10642884
TI  - Genome research: the second decade. A report on the XI Cold Spring Harbor
      Laboratory Meeting on Genome Mapping and Sequencing, May 13-17, 1998, Cold Spring
      Harbor, NY.

PMID- 10642885
TI  - Intelligent systems in molecular biology (ISMB98), 27 June-1 July, 1998,
      Montreal.

PMID- 10642886
TI  - RECOMB98. Computational molecular biology: pre- and post-genomics, March 22-25,
      1998, New York.

PMID- 10642888
TI  - An evaluation into the potential of biological processing for the removal of
      metals from sewage sludges.
AB  - The use of sewage sludge in agricultural land as a means of sludge disposal and
      recycling has been shown to be economical and suitable because of the presence of
      nutrients such as nitrogen and phosphorus. However, municipal sludges often
      contain high quantities of toxic metals and other compounds that must be removed
      for its safe use in agricultural soils. The biological leaching of metals from
      sewage sludges has been shown to be a promising technique for metal detoxifying
      in such complex matrix. The process efficiency is dependent on several physico
      chemical parameters, such as total solids concentration, metal forms, pH-ORP, and
      temperature. Scale-up of the process has not yet been defined and is still
      pursuing the correct operational design. Current research involving the
      bioleaching of metals from sewage sludge and its application to land, which
      affects soil physical properties, are presented and discussed.

PMID- 10642887
TI  - Characterization and regulation of catabolic genes.
AB  - Although a wide range of microorganisms have been discovered that are able to
      degrade highly stable, toxic xenobiotics, still many pollutants persist in the
      environment. Recent advances in the field of r-DNA technology has provided
      solutions to these problems. One important factor limiting the bioremediation of
      sites contaminated with certain hazardous wastes is the slow rate of degradation.
      This slow rate limits the practicality of using bacteria in remediating
      contaminated sites. It is possible to extend the range of substrates that an
      organism can utilize. It is even possible to endow an organism with the ability
      to degrade a predetermined range of xenobiotics. Because biotechnological
      processes are based on natural activities of microorganisms and constitute
      variations in classic domestic waste treatment processes, they are publicly more
      accepted. This is an area where genetic engineering can make a marked improvement
      by manipulating catabolic genes of microorganisms. Advances in r-DNA technology
      have opened up new avenues to move toward the goal of genetically engineered
      microorganisms to function as "designer biocatalysts" in which certain desirable
      biodegradation pathways or enzymes from different organisms are brought together
      in a single host with the aim of performing specific detoxification. In the last
      2 decades much progress has been made in this direction, and as a result
      catabolic genes have been cloned and characterized for organochlorines,
      polychlorinated biphenyls, chlorobenzoates, naphthalene etc. The aim of this
      review is to provide an insight in the recent advances made on characterization
      and expression of catabolic genes that encode the degradation/detoxification of
      these persistent and toxic xenobiotic compounds.

PMID- 10642889
TI  - Cloning and characterization of promoter of the mouse mafB gene.
AB  - The MafB transcription factor plays a pivotal role in controlling the development
      and differentiation. The author reports the isolation and analysis of genomic
      clone of the mouse mafB gene. The gene lacks intron structure, at least, within
      its coding and 5'-untranslated sequences that are similar to the chicken mafB
      gene. RNA protection analysis determined one transcription initiation site of the
      gene at 389-bp upstream from the translation initiation site. Sequence analysis
      showed that the 5'-flanking region upstream to the ATG codon did not contain a
      conventional TATA box. A TATA-like sequence (5'-GATAAAA-3') and an inverted CCAAT
      box (5'-ATTGG-3') were found to be located at nucleotide -31 and -86, referring
      to the transcription initiation site, respectively. Upstream to these sequences,
      there were several potential regulatory elements, including two GC-boxes (5'
      GGGCGG-3': from -148 to -143; and from -123 to -118), and a palindromic sequence
      (5'-GTCAGCTGAC-3': from -164 to -155) which contained two halves-MARE (Maf
      recognition element), 5'-GCTGAC-3', and an E-box (5'-CAGCTG-3'). Promoter
      activity of the 5'-flanking region was analyzed by reporter transfection assay,
      which suggested that these segments were an important transcriptional activator.
      It was also suggested that MyoD transactivated the mouse mafB promoter and this
      gene was positively autoregulated by its product, MafB.

PMID- 10642890
TI  - [Energy metabolism in the cerebrum and the brainstem-cerebellum of the rat brain
      under hypoxic conditions].
AB  - The relationship between neuronal activity, intracellular oxygenation and energy
      metabolism in the cerebrum and the brainstem-cerebellum of the rat brain in
      graded hypoxia was studied. Intracellular oxygenation was monitored by near
      infrared measurement of the redox state of cytochrome oxidase (cyt.ox.). Neuronal
      activity was assessed by EEG (electroencephalography) and the evoked potentials
      (VEP; visual, BSR; brainstem, C-SEP; cortical-sensory, S-SEP; spinal-sensory
      evoked potentials). As hypoxia progressed, neuronal activities disappeared in the
      order of VEP, C-SEP, EEG, BSR, S-SEP. However, intracellular oxygenation at the
      disappearance of each neuronal activity was significantly lower in the brainstem
      cerebellum than in the cerebrum. ATP (adenosine triphasphate), glucose, and
      lactate were measured in the cerebral cortex, subcortex, brainstem, and
      cerebellum 1-2 minutes after the disappearance of neuronal activities on EEG.
      Hypoxia caused decreases in ATP in each brain region. Marked increases in lactate
      were observed in each brain region, though the degree of increment was less in
      the cerebral cortex than the other brain regions. A decrease in glucose was
      observed only in the cerebral cortex. These results suggest that by the use of
      the energy generated via glycolysis, the brainstem functions even after oxygen
      supply has been significantly reduced, while the neuronal activity in the
      cerebrum is suppressed at the higher oxygenation level than that in the brainstem
      cerebellum. It is, thus, supposed that these differential responses of brainstem
      and cortical neurons to oxygen deprivation are inherent, and critical for
      neuronal survival in severe hypoxia.

PMID- 10642891
TI  - [Mechanisms of rejection in guinea pig (GP)-to-rat liver xenotransplantation:
      improvement of recoloration of GP liver graft and effects of perfluorochemical
      (FC43) in GP-to-rat liver xenotransplantation].
AB  - The impaired reperfusion after revascularization has not allowed guinea pig (GP)
      to-rat liver xenograft model to be widely used for xenotransplant research. This
      study was designed to clarify mechanisms responsible for the impaired
      recoloration, and to examine effects of FC43 emulsion, an anti-complement agent.
      1) Mechanisms responsible for the impaired recoloration: GP allogeneic and
      xenogeneic liver grafts flushed with 4 degrees C lactated Ringer's (LR) solution
      were poorly perfused around the porta hepatis, whereas those flushed with 15
      degrees C LR solution were immediately recolored, this being confirmed by portal
      venography. The recoloration was also ameliorated by reduction of ischemic time.
      Even recolored GP xenografts, turned uneven dark gray however, and enlarged
      around 5 min after revascularization. Histological and immunohistological
      findings of GP livers 1 h after xenografting were characteristic of sinusoidal
      congestion and hepatocytes necrosis, and the livers had remarkable C3 deposits on
      sinusoids and central veins, IgM deposits faintly stained on some small vessels
      but no detectable deposits of IgG. 2) Effects of FC43. Administration with of
      either a single dose of 10 microliters/g or repeated doses of 5 microliters/g of
      FC43 resulted in significant prolongation of xenograft survivals compared with
      controls (8.06 +/- 1.45, 9.45 +/- 3.64 vs. 4.23 +/- 0.89 h; p < 0.02), thereby
      sustaining almost normal gross appearances until abdominal closures. Thus, the
      onset of hyperacute rejection (HAR) was postponed by FC43 administration;
      however, all rats died within 14 h. No deposit of C3 was detected in GP
      xenografts of FC43 groups, while deposits of granulocytes and macrophages (M phi)
      were observed from 1 and 3 h after revascularization, respectively. In
      conclusion, the impaired recoloration in this model may be due to physiological
      defects during the initial stage of revascularization, which is followed by the
      immunological responses that probably involved M phi and granulocytes. The
      present study indicates that discordant GP liver xenotransplantation is feasible
      as a useful rodent model for either exploration of mechanisms of immunological
      responses or examination of the immunosuppressive effects of pharmacological
      agents.

PMID- 10642892
TI  - Organophosphate metabolic changes in the rat lens during the development of
      galactose-induced cataract.
AB  - Using phosphorous-31 nuclear magnetic resonance (31P-NMR) spectroscopy, we
      observed the metabolic kinetics of organophosphate compounds in the rat lens
      during cataract development induced by different doses of galactose (5%, 15%,
      25%, and 40%) added to rat chow. The metabolic and histologic changes in the
      lenses were compared among the rats fed with different doses of galactose. alpha
      Glycerophosphate significantly increased in response to the galactose doses,
      followed by a decrease to steady values of approximately 120% of the base line
      value, except in the 40% galactose group, which had a marked decrease to 68% of
      the base line value. Choline phosphate decreased rapidly during dosing in all but
      the 5% group, but no changes in those levels were observed after 2 weeks of
      galactose dosing. ATP decreased significantly when the histologic destruction
      progressed in the entire lens. Although inorganic phosphate increased
      significantly in a dose-dependent manner, it did not exceed the peak level. The
      histologic changes were closely related to the dynamic changes in the phosphorous
      compounds in the rat lens during formation of the galactose-induced cataract. Our
      results indicated that the development of a galactose-induced cataract was
      associated with the metabolic changes of the phosphate compounds.

PMID- 10642893
TI  - A gene therapy or purified CTLA4IgG treatment of experimental allergic
      encephalomyelitis.
AB  - We examined whether multiple intraperitoneal injection of a soluble form of a
      chimeric protein consisting of an extracellular portion of cytotoxic T lymphocyte
      associated protein 4 and an Fc portion of human IgG1(CTLA4IgG) at the initiation
      phase could successfully control the subsequent development of experimental
      allergic encephalomyelitis (EAE). We demonstrated that CTLA4IgG treatment could
      delay the onset and reduce the severity of EAE in early phase of disease
      development. More importantly, CTLA4IgG treatment significantly reduced the
      incidence of EAE. This was in good agreement to that spleen cells obtained from
      CTLA4IgG-treated animals responded poorly to myelin basic protein (MBP) in vitro
      as compared to those from human IgG-treated animals. However, the CTLA4IgG
      treated mice eventually developed EAE and after all, incidence of EAE was not
      significantly different from that in control group. We then tested whether a gene
      therapy using adenovirus vector containing CTLA4IgG (Adex1CACTLA4IgG) could
      inhibit the development of EAE. We demonstrated that incidence and severity of
      EAE were significantly inhibited by a single injection of intravenous
      Adex1CACTLA4IgG up to 8 months. Thus, this study demonstrated the efficacy of a
      single dose of adenovirus-mediated gene therapy in controlling EAE as compared to
      repeated injection of purified CTLA4IgG proteins.

PMID- 10642894
TI  - North-south differences in some indices of Vitamin B6 nutritional status in older
      British people.
AB  - The National Diet and Nutrition Survey, nationally representative for the British
      population aged 65 years and over, has revealed a north-south geographical
      gradient, with a decline from south to north of vitamin B6 status indices. The
      present study further explores the possible explanatory factors (dietary intake
      of vitamin B6 and riboflavin, alcohol consumption, smoking habits and some other
      lifestyle determinants) on the difference of vitamin B6 indices--plasma
      concentrations of pyridoxal phosphate (pPLP) and pyridoxic acid (pPA), between
      older people living in the north (Scotland, North of England) and the south
      (Southern England, Wales and Midlands). The results showed that older people
      living in the northern half of Britain are at greater risk of poor vitamin B6
      status, mainly as a result of low intakes of this vitamin, than the people living
      in the southern half of the country. Riboflavin intake, alcohol consumption,
      smoking and socio-economic status also correlated with the north-south gradient
      of pPLP and pPA. Other potential determinants such as use of vitamin B6
      supplements, medicines probably affecting vitamin B6 metabolism, were not
      independent correlates of the north-south gradient in vitamin B6 status indices.
      This may have important implications for disease-risk geographical gradients in
      the UK.

PMID- 10642895
TI  - Effects of intramuscular injection of alpha-tocopheryl acetate on fatty acid
      profile in lamb liver.
AB  - The effects of intramuscularly administrated vitamin E on total lipids, fatty
      acid profile, and lipid stability to oxidation was investigated in lamb liver.
      Twenty-four 5-day-old lambs were allotted to 4 groups of 6 each and given
      respectively 0 (control), 125, 200, 300 mg dl-alpha-tocopheryl acetate weekly
      from day 5 to 33. alpha-Tocopherol stored in lamb liver at the end of experiment
      showed linear correlation with the level of injected vitamin E. No effect on
      total lipids was found. A decrease in the level of liver thiobarbituric-acid
      reactive substances (TBARS), significantly correlated with liver alpha-tocopherol
      content, was found in vitamin E groups. The amount of linoleic and linolenic
      acids significantly increased in the vitamin E groups as compared to control
      group, and were correlated with the liver alpha-tocopherol content. TBARS were
      negatively correlated with the concentration of unsaturated fatty acids. Finally,
      in the liver of the treated groups, vitamin E concentrations in the range 30-50
      micrograms/g showed adequate for an efficient protection from peroxidation of
      membrane lipids, and determined an increase in the unsaturated to saturated fatty
      acid ratio.

PMID- 10642896
TI  - Serum concentrations of carotenoids, alpha-tocopherol, fatty acids, and lipid
      peroxides among Japanese in Japan, and Japanese and Caucasians in the US.
AB  - Serum concentrations of carotenoids, alpha-tocopherol, fatty acids, and
      thiobarbituric acid-reactive substances (TBARS) were measured in 217 Japanese
      residents of Japan, and in 99 Japanese and 100 Caucasian residents of the US,
      aged from 50 y to 74 y. In females, serum values of carotenoids such as beta
      carotene (BC) and zeaxanthin & lutein (ZL) were highest among Japanese in Japan,
      followed by Japanese in the US and Caucasians in the US. In males, these values,
      except for serum BC values, were also highest among Japanese in Japan. Moreover,
      serum values of n-3 polyunsaturated fatty acids (n-3PUFAs) such as
      eicosapentaenoic acid and docosahexaenoic acid were significantly higher among
      Japanese in Japan than among Japanese and Caucasians in the US in both sexes. In
      contrast, serum values of n-6 polyunsaturated fatty acids such as linoleic acid
      and arachidonic acid were lowest among Japanese in Japan. For women, serum levels
      of n-9 unsaturated fatty acids were lowest among Japanese living in Japan. Serum
      TBARS values were highest among Japanese in Japan, followed by Japanese in the US
      and Caucasians in the US. A significant positive correlation was observed between
      serum values of TBARS and n-3 PUFAs among Japanese both in Japan and in the US.
      Serum TBARS values showed a significant inverse relationship with the serum
      values of BC and ZL among Japanese in Japan and with those of BC among Japanese
      in the US. These relationships were not always observed among Caucasians in the
      US. The results of this study suggest that the high TBARS values among Japanese
      in Japan may depend in part on lipid peroxidation induced in vitro by n-3PUFAs,
      while high reduction of lipid peroxidation could be expected among Japanese in
      Japan with high antioxidants such as BC and ZL. In conclusion, serum levels of
      nonprovitamin A carotenoids such as ZL may be a useful intake marker of
      vegetables. Dietary intakes of dark green vegetables and fish rich in n-3PUFAs
      might be more important in the prevention of some sites of cancer and of ischemic
      heart disease.

PMID- 10642897
TI  - Effects of multivitamin/mineral supplementation, at nutritional doses, on plasma
      antioxidant status and DNA damage estimated by sister chromatid exchanges in
      lymphocytes in pregnant women.
AB  - The purpose of this study was to evaluate the effect of multivitamin/mineral
      supplementation during pregnancy on plasma levels of antioxidants and sister
      chromatid exchange (SCE) rate--an indicator of damage to DNA. A controlled, semi
      randomized, prospective trial was performed comparing the supplement group, who
      received multivitamin/mineral tablet once daily for 10 weeks, to the control
      group. Plasma levels of antioxidants and SCE in lymphocytes were measured
      initially (20 wk gestation) and at the end of the intervention (34 wk gestation).
      In the control group, SCE rates increased significantly at 34 wk gestation
      compared to 20 wk gestation, whereas there was no change in the supplement group.
      Plasma retinol, beta-carotene and ascorbate decreased significantly in the
      control group. In the supplement group, a significant increase in plasma beta
      carotene (55.6%), coenzyme Q10 (40.2%), folic acid (15.9%) and zinc (24.2%) was
      observed after 10 weeks of supplement. Increased plasma levels of antioxidants in
      the supplement group could not decrease SCE rates, however, they could prevent an
      increase in SCE rates which may be induced by reactive oxygen species generated
      from the enhanced steroid hormones in the last trimester, suggesting that
      multivitamin/mineral-supplement during pregnancy may prevent DNA damage due to
      the altered hormonal profile.

PMID- 10642898
TI  - Lipid and glucose utilization in hypercholesterolemic rats fed a diet containing
      heated chickpea (Cicer aretinum L.): a potential functional food.
AB  - This feeding trial evaluated the influence of a diet containing heated chickpea
      in a dietary induced rat model of hypercholesterolemia in order to assess some
      possible protective and therapeutic effects on lipid and carbohydrate metabolism
      disorders as found with other legumes. Rats fed a diet enriched with coconut oil
      (25%) and cholesterol (1%) for 42 days (HH) showed a situation of type IIa
      hyperlipoproteinemia. However, these lipid alterations were improved in the
      hypercholesterolemic rats receiving control (HC) and legume (HL) diets for 16
      days. Moreover, results confirm that the chickpea was more effective than the
      control diet containing casein in the normalization of triglycerides as well as
      total and LDL-cholesterol levels. On the other hand, the HH group showed a marked
      reduction in the liver glycogen content and Glucose-6-Phase activity (involved in
      glyconeogenesis) and an increase in Glucokinase (GK) activity (involved in
      glucose utilization). In contrast, the rats receiving chickpea re-established the
      liver glycogen deposition as compared to the HH group. Also, the chickpea intake
      increased the GK activity as compared to the control diet. The overall results
      support that chickpea intake may be recommended in humans with altered lipid
      profile such as type IIa hyperlipoproteinemia. Additionally, data concerning
      carbohydrate utilization indicated its potential positive effects in diabetes
      therapy and their role as biological active food supplements.

PMID- 10642899
TI  - Bioavailability of dried asakusanori (porphyra tenera) as a source of Cobalamin
      (Vitamin B12).
AB  - We have already reported that raw nori (Porphyra tenera) contains cobalamin (Cbl)
      but not Cbl analogues (J. Nutr. Sci. Vitaminol., 42, 497, 1996). It seems,
      therefore, that it is an excellent natural vegetable source of Cbl. On the other
      hand, it has been reported that the Cbl nutritional status of vegetarian children
      deteriorated as estimated by the hematological index, mean corpuscular volume
      (MCV), after they had dried nori as a source of Cbl. Such a discrepancy between
      raw and dried nori as a source of Cbl led us to investigate whether Cbl in dried
      nori had different properties from that in raw nori. We found that contents of
      Cbl homologues determined by a bioassay method in both raw and dried nori were
      similar. The urinary methylmalonic acid excretion increased when human female
      volunteers were given 40 g of dried nori daily during the test period. On the
      other hand, the urinary methylmalonic acid excretion did not change when
      volunteers were daily given 320 g of raw nori, which was equivalent to 40 g of
      the dried one on the basis of dehydrated weight, during the test period. By paper
      chromatography, 65% of the Cbl homologues were found to be comprised of Cbl
      analogues in dried nori, while 73% of the Cbl homologues in the raw nori were
      genuine Cbl. These results were confirmed by the finding that the bioassay method
      gave higher values for Cbl homologues than those obtained by a competitive
      binding assay method using an intrinsic factor as a Cbl-binding protein. Our
      present data demonstrated that Cbl in raw nori can be changed into harmful Cbl
      analogues by the drying process.

PMID- 10642900
TI  - Variability in selected indexes of overall diet quality.
AB  - We examined the intra- and interindividual variability in selected measures of
      overall diet quality in relation to socio-demographic, lifestyle, and health
      related characteristics. Three days of dietary data from the Continuing Survey of
      Food Intakes by Individuals (CSFII), 1989-91 (7841 respondents, 3337 men and 4504
      women, aged > or = 19 years), were examined. Measures of overall diet quality
      were: 1. the Dietary Diversity Score (DDS), a measure of variety among the major
      food groups; 2. the Overall Variety Score (OVS), examined the number of nutrient
      dense foods reported; and 3. the Nutrient Adequacy Score (NAS100), evaluated the
      number of nutrients consumed at least at the level of the RDA from a total of 11.
      The ratio of intra- to interindividual variance for DDS, OVS, and NAS100 was
      1.66, 1.09, and 1.21, respectively, indicating higher intraindividual variability
      relative to interindividual variability. For each of the three scores, gender,
      income, education, and smoking were associated with greater intraindividual
      variability; however, age, and special diet status were associated with lower
      variability. Thus, the reliability of a given dietary assessment protocol for
      evaluating "usual" diet quality is likely to vary by the socio-demographic and
      lifestyle characteristics of the study population.

PMID- 10642901
TI  - Massage the medium: global theme issue.

PMID- 10642902
TI  - The electronic medical record: its role in disseminating depression guidelines in
      primary care practice.
AB  - OBJECTIVE: Using the Agency for Health Care Policy and Research Depression
      Guideline Panel's recommendations as its focus, this article describes a step-by
      step approach for disseminating a paper-based depression guideline to primary
      care physicians via a commercially available electronic medical record (EMR)
      system. METHOD: Description of the author's approach to disseminate an evidence
      based depression treatment guideline to a group of primary care physicians using
      a commercially available EMR system and to evaluate the results. RESULTS: We
      review clinical considerations and practical barriers faced in this process with
      the expectation that our experiences can guide others attempting to disseminate
      psychiatric treatment guideline via EMR systems. CONCLUSIONS: The EMR offers
      critical efficiencies in disseminating state-of-the-art clinical practice
      guidelines and in directing the primary care physicians' use of them. Still, well
      designed, randomized controlled trials are necessary to demonstrate their
      effectiveness at enhancing patient outcomes for major depression in primary care
      settings.

PMID- 10642903
TI  - The contribution of information technology to improving clinicians' access to
      high quality evidence.
AB  - OBJECTIVE: Rapid access to the results of high quality research studies for real
      time use during clinical care is the aim of evidence-based medicine. METHODS: The
      current volume and methods of disseminating research findings are barriers to
      this goal. Electronic publishing, CD-ROMs for personal computers, and Internet
      based databases and searching are tools helping to overcome these barriers.
      RESULTS: Several examples in the United Kingdom and United States employing these
      tools are described. CONCLUSIONS: Technology is making traditional narrative
      reviews such as printed textbooks obsolete for the practice of evidence-based
      medicine.

PMID- 10642904
TI  - Health-related quality of life in primary care patients with recognized and
      unrecognized mood and anxiety disorders.
AB  - OBJECTIVE: Primary care providers have been criticized for underrecognizing and
      undertreating mental health disorders. This criticism assumes patients with
      recognized disorders and those with unrecognized disorders suffer the same burden
      of illness. This study describes differences in health-related quality of life
      (HRQOL) in patients with recognized and unrecognized mood and anxiety disorders
      in a primary care setting. METHODS: A probability sample of 500 adult ambulatory
      patients from a university-based, family practice clinic, completed the PRIME-MD
      mood and anxiety disorder modules and the SF-36 Health Survey. Computerized
      patient records were reviewed retrospectively to determine recognition of mood
      and anxiety disorders. The Mental Health (MCS) and Physical Health (PCS)
      Component Summary scales of the SF-36 served as the primary outcome measures.
      RESULTS: Sub-threshold mood and anxiety disorders were less likely to be
      recognized by physicians than disorders meeting DSM-III-R criteria. Recognized
      mood disorders were associated with a significant decrement in MCS scores (poorer
      HRQOL) compared with unrecognized disorders. In contrast, recognized mood
      disorders demonstrated slightly higher PCS scores. Recognized and unrecognized
      mood disorders differed significant ly in physical functioning, vitality, social
      functioning, role functioning related to emotional state, and mental health.
      Recognition of anxiety disorders was not related to HRQOL. CONCLUSIONS: Patients
      with mental health disorders that have been recognized by their health providers
      appear to suffer from poorer HRQOL than patients whose disorders have not been
      recognized. This relationship, though, is only apparent for mood disorders.
      Poorer physical functioning may mask less severe emotional symptoms in mood
      disorders; profound emotional symptoms make recognition easier.

PMID- 10642905
TI  - Depressed mood and subjective health symptoms as predictors of mortality in
      patients with congestive heart failure: a two-years follow-up study.
AB  - OBJECTIVE: The present study was undertaken in order to evaluate the relationship
      between depressed mood (depression, emotional distress) and disease-specific
      subjective health symptoms upon mortality risk among patients with congestive
      heart failure (CHF). METHODS AND RESULTS: Proportional hazard models were used to
      evaluate the effects of selected biomedical, subjective health and psychological
      variables on mortality among 119 clinically stable patients (71.4% men; mean age
      65.7 years +/- 9.6) with symptomatic heart failure, recruited from an outpatient
      cardiology practice. Twenty deaths were registered during the twenty-four-month
      period of data collection, all from cardiac causes. Results indicated that
      depressed mood was a significant predictor of mortality with a hazard ratio of
      1.9, p .002. In contrast, subjective health was not a significant predictor of
      mortality in a Cox regression model that included depressed mood. The hazard
      ratio for a 1-point increase in Zung Depression Scale score was equal to 1.08
      based on the multivariate model. CONCLUSIONS: Results indicate that depressed
      mood is significantly related to increased mortality risk among heart failure
      patients. This finding is of concern to clinicians and should have implications
      for treatment of patients with congestive heart failure.

PMID- 10642906
TI  - Training family practice residents in psychiatry: an ambulatory care training
      model.
AB  - OBJECTIVE: To demonstrate the importance of providing psychiatric training to
      primary care practitioners in ambulatory care settings. Additionally, to describe
      the model used for this purpose in the Department of Psychiatry and Behavioral
      Sciences of the University of Texas Medical School at Houston in order to further
      stimulate educational opportunities on this topic. METHOD: A review of the
      psychiatric curriculum offered to family practice residents during their PGY-2
      year one-month rotation in psychiatry at the University of Texas Mental Sciences
      Institute is provided. Emphasis is given to key areas of the curriculum such as:
      knowledge, skills, and attitude development. Special focus on the clinical and
      educational experiences is also offered for the purpose of providing unique
      perspectives about the curriculum methodology. RESULTS: The careful assessment of
      the feedback obtained from the family practice residents who were exposed to this
      ambulatory training model demonstrates that this type of setting was satisfactory
      for the teaching of psychiatry to primary care residents. CONCLUSIONS: Primary
      care residents have always treated a large number of psychiatric patients. Given
      the current status of our health care system, primary care practitioners should
      have even a greater role in the future delivery of psychiatric services. In this
      article, we offer a model of training for primary care residents in psychiatry,
      which emphasize cost-effectiveness, high quality of care, and ambulatory care
      settings.

PMID- 10642907
TI  - A review of the differences between somatizing and psychologizing patients in
      primary care.
AB  - OBJECTIVE: This article reviews all published studies on somatizing and
      psychologizing patients in primary care, according to Bridges and Goldberg's
      criteria [1]. METHOD: A review of the Medline base from 1985 to 1998 was carried
      out. RESULTS: Somatization is a concept valid, reliable, and stable over time.
      There are no differences between somatizers and psychologizers in
      sociodemographics, social problems or past medical and psychiatric history. The
      main clinical and diagnostic difference is a predominance of depressive symptoms
      and disorders in psychologizers. Finally, the most remarkable differences between
      somatizers and psychologizers are found in personality traits, such as
      attribution of somatic symptoms. However, some traits considered important in the
      outcome of somatizers, such as hypochondriasis or locus of control, show no
      differences between both groups of patients. CONCLUSION: Contrary to what was
      expected, the comparison between these two groups of patients give few clues for
      the etiology and treatment of somatization. Follow-up studies should be the main
      source of data to answer these questions.

PMID- 10642910
TI  - [Advances in therapy].

PMID- 10642908
TI  - Patient-centeredness and its correlates among first year medical students.
AB  - OBJECTIVE: This research was performed to study the attitudes that medical
      students hold concerning their relationships with patients, and whether such
      attitudes are gender-related, affect career plans, and influence their evaluation
      of psycho-social and biomedical issues. METHODS: One hundred fifty-three first
      year students at the Boston University School of Medicine completed the Patient
      Practitioner Orientation Scale (PPOS), a scale that differentiates between a
      patient-centered vs. doctor-centered orientation toward medical practice,
      indicated their interest in community and primary care practice, and rank ordered
      psycho-social and biomedical clinical issues in terms of their perceived relative
      importance. RESULTS: The data revealed that female medical students were more
      patient-centered, and that (across sexes) patient centeredness was positively
      associated with an interest in community and primary care practice and the
      ranking of psycho-social issues. CONCLUSIONS: These findings indicate that
      differences in the practice attitudes of males and females exist very early on in
      medical training, and that these differences are associated with anticipated
      career choices. They also suggest that the PPOS may prove useful in measuring the
      attitudes of practicing physicians toward their clinical roles and might predict
      physicians' behavioral strategies and patient medical outcomes.

PMID- 10642911
TI  - [Allogeneic transplantation of stem cells].

PMID- 10642912
TI  - [Acute necrotising pancreatitis].

PMID- 10642913
TI  - [Advances in homeopathy].

PMID- 10642914
TI  - [Are there proven therapies in homeopathy?].

PMID- 10642915
TI  - [Therapy of chronic viral hepatitis].

PMID- 10642916
TI  - [What is new in the standard therapy of inflammatory bowel diseases?].

PMID- 10642917
TI  - [Endothelial dysfunction. Therapeutic and prognostic issues].

PMID- 10642918
TI  - [Liver cirrhosis].

PMID- 10642919
TI  - [Paraneoplastic hypertrichosis lanuginosa et terminalis in a 27-year old woman
      with parotid carcinoma].

PMID- 10642920
TI  - [21-year old patient with a pituitary microadenoma and gynecomastia of recent
      onset].

PMID- 10642921
TI  - [PTCA and STENT in acute cerebral infarction].

PMID- 10642922
TI  - [Drug therapy of arterial hypertension].

PMID- 10642923
TI  - [Testing for etiologic agents in infectious diarrhea].

PMID- 10642924
TI  - [When statins alone are insufficient for lowering lipid levels. Efficacy and
      risks of lipid lowering combination therapies, in particular, that of statin
      fibrate combination].

PMID- 10642925
TI  - [Cardiology on its way into the next millenium].

PMID- 10642926
TI  - [Evaluation of coronary flow velocity and coronary flow reserve before and after
      coronary angioplasty using transthoracic Doppler echocardiography and Doppler
      guide wire].
AB  - Evaluation of left anterior descending coronary (LAD) blood flow before and after
      coronary angioplasty was carried out non-invasively by ultrasonic Doppler
      echocardiography with a newly developed digital, high-frequency, high-resolution
      transthoracic ultrasonic Doppler flowmeter and a 7.5 MHz probe. The results were
      compared with those obtained using an intracoronary Doppler guide wire. Sixteen
      patients, 12 males and 4 females (mean age 57 +/- 14 years) with old myocardial
      infarction (8 patients) and angina pectoris (8 patients) were studied. Coronary
      flow reserve was compared following intravenous administration of adenosine
      triphosphate in 12 patients. The LAD blood flow was detected in 15 of 16
      patients. There was a significant increase in the diastolic peak velocity from
      22.2 +/- 10.6 to 29.4 +/- 14.6 cm/sec (mean +/- SD) and the coronary flow reserve
      from 1.8 +/- 0.3 to 2.8 +/- 0.6 (mean +/- SD). There was a good correlation
      between the data obtained using transthoracic flow measurement and intracoronary
      flow measurement (r = 0.61, p < 0.05). LAD blood flow can be easily detected
      parasternally using a digital, high frequency, high-resolution ultrasonic Doppler
      flowmeter. This method may be applicable for judging the efficacy of coronary
      angioplasty by measuring coronary flow reserve and for observing the clinical
      course of the patient non-invasively.

PMID- 10642927
TI  - Evaluation of adjunctive intracoronary administration of acetylcholine following
      intravenous infusion of ergonovine to provoke coronary artery spasm.
AB  - A dilemma arises in patients with chest pain or other symptoms suggestive of
      coronary artery disease but without significant coronary artery stenosis or spasm
      even after the spasm provocation test by either ergonovine or acetylcholine.
      Incremental doses of intracoronary acetylcholine (up to 100 micrograms for left
      coronary artery and 50 micrograms for right coronary artery) were administered
      when intravenous infusion of ergonovine 0.4 mg showed negative results. A total
      of 39 patients were studied. Provocation test was performed because of chest pain
      suggestive of coronary artery disease (n = 19), atypical chest pain (n = 6), post
      balloon angioplasty status (n = 6), silent ischemia (n = 4), Adams-Stokes
      syndrome (n = 3), and dead-on-arrival (n = 1). Characteristics of chest pain
      indicated variant angina (n = 11), rest angina (n = 4), and effort angina (n =
      4). No electrocardiographic evidence of ischemia was detected before this test in
      any patient. Spasm was induced in 23 patients (59.0%) with complete obstruction
      in 7 (30.4%), diffuse vasoconstriction (90-99%) in 14 (60.9%), and focal spasm in
      2 (8.7%). The patients with chest pain showed the highest positive rate of 78.9%.
      Further, the patients with atypical chest pain and miscellaneous reasons also
      revealed positive rates of 33.3% and 42.9%, respectively. One ventricular
      tachycardia and 2 atrial fibrillations occurred but terminated spontaneously.
      This test is useful for detecting spasm in a variety of patients in whom
      intravenous ergonovine infusion fails to induce spasm.

PMID- 10642928
TI  - [Clinical evaluation of acute and chronic pulmonary thromboembolism using
      intravascular ultrasound and angioscopy].
AB  - Pulmonary artery thrombi and parietal lesions were observed in 13 patients (mean
      age 58 +/- 18 years) with acute pulmonary thromboembolism (n = 4) and chronic
      pulmonary thromboembolism (n = 9) using intravascular ultrasound and angioscopy
      at the time of right heart catheterization. Patients with acute pulmonary
      thromboembolism without underlying disease mainly had non-echogenic intraluminal
      mass, and good pulsatile vessel without intimal thickening. Angioscopy directly
      showed red thrombi with white fibrin coating, and no parietal lesions. Patients
      with chronic pulmonary thromboembolism could be classified into 3 groups: 1) Poor
      extensibility of the vessel wall and intimal thickening with non-echogenic
      thrombi on intravascular ultrasound, and relatively fresh parietal thrombi
      consisting of a mixture of red blood cell and fibrin, and spider web-like fibrin
      net on angioscopy (6 patients). 2) Crescent parietal thrombi and wall
      irregularity on intravascular ultrasound, and probably organized thrombi with a
      mixture of red and white surface on angioscopy (one patient). 3) Marked and
      echogenic intimal thickening and poor extensibility on intravascular ultrasound,
      and intimal surface irregularities and yellowish changes on angioscopy (one
      patient). All patients suffering acute deterioration in the chronic phase
      belonged to groups 1) or 2). Intravascular ultrasound and angioscopy are useful
      for characterizing the thrombi and related pulmonary artery lesions in patients
      with pulmonary thromboembolism. The pulmonary artery intima and thrombus differ
      between acute and chronic pulmonary thromboembolism.

PMID- 10642929
TI  - [Troublesome factors in mitral valve repair for mitral valve regurgitation].
AB  - Limitations in the long-term results of medical treatment for mitral
      regurgitation are well recognized, but the advances in its surgical repair have
      produced good results. Therefore, early surgical intervention has been the focus
      of treatment in Europe and America. Increased surgical intervention depends on
      the development of technical skills in mitral reconstruction. This study
      investigated presurgical factors making surgical reconstruction difficult in 103
      patients who underwent mitral operations performed from April 1994 to September
      1997 in our hospital. Records were reviewed retrospectively for etiology, type of
      operation, and the immediate result of operation. The etiology of mitral
      regurgitation was prolapse in 65 patients (63%), restriction in 14, normal in 11,
      infectious endocarditis in 10, and others in 3. The type of prolapse involved the
      anterior leaflet in 22 patients (34%), posterior in 28 (43%), and both leaflets
      in 15 (23%). Valve repair was attempted in 74 patients, of which 16 were switched
      to valve replacement during operation. These included anterior leaflet prolapse
      in 9 patients, posterior leaflet in 1, both leaflets in 3, restriction in 2 and
      infectious endocarditis in 1. The success rate for reconstruction of anterior
      leaflet prolapse was not high. The cause of mitral regurgitation was mostly
      prolapse of the mitral valve, in our country as well as in Europe and America.
      Prolapsed posterior leaflet is much more common in Europe and America, and there
      is a high success rate reported for its valve reconstruction. In contrast, this
      study cannot recommend earlier surgical intervention because of difficult repair
      for anterior leaflet prolapse.

PMID- 10642930
TI  - [Changes in diameter size and F-actin expression in the myocytes of patients with
      diabetes and streptozotocin-induced diabetes model rats].
AB  - Diabetes mellitus may be an independent risk factor for disturbance of cardiac
      function, but the detailed mechanism remains unclear. In the present study,
      histological examinations were carried out on 25 hearts from diabetes model rats
      as well as myocardial biopsy materials from patients with diabetes (n = 25). The
      mean diameter of the cardiac myocytes in humans was 12.2 +/- 0.5 microns in the
      control group of patients without diabetes mellitus or hypertension (n = 6), 13.7
      +/- 0.8 microns in the hypertension group (n = 3), 9.0 +/- 1.7 microns in the
      diabetes group (n = 8), and 11.9 +/- 2.0 microns in the diabetes with
      hypertension group (n = 8). The cardiac myocytes of diabetic patients appeared to
      be atrophic. Comparison of the size of myocytes in the control rats vs
      streptozotocin-induced diabetes model rats (n = 7, each) was 5.4 +/- 0.2 vs 5.2
      +/- 0.3 microns at 2 weeks; 5.9 +/- 0.1 vs 4.9 +/- 0.9 microns at 12 weeks, and
      5.7 +/- 0.1 vs 4.0 +/- 0.2 microns at 24 weeks, respectively, and gradually
      decreased in streptozotocin rats with aging. Immuno-histochemistry with phaloidin
      was used to assess F-actin in the cardiac myocytes. The relative cross-sectional
      area of F-actin in the cardiac myocytes of streptozotocin rats was compared to
      that in non-streptozotocin rat myocytes. F-actin fluorescence in streptozotocin
      rats was 89.9 +/- 3.9% at 2 weeks, 77.9 +/- 6.4% at 12 weeks, and 56.8 +/- 5.7%
      at 24 weeks, indicating a decrease in F-actin. These results suggest that the
      smaller myocytes observed in patients with diabetes and streptozotocin rats are
      related to the decrease in F-actin in myocytes.

PMID- 10642931
TI  - [Atresia of the right atrial orifice of the coronary sinus with persistent left
      superior vena cava: a case report].
AB  - A 39-year-old woman presented with atresia of the right atrial orifice of the
      coronary sinus with a persistent left superior vena cava detected at cardiac
      catheterization. She was admitted with frequent episodes of angina at rest and on
      exertion. Coronary angiography, including spasm provocation test, yielded normal
      results. However, left coronary arteriography demonstrated a dilated coronary
      sinus and a persistent left superior vena cava draining into the innominate vein.
      The contrast medium leaked slightly into the right atrial cavity through the
      obstructed orifice of the coronary sinus. Atresia of the coronary sinus orifice
      is a rare malformation usually found at autopsy. Only 3 cases have been reported
      in Japan. This is the first adult Japanese case detected when the patient was
      still alive.

PMID- 10642932
TI  - Disappearance of complete atrioventricular block after chemotherapy for malignant
      lymphoma: a case report.
AB  - A 77-year-old man with malignant lymphoma presented with dizziness and exertional
      dyspnea. Physical examination revealed marked bradycardia (36 beats/min). Twelve
      lead electrocardiography showed complete atrioventricular block with narrow QRS
      escape beats. Gallium scintigraphy demonstrated significant abnormal uptake in
      the heart. Transesophageal echocardiography showed a thick interatrial septum
      with increased echogenecity. He underwent chemotherapy under external temporary
      pacing with a suspected diagnosis of complete atrioventricular block secondary to
      cardiac invasion of malignant lymphoma. Atrioventricular conduction progressively
      improved and the complete atrioventricular block disappeared. He is currently
      well and has required no cardiac pacing for 6 months. We conclude that complete
      atrioventricular block may be reversible in some patients with malignant
      lymphoma, even in the elderly.

PMID- 10642933
TI  - [Flap-like lesion in the left main coronary artery].

PMID- 10642934
TI  - [Left and right atrial masses in a 67-year-old man with lone atrial
      fibrillation].

PMID- 10642935
TI  - Detection and typing of human papillomavirus DNA by PCR using consensus primers
      in various cervical lesions of Korean women.
AB  - The association between cervical cancers and human papillomavirus (HPV) is now
      well established. To estimate the extent of infection with common HPVs among
      Korean women, we have examined 224 cervical scrapes of various cervical lesions.
      Detection and typing of HPVs were done by polymerase chain reaction (PCR) using
      consensus primers followed by restriction enzyme digestion and PCR using type
      specific primers. The prevalence of total HPV infection in patients with cervical
      intraepithelial neoplasia (CIN) and cervical cancer were significantly higher
      than those in healthy women and patients with atypical squamous cells of
      undetermined significance (ASCUS). HPV typing in 41 invasive carcinomas of the
      cervix revealed the prevalence of HPV 16 in 15 cases, followed by HPV 58, 18, 33,
      31, 52 and 35. The distribution pattern of HPV types in CIN were not much
      different from carcinomas. HPV types except HPV 18 had a tendency to show higher
      prevalence in high-grade squamous intraepithelial lesion (HSIL) than low-grade
      squamous intraepithelial lesions (LSIL), however, HPV 18 was detected in LSIL but
      not in HSIL. HPV 18 tended to have the worse clinical stage, although it was not
      statistically significant. These findings suggest the importance of HPV typing
      other than HPV 16 and 18 and a different clinicopathologic significance of HPV
      18.

PMID- 10642936
TI  - High CD99 expression in memory T and B cells in reactive lymph nodes.
AB  - We investigated the expression of CD99 in 35 hyperplastic perigastric lymph
      nodes, which were resected for gastric carcinoma or chronic peptic ulcer.
      Essentially, all lymphocytes in lymph nodes expressed CD99, but there were two
      populations with respect to the intensity of CD99 expression--CD99high and
      CD99low cells. We showed CD99high cells were distributed in paracortical and
      medullary cords by immunohistochemical study while germinal center cells were
      CD99low. Using three-color flow cytometric analysis with CD3, CD4, CD8, CD19,
      CD23, CD45RA, CD45RO, CD69, CD138, IgM, IgD, and IgG, most of CD99high cells were
      shown to be activated/memory T cells. CD4+CD45RO+ T cells were the subset
      revealing the highest intensity of CD99 expression while CD4+CD45RA+ T cells were
      CD99low. Among B cells, IgG+ B cells revealed a higher level of CD99 molecules
      than IgM+ B cells. These results suggest that CD99 is one of activation-related
      molecules which are upregulated in recently activated lymphocytes.

PMID- 10642937
TI  - Effect of angiopeptin and aspirin on accelerated graft atherosclerosis in
      transplanted mouse heart.
AB  - In this study of the inhibitory effects of angiopeptin and aspirin on the
      development of accelerated graft atherosclerosis (AGAS), 22 B10.BR mice received
      intra-abdominal heterotopic heart transplants from B10.A mice, without
      immunosuppression. Group 1 (n = 5) received no pharmacological intervention,
      Group 2 (n = 6) was treated with angiopeptin, Group 3 (n = 5) with aspirin, and
      Group 4 (n = 6) with both. There was no significant difference in the incidence
      of AGAS among these groups. The magnitude of intimal lesion development showed
      less narrowing of large vessels (> 100 microns in diameter) in groups 2 and 4-
      i.e. the groups received angiopeptin (Group 1 = 46.9 +/- 9.3%, Group 2 = 28.5 +/-
      9.2%, Group 3 = 44.1 +/- 10.9%, Group 4 = 24.2 +/- 5.9%; p < 0.01). Comparison of
      the fraction of tropomyosin-positive staining cells in the intima revealed a
      lesser degree of staining in Group 2 (p < 0.01). No intervention was effective in
      preventing smooth muscle cell proliferation in the media or inflammatory cell
      infiltration in the adventitia. In conclusion, our data suggest that angiopeptin
      is effective in the direct inhibition of intimal smooth muscle cell proliferation
      in relatively large vessels, whereas aspirin exhibits no inhibitory role in the
      progression of AGAS. Angiopeptin appears to be a potential therapeutic agent for
      inhibiting the progression of postoperative AGAS in clinical heart
      transplantation.

PMID- 10642938
TI  - Partial liquid ventilation with perfluorocarbon improves gas exchange and
      decreases inflammatory response in oleic acid-induced lung injury in beagles.
AB  - The aim of this study was to determine the effect of partial liquid ventilation
      (PLV) using a perfluorocarbon (PFC) on gas exchange and lung inflammatory
      response in a canine acute lung injury model. After inducing severe lung injury
      by oleic acid infusion, beagle dogs were randomized to receive either gas
      ventilation only (control group, n = 6) or PLV (PLV group, n = 7) by sequential
      instillation of 10 mL/kg of perfluorodecalin (PFC) at 30 min intervals till
      functional residual capacity was attained. Measurements were made every 30 min
      till 210 min. Then the lungs were removed and bronchoalveolar lavage (BAL) (35
      mL/kg) was performed on the right lung and the left lung was submitted for
      histologic analysis. There was significant improvement in PaO2 and PaCO2 in the
      PLV group compared to the control group (p < 0.05) which was associated with a
      significant decrease in shunt (p < 0.05). There was no significant difference in
      parameters of lung mechanics and hemodynamics. There was a significant decrease
      in cell count and neutrophil percentage in BAL fluid and significantly less
      inflammation and exudate scores in histology in the PLV group (p < 0.05). We
      conclude that PLV with perfluorodecalin improves gas exchange and decreases
      inflammatory response in the acutely-injured lung.

PMID- 10642939
TI  - Detection of tumor cell contamination in peripheral blood by RT-PCR in
      gastrointestinal cancer patients.
AB  - We analyzed the peripheral blood of patients with gastrointestinal tract cancer
      at different stages to assess the presence of carcinoembryonic antigen (CEA) mRNA
      by reverse transcriptase-polymerase chain reaction (RT-PCR), which we used as an
      indicator for micrometastatic malignant cells. A total of 35 gastric, 24
      colorectal, 4 esophageal and 4 biliary tract cancer patients and nine normal
      healthy subjects were studied. No CEA mRNA was detected in the nine normal
      healthy volunteers. CEA mRNA was detected in 100% (10/10) of metastatic, 33.3%
      (3/9) of early gastric cancer (EGC), and 18.8% (3/16) resectable gastric cancer
      patients, respectively. In colorectal cancer, 55.6% (5/9) of metastatic cancers
      were positive for CEA mRNA, and 26.7% (4/15) Duke stage B/C showed positive. One
      patient with stage III gastric cancer who was negative CEA mRNA initially and
      turned positive during follow-up, developed multiple bone metastasis one month
      later. Another stage III patient, who was positive for CEA mRNA, preoperatively
      revealed early relapse in two months. These results suggest that the
      identification of circulating tumor cells using RT-PCR for the detection of CEA
      mRNA is feasible and this analysis may be a promising tool for early detection of
      micrometastatic circulating malignant cells in patients with gastrointestinal
      tract cancer.

PMID- 10642940
TI  - Factors associated with positive predictability of the anti-HCV ELISA method with
      confirmatory RT-PCR.
AB  - The positive predictability of anti-HCV ELISA is low, especially, in blood donors
      and in healthy populations. False positive anti-HCV results pose some
      difficulties in medical practice and in blood screening. The aim of this study
      was to identify the factors associated with true hepatitis C virus (HCV)
      infection among anti-HCV ELISA-positives. A case-control analysis was conducted
      using 354 subjects who were positive for anti-HCV ELISA. All subjects were tested
      for true HCV infection using the reverse transcriptase polymerase chain reaction
      (RT-PCR). Tests for serum alanine aminotransferase (ALT), fasting glucose, HBsAg,
      anti-HBc antibody, alpha-fetoprotein, platelet count and ultrasound of liver were
      also performed. Epidemiological data were obtained by self-administered
      questionnaires. Out of 354 subjects, 202 (57.1%) were positive for HCV by RT-PCR
      and 152 were negative and used as the control group. In multivariate analysis,
      blood transfusion (odds ratio, OR 2.3, 95% confidence interval, CI 1.3-4.0),
      elevated ALT (OR 2.2, 95% CI 1.2-4.3) and higher anti-HCV ELISA ratios (more than
      3; OR 1.7, 95% CI 1.3-2.1) were associated with true HCV infection.
      Thrombocytopenia was also associated with the presence of HCV in univariate
      analysis. These results suggest that a history of blood transfusion, elevated ALT
      and a high score on anti-HCV ELISA ratios are associated with true HCV infection
      among anti-HCV ELISA-positives.

PMID- 10642941
TI  - Changes in expression of cell cycle regulators and their hepatic lobular
      distribution in partial hepatectomy-induced regenerating rat liver.
AB  - Partial hepatectomy (PH) endorses quiescent hepatocytes to reenter the cell
      cycle. The regenerating liver returns to its preresection weight after 7 days,
      following one or two cell division and maintains nearly its original volume after
      then. We focused on the inhibition of further hepatocyte proliferation,
      hypothesizing possible involvement of cell cycle upregulators and inhibitors. We
      studied protein levels in expression of cyclins, cyclin dependent kinases (CDKs)
      and CDK inhibitors (CKIs), and their in situ hepatic lobular distributions in
      partial hepatectomized rat liver. Cyclin E was expressed in the same levels in
      normal liver and after PH. Expression of cyclin A, not detected in normal liver,
      increased in following times after PH and reached a maximum at 7 day. CDK2 and 4
      showed increased expression toward terminal period. Contradictory findings of
      cyclin A and these CDKs might play an important role in the inhibition of further
      cell division, although still unclear. Constitutively expressed CDK6 decreased
      after 1 day. p18 showed peak expression within 1 day, and p16, p21, p27 and p57
      were stronger at terminal periods. During the expected period of their activity,
      intranuclear translocations were observed in cyclin E, p18 and p16. There was no
      evidence of regional distribution in hepatic lobular architecture, instead,
      diffuse in situ expression, corroborating synchronous event, was found.

PMID- 10642942
TI  - Diagnostic criteria for malignancy in bile cytology and its usefulness.
AB  - Fifty three bile specimens from 42 patients were reviewed to assess the
      diagnostic role of the bile cytology and to define more reliable cytologic
      indicators of malignancy. Forty three bile specimens came from 34 patients with
      malignant biliary strictures and 10 bile specimens were from eight patients with
      benign conditions. There were no false positives. The diagnostic specificity of
      bile cytology was 100% while diagnostic sensitivity was 55.8%. Overall diagnostic
      accuracy was 64.2%. We identified four key criteria as cytologic indicators of
      malignancy among 20 variables by using multiple regression analysis: loss of
      honeycomb arrangement, hyperchromatism, increased N/C ratio, and coarse
      chromatin. When bile specimens with three or more of these four criteria are
      thought to represent malignancy, the sensitivity of diagnosis of malignancy was
      65.2%, specificity was 90% and diagnostic accuracy was 69.8%.

PMID- 10642943
TI  - Effects of BCG, lymphotoxin and bee venom on insulitis and development of IDDM in
      non-obese diabetic mice.
AB  - To investigate whether BCG, lymphtoxin (LT) or bee venom (BV) can prevent
      insulitis and development of diabetes in non-obese diabetic (NOD) mice, we
      measured the degree of insulitis and incidence of diabetes in 24 ICR and 96
      female NOD mice. NOD mice were randomly assigned to control, BCG-, LT-, and BV
      treated groups. The BCG was given once at 6 weeks of age, and LT was given in 3
      weekly doses from the age of 4 to 10 weeks. The BV was injected in 2 weekly doses
      from the age of 4 to 10 weeks. Diabetes started in control group at 18 weeks of
      age, in BCG group at 24 weeks of age, and in LT- or BV-treated group at 23 weeks
      of age. Cumulative incidences of diabetes at 25 weeks of age in control, BCG-, LT
      , and BV-treated NOD mice are 58, 17, 25, and 21%, respectively. Incidence and
      severity of insulitis were reduced by BCG, LT and BV treatment. In conclusion,
      these results suggest that BCG, LT or BV treatment in NOD mice at early age
      inhibit insulitis, onset and cumulative incidence of diabetes.

PMID- 10642945
TI  - Spinocerebellar ataxia type 2 in seven Korean families: CAG trinucleotide
      expansion and clinical characteristics.
AB  - Studies on spinocerebellar ataxias (SCA) have been hampered by a lack of disease
      markers. Clinical and pathological heterogeneity also made the classification
      unreliable. Linkage studies established that there are multiple subtypes of SCA.
      Five types are found to have unstable CAG expansion; the diagnosis can be
      established by molecular genetic study. Therefore, we systemically screened
      degenerative ataxia patients for these five SCA types, and identified eight
      patients with SCA2 (seven from six families and one sporadic case). This paper
      presents the clinical information on the seven patients, whose clinical
      information was available in detail. CAG repeat expansion in the patients ranged
      from 38 to 47 (normal control, 19 to 27). The onset ages ranged from 16 to 41
      with 27.1 years as the mean, which correlated inversely with repeat lengths. All
      patients presented dysarthria and gait ataxia. Upper limb dysmetria or
      dysdiadochokinesia appeared later but progressed, causing severe disability. Slow
      saccade (4 patients in 7) and decreased DTR (4 in 7) were common. MRIs showed
      severe atrophy of the brainstem and cerebellum in all patients. We conclude that
      SCA2 is the most frequent type in Korea and carries rather pure cerebellar
      syndrome, slow saccade, and hyporeflexia.

PMID- 10642944
TI  - Individual or combined effects of enalapril and verapamil on chronic cyclosporine
      nephrotoxicity in rats.
AB  - Previous studies have demonstrated that enalapril and verapamil seem to attenuate
      the cyclosporine nephrotoxicity. However, the mechanisms have not been completely
      understood, especially on molecular events. The aim of this study was to examine
      the effect of individual or combined treatment on osteopontin, TGF-beta,
      endothelin-1 and procollagen alpha 1(I) mRNA expressions. Enalapril (50 mg/L in
      drinking water) and verapamil (0.5 mg/kg/day, subcutaneously), alone or in
      combination, were administered to rats with chronic cyclosporine nephrotoxicity
      (cyclosporine, 25 mg/kg/day, subcutaneously) (n = 5 each). Five rats treated with
      olive oil vehicle were used as control. After 4 weeks, biochemical parameters
      were measured, and renal cortical mRNA levels were evaluated by Northern blot
      analysis. Cyclosporine reduced renal creatinine clearance significantly and
      induced renal cortical osteopontin, TGF-beta, endothelin-1 and procollagen alpha
      1(I) gene expressions around 13.5 +/- 1.3, 2.4 +/- 0.2, 1.5 +/- 0.1, 1.9 +/- 0.1
      folds, respectively. Individual treatment with enalapril or verapamil
      significantly suppressed the osteopontin and TGF-beta mRNA expression, but not
      endothelin-1 and procollagen alpha 1(I). Combined treatment also inhibited the
      osteopontin and TGF-beta mRNA expression but there was no difference between
      combined and individual treatment. In conclusion, enalapril or verapamil
      significantly blunted the cyclosporine-induced osteopontin and TGF-beta gene
      expressions. However, combined treatment did not show any additive effect.

PMID- 10642946
TI  - Differentiation characteristics of cholesteatoma epithelium determined by
      expression of transglutaminase isoenzymes.
AB  - Transglutaminase (TGase) isoenzymes are involved in the process of the
      differentiation and cornification of keratinocytes in the epidermis. This study
      investigates the presence and localization of three TGase isoenzymes to elucidate
      the nature and differentiation status of the squamous epithelium in human aural
      cholesteatoma. Twenty cholesteatoma specimens were used. The presence and
      localization of three TGase isoenzymes were studied by reverse transcription
      polymerase chain reaction (RT-PCR) and immunohistochemistry. mRNA expression of
      three TGase isoenzymes were detected in the tested cholesteatomas with variable
      levels. The immunohistochemical staining patterns of three TGase isoenzymes
      showed variations within specimens, relating to keratinizing activity. TGase K is
      the most abundant among three isoenzymes. Keratinizing epithelium of
      cholesteatoma have similar expression profiles of TGase isoenzymes with those of
      epidermis of the skin. Other areas, particularly those showing non-keratinizing
      epithelium, showed weak immunostaining of TGase E and C, suggesting its different
      maturation status from keratinizing epithelium. The results of this study
      indicate that epithelium of cholesteatoma undergoes same direction of maturation
      and differentiation characteristics as the epidermis of skin, evidenced by
      similar expressions of TGases both in mRNA level and immunohistochemistry.

PMID- 10642948
TI  - 99mTc-MIBI scan in mammary Pagets disease: a case report.
AB  - Technetium-99m methoxyisobutylisonitrile (99mTc-MIBI) uptake is known to be
      increased in breast cancer because of increased blood flow from angiogenesis and
      heightened metabolism. We performed a 99mTc-MIBI scan in a patient with mammary
      Paget's disease. The patient had underlying invasive cancer in the same side of
      the breast. 99mTc-MIBI scan exhibited a scintigraphic image of the uptake from
      the invasive cancer lesion located deeply in the breast toward the epidermis.
      99mTc-MIBI showed an uptake in the deeply located invasive cancer lesion as well
      as nipple lesion. Especially, the delayed phase of Tc-MIBI scan demonstrated the
      tumor site more accurately. In conclusion, 99mTc-MIBI scan could be a useful
      adjunct to clinical decision making in the management of Paget's disease of the
      breast.

PMID- 10642947
TI  - Hepatosplenic B-cell lymphoma associated with hemophagocytic syndrome: a case
      report.
AB  - While T-cell non-Hodgkin's lymphoma (NHL) associated with hemophagocytic syndrome
      (HPS) has been frequently observed, B-cell NHL associated with HPS has been
      rarely reported. We report a case of hepatosplenic B-cell lymphoma associated
      with HPS in a 41-year-old woman who presented with fever of unknown origin. An
      abdominal CT scan revealed splenomegaly with focal splenic infarction.
      Splenectomy and a liver wedge biopsy showed sinusoidal-pattern infiltration of
      medium to large tumor cells with positive reaction to a B-lymphocyte marker.
      Findings on bone marrow examination showed proliferation of histiocytes with avid
      hemophagocytosis.

PMID- 10642949
TI  - Macroamylasemia in a patient with acute appendicitis: a case report.
AB  - Macroamylasemia is a condition of persistent, elevated serum amylase activity
      with no apparent clinical symptoms of a pancreatic disorder. In Korea, however,
      no such case has been reported to date. We report a case of a 17-year-old female
      diagnosed with macroamylasemia and acute appendicitis. One day earlier, she
      developed epigastric and right lower quadrant abdominal pain. She was
      characterized by high level of serum amylase, but normal lipase. Amylase
      isoenzyme analysis demonstrated increased fraction of salivary type and follow-up
      amylase level was persistently increased. Immunofixation disclosed the
      macroamylase binding with an immunoglobulin, consisting of IgA and kappa chain.
      The patient was treated by appendectomy, and the abdominal pain subsided.

PMID- 10642950
TI  - Tenosynovial giant cell tumor of finger, localized type: a case report.
AB  - The authors report a typical case of tenosynovial giant cell tumor of the right
      middle finger of a 31-year-old man. Histologically, this tumor is characterized
      by a discrete proliferation of rounded synovial-like cells accompanied by a
      variable number of multinucleated giant cells, inflammatory cells, and xanthoma
      cells. Clinicopathologically, this tumor is a benign lesion that nonetheless
      possesses a capacity for local recurrence. Local excision with a small cuff of
      normal tissue is the treatment of choice in this tumor.

PMID- 10642951
TI  - Behcet's disease associated with myelodysplastic syndrome: a case report.
AB  - A rare case of Behcet's disease associated with myelodysplastic syndrome (MDS) is
      described. A 50-year-old Korean female suffering recurrent oral ulcer, genital
      ulcer, fatigue, arthralgia in both knees and fever was diagnosed as Behcet's
      disease. The findings of bone marrow aspirates were consistent with refractory
      anemia, a subtype of myelodysplastic syndrome. Chromosomal analysis of bone
      marrow cells revealed 46,XX,-8,-20,+der(8)t(8;20)(p23;p10),+der(8)
      t(8;20)(p23;q10)[30]. The chromosomal changes found in this patient were
      different from those of previous reports, which mostly revealed trisomy 8. If
      anemia, low reticulocyte count and dyspoietic cells are sustained in Behcet's
      disease, physicians should be alert to the possibility of MDS with aberration in
      chromosome 8 and perform a bone marrow study for the proper diagnosis and
      treatment of the disease. We presented a case of Behcet's disease associated with
      MDS, which is the first Korean case.

PMID- 10642952
TI  - Neural toxicity induced by accidental intrathecal vincristine administration.
AB  - Described here is a case of accidental intrathecal administration of vincristine
      with pathologic findings in the central nervous system. A 3-year-old boy with
      acute lymphoblastic leukemia, was given his ninth course chemotherapy.
      Vincristine was accidentally injected intrathecally. The clinical course was
      rapidly progressive (6-day course) and resulted in death. An autopsy was done.
      The brain and spinal cord was grossly edematous and congested without any
      specific feature. Histologically, profound loss of neuron was noted in the spinal
      cord. Remaining neurons in the spinal cord, particularly anterior horn cells were
      markedly swollen. The spinal nerves show diffuse axonal degeneration and myelin
      loss. The upstream portion of the spinal cord (brain stem, cerebellum, cerebrum)
      showed patchy loss of neurons, especially Purkinje cells and granular cells of
      the cerebellar cortex. Many neurons showed axonal reaction (chromatolysis) with
      swelling. Several neurons show intracytoplasmic eosinophilic inclusion body.
      Myelin loss, axonal swelling and enlargement of perivascular spaces were seen
      throughout the white matter of central nervous system.

PMID- 10642953
TI  - Cord occlusion techniques for selective termination in monochorionic twins.
AB  - We wished to determine the optimal method for cord obliteration to perform
      selective reduction in complicated monochorionic (MC) twin pregnancies under
      different clinical conditions. For this purpose, we reviewed our experience and
      the available published literature and unpublished reports. Indications were a
      cardiac twin pregnancy, twins discordant for fetal anomaly, and severe feto-fetal
      transfusion syndrome where one twin had a very poor prognosis. Data were
      available for the following techniques: cord embolization, fetoscopic cord
      ligation, laser coagulation, monopolar coagulation and bipolar cautery.
      Unfortunately the data are heterogeneous, incomplete and reports are only
      sporadic. Cord embolization using coils or sclerosants has a high failure rate
      and can no longer be recommended. In 23 published cases of fetoscopic cord
      ligation a failure rate of 10% was reported. After successful ligation an overall
      fetal survival rate of 71% but a risk of preterm prelabor rupture of the
      membranes (PPROM) of 30% was documented. Four cases of monopolar coagulation have
      been published--all in a cardiac twin pregnancies. In three cases the abdominal
      aorta was coagulated prior to 20 weeks and complete cessation of flow was
      demonstrated. In 10 cases of bipolar cord coagulation, all procedures were
      technically successful. Nine of 10 were performed under ultrasound guidance
      through a single port. In 2 cases, frank PPROM occurred, leading to induction of
      labor. The other eight fetuses were born at 35 weeks or more. Nd:YAG coagulation
      of the cord was much more sporadically described; the success of the procedure
      seems to be clearly dependant on gestational age. In all our attempts prior to 20
      weeks, we failed in only one out of 6 cases. In summary, there is little data to
      perform meaningful comparisons of available techniques for umbilical cord
      occlusion. Based on practical and technical considerations we use the following
      clinical algorithm: prior to 21 weeks, we attempt to coagulate the cord with
      Nd:YAG laser. If this is unsuccessful, or for gestations beyond 21 weeks, bipolar
      cord coagulation is currently our other method of choice. Sonoendoscopic cord
      ligation is reserved as backup procedure if neither of these methods are
      successful.

PMID- 10642954
TI  - Comparison of vaginal and cesarean section delivery for fetuses in breech
      presentation.
AB  - OBJECTIVES: Our purpose was to evaluate the perinatal mortality and morbidity of
      deliveries with fetuses presenting by the breech comparing outcomes of two groups
      according to mode of delivery: vaginal and cesarean section. RESULTS: Of 756
      fetuses studied, 271 were delivered vaginally and 485 by cesarean section. In
      infants weighing > or = 1500 grams, "further corrected" mortality and morbidity
      rates were low and similar for both delivery routes: one neonatal death (NNM) in
      each. Among very low birth weight (VLBW) infants (< 1500 grams) the "further
      corrected" mortality rate was higher in the vaginal group: 57.4%, and 18.0% in
      abdominal deliveries (odds ratio [OR] = 6.1, 95% CI: 3.1 to 12.1). Likewise, rate
      of depression at five minutes were higher in the vaginal group (p < 0.001).
      However, the average fetal weight among the vaginal deliveries VLBW (787 grams)
      was 250 grams less than in the cesarean section group (1040 grams). After
      adjustment for fetal weight, gestational age, and other prognostic variables the
      odds ratio for neonatal death was no longer statistically significant (adjusted
      OR = 2.1, 95% CI: 0.9 to 5.2, p = 0.105). Comparison of planned vaginal delivery
      with elective cesarean section yielded smaller differences (adjusted OR for
      neonatal death = 1.3, 95% CI: 0.6 to 2.9, p = 0.525). CONCLUSION: The poor
      perinatal outcomes of breech delivered infants are due primarily to VLBW,
      congenital malformations, and premature labor. Although abdominal delivery had a
      lower NNM rate than vaginal delivery, the difference was not significant after
      adjustment for confounding factors. The results confirm the findings of a
      previously analyzed similar series delivered at our institution between 1980 and
      1987. They suggest that, with appropriate technique, abdominal delivery is not
      mandatory in breech presentation.

PMID- 10642955
TI  - Neonatal cerebral Doppler: arterial and venous flow velocity measurements using
      color and pulsed Doppler system.
AB  - OBJECTIVE: To contribute to the establishment of reference values of blood flow
      velocity assessed by cerebral Doppler in healthy infants related to gestational
      age and birth weight during the first week of life. METHODS: Five arteries and
      three veins were evaluated respectively in 120 (74 premature) newborns and in 100
      (70 preterm) infants. In a quarter of the latter three recordings at 5-minute
      intervals were made to assess reproducibility. The relation between flow
      measurements and gestational age was assessed by linear regression, means by
      analysis of variance (or Kruskall-Wallis test) and paired samples by Student's t
      test. RESULTS: There was a significant increase of arterial velocities with
      increasing gestational age and birth weight, but not for venous velocities.
      Significant higher values were found in the internal carotid artery followed by
      the medium cerebral artery. The venous velocities were highly reproducible and
      the main patterns observed were bandlike and sinusoid type. CONCLUSION: The
      knowledge of normal cerebrovascular physiology is essential to understand the
      pathogenesis of neonatal brain damage and can help pediatricians in an accurate
      interpretation of the flow profile in neurological pathology.

PMID- 10642956
TI  - MMP/TIMP imbalance in amniotic fluid during PROM: an indirect support for
      endogenous pathway to membrane rupture.
AB  - OBJECTIVE: We theorize that excessive degradation of the fetal membrane
      extracellular matrix (ECM) by specific matrix metalloproteinases (MMPs) results
      in preterm premature rupture of the membranes (PROM). Active, inhibitor free MMP2
      and 9 (gelatinase A and B respectively) can degrade the amniochorion basement
      membrane Type IV collagen to initiate rupture. This study examines the levels of
      the gelatinases and their natural inhibitors (tissue inhibitor of matrix
      metalloproteinases-TIMPs) in the amniotic fluid during PROM, preterm labor (PTL)
      and at term. METHODS: A total of 51 AF samples were collected from the following
      groups of patients. Group 1: Women with PTL and no ROM (n = 16) Group 2: Women
      with PROM (n = 16) irrespective of labor status Group 3: Women at term with
      intact membranes undergoing cesarean delivery irrespective of labor status (n =
      19). ELISA was used to assay MMP2, MMP9, TIMP1 and TIMP2 levels in the amniotic
      fluid. The active, TIMP free levels of MMP2 were quantitated by zymography
      followed by computerized densitometry. Active MMP9 was measured using a bioassay
      that specifically detects MMP9 activity. Statistical analysis was performed by
      Tukey-Kramer multiple comparison method. RESULTS: PROM is associated with
      increased MMP2 levels (mean 2125 ng/ml;) when compared with term (mean 1455
      ng/ml; p < 0.01) or PTL where a non significant increase was seen (mean 1862
      ng/ml; p = ns). MMP9 levels were higher in PROM (mean 15.03 ng/ml) than at term
      (mean 1.14 ng/ml; p < 0.001) or PTL (mean 3.75 ng/ml; p < 0.01). TIMP1 levels
      were slightly increased during PROM (mean 3143 ng/ml) compared to term (mean 1892
      ng/ml; p < 0.05) pr PTL where a non significant change was seen (mean 2406 ng/ml;
      p = ns). TIMP2 levels were decreased in PROM (mean 98 ng/ml) compared with term
      (mean 176 ng/ml; p < 0.05) and PTL (mean 236 ng/ml; p < 0.001). Active, TIMP free
      MMP2 levels were increased during PROM (mean 233 pg/ml) compared to those at term
      (mean 132 pg/ml; p < 0.05) or PTL (mean 132 pg/ml; p < 0.05). Active forms of
      MMP9 were seen only during PROM (mean 632 pg/ml). CONCLUSION: Active, TIMP free
      forms of MMP2 and 9 are increased in the amniotic fluid of women with PROM. These
      MMPs can degrade the amniochorion basement membranes and other ECM components
      resulting in PROM.

PMID- 10642957
TI  - Pulmonary hemorrhage in neonates of early and late gestation.
AB  - Our objectives in this study of pulmonary hemorrhage (PH) were to define common
      characteristics of infants who develop PH, identify factors associated with PH
      and report the outcome. Neonates (42/2980 admissions) with PH and matched
      controls were identified. Early gestation (< or = 35 weeks) infants with PH
      [EGPH] (n = 34; 12 survived) had occurrence of PH at 3.6 +/- 1.1 (mean +/- sem)
      days and were significantly associated with multiple births (p = 0.03), RDS (p <
      0.01) and use of Survanta (p < 0.02). Among EGPH, small for gestational age (SGA)
      infants (n = 7) had a 100% mortality rate. Late gestation (> or = 36 weeks)
      infants with PH [LGPH] (n = 8; 6 survived) had occurrence of PH at 0.7 +/- 0.3
      days and were significantly associated with low 1 minute (p = 0.04) and 5 minutes
      (p = 0.01) Apgar scores. All infants were managed with increases in mean airway
      pressure (MAP) and/or use of cocaine/epinephrine through the endotracheal tube.
      We have identified 2 groups of neonates with distinct factors associated with PH;
      use of 1:10,000 epinephrine (0.1 ml/kg) and/or 4% cocaine (4 mg/kg) may be useful
      adjuncts to increases in MAP for management of PH.

PMID- 10642958
TI  - Nucleated red blood cells in cord blood of singleton term and post-term neonates.
AB  - OBJECTIVE: This study aims to determine if nucleated red blood cells are elevated
      in pregnancies that continue beyond 289 days of gestation. STUDY DESIGN: Cord
      blood was prospectively collected from term and post-term singleton gestations
      from August 1 to December 31, 1998. Umbilical artery nucleated red blood cells
      were counted per 100 white blood cells. The comparison was made between
      pregnancies ending at 261-289 days (37.1-41.2 weeks) of gestation and those
      ending after 289 days (> or = 41.3 weeks) of gestation. RESULTS: Cord blood from
      304 cases was obtained and evaluated for nucleated red blood cells per 100 white
      blood cells. The mean value of nucleated red blood cells per 100 white blood
      cells in the post-term neonate group was significantly higher than in the term
      neonate group (median 6.5, range 0-24 vs. median 3.7, range 0-14; p < 0.05). The
      values did not vary by fetal presentation, mode or duration of delivery. Neonatal
      outcome was comparable between both study groups. CONCLUSION: In post-term
      gestation after 289 days nucleated red blood cells in cord blood are
      significantly increased. These results point towards a different fetal
      oxygenation in post-term pregnancies beyond 289 days of gestation and support the
      current practice of very close testing of fetal well-being under those
      circumstances.

PMID- 10642959
TI  - Neonatal lung function in very immature infants with and without RDS.
AB  - Some infants, despite being born at low gestations (< 28 weeks gestational age)
      do not develop RDS and are not surfactant treated. The changes in lung function
      during the neonatal period in such infants have not been explored, hence it is
      unknown whether they are similar to those of surfactant treated infants with RDS
      of similar gestational age. Such data would facilitate assessment of the impact
      of surfactant administration on the lung function abnormalities of very immature
      infants with RDS. We, therefore, compared the results of neonatal lung function
      measurements from immature infants with RDS who received surfactant to those from
      infants with non-RDS respiratory distress not so treated and matched to the RDS
      infants for gestational age and within 10% of birthweight. Compliance and
      functional residual capacity (FRC) were measured daily for the first five days
      and then at 1, 2 and 4 weeks in 16 infants, median gestational age 27 weeks
      (range 25-27 weeks). Although exogenous surfactant administration to the immature
      infants with RDS was associated with improvements in lung function, the non RDS,
      non surfactant treated infants had both higher compliance (p < 0.05) and lung
      volumes (p < 0.01) throughout the perinatal period. These results demonstrate
      surfactant administration does not fully correct the perinatal lung function
      abnormalities of very immature infants with RDS.

PMID- 10642960
TI  - Doppler sonographic findings for hypertension in pregnancy and HELLP syndrome.
AB  - Doppler examinations of the umbilical artery, both uterine arteries, and the
      fetal middle cerebral artery were performed in the third trimester in 18 patients
      with pregnancy induced hypertension, 52 patients with preeclampsia, and 32
      patients with HELLP syndrome and the results were correlated with the parameters
      fetal outcome. For 74% of the patients this was the first pregnancy, in 93% of
      the cases a cesarean section was necessary; 66% of the newborn babies were
      dystrophic and 90% of them were born prematurely. The blood flow in one uterine
      artery was restricted in 95% of all 102 pregnant women, only 5% did not show any
      pathological findings. A pathological blood flow was observed on Doppler
      sonography in the umbilical artery in 70% of the group and 39% showed a
      pathologically increased perfusion of the fetal middle cerebral artery. The
      average birth weights and gestational ages in the study group were markedly
      reduced in comparison with healthy pregnant women (pregnancy induced
      hypertension: 1620 g/35 weeks; preeclampsia: 1660 g/34 weeks; HELLP syndrome:
      1160 g/31 weeks, respectively). The lowest values for average birth weight and
      gestational age occurred when all four investigated blood vessels showed
      pathological Doppler findings: 1180 g/31 weeks (0 to 1 pathological vascular
      findings: 2780 g/38 weeks; 2 pathological vascular findings: 1845 g/34.5 weeks; 3
      pathological vascular findings: 1330 g/31 weeks). This Doppler study underlines
      the importance of examining four blood vessels: the uterine, the umbilical, and
      the fetal middle cerebral arteries for a complete analysis of the fetoplacental
      hemodynamics. On account of the severely impaired hemodynamics observed in the
      placentas of our patients with hypertensive diseases in pregnancy or HELLP
      syndrome, we believe the early diagnosis of these disorders by Doppler sonography
      and an early start of therapy to be essential.

PMID- 10642961
TI  - Vitamin E status of infants at birth.
AB  - Preterm infants may be susceptible to chronic lung disease and retinopathy of
      prematurity because of deficient antioxidant mechanisms including deficiency of
      vitamin E. The aim of this study was to evaluate the status of the antioxidant
      vitamin E among preterm and term livebirths. Umbilical cord blood samples
      collected from 40 preterm and 180 term babies were analyzed for vitamin E levels
      using high performance liquid chromatography. Linear regression analysis was used
      to examine the relationship of vitamin E with gestational age, birth weight and
      appropriateness of weight for gestational age. The median vitamin E level of
      preterm babies (2.61 mg/L) was not significantly different from that of term
      babies (2.77 mg/L), p = 0.2. Linear regression analysis demonstrated a weak but
      statistically significant correlation between cord blood vitamin E levels and
      gestational age (r = 0.14, p = 0.046). Vitamin E levels did not correlate with
      birth weight or weight for gestational age. Preterm babies had a higher incidence
      of vitamin E deficiency compared to term babies (38% v 19%, p = 0.02). Our
      findings lead us to conclude that vitamin E accumulates in the fetus throughout
      the third trimester so that preterm infants are likely to have vitamin E
      deficiency.

PMID- 10642962
TI  - Successful transcutaneous arterial embolization of a giant hemangioma associated
      with high-output cardiac failure and Kasabach-Merritt syndrome in a neonate: a
      case report.
AB  - We describe the case of a patient with a neonatal giant cutaneous hemangioma with
      high-output cardiac failure and Kasabach-Merritt syndrome and successfully
      treated with transcutaneous arterial embolization aimed at controlling severe
      congestive heart failure and consumption coagulopathy. A patient was admitted to
      the neonatal care unit on the first day of age because of a large hemangioma on
      his right lateral chest wall and respiratory distress, associated with cardiac
      failure resulting from arteriovenous shunting. On the second day of age the
      platelet count decreased to 5.7 x 10(4)/microliter and fibrinogen level was 85
      mg/dl. The values of prothrombin time and activated partial thromboplastin time
      were prolonged. Intravenous predonisone therapy was started immediately, but
      bleeding tendency was getting worse and the evidence of congestive heart failure
      persisted. On the third day the patient then underwent embolization of feeding
      arteries with microcoils. The cardiac failure and thrombocytopenic coagulopathy
      had improved significantly without complications. We conclude that transcutaneous
      arterial embolization is an effective and safe treatment in this neonate and
      should be considered for the treatment of control high-output cardiac failure and
      coagulopathy in infants with hemangioma and Kasabach-Merritt syndrome.

PMID- 10642963
TI  - 1H NMR as a non-invasive probe of amniotic fluid in insulin dependent diabetes
      mellitus.
AB  - Ten amniotic fluid samples obtained from third trimester pregnant women suffering
      from insulin dependant diabetes mellitus were analysed by 1H-NMR and compared to
      ten samples from a group of normal volunteers. A subset of the metabolites
      identified; valine, lactate, alanine, acetate, citrate and glucose were
      quantitated using standard addition methods. Apart from valine and citrate, a
      general diminution in the concentration of each of these species was found,
      especially glucose, in the diabetic group. The abnormally low glucose levels in
      the diabetic group are suggestive of infection in the patient group. However, the
      depressed lactate levels in the diabetic group suggest that in these cases the
      fetus was not subjected to stress.

PMID- 10642964
TI  - Let's take PORCC (pork) out of the barrel.

PMID- 10642965
TI  - Membrane sweeping versus dinoprostone vaginal insert in the management of
      pregnancies beyond 41 weeks with an unfavorable cervix.
AB  - OBJECTIVE: To determine the best method of cervical ripening to prevent postdate
      inductions in women with an unfavorable cervix at 41 weeks' gestation. STUDY
      DESIGN: Women presenting at 41 weeks' gestation with a Bishop score of < or = 4
      received daily dinoprostone (Cervidil) vaginal inserts (group I) or daily
      membrane sweeping (group II). RESULTS: One-hundred and eighty-two women were
      prospectively randomized with 91 women in each arm. The women in group II,
      membrane sweeping, had Bishop scores significantly greater on admission for
      delivery (p < 0.001), had less time elapsed from admission to delivery (p =
      0.018), and had fewer labor inductions at 42 weeks (p = 0.04) than the women in
      group I, the dinoprostone group. In addition, a greater number of women in group
      II were admitted in spontaneous labor (p = 0.006) than in group I. Total
      antenatal costs for the membrane sweeping group was $15,120 versus $59,540 for
      the dinoprostone group. CONCLUSION: Daily membrane sweeping was more effective
      than dinoprostone administration with fewer postdate inductions at one-fourth the
      cost.

PMID- 10642966
TI  - Prediction of length of hospital stay in neonatal units for very low birth weight
      infants.
AB  - OBJECTIVE: To develop models for estimating the length of hospital stay (LOS) of
      very low birth weight infants (VLBW), based on perinatal risk factors present
      during the first week of life and during the entire hospitalization period. STUDY
      DESIGN: The files of 155 VLBW were analyzed, and the influence of individual risk
      factors were initially evaluated by univariate analysis, using multiple
      regression. Two mathematical models were built to estimate the LOS. RESULTS: The
      first model, using risk factors present during the first 3 days of life, is as
      follows: LOS = -0.074A + 22.06B + 22.85C - 16.78D - 2.07E + 10.51F + 203.12 (R2 =
      0.63). (The letters are added to show what each number represents: A: birth
      weight; B: occurrence of respiratory distress syndrome; C: endotracheal
      intubation during resuscitation; D: 1-minute Apgar score; E: gestational age; F:
      presence of complications during delivery.) The second model, using factors
      present during the entire hospitalization period, is: LOS = 0.61G + 29.19H +
      24.68I + 14.21J + 23.56K + 9.54L + 7.41M + 20.43 (R2 = 0.82). (G: age receiving
      nutritional support of > or = 120 kcal/kg per day; H: occurrence of systemic
      candidiasis; I: birth weight < 1000 gm; J: presence of delivery complication; K:
      occurrence of bronchopulmonary dysplasia; L: birth weight > or = 1000 gm and < or
      = 1249 gm; M: occurrence of anemia). CONCLUSION: Both models are applicable for
      estimating the hospitalization period, and the addition of variables present
      during the entire hospitalization period improved the accuracy of the model.

PMID- 10642967
TI  - Risk of previous very low birth weight and very preterm infants among women
      delivering a very low birth weight and very preterm infant.
AB  - OBJECTIVE: To examine the relationship of the birth of a very low birth weight
      (VLBW, < 1500 gm) and very preterm (VPT, < or = 32 week) infant to previous
      occurrences of VLBW-VPT infants among women who had two to five pregnancies.
      STUDY DESIGN: This was a case-control study using data from the 1988 National
      Maternal and Infant Health Survey (NMIHS). A case was defined as a singleton live
      birth weighing 500 to 1499 gm with a gestational age of < or = 32 weeks. Control
      infants were defined as singleton births weighing > 2500 gm with gestational ages
      of > or = 38 weeks. RESULTS: There were 128 non-black cases and 864 non-black
      controls, and 241 black cases and 1205 black controls available for analysis.
      Logistic regression was used to adjust for a history of previous stillbirth,
      mother's birth weight, pre-pregnancy weight, pregnancy interval, and
      sociodemographic risk factors. The adjusted odds ratio for the occurrence of a
      previous VLBW-VPT birth for non-black cases versus controls was 21.24 (6.87,
      65.7) and for black cases versus controls, 6.87 (3.82, 12.34). CONCLUSION: These
      results confirm the substantial risk of previous VLBW-VPT infants among women
      giving birth to such an infant, independent of sociodemographic factors and other
      prior pregnancy outcomes.

PMID- 10642968
TI  - The predictive value of fetal acoustic stimulation.
AB  - OBJECTIVE: To compare the predictive abilities, test duration times, and
      incidence of nonreactive results in the acoustic stimulation test (AST) and the
      nonstress test (NST). METHOD: Four-hundred randomly selected patients, delivering
      within 7 days of a preceding test, were divided into two groups (group I: NST;
      group II: AST). In the AST group, fetal heart rate tracing were recorded for the
      first 5 minutes as a baseline recording. If the reactivity criterion was not met,
      transabdominal acoustic stimulation to the fetal head was performed. In the NST
      group, nonreactive tests were followed by a repeat NST. In both groups,
      nonreactive tests were followed by oxytocin challenge test (OCT) on the same day.
      Depressed 5-minute Apgar scores (< 7) and an umbilical arterial blood pH of < 7.2
      were taken as indicators of fetal distress. Sensitivity, specificity, and
      predictive values of NST and AST were calculated and compared. RESULTS: The
      incidence of nonreactive tests was lower in the AST group. AST decreased the test
      duration time by 10.1 minutes. The sensitivity values were 87.5% in the NST group
      and 85.7 in the AST group; specificities of were found to be 94% for AST and 88%
      for NST. The negative predictive value was found to be 98% in each group, but the
      positive predictive value was 54.5% in the AST group and 38.8% in the NST group.
      CONCLUSION: AST offers benefits, by decreasing the incidence of nonreactive tests
      and reducing the test time. AST lowers the rate of false positives without
      changing the negative reliability of NST. It is a safe test and allows more
      efficient use of perinatal services.

PMID- 10642969
TI  - Complications associated with surgically placed central venous catheters in low
      birth weight neonates.
AB  - OBJECTIVE: To determine the incidence of complications in low birth weight
      neonates with surgically inserted central venous catheters (CVCs). STUDY DESIGN:
      Retrospective chart review of all neonates < or = 1500-gm birth weight from three
      tertiary care neonatal intensive care units who required CVC insertion. RESULTS:
      A total of 112 CVCs was inserted in 104 neonates with birth weight of 798 (490 to
      1380) gm, age 16 (3 to 179) days, for a duration of 21 (1 to 130) days. The birth
      weights of 85 neonates were < or = 1000 gm. One or more complications associated
      with the CVC occurred in 59 patients (57%). Sepsis was the commonest
      complication, with 43 episodes in 38 patients, at a rate of 14.5 episodes/1000
      catheter days. Using regression analysis, sepsis was associated with birth
      weight, male sex, and the duration for which the CVC remained in place. Five of
      the nine who developed superior vena cava syndrome and/or pleural effusions died.
      CONCLUSION: CVCs can provide venous access that is durable. However, in the LBW
      neonate, and especially in those of < or = 1000 gm, there is a high incidence of
      associated complications.

PMID- 10642970
TI  - The pediatric disposable end-tidal carbon dioxide detector role in endotracheal
      intubation in newborns.
AB  - OBJECTIVE: To determine the practical value of the new pediatric disposable ETCO2
      detector Pedi-CAP in verifying endotracheal tube placement in neonatal
      resuscitation. METHODS: Infants who required endotracheal intubation in the
      delivery room or the neonatal intensive care unit (NICU) were included in a
      prospective study in which the endotracheal tube placement was determined
      clinically and simultaneously by the Pedi-CAP and confirmed by chest radiograph.
      The Pedi-CAP and clinical evaluation determination times of the endotracheal tube
      placement were measured and compared. The accuracy and ease of the Pedi-CAP use
      were tested. RESULTS: Forty-five newborns (450 to 4620 gm) who needed
      endotracheal intubation were included in the study. Twenty-four (53.3%) were
      intubated in the delivery room and 21 (46.7%) in the NICU. The Pedi-CAP color
      indicator correlated with the clinical evaluation and radiograph findings of
      proper intubation in 30 of 33 patients (sensitivity 91%, specificity 100%,
      positive predictive value 100%, and negative predictive value 80%). There were
      three false-negative results in patients with severe cardiorespiratory
      depression. The Pedi-CAP color indicator correlated with the clinical evaluation
      for the ET-tube being in the esophagus in 12 of 12 patients (sensitivity,
      specificity, and positive and negative predictive value were all 100%). The time
      required to determine the tube position by clinical evaluation was 0 to 90
      seconds (mean = 39.7 seconds; SD +/- 15.3 seconds). The time required with the
      disposable ETCO2 detector was 4 to 12 seconds (mean = 8.1 seconds; SD +/- 2.9
      seconds; p < 0.001). CONCLUSION: The use of a disposable pediatric endotracheal
      CO2 detector significantly reduces the time spent in verifying the endotracheal
      tube position (trachea versus esophagus) in newborns, including premature babies
      with body weight < 1000 gm. This is of particular benefit to babies who are
      erroneously intubated in the esophagus, because using the device allows much
      faster detection of this problem and much earlier reintubation.

PMID- 10642971
TI  - The duration of labor in healthy women.
AB  - OBJECTIVE: To measure the duration of active labor (first and second stages) in
      low-risk women whom received intrapartum care from certified nurse-midwives in
      nine hospital settings in the United States in 1996. Clinical factors and
      morbidity indicators associated with longer labors were also examined. DESIGN: An
      observational study was conducted with healthy women at term who did not receive
      oxytocin or epidurals (n = 2511). Descriptive statistics are reported for the
      duration of the active phase--first stage (4 cm to complete cervical dilatation)
      and second stage (complete to delivery)--by parity and for subgroups of women
      according to race/ethnicity, age, insurance, activity in labor, type of fetal
      heart monitoring, and narcotic analgesia. Logistic regression was also used to
      assess the contribution of each variable to longer labors with simultaneous
      adjustment of the other variables. RESULTS: The mean length of the active-phase,
      first stage was 7.7 hours for nulliparas and 5.6 hours for multiparas
      (statistical limits of 2 standard deviations from the mean were 17.5 and 13.8
      hours, respectively). The mean length of second stage was 54 minutes for
      nulliparas and 18 minutes for multiparas (statistical limits 146 and 64 minutes,
      respectively). Variables associated with longer labors were electronic fetal
      monitoring, ambulation, maternal age over 30 years, and narcotic analgesia.
      Morbidity was not increased in longer labors. CONCLUSION: Normal labor in healthy
      women lasted longer than many clinicians expect. The criteria for distinguishing
      normal from abnormal labor, based on time, need revision.

PMID- 10642972
TI  - Seizure and electroencephalographic changes in the newborn period induced by
      opiates and corrected by naloxone infusion.
AB  - OBJECTIVE: To describe the association between opioid administration in the
      newborn period and neurologic abnormalities. STUDY DESIGN: Case reports of two
      infants who presented with seizure activity and abnormal electroencephalograms
      associated with opiate administration, and reversed by naloxone. RESULTS: The
      first was a preterm infant who developed a burst-suppression pattern on the
      electroencephalogram while receiving a continuous infusion of morphine and muscle
      paralysis. Naloxone injection during the electroencephalogram recording reversed
      the burst-suppression pattern. The second was a term infant receiving fentanyl
      infusion for pain control following surgery, who presented with motor seizure
      that was only partially controlled with barbiturates. An abnormal
      electroencephalogram recording during the opiate infusion improved with naloxone
      administration. CONCLUSION: Our observations indicate a potential for neurologic
      abnormalities, including induction of seizure activity and electroencephalogram
      abnormalities, suggesting caution when opiates are used for sedation and/or pain
      control in the newborn period.

PMID- 10642973
TI  - Are obstetrical personnel required for intraoperative fetal monitoring during
      nonobstetric surgery?
AB  - OBJECTIVE: To determine if the scientific literature supports the practice of
      electronic monitoring of the fetal heart rate (FHR) during nonobstetric surgery.
      STUDY DESIGN: A search of the literature from 1966 to 1995 was performed using
      MEDLINE. RESULTS: No fetal hypoxic mortality or morbidity has been documented
      from nonobstetric surgery without occurrence of a maternal hypoxic complication
      regardless of the use of FHR monitoring or whether alterations of the FHR
      occurred. CONCLUSIONS: Fetal monitoring is an indirect assessment of maternal
      anesthetic and surgical management that is not as specific or effective as direct
      assessment of the maternal parameters to detect respiratory compromise. Current
      clinical evidence obtained does not substantiate the need for obstetric personnel
      to monitor FHR changes during surgical procedures because no change in fetal
      outcome has been documented.

PMID- 10642974
TI  - Early detection of bacteremia in the neonatal intensive care unit using the new
      BACTEC system.
AB  - OBJECTIVE: With the newer techniques of culture analysis such as the BACTEC 9240
      fluorometric detection system, detecting bacteremia in the neonate may be
      possible in a significantly shorter time. We hypothesized that neonatal
      bacteremia can be detected in less than 48 hours by this method. STUDY DESIGN:
      Our study included a retrospective review of 613 blood cultures obtained during
      the period August 1, 1995 to March 18, 1996 taken from 325 infants who had
      cultures drawn with a sepsis work-up and/or repeat cultures who had initial
      positive cultures in our Neonatal Intensive Care Unit. Results of blood cultures
      were studied in conjunction with the variables of body weight, gestational age,
      organism grown, complete blood count (CBC), and timing of positive cultures.
      Statistical analyses were performed using Fisher's and two-tailed Student's t
      tests. RESULTS: The results showed that of 325 infant blood cultures 49 (15%)
      were positive. Of these, 64% were coagulase-negative staphylococci, 14% viridans
      streptococci, 8% Escherichia coli, 4% Enterococcus sp., 4% Pseudomonas sp., 2%
      Enterobacter sp., 2% Klebsiella sp., and 2% Candida albicans. Of the positive
      blood cultures taken from infants not on antibiotics at the time of culture, 54%
      were detected positive at 18 hours, 71% at 24 hours, and 100% by 30 hours.
      Detection time by organism type was as follows: coagulase-negative staphylococci,
      21.7 hours; viridans streptococci, 15.6 hours; E. coli, 7.5 hours; Enterococcus
      sp., 12 hours; Enterobacter sp., 5 hours; Klebsiella sp., 10 hours; and
      Pseudomonas sp., 12 hours. CONCLUSION: Our results indicate that the BACTEC 9240
      fluorometric detection system helps in early identification of neonatal
      bacteremia (in 24 to 30 hours), with Gram-negative organisms being detected
      earlier than Gram-positive organisms (p < 0.05) and having significantly higher
      immature neutrophils in a CBC (I:T ratio of > or = 0.2 (p < 0.001). Early
      detection of neonatal bacteremia using this method will allow earlier diagnosis
      and appropriate treatment of the potentially bacteremic and bacteremic infant.

PMID- 10642975
TI  - Comparison of psychosocial adjustment of mothers and fathers of high-risk infants
      in the neonatal intensive care unit.
AB  - OBJECTIVE: To compare the psychosocial adjustment of mothers and fathers to the
      birth of a premature or critically ill infant hospitalized in the neonatal
      intensive care unit (NICU). STUDY DESIGN: Using a comparative design, we studied
      165 mothers and father pairs of high-risk neonates. Mothers were 29.1 +/- 6.7 and
      fathers were 30.7 +/- 6.8 years old. All infants were hospitalized in the NICU.
      Couples completed questionnaires in either English or Spanish during the infant's
      NICU stay. RESULTS: Mothers were more poorly adjusted and were more anxious,
      hostile, and depressed than fathers, but both parents experienced levels of
      emotional distress significantly above normative values. Mothers and fathers
      reported equal levels of family functioning and social support and shared similar
      feelings of control related to the health status of their infant. CONCLUSION: The
      birth of an infant who requires care in the NICU environment is highly stressful
      for both parents. Physicians, nurses, and other health professionals working in
      the NICU should assess the psychosocial adjustment in both parents, but mothers
      may require more intense education and counseling to reduce the distress they
      experience.

PMID- 10642976
TI  - A review of HELLP syndrome.
AB  - HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome is a
      variant of severe preeclampsia which is associated with substantial maternal and
      perinatal morbidity and mortality. As with preeclampsia, the etiology and
      pathogenesis of HELLP syndrome is not completely understood. An increase in
      vascular thrombosis and activation of the coagulation system may be important in
      the clinical presentation of this disorder. Laboratory criteria for the diagnosis
      of HELLP syndrome have been classically described but lack uniformity among
      different institutions. Aggressive management of HELLP syndrome with expeditious
      delivery appears to yield the lowest perinatal mortality rates. Conservative or
      expectant management has been associated with higher stillbirth rates with
      antenatal corticosteroids not causing resolution of the laboratory abnormalities.
      Resolution of laboratory abnormalities in HELLP syndrome runs a protracted course
      over several days after delivery. Despite nearly two decades since HELLP syndrome
      has been defined as a clinical entity, treatment for the disorder still remains
      delivery of the patient.

PMID- 10642977
TI  - Fetal morbidity and mortality following motor vehicle accident: two case reports.

PMID- 10642978
TI  - Prolonged intermittent reversed end-diastolic flow in a monochorionic twin
      pregnancy associated with twin-to-twin transfusion syndrome and absence of
      Hyrtl's anastomosis.

PMID- 10642979
TI  - Bronchogenic cyst and its progress in a premature infant.
AB  - The progressive course of a congenital bronchogenic cyst in a very low birth
      weight infant with respiratory distress is presented. A bronchogenic cyst, while
      uncommon, should be in the differential diagnosis of pneumomediastinum or medial
      pneumothorax even in premature infants who are on ventilators.

PMID- 10642980
TI  - Placental pathology casebook. Choriocarcinoma in situ of placenta associated with
      transplacental hemorrhage.

PMID- 10642981
TI  - Special imaging casebook. Left-isomerism (polysplenia) with congenital
      atrioventricular block and biliary atresia.

PMID- 10642982
TI  - Umbilical cord blood gases casebook. Interpreting umbilical cord blood gases, IV.

PMID- 10642983
TI  - Neonatal cardiology casebook. Aortopulmonary window with tetralogy of Fallot and
      pulmonary atresia: echo cardiographic diagnosis and surgical repair in the
      neonatal period.

PMID- 10642984
TI  - [Idiopathic calcium oxalate urinary lithiasis: new physiopathological
      approaches].
AB  - Nephrolithiasis effects 1% to 5% of the general population in industrialized
      countries. The majority of stones is made of calcium oxalate. The formation of
      calcium oxalate nephrolithiasis depends on several factors: hypercalciuria,
      hyperoxaluria, adhesion of crystals on the surface of renal epithelial cells,
      quantitative or qualitative deficit of inhibitors of crystallization in urine,
      intervention of promotors of crystallization. In this review we report the new
      insights into calcium oxalate stone formation.

PMID- 10642985
TI  - [Renal ischemia reperfusion syndrome].
AB  - Ischemia reperfusion injury is an uncommon kind of inflammation. Oxygen
      deprivation is followed by cellular dysfunction, reversible or not and mainly
      tubular. Ischemia initiates and amplifies the fundamental events of reperfusion
      injury, that are going to occur after oxygen reintroduction. Reperfusion is
      characterized by the production of oxygen reactive species, endothelial
      activation, endothelial release of chemoattractants, chemokines and cytokines,
      expression of adhesion molecules, that are going to mediate the recruitment and
      activation of circulating leucocytes, later responsible for the main lesions of
      reperfusion injury. Studies in kidney transplantation have brought evidence that
      the fibrotic healing of reperfusion injury have long term and significant
      consequences on kidney function.

PMID- 10642986
TI  - The local production of complement in the pathogenesis of renal inflammation.
AB  - The deposition of complement components is a feature of many immune mediated
      human glomerular diseases. Experimental models provide evidence that complement
      activation within the glomerulus has a pathogenic role in immune complex and
      antibody mediated glomerulonephritis. It was thought that the complement
      components deposited within the kidney were derived from the systemic circulating
      pool. However, recent work has shown that the kidney is able to produce many of
      the components of the complement cascade. In vitro work has shown that cells of
      glomerular and tubular origin can produce complement, as can inflammatory cells
      present within the kidney during inflammation. Analysis of human biopsy material
      has shown that expression of complement genes is increased during inflammatory
      renal disease implicating local complement synthesis as a potential source of
      complement components. At present no direct evidence for a pathogenic role of
      local complement synthesis exists. In this review we consider the current
      experimental evidence which suggests that local production of complement may be
      contributing to renal injury in a variety of diseases.

PMID- 10642987
TI  - [Pulmonary infection from Rhodococcus equi after renal transplantation. Review of
      the literature].
AB  - Rhodococcus Equi, a strictly aerobic Gram positive coco-bacillus, is a pathogen
      for horses and foals. It may induce opportunistic infections and is described in
      AIDS infected patients. We report the case of a 47-year old man, breeder of
      horses, with kidney transplant who has presented, 8 years after his graft, an
      impairment of health, a fever and evidence of pulmonary disease. The pulmonary
      biopsy under scanner guidance and microbiology study, has displayed the diagnosis
      of Rhodococcus equi infection. The evolution has been favorable with double
      antibiotherapy (follow-up 27 months). Ten comparable observations have been
      published after organ transplantation: (kidney: 8; heart: 1; liver: 1). Pulmonary
      locations are widely predominant. The animal contact is found only in 30% of
      cases. The presentation of the sickness has been compared to pulmonary
      tuberculosis or to nocardiosis, pathologies often observed in this context of
      immunosuppression. The antibiotic treatment is difficult and should required two
      bactericidal antibiotics. A surgical lobectomy can be envisaged in case of
      relapse. The mortality is 30%.

PMID- 10642988
TI  - [Surgical approach for aneurysm of the anterior communicating artery].

PMID- 10642989
TI  - [Detection of the venous system of the skull base using three-dimensional CT
      angiography (3D-CTA): utility of the subtemporal approach].
AB  - Three-dimensional computed tomography angiography (3D-CTA) was compared with
      digital subtraction angiography (DSA) for the delineation of the skull base
      venous system in presurgical planning of the subtemporal approach in 201 sides of
      109 patients. The axial stereoscopic images and multi-projection images were used
      in 3D-CTA, and the anteroposterior views and lateral views were used in DSA. DSA
      showed that the vein of Labbe (VL) was the most common venous flow on the lateral
      or basal surface of the temporal lobe, whereas 3D-CTA demonstrated that the
      involvement of the temporo-basal vein (TBV) was equal to that of VL in frequency.
      3D-CTA showed that the VL flowed into the transverse sinus (TS) on 132 sides, the
      sigmoid sinus-TS junction on 29 sides, and the lateral tentorial sinus (LTS) on
      40 sides. DSA showed that the VL flowed into the TS on 157 sides and into the LTS
      only on 5 sides. DSA showed that the TBV flowed into the TS on 37 sides but axial
      3D-CTA showed that the TBV flowed into the LTS on 48 sides. This inconsistency
      reflects the difficulty in confirming and identifying these veins on the
      anteroposterior view of DSA, due to the overlapping of veins and poor
      delineation. Axial stereo and multi-projection images of 3D-CTA provided
      practical images of the deep veins of the skull base venous system and showed the
      relative anatomical relationships of the arteries and bony structures. This
      information can specify the venous inflow point, and help to determine the
      direction of approach and working space, and also help to identify intraoperative
      landmarks for the subtemporal approach. Presurgical examination of the deep
      venous system with 3D-CTA may help to minimize unexpected injury to veins and
      venous infarction.

PMID- 10642990
TI  - [Effect of epilepsy surgery based on magnetic resonance imaging (MRI)
      classification].
AB  - We prospectively analyzed the effect of surgical procedures in epilepsy patients,
      except for those with mesial temporal lobe epilepsy. Twenty patients with a mean
      age of 26 years (range 3 to 58 years, 10 male and 10 female) underwent the
      surgical procedures. These patients were divided into 3 groups according to MRI
      findings, as follows; group A (localized type): localized lesions such as
      angiomas or benign tumors, group B (widespread type): widespread lesions such as
      regional encephalitis or stroke, visible on anatomical neuroimaging, and group C
      (cryptic type): no lesion visible on anatomical neuroimaging. Following surgery,
      11 (85%) of the 13 patients in group A were seizure-free, one showed worthwhile
      improvement, and one, whose lesion was not removed totally, was unchanged. In
      group B, two patients (50%) were seizure-free and 2 (50%) showed worthwhile
      improvement. All the patients in group C showed worthwhile improvement.
      Lesionectomy, cortical excision, multiple subpial transection (MST) or a
      combination of these procedures were effective in groups A and B. Patients in
      group C had a chance to obtain worthwhile improvement by corpus callosotomy or
      cortical excision. Intracranial EEG recording provides useful information for
      epilepsy surgery in intractable cases.

PMID- 10642991
TI  - [Differential diagnosis between aneurysm and infundibular dilatation in the IC-PC
      region with 3D-CTA].
AB  - In cases of asymptomatic internal carotid-posterior communicating artery (IC-PC)
      protrusions, it is sometimes difficult to differentiate infundibular dilatation
      (ID) from aneurysm by digital subtraction angiography. We applied three
      dimensional CT angiography (3D-CTA) in 32 cases of these IC-PC protrusions.
      SOMATOM PLUS 4 was used under such conditions as to provide images with high
      spatial resolution. The shaded surface display (SSD) method was adopted to
      reconstruct the 3D images because of its advantage in separating overlapped
      vasculature. We also made reference to source images and maximum intensity
      projection (MIP) to make sure of our diagnoses. In all cases including 4
      aneurysms and 28 IDs, we were able to distinguish between ID and aneurysm. The
      accuracy of 3D-CTA was confirmed by 9 surgical cases. Our technique was as
      follows: 1) To inject a high dose of diluted contrast medium rapidly to smaller
      arteries for opacification of contrast medium. 2) To exclude neighboring useless
      structures except for the very close structures such as posterior clinoid process
      from the target image focusing on the IC-PC region. 3) To observe the
      reconstructed image of MIP and SSD from various angles. The contralateral and
      craniocaudal view were valuable. 4) To change the threshold level gradually and
      observe the configurational changes of the apex of protrusion. Poorly developed
      PcomA was mostly delineated at the optimum threshold level. Otherwise, the apex
      of protrusion remained spherical in an aneurysm and became pyramidal in shape in
      an ID when the threshold level was gradually decreased. In conclusion, 3D-CTA was
      a useful modality for IC-PC protrusions to distinguish between ID and aneurysm.

PMID- 10642992
TI  - [Advantages of stereotaxic aspiration of intracerebral hematoma using
      interventional magnetic resonance imaging: new surgical method].
AB  - We describe the usefulness of stereotaxic surgery in the brain with special focus
      on aspiration of intracerebral hematoma using interventional MRI (0.3 Tesla;
      Hitachi, Japan). A 62-year-old female was admitted to our hospital with sudden
      right incomplete hemiparesis. A CT scan on admission showed a high-density mass
      in the left putamen. Soon after admission, her consciousness gradually decreased
      and the incomplete hemiparesis quickly worsened, so we promptly initiated an
      operation for stereotaxic aspiration of an intracerebral hematoma. During the
      surgery, real-time monitoring by MR-fluoroscopy depicted the gradual decrease of
      the hematoma. Postoperatively, her consciousness recovered to an almost alert
      level, but her right hemiparesis was unchanged. Stereotaxic aspiration of
      intracerebral hematoma using interventional MRI is advantageous because it
      enables accurate and safe evacuation of intracerebral hematoma in real time with
      no risk of irradiation during the procedure.

PMID- 10642993
TI  - [Spontaneous resolution of the unruptured dissecting aneurysms of bilateral
      vertebral arteries with conservative treatment: analysis of the transient
      enlargement of aneurysmal dilatation].
AB  - A case of unruptured dissecting aneurysms of bilateral vertebral arteries was
      reported. A 47-year-old man was admitted to our hospital with right Wallenberg's
      syndrome. On the tenth hospital day, angiography revealed a pearl and string sign
      in the right vertebral artery and aneurysmal dilatation in the left vertebral
      artery. On the 38th hospital day, the pearl and string sign in the right
      vertebral artery was improved, but the aneurysmal dilatation in the left
      vertebral artery had enlarged. On the 222nd hospital day, angiography showed a
      spontaneous resolution of the aneurysmal dilatation in the left vertebral artery.
      He suffered no recurrence and returned to his previous life style. Because
      aneurysmal dilatation may be resolved spontaneously, especially in the chronic
      stage, surgery should not be undertaken lightly.

PMID- 10642994
TI  - [Non-traumatic dissecting aneurysms on the intracranial internal carotid artery:
      report of three cases].
AB  - Subarachnoid hemorrhage (SAH) due to non-traumatic dissecting aneurysms is
      uncommon. Most of such cases are reported to occur in the posterior circulation.
      We encountered three cases of non-traumatic dissecting aneurysms on the
      intracranial internal carotid artery. Two cases developing SAH from the
      dissecting aneurysms were surgically treated by such means as proximal ligation
      and trapping. Two cases, which were treated surgically during the acute phase,
      showed poor surgical outcome, because a large cerebral infarction took place
      during the course of vasospasm. Trapping of the ICA or the contralateral ICA with
      the dissecting aneurysm failed to keep enough blood supply despite hypervolemic
      hypertensive therapy. Operative results seemed to depend on the collateral
      circulation during vasospasm, so appropriate bypass surgery was recommended in
      cases of dissecting aneurysm on the ICA manifesting SAH. Furthermore, the
      mechanism of initiation of a dissecting aneurysm on the intracranial carotid
      artery was discussed from the biorheological aspect.

PMID- 10642995
TI  - [Dissecting aneurysm of the middle cerebral artery: case report].
AB  - We present a surgical case of a dissecting aneurysm of the right middle cerebral
      artery associated with subarachnoid hemorrhage and intracranial hemorrhage. A 61
      year-old woman with consciousness disturbance and left hemiplegia was referred to
      our hospital. She had suffered severe headache for a week. CT scan showed a
      subarachnoid hemorrhage in the right Sylvian fissure and intracranial hemorrhage
      in the right putamen. The right carotid angiogram revealed string sign in M1
      portion and occlusion at M2 lower branch of the right middle cerebral artery. On
      the 12th day, we undertook surgery to confirm whether it was a dissecting
      aneurysm or not. In the operation, it was reddish in the M1 portion corresponding
      to the "string sign" and dark-purplish in the lower M2 portion corresponding to
      an "aneurysm-like lesion". To prevent bleeding, the arterial wall in the M1
      portion was coated using muscle. Though the left hemiplegia was unchanged, the
      postoperative course was uneventful. The patient was transferred to another
      hospital and underwent rehabilitation. There has been no reccurrence during the
      four years since surgery. The middle cerebral artery dissecting aneurysm is
      extremely rare. We presented this case with review of the literature.

PMID- 10642996
TI  - [A successfully operated case of choriocarcinoma with recurrent intratumoral
      hemorrhage].
AB  - A 12-year-old boy with primary intracranial choriocarcinoma of the pineal region
      suffered from repeated intratumoral hemorrhage over a short period.
      Neuroradiological images demonstrated a pineal-region tumor with intratumoral
      hemorrhage and obstructive hydrocephalus. HCG-beta subunit concentration of his
      serum and cerebrospinal fluid was abnormally high. After the 24.2Gy irradiation,
      the tumor was removed almost totally. After the operation, we treated him with
      additional radiation and chemotherapy using ifosfamide, cisplatin, and etoposide
      (namely ICE therapy). No recurrence or metastasis has been noted, and he was in
      good condition during the 22 months since the operation. At present he receives
      maintenance ICE therapy every 3 months. Choriocarcinoma involves a high
      possibility of intratumoral fatal hemorrhage, so a radical operation is
      recommended as soon as possible.

PMID- 10642997
TI  - [Myelopathy caused by tentorial dural arteriovenous fistula: a rare case report].
AB  - A 51-year-old man with myelopathy due to intracranial dural arteriovenous fistula
      (dural AVF) is reported. At age 46, the patient experienced subarachnoid
      hemorrhage caused by rupture of the dural AVF and underwent embolization of the
      lesion at another hospital. At this time, the patient complained of numbness in
      his legs and showed paraplegic gait disturbance. MRI scan revealed swelling of
      the cervical spinal cord. Cerebral angiograms demonstrated the recurrence of
      tentorial dural AVF fed by bilateral meningohypopheseal trunks and the right
      posterior inferior cerebellar artery. Arteriovenous shunt (AV shunt) flow was
      drained into the anterior spinal vein. It seemed that the swelling of the spinal
      cord and myelopathy was caused by venous hypertension of spinal veins. After
      surgical interruption of the right petrosal vein which connected dAVF with
      cerebellar veins, AV shunt was obliterated successfully. Postoperative cerebral
      angiograms showed disappearance of dural AVF. The patient became ambulant and his
      cervical spinal cord appeared normal on the postoperative MRI scan. Surgical
      interruption of the draining vein was simple, effective and essential treatment.

PMID- 10642998
TI  - [Cervical pyogenic spondylodiscitis: 4 cases report and a review of the
      literature].
AB  - We report 4 cases of cervical spondylodiscitis presenting neurological and/or
      neuroradiological abnormalities. Such a lesion is rare in the cervical spine of
      adults, but should be suspected when the patient has radiculopathy and/or
      myelopathy associated with inflammatory signs. We discussed the clinical
      characteristics and the procedures of the diagnosis and treatment of cervical
      spondylodiscitis. Early and definitive diagnosis can be achieved by cervical X
      ray, MR imaging and biopsy. It is very important to evaluate the pyogen for the
      lesion by needle biopsy. When the patient has the compression of the spinal cord
      and/or nerve roots and the neurological findings of radiculopathy and/or
      myelopathy, surgical exploration and decompression of the spinal cord and/or
      nerve roots should be carried out as soon as possible. Anterior debridement and
      fusion should be performed using the effective antibiotics. We were able to
      achieve good prognosis by treatment following this procedure of diagnosis in the
      four cases of cervical spondylodiscitis mentioned.

PMID- 10642999
TI  - [Clipping of an aneurysm of the posterior cerebral artery via the transcortical
      transchoroidal-fissure approach: a case report].
AB  - A 65-year-old woman suddenly developed severe headache with nausea. Computed
      tomographic scans revealed a diffuse subarachnoid hemorrhage with thick hematoma
      of the left ambient cistern. Cerebral angiogram did not show any aneurysm. On the
      7th day after admission, 3D-CT angiogram showed an aneurysm of the left posterior
      cerebral artery. On the 14th day, axial and coronal magnetic resonance images
      showed the aneurysm, surrounding structures and the choroidal fissure. On the
      26th day after admission, successful neck clipping was performed through the
      temporal horn via the inferior temporal gyrus. The postoperative course was
      uneventful except for transient aphasia. This approach may be preferable in such
      cases, because it protects the brain from the detrimental effects of strong
      temporal retraction and provides a wider working space. In our case, thin slice
      MRI and MRA showing the aneurysm in the ambient cistern and the choroidal fissure
      were useful for deciding the appropriate approach.

PMID- 10643000
TI  - The regulation of beta globin gene expression and beta thalassemia.

PMID- 10643001
TI  - Primary T-cell-rich B-cell lymphoma in the kidney presenting with acute renal
      failure and a second malignancy.
AB  - Infiltration of the kidney is commonly found in lymphoma, but acute renal failure
      arising from bilateral renal infiltration is uncommon. Primary renal lymphoma may
      occur and is usually of B-cell lineage. It is rare for patients with lymphoma to
      develop acute renal failure as their initial clinical presentation. Recently, an
      association between primary renal lymphoma and a second primary malignancy has
      been reported. We describe the first case of a renal T-cell-rich B-cell lymphoma
      presenting as acute renal failure, which was associated with a second primary
      pulmonary malignancy.

PMID- 10643002
TI  - Placental site nodules and plaques: a clinicopathological and immunohistochemical
      study of 25 cases with ultrastructural findings.
AB  - Placental site nodules or plaques (PSN-Ps) are nodular benign lesions of the
      intermediate trophoblast (IT) cells in the endometrium, endocervix, superficial
      myometrium or fallopian tube, occurring after a remote intrauterine pregnancy. We
      present a study of 25 cases of PSN-Ps These lesions occurred in patients aged 18
      to 44 years. Most were discovered incidentally in endometrial curettage
      specimens. The specimens were received as part of clinical investigations for
      menorrhagia, per vaginal bleeding or pelvic pain. None of the PSN-Ps was visible
      grossly. Microscopically, they were mostly multiple, well-circumscribed, oval or
      plaque-like cellular nodules. The IT cells typically had abundant vacuolated or
      eosinophilic cytoplasm. The nuclei were irregular, large, hyperchromatic, often
      degenerate-looking and either mononucleated, multinucleated or multiclefted.
      Hyalinization surrounding individual or groups of IT cells, or located in the
      centre of the nodules, was a constant feature in all cases. The lesional cells
      were strongly immunoreactive to CAM 5.2, 34 beta E12, AE1/AE3, EMA and vimentin.
      Some cases showed focal positivity to HCG and HPL. PLAP staining was consistently
      negative. Ultrastructurally, the IT cells showed prominent nuclear variation in
      size and shape. The abundant, vacuolated cytoplasm contained some rough
      endoplasmic reticulum and loosely arranged filaments. This study describes the
      clinicopathological and immunophenotypic features of 25 cases of PSN-Ps including
      the ultrastructural findings of one case.

PMID- 10643003
TI  - Oncogene amplification in medulloblastoma: analysis of a case by comparative
      genomic hybridization and fluorescence in situ hybridization.
AB  - We describe amplification of the MYCC oncogene in a medulloblastoma with
      aggressive clinical behavior. The patient was a six year old boy who underwent
      gross total surgical excision of a cerebellar tumor. Despite chemotherapy and
      total neuraxis radiation, the clinical course was one of relentless progression,
      with extensive subarachnoid spread and death within eight months of presentation.
      The pathological features were consistent with the recently described, "large
      cell variant" of medulloblastoma. Tumor cells exhibited large vesicular nuclei,
      prominent nucleoli and strong immunoreactivity for synaptophysin. Polymerase
      chain reaction (PCR) and fluorescence in situ hybridization (FISH) assay revealed
      no evidence of MYCN amplification or 1p deletion in the tumor. FISH analysis
      revealed evidence of MYCC amplification in the 20- to 30-fold range. Comparative
      genomic hybridization (CGH) revealed regions of gains and amplification in three
      locations, with gains of chromosome 7, amplification of 8q24 (corresponding to
      the MYCC locus) and gains of the long arm of chromosome 17 (suggestive of
      isochromosome 17q). While conventional karyotypic analysis was not successful in
      the present case, CGH provided invaluable information about gene amplification
      and losses/gains of chromosomes and chromosomal regions. Thus, CGH is a powerful
      technique applicable to frozen or paraffin-embedded material which helps to
      ascertain the presence of gene amplification even without prior knowledge of the
      gene to be tested.

PMID- 10643004
TI  - Nail-patella syndrome and IgA nephropathy in a Chinese woman.
AB  - Nail-patella syndrome (NPS), also known as hereditary onycho-osteodysplasia, is
      an autosomal dominant pleiotropic disorder characterized by nailbed dysplasia or
      hypoplasia, absent or hypoplastic patellae, iliac horns and deformation or
      luxation of the radial head. Nephropathy is a known serious complication
      associated with NPS. In this report, we describe an adult Chinese woman with the
      clinical and radiological features of NPS who presented with the nephrotic
      syndrome. Renal biopsy disclosed focal segmental glomerulosclerosis on light
      microscopy, while immunofluorescence revealed predominant staining for IgA in the
      glomerular mesangium and along some capillary walls. Ultrastructural study
      confirmed the presence of paramesangial deposits as well as subendothelial
      collagen fibrils in the glomeruli. The histological findings were those of
      combined NPS and IgA disease, an association which has rarely been described.

PMID- 10643005
TI  - Hepatocellular carcinoma metastasizing to the orbit diagnosed by fine needle
      aspiration cytology.
AB  - Hepatocellular carcinoma (HCC) rarely metastasizes to the orbit. We report a case
      of a 78-year-old man with a past history of HCC, who presented with a periorbital
      mass, which was diagnosed as metastatic HCC by fine needle aspiration cytology
      (FNAC) and subsequently confirmed on excision biopsy. The cytological,
      histopathological and immunohistochemical findings are presented and the
      differential diagnosis is discussed. To our knowledge there has been no
      previously reported case of HCC metastatic to the orbit diagnosed by FNAC.

PMID- 10643006
TI  - Broadsheet number 52: Molecular genetics of colorectal cancer.
AB  - The molecular genetics of colorectal cancer is presented in an order that ascends
      from the basic to the applied: molecular mechanisms, morphogenesis,
      classification and diagnosis. Major consideration is given to the nature of
      genetic instability and the role of this mechanism in driving neoplastic
      progression. It is shown how the fundamental principle of genetic instability
      cuts across applied research, tissue diagnosis and clinical management with
      respect to both sporadic and inherited forms of colorectal cancer.

PMID- 10643007
TI  - Broadsheet number 53: Activated protein C resistance: diagnosis and clinical
      management.

PMID- 10643008
TI  - Test and teach. Number ninety six: Part 1. Inverted duct papilloma of minor
      salivary gland origin.

PMID- 10643009
TI  - Telomeric fusion is a major cytogenetic aberration of giant cell tumors of bone.
AB  - Giant cell tumor of bone (GCT) is regarded as a rare primary bone neoplasm
      derived from stromal cells, which have the ability to recruit and harbor
      macrophage and multinucleated osteoclast-like giant cells. Despite being often
      considered benign, GCT is a problematic neoplasm in that it is aggressive,
      unpredictable and difficult to treat effectively. Cytogenetically GCT is
      characterised by a high frequency of telomeric fusion, a process which has been
      implicated in the production of chromosome instability and tumorigenesis. To
      extend our knowledge of the significance of telomere association in GCT, the
      cytogenetics of cell lines derived from spindle-shaped stromal-like mononuclear
      cells (the tumor cells) of GCT was investigated. Cell lines from three different
      patients showed telomeric association in all passages. The rate of telomeric
      association varied from line to line and from passage to passage, but there was
      no particular pattern to the variations. Many other cytogenetic abnormalities
      were seen as well as telomeric association, but these were rarely clonal. The
      nature of most of the other abnormalities seen, such as deleted chromosomes and
      chromosomes with additional unidentifiable material, was consistent with their
      being formed as a result of breakage of the dicentric fused chromosomes at a
      telophase. Chromosomes 13, 14 and 21 were most commonly involved in telomeric
      fusion. It appears that telomeric association persists in long-term cultures of
      GCT and is responsible for the accumulation of other associated cytogenetic
      aberrations. Telomeric reduction and telomerase activity may act as oncogenic
      events, promoting and sustaining the transformed GCT phenotype.

PMID- 10643010
TI  - Detection of false-negative Papanicolaou smears by rapid rescreening in a large
      routine cervical cytology laboratory.
AB  - Rapid rescreening was established in our laboratory in 1995, following the
      publication of several studies indicating improved sensitivity for the detection
      of abnormalities in cervical smears. During the study period, 285,841 negative
      smears (representing 89.09% of the total workload) were rapidly rescreened. A
      total of 7,650 (2.68%) were identified as abnormal or suspicious and selected for
      full rescreening. Of these, 228 cases were considered abnormal following
      pathologist review and resulted in the issue of an amended report. This
      represents an increased detection rate for all abnormalities of 0.08%. Of the
      cases with histological follow-up, a high grade epithelial abnormality (HGEA) was
      confirmed in 31% of cases and a low grade epithelial abnormality (LGEA) in 42%.
      We conclude that rapid rescreening is easily incorporated into the daily workflow
      of a large routine cervical cytology laboratory, Our results support conclusions
      from previous studies that rapid rescreening is an effective quality control
      technique resulting in the detection of increased numbers of abnormal smears.

PMID- 10643011
TI  - The use of flow cytometry in the diagnosis and monitoring of malignant
      hematological disorders.
AB  - Flow cytometry is a modality with ever increasing application in modern
      hematological practice. This is due to the rapidity of obtaining results, ease of
      use and increasing power to detect abnormal populations of cells. The major uses
      of flow cytometry in malignant hematology are in the diagnosis, classification
      and monitoring of diseases such as leukemia, lymphoma and myeloma. The technique
      is now used also to detect disease-specific populations of cells in paroxysmal
      nocturnal hemoglobinuria. This review describes the use of flow cytometry in many
      disease states.

PMID- 10643013
TI  - Dermatophyte infections in Melbourne: trends from 1961/64 to 1995/96.
AB  - A comparison of dermatophyte infections, diagnosed by specimens sent to the
      laboratory, between 1961/64 and 1995/96 revealed two major trends, namely the
      site of clinical disease and the types of dermatophytes causing tinea infections.
      There was a marked decrease in scalp specimens submitted. Pedal disease and nail
      infections remained the predominant entities. There was a marked increase in
      Trichophyton rubrum isolations, such that T. rubrum now accounts for 69.5% of all
      dermatophyte infections. Possible causes for these trends include altered hygiene
      standards, changing immigration patterns and the availability, restrictions and
      diagnostic requirements for the prescription of various antifungal drugs over
      this time period.

PMID- 10643012
TI  - Fatal disseminated infection by Scedosporium prolificans during induction therapy
      for acute leukemia: a case report and literature review.
AB  - We report a case of fatal disseminated fungal infection by Scedosporium
      prolificans which occurred in a patient with acute leukemia during induction
      chemotherapy. Rapid clinical deterioration despite high-dose empirical
      amphotericin B highlights both the pathogenicity of this fungus in
      immunocompromised hosts and its resistance to standard antifungal therapy.

PMID- 10643014
TI  - An unexpected result in an evaluation of a serological test to detect syphilis.
AB  - Traditional tests for detection of syphilis are labour intensive and costly.
      Enzyme immunoassays (EIAs) are readily automated and cost effective if large
      numbers of tests are performed. Four experiments were devised to evaluate a
      syphilis EIA test kit where resources are limited: (1) testing antenatal
      patients; (2) testing refugees; (3) testing a high prevalence population; and (4)
      testing "problem sera" (containing autoantibodies or antibodies to other
      infective agents). Forty-one available syphilitic sera from antenatal patients
      were tested to evaluate sensitivity. Specificity was determined through testing
      sera determined to be nonreactive with rapid plasma reagin and Treponema pallidum
      hemagglutination tests, calculating the sample size (456) on the confidence
      interval (CI) required. Two runs were performed on antenatal sera, giving
      sensitivities of 32% (95% CI: 20%, 47%) and 37% (95% CI: 24%, 52%) and
      specificities of 92% (95% CI: 89%, 94%) and 90% (95% CI 87%, 92%), respectively.
      We present a method to evaluate a serological test where resources are limited.
      Unexpectedly, the test kit performed poorly as a screening test. New serological
      tests need to be evaluated in-house prior to adoption.

PMID- 10643015
TI  - Evaluation of two serological tests for the diagnosis of chlamydial respiratory
      disease.
AB  - Serological tests for chlamydial infection are one of the most frequently used
      methods in the diagnosis of atypical respiratory infections. Use of serological
      tests has implicated chlamydial infections in asthma, arthritis and coronary
      heart disease, but the specificity of chlamydial serology tests has been
      questioned. The immunofluorescence test is the most sensitive and specific
      serological test available for detection of chlamydial antibodies. This study
      compares two commercially available immunofluorescent antibody tests. The SeroFIA
      test using purified elementary bodies of Chlamydia pneumoniae, C. psittaci and C.
      trachomatis, detected 24 cases of acute C. pneumoniae infection, whereas the Spot
      IF test using whole cell antigen of C. psittaci and C. trachomatis, misdiagnosed
      20 of these as psittacosis and missed four cases.

PMID- 10643016
TI  - Turnaround times for reports on uncomplicated biopsies in five major anatomical
      pathology laboratories in NSW, Australia.
AB  - This paper reports on the findings of a 1997 survey of the turnaround times
      (TATs) of small, uncomplicated biopsies performed in five major anatomical
      pathology (AP) departments in NSW over a period of four weeks. A comparative
      analysis of the performance of the departments shows that in the majority of
      cases the standard of two working days between specimen receipt and availability
      for dispatch after verification (as proposed by the College of American
      Pathologists) is met. This is within the two working days of the Clinical
      Indicator of the Australian Council on Healthcare Standards. Notwithstanding the
      apparent adequacy of this result, there is an emerging-although still a minority
      view in which it is suggested that the TAT between specimen accession and
      verification of reports for uncomplicated cases should be one day. This more
      stringent benchmark is readily achievable, as is demonstrated in the results
      obtained. In this study a one day TAT was obtained in 73.4% of cases.

PMID- 10643017
TI  - Epstein-Barr virus status and the histopathological changes of parotid gland
      lymphoid infiltrates in HIV-positive children.
AB  - This study examined the EBV status and the morphology in parotid glands of a
      large cohort of HIV-positive pediatric patients. Nineteen children with
      vertically acquired HIV infection, ranging in age from three months to seven
      years and two months, were analyzed. Seventeen patients were assessed for
      serological evidence of EBV infection; nine showed evidence of past infection,
      one each re-activation and current infection and six did not have serological
      evidence of EBV. Immunohistochemistry and in situ hybridization for EBER 1 and 2
      were performed on formalin-fixed, paraffin-embedded tissue. Fourteen of the 19
      cases were classified as severe or established myoepithelial sialadenitis (MESA)
      and five were regarded as having mild MESA. The majority of intraepithelial
      lymphocytes were of B-cell lineage, while the pericystic infiltrate contained CD8
      positive T-lymphocytes. p24 immunohistochemistry for HIV showed positive
      follicular dendritic cells, lymphoid cells and macrophages. Ten of 14 cases were
      positive for EBER 1 and 2. These included cases that were serologically negative
      for EBV. This study confirms that the morphology and immunophenotype of pediatric
      HIV-associated parotid lesions are similar to those seen in adults. Ten of 14
      cases with evidence of EBV within the lymphoid infiltrate showed the same
      morphology and immunophenotype as cases in which EBV was not detected either by
      serology or by in situ hybridization. These findings indicate that EBV is not
      uniformly found in either the tissue or serum of these patients, and may not have
      a pathogenetic role in HIV-associated lymphoepithelial lesions in the pediatric
      age group.

PMID- 10643018
TI  - Capture ElISA and in vitro cell binding assay for the detection of antibodies to
      human papillomavirus type 6b virus-like particles in patients with anogenital
      warts.
AB  - To investigate human papillomavirus (HPV) virus-like particle (VLP)-specific
      antibody responses among anogenital warts patients, a VLP-based capture ELISA was
      established. Twenty-six percent (35/134) of control subjects and 50.0% (39/78) of
      patients with current anogenital warts showed IgG seropositivity to HPV 6b VLPs.
      HPV 6b VLP-specific antibody responses recognised native VLPs only, and had no
      cross-reaction with HPV type 16 VLPs. No differences in reactivity were observed
      between L1 and L1 + L2 VLPs, suggesting that L2 contributes little to the total
      immunogenicity of the papillomavirus virion. A VLP-cell binding assay was also
      established. Some sera from patients with anogenital warts specifically inhibited
      VLP binding to the surface of epithelial cells, suggesting that these antibodies
      might be functionally neutralising. These data show that serological responses to
      HPV 6b VLPs were induced among some but not all patients with anogenital warts,
      and give a proportional estimate of infection in the community.

PMID- 10643019
TI  - Atypical lipomatous tumors with smooth muscle differentiation: report of two
      cases.
AB  - Two cases of soft-tissue atypical lipomatous tumors with areas of smooth muscle
      cell differentiation are presented. The patients were a 72-year-old man (Case 1)
      and a 62-year-old woman (Case 2); their neoplasms were located in the left
      inguinal region and on the chest, respectively. The adipocytic component in Case
      1 contained cells with nuclear atypism and lipoblasts. Case 2 showed only slight
      nuclear atypism and lacked any lipoblasts. Smooth muscle fascicles were composed
      of well-differentiated cells with a few mitoses having none or only a slight
      atypism. They expressed muscle-specific actin and desmin in both cases. No
      recurrence was recorded during the follow-up time.

PMID- 10643020
TI  - Dedifferentiated chondrosarcoma with features of telangiectatic osteosarcoma.
AB  - We describe a 44-year-old female with a known history of a solitary
      osteochondroma of the scapula followed on X-ray for five years. She then
      presented with a rapidly growing lump. Imaging studies confirmed the presence of
      an aggressive looking lesion. Excision was performed and pathology showed a
      dedifferentiated chondrosarcoma with features of a telangiectatic osteosarcoma.

PMID- 10643021
TI  - Ectopic pituitary with pregnancy changes in a benign cystic teratoma of the
      ovary.
AB  - We report on the rare finding of pituitary tissue, including both adenohypophysis
      and neurohypophsis, in a mature cystic teratoma of the ovary removed from a 26
      year old female at the time of cesarean section. Immunocytochemistry of the
      ectopic anterior pituitary component showed pregnancy-related changes that have
      previously only been described in pituitaries obtained at autopsy.

PMID- 10643022
TI  - Lymphoepithelioma-like carcinoma of the renal pelvis.
AB  - We report the first documented case of undifferentiated carcinoma of the renal
      pelvis with a prominent lymphoid stroma (lymphoepithelioma-like carcinoma
      [LELC]). LELCs are morphologically identical to nasopharyngeal carcinoma and are
      rarely seen in the urinary tract, with only isolated cases involving the urinary
      bladder and ureter. The tumor was composed entirely of large pale staining
      malignant epithelial cells with ill-defined borders arranged in syncytial sheets
      separated by mainly reactive lymphocytes, occasional plasma cells and
      histiocytes. Tumor cells were immunoreactive to cytokeratin and were negative for
      leukocyte common antigen. Awareness of LELC is important, as it should be
      distinguished from lymphoma or inflammatory lesions including,
      xanthogranulomatous pyelonephritis.

PMID- 10643023
TI  - Is it time to replace the Petri dish with PCR? Application of culture-independent
      nucleic acid amplification in diagnostic bacteriology: expectations and reality.

PMID- 10643024
TI  - Comment on "prenatal screening for group B streptococci".

PMID- 10643025
TI  - [Conventional dental radiography and future prospectives].
AB  - Until recently, conventional dental radiology was performed by dentists and
      orofacial surgeons. Due to the rapid development of radiological technique, the
      demand of radiological advice is increasing. The radiologists see more and more
      dental patients in their daily routine. The aim of this article is to give an
      overview on established dental radiology and a glimpse into the future.
      Conventional dental radiology and digital radiography are presently in use.
      Intraoral technique comprises dental films, bite-wing views and occlusal
      radiographs. Panoramic views and cephalometric radiographs are done with
      extraoral technique. Digital radiography lacks all processes in behalf of film
      development. It leads to dose reduction and enables image manipulation.

PMID- 10643026
TI  - [Dental CT: examination method, radiation dosage and anatomy].
AB  - Traditionally oral surgeons and dentists have evaluated the jaws using intraoral
      films and panoramic radiographs. The involvement of radiologists has been
      limited. In the past few years dedicated CT-software-programs developed to
      evaluate dental implant patients have provided a new look at the jaws. The
      complex anatomy is described and identified on human skulls and on axial,
      panoramic, and cross-sectional images. With this anatomic description Dental-CT
      scans are used to demonstrate the anatomy of maxilla and the mandible. An
      overview of the technique of Dental-CT is provided, furthermore the radiation
      dose of different organs is explained. Suggestions to reduce these doses by
      simple modifications of the recommended protocols are given.

PMID- 10643027
TI  - [Dental CT in pathologic changes of the maxillo-mandibular region].
AB  - CT with multiplanar reconstruction of the jaws (DentaScan) is the method of
      choice for the radiographic assessment of the mandible and maxilla. It is
      instrumental in delineating the relationship between bony lesions and the
      adjacent anatomy. Therefore, this technique allows precise evaluation of the
      intricate details of the oral cavity. Using it, distinct characterization of
      pathology including infectious, metabolic, congenital and neoplastic lesions can
      be obtained.

PMID- 10643028
TI  - [Magnetic resonance tomography in dental radiology (dental MRI)].
AB  - PURPOSE: To demonstrate the usefulness of Dental-MRT for imaging of anatomic and
      pathologic conditions of the mandible and maxilla. METHODS: Seven healthy
      volunteers, 5 patients with pulpitis, 9 patients with dentigerous cysts, 5
      patients after tooth transplantation and 12 patients with atrophic mandibles were
      evaluated. Studies of the jaws using axial T1- and T2-weighted gradient echo and
      spin echo sequences in 2D and 3D technique have been to performed. The acquired
      images were reconstructed with a standard dental software package on a
      workstation as panoramic and cross sectional views of the mandible or maxilla.
      RESULTS: The entire maxilla and mandibula, teeth, dental pulp and the content of
      the mandibular canal were well depicted. Patients with inflammatory disease of
      the pulp chamber demonstrate bone marrow edema in the periapical region.
      Dentigerous cysts and their relation to the surrounding structures are clearly
      shown. After contrast media application marked enhancement of the dental pulp can
      be found. CONCLUSION: Dental-MRT provides a valuable tool for visualization and
      detection of dental diseases.

PMID- 10643029
TI  - [Dental CT in the planning of surgical procedures. Its significance in the oro
      maxillofacial region from the viewpoint of the dentist].
AB  - Dental computer assisted tomography (Dental CT) represents a valuable addition to
      the diagnostic spectrum for planning oral and maxillofacial surgery. High
      resolution CT and specially designed computer software allow representation of
      the jaws in different planes that are easy to match. They further allow the
      display of very small structures relevant to oral surgical interventions and
      reveal their spatial relationship in three dimensions. Thus communication between
      dentists and radiologists may be intensified and supported by usage of modern
      telecommunication systems. Dental CT is indicated, when clinical and conventional
      radiological techniques will not allow exact interpretation of the situation. It
      is modern oral implantology that primarily benefits from computer software
      enabling the assessment of surgical sites in the presurgical phase. Such planning
      was not yet possible using two dimensional radiographic techniques. The dental
      implantological part expects from radiography sharply defined contours of the
      external bony contours and the mandibular canal, exactly defined relation between
      slices and planes, no distortion in the orthoradial planes, tools for reliable
      measurements of distances, angles and volumes, possibility to transmit pictures
      electronically or on hardcopy without loss of quality.

PMID- 10643030
TI  - [Teleradiology in dentistry].
AB  - Teleradiology is a means of electronically transmitting radiographic patient
      images and consultative text. This offers a new way to communicate with other
      radiologists and transferring clinicians. Different applications of
      teleradiology, such as on-call services for emergency departments or rural
      regions, as well as expert consultation (second opinion) already have been
      realized. Especially in concern of dental radiography, analog (film-based)
      imaging gets progressively replaced by digital imaging. The combination with
      ultrafast data transfer offers an increasing efficacy in diagnosis and therapy,
      acceleration of communication and new means of quality assessment in patient
      care. Various applications of teleradiology concerning dental medicine are
      discussed.

PMID- 10643031
TI  - [Callus distraction of the midface. Requirements for diagnostic imaging].
AB  - Callus distraction of the midface is a recently developed surgical method for
      treatment of atrophic or hypoplastic maxillae. The treatment planning is based on
      individual shaped models, being constructed with the help of computed tomographic
      data. Our experience is based on 10 patients (3 male/7 female; age: 11-55 years).
      The demands for imaging are reported. The following imaging procedure is
      recommended: 1. preoperative: lateral x-ray, orthopantomogram, spiral CT, 2.
      during the time of callus distraction with normaly takes 4 to 5 weeks: lateral x
      ray (every 10 days), and 3. for follow up: lateral x-ray and spiral CT. The
      Radiation exposure caused by the repetitive images is calculated in detail.

PMID- 10643032
TI  - [Follow-up of TIPSS by color-coded duplex sonography using an ultrasonic signal
      enhancer. First results].
AB  - A study was performed to determine the visualization of the transjugular
      intrahepatic portosystemic stent shunt (TIPSS) and the detection of stenosis by
      the use of a capillary transversing signal enhancer. In 37 patients 37 colour
      coded duplex sonographies were performed before and after intravenous injection
      of the ultrasound signal enhancer Levovist (Schering, Berlin). The examinations
      were evaluated using a four-category score. Special attention was paid to the
      detection of stenoses in the TIPSS. Transjugular portal venograms of the same day
      were used as gold standard. The use of Levovist provided better colour and flow
      signals for the portal vein end of the shunt in only 9 of 37 sonograms and for
      the hepatic vein end of the shunt in 37 of 39 sonograms. Eleven of 13 stenoses
      requiring reintervention in portal venography could be correctly identified with
      signal enhancer. Eleven of these 13 stenoses were located in the hepatic vein end
      of the shunt. Ultrasound signal enhancer can significantly improve the
      sonomorphological visualization especially of the hepatic vein end of TIPSS in
      colour-coded duplex sonography. Stenoses which usually occur in the hepatic vein
      end of the shunt may be better detected.

PMID- 10643033
TI  - [Unusual cause of acute hip pain].

PMID- 10643034
TI  - [Radiology of the skeleton of the hand. 2. Degenerative joint diseases. Endocrine
      and metabolic bone diseases].

PMID- 10643035
TI  - [Effects of message and personal involvement on risk perception and acceptance].
AB  - The present study analyzed people's risk perception regarding driving a car with
      studded or non-studded winter tires. Subjects were 252 residents of Sapporo,
      where a recent municipal ordinance prohibited studded tires, allowing only non
      studded ones. Questionnaire data were examined concerning (1) the relationship
      between risk perception and its acceptance, (2) the effect of an inserted
      message, which was either positive or negative about the use of non-studded
      tires, and (3) the role of personal involvement, assessed with Personal
      Involvement Inventory (Zaichkowsky, 1985), regarding winter driving. Results were
      as follows: (1) The use of non-studded tires was favorably judged because of
      social benefit, but subjects hesitated to choose them because of a higher
      perceived possibility of an accident. (2) The inserted message had significant
      effects on benefit evaluation and perceived accident possibility. The effects
      were weaker for drivers who had experienced driving a car with studded tires. And
      (3) personal involvement had a weak correlation with risk judgements of the
      present study.

PMID- 10643036
TI  - [Type A behavior and cognitive processings reflected in event-related brain
      potentials to concurrent tasks].
AB  - Type A-B differences were assessed measuring the P300 component of the event
      related brain potentials that could reflect the resource demands of cognitive
      processings. Type A (9 females) and Type B (3 males and 6 females) students
      performed concurrently the reaction time (RT) and mental counting tasks. The dual
      task consisted of four conditions differing in task difficulty. The main results
      were as follows: Type A subjects performed no better on either task of the dual
      workload than type B subjects. However, Type A subjects showed higher subjective
      evaluation with NASA-Task Load Index than Type B subjects for each of the
      experimental conditions. Moreover, Type A subjects demonstrated greater amplitude
      of the P300 component for the RT targets all through the conditions than Type B
      subjects. Type A people's use of many resources in task performance seems to be
      associated with their hyperresponsivity in autonomic activities during mental
      workload that is known as a characteristic of Type A person.

PMID- 10643037
TI  - [Other perception and play-group entry in a preschoolers class].
AB  - Kindergarten children accumulate classmate information through their experience
      of spending time and doing things together. In the course of preschool lives, a
      class changes from an aggregation of children to a peer group with own history of
      interaction and involvement. In such a peer group, whether a child becomes a play
      group member is likely to depend not only on his/her social skills, but also on
      perception based on classmate information, especially whether the other is seen
      as someone whom the child would like to play with. Relationship between such
      perception and play-group entry was investigated in a kindergarten class for two
      years, from entrance as four-year olds to graduation. At the beginning, the two
      were unrelated, but they became related in later periods. A child was accepted
      into a play group without trouble when the group members thought he/she was
      someone they would like to play with. These results supported the hypothesis that
      other perception based on classmate experience and group history influenced the
      entry into classroom play groups.

PMID- 10643038
TI  - [People's functional evaluations, perception of fairness, and commitment to the
      state].
AB  - A questionnaire was mailed to a random sample of 3,000 people who were older than
      20, and 993 responded. The questionnaire was designed to measure the respondent's
      functional evaluations of Japan's political branches (the Diet, the Government,
      and its administrative agencies), its perceived fairness, his/her emotional and
      utilitarian commitment to Japan, and the political party he/she supported. Based
      on the fairness-bond theory model, we hypothesized that positive evaluations of
      political branches would increase perceived fairness, which in turn leaded to a
      stronger commitment. Path analysis indicated that the hypothesis was partially
      supported, and that functional evaluations of political branches had a direct
      effect on the commitment. It was also found that politically conservative
      respondents showed more positive evaluations and stronger commitment to Japan
      than liberal ones, suggesting political attitudes as a moderator variable for the
      fairness mediation.

PMID- 10643039
TI  - [A visual mechanism in curve detection].
AB  - To investigate how a smooth curve is processed in the human visual system, we
      introduce a new grouping principle explaining perceptual organization. Five
      observers were presented with arrays of band-pass elements, and the detection
      performance of an undulating path among randomly oriented distractors was
      measured as a function of the number of path elements and the orientation
      differences between adjacent path elements. We found that the undulating path was
      better detected when the number of path elements was large or the orientation
      differences were small and constant. Based on these results, we propose a model
      that groups the path elements to be perceived as a contour; local orientation
      differences are detected by curvature channels, the outputs of these channels are
      globally pooled with lateral inhibition, and the signals are detected by contour
      detectors of a threshold device.

PMID- 10643040
TI  - [Construction of a scale of attitude toward death in adolescence and its validity
      and reliability].
AB  - The purpose of this paper was to construct a scale that measures the
      multidimensional attitude toward death in adolescence. Based on preliminary open
      ended format survey, a scale of attitude toward death consisting of 67 items was
      constructed. This scale was administered to 1,071 adolescents. Factor analysis
      with varimax rotation indicated 6 subscales: "fear of death", "intention to live
      out own life", "meaning of death for life", "underrating of death", "belief in
      existence of afterlife", "choice of death-of-body/death-of-mind". For these
      subscales, the coefficients of alpha ranged from .60 to .84, and the coefficients
      of test-retest reliability with a three-week interval ranged from .68 to .93. The
      validity of the subscales was investigated through the relations with Templer's
      Death Anxiety Scale and several developmental indices.

PMID- 10643041
TI  - [Standard errors for the direct oblimin solution with Kaiser's normalization] [In
      Process Citation]
AB  - Kaiser's normalization is widely used in factor rotation. In this paper the
      asymptotic standard errors for rotated parameters are obtained when Kaiser's
      normalization is employed for the direct oblimin method which is one of the most
      frequently used oblique rotations. The method of estimating the standard errors
      is based on the augmented information matrix for parameters with restrictions. A
      Monte Carlo simulation is carried out to confirm the accuracy of the method.
      Further, it is shown by artificial data that the values of the standard errors
      with Kaiser's normalization can be significantly different from those without the
      normalization. That is, Kaiser's normalization tends to decrease the standard
      errors of the loadings for the variables with small communalities and to increase
      those of the correlations among oblique factors.

PMID- 10643042
TI  - [Investigation of emotional and physiological recovery from tracking tasks].
AB  - This study was conducted to investigate subjects' emotional and physiological
      recovery from tension. Subjects (N = 36) were assigned tracking tasks under three
      conditions: (1) the "Rest" condition in which subjects were not presented a task
      but asked to stay relaxed; (2) the "Non-performance" condition in which subjects
      were presented a task but were not required to perform it; (3) the "Performance"
      condition in which subjects were required to perform the task. We successively
      recorded eyeblinks, respiration, and heart rate in the pre-task rest period,
      during the task, and the post-task rest period. Subjects completed a
      questionnaire to rate their emotions for each period. Results indicated: that
      eyeblink rate decreased during the task under the non-performance and the
      performance condition; that respiratory rate and heart rate increased during the
      task in the performance conditions; and that during the post-task period these
      alterations showed a rapid recovery back to initial levels. As for subjective
      ratings of emotions, various changes were recorded in addition to recovery:
      "Disappointment" seemed to last long, "activation" recovered, and "tension"
      rebounded in the post-task period.

PMID- 10643043
TI  - [A study on standardization of the Five-Factor Personality Inventory for Children
      (FFPC)].
AB  - The purpose of this study is to construct and standardize the Five Factor
      Personality Inventory for Children (FFPC). Fifty items were chosen through two
      preliminary surveys. Then the 50-item questionnaire was administered to 3,386
      primary school children. Based on the results of principal component analysis, 40
      items were selected for the FFPC final version. The mean scores, standard
      deviations, and score distributions of the five-factor scales were computed. One
      sample of 215 children was tested twice, the interval being 9 weeks. The test
      retest correlations ranged between .778 and .854. Scale scores correlated with
      teacher nominations of the various kinds of personality. The FFPC five-factor
      scales were shown to have high internal consistency and test-retest reliability.
      The factorial validity, construct validity, and concurrent validity were also
      confirmed.

PMID- 10643044
TI  - [Effects of lesions in the central nucleus and lateral nucleus of the amygdala on
      fear conditioning with a visual conditioned stimulus in rats].
AB  - Lesions in the central nucleus or lateral nucleus of the amygdala have been known
      to interfere with the acquisition of fear conditioning when a sound is used as a
      conditioned stimulus (CS). The present study examined whether or not a similar
      interference would occur with a visual CS. Seven rats with lesions in the central
      nucleus (AMY-C group), 8 with lesions in the lateral nucleus (AMY-L group), and
      16 unoperated control rats were trained using a visual CS (25 W light, 3.7 s
      duration) paired with footshock (1.0 mA, 0.5 s). The behavioral index of fear
      conditioning was a potentiation of startle reflex in the presence of CS. All
      control rats and AMY-L group showed the potentiation, but AMY-C group did not.
      These results suggest that the lateral nucleus of the amygdala may not be
      involved in fear conditioning to a visual CS. It is possible that each modality
      of CS has a specific pathway to the central nucleus of the amygdala to mediate
      fear conditioning.

PMID- 10643045
TI  - [The effect of partial dissection of the zona pellucida on the fertilization of
      bovine oocytes in vitro and on the subsequent development of the embryos outside
      the body].
AB  - Influence of partial zona dissection (PZD) on fertilization and cleavage of cow
      oocytes and on pre-implantation development of embryos obtained by this method
      was investigated. Decreased concentration of spermatozoa in less degree
      influenced on rates of fertilization and cleavage of oocytes with partial zona
      dissection than on intact eggs. The embryos obtained by method PZD can develop in
      vitro to blastocyst stage. However, their development is slowed down and presence
      of dissection in zona pellucida can result in premature hatching such
      blastocysts.

PMID- 10643046
TI  - [Changes in the function of the nucleus and chromatin of human cells under the
      action of hormonal factors in vitro].
AB  - The influence of hormones--adrenaline, noradrenaline, hydrocortisone on the
      electronegativity of cell nuclei (ENN) was shown by the method of intracellular
      microelectrophoresis. Changes in heterochromatin state were estimated on the
      basis of heterochromatin granules (chromocenters) quantity. Adrenaline and
      noradrenaline induced the decrease in ENN, the maximum effect was revealed with
      hormones concentration observed in human blood during physical training. The
      hormonal effect increased with gradual increase of the exposition time from 5 to
      120 min. Hydrocortisone also decreased ENN. Adrenaline, and in some cases
      hydrocortisone, induced the significant increase of heterochromatin granule
      quantity. The correlation of this process with ENN decrease was shown only in the
      case of adrenaline. Obtained data are discussed in connection with regulation
      mechanisms of cell nucleus functional activity.

PMID- 10643047
TI  - [The characteristics of the distribution of HLA antigens in the families of
      children with aneuploid chromosomal pathology].
AB  - Search of possible immunogenetic markers of tendency to form aneuploid offspring
      was carried out. We have studied HLA-antigens distribution among families with
      Down syndrome and Turner syndrome children and among families with miscarriages.
      The disposition to reproduction of affected offspring is associated with
      following HLA-antigens: B40, B41 and B51. The most typical haplotypes among
      families with affected offspring were: A2B27, A2B40, A2B51, A9B51, A10B8, A10B40.
      The HLA-antigens distribution among families with miscarriages supports evidence,
      that certain haplotypes can contribute to aneuploidy in progeny.

PMID- 10643048
TI  - [Theory of integrating cellular tension and consequences from it].
AB  - Tensegrity model and implications from it have been reviewed. Experimental data
      confirming the model are shown. While signal vectorization is well confirmed and
      well depicted by the model, the vectorization of expression implied by the model
      has not yet been elaborated. Molecular mechanisms of functional connection
      between the nuclear matrix and the cytoskeleton need further observations.

PMID- 10643049
TI  - [Morphofunctional characteristics of fibroblasts in basal cell nevus and Cockayne
      syndrome].
AB  - Some morphofunctional characters of fibroblasts in two genetic disorders-
      Cockayne syndrome (CS) and Basal cell naevus syndrome (BCNS) have been examined.
      The size of nucleus in BCN1SP line has been shown to be about 1.5 times less as
      well as the total size of nucleoli per nucleus, while the number of nucleoli was
      2 times more compared with other cell lines investigated. Using the method of
      silver staining numerous nucleoli were shown to contain active loci of the
      nucleolus organizer regions. With the help of hybridization in situ the number of
      transcripts of 18S RNA molecules was shown to be 5 times more in BCN1SP cell
      line, and about 2.8 times more than in the other cell lines tested. The data
      obtained may be interpreted as a suggestion in favour of a greater activity of
      the nucleolus organizer regions in BCN1SP cell line followed by the disturbance
      in protein homeostasis of the cells.

PMID- 10643050
TI  - [Interaction of the regulatory region of the tryptophan oxygenase gene with
      transcription factors of the nuclear factor 1 (NF1) family].
AB  - Inducible hormone-dependent tryptophan oxygenase gene is expressed mostly in the
      liver under the control of glucocorticoid hormones. In the regulatory region of
      this gene there are three constitutive sites independent of hormone presence and
      gene expression. While investigating transcription factors responsible for the
      formation of specific chromatin structure in the regulatory region of inducible
      genes it is necessary to identify proteins which can bind to DNA specifically in
      these sites. The present paper reports investigation of transcription factors
      which bind to DNA from the -292nd to the -178th nucleotide of gene to in vitro.
      This DNA region contains a site corresponding to the constitutive DNase I
      hypersensitive site in vivo. Using electrophoretic mobility shift assay, we have
      analysed binding of rat liver proteins to this DNA region. NF1-rich nuclear
      protein fraction was purified from the rat liver nuclear extract by DEAE
      cellulose and heparin-sepharose chromatography. Studies of the competition with a
      consensus sequence site for NF1 recognition sites have shown that it is the NF1
      family transcription factors that are responsible for the formation of these
      specific complexes.

PMID- 10643051
TI  - [Effect of inhibitors of topoisomerases and poly(ADP-ribosylation) on homologous
      and non-homologous integration of exogenous DNA in genes of mammalian somatic
      cells].
AB  - A study was made of the influence of inhibitors of poly(ADP-ribose)polymerase,
      topoisomerase I and topoisomerase II on the frequency of gene targeting of hprt
      gene as well as on the frequency of random integration of targeting vector pRV9.1
      into genome of mouse F9 teratocarcinoma cells. We found that the treatment of
      cells with the inhibitor of poly(ADP-ribose)polymerase 3-aminobenzamide after
      electroporation resulted in 3-4-times increase of homologous integration of
      exogenic vector into chromosomal DNA, and did not affect the frequency of random
      insertion of transfected DNA. The treatment of cells after electroporation with
      inhibitors of topoisomerases VP-16, ICRF-193 enhanced random integration of
      transfected DNA but exerted no effect on the frequency of gene targeting in this
      experimental system.

PMID- 10643052
TI  - [Thermostability of DNA and its connection with the glassing process].
AB  - Using differential scanning calorimetry, the thermal denaturation of calf thymus
      DNA with different content of water (from 12 to 92%) was investigated.
      Dependences of melting temperature and enthalpy on the biopolymer hydration
      degree were established. Within the range of water concentrations from 92 to 50%
      the values of thermodynamic parameters of denaturation were obtained being in
      good agreement with the published data. Besides, a calorimetric manifestation of
      renaturation process at different cooling conditions after denaturation was
      studied. Special attention was paid to thermal properties of denatured and native
      DNA in the samples containing only the bound water. The temperature dependence of
      heat capacity in the denatured samples, which have completely lost their
      renaturation ability due to the proper thermal treatment, demonstrated a
      characteristic jump of thermal capacity. The value of this jump has been
      determined to be equal to 1.0 cal/g. degree C, related to dry weight, and almost
      not dependent on humidity. Temperature position of the jump (Tg) depends on the
      content of water which serves as a plasticizer. It is shown that the observed
      anomaly demonstrates all the properties characteristic of vitrification process
      in synthetic polymers and proteins. General similarity of thermal properties of
      the samples of native DNA, containing only the bound water, with those of
      denatured DNA also indicates a transition from the glassy into the rabber-like
      state. A possibility of existence of both native and denatured DNA in the glassy
      state at room temperature for the samples with low humidity (about 25%) has been
      demonstrated experimentally. It can be suggested that the formation of glassy
      state at dehydration of native DNA ensures its thermostability and the ability of
      restoration of its functional properties at a subsequent dehydration.

PMID- 10643053
TI  - [Structure-functional characteristics of heterodimeric phosphatidylinositol-3
      kinase and molecular mechanisms of its conjugation with other components of the
      signaling system].
AB  - This review presents literary data and results of the author own studies on
      structural and functional characteristics of regulatory (p55/p85) and catalytic
      (p110) subunits of heterodimeric phosphatidylinositol-3-kinases (PI-3-kinases),
      and on molecular mechanisms of their functional conjugation with other signaling
      system components, regulated by insulin and growth factors. Various models
      simulating the interaction of regulatory subunits of PI-3-kinase and of their
      substrates (insulin receptor sustrate proteins phosphorylated on tyrosin
      residues) with molecules of receptors-tyrosinekinases have been considered.
      Mechanisms of the functional conjugation between regulatory and catalytic enzyme
      subunits are discussed, with special reference to a possible role of the coiled
      coil interactions in this process.

PMID- 10643054
TI  - [Effect of the protein kinase C inhibitor Ro 31-8220 on Ca2+-responses, induced
      by somatotropin, in swine granulosa cells].
AB  - Somatotropin effect on Ca2+ responses in pig granulosa cells from antral
      follicles was investigated using fluorescent dye Fluo-3 AM and chlortetracycline.
      Ro 31-8220 increased the entry of extracellular calcium and the exit of calcium
      from intracellular stores. In Ca-free medium Ro 31-8220 exerted no influence on
      the level of calcium in granulosa cells. The effect of somatotropin on pig
      granulosa cells is associated with PKC activation. These data suggest the
      involvement of PKC in the changes of calcium in pig granulosa cells activated by
      somatotropin.

PMID- 10643055
TI  - [Phosphoinositide-specific phospholipase C gamma 1--a key protein for signal
      transduction, triggered by growth factors].
AB  - The review is devoted to the participation of phospholipase C gamma 1 in cell
      signaling. A great attention is paid to mechanisms of activation of phospholipase
      C gamma and its interaction with other signaling molecules. The role of
      phospholipase C gamma binding to cytoskeletal elements in cell signaling is
      discussed.

PMID- 10643056
TI  - [Role of Chlamydia pneumoniae in the pathogenesis of coronary disease].
AB  - Several studies have demonstrated an association Chlamydia pneumoniae with
      coronary artery disease, suggesting that infection with C. pneumoniae increases
      the risk for coronary artery disease by factor 2 or more. Since atherosclerosis
      is considered to be a chronic inflammatory process, these data would fit into the
      response-to-injury hypothesis of atherosclerosis rather than representing a
      completely novel concept. Several pathomechanisms as increased cytokine
      synthesis, proliferative and proaggregatory effects could transmit the effects of
      chronic C. pneumoniae infection. Animal models and first clinical trials using
      antibiotic therapy seem to support an etiological role of C. pneumoniae in
      coronary artery disease. In this paper the current knowledge of the role of C.
      pneumoniae in coronary artery disease is reviewed and possible pathomechanisms
      are discussed.

PMID- 10643057
TI  - Aortic regurgitant flow by color Doppler measurement of the local velocity 7 mm
      above the leak orifice--Part 2: Comparison with cardiac catheterization.
AB  - AIMS: An in vitro study of the flow convergence region in aortic regurgitation
      has shown that regurgitant flow rate can be derived from the local velocity V(7
      mm) at 7 mm distance above the leak orifice. This clinical study was performed to
      test this method in patients. METHODS AND RESULTS: In 67 patients with aortic
      regurgitation, the flow convergence region was imaged by color Doppler. By
      analogy with the afore mentioned in vitro study, velocity profiles of the
      acceleration across the flow convergence region were read from the color maps.
      The profiles were fitted by using a multiplicative regression model. The V(7 mm)
      was read from the regression curve, and instantaneous regurgitant flow Q was
      derived from the V(7 mm) with the equation developed in vitro (Q = V(7
      mm).cm2/0.28). Q showed a close association with the angiographic grade. Q
      derived regurgitant stroke volume correlated significantly with invasive
      measurements by the angio-Fick method (r = 0.897, SEE = 19.9 ml, y = 0.88x + 5.9
      ml). CONCLUSIONS: Within the color Doppler flow convergence region of aortic
      regurgitation, the local velocity at 7 mm distance to the leak reflects
      regurgitant flow rate.

PMID- 10643058
TI  - Comparison of Pura-Vario and Palmaz-Schatz stents following implantation using
      normal and high pressure in pigs: immediate and late results assessed by 3
      dimensional IVUS.
AB  - INTRODUCTION: The Pura-Vario stent features 2 newly designed "bridging segments"
      for enhanced longitudinal flexibility, in order to allow easier and safer stent
      implantation. METHODS: The aim of the present experimental investigation was to
      analyze the expansion characteristics of the Pura-Vario stent (PV), and to
      compare it with the Palmaz-Schatz stent (PS). Furthermore, stent implantation
      using "high pressure" (18 atm) (HP) was compared with "normal pressure" (12 atm)
      (NP). Stents (n = 16) were implanted into the left anterior descending artery
      (LAD) and the circumflex artery (CX) of 8 pigs. Stent area, lumen area and stent
      asymmetry were measured by means of three-dimensional intravascular ultrasound
      (3D-IVUS): (1) immediately after implantation, and (2) at 14-days follow-up.
      RESULTS: Stent expansion was found not to be uniform: the "bridging segments"
      were significantly larger than the "diamond segments" in either stent model at
      day 0; this difference, however, disappeared at 14-days follow-up. Despite higher
      flexibility of the Pura-Vario stent, no difference in stent expansion was found
      between both stent models, neither immediately after implantation (mean lumen
      area: 9.75 +/- 0.28 mm2 (PV) vs. 9.82 +/- 0.34 mm2 (PS)), nor at 14-days follow
      up (7.44 +/- 0.16 mm2 (PV) vs. 7.45 +/- 0.22 mm2 (PS)). Pura-Vario stents,
      however, were less asymmetric in the cross-sectional view. Implantation using
      "high pressure" resulted in larger and less asymmetric stent expansion only at
      day 0 (lumen area: 9.54 +/- 0.39 mm2 (HP) vs. 8.77 +/- 0.33 mm2 (NP) (p < 0.05));
      this difference, however, disappeared after 14 days due to higher stent recoil in
      the "high pressure" group. CONCLUSION: Despite higher flexibility of the Pura
      Vario stent, expansion characteristics of both stent models were comparable.
      "High pressure" implantation compared favorably with "normal pressure"
      implantation only at day 0, whereas no difference could be found between both
      techniques at 14-days follow-up.

PMID- 10643059
TI  - [Release of troponin T following PTCA in patients with unstable and stable angina
      pectoris].
AB  - It is still uncertain to what extent PTCA contributes to a rise of the myocardial
      ischemic marker troponin T. The purpose of this study was to determine the
      release of troponin T in patients with unstable and stable angina pectoris pre-
      and post-PTCA. Serial troponin T measurements were performed in 66 patients with
      unstable angina (group A) and 55 patients with stable angina pectoris (group B)
      pre-PTCA and 4, 8 and 24 hours post-PTCA. In group A, 39 (59%) patients with
      unstable angina pectoris showed pathologic troponin T concentrations (troponin T
      > or = 0.1 ng/ml); in 27 (41%) patients already pre-PTCA the troponin T was
      elevated beyond the normal values. Medians of troponin T rose from initially
      0.045 ng/ml pre-PTCA to a maximum of 0.21 ng/ml 8 hours post PTCA. In group B
      medians of troponin T were at all times within normal limits; there was no rise
      in the observation interval. Using the Chi-square test there were statistically
      significant differences between group A and B regarding the troponin T values pre
      and post-PTCA. In group A medians of total creatine kinase ranging between 24
      U/L and 30 U/L were to all times within normal limits. Also in group B medians of
      total creatine kinase were always within normal limits. Statistically significant
      differences between the two groups could not be shown. Our study could show a
      difference in the periinterventional course of the ischemic marker troponin T in
      patients with unstable and stable angina pectoris. The data indicate a PTCA
      induced reversible ischemia of the cardiac muscle cell with additional release of
      the cytoplasmatic bound part of troponin T in patients with unstable angina
      pectoris. Troponin T also appears to be a more sensitive marker of very short
      myocardial ischemia than creatine kinase.

PMID- 10643060
TI  - [Determination of left ventricular mass by transthoracic three-dimensional
      echocardiography in patients with dilated cardiomyopathy].
AB  - Conventional echocardiographic methods of measuring left ventricular mass (LVM)
      are limited by assumptions of ventricular geometry and image plane positioning.
      Three-dimensional (3D) echocardiography offers a promising new approach for more
      accurate determination of LVM. This study was performed to compare LVM
      measurement by one- (1D), two- (2D), and 3D echocardiography with magnetic
      resonance imaging (MRI) in patients (pts) with dilated cardiomyopathy (DCM). 36
      pts (age 18-74) with DCM underwent imaging by conventional 1D and 2D
      echocardiography as well as transthoracic 3D echocardiographic data acquisition.
      Also, pts were imaged with cardiac MRI. Due to echocardiographic and MRI quality
      and because of exclusion criteria's for MRI, it was not possible to accomplish
      each LVM determination method for each patient. LVM was determined by Devereux
      and area-length algorithm for the conventional echocardiography. 3D
      echocardiographic data was calculated after manual delineation of endo- and
      epicardial boundaries--slice by slice (5 mm)--in 3 perpendicular cut planes. LVM
      was determined by multiplying the myocardial volume by the specific density of
      the myocardium. To determine LVM in MRI, the even summation of slices method for
      myocardial volume measurement was used defined by the endo- and epicardium in
      short axis images. There was no significant correlation (r = 0.42) for measuring
      LVM between 1D echocardiography and MRI in pts with DCM. A significant
      correlation was obtained between 2D (r = 0.64, p < 0.01) echocardiography and MRI
      as well between 3D (r = 0.78, p < 0.01) and MRI in determination of LVM. Compared
      with 1D and 2D echocardiography, the 3D analysis achieved a significantly higher
      agreement with the results of the MRI (1D: 399.2 g, 2D: 285.9 g, 3D: 172.6 g
      versus MRI: 199.1 g). Interobserver variability was 5.1% for measuring LVM by 3D
      echocardiography (1D: 11.2%, 2D: 9.1%). In conclusion, in pts with DCM the
      determination of LVM was incompletely characterized by 1D and 2D echocardiography
      compared with results of MRI. The best correlation and high agreement for
      determination of LVM was obtained with 3D echocardiography compared with MRI.

PMID- 10643061
TI  - [Experiences in the diagnosis and therapy of so-called thrombus in transit].
AB  - With the increasing use of cross-sectional echocardiography in patients with
      overt or suspected pulmonary thromboembolism in the emergency rooms, more and
      more right atrial thrombi are detected. These are so-called "transitthrombi" from
      the venous system on their way to the pulmonary arteries and they are a severe
      presentation of thromboembolic disease. They appear as an imminent pulmonary
      embolism and usually coexists with an already massive embolism. In patients were
      a right atrial thrombus is associated with a patent foramen ovale, paradoxical
      arterial embolism has been observed. Right sided heart thrombi have a high
      mortality rate and need immediate treatment. In our hospital we have seen 14
      patients with right atrial thrombi and pulmonary embolism in a period of 6 years.
      Three patients had cardiac arrest with a massive pulmonary embolism, seven
      patients presented with a submassive embolism. All patients were treated
      immediately after echocardiographic diagnosis without pulmonary angiography. In
      about half of the cases transesophageal echocardiography was done additionally
      for diagnosis and monitoring. Therapeutic options were thrombectomy, fibrinolysis
      or anticoagulants. We treated one of our patients with thrombectomy, eleven
      patients with fibrinolysis and two patients with anticoagulants.

PMID- 10643062
TI  - [Surgical treatment of atrial septal aneurysms with patent foramen ovale in
      patients with cerebral ischemia as an alternative to life-long anticoagulant
      therapy: surgical strategy and results in 5 patients].
AB  - There is a significantly higher incidence of cerebral ischemia among patients
      with an atrial septal aneurysm and/or a patent foramen ovale. According to the
      information provided by modern diagnostic procedures--and in particular by
      transesophageal echocardiography--two pathogenic mechanisms should be considered
      as possible causes of the cerebral ischemia. Thrombi may develop locally in the
      left atrium or atrial septal aneurysm and lead to embolization or, alternatively,
      thrombi from the inflow region of the inferior vena cava may become trapped in
      the atrial septal aneurysm and pass through the patent foramen ovale to bring
      about embolization in the arterial bloodstream. Current treatment consists of
      life-long anticoagulation with coumarin derivatives in order to prevent further
      neurological complications. With this treatment, however, the risk of producing
      hemorrhages cannot be regarded as trivial, especially in old people. Surgical
      intervention with the insertion of a button device has so far only been attempted
      in a few isolated cases, and it is in any case no use if there is only an atrial
      septal aneurysm without a patent foramen ovale. As an alternative to
      administering anticoagulants for the rest of the patient's life, we operated on
      five cases of atrial septal aneurysm with patent foramen ovale followed by the
      appearance of cerebral ischemia. As with the surgical treatment of atrial septal
      defects in general, the risk of the operation (or of subsequent complications) is
      very slight indeed. No such problems arose in any of our patients, no blood
      transfusions were necessary, and after short postoperative treatment they could
      all be discharged. For younger patients with little risk from the treatment
      itself, we regard surgical intervention in cases of atrial septal aneurysm with a
      patent foramen ovale and cerebral ischemia as an important therapeutic
      alternative.

PMID- 10643063
TI  - [Manifestation of an anomalous origin of the right coronary artery from the
      pulmonary artery after development of significant coronary disease].
AB  - We describe a 71-year-old man with a history of a small posterior myocardial
      infarction. Angiographically he showed a coronary artery disease with major
      proximal stenosis of both branches of the left coronary artery and an occlusion
      of the marginal branch of the circumflex artery (infarct-related vessel). As an
      unexpected finding, an anomalous origin of the right coronary artery from the
      pulmonary artery was also found. This rare condition may cause development of
      ischemia with potentially lethal complications as a result of coronary steal
      phenomenon. Surgical treatment is, therefore, indicated even in asymptomatic
      patients with this anomaly. Possible surgical procedures and there indications
      are discussed.

PMID- 10643065
TI  - [Fast, sure and sparing].

PMID- 10643064
TI  - [PTCA of the LAD via the internal thoracic artery graft with Doppler ultrasonic
      control of the results: a case report and review of the literature].
AB  - The report presents a transluminal angioplasty (PTCA) of a severe stenosis of the
      left anterior descending artery (LAD) behind the anastomosis; the internal
      thoracic artery (ITA) graft was used as a conduit. Before and after the PTCA the
      changing of velocity flow patterns under rest and stress conditions with a
      handgrip-maneuver were measured with a noninvasive transthoracic ultrasound
      Doppler system. The mean diastolic velocity, which represent coronary perfusion
      through the ITA graft, increased after successful PTCA at rest and under stress
      conditions. An additional increasing of the mean diastolic velocity at rest and
      under stress conditions was seen after six months before the catheterization
      proposing no signs of restenosis. For this reason the vessel could be classified
      prospectively patient. This could be confirmed during coronary angiography. We
      also present a review of the published reports concerning PTCA of ITA grafts and
      PTCA of the native vessel using the ITA as a conduit. In this review 286 cardiac
      interventions on 273 patients with a primary rate of success of 87% could be
      counted, the documented rate of restenosis was 30%, and the rate of complication
      was approximately 1%. The PTCA in ITA grafts or of the native vessel via ITA
      grafts, respectively, represent an alternative to reoperation. The ultrasound
      duplex measurements are gaining an increasing significance for the noninvasive
      patency rate and post-interventional monitoring of the long-term PTCA result.
      With the augmentation of the ITA as a coronary bypass and expected increase of
      post-operative interventions, a noninvasive tool is necessary.

PMID- 10643066
TI  - [Magnetic resonance tomography in cardiology. Guidelines of the Commission on
      Clinical Cardiology of the German Society of Cardiology--Heart and Circulation
      Research].

PMID- 10643067
TI  - [The health revolution].

PMID- 10643068
TI  - [Internet--the targeted information source for physicians. Insurance companies
      and financial services].

PMID- 10643069
TI  - [E-mail--the super postal service].

PMID- 10643070
TI  - [Trends in general practice--electronic data processing].

PMID- 10643071
TI  - [Safely into the next century. Tips at the last minute].

PMID- 10643072
TI  - Raman spectroscopic study of microcosmic photodamage of the space structure of
      DNA sensitized by Yangzhou haematoporphyrin derivative and Photofrin II.
AB  - After calf thymus DNA has been photodamaged by Yangzhou haematoporphyrin
      derivative (YHPD) or Photofrin II, the Raman characteristic frequencies and the
      intensities of the bands assigned to various groups of the components of DNA
      change considerably. As a result of damage, homogeneous B-form calf thymus DNA
      becomes a mixture containing: (1) modified B-form DNA, which is shorter than the
      original because of double-helical DNA scission; (2) single-stranded DNA due to
      the breakage of some H-bonds and the lack of some bases, etc.

PMID- 10643073
TI  - On the combination of photodynamic therapy with ionizing radiation.
AB  - Ehrlich ascites carcinoma growth and cell damage have been examined after
      photodynamic therapy (PDT), radiotherapy (RT) and combined treatment.
      Haematoporphyrin dimethyl ether (HPde) is used as a photosensitizer for PDT and
      tested as a radiosensitizer for RT. For PDT a non-coherent light source (370 <
      lambda < 680 nm) equipped with filters is used. gamma-Irradiation consists of
      60Co irradiation at a dose of 2 Gy. Both PDT and RT induce a significant delay
      and inhibition in tumour growth (33 and 38%, respectively). Nevertheless cell
      damage after these treatments is different: after PDT the cell membrane integrity
      is damaged and no serious chromosomal aberrations are observed; whereas after
      gamma-irradiation there is no cell membrane integrity damage, but more
      significant DNA injuries are observed. It seems evident that HPde is able to act
      as a photosensitizer as well as a radiosensitizer. Combining PDT and RT produces
      an additive effect, not dependent on the sequence in which the two treatments are
      given, when a 1 h time window is used.

PMID- 10643074
TI  - Effects of photodynamic therapy on adhesion molecules and metastasis.
AB  - Photodynamic therapy (PDT) induces among numerous cell targets membrane damage
      and alteration in cancer cell adhesiveness, an important parameter in cancer
      metastasis. We have previously shown that hematoporphyrin derivative (HPD)-PDT
      decreases cancer cell adhesiveness to endothelial cells in vitro and that it
      reduces the metastatic potential of cells injected into rats. The present study
      analyzes the influence of PDT in vivo on the metastatic potential of cancers
      cells and in vitro on the expression of molecules involved in adhesion and in the
      metastatic process. Photofrin and benzoporphyrin derivative monoacid ring A (BPD)
      have been evaluated on two colon cancer cell lines obtained from the same cancer
      [progressive (PROb) and regressive (REGb)] with different metastatic properties.
      Studies of BPD and Photofrin toxicity and phototoxicity are performed by
      colorimetric MTT assay on PROb and REGb cells to determine the PDT doses inducing
      around 25% cell death. Flow cytometry is then used to determine adhesion-molecule
      expression at the cell surface. ICAM-I, MHC-I, CD44V6 and its lectins (aHt1.3,
      PNA, SNA and UEA) are studied using cells treated either with BPD (50 ng/ml, 457
      nm light, 10 J/cm2) or Photofrin (0.5 microgram/ml, 514 nm light, 25 J/cm2).
      Changes of metastatic patterns of PROb cells have been assessed by the
      subcutaneous injection of non-lethally treated BPD or Photofrin cells and
      counting lung metastases. First, we confirm the metastatic potential reduction
      induced by PDT with respectively a 71 or 96% decrease of the mean number of
      metastases (as compared with controls) for PROb cells treated with 50 ng/ml BPD
      and 10 or 20 J/cm2 irradiation. Concerning Photofrin-PDT-treated cells, we find
      respectively a 90 or 97% decrease (as compared with controls) of the mean number
      of metastases for PROb cells treated with 0.5 microgram/ml Photofrin and 25 or 50
      J/cm2 irradiation. Then, we observe that CD44V6, its lectins (aHt1.3, PNA, SNA)
      and MHC-I are significantly decreased (compared with the other molecules tested)
      in PROb and REGb cells after both BPD and Photofrin PDT treatment. These
      modifications in adhesion-molecule expression, particularly of CD44V6, can thus
      account only for part of the decrease in the metastatic potential of PDT-treated
      cancer cells. Changes in adhesion-molecule expression induced by PDT are only
      transient, implying that the rate of metastatic reduction is probably not linked
      simply to these changes.

PMID- 10643075
TI  - Tumor blood-flow changes following protoporphyrin IX-based photodynamic therapy
      in mice and humans.
AB  - The effects of aminolevulinic acid (ALA)-based photodynamic therapy (PDT) on
      tumor blood flow are controversial. This study examines the effects of ALA and
      Photofrin-based PDT on blood flow of Colon-26 tumors implanted in mice as well as
      the effects of ALA-based PDT on blood flow of human colorectal carcinomas and a
      carcinoid tumor in situ. Tumors are implanted in both flanks of mice. One tumor
      of each animal serves as a control. Blood flow is measured using a laser Doppler
      method. Tumor blood flow in mice not receiving a photosensitizer but treated with
      three different light fluences (50, 100 and 150 J/cm2) does not differ
      significantly from blood flow in the untreated tumor in the opposite flank. PDT
      after ALA administration using the three different light fluences does not
      significantly affect blood flow. In contrast, PDT after Photofrin administration
      causes a significant decrease in tumor blood flow with each light fluence, but
      this change is not as dramatic as reported in other studies. In contrast to mice,
      six patients who receive ALA prior to surgery all show a decrease in blood flow
      (mean = 51.8%, p < 0.001) after PDT using 100 J/cm2. Comparison with other
      published results suggests that it is likely that flow measurement by the laser
      Doppler method underestimates the effects of PDT on tumor blood flow due to the
      depth of laser penetration. Nevertheless, the present observations on blood flow
      suggest that the effects of ALA-based PDT on adenocarcinomas of the colon and
      rectum as well as an intra-abdominal carcinoid tumor in humans are more
      pronounced than would be predicated by some animal studies.

PMID- 10643076
TI  - Cell-cycle delay is induced in cells of a U937 promonocytic cell line by low
      intensity light irradiation at 660 nm.
AB  - Visible-light irradiation (VLI) at 660 nm and 11.5 J/cm2 inhibits proliferation
      of cells of the U937 promonocytic cell line, as monitored by autoradiographical
      analysis. The S-phase cell population is reduced at 6 h post-radiation treatment.
      Flow cytometric analysis confirms this, and also shows that light irradiation of
      cells induces a statistically significant increase in G2/M cells at 6 h post
      radiation treatment. It has been postulated that VLI at 660 nm can alter cell
      cycle progression by affecting intracellular concentrations of ions, in
      particular pH and calcium. However, no significant effects of light irradiation
      on these intracellular ions have been observed. These effects of VLI are not a
      consequence of radiation-induced DNA strand breaks, therefore events other than
      direct DNA damage are involved. These findings demonstrate a direct
      photobiological effect of VLI at 660 nm on the cell cycle, and indicate a
      previously unsuspected mechanism for the induction of cell-cycle delay that is
      neither a result of changes in the concentration of intracellular ions nor
      initiated by DNA strand breaks.

PMID- 10643077
TI  - Spectrometry supports fluorescence staging laparoscopy after intraperitoneal
      aminolaevulinic acid lavage for gastrointestinal tumours.
AB  - Conventional staging laparoscopy in combination with fluorescence diagnosis has
      proven to be an effective modality in the detection of macroscopically occult
      intraperitoneal tumours and metastases. Rats with induced peritoneal carcinosis
      are photosensibilized by intraperitoneal aminolaevulinic acid (ALA) lavage. After
      visualization of the tumour foci, the emission from the lesions is measured
      spectrometrically and the fluorescence analysed quantitatively ('optical
      biopsy'). There is a considerable accordance between imaging by fluorescence
      diagnosis laparoscopy and point spectrometry in the detection of peritoneal
      malignancies. Compared with surrounding healthy peritoneum, tumour-positive areas
      show significantly higher fluorescence intensities in spectrometry.

PMID- 10643078
TI  - No evidence for killer sperm or other selective interactions between human
      spermatozoa in ejaculates of different males in vitro.
AB  - This study examines one of the possible mechanisms of sperm competition, i.e. the
      kamikaze sperm hypothesis. This hypothesis states that sperm from different males
      interact to incapacitate each other in a variety of ways. We used ejaculates from
      human donors to compare mixes of semen in vitro from the same or different males.
      We measured the following parameters: (i) the degree of sperm aggregation,
      velocity and proportion of morphologically normal sperm after 1 and 3 h
      incubation in undiluted semen samples, (ii) the proportion of viable sperm plus
      the same parameters as in (i) in 'swim-up' sperm suspensions after 1 and 3 h
      incubation, (iii) the degree of self and non-self sperm aggregation using
      fluorescent dyes to distinguish the sperm of different males, and (iv) the extent
      of sperm capacitation and acrosome-reacted sperm in mixtures of sperm from the
      same and different males. We observed very few significant changes in sperm
      aggregation or performance in mixtures of sperm from different males compared
      with mixtures from the same male and none that were consistent with previously
      reported findings. The incapacitation of rival sperm therefore seems an unlikely
      mechanism of sperm competition in humans.

PMID- 10643079
TI  - Birth order and fluctuating asymmetry: a first look.
AB  - We investigated the hypothesis that maternal immunoreactivity to male-specific
      features of the foetus can increase developmental instability. We predicted that
      the participants' number of older brothers would be positively related to the
      fluctuating asymmetry of ten bilateral morphological traits. The participants
      were 40 adult male psychiatric patients and 31 adult male hospital employees.
      Consistent with the hypothesis, the participants' number of older brothers--but
      not number of older sisters, younger brothers or younger sisters--was positively
      associated with fluctuating asymmetry. The patients had significantly larger
      fluctuating asymmetry scores and tended to have more older brothers than the
      employees, but the positive relationship between the number of older brothers and
      fluctuating asymmetry was observed in both groups.

PMID- 10643080
TI  - Abortion rates reflect the optimization of parental investment strategies.
AB  - Parental investment decisions in human beings, including infanticide, have
      usually been considered in relation to the postnatal survival probabilities of
      their children. A number of factors which influence parental ability and
      willingness to invest in offspring have been identified from these studies. Here
      we argue that at least some of the same factors which influence investment
      decisions postpartum also affect the decision to terminate a current pregnancy
      through voluntary abortion. We show that both female age and marital status
      influence the probability of abortion, with the key variable being the likelihood
      of future marriage. Thus, abortion procedures extend a woman's ability to manage
      her reproduction into the prenatal period.

PMID- 10643081
TI  - Significance testing of clinical data using virus dynamics models with a Markov
      chain Monte Carlo method: application to emergence of lamivudine-resistant
      hepatitis B virus.
AB  - Bayesian analysis using a virus dynamics model is demonstrated to facilitate
      hypothesis testing of patterns in clinical time-series. Our Markov chain Monte
      Carlo implementation demonstrates that the viraemia time-series observed in two
      sets of hepatitis B patients on antiviral (lamivudine) therapy, chronic carriers
      and liver transplant patients, are significantly different, overcoming clinical
      trial design differences that question the validity of non-parametric tests. We
      show that lamivudine-resistant mutants grow faster in transplant patients than in
      chronic carriers, which probably explains the differences in emergence times and
      failure rates between these two sets of patients. Incorporation of dynamic models
      into Bayesian parameter analysis is of general applicability in medical
      statistics.

PMID- 10643082
TI  - Selection for intermediate mortality and reproduction rates in a spatially
      structured population.
AB  - How local interactions influence both population and evolutionary dynamics is
      currently a key topic in theoretical ecology. We use a 'well-mixed' analytical
      model and spatially explicit individual-based models to investigate a system
      where a population is subject to rare disturbance events. The disturbance can
      only propagate through regions of the population where the density of individuals
      is sufficiently high and individuals affected by the disturbance die shortly
      after. We find that populations where individuals are sessile often exhibit very
      different dynamic behaviour when compared to populations where individuals are
      mobile and spatially well mixed. When mutations are allowed which affect either
      offspring birth rates or mortality rates, the well-mixed populations always
      evolve to a state where a single disturbance event leads to extinction.
      Populations often persist substantially longer if individuals are sessile and
      they disperse their offspring locally. We also find that for sessile populations
      selection may favour short-lived individuals with limited offspring production.
      Population dynamics are found to be strongly influenced by the host characters
      that are evolving and the rate at which host variation is introduced into the
      system.

PMID- 10643083
TI  - The approach to mutation-selection balance in an infinite asexual population, and
      the evolution of mutation rates.
AB  - A method is described for calculating the dynamics of the distribution of fitness
      in an infinite asexual population which is subject to unconditionally deleterious
      mutations with independent effects. This method is applied to the problem of
      calculating the frequency of a mutator subpopulation, at equilibrium between
      mutation and indirect selection due to association with deleterious mutations.
      Many mutator alleles are produced by loss-of-function mutations in polymerase or
      mismatch repair genes. Previous calculations have ignored the fact that this
      creates a flux of higher fitness individuals into the mutator subpopulation. This
      flux raises the mean fitness of the mutator subpopulation, and when this factor
      is taken into account, the frequency of the mutator may be more than an order of
      magnitude greater than recent theoretical work has suggested.

PMID- 10643084
TI  - Sibling competition stabilizes signalling resolution models of parent-offspring
      conflict.
AB  - Young of altricial birds use conspicuous displays to solicit food from their
      parents. There is experimental evidence that the intensity of these displays is
      correlated with the level of food deprivation of young, and that parents respond
      to increased levels of solicitation by increasing the rate of food delivery to
      the nest. Game-theoretical models based on the handicap principle show that, when
      solicitation is costly, there is a signalling equilibrium at which there is a one
      to-one correspondence between the condition of the young and the intensity of
      their display. Parents use this information to adjust their levels of investment
      on the current offspring. However, the models also have a non-signalling
      equilibrium, and computer simulations show that only the non-signalling
      equilibrium is stable. Here I show that when direct sibling competition is
      introduced into the model, in such a way that parents have control on the amount
      of food provided to the nest, but not on the way the food is allocated among
      siblings, the non-signalling equilibrium disappears and the signalling
      equilibrium becomes stable.

PMID- 10643086
TI  - The perception of visual images encoded in musical form: a study in cross
      modality information transfer.
AB  - This study demonstrates the ability of blind (previously sighted) and blindfolded
      (sighted) subjects in reconstructing and identifying a number of visual targets
      transformed into equivalent musical representations. Visual images are
      deconstructed through a process which selectively segregates different features
      of the image into separate packages. These are then encoded in sound and
      presented as a polyphonic musical melody which resembles a Baroque fugue with
      many voices, allowing subjects to analyse the component voices selectively in
      combination, or separately in sequence, in a manner which allows a subject to
      patch together and bind the different features of the object mentally into a
      mental percept of a single recognizable entity. The visual targets used in this
      study included a variety of geometrical figures, simple high-contrast line
      drawings of man-made objects, natural and urban scenes, etc., translated into
      sound and presented to the subject in polyphonic musical form.

PMID- 10643085
TI  - Response kinetics and pharmacological properties of heteromeric receptors formed
      by coassembly of GABA rho- and gamma 2-subunits.
AB  - Two of the gamma-aminobutyric acid (GABA) receptors, GABAA and GABAC, are ligand
      gated chloride channels expressed by neurons in the retina and throughout the
      central nervous system. The different subunit composition of these two classes of
      GABA receptor result in very different physiological and pharmacological
      properties. Although little is known at the molecular level as to the subunit
      composition of any native GABA receptor, it is thought that GABAC receptors are
      homomeric assemblies of rho-subunits. However, we found that the kinetic and
      pharmacological properties of homomeric receptors formed by each of the rho
      subunits cloned from perch retina did not resemble those of the GABAC receptors
      on perch bipolar cells. Because both GABAA and GABAC receptors are present on
      retinal bipolar cells, we attempted to determine whether subunits of these two
      receptor classes are capable of interacting with each other. We report here that,
      when coexpressed in Xenopus oocytes, heteromeric (rho 1B gamma 2) receptors
      formed by coassembly of the rho 1B-subunit with the gamma 2-subunit of the GABAA
      receptor displayed response properties very similar to those obtained with
      current recordings from bipolar cells. In addition to being unresponsive to
      bicuculline and diazepam, the time-constant of deactivation, and the
      sensitivities to GABA, picrotoxin and zinc closely approximated the values
      obtained from the native GABAC receptors on bipolar cells. These results provide
      the first direct evidence of interaction between GABA rho and GABAA receptor
      subunits. It seems highly likely that coassembly of GABAA and rho-subunits
      contributes to the molecular organization of GABAC receptors in the retina and
      perhaps throughout the nervous system.

PMID- 10643087
TI  - The effects of skill on the eye-hand span during musical sight-reading.
AB  - The eye-hand span (EHS) is the separation between eye position and hand position
      when sight-reading music. It can be measured in two ways: in notes (the number of
      notes between hand and eye; the 'note index'), or in time (the length of time
      between fixation and performance; the 'time index'). The EHSs of amateur and
      professional pianists were compared while they sight-read music. The
      professionals showed significantly larger note indexes than the amateurs
      (approximately four notes, compared to two notes), and all subjects showed
      similar variability in the note index. Surprisingly, the different groups of
      pianists showed almost identical mean time indexes (ca. 1 s), with no significant
      differences between any of the skill levels. However, professionals did show
      significantly less variation than the amateurs. The time index was significantly
      affected by the performance tempo: when fast tempos were imposed on performance,
      all subjects showed a reduction in the time index (to ca. 0.7 s), and slow tempos
      increased the time index (to ca. 1.3 s). This means that the length of time that
      information is stored in the buffer is related to performance tempo rather than
      ability, but that professionals can fit more information into their buffers.

PMID- 10643088
TI  - Induced motion at texture-defined motion boundaries.
AB  - When a static textured background is covered and uncovered by a moving bar of the
      same mean luminance we can clearly see the motion of the bar. Texture-defined
      motion provides an example of a naturally occurring second-order motion. Second
      order motion sequences defeat standard spatio-temporal energy models of motion
      perception. It has been proposed that second-order stimuli are analysed by
      separate systems, operating in parallel with luminance-defined motion processing,
      which incorporate identifiable pre-processing stages that make second-order
      patterns visible to standard techniques. However, the proposal of multiple paths
      to motion analysis remains controversial. Here we describe the behaviour of a
      model that recovers both luminance-defined and an important class of texture
      defined motion. The model also accounts for the induced motion that is seen in
      some texture-defined motion sequences. We measured the perceived direction and
      speed of both the contrast envelope and induced motion in the case of a contrast
      modulation of static noise textures. Significantly, the model predicts the
      perceived speed of the induced motion seen at second-order texture boundaries.
      The induced motion investigated here appears distinct from classical induced
      effects resulting from motion contrast or the movement of a reference frame.

PMID- 10643089
TI  - Sports medicine in children and adolescents.

PMID- 10643090
TI  - Colorectal polyps.

PMID- 10643091
TI  - Serum cholesterol concentrations in parasuicide.
AB  - OBJECTIVE: To evaluate whether people who have committed parasuicide have low
      serum cholesterol concentrations. METHOD: All subjects admitted to the University
      Medical Unit, Ragama after parasuicide from 1.3.96 to 31.1.97 were matched for
      age, sex, presence of diabetes and arterial hypertension, substance abuse, body
      mass index and socioeconomic status with controls. Venous blood samples for
      cholesterol estimation were collected from parasuicides within 24 hours of
      admission. RESULTS: Analysis was done on 168 parasuicide patients [males 74; mean
      age for males 24 years (SD 6.2), females 19 years (SD 3.3)] and 168 matched
      controls. Of the parasuicide subjects, 33 had a psychiatric illness and 135 were
      considered to have impulsive personalities. The serum cholesterol level in
      parasuicide patients was not significantly different from that in controls.
      CONCLUSIONS: This study, the first from a developing country, did not show an
      association between low serum cholesterol concentrations and parasuicide.

PMID- 10643092
TI  - Pattern of use of medical information made available via an Internet website.
AB  - INTRODUCTION: The Internet is probably the fastest growing means of public
      communication. Those who seek health and medical information are using it
      increasingly. We decided to study the pattern of use of information made
      available via an Internet website. METHOD: Retrospective analysis of the entries
      made on the guest book and direct inquiries made to the webmaster of an
      established and well known Sri Lankan medical website from 1 February 1997 to 20
      November 1998. RESULTS: During this period 23,373 web surfers visited the site.
      There were 222 guest book entries and 12 direct inquiries to the webmaster. The
      analysis of these entries and inquiries show that there is a wide gap in use of
      the information available at this website between web surfers from the developed
      and the developing countries. CONCLUSION: Governments in developing countries
      must plan to make computers and information technology as well as
      telecommunication services affordable and widely available.

PMID- 10643093
TI  - Survival of neonates born below thirty-five weeks gestation in a developing
      country (Barbados, the West Indies).
AB  - A retrospective study of the survival of babies born below 35 weeks of gestation
      over a period of five years from 1987 to 1991 at Queen Elizabeth Hospital was
      analysed. The births of 433 were evaluated taking into consideration the birth
      weights, periods of gestation and mode of delivery. The fetal outcome in relation
      to these parameters were examined. Twin pregnancies were excluded. A poor outcome
      was noted in babies below 1000 g. Increasing survival rates were observed with
      increasing birth weight and increasing period of gestation. Babies below 30 weeks
      gestation had a poor survival rate. Caesarian section was found to be better than
      a vaginal delivery for a favourable outcome when all 425 births were considered.

PMID- 10643094
TI  - Dietary intake of vitamin E and folic acid in a defined population in Sri Lanka.

PMID- 10643095
TI  - The consultation and doctor-patient communication.

PMID- 10643096
TI  - Sirenomelia sequence (mermaid syndrome).

PMID- 10643097
TI  - The first ever report of homicidal poisoning by intramuscular injection of
      gramoxone (paraquat).

PMID- 10643098
TI  - 24% of male deaths alcohol related.

PMID- 10643099
TI  - Cervical screening program for Sri Lanka--can we afford it?

PMID- 10643100
TI  - Human papillomavirus in carcinogenesis of cervical cancer.

PMID- 10643101
TI  - A pigeon breeder with lung cancer.

PMID- 10643102
TI  - Australia's notifiable diseases status, 1998. Annual report of the National
      Notifiable Diseases Surveillance System.
AB  - In 1998 there were 85,096 notifications to the National Notifiable Diseases
      Surveillance System; slightly lower than in 1997 (89,579). The number of measles
      cases remained low, and well below the number reported in the outbreak years of
      1993 and 1994. Rubella notifications further decreased and remained low in 1998.
      The Measles Control Campaign from August to November 1998, did not impact
      significantly on the number of measles or rubella cases reported for 1998.
      Notifications of Haemophilus influenzae type b reached a record low since
      surveillance began in 1991, and appeared to have stabilised at a low rate since
      the introduction of the conjugated vaccine in 1992. The previously reported
      outbreak of pertussis in 1997 tapered off in early 1998. Food-borne disease, or
      detection of disease, appeared to be on the rise with an increase in notification
      rates of campylobacteriosis and salmonellosis. Notifications of hepatitis A
      decreased, correcting the previous high number of notifications in 1997. Sexually
      transmissible diseases (STDs) increased. Notifications for chlamydial infection
      were the highest for all sexually transmitted diseases and third highest for all
      notifiable diseases. Notifications of gonococcal infection also continued to rise
      and have doubled since 1991, whilst notifications for syphilis increased slightly
      after falling steadily over recent years. Arbovirus infections of concern in 1998
      were dengue outbreaks in Far North Queensland and the first case of Japanese
      Encephalitis for mainland Australia, highlighting the importance of surveillance
      of arboviruses and vectors for their detection and management.

PMID- 10643104
TI  - Communicable diseases surveillance.

PMID- 10643103
TI  - Preparing for refugee crises in Australia: Kosovar health surveillance.

PMID- 10643105
TI  - Public nutrition in emergencies: an overview of debates, dilemmas and decision
      making.
AB  - This paper introduces and discusses the main themes and issues arising from the
      workshop 'International Public Nutrition in Emergencies: The Potential for
      Improving Practice'. Good co-ordination within the nutrition sector of the
      international humanitarian response system has led to a range of achievements in
      recent years. Major constraints to improving programme impact remain, however,
      including misconceptions about the scope of nutrition among the wider
      humanitarian system, which tends to give it a narrow focus on malnutrition and
      feeding people. In contrast to this limited view, the Public Nutrition approach
      brings a more broad-based emphasis to assessing and responding to nutritional
      problems in emergencies, and takes into account the wider social, economic and
      political causes of malnutrition. Six case study presentations illustrated the
      various components of a Public Nutrition approach, including in-depth assessment,
      analysis and tailoring programmes accordingly. Additional presentations
      considered the nature of vulnerability, the concept of Public Nutrition, the
      responsibilities for addressing nutritional problems and some of the operational
      tools and frameworks in current use. Participants agreed on the necessity of
      raising levels of awareness and understanding among all actors in the
      humanitarian sphere about the impact of their actions on nutrition. Strategies
      for achieving this included developing better multi-sectorial working
      relationships and also strengthening relationships with donors and key decision
      makers in the humanitarian system. Other related strategies included
      institutional learning, training and capacity building, particularly in relation
      to institutions based in developing countries and building upon initiatives such
      as the Sphere Project, which has successfully brought together the various actors
      within the humanitarian system in order to improve quality of response.

PMID- 10643106
TI  - A measure of uncertainty: the nature of vulnerability and its relationship to
      malnutrition.
AB  - Terms such as 'vulnerability' and 'insecurity' are used widely in the general
      nutrition literature as well as in work on humanitarian response. Yet these words
      are used rather loosely. This paper argues that more clarity in their usage would
      benefit those seeking a bridge between development and humanitarian problems.
      Since vulnerability is not fully coincident with malnutrition, poverty or other
      conventional indices of human deprivation, public action must be based on a
      better understanding of the nature of crises and human uncertainty beyond
      physiological and nutritional outcomes. More attention is needed to be paid to
      the context-specific nature of risks, the capacity of households to manage such
      risks and the potential for public action to bolster indigenous capacity through
      targeted development investments, not just relief.

PMID- 10643107
TI  - Malnutrition in emergencies: how can we do better and where do the
      responsibilities lie?
AB  - Over many years, the international relief system has been repeatedly criticised
      in terms of slowness of response, poor inter-agency co-ordination, and technical
      incompetence on a larger or smaller scale. Notwithstanding many initiatives to
      improve co-ordination and other aspects of international relief performance,
      relief failures, including epidemic malnutrition, continue to occur. The reasons
      for these failures are discussed from the perspective of the characteristics of
      the international system, and the way in which this would be expected to perform
      under different conditions. The chief limitations of the international system
      identified are: the lack of any focus for imposing co-ordination, other than
      governments of affected countries; the lack of any requirement for donor nations
      to ensure that adequate resources are supplied; and a tendency for the system to
      respond uncritically to the international media. A broad typology of
      international responses is proposed. It is suggested that relief failure can be
      recast in terms of the lack of any system which can ensure the correct allocation
      of food and other resources between emergencies, and ensure the systematic
      distribution of such resources as are supplied. It concludes that the scope for
      further improvement in the performance of the international relief system is now
      limited, but that the most promising area for investment would, where possible,
      support governments in affected countries to take greater control of the
      management of the international relief system.

PMID- 10643108
TI  - The Sphere Project: the implications of making humanitarian principles and codes
      work.
AB  - In 1996, in recognition of concerns about humanitarian response efforts, non
      governmental organisations (NGOs) launched the Sphere Project, the first
      collaborative initiative to produce globally applicable minimum standards for
      humanitarian response. The aims of the Sphere Project are to improve the
      effectiveness of humanitarian efforts and to enhance the accountability of the
      humanitarian system, primarily to those people who have a right to protection and
      assistance in disasters, as well as to agency members and donors. This paper
      discusses the purpose of the Sphere Project, the unique process that brought it
      about and the major concerns that have been raised about its practical
      application. Finally, the paper considers the implications of this for improving
      the impact of humanitarian response and for future initiatives given the process
      that Sphere has begun. It argues that improved accountability does not start and
      stop with NGOs. They are just one element of a wider humanitarian response effort
      and more needs to be done to improve the system as a whole.

PMID- 10643109
TI  - Public nutrition from an approach to a discipline: concern's nutrition case
      studies in complex emergencies.
AB  - The Public Nutrition approach, like that of Public Health, is context specific.
      It places an emphasis on populations rather than individuals and is inter
      disciplinary in nature. Both approaches seek to understand the complex aetiology
      of a clinical outcome such as malnutrition within the widest possible framework.
      Public Nutrition uses the UNICEF conceptual framework and adapts and expands it.
      The authors of this article argue--through the examination of a number of case
      studies taken from the work of Concern Worldwide (hereafter referred to as
      Concern) in southern Sudan, Rwanda, Angola, Tanzania and DRC--that there are two
      critical constituents of the Public Nutrition approach. These are: a contextual
      analysis (including the use of surveillance information for programme design and
      advocacy) and community involvement at all stages of the project cycle. Some of
      the key obstacles to the adoption of the Public Nutrition approach are identified
      by illustrating two practical programme settings. For the Public Nutrition
      approach to be more widely used, the authors recommend a number of key strategies
      including the further dissemination of case studies and the clarification of the
      scope and boundaries of the approach. These strategies will enable Public
      Nutrition to evolve both as a practical programme framework as well as an
      academic discipline.

PMID- 10643110
TI  - The management of severe malnutrition in Burundi: an NGO's perspective of the
      practical constraints to effective emergency and medium-term programmes.
AB  - The NGO, Action contre la Faim (ACF), has been operating in Burundi since 1994,
      where the situation has dramatically hampered humanitarian programmes. These
      include poor security resulting in an inability to maintain 24-hour care for the
      severely malnourished and poor access to the beneficiaries, all within a
      politically and economically unstable context. However, ACF has been able to
      capitalise on lessons learnt and reflect on ways to move forward, which have
      included the improvement of their capacities in the treatment of severe
      malnutrition and the integration within broader disciplines and national
      structures. The protocols for the treatment of severe malnutrition currently used
      in Burundi have been developed as a result of the research of ACF over the past
      five years. Other aspects of the nutrition programme remain to be further
      developed. These include, for example, an improved capacity to care for severely
      malnourished adolescents and adults; and also a better knowledge of the
      beneficiaries to allow for stronger links between the provision of treatment and
      support for their longer-term food security.

PMID- 10643111
TI  - Ageism: a factor in the nutritional vulnerability of older people?
AB  - Unlike other population groups, the rights, needs and contributions of older
      people in developing countries are not well understood. With the absence of
      information about how to assess the nutritional status and vulnerability of older
      people, HelpAge International joined forces with the London School of Hygiene and
      Tropical Medicine in the early 1990's to launch a research programme. Seven years
      later some of the basic questions can now be answered but there remains much more
      to do. Although older people are increasingly acknowledged as a vulnerable group
      in emergencies, NGO responses often fail to meet their needs. The question is
      whether there are real difficulties in service adaptation or whether ageism is
      one of the greatest barriers to the provision of appropriate services for older
      people.

PMID- 10643112
TI  - Targeting the vulnerable: a review of the necessity and feasibility of targeting
      vulnerable households.
AB  - This article examines whether it is possible to target vulnerable households
      within a geographically defined area. It looks first at the justification for
      targeting and then reviews recent practical experience in actually trying to
      reach vulnerable groups. As complex emergencies increasingly last longer,
      strategies to target vulnerable households are common in the protracted phase of
      the emergency. While this is often necessary because of a decline in resources,
      it is not always justified by an improvement in nutritional status or food
      security of the beneficiary population. Common target groups are the poor and the
      malnourished, but in complex emergencies these are not always the most
      vulnerable. Moreover, recent practical experience has shown considerable
      difficulties in targeting the poor. Methods to target the poor rely on community
      based relief committees, whose priorities are not necessarily the same as those
      of external agencies. This paper gives examples of such targeted assistance
      programmes in Kenya, south Sudan and Tanzania. The paper concludes that
      situations where targeting vulnerable households is justified and feasible are
      extremely limited. It is suggested that if targeting has to be done because of
      scarce resources, this should be done on a geographical basis and on the basis of
      nutritional status. Case-study material shows that it is essential to understand
      the political determinants of vulnerability and to design methods that will reach
      the most vulnerable.

PMID- 10643113
TI  - Programmes in chronically vulnerable areas: challenges and lessons learned.
AB  - In the 'chronically vulnerable areas' (CVAs) of East Africa a smooth linear
      transition away from emergency programming towards rehabilitation and long-term
      development is difficult, if not impossible. This makes uncritical application of
      the 'relief-to-development' continuum to programming unhelpful at best, and
      perhaps counter-productive. This paper is the result of CARE's efforts to review
      its own programmes--and those of some of its sister agencies--in chronically
      vulnerable areas in the East Africa region, to derive important lessons learned
      and to identify areas where improvements are needed. The paper focuses on
      strategic considerations and decision-making in relation to entry, programme
      design and strategies for transition and exit.

PMID- 10643114
TI  - [Regular exercise prevents overweight].

PMID- 10643115
TI  - [Low-tension glaucoma--a disease for ophthalmology or internal medicine?].

PMID- 10643116
TI  - [Juvenile myoclonic epilepsy].

PMID- 10643117
TI  - [Should illnesses of the musculosceletal system be diagnosed clinically or with
      the help of machines?].

PMID- 10643118
TI  - [Coronary heart disease in women].

PMID- 10643119
TI  - [The story of human growth hormone--from a clone to the clinics].

PMID- 10643120
TI  - [Juvenile myoclonic epilepsy--do you recognize this common syndrome?].

PMID- 10643121
TI  - [Gastric banding - a new operative way to treat morbid obesity].

PMID- 10643122
TI  - [A massive pulmonary embolism and pulmonary hypertension as signs of
      antiphospholipid antibody syndrome].

PMID- 10643123
TI  - [A critically ill newborn and an unconscious, sweet-smelling young man].

PMID- 10643124
TI  - [Gene diagnostics and treatment of porphyrias].

PMID- 10643125
TI  - [Unclear abdominal pain and a suspicion of porphyria].

PMID- 10643126
TI  - [Atypical back pain and a newly diagnosed diabetes].

PMID- 10643127
TI  - [A dissociative disorder or a psychosis?].

PMID- 10643128
TI  - [What is a proper Finnish term for ENMG?].

PMID- 10643129
TI  - [What is normal and when to operate?].

PMID- 10643130
TI  - One hundred years of natural selection in the wild.

PMID- 10643131
TI  - What price politics? Scientists and political controversy.
AB  - There is a long tradition within scientific communities that encourages
      governments, patrons and citizens to enlist scientific expertise in the service
      of the public good. However, since the 17th century, scientists who have engaged
      in public political controversy have often been judged harshly by scientific
      colleagues, as well as by political adversaries. Some prominent scientists were
      politically active in Germany, France and England during the 1920s and 1930s;
      controversial stands were taken by the British physicist P.M.S. Blackett and the
      American chemist Linus C. Pauling against their countries' nuclear weapons policy
      following the Second World War.

PMID- 10643132
TI  - Regions of government science: John Wesley Powell in Washington and the American
      west.
AB  - Best known as the first down the Colorado River through the Grand Canyon, John
      Wesley Powell built his extraordinary career as geographer, geologist,
      anthropologist, bureaucrat, and conservationist from his knowledge of the arid
      region of the American West. Yet as much as Powell's scientific work, and his
      prescriptions for land reform, were grounded in the western landscape, they were
      equally situated in the booming Gilded Age capital of Washington, DC, where a new
      community of government scientists was gelling as part of an increasingly
      centralized federal state.

PMID- 10643133
TI  - What is a genetic test, and why does it matter?
AB  - How the term 'genetic test' is defined, matters for social policy. The past few
      years have witnessed many efforts to enact legal barriers specifically against
      genetic discrimination. To the extent that information derived from genetic tests
      receives special protection, both enthusiasts for genetic medicine and those who
      stress its perils have an incentive to adopt a broad interpretation of genetic
      testing. However, the consequences have not always been those anticipated.

PMID- 10643134
TI  - Observation and image-making in Gothic art
AB  - Since the 16th century, art historians have debated the methods of medieval
      artists. A frequent topic of discussion and one that has been invoked at times to
      distinguish the medieval artist from his early modern successor is the extent to
      which medieval art is based on the observation of nature. In this vein, much
      recent commentary has focused on selected works whose descriptiveness challenges
      the schematism of most medieval imagery. As argued here, assessing these images
      and the visual evidence they present of the artist's working method requires a
      methodology that is sensitive to the syntax of visual communication.

PMID- 10643135
TI  - Catch a falling apple: Isaac Newton and myths of genius.
AB  - Newton has become a legendary figure belonging to the distant past rather than a
      historical person who lived at a specific time. Historians and scientists have
      constantly reinterpreted many anecdotal tales describing Newton's achievements
      and behaviour, but the most famous concerns the falling apple in his country
      garden. Newton's apple conjures up multiple allegorical resonances, and examining
      its historical accuracy is less important than uncovering the mythical truths
      embedded within this symbol. Because interest groups fashion different collective
      versions of the past, analysing mythical tales can reveal fundamental yet
      conflicting attitudes towards science and its practices.

PMID- 10643136
TI  - Evolutionary progress from Darwin to Dawkins.
AB  - Is evolution 'progressive'? Biologists have been deeply divided in their answers
      to this question for over a century and a half. Darwin addressed the question in
      On the Origin of Species, prominent evolutionists debated the issue again in the
      middle decades of this century, and the issue has attracted renewed attention
      recently. Remarkably, the seeds of a solution to the problem may lie in Darwin's
      earliest private reflections on simplicity, complexity and the evolution of life.

PMID- 10643137
TI  - Marcello Malpighi and the difficult birth of modern life sciences.
AB  - All his life, Marcello Malpighi (1628-1694), the founder of modern microscopic
      anatomy, was unwillingly involved in difficult debates within a reactionary
      medical milieu that questioned the significance of modern science and its utility
      to medicine. Malpighi's responses to his detractors, included in posthumous works
      first published in 1697 by the Royal Society, offer an important insight into a
      critical phase of scientific progress in the 17th century and help to reveal the
      prevailing conception of science. In some ways, Malpighi's views predate
      important ideas in modern biology.

PMID- 10643138
TI  - The performance of surgery in enlightenment France.
AB  - During the 18th century, the reinvention of French surgery as a 'monarchical
      profession', in the words of Toby Gelfand, enabled the creation of an elite
      surgical knowledge from which uninstructed participants could be excluded. A link
      can be made between the types of resources used by surgeons to present themselves
      as expert healers, and the epistemological strategies of the operation. The
      sickbed was the scene of a performance, in which every actor's movements were
      described and constrained; the end product of an extended process of social
      negotiation, surgical training, physical restraint and submission.

PMID- 10643139
TI  - Japanese encephalitis in Sangli district, Maharashtra.
AB  - During the months June to December, 1997, 52 cases of suspected viral
      encephalitis were admitted at the Government Hospital, Sangli. These cases were
      from the congested areas of Sangli and the adjoining villages. All age groups and
      both genders were affected. IgM antibodies to Japanese encephalitis (JE) virus
      were detected in the sera of five of the 52 cases. Perhaps JE virus has
      established itself in a new locality in Maharashtra and could cause serious
      public health problems.

PMID- 10643140
TI  - Early results from indirect drug susceptibility test for tubercle bacilli.
AB  - The indirect susceptibility test results on L-J medium for tubercle bacilli
      against streptomycin, isoniazid and rifampicin were read at the end of 2 wk and
      compared with the results at 4 wk. It was found that drug resistance could be
      correctly predicted in over 70 per cent of cultures including multi-drug
      resistant tuberculosis (MDR TB) strains at the end of 2 wk. The susceptibility to
      para-nitrobenzoic acid (PNB) read at 2 wk was able to distinguish non-tuberculous
      mycobacteria from Mycobacterium tuberculosis cultures. The early detection of
      resistance by this procedure requires only minimum inputs, and can benefit the
      majority of patients harbouring drug resistant tubercle bacilli.

PMID- 10643141
TI  - Estimation & significance of serum & synovial fluid malondialdehyde levels in
      rheumatoid arthritis.
AB  - Serum and synovial fluid (SF) levels of malondialdehyde (MDA), a marker of free
      radical induced lipid peroxidation, were estimated in patients of rheumatoid
      arthritis (RA) and compared with healthy controls and patients of osteoarthritis
      (OA). While serum MDA levels were similar in healthy controls (0.24 +/- 0.10
      nmol/ml) and OA (0.28 +/- 0.11 nmol/ml), the serum levels in RA (0.47 +/- 0.19
      nmol/ml) were significantly higher as compared to both healthy controls and OA
      patients; and correlated with synovial fluid (SF) MDA levels. No difference was
      observed in SF-MDA levels in RA (0.17 +/- 0.07 nmol/ml) and OA (0.16 +/- 0.09).
      MDA levels did not correlate with markers of disease activity in RA like joint
      counts, duration of morning stiffness, erythrocyte sedimentation rate etc.
      Increased serum MDA levels in RA suggest the role of free radicals in the
      pathogenesis of this inflammatory arthropathy and support the need for further
      studies assessing the therapeutic role of free radical scavengers in RA.

PMID- 10643142
TI  - Comparison of perioperative morbidity in patients with ovarian malignancy
      undergoing radical cancer surgery with or without prior chemotherapy.
AB  - Evaluation was undertaken of the effect of chemotherapeutic drugs on the
      perioperative morbidity of patients with ovarian malignancy undergoing radical
      surgery. Twenty patients who had received cytotoxic drugs pre-operatively (group
      I) were compared with 11 patients in whom radical surgery was the first line of
      treatment (group II). Pre and post-operative cardiac, pulmonary, renal, hepatic
      and coagulation functions were compared in both groups, as well as the critical
      intra- and post-operative events like cardiac pump failure, respiratory
      dysfunction, rhythm disturbances, blood loss, etc. Demographic data, ASA status,
      biochemical and haematological parameters and cardiac ejection fractions were
      comparable in the two groups but patients in group I had significantly higher
      left ventricular end diastolic dimensions (P < 0.01). A higher number of patients
      in group I had pre-operative respiratory and coagulation factor abnormalities but
      critical intra- and post-operative events in both groups were comparable. The
      surgical time was significantly (P < 0.01) longer in group I (5.5 +/- 2.5 h) as
      compared to group II (4.5 +/- 1.5 h). One patient with extensive tumour spread
      and pre-operatively deranged coagulation profile (group I) died of disseminated
      intravascular coagulation in the post-operative period. It is concluded that
      patients with advanced ovarian malignancy, treated with cytotoxic drugs are more
      likely to have pre-operative cardiac, respiratory and coagulation abnormalities,
      which should be managed by thorough pre-operative evaluation and intensive intra-
      and post-operative monitoring.

PMID- 10643143
TI  - Optimizing radiation therapy of brain tumours by combination of 5-bromo-2-deoxy
      uridine & 2-deoxy-D-glucose.
AB  - The effects of 5-bromo-2-deoxy-uridine (BrdU) and 2-deoxy-D-glucose (2-DG) on
      60Co-gamma ray induced damage were studied in a human glioma cell line grown as
      monolayer. Radiation induced micronuclei formation was used as an index of
      cytogenetic damage. Exponentially growing cells (doubling time 16-20 h) were
      incubated in the presence of BrdU (0.8 microM, in dark) for 24 h. After removing
      BrdU, cells were irradiated (1-4 Gy), incubated with or without 2-DG (2-3 h), and
      grown further (for 18, 24, 30 or 45 h) for assay of damage. It was observed that
      (i) BrdU and 2-DG treatments did not induce micronuclei formation in unirradiated
      cultures; (ii) pre-irradiation presence of BrdU increased the gamma-ray induced
      micronuclei formation; (iii) incubation of irradiated cells under sub-optimal
      growth conditions [Dulbecco's modified minimal essential medium (DMEM) + 1%
      serum, or DMEM alone] instead of growth medium (DMEM + 5% serum) progressively
      decreased micronuclei formation; and (iv) post-irradiation presence of 2-DG
      (1.25, 2.5, 5 mM, 2-3 h in DMEM + 1% serum) enhanced the radiation damage with
      and without BrdU treatment at all the time points studied. These observations
      suggest that (i) radiation induced lesions leading to micronuclei formation in
      proliferating cells are, at least, partly repairable; (ii) the presence of 2-DG
      (2DG/glucose > or = 0.25) for short intervals (approximately 2 h), could enhance
      radiation damage in proliferating brain tumour cells, in the absence as well as
      presence of BrdU incorporation; and (iii) the combination of 2-DG could reduce
      BrdU doses required for radiosensitization of brain tumours, reducing, thereby,
      its toxic side effects.

PMID- 10643144
TI  - Gender differences in muscle strength & endurance in young Indian adults.
AB  - Muscle strength was studied in 70 males and 53 females between the ages of 17-30
      yr, using a handgrip dynamometer. In a subset group of 31 males and 20 females,
      muscle endurance during sustained isometric contraction was studied using a load
      cell based handgrip dynamometer coupled to a polygraph. The males had a
      significantly greater muscle mass and lower body fat as compared to the females.
      Males had close to twice the handgrip strength of females in absolute terms (P <
      0.01) and this difference persisted after correction for forearm muscle area (P <
      0.05). In contrast, the rate of decline of muscle strength during sustained
      isometric contraction was lower in females as compared to males (P < 0.05),
      suggestive of greater skeletal muscle endurance in females. Physical activity
      patterns were not a determinant of skeletal muscle function. These findings are
      consistent with gender specific muscle fibre characteristics reported in
      literature in other racial groups.

PMID- 10643145
TI  - Who is hematopoietic stem cell: CD34+ or CD34-?
AB  - Hematopoietic stem cells (HSC) possess multipotentiality, enabling them to self
      renew and also to produce mature blood cells, such as erythrocytes, leukocytes,
      platelets, and lymphocytes. CD34 is a marker of human HSC, and all colony-forming
      activity of human bone marrow (BM) cells is found in the CD34+ fraction. Clinical
      transplantation studies that used enriched CD34+ BM cells indicated the presence
      of HSC with long-term BM reconstitutional ability within this fraction. But
      recent studies in NOD/SCID mice, rhesus monkeys, and human/sheep competitive
      engraftment models have provided evidence for the presence of a rare cell
      population that contains progenitors capable of producing CD34+ cells in vitro.
      These progenitors are highly enriched in HSC and have competitive long-term in
      vivo repopulating potential devoid of both CD34 and lineage-marker expression.
      These new findings add to the growing evidence that some stem cells in the BM do
      not express the CD34 marker, which is currently used to select stem cells for
      transplantation.

PMID- 10643146
TI  - Thrombopoietin: biology and clinical potentials.
AB  - Thrombopoietin (TPO) is the principal physiologic regulator of platelet
      production. In vitro, TPO induces the growth of colony-forming units
      megakaryocyte (CFU-MK) and the generation of mature polyploid megakaryocytes,
      which subsequently form extended cytoplasmic processes, termed proplatelets. On
      more differentiated CFU-MK, but not on megakaryocytes, TPO is critical for
      enhancing proplatelet formation. TPO has multilineage effects in hematopoiesis,
      not only stimulating megakaryocytopoiesis but also acting in synergy with other
      cytokines to enhance proliferation and survival of committed erythroid
      progenitors and primitive hematopoietic stem cells. Surface c-MPL, the receptor
      for TPO, defines a phenotype of hematopoietic stem cells with long-term
      repopulating ability. Treatment with various cytokine combinations, including
      TPO, results in an extensive ex vivo expansion of hematopoietic stem cells and
      blood cell precursors. In normal animals, pegylated recombinant human
      megakaryocyte growth and development factor (PEG-rHuMGDF) or glycosylated TPO
      increases the number of bone marrow megakaryocytes and their progenitors and
      greatly enhance the production of morphologically and functionally normal
      platelets. In contrast, they have only minimal effects on peripheral white blood
      cell and red blood cell counts. PEG-rHuMGDF used alone markedly expands
      circulating levels of multiple types of hematopoietic progenitors, and its effect
      is enhanced in combination with granulocyte colony-stimulating factor (G-CSF).
      Although PEG-rHuMGDF augments platelet aggregation induced by agonists in vitro,
      it has no influence in an animal model of thrombus formation. PEG-rHuMGDF or
      glycosylated TPO has a profound effect in a variety of animal models of
      thrombocytopenia, including myelosuppressive therapy. PEG-rHuMGDF treatment
      accelerates multilineage hematopoietic recovery, effectively improving
      thrombocytopenia, and, in most models, neutropenia and anemia. The concurrent
      administration of PEG-rHuMGDF and G-CSF does not interfere with the in vivo
      activity of cytokines but rather has synergistic effects. To further accelerate
      hematopoietic recovery, PEG-rHuMGDF administration should start at the earliest
      time following myelosuppressive treatment; this time sensitivity may result from
      the presence of a greater number of residual hematopoietic progenitors in the
      bone marrow soon after treatment. Moreover, if a relatively large dose of PEG
      rHuMGDF is administered, a single intravenous injection is fully effective in
      improving impaired hematopoiesis. This effectiveness appears to be related to the
      persistence of PEG-rHuMGDF in the circulation. The safety and efficacy of two
      forms of the recombinant hormone, PEG-rHuMDGF and glycosylated human full-length
      TPO produced in mammalian cells, are currently under clinical investigation.

PMID- 10643147
TI  - Caspase: executioner and undertaker of apoptosis.
AB  - The caspase family of proteases play pivotal roles in the execution of apoptosis,
      a morphologically defined form of cell death observed in a variety of
      physiological and pathophysiological settings. This review focuses on the
      biochemical and cell biological aspects of caspases, including their structure,
      mechanism of activation, intracellular localization, inhibitors, substrates, and
      precise roles in cell death. Such an overview of the basic properties of caspases
      should provide insights into the apoptotic mechanism; these insights are crucial
      for understanding the contribution of deregulated apoptosis in hematological
      disorders.

PMID- 10643148
TI  - Hemolytic crisis after excessive ingestion of fava beans in a male infant with
      G6PD Canton.
AB  - After ingesting fava beans, a 26-month-old Chinese-Japanese male infant showed a
      sickly complexion and yellowish-brownish skin and was hospitalized. Severe
      hemolytic anemia was observed on admission, and transfusion of 200 ml of packed
      red cells was required. Red cell enzyme assay revealed that the patient and the
      mother were deficient in glucose-6-phosphate dehydrogenase (G6PD). Subsequent
      molecular analysis showed that the patient had a missense mutation 1376 G to T
      (G6PD Canton) and his mother was a homozygote for the mutation. The patient was a
      son of a Chinese (Taiwanese) mother and a Japanese father. Although G6PD
      deficiency is rare in the original Japanese population, the number of "imported"
      cases could be rising rapidly. This is the first reported Japanese case of G6PD
      deficiency with G6PD Canton.

PMID- 10643149
TI  - Alkaline phosphatase activity in neutrophils from patients with severe congenital
      neutropenia (Kostmann's syndrome).
AB  - The glycoprotein alkaline leukocyte phosphatase (ALP) can be used as a marker of
      maturity in neutrophilic granulocytes as the activity of ALP increases during
      neutrophilic differentiation. Severe congenital neutropenia (SCN) or Kostmann's
      syndrome is a congenital disorder characterized by a maturation arrest of myeloid
      progenitor cells at the promyelocyte/myelocyte stage that can be treated with
      recombinant human granulocyte colony-stimulating factor (rhG-CSF). Until recently
      there have been no reports on ALP activity in neutrophils of patients suffering
      from SCN, despite the fact that ALP is an important correlate of the functional
      activity of normal neutrophils. Thus, we conducted experiments to assess ALP
      activity in neutrophils from eight SCN patients before initiation of rhG-CSF
      treatment and an additional 17 SCN patients already receiving rhG-CSF. All eight
      patients analyzed before initiation of rhG-CSF treatment showed ALP activity in
      their neutrophilic cells. Four patients had normal and four patients had elevated
      ALP levels. Of the 17 patients already on treatment with rhG-CSF, 15 patients
      showed elevated ALP activity levels, one patient had normal ALP levels, and one
      patient showed abnormally low ALP activity. Thus, with the exception of a single
      patient, we observed normal or elevated ALP activity in neutrophils from SCN
      patients. As described in studies on the effect of rhG-CSF on ALP activity in
      healthy individuals, ALP activity was higher in SCN patients already on treatment
      with rhG-CSF. Therefore, our results indicate that SCN patients are not deficient
      in ALP activity and suggest that ALP is not deregulated in the majority of these
      patients.

PMID- 10643150
TI  - Association of src-kinase Lyn and non-src-kinase Syk with the granulocyte colony
      stimulating factor receptor (G-CSFR) is not abrogated in neutrophils from severe
      congenital neutropenia patients with point mutations in the G-CSFR mRNA.
AB  - Severe congenital neutropenia (SCN) is characterized by a maturation arrest of
      myeloid progenitor cells at the stage of promyelocytes in bone marrow and low
      levels of mature neutrophils in peripheral blood. To date, little is known
      regarding the underlying pathomechanism of SCN. A defective response of
      neutrophil precursors to granulocyte colony-stimulating factor (G-CSF) is a
      suggested mechanism. In the last few years, we and others described point
      mutations in the cytoplasmic domain of the G-CSF receptor (G-CSFR) mRNA in a
      subgroup of SCN patients. In one allele of the G-CSFR gene, a C to T substitution
      resulted in a change from a glutamine codon to a stop codon. The expected G-CSFR
      proteins were truncated by 83 to 98 amino acids. In this study, we show that the
      Lyn and Syk kinases are associated with the G-CSFR in neutrophils from SCN
      patients with point mutations in the cytoplasmic domain of the G-CSFR mRNA. These
      findings provide additional proof of the expression of normal G-CSFRs in these
      patients, because the possible Syk binding motif is located between amino acid
      727 and 747 in the G-CSFR.

PMID- 10643151
TI  - Long-term survival and prognostic study in acute promyelocytic leukemia treated
      with all-trans-retinoic acid, chemotherapy, and As2O3: an experience of 120
      patients at a single institution.
AB  - OBJECTIVE: All-trans-retinoic acid (ATRA), chemotherapy, and arsenic trioxide
      (As2O3) have been found to be effective in the treatment of acute promyelocytic
      leukemia (APL). Here we present a single institutional retrospective study with
      long-term follow-up to better define the prognostic factors and a rationale for
      the use of ATRA, chemotherapy, and As2O3 in the treatment of newly diagnosed and
      relapsed APL patients. PATIENTS AND METHODS: Newly diagnosed patients with APL
      entering complete remission were followed up for 3 to 95 months (n = 120).
      Univariate and multivariate analyses were performed to identify potential
      prognostic factors, including age and sex; initial white blood cell (WBC) count
      and peak WBC level of hyperleukocytosis during induction therapy; dose of ATRA in
      induction; days from induction therapy to remission; postremission therapy; type
      of PML-RAR alpha isoform; and follow-up of reverse transcription-polymerase chain
      reaction (RT-PCR). RESULTS: The median relapse-free survival (RFS) was 26 months,
      and median overall survival (OS) was still not reached. The estimated 5-year RFS
      and OS were 34.0% +/- 6.0% and 52.5% +/- 7.9%, respectively. Initial WBC count (>
      or = 20 x 10(9)/l), peak level of WBC during induction, and type of postremission
      therapy were significantly related to survival. Our multivariate study showed
      that only peak level of WBC count during induction therapy and type of
      postremission therapy were associated with RFS and that initial WBC count was
      associated with OS. In relapsed patients, As2O3 was very effective and remained
      as the most important factor for their entering remission and survival after
      relapse. CONCLUSION: Through this retrospective study with long-term follow-up,
      some conclusions can be drawn: 1) Low-dose ATRA is as effective as the standard
      dose in terms of survival; 2) Initial and peak levels of WBC count during
      induction therapy are associated with survival; 3) A combination of chemotherapy
      and ATRA is better than chemotherapy or ATRA alone as postremission therapy; 4)
      Patients with the long form of PML-RAR alpha tend to have a more favorable OS but
      not RFS when compared with patients with the short form; 5) Persistent negative
      RT-PCR in remission is associated with favorable RFS and OS; 6) As2O3 is an
      effective agent for relapsed patients.

PMID- 10643152
TI  - Infectious complications during remission induction therapy in 577 patients with
      acute myeloid leukemia in the Japan Adult Leukemia Study Group studies between
      1987 and 1991.
AB  - The Japan Adult Leukemia Study Group analyzed infectious episodes in 577 patients
      with acute myeloid leukemia during remission induction therapy between 1987 and
      1991. 542 patients (93.9%) experienced at least one infectious episode, 121
      (21.0%) had microbiologically documented infection; there was clinically
      documented infection in 184 (31.9%) and unexplained fever in 237 (41.1%). Among
      121 microbiologically documented infections, bacteremia/fungemia was observed in
      68, pneumonia in 33, and other types of infections in 20. Among the
      bacteremia/fungemia, gram-negative bacteria accounted for 41.2% (Pseudomonas
      aeruginosa was the most common), gram-positive bacteria for 39.7%, fungi for
      16.2% (Candida spp. being most frequent), and polymicrobial for 2.9%. The most
      frequent isolates among pneumonia were Pseudomonas aeruginosa and Aspergillus. A
      total of 70 patients (12.1%) died during remission induction. Mortality of 68
      patients with bacteremia/fungemia was 26.5%; in these patients, mortality with
      concomitant pneumonia increased to 41.4%; without pneumonia, mortality was 15.4%
      (P < 0.05). Mortality according to the isolated microbes was 17.2% for gram
      negative bacteria, 25% for gram-positive bacteria, and 54.5% for fungi. Mortality
      of 113 patients with pneumonia (33 microbiologically documented and 80 clinically
      documented), 20 with other microbiologically documented infections, 104 with
      other clinically documented infections, and 237 with unexplained fever was 25.7%,
      5.0%, 5.8%, and 5.1%, respectively.

PMID- 10643153
TI  - Biological characteristics and prognostic value of in vitro three-drug resistance
      to prednisolone, L-asparaginase, and vincristine in childhood acute lymphoblastic
      leukemia.
AB  - The purpose of this study was to investigate the biological characteristics and
      prognostic value of in vitro three-drug resistance to prednisolone, L
      asparaginase, and vincristine in childhood acute lymphoblastic leukemia (ALL). We
      carried out in vitro tests with a 4-day culture and a methyl-thiazol-tetrazolium
      assay on bone marrow samples from 209 children newly diagnosed with ALL. After
      testing the resistance of leukemic cells to 14 drugs, we classified the patients
      into two groups according to their sensitivity to three drugs (prednisolone, L
      asparaginase, and vincristine) used in remission induction therapy. The three
      drug resistant group (RR: sensitive to no drugs or to one drug) correlated with
      both short-term and long-term treatment failure. Three-year event-free survival
      (95% confidence interval) for the sensitive group (SS: sensitive to two or three
      drugs) was 0.813 (0.773-0.853) and that of the RR group was 0.616 (0.569-0.669)
      (P = 0.0001). Univariate analysis showed that Philadelphia-chromosome (Ph1)
      positivity and immunophenotype of mixed lineage were also prognostic factors in
      the 209 patients. The prognosis of the SS/RR drug resistance profile within 14
      Ph1 patients was marginally significant (P = 0.062). Multivariate Cox regression
      analysis showed that Ph1 was an overwhelmingly adverse factor in event-free
      survival, with a relative hazard of 5.37 (2.57-11.21, P < 0.0001), followed by
      RR, with a relative hazard of 2.98 (1.69-5.25, P = 0.0001). Furthermore, we
      clarified the characteristics of the RR group by examination of the pattern of
      drug resistance to other drugs in comparison with the SS group. The leukemic
      cells of RR patients were more resistant than those of SS patients (P < 0.0001)
      to all the drugs tested, with resistance ratios of 1.6 to 13.1 (mean 3.4). In
      conclusion, in vitro three-drug resistance at the initial stage is an important
      independent predictor of treatment failure for both induction response and long
      term outcome in childhood ALL.

PMID- 10643154
TI  - A chronic myelogenous leukemia-like myeloproliferative disorder accompanied by T
      cell lymphoblastic lymphoma with chromosome translocation t(8;13)(p11;q12): a
      Japanese case.
AB  - A 40-year-old male patient presented with leukocytosis and mild splenomegaly.
      Bone marrow aspirate showed myeloid hyperplasia and eosinophilia resembling
      chronic myelogenous leukemia in the chronic phase. Cytogenetic examination of
      bone marrow cells revealed an unusual karyotype, t(8;13)(p11;q12), in 20/20
      metaphases. Not the BCR/ABL, but the ZNF198/FGFR1 chimeric mRNA was detected by
      reverse transcription-polymerase chain reaction. Since 1992, 12 patients with a
      similar atypical myeloproliferative disorder with T-cell non-Hodgkin's lymphoma
      or eosinophilia, associated with a t(8;13) translocation in both bone marrow and
      lymph node specimens, have been described. The present case is an additional one
      that should be classified into this new clinicopathologic entity.

PMID- 10643155
TI  - Molecular evaluation of bone marrow involvement in peripheral T-cell lymphoma
      with a PCR-mediated RNase protection assay.
AB  - Bone marrow (BM) involvement in peripheral T-cell lymphoma was assessed by
      polymerase chain reaction (PCR)-mediated RNase protection assay. The sensitivity
      of this assay was approximately 10(-4) to 10(-5). In 16 of 30 patients (53.3%)
      with peripheral T-cell malignancies, consensus primers for the T-cell receptor
      (TCR)-gamma gene amplified the rearranged V(N)J region. Using the PCR products of
      diagnostic lymph nodes of the patients as probes, we analyzed the BM involvement
      of lymphoma cells in eight patients: four with peripheral T-cell lymphoma,
      unspecified; two with adult T-cell leukemia/lymphoma; and two with
      angioimmunoblastic T-cell lymphoma. BM involvement was detected by PCR-mediated
      RNase protection assay in four patients from BM smear and/or histo-pathological
      examination of clotted BM. Moreover, in two of four patients in whom BM
      involvement was not evident from morphological examination, BM involvement was
      detected by PCR-mediated RNase protection assay. Our results indicate that the
      PCR-mediated RNase protection assay targeting the TCR-gamma gene is useful in
      detecting minimal residual disease in about half of all T-cell lymphoma cases. In
      addition, in some patients with peripheral T-cell lymphoma, morphologically
      unproven BM involvement was found using the method.

PMID- 10643156
TI  - Sebastian platelet syndrome: two Japanese families originally diagnosed with May
      Hegglin anomaly.
AB  - Ultrastructural studies of granulocytes were performed on two unrelated patients
      with hereditary thrombocytopenia, giant platelets, and inclusion bodies in
      granulocytes. Each patient had been diagnosed with May-Hegglin anomaly. In both
      cases, inclusion bodies in granulocytes consisted of clusters of ribosomes and
      small segments of rough endoplasmic reticulum. Additional clinical features
      suggesting Alport syndrome were lacking in these propositi and their family
      members. These observations imply that the patients were affected not with May
      Hegglin anomaly but with Sebastian platelet syndrome. They would thus represent
      the seventh and eighth families known to carry this hereditary disease.

PMID- 10643157
TI  - Can bone marrow transplantation give the gift of a baby?

PMID- 10643158
TI  - Fifth International Symposium on Myelodysplastic Syndromes.

PMID- 10643159
TI  - Civil war, social integration and mental health in Croatia.
AB  - Research has shown that social relationships are generally beneficial for mental
      health (Thoits 1995). However, few scholars have examined this association after
      the occurrence of a significant shock to the social system as a whole. The
      purpose of this article is to examine the relationship between social integration
      and war-related distress in Croatia immediately following the recent civil war.
      Does social integration decrease war-related distress? Does social integration
      buffer the effect of traumatic events on war-related distress? We analyze these
      questions using nationally representative survey data collected in Croatia in
      1996. Results suggest that social integration has both positive and negative
      direct effects on distress. Being a member of informal organizations, such as
      sports clubs, and participating in social activities are beneficial for mental
      health. On the other hand, being a member of some formal organizations, such as
      church organizations and unions, is detrimental to mental health. There is little
      support for the idea that social integration buffers the effect of traumatic
      events on distress. Only one of thirty-six possible interactions is significant
      and supports the buffer hypothesis. Frequent participation in social activities
      buffers the effect of experiencing violence on war-related distress. Also, some
      forms of social integration appear to aggravate the effect of traumatic events on
      war-related distress. In sum, social integration does affect war-related distress
      after a system shock, but in complex and sometimes unexpected ways.

PMID- 10643160
TI  - Social support and depressed mood: a structural analysis.
AB  - Current literature on social support identifies social structure as a source of
      distress. However, past efforts tend to operationalize structure in terms of
      demographic characteristics. The present paper argues that structure should be
      conceived of as participation and involvement in community and social relations.
      Structure may include community ties, social networks and intimate ties. We
      hypothesize that the three elements represent the outer layer (belongingness),
      the intermediary layer (bonding), and the inner layer (binding) of social
      relations and should exhibit differentiated effects on mental health. We further
      hypothesize that these structural elements, in sequence, provide functional
      (i.e., instrumental-expressive, perceived-received, and routine-non-routine)
      supports which, in turn, prevent or protect against distress. Using data from the
      1993-1994 Albany survey, we construct measures for elements of structural and
      functional support to test the relationship between the two as well as their
      effects on depression. Results confirm that elements of structural support, as
      predicted, differentially affect functional supports, and that the elements of
      both structural and functional supports exert direct effects on depression.
      Further, structural supports also exert indirect effects on depression, mediated
      by functional supports.

PMID- 10643161
TI  - Gender, social status, and emotional reliance.
AB  - Past research has suggested the potential importance of considering emotional
      reliance, a dimension of interpersonal dependence, when addressing social and
      developmental risk factors for depression. Based on a probability sample of 1,393
      adults aged 18-55 residing in Toronto, Canada, this paper addresses gender
      differences in emotional reliance and the relevance of emotional reliance in
      explaining the gender-depression association. We also explore link-ages between
      emotional reliance and status factors. Findings indicate that emotional reliance
      is significantly related to depression and that women report greater reliance
      than men, independent of social status factors like marital and parental status,
      education, income, and occupational prestige. Moreover, the positive association
      between emotional reliance and depression is greater for women. Several social
      status factors modify the relationship between gender and emotional reliance.
      Both education and occupational prestige reduce reliance, and are particularly
      beneficial in this regard for women. Marriage, on the other hand, increases
      emotional reliance, especially for men. We offer interpretations of this pattern
      of findings.

PMID- 10643162
TI  - The stress process and the social distribution of depression.
AB  - Mental health generally and depression in particular have been repeatedly shown
      to vary in relation to gender, socioeconomic status, marital status, and age.
      These status differences may be linked to mental health because they tend to
      define important differences in stress exposure and in the availability of coping
      resources. This paper examines the capacity of the stress-process model to
      account for the social distribution of depression. We employ mediation analyses
      using data from a 1990-1991 survey of Toronto community residents. In general, we
      found hypothesized risk factors to vary across these statuses with depressive
      symptoms and disorder and the distribution of protective factors to vary
      inversely. Results indicate that the model as expressed in our analyses accounts
      for a substantial minority of observed depression differences across individuals
      and for a considerable portion of reliably observed variation across social
      statuses. Our findings with respect to major depressive disorder parallel those
      for depressive symptomatology. Most compelling is the nearly total explanation of
      the socioeconomic status association with depressive symptoms and the substantial
      contribution toward explaining the socioeconomic status-disorder relationship
      when stress process mediators are accounted for.

PMID- 10643163
TI  - Religion, social support, and health among the Japanese elderly.
AB  - We address three issues in this paper: (1) Is religion related to self-rated
      health, (2) do these salubrious effects arise because religion encourages people
      to provide help to significant others, and (3) is the relationship between
      religion and helping others more evident among older men than elderly women? We
      analyze the relationships among religion, support giving, and health with data
      provided by a national probability sample of 2,153 older people in Japan who were
      interviewed face-to-face in 1996. Greater involvement in religion is associated
      with providing help to others more often, but these effects emerge for older men
      only. Regardless of gender, elders who provide assistance to others more often
      rate their health more favorably than older adults who are less involved in
      helping others. These results confirm that religion is related to health, and
      that helping others may explain at least part of the reason for this
      relationship.

PMID- 10643164
TI  - The ecological effect of unemployment on the incidence of very low birthweight in
      Norway and Sweden.
AB  - Little attention has been paid to the ecological effects of unemployment, despite
      strong theory suggesting that being socially or economically connected to
      unemployed persons can induce illness. Theory suggests, for example, that the
      labor market experience of adult males should affect maternal and infant health.
      We advance this line of inquiry by testing the hypothesis that quarterly
      increases in unemployment among Norwegian and Swedish males were associated with
      increased incidence of very low weight births from 1973 through 1995. Results
      support the hypothesis. We estimate that approximately 188 very low weight births
      could have been averted in Norway, and about 329 in Sweden, if quarterly
      increases in male unemployment had been constrained to the median over the 23
      year period. Our findings imply that the social cost of unemployment may be
      underestimated by focusing on unemployment as an individual risk factor.

PMID- 10643165
TI  - Attitudes toward genetic testing and fetal diagnosis, 1990-1996.
AB  - With few exceptions, existing research on attitudes toward genetic testing and
      prenatal diagnosis is based on small studies using nonprobability samples of
      specialized populations. In this paper, we use a nationally representative sample
      from the General Social Survey to report on attitudinal change between 1990 and
      1996, and to explore socio-demographic predictors of public views on genetic
      technology and reproduction in the context of changing mass media coverage
      between 1988 and 1995. During that period, media coverage of prenatal testing
      became both less frequent and less favorable, despite increasing use of this
      technology, whereas media reports about other types of genetic testing increased
      in frequency and became more favorable. Between 1990 and 1996, attitudes toward
      genetic testing remained stable, although the attitudes of specific demographic
      subgroups may be changing in different directions. Attitudes toward abortion in
      case of genetic defect became more negative over the period studied. We explore
      some of the implications of these findings.

PMID- 10643166
TI  - From nuclear bombs to food safety: a personal odyssey.

PMID- 10643167
TI  - The toxic-tobacco law: "appropriate remedial action".
AB  - Tobacco products, despite being lethal and addictive, are highly attractive and
      accessible to children at hundreds of thousands of retail outlets. The proposed
      Toxic-Tobacco Law (the Law) will end this access by prohibiting U.S. corporations
      from making, marketing, or importing tobacco products. The Law will go into
      effect twenty years after enactment, giving all stake-holders (e.g., farmers)
      time to adjust. After this adjustment period, adults will be "free" to import
      tobacco products for personal use. Unlike Prohibition, which sought to stop
      Americans from consuming alcohol, the Toxic-Tobacco Law does not seek to restrict
      consumption by adults. The purpose of this law is to end the massive presence of
      tobacco products in American society in order to prevent the addiction of
      children to tobacco and its devastating health consequences (e.g., lung cancer).
      The U.S. Congress, under the "commerce clause" of the Constitution, has the
      authority to pass the Toxic-Tobacco Law.

PMID- 10643169
TI  - "I didn't know the gun was loaded": an examination of two safety devices that can
      reduce the risk of unintentional firearm injuries.
AB  - Some handguns contain built-in safety devices intended to prevent injuries caused
      by erroneously believing that a handgun is loaded. A loaded chamber indicator
      indicates the presence of ammunition in the gun; a magazine safety prevents the
      gun from being fired when the ammunition magazine is removed, even if one round
      remains in the firing chamber. In our patent search these devices date back to
      the turn of the century. But on 1998 pistol models, only 11% contained a loaded
      chamber indicator and 14% had a magazine safety. In our random-digit-dial
      telephone survey of U.S. adults, 34.8% of poll respondents (incorrectly) thought
      that a firearm with its ammunition magazine removed could not be shot, or said
      that they did not know. Some of the 1100 unintentional gun deaths in the U.S.
      each year might be prevented if the prevalence of these and other safety devices
      is increased through legislation, litigation, or voluntary manufacturer action.

PMID- 10643168
TI  - Effectiveness and cost-effectiveness of linking the special supplemental program
      for women, infants, and children (WIC) and immunization activities.
AB  - OBJECTIVE: To raise immunization coverage among children at risk for
      underimmunization, we evaluated the effectiveness and cost-effectiveness of
      immunization activities in the Special Supplemental Program for Women, Infants
      and Children (WIC). METHOD: A controlled intervention trial was conducted in
      seven WIC sites in Chicago between October 1990 and March 1994. At intervention
      sites, staff screened children for vaccination status at every visit, referred
      vaccine-eligible children to either an on-site WIC nurse, on-site clinic, or off
      site community provider, and issued either a 3-month supply of food vouchers to
      up-to-date children or a 1-month supply to children not up-to-date--a usual
      practice for high-risk WIC children. Our primary measure of effectiveness was the
      change in the baseline percentage of up-to-date children at the second birthday;
      cost-effectiveness was approximated for each of the three referral interventions.
      RESULTS: After one year, up-to-date vaccination coverage increased 23% above
      baseline for intervention groups and decreased 9% in the control group. After the
      second year, up-to-date vaccination further increased to 38% above baseline in
      intervention groups and did not change in the control group. The total cost per
      additional up-to-date child ranged from $30 for sites referring children off-site
      to $73 for sites referring children on-site to a nurse. CONCLUSION: This
      controlled intervention trial of screening, referral, and a voucher incentive in
      the WIC program demonstrated a substantial increase in immunization coverage at a
      low cost. Continuing to design linkages between WIC and immunization programs by
      building on WIC's access to at-risk populations is worth the investment.

PMID- 10643170
TI  - Limitations of occupational air contaminant standards, as exemplified by the
      neurotoxin N-hexane.
AB  - Available industry guidelines and federal standards have failed to fully protect
      workers from chemical toxicity: none exist for most chemicals, many are biased
      toward what can easily be achieved, and many were developed long after health
      consequences became evident. Limitations of occupational air contaminant
      standards in the United States are well illustrated by standard-setting for the
      neurotoxin n-hexane. In the 1940s, the American Conference of Governmental
      Industrial Hygienists (ACGIH) first promulgated industrial guidelines known as
      "threshold limit values" (TLVs), including an 8-hour time-weighted average of 500
      ppm for inspired n-hexane. Despite subsequent recognition of the neurotoxicity of
      n-hexane with industrial outbreaks of polyneuropathy beginning in the 1960s, the
      TLV for n-hexane remained unchanged until 1976 when a value of 100 ppm was
      adopted. Because a growing number of clinical reports have identified clinical
      and subclinical neurotoxicity from n-hexane near, at, and below the current time
      weighted average TLV of 50 ppm, even this level is too high to protect all
      workers. In part due to procedural and political constraints, the Occupational
      Safety and Health Administration (OSHA) has independently developed only a small
      number of exposure standards in the past 25 years, and has been incapable of
      providing needed revisions for existing standards. Most OSHA standards--including
      those for n-hexane--were adopted in 1971 from the 1968 ACGIH TLVs and have never
      been revised. From 1971 to 1989 the OSHA permissible exposure level (PEL) for n
      hexane remained at 500 ppm, 5-10 times as great as other contemporary standards.
      To help correct its regulatory backlong, OSHA promulgated 375 new or revised PELs
      in 1989--including a new standard of 50 ppm for n-hexane--but all of these were
      vacated by the 11th U.S. Court of Appeals in 1992. As a result, the current OSHA
      PEL for n-hexane remains at the 500 ppm level adopted in 1971, which even then
      was too high based upon available scientific evidence. New information over this
      long period, including that obtained from industrial outbreaks of disease due to
      chemical exposures, has not been incorporated into revised federal standards.

PMID- 10643171
TI  - Risks associated with tattooing and body piercing.
AB  - The purpose of this article is to highlight the importance of including cosmetic
      body-piercing and tattooing in HIV prevention and education. Little information
      about risks associated with tattoos or having one's body pierced is evident in
      the health promotion and disease prevention literature, particularly among
      adolescents, ethnic groups, and incarcerated populations. It is incumbent that
      preventionists address behaviors such as tattooing and body piercing as possible
      vectors for HIV transmission in addition to typical concerns (homosexuality, i.v.
      drug use, condom use and safer sex practices). This article draws attention to
      the need for formation of regulatory policy issues related to body piercing and
      tattooing parlors. Currently, 26 percent of the states have regulatory authority
      over tattooing establishments, while only 4 states exercise such authority over
      body-piercing establishments. Implications for future research and policy
      initiatives are identified.

PMID- 10643172
TI  - The health care counter-reform in Spain.

PMID- 10643173
TI  - From Bismarck to Beveridge: developments and trends in Social Security
      legislation. 1943.

PMID- 10643174
TI  - The multisystem adverse effects of NSAID therapy.
AB  - The clinical utility of nonsteroidal anti-inflammatory drugs (NSAIDs) to manage
      pain and inflammation is limited by adverse side effects. Although effective
      analgesic and anti-inflammatory agents, NSAIDs are associated with side effects
      that are a consequence of nonspecific inhibition of both cyclooxygenase-1 (COX-1)
      and cyclooxygenase-2 (COX-2). The primary adverse events associated with NSAID
      therapy are upper gastrointestinal (GI) ulceration, perforation, or bleeding, all
      of which involve mucosal damage of varying severity and can be asymptomatic and
      occur with little warning. Clinicians who prescribe NSAIDs should be able to
      identify patients who are at risk of an NSAID-induced GI adverse event and to
      detect and manage the event should one occur. The use of COX-2-specific
      inhibitors to manage pain and inflammation may minimize the risks of NSAID
      associated toxicities.

PMID- 10643175
TI  - COX-1 and COX-2 in health and disease.
AB  - Nearly 30 years ago, cyclooxygenase (COX) was identified as an enzyme that
      initiates the biotransformation of arachidonic acid to prostanoids. It is now
      known that COX exists as two distinct but similar isozymes, COX-1 and COX-2.
      Prostaglandins (PGs) formed by the enzymatic activity of COX-1 are primarily
      involved in the regulation of homeostatic functions throughout the body, whereas
      PGs formed by COX-2 primarily mediate pain and inflammation. Based on structural
      differences in the active sites of COX-1 and COX-2, a new class of drugs has been
      developed that specifically inhibits COX-2 but not COX-1 activity. By preserving
      the synthesis of homeostatic PGs, these specific inhibitors of COX-2 provide the
      clinical benefits of nonsteroidal anti-inflammatory drugs and minimize the
      consequences of nonspecific inhibition of PG synthesis.

PMID- 10643176
TI  - Celecoxib for the treatment of pain and inflammation: the preclinical and
      clinical results.
AB  - Inflammation and pain, the principal signs and symptoms of arthritis along with
      swelling and stiffness, are routinely controlled by treatment with a nonsteroidal
      anti-inflammatory drug (NSAID). Celecoxib, an anti-inflammatory and analgesic
      agent indicated for the treatment of osteoarthritis and rheumatoid arthritis, is
      the first cyclooxygenase (COX) inhibitor with well-defined cyclooxygenase-2 (COX
      2) specificity. Preclinical studies of celecoxib in vitro and in vivo support the
      COX-2 hypothesis that the therapeutic effects of NSAIDs are due to the inhibition
      of COX-2, and the adverse events associated with NSAID therapy are due to the
      inhibition of cyclooxygenase-1 (COX-1), the constitutively expressed isoform of
      COX. Clinical trials in patients with osteoarthritis or rheumatoid arthritis
      found that the efficacy of celecoxib is superior to that of placebo and
      comparable to that of naproxen, a conventional NSAID. Clinical studies also found
      celecoxib to be safe and well tolerated, with no evidence of alteration in
      platelet aggregation or gastrointestinal ulceration.

PMID- 10643177
TI  - COX-2-specific inhibition: implications for clinical practice.
AB  - Although conventional nonsteroidal anti-inflammatory drugs (NSAIDs) have long
      been a major therapeutic choice for the management of arthritic conditions, the
      potential adverse effects of these agents sometimes compromise their clinical
      utility. New modes of therapy have recently been introduced, and data on the
      cyclooxygenase-2 (COX-2)-specific inhibitors celecoxib and rofecoxib suggest that
      these agents will meet the need for safe and effective therapeutic alternatives
      to conventional NSAIDs.

PMID- 10643178
TI  - Community eye health.

PMID- 10643179
TI  - HIV/AIDS and ocular manifestations.
AB  - As of December, 1998, worldwide, 33.4 million people have been infected with
      human immunodeficiency virus (HIV). A wide variety of ocular disorders is
      associated with HIV. HIV can affect all structures of the eye. A large number of
      micro-organisms including virus, bacteria, fungi and protozoa, cause ocular
      diseases in HIV-infected patients. Out of these, cytomegalovirus (CMV) retinitis
      is the most common. Ocular tuberculosis (TB), syphilitic retinal diseases and
      ocular toxoplasmosis are other serious eye problems in HIV patients, especially
      in the developing countries. HIV can also cause microvascular abnormalities
      producing cotton-wool spots. Neoplasms and drug-induced ocular disorders may be
      other problems. Ophthalmologists need to have wide range of information regarding
      HIV/AIDS for better diagnosis and management of their patients with ocular
      abnormalities. Further research, data collection, continuing education and the
      latest information on eye problems of AIDS patients are essential for Indian
      ophthalmologists.

PMID- 10643180
TI  - Overview on community ophthalmology.
AB  - Community ophthalmology requires a comprehensive approach for primary, secondary
      and tertiary prevention of all eye diseases like vitamin A deficiency, trachoma,
      measles, diabetic retinopathy, refractive errors, etc. Community ophthalmology is
      based on the principles of primary health care approach. Equitable distribution,
      community involvement, focus on prevention, appropriate technology and
      multisectorial approach are to name a few in primary health care approach. In
      India, National Programme for Trachoma Control was launched in 1963 and National
      Programme for Control of Blindness was launched in 1976. Prevention of blindness
      was included in 20-point plan in early 1980s. Increase in blindness was
      reassessed in 1986-89 and the strategy was changed. World Bank came to help in
      planning 11 million cataract operations in 7 years in 7 States where there was
      the highest prevalence of cataract. Departments of community ophthalmology have
      recently been developed in several institutions. If the problem of blindness is
      to be solved, extension of community-based approach including all strata of
      society is the need of the hour.

PMID- 10643181
TI  - Squint--what to do and when.
AB  - Squint is unfortunately a neglected subject in our country. It is considered only
      a cosmetic problem without realising that any manifest squint is a one eyed
      blindness which results in lack of binocular vision. Consequently there is no
      stereopsis. The management should be undertaken at the earliest possible age when
      development of uni-ocular as well as binocular vision is taking place. Once the
      visual system is mature, only cosmetic appearance can be improved, but not the
      vision.

PMID- 10643182
TI  - Management of cataract--a revolutionary change that occurred during last two
      decades.
AB  - In the field of ophthalmology, perhaps no other surgery has undergone such rapid
      changes in the past few decades, as the surgery for cataract. Over these years
      there has been an emergence of small incision cataract surgery, especially by
      phaco-emulsification. It offers a number of attractive benefits to both the
      surgeon and the patient. Phaco has now captured the centre stage in the surgical
      management of cataract. With the advent of phaco it became imperative to design
      incision in a valvular manner to provide water tight anterior chamber, to design
      phacoprofile intra-ocular lenses specifically foldable intra-ocular lenses,
      instruments for precision and better control, better visco-elastic material and
      irrigating fluids. These advancements in this field have revolutionised the
      management of cataract surgery and have facilitated achieving new peaks in
      quality of surgery and recovery of visual acuity to precataract stage and
      correction of pre-existing astigmatism.

PMID- 10643183
TI  - Eye donation movement in India.
AB  - Late Dr RES Muthiah started the very first eye bank in India and the first
      corneal transplantation took place successfully by him in India in 1948. From
      then on a movement started for donation of eyes. The prime concept of Eye Bank
      Association of India (EBAI) is to motivate the people for eye donation. A vast
      propaganda throughout the country is going on for eye donation. The community
      should come forward shedding all inhibitions. EBAI has envisaged a master plan of
      action to regulate eye bank activities. Under this plan eye donation movement is
      catching up in the country.

PMID- 10643184
TI  - Vitamin A deficiency disorders.
AB  - The major cause of blindness in children worldwide is xerophthalmia caused by
      vitamin A deficiency. In addition it has other adverse effects, including
      increased mortality and the term vitamin A deficiency disorders (VADD) has been
      introduced to cover the whole clinical spectrum of disease. The ocular
      manifestations of xerophthalmia have been classified and a set of prevalence
      criteria for the detection of a problem of public health magnitude has been in
      use for more than two decades. The global prevalence of VADD is now well
      documented and World Health Organisation (WHO) receives information continuously
      for updating its data base on the subject. The pathogenesis of the disease is
      still imperfectly understood, it is not at all clear precisely why certain
      subjects in vulnerable communities develop xerophthalmia, while the majority are
      spared. A schedule for treatment of the established case has been available for a
      long time, but at both clinic and hospital level concentrated sources of vitamin
      A for treatment are frequently not available. More emphasis needs to be laid on
      prevention and a choice of methods consisting of large dose supplementation,
      fortification of food, control of precipitating infections and dietary
      improvement. The advantages and drawbacks of each are discussed.

PMID- 10643186
TI  - Cardiac surgery--the journey to the third millennium.

PMID- 10643185
TI  - Evaluation of prochlorperazine buccal tablets (Bukatel) and metoclopramide oral
      tablets in the treatment of acute emesis.
AB  - The dizziness associated with vertiginous disorders is often accompanied with
      nausea and/or vomiting. Antiemetic effect of prochlorperazine (PCZ) is diminished
      by its low bioavailability owing to a significant gastric and hepatic first pass
      effect. This effect could be further diminished by likelihood of regurgitation of
      nauseating patients further limiting the therapeutic effect of oral PCZ. A buccal
      preparation achieves higher plasma concentrations through direct systemic
      absorption. In this study buccal prochlorperazine (Bukatel) was compared for its
      efficacy and tolerability with commonly used metoclopramide. Bukatel was well
      tolerated and well rated by both patients and investigators with no adverse
      effects on buccal mucosa and causing less drowsiness and sedation. Results
      indicate that Bukatel is safe and effective for the treatment of nausea and/or
      vomiting in patients suffering from vertiginous disorders and could be safely and
      strongly recommended as an alternative to less bioavailable and indiscriminately
      used oral metoclopramide tablets.

PMID- 10643187
TI  - A comparative study of balloon mitral valvuloplasty and closed mitral
      commissurotomy in patients with rheumatic mitral stenosis.
AB  - Rheumatic mitral stenosis is frequently encountered in our country. It affects
      younger population and is a major cause of morbidity Mitral valvotomy is the
      definitive therapy for this disease and can be achieved by closed mitral
      commissurotomy (CMC), open mitral commissurotomy (OMC) or by percutaneous
      transluminal mitral valvuloplasty (PTMV). Compared to CMC, PTMV is less invasive
      but more expensive at this moment. With the reduction of cost, PTMV may become
      the procedure of choice for the treatment of rheumatic mitral stenosis in future.

PMID- 10643188
TI  - Current concepts in cardiopulmonary resuscitation in adults.
AB  - Cardiopulmonary resuscitation (CPR) provides artificial circulation and
      ventilation during cardiopulmonary arrest. CPR is further categorised as basic
      life support (BLS), advanced cardiac life support (ACLS) and postresuscitation
      support. BLS consists of provision of a patent upper airway, ventilation and
      circulation of blood by closed chest cardiac compressions. ACLS includes use of
      specialised equipment to maintain the airway, early defibrillation and
      pharmacologic therapy. Successful outcome from an arrest depends on the total
      duration of an arrest and early defibrillation, as ventricular fibrillation is
      the most common cardiac rhythm found in adult cardiac arrest. Initial drug
      therapy during CPR aims at correction of arterial hypoxaemia and restoring
      coronary and cerebral perfusion. Oxygen and epinephrine constitute the mainstay
      of drug therapy during CPR. In patients with ventricular tachycardia, lidocaine
      is the drug of choice, followed by bretylium. Magnesium has proved to be useful
      in both refractory pulseless ventricular tachycardia and fibrillation. Atropine
      has not been demonstrated to improve outcome from arrest but can be administered
      in bradyasystolic cardiac arrest. The routine administration of bicarbonate and
      calcium is no longer recommended but situations exist where they can be used
      appropriately. Administration of drugs during CPR should preferably be via a
      central route, but epinephrine, lidocaine and atropine can be administered via
      the endotracheal tube if intravenous access has not been established.
      Postresuscitation care includes mechanical ventilation if necessary to optimise
      oxygenation and ventilation and steps to maintain vital organ and optimal brain
      protection, which includes avoidance of hypertension, hypotension and
      hyperglycaemia.

PMID- 10643189
TI  - Dilemmas in the management of rheumatic heart disease.
AB  - Rheumatic heart disease (RHD) is a major health care problem in India and will
      continue to be so for few more decades. As there is no vaccine against RHD, it is
      difficult to control the disease. Besides RHD, most children have other
      preventable ailments as well. Hence the schools, specially for the poor, must act
      as primary and preventive health care centres. Prevention of RHD starts with
      school prophylaxis. Primary, secondary and tertiary prophylaxis play their roles
      afterwords. After the heart valves have been damaged, tertiary prevention might
      minimise further damage. For mitral stenosis, closed mitral valvotomy (CMV), open
      mitral valvotomy (OMV) and interventional mitral valvotomy (IMV) are the
      different options but none is curative. Valve replacement poses many problems and
      therefore valvotomy is deferred as far as possible. Mild or moderate mitral
      regurgitation (MR) is best treated medically. For more advanced disease repair or
      replacement is the option. For aortic stenosis (AS), valvotomy may be preferred
      to replacement wherever feasible and for aortic regurgitation (AR) repair is not
      yet well established. In combined mitral and aortic valve disease it is important
      to assess both the valves carefully and try to repair one or both the valves and
      to avoid double valve replacement as far as possible. Once the heart valve is
      damaged any treatment is palliative, hence all efforts should be directed towards
      prevention of RHD. Indian Medical Association can play a major role in this
      endeavour and help children in India to grow up free from RHD.

PMID- 10643190
TI  - Angioplasty versus coronary artery by-pass surgery: a reappraisal.
AB  - Revascularisation is the main principle of treatment of obstructive coronary
      artery disease. This technique is available either by catheter intervention like
      angioplasty or by-pass surgery. The superiority of one over the other is still
      undetermined. In symptomatic single vessel disease angioplasty may be a better
      option than by-pass surgery. In two-vessel coronary artery disease angioplasty
      may also be preferred especially with good left ventricular function. In patients
      with double-vessel disease particularly involving proximal left anterior
      descending artery in association with diabetes mellitus surgery has better long
      term results. In multivessel disease by-pass surgery is a preferred option
      although initial results of angioplasty in this group may be very satisfactory.
      The incidence of further intervention either by surgery or repeat angioplasty is
      high in patients undergoing angioplasty in multivessel disease. Left main stem
      disease should be dealt with by-pass surgery. With continued advancement in the
      revascularisation technology of coronary artery disease both in catheter
      intervention and surgical fronts there is no room for unequivocal or universal
      strategy plan in the management of coronary artery disease. Both the techniques
      are complimentary to each other. Cost consideration is a major consideration in
      India. Choice should be made after proper evaluation of coronary anatomy,
      underlying clinical condition, local experience, social and especially economic
      circumstances.

PMID- 10643191
TI  - Aortic arch aneurysms.
AB  - Aneurysms involving the aortic arch are formidable surgical challenges. Though
      the first successful surgery was performed more than 40 years ago, the risk of
      surgical treatment remained prohibitively high until recently. Intra-operative
      protection of the brain from ischaemic injury was the main concern. Deep
      hypothermic circulatory arrest with retrograde cerebral perfusion technique has
      considerably reduced the risk of surgery to acceptable levels.

PMID- 10643193
TI  - Valvular heart disease--repair or replacement?
AB  - An estimated 3 million patients in India need treatment for valvular heart
      disease. Rheumatic heart disease continues to be the major aetiologic factor. The
      mitral valve is best conserved with valvotomy or repair. The aortic valve is
      difficult to repair and is best replaced by a biological substitute (autograft or
      homograft). The tricuspid valve can be repaired in all patients. Prosthetic
      valves offer good long term durability but introduce additional risks to the
      patients. Experience over the past three decades suggests that conservation of
      natural valve mechanism is currently the best option.

PMID- 10643192
TI  - Techniques and follow-up results of coronary artery by-pass grafting with special
      reference to Indian subset of patients.
AB  - Coronary artery by-pass surgery is fast becoming the most commonly performed
      major operation even in our country. Coronary heart disease in Indian patients
      has a lot of peculiarity which distinguishes it from the western population.
      Indian patients are younger in age, more often diabetic and hyperlipidaemic.
      Smoking and obesity are not as common as in the west. The coronary arteries are
      smaller in diameter and are affected diffusely with the atherosclerotic process.
      These factors make the operation technically more difficult. The techniques have
      been perfected to a very high level and are being performed in India with results
      comparable to the western world. The average operative mortality for coronary
      artery by-pass grafting (CABG) is around 2%.

PMID- 10643194
TI  - Pulmonary atresia with intact ventricular septum--a report of two cases with
      review of literature.
AB  - Two perinatal autopsy cases are reported where a rare congenital anomaly, namely
      pulmonary atresia with intact ventricular septum in association with tricuspid
      stenosis and a hypoplastic right ventricle was encountered.

PMID- 10643195
TI  - Buerger's disease.

PMID- 10643196
TI  - A review of absorption characteristics of microemulsion cyclosporine products
      over the last 2 years in Indian subjects.
AB  - Microemulsion based cyclosporine has demonstrated better absorption with laser
      pharmacokinetic variability. For the clinical use of any new microemulsion based
      product, bioequivalence testing with existing formulation is necessary. Panimun
      Bioral (Test) and Sandimmun Neoral (Reference) were evaluated in different
      transplant centers using both volunteers as well as renal transplant patients.
      All these centres have reported that both products are bioequivalent. These
      reports offer the physician an option to convert the patients to the Test product
      for economic reasons.

PMID- 10643197
TI  - ECG of the month. Orderly misconduct. Atrial flutter.

PMID- 10643198
TI  - Tumors of the parapharyngeal space.
AB  - The parapharyngeal space may give rise to a wide variety of neoplasms. The goal
      of this article is to present a simple algorithm for the recognition and
      evaluation of parapharyngeal space lesions by primary care physicians so that
      timely referral can be made to an otolaryngologist for definitive therapy.

PMID- 10643199
TI  - Radiology case of the month. Heel pain in a 60-year-old man.

PMID- 10643200
TI  - The Journal 150 & 100 years ago. December 1849 and 1899.

PMID- 10643201
TI  - School-based health centers in Louisiana: an introduction.
AB  - Up to 20% of students in America's public schools suffer from a chronic health
      condition. Working parents and the behavioral morbidities of the late 20th
      century put children at risk for poor physical health, poor mental health, and
      poor educational outcomes. Access to care is poor for adolescents in general and
      for the uninsured. School-Based Health Centers deliver primary mental and
      physical health care inside schools where the children are. They are run by
      interdisciplinary teams of professionals. They focus their efforts on primary
      care and prevention and collaborate with schools, parents, and the community to
      deliver this care.

PMID- 10643202
TI  - Integrated school health services school-linked/based health clinics.

PMID- 10643203
TI  - School-based screening for sexually-transmitted diseases.
AB  - Chlamydia and gonorrhea are the two most common bacterial sexually transmitted
      diseases (STDs) disproportionately affecting adolescents. Compared to other
      states, in 1997, Louisiana ranked fifth and seventh in reported case rates of
      gonorrhea and chlamydia, respectively. These two diseases can now be diagnosed
      with a urine test using DNA amplification technology, making it possible to
      identify asymptomatically infected persons without having to conduct a physical
      examination. In a school screening program piloted in Louisiana school-based
      health centers, all students in 12 urban public high schools were offered the
      urine test. Most infected students had no symptoms. The infection rate in girls
      was generally at least twice as high as among boys. Over time, the prevalence of
      chlamydia infection decreased. School-based screening is feasible and acceptable
      and can identify a large number of asymptomatic, infected youth. Screening
      programs which target asymptomatic youth should be expanded in order to reduce
      the burden of chlamydia and gonorrhea in our communities.

PMID- 10643204
TI  - School-based adolescent hepatitis B vaccination.
AB  - Adolescents and young adults are at particular risk for hepatitis B infection.
      The Advisory Committee on Immunization Practices recommends vaccinating all
      children and adolescents. There are obstacles to vaccinating adolescents in
      clinical practice. School-based vaccination programs, either through school-based
      clinics or temporary vaccine clinics, can overcome these obstacles. To facilitate
      these programs, the Advisory Committee on Immunization Practices allows a 0, 2, 4
      month vaccination schedule which has been shown to be similarly seroprotective as
      the standard 0, 1, 6 month schedule.

PMID- 10643205
TI  - Risky behaviors among Louisiana youth.
AB  - The main threats to adolescents' health are the risky behaviors they engage in
      and the choices they make. There are six health-risk behaviors that adolescents
      engage in that account for the majority of morbidity and mortality in this age
      group: alcohol and drug use; tobacco use; risky sexual behaviors; behaviors
      leading to intentional and unintentional injury; physical inactivity; and
      unhealthy dietary behaviors. These behaviors also greatly impact academic
      achievement. Using morbidity and mortality data obtained from the Office of
      Public Health and survey data, risk behaviors among adolescents in Louisiana are
      considered. School-based health centers are one successful strategy for
      comprehensively addressing these behaviors.

PMID- 10643206
TI  - Prevention of common mental health problems among adolescents. National and local
      best practices in school-based health centers.
AB  - A primary goal of school-based health centers is to reduce the occurrence of high
      risk behaviors and mental health problems commonly exhibited by adolescents. This
      paper provides a review of national best practice prevention strategies for
      common adolescent problems including school dropout, violence, and other high
      risk behaviors. Specific prevention programs, currently in use in Louisiana
      school-based health centers, are described and linked to national best practice.

PMID- 10643208
TI  - New diet pill approved.

PMID- 10643207
TI  - Access to health care: Louisiana minor consent statutes.
AB  - The Louisiana minor's consent statutes enable minors to consent for medical
      treatment, emergency treatment, treatment of sexually-transmitted diseases, and
      treatment of substance abuse. The legislative intent for permitting minors to
      consent to treatment without the express consent of a parent or guardian was to
      provide minors access to high-quality health care services in order to encourage
      the betterment of the health and welfare of the citizens of our state. A minor
      cannot consent for an abortion or sterilization. The statutes do not allow a
      minor to refuse treatment consented to by his parent or guardian. However, needed
      medical treatment can be provided to a consenting minor over the objections of a
      parent or guardian. Where a minor can consent, confidentiality from parent's or
      guardian's knowledge is permitted but not assured; confidentiality is granted at
      the discretion of the physician or medical staff.

PMID- 10643209
TI  - Limitations in the use of race in the study of disease causation.
AB  - Tremendous variation exists in the rates of many chronic diseases across racial
      groups. However, serious technical and conceptual limitations hamper the ability
      of racial comparisons to illuminate the causative pathways. First, race is
      confounded by social class, which is complex, and like other confounders of race,
      may not be measured with equal validity across racial groups. Second, statistical
      "adjustments" for race effects can be misleading since residual confounding may
      be misconstrued as a genetic effect. Third, the biologic concept of race tempts
      us to ignore the context dependency of genetic expression. When trying to detect
      genetic effects, both the environmental and genetic contributions must be
      measured and potential gene-environment interactions accounted for.
      Unfortunately, this process is beyond our current technical capabilities. To move
      forward on the problem of prostate cancer and other diseases distinguished by
      marked ethnic differentials, investigators need a more comprehensive
      understanding of the factors that mediate the apparent effect of race combined
      with valid measures of those factors, as well as novel strategies that can help
      overcome the technical and interpretive limitations of statistical adjustment.
      Finally, the "grand" theories of race-based genetic susceptibility must be
      replaced with rigorous criteria to determine when a trait can be ascribed to some
      genetic origin.

PMID- 10643210
TI  - Gender differences in the aerobic fitness levels of young African-American
      adults.
AB  - This study examines gender differences in the aerobic fitness levels of young
      African-American adults. Two hundred twelve African-American college freshmen (79
      men, 133 women) completed the Houston Non-Exercise Test-Body Mass Index Model
      (HNET-BMI) questionnaire, a questionnaire designed to estimate maximum oxygen
      consumption (VO2max, mL kg-1 min-1) in adults. Using a three-point scoring system
      (below average, average, and above average), 100% of the men and 80% of the women
      were classified as having average or above average levels of VO2max. Statistical
      analysis revealed that more women than men had average or below average levels of
      aerobic fitness (chi 2 = 54.5; P = .0001). The results of this study suggest that
      a larger percentage of African-American women have lower levels of aerobic
      fitness compared with African-American men.

PMID- 10643211
TI  - New directions in type 2 diabetes mellitus: an update of current oral
      antidiabetic therapy.
AB  - This article reviewed the relevant literature including published clinical trials
      and reviews on currently available oral hypoglycemic agents. Results showed that
      the benefits of glycemic control have been established through multiple clinical
      trials. Long-term control of blood glucose levels in type 1 and type 2 diabetic
      patients will decrease the incidence and prolong the time until progression of
      diabetic retinopathy, nephropathy, and neuropathy. Our increased understanding of
      the pathophysiology behind type 2 diabetes has led to the development of many new
      agents that are aimed at treating the underlying insulin resistance and relative
      insulinopenia. The sulfonylureas as a group have been used for many years and act
      by stimulating insulin secretion. They are useful alone or as combination therapy
      with insulin or another oral hypoglycemic agent. The biguanides act by decreasing
      hepatic glucose production and by increasing peripheral insulin sensitivity. The
      alpha-glucosidase inhibitors act nonsystemically by blocking the metabolism of
      digested polysaccharides and therefore lowering the amount of carbohydrate
      absorbed in a meal. Benzoic acid derivatives act in a manner similar to that of
      sulfonylureas by enhancing pancreatic insulin production. They offer a shorter
      duration of action, lowering the risk of hypoglycemia. The thiazolidinediones
      increase peripheral insulin sensitivity and are effective as both monotherapy and
      combination therapy. Oral hypoglycemic agents, when properly administered, are
      very effective in controlling type 2 diabetes and preventing long-term
      complications.

PMID- 10643213
TI  - A systematic arrangement of laparoscopic total abdominal hysterectomy: a new
      technique.
AB  - This sequential, prospective, observational clinical trial evaluated a systematic
      arrangement of laparoscopic total abdominal hysterectomy and prophylactic,
      retroperitoneal posterior culdoplasty with vaginal vault suspension surgical
      techniques by suturing method. The uterus was extirpated laparoscopically in 25
      consecutive patients using an extra- and intra-corporeal two-turn flat square
      knot method. Upon completion of uterine excision, a new prophylactic laparoscopic
      technique of retroperitoneal posterior culdoplasty and vaginal vault suspension
      were initiated to prevent pelvic relaxation. Retroperitoneal culdoplasty was
      performed using the anterior rectal fascia, the posterior uterovaginal fascia,
      and the deep layer retroperitoneal of the uterosacral ligaments. Vaginal vault
      suspension was performed using posteriorly the deep layer of the uterosacral
      ligaments; from a lateroposterior aspect, the vaginal vault was suspended to the
      cardinal ligaments bilaterally, and anteriorly, the vesicouterine fascia provided
      support for the vaginal apex. A systematic arrangement of surgical steps was
      evaluated. All predetermined samples of laparoscopic total abdominal hysterectomy
      with posterior retroperitoneal culdoplasty and vaginal vault suspension were
      accomplished in a prearranged systematic order. Neither technical failure nor
      conversion to laparotomy or transvaginal approach was encountered. This technique
      expedites uterine extirpation and prophylactic pelvic reconstruction with a low
      complication rate, can be executed with no transvaginal approach, and eliminates
      the morbidity and mortality associated with laparotomy itself.

PMID- 10643212
TI  - Asthma care in community health centers: a study by the southeast regional
      clinicians' network.
AB  - Federally funded community health centers (CHCs) were surveyed to assess their
      ability to serve low-income asthma patients in the southeastern United States.
      Data were collected on CHC clinicians, pharmacy services, and patient
      characteristics. Twenty-six (74%) of 35 participating CHCs provided data on 83
      distinct clinic sites in eight states, representing 898,977 billable patient
      visits to 318,920 people during the one-year study period. Participating CHCs
      provided 23% of all CHC patient visits in Region IV in 1995. Sixty-two percent of
      patients had a family income below poverty level. Almost 75% of the patients were
      uninsured or receiving Medicaid. Asthma was the diagnosis code for 2.04% of all
      medical encounters. Twenty-nine percent of sites were unable to provide
      medications for uninsured asthma patients, while 66% could provide drug samples.
      Thirty-three percent of CHCs had in-house pharmacies and 33% offered pharmacy
      vouchers. Eighty-two percent could provide beta-agonist inhalers, 54% could
      provide steroid inhalers, and 17% could provide peak flow meters. Federally
      funded CHCs provide care to many asthma patients from the highest risk segments
      of the population, but often do not have the resources needed to follow current
      clinical guidelines.

PMID- 10643214
TI  - Improvement in severe insulin resistance with frequent injections of lispro
      insulin.
AB  - Extreme insulin resistance is common in obese African Americans with type 2
      diabetes. This case report describes an obese African-American woman who was
      treated with subcutaneous injections of lispro insulin every 2 hours with
      resultant decrease of mean daily blood glucose from 264.7 mg/dL to 111 mg/dL and
      in insulin requirement from 479 U/24 hours to 60 U/24 hours. This case
      demonstrates that extreme insulin resistance is reversible in the short term.

PMID- 10643215
TI  - William E. Allen, Jr, MD, FACR: pioneering physician and leader.

PMID- 10643216
TI  - [Lactic acidosis feared adverse effect of metformin treatment. New guidelines can
      increase vigilance].

PMID- 10643217
TI  - [Lobotomy versus Nazi experiments. Less rigidity is required in the debate on
      medical ethics].

PMID- 10643218
TI  - [Expert statement about oat in the treatment of celiac disease in Sweden].

PMID- 10643219
TI  - [Hypotensive resuscitation in trauma patients--a real alternative?].

PMID- 10643220
TI  - [The patient as a querulous person?].

PMID- 10643221
TI  - [Nitrous oxide and cobalamin deficiency].

PMID- 10643222
TI  - [Don't let the emergency patients wait!].

PMID- 10643223
TI  - [Vitamin B12, chronic fatigue and injection treatment].

PMID- 10643224
TI  - [Incorrect information about tobacco. How should the HSAN judge?].

PMID- 10643225
TI  - [Ritual poisoning with a hallucinogenic plant. Guidelines in severe poisoning
      with anticholinergics].

PMID- 10643226
TI  - [Combination treatment with insulin and metformin in type 2 diabetes. Improves
      glycemic control and prevents weight gain].
AB  - Type II diabetes patients on insulin often show inadequate glycaemic control and
      weight gain. The rationale for adding metformin in these cases is that it can
      reduce insulin resistance. The present article reviews the growing body of
      clinical documentation supporting combination therapy, i.e. placebo-controlled
      studies in insulin-treated patients and controlled studies with reference
      therapies in patients not yet treated with insulin. These studies show
      improvement of glycaemic control and less weight gain. Insulin dosages can be
      reduced in both type II and type I diabetes. A combination of insulin and
      metformin is recommended especially for obese type II diabetes patients on high
      insulin doses.

PMID- 10643227
TI  - [Hemodialysis cured severe lactic acidosis caused by metformin treatment].

PMID- 10643229
TI  - [Evolutionary biological discoveries can increase the understanding of
      cardiovascular diseases. It can contribute to more realistic preventive
      strategies].
AB  - Recent findings in evolutionary biology offer new insights into the historical
      emergence of widespread medical disorders such as cardiovascular disease and type
      2 diabetes. This has been named evolutionary medicine. When individuals with a
      genetic program for retention of sodium and calories (insulin resistance)
      encounter the stress and unwholesome lifestyle of modern society, cardiovascular
      disease may soon develop, potential consequences being myocardial infarction or
      stroke. Focusing on historical changes in climate, social circumstances and food
      availability in the Nordic countries, factors which very much defined living
      conditions for our ancestors, we discuss cardiovascular disease from the point of
      view of evolutionary medicine. A better understanding of this perspective will
      hopefully increase the likelihood of success in preventive efforts such as
      lifestyle intervention.

PMID- 10643228
TI  - [Arsenic efficient in acute promyelocytic leukemia].
AB  - Arsenic compounds have been utilised in medicine for over 2,000 years. Recently,
      arsenic trioxide has been shown to induce complete remission in up to 90% of
      patients with acute promyelocytic leukemia (APL), including those resistant to
      standard therapy. Randomised studies are currently investigating the potential
      clinical utility of this drug in APL. In vitro, arsenic trioxide exhibits
      antitumoral properties with respect to various other tumor species as well,
      although assessment of clinical effects will require further study. This article
      reviews clinical results and possible mechanisms of action of the drug.

PMID- 10643230
TI  - [Who seeks care and where, after a new episode of neck or low back pain? A study
      in Norrtalje shows that about half of the patients turn to alternative medicine].

PMID- 10643231
TI  - [Vademecum of a biomedical researcher: from the foundation of science to the
      threat from post-modern "nonsense"].

PMID- 10643232
TI  - [Triple X syndrome deviation with mild symptoms. The majority goes undiagnosed].

PMID- 10643233
TI  - [X-chromosome inactivation--a biological phenomenon of clinical significance for
      women].

PMID- 10643234
TI  - [How to discover unexpected adverse effects? Heart valve lesions caused by
      appetite suppressants reported in the USA, but not in Europe].

PMID- 10643235
TI  - [Increased risk of suicide among young people on New Year's Day].

PMID- 10643236
TI  - [Radiology before the year 2000. Significance of pictures for diagnosis and
      therapy will increase].

PMID- 10643237
TI  - [Active listing. Worsening of utilization of resources and a threat to medical
      ethics].

PMID- 10643238
TI  - [Secure with nuclear weapons].

PMID- 10643239
TI  - [Listen more to patients and their relatives].

PMID- 10643240
TI  - [Care programs for patients with whiplash injuries in Uppsala].

PMID- 10643241
TI  - [Unemployed physicians with foreign background need help from the labor union].

PMID- 10643242
TI  - [Rett syndrome--an odd handicap affecting girls. A current 25-year follow-up in
      Western Sweden].
AB  - Rett syndrome, a complicated neurodevelopmental disorder exclusively affecting
      girls in early childhood, is now known to be one of the major worldwide causes of
      severe mental retardation in females. Although internationally unknown until the
      mid-1980s, under another designation it had been observed in Sweden since the
      early 1960s. The article consists in a review of current clinical,
      neurobiological and genetic knowledge of the syndrome, and a systematic
      penetration of data collected from the follow-up of a west Swedish series of 54
      female patients, 5-57 years of age. Mortality in the series was 17 percent, with
      a median age at death of 24 years. In most cases death was sudden and unexpected.

PMID- 10643243
TI  - [Place of residence determines access to interferon-beta therapy in MS. Less than
      15 per cent of patients are treated--big differences between the counties].
AB  - Interferon-beta (IFNB) is the first agent to be registered in Sweden for
      modifying disease course in multiple sclerosis (MS). A nationwide survey
      uncovered a tenfold variation between counties in the prescribing of IFNB. About
      10% of patients received treatment in a few counties, while in most the figure
      was even smaller. No correlation was found between sales of IFNB and numbers of
      neurologists in the respective counties. Patients should receive treatment
      according to national medical guidelines, regardless of place of residence.

PMID- 10643244
TI  - [Stress can induce neuroendocrine disorders and pain].
AB  - In this article, a number of hormones and neuropeptides regulating pain, well
      being and stress are shown to play important roles in the association between
      stress perception and nociception. Derangements in the stress axis may be induced
      by a variety of factors in which life events, personality, psychosocial
      circumstances and gender all may contribute. When such derangements are long
      lasting, probably several neuroendocrine modifications are induced, giving rise
      to many of the symptoms seen in chronic pain syndromes including fibromyalgia.

PMID- 10643245
TI  - [Very rapid development of functional image diagnostics].

PMID- 10643246
TI  - [Mental disorders and crime--a controversial connection illuminated by
      experiences from New Zealand and Australia].

PMID- 10643247
TI  - [Apropos homocysteine measurement in primary health care: validation of new
      methods is important].
AB  - The measurement of plasma homocysteine concentrations may be important both in
      health care and preventive medicine, provided that it is applied correctly, and
      that blood sampling, transport, and assays are state-of-the art procedures.

PMID- 10643248
TI  - [Big differences in leadership and management training within health care
      services. Leadership and issues concerning cooperation should be more emphasized
      in basic medical education].
AB  - A recent survey of medical management programmes at universities across the
      country showed manifest national differences to exist, both quantitative and
      qualitative. Using a questionnaire, the Swedish Society of Medical Management
      examined the programmes for physiotherapists, occupational therapists, social
      workers, nurses and physicians, with respect to such issues as leadership, self
      awareness and communication, health economics, and administration. It was
      concluded that knowledge acquired differs between fields; that physiotherapy
      programmes tend to have a very didactic approach; that nurses are taught the
      importance of participation in developmental processes; that doctors are exposed
      to somewhat the same approach but to a large extent on a voluntary basis; and
      that social workers obtain good insight into the administrative skills necessary
      to their work. In the article it is concluded that students would benefit from
      orientation in the diverse approaches used in the other fields than their own,
      and that pooling of resources among different programmes might be a more economic
      alternative to current practice.

PMID- 10643250
TI  - [Tape as a help in sleep apnea].

PMID- 10643249
TI  - [Suicide of a young woman and the need for guidance].

PMID- 10643251
TI  - [Penicillin and the structure of DNA--the most important discoveries of the 20th
      century].

PMID- 10643252
TI  - [School health services should participate in public health activities].

PMID- 10643253
TI  - [Forensic psychiatry and the Bible].

PMID- 10643255
TI  - [It is not that all the sick cannot work!].

PMID- 10643254
TI  - [The standardized uniformity and the creative difference].

PMID- 10643256
TI  - [Asymptomatic extreme hypocalcemia in a 29-year old woman with CATCH 22].

PMID- 10643258
TI  - [Complement to the article about leadership and cooperation].

PMID- 10643257
TI  - [No nuclear weapons in the future. That does not work!].

PMID- 10643259
TI  - [Many epoch-making discoveries--but also big misjudgements].

PMID- 10643260
TI  - [Approaching the 3rd century of psychiatry: four rooms in the heart?].

PMID- 10643261
TI  - [The cardiovascular field: the heart catheter and antihypertensive agents
      constitute the greatest progress].

PMID- 10643262
TI  - [Oral fluid therapy in children with diarrhea the biggest life-saver seen from a
      global point of view].

PMID- 10643263
TI  - [New milestones in the history of genetics. Successful gene therapy can soon be a
      reality].

PMID- 10643264
TI  - [Cloning was "biologically impossible"].

PMID- 10643265
TI  - [Does the vision about the democratic treatment of the patient remain?].

PMID- 10643266
TI  - [Transplantations--the greatest surgical achievement of the 20th century].

PMID- 10643267
TI  - [Physician's role].

PMID- 10643268
TI  - [In Process Citation]

PMID- 10643269
TI  - [A Nordic voice is silent after a stormy life].

PMID- 10643270
TI  - [Febris upsaliensis at the end of th 18th century. A mysterious epidemic nearly
      stopped the scientific career of Linne].

PMID- 10643271
TI  - ["Sit still you devils, you don't understand!" About Carl Fredrik Hill, his art
      and his illness].

PMID- 10643272
TI  - [The monosaccharide composition of the glycocalyx in Mollicutes and
      phylogenetically related bacteria in the genus Bacillus].
AB  - A number of monosaccharides composing the glycocalix carbohydrates of some
      Mollicutes (Mycoplasma pneumoniae FH, M. hominis PG21, M. fermentans PG18,
      Acholeplasma laidlawii PG8, A. laidlawii var. granulum st. 118) and
      phylogenetically related bacteria from the genus Bacillus (Bacillus cereus 89, B.
      cereus DM423, B. subtilis 1/2, B. licheniformis 31, B. licheniformis 49) were
      detected using plant lectins of definite carbohydrate specificity labelled by
      colloid gold. The structure of extracellular glycopolymers of microorganisms was
      discussed concerning their role in the adhesion process and their specializations
      in colonization of the appropriate organs and tissues of macroorganisms as well
      as the action of probiotics on the basis of bacteria from the genus Bacillus. It
      was marked, that the mollicute cells typically interacted with all vegetable
      lectins tested while bacilli studied bind certain lectins only. The surface
      carbohydrates prevailing in monosaccharides from tested one for superficial
      structures of Bacillus pathogenic strains were: sialic acid, beta-D-galactose and
      alpha-N-acetyl-D-galactosamine, while L-fucose and alpha-D-glucose were observed
      in insignificant quantity or were absent. The nonpathogenic Bacillus strains
      being a basis of biopreparations were distinguished by the insignificant amount
      of sialic acid and other monosaccharides in the composition of carbohydrates of
      their glycocalix. Thus, as a result of research it was confirmed, that the
      superficial glycopolymers of Mollicutes and some related bacilli were alike as to
      presence of some monosaccharides that depended on taxonomic position of
      microorganisms and their biological activity.

PMID- 10643273
TI  - [The effect of the cultivation conditions on the properties of bacilli comprising
      the basis of probiotics].
AB  - Such biological factors as bile, gastric juice, blood serum, amino acids and pH
      of the medium have been studied for their effect on the growth intensity and
      antagonistic activity of bacilli being the basis of biosporin and subalin. It has
      been established that pH of the medium within 7.0-9.0 as well as certain
      concentrations of the gastric juice, bile, blood serum and most of amino acids
      did not affect the growth of Bacillus subtilis 3 and Bacillus subtilis 2335/105.
      A regular decrease of growth intensity in bacilli under the increase of the
      gastric juice concentration or decrease of pH of the medium to 5.0-2.0 is
      registered. The mentioned biological factors affect differently the antagonistic
      properties of the studied cultures.

PMID- 10643274
TI  - [The use of gamma-interferon for the prevention and treatment of infectious
      diseases in piglets and calves].
AB  - Administration of the homologous natural gamma-interferon for prophylaxis of
      infectious diseases showed that 2-3 injections of gamma-interferon prevented
      infectious morbidity of more than 90% of sucking pigs and new-born calves,
      sharply increased their preservation to 90% and above, increased their
      productivity by 1/3. In conditions of industrial growing of young animals therapy
      by this preparation of pigs and calves with colibacteriosis and parainfluenza in
      comparison with control significantly decreased mortality of morbid young
      animals, accelerated their recovery and promoted the weight gain in pigs and
      calves.

PMID- 10643275
TI  - [The effect of the prolonged action of cytostatics and hormones on the properties
      of Escherichia coli].
AB  - Cytostatics and hormones were studied for their effect on biological
      peculiarities of Escherichia coli--the main agent of inflammatory processes of
      kidneys and urinary tracts in children and adults. It was established that low
      doses of glucocorticoids, cytostatics and their combinations lead to changes in
      morphological properties in the strain of E. coli: M- and R-forms appeared in
      some variants. Besides, changes in a number of the biochemical peculiarities of M
      and R-forms were found. These peculiarities are taken into account during
      identification of these microorganisms. The decrease of adhesion activity in
      almost all variants of E. coli 2417 was registered under long-term cultivation
      with cytostatics and prednisolone; hemolytic activity and ability to hydrolyze
      DNA were also established in certain variants.

PMID- 10643276
TI  - [The colonization resistance of the mucous membrane of the large intestine in
      patients with rheumatoid arthritis in a period of exacerbation].
AB  - Specific and quantitative compositions of the colon mucous microflora in 36
      patients with rheumatic arthritis (RA) in the remission period were studied. The
      mucous membrane of healthy people is colonized by bifidobacteria, lactobacilli,
      Bacteroides, Escherichia and enterococci. The mucous membrane in such people is
      mainly colonized by aerobic opportunistic conventionally pathogenic
      enterobacteria (enteropathogenic Escherichia, Citrobacter [correction of
      cytobacter], Enterobacter, Klebsiella, etc.), staphylococci, enterococci and
      anaerobic bacteria (Bacteroides, peptococci, peptostreptococci, etc.). Taking
      into account significant changes of colonization resistance in the colon mucous
      membrane in remission period of RA, it is necessary to apply bacteriotherapy,
      using bacterial drugs containing bifidobacteria and lactobacteria.

PMID- 10643277
TI  - [The effect of the nutritional sources on the synthesis of exopolysaccharides and
      amino acids by Bacillus subtilis strains].
AB  - Dynamics of cell biomass accumulation and secretion to the medium extracellular
      polysaccharides and amino acids has been studied in Bacillus subtilis cultures No
      No 39 and 51 used to produce healing biopreparations--probiotics. The
      investigation data indicate to certain relation between these processes. EPS
      secretion in the studied cultures proceeded parallel with their growth and
      started in the logarithmic phase. Maximum EPS yield was observed by the beginning
      of the stationary phase after 10-12 h of growth. A successible change in the
      amino acid content in the medium was observed in the growth process of the
      studied bacteria: the bacteria first consumed amino acids of the initial medium
      and then excreted amino acids synthesized into the medium. Under the active
      production of EPS the content of extracellular amino acids in the medium was
      inconsiderable. The content of EPS was lower during accumulations of high
      concentrations of extracellular amino acids. Role of the medium components in
      regulation of the studied processes has been shown. The ratio C:N in the medium
      was of essential significance. The C:N ratio 2.0-3.0:1.0 was optimal both for the
      growth and secretion of EPS by the studied cultures while that of 1.0-1.5:1.0 was
      optimal for production of the extracellular amino acids. The increase of C:N
      ratio resulted in the decrease of metabolites secretion by the cultures.

PMID- 10643278
TI  - [The interrelation of microbial ecosystems and human immunity].
AB  - An analytical survey of literature on the problem of the study of interrelations
      between the immune status of the organism and microbial ecology of a man is
      presented. The criteria which characterize normal flora of human organism varying
      in the process of evolutionary adaptation, interaction with microorganism and
      response of the immune system, its participation in formation of protective
      functions of the organism are considered. It is shown that the proceeding
      character and the finite result of different infectious processes depend on the
      state of the organism immune system. A possibility of correction of certain
      immunological indices with the help of representatives of normal microflora has
      been considered. A conclusion has been made on the necessity to solve the problem
      of infectious diseases and complications in a complex of microbiological and
      immunological investigations.

PMID- 10643279
TI  - Future of American medicine. Part III. Is there a light at the end of the tunnel?
AB  - American medicine and health care delivery is undergoing dramatic changes. Part
      of the problem is lack of direction, communication, and the inability of the
      physicians to work together. Physicians in the future will need to join forces.
      The past, present, probable and possible future of American medicine is
      discussed.

PMID- 10643280
TI  - Decompressive craniotomy in medically uncontrollable malignant infarction.
AB  - Patients with progressive neurological deficit following large cerebral
      infarctions are viewed to have a uniformly poor prognosis. We present two
      patients with large middle cerebral artery infarctions in which a decompressive
      craniotomy was life saving and resulted in functional outcome. The clinical
      course of patients with malignant infarction and the treatment issues involved
      including patient selection and the timing and extent of cranial decompression
      are discussed.

PMID- 10643281
TI  - [Infections of the oral mucosa II. Bacterial, mycotic and viral infections].
AB  - Non-specific infections of the oral mucosa are rare; however, they may present
      during HIV infection in the form of gingivo-periodontal lesions. In some of these
      Candida albicans may play a role in the pathogenesis. Sexually transmitted
      bacterial infections such as gonorrhoea and syphilis are frequently associated
      with HIV infection. Since penicillin resistance is frequent in gonorrhoea, the
      cephalosporines are mainly used for treatment. Syphilis increases the risk for
      transmission of HIV. Lues maligna with oral manifestations has been described.
      For this, penicillin G is the therapy of choice. Tuberculosis, characterized by
      multitherapy resistance, is associated with HIV infections world-wide; oral
      manifestations are rare. Oral candidiasis during HIV infection is often
      characterized by therapy resistance against fluconazole and a shift in species,
      with Candida glabrata and Candida krusei as the emerging species. The azoles are
      still the mainstay of therapy, particularly fluconazole. Herpes simplex (HSV)
      infections run an atypical course during HIV disease; resistance against
      acyclovir is a clinical problem. The association of HSV infection with erythema
      exudativum multiforme has been clearly shown. Oral hairy leukoplakia caused by
      Epstein Barr virus is a characteristic infection during immunosuppression.
      Cytomegalovirus infection is also observed in immunodeficient patients. Cases of
      ganciclovir resistance have been described. Human herpes virus 8 (HHV 8) is
      associated with Kaposi's sarcoma. Therapeutic trials have focussed on the
      inhibition of HHV 8 replication. Over 100 different genotypes of human
      papillomaviruses are known; some can cause infections of the oral mucosa.
      Characteristic lesions caused by different HPV genotypes are verruca vulgaris,
      condyloma acuminatum and focal epithelial hyperplasia.

PMID- 10643282
TI  - [Changes in the alveolar ridge level in implantation using the osteotomy technic.
      Retrospective studies].
AB  - Due to a configuration defect, the use of membrane-guided bone regeneration or
      alveolar ridge extension is required. The bone splitting and bone spreading
      technique was modified by developing the osteotome technique and the osteotome
      kit (Summers 1994). Lateral and apical bone displacement and condensation are the
      principles of this nonablative implant bed preparation technique. Estimation of
      the periimplant bone level is one of the important prognostic parameters for
      estimating implant survival. The level of the alveolar crest near implants which
      were inserted using the osteotome technique was investigated by measuring the
      differences between the alveolar crest and the implant shoulder in postoperative
      radiographs after implant insertion and after uncovering the implants in 17
      patients. The osteotome technique was used in bone quality D2 and D3 according to
      the classification by Misch (1993). Significant differences were found between
      the bone levels after implant insertion and implant uncovering. A significant
      correlation (r = 0.5466; P = 0.023) was calculated between the differences of the
      marginal bone level at implantation and uncovering time and the bone quality.
      There should be strict indications for using the osteotome technique for
      evaluating the bone quality found at the implant site to optimize the long-term
      prognosis of the implants.

PMID- 10643283
TI  - [Significance of hemodynamic parameters of blood loss in orthognathic surgery].
AB  - INTRODUCTION: The hemodynamic parameters of 95 patients undergoing maxillary or
      bimaxillary orthognathic surgery in 1996 and 1997 at the Department of OMF
      Surgery/Plastic Surgery, Krefeld, Germany, were analyzed retrospectivly to study
      the effect of intraoperative blood loss. MATERIALS AND METHODS: The parameters
      included the blood loss volume, age, weight and sex of the patients, the mode of
      osteotomy and the operation time, the surgeon, the average blood pressure, the
      infusion volume, the anesthesiologist, the thrombocyte counts and their function,
      the activity of the coagulation factors II, V, VII, VIII, IX, X, XI, XII, XIII
      and von-Willebrand-factor, and the pathological coagulation factor counts of each
      patient, the rate of autologous blood donation and the rate of retransfusion.
      Statistical analysis was done using the Speraman-Rhotest. RESULTS: The average
      blood loss during maxillary osteotomy was 670 +/- 380 ml and during bimaxillary
      surgery 1120 +/- 510 ml. Men lost about 300 ml more than women. Operations of
      more than 3.5 h in length led to a blood loss of 1200 +/- 520 ml as opposed to
      670 +/- 310 ml. The average blood loss among various surgeons was between 670 ml
      and 1180 ml of various anesthesiologists between 730 ml and 1200 ml, without
      statistical evidence. Some 17.9% of patients showed pathological thrombocytic
      function concerning medication with aspirin; 34.7% had pathological activities of
      coagulation factors, but only 2.1% with clinical significance. CONCLUSION: Mode
      of operation, maxillary or bimaxillary, und length of operation were the most
      significant factors of intraoperative blood loss. Patients with pathological
      coagulation had nearly the same rate of blood loss as patients with physiological
      coagulation. In most cases this was determined by restriction of aspirin.
      Analysis of the rate of autologous blood retransfusion showed a significant
      correlation to blood loss in bimaxillary surgery. Maxillary osteotomy led to a
      retransfusion of only 14.2% of autologous blood unit. This should be reviewed
      critically especially concerning costs.

PMID- 10643284
TI  - [Video-endoscopy of the major salivary glands].
AB  - Videoendoscopy is a minimally invasive procedure for the diagnosis and therapy of
      sialopathies of the major salivary glands. The main indication is sialolithiasis
      of the submandibular and parotid glands. Sialoendoscopy offers, on the one hand,
      a diagnostic method for radiolucent calculi in particular and, on the other, can
      be used to simultaneously remove calculi. Furthermore, endoscopy is of high value
      for the diagnosis and treatment of other salivary gland diseases in which there
      are pathological changes of the ductal system. For example, regeneration of the
      gland is now possible in cases of chronic sialadenitis, due to the removal of a
      sialostenosis. Sialadenectomy can thereby be avoided.

PMID- 10643285
TI  - [Animal experiments on the frontal sinus development after craniofacial surgery
      on the frontal bone in Gottingen miniature pigs].
AB  - According to the literature, the development of the frontal sinus is a result of
      the active immigration of cells from the ethmoidal complex into the os frontale.
      This migration theory is in contrast to the results in patients with Apert's
      syndrome. When front-orbital advancement at the age of a few months is performed
      in these patients--at a time when the frontal suture is not yet closed--a sinus
      developed despite the distance between nasal root and os frontale, being up to 2
      cm. In order to investigate the development of the frontal sinus, an animal study
      in 12 juvenile Goettingen minipigs (age 5-6 weeks) with histologically pronen un
      developed frontal sinus was performed. To exclude the emigration of ethmoidal
      complex cells into the frontale bone an orthotopical transposition of the
      frontale bone into the os occipitale was performed. Histologically the
      development of a frontal sinus in the frontal bone was excluded before
      transplantation. The macro- and microscopic comparison with a control group
      revealed that in the orthotopical transplants in the os occipitale an epithelium
      lined sinus developed beginning from the 35th week. Based on our
      histomorphological results, a development scheme for the genesis of the sinus
      frontalis and a model is drawn.

PMID- 10643286
TI  - [Primary solitary malignant schwannoma of the trigeminal nerve, Report of a case
      and review of the literature].
AB  - We present the case of a primary solitary malignant schwannoma of the trigeminal
      nerve. A total of 55 cases have been described in the literature; however, in
      these cases two tumors were affecting the supraorbital branch. This nerve-sheath
      tumor usually affects men in the fifth decade of life. The main clinical sign of
      malignant schwannomas of the head and neck is an indolent swelling. Hematogenic
      or lymphogenic metastasis has not been described. Because of the pleomorphism of
      the tumor cells immunohistochemical study is important. The treatment of choice
      is radical resection, possibly with adjuvant radio- or chemotherapy. The 5-year
      survival rate of malignant schwannoma of the trigeminal nerve is 41.7%.

PMID- 10643287
TI  - [Mandibular fracture. An unusual implantation complication].
AB  - Complications in connection with implantological measures will occur with greater
      frequency in the future, purely from the point of view of quantity, owing to the
      increasing number of implantations. One of the most serious, yet extremely rare
      consequences of implantation is fracture of the mandible. It occurs predominantly
      in older patients with extremely atrophic mandibles, especially if the dental
      implants are anchored bicortically, or after explantation of dental implants. The
      risk of a fracture is increased in addition by weakening of the mandible as a
      result of osteomyelitis, especially in patients with weak immune systems. In
      order to avoid fractures of the mandible, therefore, endosseous implants should
      not be placed into extremely atrophic mandibles, unless the opposing corticalis
      is protected or only after alveolar augmentation. Furthermore, close scrutiny is
      advisable during clinical and radiological post-check-ups, so that any
      periimplantitis or bone infections, which additionally increase the risk of
      mandibular fracture, can be detected in good time.

PMID- 10643289
TI  - [Ocular circulation].

PMID- 10643288
TI  - [Bilateral rehabilitation with an implant-anchored orbital prosthesis].
AB  - From the aesthetic point of view, a patient can be completely rehabilitated after
      the loss of an eye with the insertion of an artificial eye made of glass. If the
      delicate structures of the eyelids have been severely damaged, however, or if the
      eye socket does not provide adequate retention for an eye prosthesis,
      rehabilitation becomes more difficult, and sometimes cannot be achieved with a
      cosmetically satisfactory result. In such cases, a facial prosthesis offers an
      alternative solution. Stable retention can be ensured with craniofacial implants.
      Single-sided rehabilitation by this method is quite common, but bilateral
      treatment is a rarity. We report on the prosthetic rehabilitation of a patient
      after exenteration on both sides due to retinoblastomas.

PMID- 10643290
TI  - [The eye and nutrition].
AB  - PURPOSE: To examine the effect of vitamins and trace elements on ocular tissue.
      MATERIALS AND METHODS: Rats or mice were fed diets deficient in the trace
      elements Zn, Cu, Mn, Se, Mg, and Cr or in vitamins A, B12, C, and E. In some rats
      Al and vitamin A were injected in excessive amounts. We studied the conjunctiva,
      cornea, retina, and optic nerve with a light microscope, transmission and
      scanning electron microscopes, an energy dispersive X-ray analyser, and an ion
      microscope. Histochemical, cytochemical, and immunohistochemical techniques were
      applied to the pathological specimens. RESULTS: Deficiencies of Zn, Cu, Mn, and
      vitamins A, C and E caused a loss of goblet cells in the conjunctiva and a
      prominent decrease of microvilli and microplicae in the conjunctiva and cornea.
      The elements in the goblet cells were changed in these conditions. In addition,
      epithelial cells showed poor fibrous development and abnormal distribution of
      chromatin in the nucleus. Zn, Cu, Mn, and vitamins A and E deficiencies caused
      photoreceptor cells to degenerate and disappear. Se deficiency reduced the
      horizontal and amacrine cells. Vitamin B12 deficiency reduced nerve fibers in the
      nerve fiber layer of the retina. Mg deficiency induced multifocal necrosis in the
      retinal pigment epithelium and apoptotic nuclear changes in the photoreceptor
      cells. Cr deficiency showed abnormal phagocytosis of the photoreceptor outer
      segment discs in the retinal pigment epithelium. Vitamin B12 was found to be
      related to the circadian rhythm in the retina. Deficiencies of Zn, Cu, Mn, and
      vitamins A, B12, and E induced degeneration and disappearance of myelin lamellae
      in the myelinated optic nerve fibers. In hypervitaminosis A, lipid droplets
      appeared in the retinal pigment epithelium and alcohol dehydrogenase disappeared
      in the retinal pigment epithelium and photoreceptor outer segments. Excessive Al
      was toxic to the retina, which showed disappearance of photoreceptor cells. Al
      deposits were seen in dendrites and neurons in the outer plexiform layer. Zn
      seemed to be necessary for corneal epithelial cell wound healing. DISCUSSION:
      Trace elements usually are contained in enzymes, which have many metabolic
      functions. They are related to synthesis and breakdown of many substances. Some
      trace elements such as Zn, Cu, Mn, and Se and vitamins including vitamins A, C,
      and E prevent peroxidation of lipids. Some vitamins have an affinity for specific
      tissues such as epithelial cells, nerve fibers, and neuronal cells and are needed
      for cell differentiation, development, and maintenance. CONCLUSION: Cu, Zn, Mn,
      Se, Mg, and Cr and vitamins A, B12, C, and E are necessary for maintenance of
      cellular structure and metabolism.

PMID- 10643291
TI  - [Introduction to genetics in ophthalmology. Value of family studies].
AB  - This paper reviews the author's personal experience with genetic eye diseases and
      discusses the significance of family studies in providing key information for the
      advancement of molecular research. CHOROIDEREMIA: This disease has long been
      known as an X-linked progressive tapetoretinal degeneration, but it was first
      described in Japan in 1974 after finding asymptomatic fundus changes in
      heterozygous female carriers that are compatible with X chromosomal inactivation.
      Mutations in the disease-causing gene (REP-1) provide a clue to the diagnosis and
      pathophysiology of the disease. LEBER'S HEREDITARY OPTIC NEUROPATHY: The clinical
      expression is so variable among affected individuals and families that mild optic
      nerve disease of insidious onset should be differentiated from autosomal dominant
      optic atrophy. Molecular assessment of mitochondrial DNA leads to a definite
      diagnosis of the disease, but mitochondrial DNA mutations do not fully account
      for the clinical manifestation and phenotypic variability of the disease. NORRIE
      DISEASE: This rare X-linked vitreoretinal dysplasia, characterized by congenital
      bilateral blindness, was documented in Japan some twenty years ago and the
      disease has been identified in four unrelated Japanese families. The disease,
      once diagnosed on the basis of elaborate clinical and familial studies, can now
      be defined by molecular assessment of the Norrie disease gene. CONGENITAL
      NYSTAGMUS: A four-generation family was described which presented with autosomal
      dominantly inherited congenital nystagmus, peripheral corneal opacity, and foveal
      hypoplasia without any iris tissue malformation. The diagnosis of this family was
      established by detection of a missense mutation in the paired domain of the PAX 6
      gene, hence conforming to a forme fruste of congenital aniridia. SORSBY'S FUNDUS
      DYSTROPHY: Two Japanese families with Sorsby's fundus dystrophy showed late-onset
      retinal dystrophy characterized by submacular hemorrhage and atrophy. Our
      patients presented with visual loss as late as 50 years of age or older due to
      macula-confined degenerative changes that were similar in all respects to
      exudative age-related macular degeneration and showed a novel mutation in the
      tissue inhibitor of the metalloproteinases-3 gene. AGE-RELATED MACULAR
      DEGENERATION (ARMD): We have studied whether there is any association of
      candidate polymorphic genes involving xenobiotic or antioxidant metabolism with
      susceptibility to ARMD. Preliminary results suggest that the genetic polymorphism
      of microsomal epoxide hydrolase is related to potential risk of ARMD.

PMID- 10643292
TI  - [In vivo measurement of ocular circulation with the laser speckle method-
      development of apparatus and application in ophthalmological research].
AB  - We have developed an apparatus utilizing laser speckle phenomenon which can
      measure the peripheral circulation in the iris, choroid, retina and optic nerve
      head (ONH) and blood velocity through retinal vessels in the living eye non
      invasively and quantitatively. A blue-component argon laser (wavelength 488 nm)
      was used for measurement of peripheral circulation in the retina and a diode
      laser (wavelength 808 nm) for measurements of peripheral circulation in the iris,
      posterior choroid and ONH, and measurement of centerline blood velocity through
      retinal vessels. A fundus camera (TRC-WT 3, Topcon) was equipped with a laser
      source and an image sensor where the speckle pattern from the fundus appears, and
      the data were analyzed with a personal computer to give a normalized blur (NB)
      value or a square blur rate (SBR) value, both quantitative indices of blood
      velocity. The NB value, whose computation requires much less time, was adopted to
      evaluate peripheral circulation because of non-linear correlation between the NB
      and actual blood velocity in the range above 20 mm/sec. The SBR value, whose
      computation requires a longer time, was adopted for measurement of blood velocity
      through retinal vessels. Measurement field in the living eye was 1.06 x 1.06 mm
      at its maximum and reproducibility index of the in vivo measurement in the rabbit
      iris, choroid, retina, and ONH was approximately 10%. When blood flow was changed
      by intraocular pressure (IOP) change in rabbit eyes, NB values obtained from the
      iris, choroid, and retina showed a significant correlation with the blood flow
      simultaneously determined with the colored microsphere technique in the same eye,
      and the NB obtained from the ONH also correlated with the blood flow determined
      with the H2 gas clearance method. Stepwise reduction in the ocular perfusion
      pressure (OPP) by stepwise increment of IOP resulted in proportional reduction in
      the iris- and choroid-NB. On the other hand, the retina- or ONH-NB remained
      almost unaltered at OPP levels above 50 mmHg, and decreased along with OPP at
      levels less than 50 mmHg. By monitoring NB values for 2 hours, presence or
      absence of autoregulatory mechanism against OPP change in the choroidal and ONH
      circulation was studied in rabbits. Throughout the experimental period of 2
      hours, the choroidal NB was changed along with the OPP change, suggesting absence
      of blood flow autoregulation in this tissue. In the ONH, however, the NB returned
      to the baseline after its transient increase or decrease when the OPP was
      continuously increased or decreased, showing the presence of an autoregulatory
      mechanism in the ONH circulation. However, the time course of the NB resumption
      depended on the extent of OPP change. These results indicated that the laser
      speckle method can be useful in investigating the autoregulatory mechanism and
      processes of peripheral circulation in ocular tissues. Unilateral instillation of
      drugs with vasodilative activity (ifenprodil, betaxolol or nipradilol) in rabbit
      eyes significantly increased ONH and/or choroidal circulation. The extent in
      change in the ONH and/or choroidal circulation correlated with the number of
      doses, but not with the extent of IOP reduction, which suggested that the
      observed effects were attributable to the drug which penetrated locally.
      Intravenous administration of a Ca(2+)-antagonist (nicardipine, nilvadipine or
      pranidipine) significantly increased choroidal or retinal circulation in rabbits.
      The ONH circulation, however, was not affected by nicardipine, but affected by
      nilvadipine or pranidipine. Given the same effect on the ONH circulation,
      systemic hypotensive effect was stronger in pranidipine than in nilvadipine,
      which suggested that nilvadipine can be used in patients with ocular circulatory
      insufficiency. A modification of the laser speckle apparatus used for animal
      experiments was devised so that the NB or SBR values could be measured in human
      eyes every 0.12 sec on a real-time basis. (ABSTRACT TRUN

PMID- 10643293
TI  - [In vivo evaluation of leukocyte dynamics in the retinal and choroidal
      circulation].
AB  - We have developed a new method to visualize leukocytes and evaluate their
      kinetics in the chorioretinal microcirculation of the living eyes. Nuclear
      staining dyes and a scanning laser ophthalmoscope were used to image leukocytes
      in the fundus. Acridine orange was used to visualize leukocytes in the retinal
      microcirculation. For imaging leukocytes in the choroid, indocyanine green was
      injected intravenously. Dynamics of leukocytes in the capillaries of the retina
      and choroid were quantitatively estimated in monkeys and rats. This method also
      allowed evaluation of leukocyte-endothelial interactions, such as rolling or firm
      adhesion, in vivo. Acridine orange leukocyte fluography was used to study
      leukocyte dynamics in the following experimentally induced microcirculatory
      disturbances of the retina: 1) interferon-associated retinopathy, 2) ischemia
      reperfusion injury of the retina, and 3) experimental diabetes mellitus. 1)
      Interferon-associated retinopathy Systemic administration of interferon alpha
      enhanced leukocyte-endothelial interactions in the retina, which resulted in
      leukocyte rolling and entrapment in the retinal capillary beds. Leukocyte
      accumulation was also detected in the lung. The entrapment or accumulation of
      leukocytes in the microcirculation was inhibited by simultaneous administration
      of corticosteroids or other agents. These results suggested that leukocytes play
      a major role in the development of adverse effects of interferon, such as
      retinopathy or interstitial pneumonia. 2) Ischemia-reperfusion injury of the
      retina During reperfusion period after transient (60 min) retinal ischemia by
      optic nerve ligation, the rolling of leukocytes in the retinal veins was
      prominent and numerous leukocytes were trapped in the retinal capillaries. The
      number of rolling leukocytes was at a maximum 12 hours after reperfusion.
      Leukocyte entrapment peaked at 24 hours after reperfusion. By blocking adhesion
      molecules on the vascular endothelium, these leukocyte-endothelial interactions
      were effectively inhibited. Postischemic retinal atrophy was also inhibited by
      blocking adhesion molecules. These results suggested that leukocytes may be major
      players in the pathophysiology of ischemia reperfusion injury of the retina. 3)
      Experimental diabetes mellitus Leukocyte dynamics in the retina were studied in
      streptozotocin-induced diabetes and spontaneous diabetes (OLETF rats). In both
      diabetic models, leukocyte entrapment in the retinal capillaries was increased
      even in the early stages of diabetes. Fluorescein angiography revealed that
      trapped leukocytes disturbed the regional capillary blood flow in the downstream.
      Enhanced expression of adhesion molecules was observed in the capillary
      endothelium of the retina in the diabetic rats. Leukocyte entrapment in the
      retinal capillaries might cause microvascular occlusions and dysfunction, in turn
      causing diabetic retinopathy.

PMID- 10643295
TI  - [Studies on the clostridial collagenases].

PMID- 10643294
TI  - [Cell biology of intraocular vascular diseases].
AB  - Diabetic retinopathy (DR) still remains the leading cause of blindness in the
      working population of Japan and western world, though therapies such as retinal
      photocoagulation and vitrectomy can be remarkably effective when administered at
      an appropriate stage in the disease process. Consequently, there is a need for
      further investigation of the pathogenesis of DR to develop better therapy. DR is
      characterized by gradually progressive alterations in the retinal
      microvasculature, leading to three fundamental morbidities: 1. vascular
      hyperpermeability, 2. vascular occlusion, and 3. neovascularization. Recent
      studies have revealed that hyperglycemia causes several metabolic disorders which
      cause DR directly or indirectly through the abnormal expression of cytokines
      including vascular endothelial growth factor (VEGF). In this study, we performed
      precise tests of the correlation between intraocular VEGF and the three
      fundamental changes in the diabetic retina mentioned above. Ultrastructural study
      of the human retina revealed that two major pathways are responsible for
      hyperpermeability of diabetic retinal vessels, i.e., intercellular or
      paracellular transport (opening of the tight junctions) and intracellular or
      transcellular transport (caveolae, intracytoplasmic vesicles, and fenestration).
      All these pathways were induced by intravitreal injection of VEGF. The major
      trigger of VEGF overexpression is tissue ischemia caused by vascular occlusion.
      However, the retinas from the eyes with background DR revealed increased
      expression of VEGF without apparent incidence of vascular occlusion. We have
      identified accumulation of advanced glycation end products (AGEs) in these
      retinas, and found that AGEs are a major stimulus for VEGF overexpression in
      background DR. Retinal vascular occlusion was caused by thrombus formation
      primarily in the capillary vessels. Thrombi mainly consisted of fibrin,
      platelets, and leucocytes in the early stage of their formation, and glial cells
      and macrophages were also involved in the later stage. The blood coagulation
      process plays an important role in fibrin formation in thrombi. The expression of
      tissue factor (TF), an initiator of extrinsic blood coagulation, was upregulated
      by VEGF in retinal vascular endothelial cells (REC). In addition, AGEs were also
      thrombogenic through the induction of TF expression and suppression of the
      expression of prostacyclin stimulating factor (PSF), which stimulate prostacyclin
      synthesis in vascular endothelial cells. These findings suggest that AGEs, VEGF,
      and TF could interact in a vicious circle because AGEs and VEGF could induce
      retinal vascular occlusion which results in further increase in VEGF expression.
      Intravitreal injection of VEGF could induce retinal neovascularization. VEGF
      stimulates vascular endothelial cell proliferation by binding to a specific
      receptor named kinase insert domain-containing receptor/fetal liver kinase
      (KDR/FIk-1, KDR). AGEs and basic fibroblast growth factor (bFGF) induced
      expression of KDR in REC, and a transcription factor Sp 1 was involved in this
      process. Since the expression of KDR as well as VEGF was already upregulated in
      the retinas with background DR, VEGF appeared to start to induce the
      proliferative changes long before the actual onset of proliferative DR. These
      findings indicated that VEGF and its receptor system plays a pivotal role all
      through the disease process of DR. We considered that amelioration of the
      activated VEGF and its receptor system could lead to the development of new
      therapy for DR. We have developed two novel methods to prevent retinal
      neovascularization by inhibiting VEGF and its receptor system. 1. An insulin
      sensitizing agent (troglitazone) inhibited proliferation, migration, and in vitro
      tube formation by REC as well as oxygen-induced retinal neovascularization in a
      mouse model. Thus, glycemic control by troglitazone could reduce the incidence of
      neovascularization in diabetic eyes. 2. (ABSTRACT TRUNCATED)

PMID- 10643296
TI  - [Studies on the zinc metalloprotease produced by Vibrio vulnificus].

PMID- 10643297
TI  - [DNA vaccines for infections with intracellular bacteria].

PMID- 10643298
TI  - [Antiinfective drugs into the 21st century].

PMID- 10643299
TI  - [Microbiology of Orientia tsutsugamushi].

PMID- 10643300
TI  - [Interface between medicinal bacteriology and agricultural chemistry--innovation
      of culturing technology of Bordetella pertussis by a cyclodextrin derivative].

PMID- 10643301
TI  - [A prospect of gene therapy for gastric cancer].

PMID- 10643302
TI  - [A case of ulcerative colitis associated with impending DIC].

PMID- 10643303
TI  - [Two cases of ischemic colitis caused by colonoscopy examination].

PMID- 10643304
TI  - [Induction of long-term remission for the first onset of severe enterocolitis
      Crohn's disease treated by leukocytapheresis alone].

PMID- 10643305
TI  - [Colorectal cancer in a young adult with X-linked agammaglobulinemia (XLA).
      Report of a case].

PMID- 10643306
TI  - [A case of pyogenic granuloma in the small intestine].

PMID- 10643307
TI  - [A case of mucinous cholangiocarcinoma with lymph node metastasis].

PMID- 10643308
TI  - [Hepatic encephalopathy following portal thrombosis associated with type B liver
      cirrhosis].

PMID- 10643309
TI  - [A case of splenic sclerosing hemangioma].

PMID- 10643310
TI  - [Venous branch occlusion due to APC resistance].
AB  - OBJECTIVE: Resistance against the anticoagulatory effect of activated protein C
      (APC) is the most common genetic risk factor for venous thromboembolism. In the
      industrialized nations, the prevalence is 4-7% of heterozygous symptom carriers
      and 0.04% individuals with homozygous defect. The hereditary form is conditioned
      by a single-point mutation in factor V gene, whose molecular characterization
      became available in 1994. The fact that so far there are no reports about this
      specific disease in the German literature signifies a lack in the diagnosis of
      thromboembolic diseases. PATIENT AND METHODS: For this reason, the disease
      process of a 43-year-old female patient is reported. The woman came to this
      hospital for the first time in 1989 presenting a retinal branch vein occlusion.
      Her history revealed that she had taken hormonal contraceptives. The etiology of
      the thromboembolism remained unknown. The patient returned in 1997 because of
      recurrent retinal bleedings. The laboratory data indicated activation of
      coagulation (APC ratio 1.4). The following molecular characterization confirmed
      the mutation G 1691 A in factor V gene and the presence of thrombophilia. The
      ensuing examination of her family for thrombophilia identified one asymptomatic
      defect carrier among the patient's three children. Alternative methods of
      contraception were recommended to that daughter to prevent a even higher
      thrombotic risk and life-threatening complications. CONCLUSION: APC resistance
      seems to be a cause of retinal venous thrombosis in patients younger than 50
      years. In patients in whom a familial thrombosis is suspected, the molecular
      genetic test for factor V Leiden should be obtained. There are no simple methods
      for the classification of the risks. The etiology of vascular diseases often
      remains unknown. Therefore it is important in special cases with typical history
      to keep in mind the APC resistance. Specialized anticoagulative therapy and
      familial prophylaxis depend on teamwork between ophthalmologists and
      hemostasiologists. This is decivise for the prevention of blindness.

PMID- 10643311
TI  - [Introduction of the lipofuscin-fluorophor A2E into the lysosomal compartment of
      human retinal pigment epithelial cells by coupling to LDL particles. An in vitro
      model of retinal pigment epithelium cell aging].
AB  - PURPOSE: Lipofuscin accumulates with age and in association with various retinal
      diseases. To investigate cellular effects of lipofuscin components in an in vitro
      RPE cell model, specific loading of the lysosomal compartment is required. Herein
      a major lipofuscin fluorophor was complexed to LDL and the subsequent subcellular
      localization of the retinoid was examined. METHODS: The lipofuscin component N
      retinylidene-N-retinylethanolamine (A2-E) was synthesized and coupled to LDL.
      Human RPE cell cultures were loaded with the A2-E/LDL complex over 4 weeks.
      Thereafter, RPE cells were harvested by trypsinization and disrupted by nitrogen
      cavitation. After ultra-centrifugation, the postnuclear supernatant was
      fractionated on a self-generating gradient and fractions were analyzed by
      measuring marker enzyme activities of various cellular compartments. RESULTS: A2
      Eaccumulated almost exclusively in the lysosomal compartment, as indicated by the
      identical peaks of the marker enzyme ss-hexosaminidase and the relative
      fluorescence of A2-E. Only a small amount of A2-E appeared to associate with the
      cell membrane, as shown by a minor peak of A2-E corresponding to the distribution
      of phosphodiesterase activity. The lysosomal marker enzyme was not present in the
      cytosolic fraction. CONCLUSIONS: The feeding of A2-E/LDL complexes to cultured
      RPE-cells proved to be highly effective in specific loading of the lysosomal
      compartment, providing a suitable in vitro cell culture model for RPE aging and
      the investigation of A2-E-effects on lysosomal functions in RPE cells. Such a
      model may contribute to the understanding of the pathogenesis of degenerative
      diseases of the outer retina associated with excessive lipofuscin accumulation,
      including age-related macular degeneration, Stargardt's disease and Best's
      disease.

PMID- 10643312
TI  - [Threshold value retinopathy of prematurity. Visual outcome of 2-year-old
      children after cryocoagulation].
AB  - BACKGROUND: The results of the Cryo-ROP group showed that cryotherapy
      significantly reduces the rate of adverse morphological and functional outcome of
      eyes with threshold retinopathy of prematurity. Structural status and visual
      acuity of 48 eyes which consecutively underwent cryocoagulation in our hospital
      between 1990 and 1994 were examined at 2 years corrected gestational age. METHOD:
      Visual acuity and fundus morphology were examined by Teller acuity-cards test,
      retinoscopy, orthoptic status and fundus examination. A favourable grating acuity
      was defined as > or = 2.2 cy/degree, a favourable morphology as no pathological
      or mild findings at the level of the posterior pole or stage 4 a. RESULTS: Fifty
      six % of cases reached a quantifiable grating acuity between 0.32 and 13.0
      cy/degree, 42% reached a favourable functional outcome, and 69% of the eyes had a
      morphologically favourable outcome. Fifty-five % of the measurable eyes were
      myopic, and 29% had a high myopia > or = -6.0 D. 47% showed a heterotropia.
      CONCLUSIONS: Our results show a discrepancy between morphological and functional
      outcome. Especially for zone 1 eyes, cryocoagulation of the avascular retina does
      not seem to allow a favourable morphological and functional outcome.

PMID- 10643313
TI  - [Intra-vitreal rt-PA and gas introduction in submacular hemorrhage].
AB  - Efficacy and complications of intravitreally injected tissue plasminogen
      activator (rt-PA) and sulfahexafluoride gas (SF6) in submacular hemorrhage are
      demonstrated. PATIENTS AND METHODS: Fifty-three patients with submacular
      hemorrhage were treated (27 women, 26 men, mean age 79 +/- 1 years). Causes of
      hemorrhage were a choroidal neovascularization in 47 patients and macroaneurysm
      in 6 patients. After i.v. administration of 500 mg acetazolamide and disinfection
      of the conjunctiva, 50 micrograms rt-PA in 0.1 ml (BSS) and 0.5 ml SF6 were
      injected intravitreally. The patient was positioned prone for 24 h. RESULTS: In
      23 patients with choroidal neovascularization visual acuity improved by 2 lines
      and more; in 12 patients vision remained unchanged. In 12 patients visual acuity
      deteriorated. In 5 of 6 patients with a macroaneurysm vision improved from less
      than 0.1 to 0.1-0.5. Postoperative complications were four cases of vitreous
      hemorrhage and one case of endophthalmitis. CONCLUSION: The intravitreal
      injection of rt-PA and SF6 is an alternative method for treatment of submacular
      hemorrhage.

PMID- 10643314
TI  - [Confocal indocyanine green angiography with 3-dimensional topography. Results in
      choroid neovascularization (CNV)].
AB  - BACKGROUND: Confocal indocyanin green angiography (ICGA) offers detailed two
      dimensional imaging of choroidal pathologies. However, the spatial extension of
      lesions is not reproduced. We developed a novel method for three-dimensional
      documentation of choroidal vascular abnormalities. METHODS: Focal series were
      performed using a laser scanning ophthalmoscope (Heidelberg Retina Angiograph).
      Thirty-two images within a distance of 4 mm were taken at a frequency of 20 Hz.
      Following correction of dislocation, a surface of normalized fluorescence
      intensity was determined and displayed topographically. RESULTS: In physiological
      eyes three-dimensional ICGA demonstrates the homogeneous concavity of the choroid
      with prominent overlay of retinal vessels. Classic choroidal neovascularization
      (CNV) imposes as substantial elevation. Occult CNV are demarcated despite
      negative conventional ICGA due to reduction of blocking phenomena. Therapeutic
      interventions such as photocoagulation, photodynamic therapy and surgery induce a
      resolution of CNV with or without residual defects within the choroidal pattern.
      CONCLUSION: Topographic ICGA allows for the first time in-vivo representation of
      prominence and depth of vascularized pathologies and provides a tool for improved
      diagnostic and therapeutic evaluation.

PMID- 10643315
TI  - [Photorefractive keratectomy. Free-running vs. q-switched Er:YAG laser (scanning
      mode)].
AB  - BACKGROUND: Examination of morphology in plane corneal ablation (in vitro)
      induced by an Er:YAG-laser (2.94 microns) in two modes: free-running (50
      microseconds) and q-switched (200 ns). METHODS: Sequences of different fluences
      in each mode were applied to freshly enucleated swine eyes. Parameters of free
      running mode: fluences 1.21-4.77 J/cm2, frequency 80 Hz, spot size 500 microns
      FWHM, hexagonal spot shape. Parameters of q-switched mode: fluences 0.79-2.33
      J/cm2, frequency 20 Hz, spot size 500 microns FWHM, round spot shape. RESULTS:
      Histology showed thermal damage of 10-25 microns in depth caused by the free
      running mode compared with 4.5-7.5 microns by the q-switched mode. In both gross
      photography and scanning electron microscopic examination, the surface was found
      to be more homogeneous and smoother in the q-switched mode. CONCLUSIONS:
      Depending on the different application modes, both laser systems could be used
      for a defined corneal ablation in photorefractive keratectomy. However, at the
      moment, results using the Er:YAG laser are not as favorable as with the excimer
      laser.

PMID- 10643316
TI  - [Age-dependent error rates in automatic screen campimetry with bright and dark
      stimuli].
AB  - PURPOSE: To assess patient reliability and compliance, most perimeters check for
      false-positive and -negative answers. In this study the results of catch trials
      were obtained with video campimetry with respect to age-related changes and
      differences for tests using increment and decrement stimuli. METHODS: Sixty-one
      ophthalmologically normal persons (aged 20-80 years) were tested with automated
      campimetry on a computer screen. Examination strategy included bright and dark 1
      degree-stimuli at 69 test locations within the central 30 degrees of the visual
      field (presented on a computer screen). Four percent of all stimulus
      presentations were used for testing false-positive answers, 4% for false-negative
      answers. RESULTS: The rate of false-positive answers was not significantly age
      related and there was no difference for tests with dark and bright stimuli.
      Concerning false-negative answers, no difference between dark and bright stimuli
      was found. There was also no strong correlation with age. CONCLUSION: In this
      study rates of false-positive and -negative answers were low at a comparable
      level for either stimulus type (bright/dark) or age of the tested persons.

PMID- 10643317
TI  - [Severe intra- and postoperative supra-choroid hemorrhage. Risk factors, therapy,
      results].
AB  - BACKGROUND: The aim of this study was to analyze risk factors, therapeutic
      strategies, and functional and anatomic results of eyes with severe
      suprachoroidal hemorrhage. PATIENTS: Eight of 11 bleeding episodes occurred
      intraoperatively and 3/11 postoperatively. Bleeding was associated with the
      following surgical procedures: perforating keratoplasty (5x), extracapsular
      cataract extraction (3x), pars plana vitrectomy (2x), intracapsular cataract
      extraction (1x). RESULTS: Nine operations were performed with general anesthesia,
      two after retrobulbar injection. Ocular risk factors (e.g., prior operations,
      ocular diseases) and general risk factors (e.g., cardiovascular diseases,
      diabetes) were analyzed. At the end of the follow-up time visual acuity had
      improved in three eyes, and it was unchanged in one eye and worse in seven eyes.
      Four eyes were amaurotic; two of them had to be enucleated. CONCLUSIONS: In spite
      of using state-of-the-art surgical techniques the prognosis of suprachoroidal
      bleeding remains serious. Patients who have a combination of several ocular and
      general risk factors almost exclusively are the ones who afflicted by this
      complication.

PMID- 10643318
TI  - [Regression of cytomegalovirus retinitis in AIDS patients without systemic
      maintenance anti-cytomegalovirus therapy treated with highly active
      antiretroviral therapy].
AB  - BACKGROUND: The purpose of this study was to evaluate the course of CMV retinitis
      after initiation of highly active antiretroviral therapy (HAART) and
      discontinuation of systemic anti-CMV maintenance therapy. PATIENTS AND METHODS:
      Case reports are presented for two AIDS patients (2 eyes, ages 34, 43, male) with
      CMV retinitis. The CD4 count at the time of CMV retinitis was 20/microliter
      (patient 1) and 35/microliter (patient 2). Under HAART the CD4 count rose up to
      202/microliter (patient 1) and 350/microliter (patient 2); the viral load was
      under detection limit in both patients. At that time systemic maintenance therapy
      was discontinued in both patients. RESULTS: There was no progression of retinitis
      during the observation period of 21 months (patient 1) and 24 months (patient 2).
      CONCLUSIONS: In selected patients with immune recovery under HAART it is possible
      to discontinue systemic anti-CMV maintenance therapy.

PMID- 10643319
TI  - [Monocular hemianopsia--sequelae of ethmoid operation? Psychogenic vision
      disorder].

PMID- 10643321
TI  - [1999 Nobel Prize for Medicine. Topogenic signals within proteins].

PMID- 10643320
TI  - [Bilateral vision loss after coronary artery bypass operation. Ischemic
      retinopathy after coronary artery bypass operation: "post-pump retinopathy"].

PMID- 10643322
TI  - [References for expert assessment in ophthalmology. Causality and finality].

PMID- 10643323
TI  - [What is your diagnosis? Sinus bradycardia].

PMID- 10643324
TI  - [Efficacy of intravenous pamidronate in osteoporosis, mineralometric evaluation].
AB  - Therapeutic efficacy of some molecules, predicted by scientific studies, is not
      systematically confirmed when the substance is used in general practice. In
      osteoporosis, certain studies show an efficacy of intravenous (i.v.) pamidronate
      similar to oral alendronate. These results could be a valuable alternative for
      non compliant patients or those suffering from digestive problems. For this
      reason we have studied the efficacy of i.v. pamidronate in osteoporotic patients,
      not available to oral alendronate. This is a retrospective study of 20 unselected
      osteoporotic patients from our general practice. Each patient had a bone mineral
      density (BMD) of less than -2.5 DS for the T-score, measured by a dual energy X
      ray (DXA) densitometer at the lumbar spine and the hip. Thirty milligrams of
      pamidronate were administered intravenously every three months. Each patient was
      controlled by a DXA after eighteen months minimum. Thirteen patients had
      increased on average their BMD by 6.2% in the lumbar spine and by 4.7% in the
      hip. All patients responded at least at one site, but seven patients did not
      improve their BMD at both sites. We have confirmed that intermittent i.v.
      pamidronate given in common practice increases BMD in the lumbar spine and the
      hip in 2/3 of the patients. The increase in bone mass in the hip is similar to
      that published in the scientific literature, but less for the lumbar spine.

PMID- 10643325
TI  - [Recurrent retrobulbar neuritis and extensive myelitis: MS or optic
      neuromyelitis?].
AB  - Two female patients with recurrent optic neuritis and severe myelitis were
      described. In the first patient the illness began with recurrent myelitis, in the
      second one with optic neuritis. In both patients spinal MRI showed extensive
      enhancing lesions of the cervical respectively thoracic spinal cord. An initial
      cranial MRI was normal. In the first patient an MRJ demonstrated after several
      years lesions not typical for multiple sclerosis. In both patients cerebrospinal
      fluid showed especially mononuclear pleocytosis with cell counts between 11 and
      126/microliter and severely elevated total protein, while intrathecal oligoclonal
      bands were not found. During exacerbations in both patients ENA-autoantibody
      screening was positive. Intravenous treatment with methylprednisolone improved
      the clinical situation for some time. In both patients cyclophosphamide at a dose
      of 100 mg daily had to be given due to relapsing neurological deficits.

PMID- 10643326
TI  - [Atrial fibrillation treated with amidarone].
AB  - A 60 year old man, whose incompetent mitral valve had been replaced, was known
      for intermittent atrial fibrillation. In 1995 a treatment with amiodarone was
      begun with sustained success. After three years of stable sinus rhythm atrial
      fibrillation reappeared. A biochemically impressive amiodarone induced
      hyperthyroidism was diagnosed with only subtitle clinical signs. The different
      forms of amiodarone induced hyperthyroidism and the therapeutic options are
      discussed.

PMID- 10643327
TI  - [Diarrhea in HIV infection].

PMID- 10643328
TI  - [PEBP2/CBF/AML1: master regulators for tissue specific gene expression].

PMID- 10643329
TI  - [Developmental regulation by Drosophila Runt domain-proteins. Runt and Lozenge].

PMID- 10643330
TI  - [Pebp2 alpha A/Cbfa1 is a master regulator of bone formation].

PMID- 10643331
TI  - [Regulation of hematopoietic cell development by AML1].

PMID- 10643332
TI  - [Mechanism of leukemogenesis induced by AML 1-MTG 8].

PMID- 10643333
TI  - [Leukemogenesis by the AML1/EVI-1 chimeric protein].

PMID- 10643334
TI  - [Loss-of-function of AML1/PEBP2 alpha B and leukemogenesis].

PMID- 10643335
TI  - [PEBP2/CBF is a nuclear target of Smads in TGF-beta super family signaling].

PMID- 10643336
TI  - [Molecular mechanisms of PEBP2/CBF as a master regulator of tissue-specific gene
      expression].

PMID- 10643337
TI  - [Ultrafast analysis of DNA by microchip and nanochip technology].

PMID- 10643339
TI  - [In Process Citation]

PMID- 10643338
TI  - [Trend of technology to fabricate the micro-chips for capillary electrophoresis].

PMID- 10643340
TI  - [Prevention after accidental exposure to HIV].

PMID- 10643341
TI  - ["New" virus infections are not always signs of disease].

PMID- 10643342
TI  - [The TT-virus. A recently discovered virus "searching for its disease"].

PMID- 10643343
TI  - [Registration of complications after transfusion--"hemovigilance"].

PMID- 10643344
TI  - [Crib death or cot death in the Nordic countries. A forensic pathologist's point
      of view].
AB  - In the 15 years between 1975 and 1989 approximately 5,000 infants succumbed to
      SIDS in the Nordic countries. Denmark and Norway were most seriously hit, with
      SIDS rates amounting to 2 and 2.5 per 1,000 live births in 1989. During the
      1970's and 1980's especially Denmark and Norway experienced a significant
      increase in SIDS rates. In 1990 a co-operative study was initiated by Nordic
      Council of Ministers. Part of the study consisted of forensic pathologists
      examining SIDS victims. They showed that neither the increase during the 1980's
      nor the decrease during the 1990's was due to changes in the classification or
      diagnostic practise. A correlation between prone sleeping position and SIDS rates
      is now well recognised. However, neither an explanation for the great discrepancy
      in SIDS rates between the Nordic countries nor a possible explanation for the
      risk of prone sleeping position has been achieved.

PMID- 10643345
TI  - [Use of antiretroviral chemoprophylaxis after occupational HIV exposure].
AB  - The study describes the use of postexposure antiretroviral prophylaxis (PEP)
      after occupational exposure to HIV in Denmark in the period 1/1 1997-31/12 1998.
      Forty-seven accidentally exposed persons received PEP in this period, of whom 14
      were nurses, 13 physicians and 11 were not employed in the health care system. In
      23 cases side effects to PEP were described. In 18 cases the index person was
      i.v. drug abuser and in 11 cases homosexual/bisexual men. In 18 cases the HIV
      status of the index person was unknown at the time of exposure. Ten of these
      index persons were subsequently tested and all found HIV-negative. It is
      concluded, that the frequency of occupational exposure to HIV is unacceptably
      high. Further it is emphasised that in cases where the HIV status of the index
      person is unknown, PEP should only be instituted if the index person is at risk
      of being HIV infected and has signs of HIV infection.

PMID- 10643346
TI  - [Fatal poisonings during a 5-year period in Eastern Denmark].
AB  - In the period 1992-1996, both years included, 1079 cases of deaths from poisoning
      by drugs or poisons were found by forensic-chemical analyses at The Institute of
      Forensic Medicine, Dept. of Forensic Chemistry, in Copenhagen, covering a
      population of 2.4 million. Morphine was by far the most frequently occurring
      compound accounting for 421 deaths, followed by methadone with 185 deaths. Then
      alcohol, ketobemidone, and carbon monoxide were represented with 80, 74 and 66
      deaths, respectively. Drug addicts dominated in the survey with 549 cases.
      According to Danish law, autopsy with following chemical analyses must be
      performed on all dead drug addicts, whereas many other deaths by poisoning are
      defined only from the medicine found in the vicinity of the dead body.

PMID- 10643347
TI  - [Randomized controlled trial of high-dose peroral methylprednisolone in attacks
      of multiple sclerosis].
AB  - The efficacy of glucocorticoid treatment in multiple sclerosis (MS) is uncertain.
      We assessed the effect of oral high-dose methylprednisolone in attacks of MS.
      Twenty-five patients with an attack of MS with a duration of less than four weeks
      were randomized to placebo, 26 patients received oral methylprednisolone (500 mg
      once daily for five days with a 10 days tapering period). Scripps Neurological
      rating scale scores differed significantly in methylprednisolone and placebo
      treated patients the first three weeks (p = 0.005) and after eight weeks (p =
      0.0007). Subjective symptom assessment on a visual analogue scale the first three
      weeks (p = 0.02) and the answers to an efficacy questionnaire administered after
      eight weeks (p = 0.05) also favoured a beneficial effect of methylprednisolone
      treatment. The risk of a new attack of MS was not influenced by the treatment at
      short-term follow up. No serious adverse events were seen. Oral high-dose
      methylprednisolone is recommended for treatment of attacks of MS.

PMID- 10643348
TI  - [Knowledge about Helicobacter pylori and antibiotic treatment of peptic ulcer. A
      model study of information dissemination and implementation of the new knowledge
      in clinical practice].
AB  - Dissemination of information concerning new knowledge on peptic ulcer disease
      caused by Helicobacter pylori and treatment with antibiotics was surveyed. In
      1996 a questionnaire was mailed to 200 gastroenterologists and 200 general
      practitioners. Physicians enumerate national medical journals as the most
      frequent source of information about the relationship between Helicobacter pylori
      and gastrointestinal ulcer. Six years after the first publication in
      international journals, 44% of the doctors had noticed this relation. Nearly all
      physicians had introduced antibiotics in treatment af peptic ulcer disease ten to
      twelve years after first announcement. The gastroenterologists preferred
      international medical journals whereas general practitioners stated national
      medical journals were the most important sources of new knowledge. General
      practitioners lacked knowledge of published guidelines for treatment of peptic
      ulcer disease.

PMID- 10643349
TI  - [National surveillance of Helicobacter pylori eradication in Denmark. Results
      based on registration of 34.582 drug prescriptions].
AB  - We wanted to characterize the use of H. pylori eradication therapy in Denmark
      (inhabitants 5,227,862). All H. pylori eradication treatments from a nation wide
      database covering all drug prescriptions in the period January 1994-June 1996
      were identified. We found 28,784 out-patients having a prescription with drugs
      for H. pylori eradication, accounting for 34,582 prescriptions in total. The
      incidence of new consumers was 220 per 10(5) inhabitants per year, with a maximum
      at 70-79 years of age. Eighty-six percent of the patients had only one treatment
      course. Forty-five percent had an anti-ulcer drug prescribed 1-12 months after
      the H. pylori eradication therapy. Consumption of antibiotics used for H. pylori
      eradication accounted for 1.4% of the total consumption of antibiotics. In
      conclusion, the incidence of H. pylori eradication therapy was fairly stable but
      with changes in the pattern of drug regimens used. Anti-ulcer drugs were often
      given after H. pylori eradication therapy, suggesting an inappropriate use of
      eradication treatment.

PMID- 10643350
TI  - [Spontaneous rupture of the left external iliac vein. A complication of deep vein
      thrombophlebitis?].
AB  - A 52 years old woman was hospitalized on suspicion of left femoral venous
      thrombosis. Within 24 hours she went into shock, and laparotomy was performed on
      suspicion of a ruptured abdominal aortic aneurysm. The operative finding was a
      ruptured iliac vein, which was repaired and anticoagulant treatment was started.
      Unfortunately the patient never stabilized and died from cardiovascular collapse
      within 12 hours.

PMID- 10643351
TI  - [Lumbar intercostal hernia--a rare condition].
AB  - Lumbar hernia is a rare condition, and as such often overlooked. We present a
      case of strangulated lumbar hernia in a 73 year-old man, with symptoms of left
      flank pain and a lumbar protrusion during three weeks. Diagnosis was achieved by
      CT scan, and a primary repair was done using a transperitoneal approach. The
      patient recovered well and was discharged in good condition.

PMID- 10643352
TI  - [Antimycotic therapy in secondary peritonitis prevents invasive mycosis].

PMID- 10643353
TI  - [Is sulfamethizole in acute cystitis not useful anymore?].

PMID- 10643354
TI  - [Synechia of the labia minor].

PMID- 10643355
TI  - [Hepatic toxicity of nitrofurantoin. Cases reported to the Center for Monitoring
      Adverse Drug Reactions 1968-1998].
AB  - Forty-four cases of nitrofurantoin-associated hepatic injury were reported to the
      Danish Center for Monitoring of Adverse Drug reactions from 1968 to 1998. Forty
      one were women with a median age of 69 years. They had been treated with
      nitrofurantoin for median one year (two days-seven years), and all had
      biochemical and clinical signs of hepatitis. In five cases the injury had been
      provoked by a rechallenge. Twenty-seven liver biopsies showed an equal amount of
      acute and chronic histopathological changes. Cirrhosis was diagnosed in seven
      cases. Four died in liver failure; the others apparently recovered without long
      term symptoms. In rare cases, nitrofurantoin can cause toxic hepatitis.
      Apparently elderly women in long-term treatment are more sensitive to develop
      this adverse reaction. The drug should be withdrawn if the patient shows any
      signs of hepatitis during treatment and the patient should be informed about the
      possible relationship to nitrofurantoin exposure. Rechallenge should not be
      performed.

PMID- 10643356
TI  - [The postcoital pill--time to switch to gestagen only?].

PMID- 10643357
TI  - [Clinical trials in Denmark in 1998].

PMID- 10643358
TI  - [Postoperative pain therapy. Still a challenge].

PMID- 10643359
TI  - [Examination of patients with syncope].

PMID- 10643360
TI  - [Incisional local anesthesia as postoperative pain control after abdominal
      surgery. A qualitative, systematic review].
AB  - A qualitative systematic review of randomized controlled trials (RCT) of
      incisional local anaesthesia for the control of postoperative pain after open
      abdominal operations was performed. Twenty-six studies with data from 1211
      patients were considered appropriate for analysis. RCT considered inguinal
      herniotomy, hysterectomy, cholecystectomy and a variety of surgical procedures.
      Outcome measures were pain scores, supplementary analgesics and time to first
      analgesic request. Efficacy was estimated by significant difference (p < 0.05) as
      reported in the original investigation. All trials of herniotomy showed a 2-7
      hour lasting, clinically relevant, improved pain relief. Five of eight
      cholecystectomy trials showed significant differences but in three studies of
      questionable clinical importance and validity. In other procedures results were
      inconsistent and in some cases of minor clinical importance. Except for
      herniotomy there is a lack of evidence for effect of incisional local anaesthesia
      on postoperative pain and further standardized studies are needed before
      recommendations can be made.

PMID- 10643361
TI  - [Knowledge about amd attitude to postoperative pain therapy of health personnel.
      A questionnaire survey].
AB  - From research results published over the last years it appears that many surgical
      patients are still undertreated for their postoperative pain. The study was
      performed in order to reveal the attitudes and knowledge of physicians and nurses
      towards postoperative pain therapy. Questionnaires were sent to physicians and
      nurses at the surgical and anaesthesiological wards at the hospital. The study
      revealed that the real purpose of postoperative pain management, to ensure early
      mobilization and nutrition of the patients, did not receive proper attention. Too
      many of the house staff accepted that the patients should have moderate or severe
      pain, especially the younger physicians. The house staff is still concerned about
      the risk of inducing dependency when using opioids. The knowledge of the
      analgesics used in the ward is not sufficient and inappropriate methods of
      administration of opioids are still used. Educational intervention to improve the
      staff's knowledge about pain management in postoperative care is strongly needed.

PMID- 10643362
TI  - [Complications after spinal analgesia using three different spinal needles:
      Sprotee, Spinocan and Atraucan].
AB  - In this prospective, randomised study 197 patients aged below 40 years received
      spinal analgesia using one of the following needles: Sprotte G24, Spinocan G27 or
      Atraucan G26. The incidence of insufficient or failed analgesia and difficulties
      handling the needles were noted. Patients were interviewed within three weeks
      after anaesthesia so as to establish the incidence of postoperative complications
      including post-dural puncture headache (PDPH). Headache was noted in 63 patients
      of which 33 (16.8%) were of PDPH type. The Sprotte needle caused significantly
      fewer cases of PDPH (Sprotte: 8.1%; Spinocan: 19.7; Atraucan: 21.7%. p < 0.05).
      Furthermore a significantly lower incidence of insufficient analgesia was
      observed with the Sprotte needle (0% versus 12.1% with the Spinocan and 11.6%
      with the Atraucan, p < 0.05). In conclusion, the Sprotte needle had the best
      profile with respect to PDPH and successful analgesia. This confirms the
      importance of the needle tip design.

PMID- 10643363
TI  - [Smoking and admission to a department of internal medicine at a county
      hospital].
AB  - On a random day in 1998 all hospitalized unselected patients on the ward of
      internal medicine, Silkeborg County Hospital were evaluated in relation to
      possible tobacco-related disease. A total of 56 (71%) of 79 had a smoking-related
      main diagnosis and of these 23 (29%) of 79 were statistically diseased as a
      direct consequence of their present and previous use of tobacco.

PMID- 10643364
TI  - [Direct costs of transient cerebral ischemia. A hospital-based study of resource
      use in Denmark during the first year following transient cerebral ischemic
      attack].
AB  - In order to obtain knowledge of costs of health care and social services for
      patients who have transient ischaemic attacks (TIA) all patients admitted to a
      university hospital in Copenhagen, Denmark, with TIA during 12 months in 1994
      1995 were included in a database. The patients were followed until one year after
      admission and data on resource use during and after the hospital stay were
      collected prospectively at interviews. The cost of the hospital stay had a mean
      of 10,100 DKK (1,800 US$) and the cost of health care and social services after
      discharge had a mean of 8,800 DKK (1,600 US$) per person.

PMID- 10643365
TI  - [Agricultural occupational accidents in the county of Ringkoebing. Local
      registration].
AB  - The aim of the study was to obtain knowledge of accidents and working conditions
      related to farm accidents for purposes of a preventive intervention. The survey
      was a prospective study following a cohort of 393 farms in the county of
      Ringkoebing in West-Jutland, Denmark. Every farm in the study registered work
      activity and farmwork related incidents that required a break in work. Every farm
      reporting an incident was interviewed by phone. The owner himself and the part
      time farmer had the highest injury rate per working hour. There was no difference
      between animal and field related work looking at the incidence rate per workhour,
      but the incidence rate whilst repairing machinery and buildings was five times
      higher and highly significant. The results indicate the existence of groups and
      areas of risk, where a preventive effort is needed. The study is followed by a
      randomised intervention study among 200 Danish farms.

PMID- 10643366
TI  - [Spontaneous cholecystocolic fistula].
AB  - Cholecystoenteric fistula is a rare complication of biliary tract diseases. The
      symptoms are abdominal pain, fever, nausea, vomiting, flatulence, fat
      intolerance, diarrhoea and weight loss. The fistula may often be asymptomatic for
      a long time. We report a 76-year-old woman with a cholecystocolic fistula between
      the gallbladder and the right flexure of the colon. The symptoms were persistent
      right upper quadrant pain and diarrhoea. Barium enema demonstrated the fistula.
      The patient was treated with an open cholecystectomy and a resection of the
      fistula.

PMID- 10643367
TI  - [Picture of the month. Pelvic injury].

PMID- 10643368
TI  - [Blood pressure and defecation].

PMID- 10643369
TI  - [Injuries among children aged 11 to 15 years].

PMID- 10643370
TI  - [Deja-vu in the Ugeskrift].

PMID- 10643371
TI  - [Tilt-table testing in syncope].

PMID- 10643372
TI  - [Poisoning with central nervous system stimulants. Amphetamine, ecstasy, cocaine
      and gamma-hydroxybutyrate].

PMID- 10643373
TI  - [Wine--good for the heart?].

PMID- 10643374
TI  - [Prioritization and the "triple"-test in prenatal diagnosis].

PMID- 10643375
TI  - [Gamma-hydroxybutyrate--an endogenous substance and a new central nervous system
      stimulant. Clinical aspects of acute poisoning].
AB  - During the last six months, the Poison Control Centre at Bispebjerg Hospital,
      Copenhagen, Denmark, has observed an increasing number of patients intoxicated
      with GHB, a drug of abuse. The patients are often admitted to the emergency ward
      shortly after having taken the drug, unconscious or comatose. If younger patients
      present with these symptoms, intoxication with GHB should be seriously
      considered. The effects are seen within 15 to 30 minutes after oral ingestion of
      the drug. Spontaneous recovery usually occurs within three to five hours. The
      most common effects are mild euphoria, sedation, vomiting, somnolence,
      bradycardia, aggressive behaviour, apnoea, respiratory depression, and coma.
      Normally the patient breathes adequately, but insufficient respiration may occur
      and deaths have been described. The drug is often consumed together with alcohol
      and other drugs of abuse, which strengthens the effect of GHB. Treatment is
      symptomatic. A review of the literature with special emphasis on clinical effects
      included toxicology and treatment is given.

PMID- 10643376
TI  - [Amphetamine, ecstasy and cocaine. Clinical aspects of acute poisoning].
AB  - Consumption of the illicit drugs amphetamine, ecstasy and cocaine is increasing
      in Denmark and Europe leading to an increasing number of intoxications with these
      drugs. Abroad, several deaths after ingestion of a few doses of the drugs have
      been reported. Amphetamine, ecstasy and cocaine increase the amount of dopamine,
      norephedrine and serotonine in the nervous system, resulting in CNS stimulation
      and a general sympathomimetic stimulation. Symptoms to be treated originate
      mainly from the CNS and the cardiovascular system, and present as tachycardia,
      hypertension and seizures, later hypotension and coma. Hyperpyrexia,
      rhabdomyolysis and affections of the kidneys, lung and liver function are also
      often seen. Hyperpyrexia is an important marker of poor prognosis, and must be
      handled aggressively. A review of the literature concerning the optimal treatment
      based on pharmacological and diagnostic considerations is given in the article.

PMID- 10643377
TI  - [The biological mechanisms underlying alcohol dependence].
AB  - Recent advances in neuroscience have enabled alcohol dependence to be
      investigated at cellular and molecular levels. Alcohol exerts biological effects
      by interacting with cell membranes and receptors, and modifies the function of
      proteins which regulate signal transduction, intracellular pathways, and gene
      expression. Adaptation to the acute effects of alcohol constitutes a major
      determinant of the development of increased tolerance, withdrawal syndrome and
      dependence. Important targets for alcohol include transmitter-regulated ion
      channels, receptors coupled to guanosine triphosphate-binding proteins, second
      messengers, and gene transcription factors. Studies of rodents bred for alcohol
      sensitivity or resistance have uncovered molecules of importance for the
      development of alcohol dependence, and certain ethanol-sensitive genes have been
      identified.

PMID- 10643378
TI  - [Fatal poisonings among drug addicts in the county of Funen in 1995 and 1996].
AB  - The aim of this investigation was to examine the deaths of drug addicts from
      poisoning in the county of Funen in 1995 and 1996. The cause of death was related
      to drugs on the illicit market. Social conditions (homelessness, involvement in
      crime, psychogenic disease, circumstance of death) are discussed. The study
      included 47 drug addicts. Median age was 34, age span: 20-43. The main cause of
      death was poisoning by heroin. In 28% of the drug addicts cocaine was detected
      and in 13% amphetamine. About half had used benzodiazepines. Few were employees,
      most were criminals and eight were homeless. Thirty-eight percent were found in
      public lavatories. Eight had a serious psychiatric diagnosis. We can conclude
      that the drug addicts are socially marginalized. They abused a mixture of drugs.
      The drugs detected in the drug addicts compared well with the drugs on the
      illicit market and cocaine had gained access to the market.

PMID- 10643379
TI  - [The connection between food and alcohol intake habits among 48.763 Danish men
      and women. A cross-sectional study in the project "Food, cancer and health"].
AB  - Variation in diet associated with drinking patterns may partly explain why wine
      seems to reduce ischaemic heart disease mortality. In a cross-sectional study
      conducted in Copenhagen and Aarhus from 1995 to 1997 including 23,284 men and
      25,479 women aged 50-64 years, the relation between intake of different alcoholic
      beverages and selected indicators of a healthy diet was investigated. In
      multivariate analyses, wine, as compared with other alcoholic drinks, was
      associated with a higher intake of fruit, fish, cooked vegetables, salad, the use
      of olive oil for cooking and not using fat spread on rye bread. In conclusion,
      the association between wine drinking and an intake of a healthy diet may have
      implications for the interpretation of previous reports of the relation between
      type of alcoholic beverage and ischaemic heart disease mortality.

PMID- 10643381
TI  - [Gamma-hydroxybutyrate, a new central nervous system stimulant].
AB  - In the last months we have seen an increasing number of younger patients admitted
      to the emergency room in a deep coma, mostly without cardio-pulmonary symptoms.
      After a few hours they suddenly woke up without any after-effects. Subsequently
      the patients related that they had taken an unknown drug for recreational
      purposes and afterwards fell asleep. The patients did not remember anything else
      about the episode. We believe they had taken gammahydroxybutyrate (GHB). This
      drug has not previously been described in Danish scientific reports.

PMID- 10643380
TI  - [Maternal serum screening for congenital abnormalities and Down syndrome in
      Sonderjylland County. Eight years of experience].
AB  - From January 1991 to December 1998 second-trimester maternal serum screening
      (Doubletest and Tripletest) for malformations and Down syndrome has been offered
      to pregnant women younger than 35 years of age living in Sonderjyllands county,
      Denmark. Follow-up of all cases of chromosome abnormalities and severe foetal
      malformations identified pre- or postnatally has been carried out. A total of
      17,023 women were screened. Sixty-eight percent (17/25) of Down Syndrome
      pregnancies were detected. Three percent of the screened women were offered an
      amniocentesis due to a calculated risk of DS greater than 1:400 at birth. The
      positive predictive value was 1:30. For the three-year period 1996-1998
      (Tripletest) the results were more promising: 91% (10/11) were detected, 3.9%
      were offered an amniocentesis, the positive predictive value was 1:21. In the
      eight-year period 80% (8/10) of the spina bifida cases were detected, all the
      cases (6/6) of anencephaly and 75% (6/8) of abdominal wall defects. One point six
      percent of the screened women were offered an amniocentesis due to high risk of a
      neural tube defect. The results confirm that second trimester maternal serum
      screening is a reliable method for determining the risk of severe foetal
      malformations and Down syndrome.

PMID- 10643382
TI  - [Fatal poisoning with Letigen].
AB  - The anorexic agent Letigen, which contains 200 mg coffeine and 20 mg ephedrine,
      has been extensively used during the last decade. The case report describes a 19
      year-old woman who ingested 50 Letigen tablets in a suicidal attempt. She
      developed severe toxic manifestations from the heart, CNS, muscles, liver and
      kidneys leading to several cardiac arrests, and died subsequently of cerebral
      oedema and incarceration on the fourth day of hospitalization. Because of the
      potentially life-threatening intoxication following an overdose, prescription of
      Letigen must be carefully administered.

PMID- 10643383
TI  - [Poisoning with gamma-hydroxybutyrate. Cases reported in connection with
      "cultural festivals" in August 1999 in Kolding].
AB  - Eight cases of poisoning with the relatively newly introduced synthetic drug
      gamma-hydroxybutyric acid (GHB) are reported. The abuse of GHB was in most cases
      mixed with alcohol intake but not any opiates. The condition of some of the
      victims was serious with bradycardia and depressed respiration. The antidote
      Naloxone appeared to have a beneficial effect on the combined intoxication with
      GHB and alcohol.

PMID- 10643384
TI  - [Has ecstasy neurotoxic effects in humans?].

PMID- 10643385
TI  - [Intramuscular steroid injection].

PMID- 10643386
TI  - [Diagnosis of osteoporosis].

PMID- 10643387
TI  - [Hypertension, obesity, ischemic heart disease].

PMID- 10643388
TI  - [Ramifentanyl--a new short-acting opioid used in anesthesia].

PMID- 10643389
TI  - [Lisfranc arthrodesis after malunited fracture healing].

PMID- 10643390
TI  - [Lisfranc arthrodesis after malunited fracture healing].
AB  - The causes of residual deformity with posttraumatic painful arthritis after
      tarsometatarsal (Lisfranc) fracture-dislocation with the need for correctional
      arthrodesis are in our experience (22 cases over 5 years) overseen injuries in
      one third, closed reduction and immobilisation or inadequate fixation technique
      with K-wires in another two thirds of cases. Foot malalignment and residual
      instability is assessed with weight-bearing radiographs of both feet,
      adduction/abduction stress films and CT scans for complex deformity. Correction
      is carried out via two longitudinal dorsal incisions, strict epiperiosteal
      preparation and debridement of the Lisfranc joint of all remaining cartilage,
      sclerosis and fibrous tissue. Reorientation begins, in the same manner as primary
      open reduction, with anatomical alignment of the second metatarsal base to the
      second cuneiform. Defects are filled with autologous bone grafting, stable fusion
      can be achieved with 3.5 mm cancellous compression screws. Full weight bearing is
      allowed in a modelled plaster shoe for 6 to 8 weeks. The functional medium-term
      results are convincing with 15 of 17 patients seen after 13 months of follow-up
      working full time. The Maryland Foot Score improved from 38.9 to 76.8 points in
      these patients.

PMID- 10643391
TI  - [Surgical treatment of injuries of the thoracolumbar transition. 1:
      Epidemiology].
AB  - The authors report on a prospective multicenter study with regard to the
      operative treatment of fractures and dislocations of the thoracolumbar spine. 18
      traumatologic centers in Germany and Austria, forming the working group "spine"
      of the German Society of Trauma Surgery, are participating in this continuing
      study. Between September 1994 and December 1996 682 patients (64% male) with an
      average age of 39 1/2 (7-83) years were entered. The entry criteria included all
      patients with acute and operatively treated (within 3 weeks after trauma)
      fractures and dislocations of the thoracolumbar spine (Th 10-L 2). Part 1 of this
      publication outlines the protocol and epidemiologic data. The incidence of
      fractures and dislocations of the thoracolumbar spine and associated injuries
      were recorded according to a standardized protocol, as well as the different
      operative methods and complications, duration of hospital stay, rehabilitation
      and incapacity. The analysis of the clinical social and radiological course was a
      second focus. The most frequent mechanism of injury was a fall (50%) or traffic
      accident (22%). Most of the fractures occurred at the L 1 level (49%). All
      injuries were classified according to the ASIF (AO) classification. 65% sustained
      an A-type fracture (compression fracture). Associated injuries were observed in
      35% and 6% were polytraumatized. Extremities and thorax were most frequently
      affected. Younger age and traffic accidents lead more often to C-type fracture
      (fracture dislocation) and polytrauma. An increased number of multisegmental or
      multilevel lesions were observed in polytraumatized patients. There were 16% with
      incomplete paraplegia (Frankel/ASIA B-D) and 5% with complete paraplegia
      (Frankel/ASIA A). The rate of patients with initial neurologic deficits
      significantly increased with the severity of spinal injury according to the
      Magerl classification. Until discharge a neurologic improvement (at least 1
      Frankel/ASIA grade) was observed in 32% of the partially paralyzed (Frankel/ASIA
      B-D) and in 12% of the patients with complete paraplegia (Frankel/ASIA A). A
      neurologic deterioration occurred in 3 patients (0.4%). As a base for further
      follow-up and late results the individual starting point was determined by
      collecting relevant data of the patients' history: 277 (40.6%) patients suffered
      from simultaneous diseases, one half was spine related. At the time of injury 559
      (82.0%) patients were employed; 429 (62.9%) doing manual work. 369 (54.1%)
      patients stated sportive activities before the injury and 561 (82.3%) designated
      their "back function" as normal. For the time before injury the patients scored
      an average of 93.4 points in the Hannover Spine Score (0-100 points concerning
      complaints and function of the back/spine).

PMID- 10643392
TI  - [CT determination of leg length and torsion in children and adolescents].
AB  - Because of different projections and axis constructions, the length and torsion
      of the lower extremities are sensitive to the measuring method. To judge
      pathological deformities in children or adolescents it is necessary to know the
      reference values. In this study, 78 children and adolescents 2-18 years old were
      included who had a femoral or tibial shaft fracture. Torsion and length were
      determined by computed tomography at least 3 months after internal fixation
      according the Ulm method. Only healthy bones were considered for this study. The
      mean internal torsion of the femur decreased during the growth period from 34.2
      degrees +/- 10.3 degrees (x +/- SD) to 19.3 degrees +/- 9.5 degrees. There was
      only a weak correlation between the age and torsion of the femur. The mean
      external torsion of the tibia was 32.3 +/- 10 degrees. The 95th percentiles of
      the intraindividual torsional differences were 14 degrees (x = 4.1 degrees) of
      the femur (n = 30) and 12 degrees (x = 4.7 degrees) of the tibia (n = 48). The
      median femoral and tibial intraindividual length differences were 2 mm. The
      corresponding 95th percentiles were 10 and 9 mm. The aim of the study was to
      determine the age-dependent torsion and length and their respective differences
      with a standardized CT method. The range of the normal values was much greater
      than published in the literature.

PMID- 10643393
TI  - [Value of MRI in traumatic disco-ligament instability of the lower cervical
      spine].
AB  - The diagnostic accuracy of magnetic resonance imaging (MRI) for traumatic
      discoligamentous instabilities of the lower cervical spine was evaluated. MRI
      findings were correlated with the intraoperative findings. Fifteen patients were
      included in the study (11 males, 4 females, 33 years old on average). Indication
      for surgery was established with dynamic a.p. instability under fluoroscopy. In
      the operation, all patients showed complete traumatic rupture of the
      intervertebral disc. In contrast, MRI sequences revealed only eight mild and four
      severe disc lesions. Intraoperatively ruptures of the anterior and posterior
      longitudinal ligaments were verified in 7 patients each. MRI studies depicted
      only five ruptures of the anterior and three ruptures of the posterior
      longitudinal ligaments. In three cases MRI demonstrated no pathological findings
      (3 of 15 false-negative results). MRI and intraoperative findings showed no
      statistical correlation. MRI is of only limited value in diagnosing traumatic
      discoligamentous instabilities of the lower cervical spine.

PMID- 10643394
TI  - [Significance of concomitant injuries in malleolar fractures. A prospective
      study].
AB  - The objective of this prospective study was to determine clinical and
      radiological results 2 years after ankle fractures and to compare them with
      preoperative arthroscopic findings. Of 135 consecutive patients undergoing
      osteosynthetic treatment, 128 (type A, 2; type B, 97; type C, 29) were reviewed 2
      years later. The Kitaokascore for functional and clinical rating and the
      Kannusscore for radiological rating were used. Initial cartilaginous lesions
      localized on the medial malleolus led to poor clinical ratings (P < 0.01) and
      cartilaginous lesions of the pilon tibiale and talus caused poor radiological
      results (P < 0.032 and P < 0.046). After rupture of the deltoid ligament, more
      pain was observed (P < 0.038). Rupture of the syndesmosis, however, did not
      affect the outcome. Clinical outcome was poor among the 30- to 65-year-old
      patients. The clinical and radiological outcome of women was poorer (P < 0.018
      and P < 0.046) than for men. The older the patients, the more radiological signs
      of arthritis were found. The outcome of ankle fracture seems to correlate
      significantly with the nature, dimension and localization of fracture-associated
      cartilaginous and ligament lesions. Age and sex also seem to play a significant
      role in the outcome.

PMID- 10643395
TI  - [Antibiotic prophylaxis and therapy in trauma surgery].

PMID- 10643396
TI  - [Bacterial coxitis caused by Salmonella enteritidis. Case report and differential
      diagnostic considerations].
AB  - Secondary haematogenous joint involvement is seen in less than 1% of patients
      with Salmonella infections. These atypical infections are frequently encouraged
      by pre-existing local or systemic disease. We present a case of a patient with
      known alcohol abuse who developed a septic infection of her right hip requiring
      resection of the femoral head. Histologic analysis showed signs of pre-existing
      osteonecrosis probably induced by alcohol intake. Cartilage and bone were invaded
      and destructed by an aggressive granulation tissue. Initially, a biopsy evaluated
      without knowledge of the positive bacteriological result had been interpreted as
      indicative of a tumour. The onset, clinical course, diagnosis and therapy of
      joint involvement by Salmonella are discussed with regard to our case and the
      relevant literature. This case illustrates the necessity for clinicians to share
      all their information about the patient with the pathologist.

PMID- 10643397
TI  - [Spontaneous healing of a juvenile bone cyst of the tibia after pathological
      fracture].
AB  - Up to the present only few cases of spontaneous healing of juvenile bone cysts
      after pathological fractures were published. Most authors will not accept the
      possibility of a "healing fracture" in bone cysts because of missing
      documentation. In our clinic we could observe spontaneous healing of a juvenile
      bone cyst of the tibia after a pathological fracture in a ten-year old boy.
      Therefore healing of bone cysts after fracture is proven. On the other hand
      healing of bone cysts following conservative treatment after a fracture is not
      sure. Conservative treatment depends on the localization and type of the
      fracture. We recommend nonoperative treatment of first pathological fractures in
      small-sized bone cysts. This kind of treatment can be especially advised for
      young patients up to the tenth year because there are only few complications in
      fracture healing and a relatively high recurrence rate following operative
      treatment. In case of a refracture there are better conditions for fracture
      healing after surgery.

PMID- 10643398
TI  - [A simple and rapid method for removal of broken unreamed tibial nails].
AB  - By using UTN in the treatment of very distal tibia fractures delayed fracture
      healing and pseudarthrosis with breakage of the nail are described. The removal
      of the distal solid part of the nail shows a special difficulty. We report about
      two cases of broken UTN in 1997. A simple extraction device to remove the distal
      part of the broken nail is demonstrated.

PMID- 10643399
TI  - [Comment on S. Arndt, L. Besch, D. Havemann: Internal knee damage in children].

PMID- 10643400
TI  - [Where is the truth? Logic and suggestions in publications].

PMID- 10643401
TI  - [Prevention of thrombosis by controlled foot and ankle movement?].

PMID- 10643402
TI  - [Preamble of the "Future Orthopedics, Trauma Surgery and Surgery" Committee.
      Modified by the ad hoc committee of DGOT/BVO 30 January 1999 and representatives
      of trauma surgery 26 June 1999].

PMID- 10643403
TI  - Biomechanical analysis of materials handling manipulators in short distance
      transfers of moderate mass objects: joint strength, spine forces and muscular
      antagonism.
AB  - Although often suggested as a control measure to alleviate musculoskeletal
      stresses, the use of mechanical assistance devices (i.e. manipulators) in load
      transfers has not been extensively studied. Without data describing the
      biomechanical effects of such devices, justification for decisions regarding
      implementation of such tools is difficult. An experimental study of two types of
      mechanical manipulators (articulated arm and overhead hoist) was conducted to
      determine whether biomechanical stresses, and hence injury risk, would be
      alleviated. Short distance transfers of loads with moderate mass were performed
      both manually and with manipulator assistance under a variety of task conditions.
      Using analysis and output from new dynamic torso models, strength demands at the
      shoulders and low back, lumbar spine forces, and lumbar muscle antagonism were
      determined. Strength requirements decreased significantly at both the shoulders
      and low back when using either manipulator in comparison with similar transfers
      performed manually. Peak spine compression and anterior-posterior (a-p) shear
      forces were reduced by about 40% on average, and these reductions were shown to
      be primarily caused by decreases in hand forces and resultant spinal moments. Two
      metrics of muscular antagonism were defined, and analysis showed that torso
      muscle antagonism was largest overall when using the hoist. The results overall
      suggest that hoist-assisted transfers, although better in reducing spine
      compression forces, may impose relatively higher demands on coordination and/or
      stability at extreme heights or with torso twisting motions. The relatively
      higher strength requirements and spine compression associated with the
      articulated arm may be a result of the high inertia of the system. Potential
      benefits of practice and training are discussed, and conclusions regarding
      implementation of mechanical manipulators are given.

PMID- 10643404
TI  - Predicting slips and falls considering required and available friction.
AB  - This study investigated the relationship among measurements of friction, the
      biomechanics of gait, and actual slip and fall events. The goal was to develop a
      method for estimating the probability of slips and falls based on measurements of
      available friction and required friction. Five subjects wearing safety harnesses
      walked down a ramp at various angles with either a tile or carpeted surface under
      dry, wet or soapy conditions. Ramp angles of 0 degree, 10 degrees and 20 degrees
      were used to vary the shear and normal foot force requirements. The dynamic
      coefficient of friction (DCOF) of shoe, floor surface and contaminant interfaces
      was measured. Required friction was assessed by examining the foot forces during
      walking trials when no slips occurred. Slips with recoveries and slips resulting
      in falls were recorded and categorized using a force plate and high-speed video
      camera. These data were then incorporated into a logistic regression to model the
      probability of a slip or fall event occurring based on the difference between the
      COF required by the foot forces generated and the measured DCOF. The results
      showed that the number of slip and fall events increased as the difference
      between the required COF and the measured DCOF increased. The logistic regression
      model fit the data well, resulting in an estimate of the probability of a slip or
      fall event based on the difference between the measured and required friction.
      This type of model could be used in the future to evaluate slip resistance
      measurement devices under various environments and assist in the design of safer
      work environments.

PMID- 10643405
TI  - A comparison of forearm and thumb muscle electromyographic responses to the use
      of laparoscopic instruments with either a finger grasp or a palm grasp.
AB  - Laparoscopic techniques allow for less-invasive treatment of common surgical
      problems. Laparoscopic instruments are different from standard surgical
      instruments and generally incorporate a pistol-grip handle configuration with
      rings for the fingers. This handle configuration has been reported as being
      uncomfortable, leading to finger compression neuropathies in some cases. As an
      alternative, the surgeon can choose to grasp laparoscopic instruments using a
      more powerful palm grip during grasping motions. This study evaluates the
      hypothesis that the use of the palm grip requires less muscle tension than the
      finger-grip when grasping with laparoscopic instruments. Nine general surgeons
      used an Autosuture laparoscopic grasper with a ringed pistol-grip handle held in
      both a finger-in-ring (F) or palm (P) hand grip position to grasp and close two
      spring-loaded metal plates. The same task was performed with a surgical haemostat
      clamp (H) for comparison. Each subject performed the grasping task in a random
      sequence for the three instrument configurations at two grasping forces levels
      (0.7 and 4.2 N), and with the instrument at three angles to the subjects'
      sagittal plane (0 degree, 45 degrees and 90 degrees). Surface electromyographic
      (EMG) signals were acquired from the flexor carpi ulnaris (FCU), flexor digitorum
      profundus (FDP), flexor digitorum superficialis (FDS), extensor carpi ulnaris
      (ECU), extensor digitorum comunis (EDC) and the thenar compartment (TH). The peak
      root mean squared (RMS) EMG voltage was averaged for five repetitions at each
      instrument, force and angle condition. Statistical analysis was carried out by
      repeated measures ANOVA. The muscle EMG RMS amplitude while using the palm grip
      was decreased in the FDS, TH and EDC, was unchanged in the ECU and FCU, and was
      slightly higher in the FDP when compared with the finger grip. These differences
      were most prominent at 90 degrees to the sagittal plane where the subjects'
      wrists neared maximal flexion. It is concluded that the palm grip is more
      powerful than the finger grip when grasping with laparoscopic instruments,
      particularly at angles perpendicular to the surgeon's sagittal plane.

PMID- 10643406
TI  - Motion sickness in public road transport: the effect of driver, route and
      vehicle.
AB  - Relationships between vehicle motion and passenger sickness have been
      investigated in a survey of 3256 passengers travelling on 56 mainland UK bus or
      coach journeys. Vehicle motion was measured throughout all journeys, yielding
      over 110 h of six-axis coach motion data from five types of coach and 17
      different drivers. Overall, 28.4% of passengers reported feelings of illness,
      12.8% reported nausea and 1.7% reported vomiting during coach travel. Passenger
      nausea and illness ratings increased with increased exposure to lateral coach
      motion at low frequencies (< 0.5 Hz). Motion in other axes correlated less well
      with sickness, although there were some intercorrelations between the motions in
      the different axes. Sickness levels among passengers were greater with drivers
      who drove to produce higher average magnitudes of fore-and-aft and lateral
      vehicle motion. Nausea occurrence was greater on routes classified as being
      predominantly cross-country where magnitudes of lateral vehicle motion were
      significantly higher. Lateral motion and motion sickness increased from the front
      to the rear of each vehicle. No significant differences in sickness were found
      between the five different vehicle types used in the study. The applicability of
      a motion sickness dose model to these data is discussed.

PMID- 10643407
TI  - Mental strain and the problem of repeated measurements.
AB  - In the past, stress and strain arising from the execution of mentally demanding
      tasks have been measured by means of surveys. Such methods require repeated
      investigation of the individual perceptions and valuations during task fulfilment
      to record time-dependent changes in strain levels. However, it is possible that
      the individual measurement procedures employed in surveys--as artefacts--may
      cause a change in the stress situation and subsequently in the resulting mental
      strain. The results of the experiments carried out to investigate this hypothesis
      verify that repeated measurements have a similar effect as a short break. The
      repeated measurements taken during progressive studies are, therefore, likely to
      affect the conditions of stress. A change in the level of mental strain recorded
      can be expected, particularly if the post-test rating is preceded by a long
      period of low stress before or during which an additional measurement of strain
      is implemented.

PMID- 10643408
TI  - Lapicque's introduction of the integrate-and-fire model neuron (1907).

PMID- 10643409
TI  - The view from inside.

PMID- 10643410
TI  - Overton on the indispensability of sodium ions.

PMID- 10643411
TI  - Sodium channels: from mechanisms to medicines?

PMID- 10643412
TI  - Intracellular traffic in nerve cells.

PMID- 10643413
TI  - Recycling of synaptic vesicle membrane within nerve terminals.

PMID- 10643414
TI  - Slow potentials in the brain: still little understood but gradually getting
      analytical attention.

PMID- 10643415
TI  - Retinal processing of visual information.

PMID- 10643417
TI  - Perception as probability.

PMID- 10643416
TI  - Bridging sensory signals in the monkey and percepts in the human mind.

PMID- 10643418
TI  - Descending control of forelimb movements in the cat.

PMID- 10643419
TI  - The significance of supraspinal control of reflex actions.

PMID- 10643420
TI  - On advances in studies of the properties of various types of neurones and their
      functional roles.

PMID- 10643421
TI  - Noise analysis at the neuromuscular junction.

PMID- 10643422
TI  - The cerebellum, a gateway to modern neuroscience.

PMID- 10643423
TI  - Arrest of firing of aminergic neurones during REM sleep: implications for dream
      theory.

PMID- 10643424
TI  - Publication of the Computer and the Brain, by John von Neumann, 1958.

PMID- 10643425
TI  - Probing consciousness with an electrode.

PMID- 10643426
TI  - How does conscious experience arise? The neural time factor.

PMID- 10643427
TI  - Specificity and diversity of cerebral transport systems: what we learned from
      brain slice preparations.

PMID- 10643428
TI  - Nerve cells in culture: the extraordinary discovery by Ross Granville Harrison.

PMID- 10643429
TI  - Discovery of nonerythroid spectrin to the demonstration of its key role in
      synaptic transmission.

PMID- 10643430
TI  - Otto Loewi and the demonstration of chemical neurotransmission.

PMID- 10643431
TI  - Dale's principle.

PMID- 10643432
TI  - Extrasynaptic receptors and parasynaptic communication in the brain.

PMID- 10643434
TI  - Purinergic cotransmission.

PMID- 10643433
TI  - Glutamate: an excitatory neurotransmitter in the mammalian CNS.

PMID- 10643435
TI  - The discovery of endogenous cannabinoids.

PMID- 10643436
TI  - Multiple direct actions of peptides on the CNS.

PMID- 10643437
TI  - Birth of neuropsychopharmacology--impact on brain research.

PMID- 10643438
TI  - The autonomic nervous system and the histochemical fluorescence method for the
      microscopical localization of catecholamines and serotonin.

PMID- 10643439
TI  - The mapping of the central aminergic pathways.

PMID- 10643440
TI  - Neurobiology thanks to microbiology: the legacy of Albert H. Coons (1912-1978).

PMID- 10643441
TI  - Mary Bernheim and the discovery of monoamine oxidase.

PMID- 10643442
TI  - The discovery of dopamine's physiological importance.

PMID- 10643443
TI  - The first miracle in neurodegenerative disease: the discovery of oral levodopa.

PMID- 10643444
TI  - The discovery of monoamine transporters and their role in CNS drug discovery.

PMID- 10643445
TI  - Tyrosine hydroxylase from cloning to neuropsychiatric disorders.

PMID- 10643446
TI  - The discovery of axonal transport.

PMID- 10643447
TI  - The intracellular HRP technique.

PMID- 10643448
TI  - Visualization of the entire trajectory of long axons of single mammalian CNS
      neurons.

PMID- 10643449
TI  - Integration of brain activities: the roles of the diffusely projecting brainstem
      systems and the corpus callosum.

PMID- 10643450
TI  - Brainstem activation of thalamocortical systems.

PMID- 10643451
TI  - The visual display of neuronal structure.

PMID- 10643452
TI  - From Cajal's chemotaxis to the molecular biology of axon guidance.

PMID- 10643453
TI  - The neuroanatomy revolution of the 1970s and the hypothalamus.

PMID- 10643454
TI  - The third quarter of the twentieth century; the golden age of the silver methods.

PMID- 10643455
TI  - Tracing pathways in CNS regeneration research.

PMID- 10643456
TI  - Functional axonal regeneration following spinal cord injury.

PMID- 10643458
TI  - The twentieth century belongs to neuropsychology.

PMID- 10643457
TI  - Sokoloff's 14C-deoxyglucose method.

PMID- 10643459
TI  - The laboratory rat, the Pied Piper of twentieth century neuroscience.

PMID- 10643460
TI  - Localizing cognitive operations.

PMID- 10643461
TI  - Circulation and metabolism of the human brain.

PMID- 10643462
TI  - In vivo biochemistry of the brain in understanding human cognition and emotions:
      towards a molecular psychology.

PMID- 10643463
TI  - The discovery and rediscovery of the role of the corpus callosum.

PMID- 10643464
TI  - The Poffenberger paradigm: a first, simple, behavioural tool to study
      interhemispheric transmission in humans.

PMID- 10643465
TI  - Two brains, one person.

PMID- 10643466
TI  - The transformation of association cortex into sensory cortex.

PMID- 10643467
TI  - Kao-Liang Chow and the visual functions of the temporal lobe.

PMID- 10643468
TI  - Ivan Divac and the neostriatum as a cognitive structure.

PMID- 10643469
TI  - Rate processing constraints may underlie developmental language impairments and
      also hemispheric specialization for speech.

PMID- 10643470
TI  - Ivan Petrovich Pavlov and the conditioned reflex.

PMID- 10643471
TI  - Neurophysiology of habituation and internal inhibition (discoveries made by
      Hernandez-Peon in the 1950s).

PMID- 10643472
TI  - D.O. Hebb: The Organization of Behavior, Wiley: New York; 1949.

PMID- 10643473
TI  - What invertebrate circuits have taught us about the brain.

PMID- 10643475
TI  - Holger Hyden and the biochemistry of memory.

PMID- 10643474
TI  - cAMP and memory: a seminal lesson from Drosophila and Aplysia.

PMID- 10643476
TI  - The perseveration-consolidation hypothesis: Mueller and Pilzecker, 1900.

PMID- 10643477
TI  - Mapping recognition memory in the primate brain: why it's sometimes right to be
      wrong.

PMID- 10643478
TI  - MacCurdy and memories: the origins of implicit processing and covert awareness.

PMID- 10643479
TI  - The Physiology of Motivation by Eliot Stellar.

PMID- 10643480
TI  - Neurochemistry of thermoregulation: two negatives make a positive.

PMID- 10643481
TI  - Angiotensin-induced drinking: a model of peptidergic control of behaviour.

PMID- 10643482
TI  - Towards a new descriptive psychopathology: a sine qua non for neurobiological
      research in psychiatry.

PMID- 10643483
TI  - Leao's spreading depression of EEG activity.

PMID- 10643484
TI  - The discovery of the poliovirus.

PMID- 10643485
TI  - The pathological anatomy of the lesion in multiple sclerosis.

PMID- 10643486
TI  - alpha-Synuclein and Parkinson's disease.

PMID- 10643487
TI  - Glutamine repeats and neurodegenerative diseases.

PMID- 10643488
TI  - Tau protein and the paired helical filament of Alzheimer's disease.

PMID- 10643489
TI  - Mutations in the Tau gene cause frontotemporal dementia.

PMID- 10643490
TI  - The unravelling of the code of nerve growth: a modern Saga of the dedication to
      science.

PMID- 10643491
TI  - Continuous high frequency stimulation of deep brain structures in brain
      pathology.

PMID- 10643492
TI  - Transplanted precursors of nerve cells: Das and Altman and the revival of neural
      transplantation research.

PMID- 10643493
TI  - Clinically significant therapeutic interactions for the practicing dermatologist.

PMID- 10643494
TI  - Acne therapy.

PMID- 10643495
TI  - Update on contact dermatitis.

PMID- 10643496
TI  - Advances in hair transplantation.

PMID- 10643497
TI  - Unwanted hair: evaluation and treatment with lasers and light source technology.

PMID- 10643498
TI  - Selected clinical applications of lasers.

PMID- 10643499
TI  - The role of human herpesvirus 8 in the pathogenesis of Kaposi's sarcoma.
AB  - Human herpesvirus 8 is a novel gamma-herpesvirus that has been linked with all
      clinical types of KS through both DNA and serologic studies. By electron
      microscopic, in situ hybridization, and in situ PCR studies, virus is found in
      tumor spindle cells, in normal-appearing endothelial cells within lesions, and in
      tumor-infiltrating leukocytes. The fact that most tumor cells are latently, as
      opposed to lytically, infected with HHV8 makes the possibility of treating KS
      patients with antiherpesviral medications unlikely. Human herpesvirus 8 infection
      is also associated with BCBL and CD and has recently been reported in patients
      with multiple myeloma and sarcoidosis (although these latter associations have
      not been substantiated). Interestingly, the HHV8 genome contains many genes that
      could be involved in evading normal immune surveillance. Importantly, B-cell
      lines derived from patients with BCBL have been extremely useful in elucidating
      the virologic and biological properties of HHV8. In summary, both HHV8 gene
      analyses and clinico-epidemiologic studies generated by many research teams
      throughout the world support the concept that HHV8 is the etiologic agent of KS.
      Future research will focus on developing in vitro model systems to study KS,
      delineating the expression pattern and function of HHV8-encoded proteins in vivo,
      determining factors that lead to the development of KS in HHV8-infected
      individuals, and devising novel therapeutic strategies for KS based on these
      advances in basic science.

PMID- 10643500
TI  - Epidermal Langerhans cells: from neurons to nature's adjuvants.
AB  - Once obscure cells of interest to only a few dermatologists, LCs have become
      perhaps the best studied of all the nonlymphoid DCs. Seminal studies carried out
      by Steinman and co-workers over a number of years have demonstrated that
      interdigitating DCs are required for the priming of naive T cells in vivo and
      that LCs (and presumably other DCs) are precursors of interdigitating DCs. These
      observations have sparked an explosion of research activity directed toward
      increasing our understanding of the biology of LCs and other DCs and exploiting
      their unique functional properties for the prevention and treatment of disease.
      This chapter represents an attempt to provide an introduction to this exciting
      field. We have briefly reviewed the history of LC research, summarized a number
      of important concepts in LC/DC biology, and highlighted the involvement of LCs in
      several diseases or pathophysiologic conditions. We have emphasized recent
      studies of DC-based immunotherapy and the roles that LCs/DCs play in genetic
      vaccination because we believe that LC/DC research will have an impact on patient
      care in these areas. The past few years have been a period of rapid progress in
      basic research in LC/DC biology, and many important discoveries have been made.
      We hope that the next decade will be a period in which applied LC/DC research is
      just as exciting.

PMID- 10643501
TI  - Acquired and inherited basal cell carcinomas and the patched gene.

PMID- 10643502
TI  - Cutaneous malignant epithelioid neoplasms.
AB  - In summary, cutaneous malignancies with an epithelioid appearance form a diverse
      group of neoplasms that may be difficult to diagnose by utilizing routine
      microscopy alone. Cutaneous malignancies, including malignant melanoma and
      metastatic carcinoma, certain benign neoplasms such as mixed tumor of the skin
      and angiolymphoid hyperplasia with eosinophils (epithelioid hemangioma), and
      infectious conditions such as bacillary (epithelioid) angiomatosis can be
      considered in this differential. However, through recognition of the
      characteristic histologic, immunocytochemical, and ultrastructural findings
      outlined above, definitive diagnosis of these challenging neoplasms is usually
      possible.

PMID- 10643503
TI  - Benign epidermal proliferations.

PMID- 10643504
TI  - Immunomicroscopy in diagnostic dermatopathology: an update on cutaneous
      neoplasms.

PMID- 10643505
TI  - Drug eruptions in children.

PMID- 10643506
TI  - Child abuse and mimickers of child abuse.

PMID- 10643507
TI  - Embryo development, pregnancy and twin delivery after microinjection of 'stump'
      spermatozoa.
AB  - Intracytoplasmic sperm injection was performed with immotile spermatozoa affected
      by tail 'stump' defect, and resulted in normal fertilization, embryo transfer and
      pregnancy in a 35-year-old female. The husband had a consanguineous ancestry. Two
      healthy babies, a male and a female, were born and this confirms that male
      infertility due to certain genetic sperm defects can be overcome by the
      intracytoplasmic sperm injection-assisted reproduction technique. The likely
      genetic origin of this sperm defect and the probability of the male offspring
      inheriting this sperm defect should be considered. The fertilization ability of
      stump spermatozoa, microinjected into the oocyte, is explained on the basis of
      experience from our previous research.

PMID- 10643508
TI  - Association of a novel human mtDNA ATPase6 mutation with immature sperm cells.
AB  - This study reports the first clearly defined heteroplasmic mutation in immature
      human sperm cells. The human sperm mitochondrial genome from residue 8186-9341
      was analysed with the aim of identifying point mutations which may be associated
      with human male infertility. The semen samples analysed were obtained from 88
      fertile men, 19 with oligozoospermia, and 12 with severe oligozoospermia. Using
      single strand conformation polymorphism analysis a heteroplasmic T to C
      transition was detected in the ATPase6 gene, at nucleotide position 8821, in
      semen samples from one out of 12 (8%) severely oligozoospermic men, but not in
      oligozoospermic men or normospermic men. This mutation changed the amino acid
      serine to proline at residue 99 of the mitochondrial ATPase6 in a region which is
      highly conserved in other vertebrates including rat, bovine, chicken, salmonids
      and Xenopus. The mutation was detected in semen samples collected from the same
      man 9 months apart and in peripheral blood lymphocytes. Single sperm cell
      analyses did not find this mutation in the mature sperm, but the mutation was
      detected in 7% of immature spermatids. Our finding suggests that immature
      spermatids with this mutation fail to develop fully.

PMID- 10643509
TI  - Significance of simultaneous determination of serum and seminal plasma alpha
      tocopherol and retinol in infertile men by high-performance liquid
      chromatography.
AB  - High-performance liquid chromatography was used for the simultaneous
      determination of alpha-tocopherol and retinol in serum and semen of 40 subfertile
      men. The serum levels of the two vitamins were significantly higher in serum than
      in semen (3- to 10-fold) (P < 0.001). The mean alpha-tocopherol levels were
      higher in the serum and semen of men with normal sperm parameters (20 +/- 5 and 5
      +/- 4 mumol L-1) than those with oligozoospermia (10 +/- 4 and 3 +/- 2 mumol L
      1), azoospermia (8 +/- 3 and 3 +/- 1 mumol L-1) and asthenozoospermia (9 +/- 6
      and 3 +/- 2 mumol L-1) (P < 0.002). Mean retinol levels in serum were similar in
      men with normal sperm parameters (2.4 +/- 2 mumol L-1) as in those with defective
      sperm parameters such as oligozoospermia (2.5 +/- 2 mumol L-) and
      asthenozoospermia (2.1 +/- 1.0 mumol L-) (P = 0.15), but significantly lower in
      men with azoospermia (1.3 +/- 0.3 mumol L-1) (P < 0.05). The alpha
      tocopherol:retinol ratio was significantly higher in semen than in serum of men
      with normal sperm parameters (11.5) and those with asthenozoospermia (10.3)
      compared with ratios in those with oligozoospermia (8.3) and azoospermia (6.3).
      This may be related to reduced antioxidant activity in sperm dysfunction as a
      result of lipid peroxidation, from increased generation of reactive oxygen
      species.

PMID- 10643510
TI  - Gossypol-induced inhibition of plasminogen activator activity in human and ovine
      acrosomal extract.
AB  - The effect of gossypol--a polycyclic compound isolated from cotton seeds--on the
      plasminogen activator activity of man and ram acrosomal extracts was explored in
      vitro. The action of gossypol on the plasminogen activator activity was
      investigated by a spectrophotometric method using the chromogenic substrate S
      2251. Gossypol, a known antispermatogenic agent, was found to effectively inhibit
      human and ovine acrosomal plasminogen activator activity. The inhibition was dose
      dependent. Plasminogen activator activity from man and ram extracts was
      completely inhibited by 350 mumol l-1 and 300 mumol l-1 of gossypol,
      respectively. In additional experiments, low, non-spermicidal concentrations of
      gossypol (2.5-40 mumol l-1) were found to significantly inhibit plasmin activity
      in a dose-dependent manner. The results suggest that inhibition of both acrosomal
      plasminogen activator and plasmin activity is a possible mechanism by which
      gossypol exerts its antifertility effect, since the plasminogen activator/plasmin
      system plays a role in the whole process of ovum fertilization.

PMID- 10643511
TI  - Normal sperm morphology and chromatin packaging: comparison between aniline blue
      and chromomycin A3 staining.
AB  - The successful implementation of ICSI has provided a unique means of allowing
      couples suffering from severe male infertility to achieve their reproductive
      goals. However, despite the great therapeutic advantages of the technique, ICSI
      often provides solutions to clinicians in the absence of an aetiological or
      pathophysiological diagnosis. The development of a sequential diagnostic schedule
      for patients consulting for fertility disturbances would be an ideal method of
      approach. Since sperm morphology recorded by strict criteria has often been
      correlated with fertilization failure, the present study aimed to evaluate the
      relationship between normal morphology and chromatin staining among fertile and
      subfertile men. Both chromomycin A3 (CMA3) and acidic aniline blue (AAB) were
      employed to record chromatin packaging quality among 58 men visiting the
      andrology laboratory. Intra- and interassay variations were initially recorded
      for fertile sperm donors. The coefficients of variation (CV) for all intra- and
      inter-assay assessments were < 12%. Chromatin packaging was significantly and
      negatively correlated with normal sperm morphology, namely r = 0.40 (P = 0.001)
      and r = 0.33 (P = 0.001) for CMA3 and AAB, respectively. Receiver operator
      characteristics illustrated sensitivity and specificity values of 75% and 82% for
      CMA3 and 60% and 91% for AAB, respectively. Significantly different CMA3 and AAB
      staining was recorded among men with severe teratozoospermia (< 4% normal forms)
      when compared with normozoospermic men (> 14% normal forms), namely 49% vs. 29%
      for CMA3 and 51% vs. 26% for AAB staining, respectively. Chromatin packaging
      assessments should be a valuable addition to the sequential diagnostic programme
      in an assisted reproduction arena.

PMID- 10643512
TI  - Penile skin diseases.
AB  - Many dermatoses become manifest in the genital region. Some of them are specific
      for this anatomical site; other lesions of the penis are associated with systemic
      dermatological diseases. Medical history, clinical inspection of the whole
      integument and optional microbiological or histological examination of the
      lesions will lead to a correct diagnosis. Dermatoses of the penis (glans penis
      and/or prepuce) may be symptoms of general diseases or specific alterations of
      the genital region. The differential diagnoses of penile dermatoses include
      infections, balanitides, neoplastic diseases, trauma, papulosqamous or systemic
      diseases, fixed drug reactions, allergic or irritant contact dermatitis and
      miscellaneous lesions. Since andrologists pay special attention to the inspection
      and palpation of the male genital region, they should possess knowledge of
      dermatologically relevant penile lesions.

PMID- 10643513
TI  - Mycotic infections of the penis.
AB  - Balanitis/balanoposthitis caused by Candida albicans is the most frequent mycotic
      infection of the penis. Its incidence is increasing and it seems to be primarily
      transmitted by sexual intercourse. Although the groin is a common site for tinea,
      dermatophytic infections of the penis are rare. Penile involvement in systemic
      mycosis is usually a sign of severe disease. In immunocompromised individuals,
      nearly every fungal agent may cause the disease. It normally presents as
      ulceration, and biopsy and culture can help to confirm the diagnosis. In most
      cases, superficial infections of the penis respond satisfactorily to local
      antifungal treatment, especially if provovatice factors and the possibility of
      sexual transmission are considered. Systemic treatment is recommended in cases of
      widespread dermatophytic infection, candidosis or systemic mycosis.

PMID- 10643514
TI  - Squamous cell carcinoma of the penis.
AB  - Squamous cell carcinoma of the penis is a rare disease in Western countries. In
      geographical locations where infantile circumcision is not routinely practised
      and genital hygiene is poor, penile cancer may comprise 10-20% of all
      malignancies. Superficial tumours (Ta-Tl) should be treated with organ-preserving
      therapy. Partial of total penectomy is recommended for invasive penile carcinoma
      (stage T2 or higher). Currently, management of the ilioinguinal lymph nodes is
      controversial. The value of radiation therapy and chemotherapy is still
      uncertain; these treatments are only palliative therapy modalities.

PMID- 10643515
TI  - Outcome after repair of congenital penile malformations.
AB  - Penile malformations seen and treated during childhood may result in voiding
      disorders and sexual malfunction in adults. Preputial synechia and phimosis will
      seldom be the reason for these problems, although some men do seek treatment to
      correct radical circumcision. Little is known about the satisfaction of men with
      neonatal or childhood circumcision. Congenital penile curvature is seen in 0.4
      0.6% of men. Slight bends do not need any operative treatment and young men
      should be given advice and counselling accordingly. If treatment is needed, a
      standard Nesbit procedure or one of its modifications is used in order to avoid
      urethral manipulation. A hypospadiac position of the urethral meatus together
      with a more or less prominent ventral bending of the penis is seen in another 0.3
      0.5% of boys. Reports on more than 200 operations to correct this deformity have
      been published. Between 5 and 25% of early complications such as fistula
      formation, stenosis of the neourethra and skin problems result from hypospadias
      repair. Long-term follow-up studies have shown that adulthood satisfaction with
      respect to voiding and sexual function is achieved in 2/3 and some degree of
      dissatisfaction in 1/3 of cases. Epispadias repair is a much more complicated
      procedure and long-term results are seldom reported. Nevertheless, quite good
      results with respect to continence (approximately 80%) and sexual function may be
      achieved.

PMID- 10643516
TI  - Micropenis and apparent micropenis--a diagnostic and therapeutic challenge.
AB  - Micropenis should be diagnosed shortly after birth and differentiated from
      associated deformities and syndromes. Calling in a paediatric endocrinologist and
      a geneticist is obligatory. Endocrine treatment should be undertaken in the
      second and third months (25 mg testosterone enanthate per month) after a positive
      HCG test. Where there is a negative endocrine response and/or associated sex
      differentiation derangement, a sex change operation towards female should be
      discussed with the family at an early stage. Where male determination is already
      established and the androgen response is poor or absent, the indication is for
      plastic surgery to elongate the phallus using the Hinman or Johnston technique,
      performed by an experienced paediatric urologist.

PMID- 10643517
TI  - New aspects in Peyronie's disease--a mini-review.
AB  - There have been several advances in elucidation of the pathogenesis of Peyronie's
      disease. Transforming growth factor beta 1 seems to play a major role in this
      disease, while the importance of penile trauma is a matter of debate. High
      resolution ultrasound sonography is the method of choice in detecting penile
      plaques, while magnetic resonance imaging is useful in the evaluation of actively
      inflamed plaques. There are still differences of opinion on the best drug therapy
      in noncalcified plaques. The results on tamoxifen or interferon therapy vary
      between useless and useful. Potassium-para-aminobenzoate seems to have a
      significant effect in decreasing plaque size and deviation angle. The operative
      strategy for big plaques or complex deviation has changed to the 'small incision'
      graft, leading to far lower post-operative impotence rates. Iontophoresis seems
      to be worthy of further trials, while the results of extracorporal shock wave
      therapy have to be discussed critically.

PMID- 10643518
TI  - Psychosomatic aspects in the diagnosis and treatment of erectile dysfunction.
AB  - After a critical review of prevalence data, psychosocial determinants and
      psychosomatic aspects in the diagnosis and treatment of erectile dysfunction are
      discussed (with reference to age-related changes). Widely used laboratory
      assessments are responsive to psychological factors (e.g. anxiety). Inclusion of
      the partner in the diagnostic process may change the clinical picture and the
      treatment recommendations considerably. As illustrated by penile prosthetis
      treatment and self-injection of vasoactive substances, acceptance and success of
      widely used surgical and medical treatments depend largely upon the patient's
      expectations, and the adaptation of the couple to the procedure. Even in cases
      with a clear organic pathology, fluctuations in erectile functioning may be
      attributable to psychological influences. As recent psychotherapeutic and
      psychoeducational approaches underscore, erectile failure is best conceived as a
      final common pathway of somatic, lifestyle, psychological and partnership
      determinants. These should be taken into account in comprehensive diagnostic and
      treatment formulations if the goal of therapy is not only to produce rigid
      erections, but to increase sexual satisfaction.

PMID- 10643519
TI  - Penile elongation and thickening--a myth? Is there a cosmetic or medical
      indication?
AB  - Penile lengthening and thickening techniques can be performed in different ways
      for treatment of congenital penile hypoplasia and dysmorphophobia in terms of
      aesthetics or function. Particularly for penile lengthening, a combination of
      surgery and stretcher device is suggested. Surgery for lengthening comprises
      three different stages: suture with plane alternating edges of the pubo-penile
      skin, infrapubic lipectomy, and section of the suspensory ligament. Our approach
      to penile thickening differs depending on whether dysmorphophobia is related to
      aesthetics or function. While pericavernosal apposition of autografts is
      suggested in the first case, a technique developed by the authors is performed in
      the latter, which comprises bilateral longitudinal incision of the corpora
      cavernosa and enlargement of the tunica albuginea by means of saphenous grafts.
      The endothelial lining, which constitutes the internal surface of the veins, is
      highly compatible with the endothelium of the corpora cavernosa; therefore, the
      incidence of postoperative subareolar fibrosis and occlusive vein pathology is
      lower than after surgery performed with techniques using grafts of other
      material. The described procedure did not cause postoperative complications in
      terms of infection, wound healing and cosmetic appearance. All subjects resumed
      regular sexual activity after 4 months without any disturbance or functional
      limitation. Diametrical measurements at the 9-month follow-up revealed an
      increase of 1.1-2.1 cm. The reliability and efficiency of these procedures are
      strongly influenced by factors other than technical problems; however, expert
      diagnosis and psychological consultation in the case of dysmorphophobia will
      confirm and specify the indications.

PMID- 10643520
TI  - New aspects in the treatment of priapism.
AB  - Recent advances in the understanding of erectile physiology have improved the
      prompt diagnosis and treatment of priapism. During initial assessment, the
      physician must distinguish between veno-occlusive low flow (ischemic) and
      arterial high flow (nonischemic) in order to choose the correct treatment option
      for each type of priapism. Patient history, physical examination, penile
      haemodynamics and corporeal metabolic blood quality assist the distinction
      between static and dynamic priapism. Normally, priapism is effectively treated
      with intracavernous vasoconstrictive agents or surgical shunting. However, when
      these two methods fail, subsequent treatment procedures are a matter for debate.
      Alternative options, such as intracavernous injection of methylene blue or
      selective penile arterial embolization, for the management of high and low flow
      priapism are described and a survey of current treatment modalities is presented.

PMID- 10643521
TI  - Physiology and pathophysiology of erection: consequences for present medical
      therapy of erectile dysfunction.
AB  - Smooth muscle relaxation of the corpus cavernosum is the key mechanism of
      erection. It depends on a cascade of consecutive regulatory systems starting in
      the central nervous system, and proceeding via peripheral neurotransmission to
      intracellular signal transmission within the cavernous smooth muscle cells.
      Knowledge of these interacting mechanisms of erection is fundamental for
      understanding of the mode of action of new and possibly selective pharmacological
      agents that are presently available or under evaluation for treatment of erectile
      dysfunction.

PMID- 10643522
TI  - Penile revascularization surgery in erectile dysfunction.
AB  - A historical survey of operative interventions and flawed techniques for
      treatment of erectile dysfunction is presented. The purpose and functioning of
      the three-vessel anastomosis are discussed, with emphasis on some avoidable
      faults that may occur during the operation.

PMID- 10643523
TI  - Long-term results of dorsal penile vein ligation for symptomatic treatment of
      erectile dysfunction.
AB  - About 20% of patients with erectile dysfunction do not react to intracavernous
      pharmacological treatment (SKAT) because of a cavernous leak. The first attempt
      to treat venous insufficiency goes back as far as the beginning of the century.
      Ligature and resection of the superficial and deep veins of the penis (DPVL) were
      performed in 122 patients (nonresponders to SKAT with a maintenance flow of less
      than 40 ml min-1). Twenty-four patients suffered from primary dysfunction and 98
      from secondary dysfunction. The average age of the patients was 49 years, and the
      average duration of the preoperative erectile dysfunction 4.4 years.
      Postoperative follow-up was carried out for 70 months. In 98% of the patients,
      cavernosography revealed a dorsal leak. Twenty-six per cent had ectopic veins,
      38% a leakage through the crural veins and 24% a glandular or spongiosal shunt.
      After the 70-month follow-up, only 14% of the 122 patients were able to achieve
      an adequate spontaneous erection and 19% also responded to SKAT. Depending upon
      the time elapsed since the operation, the rate of spontaneous reaction was
      reduced. It was found that younger patients with a short history of erectile
      dysfunction, no arterial cofactor, a maintenance flow of less than 100 ml min-1
      and a severe dorsal leakage from a DPVL were the most likely to benefit from this
      procedure. Since degeneration of smooth muscle cells of the cavernosa is in most
      patients the cause of the venous leakage, penis vein surgery is to be regarded as
      symptomatic treatment.

PMID- 10643524
TI  - Indications for penile revascularization and long-term results.
AB  - The purpose of this study was to analyse long-term results of penile
      revascularization using Hauri's method in 124 patients with a mean follow-up of
      54 months. Of 176 patients undergoing this procedure, 124 were available for
      detailed analysis. The patients ranged in age from 22 to 71. A total of 25.8% of
      the patients (32/124) responded to intracavernous injection (ICI).
      Postoperatively, 74 patients (59.7%) exhibited spontaneous erections. Patients
      were classified as 'satisfied' or 'dissatisfied'. In those who were satisfied, a
      high correlation was found (63/74 = 85%) between graft patency, as judged by
      ultrasound, and erectile function. The benefit for non-responders to ICI (60/92)
      was higher than for responders (14/32). Only five of 12 diabetics profited from
      penile revascularization. A serious complication was glans hyperemia in 9/124
      cases (7%). Based on this experience, the following indicators are recommended
      for case selection: (i) non-responder to ICI; (ii) age less than 55 years; (iii)
      nondiabetic; (iv) cavernous leakage excluded; (v) stenosis in the internal
      pudendal artery.

PMID- 10643525
TI  - Treatment of erectile dysfunction with external vacuum devices.
AB  - In a retrospective study, the medical and psychological outcome of the use of
      external vacuum devices in the treatment of erectile dysfunction in 190 patients
      was evaluated, using a questionnaire and a clinical examination. 110/190 patients
      (57.8%) answered the questionnaire. 22/110 patients (20%) rejected the device
      primarily and 34/110 (30.9%) after a period of up to 16 weeks (primary rejection
      rate 50.9%). A secondary drop-out rate of 8/110 (7.3%) was observed after an
      intermediate time of 10.5 months. 46/110 (41.8%) patients were long-term users
      (median 27.6 months, range 7-70 months). Long-term users were mainly patients who
      did not respond to intracavernosal pharmacotherapy. In the group of long-term
      users, 98% of patients and 85% of their partners were satisfied with the vacuum
      therapy. Complications were minor (hematoma 9.8%; skin injury 2.2%), 69.8% of
      long-term users never had problems with the device. 74% of users reported regular
      orgasm. Vacuum therapy is a safe and effective non-invasive treatment of erectile
      dysfunction with a limited primary acceptance and low drop-out rates in long-term
      follow-ups.

PMID- 10643526
TI  - Invasive diagnosis and therapy--are they still reasonable in the age of
      sildenafil?
AB  - Diagnosis of erectile dysfunction is important because sildenafil may not be the
      proper therapy for patients with underlying major diseases such as coronary
      sclerosis, arteriosclerosis of the stroke vessels, depression, etc., where
      erectile dysfunction is just a symptom of the disease.

PMID- 10643528
TI  - What has prevented Annals of Oncology from reaching an impact factor of 6?

PMID- 10643527
TI  - Prostaglandin E1 long-term self-injection programme for treatment of erectile
      dysfunction--a follow-up of at least 5 years.
AB  - Prostaglandin E1 (PGE1) is currently the vasoactive drug of choice for
      intracavernous self-injection therapy in the treatment of erectile dysfunction.
      PGE1 is often said to have a low incidence of side-effects. However, real long
      term follow-up reports are rare. Here, a report is presented on 32 patients who
      joined a long-term self-injection programme in which they used PGE1 for a minimum
      of 5 years under standardized protocol conditions. All these patients had an
      organic aetiology of erectile dysfunction, and their mean age was 58.7 +/- 8.6
      years. The period of observation was on average 75.4 +/- 16.9 months, and the
      PGE1 dosage 13.5 +/- 5.9 micrograms. A total of 6799 injections were registered.
      The average number of injections was 213 +/- 127 per patient, which is 2.8
      injections per month and patient. As regards side-effects, haematomas were
      registered in 1.9% of the patients and five cases of prolonged erection (0.07%)
      caused by unauthorized redosing were noted. Three patients developed reversible
      penile nodules. In 10 patients, the initial dosage had to be increased. Five
      patients dropped out after 5 years, none of them due to treatment complications.
      It is concluded that PGE1 self-injection therapy is a simple and reliable method
      for long-term use with hardly any side-effects. The patients do not stop
      treatment because of complications.

PMID- 10643529
TI  - Individuality versus conformity. Is perfection necessary in staging and
      prognostic classifications of specific primary extranodal lymphomas?

PMID- 10643530
TI  - Can more breasts be saved if chemotherapy and radiotherapy are administered
      concomitantly?

PMID- 10643531
TI  - DNA vaccines against cancer: from genes to therapy.
AB  - After an erratic history, there is at last a clear opportunity for mobilizing an
      immune attack against cancer cells. The new strategies are dependent on the
      techniques of molecular biology, which are able both to identify potential target
      tumor antigens at the gene level, and to help to unravel the complexities of
      immune mechanisms required. Vaccine delivery systems can also be genetic, with
      DNA vaccines able to act as viral mimics and enter several antigen processing
      pathways. Rational vaccine designs can be rapidly tested in models and selected
      for pilot clinical trials. One difficulty faced by tumor antigens is that they
      may be weak, and therefore fail to engage the immune system. Attaching genes
      encoding alert signals appears to solve this problem. We have focused initially
      on idiotypic determinants of B-cell tumors, where the encoding variable region
      genes can induce protective anti-idiotypic immunity if delivered as a fusion
      protein with a fragment of Tetanus toxin. This model may have relevance for
      alternative tumor antigens. A clinical trial of patients with lymphoma is in
      progress, and wider application may be limited only by the ability to bring
      patients into clinical remission prior to vaccination.

PMID- 10643532
TI  - The World Health Organization classification of neoplastic diseases of the
      hematopoietic and lymphoid tissues. Report of the Clinical Advisory Committee
      meeting, Airlie House, Virginia, November, 1997.
AB  - INTRODUCTION: Since 1995, the European Association of Pathologists (EAHP) and the
      Society for Hematopathology (SH) have been developing a new World Health
      Organization (WHO) Classification of hematologic malignancies. The classification
      includes lymphoid, myeloid, histiocytic, and mast cell neoplasms. DESIGN: The WHO
      project involves 10 committees of pathologists, who have developed lists and
      definitions of disease entities. A Clinical Advisory Committee (CAC)) of
      international hematologists and oncologists was formed to ensure that the
      classification will be useful to clinicians. A meeting was held in November,
      1997, to discuss clinical issues related to the classification. RESULTS: The WHO
      has adopted the 'Revised European American Classification of Lymphoid Neoplasms'
      (R.E.A.L.), published in 1994 by the International Lymphoma Study Group (ILSG),
      as the classification of lymphoid neoplasms. This approach to classification is
      based on the principle that a classification is a list of 'real' disease
      entities, which are defined by a combination of morphology, immunophenotype,
      genetic features, and clinical features. The relative importance of each of these
      features varies among diseases, and there is no one 'gold standard'. The WHO
      Classification has applied the principles of the R.E.A.L. Classification to
      myeloid and histiocytic neoplasms. The classification of myeloid neoplasms
      recognizes distinct entities defined by a combination of morphology and
      cytogenetic abnormalities. The CAC meeting, which was organized around a series
      of clinical questions, was able to reach a consensus on most of the questions
      posed. The questions and the consensus are discussed in detail below. Among other
      things, the CAC concluded that clinical groupings of lymphoid neoplasms were
      neither necessary nor desirable. Patient treatment is determined by the specific
      type of lymphoma, with the addition of grade within the tumor type, if
      applicable, and clinical prognostic factors such as the international prognostic
      index (IPI). CONCLUSION: The experience of developing the WHO Classification has
      produced a new and exciting degree of cooperation and communication between
      oncologists and pathologists from around the world, which should facilitate
      progress in the understanding and treatment of hematologic malignancies.

PMID- 10643533
TI  - Stage-modified international prognostic index effectively predicts clinical
      outcome of localized primary gastric diffuse large B-cell lymphoma. International
      Extranodal Lymphoma Study Group (IELSG)
AB  - BACKGROUND: The definition of prognostic parameters in early stages of gastric
      lymphoma is still controversial. The aim of this retrospective analysis was to
      assess the value of the stage-modified international prognostic index (IPI) in
      predicting the outcome of a large, consecutive series of patients with PGL of
      diffuse large B-cell histology (DLCL). PATIENTS AND METHODS: Three hundred twelve
      consecutive, newly-diagnosed, patients with localized PGL (stages I-IIE according
      to the 'Lugano staging system for GI lymphomas') referred from April 1972 to
      December 1997 to eight Italian and one Swiss centers were reviewed and their
      outcomes updated to June 1998. One hundred three patients were treated with
      single-modality therapy, while two hundred four received combined-modality
      treatment, most of which included surgery and short-term chemotherapy. RESULTS:
      After a median follow-up of 66 months (range 0.6-300 months), 195 (64%) were
      alive in first continuous complete remission (CCR). The five-year estimates of
      overall survival (OS) and event-free survival (EFS) were 75% and 67%,
      respectively. OS and EFS varied according to IPI, from, respectively, 90% and 82%
      for patients with 0-1 risk factors, to 40% and 35% for patients with > or = 3
      risk factors (P = 0.00001). Cox regression analysis showed that IPI was the
      strongest predictor of survival. CONCLUSIONS: This study shows that stage
      modified IPI is an effective predictive model in patients with primary DLCL of
      the stomach, enabling identification of patients with significantly different
      outcomes.

PMID- 10643534
TI  - Primary gastric non-Hodgkin's lymphoma: clinical features, management, and
      prognosis of 185 patients with diffuse large B-cell lymphoma.
AB  - BACKGROUND: Primary gastric non-Hodgkin's lymphoma (PG-NHL) is common in Saudi
      Arabia. This has prompted the analysis of a large series of patients with PG-NHL
      having high-grade diffuse large B-cell lymphoma (DLCL) in order to define the
      clinical features and outcome of this disease. PATIENTS AND METHODS: The data of
      all adult patients in the series with PG-NHL having DLCL histology were
      retrospectively reviewed. Patients were eligible if they had biopsy-confirmed
      diagnoses obtained by endoscopy or following laparotomy. RESULTS: Over a 16-year
      period, 185 patients with DLCL PG-NHL were identified and their data were
      reviewed. Patients had a median age of 54 years. In 53% of them only one initial
      therapeutic modality was given, while 47% were managed by a multi-modality
      approach. One hundred forty patients (76%), 19 (10%), and 26 (14%) attained
      complete remission (CR), partial remission, and no response/progressive disease,
      respectively. Multivariate analysis showed that poor performance status and
      advanced stage were negatively associated with the likelihood of attaining CR.
      Over a median follow-up of 54 months, 118 (64%) of the patients were alive and
      disease-free, 17 (9%) were alive with evidence of disease, and the remaining 50
      (27%) were dead. The projected 5-year and 10-year overall survivals (OS) (+/- SD)
      were 68% (+/- 4%) and 61% (+/- 6%), respectively. The Cox proportional hazards
      model identified the same variables of response as adverse prognostic factors of
      survival. Using the influence of performance status, and stage, a prognostic
      index was constructed to recognize three prognostically distinctive risk
      categories with overall survival proportions of 87%, 61%, and 45%, respectively.
      The unadjusted International Prognostic Index, however, failed to classify
      patients into prognostically meaningful risk strata. Of the 140 patients who
      achieved CR, the median disease-free survival (DFS) was not reached, but the
      predicted 5- and 10-year DFS were 82% and 75%, respectively. A multivariate
      analysis identified poor performance status as the only independent prognostic
      covariate that adversely influenced DFS. Our analysis showed that compared with
      single-modality management, multi-modality strategy attained significantly higher
      CR, and advantageous OS and DFS. CONCLUSIONS: This large series characterized the
      clinico-pathologic features and outcome of patients with DLCL PG-NHL. Performance
      status, and stage significantly influenced patient outcome. A prognostic index
      was developed and it identified three prognostically distinctive risk groups;
      however, prospective validation is warranted.

PMID- 10643535
TI  - Local relapse in primary breast cancer patients with unexcised positive surgical
      margins after lumpectomy, radiotherapy and chemoendocrine therapy.
AB  - BACKGROUND: Inadequate surgical excision with residual involvement of resection
      margins by tumour after breast conservation results in increased local recurrence
      rates. To reduce this risk positive margins are, therefore, usually excised.
      Systemic treatment with tamoxifen or chemotherapy reduces local recurrence, along
      with radiotherapy. However, no studies to date have examined the correlation
      between chemoendocrine treatment, together with radiotherapy, and local relapse
      in patients with unexcised involved resection margins, having had breast
      conservation treatment. PATIENTS AND METHODS: The histopathology reports were
      reviewed of 184 patients who were treated from June 1991 to August 1995 within
      our randomised study of neoadjuvant versus adjuvant chemoendocrine therapy with
      mitozantrone and methotrexate (2M) +/- mitomycin-C (3M) and tamoxifen, used
      concurrently with radiation following conservation surgical treatment.
      Histological resection margin was considered positive if ductal carcinoma in situ
      (DCIS) or invasive carcinoma was present microscopically less than 1 mm from the
      excision margin. RESULTS: Although 38% of patients had unexcised microscopically
      involved margins, local relapse rate as first site of relapse was only 1.9% after
      a median follow up of 57 months. There was no difference in distant relapse (P =
      0.2) and survival (P = 0.5) between the positive and negative margins groups.
      CONCLUSIONS: The presence of positive unexcised margins does not have a
      significant effect on outcome in patients who are treated with chemoendocrine
      therapy together with radiotherapy. Further clinical trials are required.

PMID- 10643536
TI  - Docetaxel-cisplatin combination (DC) chemotherapy in patients with anthracycline
      resistant advanced breast cancer.
AB  - PURPOSE: The safety and efficacy of a docetaxel-cisplatin combination (DC) were
      evaluated in 41 patients pretreated for advanced breast cancer (ABC). PATIENTS
      AND METHODS: The first 2 patients received 85 mg/m2 docetaxel followed, 6 hours
      later, by 80 mg/m2 cisplatin repeated every 3 weeks; the other 39 received the
      same regimen, with 75 mg/m2 docetaxel. Appropriate dose reductions but no growth
      factor administration were planned. Treatment was continued until disease
      progression, excessive toxicity or patient refusal. RESULTS: A total of 223
      chemotherapy courses were administered, with a median of 6 cycles per patient
      (range 1-8). All 41 patients were assessed for toxicity using NCI-CTC. Severe
      neutropenia was experienced by 38 patients (93%) (11 at grade 3, 27 at grade 4,
      10 with febrile neutropenia). There was one death due to neutropenic septic
      shock. Grade 3 thrombocytopenia occurred in three patients (7%). Five patients
      (12%) had grade 2 neurosensory toxicity, two (5%) experiencing partial hearing
      loss. Grade 3 fluid retention occurred in three patients (7%). Of 38
      anthracycline-resistant patients, 33 were evaluable for response. Two had a
      complete response (CR) and ten a partial response (PR), giving an objective
      response rate of 36%, (95% CI: 20%-55%). Stable disease (SD) was observed in 14
      patients (42%), 7 (21%) had progressive disease (PD). Among the three non
      resistant patients, two PRs and one SD were observed. Median duration of response
      was 29 weeks (range 18-70), median time to progression 21 weeks (4-70), and
      median overall survival 50 weeks (4-104+). CONCLUSIONS: This DC regimen is
      active, with an acceptable safety profile in anthracycline-resistant ABC
      patients. Its place as a second-line treatment alternative to docetaxel alone or
      to other second-line combination regimens remains to be determined.

PMID- 10643537
TI  - Weekly gemcitabine and cisplatin combination therapy in patients with
      transitional cell carcinoma of the urothelium: a phase II clinical trial.
AB  - PURPOSE: To determine the efficacy of gemcitabine and cisplatin combination
      therapy in patients with advanced and/or metastatic transitional cell urothelial
      carcinoma. PATIENTS AND METHODS: Forty-two chemonaive patients with Karnofsky
      performance status (KPS) > or = 70 were treated with cisplatin 35 mg/m2 followed
      by gemcitabine 1000 mg/m2 (30 min i.v. infusion) on days 1, 8, and 15 every
      twenty-eight days. RESULTS: Thirty-eight patients were evaluable for efficacy.
      Half had visceral disease. There were seven complete (18%) and nine partial
      responses (24%), for a response rate of 42% (95% confidence interval (95% CI):
      26%-59%). Responses were independently reviewed. Median response duration was
      13.5 months (95% CI: 8.5-18.1 months), median time to progressive disease 7.2
      months (95% CI: 4.0-9.1 months) and median survival 12.5 months (95% CI: 8.1-18.7
      months); one-year survival was 52%. Laboratory toxicities included leucopenia
      (44% grade 3; 17% grade 4), neutropenia (25% grade 3; 33% grade 4) and
      thrombocytopenia (29% grade 3; 49% grade 4). Four patients had grade 4
      symptomatic toxicity (three nausea and vomiting, one diarrhoea). There were no
      grade 4 infections and no toxic deaths. CONCLUSIONS: The combination of
      gemcitabine and cisplatin is active in patients with locally advanced and/or
      metastatic urothelial carcinoma. The weekly schedule of cisplatin is considered
      inappropriate.

PMID- 10643538
TI  - A multi-center prospective phase II study of high-dose chemotherapy in germ-cell
      cancer patients relapsing from complete remission.
AB  - PURPOSE: To prospectively determine the efficacy of repeated high-dose alkylating
      chemotherapy to salvage patients with germ-cell tumors who relapsed after
      adequate first-line chemotherapy. PATIENTS AND METHODS: Patients with germ-cell
      cancers relapsing from a first, second or third complete remission induced by
      chemotherapy were offered to participate in a Dutch national prospective trial
      with broad entry criteria. The salvage treatment began with a conventional dose
      of ifosfamide (4 g/m2 on day 1) and etoposide (100 mg/m2 on days 1, 2 and 3)
      followed by daily s.c. administration of G-CSF (10 micrograms/kg) until
      peripheral blood progenitor cells had been harvested. Immediately after bone
      marrow recovery, an intermediate dose chemotherapy course of carboplatin (target
      AUC: 10 mg.ml-1 min on day 1) and etoposide (500 mg/m2 on days 1, 3 and 5) was
      given with G-CSF daily s.c. After bone marrow recovery, two subsequent courses of
      high-dose 'CTC' chemotherapy were given, each containing cyclophosphamide (6
      g/m2), thiotepa (480 mg/m2) and carboplatin (target AUC: 20 mg.ml-1 min). The
      high-dose chemotherapy was administered as 30-60-minute infusions, divided over 4
      days and the stem-cell transplants were given 48-72 hours after the last
      chemotherapy infusion. Whenever possible, residual masses were resected at the
      end of treatment. RESULTS: Thirty-five patients were treated between January 1994
      and October 1997. The toxicity of the treatment was manageable. Second CTC
      courses were administered in 25 patients and were associated with hemorrhagic
      cystitis and veno-occlusive disease in 3 and 4 patients, respectively. One
      patient who had recently undergone a partial hepatectomy, died of veno-occlusive
      disease. At the time of analysis, the median follow-up of the surviving patients
      was 37 months (range 12-56 months). The median progression-free survival for all
      patients was 44 months, and the median overall survival has not been reached.
      According to the internationally accepted criteria for predicting the outcome of
      salvage chemotherapy in germ-cell cancer (Beyer et al. J Clin Oncol 1996; 14:
      2638-45), 30 patients had 'good risk' criteria. Of these, 29 received high-dose
      chemotherapy. Of this group, the salvage rate at two years was 65% (95%
      confidence interval: 49.5%-85.1%). CONCLUSIONS: Over half of the germ-cell cancer
      patients relapsing from a chemotherapy-induced complete remission can be salvaged
      by a treatment strategy that incorporates high-dose chemotherapy, even when
      treatment is given in a multi-center setting. These data confirm the
      international prognostic model proposed by Beyer et al. in a prospectively
      studied, independent patient group and provide further evidence that high-dose
      therapy has a role in the salvage setting of patients with germ-cell cancer.

PMID- 10643539
TI  - The course of long-term toxicity in patients treated with cisplatin-based
      chemotherapy for non-seminomatous germ-cell cancer.
AB  - BACKGROUND: The prognosis of advanced testicular cancer has improved considerably
      after the introduction of cisplatin-based combination chemotherapy. The improved
      prognosis of testicular cancer has brought the long-term toxicity of the
      treatment into focus. PATIENTS AND METHODS: Long-term toxicity was investigated
      prospectively until more than 10 years after after treatment in a group of 22
      patients treated with six series of cisplatin based chemotherapy (PVB) for
      testicular cancer. We have focused on nephro-, neuro-, pulmonary-, and gonadal
      toxicity. RESULTS: Glomerular filtration rate (GFR) decreased significantly
      during treatment but increased during follow-up and all the patients had normal
      values of GFR 10-15 years after treatment. Carbon monoxide diffusion capacity
      (TLco) decreased during PVB treatment in smokers. TLco remained unchanged during
      the first years after PVB treatment, but improvement of TLco was seen in some
      patients more than 43 months after treatment. Paresthesia was reported by 83% of
      the patients immediately after treatment, 50% at follow-up 4-9 years after
      chemotherapy and 14% prevalence 11-15 hears after treatment. The reported decline
      in neurotoxicity was verified by normalisation of vibration perception. Gonadal
      toxicity was severe and persistent although improvement was seen in a few
      patients even many years after treatment. CONCLUSIONS: The patients treated with
      PVB were physically and socially well-being at follow-up investigation 11-15
      years after treatment. Improvements in pulmonary- and renal function, and
      recovery from neurotoxicity was seen during the long-term follow-up period.
      Gonadal toxicity was severe and persistent.

PMID- 10643540
TI  - Feasibility of tandem autologous stem-cell transplantation (ASCT) in induction
      failure or very unfavorable (UF) relapse from Hodgkin's disease (HD). SFGM/GELA
      Study Group.
AB  - BACKGROUND: Despite high-dose therapy and ASCT some patients with aggressive HD
      fail to achieve long-term survival. PATIENTS AND METHODS: Forty-three patients
      with induction failure (n = 19) or very unfavorable (UF) relapse (n = 24) from HD
      were included in a multicentric study of tandem ASCT. They planned to receive two
      course of IVA75 with GCSF and blood stem cell collection. ASCT1 was conditioned
      with CBV + mitoxantrone (30 mg/m2) and ASCT2 (cytarabine 6 g/m2 melphalan 140
      mg/m2 and total body irradiation at 12 Gy or busulfan 16 (n = 4) than 12 mg/kg).
      After salvage therapy, response > 50% was observed in 63% of the patients (six
      patients were included for refractory relapse). Four patients had no ASCT for
      disease progression; seven patients had only ASCT1 (disease progression, n = 3)
      and thirty-two patients (74%) received the two ASCT. RESULTS: Hematologic
      recovery was normal after ASCT1 but delayed platelet recovery was observed after
      ASCT2 with busulfan in the conditioning regimen. Two VOD with one fatal occurred
      with busulfan at 16 mg/kg and one hemorrhagic cystic, no further grade 4 toxicity
      was observed with the reduced doses of busulfan (12 mg/kg). After ASCT2, 83% of
      these UF patients were in remission and 20% relapsed within the first year. On an
      intent-to-treat analysis, 22 of 43 patients are in continuous CR (including 8
      patients with induction failure). For the whole population (n = 43) and for
      patients receiving the two ASCT (n = 32), the two-year survival from the date of
      progression were respectively at 65% and at 74%. CONCLUSION: Double ASCT is
      feasible in very UF relapse from HD and may lead to some prolonged remission.

PMID- 10643541
TI  - A randomized EPOCH vs. CHOP front-line therapy for aggressive non-Hodgkin's
      lymphoma patients: long-term results.
AB  - BACKGROUND: The value of continuous-infusion chemotherapy (EPOCH) vs. the
      standard CHOP combination was evaluated in 78 patients with previously untreated
      aggressive non-Hodgkin's lymphoma in a randomized phase III clinical trial.
      PATIENTS AND METHODS: The EPOCH regimen given to 38 patients consisted of the
      drugs etoposide (50 mg/m2), vincristine (0.4 mg/m2), and doxorubicin (10 mg/m2),
      all given in a continuous infusion on days 1-4. Cyclophosphamide (750 mg/m2) was
      administered on day 6 as i.v. bolus, while prednisone was given orally 60 mg/m2
      on days 1-6. Courses were repeated every three weeks. CHOP was given to 40
      patients as routinely prescribed. RESULTS: Forty-eight patients were males and
      thirty were females. Their ages ranged from 19-75 years (median 45 years). Forty
      three (55%) had grade 2 and thirty-five (45%) had grade 3 pathologic subtype.
      Nine patients (12%) presented with stage I, fourteen (18%) with stage II, forty
      (51%) with stage III, and fifteen (19%) with stage IV disease. The different
      clinico-pathologic characteristics, including international index categories,
      were comparable in the two groups. The number of courses given ranged between 3
      and 9 (median 6) for both the EPOCH and CHOP regimens. Complete remission (CR)
      was achieved in 19 (50%), and 27 (67%) of the 38 and 40 patients for both the
      EPOCH and CHOP combinations, respectively. After a median observation time of 27
      months, the four-year overall and failure-free survival rates were 42% and 30%
      for the EPOCH and 71% and 54% for the CHOP regimen (P = 0.006 and 0.1 for the
      overall and FFS rates, respectively). Toxicities were comparable and were mostly
      of grades 1 and 2, except for hair loss, hematologic toxicities, and infectious
      episodes which were more common in the EPOCH group. In the EPOCH group, overall
      survival rates were 55% vs. 22% (P < 0.04) at four years for the low-risk (2
      prognostic factors) and high-risk (> 2 factors) groups, respectively.
      CONCLUSIONS: Thus, it may be concluded that continuous-infusion (EPOCH)
      chemotherapy did not improve treatment outcome over that of the CHOP regimen for
      aggressive non-Hodgkin's lymphoma patients.

PMID- 10643542
TI  - Pentostatin in T-cell malignancies--a phase II trial of the EORTC. Leukemia
      Cooperative Group.
AB  - PURPOSE: Within this phase II EORTC trial, we have investigated the safety and
      efficacy of pentostatin in lymphoid malignancies. We have previously reported the
      results in T- and B-cell prolymphocytic leukemia, B-cell chronic lymphocytic
      leukemia (B-CLL) and hairy cell leukemia. This report focuses on the outcome in T
      cell malignancies: T-CLL, Sezary syndrome (Sezary), mycosis fungoides (MF) and T
      zone lymphoma (TZL). PATIENTS AND METHODS: Of the 92 patients with these
      diagnoses enrolled, 76 were evaluable for response and toxicity, i.e., 25 of 28
      with T-CLL, 21 of 26 with Sezary, 22 of 26 with MF, and 8 of 12 with TZL. All
      patients had progressive and advanced disease. Pentostatin was administered at a
      dosage of 4 mg/m2 every week for the first 3 weeks, then 4 mg/m2 every 14 days
      for another 6 weeks, followed by maintenance therapy of 4 mg/m2 monthly for a
      maximum of 6 months. RESULTS: Response rates (complete and partial responses) in
      patients with Sezary (n = 22) or MF (n = 21) were 33% and 23%, respectively, and
      in patients with T-CLL (n = 21) or TZL (n = 8) 8% and 25%, respectively. Sixteen
      (21%) patients died during the first ten weeks of treatment: twelve of
      progressive disease, two of infectious complications with progressive disease,
      one of myocard infarction and one of renal failure related to administration of
      i.v. contrast. Major toxicity (grade 3-4) included infection in 11% of patients,
      nausea/vomiting in 4%, diarrhea in 3%. Hematologic toxicity was mild to non
      existent. CONCLUSIONS: We conclude that pentostatin is active in Sezary and MF
      but showed marginal activity in T-CLL or TZL. Toxicities are mild to moderate at
      the dose schedule administered. Due to its relatively specific lympholytic effect
      and its favorable toxicity spectrum, pentostatin might be especially useful for
      the palliative treatment of T-cell malignancies.

PMID- 10643543
TI  - Nasopharyngeal carcinoma in children under 15 years of age: a retrospective
      review of 65 patients.
AB  - BACKGROUND: Nasopharyngeal carcinoma constitutes comprises up to 5% of primary
      childhood cancers but literature lacks modern uniformly treated large series.
      PATIENTS AND METHODS: A retrospective review was performed of sixty-five
      previously untreated patients younger than 16 years of age diagnosed and treated
      at the Ibn Rochd Centre in Casablanca between 1988 and 1992. Forty-four percent
      of them were stage T3 to T4 and 66% stage N2 or N3. All patients were irradiated.
      Prior adjuvant chemotherapy was administered in 33 patients. Thirteen patients
      were lost to follow-up. RESULTS: Local control was obtained in 85% of the 52
      evaluable patients. The five-year overall survival was 42% and disease-free
      survival 38%. Ten relapses occurred at local and/or regional sites. Six patients
      have distant metastases. All 24 patients with relapse or persistent disease died
      despite salvage therapy. Stage, histology and dose of radiation, were
      statistically significant prognostic variables. Patients treated with
      chemotherapy followed by irradiation had a better outcome than those treated with
      radiation alone. CONCLUSIONS: Nasopharyngeal carcinoma in children is a rare
      chemosensitive tumor. However, conclusive treatment guidelines cannot be drawn
      from this series and prospective co-operative studies are needed for the
      development of more effective and less toxic therapeutic strategies.

PMID- 10643544
TI  - Gemcitabine-cisplatin: a schedule finding study.
AB  - PURPOSE: To evaluate the tolerability of four alternating cisplatin-gemcitabine
      schedules. A secondary aim was to evaluate the clinical efficacy of this
      combination. PATIENTS AND METHODS: Forty-one patients with advanced solid tumors
      received alternating sequences with a 4- and 24-hour interval of cisplatin and
      gemcitabine. Gemcitabine 800 mg/m2 was administered as a 30-min infusion on day
      1, 8 and 15, and cisplatin 50 mg/m2 over 1 hour on day 1 and 8; in case of the 24
      hour time interval the second drug was administered one day later. Four cisplatin
      gemcitabine schedules were studied: gemcitabine four hour before cisplatin (10
      patients), or vice versa (14 patients) and gemcitabine twenty-four hours before
      cisplatin (9 patients) or vice versa (8 patients). The sequence of drug
      administration was reversed in the second cycle of therapy in each individual
      patient, enabling the evaluation of sequence-dependent side effects. Twenty-six
      patients had received prior chemotherapy, of which twenty-one platinum-based.
      RESULTS: The main toxicity was myelosuppression. Overall, grade 3 and 4
      thrombocytopenia was observed in 27 out of 41 patients (66%) and was not schedule
      dependent. No serious bleeding occurred. Leukopenia was significantly different
      between the 4 alternating schedules (P = 0.01); gemcitabine 24 hours before
      cisplatin was significantly less toxic compared to both cisplatin 4 hours and 24
      hours before gemcitabine (P = 0.01 and P = 0.003, respectively). Furthermore,
      paired analysis of the 4-hour and 24-hour data sets showed that leukopenia was
      significantly more serious when cisplatin preceded gemcitabine (P = 0.005).
      Although most patients received prior treatment, both prior chemotherapy and
      radiotherapy were not related to toxicity. Overall, grade 3 and 4 leukopenia
      occurred in 19 out of 41 patients (46%). Anemia (Hb < or = 6.0 mmol/l) was not
      sequence dependent and was observed in 63% of patients. Myelotoxicity was
      cumulative between cycles and caused frequent omission of gemcitabine on day 15.
      Overall, in 51% of administered cycles there was no omission of gemcitabine. A
      mean of 3.5 therapy cycles was administered. Non-hematological toxicity was
      moderate, consisting mainly of grade 1 and 2 nausea/vomiting and fatigue, and was
      not schedule dependent. Recently, we described that the schedule in which
      cisplatin was administered 24 hours before gemcitabine produced the best
      pharmacological profile. Based on this and because toxicity was manageable, the
      schedule cisplatin 24 hours prior to gemcitabine was chosen for phase II
      evaluation. Nine out of thirty-six evaluable patients had an objective response.
      These responses were observed in head and neck squamous-cell carcinoma (HNSCC),
      non-small-cell lung cancer (NSCLC), melanoma, adenocarcinoma of unknown origin,
      ovarian and esophageal carcinoma. CONCLUSIONS: Myelosuppression was the most
      important toxicity. Leukopenia was schedule dependent: gemcitabine before
      cisplatin was less toxic than the reversed sequence, in this respect. Some
      encouraging responses were seen in patients with esophageal cancer. Currently, a
      phase II study with cisplatin 24 hours before gemcitabine is ongoing in patients
      with advanced upper gastro-intestinal tumors.

PMID- 10643545
TI  - The effects of morphine on dyspnea and ventilatory function in elderly patients
      with advanced cancer: a randomized double-blind controlled trial.
AB  - BACKGROUND: Dyspnea represents a very frequent and distressing symptom in
      patients with advanced cancer. This study was undertaken to assess the efficacy
      of morphine on dyspnea and its safety for ventilatory function in elderly
      advanced cancer patients. PATIENTS AND METHODS: Nine elderly patients with
      dyspnea due to lung involvement were randomized to receive either morphine
      subcutaneously (5 mg in seven opioid-naive patients and 3.75 mg in two patients
      on top of their regular oral dose of 7.5 mg q4 h) or placebo on day 1. On day 2,
      they were crossed over to receive the alternate treatment. Dyspnea was assessed
      every fifteen minutes using a visual analogue scale (VAS: 0-100 mm) and the
      ordinal scale developed by Borg (0-10 points). Pain, somnolence and anxiety were
      assessed using VAS. Respiratory effort, respiratory rate and oxygen saturation
      were also measured repeatedly. RESULTS: Mean changes in dyspnea 45 minutes after
      injection were -25 +/- 10 mm and -1.2 +/- 1.2 points for morphine, versus 0.6 +/-
      7.7 mm (P < 0.01) and -0.1 +/- 0.3 points (P = 0.03) for placebo on VAS and Borg
      scale, respectively. No relevant changes were observed in somnolence, pain,
      anxiety, respiratory effort and rate, and oxygen saturation. CONCLUSIONS:
      Morphine appears effective for cancer dyspnea, and it does not compromise
      respiratory function at the dose level used.

PMID- 10643546
TI  - Leukoencephalopathy in multiple myeloma: two case reports.
AB  - BACKGROUND: No case of leukoencephalopathy has been reported associated with
      multiple myeloma. PATIENTS: We report on two patients with a very rare
      association of leukoencephalopathy and multiple myeloma revealed by cognitive
      impairment. RESULTS: Chemotherapy has improved neurological and biological signs.
      Radiological abnormalities have been stabilized. CONCLUSION: The authors suggest
      that leukoencephalopathy is probably a direct cerebral expression of malignant
      gammopathy.

PMID- 10643547
TI  - Primary T-cell lymphoma of central nervous system (PTCLCNS): a case with unusual
      presentation and review of the literature.

PMID- 10643548
TI  - Rituximab therapy in Waldenstrom's macroglobulinemia: preliminary evidence of
      clinical activity.
AB  - To assess the preliminary efficacy of rituximab therapy in Waldenstrom's
      macroglobulinemia (WM), we examined the clinical and laboratory data for all
      patients with WM treated on IDEC Pharmaceuticals sponsored trials and one patient
      treated at Walter Reed Army Medical Center. Seven symptomatic patients with WM
      were treated with four (n = 6) or eight (n = 1) weekly infusions of rituximab
      (375 mg/m2). Patients had received a median of three prior therapies (range 1-4)
      which included alkylator therapy in all (five patients refractory) and
      fludarabine in four (all refractory). Therapy was tolerated well in all patients
      without decrement in cellular immune function or significant infectious
      morbidity. Partial responses were noted in three of these patients, including two
      with fludarabine-refractory disease. The median progression-free survival for
      these patients was 6.6 months (range 2.2-29+ months). These data suggest that
      rituximab has clinical activity in heavily pre-treated patients with
      Waldenstrom's macroglobulinemia. Based on these data, clinical studies of
      Rituximab in previously untreated and treated WM appear indicated.

PMID- 10643549
TI  - Radiation pneumonitis after local-regional radiotherapy following autologous stem
      cell transplant for high-risk breast cancer.

PMID- 10643550
TI  - Urinary bladder cancer death rates in Europe.

PMID- 10643551
TI  - Elevation of urinary porphyrin levels following gemcitabine administration.

PMID- 10643552
TI  - Docetaxel and epirubicin plus G-CSF mobilize hematopoietic progenitors in breast
      cancer.

PMID- 10643553
TI  - A receptor scaffold mediates stimulus-response coupling in bacterial chemotaxis.
AB  - The mechanism of stimulus-response coupling in bacterial chemotaxis has emerged
      as a paradigm for understanding general features of intracellular signal
      transduction both in bacterial and eukaryotic cells. Until recently it was
      thought that the mechanism involved reversible stochastic interactions between
      dimeric receptors freely diffusing in the cytoplasmic membrane and several
      soluble signal transduction proteins within the cytoplasm. Recent results have
      shown that this view is an oversimplification. The receptors and most of the
      signal transduction proteins are organized together in a higher ordered structure
      at one pole of the bacterial cell. The scaffolding network within this structure
      appears to be composed of C-terminal alpha-helical extensions of the membrane
      chemoreceptor proteins held together in a lattice by tandem SH3-like domains.
      Results suggest that stimuli are detected through the perturbations they induce
      in scaffolding architecture.

PMID- 10643554
TI  - The organization of INAD-signaling complexes by a multivalent PDZ domain protein
      in Drosophila photoreceptor cells ensures sensitivity and speed of signaling.
AB  - Phototransduction in Drosophila has emerged as an attractive model system for
      studying the organization of signaling cascades in vivo. In photoreceptor
      neurons, the multivalent PDZ protein INAD serves as a scaffold to assemble
      different components of the phototransduction pathway, including the effector
      PLC, the light-activated ion channel TRP, and a protein kinase C involved in
      deactivation of the light response. INAD is required for organizing and
      maintaining signaling complexes in the rhabdomeres of photoreceptors. This
      macromolecular organization endows photoreceptors with many of their signaling
      properties, including high sensitivity, fast activation and deactivation
      kinetics, and exquisite feedback regulation by small localized changes in
      [Ca2+]i. Assembly of transduction components into signaling complexes is also an
      important cellular strategy for ensuring specificity of signaling while
      minimizing unwanted cross-talk. In this report, we review INAD's role as a signal
      transduction scaffold and its role in the assembly and localization of
      photoreceptor complexes.

PMID- 10643555
TI  - G protein-dependent Ca2+ signaling complexes in polarized cells.
AB  - Polarized cells signal in a polarized manner. This is exemplified in the patterns
      of [Ca2+]i waves and [Ca2+]i oscillations evoked by stimulation of G protein
      coupled receptors in these cells. Organization of Ca(2+)-signaling complexes in
      cellular microdomains, with the aid of scaffolding proteins, is likely to have a
      major role in shaping G protein-coupled [Ca2+]i signal pathways. In epithelial
      cells, these domains coincide with sites of [Ca2+]i-wave initiation and local
      [Ca2+]i oscillations. Cellular microdomains enriched with Ca(2+)-signaling
      proteins have been found in several cell types. Microdomains organize
      communication between Ca(2+)-signaling proteins in the plasma membrane and
      internal Ca2+ stores in the endoplasmic reticulum through the interaction between
      the IP3 receptors in the endoplasmic reticulum and Ca(2+)-influx channels in the
      plasma membrane. Ca2+ signaling appears to be controlled within the receptor
      complex by the regulators of G protein-signaling (RGS) proteins. Three domains in
      RGS4 and related RGS proteins contribute important regulatory features. The RGS
      domain accelerates GTP hydrolysis on the G alpha subunit to uncouple receptor
      stimulation from IP3 production; the C-terminus may mediate interaction with
      accessory proteins in the complex; and the N-terminus acts in a receptor
      selective manner to confer regulatory specificity. Hence, RGS proteins have both
      catalytic and scaffolding function in Ca2+ signaling. Organization of Ca(2+)
      signaling proteins into complexes within microdomains is likely to play a
      prominent role in the localized control of [Ca2+]i and in [Ca2+]i oscillations.

PMID- 10643556
TI  - Protein targeting and calcium signaling microdomains in neuronal cells.
AB  - Over the last several years, a number of optical imaging, physiological, and
      molecular studies have clarified the mechanisms underlying differential calcium
      signaling in the postsynaptic neuron. These studies have revealed the existence
      of membrane-associated calcium microdomains, which are often specifically coupled
      to distinct protein signaling pathways. In this review, we discuss how these
      signaling microdomains are organized and regulated, emphasizing the structural
      and molecular features of synaptic protein complexes containing the metabotropic
      and N-methyl-D-aspartate (NMDA) glutamate receptors and the L-type voltage
      dependent calcium channels (VDCCs). We conclude with a discussion of how these
      different signaling complexes may interact with one another, relationships which
      may be important in orchestrating the complex calcium signaling underlying
      developmental and activity-dependent changes in synaptic function.

PMID- 10643557
TI  - Mitochondria as biosensors of calcium microdomains.
AB  - The notion that the agonist-dependent increases in intracellular Ca2+
      concentration, on ubiquitous signalling mechanism, occur with a tightly regulated
      spatio-temporal pattern has become an established concept in modern cell biology.
      As a consequence, the concept is emerging that the recruitment of specific
      intracellular targets and effector system mechanisms depends on exposure to local
      [Ca2+] that differs substantially from the mean [Ca2+]. A striking example is
      provided by mitochondria, intracellular organelles that have been overlooked for
      a long time in the field of calcium signalling due to the low affinity of their
      Ca(2+)-uptake pathways. We will summarize here some of the evidence indicating
      that these organelles actively participate in Ca2+ homeostasis in physiological
      conditions (with consequences not only for the control of their function, but
      also for the modulation of the complexity of calcium signals) because they have
      the capability to respond to microdomains of high [Ca2+] transiently generated in
      their proximity by the opening of Ca2+ channels.

PMID- 10643558
TI  - Calcium signal transduction from caveolae.
AB  - Caveolae are specialized membrane microdomains that are found on the plasma
      membrane of most cells. Recent studies indicate that a variety of signaling
      molecules are highly organized in caveolae, where their interactions initiate
      specific signaling cascades. Molecules enriched in this membrane include G
      protein-coupled receptors, heterotrimeric GTP binding proteins, IP3 receptor-like
      protein, Ca2+ ATPase, eNOS, and several PKC isoforms. Direct measurements of
      calcium changes in endothelial cells suggest that caveolae may be sites that
      regulate intracellular Ca2+ concentration and Ca2+ dependent signal transduction.
      This review will focus on the role of caveolae in controlling the spatial and
      temporal pattern of intracellular Ca2+ signaling.

PMID- 10643559
TI  - Targeting of PKA, PKC and protein phosphatases to cellular microdomains.
AB  - The intracellular responses to many distinct extracellular signals involve the
      direction of broad-based protein kinases and protein phosphatases to catalyse
      quite specific protein phosphorylation/dephosphorylation events. It is now clear
      that such specificity is often achieved through subcellular targeting of distinct
      pools of kinase or phosphatase towards particular substrates at specific
      subcellular locations. Given the dynamic nature of protein phosphorylation
      reactions, coordinated control of both kinase and phosphatases is often required
      and complexes formed by common scaffold or targeting proteins exist to direct
      both kinase and phosphatase to the same subcellular location. In many cases more
      than one kinase or phosphatase is required and binding proteins which target more
      than one kinase or phosphatase have now been identified. This review summarizes
      recent findings relating to the concept of targeting PKA, PKC and the major
      serine/threonine phosphatases, PP1, PP2A and PP2B, through the formation of multi
      enzyme signalling complexes.

PMID- 10643560
TI  - Scaffolding and protein interactions in MAP kinase modules.
AB  - MAP kinases are a family of protein kinases that are ubiquitously expressed and
      play roles in most signal transduction pathways. They are activated within
      protein kinase cascades consisting of at least three kinases acting in series. In
      many, if not all cases, the three-kinase cascade, conveniently referred to as a
      MAP kinase module, is organized on scaffolds with a variety of forms and
      functions. This review discusses similarities and differences in scaffolding
      proteins and mechanisms in yeast, flies, worms and mammals.

PMID- 10643561
TI  - Signaling scaffolds in immune cells.
AB  - Of the past several years progress in understanding TCR signal transduction has
      led to the discovery of new kinases, adapter molecules and multiple signaling
      pathways. The study of molecules such as LAT, SLP-76, FYB, SKAP-55 and VAV have
      revealed multiple mechanisms with which to control the activation of downstream
      signaling pathways through RAS, PLC gamma-1 and ERK/MAPK. Signaling through SLP
      76 can play a role in TCR-induced cytoskeleton changes through activation of
      effector molecules in the RAC/RHO-family of GTPases. In addition, SLP-76 through
      its association with FYB/FYN-T appears to play a role in IL-2 gene transcription
      following TCR activation. Finally, these newly identified adaptor molecules, such
      as LAT, may be crucial in T-cell activation by enhancing the recruitment of
      critical kinases to glycolipid-enriched microdomains of the activated T-cell
      receptor complex.

PMID- 10643562
TI  - Role of virus replication in a murine model of AIDS-associated interstitial
      pneumonitis.
AB  - One of the major complications of HIV infection is the development of
      interstitial pneumonitis (IP). IP is characterized by lymphocytic infiltration of
      the lung and may lead to respiratory failure in some cases. The etiology of IP is
      unknown although it is likely the result of an antiviral or autoimmune response
      occurring in the lung. To determine the role of viral replication in the
      development of IP, AZT was evaluated for the ability to inhibit development of
      lung inflammation in a murine model of retrovirus-associated IP. Mice were
      infected with LP-BM5 retrovirus, which induces murine AIDS. Infected mice develop
      IP by 4 weeks postinfection characterized by infiltration of the lung with
      activated T cells, B cells, and macrophages. Virus could be detected in the lungs
      of these mice by 2 weeks postinfection and persisted throughout the course of
      disease. To determine if reduction in viral load affected the disease process,
      infected mice were treated with AZT for varying periods postinfection and
      analyzed for the development of IP. Treatment with AZT resulted in a treatment
      time-dependent reduction of viral RNA in the lungs of infected mice compared to
      untreated infected mice. The reduction of viral burden in the lungs correlated
      with a reduction in the severity of IP and decreased production of the
      proinflammatory cytokines interleukin (IL)-1 beta and interferon (IFN)-gamma.
      These results suggest that continuous viral replication in the lung contributes
      to the pathogenesis of IP.

PMID- 10643563
TI  - New monoclonal antibodies against the epithelioid cells in sarcoid granulomas.
AB  - Sarcoidosis is a systemic granulomatous disease of unknown etiology. Extensive
      investigations of granulomas have suggested several possible causes, but these
      are still controversial. We previously developed an anti-Kveim monoclonal
      antibody, IHY-1, which reacts with sarcoid granulomas as well as with epithelioid
      cells of various granulomatous diseases including tuberculosis. In the present
      study, we developed 2 new anti-Kveim monoclonal antibodies, IHY-2 and IHY-3,
      which react with epithelioid cells in sarcoidosis but not in tuberculosis. These
      antibodies reacted with a small population of alveolar macrophages in sarcoidosis
      and hypersensitivity pneumonitis by flow cytometry, as well as with most
      epithelioid cells in sarcoid granulomas by immunoperoxidase technique, suggesting
      that these cells expressed the antigen present in the Kveim reagent. Although the
      antigens recognized by these antibodies have not yet been identified, these
      monoclonal antibodies might become useful tools to elucidate the etiology of
      sarcoidosis.

PMID- 10643564
TI  - Role of T cell subsets in the development of AIDS-associated interstitial
      pneumonitis in mice.
AB  - Idiopathic interstitial pneumonitis (IP), characterized by lymphocytic
      infiltration of the lung and pulmonary dysfunction, is a major noninfectious
      complication of human immunodeficiency virus (HIV) infection. The role of the
      CD4+ and CD8+ T cell populations and INF-gamma in the development of IP were
      analyzed using a murine model of retroviral-associated IP. Infected mice depleted
      of CD8+ T cells developed IP similarly to untreated infected mice, suggesting
      that the CD8+ T cell population does not play a role in IP. Furthermore,
      depletion of CD8+ T cells did not alter the level of viral RNA in lungs,
      suggesting that cytotoxic T cells may not serve a role in controlling virus
      burden in lungs. In contrast, depletion of CD4+ T cells in infected mice
      prevented the development of IP and inhibited inflammatory cytokine expression,
      suggesting that CD4+ T cells are important for the development of IP. IFN-gamma 
      /- mice infected with virus for 10 weeks developed IP, although the severity of
      lymphocytic infiltration was substantially reduced compared to infected wild-type
      mice. The data suggest that persistent viral antigen in the lung may drive a CD4+
      T cell-mediated immune response, resulting in the chronic production of IFN-gamma
      which amplifies a chronic inflammatory response in the lung resulting in tissue
      injury.

PMID- 10643565
TI  - Isolation of differentially expressed genes in hypertensive pulmonary artery of
      rats.
AB  - Pulmonary artery remodeling is a complex biological process, and a key molecular
      mechanism regulating this process is selective up- and downregulation of genes.
      We used reverse transcriptase-polymerase chain reaction (RT-PCR) differential
      display in a rat model of hypoxic pulmonary hypertension to identify selectively
      expressed genes relevant to pulmonary artery remodeling. We characterized the
      pattern of gene expression in hypertensive and normal arteries. Eight
      differentially expressed cDNAs were selected, isolated, and characterized.
      Homology searches identified 4 previously identified genes and 4 novel genes that
      were not further characterized. The known genes were beta-glucoronidase,
      hemeoxygenase-2 (HO-2), glycerol-3-phosphate dehydrogenase, and cytoplasmic gamma
      actin. Each of the 4 known genes was relevant to processes involved in pulmonary
      artery remodeling. We conclude that mRNA differential display was informative in
      identifying genes coding for products directly involved in pulmonary artery
      remodeling.

PMID- 10643566
TI  - Epithelial-mesenchymal interaction and insulin-like growth factors in hyperoxic
      lung injury.
AB  - To investigate the role of epithelial-mesenchymal interaction on oxygen-induced
      lung injury, we used a coculture model with lung fibroblasts (FB) embedded
      between 2 layers of collagen gel with and without human tracheobronchial
      epithelial cells (HTBE), and studied the effect of hyperoxia on the directed
      migration of FB towards epithelial cells and proliferation of fetal lung FB. The
      expression of insulin-like growth factor (IGF)-I, -II, and -IIR mRNAs and
      proteins was studied in FB and HTBE cells cultured separately in 95% oxygen and
      5% CO2 for 48 hours. There was a significant increase in directional migration of
      FB in coculture with epithelial cells when exposed to 95% oxygen and 5% CO2 (P =
      .04 compared to cocultures without oxygen exposure). Hyperoxia stimulated the
      proliferation of fibroblasts cocultured with HTBE cells (0.75 +/- 0.05 x 10(6)
      cells per well) as compared to control (0.47 +/- 0.03 x 10(6) cells per well; P =
      .01). This was inhibited by anti-IGF-I antibody (69 +/- 2% of hyperoxia alone; P
      = .002). Western blot showed a significant increase in IGF-I protein in
      epithelial cells (P = .02). IGF-I mRNA was increased in HTBE cells after
      hyperoxia (P = .003). In conclusion, HTBE cells modulate lung FB migration and
      proliferation in response to hyperoxia exposure. This is mediated in part by IGF
      I produced by epithelial cells.

PMID- 10643567
TI  - Relating to the superego.

PMID- 10643568
TI  - The logic of play in psychoanalysis.
AB  - The paper puts forward the idea that play is at work all the time in
      psychoanalysis. The play element functions continuously to sustain a paradoxical
      reality where things may be real and not real at the same time. This paradox is
      what allows the work of psychoanalysis to take place. The concept of play covers
      different activities with complex interrelations, and general definitions may be
      misleading. The essential element is the framework that makes the paradoxical
      reality possible. The logical structure of the play framework is investigated,
      and the paper clarifies the relations between the play frame, transference and
      enactment. Play and humour are compared. Spontaneity is the essence of both, and
      the criterion for analytic validity in both cases is whether they deepen the
      analytic process. The tragic and ironic aspects of psychoanalysis are related to
      the intrinsic connection between play and loss. The relation between play and
      games is discussed. The rule-bound quality of games can block more exploratory
      kinds of play, but it may be necessary to accept this, in order for analysis to
      feel safe enough. Clinical material illustrates the importance of the play
      framework, both in a case marked by prolonged hostile and negative states of
      mind, and in others where more straightforward playfulness was possible.

PMID- 10643569
TI  - The phenomenon of object-presenting and its implications for development.
AB  - On the basis of her clinical experience with psychotic children who suffer from
      severe difficulties in tolerating the autonomous existence of the external
      object, the author discusses Winnicott's concept of object-presenting, asking
      what the prerequisites are for infants' acceptance and use of the object; that
      is, for its otherness to be assimilated. An attempt is made to establish a
      connection between Winnicott's and Klein's ideas on this subject, and the
      possible importance of such issues in normal development is indicated. Three
      examples of psychotic children are used to illustrate in detail several
      manoeuvres for avoiding the perception of the not-me, in the pattern of thinking
      that Tustin examined so well. After the clinical discussion, the author concludes
      that some children may be innately more susceptible to reacting negatively to the
      perception of the caretaker's otherness, and that such a characteristic combines
      with the environmental conditions, particularly to the style of maternal care, to
      produce or prevent further pathology. The rhythm, the imitative games, the
      gradual and partial presentation of the external object, and also certain
      possible methods of controlling the object, seem to belong to the set of maternal
      'techniques' that are used spontaneously during the interactions. This style can
      also be useful at times in psychoanalytical work with severely disturbed
      children.

PMID- 10643570
TI  - A severe sexual inhibition in the course of the psychoanalytic treatment of a
      patient with a narcissistic personality disorder.
AB  - This case report illustrates how an analysis of oedipal conflicts gradually
      resolved a severe and extended inhibition of sexual desire that developed as a
      new symptom in the termination phase of psychoanalytic treatment. The enactment
      in the countertransference of castration anxiety, against which the patient was
      successfully defending himself by projective identification, produced an extended
      stalemate, which was resolved once the countertransference was transformed into
      transference interpretations. This treatment also illustrates the intimate
      connection between pre-oedipal and oedipal conflicts in the advanced stages of
      the treatment of narcissistic personalities, and the need for very careful
      assessment of the patient's sexual functioning before deciding on terminating the
      psychoanalysis of a patient with a successfully resolved narcissistic personality
      structure.

PMID- 10643571
TI  - The secret: study of a perverse transference.
AB  - This clinical communication describes the analysis of a perverse transference in
      an overtly bisexual man. An intricate interplay between heterosexual and
      homosexual relations enabled him to maintain some heterosexual functioning and to
      counteract or evacuate intolerable affects and vengeful impulses--originating
      from early traumas--through perverse acting out with sexual partners. Building on
      the notion that patients with sexual perversions recreate aspects of their
      perversion in the transference/countertransference relationship, where it must be
      analysed, the author illustrates through detailed clinical material how she was
      drawn into the fabric of her patient's perversion and how this was worked
      through. She offers an object-relational understanding of his perversion as a
      complex erotised defensive/reparative/vengeful manoeuvre permitting the disavowal
      and magical reversal into triumph and sexual pleasure of perceived threats to his
      personal or sexual identity. Engaging or changing in analysis evoked fears of
      losing his identity by surrendering to the analyst, rooted in the patient's early
      experience of serving as his mother's fetish-object. The author suggests that the
      patient needed to turn the analyst into a perverse partner (disavowing her other
      ness) in order to reverse and triumph over this core trauma. She attributes the
      good treatment outcome to the detection and working through of the perverse
      transference and monitoring of her countertransference.

PMID- 10643572
TI  - 'A cure with a defect': a previously unpublished letter by Freud concerning 'Anna
      O.'.
AB  - The authors make available in this paper the text of a previously unpublished
      letter by Freud, probably addressed to the founder of British ecology and his
      former patient, Sir Arthur Tansley, F.R.S., dating from 1932, concerning the
      treatment and later life of 'Anna O.', the first psychoanalytic patient. They
      give the full text of Freud's letter as discovered, and offer a brief commentary
      on its significance as evidence of Freud's view or views of Anna O.'s treatment,
      case-history and later life. The authors compare the view of Anna O.'s treatment
      and later life with other sources, in particular Freud's roughly contemporaneous
      letter to Stefan Zweig. The letter's principal novel formulation is to be found
      in the phrase 'a cure with a defect', with which Freud characterised Anna O.'s
      experience of her treatment with Breuer.

PMID- 10643573
TI  - A professor through the looking-glass. Contending narratives of Freud's
      relationships with the sisters Bernays.
AB  - In 1982 Peter Swales claimed that Minna Bernays, Freud's sister-in-law, aborted
      Freud's child in Merano in September 1900. Letters published subsequently reveal
      flaws in Swales's hypothesis. Drawing on current literary theories the author
      recontextualises the 'aliquis slip' within a new narrative of the Freuds' 1900
      summer holiday, revealing not an abortion crisis but Freud's momentary fear that
      his wife Martha was again pregnant. A chronological reconstruction of the
      production the 'aliquis slip' and Freud's financial error offers new ways of
      reading Freud's subsequently composed texts. A precision dating of the 'table
      d'hote dream' allows it to be set within its syntagmatic chain, thereby
      suggesting Freud's marital crisis and bitterness at his failed professorial
      application. It is a cocaine anniversary dream dredging up a sixteen-year grudge
      against Martha and the recently elevated Professor Konigstein, both of whom Freud
      still held responsible for his failure to best Koller in discovering the
      anaesthetic properties of cocaine in eye surgery.

PMID- 10643574
TI  - The process of remembering: recovery and discovery.
AB  - Experiences of gradually recovering lost memories may shed some light on the
      cognitive mechanism underlying remembering. We (1) easily remember the external
      frame (the context) of the lost memory; (2) experience the emergence of its
      internal frame (category or genre); (3) recall its configuration, its rhythmic
      skeleton or its dynamic structure; (4) and even sketch it by a gesture; (5)
      recall our evaluation of the person or our impression of the event we cannot
      remember; (6) find the central object may emerge in a disguised (symbolic) form;
      (7) find the abortive first attempt to reconstruct the lost memory may contain an
      unconscious interpretation of the hidden event or the forgotten dream. Gradual
      remembering follows on the whole the path of verbal evolution. Trying to
      recapture lost memories we are compelled to make use of preverbal forms of mental
      elaboration and expression (visual thinking, gesture language, symbols). At the
      same time, recovery of lost memories has much in common with the procedure of
      scientific discovery. Discovery could be considered as a paradoxical form of
      remembering: recovering the unknown. Scientific metaphors uncover ('remember')
      preconscious and unconscious knowledge. In his studies on Farkas Bolyai, Imre
      Hermann made an attempt to interpret scientific theories much in the same way
      that Freud, Jones, Rank, Reik, Hanns Sachs, Roheim analysed myths, rituals,
      literary and artistic works. He traces back some essential features of Bolyai's
      discovery to repressed early memories and fantasies of the great mathematician.

PMID- 10643575
TI  - 'The music of what happens' in poetry and psychoanalysis.
AB  - The author presents a close reading of a Frost poem and a detailed discussion of
      an analytic session. Using specific examples from the poem and from the analytic
      session, he then offers some thoughts concerning the relationship between the way
      he listens to the language of the poem and the way he and his patient speak with
      and listen to one another. The author illustrates in this reading of the poem and
      in the way he speaks to his patient that he is not primarily engaged in an effort
      to unearth what lies 'behind' the poem's words and symbols or 'beneath' the
      patient's report of a dream or of a life event. Instead (or perhaps more
      accurately, in addition), he attempts to listen to the sound and feel of 'what's
      going on', to the 'music of what happens'. This is achieved to a significant
      degree in the analytic setting by means of the analyst's attending to his own
      reverie experience.

PMID- 10643576
TI  - Roald Amundsen: a study in rivalry, masochism and paranoia.
AB  - The author suggests that Freud was intrigued by those who explored the still
      unknown regions of the globe; in 1928 he received a letter from a colleague who
      knew he was interested in the psychology of polar explorers, asking him to
      comment on some strange visualizations that had haunted Roald Amundsen, the great
      polar explorer, when during one of his Arctic expeditions he was attacked and
      nearly mauled to death by a polar bear. Freud emphasised the quality of
      resignation and surrender inherent in these peculiar imaginings, but he added
      that a deeper analysis would require Amundsen's associations. On the basis of
      relevant biographical data the author tries to make a further investigation of
      his strange visualizations. These are linked to an underlying masochistic
      phantasy in which conflicts involving rivalry, autonomy and separation
      individuation problems are expressed. He attained the South Pole before Scott and
      his party, who perished. His triumph and survival on the polar ice evoked an
      unbearable sense of guilt. Being unable to gain insight into his conflicts, he
      regressed to a paranoid state. The relation between masochism, the desire to beat
      and be beaten and rivalry is discussed.

PMID- 10643577
TI  - 'Memory and therapeutic action'.

PMID- 10643578
TI  - 'Shall we ever know the whole truth about projective identification?'.

PMID- 10643579
TI  - Response to Owen Renik.

PMID- 10643580
TI  - Cyclooxygenases in reproductive medicine and biology.
AB  - This review focuses on the role of cyclooxygenases in reproductive medicine and
      biology. The cyclooxygenase enzymes catalysis the role-limiting reactions for
      prostaglandins and thromboxane synthesis. Two separate isoforms, COX-1 and COX-2,
      are present, and differences in their roles are discussed in the context of
      inflammation and parturition.

PMID- 10643581
TI  - Tissue-specific protein kinase C isoform expression in rat uterine tissue.
AB  - OBJECTIVE: Activation of the phosphatidylinositol signaling pathway plays a key
      role during the generation of agonist-stimulated phasic myometrial contractions.
      Protein kinase C (PKC), a component of this signaling pathway, has been
      previously shown to produce feedback inhibition of agonist-stimulated myometrial
      contractions. The studies described in this report were performed to survey the
      tissue-specific expression of several PKC isoforms in the rat uterus. METHODS:
      Uterine tissue was obtained from timed pregnant and normally cycling adult female
      Sprague-Dawley rats. Immunohistochemical studies were performed using the
      Vectastain ABC immunostaining technique and PKC isoform-specific polyclonal
      antibodies. Western blot studies were performed using myometrial tissue separated
      into cytosol and membrane fractions by differential centrifugation. RESULTS:
      These studies confirmed significant expression of the PKC-alpha, -beta 2, -delta,
      -eta, and -zeta isoforms in myometrium from pregnant and estrus rats, whereas
      only trace or no expression of the PKC-beta 1, -gamma, -epsilon, and -theta
      isoforms was observed. Expression of the PKC-alpha, -beta 2, and -eta isoforms
      decreased modestly during the latter days of gestation; in contrast, PKC-delta
      and -zeta remained stable during this period. The immunohistochemical studies
      confirmed expression of the PKC-alpha, -beta 2, -delta, -eta, and -zeta isoforms
      in both circular and longitudinal smooth-muscle layers of the near-term pregnant
      rat uterus. CONCLUSION: In summary, these studies have confirmed significant
      levels of expression of several isoforms of PKC in estrus and near-term pregnant
      rat uterine tissue, which was most prominent in the smooth-muscle cells of the
      myometrium.

PMID- 10643582
TI  - Pregnancy induces expression of cPLA2 in ovine uterine artery but not systemic
      artery endothelium.
AB  - OBJECTIVE: To determine whether pregnancy increases cytosolic phospholipase A2
      (cPLA2) expression in uterine artery (UA) endothelial cells and vascular smooth
      muscle (VSM) cells, and whether ovarian steroids mediate this effect. METHODS:
      Uterine arteries and omental arteries (systemic control) were isolated from
      pregnant (120-130 days' gestation) ewes and from nonpregnant ewes synchronized to
      the corresponding phases of the ovarian cycle (follicular or luteal) or
      ovariectomized. In addition, ovariectomized ewes were treated with vehicle,
      estradiol-17 beta (E2 beta), progesterone (P4), or combined E2 beta/P4 for 10
      days, and UAs were collected. Arteries from all studies were separated into
      mechanically isolated endothelial and VSM fractions. Proteins were then
      solubilized and separated on 7.5% sodium dodecyl sulfate-polyacrylamide gel
      electrophoresis followed by Western immunoblotting using an affinity-purified
      mouse monoclonal antibody for cPLA2. RESULTS: Both UA endothelium and VSM
      fractions were seen to express cPLA2, detected as a single band with a molecular
      mass similar to that observed in myometrium (about 100 kD). Distribution of
      cPLA2, when expressed per microgram of protein, was observed as 40% in UA
      endothelium compared with 60% in VSM fractions. Uterine artery endothelial cPLA2
      expression was specifically increased 1.9-fold in pregnancy (P < .05), whereas
      there was no significant change from VSM. Furthermore, in ovariectomized sheep
      versus intact luteal or follicular phase animals, there was no significant change
      in cPLA2 expression in endothelium or VSM. Administration of E2 beta, P4, or
      their combination in ovariectomized sheep also failed to reproduce the pregnancy
      induced increase in cPLA2 expression in UA endothelium. Omental artery
      endothelial and VSM cPLA2 expression was observed at similar magnitudes as UA
      expression, but levels were consistently unchanged by pregnancy, the ovarian
      cycle, or ovariectomy. CONCLUSIONS: cPLA2 was expressed throughout the
      endothelium and VSM of both uterine and omental arteries, but only in UA
      endothelium was pregnancy associated with elevated cPLA2 expression. The lack of
      change in cPLA2 expression with the ovarian cycle or in ovariectomized animals,
      even after prolonged treatment with E2 beta, P4, or E2 beta/P4 combined suggests
      this pregnancy-induced increase in cPLA2 may not be estrogen and/or progesterone
      dependent.

PMID- 10643583
TI  - The passage of granulocyte-macrophage colony-stimulating factor across the human
      placenta perfused in vitro.
AB  - OBJECTIVE: The purpose of this study was to investigate the placental passage of
      granulocyte-macrophage colony-stimulating factor in a placental perfusion model
      ex vivo. METHODS: In an open system, 11 placentas were perfused on both the
      maternal and the fetal side immediately after delivery. Granulocyte-macrophage
      colony-stimulating factor was added to the maternal perfusion medium in
      concentrations from 10-55 micrograms/mL. Maternal and fetal samples were taken,
      and granulocyte-macrophage colony-stimulating factor (GM-CSF) was measured by
      enzyme-linked immunosorbent assay. RESULTS: Accumulation of granulocyte
      macrophage colony-stimulating factor in the fetal circuit averaged 2.42% of the
      concentration added initially to the arterial portion of the maternal circuit.
      CONCLUSION: There is only low transfer of GM-CSF across the fetal membranes. This
      finding is particularly remarkable in view of recently published results
      suggesting that administration of recombinant granulocyte growth factors to
      pregnant women with imminent preterm delivery helps prevent neonatal sepsis.

PMID- 10643584
TI  - Secretory component in human amniotic fluid and gestational tissues: a potential
      endogenous phospholipase A2 inhibitor.
AB  - OBJECTIVES: Prostaglandins (PGs) are essential mediators of labor during human
      pregnancy. Phospholipase A2 (PLA2) provides the essential substrate for PG
      synthesis through the liberation of arachidonic acid from membrane phospholipid
      stores. Nonlaboring amniotic fluid (NL-AF) contains secretory component (SC)-like
      protein(s) that suppress in vitro PLA2 activity. This study characterizes the
      biologic activity, identity, and tissue distribution of these protein(s) in NL-AF
      and gestational tissues. METHODS: Third-trimester NL-AF was collected by
      amniocentesis, fractionated by ammonium sulfate precipitation, and submitted to
      an in vitro PLA2 assay. Identity of the PLA2 inhibitor in NL-AF was confirmed by
      Western blot and antibody neutralization studies. Secretory component
      immunoreactive proteins were purified by immunoaffinity chromatography and
      visualized by sodium dodecyl sulfate-gel electrophoresis. Tissue distribution of
      SC in gestational tissues was determined by immunohistochemistry. RESULTS: The
      100% pellet and supernatant fractions of NL-AF suppressed PLA2 activity, and this
      activity was neutralized by a polyclonal antibody to SC. Western blot studies
      revealed an SC-reactive protein in the 70-80-kD range in the 100% pellet fraction
      of NL-AF. Two SC-reactive proteins were detected in the 60-80-kD range in the
      eluate from the SC immunoaffinity column, along with minor proteins of 30 and
      greater than 100 kD. Immunohistochemical studies revealed SC in placental
      trophoblast, amniotic membranes, and decidual epithelium. CONCLUSIONS: These
      results demonstrate that proteins homologous to SC are present in human
      gestational tissues and possess anti-PLA2 activity. These proteins may contribute
      to the maintenance of pregnancy by suppressing local PG production.

PMID- 10643585
TI  - Adrenomedullin levels in normal and preeclamptic pregnancy at term.
AB  - OBJECTIVE: To describe maternal plasma levels of adrenomedullin (AM), a
      hypotensive and natriuretic peptide, in normal and preeclamptic women at term.
      STUDY DESIGN: Maternal plasma AM levels were determined in 13 preeclamptic and 15
      normotensive primigravidas by radioimmunoassay. Plasma samples were obtained with
      the patients in the lateral recumbent position before the administration of any
      medications. RESULTS: Women with preeclampsia had significantly elevated AM
      levels when compared with normotensive controls (42.3 +/- 10.5 pg/mL versus 16.9
      +/- 3.1 pg/mL, P < .011). CONCLUSION: In this pilot study, AM levels were
      significantly increased at term in preeclamptic women.

PMID- 10643586
TI  - Estrogen decreases prostaglandin H synthase products from endothelial cells.
AB  - OBJECTIVE: Because we showed recently that estrogen replacement prevents
      prostaglandin H synthase (PGHS)-dependent vasoconstriction in rats, the aim of
      this study was to determine how estradiol affects production of PGHS-dependent
      eicosanoids. METHODS: Cultured bovine coronary microvascular endothelial cells
      were exposed to physiologic levels of 17 beta-estradiol (0.01 nM [about 2.7
      pg/mL], 0.1 nM [about 27 pg/mL], or 1.0 nM [about 270 pg/mL]) for 4, 8, or 24
      hours. Thromboxane (TXA2), prostacyclin (PGI2), and nitric oxide (NO) were
      measured as their stable metabolites, thromboxane B2 (TXB2), 6-keto prostaglandin
      F1 alpha (6-keto PGF1 alpha), and nitrite (NO2), respectively. RESULTS: Estradiol
      had no effect on nitrite production. However, exposure to 0.1 nM and 1.0 nM
      estradiol for 24 hours reduced TXB2 production to 67 +/- 16% and 69 +/- 12% of
      control, respectively. Furthermore, 0.1 nM and 1.0 nM estradiol also reduced
      production of 6-keto PGF1 alpha to 35 +/- 19% and 17 +/- 11% of control,
      respectively. Prostaglandin H synthase expression was not altered by estradiol.
      However, the estrogen receptor inhibitor, tamoxifen, reversed the inhibitory
      effect of estradiol. CONCLUSION: Estradiol acts through a receptor-dependent
      process to decrease PGHS-dependent products, thus further elucidating this novel
      effect of estradiol on the vascular system.

PMID- 10643587
TI  - Inhibitory effect of interleukin-8 on the secretion of platelet-activating factor
      acetylhydrolase by human decidual macrophages.
AB  - OBJECTIVE: To determine whether interleukin-8 (IL-8) regulates platelet
      activating factor acetylhydrolase (PAF-AH) secretion by decidual cells in vitro.
      METHODS: Decidual macrophages were obtained from human term decidual tissue by
      enzymic digestion and Ficoll-Paque centrifugation. The effect of IL-8 and phorbol
      esters on the secretion of PAF-acetylhydrolase by these cells was examined.
      RESULTS: IL-8 inhibited PAF-AH secretion by decidual macrophages in a dose
      dependent manner. The inhibition was reversed partially by antibodies against
      tumor necrosis factor-alpha and IL-1 beta. IL-8-induced inhibition was blocked
      partially by the protein kinase C (PKC) inhibitors, sphingosine, and H-7 1-(5
      isoquinoline sulfonyl)-2-methylpiperazine. A PKC activator, 12-O-tetradecanoyl
      phorbol 13-acetate, decreased PAF-AH secretion. CONCLUSION: IL-8 may increase the
      PAF concentration in the decidua via its inhibitory effect on PAF-AH secretion by
      decidual macrophages. IL-8-induced inhibition of enzyme secretion may have been
      mediated in part by PKC-dependent signal transduction.

PMID- 10643588
TI  - Characteristics and growth patterns of human peritoneal mesothelial cells:
      comparison between advanced epithelial ovarian cancer and non-ovarian cancer
      sources.
AB  - OBJECTIVE: To compare the characteristics and growth patterns of human peritoneal
      mesothelial cells (HPMCs) from advanced epithelial ovarian cancer (EOC) patients
      with those from non-EOC patients. METHODS: Peritoneal and omental biopsies were
      obtained from treatment-naive patients. Formalin-fixed biopsies and cytologic
      touch preparations were studied immunochemically. HPMCs were isolated from tissue
      biopsies or malignant ascites and cultured with or without growth factors. Cell
      growth was determined by the MTT assay. Cultured HPMCs were further characterised
      by flow cytometry analysis (FACS). RESULTS: Peritoneal biopsies showed a
      continuous flat mesothelial cell layer in non-EOC patients, whereas in advanced
      EOC, the mesothelium was a discontinuous layer of rounded cells. In all
      peritoneal biopsies, the mesothelium expressed cytokeratin 8/18, vimentin, and
      the mesothelioma cell antigen but not E-cadherin. In touch preparations,
      expression of the putative fibroblast antigen ranged from negative to weakly
      positive. HPMC from non-EOC cases grew slowly in vitro except when exposed to L
      cysteine (L-cys 30 micrograms/mL) during the initial 24 hours of culture.
      Conversely, cells from EOC sources grew more rapidly, especially when exposed to
      both epidermal growth factor (EGF 10 ng/mL) and hydrocortisone (HC 400 ng/mL).
      HPMC coexpressed cytokeratin 8/18 and vimentin in vitro, but the expression of
      the putative fibroblast antigen increased during primary culture, whereas that of
      the mesothelioma cell antigen decreased in successive passages. Furthermore, in
      FACS, cultured HPMC did not express CD14, CD16, or CD34. CONCLUSION: In
      peritoneal biopsies from non-EOC and EOC patients, HPMCs showed different
      morphology but similar immunostaining characteristics, whereas cultured cells
      from different sources were similar in both morphology and phenotype. L-cysteine
      enhanced the growth of non-EOC but not of EOC-derived HPMCs, which had a maximal
      response to EGF and HC. The growth advantage of HPMCs from EOC in vitro suggests
      these cells are in a primed or activated state.

PMID- 10643589
TI  - Molecular aspects of magnetic resonance imaging and spectroscopy.
AB  - Magnetic resonance imaging (MRI) is a well known diagnostic tool in radiology
      that produces unsurpassed images of the human body, in particular of soft tissue.
      However, the medical community is often not aware that MRI is an important yet
      limited segment of magnetic resonance (MR) or nuclear magnetic resonance (NMR) as
      this method is called in basic science. The tremendous morphological information
      of MR images sometimes conceal the fact that MR signals in general contain much
      more information, especially on processes on the molecular level. NMR is
      successfully used in physics, chemistry, and biology to explore and characterize
      chemical reactions, molecular conformations, biochemical pathways, solid state
      material, and many other applications that elucidate invisible characteristics of
      matter and tissue. In medical applications, knowledge of the molecular background
      of MRI and in particular MR spectroscopy (MRS) is an inevitable basis to
      understand molecular phenomenon leading to macroscopic effects visible in
      diagnostic images or spectra. This review shall provide the necessary background
      to comprehend molecular aspects of magnetic resonance applications in medicine.
      An introduction into the physical basics aims at an understanding of some of the
      molecular mechanisms without extended mathematical treatment. The MR typical
      terminology is explained such that reading of original MR publications could be
      facilitated for non-MR experts. Applications in MRI and MRS are intended to
      illustrate the consequences of molecular effects on images and spectra.

PMID- 10643590
TI  - The significance of lichens and their metabolites.
AB  - Lichens, symbiontic organisms of fungi and algae, synthesize numerous
      metabolites, the "lichen substances," which comprise aliphatic, cycloaliphatic,
      aromatic, and terpenic compounds. Lichens and their metabolites have a manifold
      biological activity: antiviral, antibiotic, antitumor, allergenic, plant growth
      inhibitory, antiherbivore, and enzyme inhibitory. Usnic acid, a very active
      lichen substance is used in pharmaceutical preparations. Large amounts of
      Pseudevernia furfuracea and Evernia prunastri are processed in the perfume
      industry, and some lichens are sensitive reagents for the evaluation of air
      pollution.

PMID- 10643591
TI  - Isoform-specific interactions between halothane and the ryanodine receptor Ca(2+)
      release channel: implications for malignant hyperthermia and the protein theory
      of anaesthetic action.
AB  - General anaesthetics exhibit a relatively close relationship between their
      pharmacological potency and their lipid solubility and may thus act by non
      specific perturbation of biomembranes. However, more recent data on anaesthetic
      action suggests that inhalational drugs such as halothane bind directly to
      hydrophobic protein domains, thereby modulating important receptor functions. In
      support of this protein theory of anaesthetic action our native gel analysis
      presented here shows that halothane induces oligomerization of the skeletal
      muscle ryanodine receptor (RyR) 1 Ca(2+)-release channel, but not its cardiac RyR
      2 isoform. Thus, inhalational anaesthetics are not only able to influence protein
      protein interactions directly but also appear to differentiate between protein
      isoforms and/or configurations. This suggests that distinct peptide binding sites
      exist for these pharmacological agents. In addition, similar mutations in the RyR
      2 isoform, which would trigger an episode of malignant hyperthermia in skeletal
      muscle fibres via abnormal RyR-1 isoforms, would probably not induce an increase
      in cardiac Ca(2+)-release upon administration of halothane.

PMID- 10643592
TI  - [Neuro-cognition and schizophrenia. 11th World Congress for Psychiatry. Hamburg,
      8 August 1999].

PMID- 10643593
TI  - [Regulation of inositol-1,4,5-triphosphate receptor by G(i)-protein].
AB  - The pertussis toxin (PT) inhibits thrombin-induced mobilising of Ca2+ but does
      not affect formation of inositol-1, 4, 5-triphosphate (IPh3). The latter being
      related to Gi and G0, the possibility of a direct effect of these proteins on the
      IPh3-induced release of Ca2+ from sarcoplasmic reticulum, was studied. The data
      obtained suggest existence of an association of the Gi3 protein with the IPh3-P
      on the sarcoplasmic reticulum membrane, as well as a direct modulation by the Gi
      protein of the Ca2+ release from intracellular stores.

PMID- 10643594
TI  - [Inward rectifier potassium current in the frog embryonic skeletal myocytes].
AB  - Pharmacological and kinetic properties of the inward rectifier potassium current
      Iir the frog embryonic skeletal myocytes were found to be identical to those of
      adult frog skeletal muscle fibres. The data obtained suggest that the Iir plays
      the main role in maintaining the myocytes resting membrane potential (RMP) when
      chloride conductance is insignificant. Changes of the integral conductance Gir
      and the RMP values correlated with the T-system development. The inward rectifier
      K+ channels, from the early stages of the muscle seem to be located in the T
      tubule membranes.

PMID- 10643595
TI  - [Effect of prenatal stress on learning of rats in the Morris test].
AB  - Prenatal stress was found not to affect learning capability in Morris Water Maze
      in rats, although some difference was revealed in the rats behaviour. 2-month old
      rats who had been subjected to a prenatal stress, revealed an obvious trend
      towards less flexible strategy of behaviour and perseveration. At the age of 4
      months, the difference between the control and experimental groups becomes
      negligible.

PMID- 10643596
TI  - [Changes in various parameters of the mouse immune status subjected to chronic
      social conflict].
AB  - Recurrent experience of a social confrontation was shown to increase the per cent
      of cleavage nucleus neutrophiles in both mice-participants, activation of the
      lymphocyte dehydrogenase, and reduction of number of the CDA+ and CD8+ T
      lymphocytes. Dynamic character of changes in the metabolism parameters and the
      number of lymphocytes is obviously dependent on duration of the confrontations in
      mice.

PMID- 10643597
TI  - [Study of monoamino- and amino acidergic mechanisms of the rat caudate nucleus in
      antiaversive effects of tranquilizers in various anxiety models].
AB  - Administration of anxio-sedative drugs into the rat caudate nucleus revealed that
      antiaversive effects of chlordiazepide, phemibut, and indoter only occur under
      dominating fear motivation, whereas antiaversive effects of campirone and
      campironine occur under the influence of negative or stressful zoo-social actions
      and are realised via the GABA- and serotoninergic type of synaptic switching in
      the dorsal part of the caudate nucleus.

PMID- 10643598
TI  - [Types of the peptide modulation of the vagus nerve effect on the heart rhythm].
AB  - In anaesthetised cats, effects of 24 regulatory peptides upon inhibitory tonic
      and synchronizing components of vagal chronotropic action, were studied. The
      findings allowed to divide the peptidergic vagotropic activity into three types:
      (1) a selective action upon inhibitory tonic vagal effect; (2) a selective
      modulation of synchronizing vagal effect; (3) opposite changes in the vagal
      chronotropic effect components. The peptides seem to be able to modulate both the
      vagal bradycardia and the functional structure of parasympathetic chronotropic
      effect.

PMID- 10643599
TI  - [The initial tone of arteries determines the magnitude of depressor responses
      caused by nitroglycerin].
AB  - The correlation analysis revealed a direct (within the range 80 to 120 mm Hg)
      further transforming into a reverse (within the range 121 to 160 mm Hg)
      dependence of the blood pressure depressor shifts on the initial mean arterial
      pressure in anaesthetised rats. Within the physiological range of arterial
      pressure (70 to 130 mm Hg) there is no difference in responses to nitro-glycerine
      from their initial values. The mechanisms of dependence of the systemic vascular
      responses on initial tone of arterial vessels, are discussed.

PMID- 10643600
TI  - [Thermoregulatory reaction in the rabbit fetuses developing under the reduced
      utero-placental blood flow].
AB  - Rectal temperature, temperature of the brown adipose tissue, and the heart rate
      were studied in the rabbit foetus under intact and reduced utero-placenta blood
      flow in the end of the intrauterine development. With the reduced utero-placenta
      blood flow, bradycardia and a drop in the brown fat metabolism due, probably, to
      an insufficient development and functional immaturity of this tissue, were
      revealed.

PMID- 10643601
TI  - [Modulation of the contractile activity of the fast and slow twitch rat muscle
      during continuous stimulation].
AB  - The fast- and slow-twitch muscles were tested with single pulses in the course of
      unfused tetanus formation. The tetanus decreased differences in contractile
      parameters of the test-twitch contractions and, after continuous stimulation,
      eliminated them altogether.

PMID- 10643602
TI  - [Effect of delta sleep-inducing peptide on lipid peroxidation and xanthine
      oxidase activity in rat tissues during cold stress].
AB  - I. p. administration of exogenous delta-sleep-inducing peptide (DSIP) decreased
      the amount of diene conjugates and Schiff bases in the liver and brain in rats.
      The xanthine oxidase activity, at that, did not change. Cold stress enhanced the
      xanthine oxidase activity well as the amount of diene conjugates and Schiff
      bases. Preliminary administration of the delta-sleep-inducing peptide to cold
      exposed animals diminished the xanthine oxidase activity and lipid peroxidation
      in the liver and brain. Protective effects of the DSIP under stress is discussed.

PMID- 10643603
TI  - [Effect of acute hypothermia on parameters of tetanic contraction of the rat
      skeletal muscle].
AB  - In rats under acute hypothermia, tetanic tension of the medial m. gastrocnemius
      had a higher amplitude.

PMID- 10643604
TI  - [Effect of cocaine on the contractile response to noradrenaline in the epididymal
      and prostatic regions of the vas deferens].
AB  - In the prostatic half of the rat vas deferens, the response to noradrenaline
      under the cocaine effect revealed a phasic and a tonic components, whereas in the
      epididymal portion of the vas deferens there only occurred the tonic component.
      Cocaine increased the maximal tonic contractile response to noradrenaline in the
      epididymal portion and the maximal phasic response--in the prostatic one.
      Mechanisms of direct postsynaptic action of cocaine are discussed.

PMID- 10643605
TI  - [Study of the stimulating effect of the sympathetic stem on the stomach
      contraction].
AB  - Stimulation of the sympathetic stem chest portion induces enhancement rather than
      suppression of gastric contractions. The activating effect is more obvious under
      conditions of the alpha- and beta-adrenoreceptors blockade with phenolamine and
      obsidan, and eliminated with the smooth muscle serotoninoreceptors blocking agent
      lisergol. The findings suggest that the sympathetic stem includes some
      serotoninergic neural fibres exerting a strong effect upon gastric and intestinal
      contractions. A previously unknown serotoninergic part of the vegetative nervous
      system controlling the internal organs functions, seems to exist in the organism.

PMID- 10643606
TI  - [Effect of the brain 5-HT2 receptor blockade on gastric mucosa damage caused by
      social stress in males of two mouse strains].
AB  - Mice-losers in social conflicts had an increased number of haemorrhages and
      erosions in gastric mucosa as compared with the control and winners-mice.
      Administration of ciproheptadine and/or ketanserin enhanced the neurogenic
      gastric damage both in the winners and in control mice. The CBA strain mice were
      more sensitive to the damaging effects of the drugs than the C57-strain winners.
      The experience of social confrontations seems to change the gastric mucosa
      condition and to modify the mucosa response to the brain serotonine receptor
      blockade, depending on the social confrontations outcome and the animals'
      genotype.

PMID- 10643607
TI  - [Effect of prenatal stress on the hypothalamo-hypophyseal-adrenal system activity
      and fat metabolism in the male water vole Arvicola terrestris].
AB  - The HPA axis function and the fat metabolism were studied in adult male water
      voles born to intact mothers and mothers deprived of food on the 15th and 18th
      days of their pregnancy. The HPA response to emotional stress was relatively low
      in experimental males in winter. The hormonal response to a 24-hrs food
      deprivation diminished in experimental group only in February. The blood level of
      free fatty acids was increased in experimental group as compared to the control
      one. The short maternal food deprivation modified adaptive abilities of their
      male progeny.

PMID- 10643608
TI  - [Effect of tetanization of the motor cortex on neuronal responses in the albino
      rat mesial cortex].

PMID- 10643609
TI  - [Generator layers of the electrocorticogram].

PMID- 10643610
TI  - [A two-chamber mobile incubation system for contact microfluorometry in brain
      slices].

PMID- 10643611
TI  - [Atropine effect on physostigmine- and stress-induced secretion of catecholamines
      by adrenal gland: microdialysis study in awake rats].
AB  - Physostigmine and an 1-hour immobilisation stress similarly affected functions of
      the sympatho-adrenal and cardiovascular systems activating the catecholamine
      secretion and increasing the blood pressure. Yohimbine potentiated the secretory
      effect but did not change the pressor effect. Intermediate administration of
      atropine completely eliminated both effects of physostigmine but, being
      administered prior to the immobilisation, it potentiated the secretory response
      without affecting the pressor response. The findings reveal a difference in
      central cholinergic mechanisms of neurohumoral and haemodynamic responses to
      physostigmine and stress.

PMID- 10643612
TI  - [Novel lipoprotein-binding proteins p105 and p130 in smooth muscles of human
      vessels: structure, expression, and possible physiological role].
AB  - The expression level of two new lipoprotein-binding proteins p105 and p130 was
      maximal in inactive VSMC and could be suppressed by activators of proliferation.
      Both proteins were detected by antisera against three synthetic fragments of T
      cadherin and were rendered soluble by GPI-specific phospholipase C. The findings
      suggest that the 105 kDa lipoprotein-binding protein is T-cadherin whereas p130
      is a partially processed GPI-anchored precursor of T-cadherin.

PMID- 10643613
TI  - [Spectral analysis of heart rate fluctuations: physiological basis and
      complicating factors].
AB  - The main stages of investigation into the changes of the heart rate in human
      (HRH), are presented. A satisfactory coincidence of results of the HRH
      oscillation power estimation within two frequency ranges obtained with the aid of
      two techniques: by the Yamamoto algorithm and by search for sources of non
      harmonic oscillations, was shown.

PMID- 10643614
TI  - [The role of deformability of endothelial cells in the arterial response to shear
      tension].
AB  - Treatment of the femoral artery luminal surface with glutaraldehyde dimere or
      dithiosuccinimidyl propionate reduced or eliminated flow-induced dilation, the
      responses to acetylcholine and the ATP being preserved. The findings suggest that
      the endothelial cells perceive changes in shear stress and that the cell
      stiffness is a factor subject to the influence of the magnitude of flow-induced
      arterial dilation.

PMID- 10643615
TI  - [Asymmetric responses of epicardial and endocardial fibers of the dog atrium to
      cholinergic effects].
AB  - The ACh shortened the AP in canine epicardial and endocardial cells, the effect
      being more obvious in the latter. The findings suggest that 4-aminophyridine
      sensitive transient outward current is expressed in canine atrial epicardial and
      endocardial cells, that the ACh exerts direct effects on epicardial and
      endocardial AP duration, that differential responses of epicardial and
      endocardial AP duration to the ACh may alter the gradient of repolarisation
      across the atrial wall and contribute to the vagus-indoced atrial flutter and
      fibrillation.

PMID- 10643616
TI  - [Early stage of cardiomyopathy: mechanisms of damage and compensation].
AB  - In an experimental model of cardiomyopathy in Syrian hamsters, four principal
      phases were identified: lesion, reparation, compensation, and decompensation.
      Calcium overload seems to be a leading pathogenic factor in the 1st phase. If the
      action of damaging factor persists, the reparation phase is incomplete, and the
      compensation of the cardiac contractile function occurs due to an altered protein
      composition in the cells and extracellular matrix.

PMID- 10643617
TI  - [Angiotensin II inhibits L-type voltage-dependent Ca(2+)-current in smooth muscle
      cells from the rat aorta].
AB  - Macroscopic voltage-activated L-type Ca2+ currents were blocked by angiotensin II
      (A11), the effect being inhibited by losartan. A rise in internal Ca2+ evoked by
      the A11, occurred, losartan being ineffective in these cases. The AT1 receptors
      seem to be involved in the effect of the A11 on the L-type Ca2+ current in aortic
      smooth muscle cells.

PMID- 10643618
TI  - [The role of genome repetitive sequences in primary hypertension].
AB  - Genetic determining factors of essential hypertension seems to involve a dynamic
      mutation or a similar process. The mobile elements of the genome: moderately
      recurrent sequences, play a special role in initiation of such a process. A
      possible molecular mechanism of the initiation and development of the dynamic
      mutation, is described.

PMID- 10643619
TI  - [Clinical and electrophysiologic variants of false ventricular tachycardia
      (supraventricular tachycardia with wide QRS complex)].
AB  - Electrophysiological abnormalities of the heart conduction system and their role
      in development of different forms of supraventricular tachycardias, are
      discussed. Electrophysiological mechanisms and diagnostic criteria of the
      supraventricular tachycardias with wide QRS complex, are described.

PMID- 10643620
TI  - [Distribution of recombinant pro-urokinase in the rabbit blocked carotid artery].
AB  - Distribution of recombinant pro-urokinase (PRU) in segments of blocked carotid
      arteries of rabbits was measured in 10, 20 and 30 minutes after i.v.
      administration of the RPU. Concentration of the latter in the bloodstream taken
      as 100% on the 3rd minute, after the infusion decreased to 42% in 10 min., 24% in
      20 min., and 13% in 30 min. The RPU concentration decreased to 2% at the artery
      clamp point, to 20% at 10-15 cm from the clamp point, and remained constant for
      10-30 min. A thrombolytic agent accumulated at the dead-end of the blocked
      artery, was not subject to rapid clearance in contrast to circulating pro
      urokinase.

PMID- 10643622
TI  - [Atherothrombosis in cardiology].

PMID- 10643621
TI  - [Prion phenomenon in medicine and biology].
AB  - The data obtained suggest that the fatal changes in brain tissue associated with
      the prion diseases, are initiated by a conformational rearrangement of
      constitutively expressed cellular protein PrP. Possible mechanisms of such a
      conversion of this protein are discussed. Existence of the proteins with the
      prion properties in low eukaryotes may determine the unusual mechanisms of the
      "protein" inheritance. A new experimental model for studying the proteins with
      the prion properties in the yeast Saccharomyces cerevisiae, is described.

PMID- 10643623
TI  - Liver microvascular architecture: an insight into the pathophysiology of portal
      hypertension.
AB  - Structural adaptations in the liver to constantly receive and release a large
      volume of circulating blood at low pressure are present at many levels;
      alteration of these structures can modify flow and perturb pressure gradients.
      Liver growth multiplies the lobule number by a factor of 4-5 after birth. Lobule
      configuration conforms with observations in space division, each unit being
      bordered by planes; curvature will impede expansibility and retractability among
      units. Lobular organization with hepatocytic plates and sinusoids, being radial
      centrally and reticular peripherally, maximizes its reversible distensibility.
      Resistance sites in the portal, sinusoidal, and hepatic system are subject to
      species variations; real portal sphincters are photographed in the frog. Small
      venules are demonstrably resistive. In endothelin-1-induced rat portal
      hypertension, the distal segment of preterminal portal venules constricts most
      intensely, whereas the terminal portal venules and sinusoids are flaccid. Their
      pericytes and arachnocytes (stellate cells, Ito cells, retinol-storing cells),
      respectively, possess no effective contractile machinery. In the dog, the initial
      sublobular veins react with venoconstriction to many stimulations. Well-developed
      musculature in hepatic veins, as in man and pig, can regulate flow by junctional
      constriction. These histoarchitectonics provide hepatic hemodynamics with high
      capacitance and high compliance properties. The hepatic artery supplies
      oxygenated blood to five stromal compartments: peribiliary vascular plexus,
      portal tract interstitium, portal vein vasa vasorum, hepatic capsule, and central
      sublobular-hepatic vein vasa vasorum. Its role as the nutrient vessel to the
      veins is established, but what influence it may have in the pathophysiology of
      portal hypertension awaits clarification.

PMID- 10643624
TI  - Regulation of sinusoidal perfusion: in vivo methodology and control by
      endothelins.
AB  - Considerable attention has recently been focused on the phenomenon of active
      constriction of sinusoids as a mechanisms for regulating perfusion of the liver.
      Although many methods for estimating liver blood flow have been used in the past,
      the ability to directly study vascular responses in the sinusoids required the
      spatial and temporal resolution provided by intravital microscopy. Although
      techniques for viewing microvessels in thin tissues such as the mesentery or
      cremaster muscle have been available for many years, our current ability to fully
      use intravital microscopy to study microvascular responses and related metabolic
      parameters in thick tissues such as the liver has resulted from recent advances
      in fluorescence microscopy. Intravital microscopy can be used in in vivo or
      isolated perfused liver studies to assess changes in sinusoidal perfusion.
      Additional information concerning the relationship between microvascular changes
      and metabolic parameters in the liver can be simultaneously obtained by
      exploiting various recent advances in the design of fluorescent indicators. These
      techniques have allowed the mechanisms regulating sinusoid perfusion to be
      studied in great detail. It is now clear that sinusoids constrict in vivo in a
      graded and reversible manner in response to specific mediators such as
      endothelins. This constriction is modulated by dilators such as nitric oxide and
      carbon monoxide, which are also generated within the sinusoids. It is likely that
      poorly regulated sinusoid constriction contributes to liver injury and long-term
      development of increased intrahepatic vascular resistance. This response is
      mediated by alterations in the expression of endothelin receptor subtypes and
      eventually by phenotypic transformation of the hepatic stellate cells. In
      addition, local mismatch in the stress-induced induction of vasodilator and
      vasoconstrictor influences lead to an increase in the local heterogeneity of
      blood flow and oxygen supply. This heterogeneous perfusion contributes to the
      development of focal ischemia and progression of injury. Taken together, the
      results reviewed here indicate that the sinusoid is an important site of
      regulation of liver blood flow and that dysregulation of sinusoidal perfusion
      leads to propagation of liver injury.

PMID- 10643625
TI  - Biology of hepatic stellate cells and their possible relevance in the
      pathogenesis of portal hypertension in cirrhosis.
AB  - In the past 10 years we have witnessed an exponential increase in the knowledge
      on the development and progression of liver fibrosis. At present, liver
      fibrogenesis is referred to as a dynamic process involving complex cellular and
      molecular mechanisms, resulting from the chronic activation of the tissue repair
      mechanisms that follows reiterated liver tissue injury. The identification and
      characterization of the cell types and of the different mediators involved in
      this process has allowed a "revisitation" of several issues related to liver
      cirrhosis and its immediate consequences. Among these, evaluation of the
      relationships occurring between fibrogenesis and portal hypertension,
      cholestasis, and the development of hepatocellular carcinoma represent some of
      the hottest areas of research in the field of hepatology. Our aim is to establish
      a link between the available knowledge on the biology of hepatic stellate cells
      and their possible implication in the genesis and progression of portal
      hypertension.

PMID- 10643626
TI  - Nitric oxide and portal hypertension: its role in the regulation of intrahepatic
      and splanchnic vascular resistance.
AB  - In recent years it has become well established that nitric oxide (NO) plays a
      crucial role in the hemodynamic abnormalities that develop in chronic portal
      hypertension. The purpose of this review is to summarize the available data and
      current concepts regarding the involvement of NO in the pathophysiologic changes
      in the micro-circulation of the liver and the splanchnic and systemic circulation
      that associate portal hypertension.

PMID- 10643627
TI  - Influence of pharmacological agents on portal hemodynamics: basis for its use in
      the treatment of portal hypertension.
AB  - Progress in the knowledge of the pathophysiology of portal hypertension has
      opened the door to pharmacological treatments, resulting in a dramatic change in
      the therapeutic approach to portal hypertension. This review summarizes
      pharmacological agents that have been shown to effectively decrease portal
      pressure, paying special attention to its mechanisms of action. In addition, the
      way to monitor response and clinical efficacy of pharmacological agents is
      reviewed.

PMID- 10643628
TI  - Endoscopic treatments for portal hypertension.
AB  - Endoscopic treatments for bleeding gastroesophageal varices include injection
      sclerotherapy, variceal obturation with tissue adhesives, and variceal rubber
      band ligation. Acute injection sclerotherapy remains a quick and simple technique
      for the control of active bleeding from esophageal varices. Although few trials
      have been published so far, some evidence suggests that the early administration
      of vasoactive drugs (somatostatin, octreotide, or terlipressin) is safe and may
      increase the efficacy of endoscopic treatments. Banding ligation is the optimal
      endoscopic treatment for the prevention of rebleeding from esophageal varices.
      The use of tissue adhesives and thrombin as injectates to treat bleeding fundal
      gastric varices and esophageal varices not responding to vasoactive drugs or
      sclerotherapy is promising but needs further assessment by means of randomized
      controlled trials. As of today, endoscopic treatments are not recommended for the
      primary prophylaxis of variceal bleeding.

PMID- 10643629
TI  - Transjugular intrahepatic portosystemic shunt.
AB  - The Transjugular Intrahepatic Portosystemic Shunt (TIPS) has now become an
      accepted part of the therapeutic armory available to the practicing clinician. It
      may stop variceal bleeding when traditional endoscopic techniques have failed,
      and can be used as secondary prevention of variceal bleeding, as well as a
      treatment for intractable ascites and the Budd-Chiari syndrome. It has afforded
      new insights into the mechanisms of these disorders and significantly advanced
      our knowledge of disease pathophysiology. It has done all these things, and yet
      is a procedure that may be performed without interrupting the surgical field,
      should the patient require a transplant at a later date. In this article, the
      various indications for TIPS are reviewed with a critical eye. Advances in
      placement technique, refinement of indications, and results are all discussed.
      The authors present an up-to-date assessment of the clinical trials performed
      using this radiologic shunt, as well as their conclusions regarding the various
      clinical indications.

PMID- 10643631
TI  - Ultrasonically enhanced leaching: removal and destruction of cyanide and other
      ions from used carbon cathodes.
AB  - The used carbon cathodes ('Spent Pot Lining', SPL) from aluminium smelting are
      typically contaminated with F-, CN- and Na+ which must be removed before disposal
      to produce material which satisfies environmental guidelines in respect of
      maximum rates of ion release. Leaching of powdered and crushed carbon samples in
      aqueous solution were studied in the presence and absence of ultrasound. First,
      it was demonstrated that the total leaching of F-, CN- and Na+ from the carbon
      powder could be accomplished after approximately 20 min of sonication using
      ultrasound. Second, carbon particles (< 5 mm) showed leaching characteristics
      under ultrasound which were in good quantitative agreement with the National
      River Authority (NRA) test under silent conditions; the former being a much more
      rapid (approximately 1 h compared to 24 h for the NRA test) but equivalent method
      to the latter standard test. Third, the removed CN- ions were found to be
      destroyed in the presence of ultrasound, possibly via the oxidative action of
      hydrogen peroxide generated by the sonication of water.

PMID- 10643630
TI  - Pharmacological treatment of portal hypertension: an evidence-based approach.
AB  - Continuing advances in the knowledge of the pathophysiology of portal
      hypertension result in the progressive expansion of the spectrum of drugs with a
      potential role for clinical practice, with objectives that now tend to include
      the prevention of the enlargement or even the development of esophageal varices.
      This systematic review summarizes the evidence of efficacy of drug therapy for
      portal hypertension and draws recommendations for clinical practice. Although
      there is not yet enough evidence to support the treatment for the prevention of
      the development or enlargement of varices, nonselective beta-blockers are the
      first-choice therapy to prevent the first bleeding in patients with medium or
      large-sized varices and rebleeding in patients surviving a bleeding episode. The
      clinical role of isosorbide-5-mononitrate either alone or in association with
      beta-blockers still remains unsettled. Vasoactive drugs are generally effective
      and safe in controlling acute variceal bleeding, although the evidence is not
      equivalent for each of them.

PMID- 10643632
TI  - Sonoelectrochemical and sonochemical effects of cavitation: correlation with
      interfacial cavitation induced by 20 kHz ultrasound.
AB  - Sonoelectrochemical measurements at macro-electrodes under extreme conditions
      with a very short distance between ultrasonic horn tip and electrode and
      different ultrasound intensity levels are shown to result in violent cavitation
      detected in form of current peaks superimposed on the average limiting current.
      Analysis of the current data obtained for the oxidation of ferrocene in
      dimethylformamide (0.1 M NBu4PF6) at a 4 mm diameter Pt disc electrode and for
      the reduction of Ru(NH3)6(3+) in aqueous 0.1 M KCl at a 6 mm diameter Pt disc
      electrode consistently indicate a change of the physicochemical nature of
      sonoelectrochemical processes under extreme conditions. The sonoelectrochemical
      measurement of the rate constant for the carbon bromide bond cleavage of a 3
      bromobenzophenone radical anion electrogenerated at a glassy carbon electrode in
      dimethylformamide solution in the presence of power ultrasound is shown to yield
      evidence for a breakdown of the conventional mass transport model of a planar
      diffusion layer under extreme conditions. The change can be correlated to the
      number of current data points deviating more than 10% from the mean of the
      current due to violent cavitation processes superimposed onto the average
      limiting current. Further, a study of the sonochemical destruction of aqueous
      dilute cyanide solution (in 0.1 M NaOH) demonstrates a correlation between the
      electrochemically detected cavitation violence and the sonochemical activity.
      Factors that govern the violence of interfacial cavitation appear to be directly
      proportional to the factors that make cavitation in the bulk solution chemically
      efficient.

PMID- 10643633
TI  - Sonochemical hydrosilylation of 2-substituted cyclohexanones in the presence of
      Wilkinson complex.
AB  - The sonochemical hydrosilylation of alkyl substituted cyclohexanones catalyzed by
      Rh (PPh3)3Cl is described. The application of ultrasonic irradiation during the
      reaction highly enhances the reaction rates and produces higher yields than those
      obtained in silent reactions. The stereoselectivity of the reaction has not been
      changed, the isomeric distribution, i.e. the cis/trans ratio of the 2-substituted
      cyclohexanols formed, is very close to those obtained in conventional stirred
      reactions.

PMID- 10643634
TI  - Enhancement of sonoluminescence emission from a multibubble cavitation zone.
AB  - Investigations have been performed on various methods of increasing cavitation
      activity measured by the intensity of sonoluminescence. It is shown that the
      effect of the combined action of (a) pulsed modulation of an acoustic field, (b)
      liquid degassing and cooling and (c) increasing the static pressure considerably
      exceeds the sum of the effects achieved by each of these methods individually. A
      more than 250-fold increase of the sonoluminescence intensity has been attained
      compared with continuous irradiation under normal conditions (room temperature,
      atmospheric pressure, gas-saturated liquid). An interpretation of the results
      obtained is proposed.

PMID- 10643635
TI  - Ultrasound effects on metallic (Fe and Cr); iron sesquioxides (alpha-, gamma
      Fe2O3); calcite; copper, lead and manganese oxides as powders.
AB  - Different kind of materials, as powders, were submitted to ultrasound after
      mixing in water, dodecane or dilute acetic acid (5%). After treatment, firstly a
      decrease of particle size, and secondly the formation of unexpected and unknown
      compounds was observed on a mesoscopic scale (CaO from CaCO3 for example). For
      iron and iron oxides, it was found that the magnetic properties (susceptibility
      and effective magnetic moment) were changed slightly. A shift in the Morin
      temperature transition for alpha-Fe2O3 was attributed to the formation of
      impurities. For inorganic oxides (Cu2O, PbO, Pb3O4 and Mn3O4) sonicated in dilute
      acetic acid, the formation of metallic acetates is easily achieved and it is
      rapid (10 s for PbO).

PMID- 10643636
TI  - Ultrasound-induced cracking and pyrolysis of some aromatic and naphthenic
      hydrocarbons.
AB  - The action of intense ultrasound on solutions of decahydronaphthalene (decalin)
      or tetrahydronaphthalene (tetralin) causes, in both cases, a dehydrogenation
      reaction at room temperature. According to thermodynamic calculations,
      temperatures as high as 500 degrees C are necessary to achieve the same results.
      The use of Pd and Se as dehydrogenation catalysts has confirmed the
      dehydrogenation reactions. Benzene and toluene sonication at room temperature
      causes aromatic ring breakdown with formation of acetylene and other products.
      The analogy with radiolysis was noticed. A thermodynamic analysis was conducted
      on the possible reaction products formed from benzene ring cleavage including
      polymerization products. It was concluded that acetylene formation from benzene
      is possible for instance at 650 degrees C only if it is accompanied by coke
      formation. Otherwise temperatures as high as 1700 degrees C are needed. The
      nature of the 'coke' formed during sonication is discussed, it was revealed by FT
      IR spectroscopy to be a crosslinked polystyrene and hence it is a sonopolymer
      derived from benzene or toluene ring breakdown products reacted with phenyl and
      polyphenyl radicals. Again the striking analogy between the IR spectrum of
      irradiated polystyrene and benzene sonopolymer was noticed. The formation of poly
      p-phenylene was excluded by the FT-IR pattern which did not match that of an
      authentic sample.

PMID- 10643637
TI  - Sonolysis of aqueous 4-nitrophenol at low and high pH.
AB  - The sonolysis of 4-nitrophenol in argon-saturated aqueous solution has been
      studied at 321 kHz. In order to evaluate separately the effect of OH radicals
      that are formed in the cavitational bubble and part of which react in the aqueous
      phase with this substrate, radiolytic studies in N2O-saturated solutions were
      carried out for comparison. A detailed product study of the sonolysis of 4
      nitrophenol solutions shows that at pH 10, where 4-nitrophenol is deprotonated
      (pKa = 7.1), its sonolytic degradation is fully accounted for by OH-radical
      induced reactions in the aqueous phase. At this pH, the sonolytic yield of H2O2
      resulting from OH radical recombination in the solution, measured as a function
      of the 4-nitrophenol concentration, is reduced in line with the scavenging
      capacity of the 4-nitrophenolate. In contrast, at pH 4 the formation of H2O2 is
      already fully suppressed when the solution is 7 x 10(-4) mol dm-3 in 4
      nitrophenol, and oxidative-pyrolytic degradation predominates, as exemplified by
      the large yields of CO and CO2 which are accompanied by a large H2 yield. The
      basis of this difference in behavior is a hydrophobic enrichment of 4-nitrophenol
      (which is undissociated at pH 4) at the interface of the cavitational bubble by a
      factor of about 80. The pH dependence of the yields of the pyrolytic products
      reflects the hydrolytic equilibrium concentration of 4-nitrophenol. The paper
      also demonstrates that the complexity of this sonochemical system precludes its
      use a gauge to determine the temperature in the interior of the cavitational
      bubble.

PMID- 10643638
TI  - Purification of aminophenyl mercuryacetate-activated human matrix
      metalloproteinase 1 and removal of the organomercurial in a single-step
      chromatography.
AB  - Matrix metalloproteinases are secreted from different cells as inactive zymogens.
      For their activation in vitro organomercurials may be used, the presence of
      which, however, can falsify activity assays and modulate the effects of the
      proteases in subsequent investigations. Here, we demonstrate the binding of human
      matrix metalloproteinase 1 to a thiophilic resin (mercaptoethylquinazolinedione
      derivatized agarose) and take advantage of this thiophilic interaction for the
      purification of organomercurial activated matrix metalloproteinase 1 from the
      supernatant of a thyroid carcinoma cell line in connection with the simultaneous
      removal of the activator.

PMID- 10643639
TI  - Fractionation of cellulase and beta-glucosidase in a Trichoderma reesei culture
      liquid by use of two-phase partitioning.
AB  - An aqueous two-phase system based on the two polymers poly(ethylene glycol) and
      dextran has been used for the fractionation of cellulase enzymes present in
      culture liquid obtained by fermentation with Trichoderma reesei. The activities
      of beta-glucosidase and glucanases were separated to high degree by using the two
      phase systems for a counter-current distribution process in nine transfer steps.
      While the glucanases had high affinity to the poly(ethylene glycol) rich top
      phase the beta-glucosidase was enriched in the dextran-containing bottom phase.
      Multiple counter-current distribution performed indicates the heterogeneity of
      beta-glucosidase activities assuming at least four isoenzyme forms. One step
      concentration of beta-glucosidase by using system with 46:1 phase volume ratio
      resulted in 16 times higher enzyme activity.

PMID- 10643640
TI  - Immobilization of oligonucleotides on a large pore support for plasmid
      purification by triplex affinity interaction.
AB  - Triplex affinity interaction provides a new process for the purification of
      plasmid DNA, which is especially suited to meet the demands of a gene therapy
      use. We developed a method for the functionalization of a large pore affinity
      support suitable for this application. A 5'-modified DNA oligonucleotide
      containing an aldehyde group was coupled to adipic acid hydrazide functionalized
      Sephacryl beads with a yield of 31% (over all immobilization yield 22.6% from
      starting oligonucleotide). The resulting selective and covalent immobilization of
      the ligand via a 16 atom, hydrophilic linker arm enables the oligonucleotide
      bases to freely bind to the target sequence. The proposed method provides
      affinity supports that might be used in large scale affinity purification of
      plasmid DNA.

PMID- 10643641
TI  - Affinity isolation of a cold-adapted enzyme: lactate dehydrogenase from Bacillus
      psychrosaccharolyticus.
AB  - A simple, economical and rapid affinity chromatography procedure with dyes as the
      ligand has been described for the one-step purification of a cold-adapted lactate
      dehydrogenase. Non-specific elution of Procion blue H-ERD-modified Sepharose
      yielded homogeneous preparations of lactate dehydrogenase both in column based
      procedures and in batch wise operations. Low operational temperatures resulted in
      the enhanced binding of the enzyme to the blue dye. The dissociation constants of
      the enzyme-dye complexes were 7.2 +/- 0.2 microM and 11.2 +/- 0.2 microM at 5
      degrees C and 20 degrees C respectively.

PMID- 10643642
TI  - Effect of cryopreservation on lipids and some physiological features of
      spermatozoa from rams pastured in highlands and in valleys.
AB  - The effect of low temperature preservation on the motility and morphology of
      acrosomes, acrosomal proteolytic activity, phospholipid and fatty acid
      composition of phosphatidyl choline (PC) and phosphatidyl ethanolamine (PE), and
      the cholesterol/phospholipid molar ratio in sperm from rams housed in the
      highlands or in the valleys, were studied. The indices of motility and
      morphological integrity of sperm from highland rams were much greater compared
      with those of valley rams. Phosphatidyl choline (PC) of the highland rams was
      more unsaturated, while PE was more saturated compared with those of valley rams.
      Cryopreservation of the sperm from highland rams significantly increased the
      content of choline plasmalogen, accompanied by a slight rise in the levels of
      lysophosphatidyl choline (LPC) and phosphatidyl inositol (PI) in their sperm. The
      fatty acid composition altered following cryopreservation. These variations were
      mainly due to a decrease in the amount of docosahexaenic acid and an increase in
      the amounts of linoleic and palmitic fatty acids. The results may be indicative
      of the fact that the alterations in the sperm of the valley rams were more
      pronounced and they may be attributed to the structural features of the sperm, as
      well as a reduced concentration of oxygen in the organs and tissues of the
      highland rams.

PMID- 10643643
TI  - Gypenoside induces apoptosis in human Hep3B and HA22T tumour cells.
AB  - The effect of gypenoside, an active component of the Chinese herb Gynostemma
      pentaphyllum (Thumb) Makino, on human hepatoma cell lines (Hep3B and HA22T) was
      investigated. Results demonstrated that gypenoside inhibited the proliferation or
      viability of the Hep3B and HA22T cells in a dose-dependent manner. The Hep3B and
      HA22T cells treated with gypenoside for 2 days were less DNA stainable and formed
      a sub-G1 peak. The treated cells increased cell numbers in the A0 region as well
      as shifting the ordinary S phase to the final S phase (D1 region), and induced a
      ladder pattern of fragmented DNA of about 200 base pairs. These data suggest that
      the cell death of the hepatoma cell lines Hep3B and HA22T induced by gypenoside
      was via apoptosis, and this was confirmed by morphological studies.

PMID- 10643644
TI  - Pinealectomy-induced elevation of collagen content in the intact skin is
      suppressed by melatonin application.
AB  - The pineal gland is involved in wound repair and collagen deposition in sponge
      induced granulomas. The aim of this investigation was to discover whether the
      pineal gland was able to regulate collagen accumulation in the intact skin.
      Wistar rats were divided into five groups: control, sham-operated with vehicle
      application, sham-operated with melatonin injections (30 micrograms/100 g body
      wt), pinealectomized with vehicle, and pinealectomized with melatonin
      supplementation. After 8 weeks, the collagen content was estimated as
      hydroxyproline concentration in the dry tissue of the skin. The results showed
      that melatonin markedly (p < 0.001) reduced collagen accumulation in the skin.
      Pinealectomy enhanced collagen deposition in the skin (p < 0.02) and melatonin
      application reduced the pinealectomy-induced elevation of collagen content (p <
      0.001). Results clearly indicate that collagen accumulation in the intact skin is
      under the control of the pineal gland, and that melatonin, the pineal hormone, is
      responsible for this control.

PMID- 10643645
TI  - Further studies on chromocentres and their implications in regeneration.
AB  - Previous investigations using a number of invertebrates, as well as regenerative
      tissues/organs of various vertebrates, have promulgated the hypothesis that
      heterochromatin, in the form of nuclear chromocentres, is correlated with the
      ability to regenerate. In order to test the universality of this hypothesis,
      cells from a variety of additional animals were examined for the presence of
      nuclear chromocentres. In accordance with the hypothesis, cells from these
      organisms contained numerous chromocentres. Evidence indicates that
      chromocentres, double minute chromosomes, chromosome 'dots', and telomeres may be
      different forms of the same heterochromatin entity.

PMID- 10643646
TI  - Influence of fibroblast growth factor, insulin-like growth factor I, and
      transforming growth factor beta on satellite cell type I collagen expression and
      localization during differentiation.
AB  - Expression, and temporal and spatial distribution of type I collagen were
      investigated in chicken satellite cell cultures during differentiation. There was
      no difference in the relative amounts of type I collagen after treatment with
      basic fibroblast growth factor (FGF), insulin-like growth factor-I (IGF-I), or
      transforming growth factor beta 1 (TGF-beta 1). However, myotube morphology was
      influenced by the presence of the growth factors. The temporal and spatial
      distribution of type I collagen was also modified. Control cultures maintained a
      predominant distribution of type I collagen surrounding the cellular area until
      approximately 48 h after the initiation of fusion whereas cultures with FGF or
      IGF-I maintained a cellular localization of type I collagen throughout the fusion
      process. TGF-beta 1 resulted in the early formation of an extracellular network
      of type I collagen preceding control cultures by approximately 24 h. These
      results suggest that type I collagen expression but not localization is
      independent of satellite cell proliferation and differentiation.

PMID- 10643647
TI  - Subcellular localization of the coat protein in tobacco cells infected by
      cucumber mosaic virus isolated from Catharanthus roseus.
AB  - Electron microscopy and immunolabelling with antiserum specific to cucumber
      mosaic virus coat protein were used to examine tobacco leaf cells infected by
      cucumber mosaic virus isolated from Catharanthus roseus (CMV-Cr). Crystalline and
      amorphous inclusions in the vacuoles were the most obvious cytological
      modifications seen. Immunogold labelling indicated that the crystalline inclusion
      was made up of virus particles and amorphous inclusions contained coat protein.
      Rows of CMV-Cr particles were found between membranes of dictyosomes, but
      membranous bodies and tonoplast-associated vesicles were not evident. Virus
      particles and/or free coat protein were easily detected in the cytoplasm by
      immunolabelling. No gold labelling was found within nuclei, chloroplasts and
      mitochondria.

PMID- 10643648
TI  - The GC/MS analysis of some commonly used non-steriodal anti-inflammatory drugs
      (NSAIDs) in pharmaceutical dosage forms and in urine.
AB  - All the commonly used non-steriodal anti-inflammatory drugs (NSAIDs), except
      mefenamic acid, when extracted from the pharmaceutical dosage forms or the urines
      of users, and derivatized by silylation and then analysed by GC/MS, gave the mono
      or the di-trimethylsilyl derivatives (depending on the number of derivatized
      groups in the drug) as the sole products. Mefenamic acid gave a mixture of
      products. When extracted from pharmaceutical dosage froms or from the urines of
      users, and analysed by GC/MS without derivatization, some of the NSAIDs were
      separated and detected as the unchanged molecules as the sole products, while
      others were separated and detected in altered forms as sole products or mixtures,
      depending on: (a) the solvent in which the extract was dissolved for injection
      into GC/MS, (b) the chemical structure of the drug, and (c) specifically for
      diflunisal, the presence or absence of potential methylating and/or acetylating
      agents on the GC column and/or septum. The main thermally-induced reactions of
      the underivatized NSAIDs included (i) methyl ester formation at the COOH group
      when the extract was dissolved in methanol, (ii) decarboxylation (i.e., loss of
      CO2), (iii) dehydration (i.e., loss of H2O) when the chemical structure
      permitted, such as for diclofenac, and (iv) cleavage at a carbon-heterocyclic
      nitrogen bond when one is present in an NSAID. Heating the urine in approximately
      2 M HCl at 100 degrees C for 30 min, has been found to be a satisfactory means
      for effecting hydrolysis of the NSAIDs glucuronide conjugates. No metabolites,
      resulting from aromatic-ring hydroxylation, have been detected in urine for any
      of the NSAIDs studied.

PMID- 10643649
TI  - Classifying serial killers.
AB  - We attempted to match the appearance and demeanor of 27 serial killers to the
      postmortem 'signatures' found on their victims' bodies. Our results suggest that
      a link may exist between postmortem signatures and two complementary appearance
      demeanor types.

PMID- 10643650
TI  - Delimitation of the time of death by immunohistochemical detection of insulin in
      pancreatic beta-cells.
AB  - To improve the possibilities to delimitate the time of death after longer
      laytime, it was examined if this is possible by immunohistochemical insulin
      detection. The results show that in our examination material, the pancreatic beta
      cells of up to 12-day-old corpses produce a positive immunoreaction towards
      insulin in all cases, whereas none of the corpses older than 30 days show such a
      reaction. This means that in case of a negative immunoreaction, the time of death
      can be assumed to lie more than 12 days before the autopsy. The fact that a
      negative immunoreaction occurs consistently after 30 days leads to the conclusion
      that when insulin has been stained in a specimen, the death of the respective
      person must lie a maximum of 29 days earlier, whereby these time-limits may
      change in considerably different surrounding conditions.

PMID- 10643651
TI  - Extraction of DNA from decomposed human tissue. An evaluation of five extraction
      methods for short tandem repeat typing.
AB  - Hyperpolymorphic short tandem repetitive DNA sequences, STRs or microsatellites,
      have become widely used in human identification, particularly in criminal cases
      and in mass disasters. In such cases the substrates for the analyses may be
      decomposed biological material, a fact that has to be taken into account when
      choosing the appropriate casework methods. In this paper we report the evaluation
      of five different DNA extraction methods, namely the phenol-chloroform, the
      silica based, the InstaGene Matrix (BioTest), the glass fiber filter, and the
      Chelex based methods. The substrates for the analyses are decomposed human liver
      tissue specimens from forensic autopsy cases. Extracted DNA was quantified and
      DNA profiled by a set of seven STRs. We have compared laboratory time consumption
      and costs of the five methods, showing that the Chelex method is the more rapid
      and less expensive of the methods, the phenol-chlorophorm and silica extractions
      being the most time consuming and resource demanding ones. A full profile was
      obtained by the silica method in nine out of ten cases and this method failed to
      give a reliable type in four out of 70 STR analyses. The phenol-chlorophorm and
      the glass fiber filter methods failed in 16 analyses, the InstaGene Matrix
      (BioTest) in 25 and the Chelex extracts in 56 of the 70 STR analyses. By multiple
      logistic regression we show that the difference between the silica procedure and
      the other methods are statistically significant. In our hands, the silica gel
      extraction procedure is an obvious choice when the biological material available
      is decomposed human tissue--even if this procedure is one of the more laborious
      ones.

PMID- 10643652
TI  - Fatal overdose of tramadol and alprazolam.
AB  - A 30-year-old woman, with history of depression, was found dead after the
      ingestion of an unknown quantity of Xanax (alprazolam), Tramal (tramadol) and
      alcohol. At the autopsy only a slight decomposition and a diffuse visceral
      congestion were noticed. Biological samples obtained at autopsy were analysed to
      detect the presence of alprazolam, tramadol and alcohol. Blood concentrations of
      alprazolam, alcohol and tramadol were 0.21 mg/l, 1.29 g/kg and 38.3 mg/l,
      respectively.

PMID- 10643653
TI  - Remarks on: "Percentile charts to determine the duration of child abuse by
      chronic malnutrition" [Forensic Science International 102 (1999) 173-180].

PMID- 10643654
TI  - Cytotoxicity of salicylaldehyde benzoylhydrazone analogs and their transition
      metal complexes: quantitative structure-activity relationships.
AB  - A series of salicylaldehyde benzoylhydrazone derivatives, their copper(II)
      complexes and a range of transition metal complexes of the unsubstituted ligand
      has been synthesized and evaluated for cytotoxicity against a human
      adenocarcinoma cell line. A QSAR analysis revealed ligand cytotoxicity is
      strongly correlated with electronic and transport factors and can be modeled by
      treating each 'half' of the molecule as an isolated unit. Activity increases when
      substituents in the benzoyl ring were electron withdrawing whereas, for the
      salicylaldehyde ring, electron donation was required. The cytotoxicity of the
      Cu(II) complexes was greater than, and paralleled the ligands. Activity for the
      transition metal complexes of the unsubstituted ligand mirrored charge density on
      the metal.

PMID- 10643655
TI  - Effect of cis-, trans-diamminedichloroplatinum(II) and DBP on human serum
      albumin.
AB  - Both isomers of diamminedichloroplatinum(II) bind to albumin and induce the
      formation of the albumin dimer (MW approximately 140 kDa). The trans isomer
      exhibits a much greater tendency to induce a protein dimerization than the cis
      isomer. Under similar experimental conditions, the phosphonic derivative of
      diammineplatinum(II) (DBP) does not induce any dimer formation. The amount of
      bound complex per mol of human serum albumin (HSA, for an incubation time of 7
      days) was found to be 6, 10.5 and 1 mol for cis-, trans-DDP and DBP,
      respectively. The relative fluorescence intensity of platinum-bound HSA decreases
      to about 55% for cis-DDP, 45% for trans-DDP and to 85% for DBP when compared to
      the complex-free protein, suggesting that the binding occurs in the proximity of
      the Trp214 residue. The structural studies (CD) have shown that only DDP-isomers
      cause the distinct modification of HSA native structure (alpha-helical content).
      Pt(II) complexes binding to HSA affect the affinity of HSA towards heme and
      bilirubin. High excess of DDP prevents the heme and bilirubin binding, while DBP
      affects this binding much less effectively due to the low amount of the protein
      bound complex. Reactions of platinum complexes with albumin are believed to play
      an important role in the metabolism of this anticancer drug. The minor effect of
      DBP on HSA may indicate that the toxicity of the phosphonate analog is much lower
      than toxicities of DDP isomers, most likely due to kinetic reasons.

PMID- 10643656
TI  - Manganese-dependent inhibition of human liver arginase by borate.
AB  - Full activation of human liver arginase (EC 3.5.3.1), by incubation with 5 mM
      Mn2+ for 10 min at 60 degrees C, resulted in increased Vmax and a higher
      sensitivity of the enzyme to borate inhibition, with no change in the K(m) for
      arginine. Borate behaved as an S-hyperbolic I-hyperbolic non-competitive
      inhibitor and had no effect on the interaction of the enzyme with the competitive
      inhibitors L-ornithine (Ki = 2 +/- 0.5 mM), L-lysine (Ki = 2.5 +/- 0.4 mM), and
      guanidinium chloride (Ki = 100 +/- 10 mM). The pH dependence of the inhibition
      was consistent with tetrahedral B(OH)4- being the inhibitor, rather than trigonal
      B(OH)3. We suggest that arginase activity is associated with a tightly bound Mn2+
      whose catalytic action may be stimulated by addition of a more loosely bound
      Mn2+, to generate a fully activated enzyme form. The Mn2+ dependence and partial
      character of borate inhibition are explained by assuming that borate binds in
      close proximity to the loosely bound Mn2+ and interferes with its stimulatory
      action. Although borate protects against inactivation of the enzyme by diethyl
      pyrocarbonate (DEPC), the DEPC-sensitive residue is not considered as a ligand
      for borate binding, since chemically modified species, which retain about 10% of
      enzymatic activity, were also sensitive to the inhibitor.

PMID- 10643657
TI  - Formation of modified cleavage termini from the reaction of chromium(V) with DNA.
AB  - Reaction of a 25 bp oligonucleotide with the high valent chromium complex, bis(2
      ethyl-2-hydroxybutyrato)oxochromate(V) (Cr(V)-EHBA) produced both Frank- and
      alkali-labile strand breaks that were sequence-neutral. Frank strand break
      formation was found to be O2-dependent while formation of alkali-labile strand
      breaks were O2-independent. Reaction of Cr(V)-EHBA with the 5'-32P-labeled
      oligomer under oxygenated conditions formed the modified 3'-terminus, 3'
      phosphoglycolate, as well as the 3'-phosphate terminus. Formation of the 3'
      phosphoglycolate termini, and the O2 dependence of the reactions were consistent
      with a mechanism involving abstraction of the C4' hydrogen atom from the
      deoxyribose moiety of DNA. Identical reactions using the 3'-32P-labeled oligomer
      yielded only 5'-phosphate termini as assigned by co-migration with Maxam-Gilbert
      markers. Analogous cleavage profiles and modified termini were observed for the
      reaction of Cr(V)-EHBA and DNA in the presence of hydrogen peroxide. With the
      addition of hydrogen peroxide, the DNA cleavage reactions were O2-independent and
      the level of DNA cleavage was enhanced over that observed with Cr(V)-EHBA alone.
      These findings suggest an oxidation mechanism whereby a reductive intermediate of
      the carcinogen chromate, Cr(V), can cause DNA damage that mimics oxygen radical
      DNA damaging pathways.

PMID- 10643658
TI  - Thermolysis of coenzymes B12 at physiological temperatures: activation parameters
      for cobalt-carbon bond homolysis and a quantitative analysis of the perturbation
      of the homolysis equilibrium by the ribonucleoside triphosphate reductase from
      Lactobacillus leichmannii.
AB  - The kinetics of the thermolysis of 5'-deoxyadenosylcobalamin (AdoCbl, coenzyme
      B12) in aqueous solution, pH 7.5, have been studied in the temperature range 30
      85 degrees C using AdoCbl tritiated at the adenine C2 position and the method of
      initial rates. Combined with a careful analysis of the distribution of adenine
      containing products, the results permit the dissection of the competing rate
      constants for carbon-cobalt bond homolysis and heterolysis. After correction for
      the temperature-dependent occurrence of the much less reactive base-off species
      of AdoCbl, the activation parameters for homolysis of the base-on species were
      found to be delta H++homo,on = 33.8 +/- 0.2 kcal mol-1 and delta S++homo,on =
      13.5 +/- 0.7 cal mol-1 K-1, values not significantly different from those
      determined by Hay and Finke (J. Am. Chem. Soc. 108 (1986) 4820), in the
      temperature range 85-115 degrees C. In contrast, the heterolysis of base-on
      AdoCbl was characterized by a much smaller enthalpy of activation (delta
      H++het,on = 18.5 +/- 0.2 kcal mol-1) and a negative entropy of activation (delta
      S++het,on = -34.0 +/- 0.7 cal mol-1 K-1) so that heterolysis, which is minor
      pathway at elevated temperatures, is the dominant pathway for AdoCbl
      decomposition at physiological temperatures. Using literature values for the rate
      constant for the reverse reaction, the equilibrium constant for AdoCbl homolysis
      at 37 degrees C was calculated to be 7.9 x 10(-18). Comparison with the
      equilibrium constant for this homolysis at the active site of the ribonucleoside
      triphosphate reductase from Lactobacillus leichmannii shows that the enzymes
      shifts the equilibrium constant towards homolysis products by a factor of 2.9 x
      10(12) (17.7 kcal mol-1) by binding the thermolysis products with an equilibrium
      constant of 7.1 x 10(16) M-2, compared to the bonding constant for AdoCbl of 2.4
      x 10(4) M-1.

PMID- 10643659
TI  - DNA interaction and antitumor activity of a Pt(III) derivative of 2
      mercaptopyridine.
AB  - The complex [Pt2(Spy-)4Cl2], where Spy- is deprotonated 2-mercaptopyridine, was
      prepared and analyzed spectroscopically. A single signal in the 195Pt NMR
      spectrum indicates the equivalence of the two Pt(III) ions. The interaction of
      this complex with DNA was studied by circular dichroism and the modifications
      caused by the complex in plasmid pBR322 DNA were imaged by atomic force
      microscopy. Preliminary results showed higher activity against HeLa and U937
      tumor lines for the Pt-2-mercaptopyridine complex in comparison with cisplatin.
      The values of LC50 were lower than those obtained for cisplatin. Promising
      perspectives for this compound are expected due to its similarity with the
      analogous Pt and 2-mercaptopyrimidine antitumor compound.

PMID- 10643660
TI  - In vivo coordination structural changes of a potent insulin-mimetic agent,
      bis(picolinato)oxovanadium(IV), studied by electron spin-echo envelope modulation
      spectroscopy.
AB  - Bis(picolinato)oxovanadium(IV) [VO(pic)2] is one of the most potent insulin
      mimetic vanadium complexes. To probe coordination structural changes of this
      complex in vivo and provide insights into the origin of its high potency, an
      electron spin-echo envelope modulation (ESEEM) study was performed on organs
      (kidney, liver and bone) of VO(pic)2- and VOSO4-treated rats. Kidney and liver
      samples from both types of rats exhibited a 14N ESEEM signal that could be
      attributed to equatorially coordinating amine nitrogen. The relative intensity of
      the amine signal was larger for the organs of the rat treated with the less
      potent VOSO4, suggesting that this amine coordination inhibits the insulin
      mimetic activity. The spectra of kidney and liver from the VO(pic)2-treated rat
      contained a weak signal due to the picolinate imine nitrogen. This suggests that
      some picolinato species (including both the bispicolinato and a partially
      decomposed monopicolinato species) still exist in the organs as a minor species,
      where the proportions of the picolinato species to the total amount of the EPR
      detectable VIVO species are estimated as 8-16% in the kidney and 12-24% in the
      liver. The picolinate ligand presumably serves to prevent VO2+ from being
      converted into the inactive amine-coordinated species. Bone samples from both
      types of rats exhibited an ESEEM signal due to 31P nuclei. The VO2+ in bone is
      therefore most likely incorporated into the hydroxyapatite Ca10(PO4)6(OH)2
      matrix, which is consistent with the hypothesis that the bone-accumulated VO2+ is
      gradually released and transported to other organs as is Ca2+. No 14N signals
      were observed, even in the bone samples of the VO(pic)2-treated rats, indicating
      that vanadium uptake by bone requires complete decomposition of the complex.

PMID- 10643661
TI  - Preparation, characterization, and antitumor activity of new cisplatin analogs
      with homopiperazines: crystal structure of [PtII(1
      methylhomopiperazine)(methylmalonato)].2H2O.
AB  - A series of new platinum(II) and (IV) complexes with homopiperazine have been
      synthesized and characterized by elemental analysis, infrared, and 195Pt nuclear
      magnetic resonance spectroscopic techniques. The complexes are of two types:
      [PtIILX] (where L = homopiperazine (hpip), 1-methylhomopiperazine (mhpip), or 1,4
      dimethylhomopiperazine (dmhpip), and X = 1,1-cyclobutanedicarboxylato (CBDCA), or
      methylmalonato ligand) and [PtIV(L-)trans-(Y)2Cl2] (where Y = hydroxo, acetato,
      or chloro ligand). Among the complexes synthesized, the crystal structure of
      [PtII(mhpip)(methylmalonato)].2H2O was determined by the single crystal X-ray
      diffraction method. The crystallographic parameters were orthorhombic,
      P2(1)2(1)2(1) (no. 19), a = 7.2014(14), b = 7.3348(15), c = 26.971(5) A, and Z =
      4. The structure refinements converged to R1 = 0.0641 and wR2 = 0.1847. In this
      complex, platinum has a slightly distorted square planar geometry with the two
      adjacent corners being occupied by two nitrogens of the mhpip ligand, whereas the
      remaining cis positions are coordinated with two oxygen atoms of the
      methylmalonato group. The mhpip ligand is in a boat conformation and forms five
      and six membered chelating rings with platinum. The intricate network of
      intermolecular hydrogen bonds holds the crystal lattice together. Some of these
      synthesized cisplatin analogs have good in vitro cytotoxic activity against the
      cisplatin-sensitive human ovarian A2780 (IC50 = 0.083-17.8 microM) and the
      isogenic cisplatin-resistant 2780CP (IC50 = 20.1-118.1 microM) cell lines.

PMID- 10643662
TI  - DNA binding of iron(II) mixed-ligand complexes containing 1,10-phenanthroline and
      4,7-diphenyl-1,10-phenanthroline.
AB  - Absorption spectroscopy and circular dichroism (CD) have been used to
      characterize the DNA binding of [Fe(phen)3]2+, [Fe(phen)2(DIP)]2+ and
      [Fe(phen)(DIP)2]2+ where phen and DIP stand for 1,10-phenanthroline and 4,7
      diphenyl-1,10-phenanthroline, respectively. Both [Fe(phen)3]2+ and
      [Fe(phen)2(DIP)]2+ bind weakly to calf thymus DNA (CT-DNA) in an electrostatic
      mode, while [Fe(phen)(DIP)2]2+ binds more strongly to CT-DNA, possibly in an
      intercalation mode. The hypochromicity, red shift and Kb increase in the order
      [Fe(phen)3]2+ < [Fe(phen)2(DIP)]2+ < [Fe(phen)(DIP)2]2+ in accordance with the
      increase in size and hydrophobicity of the iron(II) complexes. The thermodynamic
      parameters obtained suggest that the DNA binding of both [Fe(phen)3]2+ and
      [Fe(phen)2(DIP)]2+ is entropically driven, while that of [Fe(phen)(DIP)2]2+ is
      enthalpically driven. A strong CD spectrum in the UV and visible region develops
      upon addition of CT-DNA into the racemate solution of each iron(II) complex
      (Pfeiffer effect). This has revealed that a shift in diastereomeric inversion
      equilibrium takes place in the solution to yield an excess of one of the DNA
      complex diastereomers. The striking resemblance of the CD spectral profiles to
      those of the pure delta-enantiomer indicates that the delta-enantiomer of the
      iron(II) complexes is preferentially bound to CT-DNA. The mechanism of the
      development of Pfeiffer CD is proposed on the basis of kinetic studies on the DNA
      binding of the racemic iron(II) complexes.

PMID- 10643663
TI  - The displacement of iron(III) from its complexes with the anticancer drugs
      piroxantrone and losoxantrone by the hydrolyzed form of the cardioprotective
      agent dexrazoxane.
AB  - Piroxantrone and losoxantrone are new DNA topoisomerase II-targeting
      anthrapyrazole antitumor agents that display cardiotoxicity both clinically and
      in animal models. A study was undertaken to see whether dexrazoxane or its
      hydrolysis product ADR-925 could remove iron(III) from its complexes with
      piroxantrone or losoxantrone. Their cardiotoxicity may result from the formation
      of iron(III) complexes of losoxantrone and piroxantrone. Subsequent reductive
      activation of their iron(III) complexes likely results in oxygen-free radical
      mediated cardiotoxicity. Dexrazoxane is in clinical use as a doxorubicin
      cardioprotective agent. Dexrazoxane presumably acts through its hydrolyzed metal
      ion binding form ADR-925 by removing iron(III) from its complex with doxorubicin,
      or by scavenging free iron(III), thus preventing oxygen-free radical-based
      oxidative damage to the heart tissue. ADR-925 was able to remove iron(III) from
      its complexes with piroxantrone and losoxantrone, though not as efficiently or as
      quickly as it could from its complexes with doxorubicin and other anthracyclines.
      This study provides a basis for utilizing dexrazoxane for the clinical prevention
      of anthrapyrazole cardiotoxicity.

PMID- 10643664
TI  - Prevalence and persistence of amoxycillin-resistant bacteria in the dental
      plaques of adults.
AB  - The prevalence and persistence of amoxycillin-resistant organisms (ARO) in the
      dental plaque of adults was determined. Plaque samples from ten adults, who had
      not taken antibiotics during the previous 6 months, were screened for ARO on
      three occasions at intervals of 3 months. The ARO were tested for their
      susceptibility to amoxycillin and to amoxycillin plus clavulanic acid as well as
      their ability to produce beta-lactamases. The ARO were found in all subjects on
      at least one sampling occasion and in 87% of the 30 samples examined. Of the 36
      ARO isolated, 33% were yeasts, 19% were staphylococci, 19% Actinomycetes spp. and
      14% lactobacilli, whilst seventeen of the isolates produced a beta-lactamase and
      seven of these were sensitive to coamoxiclav. The proportion of ARO in an
      individual fluctuated widely over the study period. It is suggested that the ARO
      are frequently, though transiently, present in low numbers in the plaque of
      individuals who have not recently received antibiotics.

PMID- 10643665
TI  - Chemical composition of endotoxins produced by Fusobacterium necrophorum subsp.
      necrophorum and F. necrophorum subsp. funduliforme.
AB  - The endotoxins from two recently-classified subspecies of Fusobacterium, namely
      F. necrophorum subsp. necrophorum and F. necrophorum subsp. funduliforme, were
      compared. Chemical analysis of the isolated endotoxins revealed that they were
      clearly different. Distinct levels of polysaccharides were demonstrated. The
      endotoxins isolated were devoid of heptose and 3-deoxy-D-manno-octulosonate
      (KDO). The endotoxins of F. n. necrophorum and F. n. funduliforme contained lipid
      A in a ratio of 4:1 which may account for the variations in their virulence.

PMID- 10643666
TI  - Amidine derivatives are highly effective against Trypanosoma evansi
      trypomastigotes.
AB  - The in vitro effect of N,N'-diphenyl-4-R-benzamidine (where R = H, CN, Br, Cl,
      CH3, OCH3 and NO2) in three isolates of Trypanosoma evansi was studied. The
      compounds were solubilized in dimethysulphoxide (DMSO) and tested in a
      concentration range of 5 to 160 micrograms/ml. The parasites were isolated from a
      horse, a dog and a coati. They were maintained in immunosuppressed rats, since
      they could not be cultured in vitro, and further purified through a
      diethylaminoethanol (DEAE) column. The trypomastigotes obtained were mixed with
      different concentrations of the drugs and after incubation at 26 degrees C for 24
      h, the remaining parasites were counted in a Neubauer chamber. The percentage of
      inhibition was evaluated compared with the control, without the drugs. Most of
      the amidine derivatives showed high activity against the three T. evansi
      isolates, but different patterns of sensitivity to the tested compounds were
      observed. At least four compounds with Br, Cl, OCH3 and NO2 as substituents, were
      much more effective than Berenil [4,4'-(diazoamine)-dibenzamidine aceturate], the
      reference drug used, which is included in the same chemical class of amidines.

PMID- 10643667
TI  - A fibrinolytic enzyme from a marine green alga, Codium latum.
AB  - A fibrinolytic enzyme was isolated from a marine green alga, Codium latum, and
      designated C. latum protease (CLP). It also had fibrinogenolytic activity,
      hydrolyzing A alpha, B beta and gamma chains with preference in this order. As
      CLP hydrolyzed oxidized insulin B chain at position Arg22-Gly23, and the peptide
      map of lysozyme digested with CLP was similar to that with trypsin, CLP would be
      expected to have a high substrate specificity, similar to that of trypsin.
      Protease activity peaked at pH 10, and was completely inhibited by diisopropyl
      fluorophosphate (DFP). Therefore, we conclude that CLP is a trypsin-like serine
      protease.

PMID- 10643668
TI  - The natural genetic variation of the fatty-acyl composition of seed oils in
      different ecotypes of Arabidopsis thaliana.
AB  - The fatty-acyl composition of the seed oil was determined for 100 ecotypes of
      Arabidopsis thaliana. Despite coming from diverse geographical locations, seed
      fatty-acyl profiles of all ecotypes were remarkably similar. They contained
      identical fatty acids, including the characteristic C20 and C22 very-long-chain
      fatty acids (VLCFAs). The total proportions of seed VLCFA varied between 22% and
      35% w/w of the total seed fatty acid content.

PMID- 10643669
TI  - Plocamium hamatum and its monoterpenes: chemical and biological investigations of
      the tropical marine red alga.
AB  - The polyhalogenated monoterpene content of six samples of the tropical marine red
      alga Plocamium hamatum, collected from the southern, central and northern regions
      of The Great Barrier Reef, Australia, was assessed. In all but two of the
      samples, the polyhalogenated monoterpene content was shown to differ markedly. In
      total, eleven previously reported compounds were isolated and characterised (1
      11). Compound 2 was obtained for the first time as a pure natural product. For
      compound 4 a single crystal X-ray crystallographic analysis was undertaken which
      established its absolute configuration as (1S,2S,4R,5R,1'E)-2-bromo-1-
      bromomethyl-1,4-dichloro-5-(2'-chloroethenyl)-5-methylcyclohexa ne. Complete and
      unambiguous 1H and 13C NMR data are reported for 2 and 4. For 6-8, some prior 13C
      NMR assignments are revised. The biological activities of compounds 2-8 and 11
      were assessed and indicated 4 to have potent antialgal activity towards Chlorella
      fusca in an agar diffusion bioassay, as well as being moderately antitubercular
      and cytotoxic. Compound 6 demonstrated moderate cytotoxicity.

PMID- 10643670
TI  - Bisamides from Aglaia edulis.
AB  - The leaves of Aglaia edulis afforded a new bisamide, aglaiduline, and two new
      sulfur-containing bisamides, aglaithioduline and aglaidithioduline. Their
      structures were established from spectroscopic studies. The sulfur-containing
      amides exhibited slight antiviral activity against herpes simplex virus types 1
      and 2.

PMID- 10643671
TI  - An immunologically active arabinogalactan from Tinospora cordifolia.
AB  - An arabinogalactan of mean M(r) 2.2 x 10(6) has been isolated from the dried
      stems of Tinospora cordifolia and examined by methylation analysis, partial
      hydrolysis and carboxyl reduction. Purified polysaccharide showed polyclonal
      mitogenic activity against B-cells, their proliferation did not require
      macrophages.

PMID- 10643672
TI  - Anti-plasmodial sesquiterpenoids from the African Reneilmia cincinnata.
AB  - A new isodaucane sesquiterpenoid, 6,7,10-trihydoxyisodaucane, was isolated from
      the fruits of Reneilmia cincinnata, together with the known sesquiterpenoids
      oplodiol, oplopanone, 5E,10(14)-germacradien-1 beta, 4 beta-diol, 1(10)E,5E
      germacradien-4 alpha-ol and eudesman-1,4,7-triol. A large amount of 5-hydroxy
      3,7,4'-trimethoxyflavone was also isolated. Their structures were established by
      NMR techniques using 1D and 2D experiments. Three of the known sesquirernenoids
      exhibited noteworthy anti-plasmodial activity against Plasmodium falciparum
      strains.

PMID- 10643673
TI  - New acylated triterpenoid saponins from Maesa lanceolata.
AB  - Ten new acylated triterpenoid saponins were isolated from the leaves of Maesa
      lanceolata. For their structure elucidation extensive use was made of homo- and
      heteronuclear 2D NMR techniques such as COSY, NOESY, HSQC and HMBC. All saponins
      identified contained the same tetraglycosidic side chain, but the triterpenoid
      moiety showed a variable esterification pattern. Monoester, diester and triester
      derivatives were present. Maesasaponin I was a 21-monoester derivative, i.e. ?3
      beta-O-[alpha-L-rhamnopyranosyl-(1-->2)-beta-D-galactopyranosyl- (1-->3)]-[beta-D
      galactopyranosyl-(1-->2)]-beta-D-glucuronopyranosyl+ ++?-21 beta-angeloyloxy-13
      beta, 28-oxidoolean-16 alpha, 22 alpha, 28 alpha-triol. Maesasaponins III, IV3,
      V3 and VI2 had an additional acetyl, propanoyl, n-butanoyl and angeloyl
      substituent, respectively, in position 22. Maesasaponins II, IV2, V2, VI3 and
      VII1 were characterised as the 16-acetyl derivatives of maesasaponins I, III,
      IV3, V3 and VI2, respectively. Structures of saponins previously reported in M.
      lanceolata had to be revised.

PMID- 10643674
TI  - Ipecac alkaloids from Cephaelis acuminata.
AB  - From the dried roots of Cephaelis acuminata, five ipecac alkaloids,
      neocephaeline, 7'-O-demethylcephaeline, 10-O-demethylcephaeline, 2'-N-(1"-deoxy
      1"-beta-D-fructopyranosyl)cephaeline and 2'-N-(1"-deoxy-1"-beta-D
      fructopyranosyl)neocephaeline, were isolated, along with emetine, cephaeline,
      psychotrine, protoemetine, 9-demethylprotoemetinol and isocephaeline. Structures
      were determined by spectroscopic and chemical means.

PMID- 10643675
TI  - IV-VI semiconductor growth on silicon substrates and new mid-infrared laser
      fabrication methods
AB  - This paper reviews results from research conducted at the University of Oklahoma
      on the development of new IV-VI semiconductor (lead salt) epitaxial growth and
      laser fabrication procedures that can ultimately lead to dramatic increases in
      mid-IR laser operating temperatures. Work has focused on growth of IV-VI
      semiconductor laser structures on silicon substrates using buffer layers that
      contain BaF2. Recent experiments show that it is possible to obtain high
      crystalline quality IV-VI semiconductor layer structures on (111)-oriented
      silicon substrates using molecular beam epitaxy (MBE) or on (100)-oriented
      silicon using a combination of MBE and liquid phase epitaxy (LPE). Experimental
      data for IV-VI semiconductor layer structures grown on silicon substrates
      including crystalline quality information as determined by high resolution X-ray
      diffraction (HRXRD) measurements and absorption edge information as determined by
      Fourier transform infrared (FTIR) transmission measurements are presented.
      Results show that these materials can be used to fabricate lasers that cover the
      3 microns (3333 cm-1) to 16 microns (625 cm-1) spectral range. Removal of IV-VI
      semiconductor laser structures from the silicon growth substrate by dissolving
      BaF2 buffer layers with water is also demonstrated. This allows epitaxially-grown
      laser structures to be sandwiched between two heat sinks with a minimum of
      thermally resistive IV-VI semiconductor material. Theoretical modeling predicts
      that IV-VI lasers fabricated this way will have maximum continuous wave (cw)
      operating temperatures at least 60 degrees higher than those of IV-VI lasers
      fabricated on PbSe or PbTe substrates.

PMID- 10643676
TI  - A systematic review of interventions to improve health professionals' management
      of obesity.
AB  - OBJECTIVE: To determine the existence and effectiveness of interventions to
      improve health professionals' management of obesity or the organisation of care
      for overweight and obese people. DESIGN: A systematic review of intervention
      studies, undertaken according to standard methods developed by the Cochrane
      Effective Practice and Organisation of Care (EPOC) Group. PARTICIPANTS: Trained
      health care professionals and overweight and obese patients. MEASUREMENTS:
      Objective measures of health professionals' practice and behaviours, and patient
      outcomes including satisfaction, behaviour, psychological factors, disease
      status, risk factors, and measures of body weight, fat, or BMI. RESULTS: Twelve
      studies that met all the review inclusion criteria were identified. Three were
      randomised controlled trials of health professional-oriented interventions (such
      as the use of reminders and training) and one was a controlled before and after
      study to improve collaboration between a hospital clinic and GPs. A further eight
      randomised controlled trials were identified of interventions comparing either
      the deliverer of weight loss interventions or the setting of the delivery of the
      intervention. The heterogeneity and generally limited quality of identified
      studies make it difficult to provide recommendations for improving health
      professionals' obesity management. CONCLUSIONS: At present, decisions about
      improving the provision of services for overweight and obese people must be based
      on the evidence from patient interventions and good clinical judgement. Future
      research is required to identify cost-effective strategies for improving health
      professionals' management and the organisation of care for overweight and obese
      people.

PMID- 10643677
TI  - The effect of body weight changes and endurance training on 24h substrate
      oxidation.
AB  - OBJECTIVE: To investigate the effect of exercise training and dietary
      macronutrient composition on 24 h substrate oxidation in male, obese subjects.
      DESIGN: A 16 month exercise intervention study was executed, including a weight
      loss period with a very low energy diet (VLED) for 2 months at the start of the
      study. SUBJECTS: Twelve male, obese subjects (age 36.3+/-5.1 y; body weight
      94.6+/-13.9 kg; body mass index, BMI 30.8+/-3.0 kg/m2) and in an additional study
      15 lean, well-trained subjects (age 36.2+/-7.2 y; body weight 72.2+/-5.9 kg; BMI
      22.3+/-1.7 kg/m2) participated. MEASUREMENTS: Substrate oxidation was measured
      during a standardized 36 h stay in the respiration chamber at the start of the
      study (0 months), and at 4, 10 and 16 months. In the respiration chamber subjects
      were randomly assigned to a high-fat (Hi.F) diet (60% of energy (En%) fat) or a
      reduced-fat (Red.F) diet (30 En% fat). The well-trained group was measured once
      in the respiration chamber for 36 h according to the same protocol. RESULTS: At
      any time point, independent of the diet consumed, the 24 h carbohydrate (CHO)
      balances in the chamber were mostly negative (means ranging from +31 to -98 g/d)
      and the fat balances mostly positive (means ranging from -26 to +38 g/d) for the
      obese a well as for the lean, well-trained group. For both diets an increased
      shortage of 70 g of CHO was found at 16 months compared with 4 months, and an
      increase in fat balance of 33 g during the same time period in the obese
      subjects, indicating that CHO oxidation had increased with 12 months endurance
      training. In the well-trained group the 24h CHO balance was even more negative
      for both types of diet (-103 to -185 g/d for the Red.F and Hi.F diet,
      respectively) under similar conditions compared with the trained obese group.
      CONCLUSION: The changes in 24 h substrate utilization in the obese, as well as in
      the well-trained group, suggest that endurance training increased the reliance on
      carbohydrate oxidation and therefore did not increase 24 fat oxidation.

PMID- 10643678
TI  - Associations between physical activity, nutritional practices and health-related
      anthropometry in Flemish males: a 5-year follow-up study.
AB  - OBJECTIVE: To examine the extent to which extent health-related anthropometric
      characteristics such as body mass index, waist-hip ratio, waist girth, percentage
      of body fat and weight gain are associated with physical activity and nutritional
      habits in a prospective follow-up study. DESIGN: A 5-y prospective follow-up
      study. SUBJECTS: 132 healthy men from The Leuven Longitudinal Study on Lifestyle,
      Physical Fitness, and Health. MEASUREMENTS: The main outcome measures in this
      study were body mass index, waist-hip ratio, waist girth, percentage of body fat
      and significant weight gain at the ages of 35 and 40y. An unhealthy body
      composition was defined as a body mass index above 26, a waist-hip ratio above
      0.95, a waist girth and body fat percentage above percentile 75 at the end of the
      5-y follow-up period and a significant weight gain of 5 kg or more between the
      two examination periods. Anthropometric characteristics were derived from
      clinical examination. Physical activity at the age of 35 and 40 and nutritional
      habits at the age of 40 were determined from questionnaires. RESULTS: Physical
      activity was the most important predictor for the waist-hip ratio in this sample.
      In contrast, nutritional habits show a stronger relationship with body mass
      index. The absolute amount of energy intake is not as important as the dietary
      factors in predicting subjects with overweight or an unhealthy body composition.
      The index of occupational activities appears to be the most important physical
      activity variable. CONCLUSION: The relative contribution of physical activity and
      nutritional habits in health-related anthropometry varies with the characteristic
      considered. It is important to include all components of physical activity, and
      occupational activities in particular, in determining these relationships in a
      general population sample.

PMID- 10643679
TI  - A novel polymorphism in the proximal UCP3 promoter region: effect on skeletal
      muscle UCP3 mRNA expression and obesity in male non-diabetic Pima Indians.
AB  - OBJECTIVE: UCP2 and UCP3 are newly discovered uncoupling proteins, which are
      thought to underlie the variability in energy metabolism in humans. Mutations in
      the UCP2 and/or UCP3 gene have been associated with sleeping metabolic rate.
      Recently we reported that skeletal muscle UCP3 mRNA expression was positively
      correlated with sleeping metabolic rate in Pima Indians. To study whether genetic
      variation in the promoter region of UCP3 contributed to the variation in
      expression of UCP3, we screened part of the proximal promoter region for
      polymorphisms. METHODS: In the first part of the study, the proximal promoter
      region of UCP3 was screened by direct sequencing in 24 non-diabetic Pima Indians
      (range body mass index (BMI): 18-47 kg/m2) (Schrauwen et al. Diabetes 1999; 48:
      146-149) and skeletal muscle UCP3 mRNA expression was measured by RT-PCR. In the
      second part of the study, we typed the polymorphism found in the first part of
      the study in 67 Pima Indians (32 males, 35 females) from the upper and lower
      extremes of the BMI distribution. RESULTS: We identified a novel C to T
      substitution in the UCP3 promoter, 6bp upstream of the putative TATA signal, and
      55bp upstream of the transcription starting site. Among 18 male subjects,
      skeletal muscle UCP3 mRNA expression was significantly higher in the C/T & T/T
      group compared to the C/C homozygotes (P<0.02). However, in the group of 67 Pima
      Indians genotype frequencies were not different in the obese and lean groups.
      CONCLUSION: We identified a novel polymorphism in the proximal promoter region of
      UCP3, which was associated with increased skeletal muscle expression of UCP3 in
      male non-diabetic Pima Indians. Considering the suggested role of UCP3 in energy
      metabolism, this polymorphism might be of physiological importance in the
      regulation of energy balance.

PMID- 10643680
TI  - The effect of weight cycling on blood lipids and blood pressure in the Multiple
      Risk Factor Intervention Trial Special Intervention Group.
AB  - OBJECTIVE: To assess whether weight cycling has adverse effects on blood lipids
      or blood pressure. DESIGN: Cohort study, six years of follow-up, comparing net
      change in blood lipids and blood pressure among weight cyclers and non-cyclers.
      SUBJECTS: Men (n = 4353), age 35-57 y, at high risk for heart disease because of
      smoking, high blood pressure, and elevated cholesterol concentration in the
      Multiple Risk Factor Intervention Trial (MRFIT)--a 22-site, multi-center
      collaborative primary prevention trial conducted in the US, 1973-1983.
      MEASUREMENTS: A weight cycle was defined as loss and regain of at least 5% of
      mean weight. Outcome measures were changes from baseline to year six in total
      serum cholesterol, high density lipoprotein cholesterol (HDL), the ratio of total
      cholesterol to HDL, and diastolic blood pressure. ANALYSIS: Analysis of
      covariance models were developed, with number of weight cycles as the predictor
      variable. The hypothesis was that men who weight cycled would experience less
      improvement in blood lipids and blood pressure than those who did not cycle.
      Adjustments were made for net weight change and other factors affecting each
      outcome. RESULTS: Men who weight cycled did not have the predicted smaller
      improvements in total cholesterol, HDL, the ratio of total cholesterol to HDL, or
      diastolic blood pressure, compared with noncyclers. CONCLUSION: An adverse effect
      of weight cycling on blood pressure or blood lipids was not found. The excess
      mortality previously reported among weight cyclers in this population can
      probably not be attributed to effects on these CVD risk factors.

PMID- 10643681
TI  - Prospective cohort study of the relationship of markers of insulin resistance and
      secretion with weight gain and changes in regional adiposity.
AB  - OBJECTIVE: To examine whether fasting insulin concentrations and markers of first
      phase insulin secretion are associated with weight gain and changes in
      distribution of adiposity over 4.4y. DESIGN: Longitudinal prospective population
      based cohort study of middle-aged Caucasians. SUBJECTS: 767 subjects (40-65y at
      baseline) were followed up for a mean of 4.4y. MEASUREMENTS: 75 g oral glucose
      tolerance test performed at baseline and follow-up. Insulin was measured at
      fasting, and 30 and 120 min post-glucose load using a highly specific assay.
      RESULTS: Fasting insulin levels were correlated with baseline weight (r = 0.32,
      P<0.001), as was the 30 min insulin incremental response (r = 0.17, P<0.001).
      Mean weight gain over the 4.4y of follow-up was 2.17 kg (range: -6.17-10.5 kg)
      for men and 2.49 kg (range: -7.41-12.39 kg) for women. In women, the 30 min
      insulin incremental response was negatively associated with percentage weight
      gain (P<0.001), but there was no relationship between fasting insulin levels and
      weight gain. The baseline fasting insulin was positively correlated with
      percentage increase in waist- hip ratio (r = 0.12, P = 0.01). In stratified
      analysis, this relationship was confined to women over the age of 50 y. However,
      in men, none of these relationships were demonstrable. CONCLUSION: In middle-aged
      women reduced first-phase insulin secretion was associated with an increased risk
      of future weight gain, whereas fasting hyperinsulinaemia was associated with an
      increase in waist-hip ratio over time.

PMID- 10643682
TI  - Parent-child relationship of physical activity patterns and obesity.
AB  - OBJECTIVE: To study differences in physical activity between normal-weight and
      obese children, as well as parent-child associations of obesity and physical
      activity. DESIGN: Cross-sectional study. SUBJECTS: 129 obese children (67 girls
      and 62 boys), 142 normal-weight controls (81 boys and 61 girls), and mothers (n =
      245) and fathers (n = 222) of the children. METHODS: Physical activity was
      assessed by a 3-day physical activity record (children and parents), by a
      questionnaire (children), and by one question on habitual physical activity
      (parents). The data were analysed by stepwise linear and logistic regressions.
      Obesity was assessed from relative weight (children) and BMI (parents). RESULTS:
      Parent inactivity was a strong and positive predictor of child inactivity (beta
      coefficients 0.25 and 0.16, P<0.001, for mother and father inactivity,
      respectively). Scores of parent activity were somewhat weaker predictors of child
      vigorous activity hours and total physical activity level (beta-coefficients 0.13
      0.25, P = 0.003-0.08). Child obesity was negatively associated with child
      habitual physical activity (odds ratio 0.88, P<0.001). In addition, parent
      obesity (body mass index > or =30 kg/m2) was another strong predictor of child
      obesity (odds ratio 2.38-3.50, P<0.002). CONCLUSIONS: The present study
      underscores the parents' role in childhood activity patterns and obesity. A novel
      finding was that the parent-child relationship of inactivity appeared to be
      stronger than that of vigorous activity. Hence, parents who want to reduce their
      children's inactivity may have to pay attention to their own lifestyle.

PMID- 10643683
TI  - Effects of inactivity and diet composition on human energy balance.
AB  - OBJECTIVES: To investigate the influences of inactivity and dietary macronutrient
      composition on energy and fat balance and to look for interactions between them.
      DESIGN: Two-day measurements of energy expenditure and substrate oxidation on
      five occasions; ad libitum food intake from diets of 35% and 60% energy as fat,
      with and without imposed activity, and a fixed overfeeding at 35% fat with free
      activity. SUBJECTS: Eight normal-weight male volunteers. MEASUREMENTS: Energy
      expenditure and substrate oxidation by indirect whole-body calorimetry, and
      macronutrient intakes from food consumption on ad libitum regimens. RESULTS:
      Subjects consumed the same energy, mean 11.6 MJ/d, regardless of activity level,
      on the 35% diet. Subjects consumed more energy on the 60% than the 35% diet, mean
      14 vs. 11.6 MJ/d. Inactivity induced a strong positive energy balance: 5.1 (60%
      diet), and 2.6 MJ/d (35% diet). Energy balance with activity was not
      significantly different between diets, nor significantly different from zero: 1.1
      MJ/d (60% diet), and -0.2 MJ/d (35% diet). When intentionally overfed, subjects
      failed to compensate by raising voluntary activity. CONCLUSION: Energy intake was
      not regulated over a 2-day period in response to either imposition of inactivity
      or a high-fat diet. Activity proved essential to the avoidance of significant
      positive energy balance.

PMID- 10643684
TI  - Body composition of healthy 7-and 8-year-old children and a comparison with the
      'reference child'.
AB  - BACKGROUND: There are few longitudinal data on body composition in healthy
      children. This has prompted a reliance on notional standards such as the
      'reference child', to validate new methods of determining body composition and
      comparing cross-sectional height, weight and fatness data. OBJECTIVES: These were
      twofold-to provide normative longitudinal data on changes in body composition in
      healthy pre-pubertal children, and to compare measures of growth and body
      composition with the appropriate age-specific reference child. DESIGN: A sample
      of healthy Scottish children aged 7-8y (n = 257) was recruited during 1991/1992.
      Data on height, weight, skinfold thickness and resistance from bioelectrical
      impedance analysis were collected twice, 12 months apart. Percentage body fat was
      estimated from both skinfolds and bioelectrical impedance. RESULTS: Fat and fat
      free mass, but not body mass index, differed between boys and girls. All
      measurements increased significantly over the 12 month period except percentage
      body fat from skinfolds in boys. The reference child comparison revealed that our
      sample was taller, heavier and fatter and gained weight and fat mass at a greater
      rate than the Fomon standards. CONCLUSIONS: Data from the children in this study
      suggest that the reference child has a body composition which is now out of date.
      This may have important implications for body composition methodology. New
      references for height and weight may be required, but an upgrading of the body
      fat reference may conflict with public health aims to reduce obesity.

PMID- 10643685
TI  - Increased intensity of a single exercise bout stimulates subsequent fat intake.
AB  - BACKGROUND: The physical activity pattern in society has in recent years changed
      from necessary occupational activity to voluntary activities during leisure-time.
      How this change in lifestyle affects the selection of dietary intakes is
      presently unknown. OBJECTIVES: The aim of the present study was to investigate
      the different effects of high vs. low-intensity exercise on the following day's
      dietary energy intake and macronutrient selection. DESIGN: The study was designed
      as a controlled randomized cross-over study which compared food selection and
      energy intake the day following a low-intensity vs a high-intensity exercise
      bout. We included 32 healthy normal-weight subjects of four subgroups (young
      males, young females, old males and old females). On two different occasions they
      performed either 60 min low-intensity (30% of VO2max) or 30 min high-intensity
      (60% of VO2max) exercise during 24h measurements of energy expenditure. The
      energy intake and macronutrient selection of the subsequent day was assessed by
      offering them an adlibitum buffet at breakfast and at lunch. RESULTS: Following
      the low-intensity exercise the subjects chose a diet with an energy percentage
      from fat similar to that of their habitual diet-36.7% (95% CI: 34.3, 39.0) vs
      35.6% (95% CI: 33.0, 38.2; NS). Following the high-intensity exercise they chose
      a diet with 39.9% (95% CI: 37.2, 42.6) fat, which was 3.2% (95% CI: 0.6, 5.9)
      higher than following the low-intensity exercise (P<0.05) and 4.2% (95% CI: 1.1,
      7.4) more than their habitual diet (P<0.01). CONCLUSIONS: The present study shows
      that changing the type of activity of a single exercise bout from 30% of maximal
      aerobic capacity for 60 min to 60% for only 30 min resulted in consumption of a
      diet the following day with a higher fat energy percentage compared with the diet
      selected after the low-intensity exercise. However, the higher fat content diet
      did not result in a higher energy intake.

PMID- 10643686
TI  - Perception of body size in the Tongan community: differences from and
      similarities to an Australian sample.
AB  - OBJECTIVE: The prevalence of obesity in Tonga is high and increasing. Attempts to
      address this major health issue would be assisted by a realistic concept of
      current and preferred body sizes. In this study, body size perception in Tongans
      was compared with that of Australians. DESIGN: Cross-sectional comparative study.
      SUBJECTS: 542 Tongans, 89 of whom were enrolled in a weight-loss programme (WLP);
      481 Australians. MEASUREMENTS: Subjects were weighed and measured. Two series of
      photographs (one female, one male), representing specific body mass indexes
      (BMIs) were used to assess body perception. RESULTS: The BMIs of the Tongans were
      higher than those of the Australians (Tongans: female 32.6+/-0.35 (mean +/-
      s.e.m); male, 30.4+/-0.33; Australians: female, 25.6+/-0.33; male 26.3+/-0.26
      kg/m2). Tongan women underestimated their body size; Tongan men and Australians
      overestimated. WLP and younger Tongan women preferred smaller body sizes for
      themselves and for men and women in general. There were gender differences in
      preferred healthy and attractive female sizes (men: 27 kg/m2; non-WLP women: 25
      kg/m2; WLP women: 23 kg/m2) and male sizes (men: 29-30 kg/m2; women: 26-27 kg/m2
      chosen by Tongans. Preferred, attractive and healthy body sizes chosen by
      Australian men and women were similar; about 24 kg/m2 for males and 21-22 kg/m2
      for females. CONCLUSION: Tongans preferred larger body sizes than did
      Australians, particularly the men, but WLP women's preferences were similar to
      those of Australians. There is evidence that preferences are changing in Tonga
      with time, and probably with increasing Western influence.

PMID- 10643688
TI  - Gastric emptying in normal weight and obese children--an ultrasound study.
AB  - AIM: To investigate gastric emptying of a mixed solid and liquid meal in normal
      weight and obese children. METHODS: 114 volunteer children of school age (range 6
      11 y) entered the study. Children were considered as being underweight, normal
      weight, obese, severely obese according to their body mass index (BMI), and were
      examined using a non-invasive ultrasound method in the morning after an overnight
      fast period. The examination was always performed in an upright position by the
      same operator. The half-emptying time and fasting antral area were assessed, and
      antral area measurements were performed every 30 min for 240 min after meal
      administration. RESULTS: Five children (4.4%) were underweight, 53 (46.5%) were
      normal weight, 19 (16.6%) were obese, and 37 (32.5%) were severely obese. The
      underweight group was not considered for the analysis. No significant difference
      in t 1/2 was found among the three groups. A positive statistically significant
      correlation was found between fasting antral area and BMI (r = 0.44; P<0.0001) in
      all children. The fasting antral area value was 3.5 cm2 (range 1.6-8.1) in normal
      weight children, 3.6 cm2 (range 1.9-7.7) in obese children, and 3.9 cm2 (range
      1.5-10.8) in severely obese children. There was a significant difference between
      severely obese and normal weight children (P<.05). No significant difference was
      found in the gastric emptying between severely obese and obese children, and
      between severely obese and normal weight ones. CONCLUSION: The difference in
      fasting antral area in these groups may be considered as an early disturbance. In
      fact the increased gastric volume could cause a change in the sense of satiety
      with a consequent increase in the intake of these subjects.

PMID- 10643687
TI  - Assessment of limb muscle and adipose tissue by dual-energy X-ray absorptiometry
      using magnetic resonance imaging for comparison.
AB  - OBJECTIVE: To use magnetic resonance imaging (MRI) to validate estimates of
      muscle and adipose tissue (AT) in lower limb sections obtained by dual-energy X
      ray absorptiometry (DXA) modelling. DESIGN: MRI measurements were used as
      reference for validating limb muscle and AT estimates obtained by DXA models that
      assume fat-free soft tissue (FFST) comprised mainly muscle: model A accounted for
      bone hydration only; model B also applied constants for FFST in bone and skin and
      fat in muscle and AT; model C was as model B but allowing for variable fat in
      muscle and AT. SUBJECTS: Healthy men (n = 8) and women (n = 8), ages 41-62y; mean
      (s.d.) body mass indices (BMIs) of 28.6 (5.4) kg/m2 and 25.1 (5.4) kg/m2,
      respectively. MEASUREMENTS: MRI scans of the legs and whole body DXA scans were
      analysed for muscle and AT content of thigh (20 cm) and lower leg (10 cm)
      sections; 24h creatinine excretion was measured. RESULTS: Model A overestimated
      thigh muscle volume (MRI mean, 2.3 l) substantially (bias 0.36 l), whereas model
      B underestimated it by only 2% (bias 0.045 l). Lower leg muscle (MRI mean, 0.6 l)
      was better predicted using model A (bias 0.04 l, 7% overestimate) than model B
      (bias 0.1 l, 17% underestimate). The 95% limits of agreement were high for these
      models (thigh, +/-20%; lower leg, +/-47%). Model C predictions were more
      discrepant than those of model B. There was generally less agreement between MRI
      and all DXA models for AT. Measurement variability was generally less for DXA
      measurements of FFST (coefficient of variation 0.7-1.8%) and fat (0.8-3.3%) than
      model B estimates of muscle (0.5-2.6%) and AT (3.3-6.8%), respectively. Despite
      strong relationships between them, muscle mass was overestimated by creatinine
      excretion with highly variable predictability. CONCLUSION: This study has shown
      the value of DXA models for assessment of muscle and AT in leg sections, but
      suggests the need to re-evaluate some of the assumptions upon which they are
      based.

PMID- 10643689
TI  - Effect of obesity and insulin resistance on resting and glucose-induced
      thermogenesis in man. EGIR (European Group for the Study of Insulin Resistance).
AB  - OBJECTIVE: To assess the impact of obesity and insulin sensitivity on resting
      (REE) and glucose-induced thermogenesis (GIT). DESIGN: Data from 322 studies
      carried out in non-diabetic subjects of either gender, covering a wide range of
      age (18-80y) and body mass index (BMI, 18-50 kg/m2). MEASUREMENTS: Insulin
      sensitivity and thermogenesis were measured by combining the euglycaemic insulin
      clamp technique with indirect calorimetry. RESULTS: REE was inversely related to
      age (P = 0.001) and the respiratory quotient (P = 0.03), and positively related
      to BMI, lean body mass (LBM), fat mass, and percentage fat mass (all P<0.0001).
      In a multiple regression model, LBM-adjusted REE was estimated to decline by 9%
      between 18 and 80 y, independently of obesity and insulin sensitivity. In
      contrast, GIT was strongly associated with insulin sensitivity (P<0.0001) but not
      with gender, age or BMI. By multiple regression analysis, GIT was linearly
      related to insulin sensitivity after controlling for gender, age, BMI and steady
      state plasma insulin levels. Furthermore, both of the main components of insulin
      mediated glucose disposal (glucose oxidation and glycogen synthesis) correlated
      with GIT independently of one another. In the subset of subjects (n = 89) in whom
      waist-to-hip ratio (WHR) measurements were available, GIT was inversely
      associated with WHR (P<0.001 after adjustment by gender, age, BMI, insulin
      sensitivity and steady-state plasma insulin concentration). In this model, a
      significant interaction between WHR and gender indicated a stronger adverse
      effect on GIT of a high WHR in women than in men. CONCLUSIONS: In healthy humans,
      age, lean mass and respiratory quotient are the main independent determinants of
      resting thermogenesis. In contrast, insulin sensitivity and, to a lesser extent,
      abdominal obesity are the principal factors controlling glucose-induced
      thermogenesis.

PMID- 10643690
TI  - The prevalence of weight loss maintenance among American adults.
AB  - BACKGROUND: Previous studies suggest that few individuals achieve long-term
      weight loss maintenance. Because most of these studies were based on clinical
      samples and focused on only one episode of weight loss, these results may not
      reflect the actual prevalence of weight loss maintenance in the general
      population. DESIGN: A random digit dial telephone survey was conducted to
      determine the point prevalence of weight loss maintenance in a nationally
      representative sample of adults in the United States. Weight loss maintainers
      were defined as individuals who, at the time of the survey, had maintained a
      weight loss of > or =10% from their maximum weight for at least 1 y. The
      prevalence of weight loss maintenance was first determined for the total group (n
      = 500), and then for the subgroup of individuals who were overweight (body mass
      index BMI > or =27 kg/m2 at their maximum (n = 228). RESULTS: Weight loss was
      quite common in this sample: 54% of the total sample and 62% of those who were
      ever overweight reported that they had lost > or =10% of their maximum weight at
      least once in their lifetime, with approximately one-half to two-thirds of these
      cases being intentional weight loss. Among those who had achieved an intentional
      weight loss of > or =10%, 47-49% had maintained this weight loss for at least 1 y
      at the time of the survey; 25-27% had maintained it for 5 y or more. Fourteen
      percent of all subjects surveyed and 21% of those with a history of obesity were
      currently 10% below their highest weight, had reduced intentionally, and had
      maintained this 10% weight loss for at least 1 y. CONCLUSIONS: A large proportion
      of the American population has lost > or =10% of their maximum weight and has
      maintained this weight loss for at least 1 y. These findings are in sharp
      contrast to the belief that few people succeed in long-term weight loss
      maintenance.

PMID- 10643691
TI  - Do hormonal indices of maturation explain energy expenditure differences in
      African American and Caucasian prepubertal children?
AB  - OBJECTIVE: To examine the relationships between hormonal indices of maturation
      and total, resting and physical activity-related energy expenditure (TEE, REE and
      AEE) in African American and Caucasian prepubertal children. DESIGN: Cross
      sectional study. SUBJECTS: Sixty-four African American and 48 Caucasian
      prepubertal children. MEASUREMENTS: TEE (by doubly labeled water), REE (by
      indirect calorimetry), fat mass and fat-free mass (by dual-energy X-ray
      absorptiometry), fasting serum dehydroepiandrosterone-sulfate (DHEAS),
      androstenedione, and estrone-sulfate (by radioimmunoassay). RESULTS: Serum
      concentrations of hormones correlated significantly with REE and TEE (r values
      range from 0.33 to 0.76, P<0.001). Only androstenedione correlated significantly
      with AEE (r = 0.23, P<0.05). However, these correlations were no longer
      significant after adjusting energy expenditure components for fat-free mass. In
      multiple regression models, ethnicity was not a significant determinant of any
      energy expenditure component after adjusting for body composition and hormone
      concentrations. CONCLUSION: Hormonal indices of maturation do not influence
      energy expenditure in this group of African American and Caucasian prepubertal
      children.

PMID- 10643692
TI  - Cloning and mRNA tissue distribution of human PPARgamma coactivator-1.
AB  - OBJECTIVES: To determine human PPARgamma coactivator-1 (PGC-1) amino acid
      sequence and to study PGC-1 mRNA tissue distribution. PGC-1 is a novel
      transcriptional coactivator of nuclear receptors that may play a role in the
      control of thermogenesis. SUBJECTS: Subcutaneous adipose tissue was obtained from
      six obese and five lean male subjects. Vastus lateralis skeletal muscle was
      obtained from seven lean and six obese subjects undergoing a 5-day severe calorie
      restriction. Other tissue biopsies were from nonobese nondiabetic subjects.
      METHODS: Human PGC-1 was cloned from a skeletal muscle cDNA library. A reverse
      transcription-competitive polymerase chain reaction assay was developed to
      determine PGC-1 mRNA levels in human tissues. RESULTS: The human amino acid
      sequence showed 95% identity with mouse PGC-1. PGC-1 mRNA was expressed at very
      low levels in the small and large intestines and white adipose tissue. Heart,
      kidney, liver and skeletal muscle showed higher mRNA levels. The degree of
      obesity did not affect PGC-1 mRNA levels in adipose tissue while lean subjects
      expressed more PGC-1 mRNA than obese subjects in skeletal muscle. A 5-day severe
      calorie restriction induced PGC-1 mRNA expression in skeletal muscle of obese but
      not of lean subjects. CONCLUSION: PGC-1 shows a restricted tissue expression that
      suggests a tissue-specific role in the control of gene transcription and possible
      interaction with various members of the PPAR family. The lower expression of
      skeletal muscle PGC-1 in obesity could contribute to an alteration of
      mitochondrial gene expression.

PMID- 10643693
TI  - Initial weight loss as a predictor of response to obesity drugs.
AB  - BACKGROUND: Initial weight loss has been used as a predictor of long-term
      response to obesity drugs. Discontinuation of drugs has been recommended if
      weight loss is not > or =1.81 kg (4 lb) in the first month of treatment.
      OBJECTIVE: We compared the weight loss response at 6 months of patients losing >
      or =1.81 kg (responders) vs. < 1.81 kg (non-responders) in the first month of
      treatment with the combination of fenfluramine and phentermine. DESIGN: Outcomes
      at 6 months in 975 patients treated in a comprehensive program of phentermine (15
      30 mg/d) d,l-fenfluramine (20-60 mg/d), were compared for responders vs. non
      responders. RESULTS: In the total population, first month weight loss highly
      correlated with % reduction in body mass index (BMI) after 6 months of treatment
      (P<0.001). The reduction in baseline BMI after 6 months treatment was greater for
      the responders (15.9% vs. 10%, P<0.02). However, the North American Association
      for the Study of Obesity (NAASO) guidelines for drug treatment of obesity state
      that a 5% weight loss produces significant health benefits, and may be used as a
      criteria for success. At 6 months, 76%, 37% and 14% of the non-respondents had
      lost > or = 5%, > or = 10% and > or = 15% of baseline BMI, respectively. After 6
      months treatment the reductions in serum cholesterol, triglycerides and LDL
      cholesterol were 0.55, 0.31 and 0.42 mmol/L, respectively, (P< or =0.006), for
      the non-responders. Adverse effects after 6 months of treatment and the dropout
      rates after 1 y of treatment were not significantly different for the two groups.
      CONCLUSIONS: Although, the first month weight loss predicted the long-term
      response to phen-fen treatment, it was inadequate in identifying the non
      responders and may unnecessarily preclude potential beneficiaries of the
      treatment.

PMID- 10643694
TI  - Basic biology and clinical application of specific cyclooxygenase-2 inhibitors.
AB  - In summary, COX-2 is a highly regulated gene product that catalyzes the local
      production of PGs in pathologic and physiologic situations (Figure 1). It is
      clear that COX-2 is the isoform responsible for production of the PGs that
      mediate inflammation, pain, and fever. However, the role for COX-2 in normal
      physiology is still being defined. Specific COX-2 inhibitors represent a
      significant conceptual advance in therapy for patients with arthritis. Although
      there is no expectation of superior efficacy, clinical trials suggest that
      efficacy will be comparable with that of nonselective NSAIDs. Clinical trials
      demonstrate the potential for clinically meaningful reductions in the incidence
      of the most serious GI complications found with nonselective NSAIDs, i.e., ulcer,
      perforation, and GI bleeding. Over the next several years, treatment of large
      numbers of patients with specific COX-2 inhibitors will help to define the
      biology of COX-2. The magnitude of this advance in the therapy of rheumatic
      diseases is yet to be accurately determined, but the development of specific COX
      2 inhibitors may afford significant new treatment options for many patients.

PMID- 10643695
TI  - Response to methotrexate treatment is associated with reduced mortality in
      patients with severe rheumatoid arthritis.
AB  - OBJECTIVE: This study investigated whether efficacious methotrexate (MTX)
      treatment has an impact on mortality of patients with severe rheumatoid arthritis
      (RA). METHODS: In this prospective, observational, one-center study, patients
      with severe RA refractory to other disease-modifying antirheumatic drugs started
      MTX treatment between 1980 and 1987. Patients were divided into 4 different
      groups according to their response to MTX treatment after 1 year (>50%
      improvement [n = 99], 20-50% improvement [n = 70], no improvement [n = 52], and
      discontinued treatment [n = 35]). After a followup of 7.5-15.3 years (mean 10
      years), the numbers of deaths were assessed in the different groups. Standardized
      mortality ratios (SMR) were calculated by comparing the number of observed deaths
      in the study with the number of expected deaths in an age- and sex-matched sample
      of the general population. RESULTS: Two hundred seventy-one patients entered the
      study between 1980 and 1987. In 1995/1996, outcomes for 256 patients (94.5%)
      could be documented; 88 patients (34.4%) had died. In patients with >50%
      improvement after 1 year, the SMR was 1.47, while in patients with 20-50%
      improvement, the SMR was 1.85. In both groups combined, the SMR was 1.64 (95%
      confidence interval [95% CI] 1.11-2.17), compared with 4.11 (95% CI 2.56-5.66) in
      patients without improvement. Patients who had discontinued MTX treatment during
      the first year had an SMR of 5.56 (95% CI 3.29-7.83). CONCLUSION: Patients with
      severe RA who do not respond to MTX treatment have a poor prognosis, with >4-fold
      increased mortality compared with the general population, while RA patients who
      respond to MTX treatment have only a moderately increased mortality rate.

PMID- 10643696
TI  - Factors predicting response to treatment in rheumatoid arthritis: the importance
      of disease duration.
AB  - OBJECTIVE: To use individual patient data from rheumatoid arthritis (RA) clinical
      trials to identify factors that affect the response to treatment as defined by
      the American College of Rheumatology (ACR) criteria for improvement (the "ACR
      response"). METHODS: Primary trial data from 14 diverse, randomized, controlled
      trials of second-line drugs or devices in RA were analyzed. The trials included
      11 methotrexate (MTX) trials (5 placebo controlled and 6 comparative, of which 2
      were unpublished), 1 combination trial of cyclosporine plus MTX, 1 induction
      trial of a combination treatment in early RA (the COBRA trial), and 1 placebo
      controlled trial of a new device (Prosorba). Both patient factors and disease
      activity measures (primarily, items from the ACR core criteria set) were
      available. RESULTS: A total of 1,435 patients (549 in placebo-controlled trials,
      886 in comparative trials) were studied. In both active treatment and placebo
      groups, disease duration had a strong effect on the likelihood of patient
      response (e.g., with any active treatment, the response rate was 53% for patients
      with < or =1 year of disease, 43% for 1-2 years' disease duration, 44% for 2-5
      years, 38% for 5-10 years, and 35% for > 10 years; P = 0.001). Decreasing
      response with greater disease duration was seen during treatment with most of the
      individual active drugs, as well as with placebo. Other factors decreasing the
      rate of response to treatment included any prior use of a disease-modifying
      antirheumatic drug (DMARD), higher disease functional class (according to the
      Steinbrocker criteria), low disease activity (according to patient's global
      assessment), and female sex. Each ACR core set variable exhibited a diminished
      response to treatment in patients with long-standing disease. The difference
      between active treatment and placebo response rates was not affected by disease
      duration nor by other factors associated with the ACR response. CONCLUSION: RA
      patients with longer disease duration do not respond as well to treatment
      compared with patients with early disease, and female sex, prior DMARD use,
      disease functional class, and disease activity also have effects on the
      likelihood of patient response to treatment. This has implications for trial
      interpretation and for the clinical expectations of RA patients.

PMID- 10643697
TI  - Characterizing the quantitative genetic contribution to rheumatoid arthritis
      using data from twins.
AB  - OBJECTIVE: Twin concordance data for rheumatoid arthritis (RA) on their own
      provide only limited insight into the relative genetic and environmental
      contribution to the disease. We applied quantitative genetic methods to assess
      the heritability of RA and to examine for evidence of differences in the genetic
      contribution according to sex, age, and clinical disease characteristics.
      METHODS: Data were analyzed from 2 previously published nationwide studies of
      twins with RA conducted in Finland and the United Kingdom. Heritability was
      assessed by variance components analysis. Differences in the genetic contribution
      by sex, age, age at disease onset, and clinical characteristics were examined by
      stratification. The power of the twin study design to detect these differences
      was examined through simulation. RESULTS: The heritability of RA was 65% (95%
      confidence interval [95% CI] 50-77) in the Finnish data and 53% (95% CI 40-65) in
      the UK data. There was no significant difference in the strength of the genetic
      contribution according to sex, age, age at onset, or disease severity subgroup.
      Both study designs had power to detect a contribution of at least 40% from the
      common family environment, and a difference in the genetic contribution of at
      least 50% between subgroups. CONCLUSION: Genetic factors have a substantial
      contribution to RA in the population, accounting for approximately 60% of the
      variation in liability to disease. Although tempered by power considerations,
      there is no evidence in these twin data that the overall genetic contribution to
      RA differs by sex, age, age at disease onset, and disease severity.

PMID- 10643698
TI  - Reduction of chemokine levels and leukocyte traffic to joints by tumor necrosis
      factor alpha blockade in patients with rheumatoid arthritis.
AB  - OBJECTIVE: To verify the hypothesis that in rheumatoid arthritis (RA), tumor
      necrosis factor alpha (TNFalpha) plays a critical role in regulating leukocyte
      trafficking and chemokine levels. METHODS: Ten patients with longstanding RA
      received a single 10 mg/kg infusion of anti-TNFalpha monoclonal antibody (cA2).
      The articular localization of autologous granulocytes, separated in vitro and
      labeled with 111In, was studied by analysis of gamma-camera images both before
      and 2 weeks after treatment. At the same sequential time points, synovial biopsy
      samples were assessed for infiltrating CD3+ T cells, CD22+ B cells, and CD68+
      macrophages. Synovial tissue expression of the chemokines interleukin-8 (IL-8),
      monocyte chemotactic protein 1 (MCP-1), macrophage inflammatory protein 1alpha
      (MIP-1alpha), MIP-1beta, Groalpha, and RANTES was also determined. Serum IL-8 and
      MCP-1 concentrations were measured by enzyme-linked immunosorbent assay. RESULTS:
      Anti-TNFalpha therapy in RA significantly reduced 111In-labeled granulocyte
      migration into affected joints. There was a simultaneous and significant
      reduction in the numbers of infiltrating synovial CD3+ T cells, CD22+ B cells,
      and CD68+ macrophages and in the expression of IL-8 and MCP-1, with a trend
      toward a reduction in serum concentrations of these chemokines. CONCLUSION:
      TNFalpha blockade reduces synovial expression of the chemokines IL-8 and MCP-1
      and diminishes inflammatory cell migration into RA joints.

PMID- 10643699
TI  - Evidence of central nervous system damage in patients with neuropsychiatric
      systemic lupus erythematosus, demonstrated by magnetization transfer imaging.
AB  - OBJECTIVE: The clinical symptoms of neuropsychiatric systemic lupus erythematosus
      (NPSLE) are usually reversible, but whether the associated brain damage is also
      reversible is still a matter of debate. Since magnetization transfer imaging
      (MTI) is more sensitive than conventional magnetic resonance imaging (MRI) in
      demonstrating brain damage, it has become a useful tool in the detection and
      quantification of diffuse brain disorders such as multiple sclerosis. In this
      study, MTI was applied to investigate whether central nervous system (CNS) damage
      is present in patients with a history of NPSLE. METHODS: Eleven female patients
      with a history of NPSLE and no previous or concurrent primary neurologic or
      psychiatric disease (ages 17-49 years), 11 female patients with SLE without a
      history of NPSLE (non-NPSLE; ages 15-51 years), and 10 healthy female controls
      (ages 17-47 years) underwent MTI. From these MTI scans, quantitative data on the
      uniformity of the brain parenchyma and atrophy were derived. RESULTS: One NPSLE
      and 1 non-NPSLE patient were excluded from this study due to infarctions detected
      with conventional MRI. MTI measures normalized for intracranial volume,
      reflecting abnormalities of the brain parenchyma as well as atrophy, were lower
      (P < 0.001) in the NPSLE group than in both control groups. A higher (P < 0.005)
      mean ratio of cerebrospinal fluid to intracranial volume, indicative of atrophy,
      was present in the NPSLE group compared with either the non-NPSLE patients or
      healthy controls. Still, the MTI measures solely reflecting uniformity of the
      brain parenchyma (normalized for brain volume) were also significantly (P <
      0.001) lower in the NPSLE patients than in both control groups. CONCLUSION: This
      study demonstrates that using MTI, CNS damage can be demonstrated in patients
      with a history of NPSLE. MTI might, therefore, be an alternative and sensitive
      tool to detect brain injury in NPSLE, and might also be useful in studying the
      natural history of the disease.

PMID- 10643700
TI  - Increased soluble vascular cell adhesion molecule 1 concentrations in patients
      with primary or systemic lupus erythematosus-related antiphospholipid syndrome:
      correlations with the severity of thrombosis.
AB  - OBJECTIVE: Recent studies have shown that in vitro endothelial cells are
      activated by antiphospholipid antibodies and may support leukocyte adhesion. We
      studied levels of soluble intercellular adhesion molecule 1 (sICAM-1, sCD54),
      soluble vascular cell adhesion molecule 1 (sVCAM-1, sCD106), and soluble E
      selectin (soluble endothelial leukocyte adhesion molecule 1 [sELAM-1, sCD62E]) in
      sera from patients with primary antiphospholipid syndrome (primary APS), and
      compared them with those from patients with systemic lupus erythematosus
      associated APS (SLE-APS) or pure SLE, as well as with those from 2 control groups
      composed of healthy volunteers and patients with thrombosis unrelated to
      autoimmune diseases. METHODS: Serum samples from 24 patients with primary APS, 15
      patients with SLE-APS, 22 patients with pure SLE, 48 control patients with
      thrombosis, and 18 healthy volunteers were examined using enzyme-linked
      immunosorbent assays specific for sICAM-1, sVCAM-1, and sELAM-1. RESULTS: Serum
      levels of sVCAM-1, but not sICAM-1 or sELAM-1, were significantly increased in
      all patient study groups compared with thrombosis control patients and healthy
      volunteers, but did not differ between the groups of patients with primary APS,
      SLE-APS, or pure SLE. Concentrations of sVCAM-1 were significantly higher in
      primary APS or SLE-APS patients with severe, recurrent thrombosis and were
      negatively correlated with platelet counts in primary APS patients. In patients
      with primary APS, sVCAM-1 levels were higher if there was thrombotic kidney
      involvement and correlated with creatinemia. CONCLUSION: Serum sVCAM-1
      concentrations are increased in patients with primary APS, especially those with
      repeated thrombotic events or kidney involvement. These findings suggest that
      endothelial/ monocyte interaction may be important in the pathogenesis of primary
      APS.

PMID- 10643701
TI  - T cells that are autoreactive to beta2-glycoprotein I in patients with
      antiphospholipid syndrome and healthy individuals.
AB  - OBJECTIVE: To identify the T cells responsive to beta2-glycoprotein I (beta2GPI)
      that mediate antiphospholipid antibody production in patients with
      antiphospholipid syndrome (APS). METHODS: In vitro proliferative responses and
      anti-beta2GPI antibody production induced by beta2GPI were examined in peripheral
      blood mononuclear cell (PBMC) cultures from 12 APS patients, 13 systemic lupus
      erythematosus patients without APS, and 12 healthy donors. RESULTS: Peripheral
      blood T cells from all subjects failed to respond to beta2GPI in its native form.
      In contrast, reduced beta2GPI was able to stimulate T cells not only from all 12
      patients with anti-beta2GPI antibodies, but also from 10 of 25 individuals
      without anti-beta2GPI antibodies. The specificity of the responses to beta2GPI
      was confirmed by activation of the reduced beta2GPI-primed T cells by recombinant
      beta2GPI in secondary cultures. Characterization of the T cell response induced
      by beta2GPI revealed that the response was associated with the presence of the
      DR53-associated alleles, the responding T cells were CD4+ and restricted by HLA
      class II, and antigenic peptides were located in domains IV and/or V. Anti
      beta2GPI antibody production was induced specifically in anti-beta2GPI antibody
      positive patients, in PBMC cultures with reduced beta2GPI. Anti-beta2GPI
      antibodies produced in vitro recognized beta2GPI immobilized with cardiolipin or
      beta2GPI coated on "high-binding" polystyrene plates. CONCLUSION: These results
      strongly suggest that CD4+ and HLA class II-restricted T cells responsive to
      beta2GPI are involved in the production of antiphospholipid antibodies in APS
      patients.

PMID- 10643702
TI  - Presence of antinucleosome autoantibodies in a restricted set of connective
      tissue diseases: antinucleosome antibodies of the IgG3 subclass are markers of
      renal pathogenicity in systemic lupus erythematosus.
AB  - OBJECTIVE: To study the frequency and disease specificity of antinucleosome
      antibody reactivity in diverse connective tissue diseases (CTD), and to determine
      factors, such as antibody subclass, that may influence the pathogenicity of these
      antibodies in relation to disease activity. METHODS: IgG and IgM antinucleosome
      activities on nucleosome core particles from 496 patients with 13 different CTD
      and 100 patients with hepatitis C were measured by enzyme-linked immunosorbent
      assay (ELISA). Of the patients with CTD, 120 had systemic lupus erythematosus
      (SLE), 37 had scleroderma (systemic sclerosis; SSc), 20 had mixed connective
      tissue disease (MCTD), and 319 had other CTD, including Sjogren's syndrome,
      inflammatory myopathy, rheumatoid arthritis, primary antiphospholipid syndrome,
      Wegener's granulomatosis, Takayasu arteritis, giant cell arteritis, relapsing
      polychondritis, Behcet's syndrome, and sarcoidosis. Antinucleosome-positive sera
      were further analyzed, by isotype-specific ELISA, for antinucleosome and anti
      double-stranded DNA (anti-dsDNA) IgG subclasses. RESULTS: SLE, SSc, and MCTD were
      the only 3 CTD in which antinucleosome IgG were detected (71.7%, 45.9%, and 45.0%
      of patients, respectively). Antinucleosomes of the IgG3 subclass were present at
      high levels in patients with active SLE and were virtually absent in those with
      SSc, MCTD, or inactive SLE, and their levels showed a positive correlation with
      SLE disease activity. Of note, an increase in levels of antinucleosome of the
      IgG3 isotype was observed during SLE flares, and this increase was found to be
      closely associated with active nephritis. Levels of antinucleosome of the IgG1
      subclass showed a trend toward an inverse correlation with SLE disease activity.
      No significant fluctuation in the anti-dsDNA isotype profile was observed in
      relation to SLE severity or clinical signs. CONCLUSION: Our data suggest that IgG
      antinucleosome is a new marker that may help in the differential diagnosis of
      CTD; antinucleosome of the IgG3 isotype might constitute a selective biologic
      marker of active SLE, in particular, of lupus nephritis.

PMID- 10643704
TI  - Oligoclonal non-neoplastic B cell expansion is the key feature of type II mixed
      cryoglobulinemia: clinical and molecular findings do not support a bone marrow
      pathologic diagnosis of indolent B cell lymphoma.
AB  - OBJECTIVE: Type II mixed cryoglobulinemia (type II MC) is often characterized by
      features of indolent B cell lymphoma (IBCL) found on pathologic examination of
      bone marrow, whereas the clinical evidence does not indicate a neoplastic
      disorder. To better address the issue of indolent malignant versus nonmalignant
      bone marrow lymphoproliferation underlying type II MC, molecular analyses of B
      cell clonality were performed in the present study, in conjunction with clinical
      and pathologic characterization. METHODS: Polymerase chain reaction DNA
      amplification of immunoglobulin heavy chain genes was performed in bone marrow
      biopsy specimens obtained from 15 selected patients with type II MC, all infected
      with hepatitis C virus. Five of them had also developed overt B cell lymphoma
      (OBCL) during followup. Bone marrow features were consistent with IBCL in 9 of
      the 15 patients (group 1) and with reactive lymphoplasmacytosis in 6 of the 15
      (group 2). RESULTS: An oligoclonal B cell expansion was detected in 6 of 9
      baseline bone marrow lesions from group 1 patients (biclonal or monoclonal
      expansion in the remaining 3 cases), and in 6 of 6 from group 2 patients. OBCL
      was always monoclonal. Selected lesions were analyzed by clonospecific
      hybridization and by cloning and sequence analysis in patients who had developed
      OBCL at followup. In 4 of 5 cases, OBCL did not originate from the dominant B
      cell clones that were overexpanded in the putative neoplastic baseline bone
      marrow lesions. OBCL clones showed significant homology with rheumatoid factor
      database sequences. CONCLUSION: Based on the present results, as well as on
      evidence from previous studies of liver lesions, oligoclonal non-neoplastic B
      cell proliferation in the course of chronic infection-related inflammation
      appears to be the key feature of type II MC. Of note, molecular evidence from
      target tissues supports the clinical findings both at the time of type II MC
      diagnosis and in cases of OBCL complication. Bone marrow pathologic findings
      resembling those of IBCL should thus be considered in the light of clinical and
      molecular evidence.

PMID- 10643703
TI  - Autoantibodies to DEK oncoprotein in human inflammatory disease.
AB  - OBJECTIVE: To evaluate the specificity of anti-DEK antibodies for juvenile
      rheumatoid arthritis (JRA). METHODS: Anti-DEK autoantibodies were measured by
      enzyme-linked immunosorbent assay (ELISA) using affinity-purified his6-DEK fusion
      protein. Sera from 639 subjects (417 patients with systemic autoimmune disease,
      13 with sarcoidosis, 44 with pulmonary tuberculosis, 125 with uveitis, and 6 with
      scleritis, and 34 healthy control subjects) were screened. Reactivity was
      verified by immunoblotting and immunoprecipitation studies using baculovirus
      expressed human DEK. RESULTS: Anti-DEK activity was found at the following
      frequencies: JRA 39.4% (n = 71), systemic lupus erythematosus (SLE) 25.1% (n =
      216), sarcoidosis 46.2% (n = 13), rheumatoid arthritis 15.5% (n = 71), systemic
      sclerosis 36.0% (n = 22), polymyositis 6.2% (n = 16), and adult Still's disease
      0% (n = 21). Autoantibodies also were detected in 9.1% of tuberculosis sera (n =
      44), but were undetectable in sera from the 34 healthy controls. Western blot and
      immunoprecipitation assay results correlated well with the ELISA findings. In
      general, levels of anti-DEK autoantibodies were higher in SLE than in other
      patient subsets, including JRA. CONCLUSION: Anti-DEK autoantibodies are less
      specific for JRA than previously believed. They are produced in association with
      a variety of inflammatory conditions, many of which are associated with granuloma
      formation and/or predominant Thl cytokine production. Anti-DEK antibodies may be
      a marker for a subset of autoimmunity associated with interferon-gamma production
      rather than a particular disease subset.

PMID- 10643705
TI  - The effect of mini-dose aspirin on renal function and uric acid handling in
      elderly patients.
AB  - OBJECTIVE: Aspirin is known to have a bimodal effect on the renal handling of
      uric acid (UA). High dosages (>3 gm/day) are uricosuric, while low dosages (1-2
      gm/day) cause UA retention. Although very-low-dose (mini-dose) aspirin is used
      increasingly as a platelet aggregation inhibitor, no studies have been published
      on whether aspirin's renal effects occur at dosages of <0.5 gm/day. The aim of
      the present study was to evaluate the effects of commonly used mini-dosages of
      aspirin on renal function and UA handling in elderly patients. METHODS: The study
      included 49 elderly inpatients (age 61-94). Patients were excluded if they had
      renal failure, hyperuricemia, gout, or a history of bleeding, or if they were
      receiving anticoagulants, aspirin, or nonsteroidal antiinflammatory drugs.
      Previous medications and diet were kept unchanged. Aspirin was administered as
      follows: 75 mg/day (week 1), 150 mg/day (week 2), 325 mg/day (week 3), and 0
      mg/day (week 4). Baseline and weekly samples of blood and urine were evaluated
      for UA, creatinine, blood urea nitrogen, creatinine clearance, UA excretion, UA
      clearance, and plasma levels of aspirin. RESULTS: At the lowest dosage, aspirin
      caused a 15% decrease in the rate of UA excretion (P = 0.045 by t-test), which
      was associated with a slight but significant increase in serum levels of UA (P =
      0.009). These effects on UA levels were gradually reduced with increasing dosages
      of aspirin (multivariate analysis of variance with repeated measures showed no
      statistically significant difference in the rate of UA excretion between weeks 1
      3 and week 0 [baseline], but the difference in serum UA levels for the same
      comparison was statistically significant [P = 0.038]). Generally, creatinine and
      UA clearance rates paralleled each other during aspirin treatment. However, 1
      week after aspirin was discontinued, creatinine clearance remained decreased
      while UA clearance returned to baseline. Plasma aspirin concentrations were low
      and variable. However, patients with above-median aspirin levels had
      significantly greater changes in serum creatinine levels, urinary UA excretion
      rates, and UA clearance rates following the first week of aspirin treatment.
      Hypoalbuminemia and concomitant treatment with diuretics enhanced the effects of
      aspirin on renal function and UA retention. CONCLUSION: Mini-dose aspirin, even
      at a dosage of 75 mg/day, caused significant changes in renal function and UA
      handling within 1 week in a group of elderly inpatients, mainly in those with
      preexisting hypoalbuminemia. Given the widespread (and often unmonitored) use of
      mini-dose aspirin, especially among the elderly, these findings call for
      clinician alertness as well as for further studies to clarify the mechanisms
      underlying these phenomena.

PMID- 10643706
TI  - Evolution of chronic recurrent multifocal osteitis toward spondylarthropathy over
      the long term.
AB  - OBJECTIVE: To retrospectively assess, with a sufficiently long followup (mean
      11.6 years; median 9 years), the long-term outcome of chronic recurrent
      multifocal osteitis (CRMO), a multifocal, inflammatory bone disease. METHODS:
      Patients included were 8 children/adolescents and 7 adults with no family history
      of rheumatic disease who had been diagnosed as having CRMO between 1979 and 1995.
      Ten patients had undergone at least 1 bone biopsy of the lesions, with histologic
      examination and multiple cultures. In 1996, in addition to an in-depth interview,
      12 patients underwent an extensive physical examination, laboratory evaluation,
      HLA-A, B, C, and DR typing, bone radiography and scintigraphy, and computed
      tomography scan of the sternoclavicular and sacroiliac joints. RESULTS: Remission
      was observed in 3 patients. The other 12 patients developed various associations
      of vertebral (n = 10), sacroiliac (n = 6), anterior thoracic (n = 7), peripheral
      articular (n = 2), enthesopathic (n = 4), or dermatologic (palmoplantar
      pustulosis in 3 cases and psoriasis in 2) involvements. Spine involvement was the
      most common and occurred the earliest (median time to appearance after the onset
      of osteitis 5.63 years). Clinical sacroiliitis was always unilateral. No patients
      carried the HLA-B27 haplotype. CRMO responded well to nonsteroidal
      antiinflammatory drugs. Twelve patients met the European Spondylarthropathy Study
      Group criteria for spondylarthopathy. CONCLUSION: After 10 years, CRMO had
      usually evolved to spondylarthropathy, but with certain features not usually seen
      in the latter: predominantly, unilateral sacroiliitis, no familial form, and no
      link with HLA-B27.

PMID- 10643707
TI  - Systemic lupus erythematosus candidate genes in the Italian population: evidence
      for a significant association with interleukin-10.
AB  - OBJECTIVE: To determine whether 7 candidate genes, including tumor necrosis
      factor receptor II, bcl-2, CTLA-4, interleukin-10 (IL-10), CD19, Fcy receptor
      type IIA (CD32), and IL-1 receptor antagonist, may contribute to susceptibility
      to systemic lupus erythematosus (SLE) in the Italian population. METHODS: The
      association with SLE of intragenic markers for each candidate gene, including
      either microsatellites or dimorphisms, was analyzed. Gene frequencies of these
      gene markers were compared for patients and ethnically matched controls.
      Significance was tested by chi-square test on 2 x 2 tables and by Monte Carlo
      simulation on 2 x N tables. RESULTS: A significant increase was found in SLE
      patients (0.170 versus 0.095; chi2y = 4.11, P = 0.0425) in the frequency of the
      140-basepair allele of the IL10.G microsatellite located in the promoter region
      of the IL-10 gene. This finding was confirmed in a second independent panel
      where, again, the frequency of the 140-bp allele was found to be significantly
      increased in SLE patients versus controls (0.176 versus 0.086; chi2y = 3.95, P =
      0.0470). Considering the 2 panels together, the relative risk conferred by the
      presence of the 140-bp allele was 1.78 (95% confidence interval 1.19-2.66).
      Conversely, no significant association was detected for the remaining 6 candidate
      genes, even when the patients were stratified according to the presence of
      different clinical and immunologic features according to the presence of the
      associated HLA-DR or IL-10 alleles. CONCLUSION: Of the 7 candidate genes tested,
      only IL-10 was significantly associated with SLE in Italian patients. This
      genetic marker represents, apart from HLA, the only genetic susceptibility factor
      for SLE found so far in the Italian population.

PMID- 10643708
TI  - TNF-308A and HLA-DR3 alleles contribute independently to susceptibility to
      systemic lupus erythematosus.
AB  - OBJECTIVE: To evaluate the respective contributions of tumor necrosis factor
      (TNF) promoter polymorphisms and HLA-DR alleles to susceptibility to systemic
      lupus erythematosus (SLE). METHODS: TNF-238G/A and 308G/A promoter polymorphisms
      and HLA-DRB1 alleles were determined in 99 consecutive Caucasian SLE patients and
      177 Caucasian controls. Standard and Mantel-Haenszel odds ratios were calculated
      to assess the magnitude of the susceptibility factors. The presence or absence of
      the SLE classification criteria was determined and correlated with the TNF
      promoter and HLA-DRB1 genotypes. RESULTS: The frequency of the TNF-308A/A and
      308G/A genotypes was significantly higher in SLE patients (odds ratio 5.0).
      Conversely, TNF-238G/A and 238A/A genotypes were equally prevalent in SLE
      patients and controls. The HLA-DR3 specificity (DRBI*0301 allele) was
      significantly more prevalent in the SLE population (odds ratio 4.4).
      Stratification to correct for interdependence of the 2 loci confirmed the
      association of both TNF-308A and HLA-DR3 with SLE (Mantel-Haenszel odds ratio 3.2
      and 2.4, respectively). No correlation was found between TNF promoter and HLA
      DRB1 genotypes and any SLE classification criterion or disease manifestation.
      CONCLUSION: TNF-308A and HLA-DR3 alleles are independent susceptibility factors
      for SLE.

PMID- 10643709
TI  - Analysis of fas ligand gene mutation in patients with systemic lupus
      erythematosus.
AB  - OBJECTIVE: To investigate the possible association of a Fas ligand (FasL) gene
      mutation(s) or polymorphism(s) with systemic lupus erythematosus (SLE). METHODS:
      For amplification of the introns of the FasL gene, long polymerase chain reaction
      (PCR) using exon-based primers was utilized, followed by partial sequencing to
      construct exon-specific oligonucleotide primers for the analyses of FasL genomic
      DNA in SLE patients. Structural defects were studied by use of a composite
      analysis of reverse transcriptase-PCR/single-strand conformational polymorphism
      (SSCP) analysis of messenger RNA (mRNA) transcripts of the FasL gene in 35 SLE
      patients and PCR/SSCP analysis of FasL genomic DNA in 143 SLE patients. RESULTS:
      The sizes of the introns were approximately 0.6 kb for intron 1, 4.3 kb for
      intron 2, and 1.3 kb for intron 3. By SSCP analysis, we did not identify any
      mutations or polymorphisms in the FasL mRNA transcripts or in any of the 4 exons
      or areas of the introns adjacent to the exons. CONCLUSION: Using the same methods
      used in the present studies (PCR/SSCP), one group of investigators identified a
      structural defect of the FasL molecule in 1 of 75 SLE patients evaluated. Among
      the 143 SLE patients in the present study, however, we did not identify any
      mutations or polymorphisms of the FasL gene. Our results suggest that a FasL
      defect is not the major contributing factor in the pathogenesis of SLE.

PMID- 10643710
TI  - Antiphospholipid antibodies affect trophoblast gonadotropin secretion and
      invasiveness by binding directly and through adhered beta2-glycoprotein I.
AB  - OBJECTIVE: To investigate the in vitro ability of antiphospholipid antibodies
      (aPL) to bind human trophoblast cells and to affect gonadotropin secretion and
      invasiveness. METHODS: Antiphospholipid antibody IgG from women with recurrent
      miscarriages, beta2-glycoprotein I (beta2GPI)-independent IgG aPL human
      monoclonal antibody (mAb) (519), and IgM anti-beta2GPI human mAb (TMIG2) were
      investigated for their binding to trophoblasts cultured for various amounts of
      time, their ability to affect invasiveness of Matrigel-coated filters, and their
      release of human chorionic gonadotropin (hCG). RESULTS: Polyclonal IgG aPL, as
      well as mAb 519 and TMIG2, bound to trophoblasts, the highest binding being found
      when cells displayed the greatest amount of syncytium formation. TM1G2 binding
      was found to be betaGPI dependent. Both polyclonal and monoclonal aPL, but not
      the controls, significantly reduced hCG release and Matrigel invasiveness.
      CONCLUSION: These findings suggest that aPL recognition of both anionic PL and
      adhered beta2GPI on trophoblast cell structures might represent a potential
      pathogenetic mechanism for defective placentation in women with the
      antiphospholipid syndrome.

PMID- 10643711
TI  - Lack of evidence for an involvement of Epstein-Barr virus infection of synovial
      membranes in the pathogenesis of rheumatoid arthritis.
AB  - OBJECTIVE: To test the hypothesis that Epstein-Barr virus (EBV) infection of
      cells within the synovial membrane contributes to the pathogenesis of rheumatoid
      arthritis (RA). METHODS: Biopsy samples of synovial membrane from 37 patients
      with RA and from 51 patients with other joint diseases were studied for evidence
      of EBV infection using in situ hybridization specific for the EBV-encoded RNAs
      (EBERs). Latent membrane protein 1 (LMP1) and the lytic-cycle BZLF1 protein were
      detected by immunohistochemistry. RESULTS: Rare EBER-positive B lymphocytes were
      detected in 7 RA biopsy samples. EBV was not detectable in any other cells.
      Expression of the LMP1 and BZLF1 proteins of EBV was not observed in any of the
      samples. No EBV infection was detected in synovial membranes from patients with
      other joint diseases. CONCLUSION: Our data indicate that EBV infection is not
      directly involved in the pathogenesis of RA. Any contribution of EBV to the
      pathogenic process leading to RA is likely to be indirect.

PMID- 10643712
TI  - The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic
      citrullinated peptide.
AB  - OBJECTIVE: Since modern treatment of rheumatoid arthritis (RA) is shifting toward
      aggressive antirheumatic therapy in an early phase of the disease, diagnostic
      tests with high specificity are desirable. A new serologic test (anti-cyclic
      citrullinated peptide [anti-CCP] enzyme-linked immunosorbent assay [ELISA]) was
      developed to determine the presence of antibodies directed toward citrullinated
      peptides, using a synthetic peptide designed for this purpose. METHODS: A cyclic
      peptide variant that contains deiminated arginine (citrulline) was designed and
      used as antigenic substrate in ELISA. Test parameters and diagnostic
      characteristics of the test were studied in patients with and without RA, in
      patients with various infectious diseases, and in a group of patients from an
      early arthritis clinic (EAC). RESULTS: Using prevalent RA and non-RA sera, the
      anti-CCP ELISA proved to be extremely specific (98%), with a reasonable
      sensitivity (68%). Also, in the EAC study group, the anti-CCP ELISA appeared to
      be highly specific for RA (96%). In comparison with the IgM rheumatoid factor
      (IgM-RF) ELISA, the anti-CCP ELISA had a significantly higher specificity (96%
      for CCP versus 91% for IgM-RF; P = 0.016) at optimal cut-off values. The
      sensitivity of both tests for RA was moderate: 48% and 54% for the anti-CCP ELISA
      and the IgM-RF ELISA, respectively (P = 0.36). Combination of the anti-CCP and
      the IgM-RF ELISAs resulted in a significantly higher positive predictive value of
      91% (P = 0.013) and a slightly lower negative predictive value of 78% (P = 0.35)
      as compared with the use of the IgM-RF ELISA alone. The ability of the 2 tests
      performed at the first visit to predict erosive disease at 2 years of followup in
      RA patients was comparable (positive predictive value 91%). CONCLUSION: The anti
      CCP ELISA might be very useful for diagnostic and therapeutic strategies in RA of
      recent onset.

PMID- 10643713
TI  - Tumor necrosis factor alpha promotes the expression of stem cell factor in
      synovial fibroblasts and their capacity to induce mast cell chemotaxis.
AB  - OBJECTIVE: To investigate the expression of the stroma cell product stem cell
      factor (SCF) in synovial fibroblasts (SFB) in patients with rheumatoid arthritis
      (RA) and osteoarthritis (OA), and to analyze the capacity of SFB to induce mast
      cell (MC) chemotaxis. METHODS: Synovial tissue was obtained from 29 patients with
      RA and 25 patients with OA. Tissue was dispersed by enzymatic digestion using
      collagenase. SFB were grown in serial passage and exposed to tumor necrosis
      factor alpha (TNFalpha) or control medium. Expression of SCF in cultured SFB was
      analyzed by reverse transcription-polymerase chain reaction (RT-PCR), enzyme
      linked immunosorbent assay (ELISA), and immunostaining. The ability of SFB
      (supernatants) to induce MC migration was analyzed using a double-chamber
      chemotaxis assay and the human mast cell line HMC-1. In situ expression of SCF in
      synovial tissue from patients with RA (n = 6) and OA (n = 6) was examined by
      double immunohistochemistry using antibodies against SCF and the fibroblast
      specific antibody AS02. RESULTS: In both RA and OA, cultured SFB were found to
      express SCF messenger RNA, as assessed by RT-PCR. In addition, the SCF protein
      was detectable in cell lysates and supernatants of SFB by ELISA. Incubation of
      SFB with TNFalpha resulted in an increased expression and release of SCF.
      Recombinant human SCF (rHuSCF) and SFB supernatants induced significant migration
      of HMC-1 cells above control levels. In addition, exposure of SFB to TNFalpha led
      to an increased migration of HMC-1, and a blocking anti-SCF antibody inhibited
      the rHuSCF- and SFB-induced migration of HMC-1. In situ double immunostaining
      revealed expression of SCF in AS02-positive SFB in the synovium of patients with
      RA. CONCLUSION: Our results show that SFB (in RA and OA) express SCF and induce
      MC chemotaxis. Furthermore, TNFalpha was found to augment SCF expression in SFB.
      It is hypothesized that these cellular interactions play an important role in MC
      accumulation and related events in RA.

PMID- 10643714
TI  - Disease-modifying activity of SB 242235, a selective inhibitor of p38 mitogen
      activated protein kinase, in rat adjuvant-induced arthritis.
AB  - OBJECTIVE: To evaluate the effects of SB 242235, a potent and selective inhibitor
      of p38 mitogen-activated protein (MAP) kinase, on joint integrity in rats with
      adjuvant-induced arthritis (AIA). METHODS: Male Lewis rats with AIA were orally
      treated either prophylactically (days 0-20) or therapeutically (days 10-20) with
      SB 242235. Efficacy was determined by measurements of paw inflammation, dual
      energy x-ray absorptiometry for bone-mineral density (BMD), magnetic resonance
      imaging (MRI), microcomputed tomography (CT), and histologic evaluation. Serum
      tumor necrosis factor alpha (TNFalpha) in normal (non-AIA) rats and serum
      interleukin-6 (IL-6) levels in rats with AIA were measured as markers of the
      antiinflammatory effects of the compound. RESULTS: SB 242235 inhibited
      lipopolysaccharide-stimulated serum levels of TNFalpha in normal rats, with a
      median effective dose of 3.99 mg/kg. When SB 242235 was administered to AIA rats
      prophylactically on days 0-20, it inhibited paw edema at 30 mg/kg and 10 mg/kg
      per day by 56% and 33%, respectively. Therapeutic administration on days 10-20
      was also effective, and inhibition of paw edema was observed at 60, 30, and 10
      mg/kg (73%, 51%, and 19%, respectively). Significant improvement in joint
      integrity was demonstrated by showing normalization of BMD and also by MRI and
      micro-CT analysis. Protection of bone, cartilage, and soft tissues was also shown
      histologically. Serum IL-6 levels were decreased in AIA rats treated with the 60
      mg/kg dose of compound. CONCLUSION: Symptoms of AIA in rats were significantly
      reduced by both prophylactic and therapeutic treatment with the p38 MAP kinase
      inhibitor, SB 242235. Results from measurements of paw inflammation, assessment
      of BMD, MRI, and micro-CT indicate that this compound exerts a protective effect
      on joint integrity, and thus appears to have disease-modifying properties.

PMID- 10643715
TI  - Cell adhesion molecules in the development of inflammatory infiltrates in giant
      cell arteritis: inflammation-induced angiogenesis as the preferential site of
      leukocyte-endothelial cell interactions.
AB  - OBJECTIVE: To investigate the expression pattern of adhesion molecules involved
      in leukocyte-endothelial cell interactions in giant cell arteritis (GCA).
      METHODS: Immunohistochemical analysis was performed on frozen temporal artery
      sections from 32 patients with biopsy-proven GCA and from 12 control patients
      with other diseases. Adhesion molecules identified were intercellular adhesion
      molecule 1 (ICAM-1), ICAM-2, ICAM-3, vascular cell adhesion molecule 1 (VCAM-1),
      platelet endothelial cell adhesion molecule 1 (PECAM-1), E-selectin, P-selectin,
      L-selectin, lymphocyte function-associated antigen 1 (LFA-1), very late
      activation antigen 4 (VLA-4), Mac-1 (CD18/CD11b), and gp 150,95 (CD18/CD11c).
      Clinical and biochemical parameters of inflammation in the patients, as well as
      the duration of previous corticosteroid treatment, were prospectively recorded.
      RESULTS: Constitutive (PECAM-1, ICAM-1, ICAM-2, and P-selectin) and inducible (E
      selectin and VCAM-1) endothelial adhesion molecules for leukocytes were mainly
      expressed by adventitial microvessels and neovessels within inflammatory
      infiltrates. Concurrent analysis of leukocyte receptors indicated a preferential
      use of VLA-4/VCAM-1 and LFA-1/ICAM-1 at the adventitia and Mac-1/ICAM-1 at the
      intima-media junction. The intensity of inducible endothelial adhesion molecule
      expression (E-selectin and VCAM-1) correlated with the intensity of the systemic
      inflammatory response. Previous corticosteroid treatment reduced, but did not
      completely abrogate, the expression of the inducible endothelial adhesion
      molecules E-selectin and VCAM-1. CONCLUSION: Inflammation-induced angiogenesis is
      the main site of leukocyte-endothelial cell interactions leading to the
      development of inflammatory infiltrates in GCA. The distribution of leukocyte
      endothelial cell ligand pairs suggests a heterogeneity in leukocyte-endothelial
      cell interactions used by different functional cell subsets at distinct areas of
      the temporal artery.

PMID- 10643716
TI  - Autocrine regulation of collagenase 3 (matrix metalloproteinase 13) during
      osteoarthritis.
AB  - OBJECTIVE: To correlate the increased collagenase production previously seen in
      chondrocytes isolated from osteoarthritic (OA) lesions and the expression of
      cytokines and cytokine receptors. METHODS: Chondrocytes were isolated from OA
      cartilage and characterized for synthesis of collagenases, cytokines, and
      cytokine receptors by Northern and Western blot analyses, RNA protection assay,
      and flow cytometry. RESULTS: Chondrocytes located in cartilage proximal to the
      macroscopic OA lesions bound more tumor necrosis factor alpha (TNFalpha) and
      interleukin-1beta (IL-1beta) compared with chondrocytes isolated from
      morphologically normal cartilage from the same joint. In response to TNFalpha
      stimulation, messenger RNA (mRNA) levels for the IL-1 receptor I (IL-1RI), IL
      1RII, TNF receptor II (TNFR II), and IL-6 receptor as well as the level of
      proinflammatory cytokines, such as IL-1alpha, IL-1beta, lymphotoxin beta,
      TNFalpha, and IL-6, also increased. In contrast, treatment with transforming
      growth factor beta1 (TGFbeta1) resulted in down-regulation of matrix
      metalloproteinase 1 (MMP-1) and MMP-13 concomitant with a reduction in the levels
      of mRNA for IL-1RI, IL-1RII, TNFRI, and TNFRII and proinflammatory cytokine
      levels. In contrast, the levels of mRNA for TGFbeta receptor I, TGFbeta1, and
      TGFbeta3 were up-regulated. CONCLUSION: These data show that TGFbeta1 has
      antagonistic effects upon OA chondrocytes, in contrast to the effects seen with
      TNFalpha. The cyclical course of OA, where a period of active disease is followed
      by a period of remission, can be explained by a sequential pattern of cytokine
      stimulation followed by a feedback inhibition of autocrine cytokine production
      and cytokine receptor expression, thus affecting collagenase synthesis.

PMID- 10643717
TI  - Osteogenic protein 1 stimulates cells-associated matrix assembly by normal human
      articular chondrocytes: up-regulation of hyaluronan synthase, CD44, and aggrecan.
AB  - OBJECTIVE: To determine the effects of osteogenic protein 1 (OP-1) on hyaluronan
      (HA), CD44, and aggrecan biosynthesis as well as the contribution of these
      molecules in promoting matrix assembly by human articular chondrocytes. METHODS:
      Normal human chondrocytes were cultured with or without OP-1 treatment. Changes
      in the relative expression of messenger RNA (mRNA) for HA synthases 2 and 3 (HAS
      2 and HAS-3), CD44, and aggrecan were determined by competitive quantitative
      reverse transcriptase-polymerase chain reaction. Accumulation of HA was
      characterized by indirect staining, CD44 by flow cytometry, and aggrecan
      biosynthesis by 35SO4 incorporation. RESULTS: OP-1 stimulated the expression of
      HAS-2, CD44, and aggrecan mRNA in a time-dependent manner, resulting in increased
      expression of HA, CD44, and aggrecan. Prominent increases in HA-rich cell
      associated matrices were also observed. CONCLUSION: OP-1 stimulates not only the
      synthesis of matrix macromolecules such as aggrecan, but also the synthesis of
      other molecules required for matrix retention, namely, HA and CD44.

PMID- 10643718
TI  - The reactions of articular cartilage to experimental wounding: role of apoptosis.
AB  - OBJECTIVE: To determine the cellular and matrix responses to experimental
      wounding of articular cartilage. METHODS: Immature and mature bovine articular
      cartilage was used as an in vitro model system to study the cellular responses to
      cartilage wounding. Explant cultures were wounded centrally with a trephine and
      maintained for up to 10 days. TUNEL labeling together with ultrastructural
      analyses were used to assess the nature of the observed cell death. In vitro
      labeling with 3H-thymidine was used to detect cell proliferation, and 2
      antibodies (COL2-3/4M and BC-13) were used to detect changes in matrix turnover.
      RESULTS: Cell death was observed as a response to wounding and was considered to
      be a combination of necrosis and apoptosis. In immature tissue, cell death was
      more pronounced, particularly in the articular surface region. Within the area of
      cell death, many cells that did not die subsequently underwent proliferation. The
      collagenous network showed evidence of denaturation in the area of the wound, but
      "aggrecanase" activity was not detected. CONCLUSION: There are 2 contrasting, but
      related, responses to cartilage wounding--apoptosis and proliferation. In order
      to improve cartilage repair, future studies need to elucidate the regulatory
      mechanisms that determine these responses.

PMID- 10643719
TI  - Subacute bacterial endocarditis with positive cytoplasmic antineutrophil
      cytoplasmic antibodies and anti-proteinase 3 antibodies.
AB  - OBJECTIVE: To report a potentially important limitation of antineutrophil
      cytoplasmic antibody (ANCA) testing: positive results in patients with subacute
      bacterial endocarditis (SBE). METHODS: We describe 3 patients with SBE who
      presented with features mimicking ANCA-associated vasculitis (AAV) and positive
      findings on tests for cytoplasmic ANCA (cANCA) by indirect immunofluorescence and
      for anti-proteinase 3 (anti-PR3)antibodies by antigen-specific enzyme-linked
      immunosorbent assay (ELISA). We also reviewed the published literature describing
      infectious diseases with (misinterpreted) positive ANCA results through a Medline
      search of English-language articles published between 1966 and January 1999.
      These previously reported cases were reinterpreted using an ANCA scoring system
      that combines the findings of immunofluorescence and antigen-specific ELISA
      testing. RESULTS: We are now aware of a total of 7 cases of SBE with positive
      cANCA and anti-PR3 antibodies. We are not aware of any cases of SBE associated
      with antimyeloperoxidase/perinuclear ANCA. Clinical manifestations mimicking AAV
      included glomerulonephritis, purpura, epistaxis, or sinus symptoms in 6 of the
      patients. Streptococcal species were identified in 5 patients, and cardiac
      valvular abnormalities were demonstrated in 6. All patients except 1, who died of
      a complication of SBE, recovered with antibiotic therapy. CONCLUSION: Findings of
      tests for anti-PR3/ cANCA antibodies may be positive in patients with SBE. When
      encountering ANCA positivity in patients suspected of having systemic vasculitis,
      physicians should take appropriate steps to rule out infectious diseases,
      including SBE, before committing the patient to long-term, aggressive
      immunosuppressive therapy.

PMID- 10643720
TI  - Chronic seropositive polyarthritis associated with hepatitis B virus-induced
      chronic liver disease: a sequel of virus persistence.

PMID- 10643721
TI  - Rheumatoid arthritis remission/relapse and the Health Assessment Questionnaire:
      comment on the article by Barrett et al.

PMID- 10643722
TI  - Acute-phase response and the risk of developing ischemic complications in giant
      cell arteritis: comment on the article by Cid et al.

PMID- 10643723
TI  - Th2-type cytokines and the Fas way to pulmonary fibrosis: comment on the article
      by Atamas et al.

PMID- 10643724
TI  - Inflammatory arterial stenosis: followup with color Doppler sonography.

PMID- 10643725
TI  - Imaging the electrical activity of the brain: ELECTRA.
AB  - The construction of a tomography of neuronal sources is limited by a lack of
      information. A possible way around this problem is to change the biophysical
      model that underlies the statement of the inverse problem, i.e., searching for
      magnitudes that can be better determined from the available data. In this report,
      we describe a mathematical characterization of the type of currents that are
      actually able to produce the scalp-recorded EEG. Considering this
      characterization, we reformulate the bioelectric inverse problem. This approach,
      called ELECTRA, yields some advantages over the classical formulation in terms of
      the current density vector: (1) the number of unknowns can be reduced, which is
      equivalent to increasing the number of independent measurements, (2) the
      constraints used to reformulate the problem are undeniable since they do not
      imply any hypothesis about brain function but are instead based on the character
      of the measurements, and (3) existing experimental evidence suggests that the
      proposed source model characterizes the type of currents that arise in excitable
      tissues. We conclude that if the latter fact proves to be true for brain tissues,
      then no additional information is added to the inverse problem by using a more
      general source model than the one proposed here. Images obtained using this
      method for synthetic data, as well as early and middle components of human visual
      evoked responses to checkerboard stimuli, are presented to illustrate the
      characteristics of the reconstructed maps and their interpretation.

PMID- 10643726
TI  - Acupuncture modulates the limbic system and subcortical gray structures of the
      human brain: evidence from fMRI studies in normal subjects.
AB  - Acupuncture, an ancient therapeutic technique, is emerging as an important
      modality of complementary medicine in the United States. The use and efficacy of
      acupuncture treatment are not yet widely accepted in Western scientific and
      medical communities. Demonstration of regionally specific, quantifiable
      acupuncture effects on relevant structures of the human brain would facilitate
      acceptance and integration of this therapeutic modality into the practice of
      modern medicine. Research with animal models of acupuncture indicates that many
      of the beneficial effects may be mediated at the subcortical level in the brain.
      We used functional magnetic resonance imaging (fMRI) to investigate the effects
      of acupuncture in normal subjects and to provide a foundation for future studies
      on mechanisms of acupuncture action in therapeutic interventions. Acupuncture
      needle manipulation was performed at Large Intestine 4 (LI 4, Hegu) on the hand
      in 13 subjects [Stux, 1997]. Needle manipulation on either hand produced
      prominent decreases of fMRI signals in the nucleus accumbens, amygdala,
      hippocampus, parahippocampus, hypothalamus, ventral tegmental area, anterior
      cingulate gyrus (BA 24), caudate, putamen, temporal pole, and insula in all 11
      subjects who experienced acupuncture sensation. In marked contrast, signal
      increases were observed primarily in the somatosensory cortex. The two subjects
      who experienced pain instead of acupuncture sensation exhibited signal increases
      instead of decreases in the anterior cingulate gyrus (BA 24), caudate, putamen,
      anterior thalamus, and posterior insula. Superficial tactile stimulation to the
      same area elicited signal increases in the somatosensory cortex as expected, but
      no signal decreases in the deep structures. These preliminary results suggest
      that acupuncture needle manipulation modulates the activity of the limbic system
      and subcortical structures. We hypothesize that modulation of subcortical
      structures may be an important mechanism by which acupuncture exerts its complex
      multisystem effects.

PMID- 10643727
TI  - Event-related fMRI: comparison of conditions with varying BOLD overlap.
AB  - Recently, event-related fMRI-experiments have been reported in which subsequent
      trials were separated by only 2 sec or less. Because the BOLD response needs 10
      sec and longer to return to baseline, the event-related signal in these
      experiments has to be extracted from the overlapping responses elicited by
      successive trials. Usually it is assumed that this convolved signal is a
      summation of the overlapping BOLD responses. We tested this assumption by
      comparing event-related signals in conditions with little and with substantial
      BOLD overlap in two fMRI experiments of a task-switching paradigm. We analyzed
      the difference in the activational time course elicited by a critical task and a
      baseline task when trials of both tasks were separated by intertrial intervals of
      15 sec or when the critical trials were embedded in a stream of baseline trials
      with ISI = 1 sec. The change of the BOLD signal elicited by the critical trials
      showed a high correspondence between both experiments in five out of six cortical
      ROI. Our data support the view that BOLD overlap leads to largely linear signal
      changes. In the present study, task-related increases in the BOLD response were
      detected equally well with substantial BOLD overlap as with mostly nonoverlapping
      BOLD responses.

PMID- 10643728
TI  - Executive control, willed actions, and nonconscious processing.
AB  - Neuroimaging studies have identified a number of cortical areas involved in the
      executive control of conscious actions. The areas most frequently implicated are
      prefrontal and cingulate cortices. Evidence suggests that both of these areas may
      be essential for executive control of willed action. Prefrontal cortex, however,
      may be responsible for the initial processing. Executive control is usually
      discussed with reference to willed actions and is assumed to regulate complex
      cognitive responses. Although many implicit processes involve complex responses,
      it is not known whether these actions are also controlled by executive processes.
      Significantly, some implicit tasks like those involving motor sequence learning
      and cross-modality priming activate the same areas of prefrontal cortex that are
      implicated in the executive control of willed actions. It is, however, not clear
      whether a single executive process controls both implicit and explicit processes,
      or the implicit processes are regulated by a separate set of executive control
      having distinct neuroanatomical location and processing properties.

PMID- 10643729
TI  - Updating working memory for words: a PET activation study.
AB  - A PET study of 10 normal individuals was carried out to investigate the cerebral
      regions involved in the controlled updating of verbal working memory. Subjects
      viewed single concrete words on a computer monitor and detected occasional target
      words in an attended color. In the activating condition, a target was defined as
      a word that was identical to the previous word presented in the attended color.
      In the control condition, the target was a predesignated word. The same word
      lists, target probabilities, and target response demands were used for both
      conditions, with interword intervals constrained to ensure equivalence in the
      demand for target rehearsal. A comparison of the conditions found bilateral
      activation of dorsolateral prefrontal (middle frontal gyrus; MFG) and inferior
      parietal (supramarginal gyrus; SMG) cortical regions. Activation of the MFG is
      taken to reflect executive control by prefrontal regions over the working memory
      updating process linking posterior representations of the anticipated target
      stimulus to anterior representations of the planned response. It is proposed that
      the updating of the stimulus link is mediated via connections between the MFG and
      SMG. The role of the SMG as an amodal region binding the various modal
      representations in posterior association cortex of the word being retained in
      working memory is considered and reviewed. It is suggested that the combined
      activation of these regions is related to the executive control of goal-setting
      in planned behavior.

PMID- 10643730
TI  - Projection of rods and cones within human visual cortex.
AB  - There are two basic types of photoreceptors in the retina: rods and cones. Using
      a single stimulus viewed at two different light levels, we tested whether input
      from rods and input from cones are topographically segregated at subsequent
      levels of human visual cortex. Here we show that rod-mediated visual input
      produces robust activation in area MT+, and in the peripheral representations of
      multiple retinotopic areas. However, such activation was selectively absent in:
      (1) a cortical area selectively activated by colored stimuli (V8) and (2) the
      foveal representations of lower tier retinotopic areas. These cortical
      differences reflect corresponding differences in perception between scotopic and
      photopic conditions.

PMID- 10643731
TI  - Proton beam therapy for age-related macular degeneration: development of a
      standard plan.
AB  - Age-related macular degeneration is the leading cause of blindness in developing
      countries. Irradiating the exudative form, in which a choroidal neovascular
      membrane develops in the subfoveal area, is presently a treatment under
      investigation. In 1995, Massachusetts General Hospital, collaborating with
      Massachusetts Eye and Ear Infirmary, initiated a protocol to treat SCNV membranes
      using the proton beam at the Harvard Cyclotron Laboratory and the EYEPLAN program
      with a light-field setup. EYEPLAN requires the axial eye length, membrane
      dimensions, and manipulation of the eye to include a 4.0-mm radial margin around
      the membrane so that the aperture margin (50% isodose line on the posterior
      retina) abuts the inferior aspect of the limbus. Review of 100 individually
      prepared plans showed that 95% of the fabricated apertures were circular (aspect
      ratio < 1.095) with diameters 9.5 to 15.0 mm. This information was used to
      develop an automated standard plan. Thirty-nine plans were developed for axial
      lengths ranging from 21.0 to 25.0 mm and membrane sizes from 1.5 to 6.75 mm in
      the usual way as the reviewed ones. Circular targets were outlined centered on
      the fovea. Distal and proximal 90% ranges (modulation) to the target, and doses
      to macula, optic disc, lens, ciliary body, retina, and globe were calculated. An
      automated standard plan requiring the same input data, but avoiding the need for
      individual plans, was developed. The program outputs the aperture diameter,
      fixation angle for the light-field setup, range and modulation, and calculates
      dose to the macula and optic nerve and percentage of retina receiving > or = 50%
      and > or = 90% of the prescribed dose. Individual plans require approximately 1.5
      hours; the standard plan, 5 minutes. The standard plan could have treated 86% of
      the reviewed plans. The automated plan provides accurate and efficient treatment
      parameters for the majority of patients.

PMID- 10643732
TI  - A single isocenter technique using CT-based planning in the treatment of breast
      cancer.
AB  - Breast cancer will afflict 1 of every 9 women. With advances in mammography and
      public awareness, breast cancer is being detected at an earlier stage and is
      therefore more curable. The combination of lumpectomy and radiotherapy is a
      standard treatment option for most women with stage I and II invasive breast
      cancer. Radiotherapy treatment fields are usually tangential to encompass the
      breast, and in some cases, matched to a supraclavicular field. Due to variation
      in the size and shape of the breast, dosimetry and treatment planning can be
      challenging, yet many radiation oncology centers still achieve a treatment plan
      of the breast by using a single plane hand-generated contour 2-dimensional (2D)
      through the center of the breast. This type of planning neglects the variations
      in contours and chest-wall separation superior and inferior to that plane, which
      significantly impacts dose homogeneity and dosimetry. Computed tomography (CT)
      images are being utilized more often for planning in radiotherapy and should be
      considered for breast planning. CT-based treatment planning 3-dimensional (3D)
      allows the planner and physician to evaluate the dosimetry across the entire
      breast. Consequently, the plan can be optimized to limit lung volume with
      selective blocking, and minimize hot spots by using a higher energy and less
      wedge angle, thus improving dose homogeneity. For a larger breast, when the
      dosimetry using 6 MV is undesirable, a mix of 6 MV and higher energy may be used.
      This paper describes a single isocenter treatment technique using CT-based
      planning for tangents and a supraclavicular field and the advantages our
      department has found using 3D treatment planning vs. 2D. In addition, the
      creative planning done for larger breasts and the use of 18 MV combined with 6 MV
      to optimize a treatment plan will American Association of Medical Dosimetrists.

PMID- 10643733
TI  - Who says you can't treat pituitary carcinoma on a breast board?
AB  - A hospital-manufactured aquaplast head and neck immobilization system was
      constructed in tandem with a unique custom-built breast board. It was developed
      in conjunction with the breast board for patients unable to achieve and maintain
      the desired head flexion needed in the treatment of pituitary lesions. (This
      custom design provides an alternative to accomplishing this desired head angle
      needed to position the patient's eyes out of the treatment area, realizing that
      the lenses are situated in the anterior 1 cm of the globes.) By using the angled
      breast board, reproducibility of setup and patient comfort were addressed
      throughout the simulation, computed tomography planning and treatment process.
      The custom designed boards were constructed with available materials at
      relatively low cost to the department.

PMID- 10643734
TI  - Comparison of 2D conventional, 3D conformal, and intensity-modulated treatment
      planning techniques for patients with prostate cancer with regard to target-dose
      homogeneity and dose to critical, uninvolved structures.
AB  - The purpose of this study was to compare 2-dimensional (2D), 3-dimensional (3D)
      and intensity-modulated radiation therapy (IMRT) techniques for external-beam
      radiation treatment for prostate cancer. Dose homogeneity within the target
      volume and doses to critical, uninvolved anatomic structures were evaluated.
      Computed tomography (CT) scans of 3 patients with localized prostate cancer
      (T2NOM0) were acquired and transferred to the treatment planning systems. The
      target volume and uninvolved structures were contoured on axial CT slices
      throughout the volume of interest. A comparison of the 3 treatment techniques was
      performed using isodose distributions, dose statistics, and dose-volume
      histograms. Dose homogeneity was found to be most uniform with the 2D technique;
      however, the 2D technique delivers unnecessary radiation doses to the rectum and
      bladder. The dose conformity observed with IMRT is increased compared with that
      observed with the 3D technique, as is the sparing of critical uninvolved
      structures; however, dose homogeneity appears to be worse with IMRT than with the
      3D technique. Overall, of the 3 techniques, IMRT offers the most conformity in
      delivery of tumoricidal doses to the prostate while sparing dose to critical,
      uninvolved structures. Association of Medical Dosimetrists.

PMID- 10643735
TI  - Optimization of beam orientations and weights for coplanar conformal beams in
      treating pancreatic cancer.
AB  - In treating pancreatic cancer with external-beam radiotherapy, radiation dose
      given to the tumor volume is largely limited by the tolerance of the normal
      structures near the disease site, including the kidneys, liver, stomach, small
      bowel, and spinal cord. The purpose of this work was to investigate whether a
      coplanar conformal therapy technique with beam optimization could reduce dose to
      the normal tissues compared to the conventional 4-field technique; and if this
      was true, whether other beam arrangements were more effective than the 4-field
      technique in treating pancreatic cancer. In this study, 9 patients who were
      treated previously for T3N0 or T3N1 pancreatic cancer with external-beam therapy
      of 30 Gy in 10 fractions were selected. Beam orientations and weights were
      optimized for 4 to 6 coplanar conformal beams using a simulated annealing
      algorithm to minimize the kidney volume receiving more than 20 Gy. Optimized
      plans were compared with standard plans using a 4-field technique with respect to
      the isodose distributions and dose volume histograms. For the standard 4-field
      plans giving 30 Gy to the tumor volume, the total kidney volume above 20 Gy
      ranged from 10% to 35%, with a mean of 22% and a standard deviation of 7%.
      Optimization of the beam orientations and weights reduced this volume by
      approximately 2 times without a significant increase of dose to the liver,
      stomach, and small bowel. This indicated that the radiation toxicity to the
      kidneys could be reduced substantially by a careful selection of oblique beam
      angles and weights. Analysis of the optimized plans showed that beam arrangements
      which involved left and right anterior oblique beams were superior to the
      conventional 4-field technique for reducing the kidney dose in treating
      pancreatic cancer.

PMID- 10643736
TI  - Loading technique comparison in permanent 125I prostate implants.
AB  - Treatment of prostate cancer utilizing iodine 125 (125I) interstitial seed
      implants has become an accepted and widely used modality. Numerous variations in
      125I seed implant loading distribution techniques have developed as a result of
      the preferences of individual institutions implementing the modality. No
      particular universal standard is currently used for 1251 seed implants. A major
      concern with 125I seed implants is coverage of the prostate with the desired dose
      and the minimization of dose to the urethra. A variation of seed distribution per
      individual anatomy is desirable. Historically, brachytherapy relied on dosimetry
      systems, such as the Paris, Quimby, and Manchester systems to achieve the desired
      dose distribution. Use of various peripherally loaded 125I seed implant
      distributions to accommodate anatomic variations within the same institution
      prompted the interest of how the results compare to the Manchester system.

PMID- 10643737
TI  - Measurement and comparison of prostate treatment dose to the femoral heads with 6
      MV versus 10-MV photon energies.
AB  - The purpose of this paper is to compare the femoral head dose distribution of 6
      MV x-rays vs. 10-MV x-rays when treating prostate patients using a 4-field
      initial box technique with a Michigan technique boost. First, tissue maximum
      ratio (TMR) calculations were utilized to project the expected dose contributions
      to the femoral heads from each energy based upon the average male pelvis. Then,
      plans for both the 6- and 10-MV energies were developed for 5 prostate patients
      using the ADAC Pinnacle3 (Milpitas, CA) treatment planning computer. Average
      doses and dose gradients were determined by examination of isodose curves. The
      dose contributions to the femoral heads were analyzed and compared with the
      tolerance dose (TD) 5/5 for this region. No significant dose differences existed
      between the 6- and 10-MV photon energies. This conclusion was supported by
      examination of point doses at depths of 3, 6, 12, and 15 cm for each energy.

PMID- 10643738
TI  - A comparison of 18-MV and 6-MV treatment plans using 3D dose calculation with and
      without heterogeneity correction.
AB  - Homogeneity of the dose distribution in irradiation of the intact breast for
      stage I and II cancers is an important factor, particularly for larger breasts.
      In the present work, we have studied dose homogeneity for 6- and 18-MV treatment
      plans in 10 patients, typically with larger breasts. For each patient, 6 3
      dimensional (3D) dose distributions were calculated using patient computed
      tomography data and the ADAC Pinnacle3 treatment planning system. First, a dose
      distribution was calculated, assuming the patient was water, with the 6-MV beam
      parameters used to treat the patient. Second, the calculation was repeated using
      the actual patient anatomy. Comparison of these 2 distributions showed how
      patient heterogeneity affected dose. Third, individual beam weights were
      optimized, and the dose calculation was repeated. Each of these 3 dose
      calculations was repeated at 18 MV. Results showed that: (1) at 6 MV, the ratio
      of mean dose in the target volume calculated with heterogeneity considerations to
      that without was 1.014 +/- 0.006, and the ratio of the standard deviation of dose
      in the target volume was 0.919 +/- 0.042; (2) at 18 MV, the ratio of mean dose to
      the target volume calculated with heterogeneity considerations to that without
      was 1.001 +/- 0.005, and the ratio of the standard deviation of dose in the
      target volume was 1.15 +/- 0.09; and (3) the dose homogeneity, measured by the
      standard deviation of the dose distribution in the target volume, was 25% less
      for the 18-MV treatment plan for patients with breast volumes greater than 1600
      cm3. We conclude that: (1) 3D, heterogeneity-corrected dose calculation is
      necessary to fairly evaluate any advantage of 18 MV over 6 MV; (2) excluding the
      dose buildup region, 18 MV produces a significantly more homogeneous dose
      distribution for breast volumes greater than 1600 cm3; and (3) when prescribing
      dose using heterogeneity-corrected dose distributions, dose prescriptions should
      be increased by 1.5% at 6 MV, but no increase is needed for 18 MV.

PMID- 10643739
TI  - Three-dimensional treatment planning for central lymphatic irradiation.
AB  - The purpose of this study was to investigate the applicability of 3-dimensional
      (3D) treatment planning for central lymphatic irradiation (CLI). CLI requires
      more than 1 course of treatment with large, highly blocked, overlapping beams,
      and careful planning is required to ensure that such treatments are delivered
      safely and effectively. Three patients were selected for this study. Each patient
      completed at least 1 course of radiation therapy for CLI and was scheduled to
      receive irradiation to an adjacent area with overlapping beams. Two treatment
      plans were generated for each patient: a standard, 2-dimensional (2D) treatment
      plan and a 3D treatment plan designed to mimic the standard plan, taking
      advantage of unique 3D features. The time required to complete the treatment
      plans and differences in the treatment planning processes were noted. The time
      required to generate a 3D treatment plan was approximately the same as the time
      required to generate a standard 2D treatment plan; however, the 3D planning
      process required less redundancy of data entry than the 2D process. The 3D
      treatment plan was qualitatively similar to the standard 2D treatment plan;
      however, differences in beam penumbra and beam junctions were noted, and are most
      likely due to differences in the dose-calculation models used in these 2
      treatment planning systems. Dose-volume histograms (DVHs) were calculated for the
      spinal cord and were found to be useful to the physicians for quickly and
      accurately evaluating the presence or absence of hot spots in the junction
      region. 3D treatment-planning has some advantages over 2D treatment planning for
      CLI; the main advantage of the 3D treatment plan is that it provides a single
      plan for each patient with multiple views of the data, including different planar
      cross-sections and DVHs. For the 2D system, a separate plan was generated for
      each view, requiring redundant data entry. The quality of the output of the 3D
      treatment plans is superior to that of 2D treatment plans, but the clinical
      utility is about the same. Currently, the time required for 2D and 3D treatment
      plans is similar. However, as dosimetrists become more familiar with 3D treatment
      planning systems, we expect this familiarity and regularity of use to translate
      into a significant time advantage.

PMID- 10643740
TI  - Limit cycle models for circadian rhythms based on transcriptional regulation in
      Drosophila and Neurospora.
AB  - We examine theoretical models for circadian oscillations based on transcriptional
      regulation in Drosophila and Neurospora. For Drosophila, the molecular model is
      based on the negative feedback exerted on the expression of the per and tim genes
      by the complex formed between the PER and TIM proteins. For Neurospora,
      similarly, the model relies on the feedback exerted on the expression of the frq
      gene by its protein product FRQ. In both models, sustained rhythmic variations in
      protein and mRNA levels occur in continuous darkness, in the form of limit cycle
      oscillations. The effect of light on circadian rhythms is taken into account in
      the models by considering that it triggers degradation of the TIM protein in
      Drosophila, and frq transcription in Neurospora. When incorporating the control
      exerted by light at the molecular level, we show that the models can account for
      the entrainment of circadian rhythms by light-dark cycles and for the damping of
      the oscillations in constant light, though such damping occurs more readily in
      the Drosophila model. The models account for the phase shifts induced by light
      pulses and allow the construction of phase response curves. These compare well
      with experimental results obtained in Drosophila. The model for Drosophila shows
      that when applied at the appropriate phase, light pulses of appropriate duration
      and magnitude can permanently or transiently suppress circadian rhythmicity. We
      investigate the effects of the magnitude of light-induced changes on oscillatory
      behavior. Finally, we discuss the common and distinctive features of circadian
      oscillations in the two organisms.

PMID- 10643741
TI  - Circadian systems and metabolism.
AB  - Circadian systems direct many metabolic parameters and, at the same time, they
      appear to be exquisitely shielded from metabolic variations. Although the recent
      decade of circadian research has brought insights into how circadian periodicity
      may be generated at the molecular level, little is known about the relationship
      between this molecular feedback loop and metabolism both at the cellular and at
      the organismic level. In this theoretical paper, we conjecture about the
      interdependence between circadian rhythmicity and metabolism. A mathematical
      model based on the chemical reactions of photosynthesis demonstrates that
      metabolism as such may generate rhythmicity in the circadian range. Two
      additional models look at the possible function of feedback loops outside of the
      circadian oscillator. These feedback loops contribute to the robustness and
      sustainability of circadian oscillations and to compensation for long- and short
      term metabolic variations. The specific circadian property of temperature
      compensation is put into the context of metabolism. As such, it represents a
      general compensatory mechanism that shields the clock from metabolic variations.

PMID- 10643742
TI  - Modeling circadian rhythm generation in the suprachiasmatic nucleus with locally
      coupled self-sustained oscillators: phase shifts and phase response curves.
AB  - Circadian rhythm generation in the suprachiasmatic nucleus was modeled by locally
      coupled self-sustained oscillators. The model is composed of 10,000 oscillators,
      arranged in a square array. Coupling between oscillators and standard deviation
      of (randomly determined) intrinsic oscillator periods were varied. A stable
      overall rhythm emerged. The model behavior was investigated for phase shifts of a
      24-h zeitgeber cycle. Prolongation of either the dark or the light phase resulted
      in a lengthening of the period, whereas shortening of the dark or the light phase
      shortened the period. The model's response to shifts in the light-dark cycle was
      dependent only on the extent of the shift and was insensitive to changes in
      parameters. Phase response curves (PRC) and amplitude response curves were
      determined for single and triple 5-h light pulses (1000 lux). Single pulses lead
      to type 1 PRCs with larger phase shifts for weak coupling. Triple pulses
      generally evoked type 1 PRCs with the exception of weak coupling, where a type 0
      PRC was observed.

PMID- 10643743
TI  - The Goodwin oscillator: on the importance of degradation reactions in the
      circadian clock.
AB  - This article focuses on the Goodwin oscillator and related minimal models, which
      describe negative feedback schemes that are of relevance for the circadian
      rhythms in Neurospora, Drosophila, and probably also in mammals. The temperature
      behavior of clock mutants in Neurospora crassa and Drosophila melanogaster are
      well described by the Goodwin model, at least on a semi-quantitative level. A
      similar semi-quantitative description has been found for Neurospora crassa phase
      response curves with respect to moderate temperature pulses, heat shock pulses,
      and pulses of cycloheximide. A characteristic feature in the Goodwin and related
      models is that degradation of clock-mRNA and clock protein species plays an
      important role in the control of the oscillator's period. As predicted by this
      feature, recent experimental results from Neurospora crassa indicate that the
      clock (FRQ) protein of the long period mutant frq7 is degraded approximately
      twice as slow as the corresponding wild-type protein. Quantitative RT-PCR
      indicates that experimental frq7-mRNA concentrations are significantly higher
      than wild-type levels. The latter findings cannot be modeled by the Goodwin
      oscillator. Therefore, a threshold inhibition mechanism of transcription is
      proposed.

PMID- 10643744
TI  - Control systems models for the circadian clock of the New Zealand weta, Hemideina
      thoracica (Orthoptera: Stenopelmatidae)
AB  - The New Zealand weta, Hemideina thoracica, is a nocturnal orthopteran insect
      which emerges from holes in trees or from under bark soon after sunset to forage
      for several hours on plant and animal material before returning to its refuge
      before dawn. In tests of the internal clock hypothesis it exhibits clear
      circadian locomotor rhythms in which the period is initially somewhat less than
      24 h, but frequently spontaneously increases to over 25 h. The rhythms are
      entrainable by light and temperature cycles, obey Aschoff's Law and are
      temperature compensated. A single oscillator feedback model accounts for these
      basic properties of the weta clock, but does not explain a variety of examples of
      rhythm lability, such as day skipping, spontaneous change in period, scalloping
      and desynchrony typically found in the real data. To account for these
      characteristics the model is expanded into two linked populations of oscillators,
      which retain the basic properties of the simple model and in addition interact
      through their coupling to show the various types of free-run lability. To make
      these control systems models compatible with the molecular interpretation of
      circadian biology, each of the components in the feedback loop is matched with
      molecular function and structure.

PMID- 10643745
TI  - Commentary: molecular and cellular models of circadian systems.

PMID- 10643746
TI  - Revised limit cycle oscillator model of human circadian pacemaker.
AB  - In 1990, Kronauer proposed a mathematical model of the effects of light on the
      human circadian pacemaker. This study presents several refinements to Kronauer's
      original model of the pacemaker that enable it to predict more accurately the
      experimental results from a number of different studies of the effects of the
      intensity, timing, and duration of light stimuli on the human circadian
      pacemaker. These refinements include the following: The van der Pol oscillator
      from Kronauer's model has been replaced with a higher order limit cycle
      oscillator so that the system's amplitude recovery is slower near the singularity
      and faster near the limit cycle; the phase and amplitude of the circadian rhythm
      in sensitivity to light from Kronauer's model has been refined so that the peak
      sensitivity to light on the limit cycle now occurs approximately 4 h before the
      core body temperature minimum (CBTmin) and is three times as great as the minimum
      sensitivity on the limit cycle; the critical phase (at which type 1 phase
      response curves [PRCs] can be distinguished from type 0 PRCs) that occurs at
      CBT,n now corresponds to 0.8 h after the minimum of x (x(min) in this refined
      model rather than to the exact timing of x(min) as in Kronauer's model; a direct
      effect of light on circadian period was incorporated into the model such that as
      light intensity increases, the period decreases, which is in accordance with
      Aschoff's rule.

PMID- 10643747
TI  - Quantifying human circadian pacemaker response to brief, extended, and repeated
      light stimuli over the phototopic range.
AB  - The authors' previous models have been able to describe accurately the effects of
      extended (approximately 5 h) bright-light (>4000 lux) stimuli on the phase and
      amplitude of the human circadian pacemaker, but they are not sufficient to
      represent the surprising human sensitivity to both brief pulses of bright light
      and light of more moderate intensities. Therefore, the authors have devised a new
      model in which a dynamic stimulus processor (Process L) intervenes between the
      light stimuli and the traditional representation of the circadian pacemaker as a
      self-sustaining limit-cycle oscillator (Process P). The overall model
      incorporating Process L and Process P is intended to allow the prediction of
      phase shifts to photic stimuli of any temporal pattern (extended and brief light
      episodes) and any light intensity in the photopic range. Two time constants
      emerge in the Process L model: the characteristic duration for necessary bright
      light pulses to achieve their full effect (5-10 min) and the characteristic
      stimulus-free (dark) interval that can be tolerated without incurring an
      excessive penalty in phase shifting (30-80 min). The effect of reducing light
      intensity is incorporated in Process L as an extension of the time necessary for
      the light pulse to be fully realized (a power-law relation between time and
      intensity). This new model generates a number of new testable hypotheses,
      including the surprising prediction that 24-h cycles consisting of 8 h of
      darkness and 16 h of only approximately 3.5 lux would be capable of entraining a
      large fraction of the adult population (approximately 45%). Experimental data on
      the response of the human circadian system to lower light intensities and briefer
      stimuli are needed to allow for further refinement and validation of the model
      proposed here.

PMID- 10643748
TI  - A circadian oscillator model based on empirical data.
AB  - A model based on the van der Pol equation has been developed to predict the
      pattern of adaptation of aircrew and other travellers to rapid time-zone
      transitions, when the exposure to light cannot be quantified. The parameters of
      the model include the stiffness (mu) and the intrinsic period (T0), which
      together define the free-running period, and the external force (F). The
      parameter values were estimated by using a simplex minimization technique to fit
      the output from the model to body temperature data from 12 individuals before,
      and over a 12-day period immediately after, a 10-h eastward transition between
      London and Sydney. Data were collected at three equally spaced points during each
      sleep period and at the end of four 45-min rest periods during the day. The
      fitting procedure enabled the parameters of the temperature rhythm to be
      estimated after correcting for the masking effect of sleep. The average estimates
      of mu (0.38 h) and T0 (24.24 h) were close to earlier estimates based on forced
      desynchronization experiments, and the mean free-running period, calculated from
      these, was 24.50 h. The mean value of the external force F (0.54) was
      surprisingly high, and this may reflect the strong outdoor light levels during
      the days in Sydney. Estimates of phase, based on the model solutions, suggested
      that 11 subjects adapted by a phase delay and 1 by a phase advance. However, the
      amplitude of the rhythms was much reduced at times when the phase was changing
      rapidly. Simulations using the range of the model parameters for the 12
      individuals predicted that adaptation to within 1 h after a 10-h eastward
      transition would be achieved within between 3 and 11 days. However, since these
      predictions are dependent on the choice of external force, estimates may need to
      be more conservative in real-life situations when light exposure cannot be
      measured.

PMID- 10643749
TI  - Accuracy of human circadian entrainment under natural light conditions: model
      simulations.
AB  - The patterns of light intensity to which humans expose their circadian pacemakers
      in daily life are very irregular and vary greatly from day to day. The circadian
      pacemaker can adjust to such irregular exposure patterns by daily phase shifts,
      such as summarized in a phase response curve. It is demonstrated in this paper on
      the basis of computer simulations applying actually recorded human light exposure
      patterns that the pacemaker can substantially improve its accuracy by an
      additional response to light: For that purpose, it should additionally change its
      angular velocity (and consequently its period tau) in response to light.
      Reductions of tau in response to light in the morning and increases of tau in
      response to light in the evening can lead to an increase in entrained pacemaker
      accuracy with about 25%. Circadian pacemakers have evolved as accurate internal
      representations of external time, and investigated diurnal mammals all seem to
      respond to light by changing the period of their circadian pacemaker (in addition
      to shifting phase). The authors suggest that also human circadian systems take
      advantage of this possibility and that their pacemakers respond to light by
      shifting phase and changing period. As a consequence of this postulated
      mechanism, the simulations demonstrate that the period of the pacemaker under
      normally entrained conditions is 24 h. The maximum accuracy corresponds to a day
      to-day standard deviation of the time of phase 0 of circa 15 min. This is
      considerably more accurate than the light signal humans usually perceive.

PMID- 10643750
TI  - A simpler model of the human circadian pacemaker.
AB  - Numerous studies have used the classic van der Pol oscillator, which contains a
      cubic nonlinearity, to model the effect of light on the human circadian
      pacemaker. Jewett and Kronauer demonstrated that Aschoff's rule could be
      incorporated into van der Pol type models and used a van der Pol type oscillator
      with higher order nonlinearities. Kronauer, Forger, and Jewett have proposed a
      model for light preprocessing, Process L, representing a biochemical process that
      converts a light signal into an effective drive on the circadian pacemaker. In
      the paper presented here, the authors use the classic van der Pol oscillator with
      Process L and Jewett and Kronauer's model of Aschoff's rule to model the human
      circadian pacemaker. This simpler cubic model predicts the results of a three
      pulse human phase response curve experiment and a two-pulse amplitude reduction
      study with as much, or more, accuracy as the models of Jewett and Kronauer and
      Kronauer, Forger, and Jewett, which both employ a nonlinearity of degree 7. This
      suggests that this simpler cubic model should be considered as a potential
      alternative to other models of the human circadian system currently available.

PMID- 10643751
TI  - Commentary: models of the effect of light on the human circadian system: current
      state of the art.

PMID- 10643752
TI  - Thermoregulatory model of sleep control: losing the heat memory.
AB  - Thermoregulatory mechanisms were hypothesized to provide primary control of non
      rapid-eye-movement sleep (NREM). On the basis of this hypothesis, we incorporated
      the thermoregulatory feedback loops mediated by the "heat memory," heat load, and
      loss processes associated with sleep-wake cycles, which were modulated by two
      circadian oscillators. In addition, hypnogenic warm-sensitive neurons (HWSNs)
      were assumed to integrate thermoregulation and NREM control. The heat memory
      described above could be mediated by some sleep-promoting substances. In this
      paper, considering the possible carrier of the heat memory, its losing process is
      newly included in the model. The newly developed model can generate the
      appropriate features of human sleep-wake patterns. One of the special features of
      the model is to generate the bimodal distribution of the sleepiness. This
      bimodality becomes distinct, as the losing rate of the heat memory decreases or
      the amplitude of the Y oscillator increases. The theoretical analysis shows the
      losing rate of the heat memory control's rapidity of model response to a thermal
      perturbation, which is confirmed by simulating the responses with various losing
      rates to transient heat loads ("heat load pulse"). The sleepiness exhibits large
      responses to the heat load pulses applied in the early and late phases of wake
      period, while the response is significantly reduced to the pulse applied in the
      supposed wake-maintenance zone. This bimodality of the response appears to
      reflect the sensitivity of the HWSNs. In addition, the early pulse raises the
      immediate sleepiness rather than the nocturnal sleepiness, while the heat load
      pulse applied in the later phase of waking period significantly raises the
      sleepiness during a nocturnal sleep. In simulations of sleep deprivation, the
      discontinuous relationship between recovery sleep length and deprivation time is
      reproduced, where the critical sleep deprivation time at which the recovery sleep
      length jumps is extended as the losing rate increases. This is possibly due to
      the dissipation of the heat memory accumulated by the sleep deprivation. The
      simulation results here qualitatively reproduce the experimental observations or
      predict the intriguing phenomena of human circadian rhythms. Therefore, our model
      could provide a novel framework for investigating the relationship between
      thermoregulation and sleep control processes.

PMID- 10643753
TI  - Sleep homeostasis and models of sleep regulation.
AB  - According to the two-process model of sleep regulation, the timing and structure
      of sleep are determined by the interaction of a homeostatic and a circadian
      process. The original qualitative model was elaborated to quantitative versions
      that included the ultradian dynamics of sleep in relation to the non-REM-REM
      sleep cycle. The time course of EEG slow-wave activity, the major marker of non
      REM sleep homeostasis, as well as daytime alertness were simulated successfully
      for a considerable number of experimental protocols. They include sleep after
      partial sleep deprivation and daytime napping, sleep in habitual short and long
      sleepers, and alertness in a forced desynchrony protocol or during an extended
      photoperiod. Simulations revealed that internal desynchronization can be obtained
      for different shapes of the thresholds. New developments include the analysis of
      the waking EEG to delineate homeostatic and circadian processes, studies of REM
      sleep homeostasis, and recent evidence for local, use-dependent sleep processes.
      Moreover, nonlinear interactions between homeostatic and circadian processes were
      identified. In the past two decades, models have contributed considerably to
      conceptualizing and analyzing the major processes underlying sleep regulation,
      and they are likely to play an important role in future advances in the field.

PMID- 10643754
TI  - Commentary: models of sleep regulation: successes and continuing challenges.
AB  - Quantitative models have been developed to describe salient aspects of human
      sleep regulation. The two-process model of sleep regulation and the
      thermoregulatory model of sleep control highlight the interaction between sleep
      homeostasis and circadian rhythmicity and the association between sleep and
      temperature regulation, respectively. These models have been successful and
      inspiring, but continuing progress remains dependent on rigorous testing of some
      of their basic assumptions. Whereas it has been established that EEG slow-wave
      activity is a marker of sleep homeostasis, its causal role in regulating the
      timing of sleep and wakefulness remains to be demonstrated conclusively.
      Likewise, the causal role of the temperature regulatory system in sleep timing
      requires further investigation. In both models, many parameters have yet to be
      associated with specific physiologic processes. This makes it challenging, at
      least within the framework of these models, to account for interindividual
      differences or age-related changes in such features as sleep duration and sleep
      timing, as well as changes in the phase angle between the sleep-wake cycle and
      accepted markers of the circadian pacemaker, such as the body temperature or
      melatonin rhythm. Although the models may describe adequately global sleep
      patterns and their circadian modulation, detailed modeling of the frequent short
      awakenings from, and the subsequent transitions back to, sleep, as well as the
      variation of the propensity to awaken across the ultradian non-REM-REM cycle, is
      not addressed. Incoporation of these aspects of sleep in mathematical models of
      sleep regulation may further our understanding of a key aspect of sleep
      regulation, that is, its timing.

PMID- 10643755
TI  - Beyond the three-process model of alertness: estimating phase, time on shift, and
      successive night effects.
AB  - This paper starts by summarizing the development and refinement of the additive
      three-process model of alertness first published by Folkard and Akerstedt in
      1987. It reviews some of the successes that have been achieved by the model in
      not only predicting variations in subjective alertness on abnormal sleep-wake
      schedules but also in accounting for objective measures of sleep latency and
      duration. Nevertheless, predictions derived from the model concerning alertness
      on different shifts, and over successive night shifts, are difficult to reconcile
      with published data on accident risk. In light of this, we have examined two
      large sets of alertness ratings with a view to further refining the model and
      identifying additional factors that may influence alertness at any given point in
      time. Our results indicate that, at least for the range of sleep durations and
      wake-up times commonly found on rotating shift systems, we may assume the phase
      of the endogenous circadian component of alertness (process C) to be "set" by the
      time of waking. Such an assumption considerably enhanced the predictive power of
      the model and yielded remarkably similar phase estimates to those obtained by
      maximizing the post-hoc fit of the model. We then examined the manner in which
      obtained ratings differed from predicted values over a complete 8-day cycle of
      two, 12-h shift systems. This revealed a pronounced "first night compensation
      effect" that resulted in shift workers rating themselves as progressively more
      alert than would be predicted over the course of the first night shift. However,
      this appeared to be achieved only at the cost of lowered ratings on the second
      night shift. Finally, we were able to identify a "time on shift" effect whereby,
      with the exception of the first night shift, alertness ratings decreased over the
      course of each shift before showing a modest "end effect." We conclude that the
      identification of these additional components offers the possibility that in the
      future we may be able to predict trends in accident risk on abnormal sleep-wake
      schedules.

PMID- 10643756
TI  - Interactive mathematical models of subjective alertness and cognitive throughput
      in humans.
AB  - The authors present here mathematical models in which levels of subjective
      alertness and cognitive throughput are predicted by three components that
      interact with one another in a nonlinear manner. These components are (1) a
      homeostatic component (H) that falls in a sigmoidal manner during wake and rises
      in a saturating exponential manner at a rate that is determined by circadian
      phase during sleep; (2) a circadian component (C) that is a function of the
      output of our mathematical model of the effect of light on the circadian
      pacemaker, with the amplitude further regulated by the level of H; and (3) a
      sleep inertia component (W) that rises in a saturating exponential manner after
      waketime. The authors first construct initial models of subjective alertness and
      cognitive throughput based on the results of sleep inertia studies, sleep
      deprivation studies initiated across all circadian phases, 28-h forced
      desynchrony studies, and alertness and performance dose response curves to sleep.
      These initial models are then refined using data from nearly one hundred fifty 30
      to 50-h sleep deprivation studies in which subjects woke at their habitual
      times. The interactive three-component models presented here are able to predict
      even the fine details of neurobehavioral data from sleep deprivation studies and,
      after further validation, may provide a powerful tool for the design of safe
      shift work and travel schedules, including those in which people are exposed to
      unusual patterns of light.

PMID- 10643757
TI  - Commentary: future considerations for models of human neurobehavioral function.
AB  - Modeling human neurobehavioral functions has the goal of identifying work-rest
      schedules that are safer and more productive. The models of Folkard et al. and of
      Jewett and Kronauer illustrate excellent progress toward this goal. Examination
      of these models reveals four additional areas that need to be addressed to
      facilitate continued development of accurate models of neurobehavioral functions.
      (1) The choice of neurobehavioral metrics may have a significant influence on
      model development. The lack of correlation among different neurobehavioral
      measures may make comparisons of models difficult. Many neurobehavioral measures
      are confounded by secondary and random error variance that can lead to model
      distortion. Although different models may ultimately be required for different
      neurobehavioral functions, measures that have been extensively validated to be
      sensitive to circadian variation and sleep loss should take priority in model
      development. (2) Because error variance in neurobehavioral outcomes can be
      substantial in uncontrolled environments, model validation should proceed from
      controlled laboratory protocols to real-world scenarios. Once validated, the
      ability of a model to predict field data can be tested. (3) While neurobehavioral
      models have been developed to predict behavior over time (i.e., within-subjects),
      to be useful in the real world, models will also ultimately have to provide
      estimates of between-subject variation in vulnerability to neurobehavioral
      dysfunction during night work or sleep loss (e.g., younger versus older workers).
      (4) Finally, to be theoretically accurate and practically useful, models of human
      neurobehavioral functions should be able to predict both cumulative effects
      (i.e., across days or weeks) and the influence of countermeasures (e.g., light,
      naps, caffeine).

PMID- 10643758
TI  - Technical note: a problem with identifying nonlinear interactions of circadian
      and homeostatic processes.

PMID- 10643759
TI  - Statistical model building and model criticism for human circadian data.
AB  - Mathematical models have played an important role in the analysis of circadian
      systems. The models include simulation of differential equation systems to assess
      the dynamic properties of a circadian system and the use of statistical models,
      primarily harmonic regression methods, to assess the static properties of the
      system. The dynamical behaviors characterized by the simulation studies are the
      response of the circadian pacemaker to light, its rate of decay to its limit
      cycle, and its response to the rest-activity cycle. The static properties are
      phase, amplitude, and period of the intrinsic oscillator. Formal statistical
      methods are not routinely employed in simulation studies, and therefore the
      uncertainty in inferences based on the differential equation models and their
      sensitivity to model specification and parameter estimation error cannot be
      evaluated. The harmonic regression models allow formal statistical analysis of
      static but not dynamical features of the circadian pacemaker. The authors present
      a paradigm for analyzing circadian data based on the Box iterative scheme for
      statistical model building. The paradigm unifies the differential equation-based
      simulations (direct problem) and the model fitting approach using harmonic
      regression techniques (inverse problem) under a single schema. The framework is
      illustrated with the analysis of a core-temperature data series collected under a
      forced desynchrony protocol. The Box iterative paradigm provides a framework for
      systematically constructing and analyzing models of circadian data.

PMID- 10643760
TI  - Searching for biological rhythms: peak detection in the periodogram of unequally
      spaced data.
AB  - The classical power spectrum, computed in the frequency domain, outranks
      traditionally used periodograms derived in the time domain (such as the chi2
      periodogram) regarding the search for biological rhythms. Unfortunately,
      classical power spectral analysis is not possible with unequally spaced data
      (e.g., time series with missing data). The Lomb-Scargle periodogram fixes this
      shortcoming. However, peak detection in the Lomb-Scargle periodogram of unequally
      spaced data requires some careful consideration. To guide researchers in the
      proper evaluation of detected peaks, therefore, a novel procedure and a computer
      program have recently become available. It is recommended that the Lomb-Scargle
      periodogram be the default method of periodogram analysis in future biomedical
      applications of rhythm investigation.

PMID- 10643761
TI  - Commentary: model building, quantitative testing, and model comparison.
AB  - The final goal is to create mathematical models that are based on our current
      knowledge of the underlying physiology and that explain all of the experimental
      data available. To do this, we suggest a consideration of several potential
      mathematical structures in the formulation of models and the formal comparison of
      these various structures with other models in the literature. However, when
      making these comparisons, one must pay careful attention to the systems being
      modeled and the data sets chosen to represent those systems.

PMID- 10643762
TI  - Role of bacterial association and penetration on destruction of Escherichia coli
      O157:H7 in beef tissue by high pH.
AB  - This study was undertaken to determine if association with collagen enables
      Escherichia coli O157:H7 to resist high-pH treatments and to determine the
      effects of high pH on the survival of E. coli O157:H7 within different layers of
      beef tissue. E. coli O157:H7 was inoculated onto purified bovine type I collagen
      on 12-mm2 circular glass coverslips, plain 12-mm2 circular glass coverslips
      (control), and 12-mm2 irradiated (cobalt-60) lean beef tissue. The rates of
      destruction of E. coli O157:H7 inoculated on coverslips in pH 10.5 NaHCO3-NaOH
      buffer at 35 degrees C were determined at various sampling times. E. coli O157:H7
      cells associated with collagen and treated in the same manner were also examined
      using scanning electron microscopy to determine if association with collagen
      enabled the organism to resist high-pH treatments. The inoculated tissue was
      treated in pH 13.0 NaHCO3-NaOH buffer at 25 degrees C, and penetrating cells of
      E. coli O157:H7 were recovered using a cryostat technique. There was no
      significant difference (P < 0.05) between the rates of destruction of collagen
      associated E. coli O157:H7 and non-collagen-associated E. coli O157:H7 following
      exposure to high-pH treatments. Scanning electron micrographs showed that
      collagen-associated E. coli O157:H7 cells appeared physically damaged by exposure
      to high-pH treatments, and association of E. coli O157:H7 to collagen did not
      increase the resistance of the organism to destruction by high-pH rinses. No
      significant differences were seen between 20 ml of NaHCO3-NaOH buffer at pH 13.0
      (treatment) and 20 ml of distilled water at pH 7.0 (control) when E. coli O157:H7
      cells were recovered in beef tissue at depths of up to 2,000 microm (P < 0.05).
      The ability of E. coli O157:H7 to penetrate beef tissue may be an important
      factor in reducing the effectiveness of high-pH treatments in killing this
      organism on beef tissue. This finding should be considered in the future when
      designing treatments to decontaminate beef carcasses.

PMID- 10643763
TI  - Effect of pH on survival, thermotolerance, and verotoxin production of
      Escherichia coli O157:H7 during simulated fermentation and storage.
AB  - Heat treatment is increasingly being introduced to fermented meat processing,
      since the acid tolerance properties of Escherichia coli O157:H7 can permit this
      organism to survive traditional processing procedures. This study investigated
      the effect of growth pH and fermentation on the thermotolerance at 55 degrees C
      of E. coli O157:H7 in a model fermented meat system. E. coli O157:H7 (strain 380
      94) was grown at pH 5.6 or 7.4 (18 h at 37 degrees C), fermented to pH 4.8 or 4.4
      in brain heart infusion broth, and stored for 96 h. Cells grown at pH 5.6 had
      higher D values at 55 degrees C (D55 degrees C) than cells grown at pH 7.4 (P <
      0.001). Cells fermented to pH 4.8 had higher D55 degrees C than those fermented
      to pH 4.4 (P < 0.001). Cells fermented to pH 4.8 demonstrated an increase in D55
      degrees C during storage (P < 0.001), whereas cells fermented to pH 4.4 showed a
      decrease in D55 degrees C during the same period (P < 0.001). The effect of
      growth pH on verotoxin production by E. coli O157:H7 was assessed using the
      verotoxin assay. Cells grown at pH 5.6 had lower verotoxin production then cells
      grown at pH 7.4. This effect was not sustained over storage. These results
      indicate that a lower growth pH can confer cross-protection against heat. This
      has implications for the production of acidic foods, such as fermented meat,
      during which a heating step may be used to improve product safety.

PMID- 10643764
TI  - Roles of oxidation-reduction potential in electrolyzed oxidizing and chemically
      modified water for the inactivation of food-related pathogens.
AB  - This study investigates the properties of electrolyzed oxidizing (EO) water for
      the inactivation of pathogen and to evaluate the chemically modified solutions
      possessing properties similar to EO water in killing Escherichia coli O157:H7. A
      five-strain cocktail (10(10) CFU/ml) of E. coli O157:H7 was subjected to
      deionized water (control), EO water with 10 mg/liter residual chlorine (J.A.W-EO
      water), EO water with 56 mg/liter residual chlorine (ROX-EO water), and
      chemically modified solutions. Inactivation (8.88 log10 CFU/ml reduction) of E.
      coli O157:H7 occurred within 30 s after application of EO water and chemically
      modified solutions containing chlorine and 1% bromine. Iron was added to EO or
      chemically modified solutions to reduce oxidation-reduction potential (ORP)
      readings and neutralizing buffer was added to neutralize chlorine. J.A.W-EO water
      with 100 mg/liter iron, acetic acid solution, and chemically modified solutions
      containing neutralizing buffer or 100 mg/liter iron were ineffective in reducing
      the bacteria population. ROX-EO water with 100 mg/liter iron was the only
      solution still effective in inactivation of E. coli O157:H7 and having high ORP
      readings regardless of residual chlorine. These results suggest that it is
      possible to simulate EO water by chemically modifying deionized water and ORP of
      the solution may be the primary factor affecting microbial inactivation.

PMID- 10643765
TI  - Bactericidal activity of isothiocyanate against pathogens on fresh produce.
AB  - The bactericidal activity of allyl and methyl isothiocyanate (AITC and MITC) was
      tested with a rifampicin-resistant strain of Salmonella Montevideo and
      streptomycin-resistant strains of Escherichia coil O157:H7 and Listeria
      monocytogenes Scott A. Iceberg lettuce inoculated with high (10(7) to 10(8)
      CFU/g) and low (10(3) to 10(4) CFU/g) concentrations of bacterial pathogens was
      treated with AITC and MITC in sealed containers at 4 degrees C for 4 days. AITC
      showed stronger bactericidal activity than MITC against E. coli O157:H7 and
      Salmonella Montevideo, whereas MITC showed stronger activity against L.
      monocytogenes than E. coli O157:H7 and Salmonella Montevideo. Up to 8-log
      reduction occurred with E. coli O157:H7 and Salmonella Montevideo on lettuce
      following treatment with vapor generated from 400 microl of AITC for 2 and 4
      days, respectively. AITC was used to treat tomatoes inoculated with Salmonella
      Montevideo on stem scars and skin and apples inoculated with E. coli O157:H7 on
      stem scars. The bactericidal effect of AITC varied with bacteria species and
      exposure time. Salmonella Montevideo inoculated on tomato skin was more sensitive
      to AITC than that on stem scars. Treatment with vapor generated from 500 microl
      of AITC caused an 8-log reduction in bacteria on tomato skin but only a 5-log
      reduction on tomato stem scars. The bactericidal activity of AITC was weaker for
      E. coli O157:H7 on apple stem scars; only a 3-log reduction in bacteria occurred
      when 600 microl of AITC was used.

PMID- 10643767
TI  - Factors influencing inactivation of Salmonella enteritidis in hard-cooked eggs.
AB  - The inside of a hen's egg, once considered sterile, is now known to occasionally
      harbor Salmonella Enteritidis. At least two recent outbreaks of salmonellosis in
      which Salmonella Enteritidis PT34 was involved have been associated with hard
      cooked eggs. This study was undertaken to compare D56 degrees C values of
      Salmonella Senftenberg 775W and six strains of Salmonella Enteritidis isolated
      from outbreaks associated with eggs. D56 degrees C values for Salmonella
      Enteritidis in liquid egg yolk ranged from 5.14 to 7.39 min; the D56 degrees C
      value for Salmonella Senftenberg was 19.96 min. The two PT34 strains from
      outbreaks associated with hard-cooked eggs did not exhibit significantly higher
      resistance to heat compared with two PT4 strains and one strain each of PT8 and
      PT13a. A PT4 strain and a PT34 strain of Salmonella Enteritidis were separately
      inoculated (10(7) to 10(8) CFU) into the yolk of medium and extra large shell
      eggs at 10 and 21 degrees C, and survival was monitored using two cooking
      methods: (i) placing eggs in water at 23 degrees C, heating to 100 degrees C,
      removing from heat, and holding for 15 min (American Egg Board method) and (ii)
      placing eggs in water at 100 degrees C, then holding for 15 min at this
      temperature. Within the 15-min holding periods, inactivation was more rapid using
      the method recommended by the American Egg Board compared with method 2. Within
      each cooking method, inactivation was most rapid in medium eggs initially at 21
      degrees C. The PT4 strain survived in yolk of extra large eggs initially at 10
      degrees C when eggs were held in boiling water 9 min using method 2. The final
      temperature of the yolk in these eggs was 62.3 +/- 2 degrees C. Of the two
      methods evaluated for hard cooking eggs, the American Egg Board method is clearly
      most effective in killing Salmonella Enteritidis in the yolk.

PMID- 10643766
TI  - Contamination of carcasses, offals, and the environment with yadA-positive
      Yersinia enterocolitica in a pig slaughterhouse.
AB  - This study was carried out in order to evaluate the contamination of the pig
      slaughtering line with pathogenic Yersinia enterocolitica carrying the yadA gene.
      A total of 292 samples were collected from the slaughterhouse; 131 swab samples
      from pig carcasses, ears, livers, kidneys, and hearts; 89 swab samples from the
      environment; and 72 sedimentation samples from the air. All surface samples were
      studied with both the polymerase chain reaction (PCR) and culture methods. The
      contamination rate of edible pig offals was high with both methods. Using PCR,
      the detection rates of yadA-positive Y. enterocolitica for livers, kidneys, and
      hearts were 38, 86, and 63%, respectively, and using the culture method, the
      detection rates were 31, 69, and 50%, respectively. Pathogenic Y. enterocolitica
      was also detected from different environmental sites in the slaughterhouse. Using
      PCR, 13% of the surface samples from the environment were contaminated with yadA
      positive Y. enterocolitica. PCR-positive samples were found on the brisket saw,
      the hook from which the pluck set (heart, lungs, esophagus, trachea, diaphragm,
      liver, kidneys, and tongue with tonsils) hang, the knife used for evisceration,
      the floors in the eviscerating area and the weighing area, the meat-cutting
      table, the aprons used by trimming workers, the computer used in the meat
      inspection area, and the coffeemaker used by slaughterhouse workers. The
      respective detection rate (6%) was considerably lower when we used the culture
      method. Pathogenic Y. enterocolitica was isolated from the air in the bleeding
      area. Bioserotype 4/O:3 was the only pathogenic bioserotype isolated in this
      study. A total of 113 isolates of type 4/O:3 were characterized with pulsed-field
      gel electrophoresis using NotI and XbaI digests. By combining these profiles,
      nine different pulsotypes were obtained, the most common of which (1a) was found
      in 19 (61%) of 31 samples from different sites. This is the same type that has
      dominated in pig tonsils, which suggests that tonsils may be the source of Y.
      enterocolitica contamination in the slaughterhouse. The four pulsotypes (1a, 4g,
      6g, and 19q) found on edible offals were the same as those found in tonsils,
      which supports our hypothesis that tonsils are the contamination source for the
      liver, heart, and kidneys.

PMID- 10643768
TI  - Interventions to reduce microbiological contamination of beef variety meats.
AB  - Hot water and solutions of acetic acid, lactic acid, or trisodium phosphate
      applied by immersion or spraying, chlorine solution applied by immersion, and
      exposure to steam in a pasteurization system, in a cabinet, or in combination
      with vacuum were evaluated for their effectiveness in reducing levels of
      bacterial contamination on samples of beef cheek meat, large intestine, lips,
      liver, oxtail, and tongue. Treated samples (five per treatment) and controls were
      analyzed for aerobic plate counts (APCs) on tryptic soy agar and for total
      coliform counts (TCCs) and Escherichia coli counts (ECCs) on Petrifilm. Acetic
      acid (2%) immersion and trisodium phosphate (12%) spraying and immersion for 10 s
      were among the most effective treatments in 16, 15, and 14, respectively, of 18
      comparisons for reducing APCs, TCCs, and ECCs on four or more of the six variety
      meats tested. Acetic acid (2%) spraying, lactic acid (2%) immersion, and hot
      water (78 to 80 degrees C) spraying for 10 s were among the most effective
      treatments for reducing APCs, TCCs, and ECCs on four or more of the six variety
      meats. Chlorine (0.005%) immersion and steam were among the least effective
      treatments for reducing APCs, TCCs, and ECCs on variety meats. The results
      indicated that interventions applied to decontaminate beef carcasses can also be
      considered for decontamination of variety meats.

PMID- 10643769
TI  - Alternative indicator bacteria analyses for evaluating the sanitary condition of
      beef carcasses.
AB  - Sponge samples were obtained from 47 (study 1) and 32 (study 2) beef carcasses in
      a small plant over 6 months. In study 2, slaughter equipment surfaces were also
      sampled. In study 1, the Petrifilm method was used to count presumptive
      Escherichia coli and spread plating on kanamycin esculin azide (KEA) agar with
      and without 40% added bile was used to count presumptive Enterococcus spp.
      Qualitative testing for presumptive E. coli and Enterococcus spp. in study 1 was
      done using lauryl sulfate tryptone broth (LST) + 4-methylumbelliferyl-beta-D
      glucuronide (MUG) and KEA + 40% bile broth, respectively. In study 2, LST + MUG
      was used as a most probable number (MPN) method along with the Petrifilm method.
      In the two studies, 8 (17.0%) and 11 (34.4%) carcasses were contaminated with
      presumptive E. coli; all but one contaminated carcass contained <1 CFU/cm2.
      Presumptive Enterococcus spp. were recovered from 15 carcasses (31.9%) in study
      1, but the KEA + 40% bile agar method lacked specificity (only 31.3% of isolates
      confirmed as Enterococcus spp.) The LST + MUG and Petrifilm methods were
      significantly (P < 0.05) related in terms of detecting presumptive E. coli, but
      the presence of presumptive Enterococcus spp. was not significantly related to
      the presence of presumptive E. coli. However, on slaughter plant equipment in
      Study 2 there was a statistically significant (P < 0.05) relationship between the
      presence of presumptive E. coli and presumptive Enterococcus spp. In study 2,
      there was no significant (P < 0.05) difference in numbers of presumptive E. coli
      (obtained using Petrifilm) on carcasses chilled 1 day (n = 16) and 7 days (n =
      16), although more of the 7-day carcasses were contaminated (five and seven
      carcasses, respectively). For samples testing positive for presumptive E. coli,
      the 95% confidence intervals obtained using the LST + MUG MPN method included the
      Petrifilm value for all but one sample.

PMID- 10643770
TI  - Preservation of fish cutlet (Pangasius pangasius) at ambient temperature by
      irradiation.
AB  - Development of gamma irradiation preservation of ready-to-eat, commercially
      prepared fish cutlet and improvement of microbiological quality were studied.
      Studies on the shelf life extension by a combination of irradiation and ascorbic
      acid treatments of fish cutlets prepared at the laboratory and commercial scale
      have also been conducted. Cutlets prepared at the laboratory scale according to
      selected formulation and irradiated at a dose of 5 kGy could extend the shelf
      life up to 5 weeks at room temperature. In commercially prepared fish cutlets,
      maximum shelf life extension observed was 14 days for samples treated with 5 kGy
      of irradiation and stored at ambient temperature on the basis of combined
      microbiological, chemical, and organoleptic evaluation. The microbiological
      quality of the commercially prepared fish cutlets revealed the unhygienic
      conditions of the place where the fish was prepared and the unhygienic storage
      conditions and temperatures. As a result, the chemical and irradiation treatments
      were not effective in extending the shelf life of the cutlets under the storage
      condition used in this study compared with that of the laboratory scale-prepared
      cutlets.

PMID- 10643771
TI  - Modeling UV-induced inactivation of microorganisms on surfaces.
AB  - A model is presented to account for inactivation by UV light of microorganisms on
      the surfaces of solid materials. In the model, the surface is divided into a
      discrete number of zones, each having a characteristic exposure factor (alpha).
      This is the ratio of UV intensity actually "seen" by the microorganism to that
      incident on the surface. Application of the model requires inactivation data
      obtained under conditions where the surface microorganisms are fully exposed to
      incident UV (alpha = 1) as well as kinetic inactivation data for the same
      microorganisms actually present on the surface of interest during UV irradiation.
      The kinetics in question may apply either to a single species or to the
      characteristic microflora associated with a particular material. Standard
      nonlinear programming techniques were used to determine the number of zones among
      which the microorganisms are distributed, the alpha for each zone, and the
      fraction of the microbial population present in each zone. The model was applied
      to data previously published by Gardner and Shama for UV inactivation of Bacillus
      subtilis spores on the surfaces of filter papers and also to the data of Stermer
      et al. for UV irradiation of beef. Good representation of the kinetics was
      obtained, and a maximum of three zones was required to adequately represent the
      experimental data. One direct application of the model is that it yields
      quantitative information about the UV fluences necessary to achieve specified
      reductions in microbial viability.

PMID- 10643772
TI  - Effect of L-glucose and D-tagatose on bacterial growth in media and a cooked
      cured ham product.
AB  - Cured meats such as ham can undergo premature spoilage on account of the
      proliferation of lactic acid bacteria. This spoilage is generally evident from a
      milkiness in the purge of vacuum-packaged sliced ham. Although cured, most hams
      are at more risk of spoilage than other types of processed meat products because
      they contain considerably higher concentrations of carbohydrates, approximately 2
      to 7%, usually in the form of dextrose and corn syrup solids. Unfortunately, the
      meat industry is restricted with respect to the choice of preservatives and
      bactericidal agents. An alternative approach from these chemical compounds would
      be to use novel carbohydrate sources that are unrecognizable to spoilage
      bacteria. L-Glucose and D-tagatose are two such potential sugars, and in a series
      of tests in vitro, the ability of bacteria to utilize each as an energy source
      was compared to that of D-glucose. Results showed that both L-glucose and D
      tagatose are not easily catabolized by a variety of lactic bacteria and not at
      all by pathogenic bacteria such as Escherichia coli O157:H7, Salmonella
      Typhimurium, Staphylococcus aureus, Bacillus cereus, and Yersinia enterocolitica.
      In a separate study, D-glucose, L-glucose, and D-tagatose were added to a chopped
      and formed ham formulation and the rate of bacterial growth was monitored.
      Analysis of data by a general linear model revealed that the growth rates of
      total aerobic and lactic acid bacteria were significantly (P < 0.05) slower for
      the formulation containing D-tagatose than those containing L- or D-glucose.
      Levels of Enterobacteriaceae were initially low and these bacteria did not
      significantly (P < 0.20) change in the presence of any of the sugars used in the
      meat formulations. Compared to the control sample containing D-glucose, the shelf
      life of the chopped and formed ham containing D-tagatose at 10 degrees C was
      extended by 7 to 10 days. These results indicate that D-tagatose could deter the
      growth of microorganisms and inhibit the rate of spoilage in a meat product
      containing carbohydrates.

PMID- 10643773
TI  - The microbiological quality of ice used to cool drinks and ready-to-eat food from
      retail and catering premises in the United Kingdom.
AB  - A survey of 4,346 samples of ice from retail and catering premises examined 3,528
      samples (81%) used to cool drinks and 144 samples (3%) from food displays. For
      674 samples (15%), the origin was not recorded. Most samples of ice used to cool
      drinks or ready-to-eat food on displays did not contain coliforms, Escherichia
      coli, or enterococci. Of the ice used to cool drinks, 9% contained coliforms, 1%
      E. coli, and 1% enterococci in excess of 10(2) CFU/100 ml, and 11% had an aerobic
      plate count at 37 degrees C in excess of 10(3) CFU/ml. The microbiological
      quality of ice used to cool drinks was poorer when melt water was present in the
      ice buckets. Ice used in food displays was more contaminated than ice used to
      cool drinks, with 23% containing coliforms, 5% E. coli, and 8% enterococci at
      10(2) CFU/100 ml or more. Twenty-nine percent of samples had an aerobic plate
      count greater than 10(3) CFU/ml. Ice that had been used to cool shellfish was of
      a lower microbiological quality than samples used to cool ready-to-eat fish,
      salads, or dairy produce. Samples of ice produced in commercial production
      facilities were of higher microbiological quality than samples of ice that were
      not. The microbiological quality of ice was dependent on the type of use, the
      type of premises, and the type and place of production. Although most ice samples
      were of acceptable microbiological quality, evidence from this study suggests
      that the microbiological quality of ice prepared and used at certain premises in
      the UK is a cause for concern.

PMID- 10643774
TI  - Gut mucosa morphology and microflora changes in malnourished mice after
      renutrition with milk and administration of Lactobacillus casei.
AB  - Nutrition plays a key role in maintaining the balance of the intestinal
      microflora. Malnutrition disturbs the ecological barrier and induces histological
      damage. We evaluated modifications induced by renutrition with nonfat milk (NFM)
      and Lactobacillus casei administration (for 2 days) on the bacterial gut
      population and structural and ultrastructural gut modifications in malnourished
      mice. Balb/c mice suffering from a malnutrition process immediately after weaning
      (for 21 days) were divided into four groups and were given NFM for 0, 7, 14, and
      21 days. Another group was treated in a similar way, but after different periods
      of NFM administration, mice in this group received L. casei for two consecutive
      days. All experimental animals were sacrificed by cervical dislocation, and both
      the microflora and the histological structure of the intestine were studied. In
      malnourished animals, a decrease in the numbers of Lactobacillus and anaerobic
      microorganisms was observed, whereas there was an increase in the number of
      Enterobacteriaceae. In animals treated with NFM and NFM plus L. casei, we could
      observe an important improvement in the microflora in the small and large
      intestines but no differences between both treatments. Structural and
      ultrastructural studies showed a slight improvement 7 days after treatment with
      NFM, and for 14 and 21 days after renutrition, the mice showed normal intestinal
      villi, whereas the additional feeding with L. casei for two consecutive days,
      after different periods of renutrition, yielded an earlier improvement (7 days).

PMID- 10643775
TI  - Probabilistic modeling of Saccharomyces cerevisiae inhibition under the effects
      of water activity, pH, and potassium sorbate concentration.
AB  - Probabilistic microbial modeling using logistic regression was used to predict
      the boundary between growth and no growth of Saccharomyces cerevisiae at selected
      incubation periods (50 and 350 h) in the presence of growth-controlling factors
      such as water activity (a(w); 0.97, 0.95, and 0.93), pH (6.0, 5.0, 4.0, and 3.0),
      and potassium sorbate (0, 50, 100, 200, 500, and 1,000 ppm). The proposed model
      predicts the probability of growth under a set of conditions and calculates
      critical values of a(w), pH, and potassium sorbate concentration needed to
      inhibit yeast growth for different probabilities. The reduction of pH increased
      the number of combinations of a(w) and potassium sorbate concentration with
      probabilities to inhibit yeast growth higher than 0.95. With a probability of
      growth of 0.05 and using the logistic models, the critical pH values were higher
      for 50 h of incubation than those required for 350 h. With lower a(w) values and
      increasing potassium sorbate concentration the critical pH values increased.
      Logistic regression is a useful tool to evaluate the effects of the combined
      factors on microbial growth.

PMID- 10643776
TI  - Utilization and transport of acetic acid in Dekkera anomala and their
      implications on the survival of the yeast in acidic environments.
AB  - The yeast Dekkera anomala IGC 5153 exhibited a restricted ability to use weak
      acids as the only carbon and energy sources. Of the monocarboxylic, dicarboxylic,
      and tricarboxylic acids tested, only acetic acid was used in such a way. The
      cells were able to grow at acetic acid concentrations of 0.1 to 3% (vol/vol) over
      a pH range of 3.5 to 5.5, and the specific growth rates decreased exponentially
      with the increase of the undissociated acetic acid concentration in the culture
      medium. Transport assays carried out in cells that exhibited higher specific
      growth rates showed the presence of an acetate-proton symport associated with a
      simple diffusion component of the undissociated acetic acid, the weight of the
      latter increasing with the undissociated acid concentration in the culture media.
      The acetate carrier was shared by propionic, formic, and sorbic acids and was
      inducible and repressed by glucose and concentrations of undissociated acetic
      acid in the culture medium above 0.3% (vol/vol). In undissociated acetic acid
      repression conditions, the lowest values for the yeast specific growth rates were
      obtained, and the simple diffusion of the undissociated acid was the only
      mechanism involved in the acetic acid uptake by the cells. The results will be
      discussed in terms of the high tolerance of D. anomala to the acidic stress
      conditions present in wine.

PMID- 10643777
TI  - The influence of divalent cations and chelators on aflatoxin B1 degradation by
      Flavobacterium aurantiacum.
AB  - The influence of divalent cations (Mg2+ and Ca2+) and chelators (EDTA and 1,10
      phenanthroline) on aflatoxin B1 (AFB1) degradation by Flavobacterium aurantiacum
      was determined in an effort to elucidate the possible manner by which this
      organism degrades AFB1. AFB1 (10 microg/ml) was added to 72-h cultures of F.
      aurantiacum that had been washed and resuspended in phosphate buffer (pH 7.0).
      High-performance liquid chromatography was used to determine AFB1 concentration
      in these cultures. Incubating cells with 0.1, 1, and 10 mM Ca2+ for 48 h
      significantly increased AFB1 degradation by 11.8, 13.5, and 14.0%, respectively,
      compared with F. aurantiacum cells alone. Likewise, incubation with 0.1, 1, and
      10 mM Mg2+ for 48 h significantly increased AFB1 degradation by 13.8, 13.3, and
      13.1%, respectively. Incubating the bacterium with either divalent cation for 16
      and 24 h did not significantly affect AFB1 degradation (P < or = 0.05). Addition
      of 0.1, 1, and 10 mM EDTA and 0.1 and 1 mM 1,10-phenanthroline resulted in
      significant increases in AFB1 degradation after 24 h. Significantly less AFB1
      degradation was observed using 10 mM 1,10-phenanthroline after 24-h incubation.
      These results suggest the involvement of Mg2+ and Ca2+ cations in AFB1
      degradation by F. aurantiacum.

PMID- 10643778
TI  - Development and characterization of a carbon-based composite material for
      reducing patulin levels in apple juice.
AB  - Patulin, a heterocyclic lactone produced by various species of Penicillium and
      Aspergillus fungi, is often detected in apple juices and ciders. Previous
      research has shown the effectiveness of granular activated carbon for reducing
      patulin levels in aqueous solutions, apple juices, and ciders. In this study,
      ultrafine activated carbon was bonded onto granular quartz to produce a composite
      carbon adsorbent (CCA) with a high carbonaceous surface area, good bed porosity,
      and increased bulk density. CCA in fixed-bed adsorption columns was evaluated for
      efficacy in reducing patulin levels from aqueous solutions and apple juice.
      Columns containing 1.0, 0.5, and 0.25 g of CCA were continuously loaded with a
      patulin solution (10 microg/ml) and eluted at a flow rate of 1 ml/min. Results
      indicated that 50% breakthrough capacities for patulin on 1.0-, 0.5-, and 0.25-g
      CCA columns were 137.5, 38.5, and 19.9 microg, respectively. The effectiveness of
      CCA to adsorb patulin and prevent toxic effects was confirmed in vitro using
      adult hydra in culture. Hydra were sensitive to the effects of patulin, with a
      minimal affective concentration equal to 0.7 microg/ml; CCA adsorption prevented
      patulin toxicity until 76% breakthrough capacity was achieved. Fixed-bed
      adsorption with 1.0 g of CCA was also effective in reducing patulin
      concentrations (20 microg/liter) in a naturally contaminated apple juice, and
      breakthrough capacities were shown to increase with temperature. Additionally,
      CCA offered a higher initial breakthrough capacity than pelleted activated carbon
      when compared in parallel experiments. This study suggests that CCA used in fixed
      bed adsorption systems effectively reduced patulin levels in both aqueous
      solutions and naturally contaminated apple juice; however, the appearance and
      taste of apple juice may be affected by the treatment process.

PMID- 10643779
TI  - Content of biogenic amines in table olives.
AB  - Content of biogenic amines in flesh and brines of table olives was determined by
      high-pressure liquid chromatography analysis of their benzoyl derivatives. No
      biogenic amines were found in the flesh of fresh fruits at any stage of ripeness.
      Contents of biogenic amines in Spanish-style green or stored olives increased
      throughout the brining period but were always higher in the former. Putrescine
      was the amine found in the highest concentration. Small quantities of cadaverine
      were found in the samples taken after 3 months of brining. This compound and
      histamine, tyramine, and tryptamine were also found in samples taken after 12
      months. Gordal cultivar showed the highest contents, followed by Manzanilla and
      Hojiblanca. No relationship was found between contents of biogenic amines and
      lactic acid production or table olive spoilages, although zapatera olives had
      considerably higher amounts than those brines that had undergone a normal
      process. Concentrations in directly brined olives were markedly lower than
      contents in Spanish-style olives. With respect to partition between flesh and
      brine, there was equilibrium between both media in the case of Spanish-style
      olives, whereas the contents in directly brined olives were higher in flesh than
      brine.

PMID- 10643780
TI  - Frequency of isolation of Campylobacter from roasted chicken samples from Mexico
      City.
AB  - The presence of Campylobacter spp. was investigated in 100 samples of roasted
      chicken tacos sold in well-established commercial outlets and semisettled street
      stands in Mexico City. From 600 colonies displaying Campylobacter morphology only
      123 isolates were positive. From these isolates, 51 (41%) were identified as C.
      jejuni, 23 (19%) as C. coli, and 49 (40%) as other species of this genus. All of
      the 27 positive samples came from one location where handling practices allowed
      cross-contamination of the cooked product. The results indicate that these ready
      to-consume products are contaminated with these bacteria, representing a
      potential risk for consumers, especially in establishments lacking adequate
      sanitary measures to prevent cross-contamination.

PMID- 10643781
TI  - Fate of Campylobacter jejuni in butter.
AB  - An outbreak of Campylobacter enteritis was associated with a restaurant in
      Louisiana during the summer of 1995. Thirty cases were identified, and four
      required hospitalization. Campylobacter jejuni was isolated from the patients,
      and epidemiologic studies revealed illness associated with eating garlic butter
      served at the restaurant. Three batches of garlic butter prepared by the
      restaurant associated with the outbreak and a C. jejuni isolate obtained from a
      patient involved in the outbreak were used for studies to determine the fate of
      C. jejuni in garlic butter. Studies also were done to determine the efficacy of
      the heat treatment used by the restaurant to prepare garlic bread to kill C.
      jejuni. Garlic butter was inoculated with approximately 10(4) and 10(6) CFU/g of
      C. jejuni and held at 5 or 21 degrees C. Results revealed that the survival of C.
      jejuni differed greatly, depending on the presence or absence of garlic. At 5
      degrees C, C. jejuni populations decreased to an undetectable level (<10 CFU/g)
      within 3 h for two batches and within 24 h for another batch. In contrast, C.
      jejuni could survive at 5 degrees C for 13 days in butter with no garlic. At 21
      degrees C, C. jejuni populations decreased to an undetectable level within 5 h
      for two batches and to 50 CFU/g in 5 h for another batch. In contrast, C. jejuni
      was detected at 500 CFU/g at 28 h after inoculation but was undetectable at 3
      days in butter with no garlic held at 21 degrees C. The heating procedure (135
      degrees C, 4 min) used to make garlic bread by the implicated restaurant was
      determined not to be sufficient for killing C. jejuni, with the internal
      temperature of the buttered bread after heating ranging from 19 to 22 degrees C.
      This study revealed that C. jejuni can survive for many days in refrigerated
      butter, but large populations (10(3) to 10(5) CFU/g) are killed within a few
      hours in butter that contains garlic. Furthermore, the heat treatment used by the
      restaurant to melt garlic butter in making garlic bread was not adequate to kill
      C. jejuni.

PMID- 10643782
TI  - Evaluation of the Petrifilm rapid coliform count plate method for coliform
      enumeration from surimi-based imitation crab slurry.
AB  - The 3M Petrifilm rapid coliform count (RCC) plate method was compared with two
      conventional methods, namely violet red bile agar (VRBA) and desoxycholate
      lactose agar (DLA), for enumerating coliforms. The VRBA plating method is a
      reference method in the Bacteriological Analytical Manual and the DLA plating
      method is the method recommended by the Food Sanitation Law of Korea for
      enumeration of coliforms. Serratia sp., a coliform that was isolated from frozen
      surimi, was incubated in surimi-based imitation crab (SBIC) slurries and
      enumerated on the Petrifilm RCC, VRBA, and DLA plates. Results from the Petrifilm
      RCC plate were not significantly different from results from VRBA or DLA plates
      at P < 0.05 level. The correlation coefficient for Petrifilm RCC plates versus
      the VRBA method and for Petrifilm RCC plates versus the DLA method were 0.994 and
      0.996, respectively. With the Petrifilm RCC plate method, we were able to
      estimate presumptive coliforms (except Serratia sp.) after 14 h and to enumerate
      confirmed coliforms (including Serratia sp.) after 24 h.

PMID- 10643783
TI  - Comparison of membrane filtration rates and hydrophobic grid membrane filter
      coliform and Escherichia coli counts in food suspensions using paddle-type and
      pulsifier sample preparation procedures.
AB  - Food suspensions prepared by Pulsifier contained less debris and filtered 1.3x to
      12x faster through hydrophobic grid membrane filters (HGMFs) than those prepared
      by Stomacher 400. Coliform and Escherichia coli counts made by an HGMF method
      yielded 84 and 36 paired samples, respectively, positive by both suspending
      methods. Overall counts of pulsificates and stomachates did not differ
      significantly for either analysis, though coliform counts by Pulsifier were
      significantly higher in mushrooms and significantly lower in ground pork (P =
      0.05). Regression equations for log10 counts of coliform and E. coli by Pulsifier
      and Stomacher were: Pulsifier = 0.12 + 0.97 x Stomacher, and Pulsifier = 0.01 +
      1.01 x Stomacher, respectively.

PMID- 10643784
TI  - Survival of Listeria monocytogenes Scott A on vacuum-packaged raw beef treated
      with polylactic acid, lactic acid, and nisin.
AB  - Low-molecular-weight polylactic acid (LMW-PLA) and lactic acid (LA) were used to
      inhibit growth of Listeria monocytogenes Scott A on vacuum-packaged beef. Nisin
      was also used simultaneously as an additional hurdle to the growth of this
      pathogen. Inoculated beef cubes were immersed in a solution of 2% LMW-PLA, 2% LA,
      400 IU/ml of nisin, or combinations of each acid and nisin for 5 min and drip
      dried for 15 min. The cubes were then vacuum-packaged and stored at 4 degrees C
      for up to 42 days. Surface pH values of beef cubes treated with 2% LMW-PLA, the
      combination of 400 IU/ml of nisin and 2% LMW-PLA (2% NPLA), or 400 IU/ml of nisin
      alone were significantly reduced from 5.59 to 5.18, 5.01, and 5.19, respectively,
      whereas those decontaminated with 2% LA or 400 IU/ml of nisin and 2% LA (2% NLA)
      were significantly decreased from 5.59 to 4.92 and 4.83, respectively, at day 0
      (P < or = 0.05). The 2% LMW-PLA, 2% LA, 2% NPLA, 2% NLA, and 400 IU/ml of nisin
      showed immediate bactericidal effects on L. monocytogenes Scott A (1.22-, 1.56-,
      1.57-, 1.94-, and 1.64-log10 reduction, respectively) compared with the initial
      number of 5.33 log10 CFU/cm2 of the untreated control at day 0 (P < or = 0.05).
      These treatments, combined with vacuum-packaging and refrigeration temperature,
      succeeded to inhibit growth of L. monocytogenes during storage up to 42 days. At
      the end of 42 days, the numbers of L. monocytogenes Scott A remaining viable on
      these samples were 1.21, 0.36, 2.21, 0.84, and 0.89 log10 CFU/cm2, respectively.

PMID- 10643785
TI  - A mycological investigation of phane, an edible caterpillar of an emperor moth,
      Imbrasia belina.
AB  - Phane worm (an edible larval stage of the emperor moth Imbrasia belina Westwood)
      is an important food source, and its harvesting is an economic activity in rural
      Botswana. When the larva is feeding on leaves and later during processing, phane
      gets contaminated with fungi from the leaves and soil. We examined 73 jars, each
      containing approximately 608 g (+/-0.25 g) of processed phane stored under
      laboratory conditions (temperature range 20 to 24 degrees C and 50 to 80%
      relative humidity) and combined intestinal contents of five phane squeezed into
      each of 74 Duran bottles for fungi. Ninety seven percent of 74 samples of
      intestinal contents and 57.5% of 73 laboratory-stored phane were positive for
      either molds and/or yeasts. Yeast population in intestinal contents ranged from 2
      x 10(1) CFU/g to 5 x 10(3) CFU/g, whereas molds ranged from 1 x 10(1) CFU/g to 2
      x 10(2) CFU/g. Laboratory-stored phane had a mold population of 1 x 10(2) CFU/g
      to 6 x 10(5) CFU/g. Species of Chaetomium 13.8%, Aspergillus 12.4%, Fusarium
      5.5%, and Mucor racemosus 4.1% were the most prevalent in intestinal contents of
      phane, whereas Aspergillus 42.1%, Penicillium 33.9%, and Mucorales 5.7% were
      predominant in laboratory-stored phane. The important mycotoxigenic fungi A.
      flavus, A. parasiticus, A. ochraceus, P. aurantiogriseum, P. citrinum, and P.
      verrucosum were isolated mainly from the laboratory-stored phane. The genera
      isolated from both intestinal phane contents and laboratory-stored phane were
      Alternaria, Aspergillus, Chaetomium, Drechslera, Fusarium, Mucor, Phoma, and
      Penicillium, suggesting recontamination of phane during drying and storage.

PMID- 10643786
TI  - Hyperglycemia triggers massive neutrophil deposition in brain following transient
      ischemia in rats.
AB  - Myeloperoxidase (MPO) immunohistochemistry was used to ascertain the role of
      polymorphonuclear leukocytes in hyperglycemia-induced accentuation of brain
      injury after transient ischemia. Rats received 12.5 min of normothermic global
      cerebral ischemia by bilateral carotid occlusion plus hypotension. Hyperglycemia
      was induced before ischemia by intraperitoneal dextrose administration.
      Quantitative MPO immunohistochemistry was performed at 24 h and 3 days
      postischemia. Brains of normoglycemic-ischemic animals contained almost no MPO
      activity. By contrast, striking numbers of MPO-positive cells were present in
      brains studied 24 h after hyperglycemic ischemia, both within pial and
      parenchymal vessels and within the parenchyma. MPO deposition tended to subside
      at 3 days. These results indicate that hyperglycemia triggers the early, massive
      deposition of neutrophils in the postischemic brain--an event that may contribute
      to exacerbation of injury.

PMID- 10643787
TI  - Novel strategies for opposing murine microglial activation.
AB  - Pathologic microglial activation is believed to contribute to progressive
      neuronal damage in neurodegenerative diseases by the release of potentially
      neurotoxic agents, such as pro-inflammatory cytokines including tumor necrosis
      factor alpha (TNF-alpha). Using cultured N9 microglial cells, we have examined
      the regulation of TNF-alpha following endotoxic insult with lipopolysacharide
      (LPS), focusing on the role of the pro-inflammatory phospholipase A2/mitogen
      activated protein kinase/arachidonic acid/cyclo-oxygenase-2 cascade and the
      nitric oxide/cGMP pathway. Data show that various inhibitors of the PLA2 cascade
      markedly inhibit LPS-induced TNF-alpha release, supporting a key role of this
      pathway in the regulation of microglial activation. We also investigated the
      putative effects of cGMP-elevating agents on blocking microglial activation
      induced by LPS. Data show that each member of this class of cGMP-elevating
      compounds that we employed opposed microglial TNF-alpha release, suggesting that
      strengthening intracellular cGMP signaling mitigates against microglial
      activation. Taken together, our results suggest novel strategies for reducing
      microglial activation.

PMID- 10643788
TI  - 5-HT5a receptors in the carotid body chemoreception pathway of rat.
AB  - By using a specific antibody, 5-HT5a receptor-like immunoreactivity was revealed
      in the chemoreceptive, oxygen sensitive, carotid body (CB) type I cells, and
      neurons of the petrosal ganglion (PG) and the superior cervical ganglion (SCG) in
      rat. mRNA encoding for the 5-HTa receptor was also detected in these tissues by
      RT-PCR, and confirmed with DNA sequencing. The present study provides direct
      evidence that 5-HT5a receptors are expressed in the CB, PG and SCG, which all
      likely play fundamental roles in arterial chemoreception.

PMID- 10643789
TI  - Electrophysiological correlates of emotional and structural face processing in
      humans.
AB  - In order to study brain potentials related to decoding of facial expressions of
      emotions and those, related to basic perception of faces 16 right-handed subjects
      performed tasks on facial emotion recognition and perception of blurred faces and
      objects. Electroencephalograph (EEG) recordings during performance of the tasks
      revealed similar event-related potentials during the presentation of faces at 120
      and 170 ms after stimulus onset in both of the tasks but significant differences
      in amplitudes between 180 and 300 ms. Whereas faces in the emotion recognition
      task produced high amplitudes in that latency range, potentials in response to
      faces in the blurred object condition were virtually absent. These data point to
      the assumption that decoding of facial expressions starts early in the brain and
      might be processed separately from basic stages of face perception.

PMID- 10643791
TI  - Desensitization characteristics of rat recombinant GABA(A) receptors consisting
      of alpha1beta2gamma2S and alpha1beta2 subunits expressed in HEK293 cells.
AB  - Desensitization kinetics of rat recombinant typeA GABAergic receptors consisting
      of the subunits alpha1beta2gamma2S or alpha1beta2 was investigated on application
      of 10-0.001 mM GABA to whole cell patches using a piezo driven liquid filament
      switch for fast application and deapplication. At high GABA concentrations
      desensitization was triphasic showing increasing time constants and a decreasing
      extent of desensitization on lowering the GABA concentration. Below agonist
      concentrations of 1 mM for the trimeric receptor and 0.1 mM for the dimeric one
      desensitization was biphasic switching to monophasic kinetics at GABA
      concentrations < or = 0.01 mM for the alpha1beta2gamma2S-type and < or = 0.003 mM
      for the alpha1beta2-type, respectively. Comparison with former studies performed
      with GABAergic receptors consisting of different subunits revealed differences in
      the desensitization kinetics.

PMID- 10643790
TI  - Hypoxia induces activation of a N-methyl-D-aspartate glutamate receptor-protein
      kinase C pathway in the dorsocaudal brainstem of the conscious rat.
AB  - To study in vivo phosphorylation of N-methyl-D-aspartate (NMDA) glutamate
      receptors and the recruitment of protein kinase C isoforms during acute hypoxia,
      dorsocaudal brainstem lysates were harvested from conscious rats exposed to
      either room air or hypoxia (10% O2 for 5 and 15 min). Increased phosphorylation
      of the NR-1 subunit at serine residue 896 occurred during hypoxia and was blocked
      by pre-treatment with MK-801. Immunoblots of soluble and particulate fractions
      revealed subcellular translocation for PKC-beta, -gamma, -delta, -epsilon, and 
      iota during hypoxia with no changes in PKC-alpha, -mu, and -zeta. Translocation
      of PKC-beta, -delta and -epsilon was selectively attenuated following MK-801. We
      demonstrate that hypoxia leads to PKC-mediated activation of NMDA receptors in
      the brainstem, and that PKC-beta, -delta and -epsilon are the most likely
      candidates for NR-1 phosphorylation.

PMID- 10643792
TI  - Spin trapping agent phenyl-N-tert-butylnitrone prevents
      diisopropylphosphorofluoridate-induced excitotoxicity in skeletal muscle of the
      rat.
AB  - Indirect evidence suggests that reactive oxygen species (ROS) may mediate muscle
      fiber necrosis following muscle hyperactivity induced by the anticholinesterase
      diisopropylphosphorofluoridate (DFP). Pronounced muscle fasciculations and muscle
      fiber necrosis were seen when acetylcholinesterase (AChE) activity was reduced to
      less than 30% of control. The spin trapping agent phenyl-N-tert-butylnitrone
      (PBN) was used in vivo to directly assess the formation of ROS during DFP (1.75
      mg/kg, s.c.) induced muscle hyperactivity. Pretreatment with PBN (300 mg/kg,
      i.p.), the concentration necessary for in vivo spin trapping, prevented muscle
      hyperactivity as well as necrosis and attenuated the DFP induced AChE inhibition
      otherwise seen in DFP only treated rats. PBN had no effect when given after
      fasciculations were established. Muscle extracts from PBN and DFP treated rats
      subjected to electron spin resonance (ESR) spectroscopy tested negative for ROS.
      While the role of PBN as an antioxidant is well established, its prophylactic
      effect against excitotoxity induced by an AChE inhibitor are due to its
      protection of AChE, an unexpected non-antioxidant action.

PMID- 10643793
TI  - Lack of effect of insulin on glucose utilization of the hypothalamus in
      normotensive and hypertensive rats.
AB  - Hypertension is frequently associated with insulin resistance and enhanced
      sympathetic activity supposedly mediated by an effect of the hormone on the
      hypothalamus. In this study we sought to determine whether insulin modifies the
      functional activity of the hypothalamus and other brain areas of spontaneously
      hypertensive (SHR) and normotensive WKY rats. The study was carried out in
      control and hyperinsulinemic, normoglycemic rats. Insulin plasma levels were
      increased to 198 +/- 10 (WKY) or 220 +/- 10 microunits/ml (SHR). Brain functional
      activity was evaluated by the 2-[14C]deoxyglucose method for measuring local
      rates of glucose utilization. The results show that insulin has no effect on any
      of the brain areas examined including the hypothalamus, of both WKY and SHR rats.
      The two strains of rats have comparable cerebral metabolic rates also under basal
      conditions.

PMID- 10643794
TI  - The EcoRV genetic polymorphism of human monoamine oxidase type A is not
      associated with Parkinson's disease and does not modify the effect of smoking on
      Parkinson's disease.
AB  - We previously observed an association with Parkinson's (PD), and modification of
      the effect of smoking on PD, by a polymorphism of the monoamine oxidase B (MAO-B)
      gene. The A form of monoamine oxidase (MAO-A) shares with MAO-B many
      characteristics that could be relevant to PD, especially proneuroxicant
      bioactivation and dopamine metabolism. MAO-A is also inhibited by tobacco smoke,
      which bears an apparent protective effect on PD. We investigated the possibility
      that MAO-A genetic variants may also be involved in predisposition to PD and in
      modification of the effect of smoking. Three-hundred and seventy-one subjects-
      145 idiopathic PD cases and 226 age/gender-matched controls--were genotyped for
      the EcoRV polymorphism of MAO-A gene which has been related to increased enzyme
      activity. MAO-A EcoRV polymorphism was neither significantly associated with PD
      nor did it modify the inverse relationship with smoking. These results suggest
      that the EcoRV polymorphism of MAO-A is not an important biomarker of PD risk.

PMID- 10643795
TI  - Non-competitive inhibition of 5-HT3 receptor-mediated currents by progesterone in
      rat nodose ganglion neurons.
AB  - The effect of progesterone on the serotonin type 3 (5-HT3) receptor-mediated
      response was studied in acutely dissociated rat nodose ganglion neurons by using
      the whole-cell voltage-clamp technique. Progesterone rapidly and reversibly
      inhibited 5-HT-induced currents in a dose-dependent manner, with an EC50 of 31
      microM and a maximal inhibition of 75%. Neither the 5-HT response nor inhibition
      of the 5-HT response by extracellularly applied progesterone was significantly
      affected by inclusion of a saturating concentration of progesterone in the
      electrode buffer, arguing that progesterone acted at the extracellular surface of
      the membrane. Progesterone also inhibited the 5-HT response non-competitively by
      a voltage- and agonist-independent mechanism that was distinct from that of open
      channel blockers.

PMID- 10643796
TI  - Modulatory roles of the adenosine triphosphate P2x-purinoceptor in generation of
      the persistent nociception induced by subcutaneous bee venom injection in the
      conscious rat.
AB  - To study the role of adenosine triphosphate (ATP) P2x-purinoceptor in the
      persistent nociceptive response induced by subcutaneous (s.c.) bee venom
      injection, we used a selective P2x receptor antagonist, pyridoxal-phosphate-6
      azophenyl-2',4'-disulfonic acid (PPADS), to evaluate whether spinal P2x receptor
      play a role in development of spontaneous persistent pain. Injection s.c. of bee
      venom into the plantar surface of one hindpaw in the conscious rat produces a
      monophasic, prolonged persistent nociception characterized by continuously
      flinching reflex of the injected paw for 1-2 h. Intrathecal (i.t.) pretreatment
      with PPADS at two lower doses of 5 and 10 microg resulted in suppression of the
      flinching reflex in a dose dependent manner with the inhibitory rate 37 and 44%,
      respectively, when compared with the control group; whereas i.t. PPADS at a
      higher dose of 30 microg failed to produce any inhibitory effect. This result
      suggests that activation of P2x-purinoceptor in the spinal cord contributes to
      the induction of bee venom-induced prolonged persistent pain. However, the
      antinociceptive effect of ATP P2x-purinoceptor antagonist such as PPADS on
      clinical pathological pain seems to be limited due to its lack of effectiveness
      at higher dose.

PMID- 10643797
TI  - Suramin-sensitive suppression of paired-pulse inhibition by adenine nucleotides
      in rat hippocampal slices.
AB  - In order to assess the possible presence of presynaptic P2 receptors for
      nucleotides in the hippocampus, adenosine triphosphate and betagamma-methyleneATP
      have been examined on paired-pulse inhibition in rat hippocampal slices. Both
      compounds reproduced the effects of adenosine and reduced the amount of paired
      pulse inhibition at an interpulse interval of 10 ms and increased the amount of
      facilitation at intervals of 20 and 50 ms. These effects were prevented by 8
      phenyltheophylline and adenosine deaminase, indicating their mediation by
      adenosine. The effects were also reduced by suramin at 50 microM, suggesting the
      possible activation of P2 receptors. It is suggested that a population of P2
      receptors may exist which promote the release of endogenous adenosine in the
      hippocampus.

PMID- 10643798
TI  - A polymorphism in the tau gene associated with risk for Alzheimer's disease.
AB  - Searching for tau genetic variations which could be associated with risk for
      Alzheimer's disease (AD), we have performed a mutational analysis of a region
      containing the whole exon 11 of the tau gene, which encodes a microtubule binding
      region critical for tau self-assembly, and we have found a biallelic polymorphism
      at position +34 of intron 11 (IVS11 + 34G/A). We have analyzed the allelic
      frequencies of this polymorphism in a case-control sample (167 clinically
      diagnosed AD and 194 controls) and found that the presence of any G allele
      (genotypes AG + GG) is associated with a five-fold AD risk in individuals
      carrying the apolipoprotein E4 allele, strongly suggesting that the combined
      effect of tau and apoE is relevant in relation with AD pathogenesis.

PMID- 10643799
TI  - Cytochrome c release from mitochondria to the cytosol was suppressed in the
      ischemia-tolerance-induced hippocampal CA1 region after 5-min forebrain ischemia
      in gerbils.
AB  - Cytochrome c was detected by immunoblotting in the cytosolic fraction 3 h after 5
      min ischemia in the non-ischemia-tolerant CA1 region in which about 96% of
      neurons had developed delayed neuronal death, while less cytosolic cytochrome c
      was detected in the ischemia-tolerance-induced CA1 region where many more neurons
      survived. In the immunohistochemical study using anti-non-native cytochrome c
      monoclonal antibody, immunoreactivity was observed throughout the cytoplasm in
      the non-ischemia-tolerant CA1 neurons, but not in the normal and ischemia
      tolerant CA1 neurons. Then we determined whether Bcl-2, Bax, Bcl-xL and Bcl-xS,
      which regulate the release of cytochrome c from mitochondria, were altered in the
      ischemia-tolerant CA1 region. Bcl-2 and Bax were up-regulated in the ischemia
      tolerant group, but Bcl-xL and Bcl-xS showed no apparent difference in their
      expression. These results suggest that cytochrome c release is prevented in CA1
      neurons in gerbils in which ischemia-tolerance had been induced and that the
      altered ratio of Bcl-2 to Bax may play a part in this mechanism.

PMID- 10643800
TI  - Adenosine A1/A2a receptors mediate suppression of mismatch negativity by ethanol
      in humans.
AB  - Acute alcohol challenge suppresses the mismatch negativity (MMN) component of the
      auditory event-related potential (ERP), however, the transmitter systems
      underlying MMN generation/mediating this effect have remained vague. To test
      adenosinergic contribution, 12 healthy social drinkers participated in four
      sessions, ingesting: (1) placebo pill and placebo beverage; (2) caffeine (100 mg)
      and placebo beverage; (3) placebo pill and alcohol (0.55 g/kg in 10% (v/v)
      solution); or (4) both caffeine and alcohol. ERP measured during a dichotic
      listening task disclosed increased MMN and P3b peak latencies, and diminished
      amplitude of processing negativity (PN) with alcohol, however, only the increase
      in MMN peak latency was significantly antagonized by caffeine. The results
      suggest that A1 and A2a receptors play a role in the generation of, and mediate
      partly the suppressant effect of ethanol on, the MMN.

PMID- 10643801
TI  - Muscarinic-induced modulation of potassium conductances is unchanged in mouse
      hippocampal pyramidal cells that lack functional M1 receptors.
AB  - Activation of muscarinic acetylcholine (ACh) receptors (mAChRs) increases
      excitability of pyramidal cells by inhibiting several K+ conductances, including
      the after-hyperpolarization current (Iahp), the M-current (Im), and a leak K+
      conductance (Ileak). Based on pharmacological evidence and the abundant
      localization of M1 receptors in pyramidal cells, it has been assumed that the M1
      receptor is responsible for mediating these effects. However, given the poor
      selectivity of the pharmacological agents used to characterize these mAChR
      responses, rigorous characterization of the receptor subtypes that mediate these
      actions has not been possible. Surprisingly, patch clamp recording from CA1
      pyramidal cells in M1 knockout mice revealed no significant difference in the
      degree of inhibition of Iahp, Im, or Ileak by the mAChR agonist, carbachol (CCh),
      as compared with wildtype controls. In addition, the M1-toxin was not able to
      block CCh's inhibition of the Iahp, Im, or Ileak These data demonstrate that the
      M1 receptor is not involved in increasing CA1 pyramidal cell excitability by
      mediating ACh effects on these K+ conductances.

PMID- 10643802
TI  - Is the presenilin-1 E318G missense mutation a risk factor for Alzheimer's
      disease?
AB  - Nearly all of the presenilin-1 (PSEN-1) mutations are missense mutations leading
      to Alzheimer's disease (AD). The role of the mutation E318G (a substitution of
      glutamic acid to glycine) in the PSEN-1 is controversial. It has been found both
      in AD patients and in non-demented control individuals. Using the polymerase
      chain reaction and the restriction fragment length polymorphism method, we
      screened for E318G mutation in a total of 16 familial (FAD) cases, in 64 sporadic
      neuropathologically confirmed AD cases and in 270 non-demented controls including
      35 neuropathologically confirmed individuals. We detected the E318G mutation in
      four FAD cases, seven sporadic AD cases and 10 control individuals with highly
      varying onset-ages. Odds ratios for carrying the mutation were 7.6 and 3 in FAD
      and sporadic AD cases, respectively. Our results suggest that this mutation could
      be a risk factor in the Finnish FAD and sporadic AD population. It may be in
      linkage disequilibrium with a pathogenic change somewhere else in the PSEN-1 gene
      or in close proximity to the PSEN-1 gene.

PMID- 10643804
TI  - Localization of bcl-2 mRNA in the rabbit central nervous system.
AB  - In this study, we demonstrated bcl-2 expression in the rabbit brain using in situ
      hybridization and compared the results with the studies done on the other
      animals. Although the bcl-2 expressions of the rabbit were generally similar to
      those of the other animals, some differences were also found; the cells in
      molecular and Purkinje cell layers of the cerebellum, which were bcl-2 negative
      in the others, showed intense bcl-2 positive signals, while the ependymal cells,
      arachnoid villi and granular layer, which were positive in the other animals,
      were not well stained with bcl-2 riboprobes in the rabbit brain. Our findings
      clearly showed the similarities and differences of rabbit bcl-2 mRNA as compared
      with the other species for the first time, and provided the basis of further
      study on the properties of bcl-2 in this species.

PMID- 10643803
TI  - Repeated intracerebroventricular administration of beta-amyloid(25-35) to rats
      decreases muscarinic receptors in cerebral cortex.
AB  - The effects of repeated in vivo administration to rats of beta-amyloid(25-35)
      (betaA(25-35)) on several cholinergic markers have been studied and compared with
      those of a peptide with a scrambled sequence. Rats received
      intracerebroventricular injections of betaA(25-35) (5 or 20 microg/day) for 7
      days and they were sacrificed at 2 or 3 weeks survival. The density of total
      muscarinic receptors labeled with [3H]N-methyl-scopolamine was dose-dependently
      decreased by betaA(25-35) in the cerebral cortex at 3 weeks survival. No changes
      were observed at 2 weeks survival in cerebral cortex or in the hippocampus, at
      any time. BetaA(25-35) administration did not modify choline acetyltranferase
      activity in cerebral cortex. However, in betaA(25-35)-treated rats
      hypertrophic/hyperactive positive acetylcholinesterase nucleus basalis
      cholinergic neurons were observed at 2 weeks survival, while the density of
      acetylcholinesterase-positive fibers of cerebral cortex was increased along with
      the number of cortical positive neurons at 3 weeks survival. These results
      suggest that increased cholinergic function may be responsible of muscarinic
      receptor down-regulation. Given the involvement of cholinergic systems in memory
      and learning, repeated administration of betaA(25-35) may represent a good
      approach to explore the role of betaA in Alzheimer's disease and to develop
      therapeutic strategies relevant to it.

PMID- 10643805
TI  - Involvement of adenosine triphosphate-sensitive K+ channels in glucose-sensing in
      the rat solitary tract nucleus.
AB  - The presence of adenosine triphosphate-sensitive (ATP-sensitive) K+ channels
      (K(ATP) channels) in the caudal nucleus tractus solitarii (NTS), and their
      possible involvement in glucose-sensing, were assessed by extracellular recording
      of neuronal activity in rat hindbrain slices. In 21 out of 36 recorded cells,
      firing was increased by sulfonylureas and decreased by K+ channel opener (KCO),
      indicating the existence of K(ATP) channels in the caudal NTS. In seven out of
      the nine neurons activated by a 2 mM increase in the glucose level, the effects
      of sulfonylureas and KCO were consistent with the involvement of K(ATP) channels
      in the glucose response. Conversely, the mechanism(s) underlying the response of
      glucose-depressed neurons remains to be clarified. Finally, the presence of
      K(ATP) channels was also detected in some neurons that were unresponsive to a 2
      mM change in the glucose level. Thus, K(ATP) channels were pharmacologically
      identified in the caudal NTS, where they may be partly involved in glucose
      sensing.

PMID- 10643806
TI  - Inhibition of A beta fibril formation and A beta-induced cytotoxicity by senile
      plaque-associated proteins.
AB  - A beta neurotoxicity is generally believed to require A beta fibril formation.
      The prevention of A beta fibril formation thus seems to be a promising strategy
      for the treatment of AD. Recent studies have shown senile plaque-associated
      proteins such as laminin to have an inhibitory effect on both A beta40 and A
      beta42 fibril formation in vitro. In the present study, we thus investigated
      whether or not midkine (MK) and alpha2-macroglobulin (alpha2M), both of which are
      also senile plaque-associated proteins like laminin, affect A beta fibril
      formation and A beta-induced cytotoxicity. The present study demonstrated that
      both MK and alpha2M inhibit both A beta fibril formation and A beta-induced
      cytotoxicity in PC12 cells. The confirmation of the present results based on in
      vivo experiments is called for in future studies to clarify whether or not senile
      plaque-associated proteins such as MK and alpha2M can be a model for therapeutic
      agents in the treatment of AD.

PMID- 10643807
TI  - Differential effect of brain-derived neurotrophic factor on high-threshold
      mechanosensitivity in a rat neuropathic pain model.
AB  - We investigated the effect of the systemic infusion of brain derived neurotrophic
      factor (BDNF) on the behavioral response in a rat neuropathic pain model. One
      microgram per hour infusion of BDNF significantly attenuated mechanical
      hyperalgesia tested by the pin-prick test, however, 20 microg/h-BDNF infusion, on
      the contrary, enhanced the response. Neither 0.5 nor 10 microg/h-BDNF infusion
      influenced the mechanical hyperalgesia. Mechanical allodynia and thermal
      hyperalgesia, tested using a von Frey filament (23.0 mN) and the plantar test,
      were not influenced by BDNF treatment. These data suggest that systemic BDNF
      treatment can specifically alter high-threshold mechanosensitivity.

PMID- 10643808
TI  - Neuronal organization of the utricular macula concerned with innervation of
      single vestibular neurons in the cat.
AB  - We investigated whether cross-striolar inhibition, which may increase sensitivity
      to linear acceleration, contributed to utricular (UT) afferent innervation of
      single vestibular neurons (VNs). Excitatory and inhibitory postsynaptic
      potentials (EPSPs, IPSPs, respectively) were recorded from VNs after focal
      stimulation of the UT macula (M). From a total of 83 VNs, 25 (30%) neurons
      received inputs from both sides of the UTM, and the response patterns were
      opposite, i.e. cross-striolar inhibition was observed. In roughly 2/3 of these
      neurons, stimulation of the medial side of the UTM evoked EPSPs, while
      stimulation of the lateral side evoked IPSPs. In the remaining 1/3 neurons, the
      response patterns were opposite. Thirty-two (39%) of the 83 neurons received the
      identical pattern of inputs from both sides of the UTM: EPSPs in 26 neurons and
      IPSPs in six neurons. Twenty-six (31%) of the 83 neurons received inputs from
      either the medial or the lateral side of the UTM. These findings suggest that
      cross-striolar inhibition existed in the UT system, although it was not a
      dominant circuit that increased the sensitivity as in the saccular system [15].

PMID- 10643810
TI  - Tetrodotoxin-sensitive persistent current boosts the depolarization of retinal
      amacrine cells in goldfish.
AB  - To light illumination retinal amacrine cells respond with graded depolarization
      accompanied by a spike discharge. It has been assumed that the graded
      depolarization is produced solely by the excitatory synaptic inputs from bipolar
      cells. Here we demonstrate that a tetrodotoxin (TTX)-sensitive persistent current
      also contributes to the graded depolarization. This current was isolated in
      amacrine cells of the goldfish retinal slice preparations by the whole-cell patch
      clamp technique. The activation threshold of the persistent current was about -50
      mV, approximately 10 mV more positive than the membrane potential in the dark.
      Therefore, it is highly likely that the TTX-sensitive persistent current is a
      booster of the excitatory postsynaptic potential in amacrine cells.

PMID- 10643809
TI  - Histamine-stimulated phospholipase C activity in bovine adrenal medullary
      chromaffin cells: the effect of chloride-channel antagonists and low
      extracellular chloride concentrations.
AB  - Histamine activates phospholipase C (PLC) in a number of cell-types including
      those of neuronal and neuroendocrine origin. We report here that Cl(-)-channel
      antagonists of the niflumic acid-, but not stilbene disulphonic acid-class,
      produced a concentration-dependent inhibition of histamine-stimulated PLC
      activity in bovine adrenal medullary chromaffin cells. Low extracellular [Cl-]
      (10 mM) produced a similar degree of inhibition. While the mechanism(s)
      responsible for this inhibition are not resolved it may be significant that low
      extracellular Cl- also reduced the magnitude of the histamine-induced Ca2+
      signal. Thus, PLC inhibition may be secondary to a reduction in Ca2+-inflow, a
      conclusion consistent with the known actions of niflumic acid-type compounds and
      the previously reported importance of Ca2+-influx in supporting histamine
      stimulated PLC activity.

PMID- 10643811
TI  - Activation of mitogen-activated protein kinases in gerbil hippocampus with
      ischemic tolerance induced by 3-nitropropionic acid.
AB  - The present study investigated the activation of c-Jun NH2-terminal kinases
      (JNK), p38 mitogen-activated protein kinases (p38) and extracellular signal
      regulated kinases (ERK) in the gerbil hippocampus by immunohistochemistry to
      clarify the role of these kinases in ischemic tolerance induced by3-NP.
      Intraperitoneal administration of 3-NP (3 or 10 mg/kg) caused the activation of
      JNK in CA1 subfield, which induced tolerance to subsequent ischemia and prevented
      delayed neuronal death (DND). As concerns p38 and ERK, no activation was induced
      by intoxication of 3-NP. Our results show the activation of JNK following
      chemical preconditioning with low dose of 3-NP is closely related to the
      acquisition of resistance to DND.

PMID- 10643812
TI  - Age-dependent changes in lipid peroxide levels in peripheral organs, but not in
      brain, in senescence-accelerated mice.
AB  - The tissue concentration of lipid peroxides was determined in the brain, heart,
      liver, lung and kidney of accelerated senescence-prone (SAMP-8) and -resistant
      (SAMR-1) mice at 3, 6 and 9 months of age by a method involving chemical
      derivatization and high performance liquid chromatography. The level of lipid
      peroxides in the brain did not show an age-dependent change, but at each age the
      brain level of lipid peroxides was significantly higher in SAMP-8 than in SAMR-1.
      In contrast, the lipid peroxide levels in the peripheral organs showed increases
      with aging in both strains, and they were significantly higher in SAMP-8 than in
      SAMR-1 at both 3 and 6 months of age (except at 3 months of age in the kidney).
      These results suggest that increased oxidative stress in the brain and peripheral
      organs is a cause of the senescence-related degeneration and impairments seen in
      SAMP-8.

PMID- 10643813
TI  - Antagonistic effects of [Nphe1]nociceptin(1-13)NH2 on nociceptin receptor
      mediated inhibition of cAMP formation in Chinese hamster ovary cells stably
      expressing the recombinant human nociceptin receptor.
AB  - Nociceptin/orphanin FQ (NC) is the endogenous ligand for the nociceptin receptor
      (NCR) which is negatively coupled to adenylyl cyclase to inhibit the formation of
      cAMP. In this study we describe the inhibitory action of the novel NC analogue,
      [Nphe1]nociceptin(1-13)NH2 on cAMP formation in Chinese hamster ovary cells
      expressing the human NCR. NC, NC(1-13)NH2, the pseudopeptides [Phe1psi(CH2
      NH)Gly2]NC(1-17)NH2 and [Phe1psi(CH2-NH)Gly2]NC(1-13)NH2, the hexapeptide, acetyl
      Arg-Tyr-Tyr-Arg-Trp-Lys-NH2 and buprenorphine all produced a concentration
      dependent inhibition of forskolin stimulated cAMP formation. This inhibition was
      competitively reversed by [Nphe1]NC(1-13)NH2 with essentially identical pA2
      values (6.12-6.48). [Nphe1]NC(1-13)NH2 showed per se a negligible residual
      agonist activity (alpha < 0.15).

PMID- 10643814
TI  - Development of key neurons for learning stimulates learning ability in Lymnaea
      stagnalis.
AB  - The pond snails, Lymnaea stagnalis, change their ability of conditioned taste
      aversion (CTA) during their development, for example, stage 29 embryos can
      acquire the CTA, whereas immature snails come to use a long-term memory to
      maintain the conditioned response. We thus examined the relationships between the
      learning ability and the development of key neurons (cerebral giant cells: CGCs)
      for this CTA. The immunoreactivity of serotonin, which is a main neurotransmitter
      employed in the feeding circuitry, was first observed in the CGCs at the stage
      29. After hatching, the CGCs developed their neuropile faster than other cells in
      the buccal and cerebral ganglia, resulting in their early innervation at the
      immature stage. The present results, therefore, indicate that the development of
      key neurons for learning stimulates the developmental changes in learning
      ability.

PMID- 10643815
TI  - Human amyloid-beta1-42 applied in vivo inhibits the fast axonal transport of
      proteins in the sciatic nerve of rat.
AB  - Human amyloid-beta1-42 has been suggested to be a pathogenetic factor in
      Alzheimer's disease. The precise mechanism by which this peptide causes the
      degeneration of neurons in the affected brain is not yet fully understood. By
      using immunohistochemistry we explored the inhibitory effects of human amyloid
      beta1-42 applied in vivo on the fast axonal transport of acetylcholinesterase,
      the amyloid precursor protein, the vesicular acetylcholine transporter and
      synaptophysin in the sciatic nerve of rat. Our findings provide evidence for the
      in vivo neurotoxic effect of human amyloid-beta peptide.

PMID- 10643816
TI  - Prosaptide D5 reverses hyperalgesia: inhibition of calcium channels through a
      pertussis toxin-sensitive G-protein mechanism in the rat.
AB  - A retro-inverso 11-mer peptidomimetic of prosaposin, Prosaptide D5, induced
      neurite outgrowth in NS20Y neuroblastoma cells and enhanced [35S]GTPgammaS
      binding to rat synaptosomal membrane at low nanomolar concentrations similar to
      prosaposin. Intramuscular injection of D5 ameliorated thermal hyperalgesia in the
      Seltzer rat model of neuropathic pain, returning paw withdrawal latency to
      control levels within 3 h after treatment. The effect was sustained for at least
      48 h after injection. Prosaposin and D5 inhibited K+-stimulated synaptosomal
      45Ca2+ uptake similar to omega-conotoxin MVIIC, demonstrating that both effectors
      modulated voltage-dependent calcium channels (VDCC); inhibition was largely
      abolished by pretreatment with pertussis toxin before D5 treatment. The results
      suggest a mechanism whereby VDCC are modulated by a pertussis toxin-sensitive G
      protein coupled receptor; D5 binds to this receptor and thereby ameliorates
      hyperalgesia in the Seltzer model of neuropathic pain.

PMID- 10643817
TI  - Pain facilitatory circuits in the mammalian central nervous system: their
      behavioral significance and role in morphine analgesic tolerance.
AB  - Sensitivity to noxious stimulation is not invariant; rather, it is modulated by
      discrete pain inhibitory and facilitatory circuits. This paper reviews the neural
      circuits for pain facilitation, describes the conditions governing their
      environmental activation, and examines their role in an animal's behavioral
      repertoire. Mechanisms for pain facilitation are contrasted at both the neural
      and behavioral level with mechanisms for pain inhibition. In addition, the
      involvement of mechanisms for pain facilitation in morphine analgesic tolerance
      is discussed, and the implications of this involvement for accounts of the role
      of associative processes in analgesic tolerance are highlighted.

PMID- 10643818
TI  - Final common pathways in neurodegenerative diseases: regulatory role of the
      glutathione cycle.
AB  - Attempts to unify diverse mechanisms of neurotoxicity have led to the concept of
      final common pathways which characterize frequently occurring cellular responses
      to disruption of homeostasis. The clinical presentation and common patho
      biochemistry of reactive oxygen intermediates of Guam's disease have suggested
      that such pathways may be operative in three major neurodegenerative disorders:
      Alzheimer's dementia, amyotrophic lateral sclerosis and Parkinson's disease. A
      candidate-signaling pathway in this regard is characterized by the cascade
      arachidonic acid/HPETE/*OH/cGMP followed by activation of cGMP-dependent kinase
      and phosphorylation of NF-kB proteins and possibly CREB. This sequence may lead
      to apoptosis as well as long-term potentiation and memory and constitutes a
      biochemical correlate to excitotoxicity. The predominant control of *OH release
      from HPETE, a checkpoint in this pathway, is exerted by the glutathione cycle, a
      central biochemical process that is also intimately associated with the synthesis
      of the neurotransmitters glutamate and GABA and is connected to energy
      metabolism. Modifications in the activity of the glutathione cycle may provide
      treatment options.

PMID- 10643819
TI  - Behavioral effects of apamin, a selective inhibitor of the SK(Ca)-channel, in
      mice and rats.
AB  - Apamin, a highly selective and potent peptide that blocks the SK(Ca)-channels has
      been suggested to be a cognition enhancer. We tested apamin in the Morris water
      escape task, in shock motivated avoidance tasks, and in operant tasks in the
      Skinnerbox. We also used non-cognitive tests, such as the rat forced swimming
      test and cocaine-induced locomotor activity in the open field, and a test to
      assess the side effect profile. Mice and rats from different strains, and rats of
      different ages were used. The rat studies provided only weak support for the
      notion that apamin acts as a cognition enhancer. More convincing evidence was
      obtained from the mouse studies. Overt side effects of apamin were found at the
      dose of 0.3 mg kg(-1). This dose was close to, or even overlapped, the doses
      which improved cognition in mice. We conclude that apamin is a poor tool to
      assess the role of SK(Ca)-channels in learning and memory processes.

PMID- 10643820
TI  - 5-HT system and cognition.
AB  - The study of 5-hydroxytryptamine (5-HT) system has benefited from the
      identification, classification and cloning of multiple 5-HT receptors (5-HT1 to 5
      HT7). Growing evidence suggests that 5-HT is important in learning and memory and
      all its receptors might be implicated in this. Actually, 5-HT pathways, 5-HT
      reuptake site/transporter complex and 5-HT receptors show regional distribution
      in brain areas implicated in learning and memory. Likewise, the stimulation or
      blockade of presynaptic 5-HT1A, 5-HT1B, 5-HT(2A/2C) and 5-HT3 receptors,
      postsynaptic 5-HT(2B/2C) and 5-HT4 receptors and 5-HT uptake/transporter sites
      modulate these processes. Available evidence strongly suggests that the 5-HT
      system may be important in normal function, the treatment and/or pathogenesis of
      cognitive disorders. Further investigation will help to specify the 5-HT system
      nature involvement in cognitive processes, pharmacotherapies, their mechanisms
      and action sites and to determine under which conditions they could operate. In
      this regard, it is probable that selective drugs with agonists, neutral
      antagonist, agonists or inverse agonist properties for 5-HT1A, 5-HT(1B/1D), 5
      HT(2A/2B/2C), 5-HT4 and 5-HT7 receptors could constitute a new therapeutic
      opportunity for learning and memory alterations.

PMID- 10643821
TI  - Neuropeptides and sexual behaviour.
AB  - Many neuropeptides are involved in the control of sexual behaviour at the central
      level. Among these, the most studied are adrenocorticotropin, alpha-melanocyte
      stimulating hormone, oxytocin and opioid peptides. This attempt to review old and
      new neuropharmacological, biochemical and psychobiological studies in this field,
      shows that all these neuropeptides apparently facilitate sexual behaviour, except
      for opioid peptides, which inhibit sexual performance, in most of the species
      studied so far (rats, mice, monkeys and humans). However, gonadotropin-releasing
      hormone, corticotropin releasing factor, neuropeptide Y, galanin,
      cholecystokinin, substance P and vasoactive intestinal peptide may be also
      involved in the control of sexual behaviour. Apparently, corticotropin releasing
      factor, neuropeptide Y and cholecystokinin inhibit, while substance P and
      vasoactive intestinal peptide facilitate, sexual behaviour. In contrast,
      gonadotropin-releasing hormone has been reported to exert a facilitative,
      inhibitory or no effect at all on sexual behaviour. Galanin was also shown either
      to facilitate or inhibit sexual behaviour. The above-mentioned putative role of
      the neuropeptides in sexual behaviour derives mainly from studies done in rats.
      In these studies, neuropeptides, their antisera or drugs that act as agonists or
      antagonists of neuropeptide receptors, were tested for their effect on sexual
      behaviour after systemic, intracerebroventricular, or intracerebral
      administration. The latter were infused into brain areas relevant for sexual
      behaviour, such as the medial preoptic area, and the ventromedial and
      paraventricular nuclei of the hypothalamus. The above studies show that little
      information is available on the mechanisms by which neuropeptides influence
      sexual behaviour. Also unclear is whether the above neuropeptides influence the
      anticipatory phase (sexual arousal and/or motivation) or the consummatory phase
      (performance) of sexual behaviour, except for opioid peptides. New information
      about the role of neuropeptides may come from the application of molecular
      biology and genetic manipulation techniques to the study of sexual behaviour. Of
      these, FOS protein determination, antisense oligonucleotides aimed at the
      neutralisation of neuropeptide and/or neuropeptide receptor mRNAs in specific
      brain areas, and gene ablation seem the most promising. Although still in the
      early stages, it is likely that these methodologies will provide new insights
      into the role of neuropeptides in the control of sexual behaviour.

PMID- 10643822
TI  - Magnetic resonance anatomy of spaces in the neck.
AB  - Owing to its complex anatomy, the neck harbors multiple pathologic processes. A
      comprehensive knowledge of regional anatomy and recognition of the patterns of
      disease presentation are vital to arriving at a meaningful differential
      diagnosis. This review of basic neck anatomy has utilized magnetic resonance
      imaging in showcasing the well-accepted spatial approach that emphasizes anatomic
      imaging, surgical landmarks, and imaging principles. To permit early recognition
      of neck pathology, detailed anatomic correlation is mandatory. Current imaging
      with high-resolution helical computed tomography, high speed magnetic resonance,
      and multiplanar reformations permit a detailed analysis of the complex anatomy in
      this region and is the key to understanding many of its disorders. Through such
      understanding we can recognize the issues involved in conservative neck surgery,
      neck nodal texture and functional assessment, brachial plexopathy, and the
      treated neck, appreciate the relevant surgical anatomy of the spaces in the neck,
      and relate better with our ENT colleagues.

PMID- 10643823
TI  - Magnetic resonance imaging of nasopharyngeal carcinoma.
AB  - Nasopharyngeal carcinoma (NPC) is a malignant tumor that shows distinct
      distributions into geographical and into well-defined high-risk ethnic groups.
      Radiation therapy is the mainstay of treatment, and imaging plays a central role
      in tumor mapping and post-treatment follow-up. Magnetic resonance imaging is
      better than computed tomography in demonstrating tumor extent, tumor recurrence,
      and postradiation complications. However, differentiating postradiation changes
      from tumor recurrence may be difficult using magnetic resonance imaging. Mucosal
      recurrence is best detected with endoscopy.

PMID- 10643824
TI  - Nonsquamous cell neoplasms of the adult head and neck.
AB  - The purpose of the article is to describe the magnetic resonance imaging
      characteristics of the most frequently encountered nonsquamous neoplasms of the
      adult head and neck. The lesions are divided into those arising from the
      parapharyngeal or carotid spaces, salivary gland neoplasms, neoplasms of the
      thyroid and parathyroid glands, mesenchymal neoplasms, and lymphoreticular
      neoplasms. When appropriate, correlative features of other imaging modalities are
      included in the discussion. Although magnetic resonance imaging can provide
      critical information in the evaluation of patients with these neck masses, the
      imaging features of many of the lesions may be nonspecific and complementary data
      must be obtained from other modalities or biopsy may be necessary.

PMID- 10643825
TI  - Magnetic resonance imaging of the central skull base.
AB  - The central skull base is an anatomically complex region whose foundation is the
      sphenoid bone. It includes the sphenoid sinus, clivus, and sella turcica, as well
      as adjacent soft tissues such as the cavernous sinuses and nasopharynx. The
      central skull base may be affected by pathologies intrinsic to the sphenoid bone
      or by processes that arise in adjacent soft tissue and extend centrally to affect
      the central skull base. In general, this region is optimally imaged with magnetic
      resonance scanning, although in some cases computed tomography can provide
      complementary information. In this review, we will discuss a variety of
      pathologies that can affect the central skull base, such as neoplasms,
      infections, trauma, congenital malformations, and a variety of miscellaneous
      pathologies. We will discuss processes that can mimic neoplasia, such as
      aggressive polyposis and chronic inflammatory disease. For each pathology we will
      review clinical and imaging findings.

PMID- 10643826
TI  - "The changing face of women's health".

PMID- 10643827
TI  - News from the Society for Women's Health Research: SAM IX: more information on
      sex-based differences.

PMID- 10643828
TI  - Observations from the CDC: promoting women's health through age-appropriate
      vaccination.

PMID- 10643829
TI  - Toward optimal health: the experts respond to stress. Interviews conducted by
      Jodi Godfrey Meisler.

PMID- 10643830
TI  - Diversity and medical education.
AB  - Perhaps one measure of wisdom is our willingness to listen to the tales of that
      man of a different color on our left and that woman of a different color on our
      right as we walk together toward life's inevitable crises.

PMID- 10643831
TI  - Part I. "Behind every problem lies an opportunity": meeting the challenge of
      diversity in medical schools.
AB  - The authors describe the historical evolution and present status of affirmative
      action in medical school admission policies. The demographic transformation of
      the medical student body between 1965 and 1998 from a homogeneous white and male
      group to one that includes a significant number of women and minority students is
      presented. Challenges to affirmative action are outlined. In addition, the
      authors note the increasing diversity of the general population and discuss the
      benefits of diversity to medical practice, research, and education. However, the
      upper ranks of professors and administrators remain white and male. The rationale
      for an innovative course on the history of bias in medicine and the benefits that
      diversity brings to the medical enterprise are presented.

PMID- 10643832
TI  - Part II. Educating for diversity: a decade of experience (1989-1999)
AB  - In response to tensions created by a racial misunderstanding, the authors
      developed a course for first year medical students entitled Race and Gender in
      Medicine. The course, presented in a seminar format, enables the participants to
      discuss openly their concerns about diversity and its impact on their institution
      and the medical enterprise. Physician speakers describe their experiences with
      gender bias, racism, and other discriminatory practices and then present
      strategies they used to overcome these obstacles in their career path. Given the
      increasing heterogeneity of the population, the authors advocate integrating a
      course such as this one into the curriculum that will help prepare students to
      practice humane medicine in the multiracial, multiethnic, and multicultural
      society of the 21st century.

PMID- 10643833
TI  - The obstetrical and postpartum benefits of continuous support during childbirth.
AB  - The purpose of this article is to review the evidence regarding the effectiveness
      of continuous support provided by a trained laywoman (doula) during childbirth on
      obstetrical and postpartum outcomes. Twelve individual randomized trials have
      compared obstetrical and postpartum outcomes between doula-supported women and
      women who did not receive doula support during childbirth. Three meta-analyses,
      which used different approaches, have been performed on the results of the
      clinical trials. Emotional and physical support significantly shortens labor and
      decreases the need for cesarean deliveries, forceps and vacuum extraction,
      oxytocin augmentation, and analgesia. Doula-supported mothers also rate
      childbirth as less difficult and painful than do women not supported by a doula.
      Labor support by fathers does not appear to produce similar obstetrical benefits.
      Eight of the 12 trials report early or late psychosocial benefits of doula
      support. Early benefits include reductions in state anxiety scores, positive
      feelings about the birth experience, and increased rates of breastfeeding
      initiation. Later postpartum benefits include decreased symptoms of depression,
      improved self-esteem, exclusive breastfeeding, and increased sensitivity of the
      mother to her child's needs. The results of these 12 trials strongly suggest that
      doula support is an essential component of childbirth. A thorough reorganization
      of current birth practices is in order to ensure that every woman has access to
      continuous emotional and physical support during labor.

PMID- 10643834
TI  - Obesity, weight change, fasting insulin, proinsulin, C-peptide, and insulin-like
      growth factor-1 levels in women with and without breast cancer: the Rancho
      Bernardo Study.
AB  - Postmenopausal overweight women have an increased risk of breast cancer. The link
      between obesity and breast cancer could be mediated through hyperinsulinemia.
      Insulin and insulin-like growth factor-1 (IGF-1) stimulate mammary cell
      proliferation in vitro, and cell proliferation is directly linked to the risk of
      breast cancer. Our objective was to investigate the relationship between breast
      cancer and body composition, IGF-1, proinsulin, C-peptide, and fasting insulin. A
      case-control study was conducted of 438 community-dwelling women aged 53-90 years
      in 1992-1994 who had no history of cancer at the baseline visit in 1972-1974.
      Women were excluded who were using estrogen replacement therapy (ERT) or
      tamoxifen at the 1992-1994 visit, when IGF-1, proinsulin, fasting insulin, and C
      peptide levels were measured. Prior ERT, alcohol and tobacco use, exercise, and
      reproductive history were recorded. Weight, height, and waist/hip ratio were
      measured. The 45 women with breast cancer had similar baseline body mass indices
      to the 393 women without breast cancer but had gained significantly more weight
      between the baseline visit in 1972-1974 and 1992-1994, (age-adjusted relative
      risk [RR] 1.05/kg, 95% confidence interval [CI] 1.01-1.09, p = 0.016).
      Proinsulin, fasting insulin, and C-peptide were each significantly positively
      correlated with both current weight and weight gain. However, levels of these
      hormones and IGF-1 did not differ significantly between women with and without
      breast cancer (all 95% CI within 0.996-1.004). Past ERT was significantly more
      common among women with breast cancer (p = 0.015), and duration of use was
      significantly longer (age-adjusted RR 1.13 per year of use, 95% CI 1.08-1.18, p =
      0.000). The risk of breast cancer was significantly increased in women who had
      gained weight or used ERT. This increased risk was not associated with
      circulating levels of IGF-1, fasting insulin, proinsulin, or C-peptide.

PMID- 10643835
TI  - Effect of age on the exercise response in normal postmenopausal women during
      estrogen replacement therapy.
AB  - Postmenopausal estrogen replacement therapy (ERT) has been associated with a
      reduced risk of coronary artery disease (CAD). Whether this apparent
      cardioprotective effect is mediated by a cardiovascular benefit during exercise,
      however, has not been clearly defined. To evaluate rest and exercise variables
      with and without ERT, a randomized crossover trial was conducted in 23
      postmenopausal women, ranging in age from 44 to 75 years, mean age 57+/-8 years.
      The rest and exercise variables were compared on ERT and during a drug-free
      period. The baseline measure was compared to the effects after 4 weeks of ERT and
      after 4 drug-free weeks. Echocardiographic treadmill exercise variables of heart
      rate (HR), blood pressure, rate-pressure product (RPP), and cardiac dimensions
      were determined at baseline and at the end of each treatment period. In response
      to ERT, there was a decrease in low-density lipoprotein (LDL) cholesterol (drug
      free: 142+/-40 mg/dl, ERT: 124+/-34 mg/dl) and an increase in high-density
      lipoprotein (HDL) cholesterol (drug-free: 52+/-14 mg/dl, ERT: 62+/-15 mg/dl, both
      p<0.01). At rest, the study population had no overall significant change in HR,
      blood pressure, RPP, or left ventricular end-systolic and end-diastolic diameters
      when ERT was compared to the drug-free period. However, subjects with the fastest
      baseline resting HR had the greatest decrease in HR with ERT relative to the drug
      free period (p<0.05). During exercise, ERT effected no change in peak HR, blood
      pressure, or RPP, although end-systolic diameter decreased slightly (p<0.05).
      With ERT, subject age correlated negatively with systolic blood pressure (p<0.05)
      and RPP (p<0.01); both blood pressure and RPP decreased in older subjects. In
      conclusion, ERT has differential effects dependent on baseline HR and age.

PMID- 10643836
TI  - Secret patterns: validation of a screening tool to detect bulimia.
AB  - We prospectively validated a two-item screening tool for bulimia. Subjects
      recruited from a women's health practice completed the previously developed two
      item screening tool ("Do you ever eat in secret?" and "Are you satisfied with
      your eating patterns?") at their initial office visit. This was validated against
      a telephone interview with a licensed psychologist. The prevalence of current
      bulimia was 16% in 75 subjects, determined by psychologists' assessment
      (sensitivity 75%, specificity 49%) and 4% by DSM-III-R criteria. The positive and
      negative predictive values of one screening question positive were 22% and 91%,
      respectively, when compared with the psychologists' assessments as the gold
      standard. This screening tool allows physicians to identify patients who warrant
      further valuation for bulimia.

PMID- 10643837
TI  - Cognitive adaptation: a women's health perspective for reducing stress during
      childbearing.
AB  - The purpose of this study is to evaluate psychological changes in women of three
      minority ethnic groups in a program of psychosocial services that promoted
      positive cognitive adaptation to childbearing throughout pregnancy and the
      postpartum period. In this prospective longitudinal study, both cognitive
      adaptation and generalized stress were measured at each trimester of pregnancy as
      well as after birth and 3 months postpartum. The mean scores at each time are
      first compared with first trimester scores for women in the program and then with
      scores for comparable women in a cross-sectional sample tested before the
      program. For women in the program, results of the psychological adaptation
      measures and the stress measures had improved from their first trimester value by
      the time of birth. Stress levels of women in the program were less than for women
      in the corresponding comparison sample from the third trimester on. Enhanced
      perinatal services that include interventions and monitoring strategies aimed at
      improving the cognitive adaptation of women to childbearing are important in
      promoting stress reduction in women and infants.

PMID- 10643838
TI  - Care during menopause: comparison of a women's health practice and traditional
      care.
AB  - Despite the growth in primary care-based women's health centers, little is known
      about the characteristics of women's health patients and the quality of care
      provided in women's health centers versus traditional practices. Our objective
      was to compare a women's health practice and a general internal medicine practice
      on issues of care during menopause. A cross-sectional survey was administered
      simultaneously to patients aged 50-70 and their primary care physicians in a
      women's health practice and an affiliated general internal medicine practice. The
      survey asked patients about health behaviors, past and current hormone use,
      menopausal symptoms, and attitudes about menopause. Physicians were asked to
      estimate their patients' attitudes. Patients in women's health practices were
      younger, more likely to be smokers, and more likely to have had a prior
      hysterectomy. Women's health patients were somewhat more likely to report
      concerns related to menopausal symptoms. Women's health patients and patients
      attending the general internal medicine practice reported similar rates of past
      or current use of hormone therapy, after adjusting for prior hysterectomy and
      age. Physicians in women's health and general medicine were similar in their
      ability to estimate their patients' attitudes. In the general internal medicine
      practice, female physicians tended to better estimate their patients' attitudes
      than their male colleagues. Patients seeking care in a women's health practice
      differed in symptoms and concerns about the menopause compared with patients in a
      traditional primary care setting. Physicians' understanding of patients'
      menopausal concerns did not differ between the two practices. However, there may
      be gender differences in physicians' understanding of patients' concerns.

PMID- 10643839
TI  - Cultural diversity, stress, and depression: working women in the Americas.
AB  - Social support lengthens life, and stressors induce morbidity early in life and
      death later. Social supports and stressors, however, particularly those embedded
      in daily social interactions, exhibit important forms of cultural variation not
      yet incorporated into stress measurements. This article reports a clinically
      useful measure of stress applicable to culturally diverse populations. Ninety
      working women with a wide range of ages, educational attainments, class
      backgrounds, and historical origins (Africa, northwest Europe, Hispanic, and
      Native Americans) provided cultural data on the meaning of stress. Consensus
      analysis, principal components analysis and Cronbach's alpha, and logistic
      regression document content validity of the stress scale items and the
      reliability and construct validity of the stress scale. The meaning of social
      supports (words or acts that imply respect, equality, or help or otherwise lead
      one to feel special and important) and stressors (words or acts that demean,
      imply inferiority, impede achievement, or otherwise lead one to feel bad about
      oneself) experienced in the course of daily social interaction cuts across
      cultural differences in other realms of life. Informants with a recent history of
      stress experienced a risk of depressive symptoms 85 times higher than informants
      without such a history. Standardized cultural research methods yield an
      instrument based on potential cultural universals that can facilitate clinical
      assessment and management of stress and health outcomes, such as depression, in
      culturally diverse populations.

PMID- 10643840
TI  - Psychological factors related to stage of mammography adoption.
AB  - This study examined the differences among women at different stages of
      mammography adoption on Health Belief Model variables, response efficacy,
      knowledge, and avoidance. A random sample of 361 women aged > or =40 years were
      grouped into six stages of mammography adoption (precontemplation, contemplation,
      action, maintenance, relapse precontemplation, relapse contemplation). A
      multivariate analysis of variance (ANOVA) revealed significant differences among
      women on all components of the Health Belief Model except perceived seriousness,
      as well as differences on response efficacy, knowledge, and avoidance. Results
      indicate that there are significant differences between women who have never had
      a mammogram (precontemplation and contemplation stages) and women who have had a
      mammogram in the past but are currently noncompliant (relapse stages). Further,
      significant differences were found between compliant women who have had one
      mammogram (action) and compliant women who have had multiple mammograms
      (maintenance) on barriers, motivation, confidence, and avoidance.

PMID- 10643841
TI  - Assessing perceived health promotion needs and interests of low-income older
      women.
AB  - This study focuses on an assessment of perceived health promotion needs and
      interests among predominantly older low-income women (76%) in the state of
      Pennsylvania. A questionnaire was completed by a convenience sample of 140
      individuals attending four senior centers and two nutrition sites. In addition,
      14 focus groups with an average of 8 members per group were conducted for a total
      of 105 people from two of the four senior centers. The health topics of greatest
      interest to women were exercise (57.6%), making friends (50.9%), nutrition
      (37.5%), losing weight (33.6%), and home safety (34.6%). Compared with women, men
      were significantly more interested in exercise and its effect on mood (41.3%
      versus 24.0%) and love and sex after 60 (44.8% versus 18.2%) and significantly
      less interested in nutrition (17.2% versus 37.5%). The fitness activities of
      greatest interest to women were walking (63.1%), back exercises (37.5%), toning
      to music (22.1%), and self-defense (18.2%), none of which was significantly
      different from the men in the sample. Results suggest that many of the key health
      needs perceived by low-income older women could be addressed by a combination of
      fitness activities and health education, especially if they are also designed to
      facilitate social interactions. The barriers to participation in such programs
      most often cited were transportation, scheduling, and cost factors. Fortunately,
      many communities already have the resources to offer low-cost interventions in
      the areas of need, such as walking groups, self-defense, and home safety.
      Communities interested in serving low-income older women should more closely
      examine the barriers and the unmet needs of this group when designing
      intervention programs.

PMID- 10643842
TI  - Enzyme-linked immunosorbent assay to assess respiratory syncytial virus
      concentration and correlate results with inflammatory mediators in tracheal
      secretions.
AB  - OBJECTIVE: We developed an enzyme-linked immunosorbent assay (ELISA) for the
      quantitation of respiratory syncytial virus (RSV) in respiratory secretions in
      intubated patients infected with RSV. METHODS: We compared the quantitative ELISA
      and a standardized plaque assay in intubated children <2 years of age who were
      mechanically ventilated for severe RSV disease and enrolled in a randomized
      double blind placebo-controlled treatment trial of a monoclonal antibody to the F
      protein of RSV (palivizumab; Synagis). We also examined the relationship between
      the concentrations of virus as measured by ELISA and of three inflammatory
      indices in respiratory secretions (white blood cell count, myeloperoxidase and
      eosinophilic cationic protein). RESULTS: Quantitative ELISA and plaque assay were
      highly correlated for both tracheal aspirates (r = 0.67, P = 0.001) and nasal
      wash specimens (r = 0.75, P = 0.001). Treatment with palivizumab significantly
      neutralized RSV in tracheal aspirates as measured by plaque assay. In contrast
      quantitation of RSV by ELISA was not affected by palivizumab treatment. This
      finding is consistent with results that were obtained in preliminary studies of
      RSV-containing media treated with monoclonal antibody, where we found that the
      ELISA measured virus whether antibody-bound or not. The inflammatory indices were
      not correlated with RSV concentration measured by ELISA or plaque assay.
      CONCLUSIONS: We conclude that this quantitative ELISA is a potentially useful
      tool for measurement of RSV concentration in respiratory secretions that may help
      elucidate the pathophysiology of acute RSV infection. Specific antiviral
      strategies for the treatment of RSV disease could be evaluated by this method.

PMID- 10643843
TI  - Epidemiology of Haemophilus influenzae type b meningitis in Manila, Philippines,
      1994 to 1996.
AB  - BACKGROUND: Effective vaccines against Haemophilus influenzae type b (Hib) have
      shown impressive results in decreasing Hib meningitis in developed countries. In
      the Philippines Hib vaccines are not part of the routine immunization given to
      children. Before a decision can be made to include Hib vaccines in immunization
      program, epidemiology of Hib meningitis in Manila, Philippines, should first be
      described. METHODOLOGY: A cohort of 41,592 children <5 years of age in Central
      Manila was the study population. Confirmed cases between January, 1994, and
      December, 1996, were obtained from all hospitals in the region. Confirmation of
      cases was based on positive culture isolated from blood or cerebrospinal fluid
      (CSF) or Hib antigen identified in CSF with a clinical diagnosis of Hib
      meningitis. The progress of children with Hib meningitis postinfection was
      evaluated from hospital records. RESULTS: There were 118 episodes of Hib
      meningitis identified in the population in the study period. Sequelae occurred in
      15% of the total cases, and the case fatality rate was 11%. The annual incidence
      of Hib meningitis in Manila for children <5 years old was 95 per 100,000.
      CONCLUSIONS: Hib meningitis in Central Manila is common. The incidence is
      particularly high in children <6 months old. Adverse neurologic outcomes and a
      high case fatality rate in children younger than 1 year suggest that a
      vaccination program would be useful.

PMID- 10643844
TI  - Bronchiolitis-associated hospitalizations among American Indian and Alaska Native
      children.
AB  - BACKGROUND: Respiratory syncytial virus (RSV) is the leading cause of lower
      respiratory tract illness among infants and young children. Respiratory system
      diseases account for a large proportion of hospitalizations in American Indian
      and Alaska Native (AI/AN) children; however, aggregate estimates of RSV
      associated hospitalizations among AI/AN children have not been made. METHODS: We
      used Indian Health Service hospitalization data from 1990 through 1995 to
      describe hospitalizations associated with bronchiolitis, the most characteristic
      clinical manifestation of RSV infection, among AI/AN children <5 years old.
      RESULTS: The overall bronchiolitis-associated hospitalization rate among AI/AN
      infants < 1 year old was considerably higher (61.8 per 1,000) than the 1995
      estimated bronchiolitis hospitalization rate among all US infants (34.2 per
      1,000). Hospitalization rates were higher among male infants (72.2 per 1,000)
      than among females infants (51.1 per 1,000). The highest infant hospitalization
      rate was noted in the Navajo Area (96.3 per 1,000). Hospitalizations peaked
      annually in January or February, consistent with national peaks for RSV
      detection. Bronchiolitis hospitalizations accounted for an increasing proportion
      of hospitalizations for lower respiratory tract illnesses. CONCLUSIONS:
      Bronchiolitis-associated hospitalization rates are substantially greater for
      AI/AN infants than those for all US infants. This difference may reflect an
      increased likelihood of severe RSV-associated disease or a decreased threshold
      for hospitalization among AI/AN infants with bronchiolitis compared with all US
      infants. AI/AN children would receive considerable benefit from lower respiratory
      tract illness prevention programs, including an RSV vaccine, if and when one
      becomes available.

PMID- 10643845
TI  - Lack of association between Kawasaki syndrome and Chlamydia pneumoniae infection:
      an investigation of a Kawasaki syndrome cluster in San Diego County.
AB  - BACKGROUND: The etiology of Kawasaki syndrome (KS), the leading cause of acquired
      coronary artery disease in children, is unknown. Recent studies have suggested
      that Chlamydia pneumoniae, a common respiratory pathogen associated with an
      increased risk of heart disease, might lead to KS. OBJECTIVE: To assess whether
      KS was associated with an elevated risk of having a current or antecedent
      infection with C. pneumoniae. METHODS: Blood, urine and pharyngeal specimens from
      KS patients in San Diego County, CA, during a period of high KS incidence were
      analyzed for evidence of recent C. pneumoniae infection by culture, PCR and
      serology. Specimens collected from two control groups, family members of KS
      patients and age-matched children attending outpatient clinics for well child
      visits, were similarly analyzed. RESULTS: Thirteen cases were identified. Forty
      five outpatient controls and an average of three family members per patient were
      enrolled in the study. All specimens tested negative for the presence of C.
      pneumoniae by PCR and culture except for one blood specimen from the mother of a
      case-patient. Serologic analysis of patients and a subset of outpatient and
      family controls revealed no evidence of current C. pneumoniae infection; 4 of 13
      adult family controls had IgG titers consistent with past exposure to C.
      pneumoniae. Case patients were no more likely than outpatient controls to have
      had a respiratory illness in the preceding 2 months (11 of 13 patients vs. 35 of
      45 controls; odds ratio, 1.57; 95% confidence interval, 0.3 to 11.9).
      CONCLUSIONS: We found no evidence that C. pneumoniae infection was associated
      with KS.

PMID- 10643846
TI  - Cost effectiveness analysis of different strategies of management of chronic
      hepatitis C infection in children.
AB  - BACKGROUND: Chronic hepatitis C virus infection in the pediatric patients is
      commonly encountered by clinicians, and although interferon-based therapy has
      been shown to be reasonably effective in children no formal economic analysis of
      such treatment strategies is available. METHODS: With a Markov cycle tree
      simulation model, a cost effectiveness analysis was done to compare interferon
      based treatment strategies for chronic HCV infection in children with a strategy
      of no treatment in a cohort of 10-year-old otherwise healthy children. Clinical
      probabilities used in the model was obtained from available literature, and cost
      estimates were obtained from two teaching hospitals. Cost per patient, quality
      adjusted life years gained in each strategy and incremental cost-effective ratio
      were the primary outcome measures compared. RESULTS: In the baseline analysis the
      treatment strategies dominated the strategy of no treatment. A 12-month treatment
      strategy was better than the 6-month treatment strategy. Combination therapy for
      6 months with interferon and ribavirin was at least equally if not more effective
      than 12-month monotherapy. All treatment strategies decreased the number of
      patients developing decompensated cirrhosis, hepatocellular carcinoma and also
      number of orthotopic liver transplants in the lifetime of the model cohort.
      CONCLUSIONS: Interferon-based treatment strategies were more effective in terms
      of quality-adjusted life years saved and at the same time cheaper when compared
      with the strategy of no treatment. Combination therapy may be more cost-effective
      than interferon monotherapy, and clinical trials of combination therapy in
      pediatric patients are needed.

PMID- 10643847
TI  - Neonatal screening for congenital toxoplasmosis in the Poznan region of Poland by
      analysis of Toxoplasma gondii-specific IgM antibodies eluted from filter paper
      blood spots.
AB  - OBJECTIVES: The aims of the study were to determine the prevalence of congenital
      toxoplasmosis at birth in the Poznan region of Poland, the value of the serologic
      examination of filter paper blood specimens collected from newborns for the
      diagnosis of congenital Toxoplasma infection and the duration of anti-Toxoplasma
      specific IgM antibodies in infants' sera. MATERIALS AND METHODS: All neonates
      born in the maternity wards of the University Hospital of Gynaecology and
      Obstetrics in Poznan and in 10 selected obstetrics wards in the district
      hospitals were included. Blood samples were collected on filter paper cards,
      between the first and sixth day of life, screened for anti-Toxoplasma-specific
      IgM antibodies by an immunocapture enzyme-linked immunosorbent assay and if
      positive further analyzed for specific IgG and IgA antibodies. RESULTS: Between
      June, 1996, and October, 1998, filter paper samples from 27,516 liveborn infants
      were tested, which constituted approximately 75% of all births and 83% of
      liveborn neonates from the Poznan region. Anti-T. gondii-specific IgM antibodies
      were found in 13 newborns, equivalent to a prevalence of Toxoplasma-specific IgM
      in newborns of 1 per 2,117 liveborn children (0.47 per 1,000) or 1 per 870
      children (1.15 per 1,000) born to seronegative women at risk of primary T. gondii
      infection during pregnancy. We identified two congenitally infected infants who
      were IgM-negative at birth, had a classic triad of clinical symptoms during the
      first year of life and had high levels of specific IgG. The birth prevalence of
      congenital toxoplasmosis in the Poznan region was at least 1 per 1,834 live
      births (0.55 per 1,000) or 1 per 754 live neonates born to seronegative women
      (1.33 per 1,000). The sensitivity of the IgM assay on eluate from filter paper
      was not more than 86.7%, and the mean duration of IgM detectable by enzyme-linked
      immunosorbent assay in serum samples was the first 4.8 weeks of life. CONCLUSION:
      In Poland the screening for congenital toxoplasmosis detecting one case per each
      2,000 live births could be considered for inclusion in existing national neonatal
      screening programs for phenylketonuria and congenital hypothyroidism.

PMID- 10643848
TI  - Expression of virulence factors among Escherichia coli isolated from the
      periurethra and urine of children with neurogenic bladder on intermittent
      catheterization.
AB  - BACKGROUND: Patients with neurogenic bladder caused by spinal cord injury or
      myelomeningocele empty their bladder several times a day by intermittent
      catheterization. Bacteriuria without symptoms of infection is frequently present
      in these patients. Occasionally a clone of Escherichia coli that has been carried
      for weeks without symptoms causes a symptomatic urinary tract infection.
      Virulence factors are commonly expressed among E. coli causing infection in
      patients with normal urinary tracts. However, it is unknown whether expression of
      virulence factors by an E. coli clone colonizing the neurogenic bladder increases
      the risk of subsequent infection. In this study we examined the prevalence of
      virulence factor expression among E. coli isolated from the periurethra and urine
      of patients with neurogenic bladder. METHODS: The prevalence of virulence factors
      was examined among E. coli isolated from the periurethra and urine in patients
      with neurogenic bladder who received intermittent catheterization and were
      followed for 6 months. Representative isolates from the 37 clonal types of E.
      coli detected in the periurethra and urine of children with neurogenic bladder
      were assessed for O antigen, hemolysin, aerobactin, serum resistance and type I
      and P-adhesin. RESULTS: All clones were serum-resistant and expressed type I
      adhesin, none expressed aerobactin and two expressed hemolysin. The presence of P
      adhesin was not unique to clones associated with symptomatic infection. The
      presence of P-adhesin carried for weeks in a clone did not predict subsequent
      infection in the neurogenic bladder. CONCLUSION: Bacterial virulence factors did
      not predict infection of the neurogenic bladder.

PMID- 10643849
TI  - Impact of azithromycin on oropharyngeal carriage of group A Streptococcus and
      nasopharyngeal carriage of macrolide-resistant Streptococcus pneumoniae.
AB  - BACKGROUND: Invasive group A streptococcal (GAS) infections are a cause of
      serious morbidity and high mortality. There is a need for a simple, effective
      antimicrobial regimen that could be used to prevent invasive GAS disease in high
      risk situations. To assess azithromycin as a chemoprophylactic agent, we
      evaluated its efficacy for eradication of oropharyngeal (OP) GAS and its impact
      on the nasopharyngeal (NP) colonization rate of macrolide-resistant Streptococcus
      pneumoniae. METHODS: We obtained OP and NP swabs for GAS and pneumococcus
      culture, respectively, from 300 schoolmates of a child with an invasive GAS
      infection. GAS culture-positive students were treated with daily azithromycin (12
      mg/kg/day) for 5 days. We obtained follow-up OP and NP swabs at 9 (Day 17) and 24
      (Day 32) days post-treatment from those students identified as GAS carriers on
      Day 0 and determined macrolide susceptibility of GAS and pneumococcal isolates.
      RESULTS: Of the 300 students swabbed 152 (50%) carried GAS in their oropharynx.
      On Day 17, efficacy of azithromycin for GAS eradication was 95% (140 of 147) for
      all students. NP colonization rates for pneumococci decreased from 46% (67 of
      146) to 12% (17 of 144; P < 0.001) by Day 17 and to 20% (27 of 137; P < 0.001) by
      Day 32. The prevalence of erythromycin-resistant pneumococcal isolates increased
      from 2% (3 of 146) to 4% (6 of 144) by Day 17 and to 8% (11 of 137; P = 0.04) by
      Day 32. CONCLUSIONS: Azithromycin is an effective short course regimen for
      eradication of oropharyngeal GAS. However, azithromycin selected for macrolide
      resistant strains of pneumococci. These findings highlight the importance of
      determining the appropriate circumstances for antimicrobial prophylaxis to
      prevent invasive GAS infections.

PMID- 10643850
TI  - Comparison of ritonavir plus saquinavir- and nelfinavir plus saquinavir
      containing regimens as salvage therapy in children with human immunodeficiency
      type 1 infection.
AB  - BACKGROUND: In this retrospective study we compared the antiretroviral effect of
      regimens consisting of simultaneous administration of two protease inhibitors
      (PI) with at least one nucleoside reverse transcriptase inhibitor on plasma viral
      load (VL) and CD4 cell count in HIV-infected children intensively pretreated with
      nucleoside reverse transcriptase inhibitors and PIs. METHODS: Eleven HIV-infected
      children were changed to antiretroviral combination regimens including two PIs
      and followed for a median time of 24 weeks. Group A comprised six patients who
      were given ritonavir + saquinavir (SQV) and Group B consists of five patients who
      were changed to nelfinavir + SQV. Patients were treated with these combinations
      with 2 PIs because of treatment failure (increasing viral load) of prior PI
      therapy or clinical signs of disease progression. OUTCOME MEASURES: Serial
      determinations of plasma viral load (Amplicor, Roche) and CD4 cells were
      performed every 4 to 8 weeks. The detection limit of the Amplicor-reverse
      transcriptase-PCR assay was 50 copies/ml (1.7 log10). RESULTS: In Group A the
      median VL reduction was 1.1 log10 after 3 months and 1.4 log10 after 6 months. In
      Group B median VL decreased 0.1 and 0.2 log10 after 3 and 6 months. In both
      groups during the study period none of the patients reached undetectable VL. The
      relative changes of CD4 cells above baseline in Group A showed a median increase
      of 7% after 3 months and 23% after 6 months. In Group B after 3 months CD4 cells
      did not increase, and after 6 months the median relative increase was only 7%.
      Both combination therapies were well tolerated, not necessitating any drug
      interruption during study period. CONCLUSIONS: In children with intensive prior
      antiretroviral treatment, a salvage therapy including two PIs demonstrated
      antiretroviral efficacy in some patients. In this study the reduction of the VL
      as well as the increase of CD4 cells was more pronounced with ritonavir + SQV
      than with nelfinavir + SQV. With both combinations complete suppression of HIV
      replication was not achieved. Therefore the long term effect of these
      combinations may be limited by the emergence of resistant HIV strains.

PMID- 10643851
TI  - Comparison of standard and high dosage recombinant interferon alpha 2b for
      treatment of children with chronic hepatitis B infection.
AB  - BACKGROUND: Interferon is currently the most useful therapeutic agent for chronic
      viral hepatitis. The aim of this study was to compare the efficacy of standard
      and high dosages of interferon in children with chronic hepatitis B virus (HBV)
      infection. METHODS: Thirty children with chronic hepatitis B infection were
      randomly assigned to receive 5 million units/m2 body surface area (Group I) or 10
      million units/m2 body surface area (Group II) recombinant interferon alpha 2b
      three times weekly for 6 months. Patients were followed for at least 6 months
      (range, 6 to 18; median, 9 months) after the end of therapy, by physical and
      serologic examination every 3 months. RESULTS: Clearance of HBV DNA occurred in 4
      (27%) patients from Group I and 9 (60%) patients from Group II at the end of
      therapy. Hepatitis B e antigen (HbeAg) clearance was 7% (1 patient) and 53% (8
      patients) in the two groups, respectively (P < 0.05). HBV DNA was undetectable in
      40 and 60% of the children at the 12th month of randomization in Groups I and II,
      respectively. HBeAg/antibody to HBeAg seroconversion was found in 33% (5
      patients) who received standard dosage and 60% (9 patients) in the high dosage
      group. Sustained complete response (normal alanine aminotransferase, negative
      HBeAg and HBV DNA at 12th month) was obtained in 5 and 9 patients respectively
      from groups I and II (P > 0.05). Only mean baseline serum alanine amino
      transferase concentrations were predictive of response to interferon.
      CONCLUSIONS: A 6-month course of interferon alpha 2b in children with chronic HBV
      disease was well-tolerated by most patients. Sustained suppression of HBV was
      obtained in 60% of patients with high dosage interferon and in 33% of the
      patients receiving standard dosage. Although these results were not statistically
      significant, studies with more patients are needed to ascertain whether high
      dosage improves the response rate.

PMID- 10643852
TI  - Occurrence of nosocomial bloodstream infections in six neonatal intensive care
      units.
AB  - BACKGROUND: Nosocomial bloodstream infections (NBSIs) occur frequently in
      neonatal intensive care units (NICUs) and are associated with substantial
      morbidity and mortality. Little has been published regarding variation in NBSI
      among institutions. OBJECTIVE: To determine NBSI incidence among six NICUs and to
      explore how much variation is explained by patient characteristics and NICU
      practice patterns. METHODS: From October, 1994, to June, 1996, six regional NICUs
      prospectively abstracted clinical records of all neonates weighing <1,500 g.
      Occurrence of NBSI, defined as first positive culture occurring >48 h after
      admission, was analyzed in relation to baseline patient characteristics and
      several common therapeutic interventions. Variables significant in univariate
      analyses were analyzed by Cox proportional hazards regression. RESULTS: There
      were 258 NBSIs (incidence, 19.1%) among 1,354 inborn first admissions. Incidence
      varied significantly by site, from 8.5 to 42%. Birth weight, Broviac catheter use
      and parenteral nutrition were significantly associated with NBSI (P < 0.05). When
      controlling for these variables interinstitutional variation in NBSI occurrence
      decreased but remained significant. CONCLUSIONS: Neonatal NBSI incidence varies
      substantially among institutions despite adjustment for length of stay and some
      known risk factors. The uses of Broviac catheters and especially intravenous
      nutrition supplements were significant determinants of NBSI risk.

PMID- 10643853
TI  - Value of cerebrospinal fluid leukocyte aggregation in distinguishing the causes
      of meningitis in children.
AB  - BACKGROUND: Current laboratory tests often cannot distinguish between bacterial
      and aseptic meningitis rapidly and accurately. The ability to make a prompt
      diagnosis has important implications for the management and outcome of children
      with meningitis. The observation that leukocytes aggregate in the cerebrospinal
      fluid (CSF) has been previously reported, and it has been advocated as a reliable
      method to distinguish the causes of meningitis in children. OBJECTIVE: To
      investigate the utility of CSF leukocyte aggregation as a screening test to
      distinguish between bacterial and aseptic meningitis. METHODS: We compared the
      clinical and laboratory indices of 109 prospectively enrolled patients with
      meningitis (67 bacterial, 23 viral, 19 undefined etiology) and evaluated the
      validity of the CSF leukocyte aggregation test. The predefined leukocyte
      aggregation scores (LAS) were compared among the types of meningitis, and
      correlations with other markers of inflammation were calculated. RESULTS: The
      median LAS was significantly higher (P < 0.001) in the bacterial (32.1%; range, 0
      to 84.1%) than in the viral (0%; range, 0 to 16.6%) or undefined (0%; range, 0 to
      20.7%) groups. The optimal sensitivity of the leukocyte aggregation test, 98.5 to
      92.5%, was demonstrated with LAS values of 0 to 3%. The corresponding specificity
      was 64.3 to 88.1%. The peripheral white blood cell (WBC) count, serum C-reactive
      protein, CSF WBC count, blood culture, CSF Gram stain and CSF culture were
      inferior to the LAS as screening tests when compared individually. The LAS was as
      effective as CSF protein, TNF-alpha, IL-1-beta, IL-6 and IL-8 to predict
      bacterial meningitis. In a logistic regression model that included routine
      laboratory tests, the best predictor of bacterial meningitis was the LAS (odds
      ratio, 1.6 to 3.7). Significant correlations were demonstrated between the LAS
      and CSF protein, CSF WBC count, IL-1-beta, IL-6 and IL-8. Duration of symptoms
      before diagnosis, pretreatment with antibiotics, HIV-1 infection status and CSF
      red blood cell count did not significantly alter the LAS. CONCLUSIONS: There is
      no single test to diagnose the etiology of meningitis in children promptly and
      accurately. The finding of leukocyte aggregation in CSF might be of value as a
      sensitive adjunctive screening tool for the timely diagnosis of bacterial
      meningitis, recognizing that it has low specificity and potential practical
      limitations.

PMID- 10643854
TI  - Update on mycophenolate mofetil.

PMID- 10643855
TI  - Chlamydia pneumoniae and atherosclerosis: what we know and what we don't know.

PMID- 10643856
TI  - Severe La Crosse encephalitis with significant neurologic sequelae.
AB  - La Crosse encephalitis, a member of the California arbovirus group, is the most
      common cause of reported mosquito-borne illness in the United States.
      Approximately 70 cases of La Crosse encephalitis are reported each year. The
      principal vector is the mosquito Aedes triseriatus. During the summer the virus
      is amplified horizontally in a cycle among small mammals such as chipmunks and
      squirrels. Infected female A. triseriatus deposit eggs in the basal holes of
      hardwood trees, although man-made containers and old tires containing water also
      supply a suitable breeding site. Some of these eggs infected with La Crosse virus
      hatch the next spring and give rise to infected adult A. triseriatus, and the
      host-vector cycle is renewed. Only a minority of children infected with the virus
      become ill. Clinical disease caused by La Crosse is usually mild, and neurologic
      sequelae are relatively uncommon. In this report we describe six patients with
      severe La Crosse meningoencephalitis diagnosed within a 4-week period. All
      patients required intensive care management, and there was a high rate of
      neurologic sequelae, suggesting that La Crosse is not necessarily a benign
      meningoencephalitis.

PMID- 10643857
TI  - Fever, cough and rash in a twelve-year-old traveler.

PMID- 10643858
TI  - Serologic rebounds after one-year-long treatment for congenital toxoplasmosis.

PMID- 10643859
TI  - Severe hemolysis induced by ceftriaxone in a child with sickle-cell anemia.

PMID- 10643860
TI  - Isolated cutaneous cryptococcosis in an otherwise healthy girl.

PMID- 10643861
TI  - Bullous emphysema after Legionella pneumonia in a two-year-old child.

PMID- 10643862
TI  - Effects of gossypol on sperm viability and plasma sex steroid hormones in male
      sea lamprey, Petromyzon marinus.
AB  - Male sea lampreys Petromyzon marinus were injected with different doses of
      gossypol acetic acid in an attempt to sterilize them for use in a program for
      controlling the sea lampreys through the release of sterile males. Two lots of
      sea lamprey were used in these experiments. The first lot was divided into three
      groups and fish were injected intraperitoneally (i.p.) with 0.2 ml 50% ethanol as
      a control group or with gossypol suspended in ethanol at 100 and 200 mg/kg. The
      second lot was also divided into three groups and fish were either injected i.p.
      with vehicle as controls or gossypol at 25 and 50 mg/kg. Sperm weight,
      concentrations and motility were recorded after 31, 36 and 40 days or 24, 28 and
      33 days in lots 1 and 2, respectively. Blood was collected from the caudal vessel
      prior to injections with gossypol and after 40 or 33 days in lots 1 and 2,
      respectively. Plasma levels of estradiol-17beta (E2), testosterone (T),
      progesterone (P) and 17,20beta-dihydroxy-4-pregnen-3-one (17,20betaP) were
      measured by radioimmunoassay. At the end of the experiment, the testis were
      removed and fixed in Bouin's solution for histological examination. High
      mortality was observed at the day of injection in the group treated with 200
      mg/kg (84.6%), 100 mg/kg (41.7%), and 50 mg/kg (25%). Sperm concentrations were
      higher in control fish in comparison to most of the treated groups during the
      first sperm sampling (day 31 or 24), but then differences disappeared. At each
      sampling, sperm motility was higher in control groups than in treated groups and
      significant differences were observed (e.g. between control and 50 mg
      gossypol/kg). Fertility, evaluated at optimized sperm/egg ratio (5 x 10(4)
      sperm/egg) did not differ among treatments and controls. Changes in mean plasma
      sex steroid levels in the various treated groups were not significant, but a
      trend of decreasing plasma E2 was observed with increasing dose of gossypol. The
      structure of the testis was examined at the end of the experiment using light
      microscopy and appeared to be unchanged in gossypol-treated lampreys as compared
      to that of control animals. These findings suggest that gossypol injection into
      lamprey interferes with some of the reproductive parameters. Although high
      mortality rate precludes a single i.p. injection of gossypol as a favorable mode
      of chemosterilization in the lamprey, it would be useful to reassess the means of
      transfer of gossypol to reproductive tissues. This notion is further supported by
      the results of an in vitro sperm toxicity assay which revealed that gossypol, at
      a dose of 100 microM, has an antifertility action in this species.

PMID- 10643863
TI  - Regulatory science: a special update from the United States Food and Drug
      Administration: Preclinical issues and status of investigation of botanical drug
      products in the United States.
AB  - A recent survey was conducted across the therapeutic divisions within the CDER,
      U.S. FDA regarding the number of submissions related to botanical drug products
      over the past ten years. The overall number of botanical submissions as expressed
      in the parenthesis are as follows: 1990 (1), 1991 (4), 1992 (4), 1993 (5), 1994
      (6), 1995 (5), 1996 (13), 1997 (16), 1998 (10). In the total of 64 counted, 50 of
      them are submitted in original IND and the rest (14) in pre-IND format. The
      therapeutic categories are focused on dermatological and topical (19), anti
      AIDS/antiviral (12), oncologic (13), neuropharmacologic (8), endocrine and
      metabolic (3), urologic (2), tobacco (2), and cardio-renal products (1). The
      regulatory actions taken on these submissions showed that 68% of them are
      evaluated as safe to proceed for the human trials, while the rest (32%) of
      submissions required agency's regulatory guidance. Among the submissions that
      required further guidance, 81% were deficient in preclinical
      pharmacology/toxicology information and the rest (19%) lacks information in other
      areas (chemistry, clinical protocols). Following agency's guidance, 93% of the
      submissions that were put on hold were allowed to proceed. In summary, a total of
      94% of all the botanical INDs submitted to the agency were allowed to proceed
      without additional animal toxicity studies conducted. In conclusion, this survey
      indicates that the growing public interest in botanical supplements has prompted
      more formal evaluation of the efficacy/safety claims of these products.

PMID- 10643864
TI  - Structural improvement of higher education in environmental toxicology in Latin
      America and Europe.
AB  - Industrial development has resulted in an increased release of chemicals and
      other agents into the environment, resulting in damage to the environment as well
      as increasing the risk of adverse effects on human health. Environmental
      toxicology (ET) is the discipline responsible for assessing the risks to human
      health and the environment from the effects of new chemicals and those already
      present in the environment. The development of human resources in toxicology is
      therefore a priority in both Latin America (LA) and the European Union (EU),
      although LA professionals are more involved in risk evaluation than in risk
      assessment compared to their EU colleagues. A solid background in general
      toxicology will enable those interested in environmental issues to tackle local
      problems. Moreover, the increasing globalization of markets and, therefore, of
      the necessary regulations, requires harmonisation of postgraduate programmes to
      ensure that risk assessment and management related to the environment are dealt
      with uniformly and by highly qualified scientists. The Inaugural Meeting of the
      ALFA-OMET Toxicology', a 2-year programme supported by the European Commission,
      offered the opportunity to discuss a number of these issues. The present status
      of existing ET courses in the EU and LA and the corresponding professional
      profiles in the two regions were examined, and a harmonized academic curriculum
      for a postgraduate professional profiles in the two regions were examined, and a
      harmonized academic curriculum for a postgraduate course in environmental
      toxicology was developed. Finally, a course programme for toxicology and a
      specialization in environmental toxicology designed by a panel of experts was
      discussed, and its relevance as a model for other specialisation programmes was
      analysed. Exercises such as those performed by ALFA-OMET may be useful not only
      in promoting discussion for the implementation of national and international
      professional registers in LA, but also in encouraging the same, ongoing process
      in the EU.

PMID- 10643865
TI  - Ibuprofen-induced liver mitochondrial permeability transition.
AB  - This study examined the effect of the nonsteroidal anti-inflammatory drug
      ibuprofen on liver inner mitochondrial membrane permeability transition in the
      presence of Ca2+ and phosphate. Incubation of isolated liver mitochondria with
      ibuprofen (0.1-0.4 mM) induced inner mitochondrial membrane permeability as
      indicated by loss of inner mitochondrial membrane potential, swelling of matrix
      and loss of pre-accumulated Ca2+. The presence of cyclosporin A (1 microM) in the
      incubation medium preventing ibuprofen from causing loss of inner mitochondrial
      membrane potential, swelling and loss of pre-accumulated Ca2+. It is concluded
      that ibuprofen acted as an activator of Ca2+ and phosphate in promoting the
      opening of inner mitochondrial membrane pore.

PMID- 10643866
TI  - The nitroxide stable radical tempo prevents metal-induced inhibition of CYP1A1
      expression and induction.
AB  - Heavy metals are known to provoke oxidative stress in fish liver cells. Because
      H2O2, OH*- and intracellular superoxide are involved in this oxidation, we
      investigated the effect of nitroxide radical, 2,2,6,6-tetramethylpiperidinyl-N
      oxyl (abbreviated as TEMPO), a cell-permeable agent possessing antioxidant
      properties, on CYP1A expression in trout (Oncorhynchus mykiss) hepatocytes. 3
      methylcholanthrene (3-MC) induced the CYP1A-related EROD activity. This induction
      was inhibited by concomitant exposure to Cd (II), Cu (II), Pb (II) or Zn (II).
      CYP1A mRNA levels were also reduced. Simultaneous treatment with 3-MC, a heavy
      metal and TEMPO suppressed both the inhibition of EROD activity and the decrease
      of CYP1A mRNA expression. These results suggest a working hypothesis that heavy
      metals produce multiple oxidative effects, including generation of hydroxyl
      radicals, which could down-regulate CYP1A1 expression. This metal-induced
      inhibition was prevented by TEMPO, which might protect trout hepatocytes by
      scavenging free radicals and thus preventing their inhibitory effects on CYP1A
      induction and expression.

PMID- 10643867
TI  - Restorative effects of zinc and selenium on nitrergic relaxations impaired by
      cadmium in the mouse corpus cavernosum.
AB  - We investigated whether Cd2+ intake (in drinking water, 15 ppm) for 30 days can
      affect the nitrergic relaxations of the mouse corpus cavernosum (CC) and whether
      Zn2+ (25 mg kg(-1) via a stomach tube at 48-h intervals) or sodium selenate (8
      microg kg(-1) day(-1) intraperitoneally) has a restorative action on the
      impairment in the response. Relaxant responses of the CC obtained from Cd2+
      treated mice to electrical field stimulation (neurogenic) or acetylcholine
      (endothelium dependent) were significantly inhibited. A partial restoration was
      observed in the nitrergic relaxation of the CC obtained from Zn2+- or sodium
      selenate-co-treated animals. Neither agent exhibited any significant action on
      the responses of the tissue from control mice. There was no significant
      difference between Cd2+-treated and control mice in respect of the relaxation
      amplitude induced by sodium nitroprusside or papaverine. These results suggest
      that Cd2+ intake may impair the nitrergic relaxation of the mouse CC, and, co
      treatment with Zn2+ or sodium selenate may partially improve the nitrergic
      mechanisms in the tissue.

PMID- 10643868
TI  - Aluminum toxicity. Hematological effects.
AB  - Sequential effects of intoxication with aluminum hydroxide (Al) (80 mg/Kg body
      weight, i.p., three times a week), were studied on rats from weaning and up to 28
      weeks. The study was carried out on hematological and iron metabolism-related
      parameters on peripheral blood, at the end of the 1st, 2nd, 3rd, 4th, 5th and 6th
      months of exposure. As it was described that hematotoxic effects of Al are mainly
      seen together with high levels of uremia, renal function was measured at the same
      periods. The animals treated developed a microcytosis and was accompanied by a
      decrease in mean corpuscular hemoglobin (MCH). Significantly lower red blood cell
      counts (RBC million/microl) were found in rats treated during the 1st month.
      These values matched those obtained for control rats during the 2nd month. From
      the 3rd month onwards, a significant increase was observed as compared to control
      groups, and the following values were obtained by the 6th month: (T) 10.0 +/- 0.3
      versus (C) 8.7 +/- 0.2 (million/microl). Both MCH and mean corpuscular volume
      (MCV) were found to be significantly lower in groups treated from the 2nd month.
      At the end of the 6th month the following values were found: MCH (T) 13.3 +/- 0.1
      versus (C) 16.9 +/- 0.3 (pg); MCV (T) 42.1 +/- 0.7 versus (C) 51.8 +/- 0.9 (fl).
      Al was found responsible for lower serum iron concentration levels and in the
      percentage of transferrin saturation. Thus, although microcytic anemia
      constitutes an evidence of chronic aluminum exposure, prolonged exposure could
      lead to a recovery of hematocrit and hemoglobin concentration values with an
      increase in red cell number. Nevertheless, both microcytosis and the decrease of
      MCH would persist. These modifications took place without changes being observed
      in the renal function during the observation period.

PMID- 10643869
TI  - Effects of AFB1 on CYP 1A1, 1A2 and 3A6 mRNA, and P450 expression in primary
      culture of rabbit hepatocytes.
AB  - Although numerous studies report strong hepatic cytochrome P450 decrease during
      aflatoxicosis, the mechanisms involved in this decrease remain to be established.
      The purpose of this work is to investigate whether decreased CYP mRNA expression
      could explain decreased P450 expression and activity. Studies were conducted in
      primary cultures of rabbit hepatocytes exposed to 0.1 and 1 microM aflatoxin B1
      (AFB1) incubated in the culture medium for 72 h. In order to confirm the effects
      of the mycotoxin, 30 microM beta-naphthoflavone or rifampicin were used as
      respective inductors of P450 1A1 and 1A2 or 3A6. Dose-dependent decreases of CYP
      mRNA expression were observed in all AFB1-treated cells; however, these decreases
      were not specific. Moreover, P450 expression and activity are far less decreased
      by the AFB1 treatment than their corresponding mRNA. Taken together, these
      results suggest that the specific P450 decrease observed during aflatoxicosis was
      not the consequence of a specific decrease of their mRNA expression.

PMID- 10643870
TI  - Lipoxygenase-mediated biotransformation of p-aminophenol in the presence of
      glutathione: possible conjugate formation.
AB  - This study tested a hypothesis that soybean lipoxygenase (SLO), a model enzyme,
      may be capable of generating a glutathione (GSH) conjugate(s) from p-aminophenol
      (PAP). Horseradish peroxidase was employed as a positive control. GSH depletion
      or an increase in the absorption at 327 nm with time due to GS-PAP formation was
      used to quantitate the reaction. The rate of GS-PAP formation was dependent on
      the incubation time and the amount of SLO and exhibited Km values of 0.44 and
      0.71 mM for PAP and H2O2, respectively. Classical inhibitors of lipoxygenase and
      free radical scavengers markedly decreased the rate of GS-PAP formation in a
      concentration-dependent manner. PAP-dependent GSH depletion from the reaction
      medium occurred at a rate of 2.37 +/- 0.18 micromol/min/mg protein. Collectively,
      the results suggest that lipoxygenase pathway may be involved in the enzymatic
      formation of GSH conjugate(s) from PAP.

PMID- 10643871
TI  - Activation of telomerase by silica in rat lung.
AB  - By measuring the activity of telomerase in a silica-instilled rat lung, the study
      found a significant increase in telomerase activity compared to that of the
      control. Pneumoconiosis displays the characteristics of fibroblast-proliferation
      and accumulation of collagen, which finally causes the pathologic changes of
      irreversible and progressive fibrosis of the lung. On the basis of the hypothesis
      that cellular proliferation may trigger telomerase-activity, the experiment was
      carried out with telomerase-activation in silicosis. Silica-instilled rat lungs
      showed increased activity of telomerase, which was measured by TRAP (telomeric
      repeat amplification protocol) assay, at the time of the 1st, 5th and 8th week
      after intratracheal instillation of silica in vivo. However, no activity was
      shown in silica-co-cultured fibroblast in vitro. By summarizing these results,
      the activity of telomerase is thought to be a very sensitive marker for the
      evaluation of pathogenicity, showing cellular immortalization in an experimental
      silicosis model.

PMID- 10643872
TI  - Critical period for adverse effects on development of reproductive system in male
      offspring of rats given di-n-butyl phthalate during late pregnancy.
AB  - The objective of this study was to determine the susceptible days for the adverse
      effects of di-n-butyl phthalate (DBP) on development of reproductive system in
      male offspring following maternal administration on successive 3-day period
      during late pregnancy. Pregnant rats were given DBP by gastric intubation at 1000
      or 1500 mg/kg on days 12-14 or 18-20 of pregnancy or at 500, 1000 or 1500 mg/kg
      on days 15-17 of pregnancy. A significant decrease in the maternal body weight
      gain and/or food consumption was found in the DBP-treated groups regardless of
      the days on which DBP at 1000 and 1500 mg/kg was given. A significant increase in
      the number of resorptions per litter was found in the groups given DBP at 1500
      mg/kg on days 12-14 and 15-17 of pregnancy. The weights of male and female
      fetuses were significantly decreased in the groups given DBP at 1000 and 1500
      mg/kg on days 12-14 and 18-20 and at 1500 mg/kg on days 15-17. A significant
      increase in the incidence of fetuses with undescended testes was found at 1500
      mg/kg on days 12-14 and at all doses on days 15-17. A significant decrease in the
      anogenital distance (AGD) of male fetuses was observed in the groups treated with
      DBP regardless of the days of treatment. The AGD/body weight ratio in male
      fetuses was significantly reduced in the groups given DBP on days 15-17, but
      neither on days 12-14 nor 18-20. The AGD of female fetuses in the DBP-treated
      groups was comparable to that in the control group. It was concluded that period
      of days 15-17 of pregnancy was the most susceptible for DBP-induced undescended
      testes and decreased AGD in male offspring.

PMID- 10643873
TI  - Hypothalamo-pituitary-adrenal cortical responses to low-dose physostigmine and
      arginine vasopressin administration: sex differences between major depressives
      and matched control subjects.
AB  - Of heuristic value in understanding the neurochemistry of major depression is
      whether the hypothalamo-pituitary-adrenocortical (HPA) axis hyperactivity that
      occurs in this illness can be related to putative neurotransmitter
      dysfunction(s). Cholinergic neurotransmission stimulates hypothalamic
      corticotropin releasing hormone (CRH) and arginine vasopressin (AVP) secretion,
      both of which stimulate pituitary corticotropin (ACTH) secretion, but whether the
      HPA axis in humans is activated only by doses of cholinergic agonists that
      produce noxious side effects remains controversial. To test the hypothesis of
      increased cholinergic sensitivity in major depression, physostigmine (PHYSO), a
      reversible cholinesterase inhibitor, was administered to patients and control
      subjects at a dose that elevated plasma ACTH, cortisol, and AVP concentrations
      but produced few or no side effects. Exogenous AVP also was administered to
      determine if it would augment the effect of low-dose PHYSO on the HPA axis.
      Twelve premenopausal or estrogen-replaced female major depressives, 12
      individually matched female control subjects, eight male major depressives, and
      eight matched male control subjects underwent four test sessions 5-7 days apart:
      PHYSO (8 microg/kg IV), AVP (0.08 U/kg IM), PHYSO + AVP, and saline control.
      Serial blood samples were taken before and after pharmacologic challenge and
      analyzed for ACTH1-39, cortisol, and AVP. Estradiol and testosterone were also
      measured at each test session. PHYSO (8 microg/kg) significantly increased plasma
      ACTH, cortisol, and AVP, while producing no side effects in approximately half
      the subjects and predominantly mild side effects in the other half. These hormone
      increases following PHYSO occurred primarily in the female depressives and the
      male control subjects and were not significantly related to the presence or
      absence of side effects. The greater the ACTH and AVP responses to PHYSO, the
      stronger their correlation, suggesting that AVP may have been acting as a
      secretagogue for ACTH. Administered AVP significantly increased the secretion of
      ACTH in the patients and control subjects to a similar degree, and AVP given
      after PHYSO did not augment the HPA axis response to a greater degree in the
      depressives than in the control subjects. Plasma estradiol and testosterone were
      within the normal range for all four groups of subjects and were not
      significantly related to their HPA axis hormone responses. The study results
      support the hypothesis of heightened cholinergic sensitivity in premenopausal
      female, but not in male, patients with major depression. The low dose of PHYSO
      used may represent a useful paradigm for central cholinergic stimulation of the
      HPA axis.

PMID- 10643874
TI  - Plasma levels of tumor necrosis factor-alpha in patients with panic disorder:
      effect of alprazolam therapy.
AB  - Plasma concentrations of tumor necrosis factor-alpha (TNF-alpha) were measured in
      10 outpatients with panic disorder, twice (at a 48-h interval) before and twice
      on days 30-32 of treatment with alprazolam (2-2.5 mg/day), and twice in 10 age-
      and sex-matched healthy controls. TNF-alpha concentrations did not differ in
      patients and control subjects, either before therapy or at days 30-32 of therapy.
      In five patients before therapy, and in three of them after therapy, TNF-alpha
      values were higher than the maximal concentrations of the cytokine in controls.

PMID- 10643875
TI  - Relationship between serotonin and the temperament and character inventory.
AB  - The unified biosocial theory of personality, proposed by Cloninger,
      conceptualises personality as a combination of heritable, neurobiologically based
      traits (temperament dimensions), and traits reflecting sociocultural learning
      (character dimensions). The temperament dimensions are thought to be related to
      activity in specific central neurotransmitter systems. The relationship of the
      dimensions of the Temperament and Character Inventory, particularly harm
      avoidance (HA), and platelet 5-HT2 receptor sensitivity was investigated in a
      sample of undergraduate student volunteers (N = 49). Serotonin-receptor binding
      results in Ca2+ release from intracellular stores. The concentration of serotonin
      required to produce half maximal Ca2+ response (EC50) is indicative of 5-HT2
      receptor sensitivity such that the lower the EC50 serotonin concentration, the
      greater the 5-HT2 receptor sensitivity. A significant inverse correlation was
      found between HA and EC50 (r = -0.644, P < 0.001). Self-directedness was also
      significantly correlated with EC50 (r = 0.391, P = 0.005). Novelty seeking, a
      personality trait similar to sensation seeking, was not significantly correlated
      with serotonin.

PMID- 10643876
TI  - Psychiatric diagnoses in Gulf War veterans with fatiguing illness.
AB  - The purpose of this study was to determine whether Gulf War Illness (GWI) can be
      explained by the presence of psychiatric disorders as assessed by DSM-III-R. To
      reduce the heterogeneity amongst Persian Gulf War veterans with GWI (PGV-F), only
      those were studied who presented with severe fatigue as a major complaint and
      also fulfilled clinical case definitions for Chronic Fatigue Syndrome, Idiopathic
      Chronic Fatigue, and/or Multiple Chemical Sensitivity. A total of 95 Registry
      PGVs were examined; 53 presented with GWI and 42 did not report any post-war
      health problems (PGV-H). All subjects were assessed for the presence of DSM-III-R
      Axis I psychiatric disorders. Compared to PGV-Hs, 49% of PGV-Fs had similar post
      war psychiatric profiles: either no, or only one, psychiatric disorder was
      diagnosed. Psychiatric profiles of the remaining 51% of PGV-Fs were significantly
      different from PGV-Hs in that most of these veterans suffered from multiple post
      war psychiatric diagnoses. The presence of psychiatric disorders as assessed by
      DSM-III-R criteria cannot explain symptoms of Gulf War Illness among all Persian
      Gulf veterans with severe fatiguing illness.

PMID- 10643877
TI  - Recent life events and obsessive-compulsive disorder (OCD): the role of
      pregnancy/delivery.
AB  - Conflicting results have been reported on the possible role of life events in
      triggering OCD onset. Moreover, pregnancy and/or delivery, among life events,
      appear to influence the OCD course and, in some cases, appear related to its
      onset. Our purpose was to assess the occurrence of potentially traumatizing
      events among patients with OCD. The study also provides an initial exploration of
      the association between OCD and pregnancy or delivery. The number and type of
      stressful life events which occurred in the 12 months before the onset of OCD
      were determined for both OCD patients (N = 68, 33 women and 35 men) and a group
      of comparison subjects (N = 68, 33 women and 35 men) by using a semistructured
      interview in accordance with Paykel's list. The results did not show a
      significant excess of life events in patients compared with healthy subjects. No
      differences were detected between OCD patients according to gender. When
      examining the type of events, OCD female individuals were found to be more likely
      than normal female subjects to report exposure to postpartum events, and high
      rates of obstetric complications were observed in these patients. Subjects with
      postpartum OCD had significantly higher rates of aggressive obsessions to harm
      the newborn. OCD male subjects did not show an association between a specific
      event and onset of the disorder. The findings confirm that the postpartum period
      represents a risk factor for OCD in some individuals, and suggest that obstetric
      complications may be relevant to the development of the disorder.

PMID- 10643878
TI  - Relevance of sequential development of dermatoglyphics to schizophrenia.
AB  - Since the embryogeneses of epidermal ridges of hands and feet are reported to be
      identical, although those of the feet develop two or three weeks later, a
      tendency for symmetry or correspondence between each side finger and toe pairs
      could be envisaged. Any prenatal insult could disturb such developmental
      mechanisms, causing the lowering of either finger or toe ridge counts which might
      result in augmentation of differences between them. To test this hypothesis, the
      differences between each side thumb and big toe ridge counts of 89 schizophrenic
      patients and 65 control subjects were assessed. These samples were also
      subgrouped into those with and without identical pattern distributions on each
      side of their thumb and big toe pairs. Female schizophrenics who displayed
      identical patterns manifested significantly greater differences between their
      right thumb and big toe ridge counts in comparison to the control subjects (P =
      0.0142). To elucidate the contributory digit for such a greater difference, the
      ridge counts of the right thumbs and big toes of the female patients were
      compared with the corresponding counts of the control subjects. The mean ridge
      count of the big toes was lesser in the patient group compared with that in the
      control subjects, a difference, however, that did not attain statistical
      significance.

PMID- 10643879
TI  - Magnetic resonance imaging of the pediatric head and neck.
AB  - Although the bulk of pediatric head and neck lesions are adequately evaluated by
      computed tomography (CT) alone, magnetic resonance imaging (MRI) provides
      valuable additional information in those lesions that are difficult to resolve on
      CT, and it is almost essential for assessment of possible intracranial extension
      of disease. The ability of MRI to show intrinsic characteristics of mass lesions
      can help direct therapeutic decisions. It should be utilized early in the imaging
      evaluation of most vascular lesions, including juvenile nasal angiofibroma and
      vascular malformations, in suspected neurogenic tumors, and as an adjunct in
      those cases where CT does not adequately demonstrate the extent or true nature of
      a lesion.

PMID- 10643880
TI  - Sarcomas of the head and neck.
AB  - Sarcomas are rare malignancies of mesenchymal origin. Computed tomographic and
      magnetic resonance imaging characteristics, as well as histologic findings and
      epidemiology, of sarcomas of the head and neck are reviewed. The sarcomas
      discussed include rhabdomyosarcoma, fibrosarcoma, osteosarcoma, chondrosarcoma,
      malignant fibrous histiocytoma, leiomyosarcoma, alveolar soft part sarcoma,
      Ewing's sarcoma, and synovial sarcoma. The imaging findings of these entities
      frequently are nonspecific. Imaging, particularly magnetic resonance imaging, has
      a major role in defining the extent of these tumors. This is important because
      complete surgical excision is the preferred method of treatment. Imaging also is
      useful in planning radiation therapy and determining prognosis.

PMID- 10643881
TI  - Advanced concepts in the imaging of perineural spread of tumor to the trigeminal
      nerve.
AB  - Perineural spread of head and neck tumor represents extension of the primary
      tumor along the perineurium. Diagnosis of perineural spread of carcinoma often is
      delayed unless the clinician maintains a high index of suspicion. It may be
      insidious, and patients may be asymptomatic for years. Perineural spread of
      carcinoma has been associated with a poor prognosis; however, it is becoming
      increasingly realized that cure is possible in some cases, if the full extent of
      the disease is known and treated. Magnetic resonance imaging (MRI) can detect
      perineural spread of head and neck carcinoma and define its extent. MRI is the
      imaging modality of choice to assess perineural disease due to its superior
      tissue contrast and multiplanar capability. Perineural spread of head and neck
      carcinomas most commonly involves the trigeminal nerve. Obliteration of the fat
      within (a) the superior medial orbital (ophthalmic division territory), (b) the
      periantral fat plane (maxillary division distribution), and (c) the
      pterygopalatine fossa all are useful indicators of distal perineural disease. A
      perineural vascular plexus (PNVP) surrounds the trigeminal ganglion and proximal
      portions of the trigeminal nerve divisions. The trigeminal ganglion and proximal
      portions of its divisions usually are seen as discrete nonenhancing structures
      separate from the PNVP. Occasionally, isolated enhancement of the ganglion and
      the proximal portions of the maxillary and mandibular divisions as they exit the
      skull base may be seen. This may be an artifact related to head position or may
      represent avid enhancement of the PNVP. In these situations, evaluating all
      branches, and the entire course, of the trigeminal nerve for perineural spread
      can aid in determining whether the apparent enhancement is an isolated normal
      variant or represents nerve pathology such as perineural spread.

PMID- 10643882
TI  - Magnetic resonance imaging in ocular pathology.
AB  - MRI has become a major diagnostic tool in ophthalmology for evaluation of ocular
      pathology. There is excellent delineation of anatomy of the ocular globe with
      MRI, and specific characteristics of derangement of anatomy by pathological
      processes are well delineated by MRI. Optimum MRI technique for evaluation of
      ocular pathology were discussed. Various entities of the ocular globe where MRI
      is useful in the detection and estimation of the extent of the pathological
      process and their specific MRI characteristics were discussed, including
      retinoblastoma, ROP, PHPV, uveal melanoma, choroidal hemangioma, and simulating
      lesions.

PMID- 10643883
TI  - Targeting neurokinin-1 receptor-expressing neurons with [Sar9,Met(O2)11 substance
      P-saporin.
AB  - Neurons expressing neurokinin-1 receptors (NK-1R) are selectively destroyed by
      substance P (SP) coupled to the ribosome inactivating protein, saporin. SP
      saporin produces incomplete lesions of striatal NK-1R-expressing neurons even at
      doses that produce non-specific damage. In the present study, we sought to
      determine if the more stable, NK-1R-specific SP analog conjugated to saporin,
      [Sar9,Met(O2)11]-SP (SSP-saporin), would selectively destroy cells expressing NK
      1R, in vitro and in vivo. The results show that SSP-saporin is highly effective
      and selective, producing extensive ablation of striatal NK-1R expressing
      interneurons at doses that do not cause loss of other striatal neurons suggesting
      advantages over SP-saporin as a selective lesioning agent. SSP-saporin will be
      useful in larger species and for intraparenchymal injections.

PMID- 10643884
TI  - Post-trial administration of H1 histamine receptor blocker improves appetitive
      reversal learning and memory in goldfish, Carassius auratus.
AB  - Based on the hypothesis that neuronal histamine exerts an inhibitory influence on
      learning and reinforcement, goldfish were tested for post-trial effects of the H1
      receptor blocker chlorpheniramine (CPA) on learning the location of a food source
      in one of two compartments, one black the other white, with a feeder located in
      each compartment. Testing was carried out over 6 days. On the training day a food
      pellet was placed into the feeder of one of the compartments. After consumption
      of the food the fish were injected i.p. with either vehicle or CPA either
      immediately after training or 3 h later. Twenty-four-hours later, food was placed
      in the same compartment and the time to begin feeding was recorded. On the next
      day the location of the food pellet was reversed, and testing was continued for 4
      days. On the first test day the time to begin feeding was significantly longer
      for the vehicle injected fish as compared with those injected with CPA. The
      vehicle group also took longer to begin feeding than the CPA group on the first
      reversal test day. The results of the 3-h delay groups indicated no significant
      differences between vehicle and drug for any experimental session. These results
      suggest that post-trial blockade of the H1 histamine receptor can affect
      appetitive learning in goldfish either by improving long-term memory
      consolidation and/or by the additive reinforcing effects of CPA (known from
      previous studies) on behavior.

PMID- 10643885
TI  - Polyglutamine repeat length influences human androgen receptor/c-Jun mediated
      transcription.
AB  - The androgen receptor and c-Jun are known to interact to modulate each others
      transcriptional activities. The androgen receptor contains a polymorphic
      polyglutamine repeat and expansion of this repeat to beyond approximately 40
      causes spinobulbar muscular atrophy (SBMA; also known as Kennedy's disease), a
      genetic form of motor neurone disease. Here we show that the size of this
      polyglutamine tract influences both c-Jun regulation of androgen receptor
      mediated transcription and androgen receptor regulation of c-Jun activity. c-Jun
      is a key mediator of neuronal survival and death by apoptosis. Inappropriate
      interactions between c-Jun and androgen receptors containing pathological length
      glutamine repeats may therefore be part of the pathogenic process in SBMA.

PMID- 10643886
TI  - Strain difference in amiloride-sensitivity of salt-induced responses in mouse non
      dissociated taste cells.
AB  - The chorda tympani nerve responses to NaCl in a mouse strain, C57BL/6 are known
      to be much more sensitive than those in BALB/c. We compared the NaCl-induced
      responses obtained from taste cells of the fungiform papillae in these two
      strains of mice. Amiloride inhibited, in the same degree, the responses induced
      by a bath-application of normal extracellular solution (NES) containing 140 mM
      NaCl in either taste cells of C57BL/6 and BALB/c mice. In contrast, amiloride
      inhibited 62% of responses induced by an apically applied 0.5 M NaCl in the
      C57BL/6 strain, but only 33% of responses in the BALB/c strain. These results
      suggest that the difference in amiloride-sensitivity between taste cells in both
      strains mainly derives from the difference in density of functional amiloride
      sensitive Na+ channels at the apical receptive membrane but not at the
      basolateral membrane.

PMID- 10643887
TI  - Insulin-like growth factor-1 affects expressions of cyclin-dependent kinase 5 and
      its activator p35 in reperfused rat brain.
AB  - Insulin-like growth factor-1 (IGF-1) was applied topically on the brain surface
      of reperfused rat brain after 60 min of transient middle cerebral artery (MCA)
      occlusion. In contrast to the cases treated with vehicle, the infarct volume was
      greatly reduced at 24 h of reperfusion by the treatment with IGF-1.
      Immunohistochemical analysis in the MCA territory showed that the increase of
      cyclin-dependent kinase 5 (cdk5) was greatly reduced, and that the decrease of
      the critical regulatory subunit of cdk5, p35, was preserved with treatment of IGF
      1. The present results suggest that IGF-1 has a significant effect on
      ameliorating brain injury after transient focal brain ischemia with affecting the
      expressions of cdk5 and its activator p35.

PMID- 10643888
TI  - Cerebrospinal fluid tau protein shows a better discrimination in young old (<70
      years) than in old old patients with Alzheimer's disease compared with controls.
AB  - Tau protein is consistently reported to be elevated in cerebrospinal fluid (CSF)
      of patients with Alzheimer's disease (AD). CSF tau alone, however, is not a
      clinically useful diagnostic marker due to its relatively low diagnostic
      specificity. Therefore, efforts are under way to combine tau measurements with
      other criteria in order to improve diagnostic applicability. We investigated
      whether age could serve as an useful criterion to increase diagnostic accuracy.
      CSF levels of tau were measured in young old (<70 years) and old old (> or =70
      years) patients with probable AD, elderly patients with major depression (MD),
      and age-matched healthy controls (HC). In AD patients, CSF tau levels were
      significantly elevated compared with MD patients and HC (P < 0.001). Based on a
      previously established cut-off of 260 pg/ml, the discriminative power was higher
      in the young old than in the old old subjects. Similarly, receiver operating
      characteristics analysis revealed a statistically significant higher correct
      classification rate in the young old. Our findings indicate that the
      discriminative power of CSF tau is higher in the young than in the old old. We
      suggest that the effect of age should be considered in studies investigating CSF
      tau as a diagnostic marker for neurodegenerative disorders.

PMID- 10643889
TI  - Somatotopic mapping of the human primary somatosensory cortex by fully automated
      tactile stimulation using functional magnetic resonance imaging.
AB  - The clinical application of functional magnetic resonance imaging (fMRI) requires
      time-saving protocols insensitive to artifacts that provide robust localization
      and important information on brain function. A fully automated, pneumatically
      driven tactile stimulation is presented, that reproducibly localizes postcentral
      lip, finger and toe representations in contralateral primary somatosensory cortex
      (SI) with mean correlation coefficients (cc) and relative BOLD signal changes
      (dS) of cc approximately 0.59, dS approximately 1.95% (fingers); cc approximately
      0.52, dS approximately 1.35% (lips); cc approximately 0.47, dS approximately
      1.42% (toes). Bilateral somatotopic mapping requires 21 min of scanning time and
      has become a clinical routine fMRI application in patients with perirolandic
      tumors. Normative data may also be useful in monitoring cerebral plasticity and
      reorganization, e.g. in sensorimotor recovery after cerebral ischemia or in
      understanding mechanisms of supraspinal pain processing.

PMID- 10643890
TI  - Tau gene polymorphisms and apolipoprotein E epsilon4 may interact to increase
      risk for Alzheimer's disease.
AB  - In an effort to analyze the genetic role of tau in Alzheimer's disease (AD), 17
      polymorphisms were identified. Eleven of these polymorphisms were in complete
      linkage disequilibrium and segregated as two haplotypes, A and B. The A and B
      haplotypes were investigated in 269 AD cases and 238 controls from two different
      sources, a clinic-based group (mean age of onset 65+/-9 years), and a population
      based group (mean age of onset 80+/-5 years). A synergistic effect between the
      common tau genotype AA and apolipoprotein E (APOE epsilon4) was found in the
      clinic-based AD group. Our study suggests that the common tau genotype AA may
      interact with APOE epsilon4 in increasing the risk of AD in a subgroup of the AD
      population.

PMID- 10643891
TI  - Inhibition of prolylendopeptidase does not affect gamma-secretase processing of
      amyloid precursor protein in a human neuroblastoma cell line.
AB  - Abeta peptides are major components of the amyloid plaques that characterize
      Alzheimer's disease. The enzyme activities (beta- and gamma-secretases) involved
      in generating Abeta from amyloid precursor protein (APP) are unidentified. It has
      been suggested that prolylendopeptidase (PEP), an oligopeptidase that normally
      cleaves after proline residues, could also cleave after the alanine at position
      42 of Abeta to generate Abeta42. We investigated whether inhibition of PEP
      activity in human neuroblastoma cells affected Abeta levels in cell culture
      media. An SH-SY5Y cell line expressing SPA4CT, encoding the C-terminal 100
      residues of APP and the signal sequence, was used. Only gamma-secretase activity
      is required for Abeta production in this cell line. The PEP inhibitor Fmoc-AlaPro
      CN (10 microM) reduced PEP activity in these cells by approximately 95% in the
      absence of significant toxicity, but had no effect on Abeta40 or Abeta42 levels
      in cell culture media. We conclude that PEP is unlikely to be involved in gamma
      secretase processing of APP.

PMID- 10643892
TI  - A marker for differentiation of capabilities for processing of musical harmonies
      as detected by magnetoencephalography in musicians.
AB  - This investigation was designed to study the characteristics of a marker for
      harmonic processing and to test whether it could be used for differentiating
      harmonic processing capabilities. The first three chords of an ordinary musical
      cadenca were presented to the left ear to establish a harmonic context followed
      by a harmonic or non-harmonic target tone. Cadencas were presented rapidly and
      randomly in different keys to render the task difficult. Results showed a
      specific P3m (magnetic P300) effect to the non-harmonic targets which was only
      visible in subjects with low target recognition errors. Low resolution electro
      magnetic tomography current density maps showed P3m sources in the right
      temporoparietal, left temporoparietal and frontocentral brain areas with right
      temporoparietal sources being strongest and most reliable. The results offer new
      possibilities to selectively study harmonic variables in music processing.

PMID- 10643893
TI  - Effects of kinematics constraints on hand trajectory during whole-body lifting
      tasks.
AB  - Trajectories of the hands and whole-body center of mass were studied during whole
      body lifting tasks. The movements of different parts of the body were monitored
      with the ELITE system. Subjects were instructed to lift to shoulder height an
      object placed at one of two distances (5-45 cm) before them on the floor. The
      lifts were performed both with and without kinematics constraints (i.e. to
      produce a straight hand trajectory while lifting, and to lift without any
      instructions, respectively). Hand trajectories were roughly straight when
      performed under the constrained condition, but curved when performed without
      instruction. Hand velocity curves showed bell-shaped profiles. In both groups,
      body centers of mass (whole-body, upper and lower part) were calculated and their
      trajectories showed invariant sagittal displacements. These results support the
      idea that movement contributes to postural control and, reciprocally, that whole
      body center of mass is a robust and controlled variable which plays an important
      role in hand trajectory formation.

PMID- 10643894
TI  - Continuous blockade of brain mineralocorticoid receptors impairs spatial learning
      in rats.
AB  - Hippocampal mineralocorticoid receptors (MR) are proposed to mediate facilitation
      of cognition in the short-term. The acute central blockade of MR increases plasma
      corticosterone levels which itself can affect cognition thus complicating the
      interpretation of such studies. We therefore investigated the effects of chronic
      continuous central MR antagonism by spironolactone infused
      intracerebroventricularly (i.c.v.) (100 ng/h) via Alzet minipumps for 12 days.
      Rats given chronic i.c.v. infusion of spironolactone spent significantly less
      time (20% decrease, P < 0.05) within the platform quadrant during the watermaze
      probe test. Neither hippocampal MR nor glucocorticoid receptor mRNA expression
      were affected by spironolactone. Morning plasma corticosterone levels and adrenal
      and thymic weights were unchanged. Chronic central MR antagonism impairs spatial
      memory in the watermaze independent of changes in receptors or circulating
      glucocorticoid levels.

PMID- 10643895
TI  - Early regional cerebral glucose hypometabolism in transgenic mice overexpressing
      the V717F beta-amyloid precursor protein.
AB  - In the present study, we examined whether the relative levels of regional brain
      [14C]2-deoxyglucose (2-DG) uptake are altered in a transgenic mouse model of
      Alzheimer's disease which overexpresses a mutated form of the human beta-amyloid
      precursor protein (mutation V717F). We show that the relative levels of 2-DG
      uptake are significantly reduced in the septum, thalamus, dentate gyrus and
      parietal cortex of 3-month-old transgenic mice as compared with wild-type
      littermates. In 10-month-old transgenic mice, these alterations also extend to
      the CA3 hippocampal region, the cingulate, retrosplenial, occipital and temporal
      cortices, suggesting an age-dependent decrease in the regional 2-DG uptake. These
      results suggest that expression of a mutated APP gene induces an early regional
      cerebral hypometabolism independently of amyloid deposition per se.

PMID- 10643897
TI  - The surface density of glial fibrillary acidic protein immunopositive astrocytic
      processes in the rat supraoptic nucleus is reversibly altered by dehydration and
      rehydration.
AB  - Ultrastructural and immunohistochemical studies of the supraoptic nucleus (SON)
      have provided evidence that retraction and extension of astrocytic processes from
      between magnocellular neuroendocrine cells (MNCs) likely plays a role in the
      release of oxytocin, and/or vasopressin, that accompanies parturition, lactation
      and dehydration. The present study estimates the surface density (Sv) of glial
      fibrillary acidic protein (GFAP)-immunoreactivity, predominantly in astrocytic
      processes, in the SON of normally hydrated, dehydrated and rehydrated rats. The
      Sv of GFAP processes in dehydrated rats was significantly reduced compared with
      control levels. Rehydration returned Sv to control levels. The reversible
      reduction in Sv indicates that the previously observed reduction in optical
      density is due to a rearrangement of astrocyte processes in the SON which occurs
      at the same time as the selective functional activation of MNCs.

PMID- 10643896
TI  - Decreased frequency of apolipoprotein E epsilon4 allele from Northern to Southern
      Europe in Alzheimer's disease patients and centenarians.
AB  - Apolipoprotein E (apoE) polymorphism was studied in 79 sporadic late onset
      Alzheimer's disease (LOAD) patients, 125 unrelated caregivers or volunteers (19
      80 years), and 67 centenarians from Apulia, Southern Italy. The frequency of apoE
      epsilon2 allele was higher in centenarians than in LOAD patients, while epsilon4
      was lower. In middle-aged adults, the epsilon4 allele frequency was higher than
      in centenarians. The epsilon4 allele frequency was lower in healthy adults than
      in LOAD patients, while epsilon2 was higher. Compared with the allele frequencies
      of Northern and Central European countries, a geographic trend for epsilon3 and
      epsilon4 alleles in LOAD and middle-aged adults was observed. The frequency of
      epsilon3 increased from Northern to Southern Europe, while epsilon4 decreased
      significantly. In centenarians, epsilon2 showed a North-South increasing pattern,
      while epsilon4 was in opposite trend.

PMID- 10643898
TI  - Neuroprotective effects of an antioxidant in cortical cerebral ischemia:
      prevention of early reduction of the apurinic/apyrimidinic endonuclease DNA
      repair enzyme.
AB  - We examined the effects of the free radical scavenger, 21-aminosteroid, on
      apurinic/apyrimidinic endonuclease (APE/Ref-1) protein expression and subsequent
      infarction volume after photothrombotic cortical cerebral ischemia in mice.
      Immunohistochemistry and Western blot analysis showed a significant reduction in
      APE/Ref-1 expression 6 and 24 h after ischemia in untreated animals, whereas in
      drug-treated animals the reduction was much less at the same time points. The
      administration of 21-aminosteroid significantly decreased subsequent infarction
      volume 3 days after ischemia. These data suggest that 21-aminosteroid prevents
      the early decrease of APE/Ref-1 expression, thereby reducing cortical infarction
      after photothrombotic cerebral ischemia.

PMID- 10643899
TI  - Angiotensin-converting enzyme genotype is associated with Alzheimer disease in
      the Japanese population.
AB  - We compared the distribution of an insertion (I)/deletion (D) polymorphism of the
      gene coding for the angiotensin-converting enzyme (ACE) in 133 Japanese sporadic
      Alzheimer disease (AD) patients with 257 controls. The association between AD and
      ACE genotypes or alleles was found to be significant. The frequency of II
      genotypes was 1.4 times higher in AD than controls, while that of DD genotypes
      was only 0.4 times as high. The altered distribution of ACE alleles in patients
      with AD appeared to be independent of apolipoprotein E.

PMID- 10643900
TI  - Vasopressin selectively modulates the release of taurine within the septum of the
      rat brain.
AB  - Previous experiments have shown that arginine vasopressin (AVP) released within
      the septal brain area of adult male rats in response to defined stressor exposure
      is involved in emotionality-related behavior. We report here that a 10-min forced
      swimming session stimulated the release of glutamate, aspartate, arginine, gamma
      aminobutyric acid (GABA) and taurine but not alanine and serine in the medio
      lateral part of this brain structure. Local administration of the AVP V1 receptor
      antagonist d(CH2)5Tyr(Me)AVP by inverse microdialysis caused a significant
      increase in the concentration of taurine in microdialysates under resting
      conditions that was further potentiated during forced swimming. In contrast, the
      release of alanine, arginine, GABA and serine was unaffected by antagonist
      treatment. Taken together with previous data, our results suggest that the
      effects of intraseptally released AVP on stress-coping strategies might be
      mediated at least in part via its influence on the local release of taurine.

PMID- 10643901
TI  - A survey on canine leishmaniasis in western Turkey by parasite, DNA and antibody
      detection assays.
AB  - Human visceral leishmaniasis (VL) caused by Leishmania infantum is found
      throughout the Mediterranean Region, including Turkey, where dogs are considered
      to be the main reservoir host for this parasite. In the district of Manisa,
      western Turkey, 37 human VL cases were reported from June 1993-August 1997.
      Twenty-four villages in this district were chosen for a survey of disease
      prevalence in dogs. The dogs, 490 in total, were examined using either the
      indirect immunofluoresence assay (IFAT) or direct agglutination test (DAT). Anti
      Leishmania antibodies were found by at least one test in 5.3% (26/490) of the
      dogs. Infections were confirmed by parasitological examination of or polymerase
      chain reaction (PCR) on lymph node aspirates in 65% (13/20) and 76.4% (13/17) of
      the seropositive dogs tested, respectively. The confirmation rate was 85% by
      combining the results of PCR and microscopy. Our results demonstrate that canine
      VL is wide spread in western Turkey where human VL is endemic, and that
      serodiagnosis is a valuable tool for monitoring the infection.

PMID- 10643902
TI  - Ivermectin: concentration-dependent effects on adenosine triphosphatases in adult
      worms of Onchocerca volvulus.
AB  - The effect of increasing concentrations of ivermectin on adenosine triphosphatase
      (ATPase) activity was investigated in adult worms of Onchocerca volvulus. Mean Mg
      and Na,K-ATPase activities decreased significantly (F ratio = 29.82, P < 0.01
      and F ratio = 28.54, P < 0.01, respectively) with increasing concentrations of
      ivermectin (0-100 ng/ml) in the female worms. When male and female worms were
      mixed with equal amounts of proteins from each, only the Na,K-ATPase activity was
      significantly decreased (F ratio = 56.61, P < 0.01) over a similar range of
      ivermectin concentrations. Since ivermectin exhibits concentration-dependent
      effects on both ATPases in female adult worms, this might provide an insight into
      other effects of the drug. However, the adjustment of the dose of ivermectin to
      obtain a nodular concentration of at least 40 ng/ml is therefore recommended in
      the complete chemotherapy of onchocerciasis.

PMID- 10643903
TI  - The effects of prophylactic anthelmintic treatment on the productivity of
      traditionally managed Djallonke sheep and West African Dwarf goats kept under
      high trypanosomosis risk.
AB  - The effects of a prophylactic anthelmintic intervention on the productivity of
      village based sheep and goats was studied in an area of high trypanosomosis risk
      in The Gambia during 2 and 3 years, respectively. In total, 223 sheep and 385
      goats from five villages were included. Allocation to treatment groups (treated
      control) was randomised by village, based on age and sex. Three treatments per
      rainy season were applied with Fenbendazole (Panacur, Hoechst, 2.5%, 5 mg/kg).
      Mean nematode egg excretion per gram faeces (EPG) of the treated groups were
      significantly reduced by prophylactic anthelmintic treatment, indicating the
      efficiency of the treatment despite the risk of rapid reinfestation. Weight gain
      benefits of anthelmintic treatment were observed in all age categories (> 6
      month) of sheep but not in goats. Kidding rates were significantly increased
      whilst the same positive trends were observed for other reproductive parameters
      (litter size, parturition interval) in both goats and sheep without reaching
      statistical significance. Birth weights of offspring born out of treated does and
      ewes were higher (P < 0.05) than those from the controls. In contrast, growth
      rates until 3 months of age were not influenced by the treatment status of the
      dam. Mortality rates until the age of 3 months of kids from treated does were
      significantly lower than of those from control does. Mean Packed Red Cell Volume
      (PCV) levels during the rains were significantly higher in treated goats than in
      control goats. The same trend was observed in sheep. In general, there were no
      interactions between trypanosome infections and effect of anthelmintic treatment,
      thus both factors acted independently. Finally, the live weight productivity
      index (12 months old-offspring in kg/year per dam) for treated dams was 24% and
      47% higher than in control ewes and does, respectively. It can be concluded that,
      despite the continuous risk of trypanosome infections which has a negative impact
      on their productivity, a beneficial effect of anthelmintic treatment was observed
      in both species but most obviously in goats, measured as an increased production
      and improved health status. A cost-benefit analysis should be carried out in
      order to confirm whether prophylactic anthelmintic treatment can be recommended
      to farmers to increase their income from small ruminant production. Nevertheless,
      anthelmintic treatment will certainly optimise the trypanotolerance in these
      breeds.

PMID- 10643904
TI  - Efficacy of second line drugs on antimonyl-resistant amastigotes of Leishmania
      infantum.
AB  - In a previous paper we have demonstrated that the induction, by direct drug
      pressure, of a resistance to Sb(III) antimony at physiological concentration in
      the amastigote stage of the parasite, led to a high cross-resistance to Sb(V)
      species in the form of Glucantime. In this paper, further chemoresistant clones
      were characterized. Axenic amastigotes of Leishmania infantum were adapted to
      survive in culture medium containing 4, 20, 30 and 120 microg/ml of potassium
      antimonyl tartrate Sb(II). These mutants were 12, 28, 35 and 44-fold more
      resistant to Sb(III) than the parental wild-type clone. They were able to resist
      at concentrations of Glucantime Sb(V) as high as 160 microg/ml when growing in
      THP-1 cells. We have investigated the efficacy of second line drugs in clinical
      use (pentamidine and amphotericin B) on the antimony-resistant mutants.
      Amphotericin B was toxic for both wild-type and chemoresistant mutants at
      concentrations ranging from 0.05 to 0.15 microM. Pentamidine which is extensively
      used when the first course of antimonial pentavalent compounds is unsuccessful,
      was more toxic for all the chemoresistant organisms than for the wild-type clone.
      In the same way, chemoresistant amastigotes growing within THP-1 cells were more
      susceptible to pentamidine than the wild-type clone. Our results showed that the
      resistance of the mutants was restricted to the antimony containing drugs and did
      not led to a cross-resistance against the other clinically relevant drugs. These
      results confirmed that these two drugs (pentamidine and amphotericin B) are good
      candidates to treat pentavalent antimonial unresponsiveness.

PMID- 10643905
TI  - Disinfectants/antiseptics in the management of guinea worm ulcers in the rural
      areas.
AB  - The effectiveness of trichlorophenol (TCP), chlorhexidine gluconate plus
      cetrimide (Savlon) and Izal in inhibiting the growth of bacterial isolates from
      guinea worm ulcers was investigated. Using an adaptation of the method of Russell
      and Furr (Russell, A.D., Furr, J.R., 1977. The antibacterial activity of a new
      chloroxylenol preparation containing ethylenediamine tetraacetic acid. J. Appl.
      Bacteriol. 43, 253-260) the minimum inhibitory concentration (MIC) values of the
      three anti-microbial agents for each of the isolated bacteria was determined.
      Water drawn from the rural guinea worm endemic sites was autoclaved and used for
      the various dilutions of the anti-microbial agents. At the manufactures'
      recommended use-dilutions in cases of wounds/cuts/sores, Savlon showed greater
      effectiveness than Izal and TCP in this order. Probable organic and inorganic
      inhibitors in water that is usually employed in diluting anti-microbial agents in
      the rural areas for the dressing of guinea worm ulcers very likely had greatest
      effect(s) on TCP and least effect(s) on Savlon.

PMID- 10643906
TI  - In vitro antimalarial activity of trovafloxacin, a fourth-generation
      fluoroquinolone.
AB  - Trovafloxacin, a recently-developed fourth-generation fluoroquinolone, is more
      potent than other quinolone drugs against a wide range of organisms including
      Toxoplasma gondii. We assessed the in vitro antimalarial activity of
      trovafloxacin against three laboratory-adapted Plasmodium falciparum isolates and
      compared the results with those of ciprofloxacin and norfloxacin. Synchronous and
      asynchronous cultures were exposed to a range of drug concentrations, and growth
      inhibition was assessed using 3H-hypoxanthine incorporation. All isolates, both
      synchronous and asynchronous, exhibited comparable sensitivities with
      trovafloxacin (EC50 range, 1.8 x 10(-5) to 3.7 x 10(-5) mol/l) and ciprofloxacin
      (2.0 x 10(-5) to 3.9 x 10(-5) mol/l), but were less sensitive to norfloxacin (5.4
      x 10(-5) to 6.6 x 10(-4) mol/l). These results confirm that ciprofloxacin is
      twice as potent as norfloxacin against P. falciparum in vitro, but also show that
      trovafloxacin and ciprofloxacin have similar antimalarial potency. The EC50
      concentrations of all three drugs were generally higher than those achieved after
      conventional doses in humans, suggesting that their clinical application may be
      limited to combination therapy. Recent reports of hepatotoxicity with
      trovafloxacin may also prevent the use of this drug in humans. However, newer
      fourth-generation quinolones may prove safer and have similar antimalarial
      potency.

PMID- 10643907
TI  - Development of Wuchereria bancrofti in Culex quinquefasciatus that survived the
      exposure of sub-lethal dose of Bacillus sphaericus as larvae.
AB  - Development of Wuchereria bancrofti in Culex quinquefasciatus emerged from the
      larvae that survived the exposure of sub-lethal dose of Bacillus sphaericus was
      examined in the laboratory. Third instar larvae of Cx. quinquefasciatus were
      treated with B. sphaericus at a sub-lethal dose of 11.35 microg/250 ml. The
      female mosquitoes that emerged from the survived larvae were fed on
      microfilaraemic human blood and parasite development was monitored in the fed
      mosquitoes. Both treated and untreated mosquitoes could ingest microfilaria (mF)
      equally as there was no significant difference in mF density between them. But,
      density of developmental stages of the parasite in treated group was
      significantly lower. Since, there was no mortality of mosquitoes, the lower
      density of the developmental stages could be attributed to the loss of parasites
      in the treated mosquitoes. Consequently, the proportion of mosquitoes with
      infective larvae (L3) and number of L3 were also significantly lower in treated
      females. Delay in parasite development was also noticed in treated mosquitoes.
      The present study indicates that B. sphaericus, when applied at sub-lethal dose
      kills larvae, and in addition, inhibits development of the filarial parasite and
      consequently reduces L3 yield in adult mosquitoes that emerged from the survived
      larvae.

PMID- 10643908
TI  - Sequence diversity of the merozoite surface protein 1 of Plasmodium falciparum in
      clinical isolates from the Kilombero District, Tanzania.
AB  - Merozoite surface protein 1 of Plasmodium falciparum (PfMSP-1) is regarded as a
      key candidate antigen for malaria vaccine development. It exhibits significant
      antigenic polymorphism and has been divided into 17 building blocks based on the
      analysis of sequence diversity. Differences in the antigenic composition of PfMSP
      1 in local P. falciparum populations may result in differences in the efficacy of
      vaccines, which contain sequences of particular allelic variant(s) of PfMSP-1. To
      contribute to the required knowledge of genetic diversity of malaria parasites in
      geographically diverse regions, we have used the polymerase chain reaction (PCR)
      to analyze the sequence diversity of blocks 1-4 of PfMSP-1 in disease isolates
      from the Kilombero District in Tanzania. In the semi-conserved block 1, in which
      dimorphic amino acid variances have been described at three positions, we found
      three of the five previously described combinations of these three pairs of amino
      acids. In addition one combination was found, which has not been reported before
      in parasite isolates from different locations worldwide. Of the two sequence
      variants, which were dominating, one (S44-Q47-V52) corresponded to the 83.1
      sequence incorporated into the SPf66 malaria peptide vaccine, while the other one
      (G44-H47-I52) differed from the previous in all three dimorphic amino acids. The
      partial protection observed in a phase III SPf66 trial conducted in the Kilombero
      District in children aged 1-5, thus does not seem to be associated with a clear
      dominance of favourable variants of block 1 of PfMSP-1 in this area. All three
      different principle types of block 2, the major polymorphic region of PfMSP-1,
      were found in the Tanzanian isolates. Most of the sequences contained K1-type
      tripeptide repeats, but clones with MAD20-type repeats or no repetitive sequence
      (RO33-type block 2) were also present. K1- and MAD20-type tripeptide repeat
      motifs were never mixed within one parasite clone. In one sequence a hexapeptide
      repeat was found at the end of block 2, which has not been reported before.
      Dimorphism in 13 of the 17 previously described variable positions of the semi
      conserved block 3 and three of four recombination types of block 4 (K/K, M/K and
      M/M) were found among the Tanzanian isolates. Apart from previously described
      dimorphic amino acid positions, polymorphism was rare in the non-repeated
      building blocks. Selection and spreading of parasite variants, which contain
      amino acid exchanges at other than the dimorphic positions thus, is not a common
      event. Parasite isolates frequently harboured more than one PfMSP-1 allele. Three
      of the four heterogeneous isolates analysed contained two different general types
      of sequences. One isolate contained at least four distinct clones, demonstrating
      the high endemicity of malaria in the Kilombero District, which is a well
      established site for malaria vaccine field trials.

PMID- 10643909
TI  - Analysis of Plasmodium falciparum infections in a village community in Northern
      Nigeria: determination of msp2 genotypes and parasite-specific IgG responses.
AB  - The genetic diversity of P. falciparum and multiplicity of infection has been
      studied in a village in Northern Nigeria at the end of the rainy season, when
      transmission is high. We analysed blood samples from 104 individuals aged 5-70
      years by polymerase chain reaction (PCR) amplifying the gene for the merozoite
      surface protein MSP2 followed by genotyping based on restriction fragment length
      polymorphism (RFLP). 94.2% of all samples were parasite positive by PCR and over
      80% of those had multiple infections. The age distribution of the average number
      of parasite clones present in P. falciparum infections showed an initial
      increase, then reached a peak multiplicity in children 8-10 years of age, and
      afterwards decreased significantly with age. Mean multiplicity in those 8-10-year
      old children was 5.4 clones per carrier. Peak multiplicity and parasite diversity
      in Nigerian individuals is compared to findings from other study sites in Africa
      and PNG. The prevalence of IgG antibodies against the circumsporozoite protein
      (CSP), an indicator for malaria exposure, was over 85% in all age groups showing
      a high exposure of villagers to P. falciparum. OD values in ELISA were positively
      correlated with age. There was no correlation between the level of IgG against
      CSP and the multiplicity of P. falciparum infections determined by PCR of msp2.
      These results imply that in highly endemic areas multiplicity of infection is not
      directly correlated with exposure to P. falciparum.

PMID- 10643910
TI  - Gastrointestinal manifestations of acute falciparum malaria in children.
AB  - The gastrointestinal manifestations of acute symptomatic uncomplicated falciparum
      malaria were studied in 184 consecutive children aged from 6 months to 15 years.
      Vomiting was the most common and epigastralgia the least common presenting
      symptom. Peripheral parasite density was higher in children who were vomiting
      than in those who were not. There was no relationship between the density of
      peripheral parasitaemia and the duration of gastrointestinal symptoms at
      presentation. All gastrointestinal symptoms cleared within 3 days after
      instituting antimalarial therapy.

PMID- 10643911
TI  - Simple school questionnaires can map both Schistosoma mansoni and Schistosoma
      haematobium in the Democratic Republic of Congo.
AB  - The use of self-administered questionnaires has been shown in different African
      countries to be inexpensive and reliable for the rapid identification of
      communities at highest risk of urinary schistosomiasis. For intestinal
      schistosomiasis due to Schistosoma mansoni there is a clear need for a similar
      approach. We report the results from a large-scale study undertaken in the
      western part of the Democratic Republic of Congo (DRC, formerly Zaire). Within 4
      weeks questionnaires were correctly completed in 136 out of 160 schools (85%). In
      57 of these schools children were screened for infections with schistosomes and
      geohelminths. The prevalence of 'schistosomiasis' as reported in the
      questionnaires showed the best correlation with the prevalence of S. mansoni
      infections (r = 0.77, P < 0.0001). Calculations of the diagnostic performance of
      reported 'schistosomiasis' to detect schools with a high risk of intestinal
      schistosomiasis gave positive predictive values of 87 and 62%, and negative
      predictive values of 74 and 87% for moderate and high infection thresholds,
      respectively. Reported 'blood in stool' was another useful indicator for
      intestinal schistosomiasis. Reported 'blood in urine' showed the best correlation
      with urinary schistosomiasis (r = 0.75, P < 0.001) and the positive predictive
      values were 81 and 50%, and the negative predictive values were 89 and 95% for
      moderate and high infection thresholds, respectively. We conclude that school
      children in DRC have a distinct perception of intestinal and urinary
      schistosomiasis and that questionnaires could be useful to identify high-risk
      schools for both parasites.

PMID- 10643912
TI  - Characterization of Leishmania sp. strains isolated from autochthonous cases of
      human cutaneous leishmaniasis in Santa Catarina State, southern Brazil.
AB  - Four Leishmania sp. samples were isolated from autochthonous human cases of
      American cutaneous leishmaniasis (ACL) in Santa Catarina State, southern Brazil.
      These strains were characterized using indirect immunofluorescence with a panel
      of Leishmania-specific monoclonal antibodies (MAbs), and by PCR amplification and
      hybridization assay of the mini-exon gene with group specific probes. The results
      obtained with the MAbs were in agreement with the genetic marker. Two isolates
      (MHOM/BR/89/JSC89-H1 and MHOM/BR/89/JSC89-H2) were identified as L. (Leishmania)
      amazonensis and two (MHOM/BR/96/LSC96-H3 and MHOM/BR/97/LSC97-H4) as L. (Viannia)
      braziliensis. The southernmost autochthonous cases of ACL in Brazil are due to
      two different Leishmania sp. species, confirming the spreading of ACL on the
      American continent.

PMID- 10643913
TI  - An automated biological assay to determine levels of the trypanocidal drug
      melarsoprol in biological fluids.
AB  - For the investigation of the pharmacokinetic properties of a drug, methods for
      sensitive and precise quantification are a prerequisite. Only few functional
      methods exist for the determination of the trypanocidal drug melarsoprol in
      biological fluids: A bioassay which requires microscopical evaluation and two
      HPLC methods, which require sample extraction and are difficult to automatize due
      to the drug's properties. We report the development of an automated biological
      assay, based on the fluorescent dye Alamar blue. To validate the assay for
      melarsoprol, 108 serum and 37 cerebrospinal fluid (CSF) samples were spiked with
      melarsoprol at concentrations of 17-92 ng/ml for CSF and 17 ng/ml-2.2 microg/ml
      for serum. The precision (repeatability) expressed as the interday average
      coefficient of variation was 9.9% for serum and 18.8% for CSF samples over the
      respective concentration range. The accuracy (measurement for the systematic
      error) of the test was 99.4% for serum and 96.4% for CSF. The assay's limit of
      quantitation with the use of the trypanosome stock STI 704 BABA was 4 ng/ml for
      both serum and CSF samples.

PMID- 10643914
TI  - Physico-chemical properties of the trypanocidal drug melarsoprol.

PMID- 10643915
TI  - Study on the mechanical transmission by tsetse fly Glossina morsitans centralis
      of Trypanosoma vivax, T. congolense or T. brucei brucei to goats.

PMID- 10643916
TI  - Febrile seizures: treatment and prognosis.
AB  - Recent epidemiologic data indicate that the vast majority of children with
      febrile seizures have a normal longterm outcome. A precise knowledge of the short
      and long-term outcome with or without treatment, and short- and long-term side
      effects is an important prerequisite for assessing the various treatment
      strategies. We focus on the impact of short-term or prophylactic treatment on the
      short- and long-term outcome of various types of febrile seizures. There is
      universal agreement that daily prophylaxis with antiepileptic agents should never
      be used routinely in simple febrile seizures, but only in highly selected cases,
      if at all. Intermittent diazepam (DZP) prophylaxis at times of fever may or may
      not reduce the recurrence rate, but it does not appear to improve the long-term
      outcome as compared with short-term seizure control. The treatment may be used to
      reduce the recurrence rate for a small arbitrarily defined group with multiple
      simple febrile seizures, complex febrile seizures, especially focal, prolonged or
      both, febrile status, and when parental anxiety is severe. However, there is no
      evidence that treatment of simple febrile seizures can prevent the rare cases of
      later epilepsy, and many children with complex febrile seizures have a benign
      long-term outcome, even without treatment. Many prefer a "wait and see" policy.
      An attractive alternative is to treat new febrile seizures with rectal DZP in
      solution at seizure onset, given by the parents at home to prevent febrile
      status. Newer, less well documented short-term strategies include nasal, oral, or
      rectal administration of other benzodiazepines. Short-term seizure control of
      febrile status and careful parental counseling are the two most important targets
      of treatment.

PMID- 10643917
TI  - Enhancement of progenitor cell division in the dentate gyrus triggered by initial
      limbic seizures in rat models of epilepsy.
AB  - PURPOSE: Mitogenic effects of seizures on granule cell progenitors in the dentate
      gyrus were studied in two rat models of epilepsy. We investigated which stage of
      epileptogenesis is critical for eliciting progenitor cell division and whether
      seizure-induced neuronal degeneration is responsible for the enhancement of
      progenitor cell division. METHODS: Seizures were induced by either kainic acid
      (KA) administration or electrical kindling. Neurogenesis of dentate granule cells
      was evaluated using the bromodeoxyuridine (BrdU) labeling method, and neuronal
      degeneration was assessed by in situ DNA fragmentation analysis. RESULTS: After
      injection of KA, the number of BrdU-positive granule cells began to increase at
      day 3 after the treatment, peaked at day 5, and returned to baseline at day 10.
      By day 13, the values were lower than control. After kindling, the number of BrdU
      positive cells began to increase after five consecutive experiences of stage I
      seizures. The increase occurred from day 1 to day 3 after the last electrical
      stimulation, but returned to baseline by day 7. After generalized seizures were
      well established, repeated stimulation did not facilitate division of granule
      cell progenitors. DNA fragmentation was noted in pyramidal neurons in the CA1,
      CA3, and hilus regions at 18 h after KA injection, but not in the kindling model.
      CONCLUSIONS: These observations indicate that a mechanism in epileptogenesis
      boosts dentate progenitor cell division, but progenitor cells may become
      unreactive to prolonged generalized seizures. Pyramidal neuronal degeneration is
      not necessary for triggering the upregulation. It is suggested that newly born
      granule cells may play a role in the network reorganization that occurs during
      epileptogenesis.

PMID- 10643918
TI  - Audiogenic seizures susceptibility in transgenic mice with fragile X syndrome.
AB  - PURPOSE: To evaluate their susceptibility to audiogenic seizures, five groups of
      knockout mice with various forms of fragile X genetic involvement [hemizygous
      males (n = 46), and homozygous (n = 38) and heterozygous females (n = 45), and
      their normal male (n = 45) and female (n = 52) littermates] were studied.
      METHODS: All mouse groups were tested at ages 17, 22, 35, and 45 days. Audiogenic
      seizure susceptibility was scored, and the analysis of variance was used for the
      evaluation of the effects of age and genetic condition on seizure severity score
      (SSS). RESULTS: All groups of knockout fragile X mice exhibited SSSs
      significantly higher than those observed in their wild-type littermates; among
      knockout mice, hemizygous males and homozygous females showed the highest SSSs.
      Hemizygous males showed higher SSSs with increasing age, from 17 to 45 days;
      homozygous females showed a peak at age 22 days, followed by a decrease; finally,
      heterozygous females had their highest SSSs at age 17 days. CONCLUSIONS: This
      study demonstrates that an increased susceptibility to audiogenic seizures is
      present in fragile X knockout mice at all the ages tested. These results support
      the validity of this animal model also for epilepsy and seizures in the human
      fragile X syndrome.

PMID- 10643919
TI  - Genetic localization of the Ca2+ channel gene CACNG2 near SCA10 on chromosome
      22q13.
AB  - PURPOSE: Voltage-dependent calcium channel mutations have been associated with
      spinocerebellar ataxia in humans (SCA6) and with ataxia, progressive cerebellar
      degeneration, and epilepsy in mice (tottering, lethargic, and stargazer). A novel
      autosomal dominant spinocerebellar ataxia syndrome with epilepsy (SCA10) was
      recently mapped to chromosome 22q13. The human ortholog of the mouse stargazer
      locus, the calcium channel gamma subunit gene CACNG2, also is located in this
      region. Because the phenotypes of stargazer mice and SCA10 patients were similar,
      consisting of both cerebellar ataxia and seizures, we hypothesized that CACNG2
      was a likely candidate for the SCA10 locus. METHODS: Polymerase chain reaction
      (PCR) based assays were developed for two polymorphic microsatellite markers near
      CACNG2. The location of CACNG2 was determined by linkage and haplotype analysis
      of the genotypes of 22 individuals from a human pedigree segregating SCA10.
      RESULTS: SCA10 was previously localized distal to marker D22S1177 on chromosome
      22q13. We determined that CACNG2 was linked to D22S283 and D22S1177 with the
      marker order: centromere-D22S283-bcmDLB1 (CACNG2)-D22S1177-D22S423-telomere. Thus
      CACNG2 is located proximal to the SCA10 recombinant interval. CONCLUSIONS: Here
      we report the first genetic linkage of CACNG2 on chromosome 22q13 and exclude it
      as a candidate for SCA10. In addition, our data clarify the relation between the
      physical and genetic linkage maps of this region and will facilitate isolation of
      the SCA10 gene.

PMID- 10643920
TI  - Effects of retigabine (D-23129) on different patterns of epileptiform activity
      induced by low magnesium in rat entorhinal cortex hippocampal slices.
AB  - PURPOSE: The objective of this study was to evaluate the effect of a new
      antiseizure drug, retigabine (D-23129; N-(2-amino-4-[fluorobenzylamino]-phenyl)
      carbamic acid ethyl ester) on low-Mg2+-induced epileptiform discharges in rat in
      vitro. METHODS: Three types of epileptiform discharges (recurrent short
      discharges in the hippocampus, seizure-like events, and late recurrent discharges
      in the entorhinal cortex) were elicited in rat combined entorhinal cortex
      hippocampal slices by perfusion with low-Mg2+-artificial cerebrospinal fluid
      (ACSF). The antiepileptic properties of retigabine were evaluated as effect on
      the frequency and amplitude of the epileptiform activities as well as time of
      onset of the effect in the entorhinal cortex (EC) and in hippocampal area CA1
      (CA1) by using extracellular recording techniques. RESULTS: Retigabine (20
      microM) reversibly suppressed the recurrent short discharges otherwise sensitive
      only to high doses of valproate (VPA) but insensitive to standard antiepileptic
      drugs (AEDs) in CA1, whereas 10 microM reduced the frequency of discharges by
      34+/-18.8%, with no significant effect on the amplitude. In EC, retigabine (50
      microM) reversibly suppressed the seizure-like events, whereas 20 microM blocked
      seizure-like events in 71.5% of the slices. The seizure-like events were also
      sensitive to standard AEDs. Late recurrent discharges in EC that are not blocked
      by standard AEDs were reversibly suppressed by retigabine (100 microM), whereas
      50 microM reduced the frequency of the discharges by 94.4+/-7.7%, and 20 microM,
      by 74.2+/-18.0%, with no significant effect on the amplitude. CONCLUSIONS:
      Retigabine is an effective AED with suppressive effects on recurrent short
      discharges and on late recurrent discharges normally insensitive to standard
      AEDs.

PMID- 10643921
TI  - Lateral asymmetry in activation of hypothalamic neurons with unilateral
      amygdaloid seizures.
AB  - PURPOSE: Reproductive disorders are unusually frequent among women with temporal
      lobe seizures. The particular type of disorder may be related to the laterality
      and focality of epileptiform discharges. Here we examined whether unilateral
      amygdaloid seizures activate hypothalamic neurons involved in reproductive
      function and reproductive endocrine secretion in female rats and whether such
      activation shows lateral asymmetry. METHODS: Numbers of Fos-immunoreactive (Fos
      ir) neurons in various hypothalamic regions were compared for three groups of
      animals: (a) unilateral amygdala-kindled, (b) implanted but unstimulated, and (c)
      unimplanted. RESULTS: Fos-ir neurons showed strong ipsilateral occurrence in the
      medial preoptic, ventrolateral part of the ventromedial, and ventral
      premammillary nuclei, sexually dimorphic regions involved in reproductive
      endocrine regulation. No significant lateral asymmetry was observed for other
      investigated hypothalamic regions. CONCLUSIONS: Unilateral amygdaloid seizures
      activate hypothalamic neurons that regulate reproductive endocrine secretion in a
      laterally asymmetric fashion. This may explain the clinical association of
      different reproductive endocrine disorders with left and right temporal
      epileptiform discharges.

PMID- 10643922
TI  - Interictal cardiovascular autonomic responses in patients with temporal lobe
      epilepsy.
AB  - PURPOSE: To measure interictal cardiovascular autonomic functions in patients
      with either refractory or well-controlled temporal lobe epilepsy (TLE). METHODS:
      For autonomic assessment, heart rate variation during normal and deep breathing,
      Valsalva maneuver, and tilting were measured in 19 patients with chronic
      refractory TLE, 19 patients with well-controlled TLE, and 38 age- and sex-matched
      healthy control subjects. Blood pressure responses to tilting and isometric work
      also were evaluated. RESULTS: Heart-rate (HR) variation during normal breathing
      (p = 0.006) and tilting (p = 0.043) was lower in patients with refractory TLE
      than in control subjects. Heart-rate response to tilting (p = 0.036) was also
      lower in patients with well-controlled TLE than in control subjects. Blood
      pressure responses showed no differences between the patients and the control
      subjects. Patients taking carbamazepine (CBZ) medication had decreased HR
      responses to deep breathing (p = 0.046) and to tilting (p = 0.014) compared with
      the control subjects. CONCLUSIONS: Refractory TLE seems to be associated with
      dysfunction of the cardiovascular autonomic regulation, manifesting as impaired
      HR responses to certain stimuli. Interictal autonomic dysfunction is seen in
      patients with well-controlled TLE as well, but it may be more evident in patients
      with refractory epilepsy. CBZ medication may also be associated with altered
      autonomic cardiac control.

PMID- 10643923
TI  - Prolactin levels in sudden unexpected death in epilepsy.
AB  - PURPOSE: To assess serum prolactin levels in sudden unexpected death in epilepsy
      (SUDEP) and control groups to test the hypothesis that if seizures occur
      routinely as a terminal event in SUDEP, then raised prolactin levels may be an
      indicator of terminal seizure. METHODS: Blood was taken for measurement of
      prolactin levels from subjects with SUDEP and three control groups. The control
      groups were those with epilepsy dying from causes other than epilepsy (e.g.,
      ischemic heart disease or injuries), physiologically stressed individuals without
      epilepsy (they were admitted to the hospital after an acute illness and died
      after several hours to 3 days), and nonepileptic rapid deaths (these people
      collapsed suddenly and died at the scene). In the SUDEP group, evidence for
      terminal seizure was considered to be at least one of the following: body found
      half on, half off the bed, or urinary incontinence at the scene, or bitten lips
      or tongue at autopsy. RESULTS: There was evidence for terminal seizure at the
      scene or at autopsy in four of the 10 SUDEP cases. Serum prolactin levels were
      not significantly increased in the SUDEP group compared with the controls. None
      of the SUDEP subjects, including those with clinical evidence of a terminal
      seizure, had high prolactin levels characteristic of those observed after
      seizures in living subjects. CONCLUSIONS: Prolactin levels are not raised in
      SUDEP, even if there is evidence of terminal seizure. As prolactin takes 15-20
      min to peak after a seizure in life, there may be insufficient time for a
      prolactin increase to occur in SUDEP. Thus prolactin levels cannot be used to
      determine if a deceased individual with epilepsy had a seizure or to answer the
      broad question whether SUDEP is always associated with a terminal seizure.

PMID- 10643924
TI  - Electroclinical picture of autosomal dominant nocturnal frontal lobe epilepsy in
      a Japanese family.
AB  - PURPOSE: Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is the first
      described partial epilepsy syndrome known to be due to a single gene mutation. We
      found a first Japanese ADNFLE family with a novel mutation of the neuronal
      nicotinic acetylcholine receptor (nAChR) alpha4 subunit (CHRNA4) gene. The aim of
      this report is precisely to describe the electroclinical manifestations of ADNFLE
      in this family and to compare these findings with those of other families
      reported previously in the literature. METHODS: Three affected family members
      were investigated electroclinically by close clinical observation, interictal
      EEG, video-EEG monitoring, magnetic resonance imaging, and single-photon-emission
      tomography. Information about other affected family members was obtained from
      either the spouse or the parents. Mutations within the CHRNA4 gene were examined
      in seven family members. RESULTS: The clinical manifestations and diagnostic
      findings in the members of this family were consistent with ADNFLE. However,
      there were intrafamilial and interfamilial variations in clinical features. The
      seizures of the patients were brief tonic seizures, with hyperventilation in
      children and secondarily generalized tonic-clonic convulsions in adults. The
      onset of the children's seizures began in infancy and early childhood. The
      children's seizures were sometimes provoked by movement and sound stimulation,
      and did not respond to antiepileptic drugs. On the other hand, the adults'
      seizures disappeared spontaneously or were easily controlled with carbamazepine.
      Three children showed hyperactivity, and two children had mild mental
      retardation. All patients had impaired consciousness during their seizures and no
      auras. A novel missense mutation (c755C>T) in exon 5 of the CHRNA4 gene was found
      in four affected family members. CONCLUSIONS: The electroclinical pictures of a
      Japanese family with ADNFLE were basically the same as those of other families
      reported, but with slight differences. ADNFLE is probably not uncommon, and it is
      very likely that there are unidentified patients with this inherited disorder in
      Japan.

PMID- 10643925
TI  - Photogenic partial seizures.
AB  - PURPOSE: To establish the incidence and symptoms of partial seizures in a cohort
      of patients investigated on account of known sensitivity to intermittent photic
      stimulation and/or precipitation of seizures by environmental visual stimuli such
      as television (TV) screens or computer monitors. METHODS: We report 43
      consecutive patients with epilepsy, who had exhibited a significant EEG
      photoparoxysmal response or who had seizures precipitated by environmental visual
      stimuli and underwent detailed assessment of their photosensitivity in the EEG
      laboratory, during which all were questioned concerning their ictal symptoms.
      RESULTS: All patients were considered on clinical grounds to have an idiopathic
      epilepsy syndrome. Twenty-eight (65%) patients reported visually precipitated
      attacks occurring initially with maintained consciousness, in some instances
      evolving to a period of confusion or to a secondarily generalized seizure. Visual
      symptoms were most commonly reported and included positive symptoms such as
      coloured circles or spots, but also blindness and subjective symptoms such as
      "eyes going funny." Other symptoms described included nonspecific cephalic
      sensations, deja-vu, auditory hallucinations, nausea, and vomiting. No patient
      reported any clear spontaneous partial seizures, and there were no grounds for
      supposing that any had partial epilepsy excepting the ictal phenomenology of some
      or all of the visually induced attacks. CONCLUSIONS: These findings provide
      clinical support for the physiological studies that indicate that the trigger
      mechanism for human photosensitivity involves binocularly innervated cells
      located in the visual cortex. Thus the visual cortex is the seat of the primary
      epileptogenic process, and the photically triggered discharges and seizures may
      be regarded as partial with secondary generalization.

PMID- 10643926
TI  - Interpretation of Wada memory test for lateralization of seizure focus by use of
      (99m)technetium-HMPAO SPECT.
AB  - PURPOSE: Although the intracarotid amobarbital procedure (IAP) or Wada test is
      useful in lateralizing seizure focus in patients with temporal lobe epilepsy
      (TLE), the results of the IAP memory test are frequently nonlateralizing. An
      insufficient suppression of the medial temporal region contralateral to the
      seizure focus may contribute to the failure of lateralization. We tried to
      correlate IAP memory results with the functional changes in the contralateral
      medial temporal region as measured by single photon emission computed tomography
      (SPECT) during IAP. METHODS: We performed a (99m)technetium-(Tc) hexamethylene
      propylene-amine-oxime (HMPAO) brain SPECT in 19 medial TLE patients during a
      contralateral IAP (sodium amobarbital injected contralateral to the seizure
      focus). Regional cerebral blood flow (rCBF) was measured in the contralateral
      medial temporal region. The amount of decrease in the rCBF was calculated by
      subtracting the previous measurement from the one obtained with the interictal
      SPECT. RESULTS: Ten (53%) patients passed and nine (47%) failed the contralateral
      IAP. The mean percentage decrease in rCBF was 5.3+/-5.3%. There was a significant
      negative correlation between a decrease in the rCBF and the IAP memory-retention
      score by Spearman correlation (p = -0.53: p<0.021). Patients with smaller
      decreases in rCBF (<5%) more frequently passed the contralateral IAP memory test
      than did those with larger decreases (80 vs. 22%; p<0.023). CONCLUSIONS: We
      suggest that an insufficient suppression of the contralateral medial temporal
      function is partly responsible for nonlateralizing IAP memory tests. An IAP-SPECT
      may be useful in interpreting IAP memory tests for the lateralization of seizure
      focus in TLE patients.

PMID- 10643927
TI  - Dipole-source analysis in a realistic head model in patients with focal epilepsy.
AB  - PURPOSE: By the use of three different head models in EEG dipole analysis, we
      tried to model the origin of interictal and ictal epileptic activity as precisely
      as possible. Further, as a control, a second evaluation was made by an
      independent group to control for interindividual reliability of the dipole source
      analysis. With the realistic head model (CURRY) considering cortex, skull, and
      skin segmentation, the spike source was located. METHODS: In five patients with
      mesial temporal epileptogenesis, confirmed by successful epilepsy surgery, the
      spike source was close to the hippocampus, with a mean distance of the dipole
      source from the hippocampus of 13.6 mm (range, 9-17.2 mm). In one case the ictal
      EEG also could be analyzed and resulted in a dipole-source localization
      comparable to the interictal source. RESULTS: In both head models using either
      pure cortex segmentation only or a concentric three-shell model, the dipole
      source was systematically dislocated in a more superior position. Data analysis
      by a second group with independently chosen EEG samples and identical individual
      head model resulted in deviations of <5.3 mm. Data analysis using independently
      selected spikes and independently segmented head models resulted in deviations <
      or =16.7 mm. CONCLUSIONS: In four cases of extratemporal epileptogenesis, the
      origin of interictal epileptiform discharges was localized to the suspected
      primary epileptogenic zone.

PMID- 10643928
TI  - Discriminating between epileptic and nonepileptic events: the utility of hypnotic
      seizure induction.
AB  - PURPOSE: To determine the validity of the Hypnotic Induction Profile (HIP)
      followed by seizure induction during continuous video-electroencephalographic
      (EEG) monitoring to discriminate between epileptic (EE) and nonepileptic events
      (NEE). METHODS: Eighty-two patients admitted to the Stanford Comprehensive
      Epilepsy Center for differential diagnosis of seizure-like events were evaluated.
      Exclusion criteria included inability or refusal to complete the HIP, lack of a
      "typical" event, an IQ <70, present evidence of psychosis, or a physiological
      cause for NEE. Sixty-nine patients met these criteria. While undergoing
      continuous video-EEG monitoring, the patient completed an HIP, an inventory
      designed to measure the degree of hypnotizability. An attempt was then made to
      induce the patient's typical events under hypnosis by using a split-screen
      technique. An event without an EEG correlate was thought to represent an NEE. A
      diagnosis of NEE was made independently by the neurology team and was compared
      with results obtained with the hypnotic evaluation. RESULTS: Results for patients
      with EE were compared with those with NEE and a group consisting of both EE/NEE.
      All patients with NEE were then contrasted with the EE group. HIP scores for the
      EE patients indicated lower hypnotizability than the NEE group and were
      statistically significant when NEE patients and those with NEE/EE were combined.
      The sensitivity of seizure induction in the diagnosis of NEE was 77%, with a
      specificity of 95%. CONCLUSIONS: The HIP coupled with seizure induction is a
      useful technique to aid in the diagnosis of patients with NEE. It is sensitive
      and specific, and it may provide the patient with a useful behavioral tool to
      control NEEs. It may also furnish a conduit for long-term treatment.

PMID- 10643929
TI  - Health status of people with epilepsy compared with a general reference
      population.
AB  - PURPOSE: To study the impact of epilepsy in a representative sample of people
      with epilepsy and compare with a normal reference population. METHODS: We
      collected clinical and demographic data and information on health status by using
      the Short Form 36 (SF-36) questionnaire in two populations: (a) 397 patients with
      confirmed epilepsy attending a county hospital during a 7-year period, and (b)
      1,663 patients from a random sample representative of the entire national
      population. RESULTS: The respondents with epilepsy had well-regulated disease and
      showed the characteristics of a community sample: 70% had had no seizures during
      the last year, and 80% used antiepileptic drugs (AEDs). On six of eight SF-36
      scales, patients with epilepsy had lower scores than the normal reference
      population, and they were less likely to be married, employed, or a full-time
      student. Seizure-free patients with epilepsy had scores close to those of the
      normal reference population, with higher scores on the social functioning and
      mental health scales and lower on the role--emotional scale. There were no
      differences in health status scores between seizure-free patients using and not
      using AEDs. CONCLUSIONS: Our results confirm that patients with well-regulated
      epilepsy have a health status at the level of a general reference population.

PMID- 10643930
TI  - Reliability and validity of a Norwegian version of the quality of life in
      epilepsy inventory (QOLIE-89).
AB  - PURPOSE: To develop a Norwegian version of the Quality of Life in Epilepsy
      Inventory (QOLIE-89) and to confirm its psychometric properties. METHODS: The
      QOLIE-89 was adapted to Norwegian language through a translation-backtranslation
      procedure. The assessment included 397 patients with epilepsy. We assessed
      internal consistency and test-retest reliabilities. Construct validity was
      assessed by correlating scales with items of the 15D health status questionnaire,
      and discriminant validity was assessed by comparing scores for known groups.
      RESULTS: The internal consistency reliability (Cronbach's alpha, 0.76-0.92) and
      test-retest reliability (intraclass correlation coefficient, 0.67-0.96) for the
      individual domains were acceptable. Spearman's rank correlations between QOLIE-89
      domain scores and corresponding 15D single-item scores were high (p, 0.47-0.76),
      and generally higher than the associations between noncorresponding items. Most
      QOLIE-89 items discriminated well between patients according to seizure status,
      psychiatric comorbidity, and working status; less well after antiepileptic drug
      use and neurologic comorbidity. CONCLUSIONS: In this cross-sectional survey, the
      Norwegian version of the QOLIE-89 was reliable and showed properties supporting
      construct validity, at a level comparable with the original U.S. version.

PMID- 10643931
TI  - The stigma of epilepsy: a European perspective.
AB  - PURPOSE: To study the stigma of epilepsy in a European sample. METHODS: Clinical
      and demographic details and information about patient-perceived stigma was
      collected by using self-completed questionnaires mailed to members of epilepsy
      support groups. RESULTS: Stigma data were collected from >5,000 patients living
      in 15 countries in Europe. Fifty-one percent reported feeling stigmatised, with
      18% reporting feeling highly stigmatised. High scores were correlated with worry,
      negative feelings about life, long-term health problems, injuries, and reported
      side effects of antiepileptic drugs (AEDs). Cross-cultural comparisons revealed
      significant differences between countries. A multivariate analysis identified
      impact of epilepsy, age of onset, country of origin, feelings about life, and
      injuries associated with epilepsy as significant contributors on scores on the
      stigma scale. CONCLUSIONS: This study confirms the findings of previous studies
      that have identified the importance of both clinical and nonclinical factors in
      understanding the stigma of epilepsy. The results of cross-cultural differences
      require further explanation, and much more research should be conducted to reduce
      the stigma associated with epilepsy.

PMID- 10643933
TI  - IBE Commission Report. 2nd Workshop on "Epilepsy, Risks, and Insurance".

PMID- 10643932
TI  - Treatment of refractory complex-partial status epilepticus with propofol: case
      report.
AB  - PURPOSE: We report a case of a 65-year-old woman who had a subarachnoid and
      intraventricular hemorrhage secondary to rupture of an anterior communicating
      artery aneurysm and developed nonconvulsive status epilepticus of the complex
      partial type, refractory to phenytoin (PHT), phenobarbital (PB), valproate (VPA),
      and lorazepam (LZP). METHODS: Three weeks after diagnosis of nonconvulsive status
      epilepticus, general anesthesia was induced with propofol and titrated to burst
      suppression on the electroencephalogram (EEG). RESULTS: During propofol infusion,
      the serum VPA level declined markedly, and despite >3 g daily doses, did not
      return to the therapeutic range, until several days after propofol was
      discontinued. Continuous propofol infusion was stopped after 7 days, and the
      patient recovered consciousness. Despite further complications, she gradually
      regained normal function and was discharged home 4 months after surgery.
      CONCLUSIONS: This is the first case of nonconvulsive status epilepticus
      successfully treated with propofol.

PMID- 10643934
TI  - Herbert Henri Jasper 1906-1999: an appreciation and tribute to a founder of
      modern neuroscience.

PMID- 10643935
TI  - Physical activity and human cancer.

PMID- 10643936
TI  - Recent time trends in cancer of the oesophagus and gastric cardia in the region
      of Calvados in France, 1978-1995: a population based study.
AB  - The incidence of oesophageal cancer differs from country to country, and even
      between areas of the same country. Many studies in recent years have shown an
      upward trend of a particular histologic type: adenocarcinoma of the oesophagus.
      It is difficult to precisely locate adenocarcinomas situated at the junction
      between the oesophagus and the gastric cardia. Clear criteria to define and
      classify such tumours are essential in order to analyse their evolution. The
      present study describes the changing incidence of cancers of the oesophagus and
      gastric cardia according to histologic type from 1978 to 1995 in Calvados, the
      highest-risk French region with two different topographic classifications of
      adenocarcinomas: one based on Misumi's criteria and the other based on local
      extension of cancer. In total, 1835 cancers of the oesophagus and gastric cardia
      were diagnosed in this period. Incidence rates for oesophageal and gastric cardia
      cancers standardized on the world population were 24.4/10(5) and 2.4/10(5) in men
      and 1.4/10(5) and 0.4/10(5) in women, respectively. The time trend in the
      incidence of squamous cell cancers was downward in men -0.74 (P < 10(-6)) and
      stable in women +0.04 (P = 0.65). Regarding adenocarcinomas, with the
      classification based on Misumi's categories, there was a slight but significant
      upward trend for oesophageal adenocarcinoma in men [mean annual variation of
      +0.09 (P < 10(-5))] while the tendency was downward and significant for gastric
      cardia adenocarcinoma [mean annual variation of -0.09 (P < 10(-4))]. When
      adenocarcinomas of the oesophagus and those of the gastric cardia with
      oesophageal involvement are taken together (second classification), there was an
      upward trend which was not significant in men and was significant in women. There
      was no such upward trend in adenocarcinomas limited to the gastric cardia and/or
      involving the stomach. Because of the difficulties in determining accurate
      localization routinely in population-based studies, it seems sensible to preclude
      classification biases in recommending the grouping together of gastric cardia
      adenocarcinomas with oesophageal adenocarcinomas, at least with those among the
      latter occurring in the lower third of the oesophagus.

PMID- 10643937
TI  - Occupational and leisure-time physical activity and the risk of colorectal
      cancer.
AB  - The relation between various measures of physical activity and colorectal cancer
      risk was considered in a case-control study conducted between 1992 and 1997 in
      the Swiss canton of Vaud. Cases were 223 patients (142 men, 81 women) below age
      75, with colon (n = 119) or rectal (n = 104) cancer; controls were 491 patients
      (211 men, 280 women) admitted to hospital for acute, non-neoplastic conditions.
      Compared with the lowest level of physical activity at age 30-39 years, the odds
      ratios (OR) of colorectal cancer for the highest level were 0.44 (95% confidence
      interval, CI, 0.26-0.73) for occupational and 0.53 (95% CI 0.33-0.86) for leisure
      time activity. An inverse association was also observed for physical activity at
      age 15-19 and 50-59 years. The inverse relation between physical activity and
      colorectal cancer was observed across strata of sex, age, education, body mass
      index and alcohol drinking; was somewhat stronger in subjects reporting high
      total energy, and low vegetable and fibre intakes; and was observed across
      various colon subsites and rectum. In terms of population attributable risk,
      increasing physical activity would avoid one-fifth to one-third of incident
      colorectal cancer cases.

PMID- 10643938
TI  - Gynaecological surgical procedures and risk of colorectal cancer in women.
AB  - This study explored the relationship between certain gynaecological procedures
      and the risk of colorectal cancer in Ontario women. The cohort comprised all
      women undergoing gynaecological surgery for tubal ligation, unilateral and
      bilateral oopherectomy, and hysterectomy between 1979 and 1993 in Ontario. Person
      years were calculated until death, a cancer diagnosis, or the end of the study
      period, after linkage to the Ontario Cancer Registry and the Ontario mortality
      file. Relative risk estimates were based on comparing observed and expected
      cancers in the cohort, the expected based on population incidence rates. In a
      cohort of more than 730,000 women, mean follow-up time was approximately 7.5
      years. The risk of colorectal cancer was reduced following certain of the
      surgical procedures. Relative risk (RR) estimates for bilateral tubal
      sterilization [RR = 0.81; 95% confidence intervals (CI) = 0.70-0.93],
      hysterectomy (RR = 0.89; 95% CI = 0.81-0.97) and hysterectomy with bilateral
      salpingo-oophorectomy (RR = 0.84, 95% CI = 0.75-0.94) all were substantially
      lower than 1.0, while neither unilateral oophorectomy nor tubal sterilization
      yielded risks different from 1.0. No pattern of altered risk was evident across
      age groups or over time since the surgical procedure. While there is potential
      for uncontrolled confounding by such exposures as hormone replacement therapy,
      the observed risks are consistent with a hypothesis of lowered endogenous
      oestrogen levels being associated with reduced risk of colorectal cancer.

PMID- 10643939
TI  - Dietary iron and cancer of the rectum: a case-control study in Uruguay.
AB  - In order to examine the relationship between dietary iron intake and risk of
      rectal cancer, a case-control study was carried out in Montevideo, Uruguay. In
      the time period 1994-1998, 216 newly diagnosed and microscopically verified cases
      of adenocarcinoma and 433 controls hospitalized for diseases not related with
      long-term changes in diet were enrolled in the study. Controls were frequency
      matched to cases on age, sex, residence and urban/rural status. Both series of
      patients were interviewed face-to-face in the four major hospitals in Montevideo
      by two trained social workers. Dietary iron was associated with significant
      increases in risk in men, women, and in both sexes together [odds ratio (OR) 3.2,
      95% confidence interval (CI) 1.9-5.3 for the highest tertile of consumption
      versus the lowest one]. Since meat and its major macronutrients were potential
      confounders, iron intake was adjusted for these variables without major changes
      in the results. Furthermore, dietary iron and total fat combined its effects
      according to a multiplicative model (OR 3.3, 95% CI 1.8-5.8). Finally, an
      interaction between dietary iron and vitamin C was found. According to the
      results, iron displayed a significant increase in risk at low levels of vitamin C
      intake (OR 4.9, 95% CI 2.3-10.5). These results, together with the existing
      epidemiological and experimental evidence, suggest that dietary iron could play
      an important role in rectal carcinogenesis.

PMID- 10643940
TI  - Changes in mammographic breast density and concomitant changes in breast cancer
      risk.
AB  - Among participants of the biennial Nijmegen breast cancer screening programme, we
      examined whether diminution of mammographic breast density lowered breast cancer
      risk. Post-menopausal breast cancer cases (n = 108), who had to have participated
      in all the five screening rounds prior to their diagnosis, were matched to 400
      controls on year of birth and screening history. Controls had to be free of
      breast cancer at the time of the case's diagnosis. Changes in breast density were
      measured over a 10-year period, by a fully computerized method. Women in whom 5
      25% or >25% of the breast was composed of fibro-glandular density showed a
      threefold increased 10-year risk compared to women with <5% density. In women
      with 5-25% density initially, we observed a trend of decreasing risk with
      diminishing density: when women with <5% density throughout the whole period
      formed the reference category, the odds ratio (OR) for those who decreased from 5
      25% to <5% density was 1.9 [95% confidence interval (CI) = 0.6-6.1] in contrast
      to the OR of 5.7 (95% CI = 2.2-15.2) for those with persisting 5-25% density. In
      women who increased from 5-25% density to >25% density the OR was 6.9 (95% CI =
      2.1-22.9). In women with >25% density initially, diminishing density was not
      clearly associated with lowering risk, which may be partly explained by the low
      number of women who decreased to <5% (n = 12). Due to the limited size of the
      study these results have to be interpreted with caution. Although the results are
      not conclusive, they could indicate a trend of decreasing risk with diminishing
      breast density. Should this effect be real, it may have great implications for
      the primary prevention of breast cancer or for the identification of high-risk
      groups who would benefit by more frequent screening. Therefore, large-scale, long
      term follow-up studies on the effects of changes in breast density are needed.

PMID- 10643941
TI  - Use of mammography among women residing in Spanish provinces with breast cancer
      screening programmes.
AB  - The objective of this study was to measure use of mammography and associated
      factors among women living in Spanish provinces with breast cancer screening
      programmes. From a cross-sectional population survey in a representative sample
      of Spanish women aged 40-70 years, we selected all women aged 45-65 living in
      provinces with breast cancer screening programmes (336 women). The programmes
      invited women in this age group to have a mammogram every 2 years. Data were
      collected by oral interviews in 1994. Use of mammography was defined as having
      received at least one test in the previous 2 years. Factors associated with
      mammography were studied using a logistic regression model. In the three
      autonomous communities (totalling 11 provinces) with programmes, the percentage
      of women receiving the test was 41.1% in Castille-Leon, 41.7% in Castille-La
      Mancha and 87.6% in Navarre (mean: 55.4%). The programmes began in 1990 in
      Navarre and between 1992 and 1993 in the other two communities. The most
      important factors affecting mammography use in the multivariate analysis were:
      intention to have a mammogram [odds ratio (OR) = 5.52; 95% confidence interval
      (CI) = 3.17-9.63]; not rejecting the test for fear of cancer diagnosis (OR =
      4.23; 95% CI = 1.64-10.9); and physician recommendation of the test (OR = 3.43;
      95% CI = 1.88-6.24). In conclusion, although the more established screening
      programmes have higher mammography use than those more recently implemented,
      programmes alone may not guarantee that women receive the test. Women's attitudes
      about mammography, and the role of the physician, are fundamental factors in the
      use of mammography.

PMID- 10643942
TI  - Glutathione S-transferases as risk factors in prostate cancer.
AB  - Glutathione S-transferases are enzymes involved in the metabolism of carcinogens
      and in the defence against reactive oxygen species. Genetic polymorphisms have
      been detected in glutathione S-transferases M1, T1 and P1, and some of these
      polymorphisms have been associated with an increased risk of cancer. In a case
      control study (153 cases and 288 controls) the effect of these genetic
      polymorphisms on the risk of prostate cancer was investigated. Homozygote
      deletion of either GSTM1 or GSTT1 was not associated with a statistically
      significant increased risk, odds ratio (OR) 1.3; 95% confidence intervals (CI)
      0.9-1.9 and 1.3; 0.8-2.2, respectively. Deletion of both GSTM1 and GSTT1 gave a
      near-significant increased risk (OR 1.7; 95% CI 0.9-3.4). Two allelic variants of
      GSTP1 (codon 105) have been reported. This polymorphism was not linked to an
      increased risk (OR 0.8; 95% CI 0.5-1.1). Smokers that lack either GSTM1 or GSTT1
      activity had a slightly higher risk of prostatic cancer than smokers expressing
      the genes, OR 1.4 (95% CI 0.6-3.3) and 1.6 (0.6-3.9), respectively. Our results
      show that differences in enzymes involved in the metabolism of carcinogens
      slightly modify prostate cancer risk, especially in people exposed to carcinogens
      that are detoxified by these enzymes.

PMID- 10643943
TI  - Effects of intestinal bacteria on the development of colonic neoplasm II. Changes
      in the immunological environment.
AB  - To study the effects of intestinal bacteria on the development of colonic
      neoplasm, we have established gnotobiotic mice with a single species of
      intestinal bacteria. In the previous study, the incidence of colonic adenoma
      induced with 1,2-dimethylhydrazine (DMH) in the gnotobiotic mice with
      Lactobacillus acidophilus, gnotobiotic mice with Escherichia coli and germ-free
      mice were 30, 50 and 74%, respectively. In this study, 7-week-old mice in each
      group were sacrificed without the administration of DMH to examine the
      constituents of immuno-competent cells in various mouse organs using flow
      cytometry. In the gnotobiotic mice, CD3 intermediate interleukin (IL)-2Rbeta
      positive cells were observed predominantly in the liver. In the gnotobiotic mice
      with L. acidophilus, Mac-1 positive Gr-1 positive cells were observed
      predominantly in the colonic lamina propria. The activation of extrathymic T
      cells in the liver and granulocytes in the colonic mucosa may be related to anti
      neoplastic effects of L. acidophilus in this experimental model.

PMID- 10643944
TI  - An initial comparison of nine centres registering patients with the UK National
      Barrett's Oesophagus Registry (UKBOR).
AB  - Initial data from the first nine hospitals registering at least 50 patients each
      with UKBOR were analysed. This involved 2102 Barrett's oesophagus (BO) cases
      (M1261:F841), mean 234 patients per centre (range 73-636) and M:F ratio 1.5
      (range 1.1-2.3). There was an equal geographical distribution of the hospitals,
      three each in the north of the country (N), Midlands (Mid) and the south of the
      country (S). The catchment populations varied from 145,000 to 450,000. The M:F
      ratio for N, Mid and S was 1.6, 1.3, 1.7, respectively. The mean age at diagnosis
      in males was 62.0 years (range 53.2-66.3) and in females 67.6 years (range 59.3
      73.4), with little geographical variation. The age distribution varied somewhat
      between the centres; the peak age for males being 40-49 years in one northern
      hospital, 60-69 years in seven others and 70-79 years in one hospital. For
      females it was 60-69 years and 70-79 years in each of four hospitals, and 80-89
      years in one. The BO diagnosis rate in the under 50s was fairly constant; F mean
      14% (range 0-23%); M (eight centres) mean 23% (range 16-27%). However, in one
      northern centre it was much higher (43%). Information on patients with a
      diagnosis of oesophageal adenocarcinoma (AC) was available from seven centres. A
      total of 59 AC were diagnosed (M44:F15, ratio 2.9). The overall mean rate of AC
      in BO was 3.6% (range 0.5-7.5%). Minor variations in BO patient characteristics
      may have been due to the hospitals' different policies on diagnostic and
      reporting criteria. However, the much higher percentage of men under age 50 in
      the one N centre may reflect a genuine difference in diet and lifestyle, or
      possibly genetic susceptibility.

PMID- 10643945
TI  - To squat or not to squat--that is the question.

PMID- 10643946
TI  - The physician's role in the assessment of older drivers.

PMID- 10643947
TI  - Multiple chemical sensitivity.

PMID- 10643948
TI  - Family physicians and HIV care.

PMID- 10643949
TI  - Comments on type 2 diabetes screening and treatment.

PMID- 10643950
TI  - Comments on type 2 diabetes screening and treatment.

PMID- 10643951
TI  - Chronic abdominal pain and abdominal epilepsy.

PMID- 10643952
TI  - Diagnostic evaluation of erectile dysfunction.
AB  - Erectile dysfunction, the persistent inability to attain or maintain penile
      erection sufficient for sexual intercourse, affects millions of men to various
      degrees. The majority of cases have an organic etiology, most commonly vascular
      disease that decreases blood flow into the penis. Regardless of the primary
      cause, erectile dysfunction can have a negative impact on self-esteem, quality of
      life and interpersonal relationships. The initial step in evaluation is a
      detailed medical and social history, including a review of medication use.
      Discussion with the patient's sexual partner may clarify exacerbating issues. The
      physical examination focuses on the cardiovascular, neurologic and urogenital
      systems. Laboratory tests are useful to screen for common etiologic factors and,
      when indicated, to identify hypogonadal syndromes. Appropriate evaluation of
      erectile dysfunction leads to accurate advice, management and referral of
      patients with erectile dysfunction.

PMID- 10643953
TI  - Anticipatory guidance in infant oral health: rationale and recommendations.
AB  - If appropriate measures are applied early enough, it may be possible to totally
      prevent oral disease. The American Academy of Pediatric Dentistry recommends that
      infants be scheduled for an initial oral evaluation within six months of the
      eruption of the first primary tooth but by no later than 12 months of age. The
      rationale for this recommendation is provided, although the recommendation itself
      is not universally accepted. Specific recommendations include elimination of
      bottles in bed, early use of soft-bristled toothbrushes (with parental
      supervision) and limitation of high-carbohydrate food intake after teeth have
      been brushed.

PMID- 10643954
TI  - Contemporary management of angina: part II. Medical management of chronic stable
      angina.
AB  - Except for a small subset of patients with angina whose survival is improved with
      coronary artery bypass surgery, chronic stable angina can be appropriately
      managed with medical therapy in the vast majority of patients. Drug therapy
      includes aspirin, beta-adrenergic blockers, cholesterol-lowering agents and other
      anti-ischemic drugs that can ameliorate angina and improve the patient's quality
      of life. Understanding how and when to use these medicines involves knowledge of
      the mechanisms of these drugs as well as familiarity with the literature
      supporting their efficacy in various patient populations.

PMID- 10643955
TI  - The older adult driver.
AB  - More adults aged 65 and older will be driving in the next few decades. Many older
      drivers are safe behind the wheel and do not need intensive testing for license
      renewal. Others, however, have physiologic or cognitive impairments that can
      affect their mobility and driving safety. When an older patient's driving
      competency is questioned, a comprehensive, step-by-step assessment is
      recommended. Many diseases that impair driving ability can be detected and
      treated effectively by family physicians. Physicians should take an active role
      in assessing and reducing the risk for injury in a motor vehicle and, when
      possible, prevent or delay driving cessation in their patients. Referral to other
      health care professionals, such as an occupational or physical therapist, may be
      helpful for evaluation and treatment. When an older patient is no longer
      permitted or able to drive, the physician should counsel the patient about using
      alternative methods of transportation.

PMID- 10643956
TI  - Osteochondritis dissecans: a diagnosis not to miss.
AB  - Osteochondritis dissecans is the most common cause of a loose body in the joint
      space in adolescent patients. Because clinical findings are often subtle,
      diagnosis requires a high index of suspicion. Limited range of motion may be the
      only notable clinical sign. The diagnosis is made by radiographic examination,
      and magnetic resonance imaging has a key role in determining the stability of the
      lesion. Conservative management is the mainstay of treatment for stable lesions.
      While the majority of patients respond to conservative treatment, those with
      unstable lesions require arthroscopic management.

PMID- 10643957
TI  - 1999 USPHS/IDSA Guidelines for the Prevention of Opportunistic Infections in
      Persons Infected with HIV: Part I. Prevention of Exposure.

PMID- 10643959
TI  - Photo quiz. Cry ungual!

PMID- 10643958
TI  - Newer intranasal migraine medications.
AB  - Two new intranasal migraine medications, sumatriptan and dihydroergotamine
      mesylate, may offer specific advantages for patients who are seeking alternatives
      to various oral or parenteral migraine abortive therapies. Placebo-controlled
      clinical studies demonstrate that both intranasal forms are effective in
      relieving migraine headache pain, but published clinical trial information
      comparing these two intranasal medications with current abortive therapies is
      lacking. Both agents are generally well tolerated by patients, with the exception
      of mild, local adverse reactions of the nose and throat.

PMID- 10643960
TI  - Curbside consultation. Why can't this patient take insulin?

PMID- 10643961
TI  - The 2000 harmonized immunization schedule.

PMID- 10643962
TI  - Genomic organization and expression of the ubiquitin-proteasome complex
      associated protein Rbx1/ROC1/Hrt1.
AB  - Rbx1/ROC1/Hrt1 (Rbx1) has been recently shown to be involved in the regulation of
      protein turn-over. Here, we report the organization of the human Rbx1 gene,
      established by both a cloning and a functional genomics approach. The human gene,
      composed of five exons, encompasses 22.3 kb on chromosome 22q 13. The expression
      of Rbx1 transcripts (0.5 kb) appears developmentally regulated during mouse
      embryonic development and is prevalent in the adult mouse genital tract. A
      Genbank database search for Rbx1 related sequences in various species, from
      plants to mammals, is indicative of a high degree of evolutionary conservation in
      mouse rat and zebra fish and also, for the main functional part of the molecule,
      in other living species, although their gene structures can be significantly
      altered.

PMID- 10643963
TI  - Biological consequences of irradiation by low doses of technetium 99m:
      ultrastructural studies, p53 protein expression and cytogenetic effects.
AB  - Few studies concerning the potential genetic effects of diagnostic radionuclides
      used in nuclear medicine have been reported. The aim of this study was to
      evaluate the biological and cytogenetic consequences of two technetium 99m
      labelled radiopharmaceuticals. Ultrastructural modifications of pulmonary cells
      were first investigated after injection of 99mTc labelled microspheres in the
      rat. On the same irradiated cells, nuclear expression of p53 protein was assessed
      using immunohistochemistry. Despite very high previously calculated doses
      delivered to pulmonary cells, no morpholological cell damage and no significant
      increase of nuclear expression of the p53 were noted. There was no correlation
      between the calculated dose and the ultrastructural biological damage. Secondly,
      a specific in vitro curve, activity/number of unstable chromosomal aberrations,
      corresponding to physical characteristics of 99mTc, was established to verify the
      potentiality of 99mTc to induce such aberrations. In vivo, cytogenetic effects
      were assessed on blood samples of 5 patients with various arthrosic and
      periarthrosic diseases obtained after bone scintigraphy. Aberration frequencies
      of both in vitro and in vivo irradiated lymphocytes were determined using the
      classical Fluorescence Plus Giemsa technique. No cytogenetic effects appeared
      with the routinely 99mTc injected activities as predicted by the in vitro curve.

PMID- 10643964
TI  - DNA-binding properties of CCAAT displacement protein cut repeats.
AB  - CCAAT displacement protein (CDP) is a transcriptional repressor that contains
      four distinct DNA-binding domains; a homeodomain and three cut repeats. Each DNA
      binding domain of CDP was expressed as a glutathione S-transferase (GST)-fusion
      protein and analyzed for relative binding affinity to five CDP-binding sites
      within the gp91phox promoter. Each cut repeat exhibits a unique pattern of DNA
      binding affinities for the five binding sites in the gp91phox promoter,
      suggesting that each may make a distinct contribution to the DNA-binding behavior
      of native CDP. Although measurement of DNA/protein complex mass indicates that an
      isolated cut repeat can bind DNA as a monomer, mixing of GST-cut repeat and GST
      homeodomain fusion proteins enhances DNA-binding activity. Far-Western blot and
      two-hybrid analyses indicate, however, that the CDP domains do not directly
      interact. We hypothesize that GST-mediated dimerization leads to spatial
      juxtaposition of these DNA-binding domains, and that the resulting enhanced DNA
      binding activity mimics cooperative interactions that occur between these domains
      in native CDP.

PMID- 10643965
TI  - Calculated flexibility of histone proteins correlate with mammalian histone H1
      subtype.
AB  - We have calculated the polypeptide flexibility index for mammalian histone H1
      sequences obtained from the National Center for Biotechnology Information Histone
      Sequence Database. This database contains over 1000 histone protein entries, from
      various species, compiled from SWISS_PROT, PIR, the Protein Data Bank (PDB), and
      CDS translations from GenBank. Histone H1 proteins were analyzed because of their
      critical role in chromatin structure and gene expression. Flexibility
      calculations revealed that histone subtype H1.0, which accumulates during
      terminal differentiation, has the highest flexibility index of all mammalian H1
      subtypes. Other mammalian H1 subtypes had lower flexibility indices, including
      the human H1.2 subtype whose mRNA contains both a hairpin loop sequence and a
      poly(A) addition sequence. Histone mRNAs containing both of these structures have
      been shown to be expressed prior to and after terminal differentiation, yet these
      proteins do not necessarily accumulate in the chromatin of terminally
      differentiated cells. H1.2 and the H1.t have the lowest flexibility index (most
      ridged) of all human H1 subtypes. All human H1 proteins of the replication
      dependent subtypes have intermediate values for their flexibility indices.

PMID- 10643966
TI  - Stable maintenance of linear bovine papillomavirus 1 molecules in C127I cells.
AB  - This paper describes the characterization of cell lines that stably maintain
      linear copies of bovine papillomavirus 1 (BPV-1). Cell lines were generated by
      liposome-mediated transfection of BamH1-linearized virus into C127I cells. Two
      transfectants with morphologies differing from each other and from that of the
      parental cell line were characterized. Southern blots indicated that they contain
      ten to twelve copies of the BPV-1 genome per cell and that the predominant
      species in both cell lines are linear BPV-1 episomes. One to two copies per
      genome of a slow migrating species are also present. Both BPV-1 species found in
      these cells are sensitive to BAL31 digestion. Viral chromosomal ends were
      amplified by anchored PCR, cloned and sequenced. Our results indicate that no
      major rearrangements have occurred in the sequence flanking the BamH1 site where
      the virus used for transfection was linearized. No circular BPV-1 molecules were
      detected by PCR. The slow migrating species may serve as templates for
      replication for the linear forms by a yet unidentified mechanism.

PMID- 10643967
TI  - Somatostatin inhibits the Na+/H+ exchange activity of rat hepatocytes in short
      term primary culture.
AB  - Activation of the Na+/H+ exchanger is associated with cell growth and
      differentiation. Our study has tested whether somatostatin-14 (SS-14), which is a
      potent inhibitor of liver regeneration, has an inhibitory effect on the Na+/H+
      exchange (NHE-1) of rat hepatocytes. We treated hepatocytes with SS-14 prior and
      after cell culture. NHE-1 activity of short term cultured hepatocytes was
      estimated with the recovery rate of pHi after 9 min. acid-loading in a sodium
      free buffer. Cultured with SS-14 (100 nM) inhibited significantly the pHi
      recovery rate of hepatocytes, dpHi/dt and set point were significantly decreased
      in the presence of SS-14 in comparison to controls. The resting pHi of
      hepatocytes was not affected in the presence of SS-14. In contrast, addition of
      SS-14 after cell culture had no effect on the pHi recovery rate of hepatocytes.
      Therefore the inhibitory action of SS-14 on NHE-1 activity of rat hepatocytes
      appears to depend on the presence of the hormone in the early steps of the
      process of cell growth/adhesion. Inhibition of SS-14 on NHE-1 activity seems to
      mediate, at least in part, its inhibition on liver regeneration.

PMID- 10643968
TI  - Cellular and subcellular distribution of galectin-3 in the epiphyseal cartilage
      and bone of fetal and neonatal mice.
AB  - Galectin-3 is a 30 kDa beta-galactoside binding protein that belongs to the
      galectin family of animal lectins. By immunocytochemistry we show the presence of
      galectin-3 protein in the differentiated chondrocytes of the epiphyseal plate
      cartilage of long bones of both fetal and neonatal mice. The highest
      concentrations of galectin-3 are found in the cytoplasm of mature and early
      hypertrophic chondrocytes. Very little protein is detected in the late
      hypertrophic chondrocytes undergoing terminal maturation and cell death. Galectin
      3 has also been found in osteoblasts and osteocytes of the woven bone of the
      metaphysis and the cortical bone of the diaphysis, as well as in osteoclasts and
      mononuclear cells within bone marrow cavities. Galectin-3 is never detected
      extracellularly, the protein seems restricted to the cytoplasm of chondrocytes
      and bone cells, although it is occasionally detected in the nuclei of dense non
      hypertrophic chondrocytes in the zone of calcification and in young osteoblasts.
      The results indicate that galectin-3 is a marker of both chondrogenic and
      osteogenic cell lineages. They also suggest that galectin-3 could be involved in
      the process of endochondral bone formation, possibly as a regulator of
      chondrocyte survival.

PMID- 10643969
TI  - Modulation of free radical stress in human red blood cell membrane by forskolin
      and the prospects for treatment of cardiovascular disease and diabetes.
AB  - This study has examined the effect of oxidants and elevated levels of glucose on
      membrane lipid peroxidation of human red blood calls (RBC). Washed RBC incubated
      with varying concentrations of glucose at 37 degrees C for 24 hrs. showed a
      significant increased membrane lipid peroxidation when compared with control RBC.
      Addition of ferrous sulphate and ascorbic acid which are known oxidants caused
      greater rise in lipid peroxides compared to elevated level of glucose alone. Pre
      treatment of RBC with varying doses of forskolin (4-70 microg) was associated
      with significantly smaller rise in lipid peroxides in a dose dependent manner.
      Forskolin effect was comparable with the antioxidant effect of other drugs such
      as vitamin E, trimetazidine, ginkocer, probucol. It is possible that forskolin at
      higher concentrations may have a greater antioxidant effect than other
      antioxidant drug. However more studies, especially animal experiments, and trials
      in human would be necessary to confirm our findings.

PMID- 10643970
TI  - Effect of ischemia-reperfusion on the heterogeneous lobular distribution pattern
      of glycogen content and glucose-6-phosphatase activity in human liver allograft.
AB  - In order to examine glucose metabolism in liver grafts after cold ischemia and
      reperfusion, the heterogeneous lobular distribution pattern of glycogen content
      and glucose-6-phosphatase activity was studied using histochemical methods. The
      characteristic heterogeneous lobular distribution pattern of glycogen and glucose
      6-phosphatase was maintained after preservation and reperfusion. However, it
      appeared that glycogen content decreased in both periportal and centrilobular
      hepatocytes after reperfusion. The glycogen decrease was higher in periportal
      hepatocytes. Glucose-6-phosphatase activity was maintained after reperfusion in
      most of the cases in periportal hepatocytes. In centrilobular hepatocytes, more
      cases showed a decrease in enzyme activity. It is suggested that ischemia
      reperfusion mainly affects the glycogen content in both periportal and
      centrilobular hepatocytes and that centrilobular glucose-6-phosphatase activity
      is more sensitive to ischemia-reperfusion injury than periportal hepatocytes.

PMID- 10643971
TI  - Expression of cyclins and cdks throughout murine carcinogenesis.
AB  - The overexpression and/or amplification of cell cycle regulating genes is an
      important factor in the progression of cancer. Recent attention has been focused
      on several cyclin and cdks genes whose expression were increased in many types of
      tumor. In this study, we investigated the expression kinetics of cyclins A, B,
      D1, E and cdks 1, 2, 4, 6 by RT-PCR coupled with densitometry and correlated to
      the growth fraction (percentage of S cells). This analysis was performed using an
      experimental murine leukemic model, generated by in vivo administration of murine
      clonogenic cells Wehi-3b injected into balb-c mice. Differential expression of
      cyclins and cdks was observed between normal and tumoral cells with different
      patterns of expression between G1 and G2M cyclins-cdks. G1 cyclins cdks
      expression was significantly increased in tumor cells when compared to normal
      cells. In the same manner, G2M cyclins cdks expression was only observed in tumor
      cells at a lower level than for G1 cyclins cdks, but not detected in normal
      cells. These differences correlated with the growth fraction for both the G1
      cyclins cdks (r = 0.91, 0.94, 0.85, 0.90 and 0.96 for cyclin D1, cyclin E, cdk2,
      cdk4 and cdk6, respectively) and the G2M cyclins cdks (r = 0.96, 0.97 and 0.93
      for cyclins A, B and cdkl respectively). Analysis of cyclins cdks expression
      kinetics during tumoral progression shows that cyclins A, B and cdkl were
      expressed from the 12th day on of disease, increased until the death of the
      animals and correlated with the growth fraction (r = 0.94, 0.95 and 0.97 for
      cyclins A, B and cdk1 respectively) (n = 20). Overexpression of other cyclins
      cdks were observed, from the 6th day on for cyclin D1, the 12th day for cdk2 and
      cdk4, the 15th day for cdk6 and the 20th day for cyclin E. These increases
      persisted during tumoral progression and correlated with the growth fraction (r =
      0.85, 0.94, 0.93, 0.96, and 0.98 for cyclin D1, cyclin E, cdk2, cdk4 and cdk6,
      respectively) (n = 20). Our results demonstrated that G1 and G2-M cyclins cdks
      mRNA levels were increased at approximately the same time of maximal tumor
      growth. Only cyclin D1 overexpression occured at the initiation of tumoral
      development, and could therefore be considered as an early marker of cell
      proliferation.

PMID- 10643973
TI  - Comparative functional study of the lysyl oxidase promoter in fibroblasts, Ras
      transformed fibroblasts, myofibroblasts and smooth muscle cells.
AB  - The promoter activity of lysyl oxidase (LOX), the enzyme involved in collagen and
      elastin cross-linking and in tumor suppression, was compared in extracellular
      matrix producing cells and in tumorigenic c-Ha-ras-NIH-3T3 fibroblasts (RS485).
      The full 2 kb murine LOX promoter was very active in 3T6-5 myofibroblast-like
      cells (MFLC) and vascular smooth muscle cells (SMC) and was inhibited in ras
      transformed fibroblasts. Positive cis-acting elements were located around sites
      of transcription initiation in MFLC and SMC, but neither in RS485 fibroblasts nor
      in their non-transformed counterparts. The main positive cis-acting segment, at
      positions -808 to -585, was active in all cells, with the strongest activity in
      MFLC and SMC, and one segment, at positions -758 to -726, allowed the formation
      of one master DNA-protein complex with nuclear factors from all cells. The main
      inhibiting region, at positions -1,362 to -1,176, was active in all fibroblasts,
      but not in SMC, in an upstream position or in an enhancer/silencer position. This
      region carries two segments, called LOcoll and LOcol2 for their similarity to
      COL1A1 and COL1A2 promoter sequences, that were involved in the formation of a
      large multifactorial DNA complex with nuclear factors from all cells, though
      slightly for SMC. Another region, carrying a putative interferon response element
      (IRF) at positions -898 to -886, acted negatively on each type of cells. In
      conclusion, the LOX promoter is controlled by cross-talk between positive and
      negative cis-acting regions that are differentially active in various cells. The 
      758 to -726 region, with its putative C/EBP site, and the transcription
      initiation region are likely to play a master role in activating the LOX promoter
      in fibrocompetent MFLC and SMC. While the LOcol1/2 segment, with putative B-Myb
      binding sites, and the IRF carrying region, work negatively on the LOX promoter
      in transformed cells.

PMID- 10643972
TI  - New method for the histochemical demonstration of dipeptidyl aminopeptidase I
      activity using a novel anthraquinoyl hydrazide substrate.
AB  - A new method for the histochemical localization of dipeptidyl aminopeptidase I
      (DPP I, cathepsin C), based on a newly synthesized substrate-Gly-L-Phe-5-chloro-1
      anthraquinoyl hydrazide.HCl (Gly-Phe-CAH), is proposed. The enzyme activity
      liberates 5-chloro-1-anthraquinoyl hydrazine (CAH)--a water-insoluble brown
      reddish compound, which precipitates on the enzyme locations. The primary
      reaction product reacts simultaneously or, otherwise, by post-coupling with p
      anisaldehyde (p-AA), thus converting to the reddish-violet amorphous hydrazone-
      the final reaction product. The validity of enzyme localization is thus assured
      by the insolubility of the primary reaction product and does not depend on the
      rate of the second reaction step. The enzyme studied is successfully localized in
      different rat organs using the newly proposed technique.

PMID- 10643974
TI  - DNA typing of primate major histocompatibility complex (Mhc)-DQA1 locus by PCR
      and dot blot hybridization.
AB  - Non-human primates (NHPs) are increasingly utilized as models to investigate
      different aspects of immune responses against self (autoimmunity) and foreign
      antigens. These animals provide valuable models for testing the efficacy of
      candidate vaccines against pathogens such as human immunodeficiency virus (HIV)
      and also fertility regulating agents (immunocontraceptives). In order to fully
      understand the effects of vaccination, it may be necessary to elucidate the
      immunogenetic background of these animals. The major histocompatibility complex
      (Mhc) molecules play an important role in the generation of effective immune
      responses. Serological techniques have been used in the identification of human
      leukocyte antigens (HLA) necessary for cross-matching organs and tissues for
      transplantation. However, the application of this technique for typing monkey Mhc
      alleles has been hampered by unavailability of well characterized immunological
      reagents. Polymerase chain reaction (PCR)-based techniques such as restriction
      fragment length polymorphism (RFLP) and sequence-specific oligonucleotide probe
      hybridization (SSOP) have been extensively used for typing HLA-DP, DQ and DR
      alleles. A commercially available Kit (AmpliTypeR) designed for amplification and
      typing of HLA DQalpha alleles is routinely used in typing DNA samples for
      forensic casework. In the present study, we have evaluated this kit for possible
      application in routine typing of primate DQA1 alleles. Genomic DNA from ten
      African primate species (23 individuals) was isolated from peripheral blood
      lymphocytes and polymorphic second exon of DQA1 locus amplified using GH26 and
      GH27 PCR primers. The PCR products were hybridized on a nylon membrane containing
      immobilized sequence-specific oligonucleotide probes. Our results show seven of
      the nine probes hybridizing with primate DQA1 alleles, indicating that typing of
      equivalent primate alleles can be accomplished at lower stringency conditions.
      However, it may be necessary to design additional oligonucleotides probes (based
      on available primate DQA1 sequences) to improve the discriminating power of this
      kit for use in routine typing of Old World monkey DQA1 alleles.

PMID- 10643975
TI  - Feline papillomas and papillomaviruses.
AB  - Papillomaviruses (PVs) are highly species- and site-specific pathogens of
      stratified squamous epithelium. Although PV infections in the various Felidae are
      rarely reported, we identified productive infections in six cat species. PV
      induced proliferative skin or mucous membrane lesions were confirmed by
      immunohistochemical screening for papillomavirus-specific capsid antigens. Seven
      monoclonal antibodies, each of which reacts with an immunodominant antigenic
      determinant of the bovine papillomavirus L1 gene product, revealed that feline PV
      capsid epitopes were conserved to various degrees. This battery of monoclonal
      antibodies established differential expression patterns among cutaneous and oral
      PVs of snow leopards and domestic cats, suggesting that they represent distinct
      viruses. Clinically, the lesions in all species and anatomic sites were locally
      extensive and frequently multiple. Histologically, the areas of epidermal
      hyperplasia were flat with a similarity to benign tumors induced by
      cutaneotropic, carcinogenic PVs in immunosuppressed human patients. Limited
      restriction endonuclease analyses of viral genomic DNA confirmed the variability
      among three viral genomes recovered from available frozen tissue. Because most
      previous PV isolates have been species specific, these studies suggest that at
      least eight different cat papillomaviruses infect the oral cavity (tentative
      designations: Asian lion, Panthera leo, P1PV; snow leopard, Panthera uncia, PuPV
      1; bobcat, Felis rufus, FrPV; Florida panther, Felis concolor, FcPV; clouded
      leopard, Neofelis nebulosa, NnPV; and domestic cat, Felis domesticus, FdPV-2) or
      skin (domestic cat, F. domesticus, FdPV-1; and snow leopard, P. uncia, PuPV-2).

PMID- 10643976
TI  - Theileriosis in a Missouri beef herd caused by Theileria buffeli: case report,
      herd investigation, ultrastructure, phylogenetic analysis, and experimental
      transmission.
AB  - A 6-year-old Simmental cow infected with Theileria buffeli had a clinical disease
      characterized by theilerial parasitemia, macrocytic normochromic anemia with
      acanthocytosis and spherocytosis, lymphoid hyperplasia (lymphocytosis, edematous
      lymphadenomegaly), dysproteinemia, evidence of liver disease, and a low serum
      antibody titer against T. buffeli. The cow was in a herd in which all cattle
      originated in Missouri; 22/75 (29%) of cattle had a theilerial parasitemia and
      26/75 (35%) had titers to T. buffeli of > or =1:160. Classification of the
      Missouri bovine organism as T. buffeli was based on DNA sequencing and comparison
      to sequences for T. buffeli and Theileria sp. type A obtained from GenBank.
      Intraerythrocytic veils and piroplasms were seen during transmission electron
      microscopy. The organism was successfully transmitted to two splenectomized
      calves, which developed mild anemias while parasitemic. Blood from the second
      calf was used as the source of T. buffeli antigen for an indirect
      immunofluorescence antibody test. Theilerial isolates from a Missouri white
      tailed deer were also sequenced and resembled Theileria sp. types F and G and
      were not consistent with the bovine organism.

PMID- 10643977
TI  - Scanning electron microscopy and fluorescent in situ hybridization of
      experimental Brachyspira (Serpulina) pilosicoli infection in growing pigs.
AB  - Two groups of six 8-week-old pigs were challenged with 1x10(9) cfu Brachyspira
      (Serpulina) pilosicoli or Serpulina intermedia daily for 3 consecutive days to
      study the pathology of porcine colonic spirochetosis by scanning electron
      microscopy (SEM) and fluorescent in situ hybridization (FISH) with
      oligonucleotide probes targeting ribosomal RNA specific for B. pilosicoli and the
      genus Brachyspira/Serpulina. Six pigs served as noninoculated controls. The
      animals were euthanatized successively between postinoculation days 14 and 24. B.
      pilosicoli was reisolated in feces from all of the inoculated pigs; however, only
      two pigs developed transient watery diarrhea. S. intermedia was reisolated from
      four of the inoculated pigs, but clinical signs were not observed. Gross
      examination of the B. pilosicoli-infected pigs revealed dilated large intestines
      with a hyperemic mucosa, whereas the large intestines of the S. intermedia
      inoculated pigs and the control pigs appeared normal. SEM examination of B.
      pilosicoli-infected pigs revealed degenerated epithelial cells and spirochetal
      colonization of the colonic mucosa in four pigs. By FISH, B. pilosicoli cells
      were found colonizing and invading the surface epithelium and the crypts in all
      the pigs. Spirochetal crypt colonization markedly exceeded the occurrence of
      spirochetes on the mucosal surface. SEM examination of S. intermedia-inoculated
      pigs revealed no abnormalities, and Serpulina cells were detected only
      sporadically in the otherwise normal-appearing mucosa of four pigs by FISH. The
      results provide further evidence that B. pilosicoli is associated with colitis in
      pigs, although the gross lesions are mild. The spirochete is capable of
      colonizing the large intestine, inducing mucosal damage, invasion of the crypt
      and surface epithelium, and focal infiltration of the lamina propria. In
      addition, the study shows the applicability of FISH for specific identification
      of B. pilosicoli in formalin-fixed tissue.

PMID- 10643978
TI  - Immunohistochemical detection of p53 tumor-suppressor protein is a poor indicator
      of prognosis for canine cutaneous mast cell tumors.
AB  - Eighty-three canine cutaneous mast cell tumors were graded histologically and
      evaluated immunohistochemically for p53 tumor-suppressor protein expression. An
      avidin-biotin immunohistochemical protocol incorporated a rabbit polyclonal
      antibody (CM-1) directed against normal and mutant p53 protein. Positive staining
      was observed in 44.6% (37/83) of tumors and included 50% (12/24) of grade I (well
      differentiated) tumors, 46.9% (23/49) of grade II (intermediate differentiation)
      tumors, and 20% (2/10) of grade III (poorly differentiated) tumors. A
      statistically significantly higher proportion (P < 0.019) of tumors from the head
      and neck (83.3%, 10/12), stained positive for p53 than tumors from the thorax,
      back, abdomen, and axilla (39.4%, 13/33), legs (35.7%, 10/28), or prepuce,
      scrotal, or inguinal areas (44.4%, 4/9). No statistically significant difference
      between p53 labeling and histologic grade, breed, or tumor size was present.
      Survival data were available for 53/83 (63.9%) of dogs. Positive reactivity for
      p53 was observed in 47% (25/53) of tumors within this group, with 57.9% (11/19)
      of grade I, 43.3% (13/30) of grade II, and 25% (1/4) of grade III tumors labeled.
      Mean survival time for the 53 dogs was 12.1 months. The median survival time for
      dogs with grade III tumors or tumors >5 cm was statistically significantly
      shorter (P < 0.0001) than for dogs with grades I and II or smaller tumors.
      Although p53 protein abnormalities may play a role in tumor development or
      behavior in some canine cutaneous mast cell tumors, immunoreactivity was not
      associated with lack of tumor differentiation, tumor locations previously shown
      to demonstrate aggressive biological behavior, breed predisposition, or survival
      times.

PMID- 10643979
TI  - Immunohistochemical and clinical evaluation of p53 in canine cutaneous mast cell
      tumors.
AB  - One hundred twenty-six cutaneous mast cell tumors obtained by excisional biopsy
      from 106 dogs were evaluated using immunohistochemical staining for the presence
      of p53 protein. A standard avidin-biotin immunohistochemical protocol was used
      incorporating a polyclonal antibody of rabbit origin (CM-1) as the primary
      antibody. Histopathologic grading of tumors was performed on hemotoxylin and
      eosin-stained samples. There was a significant difference in the percentage of
      cells staining positive for p53 for the histopathologic grades (P = 0.0005).
      Grade III tumors had a significantly greater p53 content than did grade I or II
      tumors (P < 0.05). Clinical data obtained retrospectively was available for 54
      dogs. Tumor recurred in 19 of 54 (35.2%) dogs. Twenty-nine dogs died by the end
      of the study; 9 of 29 (31.0%) died of mast cell tumor disease. Histopathologic
      grade showed a significant negative association with survival time. Both clinical
      stage and histopathologic grade showed a significant negative association with
      time to recurrence. The percentage of cells staining positive for p53 did not
      significantly improve the forward analysis. Immunohistochemical detection of p53
      did not appear useful in characterizing the clinical association between
      cutaneous mast cell tumor cellular features and survival time or time to tumor
      recurrence in dogs.

PMID- 10643980
TI  - Specific in situ hybridization of Haemobartonella felis with a DNA probe and
      tyramide signal amplification.
AB  - Haemobartonella felis is an epierythrocytic bacterium suspected to be the
      causative agent of feline infectious anemia. Previous studies with a polymerase
      chain reaction assay have identified a mycoplasmal 16S rRNA gene sequence that
      coincides with clinical disease and the presence of organisms in the blood.
      Tissues from a cat experimentally infected with H. felis were used for in situ
      hybridization studies to physically link this 16S rRNA gene to the organisms on
      the red cells. A biotin-labeled probe was used in conjunction with tyramide
      signal amplification to visualize the hybridization signal. This study clearly
      demonstrates a specific hybridization signal on the red cells in the tissues of
      the H. felis-infected cat. This in situ hybridization study is the final step in
      fulfilling the molecular guidelines for disease causation and proves that H.
      felis, a mycoplasmal organism, is the causative agent of feline infectious
      anemia.

PMID- 10643981
TI  - Inactivation of p53 and retinoblastoma family pathways in canine osteosarcoma
      cell lines.
AB  - Canine osteosarcoma (OS) has been used as a model system for the study of cancer
      biology and treatment despite the lack of information regarding its pathogenesis.
      Expression of tumor suppressor genes known to participate in malignant
      transformation were studied in five different OS cell lines. Each of the cell
      lines exhibited properties of transformed cells, and those that were tested grew
      in soft agarose and formed osteoid-containing tumors when injected subcutaneously
      into nude mice. p53 function was determined to be defective in each cell line as
      indicated by the lack of induction of p53-responsive genes, p21 and mdm2,
      following treatment with 5-fluorouracil. p53 mRNA and protein levels were
      elevated in three cell lines and were extremely low in two cell lines. p53
      protein overexpression correlated with the presence of mutations within the DNA
      binding domain. Four cell lines appeared to contain normal retinoblastoma (Rb)
      mRNA and Rb protein and no detectable p16 mRNA or protein. In contrast, the
      remaining cell line contained high levels of p16 mRNA and protein and
      significantly reduced levels of Rb, p107, and p130 proteins. These results
      underscore the importance of inactivating p53 and Rb family pathways in canine OS
      and suggest that unlike human OS, cells derived from canine OS contain mutations
      that simultaneously inactivate all three Rb family members.

PMID- 10643982
TI  - In situ hybridization for the detection and localization of porcine epidemic
      diarrhea virus in the intestinal tissues from naturally infected piglets.
AB  - Detection and localization of porcine epidemic diarrhea virus (PEDV) was studied
      by in situ hybridization with a nonradioactive digoxigenin-labeled probe in
      formalin-fixed, paraffin-embedded tissues from 10 naturally infected piglets. A
      377-base pair cDNA probe for viral RNA encoding the membrane proteins of PEDV
      cell-culture-adapted strain V215/78 was generated by the reverse transcription
      polymerase chain reaction. In the retrospective study of pigs from herds with
      diarrhea, the 10 piglets naturally infected with PEDV had positive signals for
      PEDV by in situ hybridization. When intestinal tissues were hybridized with the
      PEDV probe, a strong signal was seen in the villus enterocytes of jejunum and
      ileum but not in the cecum and colon. Positive cells typically had dark brown
      reaction products in the cytoplasm. Scattered epithelial cells along the ileal
      Peyer's patches dome areas contained viral RNA. In one piglet, hybridization
      signal was also found in the duodenum. PEDV was not demonstrated in tissues
      outside of the intestinal tract. These findings indicate that jejunal and ileal
      villus enterocytes are the main target of PEDV replication during epizootic
      outbreaks of the disease.

PMID- 10643983
TI  - Experimental infection of ponies with Borrelia burgdorferi by exposure to Ixodid
      ticks.
AB  - Seven specific-pathogen-free (SPF) ponies, 1-5 years old, were exposed to
      Borrelia burgdorferi-infected adult ticks while being treated with dexamethasone
      over 5 consecutive days. One SPF pony (pony No. 178) was first exposed to
      laboratory-reared nymphs without B. burgdorferi infection and 3 weeks later was
      exposed to B. burgdorferi-infected adult ticks with concurrent dexamethasone
      treatment for 5 consecutive days. Four uninfected ponies treated with
      dexamethasone, exposed to laboratory-reared ticks without B. burgdorferi
      infection served as uninfected controls. Clinical signs, bacteriologic culture,
      polymerase chain reaction (PCR) for bacterial DNA, immunologic responses, and
      gross lesions and histopathologic changes were investigated during the experiment
      or at necropsy 9 months after tick exposure. In all of the seven challenged
      ponies, infection with B. burgdorferi was detected from monthly skin biopsies and
      various tissues at postmortem examination by culture and by PCR. However, pony
      No. 178 exposed to laboratory-reared nymphs (without B. burgdorferi infection)
      and challenged with B. burgdorferi-infected adult ticks 2 months later did not
      develop a B. burgdorferi infection. All of the infected ponies seroconverted.
      Control ponies and pony No. 178 were negative by culture, PCR, and serology.
      Except for skin lesions, we failed to induce any significant histopathologic
      changes in this study. This is the first report of successful tick-induced
      experimental infection in ponies by exposure to B. burgdorferi-infected ticks.
      This Lyme disease model will be very useful to evaluate efficacy of vaccines
      against the Lyme agent and the effect of antibiotic therapy on horses infected
      with B. burgdorferi.

PMID- 10643984
TI  - Experimental Brucella abortus induced abortion in a llama: pathologic effects.
AB  - Brucella abortus infection has not been documented in llamas. This report
      describes the abortion of the only pregnant animal in a group of 12. The llama
      was infected by inoculating 1 x 10(8) viable B. abortus organisms into the
      conjunctival sac. Forty-three days postinfection, the llama aborted a fetus of
      approximately 8 months gestational age. Brucella organisms were isolated from the
      placenta and all fetal specimens examined. These organisms were also isolated
      from the dam's mammary gland and numerous lymph nodes when the llama was
      necropsied 42 days later. Microscopically, there was a moderate, multifocal,
      lymphocytic and histiocytic, subacute placentitis with marked loss of
      trophoblastic epithelial cells. The superficial chorioallantoic stroma contained
      abundant necrotic and mineralized debris as well as numerous swollen capillaries
      protruding multifocally from the denuded surface. Immunohistochemistry revealed
      that these capillaries, as well as sloughed and intact trophoblasts, were
      expanded by large numbers of Brucella organisms. Brucellar antigen was also
      detected in occasional macrophages in the fetal kidney and lung.
      Ultrastructurally, bacteria labeled by an antibody-based colloidal gold procedure
      were located within degenerate capillaries, within necrotic leukocytes, and
      extracellularly in the placental stroma.

PMID- 10643985
TI  - Small intestinal adenomatous polyposis resulting in protein-losing enteropathy in
      a horse.
AB  - A 4-year-old Quarter Horse gelding was presented with a history of weight loss of
      6 months duration, along with extensive ventral subcutaneous edema.
      Clinicopathologic findings included a markedly low serum total protein (2.9 g/dl)
      and a low packed cell volume (24%). The mucosal surface of the distal jejunum and
      entire ileum were carpeted with numerous polypoid, papillary, and glandular
      masses comprised of pseudostratified tall columnar cells and large numbers of
      interspersed goblet cells. Neoplastic change was diffuse throughout the mucosa of
      each mass, but abrupt demarcation occurred between neoplastic masses and adjacent
      mucosa. Immunohistochemical staining for protein of the p53 tumor suppressor gene
      revealed only occasional cytoplasmic reactivity within polyps and normal mucosa.
      Nuclear staining for papillomavirus antigens was not observed. Electron
      microscopic examination revealed features of well-differentiated intestinal
      epithelial cells, including apical tight junctions and microvilli, desmosomes,
      and the presence of numerous goblet cells. Microorganisms were not detected.
      Small intestinal polyposis should be considered as a rare differential diagnosis
      for protein-losing enteropathy in the horse.

PMID- 10643986
TI  - Anthracycline cardiotoxicity in a black rhinoceros (Diceros bicornis): evidence
      for impaired antioxidant capacity compounded by iron overload.
AB  - Two weeks before dying of congestive heart failure, a juvenile black rhinoceros
      (Diceros bicornis minor) received a single low dose of doxorubicin as part of
      combination chemotherapy for acute lymphoblastic leukemia. Diffuse hemosiderosis
      was present at necropsy in a pattern indicative of dietary iron overload, but
      unique iron-positive degenerative lesions were found in isolated myocardiocytes.
      Serum analyses revealed hyperferremia, 87% transferrin saturation, and 5- to 10
      fold elevations in ferritin concentration, reflecting markedly increased tissue
      iron stores. Since both toxic and therapeutic effects of anthracyclines are
      mediated by formation of reactive free radicals via iron-catalyzed reactions,
      these observations suggest that iron overload may have enhanced myocardial
      susceptibility to cardiotoxic effects of doxorubicin. Impairments in other
      myocardial antioxidant defenses, such as deficiencies in catalase and glutathione
      S-transferase that are known to exist in rhinoceros erythrocytes, may have been
      underlying factors contributing to an inherent sensitivity of rhinoceros tissues
      to oxidant-induced injury.

PMID- 10643987
TI  - Caprine genital leiomyosarcoma.
AB  - An aged Saanen doe was euthanized following repeated severe hemorrhage from the
      vulva. Necropsy examination revealed mural thickening of tubular genitalia with
      firm, protruding intralumenal masses containing blood-filled cavitations, and
      effacement of normal cervical architecture. Histologically, uterine and cervical
      masses comprised a variably dense population of mildly pleomorphic spindle cells
      forming interlacing streams supported by variably dense collagenous stroma.
      Immunoperoxidase staining of neoplastic cells was positive for muscle-specific
      actin, supporting the diagnosis of low-grade leiomyosarcoma. Months later, the
      doe's twin was likewise euthanized due to persistent bleeding from the vulva
      associated with a large vulvar mass having histopathologic features similar to
      those of the previous case. The clinical, gross, and histologic findings are
      similar to five cases of caprine genital leiomyosarcoma identified in
      retrospectively analyzed case material. Analysis of caprine tumor accessions over
      20 years demonstrated a significantly higher incidence of genital leiomyosarcoma
      within the Saanen breed.

PMID- 10643988
TI  - Possible intraspinal metastasis of a canine spinal cord nephroblastoma.
AB  - A 2-year-old Basset Hound was admitted to the University of Florida Veterinary
      Medical Teaching Hospital with progressive spastic paraparesis. At necropsy,
      intradural extramedullary tumors produced areas of spinal cord swelling and
      softening in spinal cord segments T11-T12 and L4-L6. Histologic examination of
      the masses revealed sheets of polygonal blastemal cells, epithelial cells forming
      tubules and rosettes, and embryonal glomeruloid-like structures in the thoracic
      mass. Cells in the lumbar mass were less differentiated, forming rare tubules and
      no glomeruloid-like structures. The occurrence of two tumors in the spinal cord
      along with the less differentiated appearance of the lumbar tumor raises the
      possibility that the lumbar mass arose as a result of intraspinal metastasis. To
      our knowledge, this is the first report of multifocal or metastatic canine spinal
      nephroblastoma. In addition, the vimentin and cytokeratin immunohistochemical
      staining characteristics of these spinal cord nephroblastomas are described.

PMID- 10643989
TI  - Systemic kappaAL amyloidosis associated with bovine leukocyte adhesion
      deficiency.
AB  - Histopathologic and immunohistochemical examinations were conducted on a 5-year
      old Holstein-Friesian cow with systemic kappaAL amyloidosis associated with
      bovine leukocyte adhesion deficiency. Amyloid deposits were present in the
      perivascular and intercellular spaces of the visceral organs, such as the liver,
      kidneys, pancreas, adrenal glands, and upper alimentary tract. Amyloid was
      stained positively with Congo red with or without 5% potassium permanganate
      pretreatment and had green birefringence observed under polarized light.
      Immunohistochemically, amyloid reacted strongly against anti-bovine IgG (H+L) and
      anti-bovine kappa-light chain and reacted weakly against bovine X-light chain
      antibodies but was negative for anti-human amyloid AA antibody. This is the first
      description of AL amyloidosis immunohistochemically related to immunoglobulin
      kappa-light chains of precursor protein in cattle.

PMID- 10643990
TI  - Dermal intravascular leiomyosarcoma in a cat.
AB  - A 10-year-old female spayed domestic shorthaired cat presented with a
      subcutaneous tumor between the first and second phalanges of the left hind foot.
      Six months after excision, a similar tumor occurred on the medial aspect of the
      third phalanx of the same limb. Histologically, both tumors consisted of solid
      masses of spindle and round cells, many of which grew within endothelial-lined
      vessels. Tumor cells stained positively for smooth muscle actin and vimentin, but
      were negative for cytokeratin, S-100, desmin, synaptophysin, factor VIII-related
      antigen, and neuron-specific enolase. The diagnosis was dermal intravascular
      leiomyosarcoma.

PMID- 10643991
TI  - Localized amyloidosis in canine mammary tumors.
AB  - Histopathologic and immunohistochemical examinations were performed on localized
      amyloidosis associated with mammary tumors in two dogs. These tumors were
      identified as adenoma and adenocarcinoma. An acellular, amorphous pale
      eosinophilic material (amyloid) was observed in the lumina of acini lined by
      neoplastic cells and in the stroma of the tumors. Concentrically laminated pale
      eosinophilic bodies (corpora amylacea) were also found in the lumina of the
      acini. Amyloid and corpora amylacea stained positively with Congo red with and
      without 5% potassium permanganate pretreatment and revealed a green birefringence
      under polarized light. Corpora amylacea showed an occasional Maltese-cross
      pattern. Immunohistochemically, amyloid and corpora amylacea usually stained
      positively with anti-bovine alpha-casein antibody but negatively with anti-human
      amyloid AA, anti-bovine kappa-light and lambda-light chains, anti-human
      lactoferrin, anti-human transferrin, anti-human secretory component, and anti
      human polyglucosan antibodies. These findings suggested that the amyloid
      deposition in these canine mammary tumors was related to lactating casein.

PMID- 10643992
TI  - Tradition of basic and applied pigment cell research in Marseilles.
AB  - Melanogenesis, thyroid hormones and catecholamines synthesis share the same amino
      acid, free L-tyrosine for melanogenesis and catecholamines synthesis, L-tyrosine
      residues for thyroid hormones synthesis. The author describes basic and applied
      research on Melanogenesis and thyroid hormones metabolism in Biochemistry
      laboratory, School of Medicine, Marseilles since his arrival in 1962. He gives a
      short review of his participation in these two areas during his career in
      Marseilles, Yaounde and Boston.

PMID- 10643993
TI  - Tradition of pigment cell research at Charles University in Prague.
AB  - A short review on the history of pigment cell research at Charles University
      (Ch.U.) in Prague is presented. The famous Czech physiologist and professor J.E.
      Purkyne started the pigment cell research at Ch.U. already in 1837. He discovered
      melanin granules in the cells of substantia nigra of the brain. Later, in 1858, a
      Czech professor of medicine at Ch.U., B. Eiselt, as the first, described
      melanogenuria in 3 patients with generalized melanoma. Also some German
      professors at Ch.U. contributed to the research of melanins and melanogenuria in
      the past, especially H. Waelsch (1932). After the World War II, a Czech professor
      of medical chemistry at Ch.U., A.F. Richter with his young assistant J. Duchon
      continued in the chemical exploration of melanins (1954) and J.D. with Z. Pechan,
      B. Matous and S. Pavel devoted their attention to melanogenuria in melanoma
      patients (1962-1980). In 1967 they identified 2 new metabolites in melanoma
      urine: 5-hydroxy-6-methoxy and 6-hydroxy-5-methoxy-indole-2-carboxylic acids. J.
      Duchon with J. Borovansky and P. Hach also studied morphology and chemical
      composition of different melanosomes (1972-1979) and brought the first evidence
      that melanosomes consist of several proteins (1972). In 1980's 4 groups devoted
      to the pigment cell research and originated from Ch.U. were formed. The groups of
      J.B., of B.M. and of J. Vachtenheim in Prague and the group of S.P. who moved to
      the Netherlands (Leiden). As for the clinical aspects of the pigment cell
      research, the s.c. Hermansky-Pudlak syndrome published in 1959 and the
      histopathological classification of malignant melanomas estimated by J. Trapl
      (1957), should be mentioned. Therefore it is not surprising that, as a result of
      the tradition of pigment cell research at Ch.U., the 3rd European Workshop on
      Melanin Pigmentation was held in Prague already in 1981 and that, in 1998 again,
      Ch.U. was entrusted with the arrangement of the 8th Meeting of the European
      Society for Pigment Cell Research at the occasion of the Ch.U. 650th anniversary.

PMID- 10643994
TI  - Melanins: an old problem revisited or the usefulness of infrared spectroscopy.
AB  - This mini review remembers the implication, thirty nine years ago, of professor
      Wegmann in a fascinating adventure on the serendipitous study of melanin, after
      that a case of Dubin-Johnson's icterus had been submitted to him. To this
      investigation have been applied, one after the other and often simultaneously,
      for the first time, the diverse technologies of pathology, histochemistry,
      histoenzymology, biochemistry and infrared spectrography, having permitted to
      detect for the first time melanin in a human liver, associated with a
      melaninuria. But it was thanks to a marvellous collaboration with many colleagues
      that we came to a good end. It was the beginning of the interdisciplinary science
      of Cellular and Molecular Biology. To day remains to explain the mechanisms
      leading to the formation of melanin in liver and spleen.

PMID- 10643995
TI  - Molecular motors and their role in pigmentation.
AB  - Skin pigmentation is orchestrated through a series of complementary processes.
      After migration of melanoblasts out of the neural crest to epidermis and hair
      follicle, these cells mature into melanocytes. Differentiated melanocytes produce
      melanin in specialized organelles, the melanosomes. Moreover, the cytoplasm of
      melanocytes branches into extensions, the dendrites. Via the tips of these
      dendrites they donate their mature melanosomes to the keratinocytes resulting in
      skin pigmentation. Thus, one essential part of the process of pigmentation is the
      translocation of melanosomes from their site of origin in the perinuclear
      cytoplasm towards the dendrite tips. Motor proteins are molecules which use the
      energy derived from ATP hydrolysis to move along cytoskeletal elements, either
      actin filaments or microtubules, to transport their cargo, which can be
      organelles, vesicles or chromosomes. This review describes the different classes
      of microtubule-based and actin-based motor proteins with their characteristics
      and functional importance in cell biology and organelle transport. Some of them
      will be highlighted and several recent studies in mammalian pigment cells
      indicating their role in pigment granule transport will be discussed. As a result
      of these data and previous suggestions, a model will be proposed for the possible
      cooperation of both systems in melanosome movement.

PMID- 10643996
TI  - Signaling pathways mediating melanogenesis.
AB  - Pigmentation of the skin, due to the synthesis and dispersion of melanin in the
      epidermis, is of great cosmetic and societal significance. It is also the key
      physiologic defense against sun-induced injuries such as sunburn,
      photocarcinogenesis and photoaging. During recent decades, there has been a
      dramatic increase in skin cancers, including melanoma, due to habitual sun
      exposure (Rigel, 1992; Weinstock, 1989). At present, in the United States, about
      one in 75 individuals is projected to develop malignant melanoma during his or
      her lifetime (Rigel, 1992). Unfortunately, progress in preventing sun-related
      injuries has been slow, in part due to lack of understanding of the molecular
      mechanisms involved in pigmentation. This article reviews recent progress in
      identifying signal transduction pathways that mediate melanogenesis.

PMID- 10643997
TI  - The reconstructed epidermis with melanocytes: a new tool to study pigmentation
      and photoprotection.
AB  - The reconstruction of the epidermal melanin unit ex vivo has been achieved during
      the last decade, using the combination of previous cell culture techniques. The
      system reviewed is basically a modification of the Prunieras model, using the air
      liquid interface to grow differentiated keratinocytes, with the addition of 5%
      melanocytes in the seeding suspension, as well as the use of a more adapted
      culture medium. Repeated UVB irradiation induces a stimulation of melanogenesis
      macroscopically, and increases melanin concentration and melanosome transfer in
      reconstructs. These results have been reproduced with skin of various phototypes.
      This model allows to study the physiology of the epidermal melanin unit as well
      as pathologic conditions, like vitiligo and nevi. Recent evidence of a complex
      interaction of keratinocytes and melanocytes in photoprotection was provided by
      the use of chimeric reconstructs and by comparing autologous reconstructs made
      with and without low phototype caucasoid melanocytes. Based on these findings, we
      suggest a novel interpretation of the concept of phototype.

PMID- 10643998
TI  - A review of recent advances on the regulation of pigmentation in the human
      epidermis.
AB  - It has been recognised that the active transport of L-phenylalanine and its
      autocrine turnover to L-tyrosine via phenylalanine hydroxylase in the cytosol of
      epidermal melanocytes provides the majority of the L-tyrosine pool for
      melanogenesis. In this context, it has been shown that the cofactor 6(R)-L
      erythro 5,6,7,8 tetrahydrobiopterin (6BH4) is produced de novo, recycled and
      regulated in both epidermal melanocytes and keratinocytes to control tyrosine
      hydroxylase, phenylalanine hydroxylase and tyrosinase activity. Inhibition of the
      enzymes by excessive 6BH4 levels is reversible with alpha-MSH by specific complex
      formation between 6BH4 and the hormone. This direct mechanism of alpha-MSH is
      supported by the presence of the entire POMC processing system in the melanosome
      indicating a receptor independent control of eumelanogenesis. Finally, the role
      of tyrosinase, TRP-1 and TRP2 is discussed in association with oxidative stress
      specifically related to hydrogen peroxide. These recent findings are based on
      detailed investigations of the depigmentation disorder vitiligo and Hermansky
      Pudlak syndrome.

PMID- 10643999
TI  - The great DOPA mystery: the source and significance of DOPA in phase I
      melanogenesis.
AB  - One of the important characteristics of tyrosinase is the autocatalytic nature of
      the oxidation of natural monohydric phenol substrates, such as tyrosine. In vitro
      tyrosinase exhibits a lag phase in which the maximum velocity of oxidation is
      attained after a period of induction. This acceleration contrasts with the
      kinetics of dihydric phenol oxidation which exhibit conventional Michaelis-Menten
      kinetics. It has been known for half a century that DOPA is a co-factor in the
      oxidation of tyrosine and addition of a small amount of catechol reduces the
      length of the lag period. The significance of DOPA is in this action, and DOPA is
      known to be formed in phase I melanogenesis. Until recently there has been
      controversy regarding the source of the DOPA in the in vitro reaction system.
      Most investigators have favoured a mechanism based on the generation of DOPA by a
      direct hydroxylation of tyrosine. However, recent evidence has suggested that
      DOPA is indirectly derived by reduction of dopaquinone. In this communication the
      evidence for the indirect mechanism derived from the use of analogue substrates
      is reviewed.

PMID- 10644000
TI  - The tyrosinase related protein-1 (Tyrp1) promoter in transgenic experiments:
      targeted expression to the retinal pigment epithelium.
AB  - Transgenic experiments targeting gene expression to the retinal pigment
      epithelium (RPE) require use of a pigment cell-specific promoter. We have chosen
      1.4 kb and 4 kb from the promoter of the tyrosinase-related protein 1 gene
      (Tyrp1) for RPE-specific expression, since Tyrp1 mRNA and protein are detected
      already at midgestation in this epithelial layer. In eyes of transgenic embryos,
      expression of the Tyrp1-lacZ fusion construct led to strong and specific
      expression of beta-galactosidase in the RPE from day E10.5 onwards. The promoter
      thus proved useful to target expression of two different oncogenes to the RPE, a
      constitutively active tyrosine kinase receptor (Rfp/Ret) and SV40 T antigen
      (Tag). Tyrp1-Rfp/Ret transgenic mice developed microphthalmia, primarily induced
      by changes in the developing RPE. In addition, Tyrp1-Rfp/Ret expression induced
      proliferation of RPE cells leading to benign RPE tumors in the adult. Tyrp1-Tag
      transgenic mice developed malignant eye tumors of RPE origin, which invaded the
      optic nerve and led to metastasis into lymph nodes and spleen.

PMID- 10644001
TI  - Keratinocyte-melanocyte co-cultures and pigmented reconstructed human epidermis:
      models to study modulation of melanogenesis.
AB  - Normal human melanocytes were amplified and cultured in a new defined culture
      medium without phorbol esters or cholera toxin. The medium decreased considerably
      the doubling time and increased the possible passage number. Melanocytes were co
      seeded with normal human keratinocytes into 24 well culture dishes to screen
      potentially active modulators of melanogenesis. For the assay, the co-cultures
      were exposed to the compounds under investigation in the presence of 14C
      thiouracil and 3H-leucine. Control cultures contain L-tyrosine or kojic acid,
      modulators which served as internal calibration standards. Changes in the rate of
      melanin synthesis were measured on the basis of 14C-thiouracil incorporation into
      newly synthesized melanin. A reduction or increase in 3H-leucine incorporation
      was taken as an indication of cytotoxicity or induction of proliferation,
      respectively. The NHK-NHM co-culture screening assay provides a useful tool to
      compare the activity of known modulators of melanogenesis and to perform
      structure-activity studies with newly identified modulators to improve their
      activity. The efficacy of particularly interesting new compounds was further
      evaluated on reconstructed pigmented epidermis after repeated topical
      application. The same model was used to assess the anti-pigmenting effect of
      sunscreens on UV-induced pigmentation. Integration of melanocytes from different
      ethnic origin resulted in pigmented epidermis reflecting different skin
      phenotypes, Caucasian, Asian and African.

PMID- 10644002
TI  - Co-regulation of melanin precursors and tyrosinase in human pigment cells: roles
      of cysteine and glutathione.
AB  - Glutathione (GSH) and cysteine (CysH) have both been implicated in the biogenesis
      of the pheomelanin precursor 5-S-cysteinyldopa (5-S-CD). However, recent studies
      have shown that only CysH is transported across the membrane of isolated
      melanosomes, and that the positive regulation of CysH in pigment cells leads to
      an increased production of 5-S-CD. In the present study, the question was
      examined as to whether melanin precursors and tyrosinase could be coregulated by
      cellular thiols. To address this issue, the levels of CysH and GSH were varied in
      normal melanocytes and melanoma cells using buthionine sulfoximine (BSO), an
      inhibitor of GSH biosynthesis. Treatment with 50-100 microM BSO decreased GSH
      levels to less than 10% of control, and increased CysH levels between two- and
      five-fold in both cell types. Concomitant with this, an increase in the ratio of
      5-S-CD to DOPA and a decrease in the pigment content of the cells were observed.
      The decrease in cell pigmentation was associated with strong decreases in
      tyrosine hydroxylase activity and 14C-melanin production. Only melanoma cells
      showed a modified tyrosinase isozyme pattern on Western immunoblots in response
      to BSO, while the mRNA expression of tyrosinase and TRP-1 were unchanged in both
      cell types. These results suggest that the balance between CysH and GSH, which is
      partly determined by the rate of utilization of CysH for GSH biosynthesis,
      regulates not only the levels of 5-S-CD and DOPA but also the melanogenic
      activity of pigment cells. Since DOPA functions as a cofactor in the
      monophenolase reaction of tyrosinase, it is proposed that the ratio of 5-S-CD to
      DOPA may be an important factor in the regulation of tyrosinase activity in situ.

PMID- 10644003
TI  - Independent regulation of tyrosinase by the hypopigmenting cytokines TGF beta1
      and TNF alpha and the melanogenic hormone alpha-MSH in B16 mouse melanocytes.
AB  - In B16 melanocytes, tyrosinase activity and melanin formation are upregulated by
      alpha-MSH and downregulated by TGF beta1 and TNF alpha. Since TGF beta1 or TNF
      alpha block the differentiation programs induced by throphic hormones in other
      cell types, we studied tyrosinase regulation by alpha-MSH in the presence of the
      hypopigmenting cytokines, as well as the effects of the cytokines on several
      aspects of alpha-MSH signaling. TGF beta1 and TNF alpha only slightly diminished
      MC1 receptor gene expression, and had no effect on the intracellular levels of
      cAMP, or on the alpha-MSH-dependent cAMP rise. The intracellular levels of
      tyrosinase mRNA, protein and enzymatic activities were also upregulated by alpha
      MSH in cells pretreated with TGF beta1 or TNF alpha. Therefore the cytokines do
      not block the response to alpha-MSH. However, the cytokine-induced inhibition of
      tyrosinase gene expression, protein levels and the reduction of tyrosinase
      intracellular half-life also occurred in the presence of alpha-MSH, indicating
      that the hormone does not override TGF beta1 or TNF alpha inhibition. Thus,
      tyrosinase activity and the rate of melanin formation in B16 melanocytes might
      reflect simply the balance between alpha-MSH stimulation and TGF beta1 or TNF
      alpha inhibition, acting by independent mechanisms.

PMID- 10644004
TI  - Investigation of the intracellular transport of tyrosinase and tyrosinase related
      protein (TRP)-1. The effect of endoplasmic reticulum (ER)-glucosidases
      inhibition.
AB  - Melanin biosynthesis is completely inhibited in the B16 melanoma cells following
      their incubation with inhibitors of the two ER glucosidases. This is primarily
      due to the inactivation of tyrosinase. Under the same conditions, the DOPA
      oxidase activity of TRP-1 was only partially affected. In this report we
      investigate the effects of the perturbation of N-glycan processing in ER on the
      transport and activation of tyrosinase and TRP-1. We have localized the DOPA
      oxidase activity in normal and inhibited cells and suggest that the first DOPA
      reactive compartment of the secretory pathway (trans Golgi network) is also the
      site of tyrosinase activation. The inhibition of N-glycan processing does not
      affect the intracellular trafficking of the two melanogenic enzymes that are
      correctly transported to melanosomes. Immunoprecipitation experiments followed by
      analysis in SDS-PAGE under non-reducing conditions suggest that in inhibited
      cells, both tyrosinase and TRP-1 are synthesized in a modified conformation as
      compared to the normal proteins. These data suggest that the inhibition of
      melanin synthesis is not due to a defective transport but rather to
      conformational changes induced in the structure of tyrosinase and TRP-1 during
      their transit through the ER.

PMID- 10644005
TI  - Altered N-glycosylation in macrophage x melanoma fusion hybrids.
AB  - It was recently reported that a majority of hybrids generated in vitro between
      weakly metastatic mouse Cloudman S91 melanoma cells and human or mouse
      macrophages showed enhanced metastatic potential (Rachkovsky et al., 1998). With
      few exceptions, hybrids with enhanced metastatic potential also had elevated
      basal melanin content, enhanced chemotactic responses to fibroblast-conditioned
      media, and stronger responsiveness to MSH compared to parental cells. Analyses
      revealed that altered N-glycosylation in metastatic hybrids could explain the
      multiple phenotypic changes. Tyrosinase, TRP-2 and LAMP-1 from hybrids migrated
      more slowly on gels compared to the same proteins from parental melanoma cells,
      consistent with increased glycosylation. Migration of LAMP-1 from hybrids was
      similar to that from peritoneal macrophages which also appeared to be more
      heavily glycosylated than LAMP-1 from Cloudman cells. The incorporation of 3H
      glucosamine, as a marker of N-glycosylation, into tyrosinase and LAMP-1 was found
      to be elevated in hybrids, suppressed by N-glycosylation inhibitors and
      stimulated by MSH to a greater degree in hybrids compared to parental cells.
      These results indicate N-glycosylation as an important regulatory pathway for MSH
      induced melanogenesis, and further suggest that altered N-linked glycosylation
      may be an underlying mechanism for regulation of both melanogenesis and
      metastasis in macrophage x melanoma hybrids.

PMID- 10644006
TI  - ACTH1-17 is a more potent agonist at the human MC1 receptor than alpha-MSH.
AB  - The melanocortin receptor MC1 is expressed on melanocytes and is an important
      control point for melanogenesis and other responses. Alpha-MSH, which is
      considered to be the major ligand at the human melanocortin (MC)1 receptor
      (hMC1R), is produced from proopiomelanocortin (POMC) in the pituitary and in the
      skin by melanocytes and keratinocytes. Other POMC peptides are also produced in
      the skin and their concentrations exceed those of alpha-MSH by several fold. One
      of the most abundant is ACTH1-17. We have shown that adrenocorticotrophic hormone
      (ACTH)1-17 is more potent than alpha-MSH in stimulating melanogenesis in human
      melanocytes and unlike alpha-MSH produces a biphasic dose response curve. In this
      study we have examined the ability of ACTH1-17 to function as a ligand at the
      hMC1R. Competitive binding assays with [125I]Nle4 DPhe7 alpha-MSH as labelled
      ligand were carried out in HEK 293 cells transfected with the hMC1R. ACTH1-17
      showed high affinity for the hMC1R with a Ki value of 0.21 +/- 0.03 nM which was
      slightly higher than that of 0.13 +/- 0.005 nM for alpha-MSH. ACTH1-17 was,
      however, more potent than alpha-MSH in increasing cAMP and IP3 production in the
      transfected cells. Our results demonstrate that ACTH1-17 is a potent agonist at
      the hMC1R. It is therefore possible that ACTH1-17, which is found in the skin in
      greater concentrations than alpha-MSH, has an important role in the regulation of
      human melanocytes and other cell types that express the hMC1R.

PMID- 10644007
TI  - Macrophage migration inhibitory factor (MIF)--its role in catecholamine
      metabolism.
AB  - Macrophage migration inhibitory factor (MIF) was originally identified several
      decades ago as a lymphokine-derived protein that inhibited monocyte migration.
      Recently, it has been reported that MIF has D-dopachrome tautomerase,
      phenylpyruvate tautomerase and thiol protein oxidoreductase activities, although
      the physiological significance of those activities is not yet clear. Here we show
      that MIF is able to catalyze the conversion of dopaminechrome and
      norepinephrinechrome, toxic quinone products of the neurotransmitters dopamine
      and norepinephrine, respectively, to indole derivatives that may serve as
      precursors to neuromelanin. Since MIF is highly expressed in human brain, these
      observations raise the possibility that MIF participates in a detoxification
      pathway for catecholamine products and could therefore have an important role for
      neural tissues. The potential role of MIF in the formation of neuromelanin from
      catecholamines is also an extremely interesting possibility.

PMID- 10644008
TI  - Study of DT-diaphorase in pigment-producing cells.
AB  - DT-diaphorase is an FAD-containing enzyme capable of a two-electron reduction of
      ortho- and paraquinones. Nicotinamide coenzymes (NADH + H+ and NADPH + H+) serve
      as hydrogen sources in these reactions. The role of DT-diaphorase has been
      thoroughly investigated in situations when the enzyme is able to reduce exogenous
      and endogenous quinones, hence protecting the cells against these reactive
      intermediates. The enzyme has also been studied in connection with its ability to
      activate some quinoid cytostatics. It is surprising that DT-diaphorase has never
      been investigated in pigment-producing cells that are known to generate
      considerable amounts of ortho-quinones. Using a spectrophotometric method we
      could readily measure the activity of DT-diaphorase in epidermis and various
      cultured pigment cells. The melanocytes isolated from dark skin showed generally
      higher DT-diaphorase activity than those from fair skin samples. Also, darkly
      pigmented congenital naevus cells exhibited higher activity of this enzyme. The
      most striking was the high DT-diaphorase activity in melanoma cell cultures. In
      these cells DT-diaphorase activity could be induced by incubation of the cells
      with 4-hydroxyanisole. A similar effect was seen when a catechol-O
      methyltransferase (COMT) inhibitor (3-(3,4-dihydroxy-5-nitrobenzylidene)-2,4
      pentanedione (OR-462) was utilised. The induction was inhibited by cyclohexidine.

PMID- 10644009
TI  - Disparate behaviour of two melanosomal enzymes (alpha-mannosidase and gamma
      glutamyltransferase).
AB  - In addition to tyrosinase and its related proteins melanosomes contain a variety
      of further enzyme activities. Using spectrophotometric methods alpha-mannosidase
      and gamma-glutamyl-transferase (GGT) were studied in B 16 melanoma, in isolated
      melanosomes and in tumour host (mice C57BL6J) sera. When compared to the original
      melanoma tissue (12.8-26.7 nkat/g TP) isolated melanosomes exhibited much higher
      alpha-mannosidase activity [227-420 nkat/g of total proteins (TP)]. Strong
      activation by Zn2+ and no influence of Co2+ ions suggested that the dominant form
      of alpha-mannosidase of the enzyme present in melanosomes was of the acid
      (lysosomal) type. The GGT activity of isolated melanosomes (168-244 nkat/g TP)
      was comparable with that of the whole melanoma tissue (203-375 nkat/g TP) .
      Treatment of melanosomes with detergents (0.1% Triton X-100, 0.5% deoxycholate)
      revealed striking extractibility differences between the two enzymes investigated
      in relation to their localization: alpha-mannosidase remained immobilized in the
      melanized matrix of melanosomes whereas the membrane bound GGT was easily
      released. Unlike the alpha-mannosidase the GGT serum levels were increasing in
      relation to the melanoma growth. The demonstration of acid form of alpha
      mannosidase in melanosomes is consistent with their lysosomal ranking; the
      presence of GGT is in keeping with its expected roles both in protection against
      oxidative stress and in melanogenesis.

PMID- 10644010
TI  - SODs are involved in the regulation of ICAM-1 expression in human melanoma and
      endothelial cells.
AB  - It is well known that ICAM-1 expression can be stimulated by TNF and by oxidative
      stress, via the activation of specific transcription factors. Two of these-
      NFkappaB and AP-1--can also be activated by reactive oxygen species, including
      the superoxide anion (also produced under TNF challenge). The latter is
      inactivated by superoxide dismutase of which two forms exist: Cu/Zn-SOD
      (cytoplasmic) and Mn-SOD (mitochondrial). We investigated whether superoxide
      anion direct generation or accumulation through specific SOD inhibition, may
      affect ICAM-1 expression in human melanoma and endothelial cells. Our results
      show a 20-50% increase in both SOD activities when cells were exposed to TNF or
      to an oxidative stress produced by Paraquat (a generator of superoxide anion
      radicals), both in terms of enzymes activity (zymogram) and protein levels
      (Western blotting and ELISA). Either with TNF or Paraquat, we could measure a
      significant increase of ICAM-1 expression with maxima ranging from 140 to 200%,
      depending on the cell line. Specific inhibition of Cu/Zn-SOD activity by DTIC
      (diethyldithiocarbamic acid), in presence of Paraquat or TNF, was followed by an
      upregulation of ICAM-1 expression (60 and 20%, respectively). In contrast, the
      addition of a SOD mimetic (MnTMPyP) completely inhibited Paraquat-stimulated ICAM
      1 expression in melanoma cells and significantly decreased it in HUVEC (50%). In
      presence of TNF however, the same SOD mimetic inhibited TNF-stimulated ICAM-1
      expression by 25% in melanoma and 17% in endothelial cells. In conclusion, these
      data provide evidence that melanoma and endothelial cells exposure to TNF or
      oxidative stress results in a significant increase of both Mn- and Cu/Zn-SOD
      activities. This increase seems to be associated with a reduction in the
      stimulation of ICAM-1 expression by TNF or oxidative stress.

PMID- 10644011
TI  - Role of antioxidants in the survival of normal and vitiliginous avian
      melanocytes.
AB  - Mutant feather melanocytes from Barred Plymouth Rock (BPR) and White Leghorn (WL)
      chickens are currently being used as avian models of vitiligo. Feather
      melanocytes in BPR and WL chickens die prematurely in vivo due to low (50-66%)
      antioxidant glutathione and superoxide dismutase levels when compared to the wild
      type Jungle Fowl (JF) melanocytes. Excess superoxide anions, generated by
      xanthine:xanthine oxidase (X:XO), caused a 15-20% increase in mortality after 1
      and 2 hrs. in all three genotypes of in vitro melanocytes as compared to control
      values that received no X:XO. Overall, the JF wild type melanocytes had the
      lowest mortality rate, WL melanocytes had the highest mortality rate and the BPR
      melanocytes had an intermediate mortality rate. Superoxide anion and hydroxyl
      radical production in the WL feather were double the production in the JF wild
      type feather. The production of reactive oxygen species in BPR was intermediate
      to the other two genotypes. In an effort to mimic the low antioxidant levels of
      the BPR and WL feathers in the JF feather, JF in vitro feather melanocytes were
      treated with buthionine sulfoximine (BSO), a glutathione synthesis inhibitor.
      With BSO added to the medium, the JF mortality rates increased by 20-25%,
      reaching the mortality levels of the mutant BPR melanocytes. The addition of iron
      to the JF melanocyte X:XO medium increased their mortality rate by 20%, probably
      via the Fenton reaction. Thus, antioxidants play an extremely important role in
      both the viability of normal avian melanocytes and the premature death of the
      vitiliginous avian melanocytes. A working hypothesis, supported in part by the
      current results, is that the premature death of the mutant melanocytes could be
      precipitated in the poorly vascularized feather by low antioxidant protection due
      to both low turnover of tissue fluids which contain SOD and to genetically
      determined low levels of internal antioxidant protection in these melanocytes.
      This same mechanistic hypothesis could apply as "a" cause of premature melanocyte
      cell death in human vitiligo wherein the vitiliginous melanocytes may have a
      genetic defect in their antioxidant protection system and blood flow to an area
      may be restricted.

PMID- 10644012
TI  - Expression of genes for microphthalmia isoforms, Pax3 and MSG1, in human
      melanomas.
AB  - Microphthalmia (MITF) gene product, a transcription factor of the basic-helix
      loop-helix type, is thought to play a role in the regulation of genes encoding
      the enzymes necessary for melanogenesis. These include tyrosinase, TRP-1 and TRP
      2. Melanocyte-specific isoform of microphthalmia, MITF-M, is expressed in normal
      and malignant melanocytes. The presence of two other isoforms of microphthalmia,
      MITF-A and MITF-H, which differ from MITF-M in the amino-terminus, was
      demonstrated also in some non-melanocytic lineages. Here we have analyzed the
      presence of all three known isoforms of MITF mRNA in a panel of 17 human melanoma
      cell lines by a reverse transcriptase-polymerase chain reaction using isoform
      specific primers. While, as expected, the predominant form in melanoma cell lines
      was MITF-M, low amounts of MITF-A mRNA was found in almost all melanomas, as well
      as in most of 20 tumor cell lines of the non-melanocyte origin (lung and colon
      carcinomas, osteosarcomas and neuroblastomas). The expression of MITF-H was not
      detected, with a few exceptions, in the tested cell lines. Pax3 transcription
      factor was reported earlier to regulate positively the melanocyte-specific
      promoter of the MITF gene. We found here that the Pax 3 mRNA was expressed in all
      melanoma cell lines, even in those that had repressed the MITF-M and were
      amelanotic. This suggests that additional factors, besides Pax3, are required for
      the MITF expression. The MSG1 (melanocyte-specific gene 1), a gene originally
      isolated from melanocytes and containing a strong transcription activation
      domain, was also found expressed in all melanomas and most non-melanocyte tumor
      cell lines. Together, these data indicate that the MITF-M isoform is the major
      type of MITF mRNA present in human melanoma cell lines and show that the
      expression of the isoform MITF-A and the MSG1 is not restricted to malignant
      melanocytes and occurs in a wide range of tumor cell lines.

PMID- 10644014
TI  - The effect of intrastriatal injection of liposome-entrapped tyrosinase on the
      dopamine levels in the rat brain.
AB  - Parkinson's disease is a neurodegenerative disorder which is mainly characterized
      by degeneration of the dopaminergic cells in the nigro-striatal system. Due to a
      lowered L-tyrosine 3-monooxygenase activity, L-tyrosine is not sufficiently
      transformed to L-DOPA. To date the most common therapy is the administration of
      the dopamine precursor L-DOPA, with severe collateral effects. Therefore, the
      substitution of the lacking tyrosine hydroxylase with tyrosinase might be a novel
      therapeutical approach that would generate specifically L-DOPA from L-tyrosine.
      We present here evidence that stereotaxic injection of liposome-entrapped
      tyrosinase is able to significatively increase the levels of dopamine in the rat
      brain. The catecholamines L-DOPA, dopamine, L-epinephrine, L-norepinephrine were
      extracted by acid treatment from the brains and detected by HPLC.

PMID- 10644013
TI  - Expression of the MC1 receptor gene in normal and malignant human melanocytes. A
      semiquantitative RT-PCR study.
AB  - Alpha melanocyte-stimulating hormone (MSH) and related proopiomelanocortin
      derived (POMC) peptides bind to the melanocortin 1 receptor (MC1-R) of mammalian
      melanocytes and stimulate proliferation and melanogenesis. POMC transcripts and
      alpha-MSH-like immunoreactivity have been found in melanoma cells and a possible
      autocrine loop involving MC1-R and POMC-derived products has been proposed.
      Therefore, the alpha-MSH/MC1-R system plays a major role in the biology of
      melanocytes, and provides targets for melanoma diagnosis and therapy. However,
      the relative levels of MC1-R expression in normal melanocytes (NM) and melanoma
      cells are unknown, and it is still debated whether or not all human melanomas
      express the MC1-R. We describe a semiquantitative RT-PCR assay for MC1-R
      expression, using a competition vector generated by deleting 164 bp of the native
      gene. The competitor was employed to analyse a panel of human melanoma cells,
      tumour samples, giant congenital nevus cells (CNM) and normal melanocytes (NM).
      All samples were positive for MC1-R expression, but expression of the receptor
      gene did not correlate with that of tyrosinase. Expression levels were about 10
      and 20 times higher for surgical specimens and cultured melanoma cells,
      respectively, than for NM, but comparable for CNM and NM. Thus, high MC1-R
      expression is a frequent event in malignant melanocytes, and might lead to a
      higher activity of the alpha-MSH/MC1-R system in melanoma cells as compared to
      normal melanocytes, for equal local concentrations of the hormone or related
      melanocortins.

PMID- 10644015
TI  - Effect of colcemid on the centrosome and microtubules in dermal melanophores of
      Xenopus laevis larvae in vivo.
AB  - An electron microscopy study showed that in melanophores with dispersed and
      aggregated pigment the sensitivity of the centrosome and the stability of
      microtubules were different and depended on the colcemid concentration. The
      structure of the centrosome didn't change upon exposure to colcemid in dispersed
      melanophores. In aggregated melanophores, on exposure to 10(-6) M colcemid, the
      centrosome retained its structure; colcemid at 10(-5)-10(-3) M caused a dramatic
      collapse of the centrosome. Treatment of aggregated melanophores with colcemid
      resulted in the complete disassembly of the microtubules; though microtubules in
      dispersed melanophores appear to be colcemid resistant. Light microscopy studies
      indicated that in Xenopus melanophores with aggregated or dispersed pigment
      melanosomes didn't change their location after exposure to 10(-3)-10(-6) M
      colcemid. Subsequent incubation in colcemid-free medium revealed that the cells
      retained their ability to translocate melanosomes in response to hormone
      stimulation. Electron microscopy data revealed the inactivation of the centrosome
      as MTOC (microtubule-organizing center) in dispersed melanophores with melatonin
      substituted for MSH in the presence of colcemid. In contrast, with melanocyte
      stimulating hormone (MSH) substituted for melatonin, we observed the activation
      of the centrosome in aggregated cells. We showed that in aggregated melanophores
      pigment movement proceeded in the complete absence of microtubules, suggesting
      the involvement of a microtubule-independent component in the hormone-induced
      melanosome dispersion. However, we observed abnormal aggregation along colcemid
      resistent microtubules in dispersed melanophores, suggesting the involvement of
      not only stable but also labile microtubules in the centripetal movement of
      melanosomes. The results raise the intriguing questions about the mechanism of
      the hormone and colcemid action on the centrosome structure and microtubule
      network in melanophores with dispersed and aggregated pigment.

PMID- 10644016
TI  - Hereditary melanoblastoma in miniature pigs and its successful therapy by
      devitalization technique.
AB  - Applying selective breeding for 10 years we established the MeLiM (Melanoblastoma
      bearing Libechov Minipigs) strain. Melanoblastoma (MB) in this strain shows a
      hereditary occurrence. Cutaneous tumours are usually nodular, multiple and
      distributed on various parts of body. They appear in darkly pigmented animals
      already at the birth or during two months thereafter (57% of all animals).
      Numerous organ metastases mainly into the spleen, lymph nodes and lungs are
      regularly ascertained in animals with cutaneous MB. Tumour cells were
      surprisingly found also in the inner organs of phenotypically healthy minipigs in
      which no cutaneous MBs were observed visually (27% of all animals). About 34% of
      all affected piglets die during the first 2 months of age. These features
      document a malignancy of this tumour in the MeLiM strain. Original surgical
      technique was applied in more than 40 affected minipigs at 1-2 months of age. It
      consists in a devitalization (ischemization) of one of cutaneous tumours by the
      mattress sutures conducted around the tumour base without any excision of tumour
      tissue. This simple procedure causes a total destruction of MB cells in all
      cutaneous tumours as well as in all organ metastases during 4-6 months. Animals
      treated by this technique were fully healed of tumour cells and no relapses were
      observed. This technique could bring similar positive results also in therapy of
      human MB.

PMID- 10644017
TI  - Skin hyporeactivity in relation to patch testing.
AB  - False-negative patch tests are clinically relevant. Skin hyporeactivity has been
      suggested as one possible cause. Evidence supports that failure to respond to a
      specific antigen might be due either to a faulty immune response, a defective
      inflammatory response or both. Thus, skin hyporeactivity may have clinical
      relevance in routine patch testing. Articles on this topic are infrequent and
      there is no index keyword for skin hyporeactivity as this phenomenon is poorly
      defined and investigated. This article summarizes several observations of skin
      hyporeactivity, reviews theories of possible mechanisms and discusses further
      consequences.

PMID- 10644018
TI  - Metals and arsenic in eye shadows.
AB  - The regulations relating to cosmetic products give no limit values for toxic
      elements such as metals or arsenic occurring as impurities in cosmetic products.
      The present study of metals (lead, cobalt, nickel, chromium) and arsenic in eye
      shadows in 88 colors of 25 brands and 49 products provides a basis for assessing
      the safety of eye shadow. 66 out of 88 (75%) of the colors contained more than 5
      ppm of at least one of the elements, and all 49 products contained more than one
      1 ppm of at least 1 of the elements. In one color, the amount of all elements was
      less than 1 ppm. The highest levels of cobalt and nickel were 41 and 49 ppm,
      respectively. These levels were high enough to cause allergic symptoms in those
      previously sensitized. Furthermore, long-term exposure to such levels may
      probably sensitize. The concentrations of arsenic were extremely low, 2.3 ppm at
      most. The level of lead was less than 20 ppm in all products. Accordingly, the
      concentrations of arsenic and lead seemed to be safe. 9 colors had concentrations
      of water-soluble chromium exceeding 2 ppm, and a very high level, 318 ppm, was
      encountered in 1 case. The overall results indicate that eye-shadows probably
      have no significant systemic toxicological effects. The groups at greatest risk
      are those already sensitized to the allergenic elements. Such consumers will have
      difficulties in choosing suitable products, since these elements in the form of
      impurities are not declared in the list of ingredients. Manufacturers should
      demand certification that the raw materials they buy contain no toxic elements.
      Although some of the products studied were acceptable, many had excessive levels
      of the elements from the consumer's viewpoint.

PMID- 10644019
TI  - Activation and cross-reactivity pattern of a new allergen in adhesive plaster.
AB  - N,N'-disalicylidene-1,2-diaminopropane is a copper inhibitor present in some
      adhesive plasters, rubber products and gasoline. Upon contact with water it is
      hydrolyzed to salicylaldehyde and 1,2-diaminopropane. All patients in this study
      showed positive patch-test reactions to N,N'-disalicylidene-1,2-diaminopropane,
      and also to 1,2-diaminopropane and ethylenediamine. None reacted to
      salicylaldehyde. Patch testing with different N,N'-disalicylidene-derivatives
      showed localization of the amino groups in positions 1 and 2 to be a prerequisite
      of cross-reactivity to 1,2-diaminopropane and ethylenediamine. An extraction
      procedure and a high-performance liquid chromatography (HPLC) method for the
      analysis of adhesive plasters is described. Studies of the hydrolysis of the
      copper inhibitor at physiological pH showed rapid formation of 1,2-diaminopropane
      under biomimetic conditions.

PMID- 10644020
TI  - Antigen-presenting cells and keratinocytes express interleukin-12 in allergic
      contact dermatitis.
AB  - Interleukin-12 (IL-12) has previously been suggested as playing a major role in
      the activation of cytotoxic lymphocytes. Recent reports indicate that cytotoxic
      CD8+ cells are critically involved in the elicitation phase of contact
      hypersensitivity reactions. In this study, the in situ expression of IL-12 was
      investigated in normal human skin and in allergic contact dermatitis by
      immunohistochemistry. Skin biopsy specimens were obtained from allergic patch
      test reactions after 3 days, and from normal skin in 8 subjects. In contrast to
      normal skin, a strong enhancement of IL-12 immunoreactivity was observed in the
      mononuclear cell infiltrate of allergic contact dermatitis. IL-12
      immunoreactivity was mainly located in the cytoplasm of dermal dendritic cells
      and macrophages as well as of some Langerhans cells. IL-12-positive cells were
      often found in close apposition to lymphocytes. Furthermore, positive
      immunostaining was also detected in keratinocytes at sites of marked exocytosis
      and spongiosis in the epidermis. In conclusion, the enhanced in situ expression
      of IL-12 may contribute to the activation of cytotoxic lymphocytes and thereby
      represent an important factor in the pathogenesis of contact hypersensitivity
      reactions in humans.

PMID- 10644021
TI  - The purpuric patch test in patients with allergic contact dermatitis from azo
      dyes.
AB  - The histopathological features of the purpuric patch test have been described in
      individual cases only. We report a series of patients with allergic contact
      dermatitis, who developed purpuric patch tests at the sites of allergens from the
      azo dye group. 105 patients were clinically evaluated and tested with the TRUE
      Test and the textile color & finish series (Chemotechnique Diagnostics) because
      of suspected clothing dermatitis. Positive results to the latter were found in 31
      patients (29.5%). In 9 of these, purpuric patch tests were observed at the sites
      of the allergens Disperse Blue 124, 106 and 85. 10 biopsies were performed and
      studied. The histopathological changes of the purpuric patch test included:
      spongiosis (in 90% of cases), exocytosis (70%), and dilated blood vessels (100%)
      without signs of vasculitis, surrounded by an inflammatory infiltrate composed
      mainly of T lymphocytes. Extravasated erythrocytes were seen perivascularly, but
      also in the interstitium, surrounding the acrosyringium, at the dermoepidermal
      junction, and in the epidermis. Increased number of mast cells were found in
      22.2% of cases. Disperse Blue 124, 106, and 85 are potent allergens that can
      elicit purpuric patch test reactions. The purpuric patch test in our cases was a
      manifestation of an allergic reaction, based not only on histopathological
      changes, but also on evolution and relevance of the patch tests.

PMID- 10644022
TI  - Patch testing with corticosteroid mixes in Europe. A multicentre study of the
      EECDRG.
AB  - This study investigated whether a corticosteroid mix containing tixocortol
      pivalate, budesonide, and hydrocortisone-17-butyrate could detect contact allergy
      to corticosteroids. 2 corticosteroid mixes, 1 with a high (mix I) and 1 with a
      low (mix II) concentration and the 3 individual constituents, each at 2
      concentrations, were inserted into the standard series of 16 participating
      clinics. Tests were read on day (D) 3 or 4. 5432 patients were tested, and 110
      (2.0%) had positive reactions to at least 1 of the 8 test preparations. Of the 8
      preparations, mix I identified most allergic patients, followed by mix II,
      budesonide 0.10%, budesonide 0.002%, and tixocortol pivalate, both concentrations
      (1.0 and 0.10%) tracing the same number. With the mixes, 53.2-59.6% of tixocortol
      pivalate allergy was missed. 47 patients were allergic to either concentration of
      tixocortol pivalate, 25% of these only to 1.0% and another 25% only to 0.10%.
      Testing with mix I and tixocortol pivalate 0.10% picked up 98/110, testing with
      tixocortol pivalate 1.0% and 0.10% and budesonide 0.10% picked up 105/110. 3379
      patients were read on both D3 or D4 as well as on D7. Without a late reading
      (D7), up to 30% of contact allergy to corticosteroid markers was missed.

PMID- 10644023
TI  - Iontophoresis of nickel elicits a delayed cutaneous response in sensitized
      individuals that is similar to an allergic patch test reaction.
AB  - Wearing of patch test chambers for 1-2 days is uncomfortable for patients.
      Allergen application by iontophoresis avoids this, but it is unknown so far
      whether iontophoresis itself interferes with the delayed immune response. We
      compared the effects occurring 48 h after iontophoresis with distilled water,
      0.9% NaCl, and 0.01 M NiSO4 in normal volunteers and in nickel-sensitized
      patients (total n=36). Visual assessment was performed and transepidermal water
      loss (TEWL), stratum corneum hydration, cutaneous blood flow, and
      immunohistopathology were determined. After iontophoresis with nickel sulfate,
      only individuals sensitized to nickel reacted with a positive clinical response,
      increase in cutaneous blood flow, decline in epidermal CD-1a-positive cells,
      increase in epidermal proliferation (Ki-67-positive cells), pronounced
      infiltration of cells positive for CD4, CD11, or CLA, and cellular activation
      (expression of ICAM1, HLA-DR). Iontophoresis with distilled water or saline did
      not result in such reactions in volunteers with or without nickel sensitization,
      and the latter also tolerated nickel iontophoresis without significant skin
      reactions. We conclude that the delayed cutaneous response to nickel induced via
      iontophoresis is specific and similar to a positive patch test reaction.
      Iontophoresis may therefore be considered as an alternative to patch testing.

PMID- 10644024
TI  - Famciclovir as a possible alternative treatment in some cases of allergy to
      acyclovir.

PMID- 10644025
TI  - Patch-test positivity in cutaneous reactions to enoxaparin.

PMID- 10644026
TI  - Occupational airborne contact dermatitis from cefazolin.

PMID- 10644027
TI  - Association between tinea manuum and male manual workers.

PMID- 10644028
TI  - Occupational airborne allergic contact dermatitis from isoflurane vapour.

PMID- 10644029
TI  - Contact allergy to corticosteroids in Israeli patients.

PMID- 10644030
TI  - Allergic contact dermatitis from Primula auricula and Primula denticulata.

PMID- 10644031
TI  - Tolerance of desirudin in a patient with generalized eczema after intravenous
      challenge with heparin and a delayed-type skin reaction to high and low molecular
      weight heparins and heparinoids.

PMID- 10644032
TI  - Allergic contact dermatitis from epsilon-aminocaproic acid.

PMID- 10644033
TI  - Allergic contact dermatitis from octyl gallate in lipstick.

PMID- 10644034
TI  - Pacemaker dermatitis from titanium.

PMID- 10644035
TI  - Allergic contact dermatitis from sodium fusidate with no underlying dermatosis.

PMID- 10644036
TI  - Increased rate of patch test reactivity to methyldibromo glutaronitrile.

PMID- 10644037
TI  - Chronic fatigue syndrome and nickel allergy.

PMID- 10644038
TI  - Granulysin: a novel antimicrobial peptide of cytolytic T lymphocytes and natural
      killer cells.
AB  - Granulysin is a novel antimicrobial protein produced by human cytolytic T
      lymphocytes and natural killer cells. It is active against a broad range of
      microbes, including Gram-positive and Gram-negative bacteria, fungi, and
      parasites. The fact that it kills Mycobacterium tuberculosis is particularly
      important, since the current vaccine (Bacille Calmette-Guerin, BCG) is of limited
      efficacy and antibiotic resistance is increasing. Although functionally related
      to other antibacterial peptides, defensins and magainins, granulysin is
      structurally distinct. Like porcine NK lysin and amoebapores made by Entamoeba
      histolytica, granulysin is related to saposins, small lipid-associated proteins
      present in the central nervous system. The identification of this novel molecule
      indicates a broader and perhaps more significant role for T lymphocytes in both
      innate and acquired antimicrobial defenses.

PMID- 10644039
TI  - Development of a whole cell assay to measure methotrexate-induced inhibition of
      thymidylate synthase and de novo purine synthesis in leukaemia cells.
AB  - The cellular pharmacology of methotrexate (MTX) is complex, involving the
      inhibition of both de novo thymidylate and purine biosynthesis. Measurement of
      MTX-induced inhibition of de novo thymidylate and purine biosynthesis may allow
      optimisation of MTX therapy, and the aim of this study was to develop an assay to
      measure the activity of both pathways in the same cell sample, and so determine
      the effects of MTX treatment. In situ thymidylate synthase (EC 2.1.1.45) activity
      was measured by the release of 3H2O from [5'-3H]deoxyuridine and de novo purine
      synthesis by the incorporation of [14C]formate into adenine and guanine.
      Incubation of human leukaemia CCRF-CEM cells for 22 hr with 50 nM MTX resulted in
      approximately 90% inhibition of in situ thymidylate synthase activity, relative
      to control untreated cells, and after exposure to 1000 nM MTX activity could not
      be detected. In contrast, de novo purine synthesis, measured in the same sample,
      was not inhibited by exposure to 50 nM MTX, although activity was again
      completely abolished by exposure to 1000 nM MTX. To demonstrate the utility of
      the assay, lymphoblasts isolated from a child with acute lymphoblastic leukaemia
      (ALL) were also incubated for 22 hr with 1000 nM MTX. Both in situ thymidylate
      synthase activity and de novo purine synthesis were significantly inhibited, by
      70% and 60% respectively, relative to the activity in untreated cells.

PMID- 10644040
TI  - Isolation of a non-covalent aldose reductase-nucleotide-inhibitor complex.
AB  - A method for the isolation of an intact, non-covalent complex formed by the
      interaction of aldose reductase, NADP(H) nucleotide, and inhibitor has been
      developed to aid in the discovery and development of novel aldose reductase
      inhibitors. In the complexes isolated, both the carboxylic acid-containing
      inhibitor tolrestat and the spirohydantoin-containing inhibitor AL1576 (2,7
      difluorospirofluorene-9,5'-imidazolidine-2',4'-dione) tightly bound in a 1:1
      ratio to aldose reductase complexed with either NADPH or NADP+. Inhibitor binding
      to either the enzyme-NADP+ or enzyme-NADPH complex appeared to be equal and pH
      dependent, with maximum binding observed at a pH range of 7 to 8.5 where the
      inhibitors are ionized. These results indicated that the charge state of the
      cofactor (NADPH vs NADP+) is not critical for inhibitor binding to aldose
      reductase. Molecular modeling studies suggested that His110 plays a crucial role
      in directing charged inhibitors containing either a carboxylate or an ionizable
      hydantoin group to the active site of aldose reductase by providing charge
      interaction.

PMID- 10644041
TI  - Influence of the proto-oncogene c-fos on cisplatin sensitivity.
AB  - Cisplatin resistance has been associated with overexpression of the c-fos gene in
      a human ovarian carcinoma cell line. To determine whether the correlation between
      c-fos overexpression and cisplatin resistance was limited to this cell line or
      was a more generalized phenomenon, we investigated cisplatin sensitivity in rat
      fibroblast cells that overexpressed the c-fos gene. The cisplatin Ic50 values for
      two different c-fos transfectants, CMVc-fos and L1-3c-fos, were 7.6 +/- 0.8 and
      5.6 +/- 1.0 microM, respectively, whereas the cisplatin Ic50 value for the
      parental line, 208F, was 2.4 +/- 0.1 microM. This represented a 3.2- and 2.3-fold
      resistance to cisplatin for CMVc-fos and L1-3c-fos cells, respectively. The
      correlation between c-fos expression and cisplatin resistance also was examined
      in a human ovarian carcinoma cell line, 2008, and its cisplatin-resistant
      variant, C13*. Expression of c-fos was elevated slightly at both the mRNA and
      protein levels in the C13* cells compared with 2008 cells, and c-Fos protein
      levels were induced in C13* cells following cisplatin treatment. In addition, it
      was observed that C13* cells were significantly more sensitive than 2008 cells to
      a c-fos antisense oligonucleotide. The Ic50 values for the c-fos antisense
      oligonucleotide were 19.9 +/- 5.0 pmol for C13* cells and 58.1 +/- 6.0 pmol for
      2008 cells (P = 0.0012). Furthermore, combinations of c-fos antisense and
      cisplatin reduced the amount of cisplatin required to kill 50% of the C13* cells,
      although the interaction was not synergistic. These results suggest that
      expression of the c-fos gene can influence cisplatin sensitivity, and that c-fos
      antisense oligonucleotide based therapy may be effective at killing parental and
      cisplatin-resistant ovarian carcinoma cells, either alone or in combination with
      cisplatin.

PMID- 10644042
TI  - Potent effects of novel anti-platelet aggregatory cilostamide analogues on
      recombinant cyclic nucleotide phosphodiesterase isozyme activity.
AB  - The inhibitory potential of novel anti-platelet aggregatory cilostamide analogues
      on phosphodiesterase (PDE) isozyme activities was investigated with recombinant
      PDE isozymes expressed in a baculovirus/ Sf9 expression system. The recombinant
      enzymes (PDE1-PDE5 and PDE7) showed Km values and sensitivities to selective
      inhibitors similar to those reported previously for native enzymes purified from
      tissues. The cyclooctylurea derivative OPC-33540 (6-[3-[3-cyclooctyl-3-[(1R*,2R*)
      2-hydroxycyclohexyl]ureido]-propoxy]-2(1H)-quinolinone) inhibited recombinant
      PDE3A (IC50 = 0.32 nM) more potently and selectively than the classical PDE3
      inhibitors cilostamide, cilostazol, milrinone, and amrinone. The cyclopropylurea
      derivative OPC-33509 [(-)-6-[3-[3-cyclopropyl-3-[(1R,2R)-2
      hydroxycyclohexyl]ureido]-propoxy]-2(1H)-quinolinone] was less potent (IC50 =
      0.10 microM) than OPC-33540, demonstrating that the cyclooctyl moiety was
      important for a potent inhibitory effect. In platelets, OPC-33540 potentiated
      cyclic AMP accumulation concentration-dependently in both the absence and the
      presence of 3 nM prostaglandin E1 (PGE1) (doubling concentrations: 32.5 and 6.2
      nM, respectively). OPC-33540 inhibited thrombin-induced platelet aggregation
      potently (Ic50 = 27.8 nM). The anti-platelet aggregation effect also was
      stimulated in the presence of 3 nM PGE1 (IC50 = 6.0 nM). There was a good
      correlation between the IC50 values of PDE3 inhibitors in this study for
      recombinant PDE3A activity and their IC50 values for thrombin-induced platelet
      aggregation (r = 0.998). These data demonstrated that OPC-33540 is a highly
      selective and potent PDE3 inhibitor and a useful probe for identification of the
      intracellular functions of PDE3.

PMID- 10644043
TI  - Suppression of lipopolysaccharide-induced nuclear factor-kappaB activity by
      theaflavin-3,3'-digallate from black tea and other polyphenols through down
      regulation of IkappaB kinase activity in macrophages.
AB  - We investigated the inhibition of IkappaB kinase (IKK) activity in
      lipopolysaccharide (LPS)-activated murine macrophages (RAW 264.7 cell line) by
      various polyphenols including (-)-epigallocatechin-3-gallate, theaflavin, a
      mixture of theaflavin-3 gallate and theaflavin-3'-gallate, theaflavin-3,3'
      digallate (TF-3), pyrocyanidin B-3, casuarinin, geraniin, and penta-O-galloyl
      beta-D-glucose (5GG). TF-3 inhibited IKK activity in activated macrophages more
      strongly than did the other polyphenols. TF-3 strongly inhibited both IKK1 and
      IKK2 activity and prevented the degradation of IkappaBalpha and IkappaBbeta in
      activated macrophage cells. The results suggested that the inhibition of IKK
      activity by TF-3 could occur by a direct effect on IKKs or on upstream events in
      the signal transduction pathway. Furthermore, geraniin, 5GG, and TF-3 all blocked
      phosphorylation of IKB from the cytosolic fraction, inhibited nuclear factor
      kappaB (NFkappaB) activity, and inhibited increases in inducible nitric oxide
      synthase levels in activated macrophages. These results suggest that TF-3 may
      exert its anti-inflammatory and cancer chemopreventive actions by suppressing the
      activation of NFkappaB through inhibition of IKK activity.

PMID- 10644044
TI  - Inhibition of interleukin-8-activated human neutrophil chemotaxis by thapsigargin
      in a calcium- and cyclic AMP-dependent way.
AB  - Chemotactic migration of human neutrophils, induced by interleukin-8 (IL-8) or
      other activators, was inhibited by thapsigargin in the high nanomolar range. The
      degree of inhibition depended on the type of activator. Other inhibitors of
      Ca(2+)-ATPases associated with intracellular calcium stores, such as
      cyclopiazonic acid and 2,5-di-(tert-butyl)-1,4-benzohydroquinone, equally
      inhibited IL-8-activated migration. Inhibition of migration by thapsigargin and
      the other ATPase inhibitors occurred only in the presence of extracellular Ca2+;
      migration was not inhibited in the presence of EGTA. La3+ reversed thapsigargin
      induced inhibition to a large degree; other calcium channel blockers gave a
      partial reversal (econazole, verapamil, and SK&F 96365) or had no effect
      (gadolinium chloride and Ni2+). Using electroporated cells and Ca buffers, it was
      shown that inhibition started at about 0.2 microM and was complete at a cytosolic
      Ca concentration of about 2 microM. It appears that under certain conditions the
      thapsigargin-induced influx of extracellular calcium, causing relatively high
      local calcium concentrations, initiates or permits a process which may be
      detrimental to chemotactic migration. Cyclic AMP (cAMP; adenosine 3',5'-cyclic
      monophosphate) is probably involved in this process, because thapsigargin
      increased the cAMP level and cAMP inhibited IL-8-activated migration in a calcium
      dependent way. The hypothesis that cAMP is involved in the effect of thapsigargin
      on migration is supported by the finding that very low concentrations of
      thapsigargin stimulate neutrophil migration in the absence of other
      chemoattractants. The results suggest that thapsigargin causes a
      (compartmentalized) increase in cAMP, which results in a calcium-dependent
      modulation of migration.

PMID- 10644045
TI  - Effects of vitamin A deficiency on selected xenobiotic-metabolizing enzymes and
      defenses against oxidative stress in mouse liver.
AB  - Male and female C57B1/6 mice were rendered vitamin A-deficient, and the effects
      of this deficiency on certain xenobiotic-metabolizing enzymes and defenses
      against oxidative stress were examined. Vitamin A deficiency significantly
      increased the levels of DT-diaphorase, glutathione transferase, and catalase in
      the hepatic cytosolic fraction from male mice (5.2-, 1.6-, and 3.5-fold,
      respectively), as well as from female mice (4.8-, 3.3-, and 2.4-fold,
      respectively). In the hepatic mitochondrial fraction (containing peroxisomes)
      from male animals, the activities of urate oxidase and catalase were increased
      3.4- and 1.7-fold, respectively. The activity of catalase in the mitochondrial
      fraction from female mice was not affected by vitamin A deficiency, whereas the
      activity of peroxisomal urate oxidase was increased 2.9-fold. The hepatic level
      of ubiquinone was increased somewhat. The significance of the increases observed
      here is presently unclear, but it may be speculated that vitamin A and/or its
      metabolites are somehow involved in the down-regulation of these proteins.
      Another possibility is that these enzymes are increased as a result of hepatic
      oxidative stress caused by vitamin A deficiency. However, vitamin A deficiency
      had no effect on the activity of superoxide dismutase in this study, whereas the
      activity of glutathione peroxidase was slightly decreased (27%) in the hepatic
      cytosolic fraction from male mice. In addition, the hepatic level of alpha
      tocopherol was decreased dramatically in the vitamin A-deficient animals.

PMID- 10644046
TI  - Studies on the interaction between ethanol and serotonin metabolism in rat, using
      deuterated ethanol and 4-methylpyrazole.
AB  - The metabolic interaction between ethanol and serotonin (5-hydroxytryptamine) via
      alcohol dehydrogenase (ADH; EC 1.1.1.1) was studied in tissue homogenates of
      Sprague-Dawley rats by following the transfer of deuterium from deuterated
      ethanol over endogenous NADH to 5-hydroxytryptophol (5HTOL). Homogenates of whole
      brain, lung, spleen, kidney, liver, stomach, jejunum, ileum, colon, and caecum
      were incubated in the presence of [2H2]ethanol and 5-hydroxyindole-3-acetaldehyde
      (5HIAL), and the [2H]5HTOL formed was identified and quantified using gas
      chromatography-mass spectrometry. ADH activity was most abundant in liver,
      kidney, and within the gastrointestinal tract. The highest incorporation of
      deuterium was obtained in homogenates of kidney, lung, and colon, whereas in
      brain, which contains very low ADH activity, no incorporation could be
      demonstrated. Addition of extra NAD+ (2.4 mM) increased the formation of
      [2H]5HTOL 2.6-fold in liver homogenates, but only 1.2-fold in kidney homogenates.
      4-Methylpyrazole, a potent inhibitor of class I ADH, inhibited the 5HIAL
      reduction in homogenates of lung, kidney, jejunum, ileum, and colon, and caused a
      marked drop in 5HTOL oxidation in all tissues except stomach and spleen. These
      results demonstrate that in the rat a metabolic interaction between ethanol and
      serotonin via the ADH pathway may take place in several tissues besides the
      liver, which is the main tissue for ethanol detoxification.

PMID- 10644047
TI  - Effect of sevoflurane on Ca2+ mobilization in Madin-Darby canine kidney cells.
AB  - We investigated the effect of the volatile anesthetic sevoflurane on Ca2+
      signaling in Madin-Darby canine kidney (MDCK) cells by using the fluorescent dye
      fura-2/AM (1-[2-(5-carboxyoxazol-2-yl)-6-aminobenzofuran-5-oxy]-2-(2'-amino-5'
      methylphenoxy)-ethane-N,N,N,N-tetraacetic acid pentaace-toxymethyl ester) as the
      Ca2+ indicator. At a concentration of 0.15 mM, sevoflurane did not alter basal
      cytosolic free calcium concentration ([Ca2+]i); however, at concentrations of
      0.45-0.6 mM, sevoflurane did elevate [Ca2+]i, mainly by releasing Ca2+ from the
      endoplasmic reticulum (ER) store. Sevoflurane (0.15 mM) did not change either the
      [Ca2+]i peak evoked by high doses of ATP or UTP or inhibition of the ER Ca2+
      pump, although it did significantly slow down the decay of the [Ca2+]i rise.
      Lastly, sevoflurane inhibited the capacitative Ca2+ entry and Mn2+ quench of fura
      2 fluorescence induced by Ca(2+)-mobilizing ligands.

PMID- 10644048
TI  - Modulation of telomerase activity by zinc in human prostatic and renal cancer
      cells.
AB  - Because the up-regulation of telomerase in most cancer tissues is considered to
      be responsible for the unlimited proliferation of cancer cells, suppression of
      telomerase activity is an attractive potential target for cancer therapy. The
      mechanism for the activation of telomerase in cancer cells, however, is still
      unclear. In the present study, we demonstrated that Zn induces an enhancement of
      telomerase activity in the human renal cell carcinoma (NRC-12) and prostatic
      cancer (DU145) cell lines. The maximum elevation of the activity was observed 6
      hr after treatment with 100 microM Zn; it was diminished by the addition of
      either metal chelator or cycloheximide. Other metals such as Cd and Cu also
      enhanced telomerase activity but to a lesser extent, and no correlation between
      the activation of telomerase and the induction of metallothionein was observed.
      Our findings provide the first evidence that metals, especially Zn, can modulate
      telomerase activity in cancer cells.

PMID- 10644049
TI  - Role of c-Jun N-terminal kinase/p38 stress signaling in 1-beta-D
      arabinofuranosylcytosine-induced apoptosis.
AB  - 1-beta-D-Arabinofuranosylcytosine (ara-C) induced apoptosis in HL-60 cells, which
      was preceded by the activation of extracellular signal-regulated kinase (ERK), c
      Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK), and p38 mitogen
      activated protein kinase (MAPK). 2'-Amino-3'-methoxyflavone (PD098059) and 4-(4
      fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB203580)
      were used to inhibit the activity of ERK and p38, respectively. SEK-AL, a
      dominant-negative mutant of SEK1, was transfected into HL-60 cells (HL-60/SEK-AL)
      to assess the role of JNK/SAPK activity in apoptosis. PD098059 (25 microM)
      inhibited ara-C-induced caspase-3-like activity but was ineffective in altering
      ara-C-mediated apoptotic DNA fragmentation and clonogenicity. On the other hand,
      SB203580 (20 microM) inhibited ara-C-induced caspase-3-like activity, apoptotic
      DNA fragmentation, and clonogenicity. The inhibition of JNK1 activation in HL
      60/SEK-AL cells did not block ara-C-induced apoptotic DNA fragmentation. These
      results suggest that ara-C-induced apoptotic DNA fragmentation and loss of
      clonogenicity occur through a p38-dependent pathway.

PMID- 10644050
TI  - Protective effect of erythropoietin on the oxidative damage of erythrocyte
      membrane by hydroxyl radical.
AB  - Treatment of red blood cells with the copper (II) ascorbate system causes
      increased lipid peroxidation, increased membrane microviscosity, and phospholipid
      translocation with a concurrent decrease in cytosolic catalase and glutathione
      peroxidase activities. All these changes are prevented if the cells are treated
      with erythropoietin prior to the exposure to copper (II) ascorbate. The present
      investigation further indicates that the oxidative damage brought about by copper
      (II) ascorbate is due to generation of hydroxyl radical and that erythropoietin
      plays a unique role in protecting the membrane from oxidative damage.

PMID- 10644051
TI  - Activation of nuclear factor-kappaB by the peroxisome proliferator ciprofibrate
      in H4IIEC3 rat hepatoma cells and its inhibition by the antioxidants N
      acetylcysteine and vitamin E.
AB  - Peroxisome proliferators are a class of hepatic carcinogens in rodents and are
      proposed to act in part by increasing reactive oxygen species such as hydrogen
      peroxide. We previously showed that treatment of rats with ciprofibrate, a
      peroxisome proliferator, results in increased hepatic nuclear factor-kappaB (NF
      kappaB) DNA binding activity. In this study, we have examined the link between
      peroxisome proliferators and NF-kappaB activation in hepatoma cell lines to test
      whether increased nuclear NF-kappaB levels activate NF-kappaB-regulated genes and
      to determine the mechanism of NF-kappaB activation. Electrophoretic mobility
      shift assays demonstrated NF-kappaB induction by ciprofibrate in peroxisome
      proliferator-responsive H4IIEC3 rat hepatoma cells but not in peroxisome
      proliferator-insensitive HepG2 human hepatoma cell lines. In addition, we found
      that stably transfected NF-kappaB-regulated reporter genes were activated by
      ciprofibrate in H4IIEC3 cells. This reporter gene activation was blocked by the
      antioxidants N-acetylcysteine and vitamin E. These studies suggest that
      hepatocytes are at least partially responsible for peroxisome proliferator
      mediated hepatic NF-kappaB activation, and support the possibility that this
      activation is dependent upon reactive oxygen species.

PMID- 10644052
TI  - Biological actions of the free acid of hepoxilin A3 on human neutrophils.
AB  - In earlier reports and reviews, it was suggested that unlike its methyl ester,
      the free acid form of the 12-lipoxygenase-derived eicosanoid hepoxilin A3 (HXA3)
      does not enter neutrophils and other cells. Therefore, in the past, most studies
      on the biological activities of HXA3 on human neutrophils were conducted with its
      methyl ester. Here, we present evidence that free HXA3 is biologically active
      towards human neutrophils at submicromolar concentrations, which may occur under
      certain circumstances in vivo. Thus, HXA3 caused chemotaxis at concentrations as
      low as 30-40 nM, an effect which was attenuated at higher concentrations of this
      eicosanoid. Its chemotactic potency proved to be comparable to that of
      leukotriene B4, but higher than that of the chemotactic peptide formyl-methionyl
      leucyl-phenylalanine (fMLP), and greatly exceeded that of the other 12
      lipoxygenase metabolite, 12(S)-hydroxy-5,8,10,14-eicosatetraenoic acid, which was
      inactive at comparable concentrations. The chemotactic activity of HXA3 was not
      abolished by serum albumin, but it was suppressed by pertussis toxin. Unlike
      fMLP, at this concentration range HXA3 did not cause respiratory burst or
      aggregation of the neutrophils or activation of protein kinase C. These
      observations suggest a remarkably selective and specific receptor-mediated
      process. At concentrations higher than 1 microM, HXA3 gives rise to an
      instantaneous release of calcium from intracellular stores which causes, however,
      only a slight, if any, liberation of arachidonic acid. On the other hand,
      pretreatment of the neutrophils with submicromolar concentrations of HXA3
      significantly blunts the liberation of arachidonic acid caused by fMLP.

PMID- 10644053
TI  - Down-regulation of renal glutathione synthesis by systemic nitric oxide synthesis
      inhibition in spontaneously hypertensive rats.
AB  - Nitric oxide stimulates in vitro the synthesis of glutathione, an abundant thiol
      with a number of functions such as detoxification of xenobiotics and reactive
      oxygen species. In order to study this relationship in an animal model of
      hypertension, we treated spontaneously hypertensive rats (SHR) either with a
      nitric oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME)
      or with a nitric oxide donor isosorbide-5-mononitrate (IS-5-MN). Inhibition of
      nitric oxide synthesis led to malignant hypertension and to a marked decrease in
      glutathione synthesis through down-regulation of the rate-limiting enzyme gamma
      glutamylcysteine synthetase (GCS). The reduction in GCS activity was further
      augmented in SHR on a high sodium diet. Renal GCS activity in untreated SHR was
      234 +/- 14 and 240 +/- 18 nmol/min/mg protein (mean +/- SD) on a low and high
      sodium diet, respectively. When L-NAME was included in the diet, the activities
      dropped to 173 +/- 28 and 123 +/- 28 for the low and high sodium diets,
      respectively. IS-5-MN attenuated the rise in blood pressure induced by sodium
      chloride, but did not affect the GCS activity. The mechanism of GCS stimulation
      by nitric oxide is not known, but our results combined with the literature
      suggest that a relatively high concentration of nitric oxide is needed.

PMID- 10644054
TI  - Acetaminophen hepatotoxicity precipitated by short-term treatment of rats with
      ethanol and isopentanol: protection by triacetyloleandomycin.
AB  - Ethanol and isopentanol are the predominant alcohols in alcoholic beverages. We
      have reported previously that pretreatment of rats with a liquid diet containing
      6.3% ethanol plus 0.5% isopentanol for 7 days results in a synergistic increase
      in acetaminophen hepatotoxicity, compared with rats treated with either alcohol
      alone. Here, we investigated the role of CYP3A in acetaminophen hepatotoxicity
      associated with the combined alcohol treatment. Triacetyloleandomycin, a specific
      inhibitor of CYP3A, protected rats pretreated with ethanol along with isopentanol
      from acetaminophen hepatotoxicity. At both 0.25 and 0.5 g acetaminophen/kg,
      triacetyloleandomycin partially prevented elevations in serum levels of alanine
      aminotransferase. At 0.25 g acetaminophen/kg, triacetyloleandomycin completely
      protected 6 of 8 rats from histologically observed liver damage, and partially
      protected the remaining 2 rats. At 0.5 g acetaminophen/kg, triacetyloleandomycin
      decreased histologically observed liver damage in 7 of 15 rats. In rats
      pretreated with ethanol plus isopentanol, CYP3A, measured immunohistochemically,
      was decreased by acetaminophen treatment. This effect was prevented by
      triacetyloleandomycin. These results suggest that CYP3A has a major role in
      acetaminophen hepatotoxicity in animals administered the combined alcohol
      treatment. We also found that exposure to ethanol along with 0.1% isopentanol for
      only 3 days resulted in maximal increases in acetaminophen hepatotoxicity by the
      combined alcohol treatment, suggesting that short-term consumption of alcoholic
      beverages rich in isopentanol may be a risk for developing liver damage from
      acetaminophen.

PMID- 10644055
TI  - Molecular mechanisms of radiation-induced accelerated repopulation.

PMID- 10644056
TI  - Overexpression of the human manganese superoxide dismutase (MnSOD) transgene in
      subclones of murine hematopoietic progenitor cell line 32D cl 3 decreases
      irradiation-induced apoptosis but does not alter G2/M or G1/S phase cell cycle
      arrest.
AB  - To determine whether overexpression of the human MnSOD transgene protected 32D cl
      3 hematopoietic progenitor cells from ionizing irradiation, 32D cl 3 cells were
      co-electroporated with the pRK5 plasmid containing the human MnSOD transgene and
      SV2-neo plasmid with G418-resistant colonies selected. Two clones (1F2 and 2C6)
      were identified to overexpress the human MnSOD transgene by nested reverse
      transcriptase-polymerase chain reaction (RT-PCR) and increased biochemical
      activity. Measurement of irradiation-induced damage was determined in cells
      removed from G418 for 1 week before irradiation. Irradiation survival curves,
      apoptosis tunnel assay, and Comet assay was performed. Cell cycle distribution
      was determined for each line at 0, 1, 3, 6, 24, and 48 hr after 500 cGy by fixing
      the cells in 70% ethanol, staining with propidium iodide, and analysis by flow
      cytometer. Biochemical MnSOD activity in U/mg protein was 2.6 for 32D cl 3 and
      significantly elevated to 8.4 and 6.6 (P < 0.001) U/mg protein for subclones 1F2
      and 2C6, respectively. Irradiation survival curves demonstrated an increased
      shoulder on the irradiation survival curve for 1F2 and 2C6 cells with an n of
      4.95 +/- 0.48 (P = 0.042) and 4.95 +/- 0.13 (P = 0.011), compared with 2.77 +/-
      0.20 for 32D cl 3. A higher percent of 32D cl 3 cells demonstrated apoptosis at
      24 and 48 hr after 1,000 cGy irradiation, compared with 1F2 and 2C6 cells (at 24
      hr, 29.37% +/- 2.01% of 32D cl 3 cells were apoptotic compared with 5.21 +/- 2.61
      (P = 0.018) and 5.27 +/- 2.58 (P = 0.004) for 1F2 and 2C6, respectively).
      Significantly more DNA strand breaks were detected by Comet assay in 32D cl 3
      cells (Comet length at 600 cGy of 103.4 +/- 50.3 units, compared with 69.7 +/-
      36.3 (P < 0.001) and 48.9 +/- 27.5 (P < 0.001) for 1F2 and 2C6, respectively). In
      contrast, irradiation-induced cell cycle arrest was similar between the cell
      lines with a G2/M phase arrest at 6 hr and a G1/S phase arrest at 24 and 48 hr
      after irradiation. While overexpression of MnSOD increases the shoulder on the
      irradiation survival curve of 32D cl 3 cells, decreases irradiation-induced
      apoptosis, and DNA strand breaks by Comet assay, irradiation-induced alterations
      in cell cycle distribution were not significantly altered. These 32D cl 3
      subclonal lines overexpressing MnSOD provide a potentially valuable system with
      which to study the mechanism of irradiation-induced cell cycle arrest separate
      from irradiation-induced apoptosis.

PMID- 10644058
TI  - What is the optimal treatment volume in Hodgkin's disease patients undergoing
      high-dose chemotherapy and adjuvant radiation therapy?
AB  - To determine the optimal treatment volume in Hodgkin's disease patients
      undergoing high-dose chemotherapy (HDCT) and radiation therapy (RT), failure
      sites were reviewed in 56 patients. Twenty-one (38%) received involved-field RT
      (IFRT) before or after HDCT encompassing sites of prior disease. Failure sites
      were designated as previously involved (old) or uninvolved (new) sites. Seven
      patients (12%) died in the immediate post-HDCT period, leaving 49 evaluable
      (median follow-up, 41 months). Twenty-five patients (51%) relapsed (14 HDCT, 11
      HDCT + IFRT): seven (28%) in old, eight (32%) in new, and ten (40%) in old and
      new sites. Six of the seven who relapsed in old sites received HDCT alone,
      whereas seven of the eight who relapsed in new sites received IFRT. Relapse in
      old sites was particularly common in patients failing to achieve a complete
      response. The most common new failure site was nodal, occurring in 11 patients
      and was primarily (10/11) adjacent to an old site. Although it controls prior
      disease, IFRT is insufficient in Hodgkin's disease patients undergoing HDCT.
      Relapse is common in new nodal sites and is primarily adjacent to prior sites.
      These results suggest that extended-field RT encompassing old and adjacent
      uninvolved nodal sites may be the optimal treatment volume in these patients.

PMID- 10644057
TI  - Enhancement of radiation effects by combined docetaxel and carboplatin treatment
      in vitro.
AB  - This study was designed to evaluate the combination of docetaxel (Taxotere) and
      carboplatin for radiopotentiation in vitro. H460 human lung carcinoma cells were
      treated with docetaxel (or paclitaxel) for 1 h and rinsed. After 24 h, the cells
      were treated with carboplatin for 1 h, irradiated, and colony forming ability was
      assesed. Using various doses of docetaxel with 100 microM carboplatin, the dose
      enhancement ratio (D.E.R.) for drugs only was 1.26. When 25 nM docetaxel was used
      with various doses of radiation, the radiation D.E.R. was 1.41. With all three
      agents combined, and after normalization for combined drug effects, the radiation
      D.E.R. was 1.55. Similar values were obtained using paclitaxel with these agents.
      Significant redistribution of cells into the radiosensitive G2/M phase was
      observed using a dose of paclitaxel (750 nM), which also caused radiation
      enhancement. However, an equally cytotoxic dose of docetaxel (25 nM) did not
      result in any cell cycle redistribution; this phenomenon was only observed at
      higher doses. This study shows that the combination of docetaxel and carboplatin
      enhance the effects of radiation in vitro more effectively than either drug
      seperately. In addition, our data show that the mechanism of radiopotentiation by
      docetaxel probably does not involve a G2/M block in H460 cells.

PMID- 10644059
TI  - Anticipating prostatic volume changes due to prostate brachytherapy.
AB  - The purpose of the study was to determine which clinical parameters might predict
      individual prostate volume changes from prostate brachytherapy. Fifty
      consecutive, unselected patients treated at the University of Washington by I-125
      or Pd-103 implantation for prostatic carcinoma in 1998 were analyzed. The
      prostate contours on preimplant transrectal ultrasound (TRUS) images were
      digitized and the prostate volumes calculated. Postimplant axial CT images of the
      prostate was obtained at 0.5 cm intervals with patients in the supine position
      the morning after the implant. The postimplant prostate volume increased by an
      average factor of 1.7 (+/-0.34) compared with the preimplant volume, the size
      increase being primarily in the anterior-posterior dimension. The absolute volume
      change was similar in patients with small vs. large preimplant prostate volume (r
      = -0.39), but the proportional change was less in patients with a larger prostate
      volume (r = -0.71). Because patients with a small preimplant prostate had
      proportionately greater volume increase, their postimplant target coverage was
      generally less. No single parameter, including preimplant prostate volume,
      preimplant hormonal deprivation, or supplemental external beam radiation therapy
      (EBRT) can accurately predict the degree of swelling. The precise significance of
      and practical solution to implant-related prostate volume changes remains to be
      determined.

PMID- 10644060
TI  - Treatment of pediatric Hodgkin's disease with chemotherapy alone or combined
      modality therapy.
AB  - Optimal treatment for Hodgkin's disease during childhood is unknown. We report
      the treatment outcome of patients with Hodgkin's disease <13 years of age seen at
      the American University of Beirut Medical Center (AUBMC) between 1980 and 1996. A
      retrospective review of the medical records of 24 children treated for HD at
      AUBMC was performed. Treatment consisted of chemotherapy alone (n = 15) or
      chemotherapy plus involved field radiotherapy (n = 9). Chemotherapy consisted of
      COPP, ABVD, or alternating cycles of each for a total of 6 to 12 cycles,
      depending on clinical and radiological response; three patients received MOPP.
      Five patients in the chemotherapy group had clinical stage (CS) I and II and 10
      had CS III disease. In the combined modality group, eight patients had CS I and
      II and one had CS IV disease. At a median follow-up of 5 years, the event-free
      survival (EFS) for the combined modality group was 100% and the overall survival
      (OS) 100%. For the chemotherapy alone group, the EFS was 56% and the OS was 79%.
      Four patients (27%) in the chemotherapy alone group who had Stage IIIB disease
      relapsed. Mean time to relapse was 4.3 years. In our experience, six cycles of
      COPP or (COPP plus ABVD) alone were suboptimal for the treatment of Stage IIIB
      Hodgkin's disease patients, especially those with involvement of lower abdominal
      nodes (III2B), extensive pulmonary disease, or mixed cellularity histology.
      Radiation therapy or additional chemotherapy courses are required for these
      patients.

PMID- 10644061
TI  - Comparisons of a proposed five-seed assay method with the single-seed and batch
      assay methods for I-125 seeds in ultrasound-guided prostate implants.
AB  - A simple five-seed assay method was proposed and investigated. A commercial well
      ion chamber system with an NIST-traceable single-seed calibration constant was
      used for the single-seed assays. A batch seed holder was used for batch assays.
      For the five-seed assays, a second single-seed holder was modified such that all
      five seeds were loaded in a central region of the well ion chamber. Compared with
      the same seed in the standard single-seed holder, the relative chamber responses
      for the five seed positions were 0.993, 0.993, 1.000, 1.001, and 0.977,
      respectively, indicating little or no position-dependent chamber response and no
      self-attenuation among seeds. Subsequent comparison of assays with the single
      seed and five-seed methods indicated only 0.4% difference in charge collection.
      The five-seed calibration constant was therefore taken to be the same as the
      single-seed calibration constant. The reproducibility of the five-seed assay
      method was found to be better than 0.8%. When a dummy seed replaced an active
      seed, a nearly 20% reduction in charge was found, indicating that the proposed
      five-seed assay method can detect a dead seed. Clinical comparison of all three
      assay methods showed that they produced qualitatively the same assay results when
      the batch assay method was performed with extra care. Compared with the single
      seed assay method, the five-seed method is equally simple, rigid, and
      reproducible, but it demands much less assay time. Compared with the batch assay
      method, the five-seed method is much more reproducible and reliable because of
      its rigid assay geometry; it only demands a moderate amount of assay time and can
      detect dead seeds. The American Association of Physicists in Medicine Task Group
      40 (AAPM TG40) states that, for brachytherapy, ideally every (i.e., 100%) loose
      seed should be calibrated. For procedures involving large number of loose seeds,
      it then recommends that 10% of seeds be calibrated. The proposed five-seed assay
      is very simple to implement. It will facilitate the compliance of the "10%"
      recommendation from the AAPM TG40; it will make the "ideally 100%" statement from
      AAPM TG40 a more realistic and practical QA procedure in seed assaying.

PMID- 10644062
TI  - Improvement of X-ray beam quality for treating cancer using double focus electric
      field strings.
AB  - Accurate knowledge of the distribution and amount of contamination electrons
      arising from the gantry head at the surface and in the first few centimeters of
      tissue is essential for the clinical practice of radiation oncology. These
      electrons tend to increase the surface dose and deteriorate the buildup in the
      radiation field compared with a pure photon field. In this study, the relative
      quantity and reduction of contamination electrons in a therapeutic radiation
      photon beam (15 MV) was investigated. The contamination electrons can be
      separated out by a special device. This device, consisting of a double-focus
      electric field (8 x 10(5) V/m) made by a large number of strings 2 x 10(-4) m in
      diameter, removes contamination electrons and positrons without affecting the
      photon beam. It is located under the tray holder. In clinical practice, the
      device can decrease the relative surface charge and relative surface dose due to
      contamination electrons in the photon beam used in radiation therapy.

PMID- 10644063
TI  - An interview of a distinguished pharmaceutical scientist.

PMID- 10644064
TI  - Some important considerations in the use of cyclodextrins.

PMID- 10644065
TI  - PAMAM dendrimers as delivery agents for antisense oligonucleotides.
AB  - PURPOSE: To investigate the potential use of PAMAM dendrimers for the delivery of
      antisense oligonucleotides into cells under conditions that mimic the in vivo
      environment. METHODS: We used HeLa cells stably transfected with plasmid pLuc/705
      which has a luciferase gene interrupted by a human beta-globin intron mutated at
      nucleotide 705, thus causing incorrect splicing. An antisense oligonucleotide
      overlapping the 705 splice site, when delivered effectively, corrects splicing
      and allows luciferase expression. The ability of dendrimers to deliver
      oligonucleotides to HeLa Luc/705 cells was evaluated in the absence or presence
      of serum. RESULTS: PAMAM dendrimers formed stable complexes with oligonucleotides
      that had modest cytotoxicity and showed substantial delivery activity. The dose
      of the oligonucleotide, the charge ratio of oligonucleotide to dendrimer, and the
      size (generation) of the dendrimers were all critical variables for the antisense
      effect. The physical properties of dendrimer/oligonucleotide complexes were
      further investigated using sedimentation and gel electrophoresis methods.
      Effective oligonucleotide/generation 5 dendrimer complexes were macromolecular
      rather than particulate in nature, and were not sedimented at 100,000 RPM.
      Compared to other types of delivery agents, PAMAM dendrimers were more effective
      in delivering oligonucleotides into the nucleus of cells in the presence of serum
      proteins. CONCLUSIONS: Our results suggest that PAMAM dendrimers form
      nonparticulate delivery complexes that function in the presence of serum proteins
      and thus may be suited for in vivo therapeutic applications.

PMID- 10644066
TI  - Cationic lipid-mediated transfection of differentiated Caco-2 cells: a filter
      culture model of gene delivery to a polarized epithelium.
AB  - PURPOSE: The use of rapidly dividing in vitro cell culture systems to assess the
      efficiency of gene delivery is now recognised as a poor indicator of in vivo
      success. We investigated whether differentiated Caco-2 cell filter-cultures would
      make a more suitable model for studying gene transfer to an epithelium. METHODS:
      Caco-2 cells were cultured on semi-permeable membrane filters into differentiated
      polarised monolayers. Monolayer differentiation was assessed by monitoring the
      transport of taurocholic acid. Cells at different stages of differentiation were
      transfected with DNA/DOTAP lipoplexes and later analysed for reporter gene
      activity. The uptake of radiolabled DNA was also evaluated at various stages of
      differentiation. RESULTS: Caco-2 cultures developed a resistance to lipoplex
      mediated transfection as early as three days, when some cells were still dividing
      and undifferentiated. As cultures matured, expression of reporter gene
      progressively decreased partly due to reduced internalisation of DNA. The
      resistance to transfection could be overcome in part by pre-treatment of
      monolayers with calcium chelating agents or surfactants. However, transgene
      expression in treated monolayers was still significantly lower than that in
      dividing cultures. CONCLUSIONS: Differentiated Caco-2 cells are a more
      appropriate model for gene-transfer studies to the intestinal epithelium because
      they demonstrate a resistance to transfection similar to that observed in vivo.

PMID- 10644067
TI  - Vitamin E-TPGS increases absorption flux of an HIV protease inhibitor by
      enhancing its solubility and permeability.
AB  - PURPOSE: To investigate the effect of vitamin E-TPGS, d-alpha-tocopheryl
      polyethylene glycol 1000 succinate, on the solubility and permeability of
      amprenavir, a potent HIV protease inhibitor. METHODS: The aqueous solubility of
      amprenavir was measured as a function of vitamin E-TPGS concentration.
      Directional transport through Caco-2 cell monolayers was determined in the
      presence and absence of vitamin E-TPGS and P-glycoprotein inhibitors. Absorption
      flux was estimated from Caco-2 cell permeability and aqueous solubility. RESULTS:
      The solubility of amprenavir in a pH 7 buffer at 37 degrees C was 0.036+/-0.007
      mg/mL. The solubility linearly increased with increasing vitamin E-TPGS
      concentration (above 0.2 mg/mL). Polarized transport was demonstrated in the
      basolateral to apical direction, exceeding apical to basolateral transport by a
      factor of 6. The active efflux system was inhibited by vitamin E-TPGS and known P
      glycoprotein inhibitors verapamil and GF120918. CONCLUSIONS: The solubility of
      amprenavir was improved in the presence of vitamin E-TPGS through micelle
      solubilization. Vitamin E-TPGS inhibits the efflux system and enhances the
      permeability of amprenavir. Overall, vitamin E-TPGS enhanced the absorption flux
      of amprenavir by increasing its solubility and permeability. The enhancement is
      essential to the development of the novel soft gelatin capsule formulation of
      amprenavir for use in the clinic.

PMID- 10644068
TI  - Ionized prodrugs of dehydroepiandrosterone for transdermal iontophoretic
      delivery.
AB  - PURPOSE: The aim of this work was to synthesize ionized dehydroepiandrosterone
      (DHEA) prodrugs with higher water solubility, useful for iontophoretic
      transdermal application. METHODS: The synthesized derivatives were characterized
      and tested for sensitivity to chemical and enzymatic hydrolysis. Solid state and
      solution stability was also determined. Transdermal iontophoretic anodal
      transport in vitro was studied using excised rabbit skin. RESULTS: Two DHEA
      ionized prodrugs were synthesized: PRO1, a primary amine derivative, and PRO2, a
      quaternary ammonium salt. The two derivatives possess higher water solubility and
      lower octanol/saline partition coefficients than DHEA. Prodrugs were sensitive to
      enzymatic hydrolysis; in particular the primary amine was hydrolyzed faster than
      the quaternary salt by esterase from porcine liver in vitro. Transdermal flux of
      the two prodrugs was slightly higher than the parent drug. In the case of passive
      diffusion, only DHEA was found in the receptor compartment, indicating the
      complete breakdown of the prodrug in the skin. Current application gave higher
      drug flux and a significant amount of prodrug was found in the receptor.
      CONCLUSIONS: The use of ionized prodrugs of DHEA can increase the flux attainable
      during transdermal anodal iontophoresis by up to 7 times, but they are useful for
      passive transport as well.

PMID- 10644069
TI  - Sustained release of human growth hormone from PLGA solution depots.
AB  - PURPOSE: The effects of altering the dynamics of phase inversion of a polylactic
      glycolic acid (PLGA) solution depot on the sustained-release delivery profile of
      human growth hormone (hGH) were evaluated. The impact of adjusting the protein
      particle composition was also studied in a slow phase-inverting formulation.
      METHODS: Protein release profiles of depots prepared from four model solvents
      were generated by injecting formulations into the subcutaneous space of normal
      rats and monitoring hGH serum levels over the course of 1 month. Scanning
      electron microscopy, Coulometric Karl Fischer titration, size-exclusion liquid
      chromatography, and reversed-phase liquid chromatography were used to observe
      depot morphologies, bulk water absorption, PLGA degradation, and protein particle
      dissolution rates, respectively. RESULTS: An extended-release profile and
      significantly reduced burst effect resulted when the aqueous affinity of the
      depot solvent was reduced. As seen earlier in in vitro experiments, lowering the
      solvent's aqueous affinity slows the phase inversion rate, which in turn produces
      depot morphologies favorable to prolonged release. Protein burst on injection was
      entirely eliminated in a slow phase-inverting formulation by densifying the
      lyophilized protein particles. Unlike the use of metal cations to prolong release
      of some proteins in PLGA microsphere depots, this technique is more universal,
      and thus is potentially usable with any protein or highly soluble drug agent. The
      onset of biodegradation was observed to occur at 14 days for all depot
      formulations, however the bulk biodegradation rate slowed as the aqueous affinity
      of the depot solvent decreased. This result supports the hypothesis that, in a
      slow phase-inverting system, drug release over the first few weeks is governed by
      the diffusion rate of drug through the polymer solution. CONCLUSIONS: By taking
      advantage of the effects of low aqueous affinity and protein particle
      densification, a PLGA solution depot was produced with the capability of
      sustaining hGH levels in normal rats at a serum level of 10 to 200 ng/ml for 28
      days.

PMID- 10644070
TI  - Chitosan-gadopentetic acid complex nanoparticles for gadolinium neutron-capture
      therapy of cancer: preparation by novel emulsion-droplet coalescence technique
      and characterization.
AB  - PURPOSE: The gadopentetic acid (Gd-DTPA)-loaded chitosan nanoparticles (Gd
      nanoCPs) were prepared for gadolinium neutron-capture therapy (Gd-NCT) and
      characterized and evaluated as a device for intratumoral (i.t.) injection.
      METHODS: Gd-nanoCPs were prepared by a novel emulsion-droplet coalescence
      technique. The effects of the deacetylation degree of chitosan and Gd-DTPA
      concentration in chitosan medium on the particle size and the gadolinium content
      in Gd-nanoCPs were examined. In vitro Gd-DTPA release from Gd-nanoCPs was
      evaluated using an isotonic phosphate-buffered saline solution (PBS, pH 7.4) and
      human plasma. In vivo Gd-DTPA retention in the tumor after i.t. injection of Gd
      nanoCPs was estimated on mice bearing s.c. B16F10 melanoma. RESULTS: Gd-nanoCPs
      with the highest Gd content, which were obtained using 100% deacetylated chitosan
      in 15% Gd-DTPA aqueous solution, were 452 nm in diameter and 45% in Gd-DTPA
      content. A lower deacetylation degree of chitosan led to an increase in particle
      size and a decrease in Gd-DTPA content in Gd-nanoCPs. As Gd-DTPA concentration in
      the chitosan solution increased, Gd-DTPA content in Gd-nanoCPs increased but the
      particle size did not vary. Gd-DTPA loaded to Gd-nanoCPs was hardly released over
      7 days in PBS (1.8%) despite the high water solubility of Gd-DTPA. In contrast,
      91% of Gd-DTPA was released in plasma over 24 hours. When Gd-nanoCPs were i.t.
      injected, 92% of Gd-DTPA injected effectually without outflow was held in the
      tumor tissue for 24 hours, which was different from the case of gadopentetate
      solution injection (only 1.2%). CONCLUSIONS: Gd-nanoCPs highly incorporating Gd
      DTPA were successfully prepared by the emulsion-droplet coalescence technique.
      Their releasing properties and their ability for long-term retention of Gd-DTPA
      in the tumor indicated that Gd-nanoCPs might be useful as an i.t. injectable
      device for Gd-NCT.

PMID- 10644071
TI  - Indirect evidence that drug brain targeting using polysorbate 80-coated
      polybutylcyanoacrylate nanoparticles is related to toxicity.
AB  - PURPOSE: To investigate the mechanism underlying the entry of the analgesic
      peptide dalargin into brain using biodegradable polybutylcyanoacrylate (PBCA)
      nanoparticles (NP) overcoated with polysorbate 80. METHODS: The investigations
      were carried out with PBCA NP and with non biodegradable polystyrene (PS) NP (200
      nm diameter). Dalargin adsorption was assessed by HPLC. Its entry into the CNS in
      mice was evaluated using the tail-flick procedure. Locomotor activity
      measurements were performed to compare NP toxicities. BBB permeabilization by
      PBCA NP was studied in vitro using a coculture of bovine brain capillary
      endothelial cells and rat astrocytes. RESULTS: Dalargin loading was 11.7
      microg/mg on PBCA NP and 16.5 microg/ mg on PS NP. Adding polysorbate 80 to NP
      led to a complete desorption. Nevertheless, dalargin associated with PBCA NP and
      polysorbate 80 induced a potent and prolonged analgesia, which could not be
      obtained using PS NP in place of PBCA NP. Locomotor activity dramatically
      decreased in mice dosed with PBCA NP, but not with PS NP. PBCA NP also caused
      occasional mortality. In vitro, PBCA NP (10 microg/ml) induced a permeabilization
      of the BBB model. CONCLUSIONS: A non specific permeabilization of the BBB,
      probably related to the toxicity of the carrier, may account for the CNS
      penetration of dalargin associated with PBCA NP and polysorbate 80.

PMID- 10644072
TI  - Reduction of maturation phenomenon in cerebral ischemia with CDP-choline-loaded
      liposomes.
AB  - PURPOSE: Cerebral ischemia represents a serious therapeutic challenge. We
      investigated the therapeutic efficacy of CDP-choline-loaded liposomes against
      cerebral ischemia. The determination of post-ischemic brain recovery by EEG
      analysis was carried out to evaluate the effect of CDP-choline-loaded liposomes
      with respect to the free drug on the maturation of ischemic injury. METHODS: Long
      circulating unilamellar liposomes were prepared by a freeze and thaw procedure
      followed by an extrusion through polycarbonate membranes. Wistar rats were
      ischemized by bilateral clamping of the common carotid arteries. Free or
      liposomally entrapped drug was administered (20 mg/kg) just after ischemia and
      thereafter once a day for six days. Post-ischemic survival, neuronal membrane
      peroxidation and brain recovery (EEG analysis) were evaluated. RESULTS: The post
      ischemic reperfused rats treated with CDP-choline-loaded liposomes showed a
      higher survival rate than animals treated with the free drug. The delayed
      cerebral neurodegenerative injury due to an ischemic event, referred to as
      maturation phenomenon, was substantially reduced with the administration of the
      liposomal formulation. The liposomal carrier showed a marked protection against
      lipoperoxidative damage. CONCLUSIONS: Liposomes ensured a rapid recovery of the
      damaged membranous structure of the neuronal cells, allowing a significant
      improvement of brain functionality. The reduction of the maturation phenomenon
      may probably be of particular importance in humans, where a fundamental problem
      is the quality of life after an ischemic event.

PMID- 10644073
TI  - Tablet dissolution affected by a moisture mediated solid-state interaction
      between drug and disintegrant.
AB  - PURPOSE: To investigate the cause for decrease in delavirdine mesylate 200 mg
      tablet dissolution upon exposure to high humidity. METHODS: Dissolution testing
      was performed using the USP 2 (paddle) apparatus. Water in tablets was measured
      by Karl Fischer titration. 13C CP/MAS NMR was used to identify and quantify
      delavirdine form changes in tablets. FT-IR spectroscopy was used to monitor
      delavirdine form change in tablets and component mixes, and to investigate a
      solid state reaction with the disintegrant. RESULTS: Dissolution extent of
      delavirdine mesylate 200 mg tablets was substantially decreased after exposure to
      high humidity. This effect is related to the amount of water present in the
      tablet matrix. 13C CP/ MAS NMR detected about 30% conversion from the mesylate
      salt of delavirdine to its free base form in the tablet matrix. FT-IR
      spectroscopy demonstrated that a solid state reaction occurs between the freed
      methanesulfonic acid and the carboxyl sites on the croscarmellose sodium
      disintegrant. CONCLUSIONS: Water is thought to act as both a reaction medium and
      a plasticizer for croscarmellose sodium, facilitating protonation of the carboxyl
      sites on the disintegrant. This reaction has the potential to occur for any acid
      salt of a free base. The limiting solubility of delavirdine free base formed in
      the tablets accounts for much of the decrease in the extent of dissolution. A
      change in inter-particle bonding can explain the reduction in tablet
      deaggregation during dissolution.

PMID- 10644074
TI  - Analysis of a diffusion dryer for the respiratory delivery of poorly water
      soluble drugs.
AB  - PURPOSE: The purpose of this study was to analyze a diffusion dryer as a means to
      remove organic solvents from aerosol particles of poorly water soluble drugs.
      METHODS: Aerosols of methanol, ethanol, and ethyl acetate were generated with an
      ultrasonic nebulizer, and inflow to outflow concentration ratio of vapor in a
      annular charcoal column was determined as a function of time by gas
      chromotography at two to four different airflow rates. In addition, the particle
      transmission efficiency was determined with an ethanol solution of the test
      compound, budesonide. The results were analyzed with equations originally
      developed for assessing the loss of drug from intravenous tubing along with
      independent measures of the adsorption isotherm of the vapors onto charcoal.
      RESULTS: Aerosol production was relatively constant with time, and the
      transmission of solid particles through the column occurred with efficiency
      nearing 100%. The inlet to outlet vapor concentration ratio was adequately
      described by a model of three resistances in series composed of the inner tube,
      the screen mesh, and the charcoal bed. CONCLUSIONS: The diffusion dryer was found
      to be satisfactory for the removal of methanol, ethanol, and ethyl acetate and
      the efficiency may be assessed from the adsorption isotherms on charcoal and the
      geometry of the dryer.

PMID- 10644075
TI  - Application of supercritical carbon dioxide for the preparation of a piroxicam
      beta-cyclodextrin inclusion compound.
AB  - PURPOSE: Piroxicam is a poorly soluble NSAID, whose solubility is enhanced when
      included into beta-cyclodextrin. The preparation of a piroxicam-beta-cyclodextrin
      inclusion compound using supercritical CO2 was investigated. METHODS: The
      solubility and the stability of piroxicam in supercritical CO2 were determined.
      Then, the influence of the temperature, the pressure and the time of exposure on
      the inclusion rate was studied. RESULTS: The solubility of piroxicam varied over
      a wide range depending on the temperature and pressure (from 0.006 to 1.500 mg/g
      of CO2). The temperature and the time of exposure had a great influence on the
      inclusion yield, while pressure did not and a complete inclusion was achieved by
      keeping a physical mixture of piroxicam and beta-cyclodextrin (1:2.5 mol/mol) for
      6 hours at 150 degrees C and 15 MPa of CO2. This complex was characterized by
      Differential Scanning Calorimetry, differential solubility and Fourier Transform
      Infrared Spectrometry. CONCLUSIONS: Supercritical carbon dioxide may prove to be
      a novel useful complexation method of drugs into beta-cyclodextrin.

PMID- 10644076
TI  - Albendazole generics--a comparative in vitro study.
AB  - PURPOSE: We sought to determine whether disintegration and dissolution behavior
      differs among various albendazole generic formulations obtained from third world
      countries and to compare them with the innovator's product. METHODS: Dissolution
      behavior of various albendazole formulations was studied with USP Apparatus 2 in
      SGFsp and in a modified SGFsp which contained 0.1% of the nonionic surfactant
      Triton X 100. Disintegration was tested according to the European Pharmacopoeia.
      RESULTS: Dissolution experiments in SGFsp showed a wide range in rate and extent
      of albendazole dissolution. The innovator product released 81 percent within two
      hours, a profile matched by only one other formulation. For other formulations 32
      to 64% was released within two hours. Use of a modified SGFsp, containing 0.1%
      Triton X 100 to simulate the surface tension of gastric juice, resulted in less
      discrimination between products. The innovator product again showed the fastest
      and most complete dissolution, with ninety percent released within two hours. The
      generic formulations released between 67 and 82%, except for one formulation
      which achieved only 43% release. The results in SGFsp plus Triton X 100 may be
      more meaningful than in SGFsp since the surface tension of the medium is closer
      to the physiological value. All formulations passed the disintegration test
      according to the European Pharmacopoeia, with disintegration times ranging from
      2.5 to 11 minutes. CONCLUSIONS: Generic albendazole products vary widely in their
      dissolution behavior. Differences among products were greater in SGFsp than in
      SGFsp plus Triton X 100. These differences were not reflected in the
      disintegration behavior of the products.

PMID- 10644077
TI  - Forecasting the in vivo performance of four low solubility drugs from their in
      vitro dissolution data.
AB  - PURPOSE: To assess the usefulness of biorelevant dissolution tests in predicting
      food and formulation effects on the absorption of four poorly soluble, lipophilic
      drugs. METHODS. Dissolution was studied with USP Apparatus II in water, milk,
      SIFsp, FaSSIF, and FeSSIF. The in vitro dissolution data were compared on a rank
      order basis with existing in vivo data for the tested products under fasted and
      fed state conditions. RESULTS: All drugs/formulations showed more complete
      dissolution in bile salt/lecithin containing media and in milk than in water and
      SIFsp (USP 23). Comparisons of the in vitro dissolution data in biorelevant media
      with in vivo data showed that in all cases it was possible to forecast food
      effects and differences in absorption between products of the same drug with the
      physiologically relevant media (FaSSIF, FeSSIF and milk). Differences between
      products (both in vitro or in vivo) were less pronounced than differences due to
      media composition (in vitro) or dosing conditions (in vivo). CONCLUSIONS:
      Although biorelevant dissolution tests still have issues which will require
      further refinement, they offer a promising in vitro tool for forecasting the in
      vivo performance of poorly soluble drugs.

PMID- 10644078
TI  - An integrated model for determining causes of poor oral drug absorption.
AB  - PURPOSE: To develop an integrated absorption model for estimating the fraction of
      dose absorbed and determining the causes of poor oral drug absorption. METHODS:
      Both analytical and numerical methods were used to estimate the fraction of dose
      absorbed. RESULTS: An integrated absorption model was developed by considering
      transit flow, dissolution, and permeation processes, simultaneously. A framework
      was proposed to determine permeability-, dissolution-, and solubility-limited
      absorption. Digoxin, griseofulvin, and panadiplon were employed to illustrate the
      applications of the integrated model in identifying the causes of poor absorption
      and guiding formulation development. CONCLUSIONS: The integrated absorption model
      was successfully applied to digoxin, griseofulvin, and panadiplon to estimate the
      fraction dose absorbed and to roughly determine the causes of poor oral drug
      absorption.

PMID- 10644080
TI  - Absorption potential and its variants.

PMID- 10644079
TI  - Effects of interactions between drugs on the renal excretion of trientine in rats
      -acetazolamide and furosemide increase trientine excretion.
AB  - PURPOSE: To elucidate the effects of drug interactions on the urinary excretion
      of trientine in rats. METHOD: Trientine and various other drugs were
      intravenously administered to rats and the urinary excretion of trientine was
      investigated. To clarify the mechanisms of drug-drug interactions, we also
      investigated the effects of various drugs on spermine uptake by rat renal
      brushborder membrane vesicles. RESULTS: Cimetidine, a substrate of the H+/organic
      cation antiporter, and aminoglycoside antibiotics did not affect trientine
      excretion, while acetazolamide and furosemide, which increase the concentration
      of sodium ions in renal proximal tubules, increased the excretion of trientine.
      However, trichlormethiazide, which acts in renal distal tubules, did not affect
      trientine excretion. Acetazolamide and furosemide did not directly affect the
      Na+/spermine transporter because these diuretics had no effect on the uptake of
      spermine into the rat renal brush-border membrane vesicles. CONCLUSIONS: There is
      no interaction between trientine and the substrate of the H+/organic cation
      antiporter or aminoglycoside antibiotics. However, drugs that change the
      concentration of sodium ions in renal proximal tubules, such as diuretics, can
      increase the trientine excretion since the increase in the luminal concentration
      of sodium ion accelerates the Na+/spermine antiporter.

PMID- 10644081
TI  - Antagonistic interaction between the convulsant activities of pefloxacin and its
      main metabolite norfloxacin in rats.

PMID- 10644082
TI  - Detection and quantitation of human cytomegalovirus DNA in faeces.
AB  - The development and performance of a robust and sensitive PCR assay are described
      for the detection and quantitation of human cytomegalovirus DNA in human faecal
      specimens. In this assay, CMV DNA was purified by an optimised DNA extraction
      protocol together with internal control DNA that monitored both DNA extraction
      efficiency and PCR efficiency. The lower detection limit of the assay was reached
      at about 100 CMV particles per ml of (25-50%) faecal suspension. CMV DNA could be
      quantitated in the range of about 300-100000 molecules per ml of faecal
      suspension. CMV DNA loads obtained in clinical faeces specimens suggest that the
      assay can be used to monitor the efficacy of antiviral treatment. Reconstruction
      experiments that monitored the efficiency of DNA extraction of a preliminary DNA
      extraction protocol, showed low DNA yields for 9% of the specimens (n = 78). In
      all cases, low DNA extraction efficiency seemed to be due to a component present
      in faeces that prevented DNA binding to silica particles, presumably by
      competitive binding. Choosing the right ratio of silica particles to faeces
      specimen solved this problem. Similarly, reconstruction experiments showed that
      the strong PCR inhibition that was observed in 8% of the specimens could
      effectively be relieved by the inclusion of alpha-casein in the PCR mixtures.

PMID- 10644083
TI  - A highly sensitive heminested RT-PCR assay for the detection of citrus psorosis
      virus targeted to a conserved region of the genome.
AB  - Psorosis is a widespread and damaging disease of citrus in many parts of the
      world. The causal agent is a multipartite virus with RNA genome present in very
      low concentration in infected citrus tissue. Diagnosis is made by biological
      indexing on indicator citrus seedlings, but it is a slow and costly procedure and
      therefore it is not used generally. No sensitive wide-spectrum assay for Citrus
      Psorosis virus (CPsV) has been reported based on RT-PCR. A highly sensitive
      heminested RT-PCR assay is described for the detection of CPsV. Fragments of 313
      bp amplified from RNA 1 of different isolates were cloned and sequenced. Very
      high homology was found among six isolates from the citrus producing region of
      Argentina: 96.6-100% in nucleotide sequence. The consensus sequence obtained was
      used for the design of the primers for heminested PCR assay. It has been tested
      on different Argentine isolates, employing various methods for RNA extraction
      from infected tissue. This test is able to detect CPsV in dilutions of 10(10) of
      the original sample.

PMID- 10644084
TI  - Quantification of human polyomavirus JC in brain tissue and cerebrospinal fluid
      of patients with progressive multifocal leukoencephalopathy by competitive PCR.
AB  - Activation of human polyomavirus JC (JCV) infection is the cause of the central
      nervous system (CNS) disease progressive multifocal leukoencephalopathy (PML).
      Previous studies with uncontrolled quantification systems suggested that the
      virus load in the CNS correlates with the state of disease and might reflect
      therapeutic effects. Therefore the aim of this study was the development of a
      competitive system with standard PCR techniques that allowed rapid detection of
      JCV subtypes, simultaneous differentiation of the two human polyomaviruses JCV
      and BKV and absolute quantification of the virus burden in initial diagnosis and
      progressive disease states. Subtype- and species-specificity of the PCR was
      achieved with the development of a degenerative PCR primer pair that detected JCV
      DNA in a range regularly found in PML samples, but did not amplify BKV DNA. The
      accuracy of the system was evaluated by quantification of known amounts of cloned
      JCV DNA with a competitive JCV-specific template that exhibited a comparable
      amplification rate to that of the native product. The calibration study
      demonstrated a linear correlation over a wide range of DNA concentrations on the
      background of buffer or JCV-negative diagnostic samples. The reliability of the
      system for PML diagnosis was analysed by calibration and determination of the
      virus burden in tissue and cerebrospinal fluid (CSF) of 11 PML patients
      confirming the accuracy in both types of samples under diagnostic conditions.
      Comparison of the JCV DNA concentration in tissue and CSF by a tightly controlled
      quantification technique revealed for the first time differences in a range of
      about four orders of magnitude and a variable virus load in CSF samples taken at
      comparable states of disease. This pointed to an individual course of virus
      shedding and demonstrates that a controlled competitive PCR system of high
      accuracy is essential for reliable quantification of virus DNA either in initial
      diagnosis, in progressive disease or for the evaluation of therapeutic effects.

PMID- 10644085
TI  - A strategy for cloning infectious molecular clones of retroviruses from serum or
      plasma.
AB  - To enable biological characterisation of lentiviral variants which emerge during
      infection and development of AIDS, a method was developed to construct molecular
      clones from circulating simian immunodeficiency virus (SIV) particles present in
      as little as 20 microl of serum from infected rhesus monkeys. This technique uses
      a long distance RT-PCR method optimised for the amplification of partly
      overlapping 5-kb SIV (half genome) amplimers. Ligation of the genome halves
      resulted in the construction of full-length clones which, after transfection,
      were able to replicate well in rhesus peripheral blood mononuclear cells (PBMCs)
      and in various human T-cell lines inducing syncytia. In addition to the study of
      molecular cloned virus quasispecies emerging in circulation as a result of immune
      escape, this method may also be applied to obtain entire genes or full-length
      molecular clones. These clones may be present in other extracellular body fluids
      such as urine, saliva, tears, lymph, and bronchial or cerebral spinal fluid.
      Genes amplified in this way can be inserted quickly in new recombinant expression
      vectors and may then be applied for DNA vaccination approaches.

PMID- 10644087
TI  - A strategy for rapid cDNA cloning from double-stranded RNA templates isolated
      from plants infected with RNA viruses by using Taq DNA polymerase.
AB  - A fast and efficient cDNA cloning procedure for plant RNA viruses was developed.
      In this procedure, double-stranded RNA (dsRNA) was used as a template source.
      Standard cDNA synthesis reagents and random hexamers were then used for making
      cDNAs. Taq DNA polymerase was used to add additional (A) at the ends of cDNAs, a
      TA cloning kit to ligate the cDNAs to vectors, and an electroporator to transform
      the DNAs to E. coli cells. dsRNAs were extracted from grapevine tissues infected
      with four different viruses and used for cloning. These viruses included
      grapevine rupestris stem pitting associated virus, grapevine leafroll associated
      virus 5, and two uncharacterized grapevine viruses, one each closely related to
      marafivirus and vitivirus groups. Selected cDNA clones were sequenced and PCR
      primers were developed for RT-PCR detection of these viruses in host plants.

PMID- 10644086
TI  - Generation of full-length cDNA of the two genomic dsRNA segments of infectious
      bursal disease virus.
AB  - To determine the complete nucleotide sequence of Infectious Bursal Disease virus
      (IBDV) isolates, an efficient method was developed to generate full-length cDNA
      of both the genomic A- and B-segments. Reverse transcription was carried out at
      the highest possible temperature (50 degrees C) for the reverse transcriptase
      enzyme, and the single stranded cDNA was subsequently amplified by using an
      optimized PCR. The double stranded, full-length cDNA was efficiently cloned into
      a high copy number plasmid. Our results show that the entire cDNA of both the A-
      and B-segment of a classical attenuated isolate (CEF94), and a very virulent
      field isolate (D6948), can be cloned. The method will simplify greatly the
      procedure to generate full-length cDNA and determine the nucleotide sequence of
      the entire genome of IBDV isolates.

PMID- 10644088
TI  - Nested polymerase chain reaction and in situ hybridization for detection of
      nucleopolyhedrosis.
AB  - A nested polymerase chain reaction (PCR) and in situ hybridization were developed
      for detection of baculoviruses in insects or other arthropods with
      nucleopolyhedrosis. The nested PCR was based on the sequences of polyhedrin genes
      from baculoviruses. Two sets of primers were designed, primers set, 35/36, was
      for the first step of amplification and yielded a product of around 680 bp, the
      second primer, 35-1/36-1, was designed to yield a product of around 335bp from
      the fragment amplified by the first primer set. The sensitivity of this two-step
      amplification was 100 to 1000 times higher than that of the one-step
      amplification by primer set (35/36). Samples which contained baculovirus DNA
      yielded an amplification product showing the expected DNA fragment mobility,
      whereas nucleic acid extracted from tissue samples of clinically healthy insects
      or uninfected cells showed no such DNA fragment, thereby confirming the
      specificity of the primers. Using the 35/36 amplicon as a probe, the PenuNPV
      infected cells show positive reaction by in situ hybridization. Two-step DNA
      amplification and in situ hybridization with the DNA probe developed in the
      present paper provide effective detection and diagnostic tools for screening
      insects or other arthropods, especially crustacean species, crabs and shrimps,
      for baculovirus infections, and may be important in preventing (and/or
      controlling/enhancing) the infection of baculoviruses.

PMID- 10644089
TI  - Monitoring plasma processing steps with a sensitive Western blot assay for the
      detection of the prion protein.
AB  - Determining the risk of transmissible spongiform encephalopathy (TSE)
      transmission by blood or plasma-derived products requires sensitive and specific
      assays for the detection of either infectivity or a reliable marker for
      infectivity. To this end, a Western blot assay that is both sensitive and
      reproducible for the detection of PrP(RES), a marker for TSE infectivity, was
      developed. Using the 263K strain of TSE as a model system, the Western blot assay
      proved to be sensitive, specific and quantitative over a 3-4 log dynamic range.
      Compared to the rodent bioassay, the assay was shown to detect PrP(RES) down to
      approximately 10(3.4) IU/ml which is approximately 5-10 pg of PrP or
      approximately 10-20 ng brain equivalents. The Western blot was applied to monitor
      the partitioning of spiked PrP(Sc) through three plasma fractionation steps,
      cryoprecipitation, fraction I and fraction III, that are common to the
      purification of several human plasma-derived therapeutic products including
      albumin and immunoglobulins. The results from these studies demonstrated 1 log, 1
      log and 4 logs of PrP(Sc) partitioning away from the effluent fraction for the
      cryoprecipitation, fraction I and fraction III steps, respectively.

PMID- 10644090
TI  - Diagnosis of canine coronavirus infection using nested-PCR.
AB  - The results of polymerase chain reaction (PCR) and nested polymerase chain
      reaction (n-PCR) assays for the diagnosis of canine coronavirus (CCV) infection,
      and the comparison with other diagnostic techniques, such as electron microscopy
      (EM) and virus isolation using A-72 cell line are reported. The study was carried
      out on 71 faecal samples of pups with enteritis. Of 71 samples examined 14 were
      positive in PCR, whereas 30 samples resulted positive in the n-PCR assay. CCV was
      detected by EM examination in only four out of 45 samples, and by virus isolation
      in three out of 30 samples n-PCR positive.

PMID- 10644091
TI  - Inhibitors of RT-PCR in serum.
AB  - Amplification by RT-PCR of the RNA present in foot-and-mouth disease virus
      particles is inhibited by substances present in the sera of several species. This
      inhibition appears to be caused by a direct interaction of the substances with
      the RNA and not the enzymes used for its amplification.

PMID- 10644092
TI  - Detection of astrovirus gastroenteritis in children.
AB  - A commercial enzyme immunoassay (EIA) for the detection of astrovirus antigen was
      used to detect the virus during a 12-month survey of enteric pathogens in
      children in outpatient (n = 238) and hospital (n = 176) settings. It was found to
      have a 100% sensitivity and 98.6% specificity. Nineteen astrovirus isolates were
      detected and confirmed by northern hybridization, cell culture, and RT-PCR. The
      virus was detected mainly amongst outpatients although a comparison of the
      detection rate with that in hospitalised children did not demonstrate a
      statistically significant difference (p = 0.1347). In contrast, there was a
      strong association between hospitalization and rotavirus infection (p = 0.0371),
      and a strong association between infection detected in outpatients and adenovirus
      infection (p = 0.0193). Strains of astrovirus were sequenced, genotyped and shown
      to be: type 1 (n = 11), type 3 (n = 1), and type 4 (n = 7). Maximum genetic
      variation in type 1 isolates was 8.6% and type 4 was 7.8%. Changes did not result
      in amino acid substitutions.

PMID- 10644093
TI  - Radiology 2000--explore the new millennium.

PMID- 10644094
TI  - The past 25 years in medical imaging research: a memoir.
AB  - During the past 25 years, medical imaging research has progressed in both scope
      and quality. Factors intrinsic to the specialty and changes occurring in medicine
      and society have fostered imaging research development. The advent of new,
      computer-based technologies that can be brought to bear on research, the
      increasing sophistication of researchers, and the greater availability of
      extramural funding have been primary factors in the promulgation of research
      improvements. Radiology researchers have the opportunity to play an important
      role in the genesis of the molecular medicine of the future. Whether they do so
      is dependent on whether radiologists identify necessary resources, new
      researchers receive appropriate training, and investigators are willing to think
      differently than they have in the past about the capabilities of imaging.

PMID- 10644095
TI  - Radiology at the turn of the millennium.
AB  - Herein, the authors (a) review the status of the specialty; (b) report and
      analyze the various areas in which progress has occurred, namely, conventional
      radiology and picture archiving and communication systems (or PACS),
      ultrasonography, computed tomography, magnetic resonance imaging, interventional
      radiology, and nuclear medicine; and (c) discuss the problems radiology faces as
      it enters the new millennium. The problems are those facing medicine as a whole,
      as well as those threatening the future of radiology. These include the
      following: Will there be a need for radiologists in the future? Will radiology be
      too costly to be affordable? How can turf wars and fragmentation be solved?
      Possible remedies are suggested. Positive aspects are discussed in the light of
      the challenge to demonstrate value. Medical imaging is entering the new
      millennium with a solid record of recent advances in digital, cross-sectional,
      and interventional radiology. These advances have made the specialty
      indispensable in the treatment of patients. Careful statesmanship will be needed
      to solve the many problems that face medicine as a whole and radiology in
      particular.

PMID- 10644096
TI  - Electronic publications for RSNA.

PMID- 10644097
TI  - Current status of full-field digital mammography.

PMID- 10644098
TI  - Tamoxifen-induced uterine abnormalities: the role of imaging.
AB  - Tamoxifen citrate is an orally administered, nonsteroidal antiestrogen agent that
      is widely used for the treatment of breast cancer and that has recently been
      found to prevent breast cancer in some high-risk populations. Tamoxifen may,
      however, cause adverse effects at the uterine level. In this article, the authors
      review (a) the histopathologic uterine changes associated with tamoxifen therapy,
      (b) the spectrum of uterine imaging findings in women treated with tamoxifen, and
      (c) the recommendations of the American College of Obstetrics and Gynecology for
      women treated with tamoxifen. An algorithm for imaging evaluation of the uterus
      in women treated with tamoxifen is presented.

PMID- 10644099
TI  - Complex adnexal masses: detection and characterization with MR imaging-
      multivariate analysis.
AB  - PURPOSE: To evaluate the accuracy of magnetic resonance (MR) imaging in the
      detection and characterization of complex adnexal masses, with particular
      reference to the findings predictive of malignancy, role of gadolinium-enhanced
      contrast material, and observer variability. MATERIALS AND METHODS: Preoperative
      MR imaging of the pelvis was performed in 128 consecutive patients with
      clinically or ultrasonographically detected complex adnexal masses.
      Histopathologic examination demonstrated 187 masses, 96 of which were malignant.
      MR imaging studies were prospectively and independently reviewed by two
      radiologists, one of whom reevaluated the studies after a 6-month interval. The
      predictive value of MR imaging findings was determined with multivariate logistic
      regression analysis. The value of gadolinium enhancement was assessed by using
      receiver operating characteristic analysis. Inter- and intraobserver
      variabilities were assessed by using weighted K statistics. RESULTS: Gadolinium
      enhanced MR imaging depicted 176 (94%) of 187 adnexal masses, with an overall
      accuracy for the diagnosis of malignancy of 93%. The MR imaging findings that
      were most predictive of malignancy were necrosis in a solid lesion (odds ratio,
      107) and vegetations in a cystic lesion (odds ratio, 40). Use of gadolinium-based
      contrast material contributed significantly to lesion characterization.
      Interobserver (K, 0.79-0.85) and intraobserver (K, 0.84-0.86) agreement were
      excellent. CONCLUSION: Gadolinium-enhanced MR imaging is highly accurate in the
      detection and characterization of complex adnexal masses, with excellent inter-
      and intraobserver agreement.

PMID- 10644100
TI  - Endometrial polyps: MR imaging features and distinction from endometrial
      carcinoma.
AB  - PURPOSE: To determine the magnetic resonance (MR) imaging characteristics of
      endometrial polyps and the accuracy of MR imaging in distinguishing endometrial
      polyps from endometrial carcinomas in a case-control study. MATERIALS AND
      METHODS: Cross-referencing pathology records with MR studies from two
      institutions disclosed 35 patients with surgically proved endometrial polyp or
      carcinoma after controlling for tumor size. All MR examinations were performed at
      1.5 T with T2-weighted fast spin-echo sequences in multiple planes. Three
      independent readers blinded to histologic diagnoses and clinical data scored each
      image for the presence of several defined findings. RESULTS: A central fibrous
      core (low signal intensity on T2-weighted images) and intratumoral cysts (high
      signal intensity on T2-weighted images) were seen more frequently in endometrial
      polyps than in carcinomas; myometrial invasion and necrosis showed high
      predictive value for carcinomas. The readers' responses showed a mean sensitivity
      of 79%, specificity of 89%, accuracy of 86%, positive predictive value of 82%,
      and negative predictive value of 88% for diagnosis of carcinoma. The mean area
      under the receiver operating characteristic curve for the three readers was 0.87
      for the diagnosis of carcinoma. CONCLUSION: MR images can help to distinguish
      most polyps from endometrial carcinomas on the basis of morphologic features.
      Accuracy does not appear to be sufficient to obviate biopsy, partly because
      carcinomas and polyps frequently coexist.

PMID- 10644102
TI  - Multicentric and multifocal cancer: whole-breast US in preoperative evaluation.
AB  - PURPOSE: To evaluate preoperative whole-breast ultrasonography (US) in the
      management of breast cancer. MATERIALS AND METHODS: The ipsilateral breast in 40
      patients with known breast cancer or in whom there was high suspicion of breast
      cancer was evaluated with whole-breast US. Biopsy was performed on all discrete
      solid lesions. RESULTS: US depicted 45 (94%) of 48 invasive tumor foci and seven
      (44%) of 16 foci of ductal carcinoma in situ (DCIS). Mammography depicted 39
      (81%) of 48 invasive tumor foci and 14 (88%) of 16 foci of DCIS. The nine (14%)
      of 64 malignant foci seen only at US included three infiltrating ductal
      carcinomas, two mixed infiltrating and intraductal carcinomas, two infiltrating
      lobular carcinomas, and two foci of DCIS. Two (18%) of 11 foci of infiltrating
      lobular carcinoma were missed at both US and mammography. Of 20 patients
      mammographically suspected of having unifocal disease, three (15%) required wider
      excision on the basis of US findings. Two additional foci were depicted only at
      US in one of 16 patients mammographically suspected of having multicentric or
      multifocal disease. Of four patients with mammographically occult disease, US
      correctly depicted the diffuse (n = 2) or unifocal (n = 2) extent of the cancer.
      CONCLUSION: Whole-breast US complements mammography in the preoperative
      evaluation of patients with breast cancer, particularly when breast conservation
      is contemplated.

PMID- 10644101
TI  - Potential therapeutic effects of contrast materials in hysterosalpingography: a
      prospective randomized clinical trial. Kaiser Permanente Infertility Work Group.
AB  - PURPOSE: To evaluate the influence of the contrast material used in
      hysterosalpingography (HSG) on subsequent reproductive success, independent of
      other therapeutic interventions. MATERIALS AND METHODS: In a prospective,
      multisite, randomized trial, 666 women who had been infertile for more than 1
      year and were scheduled to undergo HSG as part of their evaluation were assigned
      to one of three groups: those receiving water-soluble contrast material (WSCM) (n
      = 260), those receiving oil-soluble contrast material (OSCM) (n = 273), and those
      receiving both OSCM and WSCM (n = 133). Possible causes of infertility and
      therapeutic interventions were abstracted from the medical records. Data on
      conception within 1 year and the outcome of conception were ascertained from
      multiple sources. RESULTS: Of 666 women, 204 (30.6%) had at least one pregnancy,
      and 136 (20.4%) had live births. The rates of live births were 20.4% (54 of 260)
      after HSG with WSCM, 19.4% (53 of 273) after HSG with OSCM, and 21.8% (29 of 133)
      after HSG with both WSCM and OSCM. Differences in reproductive outcome among
      contrast material groups were not statistically significant ((chi2)8 = 6.08, P =
      .64). Whatever the cause of infertility, the use of different contrast materials
      led to no significant differences in the rates of live births. CONCLUSION: There
      is no evidence to suggest that the choice of contrast material affects the rate
      of term pregnancy.

PMID- 10644103
TI  - Evaluation of pectoralis major muscle in patients with posterior breast tumors on
      breast MR images: early experience.
AB  - PURPOSE: To evaluate the ability to use breast magnetic resonance (MR) imaging to
      assess disease extent in patients with posterior breast masses who are suspected
      to have tumor invasion into underlying muscle. MATERIALS AND METHODS: Nineteen
      patients with posterior breast masses underwent three-dimensional, gradient-echo,
      1.5-T MR imaging before and after the administration of gadopentetate
      dimeglumine. Thirteen had deep palpable masses that were clinically determined to
      be fixed to the underlying chest wall. Twelve had mammographic findings that
      caused muscle involvement to be suspected, and seven had normal mammograms. All
      patients underwent surgery. MR images were reviewed and were correlated with
      histologic findings. RESULTS: Enhancing masses were identified on MR images in
      all 19 patients. Five (26%) of the 19 patients had masses that abutted the
      muscles, with obliteration of the fat plane and muscle enhancement. All five had
      muscle involvement at surgery. In the remaining 14 (74%) patients, no enhancement
      of muscle was seen; none of these had invasion of the muscle at surgery.
      CONCLUSION: Extension of adjacent tumor into underlying musculature was indicated
      by abnormal enhancement within these structures. Violation of the fat plane
      between tumor and muscle, without other findings, did not indicate tumor
      involvement of these deep structures.

PMID- 10644104
TI  - Lung nodule enhancement at CT: multicenter study.
AB  - PURPOSE: To test the hypothesis that absence of statistically significant lung
      nodule enhancement (< or =15 HU) at computed tomography (CT) is strongly
      predictive of benignity. MATERIALS AND METHODS: Five hundred fifty lung nodules
      were studied. Of these, 356 met all entrance criteria and had a diagnosis. On
      nonenhanced, thin-section CT scans, the nodules were solid, 5-40 mm in diameter,
      relatively spherical, homogeneous, and without calcification or fat. All patients
      were examined with 3-mm-collimation CT before and after intravenous injection of
      contrast material. CT scans through the nodule were obtained at 1, 2, 3, and 4
      minutes after the onset of injection. Peak net nodule enhancement and time
      attenuation curves were analyzed. Seven centers participated. RESULTS: The
      prevalence of malignancy was 48% (171 of 356 nodules). Malignant neoplasms
      enhanced (median, 38.1 HU; range, 14.0-165.3 HU) significantly more than
      granulomas and benign neoplasms (median, 10.0 HU; range, -20.0 to 96.0 HU; P <
      .001). With 15 HU as the threshold, the sensitivity was 98% (167 of 171 malignant
      nodules), the specificity was 58% (107 of 185 benign nodules), and the accuracy
      was 77% (274 of 356 nodules). CONCLUSION: Absence of significant lung nodule
      enhancement (< or = 15 HU) at CT is strongly predictive of benignity.

PMID- 10644105
TI  - Lung nodules: dual-kilovolt peak analysis with CT--multicenter study.
AB  - PURPOSE: To test the following hypothesis: The greater the increase in the mean
      computed tomographic (CT) number of a radiologically indeterminate lung nodule
      from the CT number on a 140-kVp CT image to that on an 80-kVp CT image, the more
      likely the nodule is benign (ie, contains calcium). MATERIALS AND METHODS: Two
      hundred forty indeterminate lung nodules were prospectively studied at four
      institutions: Mayo Clinic Scottsdale, Ariz (n = 160); Mayo Clinic Rochester, Minn
      (n = 50); Shiga Health Insurance Hospital, Otsu, Japan (n = 25); and Duke
      University Medical Center, Durham, NC (n = 5). Of the 240 nodules, 157 met the
      entrance criteria for this study and had a diagnosis. All nodules included were
      solid, 5-40-mm diameter, relatively spherical, homogeneous, and without visible
      evidence of calcification or fat. Each nodule was evaluated by using 3-mm
      collimation, nonenhanced CT scans with both 140- and 80-kVp x-ray beams. RESULTS:
      There were 86 (55%) benign and 71 (45%) malignant nodules. The median increase in
      the nodule mean CT number from the CT number on 140-kVp images to that on 80-kVp
      images was 2 HU for benign nodules and 3 HU for malignant nodules. This
      difference was not statistically significant. The area under the receiver
      operating characteristic curve was 0.505. CONCLUSION: Dual-kilovolt peak analysis
      with current CT technology does not appear to be helpful in the identification of
      benign lung nodules.

PMID- 10644106
TI  - True-lumen collapse in aortic dissection: part I. Evaluation of causative factors
      in phantoms with pulsatile flow.
AB  - PURPOSE: To investigate the causative factors in true-lumen collapse in a model
      of aortic dissection. MATERIALS AND METHODS: Phantoms with an aortic arch, true
      and false lumina with abdominal branch vessels, and a distal bifurcation were
      used to model a Stanford type B aortic dissection. The effects of anatomic
      factors (entry-tear size, branch-vessel flow distribution, fenestrations, distal
      reentry communication) and physiologic factors (peripheral resistance in the
      branch vessels, pump output and rate, vascular compliance) on true-lumen collapse
      were investigated. The morphology of the true lumen was observed. Branch
      pressures and flow rates were measured. RESULTS: True-lumen collapse was induced
      and was exacerbated by an increase in the size of the entry tear, a decrease in
      the false-lumen outflow caused by occluding the false-lumen branch vessels, and
      an increase in the true-lumen outflow caused by lowering the peripheral
      resistance in true-lumen branch vessels. Two kinds of true-lumen collapse
      depended on pump output. With low pump output and low outflow resistance from the
      true lumen, the true lumen collapsed. With high pump output and low inflow
      resistance in the false lumen, the true lumen was compressed. Distal reentry
      communication between the true and false limbs was more effective than aortic
      fenestrations in preventing true-lumen collapse. CONCLUSION: True-lumen collapse
      in this dissection model strongly depends on the difference in the ratios of
      inflow capacity to outflow capacity in the true and false lumina. Both anatomic
      and physiologic factors can affect true-lumen collapse.

PMID- 10644107
TI  - True-lumen collapse in aortic dissection: part II. Evaluation of treatment
      methods in phantoms with pulsatile flow.
AB  - PURPOSE: To discover and evaluate the effective treatment methods to prevent or
      relieve true-lumen collapse in models of aortic dissection. MATERIALS AND
      METHODS: Two phantoms were built to simulate type B aortic dissection. After true
      lumen collapse was induced, experiments were conducted to evaluate the
      effectiveness of clinically relevant variables in relieving the collapse.
      Variables included entry-tear size, branch-vessel flow distribution, distal
      reentry communication between the true and false limbs, aortic fenestrations, and
      pump output. To test the effect of closing the entry tear, a stent-graft was
      deployed over the entry tear under physiologic conditions in a mock-flow loop.
      The difference in the effect of each variable on the prevention and relief of
      true-lumen collapse was also investigated. RESULTS: It was more difficult to
      relieve true-lumen collapse than it was to prevent it. Placement of a stent-graft
      over the entry tear was the most effective method of relieving true-lumen
      collapse. Less-effective procedures included opening a false-lumen outflow branch
      and opening the distal reentry branch. Opening the fenestration-branch loops,
      meant to simulate the creation of artificial fenestrations in the intimal flap,
      did not relieve true-lumen collapse. CONCLUSION: The definitive treatment for
      true-lumen collapse in aortic dissection is direct repair of the entry tear to
      decrease false-lumen inflow. Otherwise, increasing the false-lumen outflow and/or
      creating distal fenestrations between the true and false lumina distal to the
      level of the compromised aortic branch are less-effective alternatives.

PMID- 10644108
TI  - MR hysterosalpingography: protocol development and refinement for simulating
      normal and abnormal fallopian tube patency--feasibility study with a phantom.
AB  - PURPOSE: To develop and refine a pulse sequence and protocol for testing the
      feasibility of magnetic resonance (MR) hysterosalpingography in a phantom model.
      MATERIALS AND METHODS: A phantom simulating the uterus, fallopian tubes, and
      surrounding pelvic cavity was constructed. T2-weighted acquisition strategies
      breath-hold fast spin-echo, rapid acquisition with relaxation enhancement (RARE),
      and haff-Fourier RARE-were refined to acquire sequential 70-mm coronal imaging
      volumes. Contrast agent was injected into the introducing catheter entering the
      os of the simulated uterus. Interacquisition interval, type of contrast agent
      (eg, sterile saline solution or water), and quantity of contrast agent (eg, 1-5
      mL per acquisition) were varied. Digital image subtraction was used to enhance
      image quality. Images were qualitatively analyzed and rated good, fair, or poor
      for temporal resolution, spatial resolution, fallopian tube conspicuity, and free
      spill conspicuity. Once the technique was refine, the phantom was reconfigured to
      simulate unilateral and bilateral hydrosalpinx. RESULTS: The RARE sequence with
      an 8-second interacquisition interval and a 5-mL interacquisition of sterile
      water produced good images of the simulated fallopian tubes and free spill.
      Depiction of unilateral and bilateral hydrosalpinx was also reliably
      demonstrated. CONCLUSION: This study with a phantom model demonstrates the
      feasibility of MR hysterosalpingography to depict normal and diseased fallopian
      tubes.

PMID- 10644109
TI  - Embolization with radiopaque microbeads of polyacrylonitrile hydrogel: evaluation
      in swine.
AB  - PURPOSE: To perform in vitro and in vivo studies of radiopaque microbeads of
      polyacrylonitrile (PAN) hydrogel to evaluate their characteristics as embolic
      material. MATERIALS AND METHODS: PAN microbeads were analyzed in vitro for
      swelling in different concentrations of contrast material and saline solution and
      injected through various microcatheters. In three nonsurvival swine, various
      organs were embolized with PAN microbeads. In eight survival swine, the rete
      mirabile was embolized with PAN microbeads or polyvinyl alcohol particles. Follow
      up angiograms were obtained regularly, and histopathologic analysis was performed
      at 1 and 6 months. RESULTS: The microbeads were black with a regular shape and
      smooth surface. They were easily visible in the syringe and easy to inject
      through the microcatheters. When wet, their diameters increased by 40%. The
      microbeads were sufficiently radiopaque to be visible in all vascular
      territories. Vascular occlusion was not permanent, and even when embolization was
      adequate, some revascularization was detected at 3 months. The microbeads were
      intact and still radiopaque at 6 months. Histopathologic examination demonstrated
      variable inflammatory reactions and foreign-body giant cell reaction and no
      angionecrosis or hemorrhage. CONCLUSION: Because PAN microbeads are
      biocompatible, radiopaque, and easy to handle during embolization procedures,
      they have potential as a therapeutic embolic agent.

PMID- 10644110
TI  - Patient radiation dose associated with uterine artery embolization.
AB  - PURPOSE: To evaluate the estimated absorbed radiation doses to the ovaries and
      skin entrance during uterine artery embolization (UAE) for leiomyomas. MATERIALS
      AND METHODS: Radiation dose was measured in 20 patients who underwent UAE for
      leiomyomas. Measurements were obtained by placing lithium fluoride dosimeters
      both into the posterior fornix of the vagina and on the skin at the beam entrance
      site. Patient doses were obtained with thermoluminescent dosimeters. RESULTS: The
      mean fluoroscopic time was 21.89 minutes, and the mean number of angiographic
      exposures was 44. The mean estimated absorbed ovarian dose was 22.34 cGy, and the
      mean absorbed skin dose was 162.32 cGy. These values compare to published values
      for the assessed absorbed ovarian dose during hysterosalpingography (0.04-0.55
      cGy), fallopian tube recanalization (0.2-2.75 cGy), computed tomography of the
      trunk (0.1-1.9 cGy), and pelvic irradiation for Hodgkin disease (263-3,500 cGy).
      CONCLUSION: The estimated absorbed ovarian dose during UAE is greater than that
      during common fluoroscopic procedures. On the basis of the known risks of pelvic
      irradiation for Hodgkin disease, the dose associated with UAE is unlikely to
      result in acute or long-term radiation injury to the patient or to a measurable
      increase in the genetic risk to the patient's future children.

PMID- 10644111
TI  - Postcatheterization pseudoaneurysms and arteriovenous fistulas: repair with
      percutaneous implantation of endovascular covered stents.
AB  - PURPOSE: To assess the effectiveness and safety of endovascular covered stents in
      the management of pseudoaneurysms and arteriovenous fistulas after cardiac and
      vascular catheterization. MATERIALS AND METHODS: Twenty-six endovascular covered
      stents were used to repair 16 pseudoaneurysms, nine arteriovenous fistulas, and
      one combined lesion after femoral arterial puncture for diagnostic coronary
      angiography and/or angioplasty. Fistulas and aneurysms were in the superficial
      femoral artery in 16 cases, in the deep femoral artery in six cases, and in the
      common femoral artery in four cases. Implantation was performed from the opposite
      femoral artery in most cases. It was not possible to treat three additional cases
      transcutaneously for technical reasons (three of 29 cases). RESULTS: Percutaneous
      closure of the lesions with an endovascular covered stent was successful in 26 of
      29 cases. Initial follow-up showed good stent patency. Two major complications
      were observed after stent implantation. During follow-up (about 1 year in 23 of
      26 patients [88%]), stent thromboses were detected in four of 23 patients (17%)
      with follow-up color duplex flow imaging. CONCLUSION: Implantation of
      endovascular covered stents is an effective and safe method for the percutaneous
      closure of pseudoaneurysms and arteriovenous fistulas. Thus, endoluminal vascular
      repair with covered stents offers an alternative therapeutic approach to vascular
      surgery in selected patients.

PMID- 10644112
TI  - Chronically occluded inferior venae cavae: endovascular treatment.
AB  - PURPOSE: To report the results of endoluminal recanalization and stent placement
      in patients with chronic occlusions of the inferior vena cava (IVC). MATERIALS
      AND METHODS: Seventeen consecutive patients (12 male, five female patients; mean
      age, 40.6 years; age range, 15-77 years) with chronic IVC occlusions were treated
      during a 6-year period. The mean duration of symptoms was 32 months. Underlying
      active malignancy was the cause of occlusion in four patients. Five patients with
      superimposed acute thrombus underwent catheter-directed thrombolysis prior to IVC
      recanalization. Clinical patency was defined as absence or improvement of
      symptoms. Clinical follow-up was supplemented with ultrasonography, vena
      cavography, or both in 10 patients. RESULTS: Technical success was achieved in 15
      (88%) patients. Additional thrombolytic therapy and stent placement was needed in
      two patients to maintain patency at 4 and 6 months after the procedure. Twelve
      patients had IVCs that remained patent after a mean follow-up of 19 months for a
      primary patency rate of 80%. The primary assisted patency rate was 87% (13 of
      15). There were four deaths owing to underlying disease 6-21 months after the
      procedures. There were no procedure-related complications. CONCLUSION:
      Endoluminal recanalization and stent placement in chronically occluded IVCs has a
      good intermediate-term outcome and should be considered in patients who have
      symptoms and who often do not have adequate alternative therapy.

PMID- 10644113
TI  - Interventional radiology in the removal of salivary calculi.
AB  - PURPOSE: To prospectively investigate the efficacy of a wire basket extractor in
      the retrieval of salivary calculi and establish selection criteria for suitable
      cases. MATERIALS AND METHODS: Twenty-five consecutive patients (14 male, 11
      female; age range, 13-69 years) with salivary calculi (20 submandibular, five
      parotid) were treated by using a commercially available wire basket extractor
      with intermittent fluoroscopic guidance. RESULTS: Elimination of calculi was
      accomplished in 10 (40%) cases. In an additional seven (28%) cases, either part
      of the calculus was removed or whole calculi were removed with others remaining.
      Failure to retrieve any stone occurred in eight (32%) cases. The most common
      cause of failure was attachment of the calculus to the duct wall. CONCLUSION:
      Interventional radiology provides a useful adjuvant method of calculus removal
      and complements extracorporeal lithotripsy. Basket retrieval of calculi has low
      morbidity and is rapid and less invasive than traditional surgery. It is most
      effective in retrieving mobile stones in the extraglandular parotid and
      submandibular ducts.

PMID- 10644114
TI  - Percutaneous ethanol injection of large autonomous hyperfunctioning thyroid
      nodules.
AB  - PURPOSE: To verify the effectiveness of percutaneous ethanol injection (PEI) in
      the treatment of large (>30-mL) hyperfunctioning thyroid nodules. MATERIALS AND
      METHODS: Twelve patients (eight women, four men; age range, 26-76 years) with a
      large hyperfunctioning thyroid nodule (volume range, 33-90 mL; mean, 46.08 mL)
      underwent PEI treatment under ultrasonographic (US) guidance. US was used to
      calculate the volume of the nodules and to assess the diffusion of the ethanol in
      the lesions during the procedure. When incomplete necrosis of the nodule was
      depicted at scintigraphy performed 3 months after treatment, additional PEI
      sessions were performed. RESULTS: Four to 11 PEI sessions (mean, seven) were
      performed in each patient, with an injection of 3-14 mL of 99.8% ethanol per
      session (total amount of ethanol per patient, 30-108 mL; mean, 48.5 mL). At
      scintigraphy after treatment in all patients, recovery of extranodular uptake,
      absence of uptake in the nodule, and normalization of thyroid-stimulating hormone
      (thyrotropin) levels were observed. In all patients, US showed volume reductions
      of 30%-50% after 3 months and 40%-80% after 6-9 months. Side effects were self
      limiting in all patients. During the 6-48-month follow-up, no recurrence was
      observed. CONCLUSION: PEI is an effective and safe technique for the treatment of
      large hyperfunctioning thyroid nodules.

PMID- 10644115
TI  - Breath-hold contrast-enhanced three-dimensional MR angiography of the abdomen:
      time-resolved imaging versus single-phase imaging.
AB  - PURPOSE: To evaluate a technique for time-resolved breath-hold contrast material
      enhanced three-dimensional magnetic resonance (MR) angiography of the abdomen.
      MATERIALS AND METHODS: In a prospective study, 43 patients underwent time
      resolved MR angiography (acquisition time per data set, 7 seconds). The patients
      also underwent single-phase high-spatial-resolution MR angiography (acquisition
      time, 27 seconds) (n = 6), conventional angiography (n = 7), or both (n = 30). No
      bolus timing study was performed for time-resolved MR angiography. Image quality
      (presence of artifacts, ability to prevent venous overlap on arterial phase
      images, contrast enhancement) and demonstration of anatomic variants (renal
      arterial and venous variants, vena caval anomaly, visceral arterial variants) and
      vascular diseases were assessed. RESULTS: Time-resolved MR angiographic images
      were characterized by fewer and less severe artifacts, less overlap of enhancing
      veins, and better contrast enhancement than were single-phase MR angiographic
      images (P < .05). The mean sensitivity and specificity were 90% (nine of 10) and
      100% (1 73 of 1 73), respectively, for detection of arterial anatomic variants
      and 93% (28 of 30) and 100% (324 of 325), respectively, for detection of disease.
      The technique also proved to be reliable for demonstration of venous disease.
      CONCLUSION: In comparison with current non-time-resolved MR angiographic
      techniques, time-resolved MR angiography is more robust and easier to perform and
      allows simultaneous evaluation of arterial and venous disease.

PMID- 10644116
TI  - The string of pearls sign.

PMID- 10644117
TI  - Hepatic lesion detection after superparamagnetic iron oxide enhancement:
      comparison of five T2-weighted sequences at 1.0 T by using alternative-free
      response receiver operating characteristic analysis.
AB  - PURPOSE: To compare the accuracy of five T2-weighted sequences in the detection
      of liver lesion at magnetic resonance (MR) imaging after superparamagnetic iron
      oxide (SPIO) enhancement. MATERIALS AND METHODS: Forty-nine candidates for
      hepatic resection with known coloretal metastases were examined. Before SPIO
      enhancement, fast spin-echo (SE) images were obtained. After enhancement, the
      same fast SE sequence and long; TR/short TE, short TE, long TR/TE, and T2
      weighted fast low-angle shot (FLASH) sequences were used. All images were viewed
      independently by four observers who were blinded to the results of the other
      imaging sequences, the results of the other observers, and the findings at
      surgery and histopathologic examination. Four weeks after the initial reading,
      the combined long TR/short TE and long TR/TE dual-echo images were also viewed as
      an additional set. The alternative free response receiver operating
      characteristic (ROC) method was used to analyze the results, which were
      correlated with findings at surgery, intraoperative ultrasonography, and
      histopathologic examination. RESULTS: Irrespective of lesion size, the accuracy
      of all sequences after enhancement was significantly greater than that of the
      nonenhanced fast SE sequence (P < .01). Dual-echo and FLASH sequences were
      significantly more accurate than the enhanced fast SE sequence (P < .03 or P <
      .02, respectively). For all lesions, lesions smaller than 1 cm, and lesions 1 cm
      or larger, mean accuracies were as follows: dual-echo, 0.75, 0.54, and 0.93;
      FLASH, 0.75, 0.54, and 0.95; and enhanced fast SE, 0.72, 0.49, and 0.92.
      CONCLUSION: At 1.0 T, dual-echo and FLASH sequences are the most accurate pulse
      sequences after SPIO enhancement.

PMID- 10644118
TI  - Follow-up of patients at low risk for hepatic malignancy with a characteristic
      hemangioma at US.
AB  - PURPOSE: To determine the need for follow-up imaging in patients with a low risk
      of malignancy and with ultrasonographic (US) findings typical of hepatic
      hemangioma. MATERIALS AND METHODS: A computer search of US reports completed
      between 1991 and 1994 helped identify 383 patients whose reports contained the
      word "hemangioma." One hundred eleven patients were excluded because the lesion's
      appearance was atypical (n = 16) or because the patients had a high risk of
      malignancy (prior history or current evidence of extrahepatic malignancy or
      chronic hepatic disease [n = 95]). Fifty-nine patients were excluded because they
      were lost to follow-up (n = 41) or had clinical follow-up of less than 2 years (n
      = 18). The conditions of the remaining 213 patients with typical-appearing
      hemangiomas and a low risk of malignancy were analyzed. One hundred twenty-one
      patients underwent imaging follow-up or histopathologic confirmation. Ninety-two
      had clinical follow-up of more than 2 years (mean, 46 months). RESULTS: Of the
      213 patients, four had benign lesions other than hemangiomas. One patient who
      subsequently developed a malignancy (neuroendocrine metastases from primary
      colonic carcinoma diagnosed 22 months after initial US) potentially had an early
      metastasis that was misdiagnosed as a hemangioma. CONCLUSION: On the basis of
      these results, the authors no longer recommend follow-up studies in their
      patients with a low risk of malignancy and a typical-appearing hemangioma at US.

PMID- 10644119
TI  - Biliary dilatation: differentiation of benign from malignant causes--value of
      adding conventional MR imaging to MR cholangiopancreatography.
AB  - PURPOSE: To determine the value of conventional T1 - and T2-weighted images and
      gadolinium-enhanced dynamic magnetic resonance (MR) images as a supplement to MR
      cholangiopancreatographic (MRCP) images in differentiation of benign from
      malignant causes of biliary dilatation. MATERIALS AND METHODS: MR studies in 62
      patients with biliary dilatation with proved causes included conventional T1- and
      less heavily T2-weighted images, as well as gadolinium-enhanced dynamic images
      and heavily T2-weighted MRCP images. Two radiologists reviewed MRCP images alone,
      MRCP images with nonenhanced T1 - and T2-weighted MR images, and MRCP images with
      nonenhanced and gadolinium-enhanced dynamic images. RESULTS: For differentiation
      of benign from malignant causes of biliary dilatation, the area under the
      receiver operating characteristic curve (A(z)) was significantly (P < .05) larger
      for MRCP images interpreted with T1 - and T2-weighted images (0.9547 for reader
      1, 0.8404 for reader 2) than for MRCP images alone (0.8144 for reader 1, 0.8122
      for reader 2). The addition of gadolinium-enhanced dynamic MR images to MRCP
      images with nonenhanced T1- and T2-weighted images did not significantly increase
      accuracy (A(z) = 0.9554 for reader 1 and 0.8650 for reader 2), but the level of
      confidence was increased in 17%-24% of cases. CONCLUSION: Use of nonenhanced T1-
      and less heavily T2-weighted images with MRCP images significantly improved the
      diagnostic accuracy of MR examinations of pancreaticobiliary disease.

PMID- 10644120
TI  - Presence or absence of gas in the appendix: additional criteria to rule out or
      confirm acute appendicitis--evaluation with US.
AB  - PURPOSE: To investigate whether the presence or absence of gas in the appendix
      may be considered as additional ultrasonographic (US) criteria to rule out or
      confirm acute appendicitis. MATERIALS AND METHODS: The appendices in 239 control
      subjects, 138 patients with lower right quadrant pain without acute appendicitis,
      and 80 patients with acute appendicitis were prospectively evaluated for
      intraluminal gas with US. RESULTS: The appendices in 206 (86%) control subjects
      showed gas at US, and those in 33 (14%) did not. The appendices in 109 (79%)
      symptomatic patients without acute appendicitis showed gas, and those in 29 (21%)
      did not. The appendices in 12 (15%) patients with acutely inflamed appendices
      showed gas, and those in 68 (85%) did not. The absence of gas as a criterion for
      acute appendicitis had a sensitivity of 85%; specificity, 79%; positive and
      negative predictive values, 57% and 94%, respectively; and accuracy, 81%. Gas was
      useful to exclude acute appendicitis in 64 (46%) symptomatic patients because the
      established criteria were misleading. In 19 (24%) patients, the absence of gas
      was useful for diagnosis of acute appendicitis because the other criteria were
      not convincing. CONCLUSION: US-based detection of gas in the appendiceal lumen
      helps to rule out acute appendicitis, whereas the absence of gas further confirms
      its presence, especially in cases where established US criteria are either
      insufficiently present or misleading.

PMID- 10644122
TI  - Case 22. A 9-day-old term female neonate presented with bilious vomiting

PMID- 10644121
TI  - Phlebosclerotic colitis: value of radiography in diagnosis--report of three
      cases.
AB  - Three cases sharing the following radiologic features are reported: (a) abdominal
      conventional radiography-vascular calcifications at the right hemicolon, (b)
      abdominal computed tomography-colonic wall thickening and venous calcifications,
      and (c) barium enema examination-luminal narrowing of the right hemicolon and
      thumbprinting. There were no clinical or laboratory findings suggestive of portal
      hypertension. The disease entity, "phlebosclerotic colitis," should be
      differentiated from ordinary ischemic colitis.

PMID- 10644123
TI  - Case 18: adrenocorticotropic hormone-dependent Cushing syndrome.

PMID- 10644124
TI  - Periventricular leukomalacia: relationship between lateral ventricular volume on
      brain MR images and severity of cognitive and motor impairment.
AB  - PURPOSE: To evaluate the utility of lateral ventricular volume measurements in
      predicting motor and cognitive impairment severity in children with
      periventricular leukomalacia (PVL), with or without seizures. MATERIALS AND
      METHODS: The charts of children with spastic cerebral palsy and PVL documented on
      brain magnetic resonance (MR) images were reviewed. Affected children were
      grouped by motor and cognitive impairment severity and seizure disorder. An age
      matched control group was established. Lateral ventricular volumes were measured
      on two-dimensional T2-weighted spin-echo MR images. Analysis of variance was used
      to identify significant differences in mean lateral ventricular volume between
      groups. Paired analyses of differences were performed with the Bonferroni t
      method. RESULTS: Thirty-six children (24 boys, 12 girls) with spastic cerebral
      palsy and PVL and 21 age-matched control subjects (14 boys, seven girls) were
      identified. Mean lateral ventricular volumes of the moderate and marked motor
      deficit groups were significantly larger than those of the control and mild motor
      deficit groups (F = 29.24; alpha = .01). Mean lateral ventricular volumes of all
      cognitive impairment groups were significantly larger than those of the control
      and no-cognitive-impairment groups (F = 21.101 alpha = .01). There was no
      difference in mean lateral ventricular volume between children with PVL with or
      without seizures. CONCLUSION: Lateral ventricular volume measurements can be used
      as quantitative markers of clinical impairment severity and as clinical outcome
      predictors before formal testing is possible.

PMID- 10644125
TI  - Pelvic CT morphometry in Down syndrome: implications for prenatal US evaluation-
      preliminary results.
AB  - PURPOSE: To characterize pelvic morphometric differences in patients with and
      those without Down syndrome by using computed tomography (CT) and to determine
      useful indexes for ultrasonographic (US) evaluation. MATERIALS AND METHODS:
      Pelvic CT scans in seven patients with Down syndrome and in 27 patients without
      Down syndrome were reviewed. Iliac angle, iliac length, sacroiliac joint angle,
      and anterior iliac wing separation were measured at superior, middle, and
      inferior transverse sacral levels. The effects of chromosomal status and
      transverse level were evaluated statistically. RESULTS: Significant differences
      were found for mean iliac angle (P < .007) and length (P < .005) between patients
      without Down syndrome (angle, 75 degrees; length, 8.4 cm) and those with Down
      syndrome (angle, 82 degrees; length, 7.5 cm). Depending on the level of
      measurement, variations in iliac angle between patients without and those with
      Down syndrome were as much as 13 degrees and 15 degrees, respectively, and
      variations in length were as much as 1.6 cm and 0.9 cm, respectively. The
      greatest differences were at the middle sacral level. Sacroiliac joint angle and
      the anterior iliac wing separation were not different between groups. CONCLUSION:
      Patients with Down syndrome had a larger mean iliac angle and a shorter mean
      iliac length. The most pronounced differences were at the middle sacral level,
      which suggests that this may be the optimal level for measuring these parameters
      at prenatal US.

PMID- 10644126
TI  - Familial form of intracranial cavernous angioma: MR imaging findings in 51
      families. French Society of Neurosurgery.
AB  - PURPOSE: To analyze the magnetic resonance (MR) imaging features of familial
      cerebral cavernous angioma in non-Hispanic families. MATERIALS AND METHODS:
      Between November 1996 and June 1997, 51 non-Hispanic families with familial
      cavernous angioma were identified. Cerebral MR images in 83 symptomatic subjects
      and 73 asymptomatic subjects were reviewed. Spin-echo (SE) and gradient-echo
      (GRE) MR imaging features of cavernous angioma were recorded and, in 91 subjects
      with both SE and GRE images, lesions were graded as type 1, 2, 3, or 4, according
      to a published classification scheme. MR imaging features were compared between
      symptomatic and asymptomatic subjects, and sensitivities of SE and GRE images
      were determined. RESULTS: Multiple lesions were more common than single lesions
      in both symptomatic and asymptomatic subjects, with no difference in mean number
      of lesions between groups. More lesions were detected on GRE images than on SE
      images. Type 1 and type 2 lesions were more numerous in symptomatic than in
      asymptomatic subjects. The numbers of types 2, 3, and 4 lesions increased with
      age in both groups. CONCLUSION: The familial form of cavernous angioma is
      characterized by multiple lesions and by a correlation between lesion number and
      subject age. The clinical manifestation may be more closely related to the type
      of lesion than to the number of lesions. GRE MR images are more sensitive than SE
      images for demonstration of cavernous angioma.

PMID- 10644127
TI  - Heschl and superior temporal gyri: low signal intensity of the cortex on T2
      weighted MR images of the normal brain.
AB  - PURPOSE: To study the normal signal intensity pattern in the primary auditory
      cortex (first Heschl gyrus [HG]) and the surrounding cortices in the superior
      temporal gyrus (STG) and middle temporal gyrus (MTG) on T2-weighted magnetic
      resonance (MR) images. MATERIALS AND METHODS: Coronal T2-weighted fast spin-echo
      MR images in 30 neurologically normal patients (60 hemispheres) were
      retrospectively analyzed. Two raters evaluated the cortical signal intensity of
      the first HG and the neighboring STG and compared them with those of the MTG and
      the subcortical white matter. The cortical signal intensities between the first
      HG and the STG were also directly compared. Coronal MR images, which included
      images of the anterior and posterior halves of the first HG, were evaluated
      separately. RESULTS: All first HGs were hypointense to the MTG and were either
      iso- or hypointense to the STG. Cortical hypointensity was especially prominent
      in the posterior half; the first HG was isointense to the white matter in 33
      (55%) hemispheres. The STG was hypointense to the MTG in 54 (90%) hemispheres and
      in the anterior halves of 36 (60%) hemispheres. CONCLUSION: These findings
      demonstrate lower signal intensity of the cortex on T2-weighted images in the
      first HG and surrounding STG compared with that of the MTG.

PMID- 10644128
TI  - Spontaneous involution of pilocytic astrocytoma in a patient without
      neurofibromatosis type 1: case report.
AB  - Serial magnetic resonance imaging findings are described in a patient with a
      sporadically occurring pilocytic astrocytoma that underwent spontaneous
      regression over 6 years. To the authors' knowledge, this is the first report in
      which spontaneous involution of a pilocytic astrocytoma not associated with
      neurofibromatosis type 1 has been described. A literature review regarding
      sporadic and syndrome-associated pilocytic astrocytoma was undertaken, with
      particular reference to treatment and natural history.

PMID- 10644129
TI  - Functional neuroanatomy of the frontal lobe circuits.
AB  - This article summarizes the current theories regarding the locations and
      functions of the three primary frontal lobe circuits. It forms the framework for
      structuring functional magnetic resonance imaging investigations. It can be used
      to assist in (a) detecting subtle lesions of the frontal circuits and (b)
      applying the current theories of neuropsychiatry to assess prognosis and to plan
      rehabilitation.

PMID- 10644130
TI  - Salivary gland tumors: evaluation with two-phase helical CT.
AB  - PURPOSE: To evaluate two-phase helical computed tomography (CT) in the
      characterization of salivary gland tumors. MATERIALS AND METHODS: Sixty-four
      patients with major salivary gland tumors underwent two-phase helical CT. The
      histopathologic diagnosis was obtained by means of surgical resection or biopsy
      in all patients. After the injection of 90 mL of contrast material at a rate of 3
      mL/sec, helical CT scans were obtained at early and delayed phases with scanning
      delays of 30 and 120 seconds, respectively. The attenuation change and
      enhancement patterns in the tumors were assessed. The attenuation change in the
      tumor also was assessed quantitatively as the ratio of the CT number (in
      Hounsfield units) at delayed phase scanning to that at early phase scanning.
      RESULTS: There were 35 pleomorphic adenomas, nine Warthin tumors, and 20
      malignant tumors. Two-phase helical CT showed increase in attenuation in 30 (86%)
      pleomorphic adenomas, decrease in eight (89%) Warthin tumors, and increase in 11
      (55%) and no change in eight (40%) malignant tumors at delayed phase scanning. A
      multinodular enhancement pattern was found in only 12 (34%) pleomorphic adenomas.
      The ratio of CT numbers was significantly different between Warthin tumors and
      pleomorphic adenomas and between Warthin tumors and malignant tumors. CONCLUSION:
      The analysis of enhancement patterns by using two-phase helical CT will be
      helpful in the differential diagnosis of salivary gland tumors.

PMID- 10644131
TI  - Postcricoid region and cervical esophagus: normal appearance at CT and MR
      imaging.
AB  - PURPOSE: To establish the normal variations of the postcricoid portion of the
      hypopharynx, esophageal verge, and cervical esophagus, as seen on computed
      tomographic (CT) and magnetic resonance (MR) images. MATERIALS AND METHODS: One
      hundred twenty-one CT and 92 MR images were reviewed. Diameter and wall thickness
      were measured at multiple levels. Depiction of the layers of the musculature and
      adjacent fat planes was evaluated. The frequency and size of the
      tracheoesophageal lymph nodes were noted. RESULTS: An esophageal anteroposterior
      diameter greater than 16 mm and lateral diameter greater than 24 mm were
      considered abnormal. The average wall thickness was 4.8 mm laterally and 3.8 mm
      posteriorly. Demonstration of the intramural fat planes of the postcricoid region
      decreased from the upper to the lower region of the cricoid cartilage. The
      ability to separate the esophageal wall from the trachea was highest at the
      esophageal verge and declined markedly more distally. The tracheo-esophageal
      groove nodes were seen more often on the right (mean size [+/- SD], 4.5 mm +/-
      2.2). CONCLUSION: Knowledge of the normal appearance and variations of the post
      cricoid region and cervical esophagus is essential in detecting abnormalities in
      these areas.

PMID- 10644132
TI  - Ability to use duplex US to quantify internal carotid arterial stenoses: fact or
      fiction?
AB  - PURPOSE: To determine if duplex ultrasonography (US) can help predict the degree
      of internal carotid arterial (ICA) stenosis. MATERIALS AND METHODS: ICA peak
      systolic velocity (PSV) and the ratio of the PSV in the ICA to that in the
      ipsilateral common carotid artery (VICA/VCCA) were compared with the degree of
      arteriographically measured stenosis. ICAs were arteriographically subgrouped at
      10% incremental levels of stenosis and broader ranges. Mean PSV, VICA/VCCA, and
      SDs were calculated for each category. Histograms showing the numbers of stenotic
      ICAs in subgroups and for vessels with stenoses of greater than or equal to or
      less than 70% narrowing were constructed. The number of vessels correctly
      subgrouped with typical Doppler US thresholds was calculated. RESULTS: Mean PSV
      and VICA/VCCA increased with stenosis level (P < .01); SDs were wide. Histograms
      showed Doppler US values in the central groups across all disease levels.
      Histograms differentiating at least or less than 70% stenosis showed minimal
      overlap. PSV and VICA/VCCA helped classify, respectively, 185 and 181 of 204
      vessels with stenoses of less than 50%, 15 and 21 of 46 vessels with stenoses of
      50%-69%, and 73 and 67 of 84 vessels with stenoses of 70% or greater. When
      classifying stenoses as 69% or less or 70% or more, PSV and VICA/VCCA were
      correct in 90.6% and 90.3% of vessels. CONCLUSION: Doppler US is excellent for
      classifying stenoses as above or below a single degree of severity but does not
      function well in stenosis subclassification.

PMID- 10644133
TI  - Aggressive non-Hodgkin lymphoma: early prediction of outcome with 67Ga
      scintigraphy.
AB  - PURPOSE: To evaluate use of gallium 67 scintigraphy early during chemotherapy to
      predict the outcome in patients with aggressive non-Hodgkin lymphoma. MATERIALS
      AND METHODS: Among 118 patients, 67Ga scintigraphy was performed after one cycle
      of chemotherapy in 51 patients, after a median of 3.5 cycles in 97 patients, and
      both in 30 patients. Computed tomography (CT) was performed after a median of 3.5
      cycles of treatment in 87 patients. The failure-free survival was compared
      between patients with positive or negative 67Ga or CT scans by using the log-rank
      test. Multivariate analysis helped determine the relation between 67Ga
      scintigraphic and CT findings and the outcome. RESULTS: The differences in
      failure-free survival between patients with positive versus negative 67Ga scans
      after one cycle of treatment (P < .001) and at midtreatment (P < .001) were
      significant. There was no statistically significant difference in failure-free
      survival between patients with positive versus negative CT findings during
      treatment. In multivariate analysis, 67Ga scintigraphy after one cycle (P < .045)
      and at midtreatment (P < .006) was an independent factor associated with outcome.
      CONCLUSION: Gallium 67 scintigraphic findings after one cycle of chemotherapy and
      at midtreatment are predictive of outcome in patients with aggressive non-Hodgkin
      lymphoma. CT findings are not predictive. Early 67Ga scintigraphy during
      chemotherapy is a good indicator of patients who may benefit from a change to a
      more aggressive treatment. A future study is necessary to investigate the
      potential effect of early change of treatment.

PMID- 10644134
TI  - Human articular cartilage: influence of aging and early symptomatic degeneration
      on the spatial variation of T2--preliminary findings at 3 T.
AB  - PURPOSE: To determine if age and early symptomatic degeneration alter the spatial
      dependency of cartilage T2. MATERIALS AND METHODS: In 25 asymptomatic volunteers
      and six volunteers with symptoms of patellar chondromalacia, quantitative T2 maps
      of patellar cartilage were obtained with a multiecho, spin-echo magnetic
      resonance imaging sequence at 3.0 T. Spatial variation in T2 was evaluated as a
      function of participant age and symptoms. RESULTS: All asymptomatic volunteers
      demonstrated a continuous increase in T2 from the radial zone to the articular
      surface. In the population aged 46-60 years compared with younger volunteers,
      there was a statistically significant (P < .05) increase in T2 of the
      transitional zone. In symptomatic volunteers, the increase in T2 was larger in
      magnitude and focal in distribution. In five of the six symptomatic volunteers,
      the increase in T2 was greater than the 95% prediction interval determined from
      data in the corresponding age-matched asymptomatic population. CONCLUSION: Aging
      is associated with an asymptomatic increase in T2 of the transitional zone of
      articular cartilage. Preliminary results indicate this diffuse increase in T2 in
      senescent cartilage is different in appearance than the focally increased T2
      observed in damaged articular cartilage.

PMID- 10644135
TI  - Superior labrum anterior-posterior lesions: diagnosis with MR arthrography of the
      shoulder.
AB  - PURPOSE: To determine the accuracy of magnetic resonance (MR) arthrography in the
      diagnosis of superior labrum anterior-posterior (SLAP) lesions of the shoulder.
      MATERIALS AND METHODS: From January 1995 to June 1998, MR arthrography of the
      shoulder was performed in 159 patients with a history of chronic shoulder pain or
      instability. Fifty-two patients underwent arthroscopy or open surgery 12 days to
      5 months after MR arthrography. Diagnostic criteria for SLAP lesion included
      marked fraying of the articular aspect of the labrum, biceps anchor avulsion,
      inferiorly displaced bucket handle fragment, and extension of the tear into the
      biceps tendon fibers. Surgical findings were correlated with those from MR
      arthrography. RESULTS: SLAP injuries were diagnosed at surgery in 19 of the 52
      patients (37%). Six of the 19 lesions (32%) were classified as type I, nine (47%)
      as type II, one (5%) as type III, and three (16%) as type IV. MR arthrography had
      a sensitivity of 89% (17 of 19 patients), a specificity of 91% (30 of 33
      patients), and an accuracy of 90% (47 of 52 patients). The MR arthrographic
      classification showed correlation with the arthroscopic or surgical
      classification in 13 of 17 patients (76%) in whom SLAP lesions were diagnosed at
      MR arthrography. CONCLUSION: MR arthrography is a useful and accurate technique
      in the diagnosis of SLAP lesions of the shoulder. MR arthrography provides
      pertinent preoperative information with regard to the exact location of tears and
      grade of involvement of the biceps tendon.

PMID- 10644136
TI  - Fluoroscopy-guided sacroiliac joint injections.
AB  - The authors performed fluoroscopy-guided sacroiliac (SI) joint injections. With
      the patient prone and the x-ray tube perpendicular to the fluoroscopic table, the
      skin was marked over the distal 1 cm of the SI joint. With the tube angled 20
      degrees - 25 degrees cephalad, a 22-gauge needle was inserted at the skin mark
      and advanced perpendicular to the fluoroscopic table toward the posterior joint.
      Nonionic contrast material was injected to confirm the intraarticular position of
      the needle. Of 31 SI joint injections, 30 (97%) were intraarticular. Mean
      procedure time was 108 seconds. This technique is safe, rapid, and reproducible.

PMID- 10644137
TI  - Iatrogenic femoral pseudoaneurysms: thrombin injection after failed US-guided
      compression.
AB  - Fifteen iatrogenic femoral pseudoaneurysms failed ultrasonography (US)-guided
      compression treatments. Despite concomitant antiplatelet or anticoagulation
      treatment, the 15 pseudoaneurysms were successfully and definitively treated
      without complication with US-guided thrombin injection. Results in this
      preliminary study suggest US-guided thrombin injection is a safe, expeditious,
      low-cost, and comfortable definitive treatment for femoral pseudoaneurysms that
      has advantages over both US-guided compression and open surgical repair.

PMID- 10644138
TI  - Vessel tracking: prospective adjustment of section-selective MR angiographic
      locations for improved coronary artery visualization over the cardiac cycle.
AB  - To follow the motion of the coronary artery in magnetic resonance angiography,
      the authors evaluated vessel tracking, a method for prospective adjustment of the
      section location as a function of the delay from the cardiac trigger. In 10
      volunteers and four patients, this method allowed the vessel to be maintained in
      the plane of acquisition throughout the cardiac cycle. With a single-phase
      multisection sequence, vessel-tracking acquisitions had an efficiency of 0.68 +/-
      0.04 for both the right and left coronary arteries compared with 0.19 +/- 0.03
      for a non-vessel-tracking acquisition (P < .001).

PMID- 10644139
TI  - Prostate cancer: MR imaging and thermometry during microwave thermal ablation
      initial experience.
AB  - Percutaneous interstitial microwave thermoablation of locally recurrent prostate
      carcinoma was continually guided with magnetic resonance (MR) imaging. Phase
      images and data were obtained with a rapid gradient-echo technique and were used
      to derive tissue temperature change on the basis of proton-resonance shift.
      Thermally devitalized regions correlated well with the phase image findings. MR
      imaging-derived temperatures were linearly related to the fluoroptic tissue
      temperatures. MR imaging can be used to guide thermoablation.

PMID- 10644140
TI  - Human carcinoma: early experience with phase-contrast X-ray CT with synchrotron
      radiation--comparative specimen study with optical microscopy.
AB  - Phase-contrast x-ray computed tomography (CT) indicates the distribution of the
      refractive index and has potential to reveal the structures inside soft tissues
      without a contrast agent. With a synchrotron x-ray source, phase-contrast x-ray
      CT with a triple Laue-case x-ray interferometer clearly differentiated various
      human pathologic tissues in the cases of hepatocellular carcinoma with cirrhosis
      and metastatic colon carcinoma to the liver, and the images closely corresponded
      to those obtained with low-magnification optical microscopy.

PMID- 10644141
TI  - Hemodialysis fistula: preoperative MR venography--a promising but partial view.

PMID- 10644142
TI  - Percutaneous gastrostomy: US guidance for gastric puncture.

PMID- 10644143
TI  - Copper and hepatocellular carcinoma.

PMID- 10644144
TI  - Large-format digital cine pulmonary angiography.

PMID- 10644145
TI  - Proceedings of the WHO/IABS/NIBSC International Meeting on the Control and
      Standardization of Acellular Pertussis Vaccines. 26-27 September 1996.

PMID- 10644146
TI  - Sakari Mustakallio Centennial Symposium. Helsinki, Finland, 8-9 January 1999.
      Proceedings.

PMID- 10644147
TI  - Commentary: cot death--the story so far.

PMID- 10644148
TI  - How does herd immunity work?

PMID- 10644149
TI  - Improving access to medical care. Telephone consultations are the answer.

PMID- 10644150
TI  - Managing drug misuse in general practice. Study is being done of Scottish GPs'
      involvement with users of illicit drugs.

PMID- 10644151
TI  - Stillbirth at risk factor for depression and anxiety in subsequent pregnancy.
      Depression after stillbirth may simply reflect normal process of grieving.

PMID- 10644152
TI  - Ethnic and sex differences in selection for admission to medical school.
      Discrimination is not always explicit.

PMID- 10644153
TI  - Ethnic and sex differences in selection for admission to medical school. Might
      selection criteria be surrogates for other determinants?

PMID- 10644154
TI  - Ethnic and sex differences in selection for admission to medical school.
      Reanalysis using appropriate denominators shows that results and conclusions are
      flawed.

PMID- 10644155
TI  - Infectious etiology in multiple sclerosis: the debate continues.

PMID- 10644156
TI  - Trial acronyms a trial.

PMID- 10644157
TI  - Recalling and foretelling.

PMID- 10644158
TI  - Occupational Asthma and Allergies. Symposium proceedings. Philadelphia,
      Pennsylvania, USA. November 5, 1998.

PMID- 10644159
TI  - Phospholipids and their fatty acids in mitochondria, synaptosomes and myelin from
      the liver and brain of trout and rat: a new view on the role of fatty acids in
      membranes.
AB  - The content of different phospholipids (PL) and their fatty acid (FA) composition
      in subcellular fractions from the liver and brain of rat (Rattus rattus) and
      trout (Salmo irideus) were estimated. It was shown that despite higher content of
      unsaturated fatty acids in myelin compared to synaptosomes, the unsaturation
      index of the latter is equal or higher than that of myelin. The total content of
      PL polyunsaturated fatty acids (PUFA) was shown to be higher in membrane
      structures with more active ion transport (mitochondria). This feature seemed to
      be characteristic of membranes from both representatives of homoiotherms and
      poikilotherms studied. A possible role for PUFA information within the lipid
      monolayer of areas with different capacity to accept electrons and transport them
      along a sort of intermolecular 'tunnel' is discussed. The double bonds of PUFA in
      this area seem to be able to produce bonds similar to conjugated bonds.

PMID- 10644160
TI  - Selective determination of fish aspartate aminotransferase isoenzymes by their
      differential sensitivity to proteases.
AB  - Various proteases (proteinase K, subtilisin, trypsin and chymotrypsin) were used
      to study the selective inactivation of the aspartate aminotransferase (EC
      2.6.1.1) isoenzymes of grey mullet (Mugil auratus Risso; Osteichthyes). The
      cytosolic isoenzyme was significantly inactivated by proteinase K, subtilisin and
      chymotrypsin, while the mitochondrial isoenzyme was sensitive only to proteinase
      K and to high doses of trypsin. Further identification of the aspartate
      aminotransferase isoenzymes was based on their discrete sensitivity toward
      chymotrypsin. Chymotrypsin (1 mg/ml) successfully inhibited purified cytosolic
      aspartate aminotransferase as well as cytosolic isoenzyme from plasma, whereas
      the mitochondrial form persisted unaffected. Similar results were obtained when
      examining liver and red muscle homogenates. This method revealed that the
      increased total activity of aspartate aminotransferase in fish plasma with
      induced acute liver injury, was partially a result of the mitochondrial isoenzyme
      leakage from damaged tissue.

PMID- 10644161
TI  - Sodium fusidate in steroid resistant relapses of multiple sclerosis.

PMID- 10644162
TI  - Chromosome 19 locus apolipoprotein C-II association with multiple sclerosis.

PMID- 10644163
TI  - Conformation of epicinchonine and cinchonine in view of their antimalarial
      activity: x-ray and theoretical studies.
AB  - X-ray structure analysis was carried out for a single crystal of 9-epi-10,11
      dihydrocinchonine in the form of free base obtained by stereoselective
      interconversion of cinchonine via 9-O-tosylcinchonine. An intramolecular hydrogen
      bond was found between the carbinol hydroxyl group, -O12-H12, and the
      quinuclidine nitrogen atom, N1, with the parameters: O12...N1=2.688(3)A, O12
      H12=0.84(4)A, N1...H12=2.11(4)A and O12-H12...N1=126(3) degrees. Theoretical
      calculations for isolated molecules of epicinchonine and cinchonine with the use
      of AM1 semiempirical method and comparative studies of the crystal structures
      have shown that the conformation of the alkaloid molecules with respect to the C8
      C9 bond depends on the absolute configuration at C9. The conformation with
      respect to the C9-C16 bond depends on the protonation of N1 for threo but not for
      erythro alkaloids. It was established that the ability to form inter- or
      intramolecular hydrogen bonds is determined by the energetically preferred
      conformations of erythro and threo alkaloids, respectively. In most cases the
      conformations preferred for erythro alkaloids are energetically forbidden for
      their threo epimers and vice versa. The differences in conformation and
      capability to form intramolecular hydrogen bonds may explain why their
      antimalarial activities are incomparable.

PMID- 10644164
TI  - Re: Traveling with children--J Travel Med 1998: 5:142-146.

PMID- 10644165
TI  - Re: Letter on quinacrine for treatment of Giardiasis--J Travel Med 1998;5:228.

PMID- 10644166
TI  - Changing landscape of pediatrics.

PMID- 10644167
TI  - Pediatric autopsy in the forensic setting.

PMID- 10644168
TI  - Expression of Melan-A in Spitz, pigmented spindle cell nevi, and congenital nevi:
      comparative immunohistochemical study.
AB  - The expression of the antibody Melan-A in 27 benign melanocytic skin lesions (10
      congenital nevi, 10 Spitz nevi, and 7 pigmented spindle cell nevi) was compared
      to that of S100 protein and HMB-45. To evaluate the role of Melan-A in
      differentiating melanocytic and nonmelanocytic lesions we assessed a number of
      benign nonmelanocytic skin lesions including neurofibromas, granular cell tumors,
      and dermatofibromas. Melan-A had an identical staining pattern to S100 protein in
      the melanocyte population of all lesions, but had the advantage of only staining
      cells of melanocytic lineage and no other cell types. HMB-45, although staining
      the junctional components of all lesions with a junctional component, showed
      varied intensity and distribution in the dermal components. Melan-A is much
      cleaner than S100 protein, having no background staining, and in skin appears to
      be specific for melanocytes. The nonmelanocytic lesions did not express Melan-A.

PMID- 10644169
TI  - Clinical utility of ambulatory blood pressure monitoring. Overview.

PMID- 10644170
TI  - Growth and development. Web alert.

PMID- 10644171
TI  - Subspecialty certification examination in molecular genetic pathology.

PMID- 10644172
TI  - Food and Drug Administration approval for 2 new molecular infectious disease
      assays.

PMID- 10644173
TI  - GeneClinics Medical Genetics Knowledge Base.

PMID- 10644174
TI  - Novel TIGR sequence alteration Val53Ala.

PMID- 10644175
TI  - Diet and Physical Activity--Interactions for Health. Proceedings of the
      International Life Sciences Institute (ILSI) European workshop. Chamonix, France,
      22-24 March 1999.

PMID- 10644176
TI  - The Italian Tamoxifen Prevention Trial.

PMID- 10644177
TI  - Treatment of patients with dysphagia caused by benign disorders of the distal
      esophagus.

PMID- 10644178
TI  - The "natural" history of pain in chronic pancreatitis.

PMID- 10644179
TI  - Mesenteric venous thrombosis revealing both factor II G20212A mutation and
      hyperhomocysteinemia related to pernicious anemia.

PMID- 10644180
TI  - Omeprazole and accelerated onset of atrophic gastritis.

PMID- 10644181
TI  - Omeprazole and accelerated onset of atrophic gastritis.

PMID- 10644182
TI  - Omeprazole and accelerated onset of atrophic gastritis.

PMID- 10644183
TI  - Lack of effect of acid suppression therapy on gastric atrophy.

PMID- 10644184
TI  - Eradication of Barrett's mucosa with argon plasma coagulation and acid
      suppression: immediate and mid term results.

PMID- 10644185
TI  - Comparing the treatment outcomes of endoscopic papillary dilation and endoscopic
      sphincterotomy for removal of bile duct stones.

PMID- 10644186
TI  - ASGE Guidelines for clinical application. Methods of privileging for new
      technology in gastrointestinal endoscopy. American Society for Gastrointestinal
      Endoscopy.

PMID- 10644187
TI  - ASGE guidelines for clinical application. Proctoring for hospital endoscopy
      priveleges. American Society for Gastrointestinal Endoscopy.

PMID- 10644188
TI  - ASGE guidelines for clinical application. Position statement on laboratory
      testing before ambulatory elective endoscopic procedures. American Society for
      Gastrointestinal Endoscopy.

PMID- 10644189
TI  - ASGE guidelines for clinical application. Establishment of gastrointestinal
      endoscopy areas. American Society for Gastrointestinal Endoscopy.

PMID- 10644190
TI  - ASGE guidelines for clinical application. Statement on role of short courses in
      endoscopic training. American Society for Gastrointestinal Endoscopy.

PMID- 10644191
TI  - ASGE guidelines for clinical application. The role of ERCP in diseases of the
      biliary tract and pancreas. American Society for Gastrointestinal Endoscopy.

PMID- 10644192
TI  - ASGE guidelines for clinical application. The role of colonoscopy in the
      management of patients with colonic polyps neoplasia. American Society for
      Gastrointestinal Endoscopy.

PMID- 10644193
TI  - ASGE Technology status evaluation report. Automatic endoscope reprocessors.
      February 1999. American Society for Gastrointestinal Endoscopy.

PMID- 10644194
TI  - ASGE technology status evaluation report. Injection needles. February 1999.
      American Society for Gastrointestinal Endoscopy.

PMID- 10644195
TI  - ASGE technology status evaluation report. Endoscopic retrieval devices. February
      1999. American Society for Gastrointestinal Endoscopy.

PMID- 10644196
TI  - ASGE technology evaluation report. Endoscopy simulators. May 1999. American
      Society for Gastrointestinal Endoscopy.

PMID- 10644197
TI  - ASGE technology status evaluation report. Biliary stents. Update May 1999.
      American Society for Gastrointestinal Endoscopy.

PMID- 10644198
TI  - Speed of gastric emptying and metabolism of ethanol.

PMID- 10644199
TI  - Strong evidence that the N21I substitution in the cationic trypsinogen gene
      causes disease in hereditary pancreatitis.

PMID- 10644200
TI  - Papers presented at the Congress of the European Association for Research on
      Adolescence. Budapest, Hungary, 1998.

PMID- 10644201
TI  - Proceedings of the European Association for the Study of the Liver International
      Consensus Conference on Hepatitis C. Paris, France, 26-27 February 1999.

PMID- 10644202
TI  - A quantitative profile of the synapses on the stellate cell body and axon in the
      cochlear nucleus of the chinchilla.
AB  - One of the most numerous neurons in the cochlear nucleus is the type I stellate
      cell. Previous attempts to understand the structural basis for its signal coding
      assumed that integration of synaptic potentials arising from axodendritic
      synapses should account for the generation of its response properties. However,
      the present study documents the importance of excitatory and inhibitory types of
      synapses on the soma and axon. Retrograde transport of cholera toxin B subunit,
      injected in the inferior colliculus of chinchillas, was used to label exclusively
      type I stellate cells in the anteroventral cochlear nucleus. The relative
      distribution of terminal types by vesicle morphology was pleomorphic > large
      spherical > flattened > smaller spherical. The somatic perimeter covered by
      endings ranged from almost none to nearly half. More flattened-vesicle terminals
      contacted somata in the high-frequency than in the low-frequency region. Eight of
      twenty axons received endings that contained large spherical vesicles and made
      asymmetric junctions; half of these extensively apposed the initial segment,
      forming a collar of presumed excitatory input. Thus, type I stellate cells are a
      heterogeneous group. Inhibitory synapses probably compose the majority of
      terminals. Some cells receive mostly inhibitory synapses near the presumed site
      of the spike generator, but others also have a prominent excitatory input. These
      findings call for a new look at the mechanisms for signal coding in stellate
      cells in the auditory system in particular and raise issues concerning the
      stochastic nature of information processing in sensory systems in general.

PMID- 10644203
TI  - The privatization of public hospitals.

PMID- 10644204
TI  - Are fractional clearances overestimated?

PMID- 10644205
TI  - Focal contact-related proteins in podocytes after complement-mediated injury.

PMID- 10644206
TI  - Calcium antagonists and renal disease.

PMID- 10644207
TI  - Major confounders for reactance as a marker of malnutrition in hemodialysis
      patients.

PMID- 10644208
TI  - Cyclophosphamide and mercaptoethane sulfonate therapy for minimal lesion
      glomerulonephritis.

PMID- 10644209
TI  - [Management of chronic fatigue syndrome reflects the physician's "illness belief"
      letter)].

PMID- 10644210
TI  - [Should the needle electrodes of a hyfrecator be sterilized after use?].

PMID- 10644211
TI  - [XI World Congress for Psychiatry. Hamburg, Germany, 6-11 August 1999].

PMID- 10644212
TI  - PEM Fellowship Program alive and well.

PMID- 10644213
TI  - ISOBM TD-3 International Workshop on Monoclonal Antibodies against Prostate
      Specific Antigen.

PMID- 10644214
TI  - Chronic fatigue syndrome. CDC struggles to recover from debacle over earmark.

PMID- 10644215
TI  - Cell biology. Kinesin movements revealed.

PMID- 10644216
TI  - Taxonomy. Zoology naming rules eased.

PMID- 10644218
TI  - Archaeologists and rabbis clash over human remains.

PMID- 10644217
TI  - Postdocs. Academy plans guide to improve status.

PMID- 10644219
TI  - Bt toxin: assessing GM strategies.

PMID- 10644220
TI  - Resistance to Bt toxins.

PMID- 10644221
TI  - Will tribal knowledge survive the millennium?

PMID- 10644222
TI  - Tracing the origins of Salmonella outbreaks.

PMID- 10644224
TI  - Charon's first detailed spectra hold many surprises.

PMID- 10644223
TI  - Reading the worm genome.

PMID- 10644225
TI  - Nota bene: aging. Sensing old age.

PMID- 10644226
TI  - [Ultrasonography of joints and tendons in rheumatic diseases].

PMID- 10644228
TI  - Biological and migrational characteristics of microchips.

PMID- 10644227
TI  - Does the immunocytochemical detection of epithelial cells in bone marrow
      (micrometastasis) influence the time to biochemical relapse after radical
      prostatectomy?
AB  - The detection of cytokeratin-positive bone marrow cells has been considered a
      prognostic factor in numerous malignant tumors. We investigated whether this was
      also valid for localized prostate cancer. Bone marrow aspirates were taken prior
      to radical prostatectomy from 169 consecutive patients with pT1/2 pNO G1-3
      adenocarcinoma of the prostate. The immunocytochemical detection of cytokeratin
      no. 18 (CK 18)-positive cells using monoclonal antibody CK 2 was interpreted as
      micrometastasis. Repeat marrow aspirations were performed at 6 months
      postoperatively and once a year thereafter. The patients were re-examined over a
      period of at least 10 and a maximum of 72 months (median 32 months). An increase
      in prostate specific antigen > or = 0.5 ng/ml was considered a biochemical
      "relapse". One hundred and fifty-four patients had evaluable bone marrow
      aspirates, of which 74.7% were CK 18-negative and 25.3% positive. The latency
      period for biochemical relapse was 1481 days (median) in the CK 18-negative group
      and 1106 days (median) in the CK 18-positive group. This difference was not
      statistically significant. The CK 18-positive aspirates (n = 39) showed one
      positive cell in 20 cases, two positive cells in 8 and three or more positive
      cells in 11 cases. The preoperative number of cells had no statistically
      significant effect upon the onset of biochemical relapse. Only patients with
      three or more CK 18-positive cells tended to have a poorer prognosis. One hundred
      and thirteen patients had evaluable bone marrow aspirates pre- and
      postoperatively. Postoperative persistence or occurrence of CK 18-positive cells
      did not affect the outcome of the disease. The detection of CK 18-positive cells
      in bone marrow does not influence the prognosis of patients with localized
      prostate cancer within a period fo 32 months (median). Solely a subgroup of
      patients showing a large preoperative number of CK 18-positive cells seems to
      tend to an unfavorable course of the disease. Thus, further studies are necessary
      aiming at a more detailed characterization of these cells.

PMID- 10644229
TI  - Immune tolerance in haemophilia and the treatment of haemophiliacs with an
      inhibitor. Proceedings of the 2nd Workshop on Immune Tolerance. Bonn
      Konigswinter, Germany, August 27-30, 1997.

PMID- 10644230
TI  - [The concern: is the abandonment of stomach carcinoma prophylaxis by Helicobacter
      pylori elimination unethical?].

PMID- 10644231
TI  - 4th European HTLV Pathogenesis Meeting. Paris, France, 8 June 1999. Abstracts.

PMID- 10644232
TI  - [Morphological study on peptide production and the release from anterior
      pituitary gland cells and cell communication].

PMID- 10644233
TI  - Hemorrhagic fever with renal syndrome induced chronic renal dysfunction.

PMID- 10644234
TI  - Remembrance of things past and concerns for the future.
AB  - Stanley G. Schultz received the seventh annual Arthur C. Guyton Physiology
      Teacher of the Year Award. The following is a speech he delivered as he was
      presented the award at Experimental Biology '99 in Washington, DC, in April 1999.

PMID- 10644235
TI  - Learning physiology through service.
AB  - A service-learning component has been successfully incorporated into an
      introductory physiology course at Wheaton College. In addition to regular course
      work, each of the 24 students spent 12 hours shadowing and assisting staff at
      Sturdy Memorial Hospital, Attleboro, MA, with 4 hours in the emergency room and 8
      hours in two other departments. Every student kept a log of his or her
      observations, reactions, and learning in the field and wrote a paper on a
      pathophysiological condition encountered in the hospital. To compare and contrast
      the real hospital experience with a fictional one, the students also studied
      patients from the television show ER. Each week in lab, two students showed a
      short videotape of one particular patient and discussed the diagnosis, symptoms,
      treatments, and surgical procedures involved. Questionnaire evaluations indicated
      that this program is effective in helping students learn more physiology and
      exposing them to community service. Health workers and patients also agreed that
      providing social support to patients while shadowing and assisting hospital staff
      was a valuable service.

PMID- 10644236
TI  - Teaching experimental design to biologists.
AB  - The teaching of research design and data analysis to our graduate students has
      been a persistent problem. A course is described in which students, early in
      their graduate training, obtain extensive practice in designing experiments and
      interpreting data. Lecture-discussions on the essentials of biostatistics are
      given, and then these essentials are repeatedly reviewed by illustrating their
      applications and misapplications in numerous research design problems. Students
      critique these designs and prepare similar problems for peer evaluation. In most
      problems the treatments are confounded by extraneous variables, proper controls
      may be absent, or data analysis may be incorrect. For each problem, students must
      decide whether the researchers' conclusions are valid and, if not, must identify
      a fatal experimental flaw. Students learn that an experiment is a well-conceived
      plan for data collection, analysis, and interpretation. They enjoy the
      interactive evaluations of research designs and appreciate the repetitive review
      of common flaws in different experiments. They also benefit from their practice
      in scientific writing and in critically evaluating their peers' designs.

PMID- 10644237
TI  - Predictors of success in undergraduate human physiology.
AB  - This study tested the hypothesis that measurable attributes in students'
      backgrounds are related to their successful completion of an undergraduate human
      physiology course. Demographic, general academic performance, and science
      achievement data were obtained from student records for students enrolled during
      the 1995-1996 academic year, and additional demographic data were obtained from
      students enrolled during the 1996-1998 academic years. A hierarchical logistic
      regression analysis explored the relationship fo these variables to the
      percentage of students passing the human physiology course. Predicted passing
      versus failing showed a sensitivity of 85.5% and specificity of 69.7%. Two
      independent validations of the logistical regression equation correctly predicted
      the performance of subsequent groups of students 75.9% and 77.6% of the time.

PMID- 10644238
TI  - Undergraduate students' misconceptions about respiratory physiology.
AB  - Approximately 700 undergraduates studying physiology at community colleges, a
      liberal arts college, and universities were surveyed to determine the prevalence
      of our misconceptions about respiratory phenomena. A misconception about the
      changes in breathing frequency and tidal volume (physiological variables whose
      changes can be directly sensed) that result in increased minute ventilation was
      found to be present in this population with comparable prevalence (approximately
      60%) to that seen in a previous study. Three other misconceptions involving
      phenomena that cannot be experienced directly and therefore were most likely
      learned in some educational setting were found to be of varying prevalence.
      Nearly 90% of the students exhibited a misconception about the relationship
      between arterial oxygen partial pressure and hemoglobin saturation. Sixty-six
      percent of the students believed that increasing alveolar oxygen partial pressure
      leads to a decrease in alveolar carbon dioxide partial pressure. Nearly 33% of
      the population misunderstood the relationship between metabolism and ventilation.
      The possible origins of these respiratory misconceptions are discussed and
      suggestions for how to prevent and/or remediate them are proposed.

PMID- 10644239
TI  - Basis for presentation of acid-base in two dimensions.
AB  - Buffering of "metabolic" acid in tissues other than blood correlates closely with
      a change in extracellular bicarbonate concentration rather than with a change in
      extracellular pH. Of particular importance is the evidence for an absence of
      relation to change in pH. Questions are raised with respect to buffering
      mechanism, but simplification is offered for diagnosis. A clearer focus can be
      given to the guidepost changes in PCO2 and bicarbonate concentration. Basic
      relationships of buffering in the whole body are reviewed, and a modified
      diagnostic rationale is offered, based on a two-rather than a three-dimensional
      analysis.

PMID- 10644240
TI  - Challenges of teaching physiology in a PBL school.
AB  - A problem-based learning (PBL) curriculum was introduced at McMaster University
      more than three decades ago. Not many schools have adopted the system despite its
      distinct advantages. The present paper examines the challenges of teaching
      physiology in a PBL curriculum and gleans through the literature supporting PBL.
      It appears that one of the reasons why PBL is not becoming readily acceptable is
      the lack of concrete reports evaluating the curricular outcomes. The suggestion
      (R.E. Thomas. Med Educ. 31:320-329, 1997) to standardize and internationalize all
      components of validated PBL curricula is quite valid. A database needs to be
      generated that can be easily accessed by traditional institutions to see the
      rationality and easy implementation of the PBL curriculum.

PMID- 10644241
TI  - Refresher course for teaching cardiovascular physiology.
AB  - This report presents highlights of a refresher course presented at Experimental
      Biology '99 on Saturday, April 17, 1999, in Washington, District of Columbia.

PMID- 10644242
TI  - An inquiry-based teaching tool for understanding arterial blood pressure
      regulation and cardiovascular function.
AB  - Educators are placing a greater emphasis on the development of cooperative
      laboratory experiences that supplement the traditional lecture format. The new
      laboratory materials should encourage active learning, problem-solving, and
      inquiry-based approaches. To address these goals, we developed a laboratory
      exercise designed to introduce students to the hemodynamic variables (heart rate,
      stroke volume, total peripheral resistance, and compliance) that alter arterial
      pressure. For this experience, students are presented with "unknown" chart
      recordings illustrating pulsatile arterial pressure before and in response to
      several interventions. Students must analyze and interpret these unknown
      recordings and match each recording with the appropriate intervention. These
      active learning procedures help students understand and apply basic science
      concepts in a challenging and interactive format. Furthermore, laboratory
      experiences may enhance the students' level of understanding and ability to
      synthesize and apply information. In conducting this exercise, students are
      introduced to the joys and excitement of inquiry-based learning through
      experimentation.

PMID- 10644243
TI  - Integration of myofilament response to Ca2+ with cardiac pump regulation and pump
      dynamics.
AB  - In this paper I present some ideas related to teaching cardiac pump dynamics and
      regulation to first-year medical students. I emphasize explicit presentation of
      the relation between the activity of the contractile machine in the myocytes to
      pump dynamics, pressure-volume relations, and cardiac output regulation, with
      matching oxygen supply to tissue demands serving as a focal point. Important
      ideas here are 1) the concept that regulation is at the cellular level of
      regulation; 2) that force and shortening properties of the cells are ultimately
      dependent on the number of cross bridges reacting with the thin filament and on
      the rate of cross-bridge cycling; 3) that the concepts of preload, aferload, and
      contractility originated in studies of muscle mechanics; 4) that there is a
      reserve of force-generating cross bridges, i.e., the myofilaments are not fully
      activated by Ca2+ in the basal state, and that force-generating cross bridges can
      themselves activate the thin filament; and 5) that length dependence of
      myofilament Ca2+ activation is important in the cellular basis of Starling's law
      of the heart. The elaboration of these processes serves to elucidate how these
      mechanisms play a role in coupling tissue oxygen demands to supply.

PMID- 10644244
TI  - Learning the regulation of peripheral blood flow.
AB  - Students can learn a great deal about the peripheral circulation when teaching is
      based on five building blocks: hemodynamic principles, neurohumoral control, and
      three elements of local control of blood flow (metabolic, myogenic, and
      paracrine). Study of a particular special circulation starts with the application
      of these building blocks in the context of the function of that tissue. For
      example, control of skin blood flow is largely concerned with regulation of body
      temperature (neurohumoral control) and the response to injury (paracrine
      control). Regulation of coronary blood flow is almost entirely a matter of
      meeting the metabolic needs of the myocardium (metabolic control). By mixing and
      matching the five building blocks and keeping in mind the special functions of a
      particular tissue, students can master the peripheral circulation efficiently.

PMID- 10644245
TI  - Integration and regulation of cardiovascular function.
AB  - New methods in molecular biology and genetics have made possible many of the
      dramatic advances in physiological research that have occurred in recent years.
      For those of us who spend most of our time in the research laboratory, it si
      sometimes difficult to avoid a research-oriented, reductionist mind-set when
      discussing physiology with students. This article illustrates, with a few
      examples, the importance of conveying a "big picture" conceptual framework before
      discussing the details of cardiovascular physiology. Also, I have chosen examples
      from cardiac output and blood pressure regulation that show the importance of
      discussing cardiovascular physiology in terms of feedback control systems and
      integrating information from other areas, such as renal and endocrine physiology.
      Finally, I have highlighted the importance of two principles that I believe are
      often underemphasized in teaching physiology: mass balance and time dependence of
      physiological control systems.

PMID- 10644246
TI  - Teaching the principles of hemodynamics.
AB  - Knowledge of hemodynamic principles is crucial to an understanding of
      cardiovascular physiology. This topic can be effectively taught by discussing
      simple physical principles and basic algebraic equations. A variety of examples
      from everyday observations can be used to illustrate the physical principles
      underlying the flow of blood through the circulation, thereby giving the student
      an experiential feel for the topic in addition to an understanding of theory.
      Moreover, opportunities abound for showing how each hemodynamic principle can
      explain one or another functional feature of the cardiovascular system or a
      cardiovascular pathophysiological state. Thus hemodynamics can be used as an
      organizational thread to tie together other aspects of cardiovascular physiology.

PMID- 10644247
TI  - Capillary fluid exchange.

PMID- 10644248
TI  - Teaching vascular adaptations to mechanical stress.
AB  - Blood vessels change their number and structure in attempt to meet tissue demands
      for blood flow while simultaneously controlling mechanical stresses. A great deal
      of information is emerging in this field, especially concerning the role of the
      endothelium and signaling pathways for mechanotransduction. While not delving too
      deeply into the rapidly changing details, the students can be introduced to this
      exciting field by describing the structural changes that take place and outlining
      the major theories that are being investigated. The applications to peripheral
      vascular disease, myocardial infarctions, hypertension and tumor growth are
      readily apparent.

PMID- 10644249
TI  - Cardiac arrhythmias.

PMID- 10644250
TI  - Reflexes that control cardiovascular function.

PMID- 10644251
TI  - Cardiovascular response to exercise.
AB  - This article is intended for instructors who teach cardiovascular physiology. In
      our physiology course exercise physiology is used as a tool to review and
      integrate cardiovascular and respiratory physiology. It is assumed that the
      students already have mastered the fundamentals of cardiovascular and respiratory
      physiology. Because this paper is part of a cardiovascular refresher course, I
      have deleted much of the respiratory physiology. The objectives of this
      presentation are for the student to 1) understand the relationship between
      maximal oxygen consumption and endurance during sustained exercise and be able to
      define "maximal oxygen consumption"; 2) understand the determinants of of maximal
      oxygen consumption; 3) understand the effects of dynamic exercise on the
      cardiovascular system and mechanisms for these effects; 4) understand the
      relationships between exercise intensity and major cardiorespiratory parameters,
      including heart rate, cardiac output, blood flow distribution, left ventricular
      stroke volume, arterial pressures, total peripheral resistance, and arterial and
      venous blood oxygen content; 5) be able to compare and contrast the
      cardiovascular effects of dynamic and isometric exercise in man and the
      mechanisms responsible for the major differences; and 6) be able to apply
      knowledge of the cardiovascular effects of exercise to understanding the causes
      of cardiovascular symptoms in disease and in diagnosis of disease states. This
      material contains many areas that stimulate discussion with students and allow
      exploration of concepts that are challenging for the student. This give and take
      between teachers and student is difficult to summarize in an article of this
      sort. Therefore, subjects that in my experience often stimulate questions and
      discussion with the students are indicated in the text.

PMID- 10644252
TI  - Common misconceptions that arise in the first-year medical physiology curriculum
      concerning heart failure.
AB  - There are a number of misconceptions that first-year medical students have
      concerning the pathophysiology of heart failure. These stem from 1) a poor
      definition of heart failure, 2) a lack of care in distinguishing between similar
      but distinct concepts, and 3) the inability to recognize the relationship between
      the various stages of heart failure and the clinical manifestation of the
      disease. In this paper we provide a list of some of the misconceptions that we
      have encountered, some explanations of the distinctions to be made, and some of
      the rationale behind current surgical procedures and drug treatment. The
      misconceptions include failing to differentiate between the Frank-Starling
      mechanism and cardiac dilation as well as not grasping the significance that
      changes in cardiac beta-receptor function have in limiting the positive inotropic
      actions of circulating catecholamines. Finally, we review some of the altered
      neurohumoral mechanisms in heart failure and explain the basis for some common
      therapeutic approaches, including the use of angiotensin-converting enzyme
      inhibitors, in this disease.

PMID- 10644253
TI  - Teaching critical thinking skills in physiology.
AB  - This is a report of a workshop presented at Experimental Biology '99 on April 18,
      1999, in Washington, DC.

PMID- 10644255
TI  - Using demonstrations to uncover student misconceptions: the Law of LaPlace.

PMID- 10644254
TI  - Physiology teaching in the developing world: models for quality learning.
AB  - An important initiative to develop higher education and physiology teaching was
      launched when recommendations were deliberated at the concluding session of a
      four-day international workshop, Physiology Teaching in the Developing World:
      Models for Quality Learning, held April 5-8, 1999, at the Aga Khan University,
      Karachi, Pakistan. The event was organized under the auspices of the
      International Union of Physiological Sciences (IUPS), Pakistan Physiological
      Society, and Aga Khan University. Among other major sponsors, the Islamic
      Development Bank, Islamic Educational Science and Cultural Organization. Third
      World Academy of Sciences, and Pakistan Science Foundation were prominent.

PMID- 10644256
TI  - Teaching about disinhibition.

PMID- 10644257
TI  - Skits and games to enhance students' learning of physiology.

PMID- 10644258
TI  - Biomedical device design discovery team approach to teaching physiology to
      undergraduate bioengineering students.
AB  - Teaching effectiveness is enhanced by generating student enthusiasm, by using
      active learning techniques, and by convincing students of the value of acquiring
      knowledge in the area of study. We have employed a technique to teach physiology
      to bioengineering students that couples students' enthusiasm for their chosen
      field, bioengineering, with an active learning process in which students are
      asked to design a biomedical device to enhance, replace, or create a new cellular
      or organ system function. Each assignment is designed with specific constraints
      that serve to direct students' attention to specific areas of study and that
      require students to create original designs. Preventing students from using
      existing designs spurred student invention and enthusiasm for the projects.
      Students were divided into groups or "design discovery teams" as might be done in
      a biomedical device industry setting. Students then researched the physiological
      issues that would need to be addressed to produce an acceptable design. Groups
      met with faculty to brainstorm and to obtain approval for their general design
      concepts before proceeding. Students then presented their designs to the
      instructors in a structured, written outline form and to the class as a 10-minute
      oral presentation. Grades were based on the outline, oral presentation, and peer
      evaluations (group members anonymously rated contributions of other members of
      their team). We believe that this approach succeeded in generating enthusiasm for
      learning physiology by allowing the students to think creatively in their chosen
      field of study and that it has resulted in students developing a more thorough
      understanding of difficult physiological concepts than would have been achieved
      with a traditional didactic lecture approach.

PMID- 10644259
TI  - Electrophysiology of the undergraduate neuroscience student: a laboratory
      exercise in human electromyography.
AB  - A laboratory exercise is described in which students in a neuroscience,
      psychobiology, or similar laboratory course record the electromyogram (EMG) from
      themselves, using surface electrodes (placed on the skin). This exercise is
      intended to give students a firsthand demonstration that electrical activity is
      produced within them and to allow the students to use this activity to study
      biological and psychological concepts. The students study the nature of the EMG
      (changes with tension and the temporal relationship with limb movement) and the
      concepts of flexion and extension, reaction time, and patellar ("knee jerk")
      reflex. In postlaboratory evaluations, undergraduate introductory neuroscience
      students indicated that they appreciated the opportunity to record electrical
      activity from their own bodies. The students found the exercise enjoyable,
      believed that they had learned from it, and indicated that it should be a regular
      part of the course. If electrophysiology in animal preparations is already part
      of the course, this exercise requires minimal additional equipment, some of which
      is easily constructed and the reminder of which is available inexpensively.

PMID- 10644260
TI  - A simple, inexpensive method for teaching how membrane potentials are generated.
AB  - We have developed a simple laboratory exercise that uses an inexpensive dialysis
      membrane (molecular weight cutoff = 100) to illustrate the generation of membrane
      potentials (Vm) across plasma membranes of animal cells. A piece of membrane
      approximately 2.0 cm2 is mounted in an Ussing-like chamber. One chamber half is
      designated cytosol and the other half external. Chamber sidedness helps students
      relate their findings to those of real cells. As in real cells, outward directed
      K+ concentration gradients [high cytosolic K+ concentration ([K+]c) and low
      extracellular K+ concentration] generate cytosol electrically negative Vm with a
      slope of approximately -45 mV/decade change in [K+]c. The polarity of Vm reflects
      the outward flow of potassium ions because flow of the larger counterion, H2PO4-,
      is restricted to the pores in the membrane. A slope less than Nernstian (<59
      mV/decade) suggests that the membrane is slightly permeable to H2PO4-.
      Importantly, this facilitates teaching the use of the Nernst equation to quantify
      the relationship between ion concentration ratios across membranes and magnitude
      of Vm. For example, students use their data and calculate a permeability ratio
      PK/PH2PO4 that corresponds to a slope of approximately 24% less than Nernstian.
      This calculation shows that Nernstian slopes are achieved only when permeability
      to the counterion is zero. Finally, students use the concept of membrane
      capacitance to calculate the number of ions that cross the membrane. They learn
      where these ions are located and why the bulk solutions conform to the principle
      of electroneutrality.

PMID- 10644261
TI  - Report of the worldwide survey on teaching physiology.
AB  - This report by George G. Somjen, for the Commission on Teaching Physiology,
      International Union of Physiological Sciences, presents a summary of answers
      received to a questionnaire concerning the state of Physiology Teaching. One
      hundred seventeen responses have been received from fifty countries. The results
      have been tabulated and contain information about the teaching methods and
      resources as well as the commitment in time and effort by the teaching staff.
      Free-ranging, sometimes pithy, comments made by the respondents have been
      excerpted and are included.

PMID- 10644262
TI  - A simplified paired neck chamber for the demonstration of baroreflex blood
      pressure regulation.
AB  - In this investigation a simplified variable-pressure paired neck chamber was
      developed as a practical alternative to traditional neck collar designs used to
      study the arterial baroreceptor reflex in humans. The purpose of this new design
      was to extend the use of the noninvasive neck chamber method of baroreceptor
      investigation to teachers of physiology. Performance tests indicate that these
      new chambers are capable of delineating the stimulus-response relationship for
      both the blood pressure baroreflex [sensitivity = 0.425 +/- 0.13 mmHg mean
      arterial pressure (MAP)/mmHg neck chamber pressure (NCP); range = 24.9 +/- 4.6
      mmHg MAP] and the heart rate baroreflex (sensitivity 0.273 +/- 0.12 beats.min
      1.mmHg NCP-1; range = 16.7 +/- 6.8 beats/min). This was achieved by applying
      localized positive and negative air pressures to the carotid sinuses throughout
      the range from +60 to -60 mmHg in steps of 20 mmHg. This simplified neck chamber
      method offers distinct methodological advantages over traditional neck collars,
      making it a valuable tool for demonstrating baroreflex regulation of the
      circulation.

PMID- 10644263
TI  - Construction of a model demonstrating cardiovascular principles.
AB  - We developed a laboratory exercise that involves the construction and subsequent
      manipulation of a model of the cardiovascular system. The laboratory was designed
      to engage students in interactive, inquiry-based learning and to stimulate
      interest for future science study. The model presents a concrete means by which
      cardiovascular mechanics can be understood as well as a focal point for student
      interaction and discussion of cardiovascular principles. The laboratory contains
      directions for the construction of an inexpensive, easy-to-build model as well as
      an experimental protocol. From this experience students may gain an appreciation
      fo science that cannot be obtained by reading a book or interacting with a
      computer. Students not only learn the significant physiological concepts but also
      appreciate the importance of laboratory experimentation for understanding complex
      concepts. Model construction provides a hands-on experience that may
      substantially improve performance in science processes. We believe that model
      construction is an appropriate method for teaching advanced concepts.

PMID- 10644264
TI  - Involving students in question writing: a unique feedback with fringe benefits.
AB  - A contest on question writing was organized during the undergraduate medical
      physiology teaching program. Students were asked to write and submit multiple
      choice questions of the assertion-reasoning type (type E) in physiology. The
      winners were decided after the questions submitted were graded on a six-point
      scale (0-5) that considered both thematic novelty and construct correctness. Of
      the 100 students in the class, 37 participated in the contest, and a total of 912
      questions was received. The contest encouraged the students to go through their
      subjects critically. The questions provided the instructor with insight into the
      learning habits and misconceptions of the students and provided the grist for
      animated discussions in tutorial classes. Although several types of errors were
      deciphered in these questions, with suitable modifications the questions helped
      the faculty build up a sizable question bank.

PMID- 10644265
TI  - A model circulatory system for use in undergraduate physiology laboratories.
AB  - The cardiovascular system is a central topic in physiology classes, yet it is
      difficult to provide undergraduates with quality laboratory experiences in this
      area. Thus a model circulatory system was developed to give students hands-on
      experience with cardiovascular fluid dynamics. This model system can be
      constructed from readily available materials at a reasonable cost. It has a
      realistic pressure drop across the different vessels. Using this system, students
      can investigate the effect that blood volume, vessel compliance, vessel
      construction, and heart activity have on blood pressure and flow. The system also
      demonstrates the effect of vessel diameter on resistance and fluid velocity. This
      model may give students a more concrete, intuitive feel for cardiovascular
      physiology. Another advantage is that it allows dramatic and easily controlled
      manipulations with quantitative results. Finally, its simple construction allows
      students to interchange components, giving them greater flexibility in
      experimentation.

PMID- 10644266
TI  - [Card Adarpef/Sfar. Medical information before anesthetizing your child].

PMID- 10644267
TI  - [Epidemiology of locoregional anesthesia complications in children].

PMID- 10644268
TI  - [Management and treatment of severe obstetrical hemorrhage].

PMID- 10644269
TI  - [A case of TURP syndrome].

PMID- 10644270
TI  - 45-year follow-up of hepatitis C virus infection in healthy young adults.
AB  - BACKGROUND: The sequelae during the first two decades after acute hepatitis C
      virus (HCV) infection have been well studied, but the outcome thereafter is
      unknown. OBJECTIVE: To conduct an extended study of the natural history of HCV
      infection by using archived serum specimens originally collected between 1948 and
      1954. DESIGN: Retrospective cohort study. SETTING: A university, a Veterans
      Affairs medical center, and a medical follow-up agency that had access to the
      serum specimens and accompanying demographic and medical records. PARTICIPANTS:
      8568 military recruits who were evaluated for group A streptococcal infection and
      acute rheumatic fever between 1948 and 1954. Blood samples were taken from the
      recruits and, after testing, were stored frozen for almost 45 years.
      MEASUREMENTS: The presence of antibodies to HCV was determined by enzyme-linked
      immunoassay, supplementary recombinant immunoblot assay, and polymerase chain
      reaction for HCV RNA. Morbidity and mortality were also assessed. RESULTS: Of
      8568 persons, 17 (0.2%) had positive results on enzyme-linked immunosorbent assay
      and recombinant immunoblot assay. The rate was 1.8% among the African-American
      persons and 0.1% among the white persons in the total sample (relative risk, 25.9
      [95% CI, 8.4 to 80.0]). During the 45-year follow-up, liver disease occurred in 2
      of the 17 HCV-positive persons (11.8%) and 205 of the 8551 HCV-negative persons
      (2.4%) (ethnicity-adjusted relative risk, 3.56 [CI, 0.94 to 13.52]). Seven of the
      17 HCV-positive persons (41 %) and 2226 of the 8551 HCV-negative persons (26%)
      had died by December 1996 (ethnicity-adjusted relative risk, 1.48 [CI, 0.8 to
      2.6]). Of persons who were HCV-positive, 1 (5.9%) died of liver disease 42 years
      after the original phlebotomy, 5 (29%) died of non-liver-related disease a median
      of 37 years after the original phlebotomy, and 1 (5.9%) died of unknown causes.
      One hundred nineteen HCV-negative persons (1.4%) died of liver disease.
      CONCLUSIONS: The rate of HCV infection from 1948 to 1954 among a sample of
      military recruits parallels that among present-day military recruits and
      volunteer blood donors. During 45 years of follow-up, HCV-positive persons had
      low liver-related morbidity and mortality rates. This suggests that healthy HCV
      positive persons may be at less risk for progressive liver disease than is
      currently thought.

PMID- 10644271
TI  - Prevalence of and risk factors for hepatic steatosis in Northern Italy.
AB  - BACKGROUND: Although hepatic steatosis is seen with increasing frequency in
      clinical practice, its prevalence and risk factors are unknown. OBJECTIVE: To
      investigate the prevalence of and risk factors for hepatic steatosis, such as
      alcohol consumption and obesity. DESIGN: Cross-sectional, observational study.
      SETTING: Participants in the Dionysos Study. PATIENTS: 257 participants assigned
      to one of four categories (67 controls, 66 obese persons, 69 heavy drinkers, and
      55 obese heavy drinkers). MEASUREMENTS: Ethanol intake, assessed by a validated
      questionnaire and expressed as daily (g/d) and lifetime (kg) consumption, and
      body mass, expressed as body mass index. Biochemical tests of liver and metabolic
      function and hepatic ultrasonography were done. RESULTS: The prevalence of
      steatosis was increased in heavy drinkers (46.4% [95% CI, 34% to 59%]) and obese
      persons (75.8% [CI, 63% to 85%]) compared with controls (16.4% [CI, 8% to 25%]).
      Steatosis was found in 94.5% (CI, 85% to 99%) of obese heavy drinkers. Compared
      with controls, the risk for steatosis was higher by 2.8-fold (CI, 1.4-fold to 7.1
      fold) in heavy drinkers, 4.6-fold (CI, 2.5-fold to 11.0-fold) in obese persons,
      and 5.8-fold (CI, 3.2-fold to 12.3-fold) in persons who were obese and drank
      heavily. In heavy drinkers, obesity increased the risk for steatosis by twofold
      (CI, 1.5-fold to 3.0-fold) (P < 0.001), but heavy drinking was associated with
      only a 1.3-fold (CI, 1.02-fold to 1.6-fold) increase in risk in obese persons (P
      = 0.0053). Elevated alanine aminotransferase and triglyceride levels are the most
      reliable markers of steatosis. CONCLUSIONS: Steatosis is frequently encountered
      in healthy persons and is almost always present in obese persons who drink more
      than 60 g of alcohol per day. Steatosis is more strongly associated with obesity
      than with heavy drinking, suggesting a greater role of overweight than alcohol
      consumption in accumulation of fat in the liver.

PMID- 10644272
TI  - Hepatic failure in a patient taking rosiglitazone.
AB  - BACKGROUND: Rosiglitazone maleate is the second approved oral hypoglycemic agent
      of the thiazolidinedione class. The first, troglitazone, has been associated with
      liver failure, occasionally resulting in liver transplantation or death. There
      have been no reports to date of rosiglitazone-associated elevations in the
      alanine aminotransferase level or hepatotoxicity. OBJECTIVE: To report the
      clinical characteristics of liver failure developing in a patient receiving
      rosiglitazone. DESIGN: Case report. SETTING: University hospital. PATIENT: 69
      year-old man taking rosiglitazone, 4 mg/d. INTERVENTION: Discontinuation of
      rosiglitazone therapy and treatment with lactulose, vitamin K, fresh frozen
      plasma, ventilatory assistance, and intensive care unit support. MEASUREMENTS:
      Blood test monitoring, including toxicology screening, liver function tests,
      coagulation studies, serum chemistries, and complete blood counts. RESULTS: After
      21 days of rosiglitazone therapy, hepatic failure developed. Other causes of
      hepatic failure, such as viruses and toxins, were excluded, although it is
      possible that congestive heart failure was also a causative factor. The patient
      recovered fully with supportive care. CONCLUSION: Rosiglitazone may be associated
      with hepatic failure.

PMID- 10644274
TI  - Update in rheumatology.

PMID- 10644273
TI  - Hepatocellular injury in a patient receiving rosiglitazone. A case report.
AB  - BACKGROUND: Rosiglitazone maleate (Avandia, SmithKline Beecham, Philadelphia,
      Pennsylvania) is a new oral hypoglycemic agent approved for the treatment of type
      2 diabetes. It acts primarily by increasing insulin sensitivity. In controlled
      trials, there has been no evidence of rosiglitazone-induced hepatocellular
      injury. OBJECTIVE: To report a case of hepatocellular injury in a patient
      receiving rosiglitazone. DESIGN: Case report. SETTING: Community teaching
      hospital. PATIENT: 61-year-old man receiving rosiglitazone, 4 mg/d for 2 weeks.
      INTERVENTION: Discontinuation of rosiglitazone therapy. MEASUREMENTS: Clinical
      evaluation and assessment of liver function test results were done daily during
      hospitalization and periodically after discharge. The outpatient record was also
      reviewed. RESULTS: After receiving rosiglitazone for 2 weeks, the patient
      presented with anorexia, vomiting, and abdominal pain. Liver function tests
      revealed severe hepatocellular injury. Discontinuation of rosiglitazone therapy
      led to rapid improvement of liver function and resolution of symptoms.
      CONCLUSION: Rosiglitazone may be associated with hepatocellular injury. We
      believe that patients receiving rosiglitazone should have liver enzyme levels
      monitored earlier and more frequently than initially recommended.

PMID- 10644275
TI  - Do cyclooxygenase-2 inhibitors provide benefits similar to those of traditional
      nonsteroidal anti-inflammatory drugs, with less gastrointestinal toxicity?

PMID- 10644276
TI  - Acquired C1 esterase inhibitor deficiency.
AB  - Acquired C1 esterase inhibitor deficiency is a rare condition associated with
      autoimmune or low-grade lymphoproliferative disorders. Adults or elderly patients
      are most commonly affected. The diagnosis is suspected when patients present with
      recurrent angioedema and low serum levels of C4 with normal levels of C3. Low
      levels of C1q and low C1 esterase inhibitor activity confirm the diagnosis. In
      this paper, we summarize experience with 22 cases of acquired C1 esterase
      inhibitor deficiency in the context of a review of the published literature on
      diagnosis and treatment of this condition.

PMID- 10644277
TI  - Effect of the U.S. embargo and economic decline on health in Cuba.
AB  - This article describes the ways in which economic crisis and the U.S. embargo
      have affected Cuba's health care system during the past 15 years. With the demise
      of subsidized trade, the absence of aid from the former Soviet Union, and the
      progressive tightening of U.S. sanctions, Cuba's model health care system has
      become threatened by serious shortages of medical supplies. Several public health
      catastrophes have occurred, including an epidemic of blindness that was partially
      attributed to a dramatic decrease in access to nutrients; an outbreak of the
      Guillain-Barre syndrome caused by lack of chlorination chemicals; and an epidemic
      of lye ingestion in toddlers due to severe shortages of soap. The policy of
      mandatory quarantine for HIV-infected Cubans has evolved into a less rigid
      system. Although the prevalence of HIV infection in Cuba is low compared with
      that in the United States and other Caribbean nations, it is threatened by
      prostitution, which has increased along with tourism. In general, economic
      sanctions may have an unintended but profound effect on the health and nutrition
      of vulnerable populations.

PMID- 10644278
TI  - Economic sanctions and public health: a view from the Department of State.

PMID- 10644279
TI  - The health effects of economic sanctions and embargoes: the role of health
      professionals. Ethics and Human Rights Committee.
AB  - As a widely used tool of foreign policy, economic sanctions take many forms. They
      include mandating trade restrictions (for example, limiting imports from or
      exports to a sanctioned nation), freezing bank accounts, limiting international
      travel to and from an area, imposing additional tariffs, and exerting other
      pressures that are intended to slow key economic activities. Since the end of the
      Cold War, as the global market has expanded, many countries and the United
      Nations have increasingly used economic sanctions instead of military
      intervention to compel nations to end civil or extraterritorial war or to reduce
      abuse of human rights. Similarly, the United States has attempted to influence
      international governments' domestic policies by using other economic means, such
      as relating "most favored nation" trading status to a country's human rights
      record or prohibiting the import of goods from countries in which illegal child
      labor is widespread. Repercussions from these measures influence a country's
      economic development and, therefore, can also affect the overall welfare of a
      nation's population. In contrast to war's easily observable casualties, the
      apparently nonviolent consequences of economic intervention seem like an
      acceptable alternative. However, recent reports suggest that economic sanctions
      can seriously harm the health of persons who live in targeted nations. For this
      reason, the American College of Physicians-American Society of Internal Medicine
      has undertaken this examination of physicians' roles in addressing the health
      effects of economic sanctions.

PMID- 10644280
TI  - Cleansing.

PMID- 10644281
TI  - Rosiglitazone and hepatic failure.

PMID- 10644282
TI  - Cross-cultural primary care.

PMID- 10644283
TI  - Cross-cultural primary care.

PMID- 10644284
TI  - Prostacyclin for secondary pulmonary hypertension.

PMID- 10644286
TI  - Pollen trapped in a scuba tank: a potential hazard for allergic divers.

PMID- 10644285
TI  - Cardiac asystole and bradycardia as a manifestation of left temporal lobe complex
      partial seizure.

PMID- 10644287
TI  - Faith and healing.

PMID- 10644289
TI  - Gene encoding the apo(a) protein in LPA.

PMID- 10644290
TI  - More on the effect of atorvastatin on plasma fibrinogen levels in primary
      hypercholesterolaemia.

PMID- 10644288
TI  - Oral montelukast compared with inhaled salmeterol to prevent exercise-induced
      bronchoconstriction. A randomized, double-blind trial. Exercise Study Group.
AB  - BACKGROUND: Montelukast, an oral, once-daily leukotriene receptor antagonist,
      provides protection against exercise-induced bronchoconstriction. OBJECTIVE: To
      evaluate the effect of 8 weeks of therapy with salmeterol aerosol or montelukast
      on exercise-induced bronchoconstriction in adults with asthma. DESIGN: 8-week
      multicenter, randomized, double-blind study. SETTING: 17 asthma treatment centers
      in the United States. PATIENTS: 191 adults with asthma who had documented
      exercise-induced bronchoconstriction. INTERVENTION: Qualified patients were
      randomly assigned to double-blind treatment with montelukast (10 mg once in the
      evening) or salmeterol (50 microg [2 puffs] twice daily). MEASUREMENTS: Changes
      in pre-exercise and postexercise challenge values; percentage inhibition in the
      maximal percentage decrease in FEV1; the area above the FEV1-time curve; and time
      to recovery of FEV1 at days 1 to 3, week 4, and week 8 of treatment. RESULTS: By
      day 3, similar and statistically significant reductions in maximal percentage
      decrease in FEV1 were seen with both therapies. Sustained improvement occurred in
      the montelukast group at weeks 4 and 8; at these time points, the
      bronchoprotective effect of salmeterol decreased significantly. At week 8, the
      percentage inhibition in the maximal percentage decrease in FEV1 was 57.2% in the
      montelukast group and 33.0% in the salmeterol group (P = 0.002). By week 8, 67%
      of patients receiving montelukast and 46% of patients receiving salmeterol had a
      maximal percentage decrease in FEV1 of less than 20%. CONCLUSIONS: The
      bronchoprotective effect of montelukast was maintained throughout 8 weeks of
      study. In contrast, significant loss of bronchoprotection at weeks 4 and 8 was
      seen with salmeterol. Long-term administration of montelukast provided consistent
      inhibition of exercise-induced bronchoconstriction at the end of the 8-week
      dosing interval without tolerance.

PMID- 10644291
TI  - ACE-inhibitor rather than HMG-co-enzyme-A-reductase inhibits causative for CK
      elevation? A case report.

PMID- 10644292
TI  - Evidence of case management effect on traumatic-brain-injured adults in
      rehabilitation.
AB  - The purpose of this study was to evaluate the evidence for effectiveness of case
      management during recovery from traumatic brain injury (TBI) in adults. After an
      overview of TBI incidence, prevalence, and problems, and a brief explanation of
      case management, the study methods are described, the findings are discussed and
      recommendations are made for future research. Medline, HealthSTAR, CINAHL,
      PsychINFO, and the Cochrane Library databases were searched and 83 articles met
      the criteria for review. The strongest studies (n = 3) were critically appraised
      and their design features and data were placed in two evidence tables. Due to
      methodological limitations, there was neither clear evidence of effectiveness nor
      of ineffectiveness. For future research, we recommend controlled research
      designs, standardization of measures, adequate statistical analysis and
      specification of health outcomes of importance to persons with TBI and their
      families.

PMID- 10644293
TI  - Enhancing the case manager's role through early identification of at-risk
      members.
AB  - This article describes a methodology to improve early identification and
      stratification of at-risk patients with comorbidities that could result in
      catastrophic illness. Data from the HMO line of business identified diabetic
      members. Total frequency and total cost for 19 comorbid diseases were calculated
      on data from the diabetic members who were classified as having high severity and
      comorbidity rankings. Members were further segmented into quadrants based on
      frequency and cost for referral to case management and/or educational programs. A
      total of 1312 HMO diabetic members were classified as high severity. Quadrant 4
      diabetic members consumed greater than $10,000 in health care expenses and had 6
      or more collapsed DECs. Similar types of comorbid diseases were found in both
      quadrants 2 and 4. Quadrant 2 diabetic members were identified as "in danger"
      members with the potential to incur total costs greater than $10,000.

PMID- 10644294
TI  - A review of HIV/AIDS case management research.
AB  - Published research on HIV/AIDS case management is reviewed. Twenty-five studies
      are placed within a conceptual framework that can be used to guide a research
      agenda. Unlike other case management fields, research in this field has not kept
      pace with the growth and development of HIV/AIDS case management. Reasons for the
      paucity of research in this field are offered.

PMID- 10644295
TI  - The "normal pathophysiology" of aging.

PMID- 10644296
TI  - The physical design of the home as a caregiving support: an environment for
      persons with dementia.

PMID- 10644297
TI  - NORC supportive service programs: effective and innovative programs that support
      seniors living in the community.

PMID- 10644299
TI  - The continuum of care: housing and services at James Lenox House.

PMID- 10644298
TI  - Linkage House: a case study highlighting the challenges and opportunities in
      linking housing and programs for older adults.

PMID- 10644301
TI  - Proton pump inhibitors for Barrett's oesophagus.

PMID- 10644302
TI  - Barrett's oesophagus and proton pump inhibitors: a pathological perspective.

PMID- 10644303
TI  - Haute cuisine and the colon.

PMID- 10644304
TI  - DMT1 expression: avoiding too much of a good thing.

PMID- 10644305
TI  - Fibrosing colonopathy.

PMID- 10644306
TI  - Prostaglandins and the induction of food sensitive enteropathy.

PMID- 10644307
TI  - Exogenous nitric oxide inhibits apoptosis in guinea pig gastric mucous cells.
AB  - BACKGROUND: Increased nitric oxide (NO) synthase activity and enhanced apoptosis
      are features of gastric mucosa infected with Helicobacter pylori and a causative
      relation has been suggested. However, although NO can promote apoptosis, its
      actions vary with cell type. AIMS: To determine whether exogenous NO, derived
      from an NO donor, might promote or counteract apoptosis in gastric mucous
      epithelial cells. METHODS: Primary cultures of guinea pig gastric mucosal cells
      were exposed to the NO donor S-nitroso-N-acetyl-penicillamine (SNAP) for 24
      hours. Apoptosis was detected from nuclear staining with Hoechst 33258, in situ
      nick end labelling of DNA, and the presence of DNA "ladders" in cell extracts.
      Cyclic GMP content and caspase activity were determined by immunoassay and
      fluorimetric assay respectively. RESULTS: SNAP 1 mM did not alter the small
      proportion of cells on the culture plate (3-6%) which exhibited features of
      apoptosis. However, SNAP produced an inhibition of apoptosis, and of caspase 3
      like activity, when enhanced by 25 microM N-hexanoyl-D-sphingosine (C(6)
      ceramide), or by detachment of cells from the culture plate. The guanylate
      cyclase inhibitor, 1H-1, 2, 4-oxadiazole-4, 3-a-quinoxaline-1-one (ODQ),
      prevented the stimulation of cyclic GMP by SNAP, but not the anti- apoptotic
      effects of the NO donor. The cyclic GMP analogues 8-bromo-cyclic GMP and 8-(4
      chlorophenylthio) guanosine-3',5'- cyclic monophosphate did not significantly
      inhibit apoptosis in the mucosal cells. CONCLUSIONS: Exogenous NO inhibited
      apoptosis in guinea pig gastric mucous cells by a mechanism which did not involve
      elevation of cyclic GMP. NO, if produced from NO synthase during infection with H
      pylori, may therefore counter the proapoptotic effects of this pathogen.

PMID- 10644308
TI  - Immunohistochemical analysis of the distribution of measles related antigen in
      the intestinal mucosa in inflammatory bowel disease.
AB  - BACKGROUND: Measles virus is implicated in the aetiology of Crohn's disease. This
      measles hypothesis is mainly supported by immunohistochemical findings that the
      measles related antigen is present in the intestine of patients with Crohn's
      disease. Recently we isolated this antigen from the intestine of a patient with
      Crohn's disease using a molecular cloning technique and produced the monoclonal
      antibody against it (designated 4F12). AIM: To discover whether the measles
      related antigen is uniquely present in Crohn's disease. SUBJECTS/METHODS: Colonic
      mucosa samples from 20 patients with Crohn's disease, 20 with ulcerative colitis,
      11 with non-inflammatory bowel disease (IBD) colitis, and nine controls were
      immunohistochemically stained with the anti-measles monoclonal antibody 4F12. The
      numbers of positive cells, the ratio of positive cells to nucleated cells, and
      the staining intensity of the positive cells were compared. Furthermore, the
      distribution of the measles antigen in other human organs was examined. RESULTS:
      Both the number of positive cells and the ratio of positive cells to nucleated
      cells were significantly increased in Crohn's disease, ulcerative colitis, and
      non-IBD colitis compared with controls (p<0.05) but were similar among the three
      disease groups. The staining intensity of the positive cells was also similar
      among the three disease groups. Small numbers of positive cells were observed in
      the oesophagus, stomach, duodenum, jejunum, and lung. CONCLUSIONS: The presence
      of the measles related antigen in the colonic mucosa was not unique to Crohn's
      disease. These results, together with the observation that such a measles related
      antigen was derived from host protein, do not support the hypothesis that measles
      virus causes Crohn's disease.

PMID- 10644309
TI  - Role of bile acids and bile acid binding agents in patients with collagenous
      colitis.
AB  - BACKGROUND: In a retrospective study bile acid malabsorption was observed in
      patients with collagenous colitis. AIMS: To study the occurrence of bile acid
      malabsorption and the effect of bile acid binders prospectively in patients with
      chronic diarrhoea and collagenous colitis. METHODS: Over 36 months all patients
      referred because of chronic diarrhoea completed a diagnostic programme, including
      gastroscopy with duodenal biopsy, colonoscopy with biopsies, and the (75)Se
      homocholic acid taurine ((75)SeHCAT) test for bile acid malabsorption. Treatment
      with a bile acid binder (cholestyramine in 24, colestipol in three) was given,
      irrespective of the results of the (75)SeHCAT test. RESULTS: Collagenous colitis
      was found in 28 patients (six men, 22 women), 27 of whom had persistent symptoms
      and completed the programme. Four patients had had a previous cholecystectomy or
      a distal gastric resection. The (75)SeHCAT test was abnormal in 12/27 (44%) of
      the collagenous colitis patients with (75)SeHCAT values 0.5-9.7%, and normal in
      15 patients (56%). Bile acid binding treatment was followed by a rapid, marked,
      or complete improvement in 21/27 (78%) of the collagenous colitis patients. Rapid
      improvement occurred in 11/12 (92%) of the patients with bile acid malabsorption
      compared with 10/15 (67%) of the patients with normal (75)SeHCAT tests.
      CONCLUSION: Bile acid malabsorption is common in patients with collagenous
      colitis and is probably an important pathophysiological factor. Because of a high
      response rate without serious side effects, bile acid binding treatment should be
      considered for collagenous colitis, particularly patients with bile acid
      malabsorption.

PMID- 10644310
TI  - Fracture risk is increased in Crohn's disease, but not in ulcerative colitis.
AB  - AIMS: To study fracture rates and risk factors for fractures in patients with
      Crohn's disease and ulcerative colitis. METHODS: 998 self administered
      questionnaires were issued to members of the Danish Colitis/Crohn Association,
      and 1000 questionnaires were issued to randomly selected control subjects. 845
      patients (84.5%) and 645 controls (65.4%) returned the questionnaire (p<0.01).
      817 patients and 635 controls could be analysed. RESULTS: Analysis was performed
      on 383 patients with Crohn's disease (median age 39, range 8-82 years; median age
      at diagnosis 26, range 1-75 years), 434 patients with ulcerative colitis (median
      age 39, range 11-86 years; median age at diagnosis 29, range 10-78 years), and
      635 controls (median age 43, range 19-93 years, p<0.01). The fracture risk was
      increased in female patients with Crohn's disease (relative risk (RR) = 2.5, 95%
      confidence interval (CI) 1.7-3.6), but not in male patients with Crohn's disease
      (RR = 0.6, 95% CI 0.3-1.3) or in patients with ulcerative colitis (RR = 1.1, 95%
      CI 0.8-1.6). An increased proportion of low energy fractures was observed in
      patients with Crohn's disease (15.7% versus 1.4 % in controls, 2p<0. 01), but not
      in patients with ulcerative colitis (5.4%, 2p=0.30). The increased fracture
      frequency in Crohn's disease was present for fractures of the spine, feet, and
      toes and fractures of the ribs and pelvis. Fracture risk increased with
      increasing duration of systemic corticosteroid use in Crohn's disease (2p=0.028),
      but not in ulcerative colitis (2p=0.50). CONCLUSIONS: An increased risk of low
      energy fractures was observed in female patients with Crohn's disease, but not in
      male patients with Crohn's disease or in patients with ulcerative colitis.

PMID- 10644311
TI  - Presence of sorbin in human digestive tract and endocrine digestive tumours.
AB  - BACKGROUND: Sorbin, a 153 amino acid peptide isolated from porcine intestine, was
      localised by immunohistochemistry in endocrine cells of the intestinal mucosa and
      pancreas and in the enteric nervous system in the pig. AIMS: To identify sorbin
      cells in normal human digestive tissues and to explore the expression of sorbin
      in 37 digestive endocrine tumours: 14 intestinal carcinoid tumours and 23
      endocrine pancreatic tumours including six insulinomas. METHODS: Two polyclonal
      antibodies against the C-terminal and the N-terminal sequences of porcine sorbin
      raised in rabbit were used to evaluate sorbin expression by immunohistochemistry.
      RESULTS: In the human digestive tract, sorbin, characterised by both C-terminal
      and N-terminal immunoreactivity, was found in enterochromaffin cells of the
      gastric and intestinal epithelium from the pyloric junction to the descending
      colon. C-Terminal sorbin immunoreactivity alone was found in plexii from the
      enteric nervous system and in some insulin-containing cells of normal pancreas. C
      Terminal and N-terminal antibodies disclosed sorbin in five of 14 intestinal
      carcinoid tumours; C-terminal antibody alone disclosed a C-terminal sorbin
      peptide in two of six insulinomas and three of 17 endocrine pancreatic tumours.
      The presence of sorbin was not associated with a specific clinical syndrome.
      CONCLUSIONS: Sorbin is present in the digestive tract in several forms. It is
      expressed in some intestinal and pancreatic endocrine tumours.

PMID- 10644312
TI  - Effect of olive oil on early and late events of colon carcinogenesis in rats:
      modulation of arachidonic acid metabolism and local prostaglandin E(2) synthesis.
AB  - BACKGROUND: Animal model studies have shown that the colon tumour promoting
      effect of dietary fat depends not only on the amount but on its fatty acid
      composition. With respect to this, the effect of n9 fatty acids, present in olive
      oil, on colon carcinogenesis has been scarcely investigated. AIMS: To assess the
      effect of an n9 fat diet on precancer events, carcinoma development, and changes
      in mucosal fatty acid composition and prostaglandin (PG)E(2) formation in male
      Sprague-Dawley rats with azoxymethane induced colon cancer. METHODS: Rats were
      divided into three groups to receive isocaloric diets (5% of the energy as fat)
      rich in n9, n3, or n6 fat, and were administered azoxymethane subcutaneously once
      a week for 11 weeks at a dose rate of 7.4 mg/kg body weight. Vehicle treated
      groups received an equal volume of normal saline. Groups of animals were
      colectomised at weeks 12 and 19 after the first dose of azoxymethane or saline.
      Mucosal fatty acids were assessed at 12 and 19 weeks. Aberrant crypt foci and the
      in vivo intracolonic release of PGE(2) were assessed at week 12, and tumour
      formation at week 19. RESULTS: Rats on the n6 diet were found to have colonic
      aberrant crypt foci and adenocarcinomas more often than those consuming either
      the n9 or n3 diet. There were no differences between the rats on the n9 and n3
      diets. On the other hand, administration of both n9 and n3 diets was associated
      with a decrease in mucosal arachidonate concentrations as compared with the n6
      diet. Carcinogen treatment induced an appreciable increase in PGE(2) formation in
      rats fed the n6 diet, but not in those fed the n3 and n9 diets. CONCLUSIONS:
      Dietary olive oil prevented the development of aberrant crypt foci and colon
      carcinomas in rats, suggesting that olive oil may have chemopreventive activity
      against colon carcinogenesis. These effects may be partly due to modulation of
      arachidonic acid metabolism and local PGE(2) synthesis.

PMID- 10644313
TI  - Replication error phenotype, clinicopathological variables, and patient outcome
      in Dukes' B stage II (T3,N0,M0) colorectal cancer.
AB  - AIMS: To examine the relation between the replication error (RER) phenotype and
      other genetic events, clinical features, and long term survival in patients with
      Dukes' B stage II (T3,N0,M0) colorectal cancer. METHODS: RER phenotype was
      investigated in 159 patients by PCR amplification of microsatellite marker loci
      on chromosomes 5q, 17p, 17q, and 18q from tumour DNA extracted from archival
      tissue. Data on activating c-Ki-ras mutations were available from a previous
      study. Immunohistochemical detection of p53 and c-erbB-2 expression was performed
      on paraffin wax embedded tissue. RESULTS: Of 159 colorectal cancers studied, 22
      (14%) were RER+ while 137 (86%) were RER- for two or more loci. RER+ tumours were
      more commonly located in the right colon, tended to be larger than RER- tumours,
      and were more often poorly differentiated than RER- cancers. No significant
      associations were seen between RER status and the presence of a mutant c-Ki-ras
      gene, or between RER status and p53, c-erbB-2, or c-myc gene expression.
      Univariate survival analysis showed that outcome was similar in RER+ and RER-
      cases. Multivariate survival analysis showed that the relative risk of death for
      patients with RER+ cancers was 0.95 that of patients with RER- cancers.
      CONCLUSIONS: The results suggest that, while the RER phenotype may be associated
      with some differences in tumour pathology (site, size, differentiation), it is
      not associated with the genetic alterations studied or with significant
      differences in long term survival.

PMID- 10644314
TI  - Effects of fat and carbohydrate meals on colonic motor response.
AB  - BACKGROUND: Ingestion of a meal stimulates colonic motility. It is unclear
      whether the nutrient composition of a meal affects colonic motor response. AIMS:
      To investigate and compare the effects of a predominantly fat or carbohydrate
      meal on colonic motility. METHODS: In 18 healthy subjects, ambulatory colonic
      manometry was performed by placing a six sensor, solid state probe from the mid
      transverse colon to the rectum. In a randomised, crossover design, 10 and 27
      hours after probe placement, subjects received 4.18 MJ meals containing 60%
      calories from fat or carbohydrate sources. Preprandial and postprandial pressure
      activity and motor patterns were evaluated. RESULTS: Both meals induced phasic
      activity with a greater area under the curve (p<0.03) in the first postprandial
      hour, compared with the control period. Fat induced motor activity persisted
      longer (p<0.05) than that of the carbohydrate meal, but the onset of motor
      response was slower (p<0.001). Although both meals induced more (p<0.001)
      propagating pressure waves, only the fat meal induced more (p<0.05) simultaneous
      and retrograde waves. After both meals, 50% of subjects exhibited high amplitude
      (more than 103 mm Hg), prolonged duration (more than 13 seconds) propagating
      waves. Both meals induced greater activity (p<0.05) in the transverse/descending
      colon than in the rectosigmoid colon. CONCLUSIONS: Carbohydrate meals induce
      colonic motor response, but the effects are short lived when compared with fat
      meals. The prolonged, segmental, and retrograde phasic activity induced by the
      fat meal may delay colon transit. Thus meal composition influences colonic motor
      response.

PMID- 10644315
TI  - Laser Doppler flowmetry as a measure of extrinsic colonic innervation in
      functional bowel disease.
AB  - BACKGROUND: In functional disorders it is unknown whether disturbed function is
      due to an intrinsic gut abnormality or altered extrinsic innervation. AIMS: To
      study whether measurement of mucosal blood flow could be used as a quantitative
      direct measure of gut extrinsic nerve autonomic activity in patients with
      idiopathic constipation. METHODS: Seventy two patients with idiopathic
      constipation and 26 healthy volunteers had rectal mucosal blood flow measurements
      by a laser Doppler flowmetry probe applied 10 cm from the anus. Measurements were
      made at rest and after inhaled placebo and ipratropium 40 microg. RESULTS:
      Constipated subjects had lower baseline rectal blood flow than controls. Patients
      with slow transit had lower mucosal blood flow than normal transit. The number of
      retained markers on x-ray was inversely correlated with blood flow. Ipratropium
      reduced blood flow compared with placebo, reduced it less in constipated patients
      than controls, and reduced it less in patients with slow compared with normal
      transit. Constipated patients, not controls, showed a significantly attenuated RR
      interval (the interval between successive R waves on the ECG) variability, and
      blood flow correlated with vagal function. CONCLUSIONS: Laser Doppler mucosal
      flowmetry is a gut specific, quantitative measure of extrinsic autonomic nerve
      activity. The technique has shown that patients with idiopathic constipation have
      impaired extrinsic gut nerve activity, and this is more notable in those with
      slow transit. The degree of slow transit correlates with the degree of impaired
      extrinsic innervation.

PMID- 10644316
TI  - Mucin secretion is modulated by luminal factors in the isolated vascularly
      perfused rat colon.
AB  - BACKGROUND: Mucins play an important protective role in the colonic mucosa.
      Luminal factors modulating colonic mucus release have been not fully identified.
      AIM: To determine the effect of some dietary compounds on mucus discharge in rat
      colon. METHODS: An isolated vascularly perfused rat colon model was used. Mucus
      secretion was induced by a variety of luminal factors administered as a bolus of
      1 ml for 30 minutes in the colonic loop. Mucin release was evaluated using a
      sandwich enzyme linked immunosorbent assay supported by histological analysis.
      RESULTS: The three dietary fibres tested in this study (pectin, gum arabic, and
      cellulose) did not provoke mucus secretion. Luminal administration of sodium
      alginate (an algal polysaccharide used as a food additive) or ulvan (a sulphated
      algal polymer) induced a dose dependent increase in mucin discharge over the
      concentration range 1-25 mg/l (p<0.05 for 25 mg/l alginate and p<0.05 for 10 and
      25 mg/l ulvan). Glucuronic acid and galacturonic acid, which are major
      constituents of a variety of fibres, produced significant mucin secretion
      (p<0.05). Hydrogen sulphide and mercaptoacetate, two sulphides produced in the
      colonic lumen by microbial fermentation of sulphated polysaccharides, did not
      modify mucin secretion. Among the short chain fatty acids, acetate (5-100 mM)
      induced a dose dependent release of mucus (p<0.05 for 100 mM acetate).
      Interestingly, butyrate at a concentration of 5 mM produced colonic mucin
      secretion (p<0.05), but increasing its concentration to 100 mM provoked a gradual
      decrease in mucus discharge. Propionate (5-100 mM) did not induce mucin release.
      Several dietary phenolic compounds (quercetin, epicatechin, resveratrol) did not
      provoke mucus discharge. CONCLUSIONS: Two algal polysaccharides (alginate and
      ulvan), two uronic acids (glucuronic acid and galacturonic acid), and the short
      chain fatty acids acetate and butyrate induce mucin secretion in rat colon. Taken
      together, these data suggest that some food constituents and their fermentation
      products may regulate the secretory function of colonic goblet cells.

PMID- 10644317
TI  - Generation of reactive oxygen species by the faecal matrix.
AB  - BACKGROUND: Reactive oxygen species are implicated in the aetiology of a range of
      human diseases and there is increasing interest in their role in the development
      of cancer. AIM: To develop a suitable method for the detection of reactive oxygen
      species produced by the faecal matrix. METHODS: A refined high performance liquid
      chromatography system for the detection of reactive oxygen species is described.
      RESULTS: The method allows baseline separation of the products of hydroxyl
      radical attack on salicylic acid in the hypoxanthine/xanthine oxidase system,
      namely 2,5-dihydroxybenzoic acid, 2,3-dihydroxybenzoic acid, and catechol. The
      increased efficiency and precision of the method has allowed a detailed
      evaluation of the dynamics of reactive oxygen species generation in the faecal
      matrix. The data show that the faecal matrix is capable of generating reactive
      oxygen species in abundance. This ability cannot be attributed to the bacteria
      present, but rather to a soluble component within the matrix. As yet, the nature
      of this soluble factor is not entirely clear but is likely to be a reducing
      agent. CONCLUSIONS: The soluble nature of the promoting factor renders it
      amenable to absorption, and circumstances may exist in which either it comes into
      contact with either free or chelated iron in the colonocyte, leading to direct
      attack on cellular DNA, or else it initiates lipid peroxidation processes whereby
      membrane polyunsaturated fatty acids are attacked by reactive oxygen species
      propagating chain reactions leading to the generation of promutagenic lesions
      such as etheno based DNA adducts.

PMID- 10644319
TI  - A prospective audit against national standards of the presentation and management
      of acute pancreatitis in the South of England.
AB  - BACKGROUND: The incidence of acute pancreatitis shows regional variations in the
      UK. AIMS: To document the incidence and presentation of acute pancreatitis in
      hospitals in Wessex, and to audit the process and outcome of management of
      patients against the UK guidelines. METHODS: A prospective survey was carried out
      of all patients with acute pancreatitis in a one year period, in eight
      geographically adjacent acute hospitals in the Wessex region. RESULTS: 186
      patients with acute pancreatitis were identified, an incidence of 152 per million
      in the adult population. Aetiology was: gallstones 33%, alcohol 20%, idiopathic
      32%, other 15%. There were 60 severe cases with 17 deaths. Age and APACHE-II
      score had significant relations to outcome, but delay to admission, serum amylase
      level, aetiology, and sex did not. The mortality rate (9.1%) was within the audit
      standard of 10%. Some management goals were not met: in mild cases, only one
      third of patients with gallstone pancreatitis had definitive treatment within
      four weeks. In severe cases, there was poor use of objective severity
      stratification (19%), low admission rates to a high dependency unit or intensive
      care unit (67%), and only 33% of patients had computed tomography. Only seven of
      17 patients with severe gallstone pancreatitis had an urgent endoscopic
      retrograde cholangiopancreatography. CONCLUSIONS: The incidence of clinically
      diagnosed acute pancreatitis in England continues to rise. Current management of
      acute pancreatitis is suboptimal when compared with evidence based UK guidelines
      but the mortality rate was within the guideline standard.

PMID- 10644318
TI  - Role of procalcitonin and granulocyte colony stimulating factor in the early
      prediction of infected necrosis in severe acute pancreatitis.
AB  - BACKGROUND: Infected pancreatic necrosis (IPN) is the main cause of death in
      patients with severe acute pancreatitis. Therefore an early prediction of IPN is
      of utmost importance. AIM: Analysis of new blood variables as potential early
      predictors to differentiate between IPN and sterile pancreatic necrosis (SPN).
      PATIENTS: 64 consecutive patients with acute pancreatitis were enrolled in this
      prospective study; 29 were suffering from acute oedematous pancreatitis (AIP),
      and 35 from necrotising disease (NP) as diagnosed by contrast enhanced computed
      tomography. METHODS: Procalcitonin (PCT) and granulocyte colony stimulating
      factor (G-CSF) in the serum were examined and compared with C reactive protein
      (CRP). CRP was measured with a turbidimetric immunoassay (Autokit CRP; Wako,
      Osaka, Japan), and PCT and G-CSF by ELISA (Lumitest PCT; Brahms Diagnostica,
      Berlin, Germany; G-CSF-Elisa; R&D Systems, Abingdon, Oxon, UK). Monitoring was
      performed daily and related to the onset of symptoms. RESULTS: Within the first
      week, all three variables (CRP, PCT, and G-CSF) were significantly higher in
      patients with NP than in those with AIP (CRP, p<0.001; G-CSF, p<0. 001; PCT,
      p<0.001). During the course of the study, 12 of the 35 patients with NP developed
      late IPN after a median of 20.5 (range 3-49) days. Neither the peak nor the
      lowest concentrations during the monitoring period were of any value for
      predicting IPN (median peak values in SPN v IPN: PCT, 0.93 v 1.93 ng/ml; G-CSF,
      347 v 421 pg/ml; CRP, 270 v 325 mg/l). CONCLUSIONS: Serum PCT, G-CSF, and CRP
      concentrations are of similar value for early differentiation between mild and
      severe acute pancreatitis. However, these variables are not suitable for the
      early prediction of IPN.

PMID- 10644320
TI  - Value of endoscopic ultrasound guided fine needle aspiration biopsy in the
      diagnosis of solid pancreatic masses.
AB  - AIM: To assess the feasibility and diagnostic accuracy of endoscopic ultrasound
      guided fine needle biopsy (EUS-FNAB) in patients with solid pancreatic masses.
      METHODS: Ninety nine consecutive patients with pancreatic masses were studied.
      Histological findings obtained by EUS-FNAB were compared with the final diagnosis
      assessed by surgery, biopsy of other tumour site or at postmortem examination, or
      by using a combination of clinical course, imaging features, and tumour markers.
      RESULTS: EUS-FNAB was feasible in 90 patients (adenocarcinomas, n = 59;
      neuroendocrine tumours, n = 15; various neoplasms, n = 6; pancreatitis, n = 10),
      and analysable material was obtained in 73. Tumour size (>/= or < 25 mm in
      diameter) did not influence the ability to obtain informative biopsy samples.
      Diagnostic accuracy was 74.4% (adenocarcinomas, 81.4%; neuroendocrine tumours,
      46.7%; other lesions, 75%; p<0.02). Overall, the diagnostic yield in all 99
      patients was 68%. Successful biopsies were performed in six patients with portal
      hypertension. Minor complications (moderate bleeding or pain) occurred in 5% of
      cases. CONCLUSIONS: EUS-FNAB is a useful and safe method for the investigation of
      pancreatic masses, with a high feasibility rate even when lesions are small.
      Overall diagnostic accuracy of EUS-FNAB seems to depend on the tumour type.

PMID- 10644321
TI  - Endoscopic ultrasonography for differential diagnosis of polypoid gall bladder
      lesions: analysis in surgical and follow up series.
AB  - BACKGROUND: Differential diagnosis is often difficult for small (</=20 mm)
      polypoid lesions of the gall bladder. AIM: To assess the diagnostic accuracy of
      endoscopic ultrasonography (EUS) for polypoid lesions in a surgical and follow up
      series. METHODS: A total of 194 patients with small polypoid lesions underwent
      both ultrasonography and EUS. A tiny echogenic spot or an aggregation of
      echogenic spots and multiple microcysts or a comet tail artefact indicated
      cholesterol polyp and adenomyomatosis respectively. Other lesions were diagnosed
      as neoplastic (adenoma or adenocarcinoma). In the 58 patients who underwent
      surgery, the histological diagnoses were cholesterol polyp (n = 36),
      adenomyomatosis (n = 7), adenoma (n = 4), and adenocarcinoma (n = 11). Of the
      remaining 136 patients with an EUS diagnosis of non-neoplastic lesions, 125 were
      followed up with ultrasonography alone or with EUS for 1-8.7 years (mean 2.6
      years). RESULTS: In the surgical series, EUS (97%) differentiated polypoid
      lesions more precisely than ultrasonography (76%). During follow up, the lesions
      remained unchanged in size in 109 (87%) of the 125 patients with non-neoplastic
      lesions diagnosed by EUS. No neoplastic lesions developed in these patients.
      Ultrasonography had shown lesions to be neoplastic in 13% of the follow up
      series. CONCLUSIONS: EUS is highly accurate for differentially diagnosing
      polypoid gall bladder lesions. It is recommended when ultrasonography cannot rule
      out neoplastic lesions. Non-neoplastic lesions diagnosed by EUS may be followed
      and observed with ultrasonography.

PMID- 10644322
TI  - Liver infiltrating T lymphocytes express interferon gamma and inducible nitric
      oxide synthase in chronic hepatitis C virus infection.
AB  - BACKGROUND: Pathogenesis of hepatitis C virus (HCV) associated liver injury is
      thought to be due to the host antiviral immune response. Using a quantitative,
      competitive RT-PCR technique, we recently showed that expression of interferon
      gamma (IFN-gamma) and IFN-gamma inducible type of nitric oxide synthase (iNOS) is
      increased in homogenised liver tissue of patients with chronic HCV infection.
      AIMS: To determine the cellular origin of IFN-gamma and iNOS expression and to
      examine the hypothesis that T cell derived IFN-gamma secretion induces iNOS in
      hepatocytes in chronic HCV infection. METHODS: By applying a non-radioactive in
      situ hybridisation method combined with indirect immunofluorescence, 33 liver
      biopsy specimens from patients with chronic HCV infection were studied for
      cellular expression of IFN-gamma and iNOS mRNA. RESULTS: In chronic HCV
      infection, both IFN-gamma and iNOS gene expression were significantly increased.
      IFN-gamma and iNOS mRNA were observed in CD3+ lymphocytes infiltrating portal
      tracts and hepatic lobules, but not in hepatocytes. CONCLUSIONS: Results are
      consistent with previous reports that IFN-gamma and iNOS transcripts are elevated
      in chronic HCV infection. In contrast to the hypothesis, IFN-gamma expressing T
      cells do not induce iNOS in hepatocytes, but probably in T cells. T lymphocytes
      expressing IFN-gamma and/or iNOS have the potential to participate in autocrine
      and paracrine pathways that may contribute to the pathobiology of chronic
      hepatitis C.

PMID- 10644323
TI  - Increases in intrahepatic CD68 positive cells, MAC387 positive cells, and
      proinflammatory cytokines (particularly interleukin 18) in chronic hepatitis C
      infection.
AB  - BACKGROUND: Upregulation of Th1 associated intrahepatic cytokines in chronic
      hepatitis C virus (HCV) infection should lead to a significant non-specific
      cellular immune response, a prerequisite for viral clearance. However, to date,
      the role of this non-specific response in HCV has been understudied. AIMS: To
      analyse the intrahepatic macrophage activity in chronic HCV infection by
      immunostaining and by quantitation of cytokine mRNA. METHODS: HCV positive liver
      tissues (chronic hepatitis, n=10; cirrhosis, n=5) were immunostained for CD68,
      MAC387, and semiquantitated by polymerase chain reaction for intrahepatic
      cytokine mRNAs (interferon gamma (IFNgamma), interleukin 1beta (IL-1beta), IL-6,
      IL-18, tumour necrosis factor alpha (TNFalpha), and macrophage inflammatory
      protein 1beta (MIP1beta)). HCV negative normal liver tissues (for cytokines, n=6;
      for immunostaining, n=5) were included as controls. RESULTS: MAC387(+) cells were
      focally increased in areas of erosion at the limiting plate while lobular
      staining was minimal. CD68(+) staining was diffuse in both portal (increased in
      HCV) and lobular areas. The portal tract (mean) density of CD68(+) and MAC387(+)
      cells was significantly increased in patients with HCV compared with normal
      tissue. IFNgamma and IL-18 mRNA levels were highly correlated and significantly
      upregulated in chronic hepatitis and cirrhotic tissue versus controls. TNFalpha
      mRNA was upregulated in chronic hepatitis without cirrhosis, while IL-6 mRNA was
      significantly downregulated. IL-1beta, IL-6, and MIP1beta mRNA levels were
      significantly correlated with portal tract MAC387(+) cell density. CONCLUSIONS:
      The significant upregulation of IFNgamma and IL-18 mRNA and significant
      correlations between IFNgamma and other proinflammatory cytokines, suggest a
      Th1/cell mediated intrahepatic immune response in chronic HCV infection. However,
      further clarification of the cellular sources of these cytokines is required.

PMID- 10644324
TI  - Localisation of divalent metal transporter 1 (DMT1) to the microvillus membrane
      of rat duodenal enterocytes in iron deficiency, but to hepatocytes in iron
      overload.
AB  - BACKGROUND: The mechanism of iron absorption by the intestine and its transfer to
      the main iron storage site, the liver, is poorly understood. Recently an iron
      carrier was cloned and named DMT1 (divalent metal transporter 1). AIMS: To
      determine the level of DMT1 gene expression and protein distribution in duodenum
      and liver. METHODS: A DMT1 cRNA and antibody were produced and used in in situ
      hybridisation and immunohistochemistry, respectively, in rats in which the iron
      stores were altered by feeding diets with normal, low, and high iron content.
      RESULTS: Duodenal DMT1 mRNA was low in crypts and increased at the crypt-villus
      junction in iron deficient and control rats; it fell in the iron loaded state.
      Staining for DMT1 protein was not detected in crypts. In villus enterocytes,
      protein staining was localised to the microvillus membrane in iron deficiency, in
      the cytoplasm and to a lesser extent in the membrane in controls, and entirely in
      the cytoplasm of iron loaded animals. Liver DMT1 mRNA was distributed evenly
      across hepatocytes. DMT1 protein staining was observed on hepatocyte plasma
      membranes, with highest values in the iron loaded state, lower values in control
      animals, and none after iron depletion. CONCLUSIONS: Results are consistent with
      a role for DMT1 in the transmembrane transport of non-transferrin bound iron from
      the intestinal lumen and from the portal blood.

PMID- 10644325
TI  - Liver iron is predictive of death in alcoholic cirrhosis: a multivariate study of
      229 consecutive patients with alcoholic and/or hepatitis C virus cirrhosis: a
      prospective follow up study.
AB  - BACKGROUND/AIMS: A study was undertaken of liver biopsy samples from 229
      consecutive patients with alcoholic or hepatitis C virus related cirrhosis who
      were prospectively followed until January 1996 to evaluate the influence of liver
      iron content on survival and the occurrence of hepatocellular carcinoma. METHODS:
      Hepatic iron content was measured with a validated semiquantitative score, and
      its predictive value for survival and the occurrence of hepatocellular carcinoma
      was assessed. RESULTS: 130 patients had detectable iron at enrollment. During
      follow up (57 (28) months), 95 patients died and 39 patients developed
      hepatocellular carcinoma. No significant relation was found between hepatic iron
      and the occurrence of hepatocellular carcinoma. Conversely, the presence of iron
      was predictive of death in alcoholic patients (p = 0.007) by the log rank test
      but not in patients with hepatitis C virus related (p = 0.71) or mixed (p = 0.98)
      cirrhosis. The predictive value of hepatic iron content in patients with
      alcoholic cirrhosis was confirmed by the Cox model using either a binary coding
      (p = 0.009; relative risk = 2.27; 95% confidence interval 1.2 to 4.19) or the
      continuous values (p = 0.002). CONCLUSIONS: These results suggest that hepatic
      iron enhances liver lesions caused by alcohol but not those caused by hepatitis C
      virus.

PMID- 10644326
TI  - Fibrosing colonopathy in an adult owing to over use of pancreatic enzyme
      supplements.
AB  - A woman, then in her late 20s, underwent a cholecystectomy in 1962 for gallstone
      disease and subsequent common bile duct stones were managed endoscopically.
      However, because of unrelenting pain, a pylorus preserving
      pancreaticoduodenectomy was done in 1990 and in the following years the patient
      took large amounts of pancreatic enzyme supplements. She developed large bowel
      obstruction in 1997 and a right hemicolectomy was undertaken. Histology confirmed
      fibrosing colonopathy of the ascending colon and caecum. Her pancreatic enzyme
      dose was reduced and her subsequent course has been uncomplicated.

PMID- 10644327
TI  - Peptide gene expression in gastrointestinal mucosal ulceration: ordered sequence
      or redundancy?

PMID- 10644328
TI  - Signaling activities of gammaherpesvirus membrane proteins.

PMID- 10644329
TI  - The human cytomegalovirus major immediate-early distal enhancer region is
      required for efficient viral replication and immediate-early gene expression.
AB  - The human cytomegalovirus (HCMV) major immediate-early (MIE) genes, encoding IE1
      p72 and IE2 p86, are activated by a complex enhancer region (base positions -65
      to -550) that operates in a cell type- and differentiation-dependent manner. The
      expression of MIE genes is required for HCMV replication. Previous studies
      analyzing functions of MIE promoter-enhancer segments suggest that the distal
      enhancer region variably modifies MIE promoter activity, depending on cell type,
      stimuli, or state of differentiation. To further understand the mechanism by
      which the MIE promoter is regulated, we constructed and analyzed several
      different recombinant HCMVs that lack the distal enhancer region (-300 to -582, 
      640, or -1108). In human fibroblasts, the HCMVs without the distal enhancer
      replicate normally at high multiplicity of infection (MOI) but replicate poorly
      at low MOI in comparison to wild-type virus (WT) or HCMVs that lack the
      neighboring upstream unique region and modulator (-582 or -640 to -1108). The
      growth aberrancy was normalized after restoring the distal enhancer in a virus
      lacking this region. For HCMVs without a distal enhancer, the impairment in
      replication at low MOI corresponds to a deficiency in production of MIE RNAs
      compared to WT or virus lacking the unique region and modulator. An
      underproduction of viral US3 RNA was also evident at low MOI. Whether lower
      production of IE1 p72 and IE2 p86 causes a reduction in expression of the
      immediate-early (IE) class US3 gene remains to be determined. We conclude that
      the MIE distal enhancer region possesses a mechanism for augmenting viral IE gene
      expression and genome replication at low MOI, but this regulatory function is
      unnecessary at high MOI.

PMID- 10644330
TI  - Respiratory syncytial virus infection and G and/or SH protein expression
      contribute to substance P, which mediates inflammation and enhanced pulmonary
      disease in BALB/c mice.
AB  - A distinct clinical presentation of respiratory syncytial virus (RSV) infection
      of humans is bronchiolitis, which has clinical features similar to those of
      asthma. Substance P (SP), a tachykinin neuropeptide, has been associated with
      neurogenic inflammation and asthma; therefore, we chose to examine SP-induced
      inflammation with RSV infection. In this study, we examined the production of
      pulmonary SP associated with RSV infection of BALB/c mice and the effect of anti
      SP F(ab)(2) antibodies on the pulmonary inflammatory response. The peak
      production of pulmonary SP occurred between days 3 and 5 following primary RSV
      infection and day 1 after secondary infection. Treatment of RSV-infected mice
      with anti-SP F(ab)(2) antibodies suggested that SP may alter the natural killer
      cell response to primary and secondary infection. In mice challenged after
      formalin-inactivated RSV vaccination, SP appears to markedly enhance pulmonary
      eosinophilia as well as increase polymorphonuclear cell trafficking to the lung.
      Based on studies with a strain of RSV that lacks the G and SH genes, the SP
      response to RSV infection appears to be associated with G and/or SH protein
      expression. These data suggest that SP may be an important contributor to the
      inflammatory response to RSV infection and that anti-SP F(ab)(2) antibodies might
      be used to ameliorate RSV-associated disease.

PMID- 10644331
TI  - Biochemical consequences of a mutation that controls the cholesterol dependence
      of Semliki Forest virus fusion.
AB  - The enveloped alphavirus Semliki Forest virus (SFV) infects cells via a low-pH
      triggered membrane fusion reaction that requires cholesterol and sphingolipid in
      the target membrane. Cholesterol-depleted insect cells are highly resistant to
      alphavirus infection and were used to select srf-3, an SFV mutant that is
      approximately 100-fold less cholesterol dependent for infection due to a single
      amino acid change in the E1 spike subunit, proline 226 to serine. Sensitive lipid
      mixing assays here demonstrated that the in vitro fusion of srf-3 and wild-type
      (wt) virus with cholesterol-containing liposomes had comparable kinetics,
      activation energies, and sphingolipid dependence. In contrast, srf-3 fusion with
      sterol-free liposomes was significantly more efficient than that of wt virus.
      Thus, the srf-3 mutation does not affect its general fusion properties with
      purified lipid bilayers but causes a marked and specific reduction in cholesterol
      dependence. Upon exposure to low pH, the E1 spike subunit undergoes distinct
      conformational changes, resulting in the exposure of an acid conformation
      specific epitope and formation of an E1 homotrimer. These conformational changes
      were strongly cholesterol and sphingolipid dependent for wt SFV and strikingly
      less cholesterol dependent for srf-3. Our results thus demonstrate the functional
      importance of fusogenic E1 conformational changes in the control of SFV
      cholesterol dependence.

PMID- 10644332
TI  - The human immunodeficiency virus type 1 Tat protein up-regulates the promoter
      activity of the beta-chemokine monocyte chemoattractant protein 1 in the human
      astrocytoma cell line U-87 MG: role of SP-1, AP-1, and NF-kappaB consensus sites.
AB  - It has been shown that the human immunodeficiency virus type 1 (HIV-1) Tat
      protein can specifically enhance expression and release of monocyte
      chemoattractant protein 1 (MCP-1) from human astrocytes. In this study, we show
      evidence that Tat-induced MCP-1 expression is mediated at the transcriptional
      level. Transient transfection of an expression construct encoding the full-length
      Tat into the human glioblastoma-astrocytoma cell line U-87 MG enhances reporter
      gene activity from cotransfected deletion constructs of the MCP-1 promoter. HIV-1
      Tat exerts its effect through a minimal construct containing 213 nucleotides
      upstream of the translational start site. Site-directed mutagenesis studies
      indicate that an SP1 site (located between nucleotides -123 and -115) is critical
      for both constitutive and Tat-enhanced expression of the human MCP-1 promoter, as
      mutation of this SP1 site significantly diminished reporter gene expression in
      both instances. Gel retardation experiments further demonstrate that Tat strongly
      enhances the binding of SP1 protein to its DNA element on the MCP-1 promoter.
      Moreover, we also observe an increase in the binding activities of
      transcriptional factors AP1 and NF-kappaB to the MCP-1 promoter following Tat
      treatment. Mutagenesis studies show that an upstream AP1 site and an adjacent NF
      kappaB site (located at -128 to -122 and -150 to -137, respectively) play a role
      in Tat-mediated transactivation. In contrast, a further upstream AP1 site (-156
      to -150) does not appear to be crucial for promoter activity. We postulate that a
      Tat-mediated increase in SP1 binding activities augments the binding of AP1 and
      NF-kappaB, leading to synergistic activation of the MCP-1 promoter.

PMID- 10644333
TI  - Cell recognition by foot-and-mouth disease virus that lacks the RGD integrin
      binding motif: flexibility in aphthovirus receptor usage.
AB  - Cell surface molecules that can act as virus receptors may exert an important
      selective pressure on RNA viral quasispecies. Large population passages of foot
      and-mouth disease virus (FMDV) in cell culture select for mutant viruses that
      render dispensable a highly conserved Arg-Gly-Asp (RGD) motif responsible for
      integrin receptor recognition. Here, we provide evidence that viability of
      recombinant FMDVs including a Asp-143-->Gly change at the RGD motif was
      conditioned by a number of capsid substitutions selected upon FMDV evolution in
      cell culture. Multiply passaged FMDVs acquired the ability to infect human K-562
      cells, which do not express integrin alpha(v)beta(3). In contrast to previously
      described cell culture-adapted FMDVs, the RGD-independent infection did not
      require binding to the surface glycosaminoglycan heparan sulfate (HS). Viruses
      which do not bind HS and lack the RGD integrin-binding motif replicate
      efficiently in BHK-21 cells. Interestingly, FMDV mutants selected from the
      quasispecies for the inability to bind heparin regained sensitivity to inhibition
      by a synthetic peptide that represents the G-H loop of VP1. Thus, a single amino
      acid replacement leading to loss of HS recognition can shift preferential
      receptor usage of FMDV from HS to integrin. These results indicate at least three
      different mechanisms for cell recognition by FMDV and suggest a potential for
      this virus to use multiple, alternative receptors for entry even into the same
      cell type.

PMID- 10644334
TI  - Cytokine expression, natural killer cell activation, and phenotypic changes in
      lymphoid cells from rhesus macaques during acute infection with pathogenic simian
      immunodeficiency virus.
AB  - We studied the innate and adaptive immune system of rhesus macaques infected with
      the virulent simian immunodeficiency virus isolate SIVmac251 by evaluating
      natural killer (NK) cell activity, cytokine levels in plasma, humoral and
      virological parameters, and changes in the activation markers CD25 (interleukin
      2R ?IL-2R alpha chain), CD69 (early activation marker), and CD154 (CD40 ligand)
      in lymphoid cells. We found that infection with SIVmac251 induced the sequential
      production of interferon-alpha/beta (IFN-alpha/beta), IL-18, and IL-12. IFN
      gamma, IL-4, and granulocyte-macrophage colony-stimulating factor were undetected
      in plasma by the assays used. NK cell activity peaked at 1 to 2 weeks
      postinfection and paralleled changes in viral loads. Maximum expression of CD69
      on CD3(-)CD16(+) lymphocytes correlated with NK cytotoxicity during this period.
      CD25 expression, which is associated with proliferation, was static or slightly
      down-regulated in CD4(+) T cells from both peripheral blood (PB) and lymph nodes
      (LN). CD69, which is normally present in LN CD4(+) T cells and absent in
      peripheral blood leukocyte (PBL) CD4(+) T cells, was down-regulated in LN CD4(+)
      T cells and up-regulated in PBL CD4(+) T cells immediately after infection.
      CD8(+) T cells increased CD69 but not CD25 expression, indicating the activation
      of this cellular subset in PB and LN. Finally, CD154 was transiently up-regulated
      in PBL CD4(+) T cells but not in LN CD4(+) T cells. Levels of antibodies to SIV
      Gag and Env did not correlate with the level of activation of CD154, a critical
      costimulatory molecule for T-cell-dependent immunity. In summary, we present the
      first documented evidence that the innate immune system of rhesus macaques
      recognizes SIV infection by sequential production of proinflammatory cytokines
      and transient activation of NK cytotoxic activity. Additionally, pathogenic SIV
      induces drastic changes in the level of activation markers on T cells from
      different anatomic compartments. These changes involve activation in the absence
      of proliferation, indicating that activation-induced cell death may cause some of
      the reported increase in lymphocyte turnover during SIV infection.

PMID- 10644335
TI  - Mechanism of assembly of recombinant murine polyomavirus-like particles.
AB  - VP1 is the major viral coat protein of murine polyomavirus and can be used for
      the generation of virus-like particles in vitro. Here, we demonstrate that capsid
      assembly is an equilibrium reaction followed by oxidation of intracapsomere
      disulfide bonds, which are not essential for the formation of virus-like
      particles but enable complete particle assembly and prevent capsid disassembly.

PMID- 10644336
TI  - Isolation of herpes simplex virus procapsids from cells infected with a protease
      deficient mutant virus.
AB  - Herpes simplex virus type 1 (HSV-1) capsid proteins assemble in vitro into
      spherical procapsids that differ markedly in structure and stability from mature
      polyhedral capsids but can be converted to the mature form. Circumstantial
      evidence suggests that assembly in vivo follows a similar pathway of procapsid
      assembly and maturation, a pathway that resembles those of double-stranded DNA
      bacteriophages. We have confirmed the above pathway by isolating procapsids from
      HSV-1-infected cells and characterizing their morphology, thermal sensitivity,
      and protein composition. Experiments were carried out with an HSV-1 mutant (m100)
      deficient in the maturational protease for which it was expected that procapsids
      normally, short-lived intermediates-would accumulate in infected cells. Particles
      isolated from m100-infected cells were found to share the defining properties of
      procapsids assembled in vitro. For example, by electron microscopy, they were
      found to be spherical rather than polyhedral in shape, and they disassembled at 0
      degrees C, unlike mature capsids, which are stable at this temperature. A three
      dimensional reconstruction computed at 18-A resolution from cryoelectron
      micrographs showed m100 procapsids to be structurally indistinguishable from
      procapsids assembled in vitro. In both cases, their predominant components are
      the four essential capsid proteins: the major capsid protein (VP5), the
      scaffolding protein (pre-VP22a), and the triplex proteins (VP19C and VP23). VP26,
      a small, abundant but dispensable capsid protein, was not found associated with
      m100 procapsids, suggesting that it binds to capsids only after they have matured
      into the polyhedral form. Procapsids were also isolated from cells infected at
      the nonpermissive temperature with the HSV-1 mutant tsProt.A (a mutant with a
      thermoreversible lesion in the protease), and their identity as procapsids was
      confirmed by cryoelectron microscopy. This analysis revealed density on the inner
      surface of the procapsid scaffolding core that may correspond to the location of
      the maturational protease. Upon incubation at the permissive temperature,
      tsProt.A procapsids transformed into polyhedral, mature capsids, providing
      further confirmation of their status as precursors.

PMID- 10644337
TI  - Identification of a novel cleavage activity of the first papain-like proteinase
      domain encoded by open reading frame 1a of the coronavirus Avian infectious
      bronchitis virus and characterization of the cleavage products.
AB  - The coronavirus Avian infectious bronchitis virus (IBV) employs polyprotein
      processing as a strategy to express its gene products. Previously we identified
      the first cleavage event as proteolysis at the Gly(673)-Gly(674) dipeptide bond
      mediated by the first papain-like proteinase domain (PLPD-1) to release an 87-kDa
      mature protein. In this report, we demonstrate a novel cleavage activity of PLPD
      1. Expression, deletion, and mutagenesis studies showed that the product encoded
      between nucleotides 2548 and 8865 was further cleaved by PLPD-1 at the Gly(2265)
      Gly(2266) dipeptide bond to release an N-terminal 195-kDa and a C-terminal 41-kDa
      cleavage product. Characterization of the cleavage activity revealed that the
      proteinase is active on this scissile bond when expressed in vitro in rabbit
      reticulocyte lysates and can act on the same substrate in trans when expressed in
      intact cells. Both the N- and C-terminal cleavage products were detected in virus
      infected cells and were found to be physically associated. Glycosidase digestion
      and site-directed mutagenesis studies of the 41-kDa protein demonstrated that it
      is modified by N-linked glycosylation at the Asn(2313) residue encoded by
      nucleotides 7465 to 7467. By using a region-specific antiserum raised against the
      IBV sequence encoded by nucleotides 8865 to 9786, we also demonstrated that a 33
      kDa protein, representing the 3C-like proteinase (3CLP), was specifically
      immunoprecipitated from the virus-infected cells. Site-directed mutagenesis and
      expression studies showed that a previously predicted cleavage site (Q(2583)
      G(2584)) located within the 41-kDa protein-encoding region was not utilized by
      3CLP, supporting the conclusion that the 41-kDa protein is a mature viral
      product.

PMID- 10644338
TI  - The central proline of an internal viral fusion peptide serves two important
      roles.
AB  - The fusion peptide of the avian sarcoma/leukosis virus (ASLV) envelope protein
      (Env) is internal, near the N terminus of its transmembrane (TM) subunit. As for
      most internal viral fusion peptides, there is a proline near the center of this
      sequence. Robson-Garnier structure predictions of the ASLV fusion peptide and
      immediate surrounding sequences indicate a region of order (beta-sheet), a tight
      reverse turn containing the proline, and a second region of order (alpha-helix).
      Similar motifs (order, turn or loop, order) are predicted for other internal
      fusion peptides. In this study, we made and analyzed 12 Env proteins with
      substitutions for the central proline of the fusion peptide. Env proteins were
      expressed in 293T cells and in murine leukemia virus pseudotyped virions. We
      found the following. (i) All mutant Envs form trimers, but when the bulky
      hydrophobic residues phenylalanine or leucine are substituted for proline,
      trimerization is weakened. (ii) Surprisingly, the proline is required for maximal
      processing of the Env precursor into its surface and TM subunits; the amount of
      processing correlates linearly with the propensity of the substituted residue to
      be found in a reverse turn. (iii) Nonetheless, proteolytically processed forms of
      all Envs are preferentially incorporated into pseudotyped virions. (iv) All Envs
      bind receptor with affinity greater than or equal to wild-type affinity. (v)
      Residues that support high infectivity cluster with proline at intermediate
      hydrophobicity. Infectivity is not supported by mutant Envs in which charged
      residues are substituted for proline, nor is it supported by the trimerization
      defective phenylalanine and leucine mutants. Our findings suggest that the
      central proline in the ASLV fusion peptide is important for the formation of the
      native (metastable) Env structure as well as for membrane interactions that lead
      to fusion.

PMID- 10644339
TI  - Multiepitopic B- and T-cell responses induced in humans by a human
      immunodeficiency virus type 1 lipopeptide vaccine.
AB  - We have attempted to develop an anti-human immunodeficiency virus (HIV)
      lipopeptide vaccine with several HIV-specific long peptides modified by C
      terminal addition of a single palmitoyl chain. A mixture of six lipopeptides
      derived from regulatory or structural HIV-1 proteins (Nef, Gag, and Env) was
      prepared. A phase I study was conducted to evaluate immunogenicity and tolerance
      in lipopeptide vaccination of HIV-1-seronegative volunteers given three
      injections of either 100, 250, or 500 microg of each lipopeptide, with or without
      immunoadjuvant (QS21). This report analyzes in detail B- and T-cell responses
      induced by vaccination. The lipopeptide vaccine elicited strong and multiepitopic
      B- and T-cell responses. Vaccinated subjects produced specific immunoglobulin G
      antibodies that recognized the Nef and Gag proteins. After the third injection,
      helper CD4(+)-T-cell responses as well as specific cytotoxic CD8(+) T cells were
      also obtained. These CD8(+) T cells were able to recognize naturally processed
      viral proteins. Finally, specific gamma interferon-secreting CD8(+) T cells were
      also detected ex vivo.

PMID- 10644340
TI  - Antiretroviral therapy during primary immunodeficiency virus infection can induce
      persistent suppression of virus load and protection from heterologous challenge
      in rhesus macaques.
AB  - A limited period of chemotherapy during primary immunodeficiency virus infection
      might provide a long-term clinical benefit even if treatment is initiated at a
      time point when virus is already detectable in plasma. To evaluate this strategy,
      we infected rhesus macaques with the pathogenic simian/human immunodeficiency
      virus RT-SHIV and treated them with the antiretroviral drug (R)-9-(2
      phosphonylmethoxypropyl)adenine (PMPA) for 8 weeks starting 7 or 14 days
      postinfection. PMPA treatment suppressed viral replication efficiently in all of
      the monkeys. After chemotherapy ended, virus replication rebounded and viral RNA
      in plasma reached levels comparable to that of the controls in four of the six
      monkeys. However, in the other two animals, virus loads peaked only moderately
      after withdrawal of the drug and then declined to low or even undetectable
      levels. These low levels of viremia remained stable for at least 31 weeks after
      cessation of therapy. At this time point, these two monkeys were challenged with
      SIV(8980) to evaluate whether the host responses which were able to keep RT-SHIV
      replication under control were also sufficient to protect against infection with
      a highly pathogenic heterologous virus. Both monkeys proved to be protected
      against the heterologous virus. In one of the two animals, low levels of
      SIV(8980) replication were detected. Thus, by chemotherapy during the acute phase
      of pathogenic virus replication, we could achieve not only persistent virus load
      suppression in two out of six monkeys but also protection from subsequent
      heterologous challenge. By this chemotherapeutic attenuation, the replication
      kinetics of attenuated viruses could be mimicked and a vaccination effect similar
      to that induced by live attenuated simian immunodeficiency virus vaccines was
      achieved.

PMID- 10644341
TI  - Diminished human immunodeficiency virus type 1 reverse transcription and nuclear
      transport in primary macrophages arrested in early G(1) phase of the cell cycle.
AB  - Previously, we and others have demonstrated that the process of reverse
      transcription of human immunodeficiency virus type 1 (HIV-1) is disturbed in
      nondividing macrophages and quiescent T lymphocytes. Here we analyzed which phase
      of the cell cycle in macrophages is crucial for early steps in the HIV-1
      replication cycle. HIV-1 Ba-L-inoculated macrophages arrested early in the G(1)
      phase by n-butyrate contained incomplete products of reverse transcription. In
      gamma-irradiated macrophages, reverse transcription was successfully completed
      but proviral integration could not be detected. In these cells, nuclear import
      was disturbed as reflected by the absence of two-long-terminal-repeat circles. In
      macrophages arrested late in G(1) phase by aphidicolin or 5, 6-dichloro-1-beta-D
      ribofuranosyl-benzimidazole (DRB), reverse transcription was unaffected. Proviral
      integration occurred efficiently in DRB-treated macrophages, whereas integrated
      proviral DNA could not be detected after aphidicolin treatment. Arrest at G(2)
      phase of the cell cycle by nocodazole did not affect reverse transcription or
      proviral integration. Treatment of macrophages with hydroxyurea (HU), which
      reduces the intracellular deoxynucleoside triphosphate (dNTP) pool by blocking
      the de novo synthesis of dNTP, resulted in a dose-dependent inhibition of HIV-1
      reverse transcription. This could partially be restored by the addition of
      nucleoside precursors. Addition of nucleoside precursors enhanced both reverse
      transcription and cell proliferation. However, the disturbed reverse
      transcription observed in the nonproliferating and n-butyrate-treated macrophages
      could not be restored by addition of nucleoside precursors. Similar to
      observations in quiescent T lymphocytes, incomplete proviral DNA species were
      arrested in the cytoplasm of the macrophages. Our results indicate that also in
      primary macrophages the intracellular nucleotide pools and other cellular factors
      that coincide with late G(1) phase of the cell cycle may contribute to efficient
      reverse transcription and nuclear localization.

PMID- 10644342
TI  - Multiple integrations of human foamy virus in persistently infected human
      erythroleukemia cells.
AB  - Foamy viruses are complex retroviruses whose replication strategy resembles that
      of conventional retroviruses. However, foamy virus replication also resembles
      that of hepadnaviruses in many respects. Because hepadnaviruses replicate in an
      integrase-independent manner, we were interested in investigating the
      characteristics of human foamy virus (HFV) integration. We have shown that HFV
      requires a functional integrase protein for infectivity. Our analyses have
      revealed that in single-cell clones derived from HFV-infected erythroleukemia
      derived cells (H92), there were up to 20 proviral copies per host cell genome as
      determined by Southern blot and fluorescent in situ hybridization analysis. Use
      of specific probes has also shown that a majority of the proviruses contain the
      complete tas gene, which encodes the viral transactivator, and are not derived
      from Deltatas cDNAs, which have been shown to arise rapidly in infected cells. To
      demonstrate that the multiple proviral sequences are due to integration instead
      of recombination, we have sequenced the junctions between the proviral sequences
      and the host genome and found that the proviruses have authentic long terminal
      repeat ends and that each integration is at a different chromosomal site. A virus
      lacking the Gag nuclear localization signal accumulates fewer proviruses,
      suggesting that nuclear translocation is important for high proviral load. Since
      persistently infected H92 clones are not resistant to superinfection, the
      relative importance of an intracellular versus extracellular mechanism in
      proviral acquisition has yet to be determined.

PMID- 10644343
TI  - Activated Notch1 modulates gene expression in B cells similarly to Epstein-Barr
      viral nuclear antigen 2.
AB  - Both Epstein-Barr viral nuclear antigen 2 (EBNA2) and activated Notch
      transactivate genes by interacting with the transcription factor RBP-Jkappa. The
      viral protein EBNA2 may hence be regarded as a functional equivalent of an
      activated Notch receptor. Until now, nothing has been known about the
      physiological role of Notch signaling in B cells. Here we investigated whether
      activated Notch can induce the same phenotypic changes as EBNA2 in Burkitt's
      lymphoma cells. An estrogen receptor fusion protein of the intracellular part of
      mouse Notch 1 (mNotch1-IC), mimicking in the presence of estrogen a
      constitutively active Notch receptor, was stably transfected into the Burkitt's
      lymphoma cell lines BL41-P3HR1 and HH514. Northern blot analysis revealed that
      the LMP2A gene is induced by Notch-IC in the presence of estrogen, whereas
      increased expression of LMP1 could be detected only if cycloheximide was
      simultaneously added. Concerning the cellular genes regulated by EBNA2, Notch-IC
      was able to upregulate CD21 but not CD23 expression. Immunoglobulin mu (Igmu)
      expression, which is downregulated by EBNA2, was also negatively regulated by
      Notch-IC. Similarly to EBNA2, Notch-IC was able to repress c-myc expression,
      which is under the control of the immunoglobulin heavy-chain locus in Burkitt's
      lymphoma cells with a t(8;14) translocation. The data show that Notch-IC is able
      to participate in gene regulation in B cells.

PMID- 10644344
TI  - Hepatitis C virus core protein interacts with 14-3-3 protein and activates the
      kinase Raf-1.
AB  - Persistent hepatitis C virus (HCV) infection is a major cause of chronic liver
      dysfunction in humans and is epidemiologically closely associated with the
      development of human hepatocellular carcinoma. Among HCV components, core protein
      has been reported to be implicated in cell growth regulation both in vitro and in
      vivo, although mechanisms explaining those effects are still unclear. In the
      present study, we identified that members of the 14-3-3 protein family associate
      with HCV core protein. 14-3-3 protein bound to HCV core protein in a
      phosphoserine-dependent manner. Introduction of HCV core protein caused a
      substantial increase in Raf-1 kinase activity in HepG2 cells and in a yeast
      genetic assay. Furthermore, the HCV core-14-3-3 interaction was essential for Raf
      1 kinase activation by HCV core protein. These results suggest that HCV core
      protein may represent a novel type of Raf-1 kinase-activating protein through its
      interaction with 14-3-3 protein and may contribute to hepatocyte growth
      regulation.

PMID- 10644345
TI  - Chimeric yellow fever virus 17D-Japanese encephalitis virus vaccine: dose
      response effectiveness and extended safety testing in rhesus monkeys.
AB  - ChimeriVax-JE is a live, attenuated recombinant virus prepared by replacing the
      genes encoding two structural proteins (prM and E) of yellow fever 17D virus with
      the corresponding genes of an attenuated strain of Japanese encephalitis virus
      (JE), SA14-14-2 (T. J. Chambers et al., J. Virol. 73:3095-3101, 1999). Since the
      prM and E proteins contain antigens conferring protective humoral and cellular
      immunity, the immune response to vaccination is directed principally at JE. The
      prM-E genome sequence of the ChimeriVax-JE in diploid fetal rhesus lung cells
      (FRhL, a substrate acceptable for human vaccines) was identical to that of JE
      SA14-14-2 vaccine and differed from sequences of virulent wild-type strains (SA14
      and Nakayama) at six amino acid residues in the envelope gene (E107, E138, E176,
      E279, E315, and E439). ChimeriVax-JE was fully attenuated for weaned mice
      inoculated by the intracerebral (i.c.) route, whereas commercial yellow fever 17D
      vaccine (YF-Vax) caused lethal encephalitis with a 50% lethal dose of 1.67
      log(10) PFU. Groups of four rhesus monkeys were inoculated by the subcutaneous
      route with 2.0, 3.0, 4.0, and 5. 0 log(10) PFU of ChimeriVax-JE. All 16 monkeys
      developed low viremias (mean peak viremia, 1.7 to 2.1 log(10) PFU/ml; mean
      duration, 1.8 to 2.3 days). Neutralizing antibodies appeared between days 6 and
      10; by day 30, neutralizing antibody responses were similar across dose groups.
      Neutralizing antibody titers to the homologous (vaccine) strain were higher than
      to the heterologous wild-type JE strains. All immunized monkeys and sham
      immunized controls were challenged i.c. on day 54 with 5.2 log(10) PFU of wild
      type JE. None of the immunized monkeys developed viremia or illness and had mild
      residual brain lesions, whereas controls developed viremia, clinical
      encephalitis, and severe histopathologic lesions. Immunized monkeys developed
      significant (>/=4-fold) increases in serum and cerebrospinal fluid neutralizing
      antibodies after i.c. challenge. In a standardized test for neurovirulence,
      ChimeriVax-JE and YF-Vax were compared in groups of 10 monkeys inoculated i.c.
      and analyzed histopathologically on day 30. Lesion scores in brains and spinal
      cord were significantly higher for monkeys inoculated with YF-Vax. ChimeriVax-JE
      meets preclinical safety and efficacy requirements for a human vaccine; it
      appears safer than yellow fever 17D vaccine but has a similar profile of
      immunogenicity and protective efficacy.

PMID- 10644346
TI  - The porcine humoral immune response against pseudorabies virus specifically
      targets attachment sites on glycoprotein gC.
AB  - High titers of virus-neutralizing antibodies directed against glycoprotein gC of
      Pseudorabies virus (PRV) (Suid herpesvirus 1) are generally observed in the serum
      of immunized pigs. A known function of the glycoprotein gC is to mediate
      attachment of PRV to target cells through distinct viral heparin-binding domains
      (HBDs). Therefore, it was suggested that the virus-neutralizing activity of anti
      PRV sera is directed against HBDs on gC. To address this issue, sera with high
      virus-neutralizing activity against gC were used to characterize the anti-gC
      response. Epitope mapping demonstrated that amino acids of HBDs are part of an
      antigenic antibody binding domain which is located in the N-terminal part of gC.
      Binding of antibodies to this antigenic domain of gC was further shown to
      interfere with the viral attachment. Therefore, these results show that the viral
      HBDs are accessible targets for the humoral anti-PRV response even after
      tolerance induction against self-proteins, which utilize similar HBDs to promote
      host protein-protein interactions. The findings indicate that the host's immune
      system can specifically block the attachment function of PRV gC. Since HBDs
      promote the attachment of a number of herpesviruses, the design of future
      antiherpesvirus vaccines should aim to induce a humoral immune response that
      prevents HBD-mediated viral attachment.

PMID- 10644347
TI  - Epitope mapping of human anti-adeno-associated virus type 2 neutralizing
      antibodies: implications for gene therapy and virus structure.
AB  - Recombinant adeno-associated virus type 2 (AAV) is a common vector used in human
      gene therapy protocols. We characterized the humoral immune response to AAV and
      observed that 80% of normal human subjects have anti-AAV antibodies and that 18%
      have neutralizing antibodies. To analyze the effect of neutralizing antibodies on
      AAV readministration, we attempted to deliver recombinant AAV expressing human
      factor IX (AAV-hFIX) intraportally into the livers of mice which had been
      preexposed to AAV and shown to harbor a neutralizing antibody response. While all
      naive control mice expressed hFIX following administration of AAV-hFIX, none of
      the mice with preexisting immunity expressed hFIX, even after transient
      immunosuppression at the time of the second administration with anti-CD4 or anti
      CD40L antibodies. This suggests that preexisting immunity to AAV, as measured by
      a neutralizing antibody response, may limit AAV-mediated gene delivery. Using
      human sera in an enzyme-linked immunosorbent assay for AAV and a capsid peptide
      scan library to block antibody binding, we mapped seven regions of the AAV capsid
      containing immunogenic epitopes. Using pools of these peptides to inhibit the
      binding of neutralizing antibodies, we have identified a subset of six peptides
      which potentially reconstitute a single neutralizing epitope. This information
      may allow the design of reverse genetic approaches to circumvent the preexisting
      immunity that can be encountered in some individuals.

PMID- 10644348
TI  - Prophylactic and therapeutic benefits of short-term 9-[2-(R)
      (phosphonomethoxy)propyl]adenine (PMPA) administration to newborn macaques
      following oral inoculation with simian immunodeficiency virus with reduced
      susceptibility to PMPA.
AB  - Simian immunodeficiency virus (SIV) infection of newborn macaques is a useful
      animal model of human pediatric AIDS to study pathogenesis and to develop
      intervention strategies aimed at preventing infection or delaying disease
      progression. In previous studies, we demonstrated that 9-?2-(R)
      (phosphonomethoxy)propyladenine (PMPA; tenofovir) was highly effective in
      protecting newborn macaques against infection with virulent wild-type (i.e., drug
      susceptible) SIVmac251. In the present study, we determined how reduced drug
      susceptibility of the virus inoculum affects the chemoprophylactic success.
      SIVmac055 is a virulent isolate that has a fivefold-reduced in vitro
      susceptibility to PMPA, associated with a K65R mutation and additional amino acid
      changes (N69T, R82K, A158S, S211N) in reverse transcriptase (RT). Eight newborn
      macaques were inoculated orally with SIVmac055. The three untreated control
      animals became SIVmac055 infected; these animals had persistently high viremia
      and developed fatal immunodeficiency within 3 months. Five animals were treated
      once daily with PMPA (at 30 mg/kg of body weight) for 4 weeks, starting 24 h
      prior to oral SIVmac055 inoculation. Two of the five PMPA-treated animals had no
      evidence of infection. The other three PMPA-treated infant macaques became
      infected but had a delayed viremia, enhanced antiviral antibody responses, and a
      slower disease course (AIDS in 5 to 15 months). No reversion to wild-type
      susceptibility or loss of the K65R mutation was detected in virus isolates from
      any of the PMPA-treated or untreated SIVmac055-infected animals. Several
      additional amino acid changes developed in RT, but they were not exclusively
      associated with PMPA therapy. The results of this study suggest that prophylactic
      administration of PMPA to human newborns and to adults following exposure to
      human immunodeficiency virus will still be beneficial even in the presence of
      viral variants with reduced susceptibility to PMPA.

PMID- 10644349
TI  - Abundant defective viral particles budding from microglia in the course of
      retroviral spongiform encephalopathy.
AB  - A pathogenetic hallmark of retroviral neurodegeneration is the affinity of
      neurovirulent retroviruses for microglia cells, while degenerating neurons are
      excluded from retroviral infections. Microglia isolated ex vivo from rats
      peripherally infected with a neurovirulent retrovirus released abundant mature
      type C virions; however, infectivity associated with microglia was very low. In
      microglia, viral transcription was unaffected but envelope proteins were
      insufficiently cleaved into mature viral proteins and were not detected on the
      microglia cell surface. These microglia-specific defects in envelope protein
      translocation and processing not only may have prevented formation of infectious
      virus particles but also may have caused further cellular defects in microglia
      with the consequence of indirect neuronal damage. It is conceivable that similar
      events play a role in neuro-AIDS.

PMID- 10644350
TI  - Role of the influenza virus M1 protein in nuclear export of viral
      ribonucleoproteins.
AB  - The protein kinase inhibitor H7 blocks influenza virus replication, inhibits
      production of the matrix protein (M1), and leads to a retention of the viral
      ribonucleoproteins (vRNPs) in the nucleus at late times of infection (K. Martin
      and A. Helenius, Cell 67:117-130, 1991). We show here that production of
      assembled vRNPs occurs normally in H7-treated cells, and we have used H7 as a
      biochemical tool to trap vRNPs in the nucleus. When H7 was removed from the
      cells, vRNP export was specifically induced in a CHO cell line stably expressing
      recombinant M1. Similarly, fusion of cells expressing recombinant M1 from a
      Semliki Forest virus vector allowed nuclear export of vRNPs. However, export was
      not rescued when H7 was present in the cells, implying an additional role for
      phosphorylation in this process. The viral NS2 protein was undetectable in these
      systems. We conclude that influenza virus M1 is required to induce vRNP nuclear
      export but that cellular phosphorylation is an additional factor.

PMID- 10644351
TI  - Involvement of both the V2 and V3 regions of the CCR5-tropic human
      immunodeficiency virus type 1 envelope in reduced sensitivity to macrophage
      inflammatory protein 1alpha.
AB  - To determine whether C-C chemokines play an important role in the phenotype
      switch of human immunodeficiency virus (HIV) from CCR5 to CXCR4 usage during the
      course of an infection in vivo, macrophage inflammatory protein (MIP)-1alpha
      resistant variants were isolated from CCR5-tropic (R5) HIV-1 in vitro. The
      selected variants displayed reduced sensitivities to MIP-1alpha (fourfold)
      through CCR5-expressing CD4-HeLa/long terminal repeat-beta-galactosidase
      (MAGI/CCR5) cells. The variants were also resistant to other natural ligands for
      CCR5, namely, MIP-1beta (>4-fold) and RANTES (regulated upon activation, normal T
      cell expressed and secreted) (6-fold). The env sequence analyses revealed that
      the variants had amino acid substitutions in V2 (valine 166 to methionine) and V3
      (serine 303 to glycine), although the same V3 substitution appeared in virus
      passaged without MIP-1alpha. A single-round replication assay using a luciferase
      reporter HIV-1 strain pseudotyped with mutant envelopes confirmed that mutations
      in both V2 and V3 were necessary to confer the reduced sensitivity to MIP-1alpha,
      MIP-1beta, and RANTES. However, the double mutant did not switch its chemokine
      receptor usage from CCR5 to CXCR4, indicating the altered recognition of CCR5 by
      this mutant. These results indicated that V2 combined with the V3 region of the
      CCR5-tropic HIV-1 envelope modulates the sensitivity of HIV-1 to C-C chemokines
      without altering the ability to use chemokine receptors.

PMID- 10644352
TI  - The RNA helicase and nucleotide triphosphatase activities of the bovine viral
      diarrhea virus NS3 protein are essential for viral replication.
AB  - Helicase/nucleoside triphosphatase (NTPase) motifs have been identified in many
      RNA virus genomes. Similarly, all the members of the Flaviviridae family contain
      conserved helicase/NTPase motifs in their homologous NS3 proteins. Although this
      suggests that this activity plays a critical role in the viral life cycle, the
      precise role of the helicase/NTPase in virus replication or whether it is
      essential for virus replication is still unknown. To determine the role of the
      NS3 helicase/NTPase in the viral life cycle, deletion and point mutations in the
      helicase/NTPase motifs of the bovine viral diarrhea virus (BVDV) (NADL strain)
      NS3 protein designed to abolish either helicase activity alone (motif II, DEYH to
      DEYA) or both NTPase and helicase activity (motif I, GKT to GAT and deletion of
      motif VI) were generated. The C-terminal domain of NS3 (BVDV amino acids 1854 to
      2362) of these mutants and wild type was expressed in bacteria, purified, and
      assayed for RNA helicase and ATPase activity. These mutations behaved as
      predicted with respect to RNA helicase and NTPase activities in vitro. When
      engineered back into an infectious cDNA for BVDV (NADL strain), point mutations
      in either the GKT or DEYH motif or deletion of motif VI yielded RNA transcripts
      that no longer produced infectious virus upon transfection of EBTr cells. Further
      analysis indicated that these mutants did not synthesize minus-strand RNA. These
      findings represent the first report unequivocably demonstrating that helicase
      activity is essential for minus-strand synthesis.

PMID- 10644353
TI  - Cytotoxic T-lymphocyte responses to a polymorphic Epstein-Barr virus epitope
      identify healthy carriers with coresident viral strains.
AB  - Cytotoxic T-lymphocyte (CTL) responses to Epstein-Barr virus (EBV) tend to focus
      on a few immunodominant viral epitopes; where these epitope sequences are
      polymorphic between EBV strains, host CTL specificities should reflect the
      identity of the resident strain. In studying responses in HLA-B27-positive virus
      carriers, we identified 2 of 15 individuals who had strong CTL memory to the pan
      B27 epitope RRIYDLIEL (RRIY) from nuclear antigen EBNA3C but whose endogenous EBV
      strain, isolated in vitro, encoded a variant sequence RKIYDLIEL (RKIY) which did
      not form stable complexes with B27 molecules and which was poorly recognized by
      RRIY-specific CTLs. To check if such individuals were also carrying an epitope
      positive strain (either related to or distinct from the in vitro isolate), we
      screened DNA from freshly isolated peripheral blood mononuclear cells for
      amplifiable virus sequences across the EBNA3C epitope, across a different region
      of EBNA3C with type 1-type 2 sequence divergence, and across a polymorphic region
      of EBNA1. This showed that one of the unexplained RRIY responders carried two
      distinct type 1 strains, one with an RKIY and one with an RRIY epitope sequence.
      The other responder carried an RKIY-positive type 1 strain and a type 2 virus
      whose epitope sequence of RRIFDLIEL was antigenically cross-reactive with RRIY.
      Of 15 EBV-seropositive donors analyzed by such assays, 12 appeared to be carrying
      a single virus strain, one was coinfected with distinct type 1 strains, and two
      were carrying both type 1 and type 2 viruses. This implies that a small but
      significant percentage of healthy virus carriers harbor multiple, perhaps
      sequentially acquired, EBV strains.

PMID- 10644354
TI  - Proteolytic processing of the astrovirus capsid.
AB  - To further characterize the nature of proteolytic processing of the astrovirus
      capsid, we infected Caco-2 cells with a high multiplicity of astrovirus without
      trypsin in the presence of 5 to 10% fetal calf serum. These infections were
      characterized by pulse-chase labeling with [35S]Smethionine, electron microscopy,
      gel electrophoresis of purified viral particles, and analysis of infectivity of
      such particles with and without added trypsin. Pulse-chase experiments showed
      that the astrovirus capsid protein was initially translated as an approximately
      87-kDa protein. The 87-kDa capsid protein was rapidly converted intracellularly
      to a 79-kDa form which was found in smaller amounts in the cell supernatant.
      Purification by differential centrifugation yielded particles that appeared quite
      similar to trypsin-grown astrovirus particles by negatively stained electron
      microscopy. These particles were antigenically distinct from trypsin-treated
      virions as demonstrated by their various reactions with monoclonal antibodies in
      a solid-phase immunoassay. The purified trypsin-free particles were mainly
      composed of the 79-kDa capsid protein which was found to have an amino terminus
      at residue 71 of the entire open reading frame 2 (ORF2) product. The cleavage
      site was identified in a highly conserved region of the astrovirus ORF2 product.
      These trypsin-free particles were minimally infectious in cultured Caco-2 cells
      but became highly infectious (10(5)-fold increase) after trypsin but not
      chymotrypsin treatment. This trypsin-enhanced infectivity correlated with
      conversion of the 79-kDa capsid protein to three smaller peptides of
      approximately 34, 29, and 26 kDa.

PMID- 10644355
TI  - Properties of the naturally occurring soluble surface glycoprotein of ecotropic
      murine leukemia virus: binding specificity and possible conformational change
      after binding to receptor.
AB  - Ecotropic murine leukemia virus (MuLV) infection is initiated by the interaction
      between the surface glycoprotein (SU) of the virus and its cell-surface receptor
      mCAT-1. We investigated the SU-receptor interaction by using a naturally
      occurring soluble SU which was encoded by the envelope (env) gene of a defective
      endogenous MuLV, Fv-4(r). Binding of the SU to mCAT-1-positive mouse cells was
      completed by 1 min at 37 degrees C. The SU could not bind to mouse cells that
      were persistently infected by ecotropic MuLVs (but not amphotropic or dualtropic
      MuLVs) or transfected with wild-type ecotropic env genes or a mutant env gene
      which can express only precursor Env protein that is restricted to retention in
      the endoplasmic reticulum. These cells were also resistant to superinfection by
      ecotropic MuLVs. Thus, superinfection resistance correlated with the lack of SU
      binding capacity. After binding to the cells, the SU appeared to undergo some
      conformational changes within 1 min in a temperature-dependent manner. This was
      suggested by the different properties of two monoclonal antibodies (MAbs)
      reactive with the same C-terminal half of the Fv-4(r) SU domain, including a
      proline-rich motif which was shown to be important for conformation of the SU and
      interaction between the SU and the transmembrane protein. One MAb reacting with
      the soluble SU bound to cells was dissociated by a temperature shift from 4 to 37
      degrees C. Such dissociation was not observed in cells synthesizing the SU or
      when another MAb was used, indicating that the dissociation was not due to a
      temperature-dependent release of the MAb but to possible conformational changes
      in the SU.

PMID- 10644356
TI  - Anterograde transport of herpes simplex virus type 1 in cultured, dissociated
      human and rat dorsal root ganglion neurons.
AB  - The mechanism of anterograde transport of herpes simplex virus was studied in
      cultured dissociated human and rat dorsal root ganglion neurons. The neurons were
      infected with HSV-1 to examine the distribution of capsid (VP5), tegument (VP16),
      and glycoproteins (gC and gB) at 2, 6, 10, 13, 17, and 24 h postinfection (p.i.)
      with or without nocodazole (a microtubule depolymerizer) or brefeldin A (a Golgi
      inhibitor). Retrogradely transported VP5 was detected in the cytoplasm of the
      cell body up to the nuclear membrane at 2 h p.i. It was first detected de novo in
      the nucleus and cytoplasm at 10 h p.i., the axon hillock at 13 h p.i., and the
      axon at 15 to 17 h p.i. gC and gB were first detected de novo in the cytoplasm
      and the axon hillock at 10 h p.i. and then in the axon at 13 h p.i., which was
      always earlier than the detection of VP5. De novo-synthesized VP16 was first
      detected in the cytoplasm at 10 to 13 h p.i. and in the axon at 16 to 17 h p.i.
      Nocodazole inhibited the transport of all antigens, VP5, VP16, and gC or gB. The
      kinetics of inhibition of VP5 and gC could be dissociated. Brefeldin A inhibited
      the transport of gC or gB and VP16 but not VP5 into axons. Transmission
      immunoelectron microscopy confirmed that there were unenveloped nucleocapsids in
      the axon with or without brefeldin A. These findings demonstrate that
      glycoproteins and capsids, associated with tegument proteins, are transported by
      different pathways with slightly differing kinetics from the nucleus to the axon.
      Furthermore, axonal anterograde transport of the nucleocapsid can proceed despite
      the loss of most VP16.

PMID- 10644357
TI  - Analysis of capsid formation of human polyomavirus JC (Tokyo-1 strain) by a
      eukaryotic expression system: splicing of late RNAs, translation and nuclear
      transport of major capsid protein VP1, and capsid assembly.
AB  - Human polyomavirus JC (JCV) can encode the three capsid proteins VP1, VP2, and
      VP3, downstream of the agnoprotein in the late region. JCV virions are identified
      in the nucleus of infected cells. In this study, we have elucidated unique
      features of JCV capsid formation by using a eukaryotic expression system.
      Structures of JCV polycistronic late RNAs (M1 to M4 and possibly M5 and M6)
      generated by alternative splicing were determined. VP1 would be synthesized from
      M2 RNA, and VP2 and VP3 would be synthesized from M1 RNA. The presence of the
      open reading frame of the agnoprotein or the leader sequence (nucleotides 275 to
      409) can decrease the expression level of VP1. VP1 was efficiently transported to
      the nucleus in the presence of VP2 and VP3 but distributed both in the cytoplasm
      and in the nucleus in their absence. Mutation analysis indicated that
      inefficiency in nuclear transport of VP1 is due to the unique structure in the N
      terminal sequence, KRKGERK. Within the nucleus, VP1 was localized discretely and
      identified as speckles in the presence of VP2 and VP3 but distributed diffusely
      in their absence. These results suggest that VP1 was efficiently transported to
      the nucleus and localized in the discrete subnuclear regions, possibly with VP2
      and VP3. By electron microscopy, recombinant virus particles were identified in
      the nucleus, and their intranuclear distribution was consistent with distribution
      of speckles. This system provides a useful model with which to understand JCV
      capsid formation and the structures and functions of the JCV capsid proteins.

PMID- 10644358
TI  - Expanded host cell tropism and cytopathic properties of feline immunodeficiency
      virus strain PPR subsequent to passage through interleukin-2-independent T cells.
AB  - A cytopathic variant of feline immunodeficiency virus (FIV) strain PPR emerged
      after passage of wild-type virus on an interleukin-2-independent cell line. The
      virus, termed FIV-PPRglial, displayed a phenotype markedly different from the
      parental virus, including the ability to productively infect previously
      refractory cell lines, induction of large syncytia, and accelerated kinetic
      properties. A chimeric molecular clone, FIV-PPRchim42, containing the FIV
      PPRglial envelope within the backbone of FIV-PPR, exhibited all the
      characteristics of the FIV-PPRglial phenotype, demonstrating that the viral
      envelope was responsible for the acquired traits. Subsequent molecular
      characterization revealed that the FIV-PPRglial envelope contained five amino
      acid substitutions relative to wild-type FIV-PPR. Mutagenic analyses further
      demonstrated that the acquired phenotype was minimally attributable to a
      combination of three mutations, specifically, a glutamine-to-proline change
      within the second constant domain of the surface protein (SU); a threonine-to
      proline change within the V4 loop, also in the SU; and a premature stop codon in
      the cytoplasmic tail of the transmembrane protein. All three changes were
      required to produce the FIV-PPRglial phenotype. Cotransfection studies with
      mutant viruses in combination with each other and with FIV-PPR indicated that the
      truncated cytoplasmic tail was responsible for the induction of syncytium
      formation. Receptor usage analyses were pursued, and distinctions were observed
      between FIV-PPR and FIV-PPRglial. In vitro infections with FIV-PPR, FIV-PPRglial,
      and FIV-34TF10 on two adherent cell lines were ablated in the presence of
      SDF1alpha, the natural ligand for CXCR4. In contrast, viral infection of T cells
      was not limited to CXCR4 usage, and inhibition studies indicate the potential
      involvement of a CC chemokine receptor.

PMID- 10644359
TI  - Infection of human T lymphocytes with varicella-zoster virus: an analysis with
      viral mutants and clinical isolates.
AB  - Varicella-zoster virus (VZV) disseminates in the body in peripheral blood
      mononuclear cells during chickenpox. Up to 1 in 10,000 mononuclear cells are
      infected during the viremic phase of the disease. We developed an in vitro system
      to infect human mononuclear cells with VZV by using umbilical cord blood. In this
      system, 3 to 4% of T cells were infected with VZV. VZV mutants unable to express
      certain genes, such as open reading frame 47 (ORF47) or ORF66, were impaired for
      growth in T cells, while other mutants showed little difference from parental
      virus. VZV unable to express ORF47 was even more impaired for spread from
      umbilical cord blood cells to melanoma cells in vitro. Early-passage clinical
      isolates of VZV infected T cells at a similar rate to the Oka vaccine strain;
      however, the clinical isolates were more efficient in spreading from infected T
      cells to melanoma cells. This in vitro system for infecting human T cells with
      VZV should be useful for identifying cellular and viral proteins that are
      important for virus replication in T cells and for the spread of virus from T
      cells to other cells.

PMID- 10644360
TI  - The putative natural killer decoy early gene m04 (gp34) of murine cytomegalovirus
      encodes an antigenic peptide recognized by protective antiviral CD8 T cells.
AB  - Several early genes of murine cytomegalovirus (MCMV) encode proteins that mediate
      immune evasion by interference with the major histocompatibility complex class I
      (MHC-I) pathway of antigen presentation to cytolytic T lymphocytes (CTL).
      Specifically, the m152 gene product gp37/40 causes retention of MHC-I molecules
      in the endoplasmic reticulum (ER)-Golgi intermediate compartment. Lack of MHC-I
      on the cell surface should activate natural killer (NK) cells recognizing the
      "missing self." The retention, however, is counteracted by the m04 early gene
      product gp34, which binds to folded MHC-I molecules in the ER and directs the
      complex to the cell surface. It was thus speculated that gp34 might serve to
      silence NK cells and thereby complete the immune evasion of MCMV. In light of
      these current views, we provide here results demonstrating an in vivo role for
      gp34 in protective antiviral immunity. We have identified an antigenic
      nonapeptide derived from gp34 and presented by the MHC-I molecule D(d). Besides
      the immunodominant immediate-early nonapeptide consisting of IE1 amino acids 168
      176 (IE1(168-176)), the early nonapeptide m04(243-251) is the second antigenic
      peptide described for MCMV. The primary immune response to MCMV generates
      significant m04-specific CD8 T-cell memory. Upon adoptive transfer into
      immunodeficient recipients, an m04-specific CTL line controls MCMV infection with
      an efficacy comparable to that of an IE1-specific CTL line. Thus, gp34 is the
      first noted early protein of MCMV that escapes viral immune evasion mechanisms.
      These data document that MCMV is held in check by a redundance of protective CD8
      T cells recognizing antigenic peptides in different phases of viral gene
      expression.

PMID- 10644361
TI  - The latency-associated transcript gene enhances establishment of herpes simplex
      virus type 1 latency in rabbits.
AB  - The latency-associated transcript (LAT) gene the only herpes simplex virus type 1
      (HSV-1) gene abundantly transcribed during neuronal latency, is essential for
      efficient in vivo reactivation. Whether LAT increases reactivation by a direct
      effect on the reactivation process or whether it does so by increasing the
      establishment of latency, thereby making more latently infected neurons available
      for reactivation, is unclear. In mice, LAT-negative mutants appear to establish
      latency in fewer neurons than does wild-type HSV-1. However, this has not been
      confirmed in the rabbit, and the role of LAT in the establishment of latency
      remains controversial. To pursue this question, we inserted the gene for the
      enhanced green fluorescent protein (EGFP) under control of the LAT promoter in a
      LAT-negative virus (DeltaLAT-EGFP) and in a LAT-positive virus (LAT-EGFP). Sixty
      days after ocular infection, trigeminal ganglia (TG) were removed from the
      latently infected rabbits, sectioned, and examined by fluorescence microscopy.
      EGFP was detected in significantly more LAT-EGFP-infected neurons than DeltaLAT
      EGFP-infected neurons (4.9% versus 2%, P < 0.0001). The percentages of EGFP
      positive neurons per TG ranged from 0 to 4.6 for DeltaLAT-EGFP and from 2.5 to
      11.1 for LAT-EGFP (P = 0.003). Thus, LAT appeared to increase neuronal latency in
      rabbit TG by an average of two- to threefold. These results suggest that LAT
      enhances the establishment of latency in rabbits and that this may be one of the
      mechanisms by which LAT enhances spontaneous reactivation. These results do not
      rule out additional LAT functions that may be involved in maintenance of latency
      and/or reactivation from latency.

PMID- 10644362
TI  - Characterization of the interaction between the interferon-induced protein P56
      and the Int6 protein encoded by a locus of insertion of the mouse mammary tumor
      virus.
AB  - For determining cellular functions of the interferon-inducible human cytoplasmic
      protein P56, we undertook a Saccharomyces cerevisiae two-hybrid screen that
      identified Int6 as a P56-interacting protein. That the interaction also occurs in
      human cells was confirmed by coimmunoprecipitation and the observed cytoplasmic
      displacement of nuclear Int6 upon coexpression of P56. Because Int6 has been
      claimed to be both a cytoplasmic and a nuclear protein, we investigated the
      structural basis of this discrepancy. By mutational analyses, we showed that the
      Int6 protein contains a bipartite nuclear localization signal and a nuclear
      export signal at the far end of the amino terminus. The 20 amino-terminal
      residues of Int6, when they were attached to a different nuclear protein, were
      sufficient to translocate that protein to the cytoplasm. Within this region,
      replacement of any of the three leucine residues with alanine destroyed the
      function of the export signal. The specific domain of P56 that is required for
      its interaction with Int6 was mapped using the yeast two-hybrid assay and a
      mammalian coimmunoprecipitation assay. Both assays demonstrated that the C
      terminal region of P56 containing three specific tetratricopeptide motifs is
      required for this interaction. In contrast, removal of an internal domain of P56
      enhanced the interaction, as quantified by the two-hybrid assay.

PMID- 10644363
TI  - Modulation of major histocompatibility class II protein expression by varicella
      zoster virus.
AB  - We sought to investigate the effects of varicella-zoster virus (VZV) infection on
      gamma interferon (IFN-gamma)-stimulated expression of cell surface major
      histocompatibility complex (MHC) class II molecules on human fibroblasts. IFN
      gamma treatment induced cell surface MHC class II expression on 60 to 86% of
      uninfected cells, compared to 20 to 30% of cells which had been infected with VZV
      prior to the addition of IFN-gamma. In contrast, cells that were treated with IFN
      gamma before VZV infection had profiles of MHC class II expression similar to
      those of uninfected cell populations. Neither IFN-gamma treatment nor VZV
      infection affected the expression of transferrin receptor (CD71). In situ and
      Northern blot hybridization of MHC II (MHC class II DR-alpha) RNA expression in
      response to IFN-gamma stimulation revealed that MHC class II DR-alpha mRNA
      accumulated in uninfected cells but not in cells infected with VZV. When skin
      biopsies of varicella lesions were analyzed by in situ hybridization, MHC class
      II transcripts were detected in areas around lesions but not in cells that were
      infected with VZV. VZV infection inhibited the expression of Stat 1alpha and Jak2
      proteins but had little effect on Jak1. Analysis of regulatory events in the IFN
      gamma signaling pathway showed that VZV infection inhibited transcription of
      interferon regulatory factor 1 and the MHC class II transactivator. This is the
      first report that VZV encodes an immunomodulatory function which directly
      interferes with the IFN-gamma signal transduction via the Jak/Stat pathway and
      enables the virus to inhibit IFN-gamma induction of cell surface MHC class II
      expression. This inhibition of MHC class II expression on VZV-infected cells in
      vivo may transiently protect cells from CD4(+) T-cell immune surveillance,
      facilitating local virus replication and transmission during the first few days
      of cutaneous lesion formation.

PMID- 10644364
TI  - Measles virus spread between neurons requires cell contact but not CD46
      expression, syncytium formation, or extracellular virus production.
AB  - In patients with subacute sclerosing panencephalitis (SSPE), which is associated
      with persistent measles virus (MV) infection in the brain, little infectious
      virus can be recovered despite the presence of viral RNA and protein. Based on
      studies of brain tissue from SSPE patients and our work with MV-infected NSE
      CD46(+) mice, which express the measles receptor CD46 on neurons, several lines
      of evidence suggest that the mechanism of viral spread in the central nervous
      system differs from that in nonneuronal cells. To examine this alternate
      mechanism of viral spread, as well as the basis for the loss of normal
      transmission mechanisms, infection and spread of MV Edmonston was evaluated in
      primary CD46(+) neurons from transgenic mice and differentiated human NT2
      neurons. As expected, unlike that between fibroblasts, viral spread between
      neurons occurred in the absence of syncytium formation and with minimal
      extracellular virus. Electron microscopy analysis showed that viral budding did
      not occur from the neuronal surface, although nucleocapsids were present in the
      cytoplasm and aligned at the cell membrane. We observed many examples of
      nucleocapsids present in the neuronal processes and aligned at presynaptic
      neuronal membranes. Cocultures of CD46(+) and CD46(-) neurons showed that cell
      contact but not CD46 expression is required for MV spread between neurons.
      Collectively, these results suggest that the neuronal environment prevents the
      normal mechanisms of MV spread between neurons at the level of viral assembly but
      allows an alternate, CD46-independent mechanism of viral transmission, possibly
      through the synapse.

PMID- 10644366
TI  - Bcl-2 blocks a caspase-dependent pathway of apoptosis activated by herpes simplex
      virus 1 infection in HEp-2 cells.
AB  - Earlier reports have shown that herpes simplex virus 1 (HSV-1) mutants induce
      programmed cell death and that wild-type virus blocks the execution of the cell
      death program triggered by expression of viral genes, by the Fas and tumor
      necrosis factor pathways, or by nonspecific stress agents. In particular, an
      earlier report from this laboratory showed that the mutant virus d120 lacking the
      genes encoding infected cell protein 4 (ICP4), the major regulatory protein of
      the virus, induces a caspase-3-independent pathway of apoptosis in human SK-N-SH
      cells. Here we report that the pathway of apoptosis induced by the d120 mutant in
      human HEp-2 cells is caspase dependent. Specifically, in HEp-2 cells infected
      with d120, (i) a broad-range inhibitor of caspase activity, z-vad-FMK,
      efficiently blocked DNA fragmentation, (ii) cytochrome c was released into the
      cytoplasm, (iii) caspase-3 was activated inasmuch as poly(ADP-ribose) polymerase
      was cleaved, and (iv) chromatin condensation and fragmentation of cellular DNA
      were observed. In parallel studies, HEp-2 cells were transfected with a plasmid
      encoding human Bcl-2 and a clone (VAX-3) expressing high levels of Bcl-2 was
      selected. This report shows that Bcl-2 blocked all of the manifestations
      associated with programmed cell death caused by infection with the d120 mutant.
      Consistent with their resistance to programmed cell death, VAX-3 cells
      overproduced infected cell protein 0 (ICP0). An unexpected observation was that
      ICP0 encoded by the d120 mutant accumulated late in infection in small, quasi
      uniform vesicle-like structures in all cell lines tested. Immunofluorescence
      based colocalization studies indicated that these structures were not
      mitochondria or components of the endoplasmic reticulum or the late endosomal
      compartment. These studies affirm the conclusion that HSV can induce programmed
      cell death at multiple steps in the course of its replication, that the d120
      mutant can induce both caspase-dependent and -independent pathways of programmed
      cell death, and that virus-induced stimuli of programmed cell death may differ
      with respect to the pathway that they activate.

PMID- 10644365
TI  - Cellular uptake and infection by canine parvovirus involves rapid dynamin
      regulated clathrin-mediated endocytosis, followed by slower intracellular
      trafficking.
AB  - Canine parvovirus (CPV) is a small, nonenveloped virus that is a host range
      variant of a virus which infected cats and changes in the capsid protein control
      the ability of the virus to infect canine cells. We used a variety of approaches
      to define the early stages of cell entry by CPV. Electron microscopy showed that
      virus particles concentrated within clathrin-coated pits and vesicles early in
      the uptake process and that the infecting particles were rapidly removed from the
      cell surface. Overexpression of a dominant interfering mutant of dynamin in the
      cells altered the trafficking of capsid-containing vesicles. There was a 40%
      decrease in the number of CPV-infected cells in mutant dynamin-expressing cells,
      as well as a approximately 40% decrease in the number of cells in S phase of the
      cell cycle, which is required for virus replication. However, there was also up
      to 10-fold more binding of CPV to the surface of mutant dynamin-expressing cells
      than there was to uninduced cells, suggesting an increased receptor retention on
      the cell surface. In contrast, there was little difference in virus binding,
      virus infection rate, or cell cycle distribution between induced and uninduced
      cells expressing wild-type dynamin. CPV particles colocalized with transferrin in
      perinuclear endosomes but not with fluorescein isothiocyanate-dextran, a marker
      for fluid-phase endocytosis. Cells treated with nanomolar concentrations of
      bafilomycin A1 were largely resistant to infection when the drug was added either
      30 min before or 90 min after inoculation, suggesting that there was a lag
      between virus entering the cell by clathrin-mediated endocytosis and escape of
      the virus from the endosome. High concentrations of CPV particles did not
      permeabilize canine A72 or mink lung cells to alpha-sarcin, but canine adenovirus
      type 1 particles permeabilized both cell lines. These data suggest that the CPV
      entry and infection pathway is complex and involves multiple vesicular
      components.

PMID- 10644367
TI  - A role for SKIP in EBNA2 activation of CBF1-repressed promoters.
AB  - EBNA2 is essential for Epstein-Barr virus (EBV) immortalization of B lymphocytes.
      EBNA2 functions as a transcriptional activator and targets responsive promoters
      through interaction with the cellular DNA binding protein CBF1. We have examined
      the mechanism whereby EBNA2 overcomes CBF1-mediated transcriptional repression. A
      yeast two-hybrid screen performed using CBF1 as the bait identified a protein,
      SKIP, which had not previously been recognized as a CBF1-associated protein.
      Protein-protein interaction assays demonstrated contacts between SKIP and the
      SMRT, CIR, Sin3A, and HDAC2 proteins of the CBF1 corepressor complex.
      Interestingly, EBNA2 also interacted with SKIP in glutathione S-transferase
      affinity and mammalian two-hybrid assays and colocalized with SKIP in
      immunofluorescence assays. Interaction with SKIP was not affected by mutation of
      EBNA2 conserved region 6, the CBF1 interaction region, but was abolished by
      mutation of conserved region 5. Mutation of conserved region 5 also severely
      impaired EBNA2 activation of a reporter containing CBF1 binding sites. Thus,
      interaction with both CBF1 and SKIP is necessary for efficient promoter
      activation by EBNA2. A model is presented in which EBNA2 competes with the SMRT
      corepressor complex for contacts on SKIP and CBF1.

PMID- 10644368
TI  - Selective interactions of polyanions with basic surfaces on human
      immunodeficiency virus type 1 gp120.
AB  - It is well established that the gp120 V3 loop of T-cell-line-adapted human
      immunodeficiency virus type 1 (HIV-1) binds both cell-associated and soluble
      polyanions. Virus infectivity is increased by interactions between HIV-1 and
      heparan sulfate proteoglycans on some cell types, and soluble polyanions such as
      heparin and dextran sulfate neutralize HIV-1 in vitro. However, the analysis of
      gp120-polyanion interactions has been limited to T-cell-line-adapted, CXCR4-using
      virus and virus-derived gp120, and the polyanion binding ability of gp120 regions
      other than the V3 loop has not been addressed. Here we demonstrate by monoclonal
      antibody inhibition, labeled heparin binding, and surface plasmon resonance
      studies that a second site, most probably corresponding to the newly defined,
      highly conserved coreceptor binding region on gp120, forms part of the polyanion
      binding surface. Consistent with the binding of polyanions to the coreceptor
      binding surface, dextran sulfate interfered with the gp120-CXCR4 association
      while having no detectable effect on the gp120-CD4 interaction. The interaction
      between polyanions and X4 or R5X4 gp120 was readily detectable, whereas weak or
      undetectable binding was observed with R5 gp120. Analysis of mutated forms of X4
      gp120 demonstrated that the V3 loop is the major determinant for polyanion
      binding whereas other regions, including the V1/V2 loop structure and the NH(2)
      and COOH termini, exert a more subtle influence. A molecular model of the
      electrostatic potential of the conserved coreceptor binding region confirmed that
      it is basic but that the overall charge on this surface is dominated by the V3
      loop. These results demonstrate a selective interaction of gp120 with polyanions
      and suggest that the conserved coreceptor binding surface may present a novel and
      conserved target for therapeutic intervention.

PMID- 10644369
TI  - Oligomeric modeling and electrostatic analysis of the gp120 envelope glycoprotein
      of human immunodeficiency virus.
AB  - The human immunodeficiency virus envelope glycoproteins, gp120 and gp41, function
      in cell entry by binding to CD4 and a chemokine receptor on the cell surface and
      orchestrating the direct fusion of the viral and target cell membranes. On the
      virion surface, three gp120 molecules associate noncovalently with the ectodomain
      of the gp41 trimer to form the envelope oligomer. Although an atomic-level
      structure of a monomeric gp120 core has been determined, the structure of the
      oligomer is unknown. Here, the orientation of gp120 in the oligomer is modeled by
      using quantifiable criteria of carbohydrate exposure, occlusion of conserved
      residues, and steric considerations with regard to the binding of the
      neutralizing antibody 17b. Applying similar modeling techniques to influenza
      virus hemagglutinin suggests a rotational accuracy for the oriented gp120 of
      better than 10 degrees. The model shows that CD4 binds obliquely, such that
      multiple CD4 molecules bound to the same oligomer have their membrane-spanning
      portions separated by at least 190 A. The chemokine receptor, in contrast, binds
      to a sterically restricted surface close to the trimer axis. Electrostatic
      analyses reveal a basic region which faces away from the virus, toward the target
      cell membrane, and is conserved on core gp120. The electrostatic potentials of
      this region are strongly influenced by the overall charge, but not the precise
      structure, of the third variable (V3) loop. This dependence on charge and not
      structure may make electrostatic interactions between this basic region and the
      cell difficult to target therapeutically and may also provide a means of viral
      escape from immune system surveillance.

PMID- 10644370
TI  - Disruption of the murine gammaherpesvirus 68 M1 open reading frame leads to
      enhanced reactivation from latency.
AB  - Murine gammaherpesvirus 68 (gammaHV68, or MHV-68) is a genetically tractable,
      small animal model for the analysis of gammaherpesvirus pathogenesis. The
      gammaHV68 genome is colinear with the genomes of other sequence
      gammaherpesviruses, containing large blocks of conserved genes interspersed by a
      number of putative genes without clear homologs in the other gammaherpesviruses.
      One of these putative unique genes, the M1 open reading frame (ORF), exhibits
      sequence homology to a poxvirus serine protease inhibitor, SPI-1, as well as to
      another gammaHV68 gene, M3, which we have recently shown encodes an abundantly
      secreted chemokine binding protein. To assess the contribution of the M1 ORF to
      gammaHV68 pathogenesis, we have generated a recombinant gammaHV68 in which the M1
      ORF has been disrupted through targeted insertion of a lacZ expression cassette
      (M1.LacZ). Although M1.LacZ replicated normally in tissue culture, it exhibited
      decreased splenic titers at days 4 and 9 postinfection in both immunocompetent
      and immunodeficient mice. Despite decreased levels of acute virus replication,
      M1.LacZ established a latent infection comparable to wild-type (wt) gammaHV68,
      but exhibited an approximately fivefold increase in efficiency of reactivation
      from latency. M1.LacZ also caused severe vasculitis of the great elastic arteries
      in gamma interferon receptor (IFN-gammaR)-deficient mice with a frequency
      comparable to wt gammaHV68, but did not cause the mortality or splenic pathology
      observed with wt gammaHV68 infection of IFN-gammaR-deficient mice. Restoration of
      M1 ORF sequences into M1.LacZ (M1 marker rescue, or M1.MR) demonstrated that
      M1.LacZ phenotypic alterations in growth in vivo and latency were not due to the
      presence of additional mutations located elsewhere in the M1. LacZ genome.
      Generation of a second M1 mutant virus containing a deletion at the 5' end of the
      M1 ORF (M1Delta511), but lacking the LacZ expression cassette, revealed the same
      latency phenotype observed with the M1.LacZ mutant. However, M1Delta511 was not
      attenuated for acute virus replication in the spleen. We conclude that (i) the
      induction of arteritis in gammaHV68-infected IFN-gammaR-deficient mice can occur
      in the absence of splenic pathology and mortality, (ii) replication during acute
      infection is not the primary determinant for the establishment of latent
      infection, and (iii) the M1 ORF, or a closely linked gene, encodes a gene product
      that functions to suppress virus reactivation.

PMID- 10644371
TI  - Proteolytic cleavage of the fusion protein but not membrane fusion is required
      for measles virus-induced immunosuppression in vitro.
AB  - Immunosuppression induced by measles virus (MV) is associated with
      unresponsiveness of peripheral blood lymphocytes (PBL) to mitogenic stimulation
      ex vivo and in vitro. In mixed lymphocyte cultures and in an experimental animal
      model, the expression of the MV glycoproteins on the surface of UV-inactivated MV
      particles, MV-infected cells, or cells transfected to coexpress the MV fusion (F)
      and the hemagglutinin (H) proteins was found to be necessary and sufficient for
      this phenomenon. We now show that MV fusion-inhibitory peptides do not interfere
      with the induction of immunosuppression in vitro, indicating that MV F-H-mediated
      fusion is essentially not involved in this process. Proteolytic cleavage of MV
      F(0) protein by cellular proteases, such as furin, into the F(1)-F(2) subunits
      is, however, an absolute requirement, since (i) the inhibitory activity of MV
      infected BJAB cells was significantly impaired in the presence of a furin
      inhibitory peptide and (ii) cells expressing or viruses containing uncleaved F(0)
      proteins revealed a strongly reduced inhibitory activity which was improved
      following trypsin treatment. The low inhibitory activity of effector structures
      containing mainly F(0) proteins was not due to an impaired F(0)-H interaction,
      since both surface expression and cocapping efficiencies were similar to those
      found with the authentic MV F and H proteins. These results indicate that the
      fusogenic activity of the MV F-H complexes can be uncoupled from their
      immunosuppressive activity and that the immunosuppressive domains of these
      proteins are exposed only after proteolytic activation of the MV F(0) protein.

PMID- 10644372
TI  - Mutation of predicted virion pit residues alters binding of Theiler's murine
      encephalomyelitis virus to BHK-21 cells.
AB  - Theiler's murine encephalomyelitis virus (TMEV), a natural pathogen of mice, is a
      member of the genus Cardiovirus in the family Picornaviridae. Structural studies
      indicate that the cardiovirus pit, a deep depression on the surface of the
      virion, is involved in receptor attachment; however, this notion has never been
      systematically tested. Therefore, we used BeAn virus, a less virulent TMEV, to
      study the effect of site-specific mutation of selected pit amino acids on viral
      binding as well as other replicative functions of the virus. Four amino acids
      within the pit, V1091, P1153, A1225 and P3179, were selected for mutagenesis to
      evaluate their role in receptor attachment. Three amino acid replacements were
      made at each site, the first a conservative replacement, followed by
      progressively more radical amino acid changes in order to detect variable effects
      at each site. A total of seven viable mutant viruses were recovered and
      characterized for their binding properties to BHK-21 cells, capsid stability at
      40 degrees C, viral RNA replication, single- and multistep growth kinetics, and
      virus translation. Our data implicate three of these residues in TMEV-cell
      receptor attachment.

PMID- 10644373
TI  - Varicella-zoster virus proteins in skin lesions: implications for a novel role of
      ORF29p in chickenpox.
AB  - Skin biopsy samples from varicella-zoster virus (VZV)-infected patients examined
      by immunohistochemistry demonstrated VZV replication in nonepithelial cell types.
      ORF29p, a nonstructural nuclear protein, was found in nerves of two of six
      patients with chickenpox. In tissue culture, ORF29p was secreted by VZV-infected
      fibroblasts. Extracellular ORF29p can be taken up through endocytosis by human
      neurons, implying a novel role for this protein in pathogenesis.

PMID- 10644374
TI  - CXC-chemokine receptor 4 is not a coreceptor for human herpesvirus 7 entry into
      CD4(+) T cells.
AB  - Human herpesvirus 7 (HHV-7) is a T-lymphotropic virus which utilizes the CD4
      receptor as its main receptor to enter the target cells. Hence, HHV-7 can
      interfere with human immunodeficiency virus type 1 (HIV-1) infection in CD4(+) T
      cells. It was recently suggested that the CXC chemokine receptor 4 (CXCR4), which
      was found to be a crucial coreceptor for T-tropic HIV-1 strains, may also play a
      role in the HHV-7 infection process. However, the results presented here
      demonstrate that CXCR4 is not involved in HHV-7 infection. The natural ligand of
      CXCR4, SDF-1alpha, was not able to inhibit HHV-7 infection in SupT1 cells or in
      CD8(+) T-cell-depleted peripheral blood mononuclear cells. Also, AMD3100, a
      specific CXCR4 antagonist with potent antiviral activity against T-tropic HIV
      strains (50% inhibitory concentration ?IC(50), 1 to 10 ng/ml), completely failed
      to inhibit HHV-7 infection (IC(50), >250 microg/ml). Thus, two different agents
      known to specifically interact with CXCR4 were not able to inhibit HHV-7
      infection. Other T-lymphoid cell lines, expressing both CD4 and CXCR4 (e.g., HUT
      78 and MT-4) could not be infected by HHV-7. In addition, the CD4-transfected
      cell lines HOS. CD4 and U87.CD4 and the CD4/CXCR4 double-transfected cell lines
      HOS. CD4.CXCR4 and U87.CD4.CXCR4 were not infectable with HHV-7. Also, we found
      no down-regulation of surface-bound or intracellular CXCR4 in HHV-7-infected
      CD4(+) T cells. As compared to uninfected SupT1 cells, stromal cell-derived
      factor 1alpha (SDF-1alpha)/CXCR4-mediated intracellular calcium flux was
      unchanged in SupT1 cells that were acutely or persistently infected with HHV-7.
      All these data argue against CXCR4 as a receptor involved in the HHV-7 infection
      process.

PMID- 10644375
TI  - De novo initiation of RNA synthesis by hepatitis C virus nonstructural protein 5B
      polymerase.
AB  - RNA-dependent RNA polymerase (RdRp) encoded by positive-strand RNA viruses is
      critical to the replication of viral RNA genome. Like other positive-strand RNA
      viruses, replication of hepatitis C virus (HCV) RNA is mediated through a
      negative-strand intermediate, which is generated through copying the positive
      strand genomic RNA. Although it has been demonstrated that HCV NS5B alone can
      direct RNA replication through a copy-back primer at the 3' end, de novo
      initiation of RNA synthesis is likely to be the mode of RNA replication in
      infected cells. In this study, we demonstrate that a recombinant HCV NS5B protein
      has the ability to initiate de novo RNA synthesis in vitro. The NS5B used HCV 3'
      X-tail RNA (98 nucleotides) as the template to synthesize an RNA product of
      monomer size, which can be labeled by ?gamma-(32)Pnucleoside triphosphate. The de
      novo initiation activity was further confirmed by using small synthetic RNAs
      ending with dideoxynucleotides at the 3' termini. In addition, HCV NS5B preferred
      GTP as the initiation nucleotide. The optimal conditions for the de novo
      initiation activity have been determined. Identification and characterization of
      the de novo priming or initiation activity by HCV NS5B provides an opportunity to
      screen for inhibitors that specifically target the initiation step.

PMID- 10644376
TI  - Resistance to replication of human immunodeficiency virus challenge in SCID-Hu
      mice engrafted with peripheral blood mononuclear cells of nonprogressors is
      mediated by CD8(+) T cells and associated with a proliferative response to p24
      antigen.
AB  - High levels of resistance to challenge with human immunodeficiency virus type 1
      SF162 were observed in animals engrafted with peripheral blood mononuclear cells
      of four long-term nonprogressors (LTNPs). Resistance was abrogated by depletion
      of CD8(+) T cells in vivo and was observed only in LTNPs with proliferative
      responses to p24. In a subgroup of nonprogressors, CD8(+) T cells mediated
      restriction of challenge viruses, and this response was associated with strong
      proliferative responses to p24 antigen.

PMID- 10644377
TI  - Characterization of gammaherpesvirus 68 gene 50 transcription.
AB  - Gene 50 is the only immediate-early gene that appears to be conserved among the
      characterized gammaherpesviruses. It has recently been demonstrated for the human
      viruses Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus
      (KSHV) that ectopic expression of the gene 50-encoded product in some latently
      infected cell lines can lead to the induction of virus replication, indicating
      that gene 50 is likely to play a pivotal role in regulating gammaherpesvirus
      reactivation. Here we demonstrate that the murine gammaherpesvirus 68 (gammaHV68)
      gene 50 is an immediate-early gene and that transcription of gammaHV68 gene 50
      leads to the production of both spliced and unspliced forms of the gene 50
      transcript. Splicing of the transcript near the 5' end serves to extend the gene
      50 open reading frame, as has been observed for the gene 50 transcripts encoded
      by KSHV and herpesvirus saimiri (Whitehouse et al., J. Virol. 71:2550-2554, 1997;
      Lukac et al., Virology 252:304-312, 1998; Sun et al., Proc. Natl. Acad. Sci. USA
      95:10866-10871, 1998). Reverse transcription-PCR analyses, coupled with S1
      nuclease protection assays, provided evidence that gene 50 transcripts initiate
      at several sites within the region from bp 66468 to 66502 in the gammaHV68
      genome. Functional characterization of the region upstream of the putative gene
      50 transcription initiation site demonstrated orientation-dependent promoter
      activity and identified a 110-bp region (bp 66442 to 66552) encoding the putative
      gene 50 promoter. Finally, we demonstrate that the gammaHV68 gene 50 can
      transactivate the gammaHV68 gene 57 promoter, a known early gene target of the
      gene 50-encoded transactivator in other gammaherpesviruses. These studies show
      that the gammaHV68 gene 50 shares several important molecular similarities with
      the gene 50 homologs in other gammaherpesviruses and thus provides an impetus for
      future studies analyzing the role of the gammaHV68 gene 50-encoded protein in
      acute virus replication and reactivation from latency in vivo.

PMID- 10644378
TI  - Pathogenic conversion of live attenuated simian immunodeficiency virus vaccines
      is associated with expression of truncated Nef.
AB  - Rhesus macaques infected with simian immunodeficiency virus (SIV) containing
      either a large nef deletion (SIVmac239Delta(152)nef) or interleukin-2 in place of
      nef developed high virus loads and progressed to simian AIDS. Viruses recovered
      from both juvenile and neonatal macaques with disease produced a novel truncated
      Nef protein, tNef. Viruses recovered from juvenile macaques infected with
      serially passaged virus expressing tNef exhibited a pathogenic phenotype. These
      findings demonstrated strong selective pressure to restore expression of a
      truncated Nef protein, and this reversion was linked to increased pathogenic
      potential in live attenuated SIV vaccines.

PMID- 10644381
TI  - Otorhinolaryngology.
AB  - Otorhinolaryngology, a product of the early 20th century, developed from the
      joining together of the separate departments of otology, whose practitioners were
      surgeons, and laryngology which was managed by physicians who also treated
      diseases of the nose and chest. The 20th century opened with brave attempts to
      perform skilful surgery under conditions of primitive anaesthesia and no
      antibiotics. The stimulus of two world wars led to significant advances in
      technology and greater opportunities to explore new and resurrect old surgical
      procedures. The discovery of antibiotics saw an end to acute mastoiditis and the
      complications of otitis media and sinusitis, as well as a decline in the number
      of tonsillectomy and adenoidectomy operations. Over the last 30 years the
      specialty has undergone dramatic development and has taken advantage of new
      advances in endoscopy, microsurgery, the use of lasers, cytotoxic drugs, flap
      reconstruction and microchip technology. During the same period, although still
      calling themselves otorinolaryngologists, individual surgeons have subspecialised
      in otology, otoneurosurgery and skull-base surgery, head and neck surgery,
      phonosurgery, rhinology and facioplastic surgery, and paediatric
      otothinolaryngology. Each of these subspecialties has its own societies and
      specialist journals.

PMID- 10644379
TI  - Hepatitis C virus-encoded enzymatic activities and conserved RNA elements in the
      3' nontranslated region are essential for virus replication in vivo.
AB  - Hepatitis C virus (HCV) infection is a widespread major human health concern.
      Significant obstacles in the study of this virus include the absence of a
      reliable tissue culture system and a small-animal model. Recently, we constructed
      full-length HCV cDNA clones and successfully initiated HCV infection in two
      chimpanzees by intrahepatic injection of in vitro-transcribed RNA (A. A.
      Kolykhalov et al., Science 277:570-574, 1997). In order to validate potential
      targets for development of anti-HCV therapeutics, we constructed six mutant
      derivatives of this prototype infectious clone. Four clones contained point
      mutations ablating the activity of the NS2-3 protease, the NS3-4A serine
      protease, the NS3 NTPase/helicase, and the NS5B polymerase. Two additional clones
      contained deletions encompassing all or part of the highly conserved 98-base
      sequence at the 3' terminus of the HCV genome RNA. The RNA transcript from each
      of the six clones was injected intrahepatically into a chimpanzee. No signs of
      HCV infection were detected in the 8 months following the injection. Inoculation
      of the same animal with nonmutant RNA transcripts resulted in productive HCV
      infection, as evidenced by viremia, elevated serum alanine aminotransferase, and
      HCV-specific seroconversion. These data suggest that these four HCV-encoded
      enzymatic activities and the conserved 3' terminal RNA element are essential for
      productive replication in vivo.

PMID- 10644380
TI  - Herpes simplex virus ICP0 mutants are hypersensitive to interferon.
AB  - Interferon (IFN) is an important immune system molecule capable of inducing an
      antiviral state within cells. Herpes simplex virus type 1 (HSV-1) replication is
      somewhat reduced in tissue culture in the presence of IFN, presumably due to
      decreased viral transcription. Here, we show mutations that inactivate immediate
      early (IE) gene product ICP0 render HSV-1 exquisitely sensitive to IFN
      inhibition, resulting in greatly decreased levels of viral mRNA transcripts and
      the resulting polypeptides and a severe reduction in plaque formation ability.
      Mutations in other HSV-1 genes, including the genes coding for virion
      transactivator VP16 and the virion host shutoff protein vhs, IE gene ICP22, and
      the protein kinase UL13 gene, do not increase the IFN sensitivity of HSV-1.
      Interestingly, ICP0 mutants demonstrate the same level of sensitivity to IFN as
      wild-type virus on U2OS cells, an osteosarcoma cell line that is known to
      complement mutations in ICP0 and VP16. Thus, in some cell types, functional ICP0
      is required for HSV-1 to efficiently bypass the inhibitory effects of IFN in
      order to ensure its replication. The significance of this link between ICP0 and
      IFN resistance is discussed.

PMID- 10644382
TI  - Antiplatelet use in interventional cardiology.
AB  - Thrombosis within the target vessel is one of the most feared complications
      associated with coronary intervention, as it is often associated with severe
      adverse clinical sequelae. This thrombosis is mediated via the activation and
      aggregation of platelets and therefore considerable effort has been directed at
      ways of inhibiting platelet function. It is now mandatory to consider the use of
      two and often three different antiplatelet agents, particularly when
      intracoronary stents are inserted. Using these regimes, many of the adverse
      clinical outcomes associated with platelet activation can be reduced.

PMID- 10644383
TI  - Widal agglutination test - 100 years later: still plagued by controversy.
AB  - We review the significance of the Widal agglutination test in the diagnosis of
      typhoid fever. Over 100 years since its introduction as a serologic means of
      detecting the presence of typhoid fever, the Widal test continues to be plagued
      with controversies involving the quality of the antigens used and interpretation
      of the result, particularly in endemic areas. Areas of concern with clinical and
      laboratory significance discussed in this review include: the techniques of test
      performance, interpretation of results, limitation of the value of the test
      results in endemic typhoid areas, the quality of the antigens used, and
      alternative diagnostic tests.

PMID- 10644384
TI  - Cryptococcosis in AIDS.
AB  - A total of 87 patients (17 female, 70 male) were admitted to SIRIRAJ HOSPITAL,
      MAHIDOL UNIVERSITY, BANGKOK, THAILAND, from JANUARY 1996 TO DECEMBER 1997, with a
      diagnosis of cryptococcal meningitis and underlying AIDS. The age range was 14:
      70 years, mean 32.1. Six females (35%) and thirty-one males (44%) died, while the
      others were discharged home after clinical improvement. The mean duration of
      admission of those who died was 14.5 days, which was shorter than that of the
      patients who survived (25.7 days). Cerebral cryptococcosis was diagnosed using
      culture (100%), India ink preparation (91%), latex agglutination test (100%), and
      polymerase chain reaction (86%). Polymerase chain reaction fingerprinting of
      Cryptococcus neoformans revealed 99% serotype A and 1% serotype B. The mean
      minimum inhibitory concentrations of amphotericin B, flucytosine, fluconazole and
      itraconazole against 87 isolates of C neoformans were 0.55 microg/ml (0.25-1, SD
      = 0.22), 9.5 microg/ml (2-20, SD = 4.91), 6.9 microg/ml (1-16, SD = 4.42) and
      0.36 microg/ml (0.125-1.0, SD = 0.23), respectively. These findings showed that
      the cryptococcal infections were sensitive to these antifungal agents.

PMID- 10644385
TI  - Oral care of elderly patients: nurses' knowledge and views.
AB  - It is important that healthcare professionals caring for the elderly in hospitals
      have a core knowledge of the orodental care requirements of their patients. The
      aim of this study was to determine the knowledge and views of nurses working on
      acute and rehabilitation care of the elderly wards about orodental care. One
      hundred nurses and healthcare assistants took part in this questionnaire study of
      which 58 were qualified nurses and 70 had been employed on care of the elderly
      wards for two or more years. Although the majority of the respondents were
      registered with a dentist and attended regularly, 40 did have 'some anxiety'
      about visiting their dentist. Approximately half of the study population
      regularly gave advice to their patients about dental care but their knowledge of
      and reasons for providing oral care and advice was often incorrect. The group's
      understanding of the availability of dental treatment provided by the National
      Health Service was also often inaccurate. It was concluded that a better core
      knowledge of the orodental care of older patients is required by all healthcare
      professionals who care for this group. It is also important that individuals in
      whom anxiety is associated with their own dental experience do not neglect to
      give orodental health advice to their patients.

PMID- 10644386
TI  - The impact of hearing on communication.
AB  - The study was designed to assess the impact of hearing impairment on
      communication between older hospital patients and medical staff and to see
      whether intervention to improve hearing influences perceived communication.
      Structured interviews were held with 200 mentally alert elderly hospital in
      patients before and after the introduction of voice amplifiers and acetate cards
      depicting a hearing problem. Prior to intervention 22% of patients rated
      communication with their doctor as poor or unsatisfactory. Following intervention
      there was a significant improvement (Chi-square p=0.006), with only 6% of
      patients reporting communication with their doctor as poor or unsatisfactory.
      Most of the patients who felt communication was unsatisfactory could not hear
      what was being said. We conclude that simple measures can improve the number of
      older patients hearing what their doctor says and improve their perception of
      communication with the hospital doctor.

PMID- 10644387
TI  - Spontaneous necrosis of parathyroid adenoma: biochemical and imaging follow-up
      for two years.
AB  - We report a patient with a biochemically and radiologically confirmed parathyroid
      adenoma, which underwent spontaneous resolution by necrosis. The patient was
      followed-up over the subsequent two years during which time the tumour and
      hypercalcaemia recurred. Sequential radiological and biochemical changes at the
      time of diagnosis, spontaneous necrosis and recurrence are documented fully.

PMID- 10644388
TI  - Acute myoedema: an unusual presenting manifestation of hypothyroid myopathy.
AB  - We describe a patient with primary hypothyroidism due to autoimmune thyroiditis,
      presenting with acute myoedema and spontaneous rhabdomyolysis. During his
      hospital stay, he developed altered sensorium due to hypo-osmolal hyponatraemia
      and later developed bilateral foot drop that responded to appropriate treatment.

PMID- 10644389
TI  - Hepatocellular adenomatosis associated with hereditary haemochromatosis.
AB  - A young healthy man presented with abdominal pain following an accidental fall.
      Imaging studies and laparoscopy revealed multiple yellowish well-defined hepatic
      lesions. Liver biopsies showed hepatic adenomas and iron overload. Laboratory
      investigation confirmed a diagnosis of hereditary haemochromatosis. To our
      knowledge this represents the first report of an association of hepatic
      adenomatosis and primary haemochromatosis.

PMID- 10644390
TI  - An aggressive intrasinusoidal lymphoma presenting with marked systemic
      disturbance but normal imaging studies.
AB  - A patient with an aggressive intrasinusoidal non-Hodgkins lymphoma, presenting
      with marked systemic disturbance but only a mildly raised alkaline phosphatase as
      a localising sign is described. All imaging studies of the liver were normal and
      the diagnosis was delayed until a percutaneous liver biopsy was performed. Once
      diagnosed, the patient responded extremely well to conventional anti-lymphoma
      chemotherapy.

PMID- 10644391
TI  - Aspergillus niger endocarditis in an immunocompetent patient: an unusual course.
AB  - Aspergillus is an opportunistic nosocomial fungus generally associated with a
      high mortality rate. A niger has been rarely associated with infection, and most
      cases have occurred in patients who have recently undergone heart surgery or in
      immunocompromised patients. We present a case of an immunocompetent patient with
      A niger endocarditis which illustrates the difficulties in diagnosis and the
      possible insidious course of fungal endocarditis.

PMID- 10644392
TI  - Massive splenomegaly in tropical West Africa.

PMID- 10644393
TI  - A young man with dry skin and nodules on elbows and buttocks.

PMID- 10644394
TI  - An unusual cause of cardiac failure.

PMID- 10644395
TI  - Acute Q fever in a patient returning from the tropics.

PMID- 10644396
TI  - Exertional dyspnoea and nonproductive cough in a 22-year-old man.

PMID- 10644397
TI  - Masked hypercalcaemia.

PMID- 10644398
TI  - Multiple-choice questions in thoracic transplantation medicine.

PMID- 10644399
TI  - Skull osteomyelitis and multiple brain abscesses.

PMID- 10644400
TI  - Haemolytic anaemia due to metformin.

PMID- 10644401
TI  - Medical statistics - a commonsense approach

PMID- 10644402
TI  - Current problems in epilepsy. Vol 15, benign childhood partial seizures and
      related epileptic syndromes

PMID- 10644403
TI  - Key topics in orthopaedic trauma surgery

PMID- 10644404
TI  - Implementing clinical guidelines - a practical guide

PMID- 10644405
TI  - Melanoma and insecticides: is there a connection?

PMID- 10644406
TI  - Animal-vegetal axis patterning mechanisms in the early sea urchin embryo.
AB  - We discuss recent progress in understanding how cell fates are specified along
      the animal-vegetal axis of the sea urchin embryo. This process is initiated by
      cell-autonomous, maternally directed, mechanisms that establish three unique gene
      regulatory domains. These domains are defined by distinct sets of vegetalizing
      (beta-catenin) and animalizing transcription factor (ATF) activities and their
      region of overlap in the macromeres, which specifies these cells as early
      mesendoderm. Subsequent signaling among cleavage-stage blastomeres further
      subdivides fates of macromere progeny to yield major embryonic tissues.
      Zygotically produced Wnt8 reinforces maternally regulated levels of nuclear beta
      catenin in vegetal derivatives to down regulate ATF activity and further promote
      mesendoderm fates. Signaling through the Notch receptor from the vegetal
      micromere lineages diverts adjacent mesendoderm to secondary mesenchyme fates.
      Continued Wnt signaling expands the vegetal domain of beta-catenin's
      transcriptional regulatory activity and competes with animal signaling factors,
      including BMP2/4, to specify the endoderm-ectoderm border within veg(1) progeny.
      This model places new emphasis on the importance of the ratio of maternally
      regulated vegetal and animal transcription factor activities in initial
      specification events along the animal-vegetal axis.

PMID- 10644407
TI  - A critical period for conversion of ectodermal cells to a neural crest fate.
AB  - Previously, we found that interactions between neural and nonneural ectoderm can
      generate neural crest cells, with both the ectodermal and the neuroepithelial
      cells contributing to induced population (M. A. J. Selleck and M. Bronner-Fraser,
      1995, Development 121, 525-538). To further characterize the ability of
      ectodermal cells to form neural crest, we have challenged their normal fate by
      transplanting them into the neural tube. To ensure that the ectoderm was from
      nonneural regions, we utilized extraembryonic ectoderm (the proamnion) and
      transplanted it into the presumptive midbrain of 1. 5-day-old chick embryos. We
      observed that the grafted ectoderm has the capacity to adopt a neural crest fate,
      responding within a few hours of surgery by turning on neural crest markers HNK-1
      and Slug. However, the competence of the ectoderm to respond to neural crest
      inducing signals is time limited, declining rapidly in donors older than the 10
      somite stage. Similarly, the inductive capacity of the host midbrain declines in
      a time-dependent fashion. Our results show that extraembryonic ectoderm has the
      capacity to form neural crest cells given proper inducing signals, expressing
      both morphological and molecular markers characteristic of neural crest cells.

PMID- 10644408
TI  - Loss of FGF receptor 1 signaling reduces skeletal muscle mass and disrupts
      myofiber organization in the developing limb.
AB  - The identities of extracellular growth factors that regulate skeletal muscle
      development in vivo are largely unknown. We asked if FGFs, which act as
      repressors of myogenesis in culture, play a similar role in vivo by ectopically
      expressing in the developing limb a truncated FGF receptor 1 (dnFGFR1) that acts
      as a dominant negative mutant. Hind limbs and the adjacent somites of Hamburger
      and Hamilton (HH) stage 17 chickens were infected with a replication-competent
      RCAS virus encoding dnFGFR1. By ED5, the virus had spread extensively within the
      limb and the adjacent somites with little rostral or caudal expansion of the
      infection along the axial midline. Viral infection and mutant receptor expression
      were coincident as revealed by the distribution of a viral coat protein and an HA
      epitope tag present on the carboxy terminus of dnFGFR1. Within 48 h following
      injection of dnFGFR1, we could detect no obvious changes in skeletal muscle
      precursor cell migration into the hind limb as compared to control limbs infected
      with an empty RCAN virus. However, by 3 days following infection of RCAS-dnFGFR1
      virus, the level of skeletal muscle-specific myosin heavy chain was decreased and
      the expression pattern altered, suggesting disruption of skeletal muscle
      development. Two striking muscular phenotypes were observed in dnFGFR1-expressing
      limbs, including an average loss of 30% in skeletal muscle wet weight and a 50%
      decrease in myofiber density. At all ages examined the loss of skeletal muscle
      mass was accompanied by a loss of myoblasts and an unexpected concomitant loss of
      fibroblasts. Consistent with these observations, explants of infected cells
      revealed a reduction in the number of myonuclei in myotubes. Although the
      myofiber density per unit area was decreased over 50% compared to controls there
      were no detectable effects on myofiber diameter. The loss in myofiber density
      was, however, accompanied by an increase in the space surrounding individual
      myofibers and a generalized loss of myofiber integrity. It is noteworthy that
      long-bone development was unaffected by RCAS-dnFGFR1 infection, suggesting that
      FGFR2 and FGFR3 signaling was not disrupted. Our data provide conclusive evidence
      that FGFR1 signaling is necessary to maintain myoblast number and plays a role in
      myofiber organization.

PMID- 10644409
TI  - Functional analysis of repressor binding sites in the iab-2 regulatory region of
      the abdominal-A homeotic gene.
AB  - Spatial boundaries of homeotic gene expression are initiated and maintained by
      two sets of transcriptional repressors: the gap gene products and the Polycomb
      group proteins. Previously, the Hunchback (HB) protein has been implicated in
      setting the anterior expression limit of the UBX homeotic protein in parasegment
      6. Here we investigate DNA elements and trans-acting repressors that control
      spatial expression of the Abdominal-A (ABD-A) homeotic protein. Analysis of a 1.7
      kb enhancer element [iab-2(1.7)] from the iab-2 regulatory region shows that in
      contrast to Ubx enhancer elements, both HB and Kruppel (KR) are required to set
      the ABD-A anterior boundary in parasegment 7. DNase I footprinting and site
      directed mutagenesis show that HB and KR are direct regulators of this iab-2
      enhancer. The single KR site can be moved to a new location 100 bp away and still
      maintain repressive activity, whereas relocation by 300 bp abolishes activity.
      These results suggest that KR repression occurs through a local quenching
      mechanism. We also show that the gap repressor Giant (GT) initially establishes a
      posterior expression limit at PS9, which shifts posteriorly after the blastoderm
      stage. Finally, we show that this iab-2 enhancer contains multiple binding sites
      for the Polycomb group protein Pleiohomeotic (PHO). These iab-2 PHO sites are
      required in vivo for chromosome pairing-dependent repression of a mini-white
      reporter. However, the PHO sites are not sufficient to maintain repression of a
      homeotic reporter gene anterior to PS7. Full maintenance at late embryonic stages
      requires additional sequences adjacent to the iab-2(1.7) enhancer.

PMID- 10644410
TI  - Cyclin A associates with the fusome during germline cyst formation in the
      Drosophila ovary.
AB  - Regulated changes in the cell cycle underlie many aspects of growth and
      differentiation. Prior to meiosis, germ cell cycles in many organisms become
      accelerated, synchronized, and modified to lack cytokinesis. These changes cause
      cysts of interconnected germ cells to form that typically contain 2(n) cells. In
      Drosophila, developing germ cells during this period contain a distinctive
      organelle, the fusome, that is required for normal cyst formation. We find that
      the cell cycle regulator Cyclin A transiently associates with the fusome during
      the cystocyte cell cycles, suggesting that fusome-associated Cyclin A drives the
      interconnected cells within each cyst synchronously into mitosis. In the presence
      of a normal fusome, overexpression of Cyclin A forces cysts through an extra
      round of cell division to produce cysts with 32 germline cells. Female sterile
      mutations in UbcD1, encoding an E2 ubiquitin-conjugating enzyme, have a similar
      effect. Our observations suggest that programmed changes in the expression and
      cytoplasmic localization of key cell cycle regulatory proteins control germline
      cyst production.

PMID- 10644411
TI  - Confocal imaging of early heart development in Xenopus laevis.
AB  - Xenopus laevis provides a number of advantages to studies on cardiovascular
      development. The embryos are fairly large, are easy to obtain, and can develop at
      ambient temperature in simple buffer solutions. Although classic descriptions of
      heart development exist, the ability to use whole-mount immunohistochemical
      methods and confocal microscopy may enhance the ability to understand both normal
      and experimentally perturbed cardiovascular development. We have started to
      examine the early stages of cardiac development in Xenopus, seeking to identify
      antibodies and fixatives that allow easy examination of the developing heart. We
      have used monoclonal antibodies (mAbs) raised against bovine cardiac troponin T
      and chicken tropomyosin to visualize cardiac muscle, a goat antibody recognizing
      bovine type VI collagen to stain the lining of vessels, and the JB3 mAb raised
      against chicken fibrillin, which allows the visualization of a variety of
      cardiovascular tissues during early development. Results from embryonic stages 24
      46 are presented.

PMID- 10644412
TI  - The morphology of heart development in Xenopus laevis.
AB  - We have used serial histological sections to document heart formation in Xenopus
      laevis, from the formation of a linear heart tube to the appearance of
      morphologically distinct atrial and ventricular chambers. 3D reconstruction
      techniques have been used to derive accurate models from digital images,
      revealing the morphological changes that accompany heart differentiation. To
      demonstrate the utility of this approach in analysing cardiac gene expression, we
      have reexamined the distribution of Hand1 transcripts in the linear and looped
      heart tube. Our results demonstrate that prior to looping, an initial asymmetric,
      left-sided pattern is replaced by more symmetrical localisation of transcripts to
      the ventral portion of the myocardium. After the onset of looping, Hand1
      expression is restricted to the ventral ventricular myocardium and extends along
      the entire length of the single ventricle.

PMID- 10644413
TI  - Bmp-4 requires the presence of the digits to initiate programmed cell death in
      limb interdigital tissues.
AB  - The effects of Bmp-4 on interdigital cell death were investigated in the mouse.
      Affi-Gel beads, loaded with recombinant Bmp-4 protein, were transplanted into the
      interdigital tissues of day 12.5 hindlimb, ex utero. It was established that Bmp
      4 could induce precocious interdigital cell death. Using in situ hybridization,
      the expression patterns of bmp-4 and alk-6 receptor were established. Both genes
      were found coexpressed in the interdigital region of 12.5- and 13. 5-day
      hindlimbs. This suggests that Bmp-4 may act in an autocrine fashion. We have also
      studied the effects of Bmp-4 on 12.5-day interdigital tissue cultures. In all
      specimens examined, the interdigital tissues produced cartilage instead of
      participating in cell death. The addition of exogenous Bmp-4 to the interdigital
      cultures did not induce apoptosis but instead enhanced chondrogenesis. The
      discrepancy between the effects of Bmp-4 in vitro and ex utero was attributed to
      the presence of digits. When a flanking digit was left attached to the
      interdigital tissues, in vitro, Bmp-4 promoted apoptosis instead of
      chondrogenesis. In sum, the results suggest that Bmp-4 is a multifunctional
      protein and its effect on the interdigital tissues is dependent on the modulating
      influence of the digits.

PMID- 10644414
TI  - Differential expression and regulation by 20-hydroxyecdysone of mosquito
      ultraspiracle isoforms.
AB  - Ultraspiracle (USP), the insect homologue of the vertebrate retinoid X receptor,
      is an obligatory dimerization partner for the ecdysteroid receptor (EcR). Two USP
      isoforms, USP-A and USP-B, with distinct N-termini, occur in the mosquito Aedes
      aegypti. In the fat body and ovary, USP-A mRNA is highly expressed during the pre
      and late vitellogenic stages, corresponding to a period of low ecdysteroid
      titer, while USP-B mRNA exhibits its highest levels during the vitellogenic
      period, correlating with a high ecdysteroid titer. Remarkably, 20-hydroxyecdysone
      (20E) has opposite effects on USP isoform transcripts in in vitro fat body
      culture. This steroid hormone upregulates USP-B transcription and its presence is
      required to sustain a high level of USP-B expression. In contrast, 20E inhibits
      activation of USP-A transcription. Although EcR.USP-A recognizes the same
      ecdysteroid-responsive elements, EcR.USP-B binds them with an affinity twofold
      higher than that of EcR.USP-A. Likewise, EcR.USP-B transactivates a reporter gene
      in CV-1 cells twofold more strongly than EcR.USP-A. These results suggest that
      USP-B functions as a major heterodimerization partner for EcR during the
      vitellogenic response to 20E in the mosquito.

PMID- 10644415
TI  - Acidic electrolysed water in the disinfection of the ocular surface.
AB  - Acidic electrolysed water (AEW) is a colorless solution prepared by the
      electrolysis of sodium chloride solution, which has potent anti-microbial
      activity against a wide variety of bacteria, fungi and virus. In this study, the
      safety and efficacy of an isotonic AEW solution (iAEW) was investigated both in
      vitro and in vivo using denuded corneas of guinea pigs. Povidone iodine (0.01
      1.0%) was used as control. Exposure of P. aeruginosa to iAEW for 5 sec caused
      total inhibition of bacterial growth in vitro. Comparable results were obtained
      with 1% povidone iodine, while more dilute solutions required longer exposure
      times for similar effects. Cytotoxicity of iAEW on corneal epithelial cells in
      vitro was significantly less compared to 1% povidone iodine (P<0.05), while
      minimal damage was observed in vivo by irrigation of the cornea with either iAEW
      or 1% povidone iodine. Treatment of P. aeruginosa with iAEW (15 sec)
      significantly inhibited the onset of corneal infection in guinea pigs. iAEW may
      offer an effective and safe method for disinfection of the ocular surface.

PMID- 10644416
TI  - Effects of FTY720, a novel immunosuppressant, on experimental autoimmune
      uveoretinitis in rats.
AB  - The immunosuppressive properties of FTY720, a novel immunosuppressant obtained by
      structural modification of ISP-I isolated from the fermentation broth of Isaria
      sinclairii, were studied in experimental autoimmune uveoretinitis (EAU) in rats.
      Lewis rats were immunized with S-antigen and treated with FTY720 (0. 03, 0.06,
      0.1 mg kg(-1)day(-1)) or distilled water for 16 days after the immunization.
      FTY720 suppressed the incidence and intensity of EAU in a dose-dependent manner
      as demonstrated by clinical and histological examinations. The drug significantly
      suppressed the serum levels of antibodies to S-antigen and antigens-specific
      lymphocyte proliferation. The number of peripheral lymphocytes, but not
      neutrophils, was markedly reduced by FTY720 treatment. FTY720 also suppressed the
      intensity of EAU when it was given from the day of EAU onset. These results
      indicate that FTY720 has intense immunosuppressive effects on EAU in rats and may
      be a potential candidate for use in the treatment of patients with autoimmune
      uveitis.

PMID- 10644417
TI  - The similarity of protein expression in trabecular meshwork and lamina cribrosa:
      implications for glaucoma.
AB  - The purpose of the present investigation was to compare protein expression in
      various ocular cells and tissues including the human trabecular meshwork (TM) and
      the lamina cribrosa (LC). To conduct the comparisons, we primarily utilized
      autofluorography of one-dimensional (1D) and high resolution, two-dimensional
      (2D) polyacrylamide gels of proteins from radiolabelled tissues and cultured
      cells. Results from the investigations indicated that patterns of protein
      expression from TM and LC were the most similar among the ocular cells and
      tissues compared.Specifically, these autofluorographic ' fingerprints' indicated
      that proteins in TM and LC cultured cells and tissue were exceptionally similar
      (a) in band position and intensity (1D gels) and (b) in spot congruence (2D gels)
      as compared to other ocular cells and tissues. We conclude that the TM and the
      LC, two ocular tissues intimately linked to the pathogenesis of primary open
      angle glaucoma, display remarkable similarity in protein expression. This finding
      may have implications for the molecular etiology of glaucoma.

PMID- 10644418
TI  - Induction of posterior vitreous detachment in rabbits by intravitreal injection
      of tissue plasminogen activator following cryopexy.
AB  - The purpose of this study was to generate intravitreal plasmin after intravitreal
      injection of tissue plasminogen activator (TPA) and cryopexy, and to assess its
      proteolytic effect on the vitreoretinal border region.Twenty-four hr after a mild
      cryopexy, 25 microg recombinant tissue plasminogen activator (TPA) was injected
      into the vitreous cavity, the fellow eye received an intravitreal injection of
      the same volume of buffered salt solution. Light, scanning and transmission
      electron microscopy was performed in 24 eyes that underwent vitrectomy 1 week
      later. Plasmin was measured prior and 2 hr after intravitreal TPA injection (4
      eyes). Hyaluronic acid (8 eyes) and vitronectin (4 eyes) were measured 1 week
      after TPA- or BSS-injection and compared to untreated controls. In all eyes
      treated with TPA, histopathologic examination by scanning and transmission
      electron microscopy demonstrated a complete detachment of the vitreous from the
      surface of the retina as well as from the posterior surface of the lens. After
      BSS-injection, vitreous cortex attachment to the retina was demonstrated in all
      eyes. Two hr after TPA-injection, plasmin increased to 9.75 mU ml(-1)(s.d.+/
      2.3). Neither a decrease of hyaluronic acid nor an increase of transglutaminase,
      that might alter the vitreous structure leading to a collapse of the vitreous,
      were detected in treated eyes. There was no increase of vitronectin indicating
      proliferative activity.A temporary breakdown of the blood-retinal barrier by
      cryopexy combined with intravitreal injection of TPA is a sufficient technique to
      induce a posterior vitreous detachment enzymatically. The method may be useful
      prior to mechanical vitrectomy.

PMID- 10644419
TI  - Molecular genetics of Meesmann's corneal dystrophy: ancestral and novel mutations
      in keratin 12 (K12) and complete sequence of the human KRT12 gene.
AB  - Recently, we identified the first mutations in corneal keratins K3 and K12 in
      families with Meesmann's corneal dystrophy (MCD). Here, we sequenced all regions
      of the human K12 gene, to enable mutation detection for all exons using genomic
      DNA as a template. The human K12 genomic sequence spans 5919 bp and consists of
      eight exons. A microsatellite dinucleotide repeat was identified within intron 3,
      which was highly polymorphic and which we developed for use in genotype analysis.
      In addition, two mutations in the helix initiation motif of K12 were found in
      families with MCD. A novel mutation was detected in an American kindred, 410T-
      >C, which predicts the amino acid substitution M129T. In a German family,
      mutation 428G-->C was identified, predicting amino acid change R135T. The latter
      mutation was identical to that which we identified in the original kindred
      described by Meesmann. Using the intragenic microsatellite polymorphism in K12
      and additional flanking markers, we were able to show that this family shares a
      common haplotype with the original Meesmann kindred. These results strongly imply
      that R135T represents an ancestral mutation in the German population. Both
      mutations occur in the highly conserved helix initiation motif of the K12
      polypeptide. A total of eight mutations have now been reported in the K12 gene.

PMID- 10644420
TI  - Characterization of alpha(1)-adrenoceptor subtypes in the eye.
AB  - The presence of the alpha(1)-adrenoceptor subtypes in various parts of the pig
      and rabbit eyes was investigated using [(3)H]-prazosin radioligand binding. The
      characterization of the subtypes was achieved by performing competition
      experiments with various subtype selective drugs. In the pig retina, both
      alpha(1A)- and alpha(1B)-adrenoceptors were detected and the proportion of sites
      was 70% alpha(1A)- and 30% alpha(1B)-adrenoceptors, respectively. In the pig
      iris, ciliary body and choroid, which are melanin-rich tissues, the non-specific
      binding of [(3)H]-prazosin was too high to detect any of the alpha(1)
      adrenoceptor subtypes. However, in the albino rabbit iris, ciliary body and
      retina both alpha(1A)- and alpha(1B)-adrenoceptors were detected. The proportion
      of sites in the iris was 60 % alpha(1A)- and 40% alpha(1B)-adrenoceptors,
      respectively. In the ciliary body and rabbit retina the proportion of sites were
      70% alpha(1A)- and 30% alpha(1B)-adrenoceptors. Only the alpha(1A)-adrenoceptor
      subtype was detected in the rabbit choroid.

PMID- 10644421
TI  - The significance of nitric oxide for parasympathetic vasodilation in the eye and
      other orbital tissues in the cat.
AB  - The role of nitric oxide formation in the vasodilation in the eye and other
      orbital tissues caused by pre-ganglionic stimulation of the facial nerve was
      studied in cats under alpha-chloralose anaesthesia. Regional blood flows were
      determined with radioactive microspheres during unilateral stimulation of the
      facial nerve before and after inhibition of nitric oxide synthase (NOS), alone or
      in combination with muscarinic blockade.N(omega)-nitro-L-arginine (L-NA), a non
      selective NOS-inhibitor, caused a significant increase in mean arterial blood
      pressure (MABP) and a decrease in cardiac output (CO). Concomitantly, local blood
      flows on the non-stimulated control side were reduced in most of the investigated
      tissues, indicating marked vasoconstriction. An inhibitor selective for neuronal
      NOS, 7-nitro-indazole (7-NI), had no significant effect on MABP, CO or local
      blood flows. During facial nerve stimulation at 5 Hz (n =6), choroidal blood flow
      on the stimulated side was 108+/-41% (P</=0.05) higher than on the non-stimulated
      side during control conditions, an effect that was completely abolished by L-NA.
      During stimulation at 10 Hz (n =8), the choroidal blood flow was 171+/-38%
      (P</=0.01) higher on the stimulated side during control conditions. The
      corresponding values after L-NA and subsequent administration of atropine were
      97+/-21% (P</=0.05, compared to control conditions) and 50+/-14% (P</=0.05,
      compared to control conditions), respectively. Atropine alone had no significant
      effect on the increase in choroidal blood flow caused by stimulation at 10 Hz (n
      =7), whereas subsequent administration of L-NA caused a statistically significant
      reduction. Administration of 7-NI had no significant effect on the choroidal
      vasodilation at 10 Hz (n =7), whereas subsequent administration of L-NA caused
      significant reduction, at least as compared to control conditions. These results
      suggest that nitric oxide is of greater significance for the choroidal
      vasodilation, caused by facial nerve stimulation, in the cat than it is in the
      rabbit. However, no definitive conclusions can be made concerning the source of
      the nitric oxide. Direct release of nitric oxide from the parasympathetic nerve
      fibres could contribute as well as nitric oxide formed in the vascular
      endothelium, secondary to the release of acetylcholine and/or VIP. At high
      frequencies, a part of the choroidal vasodilation seems to be independent of
      nitric oxide.

PMID- 10644422
TI  - The Nitrite/alpha crystallin reaction: a possible mechanism in lens matrix
      damage.
AB  - Recent work has explored the potential deleterious role that nitric oxide (NO)
      and its derivatives may have in human disease. The many by-products of NO include
      nitrite ion, which accumulates in the anterior chamber during ocular inflammation
      and can be derived from cigarette smoking. Cigarette smoking has been strongly
      linked to nuclear cataract formation, although the mechanism remains unknown. We
      have previously observed that nitrite reactions with the matrix proteins elastin
      and collagen produce damaging effects that mimic those observed in age- and
      smoking-related illnesses. In the present study we report on the reaction of
      nitrite with alpha crystallin, the major lens matrix protein. Incubations at
      neutral pH and body temperature of nitrite with alpha crystallin resulted in
      protein modifications indicative of oxidative damage and similar to changes seen
      in the aging lens as well as cataracts. These include increased fluorescence,
      yellowing and protein cross-linking. L-kynurenine, a tryptophan derivative, was
      identified as a reaction product. L-kynurenine was also formed from the reaction
      of nitrite with free tryptophan. Thus, this non-enzymatic nitration of alpha
      crystallin provides a novel mechanism by which lens proteins may be damaged in
      vivo. Since human exposure to nitrite is increased by cigarette smoking, this
      reaction could provide an explanation for the association between nuclear
      cataracts and smoking.

PMID- 10644423
TI  - Formation of hydroxyl radicals in the human lens is related to the severity of
      nuclear cataract.
AB  - Recent studies have identified specific hydroxylated amino acid oxidation
      products which strongly suggest the presence of hydroxyl radical (HO.)-damaged
      proteins in human cataractous lenses. In the present study, the ability of early
      stage (type II) and advanced (type IV) nuclear cataractous lens homogenates to
      catalyse HO. production in the presence of H(2)O(2)was investigated using
      electron paramagnetic resonance (EPR) spectroscopy with the free radical trap,
      5,5-dimethyl-1-pyrroline- N -oxide (DMPO). Cataractous lens homogenates incubated
      with 1 m m H(2)O(2)generated a distinct HO. signal, which was significantly more
      intense in the nuclear region of the type IV compared to the type II lenses. The
      ability of individual lens nuclei and cortices to stimulate HO. production was
      positively correlated. The DMPO-HO. signal was competitively inhibited by
      ethanol, confirming that the DMPO-HO. signal was due to HO. formation and not
      DMPO-OOH degradation. The metal ion chelator, diethylenetriaminepentaacetic acid,
      also inhibited HO. formation, indicating that lenticular metal ions play a key
      role in HO. formation. Cataractous lens homogenates also stimulated ascorbyl
      radical production, further suggesting the presence of redox-active metal ions in
      the tissue. Analysis of lenses for total Fe and Cu (using atomic absorption
      spectrometry) showed that the more advanced type IV lenses tended to have higher
      Fe, but similar Cu, levels compared to the type II lenses. The levels of both
      metals were lower in non-cataractous lenses. These data support the hypothesis
      that transition metal-mediated HO. production may play a role in the aetiology of
      age-related nuclear cataract.

PMID- 10644424
TI  - Heterogeneity in ornithine cytotoxicity of bovine retinal pigment epithelial
      cells in primary culture.
AB  - Gyrate atrophy of the choroid and retina is a chorioretinal degeneration caused
      by hyperornithinemia and a deficiency of ornithine-delta-aminotransferase (OAT).
      We recently showed that ornithine exhibits cytotoxicity to human retinal pigment
      epithelial (RPE) cell lines treated with the OAT inhibitor, 5
      fluoromethylornithine (5-FMOrn), and suggested that this system may be an in
      vitro model of gyrate atrophy. In the present study, in order to apply this
      system to primary cultured RPE cells, we freshly prepared RPE cells from bovine
      eyes and studied the effect of ornithine on cell damage. Two phenotypes,
      epithelioid and fusiform, which coexisted in the primary culture and epithelioid
      phenotype cells, but not fusiform ones, were severely damaged and partially
      detached from the substrate by 10 m m ornithine and 0.5 m m 5-FMOrn. Neither
      ornithine nor 5-FMOrn alone exhibited such cytotoxicity to both phenotypes of RPE
      cells. Proline significantly prevented the ornithine-induced cytotoxicity.
      Epithelioid and fusiform phenotypes isolated from the primary culture showed
      different distribution of actin filaments. A combination of ornithine and 5-FMOrn
      time-dependently inhibited [(3)H]thymidine incorporation in the epithelioid, but
      not fusiform, cells. Proline prevented the inhibition of [(3)H]thymidine
      incorporation by ornithine in 5-FMOrn-treated epithelioid cells. Furthermore, l 
      azetidine-2-carboxylic acid, a collagen synthesis inhibitor, reduced
      [(3)H]thymidine incorporation in epithelioid, but not fusiform, cells, which was
      reversed by proline. These results demonstrate that the epithelioid phenotype of
      bovine RPE cells becomes susceptible to ornithine following inactivation of OAT.
      The phenotypic cells and its prevention by proline may provide insight into
      biochemical triggers that induce gyrate atrophy.

PMID- 10644425
TI  - Visually induced changes in components of the retinoic acid system in fundal
      layers of the chick.
AB  - Eye growth is visually regulated via messengers that are released from the
      retina. The retina involves a yet unknown algorithm to analyse the projected
      image so that the appropriate growth rates for the back of the eye are ensured.
      One biochemical candidate that could act as a growth controller, is retinoic acid
      (RA). Previous work (Seko, Shimokawa and Tokoro, 1996; Mertz et al., 1999) has
      shown that retinal and choroidal RA levels are indeed predictably changed by
      visual conditions that cause myopia or hyperopia, respectively. We have studied
      in which fundal tissues aldehyde dehydrogenase-2 (AHD2) and retinaldehyde
      dehydrogenase-2 (RALDH2), enzymes involved in RA synthesis, are expressed and at
      which levels the effects of vision on RA levels may be controlled. Using Northern
      blot analysis, we have found that the retinal mRNA level of the AHD2 is up
      regulated after 3 days of treatment with negative lenses (negative lenses place
      the image behind the retina). The abundance of the retinal mRNA of a RA receptor,
      RAR-beta, was up-regulated already after 6 hr of treatment with positive lenses
      (positive lenses place the image in front of the retina). The up-regulation
      persisted for at least 1 week. Finally, we have studied the effects of an
      inhibitor of RA synthesis, disulfiram, on the visual control of eye growth. We
      found inhibition of myopia as induced by frosted goggles ('deprivation myopia')
      but no significant inhibitory effects on refractive errors induced by +7D or -7D
      lenses. Our results are in line with the hypothesis that RA may play a role in
      the visual control of eye growth. The RA system differs from a number of other
      candidates (dopamine, cholinergic agents, opiates) in that it distinguishes
      between positive and negative defocus, similar to the immediate early gene ZENK
      (Stell et al., 1999). The exact time kinetics of the changes have still to be
      worked out since it is possible that the changes in RA relate to already
      occurring changes in growth rather than to initial steps of the signaling
      cascade.

PMID- 10644426
TI  - Iris blood flow response to acute decreases in ocular perfusion pressure: a laser
      Doppler flowmetry study in humans.
AB  - The relationship between blood flow and ocular perfusion pressure in the iris
      vascular bed of the human eye has not been established yet. Consequently, it is
      not known whether the iris circulation has some autoregulatory capacity. The aim
      of the present study was to investigate this relationship in the particular case
      where the perfusion pressure was decreased by increasing the intraocular
      pressure. Using laser Doppler flowmetry, mean velocity, volume and flow of blood
      through the iris were measured in normal subjects during acute decreases of the
      mean ocular perfusion pressure induced by raising the intraocular pressure with a
      scleral suction cup. Two experimental paradigms were applied. In the first, the
      suction pressure was rapidly increased from baseline, in steps of 50-100 mmHg, to
      a level where the intraocular pressure was above the mean ophthalmic artery blood
      pressure. In the second, the suction pressure was increased from baseline in four
      successive steps of 50 mmHg each. The suction pressure was kept constant for 2
      min at each step. With the first paradigm (nine eyes), a 72% decrease in
      perfusion pressure induced a 63% decrease of iris blood flow due mainly to a drop
      in blood velocity. Immediately after suction release, blood flow increased by 62%
      above baseline and then returned to its baseline value within 2 min. With the
      second paradigm (six eyes), a 28% decrease in perfusion pressure resulted in a
      30% flow reduction, which was due to significant decreases (P<0. 001) of both
      blood volume and velocity. Combining the results of both paradigms, we observed a
      significant linear correlation between iris blood flow and perfusion pressure (R
      =0.964, P<0.001). These results demonstrate that a decrease of the perfusion
      pressure due to an increase of the intraocular pressure induces a decrease of the
      iris blood flow. No evidence of an autoregulatory process in the iris vascular
      bed could be demonstrated. A reactive hyperemia was observed in response to a
      sudden increase in perfusion pressure occurring after a period of decreased blood
      flow.

PMID- 10644427
TI  - Effect of prostaglandins A(2), E(1), F(2 alpha)and latanoprost on cultured human
      iridal melanocytes.
AB  - The effect of various prostaglandins on the growth, melanogenesis and
      dendrification of cultured iridal melanocytes were studied. Iridal melanocytes
      were isolated and cultured with medium supplemented with cAMP elevating agents
      and basic fibroblast growth factor (complete medium). The iridal melanocytes were
      plated into multiple well plates and cultured with complete medium, cAMP-deleted
      medium with or without various prostaglandins at different concentrations. After
      5-7 days, the numbers of cells and dendrites were counted and melanin content was
      measured and compared to controls. Prostaglandin A(2)and E(1)stimulated growth,
      melanogenesis and dendrification of cultured iridal melanocytes in cAMP-deleted
      medium. Prostaglandin F(2 alpha), PhXA85 and latanoprost showed no effect under
      similar experimental conditions. These results indicate that prostaglandin
      A(2)and E(1)stimulate growth and differentiation of iridal melanocytes through
      the activation of cAMP system. Failure of stimulation of melanogenesis of iridal
      melanocytes by prostaglandin F(2 alpha)and PhXA85 in vitro may be related to a
      different second messenger system activated by these prostaglandins and the
      selective stimulating effect of these prostaglandins on iridal melanocytes from
      mixed-colored irides.

PMID- 10644428
TI  - Novel myosin VI isoform is abundantly expressed in retina.
AB  - Several forms of sensory deficit have been associated with unconventional myosin
      defects in humans and other animals. Normal hearing in mammals has been shown to
      require functional myosin VI (Avraham et al., 1995) and myosin VIIA (Gibson et
      al., 1995; Liu et al., 1997), and the combined blindness and deafness of Usher
      syndrome type IB has been shown to be produced by specific defects in myosin VIIA
      (Weil et al., 1997). Here we report the cloning and characterization of two
      distinct myosin VI isoforms (FMVIA and FMVIB) initially identified in a
      degenerate PCR screen of retinal cDNA from the striped bass, Morone saxatilis.
      Open reading frames for FMVIA and FMVIB encode predicted proteins of 1304 and
      1270 amino acids respectively, which are 83% identical at the amino acid level.
      Both fish isoforms are likewise approximately 83-86% identical to mammalian class
      VI myosins (Hasson and Mooseker, 1994). Northern blot analysis revealed that
      FMVIA mRNA is broadly expressed and most abundant in kidney, a pattern similar to
      that previously reported for mammalian myosin VI. FMVIB expression is
      dramatically more abundant in retina than in any other tissue examined.
      Antibodies directed against pig myosin VI (Hasson and Mooseker, 1994) detect a
      doublet at approximately 150 kDa in bass retina and RPE. Since both fish VIA and
      VIB isoforms share high sequence identity with pig myosin VI within the domain
      used for antibody production, it seems likely that this antibody crossreacts with
      both FMVIA and FMVIB. Immunocytochemistry with this same affinity-purified rabbit
      anti-myosin VI antibody shows that myosin VI isoforms are primarily localized in
      photoreceptors, horizontal cells and Muller cells in both fish and primate
      retinas. This report is the first demonstration that two myosin VI genes are
      expressed in the same organism and the same cell type (RPE). The relatively high
      abundance of FMVIB expression in retina suggests that it may play an important
      role in retinal motility events.

PMID- 10644429
TI  - Autistic disorder and chromosome 15q11-q13: construction and analysis of a
      BAC/PAC contig.
AB  - Autistic disorder (AD) is a neurodevelopmental disorder that affects
      approximately 2-10/10,000 individuals. Chromosome 15q11-q13 has been implicated
      in the genetic etiology of AD based on (1) cytogenetic abnormalities; (2)
      increased recombination frequency in this region in AD versus non-AD families;
      (3) suggested linkage with markers D15S156, D15S219, and D15S217; and (4)
      evidence for significant association with polymorphisms in the gamma-aminobutyric
      acid receptor subunit B3 gene (GABRB3). To isolate the putative 15q11-q13
      candidate AD gene, a genomic contig and physical map of the approximately 1.2-Mb
      region from the GABA receptor gene cluster to the OCA2 locus was generated.
      Twenty-one bacterial artificial chromosome (BAC) clones, 32 P1-derived artificial
      chromosome (PAC) clones, and 2 P1 clones have been isolated using the markers
      D15S540, GABRB3, GABRA5, GABRG3, D15S822, and D15S217, as well as 34 novel
      markers developed from the end sequences of BAC/PAC clones. In contrast to
      previous findings, the markers D15S822 and D15S975 have been localized within the
      GABRG3 gene, which we have shown to be approximately 250 kb in size. NotI and
      numerous EagI restriction enzyme cut sites were identified in this region. The
      BAC/PAC genomic contig can be utilized for the study of genomic structure and the
      identification and characterization of genes and their methylation status in this
      autism candidate gene region on human chromosome 15q11-q13.

PMID- 10644430
TI  - A novel ribosomal S6-kinase (RSK4; RPS6KA6) is commonly deleted in patients with
      complex X-linked mental retardation.
AB  - Large deletions in Xq21 often are associated with contiguous gene syndromes
      consisting of X-linked deafness type 3 (DFN3), mental retardation (MRX), and
      choroideremia (CHM). The identification of deletions associated with classic CHM
      or DFN3 facilitated the positional cloning of the underlying genes, REP-1 and
      POU3F4, respectively, and enabled the positioning of the MRX gene in between
      these genes. Here, we report the cloning and characterization of a novel gene,
      ribosomal S6-kinase 4 (RSK4; HGMW-approved symbol RPS6KA6), which maps in the MRX
      critical region. RSK4 is completely deleted in eight patients with the contiguous
      gene syndrome including MRX, partially deleted in a patient with DFN3 and present
      in patients with an Xq21 deletion and normal intellectual abilities. RSK4 is most
      abundantly expressed in brain and kidney. The predicted protein of 746 amino
      acids shows a high level of homology to three previously isolated members of the
      human RSK family. RSK2 is involved in Coffin-Lowry syndrome and nonspecific MRX.
      The localization of RSK4 in the interval that is commonly deleted in mentally
      retarded males together with the high degree of amino acid identity with RSK2
      suggests that RSK4 plays a role in normal neuronal development. Further mutation
      analyses in males with X-linked mental retardation must prove that RSK4 is indeed
      a novel MRX gene.

PMID- 10644431
TI  - Identification of a new locus for autosomal recessive Charcot-Marie-Tooth disease
      with focally folded myelin on chromosome 11p15.
AB  - Autosomal recessive Charcot-Marie-Tooth disease type 4B (CMT4B) is a
      demyelinating hereditary motor and sensory neuropathy characterized by abnormal
      folding of myelin sheaths. A locus for CMT4B has previously been mapped to
      chromosome 11q23 in a southern Italian pedigree. We initially excluded linkage in
      two Tunisian families with CMT4B to chromosome 11q23, demonstrating genetic
      heterogeneity within the CMT4B phenotype. Subsequently, using homozygosity
      mapping and linkage analysis in the largest Tunisian pedigree, we mapped a new
      locus to chromosome 11p15. A maximum two-point lod score of 6.05 was obtained
      with the marker D11S1329. Recombination events refined the CMT4B locus region to
      a 5.6-cM interval between markers D11S1331 and D11S4194. The second Tunisian
      CMT4B family was excluded from linkage to the new locus, demonstrating the
      existence of at least a third locus for the CMT4B phenotype.

PMID- 10644432
TI  - Genetic determinants of plasma triglyceride levels in (OLETF x BN) x OLETF
      backcross rats.
AB  - Altered lipid metabolism is closely associated with diabetes in humans, although
      predisposing genetic factors that affect hyperlipidemia have not yet been
      clarified. Our previously established OLETF strain is an obese rat model of type
      II diabetes, exhibiting hypertriglycemia as well as hyperinsulinemia,
      hyperglycemia, insulin resistance, and abundant abdominal fat. To identify
      genetic factors responsible for dyslipidemic phenotypes in OLETF rats, we
      performed a whole-genome scan using 293 male (OLETF x BN) x OLETF backcross rats.
      Our analysis identified two significant quantitative trait loci (QTLs), on rat
      chromosomes 1 and 8, that are related to fasting triglyceride levels. The
      chromosome 1 QTL colocalized with Dmo1 (diabetes mellitus, OLETF type 1), a locus
      previously shown to associate strongly with both fat levels and body weight. The
      other significant QTL localizes to the chromosome 8 marker D8Mit2, in a region
      where several apo-lipoprotein genes are clustered.

PMID- 10644433
TI  - Characterization of the human glutamate receptor subunit 3 gene (GRIA3), a
      candidate for bipolar disorder and nonspecific X-linked mental retardation.
AB  - The X-chromosome breakpoint in a female patient with a balanced translocation
      t(X;12)(q24;q15), bipolar affective disorder and mental retardation was mapped
      within the glutamate receptor 3 (GRIA3) gene by fluorescence in situ
      hybridization. The GRIA3 cDNA of 5894 bp was cloned, and the gene structure and
      pattern of expression were determined. The most abundant GRIA3 transcript is
      composed of 17 exons. An additional 5 exons (2a, 2b, 5a, 5b, and 5c) from the 5'
      end of the GRIA3 open reading frame were identified by EST analysis (ESTs
      AI379066 and AA947914). Two new polymorphic microsatellite repeats, (TC)(n=12-26)
      and (AC)(n=15-19), were identified within GRIA3 5' and 3'UTRs. No mutations were
      detected in families segregating disorders mapping across GRIA3, one with X
      linked bipolar affective disorder (BP) and one with a nonspecific X-linked mental
      retardation (MRX27). To assess the possibility of the involvement of the GRIA3
      gene in familial cases of complex BP, a large set of 373 individuals from 40
      pedigrees segregating BP were genotyped using closely linked (DXS1001) and
      intragenic (DXS1212 and GRIA3 3' UTR (AC)(n))) GRIA3 STR markers. No evidence of
      linkage was found by parametric Lod score analysis (the highest Lod score was 0.
      3 at DXS1212, using the dominant transmission model) or by affected sib-pair
      analysis.

PMID- 10644434
TI  - Denaturing high-performance liquid chromatography detects reliably BRCA1 and
      BRCA2 mutations.
AB  - Denaturing high-performance liquid chromatography (DHPLC) is a recently developed
      method of comparative sequencing based upon heteroduplex detection. To assess the
      reliability of this method, 180 different mutations (54 deletions, 12 insertions,
      and 117 single base substitutions) in BRCA1 and BRCA2 were tested. Second, 25
      index individuals with complete DHPLC analysis of BRCA1 were reanalyzed by dye
      terminator sequencing. Third, 41 index individuals were analyzed concomitantly by
      both DGGE and DHPLC. Of the 180 different BRCA1 and BRCA2 mutations, 179 showed
      heterozygous DHPLC elution profiles. Dye-terminator sequencing of the entire
      BRCA1 gene, including 5592 bp of coding sequence and 5206 bp of flanking
      noncoding sequence, in 25 index individuals did not reveal additional variants
      missed by DHPLC. The concomitant analysis of 41 index cases showed that 4
      probably disease-associated mutations were identified by DHPLC while only 3 of
      those 4 sites were detected by denaturing gradient gel electrophoresis. We
      conclude that DHPLC is a sensitive and cost-effective method for the screening of
      BRCA1 and BRCA2.

PMID- 10644435
TI  - The TOR1A (DYT1) gene family and its role in early onset torsion dystonia.
AB  - Most cases of early onset torsion dystonia are caused by a 3-bp deletion (GAG) in
      the coding region of the TOR1A gene (alias DYT1, DQ2), resulting in loss of a
      glutamic acid in the carboxy terminal of the encoded protein, torsin A. TOR1A and
      its homologue TOR1B (alias DQ1) are located adjacent to each other on human
      chromosome 9q34. Both genes comprise five similar exons; each gene spans a 10-kb
      region. Mutational analysis of most of the coding region and splice junctions of
      TOR1A and TOR1B did not reveal additional mutations in typical early onset cases
      lacking the GAG deletion (N = 17), in dystonic individuals with apparent
      homozygosity in the 9q34 chromosomal region (N = 5), or in a representative
      Ashkenazic Jewish individual with late onset dystonia, who shared a common
      haplotype in the 9q34 region with other late onset individuals in this ethnic
      group. A database search revealed a family of nine related genes (50-70%
      similarity) and their orthologues in species including human, mouse, rat, pig,
      zebrafish, fruitfly, and nematode. At least four of these genes occur in the
      human genome. Proteins encoded by this gene family share functional domains with
      the AAA/HSP/Clp-ATPase superfamily of chaperone-like proteins, but appear to
      represent a distinct evolutionary branch.

PMID- 10644436
TI  - FXY2/MID2, a gene related to the X-linked Opitz syndrome gene FXY/MID1, maps to
      Xq22 and encodes a FNIII domain-containing protein that associates with
      microtubules.
AB  - Opitz G/BBB syndrome (OS) is a genetically heterogeneous disorder with an X
      linked locus and an autosomal locus linked to 22q11.2. OS affects multiple organ
      systems with often variable severity even between siblings. The clinical
      features, which include hypertelorism, cleft lip and palate, defects of cardiac
      septation, hypospadias, and anorectal anomalies, indicate an underlying
      disturbance of the developing ventral midline of the embryo. The gene responsible
      for X-linked OS, FXY/MID1, is located on the short arm of the human X chromosome
      within Xp22.3 and encodes a protein with both an RBCC (RING finger, B-box, coiled
      coil) and a B30.2 domain. The Fxy gene in mice is also located on the X
      chromosome but spans the pseudoautosomal boundary in this species. Here we
      describe a gene closely related to FXY/MID1, called FXY2, which also maps to the
      X chromosome within Xq22. The mouse Fxy2 gene is located on the distal part of
      the mouse X chromosome within a region syntenic to Xq22. Analysis of genes
      flanking both FXY/MID1 and FXY2 (as well as their counterparts in mouse) suggests
      that these regions may have arisen as a result of an intrachromosomal duplication
      on an ancestral X chromosome. We have also identified in both FXY2 and FXY/MID1
      proteins a conserved fibronectin type III domain located between the RBCC and
      B30.2 domains that has implications for understanding protein function. The
      FXY/MID1 protein has previously been shown to colocalize with microtubules, and
      here we show that the FXY2 protein similarly associates with microtubules in a
      manner that is dependent on the carboxy-terminal B30.2 domain.

PMID- 10644437
TI  - USP25, a novel gene encoding a deubiquitinating enzyme, is located in the gene
      poor region 21q11.2.
AB  - We have identified a new gene, USP25, spanning over 150 kb at 21q11. 2, one of
      the lowest gene-density regions of the human genome. USP25 is made up of 25 exons
      and encodes a 1087-aa protein. Database comparisons reveal high homology with
      members of the ubiquitin protease family (UBP). Basal expression was observed in
      all human tissues tested, and two main transcripts were identified. The
      homologous murine gene has also been characterized. In situ hybridization in
      mouse embryonic brains showed a clear correlation of expression with
      proliferative neuroepithelial cells and postmitotic neurons. Moreover, high
      expression was observed in adult mouse testis. UBPs belong to a complex family of
      deubiquitinating enzymes that specifically cleave ubiquitin conjugates on a great
      variety of substrates. These enzymes have an essential role in protein
      degradation via the 26S proteasome and thus regulate many cellular pathways. An
      increase in USP25 gene dosage in Down syndrome patients could seriously disturb
      the balance between ubiquitinated and deubiquitinated substrates.

PMID- 10644438
TI  - Molecular cloning, chromosomal mapping, and developmental expression of a novel
      protein tyrosine phosphatase-like gene.
AB  - Protein tyrosine phosphatases (PTPs) mediate the dephosphorylation of
      phosphotyrosine. PTPs are known to be involved in many signal transduction
      pathways leading to cell growth, differentiation, and oncogenic transformation.
      We have cloned a new family of novel protein tyrosine phosphatase-like genes, the
      Ptpl (protein tyrosine phosphatase-like; proline instead of catalytic arginine)
      gene family. This gene family is composed of at least three members, and we
      describe here the developmental expression pattern and chromosomal location for
      one of these genes, Ptpla. In situ hybridization studies revealed that Ptpla
      expression was first detected at embryonic day 8.5 in muscle progenitors and
      later in differentiated muscle types: in the developing heart, throughout the
      liver and lungs, and in a number of neural crest derivatives including the dorsal
      root and trigeminal ganglia. Postnatally Ptpla was expressed in a number of adult
      tissues including cardiac and skeletal muscle, liver, testis, and kidney. The
      early expression pattern of this gene and its persistent expression in adult
      tissues suggest that it may have an important role in the development,
      differentiation, and maintenance of a number of different tissue types. The human
      homologue of Ptpla (PTPLA) was cloned and shown to map to 10p13-p14.

PMID- 10644439
TI  - Identification of FLRT1, FLRT2, and FLRT3: a novel family of transmembrane
      leucine-rich repeat proteins.
AB  - FLRT1, FLRT2, and FLRT3 comprise a novel gene family isolated in a screen for
      extracellular matrix proteins expressed in muscle. The three genes encode
      putative type I transmembrane proteins, each containing 10 leucine-rich repeats
      flanked by N-terminal and C-terminal cysteine-rich regions, a
      fibronectin/collagen-like domain, and an intracellular tail. FLRT1 is expressed
      in kidney and brain, FLRT2 is expressed in pancreas, skeletal muscle, brain, and
      heart, and FLRT3 is expressed in kidney, brain, pancreas, skeletal muscle, lung,
      liver, placenta, and heart. FLRT1 localized to 11q12-q13, FLRT2 to 14q24-q32, and
      FLRT3 to 20p11. When expressed in SF9 and COS-1 cells, FLRT1 and FLRT2 migrate as
      90- and 85-kDa proteins, respectively, and both are glycosylated. Given the
      overall structure of the three proteins, a function in cell adhesion and/or
      receptor signaling is predicted.

PMID- 10644440
TI  - Characterization of the mouse Xpf DNA repair gene and differential expression
      during spermatogenesis.
AB  - The human XPF protein, an endonuclease subunit essential for DNA excision repair,
      may also function in homologous recombination. To investigate a possible link
      between mammalian XPF and recombination that occurs during meiosis, we isolated,
      characterized, and determined an expression profile for the mouse Xpf gene. The
      predicted mouse XPF protein, encoded by a 3.4-kb cDNA, contains 917 amino acids
      and is 86% identical to human XPF. Appreciable similarity also exists between
      mouse XPF and homologous proteins in budding yeast (Rad1), fission yeast (Rad16),
      and fruit fly (Mei-9), all of which have dual functions in excision repair and
      recombination. Sequence analysis of the 38.3-kb Xpf gene, localized to a region
      in proximal mouse chromosome 16, revealed greater than 72% identity to human XPF
      in 16 regions. Of these conserved elements, 11 were exons and 5 were noncoding
      sequence within introns. Xpf transcript and protein levels were specifically
      elevated in adult mouse testis. Moreover, increased levels of Xpf and Ercc1 mRNAs
      correlated with meiotic and early postmeiotic spermatogenic cells. These results
      support a distinct role for the XPF/ERCC1 junction-specific endonuclease during
      meiosis, most likely in the resolution of heteroduplex intermediates that arise
      during recombination.

PMID- 10644441
TI  - Genetic, physical, and transcript map of the fld region on mouse chromosome 12.
AB  - The fatty liver dystrophy (fld) mutation is manifested in abnormalities of lipid
      and glucose metabolism and peripheral neuropathy. To identify the gene affected
      by this mutation, we generated a genetic map of the fld region on chromosome 12
      by the analysis of F2 offspring from an intersubspecific cross between strains
      BALB/cByJ-fld and CAST/EiJ. The results localize fld to the 0.42-cM interval
      between the microsatellite markers D12Mit170 and D12Mit184. A contig of YACs and
      BACs covering the nonrecombinant genomic region has been constructed and used for
      the identification of genes. Expressed sequence tag mapping and exon trapping
      identified three transcripts within the critical interval: Ctla2b, which encodes
      a cysteine protease inhibitor, and mouse homologs of KIAA0188 and KIAA0575, two
      long human transcripts of unknown function. Expression analysis revealed that
      Kiaa0188 is expressed in wildtype but not in fld liver, implicating this gene as
      a candidate for harboring the fld mutation.

PMID- 10644442
TI  - Clustered cadherin genes: a sequence-ready contig for the desmosomal cadherin
      locus on human chromosome 18.
AB  - We describe the assembly of a cosmid and PAC contig of approximately 700 kb on
      human chromosome 18q12 spanning the DSC and DSG genes coding for the desmocollins
      and desmogleins. These are members of the cadherin superfamily of calcium
      dependent cell adhesion proteins present in the desmosome type of cell junction
      found especially in epithelial cells. They provide the strong cell-cell adhesion
      generated by this type of cell junction for which expression of both a
      desmocollin and a desmoglein is required. In the autoimmune skin diseases
      pemphigus foliaceous and pemphigus vulgaris (PV), where the autoantigens are,
      respectively, encoded by the DSG1 and DSG3 genes, severe areas of acantholysis
      (cell separation), potentially life-threatening in the case of PV, are evident.
      Dominant mutations in the DSG1 gene causing striate palmoplantar keratoderma
      result in hyperkeratosis of the skin on the parts of the body where pressure and
      abrasion are greatest, viz., on the palms and soles. These genes are also
      candidate tumor suppressor genes in squamous cell carcinomas and other epithelial
      cancers. We have screened two chromosome 18-specific cosmid libraries by
      hybridization with previously isolated YAC clones and DSC and DSG cDNAs, and a
      whole genome PAC library, both by hybridization with the YACs and by screening by
      PCR using cDNA sequences and YAC end sequence. The contigs were extended by
      further PCR screens using STSs generated by vectorette walking from the ends of
      the cosmids and PACs, together with sequence from PAC ends. Despite screening of
      two libraries, the cosmid contig still had four gaps. The PAC contig filled these
      gaps and in fact covered the whole locus. The positions of 45 STSs covering the
      whole of this region are presented. The desmocollin and desmoglein genes, which
      are about 30-35 kb in size, are quite well separated at approximately 20-30 kb
      apart and are arranged in two clusters, one DSC cluster and one DSG cluster,
      which are transcribed outward from the interlocus region. The order of the genes
      is correlated with the spatial order of gene expression in the developing mouse
      embryo, and this, and previous transgenic experiments, suggests that long-range
      genetic elements that coordinate expression of these genes may be present. The
      complete bacterial clone contig described in this paper is thus a resource not
      only for future sequencing but also for investigations into the control of
      expression of these clustered genes.

PMID- 10644443
TI  - The human BARX2 gene: genomic structure, chromosomal localization, and single
      nucleotide polymorphisms.
AB  - The BARX genes 1 and 2 are Bar class homeobox genes expressed in craniofacial
      structures during development. In this report, we present the genomic structure,
      chromosomal localization, and polymorphic markers in BARX2. The gene has four
      exons, ranging in size from 85 to 1099 bp. BARX2 is localized on human chromosome
      11q25, as determined by radiation hybrid mapping. In the mouse, Barx2 is
      coexpressed with Pitx2 in several tissues. Based on the coexpression, BARX2 was
      assumed to be a candidate gene for those cases of Rieger syndrome that cannot be
      associated with mutations of PITX2. Mutations in PITX2 cause some cases of Rieger
      syndrome, an autosomal dominant disorder affecting eyes, teeth, and umbilicus.
      DNA from Rieger patients was subjected to single-strand conformation polymorphism
      screening of the BARX2 coding region. Three single nucleotide polymorphisms were
      found in a normal population, although no etiologic mutations were detectable in
      over 100 cases of Rieger syndrome or in individuals with related ocular
      disorders.

PMID- 10644444
TI  - Cloning of rat MLH1 and expression analysis of MSH2, MSH3, MSH6, and MLH1 during
      spermatogenesis.
AB  - The mismatch repair system has been highly conserved in various species. In
      eukaryotic cells, the Mut S and Mut L homologues play crucial roles in both DNA
      mismatch repair and meiotic recombination. A full-length rat cDNA clone for rat
      MLH1 has been constructed using the RT-PCR method. The cDNA has an open reading
      frame of 2274 nucleotides for a protein of 757 amino acids. We have also obtained
      partial cDNA clones for MSH3 and MSH6. Northern blot analysis of rat MLH1, MSH2,
      MSH3, and MSH6 in the testes of rats of different ages showed differential
      expression of these genes as a function of developmental maturation of the
      testes. The expression analysis suggests that MSH3 may have a more predominant
      role in the meiotic recombination process.

PMID- 10644445
TI  - The human eukaryotic initiation factor 4AI gene (EIF4A1) contains multiple
      regulatory elements that direct high-level reporter gene expression in mammalian
      cell lines.
AB  - The gene encoding human eukaryotic initiation factor 4A (EIF4A1) is located on
      chromosome 17p13, 667 bp upstream from the gene encoding the macrophage endosomal
      protein CD68. The EIF4AI gene contains 10 intervening sequences with the 1397-bp
      first intron containing a CpG-rich methylation-free island. Sequences capable of
      enhancing gene expression reside between positions -69 and -371 and positions 
      504 and -1100 of the EIF4AI 5' flanking sequence and within introns 1, 2, 3, 7,
      and 9. In macrophage cell lines, EIF4A1 expression vectors give sustained high
      level reporter gene expression to levels 10 times higher than that obtained using
      the human cytomegalovirus immediate-early gene promoter/enhancer. Sequences of
      the human EIF4AI gene may find application in the development of new vectors for
      gene therapy and genetic vaccination.

PMID- 10644446
TI  - Identification of a mammalian angiopoietin-related protein expressed specifically
      in liver.
AB  - Based on searches of EST databases for signal sequences and amphipathic helices,
      we have identified and cloned an angiopoietin-like gene, ANGPTL3. Multiple tissue
      Northern blots show that ANGPTL3 is expressed principally in the liver. ANGPTL3
      is expressed early during liver development, and expression is maintained in
      adult liver. Human ANGPTL3 is a 460-amino-acid polypeptide with the
      characteristic structure of angiopoietins: a signal peptide, an extended helical
      domain predicted to form dimeric or trimeric coiled-coils, a short linker
      peptide, and a globular fibrinogen homology domain (FHD). Murine ANGPTL3 is a 455
      acid polypeptide encoded by seven exons on mouse chromosome 4, spanning about 11
      kb of DNA. ANGPTL3 contains the four conserved cysteines implicated in the
      intramolecular disulfide bonds within the FHD, but it does not contain two other
      cysteines that are found within the FHD of angiopoietins 1, 2, and 4. ANGPTL3
      also does not contain the characteristic calcium binding motif found in the other
      angiopoietins. By radiation hybrid mapping and the use of surrounding genes,
      human ANGPTL3 maps to the 1p31 region.

PMID- 10644447
TI  - Molecular cloning and chromosomal mapping of the human homologue of MYB binding
      protein (P160) 1A (MYBBP1A) to 17p13.3.
AB  - We have previously isolated and characterized murine MYB binding protein (p160)
      1a, a protein that specifically interacts with the leucine zipper motif within
      the negative regulatory domain of the c-Myb proto-oncoprotein. We now describe
      the molecular cloning of the human MYBBP1A cDNA and chromosomal localization to
      17p13.3 by fluorescence in situ hybridization analysis. Given the likely presence
      of a tumor suppressor gene (or genes) within this region of chromosome 17, the
      position of MYBBP1A was further mapped by radiation hybrid analysis and was found
      to lie between markers D17S1828 and D17S938. A P1 artificial chromosome clone
      containing the 5' region of MYBBP1A was isolated and indicates a physical linkage
      between MYBBP1A and the 15-lipoxygenase gene (ALOX15). A novel, polymorphic
      (CA)(25) dinucleotide repeat was also isolated from this PAC and may serve as a
      useful marker for MYBBP1A and this region of chromosome 17.

PMID- 10644448
TI  - Human ovalbumin serpin evolution: phylogenic analysis, gene organization, and
      identification of new PI8-related genes suggest that two interchromosomal and
      several intrachromosomal duplications generated the gene clusters at 18q21-q23
      and 6p25.
AB  - The human ovalbumin (ov) serpins are associated with tumorigenesis, inflammation,
      and protection from autolysis by granule proteinases. Their genes are located at
      18q21 or 6p25, falling into two structurally very similar but distinct categories
      depending on the presence or absence of a particular exon. Analysis of ov-serpin
      gene structure provides an opportunity to elucidate the mechanisms contributing
      to the formation of the larger serpin gene superfamily. Here we have identified a
      new gene (PI8L1) at 6p25 that is 72% identical to the 18q21 gene PI8. FISH
      analysis using the 3' untranslated region of PI8 yielded an additional signal at
      18q23, separable from the known 18q21.3 signal by the t(1;18)(p32;q23)
      chromosomal translocation. The presence of more than one PI8-related gene was
      confirmed by analysis of human genomic DNA using the same probe. Cloning and
      analysis of PI8 showed that its intron number and phasing are identical to those
      of the 6p25 genes PI6, PI9, and ELANH2, and it lacks the interhelical variable
      loop exon found in other 18q21 genes. PCR analysis demonstrated that PI5 at 18q21
      also lacks this exon, indicating that it is organized identically to the 6p25
      genes. By contrast, PI10 and megsin have this exon and resemble the other 18q21
      genes, PLANH2, SCCA-1, and SCCA-2, in structure. Using these data with an ov
      serpin phylogenic tree we have constructed, we propose that the ov-serpin gene
      clusters arose via interchromosomal duplication of PI5 (or a precursor) to 6p25,
      followed by duplication at 6p25, and a more recent interchromosomal duplication
      from 6p25 to 18q to yield PI8.

PMID- 10644449
TI  - Optimized multiplex PCR: efficiently closing a whole-genome shotgun sequencing
      project.
AB  - A new method has been developed for rapidly closing a large number of gaps in a
      whole-genome shotgun sequencing project. The method employs multiplex PCR and a
      novel pooling strategy to minimize the number of laboratory procedures required
      to sequence the unknown DNA that falls in between contiguous sequences. Multiplex
      sequencing, a novel procedure in which multiple PCR primers are used in a single
      sequencing reaction, is used to interpret the multiplex PCR results. Two
      protocols are presented, one that minimizes pipetting and another that minimizes
      the number of reactions. The pipette optimized multiplex PCR method has been
      employed in the final phases of closing the Streptococcus pneumoniae genome
      sequence, with excellent results.

PMID- 10644450
TI  - Striking bimodal methylation of the repeat unit of the tandem array encoding
      human U2 snRNA (the RNU2 locus).
AB  - The genes encoding human U2 small nuclear RNA are arrayed in tandem (the RNU2
      locus) and have undergone concerted evolution for >35 Myr. Tandem organization of
      repetitive sequences may facilitate recombination that underlies concerted
      evolution, but could risk instability. Since DNA methylation plays a crucial role
      in genome stability, we investigated the methylation status of the RNU2 locus to
      understand the forces maintaining array stability and homogeneity. We found that
      a region of approximately 1.5 kb spanning the U2 promoter, U2 gene sequence, and
      CT microsatellite is completely unmethylated, whereas the rest of the repeat is
      heavily methylated. Since the U2 transcription enhancer DSE and CT microsatellite
      mark the boundaries between methylated and unmethylated domains, they might
      function as cis-acting elements for establishing and maintaining proper
      methylation at the RNU2 locus. Interestingly, the RNU2 locus in human
      fibrosarcoma line HT1080 is hypomethylated, and de novo methylation did not occur
      in an artificial U2 tandem array introduced by stable transfection. The observed
      bimodal methylation pattern may be important for both efficient transcription of
      U2 gene and maintenance of nearly perfect tandem arrays in somatic cells.

PMID- 10644451
TI  - Cloning, chromosomal localization, and characterization of cDNA from a novel
      gene, SH3BP4, expressed by human corneal fibroblasts.
AB  - The cornea contains, as a major element, a transparent stroma produced and
      maintained by keratocytes (fibroblasts). Through molecular biology studies using
      cultured human corneal fibroblasts, a cDNA that was shown to be novel was
      isolated and sequenced. This novel gene product, named SH3-domain binding protein
      4 (SH3BP4), contains a 5.6-kb message that is present in normal human corneal
      fibroblasts and all tissues examined, with higher levels in pancreas, placenta,
      heart, and kidney. SH3BP4 was localized by FISH analysis to human chromosome
      2q37.1-q37.2 near the telomere. The deduced sequence for SH3BP4 was found to
      contain a 963-amino-acid open reading frame that has homology to a 479-amino-acid
      protein in GenBank called EH-binding protein. Although the entire sequence of EH
      binding protein aligns with SH3BP4, the alignment is not complete or contiguous.
      Therefore, SH3BP4 has an additional 73 amino acids at the N-terminus and an
      additional 411 amino acids near the C-terminus that are not present in EH-binding
      protein. Consensus sequence domains identified in SH3BP4 include a SH3 domain,
      three N-P-F motifs, a P-X-X-P motif noted for binding to SH3 domains, a bipartite
      nuclear targeting signal, and a tyrosine phosphorylation site. SH3BP4 homologies
      and consensus sequence sites indicate that it may be involved in a newly
      identified cascade of proteins involved in endocytosis, intracellular sorting,
      and the cell cycle.

PMID- 10644452
TI  - Expression analysis and protein localization of the human HPC-1/syntaxin 1A, a
      gene deleted in Williams syndrome.
AB  - The HPC-1/syntaxin 1A (STX1A) gene maps to the Williams syndrome (WS) commonly
      deleted region on chromosome 7q11.23 and encodes a protein implicated in the
      docking of synaptic vesicles with the presynaptic plasma membrane. To assess the
      potential role of STX1A in the WS phenotype, we carried out expression studies at
      the RNA and protein levels, in fetal and adult human tissues. RNA in situ
      hybridization on human embryo sections showed strong STX1A expression in spinal
      cord and ganglia. However, in adulthood, this gene was preferentially expressed
      in brain, as shown by Northern blot and RT-PCR experiments. Marked expression
      levels were observed in cerebellum and cerebral cortex. The STX1A protein was
      prevalently distributed in the molecular layer of the cerebellar cortex. A
      qualitative and quantitative analysis using a specific anti-STX1A antibody did
      not disclose any significant difference among frontal, temporal, and occipital
      poles of the human adult cortex in the two hemispheres. This is the first study
      focused on STX1A expression in humans. Our results indicate that this gene is
      strongly expressed in cerebral areas involved in cognitive process, supporting a
      likely role in the neurological symptoms of WS.

PMID- 10644453
TI  - Chromosomal localization of phospholipase A2 activating protein, an Ets2 target
      gene, to 9p21.
AB  - A murine Ets2 target gene isolated by differential display cloning was identified
      as the phospholipase A2 activating protein (PLAA) gene. A 2.7-kb human cDNA
      demonstrating high homology to mouse and rat Plaa genes was then isolated and
      characterized. Human PLAA contains six WD-40 repeat motifs and three different
      protein kinase consensus domains. Fluorescence in situ hybridization (FISH)
      mapping placed PLAA on chromosome 9p21, a region frequently deleted in various
      cancers. A comprehensive mapping strategy was employed to define further the
      chromosomal localization of PLAA relative to CDKN2A within the 9p21 locus.
      Radiation hybrid mapping placed the gene 7.69 cR from WI-5735 (LOD >3.0), a
      marker in close proximity to CDKN2A and CDKN2B. Yeast artificial chromosome (YAC)
      mapping localized PLAA proximal to the CDKN2A/CDKN2B genes and to a region
      flanked by D9S171 and INFA commonly deleted in many neoplasms. Two YACs contained
      both PLAA and D9S259, a marker present in a second more proximal minimal deleted
      region observed in cutaneous melanoma and squamous cell lung carcinoma. Double
      color fiber FISH mapping confirmed the location of PLAA centromeric to D9S171 and
      CDKN2A/CDKN2B. The mapping data suggest a possible tumor suppressor role for this
      gene.

PMID- 10644454
TI  - Identification of a novel gene (ADPRTL1) encoding a potential Poly(ADP
      ribosyl)transferase protein.
AB  - Poly(ADP-ribosyl)ation of nuclear proteins plays a significant role in the
      maintenance of genomic DNA stability. To date, four poly(ADP-ribosyl)ating
      proteins have been identified in humans. We now report the full-length sequence,
      expression profile, and chromosomal localization of a novel gene, ADPRTL1,
      encoding an ADP-ribosyltransferase-like protein. The predicted open reading frame
      encodes a protein of 1724 amino acids with a molecular mass of 192.8 kDa. The
      protein contains a region showing homology to the catalytic domains of the
      nuclear-localized ADP-ribosyltransferase proteins (Adprt), two recently
      identified Adprt-like proteins (Adprtl2 and Adprtl3), and the telomere-associated
      protein tankyrase. Key amino acids known to be important for the activity of
      these enzymes are conserved within this region of the Adprtl1 protein, indicating
      that Adprtl1 is a functional poly(ADP-ribosyl)transferase. As has been noted for
      tankyrase, sequence analysis of the Adprtl1 protein suggests that it is not
      capable of binding DNA directly. Thus, the transferase activity of Adprtl1 may be
      activated by other factors such as protein-protein interaction mediated by the
      extensive carboxyl terminus. We have subsequently refined the location of the
      ADPRTL1 genomic locus to 13q11, close to the recently cloned ZNF198 gene.

PMID- 10644455
TI  - Molecular cloning and mapping of a novel ADAM gene (ADAM29) to human chromosome
      4.
AB  - Members of the ADAM family (type I integral membrane protein with a disintegrin
      and metalloprotease domain) have been implicated in many important biological
      processes involving cell-cell and cell-matrix interactions, such as fertilization
      and myoblast fusion. We report here the cDNA sequence of a novel human ADAM gene
      (ADAM29) that contains a putative fusion peptide. Northern blot analysis revealed
      that the mRNA of ADAM29 is highly expressed in the testis. By radiation hybrid
      panel mapping, the ADAM29 gene was assigned to human chromosome 4q34.2-qter.

PMID- 10644457
TI  - The G protein subunit gene families.

PMID- 10644456
TI  - Identification of a novel protocadherin gene (PCDH11) on the human XY homology
      region in Xq21.3.
AB  - Protocadherins (Pcdhs) are members of the rapidly growing cadherin superfamily
      and are thought to be involved in cell-cell recognition in the central nervous
      system. Using human BH-Pcdh cDNA, we retrieved a homologous gene from the
      database. The new gene (Pcdh-X, HGMW-approved symbol PCDH11) was present on a
      genomic clone of human chromosome X (clone bWXD306), between two sequence tagged
      sites, sWXD1362 and 221. Pcdh-X therefore maps to the XY homology region in
      Xq21.3. The open reading frame consists of 1021 amino acids (aa) including seven
      cadherin repeats (EC1-7) in the extracellular domain. The Pcdh-X gene consists of
      at least three exons; the first exon encodes the 5'-untranslated region, EC1, and
      half of EC2, the second exon encodes the remainder of the Pcdh-Xa, and the third
      exon encodes the cytoplasmic tail of Pcdh-Xb and its 3'-untranslated region. The
      second exon has an alternative splice site that is used to produce two isoforms
      with different cytoplasmic tails of 10 (Pcdh-Xa) or 14 amino acids (Pcdh-Xb).
      Northern blot analysis revealed an approximately 6.0-kb transcript expressed in
      human and mouse fetal brain.

PMID- 10644458
TI  - Are gastric, jejunal, or both forms of enteral feeding gastroprotective during
      stress?
AB  - BACKGROUND: Clinical data suggest enteral nutrition prevents stress ulceration
      and intragastric nutrients prevent restraint-induced gastric injury. The purpose
      of these studies was to determine if jejunal nutrients can protect without
      gastric contact and to determine if gastric pH, motility, or mucosal perfusion is
      affected. METHODS: In Experiment 1, 27 rats were restrained for 2 h at room
      temperature followed by 2 h in cold (4 degrees C), with intragastric (IG) or
      intrajejunal (IJ) 2 ml/h infusions of saline or 25% glucose. Gastric lesions, pH,
      volumes, and glucose concentrations were measured postmortem. In Experiment 2, 23
      rats had gastric strain gauges implanted >5 days prior to a 0.5 ml/h IG or IJ
      infusion during stress. In Experiment 3, 40 rats were anesthetized for laser
      Doppler measurements of gastric mucosal perfusion and arterial catheter
      monitoring of systemic hemodynamics. Rats received 0.5-ml boluses of concentrated
      glucose or saline IG or IJ, and were monitored for 60 min. RESULTS: (1) The 2
      ml/h IJ and IG glucose infusions prevented gastric injury, but the elevated
      gastric glucose concentrations suggested equal gastric contact. (2) The 0.5 ml/h
      glucose IG and IJ infusions decreased gastric injury without reflux of the IJ
      glucose into the stomach and suppressed stress-induced hypercontractility, but
      not acidity. (3) Systemic perfusion pressures were unaffected by enteral glucose.
      IG glucose had little effect on gastric mucosal perfusion, while IJ glucose
      decreased gastric perfusion within 5 min. CONCLUSIONS: These studies show that
      large volumes of enteral glucose prevent restraint injury but IJ glucose refluxes
      into the stomach. The gastroprotective effects of small, nonrefluxing volumes of
      IJ glucose are associated with suppression of stress-induced gastric
      hypercontractility, but not with suppressed acidity or enhanced perfusion.

PMID- 10644459
TI  - Characterization of the off response to electrical field stimulation in
      gallbladder smooth muscle.
AB  - BACKGROUND: Low-frequency electrical stimulation of intramural nerves of gut
      smooth muscle produces an "off response," that is, a contraction that occurs
      after electrical field stimulation (EFS) of the intramural nerves is stopped. The
      off response coincides with a depolarization of the muscle following an EFS
      induced hyperpolarization of that muscle. The aims of our study were to determine
      if the off response is present in gallbladder smooth muscle and to determine the
      mechanisms involved in this nerve-mediated response. MATERIALS AND METHODS:
      Gallbladder strips from opossums were placed in Krebs solution and passed through
      bipolar ring electrodes for EFS of intramural nerves, and isometric force
      measurements were recorded. Dose-response curves were determined with N(G)-nitro
      L-arginine (L-NNA) a competitive inhibitor of nitric oxide (NO) synthase; 1H
      ?1,2,4oxadiazolol?4, 3aquinoxalin-1-one (ODQ), an inhibitor of soluble guanylate
      cyclase; and oxyhemoglobin, a scavenger of nitric oxide. RESULTS: A contraction
      termed the off response occurred shortly after EFS ended. The off response was
      abolished with tetrodotoxin and atropine. The amplitude of the off response
      increased with increasing voltage. The amplitude of the off response decreased by
      41% with L-NNA 1.5 mM. Preincubation of the tissue with L-arginine (1 mM)
      prevented the inhibition of amplitude seen with L-NNA. The amplitude of the off
      response decreased by 43% with oxyhemoglobin (40 microM) and by 56% with ODQ (250
      microM). CONCLUSION: We conclude that the off response is present in gallbladder
      smooth muscle after low-frequency EFS. NO may be a mediator of this off response
      and of nonadrenergic noncholinergic responses in gallbladder smooth muscle.

PMID- 10644460
TI  - A clinical pathway for inguinal hernia repair reduces hospital admissions.
AB  - BACKGROUND: Clinical pathways have been advocated as a means to improve and
      standardize patient care while reducing costs through improved efficiency. This
      study examines the hypothesis that development of a clinical pathway reduces
      hospital admissions in a Veterans Affairs (VA) medical center. MATERIALS AND
      METHODS: For the year prior to June 1997, 168 elective inguinal herniorrhaphies
      were performed. This constituted the prepathway (pre-P) group. One hundred ninety
      six elective inguinal herniorrhaphies were performed during the year following
      institution of the clinical pathway-the postpathway (post-P) group. RESULTS:
      Hospital admissions were compared between the two groups. In the pre-P group 61
      of the 168 patients (36%) were admitted while 29 of the 196 patients (15%) in the
      post-P group were admitted (P < 0.001). In the pre-P group 27 of the 53 patients
      reviewed (51%) had either no justification or inadequate justification for
      admission. In the post-P group 8 of the 29 patients admitted (28%) had inadequate
      justification (pre-P vs post-P, P = 0.124). Common reasons for admission included
      pain, perioperative complications, and concurrent medical problems or surgical
      procedures. The most common single cause other than pain was urinary retention.
      The average age of patients requiring admission was greater both pre-P and post
      P. CONCLUSIONS: We conclude that institution of a clinical pathway for inguinal
      herniorrhaphy decreased hospital admissions. The reasons for this decrease are
      probably multifactorial and include improvements in physician and staff
      awareness. The decrease in unnecessary admissions should result in more efficient
      use of hospital resources.

PMID- 10644461
TI  - Outcomes after lower-extremity reconstruction in DRGs 478 and 479.
AB  - PURPOSE: To assess outcomes for 21,261 patients in DRGs 478 and 479 hospitalized
      in Veterans Affairs Medical Centers (VAMCs) during fiscal years 1991-1994. DRGs
      478 and 479 contain patients undergoing a variety of vascular procedures
      including lower-extremity arterial reconstruction. METHODS: VA Patient Treatment
      File (PTF) data were analyzed using Patient Management Category (PMC) software
      which defined illness severity, patient complexity as defined by PMC count, and
      calculated resource intensity scale (RIS), a measure of resource utilization, for
      each admission. RESULTS: In-hospital mortality rate was 3.16% (671/21,261) for
      all patients. Mortality did not differ between the 14,155 patients who underwent
      extremity arterial reconstruction (3.22%) and the remaining patients (3.03%). The
      incidence of ICD-9-CM-coded complications was 20.4% after limb revascularization
      versus 12.8% for remaining patients (P < 0.001). Length of stay (LOS) was 18.6 +/
      17.6 days with versus 10.3 +/- 14. 5 days without limb revascularization (P <
      0.001). As defined in this study, patients who underwent limb revascularization
      were older (64.1 +/- 9.6 vs 62.2 +/- 11.0, P < 0.001); had higher illness
      severity scores (3.63 +/- 1.60 vs 2.72 +/- 1.72, P < 0.001); were more complex
      (had higher PMC count: 2.59 +/- 1.35 vs 2.54 +/- 1.34, P = 0.016); and required
      utilization of more resources (had higher RIS: 2.16 +/- 0.81 vs 1.68 +/- 0.76, P
      < 0.001) than remaining patients. Logistic regression analysis limited to those
      undergoing extremity revascularization revealed that age, presence of
      complications, patient complexity, illness severity, and acute arterial
      thromboembolism were increasingly and independently associated with greater in
      hospital mortality. The logistic regression model also showed that the type of
      arterial reconstruction was related to in-hospital mortality: arterial bypass
      (ICD-9-CM 39.29) was associated with lower mortality. Outcomes were defined for
      the subgroup (n = 7,728) undergoing arterial bypass (ICD-9-CM 39.29) who were
      assigned to Patient Management Category 4101, 4113, or 4141: Mortality rates were
      2.26, 2.19, and 5.03% for those undergoing elective bypass (n = 3003), urgent
      bypass (n = 3,513), and bypass for gangrene (n = 1212), respectively.
      Octogenarians did not experience higher mortality rates after elective bypass
      ?1.4% (1/73) vs 2.3% (67/2,930), n.s., but experienced higher mortality rates
      after urgent bypass ?8.6% (8/93) vs 2.0% (69/3,420), P < 0.001 and after bypass
      for gangrene ?11.6% (5/43) vs 4.8% (56/1,169), P < 0.045. CONCLUSIONS: Outcomes
      for patients in DRGs 478 and 479 who underwent extremity revascularization
      differed from those who did not. Outcomes varied by the type of arterial
      reconstruction and its urgency and indication and within selected subpopulations
      (i.e., octogenarians). DRG-based reimbursement would not be sensitive to these
      clinically important factors which have a major impact on outcomes and resource
      utilization.

PMID- 10644462
TI  - Peptide YY augments gross inhibition by vitamin E succinate of human pancreatic
      cancer cell growth.
AB  - BACKGROUND: Vitamin E succinate (VES) significantly inhibits cell growth in vitro
      in breast, prostate, and skin cancer cell lines. Our study demonstrated similar
      inhibitory effects on Mia PaCa-2 pancreatic cancer cells at the same
      concentration of VES (10 pg/ml). Peptide YY (PYY) also inhibits pancreatic cancer
      cell growth in vitro. We observed a significant additive effect on growth
      inhibition in Mia PaCa cells treated with both VES and PYY. METHODS: Human
      pancreatic ductal adenocarcinoma Mia PaCa-2 cells were cultured and treated once
      with either 10 pg/ml of VES or 500 pmols of PYY or with both agents together. The
      control group received an equivalent volume of solvents. MTT assay was performed
      at 24, 48, and 72 h to evaluate cell viability. RESULTS: Pancreatic cancer cell
      growth was reduced in all groups treated with PYY and VES. Student's t test was
      used to analyze the data for each treatment group. At 72 h, both PYY and vitamin
      E significantly inhibited cell growth compared to control. Combining the agents
      resulted in a dramatic additive inhibition of growth. CONCLUSION: PYY and vitamin
      E both inhibit growth of pancreatic cancer cells in vitro with a significant
      increase in effect when used in combination.

PMID- 10644463
TI  - Effects of homocysteine on smooth muscle cell proliferation in both cell culture
      and artery perfusion culture models.
AB  - BACKGROUND: Hyperhomocysteinemia is associated with increased risk for vascular
      disease. However, the pathogenic mechanisms of homocysteine are largely unknown.
      We evaluated the effects of homocysteine on smooth muscle cell (SMC) and
      endothelial cell proliferation in cell culture and on SMC proliferation of
      balloon angioplasty-injured arteries in a perfusion culture model. METHODS: Human
      and pig SMCs and endothelial cells were cultured with variable amounts of
      homocysteine for 72 h and the total cells were counted using a hemocytometer.
      Fresh pig carotid arteries were harvested from a local slaughterhouse and
      cultured in a newly designed artery perfusion culture system. Five groups of
      arteries (six per group) were cultured for 48 h under different conditions:
      normal control, balloon angioplasty injury alone, and injury with three different
      doses of homocysteine. Vessel viability was evaluated. SMC proliferation was
      assayed by bromodeoxyuridine (BrdU) DNA labeling. RESULTS: At concentrations
      equivalent to those in human hyperhomocysteinemia, homocysteine significantly
      stimulated both cultured human and pig SMC proliferation with a dose-dependent
      effect, while it inhibited cultured endothelial cell growth. Perfusion-cultured
      pig carotid arteries remained contractile in response to norepinephrine and
      relaxant to nitroglycerine, and viable cells were also isolated from the cultured
      arteries. SMC proliferation (BrdU index) showed significant differences among the
      groups. SMC proliferation was stimulated by vascular injury and further enhanced
      by homocysteine in a dose-dependent manner. The proliferative response occurred
      strongly on the luminal side of the vessel wall, with the effects tapering toward
      the adventitia. CONCLUSIONS: Homocysteine had a mitogenic effect on vascular SMCs
      and a cytotoxic effect on endothelial cells. This differential effect of
      homocysteine on vascular cells may represent a pathogenic mechanism of vascular
      lesion formation in patients with hyperhomocysteinemia.

PMID- 10644464
TI  - A new perfusion culture system used to study human vein.
AB  - BACKGROUND: Cell culture studies, ring studies, and indirect physiologic studies
      are the predominant models used to study human vascular tissue. Such studies are
      limited in their capacity to permit physiologic single-factor changes or to
      provide the proper mechanical stress or extracellular matrix present in normal
      tissues. We present a newly devised organ culture system that addresses these
      issues and permits survival of intact segments of human vascular tissue in a
      perfused environment. Our experience culturing human saphenous vein with this
      system is detailed. METHODS: Perfusion culture chambers were designed and
      constructed in our laboratory. Excess saphenous vein segments were collected from
      coronary artery bypass graft cases at our hospital and then mounted into our
      perfusion culture system for 0, 24, 48, 72, or 96 h. Vasomotor assays,
      hematoxylin and eosin staining, bromodeoxyuridine staining, and factor VIII
      staining were performed to assess tissue survival. RESULTS: A total of 24 veins
      were cultured. Average vessel length was 5 cm. The vessels contracted and relaxed
      the following amounts: time 0 (6.7% contraction, 5.0% relaxation), 24 h (5.7%,
      5.3%), 48 h (5.2%, 2.8%), 72 h (4.8%, 5.3%), 96 h (4.8%, 3.8%). Hematoxylin and
      eosin staining, bromodeoxyuridine staining, and factor VIII staining support the
      viability of the tissue segments. CONCLUSION: A new perfusion organ culture
      system has been devised that permits survival of intact human venous tissue for
      periods up to 96 h. Studies that permit physiologic single-factor changes along
      with precise control of the hemodynamic environment are possible with this
      system.

PMID- 10644465
TI  - Outcomes after abdominal aortic aneurysm repair: comparison of mortality defined
      by centralized VA Patient Treatment File data versus hospital-based chart review.
AB  - BACKGROUND: Outcomes after abdominal aortic aneurysm (AAA) repair have been
      reported by individual Veterans Affairs medical centers (VAMCs) and for the
      entire VA patient population. PURPOSE: This study was done to determine whether
      outcomes defined using VA Patient Treatment File (PTF) data were comparable to
      those defined by direct chart review in those undergoing repair of intact AAA.
      METHODS: Focused chart review was performed in all veterans undergoing such AAA
      repair in a sample of VAMCs (n = 5) for separate 1-year periods during fiscal
      years (FY) 1991-1993. A previous report of outcomes after AAA repair for all
      veterans in DRGs 110 and 111 during FY 1991-1993 was based on PTF data that were
      further analyzed by Patient Management Category (PMC) software. Outcomes after
      AAA repair were defined in a similar fashion using PTF data and PMC analysis in
      the same sample VAMCs for which direct chart review data were available. Outcomes
      defined by chart review were then compared to those based on PTF data. RESULTS:
      Three of the 69 patients undergoing repair of intact AAA for which chart review
      data were available were assigned to DRGs other than 110 and 111 and, by
      definition, were not included in the PTF-derived database. Nine of 10 additional
      patients undergoing chart review were not identified as having undergone AAA
      repair by PMC software: 7 had procedure codes 39.25 instead of more standard AAA
      repair codes 38.34 or 38.44. Two additional patients with codes 38.64 or 38.66
      were not identified as having undergone AAA repair by PMC software. The 10th
      patient not included in the PTF-derived database underwent additional operative
      procedures. Of the 13 patients missed by the combined PTF and PMC outcome
      analyses but identified by chart review, none died or had cardiac complications.
      One of these 13 patients had pulmonary complications based on chart review and
      PTF but was excluded by PMC analysis. There remained a total of 56 patients at
      the five sample VAMCs common to the PTF-derived and chart-derived databases
      identified as having undergone repair of intact AAA. There were two in-hospital
      deaths in these patients, and both were identified by each approach to outcome
      assessment. Four of these 56 patients had postoperative cardiac complications
      (ICD-9-CM code 997. 10) which were identified by both PTF and chart review.
      Postoperative pulmonary complications (ICD-9-CM code 997.30) were present in 4 of
      the 56 cases and were also identified by both PTF-based and chart-based outcome
      analyses. CONCLUSIONS: All deaths as well as cardiac or respiratory complications
      identified by chart review at the study hospitals were also affirmed by the PTF.
      Due to study methodologies (which restricted analysis to those in DRGs 110 and
      111 and which included secondary analyses of PTF data by PMC software), 19% of
      patients who underwent repair of intact AAA identified by hospital-based chart
      review were excluded from the PTF-based outcome analysis. Outcomes defined using
      large databases such as the VA PTF may be comparable to those defined by chart
      review if study methodologies permit. Discrepancies in outcome assessment between
      direct chart review and large database analysis in the present study were due to
      methodologies used, not to deficiencies, per se, in PTF data.

PMID- 10644466
TI  - Performance standards: piece of cake or pie in the sky?
AB  - BACKGROUND: Centrally mandated levels of performance are now common in the
      Veterans Health Administration. Performance standards for ambulatory procedures
      were developed based on HCFA data. The 11 procedures to be measured were
      arthroscopy, breast biopsy, eyelid procedures, lens/cataracts, bronchoscopy,
      endoscopy, colonoscopy, hernia repair, cystoscopy, laparoscopy, and cardiac
      catheterization. Were the performance standards for ambulatory procedures
      reasonable and achievable in a tertiary care VA? METHODS: Ambulatory procedure
      performance standards for the 11 selected procedures were evaluated for Fiscal
      Year 1998 at one tertiary care VA and at each of the 22 Veteran's Integrated
      Service Networks (VISNs). Further review was undertaken for those procedures in
      which performance was below the fully successful level. This included chart
      reviews at the tertiary care VA and analysis of caseloads by VISN. Descriptive
      statistics were used as well as Student's t test to analyze the difference in
      means. RESULTS: The tertiary care VA performed at the fully successful level for
      6 procedures and at the exceptional level for 3 procedures. Performance levels
      for bronchoscopy and laparoscopy were below the preset goals. At the VISN level,
      8 VISNs performed at the fully successful/exceptional level for all 11
      procedures. The remaining 14 were deficient in 1 to 4 procedures. Eight of the
      VISNs were deficient in 2 or 3 procedures. Six VISNs were deficient in
      laparoscopy. CONCLUSIONS: The majority of centrally mandated performance
      standards appear to be reasonable and achievable. One notable exception is
      laparoscopy. Surgeons should understand how performance standards are calculated
      at their institution and review the data carefully for any systematic errors.
      Underperformance can be used as an opportunity to improve both data collection
      and outcomes.

PMID- 10644467
TI  - Effect of dopamine infusion (3-30 microg/kg/min) on hepatic hemodynamics.
AB  - BACKGROUND: While dopamine produces well-characterized dose-dependent effects on
      systemic hemodynamics, there is a paucity of information regarding its effects on
      hepatic hemodynamics. Infusion rates above 10 microg/kg/min are reported to
      produce significant vasoconstriction and impair organ perfusion. Therefore,
      donors are sometimes considered unsuitable when higher doses of dopamine are in
      use. The aim of this study was to determine the effect of increasing doses of
      dopamine on hepatic hemodynamics in a nonanesthetized swine model. MATERIALS AND
      METHODS: Sixteen pigs were instrumented with indwelling catheters in a peripheral
      artery, peripheral vein, portal vein, and hepatic vein and flow probes around the
      portal vein and hepatic artery. After recovery, the following variables were
      measured 10 +/- 1 days postinstrumentation: hepatic arterial flow (HAF), portal
      venous flow (PVF), mean systemic arterial pressure (MAP), central venous pressure
      (CVP), portal venous pressure (PVP), hepatic venous pressure (HVP), heart rate
      (HR). Recordings were obtained at baseline and subsequently when dopamine was
      infused at rates of 3, 6, 12, 15, 21, and 30 microg/kg/min increasing at 1-h
      intervals. RESULTS: HAF and PVF increased linearly over the entire infusion
      range, to 69 and 13% over baseline, respectively (P < 0.001, P < 0.05). Total
      hepatic blood flow rose 23% over baseline at the 30 microg/kg/min dosage (P <
      0.01). MAP increased linearly 13% over the range 12 to 30 microg/kg/min (P <
      0.001). CVP, HVP, and PVP did not change significantly. HR decreased from 12 to
      15 microg/kg/min (P < 0.01), then increased from 15 to 30 microg/kg/min (P <
      0.05). CONCLUSION: These data show that dopamine infused at dosages of 3-30
      microg/kg/min augments HAF, PVF, and THBF and that this effect is linear. These
      results suggest high-dose dopamine infusion does not disqualify a potential donor
      liver for transplantation.

PMID- 10644468
TI  - Using the Veterans Administration National Surgical Quality Improvement Program
      to improve patient outcomes.
AB  - BACKGROUND: The primary goal of collecting quality assurance data is to
      ultimately improve patient care. The VA National Surgical Quality Improvement
      Program (NSQIP) provides each station with risk-adjusted morbidity and mortality
      data on a regular basis. This report of one medical center's use of the risk
      adjusted data shows how it can be used to improve patient care. MATERIALS AND
      METHODS: Risk-adjusted surgical outcome data for Fiscal Year 1996 (FY96) was
      received from the NSQIP coordinating center. The Salt Lake City VA medical center
      was identified as a high outlier for morbidity in general surgery. Patient charts
      were reviewed and data analyzed to determine practice patterns and to determine
      if there were any provider issues. Data analysis revealed a large number of wound
      complications and uncovered a practice pattern of closure of contaminated wounds.
      Using these data and data from the literature, wound infection and disruption
      prevention protocols were instituted in the fall of 1997. Wound complications
      from January to December 1996 (preprotocol) and January to December 1998
      (postprotocol) were compared using Student's t test. RESULTS: The total number of
      operations in 1998 was 719 compared with 634 in 1996. Superficial wound
      infections dropped from 3.6 to 1.7%, while overall wound complications dropped
      from 5.5 to 2.9%. None of these changes were statistically significant.
      CONCLUSIONS: Although introduction of wound infection and disruption prevention
      protocols did not result in a statistically significant decrease in wound
      complication, it did result in a clinically significant improvement in patient
      care.

PMID- 10644469
TI  - A reversible model of acute hepatic failure by temporary hepatic ischemia in the
      pig.
AB  - BACKGROUND: To evaluate new therapies for human fulminant hepatic failure, a
      suitable large animal model is needed. The purpose of this study was to develop a
      reversible surgical model of acute hepatic liver failure by transient ischemia in
      pigs. MATERIALS AND METHODS: Under general anesthesia, an end-to-side portacaval
      shunt was performed in 17 pigs and tape was laid around the hepatoduodenal
      ligament. Two days after construction of the functional portacaval shunt, 13
      ambulant pigs underwent transient total liver ischemia by tightening of the tape
      around the hepatoduodenal ligament for 5.5 h. During ischemia, 10% glucose was
      continuously infused intravenously to prevent hypoglycemia. RESULTS: Ten animals
      (77%) died with hepatic coma after a mean duration of 22.5 +/- 1.9 h. The 3
      remaining animals survived more than 5 days and were sacrificed. In dying
      animals, encephalopathy was observed 14 +/- 1.7 h after the onset of ischemia.
      During ischemia, similar progressive decrease of fibrinogen, platelets,
      prothrombin time, and factors V and VII activities was observed in dying and
      surviving animals. Just before death, mean prothrombin and factors V and VII
      activities were respectively 22 +/- 2, 21 +/- 4.4, and 24 +/- 5%. At 22 h, plasma
      ammonia and lactate levels were respectively 705 +/- 93 micromol/L and 10.5 +/-
      0.4 mmol/L in dying animals and 249 +/- 75 micromol/L and 2.9 +/- 0.1 mmol/L in
      surviving animals (P < 0.01). Estimation of the percentage liver cells necrosed
      was 74 +/- 4.7% in the survivors and 86 +/- 5.5% in animals who died of hepatic
      coma (NS). CONCLUSIONS: This model is reproducible and reversible and should
      allow the quantitative evaluation of new technologies, such as bioartificial
      liver, for the support of hepatic failure in humans.

PMID- 10644470
TI  - Increased sinusoidal pressure is associated with early liver weight gain in
      ischemia-reperfusion injury in isolated perfused rat liver.
AB  - BACKGROUND: Hepatic ischemia-reperfusion (I/R) is accompanied by liver weight
      gain and ascites formation. This could be caused by an increase in sinusoidal
      pressure, a determinant of hepatic transvascular fluid movement. We determined
      the role of sinusoidal pressure, assessed by triple vascular occlusion pressure
      (P(to)), in the I/R injury in isolated rat livers perfused with leukocyte-free
      diluted blood bivascularly via the portal vein and hepatic artery. MATERIALS AND
      METHODS: Ischemia was induced at room temperature by occlusion of either the
      inflow lines of the hepatic artery and portal vein (the open outflow group, n =
      10) or both the inflow and the outflow (hepatic venous) lines (the closed outflow
      group, n = 10) for 1 h, followed by 1-h reperfusion in a recirculating manner.
      RESULTS: Liver weight in both groups increased biphasically after reperfusion;
      the initial peak occurred at 3 min and the second peak at 60 min. Immediately
      after reperfusion, P(to) peaked, followed by a gradual decline. The initial
      weight increase in groups combined was significantly and positively correlated
      with an increase in P(to) (r = 0.716, P = 0.0002), but the second peak was
      independent of P(to). Liver injury, assessed by perfusate levels of hepatic
      enzymes and reduced bile flow rate, was observed at 60 min after reperfusion in
      both groups. CONCLUSIONS: These findings suggest that increased sinusoidal
      pressure contributes to only the early liver weight gain after reperfusion in
      isolated perfused rat livers. The late weight gain may be presumably due to liver
      injury.

PMID- 10644471
TI  - An in vivo evaluation of a chondroitin sulfate solution to prevent postoperative
      intraperitoneal adhesion formation.
AB  - PURPOSE: The goal of this study was to determine the efficacy of a single
      intraperitoneal administration of a chondroitin sulfate solution in preventing
      postoperative adhesion formation. METHODS. Twenty-five Sprague-Dawley rats had a
      1-cm(2) area of cecal serosa abraded. Controls (CON, n = 5) received no
      treatment, the chondroitin sulfate group (CS, n = 10) received chondroitin
      sulfate (0.013 g/kg) in 0.9% NaCl intraperitoneally (ip), and vehicle controls
      (VC, n = 10) received an equal volume of 0.9% NaCl solution ip before the abdomen
      was closed. All animals were sacrificed on postoperative day 10. The extent of
      adhesion was quantified according to Mazuji's adhesion grade (0 to 4: 0 = no
      adhesion and 4 = very dense adhesion) and quantitated after H&E, trichome, and
      immunohistochemical staining for fibrin and collagen type I and type III using
      digital image analysis. RESULTS: The mean Mazuji's adhesion grade in the CON was
      4.0 +/- 0.0, in the VC 2.60 +/- 0.37, and in the CS 1.3 +/- 0.42 (P < 0.01 for CS
      vs CON and P < 0.05 for CS vs VC comparisons). The mean gray-scale intensity (0
      255: 0 = dense amount and 255 = none) of adhesion density in the CON was 105. 5
      +/- 5.5, in the VC 125 +/- 15.0, and in the CS 178.3 +/- 21.0 (P < 0.01 for CS vs
      CON and P < 0.05 for CS vs VC comparisons). The mean adjusted intensity stain
      indices (AISI) for fibrin and collagen type I in the CON were 59 +/- 17 and 53 +/
      19, in the VC 27 +/- 3 and 25 +/- 7, and in the CS 16 +/- 5 and 6 +/- 3,
      respectively (P < 0.05 between CS and CON comparisons). The AISI of collagen type
      III was not significant among all the groups (P > 0.1). CONCLUSIONS: The extent
      of early postoperative intra-abdominal adhesion formation as determined by gross
      assessment and from quantitation of fibrin and collagen type I deposition was
      significantly reduced by a single intraperitoneal administration of a chondroitin
      sulfate solution.

PMID- 10644472
TI  - Recovery after cardioplegia in the hypertrophic rat heart.
AB  - BACKGROUND: Enhanced recovery after cardioplegic arrest has been observed in rat
      hearts with hypertrophy induced by hemodynamic overload. We hypothesize that this
      is related to altered characteristics of hypertrophied myocardium-reflected by
      increased V(3) isomyosin and glycolytic potential-other than increased left
      ventricular mass. MATERIALS AND METHODS: Isolated hearts from age-matched
      nonoperated and sham-operated control rats and from aortic-banded, hyperthyroid,
      and hypothyroid rats-groups in which hypertrophy and V(3) as a percentage of left
      ventricular myosin vary independently-underwent 2 h of multidose cardioplegic
      arrest at 8 degrees C followed by reperfusion at 37 degrees C. Left ventricular
      V(3) isomyosin was evaluated after separation by gel electrophoresis. RESULTS:
      Moderate left ventricular hypertrophy was produced by aortic banding or
      hyperthyroidism and atrophy by hypothyroidism. V(3) isomyosin was increased in
      banded (28%) and hypothyroid (75%) rats compared to control (12%) and
      hyperthyroid rats (7%). Myocardial glycogen content closely paralleled %V(3). At
      30 min of working reperfusion, functional recovery (assessed as percentage
      prearrest cardiac output) was 66 +/- 4 and 68 +/- 5% in control and hyperthyroid
      hearts and 81 +/- 2 and 80 +/- 5% in hearts from banded and hypothyroid rats
      (each P < 0.05 vs controls), respectively. At 30 min, hearts from banded and
      hypothyroid rats were also more efficient (as indexed by cardiac output at
      constant mean aortic pressure/myocardial oxygen consumption) than control and
      hyperthyroid hearts. CONCLUSIONS: The data suggest that recovery is related not
      to increased mass but to other changes in overload hypertrophy. Increased
      percentage V(3) isomyosin and glycogen reflect these changes and may themselves
      contribute to improved functional recovery after cardioplegic arrest, as may
      increased postischemic efficiency.

PMID- 10644473
TI  - Epidermal growth factor-induced cytoprotection in human intestinal cells involves
      intracellular calcium signaling.
AB  - BACKGROUND: The mechanism(s) whereby epidermal growth factor (EGF) protects
      against cellular injury remains poorly understood. Previous data in our
      laboratory have suggested that EGF-induced cellular proliferation in human
      colonic carcinoma cells (Caco-2) may involve changes in intracellular calcium
      content ([Ca(2+)](i)). Our current objective was to determine if a similar
      process was involved with EGF-induced cytoprotection. METHODS: Postconfluent Caco
      2 cells were employed for all experimentation. [Ca(2+)](i) was measured with Fluo
      3 fluorescence. Injury was measured employing Ethidium homodimer 1 uptake and
      lactate dehydrogenase (LDH) release. RESULTS: Caco-2 cells pretreated, but not
      concomitantly treated, with EGF (10-100 ng/ml, 30-60 min) significantly
      attenuated cellular injury induced subsequently by 500 microM deoxycholate (DC).
      Cells exposed to 100 ng/ml EGF demonstrated an initial increase in [Ca(2+)](i) (1
      5 min) which was blocked with neomycin, an inhibitor of inositol 1,4,5
      trisphosphate (IP(3)) generation, and the phospholipase C (PLC) inhibitor U73122,
      but not U73343 (inactive control). This was followed by sustained extracellular
      Ca(2+) influx (5-20 min), which was attenuated with calcium-free buffer and the
      store operated Ca(2+) channel blocker La(3+). [Ca(2+)](i) then returned to
      baseline (20-30 min), a process blocked with the Ca(2+)-ATPase inhibitors
      quercetin and vanadate. The above treatments, which in and of themselves did not
      induce cellular injury, were repeated and cells were subsequently exposed to DC.
      All groups exposed to 500 microM DC demonstrated significant increases in both
      Ethidium Homodimer 1 uptake and LDH release. Both indices of injury were
      significantly decreased when cells were pretreated with EGF +/- the inactive PLC
      inhibitor U73343. However, protection induced by EGF was lost when any of its
      effects on changes in [Ca(2+)](i) were prevented: internal Ca(2+) store release
      via PLC and IP(3), sustained Ca(2+) influx through store operated Ca(2+)
      channels, or subsequent Ca(2+) efflux. CONCLUSION: Taken together, these data
      strongly suggest that the cytoprotective effects of EGF may involve Ca(2+)
      signaling.

PMID- 10644475
TI  - Evaluation of pain and stress levels of animals used in experimental research.
AB  - This paper represents a contribution to researchers employing "in vivo" models in
      experimental surgery in order to obtain more reliable results in accordance with
      current legislation and Russel's "three R" statement: refinement, reduction, and
      replacement. After general consideration about the definition of pain and stress
      concerning laboratory animals, the authors suggest making an evaluation of the
      experimental protocol before approval by the local committee to allow assessment
      in terms of the costs/benefits of experimental research employing live animals.

PMID- 10644474
TI  - Role of actin cytoskeleton in prostaglandin-induced protection against ethanol in
      an intestinal epithelial cell line.
AB  - Prostaglandins (PGs) protect a variety of gastrointestinal cells against injury
      induced by ethanol and other noxious agents. This investigation attempted to
      discern the mechanism of cytoprotection as it relates to the relationship between
      actin and PGs in IEC-6 cells (a rat intestinal epithelial cell line). IEC-6 cells
      were incubated in Dulbecco's modified Eagle's medium +/- 16,16-dimethyl
      prostaglandin E(2) (dmPG, 2.6 microM) for 15 min and subsequently incubated in
      medium containing 1, 2.5, 5, 7.5, and 10% ethanol (EtOH). Cells were then
      processed for immunocytochemistry using FITC-phalloidin in order to stain the
      actin cytoskeleton, and cell viability was determined by trypan blue exclusion.
      Quantitative Western immunoblotting of fractioned G-actin (nonpolymerized; S1)
      and F-actin (polymerized; S2) was also carried out. EtOH concentrations equal to
      and greater than 5% led to the collapse of the actin cytoskeleton as depicted by
      extensive disorganization and fragmentation. In addition, these same EtOH
      concentrations significantly decreased the S2 fraction and increased the S1 pool
      of actin. Preincubation with dmPG prevented collapse of the actin cytoskeleton,
      significantly increased the S2 polymerized fraction as determined by quantitative
      immunoblotting, and increased cell viability in EtOH-treated cultures. Prior
      incubation with cytochalasin D, an actin disruptive agent, not only reduced cell
      viability but also prevented the cytoprotective effects of dmPG. Phalloidin, an
      actin stabilizing agent, had effects similar to that of dmPG as demonstrated by
      stability of the actin cytoskeleton and increased cellular viability. Such
      findings indicate that PGs are important in the organization and stability of
      actin under in vitro conditions. These effects on actin may play an essential
      role in the mechanism of PG-induced cytoprotection.

PMID- 10644476
TI  - Barrett's esophagus and associated adenocarcinoma in a mouse surgical model.
AB  - BACKGROUND: The development of Barrett's esophagus (BE) and Barrett's associated
      adenocarcinoma (BAA) in the rat after experimental inducement of esophageal
      reflux of gastric, bile, and pancreatic juice has been reported by others. The
      purpose of this study was to determine whether similar results could be
      demonstrated in the mouse model. MATERIALS AND METHODS: One hundred eight Swiss
      Webster mice were used in this study and were divided into three groups: Group I,
      37 mice with esophagojejunostomy; Group II, 39 mice with esophagojejunostomy and
      the carcinogen N-methyl-N-benzylnitrosamine (MBN); and Group III, 32 mice with
      MBN alone. The animals were sacrificed after 19 weeks. Macroscopic and
      histopathologic examinations were performed. RESULTS: One hundred mice survived
      and were available for pathologic study. Macroscopic evidence suggested
      esophagitis in 60.6% of mice in Group I, 62.8% of mice in Group II, and 9% of
      mice in Group III and suggested tumor in 3% of mice in Group I, 51.4% of mice in
      Group II, and 53.1% of mice in Group III. Histopathologic analysis disclosed BE
      in 42.4% of mice in Group I, 20% of mice in Group II, and 12.5% of mice in Group
      III. Cancer was present in 12.2% of mice in Group I, 54.3% of mice in Group II,
      and 46.9% of mice in Group III. Adenocarcinoma with or without squamous cell
      carcinoma was present in 6.1% of mice in Group I, 37.1% of mice in Group II, and
      12.5% of mice in Group III. CONCLUSIONS: Esophagojejunostomy plus MBN in the
      mouse results in BE, BAA, or both in 57.1% of animals, consistent with findings
      in the rat model after similar interventions.

PMID- 10644477
TI  - Sulfatide and monoclonal antibodies prevent reperfusion injury in skin flaps.
AB  - Sulfatide binds to P- and L-selectin, which play important roles in the
      initiation of neutrophil-endothelial interactions. Sulfatide protects skin flaps
      from ischemia-reperfusion injury. The purpose of this study was to evaluate the
      augmented protection when anti-rat ICAM-1 and anti-rat LFA-1 antibodies are
      combined with sulfatide in the ischemia-reperfusion model of rat skin flaps.
      Sulfatide was administered intravenously just before elevation of the right
      abdominal epigastric flap, and monoclonal antibodies were injected 30 min before
      clamp release. The femoral artery and vein were clamped above and below the
      epigastric vessels for 11 h and then the clamp was released. The administration
      of both sulfatide and monoclonal antibodies significantly increased the flap
      surviving area (6.58 +/- 0.61 cm(2) versus the group with monoclonal antibodies
      alone, 4.43 +/- 0.32 cm(2), P = 0.01). In the untreated rats the area was 1.86 +/
      0.36 cm(2). Histological examination 24 h after reperfusion in the group treated
      with sulfatide and monoclonal antibodies showed only slight leukocyte invasion
      into the flap, and myeloperoxidase activity 24 h after reperfusion was
      significantly reduced. This study indicates that both sulfatide and monoclonal
      antibodies protect rat skin flaps from ischemia-reperfusion injury.

PMID- 10644478
TI  - MnSOD expression is increased in metastatic gastric cancer.
AB  - BACKGROUND: Manganese superoxide dismutase (MnSOD) catalyzes the scavenging of
      superoxide radicals in order to protect cells from the damage caused by reactive
      oxygen species. Previous studies implicate MnSOD in cancer progression, but its
      role in gastric cancer metastasis is poorly understood. MATERIALS AND METHODS: To
      determine whether MnSOD expression correlates with gastric cancer metastasis, we
      compared immunostaining for MnSOD in the primary tumors of gastric cancer
      patients with (n = 15) and without (n = 9) nodal metastases. These patients were
      matched for risk factors associated with gastric cancer metastasis, such as tumor
      site, depth, and grade. MnSOD expression was scored positive (increased) if MnSOD
      staining of tumor cells was more intense than MnSOD staining in corresponding
      normal gastric epithelial cells. Statistical analyses were via chi(2) test and
      Fisher's exact test. RESULTS: MnSOD expression was increased in 14 of the 15
      (93%) metastatic tumors, compared to only 4 of the 9 (44%) nonmetastatic tumors
      (P = 0.015). There was no significant difference in staining when the two groups
      were compared based on tumor grade (P = 0.70) or depth of tumor cell invasion (T
      stage) (P = 0.22). CONCLUSIONS: MnSOD expression is upregulated in the primary
      tumors of gastric cancer patients with lymph node metastases. This finding
      supports an involvement of MnSOD and possibly the reactive oxygen status of the
      gastric tumor microenvironment in gastric cancer metastasis.

PMID- 10644479
TI  - Protease inhibitor reduces loss of tensile strength in rat anastomosis with
      peritonitis.
AB  - BACKGROUND: The tensile strength in intestinal anastomoses decreases
      postoperatively in association with degradation of the extracellular matrix, and
      these changes would be expected to be more intense in the presence of
      peritonitis. MATERIALS AND METHODS: In this study, we investigated extracellular
      matrix degradation and tensile strength in a rat model of intestinal anastomosis
      with peritonitis. In the chemical peritonitis model, peritonitis was induced 24 h
      earlier with intraperitoneal HCl. A serine protease inhibitor, nafamostat
      mesilate (NM), was given intraperitoneally to some animals every 12 h from
      immediately after the operation for 3 days. Immunostaining was performed by the
      standard streptavidin-biotin-peroxidase method after fibronectin (Fn) and factor
      XIII antigen retrieval on paraformaldehyde-fixed, paraffin-embedded tissue
      sections. RESULTS: In comparison with controls, administration of NM reduced the
      loss of tensile strength on Day 3 in a dose-dependent manner, and high-dose NM
      (20/mg/kg) significantly prevented the loss of tensile strength on Day 3 (P < 0.
      05). In the control group, degradation of the collagen layer in the anastomosis
      was associated with disappearance of Fn and factor XIII staining on Day 3. The
      administration of NM attenuated these changes with intense immunostaining for Fn
      and factor XIII seen particularly between collagen fibers on both sides of the
      anastomosis on Day 3. In the chemical peritonitis model, administration of NM
      also significantly prevented the loss of tensile strength on Day 3 without
      disappearance of collagen fibers. CONCLUSION: These findings suggest that NM may
      be clinically useful for preventing intestinal leakage, particularly when
      anastomoses are performed under protease-activating conditions, such as
      intestinal edema and inflammation.

PMID- 10644480
TI  - c-Jun does not mediate hepatocyte apoptosis following NFkappaB inhibition and
      partial hepatectomy.
AB  - Inhibition of the transcription factor nuclear factor kappa B (NFkappaB) induces
      marked hepatocyte apoptosis and liver dysfunction after partial hepatectomy (PH)
      in rats. Hepatocyte apoptosis may be due to direct inhibition of NFkappaB-induced
      hepatocyte survival genes or due to indirect increased signaling through the
      stress-activated protein kinase pathway (SAPK), resulting in increased c-Jun. c
      Jun, an AP-1 transcription factor, induces apoptosis in fibroblasts. Our aim was
      to determine if hepatocyte apoptosis following inhibition of NFkappaB and partial
      hepatectomy in rats is due to increased c-Jun. Adult male Sprague-Dawley rats
      (200 g) were injected intraportally with 6 x 10(9) PFU adenoviral vector
      containing luciferase (Ad5Luc) or superrepressor IkappaB (Ad5IkappaB) transgene
      that inhibits NFkappaB translocation into the nucleus. Two-thirds PH was
      performed 24 h after vector administration, and the remnant liver was harvested
      30 min or 24 h after PH. Northern and Western blots were performed to examine the
      presence of IkappaB and c-Jun. A GST c-Jun kinase assay was used to examine Jun-N
      terminal kinase (JNK) activity. AP-1 DNA binding activity was assessed by
      electrophoretic mobility shift assay. TUNEL assay was performed to assess
      apoptosis. All rats receiving adenoviral vectors expressed the luciferase or
      superrepressor IkappaB transgenes. c-Jun mRNA, protein levels, and DNA binding
      activity were not increased in rats treated with Ad5IkappaB at 30 min after PH
      compared to rats injected with Ad5Luc. Jun kinase activity increased following
      partial hepatectomy, but activity was similar in Ad5Luc- and Ad5IkappaB-treated
      animals. AP-1 DNA binding activity was not altered substantially in rats treated
      with Ad5IkappaB. The percentage of apoptotic hepatocytes was similar between
      Ad5Luc- and Ad5IkappaB-injected animals at 0 h, but livers from Ad5IkappaB
      treated rats had increased apoptosis at 24 h compared to Ad5Luc rats (24% vs. 4%)
      after PH. Hepatocyte apoptosis after NFkappaB inhibition and PH is not mediated
      by increased JNK activity or c-Jun.

PMID- 10644481
TI  - Evaluation of the role of intercellular adhesion molecule 1 in a rodent model of
      chronic venous hypertension.
AB  - PURPOSE: To evaluate the role of intercellular adhesion molecule 1 (ICAM-1) in
      cutaneous leukocyte trapping in venous disease, we used our rodent model of
      venous hypertension (VH). MATERIALS AND METHODS: VH was created in adult rats by
      ligation of the inferior vena cava, bilateral common iliac veins, and bilateral
      common femoral veins. In the Phase I experimental (exptl) group, anti-ICAM-1
      monoclonal antibody (1A29) was given intravenously prior to venous ligations.
      Acute venous pressures were measured in the exptl and control (ctrl) (ligation
      only) groups. Bilateral forelimb and hindlimb skin specimens were harvested for
      myeloperoxidase (MPO) assay. In Phase II, VH was created in a chronic group; in a
      sham-operated group, ties were placed around the same vessels without ligations.
      Two weeks later, venous pressures were measured and radiolabeled ((125)I and
      (131)I) monoclonal antibody (mAb) to ICAM-1 was injected and allowed to circulate
      for 5 min before the level of radiolabeled antibody within forelimb and hindlimb
      specimens was measured. RESULTS: In the acute study with 1A29, hindlimb pressures
      were significantly elevated in both the ctrl (n = 4) and exptl (n = 4) hindlimbs
      (15.4 +/- 0.239 and 13.8 +/- 1.89 mm Hg, respectively) compared with ctrl and
      exptl forelimbs (1.38 +/- 0.554 and 1.50 +/- 0.612 mm Hg, respectively). However,
      MPO activity was significantly elevated in the hindlimbs of the ctrl group
      compared with the hindlimbs of the exptl animals (19.8 +/- 1.54 U vs 6.71 +/-
      2.46 U). In the chronic VH rats (n = 5) given radiolabeled anti-ICAM-1 mAb, the
      hindlimb pressures (10.1 +/- 4.52 mm Hg) were significantly elevated (P < 0.05)
      compared with forelimb pressures (1 +/- 0.447 mm Hg) and compared with the
      forelimb and hindlimb pressures in the sham-operated animals (n = 4) (1.63 +/-
      0.813 and 4.25 +/- 2.13 mm Hg, respectively). However, there was not a
      significant difference in the quantity of ICAM-1-hindlimb versus forelimb or
      chronic VH versus sham. CONCLUSIONS: Anti-ICAM-1 mAb decreased MPO activity in
      hypertensive hindlimb skin, supporting the instrumental role of ICAM-1 in
      cutaneous leukocyte trapping. However, the constituent endothelial ICAM-1 is not
      elevated by VH.

PMID- 10644482
TI  - Metalloproteinase levels are decreased in symptomatic carotid plaques.
AB  - BACKGROUND: Matrix metalloproteinase enzymes (MMP) have been identified in
      carotid atherosclerotic plaques, but their role in the development of clinical
      symptoms remains ill defined. We correlated the activity and levels of
      metalloproteinase enzymes and their inhibitors in human carotid plaques to
      ischemic neurologic events. METHODS: Carotid plaques were collected at the time
      of endarterectomy from 23 patients with carotid stenosis. Sixteen patients were
      asymptomatic and 7 patients had symptoms of stroke or transient ischemic attack
      within 6 weeks of surgery. Protein was extracted from the plaques, proteolytic
      activity was determined by gelatin zymography, and pro-MMP and tissue inhibitor
      of metalloproteinase (TIMP) enzyme content were measured by ELISA assay.
      Macrophage accumulation in the plaque was determined using immunohistochemistry.
      RESULTS: Plaques from symptomatic patients had decreased proteolytic activity on
      substrate gel zymography at the 62- and 92-kDa regions (corresponding to active
      MMP-2 and pro-MMP-9). A decrease in pro-MMP-9 (8.21 +/- 2.35 vs 17.42 +/- 3.14
      ng, P < 0. 05) and an increase in TIMP-2 protein (12.62 +/- 0.58 vs 10.56 +/- 0.
      77 ng, P < 0.05) were noted on ELISA in plaques from symptomatic patients. No
      difference was noted in macrophage accumulation in the plaques between the two
      groups. CONCLUSIONS: Plaques from patients who present with ischemic neurologic
      symptoms have decreased proteolytic activity associated with decreased pro-MMP-9
      and increased TIMP-2 protein levels. These data suggest that metalloproteinase
      enzymes are not responsible for plaque instability in the carotid circulation and
      may in fact promote plaque stability.

PMID- 10644483
TI  - Intestinal ischemia and the gut-liver axis: an in vitro model.
AB  - BACKGROUND: Sustained intestinal ischemic injury often leads to shock and
      multiorgan failure, mediated in part by a cytokine cascade. Animal models have
      also identified a central role of Kupffer cells in amplification of cytokines
      following intestinal ischemia. To better understand this gut-liver axis, we
      developed an in vitro model. MATERIALS AND METHODS: Kupffer cells were isolated
      from rat livers by arabinogalactan gradient ultracentrifugation and adherence
      purification. Cells were grown in RPMI medium in 5% CO(2). Rat intestinal
      epithelial cells, IEC-6, were cultured under normoxic or anoxic (90% N(2), 10%
      CO(2)) conditions for 2, 12, and 24 h. Kupffer cells were then grown in the
      conditioned medium of the IEC-6 cultures. After 24 h, the medium was replaced
      with fresh medium. This final Kupffer cell supernatant was tested for tumor
      necrosis factor alpha and interleukin-6 production by ELISA. Trypan blue
      exclusion was performed to assess cell viability. RESULTS: Intestinal and Kupffer
      cells remained viable during the experimental time. Production of both tumor
      necrosis factor alpha and interleukin-6 by Kupffer cells increased with
      increasing ischemia time of the intestinal cells. CONCLUSIONS: Consistent with
      animal studies of intestinal ischemia, this study found an increase in cytokine
      production by Kupffer cells following hypoxia of intestinal cells. This in vitro
      model offers a new tool to study the expression of cytokines, proteins, and
      messengers involved in the cascade of events that follow intestinal ischemia.

PMID- 10644484
TI  - Clostridium difficile toxin: cytoskeletal changes and lactate dehydrogenase
      release in hepatocytes.
AB  - BACKGROUND: We have found that Clostridium difficile toxins can evoke hepatocyte
      acute-phase protein synthesis, and that this effect is dependent on a functioning
      interleukin-1 (IL-1) receptor. The present study was undertaken to determine if
      C. difficile toxicity, as determined by actin rearrangement and lactate
      dehydrogenase (LDH) release, also requires a functioning IL-1 receptor. METHODS:
      Primary hepatocyte cultures were prepared from normal mice, knockout mice
      deficient in the IL-1-converting enzyme (ICE), and knockout mice deficient in the
      IL-1 p80 receptor. Hepatocytes were treated for 24 h with C. difficile culture
      extract, purified C. difficile toxin A, or purified C. difficile toxin B. The
      actin cytoskeleton was examined using confocal microscopy, and LDH release was
      measured by spectrophotometric analysis. RESULTS: C. difficile culture extract,
      toxin A, and toxin B induced collapse of the actin cytoskeleton in hepatocytes
      from normal mice. Hepatocytes from both the ICE-deficient mice and the IL-1 p80
      receptor-deficient mice demonstrated similar responses to both toxins. These
      toxins also induced significant LDH release in a concentration-dependent fashion
      in the normal hepatocytes and the ICE-deficient hepatocytes. However, no
      significant increase in LDH release was observed in hepatocytes from IL-1 p80
      receptor-deficient mice. CONCLUSIONS: C. difficile toxins induce actin
      cytoskeletal collapse independent of IL-1 or the IL-1 receptor. In contrast,
      toxin-stimulated LDH release was dependent on the presence of the IL-1 receptor.
      Thus, separate pathways appear to mediate toxic effects as manifested by actin
      rearrangement and LDH release.

PMID- 10644486
TI  - Rectal pacing: pacing parameters required for rectal evacuation of normal and
      constipated subjects.
AB  - BACKGROUND AND PURPOSE: Our previous studies have demonstrated that rectal
      electric waves start at the rectosigmoid junction (RSJ) and spread caudad along
      the rectum. A rectosigmoid pacemaker was postulated to exist at the RSJ. We also
      demonstrated that electric waves in rectal inertia are so scarce that a "silent"
      electrorectogram is recorded; the myoelectric activity in such cases was
      stimulated by an artificial pacemaker placed at the RSJ. For this article we
      investigated the pacing parameters necessary for rectal evacuation in rectal
      inertia patients. METHODS: The study comprised 24 patients with rectal inertia
      divided into two groups: study group (10 women, 6 men; mean age, 38.9 +/- 10.6
      years) and control group (6 women, 2 men; mean age, 36.3 +/- 9.8 years). The main
      complaint was infrequent defecation and straining at stools. Eight healthy
      volunteers (6 women, 2 men; mean age, 37.2 +/- 9.4 years) with normal stool
      frequency were included in the study. Through a sigmoidoscope, an electrode was
      hooked to the RSJ (stimulating) and two electrodes were hooked to the rectal
      mucosa (recording). Rectal electric activity was recorded before (basal activity)
      and during electric stimulation of the RSJ electrode with an electrical
      stimulator delivering constant electric current of 5-mA amplitude and 200-ms
      pulse width. RESULTS: In the healthy volunteers, rectal pacing effected increases
      in frequency, amplitude, and velocity from a mean of 2.3 +/- 0.9 to 6.2 +/- 1.8
      cycles/min (P < 0.01), 1.2 +/- 0.6 to 1.7 +/- 0.8 mV (P < 0.05), and 4.1 +/- 1. 2
      to 6.3 +/- 1.7 cm/s (P < 0.05), respectively. No waves were recorded from rectal
      inertia patients at rest. Rectal pacing of the study group showed pacesetter
      potentials with a mean frequency of 2. 1 +/- 1.2 cycles/min, amplitude of 0.9 +/-
      0.1 mV, and velocity of 3. 3 +/- 1.6 ms. The control group, in whom the pacemaker
      was not activated, showed no electric activity. CONCLUSIONS: Rectal pacing
      succeeded in producing myoelectric activity in patients with rectal inertia. It
      is therefore suggested that this method be applied for rectal evacuation in
      patients with inertia constipation.

PMID- 10644485
TI  - Platelet-activating factor and bacteremia-induced pulmonary hypertension.
AB  - BACKGROUND: Acute lung injury is a common complication of gram-negative sepsis.
      Pulmonary hypertension and increased lung vascular permeability are central
      features of lung injury following experimental bacteremia. Platelet-activating
      factor is a prominent proinflammatory mediator during bacterial sepsis. Our
      previous studies have demonstrated that exogenous administration of platelet
      activating factor (PAF) induces pulmonary edema without causing pulmonary
      hypertension. Interestingly, inhibition of PAF activity during Escherichia coli
      bacteremia prevents the development of both pulmonary hypertension and pulmonary
      edema. These data suggest that PAF contributes to pulmonary hypertension during
      sepsis, but that this is unlikely to be a direct vascular effect of PAF. The goal
      of the present study was to investigate the mechanism by which acute E. coli
      bacteremia induces pulmonary injury and to define the role that PAF plays in this
      injury. We hypothesized that the effects of PAF on pulmonary hypertension during
      bacteremia are due to the effects of PAF on other vascular mediators. Several
      studies suggest that PAF induces the expression of endothelin-1 (ET), a potent
      peptide vasoconstrictor. Further, our previous studies have implicated ET as a
      central mediator of systemic vasoconstriction during bacteremia. We therefore
      sought to assess whether ET is modulated by PAF. E. coli has also been
      demonstrated to increase endothelial production of nitric oxide (NO), which
      contributes to maintenance of basal vascular tone in the pulmonary circulation.
      We hypothesized that PAF might increase pulmonary vascular resistance during
      bacteremia by activating neutrophils, increasing expression of ET, and decreasing
      the tonic release of NO. Furthermore, we hypothesized that hypoxic
      vasoconstriction did not contribute to pulmonary vasoconstriction during the
      first 120 min of E. coli bacteremia. METHODS: Pulmonary artery pressure (PAP),
      blood pressure (BP), heart rate (HR), and arterial blood gases (ABG) were
      measured in anesthetized spontaneously breathing adult male Sprague-Dawley rats.
      E. coli (10(9) CFU/100 g body wt) was injected at t = 0, and hemodynamic data
      were obtained at 10-min intervals and ABG data at 30-min intervals for a total of
      120 min. Sham animals were treated equally but received normal saline in place of
      E. coli. In treatment groups, a 2.5 mg/kg dose of WEB 2086, a PAF receptor
      antagonist, was administered intravenously 15 min prior to the onset of sepsis or
      sham sepsis. The groups were (1) intravenous E. coli (n = 5); (2) intravenous WEB
      2086 pretreatment + intravenous E. coli (n = 5); (3) intravenous WEB 2086 alone
      (n = 5); and (4) intravenous normal saline (n = 6). Nitric oxide metabolites
      (NOx) and ET concentrations were assayed from arterial serum samples obtained at
      the end of the protocol. Lung tissue was harvested for measurement of
      myeloperoxidase (MPO) activity and pulmonary histology. RESULTS: E. coli
      bacteremia increased HR, PAP, and respiratory rate early during sepsis (within 20
      min), while hypoxemia, hypotension, and hemoconcentration were not manifest until
      the second hour. Pretreatment with WEB 2086 completely abrogated all of these
      changes. E. coli bacteremia increased the activity of serum ET, lung MPO, and
      neutrophil sequestration in the lung parenchyma via a PAF-dependent mechanism.
      However, the mechanism of increased production of NO appears to be PAF
      independent. CONCLUSIONS: These data support the hypothesis that E. coli
      bacteremia rapidly induces pulmonary hypertension stimulated by PAF and mediated
      at least in part by endothelin-1 and neutrophil activation and sequestration in
      the lung. Microvascular injury with leak is also mediated by PAF during E. coli
      bacteremia, but the time course of resultant hypoxemia and hemoconcentration is
      slower than that of pulmonary hypertension. The contribution of hypoxic
      vasoconstriction in exacerbating pulmonary hypertension in gram-negative sepsis
      is probably a late

PMID- 10644487
TI  - Effect of acalculous cholecystitis on gallbladder neuromuscular transmission and
      contractility.
AB  - BACKGROUND: Impaired smooth muscle contractility is important in the
      pathophysiology of acalculous cholecystitis. Common bile duct ligation (CBDL) is
      a model of acalculous cholecystitis, producing acute inflammatory changes and
      decrease in gallbladder smooth muscle contractility. The aim of this study was to
      determine whether there is coexistent dysfunction of neural efferent motor
      pathways of the gallbladder after CBDL. MATERIALS AND METHODS: Gallbladder muscle
      contractility was studied in vitro in normal, CBDL, and sham-operated guinea
      pigs. Electric field stimulation (EFS; 2-16 Hz) was used to activate intrinsic
      nerves and exogenous acetylcholine (ACh) was used to directly stimulate the
      muscle. H&E-stained slides of muscle strips were scored for inflammatory changes.
      RESULTS: After CBDL, there was a progressive increase in the inflammation score
      and decrease in gallbladder muscle contractility to ACh. There was also a
      progressive decline in EFS-induced contractility when expressed as absolute force
      or normalized to the maximal muscle contractile response to ACh. The nitric oxide
      synthase inhibitor l-NNA (10 microM) increased EFS-induced contractions by 50 +/-
      25% (P = 0.05) in CBDL animals but had no effect in sham surgical controls.
      CONCLUSIONS: CBDL with its acute gallbladder inflammation affects gallbladder
      contractility by two mechanisms: (1) decreased smooth muscle contractility, and
      (2) decreased neurally mediated contractions. The neurally mediated alterations
      result from dysfunction of cholinergic excitatory nerves and upregulation of
      nitric-oxide-mediated inhibition of smooth muscle contractility.

PMID- 10644488
TI  - Transrectal ultrasound assessment of murine aorta and iliac arteries.
AB  - Recent research in arterial aneurysm formation has focused on animal model
      development. Mice are an ideal experimental organism due to their short life
      cycle, prolific progeny, and extensively studied genome. Most experiments require
      the sacrifice of the mice to observe and assess any morphological changes.
      Noninvasive or minimally invasive imaging is limited due to the relatively small
      size of the structures. The development of such a technique, therefore, is
      especially useful for allowing repeated measurement without sacrificing the mice.
      We introduce a novel technique of imaging and measuring the aorta, the
      aorta/inferior vena cava complex, and the right and the left common iliac
      artery/vein complex by the use of an intravascular ultrasound catheter. The
      catheter is inserted through the anus and rectum and into the sigmoid and left
      colon, where the aorta can be observed to fluctuate at approximately 500
      beats/min. The aortic bifurcation can also be observed. The diameters of the
      aorta and the inferior vena cava were measured first with the transrectal
      ultrasound technique and then with direct visualization upon laparotomy for 10
      mice. This revealed a percentage error between 13.7 and 14.2% for this novel
      technique. Fifteen more sets of vessel measurements were also made with 8 male
      and 7 female mice. The results demonstrated a correlation between vessel size and
      body weight in male but not female mice and suggested an intersex difference in
      vessel growth rate. We conclude that transrectal ultrasound is a useful tool in
      imaging and measuring the murine aorta and its bifurcation.

PMID- 10644489
TI  - Relationships between T lymphocyte apoptosis and anergy following trauma.
AB  - BACKGROUND: Severely injured trauma patients experience T cell depletion. A
      subset of these patients also develop T cell unresponsiveness (anergy), as
      characterized by the failure of their T cells to proliferate or to produce T
      lymphokines in response to a direct stimulus through the T cell receptor. We
      hypothesized that T cell apoptosis plays a role in the development of posttrauma
      T cell depletion and/or T cell anergy by deleting an activated T cell population.
      We found that moderately increased T cell depletion posttrauma is not innately
      deleterious or immediately responsible for anergy, but may predispose to later
      development of T cell anergy, possibly due to a more stringent requirement for
      activation of the remaining naive T cells. METHODS: A total of 30 blunt trauma
      and burn patients were assessed twice weekly for the following parameters: (1)
      clinical outcome expressed as severity of organ dysfunction as measured by the
      multiple organ dysfunction syndrome score, (2) proliferative response of highly
      purified T cells to anti-CD3/anti-CD4, (3) level of apoptosis as determined by
      flow cytometric analysis of propidium iodide-stained monocyte reduced peripheral
      blood mononuclear cells, either unstimulated or in response to mitogenic
      challenge or Fas (CD95) stimulation. RESULTS: A wide range of apoptosis levels
      are seen in the patients' T cells. Apoptosis is increased when all trauma
      patients' T cells are compared to T cells of normal volunteers. However, at the
      time a patients' T cells are anergic, there is no increased level of apoptosis.
      In fact, the point of maximum anergy (lowest proliferative response) correlates
      to diminished apoptotic response. Increased T cell apoptosis can be stimulated by
      anti-Fas antibody in trauma patients' responsive T cells but not in maximally
      anergic T cells. These data suggest that patients' T cell anergy is not an
      immediate result of apoptotic T cell depletion upon stimulation. However,
      patients who later develop T cell anergy have increased T cell apoptosis earlier
      in their clinical course than patients who never experience T cell anergy.
      CONCLUSIONS: Increased levels of apoptosis are not directly associated with
      negative trauma patient outcome nor the immediate cause of T cell anergy.
      However, unusually high levels of apoptosis and development of severe T cell
      depletion occurring before complete activation and expansion of the posttrauma T
      cell response may presage anergy and subsequent organ failure.

PMID- 10644490
TI  - Glutathione and ultrastructural changes in inflow occlusion of rat liver.
AB  - BACKGROUND: Liver ischemia/reperfusion is frequently associated with organ injury
      to which reactive oxygen species contribute. The aim of our study was to evaluate
      cytosolic and mitochondrial glutathione levels and morphological changes in
      hepatocytes of rat liver in an experimental model of ischemia/reperfusion.
      MATERIALS AND METHODS: The experimental procedure consisted of temporary
      interruption of blood flow to the left lateral and medial hepatic lobes for
      different lengths of time and, in some cases, subsequent reperfusion. Cytosolic
      and mitochondrial glutathione levels were evaluated and ultrastructural analysis
      was carried out for all samples. RESULTS: Ischemic lobes showed ultrastructural
      changes in relationship with the increase in ischemia time. Total glutathione
      levels did not show variations in ischemic lobes and sham lobes with respect to
      control rats during ischemia only. Instead, during reperfusion, significant
      ultrastructural alterations of the hepatocytes and a significant depletion of
      glutatione in cytosolic and mitochondrial compartments were evident. The sham
      lobes also showed a significant glutathione decrement. Increased oxidized
      glutathione (GSSG) levels were found during ischemia both in ischemic lobes and
      in sham lobes. During reperfusion GSSG was found to a minor extent, in the
      cytosolic compartment. In mitochondria GSSG levels were also high during
      reperfusion. CONCLUSIONS: We conclude that depletion of glutathione contributes
      to impaired liver after reperfusion following ischemia but depletion of
      glutathione alone does not induce changes in the morphology of the hepatocytes.
      Glutathione depletion and a greater quantity of GSSG, even in sham lobes, may
      indicate a metabolic alteration which spreads to compartments that are not
      involved in ischemia/reperfusion.

PMID- 10644491
TI  - Actin mediates Encephalitozoon intestinalis entry into the human enterocyte-like
      cell line, Caco-2.
AB  - Microsporidia are spore-forming obligate intracellular eucaryotes that parasitize
      eukaryotic cells. Encephalitozoon intestinalis (formerly Septata intestinalis) is
      a microsporidian species of emerging medical importance, responsible for chronic
      diarrhoea in immunocompetent patients and enteritis and systemic infections in
      HIV-1 infected patients. Infection of host enterocytes has been demonstrated in
      HIV-1-infected patients. However, the mechanisms of entry of E. intestinalis into
      host enterocytes have not been studied and remain hypothetically based on
      diacytosis, a model involving the injection of microsporidian sporoplasm through
      the polar tubule into the host cell. An electron microscopy based study recently
      challenged this hypothesis. We studied the entry of E. intestinalis into
      intestinal epithelial cells by infecting the human enterocyte-like cell line Caco
      2. Entry was mediated by directed phagocytosis, as suggested by the inhibiting
      effect of cytochalasin D on E. intestinalis uptake, colocalization of E.
      intestinalis and F-actin and engulfment of E. intestinalis into Caco-2 cell
      protrusions. Confocal- and electron microscopy observations also suggested that
      after initial contacts through the posterior pole of the microsporidian spore,
      the basolateral surface of Caco-2 cells may be the portal of entry for E.
      intestinalis sporoplasm. Our observations allowed us to propose a new, actin
      based model to describe the entry of microsporidia into enterocytes.

PMID- 10644493
TI  - The 120 kDa outer membrane protein of Ehrlichia chaffeensis: preferential
      expression on dense-core cells and gene expression in Escherichia coli associated
      with attachment and entry.
AB  - The immunodominant 120 kDa protein (p120) of Ehrlichia chaffeensis was
      demonstrated to be exposed on the surface of purified whole ehrlichial cells
      examined by immunoelectron microscopy with a rabbit antibody against a portion of
      the domain containing tandem repeat units. In the intracellular location, the 120
      kDa protein was detected by immunoelectron microscopy in the outer membrane of
      the cell wall of dense-core forms of the ehrlichiae in infected canine macrophage
      like cells and as a component of the intramorular fibrillary matrix. No 120 kDa
      protein was detected in the cell wall of ehrlichial reticulate cells. Recombinant
      Escherichia coli with a plasmid containing the entire 120 kDa protein gene, but
      no bacteria with non-recombinant plasmid, attached to the surface of HeLa cells
      as visualized by electron microscopy. Some of the recombinant 120 kDa protein
      expressing E. coli invaded the HeLa cells as determined by gentamicin protection
      assays and by intravacuolar localization ultrastructurally.

PMID- 10644492
TI  - The Salmonella YopJ-homologue AvrA does not possess YopJ-like activity.
AB  - The YopJ protein of Yersinia pseudotuberculosis inhibits several eukaryotic
      signalling pathways that are normally activated in cells following their contact
      with bacteria. Salmonella encodes a protein, AvrA, that is secreted by the
      typeIII inv/spa secretion system which is clearly homologous to YopJ (56%
      identical, 87% similarity). Since AvrA and YopJs similarity also encompassed a
      region of YopJ that had previously been shown to be critical for its biological
      activity, we were interested whether AvrA and YopJ provoked similar responses in
      eukaryotic cells. Two different approaches were used to determine whether AvrA
      possesses YopJ-like activity in modulating cytokine expression or killing
      macrophages. An avrA strain of Salmonella dublin was constructed and its activity
      was compared to an isogenic wildtype counterpart in cellular response assays. In
      a complementary approach, AvrA was expressed in and delivered into eukaryotic
      cells by a yopJ strain of Yersinia pseudotuberculosis. We show here that AvrA
      affects neither cytokine expression or plays a role in macrophage killing when
      expressed by either Salmonella or Yersinia. Additionally, AvrA does not possess
      SopB/D-like activity in promoting fluid secretion into infected calf ileal loops.
      These data indicate that Salmonella and Yersinia trigger and/or modulate
      eukaryotic cell responses by different typeIII-secreted proteins and suggests
      that despite their close evolutionary relatedness, AvrA and YopJ perform
      different functions for Salmonella and Yersinia, respectively.

PMID- 10644494
TI  - A comparative analysis of pilin genes from pathogenic and nonpathogenic Neisseria
      species.
AB  - Pathogenic Neisseria species elaborate type IV pili, which are considered
      important for virulence. In this study, we examined pilin-encoding expression
      loci (pilE) in nonpathogenic Neisseria species. PCR based screening detected
      homology to a conserved N-terminal region of pilE in 12 of 15 Neisseria species,
      including all human commensal isolates. The three species failing to display
      homology were isolated from nonhuman sources. We have also characterized complete
      pilE loci from the human commensal species N. lactamica and N. cinerea. As
      anticipated, the predicted protein sequences from these species display features
      typical of all type IV pilins. In addition, these commensal pilins possess two
      highly conserved regions, SV2 and CYS2, which are shared among all neisserial
      pilins. However, a comparative analysis of pilE loci from pathogenic and
      nonpathogenic Neisseria species reveals two distinct structural groups, one
      composed of the pilin genes from N. lactamica, N. cinerea, and the class II pilin
      producing subset of N. meningitidis isolates, the other of gonococcal and
      meningococcal class I pilin-encoding genes. Since both class I and class II pilin
      producing meningococci can act as pathogens, structural relationships among
      neisserial pilin genes do not obviously reflect either species membership or
      ability to cause human disease.

PMID- 10644496
TI  - Construction and virulence testing of a collagenase mutant of Clostridium
      perfringens.
AB  - Clostridium perfringens produces several extracellular toxins and enzymes,
      including an extracellular collagenase or kappa toxin that is encoded by the colA
      gene. To determine if the ability to produce collagenase was a significant
      virulence factor in cases of gas gangrene or clostridial myonecrosis that are
      caused by C. perfringens, a chromosomal colA mutant was constructed by homologous
      recombination and subsequently virulence tested in the mouse myonecrosis model.
      The results clearly indicate that loss of the ability to produce collagenase does
      not alter the ability of the mutant to establish a virulent infection. By
      contrast, infection with a mutant unable to produce alpha-toxin led to a marked
      decrease in virulence. These results indicate that collagenase is not a major
      determinant of virulence in C. perfringens -mediated clostridial myonecrosis.

PMID- 10644495
TI  - Evolutionary and molecular analyses of the Borrelia bdr super gene family:
      delineation of distinct sub-families and demonstration of the genus wide
      conservation of putative functional domains, structural properties and repeat
      motifs.
AB  - B. turicatae, a causative agent of relapsing fever, carries a polymorphic gene
      family that is homologous to the bdr gene family of the Lyme disease spirochetes
      (previously referred to as the rep+ or ORF-E gene family). Here we demonstrate
      that bdr related genes are widely distributed among pathogenic Borrelia species
      and exist as large, polymorphic, plasmid carried, gene families. Twenty distinct
      bdr alleles were identified in isolates of the relapsing fever spirochete, B.
      hermsii, and were localized to linear plasmids. Cloning and sequence analyses
      demonstrate that the putative Bdr functional domains (i.e. the phosphorylation
      motifs and the transmembrane C-terminal domain) are conserved across the genus
      while other regions of these proteins exhibit variability. An assessment of the
      evolutionary relationships among all known Bdr protein sequences obtained from
      five pathogenic Borrelia species revealed that there are distinct Bdr sub
      families. The recognition of distinct phyletic clusters serves as the basis of a
      revised and simplified nomenclature for the bdr proteins that can be applied
      genus wide. At the biological level the delineation of multiple bdr sub-families
      within isogeneic populations raises the possibility that there may be functional
      partitioning among alleles. In summary, the distribution and conservation of the
      Bdr proteins suggests that they are important in the biology/pathogenesis of the
      Borrelia at the genus wide level.

PMID- 10644498
TI  - Editorial

PMID- 10644497
TI  - Presence of phospholipase-D (dly) gene coding for damselysin production is not a
      pre-requisite for pathogenicity in Photobacterium damselae subsp. damselae.
AB  - The presence of the phospholipase-D (dly) gene as pre-requisite for virulence of
      Photobacterium damselae subsp. damselae for poikilotherm and homoiotherm animals
      was investigated in a total of 17 strains isolated from fish, shellfish, mammals
      and seawater. With this aim, we developed two PCR protocols. A simple PCR using
      primers flanking the almost complete dly gene, and a multiplex-PCR using two sets
      of primers directed to internal fragments of the dly and 16S rRNA genes. Only six
      of the 17 Ph. damselae subsp. damselae strains studied harboured the dly gene
      regardless of their haemolytic activity against sheep or rabbit erythrocytes as
      well as their virulence for mammals and marine fish. In fact, all strains but one
      were pathogenic for one or both animals, with LD(50)values ranging from
      1x10(3)and 3x10(5)bacteria for turbot, and 2x10(6)and 8x10(7)cells for mice. The
      PCR results were corroborated in dot blot hybridization experiments employing a
      DNA probe directed to an internal region of the dly gene. From the data obtained
      in this work, we can conclude that the presence of the dly gene is not an
      indicative of the pathogenicity of Ph. damselae subsp. damselae and, therefore,
      the role of damselysin as the main virulence factor of this marine bacterium for
      poikilotherm and homoiotherm hosts should be re-evaluated.

PMID- 10644499
TI  - Cancer treatment: the last 25 years.

PMID- 10644500
TI  - Cancer surgery: the last 25 years.
AB  - Surgery is, and always has been, the main treatment modality of solid tumours.
      For a long period, it consisted of a number of surgical procedures dictated by
      basic oncologic principles, most of which are still adhered to. Over the last few
      decades, increased understanding of the disease, new or improved diagnostic
      facilities, novel and perfected adjuvant treatments, improved surgical techniques
      and daring challenges to established dogmas have all contributed to the
      development of surgical oncology. The heritage from the past came under close
      scrutiny, and the fruits of basic and clinical science were added to an ever
      expanding body of knowledge. It is impossible to review all developments in
      surgical oncology of the last 25 years in one comprehensive paper. Therefore we
      have restricted ourselves to those items that appear most representative for the
      changes that have taken place, and those diseases that have the greatest
      numerical impact.

PMID- 10644501
TI  - Immunotherapy: the last 25 years.

PMID- 10644502
TI  - Radiotherapy: the last 25 years.
AB  - Some of the major changes in radiotherapy over the last years are reviewed in
      this paper. Radiotherapy has played a role in the changes in oncological practice
      including an increase in organ-sparing treatment and achieving good local control
      and improving survival. About half of all breast cancer patients are now treated
      with breast conserving therapy. Organ preservation, usually with multimodality
      therapy, has also been further developed in the treatment of cancers in the head
      and neck, anus, bladder and soft tissue sarcomas. Developments in radiobiology
      have led to the development of new fractionation schedules. Hyperfractionation
      allows an increase in the tumour dose whilst sparing normal tissues and
      accelerated fractionation combats accelerated tumour proliferation during
      treatment. Advances in accelerator technology and computerized treatment planning
      have enabled the development of three-dimensional conformal radiotherapy. This
      gives the oportunity to spare normal tissues and escalate the dose to the tumour.
      Quality control and standardization of dosimetry and treatment delivery at
      departmental and international level has also improved treatment results.

PMID- 10644503
TI  - Twenty-five years of chemotherapy in small cell lung cancer sends us back to the
      laboratory.

PMID- 10644504
TI  - Hypothesis: do voltage-gated H(+) channels in alveolar epithelial cells
      contribute to CO(2) elimination by the lung?
AB  - Although alveolar epithelial cells were the first mammalian cells in which
      voltage-gated H(+) currents were recorded, no specific function has yet been
      proposed. Here we consider whether H(+) channels contribute to one of the main
      functions of the lung: CO(2) elimination. This idea builds on several
      observations: 1) some cell membranes have low CO(2) permeability, 2) carbonic
      anhydrase is present in alveolar epithelium and contributes to CO(2) extrusion by
      facilitating diffusion, 3) the transepithelial potential difference favors
      selective activation of H(+) channels in apical membranes, and 4) the properties
      of H(+) channels are ideally suited to the proposed role. H(+) channels open only
      when the electrochemical gradient for H(+) is outward, imparting directionality
      to the diffusion process. Unlike previous facilitated diffusion models, HCO(-)(3)
      and H(+) recombine to form CO(2) in the alveolar subphase. Rough quantitative
      considerations indicate that the proposed mechanism is plausible and indicate a
      significant capacity for CO(2) elimination by the lung by this route. Fully
      activated alveolar H(+) channels extrude acid equivalents at three times the
      resting rate of CO(2) production.

PMID- 10644505
TI  - An ion transporter involved in congenital deafness focus on "human pendrin
      expressed in Xenopus laevis oocytes mediates chloride/formate exchange".

PMID- 10644506
TI  - Focus on "rapid entry of bitter and sweet tastants into liposomes and taste
      cells: implications for signal transduction".

PMID- 10644507
TI  - Rapid entry of bitter and sweet tastants into liposomes and taste cells:
      implications for signal transduction.
AB  - Some amphipathic bitter tastants and non-sugar sweeteners are direct activators
      of G proteins and stimulate transduction pathways in cells not related to taste.
      We demonstrate that the amphipathic bitter tastants quinine and cyclo(Leu-Trp)
      and the non-sugar sweetener saccharin translocate rapidly through multilamellar
      liposomes. Furthermore, when rat circumvallate (CV) taste buds were incubated
      with the above tastants for 30 s, their intracellular concentrations increased by
      3.5- to 7-fold relative to their extracellular concentrations. The time course of
      this dramatic accumulation was also monitored in situ in rat single CV taste buds
      under a confocal laser-scanning microscope. Tastants were clearly localized to
      the taste cell cytosol. It is proposed that, due to their rapid permeation into
      taste cells, these amphipathic tastants may be available for activation of signal
      transduction components (e. g., G proteins) directly within the time course of
      taste sensation. Such activation may occur in addition to the action of these
      tastants on putative G protein-coupled receptors. This phenomenon may be related
      to the slow taste onset and lingering aftertaste typically produced by many
      bitter tastants and non-sugar sweeteners.

PMID- 10644508
TI  - Retardation of cation channel deactivation by mitochondrial dysfunction in
      adrenal medullary cells.
AB  - The mechanism for cyanide (CN) activation of a nonselective cation (NS) channel
      coupled with a muscarinic receptor in a guinea pig chromaffin cell was studied
      with the perforated-patch method. Bath application of a protein kinase inhibitor
      resulted in a dose-dependent inhibition of muscarine-induced current (I(M)) but
      had no apparent effect on the CN-induced current (I(CN)). On the other hand,
      production of I(CN) occluded muscarine activation of NS channels in an amplitude
      dependent manner. Deactivation of I(M) after washout was retarded while I(CN) was
      also active, and the extent of the retardation increased with an increase in the
      relative production of I(CN) on muscarinic stimulation. Restoration of Na(+) pump
      activity from CN suppression was conspicuously retarded below 19-20 degrees C,
      and the apparent diminution of I(M) and I(CN) after washout was retarded in
      parallel with a decrease in temperature. The results suggest that CN activation
      of NS channels is due to suppression of deactivation of the channel.

PMID- 10644509
TI  - Lysophosphatidic acid rapidly induces protein kinase D activation through a
      pertussis toxin-sensitive pathway.
AB  - Protein kinase D (PKD) is a serine-threonine protein kinase with distinct
      structural features and enzymological properties. Herein we demonstrate that
      lysophosphatidic acid (LPA) induces rapid PKD activation in mouse Swiss 3T3 and
      Rat-1 cells. LPA induced PKD activation in a concentration-dependent fashion with
      maximal stimulation (7.6-fold) achieved at 5 microM. Treatment of Swiss 3T3 cells
      with the protein kinase C (PKC) inhibitors GF-I, Ro-31-8220, and Go-7874
      completely abrogated PKD activation induced by LPA at concentrations that did not
      inhibit PKD activity when added directly to the in vitro kinase assays. PKD
      activation induced by LPA was attenuated markedly and selectively by prior
      exposure of either Swiss 3T3 or Rat-1 cells to pertussis toxin (PTx) in a
      concentration-dependent manner. In contrast, treatment with the protein tyrosine
      kinase inhibitor genistein, the MEK inhibitor PD-098059, or the phosphoinositide
      3-kinase inhibitor wortmannin did not affect PKD activation in response to LPA.
      These results provide the first example of PTx-sensitive and PKC-dependent PKD
      activation and identify a novel G(i)-dependent event in the action of LPA.

PMID- 10644510
TI  - Temperature-sensitive gating of cation current in guinea pig ileal muscle
      activated by hyperpolarization.
AB  - The temperature dependence of hyperpolarization-activated current (I(h)) was
      investigated in freshly isolated guinea pig ileal smooth muscle cells, using the
      nystatin-perforated whole cell recording technique. Hyperpolarizing pulses (-50
      to -120 mV) from -40 mV evoked time-dependent inward rectifying currents with a
      reversal potential of -33 mV and a slow activation time course well approximated
      by a single exponential. The properties of these currents, such as steady-state
      variables, dependence on external K, modification by norepinephrine, and blockade
      by Cs or ZD-7288, coincide well with those of the "classical" I(h) discovered in
      the sinoatrial node. Raising the temperature (range: 22-33 degrees C) accelerated
      the activation time course of this I(h) and shifted its 50% activation potential
      positively (12 mV/10 degree) with much less change in the maximum conductance.
      Based on a simple closed-open model, this can be explained by a high temperature
      dependence of the opening rate constant (temperature coefficient: 3.4). The
      activation profile of reconstructed I(h) at 36 degrees C suggests that a
      considerable overlap could occur between the ranges of I(h) activation and
      physiological membrane potential.

PMID- 10644512
TI  - Rho kinase inhibitor HA-1077 prevents Rho-mediated myosin phosphatase inhibition
      in smooth muscle cells.
AB  - In smooth muscle, a Rho-regulated system of myosin phosphatase exists; however,
      it has yet to be established whether Rho kinase, one of the downstream effectors
      of Rho, mediates the regulation of myosin phosphatase activity in vivo. In the
      present study, we demonstrate in permeabilized vascular smooth muscle cells
      (SMCs) that the vasodilator 1-(5-isoquinolinesulfonyl)-homopiperazine (HA-1077),
      which we show to be a potent inhibitor of Rho kinase, dose dependently inhibits
      Rho-mediated enhancement of Ca(2+)-induced 20-kDa myosin light chain (MLC(20))
      phosphorylation due to abrogating Rho-mediated inhibition of MLC(20)
      dephosphorylation. By an immune complex phosphatase assay, we found that
      guanosine 5'-O-(3-thiotriphosphate) (GTPgammaS) stimulation of permeabilized SMCs
      caused a decrease in myosin phosphatase activity with an increase in the extent
      of phosphorylation of the 130-kDa myosin-binding regulatory subunit (MBS) of
      myosin phosphatase in a Rho-dependent manner. HA-1077 abolished both of the Rho
      mediated events. Moreover, we observed that the pleckstrin homology/cystein-rich
      domain protein of Rho kinase, a dominant negative inhibitor of Rho kinase,
      inhibited GTPgammaS-induced phosphorylation of MBS. These results provide direct
      in vivo evidence that Rho kinase mediates inhibition of myosin phosphatase
      activity with resultant enhancement of MLC(20) phosphorylation in smooth muscle
      and reveal the usefulness of HA-1077 as a Rho kinase inhibitor.

PMID- 10644511
TI  - Modulation of CFTR gene expression in HT-29 cells by extracellular
      hyperosmolarity.
AB  - Hypertonicity has pleiotropic effects on cell function, including activation of
      transporters and regulation of gene expression. It is important to investigate
      the action of hypertonicity on cystic fibrosis gene expression because cystic
      fibrosis transmembrane conductance regulator (CFTR), the cAMP-regulated Cl(-)
      channel, regulates ion transport across the secretory epithelia, which are often
      in a hypertonic environment. We found that adding >150 mosmol/l NaCl, urea, or
      mannitol to the culture medium reduced the amount of CFTR mRNA in colon-derived
      HT-29 cells in a time-dependent manner. Studies with inhibitors of various
      kinases [H-89 (protein kinase A inhibitor), bisindolylmaleimide (protein kinase C
      inhibitor), staurosporine (serine/threonine kinase inhibitor) and herbimycin A
      (tyrosine kinase inhibitor), SB-203580 and PD-098059 (mitogen-activated protein
      kinase inhibitors)] showed that CFTR gene expression and its decrease by added
      NaCl required p38 kinase cascade activity. The CFTR gene activity is regulated at
      the transcriptional level, since adding NaCl diminished the luciferase activity
      of HeLa cells transiently transfected with the CFTR promoter. This regulation
      requires protein synthesis. The complexity of the reactions involved in blocking
      CFTR gene transcription by NaCl strongly suggests that the decrease in CFTR mRNA
      is part of a general cell response to hyperosmolar stress.

PMID- 10644513
TI  - Tyrosine kinase inhibitors reduce bcl-2 expression and induce apoptosis in
      androgen-dependent cells.
AB  - The signal transduction pathway showing how androgen withdrawal induces apoptosis
      in androgen-dependent cells has not been clearly understood. In these studies, we
      focused on the behavior of tyrosine kinases in androgen-dependent cells and
      investigated its correlation with apoptosis and bcl-2 expression. We used SC2G,
      an androgen-dependent mouse mammary carcinoma cell line, which had been cloned
      from Shionogi Carcinoma 115 (SC115). When SC2G cells were cultured with
      herbimycin A (HMA), a potent tyrosine kinase inhibitor, the number of viable
      cells decreased significantly after 24 h. Terminal
      deoxyribonucleotidyltransferase-mediated dUTP-biotin nick end labeling and flow
      cytometric analysis of annexin V staining showed that HMA induced apoptosis of
      SC2G cells. The level of bcl-2 mRNA in SC2G cells was suppressed by HMA in a dose
      dependent manner on RT-PCR. Preincubation with caspase inhibitors protected HMA
      induced apoptosis of SC2G cells. When a human bcl-2 gene was transfected in SC2G
      cells and overexpressed, SC2G cells seemed to acquire tolerance for HMA. These
      data indicate that HMA-sensitive tyrosine kinase(s) can regulate apoptosis and
      inhibit bcl-2 expression in SC2G mouse androgen-dependent cells. Tyrosine
      kinase(s) seemed to be a member of signal transduction between androgen receptor
      activation and bcl-2 expression.

PMID- 10644514
TI  - Age-dependent response of the electrocardiogram to K(+) channel blockers in mice.
AB  - Developmental changes in electrocardiogram (ECG) and response to selective K(+)
      channel blockers were assessed in conscious, unsedated neonatal (days 1, 7, 14)
      and adult male mice (>60 days of age). Mean sinus R-R interval decreased from 120
      +/- 3 ms in day 1 to 110 +/- 3 ms in day 7, 97 +/- 3 ms in day 14, and 81 +/- 1
      ms in adult mice (P < 0.001 by ANOVA; all 3 groups different from day 1). In
      parallel, the mean P-R interval progressively decreased during development.
      Similarly, the mean Q-T interval decreased from 62 +/- 2 ms in day 1 to 50 +/- 2
      ms in day 7, 47 +/- 8 ms in day 14 neonatal mice, and 46 +/- 2 ms in adult mice
      (P < 0.001 by ANOVA; all 3 groups are significantly different from day 1). Q-T(c)
      was calculated as Q- interval. Q-T(c) significantly shortened from 179 +/- 4 ms
      in day 1 to 149 +/- 5 ms in day 7 mice (P < 0.001). In addition, the J junction-S
      T segment elevation observed in day 1 neonatal mice resolved by day 14.
      Dofetilide (0.5 mg/kg), the selective blocker of the rapid component of the
      delayed rectifier (I(Kr)) abolished S-T segment elevation and prolonged Q-T and Q
      T(c) intervals in day 1 neonates but not in adult mice. In contrast, 4
      aminopyridine (4-AP, 2.5 mg/kg) had no effect on day 1 neonates but in adults
      prolonged Q-T and Q-T(c) intervals and specifically decreased the amplitude of a
      transiently repolarizing wave, which appears as an r' wave at the end of the
      apparent QRS in adult mice. In conclusion, ECG intervals and configuration change
      during normal postnatal development in the mouse. K(+) channel blockers affect
      the mouse ECG differently depending on age. These data are consistent with the
      previous findings that the dofetilide-sensitive I(Kr) is dominant in day 1 mice,
      whereas 4-AP-sensitive currents, the transiently repolarizing K(+) current, and
      the rapidly activating, slowly inactivating K(+) current are the dominant K(+)
      currents in adult mice. This study provides background information useful for
      assessing abnormal development in transgenic mice.

PMID- 10644515
TI  - High glucose and insulin inhibit VSMC MKP-1 expression by blocking iNOS via p38
      MAPK activation.
AB  - Our laboratory has recently demonstrated a role for the phosphatidylinositol 3
      kinase-mediated inducible NO synthase (iNOS) signaling pathway in acute
      regulation of insulin-induced mitogen-activated protein phosphatase-1 (MKP-1)
      expression in primary cultures of rat aortic vascular smooth muscle cells (VSMCs)
      (N. Begum, L. Ragolia, M. McCarthy, and N. Duddy. J. Biol. Chem. 273: 25164
      25170, 1998). We now show that prolonged treatment of VSMCs with 100 nM insulin
      and high glucose (25 mM) for 12-24 h, to mimic hyperinsulinemia and
      hyperglycemia, completely blocked MKP-1 mRNA and protein expression in response
      to subsequent acute insulin treatment. To understand the mechanism of insulin
      resistance induced by high glucose and insulin, we studied the regulation of iNOS
      protein induction in these cells. Both high glucose and chronic insulin treatment
      caused a marked impairment of iNOS induction in response to acute insulin.
      Blocking of signaling via the p38 mitogen-activated protein kinase (MAPK) pathway
      by prior treatment for 1 h with SB-203580, a synthetic p38 MAPK inhibitor,
      completely prevented the inhibition of iNOS induced by high glucose and insulin
      and restored MKP-1 induction to levels observed with acute insulin treatment. In
      contrast, PD-98059, a MEK inhibitor, had no effect. Furthermore, high glucose and
      chronic insulin treatment caused sustained p38 MAPK activation. We conclude 1)
      that chronic insulin and high glucose-induced insulin resistance is accompanied
      by marked reductions in both iNOS and MKP-1 inductions due to p38 MAPK activation
      that leads to excessive cell growth and 2) that p38 MAPK/extracellular signal
      regulated kinase pathways regulate iNOS induction, thereby controlling MKP-1
      expression, which in turn inactivates MAPKs as a feedback mechanism and inhibits
      cell growth.

PMID- 10644516
TI  - Induction of heme oxygenase-1 by hypoxia and free radicals in human dermal
      fibroblasts.
AB  - Heme oxygenase-1 (HO-1) catalyzes the rate-limiting step in heme catabolism and
      presumably is involved in cellular iron homeostasis. It is induced by a variety
      of cellular stresses, including oxygen deprivation and free radical-mediated
      stress. We examined induction of HO-1 mRNA in skin fibroblasts and investigated
      the mechanism by which it occurs. Hypoxia did not appear to act via induction of
      oxygen free radicals: induction of HO-1 was not sensitive to the free radical
      scavenger GSH or other antioxidants. Moreover, hypoxia did not increase steady
      state levels of free radicals generated by fibroblasts. In contrast, HO-1
      induction by the oxidants, H(2)O(2) and carbonyl cyanide m-chlorophenylhydrazone
      (CCCP) was significantly attenuated in the presence of free radical scavengers.
      This correlated with increased levels of free radical production in fibroblasts
      treated with these oxidants. Iron depletion by desferrioxamine mesylate, a
      specific iron complexon, completely inhibited hypoxic stimulation of HO-1 but did
      not attenuate the effect of H(2)O(2) and CCCP on HO-1 mRNA. Addition of Fe(2+),
      Fe(3+), or holo-transferrin to fibroblasts increased levels of HO-1 mRNA.
      Treatment of cells with hypoxia, but not H(2)O(2) or an exogenous source of iron,
      significantly increased the half-life of HO-1 mRNA. The data suggest hypoxia
      regulates HO-1 gene expression by a specific posttranscriptional mechanism:
      stabilization of mRNA. Hypoxia has previously been shown to increase fibroblast
      collagen synthesis and is thought to play a role in pathogenesis of systemic
      sclerosis (SSc). Skin fibroblasts isolated from patients with SSc demonstrated
      significantly stronger induction of HO-1 by hypoxia than did fibroblasts from
      normal controls. We hypothesize that exposure of SSc fibroblasts to hypoxic
      conditions leads to in vivo selective proliferation of cells that adapt to
      hypoxia.

PMID- 10644517
TI  - Hyperosmolality induces activation of cPKC and nPKC, a requirement for ERK1/2
      activation in NIH/3T3 cells.
AB  - Protein kinase C (PKC) has been reported to be associated with the activation of
      extracellular signal-regulated kinase (ERK) by hyperosmolality. However, it is
      unclear whether hyperosmolality induces PKC activation and which PKC isoforms are
      involved in ERK activation. In this study, we demonstrate that NaCl increases
      total PKC activity and induces PKCalpha, PKCdelta, and PKCepsilon translocation
      from the cytosol to the membrane in NIH/3T3 cells, suggesting that hyperosmotic
      stress activates conventional PKC (cPKC) and novel PKC (nPKC). Further studies
      show that NaCl-inducible ERK1 and ERK2 (ERK1/2) activation is a consequence of
      cPKC and nPKC activation, because either downregulation with 12-O
      tetradecanoylphorbol 13-acetate or selective inhibition of cPKC and nPKC by GF
      109203X and rottlerin largely inhibited the stimulation of ERK1/2 phosphorylation
      by NaCl. In addition, we show that NaCl increases diacylglycerol (DAG) levels and
      that a phospholipase C (PLC) inhibitor, U-73122, inhibits NaCl-induced ERK1/2
      phosphorylation. These results, together, suggest that a hyperosmotic NaCl
      induced signaling pathway that leads to activation of ERK1/2 may sequentially
      involve PLC activation, DAG release, and cPKC and nPKC activation.

PMID- 10644518
TI  - Characterization and regulation of E2F activity during Caco-2 cell
      differentiation.
AB  - The specific mechanisms controlling intestinal cell differentiation remain
      largely undefined. The retinoblastoma (Rb) proteins (pRb, p130, and p107) appear
      crucial to the terminal differentiation process of certain cells through their
      association and repression of E2F transcription factors. We have examined the
      expression of pRb-related proteins p130 and p107 as well as the regulation of E2F
      during spontaneous differentiation of the Caco-2 intestinal cell line. Nuclear
      protein levels of p130 and p107 were increased with Caco-2 differentiation.
      Induction of a slower-migrating E2F complex was noted in postconfluent (i.e.,
      differentiated) Caco-2 cells; p130 protein was the predominant component of this
      E2F complex with a minor contribution from cyclin-dependent kinase-2. A small
      component of p107 binding was identified by deoxycholate release gel shift
      assays. In contrast, no pRb binding to E2F was noted in Caco-2 cells. In addition
      to increased association with p130, E2F-4 phosphorylation was markedly decreased
      in differentiated Caco-2 cells, whereas E2F protein levels remained unchanged.
      Taken together, our findings suggest that the regulation of E2F function may be
      an important contributing factor in the cell cycle block and spontaneous
      differentiation of Caco-2 cells. This regulation of E2F occurs most likely
      through its increased association with p130 as well as decreased phosphorylation.

PMID- 10644519
TI  - Expression of antioxidant enzymes in human inflammatory cells.
AB  - Because antioxidant enzymes may have an important role in the oxidant resistance
      of inflammatory cells, we investigated the mRNA levels and specific activities of
      manganese and copper-zinc superoxide dismutases (Mn SOD and Cu,Zn SOD), catalase
      (Cat), and glutathione peroxidase, as well as the concentrations of glutathione
      (GSH) in human neutrophils, monocytes, monocyte-derived macrophages, and alveolar
      macrophages. Levels of GSH and glutathione peroxidase activity in monocytes were
      three times higher than in neutrophils, whereas the mRNA of Cat was 50-fold and
      its specific activity 4-fold higher in neutrophils. Although Mn SOD mRNA levels
      were higher in neutrophils, enzyme activities, as well as those of Cu,Zn SOD,
      were similar in all phagocytic cells. Neutrophils lost their viability, assessed
      by adenine nucleotide depletion, within 24 h ex vivo and more rapidly if GSH was
      depleted. However, neutrophils were the most resistant cell type to exogenous
      H(2)O(2). In conclusion, high Cat activity of neutrophils appears to explain
      their high resistance against exogenous H(2)O(2), whereas low GSH content and GSH
      related enzymes seem to account for the poor survival of human neutrophils.

PMID- 10644520
TI  - Characteristics of phosphate-induced Ca(2+) efflux from the SR in mechanically
      skinned rat skeletal muscle fibers.
AB  - The effects of P(i) on sarcoplasmic reticulum (SR) Ca(2+) regulation were studied
      in mechanically skinned rat skeletal muscle fibers. Brief application of caffeine
      was used to assess the SR Ca(2+) content, and changes in concentration of Ca(2+)
      ([Ca(2+)]) within the cytosol were detected with fura 2 fluorescence.
      Introduction of P(i) (1-40 mM) induced a concentration-dependent Ca(2+) efflux
      from the SR. In solutions lacking creatine phosphate (CP), the amplitude of the
      P(i)-induced Ca(2+) transient approximately doubled. A similar potentiation of
      P(i)-induced Ca(2+) release occurred after inhibition of creatine kinase (CK)
      with 2,4-dinitrofluorobenzene. In the presence of ruthenium red or ryanodine,
      caffeine-induced Ca(2+) release was almost abolished, whereas P(i)-induced Ca(2+)
      release was unaffected. However, introduction of the SR Ca(2+) ATPase inhibitor
      cyclopiazonic acid effectively abolished P(i)-induced Ca(2+) release. These data
      suggest that P(i) induces Ca(2+) release from the SR by reversal of the SR Ca(2+)
      pump but not via the SR Ca(2+) channel under these conditions. If this occurs in
      intact skeletal muscle during fatigue, activation of a Ca(2+) efflux pathway by
      P(i) may contribute to the reported decrease in net Ca(2+) uptake and increase in
      resting [Ca(2+)].

PMID- 10644521
TI  - Effects of NO donors and synthase agonists on endothelial cell uptake of L-Arg
      and superoxide production.
AB  - It is commonly believed that the activity of NO synthase (NOS) solely controls NO
      production from its substrates, L-Arg and O(2). The Michaelis-Menten constant
      (K(m)) of NOS for L-Arg is in the micromolar range; cellular levels of L-Arg are
      much higher. However, evidence strongly suggests that cellular supply of L-Arg
      may become limiting and lead to reduced NO and increased superoxide anion (O(
      )(2)*) formation, promoting cardiovascular dysfunction. Uptake of L-Arg into
      cells occurs primarily (approximately 85%) through the actions of a Na(+)
      independent, carrier-mediated transporter (system y(+)). We have examined the
      effects of NOS agonists (substance P, bradykinin, and ACh) and NO donors (S
      nitroso-N-acetyl-penicillamine and dipropylenetriamine NONOate) on transport of L
      Arg into bovine aortic endothelial cells (BAEC). Our results demonstrate that NOS
      agonists increase y(+) transporter activity. A rapidly acting NO donor initially
      increases L-Arg uptake; however, after longer exposure, L-Arg uptake is
      suppressed. Exposure of BAEC without L-Arg to substance P and a Ca(2+) ionophore
      (A-23187) increased O(-)(2)* formation, which was blocked with concurrent
      presence of L-Arg or the NOS antagonist N(omega)-nitro-L-arginine methyl ester.
      We conclude that factors including NO itself control y(+) transport function and
      the production of NO and O(-)(2)*.

PMID- 10644522
TI  - Hypoxic preconditioning protects cultured neurons against hypoxic stress via TNF
      alpha and ceramide.
AB  - Brief "preconditioning" ischemia induces ischemic tolerance (IT) and protects the
      animal brain from subsequent otherwise lethal ischemia. Identification of the
      signaling steps most proximal to the development of the IT will allow induction
      of the resistance to ischemia shortly after the onset of stroke. Animal studies
      demonstrate a key role of tumor necrosis factor-alpha (TNF-alpha) in induction of
      IT. The sphingolipid ceramide is known as a second messenger in many of the
      multiple effects of TNF-alpha. We hypothesized that ceramide could mediate IT. We
      demonstrate that preconditioning of rat cortical neurons with mild hypoxia
      protects them from hypoxia and O(2)-glucose deprivation injury 24 h later (50%
      protection). TNF-alpha pretreatment could be substituted for hypoxic
      preconditioning (HP). HP was attenuated by TNF-alpha-neutralizing antibody. HP
      and TNF-alpha pretreatment cause a two- to threefold increase of intracellular
      ceramide levels, which coincides with the state of tolerance. Fumonisin B(1), an
      inhibitor of ceramide synthase, attenuated ceramide upregulation and HP. C-2
      ceramide added to the cultures right before the hypoxic insult mimicked the
      effect of HP. Ceramide did not induce apoptosis. These results suggest that HP is
      mediated via ceramide synthesis triggered by TNF-alpha.

PMID- 10644523
TI  - Identification of G protein-coupled signaling pathways in cardiac fibroblasts:
      cross talk between G(q) and G(s).
AB  - Cardiac fibroblasts (CFs) are an important cellular component of myocardial
      responses to injury and to hypertrophic stimuli. We studied G protein-coupled
      receptors to understand how CFs integrate signals that activate G(q), G(s), and
      G(i). We predicted that the second messenger pathways present in CFs were
      distinct from those in cardiac myocytes and that unique signaling interactions
      existed in the CFs. ANG II, bradykinin, ATP, and UTP stimulated inositol
      phosphate (IP) production 2.2- to 7-fold. Each of these agonists elevated
      intracellular Ca(2+) concentration ([Ca(2+)](i)) via release from the
      intracellular Ca(2+) storage compartment. Endothelin-1 (ET-1), carbachol, and
      norepinephrine failed to increase either IP production or [Ca(2+)](i). Although
      agonists that activated IP and Ca(2+) transients had no effect on cAMP production
      when administered alone, these agents potentiated the beta(2)-adrenergic response
      two- to fourfold. Hormones known to inhibit adenylyl cyclase activity in cardiac
      myocytes, such as ET-1 and carbachol, failed to lower the beta-adrenergic
      response in fibroblasts. Order of potency and inhibitor data indicate that the
      functional receptor subtypes in these cells are beta(2), P2Y(2), and AT(1) for
      isoproterenol, ATP, and ANG II, respectively. We conclude that CFs express
      functional G protein-linked receptors that couple to G(q) and G(s), with little
      or no coupling to G(i). The expression of receptors and their coupling to G(q)-
      but not to G(i)-linked responses distinguishes the signaling in CFs from that in
      myocytes. Furthermore, agonists that activate G(q) in CFs potentiate stimulation
      of G(s), an example of signaling cross talk not observed in adult myocytes. These
      data suggest that G protein-mediated signaling in CFs is unique and may
      contribute to the specificity of hormone and drug action on individual cell types
      within the heart.

PMID- 10644524
TI  - Na(+) entry via store-operated channels modulates Ca(2+) signaling in arterial
      myocytes.
AB  - In many nonexcitable cells, hormones and neurotransmitters activate Na(+) influx
      and mobilize Ca(2+) from intracellular stores. The stores are replenished by
      Ca(2+) influx via "store-operated" Ca(2+) channels (SOC). The main routes of
      Na(+) entry in these cells are unresolved, and no role for Na(+) in signaling has
      been recognized. We demonstrate that the SOC are a major Na(+) entry route in
      arterial myocytes. Unloading of the Ca(2+) stores with cyclopiazonic acid (a
      sarcoplasmic reticulum Ca(2+) pump inhibitor) and caffeine induces a large
      external Na(+)-dependent rise in the cytosolic Na(+) concentration. One component
      of this rise in cytosolic Na(+) concentration is likely due to Na(+)/Ca(2+)
      exchange; it depends on elevation of cytosolic Ca(2+) and is insensitive to 10 mM
      Mg(2+) and 10 microM La(3+). Another component is inhibited by Mg(2+) and La(3+),
      blockers of SOC; this component persists in cells preloaded with 1,2-bis(2
      aminophenoxy)ethane-N,N,N',N'-tetraacetic acid to buffer Ca(2+) transients and
      prevent Na(+)/Ca(2+) exchange-mediated Na(+) entry. This Na(+) entry apparently
      is mediated by SOC. The Na(+) entry influences Na(+) pump activity and
      Na(+)/Ca(2+) exchange and has unexpectedly large effects on cell-wide Ca(2+)
      signaling. The SOC pathway may be a general mechanism by which Na(+) participates
      in signaling in many types of cells.

PMID- 10644525
TI  - Hepatocyte growth factor affects satellite cell activation and differentiation in
      regenerating skeletal muscle.
AB  - Hepatocyte growth factor (HGF) is the only known growth factor that activates
      quiescent satellite cells in skeletal muscle. We hypothesized that local delivery
      of HGF may enhance regeneration after trauma by increasing the number of
      myoblasts available for restoring normal tissue architecture. Injection of HGF
      into muscle at the time of injury increases myoblast number but does not enhance
      tissue repair as determined using quantitative histological analyses. Rather,
      depending on the dose and the timing of HGF administration relative to the
      injury, regeneration can be inhibited. The greatest inhibitory effect is observed
      when HGF is administered on the day of injury and continued for 3 days,
      corresponding to the time when satellite cell activation, proliferation, and
      early differentiation normally occur. To establish a mechanism for this
      inhibition, we show that HGF can act directly on primary muscle cells to block
      differentiation. These results demonstrate that 1) exogenous HGF synergizes with
      factors in damaged muscle to increase myoblast number, 2) regeneration is not
      regulated solely by myoblast number, and 3) HGF inhibits muscle differentiation
      both in vitro and in vivo.

PMID- 10644527
TI  - Differential distribution of ERalpha and ERbeta mRNA in intrauterine tissues of
      the pregnant rhesus monkey.
AB  - Two estrogen receptor (ER) isoforms, ERalpha and ERbeta, have been described.
      However, no information is available in any species regarding the comparison of
      ERalpha and ERbeta levels in pregnant intrauterine tissues. We investigated 1)
      distribution of ERalpha and ERbeta mRNA in myometrium, amnion, choriodecidua, and
      placenta; 2) their abundance in intrauterine tissues at term not in labor (NIL)
      and in spontaneous term labor (STL); and 3) immunolocalization of ERalpha and
      ERbeta in pregnant rhesus monkey myometrium. Myometrium, amnion, choriodecidua,
      and placenta were obtained at cesarean section from monkeys in STL at 156-166
      days gestational age (GA) (n = 4) and from control monkeys NIL at 140-152 days GA
      (n = 4). RT-PCR was conducted to determine ERalpha and ERbeta and glyceraldehyde
      3-phosphate dehydrogenase mRNA abundance in four intrauterine tissues of the
      pregnant rhesus monkey. The cloned ERbeta PCR fragment was subjected to sequence
      analysis. ERalpha and ERbeta were localized in the myometrium by
      immunohistochemistry. We demonstrated that 1) rhesus monkey ERbeta shares >97%
      identity with human ERbeta in the region sequenced; 2) both ERs were expressed in
      myometrium, amnion, and choriodecidua but not in placenta in the current study;
      3) ERalpha and ERbeta were differentially distributed in myometrium and amnion;
      4) ERalpha and ERbeta were immunolocalized in myometrial smooth cells and smooth
      muscle and endothelial cells of the myometrial blood vessels. The biological
      significance of these quantitative differences in ER subtypes merits further
      study.

PMID- 10644526
TI  - Colonic H-K-ATPase alpha- and beta-subunits express ouabain-insensitive H-K
      ATPase.
AB  - Active K absorption in the rat distal colon is energized by an apical H-K-ATPase,
      a member of the gene family of P-type ATPases. The H-K-ATPase alpha-subunit
      (HKcalpha) has been cloned and characterized (together with the beta-subunit of
      either Na-K-ATPase or gastric H-K-ATPase) in Xenopus oocytes as ouabain-sensitive
      (86)Rb uptake. In contrast, HKcalpha, when expressed in Sf9 cells without a beta
      subunit, yielded evidence of ouabain-insensitive H-K-ATPase. Because a beta
      subunit (HKcbeta) has recently been cloned from rat colon, this present study was
      initiated to determine whether H-K-ATPase and its sensitivity to ouabain are
      expressed when these two subunits (HKcalpha and HKcbeta) are transfected into a
      mammalian cell expression system. Transfection of HEK-293 cells with HKcalpha and
      HKcbeta cDNAs resulted in the expression of HKcalpha and HKcbeta proteins and
      their delivery to plasma membranes. H-K-ATPase activity was identified in crude
      plasma membranes prepared from transfected cells and was 1) saturable as a
      function of increasing K concentration with a K(m) for K of 0.63 mM; 2) inhibited
      by orthovanadate; and 3) insensitive to both ouabain and Sch-28080. In parallel
      transfection studies with HKcalpha and Na-K-ATPase beta1 cDNAs and with HKcalpha
      cDNA alone, there was expression of ouabain-insensitive H-K-ATPase activity that
      was 60% and 21% of that in HKcalpha/HKcbeta cDNA transfected cells, respectively.
      Ouabain-insensitive (86)Rb uptake was also identified in cells transfected with
      HKcalpha and HKcbeta cDNAs. These studies establish that HKcalpha cDNA with
      HKcbeta cDNA express ouabain-insensitive H-K-ATPase similar to that identified in
      rat distal colon.

PMID- 10644528
TI  - Characterization of decorin mRNA in pregnant intrauterine tissues of the ewe and
      regulation by steroids.
AB  - In this study, we characterized the changes in the extracellular matrix
      proteoglycan decorin in pregnant intrauterine tissues in late gestation and in
      association with labor and delivery in sheep. In addition, we examined the
      effects of estradiol and progesterone on regulation of decorin mRNA expression in
      myometrium from the nonpregnant ovariectomized sheep. Using suppression
      subtractive hybridization in combination with Northern blot analysis, we
      identified a significant increase in decorin mRNA in the pregnant sheep
      myometrium during labor. The abundance of decorin mRNA paralleled myometrial
      contractility. The increase in decorin mRNA during labor was only demonstrated in
      the myometrium; no increase was observed in the endometrium or fetal membranes.
      Estradiol upregulated decorin mRNA and may act as a potential stimulator
      responsible for the increased decorin in the myometrium during parturition. The
      ovine decorin cDNA spans 1288 nt, includes 1083 nt of coding sequence predicted
      to encode a protein of 360 amino acids, 119 nt of 5'-untranslated region (UTR)
      and 86 nt of 3'-UTR. Over the coding region, the protein shares 79-96% nt
      sequence identity and 73-94% identity in the deduced amino acid sequence with
      homologous mammalian sequences. Using cloned decorin cDNA, we observed that the
      fibroblasts are the predominant cell type in the pregnant sheep myometrium
      containing decorin mRNA. These data suggest that increased decorin synthesis
      participates in the matrix changes that may play a role in myometrial activation.

PMID- 10644529
TI  - Human pendrin expressed in Xenopus laevis oocytes mediates chloride/formate
      exchange.
AB  - Pendred syndrome, characterized by congenital sensorineural hearing loss and
      goiter, is one of the most common forms of syndromic deafness. The gene causing
      Pendred syndrome (PDS) encodes a protein designated pendrin, which is expressed
      in the thyroid, kidney, and fetal cochlea. Pendrin functions as an iodide and
      chloride transporter, but its role in the development of hearing loss and goiter
      is unknown. In this study, we examined the mechanism of pendrin-mediated anion
      transport in Xenopus laevis oocytes. Unlabeled formate added to the uptake medium
      inhibited pendrin-mediated (36)Cl uptake in X. laevis oocytes. In addition, the
      uptake of [(14)C]formate was stimulated in oocytes injected with PDS cRNA
      compared with water-injected controls. These results indicate that formate is a
      substrate for pendrin. Furthermore, chloride stimulated the efflux of
      [(14)C]formate and formate stimulated the efflux of (36)Cl in oocytes expressing
      pendrin, results consistent with pendrin-mediated chloride/formate exchange.
      These data demonstrate that pendrin is functionally similar to the renal
      chloride/formate exchanger, which serves as an important mechanism of chloride
      transport in the proximal tubule. A similar process could participate in the
      development of ion gradients within the inner ear.

PMID- 10644530
TI  - Secretagogue response of goblet cells and columnar cells in human colonic crypts.
AB  - Crypts of Lieberkuhn were isolated from human colon, and differential
      interference contrast microscopy distinguished goblet and columnar cells.
      Activation with carbachol (CCh, 100 microM) or histamine (10 microM) released
      contents from goblet granules. Stimulation with prostaglandin E(2) (PGE(2), 5
      microM) or adenosine (10 microM) did not release goblet granules but caused the
      apical margin of columnar cells to recede. Goblet volume was lost during
      stimulation with CCh or histamine ( approximately 160 fl/cell), but not with
      PGE(2) or adenosine. Three-quarters of goblet cells were responsive to CCh but
      released only 30% of goblet volume. Half-time for goblet volume release was 3.7
      min. PGE(2) stimulated a prolonged fluid secretion that attained a rate of
      approximately 350 pl/min. Columnar cells lost approximately 50% of apical volume
      during maximal PGE(2) stimulation, with a half-time of 3.3 min. In crypts from
      individuals with ulcerative colitis, goblet cells were hypersensitive to CCh for
      release of goblet volume. These results support separate regulation for mucus
      secretions from goblet cells and from columnar cells, with control mechanisms
      restricting total release of mucus stores.

PMID- 10644531
TI  - The adipoinsular axis: effects of leptin on pancreatic beta-cells.
AB  - The prevalence of obesity and related diabetes mellitus is increasing worldwide.
      Here we review evidence for the existence of an adipoinsular axis, a dual
      hormonal feedback loop involving the hormones insulin and leptin produced by
      pancreatic beta-cells and adipose tissue, respectively. Insulin is adipogenic,
      increases body fat mass, and stimulates the production and secretion of leptin,
      the satiety hormone that acts centrally to reduce food intake and increase energy
      expenditure. Leptin in turn suppresses insulin secretion by both central actions
      and direct actions on beta-cells. Because plasma levels of leptin are directly
      proportional to body fat mass, an increase of adiposity increases plasma leptin,
      thereby curtailing insulin production and further increasing fat mass. We propose
      that the adipoinsular axis is designed to maintain nutrient balance and that
      dysregulation of this axis may contribute to obesity and the development of
      hyperinsulinemia associated with diabetes.

PMID- 10644533
TI  - Effect of exercise training on in vivo insulin-stimulated glucose uptake in intra
      abdominal adipose tissue in rats.
AB  - Intra-abdominal obesity may be crucial in the pathogenesis of the insulin
      resistance syndrome, and training may alleviate this condition. We compared
      insulin-mediated glucose uptake in vivo in three intra-abdominal adipose tissues
      (ATs; retroperitoneal, parametrial, and mesenteric) and in subcutaneous AT and
      also studied the effect of training. Rats were either swim trained (15 wk, n = 9)
      or sedentary (n = 16). While the rats were under anesthesia, a hyperinsulinemic (
      approximately 900 pM), euglycemic clamp was carried out and local glucose uptake
      was measured by both the 2-deoxy-D-[(3)H]glucose and microdialysis techniques.
      Blood flow was measured by microspheres. Upon insulin stimulation, blood flow
      generally decreased in AT. Flow was higher in mesenteric tissue than in other
      ATs, whereas insulin-mediated glucose uptake did not differ between ATs. Training
      doubled the glucose infusion rate during hyperinsulinemia, in part, reflecting an
      effect in muscle. During hyperinsulinemia, interstitial glucose concentrations
      were lower, glucose uptake per 100 g of tissue was higher in AT in trained
      compared with sedentary rats, and training influenced glucose uptake identically
      in all ATs. In conclusion, differences between ATs in insulin sensitivity with
      respect to glucose uptake do not explain that insulin resistance is associated
      with intra-abdominal rather than subcutaneous obesity. Furthermore, training may
      be beneficial by enhancing insulin sensitivity in intra-abdominal fat depots.

PMID- 10644532
TI  - Bone as an ion exchange system: evidence for a pump-leak mechanism devoted to the
      maintenance of high bone K(+).
AB  - To provide evidence of active accumulation of K(+) in bone extracellular fluid
      (BECF), electric currents driven by damaged living metatarsal bones of weanling
      mice, immersed in physiological media at different [K(+)], in the presence of
      blockers of the K(+) channels or of the Na(+)-K(+-)ATPase inhibitor, were
      measured by means of a voltage-sensitive two-dimensional vibrating probe. At 4 mM
      extracellular K(+) concentration ([K(+)](o)), an inward steady current density
      (7.85-38.53 microA/cm(2)) was recorded at the damage site, which was
      significantly dependent on [K(+)](o). At [K(+)](o) equal to that of BECF (25 mM),
      current density was reduced by 76%. At [K(+)](o) of 0 mM, the current density
      showed an increase, which was hindered by tetraethylammonium (TEA). Basal current
      density was reduced significantly after exposure to TEA or BaCl(2) and was
      unchanged after long- term exposure to ouabain. By changing control medium with a
      chloride-free medium, current density was reversed. The results support the view
      that K(+) excess in bone is maintained by a biologically active cellular system.
      Because the osteocyte-bone lining cell syncytium was at the origin of the current
      in bone, it is likely that this system controls the ionic composition of BECF.

PMID- 10644534
TI  - Mechanisms of increased gluconeogenesis from alanine in rat isolated hepatocytes
      after endurance training.
AB  - This work aimed at further investigating the mechanisms by which liver
      gluconeogenic capacity from alanine is improved after training in rats, with an
      isolated hepatocyte model. Compared with controls in hepatocytes from trained
      rats incubated with gluconeogenic precursors (20 mM), the glucogenic flux
      (J(glucose)) was increased by 64% from alanine (vs. 21% for glycerol, 18% for
      lactate-pyruvate 10:1, and 10% for dihydroxyacetone). Maximal intracellular
      alanine accumulation capacity was also increased by 50%. Further experiments
      conducted on perifused hepatocytes showed that the putative adaptation at the
      level of the phosphoenolpyruvate-pyruvate cycle, which could be involved in the
      increased J(glucose) from lactate-pyruvate, was not involved in the increased
      J(glucose) from alanine after training. For alanine concentration higher than
      approximately 1 mM, an increased flux through alanine aminotransferase appeared
      responsible for the increased J(glucose). This could, in turn, depend on an
      increased supply of cytosolic 2-oxoglutarate because of the higher mitochondrial
      respiration observed in hepatocytes from trained rats and the activation of the
      malate-aspartate shuttle. At lower alanine concentration, the increase in
      J(glucose) appeared to be entirely due to the improved transport capacity.

PMID- 10644535
TI  - Low energy availability, not exercise stress, suppresses the diurnal rhythm of
      leptin in healthy young women.
AB  - Because the effect of exercise on leptin was not established, we controlled
      energy intake (I) and exercise energy expenditure (E) to distinguish the
      independent effects of energy availability (A = I - E) and exercise stress
      (everything associated with exercise except its energy cost) on the diurnal
      leptin rhythm in healthy young women. In random order, we set A = 45 and 10 kcal.
      kg lean body mass(-1) (LBM) x day(-1) for 4 days during the early follicular
      phase of separate menstrual cycles in sedentary (S, n = 7) and exercising (X, n =
      9: E = 30 kcal x kg LBM(-1) x day(-1)) women. Low energy availability suppressed
      the 24-h mean (P < 10(-6)) and amplitude (P < 10(-5)), whereas exercise stress
      did not (both P > 0.2). Suppressions of the 24-h mean (-72 +/- 3 vs. -53 +/- 3%,
      P < 0.001) and amplitude (-85 +/- 3 vs. -58 +/- 6%, P < 0.001) were more extreme
      in S vs. X than previously reported effects on luteinizing hormone pulsatility
      and carbohydrate availability. Thus the diurnal rhythm of leptin depends on
      energy, or carbohydrate, availability, not intake, and exercise has no
      suppressive effect on the diurnal rhythm of leptin beyond the impact of its
      energy cost on energy availability.

PMID- 10644536
TI  - Testosterone and dihydrotestosterone regulate AUF1 isoforms in a tissue-specific
      fashion in the mouse.
AB  - The sex difference in the metabolism of certain mRNAs in the murine submaxillary
      gland (SMG) prompted us to determine whether androgens regulate the expression of
      any of the four isoforms of AUF1, proteins that bind differentially to AU-rich
      RNA. We found that cytosol from female SMGs contains two major isoforms (p45 and
      p40), whereas cytosol from male SMGs contains a prominent p37 and a weaker p42.
      Injecting female mice with testosterone decreases p45 levels by 81% after 7 days
      (P < 0.05, n = 4), whereas p42 and p37 increase 74 and 449% at 7 days (P < 0.05,
      n = 4, for both). Orchiectomy, conversely, decreases p37 levels in the male SMG
      by 91% (P < 0.006) while increasing p45 5-fold and p40 2.5-fold (P < 0.05, n = 5
      for both). Both male and female kidney cytosol contains a prominent p37 and a
      faint band of approximately 42 kDa, but neither shows a significant change when
      circulating androgen levels are altered. Dihydrotestosterone (DHT) changes the
      pattern of AUF1 isoforms in female SMG cytosol more rapidly than does
      testosterone. Nuclear extracts from female SMG contain predominantly p45, and DHT
      decreases its level slightly (35%, P < 0.05 at 24 h). Polysomal extracts from
      female SMG contain p45 and p42, and DHT increases p45 levels 58% (P < 0.02, n =
      6) at 24 h. In certain nonreproductive tissues, androgens may differentially
      regulate AUF1 isoform levels to modulate the metabolism of AU-rich mRNAs
      posttranscriptionally.

PMID- 10644538
TI  - Effect of carbohydrate ingestion on glycogen resynthesis in human liver and
      skeletal muscle, measured by (13)C MRS.
AB  - This study investigated the effect of carbohydrate (CHO) ingestion on
      postexercise glycogen resynthesis, measured simultaneously in liver and muscle (n
      = 6) by (13)C magnetic resonance spectroscopy, and subsequent exercise capacity
      (n = 10). Subjects cycled at 70% maximal oxygen uptake for 83 +/- 8 min on six
      separate occasions. At the end of exercise, subjects ingested 1 g/kg body mass
      (BM) glucose, sucrose, or placebo (control). Resynthesis of glycogen over a 4-h
      period after treatment ingestion was measured on the first three occasions, and
      subsequent exercise capacity was measured on occasions four through six. No
      glycogen was resynthesized during the control trial. Liver glycogen resynthesis
      was evident after glucose (13 +/- 8 g) and sucrose (25 +/- 5 g) ingestion, both
      of which were different from control (P < 0.01). No significant differences in
      muscle glycogen resynthesis were found among trials. A relationship between the
      CHO load (g) and change in liver glycogen content (g) was evident after 30, 90,
      150, and 210 min of recovery (r = 0.59-0. 79, P < 0.05). Furthermore, a modest
      relationship existed between change in liver glycogen content (g) and subsequent
      exercise capacity (r = 0.53, P < 0.05). However, no significant difference in
      mean exercise time was found (control: 35 +/- 5, glucose: 40 +/- 5, and sucrose:
      46 +/- 6 min). Therefore, 1 g/kg BM glucose or sucrose is sufficient to initiate
      postexercise liver glycogen resynthesis, which contributes to subsequent exercise
      capacity, but not muscle glycogen resynthesis.

PMID- 10644539
TI  - Acute attenuation of translation initiation and protein synthesis by
      glucocorticoids in skeletal muscle.
AB  - Glucocorticoids are diabetogenic factors that not only antagonize the action of
      insulin in target tissues but also render these tissues catabolic. Therefore, in
      rats, we endeavored to characterize the effects in skeletal muscle of
      glucocorticoids on translation initiation, a regulated process that, in part,
      governs overall protein synthesis through the modulated activities of eukaryotic
      initiation factors (eIFs). Four hours after intraperitoneal administration of
      dexamethasone (100 microg/100 g body wt), protein synthesis in skeletal muscle
      was reduced to 59% of the value recorded in untreated control animals.
      Furthermore, translation initiation factor eIF4E preferred association with its
      endogenous inhibitor 4E-BP1 rather than eIF4G. Dexamethasone treatment resulted
      in dephosphorylation of both 4E-BP1 and the 40S ribosomal protein S6 kinase
      concomitant with enhanced phosphorylation of eIF4E. Moreover, the guanine
      nucleotide exchange activity of eIF2B was unaffected as was phosphorylation of
      the alpha-subunit of eIF2. Hence glucocorticoids negatively modulate the
      activation of a subset of the protein synthetic machinery, thereby contributing
      to the catabolic properties of this class of hormones in vivo.

PMID- 10644537
TI  - Role of eIF4E in stimulation of protein synthesis by IGF-I in perfused rat
      skeletal muscle.
AB  - Insulin-like growth factor I (IGF-I) promotes anabolism by stimulating protein
      synthesis in skeletal muscle. In the present study, we have examined mechanisms
      by which IGF-I stimulates protein synthesis in skeletal muscle with a perfused
      rat hindlimb preparation. IGF-I (10 nM) stimulated protein synthesis over 2.7
      fold. Total RNA content was unaffected, but translational efficiency was
      increased by IGF-I. We next examined the effect of IGF-I on eukaryotic initiation
      factor (eIF) 4E as a mechanism regulating translation initiation. IGF-I did not
      alter either the amount of eIF4E associated with the eIF4E binding protein 4E-BP1
      or the phosphorylation state of 4E-BP1. Likewise, the phosphorylation state of
      eIF4E was unaltered by IGF-I. In contrast, the amount of eIF4E bound to eIF4G was
      increased threefold by IGF-I. We conclude that IGF-I regulates protein synthesis
      in skeletal muscle by enhancing formation of the active eIF4E x eIF4G complex.

PMID- 10644540
TI  - Glutamate ingestion: the plasma and muscle free amino acid pools of resting
      humans.
AB  - Monosodium glutamate (MSG) ingestion is known to increase plasma glutamate
      concentration, and MSG infusion stimulates insulin secretion. We investigated the
      impact of MSG ingestion on both the plasma and intramuscular amino acid pools.
      Nine postprandial adults ingested MSG (150 mg/kg) and rested for 105 min. Venous
      blood was sampled preingestion and then every 15 min; vastus lateralis muscle
      biopsies were taken preingestion and at 45, 75, and 105 min postingestion. Venous
      plasma glutamate and aspartate concentrations increased (P </= 0.05)
      approximately 700-800 and 300-400%, respectively, after 30-45 min. Although
      several other plasma amino acids increased modestly, the rise in glutamate
      accounted for approximately 80% of the increase in total plasma amino acids. In
      addition, plasma insulin increased threefold after 15 min; this occurred before a
      significant increase in plasma glutamate, indicating a feed-forward stimulation
      from the gastrointestinal tract. The intramuscular amino acid pool was remarkably
      constant, with only glutamate increasing (P </= 0.05) by 3.56 mmol/kg dry wt. By
      105 min, the plasma and muscle amino acids had returned to resting
      concentrations. This increase in muscle glutamate concentration could account for
      approximately 40% of the MSG ingested; we propose that resting skeletal muscle is
      a major sink for the glutamate and metabolizes it to aspartate.

PMID- 10644541
TI  - Metoclopramide: a novel adjunct for improving cardiac and hepatocellular
      functions after trauma-hemorrhage.
AB  - Although metoclopramide (MCP) administration after trauma-hemorrhage restores the
      depressed immune functions, it remains unknown whether this agent has any
      salutary effects on the depressed cardiovascular and hepatocellular functions
      under those conditions. Adult male Sprague-Dawley rats underwent a midline
      laparotomy (i.e., induction of soft-tissue trauma) and were then bled to and
      maintained at a mean arterial pressure (MAP) of 40 mmHg until 40% of the maximal
      shed blood volume was returned in the form of Ringer lactate (RL). The rats were
      then resuscitated with four times the shed blood volume in the form of RL over 60
      min. MCP (2 mg/kg body wt) or vehicle was administered subcutaneously at the end
      of resuscitation. At 24 h after resuscitation, cardiac index and hepatocellular
      function (i.e., the maximum velocity and the overall efficiency of indocyanine
      green clearance) were determined. Plasma levels of interleukin (IL)-6 and
      prolactin were also assayed. The results indicate that treatment with MCP after
      trauma-hemorrhage and resuscitation significantly improved the depressed cardiac
      output and hepatocellular function. Furthermore, MCP administration significantly
      increased circulating levels of prolactin and decreased the plasma levels of the
      proinflammatory cytokine IL-6. Thus, administration of MCP, which increased
      prolactin secretion, appears to be a useful adjunct for restoring the depressed
      cardiac and hepatocellular functions and downregulating inflammatory cytokine
      release after trauma and hemorrhagic shock.

PMID- 10644542
TI  - Effect of regional hyperemia on myocardial uptake of 2-deoxy-2-[(18)F]fluoro-D
      glucose.
AB  - 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) may be used to predict glucose kinetics
      when the factor relating differences in transport and phosphorylation between
      compounds remains constant ("lumped constant"). It is not clear whether hyperemia
      alters that factor. In anesthetized swine, myocardial FDG uptake was estimated by
      positron emission tomography, during an intracoronary infusion of either
      adenosine, ATP, or bradykinin (40 microg x kg(-1) x min(-1), 40 microg x kg(-1) x
      min(-1), and 2 nmol x kg(-1) x min(-1), respectively; n = 6 for all groups). In
      controls during normal perfusion (n = 6), FDG uptake was 0.78 +/- 0.32 micromol x
      g(-1) x min(-1), whereas glucose uptake by Fick was 0.71 +/- 0.25 micromol x g(
      1) x min(-1) (r = 0.73; P < 0.05). Adenosine increased blood flow from 1.29 +/-
      0.43 to 4.80 +/- 2.19 ml x g(-1) x min(-1) (P < 0.05) and glucose uptake from
      1.16 +/- 1.10 to 3.35 +/- 2.12 micromol x g(-1) x min(-1) (P < 0.05), whereas FDG
      uptake in the hyperemic region was lower than remote regions (0.46 +/- 0.29 and
      0.95 +/- 0.55 micromol x g(-1) x min(-1), respectively; P < 0.05). In the ATP and
      bradykinin groups, blood flow increased four- and twofold, respectively, with no
      net change in glucose uptake. FDG uptake in the hyperemic region was also
      significantly lower than remote regions. For all animals, the ratio of blood flow
      in the hyperemic region relative to remote region was inversely proportional to
      the ratio of FDG uptake in the same regions (r(2)=0.73; P < 0.001). Because
      nitric oxide elaboration during hyperemia could potentially alter substrate
      preference and FDG kinetics, six additional swine were studied during maximal
      adenosine before and after intracoronary N(G)-monomethyl-L-arginine (1.5 mg/kg).
      Inhibition of nitric oxide had no effect on either regional myocardial substrate
      uptake or FDG accumulation. In conclusion, hyperemia decreased regional
      myocardial FDG uptake relative to normally perfused regions and this effect on
      the lumped constant was independent of nitric oxide.

PMID- 10644543
TI  - Glucosamine-induced insulin resistance in 3T3-L1 adipocytes.
AB  - To study molecular mechanisms for glucosamine-induced insulin resistance, we
      induced complete and reversible insulin resistance in 3T3-L1 adipocytes with
      glucosamine in a dose- and time-dependent manner (maximal effects at 50 mM
      glucosamine after 6 h). In these cells, glucosamine impaired insulin-stimulated
      GLUT-4 translocation. Glucosamine (6 h) did not affect insulin-stimulated
      tyrosine phosphorylation of the insulin receptor and insulin receptor substrate-1
      and -2 and weakly, if at all, impaired insulin stimulation of
      phosphatidylinositol 3-kinase. Glucosamine, however, severely impaired insulin
      stimulation of Akt. Inhibition of insulin-stimulated glucose transport was
      correlated with that of Akt activity. In these cells, glucosamine also inhibited
      insulin stimulation of p70 S6 kinase. Glucosamine did not alter basal glucose
      transport and insulin stimulation of GLUT-1 translocation and mitogen-activated
      protein kinase. In summary, glucosamine induced complete and reversible insulin
      resistance in 3T3-L1 adipocytes. This insulin resistance was accompanied by
      impaired insulin stimulation of GLUT-4 translocation and Akt activity, without
      significant impairment of upstream molecules in insulin-signaling pathway.

PMID- 10644544
TI  - Leg free fatty acid kinetics during exercise in men and women.
AB  - We previously reported that epinephrine stimulates leg free fatty acid (FFA)
      release in men but not in women. The present studies were conducted to determine
      whether the same is true during exercise. Six men and six women bicycled for 90
      min at 45% of peak O(2) consumption, during which time systemic and leg FFA
      kinetics ([9, 10-(3)H]palmitate) were measured. The catecholamine and hormonal
      responses to exercise were not different in men and women. The baseline systemic
      and leg palmitate release was 94 +/- 15 vs. 114 +/- 5 micromol/min and 16 +/- 2
      and 20 +/- 3 micromol/min, respectively, in men and women [P = nonsignificant
      (NS)]. Systemic and leg palmitate release increased (both P < 0.001) to 251 +/-
      18 vs. 212 +/- 16 micromol/min and 73 +/- 19 vs. 80 +/- 12 micromol/min in men
      and women, respectively, during the last 30 min of exercise (P = NS, men vs.
      women). We conclude that the systemic and leg adipose tissue lipolytic response
      to exercise is not different in nonobese men and women.

PMID- 10644545
TI  - Adaptations in skeletal muscle exercise metabolism to a sustained session of
      heavy intermittent exercise.
AB  - The purpose of this study was to investigate the hypothesis that a single,
      extended session of heavy exercise would be effective in inducing adaptations in
      energy metabolism during exercise in the absence of increases in oxidative
      potential. Ten healthy males [maximal aerobic power (VO(2 peak)) = 43.4 +/- 2.2
      (SE) ml x kg(-1) x min(-1)] participated in a 16-h training session involving
      cycling for 6 min each hour at approximately 90% of maximal oxygen consumption.
      Measurements of metabolic changes were made on tissue extracted from the vastus
      lateralis during a two-stage standardized submaximal cycle protocol before (Pre)
      and 36-48 h after (Post) the training session. At Pre, creatine phosphate (PCr)
      declined (P < 0.05) by 32% from 0 to 3 min and then remained stable until 20 min
      of exercise at 60% VO(2 peak) before declining (P < 0.05) by a further 35% during
      20 min of exercise at 75% VO(2 peak). Muscle lactate (mmol/kg dry wt)
      progressively increased (P < 0.05) from 4.59 +/- 0.64 at 0 min to 17.8 +/- 2.7
      and 30.9 +/- 5.3 at 3 and 40 min, respectively, whereas muscle glycogen (mmol
      glucosyl units/kg dry wt) declined (P < 0.05) from a rest value of 360 +/- 24 to
      276 +/- 31 and 178 +/- 36 at similar time points. During exercise after the
      training session, PCr and glycogen were not as depressed (P < 0.05), and
      increases in muscle lactate were blunted (P < 0.05). All of these changes
      occurred in the absence of increases in oxidative potential as measured by the
      maximal activities of citrate synthase and malate dehydrogenase. These findings
      are consistent with other studies, namely, that muscle metabolic adaptations to
      regular exercise are an early adaptive event that occurs before increases in
      oxidative potential.

PMID- 10644546
TI  - Mice lacking insulin receptor substrate 4 exhibit mild defects in growth,
      reproduction, and glucose homeostasis.
AB  - The insulin receptor substrates (IRSs) function in insulin signaling. Four
      members of the family, IRS-1 through IRS-4, are known. Previously, mice with
      targeted disruption of the genes for IRS-1, -2, and -3 have been characterized.
      To examine the physiological role of IRS-4, we have generated and characterized
      mice lacking IRS-4. Male IRS-4-null mice were approximately 10% smaller in size
      than wild-type male mice at 9 wk of age and beyond, whereas the female null mice
      were of normal size. Breeding pairs of IRS-4-null mice reproduced less well than
      wild-type mice. IRS-4-null mice exhibited slightly lower blood glucose
      concentration than the wild-type mice in both the fasted and fed states, but the
      plasma insulin concentrations of the IRS-4-null mice in the fasted and fed states
      were normal. IRS-4-null mice also showed a slightly impaired response in the oral
      glucose tolerance test. Thus the absence of IRS-4 caused mild defects in growth,
      reproduction, and glucose homeostasis.

PMID- 10644547
TI  - Enzymatic- and renal-dependent catabolism of the intestinotropic hormone glucagon
      like peptide-2 in rats.
AB  - The intestinotropic hormone glucagon-like peptide (GLP)-2-(1-33) is cleaved in
      vitro to GLP-2-(3-33) by dipeptidyl peptidase IV (DP IV). To determine the
      importance of DP IV versus renal clearance in the regulation of circulating GLP-2
      (1-33) levels in vivo, GLP-2-(1-33) or the DP IV-resistant analog [Gly(2)]GLP-2
      was injected in normal or DP IV-negative rats and assayed by HPLC and RIA. Normal
      rats showed a steady degradation of GLP-2-(1-33) to GLP-2-(3-33) over time,
      whereas little or no conversion was detected for GLP-2-(1-33) in DP IV-negative
      rats and for [Gly(2)]GLP-2 in normal rats. To determine the role of the kidney in
      clearance of GLP-2-(1-33) from the circulation, normal rats were bilaterally
      nephrectomized, and plasma immunoreactive GLP-2 levels were measured. The slope
      of the disappearance curves for both GLP-2-(1-33) and [Gly(2)]GLP-2 were
      significantly reduced in nephrectomized compared with non-nephrectomized rats (P
      < 0.01). In contrast to both GLP-2-(1-33) and [Gly(2)]GLP-2, GLP-2-(3-33) did not
      stimulate intestinal growth in a murine assay in vivo. Thus the intestinotropic
      actions of GLP-2-(1-33) are determined both by the actions of DP IV and by the
      kidney in vivo in the rat.

PMID- 10644548
TI  - The reciprocal pool model for the measurement of gluconeogenesis by use of [U
      (13)C]glucose.
AB  - To improve upon the [U-(13)C]glucose method to estimate "gluconeogenesis" as
      described by J. Katz and J. A. Tayek (Am. J. Physiol. Endocrinol. Metab. 272:
      E476-E484, 1997, and 275: E537-E542, 1998), we describe the reciprocal pool model
      by using only the isotopomer data of plasma glucose during infusion of [U
      (13)C]glucose. The glucose pool serves as both precursor and product for the
      calculation of the fraction of molecules generated by gluconeogenesis and to
      correct for exchange and loss of labeled carbon at the level of the tricarboxylic
      acid cycle. We have applied this model to both our own data and those of other
      investigators using [U-(13)C]glucose and have demonstrated excellent agreement
      between the Katz and Tayek model and our reciprocal pool model. When we compare
      the results of the reciprocal pool model with those of Hellerstein ([2
      (13)C]glycerol) and Landau ((2)H(2)O-glucose-C-5), the results are similar in
      short- and long-term fasted adult humans. Finally, when we apply the reciprocal
      pool model to our data from premature infants, it is clear that we account for
      the inflow of unlabeled glycerol and presumably amino acids. This is not
      surprising, because the vast majority of gluconeogenesis is the result of
      recycling of glucose and pyruvate carbon.

PMID- 10644549
TI  - Glucose-induced changes in protein kinase C and nitric oxide are prevented by
      vitamin E.
AB  - Changes in activity or expression of protein kinase C (PKC), reactive oxygen
      products, and nitric oxide (NO) may account for the alteration in cell behavior
      seen in diabetes. These changes have been proposed to be part of the
      pathophysiology of erectile dysfunction. We sought to ascertain if corpus
      cavernosal vascular smooth muscle cells (CCSMC) grown in a high glucose milieu
      exhibit changes in the activity and expression of PKC isoforms, NO, and reactive
      oxygen products and to find out if these changes are prevented by alpha
      tocopherol. Rat CCSMC were grown in 5, 15, and 30 mM glucose concentrations for
      3, 7, and 14 days. PKC isoform expression was assayed with isoform-specific
      antibodies. In CCSMCs grown in 30 mM glucose for 2-wk, PKC-beta(2)-isoform was
      upregulated (n = 4; P < 0.01), whereas the expression of alpha-, delta-, epsilon
      , and beta(1)-isoforms was unchanged. NO as measured by nitrate-to-nitrite ratio
      was greatly diminished at 14 days in 30 mM (n = 4; P < 0.002) compared with 5 mM
      glucose. Reactive oxygen products were upregulated at 14 days when they were
      assayed by the fluorescent probe dichlorofluorescein diacetate bis(acetoxy
      methyl) (DCFH-DA) (n = 5; P < 0.01). When these same cells were exposed to alpha
      tocopherol for 14 days, there was a reduction of PKC-beta(2) (57.8%; P < 0.01; n
      = 4) and a reduction in reactive oxygen product formation (71.1%; P < 0.001; n =
      4), along with an increase in nitrate-to-nitrite ratio (43.9%; P < 0.01, n = 4).
      These results suggest that there may be an interrelationship between PKC, NO, and
      reactive oxygen product formation in CCSMC exposed to a high glucose environment.

PMID- 10644550
TI  - Effect of weight reduction, obesity predisposition, and aerobic fitness on
      skeletal muscle mitochondrial function.
AB  - We used (31)P magnetic resonance spectroscopy to measure maximal mitochondrial
      function in 12 obesity-prone women before and after diet-induced weight reduction
      and in 12 matched, never-obese, and 7 endurance-trained controls. Mitochondrial
      function was modeled after maximum-effort plantar flexion from the
      phosphocreatine recovery time constant (TC(PCr)), the ADP recovery time constant
      (TC(ADP)), and the rate of change in PCr during the first 14 s of recovery
      (OxPhos). Weight reduction was not associated with a significant change in
      mitochondrial function by TC(PCr), TC(ADP), or OxPhos. Mitochondrial function was
      not different between postobese and never-obese controls by TC(PCr) [35.1 +/- 2.5
      (SE) vs. 34.6 +/- 2.5 s], TC(ADP) (22.9 +/- 1.8 vs. 21.2 +/- 1.8 s), or OxPhos
      (0.26 +/- 0. 03 vs. 0.25 +/- 0.03 mM ATP/s), postobese vs. never-obese,
      respectively. However, TC(ADP) was significantly faster (14.5 +/- 2. 3 s), and
      OxPhos was significantly higher (0.38 +/- 0.04 mM ATP/s) in the endurance-trained
      group. These results suggest that maximal mitochondrial function is not impaired
      in normal-weight obesity-prone women relative to their never-obese counterparts
      but is increased in endurance-trained women.

PMID- 10644551
TI  - Concordant induction of rapid in vivo pulsatile insulin secretion by recurrent
      punctuated glucose infusions.
AB  - Insulin is largely secreted as serial secretory bursts superimposed on basal
      release, insulin secretion is regulated through changes of pulse mass and
      frequency, and the insulin release pattern affects insulin action. Coordinate
      insulin release is preserved in the isolated perfused pancreas, suggesting
      intrapancreatic coordination. However, occurrence of glucose concentration
      oscillations may influence the process in vivo, as it does for ultradian
      oscillations. To determine if rapid pulsatile insulin release may be induced by
      minimal glucose infusions and to define the necessary glucose quantity, we
      studied six healthy individuals during brief repetitive glucose infusions of 6
      and 2 mg x kg(-1) x min(-1) for 1 min every 10 min. The higher dose completely
      synchronized pulsatile insulin release at modest plasma glucose changes (
      approximately 0.3 mM = approximately 5%), with large ( approximately 100%)
      amplitude insulin pulses at every single glucose induction (n = 54) at a lag time
      of 2 min (P < 0.05), compared with small (10%) and rare (n = 3) uninduced insulin
      excursions. The smaller glucose dose induced insulin pulses at lower significance
      levels and with considerable breakthrough insulin release. Periodicity shift from
      either 7- to 12-min or from 12- to 7-min intervals between consecutive glucose (6
      mg x kg(-1) x min(-1)) infusions in six volunteers revealed rapid frequency
      changes. The orderliness of insulin release as estimated by approximate entropy
      (1.459 +/- 0.009 vs. 1.549 +/- 0.027, P = 0.016) was significantly improved by
      glucose pulse induction (n = 6; 6 mg x kg(-1) x min(-1)) compared with
      unstimulated insulin profiles (n = 7). We conclude that rapid in vivo
      oscillations in glucose may be an important regulator of pulsatile insulin
      secretion in humans and that the use of an intermittent pulsed glucose induction
      to evoke defined and recurrent insulin secretory signals may be a useful tool to
      unveil more subtle defects in beta-cell glucose sensitivity.

PMID- 10644552
TI  - L-2-[(13)C]oxothiazolidine-4-carboxylic acid: a probe for precursor mobilization
      for glutathione synthesis.
AB  - L-2-oxothiazolidine-4-carboxylic acid (OTZ), a 5-oxoproline analog, is
      metabolized by 5-oxoprolinase and converted to cysteine, the rate-limiting amino
      acid for GSH synthesis, with the release of CO(2). [(13)C]OTZ (1.5 mg/kg) was
      used in 12 healthy men and women (ages 23-73 yr) to indirectly assess precursor
      mobilization for GSH synthesis when stores were reduced by 2 g acetaminophen.
      Expired breath samples were analyzed for (13)CO(2), and results were analyzed
      using noncompartmental and two-compartment open minimal models. Results show an
      increase in (13)C excretion (higher OTZ hydrolysis) when GSH stores were reduced
      and 5-oxoprolinase substrate utilization patterns, consequently, were altered (P
      < 0. 01). A metabolic rate index (MRI) of the OTZ probe was found to be
      significantly higher after reduction of GSH content by acetaminophen (P < 0.05).
      The difference in adaptive capacity (difference between control and
      postacetaminophen metabolic rate indexes) was two times as large in the young
      than the old subjects (P < 0.01). These data support the use of [(13)C]OTZ as a
      probe to identify individuals who may be at risk for low GSH stores or who have
      an impaired capacity to synthesize GSH.

PMID- 10644553
TI  - Glycogenin activity in human skeletal muscle is proportional to muscle glycogen
      concentration.
AB  - The de novo biosynthesis of glycogen is catalyzed by glycogenin, a self
      glucosylating protein primer. To date, the role of glycogenin in regulating
      glycogen metabolism and the attainment of maximal glycogen levels in skeletal
      muscle are unknown. We measured glycogenin activity after enzymatic removal of
      glucose by alpha-amylase, an indirect measure of glycogenin amount. Seven male
      subjects performed an exercise and dietary protocol that resulted in one high
      carbohydrate leg (HL) and one low-carbohydrate leg (LL) before testing. Resting
      muscle biopsies were obtained and analyzed for total glycogen, proglycogen (PG),
      macroglycogen (MG), and glycogenin activity. Results showed differences (P <
      0.05) between HL and LL for total glycogen (438.0 +/- 69.5 vs. 305.7 +/- 57.4
      mmol glucosyl units/kg dry wt) and PG (311.4 +/- 38.1 vs. 227.3 +/- 33.1 mmol
      glucosyl units/kg dry wt). A positive correlation between total muscle glycogen
      content and glycogenin activity (r = 0.84, P < 0.001) was observed. Similar
      positive correlations (P < 0.05) were also evident between both PG and MG
      concentration and glycogenin activity (PG, r = 0.82; MG, r = 0.84). It can be
      concluded that glycogenin does display activity in human skeletal muscle and is
      proportional to glycogen concentration. Thus it must be considered as a potential
      regulator of glycogen synthesis in human skeletal muscle.

PMID- 10644554
TI  - Lessons from genetically engineered animal models. VII. Apoptosis in intestinal
      epithelium: lessons from transgenic and knockout mice.
AB  - Apoptosis plays an important role in homeostasis of intestinal epithelia and is
      also a stress response to toxic stimuli. Transgenic and knockout mice have
      provided insights into the regulation of intestinal epithelial apoptosis that
      could not have been obtained by cell culture techniques. Two broad types of
      apoptosis have been characterized: spontaneous apoptosis, which occurs
      continuously at low levels in the normal, unstressed intestine, and stress
      induced apoptosis, which occurs after genotoxic insult such as exposure to gamma
      radiation or DNA-damaging drugs. Spontaneous apoptosis occurs at the base of the
      crypt at or near the position of epithelial stem cells. Knockout studies have
      shown that spontaneous apoptosis is independent of p53 and Bax in both small and
      large intestine, whereas Bcl2 only regulates spontaneous apoptosis in the colon.
      Little is known about the regulation of the specialized form of cell death at the
      villus tip. In contrast, knockout studies have demonstrated that both p53 and
      Bcl2 are important regulators of stress-induced apoptosis but that there are
      significant differences between early and late time points. Bax plays only a
      minor role in the regulation of stress-induced apoptosis. The cumulative effect
      of stress-induced apoptosis on tissue architecture is not straightforward, and
      cell cycle arrest also plays a critical role. Nevertheless, p53 is an important
      determinant of the histopathological damage induced by 5-fluorouracil in murine
      intestinal epithelium. These studies have important implications for the
      development of more effective treatment for inflammatory bowel disease and
      cancer.

PMID- 10644555
TI  - Nutrient tasting and signaling mechanisms in the gut. IV. There is more to taste
      than meets the tongue.
AB  - The tongue is the principal organ that provides sensory information about the
      quality and quantity of chemicals in food. Other information about the
      temperature and texture of food is also transduced on the tongue, via extragemmal
      receptors that form branches of the trigeminal, glossopharyngeal, and vagal
      nerves. These systems, together with information from the gastrointestinal (GI)
      system, interact to determine whether or not food is palatable. In this themes
      article, emphasis is placed on the integrative aspects of gustatory processing by
      showing the convergence of gustatory information with somatosensory, nociceptive,
      and visceral information (from the GI system) on the tongue and in the brain. Our
      thesis is that gustation should be thought of as an integral part of a
      distributed, interacting multimodal system in which information from other
      systems, including the GI system, can modulate the taste of food.

PMID- 10644556
TI  - Reduction of EGF is associated with the delay of ulcer healing by cigarette
      smoking.
AB  - Cigarette smoking is associated with peptic ulcer diseases. Smokers have lower
      levels of salivary epidermal growth factor (EGF) than nonsmokers. We investigated
      whether reduction of EGF is involved in the delay of gastric ulcer healing by
      cigarette smoking. Rats with acetic acid-induced ulcers were exposed to cigarette
      smoke (0, 2, or 4% vol/vol) 1 day after ulcer induction. EGF level was elevated 1
      day after ulcer induction in salivary glands and serum, and 4 days after ulcer
      induction in the gastric mucosa. However, cigarette smoke depressed these
      beneficial effects and EGF mRNA expression in salivary glands and gastric mucosa.
      Cigarette smoke delayed gastric ulcer healing and reduced cell proliferation,
      angiogenesis, and mucus synthesis. Exogenous EGF (10 and 20 microg/kg i.v.)
      before smoke exposure reversed the adverse effects of cigarette smoke, whereas
      vascular endothelial growth factor level and nitric oxide synthase activity were
      unaffected. It is concluded that the detrimental effect of cigarette smoke on
      ulcer healing is a consequence of reduction of angiogenesis, cell proliferation,
      and mucus secretion through the depressive action on EGF biosynthesis and its
      mRNA expression in salivary glands and gastric mucosa.

PMID- 10644557
TI  - Motilin receptors in the human antrum.
AB  - Motilin is an intestinal peptide that stimulates contraction of gut smooth
      muscle. The motilin receptor has not been cloned yet, but motilin-receptor
      agonists appear to be potent prokinetic agents for the treatment of dysmotility
      disorders. The aim of this study was to determine neural or muscular localization
      of motilin receptors in human upper gastrointestinal tract and to investigate
      their pharmacological characteristics. The binding of (125)I-labeled motilin to
      tissue membranes prepared from human stomach and duodenum was studied; rabbit
      tissues were used for comparison. Solutions enriched in neural synaptosomes or in
      smooth muscle plasma membranes were obtained. Various motilin analogs were used
      to displace the motilin radioligand from the various tissue membranes. The
      highest concentration of human motilin receptors was found in the antrum,
      predominantly in the neural preparation. Human motilin receptors were sensitive
      to the NH(2)-terminal portion of the motilin molecule, but comparison with rabbit
      showed that both species had specific affinities for various motilin analogs
      [i.e., Mot-(1-9), Mot-(1-12), Mot-(1-12) (CH(2)NH)(10-11), and erythromycin].
      Motilin receptors obtained from synaptosomes or muscular plasma membranes of
      human antrum expressed different affinity for two motilin-receptor agonists, Mot
      (1-12) and Mot-(1-12) (CH(2)NH)(10-11), suggesting that they correspond to
      specific receptor subtypes. We conclude that human motilin receptors are located
      predominantly in nerves of the antral wall, are functionally (and probably
      structurally) different from those found in other species such as the rabbit, and
      express specific functional (and probably structural) characteristics dependent
      on their localization on antral nerves or muscles, suggesting the existence of
      specific receptor subtypes, potentially of significant physiological or
      pharmacological relevance.

PMID- 10644558
TI  - Regulation and function of p38 protein kinase in isolated canine gastric parietal
      cells.
AB  - We examined the regulation and functional role of p38 kinase in gastric acid
      secretion. p38 kinase was immunoprecipitated from cell lysates of highly purified
      gastric parietal cells in primary culture, and its activity was quantitated by in
      vitro kinase assay. Carbachol effects were dose- and time-dependent, with a
      maximal 10-fold stimulatory effect detected after 30 min of incubation. SB
      203580, a highly selective inhibitor of p38 kinase, blocked carbachol induction
      of p38 kinase activity, with maximal inhibition at 10 microM. Stimulation by
      carbachol was unaffected by preincubation of parietal cells with the
      intracellular Ca(2+) chelator BAPTA-AM, but incubation of cells in Ca(2+)-free
      medium led to a 50% inhibition of carbachol induction of p38 kinase activity.
      Because some of the effects of carbachol are mediated by the small GTP-binding
      protein Rho, we examined the role of Rho in carbachol induction of p38 kinase
      activity. We tested the effect of exoenzyme C3 from Clostridium botulinum (C3), a
      toxin known to ADP-ribosylate and specifically inactivate Rho. C3 led to complete
      ADP-ribosylation of Rho, and it inhibited carbachol induction of p38 kinase by
      50%. We then tested the effect of SB-203580 and C3 on carbachol-stimulated uptake
      of [(14)C]aminopyrine (AP). Inhibition of p38 kinase by SB-203580 led to a dose
      dependent increase in AP uptake induced by carbachol, with maximal (threefold)
      effect at 10 microM SB-203580. Similarly, preincubation of parietal cells with C3
      led to a twofold increase in AP uptake induced by carbachol. Thus carbachol
      induces a cascade of events in parietal cells that results in activation of p38
      kinase through signaling pathways that are at least in part dependent on Rho
      activation and on the presence of extracellular Ca(2+). p38 kinase appears to
      inhibit gastric acid secretion.

PMID- 10644559
TI  - Neuropeptide Y induces fasted pattern of duodenal motility via Y(2) receptors in
      conscious fed rats.
AB  - Neuropeptide Y (NPY), a 36-amino acid peptide abundantly expressed in the brain,
      has been implicated in the regulation of feeding and visceral functions. The
      present study was designed to investigate whether or not NPY specifically
      regulates duodenal motility. The manometric method was used to measure duodenal
      motility in conscious, freely moving rats. The rat duodenum showed phasic
      contractions mimicking the migrating motor complex in the fasted state that were
      replaced by irregular contractions after the ingestion of food. NPY powerfully
      affected the contractile activity after intracerebroventricular (i.c.v.)
      administration, changing fed (postprandial) patterns into phasic contractions
      characterized as fasted (interdigestive) patterns. This effect was mediated via
      receptors with pharmacological profiles similar to rat Y(2) and Y(4) receptors,
      although neither Y(1) nor Y(5) agonists had any effects on motility despite
      potent feeding-stimulatory effects. Immunoneutralization with anti-NPY antiserum
      administered i.c.v. abolished fasted patterns and induced fed-like motor
      activities. An i.c.v. dose of peptide YY produced a different effect from NPY,
      with increase in the motor activities of both fed and fasted patterns. These
      results indicate that fasted and fed motor activities are regulated processes and
      that NPY induces fasted activity through Y(2), and possibly Y(4), receptors,
      which may represent an integrated mechanism linked to the onset of feeding
      behavior.

PMID- 10644560
TI  - Role of ubiquitin in proteasomal degradation of mutant alpha(1)-antitrypsin Z in
      the endoplasmic reticulum.
AB  - A delay in intracellular degradation of the mutant alpha(1)-antitrypsin
      (alpha(1)AT)Z molecule is associated with greater retention within the
      endoplasmic reticulum (ER) and susceptibility to liver disease in a subgroup of
      patients with alpha(1)AT deficiency. Recent studies have shown that alpha(1)ATZ
      is ordinarily degraded in the ER by a mechanism that involves the proteasome, as
      demonstrated in intact cells using human fibroblast cell lines engineered for
      expression of alpha(1)ATZ and in a cell-free microsomal translocation assay
      system programmed with purified alpha(1)ATZ mRNA. To determine whether the
      ubiquitin system is required for proteasomal degradation of alpha(1)ATZ and
      whether specific components of the ubiquitin system can be implicated, we have
      now used two approaches. First, we overexpressed a dominant-negative ubiquitin
      mutant (UbK48R-G76A) by transient transfection in the human fibroblast cell lines
      expressing alpha(1)ATZ. The results showed that there was marked, specific, and
      selective inhibition of alpha(1)ATZ degradation mediated by UbK48R-G76A,
      indicating that the ubiquitin system is at least in part involved in ER
      degradation of alpha(1)ATZ. Second, we subjected reticulocyte lysate to DE52
      chromatography and tested the resulting well-characterized fractions in the cell
      free system. The results showed that there were both ubiquitin-dependent and 
      independent proteasomal mechanisms for degradation of alpha(1)ATZ and that the
      ubiquitin-conjugating enzyme E2-F1 may play a role in the ubiquitin-dependent
      proteasomal mechanism.

PMID- 10644561
TI  - Putrescine does not support the migration and growth of IEC-6 cells.
AB  - The migration of IEC-6 cells is inhibited when the cells are depleted of
      polyamines by inhibiting ornithine decarboxylase with alpha
      difluoromethylornithine (DFMO). Exogenous putrescine, spermidine, and spermine
      completely restore cell migration inhibited by DFMO. Because polyamines are
      interconverted during their synthesis and catabolism, the specific role of
      individual polyamines in intestinal cell migration, as well as growth, remains
      unclear. In this study, we used an inhibitor of S-adenosylmethionine
      decarboxylase, diethylglyoxal bis(guanylhydrazone)(DEGBG), to block the synthesis
      of spermidine and spermine from putrescine. We found that exogenous putrescine
      does not restore migration and growth of IEC-6 cells treated with DFMO plus
      DEGBG, whereas exogenous spermine does. In addition, the normal distribution of
      actin filaments required for migration, which is disrupted in polyamine-deficient
      cells, could be achieved by adding spermine but not putrescine along with DFMO
      and DEGBG. These results indicate that putrescine, by itself, is not essential
      for migration and growth, but that it is effective because it is converted into
      spermidine and/or spermine.

PMID- 10644562
TI  - Bile salt excretion in skate liver is mediated by a functional analog of
      Bsep/Spgp, the bile salt export pump.
AB  - Biliary secretion of bile salts in mammals is mediated in part by the liver
      specific ATP-dependent canalicular membrane protein Bsep/Spgp, a member of the
      ATP-binding cassette superfamily. We examined whether a similar transport
      activity exists in the liver of the evolutionarily primitive marine fish Raja
      erinacea, the little skate, which synthesizes mainly sulfated bile alcohols
      rather than bile salts. Western blot analysis of skate liver plasma membranes
      using antiserum raised against rat liver Bsep/Spgp demonstrated a dominant
      protein band with an apparent molecular mass of 210 kDa, a size larger than that
      in rat liver canalicular membranes, approximately 160 kDa. Immunofluorescent
      localization with anti-Bsep/Spgp in isolated, polarized skate hepatocyte clusters
      revealed positive staining of the bile canaliculi, consistent with its selective
      apical localization in mammalian liver. Functional characterization of putative
      ATP-dependent canalicular bile salt transport activity was assessed in skate
      liver plasma membrane vesicles, with [(3)H]taurocholate as the substrate.
      [(3)H]taurocholate uptake into the vesicles was mediated by ATP-dependent and 
      independent mechanisms. The ATP-dependent component was saturable, with a
      Michaelis-Menten constant (K(m)) for taurocholate of 40+/-7 microM and a K(m) for
      ATP of 0.6+/-0.1 mM, and was competitively inhibited by scymnol sulfate
      (inhibition constant of 23 microM), the major bile salt in skate bile. ATP
      dependent uptake of taurocholate into vesicles was inhibited by known substrates
      and inhibitors of Bsep/Spgp, including other bile salts and bile salt
      derivatives, but not by inhibitors of the multidrug resistance protein-1 or the
      canalicular multidrug resistance-associated protein, indicating a distinct
      transport mechanism. These findings provide functional and structural evidence
      for a Bsep/Spgp-like protein in the canalicular membrane of the skate liver. This
      transporter is expressed early in vertebrate evolution and transports both bile
      salts and bile alcohols.

PMID- 10644563
TI  - Rat and guinea pig pancreatic acini possess both VIP(1) and VIP(2) receptors,
      which mediate enzyme secretion.
AB  - Pancreatic acini from most species possess vasoactive intestinal peptide (VIP)
      receptors. Recently, two subtypes of VIP receptors, VIP(1)-R and VIP(2)-R, were
      cloned. Which subtype exists on pancreatic acini or mediates secretion is
      unclear. To address this, we examined pancreatic acini from both rat and guinea
      pig. VIP(1)-R and VIP(2)-R mRNA were identified in dispersed acini from both
      species by Northern blot analysis and in rat by Southern blot analysis. With the
      use of the VIP(2)-R-selective ligand Ro-25-1553 in both species, inhibition of
      binding of (125)I-labeled VIP to acini showed a biphasic pattern with a high
      affinity component (10%) and a second representing 90%. The VIP(1)-R-selective
      ligand, [Lys(15),Arg(16),Leu(27)]VIP-(1-7)-GRF-(8-27), gave a monophasic pattern.
      Binding of Ro-25-1553 was better fit by a two-site model. In both rat and guinea
      pig acini, the dose-response curve of Ro-25-1553 for stimulation of enzyme
      secretion was biphasic, with a high-affinity component of 10-15% of the maximal
      secretion and a low-affinity component accounting for 85-90%. At low
      concentrations (10 nM) of Ro-25-1553 and [Lys(15),Arg(16), Leu(27)]VIP-(1-7)
      GRF(8-27), which only occupy VIP receptors, a 4-fold and a 56-fold increase in
      cAMP occurred, respectively. These results show that both VIP(1)-R and VIP(2)-R
      subtypes exist on pancreatic acini of rat and guinea pig, their activation
      stimulates enzyme secretion by a cAMP-mediated mechanism, and the effects of VIP
      are mediated 90% by activation of VIP(1)-R and 10% by VIP(2)-R. Because VIP has a
      high affinity for both VIP-R subtypes, its effect on pancreatic acini is mediated
      by two receptor subtypes, which will need to be considered in future studies of
      the action of VIP in the pancreas.

PMID- 10644564
TI  - Changes in 5-HT-mediated pathways in radiation-induced attenuation and recovery
      of ion transport in rat colon.
AB  - Whole body exposure to high doses of ionizing radiation is associated with small
      intestinal and colonic dysfunction, the etiology of which remains unknown. In
      this study, we investigated the role of both neural and nonneural 5
      hydroxytryptamine (5-HT)-mediated pathways in radiation-induced attenuation and
      recovery of colonic secretory function. Rats were exposed to whole body 10-Gy
      gamma irradiation, and distal colonic tissues were studied in Ussing chambers 1,
      3, and 7 days after exposure. Tissue responses to exogenously added 5-HT
      (nonneural pathway) and electrical field stimulation (EFS; neural pathway) were
      performed, and 5-HT receptor subtypes implicated in both responses were
      determined using three different 5-HT receptor antagonists: methysergide (5
      HT(2/1C)), granisetron (5-HT(3)), and SDZ-205,557 (5-HT(4)). Maximal responses to
      exogenously added 5-HT were decreased at 1 and 3 days and returned to control
      values at 7 days. Responses to exogenous 5-HT were insensitive to both 5-HT(2/1C)
      and 5-HT(3) antagonists and to TTX but were totally inhibited by SDZ-205, 557 in
      both control and irradiated tissues. Responses to EFS were decreased 1 and 3 days
      after exposure and returned to control values at 7 days. In control tissues and 1
      and 3 days after exposure, EFS responses were insensitive to both 5-HT(2/1C) and
      5-HT(4) antagonists but reduced by granisetron in control (51%) and at 1 (64%)
      and 3 days (58%) after exposure. Granisetron was more effective at 7 days (73%
      inhibition), which was concomitant with the appearance of a 5-HT(4) antagonist
      sensitive pathway (40% inhibition). In conclusion, neural and nonneural 5-HT
      mediated pathways involve 5-HT(3) and 5-HT(4) receptors, respectively, in control
      as well as in irradiated tissues 1 and 3 days after exposure. Conversely, the
      recovery of colonic transport is associated with additional 5-HT(3)-mediated
      pathways, probably in combination with 5-HT(4) receptors.

PMID- 10644565
TI  - Increased lactulose/rhamnose ratio during fluid load is caused by increased
      urinary lactulose excretion.
AB  - Noninvasive assessment of intestinal permeability in vivo is based on the
      measurement of urinary excretion of orally administered sugar probes. It is
      expressed as a ratio, usually lactulose/rhamnose or 3-O-methyl-D-glucose (3
      OMG)/rhamnose. In both endotoxemic and control rats that were receiving fluid, we
      observed an increase in the recovery of lactulose and 3-OMG but not rhamnose in
      both groups, suggesting an enhancement of intestinal permeability. In the
      measurement of intestinal permeability, all pre- and postmucosal factors are
      considered equal for all sugars. We hypothesized that postmucosal factors and not
      changes in intestinal permeability caused the increased urinary lactulose and 3
      OMG recoveries observed during fluid loading. Therefore, the effects of fluid
      loading on urinary excretion of the sugar probes were studied in healthy rats
      receiving the sugars intravenously. After intravenous injection, fluid loading
      increased urinary lactulose recovery threefold but not that of 3-OMG and
      rhamnose. In conclusion, fluid loading increases the lactulose/rhamnose ratio
      independent of changes in intestinal permeability. The 3-OMG/rhamnose ratio is
      not influenced by fluid loading.

PMID- 10644566
TI  - Gene expression of activin, activin receptors, and follistatin in intestinal
      epithelial cells.
AB  - Gene expression of activin, activin receptors, and follistatin was investigated
      in vivo and in vitro using semiquantitative RT-PCR in intestinal epithelial
      cells. Rat jejunum and the intestinal epithelial cell line IEC-6 expressed mRNA
      encoding the betaA-subunit of activin, alpha-subunit of inhibin, activin
      receptors IB and IIA, and follistatin. An epithelial cell isolation study focused
      along the crypt-villus axis in rat jejunum showed that betaA mRNA levels were
      eight- to tenfold higher in villus cells than in crypt cells.
      Immunohistochemistry revealed the expression of activin A in upper villus cells.
      The human intestinal cell line Caco-2 was used as a differentiation model of
      enterocytes. Four- to fivefold induction of betaA mRNA was observed in
      postconfluent Caco-2 cells grown on filter but not in those cells grown on
      plastic. In contrast, follistatin mRNA was seen to be reduced after reaching
      confluence. Exogenous activin A dose-dependently suppressed the proliferation and
      stimulated the expression of apolipoprotein A-IV gene, a differentiation marker,
      in IEC-6 cells. These results suggest that the activin system is involved in the
      regulation of such cellular functions as proliferation and differentiation in
      intestinal epithelial cells.

PMID- 10644567
TI  - Effects of cholecystokinin on appetite and pyloric motility during physiological
      hyperglycemia.
AB  - Recent studies suggest that the interaction between small intestinal nutrient
      stimulation and the blood glucose concentration is important in the regulation of
      gastric motility and appetite. The purpose of this study was to determine whether
      the effects of cholecystokinin octapeptide (CCK-8) on antropyloric motility and
      appetite are influenced by changes in the blood glucose concentration within the
      normal postprandial range. Seven healthy volunteers were studied on 4 separate
      days. A catheter incorporating a sleeve sensor was positioned across the pylorus,
      and the blood glucose was stabilized at either 4 mmol/l (2 days) or 8 mmol/l (2
      days). After the desired blood glucose had been maintained for 90 min, an
      intravenous infusion of either CCK-8 (2 ng. kg(-1). min(-1)) or saline (control)
      was given for 60 min. Thirty minutes after the infusion began, the catheter was
      removed and subjects drank 400 ml of water with guar gum before being offered a
      buffet meal. The amount of food consumed (kcal) was quantified. The order of the
      studies was randomized and single-blinded. There were fewer antral waves at a
      blood glucose of 8 than at 4 mmol/l during the 90-min period before the infusions
      (P<0.05) and during the first 30 min of CCK-8 or saline infusion (P = 0.07). CCK
      8 suppressed antral waves (P<0.05), stimulated isolated pyloric pressure waves
      (IPPWs) (P<0.01), and increased basal pyloric pressure (P<0.005) compared with
      control. During administration of CCK-8, basal pyloric pressure (P<0.01), but not
      the number of IPPWs, was greater at a blood glucose of 8 mmol/l than at 4 mmol/l.
      CCK-8 suppressed the energy intake at the buffet meal (P<0.01), with no
      significant difference between the two blood glucose concentrations. We conclude
      that the acute effect of exogenous CCK-8 on basal pyloric pressure, but not
      appetite, is modulated by physiological changes in the blood glucose
      concentration.

PMID- 10644568
TI  - Bacterial colonization and healing of gastric ulcers: the effects of epidermal
      growth factor.
AB  - Experimental gastric ulcers are rapidly colonized by various bacteria, resulting
      in significantly impaired healing. Epidermal growth factor (EGF) is capable of
      preventing bacterial colonization of the healthy intestinal mucosa. In this
      study, we examined the possibility that EGF accelerates gastric ulcer healing by
      reducing bacterial colonization of the ulcer. Gastric ulcers were induced by
      serosal application of acetic acid. The effect of daily administration of EGF on
      ulcer healing and bacterial colonization was assessed and compared with the
      effect of daily treatment with broad-spectrum antibiotics. EGF administration
      reduced colonization levels and accelerated ulcer healing as effectively as the
      antibiotic treatment. EGF was without effect on acid secretion or neutrophil
      infiltration into the ulcer. Bacterial growth was not inhibited in the presence
      of EGF in vitro. These results demonstrate that EGF reduces bacterial
      colonization during an established infection of a compromised mucosal surface.
      This effect may contribute to the ability of EGF to accelerate gastric ulcer
      healing. This effect is acid independent and not due to an anti-inflammatory
      effect or to direct bactericidal actions.

PMID- 10644569
TI  - Lumen-to-surface pH gradients in opossum and rabbit esophagi: role of submucosal
      glands.
AB  - The opossum esophagus, like that of humans, contains a network of submucosal
      glands with the capacity to secrete bicarbonate ions into the esophageal lumen.
      To evaluate the role of these glands in protecting the epithelial surface from
      acid insult, we measured the lumen-to-surface pH gradient in opossum esophagus at
      different luminal pH and compared it to that of rabbit esophagus, an organ devoid
      of submucosal glands. Sections of opossum and rabbit esophageal epithelium were
      mounted luminal side up in a modified Ussing chamber. pH-sensitive
      microelectrodes, positioned within 5 microm of the epithelial cell surface, were
      used to monitor surface pH during perfusion with solutions of different pH. At
      luminal pH 7. 5, the pH(s) of both opossum and rabbit were similar (pH(s) = 7.5).
      Lowering luminal pH from 7.5 to 3.5 in opossum decreased pH(s) to 4.2+/-0.16, a
      value significantly higher than pH of perfusate, whereas in rabbit this maneuver
      decreased pH(s) to 3.69+/-0.08, a value not significantly different from pH of
      perfusate. In opossum but not in rabbit, addition of carbachol to the serosal
      solution increased basal pH(s) to 7.8+/- 0.1 and significantly blunted the
      decline in pH(s) on perfusion with acidic Ringer solution (pH 3.5), with pH(s)
      falling to 5.6+/-0.45. The effect of carbachol on surface buffering was inhibited
      by prior treatment with atropine. Luminal acidification to pH 2.0 in opossum (as
      in rabbit) abolished the lumen-to-surface pH gradient even after addition of
      serosal carbachol. We conclude that the presence of submucosal glands in
      esophagus contributes through bicarbonate secretion to creation of a lumen-to
      surface pH gradient. Although this gradient can be modulated by carbachol, its
      capacity to buffer (and therefore to protect) the epithelial surface against back
      diffusing H(+) is limited and dissipated at pH 2.0.

PMID- 10644570
TI  - Inhibition of gastric acid secretion in rat stomach by PACAP is mediated by
      secretin, somatostatin, and PGE(2).
AB  - Pituitary adenylate cyclase-activating polypeptide (PACAP), existing in two
      variants, PACAP-27 and PACAP-38, is found in the enteric nervous system and
      regulates function of the digestive system. However, the regulatory mechanism of
      PACAP on gastric acid secretion has not been well elucidated. We investigated the
      inhibitory action of PACAP-27 on acid secretion and its mechanism in isolated
      vascularly perfused rat stomach. PACAP-27 in four graded doses (5, 10, 20, and 50
      microg/h) was vascularly infused to determine its effect on basal and
      pentagastrin (50 ng/h)-stimulated acid secretion. To study the inhibitory
      mechanism of PACAP-27 on acid secretion, a rabbit antisecretin serum,
      antisomatostatin serum, or indomethacin was administered. Concentrations of
      secretin, somatostatin, PGE(2), and histamine in portal venous effluent were
      measured by RIA. PACAP-27 dose-dependently inhibited both basal and pentagastrin
      stimulated acid secretion. PACAP-27 at 10 microg/h significantly increased
      concentrations of secretin, somatostatin, and PGE(2) in basal or pentagastrin
      stimulated state. The inhibitory effect of PACAP-27 on pentagastrin-stimulated
      acid secretion was reversed 33% by an antisecretin serum, 80.0% by an
      antisomatostatin serum, and 46.1% by indomethacin. The antisecretin serum
      partially reduced PACAP-27-induced local release of somatostatin and PGE(2).
      PACAP-27 at 10 microg/h elevated histamine level in portal venous effluent, which
      was further increased by antisomatostatin serum. However, antisomatostatin serum
      did not significantly increase acid secretion. It is concluded that PACAP-27
      inhibits both basal and pentagastrin-stimulated gastric acid secretion. The
      effect of PACAP-27 is mediated by local release of secretin, somatostatin, and
      PGE(2) in isolated perfused rat stomach. The increase in somatostatin and PGE(2)
      levels in portal venous effluent is, in part, attributable to local action of the
      endogenous secretin.

PMID- 10644571
TI  - Differential hepatic lobar gene expression in offspring exposed to altered
      maternal dietary protein intake.
AB  - Increased plasma fibrinogen concentrations are a recognized risk factor for
      coronary heart disease, and increased fibrinogen levels in adults are associated
      with parameters of reduced early growth. We studied fibrinogen gene expression in
      adult offspring of dams fed either a 20% (control) or an 8% protein diet
      [maternal low-protein (MLP) rats] during pregnancy and lactation and determined
      whether any effects were consistent between left and right liver lobes, since the
      fetal liver has a unique blood supply that produces differential stimuli to the
      left and right lobes. In MLP offspring, there was a reduction in all three
      fibrinogen mRNA copy numbers in the left liver lobe [left vs. right lobes for
      alpha-, beta-, and gamma-fibrinogen (x10(6) copies/ng total RNA): 8.04 vs. 23.16,
      P<0.001; 4.74 vs. 13.07, P<0.001; and 4.61 vs. 16.38, P = 0.007, respectively],
      with a parallel reduction in fibrinogen concentration in the left liver lobe
      (8.53+/-0.33 vs. 10.41 +/-0.65 arbitrary units, P = 0.014, left and right lobes,
      respectively). No such effect was observed in offspring of control dams. To
      investigate the underlying mechanism, glucocorticoid receptor function and mRNA
      levels were studied, since expression of fibrinogen genes is regulated by
      glucocorticoid hormones. The binding affinity of the high-affinity glucocorticoid
      receptor was reduced only in the left liver lobe of the MLP offspring (P = 0.02,
      left. vs. right), with a parallel reduction in this lobe in glucocorticoid
      receptor mRNA level (P = 0.006, left vs. right). In conclusion, maternal dietary
      protein restriction reduces fibrinogen gene expression, fibrinogen protein, and
      mRNA level and binding affinity of glucocorticoid receptors only in the left
      liver lobe of the adult offspring.

PMID- 10644572
TI  - Contribution of NK(2) tachykinin receptors to propulsion in the rabbit distal
      colon.
AB  - The role of the tachykinin neurokinin (NK)(2) receptors on rabbit distal colon
      propulsion was investigated by using two selective NK(2)-receptor antagonists,
      MEN-10627 and SR-48968. Experiments on colonic circular muscle strips showed that
      contractile responses to [beta-Ala(8)]NKA-(4-10) (1 nM-1 microM), a selective
      NK(2)-receptor agonist, were competitively antagonized by MEN-10627 (1-100 nM),
      whereas SR-48968 (0.1-10 nM) caused an insurmountable antagonism, thus confirming
      the difference in the mode of action of the two compounds. Colonic propulsion was
      elicited by distending a mobile rubber balloon with 0.3 ml (submaximal stimulus)
      or 1.0 ml (maximal stimulus) of water. The velocity of anal displacement of the
      balloon (mm/s) was considered the main propulsion parameter. At low
      concentrations (1.0-100 nM and 0.1-10 nM, respectively), MEN-10627 and SR-48968
      facilitated the velocity of propulsion, whereas at high concentrations (100 nM
      and 1 microM, respectively) they decelerated propulsion. The excitatory and
      inhibitory effects of both antagonists were observed only with submaximal
      stimulus. We focused on the hypothesis that the facilitatory effect on propulsion
      may result from blockade of neuronal NK(2) receptors and the inhibitory effect
      from suppression of the excitatory transmission mediated by NK(2) receptors on
      smooth muscle cells. In the presence of N(G)-nitro-L-arginine (300 microM), a
      nitric oxide synthase inhibitor, MEN-10627, at a concentration (10 nM) that was
      found to accelerate propulsion in control experiments inhibited the velocity of
      propulsion. In the presence of threshold (1-10 nM) or full (1 microM)
      concentration of atropine, which inhibited to a great extent the velocity of
      propulsion, the inhibitory effect of MEN-10627 (1 microM) was markedly increased.
      In conclusion, in the rabbit distal colon NK(2) receptors may decelerate
      propulsion by activating a nitric oxide-dependent neuronal mechanism and may
      accelerate it by a postjunctional synergistic interaction with cholinergic
      muscarinic receptors.

PMID- 10644573
TI  - Heme oxygenase-2 distribution in anorectum: colocalization with neuronal nitric
      oxide synthase.
AB  - Recent investigations have suggested carbon monoxide (CO) as a putative messenger
      molecule. Although several studies have implicated the heme oxygenase (HO)
      pathway, responsible for the endogenous production of CO, in the neuromodulatory
      control of the internal anal sphincter (IAS), its exact role is not known. Nitric
      oxide, produced by neuronal nitric oxide synthase (nNOS) of myenteric neurons, is
      an important inhibitory neural messenger molecule mediating nonadrenergic
      noncholinergic (NANC) relaxation of the IAS. The present studies were undertaken
      to investigate in detail the presence and coexistence of heme oxygenase-2 (HO-2)
      with nNOS in the opossum anorectum. In perfusion-fixed, frozen-sectioned tissue,
      HO-2 immunoreactive (IR) and nNOS IR nerves were identified using
      immunocytochemistry. Ganglia containing HO-2 IR neuronal cell bodies were present
      in the myenteric and submucosal plexuses throughout the entire anorectum.
      Colocalization of HO-2 IR and nNOS IR was nearly 100% in the IAS and decreased
      proximally from the anal verge. In the rectum, colocalization of HO-2 IR and nNOS
      IR was approximately 70%. Additional confocal microscopy studies using c-Kit
      staining demonstrated the localization of HO-2 IR and nNOS IR in interstitial
      cells of Cajal (ICC) of the anorectum. From the high rate of colocalization of HO
      2 IR and nNOS IR in the IAS as well as the localization of HO-2 IR and nNOS IR in
      ICC in conjunction with earlier studies of the HO pathway, we speculate an
      interaction between HO and NOS pathways in the NANC inhibitory neurotransmission
      of the IAS and rectum.

PMID- 10644574
TI  - A novel human organic anion transporting polypeptide localized to the basolateral
      hepatocyte membrane.
AB  - We cloned and expressed a new organic anion transporting polypeptide (OATP),
      termed human OATP2, (OATP-C, LST-1; symbol SLC21A6), involved in the uptake of
      various lipophilic anions into human liver. The cDNA encoding OATP2 comprised
      2073 base pairs, corresponding to a protein of 691 amino acids, which were 44%
      identical to the known human OATP. An antibody directed against the carboxy
      terminus localized OATP2 to the basolateral membrane of human hepatocytes.
      Northern blot analysis indicated a strong expression of OATP2 only in human
      liver. Transport mediated by recombinant OATP2 and its localization were studied
      in stably transfected Madin-Darby canine kidney strain II (MDCKII) and HEK293
      cells. Confocal microscopy localized recombinant OATP2 protein to the lateral
      membrane of MDCKII cells. Substrates included 17beta-glucuronosyl estradiol,
      monoglucuronosyl bilirubin, dehydroepiandrosterone sulfate, and cholyltaurine.
      17beta-Glucuronosyl estradiol was a preferred substrate, with a Michaelis-Menten
      constant value of 8.2 microM; its uptake was Na(+) independent and was inhibited
      by sulfobromophthalein, with a inhibition constant value of 44 nM. Our results
      indicate that OATP2 is important for the uptake of organic anions, including
      bilirubin conjugates and sulfobromophthalein, in human liver.

PMID- 10644576
TI  - NF-kappaB determines between apoptosis and proliferation in hepatocytes during
      liver regeneration.
AB  - Tumor necrosis factor (TNF)-alpha is a potent inducer of apoptotic cell death in
      various tissues, whereas the transcription factor nuclear factor (NF)-kappaB is
      essential to protect against TNF-alpha-induced apoptosis. Human hepatoma cell
      lines were used to investigate the effectiveness and specificity of the fungal
      metabolite gliotoxin in inhibiting TNF-alpha-induced NF-kappaB activation in
      transformed cells. Gliotoxin-TNF-alpha cotreatment induced massive apoptosis in
      these otherwise TNF-alpha-resistant cell lines. With the use of the mouse partial
      hepatectomy model, we were also able to demonstrate in vivo the capacity of
      gliotoxin to act as inhibitor of NF-kappaB activation. Bromodeoxyuridine staining
      of liver sections showed that the lack of NF-kappaB activation correlated with
      80% reduction of DNA synthesis 48 h after hepatectomy compared with untreated
      controls. Additionally, animals treated with gliotoxin showed nuclear
      condensation and DNA laddering of hepatocytes indicative of apoptosis 24 h after
      hepatectomy. In summary, our results demonstrate that NF-kappaB is essential in
      defining the fate of liver cells in response to TNF-alpha in vivo and furthermore
      implicate gliotoxin as a potential new response modifier for TNF-alpha-based
      therapy.

PMID- 10644575
TI  - CEP-1347 inhibits caerulein-induced rat pancreatic JNK activation and ameliorates
      caerulein pancreatitis.
AB  - Pancreatic caerulein-induced activation of c-Jun NH(2)-terminal kinase (JNK) has
      been reported, and JNK has been proposed as a mediator during induction of
      hyperstimulated pancreatitis. CEP-1347 has recently been described as a specific
      JNK inhibitor. We tested whether CEP-1347 inhibits caerulein-induced pancreatic
      JNK activation in isolated acini and in vivo. CEP-1347 dose dependently inhibited
      acinar caerulein-induced JNK activation with nearly complete inhibition at 2
      microM but had no effect on digestive enzyme release. For in vivo studies, rats
      were pretreated with CEP-1347 before caerulein hyperstimulation. For assessment
      of JNK activation and histological alterations, animals were killed 30 min or 2
      and 4 h after caerulein hyperstimulation, respectively. Pancreatic wet weight,
      serum enzyme levels, and pancreatic activity of p38 and extracellular signal
      regulated kinase (ERK) were also determined. Caerulein hyperstimulation strongly
      activated JNK, p38, and ERK. CEP-1347 pretreatment dose dependently reduced
      caerulein-induced pancreatic JNK activation without p38 or ERK inhibition. JNK
      inhibition also reduced pancreatic edema formation and reduced histological
      severity of pancreatitis. Thus we show that CEP-1347 inhibits JNK activation in
      vivo and ameliorates caerulein-induced pancreatitis.

PMID- 10644577
TI  - Phosphatase inhibitor cantharidin blocks adenosine A(1) receptor anti-adrenergic
      effect in rat cardiac myocytes.
AB  - Experiments were performed to examine whether the protein phosphatase inhibitor
      cantharidin blocks the anti-adrenergic effect of adenosine A(1) receptor
      stimulation. In electrically stimulated adult rat ventricular myocytes loaded
      with the intracellular calcium concentration ([Ca(2+)](i)) indicator fluo-3,
      isoproterenol (10 nM) increased systolic [Ca(2+)](i) by 46%, increased twitch
      amplitude by 56%, and increased total cellular cAMP content by 140%. The
      adenosine A(1) receptor agonist 2-chloro-N(6)-cyclopentlyadenosine (CCPA) reduced
      isoproterenol-stimulated [Ca(2+)](i) and contractility by 87 and 80%,
      respectively, but reduced cAMP content by only 18%. Cantharidin had no effects on
      myocyte [Ca(2+)](i), contractility, or cAMP in the absence or presence of
      isoproterenol but blocked the effects of CCPA on [Ca(2+)](i) and contractility by
      approximately 44%. Cantharidin had no effect on CCPA attenuation of isoproterenol
      induced increases in cAMP. Pretreatment with CCPA also reduced the increase in
      contractile parameters produced by the direct cAMP-dependent protein kinase A
      (PKA) activator 8-bromocAMP. These results suggest that activation of protein
      phosphatases mediate, in part, the anti-adrenergic effect of adenosine A(1)
      receptor activation in ventricular myocardium.

PMID- 10644578
TI  - A novel right-heart catheterization technique for in vivo measurement of vascular
      responses in lungs of intact mice.
AB  - The present study employed a new right-heart catheterization technique to measure
      pulmonary arterial pressure, pulmonary arterial wedge pressure, and pulmonary
      vascular resistance in anesthetized intact-chest, spontaneously breathing mice.
      Under fluoroscopic guidance, a specially designed catheter was inserted via the
      right jugular vein and advanced to the main pulmonary artery. Cardiac output was
      determined by the thermodilution technique, and measured parameters were stable
      for periods of </=3 h. Pressure-flow curves in vivo were curvilinear, with mean
      pulmonary arterial pressure increasing more rapidly at low pulmonary blood flows
      of 5-10 ml/min and less rapidly at higher blood flow rates. The pressure-flow
      relationship was shifted to the left by the nitric oxide synthase inhibitor nitro
      L-arginine methyl ester (L-NAME) at higher blood flow levels, whereas the
      cyclooxygenase inhibitor sodium meclofenamate was without effect. The increase in
      pulmonary arterial pressure in response to acute hypoxia (fractional inspired
      O(2) 10%) was augmented by L-NAME but unaltered by sodium meclofenamate. The
      present results demonstrate that the right-heart catheterization technique can be
      used to measure pulmonary vascular pressures and responses in the mouse. This is,
      to our knowledge, the first report of a right-heart catheterization technique to
      measure pulmonary vascular pressures and responses in the intact-chest,
      spontaneously breathing mouse and should prove useful for the investigation of
      pulmonary vascular responses in transgenic mice.

PMID- 10644579
TI  - The 400 microsphere per piece "rule" does not apply to all blood flow studies.
AB  - Microsphere experiments are useful in measuring regional organ perfusion as well
      as heterogeneity of blood flow within organs and correlation of perfusion between
      organ pieces at different time points. A 400 microspheres/piece "rule" is often
      used in planning experiments or to determine whether experiments are valid. This
      rule is based on the statement that 400 microspheres must lodge in a region for
      95% confidence that the observed flow in the region is within 10% of the true
      flow. The 400 microspheres precision rule, however, only applies to measurements
      of perfusion to a single region or organ piece. Examples, simulations, and an
      animal experiment were carried out to show that good precision for measurements
      of heterogeneity and correlation can be obtained from many experiments with <400
      microspheres/piece. Furthermore, methods were developed and tested for correcting
      the observed heterogeneity and correlation to remove the Poisson "noise" due to
      discrete microsphere measurements. The animal experiment shows adjusted values of
      heterogeneity and correlation that are in close agreement for measurements made
      with many or few microspheres/piece. Simulations demonstrate that the adjusted
      values are accurate for a variety of experiments with far fewer than 400
      microspheres/piece. Thus the 400 microspheres rule does not apply to many
      experiments. A "rule of thumb" is that experiments with a total of at least
      15,000 microspheres, for all pieces combined, are very likely to yield accurate
      estimates of heterogeneity. Experiments with a total of at least 25,000
      microspheres are very likely to yield accurate estimates of correlation
      coefficients.

PMID- 10644580
TI  - Energetic effects of adenosine on vascular smooth muscle.
AB  - Adenosine (Ado) is a naturally occurring compound that has several important
      cardiovascular actions, including activation of ATP-sensitive K(+) channels in
      vascular smooth muscle, vasorelaxation, and an effect to alter glucose metabolism
      of cardiac muscle. The metabolic effects of Ado on vascular smooth muscle have
      not been defined and were examined in this study. Porcine carotid artery strips
      were incubated in the presence and absence of 0.5 mM Ado. Compared with the
      control, Ado had no effect on glucose uptake, glucose oxidation, or fatty acid
      (octanoate) oxidation. Ado suppressed glycolysis but enhanced glycogen synthesis.
      Relative to the rate of glycolysis, Ado increased lactate production. Ado
      stimulated O(2) consumption by 52 +/- 10%, altered the activities of the
      tricarboxylic acid cycle and malate-aspartate shuttle, and increased the content
      of ATP, ADP, AMP, and phosphocreatine. Alteration in the metabolic variables by
      Ado could not be attributed to diminished energy requirements of reduced resting
      muscle tone of the arterial strips. Relaxation of the arterial strips in response
      to Ado were abolished in arteries incubated under hypoxic conditions (95% N(2)-5%
      CO(2)). Hypoxia was associated with increased ADP content. It is concluded that
      Ado affected glucose metabolism indirectly. The metabolic and energetic effects
      of 0.5 mM Ado are mediated by alterations in the concentrations of AMP, ATP, and
      phosphorylation potential (ATP/ADP).

PMID- 10644581
TI  - Effects of natriuretic peptides on load and myocardial function in normal and
      heart failure dogs.
AB  - The effects on myocardial function and loading conditions of clinically relevant
      doses of the natriuretic peptides (NP) have not been established. The actions of
      single doses (100 ng x kg(-1) x min(-1) iv over 30 min) of atrial natriuretic
      peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide
      (CNP) were studied in conscious normal dogs and in dogs with pacing-induced heart
      failure. All three NP reduced end-diastolic pressure in normal dogs, and ANP and
      BNP reduced end-diastolic volume. In heart failure ANP and BNP reduced EDP, and
      ANP reduced EDV. Arterial elastance was unchanged in normal dogs and in dogs with
      heart failure. ANP increased end-systolic elastance (E(es)) in normal dogs,
      whereas BNP tended to increase E(es) (P = 0.06). In dogs with heart failure, no
      inotropic effect was seen. In normal dogs, all NP reduced the time constant of
      isovolumic relaxation (tau), and ANP and BNP reduced tau in dogs with heart
      failure. Increases in plasma cGMP in dogs with heart failure were blunted. The NP
      reduced preload and enhanced systolic and diastolic function in normal dogs.
      Effects of ANP and BNP on preload and diastolic function were maintained in heart
      failure. Lack of negative inotropic effects in heart failure supports the
      validity of the NP as therapeutic agents.

PMID- 10644582
TI  - Increased myometrial contracture frequency at 96-140 days accelerates fetal
      cardiovascular maturation.
AB  - Fetal cardiovascular responses to an altered intrauterine environment of
      increased myometrial contractures induced by oxytocin (OT) pulses to the ewe over
      the final 50 days of gestation were studied in chronically instrumented sheep.
      Ewes received saline (Cntl) or long-term OT treatment (LTOT, 600 microU x kg(-1)
      x min(-1) in 5-min pulses every 20 min) from 96 days gestational age. Fetal
      baroreflex responses to sodium nitroprusside (SNP) and phenylephrine (PE) were
      studied at 133 days gestation. OT increased contractures in LTOT ewes. Fetal
      blood pressure (FBP) was higher, and fetal heart rate (FHR) and slope of daily
      change in FBP and FHR were lower in LTOT fetuses. Fetal SNP-induced hypotension
      resulted in a narrow R-R interval variation range in LTOT fetuses; Cntl fetuses
      showed early breakdown in compensation. Baroreflex response slope during PE
      induced fetal hypertension was lower in LTOT than in Cntl fetuses. Although the
      cortisol-to-ACTH ratio was lower in LTOT fetuses, fetal plasma ACTH and cortisol
      changes were similar in control and LTOT fetuses. We hypothesize that contracture
      induced alterations in the intrauterine environment accelerate fetal
      cardiovascular development through mild hypoxemia, repetitive fetal pituitary
      adrenal stimulation, and/or physical stimulation.

PMID- 10644583
TI  - Effect of acidosis on transient outward potassium current in isolated rat
      ventricular myocytes.
AB  - The effect of acidosis on the transient outward K(+) current (I(to)) of rat
      ventricular myocytes has been investigated using the perforated patch-clamp
      technique. When the holding potential was -80 mV, depolarizing pulses to
      potentials positive to -20 mV activated I(to) in subepicardial cells but
      activated little I(to) in subendocardial cells. Exposure to an acid solution (pH
      6.5) had no significant effect on I(to) activated from this holding potential in
      either subepicardial or subendocardial cells. When the holding potential was -40
      mV, acidosis significantly increased I(to) at potentials positive to -20 mV in
      subepicardial cells but had little effect on I(to) in subendocardial cells. The
      increase in I(to) in subepicardial cells was inhibited by 10 mM 4-aminopyridine.
      In subepicardial cells, acidosis caused a +8.57-mV shift in the steady-state
      inactivation curve. It is concluded that in subepicardial rat ventricular
      myocytes acidosis increases the amplitude of I(to) as a consequence of a
      depolarizing shift in the voltage dependence of inactivation.

PMID- 10644585
TI  - AV blocking due to asynchronous vagal stimulation in rats.
AB  - The parasympathetic nervous system innervates the heart through two cervical
      vagal branches. The right vagal branch mainly influences the heart rate by the
      modulation of the rhythmogenesis of the sinoatrial node. The left branch
      predominantly influences the conduction properties of the atrioventricular (AV)
      node. We investigated the effect of asynchronous stimulation by the vagal nerves
      on the occurrence of irregularities in heart rate. In rats, the vagal nerves were
      isolated and cut. Different vagal stimulation patterns (continuous, pulsed) were
      applied. The heart was beating spontaneously under continuous vagal stimulation.
      In case of pulsed vagal stimulation, the atria were paced at different rates.
      Asynchronicity was induced by delaying the right stimulus with respect to the
      left stimulus (early right) or the left stimulus with respect to the right
      stimulus (early left). The value of the fraction of deviated R-R or P-Q intervals
      in the distribution in the histogram was used to characterize irregularities
      during a stimulation protocol (duration in case of continuous stimulation: 20 s;
      pulsed stimulation: 120 s). Under both stimulation patterns (continuous or
      pulsed), we found that early left vagal stimulation introduced a much larger
      fraction of deviated intervals in the R-R or P-Q histogram (in R-R: 29.1 +/-
      4.9%; in P-Q: 12.90 +/- 1.95%) than early right vagal stimulation (in R-R: 7.4 +/
      2.0%; in P-Q: 1. 05 +/- 0.50%) or synchronous stimulation (in R-R: 8.2 +/- 3.6%;
      in P-Q: 2.15 +/- 0.75%). We conclude that early stimulation by the left vagal
      nerve can introduce irregularities in heart rate, mainly due to different degrees
      of AV nodal blockade.

PMID- 10644584
TI  - Regulation of endothelial nitric oxide synthase by PGD(2) in the developing
      choroid.
AB  - We investigated if prostaglandins might regulate the increased choroidal
      endothelial (e) nitric oxide synthase (NOS) expression in the perinate.
      Prostaglandins, eNOS mRNA, immunoreactive protein and activity, and nitrite
      [stable metabolite of nitric oxide (NO)] production were markedly higher in
      newborn (1 day old) than juvenile (6-8 wk old) pig choroid. Treatment of isolated
      newborn choroids with the prostaglandin synthase inhibitor ibuprofen for 24 h
      reduced eNOS mRNA and nitrite production to values in juveniles. This effect was
      equally observed with the PGD(2) receptor (DP) blocker BW A868C and was prevented
      by cotreatment with PGD(2) but not other prostaglandins; similar observations
      were made on NOS activity in vivo. PGD(2) also increased eNOS expression on
      choroids of juveniles, and this effect was blocked by BW A868C. The manifestation
      of this upregulation of eNOS by PGD(2) on the control of choroidal vasomotor
      response was tested by using NO-dependent vasorelaxants, ACh, bradykinin (Bk),
      and substance P (SP). ACh-, Bk-, and SP-elicited choroidal vasorelaxation was
      greater in saline-treated newborn than juvenile pigs. Ibuprofen (24 h) decreased
      ACh-, Bk-, and SP-evoked vasorelaxation in newborns, whereas PGD(2) increased
      that in juveniles and prevented the ibuprofen-induced attenuated relaxation in
      newborns; infusion of N(omega)-monomethyl-L-arginine in choroids of those animals
      treated with PGD(2) reversed the augmented vasorelaxation to ACh, Bk, and SP.
      Finally, PGD(2)-induced upregulation of NOS in the perinate was also reflected by
      curtailed choroidal blood flow autoregulatory response to increased perfusion
      pressure. In conclusion, PGD(2) exhibits a major role in upregulating eNOS
      expression and activity in the choroid, which in turn results in greater NO
      mediated vasorelaxation; a new mechanism for eNOS regulation via DP is hereby
      disclosed. The relationship between PGD(2) and eNOS in the developing subject
      provides an explanation for the interactive role of these two factors in the
      absent choroidal blood flow autoregulation in the perinate.

PMID- 10644586
TI  - Adenosine is not responsible for local metabolic control of coronary blood flow
      in dogs during exercise.
AB  - The purpose of this investigation was to quantitatively evaluate the role of
      adenosine in coronary exercise hyperemia. Dogs (n = 10) were chronically
      instrumented with catheters in the aorta and coronary sinus, and a flow probe on
      the circumflex coronary artery. Cardiac interstitial adenosine concentration was
      estimated from arterial and coronary venous plasma concentrations using a
      previously tested mathematical model. Coronary blood flow, myocardial oxygen
      consumption, heart rate, and aortic pressure were measured at rest and during
      graded treadmill exercise with and without adenosine receptor blockade with
      either 8-phenyltheophylline (8-PT) or 8-p-sulfophenyltheophylline (8-PST). In
      control vehicle dogs, exercise increased myocardial oxygen consumption 4.2-fold,
      coronary blood flow 3.8-fold, and heart rate 2.5-fold, whereas mean aortic
      pressure was unchanged. Coronary venous plasma adenosine concentration was little
      changed with exercise, and the estimated interstitial adenosine concentration
      remained well below the threshold for coronary vasodilation. Adenosine receptor
      blockade did not significantly alter myocardial oxygen consumption or coronary
      blood flow at rest or during exercise. Coronary venous and estimated interstitial
      adenosine concentration did not increase to overcome the receptor blockade with
      either 8-PT or 8-PST as would be predicted if adenosine were part of a high-gain,
      negative-feedback, local metabolic control mechanism. These results demonstrate
      that adenosine is not responsible for local metabolic control of coronary blood
      flow in dogs during exercise.

PMID- 10644587
TI  - bFGF increases collateral blood flow in aged rats with femoral artery ligation.
AB  - We tested the hypothesis that aged animals are as responsive as the young adult
      animals in expanding collateral vasculature under a similar treatment of basic
      fibroblast growth factor (bFGF). Two age groups of male Fischer 344 rats (11 mo
      old; n = 32, 23 mo old; n = 43) weighing approximately 385 g were subdivided into
      normal, acute ligation [femoral artery (FA) ligated 3 days before blood flow (BF)
      measurement] or ligated groups for 16 days and received recombinant human bFGF
      intra-arterial infusion at doses of 0, 0.5, 5, and 50 microg x kg(-1) x day(-1).
      BF was determined with (85)Sr- and (141)Ce-labeled microspheres during treadmill
      running at 15 and 20 m/min at 15% grade. Blood pressure (BP) values were
      approximately 149 and approximately 163 mmHg (p < 0.05); heart rates were
      approximately 496 and approximately 512 beats/min in the aged and young adult
      groups during running, respectively. Maximal collateral BF values were confirmed
      by no additional BF increase in the calf muscle at the higher speed. Ligation of
      the FA for 3 days reduced the BF reserve to the calf muscle by approximately 90%.
      Calf muscle BF was modestly greater (10 ml x min(-1) x 100 g(-1)) by 16 days in
      the carrier group. bFGF infusion expanded collateral BF in a dose-dependent
      manner with an increase of 33 and 42 ml x min(-1) x 100 g(-1) (P < 0.001) in the
      5 and 50 microg x kg(-1) x day(-1) bFGF groups, respectively. Aged animals showed
      similar BF improvements as observed with the adult groups in response to ligation
      surgery and bFGF treatment. Our data indicate that the aged rats (approximately
      23 mo old) remain responsive to exogenous bFGF induced in developing collateral
      dependent BF as the young adult (approximately 11 mo old) controls. This suggests
      that the influence of bFGF in expanding collateral BF should not be preempted in
      the aged group, the population most affected by peripheral arterial
      insufficiency.

PMID- 10644588
TI  - Influence of simulated ischemia on apoptosis induction by oxidative stress in
      adult cardiomyocytes of rats.
AB  - Oxidative stress may cause apoptosis of cardiomyocytes in ischemic-reperfused
      myocardium. We investigated whether ischemia-reperfusion modifies the
      susceptibility of cardiomyocyte induction of apoptosis by oxidative stress.
      Ischemia was simulated by incubating isolated cardiomyocytes from adult rats in
      an anoxic, glucose-free medium, pH 6.4, for 3 h. Annexin V-fluorescein
      isothiocyanate/propidium iodide staining and the detection of DNA laddering were
      used as apoptotic markers. H(2)O(2) (7.5 micromol/l) induced apoptosis in 20.1 +/
      1.8% of cells under normoxic conditions but only 14.4 +/- 1.6% (n = 6, P < 0.05)
      after ischemia-reoxygenation. This partial protection of ischemic-reoxygenated
      cells was observed despite a reduction in their cellular glutathione content,
      from 11.4 +/- 1.9 in normoxic controls to 2.9 +/- 0.8 nmol/mg protein (n = 3, P <
      0.05). Elevation of end-ischemic glutathione contents by pretreatment with 1
      mmol/l N-acetylcysteine entirely protected ischemic-reoxygenated cells against
      induction of apoptosis by H(2)O(2). In conclusion, ischemia-reperfusion can
      protect cardiomyocytes against induction of apoptosis by exogenous oxidative
      stress. This endogenous protective effect is most clearly demonstrated when
      control and postischemic cardiomyocytes are compared at similar glutathione
      levels.

PMID- 10644589
TI  - Improved contractile performance of right ventricle in response to increased RV
      afterload in newborn lamb.
AB  - Pulmonary hypertension results in an increased afterload for the right ventricle
      (RV). To determine the effects of this increased afterload on RV contractile
      performance, we examined RV performance before and during 4 h of partial balloon
      occlusion of the pulmonary artery and again after releasing the occlusion in nine
      newborn lambs. RV contractile performance was quantified by indexes derived from
      systolic RV pressure-volume relations obtained by a combined pressure-conductance
      catheter during inflow reduction. An almost twofold increase of end-systolic RV
      pressure (from 22 to 38 mmHg) was maintained during 4 h. Cardiac output (CO)
      (0.74 +/- 0.08 l/min) and stroke volume (4.3 +/- 0.4 ml) were maintained, whereas
      end-diastolic volume (7.9 +/- 1.3 ml) did not change significantly during this
      period. RV systolic function improved substantially; the end-systolic pressure
      volume relation shifted leftward indicated by a significantly decreased volume
      intercept (up to 70%), together with a slightly increased slope. In this newborn
      lamb model, maintenance of CO during increased RV afterload is not obtained by an
      increased end-diastolic volume (Frank-Starling mechanism). Instead, the RV
      maintains its output by improving contractile performance through homeometric
      autoregulation.

PMID- 10644590
TI  - Role of the endothelial glycocalyx in dromotropic, inotropic, and arrythmogenic
      effects of coronary flow.
AB  - Coronary flow regulates cardiac functions, and it has been suggested that
      endothelial membrane glycosylated proteins are the primary shear stress
      mechanosensors. Our hypothesis was that if these proteins are the sensors for
      flow, then intracoronary perfusion of lectins or specific antibodies should
      differentially depress coronary flow-enhanced responses of different parenchymal
      cell types such as auricular-ventricular (A-V) nodal cells (dromotropic effect),
      contractile myocytes (inotropic effect), and junctional Purkinje-muscle cells
      (spontaneous ventricular rhythm). The coronary flow stimulatory effects on A-V
      delay and spontaneous ventricular rhythm were selectively depressed by six of
      eight lectins. None of the lectins depressed the coronary flow inotropic effect.
      Antibodies against endothelial surface proteins, alpha(v)beta(5)-integrin and
      sialyl-Lewis(b) glycan, depressed the dromotropic but not the inotropic effects
      of coronary flow, whereas the vascular cell adhesion molecule 1 antibody had no
      effect on the dromotropic, but enhanced the inotropic, effect. The fact that
      lectins and antibodies differentially depressed regional coronary flow effects
      suggests that there is a chemical distinctiveness in their intravascular
      endothelial cell surfaces. However, nonselective cross-linking of endothelial
      glycocalyx proteins with 2,000-kDa dextran-aldehyde or vitronectin
      indistinctively depressed the dromotropic and inotropic effects of coronary flow.
      These results indicate that coronary flow-induced stress acts on specific
      structures located in the capillary intravascular membrane glycocalyx.

PMID- 10644591
TI  - Role of cell contractions in cAMP-induced cardiomyocyte atrial natriuretic
      peptide release.
AB  - Incubation of spontaneously beating ventricular cardiomyocytes from neonatal rats
      with prostaglandin E(2) (0.1 microM) or forskolin (0.1 microM) simultaneously
      increased the rate of cellular contraction and atrial natriuretic peptide (ANP)
      secretion. Both responses were maximal within 10-20 min of application and were
      accompanied by three- to fourfold increases in cAMP formation. By contrast, a
      higher regimen of forskolin (10 microM) promoted a 20- to 30-fold increase in
      basal cAMP production, which was accompanied by the abolition of contractile
      activity and ANP release. Low regimens of forskolin (0.1 microM) doubled the
      occurrence of cytosolic Ca(2+) transients associated with monolayer contraction,
      whereas higher regimens of forskolin (10 microM) completely suppressed Ca(2+)
      transients. Moreover, in quiescent cultures that were pretreated with ryanodine,
      tetrodotoxin, nifedipine, or butanedione monoxime, prostaglandin E(2) (0.1
      microM) and forskolin (0.1 microM) failed to elicit significant ANP secretion,
      suggesting that cAMP-elevating agents promote ANP secretion to a great extent via
      an increase in cellular contraction frequency in ventricular cardiomyocytes.

PMID- 10644592
TI  - Voltage-dependent facilitation of cardiac L-type Ca channels expressed in HEK-293
      cells requires beta-subunit.
AB  - The activity of native L-type Ca channels can be facilitated by strong
      depolarizations. The cardiac Ca channel alpha(1C)-subunit was transiently
      expressed in human embryonic kidney (HEK-293) cells, but these channels did not
      exhibit voltage-dependent facilitation. Coexpression of the Ca channel beta(1a)-
      or beta(2a)-subunit with the alpha(1C)-subunit enabled voltage-dependent
      facilitation in 40% of cells tested. The onset of facilitation in alpha(1C) +
      beta(1a)-expressing HEK-293 cells was rapid after a depolarization to +100 mV
      (tau = 7.0 ms). The kinetic features of the facilitated currents were comparable
      to those observed for voltage-dependent relief of G protein inhibition
      demonstrated for many neuronal Ca channels; however, intracellular dialysis with
      guanosine 5'-O-(2-thiodiphosphate) and guanosine 5'-O-(3-thiotriphosphate) in the
      patch pipette had no effect on facilitation. Stimulation of G protein-coupled
      receptors, either endogenous (somatostatin receptors) or coexpressed (adenosine
      A(1) receptors), did not affect voltage-dependent facilitation. These results
      indicate that the cardiac Ca channel alpha(1C)-subunit can exhibit voltage
      dependent facilitation in HEK-293 cells only when coexpressed with an auxiliary
      beta-subunit and that this facilitation is independent of G protein pathways.

PMID- 10644593
TI  - Toluidine blue O and methylene blue as endothelial redox probes in the intact
      lung.
AB  - There is increasing evidence that the redox activities of the pulmonary
      endothelial surface may have important implications for the function of both
      lungs and blood. Because of the inherent complexity of intact organs, it can be
      difficult to study these activities in situ. Given the availability of
      appropriate indicator probes, the multiple-indicator dilution (MID) method is one
      approach for dealing with some aspects of this complexity. Therefore, the
      objectives of the present study were to 1) evaluate the potential utility of two
      thiazine redox indicators, methylene blue (MB) and toluidine blue O (TBO), as MID
      electron acceptor probes for in situ pulmonary endothelium and 2) develop a
      mathematical model of the pulmonary disposition of these indicators as a tool for
      quantifying their reduction on passage through the lungs. Experiments were
      carried out using isolated rabbit lungs perfused with physiological salt solution
      with or without plasma albumin over a range of flow rates. A large fraction of
      the injected TBO disappeared from the perfusate on passage through the lungs. The
      reduction of its oxidized, strongly polar, relatively hydrophilic blue form to
      its colorless, highly lipophilic reduced form was revealed by the presence of the
      reduced form in the venous effluent when plasma albumin was included in the
      perfusate. MB was also lost from the perfusate, but the fraction was considerably
      smaller than for TBO. A distributed-in-space-and-time model was developed to
      estimate the reduction rate parameter, which was approximately 29 and 1.0 ml/s
      for TBO and MB, respectively, and almost flow rate independent for both
      indicators. The results suggest the utility particularly of TBO as an electron
      acceptor probe for MID studies of in situ pulmonary endothelium and of the model
      for quantitative evaluation of the data.

PMID- 10644594
TI  - Differential effects of pressure or volume overload on myocardial MMP levels and
      inhibitory control.
AB  - Left ventricular (LV) pressure (PO) or volume (VO) overload is accompanied by
      myocardial remodeling, but mechanisms that contribute to this progressive
      remodeling process remain unclear. The matrix metalloproteinases (MMPs)
      contribute to tissue remodeling in a number of disease states. This study tested
      the hypothesis that increased MMP expression and activity occur after the
      induction of an LV overload, which is accompanied by a loss of endogenous MMP
      inhibitory control. LV MMP zymographic activity and species abundance were
      measured in dogs under the following conditions: acute PO induced by ascending
      aortic balloon inflation (6 h, n = 9), prolonged PO by aortic banding (10 days, n
      = 5), acute VO through mitral regurgitation secondary to chordal rupture (6 h, n
      = 6), prolonged VO due to mitral regurgitation (14 days, n = 7), and sham
      controls (n = 11). MMP zymographic activity in the 92-kDa region, indicative of
      MMP-9 activity, increased over threefold in acute PO and VO and fell to control
      levels in prolonged PO and VO. The MMP-9 activity-to-abundance ratio increased by
      over fourfold with acute VO and twofold in acute PO, suggesting a loss of
      inhibitory control. Endogenous MMP inhibitor content was unchanged with either PO
      or VO. Interstitial collagenase (MMP-1) content decreased by 50% with acute VO
      but not with acute PO. Stromelysin (MMP-3) levels increased by 40% with acute VO
      and increased by 80% with prolonged PO. Although changes in LV myocardial MMP
      activity and inhibitory control occurred in both acute and prolonged PO and VO
      states, these changes were not identical. These results suggest that the type of
      overload stimulus may selectively influence myocardial MMP activity and
      expression, which in turn would affect the overall LV myocardial remodeling
      process in LV overload.

PMID- 10644595
TI  - Human femoral artery diameter in relation to knee extensor muscle mass, peak
      blood flow, and oxygen uptake.
AB  - It is not known whether the diameter of peripheral conduit arteries may impose a
      limitation on muscle blood flow and oxygen uptake at peak effort in humans, and
      it is not clear whether these arteries are dimensioned in relation to the tissue
      volume they supply or, rather, to the type and intensity of muscular activity. In
      this study, eight humans, with a peak pulmonary oxygen uptake of 3.90 +/- 0.31
      (range 2.29-5.03) l/min during ergometer cycle exercise, performed one-legged
      dynamic knee extensor exercise up to peak effort at 68 +/- 7 W (range 55-100 W).
      Peak values for knee extensor blood flow (thermodilution) and oxygen uptake of
      6.06 +/- 0.74 (range 4.75-9.52) l/min and 874 +/- 124 (range 590-1,521) ml/min,
      respectively, were achieved. Pulmonary oxygen uptake reached a peak of 1.72 +/-
      0.19 (range 1.54-2.33) l/min. Diameters of common and profunda femoral arteries
      determined by ultrasound Doppler were 10.6 +/- 0.4 (range 8.2-12.7) and 6.0 +/-
      0.4 (range 4.5-8.0) mm, respectively. Thigh and quadriceps muscle volume measured
      by computer tomography were 10.06 +/- 0.66 (range 6.18-10.95) and 2.36 +/- 0.19
      (range 1.31-3.27) liters, respectively. The common femoral artery diameter, but
      not that of the profunda branch, correlated with the thigh volume and quadriceps
      muscle mass. There were no relationships between either of the diameters and the
      absolute or muscle mass-related resting and peak values of blood flow and oxygen
      uptake, peak pulmonary oxygen uptake, or peak power output during knee extensor
      exercise. However, common femoral artery diameter correlated to peak pulmonary
      oxygen uptake during ergometer cycle exercise. In conclusion, common and profunda
      femoral artery diameters are sufficient to ensure delivery to the quadriceps
      muscle. However, the common branch may impose a limitation during ergometer cycle
      exercise.

PMID- 10644596
TI  - Impaired endothelium-mediated vasodilation is not the principal cause of
      vasoconstriction in heart failure.
AB  - The extent to which abnormal endothelium-dependent vasodilator mechanisms
      contribute to abnormal resting vasoconstriction and blunted reflex vasodilation
      seen in heart failure is unknown. The purpose of this study was to test the
      hypothesis that the resting and reflex abnormalities in vascular tone that
      characterize heart failure are mediated by abnormal endothelium-mediated
      mechanisms. Thirteen advanced heart-failure patients (New York Heart Association
      III-IV) and 13 age-matched normal controls were studied. Saline, acetylcholine
      (20 microg/min), or L-arginine (10 mg/min) was infused into the brachial artery,
      and forearm blood flow was measured by venous plethysmography at rest and during
      mental stress. At rest, acetylcholine decreased forearm vascular resistance in
      normal subjects, but this response was blunted in heart failure. During mental
      stress with intra-arterial acetylcholine or L-arginine, the decrease in forearm
      vascular resistance was not greater than during saline control in heart failure
      [saline control vs. acetylcholine (7 +/- 3 vs. 6 +/- 3, P = NS) or vs. L-arginine
      (9 +/- 2 units, P = NS)]. The increase in forearm blood flow was not greater than
      during saline control in heart failure [saline control vs. acetylcholine (1. 2 +/
      0.3 vs. 1.3 +/- 0.3, P = NS), or vs. L-arginine (1.2 +/- 0.2 ml x min(-1) x 100
      ml(-1), P = NS)]. Furthermore, during mental stress with nitroprusside, the
      decrease in forearm vascular resistance was not greater than during saline
      control [saline control vs. nitroprusside (7 +/- 3 vs. 5 +/- 4 ml x min(-1) x 100
      g(-1), P = NS)], and the increase in forearm blood flow was not greater than
      during saline control [saline control vs. nitroprusside (1.2 +/- 0.3 vs. 1.3 +/-
      0.5 ml x min(-1) x 100 g(-1), P = NS)]. Because the endothelial-independent agent
      nitroprusside was unable to restore resting and reflex vasodilation to normal in
      heart failure, we conclude that impaired endothelium-mediated vasodilation with
      acetylholine-nitric oxide cannot be the principal cause of the attenuated resting
      or reflex-mediated vasodilation in heart failure.

PMID- 10644597
TI  - oxLDL specifically impairs endothelium-dependent, NO-mediated dilation of
      coronary arterioles.
AB  - Our previous studies implicated that oxidized low-density lipoprotein (oxLDL), a
      putative atherogenic agent, impairs endothelium-dependent, nitric oxide (NO)
      mediated dilation of isolated coronary arterioles to pharmacological agonists.
      However, it is not known whether oxLDL specifically affects NO-mediated dilation
      or generally impairs endothelium-dependent function, including the release of
      hyperpolarizing factors. In this regard, we investigated the dilation of isolated
      porcine coronary arterioles (50- to 100-microm luminal diameter) in response to
      the activation of various endothelium-dependent pathways before and after
      intraluminal incubation of the vessels with oxLDL (0.5 mg protein/ml for 60 min).
      In the absence of oxLDL, all vessels developed basal tone and dilated in response
      to the activation of NO synthase (by flow and adenosine), cyclooxygenase (by
      arachidonic acid), cytochrome P-450 monooxygenase (by bradykinin), and
      endothelial membrane hyperpolarization (by sucrose-induced hyperosmolarity).
      Incubation of the vessels with oxLDL for 60 min did not alter basal tone but did
      inhibit the vasodilatory responses to increased flow and adenosine in a manner
      similar to that of the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester.
      Vasodilations in response to flow and adenosine were not affected by intraluminal
      incubation of the vessels with either a vehicle solution or the native LDL (0.5
      mg protein/ml, 60 min). In contrast with the NO-mediated response, hyperosmotic
      vasodilation mediated by endothelial hyperpolarization was not affected by oxLDL.
      Endothelium-dependent dilations to the cyclooxygenase activator arachidonic acid
      and to the cytochrome P-450 monooxygenase activator bradykinin and endothelium
      independent vasodilation to sodium nitroprusside were also not altered by oxLDL.
      Collectively, these results indicate that oxLDL has a selective effect on
      endothelium-dependent dilation with specific impairment of the NO-mediated
      response, whereas cyclooxygenase and cytochrome P-450 monooxygenase-mediated
      dilations are spared from this inhibitory effect. In addition, oxLDL does not
      appear to affect vasodilation mediated by hyperpolarization of the endothelium.

PMID- 10644598
TI  - Arachidonic acid modulation of alpha1H, a cloned human T-type calcium channel.
AB  - Arachidonic acid (AA) and the products of its metabolism are central mediators of
      changes in cellular excitability. We show that the recently cloned and expressed
      T-type or low-voltage-activated Ca channel, alpha1H, is modulated by external AA.
      AA (10 microM) causes a slow, time-dependent attenuation of alpha1H current. At a
      holding potential of -80 mV, 10 microM AA reduces peak inward alpha1H current by
      15% in 15 min and 70% in 30 min and shifts the steady-state inactivation curve 
      25 mV. AA inhibition was not affected by applying the cyclooxygenase inhibitor
      indomethacin or the lipoxygenase inhibitor nordihydroguaiaretic acid. The
      epoxygenase inhibitor octadecynoic acid partially antagonized AA attenuation of
      alpha1H. The epoxygenase metabolite epoxyeicosatrienoic acid (8,9-EET) mimicked
      the inhibitory effect of AA on alpha1H peak current. A protein kinase C (PKC)
      specific inhibitor (peptide fragment 19-36) only partially antagonized the AA
      induced reduction of peak alpha1H current and the shift of the steady-state
      inactivation curve but had no effect on 8,9-EET-induced attenuation of current.
      In contrast, PKA has no role in the modulation of alpha1H. These results suggest
      that AA attenuation and shift of alpha1H may be mediated directly by AA. The
      heterologous expression of T-type Ca channels allows us to study for the first
      time properties of this important class of ion channel in isolation. There is a
      significant overlap of the steady-state activation and inactivation curves, which
      implies a substantial window current. The selective shift of the steady-state
      inactivation curve by AA reduces peak Ca current and eliminates the window
      current. We conclude that AA may partly mediate physiological effects such as
      vasodilatation via the attenuation of T-type Ca channel current and the
      elimination of a T-type channel steady window current.

PMID- 10644599
TI  - Structural and mechanical factors influencing infarct scar collagen organization.
AB  - Although large collagen fibers in myocardial infarct scar are highly organized,
      little is known about mechanisms controlling this organization. The preexisting
      extracellular matrix may act as a scaffold along which fibroblasts migrate.
      Conversely, deformation within the ischemic area could guide fibroblasts so new
      collagen is oriented to counteract the stretch. To investigate these potential
      mechanisms, we infarcted three groups of pigs. Group 1 served as infarct
      controls. Group 2 had the endocardium slit longitudinally to alter local systolic
      deformation. Group 3 had a plug sectioned from ischemic tissue and rotated 90
      degrees. The slit altered systolic deformation in the infarcted tissue, changing
      circumferential strain from expansion to compression and increasing radial strain
      and shears and the variability of collagen fiber angles but not the mean angle.
      In the plug pigs, when deformation, matrix orientation, and continuity are
      altered in the infarct area, the result is complete disarray in the organization
      of collagen within the infarct scar.

PMID- 10644600
TI  - Altered frequency characteristic of central vasomotor control in SHR.
AB  - Previous work from our laboratory has demonstrated that the very low-frequency
      (VLF: 0-0.25 Hz) and low-frequency (LF: 0.25-0.8 Hz) power of arterial pressure
      variability (APV) are related to vasomotor reactivity in response to control
      signals from the rostral ventrolateral medulla (RVLM) via the sympathetic system
      in the rat. The present study evaluated the differences in the dynamic property
      of central vasomotor control between spontaneously hypertensive rats (SHR) and
      normotensive Wistar-Kyoto rats (WKY). Experiments were carried out in 10- to 12
      wk-old rats that were anesthetized with continuous infusion of pentobarbital
      sodium, paralyzed with pancuronium, and maintained on mechanical ventilation. We
      found that SHR exhibited significantly higher arterial pressure (AP), heart rate
      (HR), and VLF, LF, and high-frequency (0.8-2.4 Hz) power of APV than WKY under
      resting state. Broad-band electrical stimulation of the RVLM elicited parallel
      APV in the VLF and LF ranges in both rat strains. The evoked APV and transfer
      magnitude of the APV to stimulus spike rate variability (RVLM-AP magnitude) were
      significantly higher in SHR, especially in the LF range. The response frequency
      of central vasomotor control, represented by the high-cut frequency of RVLM-AP
      magnitude, was also extended in SHR. The disparity in RVLM-AP transfer magnitude
      between SHR and WKY became virtually absent after combined alpha- and beta
      adrenoceptor blockade by phentolamine and propranolol. These results suggest that
      the dynamic control of RVLM on AP reactivity is enhanced in SHR, in which the
      adrenergic system may play a major role.

PMID- 10644601
TI  - C-type natriuretic peptide inhibits ANP secretion and atrial dynamics in perfused
      atria: NPR-B-cGMP signaling.
AB  - The purpose of the present experiments was to define the role of C-type
      natriuretic peptide (CNP) in the regulation of atrial secretion of atrial
      natriuretic peptide (ANP) and atrial stroke volume. Experiments were performed in
      perfused beating and nonbeating quiescent atria, single atrial myocytes, and
      atrial membranes. CNP suppressed in a dose-related fashion the increase in atrial
      stroke volume and ANP secretion induced by atrial pacing. CNP caused a right
      shift in the positive relationships between changes in the secretion of ANP and
      atrial stroke volume or translocation of the extracellular fluid (ECF), which
      indicates the suppression of atrial myocytic release of ANP into the paracellular
      space. The effects of CNP on the secretion and contraction were mimicked by 8
      bromoguanosine 3',5'-cyclic monophosphate (8-BrcGMP). CNP increased cGMP
      production in the perfused atria, and the effects of CNP on the secretion of ANP
      and atrial dynamics were accentuated by pretreatment with an inhibitor of cGMP
      phosphodiesterase, zaprinast. An inhibitor of the biological natriuretic peptide
      receptor (NPR), HS-142-1, attenuated the effects of CNP. The suppression of ANP
      secretion by CNP and 8-BrcGMP was abolished by a depletion of extracellular
      Ca(2+) in nonbeating atria. Natriuretic peptides increased cGMP production in
      atrial membranes with a rank order of potency of CNP > BNP > ANP, and the effect
      was inhibited by HS-142-1. CNP and 8-BrcGMP increased intracellular Ca(2+)
      concentration transients in single atrial myocytes, and mRNAs for CNP and NPR-B
      were expressed in the rabbit atrium. From these results we conclude that atrial
      ANP release and stroke volume are controlled by CNP via NPR-B-cGMP mediated
      signaling, which may in turn act via regulation of intracellular Ca(2+).

PMID- 10644602
TI  - Cardiovascular response to acute hypovolemia in relation to age. Implications for
      orthostasis and hemorrhage.
AB  - Venous compliance in the legs of aging man has been found to be reduced with
      decreased blood pooling (capacitance response) in dependent regions, and this
      might lead to misinterpretations of age-related changes in baroreceptor function
      during orthostasis. The hemodynamic response to hypovolemic circulatory stress
      was studied with the aid of lower-body negative pressure (LBNP) of 60 cmH(2)O in
      33 healthy men [18 young (mean age 22 yr) and 15 old (mean age 65 yr)].
      Volumetric technique was used in the study of capacitance responses in the calf
      and arm as well as transcapillary fluid absorption in the arm. LBNP led to
      smaller increase in heart rate (P < 0.001) and peripheral resistance (P < 0.01)
      and reduced transcapillary fluid absorption in the arm (P < 0.05) in old
      subjects. However, blood pooling in the calf was reduced in old subjects (1.66 +/
      0.10 vs. 2.17 +/- 0.13 ml/100 ml tissue; P < 0. 01). Accordingly, during similar
      blood pooling in the calf (LBNP 80 cmH(2)O in old subjects), no changes in
      cardiovascular reflex responses with age were found. The capacitance response in
      the arm (mobilization of peripheral blood to the central circulation) was still
      reduced, however (0.67 +/- 0.10 vs. 1.37 +/- 0.11 ml/100 ml tissue; P < 0.01).
      Thus the reduced cardiovascular reflex response found in the elderly during
      orthostatic stress seems to be caused by a reduced capacitance response in the
      legs with age and a concomitant smaller central hypovolemic stimulus rather than
      a reduced efficiency of the reflex response. With similar hypovolemic circulatory
      stress, no changes in cardiovascular reflex responses are seen with age. The
      capacitance response in the arm (mobilization of peripheral blood toward the
      central circulation) is reduced, however, by approximately 50% in the elderly.
      This might seriously impede the possibility of survival of an acute blood loss.

PMID- 10644603
TI  - Cross talk of shear-induced production of prostacyclin and nitric oxide in
      endothelial cells.
AB  - We tested the hypothesis that vessel homeostasis is maintained through the cross
      talk of shear-induced production of prostacyclin and nitric oxide (NO). Confluent
      human umbilical vein endothelial cells (HUVEC) were exposed to fluid shear stress
      at 15 dyn/cm(2) using a cone-plate device, and the concentrations of 6-keto
      PGF(1alpha) and NO metabolites (nitrate and nitrite) in the medium were measured
      with radioimmunoassay and the Greiss method, respectively. Compared with static
      control, shear stress increased cumulative prostacyclin production by twofold
      after 90 min of exposure. Inhibition of NO synthase enhanced flow-induced
      prostacyclin production by twofold without affecting the baseline production.
      Guanylyl cyclase inhibitor enhanced flow-induced prostacyclin production to the
      same degree. In contrast, a stable agonist of cGMP attenuated the rapid early
      phase of flow-dependent prostacyclin production. Shear-induced NO metabolite
      production was unaffected even after indomethacin inhibited prostacyclin
      production. We conclude that NO shows an inhibitory effect on prostacyclin
      production under shear stress and that vessel homeostasis may be maintained
      through an increase in prostacyclin production when NO synthesis is impaired in
      endothelial cells.

PMID- 10644604
TI  - Calf blood flow during prolonged tilt in idiopathic dilated cardiomyopathy and
      after cardiac transplantation.
AB  - In severe congestive heart failure (CHF), abnormal reflex control of calf blood
      flow during brief head-up tilt that appears to normalize after transplantation
      (HTX) may be present during prolonged observation also. Therefore, we studied the
      effect of prolonged (30 min) 50 degrees head-up tilt on calf skeletal muscle
      blood flow measured by the local (133)Xe washout method in CHF and after HTX and
      in patients with the presence vs. absence of native right atrium (+PNA and -PNA,
      respectively). During brief head-up tilt, skeletal muscle blood flow increased 13
      +/- 42% in 9 severe CHF patients in contrast to a -28 +/- 22% decrease (P < 0.01)
      in 11 control subjects, -24 +/- 30% decrease in 15 moderate CHF patients (P <
      0.05), -25 +/- 14% decrease in 12 patients with recent HTX (P < 0.01), and -21 +/
      24% decrease in 8 patients with distant HTX (P = 0.06). However, during
      sustained tilt, blood flow declined to similar levels of that in the other groups
      in severe CHF. HTX -PNA vs. +PNA showed blunted skeletal muscle vasomotor control
      (P < 0.05) and a higher systolic blood pressure (139 +/- 14 vs. 125 +/- 15 mmHg,
      P < 0.05) and heart rate (92 +/- 10 vs. 83 +/- 8 beats/min, P < 0.05). Thus
      paradox vasodilatation of calf skeletal muscle in severe CHF is present only
      during brief but not prolonged tilt. This may be one explanation of the rare
      presence of orthostatic intolerance in CHF and implies only a minor possible role
      for the abnormality in edema pathogenesis. Removal of all right atrium in HTX has
      an important hemodynamic impact that may possibly affect later clinical outcome.

PMID- 10644605
TI  - Phospholamban: a major determinant of the cardiac force-frequency relationship.
AB  - The cardiac force-frequency relationship has been known for over a century, yet
      its mechanisms have eluded thorough understanding. We investigated the hypothesis
      that phospholamban, a potent regulator of the sarco(endo)plasmic reticulum Ca(2+)
      ATPase (SERCA), determines the cardiac force-frequency relationship. Isolated
      left ventricular papillary muscles from wild-type (WT) and phospholamban knockout
      (KO) mice were stimulated at 2 to 6 Hz. The force-frequency relationship was
      positive in WT but negative in KO muscles, i.e., it was inverted by ablation of
      phospholamban (P < 0.01, n = 6 mice). From 2 to 6 Hz, relaxation accelerated
      considerably (by 10 ms) in WT muscles but only minimally (by 2 ms) in KO muscles
      (WT vs. KO: P < 0. 0001, n = 6). To show that the lack of frequency potentiation
      in KO muscles was not explained by the almost maximal basal contractility, twitch
      duration was prolonged in six KO muscles with the SERCA inhibitor cyclopiazonic
      acid to WT values. Relaxation still failed to accelerate with increased
      frequency. In conclusion, our results clearly identify phospholamban as a major
      determinant of the cardiac force-frequency relationship.

PMID- 10644606
TI  - Cholesterol feeding exacerbates myocardial injury in Zucker diabetic fatty rats.
AB  - We measured infarct size after coronary occlusion (30 min) and reperfusion (24 h)
      in genetic non-insulin-dependent Zucker diabetic fatty (ZDF) rats with and
      without 4-wk cholesterol feeding. Infarct size was similar in ZDF rats and lean
      control rats but was significantly larger in cholesterol-fed diabetic rats than
      in cholesterol-fed lean rats (P < 0.05). Plasma levels of glucose, insulin, and
      triglycerides were significantly higher in diabetic rats and were not influenced
      by cholesterol feeding. The increase in total plasma cholesterol induced by
      cholesterol feeding was significantly greater in diabetic rats than in lean rats
      (P < 0.05). A significant positive correlation was found between total plasma
      cholesterol and infarct size (P < 0.05). Myeloperoxidase activity, as an index of
      neutrophil accumulation, was significantly higher and expression of P-selectin
      was more marked in the ischemic myocardium of cholesterol-fed diabetic rats than
      of cholesterol-fed lean rats. Acetylcholine-induced endothelium-dependent
      relaxation (EDR) of aortic rings was markedly impaired in cholesterol-fed
      diabetic rats. Thus cholesterol feeding significantly exacerbated myocardial
      injury produced by coronary occlusion-reperfusion in non-insulin-dependent
      diabetic rats, possibly because of enhanced expression of P-selectin and
      impairment of EDR in the coronary bed.

PMID- 10644607
TI  - Inhibition by calcium antagonism of circulating and renal endothelin in
      experimental congestive heart failure.
AB  - Endothelin (ET) is a potent vasoconstrictor and sodium-regulating peptide whose
      tissue and plasma concentrations are increased in congestive heart failure (CHF).
      ET may mediate its vasoconstrictor and sodium-regulatory actions secondary to an
      increase in intracellular calcium. Calcium influx may augment ET synthesis.
      Although felodipine, a dihydropyridine calcium-channel antagonist, is effective
      in reducing vascular resistance in generalized vasoconstriction, its actions in
      CHF on circulating and local tissue ET remain undefined. The current studies were
      designed to determine the modulating actions of felodipine (oral, 40 mg/day for 7
      days; n = 6) in an experimental canine model of CHF produced by chronic thoracic
      inferior vena caval constriction (TIVCC) compared with normal (n = 7) and TIVCC
      alone (n = 7) dogs. We hypothesized that felodipine would decrease circulating
      and renal ET. Plasma ET was significantly increased in TIVCC compared with normal
      dogs (26 +/- 0. 5 vs. 12 +/- 0.7 pg/ml, P < 0.05) and was markedly decreased by
      felodipine compared with TIVCC alone (14 +/- 3 vs. 26 +/- 0.5 pg/ml, P < 0.05).
      Renal ET immunohistochemical staining demonstrated the presence of ET in normal
      kidney, which was markedly increased in renal cortex and medulla in TIVCC dogs.
      Renal cortical and medullary ET staining densities were markedly decreased with
      felodipine compared with those with TIVCC alone. In the TIVCC + felodipine group,
      cardiovascular hemodynamics also was markedly improved compared with the TIVCC
      alone group [systemic vascular resistance: 27 +/- 2 vs. 44 +/- 3 resistance units
      (RU), P < 0.05; pulmonary vascular resistance: 3.3 +/- 0.1 vs. 5.7 +/- 0.4 RU, P
      < 0.05; cardiac output: 2.9 +/- 0.2 vs. 1.7 +/- 0.1 l/min, P < 0.05]. This study
      demonstrates important modulating inhibitory actions of felodipine on renal and
      plasma ET in an experimental model of CHF.

PMID- 10644608
TI  - Endothelial cells potentiate phagocytic killing by macrophages via platelet
      activating factor release.
AB  - The immunomodulatory function of endothelial cells (EC) includes the initiation
      of leukocyte margination, diapedesis, and activation through the upregulation of
      various cell surface-associated molecules. However, the effect that EC have on
      the phagocytic function of neighboring monocytes and macrophages is less well
      described. To address this issue, microvascular EC were cocultured with murine
      peritoneal macrophages, first in direct contact, then in a noncontact coculture
      system, and macrophage phagocytosis and phagocytic killing were assessed. The
      presence of increasing concentrations of EC resulted in a dose-dependent increase
      in macrophage phagocytic killing. This stimulatory effect was inhibited in a dose
      dependent manner by the pretreatment of macrophage/EC cocultures with WEB-2086 or
      CV-6209, specific platelet-activating factor (PAF)-receptor antagonists, but not
      by anti-tumor necrosis factor-alpha, anti-interleukin (IL)-1alpha, or anti-IL
      1beta. Furthermore, the effect was reproduced in the absence of EC by the
      exogenous administration of nanomolar concentrations of PAF. Microvascular EC
      potentiate macrophage phagocytic killing via the release of a soluble signal; PAF
      appears to be an important component of that signal.

PMID- 10644609
TI  - Modified heart-lung preparation for the evaluation of systolic and diastolic
      coronary flow in rats.
AB  - A modified heart-lung preparation of the rat, which permits measuring systolic
      and diastolic coronary flow separately and enables coronary compliance to be
      evaluated, is described. The systemic circulation was substituted by a shunt
      circuit, and the elastic properties of the arterial tree were mimicked by a
      rubber balloon. Systolic and diastolic coronary flow was evaluated from the
      pulmonary and aortic flow signal. Integrated phasic pulmonary flow represented
      right ventricular stroke volume. Integrated phasic systolic aortic flow
      represented left ventricular stroke volume minus that volume flowing into the
      coronary arteries during systole, because the aortic flow probe had to be
      inserted distal to the origin of the coronary vessels. Because right and left
      ventricular stroke volume was identical under steady-state conditions, the
      difference between systolic pulmonary and systolic aortic flow resulted in
      systolic coronary flow. Diastolic coronary flow was measured by means of the
      retrograde flow through the aortic flow probe. Coronary compliance was calculated
      according to Frank's windkessel model from coronary resistance and from central
      diastolic aortic pressure, which decayed exponentially after switching out the
      rubber balloon and the shunt circuit. It could be shown that the proportion of
      systolic to diastolic coronary flow depends on coronary compliance.

PMID- 10644610
TI  - Capillary endothelial surface layer selectively reduces plasma solute
      distribution volume.
AB  - We previously reported that a 0.4- to 0.5-microm-thick endothelial surface layer
      confines Dextran 70 (70 kDa) to the central core of hamster cremaster muscle
      capillaries. In the present study we used a variety of plasma tracers to probe
      the barrier properties of the endothelial surface layer using combined
      fluorescence and brightfield intravital microscopy. No permeation of the
      endothelial surface layer was observed for either neutral or anionic dextrans
      >/=70 kDa, but a neutral Dextran 40 (40 kDa) and neutral free dye (rhodamine, 0.4
      kDa) equilibrated with the endothelial surface layer within 1 min. In contrast,
      small anionic tracers of similar size (0. 4-40 kDa) permeated the endothelial
      surface layer relatively slowly with half-times (tau(50)) between 11 and 60 min,
      depending on tracer size. Furthermore, two plasma proteins, fibrinogen (340 kDa)
      and albumin (67 kDa), moved slowly into the endothelial surface layer at the same
      rates, despite greatly differing sizes (tau(50) approximately 40 min). Dextran
      70, which did not enter the glycocalyx over the course of these experiments,
      entered at the same rate as free albumin when it was conjugated to albumin. These
      findings demonstrate that for anionic molecules size and charge have a profound
      effect on the penetration rate into the glycocalyx. The equal rates of
      penetration of the glycocalyx demonstrated by the different protein molecules
      suggests that multiple factors may influence the penetration of the barrier,
      including molecular size, charge, and structure.

PMID- 10644611
TI  - Estrogen status affects sensitivity to focal cerebral ischemia in stroke-prone
      spontaneously hypertensive rats.
AB  - Estrogen treatment has been shown to reduce ischemic brain damage. Because
      endogenous estrogen levels fluctuate markedly during the estrous cycle, we
      investigated the effect of stage of estrous cycle on ischemic brain damage.
      Halothane anesthetized 3- to 5-mo-old female Wistar-Kyoto rats (WKY) and stroke
      prone spontaneously hypertensive rats (SHRSP) in proestrus (high estradiol
      levels) or metestrus (low estradiol levels) underwent permanent middle cerebral
      artery occlusion. In SHRSP, infarct volume at 24 h postocclusion was 24% smaller
      in proestrus compared with metestrus [208.6 +/- 9.5 mm(3) (n = 7) vs. 272.7 +/-
      23.8 mm(3) (n = 7), respectively, means +/- SE; P = 0.0278, unpaired t-test]. In
      WKY, infarct volumes were similar in proestrus and metestrus [157.0 +/- 5.4 mm(3)
      (n = 5) and 131.5 +/- 16.5 mm(3) (n = 8), respectively; P = not significant
      (NS)]. Brain swelling (ipsilateral minus contralateral hemispheric volumes) was
      similar in proestrus and metestrus for SHRSP [138 +/- 9 mm(3) (n = 6) and 136 +/-
      10 mm(3) (n = 7), respectively] and for WKY [103 +/- 15 mm(3) (n = 5) and 90 +/-
      11 mm(3) (n = 8), respectively]. Thus the reduction in infarct size in SHRSP is
      caused by a true attenuation of the infarct volume and not simply by a reduction
      in brain edema.

PMID- 10644612
TI  - Extracellular Ba(2+) blocks the cardiac transient outward K(+) current.
AB  - Ba(2+) is widely used as a tool in patch-clamp studies because of its ability to
      block a variety of K(+) channels and to pass Ca(2+) channels. Its potential
      ability to block the cardiac transient outward K(+) current (I(to)) has not been
      clearly documented. We performed whole cell patch-clamp studies in canine
      ventricular and atrial myocytes. Extracellular application of Ba(2+) produced
      potent inhibition of I(to) with an IC(50) of approximately 40 microM. The effects
      were voltage independent, and the inactivation kinetics were not altered by
      Ba(2+). The potency of Ba(2+) was approximately 10 times higher than that of 4
      aminopyridine (a selective I(to) blocker with an IC(50) of 430 microM) under
      identical conditions. By comparison, Ba(2+) blockade of the inward rectifier K(+)
      current was voltage dependent; the IC(50) was approximately 20 times lower (2.5
      microM) than that for I(to) when determined at -100 mV and was comparable to
      I(to) as determined at -60 mV (IC(50) = 26 microM). Ba(2+) concentrations of </=1
      mM or higher failed to block ultrarapid delayed rectifier K(+) current. Our data
      suggest that Ba(2+) can be considered a potent blocker of I(to).

PMID- 10644613
TI  - Na(+)/H(+) exchange inhibition attenuates hypertrophy and heart failure in 1-wk
      postinfarction rat myocardium.
AB  - Na(+)/H(+) exchange (NHE) represents a major mechanism for intracellular pH
      regulation, particularly in the ischemic myocardium. NHE has also been shown to
      be important in the regulation of cell proliferation and growth. We examined
      whether inhibition of NHE results in an attenuation of early postinfarction
      myocyte remodeling responses in the rat. Male Sprague-Dawley rats were randomized
      to receive either a control diet or an identical diet supplemented with the NHE
      inhibitor cariporide. After 1 wk, animals were anesthetized, subjected to
      ligation of the left main coronary artery, and maintained for an additional week,
      after which time they were anesthetized and intraventricular pressures were
      obtained. Hearts were removed, and myocytes were isolated to obtain cell
      dimensions and determine the response to isoproterenol. Body, heart, and lung
      weights were obtained. Coronary artery ligation in control animals resulted in a
      significant elevation in left ventricular end-diastolic pressure, as well as
      increased heart weight- and lung weight-to-body weight ratios, both of which were
      abrogated by cariporide. Cell length and area significantly increased by 14 and
      19.2%, respectively, whereas cell width increased by 4.1% (P > 0.05). These cells
      exhibited a significant hyporesponsiveness to the positive inotropic responses to
      isoproterenol at the lower drug concentrations (3 and 10 nM). A <1% dimensional
      change occurred in myocytes from cariporide-fed animals, and the hyporesponse to
      isoproterenol was reversed. Cariporide had no effect on infarct size or blood
      pressure. These studies suggest that the early adaptive hypertrophic response of
      surviving myocytes is dependent on NHE activity. As such, it is attractive to
      suggest that NHE inhibition could be an effective therapeutic strategy for
      prevention of postinfarction remodeling, independent of infarct size or afterload
      reduction.

PMID- 10644615
TI  - Determinants of the natriuresis after acute, slow sodium loading in conscious
      dogs.
AB  - The relative importance of systemic volume, concentration, and pressure signals
      in sodium homeostasis was investigated by intravenous infusion of isotonic
      (IsoLoad) or hypertonic (HyperLoad) saline at a rate (1 micromol Na(+) x kg(-1) x
      s(-1)), similar to the rate of postprandial sodium absorption. IsoLoad decreased
      plasma vasopressin (-35%) and plasma ANG II (-77%) and increased renal sodium
      excretion (95-fold), arterial blood pressure (DeltaBP; +6 mmHg), and heart rate
      (HR; +36%). HyperLoad caused similar changes in plasma ANG II and sodium
      excretion, but augmented vasopressin (12-fold) and doubled DeltaBP (+12 mm Hg)
      without changing HR. IsoLoad during vasopressin clamping (constant vasopressin
      infusion) caused comparable natriuresis at augmented DeltaBP (+14 mm Hg), but
      constant HR. Thus vasopressin abolished the Bainbridge reflex. IsoLoad during
      normotensive angiotensin clamping (enalaprilate plus constant angiotensin
      infusion) caused marginal natriuresis (9% of unclamped response) despite
      augmented DeltaBP (+14 mm Hg). Cessation of angiotensin infusion during IsoLoad
      immediately decreased BP (-13 mm Hg) and increased glomerular filtration rate by
      20% and sodium excretion by 45-fold. The results suggest that fading of ANG II is
      the cause of acute "volume-expansion" natriuresis, that physiological ANG II
      deviations override the effects of modest systemic blood pressure changes, and
      that endocrine rather than hemodynamic mechanisms are the pivot of normal sodium
      homeostasis.

PMID- 10644614
TI  - Ischemic preconditioning in rats: role of mitochondrial K(ATP) channel in
      preservation of mitochondrial function.
AB  - We examined the role of the sarcolemmal and mitochondrial K(ATP) channels in a
      rat model of ischemic preconditioning (IPC). Infarct size was expressed as a
      percentage of the area at risk (IS/AAR). IPC significantly reduced infarct size
      (7 +/- 1%) versus control (56 +/- 1%). The sarcolemmal K(ATP) channel-selective
      antagonist HMR-1098 administered before IPC did not significantly attenuate
      cardioprotection. However, pretreatment with the mitochondrial K(ATP) channel
      selective antagonist 5-hydroxydecanoic acid (5-HD) 5 min before IPC partially
      abolished cardioprotection (40 +/- 1%). Diazoxide (10 mg/kg iv) also reduced
      IS/AAR (36.2 +/- 4.8%), but this effect was abolished by 5-HD. As an index of
      mitochondrial bioenergetic function, the rate of ATP synthesis in the AAR was
      examined. Untreated animals synthesized ATP at 2.12 +/- 0.30 micromol x min(-1) x
      mg mitochondrial protein(-1). Rats subjected to ischemia-reperfusion synthesized
      ATP at 0.67 +/- 0.06 micromol x min(-1) x mg mitochondrial protein(-1). IPC
      significantly increased ATP synthesis to 1.86 +/- 0.23 micromol x min(-1) x mg
      mitochondrial protein(-1). However, when 5-HD was administered before IPC, the
      preservation of ATP synthesis was attenuated (1.18 +/- 0.15 micromol x min(-1) x
      mg mitochondrial protein(-1)). These data are consistent with the notion that
      inhibition of mitochondrial K(ATP) channels attenuates IPC by reducing IPC
      induced protection of mitochondrial function.

PMID- 10644616
TI  - Hormonal regulation of renal sodium and water excretion during normotensive
      sodium loading in conscious dogs.
AB  - Saline was infused intravenously for 90 min to normal, sodium-replete conscious
      dogs at three different rates (6, 20, and 30 micromol x kg(-1) x min(-1)) as
      hypertonic solutions (HyperLoad-6, HyperLoad-20, and HyperLoad-30, respectively)
      or as isotonic solutions (IsoLoad-6, IsoLoad-20, and IsoLoad-30, respectively).
      Mean arterial blood pressure did not change with any infusion of 6 or 20 micromol
      x kg(-1) x min(-1). During HyperLoad-6, plasma vasopressin increased by 30%,
      although the increase in plasma osmolality (1.0 mosmol/kg) was insignificant.
      During HyperLoad-20, plasma ANG II decreased from 14+/-2 to 7+/-2 pg/ml and
      sodium excretion increased markedly (2.3+/-0.8 to 19+/-8 micromol/min), whereas
      glomerular filtration rate (GFR) remained constant. IsoLoad-20 decreased plasma
      ANG II similarly (13+/-3 to 7+/-1 pg/ml) concomitant with an increase in GFR and
      a smaller increase in sodium excretion (1.9+/-1.0 to 11+/-6 micromol/min).
      HyperLoad-30 and IsoLoad-30 increased mean arterial blood pressure by 6-7 mm Hg
      and decreased plasma ANG II to approximately 6 pg/ml, whereas sodium excretion
      increased to approximately 60 micromol/min. The data demonstrate that, during
      slow sodium loading, the rate of excretion of sodium may increase 10-fold without
      changes in mean arterial blood pressure and GFR and suggest that the increase may
      be mediated by a decrease in plasma ANG II. Furthermore, the vasopressin system
      may respond to changes in plasma osmolality undetectable by conventional
      osmometry.

PMID- 10644617
TI  - Volume expansion natriuresis during servo control of systemic blood pressure in
      conscious dogs.
AB  - The importance of arterial blood pressure (BP) and ANG II for the renal
      natriuretic response (NaEx) to volume expansion (3.5% body wt) was investigated
      during converting enzyme blockade (enalaprilate, 2 mg/kg). In separate
      experiments, BP was clamped either 30 mm Hg above or a few millimeters mercury
      below baseline by servo-controlled infusion of ANG II or sodium nitroprusside,
      respectively, so that volume expansion did not change BP. Enalapril decreased BP
      by 8 mm Hg. Without clamping, volume expansion returned BP to that of
      preenalapril control and increased NaEx 10-fold (40+/-10 to 377+/-69
      micromol/min). During high pressure clamping (133+/-2 mm Hg), peak NaEx after
      volume expansion was 6% of control experiments. During low pressure clamping,
      NaEx was 68% of control experiments (45+/-15 to 256+/-64 micromol/min). The
      results show that 1) in absence of ANG II, volume expansion elicited pronounced
      natriuresis without increases in BP beyond baseline, 2) in the presence of
      hypertensive amounts of ANG II, the volume expansion-induced natriuresis was
      almost eliminated, and 3) nitroprusside prevented the increase in BP but not
      sodium excretion during volume expansion. ANG II appears to dominate the control
      of NaEx; however, when absent, volume expansion may still induce marked
      natriuresis even at constant BP, possibly via nitric oxide-mediated mechanisms.

PMID- 10644618
TI  - Systemic hemodynamics and renal function in hemorrhaged dogs resuscitated with
      cross-linked hemoglobin.
AB  - Cross-linked hemoglobin (XL-Hb) infused into dogs increases mean arterial
      pressure (MAP) but decreases blood flow to the renal (RBF), mesenteric (MBF), and
      iliac (IBF) circulations. These actions differ markedly from dextran infusion
      (which increases RBF, MBF, and IBF without altering MAP) and may be due to
      scavenging of nitric oxide by XL-Hb. However, because the hormonal milieu
      regulating regional circulation is altered during hemorrhage (when XL-Hb may be
      used), we studied whether systemic hemodynamics, RBF, MBF, IBF, and renal
      excretory function in hemorrhaged dogs was altered when resuscitated with XL-Hb
      compared with dextran (n = 6 each). Hemorrhage decreased MAP by 25% due to a 75%
      decline in cardiac output. RBF, MBF, and IBF all fell by 33, 64, and 72%,
      respectively (P<0.05 each). There was also a fall in glomerular filtration rate
      (GFR), urinary flow, and sodium excretion (P<0.05 each). After resuscitation,
      MAP, cardiac output, RBF, MBF, IBF, and GFR all recovered to basal values with
      either XL-Hb or dextran. Urinary flow and sodium excretion increased to above
      basal levels with dextran (both by 3.5-fold; P<0.05) or XL-Hb (by 7.5- and 10
      fold, respectively; P<0.05). We conclude that resuscitation with XL-Hb after
      hemorrhage not only increases MAP, but also restores RBF, MBF, IBF, GFR, and
      urinary sodium and volume excretion analogously to dextran. The results contrast
      with those in normal dogs and suggest that nitric oxide inhibition does not
      impair hemodynamic and renal function recovery during hemorrhage.

PMID- 10644619
TI  - Responses of celiac and cervical vagal afferents to infusions of lipids in the
      jejunum or ileum of the rat.
AB  - Multiunit celiac and single-unit cervical recordings of vagal afferents were
      performed before and during infusions of fatty acids, triglycerides, or saline
      into either the ileum or jejunum of the rat. In multiunit recordings, lipids
      increased activity of vagal afferents to a greater extent than saline. The
      greatest increases in vagal afferent activity resulted from infusions of linoleic
      acid, conjugated linoleic acid, or oleic acid. The triglycerides, corn oil or
      Intralipid, were less effective than the fatty acids in affecting vagal afferent
      activity. Ileal pretreatment with the hydrophobic surfactant Pluronic L-81
      significantly attenuated the response of celiac vagal afferents to ileal infusion
      of linoleic acid. Single-unit recordings of cervical vagal afferents supported
      the multiunit data in showing lipid-induced increased vagal afferent activity in
      approximately 50% of ileal units sampled and 100% of a limited number of jejunal
      units sampled. These data demonstrate that free fatty acids can activate ileal
      and jejunal vagal afferents in the rat, and this effect can be attenuated by
      pretreatment with a chylomicron inhibitor. These data are consistent with the
      view that lipid-induced activation of vagal afferents could be a potential
      substrate for the inhibitory effects of intestinal lipids on gastrointestinal
      function, food intake, and body weight gain.

PMID- 10644620
TI  - Ontogeny of hypertonic preabsorptive inhibitory control of intake in neonatal
      rats.
AB  - The ontogenetic development of postingestive inhibitory control of ingestion by
      the osmotic load of a preload was examined in rats. On postnatal days 6 (P6) and
      12 (P12), pups were deprived for either 6 or 24 h. Gastric preloads (5% body wt)
      of water, mannitol (a sugar alcohol that is not absorbed) in six concentrations
      [from 0.125 M (hypotonic) to 1.0 M (hypertonic)], or sham preloads were
      administered 5 min before a 30-min intake test. Compared with sham treatment,
      isotonic mannitol (0.25 M), a probe of volumetric control, significantly reduced
      intake on P12, but not on P6. Compared with isotonic mannitol, the three highest
      hypertonic concentrations (0.5, 0.66, and 1.0 M) significantly decreased intake
      on P12, at both levels of deprivation. On P6, 0.66 and 1.0 M mannitol reduced
      intake after 24 h, but not after 6 h, of deprivation. Thus, on P6, the hypertonic
      control was detectable only after prolonged deprivation and the volumetric
      control was not present. On P12, both controls were observed and the hypertonic
      control was more potent than on P6.

PMID- 10644621
TI  - Differential role of melanocortins in mediating leptin's central effects on
      feeding and reproduction.
AB  - Leptin serves as a humoral link coupling the status of energy reserves to the
      functional activity of the reproductive system. Leptin is thought to act through
      melanocortinergic pathways in the brain to regulate ingestive behaviors; however,
      whether melanocortins mediate leptin's actions on the neuroendocrine-reproductive
      axis is unknown. We tested this hypothesis first by determining whether the
      effects of leptin on feeding behavior and reproduction in the ob/ob mouse could
      be blocked by the melanocortin receptor (MC-R) antagonist SHU9119 and second, by
      examining the effects of the MC-R agonist MTII on feeding and the endocrine
      reproductive system. Administered by intracerebroventricular injections, leptin
      inhibited food intake, raised plasma gonadotropin levels, and increased seminal
      vesicle weights compared with controls; SHU9119 (intracerebroventricularly)
      attenuated leptin's effects on food intake and body weight but did not alter
      leptin's stimulatory effect on the reproductive axis. MTII
      (intracerebroventricularly and intraperitoneally) decreased food intake and
      increased body temperature compared with controls but had no effect on the
      reproductive-endocrine axis. These results suggest that although leptin acts
      centrally through melanocortinergic pathways to inhibit ingestive behaviors and
      stimulate metabolism, leptin's activational effect on the reproductive axis is
      likely to be mediated by other, unknown neuroendocrine circuits.

PMID- 10644622
TI  - Fluid extravasation from spleen reduces blood volume in endotoxemia.
AB  - We recently demonstrated that fluid is filtered out of the splenic circulation
      and into the lymphatic system. The current experiments were designed to
      investigate the importance of this route of fluid extravasation in endotoxemia.
      Lipopolysaccharide (LPS) was infused into conscious intact and splenectomized
      rats (150 microg x kg(-1). h(-1) i.v. for 18 h). In the intact rats, mean
      arterial pressure (MAP) fell from 101+/-2.4 to 88+/-3.9 mm Hg (n = 7) and then
      stabilized at about 90 mm Hg. Hematocrit rose from 41+/-0.9 to 45+/-0.4% at 40
      min, at which time plasma volume had fallen from 4.7+/-0.12 to 4.0+/-0.05 ml/100
      g body wt. In the splenectomized rats MAP did not fall and hematocrit did not
      rise. There also was no change in plasma volume, i.e., splenectomy prevented the
      hypotension and hemoconcentration customarily induced by LPS. In a second series
      of experiments, splenic arterial and venous blood flows were simultaneously
      measured in anesthetized rats infused with LPS (150 microg x kg(-1) x h(-1)). LPS
      increased splenic fluid efflux. We conclude that during endotoxemia the initial
      fall in circulating blood volume may be attributed to fluid extravasation from
      the splenic vasculature.

PMID- 10644623
TI  - Developmental stage modifies diet-induced peripheral insulin resistance in rats.
AB  - In the present study, the effects of age and diet on glucose disappearance and
      tissue-specific glucose uptake (R'g) were examined under basal or
      hyperinsulinemic, euglycemic conditions in male Sprague-Dawley rats. Rats were
      equicalorically fed either a high-starch diet (68% of kcal), high-fat diet (HFD;
      45% of kcal), or high-sucrose diet (68% of kcal), beginning at either 5 (W;
      weanling), 10 (Y; young), 18 (M; mature), or 58 wk (O; older) of age for 5 wks (n
      = 6-9. group(-1) x diet(-1)). Body weight gain was not significantly different
      among dietary groups within a given age. Significant (P< 0.05) age effects were
      observed on basal and clamp free fatty acid concentrations. Significant diet
      effects were observed on basal and clamp triglyceride concentrations. There were
      significant diet and age effects on basal skeletal muscle R'g. This interaction
      was primarily due to an age-associated increase in basal R'g microg x g(-1). min(
      1)) in HFD (gastrocnemius R'g: 0.9+/-0.2 in W, 1.1+/-0.2 in Y, 1.8+/-0.2 in M,
      2.5+/-0.2 in O). Both age and diet significantly decreased insulin-stimulated
      muscle R'g. However, whereas age-associated reductions in both glucose-6
      phosphate concentration and glycogen synthase activity were observed, significant
      diet effects were observed on glucose-6-phosphate concentrations only. Age
      significantly reduced basal and clamp adipose tissue R'g when expressed per gram
      of tissue but significantly increased R'g when expressed per total fat pad mass.
      These data suggest that diet-induced changes in peripheral glucose metabolism are
      modulated by age.

PMID- 10644625
TI  - Postcontractile force depression in humans is associated with an impairment in SR
      Ca(2+) pump function.
AB  - To investigate the hypothesis that intrinsic changes in sarcoplasmic reticulum
      (SR) Ca(2+)-sequestration function can be implicated in postcontractile
      depression (PCD) of force in humans, muscle tissue was obtained from the vastus
      lateralis and determinations of maximal Ca(2+) uptake and maximal Ca(2+)-ATPase
      activity were made on homogenates obtained before and after the induction of PCD.
      Eight untrained females, age 20.6+/-0.75 yr (mean +/- SE), performed a protocol
      consisting of 30 min of isometric exercise at 60% maximal voluntary contraction
      and at 50% duty cycle (5-s contraction and 5-s relaxation) to induce PCD. Muscle
      mechanical performance determined by evoked activation was measured before (0
      min), during (15 and 30 min), and after (60 min) exercise. The fatiguing protocol
      resulted in a progressive reduction (P<0.05) in evoked force, which by 30 min
      amounted to 52% for low frequency (10 Hz) and 20% for high frequency (100 Hz). No
      force restoration occurred at either 10 or 100 Hz during a 60-min recovery
      period. Maximal SR Ca(2+)-ATPase activity (nmol x mg protein(-1) x min(-1)) and
      maximal SR Ca(2+) uptake (nmol. mg protein(-1) x min(-1)) were depressed (P<0.05)
      by 15 min of exercise [192+/-45 vs. 114+/-8.7 and 310+/-59 vs. 205+/-47,
      respectively; mean +/- SE] and remained depressed at 30 min of exercise. No
      recovery in either measure was observed during the 60-min recovery period. The
      coupling ratio between Ca(2+)-ATPase and Ca(2+) uptake was preserved throughout
      exercise and during recovery. These results illustrate that during PCD, Ca(2+)
      uptake is depressed and that the reduction in Ca(2+) uptake is due to intrinsic
      alterations in the Ca(2+) pump. The role of altered Ca(2+) sequestration in Ca(2)
      release, cytosolic-free calcium, and PCD remains to be determined.

PMID- 10644624
TI  - Influence of angiotensin on the early progression of heart failure.
AB  - The purpose of this study was to elucidate the role of circulating ANG II in
      mediating changes in systemic and renal hemodynamics, salt and water balance, and
      neurohormonal activation during the early progression of heart failure. This
      objective was achieved by subjecting six dogs to 14 days of rapid ventricular
      pacing (240 beats/min) while fixing plasma ANG II concentration (by infusion of
      captopril + ANG II) either at approximately normal (days 1-8, 13-14) or at high
      physiological (days 9-12) levels. Salt and water retention occurred during the
      initial days of pacing before sodium and fluid balance was achieved by day 8. At
      this time, cardiac output and mean arterial pressure were reduced to
      approximately 55 and 75% of control, respectively; compared with cardiac output,
      reductions in renal blood flow were less pronounced. Although plasma ANG II
      concentration was maintained at approximately normal levels, there were sustained
      elevations in total peripheral resistance (to approximately 135% of control),
      filtration fraction (to approximately 118% of control), and plasma norepinephrine
      concentration (to 2-3 times control). During the subsequent high rate of ANG II
      infusion on days 9-12, there were no additional sustained long-term changes in
      either systemic or renal hemodynamics other than a further rise in right atrial
      pressure. However, high plasma levels of ANG II induced sustained
      antinatriuretic, sympathoexcitatory, and dipsogenic responses. Because these same
      long-term changes occur in association with activation of the renin-angiotensin
      system during the natural evolution of this disease, these results suggest that
      increased plasma levels of ANG II play a critical role in the spontaneous
      transition from compensated to decompensated heart failure.

PMID- 10644626
TI  - Nitric oxide release and contractile properties of skeletal muscles from mice
      deficient in type III NOS.
AB  - Skeletal muscle constitutively expresses both the type I (neuronal) and type III
      (endothelial) isoforms of nitric oxide synthase (NOS). We tested the functional
      importance of type III NOS using skeletal muscles with similar levels of type III
      NOS expression (diaphragm and soleus) from wild-type, heterozygous, and type III
      NOS-deficient littermate mice. Muscles were incubated at 37 degrees C in Krebs
      Ringer solution. NO accumulation in the medium was measured by chemiluminescence;
      force-frequency and fatigue characteristics were measured using direct electrical
      stimulation. Diaphragm and soleus released NO at similar rates during passive
      incubation; these rates increased during active contraction. NO release by type
      III NOS-deficient muscle was not different from that of wild-type muscle under
      any condition tested. Force-frequency and fatigue characteristics also were
      unaffected by genotype. Because type III NOS deficiency did not alter function,
      we conclude that NO effects previously observed in wild-type muscle are likely to
      be mediated by type I NOS.

PMID- 10644627
TI  - Synthesis of gill Na(+)-K(+)-ATPase in Atlantic salmon smolts: differences in
      alpha-mRNA and alpha-protein levels.
AB  - Several parameters were analyzed to determine the mechanisms responsible for the
      enhancement of the gill Na(+)-K(+)-ATPase activity of Atlantic salmon smolts. A
      major alpha-subunit transcript of 3.7 kb was revealed by Northern blot in both
      parr and smolt gills when hybridized with two distinct cDNA probes. The alpha
      mRNA abundance demonstrated an increase to maximal levels in smolts at an early
      stage of the parr-smolt transformation. This was followed by a gradual rise in
      alpha-protein levels, revealed by Western blots with specific antibodies and by
      an increase in gill Na(+)-K(+)-ATPase hydrolytic activity, both only reaching
      maximum levels a month later, at the peak of the transformation process. Parr
      fish experienced a decrease in alpha-mRNA abundance and had basal levels of alpha
      protein and enzyme activity. Measurement of the binding of [(3)H]ouabain to Na(+)
      K(+)-ATPase was characterized in smolts and parr gill membranes showing more than
      a twofold elevation in smolts and was of high affinity in both groups
      (dissociation constant = 20-23 nM). Modulation of the enzyme due to increased
      salinity was also observed in seawater-transferred smolts, as demonstrated by an
      increase in alpha-mRNA levels after 24 h with a rise in Na(+)-K(+)-ATPase
      activity occurring only after 11 days. No qualitative change in alpha-expression
      was revealed at either the mRNA or protein level. Immunological identification of
      the alpha-protein was performed with polyclonal antibodies directed against the
      rat alpha-specific isoforms, revealing that parr, freshwater, and seawater smolts
      have an alpha(3)-like isoform. This study shows that the increase in Na(+)-K(+)
      ATPase activity in smolt gills depends first on an increase in the alpha-mRNA
      expression and is followed by a slower rise in alpha-protein abundance that
      eventually leads to a higher synthesis of Na(+)-K(+) pumps.

PMID- 10644628
TI  - Aging does not contribute to the decline in insulin action on storage of muscle
      glycogen in rats.
AB  - Increase in fat mass (FM) and changes in body composition may account for the age
      associated impairment in insulin action on muscle glycogen storage. We wish to
      examine whether preventing the increase in FM abolishes this defect seen with
      aging. We studied the novel aging model of F1 hybrids of BN/F344 NIA rats fed ad
      libitum (AL) at 2 (weighing 259+/-17 g), 8 (459+/-17 g), and 20 (492+/-10 g) mo
      old. To prevent the age-dependent growth in FM, rats were caloric restricted (CR)
      at 2 mo by decreasing their daily caloric intake by 45% (weighing 292+/-5 g at 8
      mo, 294+/-9 g at 20 mo). As designed, the lean body mass (LBM) and %FM remained
      unchanged through aging (8 and 20 mo old) in the CR rats and was similar to that
      of 2-mo-old AL rats. However, 8- and 20-mo-old AL-fed rats had three- to fourfold
      higher FM than both CR groups. Peripheral insulin action at physiological
      hyperinsulinemia was determined (by 3 mU x kg(-1). min(-1) insulin clamp).
      Prevention of fat accretion maintained glucose uptake (R(d); 29+/-2, 29+/-2, and
      31+/-4 mg x kg LBM(-1) x min(-1)) and glycogen synthesis rates (GS, 12+/-1, 12 +/
      1, and 14+/-2 mg x kg LBM(-1) x min(-1)) at youthful levels (2 mo AL) in 8- and
      20-mo-old CR rats, respectively. These levels were significantly increased
      (P<0.001) compared with AL rats with higher %FM (R(d), 22+/-1 and 22+/-2 and GS,
      7+/-1 and 8+/-2 mg x kg LBM(-1). min(-1) in 8- and 20-mo-old rats, respectively).
      The increase in whole body GS in age-matched CR rats was accompanied by
      approximately 40% increased accumulation of [(3)H] glucose into glycogen and a
      similar increase in insulin-induced muscle glycogen content. Furthermore, the
      activation of glycogen synthase increased, i.e., approximately 50% decrease in
      the Michaelis constant, in both CR groups (P<0.01). We conclude that chronic CR
      designed to prevent an increase in storage of energy in fat maintained peripheral
      insulin action at youthful levels, and aging per se does not result in a defect
      on the pathway of glycogen storage in skeletal muscle.

PMID- 10644629
TI  - Suppression of food intake is linked to enteric inflammation in nematode-infected
      rats.
AB  - Our aim was to investigate the cause-effect relationship between intestinal
      inflammation induced by infection with enteric stages of Trichinella spiralis and
      decreased host food intake. A suppression of food intake in T. spiralis-infected
      rats occurred within the first 24 h postinfection (PI) and was maximized by day 6
      PI. Food intake, cumulated over an 8-day PI period, decreased by 59% compared
      with uninfected animals. The anti-inflammatory glucocorticoid betamethasone 21
      phosphate was orally administered to rats in their drinking water to suppress T.
      spiralis-induced jejunal inflammation. When treated with a low dose of
      glucocorticoid (5.2 microg/ml), food intake in infected rats was still
      significantly reduced, but only by 21% compared with glucocorticoid-treated,
      uninfected rats. At the highest glucocorticoid dose (10.4 microg/ml)
      administered, infection-induced reduction in food intake was not different from
      that of glucocorticoid-treated, uninfected counterparts. The elevation in jejunal
      myeloperoxidase activity caused by infection was also significantly blunted by
      oral glucocorticoid treatment. Our results suggest that suppressed host food
      intake during enteric T. spiralis infection is directly linked to intestinal
      inflammation.

PMID- 10644630
TI  - Compensatory sleep response to 12 h wakefulness in young and old rats.
AB  - There is a pronounced decline in sleep with age. Diminished output from the
      circadian oscillator, the suprachiasmatic nucleus, might play a role, because
      there is a decrease in the amplitude of the day-night sleep rhythm in the
      elderly. However, sleep is also regulated by homeostatic mechanisms that build
      sleep drive during wakefulness, and a decline in these mechanisms could also
      decrease sleep. Because this question has never been addressed in old animals,
      the present study examined the effects of 12 h wakefulness on compensatory sleep
      response in young (3.5 mo) and old (21.5 mo) Sprague-Dawley and F344 rats. Old
      rats in both strains had a diminished compensatory increase in slow-wave sleep
      (SWS) after 12 h of wakefulness (0700-1900, light-on period) compared with the
      young rats. In contrast, compensatory REM sleep rebound was unaffected by age. To
      assess whether the reduced SWS rebound in old rats might result from loss of
      neurons implicated in sleep generation, we counted the number of c-Fos
      immunoreactive (c-Fos-ir) cells in the ventral lateral preoptic (VLPO) area and
      found no differences between young and old rats. These findings indicate that old
      rats, similar to elderly humans, demonstrate less sleep after prolonged
      wakefulness. The findings also indicate that although old rats have a decline in
      sleep, this cannot be attributed to loss of VLPO neurons implicated in sleep.

PMID- 10644631
TI  - Effects of food deprivation on daily changes in body temperature and behavioral
      thermoregulation in rats.
AB  - Homeothermic animals regulate body temperature (T(b)) by using both autonomic and
      behavioral mechanisms. In the latter process, animals seek out cooler or warmer
      places when they are exposed to excessively hot or cold environments.
      Thermoregulation is affected by the state of energy reserves in the body. In the
      present study, we examine the effects of 4-day food deprivation on circadian
      changes in T(b) and on cold-escape and heat-escape behaviors in rats. Continuous
      measurement of T(b) during food deprivation indicated that the peak T(b)
      amplitude was not different from baseline values, but the trough amplitude
      continuously decreased after the onset of food deprivation. Cold-escape behavior
      was facilitated by food deprivation, whereas heat-escape behavior was unchanged.
      After the termination of food deprivation, the lowered T(b) returned to normal on
      the first day. However, cold-escape behavior was still facilitated on the third
      day after food reintroduction. Autonomic and behavioral thermoregulatory
      effectors are modulated in the face of food shortage so as to maintain optimal
      performance during the active period, whereas increasing energy conservation
      occurs during the quiescent phase.

PMID- 10644632
TI  - Myotubes originating from single fast and slow satellite cells display similar
      patterns of AChE expression.
AB  - Slow- and fast-contracting skeletal muscles of both rats and mice display
      significant differences in their patterns of acetylcholinesterase (AChE)
      expression. Although neural influences are known to account for a large
      proportion of these differences, intrinsic variations between fast and slow
      myogenic precursor cells have been implicated. In the present study, we have
      capitalized on the use of Immorto transgenic mice to obtain single myogenic
      precursor cells isolated from either slow or fast muscle fibers and determined
      whether these cells generated myotubes that produced distinct patterns of AChE
      expression as observed in vivo between slow and fast muscles. These two myotube
      populations displayed similar cell-associated and secreted AChE enzyme activity
      as well as comparable levels of AChE transcripts. Both myotube populations also
      expressed nearly identical molecular form profiles. By contrast, AChE activity
      and transcript levels were approximately two- and fivefold greater in fast
      skeletal muscles compared with slow ones. Together, these findings indicate that
      differences in AChE expression between fast and slow muscles are not due to
      inherent differences in myogenic precursor cells, thereby suggesting that other
      factors, such as innervation, play a predominant role in establishing the
      distinct patterns of AChE expression in these muscle types.

PMID- 10644633
TI  - Pregnancy alters cardiac receptor afferent discharge in rats.
AB  - Reflex effects of cardiac receptor (CR) stimulation are attenuated in pregnant
      rats. We tested whether CR afferent discharge is reduced during pregnancy by
      measuring single fiber activity in response to increases in right atrial pressure
      (RAP) in anesthetized pregnant and virgin rats with sinoaortic denervation.
      Single fiber activity was isolated from fine filaments of the right cervical
      vagus nerve. Changes in CR discharge, RAP, and arterial pressure were recorded in
      response to atrial saline injections (25-300 microl). Resting RAP was similar
      between groups, and spontaneous CR discharge was similar in pregnant rats (1.95+/
      0.21 Hz) and in low-frequency (LF) receptors in virgin rats (1.30+/-0.2 Hz). In
      virgin, but not pregnant rats, a subset (24%) of CR had higher-frequency (HF)
      spontaneous discharge (9.91+/-1.19 Hz). During stimulation, the level of RAP
      above which CR firing increased was significantly higher in pregnant rats, but CR
      activity was clustered into an LF discharge range. Thus gestation appears to
      reduce the activity of CR afferents, possibly by increasing stimulus threshold or
      by selective inactivation of a subset of HF discharging receptors.

PMID- 10644634
TI  - Role of hypothermia induced by tumor necrosis factor on apoptosis and function of
      inflammatory neutrophils in mice.
AB  - Changes in body temperature and cell infiltration, mediated by cytokines
      including tumor necrosis factor-alpha (TNF-alpha), occur during inflammation, but
      a role of body temperature on inflammatory responses remains obscure.
      Intraperitoneal injection of 10% casein to mice resulted in transient hypothermia
      followed by neutrophil accumulation in peritoneal cavities. Peritoneal TNF-alpha
      was rapidly raised, and pretreatment of mice with an anti-TNF-alpha antibody
      promoted temperature restoration and partially inhibited neutrophil accumulation.
      To investigate direct effects of body temperature on neutrophils, peritoneal or
      peripheral blood neutrophils were cultured at 35 degrees C or 37 degrees C with
      or without recombinant murine TNF-alpha (100 ng/ml) or a protein synthesis
      inhibitor cycloheximide (1 microg/ml). Significant inhibition of spontaneous and
      TNF-alpha-induced apoptosis was obtained at 35 degrees C compared with 37 degrees
      C, an effect that was not altered by the addition of cycloheximide. Moreover,
      phagocytic ability of peritoneal neutrophils was significantly enhanced by
      incubating them at the lower temperature. These results indicate that mild
      hypothermia induced by endogenous TNF-alpha has enhancing roles on neutrophil
      survival and function during peritoneal inflammation.

PMID- 10644635
TI  - Adaptation to high-fat diet reduces inhibition of gastric emptying by CCK and
      intestinal oleate.
AB  - Rats maintained on low-fat (LF) or high-fat (HF) diets were fitted with gastric
      cannulas and duodenal catheters. Intraperitoneal injection of 0.250-2.0 microg/kg
      cholecystokinin (CCK) significantly inhibited gastric emptying of a 5-ml NaCl
      load in LF rats by 26.2-55. 1% compared with emptying after vehicle injection. By
      contrast, CCK-induced inhibition of gastric emptying was significantly less in HF
      rats given the same CCK doses (10.0-31.7% inhibition over the same CCK dose
      range). A 20-min intraduodenal infusion of oleate (0.03 or 0.06 kcal/ml) also
      resulted in significant inhibition of gastric emptying in LF rats (24 and 89%,
      respectively). Oleate-induced inhibition of gastric emptying was significantly
      attenuated in rats maintained on the HF diet (2 and 56%, respectively). Unlike
      CCK injections or oleate infusion, intraduodenal maltotriose infusion inhibited
      gastric emptying to a similar degree in LF and HF rats (77 and 78%,
      respectively). These results indicate that feeding HF diets diminishes the
      enterogastric inhibition of gastric emptying by intestinal oleate and diminishes
      the ability of CCK to inhibit gastric emptying.

PMID- 10644636
TI  - Effect of cardiac receptor stimulation on renal vascular resistance in the
      pregnant rat.
AB  - Stimulation of cardiac receptors (CR) evokes blunted reflex reductions in mean
      arterial pressure (MAP) in pregnant compared with virgin rats. Because CR
      mediated sympathoinhibition has preferential effects on the kidney, we tested
      whether, during pregnancy, renal vascular resistance (RVR) changes less in
      response to CR stimulation and investigated possible mechanisms. MAP, right
      atrial pressure, renal sympathetic nerve activity (RSNA), renal blood flow (RBF),
      and RVR were measured in anesthetized animals in response to CR stimulation by
      graded atrial injections of saline. Baseline MAP and RVR and reflex changes in
      these variables during CR stimulation were reduced in late-pregnant vs. virgin
      rats (P<0.05). Reflex changes in RSNA were attenuated in pregnant rats, but
      changes in RBF as a function of RSNA were similar in both groups. ANG II AT(1)
      receptor blockade increased basal RBF more in virgin rats (P<0.05), but between
      group differences in reflex changes in MAP, RSNA, and RVR were maintained after
      AT(1) blockade. Thus during CR simulation, reflex changes in RVR were reduced in
      pregnant versus virgin rats. This difference does not appear to involve
      differential effects of ANG II.

PMID- 10644637
TI  - Identification of the conjugated linoleic acid isomer that inhibits milk fat
      synthesis.
AB  - Conjugated linoleic acids (CLA) are octadecadienoic fatty acids that have
      profound effects on lipid metabolism. Our previous work showed that CLA (mixture
      of isomers) markedly reduced milk fat synthesis. In this study, our objective was
      to evaluate the effects of specific CLA isomers. Multiparous Holstein cows were
      used in a 3x3 Latin square design, and treatments were 4-day abomasal infusions
      of 1) skim milk (control), 2) 9,11 CLA supplement, and 3) 10,12 CLA supplement.
      CLA supplements provided 10 g/day of the specific CLA isomer (cis-9,trans-11 or
      trans-10,cis-12). Treatments had no effect on intake, milk yield, or milk protein
      yield. Only the 10,12 CLA supplement affected milk fat, causing a 42 and 44%
      reduction in milk fat percentage and yield, respectively. Milk fat composition
      revealed that de novo synthesized fatty acids were extensively reduced. Increases
      in ratios of C(14:0) to C(14:1) and C(18:0) to C(18:1) indicated the 10,12 CLA
      supplement also altered Delta(9)-desaturase. Treatments had minimal effects on
      plasma concentrations of glucose, nonesterified fatty acids, insulin, or insulin
      like growth factor-I. Overall, results demonstrate that trans-10,cis-12 CLA is
      the isomer responsible for inhibition of milk fat synthesis.

PMID- 10644638
TI  - Effects of feeding on metabolism, gas transport, and acid-base balance in the
      bullfrog Rana catesbeiana.
AB  - Massive feeding in ectothermic vertebrates causes changes in metabolism and acid
      base and respiratory parameters. Most investigations have focused on only one
      aspect of these complex changes, and different species have been used, making
      comparison among studies difficult. The purpose of the present study was,
      therefore, to provide an integrative study of the multiple physiological changes
      taking place after feeding. Bullfrogs (Rana catesbeiana) partly submerged in
      water were fed meals (mice or rats) amounting to approximately (1)/(10) of their
      body weight. Oxygen consumption increased and peaked at a value three times the
      predigestive level 72-96 h after feeding. Arterial PO(2) decreased slightly
      during digestion, whereas hemoglobin-bound oxygen saturation was unaffected. Yet,
      arterial blood oxygen content was pronouncedly elevated because of a 60% increase
      in hematocrit, which appeared mediated via release of red blood cells from the
      spleen. Gastric acid secretion was associated with a 60% increase in plasma HCO3(
      ) concentration ([HCO3(-)]) 48 h after feeding. Arterial pH only increased from
      7.86 to 7.94, because the metabolic alkalosis was countered by an increase in
      PCO(2) from 10.8 to 13.7 mm Hg. Feeding also induced a small intracellular
      alkalosis in the sartorius muscle. Arterial pH and HCO3(-) returned to control
      values 96-120 h after feeding. There was no sign of anaerobic energy production
      during digestion as plasma and tissue lactate levels remained low and
      intracellular ATP concentration stayed high. However, phosphocreatine was reduced
      in the sartorius muscle and ventricle 48 h after feeding.

PMID- 10644639
TI  - Behavioral components of high-fat diet hyperphagia: meal size and postprandial
      satiety.
AB  - Previously, rats fed a high-fat liquid diet (HF) ad libitum consumed more
      kilocalories and had greater weight gain than rats fed a liquid high-carbohydrate
      diet (HC) of equivalent energy density (Warwick, Z. S., and H. P. Weingarten. Am.
      J. Physiol. Regulatory Integrative Comp. Physiol. 269: R30-R37, 1995). The
      present series of experiments sought to clarify the behavioral expression of HF
      hyperphagia by comparing HF and HC with regard to meal size and magnitude of
      postingestive satiety effect. Meal size of HF was greater than HC at 2.3 kcal/ml
      and also when diets were formulated at 1.15 kcal/ml. In a preload-test meal
      paradigm, an orally consumed HF preload was less satiating than a calorically
      equivalent HC preload across a range of preload volumes and intermeal intervals.
      Sensory-specific satiety was ruled out as an explanation of the relatively
      greater intake of test meal after an HF preload meal; an intragastrically
      delivered HF preload was less satiating than intragastric HC. Furthermore, a fat
      (corn oil emulsion) preload was less satiating than a carbohydrate (sucrose)
      preload when an evaporated milk test meal was used. These findings indicate that
      hyperphagia on an HF diet is expressed in increased meal size and decreased
      intermeal interval.

PMID- 10644640
TI  - Bright light during lactation alters the functioning of the circadian system of
      adult rats.
AB  - To examine the role of light in the maturation of the circadian pacemaker, twelve
      groups of rats were raised in different conditions of exposure to constant bright
      light (LL) during lactation: both duration and timing of LL were varied. We
      studied the motor activity rhythm of the rats after weaning, first under LL and
      then under constant darkness (DD). In DD, two light pulses [at circadian time 15
      (CT15) and CT22] were applied to test the response of the pacemaker. Greater
      exposure to LL days during lactation increased the number of rhythmic animals and
      the amplitude of their motor activity rhythm in the LL stage and decreased the
      phase delay due to the light pulse at CT15. The timing of LL during lactation
      affected these variables too. Because the response of the adult to light depended
      on both the number and timing of LL days during lactation, the exposure to light
      at early stages may influence the development of the circadian system by
      modifying it structurally or functionally.

PMID- 10644641
TI  - Expression of heat shock proteins in turtle and mammal hearts: relationship to
      anoxia tolerance.
AB  - Heat shock proteins (HSPs) may play a cardioprotective role during hypoxia or
      ischemia. We hypothesized that cardiac tissue from hypoxia-tolerant animals might
      have high levels of specific HSPs. We measured myocardial HSP60 and HSP72/73 in
      painted and softshell turtles during normoxia and anoxia (12 h) and after
      recovery (12 or 24 h). We also measured myocardial HSPs in normoxic rats and
      rabbits. During normoxia, hearts from the most highly anoxia-tolerant species,
      the painted turtle, expressed the highest levels of HSP60 (22.6+/-2.0 mg/g total
      protein) followed by softshells (11.5+/-0.8 mg/g), rabbits (6.8+/-0.9 mg/g), and
      rats (4.5+/-0.5 mg/g). HSP72/73 levels, however, were not significantly
      different. HSP60 levels in hearts from both painted and softshell turtles did not
      deviate significantly from control values after either 12 h of anoxia or 12 or 24
      h of recovery. The pattern of changes observed in HSP72/73 was quite different in
      the two turtle species. In painted turtles anoxia induced a significant increase
      in myocardial HSP72/73 (from 2.8+/-0.1 mg/g normoxic to 3.9+/-0.2 mg/g anoxic,
      P<0.05). By 12 h of recovery, HSP72/73 had returned to control levels (2.7+/-0.1
      mg/g) and remained there through 24 h (2.6+/-0.2 mg/g). In softshell turtles,
      HSP72/73 decreased significantly after 12 h of anoxia (from 2.4+/-0.4 mg/g
      normoxic to 1.3+/-0.2 mg/g anoxic, P<0.05). HSP72/73 levels were still slightly
      below control after 12 h of recovery (2.1+/-0.1 mg/g) and then rose to
      significantly above control after 24 h of recovery (4.1+/-0.7 mg/g, P<0.05). We
      also conclude that anoxia-tolerant and anoxia-sensitive turtles exhibit different
      patterns of myocardial HSP changes during anoxia and recovery. Whether these
      changes correlate with their relative degrees of anoxia tolerance remains to be
      determined.

PMID- 10644642
TI  - Short-term and long-term blood pressure and heart rate variability in the mouse.
AB  - Knowledge on murine blood pressure and heart rate control mechanisms is limited.
      With the use of a tethering system, mean arterial pressure (MAP) and pulse
      interval (PI) were continuously recorded for periods up to 3 wk in Swiss mice.
      The day-to-day variation of MAP and PI was stable from 5 days after surgery.
      Within each mouse (n = 9), MAP and PI varied by 21+/-6 mm Hg and 17+/-4 ms around
      their respective 24-h averages (97+/-3 mm Hg and 89+/-3 ms). Over 24-h periods,
      MAP and PI were bimodally distributed and clustered around two preferential
      states. Short-term variability of MAP and PI was compared between the resting
      (control) and active states using spectral analysis. In resting conditions,
      variability of MAP was mainly confined to frequencies <1 Hz, whereas variability
      of PI was predominantly linked to the respiration cycle (3-6 Hz). In the active
      state, MAP power increased in the 0.08- to 3-Hz range, whereas PI power fell in
      the 0.08- to 0.4-Hz range. In both conditions, coherence between MAP and PI was
      high at 0.4 Hz with MAP leading the PI fluctuations by 0.3-0.4 s, suggesting that
      reflex coupling between MAP and PI occurred at the same frequency range as in
      rats. Short-term variability of MAP and PI was studied after intravenous
      injection of autonomic blockers. Compared with the resting control state, MAP
      fell and PI increased after ganglionic blockade with hexamethonium. Comparable
      responses of MAP were obtained with the alpha-blocker prazosin, whereas the beta
      blocker metoprolol increased PI similarly. Muscarinic blockade with atropine did
      not significantly alter steady-state levels of MAP and PI. Both hexamethonium and
      prazosin decreased MAP variability in the 0.08- to 1-Hz range. In contrast, after
      hexamethonium and metoprolol, PI variability increased in the 0.4- to 3-Hz range.
      Atropine had no effect on MAP fluctuations but decreased those of PI in the 0.08-
      to 1-Hz range. These data indicate that, in mice, blood pressure and its
      variability are predominantly under sympathetic control, whereas both vagal and
      sympathetic nerves control PI variability. Blockade of endogenous nitric oxide
      formation by N(G)-nitro-L-arginine methyl ester increased MAP variability
      specifically in the 0.08- to 0.4-Hz range, suggesting a role of nitric oxide in
      buffering blood pressure fluctuations.

PMID- 10644643
TI  - Oxytocin-induced renin secretion in conscious rats.
AB  - Arterial hypotension and hypovolemia are known to stimulate neurohypophysial
      secretion of oxytocin (OT) in rats, although the physiological function of OT
      under these circumstances is uncertain. We now report that OT infused
      intravenously into conscious rats at 125 ng x kg(-1) x h(-1), a dose selected to
      mimic plasma OT levels during hypotension or hypovolemia, increased plasma renin
      concentration and plasma renin activity by twofold. This effect was prevented by
      systemic pretreatment with an OT receptor antagonist [[1-(3-mercaptopropionic
      acid)-2-O-ethyl-D-Tyr-Thr(4)-Orn(8)]-OT]. The OT antagonist did not block renin
      secretion induced by systemic injection of the beta-adrenergic receptor agonist
      isoproterenol, indicating that the OT antagonist does not interfere
      nonselectively with renin release. Pretreatment of rats with the beta-adrenergic
      receptor antagonist nadolol also prevented OT-induced renin secretion. Similarly,
      nadolol injected during infusion of OT markedly reduced the elevated plasma renin
      levels. These observations raise the possibility that pituitary OT secretion
      during hypotension or hypovolemia in rats may serve to support blood pressure by
      enhancing activation of the renin-angiotensin system via a beta-adrenergic
      receptor-dependent mechanism.

PMID- 10644644
TI  - Defense of body weight against chronic caloric restriction in obesity-prone and 
      resistant rats.
AB  - Half of Sprague-Dawley rats develop and defend diet-induced obesity (DIO) or diet
      resistance (DR) when fed a high-energy (HE) diet. Here, adult male rats were made
      DIO or DR after 10 wk on HE diet. Then half of each group was food restricted for
      8 wk on chow to maintain their body weights at 90% of their respective baselines.
      Rate and magnitude of weight loss were comparable, but maintenance energy intake
      and the degree of sympathetic activity (24-h urine norepinephrine) inhibition
      were 17 and 29% lower, respectively, in restricted DR than DIO rats. Restricted
      DIO rats reduced adipose depot weights, plasma leptin, and insulin levels by 35%.
      Restricted DR rats reduced none of these. When fed ad libitum, both DR and DIO
      rats returned to the body weights of their respective chow-fed phenotype controls
      within 2 wk. This was associated with increased adipose mass and leptin and
      insulin levels only in DIO rats. Thus DR rats appear to alter primarily their
      lean body mass, whereas DIO rats primarily alter their adipose mass during
      chronic caloric restriction and refeeding.

PMID- 10644645
TI  - Influence of temperature on activity of the isolated whole bladder preparation of
      neonatal and adult rats.
AB  - The temperature sensitivity of in vitro whole bladder preparations from neonatal
      and adult rats with or without chronic partial urethral obstruction was
      investigated. After the bladder was filled to a volume eliciting isovolumetric
      contractions, temperature was changed between 19 and 38 degrees C. In all
      preparations, higher temperatures were associated with higher frequencies of
      spontaneous intravesical pressure waves (IVPW). In 1- to 2-wk-old neonates, IVPW
      amplitude increased as the temperature increased; however, in older neonates and
      normal adults, the opposite occurred. The transition period was at 3 wk of age
      when bladder volume also markedly increased. At this age as well as in adult rats
      with outlet obstruction, changing temperature had little influence on the
      amplitude of IVPW. Thus obstructed outlet bladders and 3-wk-old bladders had
      similar properties. It is concluded that the properties of bladder muscle are
      changed during postnatal maturation and that in 3-wk-old rats, when brain control
      of voiding is emerging, micturition is abnormal, leading to obstructive changes
      in bladder muscle.

PMID- 10644646
TI  - Expression of CD44 in kidney after acute ischemic injury in rats.
AB  - De novo CD44 and ligand expression at wound margins accompanies cellular
      proliferation and migration that effect repair of injured mucosal and vascular
      endothelial tissues. To determine whether CD44 could play a role in recovery from
      acute ischemic renal injury, we characterized its renal expression and those of
      two of its ligands, hyaluronic acid and osteopontin. Although no expression is
      detectable in nonischemic kidneys, several mRNAs for CD44 are present within 1
      day after injury. CD44 mRNA is expressed in proximal tubules undergoing repair.
      CD44 peptide is present in basal and lateral cell membranes. Hyaluronic acid is
      normally expressed in the interstitium of the renal papilla only. By 1 day
      postischemia, hyaluronic acid can be detected, in addition, in the interstitium
      surrounding regenerating tubules. Osteopontin, not normally expressed in the
      renal proximal tubule, is expressed in regenerating tubules by 3 days after
      induction of acute ischemic injury. Immunoreactive osteopontin peptide continues
      to be localized in those tubules still undergoing repair for as long as 7 days
      after the injury. Our data are consistent with a role for CD44-ligand
      interactions in the regenerating proximal tubule participating in the process of
      recovery after ischemic injury.

PMID- 10644647
TI  - Concurrent reductions in blood pressure and metabolic rate during fasting in the
      unrestrained SHR.
AB  - Fasting produces multiple cardiovascular, metabolic, and behavioral responses. To
      examine the interrelationship between these responses, male spontaneously
      hypertensive rats (SHR; n = 8) implanted with cardiovascular telemetry devices
      were housed in metabolic chambers at 23 degrees C for 22-h daily measurements of
      physiological variables. The experimental apparatus was designed so that
      ingestive behavior was detected by photobeams and locomotion was detected by a
      load sensor. Cardiovascular and metabolic status were determined as both a
      function of the circadian cycle (12-h dark and 10-h light), as well as during
      periods of inactivity (no ingestion and minimal locomotion) within the dark and
      light phases. Data were obtained during baseline, 48-h of caloric deprivation,
      and 6 days of refeeding. Fasting produced significant reductions in mean arterial
      pressure (dark: -9.2+/-1.3 from 143.7+/-3.7 mm Hg; light: -8.6+/-1.8 from 140.1+/
      3.7 mm Hg), heart rate (dark: -43.4+/-5.2 from 330.0+/-5.2 beats/min; light: 
      27.4+/-5.2 from 294.0+/-5.2 beats/min), and oxygen consumption (dark: -5.0+/-0.6
      from 20.6+/-0.3 ml x min(-1) x kg (0.75); light: -2.7+/-0.2 from 14.9 +/-0.2 ml x
      min(-1) x kg(0.75)). Analysis of inactive periods during both light and dark
      phases revealed that these reductions were not dependent on behavioral effects.
      We conclude that fasting produces concurrent and interrelated reductions in
      cardiovascular and metabolic function in the SHR. The merging of cardiovascular
      telemetry, indirect calorimetry, and behavioral monitoring provides a powerful
      approach for investigation of the integrative physiological responses to
      energetic challenges.

PMID- 10644648
TI  - Interleukin-1beta deficiency results in reduced NF-kappaB levels in pregnant
      mice.
AB  - Interleukin (IL)-1beta-deficient (IL-1beta(-/-)) mice were assessed for cytokine
      production during pregnancy. A significant reduction in nuclear factor (NF)
      kappaB p65 protein content was observed in the uteri and spleens of pregnant IL
      1beta(-/-) mice, as demonstrated by immunohistochemistry and Western immunoblot
      analysis. In addition, electromobility gel shift assay revealed less DNA binding
      activity of NF-kappaB p65-containing complex in pregnant IL-1beta(-/-) mice. To
      investigate differences in cytokine production regulated by NF-kappaB, the levels
      of tumor necrosis factor-alpha, macrophage inflammatory protein-1alpha, and
      interferon-gamma were measured in the uterine wall, spleen homogenates, and
      spleen cell cultures obtained from pregnant mice. Endocervical administration of
      lipopolysaccharide (LPS) increased cytokine levels in both wild-type (IL
      1beta(+/+)) and IL-1beta(-/-) animals, but in IL-1beta(-/-) mice this response
      was 50-75% lower. Splenocytes from nonpregnant mice exhibited decreased LPS
      induced cytokine production when primed in vitro with progesterone. This
      suppression was 25% greater in IL-1beta(-/-) than in IL-1beta(+/+) mice. These
      data suggest that constitutive NF-kappaB p65 protein synthesis is regulated by IL
      1beta, particularly during pregnancy.

PMID- 10644649
TI  - Photoperiod regulates arcuate nucleus POMC, AGRP, and leptin receptor mRNA in
      Siberian hamster hypothalamus.
AB  - Siberian hamsters decreased body weight by 30% during 18 wk in short day (SD) vs.
      long day (LD) controls. Subsequent imposed food deprivation (FD; 24 h) caused a
      further 10% decrease. In the hypothalamic arcuate nucleus (ARC), SDs reduced
      proopiomelanocortin (POMC) gene expression and agouti-related protein (AGRP) mRNA
      was elevated, changes that summate to reduced catabolic drive through the
      melanocortin receptors. There was no effect of photoperiod on neuropeptide Y
      (NPY), melanin concentrating hormone, orexin, or corticotropin-releasing factor
      mRNAs. Superimposed FD increased AGRP gene expression and caused a localized
      elevation of NPY mRNA in the ARC. Both adipose tissue leptin and ARC leptin
      receptor (OB-Rb) mRNAs were downregulated in SDs, whereas FD increased OB-Rb gene
      expression. Thus OB-Rb mRNA is differentially regulated by acute and chronic
      changes in plasma leptin in this species. In a separate experiment in LDs, AGRP
      gene expression was increased by 24 or 48 h FD, whereas POMC mRNA was
      downregulated in the caudal ARC. AGRP and NPY mRNAs were extensively coexpressed
      in the ARC, and their differential regulation by photoperiod and FD is suggestive
      of transcript-specific regulation at the level of individual neurons.

PMID- 10644650
TI  - Circadian rhythms in the chemoreflex control of breathing.
AB  - Mechanisms underlying the circadian rhythm in lung ventilation were investigated.
      Ten healthy male subjects were studied for 36 h using a constant routine protocol
      to minimize potentially confounding variables. Laboratory light, humidity, and
      temperature remained constant, subjects did not sleep, and their meals and
      activities were held to a strict schedule. Respiratory chemoreflex responses were
      measured every 3 h using an iso-oxic rebreathing technique incorporating prior
      hyperventilation. Subjects exhibited circadian rhythms in oral temperature and
      respiratory chemoreflex responses, but not in metabolic rate. Basal ventilation
      [i.e., at subthreshold end-tidal carbon dioxide partial pressure (PET(CO(2)))]
      did not vary with time of day, but the ventilatory response to suprathreshold
      PET(CO(2)) exhibited a rhythm amplitude of approximately 25%, mediated mainly by
      circadian variations in the CO(2) threshold for tidal volume. We conclude that
      the circadian rhythm in lung ventilation is not a simple consequence of circadian
      variations in arousal state and metabolic rate. By raising the chemoreflex
      threshold, the circadian timing system may increase the propensity for
      respiratory instability at night.

PMID- 10644651
TI  - Acute renal failure. II. Experimental models of acute renal failure: imperfect
      but indispensable.
AB  - Acute renal failure (ARF) due to ischemic or toxic renal injury, a clinical
      syndrome traditionally referred to as acute tubular necrosis (ATN), is a common
      disease with a high overall mortality of approximately 50%. Little progress has
      been made since the advent of dialysis more than 30 years ago in improving this
      outcome. During this same period, a considerable amount of basic research has
      been devoted to elucidating the pathophysiology of ATN. The ultimate goal of this
      research is to facilitate the development of therapeutic interventions that
      either prevent ARF, ameliorate the severity of tubular injury following an acute
      ischemic or toxic renal insult, or accelerate the recovery of established ATN.
      This research endeavor has been highly successful in elucidating many vascular
      and tubular abnormalities that are likely to be involved in ischemic and toxic
      ARF. This information has led to impressive advances in the development of a
      number of different pharmacological interventions that are highly effective in
      ameliorating the renal dysfunction in animal models of ARF. Although these
      developments are exciting and promising, enthusiasm of investigators involved in
      this endeavor has been tempered somewhat by the results of a few recent clinical
      studies of patients with ATN. These trials, designed to examine the efficacy in
      humans of some of the interventions effective in animal models of ARF, have
      resulted in little or no benefit. This is therefore an important time to
      reevaluate the approaches we have taken over the past three to four decades to
      develop new and effective treatments for ATN in humans. The major goals of this
      review are 1) to evaluate the relevance and utility of the experimental models
      currently available to study ischemic and toxic renal injury, 2) to suggest novel
      experimental approaches and models that have the potential to provide advantages
      over methods currently available, 3) to discuss ways of integrating results
      obtained from different experimental models of acute renal injury and of
      evaluating the relevance of these findings to ATN in humans, and 4) to discuss
      the difficulties inherent in clinical studies of ATN and to suggest how studies
      should be best designed to overcome these problems.

PMID- 10644652
TI  - Structure and function of aquaporin water channels.
AB  - The aquaporins (AQPs) are a family of small membrane-spanning proteins (monomer
      size approximately 30 kDa) that are expressed at plasma membranes in many cells
      types involved in fluid transport. This review is focused on the molecular
      structure and function of mammalian aquaporins. Basic features of aquaporin
      structure have been defined using mutagenesis, epitope tagging, and spectroscopic
      and freeze-fracture electron microscopy methods. Aquaporins appear to assemble in
      membranes as homotetramers in which each monomer, consisting of six membrane
      spanning alpha-helical domains with cytoplasmically oriented amino and carboxy
      termini, contains a distinct water pore. Medium-resolution structural analysis by
      electron cryocrystallography indicated that the six tilted helical segments form
      a barrel surrounding a central pore-like region that contains additional protein
      density. Several of the mammalian aquaporins (e.g., AQP1, AQP2, AQP4, and AQP5)
      appear to be highly selective for the passage of water, whereas others (recently
      termed aquaglyceroporins) also transport glycerol (e.g., AQP3 and AQP8) and even
      larger solutes (AQP9). Evidence for possible movement of ions and carbon dioxide
      through the aquaporins is reviewed here, as well as evidence for direct
      regulation of aquaporin function by posttranslational modification such as
      phosphorylation. Important unresolved issues include definition of the molecular
      pathway through which water and solutes move, the nature of monomer-monomer
      interactions, and the physiological significance of aquaporin-mediated solute
      movement. Recent results from knockout mice implicating multiple physiological
      roles of aquaporins suggest that the aquaporins may be suitable targets for drug
      discovery by structure-based and/or high-throughput screening strategies.

PMID- 10644653
TI  - Localization and regulation of PKA-phosphorylated AQP2 in response to V(2)
      receptor agonist/antagonist treatment.
AB  - Phosphorylation of Ser(256), in a PKA consensus site, in AQP2 (p-AQP2) appears to
      be critically involved in the vasopressin-induced trafficking of AQP2. In the
      present study, affinity-purified antibodies that selectively recognize AQP2
      phosphorylated at Ser(256) were developed. These antibodies were used to
      determine 1) the subcellular localization of p-AQP2 in rat kidney and 2) changes
      in distribution and/or levels of p-AQP2 in response to [desamino-Cys(1),D
      Arg(8)]vasopressin (DDAVP) treatment or V(2)-receptor blockade. Immunoelectron
      microscopy revealed that p-AQP2 was localized in both the apical plasma membrane
      and in intracellular vesicles of collecting duct principal cells. Treatment of
      rats with V(2)-receptor antagonist for 30 min resulted in almost complete
      disappearance of p-AQP2 labeling of the apical plasma membrane with only marginal
      labeling of intracellular vesicles remaining. Immunoblotting confirmed a marked
      decrease in p-AQP2 levels. In control Brattleboro rats (BB), lacking vasopressin
      secretion, p-AQP2 labeling was almost exclusively present in intracellular
      vesicles. Treatment of BB rats with DDAVP for 2 h induced a 10-fold increase in p
      AQP2 labeling of the apical plasma membrane. The overall abundance of p-AQP2,
      however, was not increased, as determined both by immunoelectron microscopy and
      immunoblotting. Consistent with this, 2 h of DDAVP treatment of normal rats also
      resulted in unchanged p-AQP2 levels. Thus the results demonstrate that AQP2
      phosphorylated in Ser(256) is present in the apical plasma membrane and in
      intracellular vesicles and that both the intracellular distribution/trafficking,
      as well as the abundance of p-AQP2, are regulated via V(2) receptors by altering
      phosphorylation and/or dephosphorylation of Ser(256) in AQP2.

PMID- 10644654
TI  - Cellular localization of P2Y(2) purinoceptor in rat renal inner medulla and lung.
AB  - Physiological and pharmacological studies have demonstrated that extracellular
      ATP, acting through P2Y(2) purinoceptor, modulates water permeability of renal
      medullary collecting duct cells and the secretion of ions, mucin, and surfactant
      phospholipids by respiratory epithelia. Here we provide direct molecular evidence
      for the expression of P2Y(2) purinoceptor in these cells. RT-PCR confirmed P2Y(2)
      purinoceptor mRNA expression in rat lung and kidney and demonstrated expression
      in renal collecting ducts. Northern analysis showed that both lung and kidney
      express one 3.6-kb P2Y(2) purinoceptor mRNA transcript. Immunoblots using peptide
      derived polyclonal antibody to P2Y(2) purinoceptor showed that inner medullary
      collecting ducts (IMCD) express two distinct and specific products (47 and 105
      kDa) and account for the majority of the receptor expression in inner medulla,
      whereas the 105-kDa form is predominant in lung. Immunoperoxidase labeling on
      cryosections showed localization of receptor protein in the apical and
      basolateral domains of IMCD principal cells and in the secretory cells (Clara
      cells and goblet cells) of the terminal respiratory bronchioles.

PMID- 10644655
TI  - UT-A2: a 55-kDa urea transporter in thin descending limb whose abundance is
      regulated by vasopressin.
AB  - The renal urea transporter gene (UT-A) produces different transcripts in the
      inner medullary collecting ducts (UT-A1) and thin descending limbs of Henle's
      loop (UT-A2), coding for distinct proteins. Peptide-directed rabbit polyclonal
      antibodies were used to identify the UT-A2 protein in renal medulla of mouse and
      rat. In the inner stripe of outer medulla, an antibody directed to the COOH
      terminus of UT-A recognized a membrane protein of 55 kDa. The abundance of this
      55-kDa protein was strongly increased in response to chronic infusion of the
      vasopressin analog 1-deamino-[8-D-arginine]vasopressin (DDAVP) in Brattleboro
      rats, consistent with previous evidence that UT-A2 mRNA abundance is markedly
      increased. Immunofluorescence labeling with the COOH-terminal antibody in
      Brattleboro rats revealed labeling in the lower portion of descending limbs from
      short-looped nephrons (in the aquaporin-1-negative portion of this segment). This
      UT-A labeling was increased in response to DDAVP. Increased labeling was also
      seen in descending limbs of long-looped nephrons in the base of the inner
      medulla. These results indicate that UT-A2 is expressed as a 55-kDa protein in
      portions of the thin descending limbs of Henle's loop and that the abundance of
      this protein is strongly upregulated by vasopressin.

PMID- 10644656
TI  - Oxidant stress in hyperlipidemia-induced renal damage.
AB  - Hyperlipoproteinemia can aggravate glomerulosclerosis and chronic
      tubulointerstitial (ti) damage in kidneys without primary immunologic disease. We
      evaluated whether the effect of hyperlipidemia on progression of renal damage
      differed between kidneys without preexisting glomerular disease and kidneys with
      mesangioproliferative glomerulonephritis and whether the renal actions of
      hyperlipidemia were dependent on oxidant-antioxidant balance. Hyperlipidemia was
      induced by high-fat and high-cholesterol diet in uninephrectomized rats. In rats
      without glomerulonephritis, hyperlipidemia led to a rise in glomerular and ti
      generation of reactive oxygen species (ROS). Oxygen radicals were mainly
      generated by enhanced xanthine oxidoreductase (XO), which rose with protein
      concentration and activity during hyperlipidemia; concurrently,
      glomerulosclerosis and chronic ti injury were noticed during hyperlipidemia [ti
      damage (% of total tubulointerstitium (TI) after 150 days): normolipidemia 0.1 +/
      0% vs. hyperlipidemia 3.4 +/- 0. 9%; P < 0.05]. In mesangioproliferative Thy-1
      nephritis, ti injury was significantly accelerated by hyperlipidemia (ti damage
      after 150 days: normolipidemic Thy-1 nephritis 2.5 +/- 0.6% vs. hyperlipidemic
      Thy-1 nephritis 12.5 +/- 3.1%; P < 0.05). Antioxidant enzyme activities decreased
      and XO activity rose markedly in the TI (XO activity in TI after 150 days:
      normolipidemic Thy-1 nephritis 2.2 +/- 0.5 vs. hyperlipidemic Thy-1 nephritis 4.5
      +/- 0.7 cpm/microg protein; P < 0.05). In hyperlipidemic Thy-1 nephritis rats,
      which had a higher urinary protein excretion than normolipidemic rats,
      hypochlorite-modified proteins, an indirect measure for enhanced myeloperoxidase
      activity, were detected in renal tissue and in urine, respectively. During
      hyperlipidemia, chronic damage increased in renal TI. Enhanced generation of ROS,
      rise in oxidant enzyme activity, and generation of hypochlorite-modified proteins
      in renal tissue and urine were noticed. These data suggest that oxidant stress
      contributed to the deleterious effects of hyperlipidemia on the renal TI.

PMID- 10644657
TI  - Abnormal water metabolism in mice lacking the type 1A receptor for ANG II.
AB  - Mice lacking AT(1A) receptors for ANG II have a defect in urinary concentration
      manifested by an inability to increase urinary osmolality to levels seen in
      controls after thirsting. This defect results in extreme serum hypertonicity
      during water deprivation. In the basal state, plasma vasopressin levels are
      similar in wild-type controls and Agtr1a -/- mice. Plasma vasopressin levels
      increase normally in the AT(1A) receptor-deficient mice after 24 h of water
      deprivation, suggesting that the defect in urine concentration is intrinsic to
      the kidney. Using magnetic resonance microscopy, we find that the absence of
      AT(1A) receptors is associated with a modest reduction in the distance from the
      kidney surface to the tip of the papilla. However, this structural abnormality
      seems to play little role in the urinary concentrating defect in Agtr1a -/- mice
      since the impairment is largely reproduced in wild-type mice by treatment with an
      AT(1)-receptor antagonist. These studies demonstrate a critical role for the
      AT(1A) receptor in maintaining inner medullary structures in the kidney and in
      regulating renal water excretion.

PMID- 10644658
TI  - Effects of chloride channel inhibitors on H(2)O(2)-induced renal epithelial cell
      injury.
AB  - Oxidative stress contributes to renal epithelial cell injury in certain settings.
      Chloride influx has also been proposed as an important component of acute renal
      epithelial cell injury. The present studies examined the role of Cl(-) in
      H(2)O(2)-induced injury to LLC-PK(1) renal epithelial cells. Exposure of LLC
      PK(1) cells to 1 mM H(2)O(2) resulted in the following: depletion of
      intracellular ATP content; DNA damage; lipid peroxidation; and a loss of membrane
      integrity to both small molecules, e.g., trypan blue, and macromolecules, e.g.,
      lactate dehydrogenase (LDH), and cell death. Substitution of Cl(-) by isethionate
      or the inclusion of certain Cl(-) channel blockers, e.g., diphenylamine-2
      carboxylate (DPC), 5-nitro-2-(3-phenylpropylamino). benzoate (NPPB), and niflumic
      acid, prevented the H(2)O(2)-induced loss of membrane integrity to LDH. In
      addition, the H(2)O(2)-induced loss of membrane integrity was prevented by
      raising the osmolality of the extracellular solutions, by depletion of cell ATP,
      and by inhibitors of volume-sensitive Cl(-) channels. However, these maneuvers
      did not prevent the H(2)O(2)-induced permeability to small molecules or H(2)O(2)
      induced ATP depletion, DNA damage, lipid peroxidation, or cell death. These
      results support the view that volume-sensitive Cl(-) channels play a role in the
      progressive loss of cell membrane integrity during injury.

PMID- 10644659
TI  - High glucose induces the activity and expression of Na(+)/H(+) exchange in
      glomerular mesangial cells.
AB  - Changes in activity or expression of transporters may account for alterations in
      cell behavior in diabetes. We sought to ascertain if mesangial cells (MC) grown
      in different glucose concentrations exhibit changes in activity and expression of
      acid-extruding transporters, the Na(+)/H(+) and Na(+)-dependent Cl(-)/HCO(-)(3)
      exchanger. pH(i) was determined by the use of the fluorescent pH-sensitive dye
      BCECF. In MCs grown in 5 mM glucose (control), the Na(+)/H(+) exchanger was
      responsible for 31.8 +/- 5.1% of steady-state pH(i), whereas Na(+)-dependent Cl(
      )/HCO(-)(3) contributed 62.9 +/- 4.0% (n = 11). In MCs grown in high glucose for
      2 wk, Na(+)/H(+) exchange contribution to acid-extrusion increased as follows:
      42.3 +/- 4.6% [n = 8, 10 mM, not significant (NS)], 51.1 +/- 5.1% (n = 8, 20 mM,
      P < 0.01), and 64.8 +/- 5.5% (n = 7, 30 mM, P < 0.001). The Na(+)-dependent Cl(
      )/HCO(-)(3) exchanger contributed less [47.0 +/- 4.6, 38.6 +/- 5.8, and 21.1 +/-
      3.8%, for 10, 20, and 30 mM glucose, respectively (n > 7)]. We sought to
      ascertain if the magnitude of the acute stimulated response to ANG II by the
      Na(+)/H(+) and Na(+)-dependent Cl(-)/HCO(-)(3) exchanger is changed. Na(+)/H(+)
      exchanger (1.89-fold increase in 30 vs. 5 mM, P < 0.002), but not Na(+)-dependent
      Cl(-)/HCO(-)(3) exchange (0. 17-fold, NS), exhibited an enhanced response to ANG
      II (1 microM). Na(+)/H(+) exchange (NHE1) expression was significantly different
      (1. 72-fold) after prolonged exposure to high glucose. These results suggest that
      the Na(+)/H(+) exchanger, but not Na(+)-dependent Cl(-)/HCO(-)(3) exchanger, may
      play an early role in the response to hyperglycemia in the diabetic state.

PMID- 10644660
TI  - Dihydropyridine-sensitive Ca(2+) channels in human glomerular mesangial cells.
AB  - In mesangial cells (MC), the response of intracellular Ca(2+) concentration
      ([Ca(2+)](i)) to a contractile agonist is biphasic with a large, transient
      increase in [Ca(2+)](i) followed by a smaller but sustained elevation as Ca(2+)
      flows into the cell from the extracellular fluid. It has been postulated that
      membrane depolarization precedes opening of Ca(2+) channels in the plasmalemmal
      membrane. However, a role for voltage-gated Ca(2+) channels (VGCC) in human MC
      has been controversial, and their existence has not been verified with single
      channel analysis. We used fura 2 fluorescence and patch-clamp techniques to
      determine the properties of the Ca(2+) entry pathway responsible for the
      sustained response of [Ca(2+)](i) in human MC. We found that ANG II at 10 nM, 100
      nM, and 1 microM increased [Ca(2+)](i) to sustained levels of 22%, 35%, and 49%,
      respectively, above baseline. The sustained response to 1 microM ANG II was
      attenuated by diltiazem and was reduced to a value less than baseline in the
      absence of external Ca(2+). None of the peak responses (due to release of
      intracellular stores of Ca(2+)) were affected by removal of external Ca(2+) or
      addition of diltiazem. Upon elevating the extracellular [K(+)] from 5 mM to 75
      mM, [Ca(2+)](i) reached a sustained level of 48% greater than baseline. This
      effect of high K(+) was attenuated by either Ca(2+) removal or addition of
      diltiazem. In the presence of 75 or 140 mM K(+), the dihydropyridine agonist BAY
      K 8644 (1 microM and 10 microM) initiated sustained [Ca(2+)](i) responses
      averaging 18% and 25%, respectively, greater than baseline. With <10 nM Ca(2+) in
      the external solution, BAY K 8644 did not significantly affect [Ca(2+)](i). In
      separate patch-clamp experiments, barium-selective channels were found in cell
      attached patches with 90 mM BaCl(2) and 10 microM BAY K 8644 in the pipette
      solution. The single-channel conductance was 11.2 pS, and the open probability
      increased steeply at membrane potentials between -30 mV and 0 mV. It is concluded
      that human glomerular MC contain dihydropyridine-sensitive Ca(2+) channels
      responsible for the voltage-regulated entry of Ca(2+) into the cell during an
      agonist-induced contraction.

PMID- 10644661
TI  - PKC regulation of organic anion secretion in perfused S2 segments of rabbit
      proximal tubules.
AB  - To examine the role of protein kinase C (PKC) in organic anion (OA) secretion, we
      used epifluorescence microscopy to study steady-state transepithelial secretion
      of 1 microM fluorescein (FL) by isolated perfused S2 segments of rabbit renal
      proximal tubules. Addition of 100 nM phorbol 12-myristate 13-acetate (PMA), a
      known PKC activator, to the bathing medium decreased steady-state secretion of FL
      by approximately 30% after 25 min. This inhibition was irreversible and, indeed,
      increased to approximately 40% at 25 min following removal of PMA [10 microM 1,2
      dioctanoyl-sn-glycerol (DOG) produced a comparable inhibition]. The inhibition
      produced by PMA was blocked when 100 nM of either staurosporine (ST) or
      bisindolylmaleimide I (BIM), both known PKC inhibitors, was added to the bath for
      a 20-min preexposure followed by the addition of PMA. ST or BIM alone had no
      significant effect on FL secretion, suggesting that the basal FL secretion rate
      was not under influence of PKC. Addition of 1 microM of either the peptide
      hormone bradykinin (BK) or the alpha(1)-receptor agonist phenylephrine (PE), both
      of which stimulate PKC via a ligand-receptor-PKC coupling reaction, to the bath
      also inhibited FL secretion by approximately 22 and approximately 27%,
      respectively. However, the inhibition was completely reversible after removal of
      BK or PE. Pretreatment of tubules with 100 nM BIM eliminated the inhibition of FL
      secretion produced by exposure to PE. We conclude that PKC negatively regulates
      the net secretion of OAs in rabbit renal proximal tubules. The data indicate that
      BK or catecholamines can play a physiological role in regulating OA secretion via
      PKC activation.

PMID- 10644662
TI  - Osteopontin expressed by renal tubular epithelium mediates interstitial monocyte
      infiltration in rats.
AB  - In this study, we have shown that intravenously administered antisense
      oligodeoxynucleotide (ODN) was demonstrated to be taken up by tubular epithelium,
      after which it blocked mRNA expression of target genes in normal and nephritic
      rats. Therefore, we injected osteopontin (OPN) antisense ODN to Goodpasture
      syndrome (GPS) rats every second day between days 27 and 35, the time when renal
      OPN expression increased and interstitial monocyte infiltration was aggravated.
      In parallel to blockade of tubular OPN expression, this treatment significantly
      attenuated monocyte infiltration and preserved renal plasma flow in GPS rats at
      day 37, compared with sense ODN-treated and untreated GPS rats. No significant
      changes were observed in OPN mRNA level by RT-PCR and histopathology of the
      glomeruli after ODN treatment, which was compatible with an absence of
      differences in the urinary protein excretion rate. In conclusion, OPN expressed
      by tubular epithelium played a pivotal role in mediating peritubular monocyte
      infiltration consequent to glomerular disease.

PMID- 10644663
TI  - Age-related progressive renal fibrosis in rats and its prevention with ACE
      inhibitors and taurine.
AB  - Our previous studies demonstrated an increased reactive oxygen species (ROS)
      production, as well as transforming growth factor-beta1 (TGF-beta1) expression in
      the rat kidney with aging. In the present study, we examined the effect of aging
      on extracellular matrix (ECM) accumulation and the effects of treatment with
      angiotensin-converting enzyme inhibitors (captopril and lisinopril) and taurine,
      an antioxidant amino acid. Age-related increases in types I and IV collagen and
      fibronectin mRNA expression were found at 24 and 30 mo of age. In contrast, type
      III collagen only increased in 30-mo-old rats. Captopril-, lisinopril-, and
      taurine-treated animals showed a statistically significant decrease in ECM
      protein expression at both ages. Moreover, treatment with taurine reduced the TGF
      beta1 mRNA levels in 24- and 30-mo-old rats by 40%. Taurine also completely
      blocked increases in type I and type IV collagen expression in mesangial cells in
      response to TGF-beta1. Our results demonstrate a protective role from both
      converting enzyme inhibitors and taurine in the age-related progressive renal
      sclerosis. In addition, taking into account that taurine is considered as an
      antioxidant amino acid, present data suggest a role for ROS in age-related
      progressive renal fibrosis, perhaps through interactions with the TGF-beta1
      pathway.

PMID- 10644664
TI  - Regulation of renal epithelial cell affinity for calcium oxalate monohydrate
      crystals.
AB  - The binding and internalization of calcium oxalate monohydrate (COM) crystals by
      tubular epithelial cells may be a critical step leading to kidney stone
      formation. Exposure of MDCK cells to arachidonic acid (AA) for 3 days, but not
      oleic or linoleic acid, decreased COM crystal adhesion by 55%. Exogenous
      prostaglandin PGE(1) or PGE(2) decreased crystal binding 96% within 8 h, as did
      other agents that raise intracellular cAMP. Actinomycin D, cycloheximide, or
      tunicamycin each blocked the action of PGE(2), suggesting that gene
      transcription, protein synthesis, and N-glycosylation were required. Blockade of
      crystal binding by AA was not prevented by the cyclooxygenase inhibitor
      flurbiprofen, and was mimicked by the nonmetabolizable AA analog eicosatetryanoic
      acid (ETYA), suggesting that generation of PGE from AA is not the pathway by
      which AA exerts its effect. These studies provide new evidence that binding of
      COM crystals to renal cells is regulated by physiological signals that could
      modify exposure of cell surface molecules to which the crystals bind. Intrarenal
      AA, PGs, and/or other agents that raise the intracellular concentration of cAMP
      may serve a protective function by preventing crystal adhesion along the nephron,
      thereby defending the kidney against crystal retention and stone formation.

PMID- 10644665
TI  - alpha(1)-adrenoceptor subtypes in rat renal resistance vessels: in vivo and in
      vitro studies.
AB  - This study provides new information about the relative importance of different
      alpha(1)-adrenoceptors during norepinephrine (NE) activation in rat renal
      resistance vessels. In Sprague-Dawley rats, we measured renal blood flow (RBF)
      using electromagnetic flowmetry in vivo and the intracellular free calcium
      concentration ([Ca(2+)](i)) utilizing ratiometric photometry of fura 2
      fluorescence in isolated afferent arterioles. Renal arterial bolus injection of
      NE produced a transient 46% decrease in RBF. In microdissected afferent
      arterioles, NE (1 microM) elicited an immediate square-shaped increase in
      [Ca(2+)](i), from 90 to 175 nM (P < 0.001). Chloroethylclonidine (CEC) (50
      microM) had no chronic irreversible alkylating effect in vitro but exerted acute
      reversible blockade on norepinephrine (NE) responses both on [Ca(2+)](i) in vitro
      and on RBF in vivo. The RBF response was attenuated by approximately 50% by the
      putative alpha(1A)-adrenoceptor and alpha(1D)-adrenoceptor antagonists 5
      methylurapidil (5-MU), and 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8
      azaspiro[4. 5]decane-7,9-dione dihydrochloride (BMY-7378) (12.5 and 62.5
      microg/h), respectively. The in vitro [Ca(2+)](i) response to NE was blocked
      approximately 25% and 50% by 5-MU (100 nM and 1 microM). BMY-7378 (100 nM and 1
      microM) attenuated the NE-induced response by approximately 40% and 100%. The
      degree of inhibition in vitro was similar to the in vivo experiments. In
      conclusion, 5-MU and BMY-7378 attenuated the NE-induced responses, although
      relatively high concentrations were required, suggesting involvement of both the
      alpha(1A)-adrenoceptor and alpha(1D)-adrenoceptor. Participation of the alpha(1B)
      adrenoceptor is less likely, as we found no evidence for CEC-induced alkylation.

PMID- 10644666
TI  - Internalization of proximal tubular type II Na-P(i) cotransporter by PTH:
      immunogold electron microscopy.
AB  - Physiological/pathophysiological alterations in proximal tubular P(i)
      reabsorption are associated with an altered brush-border membrane (BBM)
      expression of type II Na-P(i) cotransporter molecules. Reduction is achieved by
      an internalization and lysosomal degradation and an increase in P(i) reabsorption
      by new synthesis and BBM insertion of type II Na-P(i) cotransporters. In the
      present study, we investigated by immunohistochemistry and immunogold electron
      microscopy the routing of internalized rat type II Na-P(i) cotransporters (NaPi
      2). In kidney of rats on a chronic low-P(i) diet, NaPi-2 is mainly localized in
      the BBM, in cisterns of the Golgi apparatus and sparsely also in large
      endocytotic vacuoles and lysosomes. Fifteen minutes after the injection of the 1
      34 analog of parathyroid hormone (PTH), the amount of NaPi-2 was decreased in the
      BBM and increased in endocytotic vesicles. NaPi-2 molecules colocalized with
      horseradish peroxidase injected prior to the injection of PTH. Vesicles labeled
      for NaPi-2 were occasionally also labeled for clathrin or the adaptor protein
      AP2. We conclude that NaPi-2 molecules enter the subapical compartment from where
      NaPi-2-containing vesicles are segregated off and directed to the lysosomes. A
      clathrin-mediated pathway may contribute to the PTH-induced internalization of
      NaPi-2.

PMID- 10644667
TI  - PI3K signaling in the murine kidney inner medullary cell response to urea.
AB  - Growth factors and other stimuli increase the activity of phosphatidylinositol-3
      kinase (PI3K), an SH2 domain-containing lipid kinase. In the murine kidney inner
      medullary mIMCD3 cell line, urea (200 mM) increased PI3K activity in a time
      dependent fashion as measured by immune complex kinase assay. The PI3K effector,
      Akt, was also activated by urea as measured by anti-phospho-Akt immunoblotting.
      In addition, the Akt (and PI3K) effector, p70 S6 kinase, was activated by urea
      treatment in a PI3K-dependent fashion. PI3K inhibition potentiated the
      proapoptotic effect of hypertonic and urea stress. Urea treatment also induced
      the tyrosine phosphorylation of Shc and the recruitment to Shc of Grb2.
      Coexistence of activated Shc and PI3K in a macromolecular complex was suggested
      by the increase in PI3K activity evident in anti-Shc immunoprecipitates prepared
      from urea-treated cells. Taken together, these data suggest that PI3K may
      regulate physiological events in the renal medullary cell response to urea stress
      and that an upstream tyrosine kinase conferring activation of both PI3K and Shc
      may govern urea signaling in these cells.

PMID- 10644668
TI  - Protein tyrosine kinase regulates the number of renal secretory K channels.
AB  - The apical small conductance (SK) channel plays a key role in K secretion in the
      cortical collecting duct (CCD). A high-K intake stimulates renal K secretion and
      involves a significant increase in the number of SK channels in the apical
      membrane of the CCD. We used the patch-clamp technique to examine the role of
      protein tyrosine kinase (PTK) in regulating the activity of SK channels in the
      CCD. The application of 100 microM genistein stimulated SK channels in 11 of 12
      patches in CCDs from rats on a K-deficient diet, and the mean increase in NP(o),
      a product of channel number (N) and open probability (P(o)), was 2.5. In
      contrast, inhibition of PTK had no effect in tubules from animals on a high-K
      diet in all 10 experiments. Western blot analysis further shows that the level of
      cSrc, a nonreceptor type of PTK, is 261% higher in the kidneys from rats on a K
      deficient diet than those on a high-K diet. However, the effect of cSrc was not
      the result of direct inhibition of channel itself, because addition of exogenous
      cSrc had no effect on SK channels in inside-out patches. In cell-attached
      patches, application of herbimycin A increased channel activity in 14 of 16
      patches, and the mean increase in NP(o) was 2.4 in tubules from rats on a K
      deficient diet. In contrast, herbimycin A had no effect on channel activity in
      any of 15 tubules from rats on a high-K diet. Furthermore, herbimycin A
      pretreatment increased NP(o) per patch from the control value (0.4) to 2.25 in
      CCDs from rats on a K-deficient diet, whereas herbimycin failed to increase
      channel activity (NP(o): control, 3.10; herbimycin A, 3.25) in the CCDs from
      animals on a high-K diet. We conclude that PTK is involved in regulating the
      number of apical SK channels in the kidney.

PMID- 10644669
TI  - Molecular regulation of hepatic fibrosis, an integrated cellular response to
      tissue injury.

PMID- 10644670
TI  - Mouse toll-like receptor 4.MD-2 complex mediates lipopolysaccharide-mimetic
      signal transduction by Taxol.
AB  - Taxol, an antitumor agent derived from a plant, mimics the action of
      lipopolysaccharide (LPS) in mice but not in humans. Although Taxol is
      structurally unrelated to LPS, Taxol and LPS are presumed to share a receptor or
      signaling molecule. The LPS-mimetic activity of Taxol is not observed in LPS
      hyporesponsive C3H/HeJ mice, which possess a point mutation in Toll-like receptor
      4 (TLR4); therefore, TLR4 appears to be involved in both Taxol and LPS signaling.
      In addition, TLR4 was recently shown to physically associate with MD-2, a
      molecule that confers LPS responsiveness on TLR4. To determine whether TLR4.MD-2
      complex mediates a Taxol-induced signal, we constructed transformants of the
      mouse pro-B cell line, Ba/F3, expressing mouse TLR4 alone, both mouse TLR4 and
      mouse MD-2, and both mouse MD-2 and mouse TLR4 lacking the cytoplasmic portion,
      and then examined whether Taxol induced NFkappaB activation in these
      transfectants. Noticeable NFkappaB activation by Taxol was detected in Ba/F3
      expressing mouse TLR4 and mouse MD-2 but not in the other transfectants.
      Coexpression of human TLR4 and human MD-2 did not confer Taxol responsiveness on
      Ba/F3 cells, suggesting that the TLR4. MD-2 complex is responsible for the
      species specificity with respect to Taxol responsiveness. Furthermore, Taxol
      induced NFkappaB activation via TLR4.MD-2 was blocked by an LPS antagonist that
      blocks LPS-induced NFkappaB activation via TLR4.MD-2. These results demonstrated
      that coexpression of mouse TLR4 and mouse MD-2 is required for Taxol
      responsiveness and that the TLR4.MD-2 complex is the shared molecule in Taxol and
      LPS signal transduction in mice.

PMID- 10644671
TI  - Association of heterotrimeric G(i) with the insulin-like growth factor-I
      receptor. Release of G(betagamma) subunits upon receptor activation.
AB  - The insulin-like growth factor-I receptor (IGF-IR) is a key regulator of cell
      proliferation and survival. Activation of the IGF-IR induces tyrosine
      autophosphorylation and the binding of a series of adaptor molecules, thereby
      leading to the activation of MAPK. It has been demonstrated that pertussis toxin,
      which inactivates the G(i) class of GTP-binding proteins, inhibits IGF-I-mediated
      activation of MAPK, and a specific role for G(betagamma) subunits in IGF-I
      signaling was shown. In the present study, we have investigated the role of
      heterotrimeric G(i) in IGF-IR signaling in neuronal cells. Pertussis toxin
      inhibited IGF-I-induced activation of MAPK in rat cerebellar granule neurons and
      NG-108 neuronal cells. G(alphai) and G(beta) subunits were associated with IGF-IR
      immunoprecipitates. Similarly, in IGF-IR-null mouse embryo fibroblasts
      transfected with the human IGF-IR, G(i) was complexed with the IGF-IR. G(alphas)
      was not associated with the IGF-IR in any cell type. IGF-I induced the release of
      the G(beta) subunits from the IGF-IR but had no effect on the association of
      G(alphai). These results demonstrate an association of heterotrimeric G(i) with
      the IGF-IR and identify a discrete pool of G(betagamma) subunits available for
      downstream signaling following stimulation with IGF-I.

PMID- 10644672
TI  - The trans-spliceosomal U4 RNA from the monogenetic trypanosomatid Leptomonas
      collosoma. Cloning and identification of a transcribed trna-like element that
      controls its expression.
AB  - U4 small nuclear RNA is essential for trans-splicing. Here we report the cloning
      of U4 snRNA gene from Leptomonas collosoma and analysis of elements controlling
      its expression. The trypanosome U4 RNA is the smallest known, it carries an Sm
      like site, and has the potential for extensive intermolecular base pairing with
      the U6 RNA. Sequence analysis of the U4 locus indicates the presence of a tRNA
      like element 86 base pairs upstream of the gene that is divergently transcribed
      to yield a stable small tRNA-like RNA. Two additional tRNA genes, tRNA(Pro) and
      tRNA(Gly), were found upstream of this element. By stable expression of a tagged
      U4 RNA, we demonstrate that the tRNA-like gene, but not the upstream tRNA genes,
      is essential for U4 expression and that the B box but not the A Box of the tRNA
      like gene is crucial for expression in vivo. Mapping the 2'-O-methyl groups on U4
      and U6 small nuclear RNAs suggests the presence of modifications in canonical
      positions. However, the number of modified nucleotides is fewer than in mammalian
      homologues. The U4 genomic organization including both tRNA-like and tRNA genes
      may represent a relic whereby trypanosomatids "hired" tRNA genes to provide
      extragenic promoter elements. The close proximity of tRNA genes to the tRNA-like
      molecule in the U4 locus further suggests that the tRNA-like gene may have
      evolved from a tRNA member of this cluster.

PMID- 10644673
TI  - Assessment of protein-tyrosine phosphatase 1B substrate specificity using
      "inverse alanine scanning".
AB  - An "inverse alanine scanning" peptide library approach has been developed to
      assess the substrate specificity of protein-tyrosine phosphatases (PTPases). In
      this method each Ala moiety in the parent peptide, Ac-AAAApYAAAA-NH(2), is
      separately and sequentially replaced by the 19 non-Ala amino acids to generate a
      library of 153 well defined peptides. The relatively small number of peptides
      allows the acquisition of explicit kinetic data for all library members, thereby
      furnishing information about the contribution of individual amino acids with
      respect to substrate properties. The approach was applied to protein-tyrosine
      phosphatase 1B (PTP1B) as a first example, and the highly potent peptide
      substrate Ac-ELEFpYMDYE-NH(2) (k(cat)/K(m) 2.2 +/- 0.05 x 10(7) M(-1) s(-1)) has
      been identified. More importantly, several heretofore unknown features of the
      substrate specificity of PTP1B were revealed. This includes the ability of PTP1B
      to accommodate acidic, aromatic, and hydrophobic residues at the -1 position, a
      strong nonpreference for Lys and Arg residues in any position, and the first
      evidence that residues well beyond the +1 position contribute to substrate
      efficacy.

PMID- 10644674
TI  - Structural analysis of glycosaminoglycans in Drosophila and Caenorhabditis
      elegans and demonstration that tout-velu, a Drosophila gene related to EXT tumor
      suppressors, affects heparan sulfate in vivo.
AB  - We have devised a sensitive method for the isolation and structural analysis of
      glycosaminoglycans from two genetically tractable model organisms, the fruit fly,
      Drosophila melanogaster, and the nematode, Caenorhabditis elegans. We detected
      chondroitin/chondroitin sulfate- and heparan sulfate-derived disaccharides in
      both organisms. Chondroitinase digestion of glycosaminoglycans from adult
      Drosophila produced both nonsulfated and 4-O-sulfated unsaturated disaccharides,
      whereas only unsulfated forms were detected in C. elegans. Heparin lyases
      released disaccharides bearing N-, 2-O-, and 6-O-sulfated species, including mono
      , di-, and trisulfated forms. We observed tissue- and stage-specific differences
      in both chondroitin sulfate and heparan sulfate composition in Drosophila. We
      have also applied these methods toward the analysis of tout-velu, an EXT-related
      gene in Drosophila that controls the tissue distribution of the growth factor
      Hedgehog. The proteins encoded by the vertebrate tumor suppressor genes EXT1 and
      2, show heparan sulfate co-polymerase activity, and it has been proposed that
      tout-velu affects Hedgehog activity via its role in heparan sulfate biosynthesis.
      Analysis of total glycosaminoglycans from tout-velu mutant larvae show marked
      reductions in heparan sulfate but not chondroitin sulfate, consistent with its
      proposed function as a heparan sulfate co-polymerase.

PMID- 10644675
TI  - Functional analysis of the two interacting cyclase domains in ent-kaurene
      synthase from the fungus Phaeosphaeria sp. L487 and a comparison with cyclases
      from higher plants.
AB  - We report here kinetic analysis and identification of the two cyclase domains in
      a bifunctional diterpene cyclase, Phaeosphaeria ent-kaurene synthase (FCPS/KS).
      Kinetics of a recombinant FCPS/KS protein indicated that the affinity for copalyl
      diphosphate is higher than that for geranylgeranyl diphosphate (GGDP). ent
      Kaurene production from GGDP by FCPS/KS was enhanced by the addition of a plant
      ent-kaurene synthase (KS) but not by plant CDP synthase (CPS), suggesting that
      the rate of ent-kaurene production of FCPS/KS may be limited by the KS activity.
      Site-directed mutagenesis of aspartate-rich motifs in FCPS/KS indicated that the
      (318)DVDD motif near the N terminus and the (656)DEFFE motif near the C terminus
      may be part of the active site for the CPS and KS reactions, respectively. The
      other aspartate-rich (132)DDVLD motif near the N terminus is thought to be
      involved in both reactions. Functional analysis of the N- and C-terminal
      truncated mutants revealed that a N-terminal 59-kDa polypeptide catalyzed the CPS
      reaction and a C-terminal 66-kDa polypeptide showed KS activity. A 101-kDa
      polypeptide lacking the first 43 amino acids of the N terminus reduced KS
      activity severely without CPS activity. These results indicate that there are two
      separate interacting domains in the 106-kDa polypeptide of FCPS/KS.

PMID- 10644676
TI  - Protection of thrombin receptor expression under hypoxia.
AB  - Thrombin receptor (ThR) plays a significant role in myocyte contractility and
      hypertrophy. Heart myocyte ischemic damage, caused by insufficient blood supply,
      is the leading cause of heart infarction. Here we demonstrate that when primary
      myocyte cultures are subjected to hypoxic stress, ThR mRNA levels are reduced
      markedly. This takes place also in vivo in a model of ischemic pig heart,
      exhibiting reduced levels of ThR compared with normal heart sections. Prior
      activation of ThR however, by either thrombin receptor-activating peptide (TRAP)
      or by alpha-thrombin resulted in full protection of ThR mRNA levels under
      hypoxia. The effect appeared specific to ThR because the addition of TRAP did not
      affect the hypoxic damage as shown by the levels of lactic dehydrogenase release
      and up-regulated GLUT-1, a glucose transporter gene. This protection effect took
      place not only in primary myocytes but also in NIH3T3 fibroblasts. ThR protection
      occurs via specific cell signaling events because activation of the receptor by
      TRAP, following interruption of the signaling cascade by calphostin C, a protein
      kinase C inhibitor, resulted in loss of ThR mRNA protection. Because Ras and Src
      are part of the ThR signaling cascade, the introduction of either dominant ras or
      src oncogenes to NIH3T3 murine fibroblasts gave rise to similar protection of ThR
      mRNA levels under hypoxic conditions without the exogenous addition of TRAP.
      Likewise, ThR mRNA protection was obtained after transfection with proto-oncogene
      vav. The 95-kDa protein Vav undergoes tyrosine phosphorylation after ThR
      activation, serving thus as part of the receptor machinery cascade. We therefore
      conclude that the initiation of the signaling cascades either exogenously by TRAP
      or within the cell via src or ras, as well as via vav oncogene interconnecting G
      binding protein to the tyrosine kinase pathway, ultimately results in ThR
      protection under hypoxia. We present hereby, a novel concept of activated
      receptors, which under minimal oxygen tension protect their otherwise decaying
      mRNA. Maintaining the level of ThR that plays an active role in normal myocyte
      function may provide a significant repair mechanism in ischemic tissue, assisting
      in the regaining of normal myocyte functions.

PMID- 10644677
TI  - Yeast RNA polymerase II subunit RPB9. Mapping of domains required for
      transcription elongation.
AB  - The RPB9 subunit of RNA polymerase II regulates transcription elongation activity
      and is required for the action of the transcription elongation factor, TFIIS.
      RPB9 comprises two zinc ribbon domains joined by a conserved linker region. The C
      terminal zinc ribbon is similar in sequence to that found in TFIIS. To elucidate
      the relationship between the structure and transcription elongation function of
      RPB9, we initiated a mutagenesis study on the Saccharomyces cerevisiae homologue.
      The individual zinc ribbon domains, in isolation or in combination, could not
      stimulate transcription by a polymerase lacking RPB9, pol IIDelta9. Mutations in
      the N-terminal zinc ribbon had little effect on transcription activity. By
      contrast, mutations in the acidic loop that connects the second and third beta
      strands of the C-terminal zinc ribbon were completely inactive for transcription.
      Interestingly, the analogous residues in TFIIS are also critical for elongation
      activity. A conserved charged stretch in the linker region (residues 89-95,
      DPTLPR) mediated the interaction with RNA polymerase II.

PMID- 10644678
TI  - Uroporphyrinogen III synthase. An alternative promoter controls erythroid
      specific expression in the murine gene.
AB  - Uroporphyrinogen III synthase (URO-synthase, EC 4.2.1.75) is the fourth enzyme of
      the heme biosynthetic pathway and is the defective enzyme in congenital
      erythropoietic porphyria. To investigate the erythroid-specific expression of
      murine URO-synthase, the cDNA and approximately 24-kilobase genomic sequences
      were isolated and characterized. Three alternative transcripts were identified
      containing different 5'-untranslated regions (5'-UTRs), but identical coding
      exons 2B through 10. Transcripts with 5'-UTR exon 1A alone or fused to exon 1B
      were ubiquitously expressed (housekeeping), whereas transcripts with 5'-UTR exon
      2A were only present in erythroid cells (erythroid-specific). Analysis of the
      TATA-less housekeeping promoter upstream of exon 1A revealed binding sites for
      ubiquitously expressed transcription factors Sp1, NF1, AP1, Oct1, and NRF2. The
      TATA-less erythroid-specific promoter upstream of exon 2A had nine putative GATA1
      erythroid enhancer binding sites. Luciferase promoter/reporter constructs
      transfected into NIH 3T3 and mouse erythroleukemia cells indicated that the
      housekeeping promoter was active in both cell lines, while the erythroid promoter
      was active only in erythroid cells. Site-specific mutagenesis of the first GATA1
      binding site markedly reduced luciferase activity in K562 cells (<5% of wild
      type). Thus, housekeeping and erythroid-specific transcripts are expressed from
      alternative promoters of a single mouse URO-synthase gene.

PMID- 10644679
TI  - The interaction of calmodulin with alternatively spliced isoforms of the type-I
      inositol trisphosphate receptor.
AB  - A 592-amino acid segment of the regulatory domain of the neuronal type-I inositol
      1,4,5-trisphosphate receptor (IP(3)R) isoform (type-I long, amino acids1314-1905)
      and the corresponding 552-amino acid alternatively spliced form present in
      peripheral tissues (type-I short, amino acids 1693-1733 deleted) were expressed
      as glutathione S-transferase fusion proteins. These domains encompass a putative
      calmodulin (CaM) binding domain and two protein kinase A phosphorylation sites.
      Both long and short fusion proteins retained the ability to bind CaM in a Ca(2+)
      dependent manner as measured by CaM-Sepharose chromatography or a dansyl-CaM
      fluorescence assay. Both assays indicated that the short fusion protein bound
      twice the amount of CaM than the long form at saturating concentrations of CaM.
      In addition, the binding of the short form to CaM-Sepharose was inhibited by
      phosphorylation with protein kinase A, whereas the binding of the long form was
      unaffected. Full-length cDNAs encoding type-I long, type-I short, and type-III
      IP(3)R isoforms were expressed in COS cells, and the Ca(2+) sensitivity of
      [(3)H]IP(3) binding to permeabilized cells was measured. The type-I long isoform
      was more sensitive to Ca(2+) inhibition (IC(50) = 0.55 microM) than the type-I
      short (IC(50) = 5.7 microM) or the type-III isoform (IC(50) = 3 microM). In
      agreement with studies on the fusion proteins, the full-length type-I short bound
      more CaM-Sepharose, and this binding was inhibited to a greater extent by protein
      kinase A phosphorylation than the type-I long IP(3)R. Although type-III IP(3)Rs
      did not bind directly to CaM-Sepharose, hetero-oligomers of type-I/III IP(3)Rs
      retained the ability to interact with CaM. We conclude that the deletion of the
      SII splice site in the type-I IP(3)R results in the differential regulation of
      the alternatively spliced isoforms by Ca(2+), CaM, and protein kinase A.

PMID- 10644680
TI  - Identification, functional characterization, and regulation of a new cytochrome
      P450 subfamily, the CYP2Ns.
AB  - The screening of liver and heart cDNA libraries from the teleost Fundulus
      heteroclitus with degenerate oligonucleotide probes to conserved alpha-helical
      regions in mammalian P450s resulted in the identification of two cDNAs that
      together represent a novel P450 subfamily, the CYP2Ns. Northern analysis
      demonstrated that CYP2N1 transcripts are most abundant in liver and intestine,
      whereas CYP2N2 mRNAs are most abundant in heart and brain. CYP2N1 and CYP2N2
      proteins were co-expressed with NADPH-cytochrome P450 oxidoreductase in Sf9
      insect cells, and their ability to metabolize arachidonic acid and xenobiotic
      substrates was examined. Both CYP2N1 and CYP2N2 metabolize arachidonic acid to
      epoxyeicosatrienoic acids. Epoxidation is highly regio- and enantioselective with
      preferential formation of (8R,9S)-epoxyeicosatrienoic acid (optical purities are
      91 and 90% for CYP2N1 and CYP2N2, respectively) and (11R, 12S)
      epoxyeicosatrienoic acid (optical purities are 92 and 70% for CYP2N1 and CYP2N2,
      respectively). CYP2N1 and CYP2N2 also catalyze the formation of a variety of
      hydroxyeicosatetraenoic acids. Both P450s have benzphetamine N-demethylase
      activities but show minimal alkoxyresorufin O-dealkylase activities. To
      investigate factors affecting CYP2N expression in vivo, CYP2N transcripts were
      examined following starvation and/or treatment with 12-O-tetradecanoyl phorbol-13
      acetate. Intestinal CYP2N1 mRNAs decrease in starved and/or phorbol ester-treated
      fish, whereas intestinal CYP2N2 transcripts decrease only following phorbol ester
      treatment. Interestingly, cardiac CYP2N2 expression decreases following phorbol
      ester treatment but increases following starvation. These results demonstrate
      that members of this novel P450 subfamily encode early vertebrate forms of
      arachidonic acid catalysts that are widely expressed and are regulated by
      environmental factors. Given the wealth of information on the functional role of
      P450-derived arachidonate metabolites in mammals, we postulate that CYP2N1 and
      CYP2N2 products have similar biological functions in early vertebrates. The
      identity of the mammalian orthologue(s) of the CYP2Ns remains unknown.

PMID- 10644681
TI  - p38 mitogen-activated protein kinase negatively regulates the induction of phase
      II drug-metabolizing enzymes that detoxify carcinogens.
AB  - Phase II drug-metabolizing enzymes, such as glutathione S-transferase and quinone
      reductase, play an important role in the detoxification of chemical carcinogens.
      The induction of these detoxifying enzymes by a variety of agents occurs at the
      transcriptional level and is regulated by a cis-acting element, called the
      antioxidant response element (ARE) or electrophile-response element. In this
      study, we identified a signaling kinase pathway that negatively regulates ARE
      mediated gene expression. Treatment of human hepatoma HepG2 and murine hepatoma
      Hepa1c1c7 cells with tert-butylhydroquinone (tBHQ) stimulated the activity of
      p38, a member of mitogen-activated protein kinase family. Inhibition of p38
      activation by its inhibitor, SB203580, enhanced the induction of quinone
      reductase activity and the activation of ARE reporter gene by tBHQ. In contrast,
      SB202474, a negative analog of SB203580, had little effect. Consistent with this
      result, interfering with the p38 kinase pathway by overexpression of a dominant
      negative mutant of p38 or MKK3, an immediate upstream regulator of p38,
      potentiated the activation of the ARE reporter gene by tBHQ, whereas the wild
      types of p38 and MKK3 diminished such activation. In addition, inhibition of p38
      activity augmented the induction of ARE reporter gene activity by tert
      butylhydroxyanisole, sulforaphane, and beta-naphthoflavone. Thus, p38 kinase
      pathway functions as a negative regulator in the ARE-mediated induction of phase
      II detoxifying enzymes.

PMID- 10644682
TI  - Binding of Clostridium botulinum C2 toxin to asparagine-linked complex and hybrid
      carbohydrates.
AB  - Clostridium botulinum C2 toxin is a binary toxin composed of an enzymatic subunit
      (C2I) capable of ADP-ribosylating actin and a binding subunit (C2II) that is
      responsible for interaction with receptors on eukaryotic cells. Here we show that
      binding of C2 toxin depends on the presence of asparagine-linked carbohydrates. A
      recently identified Chinese hamster ovary cell mutant (Fritz, G., Schroeder, P.,
      and Aktories, K. (1995) Infect. Immun. 63, 2334-2340) was found to be deficient
      in N-acetylglucosaminyltransferase I. C2 sensitivity of this mutant was restored
      by transfection of an N-acetylglucosaminyltransferase I cDNA. C2 toxin
      sensitivity was reduced after inhibition of alpha-mannosidase II. In contrast,
      Chinese hamster ovary cell mutants deficient in sialylated (Lec2) or
      galactosylated (Lec8) glycoconjugates showed an increase in toxin sensitivity
      compared with wild-type cells. Our results show that the GlcNAc residue linked
      beta-1,2 to the alpha-1,3-mannose of the asparagine-linked core structure is
      essential for C2II binding to Chinese hamster ovary cells.

PMID- 10644683
TI  - Inteins of Thermococcus fumicolans DNA polymerase are endonucleases with distinct
      enzymatic behaviors.
AB  - The DNA polymerase gene of Thermococcus fumicolans harbors two intein genes. Both
      inteins have been produced in Escherichia coli and purified either as naturally
      spliced products from the expression of the complete DNA polymerase gene or
      directly from the cloned inteins genes. Both recombinant inteins exhibit
      endonuclease activity, with an optimal temperature of 70 degrees C. The Tfu pol-1
      intein, which belongs to the Psp KOD pol-1 allelic family, recognizes and cleaves
      a minimal sequence of 16 base pairs (bp) on supercoiled DNA with either Mn(2+) or
      Mg(2+) as cofactor. It cleaves linear DNA only with Mn(2+) and requires a 19-bp
      minimal recognition sequence. The Tfu pol-2 intein, which belongs to the Tli pol
      2 allelic family, is a highly active homing endonuclease using Mg(2+) as
      cofactor. Its minimal recognition and cleavage site is 21 bp long either on
      linear or circular DNA substrates. Its endonuclease activity is strongly
      inhibited by the 3' digestion product, which remains bound to the enzyme after
      the cleavage reaction. According to current nomenclature, these endonucleases
      were named PI-TfuI and PI-TfuII. These two inteins thus exhibit different
      requirements for metal cofactor and substrate topology as well as different
      mechanism of action.

PMID- 10644684
TI  - Erythrocytes possess an intrinsic barrier to nitric oxide consumption.
AB  - It has been reported that free hemoglobin (Hb) reacts with NO at an extremely
      high rate (K(Hb) approximately 10(7) M(-1) s(-1)) and that the red blood cell
      (RBC) membrane is highly permeable to NO. RBCs, however, react with NO 500-1000
      times slower. This reduction of NO reaction rate by RBCs has been attributed to
      the extracellular diffusion limitation. To test whether additional limitations
      are also important, we designed a competition test, which allows the
      extracellular diffusion limitation to be distinguished from transmembrane or
      intracellular resistance. This test exploited the competition between free Hb and
      RBCs for NO generated in a homogenous phase by an NO donor. If the extracellular
      diffusion resistance is negligible, then the results would follow a kinetic model
      that assumes homogenous reaction without extracellular diffusion limitation. In
      this case, the measured effective reaction rate constant, K(RBC), would remain
      invariant of the hematocrit, extracellular-free Hb concentration, and NO donor
      concentration. Results show that the K(RBC) approaches a constant only when the
      hematocrit is greater than 10%, suggesting that at higher hematocrit, the
      extracellular diffusion resistance is negligible. Under such a condition, the NO
      consumption by RBCs is still 500-1000 times slower than that by free Hb. This
      result suggests that intrinsic RBC factors, such as transmembrane diffusion
      limitation or intracellular mechanisms, exist to reduce the NO consumption by
      RBCs.

PMID- 10644685
TI  - Biosynthesis and enzymatic characterization of human SKI-1/S1P and the processing
      of its inhibitory prosegment.
AB  - Biochemical and enzymatic characterization of the novel human subtilase hSKI-1
      was carried out in various cell lines. Within the endoplasmic reticulum of LoVo
      cells, proSKI-1 is converted to SKI-1 by processing of its prosegment into 26-,
      24-, 14-, 10-, and 8-kDa products, some of which remain tightly associated with
      the enzyme. N-terminal sequencing and mass spectrometric analysis were used to
      map the cleavage sites of the most abundant fragments, which were confirmed by
      synthetic peptide processing. To characterize its in vitro enzymatic properties,
      we generated a secreted form of SKI-1. Our data demonstrate that SKI-1 is a
      Ca(2+)-dependent proteinase exhibiting optimal cleavage at pH 6.5. We present
      evidence that SKI-1 processes peptides mimicking the cleavage sites of the SKI-1
      prosegment, pro-brain-derived neurotrophic factor, and the sterol regulatory
      element-binding protein SREBP-2. Among the candidate peptides encompassing
      sections of the SKI-1 prosegment, the RSLK(137)- and RRLL(186)-containing
      peptides were best cleaved by this enzyme. Mutagenesis of the latter peptide
      allowed us to develop an efficiently processed SKI-1 substrate and to assess the
      importance of several P and P' residues. Finally, we demonstrate that, in vitro,
      recombinant prosegments of SKI-1 inhibit its activity with apparent inhibitor
      constants of 100-200 nM.

PMID- 10644686
TI  - Cloning, expression, and functional characterization of the beta regulatory
      subunit of human methionine adenosyltransferase (MAT II).
AB  - MAT II, the extrahepatic form of methionine adenosyltransferase (MAT), consists
      of catalytic alpha(2)/alpha(2') subunits and a noncatalytic beta subunit,
      believed to have a regulatory function. The full-length cDNA that encodes the
      beta subunit of human MAT II was cloned and found to encode for a 334-amino acid
      protein with a calculated molecular weight of 37,552. Analysis of sequence
      homology showed similarity with bacterial enzymes that catalyze the reduction of
      TDP-linked sugars. The beta subunit cDNA was cloned into the pQE-30 expression
      vector, and the recombinant His tagged protein, which was expressed in
      Escherichia coli, was recognized by antibodies to the human MAT II, to synthetic
      peptides copying the sequence of native beta subunit protein, and to the rbeta
      protein. There is no cross-reactivity between the MAT II alpha(2) or beta
      subunits. None of the anti-beta subunit antibodies reacted with protein extracts
      of E. coli host cells, suggesting that these bacteria have no beta subunit
      protein. Interestingly, the rbeta subunit associated with E. coli as well as
      human MAT alpha subunits. This association changed the kinetic properties of both
      enzymes and lowered the K(m) of MAT for L-methionine. Together, the data show
      that we have cloned and expressed the human MAT II beta subunit and confirmed its
      long suspected regulatory function. This knowledge affords a molecular means by
      which MAT activity and consequently the levels of AdoMet may be modulated in
      mammalian cells.

PMID- 10644687
TI  - Regulation of Xenopus p21-activated kinase (X-PAK2) by Cdc42 and maturation
      promoting factor controls Xenopus oocyte maturation.
AB  - Signal transduction cascades involved in regulation of the cell cycle machinery
      are poorly understood. In the Xenopus oocyte model, meiotic maturation is
      triggered by MPF, a complex of p34(cdc2)-cyclin B, which is activated in response
      to a progesterone signal by largely unknown mechanisms. We have previously shown
      that the p21-activated kinase (PAK) family negatively regulates the MPF
      amplification loop. In this study, we identify the endogenous PAK2 as a key
      enzyme in this regulation and describe the pathways by which PAK2 is regulated.
      We show that the small GTPase Cdc42 is required for maintenance of active
      endogenous X-PAK2 in resting stage VI oocytes, whereas Rac1 is not involved in
      this regulation. During the process of maturation, X-PAK2 phosphorylation results
      in its inactivation and allows maturation to proceed to completion. Activation of
      mitogen-activated protein kinase and cyclin B-p34(cdc2) is coincident with X-PAK2
      inactivation, and purified active MPF inhibits X-PAK2, demonstrating the
      existence of a new positive feedback loop. Our results confirm and extend the
      importance of p21-activated kinases in the control of the G(2)/M transition. We
      hypothesize that the X-PAK2/Cdc42 pathway could link p34(cdc2) activity to the
      major cytoskeleton rearrangements leading to spindle migration and anchorage to
      the animal pole cortex.

PMID- 10644688
TI  - Guanabenz-mediated inactivation and enhanced proteolytic degradation of neuronal
      nitric-oxide synthase.
AB  - Guanabenz, a metabolism-based irreversible inactivator of neuronal nitric-oxide
      synthase (nNOS) in vitro, causes the loss of immunodetectable nNOS in vivo. This
      process is selective in that the slowly reversible inhibitor N(G)-nitro-L
      arginine did not decrease the levels of nNOS in vivo. To better understand the
      mechanism for the loss of nNOS protein in vivo, we have investigated the effects
      of guanabenz and N(G)-nitro-L-arginine in HEK 293 cells stably transfected with
      the enzyme. We show here that guanabenz, but not N(G)-nitro-L-arginine, caused
      the inactivation and loss of nNOS protein in the HEK 293 cells. In studies with
      cycloheximide or in pulse-chase experiments with [(35)S]methionine, we
      demonstrate that the loss of nNOS was due in large part to enhanced proteolysis
      of the protein with the half-life decreasing by one-half from 20 to 10 h. Other
      metabolism-based irreversible inactivators to nNOS, N(G)-methyl-L-arginine, and
      N(5)-(1-iminoethyl)-L-ornithine, but not the reversible inhibitor 7-nitroindazole
      (7-NI), caused a similar decrease in the half-life of nNOS. Proteasomal
      inhibitors, lactacystin, Cbz-leucine-leucine-leucinal, and N-acetyl-leucine
      leucine-norleucinal, but not the lysosomal protease inhibitor leupeptin, were
      found to effectively inhibit the proteolytic degradation of nNOS. Thus we have
      shown for the first time that the irreversible inactivators of nNOS, perhaps
      through covalent alteration of the enzyme, enhance the proteolytic turnover of
      the enzyme by a mechanism involving the proteasome.

PMID- 10644689
TI  - Structural implication for receptor oligomerization from functional
      reconstitution studies of mutant V2 vasopressin receptors.
AB  - Previous studies have established that G-protein-coupled receptors (GPCRs) are
      composed of independent folding domains. Based on this findings we attempted to
      rescue the function of clinically relevant missense mutations (R137H, S167L, and
      R181C) within the N-terminal domain of the V2 vasopressin receptor (V2-R), by
      coexpressing mutated full-length (Y280C) and C-terminally truncated (E242X)
      receptor constructs in COS-7 cells. Coimmunoprecipitation and enzyme-linked
      immunosorbent assay studies demonstrated a specific association of E242X with
      full-length V2-Rs even in the presence of missense mutations. Systematic analysis
      of the structural requirements for the observed receptor/fragment association
      showed that N-terminal fragments containing at least transmembrane regions 1-3
      interact with the full-length V2-R. Despite this specific interaction, no
      functional reconstitution was achieved for mutant V2-Rs following coexpression
      with E242X and Y280C. However, functional activity of R137H and R181C upon
      coexpression with E242X was regained by mutational disruption of the
      extracellular disulfide bond, which is highly conserved among GPCRs. Our data
      with the V2-R are consistent with a structural model in which class I GPCRs form
      contact oligomers by lateral interaction rather than by a domain-swapping
      mechanism.

PMID- 10644690
TI  - Epidermal growth factor receptor activation of calpain is required for fibroblast
      motility and occurs via an ERK/MAP kinase signaling pathway.
AB  - To become migratory, cells must reorganize their connections to the substratum,
      and during locomotion they must break rear attachments. The molecular and
      biochemical mechanisms underlying these biophysical processes are unknown. Recent
      studies have implicated both extracellular signal-regulated kinase/mitogen
      activated protein (ERK/MAP) kinase and calpain (EC 3.4.22.17) in these processes,
      but it is uncertain whether these are two distinct pathways acting on different
      modes of motility. We report that cell deadhesion involved in epidermal growth
      factor (EGF) receptor-mediated fibroblast motility requires activation of M
      calpain downstream of ERK/MAP kinase signaling. NR6 fibroblasts expressing full
      length wild type epidermal growth factor receptor required both calpain and ERK
      activation, as demonstrated by pharmacological inhibitors (calpeptin and calpain
      inhibitor I and PD98059, respectively) for EGF-induced deadhesion and motility.
      EGF induced rapid activation of calpain that was preventable by molecular
      inhibition of the Ras-Raf-MEK but not phospholipase Cgamma signaling pathway, and
      calpain was stimulated by transfection of constitutively active MEK. Enhanced
      calpain activity was not mirrored by increased calpain protein levels or
      decreased levels of its endogenous inhibitor calpastatin. The link between
      ERK/MAP kinase signaling and cell motility required the M-isoform of calpain
      (calpain II), as determined by specific antisense-mediated down-regulation. These
      data promote a previously undescribed signaling pathway of ERK/MAP kinases
      activating calpain to destabilize cell-substratum adhesions in response to EGF
      stimulation.

PMID- 10644691
TI  - Protein phosphatase 2Calpha dephosphorylates axin and activates LEF-1-dependent
      transcription.
AB  - The Dishevelled (Dvl) gene family encodes cytoplasmic proteins that are necessary
      for Wnt signal transduction. Utilizing the yeast two-hybrid system, we identified
      protein phosphatase 2Calpha (PP2C) as a Dvl-PDZ domain-interacting protein. PP2C
      exists in a complex with Dvl, beta-catenin, and Axin, a negative regulator of Wnt
      signaling. In a Wnt-responsive LEF-1 reporter gene assay, expression of PP2C
      activates transcription and also elicits a synergistic response with beta-catenin
      and Wnt-1. In addition, PP2C expression relieves Axin-mediated repression of LEF
      1-dependent transcription. PP2C utilizes Axin as a substrate both in vitro and in
      vivo and decreases its half-life. These results indicate that PP2C is a positive
      regulator of Wnt signal transduction and mediates its effects through the
      dephosphorylation of Axin.

PMID- 10644692
TI  - Conformational distributions and proximity relationships in the rigor complex of
      actin and myosin subfragment-1.
AB  - Cyclic conformational changes in the myosin head are considered essential for
      muscle contraction. We hereby show that the extension of the fluorescence
      resonance energy transfer method described originally by Taylor et al. (Taylor,
      D. L., Reidler, J., Spudich, J. A., and Stryer, L. (1981) J. Cell Biol. 89, 362
      367) allows determination of the position of a labeled point outside the actin
      filament in supramolecular complexes and also characterization of the
      conformational heterogeneity of an actin-binding protein while considering donor
      acceptor distance distributions. Using this method we analyzed proximity
      relationships between two labeled points of S1 and the actin filament in the acto
      S1 rigor complex. The donor (N-[[(iodoacetyl)amino]ethyl]-5-naphthylamine-1
      sulfonate) was attached to either the catalytic domain (Cys-707) or the essential
      light chain (Cys-177) of S1, whereas the acceptor (5-(iodoacetamido)fluorescein)
      was attached to the actin filament (Cys-374). In contrast to the narrow
      positional distribution (assumed as being Gaussian) of Cys-707 (5 +/- 3 A), the
      positional distribution of Cys-177 was found to be broad (102 +/- 4 A). Such a
      broad positional distribution of the label on the essential light chain of S1 may
      be important in accommodating the helically arranged acto-myosin binding relative
      to the filament axis.

PMID- 10644693
TI  - The human Cdc14 phosphatases interact with and dephosphorylate the tumor
      suppressor protein p53.
AB  - The yeast Cdc14 phosphatase has been shown to play an important role in cell
      cycle regulation by dephosphorylating proteins phosphorylated by the cyclin
      dependent kinase Cdc28/clb. We recently cloned two human orthologs of the yeast
      CDC14, termed hCDC14A and -B, the gene products of which share approximately 80%
      amino acid sequence identity within their N termini and phosphatase domains. Here
      we report that the hCdc14A and hCdc14B proteins interact with the tumor
      suppressor protein p53 both in vitro and in vivo. This interaction is dependent
      on the N termini of the hCdc14 proteins and the C terminus of p53. Furthermore,
      the hCdc14 phosphatases were found to dephosphorylate p53 specifically at the
      p34(Cdc2)/clb phosphorylation site (p53-phosphor-Ser(315)). Our findings that
      hCdc14 is a cyclin-dependent kinase substrate phosphatase suggest that it may
      play a role in cell cycle control in human cells. Furthermore, the identification
      of p53 as a substrate for hCdc14 indicates that hCdc14 may regulate the function
      of p53.

PMID- 10644694
TI  - Lipoglycans are putative ligands for the human pulmonary surfactant protein A
      attachment to mycobacteria. Critical role of the lipids for lectin-carbohydrate
      recognition.
AB  - The human pulmonary surfactant protein A (hSP-A) has been implicated in the early
      capture and phagocytosis of the pathogenic Mycobacterium tuberculosis by alveolar
      macrophages. In this report, we examined the interaction of alveolar proteinosis
      patient hSP-A with Mycobacterium bovis BCG, the vaccinating strain, as a model of
      pathogenic mycobacteria, and Mycobacterium smegmatis, a nonpathogenic strain. We
      found that hSP-A binds to the surface of M. bovis BCG, but also to a slightly
      lesser extent, to M. smegmatis, indicating that hSP-A does not discriminate
      between virulent and nonpathogenic strains. Among the various glycoconjugates
      isolated from the mycobacterial envelope, we found that the best ligands are the
      two major lipoglycans: the mannosylated lipoarabinomannan (ManLAM) and the
      lipomannan. In contrast, the mannose-capped arabinomannan, structurally close to
      the ManLAM, as well as the LAMs from the non pathogenic M. smegmatis are poorly
      recognized by hSP-A. These results clearly show that the presence of both the
      terminal mannose residues and the phophatidyl-myo-inositol anchor are necessary
      to achieve the highest binding affinity. Selective removal of either the terminal
      mannose or the acyl residues esterifying the glycerol moiety of the ManLAM
      abrogates the interaction with hSP-A, further supporting the notion that the hSP
      A recognition of the carbohydrate epitopes of the lipoglycans is dependent of the
      presence of the fatty acids.

PMID- 10644695
TI  - A novel heptameric sequence (TTAGTAA) is the binding site for a protein required
      for high level expression of pcbAB, the first gene of the penicillin biosynthesis
      in Penicillium chrysogenum.
AB  - The first two genes pcbAB and pcbC of the penicillin biosynthesis pathway are
      expressed from a 1.01-kilobase bidirectional promoter region. A series of
      sequential deletions were made in the pcbAB promoter region, and the
      constructions with the modified promoters coupled to the lacZ reporter gene were
      introduced as single copies at the pyrG locus in Penicillium chrysogenum npe10.
      Three regions, boxes A, B, and C, produced a significant decrease in expression
      of the reporter gene when deleted. Protein-DNA complexes were observed by using
      the electrophoretic mobility shift assay with boxes A and B (complexes AG1, BG1,
      BG2, and BL1) but not with box C. Uracil interference assay showed that a protein
      in P. chrysogenum cell extracts interacts with the thymines in a palindromic
      heptanucleotide TTAGTAA. Point mutations and deletion of the entire TTAGTAA
      sequence supported the involvement of this sequence in the binding of a
      transcriptional activator named penicillin transcriptional activator 1 (PTA1). In
      vivo studies using constructions carrying point mutations in the TTAGTAA sequence
      (or a deletion of the complete heptanucleotide) confirmed that this intact
      sequence is required for high level expression of the pcbAB gene. The TTAGTAA
      sequence resembles the target sequence of BAS2 (PHO2), a factor required for
      expression of several genes in yeasts.

PMID- 10644696
TI  - Specificity determinants of substrate recognition by the protein kinase DYRK1A.
AB  - DYRK1A is a dual-specificity protein kinase that is thought to be involved in
      brain development. We identified a single phosphorylated amino acid residue in
      the DYRK substrate histone H3 (threonine 45) by mass spectrometry, phosphoamino
      acid analysis, and protein sequencing. Exchange of threonine 45 for alanine
      abolished phosphorylation of histone H3 by DYRK1A and by the related kinases
      DYRK1B, DYRK2, and DYRK3 but not by CLK3. In order to define the consensus
      sequence for the substrate specificity of DYRK1A, a library of 300 peptides was
      designed in variation of the H3 phosphorylation site. Evaluation of the phosphate
      incorporation into these peptides identified DYRK1A as a proline-directed kinase
      with a phosphorylation consensus sequence (RPX(S/T)P) similar to that of ERK2
      (PX(S/T)P). A peptide designed after the optimal substrate sequence (DYRKtide)
      was efficiently phosphorylated by DYRK1A (K(m) = 35 microM) but not by ERK2. Both
      ERK2 and DYRK1A phosphorylated myelin basic protein, whereas only ERK2, but not
      DYRK1A, phosphorylated the mitogen-activated protein kinase substrate ELK-1. This
      marked difference in substrate specificity between DYRK1A and ERK2 can be
      explained by the requirement for an arginine at the P -3 site of DYRK substrates
      and its presumed interaction with aspartate 247 conserved in all DYRKs.

PMID- 10644697
TI  - Neurofilament-L is a protein phosphatase-1-binding protein associated with
      neuronal plasma membrane and post-synaptic density.
AB  - Far Westerns with digoxigenin-conjugated protein phosphatase-1 (PP1) catalytic
      subunit identified PP1-binding proteins in extracts from bovine, rat, and human
      brain. A major 70-kDa PP1-binding protein was purified from bovine brain cortex
      plasma membranes, using affinity chromatography on the immobilized phosphatase
      inhibitor, microcystin-LR. Mixed peptide sequencing following cyanogen bromide
      digestion identified the 70-kDa membrane-bound PP1-binding protein as bovine
      neurofilament-L (NF-L). NF-L was the major PP1-binding protein in purified
      preparations of bovine spinal cord neurofilaments and the cytoskeletal
      compartment known as post-synaptic density, purified from rat brain cortex.
      Bovine neurofilaments, at nanomolar concentrations, inhibited the phosphorylase
      phosphatase activity of rabbit skeletal muscle PP1 catalytic subunit but not the
      activity of PP2A, another major serine/threonine phosphatase. PP1 binding to
      bovine NF-L was mapped to the head region. This was confirmed by both binding and
      inhibition of PP1 by recombinant human NF-L fragments. Together, these studies
      indicate that NF-L fulfills many of the biochemical criteria established for a
      PP1-targeting subunit and suggest that NF-L may target the functions of PP1 in
      membranes and cytoskeleton of mammalian neurons.

PMID- 10644698
TI  - The C-terminal subdomain (IF2 C-2) contains the entire fMet-tRNA binding site of
      initiation factor IF2.
AB  - Previous protein unfolding studies had suggested that IF2 C, the 24. 5-kDa fMet
      tRNA binding domain of Bacillus stearothermophilus translation initiation factor
      IF2, may consist of two subdomains. In the present work, the four Phe residues of
      IF2 C (positions 531, 599, 657, and 721) were replaced with Trp, yielding four
      variant proteins having intrinsic fluorescence markers in different positions of
      the molecule. Comparison of the circular dichroism and Trp fluorescence changes
      induced by increasing concentrations of guanidine hydrochloride demonstrated that
      IF2 C indeed consists of two subdomains: the more stable N-terminal (IF2 C-1)
      subdomain containing Trp-599, and the less stable C-terminal (IF2 C-2) subdomain
      containing Trp-721. Isolated subdomain IF2 C-2, which consists of just 110 amino
      acids (from Glu-632 to Ala-741), was found to bind fMet-tRNA with the same
      specificity and affinity as native IF2 or IF2 C-domain. Trimming IF2 C-2 from
      both N and C termini demonstrated that the minimal fragment still capable of fMet
      binding consists of 90 amino acids. IF2 C-2 was further characterized by circular
      dichroism; by urea-, guanidine hydrochloride-, and temperature-induced unfolding;
      and by differential scanning calorimetry. The results indicate that IF2 C-2 is a
      globular molecule containing predominantly beta structures (25% antiparallel and
      8% parallel beta strands) and turns (19%) whose structural properties are not
      grossly affected by the presence or absence of the N-terminal subdomain IF2 C-1.

PMID- 10644699
TI  - beta-carbolines that accumulate in human tissues may serve a protective role
      against oxidative stress.
AB  - beta-Carbolines are tricyclic nitrogen heterocycles formed in plants and animals
      as Maillard reaction products between amino acids and reducing sugars or
      aldehydes. They are being detected increasingly in human tissues, and their
      physiological roles need to be understood. Two beta-carboline carboxylates have
      been reported to accumulate in the human eye lens. We report here on the
      identification of another beta-carboline, namely 1-methyl-1-vinyl -2, 3,4
      trihydro-beta-carboline-3-carboxylic acid, in the lenses of some cataract
      patients from India. Analysis of these three lenticular beta-carbolines using
      photodynamic and antioxidant assays shows all of them to be inert as sensitizers
      and effective as antioxidants; they quench singlet oxygen, superoxide and
      hydroxyl radicals and inhibit the oxidative formation of higher molecular weight
      aggregates of the test protein, eye lens gamma-crystallin. Such antioxidative
      ability of beta-carbolines is of particular relevance to the lens, which faces
      continual photic and oxidative stress. The beta-carboline diacid IV is also seen
      to display an unexpected ability of inhibiting the thermal coagulation of gamma
      crystallin and the dithiothreitol-induced precipitation of insulin. These results
      offer experimental support to earlier suggestions that one of the roles that the
      beta-carbolines have is to offer protection against oxidative stress to the human
      tissues where they accumulate.

PMID- 10644700
TI  - The anaerobic (class III) ribonucleotide reductase from Lactococcus lactis.
      Catalytic properties and allosteric regulation of the pure enzyme system.
AB  - Lactococcus lactis contains an operon with the genes (nrdD and nrdG) for a class
      III ribonucleotide reductase. Strict anaerobic growth depends on the activity of
      these genes. Both were sequenced, cloned, and overproduced in Escherichia coli.
      The corresponding proteins, NrdD and NrdG, were purified close to homogeneity.
      The amino acid sequences of NrdD (747 residues, 84.1 kDa) and NrdG (199 residues,
      23.3 kDa) are 53 and 42% identical with the respective E. coli proteins.
      Together, they catalyze the reduction of ribonucleoside triphosphates to the
      corresponding deoxyribonucleotides in the presence of S-adenosylmethionine,
      reduced flavodoxin or reduced deazaflavin, potassium ions, dithiothreitol, and
      formate. EPR experiments demonstrated a [4Fe-4S](+) cluster in reduced NrdG and a
      glycyl radical in activated NrdD, similar to the E. coli NrdD and NrdG proteins.
      Different from E. coli, the two polypeptides of NrdD and the proteins in the NrdD
      NrdG complex were only loosely associated. Also the FeS cluster was easily lost
      from NrdG. The substrate specificity and overall activity of the L. lactis enzyme
      was regulated according to the general rules for ribonucleotide reductases.
      Allosteric effectors bound to two separate sites on NrdD, one binding dATP, dGTP,
      and dTTP and the other binding dATP and ATP. The two sites showed an unusually
      high degree of cooperativity with complex interactions between effectors and a
      fine-tuning of their physiological effects. The results with the L. lactis class
      III reductase further support the concept of a common origin for all present day
      ribonucleotide reductases.

PMID- 10644701
TI  - Non-bilayer lipids stimulate the activity of the reconstituted bacterial protein
      translocase.
AB  - To determine the phospholipid requirement of the preprotein translocase in vitro,
      the Escherichia coli SecYEG complex was purified in a delipidated form using the
      detergent dodecyl maltoside. SecYEG was reconstituted into liposomes composed of
      defined synthetic phospholipids, and proteoliposomes were analyzed for their
      preprotein translocation and SecA translocation ATPase activity. The activity
      strictly required the presence of anionic phospholipids, whereas the non-bilayer
      lipid phosphatidylethanolamine was found stimulatory. The latter effect could
      also be induced by dioleoylglycerol, a lipid that adopts a non-bilayer
      conformation. Phosphatidylethanolamine derivatives that prefer the bilayer state
      were unable to stimulate translocation. In the absence of SecG, activity was
      reduced, but the phospholipid requirement was unaltered. Remarkably, non-bilayer
      lipids were found essential for the activity of the Bacillus subtilis SecYEG
      complex. Optimal activity required a mixture of anionic and non-bilayer lipids at
      concentrations that correspond to concentrations found in the natural membrane.

PMID- 10644702
TI  - beta-arrestin differentially regulates the chemokine receptor CXCR4-mediated
      signaling and receptor internalization, and this implicates multiple interaction
      sites between beta-arrestin and CXCR4.
AB  - The chemokine receptor CXCR4 has recently been shown to be a co-receptor involved
      in the entry of human immunodeficiency virus type 1 into target cells. This study
      shows that coexpression of beta-arrestin with CXCR4 in human embryonic kidney 293
      cells attenuated chemokine-stimulated G protein activation and inhibition of cAMP
      production. Truncation of the C-terminal 34 amino acids of CXCR4 (CXCR4-T)
      abolished the effects of beta-arrestin on CXCR4/G protein signaling, indicating
      the functional interaction of the receptor C terminus with beta-arrestin. On the
      other hand, receptor internalization and the subsequent activation of
      extracellular signal-regulated kinases were significantly promoted by
      coexpression of beta-arrestin with CXCR4, whereas the C-terminal truncation of
      CXCR4 did not affect this regulation of beta-arrestin, suggesting that beta
      arrestin can functionally interact with CXCR4 with or without the C terminus.
      Moreover, beta(2)V54D, the dominant inhibitory mutant of beta-arrestin 2, exerted
      no effects on CXCR4/G protein signaling, but strongly influenced receptor
      internalization and extracellular signal-regulated kinase activation. Further
      cross-linking experiments demonstrated that beta-arrestin as well as beta(2)V54D
      could physically contact both CXCR4 and CXCR4-T. Glutathione S-transferase pull
      down assay showed that beta-arrestin was able to bind efficiently in vitro to
      both the third intracellular loop and the 34-amino acid C terminus of CXCR4.
      Taken together, our data clearly establish that beta-arrestin can effectively
      regulate different functions of CXCR4 and that this is mediated through its
      distinct interactions with the C terminus and other regions including the third
      loop of CXCR4.

PMID- 10644703
TI  - Inhibitory effect of isoproterenol on NADPH-dependent H(2)O(2) generation in
      human adipocyte plasma membranes is mediated by betagamma-subunits derived from
      G(s).
AB  - Previous studies revealed that human fat cell plasma membranes contain a
      multireceptor-linked H(2)O(2)-generating system that is under antagonistic
      control by hormones and cytokines and is stimulated by insulin via Galpha(i2). In
      this report, it is shown that the inhibitory action of the beta-adrenergic
      agonist isoproterenol is mediated by G protein betagamma-subunits, based on
      observations that its action was specifically reversed by anti-Gbeta antibodies
      or a C-terminal beta-adrenergic receptor kinase-1 fragment containing the
      Gbetagamma-binding site of the enzyme, and was mimicked by exogenously supplied G
      protein betagamma-subunits. Isoproterenol signals through a prototypical G(s)
      coupled receptor. Consistent with these results, direct activation of G(s) by
      cholera toxin or by an anti-Galpha(s) antibody exhibiting beta-adrenergic
      receptor-mimetic properties (K-20) resulted in an isoproterenol-like inhibition
      of NADPH-dependent H(2)O(2) generation. In addition, a peptide corresponding to
      the target sequence of K-20 blocked the action of the catecholamine, apparently
      by competition between the peptide and G(s) for activated beta-adrenergic
      receptors, indicating that the G protein betagamma-subunits mediating the
      inhibitory effects of the catecholamine were in fact derived from G(s).

PMID- 10644705
TI  - Specific analysis in plasma and urine of 2,3-dinor-5, 6-dihydro-isoprostane
      F(2alpha)-III, a metabolite of isoprostane F(2alpha)-III and an oxidation product
      of gamma-linolenic acid.
AB  - F(2)-isoprostanes (iPs) are free radical-catalyzed isomers of prostaglandin
      F(2alpha). Circulating and urinary iPs have been used as indices of lipid
      peroxidation in vivo. Utilizing an (18)O-labeled homologous internal standard, we
      developed a gas chromatography/mass spectrometry assay for the 2,3-dinor-5,6
      dihydro (dinor-dihydro) metabolite of iPF(2alpha)-III. Although urinary excretion
      of iPF(2alpha)-III reflects systemic lipid peroxidation, the metabolite is more
      abundant (median of 877 (range of 351-1831) versus 174 (range of 56-321) pg/mg of
      creatinine; p < 0.01) than the parent iP in urine and can be measured in plasma.
      Metabolite analysis may be preferable in plasma due to the abundance of
      arachidonic acid as a source of ex vivo lipid peroxidation. Also, iPF(2alpha)-III
      may be formed in blood samples in a cyclooxygenase-dependent manner by platelets
      ex vivo. By contrast, the metabolite is not formed by aggregated platelets (0.71
      +/- 0.08 versus 0.65 +/- 0.09 pg/ml). Although the metabolite/parent ratio is
      altered in cirrhosis, urinary dinor-dihydro-iPF(2alpha)-III is elevated and
      increases further during reperfusion following orthoptic liver transplantation.
      In addition to its formation as an iPF(2) metabolite, analysis of gamma-linolenic
      acid autooxidation products and the compound present in freeze-thawed plasma
      suggests that gamma-linolenic acid may also be an important source of dinor
      dihydro-iPF(2alpha)-III.

PMID- 10644704
TI  - Sequential MCM/P1 subcomplex assembly is required to form a heterohexamer with
      replication licensing activity.
AB  - Replication licensing factor (RLF) is a multiprotein complex involved in ensuring
      that chromosomal DNA replicates only once in a single cell cycle. It comprises
      two components, termed RLF-M and RLF-B. Purified RLF-M consists of a mixture of
      complexes containing all six members of the MCM/P1 family of minichromosome
      maintenance proteins. The precise composition of these different complexes and
      their contribution to RLF-M activity has been unclear. Here we show that in
      Xenopus extracts, MCM/P1 proteins mainly form heterohexamers containing each of
      the six proteins. This heterohexamer is readily split into subcomplexes, whose
      interactions and subunit composition we characterize in detail. We show for the
      first time an ordered multistep assembly pathway by which the heterohexamer can
      be reformed from the subcomplexes. Importantly, this novel pathway is essential
      for DNA replication, since only the full heterohexamer can bind productively to
      chromatin and provide RLF-M activity.

PMID- 10644706
TI  - Thioredoxin 2 is involved in the oxidative stress response in Escherichia coli.
AB  - Two genes encoding thioredoxin are found on the Escherichia coli genome. Both of
      them are capable of reducing protein disulfide bonds in vivo and in vitro. The
      catalytic site contains a Cys-X(1)-X(2)-Cys motif in a so-called thioredoxin
      fold. Thioredoxin 2 has two additional pairs of cysteines in a non-conserved N
      terminal domain. This domain does not appear to be important for the function of
      thioredoxin 2 in donating electrons to ribonucleotide reductase, 3'
      phosphoadenylsulfate-reductase, or the periplasmic disulfide isomerase DsbC. Our
      results suggests that the two thioredoxins are equivalent for most of the in vivo
      functions that were tested. On the other hand, transcriptional regulation is
      different. The expression of trxC is regulated by the transcriptional activator
      OxyR in response to oxidative stress. Oxidized OxyR binds directly to the trxC
      promoter and induces its expression in response to elevated hydrogen peroxide
      levels or the disruption of one or several of the cytoplasmic redox pathways.
      Mutants lacking thioredoxins 1 and 2 are more resistant to high levels of
      hydrogen peroxide, whereas they are more sensitive to diamide, a disulfide bond
      inducing agent.

PMID- 10644707
TI  - Identification of a human brain-specific isoform of mammalian STE20-like kinase 3
      that is regulated by cAMP-dependent protein kinase.
AB  - A novel isoform of mammalian STE20-like kinase 3 (MST3) with a different 5'
      coding region from MST3, termed MST3b, was identified by searching through
      expressed sequence tag data base and obtained by rapid amplification of cDNA 5'
      ends. MST3b was assigned to the long arm of human chromosome 13, D13S159-D13S280,
      by use of the National Center for Biotechnology Information sequence-tagged sites
      data base. Reverse transcription-polymerase chain reaction and Northern blot
      analysis with a probe derived from 5' distinct sequence of MST3b revealed that
      the expression of MST3b mRNA is restricted to the brain, in contrast to
      ubiquitous distribution of MST3 transcript. Western analysis confirmed the brain
      specific expression of MST3b protein. In situ hybridization of rat brain sections
      with a MST3b-specific probe indicated that MST3b is widely expressed in different
      brain regions, with especially high expression in hippocampus and cerebral
      cortex. When expressed in human embryonic kidney 293 (HEK293) cells, MST3b
      effectively phosphorylated myelin basic protein, as well as undergoing
      autophosphorylation. Interestingly, expression of MST3, but not MST3b, in HEK293
      cells was able to activate the endogenous p42/44 mitogen-activated protein kinase
      (MAPK) up to 4-fold, whereas neither isoform activated p38 MAPK under the same
      conditions. Further experiments demonstrated that MST3b, but not MST3, was
      effectively phosphorylated by activation of cyclic AMP-dependent protein kinase
      (PKA) in both in vivo and in vitro assays. The mutation of Thr-18 into Ala in
      MST3b (T18A), a putative PKA phosphorylation site that is absent in MST3,
      abolished its phosphorylation by PKA. Consequently, expression of the T18A mutant
      in HEK293 cells led to partial activation of p42/44 MAPK, indicating that MST3b
      is under the regulation of PKA. Taken together, our data provide evidence that
      the two isoforms of STE20-like kinase 3 are differentially distributed and
      regulated.

PMID- 10644709
TI  - Selenite inhibits the c-Jun N-terminal kinase/stress-activated protein kinase
      (JNK/SAPK) through a thiol redox mechanism.
AB  - Selenium, an essential biological trace element, has been shown to modulate
      functions of many regulatory proteins involved in signal transduction and to
      affect a variety of cellular activities including cell growth, survival, and
      death. The molecular mechanism by which selenium exerts its action on the
      cellular events, however, remains unclear. In our present study, we observed that
      selenite suppresses both the c-Jun N-terminal kinase/stress-activated protein
      kinase (JNK/SAPK) and the p38 mitogen-activated protein kinase pathway in 293T
      cells. In contrast, selenite had little effect on the extracellular signal
      regulated kinase pathway. Furthermore, selenite directly inhibited JNK/SAPK
      activity in vitro but not the p38 activity. The in vitro inhibition of JNK/SAPK
      by selenite was reversed by the addition of reducing agents such as
      dithiothreitol and beta-mercaptoethanol. Replacement of cysteine 116 in JNK1 by
      serine abolished the inhibitory effect of selenite on JNK1 activity both in vitro
      and in vivo. Selenite also suppressed a c-Jun-dependent luciferase reporter
      activity stimulated through the JNK signaling pathway. Taken together, our
      findings strongly suggest that selenite differentially modulates the mammalian
      mitogen-activated protein kinase pathways and that it can repress the JNK/SAPK
      signaling pathway by inhibiting JNK/SAPK through a thiol redox mechanism.

PMID- 10644708
TI  - Action mechanism of antitubercular isoniazid. Activation by Mycobacterium
      tuberculosis KatG, isolation, and characterization of inha inhibitor.
AB  - Activation of the antitubercular isoniazid (INH) by the Mycobacterium
      tuberculosis KatG produces an inhibitor for enoyl reductase (InhA). The mechanism
      for INH activation remains poorly understood, and the inhibitor has never been
      isolated. We have purified the InhA-inhibitor complex generated in the M.
      tuberculosis KatG-catalyzed INH activation. The complex exhibited a 278-nm
      absorption peak and a shoulder around 326 nm with a characteristic A(326)/A(278)
      ratio of 0.16. The complex was devoid of enoyl reductase activity. The inhibitor
      noncovalently binds to InhA with a K(d) < 0.4 nM and can be dissociated from
      denatured InhA for chromatographic isolation. The free inhibitor showed
      absorption peaks at 326 (epsilon(326) 6900 M(-1) cm(-1)) and 260 nm (epsilon(260)
      27,000 M(-1) cm(-1)). The inactive complex can be reconstituted from InhA and the
      isolated inhibitor. The InhA inhibitor from the KatG-catalyzed INH activation was
      identical to that from a slow, KatG-independent, Mn(2+)-mediated reaction based
      on high pressure liquid chromatography analysis and absorption and mass spectral
      characteristics. By monitoring the formation of the InhA-inhibitor complex, we
      have found that manganese is not essential to the INH activation by M.
      tuberculosis KatG. Furthermore, the formation of the InhA inhibitor in the KatG
      reaction was independent of InhA.

PMID- 10644710
TI  - Distinct roles for the helicases of TFIIH in transcript initiation and promoter
      escape.
AB  - To provide an explanation of some clinical features observed within rare
      xeroderma pigmentosum (XP) patients and to further define the role of XPB, XPD,
      and cdk7, the three enzymatic subunits of TFIIH, in the transcription reaction,
      we have examined two defined enzymatic steps: phosphodiester bond formation and
      promoter escape. We provide evidence that the XPB helicase plays a dominant role
      in initiation, whereas the XPD helicase plays a minor contributing role in this
      step. The cyclin-activating kinase subcomplex of TFIIH improves the efficiency of
      initiation, but this involves only the structural contributions of cyclin
      activating kinase rather than enzymatic activity. We demonstrate that XPB patient
      derived mutants in TFIIH suffer from defects in initiation. Moreover, mutant
      analysis shows that in addition to its crucial role in initiation, the XPB
      helicase plays a critical enzymatic role in the promoter escape, whereas XPD
      plays an important structural role in the promoter escape process. Finally, using
      patient-derived mutations in TFIIH, we demonstrate deficiencies in promoter
      escape for both mutants of the class that suffer from combined xeroderma
      pigmentosum/Cockayne's syndrome.

PMID- 10644711
TI  - Membrane localization of TRAF 3 enables JNK activation.
AB  - Members of the tumor necrosis factor receptor family as well as other receptors
      achieve their diverse biological effects through the activation of intracellular
      signals including the c-Jun N-terminal kinase (JNK) pathway. Such signals are
      believed to be delivered through mediators known as TNF receptor-associated
      factors (TRAFs). Although the N-terminal zinc finger region of TRAFs has been
      shown to be essential for downstream signaling, there is no indication yet as to
      the nature of its role or of the factors that distinguish the N terminus of TRAF
      3, which does not activate JNK in the systems examined thus far, from those of
      other TRAFs, which do activate this pathway. In the present study, it is shown
      that, among the known TRAFs, localization to the insoluble cell pellet fraction
      consistently correlates with JNK activation and that both characteristics map to
      the TRAF N terminus. Furthermore, it is demonstrated that forced localization of
      TRAF 3 to the cell membrane is sufficient to convert this molecule into an
      activator of JNK. This suggests that one of the roles of the TRAF N terminus may
      be to participate in interactions that promote the recruitment of TRAFs to the
      membrane and that this localization effect plays an important role in TRAF
      mediated JNK activation.

PMID- 10644712
TI  - Engineering microsomal cytochrome P450 2C5 to be a soluble, monomeric enzyme.
      Mutations that alter aggregation, phospholipid dependence of catalysis, and
      membrane binding.
AB  - Deletion of the N-terminal membrane-spanning domain from microsomal P450s 2C5 and
      2C3 generates the enzymes, 2C5dH and 2C3dH, that exhibit a salt-dependent
      association with membranes indicating that they retain a monofacial membrane
      interaction domain. The two proteins are tetramers and dimers, respectively, in
      high salt buffers, and only 2C5dH requires phospholipids to reconstitute fully
      the catalytic activity of the enzyme. Amino acid residues derived from P450 2C3dH
      between residues 201 and 210 were substituted for the corresponding residues in
      P450 2C5 to identify those that would diminish the membrane interaction, the
      phospholipid dependence of catalysis, and aggregation of 2C5dH. Each of four
      substitutions, N202H, I207L, S209G, and S210T, diminished the aggregation of P450
      2C5dH and produced a monomeric enzyme. The N202H and I207L mutations also
      diminished the stimulation of catalytic activity by phospholipid and reduced the
      binding of P450 2C5dH to phospholipid vesicles. The modified enzymes exhibit
      rates of progesterone 21-hydroxylation that are similar to that of P450 2C5dH.
      These conditionally membrane-bound P450s with improved solubility in high salt
      buffers are suitable for crystallization and structural determination by x-ray
      diffraction studies.

PMID- 10644713
TI  - Identification of an alternatively spliced seprase mRNA that encodes a novel
      intracellular isoform.
AB  - Seprase is a homodimeric 170-kDa integral membrane gelatinase that is related to
      the ectoenzyme dipeptidyl peptidase IV. We have identified an alternatively
      spliced seprase messenger from the human melanoma cell line LOX that encodes a
      novel truncated isoform, seprase-s. The splice variant mRNA is generated by an
      out-of-frame deletion of a 1223-base pair exonic region that encodes part of the
      cytoplasmic tail, transmembrane, and the membrane proximal-central regions of the
      extracellular domain (Val(5) through Ser(412)) of the seprase 97-kDa subunit
      (seprase-l). The seprase-s mRNA has an elongated 5' leader (548 nucleotides) that
      harbors at least two upstream open reading frames that inhibit seprase-s
      expression from a downstream major open reading frame. Deletion mutagenesis of
      the wild type splice variant cDNA confirms that initiation of the seprase-s
      coding sequence begins with an ATG codon that corresponds to Met(522) of seprase
      l. The seprase-s open reading frame encodes a 239-amino acid polypeptide with an
      M(r) approximately 27,000 that precisely overlaps the carboxyl-terminal catalytic
      region of seprase-l.

PMID- 10644714
TI  - Insulin-responsive aminopeptidase trafficking in 3T3-L1 adipocytes.
AB  - The insulin-responsive aminopeptidase (IRAP/VP165/gp160) was identified
      originally in GLUT4-containing vesicles and shown to translocate in response to
      insulin, much like the glucose transporter 4 (GLUT4). This study characterizes
      the trafficking and kinetics of IRAP in exocytosis, endocytosis, and recycling to
      the membrane in 3T3-L1 adipocytes. After exposure of 3T3-L1 adipocytes to
      insulin, IRAP translocated to the plasma membrane as assessed by either cell
      fractionation, surface biotinylation, or the plasma membrane sheet assay. The
      rate of exocytosis closely paralleled that of GLUT4. In the continuous presence
      of insulin, IRAP was endocytosed with a half-time of about 3-5 min. IRAP
      endocytosis is inhibited by cytosol acidification, a property of clathrin
      mediated endocytosis, but not by the expression of a constitutively active
      Akt/PKB. Arrival in an LDM fraction derived via subcellular fractionation
      exhibited a slower time course than disappearance from the cell surface,
      suggesting additional endocytic intermediates. As assayed by membrane "sheets,"
      GLUT4 and IRAP showed similar internalization rates that are wortmannin
      insensitive and occur with a half-time of roughly 5 min. IRAP remaining on the
      cell surface 10 min following insulin removal was both biotin- and avidin
      accessible, implying the absence of thin-necked invaginations. Finally,
      endocytosed IRAP quickly recycled back to the plasma membrane in a wortmannin
      sensitive process. These results demonstrate rapid endocytosis and recycling of
      IRAP in the presence of insulin and trafficking that matches GLUT4 in rate.

PMID- 10644715
TI  - Protein kinase C-dependent alpha-secretase competes with beta-secretase for
      cleavage of amyloid-beta precursor protein in the trans-golgi network.
AB  - The release of amyloidogenic amyloid-beta peptide (Abeta) from amyloid-beta
      precursor protein (APP) requires cleavage by beta- and gamma-secretases. In
      contrast, alpha-secretase cleaves APP within the Abeta sequence and precludes
      amyloidogenesis. Regulated and unregulated alpha-secretase activities have been
      reported, and the fraction of cellular alpha-secretase activity regulated by
      protein kinase C (PKC) has been attributed to the ADAM (a disintegrin and
      metalloprotease) family members TACE and ADAM-10. Although unregulated alpha
      secretase cleavage of APP has been shown to occur at the cell surface, we sought
      to identify the intracellular site of PKC-regulated alpha-secretase APP cleavage.
      To accomplish this, we measured levels of secreted ectodomains and C-terminal
      fragments of APP generated by alpha-secretase (sAPPalpha) (C83) versus beta
      secretase (sAPPbeta) (C99) and secreted Abeta in cultured cells treated with PKC
      and inhibitors of TACE/ADAM-10. We found that PKC stimulation increased sAPPalpha
      but decreased sAPPbeta levels by altering the competition between alpha- versus
      beta-secretase for APP within the same organelle rather than by perturbing APP
      trafficking. Moreover, data implicating the trans-Golgi network (TGN) as a major
      site for beta-secretase activity prompted us to hypothesize that PKC-regulated
      alpha-secretase(s) also reside in this organelle. To test this hypothesis, we
      performed studies demonstrating proteolytically mature TACE intracellularly, and
      we also showed that regulated alpha-secretase APP cleavage occurs in the TGN
      using an APP mutant construct targeted specifically to the TGN. By detecting
      regulated alpha-secretase APP cleavage in the TGN by TACE/ADAM-10, we reveal ADAM
      activity in a novel location. Finally, the competition between TACE/ADAM-10 and
      beta-secretase for intracellular APP cleavage may represent a novel target for
      the discovery of new therapeutic agents to treat Alzheimer's disease.

PMID- 10644716
TI  - Effect of arginine 172 on the binding of apolipoprotein E to the low density
      lipoprotein receptor.
AB  - The region of apolipoprotein E (apoE) that interacts directly with the low
      density lipoprotein (LDL) receptor lies in the vicinity of residues 136-150,
      where lysine and arginine residues are crucial for full binding activity.
      However, defective binding of carboxyl-terminal truncations of apoE3 has
      suggested that residues in the vicinity of 170-183 are also important. To
      characterize and define the role of this region in LDL receptor binding, we
      created either mutants of apoE in which this region was deleted or in which
      arginine residues within this region were sequentially changed to alanine.
      Deletion of residues 167-185 reduced binding activity (15% of apoE3), and
      elimination of arginines at positions 167, 172, 178, and 180 revealed that only
      position 172 affected binding activity (2% of apoE3). Substitution of lysine for
      Arg(172) reduced binding activity to 6%, indicating a specific requirement for
      arginine at this position. The higher binding activity of the Delta167-185 mutant
      relative to the Arg(172) mutant (15% versus 2%) is explained by the fact that
      arginine residues at positions 189 and 191 are shifted in the deletion mutant
      into positions equivalent to 170 and 172 in the intact protein. Mutation of these
      residues and modeling the region around these residues suggested that the
      influence of Arg(172) on receptor binding activity may be determined by its
      orientation at a lipid surface. Thus, the association of apoE with phospholipids
      allows Arg(172) to interact directly with the LDL receptor or with other residues
      in apoE to promote its receptor-active conformation.

PMID- 10644718
TI  - Isoform diversity among fibroblast growth factor homologous factors is generated
      by alternative promoter usage and differential splicing.
AB  - Fibroblast growth factor (FGF) homologous factors-1, -2, -3, and -4 (FHFs 1-4;
      also referred to as FGFs 11-14) comprise a separate branch of the FGF family and
      have been implicated in the development of the nervous system and limbs. We
      report here the characterization of multiple isoforms of FHF-1, -2, -3, and -4
      which are generated through the use of alternative start sites of transcription
      and splicing of one or more of a series of alternative 5'-exons. Several isoforms
      show different subcellular distributions when expressed in transfected tissue
      culture cells, and the corresponding differentially spliced transcripts show
      distinct expression patterns in developing and adult mouse tissues. Together with
      the evolutionary conservation of the FHF isoforms among human, mouse, and
      chicken, these data indicate that alternative promoter use and differential
      splicing are important regulatory processes in controlling the activities of this
      subfamily of FGFs.

PMID- 10644717
TI  - Characterization of a novel human serine protease that has extensive homology to
      bacterial heat shock endoprotease HtrA and is regulated by kidney ischemia.
AB  - We report the isolation and characterization of a cDNA encoding the novel
      mammalian serine protease Omi. Omi protein consists of 458 amino acids and has
      homology to bacterial HtrA endoprotease, which acts as a chaperone at low
      temperatures and as a proteolytic enzyme that removes denatured or damaged
      substrates at elevated temperatures. The carboxyl terminus of Omi has extensive
      homology to a mammalian protein called L56 (human HtrA), but unlike L56, which is
      secreted, Omi is localized in the endoplasmic reticulum. Omi has several novel
      putative protein-protein interaction motifs, as well as a PDZ domain and a Src
      homology 3-binding domain. Omi mRNA is expressed ubiquitously, and the gene is
      localized on human chromosome 2p12. Omi interacts with Mxi2, an alternatively
      spliced form of the p38 stress-activated kinase. Omi protein, when made in a
      heterologous system, shows proteolytic activity against a nonspecific substrate
      beta-casein. The proteolytic activity of Omi is markedly up-regulated in the
      mouse kidney following ischemia/reperfusion.

PMID- 10644719
TI  - Characterization of myosin V binding to brain vesicles.
AB  - Myosin II and V are important for the generation and segregation of subcellular
      compartments. We observed that vesicular myosin II and V were associated with the
      protein scaffolding of a common subset of vesicles by density sedimentation,
      electron microscopy, and immunofluorescence. Solubilization of either myosin II
      or V was caused by polyphosphates with the following efficacy at 10 mM: for
      myosin II ATP-Mg(2+) = ATP = AMP-PNP (5'-adenylyl imidodiphosphate) >
      pyrophosphate = tripolyphosphate > tetrapolyphosphate = ADP > cAMP = Mg(2+); and
      for myosin V pyrophosphate = tripolyphosphate > ATP-Mg(2+) = ATP = AMP-PNP > ADP
      = tetrapolyphosphate > cAMP = Mg(2+). Consequently, we suggest solubilization was
      not an effect of phosphorylation, hydrolysis, or disassociation of myosin from
      actin filaments. Scatchard analysis of myosin V binding to stripped dense
      vesicles showed saturable binding with a K(m) of 10 nM. Analysis of native
      vesicles indicates that these sites are fully occupied. Together, these data show
      there are over 100 myosin Vs/vesicle (100-nm radius). We propose that
      polyphosphate anions bind to myosin II and V and induce a conformational change
      that disrupts binding to a receptor.

PMID- 10644721
TI  - Steady-state and rapid kinetic analysis of topoisomerase II trapped as the closed
      clamp intermediate by ICRF-193.
AB  - DNA topoisomerase II uses a complex, sequential mechanism of ATP hydrolysis to
      catalyze the transport of one DNA duplex through a transient break in another.
      ICRF-193 is a catalytic inhibitor of topoisomerase II that is known to trap a
      closed-clamp intermediate form of the enzyme. Using steady-state and rapid
      kinetic ATPase and DNA transport assays, we have analyzed how trapping this
      intermediate by the drug perturbs the topoisomerase II mechanism. The drug has no
      effect on the rate of the first turnover of decatenation but potently inhibits
      subsequent turnovers with an IC(50) of 6.5 +/- 1 microM for the Saccharomyces
      cerevisiae enzyme. This drug inhibits the ATPase activity of topoisomerase II by
      an unusual, mixed-type mechanism; the drug is not a competitive inhibitor of ATP,
      and even at saturating concentrations of drug, the enzyme continues to hydrolyze
      ATP, albeit at a reduced rate. Topoisomerase II that was specifically isolated in
      the drug-bound, closed-clamp form continues to hydrolyze ATP, indicating that the
      enzyme clamp does not need to re-open to bind and hydrolyze ATP. When rapid
      quench ATPase assays were initiated by the addition of ATP, the drug had no
      effect on the sequential hydrolysis of either the first or second ATP. By
      contrast, when the drug was prebound, the enzyme hydrolyzed one labeled ATP at
      the uninhibited rate but did not hydrolyze a second ATP. These results are
      interpreted in terms of the catalytic mechanism for topoisomerase II and suggest
      that ICRF-193 interacts with the enzyme bound to one ADP.

PMID- 10644720
TI  - Role of lumican in the corneal epithelium during wound healing.
AB  - Lumican regulates collagenous matrix assembly as a keratan sulfate proteoglycan
      in the cornea and is also present in the connective tissues of other organs and
      embryonic corneal stroma as a glycoprotein. In normal unwounded cornea, lumican
      is expressed by stromal keratocytes. Our data show that injured mouse corneal
      epithelium ectopically and transiently expresses lumican during the early phase
      of wound healing, suggesting a potential lumican functionality unrelated to
      regulation of collagen fibrillogenesis, e. g. modulation of epithelial cell
      adhesion or migration. An anti-lumican antibody was found to retard corneal
      epithelial wound healing in cultured mouse eyes. Healing of a corneal epithelial
      injury in Lum(-/-) mice was significantly delayed compared with Lum(+/-) mice.
      These observations indicate that lumican expressed in injured epithelium may
      modulate cell behavior such as adhesion or migration, thus contributing to
      corneal epithelial wound healing.

PMID- 10644722
TI  - An artificial gene for human porphobilinogen synthase allows comparison of an
      allelic variation implicated in susceptibility to lead poisoning.
AB  - Porphobilinogen synthase (PBGS) is an ancient enzyme essential to tetrapyrrole
      biosynthesis (e.g. heme, chlorophyll, and vitamin B(12)). Two common alleles
      encoding human PBGS, K59 and N59, have been correlated with differential
      susceptibility of humans to lead poisoning. However, a model for human PBGS based
      on homologous crystal structures shows the location of the allelic variation to
      be distant from the active site with its two Zn(II). Previous microbial
      expression systems for human PBGS have resulted in a poor yield. Here, an
      artificial gene encoding human PBGS was constructed by recursive polymerase chain
      reaction from synthetic oligonucleotides to rectify this problem. The artificial
      gene was made to resemble the highly expressed homologous Escherichia coli hemB
      gene and to remove rare codons that can confound heterologous protein expression
      in E. coli. We have expressed and purified recombinant human PBGS variants K59
      and N59 in 100-mg quantities. Both human PBGS proteins purified with eight
      Zn(II)/octamer; Zn(II) binding was shown to be pH-dependent; and Pb(II) could
      displace some of the Zn(II). However, there was no differential displacement of
      Zn(II) by Pb(II) between K59 and N59, and simple Pb(II) inhibition studies
      revealed no allelic difference.

PMID- 10644723
TI  - PAR1 thrombin receptor-G protein interactions. Separation of binding and coupling
      determinants in the galpha subunit.
AB  - Signal transfer between the protease-activated PAR1 thrombin receptor and
      membrane-associated heterotrimeric G proteins is mediated by protein-protein
      interactions. We constructed a yeast signaling system that resolves domain
      specific functions of binding from coupling in the Galpha subunit. The endogenous
      yeast Galpha subunit, Gpa1, does not bind to PAR1 and served as a null structural
      template. N- and C-terminal portions of mammalian G(i2) and G(16) were
      substituted back into the Gpa1 template and gain-of-function assessed. The C
      terminal third of G(16), but not of G(i2), provides sufficient interactions for
      coupling to occur with PAR1. The N-terminal two-thirds of G(i2) also contains
      sufficient determinants to bind and couple to PAR1 and overcome the otherwise
      negative or missing interactions supplied by the C-terminal third of Gpa1.
      Replacement of the N-terminal alpha-helix of G(i2), residues 1-34, with those of
      Gpa1 abolishes coupling but not binding to PAR1 or to betagamma subunits. These
      data support a model that the N-terminal alphaN helix of the Galpha subunit is
      physically interposed between PAR1 and the Gbeta subunit and directly assists in
      transferring the signal between agonist-activated receptor and G protein.

PMID- 10644724
TI  - Cholesterol 3-sulfate interferes with cornified envelope assembly by diverting
      transglutaminase 1 activity from the formation of cross-links and esters to the
      hydrolysis of glutamine.
AB  - The loss of transglutaminase 1 enzyme (TGase 1) activity causes lamellar
      ichthyosis. Recessive X-linked ichthyosis (XI) results from accumulation of
      excess cholesterol 3-sulfate (CSO(4)) in the epidermis but the pathomechanism how
      elevated epidermal CSO(4) causes ichthyosis is largely unknown. Here we provide
      evidence that XI is also a consequence of TGase 1 dysfunction. TGase 1 is a key
      component of barrier formation in keratinocytes: it participates in the cross
      linking of cell envelope (CE) structural proteins, and also forms the lipid bound
      envelope by esterification of long chain omega-hydroxyceramides onto CE proteins.
      Using involucrin and an epidermal omega-hydroxyceramide analog as substrates,
      kinetic analyses revealed that at membrane concentrations above 4 mol %, CSO(4)
      caused a marked and dose-dependent inhibitory effect on isopeptide and ester bond
      formation. Sequencing of tryptic peptides from TGase 1-reacted involucrin showed
      a large increase in deamidation of substrate glutamines. We hypothesize that
      supraphysiological levels of CSO(4) in keratinocyte membranes distort the
      structure of TGase 1 and facilitate the access of water into its active site
      causing hydrolysis of substrate glutamine residues. Our findings provide further
      evidence for the pivotal role of the TGase 1 enzyme in CE formation.

PMID- 10644725
TI  - Molecular cloning and characterization of Amida, a novel protein which interacts
      with a neuron-specific immediate early gene product arc, contains novel nuclear
      localization signals, and causes cell death in cultured cells.
AB  - Amida was isolated by the yeast two-hybrid system as a novel protein which
      associated with Arc, a non-transcriptional immediate early gene specific to the
      brain. Amida was confirmed to be associated with Arc in vitro and in vivo. Amida
      shows no homology to known proteins. Amida is ubiquitously expressed, although it
      is abundant in the brain. A transfection study revealed that Amida was localized
      in the nucleus and after 72 h the transfected cells underwent apoptosis.
      Furthermore, we found two nuclear localization signals and a domain needed for
      interacting with Arc was encompassed by two nuclear localization signals. Co
      transfection experiment with Amida and Arc suggested that Amida transported Arc
      into the nucleus and negatively regulated Amida-induced cell death. These results
      indicate that Arc together with Amida may modulate cell death in the brain.

PMID- 10644726
TI  - The nuclear receptor chicken ovalbumin upstream promoter transcription factor
      interacts with HIV-1 Tat and stimulates viral replication in human microglial
      cells.
AB  - Human immunodeficiency virus type 1 (HIV-1) infects the central nervous system
      and plays a direct role in the pathogenesis of AIDS dementia. However, the
      molecular mechanisms underlying HIV-1 expression in the central nervous system
      are poorly understood. We have recently reported that the nuclear receptor
      chicken ovalbumin upstream promoter transcription factor (COUP-TF), an orphan
      member of the nuclear receptor superfamily, is an activator of HIV-1 gene
      transcription. Here, our results show that COUP-TF stimulates HIV-1 transcription
      in primary cultured human microglial cells, the primary target for HIV-1
      infection in brain. Run-on assays indicated that COUP-TF acts on the initiation
      step of transcription. Results from reverse transcription-polymerase chain
      reaction and immunocytochemistry analysis further revealed the importance of this
      factor by demonstrating that overexpression of COUP-TF leads to initiation of
      viral replication in primary HIV-infected human microglia. In addition, COUP-TF
      is able to physically interact and cooperate with the viral transactivator Tat.
      The combination of COUP-TF and Tat leads to NF-kappaB- and Sp1-independent
      enhanced transcriptional stimulation. In vitro binding studies showed that COUP
      TF interacts with Tat through amino acids within the N-terminal DNA-binding
      domain of COUP-TF. Amino acids 48-72 in the basic and C-terminal regions of Tat
      are required for the binding of Tat to COUP-TF. These results suggest that COUP
      TF is an essential transcription factor involved in HIV-1 expression in microglia
      and reveal a novel interplay of Tat and COUP-TF during regulation of viral
      expression.

PMID- 10644727
TI  - Characterization of the monomeric and dimeric forms of latent and active matrix
      metalloproteinase-9. Differential rates for activation by stromelysin 1.
AB  - Matrix metalloproteinase-9 (MMP-9) is a member of the MMP family that has been
      associated with degradation of the extracellular matrix in normal and
      pathological conditions. A unique characteristic of MMP-9 is its ability to exist
      in a monomeric and a disulfide-bonded dimeric form. However, there exists a
      paucity of information on the properties of the latent (pro-MMP-9) and active MMP
      9 dimer. Here we report the purification to homogeneity of the monomer and dimer
      forms of pro-MMP-9 and the characterization of their biochemical properties and
      interactions with tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2. Gel
      filtration and surface plasmon resonance analyses demonstrated that the pro-MMP-9
      monomeric and dimeric forms bind TIMP-1 with similar affinities. In contrast,
      TIMP-2 binds only to the active forms. After activation, the two enzyme forms
      exhibited equal catalytic competence in the turnover of a synthetic peptide
      substrate with comparable kinetic parameters for the onset of inhibition with
      TIMPs and for dissociation of the inhibited complexes. Kinetic analyses of the
      activation of monomeric and dimeric pro-MMP-9 by stromelysin 1 revealed K(m)
      values in the nanomolar range and relative low k(cat) values (1.9 x 10(-3) and
      4.1 x 10(-4) s(-1), for the monomer and dimer, respectively) consistent with a
      faster rate (1 order of magnitude) of activation of the monomeric form by
      stromelysin 1. This suggests that the rate-limiting event in the activation of
      pro-MMP-9 may be a requisite slow unfolding of pro-MMP-9 near the site of the
      hydrolytic cleavage by stromelysin 1.

PMID- 10644728
TI  - Rhodopsin recognition by mutant G(s)alpha containing C-terminal residues of
      transducin.
AB  - The C-terminal regions of the heterotrimeric G protein alpha-subunits play key
      roles in selective activation of G proteins by their cognate receptors. In this
      study, mutant G(s)alpha proteins with substitutions by C-terminal residues of
      transducin (G(t)alpha) were analyzed for their interaction with light-activated
      rhodopsin (R*) to delineate the critical determinants of the G(t)alpha/R*
      coupling. In contrast to G(s)alpha, a chimeric G(s)alpha/G(t)alpha protein
      containing only 11 C-terminal residues from transducin was capable of binding to
      and being potently activated by R*. Our results suggest that Cys(347) and
      Gly(348) are absolutely essential, whereas Asp(346) is more modestly involved in
      the G(t) activation by R*. In addition, the analysis of the intrinsic nucleotide
      exchange in mutant G(s)alpha indicated an interaction between the C terminus and
      the switch II region in G(t)alpha.GDP. Mutant G(s)alpha containing the G(t)alpha
      C terminus and substitutions of Asn(239) and Asp(240) (switch II) by the
      corresponding G(t)alpha residues, Glu(212) and Gly(213), displayed significant
      reductions in spontaneous guanosine 5'-O-(3-thiotriphosphate)-binding rates to
      the levels approaching those in G(t)alpha. Communication between the C terminus
      and switch II of G(t)alpha does not appear essential for the activational
      coupling between G(t) and R*, but may represent one of the mechanisms by which
      Galpha subunits control intrinsic nucleotide exchange.

PMID- 10644729
TI  - De novo design of peptides targeted to the EF hands of calmodulin.
AB  - This report describes the use of the concept of inversion of hydropathy patterns
      to the de novo design of peptides targeted to a predetermined site on a protein.
      Eight- and 12-residue peptides were constructed with the EF hands or Ca(2+)
      coordinating sites of calmodulin as their anticipated points of interaction.
      These peptides, but not unrelated peptides nor those with the same amino acid
      composition but a scrambled sequence, interacted with the two carboxyl-terminal
      Ca(2+)-binding sites of calmodulin as well as the EF hands of troponin C. The
      interactions resulted in a conformational change whereby the 8-mer peptide
      calmodulin complex could activate phosphodiesterase in the absence of Ca(2+). In
      contrast, the 12-mer peptide-calmodulin complex did not activate
      phosphodiesterase but rather inhibited activation by Ca(2+). This inhibition
      could be overcome by high levels of Ca(2+). Thus, it would appear that the
      aforementioned concept can be used to make peptide agonists and antagonists that
      are targeted to predetermined sites on proteins such as calmodulin.

PMID- 10644730
TI  - Carbon dioxide permeability of aquaporin-1 measured in erythrocytes and lung of
      aquaporin-1 null mice and in reconstituted proteoliposomes.
AB  - Measurements of CO(2) permeability in oocytes and liposomes containing water
      channel aquaporin-1 (AQP1) have suggested that AQP1 is able to transport both
      water and CO(2). We studied the physiological consequences of CO(2) transport by
      AQP1 by comparing CO(2) permeabilities in erythrocytes and intact lung of wild
      type and AQP1 null mice. Erythrocytes from wild-type mice strongly expressed AQP1
      protein and had 7-fold greater osmotic water permeability than did erythrocytes
      from null mice. CO(2) permeability was measured from the rate of intracellular
      acidification in response to addition of CO(2)/HCO(3)(-) in a stopped-flow
      fluorometer using 2',7'-bis-(2-carboxyethyl)-5-(and -6)-carboxyfluorescein
      (BCECF) as a cytoplasmic pH indicator. In erythrocytes from wild-type mice,
      acidification was rapid (t((1)/(2)), 7.3 +/- 0.4 ms, S.E., n = 11 mice) and
      blocked by acetazolamide and increasing external pH (to decrease CO(2)/HCO(3)(-)
      ratio). Apparent CO(2) permeability (P(CO(2))) was not different in erythrocytes
      from wild-type (0.012 +/- 0.0008 cm/s) versus null (0.011 +/- 0.001 cm/s) mice.
      Lung CO(2) transport was measured in anesthetized, ventilated mice subjected to a
      decrease in inspired CO(2) content from 5% to 0%, producing an average decrease
      in arterial blood pCO(2) from 77 +/- 4 to 39 +/- 3 mm Hg (14 mice) with a
      t((1)/(2)) of 1.4 min. The pCO(2) values and kinetics of decreasing pCO(2) were
      not different in wild-type versus null mice. Because AQP1 deletion did not affect
      CO(2) transport in erythrocytes and lung, we re-examined CO(2) permeability in
      AQP1-reconstituted liposomes containing carbonic anhydrase (CA) and a fluorescent
      pH indicator. Whereas osmotic water permeability in AQP1-reconstituted liposomes
      was >100-fold greater than that in control liposomes, apparent P(CO(2))
      (approximately 10(-3) cm/s) did not differ. Measurements using different CA
      concentrations and HgCl(2) indicated that liposome P(CO(2)) is unstirred layer
      limited and that HgCl(2) slows acidification because of inhibition of CA rather
      than AQP1. These results provide direct evidence against physiologically
      significant AQP1-mediated CO(2) transport and establish an upper limit to the
      CO(2) permeability through single AQP1 water channels.

PMID- 10644731
TI  - Recruitment of Stat4 to the human interferon-alpha/beta receptor requires
      activated Stat2.
AB  - Stat4 activation is involved in differentiation of type 1 helper (Th1) T cells.
      Although Stat4 is activated by interleukin (IL)-12 in both human and murine T
      cells, Stat4 is activated by interferon (IFN)-alpha only in human, but not
      murine, CD4(+) T cells. This species-specific difference in cytokine activation
      of Stat4 underlies critical differences in Th1 development in response to
      cytokines and is important to the interpretation of murine models of
      immunopathogenesis. Here, we sought to determine the mechanism of Stat4
      recruitment and activation by the human IFN-alpha receptor. Analysis of
      phosphopeptide binding analysis suggests that Stat4 does not interact directly
      with tyrosine-phosphorylated amino acid residues within the cytoplasmic domains
      of either of the subunits of the IFN-alpha receptor complex. Expression of murine
      Stat4 in the Stat1-deficient U3A and the Stat2-deficient U6A cell lines shows
      that IFN-alpha-induced Stat4 phosphorylation requires the presence of activated
      Stat2 but not Stat1. Thus, in contrast to the direct recruitment of Stat4 by the
      IL-12 receptor, Stat4 activation by the human IFN-alpha receptor occurs through
      indirect recruitment by intermediates involving Stat2.

PMID- 10644732
TI  - Critical role of the linker region between helix D and strand 2A in heparin
      activation of antithrombin.
AB  - The binding of pentasaccharide heparin to antithrombin induces a conformational
      change that is transmitted to the reactive center loop and increases the rate of
      inhibition of factor Xa by approximately 300-fold. The mechanism of such
      transmission is not known. To test the role of residues 134-137, which link helix
      D to beta-sheet A, in this signal transduction, we created variant antithrombins
      in which we removed amino acids 134-137 stepwise and cumulatively. Although the
      deletions did not compromise the fundamental ability of antithrombin to bind to
      heparin or to inhibit target proteinases thrombin and factor Xa, they did largely
      decouple conformational changes in the heparin-binding site from conformational
      activation of the reactive center loop. Because the variant with only Ala(134)
      removed was as compromised as variants with larger deletions, yet the variant
      with Ser(137) removed was normal, we concluded that the length of the linker is
      less important than the precise interrelationship between residues in this region
      and other residues involved in conformational activation of antithrombin.

PMID- 10644733
TI  - Probing the structure of the PI-SceI-DNA complex by affinity cleavage and
      affinity photocross-linking.
AB  - The PI-SceI protein is an intein-encoded homing endonuclease that initiates the
      mobility of its gene by making a double strand break at a single site in the
      yeast genome. The PI-SceI protein splicing and endonucleolytic active sites are
      separately located in each of two domains in the PI-SceI structure. To determine
      the spatial relationship between bases in the PI-SceI recognition sequence and
      selected PI-SceI amino acids, the PI-SceI-DNA complex was probed by photocross
      linking and affinity cleavage methods. Unique solvent-accessible cysteine
      residues were introduced into the two PI-SceI domains at positions 91, 97, 170,
      230, 376, and 378, and the mutant proteins were modified with either 4
      azidophenacyl bromide or iron (S)-1-(p-bromoacetamidobenzyl)
      ethylenediaminetetraacetate (FeBABE). The phenyl azide-coupled proteins cross
      linked to the PI-SceI target sequence, and the FeBABE-modified proteins cleaved
      the DNA proximal to the derivatized amino acid. The results suggest that an
      extended beta-hairpin loop in the endonuclease domain that contains residues 376
      and 378 contacts the major groove near the PI-SceI cleavage site. Conversely,
      residues 91, 97, and 170 in the protein splicing domain are in close proximity to
      a distant region of the substrate. To interpret our results, we used a new PI
      SceI structure that is ordered in regions of the protein that bind DNA. The data
      strongly support a model of the PI-SceI-DNA complex derived from this structure.

PMID- 10644734
TI  - Combinatorial analysis of the structural requirements of the Escherichia coli
      hemolysin signal sequence.
AB  - We have investigated the substrate specificity of the Escherichia coli hemolysin
      transporter system. Translocation of hemolysin is dependent on a C-terminal
      signal sequence located within the last 60 amino acids of this protein. Previous
      comparative studies of the signal sequence have revealed a conserved
      helix(alpha1)-linker-helix(alpha2) motif, suggesting that secondary structure is
      important for transport. In this study, we generated three random libraries in
      the alpha1, linker, and alpha2 regions, as well as an alpha1-amphiphilic helical
      library to identify features buried within the structural motif that contribute
      to transport. Combinatorial variants were generated by altering the primary
      sequence of specific regions, and correlation between the genotype and phenotype
      of the mutant populations allowed us to objectively identify any functional
      features involved. It was found that the alpha1-amphiphilic helix and the linker
      are both important for function. To our surprise, the second helix of the
      conserved structural motif was not essential for transport. The finding that a
      predicted amphiphilic helix and hydrophobicity, rather than primary sequence,
      contribute to transport in the alpha1 region allows us to speculate on the
      mechanism of multiple substrate recognition. This may have implications for
      understanding the broad substrate specificity common among other ATP-binding
      cassette transporters.

PMID- 10644735
TI  - Reciprocal regulation of Hck activity by phosphorylation of Tyr(527) and
      Tyr(416). Effect of introducing a high affinity intramolecular SH2 ligand.
AB  - The Src family tyrosine kinase Hck possesses two phosphorylation sites, Tyr(527)
      and Tyr(416), that affect the catalytic activity in opposite ways. When
      phosphorylated, Tyr(527) and residues C-terminal to it are involved in an
      inhibitory intramolecular interaction with the SH2 domain. However, this sequence
      does not conform to the sequence of the high affinity SH2 ligand, pYEEI. We
      mutated this sequence to YEEI and show that this mutant form of Hck cannot be
      activated by exogenous SH2 ligands. The SH3 domain of Hck is also involved in an
      inhibitory interaction with the catalytic domain. The SH3 ligand Nef binds to and
      activates YEEI-Hck mutant in a similar manner to wild-type Hck, indicating that
      disrupting the SH3 interaction overrides the strengthened SH2 interaction. The
      other phosphorylation site, Tyr(416), is the autophosphorylation site in the
      activation loop. Phosphorylation of Tyr(416) is required for Hck activation. We
      mutated this residue to alanine and characterized its catalytic activity. The
      Y416A mutant shows a higher K(m) value for peptide and a lower V(max) than
      autophosphorylated wild-type Hck. We also present evidence for cross-talk between
      the activation loop and the intramolecular binding of the SH2 and SH3 domains.

PMID- 10644736
TI  - Methylation patterns of the E-cadherin 5' CpG island are unstable and reflect the
      dynamic, heterogeneous loss of E-cadherin expression during metastatic
      progression.
AB  - Metastatic progression of most common epithelial tumors involves a heterogeneous,
      transient loss of expression of the homotypic cell adhesion protein, E-cadherin,
      rather than the uniform loss of a functional protein resulting from coding region
      mutation. Indeed, whereas E-cadherin loss may promote invasion, reexpression may
      facilitate cell survival within metastatic deposits. The mechanisms underlying
      such plasticity are unclear. We now show that the heterogeneous loss of E
      cadherin expression in primary human breast cancers reflects a heterogeneous
      pattern of promoter region methylation, which begins early prior to invasion. In
      cultured human tumor cells, such heterogeneous methylation is dynamic, varying
      from allele to allele and shifting in relation to the tumor microenvironment.
      Following invasion in vitro, which favors diminished E-cadherin expression, the
      density of promoter methylation markedly increased. When these cells were
      cultured as spheroids, which requires homotypic cell adhesion, promoter
      methylation decreased dramatically, and E-cadherin was reexpressed. These data
      show that the methylation associated with E-cadherin loss in human breast cancer
      is heterogeneous and unstable and suggest that such epigenetic plasticity may
      contribute to the dynamic, phenotypic heterogeneity that drives metastatic
      progression.

PMID- 10644737
TI  - Mitochondrial activity is involved in the regulation of myoblast differentiation
      through myogenin expression and activity of myogenic factors.
AB  - To characterize the regulatory pathways involved in the inhibition of cell
      differentiation induced by the impairment of mitochondrial activity, we
      investigated the relationships occurring between organelle activity and
      myogenesis using an avian myoblast cell line (QM7). The inhibition of
      mitochondrial translation by chloramphenicol led to a potent block of myoblast
      differentiation. Carbonyl cyanide p-(trifluoromethoxy) phenylhydrazone and
      oligomycin, which affect the organelle at different levels, exerted a similar
      influence. In addition, we provided evidence that this phenomenon was not the
      result of an alteration in cell viability. Conversely, overexpression of the
      mitochondrial T3 receptor (p43) stimulated organelle activity and strongly
      potentiated myoblast differentiation. The involvement of mitochondrial activity
      in an actual regulation of myogenesis is further supported by results
      demonstrating that the muscle regulatory gene myogenin, in contrast to CMD1
      (chicken MyoD) and myf5, is a specific transcriptional target of mitochondrial
      activity. Whereas myogenin mRNA and protein levels were down-regulated by
      chloramphenicol treatment, they were up-regulated by p43 overexpression, in a
      positive relationship with the expression level of the transgene. We also found
      that myogenin or CMD1 overexpression in chloramphenicol-treated myoblasts did not
      restore differentiation, thus indicating that an alteration in mitochondrial
      activity interferes with the ability of myogenic factors to induce terminal
      differentiation.

PMID- 10644738
TI  - A developmentally regulated aconitase related to iron-regulatory protein-1 is
      localized in the cytoplasm and in the mitochondrion of Trypanosoma brucei.
AB  - Mitochondrial energy metabolism and Krebs cycle activities are developmentally
      regulated in the life cycle of the protozoan parasite Trypanosoma brucei. Here we
      report cloning of a T. brucei aconitase gene that is closely related to mammalian
      iron-regulatory protein 1 (IRP-1) and plant aconitases. Kinetic analysis of
      purified recombinant TbACO expressed in Escherichia coli resulted in a K(m)
      (isocitrate) of 3 +/- 0.4 mM, similar to aconitases of other organisms. This was
      unexpected since an arginine conserved in the aconitase protein family and
      crucial for substrate positioning in the catalytic center and for activity of pig
      mitochondrial aconitase (Zheng, L., Kennedy, M. C., Beinert, H., and Zalkin, H.
      (1992) J. Biol. Chem. 267, 7895-7903) is substituted by leucine in the TbACO
      sequence. Expression of the 98-kDa TbACO was shown to be lowest in the slender
      bloodstream stage of the parasite, 8-fold elevated in the stumpy stage, and
      increased a further 4-fold in the procyclic stage. The differential expression of
      TbACO protein contrasted with only minor changes in TbACO mRNA, indicating
      translational or post-translational mechanisms of regulation. Whereas animal
      cells express two distinct compartmentalized aconitases, mitochondrial aconitase
      and cytoplasmic aconitase/IRP-1, TbACO accounts for total aconitase activity in
      trypanosomes. By cell fractionation and immunofluorescence microscopy, we show
      that native as well as a transfected epitope-tagged TbACO localizes in both the
      mitochondrion (30%) and in the cytoplasm (70%). Together with phylogenetic
      reconstructions of the aconitase family, this suggests that animal IRPs have
      evolved from a multicompartmentalized ancestral aconitase. The possible functions
      of a cytoplasmic aconitase in trypanosomes are discussed.

PMID- 10644739
TI  - Molecular cloning of an N-terminal splice variant of the capsaicin receptor. Loss
      of N-terminal domain suggests functional divergence among capsaicin receptor
      subtypes.
AB  - Recently a cDNA clone, vanilloid receptor subtype-1 (VR1), was isolated and found
      to encode an ion channel that is activated by both capsaicin, the pain producing
      compound in chili peppers, and by noxious thermal stimuli. Subsequently, two
      related cDNAs have been isolated, a stretch inactivating channel with
      mechanosensitive properties and a vanilloid receptor-like protein that is
      responsive to high temperatures (52-53 degrees C). Here, we report the isolation
      of a vanilloid receptor 5'-splice variant (VR.5'sv) which differs from VR1 by
      elimination of the majority of the intracellular N-terminal domain and ankyrin
      repeat elements. Both VR.5'sv and VR1 mRNA were shown to be expressed in tissues
      reportedly responsive to capsaicin including dorsal root ganglion, brain, and
      peripheral blood mononuclear cells. Functional expression of VR.5'sv in Xenopus
      oocytes and mammalian cells showed no sensitivity to capsaicin, the potent
      vanilloid resiniferatoxin, hydrogen ions (pH 6.2), or noxious thermal stimuli (50
      degrees C). Since VR.5'sv is otherwise identical to VR1 throughout its
      transmembrane spanning domains and C-terminal region, these results support the
      hypothesis that the N-terminal intracellular domain is essential for the
      formation of functional receptors activated by vanilloid compounds and noxious
      thermal stimuli.

PMID- 10644740
TI  - Nuclear orphan receptors regulate transcription of the gene for the human
      luteinizing hormone receptor.
AB  - An imperfect estrogen receptor half-site response element direct-repeat, located
      within the TATA-less promoter of the human luteinizing hormone receptor (hLHR),
      was identified as an inhibitory site for Sp1/Sp3-driven basal transcription.
      Isolation of proteins recognizing this site by yeast one-hybrid screening of a
      human placenta cDNA library revealed three nuclear orphan receptors, EAR2,
      EAR3/COUP-TFI, and TR4. Electrophoresis mobility shift assays demonstrated that
      the in vitro translated nuclear orphan receptors specifically bound the direct
      repeat motif of the hLHR promoter. Also, endogenous EAR2 and EAR3/COUP-TFI from
      JAR cell and human testis and TR4 from testes bound this motif in electrophoresis
      mobility shift assays. Functional analyses in CV-1 cells showed that EAR2 and
      EAR3/COUP-TFI repressed the hLHR promoter activity by up to 70% in a dose
      dependent and sequence-specific manner. Conversely, TR4 activated the hLHR
      promoter activity up to 2.5-fold through binding to the same cis-element. The
      stimulation was reversed by coexpression of EAR2 or EAR3/COUP-TFI, indicating
      their competitive binding for this site. Such recognition of a common cognate
      site by the proteins with antagonistic functions implies that a net regulation of
      the hLHR gene may result from the relative availability of repressors and
      activator in a physiological state. This also may contribute to the differential
      expression of the hLHR gene in gonadal and non-gonadal tissues.

PMID- 10644741
TI  - Linker scanning analysis of TBP promoter binding factor DNA binding, activation,
      and repression domains.
AB  - The transcription activator TATA box-binding protein promoter-binding factor
      (TPBF) is both an activator and repressor of TBP gene expression in Acanthamoeba.
      TPBF bears little similarity to previously characterized families of factors. In
      order to identify domains that are involved in DNA binding, activation, and
      repression, we constructed several alanine linker scanning mutants and tested
      them for their ability to function in a variety of assays. The DNA binding domain
      comprises a large 100-amino acid domain within the central third of the protein,
      suggesting that DNA recognition is accomplished by interactions derived from
      several structural units within this domain. Surprisingly, transcription
      activation and repression are impaired by mutations within either of two discrete
      amino acid sequences located on either side of the DNA binding domain. These data
      suggest that TPBF activation and repression are accomplished by interactions with
      the same target. Since TATA elements can function bidirectionally, and in
      solution TBP can bind to TATA elements in either orientation, we propose that
      TPBF functions in part by orienting TBP or TFIID correctly on the TATA box.

PMID- 10644742
TI  - BRCA1 effects on the cell cycle and the DNA damage response are linked to altered
      gene expression.
AB  - The breast and ovarian cancer susceptibility gene product BRCA1 has been reported
      to be expressed in a cell cycle-dependent manner; possess transcriptional
      activity; associate with several proteins, including the p53 tumor suppressor;
      and play an integral role in certain types of DNA repair. We show here that
      ectopic expression of BRCA1 using an adenovirus vector (Ad-BRCA1) leads to
      dephosphorylation of the retinoblastoma protein accompanied by a decrease in
      cyclin-dependent kinase activity. Flow cytometric analysis on Ad-BRCA1-infected
      cells revealed a G(1) or G(2) phase accumulation. High density cDNA array
      screening of colon, lung, and breast cancer cells identified several genes
      affected by BRCA1 expression in a p53-independent manner, including DNA damage
      response genes and genes involved in cell cycle control. Notable changes included
      induction of the GADD45 and GADD153 genes and a reduction in cyclin B1
      expression. Therefore, BRCA1 has the potential to modulate the expression of
      genes and function of proteins involved in cell cycle control and DNA damage
      response pathways.

PMID- 10644743
TI  - GroEL/GroES promote dissociation/reassociation cycles of a heterodimeric
      intermediate during alpha(2)beta(2) protein assembly. Iterative annealing at the
      quaternary structure level.
AB  - Whereas the mechanism of GroEL/GroES-mediated protein folding has been
      extensively studied, the role of these chaperonins in oligomeric protein assembly
      remains poorly understood. In the present study, we investigated the interaction
      of the chaperonins with an alphabeta heterodimeric intermediate during the
      alpha(2)beta(2) assembly of human mitochondrial branched-chain alpha-ketoacid
      dehydrogenase/decarboxylase (BCKD). Incubation of the recombinant His(6)-tagged
      BCKD in 400 mM KSCN for 45 min at 23 degrees C caused a complete dissociation of
      the alpha(2)beta(2) heterotetramers into inactive alphabeta heterodimers.
      Dilution of the denaturant resulted in a rapid recovery of BCKD independent of
      the chaperonins GroEL/GroES. Prolonged incubation of BCKD in 400 mM KSCN resulted
      in the generation of nonproductive or "bad" heterodimers, which were unable to
      undergo spontaneous reactivation but capable of binding to GroEL to form a stable
      GroEL-alphabeta complex. Incubation of this complex with GroES and Mg-ATP led to
      the slow reactivation of BCKD with a second-order rate constant k = 480 M(-1) s(
      1). Mixing experiments with radiolabeled and unlabeled protein substrates
      provided direct evidence that GroEL/GroES promote dissociation and subunit
      exchange between bad heterodimers. This was accompanied by the transformation of
      bad heterodimers to their "good" or productive counterparts. The good
      heterodimers were capable of spontaneous dimerization to initially form an
      inactive heterotetrameric species, followed by conversion to active
      heterotetramers. However, a large fraction of bad heterodimers were regenerated
      and rebound to GroEL. The cycle was perpetuated until the reconstitution of
      active BCKD was complete. Our data support the thesis that chaperonins
      GroEL/GroES mediate iterative annealing of nonproductive assembly intermediates
      at the quaternary structure level. This step is essential for an efficient
      subsequent higher order oligomerization.

PMID- 10644744
TI  - Correlation between in vitro stability and in vivo performance of anti-GCN4
      intrabodies as cytoplasmic inhibitors.
AB  - A cellular assay system for measuring the activity of cytoplasmically expressed
      anti-GCN4 scFv fragments directed against the Gcn4p dimerization domain was
      established in the budding yeast Saccharomyces cerevisiae. The inhibitory
      potential of different constitutively expressed anti-GCN4 scFv intrabodies was
      monitored by measuring the activity of beta-galactosidase expressed from a GCN4
      dependent reporter gene. The in vivo performance of these scFv intrabodies in
      specifically decreasing reporter gene activity was related to their in vitro
      stability, measured by denaturant-induced equilibrium unfolding. A framework
      engineered stabilized version showed significantly improved activity, while a
      destabilized point mutant of the anti-GCN4 wild-type showed decreased effects in
      vivo. These results indicate that stability engineering can result in improved
      performance of scFv fragments as intrabodies. Increasing the thermodynamic
      stability appears to be an essential factor for improving the yield of functional
      scFv in the reducing environment of the cytoplasm, where the conserved
      intradomain disulfides of antibody fragments cannot form.

PMID- 10644745
TI  - Identification of the guanylyltransferase region and active site in reovirus mRNA
      capping protein lambda2.
AB  - The 144-kDa lambda2 protein of mammalian reovirus catalyzes a number of enzymatic
      activities in the capping of reovirus mRNA, including the transfer of GMP from
      GTP to the 5' end of the 5'-diphosphorylated nascent transcript. This reaction
      proceeds through a covalently autoguanylylated lambda2-GMP intermediate. The
      smaller size of RNA capping guanylyltransferases from other organisms suggested
      that the lambda2-associated guanylyltransferase would be only a part of this
      protein. Limited proteinase K digestion of baculovirus-expressed lambda2 was used
      to generate an amino-terminal M(r) 42,000 fragment that appears to be both
      necessary and sufficient for guanylyltransferase activity. Although lysine 226
      was identified by previous biochemical studies as the active-site residue that
      forms a phosphoamide bond with GMP in autoguanylylated lambda2, mutation of
      lysine 226 to alanine caused only a partial reduction in guanylyltransferase
      activity at the autoguanylylation step. Alanine substitution for other lysines
      within the amino-terminal region of lambda2 identified lysine 190 as necessary
      for autoguanylylation and lysine 171 as an important contributor to
      autoguanylylation. A novel active-site motif is proposed for the RNA
      guanylyltransferases of mammalian reoviruses and other Reoviridae members.

PMID- 10644746
TI  - Nitric oxide activation of p38 mitogen-activated protein kinase in 293T
      fibroblasts requires cGMP-dependent protein kinase.
AB  - An increase in cellular levels of cyclic nucleotides activates serine/threonine
      dependent kinases that lead to diverse physiological effects. Recently we
      reported the activation of the p38 mitogen-activated protein kinase (MAPK)
      pathway in neutrophils by a cGMP-dependent mechanism. In this study we
      demonstrated that exogenously supplied nitric oxide leads to activation of p38
      MAPK in 293T fibroblasts. Phosphorylation of p38 corresponded with an increase in
      ATF-2-dependent gene expression. The effect of nitric oxide was mimicked by
      addition of 8-bromo-cGMP, indicating that activation of soluble guanylyl cyclase
      was involved. The importance of cGMP-dependent protein kinase in the activation
      of p38 MAPK by nitric oxide in 293T cells was assessed in a transfection based
      assay. Overexpression of cGMP-dependent protein kinase-1alpha caused
      phosphorylation of p38 in these cells and potentiated the effectiveness of cGMP.
      Overexpression of a catalytically inactive mutant form of this enzyme (T516A)
      blocked the ability of both nitric oxide and 8-bromo-cGMP to activate p38 as
      measured by both p38 phosphorylation and ATF-2 driven gene expression. Together,
      these data demonstrate that nitric oxide stimulates a novel pathway leading to
      activation of p38 MAPK that requires activation of cGMP-dependent protein kinase.

PMID- 10644747
TI  - Mapping the inter-RNA interaction of bacterial virus phi29 packaging RNA by site
      specific photoaffinity cross-linking.
AB  - During replication, the lengthy genome of double-stranded DNA viruses is
      translocated with remarkable velocity into a limited space within the procapsid.
      The question of how this fascinating task is accomplished has long been a puzzle.
      Our recent investigation suggests that phi29 DNA packaging is accomplished by a
      mechanism similar to the driving of a bolt with a hex nut and that six packaging
      RNAs (pRNAs) form a hexagonal complex to gear the DNA-translocating machine
      (Chen, C., and Guo, P. (1997) J. Virol. 71, 3864-3871; Zhang, F., Lemieux, S.,
      Wu, X., St.-Arnaud, S., McMurray, C. T., Major, F., and Anderson, D. (1998) Mol.
      Cell 2, 141-147; Guo, P., Zhang, C., Chen, C., Garver, K., and Trottier, M.,
      (1998) Mol. Cell 2, 149-155). In the current study, circularly permuted pRNAs
      were used to position an azidophenacyl photoreactive cross-linking agent
      specifically at a strategic site that was predicted to be involved in pRNA-pRNA
      interaction. Cross-linked pRNA dimers were isolated, and the sites of cross-link
      were mapped by primer extension. The cross-linked pRNA dimer retained full
      activity in phi29 procapsid binding and genomic DNA translocation, indicating
      that the cross-link distance constraints identified in dimer formation reflect
      the native pRNA complex. Both cross-linked dimers either containing or not
      containing the interlocking loops for programmed hexamer formation bound
      procapsid equally well; however, only the one containing the interlocking loops
      programmed for hexamer formation was active in phi29 DNA packaging. The cross
      linked pRNA dimers were also identified as the minimum binding unit necessary for
      procapsid binding. Primer extension of the purified cross-linked pRNA dimers
      revealed that base G(82) was cross-linked to bases G(39), G(40), A(41), C(49),
      G(62), C(63), and C(64), which contribute to the formation of the three-way
      junction, suggesting that these bases are proximate in the formation of pRNA
      tertiary structure. Interestingly, the photoaffinity agent in the left
      interacting loop did not cross-link directly to the right loop as expected but
      cross-linked to bases adjacent to the right loop. These data provide a background
      for future modeling of pRNA tertiary structure.

PMID- 10644748
TI  - Autocrine signaling through Ras prevents apoptosis in vascular smooth muscle
      cells in vitro.
AB  - Vascular smooth muscle cell (SMC) apoptosis contributes to physiological and
      pathological vascular remodeling. Autocrine fibroblast growth factor (FGF)
      signaling promotes survival in SMC in vitro. Interruption of autocrine FGF
      signaling results in apoptosis that can be rescued by other growth factors such
      as PDGF (platelet-derived growth factor) or EGF (epidermal growth factor). Such
      heterologous growth factor rescue is prevented by pharmacological inhibition of
      MAPK, implicating signaling through Ras in mediating survival. This study was
      designed to test the hypothesis that signaling through Ras is both necessary and
      sufficient to mediate SMC survival in vitro. Recombinant adenoviruses encoding
      dominant-negative (Ras(N17)) and constitutively active (Ras(L61)) mutants of Ras
      were used. Ras(N17) blocks growth factor-mediated MAPK activation and can itself
      induce SMC apoptosis. Ras(N17) is synergistic with inhibition of autocrine FGF
      signaling in triggering apoptosis and prevents heterologous growth factor rescue.
      Conversely, Ras(L61) prevents apoptosis resulting from inhibition of autocrine
      FGF signaling. Rescue by Ras(L61) can be partially prevented by pharmacological
      inhibition of MEK or phosphatidylinositol 3-kinase, two downstream effectors of
      Ras. These results suggest that Ras signaling is both necessary and sufficient to
      mediate survival in SMC in vitro. Further work is required to determine how these
      signaling events are regulated in the context of vascular remodeling in vivo.

PMID- 10644749
TI  - The amino-terminal domain of the golgi protein giantin interacts directly with
      the vesicle-tethering protein p115.
AB  - Giantin is thought to form a complex with p115 and Golgi matrix protein 130,
      which is involved in the reassembly of Golgi cisternae and stacks at the end of
      mitosis. The complex is involved in the tethering of coat protomer I vesicles to
      Golgi membranes and the initial stacking of reforming cisternae. Here we show
      that the NH(2)-terminal 15% of Giantin suffices to bind p115 in vitro and in vivo
      and to block cell-free Golgi reassembly. Because Giantin is a long, rod-like
      protein anchored to the membrane by its extreme COOH terminus, these results
      support the idea of a long, flexible tether linking vesicles and cisternae.

PMID- 10644751
TI  - Masking of an endoplasmic reticulum retention signal by its presence in the two
      subunits of the asialoglycoprotein receptor.
AB  - Human asialoglycoprotein receptor H1 and H2b subunits assemble into a hetero
      oligomer that travels to the cell surface. The H2a variant on the other hand is a
      precursor of a cleaved soluble form that is secreted. Uncleaved H2a precursor
      molecules cannot exit the endoplasmic reticulum (ER), a lumenal juxtamembrane
      pentapeptide being responsible for their retention. Insertion of this
      pentapeptide into H1 (H1i5) causes its complete ER retention but not fast
      degradation as happens to H2a. Cotransfection of H2a elicited, by
      heterodimerization, the Golgi processing of H1i5 and its surface expression. This
      occurred to a much lesser extent by cotransfection of H2b. Likewise, coexpression
      of H1i5 and not H1 stabilized H2a and caused its export to the cell surface.
      Homodimerization of molecules containing the pentapeptide did not cancel the
      retention. Thus, only when the pentapeptide is present in both subunits is the ER
      retention efficiently abrogated. The results show the unexpected finding that
      identical ER retention signals present in two associated chains can mask and
      cancel each other's effect. This could have important implications as similar
      abrogation of ER retention of other proteins could eventually be obtained by
      engineering and coexpressing an associated protein containing the same retention
      signal.

PMID- 10644750
TI  - Regulation of cyclooxygenase-2 by hypoxia and peroxisome proliferators in the
      corneal epithelium.
AB  - Hypoxic injury provokes inflammation of many tissues including the ocular
      surface. In rabbit corneal epithelial cells, both peroxisome proliferator
      activated receptor (PPAR)-inducible cytochrome P450 4B1 and cyclooxygenase-2 (COX
      2) mRNAs were increased by hypoxia. PPAR alpha and beta but not gamma mRNAs were
      detected in these cells. The PPAR activator, WY-14,643 increased COX-2
      expression. Similarly, non-steroidal anti-inflammatory drugs with the ability to
      activate PPARs induced COX-2 independently of prostaglandin synthesis inhibition.
      COX-2 protein overexpression by hypoxia and PPAR activation was not associated
      with a parallel increase in prostaglandin E(2) accumulation. However, the enzyme
      regained full catalytic activity when: 1) hypoxic cells were re-exposed to
      normoxic conditions in the presence of heme and arachidonic acid, and 2) WY
      14,643-treated cells were depleted of intracellular GSH. Consistent with previous
      observations showing that the corneal production of cytochrome P450-derived
      inflammatory eicosanoids is elevated by hypoxia and inflammation, the current
      data suggest that hypoxic injury is a model of inflammation in which molecules
      other than COX-derived arachidonic acid metabolites play a major proinflammatory
      role. This study also suggests that increased cellular GSH may be the mechanism
      responsible for the characteristic dissociation of PPAR-induced COX-2 expression
      and activity. Moreover, we provide new insights into the commonly observed lack
      of efficacy of classical non-steroidal anti-inflammatory drugs in the treatment
      of hypoxia-related ocular surface inflammation.

PMID- 10644752
TI  - Cloning of factors related to HIV-inducible LBP proteins that regulate
      steroidogenic factor-1-independent human placental transcription of the
      cholesterol side-chain cleavage enzyme, P450scc.
AB  - The cholesterol side-chain cleavage enzyme, cytochrome P450scc, initiates the
      biosynthesis of all steroid hormones. Adrenal and gonadal strategies for P450scc
      gene transcription are essentially identical and depend on the orphan nuclear
      receptor steroidogenic factor-1, but the placental strategy for transcription of
      P450scc employs cis-acting elements different from those used in the adrenal
      strategy and is independent of steroidogenic factor-1. Because placental
      expression of P450scc is required for human pregnancy, we sought factors that
      bind to the -155/-131 region of the human P450scc promoter, which participates in
      its placental but not adrenal or gonadal transcription. A yeast one-hybrid screen
      of 2.4 x 10(6) cDNA clones from human placental JEG-3 cells yielded two unique
      clones; one is the previously described transcription factor LBP-1b, which is
      induced by HIV, type I infection of lymphocytes, and the other is a new factor,
      termed LBP-9, that shares 83% amino acid sequence identity with LBP-1b. When
      expressed in transfected yeast, both factors bound specifically to the -155/-131
      DNA; antisera to LBP proteins supershifted the LBP-9.DNA complex and inhibited
      formation of the LBP-1b.DNA complex. Reverse transcriptase-polymerase chain
      reaction detected LBP-1b in human placental JEG-3, adrenal NCI-H295A, liver
      HepG2, cervical HeLa, and monkey kidney COS-1 cells, but LBP-9 was detected only
      in JEG-3 cells. When the -155/-131 fragment was linked to a minimal promoter, co
      expression of LBP-1b increased transcription 21-fold in a dose-dependent fashion,
      but addition of LBP-9 suppressed the stimulatory effect of LBP-1b. The roles of
      LBP transcription factors in normal human physiology have been unclear. Their
      modulation of placental but not adrenal P450scc transcription underscores the
      distinctiveness of placental strategies for steroidogenic enzyme gene
      transcription.

PMID- 10644753
TI  - The occurrence of three isoforms of heparan sulfate 6-O-sulfotransferase having
      different specificities for hexuronic acid adjacent to the targeted N
      sulfoglucosamine.
AB  - We previously cloned heparan sulfate 6-O-sulfotransferase (HS6ST) (Habuchi, H.,
      Kobayashi, M., and Kimata, K. (1998) J. Biol. Chem. 273, 9208-9213). In this
      study, we report the cloning and characterization of three mouse isoforms of
      HS6ST, a mouse homologue to the original human HS6ST (HS6ST-1) and two novel
      HS6STs (HS6ST-2 and HS6ST-3). The cDNAs have been obtained from mouse brain cDNA
      library by cross-hybridization with human HS6ST cDNA. The three cDNAs contained
      single open reading frames that predicted type II transmembrane proteins composed
      of 401, 506, and 470 amino acid residues, respectively. Amino acid sequence of
      HS6ST-1 was 51 and 57% identical to those of HS6ST-2 and HS6ST-3, respectively.
      HS6ST-2 and HS6ST-3 had the 50% identity. Overexpression of each isoform in COS-7
      cells resulted in about 10-fold increase of HS6ST activity. The three isoforms
      purified with anti-FLAG antibody affinity column transferred sulfate to heparan
      sulfate and heparin but not to other glycosaminoglycans. Each isoform showed
      different specificity toward the isomeric hexuronic acid adjacent to the targeted
      N-sulfoglucosamine; HS6ST-1 appeared to prefer the iduronosyl N-sulfoglucosamine
      while HS6ST-2 had a different preference, depending upon the substrate
      concentrations, and HS6ST-3 acted on either substrate. Northern analysis showed
      that the expression of each message in various tissues was characteristic to the
      respective isoform. HS6ST-1 was expressed strongly in liver, and HS6ST-2 was
      expressed mainly in brain and spleen. In contrast, HS6ST-3 was expressed rather
      ubiquitously. These results suggest that the expression of these isoforms may be
      regulated in tissue-specific manners and that each isoform may be involved in the
      synthesis of heparan sulfates with tissue-specific structures and functions.

PMID- 10644754
TI  - A protein kinase from neutrophils that specifically recognizes Ser-3 in cofilin.
AB  - Cofilin promotes the depolymerization of actin filaments, which is required for a
      variety of cellular responses such as the formation of lamellipodia and
      chemotaxis. Phosphorylation of cofilin on serine residue 3 is known to block
      these activities. We now report that neutrophils contain a protein kinase that
      selectively catalyzes the phosphorylation of cofilin on serine 3 (>/=70%) and a
      nonspecific kinase that recognizes multiple sites in this protein. The selective
      serine 3 cofilin kinase binds to a deoxyribonuclease I affinity column, whereas
      the nonspecific cofilin kinase does not. Deoxyribonuclease I forms a very tight
      complex with actin, and deoxyribonuclease affinity columns have been utilized to
      identify a variety of proteins that interact with the cytoskeleton. The serine 3
      cofilin kinase did not react with antibodies to LIM kinase 1 or 2, which can
      catalyze the phosphorylation of cofilin in other cell types. The activity of the
      serine 3 cofilin kinase was insensitive to a variety of selective antagonists of
      protein kinases but was blocked by staurosporine. This pattern of inhibition is
      similar to that observed for the kinase that is active with cofilin in intact
      neutrophils. Thus, neutrophils contain a protein kinase distinct from LIM kinase
      1/2 that selectively recognizes serine 3 in cofilin.

PMID- 10644755
TI  - Homodimer of two F-box proteins betaTrCP1 or betaTrCP2 binds to IkappaBalpha for
      signal-dependent ubiquitination.
AB  - We found previously that overexpression of an F-box protein betaTrCP1 and the
      structurally related betaTrCP2 augments ubiquitination of phosphorylated
      IkappaBalpha (pIkappaBalpha) induced by tumor necrosis factor-alpha (TNF-alpha),
      but the relationship of the two homologous betaTrCP proteins remains unknown.
      Herein we reveal that deletion mutants of betaTrCP1 and betaTrCP2 lacking the F
      box domain suppressed ubiquitination and destruction of pIkappaBalpha as well as
      transcriptional activation of NF-kappaB. The ectopically expressed betaTrCP1 and
      betaTrCP2 formed both homodimer and heterodimer complexes without displaying the
      trimer complex. Dimerization of betaTrCP1 and/or betaTrCP2 takes place at their
      conserved NH(2)-terminal regions, termed a "D-domain" (for dimerization domain),
      located upstream of the F-box domain. The D-domain was necessary and sufficient
      for the dimer formation. Intriguingly, the betaTrCP homodimer, but not the
      heterodimer, was selectively recruited to pIkappaBalpha induced by TNF-alpha.
      These results indicate that not only betaTrCP1 but also betaTrCP2 participates in
      the ubiquitination-dependent destruction of IkappaBalpha by forming SCF(betaTrCP1
      betaTrCP1) and SCF(betaTrCP2-betaTrCP2) ubiquitin-ligase complexes.

PMID- 10644756
TI  - Platelet-derived growth factor and lysophosphatidic acid inhibit growth hormone
      binding and signaling via a protein kinase C-dependent pathway.
AB  - Growth hormone (GH) regulates body growth and metabolism. GH exerts its
      biological action by stimulating JAK2, a GH receptor (GHR)-associated tyrosine
      kinase. Activated JAK2 phosphorylates itself and GHR, thus initiating multiple
      signaling pathways. In this work, we demonstrate that platelet-derived growth
      factor (PDGF) and lysophosphatidic acid (LPA) down-regulate GH signaling via a
      protein kinase C (PKC)-dependent pathway. PDGF substantially reduces tyrosyl
      phosphorylation of JAK2 induced by GH but not interferon-gamma or leukemia
      inhibitory factor. PDGF, but not epidermal growth factor, decreases tyrosyl
      phosphorylation of GHR (by approximately 90%) and the amount of both total
      cellular GHR (by approximately 80%) and GH binding (by approximately 70%). The
      inhibitory effect of PDGF on GH-induced tyrosyl phosphorylation of JAK2 and GHR
      is abolished by depletion of 4beta-phorbol 12-myristate 13-acetate (PMA)
      sensitive PKCs with chronic PMA treatment and is severely inhibited by GF109203X,
      an inhibitor of PKCs. In contrast, extracellular signal-regulated kinases 1 and 2
      and phosphatidylinositol 3-kinase appear not to be involved in this inhibitory
      effect of PDGF. LPA, a known activator of PKC, also inhibits GH-induced tyrosyl
      phosphorylation of JAK2 and GHR and reduces the number of GHR. We propose that
      ligands that activate PKC, including PDGF, LPA, and PMA, down-regulate GH
      signaling by decreasing the number of cell surface GHR through promoting GHR
      internalization and degradation and/or cleavage of membrane GHR and release of
      the extracellular domain of GHR.

PMID- 10644757
TI  - Agonist-induced phosphorylation of the angiotensin II (AT(1A)) receptor requires
      generation of a conformation that is distinct from the inositol phosphate
      signaling state.
AB  - G protein-coupled receptors are thought to isomerize between distinct inactive
      and active conformations, an idea supported by receptor mutations that induce
      constitutive (agonist-independent) activation. The agonist-promoted active state
      initiates signaling and, presumably, is then phosphorylated and internalized to
      terminate the signal. In this study, we examined the phosphorylation and
      internalization of wild type and constitutively active mutants (N111A and N111G)
      of the type 1 (AT(1A)) angiotensin II receptor. Cells expressing these receptors
      were stimulated with angiotensin II (AngII) and [Sar(1),Ile(4),Ile(8)]AngII, an
      analog that only activates signaling through the constitutive receptors. Wild
      type AT(1A) receptors displayed a basal level of phosphorylation, which was
      stimulated by AngII. Unexpectedly, the constitutively active AT(1A) receptors did
      not exhibit an increase in basal phosphorylation nor was phosphorylation enhanced
      by AngII stimulation. Phosphorylation of the constitutively active receptors was
      unaffected by pretreatment with the non-peptide AT(1) receptor inverse agonist,
      EXP3174, and was not stimulated by the selective ligand,
      [Sar(1),Ile(4),Ile(8)]AngII. Paradoxically, [Sar(1),Ile(4), Ile(8)]AngII produced
      a robust ( approximately 85% of AngII), dose-dependent phosphorylation of the
      wild type AT(1A) receptor at sites in the carboxyl terminus similar to those
      phosphorylated by AngII. Moreover, internalization of both wild type and
      constitutive receptors was induced by AngII, but not [Sar(1),Ile(4),Ile(8)]AngII,
      providing a differentiation between the phosphorylated and internalized states.
      These data suggest that the AT(1A) receptor can attain a conformation for
      phosphorylation without going through the conformation required for inositol
      phosphate signaling and provide evidence for a transition of the receptor through
      multiple states, each associated with separate stages of receptor activation and
      regulation. Separate transition states may be a common paradigm for G protein
      coupled receptors.

PMID- 10644758
TI  - The visual G protein of fly photoreceptors interacts with the PDZ domain
      assembled INAD signaling complex via direct binding of activated Galpha(q) to
      phospholipase cbeta.
AB  - Visual transduction in the compound eye of flies is a well-established model
      system for the study of G protein-coupled transduction pathways. Pivotal
      components of this signaling pathway, including the principal light-activated
      Ca(2+) channel transient receptor potential, an eye-specific protein kinase C,
      and the norpA-encoded phospholipase Cbeta, are assembled into a supramolecular
      signaling complex by the modular PDZ domain protein INAD. We have used
      immunoprecipitation assays to study the interaction of the heterotrimeric visual
      G protein with this INAD signaling complex. Light-activated Galpha(q)- guanosine
      5'-O-(thiotriphosphate) and AlF(4)(-)-activated Galpha(q), but not Gbetagamma,
      form a stable complex with the INAD signaling complex. This interaction requires
      the presence of norpA-encoded phospholipase Cbeta, indicating that phospholipase
      Cbeta is the target of activated Galpha(q). Our data establish that the INAD
      signaling complex is a light-activated target of the phototransduction pathway,
      with Galpha(q) forming a molecular on-off switch that shuttles the visual signal
      from activated rhodopsin to INAD-linked phospholipase Cbeta.

PMID- 10644759
TI  - ATP-dependent transport of bile salts by rat multidrug resistance-associated
      protein 3 (Mrp3).
AB  - We have previously shown that cloned rat multidrug resistance-associated protein
      3 (Mrp3) has the ability to transport organic anions such as 17beta-estradiol 17
      beta-D-glucuronide (E(2)17betaG) and has a different substrate specificity from
      MRP1 and MRP2 in that glutathione conjugates are poor substrates for Mrp3
      (Hirohashi, T., Suzuki, H., and Sugiyama, Y. (1999) J. Biol. Chem. 274, 15181
      15185). In the present study, the involvement of Mrp3 in the transport of
      endogenous bile salts was investigated using membrane vesicles from LLC-PK1 cells
      transfected with rat Mrp3 cDNA. The ATP-dependent uptake of [(3)H]taurocholate
      (TC), [(14)C]glycocholate (GC), [(3)H]taurochenodeoxycholate-3-sulfate (TCDC-S),
      and [(3)H]taurolithocholate-3-sulfate (TLC-S) was markedly stimulated by Mrp3
      transfection in LLC-PK1 cells. The extent of Mrp3-mediated transport of bile
      salts was in the order, TLC-S > TCDC-S > TC > GC. The K(m) and V(max) values for
      the uptake of TC and TLC-S were K(m) = 15.9 +/- 4.9 microM and V(max) = 50.1 +/-
      9.3 pmol/min/mg of protein and K(m) = 3.06 +/- 0.57 microM and V(max) = 161.9 +/-
      21.7 pmol/min/mg of protein, respectively. At 55 nM [(3)H]E(2)17betaG and 1.2
      microM [(3)H]TC, the apparent K(m) values for ATP were 1.36 and 0.66 mM,
      respectively. TC, GC, and TCDC-S inhibited the transport of [(3)H]E(2)17betaG and
      [(3)H]TC to the same extent with an apparent IC(50) of approximately 10 microM.
      TLC-S inhibited the uptake of [(3)H]E(2)17betaG and [(3)H]TC most potently
      (IC(50) of approximately 1 microM) among the bile salts examined, whereas cholate
      weakly inhibited the uptake (IC(50) approximately 75 microM). Although TC and GC
      are transported by bile salt export pump/sister of P-glycoprotein, but not by
      MRP2, and TCDC-S and TLC-S are transported by MRP2, but not by bile salt export
      pump/sister of P-glycoprotein, it was found that Mrp3 accepts all these bile
      salts as substrates. This information, together with the finding that MRP3 is
      extensively expressed on the basolateral membrane of human cholangiocytes,
      suggests that MRP3/Mrp3 plays a significant role in the cholehepatic circulation
      of bile salts.

PMID- 10644760
TI  - The homeodomain protein Arix promotes protein kinase A-dependent activation of
      the dopamine beta-hydroxylase promoter through multiple elements and interaction
      with the coactivator cAMP-response element-binding protein-binding protein.
AB  - The differentiation and maintenance of a neurotransmitter phenotype is guided by
      the interaction of exogenous cues with intrinsic genetic machinery. For the
      noradrenergic phenotype, these influences combine to activate the expression of
      the catecholaminergic biosynthetic enzymes tyrosine hydroxylase and dopamine beta
      hydroxylase (DBH). In this study, we evaluate the molecular mechanisms by which
      the transcription factor Arix/Phox2a contributes to DBH gene transcription. We
      have evaluated the contribution of individual homeodomain binding sites in the
      rat DBH promoter region and find that all are essential for both basal and cAMP
      dependent protein kinase A (PKA)-stimulated transcription. Using mammalian one
      hybrid and two-hybrid systems, we demonstrate that recruitment of Arix to the
      positions of homeodomain core recognition sites 1 and 2 at -153 to -166 of the
      DBH gene restores complete responsiveness of the promoter to PKA in SHSY-5Y
      neuroblastoma and HepG2 hepatoma cells. Intracellular Arix-Arix interactions are
      evident and may contribute to the interdependence of homeodomain binding sites.
      Analysis of functional domains of Arix reveals an N-terminal activation domain
      and a C-terminal repression domain. The N terminus of Arix contains an amino acid
      motif similar to a region in Brachyury and Pax9 transcription factors. The N
      terminal activation domain of Arix interacts with the transcriptional co
      activator, cAMP-response element-binding protein-binding protein, which
      potentiates transcription from the DBH promoter in a PKA-dependent manner. The
      present study supports the hypothesis that the paired-like homeodomain protein,
      Arix, acts as a critical phenotype-specific regulator of the DBH promoter by
      serving as an integrator of signal-dependent transcription activators within the
      network of the general transcription machinery.

PMID- 10644761
TI  - Thioredoxin-dependent hydroperoxide peroxidase activity of bacterioferritin
      comigratory protein (BCP) as a new member of the thiol-specific antioxidant
      protein (TSA)/Alkyl hydroperoxide peroxidase C (AhpC) family.
AB  - Escherichia coli bacterioferritin comigratory protein (BCP), a putative bacterial
      member of the TSA/AhpC family, was characterized as a thiol peroxidase. BCP
      showed a thioredoxin-dependent thiol peroxidase activity. BCP preferentially
      reduced linoleic acid hydroperoxide rather than H(2)O(2) and t-butyl
      hydroperoxide with the use of thioredoxin as an in vivo immediate electron donor.
      The value of V(max)/K(m) of BCP for linoleic acid hydroperoxide was calculated to
      be 5-fold higher than that for H(2)O(2), implying that BCP has a selective
      capability to reduce linoleic acid hydroperoxide. Replacement of Cys-45 with
      serine resulted in the complete loss of thiol peroxidase activity, suggesting
      that BCP is a new bacterial member of TSA/AhpC family having a conserved cysteine
      as the primary site of catalysis. BCP exists as a monomer, and its functional Cys
      45 appeared to exist as cysteine sulfenic acid. The expression level of BCP
      gradually elevated during exponential growth until mid-log phase growth, beyond
      which the expression level was decreased. BCP was induced 3-fold by the oxidative
      stress given by changing the growth conditions from the anaerobic to aerobic
      culture. Bcp null mutant grew more slowly than its wild type in aerobic culture
      and showed the hypersensitivity toward various oxidants such as H(2)O(2), t-butyl
      hydroperoxide, and linoleic acid hydroperoxide. The peroxide hypersensitivity of
      the null mutant could be complemented by the expression of bcp gene. Taken
      together, these data suggest that BCP is a new member of thioredoxin-dependent
      TSA/AhpC family, acting as a general hydroperoxide peroxidase.

PMID- 10644762
TI  - Cysteine 111 affects coupling of single-stranded DNA binding to ATP hydrolysis in
      the herpes simplex virus type-1 origin-binding protein.
AB  - Herpes simplex virus type-1 origin-binding protein (UL9 protein) initiates viral
      replication by unwinding the origins. It possesses sequence-specific DNA-binding
      activity, single-stranded DNA-binding activity, DNA helicase activity, and ATPase
      activity that is strongly stimulated by single-stranded DNA. We have examined the
      role of cysteines in its action as a DNA helicase. The DNA helicase and DNA
      dependent ATPase activities of UL9 protein were stimulated by reducing agent and
      specifically inactivated by the sulfhydryl-specific reagent N-ethylmaleimide. To
      identify the cysteine responsible for this phenomenon, a conserved cysteine in
      the vicinity of the ATP-binding site (cysteine 111) was mutagenized to alanine.
      UL9C111A protein exhibits defects in its DNA helicase and DNA-dependent ATPase
      activities and was unable to support origin-specific DNA replication in vivo. A
      kinetic analysis indicates that these defects are due to the inability of single
      stranded DNA to induce high affinity ATP binding in UL9C111A protein. The DNA
      dependent ATPase activity of UL9C111A protein is resistant to N-ethylmaleimide,
      while its DNA helicase activity remains sensitive. Accordingly, sensitivity of
      UL9 protein to N-ethylmaleimide is due to at least two cysteines. Cysteine 111 is
      involved in coupling single-stranded DNA binding to ATP-binding and subsequent
      hydrolysis, while a second cysteine is involved in coupling ATP hydrolysis to DNA
      unwinding.

PMID- 10644763
TI  - Distinct protein domains are responsible for the interaction of Hrs-2 with SNAP
      25. The role of Hrs-2 in 7 S complex formation.
AB  - Regulated secretion of neurotransmitter at the synapse is likely to be mediated
      by dynamic protein interactions involving components of the vesicle (vesicle
      associated membrane protein; VAMP) and plasma membrane (syntaxin and synaptosomal
      associated protein of 25 kDa (SNAP-25)) along with additional molecules that
      allow for the regulation of this process. Recombinant Hrs-2 interacts with SNAP
      25 in a calcium-dependent manner (they dissociate at elevated calcium levels) and
      inhibits neurotransmitter release. Thus, Hrs-2 has been hypothesized to serve a
      negative regulatory role in secretion through its interaction with SNAP-25. In
      this report, we show that Hrs-2 and SNAP-25 interact directly through specific
      coiled-coil domains in each protein. The presence of syntaxin enhances the
      binding of Hrs-2 to SNAP-25. Moreover, while both Hrs-2 and VAMP can separately
      bind to SNAP-25, they cannot bind simultaneously. Additionally, the presence of
      Hrs-2 reduces the incorporation of VAMP into the syntaxin.SNAP-25.VAMP (7 S)
      complex. These findings suggest that Hrs-2 may modulate exocytosis by regulating
      the assembly of a protein complex implicated in membrane fusion.

PMID- 10644765
TI  - Platelet-derived growth factor-stimulated migration of murine fibroblasts is
      associated with epidermal growth factor receptor expression and tyrosine
      phosphorylation.
AB  - Previous studies have shown that epidermal growth factor (EGF) synergizes with
      various extracellular matrix components in promoting the migration of B82L
      fibroblasts expressing wild-type EGF receptors and that functional EGF receptors
      are critical for the conversion of B82L fibroblasts to a migratory cell type ().
      In the present study, we examined the effects of platelet-derived growth factor
      (PDGF) on the motility of B82L fibroblasts using a microchemotaxis chamber. We
      found that PDGF can enhance fibronectin-induced migration of B82L fibroblasts
      expressing wild-type EGF receptors (B82L-clone B3). However, B82L cells that lack
      the EGF receptor (B82L-parental) or that express an EGF receptor that is kinase
      inactive (B82L-K721M) or C-terminally truncated (B82L-c'973) exhibit little PDGF
      stimulated migration. In addition, none of these three cell lines exhibit the
      capacity to migrate to fibronectin alone. These observations indicate that,
      similar to cell migration toward fibronectin, PDGF-induced cell migration of B82L
      fibroblasts is augmented by the expression of an intact EGF receptor kinase. The
      loss of PDGF-stimulated motility in B82L cells that do not express an intact EGF
      receptor does not appear to result from a gross dysfunction of PDGF receptors,
      because ligand-stimulated tyrosine phosphorylation of the PDGF-beta receptor and
      the activation of mitogen-activated protein kinases are readily detectable in
      these cells. Moreover, an interaction between EGF and PDGF receptor systems is
      supported by the observation that the EGF receptor exhibits an increase in
      phosphotyrosine content in a time-dependent fashion upon the addition of PDGF.
      Altogether, these studies demonstrate that the expression of EGF receptor is
      critical for PDGF-stimulated migration of murine B82L fibroblasts and suggest a
      role for the EGF receptor downstream of PDGF receptor activation in the signaling
      events that lead to PDGF-stimulated cell motility.

PMID- 10644764
TI  - Aromatic hydrocarbon receptor interaction with the retinoblastoma protein
      potentiates repression of E2F-dependent transcription and cell cycle arrest.
AB  - Polyhalogenated aromatic hydrocarbons, of which 2,3,7, 8-tetrachloro-p-dioxin
      (TCDD) is the prototype compound, elicit a variety of toxic, teratogenic, and
      carcinogenic responses in exposed animals and in humans. In cultured cells, TCDD
      shows marked effects on the regulation of cell cycle progression, including
      thymocyte apoptosis, induction of keratinocyte proliferation and terminal
      differentiation, and inhibition of estrogen-dependent proliferation in breast
      cancer cells. The presence of an LXCXE domain in the dioxin aromatic hydrocarbon
      receptor (AHR), suggested that the effects of TCDD on cell cycle regulation might
      be mediated by protein-protein interactions between AHR and the retinoblastoma
      protein (RB). Using the yeast two-hybrid system, AHR and RB were in fact shown to
      bind to each other. In vitro pull-down experiments with truncated AHR peptides
      indicated that at least two separate AHR domains form independent complexes with
      hypophosphorylated RB. Coimmunoprecipitation of whole cell lysates from human
      breast carcinoma MCF-7 cells, which express both proteins endogenously, revealed
      that AHR associates with RB in vivo only after receptor transformation and
      nuclear translocation. However, the AHR nuclear translocator and transcriptional
      heterodimerization partner, is not required for (nor is it a part of) the AHR.RB
      complexes detected in vitro. Ectopic expression of AHR and RB in human
      osteosarcoma SAOS-2 cells, which lack endogenous expression of both proteins,
      showed that AHR synergizes with RB to repress E2F-dependent transcription and to
      induce cell cycle arrest. Furthermore, AHR partly blocked T-antigen-mediated
      reversal of RB-dependent transcriptional repression. These results uncover a
      potential function for the AHR in cell cycle regulation and suggest that this
      function may be that of serving as an environmental sensor that signals cell
      cycle arrest when cells are exposed to certain environmental toxicants.

PMID- 10644766
TI  - Targeting of SNAP-25 to membranes is mediated by its association with the target
      SNARE syntaxin.
AB  - The docking and fusion of synaptic vesicles with the presynaptic plasma membrane
      require the interaction of the vesicle-associated membrane protein VAMP with the
      plasma membrane proteins syntaxin and SNAP-25. Both of these proteins behave as
      integral membrane proteins, although they are unusual in that they insert into
      membranes post-translationally. Whereas VAMP and syntaxin possess hydrophobic
      transmembrane domains, SNAP-25 does not, and it is widely believed that SNAP-25
      traffics to and inserts into membranes by post-translational palmitoylation. In
      pulse-chase biosynthesis studies, we now show that SNAP-25 and syntaxin rapidly
      bind to each other while still in the cytosol of neuroendocrine and transfected
      heterologous cells. Cell fractionation studies revealed that cytosolic SNAP
      25.syntaxin complexes then traffic to and insert into membranes. Furthermore, the
      association of SNAP-25 with membranes is dramatically enhanced by syntaxin, and
      the transmembrane domain of syntaxin is essential for this effect. Surprisingly,
      despite the importance of the SNAP-25 palmitoylation domain for membrane
      anchoring at steady state, removal of this domain did not inhibit the initial
      association of newly synthesized SNAP-25 with membranes in the presence of
      syntaxin. These data demonstrate that the initial attachment of newly synthesized
      SNAP-25 to membranes is a consequence of its association with syntaxin and that
      it is only after syntaxin-mediated membrane tethering that SNAP-25 is
      palmitoylated.

PMID- 10644767
TI  - Three isoforms of synaptic scaffolding molecule and their characterization.
      Multimerization between the isoforms and their interaction with N-methyl-D
      aspartate receptors and SAP90/PSD-95-associated protein.
AB  - The synaptic scaffolding molecule (S-SCAM) has been identified as a protein
      interacting with SAP90/PSD-95-associated protein (SAPAP) (also called guanylate
      kinase-associated protein/hDLG-associated protein). S-SCAM has six PDZ (we have
      numbered them PDZ-0 to -5), two WW, and one guanylate kinase (GK) domains and
      interacts with N-methyl-D-aspartate (NMDA) receptor via PDZ-5 and SAPAP via the
      GK domain. We have identified here shorter isoforms of S-SCAM that start at the
      164th or 224th methionine, and we renamed the original one, S-SCAMalpha, the
      middle one, S-SCAMbeta, and the shortest one, S-SCAM-gamma. S-SCAMbeta and -gamma
      have five PDZ (PDZ-1 to -5), two WW, and one GK domains. S-SCAMalpha interacted
      with S-SCAMbeta and -gamma through the region containing PDZ-4 and -5. The region
      containing both of PDZ-4 and -5 is sufficient for the clustering of NMDA
      receptors and forms a dimer in gel filtration, suggesting that S-SCAM forms
      multimers via the interaction between the C-terminal PDZ domains and assembles
      NMDA receptors into clusters. S-SCAMbeta and -gamma also interacted with SAPAP,
      suggesting that the N-terminal region of the GK domain is not necessary for the
      interaction. Finally, we have identified the interaction of the PDZ domains of S
      SCAM with the GK domain of PSD-95/SAP90. S-SCAM, PSD-95/SAP90, and SAPAP are
      colocalized at least in some part in brain. Therefore, S-SCAM, PSD-95/SAP90, and
      SAPAP may form a complex in vivo.

PMID- 10644768
TI  - Identification of a novel tumor necrosis factor-alpha-inducible gene, SCC-S2,
      containing the consensus sequence of a death effector domain of fas-associated
      death domain-like interleukin- 1beta-converting enzyme-inhibitory protein.
AB  - We report here the isolation and characterization of a novel tumor necrosis
      factor-alpha (TNF-alpha)-inducible gene, SCC-S2. Based on the nucleotide
      sequence, the SCC-S2 open reading frame contains a sequence in the amino terminus
      that shows a significant homology to death effector domain II of cell death
      regulatory protein, Fas-associated death domain-like interleukin-1beta-converting
      enzyme-inhibitory protein (FLIP). Unlike FLIP, the SCC-S2 open reading frame
      contains only one death effector domain and lacks the carboxyl-terminal caspase
      like homology domain, raising the possibility that SCC-S2 may be a novel member
      of the FLIP family. SCC-S2 mRNA expression is found in most normal tissues and
      malignant cells. The steady state level of SCC-S2 mRNA is significantly induced
      by TNF-alpha in different tumor cells (TNF-alpha at 20 ng/ml for 3 h: A549,
      approximately 2-9-fold; SKOV-3, approximately 3-fold; PCI-04A, approximately 3-6
      fold). TNF-alpha treatment (100 ng/ml, 4 h) of HeLa cells transiently transfected
      with FLAG epitope-tagged SCC-S2 cDNA or expression vector alone led to an
      increase in the number of apoptotic cells as compared with the untreated
      counterpart. Interestingly, however, SCC-S2 transfectants revealed a significant
      decrease in the number of apoptotic cells as compared with the vector
      transfectants (p < 0.001). These data implicate a role of SCC-S2 as a negative
      mediator of apoptosis in certain cell types.

PMID- 10644769
TI  - Transcriptional activation of the MDR1 gene by UV irradiation. Role of NF-Y and
      Sp1.
AB  - The MDR1 promoter is subject to control by various internal and external stimuli.
      We have previously shown that the CCAAT box-binding protein, NF-Y, mediates MDR1
      activation by the histone deacetylase inhibitors, trichostatin A and sodium
      butyrate, through the recruitment of the co-activator, P/CAF. We have now
      extended our investigation to the activation of MDR1 by genotoxic stress. We show
      that activation of the MDR1 promoter by UV irradiation is also dependent on the
      CCAAT box (-82 to -73) as well as on a proximal GC element (-56 to -42). Gel
      shift and supershift analyses with nuclear extracts prepared from human KB-3-1
      cells identified NF-Y as the transcription factor interacting with the CCAAT box,
      while Sp1 was the predominant factor binding to the GC element. Mutations that
      abrogated binding of either of these factors reduced or abolished activation by
      ultraviolet irradiation; moreover, co-expression of a dominant-negative NF-Y
      protein (NF-YA29) reduced UV-activated transcription. Interestingly, YB-1, a
      transcription factor that also recognizes the CCAAT motif and had been reported
      to mediate induction of the MDR1 promoter by ultraviolet light, was incapable of
      interacting with the double-stranded MDR1 CCAAT box oligonucleotide in nuclear
      extracts, although it did interact with a single-stranded oligonucleotide.
      Furthermore, a mutation that abolished activation of MDR1 by UV-irradiation had
      no effect on YB-1 binding and co-transfection of a YB-1 expression plasmid had a
      repressive effect on UV-inducible transcription. Taken together, these results
      indicate a role for both NF-Y and Sp1 in the transcriptional activation of the
      MDR1 gene by genotoxic stress, and indicate that YB-1, if involved, is not
      sufficient to mediate this activation.

PMID- 10644770
TI  - ESE-3, a novel member of an epithelium-specific ets transcription factor
      subfamily, demonstrates different target gene specificity from ESE-1.
AB  - Most cancers originate as a result of aberrant gene expression in mainly
      glandular epithelial tissues leading to defects in epithelial cell
      differentiation. The latter is governed by distinct sets of transcriptional
      regulators. Here we report the characterization of epithelium-specific Ets
      factor, family member 3 (ESE-3), a novel member of the ESE subfamily of Ets
      transcription factors. ESE-3 shows highest homology to two other epithelium
      restricted Ets factors, ESE-1 and ESE-2. ESE-3, like ESE-1 and ESE-2, is
      exclusively expressed in a subset of epithelial cells with highest expression in
      glandular epithelium such as prostate, pancreas, salivary gland, and trachea. A
      potential role in branching morphogenesis is suggested, since ESE-3
      transactivates the c-MET promoter via three high affinity binding sites.
      Additionally, ESE-3 binding to DNA sequences in the promoters of several
      glandular epithelium-specific genes suggests a role for ESE-3 in later stages of
      glandular epithelium differentiation. Although ESE-3 and ESE-1 bind with similar
      affinity to various Ets binding sites, ESE-3 and ESE-1 differ significantly in
      their ability to transactivate the promoters containing these sites. Our results
      support the notion that ESE-1, ESE-2, and ESE-3 represent a unique epithelium
      specific subfamily of Ets factors that have critical but distinct functions in
      epithelial cell differentiation and proliferation.

PMID- 10644771
TI  - Mechanism of inverted activation of ClC-1 channels caused by a novel myotonia
      congenita mutation.
AB  - The voltage-gated chloride channel ClC-1 is the major contributor of membrane
      conductance in skeletal muscle and has been associated with the inherited
      muscular disorder myotonia congenita. Here, we report a novel mutation identified
      in a recessive myotonia congenita family. This mutation, Gly-499 to Arg (G499R)
      is located in the putative transmembrane domain 10 of the ClC-1 protein. In
      contrast to normal ClC-1 channels that deactivate upon hyperpolarization,
      functional expression of G499R ClC-1 yielded a hyperpolarization-activated
      chloride current when measured in the presence of a high (134 mM) intracellular
      chloride concentration. Current was abolished when measured with a physiological
      chloride transmembrane gradient. Electrophysiological analysis of other Gly-499
      mutants (G499K, G499Q, and G499E) suggests that the positive charge introduced by
      the G499R mutation may be responsible for this unique gating behavior. To further
      explore the function of domain 10, we mutated two charged residues near Gly-499
      of ClC-1. Functional analyses of R496Q, R496Q/G499R, R496K, and E500Q mutant
      channels suggest that the charged residues in domain 10 are important for normal
      channel function. Study of these mutants may shed further light on the structure
      and voltage-gating of this channel.

PMID- 10644773
TI  - Assessment and treatment of dizziness.

PMID- 10644774
TI  - Who should treat psychiatric disorders in neurology patients?

PMID- 10644772
TI  - A model for Escherichia coli DNA polymerase III holoenzyme assembly at
      primer/template ends. DNA triggers a change in binding specificity of the gamma
      complex clamp loader.
AB  - The gamma complex of the Escherichia coli DNA polymerase III holoenzyme assembles
      the beta sliding clamp onto DNA in an ATP hydrolysis-driven reaction.
      Interactions between gamma complex and primer/template DNA are investigated using
      fluorescence depolarization to measure binding of gamma complex to different DNA
      substrates under steady-state and presteady-state conditions. Surprisingly, gamma
      complex has a much higher affinity for single-stranded DNA (K(d) in the nM range)
      than for a primed template (K(d) in the microM range) under steady-state
      conditions. However, when examined on a millisecond time scale, we find that
      gamma complex initially binds very rapidly and with high affinity to
      primer/template DNA but is converted subsequently to a much lower affinity DNA
      binding state. Presteady-state data reveals an effective dissociation constant of
      1.5 nM for the initial binding of gamma complex to DNA and a dissociation
      constant of 5.7 microM for the low affinity DNA binding state. Experiments using
      nonhydrolyzable ATPgammaS show that ATP binding converts gamma complex from a low
      affinity "inactive" to high affinity "active" DNA binding state while ATP
      hydrolysis has the reverse effect, thus allowing cycling between active and
      inactive DNA binding forms at steady-state. We propose that a DNA-triggered
      switch between active and inactive states of gamma complex provides a two-tiered
      mechanism enabling gamma complex to recognize primed template sites and load
      beta, while preventing gamma complex from competing with DNA polymerase III core
      for binding a newly loaded beta.DNA complex.

PMID- 10644775
TI  - Neurological aspects of tropical disease

PMID- 10644776
TI  - Neurocysticercosis and epilepsy in developing countries.
AB  - Neurocysticercosis is a disease of poverty and underdevelopment. Little is known
      about the natural history of the infection in humans, but some of the mechanisms
      whereby the parasite remains silent and evades the host immune response are
      understood. Symptomatic neurocysticercosis usually results from host inflammatory
      response after parasite death, and the clinical manifestations can be diverse.
      There is no evidence that cysticidal treatment does more good than harm in
      addition to conventional antiepileptic treatment. Population control measures
      involving immunisation or mass treatment have not shown long term
      effectiveness.Epilepsy, similarly to neurocysticercosis, is a largely
      unrecognised but increasing burden on the welfare and economies of developing
      countries. The technology of drug treatment and psychosocial rehabilitation is
      well known but requires widespread and effective dissemination at low cost. There
      is little epidemiological data on risk factors for epilepsy in developing
      countries on which to base prevention strategies. The public health
      prioritisation of chronic disorders such as epilepsy remains a challenge for
      policy and practice in developing countries. For both neurocysticercosis and
      epilepsy, there is a dilemma about whether limited public resources would better
      be spent on general economic development, which would be expected to have a broad
      impact on the health and welfare of communities, or on specific programmes to
      help individual affected people with neurocysticercosis and epilepsy. Either
      approach requires detailed economic evaluation.

PMID- 10644777
TI  - Treatment of multiple sclerosis with interferon beta: an appraisal of cost
      effectiveness and quality of life.
AB  - OBJECTIVE: To evaluate the cost-effectiveness of interferon beta-1b (IFbeta-1b)
      for relapsing-remitting multiple sclerosis (RRMS). METHODS: Construction of a
      cost-effectiveness model using published data on IFbeta-1b effectiveness and the
      natural history of RRMS, and new data on costs and quality of life (QoL) from a
      sample of 102 patients with RRMS and resident in northern England. RESULTS:
      Poorer QoL was found for patients with multiple sclerosis compared with the
      general population; those who had had a relapse; those with worse states
      identified by a clinical measure (expanded disability status scale (EDSS)).
      Relapses have effects over several months. Health state valuations were higher
      than in the general population. Costs were higher in relapse than remission and
      for worse EDSS states. IFbeta-1b costs were larger than cost savings. The best
      cost-effectiveness estimate was pound28 700 per relapse avoided, which is
      pound809 900 per QALY gained; or pound328 300 per QALY gained allowing for
      effects of progression over 5 years. Estimates were robust to changes in
      assumptions. CONCLUSIONS: The impact of multiple sclerosis on QoL is substantial.
      Future trials should base outcomes measurement on QoL and be better linked to
      natural history and cost data. IFbeta-1b produces important occasional short term
      QoL gains, but small gains in QALYs overall and large additional costs.

PMID- 10644778
TI  - Gowers' sign.

PMID- 10644779
TI  - Clinical appropriateness: a key factor in outcome measure selection: the 36 item
      short form health survey in multiple sclerosis.
AB  - OBJECTIVES: Understanding the properties of an outcome measure is essential in
      choosing the appropriate instrument and interpreting the information it
      generates. The MOS 36 item short form health survey questionnaire (SF-36) is
      widely acknowledged as the gold standard generic measure of health status; few
      studies however have evaluated its use for clinical trials in multiple sclerosis.
      Its clinical appropriateness, internal consistency reliability, validity, and
      responsiveness was investigated across a broad range of patients with multiple
      sclerosis. METHODS: A prospective study in which 150 adults with clinically
      definite multiple sclerosis completed a battery of questionnaires evaluating
      generic health status, disability, handicap, and emotional wellbeing. Of these,
      44 patients undergoing inpatient rehabilitation completed the questionnaires
      before and after intervention to evaluate responsiveness. RESULTS: Score
      distributions demonstrated significant floor and ceiling effects in four of the
      eight dimensions which were particularly marked when patient selection was
      restricted to a narrow band of disease severity (as is the case in most clinical
      trials). Internal consistency exceeded the standard for group comparisons for all
      dimensions. Convergent and discriminant construct validity was supported by the
      direction, magnitude, and pattern of correlations with other health measures. In
      comparison with instruments measuring associated constructs, the responsiveness
      of the SF-36 was poor in evaluating change in moderate to severely disabled
      patients participating in a programme of inpatient rehabilitation. CONCLUSIONS:
      The SF-36 has some limitations as an outcome measure in multiple sclerosis. The
      results highlight the need for all instruments to be examined in the specific
      sample population under question and for the specific research question being
      investigated. In multiple sclerosis clinical trials, the SF-36 should be
      supplemented with other relevant measures.

PMID- 10644780
TI  - Changes in the normal appearing brain tissue and cognitive impairment in multiple
      sclerosis.
AB  - OBJECTIVES: To assess (a) whether the changes in the normal appearing brain
      tissue (NABT), as revealed by magnetisation transfer (MT) histogram analysis,
      correlates with cognitive dysfunction in patients with multiple sclerosis and (b)
      the relative contribution of these changes by comparison with that of multiple
      sclerosis lesions visible on conventional MRI. METHODS: Dual echo, T1 weighted
      and MT scans of the brain were obtained in 12 patients with multiple sclerosis
      with cognitive impairment and in seven without cognitive impairment. Lesion loads
      were assessed from T2 and T1 weighted scans. To create MT histograms of the NABT,
      multiple sclerosis lesion outlines from dual echo scans were superimposed
      automatically and nulled out from the coregistered and scalp stripped MTR maps.
      Average lesion MT ratio (MTR) and brain size were also measured. RESULTS: T2 and
      T1 lesion loads were significantly higher and the average lesion MTR and brain
      size were significantly lower in the group of cognitively impaired patients.
      Patients with cognitive deficits also had significantly lower average MTR and
      peak location of the NABT histogram. Logistic regression analysis showed that 68%
      of the total variance was explained by average NABT-MTR alone. A multivariable
      regression model showed that NABT-MTR was the only factor that significantly
      correlated with cognitive impairment in these patients (p=0.001). CONCLUSIONS:
      The extent of abnormalities which go undetected when using conventional MRI is
      relevant in determining cognitive impairment in multiple sclerosis.

PMID- 10644781
TI  - Reduction of frontal neocortical grey matter associated with affective aggression
      in patients with temporal lobe epilepsy: an objective voxel by voxel analysis of
      automatically segmented MRI.
AB  - BACKGROUND: Interictal episodes of aggression are often reported in patients with
      epilepsy. Some have characteristics of what has been referred to as episodic
      dyscontrol or intermittent explosive disorder (IED). Although structural brain
      abnormalities are thought to play a part in the pathophysiology of aggression,
      there are few in vivo studies of structural cerebral changes in patients with
      epilepsy and aggression. Using quantitative MRI, subtle structural brain
      abnormalities can be investigated in subgroups of patients with both epilepsy and
      episodes of affective aggression. METHODS: After automated segmentation of
      cerebral grey matter from T1 weighted MRI, the objective technique of statistical
      parametric mapping (SPM) was applied to the analysis of 35 control subjects, 24
      patients with temporal lobe epilepsy (TLE) with a history of repeated, interictal
      episodes of aggression, and 24 patients with TLE without episodes of aggression.
      Both TLE patient groups were compared with each other and with the control
      subjects on a voxel by voxel basis for increases and decreases of grey matter.
      RESULTS: The patients with TLE with aggressive episodes had a decrease of grey
      matter, most markedly in the left frontal lobe, compared with the control group
      and with patients with TLE without aggressive episodes. CONCLUSION: These
      findings suggest that a reduction of frontal neocortical grey matter might
      underly the pathophysiology of aggression in TLE. These voxel by voxel
      comparisons can guide further in vivo studies into aggression.

PMID- 10644782
TI  - Ilya Metchinikoff (1845-1908).

PMID- 10644783
TI  - Brain involvement in systemic immune mediated diseases: magnetic resonance and
      magnetisation transfer imaging study.
AB  - OBJECTIVE: Magnetisation transfer imaging (MTI) provides information about brain
      damage with increased pathological specificity over conventional MRI and detects
      subtle abnormalities in the normal appearing brain tissue, which go undetected
      with conventional scanning. Brain MRI and MTI findings were compared in patients
      with multiple sclerosis (MS) and systemic immune mediated diseases (SIDs)
      affecting the CNS to investigate their roles in understanding the nature of brain
      damage in these diseases. METHODS: Brain dual echo, T1 weighted and MTI scans
      were obtained in patients affected by systemic lupus erithematosus (SLE) with
      (NSLE, n=9) and without clinical CNS involvement (n=15), Behcet's disease (BD)
      (n=5), Wegener's granulomatosis (WG) (n=9), and antiphospholipid antibody
      syndrome (APLAS) (n=6). Ten patients with clinically definite MS and 15 healthy
      controls also underwent the same scanning protocol. Brain MRI and MT ratio (MTR)
      images of the same subject were coregistered and postprocessed to obtain MTR
      histograms of the whole brain and of the NABT. RESULTS: Brain hyperintense
      lesions were found in all patients with MS and with NSLE and in 5/15 patients
      with SLE, 5/9 with WG, 1/5 with BD, and 3/6 with APLAS. The lesion burden in the
      brain was significantly higher in patients with MS compared with all the other
      disease groups. All MTR histogram parameters were significantly different among
      patient subgroups. Patients with MS had significantly lower average MTR than all
      except patients with NSLE and significantly lower peak height and location than
      patients with SLE. patients with NSLE had significantly lower average MTR than
      patients with SLE. CONCLUSIONS: Microscopic brain tissue damage is relevant in
      patients with MS, but, apart from patients with NSLE, it seems to be absent in
      systemic immune mediated diseases, even in the presence of macroscopic MRI
      lesions or clinical evidence of CNS involvement.

PMID- 10644784
TI  - Resolution of disorientation and amnesia during post-traumatic amnesia.
AB  - OBJECTIVES: Despite the growing number of instruments for the prospective
      measurement of post-traumatic amnesia (PTA) after traumatic brain injury,
      fundamental issues about the natural history of its resolution and methods of
      examination remain unresolved. The aims of the present study were to: (1) examine
      the sequence of resolution of disorientation and amnesia, and (2) determine if
      the method of measuring the memory component affected the duration of PTA.
      METHODS: The sample comprised 31 severely injured patients admitted to a brain
      injury rehabilitation unit who were examined daily until they emerged from PTA.
      They were administered a composite PTA scale, covering orientation and memory
      items from standard PTA scales. Patients were consecutively allocated to one of
      two groups according to the method of measuring the memory component. Each group
      was administered identical materials with a different procedure. RESULTS: The
      most common sequence for resolution of disorientation in both groups was person,
      followed by place, then time. Overall, amnesia resolved before disorientation in
      94% of cases. Correlation coefficients between return of components of
      orientation and memory were all highly significant, ranging from r=0. 81 to 0.93.
      Significant variability occurred in the number of days to emerge from PTA
      according to the scale used. There was evidence that the method of measuring
      memory influenced the patient's capacity to consistently sustain criterion scores
      on the scale. CONCLUSIONS: These results are contrary to findings in mildly
      injured patients, in whom orientation usually returns before memory. They also
      demonstrate that the duration of PTA will be dictated by the method used. These
      findings raise validity issues with respect to the prospective measurement of
      PTA, and in particular determining when an individual patient has emerged from
      PTA, which require further investigation.

PMID- 10644785
TI  - Tardive and idiopathic oromandibular dystonia: a clinical comparison.
AB  - OBJECTIVE: Most patients with tardive dystonia have a focal onset involving the
      cranial-cervical region. Because of its resemblance to idiopathic cranial
      dystonia, a common form of dystonia, it often poses a diagnostic problem. To
      compare clinical features and response to botulinum toxin (BTX) injections
      between patients with tardive and idiopathic oromandibular dystonia (OMD).
      METHODS: Patients seen in a movement disorder clinic who satisfied the inclusion
      criteria for tardive or idiopathic OMD were studied. The clinical variables and
      responses to BTX between the two groups of patients were compared. In the tardive
      group, we also compared the clinical variables between those with oro-facial
      lingual stereotypies, and those without. RESULTS: Twenty four patients with
      tardive OMD and 92 with idiopathic OMD were studied. There were no differences in
      the demographic characteristics. Most were women, with duration of symptoms
      longer than 8 years. The mean duration of neuroleptic exposure was 7.1 (SD 7.9)
      years. Jaw closure was the most frequent subtype of OMD (tardive=41.7%,
      idiopathic=51.1%). Idiopathic patients were more likely to have coexistent
      cervical dystonia (p<0.05), whereas isolated OMD was significantly higher in
      tardive patients (p<0.05). Limb stereotypies, akathisia, and respiratory
      dyskinesia were seen only in the tardive OMD. Frequency of oro-facial-lingual
      stereotypy was significantly higher in the tardive than the idiopathic group
      (75.0% v 31.5%, p<0.0001). The peak effect of BTX was similar in both groups.
      CONCLUSIONS: Oro-facial-lingual stereotypies were significantly more frequent in
      the tardive than the idiopathic group. Presence of stereotypic movements in the
      limbs, akathisia, and respiratory dyskinesias in patients with OMD strongly
      suggests prior neuroleptic exposure. Dystonia in tardive OMD is more likely to be
      restricted to the oromandibular region, whereas in patients with idiopathic OMD,
      there is often coexistent cervical dystonia. BTX is equally effective in both
      groups of patients.

PMID- 10644786
TI  - Isolated absence of F waves and proximal axonal dysfunction in Guillain-Barre
      syndrome with antiganglioside antibodies.
AB  - OBJECTIVES: To investigate the pathophysiology of selective absence of F waves
      and its relation with antiganglioside antibodies in Guillain-Barre syndrome
      (GBS). Some patients with GBS show the absence of F waves as an isolated
      conduction abnormality, which has been interpreted as demyelination in the
      proximal nerve segments. METHODS: In 62 consecutive patients with GBS, sequential
      nerve conduction and F wave studies were reviewed, and antibodies against
      ganglioside GM1, GM1b, GD1a, GalNAc-GD1a, GD1b, and GQ1b were measured by an
      enzyme linked immunosorbent assay. RESULTS: In the first electrophysiological
      studies, isolated absence of F waves was found in 12 (19%) patients. Sequential
      studies in 10 of these patients showed two electrophysiological sequel patterns;
      rapid restoration of F waves (six patients), and persistent absence of F waves
      with distal motor nerve degeneration (acute motor axonal neuropathy, four
      patients). None of the 10 patients showed evidence of demyelination in the
      proximal, intermediate, or distal nerve segments throughout the course. Of the 62
      patients, IgG antibodies against GM1, GM1b, GalNAc-GD1a, or GD1b were
      significantly associated with the electrodiagnosis of acute motor axonal
      neuropathy, and patients with these antibodies more often had isolated absence of
      F waves than patients without them (11 of 36 (31%) v one of 26 (4%); p<0.01).
      Eleven of the 12 patients with isolated absence of F waves had positive serology
      for one or more antiganglioside antibodies. CONCLUSIONS: In GBS with
      antiganglioside antibodies, isolated absence of F waves is a frequent conduction
      abnormality especially in the early phase of the disease, and may be caused by
      axonal dysfunction, such as physiological conduction block or axonal degeneration
      at the nerve roots.

PMID- 10644787
TI  - An ambulatory dyskinesia monitor.
AB  - OBJECTIVES: New treatments are now becoming available for the management of
      levodopa induced dyskinesias in Parkinsons's disease. However, assessment of
      their efficacy is limited by the inadequacies of current methods of dyskinesia
      measurement. The objective was to develop and validate a portable device capable
      of objectively measuring dyskinesias during normal daily activities. METHODS: A
      portable device was developed based on a triaxial accelerometer, worn on the
      shoulder, and a data recorder that can record levodopa induced dyskinesias. A
      computer program plots raw acceleration and acceleration over 0.5 Hz frequency
      bands against time. The acceleration in the different bands can then be compared
      with the raw acceleration trace, enabling identification and exclusion of
      confounding activities such as tremor and walking, which have a characteristic
      appearance on the trace. The validity of this device was assessed on 12 patients
      and eight age matched controls by comparing accelerations in the 1-3 Hz frequency
      band with established clinical dyskinesia rating scales. While wearing the
      monitor, subjects were videorecorded sitting and during dyskinesia provocation
      tasks, including mental activation tasks, eating, drinking, writing, putting on a
      coat, and walking. The dyskinesias were graded with both modified abnormal
      involuntary movement (AIM) and Goetz scales. The clinical ratings were then
      compared with the mean acceleration scores. RESULTS: Acceleration in the 1-3 Hz
      frequency band correlated well against both scales, during all individual tasks.
      Acceleration produced by normal voluntary activity (with the exception of
      walking, which produced large accelerations, even in controls) was small compared
      with dyskinetic activity. With walking excluded, the mean acceleration over the
      rest of the recording time correlated strongly with both the modified AIM
      (Spearman's rank (r=0.972, p<0.001) and Goetz (r=0.951, p<0.001) scales.
      CONCLUSIONS: This method provides an accurate, objective means for dyskinesia
      assessment, and compares favourably with established methods currently used.

PMID- 10644788
TI  - Neurological disease, emotional disorder, and disability: they are related: a
      study of 300 consecutive new referrals to a neurology outpatient department.
AB  - OBJECTIVES: To determine the prevalence of anxiety and depressive disorders in
      patients referred to general neurology outpatient clinics, to compare disability
      and number of somatic symptoms in patients with and without emotional disorder,
      the relation to neurological disease, and assess the need for psychiatric
      treatment as perceived by patients and doctors. METHODS: A prospective cohort
      study set in a regional neurology service in Edinburgh, Scotland. The subjects
      were 300 newly referred consecutive outpatients who were assessed for DSM IV
      anxiety and depressive disorders (PRIME-MD, and HAD), health status, and
      disability (SF-36), and patients', GPs' and neurologists' ratings of the need for
      patient to receive psychiatric or psychological treatment. RESULTS: Of 300 new
      patients, 140 (47%) met criteria for one or more DSM IV anxiety or depressive
      diagnosis. Major depression was the most common (27%). A comparison of patients
      with and without emotional disorder showed that physical function, physical role
      functioning, bodily pain, and social functioning were worse in patients with
      emotional disorders (p<0. 0005). The median number of somatic symptoms was
      greater in patients with emotional disorders (p<0.0005). These differences were
      independent of the presence of neurological disease. Few patients wished to
      receive psychiatric or psychological treatments. Both general practitioners and
      neurologists were more likely to recommend psychiatric treatment when the
      patients' symptoms were medically unexplained. CONCLUSIONS: Almost half of new
      referrals to general neurology clinics met criteria for a DSM IV psychiatric
      diagnosis. These patients were more disabled, and had more somatic symptoms. They
      expressed little enthusiasm for receiving psychiatric treatment.

PMID- 10644789
TI  - Do medically unexplained symptoms matter? A prospective cohort study of 300 new
      referrals to neurology outpatient clinics.
AB  - OBJECTIVES: To determine (a) the proportion of patients referred to general
      neurology outpatient clinics whose symptoms are medically unexplained; (b) why
      they were referred; (c) health status and emotional disorder in this group
      compared with patients whose symptoms are explained by "organic" neurological
      disease. METHODS: The prospective cohort study with case note follow up at 6
      months was carried out in the regional neurology service in Lothian, Scotland
      with 300 newly referred outpatients. Neurologists rated the degree to which
      patients' symptoms were explained by organic disease (organicity), GPs' reasons
      for referral, health status (SF-36), anxiety, and depressive disorders (PRIME
      MD), RESULTS: Of 300 new patients 11% (95% confidence interval (95% CI) 7%-14%)
      had symptoms that were rated as "not at all explained" by organic disease, 19%
      (15% to 23%) "somewhat explained", 27% (22% to 32%) "largely explained", and 43%
      (37% to 49%) "completely explained" by organic disease. Reason for referral was
      not associated with "organicity". Comparison of these groups showed that although
      physical function was similar, the median number of physical symptoms and pain
      were greater in patients with lower organicity ratings (p<0.0005, p<0. 0005).
      Depressive and anxiety disorders were more common in patients with symptoms of
      lower organicity (70% of patients in the not at all group had an anxiety or
      depressive disorder compared with 32% in the completely explained group
      (p<0.0005). CONCLUSION: One third of new referrals to general neurology clinics
      have symptoms that are poorly explained by identifiable organic disease. These
      patients were disabled and distressed. They deserve more attention.

PMID- 10644790
TI  - Sudden unexpected death in epilepsy: a series of witnessed deaths.
AB  - OBJECTIVES: Sudden unexpected death in epilepsy (SUDEP) represents a significant
      category of mortality in the population with chronic epilepsy. A consistent
      feature is that most of these deaths are unwitnessed. The aim was to identify
      witnessed deaths, examine the circumstances, and relate these findings to the
      proposed mechanisms for SUDEP. METHODS: During the course of case ascertainment
      for a control study on SUDEP, witnessed deaths were identified and the
      circumstances examined in detail. Cases were notified by coroners, neurologists,
      and bereaved families. The findings were related to the proposed mechanisms for
      SUDEP which include central and obstructive apnoea and cardiac arrhythmia.
      RESULTS: One hundred and thirty five SUDEP cases have been identified to date, of
      which 15 were witnessed deaths. Twelve deaths were associated with convulsive
      seizures, one collapse occurred 5 minutes after a generalised seizure, another
      collapse occurred after an aura and one patient died while in a probable post
      ictal state. Witnesses reported that 12 of the 15 cases experienced respiratory
      difficulty. CONCLUSIONS: Most sudden epilepsy deaths are unwitnessed. Where
      witnessed most occur in association with a seizure and respiratory compromise is
      a prominent feature. Positioning or stimulation of respiration may be important
      in the prevention of these deaths.

PMID- 10644791
TI  - Extraocular muscle responses to high dose intravenous methylprednisolone in
      myasthenia gravis.
AB  - Three patients with generalised myasthenia gravis and three with ocular
      myasthenia gravis received two to five courses of high dose intravenous
      methylprednisolone because of the failure of standard immunomodulating therapies.
      Changes in myasthenic signs were assessed using a four step system for grading
      muscle weakness and fatiguability in 10 test items. Although a brief and modest
      amelioration was found from day 1 to day 2 after the initial infusion in two
      patients with generalised myasthenia gravis, all three experienced a prolonged
      phase of worsening followed by improvement before the next course. Conversely,
      for two of the patients with ocular myasthenia gravis, a transient but dramatic
      improvement of ptosis and ocular immobility was noted from 90 minutes to 5 hours
      after initiating the first infusion, followed by mild or no exacerbation. This 3
      hour improvement may be related not only to possible differences in the
      neuromuscular junction, but also to corticosteroids unmasking the central
      adaptation for the peripheral ocular muscle weakness by increasing the
      acetylcholine release.

PMID- 10644792
TI  - Aseptic meningitis after posterior fossa surgery treated by pseudomeningocele
      closure.
AB  - Aseptic meningitis is a recognised complication after posterior fossa surgery. It
      is often self limiting but occasionally runs a protracted course requiring
      repeated CSF examination to exclude infection, and treatment with systemic
      steroids. A patient is described with aseptic meningitis after posterior fossa
      surgery who underwent posterior fossa re-exploration nearly 3 years after the
      initial operation. This disclosed a pseudomeningocele, which was closed. The
      patient remains symptom free almost 2 years after closure. In this case of
      chronic aseptic meningitis after posterior fossa surgery, closure of the
      pseudomeningocele found at exploratory surgery led to resolution of the symptoms.

PMID- 10644793
TI  - Novel presenilin-1 mutation with widespread cortical amyloid deposition but
      limited cerebral amyloid angiopathy.
AB  - OBJECTIVE: To clarify the phenotypic heterogeneity in deposition of amyloid beta
      (Abeta) in the parenchyma and in cerebral vessels of the brains of the patients
      having presenilin-1 (PS1) mutations. Mutations in PS1 induce increased production
      of Abeta42(43), resulting in an enhanced overall deposition of Abeta protein
      within the cerebral cortex. METHODS: Sequence analysis of the PS1 gene of DNA
      from patients with early onset Alzheimer's disease, and immunostaining of brain
      tissues by end specific monoclonal antibodies against Abeta. RESULTS: Sequence
      analysis disclosed a novel mutation (N405S) in the PS1 gene in a Japanese patient
      with early-onset Alzheimer's disease. Postmortem examination of one patient with
      N405S showed limited cerebral amyloid angiopathy, whereas postmortem examination
      of another Japanese patient with Alzheimer's disease with the E184D mutation
      disclosed severe cerebral amyloid angiopathy. The brains of both patients showed
      widespread neuritic plaques, neurofibrillary tangles, and neuronal loss.
      Immunostaining showed that Abeta42 was predominant over Abeta40 in neuritic
      plaques in both patients, whereas Abeta40 was found to be predominant over
      Abeta42 in cerebral amyloid angiopathy in the patient with E184D. However, most
      cortical vessels of the patient with N405S were not reactive with either of the
      antibodies. CONCLUSION: The N405S mutation of PS1 is a major determinant of
      cortical Abeta deposition but not cerebral amyloid angiopathy in Alzheimer's
      disease.

PMID- 10644794
TI  - Forced hyperphasia and environmental dependency syndrome.
AB  - A distinctive, language related fragment of the environmental dependency syndrome
      is described: compulsive, involuntary, environmentally dependent speaking.
      Because this syndrome represents the observe of aphasia, it is named forced
      hyperphasia. An 84 year old woman with acute left frontal infarction was admitted
      to hospital with gait disturbance, forced grasp reflex, and striking imitation
      behaviour. After 2 weeks her imitation behaviour disappeared, but an equally
      striking new behaviour emerged. In the presence of others she would call out the
      names of objects in the room, and also call out the actions and gestures of
      people in the room, even though she was not asked to do so, and even though she
      was asked to stop. For example, if the doctor scratched his nose, she said, "The
      doctor is scratching his nose." Brain CT, MRI, and SPECT showed cerebral atrophy
      and a left superior frontal subcortical infarct. It is suggested that "forced
      hyperphasia" is a clinical fragment of the environmental dependency syndrome and
      that her compulsive, impulsive, involuntary release of spoken language resulted
      from the release of frontal inhibition of the complex reflex linking
      environmental cues to the set of motor, limbic, spatial, and linguistic
      associations underlying spoken language.

PMID- 10644795
TI  - Factors that ameliorate or aggravate spasmodic torticollis.
AB  - A sample of 72 patients with adult onset torticollis were asked to complete a
      checklist to indicate how a list of situations and activities affected the
      severity of their torticollis. Stress and self consciousness were reported as
      aggravating factors by more than 80% of the sample, whereas walking, fatigue, and
      carrying objects were noted as exacerbators by over 70% of the patients. For more
      than 40% of the sample, torticollis improved in the supine position, by
      relaxation, sleep, and lying on the side. However, the last four factors also
      worsened the head deviation in 16% to 25% of the patients. Use of a "geste
      antagoniste" to maintain the head in the body midline, was reported by 64 (88.9%)
      of the patients, which was still effective in correcting head position in 47%.
      The sensitivity of torticollis to social and emotional factors can be best
      explained in terms of a possible link between extrapyramidal and affective
      disorders through overlapping changes in catecholamine metabolism. The worsening
      of torticollis with peripheral motor activity (walking, running, writing) or its
      improvement with changes in body posture or with the geste antagoniste is best
      viewed in terms of alterations of peripheral proprioceptive feedback or central
      corollary discharge provoked by the motor output or command.

PMID- 10644796
TI  - A case of inclusion body myositis with benign monoclonal gammopathy successfully
      responding to repeated immunoabsorption.
AB  - A 69 year old woman with inclusion body myositis is described. She presented with
      benign monoclonal gammopathy. She was resistant to steroid therapy, but responded
      to repeated immunoabsorption. Up to now, there has been no established therapy
      for inclusion body myositis, including IVIg. It is suggested that
      immunoabsorption could be an alternative therapy for inclusion body myositis,
      when it was accompanied by immunological abnormality.

PMID- 10644797
TI  - Auditory saccade impairment after central thalamus lesions.
AB  - Visual and auditory saccades were studied in three patients with an isolated
      lesion located in the central thalamus. Visual saccades proved to be normal,
      whereas for auditory stimuli, the amplitude of the first saccade was asymmetric:
      saccades ipsilateral to the lesion were significantly smaller than those directed
      to the contralateral side. The patients were able to make a corrective saccade
      and hence to improve gain and to decrease gain asymmetry. It is suggested that
      patients were able to localise auditory targets correctly, but did not correctly
      take into account eye position during the saccade, probably as a consequence of
      an inaccurate efference copy (corollary discharge) signal. The findings are in
      keeping with the hypothesis that the central thalamus deals with saccades that
      are based on extraretinal signals.

PMID- 10644798
TI  - Late onset levodopa responsive Huntington's disease with minimal chorea
      masquerading as Parkinson plus syndrome.
AB  - Huntington's disease is characterised by hyperkinetic movements, mainly chorea,
      cognitive dysfunction, and psychiatric abnormalities. Non-dopa responsive
      parkinsonism occurs in the later stages of choreic disease or as the predominant
      feature of juvenile patients (Westphal variant). Late onset Huntington's disease
      presenting as levodopa responsive parkinsonism is rare. A series of four patients
      with late onset Huntington's disease presenting as levodopa responsive
      parkinsonism and cardiovascular dysautonomia, initially misdiagnosed as multiple
      system atrophy (MSA) in three patients, is reported. Levodopa treatment did not
      unmask significant chorea. These cases suggest the presence of a distinct
      phenotypic variant of Huntington's disease to be added to the differential
      diagnosis of other akinetic rigid syndromes.

PMID- 10644799
TI  - Neuropathological abnormalities of the corpus callosum in schizophrenia: a
      diffusion tensor imaging study.
AB  - OBJECTIVES: Diffusion tensor imaging (DTI), a technique capable of examining
      water diffusion in different tissues and the organisation of white matter tracts,
      was used to investigate the neuropathology of the corpus callosum in vivo in
      patients with schizophrenia. METHODS: Diffusion tensor imaging was performed in
      20 schizophrenic patients and 25 healthy controls. Two complementary measures,
      mean diffusivity and fractional anisotropy, which are considered to be sensitive
      indices of axonal integrity, were obtained from regions of interest in the genu
      (anterior) and splenium (posterior) of the corpus callosum. RESULTS: Mean
      diffusivity was significantly increased and fractional anisotropy significantly
      reduced in the splenium but not the genu of the corpus callosum in the
      schizophrenic group compared with controls. There were no significant sex
      differences in the DTI measures for either the schizophrenic or control group.
      Clinical variables such as age, duration of illness, dose of antipsychotic
      medication, and schizophrenic symptoms did not predict the DTI changes in the
      schizophrenic patients. CONCLUSIONS: The presence of DTI changes in the splenium
      but not the genu of the corpus callosum suggests that there may be a focal
      disruption of commisural connectivity in schizophrenia. However, these findings
      do not exclude the possibility of abnormalities in other areas of the corpus
      callosum or other regions of white matter and further research using different
      methods of analysis may enable us to clarify this. Diffusion tensor imaging is a
      valuable tool in investigating the structure of white matter in schizophrenia.

PMID- 10644801
TI  - Advances in research on neurodegeneration

PMID- 10644800
TI  - Cervical subdural haematoma.

PMID- 10644803
TI  - TRANSFUSION in the new year

PMID- 10644802
TI  - Atlas of psychiatric pharmacotherapy

PMID- 10644804
TI  - Hepatitis C virus lookback: emerging science and public policy.

PMID- 10644805
TI  - Quantification of anti-D and fetomaternal hemorrhage by flow cytometry.

PMID- 10644806
TI  - Use of third-generation hepatitis C virus (HCV) enzyme immunoassay (EIA) to
      resolve second-generation HCV EIA-reactive and second-generation recombinant
      immunoblot assay-indeterminate blood samples: data to support current Food and
      Drug Administration guidance on HCV lookback.

PMID- 10644807
TI  - Lookback on donors who are repeatedly reactive on first-generation hepatitis C
      virus assays:justification and rational implementation.
AB  - BACKGROUND: The purpose of this study was to explore strategies to minimize the
      number of unwarranted consignee notifications resulting from hepatitis C virus
      (HCV) first-generation (single-antigen) enzyme immunoassay (EIA 1.0) targeted
      lookback. STUDY DESIGN AND METHOD: The four blood centers participating in this
      study contributed data on 3753 HCV EIA 1.0-repeatably reactive (RR) donations.
      The analysis focused on 1) statistical evaluation of HCV EIA 1.0 signal-to-cutoff
      (S/CO) ratios versus HCV second-generation recombinant immunoblot assay (RIBA
      2.0) interpretation from all participating blood centers and 2) RNA testing using
      transcription-mediated amplification on all HCV EIA 1.0 RR/RIBA 2. 0-positive or 
      indeterminate specimens and a subset of RIBA 2. 0-negative donations for which
      specimens were available. RESULTS: Analysis of HCV EIA 1.0 S/CO ratios versus
      RIBA 2.0 indicated that 1180 (89%) of 1326 RIBA 2.0-positive specimens had an
      S/CO ratio >2. 5, while 146 (11%) had a ratio </=2.5. In contrast, of 2253 RIBA
      2. 0-negative specimens, 299 (13%) had an S/CO ratio >2.5, while 1954 (87%) had a
      ratio </=2.5. Of 248 HCV EIA 1.0-RR/RIBA 2.0-positive samples with stored
      specimens available for additional testing, 198 (80%) were HCV RNA positive; 15
      (7.5%) of these specimens had an S/CO ratio </=2.5, while 183 (92%) had a ratio
      >2.5. HCV RNA was detected in only 2 (1.5%) of 137 HCV EIA 1.0-RR/RIBA 2.0
      negative specimens: 1 of these 2 specimens had an S/CO >2.5, while the other had
      an S/CO </=2.5. CONCLUSION: A highly significant (<0.0001) correlation was found
      between the S/CO ratio on HCV EIA 1.0- and RIBA 2.0-positive or -negative
      results. An S/CO ratio >2.5 yielded an 89- percent sensitivity for RIBA 2.0
      positive specimens, and donations with an S/CO ratio >2.5 had a 75-percent
      probability of being RIBA 2.0 positive. A policy recommendation to use the S/CO
      ratio to triage lookback would prevent unwarranted notification of 87 percent of
      recipients of blood from RIBA 2.0-negative donors and would result in a failure
      to notify only 5 to 10 percent of recipients potentially exposed to infectious
      units.

PMID- 10644808
TI  - Immune response to blood transfusion invery-low-birthweight infants.
AB  - BACKGROUND: Allogeneic blood transfusion is common in the treatment of neonatal
      anemia of prematurity or anemia due to multiple phlebotomies. The immune response
      of neonates to passenger leukocytes from allogeneic red cells was investigated.
      STUDY DESIGN AND METHODS: Fourteen infants (4 male, 10 female) prospectively were
      randomly assigned to receive either white cell-reduced (Group 1) or non-white
      cell reduced (Group 2) irradiated blood. Blood samples were taken before and at
      various time intervals after transfusion (Days 1, 5-7,and 10-14). Cord blood from
      11 healthy term infants was used for comparison. The following surface markers
      were used to assess immune modulation by flow cytometry: CD45RA/CD45RO, CD4/CD8,
      CD25/CD28, CD3/DR, CD14/B7, and CD3/CD56+CD16. Donor cell microchimerism was
      studied using semi-quantitative polymerase chain reaction Y-chromosome detection
      in female infants who received male donor blood. Donor and recipient HLA class II
      typing was performed with polymerase chain reaction with sequence specific
      primers. RESULTS: The lymphocyte counts in both groups were significantly
      increased after transfusion, and there was a significant increase in lymphocytes
      expressing CD45RA, CD3-/CD16+CD56, CD80, and CD3-/DR on Day 14. The premature
      infants' pretransfusion natural killer cell population (CD3-/CD16+CD56) was
      significantly lower than that of term infants, but it reached a similar level by
      Days 10-14. CD8 subpopulations were increased but not CD4+ cells. Two female
      infants (of 6) had circulating Y chromosomes 1 day after transfusion, and most of
      the infants effectively cleared the donor cells within 24 hours of transfusion.
      Two Group 2 infants who by chance received presumably HLA-haploidentical donor
      blood developed necrotizing enterocolitis. CONCLUSION: Blood transfusion alters
      immune cell antigen expression in premature neonates and may initially be
      immunostimulatory and later immunosuppressive.

PMID- 10644809
TI  - Isolation of CD34+ progenitor cells from peripheral blood by use of an automated
      immunomagnetic selection system: factors affecting the results.
AB  - BACKGROUND: The isolation of CD34+ cells from mobilized peripheral blood is being
      increasingly used in the setting of allogeneic or autologous hematopoietic cell
      transplantation. Investigation of variables that may influence the effectiveness
      of CD34+ cell selection is of interest. STUDY DESIGN AND METHODS: Fifty-one CD34+
      cell selections from peripheral blood progenitor cells (PBPCs) (39 allogeneic and
      12 autologous) were performed using a magnetic cell separator (Isolex 300i,
      Baxter), including version 2.0 software. The results obtained were analyzed for
      different processing variables. The feasibility of transplanting these isolated
      CD34+ cells was also analyzed. RESULTS: The isolated CD34+ cell fraction had a
      median purity of 88.9 percent (range, 47.8-98.3). The median recovery of CD34+
      cells was 45.1 percent (13.8-76.2), and the median colony-forming unit-
      granulocyte-macrophage (CFU-GM) content was 17. 2 percent (0.8-58.6). Logarithms
      of T- and B-cell depletion had median values of 3.7 and 2.8, respectively. The
      version 2.0 software of the Isolex 300i gave a higher CD34+ cell recovery in the
      enriched cell fraction (median 57.8%) than did version 1.11 (39.4%) or 1.12
      (44.4%) (p = 0.01). The use of recombinant human deoxyribonuclease I during cell
      processing yielded more CD34+ cells (53% vs. 41%, p = 0. 01) and higher purity
      (92.8% vs. 87%, p = 0.03). There was a correlation between the percentage of
      CD34+ cells labeled with the monoclonal antibody 8G12 clone and the percentage of
      CD34+ cells labeled with the monoclonal antibody used during the processing
      technique (9C5 clone) in the initial, enriched, and depleted CD34+ cell fractions
      (R(2) = 0.95; 0.92; 0.78, p< 0.005, respectively). Median times for recovering
      >0.5 x 10(9) per L of granulocytes and >20 x 10(9) per L of platelets were 13 and
      16 days in the allograft patients and 13 and 14 days in the autograft patients.
      CONCLUSION: CD34+ cells can be highly and effectively isolated from allogeneic
      and autologous grafts by use of this automated technique, with a high grade of T-
      and B-cell depletion. These purified CD34+ cell components can engraft normally.

PMID- 10644810
TI  - Distinguishing full siblings from half-siblings in limited pedigrees.
AB  - BACKGROUND: Full siblings were compared with half-siblings to observe how well
      the two relationships could be distinguished by informative tests. STUDY AND
      DESIGN METHODS: Parentage analysis ascertained 25 pairs of full siblings and 25
      pairs of half-siblings. The pairs were then examined for the sharing of alleles
      at three independent variable number of tandem repeat (VNTR) loci. A sibling
      index (SI) and a half-sibling index (HSI) were calculated for each pair, and an
      SI:HSI ratio was determined. RESULTS: The SI:HSI ratio favored full siblings in
      18 of 25 full sibling pairs. The SI:HSI ratio exceeded 100 in 8 of those 25
      pairs. Although the ratio favored half-siblings in 23 of 25 half-sibling pairs,
      as was expected with the use of only 3 loci, it exceeded 0.1 in all 25 pairs.
      CONCLUSION: Study of more than three highly informative loci is required to
      improve the identification of full siblings and might well permit the
      identification of half-siblings.

PMID- 10644811
TI  - DNA from blood samples can be used to genotype patients who have recently
      received a transfusion.
AB  - BACKGROUND: The use of hemagglutination to phenotype red cells from recently
      transfused patients or of red cells that are coated with IgG can be time
      consuming and difficult to interpret. Because the molecular bases of many blood
      group antigens are known, it was investigated whether polymerase chain reaction
      (PCR) analysis of DNA, from white cells in blood from transfused patients, could
      be used to predict the blood group antigen profile of a patient. STUDY DESIGN AND
      METHODS: To prevent problems arising from potentially poor-quality DNA in
      clinical samples, primers that flanked the polymorphism of interest and that
      replicated a relatively short PCR amplicon were used. The PCR products, with or
      without digestion with the appropriate restriction enzyme, were analyzed on gels.
      Samples were collected from 60 patients who had received from 2 to 50 units of
      RBCs in the 7 days before sample collection. RBCs from some of these patients
      were coated with IgG. Analyses for RHD/non-D, RHE/RHe, KEL1/KEL2, FYA/FYB, FY
      GATA, JKA/JKB, and GYPA M/N were performed by using assays that had been
      validated with DNA prepared from untransfused volunteers of known phenotype. The
      genotyping assays were performed without knowledge of the expected result.
      RESULTS: The predicted genotype after analysis of the 60 patient samples was that
      expected from the results of phenotyping. In all cases, the molecular analysis
      gave a single result; no evidence of chimerism was obtained. CONCLUSION: In each
      case, the molecular genotype results were in agreement with the blood group
      antigen as determined by historical phenotyping, phenotyping after hypotonic
      washing, detection of alloantibodies in the patient's serum, or elution of
      alloantibody(ies). Under the conditions of these assays, reliable determination
      of a blood group allele can be made by PCR-restriction fragment length
      polymorphism testing.

PMID- 10644812
TI  - Genomic typing of human red cell miltenberger glycophorins in a Taiwanese
      population.
AB  - BACKGROUND: Antigens in the human red cell Miltenberger series are glycophorin
      variants of the MN (MNS) blood group system that are due to the rearrangement of
      glycophorin A (GPA) and glycophorin B (GPB) genes. STUDY DESIGN AND METHODS:
      Taking advantage of the differences between the GPA and GPB genes, a polymerase
      chain reaction-based method was developed to detect all the Miltenberger
      glycophorin variants and St(a) subtype. GPA- and GPB-specific primers were used
      to amplify the GPA or GPB gene, and the amplified products were used to recognize
      the different hybrid genes after restriction enzyme digestions. RESULTS: Among
      264 Taiwanese subjects studied, Mi.III and St(a) are the most common types of
      Miltenberger variants found. Mi.III was present in 13 (4.92%) of 264, and St(a)
      was found in 8 (3. 03%) of 264; 1 case (0.4%) of Mi.V was also identified from
      the study group. CONCLUSION: This is the first polymerase chain reaction-based
      method of detecting most of the Miltenberger variants and St(a). The genomic
      typing results were confirmed by control DNA of identified Miltenberger
      phenotypes. The prevalence rates of Mi. III and St(a) in this study were also
      consistent with other previous reports using different methods.

PMID- 10644813
TI  - B-lymphoblastoid cell lines as a source of reference DNA for human platelet and
      neutrophil antigen genotyping.
AB  - BACKGROUND: Human platelet and neutrophil antigens (HPAs, HNAs) are targets for
      platelet or granulocyte antibodies causing immune thrombocytopenia or
      neutropenia, respectively. Currently, genotyping is replacing phenotyping as the
      preferred method of diagnosis of immune cytopenia. To establish a reliable
      genotyping analysis, however, the availability as reference DNA of genomic DNA
      from persons of known genotype is essential. STUDY DESIGN AND METHODS: By the use
      of Epstein-Barr virus transformation, panels of B-lympho-blastoid cell lines (B
      LCLs) from HPA- and HNA-phenotyped individuals were developed. Genomic DNA was
      isolated from these cell lines and tested as reference DNA for genotyping of
      persons for HPAs and HNAs. RESULTS: DNA derived from these B-LCLs was typed by
      polymerase chain reaction-restriction fragment length polymorphism and -sequence
      specific primers. The results were in accordance with the genotyping from
      peripheral blood cells. These results were confirmed by 24 laboratories in
      Germany in a blind study. CONCLUSION: The inexhaustible source of reference DNA
      derived from B-LCLs allowed the evaluation of reliable HPA and HNA genotyping for
      quality control purposes. It should facilitate the development of DNA typing in
      blood centers and clinical laboratories.

PMID- 10644814
TI  - Genomic characterization of the kidd blood group gene:different molecular basis
      of the Jk(a-b-) phenotype in Polynesians and Finns.
AB  - BACKGROUND: The clinically important Kidd (JK) blood group antigens are carried
      by the urea transporter in red cells. The rare Jk(a-b-) phenotype can be caused
      by homozygosity at the JK locus for a silent allele, JK: This phenotype has been
      recorded in many ethnic groups, but it is most abundant among people originating
      from the Polynesian Islands and Finland. The molecular basis for Jk(a-b-) is
      unknown in these populations. STUDY DESIGN AND METHODS: Blood samples from
      individuals of Swedish, Polynesian, and Finnish origin were collected and
      characterized by routine JK blood group serology and JK genotyping. Genomic DNA
      covering the exons and intervening introns of the JK gene coding region was
      amplified by polymerase chain reaction, and fragments were directly sequenced.
      RESULTS: Exon and partial intron sequences in the coding region of the JK gene
      were determined. Finnish and Polynesian Jk alleles were analyzed; the only
      deviations from consensus were a splice-site mutation (G-->A) in Polynesians,
      causing skipping of exon 6, and a T871C substitution predicted to disrupt a
      potential N-glyco-sylation motif (NSS-->NSP) in Finns. Methods for rapid
      detection of silent Jk alleles were developed for clinical application.
      CONCLUSION: Polynesians and Finns have two different molecular alterations in
      their Jk alleles, both of which can now be determined by polymerase chain
      reaction.

PMID- 10644815
TI  - Immune hemolytic anemia induced by 6-mercaptopurine.
AB  - BACKGROUND: Myelosuppression is the main hematotoxic effect of 6-mercaptopurine
      (6-MP), which is an antimetabolite chemotherapy drug. Immune hemolytic anemia
      associated with this drug has not been previously reported. CASE REPORT: A 67
      year-old man with chronic myelomonocytic leukemia presented with anemia 2 weeks
      after 6-MP therapy had been initiated. Additional tests provided laboratory
      evidence of hemolysis. When treatment was stopped, the patient's condition and
      laboratory results showed a progressive improvement. RESULTS: The direct
      antiglobulin test was positive for IgG. The eluate and the serum were not
      reactive with panel red cells but reacted with 6-MP-treated red cells, while the
      normal serum pool was unreactive. The direct antiglobulin test was no longer
      positive by 20 days after the cessation of 6-MP therapy. CONCLUSION: This drug, 6
      MP, should be added to the list of drugs that have been reported to cause immune
      hemolytic anemia by means of the so-called hapten mechanism.

PMID- 10644816
TI  - Anti-D quantification by flow cytometry:a comparison of five methods.
AB  - BACKGROUND Three flow cytometric methods for anti-D quantification have been
      published. All use different cell sensitization and antibody detection conditions
      that may lead to varied results. Therefore, a direct comparison of the three
      methods is timely. STUDY DESIGN AND METHODS: The published flow cytometric
      methods and two new in-house modifications were compared. Ten serum samples
      containing anti-D at levels between 11.6 and 915 IU per mL were selected for
      analysis, and each was tested a minimum of three times. Anti-D bound to cells was
      detected with fluorescence-labeled anti-human IgG reagents. RESULTS The
      interassay CV of the standard curves for each of the five methods was less than
      10 percent. The intra-assay CV was consistently <10 percent with four out of the
      five methods, but, by the fifth method, it was >20 percent in more than one-third
      of the tests. In 72 percent of the sample and method combinations, the interassay
      CV was <25 percent. Plotting of the mean anti-D value for each sample as a
      percentage of the value determined by an automated technique (AutoAnalyzer)
      revealed wide variability between the methods. CONCLUSION: Anti-D quantification
      by flow cytometry is influenced by the serum antibody characteristics and the
      method used. The differences between the flow cytometric and AutoAnalyzer
      techniques indicate that further validation of the flow cytometric method is
      required before routine use.

PMID- 10644817
TI  - Viral safety of solvent/detergent-treated plasma.
AB  - BACKGROUND: Pooling of plasma donations increases the risk for blood-borne
      infections. In solvent/detergent (SD)-treated plasma, lipid-enveloped viruses are
      efficiently inactivated. This method, however, does not affect non-lipid
      enveloped viruses. The current study investigated the viral safety of SD-treated
      plasma (Octaplas) and paid particular attention to the transmission of non-lipid
      enveloped viruses. STUDY DESIGN AND METHODS: The study comprised 343 adults
      undergoing cardiac surgery. Follow-up was performed 6 to 12 months and 2 years
      after operation. The sera were tested for hepatitis B surface antigen and
      specific antibodies against hepatitis A, B, and C; cyto-megalovirus; HIV, human T
      lymphotropic virus types I and II; and human parvovirus B19 (B19). A total of 25
      batches of SD-treated plasma prepared from Norwegian plasma were used. All
      batches were tested for hepatitis A virus and B19 by nucleic acid amplification
      testing and investigated for neutralizing antibodies directed against these
      viruses. RESULTS: In patients who received SD-treated plasma, B19 seroconversion
      occurred at a rate similar to that in nontransfused patients. No other
      seroconversions could be ascribed to the transfusion of SD-treated plasma. All 25
      SD-treated plasma batches contained neutralizing antibodies against hepatitis A
      virus and B19. In nucleic amplification testing, all SD-treated plasma batches
      tested positive for B19, while five demonstrated borderline reactions for
      hepatitis A virus. CONCLUSION: Transfusion of SD-treated plasma was found to be
      safe with regard to lipid-enveloped viruses. Immune antibodies neutralize viral
      particles in plasma and are of importance in avoiding clinical disease with the
      non-lipid-enveloped hepatitis A virus and B19.

PMID- 10644818
TI  - Preparation and storage characteristics of white cell-reduced high-concentration
      platelet concentrates collected by anapheresis system for transfusions in utero.
AB  - BACKGROUND: Important concerns with regard to in utero platelet transfusions are
      avoidance of volume overload and the immunomodulatory effects of residual white
      cells (WBCs). This study evaluated a modification of a leukocyte-reduction system
      (LRS, Spectra, COBE BCT) for apheresis, which collects high-concentration WBC
      reduced platelets (HCPs) for in utero transfusion. STUDY DESIGN AND METHODS: The
      LRS procedure was modified by running the platelet collection pump at specified
      low flow rates (Q(col)) for the first part of the procedure, collecting HCPs by
      gently purging them from the LRS chamber into a designated collection bag and
      then restoring the original LRS procedure settings to collect a second standard
      apheresis platelet concentrate (PC). Two centers carried out 32 procedures.
      Platelet yield, residual WBCs, and in vitro platelet function studies were
      evaluated. RESULTS: Platelet concentrations in 60 mL of HCPs were predictable
      according to Q(col) (r(2) = 0.735). HCP yields varied from 0.9 to 3.2 x 10(11),
      depending on the desired final platelet concentrations in 60 mL, with an overall
      average of 1. 92 x 10(11) (n = 32). Apheresis PCs had a mean platelet yield of
      2.9 x 10(11) (1.3-4.4 x 10(11), n = 20) and 3.9 x 10(11) (2.2-5.8 x 10(11), n =
      12) at concentrations of 1.3 x 10(12) per L for single-needle and dual- needle
      procedures, respectively. Median WBC counts were 5.6 x 10(3) for HCPs and 2.0 x
      10(4) for apheresis PCs, with >99 percent expected to be less than 1 x 10(6). HCP
      in vitro characteristics were equivalent to those of apheresis PCs at 24 hours
      after collection. In vitro performance declined over storage as a function of HCP
      yield. HCP pH at 22(o)C was maintained at a level of >6.2 for more than 3 days
      for yields >1.6 x 10(11), less than 2 days for yields 1.6 to 2.2 x 10(11), and
      less than 24 hours for yields >2.2 x 10(11). HCPs showed good in vitro
      characteristics and could be stored for 1 to 3 days, depending on the total
      number of platelets collected. CONCLUSION: A standard apheresis PC and an HCP
      requiring no secondary processing can be collected with the Spectra LRS. The
      platelet concentration may be determined by clinical need. HCPs meet the
      requirements for components that are transfused in utero.

PMID- 10644819
TI  - Length of storage of transfused red cells and postoperative morbidity in patients
      undergoing coronary artery bypass graft surgery.
AB  - BACKGROUND: The transfusion of old red cells (RBCs) may be associated with
      reduced delivery of oxygen to tissues and an increased risk of transfusion
      complications. The association of postoperative morbidity with the length of
      storage of perioperatively transfused RBCs was studied in 268 consecutive
      patients receiving a blood transfusion for coronary artery bypass graft surgery.
      STUDY DESIGN AND METHODS: The postoperative length of hospitalization, the
      postoperative length of stay in the intensive care unit, and the length of
      endotracheal intubation after the day of the operation were used as surrogate
      measures of global postoperative morbidity. The length of storage of the oldest
      transfused RBC unit, the mean length of storage of the oldest and second oldest
      RBC units, and the mean length of storage of all RBC units transfused to each
      patient were tested for association with the three outcome variables. Multiple
      linear regression analysis and Cox proportional-hazard analysis were used to
      adjust for the effects of confounding factors that pertained to each patient's
      severity of illness and the difficulty of each operation. RESULTS: There were no
      significant associations after adjustment for the effects of confounding factors.
      CONCLUSION: This study did not corroborate the previously reported association
      between transfusion of old RBCs and increased morbidity. However, there is
      surprisingly little research on the clinical outcomes of the transfusions of old
      RBCs, and this hypothesis should be investigated further.

PMID- 10644820
TI  - The first blood banker: Oswald Hope Robertson.

PMID- 10644821
TI  - Microfiltration and microemboli: a history.

PMID- 10644822
TI  - Anaphylactic transfusion reactions associated with anti-haptoglobin in a patient
      with ahaptoglobinemia.

PMID- 10644823
TI  - Adverse effects associated with extracorporeal photochemotherapy.

PMID- 10644824
TI  - The absence of swirling in platelet concentrates is highly predictive of poor
      posttransfusion platelet count increments and increased risk of a transfusion
      reaction.

PMID- 10644825
TI  - Reasons for discard of umbilical cord blood units before cryopreservation.

PMID- 10644826
TI  - Reasons for deferral of potential umbilical cord blood donors.

PMID- 10644827
TI  - The pitfalls of cost-effectiveness analyses in guiding patient care.

PMID- 10644828
TI  - Analysis of a genomic segment of white spot syndrome virus of shrimp containing
      ribonucleotide reductase genes and repeat regions.
AB  - White spot syndrome is a worldwide disease of penaeid shrimp. The disease agent
      is a bacilliform, enveloped virus, white spot syndrome virus (WSSV), with a
      double-stranded DNA genome that probably contains well over 200 kb. Analysis of a
      12.3 kb segment of WSSV DNA revealed eight open reading frames (ORFs), including
      the genes for the large (RR1) and small (RR2) subunits of ribonucleotide
      reductase. The rr1 and rr2 genes were separated by 5760 bp, containing several
      putative ORFs and two domains with multiple sequence repeats. The first domain
      contained six direct repeats of 54 bp and is part of a coding region. The second
      domain had one partial and two complete direct repeats of 253 bp at an intergenic
      location. This repeat, located immediately upstream of rr1, has homologues at
      several other locations on the WSSV genome. Phylogenetic analysis of RR1 and RR2
      indicated that WSSV belongs to the eukaryotic branch of an unrooted parsimonious
      tree and, further, seems to suggest that WSSV and baculoviruses probably do not
      share an immediate common ancestor. The present analysis of WSSV favours the view
      that this virus is either a member of a new genus (Whispovirus) within the
      Baculoviridae or a member of an entirely new virus family.

PMID- 10644829
TI  - Analysis of human papillomavirus type 16 E6 variants in relation to p53 codon 72
      polymorphism genotypes in cervical carcinogenesis.
AB  - This study aimed to assess the role of specific human papillomavirus type 16 (HPV
      16) variants, in combination with p53 codon 72 polymorphism genotypes, in
      cervical carcinogenesis. An initial sequence analysis of HPV-16 long control, E6
      and E7 regions of 53 well-defined cervical samples containing HPV-16 revealed
      that a T to G transition at nucleotide position 350 within the E6 open reading
      frame was the most common variation, the frequency of which seemed to decrease
      with increasing severity of the lesion. Therefore, a total of 246 cervical
      samples of residents of The Netherlands was specifically analysed for HPV-16
      350G/T variants and/or p53 codon 72 genotypes. These comprised HPV-negative
      normal cervical scrapes (n=40), normal cervical scrapes containing HPV-16 (n=46),
      scrapes containing HPV-16 from women with abnormal cervical cytology
      participating in a non-intervention follow-up study without (n=38) and with
      (n=51) a histologically proven cervical intraepithelial neoplasia (CIN) III
      lesion at the end of the study, and cervical squamous cell carcinomas (n=71).
      Neither specific HPV-16 350G/T variants nor specific p53 genotypes were
      associated with a higher risk of developing CIN III or cervical cancer. However,
      HPV-16 350T variants were significantly over-represented in p53 Arg homozygous
      women with cervical cancer. This suggests that, in p53 Arg/Arg women, infection
      with HPV-16 350T variants confers a higher risk of cervical cancer.

PMID- 10644830
TI  - alpha6 integrin is not the obligatory cell receptor for bovine papillomavirus
      type 4.
AB  - Recently, alpha6 integrin has been proposed as the epithelial cell receptor for
      papillomavirus. This study investigated whether alpha6 integrin is the cellular
      receptor for bovine papillomavirus type 4 (BPV-4), which is strictly
      epitheliotropic and infects the mucous epithelium of the upper digestive tract.
      Primary bovine mucosal keratinocytes from the palate of a foetus (PalK) displayed
      high levels of alpha6 integrin; matched primary fibroblasts from the same biopsy
      (PalF) expressed almost no alpha6 integrin. However, BPV-4 bound both PalK and
      PalF to similar, saturable levels. Native BPV-4 virions infected PalK in vitro,
      as detected by RT-PCR of E7 RNA. Infection could be blocked by excess virus-like
      particles (VLPs) and by neutralizing antisera against L1-L2 and L1 VLPs or by
      denaturation of the virions, supporting the view that infection in vitro mimics
      the process in vivo. alpha6 integrin-negative human keratinocyte cell lines were
      derived from patients affected by junctional epidermolysis bullosa presenting
      genetic lesions in their hemidesmosomes. The level of alpha6 integrin expression
      was determined in these cell lines by in situ immunofluorescence and FACS.
      Despite the absence of alpha6 integrin expression by BO-SV cells, they were bound
      by BPV-4 to similar, saturable levels as normal keratinocytes, KH-SV.
      Furthermore, BO-SV and KH-SV cells were both infected by BPV-4 to apparently the
      same extent as PalK cells. These results are consistent with the conclusion that
      alpha6 integrin is not the obligatory receptor for a bovine mucosotropic
      papillomavirus.

PMID- 10644831
TI  - Replication of Aleutian mink disease parvovirus in mink lymph node histocultures.
AB  - Aleutian mink disease parvovirus (ADV), causes an immune disorder with a
      persistent infection of lymphoid organs in adult mink. We studied replication of
      ADV in gel-supported histocultures prepared from adult mink mesenteric lymph node
      (MLN). Evidence of virus replication in the histocultures was first observed by
      indirect immunofluorescence 72 h after incubation with virus. Cells resembling
      lymphocytes and macrophages contained both ADV capsid (VP2) and nonstructural
      (NS1 and NS2) proteins, and were present in a distribution suggestive of infected
      cells within germinal centres. ADV replicative form and encapsidated virion DNA
      were also detected in infected histocultures at time-points after 72 h. In
      addition, we were able to passage ADV-Utah to a new round of histocultures. These
      results suggested that the infected cells were actual target cells for ADV
      replication and that productive ADV-Utah replication, complete with the
      generation of virus, was occurring in the histocultures. The mink MLN
      histocultures provide a system to study the replication and molecular
      pathogenesis of ADV in target tissues.

PMID- 10644832
TI  - Genetic characterization of feline parvovirus sequences from various carnivores.
AB  - Infections with viruses of the feline parvovirus subgroup such as feline
      panleukopenia virus (FPV), mink enteritis virus (MEV) and canine parvovirus (CPV
      2) [together with its new antigenic types (CPV-2a, CPV-2b)] have been reported
      from several wild carnivore species. To examine the susceptibility of different
      species to the various parvoviruses and their antigenic types, samples from wild
      carnivores with acute parvovirus infections were collected. Viral DNA was
      amplified, and subsequently analysed, from faeces or formalin-fixed small
      intestines from an orphaned bat-eared fox (Otocyon megalotis), a free-ranging
      honey badger (Mellivora capensis), six captive cheetahs (Acinonyx jubatus), a
      captive Siberian tiger (Panthera tigris altaica) and a free-ranging African wild
      cat (Felis lybica). Parvovirus infection in bat-eared fox and honey badger was
      demonstrated for the first time. FPV-sequences were detected in tissues of the
      African wild cat and in faeces of one cheetah and the honey badger, whereas CPV
      2b sequences were found in five cheetahs and the bat-eared fox. The Siberian
      tiger (from a German zoo) was infected with a CPV-type 2a virus. This
      distribution of feline parvovirus antigenic types in captive large cats suggests
      an interspecies transmission from domestic dogs. CPV-2 sequences were not
      detected in any of the specimens and no sequences with features intermediate
      between FPV and CPV were found in any of the animals examined.

PMID- 10644833
TI  - BAG-1, a novel Bcl-2-interacting protein, activates expression of human JC virus.
AB  - Transcription of the human polyomavirus JC virus (JCV) genome is regulated by
      cellular proteins and the large tumour (T) antigen. Earlier studies led to the
      identification of nuclear factor-1 (NF-1)-binding sites in the JCV enhancer by
      DNase I protection assays of extracts from retinoic acid (RA)-differentiated P19
      embryonal carcinoma (EC) cells. In this study, a cDNA clone that encodes a
      protein capable of binding to the JCV NF-1 sites was isolated from an RA
      differentiated EC cell cDNA library. Sequence analysis revealed that the cDNA
      isolated was identical to the previously described Bcl-2-interacting protein BAG
      1 (Bcl-2-associated athano gene-1). Results from RNA studies indicated that BAG-1
      is expressed in several cell types. Co-transfection of a recombinant BAG-1
      expression plasmid with JCV promoters indicated that BAG-1 stimulates
      transcription of the JCV(E) promoter and to a lesser extent the JCV(L) promoter.
      Mutations in the NF-1 sites in the JCV(E) promoter eliminated the activation by
      BAG-1. Thus, BAG-1 is a novel transcription factor that may play a role in JCV
      expression.

PMID- 10644834
TI  - Agnoprotein-1a of avian polyomavirus budgerigar fledgling disease virus:
      identification of phosphorylation sites and functional importance in the virus
      life-cycle.
AB  - The avian polyomavirus budgerigar fledgling disease virus (BFDV) encodes an
      unusual set of four agnoproteins in its late upstream region. Of the two pairs of
      these proteins, which overlap each other in two different reading frames, the
      p(L1)-promoted agnoprotein-1a (agno-1a) is the dominant species and is able to
      support virus propagation in the absence of the other three polypeptides. Viral
      BFDV agno-1a, and also agno-1a expressed via an influenza virus vector, consists
      of a complex series of electrophoretically separable subspecies that can be
      reduced by phosphatase action down to a primary unphosphorylated protein with an
      apparent molecular mass of 31 kDa. Through peptide mass spectrometry and site
      directed mutagenesis, the positions of four serine and three threonine residues
      have been determined as phosphate-accepting groups, which are partially modified
      by the combined action of three different cellular kinases. Since extensively
      phosphorylated agno-1a is required for its intracellular function, control over
      VP protein expression, and unphosphorylated agno-1a is observed as an additional
      component in the BFDV virion, both extreme subspecies appear to be drawn from
      that complex mixture, which also includes the intermediate stages of
      phosphorylation.

PMID- 10644836
TI  - Relationships within and between genotypes of hepatitis B virus at points across
      the genome: footprints of recombination in certain isolates.
AB  - Hepatitis B virus (HBV) was partitioned into type, subtype and isolate categories
      and the average evolutionary distances within and between categories was plotted
      at each of 54 points along the genome. The graphs showed alternating variable and
      conserved domains within and between HBV subtypes and revealed that some
      specimens assigned to different groups are more similar across several contiguous
      intervals than specimens belonging to the same group. Isolates were screened
      individually to determine their conformation to type and mosaic structure was
      identified in 14/65 specimens. Two entire clades (six specimens) of genotype B
      had a B/C sequence switch in the core gene region, whereas six genotype D
      specimens showed D/A switching in one or more regions of the genome. Genotype E
      was not separate from genotype D in the X and C subgenomic regions. The nature
      and distribution of polymorphic sites in mosaic regions was mapped at both the
      nucleotide and protein levels and the position of the variant fragments was
      related to mutational hot spots and linear epitopes of HBV. Mosaic structure was
      demonstrated statistically in 11 isolates using bootstrap resampling and
      recombination, rather than random change, appeared to be the mechanism
      responsible. The sequence between and including the two DR regions was
      represented in all putative recombinants. The distribution of genetic distances
      over subgenomic regions showed that substitution rates are not constant among the
      lineages of HBV in the preS regions. Genotype F is the most diverse group. Only
      genotypes A, C and F partition consistently into subtypes.

PMID- 10644835
TI  - Mapping of immunodominant B-cell epitopes and the human serum albumin-binding
      site in natural hepatitis B virus surface antigen of defined genosubtype.
AB  - Twelve MAbs were generated by immunization of BALB/c mice with plasma-derived
      hepatitis B virus surface spherical antigen particles subtype ayw2 (HBsAg/ayw2
      genotype D). Their epitopes were mapped by analysis of reactivity with plasma
      derived HBsAg/ayw2 and HBsAg/adw2 (genotype A) in enzyme immunoassays and blots.
      Mapping was supported by nested sets of truncated preS2 proteins and preS2
      peptides. Five antibodies were S domain-specific, seven were preS2-specific and
      11 had a preference for genotype D. According to our data, group I of the three
      known epitope groups of preS2 has to be divided into IA and IB. Three preS2
      specific MAbs forming the new group IA reacted with genotype D residues 3-15
      which have not yet been described as an epitope region. IA antibodies strongly
      inhibited the binding of polymerized human serum albumin. Two antibodies (group
      II) reacted with the glycosylated N-terminal region of preS2 in plasma-derived
      HBsAg, but not with a preparation from transfected murine cells. One group III
      antibody was subtype-specific and reacted with the highly variable preS2 sequence
      38-48. Only one antibody (group IB) mapped to the region (old group I) which was
      believed to be immunodominant and genotype-independent. Geno(sub)type-specific
      epitopes of preS2 are obviously the immunodominant components of natural HBsAg in
      BALB/c mice, but these epitopes may be masked by serum albumins in humans. The
      data may explain why it is difficult to detect anti-preS2 antibodies in human
      recipients of preS2-containing vaccines, in spite of the preS2 immunodominance in
      mice.

PMID- 10644837
TI  - Monocyte-derived dendritic cells are permissive to the complete replicative cycle
      of human cytomegalovirus.
AB  - The susceptibility of monocyte-derived immature dendritic cells (DC) to infection
      by various strains of human cytomegalovirus (HCMV) was analysed. Immature DC were
      generated by incubation of peripheral blood monocytes with interleukin-4 and
      granulocyte-macrophage colony-stimulating factor for 7 days and were
      characterized by a CD1a+/CD40+/CD80+/CD86+/HLA-DR+/CD14- phenotype. Viral antigen
      expression and production of infectious progeny virus were analysed in infected
      immature DC cultures. Immature DC were 80-90 % susceptible to HCMV strains that
      had been propagated in endothelial cell culture, whereas the infection rate was
      negligible with fibroblast-adapted HCMV strains. Immature DC infection resulted
      in expression of viral immediate early, early and late genes. Productive
      infection was proven by the detection of infectious virus in single-step growth
      curves and in infectious centre assays. It is concluded that HCMV might interfere
      with the host immune reaction by permissive, lytic infection of immature DC.

PMID- 10644838
TI  - Mitochondrial distribution and function in herpes simplex virus-infected cells.
AB  - In this study, mitochondria migrated to a perinuclear region in the cytoplasm in
      herpes simplex virus (HSV)-infected cells. HSV infection did not promote the
      expression of cytochrome c oxidase subunit 2 but did promote that of stress
      responsive HSP60, both of which are known to be components of mitochondria. The
      levels of cellular ATP and lactate and mitochondrial membrane potential were
      maintained for at least 6 h but decreased at the late stage of infection. It was
      also found that the UL41 and UL46 gene products, both of which are known to be
      tegument proteins, accumulated in the perinuclear region. The clustering of
      mitochondria and the accumulation of tegument proteins were completely blocked by
      the addition of nocodazole and vinblastine. These results suggest that
      mitochondria respond to the stimulation of HSV infection, migrating with tegument
      proteins along microtubules to a site around the nucleus, and maintain function
      until at least the middle stage of infection.

PMID- 10644839
TI  - Diminished secondary CTL response in draining lymph nodes on cutaneous challenge
      with herpes simplex virus.
AB  - We have shown that C57BL/6-derived CD8(+) CTL specific for an immunodominant
      herpes simplex virus type 1 (HSV-1) glycoprotein B (gB) determinant express a
      highly conserved Vbeta10/junctional sequence combination. This extreme T cell
      receptor beta-chain bias can be used to track the activation of gB-specific CTL
      in lymph nodes draining the site of HSV-1 infection. In this report we have
      examined the accumulation of gB-specific CTL in the primary and secondary or
      recall CTL responses to HSV-1 infection. We found that gB-specific cytolytic
      activity present within popliteal lymph nodes draining HSV-infected foot-pads
      peaked at day 5 post-infection during the primary response. As found previously,
      this correlates with the accumulation of Vbeta10(+)CD8(+) CTL in the activated T
      cell subset. Lymph node-derived cytotoxicity peaked between days 3 and 4 on
      secondary challenge with virus and, somewhat surprisingly, was considerably below
      that seen in the primary response. This reduced gB-specific cytolytic activity
      mirrored a near absence of Vbeta10(+)CD8(+) T cell enrichment found within the
      draining lymph nodes during this recall response, consistent with the overall
      diminution of gB-specific CTL accumulation in this site. Finally, there was a
      second wave of biased accumulation of Vbeta10(+)CD8(+) activated T cells within
      the popliteal lymph nodes well after the resolution of infection in both the
      primary and secondary responses. These results are discussed in terms of
      preferential activation of virus-specific memory T cells directly in infected
      tissues during a secondary CTL response at the expense of draining lymphoid
      organs.

PMID- 10644840
TI  - A putative latency promoter/enhancer (P(LAT2)) region of pseudorabies virus
      contains a virulence determinant.
AB  - Contradictory data have recently been reported on the role of the unique long
      internal repeat junction area of pseudorabies (Aujeszky's disease) virus (PrV)
      genome in the virulence of the virus. To investigate the basis of the difference,
      four recombinant PrVs mutated at the outer region of inverted repeats that
      involved a putative latency promoter (P(LAT2)) were constructed in this study.
      Propagation characteristics of mutant viruses in cultured cells were similar to
      those of the wild-type virus. However, a 757 bp deletion at this location caused
      significant reduction in the virulence of PrV after intraperitoneal inoculation
      of mice and a moderate decrease in the virulence after intracranial inoculation.
      These results indicate that the P(LAT2) region is an important virulence
      determinant that may be implicated in the neuroinvasive capability of the virus.

PMID- 10644841
TI  - Infection of intestinal epithelial cells and development of systemic disease
      following gastric instillation of murine gammaherpesvirus-68.
AB  - Murine gammaherpesvirus-68 (gammaHV-68) induces a lymphocytosis in mice and
      establishes a latent infection of B lymphocytes following intranasal
      administration in anaesthetized animals. Because gammaHV-68 is a
      gammaherpesvirus, it has been used as a model to understand the pathogenesis of
      Epstein-Barr virus (EBV) and human herpesvirus-8 (HHV-8) infections. In this
      study, we investigated the unlikely possibility that gammaHV-68 could survive the
      harsh gastrointestinal environment to efficiently infect intestinal epithelial
      cells, and then disseminate from mucosal sites to cause systemic disease.
      Surprisingly, oral administration, or gastric instillation which by-passed the
      oral cavity, readily caused a systemic lymphocytosis and established a latent
      infection in splenic leukocytes. The finding that gammaHV-68 could readily infect
      adult mice following gastric instillation strongly suggested that intestinal
      epithelial cells could be productively infected. Unlike the more routinely used
      method of intranasal inoculation, gammaHV-68 given intragastrically resulted in
      lytic virus, viral RNA and viral DNA being present in isolated intestinal
      epithelial cells. Furthermore, gammaHV-68 RNA and DNA, but not latent virus,
      could be detected in epithelial cells as long as 30 days post-infection,
      suggesting that some of these cells might be persistently infected. Taken
      together, these studies demonstrate that gammaHV-68 can survive passage through
      the gastrointestinal tract and infect intestinal epithelial cells. Following
      infection of gut epithelial cells, gammaHV-68 can disseminate from mucosal sites
      to induce a systemic lymphocytosis which is similar to the disease induced
      following intranasal inoculation.

PMID- 10644842
TI  - Insertion sites for recombinant vaccinia virus construction: effects on
      expression of a foreign protein.
AB  - The expression of antigens or other molecules from recombinant vaccinia viruses
      requires the insertion of coding sequence at specific sites in the viral genome.
      Here we investigate the influence of two different sites on the level of protein
      expressed during a viral infection. The level of immune response in mice to
      vaccinia virus-expressed murine interleukin 2 (IL-2) or IL-4 varied depending on
      whether the coding sequence was inserted into the vaccinia virus thymidine kinase
      (tk) gene or into the HindIII F fragment of the viral genome where herpes simplex
      virus (HSV) tk was used as a selectable marker. In each case the intensity of the
      response was greater when the relevant gene was expressed from the HindIII F
      insertion site. In order to quantify these differences a series of recombinant
      viruses expressing luciferase was constructed. Luciferase activity from coding
      sequence inserted into the HindIII F fragment was significantly higher than that
      from the tk gene insertion, provided HSV tk(+) constructs were compared.
      Insertion of a marker gene (HSV tk) into the HindIII F site with disruption of
      the F7L open reading frame led to a reduced level of luciferase expressed from
      the tk insert, despite more than 45 kb of intervening sequence. In mice,
      luciferase expression was higher from the HindIII F inserted gene than from the
      tk insert in both lungs and ovaries.

PMID- 10644843
TI  - Recombinant measles virus requiring an exogenous protease for activation of
      infectivity.
AB  - Proteolytic cleavage of the fusion protein (F) is an important control mechanism
      of the biological activity of paramyxoviruses. The sequence R-R-H-K-R(112) at the
      cleavage site of the F protein of measles virus (MV) was altered by site-directed
      mutagenesis to R-N-H-N-R(112), which is not recognized by the ubiquitous cellular
      protease furin. When transiently expressed in cell cultures standard F protein
      was cleaved, whereas the mutant remained in the uncleaved form. Syncytium
      formation by the mutant that was analysed after coexpression with haemagglutinin
      protein depended on the presence of trypsin. Recombinant MV containing the
      mutation required trypsin activation for fusion and infectivity in cell culture.
      Intranasal infection of transgenic mice susceptible to MV infection (Ifnar(tm)
      CD46Ge) resulted in a moderately productive infection and inflammation of the
      lung. In contrast to parental virus, intracerebral inoculation did not induce
      neural disease. The possible effects of the change in cleavage activation on
      tissue tropism and pathogenicity are discussed.

PMID- 10644844
TI  - Interactions of bovine viral diarrhoea virus glycoprotein E(rns) with cell
      surface glycosaminoglycans.
AB  - Recombinant E(rns) glycoprotein of bovine viral diarrhoea virus (BVDV) has been
      tagged with a marker epitope or linked to an immunoglobulin Fc tail and expressed
      in insect and mammalian cell lines. The product was shown to be functional, both
      having ribonuclease activity and binding to a variety of cells that were
      permissive and non-permissive for replication of BVDV. Addition of soluble E(rns)
      to the medium blocked replication of BVDV in permissive cells. Binding of epitope
      tagged E(rns) to permissive calf testes (CTe) cells was abolished and virus
      infection was reduced when cells were treated with heparinases I or III. E(rns)
      failed to bind to mutant Chinese hamster ovary (CHO) cells that lacked
      glycosaminoglycans (pgsA-745 cells) or heparan sulphate (pgsD-677 cells) but
      bound to normal CHO cells. E(rns) also bound to heparin immobilized on agarose
      and could be eluted by heparin and by a high concentration of salt. Flow
      cytometric analysis of E(rns) binding to CTe cell cultures showed that
      glycosaminoglycans such as heparin, fucoidan and dermatan sulphate all inhibit
      binding but dextran sulphate, keratan sulphate, chondroitin sulphate and mannan
      fail to inhibit binding. The low molecular mass polysulphonated inhibitor suramin
      also inhibited binding to CTe cells but poly-L-lysine did not. Furthermore,
      suramin, the suramin analogue CPD14, fucoidan and pentosan polysulphate inhibited
      the infectivity of virus. It is proposed that binding of E(rns) to cells is
      through an interaction with glycosaminoglycans and that BVDV may bind to cells
      initially through this interaction.

PMID- 10644845
TI  - Identification of a human epitope in hepatitis C virus (HCV) core protein using a
      molecularly cloned antibody repertoire from a non-symptomatic, anti-HCV-positive
      patient.
AB  - Healthy carriers of hepatitis C virus (HCV) infection exhibit a specific antibody
      response against all HCV antigens, which could play a role in disease control.
      Generation of panels of human antibodies may permit a thorough characterization
      of this response and further identify particular antibodies with potential
      clinical value. To this effect, we have established a human phage-display
      antibody library from a patient exhibiting a high antibody response against HCV
      antigens and no clinical symptoms of disease. This library was screened against a
      recombinant core antigen [amino acids (aa) 1-119] produced in E. coli. Two
      recombinant Fab-carrying phages (rFabCs) were isolated and characterized. Both
      rFabC3 and rFabC14 recognize aa 1-48 on core antigen, but rFabC14 is competed out
      by a synthetic peptide, C(2-20) (aa 1-20), at much lower concentrations than
      rFabC3. In order to identify more precisely the recognition sites of these
      antibodies, we produced soluble forms of the rFabs (sFabs), and used them to pan
      a random phage-display peptide library. A single peptide sequence, QLITKPL, was
      identified with sFabC3, while two equally represented sequences, HAFPHLH and
      SAPSSKN, were isolated using sFabC14. The QLITKPL sequence was partially
      localized between aa 8 and 14 of core protein, but no clear homology was found
      for the two sFabC14 peptides. However, we confirmed the specificity of these
      peptides by competition experiments with sFabC14.

PMID- 10644846
TI  - Re-emergence of Chikungunya and O'nyong-nyong viruses: evidence for distinct
      geographical lineages and distant evolutionary relationships.
AB  - Chikungunya (CHIK) virus is a member of the genus Alphavirus in the family
      TOGAVIRIDAE: Serologically, it is most closely related to o'nyong-nyong (ONN)
      virus and is a member of the Semliki Forest antigenic complex. CHIK virus is
      believed to be enzootic throughout much of Africa and historical evidence
      indicates that it spread to other parts of the world from this origin. Strains
      from Africa and Asia are reported to differ biologically, indicating that
      distinct lineages may exist. To examine the relatedness of CHIK and ONN viruses
      using genetic data, we conducted phylogenetic studies on isolates obtained
      throughout Africa and Southeast Asia. Analyses revealed that ONN virus is indeed
      distinct from CHIK viruses, and these viruses probably diverged thousands of
      years ago. Two distinct CHIK virus lineages were delineated, one containing all
      isolates from western Africa and the second comprising all southern and East
      African strains, as well as isolates from Asia. Phylogenetic trees corroborated
      historical evidence that CHIK virus originated in Africa and subsequently was
      introduced into Asia. Within the eastern Africa and southern Africa/Asia lineage,
      Asian strains grouped together in a genotype distinct from the African groups.
      These different geographical genotypes exhibit differences in their transmission
      cycles: in Asia, the virus appears to be maintained in an urban cycle with Aedes
      aegypti mosquito vectors, while CHIK virus transmission in Africa involves a
      sylvatic cycle, primarily with AE: furcifer and AE: africanus mosquitoes.

PMID- 10644847
TI  - Identification of a new cleavage site of the 3C-like protease of rabbit
      haemorrhagic disease virus.
AB  - The calicivirus rabbit haemorrhagic disease virus (RHDV) possesses a 3C-like
      protease which processes the RHDV polyprotein. In order to monitor the
      proteolytic activity of the RHDV 3C-like protease on its putative target
      sequences, i.e. the 10 EG dipeptide bonds distributed along the large
      polyprotein, a new approach was carried out. Preliminary experiments showed that
      the luciferase gene when fused in-frame with a long gene yielded a fusion protein
      almost devoid of luciferase activity. This reporter system was used to test which
      EG dipeptide bonds were cleaved by the RHDV protease when the coding sequences of
      the dipeptides and their flanking sequences were inserted at the junction between
      the protease and luciferase genes. The coding sequences of the fusion proteins
      were cloned downstream of the T7 promoter and the proteolytic activity was
      evaluated by measuring the luciferase activity in both in vitro and 'in vivo'
      systems. The EG dipeptide bonds at positions 718-719, 1108-1109 and 1767-1768
      were confirmed as cleavage sites and a new cleavage site EG (143-144) was
      identified.

PMID- 10644848
TI  - Characterization of the sialic acid binding activity of transmissible
      gastroenteritis coronavirus by analysis of haemagglutination-deficient mutants.
AB  - Transmissible gastroenteritis coronavirus (TGEV) agglutinates erythrocytes of
      several species by virtue of sialic acid binding activity of the surface protein
      S. We have isolated and characterized five haemagglutination-defective (HAD)
      mutants. In contrast to the parental virus, the mutants were unable to bind to
      porcine submandibulary mucin, a substrate rich in sialic acid. Each of the
      mutants was found to contain a single point mutation in the S protein (Cys155Phe,
      Met195Val, Arg196Ser, Asp208Asn or Leu209Pro), indicating that these amino acids
      are affecting the sialic acid binding site. In four of the HAD mutants a nearby
      antigenic site is affected in addition to the sialic acid binding site, as
      indicated by reactivity with monoclonal antibodies. The parental virus was found
      to have an increased resistance to the detergent octylglucoside compared to the
      HAD mutants. This effect depended on cellular sialoglycoconjugates bound to the
      virion. If the binding of sialylated macromolecules was prevented by
      neuraminidase treatment, the parental virus was as sensitive to octylglucoside as
      were the HAD mutants. We discuss the possibility that the sialic acid binding
      activity helps TGEV to resist detergent-like substances encountered during the
      gastrointestinal passage and thus facilitates the infection of the intestinal
      epithelium. An alternative function of the sialic acid binding activity -
      accessory binding to intestinal tissues - is also discussed.

PMID- 10644849
TI  - Changes of leukocyte phenotype and function in the broncho-alveolar lavage fluid
      of pigs infected with porcine reproductive and respiratory syndrome virus: a role
      for CD8(+) cells.
AB  - Porcine reproductive and respiratory virus (PRRSV) primarily infects and destroys
      alveolar macrophages of the pig. The aim of the present study was to characterize
      the changes of leukocyte populations in the broncho-alveolar lavage fluid (BALF)
      of PRRSV-infected pigs. Piglets were inoculated intranasally with PRRSV strain LV
      ter Huurne. On various days post-infection the piglets were sacrificed and the
      lungs removed, washed semi-quantitatively and analysed by flow cytometry. The
      total number of recovered BALF cells increased approximately 10 times between day
      10 and day 21 of infection and decreased thereafter. The number of small low
      autofluorescent cells (SLAC), i.e. lymphocytic and monocytic cells, increased
      very strongly from day 2 until day 21 of infection; in contrast, the number of
      large highly autofluorescent cells (LHAC), i.e. mostly macrophages, remained
      constant until day 14 of infection, increased slightly on day 21 and then
      decreased. On day 21 of infection in specific-pathogen-free piglets approximately
      60% of the SLAC consisted of CD2(+)CD8(+)CD4(-)gammadeltaTCR(-) cells, which were
      partly CD8(+)CD6(+) and partly CD8(+)CD6(-). These phenotypes correspond to that
      of cytotoxic T-cells and natural killer cells respectively. From these results we
      can conclude that during a PRRSV infection the total number of BALF cells
      increases mainly due to an influx of lymphocytic cells with a cytolytic
      phenotype.

PMID- 10644850
TI  - Broadening of coreceptor usage by human immunodeficiency virus type 2 does not
      correlate with increased pathogenicity in an in vivo model.
AB  - The pathogenic properties of four primary human immunodeficiency virus type 2
      (HIV-2) isolates and two primary HIV-2 biological clones were studied in an in
      vivo human-to-mouse chimeric model. The cell-associated viral load and the
      ability to reduce the severity of the induced graft-versus-host disease symptoms,
      the CD4/CD8 ratio and the level of repopulation of the mouse tissues by the
      graft, were determined. All HIV-2 strains, irrespective of their in vitro
      biological phenotype, replicated to high titres and significantly reduced graft
      versus-host disease symptoms as well as the CD4/CD8 ratios. Reduction of graft
      repopulation caused by infection with the respective HIV-2 strains showed that
      the in vitro replication rate, syncytium-inducing capacity and ability to infect
      human macrophages did influence the in vivo pathogenic potential whereas
      broadening of coreceptor usage did not.

PMID- 10644851
TI  - Spread of distinct human immunodeficiency virus type 1 AG recombinant lineages in
      Africa.
AB  - To identify new subtype G human immunodeficiency virus type 1 (HIV-1) strains and
      AG recombinant forms, we collected 28 serum samples from immigrants to the
      Netherlands from 12 countries throughout Africa. Based on the gag sequences 22
      isolates were identified as subtype A or G. Phylogenetic analysis of
      discontinuous regions of the gag (726 nt), pol (1176 nt) and env (276 nt) genes
      revealed 13 AG recombinants with the mosaic structure A(gag)/G(pol)/A(env), three
      with A(gag)/G(pol)/G(env) and one other with A(gag) /G(pol)/G(env), in addition
      to 'pure' subtypes A(gag)/A(pol)/A(env) (n=1) and G(gag)/G(pol)/G(env) (n=4). To
      analyse the crossover points in more detail, a new RT-PCR was developed resulting
      in a large contiguous sequence of 2600 nt from the gag region to half the pol
      region. All the 13 A(gag)/G(pol)/A(env) recombinants appeared to belong to the
      circulating recombinant form (CRF) AG (IbNG). The three A(gag)/G(pol) /G(env)
      recombinants differed from the CRF AG (IbNG) subtype, suggesting the
      identification of a new CRF subtype. The recovery of AG recombinants from African
      countries a thousand miles apart indicates the active spread of new recombinants.

PMID- 10644852
TI  - Effects of recombinant ovine interferon-tau on ovine lentivirus replication and
      progression of disease.
AB  - The antiviral effects of recombinant ovine interferon-tau (roIFN-tau) were
      studied in 26 lambs inoculated with ovine lentivirus (OvLV) or mock-infected. Six
      of the OvLV-infected lambs and three of the mock-infected lambs were treated with
      10(6) antiviral units (AVU) per kg roIFN-tau daily for 30 days starting at day 0
      post-inoculation (p.i.) and twice a week thereafter (early treatment). Six of the
      OvLV-infected lambs and three of the mock-infected lambs were treated with 10(6)
      AVU/kg roIFN-tau daily for 30 days starting at day 150 p.i. and twice a week
      thereafter (late treatment). Six OvLV-infected and two mock-infected lambs were
      treated either early or late with placebo. Cell-associated viraemia was
      quantified by an end-point dilution method. The weekly antibody response against
      OvLV proteins was studied by ELISA. All experimental animals were killed at 27
      weeks p.i. and histological sections of lung were scored for the degree of
      lymphoid interstitial pneumonia (LIP). A 90% reduction in OvLV titres was
      detected at 4 weeks post-treatment in lambs that received early roIFN-tau
      treatment (P<0.01). Differences in virus titres were also found at weeks 2 and 6
      (P<0.05). Scores for LIP degree were higher in infected lambs treated with
      placebo or late roIFN-tau than in the mock-infected lambs or in the infected
      lambs that received early roIFN-tau (P<0.05). LIP scores were not different
      between mock-infected lambs and infected lambs that received early roIFN-tau.
      These results indicate that roIFN-tau curtails OvLV replication in vivo and
      reduces the likelihood of development of lentivirus-induced LIP when infected
      lambs are treated during the initial phases of OvLV infection.

PMID- 10644853
TI  - Chimeras in noncoding regions between serotypes I and II of segment A of
      infectious bursal disease virus are viable and show pathogenic phenotype in
      chickens.
AB  - Two serotypes, I and II, have been identified for infectious bursal disease virus
      (IBDV), a member of the family BIRNAVIRIDAE: Here, the generation by reverse
      genetics of IBDV chimeras in segment A of the bisegmented genome is reported. The
      5- and 3'-noncoding regions (NCRs) of a serotype II strain were exchanged with
      the NCRs of a full-length cDNA clone of segment A of a serotype I strain.
      Isolated chimeric viruses were characterized in cell culture and susceptible
      chickens. The results show that IBDV chimeras in segment A were able to replicate
      in cell culture and that VP1 encoded by a serotype I segment B is functionally
      active with serotype I NCRs as well as with serotype II NCRs. Chimeric viruses
      infected susceptible chickens and caused mild depletion of bursal cells. Thus,
      the noncoding regions of segment A are not responsible for the different
      pathotypes of IBDV serotypes I and II.

PMID- 10644854
TI  - Nucleotide sequence and genome organization of apple latent spherical virus: a
      new virus classified into the family Comoviridae.
AB  - A virus with isometric virus particles (ca. 25 nm) was isolated from an apple
      tree and named Apple latent spherical virus (ALSV). Virus particles purified from
      infected Chenopodium quinoa formed two bands with densities of 1.41 and 1.43
      g/cm(3) in CsCl equilibrium density-gradient centrifugation, indicating that the
      virus is composed of two components. The virus had two ssRNA species (RNA1 and
      RNA2) and three capsid proteins (Vp25, Vp24 and Vp20). The complete nucleotide
      sequences of RNA1 and RNA2 were determined to be 6815 nt and 3384 nt excluding
      the 3' poly(A) tail, respectively. RNA1 contains two partially overlapping ORFs
      encoding polypeptides of molecular mass 23 kDa ('23K'; ORF1) and 235 kDa ('235K';
      ORF2); RNA2 has a single ORF encoding a polypeptide of 108 kDa ('108K'). The 235K
      protein has, in order, consensus motifs of the protease cofactor, the NTP-binding
      helicase, the cysteine protease and the RNA polymerase, in good agreement with
      the gene arrangement of viruses in the COMOVIRIDAE: The 108K protein contains an
      LPL movement protein (MP) motif near the N terminus. Direct sequencing of the N
      terminal amino acids of the three capsid proteins showed that Vp25, Vp20 and Vp24
      are located in this order in the C-terminal region of the 108K protein. The
      cleavage sites of the 108K polyprotein were Q/G (MP/Vp25 and Vp25/Vp20) and E/G
      (Vp20/Vp24). Phylogenetic analysis of the ALSV RNA polymerase domain showed that
      ALSV falls into a cluster different from the nepo-, como- and fabavirus lineages.

PMID- 10644855
TI  - Molecular characterization of the genome of a partitivirus from the basidiomycete
      Rhizoctonia solani.
AB  - The bisegmented genome of a double-stranded (ds) RNA virus from the fungus
      Rhizoctonia solani isolate Rhs 717 was characterized. The larger segment, dsRNA
      1, is 2363 bases long whereas the smaller segment, dsRNA 2, has 2206 bases. The
      5' ends of the coding strands of dsRNA 1 and dsRNA 2 are highly conserved (100%
      identity over 47 bases), and contain inverted repeats capable of forming stable
      stem-loop structures. Analysis of the coding potential of each of the two
      segments showed that dsRNAs 1 and 2 could code for polypeptides of 730 aa (bases
      86-2275; molecular mass 86 kDa) and 683 aa (bases 79-2130; molecular mass 76
      kDa), respectively. The 86 kDa polypeptide has all the motifs of dsRNA RNA
      dependent RNA polymerases (RDRP), and has significant homology with putative
      RDRPs of partitiviruses from Fusarium poae and Atkinsonella hypoxylon. The 76 kDa
      protein shows homology with the putative capsid proteins (CP) of the same
      viruses. Northern blot analysis revealed no subgenomic RNA species, consistent
      with the fact that the long open reading frames encoding the putative RDRP and CP
      cover the entire length of the respective dsRNAs.

PMID- 10644856
TI  - Recent advances in liquid-phase combinatorial chemistry.
AB  - In combination with high throughput screening, combinatorial organic synthesis of
      large numbers of pharmaceutically interesting compounds may revolutionize the
      drug discovery process. Although combinatorial organic synthesis on solid
      supports is a useful approach, several groups are focusing their research efforts
      on liquid-phase combinatorial synthesis by the use of soluble polymer supports to
      generate libraries. This macromolecular carrier, in contrast to an insoluble
      matrix, is soluble in most organic solvents and has a strong tendency for
      precipitation in particular solvents. Liquid-phase combinatorial synthesis is a
      unique approach since homogeneous reaction conditions can be applied, but product
      purification similar to the solid-phase method can be carried out by simple
      filtration and washing. This method combines the positive aspects of classical
      solution-phase chemistry and solid-phase synthesis. This review examines the
      recent applications (1995-1999) of soluble polymer supports in the synthesis of
      combinatorial libraries.

PMID- 10644858
TI  - A multiple electrospray interface for parallel mass spectrometric analyses of
      compound libraries.
AB  - A parallel spray interface for mass spectrometry is described. This new
      electrospray interface enables effluent flow streams from an array of HPLC
      columns to be sampled independently and sequentially on a chromatographic time
      scale. Unlike our previously reported parallel LC-MS interface, which
      incorporated a dual-sheath spray interface accommodating up to four flow streams
      that are sampled simultaneously, this new interface permits up to four columns to
      be sampled sequentially by means of a stepping motor and rotating plate assembly.
      Effluent flow streams from an array of four HPLC columns are connected to a
      parallel arrangement of electrospray needles co-axial to the mass spectrometer
      entrance aperture. Within the needle assembly, the individual spray tips are
      oriented in a circular array, where each needle is situated 90 degrees relative
      to one another for four-column operation. An eight-column system is described
      with needles spaced at 45 degree intervals. In between the needle assembly and
      the mass spectrometer entrance aperture is a Teflon disk with a through-hole that
      is mounted to a stepping motor assembly. By precisely controlling the stepping of
      the motor assembly, it is possible to sample each of the spray positions multiple
      times per second. By operating the quadrupole mass spectrometer in the single ion
      monitoring (SIM) mode, it was possible to acquire data at each of the spray
      positions during the course of the elution of compounds from the HPLC column
      array while maintaining both good sensitivity and peak shape. Preliminary results
      suggest this technique will be useful for high throughput combinatorial library
      analysis and profiling.

PMID- 10644857
TI  - Generation of a polyclonal Fab phage display library to the protozoan parasite
      Cryptosporidium parvum.
AB  - We had developed a technology for creation of recombinant polyclonal antibody
      libraries, standardized perpetual mixtures of polyclonal whole antibodies for
      which the genes are available and can be altered as desired. We report here the
      first phase of generating a polyclonal antibody library to Cryptosporidium
      parvum, a protozoan parasite that causes severe disease in AIDS patients, for
      which there is no effective treatment. BALB/c mice, immunized by neonatal oral
      infection with oocysts followed by intraperitoneal immunization with a
      sporozoite/oocyst preparation of C. parvum, were used for construction of a Fab
      phage display library in a specially-designed bidirectional vector. This library
      was selected for reactivity to an oocyst/sporozoite preparation, and was shown to
      be antigen-specific and diverse. Following mass transfer of the selected variable
      region gene pairs to appropriate mammalian expression vectors, such anti-C.
      parvum Fab phage display libraries could be used to develop chimeric polyclonal
      antibody libraries, with mouse variable regions and human constant regions, for
      passive immunotherapy of C. parvum infection.

PMID- 10644859
TI  - Parallel solution synthesis of a "Carbohybrid" library designed to inhibit
      galactose-binding proteins.
AB  - Parallel solution S-alkylations of a 1-thio-beta-D-galactopyranoside derivative
      with Michael acceptors and alpha-chloroketones, followed by ketone reductions,
      reductive aminations, and acylations were developed to yield a library of 1-thio
      beta-D-galactopyranosides carrying small and diverse polar-neutral, hydrophobic,
      aromatic, cationic, or anionic non-carbohydrate aglycon structures. Screening of
      the library against a panel of galactose recognizing plant lectins revealed
      microM inhibitors of toxin A of A. precatorius superior to the reference ligands
      lactose and N-acetyl lactosamine. Such small, monosaccharide based inhibitors are
      attractive lead-molecules for therapeutic development, since they are low
      molecular, hydrolytically stable and more hydrophobic than natural
      oligosaccharides.

PMID- 10644860
TI  - Assays of ligand-human serum albumin binding using pulsed ultrafiltration and
      liquid chromatography-mass spectrometry.
AB  - Two approaches were utilized to increase the throughput of pulsed ultrafiltration
      assays of ligand binding to human serum albumin, reducing the volume of the
      ultrafiltration chamber and combining pulsed ultrafiltration with high
      performance liquid chromatography-atmospheric pressure chemical ionization mass
      spectrometry (LC-MS). Affinity constants for binding of ligands to human serum
      albumin were determined using pulsed ultrafiltration with ultraviolet absorbance
      detection. The first affinity constants (Ka1) were measured for the binding of
      dansylsarcosine, dansylamide, 7-anilinocoumarin-4-acetic acid and warfarin, and
      were determined to be 1.8 x 105, 5 x 104, 8 x 104, and 2.0 x 105 M-1,
      respectively. The throughput of pulsed ultrafiltration analyses was tripled
      compared to previous pulsed ultrafiltration measurements by reducing the volume
      of the chamber. In addition, the use of LC-MS with pulsed ultrafiltration
      permitted the simultaneous comparison and rank ordering of ligand mixtures for
      binding to serum albumin. For example, the throughput of these pulsed
      ultrafiltration measurements was tripled by analyzing three ligands as a mixture.

PMID- 10644861
TI  - Hepatitis B virus infection in dialysis patients.

PMID- 10644862
TI  - Pravastatin treatment of very low density, intermediate density and low density
      lipoproteins in hypercholesterolemia and combined hyperlipidemia secondary to the
      nephrotic syndrome.
AB  - BACKGROUND/AIMS: In the current study pravastatin was used in nephrotic syndrome
      patients with hypercholesterolemia and combined hyperlipidemia to test whether
      the drug decreases production of LDL and reduces levels of VLDL and IDL. METHODS:
      Thirteen patients (7 with high LDL alone and 6 with high VLDL, IDL and LDL) were
      randomized in a placebo-controlled study that had a crossover design. Patients
      were treated 8 weeks with pravastatin (40 mg/day) (or placebo) and switched to
      the corresponding placebo/drug for another 8 weeks. During each phase of the
      trial, patients had measurement of plasma levels of lipoprotein lipids, and
      turnover rates of autologous LDL apo B. RESULTS: Pravastatin increased LDL
      clearance by 16.7% and reduced total cholesterol content per LDL particle in
      patients with hypercholesterolemia. In combined hyperlipidemia, LDL clearance
      increased by 19% and there was no significant change in the production of LDL-apo
      B. Levels of VLDL+IDL apo B were not reduced significantly, while the total
      cholesterol content of these particles was reduced by 31.7%. CONCLUSION:
      Pravastatin effectively reduced LDL levels in both types of dyslipidemia by
      increasing LDL clearance. Treatment had no effect on production of LDL or on
      levels of VLDL+IDL-apo B. Thus, pravastatin increases LDL clearance. Statins do
      not seem to affect production rates of apo B-containing lipoproteins. Treatment
      of combined hyperlipidemia may require pravastatin and an added drug targeted to
      normalize levels of VLDL and IDL.

PMID- 10644863
TI  - Ex vivo flow cytometry determination of intracytoplasmic expression of IL-2, IL
      6, IFN-gamma, and TNF-alpha in monocytes and T lymphocytes, in chronic
      hemodialysis patients.
AB  - AIMS: To determine the intracytoplasmic expression of TNF-alpha, IL-2, IL-6 and
      IFN-gamma, ex vivo and in vitro, in both monocytes and T lymphocytes by flow
      cytometry after appropriate stimulation using phorbol myristate acetate
      (PMA)/ionomycin or lipopolysaccharides (LPS) in the presence of monensin, in
      order to assess the bio(in)compatibility of different dialysis membranes.
      METHODS: We examined monocytes and T lymphocytes taken from chronic hemodialysis
      patients (using either cuprophane (CUP), n = 6; polyacrylonitrile (AN 69), n = 6;
      or polysulfone (PS), n = 6 membranes), before and after a dialysis session. We
      compared the results with those obtained from end-stage chronic renal failure
      patients (n = 3) and healthy volunteers (n = 11). RESULTS: Before any stimulation
      there was a statistically significant difference in the percentages of TNF-alpha,
      IL-6, and IFN-gamma- expressing monocytes with respect to the dialysis membrane
      used. The highest percentages were observed for CUP and AN69 patients with
      figures of around 30% for each cytokine; the lowest percentages were found in PS
      patients and healthy volunteers. One hour after LPS stimulation the patterns
      remained unchanged for TNF-alpha and IFN-gamma, whereas the percentages of IL-6
      expressing cells in PS patients and in healthy volunteers reached the figures
      obtained in the other groups. When we examined the percentage of IFN-gamma-, TNF
      alpha- and IL-6-expressing monocytes in patients before and after a dialysis
      session, before any stimulation, we found that the results were significantly
      different for the three membranes (p = 0.01). Thus, a dialysis session with
      polysulfone membranes had no significant effect on the precentages of IFN-gamma-,
      TNF-alpha-, and IL-6-expressing monocytes, whereas percentages were significantly
      lower after the dialysis session when using cuprophane or AN69 membranes,
      suggesting a release of these cytokines by the monocytes during dialysis. A
      significant number of IFN-gamma- and IL-2-expressing T lymphocytes were only
      detected after 18 hours of PMA/ionomycin stimulation. The percentages of IFN
      gamma-expressing T cells recorded for the different membranes were not
      statistically different from those recorded for healthy subjects or pre-dialysis
      patients, i.e., they were between 11.5 and 20%. However, the percentages of IL-2
      expressing T lymphocytes were significantly different between the 5 groups, i.e.,
      31.3, 30.5, 18.6, 13.9 and 7. 6%, respectively, for CUP patients, pre-dialysis
      patients, healthy volunteers, PS and AN69 patients. This suggests that pre
      dialysis and CUP patients have, at baseline, a stimulation of their T
      lymphocytes. Finally, a 4-hour dialysis session had no impact on the percentages
      of IL-2-expressing T lymphocytes, whereas it was associated with a significant
      decrease in the percentage of IFN-gamma-expressing cells, but only when
      cuprophane membranes were used. CONCLUSION: Cytokine flow cytometry enables one
      to study, ex vivo, i.e., without any stimulation of the cells, and in vitro after
      appropriate stimulation, the bio(in)compatibility of dialysis membranes assessed
      by the intracytoplasmic cytokine profiles of TNF-alpha, IFN-gamma, IL-6 and IL-2,
      evaluated at the single cell level.

PMID- 10644864
TI  - Morphologic abnormalities in the brain of chronically hemodialyzed patients
      without cerebrovascular disease.
AB  - In this study, the authors evaluated the cerebral atrophy in 56 chronic
      hemodialyzed patients, who did not have clinical episodes or radiologic findings
      of cerebrovascular diseases, and 42 controls. Using computed tomography (CT)
      images, brain atrophy index (BAI), the proportion of subarachnoidal plus
      ventricular space in the cranial cavity, and ventricular area index (VAI),
      percent area of ventricle in the brain, were calculated. CT of the brain
      demonstrated an age-dependent increase in BAI in both hemodialyzed patients and
      controls. BAI and VAI were greater in hemodialyzed patients than healthy controls
      and the difference was significant at ages under 60 years in BAI and at ages less
      than 50 years in VAI. The atrophy of the frontal parts of the brain in patients
      on hemodialysis for 10 years or more was significantly greater than in patients
      dialyzed for less than 10 years. There was a significant negative correlation
      between BAI or VAI and hematocrit. These findings indicate that renal failure or
      hemodialysis itself might cause cerebral atrophy, and that the cerebral atrophy
      is more prominent in patients on hemodialysis for a long duration and with low
      hematocrit.

PMID- 10644865
TI  - Elevation of serum levels of metalloproteinase-1, tissue inhibitor of
      metalloproteinase-1 and type IV collagen, and plasma levels of metalloproteinase
      9 in polycystic kidney disease.
AB  - Several studies on polycystic kidney disease (PKD) have revealed a number of
      extracellular matrix (ECM) abnormalities, suggesting that an abnormal ECM plays a
      role in the development of tubular cysts. Cystic kidney tubules synthesize and
      secrete high levels of metalloproteinases (MMP), which may participate in the
      restructuring of the tubular basement membrane. The aim of the present study was
      to determine whether serum MMP-1, tissue inhibitor of metalloproteinase (TIMP)-1,
      and type IV collagen levels, and plasma MMP-9 levels were altered in patients
      with PKD. Sixteen patients with autosomal dominant polycystic kidney disease, and
      20 healthy controls were included in this study. Specific enzyme immunoassays
      were used to measure MMP-1, MMP-9, TIMP-1, and type IV collagen levels. Serum MMP
      1 (14.8 +/- 3.6 ng/ml), TIMP-1 (288.6 +/- 48.6 ng/ml), and type IV collagen
      (192.6 +/- 38.8 ng/ml) concentrations, and plasma MMP-9 (90.2 +/- 26.8 ng/ml)
      concentrations in patients with PKD were significantly higher than those in
      healthy controls (MMP-1; 6.6 +/- 0.9 ng/ml, p < 0.01, MMP-9; 36.4 +/- 12.2 ng/ml,
      p < 0.01, TIMP-1; 164.6 +/- 22.8 ng/ml, p < 0.01, and type IV collagen; 86.6 +/-
      14.2 ng/ml, p < 0.001). The present results suggest that ECM abnormalities
      associated with cystic kidney may result from aberrant degradation as well as
      from abnormal synthesis of ECM components.

PMID- 10644866
TI  - Hyponatremia in acute-phase response syndrome patients in general surgical wards.
AB  - BACKGROUND: In surgical patients, hypoalbuminemia may occur as a component of
      acute-phase response (APR) syndrome, which we hypothesized could decrease serum
      sodium levels. AIM: To compare the frequency of hyponatremia in adult surgical
      inpatients with or without APR syndrome. METHODS: All the simultaneous plasma
      sodium and albumin results (n = 168), obtained from adults in surgical wards and
      corresponding to a 6-month period, were searched in the hospital mainframe. Other
      relevant laboratory and clinical data were also registered. APR was ascertained
      by the presence of major physical trauma, surgery or infection, plus
      hypoalbuminemia (serum albumin <3.5 g/dl) and neutrophil left shift (>/=7% of
      band count) associated with peripheral leukopenia (white blood cells <4,
      000/mm(3)) or leukocytosis (WBC >9,000/mm(3)). Hyponatremia was defined by serum
      sodium concentration <135 mEq/l. RESULTS: APR-positive patients (n = 113) had
      lower blood hemoglobin (10.92 +/- 2.18 vs. 13.53 +/- 2.30 g/dl), and serum
      albumin levels (median, range: 2.8, 1.9-3.4 vs. 3.7, 3.5-4.2 g/dl) than APR
      negative (n = 55) ones, the same occurring in relation to antibiotics (54.8 vs.
      10. 9%) and intravenous 5% dextrose in water (55.7 vs. 20.0%) or isotonic saline
      (46.0 vs. 9.1%) infusion. The hyponatremia frequency was higher among APR
      positive patients (31.0 vs. 10.9%). CONCLUSION: The higher percentage of
      hyponatremia among APR-positive patients could be attributed to decreased serum
      albumin levels associated with APR.

PMID- 10644867
TI  - Regulation of the urine concentration mechanism by the oropharyngeal afferent
      pathway in man.
AB  - BACKGROUND: It has been reported that the oropharyngeal afferent pathway behaves
      as a first-order factor regulating body fluid. However, the neural mechanism has
      not yet been clear. This study was designed to elucidate the characteristics of
      the neural mechanism in man. METHODS: Healthy human subjects kept either an
      isotonic or hypertonic solution in the oral cavity so as to moisten the
      oropharyngeal mucosa without intake for 20 min. Plasma vasopressin (AVP)
      concentration, urine volume and urine and plasma osmolalities were measured
      before and after the application. RESULTS: The oropharyngeal application of
      isotonic saline induced no significant changes in plasma AVP concentration, urine
      volume and osmolality, while that of hypertonic saline induced a significant
      decrease and increase in urine volume and osmolality, respectively. The plasma
      AVP concentration increased significantly after the application of hypertonic
      saline. Mannitol also induced a significant decrease and increase in urine volume
      and osmolality, respectively. However, the urinary responses after the
      application of mannitol were delayed compared with those of hypertonic saline.
      There were no significant changes in plasma osmolality before and after each
      application. CONCLUSION: These results suggest that the oropharyngeal afferent
      pathway from the oropharynx to hypothalamic AVP-producing cells takes part in the
      thirst mechanism regulating body fluid in humans. The oropharyngeal afferent
      signals may behave as sodium-chloride-sensitive osmoreceptor.

PMID- 10644868
TI  - Acute effects of oral calcium load on parathyroid function and on bone resorption
      in young men.
AB  - AIM: The aim of the present study was to check whether a calcium oral load was
      able to inhibit bone resorption as assessed by urinary excretion of a new bone
      marker, type 1 collagen cross-linked C-telopeptide (CrossLaps(TM)), in healthy
      young male adults. METHODS: Twenty healthy young male adults (age 22 +/- 2 years)
      were studied. In one series of assays, an oral calcium load of 1 g of elemental
      calcium as calcium citrate dissolved in 200 ml of low-calcium water was ingested,
      while in another series of assays the subjects ingested 200 ml of water alone.
      Blood samples were collected before and 1, 2, 3 and 4 h after the intake of
      calcium. Urine was collected at 2-hour intervals, i.e. before and for 4 h after
      the intake of calcium. Serum ionized calcium, phosphate and intact parathormone
      (iPTH) were measured at each time point. Urinary calcium, phosphate, creatinine
      and CrossLaps (as a ratio to creatinine) were measured in each urine sample.
      RESULTS: Calcium intake was associated with very significant (ANOVA, p < 0.001)
      increases in serum ionized calcium and decreases in PTH. After calcium intake,
      measurements of urinary CrossLaps showed a progressive statistically significant
      (ANOVA, p < 0.001) decrease (-20% at 2 h and -55% at 4 h), whereas after
      ingestion of water, the changes were modest and not statistically significant.
      CONCLUSIONS: The present results show that bone resorption as assessed by urinary
      excretion of CrossLaps can be significantly suppressed by the ingestion of a 1
      gram calcium load and attest that calcium supplementation has an acute effect on
      bone metabolism.

PMID- 10644869
TI  - Granulocyte-macrophage colony-stimulating factor as an adjuvant to hepatitis B
      vaccination in maintenance hemodialysis patients.
AB  - Patients on maintenance hemodialysis (HD) have poor seroconversion rate after
      hepatitis B vaccination. The present study was designed to test the efficacy of
      granulocyte-macrophage colony-stimulating factor (GM-CSF) as an adjuvant to
      hepatitis B vaccination for improving seroconversion rate in maintenance HD
      patients. Twelve chronic HD patients were randomly assigned to receive either
      hepatitis B vaccination alone or hepatitis B vaccination 24 h after 1 dose of GM
      CSF for primary immunization. A group of 16 chronic HD patients who had not
      seroconverted after a standard two-dose hepatitis B vaccination were randomly
      assigned either to a booster dose of hepatitis B vaccine alone or a booster dose
      given 24 h after one dose of GM-CSF. In the primary immunization group only 2 of
      6 patients (33%) who had received vaccination alone, versus 5 of 6 patients (83%)
      who had received hepatitis B vaccine after one dose of GM-CSF, developed
      seroprotective antibody titers. Moreover, seroprotective antibody titers (IU/ml)
      were significantly higher in the latter group (275 +/- 286.5 vs. 14 +/- 22, p <
      0.05). In patients who had not seroconverted with prior hepatitis B vaccination,
      GM-CSF adjuvant therapy significantly increased the seroconversion rate versus
      booster dose alone (87.5 vs. 25%, respectively, p < 0.02), with significantly
      higher seroprotective antibody titers (84 +/- 80 vs. 19 +/- 33 IU/ml,
      respectively, p < 0. 05). These findings suggest that administration of one dose
      of GM-CSF, as adjuvant therapy, prior to primary or booster dose hepatitis B
      vaccination may significantly increase seroconversion rate and seroprotective
      antibody titers in chronic HD patients.

PMID- 10644870
TI  - Clinical implications of antineutrophil cytoplasmic antibody test in lupus
      nephritis.
AB  - To elucidate the prevalence and clinical implications of antineutrophil
      cytoplasmic antibody (ANCA) in lupus nephritis (LN), we examined ANCA by indirect
      immunofluorescence and by ELISA against antilactoferrin (anti-LF) and
      antimyeloperoxidase (anti-MPO) antibody. To discriminate perinuclear ANCA (pANCA)
      with antinuclear antibody (ANA), all the ANCA-positive sera were tested again
      after incubating patients' sera with single-stranded (SS) and double-stranded
      (ds) DNA. These results were compared with clinicopathologic manifestations and
      clinical courses of LN. ANCA was positive in 19 (37.3%) of 51 LN patients. Among
      these LN patients, 3 had cytoplasmic ANCA (cANCA) and 16 had pANCA. ANCA was not
      found in 8 SLE patients without nephritis and 30 normal controls. The presence of
      ANCA, particularly pANCA, was associated with the presence of nephritis (18/51
      cases vs. 0/8 cases, p < 0.05), especially with diffuse proliferative lupus
      nephritis, WHO class IV (17/18 cases vs. 21/31 cases, p < 0.05) as well as the
      presence of anti-dsDNA antibody (17/19 cases vs. 18/30 cases, p < 0.05). Patients
      with ANCA frequently had deterioration of renal function (3/16 vs. 0/26 cases).
      Anti-LF antibody was positive in 13 patients. Among those, 12 patients had
      nephritis. Five patients with anti-LF antibody did not have ANCA, but 7 had
      pANCA, and 1 had cANCA. Patients with anti-LF antibody had lower initial
      creatinine levels than those without it [serum creatinine (mg/dl): 0.78 (0.6-1.0)
      vs. 1.43 (0.5-5.0), p < 0.05]. Anti-MPO antibody was positive in only 1 patient,
      suggesting that MPO is a rare antigen for ANCA in LN.

PMID- 10644871
TI  - Malignant hypertension with a rare complication of pulmonary alveolar hemorrhage.
AB  - A 34-year-old Japanese male was admitted to Okayama University Hospital with
      severe hypertension, rapidly progressive renal failure, blurred vision, dyspnea
      and hemoptysis. Clinical diagnosis of malignant hypertension was given and
      antihypertensive therapy and hemodialysis were immediately started. Renal biopsy
      was performed on the sixth day in hospital to examine the underlying disease,
      such as microscopic form of polyarteritis, since the complaint of hemoptysis and
      pulmonary alveolar hemorrhage was noted by computed tomography of the lungs.
      Typical pathological changes of malignant hypertension, i.e. fibrinoid necrosis
      of the afferent arterioles and proliferative endoarteritis at the interlobular
      arteries were observed. There was no evidence of active necrotizing
      glomerulonephritis and crescent formation. Renal function was gradually recovered
      and pulmonary hemorrhage completely disappeared by treatment with
      antihypertensive agents. The authors report a case of malignant hypertension with
      a rare complication of pulmonary alveolar hemorrhage and speculate that it may be
      related to vascular injuries at the alveolar capillary level caused by malignant
      hypertension.

PMID- 10644872
TI  - Behcet's disease and AA-type amyloidosis.
AB  - Behcet's disease (BD) is a multisystem disorder characterized by vasculitis. To
      our knowledge, 52 patients with BD and amyloidosis have previously been described
      in the literature. Nephrotic syndrome was the most common type of presentation of
      amyloidosis in these patients. The prognosis of patients with BD and amyloidosis
      has not been reported before. In this report, we present a patient with BD and AA
      type amyloidosis and analyze the prognosis in these patients. Follow-up and
      prognosis have been reported in 23 patients. Ten of these 23 patients died and
      most of these deaths occurred within 3 months after the diagnosis of amyloidosis.
      End-stage renal disease developed shortly in 4 patients. BD should be considered
      in the differential diagnosis of AA amyloidosis. In conclusion, the cases with BD
      and amyloidosis carry poor prognosis.

PMID- 10644873
TI  - Delayed graft function complicated by spontaneous renal allograft rupture without
      acute rejection.
AB  - We report a young male patient who developed spontaneous renal allograft rupture
      7 days after cadaveric renal transplant, complicated by delayed graft function,
      without evidence of rejection on allograft biopsy.

PMID- 10644874
TI  - Influence of NH(4)CI on polarized release of endogenous protein degradation
      products and on morphology in LLC-PK(1) cells.
AB  - Increased renal ammoniagenesis is thought to be a causative factor for renal
      hypertrophy which occurs in several disorders accompanied by metabolic acidosis.
      We studied the influence of ammonia on the polarized release of degradation
      products of endogenous proteins in LLC-PK(1) cells. Release of acid-soluble
      radioactivity to the extracellular space decreased under the influence of NH(4)Cl
      with a remarkable transient reduction of basolateral release. Electron
      microscopically NH(4)Cl-treated cells showed numerous enlarged lysosomes
      suggesting an accumulation of incompletely degraded cytoplasmatic material in the
      lysosomal compartment. We conclude that split products of lysosomal degradation
      of endogenous proteins are preferentially transported to the extracellular space
      via the basolateral plasma membrane.

PMID- 10644875
TI  - Pentoxifylline reduces in vitro renal myofibroblast proliferation and collagen
      secretion.
AB  - Interstitial myofibroblasts (MF) are cells with features of both smooth muscle
      cells and fibroblasts. They have been universally recognized in situations of
      tubulointerstitial injury, where their presence has been shown to be a marker of
      disease progression. The objective of this study was to determine if functions of
      MF relevant to fibrogenesis can be modified in vitro by the phosphodiesterase
      inhibitor pentoxifylline (PTX). MF were obtained from sub-culture of normal rat
      kidney explant outgrowths maintained in DMEM + 20% fetal calf serum (FCS),
      supplemented with antibiotics. Cells were characterized on the basis of growth
      characteristics and immunohistochemistry. MF constituted >95% of cells at passage
      3. Cell culture media was supplemented with the potential antagonist PTX alone
      (0, 1, 10, 100 microg/ml) and in combination with TGFbeta(1) (5 ng/ml).
      Population kinetics, proliferation and collagen production were determined from
      cell growth, [(3)H]thymidine incorporation and [(3)H]proline incorporation in
      collagenous proteins, respectively. Both serum-stimulated population growth and
      proliferation were reduced in a linear fashion by 1, 10 and 100 microg/ml PTX
      (all p < 0.05 versus 0 microg/ml). Effect of PTX on cell population growth was
      however reversible when PTX was removed. Basal collagen secretion was decreased
      by PTX at 10 and 100 microg/ml (p < 0.05 versus 0 microg/ml although layer
      collagen remained unchanged. Collagen production (secreted and cell layer) was
      augmented by 5 ng/ml TGFbeta(1). These effects on collagen production were
      partially reduced when 100 microg/ml PTX was added. The authors conclude that
      myofibroblast function can be altered with agonists/antagonists. Attempts to down
      regulate fibrogenic functions of MF may therefore offer a valuable therapeutic
      strategy.

PMID- 10644876
TI  - Animal models of Alport syndrome: advancing the prospects for effective human
      gene therapy.
AB  - Several animal models for Alport syndrome have been described. These are
      available for studies on the pathogenetic mechanisms of the disease, as well as
      for the development of new technologies for gene therapy in this progressive
      hereditary kidney disease. This review summarizes current knowledge on the
      molecular basis of Alport syndrome, and on the animal models which all remarkably
      well resemble the human disease. Recent work aimed at the development of gene
      therapy, including hurdles and progress are discussed.

PMID- 10644877
TI  - Role of endonucleases in renal tubular epithelial cell injury.
AB  - The study of cell death has emerged as an important and exciting area of research
      in cell biology. Although two kinds of cell death, apoptosis and necrosis, are
      recognized, one of the major advances in our understanding of cell death has been
      the recognition that the pathways traditionally associated with apoptosis may be
      very critical in the form of cell injury associated with necrosis. Renal tubular
      epithelial cell injury from ischemia or toxins has generally been regarded as a
      result of a necrotic form of cell death. We briefly describe recent evidence
      indicating apoptotic mechanisms including endonuclease activation in renal
      tubular injury and some mediators (oxidants, caspases and ceramide) which
      regulate this process. The pathway that is followed by the cell is dependent on
      both the nature and severity of insults, and it is likely that the cascades that
      lead to the apoptotic or necrotic mode of cell death are activated almost
      simultaneously and may share some common pathways.

PMID- 10644878
TI  - 15-Lipoxygenase in glomerular inflammation.
AB  - Glomerulonephritis is a significant factor fueling the rapid increase in the
      population of patients with end-stage renal disease. Novel therapeutic strategies
      targeting specific mechanisms of glomerular destruction are the most reasonable
      approaches to arrest ongoing injury. In this review, we summarize some of our
      results obtained in our effort to characterize the role of 15-lipoxygenase
      activation as one of the mechansisms operative during the early, prefibrotic
      stage of glomerular immune injury. We also summarize the effects of cytokines
      released during these processes, as well as the activation by aspirin of the
      synthesis of 15-R-HETE (see text). Finally, we will propose a clinical approach
      to this group of disorders, based on emerging concepts of the pathophysiology of
      glomerulonephritis from our work and that of several other investigators.

PMID- 10644879
TI  - Caldesmon isoform associated with phenotypic modulation of mesangial cells.
AB  - Caldesmon (CaD) is a major calmodulin- and actin-binding protein distributed in
      smooth muscle cells (SMC) and nonmuscle cells. There are at least two high
      molecular-weight CaD (h-CaD) isoforms and four low-molecular-weight CaD (l-CaD)
      isoforms produced by alternative splicing. Isoformal interconversion is
      associated with phenotypic modulations of vascular SMC. We investigated the CaD
      isoform in human and rat glomerular mesangial cells (MC) to characterize the
      phenotypic changes of MC involved in glomerular diseases. A Western blot analysis
      and reverse-transcription analysis using exon-specific primers revealed that one
      l-CaD isoform lacking exons 1, 3b and 4 was predominantly expressed in human
      cultured MC. The expression of this isoform was markedly enhanced in anti-Thy1.1
      nephritis rats and streptozotocin-induced diabetic rats, while little expression
      was observed in the normal glomerulus. Isoformal interconversion did not occur
      during the phenotypic changes of MC. These data suggested that the activated MC
      resembled dedifferentiated SMC in terms of the CaD expression pattern, and that
      CaD is a useful marker of the phenotypic modulations of MC.

PMID- 10644880
TI  - Topographic distribution of aquaporin 2 mRNA in the kidney of dehydrated rats.
AB  - BACKGROUND: Stimulation of arginine vasopressin results in an immediate
      redistribution of water channels (aquaporin 2; AQP2) in the apical membrane of
      the collecting ducts, leading to water reabsorption. Water restriction for >/=24
      h increases AQP2 proteins in the whole collecting duct which is highest in the
      inner medulla of the kidney, indicating that dehydration enhances synthesis of
      this protein. Although increased expression of AQP2 mRNA under this condition has
      been reported, the increased ratio of mRNA expression in the three regions of the
      kidney, cortex, outer medulla, and inner medulla, during the dehydration is still
      unclear. METHODS: We investigated the AQP2 transcripts using male Sprague-Dawley
      rats deprived of water for 24 h. Mimic cDNA for competitive polymerase chain
      reaction (PCR) was constructed by deleting 180 bp at the middle of a 780-bp
      partial PCR product for rat AQP2 cDNA. In situ hybridization of the kidney and
      Northern blotting of inner medulla were performed using a 60-bp oligo-cDNA probe
      which identified rat AQP2 transcripts in the collecting duct. RESULTS:
      Dehydration resulted in a significant increase in plasma osmolality and arginine
      vasopressin concentration and urinary osmolality. Competitive PCR demonstrated
      that dehydration increased AQP2 transcripts in all parts of the kidney, but was
      highest in the inner medulla. Northern blotting confirmed the high increased rate
      of AQP2 transcription in the inner medulla. In situ hybridization showed markedly
      intensified signals in the inner medulla of dehydrated rats. CONCLUSIONS: Our
      data indicate that dehydration increases the abundance of AQP2 transcripts which
      may be closely associated with enhancement in AQP2 protein synthesis reported
      previously. This topographically variable increase in transcription is considered
      to be one of the mechanisms involved in long-term regulation of water
      permeability in the collecting duct.

PMID- 10644881
TI  - Selective induction of MCP-1 in human mesangial cells by the IL-6/sIL-6R complex.
AB  - Interleukin (IL) 6, an autocrine growth factor for mesangial cells, and
      chemokines, which are released from activated mesangial cells and induce
      leukocyte infiltration, play a critical role in the progression of immune system
      mediated renal diseases. Since the reciprocal relationship between IL-6 and
      chemokines in renal inflammation has been barely investigated, we have analyzed
      whether IL-6 (500 ng/ml), alone or in combination with the soluble form of its
      receptor (sIL-6R, 200 ng/ml), can induce normal human mesangial cells (NHMC) to
      release alpha and/or beta chemokines: MCP-1 (monocyte chemoattractant protein 1),
      IL-8, Rantes (regulated on activation, normal T cell expressed and secreted), and
      MIP-1alpha (macrophage inflammatory protein 1alpha). Whereas IL-6 or sIL-6R alone
      were ineffective in inducing significant chemokine release from NHMC, the
      simultaneous treatment with IL-6 and sIL-6R showed a significant interaction,
      leading to a strong synergic effect on MCP-1 synthesis and release without
      exerting any relevant activity on IL-8, Rantes, or MIP-1alpha. Consistently with
      the unresponsiveness to IL-6, mRNA and protein expression analysis of the two
      subunits which form the functional IL-6 receptor showed that NHMC express only
      the gp130 signal-transducing chain and not the subunit-specific IL-6R (gp80).
      These findings support an unexpected role of the IL-6 system in kidney
      inflammatory reactions through the selective regulation of monocyte recruitment.

PMID- 10644882
TI  - Effects of changes in dietary intake of sodium and potassium and of metabolic
      acidosis on 11beta-hydroxysteroid dehydrogenase activities in rat kidney.
AB  - BACKGROUND/AIM: Glucocorticoid activity is modulated by NADP(+)- and NAD(+)
      dependent isoforms of the enzyme 11beta-hydroxysteroid dehydrogenase (11betaHSD)
      which convert glucocorticoids to their inactive metabolites. The NAD(+)-dependent
      isoform, 11betaHSD2, is present in the distal nephron where it confers
      aldosterone specificity on mineralocorticoid receptors. The objective of this
      study was to establish whether renal 11betaHSD activities are affected by changes
      in sodium and potassium balance and by metabolic acidosis. METHODS: Renal
      11betaHSD activities were measured ex vivo from rats fed normal and high- and low
      potassium diets and a low-sodium diet or given 1.5% NH(4)Cl to drink. RESULTS:
      Rats maintained on high-potassium and low-sodium diets exhibited 59% (p < 0.01)
      and 28% (p < 0.05) decreases, respectively, in NAD(+)-dependent renal 11betaHSD
      activity (relative to rats fed control diet) with no changes in NADP(+)-dependent
      cortisol oxidation. Short-term (3 day) and longer-term (10 day) metabolic
      acidosis also decreased NAD(+)-dependent 11betaHSD activity by 50 and 52%,
      respectively, without affecting NADP(+)-dependent cortisol oxidation. The low
      potassium diet had no detectable effect on renal 11betaHSD activities.
      CONCLUSION: These results suggest that adaptations to a high-potassium or a low
      sodium diet and to metabolic acidosis involve decreases in renal 11betaHSD2
      activity, enhancing the access of glucocorticoids to renal corticosteroid
      receptors.

PMID- 10644883
TI  - Proinflammatory effects in experimental mesangial proliferative
      glomerulonephritis of the immunosuppressive agent SDZ RAD, a rapamycin
      derivative.
AB  - BACKGROUND/AIM: The new immunosuppressant SDZ RAD, a rapamycin derivative,
      inhibits growth factor driven cell proliferation. SDZ RAD designed for
      transplantation may also be a candidate agent to treat inflammatory kidney
      diseases. Therefore, we investigated the effects of SDZ RAD in two different
      animal models of glomerulonephritis, in anti- Thy1.1 nephritis and in acute
      puromycin aminonucleoside (PAN) nephrosis. METHODS: Eighty-seven male Wistar rats
      were investigated. Anti-Thy1.1 nephritis: healthy rats (n = 9), SDZ RAD-treated
      healthy rats (n = 6), nephritic rats (n = 9), SDZ RAD placebo treated nephritic
      rats (n = 6), SDZ RAD-pretreated nephritic rats (n = 9), and early (n = 6) as
      well as delayed (n = 6) SDZ RAD-posttreated nephritic rats. PAN nephrosis:
      healthy rats (n = 6), SDZ RAD-treated healthy rats (n = 6), nephritic rats (n =
      12), and SDZ RAD-pretreated nephritic rats (n = 12). In a separate study, 12 male
      Sprague-Dawley rats were analyzed in anti-Thy1.1 nephritis: healthy rats (n = 3),
      nephritic rats (n = 3) and pretreated nephritic rats (n = 6). SDZ RAD and SDZ RAD
      placebo were given at single doses of 2.5 mg/kg body weight per day by gavage.
      The experiments lasted until days +2 and +9 after induction of anti-Thy1. 1
      nephritis and until day +13 in the case of PAN nephrosis. RESULTS: In anti-Thy1.1
      nephritis, SDZ RAD demonstrated marked proinflammatory effects in a time
      dependent manner, as reflected by severe focal damage to glomerular histology
      including inhibition of mesangial cell proliferation, reduction of creatinine
      clearance, and increase in plasma creatinine levels as well as proteinuria.
      Almost identical results were obtained in both rat strains. In contrary, SDZ RAD
      ameliorated significantly the development of PAN nephrosis. Animals pretreated by
      this agent showed a significant reduction of proteinuria and of glomerular
      invasion of monocytes/macrophages. CONCLUSION: Some caution is warranted for the
      use of SDZ RAD in inflammatory glomerular diseases, since it accentuated
      glomerular damage induced by anti-Thy1.1 antibodies.

PMID- 10644884
TI  - Mitochondrial role in life and death of the cell.
AB  - Mitochondria are the major ATP producer of the mammalian cell. Moreover,
      mitochondria are also the main intracellular source and target of reactive oxygen
      species (ROS) that are continually generated as by-products of aerobic metabolism
      in human cells. A low level of ROS generated from the respiratory chain was
      recently proposed to take part in the signaling from mitochondria to the nucleus.
      Several structural characteristics of mitochondria and the mitochondrial genome
      enable them to sense and respond to extracellular and intracellular signals or
      stresses in order to sustain the life of the cell. It has been established that
      mitochondrial respiratory function declines with age, and that defects in the
      respiratory chain increase the production of ROS and free radicals in
      mitochondria. Within a certain concentration range, ROS may induce stress
      responses of the cell by altering the expression of a number of genes in order to
      uphold energy metabolism to rescue the cell. However, beyond this threshold, ROS
      may elicit apoptosis by induction of mitochondrial membrane permeability
      transition and release of cytochrome c. Intensive research in the past few years
      has established that mitochondria play a pivotal role in the early phase of
      apoptosis in mammalian cells. In this article, the role of mitochondria in the
      determination of life and death of the cell is reviewed on the basis of recent
      findings gathered from this and other laboratories.

PMID- 10644885
TI  - Nitric oxide and the cerebral vascular function.
AB  - The presence of a cholinergic vasodilator innervation to cerebral circulation is
      well established. Despite its high endogenous concentration in cerebral blood
      vessels, acetylcholine (ACh) is not the transmitter for vasodilation. This
      finding has led to the discovery that nitric oxide (NO), which is coreleased with
      ACh and neural peptides such as vasoactive intestinal polypeptide (VIP) from the
      respective cholinergic-nitrergic (nitric oxidergic) nerves and the VIPergic
      nitrergic nerves, is the primary transmitter in relaxing smooth muscle. ACh and
      VIP act presynaptically to inhibit and facilitate, respectively, the release of
      NO. Release of NO from cerebral vascular endothelial cells is also well
      established. A similar system for recycling L-citrulline to L-arginine for
      synthesizing more NO has been demonstrated in both cerebral perivascular nerves
      and endothelial cells. Neuronal and endothelial NO appears to play an important
      role in controlling cerebral vascular tone and circulation in health and disease.

PMID- 10644886
TI  - Transcription factors involved in pancreatic islet development.
AB  - The endocrine pancreas is an organ of enormous importance, since its dysfunction
      causes diabetes, one of the most common human diseases in the world. Regulation
      of pancreatic endocrine cell determination and differentiation requires a unique
      set of transcription factors, including basic helix-loop-helix and homeodomain
      containing proteins. The physiological role of individual transcription factor
      has been characterized by gene disruption in the mouse. The results indicate that
      these genes are not only involved in tissue-specific activation of downstream
      target genes for islet-specific hormones, but also critical for the proper islet
      morphogenesis. Future elucidation of the genetic relationship of these genes will
      lead to a better understanding of the molecular mechanisms controlling endocrine
      pancreas formation and will contribute to the development of new therapeutic
      approaches to diabetes.

PMID- 10644887
TI  - Discrete intracellular Ca(2+) pools coupled to two distinct Ca(2+) influx
      pathways in human platelets.
AB  - Ca(2+) influx is an important event associated with platelet activation and
      regulated by the content of intracellular Ca(2+). Previous studies have suggested
      two different Ca(2+) pools and two Ca(2+) influx pathways exist in platelets. In
      the present study, we have investigated the regulation of thrombin- and
      thapsigargin-induced Ca(2+) entry into human platelets, using fluorescent
      indicators to monitor Ca(2+) mobilization and membrane potential. It was found
      that depletion of thapsigargin-sensitive Ca(2+) stores was coupled to Ca(2+)
      influx through a Ca(2+)-selective pathway. Additional release of Ca(2+) from the
      thapsigargin-insensitive pool by thrombin caused the opening of a nonselective
      cation channel.

PMID- 10644888
TI  - Receptor-mediated endocytosis as a selection force to enrich bacteria expressing
      rhodostomin on their surface.
AB  - Previously, we developed a TraT display system to express snake venom rhodostomin
      (RHO), a disintegrin, on the external surface of Escherichia coli [J Biomed Sci
      6:64-70;1999]. To show a new potential use of the TraT display system, we
      employed a biotin labeling technique coupled with SDS-PAGE and flow cytometry
      analyses to further demonstrate and confirm the expression of TraT-RHO on the E.
      coli surface. We also showed that the expression of TraT-RHO on the cell surface
      not only facilitated the bacteria adhesion to BHK-21 cells but also induced
      bacterial internalization into BHK-21 cells. This feature allowed us to enrich
      the TraT-RHO expression bacteria about 10,000-fold starting with a mixture of
      TraT-RHO bacteria with beta-galactosidase-positive bacteria in a ratio of
      10(2):10(7) through four cycles of BHK-21 cell endocytosis and replating of
      engulfed bacteria on agar plates. We therefore suggest that the TraT display
      system can be applied to select out bacteria expressing a specific peptide
      sequence from a large population of display library through the process of
      receptor-mediated endocytosis and reamplification cycles.

PMID- 10644889
TI  - DNA vaccination using the fragment C of botulinum neurotoxin type A provided
      protective immunity in mice.
AB  - Botulinum neurotoxin (BoNT) is one of the most toxic substances known to produce
      severe neuromuscular paralysis. The currently used vaccine is prepared mainly
      from biohazardous toxins. Thus, we studied an alternative method and demonstrated
      that DNA immunization provided sufficient protection against botulism in a murine
      model. A plasmid of pBoNT/A-Hc, which encodes the fragment C gene of type A
      botulinum neurotoxin, was constructed and fused with an Igkappa leader sequence
      under the control of a human cytomegalovirus promoter. After 10 cycles of DNA
      inoculation with this plasmid, mice survived lethal doses of type A botulinum
      neurotoxin challenges. Immunized mice also elicited cross-protection to the
      challenges of type E botulinum neurotoxin. This is the first study demonstrating
      the potential use of DNA vaccination for botulinum neurotoxins.

PMID- 10644890
TI  - Induction of Fas and Fas-ligand expression in plasmacytoma cells by a cytotoxic
      factor secreted by murine macrophages.
AB  - Induction of tumoricidal activity is one of the major functions of activated
      macrophages. Our previous study demonstrated that P388D1 murine macrophage-like
      cells secreted a plasmacytoma cytotoxic factor (PCF) that selectively killed
      certain tumor cell lines including MOPC-315 plasmacytoma in vitro. Our subsequent
      studies demonstrated that PCF killed MOPC-315 cells by induction of apoptosis. In
      this report, the involvement of Fas and Fas ligand (FasL) in PCF-induced
      apoptosis was investigated. Results suggest that expression of Fas mRNA time
      dependently increased in PCF-treated cells and reached an optimal level after 36
      h of treatment. The augmented effect of PCF on Fas mRNA expression was
      significantly reduced by the addition of CB7.C2, an anti-PCF monoclonal antibody.
      The expression of FasL mRNA was also induced by PCF and reached an optimal level
      at 24 h, but sharply decreased after 36 h of treatment. Caspase-3 is one of the
      proteolytic enzymes that can be activated by the Fas-FasL interaction. In our
      studies, the enzymatic activity of caspase-3 was significantly induced by PCF
      after 6 h of treatment and reached an optimal level at 12 h. The augmented effect
      of PCF on caspase activity was significantly reduced by the addition of CB7.C2
      and the caspase-3-specific inhibitor, DEVD-fmk. Therefore, PCF-treated
      plasmacytoma cells might undergo apoptosis via interaction between Fas and FasL.

PMID- 10644891
TI  - p53 gene status modulates the chemosensitivity of non-small cell lung cancer
      cells.
AB  - This study examined the effects of p53 gene status on DNA damage-induced cell
      death and chemosensitivity to various chemotherapeutic agents in non-small cell
      lung cancer (NSCLC) cells. A mutant p53 gene was introduced into cells carrying
      the wild-type p53 gene and also vice versa to introduce the wild-type p53 gene
      into cells carrying the mutant p53 gene. Chemosensitivity and DNA damage-induced
      apoptosis in these cells were then examined. This study included five cell lines,
      NCI-H1437, NCI-H727, NCI-H441 and NCI-H1299 which carry a mutant p53 gene and NCI
      H460 which carries a wild-type p53 gene. Mutant p53-carrying cells were
      transfected with the wild-type p53 gene, while mutant p53 genes were introduced
      into NCI-H460 cells. These p53 genes were individually mutated at amino acid
      residues 143, 175, 248 and 273. The representative cell line NCI-H1437 cells
      transfected with wild-type p53 gene (H1437/wtp53) showed a dramatic increase in
      susceptibility to three anticancer agents (7-fold to cisplatin, 21-fold to
      etoposide, and 20-fold to camptothecin) compared to untransfected or
      neotransfected H1437 cells. An increase in chemosensitivity was also observed in
      wild-type p53 transfectants of H727, H441, H1299 cells. The results of
      chemosensitivity were consistent with the observations on apoptotic cell death.
      H1437/wtp53 cells, but not H1437 parental cells, exhibited a characteristic
      feature of apoptotic cell death that generated oligonucleosomal-sized DNA
      fragments. In contrast, loss of chemosensitivity and lack of p53-mediated DNA
      degradation in response to anticancer agents were observed in H460 cells
      transfected with mutant p53. These observations suggest that the increase in
      chemosensitivity was attributable to wild-type p53 mediation of the process of
      apoptosis. In addition, our results also suggest that p53 gene status modulates
      the extent of chemosensitivity and the induction of apoptosis by different
      anticancer agents in NSCLC cells.

PMID- 10644892
TI  - Visualisation of phenotypically mixed HIV-1 and HTLV-I virus particles by
      electron microscopy.
AB  - Virions produced after HIV-1 infection of HTLV-I transformed cells have an
      expanded tropism that has been attributed to the presence of HTLV-I glycoproteins
      in the envelope. This report now directly identifies these phenotypically mixed
      virions by immunogold labelling electron microscopy. Furthermore we estimate
      there are 2% of these in cell-free supernatant, which represents up to 1 x 10(7)
      particles/ml from an in vitro infection. HTLV-1 envelope labelling was localised
      to a single region, suggesting a defined event in packaging of foreign envelope
      proteins into HIV-1 virus particles.

PMID- 10644893
TI  - Stimulation of the gonadotropic axis by the neuropeptide Y receptor Y1
      antagonist/Y4 agonist 1229U91 in the male rat.
AB  - Neuropeptide Y (NPY) is a highly potent orexigenic substance that is also known
      to modulate gonadotropin secretion. Five receptor subtypes for NPY have been
      identified, and a potent antagonist for the receptor subtype 1 (Y1), 1229U91,
      also known as GW1229 or GR231118, has been described. Subsequently, 1229U91 was
      also shown to represent a highly potent agonist for the Y4 receptor subtype. Very
      unexpectedly, intracerebroventricular administration of 1229U91 elicited an
      intense, dose-dependent surge of both luteinizing hormone (LH) and follicle
      stimulating hormone (FSH) in intact male rats that lasted for 6 h. Such
      stimulation was absent when a potent gonadotropin-releasing hormone antagonist
      was administered systemically, suggesting that 1229U91 acts centrally to
      stimulate gonadotropin-releasing hormone release. 1229U91 administration had no
      effect on growth hormone, thyroid-stimulating hormone, and corticosterone
      secretions. In addition to 1229U91, four other parent dimer molecules described
      earlier produced a marked and sustained stimulation of LH when injected
      intracerebroventricularly that was proportional to their binding affinity for the
      Y4 receptor. Central administration of the specific Y1 antagonist BIBO3304 (20
      microgram) had no effect on LH secretion, making it unlikely for 1229U91 to
      stimulate LH secretion by an antagonistic action on the Y1 receptor subtype, thus
      suggesting a Y4 receptor mediation. In conclusion, the 1229U91 molecule displays
      an interesting conformational epitope that is able to generate large LH surges,
      possibly by activating Y4 or Y4-like receptor subtypes or by acting on a NPY
      receptor unrelated target.

PMID- 10644894
TI  - Activation of gene expression of the gamma-aminobutyric acid rather than the
      glutamatergic system in the preoptic area during the preovulatory gonadotropin
      surge of the rat.
AB  - There is increasing evidence that in the rat prior to and during the preovulatory
      LH surge, release rates of GABA in the preoptic area (POA) are decreased while no
      such changes occurred in the mediobasal hypothalamus (MBH). In addition, GnRH
      release appears to be facilitated by an increased preoptic excitation of
      glutamate (GLU). To investigate whether such changes of secretory activity of
      intrahypothalamic GABA or GLU neurons are associated with altered gene expression
      of biosynthetic enzymes or transporter proteins characteristic for either
      neuronal system, we determined mRNA levels of the two forms of the GABA
      synthesizing enzyme glutamate decarboxylase (GAD65 and GAD67), the glutamate
      synthesizing enzyme glutaminase (GLS), the GABA transporter type 1 (GAT-1) and
      the glutamate-aspartate transporter type 1 (GLAST). Competitive RT-PCRs using
      mutant cRNAs as internal standards were conducted with mRNA extracted from
      microdissected tissue of POA and MBH from diestrous, proestrous, and estrous
      rats. Proestrous animals were subgrouped according to their endocrine status as
      follows: 'prior to', on the 'ascending' or on the 'descending' limb of the LH
      peak, and 'after the LH surge (post)'. During the preovulatory LH surge, mRNA
      concentrations of GAD67 and GAT-1 in the POA were significantly increased
      compared to those observed on diestrous (2.8-fold for GAD67 and 2.5-fold for GAT
      1, p < 0.01), while in the MBH the amount of both mRNAs remained constant. The
      expression levels of GAD65, GLS and GLAST were without any changes in the POA as
      well as in the MBH. These findings support the hypothesis that in rats induction
      of the preovulatory LH surge is controlled at the level of GnRH perikarya, and
      suggest that altered activities of intrapreoptic GABA neurons at both
      transcriptional and secretory levels are pivotal for the preovulatory activation
      of GnRH neurons.

PMID- 10644895
TI  - Galanin's functional significance in the regulation of the neuroendocrine
      reproductive axis of the monkey.
AB  - Galanin stimulates the neuroendocrine reproductive axis in the rat, but whether
      galanin acts similarly in primate species is unknown. To test the hypothesis that
      galanin acts within the hypothalamo-hypophyseal axis to stimulate luteinizing
      hormone (LH) and gonadotropin-releasing hormone (GnRH) secretion in the primate,
      galanin was administered either systemically or directly into the arcuate nucleus
      median eminence of ovariectomized macaques (pigtailed or rhesus, respectively)
      that were maintained on estradiol. The mean plasma levels of LH were
      significantly elevated in pigtailed macaques after peripheral injection of
      galanin (2 mg) as compared with vehicle treatment. In rhesus monkeys, galanin (80
      microM) administered by push-pull perfusion into the arcuate nucleus-median
      eminence did not significantly alter either GnRH or LH release. To determine
      whether in the monkey, as in the rat, subpopulations of medial forebrain GnRH
      neurons coexpress galanin mRNA, we used single- and double-label in situ
      hybridization and computerized imaging techniques. GnRH mRNA-containing cells
      were identified in both the medial and lateral forebrain of the female pigtailed
      macaque. No galanin mRNA expression was detectable in GnRH neurons located in
      either the medial preoptic area or mediobasal hypothalamus; however, within the
      substantia innominata a subset of GnRH mRNA-expressing neurons did coexpress
      galanin mRNA. Taken together, these results suggest that galanin induces LH
      release in primates, but galanin may not act directly on hypothalamic GnRH
      neurons. Presently, we have confirmed in another primate species the existence of
      GnRH gene expression in the lateral forebrain and discovered that a small subset
      of these neurons coexpress galanin. These particular cells may have a unique and
      as of yet undefined physiological function that is distinct from those GnRH
      neurons serving a hypophysiotropic function.

PMID- 10644896
TI  - Galanin immunoreactivity in mouse basal forebrain: sex differences and discrete
      projections of galanin-containing cells beyond the blood-brain barrier.
AB  - The distribution of galanin-immunoreactive (GAL-IR) cell bodies in the basal
      forebrain of mice was investigated. The overall pattern of staining for GAL in
      the area of brain analyzed was similar to that reported in other species with
      noticeable variations. Distinctive groups of GAL-IR cells were present in the bed
      nucleus of stria terminalis (BNST), supraoptic nucleus, retrochiasmatic
      supraoptic nucleus (SOR), magnocellular paraventricular nucleus, arcuate nucleus
      (ARC) and the nucleus circularis which is one of the cell groups belonging to the
      accessory magnocellular system. Comparison of the number of GAL-IR cells between
      the sexes indicated sexual dimorphism in the BNST, SOR and the ARC. As compared
      with female mice, the mean number of GAL-IR cells/section in the BNST and the SOR
      was higher and that in the ARC was lower in the males. Unlike in rats, the
      preoptic area contained mostly scattered GAL-IR cell bodies. Intraperitoneal
      injection of the retrograde tracer fluoro-gold in male mice resulted in uptake of
      fluoro-gold by selective GAL-IR cell groups in the basal forebrain suggesting
      that only some of these cell groups may project outside the blood-brain barrier
      whereas others may be involved in intracerebral neural transmission.

PMID- 10644897
TI  - Perimembrane localization of the estrogen receptor alpha protein in neuronal
      processes of cultured hippocampal neurons.
AB  - There is clear evidence of rapid, nongenomic responses to estrogen in a variety
      of neuronal model systems. To address the question of whether some of these rapid
      estrogen signals might be transduced by the classical estrogen receptor (ER)
      alpha or a closely related protein in nontransformed neurons, we undertook the
      present study using isolated fetal rat hippocampal neurons. Several antibodies
      developed to detect ERalpha were tested in this system and showed positive
      membrane staining in nonpermeabilized neurons. MC-20, an affinity purified anti
      ERalpha, rabbit polyclonal IgG antibody which does not recognize ERbeta was
      selected to carry out the majority of the experiments. When permeabilized, the
      hippocampal neurons exhibited low levels of nuclear staining for ERalpha, but
      abundant labeling for ERalpha throughout the entire cell including the neurites.
      In addition to traditional immunocytochemistry controls, incubation of neurons
      for 24 h in the presence of 10 microM antisense oligonucleotide directed against
      the translation start site of ERalpha reduced ERalpha immunoreactivity throughout
      the neurons providing further evidence that the immunostaining was specific for
      ERalpha. Confocal and conventional microscopy demonstrated that the antigen was
      predominately extranuclear and localization of ERalpha in the neurites suggests
      that the receptor is in close proximity to the plasma membrane. This localization
      is consistent with a role for ERalpha as a transducer of rapid, nongenomic
      estrogen responses in hippocampal neurons.

PMID- 10644898
TI  - Neuronal elements in the testis of the rhesus monkey: ontogeny, characterization
      and relationship to testicular cells.
AB  - Intrinsic neuron-like cells expressing the catecholamine-biosynthetic enzyme
      tyrosine hydroxylase (TH) were recently identified in the testis of the
      prepubertal rhesus monkey. In this study, we characterized the neuron-like nature
      of these cells and examined distribution and frequency of neuronal elements in
      the testes of monkeys during postnatal development, puberty and adulthood. Using
      immunohistochemical methods, we detected both nerve fibers and cell bodies,
      immunoreactive for the neuronal markers neurofilament 200 (NF-200) and
      synaptosomal associated protein of 25 kDa (SNAP-25), TH and neuropeptide Y (NPY)
      in perivascular locations, intermingled with interstitial cells and close to the
      wall of seminiferous tubules. Marked age-related differences in the numbers of
      these neuronal elements became apparent, when we quantified NF-200-immunoreactive
      neuronal elements. Thus, intrinsic neuron-like cell bodies were found only in the
      testes from immature animals (i.e. , until about 3 years of age). Conversely,
      nerve fibers, presumably representing mainly the extrinsic innervation, were
      observed at all ages although they became more prominent after the pubertal
      increase in LH and testosterone levels. Interestingly, another testicular cell
      type known to contain potent regulatory substances, mast cells, was found to be
      in close anatomical proximity to nerve fibers. The number of these cells,
      positively identified with an antibody to tryptase, increased significantly after
      puberty following the same pattern as nerve fibers. These results confirm that
      the testicular nervous system of the monkey is composed of two components,
      intrinsic nerve cells and extrinsic fibers, both of which are catecholaminergic
      and peptidergic in nature. Furthermore, both components show a marked degree of
      plasticity during development, especially around the time of puberty. The
      intratesticular locations of neuron-like cells and fibers suggest that
      catecholamines and neuropeptides are likely to have multiple sites of actions,
      and may affect Leydig cells, cells of the tubular wall and vascular cells
      directly and/or indirectly via intermediation of mast cells.

PMID- 10644899
TI  - Acute effects of estradiol pretreatment on the response to d-amphetamine in
      women.
AB  - Little is known about the interactions between ovarian hormones and responses to
      psychoactive drugs in humans. Preclinical studies suggest that ovarian hormones
      such as estrogen and progesterone have direct and indirect central nervous system
      actions and that these hormones can influence behavioral responses to
      psychoactive drugs. In the present study, we assessed the subjective and
      physiological effects of d-amphetamine (AMPH; 10 mg p.o.) after pretreatment with
      estradiol. Two groups of healthy, regularly cycling women participated in two
      sessions scheduled during the early follicular phases of two menstrual cycles.
      One group received estradiol patches (Estraderm TTS; 0.8 mg) which elevated
      plasma estradiol levels to approximately 750 pg/ml on both sessions; the other
      group received placebo patches on both sessions. Both groups received AMPH (10.0
      mg) and placebo in a randomized and counterbalanced order on the two sessions.
      Dependent measures included self-report questionnaires, physiological measures,
      and plasma hormone levels. Most of the subjective and physiological effects of
      AMPH were not affected by acute estradiol treatment. Nevertheless, estradiol
      pretreatment increased the magnitude of the effects of AMPH on subjective ratings
      of 'pleasant stimulation' and decreased ratings of 'want more'. Also, estradiol
      produced some subjective effects when administered alone: It increased subjective
      ratings of 'feel drug', 'energy and intellectual efficiency', and 'pleasant
      stimulation'. These results provide limited evidence that the stimulating effects
      of AMPH are increased by acute estradiol pretreatment.

PMID- 10644900
TI  - Noradrenergic and dopaminergic activity in the hypothalamic paraventricular
      nucleus after naloxone-induced morphine withdrawal.
AB  - Previous research has shown an increase in hypothalamo-pituitary-adrenal axis
      activity following naloxone administration to morphine-dependent rats. In the
      present study, we investigated the adaptive changes in the noradrenaline (NA) and
      dopamine (DA) systems in the hypothalamic paraventricular nucleus (PVN) during
      morphine dependence and withdrawal. Additionally, we examined the possible change
      in 3',5'-cyclic adenosine monophosphate (cAMP) levels in that nucleus under the
      same conditions. Rats were made dependent on morphine by morphine or placebo
      (naive) pellet implantation for 7 days. On day 8, rat groups received an acute
      injection of saline or naloxone (1 mg/kg subcutaneously) and were decapitated 30
      min later. NA and DA content as well as their metabolite production in the PVN
      were estimated by HPLC/ED. Both plasma corticosterone levels and cAMP
      concentration in the PVN were measured by RIA. Naloxone administration to
      morphine-dependent rats (withdrawal) induced a pronounced increase in the
      production of both the NA metabolite MHPG and the DA metabolite DOPAC and an
      enhanced NA and DA turnover. Furthermore, an increase in corticosterone secretion
      was observed in parallel to the changes in catecholamine turnover. However, no
      alterations in cAMP levels were seen during morphine withdrawal. These results
      raise the possibility that catecholaminergic afferents to the PVN could play a
      significant role in the alterations of PVN functions and consequently in the
      pituitary-adrenal response during morphine abstinence syndrome. These data
      provide further support for the idea of adaptive changes in catecholaminergic
      neurons projecting to the PVN during chronic morphine exposure.

PMID- 10644901
TI  - Dopaminergic agonists normalize elevated hypothalamic neuropeptide Y and
      corticotropin-releasing hormone, body weight gain, and hyperglycemia in ob/ob
      mice.
AB  - Hypothalamic neuropeptide Y (NPY) and corticotropin-releasing hormone (CRH)
      influence feeding and levels of plasma glucose, insulin, free fatty acids, and
      triglycerides. Treatment of genetically obese, ob/ob mice, with dopamine receptor
      D(1)/D(2) agonists normalizes hyperphagia, body weight gain, hyperglycemia, and
      hyperlipidemia. We therefore examined whether levels of NPY and CRH
      immunoreactivity in discrete hypothalamic nuclei are altered in ob/ob mice, and
      whether dopaminergic treatment reverses this alteration. Female ob/ob mice were
      treated daily at 1 h after light onset with the D(1)/D(2) agonists, SKF-38393 (20
      mg/kg) and bromocriptine (15 mg/kg), respectively or vehicle for 2 weeks. Such
      treatment, while normalizing body weight gain and hyperglycemia, also
      significantly reduced elevated NPY immunoreactivity in the suprachiasmatic (by
      39%), intergeniculate (by 43%), paraventricular (PVN; by 31%), and arcuate (by
      41%) nuclei in obese mice to levels observed in lean mice. This treatment also
      caused a 45-50% decline in levels of CRH in the PVN and dorsomedial hypothalamus
      compared to obese controls to levels observed in lean mice. Taken together, these
      findings suggest that dopaminergic D(1)/D(2) receptor coactivation may improve
      hyperphagia, hyperglycemia, and obesity in the ob/ob mouse, in part, by
      normalizing elevated levels of both NPY and CRH.

PMID- 10644902
TI  - Obstructive nephropathy: lessons from cystic kidney disease.
AB  - Obstructive nephropathy is one of the most important causes of renal failure in
      infants and children, while polycystic kidney disease (PKD) is a major cause of
      renal failure in the adult population. This review summarizes the evidence that
      there may be a number of mechanisms common to the pathophysiology of both
      conditions. In animal models of obstructive nephropathy and PKD, the renal
      tubular expression of epidermal growth factor is suppressed, and expression of
      clusterin is increased, both of which suggest arrested maturation or
      dedifferentiation of the tubular cell. There is a marked increase in apoptosis of
      epithelial cells in dilated tubules, associated with an increase in apoptotic
      stimuli. The renin-angiotensin system is activated in both obstructive
      nephropathy and PKD, which may contribute to tubular atrophy and interstitial
      fibrosis, which characterize the progression of both conditions. Focal cystic
      dilatation of the tubule is found in obstructive nephropathy, while tubular
      obstruction is present in cystic kidney disease. It is therefore likely that
      elucidation of the effects of mechanical stretch on renal tubular epithelial
      cells will contribute to our understanding of both conditions.

PMID- 10644903
TI  - Hypoparathyroidism potentiates cardiovascular complications through disturbed
      calcium metabolism: possible risk of vitamin D(3) analog administration in
      dialysis patients with end-stage renal disease.
AB  - BACKGROUND/AIM: Progressive cardiovascular calcification in dialysis patients
      with end-stage renal disease (ESRD) is a serious complication; however, the
      precise mechanism remains uncertain. We tested whether metabolic calcium
      abnormalities and hypoparathyroidism might have a correlation with cardiovascular
      complications in ESRD patients. METHODS: A series of 48 ESRD patients with
      cardiovascular diseases and/or congestive heart failure, aged 36-82 (61 +/- 12)
      years, 23 male and 25 female, were enrolled in this study. Serum total calcium
      (Ca, mmol/l), inorganic phosphate (mmol/l), and intact parathyroid hormone (iPTH,
      pg/ml) levels were determined in all cases. RESULTS: Organic heart disease was
      confirmed in 28 patients (58.3%), including 15 with coronary artery disease: 8
      with aortic aneurysm, 8 with stenotic valvular heart disease, 9 with excessive
      mitral annular calcification, 3 with dialysis cardiomyopathy, and 7 with
      obstructive arterial disease. Serum iPTH measurement revealed hypoparathyroidism
      (iPTH <60) in 20 of 48 (41.7%) and hyperthyroidism (iPTH >/=200) in 13 of 48
      (27.1%) subjects. The 20 patients with low iPTH had a higher prevalence of
      valvular heart disease, a higher total Ca level corrected for serum albumin (2.70
      +/- 0.30 in low iPTH vs. 2.47 +/- 0.30 in normal iPTH, 2.35 +/- 0.20 in high
      iPTH, p = 0.003) and a higher tendency of vitamin D(3) analog use (65% in low
      iPTH vs. 33% in normal iPTH and 46% in high iPTH, p = 0.078). Moreover, corrected
      serum Ca exhibited a negative logarithmic correlation with serum iPTH: corrected
      Ca = -0.284x log (iPTH) + 3.021 (r = 0.637, p = 0.0001). Multiple logistic
      regression analysis revealed diabetes and hypoparathyroidism (iPTH <60) as risk
      factors for cardiovascular complications in ESRD. CONCLUSION: These results
      suggest that hypercalcemia and hypoparathyroidism in conjunction with vitamin
      D(3) use might play an important role in cardiovascular complications of chronic
      dialysis patients.

PMID- 10644904
TI  - Risk factors for chronic renal dysfunction in cardiac allograft recipients.
AB  - Renal dysfunction is one of the most common and threatening complications in
      heart transplant recipients. Even if ciclosporin seems to play a central role in
      inducing renal damage, other factors may concur or predispose to renal injury. In
      order to identify factors responsible for renal dysfunction, we retrospectively
      studied a cohort of 114 cardiac transplant recipients during a follow-up period
      of at least 3 years. The patients had a normal renal function before and 0.5
      months after heart transplantation. Doubling of baseline serum creatinine or
      attainment of serum creatinine steadily above 176.8 micromol/l (2.0 mg/dl) was
      used as criterion to define the end-point renal dysfunction. A series of clinical
      and laboratory variables were obtained from the patients' charts at different
      time intervals, and their prognostic value for the occurrence of renal
      dysfunction was calculated by Cox proportional hazards models. 23 out of 114
      patients reached the end point after a median time period of 21 months. High
      serum triglyceride, alanine aminotransferase, alkaline phosphatase, ciclosporin,
      urea, glucose, and hemoglobin levels were shown to be associated with the
      development of renal dysfunction. Four variables, i.e., triglyceride,
      ciclosporin, urea, and alkaline phosphatase, had an independent prognostic value.
      Our results confirm a role for ciclosporin in inducing renal dysfunction and
      identify hyperlipidemia and an increased plasma urea level as risk factors for
      renal dysfunction in heart transplant recipients.

PMID- 10644905
TI  - Relationship between gingival hyperplasia and class II histocompatibility
      antigens in renal transplant recipients.
AB  - Gingival hyperplasia, a well-known side effect of ciclosporin A (CS-A), is much
      more prominent when CS-A is used in combination with calcium channel blockers,
      especially dihydropyridines. On the other hand, it is interesting to note that
      this complication is not observed in all patients using this drug combination.
      This study was conducted in order to investigate the relationship (if any)
      between major histocompatibility complex antigens and gingival hyperplasia.
      Seventy-six renal transplantation patients were evaluated by an experienced
      dentist for gingival hyperplasia. The patients were then divided into two groups
      according to the presence (group 1, n = 18) or absence (group 2, n = 58) of
      gingival hyperplasia. There was no significant difference between the two groups
      regarding age, sex, transplant age, donor type, antihypertensive and
      immunosuppressive therapy protocols, and CS-A levels. HLA-DR2 antigen was present
      in 63% of the patients with gingival hyperplasia and in 34% of the patients
      without gingival hyperplasia. However, the HLA-DR1 antigen frequencies were found
      to be 11 and 22% in group 1 and group 2, respectively. In patients receiving
      nifedipine as an antihypertensive therapy, gingival hyperplasia developed more
      often than in patients receiving verapamil or diltiazem. As a result, in renal
      allograft recipients with HLA-DR1 antigen, gingival hyperplasia was seen less
      frequently than in HLA-DR2-positive patients. It is believed that the presence of
      these antigens regulates the response of the patients to either CS-A and/or
      calcium channel blockers.

PMID- 10644906
TI  - Renal clearance of N(1)-methylnicotinamide: a sensitive marker of the severity of
      liver dysfunction in cirrhosis.
AB  - BACKGROUND/AIMS: Data have appeared suggesting that an impairment of renal
      tubular secretion is present in liver cirrhosis, even in the absence of a
      clinically evident renal dysfunction. To address this question, we evaluated the
      renal clearance of N(1)-methylnicotinamide (NMN), a marker of the renal secretory
      function, in healthy subjects and patients with liver cirrhosis of increasing
      severity, but with a normal glomerular filtration rate. METHODS: The renal
      clearances of endogenous NMN, inulin, and creatinine were measured in 14 normal
      subjects and in two groups of age-matched cirrhotic patients (10 Child A and 10
      Child C). In 6 subjects, 2 per group, the concentration dependence of the NMN
      clearance was also studied, following an oral nicotinamide load. RESULTS:
      Contrary to expectations, the renal NMN clearance increased in cirrhotic
      patients, in relation to the severity of liver disease (r = 0.83 with Pugh's
      score; p < 0.001). The NMN-to-inulin clearance ratio increased from a control
      value of 2.2 +/- (SD) 0.4 to 3.1 +/- 0.2 and 5.2 +/- 0.9 in Child A and Child C
      cirrhotics, respectively (p < 0.001 for all comparisons), indicating that NMN was
      completely cleared from plasma in the latter patients. Consistently, the analysis
      of the concentration dependence of the renal NMN clearance revealed the presence
      of a carrier-mediated reabsorption which apparently was no longer operating in
      the decompensated patients. Discriminant analysis showed that renal NMN
      clearance, and NMN-to-creatinine and NMN-to-inulin clearance ratios could all
      distinguish between the three study groups, with sensitivities and specificities
      equal or greater than 90%. CONCLUSIONS: Contrary to previous proposals, NMN is
      not a probe of general validity for renal tubular secretion. In particular, due
      to an imbalance between secretion and reabsorption, its renal clearance in liver
      cirrhosis cannot be used to determine the degree of tubular secretion of which an
      individual is capable. However, renal NMN clearance appears to be a very
      sensitive marker of the severity of liver dysfunction in cirrhosis. The
      potentialities of this renal parameter as a diagnostic and prognostic test in
      liver cirrhosis deserve further study.

PMID- 10644907
TI  - Glomerular extracellular matrix accumulation in experimental anti-GBM Ab
      glomerulonephritis.
AB  - Thickening of the glomerular basement membrane (GBM) results from excessive
      accumulation of extracellular matrix (ECM) proteins following glomerular injury.
      We studied the temporal relationship between the expression of growth factors,
      ECM accumulation, ECM degrading proteinases, and their inhibitors in a rat model
      of anti-GBM antibody (Ab) glomerulonephritis (GN) by the RNase protection assay
      and immunohistochemistry. There were two- or fourfold increases in the expression
      of transforming growth factor-beta(1) (TGF-beta(1)) and platelet-derived growth
      factor (PDGF) A and B chain mRNAs 4 days after anti-GBM Ab administration. These
      changes were temporally associated with increased accumulation of alpha1(III) and
      alpha2(IV) collagens, fibronectin, and heparan sulfate proteoglycan along the
      GBM. The increase in matrix accumulation was associated with little or no
      increases in the proteinases, urokinase plasminogen activator (u-PA) and transin,
      respectively. There was a 1.6x increase in the u-PA/28s mRNA ratio on day 4 in
      rats with anti-GBM Ab GN, but this was not associated with an increase in u-PA
      biologic activity. By comparison, the mRNAs of the proteinase inhibitors,
      plasminogen activator inhibitor-1 (PAI-1) and tissue inhibitor of
      metalloproteinase (TIMP) were 5x greater than that of control rats on day 4. PAI
      1 mRNA correlate with increased biologic activity. These data demonstrate a
      temporal association between TGF-beta(1) and PDGF expression and matrix
      accumulation within the GBM in anti-GBM Ab GN. In addition, it suggest that this
      matrix accumulation results from an imbalance between matrix synthesis and
      degradation.

PMID- 10644908
TI  - Time course of cytokine mRNA expression in kidneys of rats with unilateral
      ureteral obstruction.
AB  - The development of renal interstitial fibrosis (RIF) is related to the expression
      and excretion of cytokines and growth factors. Thus, we investigated the time
      course of mRNA expression of cytokines known as causative factors in a model of
      RIF in rats before and on day 10 after unilateral ureteral obstruction (UUO),
      when first signs of fibrosis were visible, as well as during progressive RIF. UUO
      causes a fivefold increase in mRNA expression of monocyte chemoattractant protein
      1 15 days after surgery as compared with contralateral kidneys. The level remains
      elevated about three-fold up to day 25. The mRNA of the fibrogenic cytokine
      transforming growth factor beta 1 (TGF-beta1) is increased two- to threefold
      during the time course, whereas the mRNAs of platelet-derived growth factor B
      chain (PDGF-B) and its receptor beta (PDGF-Rbeta) increase after UUO, reaching
      their maxima on days 10-15. PDGF-B mRNA increase up to day 15, marking the onset
      of fibrosis, and decreases thereafter, whereas the expression of the PDGF-Rbeta
      mRNA remains elevated more than threefold over the entire study period.
      Incubation of cultured renal fibroblasts with TGF-beta1 and/or PDGF-B suggests
      that their specific action on cell growth and proliferation is maintained even
      when they are used in combination. The sustained elevation of TGF-beta1 and PDGF
      B/PDGF-Rbeta mRNA levels confirms the assumption of a particular involvement of
      these cytokines in the pathogenesis of RIF. The mRNA expression of the gap
      junctional protein connexin 43 in ureteral ligated kidneys is increased sixfold
      already 5 days after UUO. In this way, the increased connexin 43 mRNA levels
      indicate a possible function in the remodeling of the kidney tissue after tubular
      damage and fibrosis.

PMID- 10644909
TI  - Type IV phosphodiesterase inhibitor is effective in prevention and treatment of
      experimental crescentic glomerulonephritis.
AB  - BACKGROUND: Tumour necrosis factor alpha (TNF-alpha) has an important role in
      acute glomerular inflammation. Rolipram, a type IV phosphodiesterase inhibitor,
      has multiple anti-inflammatory effects including inhibition of TNF-alpha
      synthesis. METHODS: We investigated the effects of rolipram in prevention and
      delayed treatment of crescentic glomerulonephritis in Wistar Kyoto rats.
      Glomerulonephritis was induced by injection of nephrotoxic serum. RESULTS: In the
      preventive study, rolipram (6.25 mg/kg i.p. twice daily) was started 2.5 h before
      injection of nephrotoxic serum. Rolipram reduced the expression of TNF-alpha in
      glomeruli and renal tubules and abrogated glomerular injury on day 4 (99.7%
      reduction in albuminuria and 96.4% reduction in fibrin deposition). In the
      delayed-treatment experiment, rolipram was started 4 days after injection of
      nephrotoxic serum. Rolipram reduced renal excretion of TNF-alpha by 63% on day 7.
      TNF-alpha was not detected in the sera of treated or control rats. Delayed
      treatment was effective in crescentic glomerulonephritis, as shown by reduction
      in albuminuria by 38.1%, fibrin deposition by 60.8%, and crescent formation by
      67% on day 7. CONCLUSIONS: Rolipram is effective both in prevention and treatment
      of experimental crescentic glomerulonephritis. This was associated with a
      reduction of renal production of TNF-alpha.

PMID- 10644910
TI  - Renal artery stenosis associated with epidermal nevus syndrome.
AB  - Epidermal nevus syndrome is an unusual neurocutaneous disorder in which epidermal
      nevi are associated with abnormalities of the skeleton and central nervous
      system, including the eyes and somtimes the cardiovascular system. We treated a
      patient in whom the latter included renal artery stenosis. An 18-year-old man
      with epidermal nevi was diagnosed as having the syndrome based on the additional
      presence of scoliosis, an arachnoid cyst in the middle cranial fossa, and
      microphthalmos. Hypertension was diagnosed when the patient was 15 years old. The
      plasma renin activity (9.7 ng/ml/h) was elevated. Right renal artery stenosis was
      demonstrated by angiography, and the abdominal aorta was narrowed distal to the
      ostium of the superior mesenteric artery. The plasma renin activity in the right
      renal vein (16 ng/ml/h) was higher than contralaterally (10 ng/ml/h). Several
      cardiovascular manifestations have been reported as a complication of epidermal
      nevus syndrome. Hypertension in an individual with epidermal nevi and congenital
      anomalies should prompt a search for a vascular anomaly.

PMID- 10644911
TI  - Pleural mesothelioma and membranous nephropathy.
AB  - Underlying malignancy has been thought to be responsible for 5-10% of the cases
      of membranous nephropathy in adults, with the risk being highest in patients over
      the age of 60 years. Solid tumors such as carcinomas of lung or colon, are most
      often involved. It is presumed that tumor antigens are deposited in the
      glomeruli; this is followed by antibody deposition and complement activation,
      leading to epithelial cell and basement membrane injury and proteinuria due to
      the associated increase in glomerular permeability. We describe a patient with a
      resistant nephrotic syndrome and massive proteinuria due to membranous
      nephropathy associated with pleural mesothelioma.

PMID- 10644913
TI  - Critical study on the significance of histocompatibility testing in renal
      transplantation: single-centre experience.

PMID- 10644912
TI  - Nephrotic syndrome due to membranous nephropathy associated with metastatic
      prostate cancer: rapid remission after initial endocrine therapy.
AB  - A case of severe nephrotic syndrome (urinary protein excretion 12.9 g/day) due to
      membranous nephropathy associated with untreated prostate cancer and multiple
      bone metastases is described. A combination of initial endocrine treatment and
      steroid therapy resulted in normalization of prostate-specific antigen levels
      followed by a rapid decrease of urinary protein excretion within 4 months. No
      proteinuria was subsequently detected. Seven months after the initiation of
      therapy, the patient remained well with complete clinical remission from the
      nephrotic syndrome. This rapid achievement of remission may have been due to
      tumor shrinkage by androgen ablation in addition to steroid therapy of the
      membranous nephropathy. The nephrotic syndrome is a rare complication of prostate
      cancer, and, to the best of our knowledge, no previous cases have been reported
      of membranous nephropathy as one of the first disease manifestations.

PMID- 10644914
TI  - Which dosage of simvastatin in renal transplant patients?

PMID- 10644915
TI  - Serum vascular endothelial growth factor is a candidate biomarker of renal cell
      carcinoma in hemodialysis patients.

PMID- 10644916
TI  - Dialysate calcium concentration of</=1.25 mmol/l: is it effective in suppressing
      uremic pruritus?

PMID- 10644917
TI  - Intrarenal hemodynamics in vesicoureteric reflux.

PMID- 10644918
TI  - Immunohistochemical localization of uroguanylin in the human kidney.

PMID- 10644919
TI  - Effect of dilazep hydrochloride, an antiplatelet agent, on the proliferation of
      cultured mouse glomerular mesangial cells.

PMID- 10644920
TI  - Different effects of chronic renal failure on erythrocyte nucleotide
      concentrations in humans and rats.

PMID- 10644921
TI  - Von Hippel-Lindau disease: the role of gene analysis in affected families.

PMID- 10644922
TI  - Cough is common in children prescribed converting enzyme inhibitors.

PMID- 10644923
TI  - Effects of combination therapy consisting of moderate-dose intravenous
      immunoglobulin G, pulsed methylprednisolone and pravastatin in children with
      steroid-resistant nephrosis.

PMID- 10644924
TI  - D-penicillamine-induced crescentic glomerulonephritis in a patient with
      scleroderma.

PMID- 10644925
TI  - Effect of lithium carbonate on the enhancement of serotonin 2A receptor elicited
      by dexamethasone.
AB  - The purpose of this study was to investigate whether chronic dexamethasone (Dex)
      administration induces serotonin (5-HT) 2A receptor supersensitivity and if
      chronic lithium carbonate (Li) administration contributes to the normalization of
      5-HT2A receptor supersensitivity induced by Dex in rat brain. We investigated the
      effects of a 14-day administration of Dex and/or Li on changes in body weight
      (BW), on plasma corticosterone levels, on plasma lithium levels, on 5-HT2A
      receptor binding sites, and on (+/-)-1-(2, 5-dimethoxy-4-iodophenyl)-2
      aminopropane (DOI)-induced wet dog shake (WDS), which is mediated by 5-HT2A
      receptor in rats. Dex significantly reduced the BW of rats. Li did not have any
      effect on BW gain and did not prevent the BW loss induced by Dex. The plasma
      corticosterone levels of rats treated with Dex were too low to be detected. Li
      did not have any effect on corticosterone levels and did not prevent the decrease
      in the corticosterone levels induced by Dex. Six hours after the last treatment,
      the plasma lithium levels of rats treated with Li were significantly higher than
      those of rats treated with Dex/Li. Chronic Dex administration resulted in a
      significant increase in the density (B(max)) of the 5-HT2A receptor without a
      significant change in the affinity (K(d)). The increase in the B(max) induced by
      Dex was not prevented by chronic combined treatment with Dex and Li. Chronic Dex
      administration potentiated the WDS, and this increase was prevented by chronic
      combined treatment with Dex and Li. Chronic Li administration did not have any
      effect on WDS. These results indicate that chronic Li administration may improve
      the supersensitivity of the 5-HT2A receptor elicited by chronic Dex
      administration without decreasing the density of the 5-HT2A receptor, and the
      effect of Li was also independent of hypothalamo-pituitary-adrenal axis function.

PMID- 10644926
TI  - Influence of method on seasonal distribution of attempted suicides in italy.
AB  - To verify if attempted suicides follow different seasonal distributions according
      to the method chosen, we studied the Italian monthly distribution of admissions
      for attempted suicide in the period 1984-1995 according to gender and age,
      distinguishing between non-violent (ICD 950-952) and violent (ICD 953-958)
      attempted suicides. The effect of temperature was also taken into account. A
      clear asymmetry in seasonal distribution of events can be observed in the oldest
      age groups in both genders, with a peak in warmer months. Only male attempted
      suicides by violent methods show a clear asymmetry in seasonal distribution, with
      a peak in spring months and a trough in autumn months. Spectral analysis, more
      accurate in detecting seasonal rhythms than analyses that only compare monthly
      seasonal means, identifies a circannual rhythm for violent suicides in both
      genders. The seasonal components of total variance in attempted suicides account
      for 16.5 and 12.4%, respectively, of violent male and female attempted suicides.
      Among males, a significant (p < 0.05) 4 cycles/year pattern is seen alongside the
      more relevant (89.4%, p < 0.01) 1 cycle/year distribution. Among females, aside
      from the 1 cycle/year distribution (63.3%, p < 0.01) noted, a 6 cycles/year
      pattern is found to contribute significantly (16.9%, p < 0.05) to the seasonal
      component of variance. A clear relationship with temperature indicators is noted
      among males: higher temperatures positively correlate with attempted suicides,
      whereas cooler temperatures seem to exert a protective action. Female attempts
      show a less evident correlation with indicators of temperature. Sample
      composition by age and gender and the lack of distinction between methods of
      attempted suicide may have obscured the seasonal component of some classes of
      attempted suicide in previous studies. The circannual rhythm found in this study
      of violent attempted suicide in relation to climate seasonal change confirms the
      importance of taking chronobiological variables into account in the evaluation of
      patients at risk of suicide.

PMID- 10644927
TI  - Age-sensitive cognitive function, growth hormone and insulin-like growth factor 1
      plasma levels in healthy older men.
AB  - Circulating levels of growth hormone (GH) change during the process of aging.
      Decline of cognitive functioning with aging is also well established. In this
      study, we investigated whether insulin-like growth factor 1 (IGF-1) and the GH
      response to a challenge of GH-releasing hormone and GH-releasing peptide 6 were
      associated with age-sensitive cognitive functions, but not with functions that do
      not decline with aging, in 17 healthy male subjects aged between 66 and 76 years.
      In addition, relations with anthropometric measures were examined.
      Neuropsychological performance was scored on tests of variables not sensitive to
      aging (general knowledge, vocabulary, basic visual perception and reading
      ability), and of variables sensitive to aging (visuoconstructive ability,
      perceptual motor and mental processing speed, and verbal long-term memory). After
      correcting for education, the serum GH response was significantly associated with
      two age-sensitive cognitive tests (measures of mental processing speed), but with
      none of the tests not sensitive to aging. However, the direction of the
      association was opposite to the relation between IGF-1 and these cognitive tests:
      higher levels of GH response were associated with poorer cognitive performance,
      whereas higher levels of IGF-1 were associated with better performance. GH
      response, but not IGF-1, was inversely correlated with body mass index. The
      results are in accordance with previous research suggesting a disruption of the
      relation between IGF-1 and GH secretion in older age.

PMID- 10644928
TI  - Associations between plasma glucose and DSM-III-R cluster B personality traits in
      psychiatric outpatients.
AB  - Associations between personality traits, measured with the Karolinska Scales of
      Personality, the Impulsiveness subscale from the Impulsiveness, Venturesomeness
      and Empathy (IVE) Inventory, and with self-assessed personality traits and
      disorders (SCID-II Screen Questionnaire), and plasma insulin, glucagon and
      glucose, respectively, were explored in a sample of 101 psychiatric outpatients
      of both sexes. No relationships between the peptide hormones and personality
      measures were found. However, fasting glucose values, which were all essentially
      within the normal biological variation, were significantly related to several
      personality measures. For males, a low blood glucose was associated with low
      stable general level of functioning, with high IVE Impulsiveness, and with self
      assessed histrionic and narcissistic traits. High number of self-assessed
      personality traits for all cluster B personality disorders was strongly
      associated with high IVE Impulsiveness. The results of the present study support
      the generalizability of earlier findings from alcoholic impulsive offenders: in
      males, low blood glucose is associated with an extrovert and impulsive, acting
      out behavior that includes the breaking of societal norms and rules. In contrast,
      for females a positive relationship between fasting glucose and self-assessed
      histrionic personality traits was found. Because no association between global
      level of functioning and glucose was found in women, these personality traits may
      not necessarily be maladaptive, as was the case for males.

PMID- 10644929
TI  - Peripheral and central nervous system alterations in hypothyroidism:
      electrophysiological findings.
AB  - The purpose of this study is to evaluate objectively the functional changes in
      the nervous system in hypothyroidism by different electrophysiological parameters
      and to determine the frequencies of these changes in patients with
      hypothyroidism. We enrolled 23 patients (17-64 years old, mean 38.2) with
      biochemical evidence of hypothyroidism, with thyroxine less than 4 microg/dl and
      thyrotropin above 4.5 mU/ml, and 200 age- and sex-matched normal subjects.
      Detailed clinical examination and electrophysiological measurements included
      electromyography, motor conduction velocity, visual-evoked potentials (VEPs),
      brainstem auditory-evoked potentials (BAEPs) and event-related potentials.
      Determinations of P300, Wechsler Adult Intelligence Scale (IQ) and
      electroencephalography (EEG) were performed. Of the hypothyroid patients 52% had
      peripheral nervous system (PNS) involvement. Entrapment neuropathy was the
      commonest (35%). Axonal neuropathy was recorded in 9% and myopathy was recorded
      in another 9%. The central nervous system (CNS) was affected in 78% of the cases.
      Significant prolongations of P100 latency of VEP, latency and interpeak latency
      of BAEPs of different waves of hypothyroid patients were compared to the control
      group. 52% had abnormal VEPs and BAEPs above the mean +/- 2 SD of the normal
      control group. Six patients (26%) had prolonged P300 latency while 16 patients
      had an IQ below 90. Eight patients (35%) had EEG changes. Diffuse slowing of
      background activity was the commonest. No significant correlation was observed
      between hormonal levels and the different electrophysiological parameters. Thus,
      the CNS is more vulnerable to the effect of hypothyroidism than the PNS.
      Therefore, we suggest performing electrophysiological studies in hypothyroid
      patients, even in the asymptomatic ones, early in the course of disease in order
      to detect the nervous system involvement.

PMID- 10644930
TI  - Lateralized cognitive visuospatial processing: is it primarily gender-related or
      due to quality of performance? A HMPAO-SPECT study.
AB  - The brain activity of 13 right-handed students (6 men and 7 women) was determined
      using high resolution (99m)Tc-HMPAO brain SPECT images during visuospatial tasks.
      The results showed that there was no significant gender-specific difference in
      solving the visuospatial tasks and that no meaningful statistical difference in
      brain activity between the two sexes could be found. When the sample was split
      into groups of good and poor performers, the results showed that there was a
      relatively symmetrical brain activity both frontal and parietal in subjects with
      poor test results. The results for those who performed the tests well, on the
      other hand, showed increased left frontal and right parietal brain activity.
      These results would suggest an asymmetric type of processing for better
      visuospatial brain performance independent of gender.

PMID- 10644931
TI  - A comparison of ADAS and EEG in the discrimination of patients with dementia of
      the Alzheimer type from healthy controls.
AB  - Neuropsychometric tests (for instance the Alzheimer's Disease Assessment Scale,
      ADAS) and the EEG are often used in the diagnostic procedure of dementia. The
      validity of the instruments is only poorly investigated. The study aimed to
      investigate the accuracy of the discrimination between healthy controls and
      patients with dementia of the Alzheimer type (DAT) by ADAS and EEG. Thirty-six
      patients with DAT and 44 healthy controls were included. In a discriminant
      analysis of the 21 ADAS items and 18 EEG parameters (6 frequency bands, 12
      topographic parameters), 6 ADAS items turned out to discriminate both groups with
      100% sensitivity and specificity (remembering instructions, depression, following
      commands, pacing, restlessness and word finding difficulties). Regarding EEG
      parameters, 4 (topography of beta- and delta-activity and amplitude of delta
      activity) led to a sensitivity and specificity of over 90%. Thus, both methods
      demonstrated an excellent discrimination between healthy controls and DAT. The
      slightly higher discrimination with the ADAS may depend on its closer relation to
      clinical symptoms. However, the EEG measuring functional activity reached nearly
      the same result. Both methods provide complementary information. A combination of
      both methods in the diagnostic procedure to detect dementia is recommended.

PMID- 10644932
TI  - Appearance of frontal midline theta activity in patients with generalized anxiety
      disorder.
AB  - The appearance of frontal midline theta activity (Fm&theta;), recognized as
      distinct EEG theta rhythm in the frontal midline area during performance of a
      mental task, reflects feelings of relief from anxiety in humans. In the present
      study, EEGs were recorded, and the Hamilton Rating Scale for Anxiety and the
      state anxiety scale of Spielberger's State-Trait Anxiety Inventory were evaluated
      once a week in 28 patients with generalized anxiety disorder. The Taylor Manifest
      Anxiety Scale and the trait anxiety scale of Spielberger's State-Trait Anxiety
      Inventory were used to assess anxiety before and after the tests. The present
      results suggest that the appearance of Fm&theta; might be closely related to an
      improvement in the anxiety symptoms associated with generalized anxiety disorder.

PMID- 10644933
TI  - First-line chemotherapy with vinorelbine and paclitaxel as simultaneous infusion
      in advanced breast cancer.
AB  - Based on preclinical data showing a synergistic activity of simultaneous
      administration of vinorelbine and paclitaxel, we carried out a phase II trial in
      previously untreated advanced breast cancer patients. Treatment consisted of
      vinorelbine 25 mg/m(2) and paclitaxel 150 mg/m(2), both drugs given by
      intravenous infusion over 3 h on day 1, with cycles repeated every 3 weeks.
      Granulocyte colony-stimulating factor, 300 microg subcutaneously, was given on
      days 7-12 to the first 10 patients. From October 1995 to January 1997, 43
      patients with advanced breast cancer entered the study, and 41 were evaluable for
      response. We obtained 2 complete responses (5%) and 18 partial responses (44%),
      for an overall response rate of 49% (95% CI 34-64%). Median time to response,
      time to progression and survival were 2, 7 and 22 months, respectively.
      Myelosuppression was the dose-limiting toxicity, with G4 neutropenia in 21% and
      neutropenic fever in 7% of the patients. Other toxicities were mild. Simultaneous
      infusion of vinorelbine and paclitaxel is a well-tolerated and active regimen in
      metastatic breast cancer, with overall results similar to those reported with
      more toxic regimens; furthermore, it may be a good option in patients with
      anthracycline contraindications.

PMID- 10644934
TI  - Vinorelbine + mitomycin C as second-line treatment of metastatic breast cancer: a
      two-stage phase 2 study.
AB  - Second-line treatment of patients with metastatic breast cancer resistant to
      anthracyclines is an important clinical issue. The aim of the present two-stage
      phase II study was to evaluate activity and toxicity of vinorelbine + mitomycin C
      (VM) in such patients. Fifty-five patients were entered and received vinorelbine
      30 mg/m(2) on days 1 and 8 + mitomycin C 10 mg/m(2) on day 1, every 4 weeks, up
      to 9 cycles. Two complete and 23 partial responses were observed for an overall
      response rate of 45.4% (95% CI 32.0-59.4). Median survival was 13 months and
      probability of surviving after a 1-year follow-up was 58%. Toxicity was never
      life-threatening, but G-CSF was used in 45% of cycles to contrast neutropenia
      that was the most frequent side effect. These results are consistent with
      previous studies and strongly support VM being considered among the optimal
      polychemotherapy regimens for second-line treatment of metastatic breast cancer
      in clinical practice; for clinical research aims, VM should be used as control
      arm for randomized trials evaluating the activity of new drugs against breast
      cancer.

PMID- 10644935
TI  - Successful primary radiation therapy of adenoid cystic carcinoma of the lung.
AB  - Adenoid cystic carcinoma is a distinctive malignant neoplasm generally arising
      from minor salivary glands, that arises infrequently as a primary tumor in the
      lung. Surgery has been considered the primary treatment, with radiotherapy
      generally utilized as adjuvant or palliative treatment. We report a patient in
      whom primary radiotherapy was sucessfully applied to treat adenoid cystic
      carcinoma involving the distal trachea, carina, and both main stem bronchi. A
      total dose of 66 Gy was delivered in 2-Gy fractions over a 7-week period.
      Clinically and histologically complete remission was achieved without evidence of
      disease during a 27-month follow up.

PMID- 10644936
TI  - Scintigraphic imaging of sarcomatous tumors with [(111)In-DTPA-phe-1]-octreotide.
AB  - The objective of the present study was to investigate the efficacy of (111)In
      DTPA-octreotide (OC) for in vivo scintigraphic imaging of these relatively
      uncommon tumors. Thirteen patients (9 males, 4 females, mean age 59 years) with
      known sarcomatous lesions were studied. All patients had known lesions as
      demonstrated by previous investigation with other modalities, e.g. CAT, MRI.
      Following intravenous injection of 10 microg of OC labeled with 2.8-4.2 mCi
      (111)In, planar imaging was done at 6 +/- 1 and 22 +/- 2 h, respectively.
      Histologic verification was obtained in all cases, either from fine needle
      aspiration or from surgically removed tissue. Positive imaging was observed in
      12/13 cases (92.3%). One scan was false-negative (7.7%). Occult lesions were
      demonstrated in two patients. The histologic typing and the scintigraphy results
      were: fibrosarcoma (1+/1), embryonic rhabdomyosarcoma (1+/1), leiomyosarcomas
      (3+/3), liposarcomas (2+/2), uterine sarcomas (2+/2), HIV (-) Kaposi sarcoma
      (1+/1), osteosarcoma (1+/1), chondrosarcoma (1-/1) and neurogenous sarcoma
      (1+/1). OC appears to have properties that lead to a new indication for its use.
      Other possible applications relate to the therapeutic use of octreotide either
      unlabeled or labeled with a beta-emitting radionuclide, as well as its use in
      radioimmunoguided surgery. Regarding the latter, our preliminary results are
      encouraging.

PMID- 10644938
TI  - Phase II study of irinotecan and cisplatin as first-line chemotherapy in advanced
      or recurrent cervical cancer.
AB  - Irinotecan (CPT-11) and cisplatin are singly active against cervical cancer. We
      evaluated the efficacy and toxicity of CPT-11 plus cisplatin as first-line
      chemotherapy in patients with advanced or recurrent cervical cancer. Twenty-nine
      chemotherapy-naive patients with advanced or recurrent cervical cancer were
      treated with CPT-11 (60 mg/m(2)) on days 1, 8, and 15 by intravenous infusion
      over 90 min, followed by cisplatin (60 mg/m(2) i.v.) on day 1 over 90 min. The
      patients' median age was 57 years (range 35-75). Nineteen patients (66%) had
      advanced primary disease. Six patients with recurrent disease (21%) had been
      treated with prior radiotherapy. The remaining 4 patients (14%) had residual or
      recurrent disease after radical surgery. The histologic diagnoses were squamous
      cell carcinoma in 25 patients (87%), adenocarcinoma in 3, and adenosquamous cell
      carcinoma in 1. All eligible patients were included in the toxicity and response
      analysis based on the intent to treat. Two patients (7%) achieved a complete
      response and 15 (52%) a partial response (overall response rate: 59%, 95%
      confidence interval; 41-74%). Stable disease was recorded in 6 patients (21%) and
      progressive disease in 3 patients (10%). In 3 patients, image-guided evaluation
      of response was judged to be unfeasible at the time of independent extramural
      review (10%). The median time to response was 32 days (range 16-62 days). The
      median survival was 27. 7+ months (range, 6.4-52.8+ months). Two dose-limiting
      side effects were observed: grade 3 (28%) or 4 (45%) neutropenia and grade 3 (7%)
      or 4 (7%) diarrhea. Other severe toxicities included anemia (45%),
      thrombocytopenia (3%), nausea/vomiting (31%), and alopecia (7%). The combination
      of CPT-11 with cisplatin is an active regimen for treatment of advanced or
      recurrent cervical cancer albeit with a significant degree of myelosuppression.

PMID- 10644937
TI  - Vinorelbine and alternating cisplatin and ifosfamide in the treatment of non
      small cell lung cancer.
AB  - In order to explore the activity of a combination of vinorelbine (VNL) and
      alternating cisplatin (CDDP) and ifosfamide (IFX) in non-small cell lung cancer
      (NSCLC), a phase II study was performed. Seventy chemoradiotherapy naive patients
      with NSCLC, stage IIIA, IIIB and IV disease, PS (ECOG) </=2, were treated with
      CDDP 40 mg/m(2) on days 1, 2, 3, IFX 1,800 mg/m(2) on days 22, 23, 24 and VNL 30
      mg/m(2) on days 1, 8, 22, 29 every 6 weeks up to 6 courses. In the 67 evaluable
      patients, an objective response rate was observed in 47.8 +/- 12% (95% CI) with
      complete responses in 6%; responses occurred more frequently in patients with
      locally advanced disease (stage IIIA/IIIB) and/or performance status 0. The
      median duration of survival was 12 months: 19.9 months in stage III patients who
      received an integrated treatment and 10 months in metastatic disease. The median
      time to treatment failure was 10.5 months. Toxicity was mainly hematological,
      even though it was not dose-limiting and easily manageable. This combination
      seems to be active, and the good safety profile is probably the result of the use
      of an alternating schedule of CDDP and IFX. Median overall survival was also
      encouraging in stage IV disease. The prolongation of survival obtained when
      surgery and/or radiotherapy is applicable needs confirmation through a larger
      study.

PMID- 10644939
TI  - Detection and clinical significance of lymph node micrometastasis determined by
      reverse transcription-polymerase chain reaction in patients with esophageal
      carcinoma.
AB  - We investigated micrometastasis in lymph nodes by detecting carcinoembryonic
      antigen (CEA) mRNA. A total of 400 lymph nodes obtained from 21 patients with
      esophageal carcinoma were examined by CEA-specific reverse transcription
      polymerase chain reaction (RT-PCR). Serial sections of positive lymph nodes were
      reexamined histologically and immunohistologically. Twenty-seven lymph nodes of
      11 patients were diagnosed as being positive by conventional histologic
      examination. CEA-mRNA positivity was found in 18 of 21 patients. Among 373
      histologically negative nodes, 79 (21.2%) were positive for CEA mRNA. Of these,
      micrometastasis was detected in 2 by histological reexamination and in 11 by
      immunohistochemical staining using cytokeratin antibody. Two of 6 RT-PCR-positive
      patients (33.3%) had recurrent disease. Four of 11 patients (36.4%) whose nodal
      involvement was discovered by routine histological examination also had recurrent
      cancer. CEA-specific RT-PCR detected micrometastasis in lymph nodes at a higher
      rate than histological or immunohistochemical analysis of serial sections. Since
      the incidence of CEA-mRNA positivity is high in the lymph nodes of esophageal
      cancer patients except for those with early cancer, these patients should be
      treated with adjuvant therapy.

PMID- 10644940
TI  - Prognostic significance of p27(kip1) protein expression and spontaneous apoptosis
      in patients with colorectal adenocarcinomas.
AB  - Tumor cell apoptosis, proliferation and p27 expression using an in situ apoptosis
      detection kit, anti-Ki67 antibody and anti-p27 antibody were investigated in 171
      colorectal adenocarcinoma specimens, together with the assessment of mutated p53
      expression. No apparent association was observed among p27 expression, mutated
      p53 accumulation, the Ki67 labeling index and the apoptotic index (AI). In the
      multivariate analysis using the median values as the cut-off points (46.8% for
      p27 expression and 0.89% for AI), p27 expression was identified as an independent
      and significant predictor for overall survival. When the present series of
      patients were dichotomized by these cut-off points to categorize the cases into 4
      subgroups, the patients in the group with low p27 expression and a low AI had the
      poorest prognosis. The assessment of p27 expression and AI therefore may prove
      valuable in identifying patients with colorectal adenocarcinoma who may have a
      poor prognosis.

PMID- 10644941
TI  - p53 gene mutation, microsatellite instability and adjuvant chemotherapy: impact
      on survival of 388 patients with Dukes' C colon carcinoma.
AB  - Two common genetic alterations in colon carcinoma, p53 mutation and
      microsatellite instability (MSI), were investigated to determine their prognostic
      importance for cancer-specific survival and response to adjuvant chemotherapy in
      patients with Dukes' C colon cancer. The p53 tumour suppressor gene encodes for a
      nuclear phosphoprotein involved in cellular response to DNA damage, while MSI is
      a characteristic feature of tumours with defective DNA mismatch repair. The
      cellular response mechanisms to DNA-damaging agents in tumours with mutant p53 or
      MSI may as a consequence differ, and this might translate into different outcomes
      following adjuvant chemotherapy. A consecutive series of 388 Dukes' C colon
      carcinomas with 5-year median follow-up was analysed for p53 mutation and for MSI
      (in proximal/transverse carcinomas only) using polymerase chain reaction single
      strand conformation polymorphism. The incidence of p53 mutation was 28% in all
      carcinomas while that of MSI in proximal/transverse carcinomas was 19%. One
      hundred and thirty-three patients (34%) received adjuvant chemotherapy (5
      fluorouracil/levamisole) with curative intent. The presence of p53 mutation did
      not predict for survival in either the treated or untreated groups. The presence
      of MSI in the proximal/transverse colon carcinoma group was associated with
      significantly better 5-year survival: 58 versus 32% (p = 0.015, log rank test).
      This was largely due to better survival observed in the MSI subgroup that
      received adjuvant chemotherapy (p = 0.017, log rank test). Further work in
      prospective, randomised clinical trials investigating the effects of adjuvant
      therapy should consider incorporating MSI status in order to determine whether
      this is an independent predictive factor for survival and/or response to adjuvant
      chemotherapy.

PMID- 10644942
TI  - Identification of exon-deleted progesterone receptor mRNAs in human uterine
      endometrial cancers.
AB  - We demonstrated the expression of various exon-deleted progesterone receptor (PR)
      variant mRNAs in human uterine endometrial cancers using the reverse
      transcription-polymerase chain reaction-DNA sequencing analyses. In addition to
      PR wild-type mRNA, exon 4-deleted, exon 6-deleted, exon 3,4-deleted, exon 5,6
      deleted, exon 4,5,6-deleted and exon 3,4,5,6-deleted PR variant mRNAs were
      identified. The exon 6-deleted and exon 5,6-deleted PR variant mRNAs lacked
      encoding for the steroid-binding domain. The exon 4-deleted, exon 3,4-deleted,
      exon 4,5,6-deleted and exon 3,4,5,6-deleted PR variant mRNAs lacked encoding for
      the DNA-binding domain in addition to encoding for the steroid-binding domain.
      While the exon 4-deleted, exon 6-deleted and exon 3,4-deleted PR variant mRNAs
      were observed in all samples analyzed, the exon 5,6-deleted, exon 4,5,6-deleted
      and/or exon 3,4,5,6-deleted PR variant mRNAs could not be detected in some cases,
      especially in poorly differentiated adenocarcinoma as compared with well
      differentiated and moderately differentiated adenocarcinomas. The present study
      demonstrates the coexpression of PR exon-deleted variant mRNAs with the wild-type
      in uterine endometrial cancers. All translated variant proteins might possess
      functional diversity and might modify the progestational action of wild-type PR,
      and the expression of some PR variant mRNAs may be lost as endometrial cancer
      cells undergo dedifferentiation.

PMID- 10644943
TI  - Prognostic relevance of a histological grading system using MIB-1 for adult soft
      tissue sarcoma.
AB  - Several histological grading systems have been proposed and found as strong
      indicators of outcome in soft-tissue sarcomas. However, a putative independent
      prognostic influence of recently developed biological and molecular markers
      remains to be established. This study investigated the prognostic relevance of a
      histological grading system based on the assessment of proliferative activity in
      adult soft-tissue sarcomas of the extremities, trunk, head, and neck. Tissue
      blocks from 95 of 108 patients without distant metastases or regional lymph node
      involvement were available. Immunohistochemical staining for MIB-1 and p53 was
      done on paraffin-embedded sections. All clinicopathologic and immunohistochemical
      variables and patient survival were assessed using univariate and multivariate
      analyses. Variables included histological grading based on the modified
      Federation Nationale des Centres de Lutte Contre le Cancer (FNCLCC) system using
      the MIB-1 score for the estimation of the proliferative potential of the tumors.
      Variables associated with overall survival were tumor site in the trunk, head and
      neck, mitosis count, necrosis, MIB-1 score, FNCLCC grade, modified FNCLCC grade
      using the MIB-1 score, and stage (all p values <0.05). In multivariate analysis,
      the modified grade proved to be the most significant predictor of shortened
      overall survival, in addition to tumor site in the trunk, head, and neck.
      Overexpression of p53 did not correlate with increased risk of tumor mortality.
      Using MIB-1 to replace mitosis counts in the FNCLCC system improves grading of
      soft-tissue sarcomas, and this in conjunction with other important factors appear
      to be more accurate prognostic factors for survival, and for patient selection in
      investigational adjuvant treatment trials.

PMID- 10644944
TI  - Second malignancies following pure seminoma.
AB  - PURPOSE: Second malignancies in patients with pure testicular seminoma were
      studied in order to look for adverse late effects of treatment and to study the
      significance of second malignancies during follow-up. PATIENTS, METHODS: In a
      multicentric investigation, 839 consecutive patients with pure testicular
      seminoma were observed for a median follow-up of 3.9 years. Thirty-seven patients
      had been excluded from the study because they already had had either a
      contralateral testicular germ cell tumor or another malignancy. 758 patients
      received radiotherapy, 76 underwent chemotherapy, 5 had surveillance only. The
      expected rate of second cancers was calculated according to the data of the
      cancer registry of Saarland, Germany. RESULTS: Twenty-two second cancers (13
      contralateral testicular tumors, 9 extratesticular malignancies) were recorded.
      The overall risk of having a second cancer was RR = 4.8 (95% CI 3. 0-7.3). The
      risk of having a subsequent testicular tumor is RR = 44. 8 (95% Cl 23.9-76.7).
      1.1% of the patients developed a nontesticular second tumor. The risk of having a
      nontesticular second cancer is RR = 2.1 (95% CI 1.0-4.0). A significantly
      increased risk was observed for renal cell cancer as well (RR = 12.5; 95% Cl: 1.5
      45.1). Increased RR without reaching statistical significance were found for
      rectal cancer (RR = 5.0; 95% Cl: 0.1-27.9) and non-Hodgkin lymphoma (RR = 6.7;
      95% CI 0.2-37.1). None of the second cancers were directly located within the
      radiation field; 5 neoplasms arose at the border of the radiation field.
      CONCLUSIONS: This study confirmed the increased risk of having a second
      testicular germ cell cancer. There is also a small but definitely increased
      overall risk of having a nontesticular second cancer. Treatment-unrelated factors
      - possibly genetic predisposition - must be considered for a substantial number
      of these second tumors, since in the present study the follow-up was rather short
      and most of the second cancers were located outside of the radiation fields. In
      particular, the association of renal cancer with testicular cancer appears to be
      a more than chance occurrence. Second cancer is a real hazard following treatment
      of testicular cancers and should always be considered during follow-up.

PMID- 10644945
TI  - Expression of the cell adhesion molecules ICAM-1, VCAM-1 and NCAM in uveal
      melanoma: a clinicopathological study.
AB  - To investigate the relationship between the expression of the cell adhesion
      molecules intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion
      molecule-1 (VCAM-1) and neural cell adhesion molecule (NCAM) in uveal melanoma
      and the metastatic spread in the first 5 years after diagnosis, we performed a
      hospital-based case-control study with human tissue from 90 patients who
      underwent enucleation for primary uveal melanoma (iris melanoma excluded). Thirty
      five patients developed metastasis within the first 5 years, and 55 patients
      lived metastasis-free for at least 5 years after enucleation. The paraffin
      embedded and formalin-fixed globes were studied by immunohistochemistry with
      monoclonal antibodies for ICAM-1, VCAM-1 and NCAM. A strong ICAM-1 positivity
      (more than 75% of the tumor cells stained positive) was detected in 73 tumors
      (81%). The expression of 75% or less ICAM-1 positive cells in tumors was strongly
      associated with the development of metastases (odds ratio: 7.5, p = 0.001).
      Multiple logistic regression models showed that ICAM-1 is an independent risk
      factor for metastasis even after control for important prognostic markers like
      extraocular growth, ciliary body involvement, scleral infiltration and cell type.
      VCAM-1 was expressed in 24 out of 88 tumors (27.3%) and NCAM only in 14 out of 87
      tumors (16%). Only spindle cells stained positive with anti-NCAM. NCAM and VCAM-1
      expression was not related to metastasis. Our results show that the loss of ICAM
      1 expression is associated with an increased risk of metastasis within the first
      5 years after diagnosis.

PMID- 10644946
TI  - The distribution of structures in evolving protein populations.
AB  - Proteins exhibit a nonuniform distribution of structures. A number of models have
      been advanced to explain this observation by considering the distribution of
      designabilities, that is, the fraction of all sequences that could successfully
      fold into any particular structure. It has been postulated that more designable
      structures should be more common, although the exact nature of this relationship
      has not been addressed. We find that the nonuniform distribution of protein
      structures found in nature can be explained by the interplay of evolution and
      population dynamics with the designability distribution. The relative frequency
      of different structures has a greater-than-linear dependence on designability,
      making the distribution of observed protein structures more uneven than the
      distribution of designabilities. The distribution of structures is also affected
      by additional factors such as the topology of the sequence space and the
      similarity of other structures.

PMID- 10644947
TI  - Backbone motions in a crystalline protein from field-dependent 2H-NMR relaxation
      and line-shape analysis.
AB  - We have used 2H-nmr to study backbone dynamics of the 2H-labeled, slowly
      exchanging amide sites of fully hydrated, crystalline hen egg white lysozyme.
      Order parameters are determined from the residual quadrupole coupling and values
      increase from S2 = 0.85 at 290 K to S2 = 0.94 at 200 K. Dynamical rates are
      determined from spin-lattice relaxation at three nmr frequencies (38.8, 61.5, and
      76.7 MHz). The approach used here is thus distinct from solution nmr studies
      where dynamical amplitudes and rates are both determined from relaxation
      measurements. At temperatures below 250 K, relaxation is independent of the nmr
      frequency indicating that backbone motions are fast compared to the nmr
      frequencies. However, as the temperature is increased above 250 K, relaxation is
      significantly more efficient at the lowest frequency, which shows, in addition,
      the presence of motions that are slow compared to the nmr frequencies. Using the
      values of S2 determined from the residual quadrupole coupling and a model-free
      relaxation formalism that allows for fast and slow internal motions, we conclude
      that these slow motions have correlation times in the range of 0.1 to 1.0
      microsecond and are effectively frozen out at 250 K where fast motions of the
      amide planes with approximately 15 ps effective correlation times and 9 degrees
      rms amplitudes dominate relaxation. The fast internal motions increase slightly
      in amplitude as the temperature rises toward 290 K, but the correlation time, as
      is also observed in solution nmr studies of RNase H, is approximately constant.
      These findings are consistent with hypotheses of dynamic glass transitions in
      hydrated proteins arising from temperature-dependent damping of harmonic modes of
      motion above the transition point.

PMID- 10644948
TI  - New evidence of the nonequilibrium nature of the "slow modes" of diffusion in
      polyelectrolyte solutions.
AB  - The time-dependent behavior of the dissolution of polyelectrolyte powders in pure
      water and moderate ionic strength aqueous solvent was monitored by flowing
      dissolving material through an online filter, and then through a multiangle light
      scattering unit, a refractometer, and a capillary viscometer. When the
      polyelectrolytes were dissolved in solutions of moderate ionic strength, their
      dissolution behavior was similar to that of neutral polymers. When dissolved in
      pure water, however, there was consistently a small population of aggregates that
      appeared at the beginning of the dissolution process, which then rapidly
      diminished. For large pore filtration, the aggregates reached a final low level,
      and slowly disappeared over the span of many days, whereas for small pore
      filtration the aggregates disappeared completely over a scale of minutes. The
      real-time data, together with size exclusion chromatography analysis, shed light
      on previously unanswered questions concerning the nonequilibrium nature of this
      small population of polyelectrolyte aggregates in low ionic strength solutions,
      and its relation to the "extraordinary phase" of diffusion (or "slow modes").
      Further evidence is also provided that both angular scattering maxima due to
      interpolyion correlations and the maximum of reduced viscosity vs polyion
      concentration ("electroviscous" effect) at low ionic strength are equilibrium
      properties that are unrelated to these aggregates.

PMID- 10644949
TI  - Separation of the variables of time and temperature in the mechanical properties
      of high sugar/polysaccharide mixtures.
AB  - Experimental results from previous studies were analyzed in order to separate the
      dynamic mechanical properties of high sugar/polysaccharide mixtures into a basic
      function of temperature alone and a basic function of time alone. In doing so,
      the energy of vitrification as derived from the Williams, Landel, and Ferry
      equation, and the distribution function of relaxation times were used. It was
      found that the temperature course of vitrification depends on the nature of the
      polymer and the composition of the mixture. Thus, at the same level of cosolute,
      the glass transition temperature of the mixture is determined by the structural
      behavior of the macromolecule and, it appears, that cation-mediated associations-
      for example, of kappa-carrageenan--are more efficient "vitrifiers" than the
      neutral associations of agarose. Regardless of the glass transition temperature,
      vitrification requires five times the activation energy of elementary flow in the
      melt or of the viscoelastic relaxation in the rubbery state. In the region of
      long time scales of measurement, the time function is determined by the molecular
      weight distribution and the ability of the polysaccharide to form a three
      dimensional network. In the area of short times, free volume effects leading to
      vitrification are similar for all materials.

PMID- 10644950
TI  - Water regulation of actinomycin-D binding to DNA: the interplay among drug
      affinity, DNA long-range conformation, and hydration.
AB  - Actinomycin-D (actD) binds to natural DNA at two different classes of binding
      sites, weak and strong. The affinity for these sites is highly dependent on DNA
      sequence and solution conditions, and the interaction appears to be purely
      entropic driven. Although the entropic character of this reaction has been
      attributed to the release of water molecules upon drug to DNA complex formation,
      the mechanism by which hydration regulates actD binding and discrimination
      between different classes of binding sites on natural DNA is still unknown. In
      this work, we investigate the role of hydration on this reaction using the
      osmotic stress method. We show that the decrease of solution water activity, due
      to the addition of sucrose, glycerol, ethylene glycol, and betaine, favors drug
      binding to the strong binding sites on DNA by increasing both the apparent
      binding affinity delta G, and the number of DNA base pairs apparently occupied by
      the bound drug nbp/actD. These binding parameters vary linearly with the
      logarithm of the molar fraction of water in solution log(chi w), which indicates
      the contribution of water binding to the energetic of the reaction. It is
      demonstrated that the hydration change measured upon binding increases
      proportionally to the apparent size of the binding site nbp/actD. This indicates
      that nbp/actD, measured from the Scatchard plot, is a measure of the size of the
      DNA molecule changing conformation due to ligand binding. We also find that the
      contribution of DNA deformation, gauged by nbp/actD, to the total free energy of
      binding delta G, is given by delta G = delta Glocal + nbp/actD x delta GDNA,
      where delta Glocal = -8020 +/- 51 cal/mol of actD bound and delta GDNA = -24.1 +/
      1.7 cal/mol of base pair at 25 degrees C. We interpret delta Glocal as the
      energetic contribution due to the direct interactions of actD with the actual
      tetranucleotide binding site, and nbp/actD x delta GDNA as that due to the change
      in conformation, induced by binding, of nbp/actD DNA base pairs flanking the
      local site. This interpretation is supported by the agreement found between the
      value of delta GDNA and the torsional free energy change measured independently.
      We conclude suggesting an allosteric model for ligand binding to DNA, such that
      the increase in binding affinity is achieved by increasing the relaxation of the
      unfavorable free energy of binding storage at the local site through a larger
      number of DNA base pairs. The new aspect on this model is that the "size" of the
      complex is not fixed but determined by solutions conditions, such as water
      activity, which modulate the energetic barrier to change helix conformation.
      These results may suggest that long-range allosteric transitions of duplex DNA
      are involved in the inhibition of RNA synthesis by actD, and more generally, in
      the regulation of transcription.

PMID- 10644951
TI  - Inhomogeneous alginate gel spheres: an assessment of the polymer gradients by
      synchrotron radiation-induced X-ray emission, magnetic resonance microimaging,
      and mathematical modeling.
AB  - It has been previously demonstrated that calcium alginate gels prepared by
      dialysis often exhibit a concentration inhomogeneity being the polymer
      concentration considerably lower in the center of the gel than at the edges.
      Inhomogeneity may be a preferred structure in microcapsules due to low porosity
      and higher stability so that it is interesting to evaluate the polymer gradient
      in spherically symmetrical small alginate beads (1.0-0.7 mm diameter) obtained in
      different conditions. In this paper, two complementary techniques have been used
      to investigate this aspect. The concentration gradient of alginate has been
      analyzed by measuring both the spatial distribution of calcium ions in sections
      of alginate gel spheres, by means of x-ray fluorescence spectroscopy, and the T2
      relaxation behavior on intact gel beads using magnetic resonance microimaging.
      The experimentally determined gradients from three-dimensional gels provide data
      to reevaluate the parameter estimates in the recently reported mathematical model
      for alginate gel formation (A. Mikkaelsen and A. Elgsaeter, Biopolymers, 1995,
      Vol. 36, pp. 17-41). The model may account for the gels being less inhomogeneous
      when nongelling sodium or magnesium ions are added during gelation.

PMID- 10644952
TI  - Thermodynamic origin of cis/trans isomers of a proline-containing beta-turn model
      dipeptide in aqueous solution: a combined variable temperature 1H-NMR, two
      dimensional 1H,1H gradient enhanced nuclear Overhauser effect spectroscopy
      (NOESY), one-dimensional steady-state intermolecular 13C,1H NOE, and molecular
      dynamics study.
AB  - The cis/trans conformational equilibrium of the two Ac-Pro isomers of the beta
      turn model dipeptide [13C]-Ac-L-Pro-D-Ala-NHMe, 98% 13C enriched at the acetyl
      carbonyl atom, was investigated by the use of variable temperature gradient
      enhanced 1H-nmr, two-dimensional (2D) 1H,1H nuclear Overhauser effect
      spectroscopy (NOESY), 13C,1H one-dimensional steady-state intermolecular NOE, and
      molecular dynamics calculations. The temperature dependence of the cis/trans
      Ala(NH) protons are in the region expected for random-coil peptides in H2O (delta
      delta/delta T = -9.0 and -8.9 ppb for the cis and trans isomers, respectively).
      The trans NH(CH3) proton indicates smaller temperature dependence (delta
      delta/delta T approximately -4.8 ppb) than that of the cis isomer (-7.5 ppb). 2D
      1H,1H NOESY experiments at 273 K demonstrate significant NOEs between ProH alpha
      AlaNH and AlaNH-NH(R) for the trans isomer. The experimental NOE data, coupled
      with computational analysis, can be interpreted by assuming that the trans isomer
      most likely adopts an ensemble of folded conformations. The C-CONH(CH3) fragment
      exhibits significant conformational flexibility; however, a low-energy conformer
      resembles closely the beta II-turn folded conformations of the x-ray structure of
      the related model peptide trans-BuCO-L-Pro-Me-D-Ala-NHMe. On the contrary, the
      cis isomer adopts open conformations. Steady-state intermolecular solute-solvent
      (H2O) 13C,1H NOE indicates that the water accessibility of the acetyl carbonyl
      carbons is nearly the same for both isomers. This is consistent with rapid
      fluctuations of the conformational ensemble and the absence of a highly shielded
      acetyl oxygen from the bulk solvent. Variable temperature 1H-nmr studies of the
      cis/trans conformational equilibrium indicate that the trans form is
      enthalpically favored (delta H degree = -5.14 kJ mole-1) and entropically (delta
      S degree = -5.47 J.K-1.mole-1) disfavored relative to the cis form. This
      demonstrates that, in the absence of strongly stabilizing sequence-specific
      interresidue interactions involving side chains and/or charged terminal groups,
      the thermodynamic difference of the cis/trans isomers is due to the combined
      effect of intramolecular and intermolecular (hydration) induced conformational
      changes.

PMID- 10644953
TI  - Comparison of helix-stabilizing effects of alpha,alpha-dialkyl glycines with
      linear and cycloalkyl side chains.
AB  - The ability of alpha, alpha-di-n-alkyl glycines with linear and cyclic alkyl side
      chains to stabilize helical conformations has been compared using a model
      heptapeptide sequence. The conformations of five synthetic heptapeptides (Boc-Val
      Ala-Leu-Xxx-Val-Ala-Leu-OMe, Xxx = Ac8c, Ac7c, Aib, Dpg, and Deg, where Ac8c = 1
      aminocyclooctane-1-carboxylic acid, Ac7c = 1-aminocycloheptane-1-carboxylic acid,
      Aib = alpha-aminoisobutyric acid, Dpg = alpha,alpha-di-n-propyl glycine, Deg =
      alpha,alpha-di-n-ethyl glycine) have been investigated. In crystals, helical
      conformations have been demonstrated by x-ray crystallography for the peptides, R
      Val-Ala-Leu-Dpg-Val-Ala-Leu-OMe, (R = Boc and acetyl). Solution conformations of
      the five peptides have been studied by 1H-nmr. In the apolar solvent CDCl3, all
      five peptides favor helical conformations in which the NH groups of residues 3-7
      are shielded from the solvent. Successive NiH<-->Ni + 1H nuclear Overhauser
      effects over the length of the sequence support a major population of continuous
      helical conformations. Solvent titration experiments in mixtures of CDCl3/DMSO
      provide evidence for solvent-dependent conformational transitions that are more
      pronounced for the Deg and Dpg peptides. Solvent-dependent chemical shift
      variations and temperature coefficients in DMSO suggest that the conformational
      distributions in the Deg/Dpg peptides are distinctly different from the Aib/Acnc
      peptides in a strongly solvating medium. Nuclear Overhauser effects provide
      additional evidence for the population of extended backbone conformations in the
      Dpg peptide, while a significant residual population of helical conformations is
      still detectable in the isomeric Ac7c peptide in DMSO.

PMID- 10644954
TI  - Conformational analysis and stability of collagen peptides by CD and by 1H- and
      13C-NMR spectroscopies.
AB  - Four small type I collagen CNBr peptides containing complete natural sequences
      were purified from bovine skin and investigated by CD and 1H- and 13C-nmr
      spectroscopies to obtain information concerning their conformation and thermal
      stability. CD showed that a triple helix was formed at 10 degrees C in acidic
      aqueous solution by peptide alpha l(I) CB2 only, and to lesser extent, by alpha
      1(I) CB4, whereas peptides alpha 1(I) CB5 and alpha 2(I) CB2 remained
      unstructured. Analytical gel filtration confirmed that peptides alpha 1(I) CB2
      and alpha 1(I) CB4 only were able to form trimeric species at temperature between
      14 and 20 degrees C, and indicated that the monomer = trimer equilibrium was
      influenced by the chaotropic nature of the salt present in the eluent, by its
      concentration, and by temperature variations. CD measurements at increasing
      temperatures showed that alpha 1(I) CB2 was less stable than its synthetic
      counterpart due to incomplete prolyl hydroxylation of the preparation from the
      natural source. 1H- and 13C-nmr spectra acquired in the temperature range 0-47
      and 0-27 degrees C, respectively, indicated that with decreasing temperature the
      most abundant from of alpha 1(I) CB2 was in slow exchange with an assembled form,
      characterized by broad lines, as expected for the triple-helical conformation. A
      large number of trimer cross peaks was observed both in the proton and carbon
      spectra, and these were most likely due to the nonequivalence of the environments
      of the three chains in the triple helix. This nonequivalence may have
      implications for the aggregation of collagen molecules and for collagen binding
      to other molecules. The thermal transition from trimer to monomer was also
      monitored by 1H-nmr following the change in area of the signal belonging to one
      of the two beta protons of the C-terminal homoserine. The unfolding process was
      found to be fully reversible with a melting temperature of 13.4 degrees C, in
      agreement with CD results. The qualitative superposition of the melting curves
      obtained by CD for the peptide bond characteristics and by nmr for a side chain
      suggests that triple-helical backbone and side chains constitute a single unit.

PMID- 10644956
TI  - Crystal polymer interaction with new injectable bone substitute; SEM and Hr TEM
      study.
AB  - A composite constituted of calcium phosphate (CaP) granules and a hydrophilic
      polymer as a carrier (hydroxy-propyl-methyl cellulose, HPMC) was developed to be
      an injectable bone substitute (IBS, CNRS patent). IBS is a composite and not an
      ionic cement. The composite obtained is ready to use and sterile. Chemical
      interactions between organic and inorganic components appeared during the
      association of the two. The interactions of the CaP and the polymer have been
      studied using scanning electron microscopy (SEM), electron microprobe (EDX), and
      high-resolution transmission electron microscopy (HrTEM) SEM revealed a
      degradation of the granules into smaller particles while EDX was unable to show
      significant changes in the Ca/P ratio during aging of the composite. With Hr TEM,
      however, we observed hydrolysis (process of dissolution and precipitation) from
      the surface to about 13 nm into the HA crystals and occasional dissolution with
      precipitation of beta-TCP crystals. In HA, the first zone of interaction
      consisted of a single layer of small globular crystals of 2 to 3 nm in diameter.
      Numerous lattice patterns in all three axes could be observed. Under the globular
      crystals zone, the inter-reticular distances of the single crystals appeared
      enlarged by 1.2% (from 0.817 to 0.827 nm). The enlargement seems to correspond to
      diffusion of HPO(4) into the crystal lattice. In beta-TCP crystals, dissolution
      was observed to be several nanometers deep, but globular surface precipitation
      rarely was observed. With time or after steam sterilization, no changes were
      observed. These data demonstrate the strong interactions of the hydrophylic
      polymer with calcium phosphate, but only in the first several nanometers of
      thickness.

PMID- 10644957
TI  - Press-formable CaO-MgO-SiO(2)-TiO(2)-Ag(2)O glass as a biomaterial.
AB  - Glass-ceramics were investigated to obtain a glass with a composition of CaO.
      MgO. 2SiO(2). 0.375TiO(2). 0.007Ag(2)O. The glass melted at 1500 degrees C and
      could be cast. Crystallization of diopside of this glass is controlled by volume
      nucleation and growth processes. In a crystallization treatment at 850 degrees 
      870 degrees C, this glass presented a milky white, semitransparent color. The
      crystals formed were diopside, their crystal grain diameter was 1-2 micrometer,
      and crystallization was 15-25%. The bending strength of the glass produced by a
      crystallization treatment of 25 min at 850 degrees C was 400 MPa, which is
      suitable for artificial bones. This crystallized glass also was extremely stable,
      with no weight loss after stability testing in artificial saliva. The softening
      point, as determined from the viscosity curve, was 830 degrees C, and the
      crystallization temperature was 895 degrees C. Thus this glass can be press
      formed at a temperature of 830 degrees -880 degrees C. Actual press-forming at a
      pressure of 0.64 MPa was carried out for 40 min at 850 degrees C and resulted in
      the formation of desired shapes. Given its ready formation into desired shapes
      and its great strength after crystallization, such glass is applicable for use as
      artificial bones and as dental roots and crowns.

PMID- 10644958
TI  - Apatite formation on organic monolayers in simulated body environment.
AB  - Organic monolayer films with the same functional groups as collagen were prepared
      by a Langmuir-Blodgett (LB) method and the LB monolayers were soaked in a
      simulated body fluid. Nucleation of hydroxyapatite (HA) took place on the
      monolayers of the carboxyl group, while no nucleation occurred on the monolayers
      of amino groups. From IR spectra analyses it was found that an interfacial
      interaction between carboxyl groups and Ca ions was important for the HA
      nucleation, causing the formation of HA crystals from the simulated body
      environment.

PMID- 10644959
TI  - Sister chromatid exchanges and ion release in patients wearing fracture fixation
      devices.
AB  - The quantification of sister chromatid exchange (SCE) during mitosis is a useful
      index for evaluating genotoxic effects in subjects occupationally or incidentally
      exposed to potentially toxic substances. The authors investigated the hypothesis
      that ions released by corrosion from prosthetic components of fracture fixation
      devices are associated with change in SCE incidence. In the present study, ten
      patients with implants were examined, and fifteen subjects with no implants were
      used as controls. SCE and high frequency cell (HFC) numbers were evaluated in
      circulating lymphocytes. In addition, nickel (Ni) and chromium (Cr) ion values in
      the serum were measured because, after iron, these metals are major components of
      stainless steel. A significant increase in SCE numbers was observed in patients
      compared to the control population (4.9 +/- 1.3 vs. 3.5 +/- 1.4). Ni
      concentration was 1.71 +/- 1.49 ng/mL in patients and 0.72 +/- 0.52 ng/mL in
      control subjects; Cr concentration was, respectively, 1.01 +/- 0.77 ng/mL and
      0.19 +/- 0. 27 ng/mL. The increase of serum Cr and Ni was statistically
      significant. No correlation was found between the increased Cr concentrations and
      SCE number while Cr ion levels were found to be significantly correlated to HFC.
      An inverse correlation between Ni level and SCE numbers was observed. Our
      findings suggest that Cr release by stainless steel implants could have a
      genotoxic effect; thus it would be useful to carefully monitor implanted subjects
      with regard to serum ion dosage, SCE analysis, and HFC evaluation. In any case,
      it would be appropriate to remove the implant when fracture fixation is reached.

PMID- 10644960
TI  - Production of porous hydroxyapatite by the gel-casting of foams and cytotoxic
      evaluation.
AB  - This study presents the manufacture of highly porous hydroxyapatite by a novel
      technique that employs the foaming of suspensions prior to the in situ
      polymerization of organic monomers contained in the compositions. This method
      produces strong gelled bodies with up to 90% porosity that can withstand
      machining in the green state. Complex-shaped components can be obtained if the
      process comprises casting in one of the processing steps. The organic additives
      are eliminated at temperatures above 300 degrees C, and sintering is carried out
      for consolidation of the ceramic matrix. Spherical interconnected cells with
      sizes ranging from 20 to 1000 micrometer characterize the porous structure,
      depending on the specimen density. Cytotoxicity tests were conducted on extracts
      from sintered HA foams based on a quantitative method of cell colony formation
      and the determination of cell death after indirect contact of the porous material
      with mammalian cells. This in vitro test of biological evaluation revealed that
      the original purity of the biomedical-grade hydroxyapatite powder was affected
      neither through processing nor by the employed reagents.

PMID- 10644961
TI  - Bioactive tantalum metal prepared by NaOH treatment.
AB  - Untreated tantalum metal formed an apatite on its surface in simulated body fluid
      (SBF) with ion concentrations nearly equal to those of human blood plasma.
      However, it took an induction period as long as 4 weeks for apatite formation.
      The tantalum metal formed the apatite within 1 week when it was previously soaked
      in a 0.2 or 0.5M NaOH aqueous solution at 60 degrees C for 24 h to form a sodium
      tantalate hydrogel layer on its surface. The decrease in the induction period of
      apatite formation was attributed to the catalytic effect of the Ta-OH groups on
      the surface of the tantalum metal for apatite nucleation and acceleration of the
      apatite nucleation by an increased ionic activity product of the apatite in the
      fluid due to the release of Na(+) ions. The NaOH-treated tantalum metal can form
      apatite in a short period even in the living body and bond to the bone through
      this apatite layer. This indicates that a highly bioactive tantalum metal can be
      obtained by a simple chemical treatment.

PMID- 10644962
TI  - Proinflammatory cytokine expression of IL-1beta and TNF-alpha by human osteoblast
      like MG-63 cells upon exposure to silicon nitride in vitro.
AB  - This study was designed to determine the effect of Si(3)N(4) disks and
      particulates on human osteoblast-like MG-63 cells in vitro. The MG-63 (10(5)/mL)
      cells were plated onto 24-well polystyrene plates fitted with either sintered
      reaction-bonded (SRBSN) or reaction-bonded (RBSN) 15-mm disks. Controls consisted
      of wells without Si(3)N(4) disks. Cells propagated at 37 degrees C, 5% CO(2) for
      48 h on Si(3)N(4) disks and control polystyrene surfaces exhibited similar
      proliferative capacities (7000 and 4000 cpm/10(5) cells, respectively, p > 0.05).
      Cells incubated with 1, 10, or 100 microgram/ml of Si(3)N(4) particles (<1.00 to
      5.00 micrometer) for 24 h did not exhibit a decrease in DNA synthetic activity:
      12 +/- 1.3 x 10(4), 10.5 +/- 1.5 x 10(4), and 11.0 +/- 1.7 x 10(4) cpm,
      respectively, compared to 11.6 +/- 2.6 x 10(4) cpm/10(5) for the control cells,
      as indicated by (3)H-thymidine uptake. Cells propagated on RBSN displayed
      increased expression of cytokines IL-1beta and TNF-alpha compared to the control
      cells, as shown by reverse transcriptase-polymerase chain reaction (RT-PCR). In
      contrast, cells propagated on SRBSN surfaces expressed the same level of IL-1beta
      and TNF-alpha as that of control cells. Incubation of MG-63 cells with 1-10
      microgram/mL of particles did not increase IL-1beta expression. However, at 100
      microgram/mL, TNF-alpha expression was greater than that of the control cells.
      Silicon nitride, evaluated here as disks or as particulates (1-10 microgram/mL),
      is biocompatible and does not hinder the proliferation or induce proinflammatory
      cytokine expression of human osteoblast-like MG-63 cells in vitro.

PMID- 10644963
TI  - Growth of continuous bonelike mineral within porous poly(lactide-co-glycolide)
      scaffolds in vitro.
AB  - Strategies to engineer bone have focused on the use of natural or synthetic
      degradable materials as scaffolds for cell transplantation or as substrates to
      guide bone regeneration. The basic requirements of the scaffold material are
      biocompatibility, degradability, mechanical integrity, and osteoconductivity. A
      major design problem is satisfying each of these requirements with a single
      scaffold material. This study addresses this problem by describing an approach to
      combine the biocompatibility and degradability of a polymer scaffold with the
      osteoconductivity and mechanical reinforcement of a bonelike mineral film. We
      report the nucleation and growth of a continuous carbonated apatite mineral on
      the interior pore surfaces of a porous, degradable polymer scaffold via a one
      step, room temperature incubation process. A 3-dimensional, porous scaffold of
      the copolymer 85:15 poly(lactide-co-glycolide) was fabricated by a solvent
      casting, particulate leaching process. Fourier transform IR spectroscopy and
      scanning electron microscopy (SEM) analysis after different incubation times in a
      simulated body fluid (SBF) demonstrate the growth of a continuous bonelike
      apatite layer within the pores of the polymer scaffold. Quantification of
      phosphate on the scaffold displays the growth and development of the mineral film
      over time with an incorporation of 0.43 mg of phosphate (equivalent to 0.76 mg of
      hydroxyapatite) per scaffold after 14 days in SBF. The compressive moduli of
      polymer scaffolds increased fivefold with formation of a mineral film after a 16
      day incubation time as compared to control scaffolds. In summary, this biomimetic
      treatment provides a simple, one step, room temperature method for surface
      functionalization and subsequent mineral nucleation and growth on biodegradable
      polymer scaffolds for tissue engineering.

PMID- 10644964
TI  - Particulate retrieval of hydrolytically degraded poly(lactide-co-glycolide)
      polymers.
AB  - This article describes a technique for the retrieval of polymeric particulate
      debris following advanced hydrolytic in vitro degradation of a biodegradable
      polymer and presents the results of the subsequent particle analysis. Granular
      80/20 poly(L-lactide-co-glycolide) (PLG) was degraded in distilled, deionized
      water in Pyrextrade mark test tubes at 80 degrees C for 6 weeks. Subsequently, a
      density gradient was created by layering isopropanol over the water, followed by
      a 48-h incubation. Two opaque layers formed in the PLG tubes, which were removed
      and filtered through 0.2-micrometer polycarbonate membrane filters. In addition,
      Fourier transform IR spectroscopy (FTIR) was performed to confirm the presence of
      polymer in the removed layers. The filters were gold sputter coated, and scanning
      electron microscopy (SEM) images were made. FTIR analysis confirmed that the
      removed material was PLG. SEM images of the extracts from the upper (lowest
      density) opaque layer showed a fine, powderlike substance and globular structures
      of 500-750 nm. The SEM images of the lower (highest density) opaque layer showed
      particles with a crystalline-like morphology ranging in size from 4 to 30
      micrometer. Particulate PLG debris generated with the described technique can be
      useful for further studies of its biological role in complications associated
      with poly(alpha-hydroxy)ester implants. This study shows the presence of very
      persistent nano- and microparticles in the degradation pathway of PLG.

PMID- 10644965
TI  - Transforming growth factor-beta1 incorporated during setting in calcium phosphate
      cement stimulates bone cell differentiation in vitro.
AB  - Growth stimulation of periimplant tissues by growth factors like transforming
      growth factor-beta1 (TGF-beta1) may increase the indication for and success of
      implant use. Calcium phosphate as a material for implants or for coating of
      implants is known for its good biologic interaction with bone. Therefore, calcium
      phosphate implants combined with TGF-beta1 might improve osseointegration. In
      this study we hypothesise that the addition of recombinant human TGF-beta1 (rhTGF
      beta1) to calcium phosphate cement (CPC) affects the differentiation of bone
      cells growing on the cement layer. rhTGF-beta1 incorporated during setting in a
      CPC layer at 20 ng rhTGF-beta1/60 mg cement was found to be gradually released
      into tissue culturing medium leading to a 20% release after 24 h. Two cell
      populations were obtained from collagenase-treated fragments of adult rat long
      bones: preosteoblastic cells, which were released by the collagenase treatment,
      and osteoblastic cells, which grew from the collagenase-stripped bone fragments.
      Both cell populations were tested for their osteoblastic characteristic phenotype
      by measuring their alkaline phosphatase (ALP) activity after vitamin D treatment
      and cyclic AMP after parathyroid hormone stimulation. After preculture the cells
      were plated on a layer of CPC containing 0 (control), 10, or 20 ng rhTGF-beta1/60
      mg CPC. Bone cell differentiation was analyzed after 10 days by measuring the ALP
      activity, as well as the protein content of the cell layer. Incorporation of
      rhTGF-beta1 in the CPC did not change the ALP activity in osteoblastic cells, but
      a significant (analyzed by multivariate analysis of variance) increase was
      observed in preosteoblastic cells. Incorporation of 10 ng of rhTGF-beta1 in 60 mg
      of CPC increased the ALP activity in preosteoblastic cells by threefold and 20 ng
      rhTGF-beta1/60 mg CPC increased it by fivefold. The total protein content was not
      affected by rhTGF-beta1 in either of the cell populations. We conclude that rhTGF
      beta1 incorporated during setting in CPC stimulates the differentiation of
      preosteoblastic cells in vitro. These results provide a basis for further studies
      on the use of this combination as an implant material in vivo.

PMID- 10644966
TI  - Ligand accessibility as means to control cell response to bioactive bilayer
      membranes.
AB  - We report a new method to create a biofunctional surface in which the
      accessibility of a ligand is used as a means to influence the cell behavior.
      Supported bioactive bilayer membranes were created by Langmuir-Blodgett (LB)
      deposition of either a pure poly(ethylene glycol) (PEG) lipid, having PEG head
      groups of various lengths, or 50 mol % binary mixtures of a PEG lipid and a novel
      collagen-like peptide amphiphile on a hydrophobic surface. The peptide amphiphile
      contains a peptide synthetically lipidated by covalent linkage to hydrophobic
      dialkyl tails. The amphiphile head group lengths were determined using neutron
      reflectivity. Cell adhesion and spreading assays showed that the cell response to
      the membranes depends on the length difference between head groups of the
      membrane components. Cells adhere and spread on mixtures of the peptide
      amphiphile with the PEG lipids having PEG chains of 120 and 750 molecular weight
      (MW). In contrast, cells adhered but did not spread on the mixture containing the
      2000 MW PEG. Cells did not adhere to any of the pure PEG lipid membranes or to
      the mixture containing the 5000 MW PEG. Selective masking of a ligand on a
      surface is one method of controlling the surface bioactivity.

PMID- 10644967
TI  - Rapid cell sheet detachment from poly(N-isopropylacrylamide)-grafted porous cell
      culture membranes.
AB  - Fabrication of functional tissue constructs using sandwiched layers of cultured
      cells could prove to be an attractive approach to tissue engineering. Rapid
      detachment of cultured cell sheets is a very important recovery method that
      permits facile manipulation of the sheet and prevents functional damage. To
      accelerate the required culture substrate hydrophilic and hydrophobic structural
      changes in response to culture temperature alteration, poly(N
      isopropylacrylamide) (PIPAAm) was grafted onto porous culture membranes by
      electron beam irradiation. Analyses by attenuated total reflection-Fourier
      transform IR and electron spectroscopy for chemical analysis revealed that PIPAAm
      was successfully grafted to surfaces of porous membranes. Atomic force microscopy
      (AFM) results showed that PIPAAm-grafted membranes had smoother surfaces than
      ungrafted controls while retaining their porous structure. The mean roughness of
      PIPAAm-grafted and -ungrafted porous membrane surfaces determined by digital AFM
      autocalculation was 4.40 +/- 0.4 and 5.9 +/- 0.4 nm, respectively. Tissue culture
      polystyrene (TCPS) dishes grafted with PIPAAm were compared with PIPAAm-grafted
      porous membranes in cell sheet detachment experiments. Approximately 75 min was
      required to completely detach cell sheets from PIPAAm-grafted TCPS surfaces
      compared to only 30 min to detach cell sheets from PIPAAm-grafted porous
      membranes. With porous membranes, the water accesses the PIPAAm-grafted surface
      from underneath and peripheral to the attached cell sheet, resulting in rapid
      hydration of grafted PIPAAm molecules and detachment of the cell sheet. With TCPS
      PIPAAm-grafted surfaces the water is supplied from only the periphery of a cell
      sheet, slowing detachment.

PMID- 10644968
TI  - Quantification of the surface density of a fluorescent label with the optical
      microscope.
AB  - Fluorescence microscopy can offer unique advantages for biomaterials
      characterization. Like spectroscopy or radioactivity, it can be used to quantify
      specific binding to surfaces, but it can also assess surface homogeneity at the
      micron scale or detect protein aggregation. To fully utilize the potential of
      this technique, there must be a way to calibrate the microscope in terms of the
      moles of a fluorophore per unit area. The method we propose involves the
      following steps: fluorescent labeling of erythrocytes and quantification of the
      label by flow cytometry; flattening of fluorescent erythrocytes for microscopic
      observation; imaging and digital analysis to relate the gray level intensities to
      the fluorophore density; and using this procedure to characterize a different,
      more easily obtainable, standard. The latter can be a 50% solution of Na
      fluorescein that yields a highly reproducible and uniform fluorescence.
      Concentrated fluorescein solution can also be used to correct images for the
      spatial nonuniformity of illumination and detection (shading correction). By
      applying this method to study the binding of IgG and fibrinogen to glass or
      amidated glass, we showed that protein adsorption to glass may result in protein
      aggregation that may affect the biological activity of the adsorbed protein.

PMID- 10644969
TI  - Mono- and dibasic proteolytic cleavage sites in insect neuroendocrine peptide
      precursors.
AB  - Regulatory peptides are synthesized as part of larger precursors that are
      subsequently processed into the active substances. After cleavage of the signal
      peptide, further proteolytic processing occurs predominantly at basic amino acid
      residues. Rules have been proposed in order to predict which putative proteolytic
      processing sites are actually used, but these rules have been established for
      vertebrate peptide precursors and it is unclear whether they are also valid for
      insects. The aim of this paper is to establish the validity of these rules to
      predict proteolytic cleavage sites at basic amino acids in insect neuropeptide
      precursors. Rules describing the cleavage of mono- and dibasic potential
      processing sites in insect neuropeptide precursors are summarized below. Lys-Arg
      pairs not followed by an aliphatic or basic amino acid residue are virtually
      always cleaved in insect regulatory peptide precursors, but cleavages of Lys-Arg
      pairs followed by either an aliphatic or a basic amino acid residue are
      ambiguous, as is processing at Arg-Arg pairs. Processing at Arg-Lys pairs has so
      far not been demonstrated in insects and processing at Lys-Lys pairs appears very
      rare. Processing at single Arg residues occurs only when there is a basic amino
      acid residue in position -4, -6, or -8, usually an Arg, but Lys or His residues
      work also. Although the current number of such sites is too limited to draw
      definitive conclusions, it seems plausible that cleavage at these sites is
      inhibited by the presence of aliphatic residues in the +1 position. However,
      cleavage at single Arg residues is ambiguous. When several potential cleavage
      sites overlap the one most easily cleaved appears to be processed. It cannot be
      excluded that some of the rules formulated here will prove less than universal,
      as only a limited number of cleavage sites have so far been identified. It is
      likely that, as in vertebrates, ambiguous processing sites exist to allow
      differential cleavage of the same precursor by different convertases and it seems
      possible that the precursors of allatostatins and PBAN are differentially cleaved
      in different cell types. Arch. Insect Biochem. Physiol. 43:49-63, 2000.

PMID- 10644970
TI  - Insect immunity: a genetic factor (hrtp) is essential for antibacterial peptide
      expression in Drosophila after infection by parasitoid wasps.
AB  - We have used a parasitoid wasp Drosophila melanogaster system to investigate the
      relationship between the humoral and cellular immune responses in insects.
      Expression of the gene encoding diptericin, an antibacterial peptide in various
      D. melanogaster strains parasitized by several species of parasitoid wasps, was
      studied by Northern blot. These strains have the capacity to encapsulate
      parasitoid eggs. Two strains appeared to produce diptericin mRNA after parasitoid
      challenge, regardless of their cellular immune reaction to the wasp species. This
      suggests that a specific genetic factor, or factors, here designated humoral
      response to parasitoid (hrtp), is present in these two strains of D. melanogaster
      and is implicated in the expression of the antibacterial gene after parasite
      infection. This hrtp genetic factor is recessively expressed and located on the
      second chromosome, suggesting that it is monofactorial. The transgenic strain
      Dipt.2.2-lacZ:1, in which the transgene is present on the first chromosome, is
      normally susceptible to the parasitoid wasp. The chromosome bearing the hrtp
      factor was transferred to this transgenic strain, which then became reactive when
      triggered by wasp infection. The hrtp factor appears necessary for the activation
      of diptericin by the parasitoid wasp. No correlation between the cellular immune
      capacity and the humoral response was observed, suggesting that the two
      components of insect immunity are regulated independently. Arch.

PMID- 10644971
TI  - Adenosine modulates the (Na(+)+K(+))ATPase activity in malpighian tubules
      isolated from Rhodnius prolixus.
AB  - The role of adenosine on regulation of the (Na(+)+K(+))ATPase activity present in
      the Malpighian tubules isolated from Rhodnius prolixus was investigated.
      Adenosine decreases the (Na(+)+K(+)) ATPase specific activity by 88%, in a dose
      dependent manner, with maximal effect at a concentration of 10(-9) M. This effect
      was mimicked by N(6)-cyclohexyladenosine (CHA) at 10(-8) M, an agonist for A(1)
      adenosine receptor, and was reversed by 10(-9) M 8-cyclopentyl-1,3
      dipropylxanthine (DPCPX), an antagonist for A(1) adenosine receptor. On the other
      hand, 5'-N-ethyl-carboxamide adenosine (NECA), an agonist for A(2) adenosine
      receptor, used in the range of 10(-9)-10(-5) M, did not change the
      (Na(+)+K(+))ATPase specific activity. In the same way, 10(-8) M 3, 7-dimethyl-1
      propargylxanthine (DMPX), an antagonist for A(2) adenosine receptor, did not
      modify the inhibitory effect of adenosine. These data suggest that the inhibitory
      effect of adenosine on the (Na(+)+K(+))ATPase specific activity present in
      Malpighian tubules from Rhodnius prolixus is mediated by A(1) adenosine receptor
      activation. Arch.

PMID- 10644972
TI  - Allatotropic activity in the suboesophageal ganglia and corpora cardiaca of the
      adult male loreyi leafworm, Mythimna loreyi.
AB  - Allatotropic activity was found in the methanolic extract of the suboesophageal
      ganglia (SOG) and the corpora cardiaca (CC) of the Mythimna loreyi virgin males.
      No allatotropic activity was observed in the extract of brain or corpora allata
      (CA). Although CA can be activated by the SOG and CC extract, respectively, CC
      extract inhibited the response to the SOG extract. A significant in vitro
      allatotropic effect was exerted by the SOG and CC extract within 10 and 15 min,
      respectively, and this effect can be sustained for several hours even after
      transferring to fresh medium without extracts. The time course pattern of the CA
      activation ratio in both the SOG and CC extract-treated group is very similar to,
      but with significantly higher level than, that in the control group, suggesting
      the existence of an intrinsic pacemaker or an in vitro effect that controls the
      fluctuation of the CA biosynthetic activity. Synthetic Manduca sexta allatotropin
      had no significant effect on the M. loreyi CA. The results of treatment with the
      adenylate cyclase activator forskolin, the phosphodiesterase inhibitor IBMX, and
      the cAMP analogue dibutyryl-cAMP did not indicate that cAMP might be involved in
      the allatotropic control of CA. Arch.

PMID- 10644973
TI  - Evidence for expression of EcR and USP components of the 20-hydroxyecdysone
      receptor by a mosquito cell line.
AB  - The reverse transcriptase polymerase chain reaction (RT-PCR) was used to examine
      whether the C7-10 cell line from the mosquito, Aedes albopictus, expresses
      transcripts encoding 20-hydroxyecdysone receptor (EcR) and ultraspiracle (USP)
      isoforms known to constitute a functional 20-hydroxyecdysone receptor. Here we
      describe recovery and analysis of products with high similarity to the EcR and to
      the USP isoform "a" that have been reported from the related mosquito, Aedes
      aegypti. The C7-10 EcR was 97% identical to Aedes aegypti EcR in amino acid
      sequence. Key features of the nuclear/steroid hormone receptor superfamily,
      including the zinc fingers, proximal (P)-box, and distal (D)-box were well
      conserved. However, the C7-10 EcR contained 5 additional amino acids in the C
      terminal domain F, which required introduction of gaps to maximize alignment. The
      5'-untranslated regions of the two mosquito EcRs were 98% identical, but the
      function of this region remains unknown. The C7-10 USP was 95% identical in amino
      acid sequence to the longer Aedes aegypti isoform "a." Although only the C7-10
      EcR was detected on Northern blots using total RNA from the cell line,
      transcripts for both EcR and USP were detected using the RT-PCR procedure. These
      transcripts appeared to be expressed constitutively and expression levels were
      not affected by treatment of cells with 20-hydroxyecdysone. Arch.

PMID- 10644974
TI  - A mutant oncolytic adenovirus targeting the Rb pathway produces anti-glioma
      effect in vivo.
AB  - Effective anti cancer strategies necessitate the use of agents that target tumor
      cells rather than normal tissues. In this study, we constructed a tumor-selective
      adenovirus, Delta24, that carries a 24-bp deletion in the E1A region responsible
      for binding Rb protein. Immunoprecipitation analyses verified that this deletion
      rendered Delta24 unable to bind the Rb protein. However, titration experiments in
      293 cells demonstrated that the Delta24 adenovirus could replicate in and lyse
      cancer cells with great efficiency. Lysis of most human glioma cells was observed
      within 10 - 14 days after infection with Delta24 at 10 PFU/cell. In vivo, a
      single dose of the Delta24 virus induced a 66.3% inhibition (P<0.005) and
      multiple injections, an 83.8% inhibition (P<0.01) of tumor growth in nude mice.
      However, normal fibroblasts or cancer cells with restored Rb activity were
      resistant to the Delta24 adenovirus. These results suggest that the E1A-mutant
      Delta24 adenovirus may be clinically and therapeutically useful against gliomas
      and possibly other cancers with disrupted Rb pathway.

PMID- 10644975
TI  - Loss of Rho function in the thymus is accompanied by the development of thymic
      lymphoma.
AB  - In vitro studies in model cell lines have implicated the GTPase Rho in the
      control of diverse cellular responses including the control of the actin
      cytoskeleton and the regulation of cell cycle progression. It is also reported
      that the transformation of fibroblasts via oncogenic Ras requires intact Rho
      signalling. An invaluable tool used to investigate Rho function is the bacterial
      toxin C3 transferase derived from Clostridium botulinum. C3 transferase
      ribosylates Rho in its effector domain thereby abolishing interaction with
      downstream effectors. We have previously reported the use of C3 transferase under
      the control of the thymocyte specific lck promoter to explore the role of Rho in
      T cell biology. Strikingly, lck-C3 mice develop aggressive malignant thymic
      lymphoblastic lymphomas between 4 and 8 months of age. These studies reveal that
      loss of Rho function is associated with prediposition to lymphoid cell
      transformation. Inhibition of Rho function has been suggested as a therapeutic
      strategy for treatment of Ras-transformed tumours. The development of lymphomas
      in mice devoid of functional Rho in their T cell compartment shows that such a
      strategy would need to be used with caution.

PMID- 10644976
TI  - A unique, short sequence determines p53 gene basal and UV-inducible expression in
      normal human cells.
AB  - The p53 tumor suppressor protein plays a central role in the cellular defence
      against agents which cause genetic damage. The induction and activation of p53
      upon stress has been shown at post-transcription level by multiple mechanisms,
      while the regulatory role of p53 gene transcription is still poorly understood.
      Here we show that the causative mechanisms underlying this activation are
      attributed in part to the promoter function of p53. In various normal human
      cells, p53 gene expression is induced transcriptionally by ultraviolet (UV) but
      not X-ray irradiation. We determined that, by p53 promoter dissection, the 21 bp
      element (PE21) responsible for this UV activation resides adjacent to, and
      upstream to the putative NFkappaB binding site. Moreover, the PE21 sequence was
      found to be a primary determinant for human p53 gene basal expression carrying bi
      directional transcriptional initiation activity, which controls the initiation of
      RNA synthesis about 50 bases downstream, indicating that the sequence plays a
      critical role in both basal and inducible transcription. Finally, we detected the
      putative PE21 binding factor(s) in nuclear extracts from non-irradiated and
      irradiated cells. Since the PE21 sequence does not show any homologies to the
      conventional TATA or GC box, or to an 'initiatior', all of which determine the
      initiation site for transcription, the PE21 sequence appears to be a new class in
      eukaryotic promoter elements. Our results indicate that the mechanism of PE21
      directed p53 mRNA transcription has an important role in the cellular stress
      response as well as tumor suppression.

PMID- 10644977
TI  - Heritable lympho-epithelial thymoma resulting from a transgene insertional
      mutation.
AB  - Thymoma is the most common tumor of the anterior-superior mediastinum. We have
      identified a line of transgenic mice which spontaneously and heritably develop
      thymomas at a very high penetrance. The available data suggest that thymoma
      formation in these mice results as a consequence of transgene insertional
      mutagenesis. Immune histologic analyses indicate that the thymomas are of
      epithelial cell origin. Survival studies indicate that tumor progression is more
      aggressive in females as compared to males (73.9 vs 41.7% mortality at 20 weeks
      of age, respectively). Fluorescent in situ hybridizations have localized the
      transgene integration site to the F2-G region of mouse chromosome 2.
      Translocation encompassing the syntenic region in humans has been implicated in
      lympho-epithelial thymoma. These animals may constitute a useful resource for the
      identification of gene(s) which participate in thymoma progression, as well as a
      model system for screening anti-thymoma therapeutic agents.

PMID- 10644978
TI  - PSM, a mediator of PDGF-BB-, IGF-I-, and insulin-stimulated mitogenesis.
AB  - PSM/SH2-B has been described as a cellular partner of the FcepsilonRI receptor,
      insulin receptor (IR), insulin-like growth factor-I (IGF-I) receptor (IGF-IR),
      and nerve growth factor receptor (TrkA). A function has been proposed in neuronal
      differentiation and development but its role in other signaling pathways is still
      unclear. To further elucidate the physiologic role of PSM we have identified
      additional mitogenic receptor tyrosine kinases as putative PSM partners including
      platelet-derived growth factor (PDGF) receptor (PDGFR) beta, hepatocyte growth
      factor receptor (Met), and fibroblast growth factor receptor. We have mapped Y740
      as a site of PDGFR beta that is involved in the association with PSM. We have
      further investigated the putative role of PSM in mitogenesis with three
      independent experimental strategies and found that all consistently suggested a
      role as a positive, stimulatory signaling adapter in normal NIH3T3 and baby
      hamster kidney fibroblasts. (1) PSM expression from cDNA using an ecdysone
      regulated transient expression system stimulated PDGF-BB-, IGF-I-, and insulin-
      but not EGF-induced DNA synthesis in an ecdysone dose-responsive fashion; (2)
      Microinjection of the (dominant negative) PSM SH2 domain interfered with PDGF-BB-
      and insulin-induced DNA synthesis; and (3) A peptide mimetic of the PSM Pro-rich
      putative SH3 domain-binding region interfered with PDGF-BB-, IGF-I-, and insulin-
      but not with EGF-induced DNA synthesis in NIH3T3 fibroblasts. This experiment was
      based on cell-permeable fusion peptides with the Drosophila antennapedia
      homeodomain which effectively traverse the plasma membrane of cultured cells.
      These experimental strategies independently suggest that PSM functions as a
      positive, stimulatory, mitogenic signaling mediator in PDGF-BB, IGF-I, and
      insulin but not in EGF action. This function appears to involve the PSM SH2
      domain as well as the Pro-rich putative SH3 domain binding region. Our findings
      support the model that PSM participates as an adapter in various mitogenic
      signaling mechanisms by linking an activated (receptor) phospho-tyrosine to the
      SH3 domain of an unknown cellular partner.

PMID- 10644979
TI  - p27Kip1 accumulation is associated with retinoic-induced neuroblastoma
      differentiation: evidence of a decreased proteasome-dependent degradation.
AB  - Development of human neuroblastoma is due to an arrest in the differentiation
      program of neural crest sympathoadrenal progenitor cells. However,
      neuroblastomas, as well as their derived cell lines, maintain the potentiality of
      terminal differentiation. We investigated the molecular mechanisms by which
      retinoic acid, a molecule introduced in clinical trials for chemotherapy, induces
      differentiation in neuroblastoma cell lines. Our findings demonstrate that the
      retinoic acid-dependent growth arrest of LAN-5 neuroblastoma cell line is
      associated to a very large accumulation (>tenfold) of p27Kip1 protein, a cyclin
      dependent kinase inhibitor; the protein binds and inhibits cyclin-dependent
      kinase 2, 4 and 6 activities, thus hampering pRb and p107 phosphorylation.
      p27Kip1 build-up was observable as an early phenomenon (12 - 24 h) after retinoic
      exposure and resulted in a time-dependent accumulation of high quantities of a
      free p27Kip1 form. Furthermore, retinoic treatment causes an increase of cyclin
      dependent kinase 5 level and activity; however, immunoprecipitation studies
      proved the absence of interaction with p27kip1. No noticeable variation of other
      components of G1 phase cell cycle engine was observed. Pulse-chase experiments
      showed a remarkable elongation of p27Kip1 half-life in retinoic-treated LAN-5,
      while no enhancement of p27Kip1 gene expression and of the translational
      efficiency of its messenger RNA were demonstrated. In vivo degradation of p27Kip1
      was sensitive to two highly specific proteasome inhibitors, LLnL and lactacystin,
      while the calpain inhibitor II ALLM and the cysteine protease inhibitor E64 did
      not modify the level of the protein. LLnL treatment caused a very rapid (2 h)
      build-up of the Cdk inhibitor content and the accumulation of higher molecular
      weight anti-p27Kip1 immunoreactive bands, which probably represent ubiquitinated
      forms of the protein. Finally, in vitro experiments demonstrated that extracts
      prepared from retinoic-treated LAN-5 cells degraded recombinant p27Kip1 at a rate
      remarkably slower than the untreated cells. Our results indicate that retinoic
      acid strongly increases p27Kip1 levels by down-regulating the ubiquitin
      proteasome p27Kip1 degrading pathway.

PMID- 10644980
TI  - Induction of p21Waf1/Cip1 by TNFalpha requires NF-kappaB activity and antagonizes
      apoptosis in Ewing tumor cells.
AB  - The Ewing family of tumors is characterized by recurrent reciprocal
      translocations that generate chimeric proteins, either EWS - FLI-1 or EWS - ERG.
      These proteins are potent transcriptional activators and are responsible for
      maintaining the oncogenic properties of tumor cells. Since apoptosis appears to
      be the main mechanism whereby chemotherapy and radiation kill tumor cells,
      identification of events that can antagonize apoptosis in Ewing tumors is
      essential for improving their response to conventional therapies. Here, we report
      that the transcriptional factor NF-kappaB is a survival factor for Ewing tumor
      derived cells. In fact, inhibition of NF-kappaB activation as a consequence of
      the overexpression of a degradation-resistant form of IkappaBalpha, IkappaBalpha
      (A32/36), sensitized these cells to TNFalpha-induced killing. Although treatment
      with TNFalpha did not modify the cellular expression of Bcl-2, c-IAP1, c-IAP2,
      p53 and EWS - FLI-1 proteins, it increased p21Waf1/Cip1 levels. This induction
      required NF-kappaB activation since it was not observed in the IkappaBalpha
      (A32/36) expressing cells. Moreover, overexpression of p21Waf1/Cip1 in these
      IkappaBalpha (A32/36)-expressing cells, in which NF-kappaB and consequently
      p21Waf1/Cip1 are no longer inducible by TNFalpha, decreased their susceptibility
      to TNFalpha-induced killing. Our results therefore identify p21Waf1/Cip1 as a
      mediator of the antiapoptotic effect of TNFalpha-induced NF-kappaB in Ewing tumor
      cells.

PMID- 10644981
TI  - Nuclear localization and transactivating capacities of the papillary renal cell
      carcinoma-associated TFE3 and PRCC (fusion) proteins.
AB  - The papillary renal cell carcinoma-associated t(X;1)(p11;q21) leads to fusion of
      the transcription factor TFE3 gene on the X-chromosome to a novel gene, PRCC, on
      chromosome 1. As a result, two putative fusion proteins are formed: PRCCTFE3,
      which contains all known domains for DNA binding, dimerization, and
      transactivation of the TFE3 protein, and the reciprocal product TFE3PRCC. Upon
      transfection into COS cells, both wild type and fusion proteins were found to be
      located in the nucleus. When comparing the transactivating capacities of these
      (fusion) proteins, significant differences were noted. PRCCTFE3 acted as a
      threefold better transactivator than wild type TFE3 both in a TFE3-specific and
      in a general (Zebra) reporter assay. In addition, PRCC and the two fusion
      proteins were found to be potent transactivators in the Zebra reporter assay. We
      propose that, as a result of the (X;1) translocation, fusion of the N-terminal
      PRCC sequences to TFE3 alters the transactivation capacity of the transcription
      factor thus leading to aberrant gene regulation and, ultimately, tumor formation.

PMID- 10644982
TI  - Roles for the protein tyrosine phosphatase SHP-2 in cytoskeletal organization,
      cell adhesion and cell migration revealed by overexpression of a dominant
      negative mutant.
AB  - SHP-2, a SRC homology 2 domain-containing protein tyrosine phosphatase, mediates
      activation of Ras and mitogen-activated protein kinase by various mitogens and
      cell adhesion. Inhibition of endogenous SHP-2 by overexpression of a
      catalytically inactive (dominant negative) mutant in Chinese hamster ovary cells
      or Rat-1 fibroblasts has now been shown to induce a marked change in cell
      morphology (from elongated to less polarized) that is accompanied by substantial
      increases in the numbers of actin stress fibers and focal adhesion contacts.
      Overexpression of the SHP-2 mutant also increased the strength of cell-substratum
      adhesion and resulted in hyperphosphorylation of SHPS-1, a substrate of SHP-2
      that contributes to cell adhesion-induced signaling. Inhibition of SHP-2 also
      markedly increased the rate of cell attachment to and cell spreading on
      extracellular matrix proteins such as fibronectin and vitronectin, effects that
      were accompanied by enhancement of adhesion-induced tyrosine phosphorylation of
      paxillin and p130Cas. In addition, cell migration mediated by fibronectin or
      vitronectin, but not that induced by insulin, was impaired by overexpression of
      the SHP-2 mutant. These results suggest that SHP-2 plays an important role in the
      control of cell shape by contributing to cytoskeletal organization, and that it
      is an important regulator of integrin-mediated cell adhesion, spreading, and
      migration as well as of tyrosine phosphorylation of focal adhesion contact
      associated proteins.

PMID- 10644983
TI  - Non-activated p53 co-localizes with sites of transcription within both the
      nucleoplasm and the nucleolus.
AB  - The p53 tumour suppressor functions as a sensor of genotoxic stress and, once
      activated, induces cell growth arrest or apoptosis. The precise intranuclear
      localization of latent p53 protein in non-stressed cells is unknown. Such
      information is essential in order to understand how relatively few molecules of
      p53 can detect and respond to DNA damage. Here we present the first detailed
      supramolecular localization of p53 in the nuclei of cells under normal conditions
      of growth. We show that soluble, non-bound p53 is released by permeabilization,
      leaving structurally bound p53 in both the nucleus and nucleolus. In situ
      biochemical studies reveal (i) that nuclear-bound p53 is tethered by RNA
      (directly or indirectly) and (ii) that a sub-population of nuclear-bound p53 co
      localizes with sites of RNA synthesis. Transcriptional co-localization appeared
      to be independent of p53 conformation but dependent upon its quaternary
      structure. In the nucleolus p53 was observed at sites of rRNA synthesis and also
      adjacent to such sites. In contrast, nucleolar hdm-2 (shown by others to complex
      p53 and 5S RNA) was excluded from sites of rRNA synthesis. Our discovery that p53
      is physically linked with sites of transcription may explain how relatively few
      p53 protein molecules can monitor genetic stress and respond preferentially to
      damage of actively transcribed genes.

PMID- 10644984
TI  - Involvement of Shc and Cbl-PI 3-kinase in Lyn-dependent proliferative signaling
      pathways for G-CSF.
AB  - Granulocyte colony-stimulating factor (G-CSF) is the major hematopoietic factor
      which controls the production and differentiation of granulocytes. The G-CSF
      receptor (G-CSFR) belongs to the superfamily of the cytokine receptors, which
      transduce signals via the activation of cytosolic protein tyrosine kinases (PTK).
      To determine the role of specific PTK in G-CSF signaling we expressed the human G
      CSFR in cell lines derived from DT40 B cells, which lack either the Src-related
      Lyn or Syk. Wild-type (wt) and syk-deficient cells underwent increased DNA
      synthesis in response to G-CSF; lyn-deficient cells did not. The purpose of these
      studies is to identify Lyn's downstream effectors in mediating DNA synthesis.
      While G-CSF stimulated Ras activity in all cell lines, G-CSF failed to induce the
      tyrosine phosphorylation of Shc in lyn-deficient cells. G-CSF induced a
      statistically significant activation of Erk1/Erk2 Kinase or p90Rsk only in the wt
      cells. G-CSF induced the tyrosine phosphorylation of Cbl and increased activity
      of PI 3-kinase in wild-type and syk-deficient, but non in lyn-deficient, cells.
      Inhibition of Shc by over-expression of its SH2 or PTB domains or PI 3-kinase by
      either treatment with wortmannin or expression of the CblY731F mutant decreased G
      CSF-induced DNA synthesis. Thus, the Lyn, Cbl-PI 3-kinase, and Shc/non-Ras
      dependent pathways correlate with the ability of cells to respond to G-CSF with
      increased DNA synthesis.

PMID- 10644985
TI  - Indispensable role of the transcription factor PEBP2/CBF in angiogenic activity
      of a murine endothelial cell MSS31.
AB  - Mice lacking the AML1/PEBP2alphaB/CBFa2 gene or PEBP2beta/CBFb gene exhibit a
      defect in definitive hematopoiesis and die in utero because of hemorrhage in the
      central nervous system. Hematopoiesis in the embryo is considered to be tightly
      associated with vascular development. Here we examined whether PEBP2/CBF plays
      any role in angiogenesis besides that in definitive hematopoiesis. We found that
      AML1/PEBP2alphaB/CBFa2, PEBP2alphaA/CBFa1, and PEBP2beta/CBFb were expressed in a
      murine endothelial cell line MSS31. The expression of these molecules as well as
      the DNA binding activity of PEBP2/CBF were augmented by angiogenic growth factors
      such as bFGF and VEGF. Moreover, the expression of PEBP2 alpha/CBFa protein in
      endothelial cells was confirmed at the site of angiogenesis in vivo. To further
      clarify the role of PEBP2/CBF in angiogenesis, we established permanent
      transfectants of PEBP2 beta-MYH11 gene, one that interacts with the runt domain
      of the alpha subunit and deregulates PEBP2/CBF in a dominant interfering manner.
      Proliferation, migration, and tube formation of the PEBP2 beta-MYH11
      transfectants were significantly reduced in comparison with those activities of
      the mock transfectants. These results suggest that transcription factor PEBP2/CBF
      plays an important role in angiogenesis.

PMID- 10644986
TI  - Ras/MEK signaling suppresses Myc-dependent apoptosis in cells transformed by c
      myc and activated ras.
AB  - Cooperation of myc and activated ras has been suggested to cause malignant cell
      transformation but the mechanism is still unknown. Here we isolated a transformed
      cell line in which activation of c-Myc and Ras are independently controllable,
      and show that after establishment of the transformed state by c-myc and activated
      ras, removal of activated Ras initiates apoptosis that is dependent on c-Myc
      activity. Apoptosis is also initiated by an inhibitor of MEK (MAPK/ERK kinase), a
      kinase downstream of Ras, and apoptosis is blocked by activated Mek1. These
      results suggest that one of the conditions required for establishment of the
      transformed state is a block of apoptosis involving MEK activity. We tested the
      effect of MEK inhibition on cells transformed by various oncogenes. Suppression
      of apoptosis by MEK is not critical in general, but in cells transformed by c-myc
      plus a gene that activates the MAPK cascade it is necessary to avoid cell death.
      Activated Ras/MEK did not suppress c-myc-dependent apoptosis due to serum
      limitation. Overexpression of chicken bcl-xL suppressed apoptosis under serum
      limiting conditions, but not apoptosis initiated by Ras/MEK inhibition in cells
      transformed by myc and activated ras. Altogether, these results suggest the
      existence of a novel regulatory mechanism for myc-dependent apoptosis in certain
      transformed cells.

PMID- 10644987
TI  - Transforming growth factor beta2 inhibition of hepatocyte growth factor-induced
      endothelial proliferation and migration.
AB  - Angiogenesis is a highly controlled event which depends on the proper equilibrium
      of activators and inhibitors present within the microenvironment. Hepatocyte
      Growth Factor (HGF) activates migration and proliferation of endothelial cells
      and is angiogenic, acting through the tyrosine kinase receptor encoded by the Met
      protooncogene. To get insights into the molecular mechanisms involved in HGF
      induced angiogenesis, we searched for cDNAs differentially expressed in human
      endothelial cells exposed to HGF, a potent angiogenic factor. We found that HGF
      treated endothelial cells upregulated the expression of Transforming Growth
      Factor (TGF) beta2. To understand the significance of this finding, we cultured
      endothelial cells with HGF and TGF beta2 simultaneously. We found that TGF beta2
      impairs HGF-dependent proliferative and migratory responses. TGF beta2 did not
      prevent the tyrosine phosphorylation of Met, but it inhibited some signalling
      pathways activated by HGF. We show that endothelial proliferation induced by HGF
      required the activation of the MAPK cascade, while HGF-induced endothelial
      migration was dependent on the tyrosine phosphorylation of Src. Indeed, TGF beta2
      inhibited HGF effects because it prevented HGF-induced MAP kinase activation and
      tyrosine phosphorylation of Src. We suggest that the induction of TGF beta2 by
      HGF in endothelial cells may represent a physiologic mechanism to counterbalance
      HGF angiogenic activity.

PMID- 10644988
TI  - Inhibitory interaction of c-Myb and GATA-1 via transcriptional co-activator CBP.
AB  - Gene targeting experiments have revealed that transcription factors such as c-Myb
      and GATA-1 play crucial roles during hematopoietic differentiation. c-Myb is
      necessary in the immature cells of almost every hematopoietic lineage and GATA-1
      is essential for the development of the erythroid lineage. In addition, CREB
      binding protein (CBP) acts as a transcriptional adapter for various transcription
      factors, including c-Myb and GATA-1. In this paper, we show that the
      transcription factors c-Myb and GATA-1 each inhibit the transcriptional activity
      of the other and that any possible bipartite complexes c-Myb, GATA-1, and CBP
      could be formed, but the tripartite complex was hardly formed. The exclusive
      binding of GATA-1 and c-Myb to CBP is probably the molecular basis for the mutual
      inhibition of their transcriptional activity. Our data suggest that cross-talk
      between these three factors might be important for hematopoietic differentiation
      and that CBP functions as a key molecule during the process.

PMID- 10644989
TI  - Acquired alkylating drug resistance of a human ovarian carcinoma cell line is
      unaffected by altered levels of pro- and anti-apoptotic proteins.
AB  - In a systematic study to elucidate the involvement of pro- and anti-apoptotic
      proteins in alkylating drug resistance of tumor cells, we utilized the A2780(100)
      line, that was selected by repeated exposure of A2780 cell line (human ovarian
      carcinoma line) to chlorambucil (CBL). A2780(100) was 5 - 10-fold more resistant
      to nitrogen mustards (IC50 of 50 - 60 microM) and other DNA crosslinking agents,
      e.g., cisplatin, and also to DNA topoisomerase inhibitor etoposide (ETO) than
      A2780. CBL (125 microM) induced extensive apoptosis in A2780 associated with
      mitochondrial damage but not in A2780(100). No significant differences were
      observed between A2780 and A2780(100) cells in the basal levels, or the enhanced
      levels in some cases after CBL treatment, of DNA repair proteins involved in
      repair of alkyl base adducts or in repair of DNA crosslinks or double strand
      break repair. However, the basal levels of anti-apoptotic proteins Bcl-xL and Mcl
      1 were 4 - 8-fold higher in A2780(100) than in A2780 neither of which expressed
      Bcl-2. In contrast, the levels of pro-apoptotic Bax and Bak were 3 - 5-fold
      higher in the CBL-treated A2780 but not in A2780(100). ETO (5 microM) induced
      apoptosis in A2780 without altering the levels of Bax and Bak in these cells. At
      the same time, neither overexpression of Bcl-xL in A2780, nor its antisense
      expression in A2780(100), and nor overexpression of Bax in A2780(100),
      significantly affected drug sensitivity of either line. Our results suggest that
      a change in an early step in DNA damage processing which affects intracellular
      signaling, such as enhanced DNA double-strand break repair, could be the primary
      cause for development of resistance in A2780(100) cells to drugs which induce DNA
      crosslinks or double strand-breaks.

PMID- 10644990
TI  - Over-expression of ERT(ESX/ESE-1/ELF3), an ets-related transcription factor,
      induces endogenous TGF-beta type II receptor expression and restores the TGF-beta
      signaling pathway in Hs578t human breast cancer cells.
AB  - The epithelium-specific transcription factor, ERT/ESX/ESE-1/ELF3, binds to the
      TGF-beta RII promoter in a sequence specific manner and regulates its expression.
      In this study, we investigated whether ERT could regulate endogenous TGF-beta RII
      expression in Hs578t breast cancer cells. Analyses of the Hs578t parental cell
      line revealed low RII mRNA expression and resistance to the growth inhibitory
      effects of TGF-beta. Infection of this cell line with a retroviral construct
      expressing ERT induced higher levels of endogenous RII mRNA expression and
      protein expression relative to cells infected with chloramphenicol
      acetyltransferase (CATneo) as a control. Relative to control cells, the ERTneo
      expressing Hs578t cells show approximately a 50% reduction in cell growth in the
      presence of exogenous TGF-beta1, as well as a fourfold higher induction of
      activation in transient transfection assays using the 3TP-luciferase reporter
      construct. When transplanted into athymic mice, ERT-expressing Hs578t cells
      showed decreased and delayed tumorigenicity compared with control cells. This
      data strongly suggests that ERT plays an important role as a transcriptional
      activator of TGF-beta RII expression, and that deregulated ERT expression may
      play a critical role in rendering Hs578t human breast cancer cells insensitive to
      TGF-beta's growth inhibitory effects.

PMID- 10644991
TI  - The SH3 and SH2 domains are capable of directing specificity in protein
      interactions between the non-receptor tyrosine kinases cSrc and cYes.
AB  - The c-src and c-yes proto-oncogenes encode 60 000 and 62 000 Dalton non-receptor
      tyrosine kinases of the Src family, pp60c-src and pp62c-yes, respectively. These
      kinases are over 80% homologous outside of their unique amino termini, yet
      several studies suggest that differences exist in the regulation, activation, and
      function of cSrc and cYes. The determinants of specificity in signaling between
      these proteins, however, remain unclear. In order to investigate the roles of the
      Src Homology (SH) 3 and 2 domains in mediating signaling specificity between cSrc
      and cYes, chimeras were created in which the SH3 and/or SH2 domains of cSrc or
      the fully activated variant Src527F were replaced by the corresponding domains of
      cYes. These constructs were used to assess the effects of the Yes SH3 and SH2
      domains on the ability of Src to form stable complexes with and induce tyrosine
      phosphorylation of Src SH3 and SH2 domain binding partners in vivo. Both the Yes
      SH3 and SH2 domains were found to alter the capacity of Src to form stable
      associations with heterologous proteins. The Yes SH3 domain was unable to
      affinity absorb the Src SH3/SH2 binding partner AFAP-110 from COS-1 cell lysates,
      and chimeric constructs of Src527F containing the cYes SH3 domain were unable to
      efficiently co-immunoprecipitate with AFAP-110 from chicken embryo fibroblasts.
      Interactions with the Src SH2 domain binding partner pp130cas were unaffected.
      Additionally, only chimeras containing the cYes SH2 domain were able to co
      immunoprecipitate with an unidentified 87 kDa tyrosine-phosphorylated protein.
      These results indicate that the SH3 and SH2 domains are capable of directing
      specificity in substrate binding between Src and Yes, suggesting potential
      mechanisms for generating specificity in signaling between these two highly
      related non-receptor tyrosine kinases.

PMID- 10644992
TI  - The putative tumour suppressor Fus-2 is an N-acetyltransferase.
AB  - Acetyltransferases are essential enzymes for a wide variety of cellular processes
      and mutations in acetyltransferase genes have been associated with the
      development of certain cancers. For this reason, we conducted a computerized
      sequence homology search for novel acetyltransferases. Here, we show that the
      putative tumour suppressor protein Fus-2 has homology to the catalytic domain of
      acetyltransferases. We demonstrate that Fus-2 can acetylate the N-terminus of
      proteins using a ping-pong mechanism and that it has a specificity for
      substrates. Consistent with other N-acetyltransferases, Fus-2 localizes to the
      cytoplasm, as shown by GFP-tag experiments. Since the Fus-2 gene maps to the
      chromosomal region 3p21.3, which contains at least one tumour suppressor gene,
      the N-acetyltransferase functions of Fus-2 may be relevant to its potential role
      in cancer.

PMID- 10644993
TI  - Epigenetic inactivation of LKB1 in primary tumors associated with the Peutz
      Jeghers syndrome.
AB  - Germ-line mutations of the LKB1 gene cause Peutz-Jeghers syndrome (PJS)
      characterized by mucocutaneous pigmentation, predisposition to benign hamartomas
      of the gastrointestinal tract and also to several types of tumors. However,
      somatic mutations of this gene are very rare. To examine inactivation of LKB1 by
      epigenetic mechanisms, we investigated a series of primary tumors and cancer cell
      lines, for hypermethylation affecting the CpG island located in the 5' region of
      the LKB1 gene using Methylation-specific PCR (MSP). First, we screened 51 cancer
      cell lines. Only three colorectal and one cervical carcinoma cell lines were
      methylated at LKB1, and loss of the LKB1 transcript was demonstrated. Treatment
      with the demethylating agent 5-aza-2'-deoxycytidine restored LKB1 expression. To
      address the incidence of LKB1 epigenetic inactivation in primary tumors, we
      analysed colorectal, breast, gastric, pancreatic, thyroid, bladder and testicular
      carcinomas (n=195). Normal tissues from the mentioned organs were unmethylated in
      this region. Among the described tumors, only one colorectal carcinoma and three
      testicular tumors displayed LKB1 promoter hypermethylation. Further study of
      those histological types more commonly associated with PJS, demonstrated that
      LKB1 promoter hypermethylation was present in five of 11 (45%) papillary breast
      carcinomas. Finally, in three patients with a strong family story suggestive of
      PJS disease, abnormal LKB1 methylation was found in four of 22 (18%)
      hamartomatous polyps lesions. Our findings provide an alternative pathway for
      inactivation of the LKB1 tumor suppressor gene involving promoter
      hypermethylation.

PMID- 10644994
TI  - Mitogenic signaling of Ras is regulated by differential interaction with Raf
      isozymes.
AB  - In the mitogenic signaling cascade interaction of Ras with Raf represents a
      critical step for the regulation of cell growth and differentiation. The major
      effector of Ras, the serine/threonine kinase Raf exists as three isoforms with
      different tissue distributions. We demonstrate that transient transfection of
      oncogenic Ha-Ras leads to a preferential activation of endogenous c-Raf-1 in HEK
      293 cells as opposed to A-Raf. In vitro binding studies using purified Ras
      binding domains of Raf as well as in vivo bindings tests with full length
      molecules reveals significantly lower binding affinities of A-Raf to Ha-Ras as
      compared to other Raf isoforms. The Ras-binding interface of c-Raf differs from A
      Raf by a conservative Arg to Lys exchange at residue 59 or 22 respectively.
      Mutational analysis reveals that this residue represents a point of isozyme
      discrimination: c-Raf-R59K binds Ha-Ras weaker than the wildtype, likewise A-Raf
      K22R increases its affinity to Ha-Ras in vivo and in vitro. Differential binding
      affinities are reflected in downstream signaling. Immunecomplex kinase assays
      reveal that Ha-Ras mediated Raf activation is decreased for c-Raf-R59K and
      increased for A-Raf-K22R when compared to the respective wildtype forms. Thus our
      observations introduce a new level of isoform discrimination in Ras/Raf signaling
      as a functional consequence of a conservative amino acid exchange in the Ras
      binding domains.

PMID- 10644995
TI  - Replacing two conserved tyrosines of the EphB2 receptor with glutamic acid
      prevents binding of SH2 domains without abrogating kinase activity and biological
      responses.
AB  - Eph receptor tyrosine kinases play key roles in pattern formation during
      embryonic development, but little is known about the mechanisms by which they
      elicit specific biological responses in cells. Here, we investigate the role of
      tyrosines 605 and 611 in the juxtamembrane region of EphB2, because they are
      conserved Eph receptor autophosphorylation sites and demonstrated binding sites
      for the SH2 domains of multiple signaling proteins. Mutation of tyrosines 605 and
      611 to phenylalanine impaired EphB2 kinase activity, complicating analysis of
      their function as SH2 domain binding sites and their contribution to EphB2
      mediated signaling. In contrast, mutation to the negatively charged glutamic acid
      disrupted SH2 domain binding without reducing EphB2 kinase activity. By using a
      panel of EphB2 mutants, we found that kinase activity is required for the changes
      in cell-matrix and cell - cell adhesion, cytoskeletal organization, and
      activation of mitogen-activated protein (MAP) kinases elicited by EphB2 in
      transiently transfected cells. Instead, the two juxtamembrane SH2 domain binding
      sites were dispensable for these effects. These results suggest that
      phosphorylation of tyrosines 605 and 611 is critical for EphB2-mediated cellular
      responses because it regulates EphB2 kinase activity.

PMID- 10644996
TI  - p53 is involved in the p120E4F-mediated growth arrest.
AB  - Control of cell growth and division by the p53 tumor suppressor protein requires
      its abilities to transactivate and repress specific target genes and to associate
      in complex with other proteins. Here we demonstrate that p53 binds to the E1A
      regulated transcription factor p120E4F, a transcriptional repressor of the
      adenovirus E4 promoter. The interaction involves carboxy-terminal half of p120E4F
      and sequences located at the end of the sequence-specific DNA-binding domain of
      p53. Ectopic expression of p120E4F leads to a block of cell proliferation in
      several human and murine cell lines and this effect requires the association with
      wild-type (wt) p53. Although p120E4F can also bind to mutant p53, the growth
      suppression induced by overexpression of the protein is severely reduced in a
      cell line that contains mutant p53. These data suggest that p120E4F may represent
      an important element within the complex network of p53 checkpoint functions.

PMID- 10644997
TI  - The MMAC1 tumor suppressor phosphatase inhibits phospholipase C and integrin
      linked kinase activity.
AB  - Loss of the tumor suppressor MMAC1 has been shown to be involved in breast,
      prostate and brain cancer. Consistent with its identification as a tumor
      suppressor, expression of MMAC1 has been demonstrated to reduce cell
      proliferation, tumorigenicity, and motility as well as affect cell-cell and cell
      matrix interactions of malignant human glioma cells. Subsequently, MMAC1 was
      shown to have lipid phosphatase activity towards PIP3 and protein phosphatase
      activity against focal adhesion kinase (FAK). The lipid phosphatase activity of
      MMAC1 results in decreased activation of the PIP3-dependent, anti-apoptotic
      kinase, AKT. It is thought that this inhibition of AKT culminates with reduced
      glioma cell proliferation. In contrast, MMAC1's effects on cell motility, cell -
      cell and cell - matrix interactions are thought to be due to its protein
      phosphatase activity towards FAK. However, recent studies suggest that the lipid
      phosphatase activity of MMAC1 correlates with its ability to be a tumor
      suppressor. The high rate of mutation of MMAC1 in late stage metastatic tumors
      suggests that effects of MMAC1 on motility, cell - cell and cell - matrix
      interactions are due to its tumor suppressor activity. Therefore the lipid
      phosphatase activity of MMAC1 may affect PIP3 dependent signaling pathways and
      result in reduced motility and altered cell - cell and cell - matrix
      interactions. We demonstrate here that expression of MMAC1 in human glioma cells
      reduced intracellular levels of inositol trisphosphate and inhibited
      extracellular Ca2+ influx, suggesting that MMAC1 affects the phospholipase C
      signaling pathway. In addition, we show that MMAC1 expression inhibits integrin
      linked kinase activity. Furthermore, we show that these effects require the
      catalytic activity of MMAC1. Our data thus provide a link of MMAC1 to PIP3
      dependent signaling pathways that regulate cell - matrix and cell - cell
      interactions as well as motility. Lastly, we demonstrate that AKT3, an isoform of
      AKT highly expressed in the brain, is also a target for MMAC1 repression. These
      data suggest an important role for AKT3 in glioblastoma multiforme. We therefore
      propose that repression of multiple PIP3 dependent signaling pathways may be
      required for MMAC1 to act as a tumor suppressor.

PMID- 10644998
TI  - EB3, a novel member of the EB1 family preferentially expressed in the central
      nervous system, binds to a CNS-specific APC homologue.
AB  - APCL, a homologue of the adenomatous polyposis coli (APC) tumor suppressor, can
      deplete cytoplasmic beta-catenin like APC. However, as its biological function
      remains unclear, we have been using a yeast two-hybrid system to search for
      proteins that associate with its carboxyl region. Among several cDNA clones we
      isolated from a fetal-brain cDNA library as candidates, six included an identical
      sequence with significant homology to EB1, a protein known to bind to APC. The
      full-length cDNA of this novel homologue of EB1, named EB3, encoded a protein of
      282 amino acids with 54% identity to EB1, and it was expressed preferentially in
      brain tissue on Northern blots. Confocal microscopy demonstrated that exogenous
      EB3, like EB1, is associated with the cytoplasmic microtubule network. Moreover,
      in these experiments EB3 and APCL appeared together in the perinucleus and the
      cytoplasmic microtubule network. Since APCL is also expressed highly and
      specifically in the central nervous system, APCL-EB3 interaction may be specific
      to the CNS, possibly involving stability and/or extension of microtubules during
      neuritogenesis.

PMID- 10644999
TI  - Identification of a YAC from 16q24 carrying a senescence gene for breast cancer
      cells.
AB  - We have identified a 360 kb YAC that carries a cell senescence gene, SEN16. In
      our earlier studies, we localized SEN16 within a genetic interval of 3 - 7 cM at
      16q24.3. Six overlapping YACs spanning the chromosomal region of senescence
      activity, were assembled in a contig. Candidate YACs, identified by the markers
      located in the vicinity of SEN16, were retrofitted to introduce a neo selectable
      marker. Retrofitted YACs were first transferred into mouse A9 cells to generate
      A9/YAC hybrids. YAC DNA present in A9/YAC hybrids was further transferred by
      microcell fusion into immortal cell lines derived from human and rat mammary
      tumors. YAC d792t2 restored senescence in both human and rat mammary tumor cell
      lines, while an unrelated YAC from chromosome 6q had no senescence activity.

PMID- 10645000
TI  - Identification of a novel NOTCH-4/INT-3 RNA species encoding an activated gene
      product in certain human tumor cell lines.
AB  - Ectopic expression of the intracellular domain of NOTCH-4/INT-3 leads to
      tumorigenesis in the mouse mammary gland. This results from a gain-of-function
      mutation. To evaluate gain-of-function NOTCH-4/INT-3 activity in human cancers we
      have surveyed human breast, lung, and colon carcinoma tissue culture cell lines
      for evidence of increased NOTCH-4/INT-3 RNA expression. High levels of a 1.8 Kb
      NOTCH-4/INT-3 RNA species are detected in normal human testis but not in other
      tissues where a 6.5 Kb species is prevalent. Transformed human cancer cell lines
      express the 1.8 Kb NOTCH-4/INT-3 RNA species. We show that this RNA species
      encodes a truncated form of the NOTCH-4/INT-3 intracellular domain (ICD). This
      novel NOTCH-4/INT-3 protein includes the CDC10 repeats and amino acid residues C
      terminal to them, but is missing the CBF-1 binding region of the NOTCH-4/INT-3
      ICD. This suggests that it has a different mode of action. Furthermore, we show
      that a transgene which expresses the 1.8 Kb NOTCH-4/INT-3 RNA species in the
      'normal' human mammary epithelial cell line MCF-10A enables these cells to grow
      in soft agar.

PMID- 10645001
TI  - Nuclear exclusion of p53 in a subset of tumors requires MDM2 function.
AB  - Wild type p53 accumulates in the cytoplasm in a subset of tumors such as
      neuroblastomas and breast carcinomas through an unknown mechanism. Exclusion of
      p53 from the nucleus may lead to inactivation of p53 during tumor development. We
      present evidence that MDM2 plays a significant role in promoting the degradation
      of nuclear p53 in tumor cells with a cytoplasmic p53 phenotype. Inhibition of
      MDM2 expression using antisense oligonucleotide, inhibition of MDM2 function by
      the tumor suppressor ARF or a MDM2 deletion mutant result in the accumulation of
      nuclear p53. p53 point mutants deficient in MDM2 binding have increased nuclear
      localization. Inhibition of nuclear export by leptomycin B also results in
      retention of nascent p53 in the nucleus, suggesting that cytoplasmic distribution
      of p53 results from efficient export of nuclear p53 in combination with MDM2
      mediated degradation. These results suggest that MDM2 is an important determinant
      of p53 subcellular distribution and may contribute to p53 inactivation without
      overexpression.

PMID- 10645002
TI  - Autotaxin (ATX), a potent tumor motogen, augments invasive and metastatic
      potential of ras-transformed cells.
AB  - Autotaxin (ATX), an exo-nucleotide pyrophosphatase and phosphodiesterase, was
      originally isolated as a potent stimulator of tumor cell motility. In order to
      study whether ATX expression affects motility-dependent processes such as
      invasion and metastasis, we stably transfected full-length ATX cDNA into two non
      expressing cell lines, parental and ras-transformed NIH3T3 (clone7) cells. The
      effect of ATX secretion on in vitro cell motility was variable. The ras
      transformed, ATX-secreting subclones had enhanced motility to ATX as
      chemoattractant, but there was little difference in the motility responses of
      NIH3T3 cells transfected with atx, an inactive mutant gene, or empty vector. In
      MatrigelTM invasion assays, all subclones, which secreted enzymatically active
      ATX, demonstrated greater spontaneous and ATX-stimulated invasion than
      appropriate controls. This difference in invasiveness was not caused by
      differences in gelatinase production, which was constant within each group of
      transfectants. In vivo studies with athymic nude mice demonstrated that injection
      of atx-transfected NIH3T3 cells resulted in a weak tumorigenic capacity with few
      experimental metastases. Combination of ATX expression with ras transformation
      produced cells with greatly amplified tumorigenesis and metastatic potential
      compared to ras-transformed controls. Thus, ATX appears to augment cellular
      characteristics necessary for tumor aggressiveness.

PMID- 10645003
TI  - Inhibition of collagenase-3 (MMP-13) expression in transformed human
      keratinocytes by interferon-gamma is associated with activation of extracellular
      signal-regulated kinase-1,2 and STAT1.
AB  - Collagenase-3 (MMP-13) is characterized by an exceptionally wide substrate
      specificity and restricted expression. MMP-13 is specifically expressed by
      transformed human keratinocytes in squamous cell carcinomas in vivo and its
      expression correlates with their invasion capacity. Here, we show, that
      interferon-gamma (IFN-gamma) markedly inhibits expression of MMP-13 by human
      cutaneous SCC cells (UT-SCC-7) and by ras-transformed human epidermal
      keratinocytes (A-5 cells) at the transcriptional level. In addition, IFN-gamma
      inhibits collagenase-1 (MMP-1) expression in these cells. IFN-gamma abolished the
      enhancement of MMP-13 and MMP-1 expression by transforming growth factor-beta
      (TGF-beta) and tumor necrosis factor-alpha (TNF-alpha), and inhibited invasion of
      A-5 cells through type I collagen. IFN-gamma also rapidly and transiently
      activates extracellular signal-regulated kinase 1,2 (ERK1,2) and blocking ERK1,2
      pathway (Raf/MEK1,2/ERK1,2) by specific MEK1,2 inhibitor PD98059 partially (by
      50%) prevents Ser-727 phosphorylation of STAT1 and suppression of MMP-13
      expression by IFN-gamma. Furthermore, Ser-727 phosphorylation of STAT1 by ERK1,2,
      or independently of ERK1,2 activation is associated with marked reduction in MMP
      13 expression. These observations identify a novel role for IFN-gamma as a potent
      inhibitor of collagenolytic activity and invasion of transformed squamous
      epithelial cells, and show that inhibition of MMP-13 expression by IFN-gamma
      involves activation of ERK1,2 and STAT1.

PMID- 10645004
TI  - Ovarian cancer cells that coexpress endogenous Rb and p16 are insensitive to
      overexpression of functional p16 protein.
AB  - Defects of the 'Rb/cyclin D1/p16 pathway' have been shown to play a critical role
      in the development of virtually all human malignancies assessed. To determine the
      contribution of G1 phase cell cycle defects to ovarian tumorigenesis, we have
      examined a panel of normal and tumor ovarian tissues and ovarian cancer cell
      lines for the expression of Rb, p16 and cyclin D1 proteins. Unlike most types of
      human cancer whose development involves the loss of either Rb or p16 expression,
      we observed the coexpression of Rb, p16 and cyclin D1 in 82% of ovarian cancer
      tissues and cell lines. Furthermore, the growth and cell cycle distribution
      profiles of three ovarian cancer cell lines (ES-2, PA-1 and NIH OVCAR-3) that
      coexpressed Rb and p16, were found to be unaffected by adenoviral-mediated
      overexpression of functional p16 protein, indicating the existence of a defect(s)
      downstream from p16 in these cells. By contrast overexpression of ectopic p16 in
      the one ovarian cancer cell line (SK-OV-3) that expressed Rb but lacked p16
      protein, resulted in a G1 growth arrest. These data suggest that defects of the
      'Rb/cyclin D1/p16 pathway', other than the loss of Rb or p16, may play a major
      role in the development of ovarian cancer.

PMID- 10645005
TI  - Regulation of CD26/DPPIV gene expression by interferons and retinoic acid in
      tumor B cells.
AB  - Interferons (IFNs alpha, beta and gamma) and all trans retinoic acid (RA) have
      the ability to activate genes with GAS sites. We have found that the promoter of
      CD26/dipeptidylpeptidase IV (DPPIV) contains a consensus GAS site TTCnnnGAA
      located at bp-35 to -27, and computer analysis confirmed this sequence to be a
      putative Stat binding site. Consistent with this finding, we show that IFNs and
      RA rapidly enhanced CD26 gene and protein expression in chronic B lymphocytic
      leukemia (B-CLL) cells. Immunoblot analyses revealed that unstimulated B-CLL
      cells expressed detectable levels of serine/tyrosine-phosphorylated Stat1alpha,
      and RA and IFN-gamma treatment led to increased levels of tyrosine
      phosphorylation of Stat1alpha and its nuclear accumulation. As shown by
      electrophoretic mobility shift assay, RA and IFN-gamma increased the binding of a
      nuclear protein to the GAS-CD26 element. Shift-Western blotting identified
      Stat1alpha as the GAS-CD26 binding factor. Augmented levels of CD26 protein in
      malignant B cells cultured with IFNs or RA coincided with the enhancement of
      DPPIV activity. Taken together, our results are in favor of the IFN-/RA-mediated
      upregulation of CD26/DPPIV in B-CLL through the signaling pathway involving
      Stat1alpha and the GAS response element of CD26 promoter.

PMID- 10645006
TI  - Clustered cysteine residues in the kinase domain of v-Src: critical role for
      protein stability, cell transformation and sensitivity to herbimycin A.
AB  - We have previously reported the activation of Src by mercuric chloride based on
      the sulfhydryl modification. To evaluate the significance of cysteine residues in
      v-Src, we replaced each cysteine to alanine by oligonucleotide-directed
      mutagenesis and examined its effect on cell transformation. Of ten cysteine
      residues scattered over v-Src, four cysteines clustered in kinase domain, Cys483,
      Cys487, Cys496 and Cys498, were important for protein stability and cell
      transformation, whereas those in SH2 domain were dispensable. A single mutation
      in Cys498 yielded suppression of kinase activity and a temperature-sensitivity in
      anchorage independent growth. Double mutation either in Cys483/Cys487 or in
      Cys496/Cys498 yielded clear temperature-sensitivity in cell transformation and in
      stability of Src protein. Instability of Src protein was magnified by quadruple
      mutation in the cysteines, which decreased the half-life of Src to be less than
      one quarter of that of wild-type. In addition, both Cys483/Cyr487 and
      Cys496/Cys498 kinases became resistant to in vitro inactivation by herbimycin A,
      which directly inactivates v-Src in addition to its effect on HSP90. Taken
      together, our results strongly suggest that the cysteine clustered motif of v-Src
      are critical for protein stability, cell transformation and in vitro inactivation
      by herbimycin A.

PMID- 10645007
TI  - AP-2 transcription factors in the regulation of ERBB2 gene transcription by
      oestrogen.
AB  - Transcription of the ERBB2 oncogene is repressed by oestrogen in human breast
      cancer cells. We show that a 218 bp fragment of the human ERBB2 gene promoter is
      responsive to oestrogen in transient transfection in ZR75.1 and SKBR.3 cells when
      the oestrogen receptor is expressed. Deletion analysis of this fragment shows
      that a sequence located at the 5' end, which is known to mediate ERBB2
      overexpression in breast cancer, is also responsible for the oestrogen response.
      This sequence binds AP-2 transcription factors and appears functionally identical
      to an element of the oestrogen-dependent enhancer described in the first intron
      of human ERBB2. We observed that oestrogen treatment down-regulates expression of
      AP-2 proteins but does not affect the DNA binding activity of AP-2. Constitutive
      expression of AP-2beta or AP-2gamma, but not AP-2alpha, abrogates the estrogenic
      repression. Our results demonstrate that AP-2 transcription factors are
      implicated in the oestrogenic regulation of ERBB2 gene expression and suggest a
      complex interplay involving the different AP-2 isoforms and other unidentified
      factors.

PMID- 10645008
TI  - Characterization of the gene encoding pinin/DRS/memA and evidence for its
      potential tumor suppressor function.
AB  - Several cell adhesion-related proteins have been shown to act as tumor
      suppressors (TS) in the neoplastic progression of epithelial-derived tumors.
      Pinin/DRS/memA was first identified in our laboratory and it was shown to be a
      cell adhesion-related molecule. Our previous study demonstrated that restoration
      of pinin expression in transformed cells not only positively influenced cellular
      adhesive properties but also reversed the transformed phenotype to more
      epithelial-like. Here, we show by FISH analysis that the gene locus for pinin is
      within 14q13. The alignment of the pinin gene with STS markers localized the gene
      to the previously identified TS locus D14S75-D14S288. Northern analyses revealed
      diminished pinin mRNA in renal cell carcinomas (RCC) and certain cancer cell
      lines. Immunohistochemical examination of tumor samples demonstrated absent or
      greatly reduced pinin in transitional cell carcinoma (TCC) and RCC tumors. TCC
      derived J82 cells as well as EcR-293 cells transfected with full-length pinin
      cDNA demonstrated inhibition of anchorage-independent growth of cells in soft
      agar. Furthermore, methylation analyses revealed that aberrant methylation of
      pinin CpG islands was correlated with decreased/absent pinin expression in a
      subset of tumor tissues. These data lend significant support to the hypothesis
      that pinin/DRS/memA may act as a tumor suppressor in certain types of cancers.

PMID- 10645009
TI  - Regulation of B-Myb activity by cyclin D1.
AB  - Evidence obtained during recent years suggests that B-Myb, a highly conserved
      member of the Myb transcription factor family, plays a key role in cell
      proliferation. We have shown previously that the activity of B-Myb is stimulated
      by cyclin A/Cdk2-dependent phosphorylation of the carboxyl-terminus of B-Myb. We
      have now investigated in more detail the effect of other cyclins on B-Myb. Here,
      we show that cyclin D1, in contrast to cyclin A, strongly inhibits the activity
      of B-Myb. This inhibitory effect does not involve increased phosphorylation of B
      Myb but seems to rely on the formation of a specific complex of B-Myb and cyclin
      D1. Our work identifies B-Myb as an interacting partner for cyclin D1 and suggest
      that the activity of B-Myb during the cell cycle is controlled by the
      antagonistic effects of cyclin D1 and A. The results presented here suggest a
      more general role of cyclin D1 as regulator of transcription in addition to the
      known effect on RB phosphorylation.

PMID- 10645010
TI  - Oxidation of a critical thiol residue of the adenine nucleotide translocator
      enforces Bcl-2-independent permeability transition pore opening and apoptosis.
AB  - Mitochondrial membrane permeabilization is a critical event in the process
      leading to physiological or chemotherapy-induced apoptosis. This permeabilization
      event is at least in part under the control of the permeability transition pore
      complex (PTPC), which interacts with oncoproteins from the Bcl-2 family as well
      as with tumor suppressor proteins from the Bax family, which inhibit or
      facilitate membrane permeabilization, respectively. Here we show that thiol
      crosslinking agents including diazenedicarboxylic acid bis 5N, N-dimethylamide
      (diamide), dithiodipyridine (DTDP), or bis-maleimido-hexane (BMH) can act on the
      adenine nucleotide translocator (ANT), one of the proteins within the PTPC. ANT
      alone reconstituted into artificial lipid bilayers suffices to confer a membrane
      permeabilization response to thiol crosslinking agents. Diamide, DTDP, and BMH
      but not tert-butylhydroperoxide or arsenite cause the oxidation of a critical
      cysteine residue (Cys 56) of ANT. Thiol modification within ANT is observed in
      intact cells, isolated mitochondria, and purified ANT. Recombinant Bcl-2 fails to
      prevent thiol modification of ANT. Concomitantly, a series of different thiol
      crosslinking agents (diamide, DTDP, and BMH, phenylarsine oxide) but not tert
      butylhydroperoxide or arsenite induce mitochondrial membrane permeabilization and
      cell death irrespective of the expression level of Bcl-2. These data indicate
      that thiol crosslinkers cause a covalent modification of ANT which, beyond any
      control by Bcl-2, leads to mitochondrial membrane permeabilization and cell
      death.

PMID- 10645011
TI  - Deregulated expression of cyclin D1 overrides antimitogenic signals.
AB  - Several types of epithelial neoplasms exhibit high expression of transforming
      growth factor beta1 (TGFbeta-1), indicating that they have acquired tolerance to
      this normally growth inhibitory cytokine. Since cyclin D1 is expressed at high
      levels in murine skin tumors coincident with high levels of TGFbeta-1 expression,
      we hypothesized that cyclin D1 may override TGFbeta-1 induced growth arrest. We
      observed that in primary murine keratinocytes treated with TGFbeta-1, cyclin D1
      is quickly suppressed at both the mRNA and protein level. Since changes in other
      cell cycle proteins occur at a later time during TGFbeta-1 treatment, the early
      suppression of cyclin D1 suggests that this gene is a critical target for TGFbeta
      1 growth suppression. Using primary keratinocytes from transgenic mice that
      overexpress cyclin D1 (K5-D1 mice), we observed partial resistance to TGFbeta-1
      growth inhibition. This resistance involves changes in the cyclin/cdk/inhibitor
      complexes rather than differences in expression of the TGFbeta receptors or
      signaling. Comparison of cdk associated kinase activity between wild-type and K5
      D1 cells shows differential regulation. We conclude that deregulated cyclin D1
      and subsequent alterations in cell cycle machinery provides keratinocytes the
      ability to at least partially override growth inhibitory signals.

PMID- 10645012
TI  - [Neck phlebectasia].
AB  - Neck phlebectasia is an infrequent anomaly of the venous system, possibly a
      congenital condition, becoming apparent as a neck mass triggered by the Valsalva
      maneuver or any other exploratory afford with closed nose. Commonly localized in
      the jugular venous system, although it can turn-up, the ectasia, to other
      cervicofacial veins. In this paper are reported 3 neck phlebectasis including one
      of them affecting the anterior facial vein, occurrence exceedingly uncommon, of
      which case we don't know even a single reference in the literature. We make a
      perusal of the subject's bibliography and also discuss the clinic, diagnostic and
      therapeutical most important features of this entity.

PMID- 10645013
TI  - [Labyrinth aspects of cranial Paget's disease].
AB  - We report the case of a 44-year-old woman suffering, since 5 years, from
      repetitive vertigo seizures, lasting less than one hour, together with light
      neuro-sensorial deafness, fullness of the left ear and left ear tinnitus. After
      analysis of audiologic and imagery tests a Meniere's syndrome secondary to Paget
      disease--confirm histologically through cortical cranial biopsy--was established.

PMID- 10645014
TI  - [Warthin's tumor in the neck].
AB  - Papillar lymphomatous cystoadenoma on the neck as first stage of development.
      Other lesions of this nature in atypical areas as larynx, minor salivary glands
      or oropharynx has been described, but is not frequent on heterotopic location so
      peculiar. In that case the real diagnostic problem was the differential with neck
      masses. Description of the case and review of the literature.

PMID- 10645015
TI  - [Multiple extramedullary plasmocytoma of the upper respiratory and digestive
      tracts. A case report].
AB  - Solitary or multiple extramedullary plasmacytoma is and odd condition. We report
      one case of multiple extramedullary plasmacytoma of pharyngolaryngeal site,
      stressing the importance of the area covered in order to rule out the most
      frequent systemic disease, that is the multiple myeloma. Comments about
      pathological anatomy features of the diagnosis and elective treatment as well.

PMID- 10645016
TI  - [Solitary extramedullary plasmocytoma of oropharynx].
AB  - Report on a solitary extramedullary plasmacytoma case, an entity rarely diagnosed
      in daily practice, because of its low incidence. When the process occurs is seen
      fundamentally located at upper aero-digestive tract. Our patient was a 34-year
      old man, who was diagnosed as oropharyngeal plasmacytoma with the peculiarity
      that the lesion feigned a benign one wether for the clinical features or the
      macroscopical aspect. The patient underwent surgery and postoperative
      rontgentherapy, after discarding a systemic disease. Till now the evolution
      proved good.

PMID- 10645017
TI  - [Postoperative clinical and ct-xray evaluation of the septic inflammatory sinus
      pathology].
AB  - It is classically been though that radical sinus surgery implies a difficulty for
      ulterior image diagnosis. The reason is postoperative fibrosis of soft tissue may
      be shown at TC scan as an occupation of paranasal sinuses. We realized that it
      does not usually happen. The aim of our study is to find out the appearance of
      sinuses after radical surgery performed to treat chronic sinusitis, mucocele and
      sinusal cysts. For so doing we have reviewed symptoms and radiological signs
      before and after surgery.

PMID- 10645018
TI  - [Nasal encephalocele: differential diagnosis with nasal glioma].
AB  - Congenital nose neoplasms are infrequent, between them neurogenic tumors of the
      middle line include nasal gliomata (glial ectopies) and nasal encephaloceles,
      according to an existing or lacking communicating link with the intracranial
      cavity. We report one congenital naso-encephalocele case in a 16-year-old girl
      suffering from repeated meningitis events after several nasal polypectomies
      performed in other departments. She underwent complete removal through fronto
      neurosurgical and paralateronasal approach, being the young woman asymptomatic
      for 3 years. We discuss about both intranasal gliomata and encephaloceles,
      certainly of not easy pathologic identification, stressing the decisive value of
      imaging techniques, as magnetic resonance, in order to clearcut both the
      diagnosis and the therapeutical planning.

PMID- 10645019
TI  - [Nasopharyngeal cysts. Report of four cases and literature review].
AB  - Nasopharyngeal cysts although common are not completely understood. They are
      classified according to their localization and pathogenesis in congenital or
      acquired and medial or lateral. We report 4 cases: a branchiogenic causing
      serious otitis, a Tornwaldt's cyst also producing otitis serosa, another
      asymptomatic Tornwaldt's cyst and a retention cyst which produce an obstructive
      apnea syndrome. All but the asymptomatic one were operated on transoral, by
      grasping the cyst and its implantation site. They all remain till now
      asymptomatic. We review the chapter of nasopharyngeal cysts, discussing their
      clinicopathological classification, their diagnosis and treatment.

PMID- 10645020
TI  - Manipulations of exposure-based therapy to reduce return of fear: a replication.
AB  - Using exposure-based treatment for fear of heights, we tested two different
      manipulations, namely administering blocks of exposure trials on an expanding
      spaced schedule and varying the nature of the exposure, both of which have been
      shown to reduce return of fear [Rowe, M. K., & Craske, M. G. (1998a). Effects of
      an expanding-spaced versus massed exposure schedule on fear reduction and return
      of fear. Behaviour Research and Therapy, 36, 701-718; Rowe, M. K., & Craske, M.
      G. (1998b). Effects of varied-stimulus exposure training on fear reduction and
      return of fear. Behaviour Research and Therapy, 36, 719-734.]. The samples for
      these two studies included 23 and 34 undergraduates, respectively. Fear was
      assessed before, immediately after and one month after treatment using self
      report and physiological measures. Study hypotheses were not strongly supported,
      but the manipulations did lead to different responses during treatment. The data
      suggest that physiological habituation is not necessary for fear reduction.
      Expanding spaced treatment may have increased generalization, and those in the
      constant and varied conditions responded to different aspects of the exposure.
      Reasons for the failure to replicate previous research and ideas for future
      research are discussed.

PMID- 10645021
TI  - Extent and nature of anxiety experienced during physical examination of chronic
      low back pain.
AB  - There is strong evidence to suggest that anxiety is a common problem for many
      chronic pain patients and can exacerbate a patient's pain condition.
      Notwithstanding, there is little information about the extent and nature of
      anxiety experienced during physical examination of pain, or the primary factors
      associated with anxiety in this context. In the present study, 45 chronic low
      back pain patients completed a questionnaire battery at the time of intake to an
      interdisciplinary treatment program. After approximately four weeks on program,
      patients underwent a routine standardized physiotherapy review of their condition
      following which they completed a second questionnaire battery. The examination
      was videotaped and coded for pain behavior. Physiotherapists provided objective
      scoring of non-organic signs and physical impairment. Results suggested that
      participants experienced substantial anxiety at the point of examination with
      scores on the Beck Anxiety Inventory (M = 30.47, S.D. = 6.96) comparable to
      scores that have been found with DSM-IV panic disorder patients. Regression
      analyses revealed that catastrophic cognitions, behavioral displays of pain and
      somatic sensations measured during examination uniquely predicted anxiety
      experienced during examination. Demographic, injury-related, personality, and
      patient-practitioner variables did not significantly contribute to explaining
      examination anxiety. Findings support cognitive-behavioral formulations of
      anxiety and strongly suggest that anxiety may complicate the assessment process.
      Implications for the assessment and treatment of pain are presented along with
      future research directions.

PMID- 10645022
TI  - A clinical study of child dental anxiety.
AB  - Dental fear in children was studied using Rachman's theory of fear acquisition.
      Sixty children from two age groups (7-10 years, 11-14 years) participated in the
      project. The children were new patients attending a paediatric consultation
      clinic for specialised dental treatment. Thirty-one were diagnosed as being
      clinically anxious regarding dentistry and 29 were found to be nonanxious.
      Information regarding children's past experiences and present level of anxiety
      was obtained from the examining dentist, the children and their parents. Mothers
      were also interviewed and observed to ascertain their own anxieties and
      behaviour. The results showed that of Rachman's three pathways to fear,
      conditioning appeared largely responsible for the children's development of
      dental fear. Children's fear was more strongly associated with subjective
      experience of pain and trauma than with objective dental pathology. Indirect
      learning processes were found to be of only minor importance in this study.

PMID- 10645023
TI  - Heartbeat perception in panic disorder: a reanalysis.
AB  - This article describes a reanalysis of seven studies on heart beat perception
      (HBP) in panic disorder. The pooled sample had 709 participants from eight
      diagnostic categories. Accurate HBP was uncommon, but more prevalent among panic
      disorder patients than among healthy controls, depressed patients, patients with
      palpitations and individuals with infrequent panic attacks. No differences were
      found between panic disorder patients and patients with other anxiety disorders.
      Accurate perceivers had higher anxiety sensitivity scores than inaccurate
      perceivers. The data remain inconclusive as to whether perceived heart rate is
      correlated with anxiety in inaccurate perceivers. Physical exercise, distraction,
      variations in instructions and treatment each influenced HBP. However, the
      influence was different than previously thought. Finally, it is suggested that
      HBP may be understood in terms of schema-guided information processing.

PMID- 10645024
TI  - Selective attention for cardiac information in panic patients.
AB  - With various reaction time paradigms, panic patients have been shown to have
      selective attention for threatening sensations. However, almost all of these
      paradigms use words describing sensations and not the threatening sensations
      themselves. To increase the ecological validity, in the current study selective
      attention for heartbeat information was measured with a paradigm derived from the
      dot probe detection task but using 'real' heartbeat information instead of words.
      The results indeed showed selective attention for ECG information in panic
      patients. However, an accelerated ECG did not attract the attention of panic
      patients more than a slower ECG. Against expectation, both panic patients and
      normal controls shifted their attention away from an accelerated ECG. Possible
      explanations are explored.

PMID- 10645025
TI  - Factor analysis of the English version of the Kategoriensystem fur
      Partnerschaftliche Interaktion [Interaction Coding System].
AB  - The Kategoriensystem fur Partnerschaftliche Interaktion (KPI), or Interaction
      Coding System, is an observational coding system used to study behaviors
      occurring during dyadic interactions. The KPI offers several summary categories
      (e.g. positive, negative, neutral) to facilitate data analysis, but empirical
      evidence supporting these rationally derived groupings is lacking. Reported here
      are the results of a factor analysis of data obtained from 121 spouses or other
      close relatives of patients with anxiety disorders who participated in dyadic
      problem-solving interactions with the patients. A three-factor solution
      accounting for 50% of the variance emerged. The factors were Negativity, Problem
      Solving Focus and Emotional Engagement. Confidence in the reliability of the
      first two factors is bolstered by their similarity to factors detected in prior
      research on a different coding system, the Marital Interaction Coding System.

PMID- 10645026
TI  - Illness Attitudes Scale dimensions and their associations with anxiety-related
      constructs in a nonclinical sample.
AB  - The Illness Attitudes Scale (IAS) is a self-rated measure that consists of nine
      subscales designed to assess fears, attitudes and beliefs associated with
      hypochondriacal concerns and abnormal illness behavior [Kellner, R. (1986).
      Somatization and hypochondriasis. New York: Praeger; Kellner, R. (1987). Abridged
      manual of the Illness Attitudes Scale. Department of Psychiatry, School of
      Medicine, University of New Mexico]. The purposes of the present study were to
      explore the hierarchical factor structure of the IAS in a nonclinical sample of
      young adult volunteers and to examine the relations of each illness attitudes
      dimension to a set of anxiety-related measures. One-hundred and ninety-seven
      undergraduate university students (156 F, 41 M; mean age = 21.9 years) completed
      the IAS as well as measures of anxiety sensitivity, trait anxiety and panic
      attack history. The results of principal components analyses with oblique
      (Oblimin) rotation suggested that the IAS is best conceptualized as a four-factor
      measure at the lower order level (with lower-order dimensions tapping illness
      related Fears, Behavior, Beliefs and Effects, respectively), and a unifactorial
      measure at the higher-order level (i.e. higher-order dimension tapping General
      Hypochondriacal Concerns). The factor structure overlapped to some degree with
      the scoring of the IAS proposed by Kellner (1986, 1987), as well as with the
      factor structures identified in previously-tested clinical and nonclinical
      samples [Ferguson, E. & Daniel, E. (1995). The Illness Attitudes Scale (IAS): a
      psychometric evaluation on a nonclinical population. Personality and Individual
      Differences, 18, 463-469; Hadjistavropoulos, H. D. & Asmundson, G. J. G. (1998).
      Factor analytic investigation of the Illness Attitudes Scale in a chronic pain
      sample. Behaviour Research and Therapy, 36, 1185-1195; Hadjistavropoulos, H. D.,
      Frombach, I. & Asmundson, G. J. G. (in press). Exploratory and confirmatory
      factor analytic investigations of the Illness Attitudes Scale in a nonclinical
      sample. Behaviour Research and Therapy; Speckens, A. E., Spinhoven, P., Sloekers,
      P. P. A., Bolk, J. H. & van Hemert, A. M. (1996). A validation study of the
      Whitley Index, the Illness Attitude Scales and the Somatosensory Amplification
      Scale in general medical and general practice patients. Journal of Psychosomatic
      Research, 40, 95-104]. The Fears, Beliefs and Effects lower-order factors and the
      General Hypochondriacal Concerns higher-order factor, were shown to be strongly
      associated with anxiety sensitivity, even after accounting for trait anxiety and
      panic history. Implications for understanding the high degree of comorbidity
      between the diagnoses of panic disorder and hypochondriasis, as well as future
      research directions for exploring the utility of various IAS dimensions in
      predicting responses to lab-based bodily symptom-induction procedures, are
      discussed.

PMID- 10645027
TI  - 31P NMR investigation of free intracellular magnesium, pH and energy balance in
      striated muscle of patients with kidney disease: relation to insulin resistance.
AB  - BACKGROUND: High prevalence (48%) of insulin resistance (IR) in patients with
      mild to moderate kidney function reduction, and the potential pathogenetic role
      of magnesium (Mg) deficiency in IR prompted us to study skeletal muscle free Mg
      (fMg) concentration in patients with impaired kidney function. METHODS: fMg
      concentration, intracellular pH (pHi) and parameters of energy balance were
      determined employing 31P NMR spectroscopy in the calf muscle of the dominant leg
      of 18 healthy controls (C) and 22 patients (P) with decreased kidney function. 10
      patients suffered from insulin resistance (IR). RESULTS: No difference in fMg
      concentration in skeletal muscle was observed (C: 0.929 +/- 0.075; P: 0.948 +/-
      0.062 mmol/l; x +/- SEM). In patients a slight shift of pHi towards acidic values
      was found (C: 7.036 +/- 0.0.004; P: 7.013 +/- 0.004; p < 0.004), which was even
      more expressed in IR patients (7.008 +/- 0.005). Serum creatinine levels and
      creatinine clearance correlated with pHi in the patient's group.
      Adenosintriphosphate (ATP) to inorganic phosphate (Pi) ratio in skeletal muscle
      was lower, phosphocreatine (Pcr)/ATP ratio was higher, while that of Pcr/Pi
      showed only a trend towards an increase in the patient's group. CONCLUSION: In
      patients with reduction of kidney function IR does not associate with a change in
      skeletal muscle free magnesium concentration, or deficiency in macroergic
      phosphate levels. Shift in intracellular pH towards acidic values may participate
      in IR. Decreased activity of Na+/H+ antiporter is suggested. (Fig. 5, Tab. 2,
      Ref. 22.)

PMID- 10645028
TI  - Update on gene therapy for intimal hyperplasia.
AB  - Trauma to the vessel wall leads to smooth muscle cell (SMC) activation and
      eventual intimal hyperplasia. This process occurs in restenosis following balloon
      angioplasty, particularly with stent placement, occlusion of vascular bypasses,
      and arteriopathy of chronic allograft rejection. Genetic interventions affecting
      the cell cycle or early postinjury events have been successful in limiting SMC
      proliferation in vitro and in animal models. Gene therapy strategies have
      included the use of antisense oligonucleotides to block protein synthesis,
      transduced genes to cause cytotoxicity, and genetically engineered cells to
      decrease the response to injury. The clinical application of gene therapy in
      vascular diseases should follow the evolution of delivery systems that enable
      efficient local gene transfer to the arterial wall. (Tab. 1, Fig. 1, Ref. 30.)

PMID- 10645029
TI  - [Use of the Cocroft and Gault formula for evaluation of 24-hour urinary excretion
      of electrolytes].
AB  - Measurement of 24-hour electrolyte elimination requires exact urine collection
      over the period or study and cooperation of the individual being examined. These
      conditions are often not fulfilled. In an effort to be able to assess 24-hour
      elimination of Na+ and K+ in situations where urine collection is not absolutely
      complete, we developed a formula allowing to calculate the urinary elimination of
      the monitored electrolyte on the basis of its urinary concentration, urinary
      creatinine concentration, and urinary creatinine excretion using Cocroft and
      Gault's formula. The proposed formula is as follows: [formula: see text] This
      formula applies to men, when using it in women, a factor of 0.0015 has to be used
      instead of 0.0018. The method was used to measure urinary Na+ and K+ elimination
      in 60 hospitalized individuals after renal transplantation. Significant linear
      correlations were found between the values obtained by careful urine collection
      and the calculated (predicted) values using the above formula: r = 0.939, p <
      0.001 with Na+ and r = 0.924, p < 0.001 with K+. The results provide support to
      the assumption that calculation of urinary Na+ and K+ elimination using the above
      formula may be useful in cases where urine collection over a period of 24 hours
      is not absolutely complete. (Tab. 1, Fig. 4, Ref. 2.)

PMID- 10645030
TI  - [Vitamin levels in the serum and erythrocytes during erythropoietin therapy in
      hemodialyzed patients].
AB  - BACKGROUND: The treatment of anaemia by erythropoietin is the method of choice in
      chronic renal failure patients without dialysis treatment, in hemodialyzed
      patients and during CAPD. Erythropoietin treatment influenced supplementary doses
      of vitamins especially those participating in haem formation. OBJECTIVES: The aim
      of the study was to investigate the influence of erythropoietin treatment during
      long-term 15 months study on serum vitamin A levels and its protein carriers,
      prealbumin and retinol-binding protein, on erythrocyte vitamin B1, B2 and B6 and
      folic acid and on serum or plasma vitamins B12, C and E levels in hemodialyzed
      patients. METHODS: The authors investigated the influence of erythropoietin on
      the biochemical parameters mentioned above in 30 hemodialyzed patients during the
      period of 15 months. Patients were divided into two groups. Group A was formed by
      patients without erythropoietin treatment and group B was treated by subcutaneous
      administration of erythropoietin. Total weekly dose of erythropoietin was 50-100
      U/kg of body weight. All patients received perorally pyridoxine 5 mg/day. B group
      of patients was supplemented by pyridoxine 20 mg/day and by folic acid 10 mg/day
      from the 12th to 15th month of the study. Erythrocyte vitamins B1, B2 and B6
      values were determined by indirect enzymatic methods and were expressed as the
      effects of their coenzymes, thiamine pyrophosphate, flavine adenine dinucleotide
      and pyridoxal-5-phosphate in per cents. RESULTS: Long-term erythropoietin
      treatment led in the 12th month to a significant decrease of serum vitamin A and
      its protein carriers which were significantly increased in both groups of
      patients during the whole study. Erythrocyte vitamin B6 and folic acid
      significantly decreased due to erythropoietin treatment. Supplementary doses of
      pyridoxine and folic acid given perorally to the patients in B group during the
      last three months of our study influenced the deficiency of erythrocyte vitamin
      B6 and folic acid. CONCLUSIONS: Supplementations of pyridoxine in the dose of 20
      mg/day and of folic acid 5 mg/week in hemodialyzed patients during erythropoietin
      treatment are necessary. (Tab. 5, Ref. 28.)

PMID- 10645031
TI  - [Treatment of renal anemia with erythropoietin].
AB  - During the last decade, a considerable amount of new information has accumulated
      regarding therapy optimalization of renal anaemia with recombinant human
      erythropoietin (EPO). Key question involved is EPO hyporesponsiveness caused by
      absolute or functional iron deficiency. Most controversial issue in the treatment
      of renal anaemia in patients with chronic renal insufficiency is the definition
      of optimal target haemoglobin. Many questions about optimizing EPO therapy were
      considered at the 2nd European Epoetin Symposium which was held in April 1998 on
      Crete. Discussion was devoted also to revision of a draft version of the European
      Best Practice Guidelines for the Management of Anaemia in Patients with Chronic
      Renal Failure. The presented review is on summary of new insights presented at
      the symposium. (Ref. 85.)

PMID- 10645032
TI  - [Parameters of energy metabolism in patients after vascular reconstructive
      surgical procedures].
AB  - Revascularization surgery in patients with peripheral arterial occlusive disease
      presents an acceptable clinical model for studying the rate of ischaemia
      reperfusion injury of cells and other structures of skeletal muscle of the
      affected extremity. Validity of carefully chosen set of biochemical parameters
      for determination of this injury during and after surgery as well as in the early
      and late reperfusion periods and during the readaptation to situation after
      restoration of blood circulation was verified. Blood samples were taken from the
      regional common femoral vein which allowed to obtain information directly from
      the ischaemized extremity. Analyzed biochemical parameters have given useful
      information about the situation in acid-base regulation, in energy metabolism as
      well as antioxidant capacity. These parameters were estimated in four time
      intervals: before aorta cross-clamping (preischaemic phase), then 30 min (early
      reperfusion) and 18 hours (readaptation period) after aorta-declamping. In the
      early reperfusion period a marked acidosis and raised carbon dioxide tension,
      significant increase of lactate and pyruvate levels as well as increased
      hypoxanthine plasma level were observed. On the contrary, in this period the
      lowest lipoperoxide level was found, evident in the wake of relative stability of
      concentration of endogenous antioxidants documented by a constant glutathione
      redox status that at the first postoperative day even significantly decreased as
      a consequence of a drop of oxidized and increased of reduced form of glutathione.
      Therefore, the applied biochemical parameters allow to monitor the ischaemia
      reperfusion damage of afflicted region and could be used even in the study of
      compounds with a protective effect against possible injury of ischaemized and
      reoxygenized tissues. (Tab. 3, Fig. 4, Ref. 32.)

PMID- 10645033
TI  - [Bone turnover and bone density in type 1 diabetics in the initial stages of
      diabetic nephropathy].
AB  - OBJECTIVE: To compare the bone turnover and bone mineral density in type 1
      diabetic patients with normoalbuminuria and type 1 diabetic patients with
      diabetic nephropathy with microalbuminuria or mild proteinuria. METHODS: We
      studied 18 type 1 diabetic patients (Group A) with normoalbuminuria (UAE < 10
      micrograms/min) and 8 type 1 diabetic patients (Group B) with UAE 100-1000
      micrograms/min and serum creatinine below 150 mumol/l. Markers of bone formation
      (bone alkaline phosphatase--ALP-B, serum osteocalcin) and bone resorption (serum
      tartrate-resistant acid phosphatase--ACP-TR, urinary hydroxyproline) were
      determined. Bone mineral density (BMD) was measured at lumbar spine and right
      femoral neck. RESULTS: Serum ALP-B was higher in group B [median (95% CI), 518
      (405-1070) nkat/l] compared with group A [380 (355-510) nkat/l] (p < 0.05).
      Urinary hydroxyproline excretion was higher in group B [U-Hxp/U-creat 46.7 (22.9
      80) mumol/mmol] compared with group A [18.3 (8.9-22.7) mumol/mmol] (p < 0.001).
      No difference was found in serum osteocalcin and ACP-TR and in BMD at L2-L4 and
      femoral neck. CONCLUSIONS: We conclude that bone turnover was increased in type 1
      diabetic patients with incipient stage of diabetic nephropathy but there was no
      difference in BMD as compared with type 1 diabetic patients without nephropathy.
      This finding might indicate that biochemical markers unlike densitometry reflect
      initial changes in bone metabolism in preclinical diabetic nephropathy earlier.
      (Tab. 2, Ref. 17.)

PMID- 10645034
TI  - [The effect of monotherapy with ciprofibrate and in combination with
      acetylsalicylic acid on the spectrum of lipids, thromboxane and fibrinogen in
      patients with atherosclerosis and hyperlipoproteinemia].
AB  - Ciprofibrate is one of the basic drugs used to lower risk values of lipid
      parameters and fibrinogen in atherosclerosis patients. Since antiaggregation
      treatment with acetylsalicylic acid is a complex part of obligatory therapy of
      these patients, the authors studied the influence of ciprofibrate on chosen lipid
      parameters, fibrinogen and thromboxane in monotherapy, and also in combination
      with acetylsalicylic acid (ASA) in patients with advanced atherosclerosis and
      hyperlipoproteinemia. In the first group of patients (A-C, n = 12) after one
      month of low-lipid diet acetylsalicylic acid in a dose of 100 mg was administered
      daily during a period of 2 months followed by addition of 100 mg of ciprofabrate
      daily during the next 2 months. In the second group of patients (C-A, n = 11)
      after one month of low-lipid diet the same drugs were administered but in
      opposite order. Ciprofibrate was most effective in lowering the levels of
      triacylglycerids (-41%) and VLDL-cholesterol (-34%), but effectively lowered also
      the values of total cholesterol and LDL-cholesterol. In both studied groups it
      led to mild increase of HDL-cholesterol levels. Simultaneous administration of
      ASA did not significantly influence its hypolipemic activity. Ciprofibrate also
      significantly lowered the level of fibrinogen (-17%). Increase of the total
      number of platelets by about 10% was not accompanied by changes of the values and
      production of thromboxane. Simultaneous administration of ASA caused more than
      90% inhibition of thromboxane production in monotherapy and in combination with
      ciprofibrate. Ciprofibrate is an effective hypolipidemic agent, also lowering the
      level of fibrinogen. Its combination with ASA is adequate, safe and without
      negative interaction influencing treatment. (Tab. 6, Fig. 1, Ref. 16.)

PMID- 10645035
TI  - Reproductive medicine in the second half of the 20th century.
AB  - This communication reviews the most important achievements of human reproductive
      medicine during the last 50 years. The progress in this discipline has been so
      profound and unexpected that it has raised ethical questions of a fundamental
      character. Over the last 50 years of this century, new insight into reproductive
      processes enabled the following development: hormonal contraception, gonadotropin
      releasing hormone (GnRH) and its agonistic and antagonistic analogues,
      prostaglandins: induction of labor and conquering dysmenorrhea, selective
      estrogen receptor modulators (SERM), assisted reproductive technologies (ART),
      and recombinant DNA technology and cloning. Currently, safe and effective
      contraceptive methods are available. Control of the world population growth is
      not a medical issue anymore: it is a political and social problem. Governments,
      and national and ideological leaders must share the responsibility for creating a
      social and economic milieu that facilitates women's education, provides access to
      birth control methods, and motivates the population to limit its own growth. At
      the same time, society must foster traditional family and moral values Vis a Vis
      sex. (Fig. 6, Ref. 22.)

PMID- 10645036
TI  - Enalapril treatment of proteinuria in normotensive children.
AB  - A retrospective study was performed in 48 normotensive proteinuric children to
      evaluate the effect of enalapril (n = 17), a combination of enalapril and
      prednisone (n = 11) and prednisone alone (n = 20) on urinary protein excretion
      and systemic blood pressure. Enalapril treatment was associated with significant
      and persistent diminution of proteinuria from 1.32 +/- 0.23 to 0.53 +/- 0.11 and
      0.44 +/- 0.07 g/day on the 4th and 8th week of treatment, respectively. Combined
      therapy with enalapril and prednisone resulted in a comparable significant
      reduction of proteinuria from a pre-treatment value of 2.06 +/- 0.42 to 0.63 +/-
      0.22 and 0.52 +/- 0.17 g/day on the 4th and 8th week of treatment, respectively.
      In contrast to this, in the group treated with prednisone alone, proteinuria
      decreased significantly only from the 6th week of therapy (p < 0.02).
      Consequently, these children had significantly higher urinary protein losses at
      the 4th week of treatment as compared to patients on enalapril treatment (given
      either alone or combined with prednisone) (p < 0.01 and p < 0.05, respectively).
      Importantly, the enalapril-induced reduction of proteinuria was unrelated to
      variations in arterial blood pressure and no significant changes in this
      parameter were observed. The results indicate that enalapril can be used safety
      and effectively for symptomatic treatment of proteinuria in normotensive children
      with preserved renal function. ACE inhibitor provides additive antiproteinuric
      effect to corticosteroids by accelerating the rate of diminution of proteinuria.
      Its combination with prednisone may be of particular importance in those cases,
      where the degree of hypoproteinemia is a concern. (Tab. 2, Fig. 1, Ref. 29.)

PMID- 10645037
TI  - Partial liquid ventilation in the therapy of pediatric acute respiratory distress
      syndrome.
AB  - BACKGROUND: Acute respiratory failure represents life-threatening disease with
      persistently marked mortality and late morbidity in pre-term newborns (RDS-
      respiratory distress syndrome), children as well as, adults (ARDS--acute
      respiratory distress syndrome). We are probably in the period when better
      understanding of pulmonary pathophysiology enables the development of new
      technologies that can help in decreasing the morbidity and mortality of patients
      with respiratory failure. One of these unconventional methods is partial liquid
      ventilation (PLV). MAIN PURPOSE: The main aim of the study was to verify the
      possibility of treating potentially reversible respiratory failure in patients
      where extracorporeal life support (ECLS) was contraindicated and extracorporeal
      membrane oxygenation (ECMO) could not be used, or the patient had not met the
      criteria for ECMO. METHODS: PLV was used in 6 children totally, in 7 applications
      with severe hypoxemic respiratory failure. Preoxygenated perfluorocarbon Rimar
      101 (Miteni, Milan, Italy) warmed to 37 degrees C was applied intratracheally in
      the doses which corresponds with the functional residual capacity of lungs, the
      dose of perfluorocarbon was repeated every hour. Following parameters were
      recorded before, during and after PLV: pH, blood gases, ventilator setting,
      alveoloarterial difference for oxygen, dynamic compliance, and indices-
      oxygenation index and hypoxemia score (PaO2/FiO2). The values obtained 1 hour
      before PLV were compared with the values during PLV; the data before PLV and in
      the 3rd hour of PLV were evaluated statistically. RESULTS: Statistically
      significant increase of pH (7.22 vs 7.34, p < 0.05) and PaO2/FiO2 (72 vs 100
      Torr, p < 0.01) and decrease of FiO2 (82% vs 64%, p < 0.05) and oxygenation index
      (23 vs 17, p < 0.05) occurred during 3 hours of PLV. CONCLUSION: Partial liquid
      ventilation is an effective method for controlling ARDS in certain groups of
      patients with severe lung disease. (Tab. 4, Ref. 15.)

PMID- 10645038
TI  - [The effect of glycosaminoglycan sulodexide on albuminuria in patients with
      diabetes mellitus].
AB  - BACKGROUND: Experimental and clinical studies showed a decrease in albuminuria, a
      marker of diabetic nephropathy after administration of heparin or other
      glycosaminoglycans (GAG). OBJECTIVES: To study the effect of sulodexide on
      albumin excretion rate (AER) in patients with type 1 or type 2 diabetes mellitus
      (DM). METHODS: Twenty patients (12 of type 1 DM) aged 33-63 yrs (median 45) with
      microalbuminuria (AER 20-200 micrograms/min) or macroalbuminuria (AER > 200
      micrograms/min) were enrolled in open study and received sulodexide 60 mg/day
      i.m. for 3 weeks with further 6-week follow-up without treatment. In the 2nd
      phase, sulodexide 100 mg/day was given p.o. for 8 weeks with further 8-weeks
      follow-up. Albuminuria in overnight urine samples was analyzed by the RIA method
      and results (medians with lower and upper quartiles) were compared by the
      Wilcoxon test. RESULTS: In the 1st phase, AER (microgram/min) decreased from 167
      (54-378) at baseline to 118 (78-220) at week 1 (p < 0.05), 105 (68-341) at week 2
      (p < 0.05), and to 114 (56-354) at week 3 (NS). After stopping the treatment, AER
      gradually raised to baseline values. During the oral phase, AER decreased from
      253 (37-961) to 137 (35-323) after 1 month (p < 0.05) and to 144 (47-588) after 2
      months (NS). This effect was prolonged for further 2 months after treatment
      withdrawal (AER 110 (65-363) micrograms/min, p < 0.05). In both phases, the
      decrease in AER was shown only in patients with macroalbuminuria, but not in
      those with microalbuminuria. Blood pressure, glomerular filtration rate and
      metabolic compensation of DM were not changed. CONCLUSION: A short-term treatment
      with sulodexide i.m. or p.o. significantly decreased albuminuria in DM patients.
      This effect was prolonged for further 2 months after oral administration.
      Therefore, sulodexide could be useful in the treatment of diabetic nephropathy.
      (Tab. 3, Ref. 20.)

PMID- 10645039
TI  - [General principles of drug evaluation within the framework of drug policy].
AB  - This paper reviews the problems connected with drug evaluation in particular
      periods of its development. Requirements for drug registration, which represents
      the entrance of the drug on the market, are created by legislation. Drug
      application in the therapeutic process is determined by several factors and state
      regulations. The amount of evidence, reliability and validity of the facts should
      be the key factors of drug selection within the ambit of drug politics.
      Categorization of drugs means drug selection with regard to state reimbursement
      by means of health-insurance companies. Methods of drug categorization together
      with further regulations by means of positive letters, hospital blanks, should
      respect the criteria of professionality, transparency and sociopharmacology.
      Effective prognostication of drug use should ensure well-proportioned
      accessibility of effective safe drugs within the ambit of rational
      pharmacotherapy.

PMID- 10645040
TI  - [Hypertension in pregnancy].
AB  - Hypertensive disorders are the most common medical complications of pregnancy and
      are an important cause of maternal and perinatal morbidity and mortality. The
      author presents a review on Hypertension in pregnancy from the point of view of
      classification, diagnosis and treatment. According to JNC 6 and WHO/ISH
      recommendations hypertensive disorders of pregnancy can be divided into three
      categories: 1. chronic hypertension, 2. transient hypertension, 3. preeclampsia;
      preeclampsia superimposed on chronic hypertension. (Tab. 3, Ref. 23.)

PMID- 10645041
TI  - [Carnosine in patients with type I diabetes mellitus].
AB  - Examination of carnosine in patients with diabetes mellitus type I, showed that
      the plasma levels of carnitine were non significantly increased compared to the
      levels in healthy population, while the levels in red cells were decreased
      Lowered levels of carnosine in red cells could point out similar deficit in other
      cells. Due to low levels in cells carnosine is less available for metabolic
      processes, like antioxidant reactions and its participation in antioxidants
      defense reactions is limited non-enzymatic glycosylation of proteins. Therefore
      it should be supplemented. (Tab. 1, Fig. 1, Ref. 15.)

PMID- 10645042
TI  - [Nutrition and female breast tumors].
AB  - This review presents current knowledge of diet and breast cancer. In the first
      part it reviews current knowledge of nutritional risk factors. Obesity, total
      energy intake, intake of saturated fatty acids and alcohol were considered as
      high risk factors for breast cancer in the past. In addition to these factors
      intake of n-6 and n-3 polyunsaturated fatty acids has been discussed. Possible
      differences between their carcinogenic activity are summarized. The mechanisms of
      promotion and inhibition are described in the present review. In the second part
      there protective nutritional factors are reviewed: fiber, antioxidant
      micronutrients (vitamin C, vitamin b-A, carotene and other carotenoids, vitamin
      E, antioxidant trace elements), n-3 polyunsaturated fatty acids, olive oil and
      oestrogen compounds of plant origin. Influence of several diet components can not
      be considered individually. Nutrition has to be taken into account as a whole
      complex of protective and risk components. It is necessary to increase the intake
      of probably protective nutrients and minimize all cancer risk factors including
      nutrition. (Tab. 2, Fig. 3, Ref. 181.)

PMID- 10645043
TI  - [Recurrent eruptions of herpes zoster].
AB  - BACKGROUND: Repeated eruptions of herpes zoster are frequently detected in
      immunocompromised patients, but rarely may occur also in immunocompetent persons.
      While detailed analyses of repeated manifestations of this disease in the
      literature are scarce, experience with a small group of affected persons is
      presented. AIMS OF THE STUDY: To search for the nature of herpes zoster relapses
      occurrence and to use it in treatment quality improvement. METHODS: Analysis and
      processing of clinical documentation of the first and repeated eruptions of
      herpes zoster in 12 patients. Study of sex and age, presence of accompanying
      diseases, duration of the interval from the first eruption to the relapse,
      localization, complications and relation to antiviral therapy. RESULTS: The
      interval between the first and repeated manifestation ranged from 1 week to 30
      years. The male to female ratio was 10/2. In 3 patients the disease was
      accompanied by malignancy, in 3 by diabetes mellitus and in 1 by proved
      immunodeficiency. The most frequent eruption localization was intercostal space.
      In 6 patients the relapse was localized at the same site, in 6 of them at
      different. Early relapses in the same localization appeared in immunodeficient
      persons and also in persons after the first attack treatment with acyklovir.
      Primary manifestation was accompanied by complications in 42%, repeated in 92%.
      CONCLUSIONS: Early herpes zoster relapses following shortly after the primary
      attack treated with acyklovir should be considered as a manifestation of immunity
      disorder requiring immediate treatment with other antiviral drug. Late relapses
      can be treated with acyclovir. (Tab. 2, Fig. 2, Ref. 22.)

PMID- 10645044
TI  - Clinical significance of changes in serum hepatitis B virus DNA titer in patients
      with chronic hepatitis B treated with interferon.
AB  - BACKGROUND: Interferon (IFN) has been used in the treatment of patients with
      chronic hepatitis B virus (HBV) infection. Nonetheless, the changes in serum HBV
      DNA titer during IFN treatment and the effect of these changes on the therapeutic
      results have not been well studied. METHODS: Twenty patients with chronic
      hepatitis B who were positive for serum hepatitis B e antigen (HBeAg) and HBV DNA
      received IFN-alpha 2a 4.5 million units by subcutaneous injection three times a
      week for 24 weeks. Twenty age- and sex-matched patients with chronic hepatitis B
      were selected as a control group. Treatment response was defined as the
      normalization of serum alanine aminotransferase (ALT) and the seroconversion of
      serum HBeAg 24 weeks after discontinuation of the IFN treatment. Serum HBV DNA
      was measured using the branched DNA (bDNA) signal amplification assay. RESULTS:
      There was no significant difference in pretreatment mean serum ALT and HBV DNA
      titer in either the IFN-treated or the control group. Treatment response was
      found in six (30%) of 20 IFN-treated patients and in four (20%) of 20 control
      patients (p > 0.05). Serum HBV DNA titer fell after IFN treatment and remained
      undetectable only in patients with final treatment response. Serum HBV DNA was
      negative at week 12 of the IFN treatment in four (67%) of six patients with
      treatment responses, significantly higher than in none (0%) of 14 patients
      without a treatment response (p = 0.001). Multivariate logistic regression
      revealed that the negativity of serum HBV DNA at week 12 of the IFN treatment
      successfully predicted treatment response. CONCLUSIONS: Thirty percent of the
      patients with chronic hepatitis B responded to IFN-alpha 2a 4.5 million units
      subcutaneously injected three times a week for 24 weeks. Negativity of serum HBV
      DNA measured by bDNA assay at week 12 of the IFN treatment may suggest a
      beneficial treatment outcome.

PMID- 10645045
TI  - Safety and efficacy of the platelet glycoprotein IIb/IIIa inhibitor abciximab in
      Chinese patients undergoing high-risk angioplasty.
AB  - BACKGROUND: Platelets are believed to play a role in the ischemic complications
      of coronary angioplasty, such as abrupt closure of coronary vessels during or
      soon after the procedure. Accordingly, we evaluated the effect of a chimeric
      monoclonal antibody abciximab, directed against the platelet glycoprotein
      IIb/IIIa receptor, in patients undergoing angioplasty who were at high risk for
      ischemic complications. This receptor is the final common pathway for platelet
      aggregation. METHODS: In a prospective, double-blind trial, we randomly assigned
      42 patients to receive a bolus and an infusion of placebo or a bolus and an
      infusion of abciximab. Low-dose, weight-adjusted heparin (initial dose of 70 U/kg
      of body weight) was used in both groups. Patients underwent coronary angioplasty
      for high-risk clinical situations involving unstable angina or high-risk coronary
      morphologic characteristics. The primary study end-point consisted of any of the
      following: death, nonfatal myocardial infarction, unplanned surgical
      revascularization, unplanned repeat percutaneous procedure, unplanned
      implantation of a coronary stent, or insertion of an intra-aortic balloon pump
      for refractory ischemia within 30 days of randomization. RESULTS: Compared with
      placebo, the abciximab resulted in a trend toward reduction in periprocedural
      myocardial infarction from 15% to 0%, although the differences were not
      statistically significant (p = 0.099). There were no significant differences
      between the two groups in the risk of major and minor bleeding and the need for
      blood transfusion. CONCLUSIONS: Inhibition of platelet glycoprotein IIb/IIIa
      receptor with abciximab, together with low-dose, weight-adjusted heparin, had a
      favorable trend toward the reduction of periprocedural myocardial infarction in
      patients undergoing high-risk angioplasty, without increasing the risk of
      hemorrhage.

PMID- 10645046
TI  - Survival rate for liver cancer in Taiwan.
AB  - BACKGROUND: There is no nationwide population-based study of the survival rate
      for liver cancer in Taiwan. Consequently, the true rate of liver cancer survival
      is unknown. Our aim was to determine the survival rate for liver cancer patients
      in Taiwan. METHOD: The Taiwan Cancer Registry was searched for liver cancer cases
      in 1987 and 2,558 cases were found. Of these, 485 lacked an identification
      number, 29 lacked documentation of age, 33 were metastatic, nine lived in Kinmen
      and Lienkiang Hsien of Fukien Province leaving 2,002 to be studied. With the help
      of identification numbers, we linked our cases with the Death Registry of the
      Department of Health, Executive Yuan, ROC, for the 1987 to 1992 period and
      calculated the five-year survival rate using actuarial life tables. For analyzing
      factors affecting the five-year survival rate, multivariate analysis with the Cox
      proportional hazards model was used. RESULTS: Of the 2,002 patients, 752 were
      diagnosed histopathologically and 1,250 patients were diagnosed clinically. A
      total of 15% of patients survived for five years or longer after diagnosis. Of
      those diagnosed histopathologically, 17% survived for five or more years, and of
      those diagnosed clinically, 13% survived for five or more years. The sex, age,
      residential area and ethnic origin did not affect the five-year survival rate
      significantly. Only diagnosis type affected the five-year survival rate
      significantly (p < 0.05). The 660 pathologically diagnosed liver cancer patients
      had a better survival rate than the 1,250 patients diagnosed clinically.
      CONCLUSIONS: The overall five-year survival rate for liver cancer in Taiwan was
      15%. The prognosis for liver cancer patients in Taiwan is still unfavorable. The
      aim is to persuade affected patients to accept treatment.

PMID- 10645047
TI  - Grip and key pinch strength: norms for 15- to 22-year-old Chinese students.
AB  - BACKGROUND: Establishment of norms for hand strength is emerging worldwide and is
      both important and necessary in public health and hand surgery. The purpose of
      this study was to establish normative data for hand grip and key pinch strength
      for 15- to 22-year-old Chinese students. METHODS: The Jamar dynamometer was used
      to measure grip strength and the Jamar pinch gauge to measure key pinch strength.
      All subjects were free of disease or injury that might affect hand strength. All
      complementary factors such as age, sex, height, weight, dominant hand for writing
      and exercise were recorded. The influences of injury, exercise and living habits
      on the performance of hand strength were also examined. RESULTS: Out of a total
      of 2,982 students examined, there were nine men (0.39%) who used the left hand
      for writing, 143 men (6.27%) who used the left hand during exercise, two women
      (0.28%) who wrote with the left hand and 26 women (3.70%) who used the left hand
      during exercise. The mean grip and key pinch strength of the left hand was about
      90% that of the right hand. The mean grip and key pinch strength of the women was
      about 60% that of men. CONCLUSIONS: A strong correlation between the right hand
      and the left hand in grip and key pinch strength was found. Whether
      nonanthropometric factors may affect hand strengths was explored as well.

PMID- 10645048
TI  - Effect of mitomycin C for combined trabeculectomy and phacoemulsification.
AB  - BACKGROUND: To evaluate the efficacy and safety of intraoperative mitomycin C
      (MMC) for trabeculectomy combined with phacoemulsification (phacotrab) in
      patients with coexisting glaucoma and cataract. METHODS: We retrospectively
      reviewed the charts of consecutive patients who underwent phacotrab from July,
      1996, to March, 1998. The pre- and postoperative intraocular pressure (IOP),
      number of glaucoma medications, visual acuity (VA), and postoperative
      complications were compared among 22 patients (22 eyes) who received
      intraoperative MMC and 18 patients (18 eyes) who did not receive MMC, served as
      the control group. Data of age, gender, type of glaucoma, number of glaucoma
      medications, cup-to-disc ratio of the optic nerve and the extent of visual field
      defects were also evaluated. Kaplan-Meier survival analysis was used to compare
      the surgical success rates between two groups. RESULTS: The mean IOP decreased
      from 16.1 +/- 4.2 mmHg to 10.94 +/- 3.6 mmHg in the MMC group, and from 18.7 +/-
      6.9 mmHg to 14.6 +/- 1.9 mmHg in the control group at one year of follow-up. The
      mean postoperative IOPs were significantly lower in the MMC group than in the
      control group at one week, two weeks, and one, two, nine and 12 months.
      Postoperative mean VA log10 minimum angle of resolution (MAR) improved
      significantly in both groups. The mean number of medications decreased from 1.91
      +/- 0.75 to 0.18 +/- 0.50 in the MMC group, and from 1.89 +/- 0.47 to 0.72 +/-
      0.75 in the control group (p < 0.001 for both). The one-year complete success
      rate was significantly higher in the MMC group (p = 0.0038) than in the control
      group. No major complication was found throughout the study. CONCLUSIONS:
      Intraoperative MMC in phacotrab may improve postoperative filtration with less
      dependence on glaucoma medication. No significant adverse effects were associated
      with MMC application.

PMID- 10645049
TI  - Clinicopathologic analysis of renal and extrarenal angiomyolipomas: report of 44
      cases.
AB  - BACKGROUND: Angiomyolipoma (AML) is a rare soft tissue tumor involving the
      kidneys, liver and other visceral organs. It is composed of smooth muscle cells,
      adipocytes and small- to medium-sized hyalinized vessels. The purpose of this
      study was to investigate the characteristic clinicopathologic manifestations of
      AML in different tissues. METHODS: We collected 37 renal, four hepatic, one lymph
      node, one subcutaneous and one uterine cervical AML to analyze the clinical,
      histologic, histochemical and immunohistochemical variations of AML in different
      tissues. RESULTS: Clinically, renal and hepatic AML were associated with tuberous
      sclerosis complex and predominate in women. There were several prominent
      pathologic differences between renal and extrarenal AML. First, none of the
      tumors were encapsulated except for the subcutaneous AML, which had a
      pseudocapsule. Secondly, the smooth muscle cells were usually epithelioid shaped
      in hepatic AML and occasionally in renal AML, but not in subcutaneous or uterine
      AML. Furthermore, hepatic AML characteristically showed extramedullary
      hematopoiesis and eosinophilic hyaline granules. Finally, only the tumor cells of
      renal, lymph node and hepatic AML had periodic acid-Schiff (PAS), PAS-D (after
      diastase digestion) positive granules and monoclonal mouse anti-human melanosome
      clone (HMB-45) immunoreactivity. CONCLUSIONS: By combining the clinical,
      histologic, histochemical and immunohistochemical features, some discrepancies
      between the renal and extrarenal AML were observed, such as female predominance,
      association with tuberous sclerosis complex, morphology of the smooth muscle
      cells, presence of PAS, PAS-D positive granules and HMB-45 immunoreactivity in
      tumor cells. Extramedullary hematopoiesis and hyaline globules are unique to
      hepatic AMLs. These specific pathologic manifestations not only implicate the
      histogenesis of AML from different organs, but also assist in making a correct
      diagnosis.

PMID- 10645050
TI  - Acute lymphoblastic leukemia in young adults: two chemotherapeutic protocols for
      the treatment of 46 patients.
AB  - BACKGROUND: Acute lymphoblastic leukemia (ALL) in adults has a very poor
      prognosis. Many chemotherapeutic protocols have been designed to try to improve
      treatment results for adult ALL. Two chemotherapeutic protocols were used to
      treat young adult ALL patients in our institute and treatment results are
      reported. METHODS: From 1984 through 1997, 46 young adult patients with ALL were
      treated. There were 43 males and three females. Their ages ranged from 16 to 38
      years, with a median of 24 years. Thirty-two patients (group A) received a four
      week conventional induction regimen with daunomycin, vincristine, prednisolone,
      and L-asparaginase, followed by prophylaxis of the central nervous system (CNS)
      with intrathecal methotrexate and cranial irradiation, as well as maintenance
      therapy with oral 6-mercaptopurine and methotrexate. Fourteen patients (group B)
      received the modified protocol of the German multicenter trial for adult ALL
      (GMALL) with a two-phase induction regimen, CNS prophylaxis and maintenance
      therapy. RESULTS: In group A, 25 of 32 patients achieved complete remission (CR),
      three obtained partial remission and four died of treatment-related complications
      during induction therapy. The median duration of remission (DR) was 12 months
      (range, 3-39 months) and the median overall survival time (OST) was 13 months
      (range, 0.5-50 months). Of the 25 patients who achieved CR, 21 relapsed and died.
      In group B, 11 of 14 patients obtained CR and three died of leukopenia-related
      infectious complications during induction. The median DR was 12 months (range, 8
      37 months) and the median OST was 15 months (range, 0.5-39 months). During follow
      up, 10 of 11 patients relapsed from ALL and died. Only one patient who received
      allogeneic bone marrow transplantation first CR is still alive. No statistical
      differences between the two groups were noted in terms of CR rate, DR (p = 0.87)
      and OST (p = 0.34). However, the the GMALL protocol had during the significantly
      more hematologic toxicity during induction therapy. CONCLUSIONS: Our results
      suggest that young adult ALL is a disease with a very poor prognosis and
      conventional chemotherapy is not adequate for its treatment. The notion that
      GMALL protocol is better than conventional therapy in the treatment of adult ALL
      cannot be justified by our data.

PMID- 10645051
TI  - Hepatocellular carcinoma presenting as a pyogenic liver abscess in a patient with
      hemochromatosis.
AB  - Primary hemochromatosis is rare in Taiwan. Hepatocellular carcinoma (HCC) is
      endemic in Taiwan, but HCC with initial presentation as pyogenic liver abscess is
      unusual. We report a case of HCC presenting as pyogenic liver abscess in a
      hemochromatotic patient with cirrhosis. The patient underwent hepatectomy and had
      a smooth postoperative course. Unfortunately, he died of pneumonia eight months
      after surgery. HCC should be considered in the differential diagnosis in
      hemochromatotic patients with a pyogenic liver abscess.

PMID- 10645052
TI  - Precipitate delivery and postpartum hemorrhage after term induction with 200
      micrograms misoprostol.
AB  - Misoprostol has been widely applied in early pregnancy termination and term
      pregnancy induction. However, the upper dosage limit of misoprostol through
      vaginal route has not been firmly established. Most popular dosages of vaginal
      misoprostol recommended are 25, 50 or 100 micrograms. There are no reports on the
      dangers of high-dosage misoprostol 200 micrograms as used in term labor
      induction. We present a primiparaous woman who was administered 200 micrograms
      misoprostol vaginally for term labor induction. The following precipitate
      delivery resulted in multiple lacerations of the isthmus, cervix and vagina,
      postpartum hemorrhage and disseminated intravascular coagulopathy. Inevitably, a
      hysterectomy was performed. A postsurgical check of the uterus confirmed
      lacerations of the isthmus and internal cervix. This rare complication suggests
      the possible dangers of vaginal misoprostol doses as high as 200 micrograms for
      term induction of labor at term.

PMID- 10645053
TI  - Angiotropic lymphoma manifesting as a solitary adrenal tumor in a case of
      ankylosing spondylitis.
AB  - Angiotropic lymphoma is an extremely rare disease characterized by intravascular
      accumulation of large neoplastic lymphocytes, with the clinical manifestations of
      fever, skin lesions and neurologic deficits. We report a patient who developed
      angiotropic lymphoma after a 10-year history of ankylosing spondylitis. The
      clinical disease manifested as a unilateral, solitary adrenal tumor, fever and
      body weight loss. The fever subsided after surgical removal of the adrenal tumor.
      Systemic chemotherapy was administered postoperatively. The patient was leading
      an uneventful life 44 months after the initial diagnosis. To our knowledge, this
      is the first case of angiotropic lymphoma associated with ankylosing spondylitis.
      It is also the second reported case manifesting with a unilateral solitary
      adrenal tumor without systemic involvement.

PMID- 10645054
TI  - Combined spinal-epidural anesthesia for cesarean section in a patient with
      Takayasu's disease.
AB  - We describe a successful episode of anesthesia management in a parturient
      affected with Takayasu's disease who underwent elective cesarean section under
      combined spinal-epidural anesthesia. Takayasu's disease is characterized by
      chronic occlusive inflammation of the arteries (panarteritis) of unknown origin
      that usually involves the aorta and its main branches. Progression of the disease
      may be marked by aneurysmal dilation of the affected arteries and may lead to a
      fatal outcome, usually from cerebral ischemia or heart failure. The impact of
      pregnancy on Takayasu's disease is unclear, but worsening of ischemic symptoms,
      cardiac failure, aggravation of hypertension and cerebral hemorrhage have been
      reported in sufferers who are in the later stages of pregnancy. Nonetheless,
      anesthesia management of a parturient with advanced Takayasu's disease presents a
      challenge to anesthetists.

PMID- 10645055
TI  - Phenotypic heterogeneity in a Chinese family with mitochondrial disease and
      A3243G mutation of mitochondrial DNA.
AB  - The A3243G mutation of mitochondrial DNA (mtDNA) has been shown to be responsible
      for or associated with mitochondrial myopathy, encephalopathy, lactic acidosis,
      strokelike episodes (MELAS) syndrome, diabetes mellitus (DM) and several other
      neuromuscular diseases. We used polymerase chain reaction (PCR)-restriction
      fragment length polymorphism (RFLP) to identify the A3243G mtDNA mutation and an
      electron microscope to examine mitochondrial derangement in the muscle biopsies
      of a 38-year-old man suspected to have MELAS syndrome with DM. We found great
      variability in the clinical presentation and in the proportion of mtDNA with the
      A3243G mutation in the matrilineal family members of the patient. The proband had
      atypical MELAS syndrome, recurrent vascular headache, and DM (MELASDM), and his
      mother manifested chronic progressive ptosis and DM (CPPDM). Brain magnetic
      resonance imaging of the proband showed high signal intensity in the left
      temporoparieto-occipital area on T2 weighted images (T2WI). The blood lactate
      level ranged from 2.32 to 4.70 mmol/l, and two-hour postprandial glucose ranged
      from 124 mg/dl to 148 mg/dl. The blood lactate and postprandial glucose of the
      proband's mother were 3.15 mmol/l and 192 mg/dl, respectively. Electron
      microscopic examination of a muscle biopsy of the patient showed abnormal
      mitochondria with decreased density of cristae and membrane degeneration. No
      ragged-red fibers were detected in muscle upon staining with modified Gomori
      trichrome. The hair follicles and blood cells of the patient and his mother
      showed the A3243G mutation in the tRNA(Leu)(UUR) gene. The proportions of the
      mutant DNA in the hair follicles and blood cells of the proband were 36.8% and
      35.2%, respectively, and those of the patient's mother were 28.8% and 13.9%,
      respectively. We conclude that the A3243G mtDNA mutation may manifest with
      MELASDM or CPPDM in different matrilineal members of the same family as a result
      of differences in random segregation of the heteroplasmic A3243G mutant mtDNA in
      the affected tissues of patients.

PMID- 10645056
TI  - Pancreaticocolonic fistula after extensive corrosive injury from esophagus to
      jejunum.
AB  - We report a case of extensive corrosive injury to the jejunum after ingestion of
      about 200 ml of hydrochloric acid as an attempted suicide. Subtotal
      esophagectomy, total gastroduodenectomy, segmental resection of the jejunum and
      partial pancreatectomy were performed in the first two operations. Forty-five
      days after surgery, the patient was well and discharged. Six months later, the
      patient underwent esophageal reconstruction surgery. During surgery, a
      pancreaticocolonic fistula between the head of the pancreas and the transverse
      colon was found. The esophageal reconstruction using the transverse colon was
      performed via the retrosternal route.

PMID- 10645057
TI  - Cholesterol crystal embolization causing acute renal failure.
AB  - Acute renal failure due to cholesterol embolization is a complication of severe
      generalized arteriosclerotic disease. It occurs spontaneously, or more often, as
      a complication of major medical or surgical procedures such as angiography and
      vascular surgery. The demonstration of characteristic cholesterol crystals in
      tissue biopsy specimens is a pathognomonic finding. However, renal cholesterol
      embolism may be clinically diagnosed when renal failure develops after known
      inciting factors or together with systemic manifestations of atheromatous
      embolization such as lower extremity livedo reticularis and focal digital
      ischemia. We report two cases of acute renal failure in which cholesterol
      embolization was found in skin and renal biopsies. One patient's renal function
      stabilized, but not to the basal level and the other patient developed end-stage
      renal disease.

PMID- 10645058
TI  - Tubulocystic ovarian clear cell carcinoma with abundant fibrous stroma: malignant
      clear cell adenofibroma.
AB  - We report a case of tubulocystic ovarian clear cell carcinoma (OCCC) with
      abundant fibrous stroma associated with an endometriotic cyst. Most OCCC show a
      small amount of fibrous stroma; however, the tumor presented in this case had
      abundant stroma, that qualifies it as a malignant clear cell adenofibroma. This
      unusual type of clear cell carcinoma may be misinterpreted as a benign lesion or
      as metastatic carcinoma on frozen section. In permanent sections, the stromal
      invasive foci are focal, small and subtle. Therefore, extensive sampling of the
      specimen to search for evidence of invasion is recommended for a fibrous ovarian
      tumor that appears benign on gross examination.

PMID- 10645059
TI  - [Anatomo-clinical incongruities in acute cholecystitis. Apropos of 271 cases
      treated by laparoscopic surgery].

PMID- 10645060
TI  - [Liver abscess secondary to ingestion of foreign body. A case report].
AB  - Hepatic abscess is a serious surgical problem with a high mortality rate. The
      Authors report a case of a liver abscess following the migration of a toothpick
      from the stomach into the hepatic left lobe. Percutaneous abscess drainage
      combined with endoscopical removal of the foreign body were the goal treatment.
      The Authors stress importance of the laparoscopy-guided drainage with placement
      of intra-hepatic drains.

PMID- 10645061
TI  - [Acute postoperative acalculous cholecystitis: case report and review of the
      literature].
AB  - Postoperative acute acalculous cholecystitis is condition observed after
      gastrointestinal operations, traumatism or long assisted ventilation periods. The
      Author report the case of a patient operated for gastric carcinoma with the
      evolution of an acute cholecystitis on 5th postoperative day. The clinic and the
      diagnostic findings weren't able to remove the doubts and the patient is
      reoperated: there was not anastomotic leak, but the evidence of an acute
      acalculous cholecystitis, with thickened walls. The review of the literature show
      that few cases of the acute acalculous postoperative cholecystitis are reported.

PMID- 10645062
TI  - [Synchronous and metachronous colorectal cancers: a case series contribution].
AB  - The Authors, on the basis of their experience with neoplastic colorectal
      pathology and after a review of the Literature, report a reappraisal of the
      problems related to colorectal multiple carcinomas. They emphasize the importance
      of routine preoperative pancolonoscopy for the identification of possible
      synchronous tumors (both benign and malignant) and periodic endoscopic follow-up
      (ideally a life-long one) for the detection and removal of all adenomatous polyps
      as well as early stage metachronous carcinomas, especially for patients with
      HNPCC. Besides, they stress the importance of sensibilization of the population
      about the heritability of colorectal carcinomas.

PMID- 10645063
TI  - Post traumatic pseudocyst of the spleen: case report on a conservative management
      through percutaneous drainage.
AB  - Non-parasitic cysts of the spleen are uncommon and often result from blunt
      abdominal trauma. These lesions are classified as splenic pseudocysts. Until
      recently, splenectomy has been the primary choice of treatment of these
      pseudocysts. The trend for treatment of spleen cysts is now towards a
      conservative management. The case reported herein is an example of a post
      traumatic splenic pseudocyst successfully treated with a conservative approach
      (ultrasound aided percutaneous drainage). In most tropical countries, also in
      view of lack of resources and expertise, a conservative non-surgical of post
      traumatic spleen cysts management could be appropriate and feasible under certain
      circumstances.

PMID- 10645064
TI  - [Cholelithiasis in men. Observations on a case series of surgically treated 3,047
      patients].
AB  - Age and clinical presentation as acute cholecystitis have widely been found to be
      predictors of outcome after cholecystectomy. Recently, male gender has been cited
      in several studies as a possible prognostic factor. A single Institution
      cholecystectomy registry (3.047 cases between 1959-1997) comprising 966 (31.7%)
      men and 2.81 (68.3%) women was retrospectively analysed. Men experienced
      significantly higher rate of major complications (5.3% vs 3.2%; p < 0.01) and
      mortality (1.55% vs 0.62%; p < 0.03). By logistic regression analysis, it was
      found that male gender, acute cholecystitis, respiratory and cardiovascular
      system disease were significantly related to postoperative morbidity. Age older
      than 65 years, male gender, respiratory and cardiovascular diseases were factors
      negatively affecting operative mortality.

PMID- 10645065
TI  - [Splenectomy in immune thrombocytopenia and other hematological diseases].
AB  - The Authors report a retrospective study of 74 splenectomies performed for
      hematologic diseases. The role of splenectomy has changed over recent years with
      increased indications for immune thrombocytopenic purpura (ITP). The aim of this
      study was to assess indications to surgery in relation to clinical presentation
      with typical hemorrhagic features or severe thrombocytopenia only; interval
      between onset of symptoms and splenectomy; failure of medical management and
      complications from steroid administration; scintigraphic studies predictive of
      response to splenectomy and preoperative treatment in patients with severe
      thrombocytopenia were also studied. The Authors reported response rates to
      splenectomy of 84% without mortality and only 11% of postoperative complications.
      These results encouraged to surgery for treatment of those patients with severe
      thrombocytopenia, who fail to obtain remission or develop serious complications
      after medical therapy. The splenectomy cured severe thrombocytopenia also in some
      patients with acquired immunodeficiency (HIV+). Moreover the Authors discuss the
      indications in patients with chronic lymphatic leukaemia and lymphoma diseases.
      In selected patients the splenectomy has the potential to relieve symptoms due to
      splenomegaly, correct cytopenias, specify hystological diagnosis and modify the
      disease course of malignant lymphomas. In fact splenomegaly sometimes complicated
      the course of malignant lymphomas because of hematologic abnormalities that are
      inconsistent with active chemotherapy.

PMID- 10645066
TI  - [A case of strangulated trans-omentum hernia].
AB  - After a review of the Literature, the Authors report a case of intestinal
      obstruction caused by trans-omentum hernia. This unusual disease is due to a
      defect of the greater omentum with herniation and secondary strangulation of
      small bowel. The clinical presentation was that of an intestinal obstruction with
      rare possibility of preoperative diagnosis. Therefore, a correct knowledge of
      this pathology and immediate surgery are necessary for the prognosis.

PMID- 10645067
TI  - [Recurrent esophageal obstruction by a foreign body: a case report and review of
      the literature].
AB  - The Authors report a clinical case of a patient endoscopically treated for
      recurrent oesophageal obstruction by a foreign body. A review of the recent
      medical literature confirms that immediate endoscopic treatment is the best
      approach in the oesophageal retention of foreign bodies.

PMID- 10645068
TI  - [The role of the surgeon in a domiciliary peritoneal dialysis program].
AB  - The Authors report their surgical experience with 54 ESRD patients treated with
      peritoneal dialysis (PD). Guidelines on videolaparoscopic surgical treatment have
      been described and in 13 patients peritoneal catheter (PC) was inserted by
      videolaparoscopy (VL). They performed five VL cholecystectomies, in four cases
      combined with the PC insertion, in one PD patient without PD interruption. In
      three cases VL was useful in diagnosis and treatment of PC malfunction. A
      protocol has been done to treat hernias or laparocele before starting PD or
      during the course of PD and to prevent their recurrence. Two patients were
      operated for hernia or laparocele before PC insertion, seven patients during PC
      insertion. Seven patients were operated for hernia or laparocele developed during
      PD treatment, one of them in emergency for intestinal strangulation. One patient
      was operated for epigastric laparocele after an hypogastric laparocele
      correction. Prosthetic mesh repair was performed in every patient.

PMID- 10645069
TI  - [Problems inherent in the diagnosis and treatment of common bile duct calculi
      during video-laparoscopic cholecystectomy. Report on 700 cases, February 1991 to
      December 1997].
AB  - Conditions of predictivity seem to make treatment of common bile duct (CBD)
      stones during VLC more safe and adequate. IV cholangiography (or, nowadays, MRI
      and echoendoscopy) drive to a selective use of ERCP and cholangiography, help to
      reduce the incidence of residual lithiasis and give a "topographical map" of the
      CBD that can be useful, during VLC, in the search of the hilum structures,
      especially when the anatomical situation is not clear.

PMID- 10645070
TI  - [Identification of an experimental model of partial portocaval shunt].
AB  - Portacaval shunt with interposition of 6 mm H-graft of PTFE is a real partial
      shunt. In this experimental study, the operation has been well tolerated and has
      been compared with 8 mm H-graft and direct "vein to vein" portacaval shunt.
      Intraoperative data show that 6 mm is the ideal diameter for a portacaval shunt
      to prompt an experimental model based on partial decompression of portal bed in
      animals in this size.

PMID- 10645072
TI  - The rise and fall of the physician practice management industry.
AB  - The dominant view among academic economists is that the financial markets value
      financial securities "efficiently," in the sense that the prevailing prices of
      widely traded securities fully and properly reflect, at any time, all publicly
      available information that bears on these securities. Although that theory has
      great intuitive appeal, it requires intellectual effort to reconcile it with the
      rise and fall of the physician practice management industry. This paper explores
      how acquisition-driven firms are valued in the financial markets and what
      structural factors may stand in the way of truly efficient security valuation.

PMID- 10645071
TI  - The fall of the house of AHERF: the Allegheny bankruptcy.
AB  - The $1.3 billion bankruptcy of the Allegheny Health, Education, and Research
      Foundation (AHERF) in July 1998 was the nation's largest nonprofit health care
      failure. Many actors and factors were responsible for AHERF's demise. The system
      embarked on an ambitious strategy of horizontal and vertical integration just as
      reimbursement from major payers dramatically contracted, leaving AHERF overly
      exposed. Hospital and physician acquisitions increased the system's debt and
      competed for capital, which sapped the stronger institutions and led to massive
      internal cash transfers. Management failed to exercise due diligence in many of
      these acquisitions. Several external oversight mechanisms, ranging from AHERF's
      board to its accountants and auditors to the bond market, also failed to protect
      these community assets.

PMID- 10645073
TI  - Capital finance and ownership conversions in health care.
AB  - This paper analyzes the for-profit transformation of health care, with emphasis
      on Internet start-ups, physician practice management firms, insurance plans, and
      hospitals at various stages in the industry life cycle. Venture capital,
      conglomerate diversification, publicly traded equity, convertible bonds, retained
      earnings, and taxable corporate debt come with forms of financial accountability
      that are distinct from those inherent in the capital sources available to
      nonprofit organizations. The pattern of for-profit conversions varies across
      health sectors, parallel with the relative advantages and disadvantages of for
      profit and nonprofit capital sources in those sectors.

PMID- 10645074
TI  - Tax subsidies for health insurance: costs and benefits.
AB  - The continued rise in the uninsured population has lead to considerable interest
      in tax-based policies to raise the level of insurance coverage. Using a detailed
      microsimulation model for evaluating these policies, we find that while tax
      subsidies could significantly increase insurance coverage, even very generous tax
      policies could not cover more than a sizable minority of the uninsured
      population. For example, a generous refundable credit that costs $13 billion per
      year would reduce the ranks of the uninsured by only four million persons. We
      also find that the efficiency of tax policies, in terms of the cost per newly
      insured, inevitably would fall as more of the uninsured were covered.

PMID- 10645075
TI  - Growing an industry: how managed is TennCare's managed care?
AB  - In 1994 Tennessee moved virtually its entire Medicaid population and new
      eligibles into fully capitated managed care (TennCare). We analyze Tennessee's
      strategy, given limited existing managed care; and health plans' development of
      managed care infrastructure. We find signs of progress and developing
      infrastructure, but these are threatened by concerns over TennCare's financial
      viability and the state's commitment to TennCare's objectives. State policymakers
      seeking systems change need to recognize the substantial challenges and be
      committed to long-term investment.

PMID- 10645076
TI  - Use of preventive services by managed care enrollees: an updated perspective.
AB  - We examined whether enrollees in managed care plans received more preventive
      services than enrollees in non-managed care plans did, by conducting an updated
      literature synthesis of studies published between 1990 and 1998. We found that 37
      percent of comparisons indicated that managed care enrollees were significantly
      more likely to obtain preventive services; 3 percent indicated that they were
      significantly less likely to do so; and 60 percent found no difference. Enrollees
      in group/staff-model health maintenance organizations (HMOs) were more likely to
      receive preventive services, but there was little evidence, outside of Medicaid
      managed care, that managed care plans are worse at providing preventive services.
      However, most of the evidence is equivocal: Provision of preventive services was
      neither better nor worse in managed versus non-managed care plans. Because of the
      blurred distinctions among types of health plans, more research is needed to
      identify which plan characteristics are most likely to encourage appropriate
      utilization.

PMID- 10645077
TI  - Looking back, looking forward: straight talk about U.S. medicine. Interview by
      Fitzhugh Mullan.

PMID- 10645078
TI  - Health spending in 1998: signals of change. The Health Accounts Team.

PMID- 10645079
TI  - Who helps employers design their health insurance benefits?

PMID- 10645080
TI  - Private employer-sponsored health insurance: new estimates by state.

PMID- 10645081
TI  - How will the Internet change our health system?

PMID- 10645082
TI  - Managed care at a crossroads.

PMID- 10645083
TI  - Subcutaneous scars.

PMID- 10645084
TI  - Out of the shadow.

PMID- 10645085
TI  - Health insurance coverage after welfare.
AB  - This DataWatch examines the health insurance coverage of former welfare
      recipients who left welfare between January 1995 and mid-1997, using data from
      the 1997 National Survey of America's Families. Although the majority of women
      who left welfare were working, only 33 percent of these women obtained health
      coverage through their jobs. Rates of uninsurance increase with the number of
      months since leaving welfare and with declines in Medicaid coverage. A year or
      more after leaving welfare, 49 percent of women and 30 percent of children were
      uninsured.

PMID- 10645086
TI  - Safety-net health plans: a status report.
AB  - This paper reports on a national survey of Medicaid managed care plans sponsored
      by safety-net provider organizations that have a mission of service to low-income
      populations. We identified ninety-nine safety-net plans and obtained data from
      eighty of them regarding their sponsorship, age and size, relationships to
      sponsors, managed care practices, and measures of success. Most plans engage in
      active managed care and have achieved at least some of their goals. However, 60
      percent of plans lost money in 1997, and economic trends have been unfavorable.

PMID- 10645087
TI  - Medicaid managed care's impact on safety-net clinics in California.
AB  - A growing percentage of Medicaid patients are receiving medical care within a
      managed care system. This policy change has raised concerns about whether safety
      net providers can maintain their share of Medi-Cal (California Medicaid)
      patients. From 1995 to 1997 several of California's counties implemented
      mandatory Medi-Cal managed care. The majority of California's safety-net primary
      care clinics experienced a decline in the percentage of their patients insured by
      Medi-Cal. However, after the overall decline in the number of Medi-Cal
      beneficiaries was controlled for, the increased penetration of Medi-Cal managed
      care in a county was not independently associated with a decline in clinics'
      share of Medi-Cal patients. Despite this fact, it may become increasingly
      difficult for clinics to maintain their current level of services with declining
      Medi-Cal enrollment and other anticipated reforms in their funding.

PMID- 10645088
TI  - Chronic illness and plan satisfaction under managed care.
AB  - This DataWatch uses data from the 1993 Employee Health Care Value Survey (EHCVS)
      to compare the experiences of respondents with and without chronic illnesses
      under managed care. After controlling for potential confounders, we found that
      chronic illness was associated with increased odds of dissatisfaction in both
      independent practice association plans and prepaid group practices, but not under
      fee-for-service coverage. Chronic illness appeared to exacerbate difficulties and
      to attenuate the benefits experienced by healthy persons under managed care. We
      conclude that persons with chronic illnesses may be at particular risk under
      managed care; their experiences may warrant particular attention when health plan
      performance is being monitored.

PMID- 10645089
TI  - Who is enrolled in for-profit vs. nonprofit Medicare HMOs?
AB  - We compare the characteristics of enrollees in for-profit and nonprofit Medicare
      health plans using nationwide data from the 1996 Medicare Current Beneficiary
      Survey. We find few differences in overall health status, limitations in
      activities of daily living (ADLs), or history of chronic disease. However, older
      Americans enrolled in for-profit plans are substantially poorer and less educated
      than those enrolled in nonprofit plans, are more likely to have joined their plan
      recently, and are more likely to have joined a plan with the expectation of
      reducing their out-of-pocket health care costs.

PMID- 10645090
TI  - Medicaid's role in financing graduate medical education.
AB  - Medicaid is the second-largest explicit payer of graduate medical education
      (GME). All but five states pay for GME ($2.4 billion in 1998). As states rapidly
      move their Medicaid populations to managed care, Medicaid support for GME is
      subject to change. Just sixteen states and the District of Columbia carve out
      Medicaid GME payments from capitated rates to managed care plans and rechannel
      them to teaching programs. Concurrently, managed care has motivated several
      states to distribute Medicaid GME funds in ways more explicitly accountable to
      the public. Ten states require that GME payments be directly linked to state
      policy goals intended to vary the distribution of or limit the health care
      workforce.

PMID- 10645091
TI  - Trends in specialized surgical procedures at teaching and nonteaching hospitals.
AB  - Teaching hospitals are the principal site of many specialized surgical
      procedures. The recipients of these procedures tend to be younger, male, and
      nonwhite and tend to reside in either the poorest or the most affluent
      neighborhoods. Although the numbers of these procedures performed at major
      teaching hospitals increased dramatically between 1989 and 1995, they accounted
      for only a modest proportion of hospital discharges and patient days.
      Concentration of specialized surgical procedures in major teaching hospitals will
      likely continue. This trend has implications not only for these hospitals but for
      health care purchasers, policymakers, medical educators, and clinical researchers
      as well.

PMID- 10645092
TI  - The Health Rights Hotline: role of a model independent-assistance program.

PMID- 10645094
TI  - Needed: physician advocacy for durable medical equipment.

PMID- 10645093
TI  - New roles for states in financing graduate medical education: Minnesota's Trust
      Fund.

PMID- 10645095
TI  - Relating policy and experience.

PMID- 10645096
TI  - Correcting Medicare estimates, and continuing the dialogue.

PMID- 10645097
TI  - HIV seroprevalence & awareness about AIDS among pregnant women in rural areas of
      Pune district, Maharashtra, India.
AB  - The present unlinked anonymous study was done among sexually active rural women
      to assess the extent of spread of HIV and its awareness. Peripheral blood samples
      were collected on filter paper strips from 1251 pregnant women residing in
      villages in three Primary Health Centres in Pune district of Maharashtra. Elutes
      were tested for HIV antibodies in two different ELISA systems. Awareness on
      HIV/AIDS was assessed using a structured questionnaire. Fifteen (1.2%) samples
      were detected to be HIV seropositive. HIV seroprevalence was significantly higher
      among villages situated close to highways (P < 0.025). Majority (> 95%) of the
      participating women were housewives. Although 70 per cent were aware of the
      existence of AIDS, only 33 per cent knew about all the main modes of HIV
      transmission. Their main sources of information on AIDS were health camps, health
      workers (70%) and television (45%). Awareness was associated with higher level of
      literacy (P < 0.001). Many women had misconceptions about the modes of spread of
      HIV. Greater emphasis needs to be placed on instituting long-term and sustainable
      strategies to create awareness among young couples with an emphasis on
      involvement of health workers in rural areas.

PMID- 10645098
TI  - Prevalence of hepatitis C virus antibody in healthy blood donors.
AB  - The present study was conducted to find the prevalence of HCV antibody in blood
      donors with an aim to provide safe blood for transfusion. A total of 44,086 blood
      samples from healthy blood donors was screened for HCV antibody by third
      generation ELISA assay and a prevalence of 0.53 per cent was found in our study.
      We suggest that routine screening of all donor blood should be done.

PMID- 10645099
TI  - Outbreak of cholera in arid zone of Bikaner.
AB  - Bikaner being an arid zone was more or less unaffected by cholera until 1994 when
      an outbreak of clinical cholera occurred. We isolated 64 Vibrio cholerae strains
      out of 475 stool samples received (isolation rate 13.47%). All the Vibrio strains
      belonged to biotype El Tor serotype Ogawa. Low isolation rate was probably
      related to the poor transportation and medical facilities available at remote
      areas and indiscriminate and irrational use of antibiotics. The antimicrobial
      susceptibility testing of the isolates has not shown significant resistance
      against commonly used antimicrobials.

PMID- 10645101
TI  - Paraoxonase (PON1) polymorphism & its relation with lipids in north west Indian
      Punjabis.
AB  - We investigated 190 healthy, unrelated and randomly selected, north-west Indian
      Punjabis (M:102; F:88) for paraoxonase (PON1) polymorphism by dual substrate
      method and also determined lipid variables i.e., total cholesterol (TC), high
      density lipoprotein cholesterol (HDL), low density lipoprotein cholesterol (LDL)
      and triglycerides (TG) in them to determine any relationship between PON1
      activity, PON1 phenotypes and lipids. The basal plasma paraoxonase (PON)
      activity, and PON activity in presence of 1 Mol NaCl (salt activated paraoxonase
      i.e., SAP) were estimated by using paraoxon as substrate whereas the, phenyl
      acetate esterase (A) activity was estimated by using phenylacetate as substrate.
      Based on the ratio of SAP/A activity, three distinct phenotypes of PON1 could be
      determined with gene frequencies of PON*A (low activity) and PON*B (high
      activity) allele being 0.847 and 0.153 respectively. In the whole population on
      partial correlation after normalising the variables and after adjusting the
      lipids for age and body mass index (BMI), a significant negative correlation was
      observed between SAP/A ratio and TC (r = -0.290; P < 0.01) and LDL (r = -0.154; P
      < 0.05). However, on analysis of covariance (ANCOVA) after normalizing the lipid
      variables and adjusting these for age and body mass index (BMI), no significant
      difference could be observed in lipid profile of these three phenotypes. The lack
      of a significant relationship between lipids and PON1 phenotypes, suggests that
      PON phenotype does not significantly influence the lipid profile in north-west
      Indian Punjabis. However, a significant negative correlation between the PON
      activity and TC and LDL suggests that low PON activity could be a risk factor for
      atherosclerosis in these subjects.

PMID- 10645100
TI  - Field evaluation of Spicbiomoss, a biolarvicidal formulation of Bacillus
      sphaericus against immatures of Culex quinquefasciatus & Anopheles species.
AB  - Spicbiomoss, an aqueous suspension formulation of Bacillus sphaericus was
      evaluated for its efficacy against immatures of Culex quinquefasciatus at the
      application rate of 120 l/ha in cement tanks, cesspits and drains in Pondicherry
      and in drains in Kochi, Kerala. The formulation was also tested against
      anophelines (Anopheles fluviatilis and An. culicifacies) breeding in stream pools
      in Malkangiri district, Orissa. In cement tanks and cesspits more than 80 per
      cent reduction in immature density was observed for a period of 6-13 days (mean
      9.8 +/- 1.25 days) and 3-8 days (mean 5.2 +/- 0.7 days) respectively. The same
      level of reduction was found to last for 1-4 days (mean 2.2 +/- 0.52 days) in
      drains in Pondicherry and 2-9 days (mean 4.8 +/- 1.17 days) in Kochi. In bunded
      stream pools 40-79 per cent reduction in immature density of Anopheles was
      obtained for an average period of 1-7 (mean 3.83 +/- 0.98) days. There was no
      improvement in the efficacy of the formulation against anophelines even at the
      higher application rate (240 l/ha). Thus, Spicbiomoss can be used against Cx.
      quinquefasciatus in an integrated vector management programme.

PMID- 10645102
TI  - Exposure limits of women in hot environment.
AB  - The tolerance of six women to work in hot environments was examined under four
      environmental conditions from 38 to 44 degrees C dry bulb temperature and 50 to
      80 per cent relative humidity, i.e., 32 to 36.5 degrees C effective temperature
      [ET (normal scale)] in a climatic chamber. The subjects performed bicycle
      ergometric work at an intensity of 50 W and the exposure duration was determined
      by the cardiorespiratory, body temperature and sweating responses. At the limit
      of tolerance, the body core temperature (Tcr) reached over 38.5 degrees C and the
      heart rates attained a peak level (i.e., about 172 beats/min). The total oxygen
      demand decreased significantly with higher environmental load, particularly
      beyond 33.5 degrees C ET (N). While the tolerance time decrement was evident with
      the higher heat stress, on an average, an increase or decrease of every liter of
      total oxygen demand was equivalent to a 0.8 min change in the tolerance time. As
      such, the women volunteers were not susceptible to heat; only in extreme hot
      situations beyond 33.5 degrees C ET (N), they had unacceptable levels of
      physiological and psychophysical reactions. Based on the distribution of
      tolerance time of the women in different exposure conditions, the safe exposure
      times were estimated, which varied from 43 min [32.0 degrees C ET (N)] to 16 min
      [36.5 degrees C ET (N)].

PMID- 10645103
TI  - The diffusion of new medical technologies in the private sector of the U.K.
      health care system.
AB  - Eleven percent of the U.K. population holds private health care insurance, and
      2.2 billion Pounds are spent annually in the acute sector of private health care.
      Although isolated from policy discussions about new medical technology in the
      National Health Service, the private sector encounters these interventions
      regularly. During 18 months in one company, a new medical technology was
      encountered on average every week; 59 leading edge technologies were submitted
      for authorization (18 on multiple occasions). There are certain constraints on
      purchasers of health care in the private sector in dealing with new technology;
      these include fragmentation of the sector, differing rationalities within
      companies about limitations on eligibility of new procedures while competing for
      business, the role and expertise of the medical adviser, and demands of
      articulate customers. A proactive approach by the private sector to these
      challenges is hampered by its independence. Poor communication between the public
      and private sectors, and the lack of a more inclusive approach to policy
      centrally, undermine the rational diffusion and use of new medical technology in
      the U.K. health care system.

PMID- 10645104
TI  - Which factors determine the use of diagnostic imaging technologies for
      gastrointestinal complaints in general medical practice?
AB  - OBJECTIVE: Even though gastrointestinal complaints are among the most frequent
      reasons to contact general medical practitioners, little is known about the
      actual care of these patients, especially the use of diagnostic imaging
      technologies. METHODS: In a network of 57 family practitioners and 29 general
      internists in Lower Saxony, Germany, 1,217 contacts with patients with
      gastrointestinal diseases (16%, gastritis; 12%, gastroenteritis; 6%,
      cholelithiasis; 5% each, ulcus ventriculi and duodeni, and 14%, no final
      diagnosis) were documented. The effects of patient and physician/practice side
      factors on the use of ultrasonography and radiography were modeled using
      multivariate logistic regression. RESULTS: For ultrasonography, diagnosis and
      ownership of an ultrasound unit (odds ratio [OR] = 3.33) were highly significant
      predictors (p < .0001), followed by unknown diagnosis at beginning of contact (OR
      = 1.92; p = .0019), physician specialty (OR for internists = 1.89; p = .0025),
      and severity (p = .0085). For radiography, ownership of an ultrasound unit was
      the most significant factor (OR = 0.34; p < .0001), followed by severity (p <
      .0009), ownership of x-ray apparatus (OR = 2.56; p = .0025), physician specialty
      (OR for internists = 1.98; p = .0358), and unknown diagnosis at beginning of
      contact (OR = 1.79; p = .0451). Not significant were age and sex of patient and
      diagnosis for radiography. CONCLUSIONS: Physicians use diagnostic imaging
      technologies for patients with gastrointestinal complaints according to severity
      and knowledge about the diagnosis, but ownership of technology is the most
      predictive factor.

PMID- 10645105
TI  - Assessment and regulation of health care technology. The Dutch experience.
AB  - OBJECTIVES: To evaluate the characteristics, methods, and results of the Dutch
      Investigative Medicine Program ("ontwikkelingsgeneeskunde") in policy and health
      care. METHODS: Project database analyses of the initial 9 years of the program;
      description of characteristics, methods, and effects of the program. RESULTS: By
      the end of 1997, 53 projects had been completed, including implementation in
      health care policy. In 20 of 53 cases the program worked as an instrument to
      prevent the introduction of ineffective, inefficient, or even harmful medical
      interventions. In most other cases the program assisted with proper placement or
      appropriate application of new technologies. Apart from new or emerging
      technologies, already existing technologies are evaluated. CONCLUSION: The Dutch
      Investigative Medicine Program ("ontwikkelingsgeneeskunde") of the Sickness Funds
      Council is an effective collaboration of health care providers, medical science,
      health economics, and a regulatory body in empirical technology assessment. It is
      also an example not only of a substantial contribution of technology assessment
      to decision making in practice and policy but also of a means of regulation of
      health care by the very activity of technology assessment itself. It appears that
      the program has evolved into an instrument to rationalize health care and health
      care policy, although some further possible improvements are identified.

PMID- 10645106
TI  - Population-based and opportunistic screening and eradication of Helicobacter
      pylori. An analysis using trial baseline data. Leeds H. pylori Study Group.
AB  - OBJECTIVES: To examine whether screening and eradication of Helicobacter pylori
      by population-based invitation or opportunistic screening by general
      practitioners reduces costs to the National Health Service (NHS) of treating
      dyspepsia. METHODS: A limited dependent, variable, two-step regression analysis
      was used to explore the baseline annual health care costs of dyspepsia for men
      and women aged 40-49 enrolled in the Leeds H. pylori screening and eradication
      trial. RESULTS: Epidemiological and clinical questionnaires, general practitioner
      notes, and 13C urea breath test results were available for 4,754 individuals.
      After adjusting for covariates H. pylori was associated with a 6.7% increased
      probability of incurring gastrointestinal-related NHS costs (p < .0001) in the
      population aged 40-49. Additionally, H pylori increased average costs in those
      who seek medical care (p = .001). In consequence, H. pylori is associated with an
      average increased cost to the NHS of 0.30 Pound per year (95% CI: 0.17 Pound to
      0.45 Pound) per adult aged 40-49. In those consulting for dyspepsia, the
      increased cost to the NHS was 1.04 Pounds per year (95% CI: 0.42 Pound to 1.75
      Pounds) per patient. The cost of population screening and treatment would not be
      recovered in reduced dyspepsia costs in the lifetime of those screened. Assuming
      laboratory-based serology screening is used opportunistically in patients
      presenting with dyspepsia, it is estimated that costs would be recouped in 18
      years. CONCLUSIONS: This observational data set suggests that the costs of
      screening and treatment in all individuals aged 40-49 or in those presenting in
      primary care with dyspeptic symptoms are unlikely to be attractive on the basis
      of cost savings alone.

PMID- 10645107
TI  - Health technology assessment and policy decisions on hyperbaric oxygen treatment.
AB  - OBJECTIVES: To provide information to health authorities and others on the
      effectiveness of hyperbaric oxygen treatment (HBOT) and the impact on health
      services should an additional HBOT facility be established in the provincial
      health care system. METHODS: A literature review on the clinical use of HBOT was
      conducted, drawing on MEDLINE, EMBASE, and HealthSTAR. For each of 13 conditions,
      the effectiveness of HBOT was assessed, with reference to a widely used
      classification of level of evidence. Cost implications were considered for each
      condition for which there was sufficient evidence of effectiveness. The
      perspective was that of the payer. RESULTS: Good evidence of effectiveness exists
      for HBOT for four conditions and HBOT is established as the clinical standard of
      care for two others. Available evidence did not support the routine use of HBOT
      for a further seven indications. An additional 59-87 patients per year would be
      eligible for HBOT if a second facility were established in the province.
      Improvement in quality of life could be expected for 30-60 persons per year. A
      new facility would result in identified additional annual expenditure of
      $108,000. Capital costs could exceed $600,000. CONCLUSIONS: On the basis of the
      available evidence on benefits and costs to routine health care, there did not
      seem to be a particularly strong case for establishing a second HBOT center in
      the province. Following the assessment, the health authority made a decision not
      to provide funding for this additional service.

PMID- 10645108
TI  - Quality-assessed reviews of health care interventions and the database of
      abstracts of reviews of effectiveness (DARE). NHS CRD Review, Dissemination, and
      Information Teams.
AB  - OBJECTIVES: Database of Abstracts of Reviews of Effectiveness (DARE)
      (http:@www.york.ac.uk/inst/crd/) at the NHS Centre for Reviews and Dissemination
      provides a unique international resource of structured summaries of quality
      assessed reviews of health care interventions. These reviews have been identified
      from searches of electronic databases and by hand-searching journals. This paper
      describes and summarizes the DARE database, including the topic areas covered and
      the review methods used. METHODS: The first 480 structured abstracts on the DARE
      database were summarized. Data were extracted from each database field and coded
      for analysis. RESULTS: Most of the systematic reviews investigated the
      effectiveness of treatments: 54% investigated the effectiveness of medical
      therapies, and 10% assessed surgical interventions. Around two-thirds used meta
      analytic methods to combine primary studies. The quality of the reviews was
      variable, with just over half of the reviews (52%, n = 251) having systematically
      assessed the validity of the included primary studies. Narrative reviews were
      more likely than meta-analyses to reach negative conclusions (42% vs. 25%, p =
      .0001). The 21 reviews that reported drug company funding were more likely to
      reach positive conclusions (81% vs. 66%, p = .15). CONCLUSION: The DARE database
      is a valuable source of quality-assessed systematic reviews, and is free and
      easily accessible. It provides a valuable online resource to help in filtering
      out poorer quality reviews when assessing the effectiveness of health
      technologies.

PMID- 10645109
TI  - Bone mineral density testing in social context.
AB  - Bone mineral density (BMD) testing of healthy women continues to increase,
      despite widespread discrediting of this test as a valid means to predict fracture
      risk. To find an explanation for this expanding utilization, we turn to the
      literature of sociology and political science. Two interdisciplinary approaches
      proved particularly useful in critical examination of technologies related to
      women and aging: feminist analysis and cross-cultural analysis. BMD testing has
      grown because it is marketed in ways that draw upon and perpetuate two trends in
      western popular culture: a) the medical model of the aging female body; and b)
      the fear of aging, with its associated disability, dependency, and immobility.
      The feedback loop between popular and scientific knowledge has created and
      perpetuated the notion that the aging female body is a diseased body. The trend
      toward defining osteoporosis entirely on the basis of BMD diagnostic criteria has
      resulted in the transformation of a risk factor into a disease entity. As the
      onus for managing risk falls increasingly on women as individuals, and as they
      strive to reach the preferred ideal of normality, the area that defines normality
      on the continuum is shrinking, while that defining abnormality is increasing. The
      power relations and private interests served by this altered continuum remain
      largely unexamined. The effect, however, is to encourage the demand for screening
      and diagnostic technologies, giving rise to the rapid diffusion of such
      technologies, even where the research evidence does not support their use.

PMID- 10645110
TI  - Health financing policies. Providers' opinions and prescribing behavior in rural
      China.
AB  - OBJECTIVES: To describe effects of health financing on providers' opinions and
      prescribing behavior in rural China. METHODS: A multi-stage sampling procedure
      was used to select county, township, and village health care facilities. A total
      of 1,064 health care providers in county, township, and village health care
      facilities in six counties in central China were randomly selected and surveyed
      during one week by written questionnaire. RESULTS: Patient's health financing
      systems (insurance or out-of-pocket payment), financing methods for health
      facilities (general budget or fee for service), and payment methods for providers
      (salary or bonus) influenced provider prescribing. Bonuses could improve the
      quality of health care, but could also be an incentive to prescribe more drugs or
      more expensive drugs and other services. The providers were of the view that
      patients' health financing and ability to pay were the main determinants of the
      type of treatment. Insured patients could have more access to expensive drugs,
      referred to specialized health care facilities, and have a higher cure rate
      (according to the doctor's opinion) for tuberculosis. Most of the clinical
      doctors said that they prescribed more expensive antibiotics for insured patients
      and changed prescriptions according to patients' demands, financial ability, and
      health financing systems in the treatment of some diseases, such as chronic
      bronchitis, tuberculosis, and hypertension. CONCLUSION: The empirical data
      suggest that the main factor influencing provider prescribing behavior is the
      economic incentives in relation to health care financing for both health care
      providers and consumers.

PMID- 10645111
TI  - How urgent are emergency admissions? An evaluation of emergency admissions to
      general hospitals in a Norwegian county.
AB  - OBJECTIVES: To assess necessary treatment and degree of urgency for patients
      admitted to emergency rooms, and potential health consequences of transfer to
      nearest alternative hospital. METHODS: During 1 month, we included all 1,300
      emergently admitted patients in all seven general hospitals in a Norwegian county
      with a population of 236,921 inhabitants. The number of patients in need of
      surgical and/or intensive medical treatment, the urgency of the necessary
      treatment, and the risk to each patient of adverse permanent health consequences
      of further transport to nearest alternative hospital were assessed by a
      multidisciplinary expert panel. RESULTS: Ninety-four patients (7.2% of 1300
      patients) were considered in need of either surgical (n = 22) or intensive
      medical treatment (n = 70) or both (n = 2) within 8 hours of arrival in hospital.
      Medical treatment had the greatest urgency, while surgery most often could be
      postponed. In cases where the patients were initially to be given only
      stabilizing treatment and then transported (assisted by qualified personnel) to
      another hospital, the panel estimated the risk of losing health benefit to be
      high for 14 patients. In six of these cases the risk was linked to delay of
      thrombolytic treatment. CONCLUSIONS: Fewer than 10% of the patients who are
      admitted as emergency cases to general hospitals in Norway need surgical or
      intensive medical treatment within 8 hours of their arrival. The medical
      consequences of transport of patients to the nearest alternative hospital are
      generally small and can often be further reduced by simple means.

PMID- 10645112
TI  - Comparison of an ordinal and a continuous outcome measure of muscle soreness.
AB  - The relationship between an ordinal (Likert) and a continuous (visual analog)
      measure of pain was investigated in 400 long-distance runners experiencing
      delayed-onset muscle soreness. Subjects completed a 100-mm visual analog scale
      (VAS) and a 7-point Likert scale twice a day for 5 days, starting at 9:00 PM on
      the evening of the run. The relationship between scales was modeled by
      calculating the median VAS for each Likert score and the modal Likert score for
      each point on the VAS. Standardized means were calculated by dividing the total
      of 5 day scores by the standard error of 5 day scores for all subjects. The
      relationship between scales was approximately linear, but VAS scores recorded
      concurrently with each Likert score varied enormously. VAS responses for a Likert
      score of zero were lower than expected, apparently because subjects chose zero
      only if they were completely free of soreness. The standardized mean of the
      Likert scale was higher (34.1 [SD 20] versus 30.4 [SD20] p < < < .0001),
      suggesting greater responsiveness. The Likert scale can be recommended as a
      method of measuring muscle soreness, but researchers should not anchor the lowest
      score to zero pain.

PMID- 10645113
TI  - Technologies to minimize blood transfusion in cardiac and orthopedic surgery.
      Results of a practice variation survey in nine countries. International Study of
      Peri-operative Transfusion (ISPOT) Investigators.
AB  - OBJECTIVES: Due to the discovery in the 1980s that blood transfusion can transmit
      HIV, there has been increased interest in technologies that reduce the amount of
      allogeneic blood used during and after surgery. These technologies include drugs
      (aprotinin, tranexamic acid, epsilon-aminocaproic acid, erythropoietin), devices
      (cell salvage), and techniques (acute hemodilution, predeposited autologous
      donation). The purpose of this study was to ascertain the degree of practice
      variation, if any, that exists for eight technologies in nine countries in
      orthopedic and cardiac surgery. METHODS: In each country, either all hospitals or
      a random sample of hospitals with medical/surgical beds were surveyed between
      1995 and 1997. Two instruments were used. The first instrument was a postcard
      that asked recipients whether the technologies were currently being used in their
      hospital for orthopedic and/or cardiac surgery to reduce perioperative allogeneic
      transfusion. The second questionnaire elicited information regarding the degree
      of use both in qualitative and quantitative terms. Data were collected, entered,
      and analyzed in each country, with summary results submitted to the Canadian
      coordinating center on a standardized data collection form. RESULTS:
      Pharmaceuticals were generally used in a much smaller proportion of hospitals in
      orthopedic than in cardiac surgery. Aprotinin and tranexamic acid were the drugs
      most frequently used in cardiac surgery. Nonpharmacological technologies were
      used to a greater degree than drugs in orthopedic surgery, although there was
      wide variation among technologies and countries. Acute hemodilution and cell
      salvage were used in a greater proportion of hospitals for cardiac surgery than
      orthopedic surgery. CONCLUSIONS: The results of this survey indicate that there
      is considerable practice variation in the use of technologies to minimize
      exposure to perioperative allogeneic transfusion within and between countries.

PMID- 10645114
TI  - Women, the media, and heart disease. For better or for worse?
AB  - OBJECTIVE: To analyze the nature and presentation of print media messages
      regarding cholesterol and heart disease in women. The hypothesis is that print
      media messages about cholesterol and heart disease may encourage and perpetuate
      the use of cholesterol-lowering drugs in women. METHODS: A hand-search of the
      "seven sisters" of American women's magazines and of two Canadian women's
      magazines. All print material related to cholesterol and heart disease in women
      was photocopied and the content analyzed qualitatively. The print media content
      was divided into two categories: magazine articles and drug industry-sponsored
      advertisements. Themes were identified and were analyzed for the messages they
      contained about heart disease, cholesterol, and the use of cholesterol-lowering
      drugs in women. RESULTS: From the magazine articles, three main messages were
      identified. First, heart disease is the number one killer of women. Second, women
      must demand recognition of their hig risk of heart disease and demand equal
      access to prevention and treatment services for heart disease. Third, lifestyles
      changes are not enough. Cholesterol-lowering drugs should be considered. Drug
      advertisements also emphasize that postmenopausal women are at high risk of heart
      disease and that lifestyle changes are inadequate or insufficient to lower this
      risk. In both cases, high blood cholesterol is considered not as a risk factor
      for heart disease but as the disease itself. CONCLUSIONS: Magazine articles and
      drug advertisements act synergistically and may encourage and promote the use of
      cholesterol-lowering drugs in women. Postmenopausal women not on hormone therapy
      are particularly targeted.

PMID- 10645115
TI  - Life-saving treatments and disabilities. Are all QALYs created equal?
AB  - OBJECTIVES: Decision-makers and the general public are often reluctant to adopt
      policy recommendations based exclusively upon cost-utility analyses. One possible
      reason explored here is that patients' previous health state before experiencing
      the onset of an acute life-threatening illness may influence the value of saving
      those patients' lives. METHODS: We surveyed members of the general public to see
      the relative importance of saving patients' lives when some patients could be
      returned to perfect health and others would live the remainder of their years
      with paraplegia. Among this latter group, some were described as having pre
      existing paraplegia. Others were described as having as having the onset of
      paraplegia. The relative importance of saving each of these lives was measured
      using the person trade-off method. RESULTS: Six hundred five subjects completed
      questionnaires, and 250 met pre-established consistency criteria and were
      included in the final analysis. Overall, subjects placed equal importance on
      saving the lives of people with pre-existing paraplegia versus those who could be
      returned to perfect health because they did not have pre-existing paraplegia. In
      contrast, respondents gave lower priority to patients who would experience the
      onset of paraplegia after having their lives saved, especially if their
      paraplegia was avoidable with an alternative treatment. CONCLUSION: People do not
      think that all quality-adjusted life-years are created equal. Instead, the value
      that people place on treatment programs depends on patients' state of health
      before developing life-threatening illnesses, and on whether alternative
      treatments are available that provide better health outcomes for the patients.
      These results may explain, in part, public discomfort over basing health care
      priorities on cost-utility analysis.

PMID- 10645116
TI  - Using telehealth interventions to prevent pressure ulcers in newly injured spinal
      cord injury patients post-discharge. Results from a pilot study.
AB  - OBJECTIVE: To determine which of three approaches to care produces the lowest
      incidence of pressure ulcers, promotes the most effective care of sores that
      develop, and leads to the fewest hospitalizations in newly injured patients with
      spinal cord injury after discharge. METHODS: Spinal cord injury patients (n = 12)
      were recruited for a telehealth intervention after initial injury, and matched
      cases were recruited for telephone counseling and standard care groups. Patients
      were monitored for 6-8 months after discharge. RESULTS: The video group had the
      greatest number of reported and identified pressure ulcers. Differences in health
      care utilization between the video and telephone telehealth groups were small.
      The standard care group reported the lowest number of pressure ulcers and lowest
      frequency of health care utilization. Substantial differences existed in
      employment rates before and after injury. The video group had the lowest pre
      injury rate of employment and the highest post-injury rate of employment.
      CONCLUSIONS: Tracking pressure ulcer incidence, particularly stage I sores, is
      difficult. Self-report is likely to lead to substantial underreporting.
      Similarly, self-report on health care utilization over extended periods may lead
      to undercounting of encounters. Telehealth interventions appear to improve ulcer
      tracking and management of all ulcer occurrences. Video interventions may affect
      outcomes, such as employment rates, which are not conventionally measured.

PMID- 10645117
TI  - Cardiac catheterization in Germany. Diffusion and utilization from 1984 to 1996.
AB  - OBJECTIVE: To describe the diffusion of cardiac catheterization technologies and
      time trends of their use according to setting and geographic region in Germany
      during a 13-year period. It is hypothesized that the cardiac catheterization
      technology has matured from an experimental state to a broadly accepted
      technology. METHODS: Data come from the annual survey of the German Society for
      Cardiovascular Research. All German cardiac catheterization units are requested
      to provide data on volume and type of catheterization procedures. Data are
      available from 1984 to 1996. Number and type of procedure, type of unit,
      diagnoses, and complications are all recorded. The overall response rate is 90%,
      on average. RESULTS: The total number of catheterization units was 324 in 1996,
      or an average of 3.69 units per 1 million population. In 1996, all of the East
      German Lander and districts were below average. Utilization of cardiac
      catheterization procedures increased exponentially during the study period. The
      number of angiographies rose from about 45,000 in 1984 to more than 450,000 in
      1996; the number of angioplasties increased almost by a factor of 50 to 125,000
      procedures in 1996. Inverse correlations between the rates per million population
      of either coronary angiographies or PTCAs and mortality rates from ischemic heart
      disease were observed at the level of the German Lander. CONCLUSION: Further
      studies taking patient characteristics, long-term outcomes, and other factors in
      account are necessary to clarify the large geographic variations and the negative
      relationship between utilization rates and coronary heart disease mortality found
      in this study.

PMID- 10645118
TI  - Report from the Catalan Agency for Health Technology Assessment (CAHTA). Review
      of the scientific evidence of the clinical and economic implications of
      resistance of enterococcus to vancomycin.

PMID- 10645119
TI  - Report from the Danish Medical Research Council and Danish Institute for Health
      Services Research and Development. Consensus statement on depression: a common
      illness to be treated?

PMID- 10645120
TI  - Reports from the Spanish Agency for Health Technology Assessment (AETS).
      Ultrasonography in primary health care.

PMID- 10645121
TI  - Report from the Swiss Science Council Programme on Technology Assessment.
      Technology assessment of xenotransplantation.

PMID- 10645122
TI  - Modified stages of acquisition of gateway drug use: a primary prevention
      application of the stages of change model.
AB  - The purpose of the study was to identify the stages of acquisition of gateway
      drugs in fourth, fifth, and sixth graders. The Stages of Acquisition model is a
      primary prevention application of the Stages of Change model. The subjects in the
      study were 811 students from seventeen elementary schools in Arkansas and
      Missouri. The instrument elicited information regarding the stages of acquisition
      and individual self-reported drug use. The data were analyzed using frequency,
      distribution, discriminant analysis, and correlation analyses. Stage placement
      was confirmed using a series of drug use measures. Results confirmed the
      existence of discrete stages of acquisition. Results supported the concept of
      gateway drugs in that subjects indicated they had progressed further through the
      stages of acquisition of alcohol use than through the stages of acquisition of
      cigarettes use, smokeless tobacco use, or marijuana use.

PMID- 10645123
TI  - Peer cluster theory and adolescent alcohol use: an explanation of alcohol use and
      a comparative analysis between two causal models.
AB  - This study tests the premise of peer cluster theory as it applies to individual
      alcohol use, and makes a comparative analysis between its ability to explain
      alcohol use and marijuana use. Using the results of a 1996 drug and alcohol
      survey of 1312 Western Kentucky University students, path analysis was used to
      measure the influence of six of peer cluster theory's psychosocial
      characteristics on the percentage of the respondent's college friends who use
      alcohol. All of these variables were then regressed on the respondent's alcohol
      use. The results of the causal models did show some support for peer cluster
      theory. The direct effect of the student's association with alcohol-using peers
      on individual alcohol use was shown to have the strongest direct influence on
      this outcome variable. However, a few limitations of this theoretical perspective
      were identified. The causal model for alcohol use showed that the indirect
      influence of two of these psychosocial characteristics (parental attitudes on
      alcohol use and success in school) was weaker than their direct influence on
      individual alcohol use. And, the comparative analysis showed that peer cluster
      theory is better suited to explain the use of marijuana than the use of alcohol.

PMID- 10645124
TI  - A qualitative exploratory study of substance abuse prevention outcomes in a
      heterogeneous prevention system.
AB  - The prevention of abuse of alcohol and other drugs is a concern for parents,
      policy-makers, educators, and social service professionals. Prevention programs
      are sponsored by many different types of social and educational agencies using a
      variety of intervention strategies. This article reports a study of a sample of
      such programs in the state of Nevada. The overall prevention system in the state
      espouses a "risk and resiliency" approach to prevention. Focus group methodology
      was used to study perception of outcomes of these programs from the viewpoints of
      various program stakeholders (youth participating in the programs, parents of
      participants and program staff). Analysis of the qualitative data yielded
      findings about potential outcomes as well as implicit program theories.
      Implications for future planning efforts as well as further evaluation efforts
      are discussed.

PMID- 10645125
TI  - Examining the relationship between gender and drug-using behaviors in
      adolescents: the use of diagnostic assessments and biochemical analyses of urine
      samples.
AB  - The present study examined the relationship between gender and drug-use among
      adolescents using diagnostic assessments and biochemical analyses of urine
      samples. The data were collected in the context of a referral and assessment
      program for adolescents suspected of using drugs, using the Adolescent Substance
      Battery [1]. A six-month random sample of 20 percent of adolescents assessed for
      drug use were targeted for biochemical assay. Compliance for urine delivery was
      relatively high at 91 percent. Urine samples were quantitatively screened for
      pharmaceuticals using a standard thin-layer chromatography (TLC) technique [2].
      Statistical significance was found in the relationship between gender and
      marijuana use (p < .05). This study confirms that gender and drug-using behaviors
      among adolescents need additional research and evaluation.

PMID- 10645127
TI  - Alcohol and drug use of inter-city versus rural school age children.
AB  - The purpose of this study of seventy-nine children was to determine: 1) the
      prevalence and type of substance use in inter-city and rural eight to twelve-year
      old children; and 2) the relationships between child substance use, self-esteem,
      peer substance use, and family climate. The conceptual framework for the study
      was a modification of Kumpfer and Turner's Social Ecology Model (1991). Nineteen
      percent of the children had used alcohol or drugs. Thirty-three percent of the
      children acknowledged having friends who used substances. Inter-city children
      reported more alcohol and marijuana use, while the rural children reported more
      use of inhalants. The responses of both inter-city and rural children also
      indicated that there were problems with substance use and family violence in the
      home. Self-esteem and affiliation with drug using peers were significantly
      correlated with substance use of the child.

PMID- 10645126
TI  - Social skills, competence, and drug refusal efficacy as predictors of adolescent
      alcohol use.
AB  - Numerous alcohol and drug abuse prevention trials have included social resistance
      training as a strategy for reducing early-stage adolescent alcohol use.
      Evaluations of these trials has shown them to be moderately effective, although
      the precise impact of the resistance training in comparison to other programmatic
      features has not been clearly identified. The current study examined the extent
      to which assertiveness and related social skills, personal competence (perceived
      cognitive mastery), and refusal efficacy predict alcohol involvement. Males were
      at greater risk for poor refusal skills and reported higher alcohol involvement.
      Cross-sectionally, youth characterized by poor social skill development reported
      lower refusal efficacy, lower grades, poor competence, and more alcohol use. Poor
      refusal efficacy was associated with more risk-taking, lower grades, less
      competence, and more alcohol use. Longitudinally, both poor refusal skills and
      risk-taking were associated with higher alcohol use. High personal competence was
      associated with lower alcohol use in both the eighth and tenth grades, but had no
      long-term effects on alcohol use. Findings highlight the close interplay between
      perceived competence and refusal skill efficacy, both of which should be included
      as essential components of school-based prevention strategies.

PMID- 10645128
TI  - Difference of plasma leptin levels in venous and arterial cord blood: relation to
      neonatal and placental weight.
AB  - To investigate the physiological significance of umbilical plasma leptin in the
      fetal growth and its possible origin of production during pregnancy, plasma
      leptin concentrations in venous and arterial cord bloods were measured in 42
      neonates (male = 23, female = 19, gestational age 36-41 weeks, birth weight 2600
      4000 g). Leptin concentrations in umbilical veins (5.65 +/- 0.53 ng/mL, n = 42)
      and umbilical arteries (0.56 +/- 0.07 ng/mL, n = 42) were significantly (P <
      0.001) lower than those in maternal peripheral veins (22.36 +/- 1.06 ng/mL, n =
      42). Mean plasma leptin concentration (+/- SEM) in venous cord blood was
      significantly (P < 0.001) higher than that of arterial cord blood. There was
      significantly positive correlation (r = 0.447, P < 0.01) between umbilical venous
      leptin levels and neonatal body mass index (BMI). A positive correlation (r =
      0.435, P < 0.01) was also found between umbilical arterial leptin and neonate
      BMI. There was no positive correlation between umbilical leptin levels in venous
      cord blood and placental weight. We thus conclude that umbilical plasma leptin
      may play an essential role in the fetal growth and metabolism during pregnancy
      and placenta is one of the major sources of leptin production, but the level of
      leptin in umbilico-placental circulation is independent of the weight of
      placenta.

PMID- 10645129
TI  - Association between serum uric acid and cardiovascular risk factors among elderly
      people in Taiwan.
AB  - In order to understand the distribution of serum uric acid and the relationship
      between serum uric acid and the cardiovascular risk factor among elderly people,
      a cross-sectional study was conducted in Chung-Shing-Shin-Tseun community in
      Taiwan in May 1998. All individuals aged 65 and over were collected. A total of
      1123 persons, out of 1774 registered residents, were contacted by face-to-face
      interview. The response rate was 63.3%. However, only 586 respondents had blood
      tests and completed questionnaires. Analysis in this study was based on these 586
      subjects. The mean uric acid values were 7.4 +/- 1.8 mg/dl in men and 6.3 +/- 1.6
      mg/dl in women, respectively (p < 0.001). Multivariate linear regression showed
      that serum uric acid was significantly correlated with sex and body mass index.
      Simple correlation showed that serum uric acid was significantly correlated with
      diastolic pressure, total cholesterol, triglyceride and creatinine. Age, systolic
      pressure and fasting glucose were not related to serum uric acid. In our
      conclusion, the uric acid values are high among elderly people. The serum uric
      acid levels are significantly associated with the cardiovascular risk factors
      among elderly people.

PMID- 10645130
TI  - Pituitary adenomas in adolescence--ten-year experience and literature review.
AB  - Pituitary adenomas account for less than 6% of all intracranial tumors in
      adolescence. Between November 1987 and October 1996, 8 patients were treated by
      transsphenoidal resection at Kaohsiung Medical College Hospital. This series
      included 4 girls and 4 boys with ages ranging from 14 to 19 years. Symptoms
      reflecting endocrine dysfunction such as scanty pubic hairs in males and
      amenorrhea in females, were more often found than neurological problems in all
      adolescents at presentation. Macroadenoma occurred in five of our eight cases
      (62%) of adolescent pituitary adenoma. In one case (12%), the tumor was
      plurihormonal tumor. Long-term follow-up (mean 4.5 +/- 2.7 years) revealed the
      majority of patients had good endocrine function. Significant operative morbidity
      included steroid-induced psychosis in one patient and transient diabetes
      insipidus in three, which resolved in all three within two weeks. Our study
      showed that 1) pituitary tumors in children were uncommon, and when they occurred
      they were frequently large and invasive; 2) the endocrine disturbance caused by
      pituitary adenomas alerted the patients to seek medical help more often than
      neurological deficit; 3) in adolescence, almost all pituitary adenomas were
      functioning; nonfunctioning pituitary adenomas were rare in adolescence; and 4)
      transsphenoidal surgery was feasible and safe in adolescence, even with poor
      pneumatization of the sphenoid sinus, which remains controversial in the
      literature.

PMID- 10645131
TI  - Hip arthroplasty for osteonecrosis in patients with systemic lupus erythematosus.
AB  - Thirty-seven hip arthroplasties including 19 bipolar hemiarthroplasties (BH) and
      18 total hip arthroplasties (THA) were performed in our hospital in 23 patients
      with systemic lupus erythematosus (SLE) for femoral head osteonecrosis between
      July 1984 and July 1996. These patients were followed up retrospectively to
      compare the results of BH and THA. One case with right side BH and left side THA
      expired about 1 year after operation and was excluded from this study. In both
      groups, these hips with pre-operative osteonecrosis were subclassified in Ficat
      and Arlet classification. The mean duration of follow-up was 44.5 months (24-85
      months) for THA was 70.2 months (24-119 months) for BH. The mean Harris scores
      pre-operatively were 56.7 +/- 1.09 points in the BH group and 50.7 +/- 1.29
      points in the THA group. The mean post-operative scores were 81.9 +/- 4.37 points
      in the BH group and 95.5 +/- 0.80 points in the THA group at final follow up. The
      clinical results of the THA group were better than those of the BH group.
      However, at an early stage before collapse of the femoral head (Ficat stage II),
      the results of BH were as good as those of THA. Five BH were converted to THA at
      the time ranging from 39 months to 113 months (mean 63.2 months) after primary
      operation due to acetabular cartilage wearing or severe groin pain. The failure
      rate of BH group was 27.8% (5/18). There was no loosening or revision in the THA
      group. Although the follow-up durations were different in these two groups, the
      clinical result was obviously superior in the THA group, particularly after the
      femoral heads had collapsed. Considering the relatively short life span of SLE
      patients, we prefer THA over BH in the treatment of the femoral head
      osteonecrosis in SLE patients. However, based on our results, BH is still a very
      good choice of treatment before the collapse of the femoral head.

PMID- 10645132
TI  - The skill components of a therapeutic chopsticks task and their relationship with
      hand function tests.
AB  - Chopsticks are the primary tools used for eating and the physical movements of
      control are familiar to Chinese people. Chopsticks are easy to obtain in most
      rehabilitative settings. Occupational therapists often guide patients to practice
      miscellaneous chopsticks tasks to increase hand function in any case. The
      objective of this study was to investigate the skill components of the
      therapeutic chopsticks task and their relationship with hand function tests, and
      to identify clinical value. Eighty normal subjects (41 males and 39 females)
      whose age ranged from 17 to 26 years old participated in this study. Five
      standard hand function tests including three dexterity tests [Minnesota Rate of
      Manipulation Test (MRMT), Purdue Pegboard Test, and O'Connor Tweezer Dexterity
      Test (OTDT)], and two strength tests (Jamar Handgrip Test, and Pinchometer Test)
      were chosen to measure the dexterity and strength of hands. Additionally, the
      Test of Chopsticks Manipulation (TCM) was designed and used to assess the
      chopsticks manipulation skills. Subjects were tested with all the hand function
      tests and TCM in a random sequence. Results of six tests were obtained for each
      subject. Factor analysis showed that the skill components of TCM should be
      categorized into the "dexterity" component. In addition, a significant
      relationship (p < 0.05) was only seen between TCM and OTDT, there was no
      significant correlation between TCM and the other hand function tests. Findings
      in this study are valuable in setting the rehabilitation programs for patients
      with dexterity problems.

PMID- 10645133
TI  - Brucella disc infection mimicking lumbar disc herniation: a case report.
AB  - Brucellosis is a zoonotic disease and still a major health problem in many
      geographical areas. In this paper a forty year-old woman with spinal brucellosis
      associated with epidural abscess formation and mimicking lumbar disc herniation
      is presented. Compression of spinal nerve root(s) by epidural masses due to
      brucella disc infection is a rare condition and should be kept in mind in
      differential diagnosis of lumbar disc herniation. The crucial role of magnetic
      resonance imaging in differential diagnosis is also emphasised.

PMID- 10645134
TI  - Delayed onset of intestinal injury after laparoscopic assisted vaginal
      hysterectomy: a case report.
AB  - Because of the increasing popularity of laparoscopic surgery for gynecological
      diseases, it is inevitable that complications from such procedures will become
      more common. The majority of complications occur during operation where they are
      immediately identified and managed; recovery and outcome are relatively good
      after immediate repair. However, there are still a few cases that are not
      diagnosed until severe complications become evident. Herein, we report a
      relatively rare complication--a delayed onset of small intestinal perforation
      detected one week after initial laparoscopic assisted vaginal hysterectomy.
      Although we performed an emergent exploratory laparotomy to repair this
      complication, the patient died of uncontrolled sepsis and possible sudden onset
      of arrhythmia. Through a review of the literature, possible mechanisms of this
      complication are discussed. In addition, we hope that this case review will help
      avoid such complications in the future.

PMID- 10645135
TI  - Person of the year. Steven A. Schroeder, MD.
AB  - The mission of the Robert Wood Johnson Foundation is to improve the health and
      health care of all Americans. An ambitious goal, but the Foundation has the
      financial resources to do just that. The Foundation also has another resource:
      President and Chief Executive Officer Steven A. Schroeder, MD, who has led the
      philanthropic organization since 1990. For his work with the Robert Wood Johnson
      Foundation, Dr. Schroeder is New Jersey Medicine's 1999 Person of the Year.

PMID- 10645136
TI  - Myth and reality. Recent NJ Supreme Court decisions and the physician-patient
      relationship.
AB  - The NJ Supreme Court recently decided that a physician must obtain the patient's
      informed consent based on a discussion of all medically reasonable alternative
      treatments, regardless of whether the recommended course is noninvasive. The
      meaning of the phrase "medically reasonable," however, poses its own problems.

PMID- 10645137
TI  - Polypharmacy. Reducing adverse events among the elderly in NJ. Part 1.
AB  - This is the first of a two-part series that focuses on reducing polypharmacy and
      adverse drug events in the community-dwelling elderly. Part 1 provides a
      rationale for the design of public health interventions to reduce this problem
      and explores technology development. The components of an integrated system
      linking computer-based technology, pharmacists, and physicians are outlined.

PMID- 10645138
TI  - Electronic claims. The "bottom line" answer.
AB  - Three good reasons why you should file claims electronically: lowering postage
      and handling charges, improving response time, and receiving immediate feedback
      on errors and rejections.

PMID- 10645139
TI  - Simulating patient care.
AB  - In a pioneering program, medical students are introduced to the unique challenges
      of taking a medical history and examining patients who cannot speak because of
      severe developmental disabilities. Contact with patient simulators helps the
      medical students develop the interpersonal skills needed to elicit vital
      information directly from nonverbal patients.

PMID- 10645140
TI  - The benefits of biomedical research. FASEB Office of Public Affairs.

PMID- 10645141
TI  - Individual impact factors for AJP journals in 2000.

PMID- 10645142
TI  - [Individual predisposition to lung neoplasm--the role of genes involved in
      metabolism of carcinogens].
AB  - Molecular epidemiology of lung cancer analyses relationship between environment
      and individual susceptibility. Studying biomarkers of risk at the molecular level
      allows better understanding of chemical carcinogenesis processes and makes
      possible early detection of the disease as well as helps its prevention. Risk
      biomarkers include genetic polymorphism of CYP, GST and NAT genes that
      participate in metabolic biotransformation of various endo- and exogenous
      compounds including carcinogens. Exposure to potentially carcinogenic
      environmental factors plays an important role in etiology of lung cancer, which
      remains a leading cause of cancer death worldwide. This review presents current
      knowledge about molecular basis and impact of individual variations in carcinogen
      metabolism on lung cancer risk.

PMID- 10645143
TI  - [Progress in research for new drugs against the herpes virus].
AB  - Significant advances have been made in the development of effective antiherpes
      virus chemotherapy in the last decades. Acyclovir was approved for the treatment
      of HSV infections over 15 years ago and it remains an important and reliable
      antiviral agent. In this review the most promising new antiviral drugs are
      described. It will focus on the drugs that have just entered the therapy, or will
      do so within a short period of time. Some of the them are still under clinical
      investigation. Antiviral activity, results of clinical trials and adverse effects
      will be presented.

PMID- 10645144
TI  - [Protein glycation--clinical and chemical aspects].
AB  - Glucose as well as other reducing sugars react nonenzymatically with amino groups
      of free amino acids, peptides and proteins. Glycation reaction is responsible for
      forming inter- and intramolecular cross-links of proteins, known as advanced
      glycation end-products (AGEs). In old people, patients with diabetes and chronic
      failure AGEs accumulate in the circulation and tissues, and play a significant
      role in pathogenesis of cardiovascular and other complications. Glycation
      reactions has been used for synthesis of artificial glycoconjugates.

PMID- 10645145
TI  - [Beta-3 adrenergic receptor--structure and role in obesity and metabolic
      disorders].
AB  - Structure and essential motifs of beta 3-adrenergic receptor (known previously as
      atypical beta-AR), which plays a central role in regulation of lipid metabolism
      have been described. Obesity results from an imbalance between caloric intake and
      energy expenditure. The consequence of catecholamine activation of beta 3-AR is
      increased mobilization of fatty acids from triglyceride stores (lipolysis) in
      brown and white adipose tissue as well as increased fatty acid beta-oxidation and
      heat-production via UCP-1 (thermogenesis) in brown adipose tissue. A
      pharmacokinetic effects of beta 3-agonists and putative involvement of Trp/Arg
      mutation in beta 3-AR gene in obesity and another metabolic disorders have been
      discussed.

PMID- 10645146
TI  - [Structure and function of Tamm-Horsfall protein in human physiologic and
      pathologic states].
AB  - Tamm-Horsfall protein (THP), the most abundant glycoprotein in normal human
      urine, is produced by kidney. THP is heavily glycosylated by N-linked glycans,
      which are responsible for most of its properties. The sugar moiety is also
      modified in some diseases. THP plays an important role in ion transport and in
      maintaining water impermeability of the TALH and also protects the urinary system
      from uropathogens. It is also involved in immunoregulatory processes. THP was
      reported to influence many pathological conditions, such as formation of kidney
      stones, development of interstitial nephritis and tubular blockade.

PMID- 10645147
TI  - [The influence of cadmium on the circulatory system].
AB  - This review describes the effect of cadmium on the heart, blood vessels and
      different levels of the endocrine system of the organism, which are of essential
      importance to the circulatory system function. The results of the experimental
      studies on animals, on isolated blood vessels in vitro and on people
      professionally or environmentally exposed to cadmium were presented.

PMID- 10645148
TI  - [Mixed connective tissue disease--etiology, pathogenesis, clinical significance,
      treatment].
AB  - Some patients have features of more than one rheumatic disease and thus do not
      fit into traditional classification. Patients with combination of clinical
      finding similar to those of systemic lupus erythematosus (SLE), progressive
      systemic sclerosis (PSS), polymyositis, rheumatoid arthritis (RA) and with
      unusually high titers of circulating antinuclear antibody with specificity for
      nuclear ribonucleoprotein (RNP) are considered to have mixed connective tissue
      disease (MCTD). The overlap was described by Sharp and colleagues in 1972. During
      the post 20 years many studies exposed the clinical correlates of this antibody
      system (now called anti U1RNP). Controversy arose about whether MCTD was a
      distinct entity or would be better defined as subset of SLE. Anti RNP antibodies
      precipitate three proteins uniquely associated with U1RNP. Clinical correlates
      considered to be distinctive of MCTD are associated with 68 kD antigen
      specificity. Its to be expected that T cells receptors and HLA molecules are
      involved in the generation of these antibodies. Several observations have
      indicated, that 68 kD anti U1RNP antibody response in associated with HLA DR 4
      and DR2 phenotype. Several studies have pointed a role of viruses initiating an
      antibody response against URNPs. Initial observations of MCTD suggested
      infrequent renal disease, a good response to corticosteroids and favourable
      prognosis. Future study has shown that some patients may require aggressive and
      prolonged pharmacologic therapy and that pulmonary involvement is common.
      Pulmonary hypertension associated proliferative vascular lesions may be serious
      complication with not always favourable prognosis.

PMID- 10645149
TI  - The influence of the degree of cerebral atherosclerosis on the changes in
      hemostatic system in patients with ischemic brain disease and atherosclerotic
      encephalopathy.
AB  - Vascular brain diseases are ranked the third as the cause of morbidity and
      mortality, in spite of the progress in diagnostic, therapeutic and preventive
      procedures. In the majority of cases of vascular brain diseases, it is ischemic
      brain disease, which is the final and the most severe stage of cerebral arteries
      atherosclerosis. Etiopathogenesis of atherosclerosis is not closer defined yet,
      but oxidative hypothesis is distinguished among the numerous theories. Within
      this theory, main place is attached to oxidative modification of LDL and Lp(a),
      together with numerous physiopathologic facts with the central role of reactive
      oxidative matters, where endothelial dysfunction is the main disorder responsible
      for the onset of numerous impairments, such as changes in coagulation
      anticoagulation system. Considering these facts, it was established the
      hypothesis that in patients with IBD existed changes in hemostatic system, which
      were in positive correlation with the degree of cerebral atherosclerosis. The
      study comprised 36 patients with acute IBD and 28 patients with atherosclerotic
      encephalopathy. Control group was comprised of 30 patients with non-vascular
      diseases of similar characteristics. We investigated the correlation of the
      changes in hemostatic system (platelet aggregation, anti-thrombin III, D-dimer,
      protein C, factor VII, factor VIII, PAI-1) compared to the degree of cerebral
      atherosclerosis (ultrasonographically) and compared to the observed groups of
      patients. On the basis of all, the results of this study revealed significant
      increase of procoagulant factors concentration in patients with IBD, and similar
      changes were observed in patients with atherosclerotic encephalopathy, but less
      pronounced. All these changes in the total sample of patients, and particularly
      in patients with the pronounced cerebral atherosclerosis, are of primary and
      chronic character.

PMID- 10645150
TI  - The effects of local application of 1% dopamine on intraocular pressure and
      pupillary diameter.
AB  - This paper deals with the experimental results of the effect of 1% dopamine on
      intraocular pressure, pupillary diameter and hemodynamic parameters after its
      local application in the rabbit eye. Our results show that locally applied
      dopamine caused an initial increase of intraocular pressure (IOP) (1 h), followed
      by its decrease that was the most pronounced 3 hours later. Mydriasis was an
      immediate effect of dopamine, which persisted until the end of the second hour.
      There were no changes in blood pressure and heart rate. Although the exact
      mechanism of dopamine effect on IOP is not known yet, our results point out that
      this is mainly due to the decrease fo aqueous humor formation.

PMID- 10645151
TI  - [Transnasal transsphenoidal approach to pituitary adenomas].
AB  - The results of transnasal transsphenoidal surgery of pituitary adenomas were
      retrospectively analyzed in a group of 42 patients, 22 females and 20 males, aged
      19-70, of average age 43 years. Histopathological examination showed null-cell
      adenomas in 4, growth-cell in 11, prolactin-cell in 3, adrenocorticotropin-cell
      in 6, plurihormonal adenomas in 6, craniopharingeoma in 1, metastasis of
      pulmonary carcinoma in 1, pituitary abscess in 1, and normal pituitary tissue in
      9 cases, respectively. Out of 30 patients with adenomas, 21 had macro (> 1 cm)
      and 9 had microadenomas (< 1 cm). Cerebrospinal fluid leakage (8.7%) and
      meningitis (6.5%) were the most frequent postoperative complications. There was
      no operative mortality. Full adenoma recurrence (clinical, hormonal, and
      radiological) was found in 3, clinical and hormonal in 3, hormonal and
      radiological in 1, and radiological in 2 patients, respectively. The repeated
      transsphenoidal surgery was performed in 4 patients. The transnasal
      transsphenoidal approach is the procedure of choice for surgical treatment
      pituitary adenomas.

PMID- 10645152
TI  - [Temperature of the skin in microvascular flaps].
AB  - Transferred free flaps by their defined vascular net improve the perfusion of the
      recipient region. Skin temperature depends on the skin perfusion, temperature
      conduction of the visceral organs, muscles and blood vessels, as well as on the
      heat loss by the evaporation and air convection in the environment. At the Clinic
      for Plastic Surgery and Burns and at the Institute of Hygiene of the Military
      Medical Academy, skin temperature of the transferred free flaps and the recipient
      region surrounding were analyzed and measured in controlled microclimate
      conditions. The analysis was performed in 31 subjects, 20.23 months after the
      free tissue transfer. The aim of the study was to determine the differences
      between the skin temperature of the transferred free flaps and the recipient
      region surrounding, as wall as of the donor's region surrounding. The results of
      the investigation revealed that skin temperature of the transferred free flaps
      was lower in 28 (90.3%) patients than the temperature of the donor's region
      surrounding. Skin temperature of the transferred free flaps was higher in 25
      subjects (80.6%) than the temperature of the recipient region surrounding. Skin
      temperature of free flaps transferred to the foot and the lower leg was higher
      than the skin temperature of the recipient region surrounding but was also lower
      in the flaps transferred on the head. The temperature of the recipient region
      surrounding influenced the skin temperature of the transferred free flaps,
      besides the flap tissue perfusion.

PMID- 10645153
TI  - [The effect of cell phones on pacemaker function].
AB  - The aim of the study was to examine if there existed a risk from interference of
      cellular phones on patients with implanted permanent pacemakers. The study
      comprised 144 patients (134 VVI/VVIR and 10 DDD/DDDR) with permanent pacemakers
      of different manufactures. METHODS: During the routine pacemaker check, cellular
      phone aerial (Nokia 1610; GSM Standard) was placed against the skin of patients
      above the spot of pacemaker implantation, while the phone calls were repeated and
      ECG was continuously monitored. The effect of cellular phone on pacemaker was
      established upon: a) preexisting parameters of electric pacemaker stimulation; b)
      minimal ventricular rate of 90 beats/min, while electric stimulation parameters
      were set to their most sensitive values (MSV). RESULTS: Only in 9 (6.25%)
      patients was observed intermittent pacemaker inhibition, when pacemaker settings
      were on preexisting values of electric stimulation, while in 17 patients (11.8%)
      inhibition was noticed, when pacemaker settings were changed to their MSV.
      Besides, programmed values of electric stimulation in our patients remained
      unchanged. CONCLUSION: Although the electromagnetic interference interactions of
      cellular phones on pacemaker function were observed in relatively small number of
      our patients, we were of the opinion that pacemaker-dependent patients should
      avoid the use of cellular phones.

PMID- 10645154
TI  - [Physiological duration of the silent period in masticatory muscles].
AB  - "Silent period" is the reflex pause or the period of suppressive activity that is
      subsequent to some sort of stimuli during or after the muscle contraction. In
      current dentistry, "silent period" registered by electromyography presents in
      functional diagnosis one of the parameters in revealing the functional
      disturbances of neuromuscular system. The aim of the study was to investigate the
      physiological duration of "silent period" in masticatory muscles. The group of
      examinees comprised 4 males and 4 females of average age 29 years. All the
      examinees were with healthy stomatognathic system and natural dentition. "Silent
      period" was registered by the apparatus "Medlec" Mystro-MS 20 using intramuscular
      electrodes. The results of the investigation indicated the different duration of
      physiological "silent period", depended on the type of investigated muscle.

PMID- 10645155
TI  - [Modern principles in the treatment of autoimmune thrombocytopenia].

PMID- 10645156
TI  - [Treatment of aggressive and agitated behavior in psychiatric practice].

PMID- 10645157
TI  - [Otalgia].

PMID- 10645158
TI  - [Indications for the use of coronary stents].

PMID- 10645159
TI  - [Management of war injuries of blood vessels in prolonged ischemia].
AB  - We present a successful management of a gunshot wound of major blood vessels of
      the leg, in condition of prolonged ischemia. The patient has been sent to our
      hospital for the complete vascular management of the complete interruption of the
      major blood vessels of the left leg that were primarily ligated and marked.
      Because of the difficulties in evacuation, the patient arrived 20 hours after the
      wounding. There was no indication for the arteriography. The interruptions of the
      continuity of the superficial femoral artery in length of approximately 10 cm and
      of deep femoral vein in length of 8 cm were managed by interposition of
      autovenous grafts taken from the large subcutaneous vein of the other leg.
      Standard fasciotomy and partial exclusion of muscles of the left lower leg with
      relaxing fasciotomy of the left upper leg muscles were performed in the operative
      procedure. A successful rehabilitation has been completed and five years after
      the wounding, completely correct vascular and functional condition of the wounded
      leg was observed.

PMID- 10645160
TI  - [Staphylococcal pneumonia associated with pneumatoceles, bilateral
      pyopneumothorax and sepsis].
AB  - A case of soldier with community acquired staphylococcal pneumonia and multiple
      pneumatoceles as the rare complication in adults is presented. Their recognition
      provides appropriate treatment. In the patient were developed bilateral
      pneumothorax, pleural empyema and sepsis. Surgical treatment was performed by
      thoracic drainage. Recovery of pulmonary function was poor, as distinguished from
      children.

PMID- 10645162
TI  - [Urticarial vasculitis--a syndrome with low complement levels and secondary
      glomerulopathy].
AB  - In female patient, aged 41, 3 years ago appeared skin changes of urticarial type,
      and occasional pain in the joints of shoulders and hands, followed by complete
      weakness and exhaustion, as well as the occurrence of face and eyelid edema.
      Laboratory findings confirmed the presence of hypocomplentemia with proteinuria,
      microhematuria and cylindruria. Histopathologic (HP) finding of skin biopsy was
      leukocytoclastic vasculitis, and HP finding of the kidneys was
      mesangioproliferative glomerulonephritis. The regression of skin changes was
      observed during hospitalization after Dapsone was administered. The therapy
      started with corticosteroids (Prednisone 40 mg/day with weekly dose from 5 mg to
      30 mg). In spite of the therapy, hypocomplementemia and proteinuria up to 335
      mg/24 h have maintained for a year in the later controls in an outpatient
      department. The patient is without discomfort, and renal function is stable.

PMID- 10645161
TI  - [Eclampsia with a transient neurological deficit].
AB  - The results of certain clinical studies indicated the possibility of the onset
      and development of cerebrovascular diseases during pregnancy. Pathogenesis of
      this cascade of developments is frequently unknown. Eclampsia is the leading
      clinical syndrome, associated with numerous neurological complications. This is a
      case report of a 24 years old patient, who in a short period became extremely
      psychomotorically, agitated, with bilateral iridoplegia and positive Babinsky
      reflex during the development of eclampsia. Soon, a series of grand-mal epileptic
      attacks developed in the patient. However, the revealed clinical phenomenology
      was completely withdrawn within 6 hours, after the adequate estimation of
      clinical status and timely therapeutic measures. We have concluded that the
      patient had transient global cerebral ischemia, as a part of acute hypertensive
      endephalopathy.

PMID- 10645163
TI  - Performance of acute flaccid paralysis (AFP) surveillance and incidence of
      poliomyelitis, 1998-1999 (as of 25 November 1999).

PMID- 10645164
TI  - Hepatitis C--global prevalence (update).

PMID- 10645165
TI  - Web-based surveillance data system (CISID), WHO European Region.

PMID- 10645166
TI  - 3rd Baltic bone and cartilage conference. Ronneby, August 26-29, 1999. Abstracts.

PMID- 10645167
TI  - Swedish Orthopedic Society. Skovde, May 25-27, 1999. Abstracts.

PMID- 10645168
TI  - Pitfalls and delay in the diagnosis of Pancoast tumour presenting in orthopaedic
      units.
AB  - Pancoast tumours present a difficult and peculiar problem. Their clinical
      manifestations may be extrapulmonary. The underlying lesion may be missed in
      patients presenting with predominantly orthopaedic symptoms. We present four
      consecutive cases, which were referred to our clinic and the diagnosis was made
      with mean delay of 18.5 months from the beginning of symptoms.

PMID- 10645169
TI  - Solitary nodal metastases presenting as branchial cysts: a diagnostic pitfall.
AB  - Two patients with metastatic squamous cell carcinoma are presented. Both were
      initially clinically diagnosed as branchial cysts. The importance of a full
      examination of the upper aerodigestive tract, and fine needle aspiration cytology
      is emphasised to avoid the possibility of excision as a branchial cyst, which
      could lead to tumour dissemination.

PMID- 10645170
TI  - Clinically benign parotid tumours: local dissection as an alternative to
      superficial parotidectomy in selected cases.
AB  - In a personal series of 162 tumours, 101 were pleomorphic adenomas 28 of which
      were removed by elective local extra capsular dissection and 73 by a conventional
      nerve dissection. There were no recurrences in either group after a mean follow
      up 10.3 years, range 3-21 years for local dissection and 8.3 years, range 3-22
      years for nerve dissection. Frey's syndrome did not occur after local dissection
      but was present in 25% of patients after a nerve dissection. Of the 162 parotid
      lumps, 17 proved to be a carcinoma but only one was deemed suitable for a local
      removal, a low grade muco epidermoid carcinoma of the accessory lobe and no
      recurrence has occurred after 8 years. In benign disease, local dissection gives
      similar results to conventional nerve dissection with less morbidity and confirms
      that tumour recurrence cannot be ascribed to any properties of the tumour but
      lies in the hands of the surgeon and depends on the care with which the tumour is
      removed.

PMID- 10645171
TI  - Drains for thyroidectomy/parathyroidectomy: fact or fiction?
AB  - BACKGROUND: Many authorities advocate draining the neck routinely after thyroid
      and parathyroid surgery with no scientific evidence to support this practice. We
      aimed to establish if the routine use of drains following thyroid/parathyroid
      surgery is of any value. METHOD: Medical records of patients who underwent
      thyroidectomy or parathyroidectomy under the care of a single endocrine surgeon
      (GP) over a 14-year period were reviewed. For the first 6 years, the neck was
      routinely drained (drain group) and for the subsequent 8 years the neck was only
      drained if the surgeon felt it necessary according to the operative situation
      (selective group). RESULTS: A total of 606 procedures (425 thyroidectomy and 181
      parathyroidectomy) were performed on 582 patients. Drains were routinely used in
      134 (22%) procedures (drain group) and were selectively used in 472 (78%)
      (selective group) of which 191 (40%) were drained. In all patients, there was a
      significant increase in the rate of postoperative bleeding/haematoma in patients
      with a drain (8/314 versus 1/282, Fisher's exact, P < 0.05). Wound infection
      occurred only in the patients with a drain. There was no difference in the
      incidence of postoperative bleeding and airways obstruction between the drain and
      selective groups. CONCLUSION: We conclude that the routine use of neck drains is
      unnecessary and may indeed be harmful, drain insertion being associated with an
      increased incidence of wound infection. Drains should, therefore, be used
      selectively after thyroidectomy and parathyroidectomy.

PMID- 10645172
TI  - Angiogenesis in cancer: the role of endothelin-1.
AB  - This review summarises the process of angiogenesis, its role in tumourigenesis
      and suggests a mechanism by which endothelin-1 may influence these processes.

PMID- 10645173
TI  - The molecular biology of colorectal cancer development and the associated genetic
      events.
AB  - Colorectal carcinoma remains the second most common malignancy in the western
      world. Mortality has remained stable despite advances in surgical and adjuvant
      radio- and chemotherapy regimens. This has renewed interest in the understanding
      of the basic principles of the molecular biology of colorectal carcinogenesis.
      The condition is characterised by multiple mutations in common oncogenes and
      tumour suppressor genes encompassing the inherited conditions familial
      adenomatous polyposis and hereditary nonpolyposis colorectal cancer. The latter
      is characterised by genomic instability due to mismatch repair gene defects.
      These conditions and the role of the tumour protease systems, e.g. the
      plasminogen activation system and the matrix metalloproteinases, involved in the
      degradation of the extracellular matrix, provide an ideal role model for the
      study of carcinogenesis. The understanding and future application of these basic
      mechanisms, combined with the recent innovative work on the potential
      prophylactic role of COX2 inhibition, may provide further insight in the ultimate
      quest for a 'cure'. In the long-term, this concept may have to be achieved at the
      molecular level.

PMID- 10645175
TI  - Tension-free mesh hernia repair: recovery and recurrence after one year.
AB  - The outcome of 200 consecutive patients with inguinal hernias repaired by the
      tension-free mesh technique at a specialist clinic was assessed one year after
      operation. There were no recurrences and no major complications. The wound
      infection rate was 1%. Less than 10% of patients had only minor complaints and
      99% of patients were satisfied or very satisfied with the operation and its
      outcome. Low recurrence rates after one year imply low long-term recurrence and
      testify to the benefits of a specialist approach.

PMID- 10645176
TI  - Six-fold suture:wound length ratio for abdominal closure.
AB  - Midline laparotomy incision is generally closed as a continuous single layer with
      monofilament suture. To achieve safe abdominal closure, it is advised to have a
      suture:wound length (SL:WL) ratio of more than 4:1. The importance of a high
      SL:WL ratio led us to standardise a safe abdominal closure technique. We
      calculated the subsequent SL:WL ratio and support our finding with a mathematical
      model. Between March 1996 and February 1997, 100 consecutive patients undergoing
      elective or emergency laparotomy through a midline incision were entered into
      this prospective study. The wounds were closed with a single layer continuous
      suture to approximate the abdominal muscles. Suture and wound lengths were
      recorded. Patients were followed for one year. Five patients developed incisional
      hernia at 12 months postoperatively. There was no burst abdomen. The mean SL:WL
      ratio: was 6.2:1. A mathematical model confirms that a SL:WL ratio of 6:1 should
      be achieved with this suture technique. We recommend an optimal SL:WL ratio:
      greater than or equivalent to 6:1 to achieve safe closure of midline laparotomy
      incision.

PMID- 10645174
TI  - A review of the management of small bowel obstruction. Members of the Surgical
      and Clinical Adhesions Research Study (SCAR).
AB  - Small bowel obstruction is a significant surgical problem and is commonly caused
      by postoperative adhesions. Patients suffering from this condition are often
      difficult to assess and require careful evaluation and management. Articles
      regarding the diagnosis, evaluation and management of small bowel obstruction
      have been identified from the Ovid, Embase and Silver Platter electronic
      databases and then reviewed by the authors. Particular emphasis has been placed
      on randomised controlled trials or large prospective series. Anecdotal reports or
      those containing small numbers have been largely excluded, but where they have
      been included it has been made clear in the text. The management of small bowel
      obstruction is predominantly the management of obstruction due to postoperative
      adhesions. The selective use of radiological techniques, such as water soluble
      contrast and CT studies, often help to characterise the nature of the obstruction
      and may even help with its resolution. Techniques involving the use of
      laparoscopy and barrier membranes may reduce morbidity but there is a need to
      evaluate these strategies further with prospective clinical trials.

PMID- 10645177
TI  - A long left subcostal incision improves exposure for the conventional spleno
      renal shunt.

PMID- 10645178
TI  - Preserving function and long-term patency of dialysis access.
AB  - Of the 283, 932 patients with end stage renal disease (ESRD) receiving
      replacement therapy in the US in 1996, 62% were being treated with haemodialysis.
      Improved survival of haemodialysis patients coupled with the inability to provide
      enough renal transplants for the growing ESRD population has resulted in an
      increase in the average length of time patients spend on dialysis. Vascular
      accesses are, therefore, required to function for longer periods of time.
      Maintenance of a reliable access to the circulation has been described as the
      Achilles' heel of modern haemodialysis. Preserving access function and long-term
      patency are essential for efficient dialysis delivery.

PMID- 10645179
TI  - Does the introduction of HDU reduce surgical mortality?
AB  - The aim of this study was to assess the change in workload in a general surgery
      department over 2 consecutive 1-year periods and document the impact of a high
      dependency unit (HDU) on hospital mortality. Data were collected on all
      admissions, the number and type of operations performed for a 1-year period
      before and after a purpose-built HDU was opened. During the study period, the
      total number of admissions increased by 15%, with a disproportionately large
      increase (27%) in the number of emergency admissions. This was reflected by
      increases in the emergency out-of-hours operating by 12%. During the study
      period, the overall in-patient mortality rose from 2.16% to 3.2%. Introduction of
      HDU facilities alone does not lead to a reduction in hospital mortality.
      Alterations in emergency workload and changes in case-mix are important in
      determining outcome. League tables of hospital mortality are likely to be
      difficult to interpret without adequate information about facilities and case
      mix.

PMID- 10645180
TI  - How long should patients be followed-up after total hip replacement? Current
      practice in the UK.
AB  - Some 1000 postcard questionnaires were sent to Fellows of the British Orthopaedic
      Association (BOA) to establish current follow-up practice of primary total hip
      replacement (THR) patients. For cemented THRs, 50% of surgeons saw their patients
      for under 1 year, 78% under 5 years with indefinite follow-up being performed by
      14%. There was significantly more follow-up of uncemented and hybrid prostheses
      with the proportions being 25%, 56% and 30% respectively (chi 2, P < 0.0001).
      This study has revealed a wide variation in practice between individual surgeons
      and has shown over one-third of surgeons feel they are prevented from performing
      as much follow-up as they would wish by the availability of clinic resources.
      Higher follow-up rates of uncemented components may reflect a lack of confidence
      in their long-term performance.

PMID- 10645182
TI  - Psoas abscesses complicating colonic disease: imaging and therapy.

PMID- 10645181
TI  - Disorders of ejaculation.
AB  - Following John Hunter's example set over 200 years ago, it is clear that there is
      much to study and understand in disorders of ejaculation. Congenital
      malformations and their relationship to genetic disorders are now more clearly
      understood: these are matters of the utmost importance in the present era of
      assisted reproduction, if perpetuation of serious anomalies, such as fibrocystic
      disease, is to be avoided. Surgically induced injuries that impact upon male
      reproductive function are now recognized and largely preventable by careful
      attention to preservation of normal structures during extirpative surgery. Much
      work remains to be done on functional disorders, especially on the side effects
      of drug therapy, where some insight may be gained into the function and disorders
      of the basal ganglia--the 'dark basements of the mind'.

PMID- 10645183
TI  - Has the change in junior doctors' hours resulted in an increased number of normal
      appendices being removed?

PMID- 10645184
TI  - Delegation of orthopaedic workload.

PMID- 10645185
TI  - Impact of the introduction of a daily trauma list on out-of-hours operating.

PMID- 10645186
TI  - Midline laparotomy incision: a technique with a different slant.

PMID- 10645187
TI  - Midline laparotomy incision: a technique with a different slant.

PMID- 10645188
TI  - The indications for scrotal ultrasound.
AB  - Scrotal ultrasound scanning is now a routine and mandatory investigation of the
      patient presenting with scrotal symptoms. The need for scrotal ultrasound
      scanning when the physical examination reveals no significant abnormality has not
      been previously assessed. We conducted a retrospective study of 160 patients
      attending for scrotal ultrasound over a period of 1 year. The accuracy of
      clinical examination was compared with the gold standard of ultrasound for
      identifying clinically significant lesions. The sensitivity, specificity and
      positive and negative predictive values were calculated. Four clinically relevant
      groups were used for analysis purposes: Group I, acutely painful scrotum with or
      without swelling; Group II, chronic testicular pain without swelling; Group III,
      chronic scrotal swelling with or without pain; and Group IV, the asymptomatic
      testis. In Group I, sensitivity was 100%, specificity was 81.3%, the positive
      predictive value was 92.1% and the negative predictive value was 100%. In Group
      II, sensitivity was 71.4%, specificity was 90.9%, the positive predictive value
      was 76.9% and the negative predictive value was 88.2%. In Group III, sensitivity
      was 88.9%, specificity was 66.7%, the positive predictive value was 92.3% and the
      negative predictive value was 57.1%. In Group IV, sensitivity was 33.3%,
      specificity was 100%, the positive predictive value was 100% and the negative
      predictive value was 93.9%. All clinically significant abnormalities were
      identified on clinical examination. Clinically insignificant lesions identified
      by ultrasound alone did not affect the clinical management. It is recommended
      that scrotal ultrasound is used in the acutely painful scrotum where a confident
      diagnosis cannot be made or there is failure to respond to treatment, and in the
      chronic swelling where a confident clinical diagnosis cannot be made.

PMID- 10645189
TI  - In vivo anatomical analysis of arterial contact with trigeminal nerve: detection
      with three-dimensional spoiled grass imaging.
AB  - The purpose of this study was to review the normal in vivo neurovascular
      relationship between the trigeminal nerve and surrounding arteries without the
      use of volunteers. 290 nerves in 145 cases were reviewed during a 1-year period.
      Axial source images and multiplanar reconstructed (MPR) images were used to
      determine the neurovascular contact and direction of contact. Multiplanar volume
      reformation (MPVR) was used to identify the contact vessels and to demonstrate
      the relationship between the nerve and arteries. Vascular contact was found in
      29% of the 290 nerves (83 nerves). The arteries involved were the superior
      cerebellar artery (SCA) or the anterior inferior cerebellar artery (AICA).
      Vascular contact with two arteries was found in 3%. Of the 286 asymptomatic
      nerves, the nerve was located between the two vessels in 3% and compression was
      seen in 1%. Three points of vascular contact by the two arteries were identified
      in one asymptomatic nerve. The direction of contact between the SCA and the nerve
      was superior (38%), superomedial (32%) or medial (15%) in most cases. The
      direction of contact between the AICA and the nerve was inferior, inferolateral
      or lateral in all cases. Vascular contact at the root entry zone (REZ) was noted
      in 90%. Four nerves were affected by trigeminal neuralgia, one of which touched
      an artery and two were compressed. It was concluded that arterial contact can be
      assessed without difficulty but evaluation of vascular compression is not easy.

PMID- 10645190
TI  - Real-time portal monitoring to estimate dose to skin of patients from high dose
      fluoroscopy.
AB  - Since doses to skin of patients from fluoroscopically-guided interventional
      procedures can be very high, real-time monitoring of skin dose is important for
      both patient management and quality control. The use of a scintillation detector,
      placed on the X-ray port to measure potential skin dose, was investigated,
      focusing on the uncertainties related to the technique. Sources of uncertainty
      include performance characteristics of the dosemeter, errors in calibration,
      patient set-up and changes during the procedure. Some of the largest sources of
      error include uncertainty in source-to-skin distance, heel effect, difficulty in
      identifying the area of skin principally exposed, calibration error, energy
      dependence of the dosemeter and the dose rate dependence of the monitor. This
      technique is found to be beneficial for radiation management, but users must be
      cognizant of the potential errors of the method and the limitations that these
      place on quality control and patient management. Knowing the limitations and
      minimizing the sources of error enhance the utility of the technique.

PMID- 10645191
TI  - Comparison of film, hard copy computed radiography (CR) and soft copy picture
      archiving and communication (PACS) systems using a contrast detail test object.
AB  - This paper describes two experiments where a widely available test object (FAXIL
      TO20) was used to compare film, hard copy computed radiography (CR) and soft copy
      picture archiving and communication systems (PACS) images. Baseline images were
      produced with a fixed mAs. All images were scored by four experienced medical
      physicists. Contrast detail curves for the three types of images were almost
      identical. A second series of images was produced with the mAs varying from 1 mAs
      to 250 mAs. The contrast detail curves were plotted for each mAs value and the
      wider exposure latitude of CR compared with film was demonstrated. Use of PACS
      provided no further increase in exposure latitude. The density of the film images
      increased with mAs but the density of the CR hard copy images remained constant.
      It is of concern that the wider latitude of the CR images extends to exposures
      that are much higher than those used for film with no noticeable change in CR
      image density but with better images at higher exposures, because the potential
      exists for patient doses to increase. Hard copy CR images provide information
      about the exposure index which relates to the input dose to the plate and hence
      approximately to the dose to the patient. However, since such information is
      currently not available on default soft copy images, the authors suggest that all
      manufacturers of PACS should provide an indication of dose as a mandatory default
      setting.

PMID- 10645192
TI  - The effect of region of interest selection on dual energy X-ray absorptiometry
      measurements of the calcaneus in 55 post-menopausal women.
AB  - Bone mineral density (BMD) of the calcaneus was assessed by dual energy X-ray
      absorptiometry (DXA) in four different regions of the calcaneus in 20 pre
      menopausal and 55 post-menopausal women, none of whom were on treatment or
      suffering from conditions affecting bone. The total body option in the small
      animal software package of a Lunar DPX-L bone densitometer was used. The
      precision of the technique (%CV) varied from 0.7 to 2.2% depending on the region
      scanned. For post-menopausal women, BMD results in the mid and posterior parts of
      the calcaneus varied by < 7% while BMD in the anterior region was about 20%
      lower. DXA of the calcaneus was compared with measurements at the spine (L2-L4)
      and hip (femoral neck) and changes with age were estimated from cross-sectional
      data. BMD of the calcaneus was significantly reduced in 28 post-menopausal women
      with low lumbar spine BMD (-2SD) compared with women with normal spine BMD.
      Calcaneal BMD was significantly correlated to axial BMD (r = 0.45-0.77) and to
      age (r = 0.45 to -0.63). For a subgroup of 33 post-menopausal women measured
      twice after approximately 1 year, calcaneus BMD decreased by between 1.2% and
      2.5% while axial BMD showed no significant change. Unlike spine or femoral neck
      BMD, the decrease in calcaneus BMD was significantly greater in women with low
      spine BMD than in normal women, possibly indicating improved detection of
      skeletal changes. The optimum measurement sites for BMD in the calcaneus were
      within the mid or posterior part of the calcaneus or enclosing the whole
      posterior calcaneus. The calcaneus was shown to be a precise, sensitive and
      simple measurement site suitable for the assessment of osteoporosis, especially
      in the elderly where degenerative changes in the spine and hip can complicate BMD
      assessment.

PMID- 10645193
TI  - A transformation cross-talk technique for simultaneous dual radionuclide imaging:
      a myocardial perfusion 201Tl/99Tcm sestamibi dog SPECT study.
AB  - We have developed a novel transformation method for the correction of cross-talk
      in simultaneous dual radionuclide single photon emission CT (SPECT) imaging. It
      is based on the assumption that the transformations, which transform the primary
      energy window images into the scatter images as viewed in the other energy
      windows, are known. The method was tested on a dog model. These transformations
      were found by measuring the point response functions (prf) in different energy
      windows for both radionuclides in water. The dual radionuclide correction method
      described takes into account the different spatial distributions of the primary
      and scatter cross-talk photons in different energy windows. This method also
      includes the sequential application of restoration filters to the resulting cross
      talk corrected images. We used a dog model in three separate studies: two single
      radionuclide studies used as references and one dual radionuclide study. Contrast
      between the left ventricular cavity (LVC) and the myocardium was used in
      horizontal long axis (HLA) slices as a parameter to evaluate the results of the
      dual radionuclide correction method with restoration. The increase of the
      contrast in the dual radionuclide corrected images in both energy windows, i.e.
      201Tl primary window (70 keV) and 99Tcm primary window (140 keV), was
      significant. The cross-talk corrected 70 keV dual radionuclide HLA slice had a
      contrast of 0.62 compared with 0.35, which was the value in the non-corrected
      dual radionuclide HLA slice. Restoration improved the contrast to 0.68. In the
      single radionuclide 201Tl image, the same contrast was 0.59, improving to 0.70
      after restoration. For the dual radionuclide 140 keV HLA slice, the contrast
      increased from 0.69 to 0.76 after cross-talk correction. Additional increase of
      the contrast to 0.83 resulted from restoration filtering. In the single
      radionuclide 99Tcm sestamibi 140 keV HLA slice the improvement of contrast was
      from 0.63 to 0.86 as a result of the restoration. The transformation three
      window, dual radionuclide correction method with restoration improves the quality
      of the simultaneous rest 201Tl/stress 99Tcm sestamibi SPECT imaging.

PMID- 10645194
TI  - In the radiotherapy of prostate cancer, technique determines the doses to the
      penile structures.
AB  - For 11 consecutive prostate cancer patients undergoing three-dimensional
      conformal radiotherapy (3DCRT) in our institution, penile structures (PNS) were
      outlined in CT images obtained for treatment planning purposes. Dose-volume
      histograms (DVHs) were compared in order to study dose-volume relations for three
      techniques: 4FLD, an axial coplanar, four-field box technique; 6FLD, a six-field
      coplanar technique; and 4NAX, a coplanar but non-axial, four-field technique. All
      three techniques delivered equal doses to the planning target volumes (PTV). Our
      statistical analyses strongly indicate that the three techniques can be ranked as
      6FLD better than 4FLD (and 4FLD better than 4NAX) as far as irradiating PNS
      volume during treatment of prostate cancer (PC) is concerned. For each technique,
      there is a "spread" owing to differences in patient anatomy and/or target size,
      position, and extent, but each technique has a similar "profile" or "shape"
      distinct from other techniques. Whether irradiating smaller volumes of PNS will
      influence the sexual potency outcome remains to be demonstrated. However, PNS
      should be considered as another critical structure in addition to rectum, bladder
      and femoral heads in the radiotherapy (RT) of PC, especially in 3DCRT dose
      escalation studies. Sexual potency outcomes can be correlated to dose-volume
      relations in the future and this will help refine radiotherapy techniques
      further.

PMID- 10645195
TI  - The bead bag immobilization device.
AB  - Our aim was to reduce motion artefact during radiographic angiography and MRI of
      the lower limbs. The legs were immobilized using a bead bag with a filtered
      closeable valve. Air was removed by suction and the bag moulded into a rigid
      restraint. The bead bag is an effective, well tolerated and easily used
      immobilization device that is suitable for use in radiological imaging.

PMID- 10645196
TI  - In vivo dosimetry using diodes as a quality control tool--experience of 2 years
      and 2000 patients.
AB  - This paper reports the use of diodes as a quality control tool on more than 95%
      of patients undergoing megavoltage radiotherapy during the past 2 years. The
      paper describes a simple method for using the diodes, a number of possible
      pitfalls and a quality issue raised by the measurements. In general, the results
      have been reassuring with very few patients falling outside a +/- 5% action
      level.

PMID- 10645197
TI  - Endorectal magnetic resonance imaging of a rectal duplication cyst.
AB  - A case of a duplication cyst of the rectum is presented. This case highlights the
      potential role of endoluminal magnetic resonance imaging in the diagnosis of this
      uncommon condition. Alternative imaging modalities and differential diagnoses are
      discussed.

PMID- 10645198
TI  - Dual phase helical CT of a primary malignant fibrous histiocytoma of the right
      renal vein.
AB  - A case is reported of primary malignant fibrous histiocytoma of the right renal
      vein involving the ipsilateral kidney which showed early enhancement on dual
      phase helical CT. The correct diagnosis of a primary tumour of the renal vein
      involving the kidney was not made but in retrospect could have been achieved pre
      operatively by considering several CT features.

PMID- 10645199
TI  - Ultrasound evidence of gas in the fissure for ligamentum teres: a sign of
      perforated duodenal ulcer.
AB  - We present a case of confined duodenal ulcer perforation diagnosed on ultrasound.
      Locules of gas were visible in the fissure for ligamentum teres along with a
      small amount of free fluid in Morrison's pouch and thickening of the gall bladder
      wall. To our knowledge, "free" intraperitoneal gas confined to the fissure for
      ligamentum teres has not previously been reported as an ultrasound finding in
      perforated duodenal ulcer.

PMID- 10645200
TI  - Aberrant gastric venous inflow to the left lobe of the liver parenchyma adjacent
      to the falciform ligament.
AB  - Direct inflow of the aberrant right gastric vein independent of the portal venous
      system to the liver parenchyma is a well known cause of non-tumorous
      abnormalities on CT angiography. However, there have been no previous reports of
      aberrant gastric venous drainage as the cause of non-tumorous abnormalities in
      the left lobe of the liver parenchyma adjacent to the falciform ligament on CT
      angiography. We present a case of direct inflow of an aberrant gastric vein to
      this region of the liver, which influenced the non-tumorous enhancement shown by
      CT hepatic arteriography.

PMID- 10645201
TI  - Imaging features of focal intrahepatic extramedullary haematopoiesis.
AB  - The imaging findings of focal intrahepatic extramedullary haematopoiesis (EMH) in
      a 51-year-old woman with beta-thalassaemia intermedia are described with
      particular reference to MRI and CT. Bone marrow colloid scintigraphy was
      unhelpful in confirming the diagnosis, which was made from fine needle
      aspiration. This is the first description of stellate scars occurring in an EMH
      lesion. A review of the radiological appearances of this rare condition is
      presented.

PMID- 10645202
TI  - Female adnexal tumour of probable Wolffian origin: MR findings.
AB  - Female adnexal tumour of probable Wolffian origin is a rare tumour that arises
      from remnants of the Wolffian duct. Clinical and pathological findings of this
      tumour have been documented, but the MR findings have not been previously
      reported. We report the MRI features of an adnexal tumour of probable Wolffian
      origin.

PMID- 10645203
TI  - Echoplanar MRI in patients with an acute stroke syndrome.
AB  - An increasing number of patients with an acute stroke syndrome are being admitted
      to hospitals with on-site echoplanar MRI scanners. In this pictorial review, we
      describe our experience of an MRI protocol in the first 150 such patients scanned
      in our hospital. We illustrate some of the advantages of using echoplanar MRI.
      Diffusion and susceptibility weighted acquisitions may supplement conventional MR
      sequences by providing useful additional information about the age and location
      of the lesion, together with a high sensitivity to the presence of blood
      breakdown products.

PMID- 10645204
TI  - Hyperstimulation--brain attack.

PMID- 10645205
TI  - Breast radiation injury litigation.

PMID- 10645206
TI  - Raltitrexed (Tomudex) in combination treatment for colorectal cancer: new
      perspectives.
AB  - In recent years, significant advances have been achieved in the treatment of
      colorectal cancer, including the use of adjuvant chemotherapy following surgery
      in patients with colon cancer and the use of palliative chemotherapy for
      metastatic disease. Further potential for improvements in outcome for patients
      with colorectal cancer is provided by the introduction of new agents in combined
      treatment modalities. Although some of these new agents, such as raltitrexed,
      oxaliplatin and irinotecan, are active in colorectal cancer, single-agent therapy
      as first-line treatment has failed to demonstrate a substantial increase in
      survival. However, preclinical studies have indicated that combination treatments
      have the potential benefit of enhanced response rates. One such agent,
      raltitrexed, is currently under investigation in combination with 5-FU (bolus and
      infusional), oxaliplatin, cisplatin, irinotecan and anthracyclines, principally
      in patients with advanced colorectal cancer, but also in patients with other
      tumours. Similarly, combinations of adjuvant or neo-adjuvant radiotherapy and
      chemotherapy are being investigated and can offer a benefit in the treatment of
      rectal, oesophageal, pancreatic and gastric cancer. Promise for the future,
      therefore, appears to lie in combined treatment modalities which are expected to
      provide superior alternatives to current standard treatments.

PMID- 10645207
TI  - Combination of raltitrexed with other cytotoxic agents: rationale and preclinical
      observations.
AB  - Agents for use in combination therapy should be effective as monotherapy in the
      tumour type of interest, have different mechanisms of action or pharmacology, and
      preferably non-overlapping toxicity profiles. Raltitrexed is effective as
      monotherapy in a number of tumour types, but it is hoped that combining it with
      other cytotoxic agents will lead to enhanced efficacy. Raltitrexed and 5
      fluorouracil (5-FU) are specific and non-specific inhibitors, respectively, of
      thymidylate synthase, a critical enzyme in the de novo synthesis of DNA.
      Preclinical studies have indicated that raltitrexed and 5-FU have an incompletely
      overlapping spectrum of antitumour activity and may have additive or synergistic
      effects on colon carcinoma cells. These interactions are schedule-dependent
      (raltitrexed should precede 5-FU). Pre-treatment of colon carcinoma cells with
      raltitrexed has also been shown to increase intracellular levels of
      phosphoribosyl pyrophosphate resulting in increased incorporation of 5-FU
      nucleotides into RNA. Raltitrexed has a different mechanism of action from two
      other new agents active in colorectal cancer, irinotecan and oxaliplatin, and
      tumours are therefore not necessarily cross-resistant. Short pre-exposure of
      colon carcinoma cells to the irinotecan active metabolite, 7-ethyl-10-hydroxy
      camptothecin (SN-38), prior to exposure to raltitrexed has consistently resulted
      in synergistic cell kill, whereas the reverse sequence is antagonistic.
      Preliminary results indicate that equitoxic doses of raltitrexed and cisplatin,
      or oxaliplatin, are antagonistic in two colon carcinoma cell lines. However,
      because there are major difficulties in translating preclinical drug combination
      results to the clinical settings, these results should be interpreted with
      caution.

PMID- 10645208
TI  - Raltitrexed (Tomudex) in combination with 5-fluorouracil for the treatment of
      patients with advanced colorectal cancer: preliminary results from phase I
      clinical trials.
AB  - The potential of raltitrexed (Tomudex) in combination with 5-fluorouracil (5-FU)
      as treatment for advanced colorectal cancer has been investigated in two phase I
      clinical trials. In the first study, raltitrexed was combined with bolus 5-FU;
      patients received raltitrexed as a 15-min infusion followed 24 h later by bolus 5
      FU every 3 weeks. In the second study, 5-FU was administered as a weekly 24-h
      infusion for 5 weeks of a 6-week cycle and raltitrexed was given 15-min prior to
      5-FU on days 8 and 29. The recommended dose for bolus 5-FU in combination with
      raltitrexed is likely to be 1200 mg/m2 as dose-limiting toxicity (DLT) of febrile
      neutropenia was observed at 1350 mg/m2, but escalation of raltitrexed above the
      dose used for single-agent use (3.0 mg/m2) continues. In the
      raltitrexed/infusional 5-FU study, dose escalation is also still continuing, but
      only in men as no DLT has been observed in men; 2 of 3 female patients had DLT of
      myelosuppression and diarrhoea at raltitrexed 3.0 mg/m2 and infusional 5-FU 2400
      mg/m2. Raltitrexed had a significant effect on the pharmacokinetics of 5-FU
      irrespective of 5-FU regimen. Preliminary response data is encouraging with 53%
      of patients receiving raltitrexed/infusional 5-FU showing a partial response. In
      addition, significant disease stabilisation was observed in patients receiving
      raltitrexed combined with bolus 5-FU who had previously failed 5-FU therapy.
      Recruitment has recently commenced in two studies in which raltitrexed is
      combined with oral derivatives of 5-FU. In conclusion, preliminary data from
      these phase I studies indicate that the combination of raltitrexed and 5-FU is
      well tolerated and has encouraging clinical activity.

PMID- 10645209
TI  - Raltitrexed (Tomudex) in combination with platinum-based agents and/or
      anthracyclines: preliminary results of phase I clinical trials.
AB  - Three ongoing, dose-escalation, phase I studies are evaluating the combination of
      raltitrexed with oxaliplatin or anthracyclines (with and without cisplatin). In
      study 1, patients with advanced solid tumours received 2.0-3.75 mg/m2
      raltitrexed, followed 45 min later by 85-130 mg/m2 oxaliplatin (2-h infusion)
      every 3 weeks. In study 2, patients with advanced oesophageal or gastric
      adenocarcinoma received 2.0-3.0 mg/m2 raltitrexed with 50 mg/m2 intravenous
      (i.v.) epirubicin and 60 mg/m2 i.v. cisplatin every 3 weeks. In study 3, patients
      with advanced or metastatic gastric cancer received 2.5-3.5 mg/m2 raltitrexed
      followed by 30-60 mg/m2 i.v. doxorubicin every 3 weeks. In all studies,
      raltitrexed was given as a 15-min infusion. All the combinations evaluated were
      administered in convenient 3-weekly schedules and were generally well tolerated.
      Recommended doses for raltitrexed and oxaliplatin are the same in combination as
      for single-agent use, i.e. 3.0 mg/m2 raltitrexed and 130 mg/m2 oxaliplatin. The
      recommended dose of raltitrexed in combination with cisplatin and epirubicin is
      2.5 mg/m2. No dose-limiting toxicities were observed during co-administration of
      the full single-agent doses of raltitrexed and doxorubicin (3.0 mg/m2 and 60
      mg/m2, respectively); dose escalation is continuing. Preliminary efficacy results
      were encouraging, particularly for the combination of raltitrexed and oxaliplatin
      in patients with mesothelioma and advanced colorectal cancer. Preliminary data
      from these phase I studies suggest that the combination of raltitrexed with
      platinum-based agents and/or anthracyclines may represent useful regimens for the
      treatment of patients with advanced cancer. Further studies are required to
      identify the most effective combinations of raltitrexed with both established and
      new anticancer agents.

PMID- 10645211
TI  - Molecular aspects of the GM-CSF receptor: an example of the cell signalling
      mechanisms used by type 1 cytokine receptors.

PMID- 10645210
TI  - Raltitrexed (Tomudex) concomitant with radiotherapy as adjuvant treatment for
      patients with rectal cancer: preliminary results of phase I studies.
AB  - Radiotherapy, either alone or in combination with chemotherapy, may reduce local
      recurrence of rectal cancer following surgery and improve survival of patients
      with operable and advanced/recurrent/inoperable disease. Chemotherapy with 5
      fluorouracil in combination with radiotherapy has been used both before and after
      surgery; however, the optimum schedule is unclear. In addition, alternative
      chemotherapy with raltitrexed (Tomudex) may be more convenient and better
      tolerated. The preliminary results of three phase I dose-finding studies are
      described, combining escalating doses of raltitrexed with radiotherapy as pre- or
      postoperative treatment for operable rectal cancer or as treatment for
      advanced/inoperable/recurrent rectal cancer. The recommended dose of raltitrexed
      when combined with adjuvant radiotherapy is likely to be 2.6 mg/m2. This is a
      small dose reduction compared with the dose of raltitrexed for the treatment of
      advanced colorectal cancer (3.0 mg/m2); however, toxicity appears to be lower
      using the pre-operative approach. Neo-adjuvant therapy with raltitrexed plus
      radiotherapy also demonstrated clinical activity in the pre-operative study,
      which showed that 22% of patients achieved a complete response and 56% a partial
      response. Once the recommended dose has been defined in each setting, large-scale
      studies will be undertaken as appropriate.

PMID- 10645212
TI  - Febrile neutropenia: prophylactic and therapeutic use of GM-CSF.

PMID- 10645213
TI  - Use of granulocyte-macrophage colony stimulating factor (GM-CSF) in prevention
      and treatment of fungal infections.

PMID- 10645214
TI  - GM-CSF in haematopoietic stem cell transplantation.

PMID- 10645215
TI  - Local use of GM-CSF for severe mucositis.

PMID- 10645216
TI  - GM-CSF and stimulation of monocyte/macrophage function in vivo relevance and in
      vitro observations.

PMID- 10645217
TI  - GM-CSF can cause T cell activation; results of sequential chemo-immunotherapy.

PMID- 10645218
TI  - GM-CSF as adjuvant for immunotherapy with bispecific antibodies.

PMID- 10645219
TI  - Local low-dose of soluble GM-CSF significantly augments an immune response
      against tumour antigens in man.

PMID- 10645220
TI  - Combination of GM-CSF with antitumour vaccine strategies.

PMID- 10645221
TI  - Dendritic cells or their exosomes are effective biotherapies of cancer.

PMID- 10645222
TI  - Two distinct cell populations are obtained from human blood monocytes cultured
      with M-CSF, GM-CSF and IL-4.

PMID- 10645223
TI  - Intra-alveolar haemorrhage in sudden infant death syndrome: a cause for concern?

PMID- 10645225
TI  - Cyclin D1 expression and HHV8 in Kaposi sarcoma.
AB  - BACKGROUND: Human herpesvirus 8 (HHV8) appears to be the agent responsible for
      Kaposi sarcoma. The mechanism remains undetermined but may involve cell cycle
      regulating genes including D type cyclins which are pivotal in cell cycle
      progression. Recent HHV8 genetic analysis has revealed the presence of a v-cyclin
      which is homologous to D type cyclins. AIMS: First, to assess whether there is an
      independent relation between endogenous cyclin D1 expression in Kaposi sarcoma
      and HHV8 status; second to determine whether v-cyclin mRNA expression varies with
      Kaposi sarcoma stage. METHODS: Cyclin D1 immunohistochemistry was performed on 17
      paraffin embedded Kaposi sarcoma samples from 16 patients. HHV8 status was
      assessed in 15 of these using nested polymerase chain reaction (PCR) to ORF 26
      and the newly described technique of TaqMan PCR. An additional 10 fresh Kaposi
      sarcoma samples (early and nodular) were examined for HHV8 v-cyclin RNA. RESULTS:
      One case, which did not contain amplifiable HHV8, showed strong cyclin D1
      staining. The remaining cases were negative or weakly staining; v-cyclin
      transcript load was higher in early Kaposi sarcoma. CONCLUSIONS: While endogenous
      cyclin D1 expression is independent of HHV8 status, v-cyclin transcription is
      higher in early lesions, supporting the "viral hit" hypothesis.

PMID- 10645224
TI  - Cell cycle regulators: mechanisms and their role in aetiology, prognosis, and
      treatment of cancer.

PMID- 10645226
TI  - Prognostic value of tumour associated antigen immunoreactivity and apoptosis in
      cerebral glioblastomas: an analysis of 168 cases.
AB  - AIMS: To evaluate a possible association between clinical outcome in patients
      with glioblastoma and expression of some immunohistochemical variables and
      apoptosis. METHODS: 168 selected patients with cerebral glioblastomas were
      studied retrospectively. Tumour specimens were examined immunohistochemically
      with antibodies to proliferating cell nuclear antigen (PCNA), p53, bcl-2, and
      epidermal growth factor receptor (EGFR) to detect the intracellular receptor
      domain. Apoptosis was detected by in situ end labelling. Multivariate analysis
      was performed using the Cox proportional hazard model. RESULTS: On univariate
      analysis the PCNA labelling index, immunoexpression of EGFR, and the apoptotic
      index were significantly related to glioblastoma outcome. Survival time was
      reduced as PCNA labelling index increased and apoptotic index decreased (p =
      0.0073 and p = 0.00031, respectively). Survival time in patients with EGFR
      positive tumours was found to be reduced (p = 0.00024). Multivariate analysis
      showed independent prognostic value for the EGFR positivity and apoptotic index
      only (p = 0.0053 and p = 0.0039, respectively). There was no association between
      clinical outcome of glioblastoma and p53 or bcl-2 immunostaining. CONCLUSIONS:
      EGFR immunoreactivity and apoptotic index were found to be useful for assessing
      prognosis of individual glioblastomas but it seems unlikely that p53 and bcl-2
      immunohistochemistry will be of value in determining survival in such patients.

PMID- 10645227
TI  - Intra-alveolar haemorrhage in sudden infant death syndrome: a cause for concern?
AB  - BACKGROUND: The "Back to Sleep" campaign in 1991 resulted in a dramatic decrease
      in the incidence of sudden infant death syndrome (SIDS). The proportion of
      presumed SIDS deaths being actually suspicious deaths from airway obstruction is
      likely to have become relatively greater. There is usually little pathological
      evidence to suggest smothering, but intra-alveolar haemorrhage appears to be more
      prominent in cases where interference with the airway is suspected. AIM: To
      attempt to quantify intra-alveolar haemorrhage to see whether it could be used as
      a marker to distinguish between smothering/overlaying and SIDS. METHODS: Intra
      alveolar haemorrhage was quantified using digital image analysis on
      haematoxylin/eosin stained sections taken from the lungs of 62 consecutive
      infants who had died suddenly and unexpectedly. Cases were initially classified
      according to the original cause of death. After quantitation, the case histories
      were critically reviewed. Three pathologists independently made microscopic
      assessments of the degree of intra-alveolar haemorrhage in the first 24 cases to
      see whether these accurately reflected the quantitative results. RESULTS: 73% of
      those infants with a history suggesting possible involuntary overlaying and 45%
      of those with a history suspicious of smothering had significant intra-alveolar
      haemorrhage (> 5% of total lung surface area assessed). From the history, the
      cause of death in 11 cases initially classified as SIDS would better have been
      given as "Unascertained." Simple microscopic assessments underestimated the true
      extent of the haemorrhage in 33% (8/24). CONCLUSIONS: If a moderate degree (at
      least 5%) of pulmonary parenchymal haemorrhage is observed, this may be an
      indicator of airway obstruction for a significant period, either from overlaying
      or possibly smothering. The diagnosis of SIDS may be being used inappropriately
      in such cases.

PMID- 10645228
TI  - Telomerase activity in gestational trophoblastic disease.
AB  - AIMS: To investigate the pattern of telomerase activity in hydatidiform mole as
      compared with normal placenta and choriocarcinoma, and to determine the
      prognostic significance of telomerase activity in hydatidiform mole. METHODS:
      Telomerase activity in 35 cases of hydatidiform mole, 35 normal placentas, one
      choriocarcinoma sample, and two choriocarcinoma cell lines (JAR, JEG3) was
      determined using the sensitive polymerase chain reaction based telomeric repeat
      amplification protocol (TRAP) assay. Two cases of breast carcinoma and two cases
      of ovarian carcinoma were also included as positive controls in the telomerase
      assay. RESULTS: Telomerase activity was detected in 11 of 30 early placentas
      (36.7%), one of five term placentas (20%), five of 27 hydatidiform moles which
      regressed spontaneously (18.5%), and six of eight hydatidiform moles which
      developed persistent trophoblastic disease (75%) (including three which developed
      metastases). Hydatidiform moles which subsequently developed persistent disease,
      especially those which metastasised, were more likely to express telomerase
      activity (p < 0.01). However, there was no significant difference in the
      frequency of telomerase activity between early placentas and hydatidiform mole.
      Strong telomerase activity was observed in choriocarcinoma tissue,
      choriocarcinoma cell lines, and ovarian and breast carcinomas. CONCLUSIONS:
      Telomerase activation occurs in hydatidiform mole with a similar incidence to
      early normal placentas. This supports the concept that hydatidiform mole is
      essentially an abnormal conceptus. There is an association between telomerase
      activation and the development of persistent trophoblastic disease. Further study
      is warrant to confirm the prognostic significance of telomerase activity in
      hydatidiform mole.

PMID- 10645229
TI  - Measurement of vascularity as a diagnostic and prognostic tool for well
      differentiated thyroid tumours: comparison of different methods of assessing
      vascularity.
AB  - AIMS: To determine whether the measurement of vascularity can be used to
      differentiate follicular adenomas from follicular carcinomas or to reflect the
      prognosis of follicular carcinomas and papillary carcinomas of the thyroid gland,
      and to compare four methods of assessing vascularity. METHODS: Tissue sections
      from 26 papillary carcinomas, 15 follicular adenomas, and 15 follicular
      carcinomas were stained with an antibody to CD34. A computerised image analysis
      system was used to calculate, for each tumour, mean endothelial areas and the
      mean endothelium to tumour epithelial nucleus area ratio from 10 systematically
      selected fields across one dimension of the tumour ("systematic field" analysis)
      or from the three most vascularised fields of the tumour ("hot spot" analysis). A
      European Organisation for Research on Treatment of Cancer (EORTC) prognostic
      index was calculated for each papillary carcinoma and follicular carcinoma.
      RESULTS: Significant differences in vascularity between the three tumour groups
      could only be shown by comparing mean endothelial area values measured from hot
      spots. While the hot spot median mean endothelial area of follicular carcinomas
      was significantly greater than that of follicular adenomas, there was a large
      overlap between the two groups. For follicular carcinomas, higher hot spot mean
      endothelial area values were related to worse prognosis as indicated by the EORTC
      prognostic indices. No association between vascularity and prognosis was found
      for the papillary carcinomas, regardless of the method of assessing vascularity.
      CONCLUSIONS: Measuring endothelial area from hot spots using a computerised image
      analysis system is a sensitive method of assessing the vascularity of thyroid
      tumours. While vascularity measurement cannot be recommended as a practical tool
      for differentiating between malignant and benign follicular tumours, the
      suggestion that vascularity may reflect prognosis for follicular carcinomas
      deserves further study.

PMID- 10645230
TI  - Thymidine phosphorylase expression in progression of cervical cancer: correlation
      with microvessel count, proliferating cell nuclear antigen, and apoptosis.
AB  - AIMS: To determine how epithelial and stromal thymidine phosphorylase expression
      affects angiogenesis, rapid tumour growth, and decreased apoptotic activity in
      cervical cancer at varying stages of progression. METHODS: Epithelial and stromal
      thymidine phosphorylase expression, the microvessel count (reflected by factor
      VIII related antigen), and proliferating cell nuclear antigen (PCNA) were
      assessed immunohistochemically in 25 specimens of normal cervical epithelium, 35
      of carcinoma in situ (CIS), 34 of microinvasive carcinoma, and 34 of invasive
      cervical squamous cell carcinoma. Apoptosis was evaluated by the terminal
      deoxynucleotidyl transferase mediated dUTP-biotin nick end labelling (TUNEL)
      method. The relation of epithelial and stromal thymidine phosphorylase expression
      to microvessel count, PCNA index, and apoptotic index was examined. RESULTS:
      Epithelial and stromal thymidine phosphorylase expression progressively increased
      along a continuum from normal epithelium to invasive squamous cell carcinoma.
      Epithelial and stromal thymidine phosphorylase expression showed a significant
      positive correlation with microvessel counts. Within each histological stage, CIS
      cases with high stromal thymidine phosphorylase expression, invasive squamous
      cell carcinoma cases with high epithelial thymidine phosphorylase expression, and
      microinvasive carcinoma cases with high thymidine phosphorylase expression in
      both epithelium and stroma had a significantly higher microvessel count. High
      epithelial thymidine phosphorylase expression was associated with a significantly
      higher PCNA index in CIS and microinvasive carcinoma, but not in invasive
      squamous cell carcinoma. No significant correlation was seen between apoptotic
      index and either epithelial or stromal thymidine phosphorylase expression or
      microvessel count. CONCLUSIONS: Epithelial and stromal thymidine phosphorylase
      expression may combine to promote angiogenesis during progression of cervical
      cancer, and epithelial thymidine phosphorylase expression may stimulate tumour
      cell proliferation in the early stages.

PMID- 10645231
TI  - Short-term significance of DNA ploidy and cell proliferation in breast carcinoma:
      a multivariate analysis of prognostic markers in a series of 308 patients.
AB  - AIM: To determine the importance of tumour DNA ploidy and cell proliferation, as
      measured by the S phase fraction (SPF), in relation to other established
      clinicopathological indicators of prognosis in breast cancer. METHODS: A
      prospective study of 308 patients. Tumours were staged following the TNM system
      criteria and were classified according to the histological type and grade. DNA
      flow cytometry was performed on fresh/frozen samples stained with propidium
      iodide. Hormone receptors were analyzed by immunocytochemistry. A Cox
      proportional hazards regression model was used for statistical evaluation of the
      prognostic factors. RESULTS: Median follow up time was 39.6 months (range 3 to
      84). A DNA diploid pattern was found in 134 tumours (43.5%) and aneuploid in 174
      (56.5%). Median SPF value was 6.1% (range 1% to 27.8%). DNA ploidy and SPF were
      strongly correlated (p < 0.001), and both were related to histological type (p <
      0.001), grade of differentiation (p < 0.001), tumour size (p = 0.006 and p =
      0.002), and hormone receptor activity (p < 0.001). DNA ploidy was also related to
      node status (p = 0.022), but SPF was not. In univariate analysis, there were
      significant correlations between disease-free survival and age, histological
      grade, tumour size, node status, DNA ploidy, SPF, and hormone receptor activity;
      age, tumour size, node status, DNA ploidy, and hormone receptors were predictors
      of overall survival. In multivariate analysis, only node status (p = 0.001) and
      DNA ploidy (p = 0.006) retained independent prognostic significance in relation
      with overall survival, while node status (p < 0.001) and SPF (p < 0.001) were
      predictors of disease-free survival. DNA ploidy and SPF continued to predict
      disease-free and overall survival in lymph node positive (pN1) patients but not
      in the lymph node negative (pN0) group. CONCLUSIONS: DNA ploidy and SPF are
      strongly intercorrelated and have independent prognostic value for predicting the
      short term clinical outcome of breast carcinoma patients.

PMID- 10645232
TI  - Interobserver variation in the histopathological scoring of Helicobacter pylori
      related gastritis.
AB  - AIM: To test the reproducibility between two histopathologists of features of
      Helicobacter pylori gastritis, using the updated Sydney classification. METHODS:
      290 dyspeptic Dutch patients with biopsy proven H pylori infection were enrolled
      in the study. Gastric antral mucosal biopsy specimens were analysed before and
      after H pylori eradication treatment. The biopsies were scored semi
      quantitatively by two histopathologists, according to the updated Sydney
      classification system. Variables analysed included the density of H pylori
      infection, the degree of chronic inflammation, inflammatory activity, atrophy,
      intestinal metaplasia, and surface epithelial damage. Before grading biopsy
      specimens, both pathologists reached a consensus on the scoring of gastritis
      through interactive sessions using a multiheaded microscope. Subsequently all
      biopsy specimens were graded. Interobserver variability was also analysed using
      weighted kappa scores. RESULTS: For interobserver agreement on scoring the
      various gastritis features a high degree of reproducibility was reached overall.
      Agreement on grading of atrophy was the lowest; however, moderate to good
      reproducibility was achieved, with weighted kappa values of 0.49 in the
      pretreatment biopsies and 0.52 in the post-treatment biopsies. Disagreement was
      most common in biopsy specimens with lesser degrees of atrophy. A high degree of
      agreement was obtained for intestinal metaplasia, with weighted kappa values of
      0.72 in the pretreatment biopsies and 0.73 in the post-treatment biopsies. The
      best agreement was reached in the assessment of the density of H pylori both
      before and after H pylori eradication treatment, with excellent weighted kappa
      values of 0.76 and 0.95, respectively. The grade of reproducibility of
      inflammatory activity, superficial epithelial damage, and chronic inflammation
      was high, with weighted kappa values varying from 0.60 to 0.76 and 0.62 to 0.83
      before and after eradication, respectively. CONCLUSIONS: Reproducibility of
      grading H pylori related gastritis is high using the updated Sydney system.
      Despite the novel criteria for scoring atrophy, there was imperfect agreement on
      this feature between two independent histopathologists.

PMID- 10645234
TI  - Detection of human herpesviruses 6 and 7 genomic sequences in brain tumours.
AB  - BACKGROUND: Human herpesviruses 6 and 7 (HHV-6, HHV-7) are ubiquitous, with
      primary infection occurring early in life followed by persistence, which may
      involve neural tissue. While HHV-6 and HHV-7 are predominantly T lymphotropic,
      the extent of tissue tropism in persistent infection is not known. AIM: To
      investigate neuropersistence and the role of HHV-6 and HHV-7 in brain
      tumorigenesis. METHODS: Nested polymerase chain reaction was used to detect HHV-6
      and HHV-7 genomic sequences in preparations of total DNA extracted from 98
      formalin fixed, paraffin embedded primary brain tumours. HHV-6 detected was
      further characterized into variants A and B by restriction fragment length
      analysis. RESULTS: HHV-6 was detected in 8.2% of cases and HHV-7 in 14.3%
      (14/98). None of the positive samples contained both viruses. Among the eight HHV
      6 positive tumours, three harboured variant A and five variant B. Four of the
      five ependymomas studied contained viral DNA. Otherwise, both HHV-6 and HHV-7
      were present at similar low frequencies in most of the tumour types investigated.
      CONCLUSIONS: The findings do not support an aetiological role of HHV-6 and HHV-7
      in primary brain tumour, but they suggest that HHV-6 and HHV-7 are neurotropic in
      vivo and that the central nervous system seems to be one of the reservoirs for
      persistent infection.

PMID- 10645233
TI  - A comparison of lysis centrifugation, pour plate, and conventional blood culture
      methods in the diagnosis of septicaemic melioidosis.
AB  - AIMS: To determine whether quantitative blood culture methods could improve the
      diagnosis of septicaemic melioidosis. METHODS: A comparison of conventional broth
      based blood cultures, a pour plate method, and a commercial lysis centrifugation
      (Isolator 10) blood culture system was conducted in 71 Thai patients with severe
      melioidosis. The time to identification of B pseudomallei was recorded for each
      method. RESULTS: 42 patients (59%) were septicaemic. Compared with conventional
      blood culture, the Isolator and pour plate methods had sensitivities of 81% and
      61%, respectively. The median times to a positive culture were: Isolator 39.3
      hours, pour plates 45.5 hours, broth culture 61.8 hours (p < 0.001 Isolator v
      broth). There was a significant inverse correlation between Isolator tube or pour
      plate quantitative counts and time to detection (r = -0.44 and -0.57,
      respectively). Mortality was higher in patients who were septicaemic.
      CONCLUSIONS: Routine use of one of these quantitative methods, in addition to
      conventional broth culture, may lead to earlier diagnosis of septicaemic
      melioidosis.

PMID- 10645236
TI  - Proinsulin and insulin responses to a mixed meal in hypertriglyceridaemic men.
AB  - AIM: To investigate the contribution of proinsulin to the "hyperinsulinaemia" of
      hypertriglyceridaemia. METHODS: Plasma glucose, triglyceride, immunoreactive
      insulin, and intact proinsulin concentrations were measured before and after a
      mixed meal in 11 hypertriglyceridaemic men and six healthy normotriglyceridaemic
      male controls. RESULTS: Hypertriglyceridaemic subjects had greater fasting (101 v
      50 pmol/l) and integrated (139 v 81 x 0(-3) pmol/l/h) insulin concentrations than
      controls. Fasting and integrated glucose and proinsulin concentrations were
      similar in the two groups. CONCLUSIONS: Proinsulin does not contribute to the
      hyperinsulinaemia observed in hypertriglyceridaemic subjects and is therefore
      unlikely to contribute to the increased cardiovascular risk associated with
      hypertriglyceridaemia.

PMID- 10645235
TI  - The enhanced peroxidase one step method increases sensitivity for detection of Ki
      67 in pituitary tumours.
AB  - AIM: To compare the Ki-67 labelling index determined using the enhanced
      peroxidase one step (EPOS) method with that using the standard ABC technique in
      pituitary tumours. METHODS: Adjacent sections were immunostained using the EPOS
      and ABC techniques with the same Ki-67 antibody and same antigen retrieval
      method. RESULTS: The labelling index measurements with the EPOS Ki-67 antibody
      were significantly higher than when using the traditional ABC method, and there
      was a positive correlation between the two techniques when performed on the same
      cases. This suggests that a higher proportion of cells are within the cell cycle
      than previously thought, although it gives no direct information on the rate of
      proliferation of the tumour. CONCLUSIONS: It appears that the EPOS system is not
      only more convenient but may be more sensitive than traditional techniques for
      detecting Ki-67 in the nuclei of cells, thus demonstrating more accurately which
      cells have entered the cell cycle.

PMID- 10645237
TI  - Colonisation of point of use water filters by silver resistant non-tuberculous
      mycobacteria.

PMID- 10645238
TI  - Laboratory diagnosis of vaginal discharge (ACP Broadsheet No 153)

PMID- 10645239
TI  - Evidence for the presence of luteinizing hormone-chorionic gonadotrophin
      receptors in the pig umbilical cord.
AB  - Pig umbilical cord, like that of humans, contains two arteries and a vein
      surrounded by Wharton's jelly with amnion covering the exterior surface. The aim
      of the present study was to investigate whether LH-hCG receptors are present in
      the pig umbilical cord, using light microscope immunohistochemistry,
      semiquantitative autoradiography, western blotting and reverse transcription
      polymerase chain reaction. Umbilical cords were collected on days 48, 71 and 103
      of fetal life (n = 6). Monoclonal and polyclonal anti-LH receptor antibodies were
      used to study receptor distribution. Immunoreactivity was observed in the
      umbilical blood vessels, the epithelium of umbilical amnion and cells in the
      Wharton's jelly. No differences in LH-hCG receptor distribution related to the
      sex of the fetus, period of fetal life or section of the umbilical cord were
      observed. Strong immunostaining was observed in umbilical vein and in umbilical
      arteries. However, in the arteries, the tunica media expressed weaker receptor
      immunostaining than did the tunica intima and tunica adventitia. No
      immunoactivity was detected in non-target tissue (skeletal muscle) but LH
      receptors were immunostained in the pig ovary. Topical autoradiography showed
      that vein and arteries in the umbilical cord bind 125I-labelled hCG, which was
      highly diminished after co-incubation with an excess of unlabelled hCG. The
      binding of 125I-labelled hCG to the Wharton's jelly and epithelial amnion was
      less intense than it was to vessels. Gonadotrophin binding sites were not present
      in the skeletal muscle. The pig umbilical arteries, vein and Wharton's jelly
      contained a 75 kDa immunoreactive LH-hCG receptor protein similar to that found
      in corpora lutea. Southern blot analysis of reverse transcription-polymerase
      chain reaction products, performed to enhance the sensitivity and specificity of
      LH receptor transcripts determination in umbilical cord tissues, revealed that
      the expected fragments of 740 and 470 bp were present in the arteries, vein,
      Wharton's jelly and corpora lutea (positive control). An additional product of
      670 bp was found in the corpora lutea and arteries of umbilical cord, but not in
      the vein and Wharton's jelly. This is probably the first reported evidence of the
      presence of LH-hCG receptors in the umbilical cord of a non-human female mammal.

PMID- 10645240
TI  - Effect of stress-like concentrations of cortisol on follicular development and
      the preovulatory surge of LH in sheep.
AB  - Stress-like concentrations of cortisol increase the negative feedback potency of
      oestradiol in castrated male sheep. A similar cortisol-dependent response in
      female sheep might be expected to suppress gonadotrophin secretion and impair
      follicular development and ovulation. The oestrous activity of 21 female sheep
      was synchronized using progestogen-treated vaginal pessaries to test this
      hypothesis. Stress-like concentrations of cortisol (60-70 ng ml-1) were
      established by continuous infusion of cortisol (80 micrograms kg-1 h-1; n = 13)
      beginning 5 days before, and continuing for 5 days after, pessary removal.
      Control animals (n = 8) received a comparable volume of vehicle (50% ethanol
      saline) over the 10 day infusion period. Serum concentrations of oestradiol
      increased progressively in control sheep during the 48 h immediately after
      pessary removal. This increase in serum oestradiol was blocked or significantly
      attenuated in sheep receiving stress-like concentrations of cortisol.
      Preovulatory surge-like secretion of LH was apparent in control animals 58.5 +/-
      2.1 h after pessary removal. In contrast, surge-like secretion of LH was not
      observed during the 5 days after pessary removal in 54% (7 of 13) of sheep
      receiving cortisol. Moreover, the onset of the surge was significantly delayed in
      the cortisol-treated ewes that showed surge-like secretion of LH during the
      infusion period. The ability of episodic pulses of exogenous GnRH to override the
      anti-gonadal effect of cortisol was examined in a second study. Oestrous activity
      of 12 ewes was synchronized using progestogen-containing pessaries as described
      above. Ewes were randomly assigned to one of three treatment groups (n = 4 ewes
      per group). Animals received cortisol (100 micrograms kg-1 h-1; groups 1 and 2)
      or a comparable volume of vehicle (group 3) beginning 5 days before, and
      continuing for 2 days after, pessary removal. Pulses of GnRH (4 ng kg-1 h-1,
      i.v.; group 1) or saline (groups 2 and 3) at 1 h intervals were initiated at
      pessary removal and continued for 48 h. Serum concentrations of oestradiol were
      not significantly increased after pessary removal in sheep receiving cortisol
      alone. Conversely, serum concentrations of oestradiol increased progressively
      during the 48 h after pessary removal in control ewes and in ewes receiving
      cortisol and GnRH. At the end of infusion, serum concentrations of oestradiol did
      not differ (P > 0.05) between control (7.7 +/- 0.8 pg ml-1) ewes and ewes
      receiving cortisol and episodic GnRH (6.4 +/- 1.3 pg ml-1). Moreover, these
      values were significantly greater (P < 0.05) than the serum concentrations of
      oestradiol in animals receiving cortisol (1.0 +/- 0.4 pg ml-1) alone.
      Collectively, these data indicate stress-like concentrations of cortisol block or
      delay follicular development and the preovulatory surge of LH in sheep. In
      addition, episodic GnRH overrides cortisol-induced delay in follicular
      maturation.

PMID- 10645241
TI  - Role of intra-acrosomal antigenic molecules acrin 1 (MN7) and acrin 2 (MC41) in
      penetration of the zona pellucida in fertilization in mice.
AB  - In this study the role of two intra-acrosomal molecules, acrin 1 (MN7) and acrin
      2 (MC41), during in vitro fertilization (IVF) was examined. The pertinent
      monoclonal antibodies mMN7 and mMC41 specifically recognize a 90 kDa protein
      (acrin 1) localized to the entire acrosome and a 200 kDa protein (acrin 2)
      localized to the cortex region of the anterior acrosome, respectively.
      Experiments were designed to assess the effects of mMN7 and mMC41 on
      fertilization in mice using TYH medium containing mMN7 or mMC41 at 0.0, 0.025,
      0.05 and 0.1 mg ml-1. Under these conditions, capacitated spermatozoa inseminated
      the cumulus-invested oocytes. Acrosome-reacted spermatozoa inseminated the zona
      pellucida-free oocytes. The antibodies had no effect on sperm motility and
      primary binding to the zona pellucida, but significantly inhibited the rate of
      fertilization of zona pellucida-intact oocytes in a dose-dependent manner. A
      significantly small number of spermatozoa remained attached to the zona pellucida
      at 5 h after insemination in the presence of mMC41. mMC41 and mMN7 antibodies did
      not affect the fertilization rate of zona pellucida-free oocytes. Confocal laser
      scanning microscopy with indirect immunofluorescence traced the effect of the
      monoclonal antibodies on the zona pellucida-induced acrosome reaction, and
      revealed that mMN7 prevented completion of acrosomal matrix dispersal, whereas
      mMC41 did not affect the acrosome reaction. mMC41 appeared to inhibit secondary
      binding or some biochemical steps on the zona pellucida after the acrosome
      reaction but before penetration of the zona pellucida. Thus, the intra-acrosomal
      antigenic molecules acrin 1 and acrin 2 are essential for distinct events before
      sperm penetration of the zona pellucida in mice.

PMID- 10645242
TI  - Osmotically inactive volume, hydraulic conductivity, and permeability to dimethyl
      sulphoxide of human mature oocytes.
AB  - Controlled ovarian stimulation during an in vitro fertilization cycle usually
      produces large numbers of oocytes and, consequently, it is likely that more
      embryos will be generated than can be transferred in a given cycle. It is
      desirable to freeze-bank surplus oocytes before insemination to avoid the ethical
      and legal complications of disposing of or storing embryos. Although many
      attempts have been made to cryopreserve human oocytes, to date, post-thaw
      survival has been poor, and viable pregnancies after in vitro fertilization have
      been rare. A possible explanation for the lack of success is that the freezing
      methods have been adapted from animal studies but have not been optimized for the
      human oocyte. In this study, video microscopy was used to determine the
      volumetric responses of mature human oocytes to changes in osmolarity during
      preparation for freezing. A Boyle van't Hoff plot of data collected in static
      experiments with fresh human oocytes gave a value of 0.19 +/- 0.01 (mean +/- SEM)
      for the osmotically inactive volume. Dynamic measurements during exposure to
      dimethyl sulphoxide at room temperature (22 degrees C) were analysed by a two
      parameter transport model and produced values of 1.30 x 10(-6) cm atm-1 s-1 for
      the hydraulic conductivity of the plasma membrane and 3.15 x 10(-5) cm s-1 for
      dimethyl sulphoxide permeability (chi-squared = 0.43, df = 20) of fresh human
      oocytes. Oocytes that had failed to fertilize had a slightly lower hydraulic
      conductivity and dimethyl sulphoxide permeability and, after exposure to 1.5 mol
      dimethyl sulphoxide l-1, these cells appeared to become permeable to normally
      impermeable solutes. These permeability properties have been used to design a
      protocol for the addition and removal of dimethyl sulphoxide to control the
      magnitude of volumetric changes.

PMID- 10645243
TI  - Effects of nutrient intake and number of oestrous cycles on in vitro development
      of preimplantation pig embryos.
AB  - The effects of nutrient intake and insemination of gilts at first versus third
      oestrus on the in vitro development of preimplantation pig embryos were
      investigated. Standard swine management involves ad libitum feeding of gilts at
      first oestrus and restricted feeding of gilts at third oestrus. According to
      previous research, gilts inseminated at first oestrus demonstrate greater
      embryonic mortality than gilts inseminated at third oestrus, and it is possible
      that differences in nutrient intake between gilts inseminated at first versus
      third oestrus affect the viability of eggs or embryos. In the present study,
      experimental gilts were assigned to three treatments: animals designated 1A were
      inseminated at first oestrus and fed ad libitum; animals designated 3R were
      inseminated at third oestrus and were fed a restricted diet; and 3A animals were
      inseminated at third oestrus and fed ad libitum. Embryos collected from each
      treatment group were cultured in vitro, and data were evaluated according to cell
      stage at collection. Comparison of treatments 1A and 3R supported the contention
      of increased embryo mortality in gilts inseminated at first oestrus under normal
      management conditions. When cultures were initiated at the one- to two-cell or
      two- to four-cell stages, the percentage of 1A embryos developing to the morula
      stage (50.9%, 68.0%) was significantly lower than that of 3R embryos (88.9%,
      90.9%; P < 0.05). Comparison of treatments 1A and 3A addressed effects due to the
      number of oestrous cycles. Significantly more two- to four-cell embryos from
      gilts inseminated at third oestrus and fed ad libitum reached the morula and
      expanded blastocyst stages of development (87.0%, 41.3%) compared with embryos
      from gilts inseminated at first oestrus and fed ad libitum (68.0%, 20.3%; P <
      0.05). Finally, the effects of ad libitum feeding were determined by comparing
      treatments 3A and 3R. These data were inconclusive, as both positive and negative
      effects were observed. More one- to two-cell embryos from treatment 3R developed
      to the morula stage (88.9%) compared with 3A embryos collected at the same stage
      (64.7%), whereas a greater number of 3A embryos in the two- to four-cell category
      reached the expanded blastocyst stage (41.3%) than 3R embryos (21.2%; P < 0.05).
      These results support the hypothesis of lower in vitro developmental capacity for
      embryos collected from gilts inseminated at first oestrus. Furthermore, the
      findings indicate that differences in embryo viability between gilts inseminated
      at first versus third oestrus are related to the number of oestrous cycles and
      possibly to differential nutrition.

PMID- 10645244
TI  - Influence of protein supplements on the secretion of leukaemia inhibitory factor
      by mitomycin-pretreated Vero cells: possible application to the in vitro
      production of bovine blastocysts with high cryotolerance.
AB  - A co-culture system for bovine embryos using mitomycin-treated Vero cells and
      serum-supplemented modified synthetic oviduct fluid (mSOF) supports the
      development of in vitro maturation and fertilization-derived oocytes to hatched
      blastocysts. In this system, it has been suggested that one contribution made by
      the co-culture cells to embryo development is production of the cytokine
      leukaemia inhibitory factor (LIF). However, there are concerns about exposure of
      early embryos to serum due to its incompatibility with embryo cryosurvival. In
      this study, the influence of two protein supplements (synthetic serum substitute
      (SSS), a lipid-free human serum-derived product) and oestrous cow serum (ECS)) on
      Vero cell LIF secretion was compared, with the aim of designing a co-culture
      system that is supportive of bovine embryo cryopreservation. Vero cells cultured
      for 72 h in medium 199 + 5% fetal bovine serum (FBS) (recommended maintenance
      medium for this cell line) secreted detectable amounts of LIF (13.1 +/- 0.9 pg
      LIF per 10(5) cells). Culture in mSOF, the medium routinely used in this
      laboratory for embryo culture, also supported LIF secretion in Vero cells.
      However, the amount of LIF was tenfold higher (24.7 +/- 6.2 pg LIF per 10(5)
      cells; P < 0.05) when mSOF was supplemented with 10% (v/v) ECS compared with
      supplementation with 2% (v/v) SSS. Results of a second series of experiments in
      which supplementation with each protein was normalized to 10% revealed similar
      differences in LIF secretion, indicating that LIF secretion was affected by the
      type, not the amount, of protein. Time course analysis revealed stepwise
      increases (P < 0.05) in cumulative LIF secretion with every 24 h of culture in
      mSOF + either SSS or ECS. In terms of embryo development and post
      cryopreservation viability, medium supplementation with 2% (v/v) SSS alone versus
      the two-step system of 2% (v/v) SSS (days 1-4) + 10% (v/v) ECS (days 4-10) had no
      influence (P > 0.05) on the ability of bovine blastocysts to hatch, with or
      without intervening cryostorage. However, the rate of blastocyst formation
      (expressed as the percentage of cleaved embryos) was only 27% in the presence of
      2% (v/v) SSS, and increased almost twofold (P < 0.05) when ECS was added
      beginning on day 4 of co-culture. In summary, Vero cell LIF secretion was
      increased markedly by ECS. A two-step system of medium supplementation, in which
      embryos are exposed to ECS beginning on day 4 of in vitro development combined
      high rates of blastocyst formation with cryotolerance. This effect may be a
      result of limiting embryo exposure to serum-derived lipid until after the eight
      cell stage and providing an increase in LIF during the critical developmental
      stages of compaction and cavitation.

PMID- 10645245
TI  - Mitogen-activated protein kinase activation and regulation of cyclooxygenase 2
      expression by platelet-activating factor and hCG in human endometrial
      adenocarcinoma cell line HEC-1B.
AB  - The activation of mitogen-activated protein kinase (MAP kinase) and the
      regulation of cyclooxygenase 2 (COX-2) were investigated in the human endometrial
      adenocarcinoma cell line HEC-1B by treatment with platelet-activating factor
      (PAF) and hCG. Pre-treatment of the cells with both oestradiol and
      medroxyprogesterone acetate was required for MAP kinase activation and COX-2
      expression to respond to PAF and hCG. PAF-induced MAP kinase activation was
      sensitive to MAP kinase kinase (MEK) inhibitor, PD098059, and
      phosphatidylinositol-3-OH kinase (PI3K) inhibitor, wortmannin. In contrast, hCG
      induced MAP kinase activation was sensitive to PD098059 and protein kinase A
      inhibitor, H-89, but not to wortmannin. PAF-induced COX-2 expression was
      insensitive to PD098059 but sensitive to wortmannin, whereas hCG-induced COX-2
      expression was sensitive to PD098059 and H-89 but insensitive to wortmannin. 8-(4
      chlorophenylthio)-cAMP, a potent cAMP analogue, induced activation of MAP kinase
      and expression of COX-2. These results indicate that MAP kinase is activated with
      PAF and hCG in HEC-1B cells. In addition, COX-2 expression is stimulated through
      the MAP kinase activation pathway with hCG and the wortmannin sensitive pathway
      with PAF in HEC-1B cells. These results also imply that protein kinase A remains
      upstream of hCG-induced activation of MAP kinase in HEC-1B cells.

PMID- 10645246
TI  - Expression of growth factor ligand and receptor genes in preimplantation stage
      water buffalo (Bubalus bubalis) embryos and oviduct epithelial cells.
AB  - The temporal pattern of expression of genes for several growth factor ligands and
      receptors was examined in preimplantation water buffalo embryos and oviduct
      epithelial cells using RT-PCR. The identity of the resulting PCR products was
      confirmed by their expected size, restriction analysis, Southern blot
      hybridization and nucleotide sequence analysis. Preimplantation stage embryos
      from the one-cell to the blastocyst stage were derived after maturation,
      fertilization and culture of oocytes in vitro. Expression of members of the
      insulin-like growth factor (IGF) family was observed predominantly in
      preimplantation stage embryos and oviduct epithelial cells. Similarly,
      transcripts encoding insulin and IGF-I receptors were detected at each stage of
      embryonic development. The mRNA transcript of the IGF-I receptor was not detected
      in oviduct epithelial cells, but a prominent band corresponding to the insulin
      receptor was observed. Insulin and IGF-II mRNA were expressed as maternal
      transcripts that were not detected at the two- to four-cell stage but were
      present as zygotic transcripts at the eight-cell stage. Transcripts encoding IGF
      I were detected in oviduct epithelial cells, but were not observed in any of the
      preimplantation stage embryos. Transforming growth factor (TGF) alpha and beta
      and epidermal growth factor mRNA transcripts were not detected in any of the
      preimplantation stage embryos. These results indicate that IGF-I acts via a
      paracrine mechanism to promote growth and development of preimplantation water
      buffalo embryos. Similarly, IGF-II appears to act through a heterologous
      autocrine mechanism via the IGF-I or the insulin receptor. Furthermore, the
      presence of TGF-alpha in oviduct epithelial cells indicates that it may have a
      critical role during development.

PMID- 10645247
TI  - Reduction of the developmental competence of sheep oocytes by inhibition of LH
      pulses during the follicular phase with a GnRH antagonist.
AB  - A GnRH antagonist (Antarelix) treatment was used during the breeding season of
      Romanov ewes, to investigate whether LH pulses are required the day before the
      preovulatory surge for normal early embryo development in vivo (Expt 1) and in
      vitro (Expt 2). In Expt 1, at the onset of oestrus after removal of a
      fluorogestone acetate sponge, group A0.5 (n = 22) received a subcutaneous
      injection of 0.5 mg Antarelix, and ovulation was induced with an intravenous
      injection of 3 mg pig LH 24 h later. The control group (group C, n = 20) were
      untreated. All ewes were mated naturally at 36 and 48 h after oestrus and embryos
      were recovered 8 days after sponge removal. There were significant differences in
      the decrease in LH and in the increase in FSH concentration after Antarelix
      treatment between treated and control groups. The ovulation rate and embryo
      recovery rate were not significantly different between the two groups but the
      blastocyst rate was lower (P < 0.0001) in group A0.5 than in group C, with more
      unfertilized or degenerated oocytes in group A0.5 (69.2%). In Expt 2, 24 h after
      sponge removal, group A (n = 10) and group B (n = 10) received one subcutaneous
      injection of 0.5 mg Antarelix. The control group (group C, n = 10) was left
      untreated. LH pulsatility was re-established in group B with hourly intravenous
      injections of 5 micrograms ovine LH for 24 h. Oocytes were collected by flushing
      the oviducts 28 h after the LH surge, and were fertilized and cultured in vitro
      for 7 days. Ovulation and cleavage rates were not significantly different among
      the three groups but a higher rate of blastocysts (P < 0.01) was obtained after
      Antarelix treatment when LH pulsatility was re-established (group B). Oestradiol
      concentration was strongly depressed (P < 0.0003) after Antarelix treatment in
      group A, but was maintained after injection of LH pulses in group B, although at
      a lower value than before the preovulatory surge in the control group. In
      conclusion, inhibition of endogenous LH pulses 1 day before the preovulatory
      surge was not essential for ovulation and in vitro fertilization but was
      associated with a decrease in plasma oestradiol concentrations and inferior
      embryo development both in vivo and in vitro. When LH pulsatility was re
      established, oestradiol concentrations increased and embryo development was
      restored.

PMID- 10645248
TI  - A 33 kDa molecular marker of sperm acrosome differentiation and maturation in the
      tammar wallaby (Macropus eugenii).
AB  - This study was undertaken to identify potential molecular markers of acrosomal
      biogenesis and post-testicular maturation in marsupials, using the tammar wallaby
      as a model species. A two-step sperm extraction procedure yielded two protein
      extracts of apparent acrosomal origin and a tail extract. The extracts were
      analysed by SDS-PAGE under reducing conditions. Several prominent polypeptide
      bands (45, 38 and 33 kDa) appeared common to both acrosomal extracts. Antiserum
      raised against the 33 kDa polypeptide from the inner acrosomal membrane matrix
      (IAMM) extract showed immunoreactivity with 45, 38 and 33 kDa polypeptides in
      both acrosomal extracts, indicating that the 33 kDa polypeptide was related to
      the proteins in the 45 and 38 kDa bands. Therefore, the antiserum was used as a
      molecular probe. Indirect immuno-fluorescence indicated that the acrosome was the
      major location of the 33 kDa polypeptide. This contention was confirmed by
      ultrastructural study: immunogold labelling indicated that the 33 kDa polypeptide
      associated with acrosomal matrix components throughout acrosomal development in
      the testes and throughout post-testicular maturation in the epididymis. The label
      clearly delineated the changing morphology of the maturing marsupial acrosome.
      This is the first study to use immunocytochemical techniques to chart testicular
      and post-testicular development of any sperm organelle in a marsupial. As a
      result of this study, a 33 kDa molecular marker of marsupial acrosome
      differentiation and maturation has been identified. It may be possible to chart
      similar events in other marsupial species and identify opportunities for
      manipulating fertility.

PMID- 10645249
TI  - Demonstration of oestrogenic control of H-type-1 carbohydrate antigen in the
      murine endometrial epithelium by use of ICI 182,780.
AB  - The carbohydrate H-type-1 antigen has been implicated in attachment of the murine
      blastocyst to the endometrial epithelium. Monoclonal antibody 667/9E9 was used to
      investigate the steroidal dependency of expression of this antigen in the murine
      endometrial epithelium using intact or ovariectomized mice treated with oestrogen
      or the pure anti-oestrogen, ICI 182,780. The effects of this anti-oestrogen were
      also investigated in the endometrial epithelium from intact rats. In both
      ovariectomized, oestrogen-supplemented and intact mice after treatment with ICI
      182,780, staining with monoclonal antibody 667/9E9 was abolished in the luminal
      epithelium on both the apical and lateral cell surfaces, whereas basal staining
      remained. Glandular staining in mice was not affected in the same manner. In
      intact rats, where H-type-1 antigen expression has been reported to be
      predominantly controlled by progesterone, the anti-oestrogen had little effect,
      in accordance with previous reports.

PMID- 10645250
TI  - Analysis of apoptosis in the preimplantation bovine embryo using TUNEL.
AB  - The occurrence of cell death by apoptosis was examined in blastocyst and
      preblastocyst stage bovine embryos. Zygotes were obtained by in vitro maturation
      and in vitro fertilization of oocytes from abattoir derived ovaries. Two-cell to
      hatched blastocyst stage embryos were stained with propidium iodide to label all
      nuclei and by terminal deoxynucleotidyl transferase (TdT)-mediated d-UTP nick end
      labelling (TUNEL) to label apoptotic nuclei, and were analysed by epifluorescent
      and confocal microscopy. Apoptosis was first observed at the 9-16-cell stage of
      development, decreasing at the morula stage before increasing at the blastocyst
      stage. Apoptotic dead cell index in day 7 blastocysts was negatively correlated
      with the total number of cells; the percentage of dead cells ranged from
      approximately 1 to 10% and occurred predominantly within the inner cell mass. In
      addition, apoptotic dead cell index was significantly higher (P < 0.05) in
      blastocysts cultured (from the two-cell stage) in the presence of 10% fetal
      bovine serum compared with those developed in serum-free medium. Embryos selected
      for early cleavage at < 29 h after fertilization and cultured together until the
      blastocyst stage showed a significantly lower rate of apoptosis (P < 0.01)
      compared with slower cleaving embryos.

PMID- 10645251
TI  - Marmoset monkey trophoblastic tissue growth and matrix metalloproteinase
      secretion in culture.
AB  - Marmoset monkey blastocysts maintained in culture produced trophoblastic vesicles
      up to 4 mm in diameter that were subdivided into fragments and subcultured to
      produce new vesicles. These tissues are composed of an outer layer of trophoblast
      like cells and an inner layer of endoderm-like cells, and resemble a blastocyst
      wall. When such vesicles were cultured in serum-free medium for 14 days, they
      increased in size but there was no significant difference in their protein
      content at the end of culture. The proliferation index, measured by BrdU
      incorporation, varied considerably within and between vesicles. The purpose of
      this investigation was to determine which matrix metalloproteinases are secreted
      by marmoset monkey trophoblastic tissue in vitro, and the effect of extracellular
      laminin on this secretion. It was determined by zymography that the vesicles
      secreted matrix metalloproteinase 2, but not matrix metalloproteinase 9, and that
      matrix metalloproteinase 2 was secreted as the proenzyme (72 kDa). Matrix
      metalloproteinases 1, 3 and 7 were not detectable in the culture medium. The
      addition of laminin (5-20 micrograms ml-1), either as a substrate or in solution
      in the medium, did not have a consistent effect on matrix metalloproteinase 2
      secretion during the culture period. The vesicles were found to express both
      matrix metalloproteinases 2 and 9 in both types of cell when examined by
      immunohistochemistry. The expression of matrix metalloproteinase 9 in the
      vesicles, but the absence of its secretion, indicates that specific factors,
      possibly of endometrial origin, may be required for inducing secretion.

PMID- 10645252
TI  - Characterization of cellular and vascular changes in equine follicles during hCG
      induced ovulation.
AB  - In contrast to other species, the histology of the equine follicle during
      ovulation has not been described. Preovulatory follicles were isolated during
      oestrus at 0, 12, 24, 30, 33, 36 and 39 h (n = 5-6 follicles per time point)
      after an ovulatory dose of hCG to characterize the cellular and vascular changes
      associated with ovulation in mares. Pieces of follicle wall were formalin-fixed
      and processed for light microscopy to evaluate the general follicular morphology
      and quantify selected parameters. Marked changes were observed in the histology
      of equine follicles in the hours before ovulation. The thickness of the granulosa
      cell layer doubled between 0 and 39 h after hCG (77.8 +/- 4.8 versus 158.8 +/-
      4.8 microns, respectively; P < 0.01). This expansion was caused primarily by a
      pronounced accumulation of acid mucosubstances between granulosa cells, which was
      first detected at 12 h after hCG and peaked at 36-39 h. In contrast, a
      significant thinning of the theca interna was observed after hCG treatment. Fewer
      cell layers were present; theca interna cells appeared smaller than before hCG;
      and the presence of occasional pyknotic cells was noted at 36 and 39 h after hCG.
      In addition, the theca layers were invaded by numerous eosinophils. No
      eosinophils were observed in preovulatory follicles isolated between 0 and 24 h
      after hCG, but the number increased to 14.0 +/- 0.8 and 5.6 +/- 0.3 eosinophils
      per field (x 400) in theca interna and theca externa, respectively, 39 h after
      hCG treatment (P < 0.01). Severe oedema, hyperaemia and haemorrhages, and
      significant increases in the number of blood vessels in theca interna and externa
      were observed at 33, 36 and 39 h after hCG. This study provides the first in
      depth characterization of the sequential cellular and vascular changes that occur
      in equine follicles before ovulation.

PMID- 10645253
TI  - Synthetic profiles of polypeptides of human oocytes and normal and abnormal
      preimplantation embryos.
AB  - There is considerable variation in the rate of development in vitro of individual
      preimplantation human embryos. The relationship between the rate of development
      and patterns of polypeptide synthesis in individual embryos was examined using
      SDS-PAGE and autoradiography. After incubation in [35S]methionine, 19 polypeptide
      bands were identified that change between fertilization and the morula stage.
      Although changes in two of the bands occurred in embryos that were developing
      normally and in ageing oocytes, and are thus independent of fertilization, the
      changes identified in the remaining 17 bands occurred only after fertilization.
      In embryos that were developing abnormally, as assessed by delayed cleavage,
      cleavage arrest or extensive fragmentation, the alteration in polypeptide
      synthetic profiles increased with increasing abnormality.

PMID- 10645254
TI  - Changes in equine endometrial oestrogen receptor alpha and progesterone receptor
      mRNAs during the oestrous cycle, early pregnancy and after treatment with
      exogenous steroids.
AB  - Two experiments were performed to determine changes in the abundance of oestrogen
      and progesterone receptor (ER alpha and PR) mRNAs in equine endometrium during
      the oestrous cycle and early pregnancy, and under the influence of exogenous
      steroids. In Expt 1, endometrial biopsies were obtained from non-mated mares
      during oestrus and at days 5, 10 and 15 after ovulation, and from pregnant mares
      at days 10, 15 and 20 after ovulation. There were overall effects of day on the
      abundance of ER alpha (P = 0.0001) and PR (P = 0.0014) mRNAs. The amount of ER
      alpha mRNA decreased at day 10 of pregnancy, and PR mRNA was reduced at day 5 in
      non-mated mares and at day 15 of pregnancy, compared with oestrous values.
      Experiment 2 was conducted to determine the effects of exogenous steroids on
      endometrial ER alpha and PR mRNAs. Endometrial biopsies were obtained from 19
      anoestrous mares that had been treated with vehicle, oestradiol, progesterone, or
      oestradiol followed by progesterone for either a short or a long duration. The
      steroid treatment affected the abundance of ER alpha mRNA (P = 0.0420), which was
      higher (P < 0.05) in the oestradiol group than in the group treated with
      oestradiol followed by long duration progesterone. The steroid treatment did not
      affect the abundance of PR mRNA. These results demonstrate that the amount of
      steroid receptor mRNA changes with the fluctuating steroid environment in the
      uterine endometrium of cyclic and early pregnant mares, and that the duration of
      progesterone dominance may affect ER alpha gene expression. In addition, factors
      other than steroids may regulate ER alpha and PR gene expression in equine
      uterine endometrium.

PMID- 10645255
TI  - Cell proliferation patterns during development of the equine placenta.
AB  - Placentation involves considerable growth and reorganization of both maternal and
      fetal tissues. In this investigation, immunohistochemical localization of the
      proliferation marker Ki-67 antigen was used to monitor cell division during
      placentation in mares. Endometrial biopsies were obtained from eight mares
      between day 14 and day 26 of pregnancy and from eight anoestrous mares that had
      been treated with various combinations of progesterone and oestrogen. Samples of
      endometrium and fetal membranes were obtained from 19 mares carrying normal horse
      conceptuses between day 30 and day 250 of gestation and from three failing
      extraspecific donkey-in-horse pregnancies. Proliferation in the superficial
      strata of the endometrium was increased by day 18 of gestation and this effect
      could be mimicked by supplementing with oestradiol benzoate during the last 6
      days of a prolonged period (18-36 days) of progesterone administration. Fetal
      chorionic girdle cells were proliferating vigorously at days 30-32 of gestation,
      but stopped dividing after they invaded the endometrium, while the trophoblast
      cells of the allantochorion showed an increase in mitotic activity after day 38.
      The luminal epithelium of the endometrium started to proliferate only after the
      primary villi of the true epitheliochorial placenta had been formed, and during
      days 58-70 this effect was seen only in the pregnant horn in which placentation
      was further advanced. During the second half of gestation, most of the mitotic
      activity was confined to the periphery of the microcotyledons which were still
      growing. In the donkey-in-horse pregnancies, proliferation rates of the maternal
      and fetal epithelial at day 70 of gestation were markedly reduced in areas of
      heavy endometrial lymphocyte infiltration and poor placentation. These results
      provide a basis for further studies on factors that influence invasive and non
      invasive placentation.

PMID- 10645256
TI  - Modulation of force induced by pH in the guinea-pig uterus examined at two stages
      of the oestrous cycle.
AB  - Changes in pH have a marked influence on uterine contractility. Changes in
      uterine pH occur during pregnancy and labour, when marked endocrine changes are
      occurring. As hormonal status can also influence contractility, this study
      investigated whether pH-induced modulation of uterine force in influenced by
      hormonal changes. The effects of altering intracellular and extracellular pH on
      uterine contractions were studied in guinea-pigs on day 7 (high progesterone) and
      day 15 (low progesterone) of the oestrous cycle. Resting values of pH were
      significantly more acidic on day 15 compared with day 7, and more force was
      produced on day 15. Changing external pH produced similar changes in
      intracellular pH and force on both days. External acidification was associated
      with a large increase in force. In contrast, intracellular acidification, at
      constant external pH, reduced force. In conclusion, the stage of the oestrous
      cycle has a large effect on resting pH in the myometrium but only small effects
      on the pH-induced modulation of force, and the link between pH and force is
      complex.

PMID- 10645257
TI  - Effect of time interval from insemination to first cleavage on the developmental
      characteristics, sex ratio and pregnancy rate after transfer of bovine embryos.
AB  - In vitro produced bovine zygotes show substantial variation in the time required
      to complete the first cell cycle and in their in vitro development potential. A
      number of reports have highlighted the fact that the fastest developing embryos
      in vitro are most likely to be comparable with their in vivo counterparts. At 24
      h after IVF, presumptive zygotes were cultured in droplets of synthetic oviduct
      fluid medium. Droplets were examined at regular intervals and all cleaved embryos
      at each time point were transferred into new droplets and cultured separately for
      the duration of the experiment. All uncleaved zygotes were returned to the
      incubator and re-examined at the successive time points until 48 h after
      insemination, at which time the remaining uncleaved oocytes were retained as a
      group. A representative number of day 7 blastocysts from zygotes that had cleaved
      by 30 or 36 h were transferred to synchronized recipients and pregnancy was
      diagnosed by ultrasonography at day 35. Glucose and glutamine metabolism was
      examined in zygotes and blastocysts and compared retrospectively with time of
      first cleavage. A representative number of blastocysts from each of the cleavage
      groups was sexed using PCR. Data were analysed by chi-squared and regression
      analysis. Development to the blastocyst stage decreased as the time from
      insemination to first cleavage increased (r = 0.97, P < 0.03). There was no
      difference in blastocyst hatching, number of blastocyst cells or pregnancy rate
      between the 30 and 36 h groups. The overall sex ratio was 62% males (n = 258, P <
      0.0001) and was not different in the 30 and 36 h groups (61%, n = 155 versus 63%,
      n = 95, respectively). These results indicate that although time of first
      cleavage has a major influence on the probability of an embryo developing to the
      blastocyst stage, once that stage is attained, subsequent developmental
      characteristics are unrelated to the time of first cleavage.

PMID- 10645258
TI  - Effect of inhibition of matrix metalloproteinases on endometrial decidualization
      and implantation in mated rats.
AB  - Implantation of the embryo into the endometrium is a highly regulated event that
      is critical for establishment of pregnancy. Molecules involved in this process
      provide potential targets for post-coital contraception. The aims of this study
      were to determine whether matrix metalloproteinases (MMPs) are present at
      implantation sites in rats and whether administration of a broad-based inhibitor
      of MMPs could inhibit embryo implantation. Uterine extracts from non-pregnant
      rats and from rats on days 3-9 of pregnancy were examined for the presence of
      MMPs. Doxycycline (5 or 15 mg day-1) was administered by gavage to rats from the
      day of mating (day 0) to day 7 of pregnancy and the uterus was examined for
      implantation sites. A number of MMPs were present in all uterine samples. MMP-2
      reached a peak on day 3, whereas the highest expression of MMP-7 occurred on day
      7. MMP-13 and MMP-3 were present in smaller amounts. MMP-9 was detectable only on
      day 9. Treatment of rats with doxycycline had no effect on the number of
      implantation sites or on the total uterine mass. However, in treated rats, the
      process of decidualization was impaired and both the width and length of the
      decidual zone was reduced, resulting in a decrease in total decidual area from
      1.20 +/- 0.07 to 0.91 +/- 0.07 mm2 (mean +/- SEM, controls versus doxycycline
      treated, P < 0.02). It is concluded that administration of MMP inhibitors during
      early pregnancy retards decidual development, but does not block implantation.

PMID- 10645259
TI  - Ovarian function in nutritionally induced anoestrous cows: effect of exogenous
      gonadotrophin-releasing hormone in vivo and effect of insulin and insulin-like
      growth factor I in vitro.
AB  - Ovarian function of nutritionally induced anoestrus cows was evaluated in vivo
      (Expt 1) and in vitro (Expt 2). In Expt 1, 32 nutritionally induced anoestrous
      beef cows were divided into four treatment groups receiving: (1) saline infusions
      at one pulse every 4 h for 13 days (control); (2) 2 micrograms GnRH at one pulse
      every 4 h (2 micrograms infused in 1.8 ml saline over 5 min) for 13 days (GnRH
      4); (3) 2 micrograms GnRH at one pulse every 1 h for 13 days (GnRH-1); and (4)
      continuous infusion of 2 micrograms GnRH (a total of 2 micrograms in 34 ml h-1)
      for 13 days (GnRH-C). On the last day of treatment, cows were killed, ovaries
      were removed and follicular fluid samples (n = 149) were collected. The
      percentage of cows with luteal activity on day 13 was significantly different (P
      < 0.01) among treatments (0, 25, 75 and 25% for control, GnRH-4, GnRH-1 and GnRH
      C cows, respectively). Owing to the large percentage of ovulatory cows in the
      GnRH-1 group (n = 6), anovulatory cows (n = 2) were removed from this treatment
      group for statistical analysis, as were cows with luteal tissue from the GnRH-4
      (n = 2) and GnRH-C (n = 2) groups. The numbers of small (1.0-4.9 mm) and medium
      plus large (> or = 5 mm) follicles were not affected (P > 0.10) by treatment.
      However, GnRH-4 cows (n = 6) had greater (P < 0.05) concentrations of oestradiol
      in follicular fluid than did control (n = 8) but not GnRH-1 (n = 6) or GnRH-C (n
      = 6) cows. Concentrations of insulin-like growth factor I were greater (P < 0.05)
      in the follicular fluid of GnRH-1 cows than in all other treatment groups.
      Concentrations of androstenedione and progesterone in follicular fluid were not
      affected (P > 0.10) by treatment or follicle size. The binding activity of
      insulin-like growth factor binding proteins was not affected by GnRH treatment.
      However, the binding activity of insulin-like growth factor binding protein 2, 29
      32 kDa and 22 kDa insulin-like growth factor binding proteins were greater (P <
      0.05) in small versus medium plus large follicles. In Expt 2, granulosa cells
      were collected from nutritionally anoestrous cows to determine whether ovarian
      cells from anoestrous cows have the capacity to respond to insulin-like growth
      factor I or insulin in vitro. Both insulin-like growth factor I (20 and 200 ng ml
      1) and insulin (10, 100 and 1000 ng ml-1) increased (P < 0.05) granulosa cell
      proliferation and progesterone production. In conclusion, pulsatile infusion of 2
      micrograms GnRH (every 1 or 4 h) for 13 days into nutritionally induced
      anoestrous cows results in increased intrafollicular oestradiol and insulin-like
      growth factor I concentrations and can stimulate ovulation without markedly
      affecting concentrations of androstenedione or progesterone, or the binding
      activity of insulin-like growth factor binding proteins, in follicular fluid. In
      addition, granulosa cells from nutritionally induced anoestrous cows have the
      capacity to respond to insulin-like growth factor I and insulin in vitro,
      indicating that the decrease in trophic factors observed with restricted feeding
      does not reduce the response of the ovary to insulin-like growth factor I and
      insulin.

PMID- 10645260
TI  - Effect of gonadal steroids and gamma-aminobutyric acid on LH release and dopamine
      expression and activity in the zona incerta in rats.
AB  - A dopaminergic system in the zona incerta stimulates LH release and may mediate
      the positive feedback effects of the gonadal steroids on LH release. In this
      study the mechanisms by which steroids might increase dopamine activity in the
      zona incerta were investigated. In addition, experiments were conducted to
      determine whether the inhibitory effects of gamma-aminobutyric acid (GABA) on LH
      release in the zona incerta are due to suppression of dopamine activity in this
      area or conversely whether the stimulatory effects of dopamine on LH release are
      due to suppression of a tonic inhibitory GABAergic system. Ovariectomized rats
      were treated s.c. with oil, 5 micrograms oestradiol benzoate or 5 micrograms
      oestradiol benzoate followed 48 h later by 0.5 mg progesterone, and killed 54 h
      after the oestradiol benzoate injection. At this time the LH concentrations were
      suppressed in the oestradiol benzoate group and increased in the group treated
      with oestradiol benzoate and progesterone. The ratio of tyrosine hydroxylase:beta
      actin mRNA in the zona incerta was significantly increased by the oestradiol
      benzoate treatment, but the addition of progesterone resulted in values similar
      to those in the control group. At the same time, the progesterone treatment
      increased tyrosine hydroxylase activity in the zona incerta as indicated by an
      increase in L-dihydroxyphenylalanine (L-DOPA) accumulation after 100 mg 3
      hydroxybenzylhydrazine hydrochloric acid (NSD1015) kg-1 and an increase in
      dopamine release as indicated by a increase in dihydroxyphenylacetic acid (DOPAC)
      concentrations (one of the major metabolites of dopamine). Ovariectomized rats
      treated with oestradiol benzoate plus progesterone were also injected i.p. with
      75 mg gamma-acetylenic GABA kg-1 (a GABA transaminase inhibitor) to increase GABA
      concentrations in the brain. This treatment had no effect on the ratio of
      tyrosine hydroxylase:beta-actin mRNA but decreased L-DOPA accumulation and DOPAC
      concentrations in the zona incerta, indicating a post-translational inhibition of
      dopamine synthesis and release. Treatment of ovariectomized rats with oestradiol
      benzoate followed by 100 mg L-DOPA i.p. to increase dopamine concentrations in
      the whole brain had no effect on glutamic acid decarboxylase mRNA expression in
      the zona incerta, although it increased the glutamic acid decarboxylase:beta
      actin mRNA ratio in other hypothalamic areas (that is, the medical preoptic area,
      ventromedial nucleus and arcuate nucleus). In conclusion, the steroids act to
      increase dopamine activity in different ways: oestrogen increases tyrosine
      hydroxylase mRNA expression and progesterone acts after translation to increase
      tyrosine hydroxylase activity and dopamine release (as indicated by increases in
      DOPAC concentrations). This latter effect may be due to progesterone removing a
      tonic GABAergic inhibition from the dopaminergic system.

PMID- 10645261
TI  - Fluid and electrolyte reabsorption in the ductuli efferentes testis.
AB  - The efferent ducts of mammals are a series of ducts that are arranged in parallel
      and reabsorb most of the fluid released with spermatozoa from the testis. This
      function is essential for spermatogenesis, and for sperm maturation and storage
      in the epididymis. There is evidence for the involvement of three major transport
      processes in the bulk reabsorption of water and low molecular weight solutes from
      the ducts: active solute transport, passive (presumably paracellular) diffusion
      and fluid phase endocytosis. A small back-flux into the ducts via anion secretion
      also appears to occur. Control of fluid reabsorption by the efferent ducts is
      emerging as a complex process with multiple components. Reabsorption is flow
      dependent which provides local control of reabsorption with a rapid response to
      changes in luminal conditions. Sex steroids (oestrogen as well as androgen), but
      not mineralocorticosteroids, are involved in the chronic control of reabsorption
      in the ducts. Control of epithelial transport in the efferent ducts appears to be
      mediated by cAMP and probably other signal transduction systems.

PMID- 10645262
TI  - The role of local angiotensins and prostaglandins in the control of anion
      secretion by the rat epididymis.
AB  - Secretion of electrolytes and water by the epididymal epithelium is important in
      the formation of an optimal fluid environment for sperm maturation and storage.
      Recently, evidence has been obtained that anion/fluid secretion by the epididymis
      is subject to control by local humoral factors, among which the angiotensins play
      a significant role. This assertion is based on the morphological localization of
      various components of a local renin-angiotensin system (RAS) in the rat
      epididymis and the functional studies of angiotensins and their antagonists on
      anion secretion in cultured rat epididymal epithelia. More recent study has
      indicated that the effects of angiotensin II and other vasoactive peptides on
      anion secretion are mediated through an increase in prostaglandin formation. The
      pathway of synthesis involves the PLA2-coupled receptor mediated breakdown of
      membrane phospholipids to arachidonic acid followed by conversion of arachidonic
      acid into the prostanoids by cyclooxygenases and other enzymes. The newly formed
      PGE2 then diffuses out of the cells and acts on the EP2/4 receptors on the same
      or adjacent cells to increase intracellular cAMP. Accordingly, the pathways of
      activation by the paracrine factors all converge on the cystic fibrosis
      transmembrane conductance regulator (CFTR) as the final common effector in
      secretion. Studies on the biochemical pathways of paracrine control of fluid
      secretion may provide insight into the causes of epididymal irregularities in
      some forms of male infertility.

PMID- 10645263
TI  - Sperm maturation in vitro: co-culture of spermatozoa and epididymal epithelium.
AB  - Sperm maturation involves an intimate interaction between spermatozoa and the
      epididymal epithelium. Aspects of this relationship can be examined by co
      incubating epididymal spermatozoa with epididymal epithelium in vitro. Plaques of
      epididymal epithelium from a variety of species (for example rodents, dogs,
      humans) can be maintained in culture medium supplemented with growth factors and
      androgens. When co-incubated with these epithelial cultures, immature epididymal
      spermatozoa undergo maturation changes that lead to the acquisition of
      progressive motility, zona binding and, in some instances, fertilizing capacity
      in vitro. The use of such co-culture techniques for the understanding of sperm
      maturation in vitro and in vivo is reviewed with reference to recent experiments.

PMID- 10645264
TI  - The dog as a model system to study epididymal gene expression.
AB  - Advances in understanding the role of the epididymis in human sperm maturation
      and fertility are dependent upon the availability of appropriate model systems in
      which to examine regulatory mechanisms and functions in a controllable fashion.
      Of a number of mammalian species studied by us and others, we suggest that the
      dog epididymis offers an excellent compromise in terms of the similarity of the
      specific genes expressed to those in the human, their mode of regulation, and the
      availability of tissues suitable for cell culture studies. We have developed a
      set of important tools in the form of epididymis-specific canine cDNA clones and
      cell culture methods, with which to examine the functioning of the epididymal
      epithelial cells in vitro, as well as the expression of specific genes in vivo,
      under normal and pathological conditions (e.g. cryptorchidism). Using this model
      system, we have elaborated the regional patterns of gene expression in vivo for
      several of the major secretory protein genes of the canine epididymis, and we
      have examined the importance of androgens and temperature on gene expression in
      vitro.

PMID- 10645265
TI  - Testicular regulation of epididymal gene expression.
AB  - Normal epididymal function is regulated by androgens and testicular factors. Our
      studies have been directed towards identifying testicular factors that regulate
      the function of the initial segment and the mechanisms by which this is achieved.
      The initial segment appears to be critical for normal sperm maturation in view of
      recent gene knock-out studies. Previous and ongoing studies from this and other
      laboratories have shown that the expression of several genes including
      proenkephalin, cystatin-related epididymal specific (CRES), 5 alpha-reductase and
      gamma-glutamyl transpeptidase (GGT) within the initial segment is highly
      dependent upon the presence of testicular factors. A lumicrine mechanism of
      regulation of these genes is proposed. The regulation of gamma-glutamyl
      transpeptidase (GGT) is described as a model enzyme for studying the role and
      identification of testicular factors. GGT appears to play an important role in
      the protection of spermatozoa from oxidative stress. Multiple GGT mRNAs (II-IV)
      are expressed within the epididymis, but GGT mRNA IV is the only form that is
      highly expressed in the initial segment, especially within zone 1A, and is
      regulated by testicular factors. Testicular factors control this transcript by
      regulating both its rate of transcription and its stability. Evidence is
      presented to suggest that basic fibroblast growth factor (bFGF) is a candidate
      testicular factor that regulates GGT activity in the epididymis. Basic FGF may
      regulate gene expression in the epididymis via the ras-raf-MAPK second messenger
      pathway and by members of the Ets transcription family.

PMID- 10645266
TI  - Structure and putative function of a murine epididymal retinoic acid-binding
      protein (mE-RABP).
AB  - Vitamin A is required to maintain the epididymal epithelium. In this report, the
      characterization and putative functions of a murine epididymal retinoic acid
      binding protein (mE-RABP) that is secreted into the lumen from the mid-/distal
      caput epididymidis are discussed. The amino acid sequence analysis of the mE-RABP
      preprotein shows that mE-RABP is the mouse orthologue of the rat epididymal
      secretory protein I (ESPI). These proteins belong to the lipocalin superfamily
      and bind to active retinoids but not to retinol. Therefore, we propose that mE
      RABP may function as an extracellular retinoid carrier-protein involved in the
      paracrine regulation of epididymal function by retinoids.

PMID- 10645267
TI  - Expression of CRISP proteins in the male equine genital tract.
AB  - Cysteine rich secretory proteins (CRISPs) have been detected immunochemically in
      the equine male genital tract. CRISPs are secretory products of the epididymis,
      the ampulla and the seminal vesicle. A particular feature of the horse is the
      abundance of CRISPs in seminal plasma. CRISPs can also be detected in extracts of
      testicular, epididymal and ejaculated spermatozoa in increasing amounts. Unlike
      other seminal plasma proteins, they cannot be removed completely from spermatozoa
      by high salt treatment. The remaining CRISP antigens are localized on the
      midpiece, and the postacrosomal and equatorial region of the sperm head. Tissue
      distribution and localization of CRISPs on equine spermatozoa point to a role of
      these proteins in epididymal sperm maturation and equine reproduction.

PMID- 10645268
TI  - Plasma membrane structure and remodelling during sperm maturation in the
      epididymis.
AB  - All mammalian spermatozoa are surrounded by a limiting plasma membrane that
      mediates many of the early events during fertilization. The membrane is derived
      originally from spermatogonia/spermatocytes in the testis but is then modified
      considerably during spermiogenesis, epididymal maturation and capacitation. It is
      characterized by an unusually high proportion of polyunsaturated phospholipids
      that give it special physical characteristics and compartmentalization of many of
      its component proteins and lipids into discrete domains on the head and tail.
      During passage of spermatozoa through the epididymis remodelling of the plasma
      membrane is commensurate with acquisition of motility and fertilizing capacity.
      Remodelling processes include uptake of secreted epididymal glycoproteins,
      removal or utilization of specific phospholipids from the inner leaflet of the
      bilayer, processing of existing or acquired glycoproteins by endoproteolysis and
      re-positioning of both protein and lipid components to different membrane
      domains. These modifications are carefully coordinated at different zones of the
      epididymis and indirectly affect intracellular membranes, organelles and even
      nucleoprotein. Maturation changes are described and appraised within the context
      of current concepts of membrane structure and fertilization.

PMID- 10645269
TI  - Role of luminal fluid glycosyltransferases and glycosidases in the modification
      of rat sperm plasma membrane glycoproteins during epididymal maturation.
AB  - It is generally accepted that mammalian spermatozoa undergo biochemical and
      morphological changes during epididymal transit, collectively termed epididymal
      maturation. Although many details of the biochemical modification are not fully
      understood, lectin binding studies from several laboratories strongly suggest
      that glycan moieties of sperm plasma membrane glycoproteins are extensively
      modified as spermatozoa transit from the proximal to the distal epididymis. In
      the present article, we summarize our studies with two sets of glycan modifying
      enzymes, namely glycosyltransferases (synthetic enzymes) and glycosidases
      (hydrolytic enzymes) in rat spermatozoa collected from different regions of the
      epididymis, and similar enzyme activities present in the epididymal luminal
      fluid. Our data show that the activities of these enzyme are high in the
      epididymal luminal fluid (> 80% of the total enzyme activities was in the
      plasma). Evidence presented in this report also demonstrates that: (1) at least
      one sperm surface glycoprotein (apparent molecular mass of 86 kDa) is fucosylated
      in vitro when caput spermatozoa are incubated with GDP [14C]fucose; and (2) a
      peanut agglutinin (PNA)-positive glycoprotein of 135-150 kDa present on plasma
      membrane of sperm from the caput (but not cauda) epididymidis is degalactosylated
      by digestion with purified luminal fluid beta-D-galactosidase. Taken together,
      these results strongly suggest a role for glycoprotein modifying enzymes in the
      modification of sperm surface glycoproteins during epididymal maturation.

PMID- 10645270
TI  - Role of epididymal secretory proteins in sperm maturation with particular
      reference to the boar.
AB  - This review considers the role of proteins secreted by the epididymis on post
      testicular sperm maturation and storage. Two-dimensional gels show that 150 to
      200 proteins are secreted into the epididymal lumen. Most are secreted in
      relatively small amounts; in rams, for example, fewer than ten contribute 90% of
      the total secretion and only two contribute 52% of the total protein secreted.
      Most of the proteins are confined to specific regions of the epididymis. The
      changing pattern of protein secretion along the epididymis corresponds to change
      in surface protein on spermatozoa, but no epididymal proteins have been
      identified that appear to be directly involved in modifying the sperm membrane.
      Most of the major proteins that have been identified seem to be playing a
      homeostatic role in maintaining the epididymal milieu for spermatozoa.

PMID- 10645271
TI  - Maturation of redox regulatory mechanisms in the epididymis.
AB  - As spermatozoa pass through the epididymis they complete a maturation process
      that enables these cells to participate in the process of fertilization.
      Epididymal maturation involves a complex cascade of changes involving the
      remodelling of the sperm surface, the induction of chromatin condensation, the
      acquisition of movement, and development of the potential for capacitation. In
      this review we shall consider how changes in the redox status of mammalian
      spermatozoa may contribute to the completion of these maturation events.
      Spermatozoa from all regions of the epididymis exhibit a spontaneous capacity for
      superoxide anion production which can be enhanced by exposure to NADPH,
      particularly in the caput region. It is hypothesized that this spontaneous free
      radical generating activity is mediated by a membrane-bound NADPH oxidase, the
      function of which is to generate the peroxides that are needed to serve as
      hydrogen acceptors for phospholipid hydroperoxide glutathione peroxidase in the
      induction of sperm chromatin condensation. As spermatozoa enter the cauda
      epididymidis they also express a capacity for hydrogen peroxide (H2O2) generation
      when released into simple, defined culture media. The onset of this activity is
      thought to be associated with the induction of sperm capacitation through
      stimulation of the tyrosine phosphorylation events involved in the attainment of
      a capacitated state. It is concluded that sperm maturation is a dynamic, redox
      regulated process, any imbalance in which could lead to the production of
      spermatozoa that are compromised in terms of their potential for fertilization
      and the integrity of their DNA.

PMID- 10645272
TI  - Interactions between epididymal secretions and spermatozoa.
AB  - The interactions between spermatozoa and epididymal secretions are reviewed with
      respect to the nature of the interactions, the maturity of the spermatozoa and
      the environment in which spermatozoa mature. The estimated ionic strength of
      epididymal fluid is low enough for all peripheral proteins to be in close contact
      with the membrane. Two sorts of interactions are evident, those dependent on the
      state of the maturity of the spermatozoa (for example peripheral proteins and
      some integral proteins) and those independent of it (many integral proteins). For
      the former, a change in the sperm membrane charge must occur to permit
      recognition of peripheral proteins and the insertion of secreted charged integral
      membrane proteins may precede the interaction with more distally secreted
      products. For integral proteins, partition into the membrane may depend on the
      composition of the plasma membrane. Changes in the sterol content of particular
      domains have been documented and an array of lipid-binding proteins secreted by
      the epididymis may mediate these changes. The dependence of the transfer of lipid
      anchored proteins to spermatozoa on membranous vesicles invites reassessment of
      the situation of spermatozoa within the epididymis and their contact with
      membranous vesicles and merocrine secretions that may be crucial to promoting
      physiological changes in spermatozoa.

PMID- 10645273
TI  - Receptor tyrosine kinase c-ros knockout mice as a model for the study of
      epididymal regulation of sperm function.
AB  - Despite recent advances in understanding sperm function and characterization of
      epididymal secretion products, little is known about the mechanisms regulating
      the fertilizing capacity of spermatozoa during maturation. The recently produced
      receptor tyrosine kinase c-ros knockout mouse has provided the first transgenic
      model for such study. The only abnormalities in these transgenic mice are shown
      in homozygous mutant males whose epididymis fails to develop the initial segment.
      Normal matings by these mice do not result in oocyte fertilization, but in vitro
      fertilization is successful. Detailed analysis of the development of sperm
      motility per se did not reveal any gross abnormalities that could explain
      infertility in vivo. Studies on c-ros, which is expressed temporarily in a few
      embryonic organs but solely and at high levels in the epididymis in adults, are
      few and nothing is known about its putative ligand or substrates. Review of the
      literature on other family members of receptor tyrosine kinases throws hardly any
      light on its role in epididymal function affecting sperm maturation. The
      preliminary observations that the majority of motile spermatozoa exhibit
      angulation in the tail and further findings suggest a defect in the volume
      regulation mechanism which would normally develop during sperm maturation. This
      finding has provided a starting point for further research to establish the link
      between abnormal epididymides and sterility.

PMID- 10645274
TI  - The MDC family of proteins and their processing during epididymal transit.
AB  - All members of the MDC family of integral membrane proteins contain a
      metalloproteinase-like domain, a disintegrin-like domain and a cysteine-rich
      domain. They have been identified in a wide range of mammalian tissues and many
      are abundantly expressed in the male reproductive tract. We have previously
      cloned and sequenced several MDC transcripts expressed in the testes of the
      macaque (Macaca fascicularis). Using polyclonal antisera we have localized a
      number of these MDC proteins (fertilin alpha, fertilin beta, tMDC I, tMDC II and
      tMDC III) to spermatogenic cells and demonstrated that they are processed as
      spermatozoa pass through the epididymis, yielding proteins that retain their
      disintegrin domain on mature, fertilization-competent cauda spermatozoa. In
      rodents, two of these MDC proteins (fertilin beta and tMDC I) have been
      implicated in egg recognition, mediated by a disintegrin-integrin interaction. It
      is possible that the additional MDC proteins expressed on macaque spermatozoa may
      also be involved in this process.

PMID- 10645275
TI  - Characterization, regulation of the expression and putative roles of two
      glutathione peroxidase proteins found in the mouse epididymis.
AB  - Two glutathione peroxidase genes (gpx5 and gpx3) were found to be expressed in
      the mouse epididymis. Gpx5 was shown to be epididymis specific and restricted to
      the caput epididymidis, while gpx3 was found to be expressed in a wide array of
      tissues including the caput, corpus and cauda epididymides. Both single copy
      genes are regulated by androgens as well as being developmentally regulated
      during postnatal ontogenesis of the epididymis. In this report data collected to
      date concerning the mechanisms by which these genes are regulated in the mouse
      epididymis are summarized. The putative roles of these antioxidant enzymes in the
      sperm maturation process are discussed.

PMID- 10645276
TI  - Evolution of the vertebrate epididymis.
AB  - This review examines the structure and function of the extratesticular sperm
      ducts of vertebrates in terms of their evolutionary development and adaptive
      significance. The primitive extratesticular duct system of Chondrichthyes is
      described as an example of the vertebrate archetype. Adaptations of the duct
      system in higher vertebrates have involved a loss of some structures and
      specialization of others. The duct system probably evolved as a homeostatic
      mechanism to facilitate fertilization and some embryological development under
      conditions protected from the external environment. However, it is argued that
      the ducts also play an important role in the competition between males to achieve
      paternity. In vertebrates that practise internal fertilization the ducts are
      involved in post-testicular maturation and storage of spermatozoa. The biological
      significance of post-testicular sperm maturation has not been resolved. By
      contrast, sperm storage is essential in most male vertebrates because of the slow
      rate of spermatogenesis, particularly in ectotherms. Sperm storage is also
      important in the competition between males for paternity as it enables a male to
      mate a 'partner' a number of times during an oestrus in order to reduce the
      prospect of being cuckolded by another male. The extent of sperm maturation and
      storage in the epididymis of particular vertebrates depends on the relative roles
      of the testis and its extragonadal ducts in the competition between males for
      paternity. These roles depend on a number of factors, including allometric
      limitations to testis size, metabolic rate and the development of endothermy, and
      the reproductive strategy of females of the species.

PMID- 10645277
TI  - Development and use of surgical procedures to bypass selected regions of the
      mammalian epididymis: effects on sperm maturation.
AB  - Microsurgical procedures have been used to examine the function of selected
      regions of the epididymis. Vasoepididymostomy in the rabbit and rat confirmed
      that spermatozoa require some exposure to the epididymal environment for normal
      development of motility and fertilizing ability. In both of these species
      surgical redirection of spermatozoa from a region just distal to the initial
      segment into the vas deferens resulted in a significant reduction in sperm
      viability, motility and fertility compared with untreated animals. Surgical
      bypass of the distal cauda epididymidis in the rabbit did not significantly
      reduce the number of spermatozoa in ejaculates or the total sperm output
      accumulated during exhaustive ejaculations. The capacity of these bypass animals
      to store spermatozoa may be explained by the post-surgical formation of
      convolutions in the normally straight segment of the rabbit vas deferens. Vas
      autografts in the rabbit and rat were used to bypass selected epididymal
      segments. In rabbits, vascularized grafts were used as bridges to bypass the
      distal caput and proximal corpus epididymidis. Despite high rates of graft
      survival and patency in this species, the motility and viability of ejaculated
      spermatozoa were similar to those observed following high level
      vasoepididymostomy. In rats, non-vascularized vas grafts also showed a high
      survival and patency rate. There was a transitory reduction in sperm viability
      and motility 2 weeks after surgery which was associated with structural changes,
      especially in the epithelium, in vas bridge autografts during revascularization.
      Longer term observations (3 and 6 months) showed recovery of epithelial
      morphology and by three months after surgery, no difference was observed in sperm
      motility, sperm viability or fertility between experimental groups and controls.
      Similar results were obtained when epididymoepididymostomy was used as the
      surgical procedure to bypass the same regions of the epididymis. The evidence
      considered in this review clearly shows that the proximity of vasoepididymal
      bypass to the testis is inversely related to the state of maturity of ejaculated
      spermatozoa. More surprisingly, perhaps, it reveals that exposure of spermatozoa
      to the distal caput and proximal corpus regions of the epididymis in the rat is
      not obligatory for spermatozoa to develop a level of maturation in the remaining
      regions of the epididymis sufficient to ascend the female tract and fertilize
      ova. This finding suggests that the epididymis is more flexible in its functions
      than had been considered previously and that sperm maturation may not be as
      dependent on specific regional functions of the epididymis as had been previously
      proposed.

PMID- 10645278
TI  - The specificity of epididymal secretory proteins.
AB  - Early studies in which the electrophoretic profiles of fluid from different
      regions of the epididymis were compared with other body fluids, such as blood
      serum, suggested that many proteins present in epididymal fluid were not found in
      other secretions and thus might be tissue specific. Comparative studies of
      epididymal fluid from different species further emphasized differences so that
      some epididymal proteins are considered both tissue and species specific. Such
      proteins are the putative molecular agents responsible for the array of changes
      undergone by spermatozoa during maturation. Thus a complete characterization of
      all the specific proteins secreted by the epididymis would yield important
      information for understanding the molecular events of maturation. Comparison of
      these proteins across species would determine whether the proteins and mechanisms
      at the centre of changes such as acquisition of fertilizing ability are conserved
      during evolution. This review critically examines the evidence for both tissue
      and species specificity of epididymal secreted proteins, describes how advances
      in molecular biology can be used to clarify this issue and concludes with a
      description of some preliminary work with different lagomorph species involving
      the REP 52 protein, an epididymal secretory protein that binds specifically to
      spermatozoa in New Zealand white rabbits.

PMID- 10645279
TI  - Regulation of apoptotic cell death in the rat epididymis.
AB  - The rat epididymis decreases markedly in weight after orchidectomy. In these
      studies, we demonstrate that a time-dependent wave of apoptotic cell death occurs
      in some principal cells after orchidectomy. This wave moves coincidentally with
      the luminal content of the epididymis. Androgen treatment at the time of
      orchidectomy can prevent apoptotic death in all regions of the epididymis except
      the initial segment (Robaire and Hermo, 1988, similar to zone 1a defined by Reid
      and Cleland, 1957). After unilateral efferent duct ligation, apoptotic cell death
      in the initial segment of the epididymis is similar to that seen after
      orchidectomy, reduced in the caput (zones 1b,c, 2 and 3 as defined by Reid and
      Cleland, 1957) and absent from the corpus (defined as zones 4, by Reid and
      Cleland, 1957) and cauda epididymidis (defined as zones 5 and 6 by Reid and
      Cleland, 1957). Together, these results indicate that principal cells differ in
      their responses to androgens and other testicular factors both in any given cross
      section and with respect to their position along the epididymis.

PMID- 10645280
TI  - HE2/EP2, an androgen-dependent protein from the epididymis of the chimpanzee, Pan
      troglodytes.
AB  - A cDNA clone of chimpanzee EP2 was obtained from epididymal RNA by RT-PCR and was
      sequenced. Chimpanzee EP2 and human HE2 cDNA were > 99% identical and the
      proteins were 100% identical. The derived amino acid sequence of chimpanzee EP2
      showed a consensus sequence for a leader peptide typical of secreted proteins.
      Northern blot analysis indicated that expression of the gene encoding chimpanzee
      EP2 is specific to the epididymis and not to other chimpanzee tissues examined.
      RT-PCR and northern blot analysis of epididymides recovered from an androgen
      deprived adult male chimpanzee showed that the expression of EP2 is androgen
      dependent.

PMID- 10645281
TI  - Extratesticular sperm maturation in the brush-tail possum, Trichosurus vulpecula.
AB  - The changes in distribution of protein and sugar components in, and on, the
      plasmalemma of the spermatozoon during epididymal transit of a marsupial, the
      brush-tail possum, Trichosurus vulpecula, are described. Freeze-fracture studies
      indicate a change in organization of plasmalemma intramembranous particles of
      both the head and midpiece of the tail as the spermatozoa pass from the caput to
      cauda epididymides. Staining with fluorescein isothiocyanate (FITC)-lectins
      shows, that heads of caput spermatozoa stain with Con A, WGA, RCA120, LCA and
      JAC, whereas those from the cauda epididymides stain only with LCA and JAC, thus
      suggesting that N-acetyl-beta-D-glucosamine, alpha-D-glucose, or beta-D-galactose
      may either become lost or masked during epididymal transit. A reduction of alpha
      D-mannose is also suggested. Collectively these results show that the plasmalemma
      of the spermatozoon of at least this marsupial species undergoes both protein and
      saccharide modification during transit of the epididymis. How these findings
      relate to sperm maturation in preparation for sperm-egg binding has yet to be
      determined.

PMID- 10645282
TI  - Chemical interference with sperm metabolic pathways.
AB  - During the 1960s, the quest for a simple non-steroidal chemical possessing male
      antifertility activity culminated with the discovery of the activity of alpha
      chlorohydrin in 1970. Investigations into the mechanism of action of this
      compound revealed that it was affecting the glycolytic pathway within mature
      spermatozoa through its conversion to an inhibitory metabolite. Use of these and
      other simple chemical inhibitors has subsequently led to a clearer understanding
      of the metabolic pathways involved in the generation of ATP, which is necessary
      for sperm motility. Mature boar spermatozoa from the cauda epididymidis are
      almost totally reliant on the glycolytic pathway, not necessarily for the
      immediate generation of ATP, but for the ultimate production of lactate, which
      appears to be the sole substrate used for the mitochondrial production of ATP.
      The only exogenous substrates that support lactate production in vitro are
      fructose, glucose, glycerol and glycerol 3-phosphate and when these substrates
      are plentiful, there is evidence that compounds can be retained as such or as
      intermediates of the glycolytic pathway. When exogenous substrates are limited,
      the cells have the capability to mobilize endogenous compounds and to maintain
      the continuous synthesis of ATP.

PMID- 10645283
TI  - Immune responses in the epididymis: implications for immunocontraception.
AB  - In recent years the need to develop vaccines against a variety of sexually
      transmitted diseases, the desire to treat male infertility and interest in
      developing alternative contraceptive methods have focused research interest on
      the immunology of the male reproductive tract. This paper reviews the current
      state of knowledge of immunity in the male tract. Both physical and immune
      mechanisms that operate to maintain the blood-testis barrier are discussed with
      regard to (i) their importance in preventing autoimmune responses against
      spermatozoa and (ii) how these can be overcome to induce specific immunity in the
      testis and efferent ducts. The role of both the systemic and mucosal arms of the
      humoral immune response are discussed both in terms of immune-mediated
      infertility and the induction of specific immunity. Finally some novel approaches
      to elicit immunity in the male reproductive tract are discussed.

PMID- 10645284
TI  - Effects of environmental toxicants on the efferent ducts, epididymis and
      fertility.
AB  - Many of the reproductive toxicants have primary effects on the testis, which
      potentially overshadow effects downstream on the efferent ducts and epididymis.
      The specific target of these effects depends upon the dosage and time response.
      It is often necessary to design experiments that separate testosterone-dependent
      responses arising in the testis from direct effects on epididymal tissues and
      spermatozoa, to uncover the mechanisms of toxicity in excurrent ducts. Recent
      studies have confirmed that chemicals can also alter the time required for sperm
      transport through the epididymis. Currently there are approximately twenty
      chemicals that can be classified as epididymal toxicants. There are fewer
      toxicants reported for the efferent ducts, but a few overlap with epididymal
      effects. The benzimidazole carbamates, like many efferent ductal toxicants,
      induce occlusions and subsequent testicular atrophy. The mechanisms appear to be
      related to fluid reabsorption, sperm stasis, followed by leukocyte chemotaxis,
      sperm granulomas, fibrosis and often the formation of abnormal microcanals.
      Disruption of oestrogen receptor function in the efferent ducts also interferes
      with fluid reabsorption and results in testicular swelling and seminiferous
      tubular atrophy. Thus, studies in which testicular atrophy occurs after chronic
      or subchronic exposures should be examined for lesions in efferent ducts and head
      of the epididymis. Such lesions can lead to permanent infertility.

PMID- 10645285
TI  - Expression of the cystic fibrosis transmembrane conductance regulator (CFTR) mRNA
      in normal and pathological adult human epididymis.
AB  - The pathogenesis of the aberrant development of the male genital tract
      (epididymis, vas deferens and seminal vesicles) seen in patients with congenital
      bilateral absence of the vas deferens (CBAVD) is still unclear. Since men with
      CBAVD carry mutations in the cystic fibrosis transmembrane conductance regulator
      gene (CFTR), it is likely that CFTR mRNA of the translated protein plays a major
      role in the pathogenesis of CBAVD. The aim of this study was to compare the
      pattern of expression of CFTR mRNA in epididymides of men with CBAVD and other
      types of obstruction (post-vasectomy and post-inflammatory) with that of normal
      non-obstructed adult epididymis. Epididymal biopsies were obtained at the time of
      microsurgical epididymal sperm aspiration procedures or during vaso
      epididymostomy reanastomosis. A normal epididymis was obtained from an
      orchiectomy specimen. After standard processing for in situ hybridization, tissue
      sections were hybridized with CFTR gene-probe labelled by incorporation of
      digoxigenin-dUTP. After hybridization the signal was detected by an alkaline
      phosphatase-tagged antidigoxigenin antibody. CFTR mRNA was clearly identified in
      the columnar epithelium of the normal adult epididymis and vas deferens and the
      signal intensity was greatest in the most proximal regions of the caput
      epididymis. In contrast, men with genital tract obstructions due to CBAVD or post
      vasectomy or post-inflammatory obstructions, had sloughing of the epithelial
      cells lining the lumen and as a consequence CFTR mRNA expression was lacking. In
      one subject (post-vasectomy obstruction), some residual caput epididymal
      epithelium was preserved and CFTR mRNA was detected. The abundant CFTR mRNA
      expression in the proximal caput of the epididymis and vas deferens under normal
      conditions strongly favours the hypothesis of an early obstructive process in the
      pathogenesis of CBAVD. The absent or severely reduced activity of CFTR protein
      affects the ionic exchange and fluid content within the epididymal lumen and
      this, in turn, can lead to excessive viscosity of the epididymal fluid, sloughing
      of epithelial cells expressing CFTR and further reduction in the amount of CFTR
      activity. As a consequence, variable segments of the epididymis and the vas
      deferens may be blocked and progressively obliterated. The epididymal lumen
      obstruction could also sustain the anatomical defects by not allowing
      testosterone to exert a local action on the mesonephric duct.

PMID- 10645286
TI  - The role of the epididymis in human infertility.
AB  - This review describes the role of the epididymis in human infertility, by
      analysing the results of epididymovasostomies which confirm that the more distal
      the site of obstruction the greater the chance of fertility. The use of
      epididymal spermatozoa for in vitro fertilization (IVF) yielded poor results in
      contrast to intracytoplasmic sperm injection using either epididymal or
      testicular spermatozoa. The nature of the pathology causing obstructive
      azoospermia is examined reviewing in particular the possible role of mercury
      toxicity in Young's syndrome. This review describes the results of studies that
      show that the level of obstruction within the epididymis is correlated with the
      presence of sperm antibodies and distal obstructions are associated with the
      presence of sperm antibodies. The demonstration that necrozoospermia decreases
      with increased sperm transport through the epididymis, when combined with the
      observation of normal testicular sperm morphology, represents the basis for the
      disorder termed epididymal necrozoospermia. However, to date the nature of the
      epididymal pathology causing this disorder remains obscure.

PMID- 10645287
TI  - The use of epididymal spermatozoa in assisted reproduction.
AB  - The use of epididymal spermatozoa in assisted reproduction (ART) permits
      fertility in men with surgically irremediable obstructive azoospermia. When used
      for conventional IVF (sperm-oocyte co-culture), epididymal spermatozoa show
      reduced fertilization and pregnancy rates (compared with ejaculated spermatozoa
      from men with a range of spermatogenic disorders) as evidence of their functional
      immaturity. However, when used with intracytoplasmic sperm injection (ICSI)
      either fresh or frozen-thawed epididymal spermatozoa produce ART success rates
      similar to those of ejaculated spermatozoa. The clinical place of epididymal
      sperm retrieval for ICSI has come under review as a result of data showing
      similarly good outcomes with testicular spermatozoa obtained by needle
      aspiration. In Australia ICSI using epididymal or testicular spermatozoa is an
      increasingly favoured option for vasectomy-related infertility and in other types
      of obstructive azoospermia for a number of reasons including better pregnancy
      outcomes, the less invasive nature of the procedures and less expense involved;
      however, this cost-benefit analysis will vary in other health systems.

PMID- 10645288
TI  - The epididymis across 24 centuries.

PMID- 10645289
TI  - E-biomed.

PMID- 10645290
TI  - The struck-off mystery.
AB  - Observations on ward rounds suggested that psychiatric patients might be at
      special risk of removal from their general practitioner's list. Little has been
      published on why patients are struck off and our first attempt at investigation
      was by direct appeals for patients. This drew a small and unsatisfactory sample.
      We then asked two family health services authorities to distribute questionnaires
      to struck-off patients. One agreed, but later withdrew cooperation. There is a
      danger that struck-off patients will become an underclass excluded from primary
      care. We propose anonymous collection of information by health authorities, so
      that policy can be reviewed if necessary.

PMID- 10645291
TI  - How do general practitioners respond to reports of abnormal chest X-rays?
AB  - General practitioners (GPs) in the UK have long had direct access to hospital
      radiological services, which in theory shortens investigation time and improves
      the quality of service. Chest X-rays (CXRs) account for a substantial proportion
      of requests, and we investigated what happened when an abnormality was detected.
      In one year, 204 GPs in the Nottingham area requested CXRs in 605 patients. 362
      were reported normal, 165 abnormal but hospital follow-up not indicated and 71
      abnormal with radiological follow-up or hospital referral indicated (mass lesion
      suspicious of tumours 27, infective shadowing 35, other 9). 64 of the 71 were
      seen in hospital within three months, and in those with suspected cancer the
      median time to follow-up was 20 days. These results show that GPs do act on the
      results of abnormal CXRs, but only 37% of those with a mass suspicious of cancer
      were seen in hospital within two weeks as recommended by the British Thoracic
      Society. Time might be saved if GPs agreed to direct referral from the radiology
      department to respiratory physicians.

PMID- 10645292
TI  - Traumatic pseudocyst of the spleen.
AB  - Four patients with pseudocyst of the spleen gave histories of abdominal trauma.
      In one patient the pseudocyst had ruptured, necessitating emergency splenectomy
      34 years after the original injury. In a second patient the pseudocyst was
      discovered incidentally, and was managed by spleen-preserving excision; and the
      third and fourth presented with abdominal pain and had splenectomy and spleen
      preserving surgery, respectively. All patients with conservatively treated
      splenic injury are at risk of developing a pseudocyst of the spleen, and the
      lesion can be detected by computed tomography or ultrasound. When there are no
      symptoms the natural history is unknown; but if surgery is necessary, splenectomy
      can sometimes be avoided.

PMID- 10645293
TI  - Attention deficit hyperactivity disorder: diagnosis and management in the USA.

PMID- 10645295
TI  - Pulled elbow.

PMID- 10645294
TI  - Pathogenesis and treatment of ANCA-associated systemic vasculitis.

PMID- 10645296
TI  - Secondary inflammation of the appendix via the vagina.

PMID- 10645297
TI  - A hazard of goat soup.

PMID- 10645299
TI  - Perianal recurrence in colonic cancer.

PMID- 10645298
TI  - A tuberculous anal fistula.

PMID- 10645300
TI  - Pancreatic pseudocyst drainage by endoscopic sphincterotomy.

PMID- 10645301
TI  - Spontaneous compartment syndrome after thrombolytic therapy.

PMID- 10645302
TI  - Life-threatening chickenpox pneumonitis in two previously healthy adults.

PMID- 10645304
TI  - Gulf health research--past, present and future.

PMID- 10645303
TI  - Serotonin syndrome with fluoxetine plus tramadol.

PMID- 10645306
TI  - Three ways to improve the supply of cadaveric organs for transplantation.

PMID- 10645305
TI  - The puzzle of pink disease.

PMID- 10645307
TI  - Samson Wright (1899-1956): physiologist extraordinary.

PMID- 10645308
TI  - Euthanasia in The Netherlands.

PMID- 10645309
TI  - Information resources for psoriasis patients.

PMID- 10645310
TI  - Salmonella osteoarticular infection without predisposing factors.

PMID- 10645311
TI  - Attention deficit hyperactivity disorder (ADHD)

PMID- 10645312
TI  - Issues in organ donation and transplantation.

PMID- 10645313
TI  - Healthcare in the UK.

PMID- 10645314
TI  - Local radiotherapy for alveolar airleak.

PMID- 10645315
TI  - Surgical training in shorter hours.

PMID- 10645316
TI  - A bibliometric survey and a citation-based bibliography.

PMID- 10645317
TI  - 44th Annual meeting of the Biophysical Society. New Orleans, Louisiana, USA.
      February 12-16, 2000. Abstracts.

PMID- 10645318
TI  - Northern Ireland. The victims.

PMID- 10645319
TI  - Classification in psychiatry: ICD-10 v. DSM-IV. A response.

PMID- 10645320
TI  - "To see oursels as others see us". Aubrey Lewis's insight.
AB  - BACKGROUND: This paper takes as its starting point the paper by Aubrey Lewis
      entitled "The psychopathology of insight" published in 1934, unreferenced. AIMS:
      To attempt to explore the historical antecedents and consequences of this work.
      METHOD: Speculative review. RESULTS: Lewis's approach to phenomenology,
      contemporaneous movements in psychology and Lewis's own life and times--notably
      the eugenics legislation in Nazi Germany--probably shaped his conclusions. Modern
      concepts of insight, which emphasise neuropsychology as well as social
      psychology, were anticipated in Lewis's writings. CONCLUSIONS: The concept of
      insight has stimulated research into difficult theoretical and practical areas
      such as self-awareness and treatment compliance, respectively. Concern over a
      patient's capacity for insight has the potential to humanise psychiatry.

PMID- 10645321
TI  - Pragmatic randomised controlled trials in psychiatry.
AB  - BACKGROUND: Randomised controlled trials (RCTs) are the most important method of
      evaluating new treatments and treatment policies. Despite this, there are
      relatively few large pragmatic RCTs in psychiatry. AIMS: To explore the main
      advantages of large pragmatic RCTs and the obstacles to performing them in
      psychiatry. METHOD: A narrative review of literature on pragmatic RCTs with
      examples drawn from psychiatry and other medical specialities. RESULTS: Obstacles
      to performing pragmatic RCTs in psychiatry include the complexity of psychiatric
      interventions, the complexity of outcomes used in psychiatry and the difficulties
      of blinding subjects and investigators to some psychiatric interventions.
      CONCLUSIONS: Researchers need to frame questions in a form that is relevant to
      clinicians and to convince clinicians to cooperate in simple large pragmatic
      trials.

PMID- 10645322
TI  - Route of discharge for special (high-security) hospital patients with personality
      disorder. Relationship with re-conviction.
AB  - BACKGROUND: A considerable proportion of patients with personality disorder are
      discharged directly to the community from special (high-security) hospitals.
      AIMS: To examine whether patients with personality disorder discharged directly
      to the community are more likely to be re-convicted than those transferred to
      psychiatric hospitals of lesser security. METHOD: Re-conviction data for a five-
      to nine-year follow-up were collected for a four-year (1988-1991) special
      hospital discharge cohort of patients with personality disorder. RESULTS:
      Individuals discharged directly to the community were not significantly more
      likely to be re-convicted than those transferred to less secure psychiatric
      hospitals. However, patients discharged to the community without formal
      conditions of supervision were more likely to be re-convicted than those
      discharged to the community with conditions or those transferred to other
      psychiatric hospitals. CONCLUSIONS: Formal supervision after discharge may be
      more important than actual destination in influencing the likelihood of re
      conviction.

PMID- 10645323
TI  - Use of electroconvulsive therapy in young people.
AB  - BACKGROUND: Electroconvulsive therapy (ECT) is a controversial treatment for
      psychiatric disorders, particularly when it is administered to young people.
      AIMS: To assess how frequently ECT is administered to people under the age of 18
      years in the UK, and why it is given. METHOD: Electroconvulsive therapy clinics,
      private hospitals, adolescent units and UK members of the Royal College of
      Psychiatrists were surveyed to ask if they were aware of ECT being administered
      during 1996 to a young person under the age of 18 years. Consultants identified
      as having prescribed ECT were sent a follow-up questionnaire. RESULTS: Twelve
      young people were identified as having received ECT; three were aged 15 years or
      younger and eight were female. Nine patients were rated as improved following
      ECT. The indications for its use were similar to those for adults. CONCLUSIONS:
      Electroconvulsive therapy is rarely administered to young people in the UK.

PMID- 10645324
TI  - In vivo occupancy of striatal and temporal cortical D2/D3 dopamine receptors by
      typical antipsychotic drugs. [123I]epidepride single photon emission tomography
      (SPET) study.
AB  - BACKGROUND: The dopamine hypothesis proposes that antipsychotic drugs act
      primarily through limbic cortical D2/D2-like dopamine receptor blockade. AIM: To
      evaluate this hypothesis with the D2/D3-selective SPET probe [123I]-epidepride.
      METHOD: [123I]-epidepride SPET scans were performed on 12 patients with
      schizophrenia treated with antipsychotics and II age-matched healthy controls.
      [123I]-epidepride 'specific binding' to D2/D3 dopamine receptors was estimated,
      and relative percentage D2/D3 receptor occupancy by typical antipsychotic drugs
      determined. RESULTS: Mean (s.d.) daily dose was 669.12 (516.8) mg chlorpromazine
      equivalents. Mean percentage D2/D3 receptor occupancy was 81.6 (8.1) and 73.2
      (13.9) in the temporal cortex and striatum respectively. CONCLUSIONS: Typical
      antipsychotic drug treatment is associated with substantial temporal cortical
      D2/D3 receptor occupancy. The relationship between this and efficacy is poor in
      patients with treatment-resistant schizophrenia.

PMID- 10645325
TI  - Preterm birth and intra-uterine growth retardation among children of women with
      schizophrenia.
AB  - BACKGROUND: There is conflicting evidence about the frequency of adverse
      pregnancy outcomes among women with schizophrenia. AIMS: To investigate the risk
      of preterm birth, low birth weight and intra-uterine growth retardation among
      women with schizophrenia. METHOD: A total of 2212 births to 1537 women with
      schizophrenia in Denmark were compared with a random sample of all deliveries in
      Denmark in 1973-1993 (122,931 births to 72,742 women). RESULTS: The children of
      women with schizophrenia were at increased risk of preterm delivery (relative
      risk = 1.46, 95% CI = 1.19-1.79), low birth weight (relative risk = 1.57, 95% CI
      = 1.36-1.82) and small for gestational age (relative risk = 1.34, 95% CI = 1.17
      1.53). CONCLUSIONS: Women with schizophrenia are at increased risk of adverse
      pregnancy outcome. This may be associated with an increased mortality and general
      morbidity and risk of schizophrenia in their children.

PMID- 10645326
TI  - Neuropsychological function in euthymic patients with bipolar disorder.
AB  - BACKGROUND: The assumption that patients with bipolar disorder make a full inter
      episode recovery has been challenged by limited evidence that suggests that
      neuropsychological dysfunction in bipolar disorder may persist beyond episodes of
      illness. AIMS: To test the hypothesis that patients with euthymic bipolar
      disorder show neuropsychological impairment. METHOD: A battery of
      neuropsychological tests (assessed attention, working memory, learning and
      executive function) was administered to three matched groups of subjects: good
      outcome patients with bipolar disorder (n = 21); poor-outcome patients with
      bipolar disorder (n = 20); controls (n = 20). All patients were clinically
      euthymic, although some had low levels of depressive symptoms. RESULTS: Patients
      performed worse than controls on a number of neuropsychological tests. When age,
      premorbid IQ and depressive symptoms were controlled for, the results indicated
      impairment of executive function. CONCLUSIONS: These findings provide good
      evidence for the existence of neuropsychological impairment in patients with
      euthymic bipolar disorder, although the possible effect of medication should not
      be overlooked. This may be of clinical relevance and raises questions about the
      course and outcome of the illness.

PMID- 10645327
TI  - Follow-up study of depression in the elderly. Clinical and SPECT data.
AB  - BACKGROUND: Imaging studies in depression of the elderly are often small and
      highly selective. AIMS: To investigate a large group of elderly depressed
      patients in order to assess changes in clinical, imaging and neuropsychological
      variables at follow-up. METHOD: Patients (n = 175, age range 65-91 years) with
      clinical depression were identified from consecutive local referrals. Clinical
      interviews, neuropsychological tests and SPECT scans were carried out at referral
      and at two-year follow-up. RESULTS: Of 84 re-examined patients, 46.5% were well,
      9.5% were ill, 33% partially recovered and 11% had developed dementia. Duration
      of illness before index assessment was the only factor to predict outcome. Thirty
      nine patients could be scanned and followed up. There were no differences between
      patients with good or poor depressive outcome on SPECT. Ten clinically improved
      patients could be re-examined with SPECT. There were relative increases in right
      cingulate gyrus and right cerebellum at follow-up. CONCLUSIONS: The patients
      group was comparable with other studies showing high levels of residual
      depressive symptoms. Activity changes in limbic cortex are implicated in
      depression of old age.

PMID- 10645328
TI  - Association of low serum total cholesterol with major depression and suicide.
AB  - BACKGROUND: It has been suggested that low serum total cholesterol is associated
      with an increased risk of suicide. AIMS: To study the association between serum
      total cholesterol, depression and suicide using versatile, prospective data.
      METHOD: A total of 29,133 men aged 50-69 years were followed up for 5-8 years.
      Baseline blood samples were analysed for serum total and high-density lipoprotein
      cholesterol concentrations. Self-reported depression was recorded, data on
      hospital treatments due to depressive disorders were derived from the National
      Hospital Discharge Register and deaths from suicide were identified from death
      certificates. RESULTS: Low serum total cholesterol was associated with low mood
      and subsequently a heightened risk of hospital treatment due to major depressive
      disorder and of death from suicide. CONCLUSIONS: Our results suggest that low
      serum total cholesterol appears to be associated with low mood and thus to
      predict its serious consequences.

PMID- 10645329
TI  - Suicide and unemployment in young people. Analysis of trends in England and
      Wales, 1921-1995.
AB  - BACKGROUND: The influence of the macro-economic climate on suicide is unclear.
      During the recent recession, rates have increased in young males but declined in
      females. AIMS: To investigate associations between unemployment and suicide in 15
      to 44-year-old men and women over a period spanning two major economic
      recessions (1921-1995). To minimise confounding by changes in method
      availability, analyses are restricted to suicides using methods other than
      poisons and gases. METHOD: Time-series analysis using routine mortality and
      unemployment data. RESULTS: There were significant associations between
      unemployment and suicide in both males and females. Associations were generally
      stronger at younger ages. CONCLUSIONS: Secular trends in youth suicide may be
      influenced by unemployment or other factors associated with changes in the macro
      economic climate. These factors appear to affect women to the same extent as men.
      Although it is not possible to draw firm aetiological conclusions from time-trend
      data, our findings are in keeping with those of person-based studies.

PMID- 10645330
TI  - Suicide in young people. Study of 174 cases, aged under 25 years, based on
      coroners' and medical records.
AB  - BACKGROUND: Suicide rates in young males in the UK have risen markedly in recent
      years. AIMS: To investigate the characteristics of a series of consecutive
      suicides in under-25-year-olds. METHOD: We studied coroners' inquest notes,
      general practitioners' records and psychiatric case notes of 174 individuals (148
      males and 26 females) whose deaths received a verdict of suicide or an open or
      accidental verdict (excluding traffic accidents) where the circumstances strongly
      suggested suicide. RESULTS: More individuals were of lower social class and
      unemployed than in the local population. Hanging and carbon monoxide poisoning
      were the most frequent methods of suicide, and coproxamol was the drug most often
      used in overdoses. Previous self-harm had occurred in 44.8%, nearly half of these
      having carried out multiple episodes and 80% having self-harmed within the
      previous year. Little support was found for an earlier finding of increasing
      frequency of general practitioner visits shortly before death. Only 22.4% of
      individuals were in the care of psychiatric services. CONCLUSIONS: Diverse
      strategies are required to prevent suicide in the very young.

PMID- 10645331
TI  - Suicide among drug addicts in the UK.
AB  - BACKGROUND: The extent of suicide among addicts in the UK has not been
      sufficiently examined. AIMS: To examine suicide trends among registered addicts
      in the UK over a 25-year period. METHOD: We quantified suicide using
      International Classification of Diseases (ICD) external death codes E950-959,
      calculated annual age-standardised suicide rates, standardised mortality ratios
      (SMRs) and described trends in methods of suicide and drug overdose suicides in
      five successive cohorts of registered addicts. RESULTS: Male and female suicide
      rates are 69.0 and 44.8 per 100,000 person-years, respectively. There was a
      consistent decline in suicide rate throughout the 25-year period. Among males,
      the SMR for suicide declined from 17.2 in 1968-1972 to 4.4 in 1988-1992 (SMR
      ratio = 3.9, 95% CI = 2.5-6.1); among females it declined from 52.6 to 11.3 in
      the same period (SMR ratio = 4.7, 95% CI = 1.9-10.8). Drug overdose was the most
      common method of suicide, accounting for 45% of cases. Significant increase in
      antidepressant (percentage difference = 23.5%, 95% CI = 15.2-31.8) and methadone
      (percentage difference = 11.0%, 95% CI = 0.5, 21.5) overdose in 1988-1992
      compared with 1968-1972 was reported. CONCLUSIONS: The findings confirm that
      addicts are still at higher risk of suicide than the general population and that
      prescribed drugs, notably antidepressants and methadone, influence this
      heightened risk.

PMID- 10645332
TI  - A Jamaican psychiatrist evaluates diagnoses at a London psychiatric hospital.
AB  - BACKGROUND: Authors have suggested that the high rate of schizophrenia reported
      for African-Caribbeans living in the UK is due to misdiagnosis by British
      psychiatrists. AIMS: To compare the diagnoses made by a Black Jamaican
      psychiatrist with those of White British psychiatrists. METHOD: All in-patients
      on four wards at the Maudsley hospital were approached for the study; 66
      participated: 24 White, 29 Black African-Caribbeans and 13 Blacks from other
      countries of origin. F.W.H., a Black Jamaican psychiatrist, conducted his
      standard clinical assessment and performed the Present State Examination (PSE) on
      these patients. His diagnoses were compared with the case note diagnoses made by
      British psychiatrists, and with the PSE CATEGO diagnoses. RESULTS: Of 29 African
      and African-Caribbean patients diagnosed with schizophrenia, the diagnoses of the
      British and the Jamaican psychiatrists agreed in 16 instances (55%) and disagreed
      in 13 (45%). Hence, interrater reliability was poor (kappa = 0.45). PSE CATEGO
      diagnosed a higher proportion of subjects as having schizophrenia than the
      Jamaican psychiatrist did (chi 2 = 3.74, P = 0.052). CONCLUSIONS: Agreement
      between the Jamaican psychiatrist and his UK counterparts about which patients
      had schizophrenia was poor. PSE CATEGO may overestimate rates of schizophrenia.

PMID- 10645333
TI  - A Jamaican psychiatrist evaluates diagnoses at a London psychiatric hospital. Are
      there bullets in the smoking gun?

PMID- 10645334
TI  - A Jamaican psychiatrist evaluates diagnoses at a London psychiatric hospital.
      Jury is still out.

PMID- 10645335
TI  - Do SSRIs affect personality traits.

PMID- 10645336
TI  - Lipid supplementation in schizophrenia.

PMID- 10645337
TI  - Pharmacokinetics of clozapine.

PMID- 10645338
TI  - Medial prefrontal glutamine and dreaming.

PMID- 10645339
TI  - Quick rating of depressed mood.

PMID- 10645340
TI  - The difficult patient--Schreber revisited.

PMID- 10645341
TI  - EURODEP study.

PMID- 10645342
TI  - Psychosis associated with gonadorelin agonist administration.

PMID- 10645343
TI  - Manic episode due to gabapentin treatment.

PMID- 10645344
TI  - Polydactyly and functional psychosis.

PMID- 10645345
TI  - Occurrence of fumonisin B1 and B2 in beer.
AB  - A total of 29 nationally distributed brands of beer, representing 25 domestic US
      and four imported brands, were purchased in retail outlets in Lincoln, Nebraska
      and analysed for concentrations of fumonisin B1(FB1) and B2(FB2). Immunoaffinity
      column extraction and cleanup of fumonisins from the beer samples, coupled with
      detection and analysis by gradient high performance liquid chromatography (HPLC),
      provided a limit of quantitation for each toxin of 0.3 ng/ml. Of the brands of
      beer sampled, 86% were positive for FB1 and 41% were positive for FB2. No beer
      contained a detectable quantity of FB2 without a detectable quantity of FB1. The
      total fumonisin (FB1 + FB2) content of positive samples ranged from 0.3 to 12.7
      ng/ml, with a mean concentration for all positive samples of 4.0 +/- 3.4 ng/ml (n
      = 25). Considering that the level of fumonisin contamination of corn in recent
      harvest years has been minimal, the results of this limited survey could
      represent levels associated with current agricultural and brewing practices.

PMID- 10645346
TI  - A survey of fumonisins, deoxynivalenol, zearalenone and aflatoxins contamination
      in corn-based food products in Argentina.
AB  - The presence of mycotoxins in corn-based foods available in Argentina was
      determined in order to make a preliminary exposure assessment. Thirty-eight
      samples [corn meal ('polenta') and corn flakes] of different local brands were
      analysed for zearalenone, deoxynivalenol and aflatoxins by TLC and fumonisins
      (FB1, FB2 and FB3) by HPLC. None of the 38 samples contained any detectable
      amount of aflatoxins (< 2 micrograms/kg), zearalenone (< 50 micrograms/kg) and
      deoxynivalenol (< 50 micrograms/kg). By contrast fumonisin contamination was
      found in 95% of the samples. The highest fumonisin levels were found in corn
      meal: FB1 (range positives: 60-2860 micrograms/kg; mean positive value: 556
      micrograms/kg), FB2 (61-1090 micrograms/kg; 232 micrograms/kg) and FB3 (18-1015
      micrograms/kg; 150 micrograms/kg). Low levels of fumonisin B1 were detected in
      16/17 corn flakes samples (2-38 micrograms/kg). Total fumonisin levels in corn
      meal were more than 1000 micrograms/kg in 24% (5/21) of the samples. Although it
      is not the staple food in Argentina, maize consumption is very important,
      especially among children. A daily fumonisin intake of 11.3 micrograms/kg of body
      weight was estimated for child consumers (1-5 years old) based on an average
      consumption of 200 g of corn meal/day. Calculated at an average rate for all
      children (consumers or not) the intake estimate was 0.9 microgram/kg of body
      weight.

PMID- 10645347
TI  - Investigation of various extractants for the analysis of aflatoxin B1 in
      different food and feed matrices.
AB  - Various extractants were investigated concerning their suitability for aflatoxin
      B1 determinations in different matrices including spices, infant formula and
      animal feed employing an immunoaffinity clean-up procedure. It was shown that the
      use of aqueous acetonitrile extractants was limited due to the fact that dry
      sample material can absorb significant amounts of water from the extractant. This
      can result in recoveries that are too high and therefore in incorrect values for
      the aflatoxin concentration if aliquots are taken for further analysis. A
      correction of the results by recovery calculation using spiked blank material is
      unsuitable, since material from the same group of food (e.g. paprika powder) or
      feed can vary significantly in the recovery values. Therefore it is recommended
      that aqueous methanol extractants are used, since no significant interaction with
      matrix constituents was observed. In addition, aqueous acetone extractants are a
      useful alternative with some limitations.

PMID- 10645348
TI  - Microbiological and chemical identification of antimicrobial drugs in kidney and
      muscle samples of bovine cattle and pigs.
AB  - Microbiological and chemical identification of antimicrobial drug residues was
      attempted in 95 kidney and 76 muscle samples from 58 cattle, 36 pigs and one
      horse which had revealed kidneys positive to an inhibitor test. Information on
      pre-slaughter medication with one antimicrobial drug was available for 63% of the
      carcasses. Microbiological identification was performed by agar diffusion using
      17 or 18 combinations of eight test bacteria, varying medium pH and three
      substances blocking the action of certain antimicrobials. Sample activity
      patterns compiled from inhibition zone diameters on test plates were compared
      with those obtained with standard antimicrobial solutions both visually and by
      locating the minimal sum of absolute pairwise differences over the tests.
      Chemical identification of residues was based on liquid chromatography. In kidney
      samples containing one microbiologically-identified antimicrobial the two methods
      gave fully consistent results with tetracyclines (15/15) and fluoroquinolenes
      (8/8). Preparation and storage of the kidney samples before chemical analyses
      appeared to influence the chemical identification of penicillin G. The results
      were consistent in 37 of the 41 samples stored without homogenization at -70
      degrees C. The residue was identified by chemical means only in six and neither
      microbiologically nor chemically in four kidney samples with information on pre
      slaughter medication. The same residue as in the kidney samples was identifiable
      microbiologically in 41% of the muscle samples of the same carcasses. The results
      show that the microbiological method is well suited for identification of
      antibiotic residues. They indicate further that an enhanced resolution with a
      reduced combination of plates is attainable.

PMID- 10645349
TI  - Study of diffusion through LDPE film of Di-n-butyl phthalate.
AB  - The apparent diffusion coefficients (D) across a PE-LD film of Di-n-butyl
      phthalate (DnBP) dissolved in isooctane and ethanol, were calculated in different
      ways and compared. DnBP, a common plasticizer of plastics and printing inks, may
      be a possible contaminant of flexible packaging and PE-LD is the most common food
      contacting polymer. To perform diffusion measurements, small plastic sachets
      filled with solutions of the contaminant were used at three different
      temperatures. The D coefficients of the two solvents and dissolved DnBP were
      calculated using the lag time method, a formula taking into account the molar
      weight and absolute temperature, and an equation based on the initial
      concentration and the amounts migrated after subsequent times. The results
      demonstrated great solvent interference in the plasticizer diffusion across
      polyethylene; in particular as far as isooctane is concerned, a remarkable co
      diffusion of both the plasticizer and the non-polar solvent must be assumed.
      Isooctane quickly penetrates PE-LD but ethanol also diffuses across PE-LD,
      although at a greatly reduced speed. These facts must be considered for realistic
      prediction of migration or effectiveness of the functional barrier.

PMID- 10645350
TI  - Multidisciplinary trauma surgery: who should or could do what?

PMID- 10645351
TI  - 200 years of military surgery.

PMID- 10645352
TI  - Management of paediatric blunt splenic injury in Zaria, Nigeria.
AB  - The management of paediatric blunt splenic injury is predominantly non-operative
      in developed countries at the present time. In developing countries however,
      imaging facilities for diagnosis and monitoring are frequently not readily
      available. Over a decade, 32 children had blunt splenic injury in Zaria. 28
      (87.5%) injuries were isolated. Nineteen (59.4%) had grade II or III injuries and
      their spleens were preserved (splenorrhaphy, 12; partial splenectomy, 4;
      laparotomy only, 2; observation, 1) while 13 (40.6%) had grade IV or V injury
      necessitating total splenectomy. There was no difference in blood transfusion
      requirements in any group. The average duration of hospital stay was 17 days for
      splenic preservation and 20 days for total splenectomy. Mortality was 2 (6.3%),
      both patients had total splenectomy and one had associated liver injury. With
      adequate facilities, laparotomy would have been avoided in 16 (51.6%) patients.
      It is hoped that as appropriate imaging facilities become more readily available
      in developing countries, less children with blunt splenic injury will be
      subjected to surgery.

PMID- 10645353
TI  - Intra-articular lignocaine versus Entonox for reduction of acute anterior
      shoulder dislocation.
AB  - We assessed, in a prospective randomised trial, the relative analgesic effects of
      Entonox and intra-articular lignocaine (IAL) in patients with acute anterior
      dislocation of the shoulder. A statistically significant reduction in pain scores
      was achieved with IAL (7.9 vs 5.2, P < 0.05), but the effect with Entonox was
      greater (7.8 vs 2.9, P < 0.001). We conclude that Entonox provides better
      analgesia than IAL in patients with acute anterior shoulder dislocation.

PMID- 10645354
TI  - The treatment of difficult proximal femoral fractures with the Russell-Taylor
      reconstruction nail.
AB  - The outcome of 30 proximal femoral fractures and pathological lesions in 29
      patients treated with the Russell-Taylor reconstruction nail are reported. Four
      patients had fractures involving both the femoral neck and shaft (segmental).
      Fifteen patients had extensive comminuted fractures of the proximal femur and ten
      patients underwent nailing because of pathological fractures (one bilateral). In
      nineteen operations there were technical difficulties, nail insertion and
      proximal interlocking being the commonest. In the elderly there was a high post
      operative complication rate. Three nails needed to be revised for failure of
      fixation. On review, all patients under sixty years of age regained full mobility
      and returned to their pre-fracture level of activities. Patients with per
      trochanteric fractures over the age of sixty had less favourable results. No
      cancer patient returned to their prefracture mobility level. The Russell-Taylor
      reconstruction nail proved to be useful in the treatment of segmented and, in a
      lesser degree, pathological fractures. However, the surgical technique is
      demanding and there is a high incidence of post-operative complications in the
      patients over the age of sixty.

PMID- 10645355
TI  - Early mobilisation versus immobilisation of surgically treated ankle fractures.
      Prospective randomised control trial.
AB  - In a randomised prospective controlled trial of 52 patients aged 16 to 65 we
      compared early non-weightbearing ankle mobilisation with ankle immobilisation
      following surgical treatment of bimalleolar ankle fractures. At 3 months there
      was no significant difference between the two groups in the range of ankle
      movements or pain. There was however a significant difference in the gait pattern
      with a higher proportion of cases in the early ankle mobilisation group having a
      symmetrical gait (P = 0.0001).

PMID- 10645356
TI  - Three-dimensional dynamic external fixation of distal radial fractures. A
      prospective study.
AB  - This prospective study describes the experience with a new dynamic external
      fixator which provides three degrees of freedom, while the centre of rotation of
      all these movements is located in the wrist. 44 patients with unstable fractures
      of the distal radius were included. During the period of dynamisation, with a
      median flexion of 30 degrees, extension of 18 degrees, radial deviation of 0
      degree and ulnar deviation of 20 degrees the range of motion needed to perform
      activities of daily living was approached. In spite of early mobilisation
      reduction was maintained. The radiological result was excellent or good in 82% of
      the patients and the functional result was excellent or good in 92% of the cases.
      Pin track infections were noted rather frequently, possibly related to the
      interaction between the soft tissues and the fixator pins. Based on the
      experiences of the study the device needs further improvement.

PMID- 10645357
TI  - Outcomes in acute orthopaedic trauma: a review of 130,506 patients by age.
AB  - There is a paucity of large cohort studies that address outcomes after acute
      orthopaedic trauma. The regional trauma registry is a powerful tool to study
      trends of large populations over long periods of time. We used such a regional
      trauma registry to review retrospectively a large subset of orthopaedic trauma
      patients over a long period of time and to evaluate the relationship between
      initial presentation, hospital course, hospital charges, and outcomes as a
      function of age. A retrospective review of 130,506 level I and II trauma
      admissions with acute orthopaedic injuries over 10 years (1985-1995) was
      conducted. Aggregate data were analyzed among five age groups. Descriptive
      analyses were conducted for mechanism of injury, mortality, time to death, injury
      type, injury severity score (ISS), Glasgow Coma Scale (GCS) on presentation,
      length of stay (LOS), discharge destination, and hospital charges. Forty-six
      percent of the patients were in the 18-35-year-old age group; however, 21% of all
      patients were older than 65 years of age at the time of injury. There were no
      differences in GCS or ISS on admission. Injury types were similar across all age
      groups, mostly extremity fractures. Younger patients were much more likely to be
      injured in a motor vehicle accident (MVA), whereas older patients were injured in
      a fall. Penetrating trauma was seen almost exclusively in the young. LOS in the
      hospital was longer in the elderly; however, LOS in the intensive care units were
      similar across all age groups. Time to death from initial presentation differed
      across age groups. Elderly patients who eventually died were much more likely to
      survive more than 24 h in the hospital as compared with young patients. Hospital
      charges per hospitalization increased with age, although the total charges to the
      youngest age group were higher due to the group's high volume. Younger American
      trauma patients with acute orthopaedic injuries are much more likely than their
      older counterparts to sustain penetrating trauma and pass the socioeconomic
      burden to society by way of large opportunity costs, lack of insurance, and high
      rates of recidivism. Elderly patients fared as well as younger patients after
      acute orthopaedic trauma, although their hospital stays were longer and resulted
      in increased hospital charges. The excessive costs of trauma, $100 billion and
      more than 150,000 deaths annually, necessitate study of general population
      trends. Indirect costs, including rehabilitation costs and opportunity costs, as
      well as direct costs, are incurred during the post-trauma hospitalization.
      Attention must focus on prevention of penetrating injuries in the young and falls
      in the elderly to reduce morbidity, mortality, and the costs of trauma.

PMID- 10645358
TI  - Closed reduction of tibial shaft fractures using a sling.
AB  - We wish to report a simple technique for closed reduction of tibial shaft
      fractures. The patient is put in the supine position. Longitudinal traction is
      applied through a plaster boot on the corresponding foot and ankle. A gauze sling
      (Fig. 1) placed behind the calf at the fracture site allows suspension of the
      limb whilst controlling posterior angulation and displacement. This allows
      control of the limb whilst alignment is checked with the image intensifier in two
      planes. When satisfactory reduction is obtained, a long leg plaster can be
      applied to immobilize the fracture. The technique was applied to 21 closed tibial
      shaft fractures in 21 patients. Satisfactory results were obtained in 20
      patients. Analysis of the initial post-manipulation X-rays showed an average of
      5.2 mm shortening (range 0-15 mm). The average coronal angulation was 1.9 degrees
      (range 0-5 degrees), and sagittal angulation was 2.0 degrees (range 0-8 degrees).
      Average percentage overlap of the fracture fragments was 79% in the coronal plane
      (range 40-100%) and 82% in the saggital plane (range 50-100%). We found this
      technique to be simple and reliable. It is particularly useful as the first phase
      of non-operative treatment of tibial shaft fractures by functional bracing.

PMID- 10645359
TI  - An unusual cause of false aneurysm of the descending aorta due to traumatic
      disruption of the aorta.

PMID- 10645360
TI  - Femoral neck fracture complicating intramedullary nailing of femoral shaft.
AB  - Intramedullary nailing of the femur is now established as a routine treatment for
      femoral shaft fractures. A recognised complication of this technique is the
      occasional jamming of the intramedullary reaming device within the femoral canal
      although surprisingly we could not find any reports in the literature. We
      describe a case in which the removal of such a reamer resulted in an iatrogenic
      intracapsular fracture of the femoral neck, a serious complication of this
      problem not previously described in the English literature. This resulted in an
      intraoperative decision to change the fixation device to accommodate this.

PMID- 10645361
TI  - Hypothenar hammer syndrome diagnosed by ultrasound.

PMID- 10645362
TI  - An introduction to selected chapters in bone biomechanics.
AB  - In the introduction to this Injury supplement, an attempt is made to elaborate on
      important rules of biomechanical research such as were developed and used in the
      Davos school of biomechanics. Tribute is acknowledged to the important
      contributions of S.M. Perren, M. Russenberger and S.G. Steinemann. The following
      principles are illustrated: 1. The development of a new technique or a new
      implant is justified when it is the solution of a clinical problem or a clinical
      complication. 2. The appropriate solution in engineering is often simple and
      elegant. 3. The first step of a biomechanical investigation concerning fracture
      treatment consists in establishing to which patients this study will apply. 4.
      For a testing instrument, freedom is important at the junction between the bone
      and the loading device. 5. A selection of bones should be made prior to the
      experiment in regard to the clinical population involved. 6. In our biomechanical
      investigations, we are not interested in a "statistically significant"
      difference, but in a "clinically significant" difference. The communications
      presented in this supplement of Injury are a tribute to the 30 "Perren'sche
      Jahre" (Perrenic Years) of what I call the School of Biomechanics in Davos.

PMID- 10645363
TI  - Strain gauges used in the mechanical testing of bones. Part I: Theoretical and
      technical aspects.
AB  - The internal restructuring of bone as a reaction to physiological load described
      by Wolff's law is related to both stress and strain in the bone. Bone is a rather
      brittle material, with nearly equal properties in tension and in compression:
      Elastic modulus E = 20 Gpa, tensile strength sigma tens = 200 Mpa (cortical
      bone). In biomechanics, it is very easy to assess strain using strain gauges. The
      theoretical and technical aspects specific to the use of strain gauges on bones
      are presented in this paper including how the measurements are taken and how the
      data is analyzed.

PMID- 10645364
TI  - Strain gauges used in the mechanical testing of bones. Part II: "In vitro" and
      "in vivo" technique.
AB  - How to choose and prepare the strain gauges for bonding on bones "in vitro" and
      "in vivo"? This communication aims to elucidate technical details and some
      applications: direct assessment of the axial load, the bending moment, and the
      torque applied to long bones by the physiological loads. As a typical example of
      application, we will show the assessment of stress protection due to plates on
      the bones in the sheep tibia.

PMID- 10645365
TI  - Strain gauges used in the mechanical testing of bones. Part III: Strain analysis,
      graphic determination of the neutral axis.
AB  - The problem addressed in this part is the analysis of the strain pattern within
      the bone, when the strain has been measured using strain gauges along the long
      axis of the diaphysis of a bone subjected to axial load, bending, or eccentric
      axial load. It is first necessary to obtain the position of the strain gauges
      using, for instance, computed tomography. The linear bending theory is then used
      to determine graphically the position of the neutral axis in a cross section and
      the strain field within the bone. An example of application is taken from the
      literature: Rybicky et al. (1) measured the reduction of strain within a plated
      horse metatarsus, relative to that of the intact bone. They made an analytical
      strain analysis. A comparison is made between the analytical results and the
      graphic ones, validating the graphic method.

PMID- 10645366
TI  - Loading model for the human femur taking the tension band effect of the ilio
      tibial tract into account.
AB  - A loading model permitting the application of relevant loads to the diaphysis and
      constructed on the basis of current knowledge of the biomechanics of the femur
      will be presented. This model takes into account the force acting through the
      ilio-tibial tract in the frontal plane and the forces acting on the condyles in
      the sagittal plane. There is compression on the femoral head and on the condyles
      and tension on the greater trochanter. Experimental verification using human
      cadaveric femora instrumented with strain gauges has shown that the adequate
      loading condition is: a line of force tangential to the femoral head a line of
      force tangential to the dorsal aspect of the distal junction of the diaphysis and
      metaphysis. Under these conditions, the calculated forces will accord well with
      values assessed in vivo. The model described here represents a simple procedure
      for experimental load application, producing realistic strain values. The
      proximal part of the bone is placed under tension on the dorsal aspect; the
      medial aspect is under compression. The strain pattern develops such that the
      tensile forces affect the anterior aspect distally and compression the dorsal
      aspect.

PMID- 10645367
TI  - The mechanics of internal fixation of fractures of the distal femur: a comparison
      of the condylar screw (DCS) with the condylar plate (CP).
AB  - Distal femoral fractures are rare and usually complex. Mostly, they are fixed
      with the Dynamic Condylar Screw (DCS) or the 95 degrees condylar plate (CP). The
      simplicity of applying the DCS compared with the CP led us to investigate whether
      any possible mechanical deficiencies of the CP would detract from its technical
      advantages, thus limiting the indications for its use in the treatment of
      fractures of the distal femur. An in vitro investigation was carried out to
      measure the stability of a Y-osteotomy (with and without medial metaphyseal bone
      defect) stabilized either with the CP or the DCS. 8 pairs of human cadaveric
      femora classified according to their bone density were used. CP and DCS were
      applied to 1 bone in each pair by means of three lag screws (anterior, posterior
      and through the plate). Physiological loading was simulated and measurements were
      taken at the level of the osteotomy in the frontal and sagittal planes in order
      to assess rotational instability and the amount of gap opening in the vertical
      branch of the osteotomy. There was no relevant difference in the mechanical
      properties of the two fixations for fractures without medial defect, even if the
      stability of the fixation was reduced by removing the distal screw. Furthermore,
      interfragmental movement was minimal. In the frontal plane, simulated closure
      resulted in closure of the medial branch of the osteotomy in every case without
      any opening of the vertical branch of the osteotomy. In the sagittal plane, the
      closure of all branches of the osteotomy was confirmed for 11 bones and a
      rotation of the condyle was observed in 5 bones (3 CP, 2 DCS). Removing the
      distal lag screw did not increase the instability. Even in osteoporotic bones,
      the DCS provided the same stability as the CP. For simple Y-osteotomies, the CP
      did not offer any technical or mechanical advantages. The stability in the
      frontal plane however was significantly reduced in osteotomies with medial
      defect. The amplitude of interfragmental movement on all bones fixed by the CP,
      except for 1 pair, was greater than those fixed by the DCS. The absence of the
      anterior lag screw did not reduce stability. However, the absence of the lag
      screw within the implant considerably weakend the fixation--more so for the CP
      than for the DCS. Instability reached a maximum without any lag screw at all,
      which again was more pronounced for the CP than for the DCS. The Dynamic Condylar
      Screw (DCS) must be regarded as the implant of choice both technically and
      mechanically even in osteoporotic bones, but the distal condylar block must be at
      least 4 cm in length.

PMID- 10645368
TI  - A biomechanical comparison of the antegrade inserted universal femoral nail with
      the retrograde inserted universal tibial nail for use in femoral shaft fractures.
AB  - Femoral shaft fractures with and without bony contact were simulated in cadaver
      specimens fixed with one of two different types of intramedullary locked nail
      systems; conventional antegrade nail fixation of the femur with the universal AO
      femoral nail or retrograde insertion in the femur with the universal tibial nail
      (a smaller diameter slotted nail) were utilized. Mechanical testing simulated one
      leg stance, and resultant deformation was measured in bending, torsion, and
      shortening. In stable fractures, fracture stability was similar to both devices,
      while in unstable fractures, the larger femoral nail was more stable.
      Furthermore, the simulation of single leg stance led to a coupled deformation of
      varus bending, axial shortening, and external rotation, which was dependent on
      bone geometry.

PMID- 10645369
TI  - Fracture healing of the sheep tibia treated using a unilateral external fixator.
      Comparison of static and dynamic fixation.
AB  - It is generally accepted that when a fracture is treated with external fixation,
      dynamization of the fixation accelerates formation of the bony callus by
      transferring part of the functional loads. The aim of the research presented here
      was to validate this principle using in vivo measurements of callus stiffness. We
      created a transverse fracture in the mid third of the tibial shaft in 12 sheep
      and maintained a 3 mm gap between the fragments for 3 weeks. Two types of
      unilateral external fixators were applied. Axial loading was permitted
      (dynamization) from the fourth week onwards in 6 animals. In the other 6 animals,
      fixation remained static for both types of fixation. Weekly measurements of
      callus stiffness were obtained using a goniometer and load cell to assess bending
      stiffness. Two slightly different fixators were used. Callus formed in all 12
      animals. Callus stiffness increased exponentially to reach the degree of
      stiffness measured on the contralateral side. There was no clear difference in
      healing between the two types of fixations nor between dynamic and static
      fixation. If a unilateral fixator was applied which did not maintain absolutely
      rigid fixation, the fracture generally healed well even without contact between
      the fragment ends. If the process of callus formation had begun normally, dynamic
      fixation offered no further benefit. Measuring the stiffness of the callus with
      an adequate measurement apparatus in vivo indicated that the fixator could be
      removed earlier than would have been authorized on the basis of radiological
      evidence alone.

PMID- 10645370
TI  - Measuring infant spatial working memory using a modified delayed-response
      procedure.
AB  - Infant spatial working memory was assessed in 96 nine-month-old human infants
      using a modification of the delayed-response procedure. A person was the hidden
      stimulus, gaze was used as the response modality, the response context was a
      naturalistic "peek-a-boo" game, and a salient cue (i.e. curtains opening to
      reveal two windows) was used to evoke responses. Infants responded on most trials
      and performed significantly above chance in delay conditions of 10 and 20
      seconds. Reinforcement affected performance, but performance was above chance
      even in a 0% reinforcement condition. These procedural variations boost estimates
      of infant spatial working memory over previous estimates and enhance the
      usefulness of the delayed-response procedure as a marker task for infant spatial
      working memory.

PMID- 10645371
TI  - The role of distinct components of visuo-spatial working memory in the processing
      of texts.
AB  - Three experiments examined whether visuo-spatial working memory is involved in
      processing spatial descriptions and tested whether different processes within the
      visuo-spatial working memory are involved in processing different kinds of
      descriptions. Experiment 1 considered the performance of two groups with low and
      high visuo-spatial working memory abilities in memorizing the description of a
      city. The high visuo-spatial working memory group had a better memory performance
      than the low visuo-spatial working memory group. In Experiment 2, the Brooks'
      (1967) task was adapted to investigate the selective interference of four
      different concurrent tasks (a verbal, a visual, a spatial-sequential, and a
      spatial-simultaneous task) on the recall of short abstract, visual and spatial
      texts. In Experiment 3, the same distinction was extended to longer and natural
      descriptions of different environments. Participants listened to three
      descriptions: a description that mainly stressed the visual properties of an
      environment, a description from a route perspective, and a description from a
      survey perspective. They also performed the concurrent visual and the two
      concurrent spatial tasks proposed in Experiment 2. Results of Experiments 2 and 3
      demonstrated that tasks involving different cognitive resources (i.e. the verbal,
      visual, spatial-simultaneous, and the spatial-sequential tasks) had a
      differential interference with the free recall of different kinds of
      descriptions.

PMID- 10645372
TI  - Metacognition and memory for nonoccurrence.
AB  - A familiar hypothesis about the recognition of distractor items as "new" is that
      it depends heavily on a metacognitive strategy in which the memorability or
      salience of the distractor is evaluated: if the item was deemed salient or
      memorable and yet no memory trace for it can be found, then it must not have been
      studied (e.g. Strack & Bless, 1994). In four experiments, no evidence was found
      to support this metamemory hypothesis. Experiments 1a, 1b, and 2 demonstrated
      that the judged salience of the stimuli did not predict participants' recognition
      judgements for distractors. In Experiments 3a and 3b, instructional manipulations
      designed to affect the ostensible metacognitive process failed to affect the
      recognition judgements. Finally, Experiment 4 indicated that confidence
      judgements do not support the predictions of the metamemory hypothesis.

PMID- 10645373
TI  - The specificity of memory enhancement during interaction with a virtual
      environment.
AB  - Two experiments investigated differences between active and passive participation
      in a computer-generated virtual environment in terms of spatial memory, object
      memory, and object location memory. It was found that active participants, who
      controlled their movements in the virtual environment using a joystick, recalled
      the spatial layout of the virtual environment better than passive participants,
      who merely watched the active participants' progress. Conversely, there were no
      significant differences between the active and passive participants' recall or
      recognition of the virtual objects, nor in their recall of the correct locations
      of objects in the virtual environment. These findings are discussed in terms of
      subject-performed task research and the specificity of memory enhancement in
      virtual environments.

PMID- 10645374
TI  - Memory for word locations in reading.
AB  - Sentences were presented in various spatial formats, and readers localised one
      word of each sentence using a mouse cursor directly after reading. There was a
      localisation advantage for cumulative over single-word displays, for left-to
      right presentation over presentation in a 3 x 3 grid, and for complete over
      incomplete sentences. Comparing performance for predictable and unpredictable
      word locations suggests that word location memory in reading decays within three
      seconds to a span of only 2-3 entries, and that readers can then reconstruct word
      locations from item memory. Implications for the role of spatial cognition in
      reading are discussed.

PMID- 10645375
TI  - Mood and prospective memory.
AB  - This study considered the relationship between mood states, prospective memory,
      and retrospective memory among a non-clinical sample of undergraduate students.
      Multiple regression analyses with simultaneous entry of variables were undertaken
      to examine the unique contributions of the alternate memory test and the
      emotional states to memory test performance. As expected, retrospective free
      recall performance and anxiety made unique and significant contributions to
      performance on the prospective memory task. However, only prospective memory
      performance emerged as a significant predictor of retrospective free recall. It
      is suggested that none of the mood measures emerged as a significant predictor of
      retrospective memory performance because they do not account for unique variance.
      In contrast, the relationship between anxiety and prospective memory appears to
      be due to factors uniquely associated with anxiety, and unrelated to depression.

PMID- 10645376
TI  - Cognitive effort and recollective experience in recognition memory.
AB  - The difficulty of the cognitive operations required to process study items was
      manipulated in two experiments investigating recollective experience. In
      subsequent recognition tests, subjects indicated whether their recognition
      judgements for items processed in these tasks were based on recollection
      ("remember" responses) or on familiarity ("know" responses). In Experiment 1
      target items were presented in the context of a category decision task. It was
      found that remember responses increased with the difficulty of the category
      decision. For positive instances, remember responses were greater for items of
      low instance frequency than for items of high instance frequency, while for
      negative instances remember responses were greater for items from similar
      categories than for items from dissimilar categories. These effects were not
      present in know responses. In Experiment 2, remember responses were more frequent
      when study items had been presented in the form of anagrams to be solved than
      when they had been presented in the form of words to be read aloud. The incidence
      of know responses was not affected by the format in which study items were
      presented. Source judgements were also more accurate when recognition was based
      on recollection. It is argued that the type of conscious awareness experienced
      during recognition is determined by the knowledge activated by items presented in
      the recognition test, which in turn is determined by the nature of the operations
      engaged at encoding.

PMID- 10645377
TI  - When the event is more than the sum of its parts: 9-month-olds' long-term ordered
      recall.
AB  - Research suggests that 9-month-old infants are able to recall single object
      specific actions over delays of 24 hours. In the present research we investigated
      whether 9-month-olds are able to recall over more extended delays, and to recall
      the temporal order of events, as well as the individual actions in them. In
      addition, we investigated whether recall can be enhanced by pre- and/or re
      exposure to target events. Using elicited imitation of novel, multi-step event
      sequences, we demonstrated that, as a group, 9-month-olds are able to recall
      target actions after delays of five weeks. However, after this long delay, only
      45% of the infants recalled the temporal order of the events. Re-exposure to
      events during the delay interval proved necessary for boys, but not for girls;
      pre-exposure to events did not affect later recall. The implications of
      individual differences in infants' recall ability for the understanding of the
      development of the neural correlates of declarative memory are discussed.

PMID- 10645378
TI  - Mood congruence and depressive deficits in memory: a forced-recall analysis.
AB  - Two experiments examined the contribution of reporting biases to mood-congruent
      recall patterns and diminished levels of recall frequently associated with
      depressed mood states. In Experiment 1, participants classified as dysphoric (n =
      14) or nondepressed (n = 21) on the basis of scores on the Beck Depression
      Inventory and the Profile of Mood States made self-referential judgements
      regarding a series of affectively valenced words. Subsequently they were given an
      unexpected forced-recall test, which encouraged guessing to meet the output
      requirement (i.e. 40 responses) of the test. Nondepressed subjects confidently
      reported more positive words than dysphoric subjects, but the latter produced
      significantly more correct guesses of words that were positively valenced.
      Similar findings were obtained in Experiment 2, in which dysphoric (n = 40) and
      nondepressed subjects (n = 40) performed both self-referent and orthographic
      judgements of affectively valenced words, followed by either a free- or forced
      recall test. The findings suggest that positive and negative trait words were
      adequately encoded in memory, but, consistent with cognitive theories of
      depression, their accessibility to retrieval was differentially limited. In
      addition, however, the results implicate an important contribution of diminished
      motivation and/or conservative report criterion in the manifestation of
      depression-related biases and deficits in recall.

PMID- 10645379
TI  - The effects of recent exposure on general-knowledge estimation.
AB  - Recent exposure to general-information facts creates a tendency to claim that the
      facts had been known prior to their exposure. In Experiment 1, this "illusory
      knowledge effect" occurred even when participants did not have to demonstrate
      their knowledge by recalling part of the fact. In Experiment 2, the effect was
      found for both true and false facts. These findings suggest that the tendency to
      claim that recently presented facts had been previously known is caused by their
      enhanced familiarity. Accounts that would attribute this effect entirely to an
      underestimation of participants' knowledge of the new facts or to participants'
      intentional inflation of their prior knowledge states are not supported by these
      results.

PMID- 10645380
TI  - The role of memory in the Tower of London task.
AB  - The Tower of London (TOL) task is widely used as a neuropsychological test of
      planning. Relatively little is known of the cognitive components of the task, and
      in particular the role of memory in performance. The current studies on normal
      adults looked at the role of verbal and spatial working memory in the TOL. The
      effects of verbal and visuospatial dual-task manipulations on TOL performance
      were examined in an experiment with 36 participants. Both verbal and visuospatial
      executive secondary tasks caused poorer performance on the TOL; however,
      concurrent articulatory suppression enhanced performance. The results suggest
      that executive and spatial components are important in the task, and raise
      questions about the role of preplanning in the TOL.

PMID- 10645381
TI  - Recall accuracy and illusory memories: when more is less.
AB  - In two experiments it was revealed that manipulations that increased recall of
      studied list items also increased false recall of theme-related, critical
      nonpresented words. In Experiment 1 subjects listened to a series of short word
      lists, each containing items associatively related to a theme, while engaging in
      either semantic or nonsemantic processing. On an immediate free recall test
      semantic processors demonstrated greater correct recall as well as more illusory
      memories of critical nonpresented items than nonsemantic processors. In
      Experiment 2, the short study lists were combined to form longer lists that were
      presented either blocked by theme or in a random presentation order. Retention
      interval was also varied as participants were tested either immediately, one week
      after, or three weeks after the study phase. Presenting the target items in a
      blocked, as opposed to random, format increased recall accuracy, but this was at
      the expense of a higher intrusion rate for theme-consistent items. Interestingly,
      the level of false memories was not affected by retention interval even though
      typical decrements in the recall of study items were observed over time. The
      results of these experiments highlight the persistence of the false memory
      effect, as well as pointing to several factors, primarily semantic processing,
      that may lead to the creation of false memories. Interpretations are offered
      within the theoretical frameworks of source monitoring and fuzzy trace theory.

PMID- 10645382
TI  - Do visual problems cause dyslexia?

PMID- 10645383
TI  - Both coloured overlays and coloured lenses can improve reading fluency, but their
      optimal chromaticities differ.
AB  - Some individuals read more fluently when the text is coloured: i.e., when
      coloured sheets of plastic (overlays) are placed upon the page, or when coloured
      lenses are worn. Overlays provide a surface colour whereas lenses mimic a change
      in the colour of a light source. The neural mechanisms that underlie colour
      constancy ensure that the chromaticity of overlays and lenses is processed
      differently by the visual system. We investigated (1) the relationship between
      the optimal colours of overlays and lenses, and (2) how reading rate is affected
      by a particular colour in overlays and lenses. In 100 patients we noted (1) the
      overlay(s) chosen from among the 29 combinations of the 10 IOO Intuitive Overlays
      which sample chromaticity systematically and (2) the chromaticity co-ordinates of
      the lenses subsequently chosen using the intuitive Colorimeter, a device
      providing a light source that can be adjusted in hue, saturation and luminance
      independently. The relationship between the chromaticities of the overlays and
      the lenses showed considerable variation. In a second study, patients attending
      the Specific Learning Difficulties clinic at the Institute of Optometry, London,
      were given overlays to use for two months. Seventeen who derived benefit were
      examined using the Intuitive Colorimeter. Patients were asked to read aloud
      randomly ordered common words (Wilkins Rate of Reading Test): (1) with no colour,
      (2) with the chosen overlay, (3) with lenses matching the chosen overlay and (4)
      with lenses matching the Colorimeter setting. The aids increased reading rate
      significantly only in conditions (2) and (4). There was no significant
      improvement when lenses matching the overlay colour were used, and under this
      condition the reading rate was significantly poorer than in conditions (2) and
      (4). The colour of a lens will improve reading only if it is selected under
      conditions that mimic a change in the colour of a light source: coloured overlays
      give no clinically reliable guide to optimal lens colour.

PMID- 10645384
TI  - The development of myopia in Hong Kong children between the ages of 7 and 12
      years: a five-year longitudinal study.
AB  - The purpose of this work was to characterize the development of refractive error
      in Hong Kong children between the ages of 7 and 12 years. A non self-selected
      sample of 7-year old children was recruited and followed for 5 years, non
      cycloplegic refractions being carried out annually. A life-table was used to
      determine myopia incidence and prevalence. The mean annual change in the
      spherical equivalent refraction (SER) was -0.32 D; 75 out of 83 subjects followed
      for 5 years became less hyperopic or more myopic, the maximum progression
      occurring between 9 and 11 years of age. The mean change in SER over the 5 years
      in children who were myopic at age 12 years was significantly greater than that
      in children who remained non-myopic. The incidence of myopia at age 7-8 years was
      9% and at age 11-12 years was 18-20%. At age 7 years the prevalence of
      progressive myopia was 1.6% and 2.5% of subjects had anisometropia. Any treatment
      to prevent myopia should start by the age of 6 years and treatment to retard
      development should commence before age 9 years.

PMID- 10645385
TI  - Paediatric community vision screening--a new model.
AB  - The purpose of this study was to establish if a community based model using a
      Hospital Optometrist and Community Orthoptist can provide a practical secondary
      vision screening service for children. These professionals working in an Inner
      London Health Centre, assessed children who had failed primary vision screening.
      In total 483 new patients were seen between April 1994 and March 1996 with the
      largest referral source being the school nurse screening programme. The majority
      were managed by the team with a total onward referral rate to the Hospital Eye
      Service of 14%. In 78% of these cases the consultant's diagnosis agreed with the
      reason for referral. Where the consultant's diagnosis differed the children were
      identified as normal or a variant of normal. This model of care provides a 'one
      stop service' where a child identified as having a potential visual problem at
      primary screening can be assessed, refracted and provided with spectacles in a
      local setting without hospital referral. Referrals to the Hospital Eye Service
      are considerably reduced and a convenient service is provided for parents and
      children.

PMID- 10645386
TI  - Smoking and lens optical density.
AB  - Epidemiological evidence indicates that smoking increases the risk of age-related
      cataract. No information is currently available, however, on the effects of
      smoking on the lens prior to cataract development. In this study, we relate
      smoking behavior to lens optical density (OD) in younger individuals without
      frank cataract. Fifty three never smokers and 41 current smokers were compared
      directly. Thirty one past smokers were tested to examine the relationship between
      years since smoking cessation and lens OD. Lens OD was measured psychophysically
      by comparing scotopic thresholds obtained at 410 (measuring) and 550 nm
      (reference). Stimuli were presented in Maxwellian view. The smokers in the sample
      smoked an average of 17.3 +/- 11.3 cigarettes/day for 20.4 +/- 12 years. No
      significant differences (other than in fat intake) were found between the smokers
      and nonsmokers in iris color, dietary patterns, or age. Despite their overall
      similarity, lens OD was significantly (p = 0.005) higher in the smokers.
      Moreover, we found a significant dose-response relationship (p = 0.02) between
      smoking frequency and lens OD. There was also a weak relationship between smoking
      frequency and lens OD for past smokers (p = 0.06), but no relationship between
      lens OD and years since smoking cessation. Our data indicate that smoking is
      directly related to age-related increases in lens OD throughout life and that
      these increases persist even after smoking cessation.

PMID- 10645387
TI  - Multifocal ERG changes in glaucoma.
AB  - The multifocal electroretinogram (MERG) can assess regional retinal responses
      using analysis which gives both first-order and second-order nonlinear responses
      from multiple retinal regions. The retinal responses from both types of analysis
      showed amplitude reduction in glaucoma, suggesting that the outer and inner
      retinal layers are affected. These findings are in accord with the damage which
      has been reported in advanced glaucoma. The macular response showed a larger
      amplitude reduction in b-waves (first-order response) and N2P (second-order
      response) than did peripheral retinal responses. This indicates that loss of
      macular response is an important sign in glaucoma.

PMID- 10645388
TI  - The far interpupillary distance. A gender-specific variation with advancing age.
AB  - A knowledge of the magnitude of the far interpupillary distance (FIPD) in
      relation to a specific population is of clinical, practical and theoretical
      interest. A FIPD database is presented here, comprising material collated from
      the spectacle dispensing records of n = 1800 subjects seen in routine optometric
      practice. All measurements were taken by the author on healthy Caucasian (white,
      Northern European) males and females. The data were equi-partitioned either
      across three age bands (16-25, 26-40, 41-65 years: mixed refractive types, total
      n = 900) or between the three distance refractive types (emmetropia,
      hypermetropia, myopia: all subjects aged between 41-65 years, total n = 900). A
      consistent gender difference (male > female) was confirmed throughout this
      material, irrespective of age group; refractive type, however, had no influence
      on the magnitude of this facial parameter. Summary results of this anthropometric
      survey are presented in tabular form, facilitating reference by ophthalmic and
      dental clinicians and by the designers of binocular optical instruments. There
      was also revealed evidence of a gender-specific pattern of change in the FIPD
      variable with advancing age. An approximately 3% increase in the magnitude of the
      human FIPD from the mid-teens to later middle age was attained in males by early
      middle age, being little altered thereafter: in contrast females continued to
      record an increase in this facial parameter into later middle age. An explanation
      for this hitherto unremarked feature of human facial anthropometry might be
      sought in the gender-specific changes post-puberty of the cranial skeletal
      anatomy and in the soft tissues of the orbital region.

PMID- 10645389
TI  - Prevention of form-deprivation myopia with pirenzepine: a study of drug delivery
      and distribution.
AB  - The present study investigated the drug distribution and elimination profiles in
      ocular tissues of pirenzepine, a selective M1 muscarinic antagonist known to
      inhibit myopia. Results demonstrate that (1) Intravitreal injections of the M1
      selective antagonist pirenzepine were more effective at preventing form
      deprivation myopia than subconjunctival injections. (2) Maximum drug levels were
      reached within 1 hr for both retina and sclera following intravitreal (28 and 11
      nanomole) and subconjunctival (0.25 and 1 nanomole) injection. Intravitreal
      injection proved a more effective route of drug delivery to all ocular tissues
      compared to subconjunctival injection. (3) Elimination times of pirenzepine from
      ocular tissues were much shorter than those reported for blood plasma. (4)
      Histological examination revealed no evidence of gross toxic effects at doses
      effective in inhibiting induced axial myopia. In conclusion, pirenzepine was
      effective at reducing form-deprivation myopia in a dose-dependent manner with no
      evidence of disruption to the retina. However, results were not conclusive as to
      where pirenzepine may have its site of action in preventing form-deprivation
      myopia.

PMID- 10645390
TI  - Effects of induced transverse chromatic aberration from an afocal prismatic lens
      on spatio-temporal sensitivity.
AB  - The goal of this study was to evaluate the effect of ophthalmic lens-induced
      transverse chromatic aberrations (TCA) in natural viewing conditions on spatio
      temporal thresholds. Three psychophysical experiments were performed; the first
      isolating the spatial component, the second isolating the temporal component and
      the third assessing spatio-temporal combinations. Taken together, the results
      show that TCA has profound effects on medium to high spatial frequencies (above 1
      cpd) consistent with previous studies, and that the ratio of deficit TCA/blur can
      be higher than 2:1 for equivalent dioptric strengths. Furthermore, the results of
      Experiment 1 and 3 taken together show that the relative sensitivity loss caused
      by TCA can differ significantly between individuals and that a possible factor
      for this differential loss is the overall baseline spatio-temporal sensitivity
      profile of the individual.

PMID- 10645391
TI  - The influence of heterophoria measurements on subsequent associated phoria
      measurement in a refractive routine.
AB  - The influence of measuring heterophoria on a subsequent associated phoria
      measurement was investigated in 50 subjects. After refraction, heterophoria was
      measured by either von Graefe's technique or Maddox rod and wing. The effect of
      these procedures was assessed by associated phoria measurements taken before and
      after the dissociated measures. It is shown that subjects with a history of
      unstable binocular vision are likely to have an associate phoria induced or
      changed by the previous dissociated phoria measurement, particularly if von
      Graefe's technique is employed. It is recommended that, especially for near,
      associated phoria should be assessed before the dissociated phoria in subjects
      who are regarded as having a history of unstable binocular vision.

PMID- 10645392
TI  - An extended role for the hospital optometrist.
AB  - The management of patients within shared care programmes would seem to have
      significant benefits in terms of individuals' convenience, addressing resource
      needs and expanding professional horizons. To date, these schemes have typically
      concentrated on the monitoring of patients with diabetes and glaucoma. At
      Moorfields Eye Hospital, we attempted to develop the role of the hospital
      optometrist by establishing a study to evaluate the clinical appraisal of new
      referrals in a busy out-patient clinic. The results showed a high level of
      diagnostic accuracy which suggests that the role of hospital optometrists may be
      successfully extended to include some aspects of patient evaluation not typically
      undertaken.

PMID- 10645393
TI  - Assessment of fogging resistance of anti-fog personal eye protection.
AB  - The propensity for occupational eye protectors to fog in warm and moist
      conditions is often offered as a reason by workers not to wear occupational eye
      protection even where mandatory eye protection areas have been specified. A study
      of eye protection practices in the New South Wales coal mining industry
      identified the number one issue in underground coal mine conditions as being
      fogging of eye safety wear. Conventional anti-fog treatments and cleaners were
      considered by the miners as completely inadequate in these conditions. At the
      time of the study claims were being made for a new generation of lens treatments.
      These merited evaluation. Spectacles and goggles claimed to be fog resistant were
      obtained from manufacturers and suppliers and subjected to the test set out in BS
      EN 168 and the compliance criterion of BS EN 166. Some lenses claimed to be fog
      resistant failed the requirement, some new technology lenses showed arguably
      superior performance but failed the criterion of the standard. Modifications to
      the test procedure of BS EN 168 and acceptance criteria of BS EN 166 are
      proposed.

PMID- 10645394
TI  - Ocular adverse reactions to tamoxifen--a review.

PMID- 10645395
TI  - Management of patients with age-related cataract.
AB  - The majority of patients referred because of age-related cataract should be
      referred when their ability to function in their desired lifestyle is reduced due
      to poor vision. Generally the decision to refer should not be based on visual
      acuity, and the referral letter should reflect this. Patients who are not
      referred should not just be monitored until referral. There are several simple
      strategies for improving their vision which should be discussed with the patient,
      such as broad-brimmed hats or caps, typoscopes, anti-reflection coats and UV
      blocking tints. There are also several strategies which may delay the progress of
      their cataract, which include reducing UV exposure and cigarette smoking and
      taking anti-oxidant vitamin supplements. These could also be discussed with the
      patient.

PMID- 10645396
TI  - Optometrists' referrals to the Hospital Eye Service.

PMID- 10645397
TI  - Advocating clinical optometry.

PMID- 10645398
TI  - Proliferative verrucous leukoplakia and its related lesions.
AB  - Proliferative verrucous leukoplakia (PVL) is a unique type of clinical oral
      leukoplakia. Enigmatic in etiology, PVL behaves in a far more aggressive fashion
      than other forms of leukoplakia. Its aggressiveness relates not only to a high
      recurrence rate, but more so to a very high level of and relentless progression
      from a localized simple keratosis to extensive oral disease and squamous
      carcinomas of verrucous, or conventional squamous cell type. Diagnosis is often
      late in the protracted course of PVL with the disease in an advanced stage when
      it is especially refractory to treatment. Within the histologic spectrum that is
      seen in PVL, usually as a function of time, are: (1) verrucous hyperplasia (VH),
      a histologically defined lesion; (2) varying degrees of dysplasia; and (3) three
      forms of squamous cell carcinoma: verrucous, conventional and, according to some,
      papillary squamous cell carcinoma. Each of these are discussed both within and
      outside the context of PVL. VH is a forerunner of verrucous carcinoma and the
      transition is so consistent that the hyperplasia, once diagnosed, should be
      treated like verrucous carcinoma. VH is not only an oral lesion; it can occur in
      the upper airway (sinonasal tract and larynx) where it is not usually found
      within a maternal soil of PVL. Papillary squamous cell carcinoma has been a
      loosely defined neoplasm, more often considered a verrucal type of malignancy. It
      nonetheless is a distinct clinicopathologic entity, separate from verrucous
      carcinoma and without a predilection for the oral cavity or an association with
      PVL.

PMID- 10645399
TI  - Familial risk in head and neck squamous cell carcinoma diagnosed before the age
      of 45: a population-based study.
AB  - This population-based study analyses familial risk as a factor in the development
      of head and neck squamous cell carcinoma before the age of 45. Two different
      designs were used: (1) estimation of standardised incidence ratios (SIRs) for
      cancer among first-degree relatives of 127 young head and neck cancer probands;
      and (2) estimation of odds ratios (ORs) for developing head and neck cancer
      associated with cancer in a first-degree relative. SIRs of cancer of the
      respiratory and upper digestive tract (lungs, oesophagus, and smoking-related
      head and neck sites [RUDT]) for first-degree relatives were 4.3 (95% confidence
      intervals or 95% CI of 1.6-9.5) for female patients, 1.0 (95% CI = 0.3-2.6) for
      male patients and 1.9 (95% CI = 0.9-3.5) for both sexes combined. ORs for head
      and neck cancer before the age of 45, in association with cancer of RUDT in a
      first-degree relative were 5.0 (95% CI = 1.4-17.3) for women, 1.1 (95% CI = 0.3
      3.3) for men, and 2.0 (95% CI = 0.9-4.4) for both sexes combined. Hence, when
      analysing both sexes combined, our familial risk estimates for head and neck
      cancer showed non-significant increases. An explanation for the unexpected sex
      asymmetry in familial risk could be an interaction between inherent cancer
      susceptibility and a female biological characteristic. Alternatively, it could be
      artefacts caused by differences in familial smoking habits.

PMID- 10645400
TI  - Modulation of thyroid hormone-dependent Na+,K(+)-ATPase induction in cultured
      human submandibular gland cell lines, HSG cells.
AB  - The hormonal regulation of Na+,K(+)-ATPase enzyme activities and induction of the
      alpha subunit protein of the enzyme in the human submandibular gland (HSG) were
      studied by use of cultured HSG cells. We treated HSG cells with thyroid hormone,
      androgen, mineralocorticoid, and glucocorticoid, singly or in combination. 3,5,3'
      Triiodothyronine (T3), 5 alpha-dihydrotestosterone (DHT), and aldosterone (Ald)
      induced neither Na+,K(+)-ATPase enzyme activity nor its protein. On the other
      hand, dexamethasone (Dex) induced both Na+,K(+)-ATPase enzyme activity and the
      alpha subunit protein level to 128% of the control. The effects of Dex in
      combination with either T3 or DHT were similar to the effect of Dex alone.
      Treatment in combination with Dex and Ald increased the enzyme activity and alpha
      subunit protein level to 160%, synergistically. These increased Na+,K(+)-ATPase
      enzyme activities were shown to be dependent on their protein levels induced by
      the hormones. Contrary to the previous evidence that Na+,K(+)-ATPase of ducts in
      the salivary gland are thyroid hormone inducible, HSG cells had an insignificant
      response to thyroid hormone in the present study. Also, Na+,K(+)-ATPase enzyme
      activity and its alpha subunit protein were not induced by any kind of combined
      treatments with T3. Furthermore, T3 did not cause intracellular calcium
      mobilization in HSG cells. In view of all data taken together, we suggest that
      HSG cells lack the thyroid hormone receptor, which is necessary for Na+,K(+)
      ATPase induction in human salivary gland.

PMID- 10645401
TI  - Risk factors for oral and pharyngeal cancer in never smokers.
AB  - Information on the etiology of oral and pharyngeal cancer in never smokers should
      help us to understand and quantify risk factors for the disease in the absence of
      the residual confounding and interaction by smoking. Out of a total of 528 cases
      with histologically confirmed incident cancers of the oral cavity and pharynx, 42
      (10 men and 32 women) who described themselves as lifelong non-smokers were
      considered. Controls were 864 lifelong non-smokers (442 men and 422 women)
      admitted to hospital for acute, non-neoplastic, non-alcohol-related conditions.
      The major risk factor for cancer of the oral cavity and pharynx in never smokers
      was alcohol consumption (mainly wine) with an odds ratio (OR) about three-fold
      higher in drinkers than non-drinkers. A direct relation was also found for the
      duration of the habit, with an OR of 3.6 (95% confidence intervals, CI, 1.2-11.2)
      for drinking for 35 years or longer. Among the few selected indicator foods
      considered, a direct association was found with butter (OR 2.7, 95% CI 1.4-5.1
      for high intake compared to low), and a non-significant inverse association with
      carrots (OR 0.6, 95% CI 0.3-1.3) and fresh fruit (OR 0.7, 95% CI 0.3-1.6) for the
      highest tertile of intake compared to the lowest. Thus, even in the absence of
      smoking, reducing alcohol and saturated fat intake and increasing fruit and
      carrot consumption may have favorable effects on oral and pharyngeal cancer risk.

PMID- 10645402
TI  - p53, p21, Rb, and MDM2 proteins in tongue carcinoma from patients < 35 versus >
      75 years.
AB  - Relatively rare squamous cell carcinomas of the tongue in young patients may be
      associated with different etiologic factors and pathogenetic mechanisms than
      carcinomas from the same site in older patients. Alterations in cell cycle
      proteins likely contribute to the biologic behavior of these neoplasms. The
      purpose of this investigation was to evaluate cell cycle proteins (p53, p21, Rb,
      MDM2) in lateral tongue cancers from patients at the two ends of the age
      spectrum. All available archived lateral tongue carcinomas from patients < 35
      years (n = 36, 23 males and 13 females) were sectioned, immunohistochemically
      stained, and evaluated. Protein expression was scored as percent positive nuclei.
      An equal number of sequentially accessioned lateral tongue specimens from
      patients > 75 years (23 males and 13 females) were stained and compared. Positive
      p53 staining was seen in 18/36 of the < 35-year group versus 24/36 of the > 75
      year group (p = 0.149). Increased p21 staining (both percent of positive cells
      and intensity) was evident in 25/32 of the < 35-year group versus 24/32 of the >
      75-year group (p = 1.0). Increased p21 expression was seen in both p53-positive
      and -negative cases in both age groups. Rb protein was increased in 16/29 of the
      < 35-year group versus 17/26 of the > 75-year group (p = 0.58). Fourteen cases
      (4/35 vs 10/36, p = 0.135) showed positive MDM2 staining; MDM2-positive cases
      were also p53 positive in 4/4 younger and 8/10 older patients. We conclude that
      p53, p21, Rb, and MDM2 are over-expressed in lateral tongue cancers, and that
      immunohistochemical profiles are heterogeneous. A p53-independent pathway of p21
      induction is supported by the results; p53 suppression may be associated with
      MDM2 protein expression in a subset of cancers. Significant differences in the
      expression of p53, p21, Rb, and MDM2 proteins are not evident in lateral tongue
      carcinomas from patients < 35 years as compared to patients > 75 years.

PMID- 10645403
TI  - p53 tumor suppressor gene as a clonal marker in head and neck squamous cell
      carcinoma: p53 mutations in primary tumor and matched lymph node metastases.
AB  - In order to define the diagnostic value of p53 tumor suppressor gene as a clonal
      marker in head and neck squamous cell carcinoma (HNSCC), we investigated p53
      mutations in primary tumors (PT) and matched lymph node metastases (LNM); the
      underlying question being whether differentiation between metastatic disease of a
      known PT or (a metastasis of) a synchronous or metachronous second tumor is
      possible by means of p53 sequencing-based mutation analysis. In 15 PT, the p53
      status was analyzed, following RNA isolation, cDNA synthesis and polymerase chain
      reaction amplification, by direct sequencing full-length mRNA. Mutations thus
      found were confirmed by DNA sequencing analysis of the corresponding exon in the
      PT. When RNA isolation was defective, DNA sequencing analysis of exons 1 through
      11 was performed. In the matched LNM, DNA analysis of the corresponding exon was
      performed to prove the presence of the same p53 mutation. In the event of small
      clones not detectable by direct sequencing, an oligo ligation assay was developed
      to detect a specific mutation. The presence of germline mutations was excluded by
      DNA sequencing analysis of the corresponding exon of peripheral blood leucocytes.
      In 14 PT (94%), a mutation was identified. In one PT, no p53 mutation could be
      identified either after full-length mRNA sequencing or after sequencing exons 1
      through 11. In all cases of PT and matched LNM, the mutations proved to be
      identical. We conclude that p53 mutations develop in carcinogenesis before
      metastases occur and are maintained during metastasis. Consequently, p53 may
      serve as a clonal marker not susceptible to change during tumor metastasis. This
      merits further exploration of the application of p53 mutation analysis in
      differentiating between metastatic disease from a known PT versus a metastasis of
      another second PT.

PMID- 10645404
TI  - The detection of unknown primary tumors in patients with cervical metastases by
      dual-head positron emission tomography.
AB  - A dilemma may occur in relation to patients with cervical metastases appearing as
      the first sign of malignancy in the head and neck region. In these patients, the
      location of the involved lymph nodes may indicate the location of the primary
      tumor. However, in two or three per cent of the patients, the primary tumor
      cannot be identified in the diagnostic workup. The aim of the present study was
      to investigate the possibility of identification of primary tumors in patients
      with cervical metastases of unknown origin, by the use of 2-(fluorine-18)fluoro
      deoxy-D-glucose (FDG) dual-head positron emission tomography (PET). Ten
      consecutive patients with a cervical metastases of unknown origin were studied
      with FDG, using a dual-head PET camera. After the injection of 185 MBq (5 mCi) of
      FDG, images were performed of the head, neck and chest. In addition, endoscopy
      and biopsies were carried out with knowledge of the PET study. In patients in
      whom a primary tumor could not be identified, a follow-up of at least 6 months
      was used as a control. In five out of 10 patients a primary tumor was identified
      by FDG-PET. In one patient multiple sites of uptake were seen, and this was found
      to be consistent with non-Hodgkin lymphoma. In five patients, additional sites of
      increased uptake were found, these being consistent with unknown metastatic
      disease. Finally, in six patients, the initial treatment plan was changed due to
      the PET result in five of them. In one patient, the primary tumor was resected
      revealing a lesion with a diameter of 6 mm. The detection of FDG in patients with
      cervical metastases of unknown origin by the use of a dual-head PET camera is a
      valuable diagnostic tool in the identification of primary lesions.

PMID- 10645405
TI  - Development of diffuse invasive (grade 4D) human oral squamous cell carcinoma
      model in severe combined immunodeficiency mice: microangioarchitectural analysis
      and immunohistochemical study.
AB  - Among oral squamous cell carcinomas (OSCCs), the diffuse invasive (grade 4D)
      tumour exhibits the highest degree of malignancy. The TSU cell line, which has
      been established from a grade 4D OSCC, has not been successfully grown even in
      immuno-suppressed hosts. Here, invasive cells were selected by the repeated
      inoculation of TSU cells with Matrigel and gelatin sponge into the subcutaneous
      tissue of nude mice. The selected cells formed oral tumours temporarily in nude
      mice and produced lethal tumourgenicity in severe combined immunodeficiency
      (SCID) mice without the addition of other materials. The microangioarchitecture
      of the tumours in SCID mice showed neovascularization and the formation of a
      vascular network. An immunohistochemical study demonstrated that the expressions
      of vascular endothelial growth factor and matrix metalloproteinase-2 were strong,
      whereas desmoglein-1 and type-IV collagen were absent. These findings suggested
      that the loss of intercellular junctions and dissolution of basement membranes
      may underlie the pathogenesis of diffuse invasive growth in grade 4D tumours.

PMID- 10645406
TI  - Induction of apoptosis in human oral squamous carcinoma cell lines by protein
      phosphatase inhibitors.
AB  - To determine whether protein phosphorylation and dephosphorylation can affect
      apoptosis in oral epithelial cells we examined the effects of protein phosphatase
      inhibitors, okadaic acid (OA) and calyculin A (CA), on cultured human oral
      squamous carcinoma (SCC) cell line, SCC-25 cells. After reaching subconfluence
      these cells were exposed to varying concentrations of the protein phosphatase
      inhibitors, OA and CA. Both OA and CA induced cell death in SCC-25 cells in a
      dose-dependent fashion as determined by phase-contrast microscopy and WST-1 cell
      viability assay. By using the Hoechst 33342 staining, marked nuclear condensation
      and fragmentation of chromatin was observed. DNA ladder formation also was
      detected in SCC-25 cells by treatment with OA and CA. The induced nuclear
      fragmentation and DNA ladder formation were dose-dependent with maximal effect at
      concentrations of 20 nM OA and 2 nM CA, respectively. OA also induced DNA ladder
      formation in other human oral SCC cell lines, SCCKN and SCCTF. To further
      determine if new gene transcription and protein synthesis are required for OA
      induced apoptosis in SCC-25 cells, the cells were treated for 48 h with varying
      concentrations of cycloheximide in the presence of 20 nM OA. Cycloheximide did
      not protect the cells against OA-induced cytotoxicity and DNA ladder formation.
      Based on the known selectivity of OA and CA, the present results indicate that
      the pathway of the apoptosis in the cultured oral SCC cells is in part regulated
      by protein phosphatase type 1 and type 2A. Our results also indicate that new
      protein synthesis is not involved in OA-induced apoptosis in SCC-25 cells.

PMID- 10645407
TI  - The association between epithelial proliferation and disease progression in the
      oral mucosa.
AB  - The purpose of this study was to examine the possible association between
      epithelial proliferation and disease progression in the oral mucosa. Archival
      specimens of normal oral mucosa (n = 12), dysplasia (n = 17) and squamous cell
      carcinoma (n = 18) were sectioned and proliferating cells visualised by staining
      with Ki-67 antibody. The proliferative index of the epithelium (PI) was
      determined by total cell counts and point counting. Similar results were obtained
      using either method. Comparison of the three groups of tissues by one-way
      analysis of variance showed a significant increase in PI with increasing lesion
      severity (p < 0.001). The PI of both dysplasia and carcinoma groups was
      significantly higher than that of normal oral mucosa (p < 0.001). However, the
      difference between dysplasia and carcinoma groups was not significant. PI was not
      associated with tobacco or alcohol consumption. We therefore conclude that Ki-67
      expression is an early marker of disease progression in the oral mucosa but, on
      its own, is not a good indicator of neoplastic transformation.

PMID- 10645408
TI  - Expression of human papillomavirus E7 mRNA in human oral and cervical neoplasia
      and cell lines.
AB  - Human papillomaviruses (HPVs) have been strongly linked to progression of human
      cancers, such as cervical and oral cancers. Two HPV oncoproteins, E6 and E7, can
      inhibit the tumor suppressor proteins, p53 and pRB, respectively, resulting in a
      deregulation of the cell cycle. In order to further test the significance of HPV
      expression in oral and cervical carcinogenesis, we analyzed HPV E7 mRNA in oral
      and cervical neoplasia and cell lines by reverse transcriptase-polymerase chain
      reaction (RT-PCR). We found that HPV E7 mRNA was present in 90% of patients with
      oral neoplasia and 100% of patients with cervical neoplasia. Quantitative RT-PCR
      and western blot analysis on both transformed cervical and oral epithelial cell
      lines demonstrated that the mRNA level of HPV-16 E7 corresponded to E7 protein
      level, suggesting that HPV oncogene expression is primarily regulated at the
      transcriptional or post-transcription level. The potential clinical application
      of quantitative RT-PCR for HPV E7 mRNA expression in cancer screening and
      treatment evaluation requires further investigation.

PMID- 10645409
TI  - Analysis of the expression of Fas-L in nasopharyngeal carcinoma tissues.
AB  - Nasopharyngeal carcinoma (NPC) is an epithelial cancer with a high incidence in
      Southeast Asia. How it escapes attack from the host immune system is not fully
      understood. Recently, pieces of evidence show that Fas-ligand (Fas-L)-mediated
      apoptosis may be involved in immune privilege of tumours. To determine whether a
      similar mechanism may exist in NPC, the expression of Fas-L was analysed. Biopsy
      specimens of the nasopharynx were taken from 27 NPC patients. Histologically,
      they were either non-keratinizing or undifferentiated carcinomas. Nasopharyngeal
      biopsies of 11 other patients that proved to have no tumour served as control.
      The transcripts of Fas-L were detected by reverse transcription-polymerase chain
      reaction. Localization of Fas-L protein was performed with immunohistostaining
      using an antibody recognizing human Fas-L. All nasopharyngeal tissues have a
      similar amount of transcripts of Fas-L. However, the Fas-L protein was detected
      exclusively on the cell surface of malignant epithelial cells of NPC. The present
      findings suggest that Fas-L protein may be involved in evading immune attack of
      NPC.

PMID- 10645410
TI  - Malignant melanoma of the oral cavity: diagnosis and treatment experience in a
      Mexican population.
AB  - Oral malignant melanoma is uncommon, accounting for 1-8% of all malignant
      melanomas. All previous papers have reported small numbers of cases or have
      retrospectively reviewed case reports from the literature. The following case
      reports concern malignant melanoma of the oral cavity seen at the Instituto
      Nacional de Cancerologia, Mexico City, during the period of 1982-96. Demographic,
      clinical and histopathological data were collected. Our 15 patients consisted of
      6 males and 9 females. The mean age was 52.6 years (range: 35 to 80 years). The
      hard palate was the most common area affected with 11 cases (73%). At the time of
      the initial examination, a pigmented mass was apparent in 100% of the patients.
      All our surgical cases were treated with wide resection; 8 patients received
      adjuvant radiation, 4 were treated with surgery alone and 1 case received
      radiation and chemotherapy before the surgery. Local control of the primary
      lesion was possible in 14 of the 15 cases. Some patients received therapeutic or
      elective lymph node dissection. The median survival was 16.9 months (mean: 12.5
      months). The 2- and 5-year survival rates were 26.6 and 6.6%, respectively.

PMID- 10645411
TI  - Intraosseous squamous cell carcinoma arising in association with a squamous
      odontogenic tumour of the mandible.
AB  - We report a rare occurrence of intraosseous squamous cell carcinoma (SCC) arising
      in association with a squamous odontogenic tumour (SOT), which had not previously
      been documented in the literature. A 53-year-old man had, for 5 years, a well
      demarcated radiolucency attached to the impacted third molar of the mandible. The
      enucleated specimen had a characteristic pattern of SOT, but in which a few
      epithelial islands showed atypical features suggestive of SCC. Intense p53-,
      proliferating cell nuclear antigen- and Ki-67-positive cells were detected in
      carcinoma areas. Within 2 months, aggressive bone destruction showing typical
      findings of intraosseous SCC appeared. The present tumour is presumably a
      malignant variant of SOT.

PMID- 10645412
TI  - Epithelioid hemangioma (angiolymphoid hyperplasia with eosinophilia) in the oral
      mucosa. A case report and review of the literature.
AB  - Angiolymphoid hyperplasia with eosinophilia (ALHE) is a benign uncommon entity
      whose aetiology and pathogenesis is under debate. Clinically, it is characterised
      by cutaneous papules or nodules. Cases of this entity reported in the oral mucosa
      are very rare. We describe such a case, discuss the problems of histological
      differential diagnosis between ALHE and other diseases of the region and review
      the literature.

PMID- 10645413
TI  - Epithelial odontogenic ghost cell tumour of the mandibular gingiva.
AB  - The epithelial odontogenic ghost cell tumour (EOGCT) is considered as a solid
      'neoplastic' variant of the calcifying odontogenic cyst and is an uncommon lesion
      for which various names have been proposed over the years. We describe here an
      extraosseous case occurring on the edentulous mandibular gingiva in the right
      bicuspid area of a 70-year-old woman. The lesion was a painless nodule that
      appeared clinically as a hyperplastic mass, which was considered to be of
      reactive nature. Radiographic examination showed a localised resorption of the
      underlying mandibular bone. The tumour was excised; there was no recurrence at a
      2-year follow-up examination.

PMID- 10645414
TI  - Critique of the 1995 review by Reichart et al. of the biologic profile of 3677
      ameloblastomas.
AB  - This article evaluates the most extensive review of ameloblastomas ever
      published. Because it suffers from the same limitations as any retrospective
      review of the literature, its figures cannot be used as an accurate source for
      such information as prevalence and incidence, racial predilection and recurrence
      rates. Additional knowledge about the biologic profile of ameloblastomas would
      come most effectively from a large, long-term prospective study, but the
      difficulties of establishing one are formidable. A practical alternative would be
      the pooling of data from several experienced centers. The data obtained, and that
      contained in future case reports, should address, in a standardized manner, the
      variables listed in the present article. Incidence figures can be obtained only
      if all new cases from a well-defined population are recorded in an appropriate
      registry. The author considers the concept of a 'multilocular' unicystic
      ameloblastoma, as discussed in the review, to be contradictory.

PMID- 10645415
TI  - Oral cancer in the UK: to screen or not to screen.

PMID- 10645416
TI  - Myofibroma versus infantile fibrosarcoma.

PMID- 10645417
TI  - Dissecting embryonic and seedling morphogenesis in Arabidopsis by promoter trap
      insertional mutagenesis.
AB  - Development can be considered to comprise the co-ordinated regulation of
      patterning at different levels: patterning of cells to form tissues, patterning
      of tissues to form organs, and patterning of organs to generate the
      characteristic architecture of the organism. These processes are expected, in
      turn, to be mediated by the precise spatial and temporal regulation of patterns
      of gene expression during development, which depend on appropriate signalling
      mechanisms. In order to investigate molecular events of morphogenesis in plants,
      we have utilized a system of promoter trap insertional mutagenesis in
      Arabidopsis, to generate both phenotypic mutants and gene fusions that represent
      markers useful in studying the regulation of patterning. A screen of transgenic
      seedlings containing a T-DNA promoter trap has led to the identification of
      mutants defective in seedling shape and embryonic development, and of GUS fusion
      genes that are expressed in spatially restricted patterns. Mutants have been
      crossed with marker lines expressing cell type-specific GUS activities, to
      investigate their cellular organization. For example, the POLARIS marker gene is
      expressed in the embryonic and seedling root tip. When crossed with hydra, which
      lacks an embryonic root, and with emb30, which lacks both embryonic and seedling
      roots, it is nevertheless expressed in the correct relative position, and we
      hypothesize that it represents a novel marker of root positional information,
      independent of root morphogenesis.

PMID- 10645418
TI  - Cell fate in plants. Lessons from the Arabidopsis root.
AB  - Classical studies in plant development have indicated that the fate of plant
      cells is fixed late, after cell division has ceased. Earlier commitment events
      are therefore considered reversible. To gain a mechanisatic understanding of the
      processes involved in specification and fixation of cell fate in plants, we are
      using the Arabidopsis root epidermis as a model system. The Arabidopsis root
      epidermis is composed of two cell types whose pattern of differentiation is
      directed by positional cues during development. Examination of mutations has
      identified genes involved in the establishment of cell fate specification in this
      tissue. TRANSPARENT TESTA GLABRA (TTG) and GLABRA2 (GL2) are positive regulators
      of non-hair fate and are active during the early differentiation of the epidermis
      in the meristem. GL2 encodes a homeobox protein which is expressed in non-hair
      cells in the meristem and is positively regulated by TTG. Mutations in genes
      involved in the regulation of ethylene biosynthesis and signal transduction
      indicate that ethylene is a positive regulator of hair cell fate. Treatment of
      ttg and gl2 plants with modulators of ethylene biosynthesis indicate that
      ethylene acts down stream of TTG and GL2 during the fate specification process.
      The relationship between meristem organisation and the mechanism underpinning the
      establishment of cell fate in other systems is also discussed.

PMID- 10645419
TI  - Multiple modes of cell division control in Arabidopsis flower development.
AB  - Control of the pattern of cell divisions is central to plant development. Several
      different types of control exist: examples include control of overall cell number
      in floral meristems, control of relative cell numbers in floral whorls, and
      control of the relative spacing of the cell divisions that establish floral
      organs. Mutations that change each of these levels of control are described:
      mutations in the SUPERMAN gene affect relative amounts of cell division in
      adjacent floral whorls; mutations in the CLAVATA genes affect overall
      meristematic cell number; and mutations in PERIANTHIA affect the spacing of
      floral organs.

PMID- 10645420
TI  - Cellular differentiation in the maize leaf is disrupted by bundle sheath
      defective mutations.
AB  - The mature maize leaf is characterised by a series of parallel veins that are
      surrounded by concentric rings of bundle sheath (BS) and mesophyll (M) cells. To
      identify genes that control cellular differentiation patterns in the leaf, we
      have isolated a group of mutations that specifically disrupt the differentiation
      of a single cell type. In maize bundle sheath defective (bsd) mutants, C4
      photosynthetic development is perturbed in BS cells while M cells appear to
      develop normally. Two mutants, bsd1 and bsd2, have been characterised in detail.
      Analysis of these mutants, and the corresponding Bsd1 and Bsd2 genes is providing
      an insight into cellular processes regulating photosynthetic cell type
      differentiation in maize.

PMID- 10645421
TI  - Signals involved in control of polarity, cell fate and developmental pattern in
      plants.
AB  - The plant extracellular matrix has multiple roles in determining pattern during
      plant development. These include provision of anchorage sites for focal adhesion
      like structures which may play a direct signalling role and provide a reference
      for cytoskeletal elements involved in nuclear rotation and orientation of the
      cell division plane. The activity of mechanosensitive ion channels in the plasma
      membrane can also be regulated by the mechanical properties of the cell wall.
      Moreover, there is increasing evidence from a variety of systems suggesting that
      the cell wall may be a direct source of factors which specify cell fate in
      response to position. These may be inserted into the wall by differentiating
      cells and may act by providing signals to adjacent cells or by providing positive
      feedback to the protoplast contained therein, maintaining its fate according to
      its position.

PMID- 10645422
TI  - Plasmodesmata: gateways for information transfer.
AB  - Intercellular communication in plants has evolved to occur via elongated
      cytoplasmic bridges, called plasmodesmata, that traverse the thick cell walls
      that surround plant cells. Historically, plasmodesmata have been assigned the
      mostly passive role of creating cytoplasmic continuity between plant cells
      enabling free transport of the wealth of small plant metabolites and growth
      hormones under 1 kDa. When it was discovered that plant viruses pirate
      plasmodesmata for movement of viral genomes during infection, it was proposed
      that viruses modified plasmodesmata for transport of very large molecules. Now,
      there is compelling evidence that plasmodesmata are inherently dynamic, rapidly
      altering their dimensions to increase their transport capabilities, upon contact
      with viral as well as developmentally important plant proteins. Further, the
      study of intercellular transport has prompted analyses of intracellular transport
      pathways, implicating the cytoskeleton as a major tracking system to
      plasmodesmata. Thus, plasmodesmata form a three-dimensional network of
      transportation channels and major checkpoints for information transfer. In the
      following, current knowledge about structure and function of these connective
      organelles, and about routing of molecules towards plasmodesmata, will be
      summarized.

PMID- 10645423
TI  - Pollen-stigma interactions in Brassica.
AB  - The pollen grain coating of Brassica oleracea contains a polymorphic family of
      highly charged small proteins (PCP-A, pollen coat protein, class A) related to
      the defensin class of seed proteins. On pollination these proteins are released
      from the grain and in vitro data suggest that at least one member of the family
      (PCP-A1) interacts specifically with elements of the stigmatically-expressed
      S(self-incompatibility) receptor complex. A new in vivo bioassay has demonstrated
      the male determinant of the self incompatibility system to be contained within
      the pollen coating, and this determinant to be a low molecular mass protein. A
      combination of data from interspecific studies and molecular analysis of PCP-A
      proteins indicates that the primary interaction between PCP-A1 and the receptor
      complex may be involved in establishing compatibility, while other molecular
      interactions, perhaps involving other PCP-A class proteins, are responsible for
      regulating S-specific rejection of self grains. The evolution of the self
      incompatibility system on the dry sigma of Brassica is discussed in the context
      of these data.

PMID- 10645424
TI  - 'Two-component' ethylene signaling in Arabidopsis.
AB  - The Arabidopsis ETR1 gene codes for an ethylene hormone receptor that has
      striking sequence similarity with bacterial two-component regulators. This
      finding predicts that the ETR1 receptor transduces the ethylene signal through
      the phosphotransfer mechanisms established for a number of the bacterial
      regulators. To test this hypothesis, we have performed in vitro assays for ETR1
      autokinase activity as well as for transfer of phosphate to the ETR1 receiver. So
      far, we have not detected either of these activities. Another question we are
      focusing on is the identity of protein substrates of the ETR1 receptor. Using the
      yeast two-hybrid system, we have obtained several clones to be subsequently
      characterized as potential interactors with ETR1.

PMID- 10645425
TI  - The role of ABI1 in abscisic acid signal transduction: from gene to cell.
AB  - The semi-dominant abi1-1 mutation of Arabidopsis interferes with multiple aspects
      of abscisic acid signal transduction resulting in reduced seed dormancy and
      sensitivity of root growth in ABA. Furthermore, the mutant transpires excessively
      as a result of abnormal stomatal regulation leading to a wilty phenotype. The
      ABI1 gene has been cloned. The carboxyl-terminal domain of the predicted ABI1
      protein is related to the 2C class of serine-threonine phosphatases while no
      overt homology was found in the extended amino terminus. A combination of in
      vitro assays and yeast mutant complementation studies confirmed that ABI1 is a
      functional protein phosphatase 2C. The abi1-1 mutation converts the amino acid
      glycine180 to aspartic acid, and in the above test systems, causes a partial loss
      of the phosphatase activity. In transgenic Nicotiana benthamiana guard cells, the
      abi1-1 gene causes a reduction in the background current of the outward
      rectifying potassium channels, and also in the abscisic acid-sensitivity of both
      the outward- and the inward-rectifying potassium channels in the plasma membrane.
      However, normal sensitivity of both potassium channels to, and stomatal closure
      in, abscisic acid was recovered in the presence of H7 and staurosporine, both
      broad-range protein kinase antagonists. These results suggest the aberrant
      potassium channel behavior as a major consequence of abi1-1 action and implicate
      ABI1 as part of a phosphatase/kinase pathway that modulates the sensitivity of
      guard-cell potassium channels to abscisic acid-evoked signal cascades.

PMID- 10645427
TI  - Gene expression during adventitious root formation in apple.
AB  - A model system for adventitious root formation in woody plants was used to
      identify transcripts that are up-regulated during this process. 1 mm stem-disks
      from micropropagated shoots of the apple cultivar Jork 9 can be induced to form
      roots by treatment with the auxin indole butyric acid (IBA). Stem discs are
      placed on medium containing IBA for 24 hours and then transferred to IBA-free
      medium. Root initials become visible after 5-6 days and root elongation occurs
      within 7-9 days. The first visible cell divisions, which will give rise to the
      adventitious roots, are detectable 48 hours following IBA treatment. We have used
      this system to identify transcripts that are induced during adventitious root
      formation. Two techniques were employed in this analysis: differential messenger
      RNA display (DDRT) and mRNA representational difference analysis (RDA), a
      technique that couples PCR and subtractive hybridisation. Using both of these
      techniques a number of clones have been isolated that exhibit differential
      expression during auxin induced root formation. Both up-regulated and down
      regulated transcripts have been identified. Expression of these genes has
      initially been verified by reverse northern blot analysis. Northern blot analysis
      with individual clones has confirmed the expression pattern observed in the
      reverse northern analysis. Tentative identities of some of the clones have been
      established by sequencing the partial cDNAs. Among the up-regulated transcripts
      are clones that share sequence homology with polygalacturonase and MAP kinases. A
      full-length cDNA for the most abundant up-regulated mRNA, a 2-oxoacid dependent
      dioxygenase, was characterised. This mRNA is expressed between 24 and 72 hours
      following IBA treatment of apple stem disks.

PMID- 10645426
TI  - SPINDLY's role in the gibberellin response pathway.
AB  - The SPINDLY (SPY) locus of Arabidopsis thaliana is believed to be involved in
      gibberellin (GA) signal transduction. The six known mutations at this locus cause
      a phenotype that is consistent with constitutive activation of the GA signal
      transduction pathway. spy alleles are epistatic to gai, a mutation conferring
      gibberellin-insensitivity, indicating that SPY acts as a negative regulator of GA
      signal transduction, downstream of GAI. SPY was cloned using a T-DNA insertion in
      the spy-4 allele. SPY encodes a 914 amino acid protein with an N-terminal TPR
      region (a likely protein-protein interaction domain) and a novel C-terminal
      domain. The spy mutants show that both the N- and C-terminal domains of SPY are
      functionally important, spy-4 is likely to be a null allele and displays some
      morphological defects not seen in the other alleles. A 35S:SPY construct rescues
      the spy mutant phenotype, but does not show any gain-of-function SPY phenotypes.
      Smaller constructs overexpressing different domains of the SPY protein have no
      effect on plant development.

PMID- 10645428
TI  - The phytochromes: photosensory perception and signal transduction.
AB  - Phytochromes are regulatory photoreceptors which primarily absorb red (R) and far
      red (FR) light. A great deal is known about the spectroscopic properties, primary
      structure, gene regulation and gross structure of phytochromes, and about the set
      of developmental changes which they control, but the early steps in signal
      transduction from phytochrome which result in these changes are still mysterious.
      In angiosperms, phytochromes are encoded by a small gene family, and as a result
      of recent work with mutants and transgenic overexpressors it is possible to
      assign distinct functions to some of the individual types of phytochrome. For two
      of these, phytochrome A and phytochrome B, overexpression of chimeras has
      revealed that the determinants for their photosensory specificity and the light
      promoted degradation of phytochrome A reside on the amino-terminal halves of the
      molecules. The interchangeability of the C-terminal halves suggests that they may
      share a common signal transduction mechanism. These results also invite a
      reappraisal of the various models that have been proposed over the years to
      explain the complexity of phytochrome sensitivity to various light regimes.

PMID- 10645429
TI  - Light control of Arabidopsis developmental pattern.
AB  - As sessile organisms, higher plants are characterized by a high degree of
      developmental pattern plasticity in response to environmental signals, and in
      many cases respond to the changing environment by tailoring their developmental
      patterns in a way that maximizes their chances of survival and reproduction.
      Given the importance of photosynthesis to plant survival, light signals are
      arguably among the most important environmental cues to plant development.
      Genetic analysis of the light control of the Arabidopsis seedling development
      pattern has revealed that the pleiotropic COP/DET/FUS genes play a key role in
      integrating light signals and modulating developmental pattern formation. Recent
      studies support a working model in which COP1 act within the nucleus to sequester
      and inactivate transcription factors in darkness, while light abrogates this
      association by modulating COP1 nuclear abundance. This results in activation of
      the transcription factors and expression of genes responsible for
      photomorphogenic development. The other pleiotropic COP/DET/FUS proteins act to
      maintain the proper nuclear localization or retention of COP1 in darkness.

PMID- 10645430
TI  - Methylation controls the low temperature induction of flowering in Arabidopsis.
AB  - Control of the transition to flowering is critical for reproductive success of a
      plant. Studies in Arabidopsis have led us to suggest how this species has
      harnessed the environmental cue of a period of low temperature to ensure
      flowering occurs at an appropriate time. We propose that Arabidopsis has both
      vernalization-independent and vernalization-dependent pathways for the initiation
      of inflorescence development in the shoot apex. The vernalization-independent
      pathway may be concerned with the supply of carbohydrate to the shoot apex. In
      late flowering ecotypes which respond to vernalization the vernalization
      independent pathway is blocked by the action of two dominant repressors of
      flowering, FRI and FLC, which interact to produce very late flowering plants
      which respond strongly to vernalization. We have isolated a gene which may
      correspond to FLC. We suggest the vernalization-dependent pathway, which may be
      concerned with apical GA biosynthesis, is blocked by methylation of a gene
      critical for flowering. This gene may correspond to that encoding kaurenoic acid
      hydroxylase (KAH), an enzyme catalysing a step in the GA biosynthetic pathway.
      Under this scheme vernalization causes unblocking of this pathway by
      demethylation possibly of the KAH gene and consequent biosynthesis of active GAs
      in the apex.

PMID- 10645431
TI  - The regulation of flowering time by daylength in Arabidopsis.
AB  - We are studying several Arabidopsis mutants that show altered regulation of
      flowering time in response to daylength. One of the mutations we are studying,
      constans, delays flowering under long days but has no effect under short days.
      Analysis of the expression of the CONSTANS gene, and modification of its
      expression in transgenic plants, suggests that this gene promotes flowering in
      response to long days and that the delay in flowering that occurs in wild-type
      plants under short days is at least in part due to regulation of CONSTANS gene
      transcription. We describe genetic approaches that we are taking to identify
      genes that act in the same genetic pathway as CONSTANS, and in particular the
      relationship between CONSTANS and two other genes that we are studying. These are
      LATE ELONGATED HYPOCOTYL, for which we have a dominant mutant allele that causes
      late flowering, and EARLY SHORT DAYS 4, whose inactivation causes early
      flowering. In addition to their effects on flowering time, the over-expression of
      CONSTANS and the inactivation of EARLY SHORT DAYS 4 cause the Arabidopsis shoot
      to become determinate and therefore to terminate development prematurely. This
      phenotype is discussed in light of other genes that have previously been shown to
      be required to maintain indeterminate development of the shoot.

PMID- 10645432
TI  - Molecular, genetic and physiological analysis of Cladosporium resistance gene
      function in tomato.
AB  - Characterization of the DNA sequence of 4 tomato leaf mould disease resistance
      genes (Cf-2, Cf-4, Cf-5 and Cf-9) leads to the prediction that they encode C
      terminally membrane anchored glycopeptides with many extracytoplasmic leucine
      rich repeats (LRRs). The N terminal LRRs are variable between the Cf-genes,
      suggesting a role in specificity, and the C terminal LRRs are more conserved,
      suggesting a role in signal transduction. Genetic analysis has revealed several
      Rcr genes that are required for Cf-gene function; their isolation will help us
      understand how Cf-genes work. Cf-9 confers responsiveness to pathogen-encoded
      Avr9 peptide on introduction to tobacco. Tobacco suspension cultures carrying the
      Cf-9 gene produce reactive oxygen species in response to Avr9 peptide, whereas
      untransformed cultures do not. The significance of these observations is
      discussed.

PMID- 10645433
TI  - Transposable elements and the evolution of gene expression.
AB  - Most plant genomes are populated with enormous quantities of transposable
      elements (TEs) or sequences derived from TEs. The impact of TEs on their host has
      been addressed by characterizing mutations of the maize waxy and R genes caused
      by TE insertions. Association between a new class of TEs (called MITEs) and
      normal plant genes is also reviewed. The notion that different classes of TEs
      have found their respective niches in the maize genome is discussed.

PMID- 10645434
TI  - The evolution of grass genome organisation and function.
AB  - New cloning technologies and more efficient DNA sequencing now permit
      comprehensive structural studies of complex eukaryotic genomes. Previous global
      investigations of genome organisation in plants had shown that abundant
      repetitive DNAs were intermixed with genes. However, the nature of the major
      repeats, their possible biological roles, their origins, and their precise
      patterns of organisation were not clearly defined. My laboratory has used large
      clones derived from homologous regions of the maize, sorghum and rice genomes to
      investigate the nature, functional properties and evolution of grass genome
      organisation. Unexpectedly simple patterns of genome composition and arrangement
      have been seen, and these appear to be similar in different grasses. Our detailed
      studies of the maize genome indicate that short (2-20 kb) blocks of gene
      containing DNA alternate with large (2-200 kb) blocks of intermixed middle and
      highly repetitive DNAs. Most of the highly repetitive sequences, and many of the
      middle repetitive DNAs, are retrotransposons that have inserted within each
      other. These repetitive DNAs are usually methylated and mostly inactive, but they
      are homologous to transcripts found in many different tissues. The unmethylated
      DNA is composed primarily of genes interspersed with lower-copy-number
      retroelements and inverted-repeat transposable elements. Gene order and sequence
      are highly conserved, but the mobile DNAs between genes appear to be different
      due to their rapid evolution and their variable presence or locations in
      different grasses.

PMID- 10645435
TI  - Maize as a model system for investigating the molecular basis of morphological
      evolution in plants.
AB  - The genetic and molecular bases of morphological evolution in plants are largely
      unknown. To address questions surrounding this issue, my laboratory has been
      investigating the evolution of maize from its wild ancestor, teosinte. Our
      research suggests that a few gene changes of large effect were involved in the
      evolution of several different traits including plant and ear architecture and
      kernel color. In cases where gene function could be identified, the genes
      involved in maize evolution were regulatory in nature. Additional evidence
      suggests that changes in cis regulatory elements of the regulatory genes rather
      than changes in protein function underlie the evolution of the traits analyzed.
      Future work with other plant species, especially wild plants, will be required to
      test the generality of our observations with maize.

PMID- 10645436
TI  - Antirrhinum and Asteridae--evolutionary changes of floral symmetry.
AB  - Lamiales s.l., a prominent clade in the Asteridae, commonly have pentamerous
      monosymmetric flowers with the upper (odd) stamen reduced or lacking. Of the five
      largest families of the Lamiales s.l. (Gesneriaceae, Scrophulariaceae,
      Bignoniaceae, Acanthaceae, and Verbenaceae/Lamiaceae), perhaps the most
      phylogenetically basal, the Gesneriaceae, is the only one with odd staminodes or
      stamens occurring in all genera. In addition, Gesneriaceae have relatively large
      odd staminodes often with a differentiation in filament and reduced anther. They
      also have the largest proportion of genera (approx. 8%) with more or less
      polysymmetric flowers with five fertile stamens. In the more advanced families of
      the Lamiales s.l. the pattern varies. In Bignoniaceae an odd staminode is also
      commonly present. The traditional Scrophulariaceae is the most diverse family
      with some tribes constantly having an odd staminode (e.g. Antirrhineae) and
      others missing it (e.g. Manuleae, Pedicularieae), reflecting its probable
      polyphyly. In Acanthaceae, and still more in Verbenaceae/Lamiaceae with their
      extremely monosymmetric flowers an odd staminode is more often missing than
      present. From the systematic distribution of the different floral forms it is
      most likely that monosymmetric flowers were already present at the base of the
      Lamiales s.l. but 'reversal' to polysymmetry was still easy in the basal groups
      with only weak expression of monosymmetry. The evolution of more pronounced
      monosymmetry proceeded in different lineages and loss of the odd stamen occurred
      in various clades. The developmentally most intriguing groups are those with loss
      of the perianth and reduction of floral organ numbers to two or one, Callitriche
      being the most extreme genus.

PMID- 10645437
TI  - Reversible male sterility: a novel system for the production of hybrid corn.
AB  - Hybrid corn seed is traditionally produced using either mechanical/hand
      detasseling or cytoplasmic male sterility, or a combination of both. In recent
      years, the development of transgenic systems to produce hybrid seed in several
      crops has attracted much attention. Here we describe a transgenic mechanism for
      production of hybrid corn, reversible male sterility (RMS), in which the action
      of the cytotoxic gene used to introduce male sterility is suppressed by the
      application of a chemical to the plant. Reversion of the sterility allows the RMS
      parent to be self-fertilized, a step which overcomes the need to remove fertile
      sib plants prior to making the hybrid cross. The key enabling technology in RMS
      is the use of a plant gene promoter which is specifically induced by chemical
      application. We have exemplified RMS in transgenic corn plants and believe that
      it provides specific benefits in the production of hybrid corn seed.

PMID- 10645438
TI  - Specificity of acyltransferases and their genetic manipulation for environmental
      adaptation and development of new industrial oils.
AB  - The biosynthesis of complex lipids involves specific acylation reactions
      catalysed by acyltransferases. These reactions are important for the formation of
      both storage lipids, triacylglycerols, as well as structural lipids such as
      phospholipids and galactolipids. The current status of our understanding of the
      specificity, selectivity, structure, cloning and genetic manipulation of these
      enzymes is reviewed. These studies clearly indicate the possibilities of
      selecting appropriate acyltransferases to produce designer lipids with defined
      acyl groups at different positions of the triglyceride molecule. In separate
      transgenic studies manipulation of these enzymes has demonstrated a dramatic
      alteration in the chilling sensitivity of plants.

PMID- 10645439
TI  - Molecular genetic basis of antimicrobial agent resistance in Mycobacterium
      tuberculosis: 1998 update.
AB  - Knowledge of the molecular genetic basis of resistance to antituberculous agents
      has advanced rapidly since we reviewed this topic 3 years ago. Virtually all
      isolates resistant to rifampin and related rifamycins have a mutation that alters
      the sequence of a 27-amino-acid region of the beta subunit of ribonucleic acid
      (RNA) polymerase. Resistance to isoniazid (INH) is more complex. Many resistant
      organisms have mutations in the katG gene encoding catalase-peroxidase that
      result in altered enzyme structure. These structural changes apparently result in
      decreased conversion of INH to a biologically active form. Some INH-resistant
      organisms also have mutations in the inhA locus or a recently characterized gene
      (kasA) encoding a beta-ketoacyl-acyl carrier protein synthase. Streptomycin
      resistance is due mainly to mutations in the 16S rRNA gene or the rpsL gene
      encoding ribosomal protein S12. Resistance to pyrazinamide in the great majority
      of organisms is caused by mutations in the gene (pncA) encoding pyrazinamidase
      that result in diminished enzyme activity. Ethambutol resistance in approximately
      60% of organisms is due to amino acid replacements at position 306 of an
      arabinosyltransferase encoded by the embB gene. Amino acid changes in the A
      subunit of deoxyribonucleic acid gyrase cause fluoroquinolone resistance in most
      organisms. Kanamycin resistance is due to nucleotide substitutions in the rrs
      gene encoding 16S rRNA. Multidrug resistant strains arise by sequential
      accumulation of resistance mutations for individual drugs. Limited evidence
      exists indicating that some drug resistant strains with mutations that severely
      alter catalase-peroxidase activity are less virulent in animal models. A diverse
      array of strategies is available to assist in rapid detection of drug resistance
      associated gene mutations. Although remarkable advances have been made, much
      remains to be learned about the molecular genetic basis of drug resistance in
      Mycobacterium tuberculosis. It is reasonable to believe that development of new
      therapeutics based on knowledge obtained from the study of the molecular
      mechanisms of resistance will occur.

PMID- 10645440
TI  - Characterization of the phylogenetic distribution and chromosomal insertion sites
      of five IS6110 elements in Mycobacterium tuberculosis: non-random integration in
      the dnaA-dnaN region.
AB  - SETTING: Five IS6110 chromosomal insertion sites were characterized in the
      multidrug resistant Mycobacterium tuberculosis 'W' strain. OBJECTIVE: To use
      insertion site probes to study the phylogenetic distribution of IS6110 in the M.
      tuberculosis genome. DESIGN: A total of 722 M. tuberculosis isolates, previously
      genotyped using the standard IS6110 Southern blot hybridization methodology, were
      re-hybridized with the Region A insertion site probe and representative strains
      were further hybridized with the Region B and C probes. Strains were grouped on
      the basis of having IS6110 insertions in these different regions and their
      relatedness was further compared by sequencing the IS6110 insertion sites.
      RESULTS: The insertion site probes revealed that the collection of Chinese
      isolates previously grouped as the Beijing strain family shared IS6110 insertions
      in common with the W and other genotypic group 1 strains. Unexpectedly, we found
      that IS6110 integrated at least 10 independent times between the dnaA and dnaN
      genes encoding deoxyribonucleic acid replication proteins. CONCLUSIONS: IS6110
      insertion site mapping is able to identify genetic relatedness among a collection
      of M. tuberculosis clinical strains representing the breadth of species
      diversity. The mapping data indicate that IS6110 insertion sites are not always
      random.

PMID- 10645441
TI  - Identification of an immunogenic histone-like protein (HLPMt) of Mycobacterium
      tuberculosis.
AB  - We report the identification of the first histone-like protein of Mycobacterium
      tuberculosis (MTB) (HLPMt). The T cell blot assay was used to identify antigens
      of MTB associated with human immune response in healthy contacts. Fraction 21
      corresponding to proteins in the molecular weight range of approximately 30 kDa
      were found to be immunogenic in tuberculin reactors. None of the fractions were
      found to be immunogenic by this assay in non-reactors to tuberculin. All sera,
      irrespective of the source, showed reactivity with MTB antigen(s) over a wide
      molecular weight range (205-->16 kDa). In the present study fraction 21 was
      processed for the generation of murine polyclonal sera and amino acid sequencing.
      The sequence of a 16-amino acid long peptide showed a 100% homology with an open
      reading frame (ORF) in the translated sequence of cosmid cY349 (Sanger Centre,
      Cambridge, UK). The ORF was predicted to code for a protein of 214 amino acids.
      Oligonucleotide primers were synthesized based on the nucleotide sequence located
      at the 5' and 3' regions of the gene. The gene encoding the predicted protein was
      PCR-amplified, cloned, sequenced and expressed in Escherichia coli as a protein
      of 28 kDa. The expressed HLPMt protein was shown to react with the polyclonal
      murine sera originally raised against fraction 21. Human immune response to the
      recombinant HLPMt protein was demonstrated by its ability to induce
      lymphoproliferation in peripheral blood derived mononuclear cells, and the
      presence of anti-HLPMt antibodies in pooled patient sera by immunoblot. The
      recombinant HLPMt protein elicited a vigorous lymphoproliferative response
      especially in healthy tuberculin reactors compared to non-reactors and patients
      of tuberculosis, (P < 0.05). The protein has unique dual domains with homology to
      both bacterial histone-like proteins (HU) and eukaryotic histone H1. Homology to
      prokaryotic and eukaryotic deoxyribonucleic acid (DNA)-binding proteins suggested
      that HLPMt could bind DNA. DNA-binding properties were confirmed by South-Western
      analysis strongly suggesting an interaction between HLPMt and the MTB chromosome.

PMID- 10645442
TI  - Rib lesions and tuberculosis: the palaeopathological evidence.
AB  - SETTING: Tuberculosis diagnosis in past populations relies on lesions in the
      spine and major weight bearing joints of the body. Bone formation on visceral
      surfaces of ribs has also been suggested to be the result of chronic pulmonary
      disease. OBJECTIVE: To test whether these lesions are the result of pulmonary
      infection (most likely tuberculosis), by reviewing past work, and to discuss
      whether these lesions could be considered another diagnostic criterion for
      pulmonary tuberculosis. DESIGN: A review of the literature on new bone formation
      on ribs, and consideration of further evidence from archaeological skeletal
      material from the UK. RESULTS: Results from modern studies suggest that bone
      formation on ribs is often the result of pulmonary tuberculosis, that lesions are
      relatively common in archaeological skeletal material, and that some skeletons
      have rib lesions plus pathognomonic changes of tuberculosis. CONCLUSION: Evidence
      suggests that new bone formation on visceral surfaces of ribs should be
      considered a possible indicator of tuberculosis. If accepted, historical
      evidence, when correlated with rib data, produces closer approximations to the
      frequency of the disease in the past. This study indicates the importance of
      palaeopathology in identifying sometimes subtle lesions that may not be noted by
      clinicians because of their non-visibility on radiographs.

PMID- 10645443
TI  - Mycobacteriophage TM4: genome structure and gene expression.
AB  - Mycobacteriophage TM4 is a dsDNA-tailed phage that infects both fast-growing and
      slow-growing strains of mycobacteria. While TM4 has been used extensively for the
      construction of mycobacterial shuttle phasmids and for the delivery of reporter
      genes and transposons into mycobacterial cells, little is known about its
      genetics or molecular biology. We describe here the complete 52,797 bp genome
      sequence of TM4 and a map of its genome organization. While not a close relative
      of other mycobacteriophages, TM4 encodes several proteins with sequence
      similarity to those of other bacteriophages--including L5 and D29--indicating
      that they have common ancestry. In addition, TM4 encodes proteins with similarity
      to haloperoxidases, glutaredoxins and the WhiB family of transcriptional
      regulators. Following infection, TM4 genes are expressed in a defined temporal
      pattern, with the virion structural proteins expressed late in the phage growth
      cycle. Understanding the genetics of TM4 will greatly facilitate its use as a
      tool for the genetic manipulation of the mycobacteria.

PMID- 10645444
TI  - Identification of a restriction fragment length polymorphism associated with a
      deletion that maps in a transcriptionally active open-reading frame, orfX, in
      Mycobacterium tuberculosis Erdman.
AB  - A two-component system of Mycobacterium tuberculosis H37Rv, designated as devR
      devS, was identified in our laboratory, that encodes a response regulator and a
      histidine sensor-kinase respectively. Southern analysis of the devR-devS locus in
      the genomes of M. tuberculosis H37Rv, H37Ra and Erdman indicated the presence of
      an EcoRI restriction fragment length polymorphism (RFLP) in the Erdman strain.
      Studies employing polymerase chain reaction (PCR), suggested that the RFLP is
      associated with a deletion in M. tuberculosis Erdman. Deoxyribonucleic acid
      sequence analysis of this region in the Erdman strain confirmed a deletion of 330
      bp. The deletion maps in an open reading frame (ORF) designated as orfX (which
      maps upstream of the devR-devS locus) that is present in M. tuberculosis H37Rv
      and H37Ra, and in all five isolates of M. tuberculosis examined in this study.
      OrfX is transcriptionally active in M. tuberculosis H37Rv and H37Ra but not in
      the Erdman strain. These observations point towards variations in genomic
      organization and in transcriptional activity of virulent strains of M.
      tuberculosis. OrfX gene deletion can be utilized in a rapid PCR-based assay to
      differentiate between H37Rv and Erdman strains.

PMID- 10645445
TI  - Assessment of the interleukin 1 gene cluster and other candidate gene
      polymorphisms in host susceptibility to tuberculosis.
AB  - SETTING: A study of tuberculosis cases and healthy blood donor controls from the
      Western Region of The Gambia, West Africa. OBJECTIVE: To investigate the
      potential role of candidate gene polymorphisms in host susceptibility to
      tuberculosis. DESIGN: Single base change polymorphisms in interleukin 1 beta (IL1
      beta), interleukin 10 (IL10) and fucosyltransferase-2 (FUT-2), microsatellite
      polymorphisms in interleukin 1 alpha (IL1 alpha) and IL10 and a minisatellite
      polymorphism in interleukin 1 receptor antagonist (IL1RA) were typed in over 400
      tuberculosis cases and 400 healthy blood donor controls. RESULTS: IL1 gene
      cluster polymorphisms (IL1RA and possibly IL1 alpha) showed marginally
      significant association with tuberculosis. In particular IL1RA allele 2
      heterozygotes were less frequent among tuberculosis cases than controls (P =
      0.03). IL1 beta, IL10 and FUT-2 polymorphisms were not associated with
      tuberculosis. CONCLUSION: Genetic susceptibility to tuberculosis among Gambians
      may be partly determined by genes in the IL1 gene cluster on chromosome 2.
      Further association studies will be required on other population groups to
      confirm whether these results are of biological significance.

PMID- 10645446
TI  - Extra and intracellular expression of Mycobacterium tuberculosis genes.
AB  - To understand how Mycobacterium tuberculosis survives and grows in an infected
      host, we are studying the mycobacterial transcriptional machinery and its
      response to stresses encountered in vitro and in vivo. Much has been learned
      about sigma factors and other transcriptional regulators concerning their roles
      in controlling mycobacterial gene expression. It has recently been shown that
      sigma A is the essential housekeeping sigma factor and the alternative sigma
      factor sigma B, not essential for growth in a laboratory setting, is required for
      a robust protective response to various environmental stresses. We are also
      studying the mechanism by which the R522H mutation in sigma A prevents the
      transcription of certain genes, including some that are believed necessary for
      virulence. Also under investigation is the mycobacterial iron acquisition
      apparatus and its regulation, as metabolism of this essential element plays a key
      role in microbial pathogenesis. We have identified and characterized the major
      mycobacterial iron regulator IdeR that blocks the synthesis of the iron uptake
      machinery and have identified target genes in M. smegmatis and M. tuberculosis
      that are directly repressed by IdeR. Recent studies have examined the control of
      M. tuberculosis gene expression in vivo. Among these new approaches are an in
      vivo expression technology system to identify M. tuberculosis genes that are
      induced in macrophages and mice and a novel RT-PCR method that allows an accurate
      comparison between the levels of specific mRNAs in M. tuberculosis grown in vitro
      with those found in bacteria growing in human macrophages.

PMID- 10645447
TI  - Protective role of the Mycobacterium smegmatis IdeR against reactive oxygen
      species and isoniazid toxicity.
AB  - OBJECTIVE: To understand the mechanism by which IdeR is necessary for maintaining
      wild type levels of KatG and SodA enzyme activity and normal isoniazid (INH)
      resistance. DESIGN: To identify the step(s) of SodA and KatG function that were
      affected by the ideR mutation, quantitative western immunoassays and ribonucleic
      acid (RNA) hybridizations were performed. To see if the increased INH sensitivity
      of the ideR mutant was caused by lower SodA activity, the Mycobacterium smegmatis
      sod gene was inactivated. RESULTS: The levels of KatG and SodA mRNA and protein
      in the M. smegmatis IdeR mutant are decreased to approximately 20-40% of those
      observed in the wild type parent strain. This is quantitatively similar to the
      decrease in KatG and SodA enzyme activities originally observed in the ideR
      strain. The M. smegmatis sodA mutant was slightly more sensitive to INH, compared
      to the wild type strain and was more resistant than the ideR mutant. CONCLUSION:
      IdeR is necessary for full expression of the M. smegmatis katG and sodA genes. It
      is not yet known whether this protein acts directly at the gene level. The lower
      levels of SodA contribute slightly to the increased susceptibility to INH of the
      ideR mutant, but cannot explain the magnitude of the INH sensitivity observed
      when IdeR is not present. These data suggest that IdeR is a regulator of the
      cellular stress response, as it has a protective role in cells facing
      environmental stresses, such as increased levels of reactive oxygen species and
      INH toxic intermediates. These conclusions do not necessarily apply to IdeR's
      role in M. tuberculosis physiology, since we have not inactivated its gene in
      this pathogen.

PMID- 10645448
TI  - Antibacterial spectra of drugs used for chemotherapy of mycobacterial infections.
AB  - The mechanism of action of many antimycobacterial agents is poorly understood. To
      obtain preliminary information on whether the targets for some of these drugs
      might also occur in other bacteria, the in vitro activities of selected agents
      against Escherichia coli, Bacillus subtilis and Staphylococcus aureus were
      determined. Dapsone, p-aminosalicylic acid and thiacetazone failed to inhibit the
      above organisms (MIC values > 100 micrograms/ml) that may therefore lack targets
      for these drugs. Capreomycin, viomycin and clofazimine demonstrated activity
      against some of the organisms (MIC values < 100 micrograms/ml) suggesting that
      the targets of these drugs may not be restricted to mycobacterial species. The
      agents were all potent inhibitors of Mycobacterium bovis bacille Calmette-Guerin
      (MIC values 0.08-0.5 microgram/ml).

PMID- 10645449
TI  - Genotypic characterization of drug-resistant Mycobacterium tuberculosis isolates
      from Peru.
AB  - SETTING: Twenty-nine epidemiological unrelated and mostly multidrug-resistant
      Mycobacterium tuberculosis (MDR-TB) strains from Peruvian patients. OBJECTIVE: To
      investigate the molecular genetics of MDR-TB strains recovered in a Latin
      American country. DESIGN: Antimicrobial agent susceptibility testing, major
      genetic group designation, IS6110 fingerprinting, spoligotyping, and automated
      deoxyribonucleic acid sequencing of regions of the katG, rpoB, embB, gyrA, and
      pncA genes with mutations commonly associated with drug resistance. RESULTS:
      Nineteen isolates were found to be multidrug-resistant by susceptibility testing.
      IS6110 typing showed that virtually all isolates were unique and therefore had
      independently acquired drug resistance. Seventy-nine percent of isoniazid
      resistant strains had a Ser315Thr amino acid change in KatG. Ninety-five percent
      of rifampin-resistant isolates had amino acid replacements in the rifampin
      resistance determining region of RpoB. Six of 11 ethambutol-resistant strains had
      EmbB alterations. Eleven pyrazinamide-resistant strains had distinct mutations in
      pncA. CONCLUSION: Virtually all organisms evolved drug resistance independently.
      The types of drug resistance-associated mutations identified were very similar to
      changes occurring in isolates from other areas of the world. Nucleotide sequence
      based strategies for rapid detection of drug resistance-conferring mutants will
      be applicable to organisms recovered in Peru, and potentially other areas of
      Latin America.

PMID- 10645451
TI  - Nitrate reduction as a marker for hypoxic shiftdown of Mycobacterium
      tuberculosis.
AB  - SETTING: In vitro cultures. OBJECTIVE: To characterize nitrate reduction during
      aerobic growth and hypoxic shiftdown to non-replicating persistence of
      Mycobacterium tuberculosis cultures. DESIGN: The rates of reduction of nitrate to
      nitrite were measured in cultures of M. tuberculosis growing aerobically or
      undergoing hypoxic shiftdown. RESULTS: Tubercle bacilli growing aerobically in
      the presence of nitrate reduce nitrate at a rate proportional to the substrate
      concentration, continuing until the substrate is exhausted. When the bacilli in
      an oxygen restricted model enter microaerophilic non-replicating persistence
      (NRP) stage 1, they exhibit a marked increase in rate of nitrate reduction that
      is independent of substrate concentration, and terminates by feedback inhibition
      when the concentration of nitrite produced approaches 2.5 mM. When bacilli in the
      oxygen restricted model are not supplemented with nitrate until they enter
      microaerophilic NRP stage 1, they exhibit an induction period before the rapid
      nitrate reduction starts. When the nitrate is not added until the bacilli have
      entered the anaerobic NRP stage 2, reduction of the substrate starts immediately.
      Nitrite is not reduced by M. tuberculosis in any stage of its growth or NRP.
      CONCLUSION: The hypoxically induced nitrate reduction probably serves a
      respiratory function in supporting hypoxic shiftdown of M. tuberculosis from
      aerobic growth to non-replication persistence and represents a useful new marker
      for monitoring that shiftdown. This response may help the bacilli survive in
      oxygen depleted regions of inflammatory or necrotic tissue, where nitrate can
      occur as a degradation product of nitric oxide.

PMID- 10645450
TI  - Suppression of lymphoproliferation by alveolar macrophages in the guinea pig.
AB  - SETTING: The relationship between alveolar macrophages (AM) and lymphocytes may
      be important in the early establishment of infection with Mycobacterium
      tuberculosis. AM in several species have been shown to suppress
      lymphoproliferation by producing inhibitors that include nitric oxide (NO).
      OBJECTIVE: To study this phenomenon in the guinea pig, the mitogen-induced
      proliferation of splenic lymphocytes was quantified under various conditions of
      co-culture with resident AM. RESULTS: Guinea pig AM consistently and profoundly
      suppressed proliferation in the co-cultures at AM:lymphocyte ratios of 1:4 or
      greater. The inclusion of a NO synthesis inhibitor, N-monomethyl-L arginine
      (NMMA), in the co-culture medium did not influence the suppression of Con A
      induced lymphoproliferation by resident guinea pig AM. No nitrite could be
      detected in supernatant fluids of co-cultured AM and splenocytes. Attempts to
      stimulate guinea pig AM with LPS in combination with recombinant murine and human
      IFN-gamma, infection with live Listeria monocytogenes, or incubation with the
      supernatants from ConA-activated guinea pig lymphocytes failed to generate NO
      metabolites. The addition of catalase or indomethacin to the Con A-induced AM
      splenocyte co-cultures, to inhibit hydrogen peroxide (H2O2) or prostaglandin E2
      (PGE2), respectively, did not counteract the suppression mediated by AM. Cell
      contact was necessary for the co-cultures to generate their inhibitory effects on
      lymphoproliferation, however, the suppression was actually mediated, at least in
      part, by soluble factors produced in the co-cultures. CONCLUSION: These results
      suggest that resident alveolar macrophages suppress lymphocyte proliferation in
      the guinea pig, but that the effect is not mediated by NO, PGE2 or H2O2. The
      failure to demonstrate NO synthesis under a variety of stimulatory conditions,
      which resulted in macrophage activation, suggests that the guinea pig is similar
      to the human in that regard.

PMID- 10645452
TI  - The influence of a perceptually linearized display on observer performance and
      visual search.
AB  - RATIONALE AND OBJECTIVES: The purpose of this study was to determine whether
      perceptual linearization of the tone scale affects the detection and visual
      search behaviors of radiologists searching mammograms for masses and
      microcalcifications. A perceptually linearized display is designed to match the
      capabilities of the human visual system more closely than a nonlinearized
      display. MATERIALS AND METHODS: Six radiologists viewed 50 pairs of mammograms,
      once on a perceptually linearized cathode-ray tube (CRT) monitor and once on a
      non-linearized CRT monitor. Eye position also was recorded as the observers
      searched the images for masses and microcalcifications. RESULTS: Observer
      performance was significantly (P = .003) better with the perceptually linearized
      display. Dwell times associated with true-negative decisions were significantly
      longer with use of the nonlinearized display. The number of fixation clusters
      generated during search was also greater with use of the nonlinearized display
      for the lesion-free images. CONCLUSION: A perceptually linearized display yields
      better detection performance and a more efficient visual search. Perceptually
      linearized displays should be used for reading radiographs displayed on CRT
      monitors.

PMID- 10645453
TI  - Physicians' attitudes toward misdiagnosis of pulmonary embolism: a utility
      analysis.
AB  - RATIONALE AND OBJECTIVES: The purpose of this study was to measure physicians'
      utilities for outcomes after ventilation-perfusion lung scanning and to explore
      physicians' attitudes toward misdiagnosis and the treatment of patients suspected
      of having pulmonary embolism (PE) in a quantitative manner by using a utility
      analysis. MATERIALS AND METHODS: Before ordering lung scanning for suspected PE,
      physicians rated five possible outcomes on a scale of 0-100 by using a computer
      order-entry system. These responses were rescaled and transformed to a utility
      measure by using the Torrance transformation. RESULTS: The mean utility for the
      potential outcomes after 341 lung scans were (a) no PE and no treatment (true
      negative, 93 +/- 22 [mean +/- standard deviation]), (b) PE with appropriate
      treatment (true-positive, 84 +/- 24), (c) no PE but patient received treatment
      (false-positive, 54 +/- 32), (d) PE but patient did not receive treatment (false
      negative, 14 +/- 23), and (e) death during pulmonary angiography (2 +/- 11).
      After lung scanning for acute PE, physicians placed greatest value on excluding
      the diagnosis (true-negative). Providing unnecessary treatment (false-positive)
      was valued in the midrange of utilities. The value of missing PE (false-negative)
      was rated almost equal to that of dying during pulmonary angiography. CONCLUSION:
      Physicians consider providing treatment for PE without objective confirmation of
      an embolus to be preferable to missing a case of PE.

PMID- 10645454
TI  - Binocular three-dimensional perception through stereoscopic generation from
      rotating images.
AB  - RATIONALE AND OBJECTIVES: The authors evaluated the clinical utility and
      potential applications of a binocular three-dimensional (3D) image display in
      diagnostic radiology. MATERIALS AND METHODS: Rotating video displays of computed
      tomographic (CT), magnetic resonance (MR) angiographic, and digital subtraction
      angiographic (DSA) image data were used to generate stereoscopic image displays
      with a 3D appearance. Eight physicians viewed and scored eight skeletal and eight
      vascular-interventional studies with a planar display mode and a cathode ray
      tube. Each physician then viewed the 3D display of the same data and assessed the
      change in image findings, as well as any corresponding changes in level of
      diagnostic confidence. RESULTS: Image findings changed in 78 (61%) of the 128
      studies after viewing the 3D displays. In 94 (73%) of all 128 studies, the
      interpreters reported increased confidence in their perception of the findings.
      Results for the vascular-interventional and skeletal cases were generally very
      similar. CONCLUSION: Binocular 3D stereoscopic displays from rotating images were
      reported to provide better image conceptualization and a higher degree of
      confidence in the findings on the images.

PMID- 10645455
TI  - Imaging the microcirculatory proton fraction of muscle with diffusion-weighted
      echo-planar imaging.
AB  - RATIONALE AND OBJECTIVES: The diagnosis of exertional compartment syndrome is
      challenging. In this feasibility study, diffusion-weighted echo-planar magnetic
      resonance imaging was performed in human subjects to determine whether
      alterations in the circulating blood volume of muscle secondary to exercise or
      changes in compartment pressure could be visualized. MATERIALS AND METHODS: The
      calf muscles of six subjects were studied before and after exercise and also
      during the application of external pressure to the calf. Gated, single-shot,
      diffusion-weighted echo-planar imaging (1.5 T) was implemented with signal
      averaging. Parametric images of the "perfusion" fraction (f) were generated, and
      regions of interest from anatomic compartments were analyzed. The precision of f
      was estimated by using propagation of error analysis. RESULTS: Parametric images
      depicted visible increases in the microcirculatory proton fraction (f) of calf
      muscle after exercise (mean change, +0.016) and visible decreases in f on the
      application of 40 mm Hg to the calf after exercise (mean change, -0.023). Mean
      changes in f were only significantly different from zero for the group, however,
      under conditions of applied pressure to the calf after exercise. Changes in f
      were not significantly different across muscle compartments. The error variance
      in f was approximately 0.01. CONCLUSION: Parametric images of f generated by
      diffusion-weighted echo-planar imaging may depict alterations in the circulating
      blood volume of muscle induced by exercise and changes in compartment pressure.
      The inherent imprecision of this technique, however, appears to limit its
      clinical utility.

PMID- 10645457
TI  - Radiology clerkships are necessary for teaching medical students appropriate
      imaging work-ups.

PMID- 10645456
TI  - Normalized BMD as a predictor of bone strength.
AB  - RATIONALE AND OBJECTIVES: In the noninvasive evaluation of bone quality, bone
      mineral density (BMD) has been shown to be the single most important predictor of
      bone strength and osteoporosis-related fracture. Among the methods of measuring
      BMD, dual x-ray absorptiometry (DXA) has widespread acceptance due to its low
      radiation, low cost, and high precision. However, DXA measures area BMD instead
      of true volumetric density; thus, a larger bone will tend to have a high BMD than
      will a smaller bone. Therefore, the comparison of BMDs of bones of different
      sizes can be misleading. In this study, the authors tried to compensate for the
      size effect by normalizing the area BMD with bone size as measured from a
      standard pelvic radiograph. MATERIALS AND METHODS: The overall method for
      calculation of normalized BMD included conventional area-based BMD from DXA and
      the extraction of geometric measures from pelvic radiographs. The database for
      analysis included 34 femoral neck specimens. Regression analysis was performed
      between the normalized volumetric BMD, measured from femoral neck region, and the
      mechanical properties obtained from trabecular bone cubes machined from the same
      region. RESULTS: After normalization of the area BMD, the coefficient of
      determination increased from 0.30 to 0.43 for the Young modulus and from 0.27 to
      0.37 for bone compressive strength. CONCLUSION: A noninvasive method of
      normalizing BMD can improve the prediction of bone mechanical properties and has
      potential in monitoring changes in growing skeletons and in the clinical
      evaluation of bone quality.

PMID- 10645458
TI  - Personal diary: a radiology nurse's perspective.

PMID- 10645459
TI  - Thin-section CT imaging of patients suspected of having appendicitis or
      diverticulitis.

PMID- 10645460
TI  - Testing for cancer susceptibility genes in children.
AB  - It is currently estimated that about 5% of all cancers are inherited or
      associated with a hereditary susceptibility or predisposition. This relatively
      small proportion has received a great deal of attention and publicity. Primary
      care physicians and pediatricians are frequently confronted with their patients'
      desire to know whether they and their children and relatives are at increased
      risk to develop cancer, whether it is possible to identify those who are, and
      what can be done in terms of prevention and management. This chapter addresses
      the complexities of recent cancer genetics information to aid the pediatrician in
      (1) identifying families at increased risk for inherited cancer susceptibility,
      and (2) recognizing those patients in the pediatric population who might benefit
      from presymptomatic gene testing.

PMID- 10645461
TI  - Effects of fitness training on endocrine systems in children and adolescents.

PMID- 10645462
TI  - Genetic errors of sexual differentiation.

PMID- 10645463
TI  - Advances in the recognition and treatment of endocrine complications in children
      with chronic illness.
AB  - Children with chronic illness live with the specific consequences of their
      illness, as well as secondary endocrine abnormalities that further compromise
      growth and pubertal development. These secondary abnormalities may significantly
      add to their physiologic and psychological burden. Although these endocrine
      abnormalities theoretically arise as adaptations to the chronic illness, they may
      have deleterious effects if they persist untreated. Children with HIV infection
      and other wasting disorders, for example, show growth suppression out of
      proportion to the severity of their primary illness as a result of growth hormone
      resistance and enhanced cortisol secretion. In hematologic conditions such as
      sickle cell anemia, thalassemia, or bone marrow transplant, damage to the
      hypothalamus and/or pituitary may lead to growth hormone deficiency, gonadal
      insufficiency, and hypothyroidism. Growth and pubertal delay are also common
      among children with cystic fibrosis, along with insulin-dependent diabetes
      mellitus caused by pancreatic fibrosis. Similarly, children receiving long-term
      steroid therapy have delays in growth and pubertal development, accompanied by
      risk for osteoporosis, whereas chronic renal disease is associated with growth
      and pubertal delay, as well as secondary hyperparathyroidism. Recognition of
      potential endocrinopathies in children with chronic illness is an important
      aspect of the care of these children because the disturbances are frequently
      amenable to treatment, permitting full or partial restoration of normal growth
      and development in these children. In this chapter, the endocrine consequences of
      common chronic conditions of childhood are reviewed, as well as the etiology of
      the endocrine disturbance, the clinical consequences, and recommendations for
      treatment.

PMID- 10645464
TI  - Leptin: molecular biology, physiology, and relevance to pediatric practice.

PMID- 10645465
TI  - Newer pediatric pathogens.
AB  - Newer laboratory techniques have allowed the detection of previously unrecognized
      microbial agents that are now pathogenic in children, as well as newly recognized
      manifestations of previously known pathogens. Clinical reports of these newer
      agents or manifestations are reviewed so that pediatricians can become familiar
      with these emerging infectious diseases. Physicians need to consider these
      organisms in the differential diagnosis in appropriate clinical illnesses.

PMID- 10645466
TI  - Viral hepatitis: expanding the alphabet.
AB  - Progress in understanding viral hepatitis has occurred at a rapid pace during the
      last 10 years; this has led directly to improvements in prevention, detection,
      and treatment. In previous reviews of viral hepatitis, only two forms of
      infectious hepatitis, hepatitis A and B, were recognized, and other unrecognized
      or uncharacterized agents were classified as "non-A, non-B." Currently, many more
      letters of the alphabet are required to designate the growing number of viral
      agents discovered through the application of the techniques of epidemiology and
      molecular virology. Furthermore, understanding of these viruses on the molecular
      level has led to the discovery of multiple subsets of these agents. This
      expansion of knowledge has immediate implications for bedside management,
      including the use of polymerase chain assays for diagnosis and management of
      chronic viral hepatitis, potent therapeutic antiviral drugs, and new vaccination
      strategies. In this chapter, we discuss these recent advances in the detection
      and management of viral hepatitis in children.

PMID- 10645467
TI  - Parvovirus infections in children and adults.

PMID- 10645468
TI  - Syndromes associated with immunodeficiency.
AB  - Immunodeficiency often has a genetic basis. Immune defects are the predominant
      manifestation in primary immunodeficiency disorders, and immune defects may also
      be associated with a number of other recognizable syndromes. There are 45
      recognized primary immunodeficiency disorders, but immunodeficiency has been
      reported in 105 other syndromes. Abnormalities associated with these syndromes
      include growth deficiency (19 syndromes with disproportionate or proportionate
      short stature); specific organ system dysfunction (39 with gastrointestinal,
      dermatologic, or neurologic abnormalities); inborn errors of metabolism (17);
      miscellaneous anomalies (17); and chromosome anomalies (13). In most of these
      disorders, immunodeficiency is present in only a portion of the patients.
      However, in 49 syndromes, immunodeficiency is present in the vast majority. We
      review the clinical manifestations of each syndrome and delineate the associated
      immune defects. For most, the underlying mechanism linking the immune defect and
      other anomalies is unclear. Recognition of these conditions involving both the
      immune and other organ systems may facilitate accurate diagnosis and management,
      as well as yield information regarding genes critical for the development of the
      involved systems.

PMID- 10645469
TI  - Protective nutrients and bacterial colonization in the immature human gut.
AB  - The normal human microflora is a complex ecosystem that is in part dependent on
      enteric nutrients for establishing colonization. The gut microbiota are important
      to the host with regard to metabolic functions and resistance to bacterial
      infections. At birth, bacterial colonization of a previously germ-free human gut
      begins. Diet and environmental conditions can influence this ecosystem. A breast
      fed, full-term infant has a preferred intestine microbiota in which
      bifidobacteria predominate over potentially harmful bacteria, whereas in formula
      fed infants, coliforms, enterococci, and bacteroides predominate. The pattern of
      bacterial colonization in the premature neonatal gut is different from that in
      the healthy, full-term infant gut. Those infants requiring intensive care acquire
      intestinal organisms slowly, and the establishment of bifidobacterial flora is
      retarded. A delayed bacterial colonization of the gut with a limited number of
      bacterial species tends to be virulent. Bacterial overgrowth is one of the major
      factors that promote bacterial translocation. The aberrant colonization of the
      premature infant may contribute to the development of necrotizing enterocolitis.
      Breast-feeding protects infants against infection. Oligo-saccharides and
      glycoconjugates, natural components in human milk, may prevent intestinal
      attachment of enteropathogens by acting as receptor homologues. Probiotics and
      prebiotics modulate the composition of the human intestinal microflora to the
      benefit of the host. These beneficial effects may result in the suppression of
      harmful microorganisms, the stimulation of bifidobacterial growth, or both. In
      the future, control and manipulation of the bacterial colonization in the
      neonatal gut may be a new approach to the prevention and treatment of intestinal
      infectious diseases of various etiologies.

PMID- 10645470
TI  - Umbilical cord blood banking.

PMID- 10645471
TI  - Hydrops fetalis: lysosomal storage disorders in extremis.
AB  - In recent years there has been an increased recognition that hydrops fetalis may
      be an extreme presentation of many of the lysosomal storage disorders. Hydrops
      fetalis, the excessive accumulation of serous fluid in the subcutaneous tissues
      and serous cavities of the fetus, has many possible etiologies, providing a
      diagnostic challenge for the physician. Ten different lysosomal storage disorders
      have now been diagnosed in infants with hydrops fetalis, including
      mucopolysaccharidosis (MPS) VII and IVA, type 2 Gaucher disease, sialidosis, GMI
      gangliosidosis, galactosialidosis, Niemann-Pick disease type C, disseminated
      lipogranulomatosis (Farber disease), infantile free sialic acid storage disease
      (ISSD), and mucolipidosis II (I-cell disease). Frequently, these inborn errors of
      metabolism are recognized only after the unfortunate recurrence of hydrops
      fetalis in several pregnancies of a family. Making the diagnosis relies on the
      physician having a high index of suspicion and ordering appropriate testing,
      which can often be performed prenatally. In several of these disorders, including
      MPS VII, infantile galactosialidosis, type 2 Gaucher disease, and ISSD, hydrops
      fetalis is a relatively common presentation. A greater physician awareness of
      hydrops fetalis as a presentation of lysosomal disease will facilitate
      establishing a diagnosis in cases that would have previously been considered
      idiopathic and will enable a better estimation of the incidence of this
      association. Lysosomal disorders are among the few causes of nonimmune hydrops
      fetalis in which an accurate recurrence risk can be ascertained. With an early
      and accurate diagnosis, genetic counseling and family planning can be offered in
      these difficult cases.

PMID- 10645472
TI  - Overgrowth syndromes: an update.

PMID- 10645473
TI  - Recent advances in Canavan disease.
AB  - More studies are needed to elucidate the pathophysiology of Canavan disease and
      how the inability to hydrolyze NAA leads to spongy degeneration. The creation of
      an animal model would be helpful in the understanding of the disease and the
      formulation of gene therapy.

PMID- 10645474
TI  - Advances in pediatric pharmacology, toxicology, and therapeutics.

PMID- 10645475
TI  - [Synthetic ribonucleases. 1. Synthesis and properties of conjugates, containing
      an RNA-binding fragment based on lysine residues and an RNA hydrolyzing fragment,
      bearing an imidazole residue].
AB  - A series of RNA-hydrolyzing constructions was synthesized on the basis of peptide
      like molecules containing residues of L-lysine, histamine and histidine methyl
      ester. These were shown to hydrolyze RNA effectively at neutral pH values. The in
      vitro transcript of tRNA(Lys) from human mitochondria and a tRNA-like fragment of
      RNA of Turnip Yellow Mosaic Virus were used in the experiments. Our chemical
      RNases quantitatively depolymerize some definite sequences (CA > or = UA > CG >>
      UC, CC, or CU) in both RNA molecules under optimum conditions. Moreover, no other
      sites were affected and no statistical hydrolysis was observed even after
      prolonged RNA incubation with the compounds of this series. The depolymerization
      rate of the RNA substrates exhibits a complex dependence on the concentration of
      ions of monovalent metals and on the concentration of the artificial
      ribonucleases.

PMID- 10645476
TI  - [Isolation and characteristics of high molecular weight cytolysins from the sea
      anemone Radianthus macrodactylus].
AB  - Three cytolytic toxins (RTX: RTX-A, RTX-S, and RTX-G) were isolated from the sea
      anemone Radianthus macrodactylus and characterized. The purification scheme
      involved hydrophobic chromatography on Polychrom-1, batch-chromatography on CM-23
      cellulose, gel filtration on Akrilex P-4, cation-exchange chromatography on CM-32
      cellulose, and HPLC on an ion-exchange Ultropac TSK CM-3SW column and a reversed
      phase Silasorb C18 column. The molecular masses of RTXs (ca. 20 kDa) were
      determined by SDS-PAGE in a density gradient of PAG. They are highly basic
      polypeptides (pI of 9.8 for RTX-A and RTX-S and 10.5 for RTX-G) containing
      similar amino acid compositions with a high content of basic and hydrophobic
      residues and the absence of Cys residues. The hemolytic activities of RTX-A, RTX
      S, and RTX-G were determined to be 3.5, 5.0, and 1.0 x 10(4) HU/mg, respectively.
      Exogenous sphingomyelin inhibits their action on the erythrocyte membrane. The N
      terminal sequence of RTX-A was determined to be ALAGAIIAGAGL/KGLKI/FLIEVLGEG-
      V/NKVKI-.

PMID- 10645477
TI  - [Point amino acid substitutions in the Ca2+-binding centers of recoverin. I.
      Mechanism of successive filling of Ca2+-binding centers].
AB  - The molecule of photoreceptor Ca(2+)-binding protein recoverin contains four
      potential Ca(2+)-binding sites of the EF-hand type, but only two of them (the
      second and the third) can actually bind calcium ions. We studied the interaction
      of Ca2+ with recoverin and its mutant forms containing point amino acid
      substitutions at the working Ca(2+)-binding sites by measuring the intrinsic
      protein fluorescence and found that the substitution of Gln for Glu residues
      chelating Ca2+ in one (the second or the third) or simultaneously in both (the
      second and the third) Ca(2+)-binding sites changes the affinity of the protein to
      Ca2+ ions in different ways. The Gln for Glu121 substitution in the third site
      and the simultaneous Gln substitutions in the second (for Glu85) and in the third
      (for Glu121) sites result in the complete loss of the capability of recoverin for
      a strong binding of Ca(2+)-ions. On the other hand, the Gln for Glu85
      substitution only in the second site moderately affects its affinity to the
      cation. Hence, we assumed that recoverin successively binds Ca(2+)-ions: the
      second site is filled with the cation only after the third site has been filled.
      The binding constants for the third and the second Ca(2+)-binding sites of
      recoverin determined by spectrofluorimetric titration are 3.7 x 10(6) and 3.1 x
      10(5) M-1, respectively.

PMID- 10645478
TI  - [Mechanism of action of aspartyl proteinases. VI. Nonvalent enzyme-inhibitory and
      enzyme-substrate complexes of the aspartyl proteinase rhizopus pepsin].
AB  - The structure of a complex of rhizopuspepsin, a fungal aspartyl protease, with
      Pro1-Phe2-His3-Phe4-psi[CH2-NH]-Phe5-Val6, its substrate-like inhibitor, was
      calculated by theoretical conformational analysis. The search for energetically
      favorable conformational variants of the ligand structure was based on the
      fragmental approach using the dynamic library of peptide fragments, which were
      successively extended in the potential field of the protein. The root-mean-square
      deviation of atom positions in the calculated and experimental inhibitor
      conformations was 0.56 A. A similar approach was used to model a noncovalent
      complex of rhizopuspepsin with Pro1-Phe2-His3-Lys4-Phe5-Val6, its specific
      substrate. As a result, two isoenergetic structures of the complex with different
      arrangements of the cleavable peptide group and a nucleophilic water molecule
      were calculated. The possibility of the achieving each of these conformations
      during the catalytic act is considered. It is shown that there are no structural
      prerequisites for the distortion of the cleavable bond in the active site of the
      enzyme. On the basis of the resulting structural data, the assumption was made
      that Asp35 may be protonated at a late stage of formation of the tetrahedral
      intermediate rather than at the basic state of the complex.

PMID- 10645479
TI  - [Interaction of 3'-fluoro-3'-deoxyanalogs of a trimer of (2'-5')oligoadenylic
      acid with (2'-5')A3-antibodies: stereochemical aspect].
AB  - Mouse antibodies to (2'-5')oligoadenylates were obtained by the immunization of
      animals with the (2'-5')oligoadenylic acid trimer conjugated with bovine serum
      albumin through a 2',3'-levulinic acid residue. Using radioimmunoassay, the
      reactivity of mouse polyclonal antibodies to the (2'-5')oligoadenylic acid trimer
      was studied for the trimer analogues containing 9-(3-deoxy-3-fluro-beta-D-
      xylofuranosyl)adenine and 3'-deoxy-3'-fluoro-adenosine in various positions of
      the chain. It was found that (a) the three-dimensional structure of short
      oligonucleotides is an important factor in the antibody recognition; (b)
      antibodies are more sensitive to modifications of the 5'-terminal and central
      ribose fragments of the (2'-5')oligoadenylic acid trimer; (c) the 3'-hydroxyl
      group plays a secondary role in the formation of the antigen determinant.

PMID- 10645480
TI  - [Comparative study of the reactability of phosphoric acid residues in tRNA(Ser)
      and tRNA(Leu) from Thermus thermophilus].
AB  - The reactivity of phosphates in the Thermus thermophilus tRNA(Ser) (GCU) and
      tRNA(Leu) (CAG) was studied using the ethylnitrosourea modification. It was shown
      that phosphates of nucleotides 58-60 (T loop), 20-22 (D loop), and 48 (at the
      junction of the variable and T stems) were poorly modified in both tRNAs. The
      most pronounced differences in the reactivity were observed for phosphates at the
      junctions of the variable stem with T-stem (47q, 49) and anticodon stem (45).
      This indicates differences in orientations of the long variable arm relative to
      the backbone in the tRNAs studied.

PMID- 10645481
TI  - [Pentacyclic steroid analogs: interaction of 16 alpha,17 alpha
      cyclopentanoprogesterone with rat uterus proteins].
AB  - Using 3H-labeled derivatives, kinetic parameters of specific binding of
      progesterone (I) and 16 alpha, 17 alpha-cyclopentanoprogesterone (II) to proteins
      of the uterus soluble fraction in rats were measured. It was shown that their
      affinities to proteins are comparable (K 10.5 +/- 2.4 and 6.7 +/- 3.4 nM for (I)
      and (II), respectively, upon 22 h incubation). The unlabeled compound (II) can
      displace [3H]progesterone from complexes with the protein with a concentration
      independent efficiency corresponding to the ratio of K values for compounds (I)
      and (II). At the same time, the efficiency of the unlabeled progesterone in the
      displacement of [3H]compound (II) from protein complexes fell with an increase in
      the progesterone concentration. The concentration of high-affinity sites of
      [3H]compound (II) exceeded by 1.5 to 2 times the concentration of sites for
      [3H]progesterone. Dynamics of dissociation of proteins complexes of
      [3H]progesterone and 3H]compound (II) had a two-phase character with a decrease
      in the dissociation rate constants for both phases as the times of exposition of
      [3H]ligands to proteins grew. The ratio of slow- and fast-dissociating ligand
      receptor complexes was thereby unchanged. These data suggest the presence in the
      rat uterus soluble fraction of two types of proteins differing in the capacity to
      recognize the additional five-membered ring D' in the steroid molecule.

PMID- 10645482
TI  - [Preparation and certain properties of the liposomal substance 2,4-di(1-methyl-3
      hydroxybutyl)deuteroporphyrin-IX].
AB  - A liposome preparation of a porphyrin photosensitizer for photodynamic therapy of
      tumors (PDT) was obtained. The in vitro efficiency of the photosensitizer was
      enhanced 2.5-fold through the liposome formulation. The composition and some
      properties of the new preparation were studied. An algorithm for a complex
      approach to the prediction of photosensitizer efficiencies by model experiments
      in vitro was developed. This approach is based on the use of two models: the
      determination of coefficient of distribution between n-octanol and a phosphate
      buffer, pH 7.4, and the determination of the cytotoxic effect on the culture of
      CaOv ovarian adenocarcinoma cells.

PMID- 10645483
TI  - [Characteristics of the cDNA of the Schizosaccharomyces pombe rpa43+ gene:
      structural similarity of the Rpa43 subunit of RNA-polymerase I with the Rpc25
      subunit of RNA-polymerase III].
AB  - We isolated and characterized full-length cDNA of the rpa43+ gene encoding one of
      subunits of the nuclear RNA polymerase I of Schizosaccharomyces pombe. The gene
      contains two introns and is located on chromosome II. Comparison of the primary
      structure of the subunit Rpa43 of Sz. pombe (173 aa; M 19,385 Da; pl 5.36),
      deduced from the cDNA obtained, with the amino acid sequences of subunits A43
      from Saccharomyces cerevisiae and Drosophila melanogaster demonstrates a high
      divergence of this protein in evolution. A comparison of the Rpa43 with other
      proteins from the SwissProt database revealed a similarity of this subunit to
      subunit Rpc25 of RNA polymerase III, which, as was shown previously, is
      structurally similar to subunit Rpb7 of RNA polymerase II. Thus, including the
      Rpa43<-->Rpc25<-->Rpb7 family, nuclear RNA polymerases I-III contain at least 11
      identical and/or similar subunits. This fact illustrates a pronounced resemblance
      of the organization of all three enzymes of the eukaryotic transcription
      apparatus. Moreover, at least ten out of these eleven families of eukaryotic RNA
      polymerase subunits have homologues in the 13-subunit archaeal RNA polymerase.

PMID- 10645484
TI  - [alpha-Neurotoxins and alpha-conotoxins--nicotinic cholinoreceptor blockers].
AB  - The review is devoted to the competitive blockers of different nicotinic
      acetylcholine receptors, alpha-neurotoxins from snake venoms, and alpha
      conotoxins from marine snails of the Conidae family. The relationship between the
      structure and function of these toxins is discussed. Recent data on the mechanism
      of alpha-neurotoxin and alpha-conotoxin interaction with the nicotinic
      acetylcholine receptor are presented.

PMID- 10645485
TI  - [Endogenous immunoregulatory peptides (myelopeptides): structure, function, and
      mechanism of action].
AB  - Previously unknown bioregulators from bone marrow, myelopeptides, were isolated,
      identified, and synthesized, and their biological properties and mechanism of
      action were studied in detail. Phe-Leu-Gly-Phe-Pro-Thr (MP-1) manifests an
      immunocorrecting effect by restoring the level of antibody production in animals
      suffering from immunodeficiencies of various etiologies; Leu-Val-Val-Tyr-Pro-Trp
      (MP-2) manifests an antitumor effect by abolishing the inhibitory action of tumor
      cells on the functional activity of T-lymphocytes; Leu-Val-Cys-Tyr-Pro-Gln (MP-3)
      stimulates phagocytosis by macrophages and, in this way, protects animals from
      infections caused by pathogenic microorganisms; and Phe-Pro-Arg-Ile-Met-Thr-Pro
      (MP-4) is a new factor of cell differentiation inducing terminal cell
      differentiation in the HL-60 and K-562 leukemic cell lines.

PMID- 10645487
TI  - [Retroviral regulators of gene expression in the human genome as possible factors
      for its evolution].
AB  - Human endogenous viruses, including their possible role in evolution, are
      reviewed.

PMID- 10645488
TI  - [Molecular evolution and structure of eukaryotic nuclear RNA polymerase subunits
      in light of the exon-intron organization of their genes].
AB  - Analysis of literary data (for Saccharomyces cerevisiae, Caenorhabditis elegans,
      Arabidopsis thaliana, Homo sapiens, and some other Eucarya) and our data (for
      Schizosaccharomyces pombe) on the exon-intron organization of the genes encoding
      subunits of nuclear RNA polymerases showed that introns in the orthologous genes
      from different organisms are arranged nonrandomly, namely, their positions, if
      projected on the map of the comparison of the amino acid sequences of the
      orthologous subunits, not infrequently coincide in evolutionarily distant
      species. As a rule, intron positions correspond to the boundaries of the
      structurally conserved regions (domains) or to the sites of possible turns of the
      polypeptide chain. For example, introns flank the secondary structure elements in
      the Rpb8 subunit with the known three-dimensional structure or the structure
      function modules in subunits Rpb10 and Rpc10. These facts are in agreement with
      the idea of the ancient origin of introns, and with the notion of evolution of
      ancient protein sequences through the assembly of their genes from short
      protoexons selected by the nature as far back as the RNA world times. Comparative
      analysis of the primary structures of the subunits of eukaryotic RNA polymerases
      allowed us to reveal a nuclear localization signal in subunit Rpb10 and some
      hypothetical archaeal homologues of subunit Rpc10.

PMID- 10645486
TI  - [L-glutamic acid--a modulator of the physiological status of myeloid series blood
      cells].
AB  - The effects of L-glutamic acid on the differentiation of HL-60 and K-562 cell
      lines and on the expression level of mRNAs encoding IL-1 beta, IL-6, and TNF
      alpha were studied. It was shown that TNF alpha actively induces the
      differentiation of these cell lines, whereas L-glutamic acid enhances its effect.
      Our results indicated that L-glutamic acid modulates the physiological state of
      the myeloid cell line in blood, in particular, by affecting both the reception
      and expression of cytokines functionally important for these cells.

PMID- 10645489
TI  - [Fluorescence resonance energy transfer in the study of nucleic acids].
AB  - Recent data are reviewed on the employment of fluorescence resonance energy
      transfer (FRET) in studying hybridization and higher structures of nucleic acids
      as well as their enzyme- and ribozyme-catalyzed reactions.

PMID- 10645490
TI  - [Conjugates of polyacrylamide with oligonucleotides and their mimetics for
      diagnostic purposes].
AB  - Approaches to preparing acrylamide and polyacrylamide conjugates with
      oligonucleotides and some peptide nucleic acid-related DNA mimics are considered.
      Their physicochemical properties and application to the nucleic acid analysis are
      discussed.

PMID- 10645491
TI  - [Fluorescent lipid probes: properties and application].
AB  - This review is devoted to fluorescent lipid probes: the characteristics of their
      fluorophores; the main methods of their synthesis; and the potentialities, scope,
      and limitations of their use in studies of biological systems (cells, membranes
      and their models, enzymes of lipid metabolism, etc.). Particular attention is
      paid to the lipid specificity of the probes, i.e., the correspondence of their
      physicochemical characteristics and behavior in biological systems to those of
      natural lipids.

PMID- 10645492
TI  - [Molecular design of polymeric materials for biotechnology and medicine].
AB  - This review describes new polymer materials for biomedical applications developed
      in the Polymers for Biology Laboratory of the Shemyakin-Ovchinnikov Institute of
      Bioorganic Chemistry, Russian Academy of Sciences. These include composite rigid
      sorbents for biochromatography, polymer dispersions for immunoassay, polymer
      hydrogels for immobilization of enzymes and cells, and polymer ultra thin films
      as biomembrane models and materials for biosensors. Some general and specific
      properties of these new materials and models as well as examples of their
      applications are discussed.

PMID- 10645493
TI  - Palliative care and rehabilitation of cancer patients.

PMID- 10645494
TI  - Pain management: pharmacological approaches.

PMID- 10645495
TI  - Cancer anorexia/cachexia.

PMID- 10645496
TI  - Palliation of abdominal symptoms.

PMID- 10645497
TI  - Palliation of breathlessness.

PMID- 10645498
TI  - Physical rehabilitation of the cancer patient.
AB  - Significant numbers of cancer patients have physical limitations as a result of
      their cancer or its treatment. Most commonly, this impairment results from
      prolonged bed rest and deconditioning syndrome or neurologic loss frequently
      coupled with deconditioning. What few studies have been done show that functional
      improvement through rehabilitation does occur. For many cancer patients,
      rehabilitation is an appropriate option, viewed favorably by patients and their
      families. However, as opposed to other causes of impairment, the benefits and
      goals of rehabilitation must be carefully weighed in concert with the goals of
      the cancer patient, all in an effort to add to his or her quality of life.

PMID- 10645499
TI  - Rehabilitation of head and neck cancer patients.

PMID- 10645500
TI  - Rehabilitation of breast cancer.
AB  - Breast cancer is a complicated disease treated with multimodality therapy. Adult
      women of any age can develop breast cancer, and most will be cured. Treatment of
      primary disease is associated with more side effects than the cancer. The process
      of metastatic cancer to death can be long. The entire family is affected by
      breast cancer whether early or late. A rehabilitation program must address the
      physical and psychosocial aspects of breast cancer, both at presentation and at
      recurrence. For a patient with early breast cancer, lifestyle changes may be
      important. A primary goal of a rehabilitation program is that each breast cancer
      patient should become well informed regarding treatment and its consequences
      (Table 9) in order to continue with her life. Treatment to recover the patient to
      her former physical and psychosocial state, and therapy for chronic problems from
      breast cancer or its treatment, requires an approach distinct from that given to
      other malignancies. Issues regarding survival prevail in any rehabilitation
      program for both early and late breast cancer.

PMID- 10645501
TI  - Rehabilitation of prostate cancer.

PMID- 10645502
TI  - The research palliative care unit.

PMID- 10645503
TI  - Palliative care education: a global imperative.

PMID- 10645504
TI  - Assessing quality of life in palliative care.

PMID- 10645505
TI  - Family practice and its midlife crisis.

PMID- 10645506
TI  - Learning from patient noncompliance.

PMID- 10645507
TI  - Evaluation as a dynamic process.

PMID- 10645508
TI  - Finding solutions through the eyes of our patients.

PMID- 10645509
TI  - Illinois RMED: a comprehensive program to improve the supply of rural family
      physicians.
AB  - BACKGROUND: Rural areas of the United States are perennially medically
      underserved, and the state of Illinois is no exception. A recent survey showed
      that 75 of Illinois' 84 rural counties are primary care physician shortage areas.
      In response to this chronic physician shortage, the Illinois Rural Medical
      Education (RMED) Program was developed by the University of Illinois College of
      Medicine at Rockford. The RMED program is a comprehensive, multifaceted program
      that combines recruitment, admissions, curriculum, support, and evaluation
      components and is longitudinal across all 4 years of the medical school
      experience. The admissions process seeks to select students who possess traits
      indicative of success in eventual rural family practice. These traits are
      fostered and developed by the 4-year rural curriculum, which emphasizes family
      medicine, community-oriented primary care, the physician functioning in the
      context of community, relevant aspects of the "hidden" curriculum, and service
      learning. After 6 years, RMED has graduated 39 physicians; 69% have gone into
      family practice, and a total of 82% have selected primary care residencies.

PMID- 10645510
TI  - An evaluation of statewide strategies to reduce antibiotic overuse.
AB  - BACKGROUND: The rapid increase of antibiotic resistance poses a significant
      threat to human health. Overuse of antibiotics has been linked to rates of
      antibiotic resistance. This study assessed the utility of two common
      interventions--1) practice profiling and feedback and 2) patient education
      materials--implemented to decrease antibiotic prescribing for pediatric upper
      respiratory infections (URIs). METHODS: Based on Medicaid regions in Kentucky,
      primary care physicians managing pediatric respiratory infections in Medicaid
      were randomized into four groups. Groups received either 1) performance feedback
      only, 2) patient education materials only, 3) both feedback and education
      materials, or 4) no intervention. Participating physicians had their antibiotic
      prescribing assessed for the period of July 1, 1996, to November 30, 1997, with
      an intervention in June 1997. The study included 216 physicians and 124,092
      episodes of care. RESULTS: All groups increased in proportion of episodes with
      antibiotics between the pre-intervention and post-intervention periods.
      Prescribing in the patient education group and the patient education and feedback
      group increased at a significantly lower rate than in the control group.
      Physicians did not change their coding of illness to justify antibiotics after
      the intervention, and there was no significant generalization of effect of the
      pediatric intervention on prescribing for adult URIs. CONCLUSIONS: These
      interventions demonstrate little if any impact on promoting appropriate
      antibiotic prescribing. Antibiotic prescribing for viral respiratory infections
      continues to increase, suggesting concomitant increases in antibiotic resistance.

PMID- 10645511
TI  - Suggested curriculum guidelines on complementary and alternative medicine:
      recommendations of the Society of Teachers of Family Medicine Group on
      Alternative Medicine.
AB  - BACKGROUND AND OBJECTIVES: The widespread use of alternative and complementary
      therapies by the public provides a new challenge to medical education. No
      standardized curriculum is available for medical educators in this field.
      Providing an adequate background on these therapies and reliable, useful
      information to our learners was a task addressed by the Society of Teachers of
      Family Medicine (STFM) Group on Alternative Medicine over the past 2 years.
      METHODS: The group met at conferences and communicated via e-mail to develop a
      consensus of recommended knowledge, skills, and attitudes in complementary and
      alternative medicine for incorporation into the family practice residency
      training curriculum. CONCLUSION: This article suggests guidelines as developed by
      this STFM group to assist programs wishing to include formal training in
      complementary and alternative medicine in residency training.

PMID- 10645512
TI  - Why geriatrics? Academic geriatricians' perceptions of the positive, attractive
      aspects of geriatrics.
AB  - BACKGROUND: Recruitment of geriatrics trainees has been poor, and the current
      shortage of academic geriatricians is expected to worsen. Although barriers to
      entering geriatrics practice have been identified, a review of the literature
      found few studies about why people choose to enter geriatrics. METHODS: We used
      qualitative methods to investigate the positive, attractive aspects of
      geriatrics. Long interviews with six academic geriatricians were taped and
      transcribed. Transcripts were entered into a textual database computer program
      and reviewed independently by two investigators. RESULTS: Six themes emerged: 1)
      traditional learning experiences, 2) value on personal relationships, 3) a
      perception of distinctive differences, 4) a desire to feel needed personally and
      societally, 5) prefer democracy versus autocracy, and 6) desire intellectual
      challenges. Academic geriatrics, therefore, is particularly attractive to people
      who value enduring relationships, see challenges in complexity, practice social
      responsibility, prefer working within a multidisciplinary team, and derive
      satisfaction from making seemingly small but nonetheless important changes in
      peoples' lives. CONCLUSIONS: If further studies validate these findings, they
      could promote geriatrics as a career, by, for example, identifying students and
      family practice and internal medicine residents who share these values, beliefs,
      and attitudes and encouraging them to consider this important field.

PMID- 10645513
TI  - Cardioprotection of SM-15681, an Na+/H+ exchange inhibitor in ischemic and
      hypoxic isolated perfused rat hearts.
AB  - We investigated the effects of SM-15681 (N-(aminoiminomethyl)-1-methyl-1H-indole
      2-carboxamide monohydrochloride) on Na+/H+ exchange activity in the myocardium
      and in ischemic and hypoxic injury in isolated perfused rat hearts. These effects
      were compared with those of ethylisopropyl amiloride (EIPA). Na+/H+ exchange
      activity was studied with a NH4Cl prepulse technique under HCO3(-)-free
      conditions. SM-15681 (10(-8)-10(-7) M) inhibited pH recovery of acidosis in the
      rat myocardium in a concentration-dependent manner and the IC50 value of SM-15681
      (80 nM) was similar to that of EIPA. In perfused rat hearts, SM-15681 (10(-6) M)
      and EIPA (10(-6) M) significantly improved cardiac functions and prevented enzyme
      release and abnormal elevation of tissue Ca2+ content during 20 min of
      reperfusion after 40 min of ischemia and 20 min of reoxygenation after 30 min of
      hypoxia. We conclude that an Na+/H+ exchange inhibitor, SM-15681, shows
      cardioprotective effects on ischemia/reperfusion and hypoxia/reoxygenation
      injury. Our results also support the hypothesis that Na+/H+ exchange contributes
      to the pathophysiology of cardiac ischemic reperfusion injury.

PMID- 10645514
TI  - The beneficial antiinflammatory effect of dexamethasone administration prior to
      reperfusion on the viability of cold-stored skin flaps.
AB  - The main purpose of this study was to investigate the possible protective effect
      of a single dose of glucocorticoid dexamethasone administered just before
      reperfusion on the viability of cold-stored inferior epigastric rat skin flaps.
      We also sought evidence for the antiinflammatory mechanism of action of
      dexamethasone involved in this model of cold ischemia-reperfusion. The viability
      of flaps on reperfusion day 7, after 1, 2, 3, 4, or 5 days of cold ischemia, was
      80, 74, 60, 47 and 12% respectively. Four days' cold ischemia time was chosen to
      test the effect of intraperitoneal dexamethasone administration (2.5 mg/kg) 30
      min prior to reperfusion. Flap survival after 4 days' cold ischemia/7 days'
      reperfusion increased significantly from a mean of 37.0% survival in saline
      treated controls to 73.3% in dexamethasone-treated rats (p < 0.05). Dexamethasone
      treatment also resulted in significantly lower skin flap water content (a measure
      of edema) and myeloperoxidase activity (an indicator of neutrophil infiltration)
      but had no significant effect on skin levels of hydroperoxides (a measure of free
      radical activity). In conclusion, dexamethasone attenuates ischemia-reperfusion
      injury in cold-stored skin flaps by reducing the tissue levels of several
      proinflammatory mediators.

PMID- 10645515
TI  - Prostaglandin E1 influences serum cholesterol esterase and lipase activity in
      different ways.
AB  - The in vitro and in vivo effects of prostaglandin E1 on cholesterol ester
      hydrolase (CEase) and lipase [glycerol ester hydrolase (GEH)] activity in human
      serum were examined. Cholesterol esterase and lipase activity in the sera of men
      with atherosclerosis differed substantially from that in the control subjects.
      CEase activity was raised and GEH activity suppressed in the serum of men with
      atherosclerosis compared with controls. Prostaglandin E1 in vitro was found to
      suppress lipase but to increase cholesterol esterase activity to some extent.
      However, in vivo activities of GEH and CEase in the sera of men with chronic
      arterial occlusions of the lower limbs treated with prostaglandin E1 revealed
      that lipase activity was increased but that cholesterol esterase activity was
      unchanged. Recent studies have demonstrated that by altering the metabolic
      pathways of acylcholesterols and triacylglycerols, prostaglandin E1 may lead to
      the development of new strategies for retarding atherosclerosis.

PMID- 10645516
TI  - A comparative study of policosanol Versus acipimox in patients with type II
      hypercholesterolemia.
AB  - An 8-week, randomized, double-blind study comparing the efficacy and tolerability
      of policosanol and acipimox was conducted in patients with type II
      hypercholesterolemia. Prior to entry into active treatment, all patients followed
      a standard cholesterol-lowering diet for 12 weeks. Sixty-three patients were
      randomized to receive either policosanol (10 mg/day) or acipimox (750 mg/day)
      tablets for 8 weeks under double-blind conditions. Both groups were similar at
      randomization. Policosanol significantly reduced total cholesterol (p < 0.0001)
      (15.8%), low-density lipoprotein (LDL)-cholesterol (21%) and the ratios of LDL
      cholesterol to high-density lipoprotein (HDL)-cholesterol (15.8%) and cholesterol
      to HDL-cholesterol (11.5%). Acipimox significantly lowered both cholesterol and
      LDL cholesterol by 7.5%. The percent changes of total cholesterol, LDL
      cholesterol and both ratios were larger in the policosanol group than in the
      acipimox group. Both drugs were well tolerated. Acipimox significantly increased
      (p > 0.001) aspartate amino transferase levels but only four patients showed
      increases above the normal limit. Policosanol significantly reduced creatinine
      values (p > 0.05) but no patients had values out of the normal range. Four
      patients withdrew from the study (two from each group) but none withdrew because
      of adverse effects. No adverse effects were reported in the policosanol group,
      while five patients on acipimox reported adverse effects (hot flushes, nausea,
      vomiting, headache, hypochondrial pain and leg edema). These results indicate
      that policosanol (10 mg/day) was more effective and well tolerated than was
      acipimox (750 mg/day) in this study population.

PMID- 10645517
TI  - Staging of twin-twin transfusion syndrome.
AB  - OBJECTIVE: The purpose of this study was to evaluate the prognostic value of
      sonographic and clinical parameters to develop a staging classification of twin
      twin transfusion syndrome (TTTS). STUDY DESIGN: Severe TTTS was defined as the
      presence of polyhydramnios (maximum vertical pocket of > or = 8 cm) and
      oligohydramnios (maximum vertical pocket of < or = 2 cm). Nonvisualization of the
      bladder in the donor twin (-BDT) and absence of presence of hydrops was also
      noted. The middle cerebral artery, umbilical artery, ductus venosus, and
      umbilical vein in both fetuses were assessed with pulsed Doppler. Critically
      abnormal Doppler studies (CADs) were defined as absent/reverse end-diastolic
      velocity in the umbilical artery, reverse flow in the ductus venosus, or
      pulsatile flow in the umbilical vein. TTTS was staged as follows: stage I, BDT
      still visible; stage II, BDT no longer visible, no CADs; stage III, CADs; stage
      IV, hydrops; stage V, demise of one or both twins. Laser photocoagulation of
      communicating vessels (LPCV) or umbilical cord ligation was performed depending
      on the severity of the condition. The study was approved by the Institutional
      Review Board of St. Joseph's Hospital in Tampa and by the Fetal Therapy Board at
      Hutzel Hospital, Detroit, and all patients gave informed consent. RESULTS: A
      total of 80 of 108 referred patients met criteria for surgery, but only 65 were
      treated surgically: 48 with LPCV and 17 with umbilical cord ligation. Complete
      Doppler data were obtainable in 41 of 48 LPCV patients. Survival rates by stage
      for one or two fetuses were statistically different (chi-squared analysis = 12.9,
      df = 6, p = 0.044). Neither percent size discordance nor gestational age at
      diagnosis were predictive of outcome. CONCLUSION: Staging of TTTS using the
      proposed criteria has prognostic significance. This staging system may allow
      comparison of outcome data of TTTS with different treatment modalities.

PMID- 10645518
TI  - A 12-hour urine collection accurately assesses proteinuria in the hospitalized
      hypertensive gravida.
AB  - OBJECTIVE: To determine whether a urine collection of < 24 hours duration
      accurately assesses the level of proteinuria in inpatients being evaluated for
      preeclampsia. STUDY DESIGN: Patients admitted to the University of Mississippi
      between January and June of 1998 for evaluation of preeclampsia underwent two
      consecutive 12-hour urine collections. Each collection was analyzed for total
      protein, total calcium, total volume, and urine creatinine. A concurrent serum
      creatinine value was obtained. The protein:creatinine ratio, calcium: creatinine
      ratio, and creatinine clearance were calculated. Pearson's correlation,
      sensitivity, specificity, and positive and negative predictive values were
      assessed. RESULTS: A total of 25 patients (86%) were preeclamptic. Total protein,
      the protein: creatinine ratio, and serum creatinine were significantly correlated
      between the first and second urine collection. The sensitivity and specificity of
      the 12-hour urine collection was 96% and 100%, respectively. CONCLUSION: A 12
      hour urine collection accurately depicts the amount of proteinuria in
      hospitalized gravidas being evaluated for preeclampsia.

PMID- 10645519
TI  - Recommended permissible noise criteria for occupied, newly constructed or
      renovated hospital nurseries. The Sound Study Group of the National Resource
      Center.
AB  - OBJECTIVE: To base permissible noise criteria for occupied, new nurseries on
      research findings. STUDY DESIGN: An interdisciplinary group of clinicians
      reviewed the literature regarding the effect of sound on the fetus, newborn, and
      preterm infant and based recommended criteria on the best evidence. An external
      panel subsequently reviewed the criteria. RESULTS: The recommended criteria:
      Patient bed areas and the spaces opening onto them shall be designed to produce
      minimal ambient noise and to contain and absorb much of the transient noise that
      arises within the nursery. The overall, continuous sound in any bed space or
      patient care area shall not exceed: (1) an hourly Leq of 50 dB and (2) an hourly
      L10 of 55 dB, both A-weighted, slow response. The 1-second duration Lmax shall
      not exceed 70 dB, A-weighted, slow response. CONCLUSION: The permissible noise
      criteria will protect sleep, support stable vital signs, and improve speech
      intelligibility for many infants most of the time.

PMID- 10645520
TI  - Predicting the risk of jaundice in full-term healthy newborns: a prospective
      population-based study.
AB  - OBJECTIVE: The need to recognize infants that are at high risk for developing
      significant jaundice is apparent in the era of routine early discharge. The aim
      of the present study was to prospectively determine the ability to predict severe
      hyperbilirubinemia in term healthy newborns (defined as total serum bilirubin of
      > 10.0 mg/dl at day 2, > 14.0 mg/dl at day 3, and > 17.0 mg/dl at days 4 and 5 of
      life). DESIGN: Prospective study of 1177 healthy term newborns. SETTING: Two
      university-affiliated community hospitals in Jerusalem. RESULTS: Using a multiple
      logistic regression analysis, neonatal jaundice was best predicted (p < 0.0001)
      by day 1 serum bilirubin (adjusted odds ratio of 3.1 [per mg/dl] [95% confidence
      limits of 2.4 to 4.1]) and by a change in serum bilirubin from the first to the
      second day of life (2.4 [per mg/dl] [1.9 to 3.0]). Maternal blood type 0 (2.9
      [1.5 to 5.8]), age (1.1 [per year] [1.0 to 1.2]), schooling (0.8 [per year] [0.7
      to 0.9]), and full breastfeeding (0.4 [0.2 to 0.9]) were also associated with
      jaundice (p < 0.005). Other factors considered in the regression model but not
      found to be significantly related to jaundice included maternal ethnic origin,
      smoking, hypertension, diabetes mellitus, intranatal administration of oxytocin,
      meperidine, anesthesia, premature rupture of the membranes, parity, newborn sex,
      birth weight, gestational age, presentation. Apgar scores, blood type,
      hematocrit, cephalohematoma, and history of jaundice in other siblings. A model
      for predicting neonatal jaundice based on the above factors had a sensitivity of
      81.8%, a specificity of 82.9%, a false positive rate of 80.2%, and a false
      negative rate of 1.1%. CONCLUSION: Individual risk assessment on discharge in
      association with day 1 total serum bilirubin is of value in identifying infants
      at greater risk for neonatal jaundice.

PMID- 10645521
TI  - Parenteral selenium supplementation in extremely low birth weight infants:
      inadequate dosage but no correlation with hypothyroidism.
AB  - OBJECTIVE: Selenium is an essential trace element, known to be important in
      thyroid metabolism. We speculated that parenteral selenium supplementation is
      inadequate in preterm infants and may contribute to the development of
      hypothyroidism. STUDY DESIGN: Serum selenium and thyroid function were evaluated
      on day 10 of life in extremely low birth weight infants. Selenium intake provided
      by parenteral nutrition was prospectively evaluated. RESULTS: Selenium intake was
      close to the recommended 2 micrograms/kg per day. Serum selenium values were 0.54
      +/- 0.13 microM (mean +/- SD, n = 29). Selenium serum levels were low in 26 of 29
      infants. In infants with subnormal serum selenium levels, free T4 was transiently
      low in 10 of 26 infants but was normal in 16 of 26 infants. No significant
      correlation was found between serum selenium levels and hypothyroidism.
      CONCLUSION: Current selenium supplementation guidelines may be inadequate in
      extremely low birth weight infants. However, selenium deficiency does not seem to
      play a major role in neonatal hypothyroidism.

PMID- 10645522
TI  - Early postnatal dexamethasone increases the risk of focal small bowel perforation
      in extremely low birth weight infants.
AB  - OBJECTIVE: We observed two clusters of spontaneous pneumoperitoneums in extremely
      low birth weight infants during the use of a protocol for early dexamethasone
      prophylaxis (EDP) for bronchopulmonary dysplasia from 1996 to 1997. During
      surgery, focal small bowel perforation (FSBP) was found in eight of nine cases. A
      retrospective study was designed to identify risk factors for FSBP in these
      extremely low birth weight infants. METHODS: A case-controlled analysis was
      performed using all infants born weighing < 1001 gm and admitted to the
      University of Washington Medical Center Neonatal Intensive Care Unit during a 13
      month period. A total of 51 infants were identified and divided into groups based
      on treatment or not with dexamethasone and indomethacin. These cohorts were
      homogeneous for gestational age, birth weight, and perinatal stability. Relative
      risk and confidence intervals were calculated for each of the comparisons.
      Routine pathology was performed on all surgical specimens and additional sections
      were cut and stained for further study. RESULTS: Infants who received EDP had a
      relative risk of perforation that was 12.3 times that of untreated infants. Those
      treated with indomethacin had a risk that was comparable with that for infants
      who did not receive indomethacin. Infants who received both EDP and indomethacin
      tended to have higher rates of pneumoperitoneum than infants who received EDP
      alone but comprised a cohort too small for valid analysis. The pathology of
      surgical specimens revealed FSBP with segmental loss of the muscularis externa.
      There was no evidence of fungal or bacterial infection in any of the surgical
      specimens. CONCLUSION: These findings implicate EDP, but not indomethacin, as a
      significant risk factor for FSBP.

PMID- 10645523
TI  - Impact of antenatal corticosteroid therapy in very low birth weight infants on
      chronic lung disease and other morbidities of prematurity.
AB  - OBJECTIVE: To assess the effect of antenatal corticosteroids on very low birth
      weight (VLBW) infants through 36 weeks' postconceptional age. STUDY DESIGN: Data
      were collected prospectively on all VLBW (< or = 1500 gm) infants (n = 670)
      admitted to a single newborn intensive care unit from 1991 to 1996. Mortality
      rate and the frequency of medical morbidities attributable to prematurity were
      compared between VLBW infants who received antenatal corticosteroid therapy and
      those who did not. RESULTS: Antenatal steroid therapy was associated with a
      significantly lower rate of mortality (p = 0.02) and of mortality due to
      respiratory causes (p = 0.01). Although the frequency of chronic lung disease
      (oxygen requirement at 36 weeks' postconceptional age) was not significantly
      different between the groups (p = 0.48), the frequency of infants surviving
      without chronic lung disease was significantly greater in the steroid-exposed
      group (p = 0.02). There were no significant differences between the groups in the
      frequency of sepsis, necrotizing enterocolitis, length of hospital stay, or
      retinopathy of prematurity requiring surgery. CONCLUSION: In our study, antenatal
      corticosteroid therapy was associated with a beneficial effect on mortality and
      respiratory morbidity for VLBW infants and was not associated with any known
      increased risks.

PMID- 10645524
TI  - Medically resistant neonatal hypertension: revisiting the surgical causes.
AB  - OBJECTIVE: To present the importance of searching for the surgical causes of
      pharmacologically resistant hypertension in the neonatal population. STUDY
      DESIGN: A case report and discussion are provided. RESULTS: Severe hypertension
      in the neonatal period is uncommon and almost always has a secondary cause.
      Although a majority of hypertensive neonates can be successfully managed with
      medical therapy, some cases are resistant to pharmacological treatment. We report
      three hypertensive neonates who failed to respond to intensive multidrug therapy.
      This led to further evaluation and identification of obstructive uropathies in
      two neonates and renovascular disease that necessitated surgical intervention.
      Subsequently, all patients had prompt resolution of hypertension and
      normalization of renal function. All are now off antihypertensive medications and
      have normal renal function at 12 months of follow-up. CONCLUSION: Our report
      exemplifies the importance of the consideration of surgical etiologies for
      differential diagnosis in neonates with severe hypertension that is unresponsive
      to pharmacological therapy. Early diagnosis and prudent management of these
      etiologies reduce morbidity and mortality and preserve of renal function.

PMID- 10645525
TI  - Regionalization of perinatal health care: a lesson learned but lost.
AB  - Regionalization of perinatal health care has offered appropriate services to
      mothers and babies as close to their homes as possible. The need for regionalized
      service has not changed, but the concept has been challenged by the managed care
      dictate that patients receive referral services at the least expensive option
      available that qualifies to give that service by virtue of an assigned
      designation of level of care. When regionalization first became extant, hospitals
      qualified as tertiary (highest level) perinatal centers if they had
      neonatologists on staff. Now, however, far more is required of a hospital if it
      is to qualify to provide the highest level of care available. The so-called
      national guidelines of perinatal health care do not clearly specify this, and
      thus hospitals with limited scopes of perinatal services may still be recognized
      as tertiary or subspecialty centers. Third-party payers contract with such
      hospitals to provide tertiary care and are able to do so at a lower cost because
      these hospitals are not capable of offering more complex and thus more expensive
      services. However, some patients require the more comprehensive services and are
      at least initially denied them because of the costs involved. I believe it is
      improper for third-party payers to dictate what services patients receive and
      where they receive them. This has been and should be the province of physicians
      and physicians alone. Furthermore, I believe that a more detailed and descriptive
      system of guidelines for perinatal health care at the state level could help to
      clarify the true level of functioning of any hospital and thus make it more
      difficult for third-party payers to opt only for the least expensive services.

PMID- 10645526
TI  - Can full-term and near-term infants at risk for sepsis be managed safely without
      antibiotics?

PMID- 10645527
TI  - Fetal influences on neonatal blood pressure.
AB  - OBJECTIVE: To identify if there is a relationship between some newborn variables
      (baby's sex, Apgar score, postnatal age, birth weight, birth length, and head
      circumference) and blood pressure (BP) in healthy term newborns. STUDY DESIGN: A
      cross-sectional hospital-based study was carried out to determine BP levels and a
      cutoff point for hypertension in healthy term newborns. Afterward, a comparative
      study was conducted to identify fetal factors that could influence BP in this
      specific group. RESULTS: According to the cutoff point (95th percentile), 34
      infants were considered to be hypertensive. During the univariate analyses,
      infants with higher BP were heavier, longer, and had larger head circumference.
      After the multivariate analyses, birth weight was the only variable associated
      with higher BP in babies. Other newborn variables analyzed (baby's sex, Apgar
      score, and postnatal age) showed no influence on the babies' BP. CONCLUSION:
      There is a positive relationship between birth weight and BP in healthy term
      newborns.

PMID- 10645528
TI  - Fatal rupture of a sacrococcygeal teratoma during delivery.
AB  - We report the case of premature infant born at 32 weeks' gestation with a
      sacrococcygeal teratoma diagnosed in utero. During delivery by cesarean section,
      profound bleeding due to rupture of the teratoma occurred. Despite volume
      expansion with saline, albumin, and whole blood, a satisfactory peripheral
      perfusion of the infant was only briefly achieved. Surgical intervention to stop
      the bleeding was unsuccessful. Resuscitation of the infant was discontinued after
      55 minutes. The relevant literature is discussed, and suggestions for the
      management of infants with sacrococcygeal teratomas are made.

PMID- 10645529
TI  - Idiopathic neonatal hepatitis associated with a fatal coagulopathy.
AB  - Idiopathic neonatal hepatitis (INH) remains a diagnosis of exclusion in the
      neonate with conjugated hyperbilirubinemia. The major diagnostic challenge for
      the clinician is to distinguish this condition from other treatable liver
      disorders such as biliary atresia. Although the prognosis varies for the familial
      and sporadic forms of neonatal hepatitis, a poor outcome is generally
      distinguished by chronic and progressive liver failure. After careful review of
      the literature, we were unable to find a case of INH associated with a profound,
      irreversible coagulopathy. Herein, we present a case with the primary presenting
      findings of persistent prolongation of the prothrombin time (PT) and
      hypofibrinogenemia, resulting in a catastrophic intracranial hemorrhage and
      death.

PMID- 10645530
TI  - Collaborative primary care of the prematurely born infant.

PMID- 10645531
TI  - Umbilical cord blood gases casebook. Interpreting umbilical cord blood gases, VI.

PMID- 10645532
TI  - Special imaging casebook. Prune-belly syndrome with urachal diverticular
      calcification, posterior urethral valves, and patent utricle.

PMID- 10645533
TI  - The length of hospital stay for very low birth weight infants.

PMID- 10645534
TI  - Introduction: host-parasite interrelations in the genomic age.

PMID- 10645535
TI  - Erythrocyte membrane transport.
AB  - Erythrocytes are endowed with functional entities that support either cellular
      functions or the systemic delivery of O2 from lung to tissue and removal of CO2
      from tissue to lung. The latter depend largely on the blood's circulatory
      capacity. They are associated, respectively, with cytosolic haemoglobin and the
      major membrane polypeptide band 3 (anion exchanger 1, AE1). As a membrane
      transporter, AE1 mediates Cl-/HCO3- exchange, thus enhancing the blood capacity
      for carrying CO2 and for acid-base homeostasis. By interacting with lipids and
      proteins, the multifunctional AE1 tethers the membrane cytoskeleton multiprotein
      complex to the membrane and confers upon erythrocytes both mechanical and
      viscoelastic properties. Those in turn allow cells to withstand the shear forces
      of circulation and squeeze through capillaries. Most other major membrane
      transporters are apparently essential for maintaining a stable erythrocyte cell
      shape and flexibility via a functional membrane cytoskeleton. These include the
      membrane transporters of glucose, nucleoside and purine for fueling the Na/K and
      Ca pumps via ATP production, and of amino acid and oxidized glutathione transport
      for maintaining the cell redox status. All membrane transporters detected in
      mature erythrocytes are synthesized early in erythrocyte differentiation. Their
      contribution to erythrocyte and to systemic physiology is presently being re
      assessed by targeted gene disruption and replacement. For example, organisms with
      reduced or disrupted AE1 gene expression showed major erythrocyte instabilities
      and defective anion exchange capacity and acidosis, but remain alive.

PMID- 10645536
TI  - Chemical and physical in vitro alterations of the erythrocyte membrane: a model
      for its pathophysiological states?
AB  - Plasmodia induce conspicuous structural and functional changes in the erythrocyte
      membrane. Besides the insertion and apposition of 'xenoproteins', and alterations
      of lipid composition (fatty acid pattern) and dynamics (transbilayer mobility and
      disposition of phospholipids, or related probes), new permeation pathways (NPP)
      are formed, which are still ill-defined in terms of their molecular origin. A
      remarkable ion selectivity and a high and complete sensitivity of the NPP to
      inhibitors indicate a rather specific nature. On the other hand, numerous
      experimental perturbations of the erythrocyte membrane structure induce
      unspecific alterations of its barrier function. In view of the apparent
      similarities--in simple physicochemical terms--between the experimentally and the
      plasmodially induced structural perturbations, one would expect, in Plasmodium
      invaded cells, unspecific alterations of permeability and phospholipid dynamics
      of the type observed after in vitro modification, in contrast to much of the
      experimental evidence. In order to highlight this puzzling discrepancy, this
      chapter outlines techniques of producing and analysing experimental barrier
      defects in erythrocytes, and summarizes the properties of the defects induced by
      electroporation and oxidative damage, in terms of solute permeability,
      transbilayer mobility of phospholipid probes and the disposition of native
      phospholipids. The possible absence of comparable unspecific defects in
      Plasmodium-modified cells may provide an interesting example for the evolutionary
      adaptation of the parasite.

PMID- 10645537
TI  - The effects of transport perturbations on the homeostasis of erythrocytes.
AB  - The control of erythrocyte volume, pH, membrane potential and ion content results
      from the interaction of many passive and active transport systems, cytoplasmic
      buffers, and from the charge and osmotic properties of haemoglobin and other
      impermeant solutes. The complexity of the system is such that the understanding
      of cell responses to experimental, physiological and pathophysiological
      challenges is beyond intuitive grasp. Mathematical models of erythrocyte and
      reticulocyte homeostasis have delivered a wealth of novel and unexpected
      predictions that have been confirmed experimentally. Those concerning effects of
      Ca(2)+ and K+ permeabilization on cell volume, pH and osmolality have helped
      solve long-standing issues on the pathophysiology of sickle-cell dehydration and
      will be briefly reviewed here. To study the effects of parasite growth and of new
      permeation pathways (NPP) on host cell homeostasis, we have developed a model of
      a Plasmodium falciparum- infected erythrocyte. Modelling NPP to fit reported
      changes in both Na+/K+ fluxes and gradients predicted large variations in host
      cell haemoglobin concentration, [Hb]. However, preliminary estimates seem to
      indicate that host cell [Hb] is conserved throughout the parasite's asexual
      cycle, suggesting that the properties of the NPP vary in subtle, stage-dependent
      ways.

PMID- 10645538
TI  - Transport properties of the host cell membrane.
AB  - The malaria-infected erythrocyte shows an increased permeability to a wide range
      of solutes. The increase is mediated in part by parasite-induced new permeation
      pathways (NPP) and in part (for some solutes, under some conditions) by increased
      activity of endogenous transporters. The NPP provide the major route for the
      influx into the infected cell of a number of essential nutrients, but although
      the functional characteristics of these pathways are understood in some detail,
      they are yet to be identified at a molecular level. Lucifer yellow, a fluorescent
      anion, is taken up by malaria-infected erythrocytes to a much greater extent than
      uninfected erythrocytes via a pathway that differs in its pharmacological
      characteristics from the NPP. The nature, origin and location of this pathway
      remain to be established.

PMID- 10645539
TI  - Transport of phospholipid synthesis precursors and lipid trafficking into malaria
      infected erythrocytes.
AB  - Phospholipid biosynthesis in Plasmodium is of crucial importance considering the
      high degree of membrane biogenesis. In the de novo phosphatidylcholine pathway,
      the major plasmodial phospholipid, choline, first enters infected erythrocytes by
      a transport-mediated process, whose main kinetic characteristics are the same as
      in normal cells except for a considerable increase in Vm. The kinetic and
      functional characterizations of the choline carrier (affinity, specificity,
      stereoselectivity, asymmetric cyclic model, ionic dependence, limiting step in
      carrier translocation) have now been done, although there is no information
      concerning its nature and structure, despite the fact that it is likely an
      outstanding pharmacological target. Other unanswered questions concern the
      mechanisms for choline entry into the parasite. The intense lipid trafficking
      between the intracellular parasite and the host cell membrane also indicates that
      Plasmodium controls its own lipid composition as well as that of its host cell.
      Organelles that house the machinery for lipid synthesis, and mechanisms for
      trafficking and sorting, have not yet been described because of the lack of
      appropriate tools, but they could address fundamental questions in the
      contemporary cell biology of this parasite.

PMID- 10645540
TI  - A nutrient-permeable channel on the intraerythrocytic malaria parasite.
AB  - The intraerythrocytic malaria parasite Plasmodium falciparum faces at least three
      membranous barriers to acquisition of nutrients from serum: the human erythrocyte
      membrane, the parasitophorous vacuole membrane (PVM) and the parasite plasma
      membrane. The PVM is a specialized parasite-derived membrane that separates the
      parasite from erythrocyte cytosol. I used the patch clamp method to identify and
      characterize the main transport pathway on the PVM. Gigaohm seals, formed on
      mature freed trophozoites, revealed a 140 pS channel permeable to both cations
      and anions on the PVM. This channel is present at high density, is open more than
      95% of the time at the PVM resting potential, and is capable of transporting
      amino acids and monosaccharides across the PVM. This nutrient-permeable channel
      was then reconstituted into artificial lipid bilayers, where it exhibited similar
      slope conductances, gating, voltage dependence and permeability to soluble
      nutrients. In bilayers, the channel was found to have non-saturating kinetics and
      an effective pore diameter of 23 A. These experiments, together with the patch
      clamp findings, suggest a high capacity molecular sieve that allows the parasite
      to acquire soluble nutrients from erythrocyte cytosol.

PMID- 10645541
TI  - The permeability properties of the parasite cell membrane.
AB  - The asexual development of the malaria parasite takes place inside the host's
      erythrocyte, an environment that is different from that of most other eukaryotic
      organisms. The intense and rapid development of the parasite, as well as the
      homeostatic regulation of its cellular composition, require an extensive exchange
      of material between the parasite and its immediate surroundings. Studies on free
      murine parasite species suggest that a plasma membrane H+ pump is responsible for
      the maintenance of membrane potential and pH gradient, which are used as driving
      forces for the uptake of glucose and extrusion of Ca2+ by means of a symporter
      and an antiporter, respectively. In Plasmodium falciparum, a similar transport of
      Ca2+ may prevail. Several other transporters have been assigned to the plasma
      membrane of this parasite, either by direct measurements or by inference: D
      glucose, nucleosides, L-amino acids, L-lactate and pantothenic acid. A Na+/H+
      antiporter has been demonstrated, and implicated in the regulation of pH, and an
      ATP/ADP antiporter, whose function remains controversial, has been characterized.
      The presence of Mg2+ and Na+/K+ pumps and an active extrusion of oxidized
      glutathione can be inferred from the composition of the parasite cytosol vs. that
      of the host cell. Several genes coding for cation pumps have been cloned and
      their functions await characterization.

PMID- 10645542
TI  - Macromolecular transport in malaria-infected erythrocytes.
AB  - Transport of macromolecules in the external medium or host cell cytosol to
      intracellular Plasmodium falciparum malaria parasites occurs by two distinct
      pathways. Macromolecules in the erythrocyte cytosol are ingested by the parasite
      via a specialized organelle, the cytostome, and are transported to the parasite
      food vacuole. By contrast, blood-stage parasites internalize macromolecules from
      the external medium through a pathway that bypasses the erythrocyte cytosol. We
      coined this pathway the 'parasitophorous duct'. Since our original report, a
      number of permutations of this model have been proposed. (Macro)molecules in the
      aqueous compartment bounded by the parasitophorous vacuole membrane (PVM) and the
      parasite plasma membrane are internalized by parasite fluid-phase endocytosis.
      Serial sections of parasites fixed and stained by various methods for
      transmission electron microscopy revealed areas of apparent membrane continuity
      between the erythrocyte membrane and the PVM, which could leave the parasites
      exposed to the external medium. Macromolecules up to 50-70 nm in diameter have
      direct access to intraerythrocytic parasites. This size exclusion is consistent
      with the dimensions of the parasitophorous duct pathway revealed by electron
      microscopy. The identification and characterization of this new pathway has
      stimulated investigators to pursue new areas in malaria research, including
      parasite transfection, antisense RNA and chemotherapy using membrane-impermeable
      drugs.

PMID- 10645543
TI  - Expression of parasite transporters in Xenopus oocytes.
AB  - The Xenopus laevis oocyte heterologous expression system is particularly useful
      for the study of transporter proteins. We demonstrated the utility of this
      expression system for studies on Plasmodium falciparum transporters by inducing
      increased uptake of metabolites or their analogues (nucleosides, nucleobases,
      lactate and glucose) into oocytes after microinjection of mRNA obtained from
      asexual stages of P. falciparum. We identified a hexose transporter of P.
      falciparum (PfHT1) and studied its function. Higher levels of functional activity
      are obtained when 5' and 3' untranslated Xenopus globin gene sequences and a
      strong Kozak consensus are included in RNA used for microinjection studies. PfHT1
      is a saturable, sodium-independent and stereospecific transporter with a
      relatively high affinity for glucose (K(m) = 0.48 mM). Competition experiments
      with glucose analogues show that hydroxyl groups at positions C3 and C4 are
      important for ligand binding. mRNA levels for PfHT1 are highest during the small
      ring stages of infection and lowest in gametocytes. Confocal immunofluorescence
      microscopy localizes PfHT1 to the region of the parasite plasma membrane and not
      to host structures. When hypoglycaemia complicates cerebral malaria, modelling
      studies using data obtained from oocyte experiments suggest that the high
      affinity of PfHT1 may increase the proportion of glucose taken up by parasites
      compared with that transported across the blood-brain barrier.

PMID- 10645544
TI  - Reconstitution of protein transport across the vacuolar membrane in Plasmodium
      falciparum-infected permeabilized erythrocytes.
AB  - The parasite Plasmodium falciparum induces morphological and biochemical
      alterations of its host erythrocyte. Some of these changes are mediated by
      parasite proteins that are transported to specific destinations within the
      erythrocyte or to the erythrocyte plasma membrane. The pathways underlying this
      transport are still unknown. We anticipate that at least some aspects of these
      pathways may be biologically unique and therefore potential targets for
      chemotherapeutic intervention. We have utilized bacterial pore-forming proteins
      to establish an experimental system that allows selective permeabilization of the
      erythrocyte plasma membrane, without affecting the integrity of the vacuolar
      membrane and the parasite plasma membrane, in order to study protein transport
      from the parasite into the host erythrocyte. Physiological properties of the
      parasite within permeabilized erythrocytes, such as the ability to synthesize
      proteins, will be described. The permeabilization of infected erythrocytes has
      allowed the dissection of individual steps in protein transport from the parasite
      surface across the vacuolar membrane. Possible pathways involved in the
      trafficking of parasite proteins within the erythrocyte cytosol, i.e. in a cell
      that normally has no need to transport proteins, will be discussed.

PMID- 10645545
TI  - Export of parasite proteins to the erythrocyte cytoplasm: secretory machinery and
      traffic signals.
AB  - To the malaria parasite, the prospect of setting up residence within a human
      erythrocyte represents a formidable challenge. The mature human erythrocyte is
      essentially a bag of haemoglobin with no internal organelles and no protein
      synthesis machinery. The parasite needs, therefore, to assemble all the essential
      amenities--foundations, plumbing and furnishings--from scratch. The parasite
      remodels its adopted home by exporting proteins to the erythrocyte membrane. To
      reach their final destinations, the exported proteins must cross the parasite
      plasma membrane, the parasitophorous vacuole membrane and the erythrocyte
      cytosol. To further understand this unusual and complex trafficking pathway, we
      have searched for proteins that may form part of the trafficking machinery of the
      infected erythrocyte. We have identified an ER-located, calcium-binding homologue
      of reticulocalbin (PfERC) that co-localizes with the ER molecular chaperone,
      PfGRP. We have also identified a homologue of the GTP-binding protein, Sar1p, a
      small GTPase that, in other eukaryotic cells, is thought to play a crucial role
      in trafficking proteins between the ER and the Golgi. PfSar1p is located in
      discrete structures near the periphery of the parasite cytoplasm that may
      represent specialized export compartments. PfSar1p is exported to structures
      outside the parasite in the erythrocyte cytoplasm. The malaria parasite appears
      to be capable of elaborating components of the 'classical' vesicle mediated
      trafficking machinery outside the boundaries of its own plasma membrane.

PMID- 10645546
TI  - Transport and trafficking: Toxoplasma as a model for Plasmodium.
AB  - Like Plasmodium, the protozoan parasite Toxoplasma gondii is a member of the
      phylum Apicomplexa, and an obligate intracellular pathogen. Unlike Plasmodium,
      however, Toxoplasma is highly amenable to experimental manipulation in the
      laboratory. The development of molecular transformation protocols for T. gondii
      has provided both scientific precedent and practical selectable markers for
      Plasmodium. Beyond the feasibility of molecular biological experimentation now
      possible in both systems, the high frequency of stable transformation in
      Toxoplasma allows this parasite to be used for molecular genetic analysis. The
      ability to control homologous vs. non-homologous recombination in T. gondii
      permits gene knockouts/allelic replacements at previously cloned loci, and
      saturation insertional mutagenesis of the entire parasite genome (and cloning of
      the tagged loci). T. gondii also exhibits unusual ultrastructural clarity,
      facilitating cell biological analysis. The accessibility of Toxoplasma as an
      experimental system allows this parasite to be used as a surrogate for asking
      many questions that cannot easily be addressed in Plasmodium itself. T. gondii
      also serves as a model system for genetic exploration of parasite biology and
      host-parasite interactions. Success stories include: biochemical analysis of
      antifolate resistance mechanisms; pharmacological studies on the mechanisms of
      macrolide activity; genetic identification of nucleobase/nucleoside transporters
      and metabolic pathways; and cell biological characterization of the apicomplexan
      plastid. As with any model system, not all questions of interest to
      malariologists can be addressed in Toxoplasma; differentiating between sensible
      and foolish questions requires familiarity with the biological similarities and
      differences of these systems.

PMID- 10645547
TI  - An alternative secretory pathway in Plasmodium: more questions than answers.
AB  - The malaria parasite extensively modifies the host erythrocyte. Many of these
      modifications are mediated by proteins exported from the parasite and targeted to
      specific locations within the infected erythrocyte. However, little is known
      about how the parasite targets proteins to specific locations beyond its own
      plasma membrane. Treatment of infected erythrocytes with brefeldin A results in
      the accumulation of many exported Plasmodium proteins into a compartment distinct
      from the ER. Proteins destined for the host erythrocyte membrane, the
      parasitophorous vacuole or inclusions within the erythrocyte cytoplasm accumulate
      in this novel compartment, and co-localization studies indicate that there is a
      single compartment per parasite. Exported proteins only accumulate in this novel
      compartment if brefeldin A treatment is concurrent with their synthesis. This
      novel compartment is probably a membrane-bound organelle located at the parasite
      periphery, and may be the first step in an alternative secretory pathway that
      specializes in the export of proteins into the host cell. Such an alternative
      secretory pathway raises questions about how exported proteins are differentially
      targeted to this novel organelle versus the ER and the fate of exported proteins
      after this novel organelle.

PMID- 10645548
TI  - The transport of the histidine-rich protein I from Plasmodium falciparum is
      insensitive to brefeldin A.
AB  - During its intraerythrocytic development, Plasmodium falciparum synthesizes
      several proteins that are exported beyond its membrane. Some of these secreted
      antigens are involved in the formation of protuberances or knobs, a major
      virulence factor, at the erythrocyte membrane. Various secreted malarial
      polypeptides, the transport of which is sensitive to brefeldin A, are
      translocated in vitro into dog pancreatic microsomes. We present evidence that
      the histidine-rich protein I (PfHRPI) is secreted by the parasite via a novel
      pathway, independent of the ER/Golgi apparatus. The secretion of PfHRPI was not
      blocked by incubation of parasite cultures at 15 degrees C and 20 degrees C or 37
      degrees C in the presence of brefeldin A. PfHRPI was not translocated into
      microsomes in an in vitro translation-translocation cell-free system. Unlike
      other polypeptides from eukaryotic cells that bypass the ER/Golgi pathway and do
      not have a signal peptide, PfHRPI has an atypical signal sequence consisting of
      21 amino acids, including eight positively charged residues followed by 11
      hydrophobic residues. We also found that the unusually charged PfHRPI signal
      sequence diverts Exp-1, which is usually exported, away from the translocation
      machinery of microsomal membranes.

PMID- 10645549
TI  - Protein transport in the host cell cytoplasm and ATP-binding cassette proteins in
      Plasmodium falciparum-infected erythrocytes.
AB  - The main interest of our experiments is the study of ATP-binding cassette (ABC)
      proteins in Plasmodium parasites and their infected host cells. Here, we report
      on results obtained by studying the plasmodial PfGCN20 ABC protein. Employing
      immunomicroscopy and cell fractionation techniques, we found that PfGCN20 is
      localized to multiple regions of the infected erythrocyte, including membranous
      and non-membranous compartments inside and outside of the parasite cell. PfGCN20
      was found to complement the function of its yeast homologue Gcn20p by acting as
      part of the yeast translation regulatory pathway. These results open up several
      hypotheses about a possible biological function of PfGCN20, such as being a
      component of plasmodial translation regulation, or functioning as an ATP-binding
      subunit of a multimeric ABC transporter, or acting as a molecular chaperone-like
      enzyme contributing to the protein translocation across multiple membranes in
      infected erythrocytes. More experiments are presently being performed to fully
      understand the biological function of this protein, abundant in multiple
      compartments of erythrocytes infected with the Plasmodium falciparum malaria
      parasite.

PMID- 10645550
TI  - Chloroquine uptake and activity is determined by binding to ferriprotoporphyrin
      IX in Plasmodium falciparum.
AB  - The selective antimalarial activity of chloroquine and related compounds stems
      from the extensive saturable uptake of these drugs into malaria parasites.
      Chloroquine resistant strains of Plasmodium falciparum have evolved a mechanism
      to reduce the saturable uptake. The molecular mechanism of saturable chloroquine
      uptake is controversial and attention is currently focused on mutually exclusive
      models of active chloroquine uptake and intracellular chloroquine binding. We sum
      up recent evidence which conclusively proves that the saturable accumulation of
      chloroquine is due to intracellular binding to ferriprotoporphyrin IX rather than
      active transport into the parasite via the sodium/hydrogen exchanger. We discuss
      recent findings that the affinity of chloroquine binding to ferriprotoporphyrin
      IX is reduced in resistant parasites. The mechanism responsible for reduced
      binding affinity can be overcome by verapamil and various lysosomotropic agents,
      and is thought to be the basis of chloroquine resistance.

PMID- 10645551
TI  - Chloroquine uptake, altered partitioning and the basis of drug resistance:
      evidence for chloride-dependent ionic regulation.
AB  - The biochemical mechanism of chloroquine resistance in Plasmodium falciparum
      remains unknown. We postulated that chloroquine-resistant strains could alter ion
      fluxes that then indirectly control drug accumulation within the parasite by
      affecting pH and/or membrane potential ('altered partitioning mechanism'). Two
      principal intracellular pH-regulating systems in many cell types are the
      amiloride-sensitive Na+/H+ exchanger (NHE), and the sodium-independent, stilbene
      sensitive Cl-/HCO3- antiporter (AE). We report that under physiological
      conditions (balanced CO2 and HCO3-) chloroquine uptake and susceptibility are not
      altered by amiloride analogues. We also do not detect a significant difference in
      NHE activity between chloroquine-sensitive and chloroquine-resistant strains via
      single cell photometry methods. AE activity is dependent on the intracellular and
      extracellular concentrations of Cl- and HCO3- ions. Chloroquine-resistant strains
      differentially respond to experimental modifications in chloride-dependent
      homeostasis, including growth, cytoplasmic pH and pH regulation. Chloroquine
      susceptibility is altered by stilbene DIDS only on chloroquine-resistant strains.
      Our results suggest that a Cl(-)-dependent system (perhaps AE) has a significant
      effect on the uptake of chloroquine by the infected erythrocyte, and that
      alterations of this biophysical parameter may be part of the mechanism of
      chloroquine resistance in P. falciparum.

PMID- 10645552
TI  - [The malariology centenary (1898-1998). 1898].
AB  - This editorial note presents the journal initiative to celebrate the Malariology
      Centenary. It includes the reprint of the first annual report of the Society for
      Malaria Studies (founded in 1898), presented by Angelo Celli on December 3rd,
      1898, to the first meeting of the Society and published in the Journal of the
      Royal Italian Society of Hygiene (volume 20, issue 12, 31st December 1898). The
      text is followed by explanatory footnotes and relevant references. An exhaustive
      historical essai, including the english version of the Celli's report, is
      scheduled to appear as supplement to volume 41, and the same volume will host the
      contributions issued from the international conference. "The malaria challenge
      after one hundred years of malariology", held in Roma at the Accademia Nazionale
      dei Lincei on November 16-19, 1998.

PMID- 10645553
TI  - [Anna Fraentzel Celli (1878-1958)].
AB  - This paper provides a short history of Anna Fraentzel Celli life, from her
      arrival in Italy in 1898 to her death in 1958, reviewing available documents and
      written testimonies. Anna Fraentzel was born in Berlin in 1878, third of four
      daughters from a bourgeois family; her maternal grandfather, Luigi Traube, was a
      very well known physician, as well as her father Oscar, and she developed an
      early interest in medicine that she couldn't fulfill: actually after her father's
      death she was forced to shorten her education, she couldn't enter the medical
      school, as she would have liked to, and she attended the nursing school, instead,
      displaying a lot of good practical sense. As a nurse in Hamburg in 1896 she met
      Prof. Angelo Celli, who was there on a professional visit, and who assisted the
      young nurse in finding a job at the city hospital. She was much younger than him,
      who was already a middle aged respected scientist; anyhow, even after his
      departure, they kept in touch and eventually fell in love. They married in 1899
      and she moved to Rome to work at the S. Spirito Hospital joining a brilliant
      group of physicians and researchers as Tommasi-Crudeli, Marchiafava, Bignami,
      Bastianelli, Dionisi, Grassi, and her husband Angelo. They had long been studying
      the mode of transmission of the malaria infection and in 1898 they had identified
      the mosquito Anopheles as the vector of the malaria parasite. She got
      enthusiastically involved both in the scientific work and in the antimalarial
      campaign which Celli promoted in the Agro Romano. The strong personality of Anna
      Celli, her active involvement in social problems, her passionate dedication to
      her work, her peculiar way of being feminist, expressed fully her commitment to
      the struggle against malaria and illiteracy in the Agro Romano and in the Paludi
      Pontine at the beginning of the twentieth century. She must be credited as a
      major force in the creation and functioning of the Peasant Schools, as well as in
      the organisation of the experimental antimalarial health clinics. After her
      husband's death in 1914 she continued as a promoter of the antimalarial campaign,
      co-operating with the Red Cross and other institutions. Moreover, she edited the
      scientific and historical papers which Angelo Celli had collected and written
      during his life. She was also a prolific writer and lecturer on these issues and
      gained widespread appreciation both in Italy and in Germany. Toward the end of
      her life she retired to a nursing home in Rome where she died almost alone in
      1958.

PMID- 10645554
TI  - [Zooprophylaxis: old and new problems].
AB  - In the present note the authors report on the most important works which have
      examined the application of zooprophylaxis as a means for malaria control from
      the onset of this century to the present day. The method of zooprophylaxis has
      evolved throughout the years in close connection with other problems, undoubtedly
      more important in the history of malaria, which in the present paper are amply
      discussed. From the very beginning this subject was the object of heated debates
      by those who retained it a valid method of malaria control and those who denied
      its validity, among whom some of the most important Italian and foreign
      malariologists. The experiments of zooprophylaxis received most attention in the
      twenties, but, following the works of Missiroli and co-workers in the early
      thirties by which the varieties of the "complex maculipennis" were identified,
      the interest on zooprophylaxis was less heightened. It should be noted, however,
      that the increase of cattle, and especially land reclamation, reduced
      considerably malaria endemicity in northern Italy where zoophilic varieties were
      most prevalent. Recently, renewed interest on zooprophylaxis has been shown in
      Pakistan, where some experiments on the use of cattle have led to an unexpected
      increase of malaria transmission.

PMID- 10645555
TI  - [Residual mosquitoes in the northern Adriatic seacoast 50 years after the
      disappearance of malaria].
AB  - The Northern Adriatic Sea littoral was heavily malarious; intensive land
      drainages, agricultural development and socioeconomic improvement were the key
      factors which led to malaria eradication, sped up by indoor insecticide spraying,
      achieved soon after World War II. Regular observations on anophelism were carried
      out by the Istituto Interprovinciale per la Lotta Antimalarica nelle Venezie from
      middle 20's until early 60's. The main vector was Anopheles sacharovi, a species
      which typically bred in coastal brackish swamps; other species were An.
      atroparvus (which was a probable secondary vector) and the usually strictly
      zoophilic An. maculipennis, An. melanoon, An. messeae and An. subalpinus. From
      1995 to 1997 surveys were carried out in order to review the genus Anopheles in
      the coastal area of Friuli-Venezia Giulia and Veneto regions. A total of 11,346
      females were collected from animal shelters (cow-shed, pigsties, horse stables)
      of 52 sites along 180 km of coast crossing 5 provinces (from North: Gorizia,
      Udine, Venezia, Padova and Rovigo). All specimens belonging to the An.
      maculipennis complex were scored for the presence of the differential characters
      of An. sacharovi, the only species of the complex morphologically characterized
      at the adult stage. The examination of morphological characters of single egg
      batches obtained from field collected females was the main diagnostic tool for
      the other species. Species identification was subject to confirmation by larval
      chaetotaxy analysis (number of branches of antepalmate hairs of IV and V
      abdominal segments) in representative samples of laboratory-reared mature larvae,
      while biochemical analysis (enzyme electrophoresis) on some samples of identified
      females was performed in the laboratory of Prof. L. Bullini and Dr. R. Cianchi of
      the University of Rome "La Sapienza" and partly in our laboratory. No An.
      sacharovi female was recorded. The examination of 6,361 single ovipositions led
      to the identification of three species of the An. maculipennis complex: An.
      atroparvus, An. maculipennis and An. messeae; An. claviger s.str. was also
      recorded. Larval chaetotaxy examination carried out on 1,608 larvae and the
      biochemical identification of 467 females confirmed the previous diagnosis based
      on egg characters. The relative frequency of the three species varied depending
      on the site: An. maculipennis was the most abundant species north of Venice;
      south of Venice, and particularly in the Po river delta, the most abundant
      species were An. atroparvus and, in some sites, An. messeae. In view of the high
      density recorded for An. atroparvus in some sites (corresponding to various
      thousands females in a single animal shelter), the vectorial capacity values may
      be significant and should be assessed.

PMID- 10645556
TI  - [Research on Culicidae attracted to dog bait in Piedmont].
AB  - Dog attracted mosquitoes were collected in Piedmont (NW Italy) in 1992 and 1993.
      Sampling sites where chosen on ecological and epidemiological basis, according to
      the results of a previous study on the distribution and prevalence of canine
      filariosis in this region. Dog baited traps were operated monthly (two
      nights/site from June to September) in six plain sites differing in the
      prevalence of heartworm infected dogs (including two sites where no positivity
      was recorded). A single capture was carried out in July-August in three more
      plain and four hill localities, as well as in a prealpine and a suburban zone
      inside the heartworm endemic area. The following species were collected (number
      of specimens in brackets): Aedes caspius (2255), Ae, cantans (1), Ae. cinereus
      (1), Ae, geniculatus (7), Ae. vexans (58), Aedes spp. (221), Anopheles claviger
      (1), An. maculipennis s.l. (405), Coquillettidia richiardii (16), Culex modestus
      (6361), Cx. pipiens (2032), Cx. territans (2), Culex spp. (94), Culiseta annulata
      (1). Cx. pipiens was captured in 15 sites, Cx. modestus and Ae. caspius in 13,
      and 12, respectively, An. maculipennis s.l. in 7, Ae. vexans in 6, Cq. richiardii
      in 4, Ae. geniculatus in 3, Cx. territans in 2, Ae. cantans, Ae. cinereus, An.
      claviger and Cs. annulata in one. Species abundance and relative composition
      differed between habitats and between similar habitats with a different
      prevalence of microfillaraemic dogs. Regression analysis of heartworm prevalence
      vs. mosquitoes abundance demonstrated a positive linear relationship. Data
      suggest that four species (Ae. caspius, An. maculipennis s.l., Cx. modestus and
      Cx. pipiens) are playing a major role in the transmission of canine filariosis in
      Piedmont.

PMID- 10645557
TI  - Sarcocystis infections among snakes in Israel.
AB  - Natural infection with Sarcocystis has been recovered from 11 species of snakes
      from Israel and the adjacent territories (Cisjordan), infection was most abundant
      in subadults. Sporocyst dimensions obtained from the different snakes overlapped
      in size, but even in a same host species formed distinct size cohorts clustering
      either around 8.5 x 6.5 microns and 11.0 x 8.5 microns or around 11.0 x 8.5
      microns and 12 x 10 microns. Sporocyst-size distribution was, however, altered
      following cross infections or in consecutively emitted feces. The largest cohort
      size conformed with the sporocyst dimensions of S. murivipera Matuscka, Heydorn,
      Mehlhorn, Abd-Al-Az, Diesing, Bichler 1987, described from Vipera palaestinae,
      one of the snake species included in the present study. Among infected snakes
      were rodent predators but also species feeding on smaller prey (reptiles).
      Sporocysts from eight of these species including some small-prey feeders, were
      available for infecting rodents, all, like S. murivipera, developed into
      sarcocysts in laboratory white mice (Mus musculus), but in none of the inoculated
      rodents from other genera, or reptiles. Sarcocysts found in free-ranging house
      mice infected V. palaestinae. Despite of an apparent conspecificity, Sarcocystis
      from the different snake species demonstrated a pronounced variation in their
      virulence to mice. Primary wall was identical in all ultrastructurally studied
      sarcocysts found in both house mice and laboratory mice fed on sporocysts from
      the diverse snake species.

PMID- 10645558
TI  - The prevention of Dirofilaria repens infection with ivermectin/pyrantel
      chewables.
AB  - This trial was conducted to test the efficacy of ivermectin/pyrantel chewables in
      preventing the development of Dirofilaria repens in dogs. The trial included 155
      dogs from an endemic area in North-Western Italy. Prior to enrollment in the
      study, none of the dogs had microfilariae of D. immitis or D. repens in a
      concentration test, and all dogs were also seronegative for adult heartworm
      antigen. Animals remained with their owners and were dosed six times, at monthly
      intervals according to body weight. Efficacy against D. repens was evaluated
      approximately 6 and 12 months after the first dosing. None of the treated dogs
      was found to harbour microfilariae of D. repens or D. immitis on either occasion,
      whereas 6 of 24 untreated controls had circulating D. repens microfilariae at the
      final testing. The treatment was well accepted by all dogs.

PMID- 10645559
TI  - Nine more cases of human infections by Dirofilaria repens diagnosed in Italy by
      morphology and recombinant DNA technology.
AB  - Dirofilariosis is a mosquito-borne disease of carnivors due, in Italy, to
      Dirofilaria repens and D. immitis species which are sympatric in many areas. Nine
      more cases of human infection are here reported, detected in Italian patients
      living in northern regions (where D. immitis and D. repens are largely present),
      in Tuscany (where D. repens is more frequent than D. immitis), and in Sicily
      (where D. immitis is present only sporadically). The nematodes surgically removed
      (7 female and 2 male specimens) have been identified by a PCR-based method and by
      morphology as D. repens. Morphological, clinical, and epidemiological data of
      these human infections are discussed.

PMID- 10645560
TI  - [A case of 'contagious delusional parasitosis' in an adult pair of twin sisters].
AB  - In July 1992, a 50-year-old married woman, who was a hospital administrative
      clerk with an adult daughter, stated that, for over 5 years, she had been
      parasitised by 'small animals coming out from her skin'. While physical and
      microscopical examinations did not show either lesions or parasites on the skin,
      both the patient's medical history and the conviction with which she reported the
      phenomenon, led to a diagnosis of Delusory Parasitosis, a condition which has
      been well-defined for over 50 years and considered of prevailingly psychiatric
      competence. The patient was examined several times during the course of 6 years.
      She exhibited varying levels of anxiety, and brought with her different species
      of insects which she had captured 'when she saw them coming out of her skin'. In
      July 1998 the patient returned with her twin sister, who 'had been infected by
      her'. Indeed, she too 'had discharged various insects from her skin' for more
      than a year. The authors provide information on the response of this
      hallucinatory syndrome to therapy which, as in this case, appears to be resistant
      to treatment, unless appropriate psychoactive drugs are used.

PMID- 10645561
TI  - Seroprevalence of Toxocara canis-IgG antibodies in two rural Bolivian
      communities.
AB  - A survey on toxocara canis-IgG seroprevalence was carried out in two Bolivian
      communities (Mora and Zanja Honda) living in the Cordillera Province, Department
      of Santa Cruz. Two hundred and sixteen people, both males and females, 2 to 85
      years old were sampled. Altogether, 73 people were positive (34%). The
      seroprevalence was 27% in Mora and 42% in Zanja Honda (p = 0.022). No statistical
      correlations were found with sex and age. High prevalences were also found for
      intestinal helminths (hookworms, Trichuris trichiura, Ascaris lumbricoides,
      Hymenolepis nana and Strongyloides stercoralis). Positive association between T.
      canis seropositivity and presence of T. trichiura and between T. trichiura and
      hookworms were found. T. canis egg prevalence in dog population was found
      consistently higher in Zanja Honda than in Mora (40% vs 27%).

PMID- 10645562
TI  - The distribution and inversion polymorphism of chromosomally recognized taxa of
      the Anopheles gambiae complex in Mali, West Africa.
AB  - Data from polytene chromosome studies on the Anopheles gambiae complex in Mali
      were reviewed. The banding pattern was successfully scored in 17,705 specimens
      from 76 sampling sites representing the main ecological strata of the country.
      Two members of the complex, namely An. arabiensis and An. gambiae, were found
      widespread and frequently sympatric, with the latter prevalent in most
      localities. Population genetic analysis of the inversion polymorphisms indicated
      the existence of panmictic conditions for An. arabiensis only, whereas the
      parallel study of An. gambiae supported its splitting into at least three
      reproductive units, characterized by different 2R chromosome arrangements,
      designated Bamako, Mopti and Savanna. The chromosomal evidence was consistent
      with the hypothesis of complete reproductive isolation between Bamako and Mopti.
      Partial isolation between these two taxa and Savanna was suggested by the scoring
      of hypothetical hybrid 2R heterokaryotypes in various samples, but the actual
      hybrid origin of these specimens was not confirmed. Different patterns of
      geographical and seasonal distribution were shown as follows. An. arabiensis
      prevails in arid savannas (Sahel and Northern Sudan savanna) out of the flooded
      or irrigated zones; it is able to withstand the most arid conditions of Saharan
      localities and its breeding might extend throughout the dry season. An. gambiae
      Savanna and Bamako prevail in relatively humid savannas (Southern Sudan savanna)
      and their breeding generally occurs only during the rainy season. The Savanna
      taxon was almost absent in flooded or irrigated zones and in riverine localities;
      the Bamako taxon is distributed along the upper river Niger and its tributaries.
      An. gambiae Mopti extends its range in all ecological zones present in Mali
      including the Sahel and predesertic areas, showing high relative frequencies up
      to absolute dominance in flooded or irrigated areas; its breeding is highly
      successful also during the dry season. Rainfall at the sampling sites was found
      to correlate positively with the frequency of Savanna and negatively with the
      frequency of Mopti. The remarkable ecological flexibility of the latter was found
      associated with wide seasonal and geographical variations in its 2R inversion
      polymorphism bc/u. Higher frequencies of the bc arrangement were recorded both in
      the Southern localities during the dry season and in the Northern more arid
      localities during the rainy season. The absence or scarcity of An. arabiensis and
      An. gambiae Savanna in most flooded or irrigated zones suggests their competitive
      exclusion by An. gambiae Mopti.

PMID- 10645564
TI  - [Fractures due to bone loss in elderly patients].

PMID- 10645563
TI  - [Falls, fragility and osteoporosis in elderly persons: a public health problem].

PMID- 10645565
TI  - [Risk assessment and prevention of fractures of the upper segment of the femur in
      elderly persons].

PMID- 10645566
TI  - [Medical and surgical treatment of osteoporosis fractures in elderly patients].

PMID- 10645567
TI  - [Historical observations on nosocomial infections].

PMID- 10645568
TI  - [The epidemiology of bacterial nosocomial infections in intensive care].

PMID- 10645569
TI  - [Non-bacterial nosocomial infections].

PMID- 10645570
TI  - [Medical liability and nosocomial infections].

PMID- 10645571
TI  - [Present-day fiber endoscopy in the diagnosis and therapeutic tactics in foreign
      bodies of the upper digestive tract].
AB  - Characterization of foreign bodies and their localization in the digestive tract
      in 404 patients is given. Surgical methods of treatment of such patients are
      described. Endoscopy was used for examination and treatment. The adequate
      anesthesia is thought by the authors to be necessary for a successful endoscopic
      removal of the foreign bodies. The indications for general anesthesia are
      enumerated. The endoscopic removal of the foreign bodies during surgical
      interventions are indicated in patients with the perforation of the esophagus by
      a foreign body.

PMID- 10645572
TI  - [Helicobacteriosis of the operated stomach in peptic ulcer].
AB  - After Billorth-II resection of the stomach for ulcer the contamination of the
      stump with Helicobacter pylori (HP) was detected in 73.7% of the cases, for ulcer
      of the duodenum--in 81.8% of the patients. At later terms after selective
      proximal vagotomy (SPV) all the patients were HP-positive, after SPV with
      draining operations 92.3% of the patients were HP-positive. The degree of
      inflammatory alterations in the mucosa was proportional to the degree of its
      bacterial dissemination. The HP contamination of the gastric mucosa after
      operation had no marked influence on the clinical course of the remote
      postoperative period. Spontaneous elimination of HP was observed in 42.9% of the
      patients with the developing achlorhydria of the operated stomach.

PMID- 10645573
TI  - [Sympathectomy and intra-arterial perfusion therapy in critical ischemia of the
      lower limbs].
AB  - The results of 177 sympathectomies fulfilled in 152 patients with critical
      ischemia of the lower extremities are presented. Good and satisfactory results
      were obtained in 69.3% of patients after lumbar sympathectomy only. When the
      operation was combined with prolonged intraarterial catheter therapy positive
      effects were noted in 79.7% of the cases. This combined method of treatment is
      thought to be expedient for patients with the IV degree ischemia.

PMID- 10645574
TI  - [Intraoperative diagnosis of different forms of acute appendicitis].
AB  - Acute appendicitis is an actual problem of urgent surgery. Diagnostic errors make
      5-50% depending upon the morphological form of acute appendicitis. The Z.M. Sigal
      method of transillumination pulsomotorographic monitoring was used for functional
      characterization of the vermiform process and caecum during the operation. The
      method is based on phototransformation of pulse and motility into electrical
      signals with the graphic registration of intraorganic haemomotorodynamics.
      Specific haemomotorodynamic disturbances were found out when investigating
      different morphological forms of acute appendicitis. This express method was
      successfully used in one hundred patients during operation. The regional
      electrostimulation of the caecum was used in cases of ischemia of the latter
      after appendectomy.

PMID- 10645575
TI  - [Surgical treatment of patients with terminal stages of occlusive diseases of the
      lower limb peripheral arteries].
AB  - During the period of 1987-1998 operations for obliterating diseases of the
      peripheral arteries were performed on 104 patients having critical ischemia of
      the diseased extremity. The microsurgical technique was used. Indirect
      revascularization of the ischemic extremity with the soft tissue flap was
      fulfilled in 56 patients, femoro-distal-crural bypass was used in 38 patients, in
      11 of them the bypass was "unloaded" into the flap of the broadest dorsal muscle,
      in 10 patients arterialization of the origins of the major subcutaneous veins was
      made. In cases of shunting with the "unloading" into the flap the extremity was
      saved in all the patients, after revascularization the extremity was saved in 89%
      of the patients, two years after the operation these patients had chronic
      ischemia of the operated extremity of the IIA degree. After arterialization of
      the foot vein 60% of the patients avoided amputation of the extremity.

PMID- 10645576
TI  - [Enteral infusion-nutritional correction of homeostasis in patients with postburn
      cicatricial stenosis of the esophagus and stomach].
AB  - The metabolic status was studied in 67 patients with postburn cicatricial
      strictures of the esophagus (39) and of the pyloric part of the stomach (28). The
      aim of the work was to find the methods of enteral nutrition with special
      mixtures. The composition of the mixtures must be close to that of the chyme. In
      addition to changes of the standard parameters (pH, enzymatic and electrical
      activity) the assessment of the state of the digestive tract included the
      estimation and description of certain disorders in the system of heterophasic
      hydrolysis in the gastrojejunal tract (enzyme activity in fractions of the
      duodenal juice, enzyme sorption on the flocular structures) in the both
      categories of the patients. The authors recommend to treat such patients with the
      special mixtures "Nutrichim" or using the new corrector "Flokozim".

PMID- 10645577
TI  - [Myocardial cytoprotection with trimetazidine in patients with ischemic heart
      disease during surgical stress].
AB  - Fluctuations of the thiol disulfide system were shown to be interrelated with
      changes in the ECG indices. Trimetazidine since it has antioxidant properties was
      found to be effective in patients with low thiol disulfide ratios. A single dose
      of 0.8 mg/kg of the body mass was shown to inhibit the appearance of stress
      dependent ischemic symptoms during surgical procedures.

PMID- 10645578
TI  - [Monitoring of the auditory stem evoked potentials in removal of tumors of the
      posterior cranial fossa].
AB  - The material of intraoperative monitoring of the acoustic stem evoked potentials
      (ASEP) in 9 patients with tumors of the stem and in 28 patients with the parastem
      localization was analyzed. It was shown that changes in the amplitude of ASEP
      rather than latency were the decisive factor in the assessment of the functional
      state of the brain stem. It was found that even the pronounced changes of the
      bioelectrical activity recorded during the excision of the tumor could be
      reversible after a change of the strategy of the operative intervention and/or
      after performing the necessary therapeutic measures. An important test of
      favorable prognosis of the postoperative course is considered to be the
      normalization of brain activity, ASEP included, at the final stages of the
      operation.

PMID- 10645580
TI  - [Surgical treatment of atrial septal defects and associated congenital heart
      diseases].
AB  - The results of radical correction of interatrial septum defects and heart
      diseases associated with it were analyzed after treatment of 502 patients at the
      age from 5 to 48 years. In most cases (58.4%) the patients were adults. The
      isolated defect of the interatrial septum was diagnosed in 377 patients.
      Correction of the defect was performed in 82 patients (16.3%) under mild
      hypothermia and 420 patients (83.6%) were operated upon under conditions of
      artificial circulation. General lethality was 7.7%.

PMID- 10645579
TI  - [Results of the surgical treatment of patients with basal extracerebral parastem
      tumors of large and giant dimensions].
AB  - A retrospective analysis of the results of treatment of 123 patients with large
      and giant basal extracerebral parastem tumors was made. The majority of the
      neoplasms (81%) were acoustic neuromas and meningiomas. The nearest results of
      the treatment were good in 103 patients and unfavorable results were noted in 20
      patients. Postoperative mortality was 8.9%. Four factors negatively influencing
      the outcome were revealed during the statistical analysis (p < 0.05): low
      Karnofsky score at admission, regrowth (recurrence) of the tumor, previously
      performed radiation therapy and shunt surgery as the first stage of treatment.
      These prognostic factors must be taken into account when choosing the best
      treatment of patients with parastem tumors.

PMID- 10645581
TI  - [Use of constant electric current in prevention of postoperative bronchopulmonary
      complications in patients with hiatal hernia].
AB  - The prophylactics of bronchopulmonary complications was performed by the authors
      original method of intrapulmonary electrophoresis. It was shown to be effective
      and allowed the amount of postoperative bronchitis and pneumonia to be reduced
      from 15-20% to 4.4%.

PMID- 10645582
TI  - [Lymph node dissection in esophageal cancer].
AB  - Results of surgical treatment of 70 patients with carcinoma of the thoracic part
      of the oesophagus were analyzed. The extended two-levels (intraabdominal and
      intrathoracic) lymphodissection is the necessary part of the operation.
      Postoperative lethality was 2.9%, one year and 2 years survival was 85.8 and 69%
      correspondingly. The data obtained show that it is expedient to introduce the
      extended two-levels lymphodissection into clinical practice.

PMID- 10645583
TI  - [Surgical treatment of recurrent goiter].
AB  - The authors have analyzed and generalized their 20-years experience with surgical
      treatment of 247 patients with recurrent goiter. Among them 48 patients had
      recurrent toxic goiter and 199 patients had nontoxic goiter. Postoperative
      complications developed in 8.3% of the patients with recurrent toxic goiter and
      in 6% of the patients with nontoxic goiter. The overall postoperative lethality
      was 1.2%. Operative treatment is recommended by the authors for recurrent toxic
      and nontoxic goiter, conservative treatment with radioactive iodine is thought to
      be expedient for a repeated recurrence. For preventing recurrences of toxic and
      nontoxic goiter after the first operation the administration of small does of the
      thyroid hormones is considered to be expedient during 1.5-2 months.

PMID- 10645584
TI  - [Gastrectomy in the treatment of gastric hemorrhage].
AB  - The results of gastrectomies performed in 7 women and 13 men (aged from 41 to 73)
      with various diseases of the stomach (cancer, non-epithelial tumors, erosive and
      ulcerous gastritis, ulcer and phlegmonous gastritis) are analyzed. The surgical
      interventions included operations from gastrectomy to
      gastropancreatosplenoduodenocholecystectomy with phleboplasty of the portal vein
      and extended parietal lymphadenectomy. Ten operations were made for profuse
      bleedings with 4 fatal outcomes. During the first 48 hours after the appearance
      of the complication 10 patients were operated upon for the recurrence of the risk
      of recurrent hemorrhage. The formation of muff-like variants of
      esophagojejunostomy was preferred. The results are considered to be promising.

PMID- 10645585
TI  - [Surgeon's strategy in perforated bleeding cancerous tumor of the stomach in aged
      patients].
AB  - Radical emergency operations were performed on 5 elderly patients with a
      combination of cancerous tumor of the stomach and such complications as bleeding
      and perforation. Based on this material the authors make a well-reasoned
      conclusion that such surgical strategy is justified.

PMID- 10645586
TI  - [A methods of laparoscopic suturing of perforated pyloro-bulbar ulcers].
AB  - The article describes a method of laparoscopic suturing perforated ulcers of the
      pylorobulbar zone. The elements of all steps of the operation are analyzed
      including the places of introducing the trocar, the method of putting the
      intracorporeal stitches, means of sanitation and drainage of the abdominal
      cavity. The method was successfully used in operations on 43 patients with
      perforated ulcers without any complications.

PMID- 10645587
TI  - [Laparoscopic surgery in colorectal tumors].
AB  - The authors describe their first experience with using less invasive laparoscopic
      methods in patients with tumors of the rectum and the colon. Twelve operative
      interventions were performed. The method and technique of endovideosurgical
      operations on the colon are described. The intraoperative and postoperative
      complications are analyzed. The authors not rich experience with performing
      laparoscopic interventions on the colon shows the necessity of stepwise and
      thorough mastering the method and of using strictly individual indications for
      such operations.

PMID- 10645588
TI  - [Substernal goiter with localization in the posterior mediastinum].

PMID- 10645589
TI  - [Stepwise treatment of patients with ischemic heart disease and obliterating
      atherosclerosis of the lower limb vessels].

PMID- 10645590
TI  - [Angioplasty and stenting of coronary arteries in a patient with unstable
      angina].

PMID- 10645591
TI  - [A 15-year follow-up of regression of atherosclerotic plaque of the coronary
      artery after partial ileal bypass].

PMID- 10645592
TI  - [Multiple small intestine fistulas and subdiaphragmatic abscess in an emaciated
      patient wounded in the abdomen].

PMID- 10645593
TI  - [Strangulation of paracolostomic hernia].

PMID- 10645594
TI  - [A computation method in determining the price of treatment of surgical patients
      and economic efficiency of the introduction of certain therapeutic-diagnostic
      procedures].

PMID- 10645595
TI  - [Improvement of ambulatory surgery as an alternative way to decrease the
      frequency of suppurative-inflammatory complications after surgical
      interventions].

PMID- 10645596
TI  - [The Fourth Russian Gastroenterological Week, Moscow, November 14-20, 1998].

PMID- 10645597
TI  - [Minimally invasive methods in complex treatment of patients with acute
      pancreatitis and its complications].

PMID- 10645598
TI  - [Prospects in the use of vascular prostheses with preliminary endothelial
      seeding].

PMID- 10645599
TI  - [Surgical treatment in post-thrombotic diseases with unilateral occlusion of the
      iliac vein].

PMID- 10645600
TI  - [History of the surgery of military injuries].

PMID- 10645601
TI  - [Evolution of scientific work of Ivan Petrovich Pavlov: from the physiology of
      the visceral systems to the physiology of the higher nervous activity].

PMID- 10645602
TI  - [Stereotypes of evolution? Skeletal muscles of insects and mammals].

PMID- 10645603
TI  - [Roles of the right and the left brain hemispheres in analysis of the speech
      information in patients with affective pathology].

PMID- 10645604
TI  - [Adaptation of chimpanzee offspring to changes in experimental situation].

PMID- 10645606
TI  - [Subfebrity and fever: the comparative physiological aspect].

PMID- 10645605
TI  - [Dissolution of the central nervous system and the wakefulness-sleep cycle].

PMID- 10645607
TI  - [Peptidase distribution in various layers of the small intestine in rats
      depending on their age].

PMID- 10645608
TI  - [2,3-Diphosphoglycerate level in the mammalian erythrocytes: interspecies
      relations with hematologic and rheologic parameters of cells].

PMID- 10645609
TI  - [Electrophysiological evidence of the multiple origin of vestibulospinal axons in
      the frog Rana ridibunda].

PMID- 10645610
TI  - [Aleksei Valentinovich Voino-Iasenetskii (1909-1985)].

PMID- 10645611
TI  - [The nature and origins of the early excitation rhythms].

PMID- 10645612
TI  - [Rhythmic processes in the developing organism and their synchronization].

PMID- 10645613
TI  - [Fast temperature oscillations as the synchronization factor of spontaneous
      excitation in rat offspring].

PMID- 10645614
TI  - [Cortico-striatal interrelations in the wakefulness-sleep cycle during the
      central nervous system dissolution].

PMID- 10645615
TI  - [Phylo- and ontogenic comparison of sleep deprivation effects].

PMID- 10645617
TI  - [Long-term changes in the latent period of afferent and efferent responses of
      neurons in the rat vibrissal motor cortex following unilateral transsection of
      the infraorbital nerve of offspring].

PMID- 10645616
TI  - [Electroencephalogram before and after the human body macromovement during the
      night sleep].

PMID- 10645619
TI  - [Biological aspects of hyperoxia].

PMID- 10645618
TI  - [Adrenergic and cholinergic regulation of the cardiac output in the developing
      organism].

PMID- 10645620
TI  - [Volumes and rhythms of their movement in space-time in living organisms].

PMID- 10645621
TI  - Resolution of 1,2-epoxyhexane by Rhodotorula glutinis using a two-phase membrane
      bioreactor.
AB  - Large-scale resolution of epoxides by the yeast Rhodotorula glutinis was
      demonstrated in an aqueous/organic two-phase cascade membrane bioreactor. Due to
      the chemical instability and low solubility of epoxides in aqueous phases, an
      organic solvent was introduced into the reaction mixture in order to enhance the
      resolution of epoxide. A cascade hollow-fiber membrane bioreactor was used (1) to
      minimize the toxicity of organic solvents towards the epoxide hydrolase of R.
      glutinis, and (2) to remove inhibitory amounts of formed diol from the yeast cell
      containing aqueous phase. Dodecane was selected as a suitable solvent and 1,2
      epoxyhexane as a model substrate. By use of this membrane bioreactor, highly
      concentrated (0.9 M in dodecane) enantiopure (> 98% ee) (S)-1,2-epoxyhexane (6.5
      g, 30% yield) was obtained from the racemic mixture.

PMID- 10645622
TI  - Enhanced sterol-acyl transferase activity promotes sterol accumulation in
      Saccharomyces cerevisiae.
AB  - The sterol-acyl transferase encoded by the gene ARE2 was transcriptionally
      deregulated in the yeast Saccharomyces cerevisiae to understand its role in
      sterol storage and sterol enrichment. Our results show that sterols can indeed be
      enriched in yeast by enhancing the capacity of the cells to esterify sterols.
      ARE2 overexpression had no impact on the accumulation of the early sterols such
      as lanosterol, but influenced the later intermediates and the end product
      ergosterol. Thus an enhanced conversion of free sterols to their esterified
      counterparts may provide a tool to increase the overall sterol content of the
      yeast cell. We have previously shown that the overexpression of a truncated
      version of the key enzyme of the early sterol pathway, HMG-CoA reductase (HMG1),
      leads to an increase in the early sterols such as lanosterol and zymosterol. The
      simultaneous deregulation of both genes in one strain produces a cumulative
      effect in that both early and late sterols are enhanced. Karmellae-like
      structures can be detected when Are2p is overexpressed. Are2p therefore
      constitutes a new member of the karmellae-inducing protein family.

PMID- 10645623
TI  - Nucleotide sequence and thermostability of pND324, a 3.6-kb plasmid from
      Lactococcus lactis.
AB  - A 3.6-kb plasmid, designated pND324, was isolated from Lactococcus lactis subsp.
      lactis LL57-1. Sequence analysis revealed the presence of three open reading
      frames, rep324, orfX1 and orfX2, which are flanked by two non-coding regions,
      ori324 and cisE. The minimal replication region of pND324 consists of ori324 and
      rep324, which is closely related to the lactococcal theta-type replicons of the
      pWV02/pCI305 family. pND324 was stable at both 30 degrees C and 37 degrees C,
      whereas derivatives that lack cisE were highly unstable at 37 degrees C,
      indicating that cisE is essential for thermostability. Sequences that are similar
      to orfX1 are commonly present in the lactococcal theta-type plasmids. The orfX2
      product is homologous to TrfA, a 43-kDa protein of the E. coli theta-type plasmid
      RK2 required for replication and maintenance. Plasmid deletion and stability
      analyses showed that orfX2 is involved in the thermostability of pND324. Based on
      the minimal replication region of pND324, an integrative cloning vector,
      designated pND421, was constructed. In L. lactis LM0230, cells that carried
      pND421 integrated into its host chromosomal DNA could be recovered readily
      following incubation at 37 degrees C for 40 generations. The integrated plasmid
      was totally stable for at least 100 generations without selection at 30 degrees
      C.

PMID- 10645624
TI  - Metabolic approaches for the optimisation of recombinant fermentation processes.
AB  - The aim of this work was the establishment of a novel method to determine the
      metabolic load on host-cell metabolism resulting from recombinant protein
      production in Escherichia coli. This tool can be used to develop strategies to
      optimise recombinant fermentation processes through adjustment of recombinant
      protein expression to the biosynthetic capacity of the host-cell. The signal
      molecule of the stringent-response network, guanosine tetraphosphate (ppGpp), and
      its precursor nucleotides were selected for the estimation of the metabolic load
      relating to recombinant-protein production. An improved analytical method for the
      quantification of nucleotides by ion-pair, high-performance liquid chromatography
      was established. The host-cell response upon overexpression of recombinant
      protein in fed-batch fermentations was investigated using the production of human
      superoxide dismutase (rhSOD) as a model system. E. coli strains with different
      recombinant systems (the T7 and pKK promoter system) exerting different loads on
      host-cell metabolism were analysed with regard to intracellular nucleotide
      concentration, rate of product formation and plasmid copy number.

PMID- 10645625
TI  - Transient gene expression in mammalian and mosquito cells using a recombinant
      Semliki Forest virus expressing T7 RNA polymerase.
AB  - In this report, we describe a novel recombinant Semliki Forest virus (SFV)
      expressing T7 RNA polymerase (T7-RP), which was shown to drive transient
      expression of the chloramphenicol acetyltransferase (cat) gene in mammalian and
      mosquito cells after transfection of plasmids carrying the reporter gene under
      the control of the T7 promoter. To our knowledge, this is the first description
      of a T7-RP-based expression in mosquito cells. Expression of the cat gene was
      significantly enhanced in mammalian cells by inserting the sequence of the
      encephalomyocarditis virus internal ribosome entry site between the T7 promoter
      and the 5' end of the cat gene. In mosquito cells, the level of chloramphenicol
      acetyltransferase activity was increased by flanking the cat gene with the
      Autographa californica baculovirus p10 gene 5' and 3' untranslated regions. SFV
      expressing T7-RP appears, therefore, to be an alternative to other virus-based
      gene-expression systems in mammalian cells and a powerful tool for protein
      expression in mosquito cells.

PMID- 10645626
TI  - Molecular basis for enhanced biosynthesis of clavulanic acid by a redox-cycling
      agent, phenazine methosulfate, in Streptomyces clavuligerus.
AB  - Phenazine methosulfate (PMS), a generator of superoxide, evoked the transcription
      of cas2 and cefF, ultimately resulting in the enhanced biosyntheses of clavulanic
      acid (CA) and cephamycin C (CMC) in Streptomyces clavuligerus. The
      transcriptional activation of cas2 and cefF was accompanied with that of ccaR, a
      regulatory gene for biosyntheses of CA and CMC. PMS or H2O2 in cell-free extract
      exerted a positive regulation on in vitro protein phosphorylation. The PMS
      mediated activation of protein phosphorylation was significantly offset by
      butylated hydroxyanisole, a radical scavenger. Staurosporine, a protein kinase
      inhibitor, was shown to have a negative effect on PMS-promoted CA accumulation.
      Therefore, it is suggestive that PMS-activated transcription of cas2 and cefF is
      mediated by protein phosphorylation and the expression of a pathway-specific
      transcriptional activator as found in other streptomycetes. These experimental
      results present an example of the functional relationship between oxidative
      stimuli and secondary metabolite production in streptomycetes.

PMID- 10645627
TI  - Isolation and characterisation of a ropy Lactobacillus strain producing the
      exopolysaccharide kefiran.
AB  - A capsular-polysaccharide-producing strain, LM-17, was isolated from kefir grains
      and was identified as a slime-forming, rod-shaped Lactobacillus. According to 1H-
      and 13C-NMR spectral data, the exopolysaccharide produced by the isolated
      bacterial strain is identical to the glucogalactan extracted from kefir grains
      and therefore known as kefiran. The kefiran produced was characterised by means
      of viscosity, optical rotatory power, circular dichroism and IR spectral
      measurements. A batch procedure was set up for the culture and extraction of the
      exopolysaccharide in laboratory conditions, resulting in a yield of 2 g/l
      purified kefiran from the culture supernatant of the LM-17 strain.

PMID- 10645628
TI  - Enhanced production of penicillin V acylase from Streptomyces lavendulae.
AB  - A 28 degrees C, Streptomyces lavendulae produced high levels of penicillin V
      acylase (178 IU/l of culture) when grown on skim milk as the sole nutrient source
      for 275 h. The enzyme showed catabolite repression by glucose and was produced in
      the stationary phase of growth. Penicillin V was a good inducer of penicillin V
      acylase formation, while phenoxyacetic acid, the side-chain moiety of penicillin
      V, did not alter enzyme production significantly. The enzyme was stable between
      pH 6 and 11 and at temperatures from 20 degrees C to 55 degrees C. This
      extracellular enzyme was able to hydrolyse natural penicillins and unable to
      hydrolyse penicillin G.

PMID- 10645629
TI  - Degradation of phenanthrene by different bacteria: evidence for novel
      transformation sequences involving the formation of 1-naphthol.
AB  - Four polycyclic aromatic hydrocarbon (PAH)-degrading bacteria, namely
      Arthrobacter sulphureus RKJ4, Acidovorax delafieldii P4-1, Brevibacterium sp. HL4
      and Pseudomonas sp. DLC-P11, capable of utilizing phenanthrene as the sole source
      of carbon and energy, were tested for its degradation using radiolabelled
      phenanthrene. [9-14C]Phenanthrene was incubated with microorganisms containing
      100 mg/l unlabelled phenanthrene and the evolution of 14CO2 was monitored: within
      18 h of incubation, 30.1, 35.6, 26.5 and 2.1% of the recovered radiolabelled
      carbon was degraded to 14CO2 by RKJ4, P4-1, HL4 and DLC-P11, respectively. When
      mixtures of other PAHs such as fluorene, fluoranthene and pyrene, in addition to
      phenanthrene, were added as additional carbon sources, there was a 36.1 and 20.6%
      increase in 14CO2 production from [9-14C]phenanthrene in the cases of RKJ4 and
      HL4, respectively, whereas P4-1 and DLC-P11 did not show any enhancement in 14CO2
      production. Although, a combination of many bacteria enhances the degradation of
      organic compounds, no enhancement in the degradation of [9-14C]phenanthrene was
      observed in mixed culture involving all four microorganisms together. However,
      when different PAHs, as indicated above, were used in mixed culture, there was a
      68.2% increase in 14CO2 production. In another experiment, the overall growth
      rate of P4-1 on phenanthrene could be enhanced by adding the non-ionic surfactant
      Triton X-100, whereas RKJ4, HL4 and DLC-P11 did not show any enhancement in
      growth. Pathways for phenanthrene degradation were also analysed by thin-layer
      chromatography, gas chromatography and gas chromatography-mass spectrometry.
      Common intermediates such as o-phthalic acid and protocatechuic acid were
      detected in the case of RKJ4 and o-phthalic acid was detected in the case of P4
      1. A new intermediate, 1-naphthol, was detected in the cases of HL4 and DLC-P11.
      HL4 degrades phenanthrene via 1-hydroxy-2-naphthoic acid, 1-naphthol and
      salicylic acid, whereas DLC-P11 degrades phenanthrene via the formation of 1
      hydroxy-2-naphthoic acid, 1-naphthol and o-phthalic acid. Both transformation
      sequences are novel and have not been previously reported in the literature. Mega
      plasmids were found to be present in RKJ4, HL4 and DLC-P11, but their involvement
      in phenanthrene degradation could not be established.

PMID- 10645630
TI  - A computer-controlled system to simulate conditions of the large intestine with
      peristaltic mixing, water absorption and absorption of fermentation products.
AB  - This paper introduces a new type of system to simulate conditions in the large
      intestine. This system combines removal of metabolites and water with peristaltic
      mixing to obtain and handle physiological concentrations of microorganisms, dry
      matter and microbial metabolites. The system has been designed to be
      complementary to the dynamic multi-compartmental system that simulates conditions
      in the stomach and small intestine described by Minekus et al. [Minekus M,
      Marteau P, Havenaar R, Huis in't Veld JHJ (1995) ATLA 23:197-209]. High densities
      of microorganisms, comparable to those found in the colon in vivo, were achieved
      by absorption of water and dialysis of metabolites through hollow-fibre membranes
      inside the reactor compartments. The dense chyme was mixed and transported by
      peristaltic movements. The potential of the system as a tool to study
      fermentation was demonstrated in experiments with pectin, fructo-oligosaccharide,
      lactulose and lactitol as substrates. Parameters such as total acid production
      and short-chain fatty acid (SCFA) patterns were determined with time to
      characterize the fermentation. The stability of the microflora in the system was
      tested after inoculation with fresh fecal samples and after inoculation with a
      microflora that was maintained in a fermenter. Both approaches resulted in total
      anaerobic bacterial counts higher than 10(10) colony-forming units/ml with
      physiological levels of Bifidobacterium, Lactobacillus, Enterobacteriaceae and
      Clostridium. The dry matter content was approximately 10%, while the total SCFA
      concentration was maintained at physiological concentrations with similar molar
      ratios for acetic acid, propionic acid and butyric acid as measured in vivo.

PMID- 10645631
TI  - Interleukin-1 beta affects the macrophage recruitment and proliferation in the
      injured brain of 6-day-old rat.
AB  - Six-day-old male rats received a mechanical lesion in the left cerebral
      hemisphere. Thereafter, a single dose of either 5, 50 or 500 units (U) of
      recombinant rat interleukin-1 beta (IL-1 beta) was injected into the lesion
      cavity. One or 2 days after the injury, the rats were injected with 3H-thymidine.
      Brain sections were subjected to BSI-B4 lectin histochemistry and autoradiography
      to visualise proliferating and non-proliferating macrophages located within the
      region of injury. A mitogenic effect of IL-1 beta on macrophages was observed on
      day 2 in brains injected with the lowest 5 U dose of cytokine. Following
      administration of higher 50 U and 500 U doses, infiltration of the injured tissue
      by macrophages was significantly intensified on day 1. However, on day 2, dose
      dependent reductions of the total number of macrophages as well as their
      proliferative activity were recorded. The findings suggest that the higher the
      initial quantity of macrophages, the sooner they disappeared from the injury
      site. It may therefore be hypothesised that IL-1 beta-induced increase in
      macrophage recruitment at the beginning of the inflammatory response speeded the
      removal of tissue debris and, therefore, accelerated healing of the injured
      nervous tissue.

PMID- 10645632
TI  - Branching neurones in the cervical spinal cord with axons that reach sacral
      segments and the lateral reticular nucleus. An electrophysiological study in the
      cat.
AB  - Branching neurones in the cervical enlargement of the spinal cord were
      electrophysiologically studied in alpha-chloralose anaesthetized cats with the
      method of antidromic activation of axons. Stimulating electrodes were placed
      bilaterally at levels of lower thoracic and sacral segments and in the lateral
      reticular nucleus (LRN), ipsilaterally to the recording sites in C6/C7 segments.
      Thirty-nine out of a total one hundred neurones could be classified as
      bidirectional neurones with both descending and ascending collaterals. In the
      remaining cases only long descending projections to spinal segments were found.
      Comparison of conduction velocities measured in descending branches revealed no
      significant differences between individual neurones. On the other hand,
      descending collaterals of double direction neurones conducted impulses
      considerably faster than their axonal branches ascending to LRN. Our results
      suggest that parallel transmission of information to various, spinal or
      supraspinal centres of the nervous system is more common than reported before.

PMID- 10645633
TI  - Augmentation of ventral tegmental area stimulation-induced feeding by both
      stimulation and lesion of the contralateral ventral tegmental area in the rat.
AB  - Unilateral lesions of the ventral tegmental area (VTA) facilitate behavioral
      responses (feeding and exploration) induced by electrical stimulation of the VTA
      in the contralateral hemisphere. It was hypothesized that this facilitation may
      result from a lesion-induced compensatory increase in dopamine transmission in
      the intact hemisphere. In the present study we tested on the functional level the
      hypothesis that the activity of bilateral mesocorticolimbic systems is inversely
      related. For this purpose we compared the effect of unilateral subthreshold
      activation with the effect of subsequent unilateral lesion of VTA on feeding
      response evoked by electrical stimulation of the contralateral VTA. In male
      Wistar rats implanted with bilateral VTA electrodes stimulation-induced feeding
      was tested in a latency to feed-stimulation frequency curve-shift paradigm. One
      electrode was used for induction of feeding reaction and the other electrode was
      used for concurrent stimulation (with the subthreshold current) and subsequent
      electrolytic lesioning of the contralateral VTA. It was found that both
      contralateral stimulation and subsequent lesion performed through the same
      electrode facilitated a feeding response that manifested as a decrease in the
      reaction's threshold and a leftward shift of the latency-frequency curve. The
      paradoxical similarity of the effects of the stimulation and lesion is discussed
      in terms of functional organization of the mesocorticolimbic system and adaptive
      changes in dopaminergic transmission.

PMID- 10645634
TI  - Influence of bombesin on threshold for feeding and reward in the rat.
AB  - Bombesin's purported role in satiety mechanisms prompted this investigation of
      its effects on thresholds for stimulation-induced feeding and self-stimulation in
      the rat. Single electrodes were implanted in the lateral hypothalamus and the
      ability of each electrode to support self-stimulation and stimulation-induced
      feeding was evaluated at four current levels between 80 and 320 microA. The
      frequency thresholds associated with each current value were assessed following
      four intraperitoneal doses of bombesin, 2, 4, 8, and 16 micrograms/kg, as well as
      a saline dose. Bombesin increased the thresholds for stimulation-induced feeding
      at doses known to reduce food intake without influencing self-stimulation
      thresholds. From these findings we conclude that (1) the effects of peripheral
      bombesin on stimulation-induced feeding are analogous to its effects on normal
      feeding and (2) the data provide additional evidence for a pharmacological
      dissociation between stimulation-induced feeding and reward.

PMID- 10645635
TI  - Effects of the anterior temporal lobe lesions, separate or combined with
      hippocampal damage, on spatial delayed responses guided by auditory stimulus.
AB  - Seventeen dogs were trained in a three-choice auditory spatial delayed response
      task, guided by auditory stimulus, at a 10 s delay to a criterion of 90% correct
      responses in 90 consecutive trials. Four dogs then received bilateral anterior
      temporal lobe lesions (AT), 6 dogs received hippocampal lesions (H), and 7 dogs
      served as controls (C). Group C reached postoperative criterion immediately while
      groups AT and H needed additional training. When subsequently tested at longer
      delays and with distractions, the group H animals performed more poorly than
      either the AT or C animals. Further, the group H dogs were again impaired when
      they retrained at a 10 s delay. In the second phase, the group H and AT animals
      received a second lesion forming a group (HAT) with bilateral lesions to both the
      hippocampus and the anterior temporal lobe. Unexpectedly, dogs from group HAT
      were unimpaired in either postoperative retraining or during performance task and
      distractions. The results emphasize the importance of the hippocampus in spatial
      delayed response with an acoustic cue. Effect of combined lesions after extensive
      training is discussed. Data might support the view, that the hippocampus plays
      time limited role in memory storage.

PMID- 10645636
TI  - Quantitative measure of complexity of EEG signal dynamics.
AB  - Since electroencephalographic (EEG) signal may be considered chaotic, Nonlinear
      Dynamics and Deterministic Chaos Theory may supply effective quantitative
      descriptors of EEG dynamics and of underlying chaos in the brain. We have used
      Karhunen-Loeve decomposition of the covariance matrix of the EEG signal to
      analyse EEG signals of 4 healthy subjects, under drug-free condition and under
      the influence of Diazepam. We found that what we call KL-complexity of the signal
      differs profoundly for the signals registered in different EEG channels, from
      about 5-8 for signals in frontal channels up to 40 and more in occipital ones.
      But no consistency in the influence of Diazepam administration on KL-complexity
      is observed. We also estimated the embedding dimension of the EEG signals of the
      same subjects, which turned to be between 7 and 11, so endorsing the presumption
      about existence of low-dimensional chaotic attractor. We are sure that nonlinear
      time series analysis can be used to investigate the dynamics underlying the
      generation of EEG signal. This approach does not seem practical yet, but deserves
      further study.

PMID- 10645637
TI  - Lidocaine inhibits neurite growth in mouse dorsal root ganglion cells in culture.
AB  - Recent clinical and experimental studies suggest the effectiveness of lidocaine
      in blocking neuropathic pain. Because it has been demonstrated that the
      pathogenetic mechanisms of neuropathic pain involve morphological changes in
      afferent neuronal terminals onto spinal cord, we examined the effects of
      lidocaine on neurite growth in isolated mouse dorsal root ganglion cells in
      culture. Incubation for 2-42 h with various concentrations of lidocaine (0.006
      mM, 0.6 mM, and 30 mM) reduced the number of cells exhibiting neurites. The
      effects were time- and dose-dependent. Lidocaine therefore may exert its
      pharmacological effect, at least in part, by changing neuronal structures derived
      from sensory neurons.

PMID- 10645638
TI  - Evoked cardiac response components in cognitive processing: differential effects
      of amyotrophic lateral sclerosis.
AB  - We investigated the mechanism of two evoked cardiac response components
      associated with different aspects of information processing. Innocuous stimuli
      presented in an irrelevant condition elicit a simple cardiac deceleration termed
      ECR1. The same stimuli presented in a relevant condition (such as results from
      requesting subjects to silently count the stimuli) elicit a complex biphasic
      response with a large secondary acceleration in heart rate. This difference is
      attributed to the additional effect of cognitive task performance, resulting in
      an addition response component, ECR2. This may be realised by subtraction of the
      two responses. We investigated the mechanisms involved by comparing cardiac
      response profiles from a neurologically-impaired group with those from a control
      group amyotrophic lateral sclerosis (ALS) has been associated with a loss of
      synaptic connections in the frontal lobe. Twelve ALS clinically non-demented
      patients were age-matched with twelve neurological patients without pathological
      changes in the brain. Cardiac response profiles for ECR1 and ECR2 were examined
      as a function of group. ECR1 did not differ between the groups, but ECR2 was
      significantly impaired in the ALS patients. The results are discussed in terms of
      different brain regions associated with these two cardiac response components.
      ECR1 may be associated with automatic preattentive stimulus registration
      involving, in the case of auditory stimuli, the auditory analyser and associated
      pathways, while ECR2 appears to be a correlate of controlled executive
      processing, involving the frontal cortex.

PMID- 10645639
TI  - [Transplantation of bone marrow from unrelated donors in Italy: activity and
      results].
AB  - Unrelated donor (UD) bone marrow transplantation (BMT) represents an attractive
      option for patients with haematological, oncological or genetic diseases lacking
      a compatible familiar donor. Between September 1988 and December 1997 the search
      of a donor has been activated for 1724 patients in Italy. Until May 1998, 413 BMT
      from UD have been performed in 28 different authorized italian centres. Forty out
      of these patients were affected by genetic diseases apart from SCID (severe
      combined immunodeficiency). Sixty-month disease free survival (DFS) of this group
      was 62%. Seventy-four out of 215 children with acute lymphoblastic leukemia (ALL)
      for whom a donor search was started underwent a BMT. Six year DFS was 25%. Fifty
      nine out of 379 patients with chronic myeloid leukemia (CML) for whom a donor
      search was activated underwent BMT. Forty-eight month DFS was 41.5%. Inborn
      errors curable with BMT, relapsed ALL and CML represent an absolute indication
      for UD BMT. In these cases donor search should be activated yearly.

PMID- 10645640
TI  - [The Italian Registry of Bone Marrow Donors].
AB  - Following a synthetic statement of the scientific, genetic and practical
      assumptions of the bone marrow transplantation (BMT) from marrow unrelated donor
      (MUD), which, in turn, have represented the basis for the establishment of the
      Italian Bone Marrow Donor Registry (IBMDR), the paper reports the registry
      activity on 30 November 1998. At that date, Italian volunteers were 232,876,
      number which put the IBMDR as the fourth registry all over the world and as the
      third in Europe. The mean age of the donors is 34 years, and this means that
      IBMDR is one of the youngest among international registries. Using Italian
      donors, 426 BMT, altogether, have been performed, (248 for Italian patients and
      178 for foreign patients). Donor search activations performed by national and
      international transplant centres have been, at the same date, 5729 (1821 for
      Italian patients and 3908 for foreign patients). Operating standards and
      guidelines for all centres participating in the IBMDR are reported in this issue.

PMID- 10645641
TI  - [The Italian Registry of Bone Marrow Donors: genetic structure and recruitment
      strategy].
AB  - The genetic structure of the Italian bone marrow donor population was analysed by
      estimating the HLA-A, -B and -DR gene and haplotype frequencies for the total
      population and for the Italian administrative regions. The haplotype frequencies
      were used to predict the probability of finding HLA-compatible donors for Italian
      patients depending on the registry size, and the probability of recruiting in the
      different Italian regions a donor with a new phenotype. The analysis of these
      probabilities allows us to propose strategies for donors recruitment in order to
      increase the phenotypic variability of the registry, then its efficiency.

PMID- 10645642
TI  - [Genetic analysis of Italian hematologic patients candidates for bone marrow
      transplantation from unrelated donors].
AB  - Frequencies of HLA-A, -B and -DR antigens and haplotypes were determined in 1945
      Italian patients suffering from hematologic diseases and requiring bone marrow
      transplantation from unrelated donors. These frequencies were compared with those
      obtained from the Italian bone marrow donor population. No significant
      differences were found when considering the number of comparisons made,
      suggesting that the genetic structure of the Italian patients is not different
      from that of the Italian donor population.

PMID- 10645643
TI  - [National quality control of serologic HLA typing].
AB  - Since 1995 the Istituto Superiore di Sanita, in collaboration with the Italian
      Red Cross, has been organising annually the quality control of serological HLA
      class I and II typing on histocompatibility laboratories which perform typing for
      organ and bone marrow transplantation. Improvement has been obtained every year;
      in fact, results of the 1997 control show that the 77% of the laboratories typed
      the major specificities correctly. Despite the remarkable improvement achieved
      during the first three years of quality controls, a new organisation has been
      designed for further years to ensure the participation of all the Italian
      laboratories (more than 100) and to promote a quality control scheme that will be
      acceptable at international level.

PMID- 10645644
TI  - [National quality control of genomic HLA typing].
AB  - Since 1996 the Immunogenetics Laboratory of the National Cancer Institute/CBA,
      Genoa, in collaboration with the Immunohematology Research Centre of Bergamo has
      organized on behalf of Associazione Italiana di Immunogenetica e Biologia dei
      Trapianti (AIBT) and Istituto Superiore di Sanita (ISS) the quality control
      programme of HLA genomic typing for class I and II antigens for the laboratories
      performing HLA typing for organ and bone marrow transplantations. Herewith are
      reported the results and comments to the 1997 quality control programme along
      with some overall data.

PMID- 10645645
TI  - [Regulatory problems regarding bone marrow transplantation from non-consanguinous
      donors].
AB  - The paper reports the normative rules and the Italian Ministry of Health
      administrative instructions concerning the bone marrow unrelated donor (MUD)
      search in the Italian Bone Marrow Donor Registry (IBMDR) and in international
      registries from the preliminary activation to a MUD bone marrow transplant (BMT),
      when a volunteer donor, perfectly compatible with a recipient lacking a HLA
      identical sibling, is found. The article describes all the expenses pertinent to
      the different stages of search and the documents necessary to obtain the
      reimbursement of these expenses. A very recent Ministry Decree establishing that
      all the search costs will be charged to the competent local sanitary authority is
      added.

PMID- 10645646
TI  - [Human reproduction and environmental risk factors].
AB  - Environmental pollution is a great cause of concern, in particular, growing
      attention is being paid to the potential of many chemicals to affect the
      reproductive system in humans. The key role of prevention and control of
      reproductive hazards is recognized world-wide. Many chemicals have been shown to
      impair fertility and/or prenatal and perinatal development in experimental
      studies. However, a sufficient evidence of an effect on human reproduction is
      available for some compounds only. The use of biological markers may improve the
      assessment of exposure to chemicals, contribute to identify mechanisms of action
      and put into evidence early, reversible, biological effects. Valid biological
      markers are also needed in epidemiological studies: without reliable data on the
      level of current and past exposures it is difficult to establish a causal
      relationship between a pollutant and the occurrence of adverse health effects. A
      multidisciplinary approach to risk assessment is required. Priorities for
      interdisciplinary research on environmental chemicals and reproduction include
      the identification of susceptible population subgroups and risk assessment of
      exposure to multiple chemicals.

PMID- 10645647
TI  - [The role of biological monitoring in the evaluation of the risk of from chemical
      compounds].
AB  - Over the years, the assessment of the risk to human health from occupational and
      environmental exposure to chemicals has become increasingly important. Exposure
      to chemicals, their biochemical effects and individual susceptibility can be
      estimated by biological monitoring carried out on potentially exposed subjects.
      Valid markers are needed to be effectively used within the framework of
      biological monitoring programs. Quality assurance, which includes all those
      activities necessary to provide adequate confidence that the results of
      laboratory test are reliable, is of the utmost importance. Among these activities
      the participation in external quality assessment schemes is strongly recommended.
      Biological monitoring has a key role also in the field of human reproduction
      since the level of exposure to many chemicals which are known or suspected to be
      reproductive toxicants can be assessed by specialized laboratories.

PMID- 10645648
TI  - [New aspects in the evaluation of risk factors for fetal development].
AB  - Much knowledge concerning the effects of xenobiotics on prenatal development
      derive from experimental studies, which are generally performed on laboratory
      animals according to standardized protocols. Conventional in vivo studies should
      be integrated by other models within a scientifically-based risk assessment
      strategy. The paper reviews a few in vitro and/or in vivo approaches:
      identification of critical effects through the characterization of the
      pathogenesis as well as the use of dose-response relationships; alternative
      models to identify reproductive risks from single substances and/or mixtures
      present in the environment; interactions between in vitro and in vivo studies in
      the risk assessment of solvents: embryonic metabolism in teratogenicity;
      interactions between experimental and epidemiological studies to understand the
      pathogenesis of embryolethality; risk assessment of the effects of prenatal
      exposure to ionizing radiations.

PMID- 10645649
TI  - [Genetic diseases:recent scientific findings and health and ethical problems].
AB  - Genetic diseases are very numerous, even though rare as single conditions:
      therefore, overall they represent a significant portion of morbidity at
      population level. The improvement of molecular genetic techniques has brought a
      great increase in the diagnostic potential toward genetic diseases, concerning
      either symptomatic or pre-symptomatic individuals and healthy carriers. However,
      this has frequently unforeseen consequences, such as a discrepancy between
      diagnostic and therapeutic potentials. Moreover, the development of genetic tests
      has raised a number of questions regarding ethical, legal e social problems. The
      Italian guidelines for genetic tests (available on the Internet site of Istituto
      Superiore di Sanita: http:@www.iss.it) have been elaborated in 1998 to define
      general principles for performing and managing genetic tests as well as for
      programming and promoting genetic testing within the public health system. In
      accordance with recommendations by international bodies (WHO, EU), the Guidelines
      give emphasis to the appropriate use of both safe and efficacious tests, the
      performance in laboratories with high quality standards. A further crucial point
      is the relationship between the health system and individuals: authonomy of
      decision, psychological and social assistance, as well as adequate attention to
      ethical and privacy problems should be guaranteed.

PMID- 10645650
TI  - [Familial hypercholesterolemia and mutations of the gene for low-density
      lipoproteins in Italy].
AB  - The review takes into account molecular bases and major implications for public
      health in our country of familial hypercholesterolemia (FH) caused by mutations
      in LDL receptor (LDLR) gene. The relevance of the problem is evidenced by the
      fact that (a) about 120,000 Italians affected by heterozygous FH face a
      cardiovascular risk much higher than normal individuals, and (b) their
      identification is difficult because of the plethora of mutations existing in the
      country. This report deepens also the relationships between alterations in the
      coding sequence of LDLR gene and in the function of LDLR protein. Furthermore, it
      describes, in terms of molecular characteristics and diffusion, the 42 mutations
      so far detected in Italy that cause about 30% of FH cases. This led us to
      hypothesize the existence in our country of over hundred different mutations
      present within defined geographical areas where, in a few cases, they may also
      have a relatively high incidence (i.e., the so-called FH-clusters). Finally,
      preliminary studies mentioned here point out the existence of significant
      correlations between phenotype and genotype of FH and suggest the possibility of
      realizing on a large scale an early diagnosis and therapy of pathologies caused
      by a function deficit in LDL receptor.

PMID- 10645651
TI  - [Adrenoleukodystrophy: genetics, phenotypes, pathogenesis, and treatment].
AB  - Adrenoleukodystrophy is a genetically determined disorder inherited as an X
      linked recessive trait due to the defective peroxisomal oxydation of very long
      chain fatty acids (VLCFA). It is hallmarked by demyelination of the central
      nervous system and adrenal insufficiency. Even though the studies concerning the
      molecular basis of the disease are in progress, the role of VLCFA in the
      demyelination is still unclear. In this paper we report the most recent
      knowledges about genetics, pathogenesis and treatment of this disorder. 117 cases
      have been recognized in Italy in the period 1985-1997, but many cases could be
      missing due to the heterogeneus clinical manifestations that vary from mild to
      very severe forms. To control the devastating course of this disease two
      therapeutic approaches are under evaluation: bone marrow transplantation and
      dietary treatment based on a mixture of glyceroyl trioleate and glyceroyl
      trierucate. Nevertheless this dietary treatment provides normalization of plasma
      VLCFA, no significant modification of the natural course of the disease has been
      demonstrated. For what concerns bone marrow transplantation, in recent years a
      more accurate selection of patients and donors has been giving favourable
      results, but some strict criteria should be respected.

PMID- 10645652
TI  - [Glucose-6-phosphate dehydrogenase deficiency and hereditary hemolytic anemia].
AB  - G6PD deficiency is the most common enzymopathy in the world. The highest
      frequency values are found in tropical Africa, in the Middle East, in some areas
      of the Mediterranean, in tropical and sub-tropical Asia and in Oceania. This
      genetic defect shows sex linked inheritance and a marked heterogeneity. At least
      400 abnormal variants with different biochemical characteristics and about 100
      diverse mutations have been identified. In most cases the phenotypic expression
      is a marked decrease in erythrocyte G6PD activity. The most common clinical
      consequences are neonatal jaundice and sporadic haemolytic crises caused by a
      number of drugs, by infections or by ingestion of fava beans. A few cases of
      chronic non-spherocytic haemolytic anaemia associated with rare molecular
      variants have been reported. Early diagnosis, education and epidemiologic
      surveillance have been proved to be cornerstones in the prevention of the
      haemolytic disease. Therefore they should be taken into account in the national
      health programmes, especially in the countries with high prevalence rates.

PMID- 10645653
TI  - Oxidative stress in cancer prone genetic diseases: a review.
AB  - A number of congenital conditions include oxidative stress as a phenotypic
      hallmark, in spite of very distinct genotypic assets. These disorders include
      some rare chromosomal instability syndromes and two frequent congenital
      conditions, Down's syndrome and cystic fibrosis. All of these disorders generate
      severe biomedical and social handicaps in their progression, resulting in
      neurological symptoms or malformations, early ageing and cancer proneness. The
      onset of oxidative stress has been related to excess formation or defective
      detoxification of reactive oxygen species. Investigations conducted so far have
      focussed on individual disorders and have utilised a range of different
      methodologies, so leading to a number of unanswered questions regarding the
      role(s) for oxidative stress in these disorders. Comparative studies are
      required, based on homogeneous methods, to provide insights into the pathogenesis
      of each individual condition, which may open up new avenues for studying ageing
      and cancer.

PMID- 10645654
TI  - [Williams syndrome].
AB  - Williams syndrome (WS) is a rare (2-5/100,000) genetic human disorder
      characterised by a typical facies and mental retardation with a deficit in the
      visuospatial cognitive function and a relative preservation of linguistic
      abilities in general, and spoken language in particular. This syndrome also
      includes morphological anomalies, metabolic functional impairments, and likely
      deficits in the pattern of brain ontogenesis. The genetic basis of WS, recently
      identified, are presented. A cognitive profile of the WS individuals is defined
      and compared to Down syndrome (DS) and autism cognitive profiles. Neuroanatomical
      features of WS, including a reduction in brain volume, preservation of cerebellum
      and frontal lobes, and a reduction of posterior cortical systems, are described.
      The possible role of NGF (nerve growth factor)--a neurotrophin involved in the
      development of brain cholinergic systems and the associated behavioural functions
      -in the aetiology of the typical mental retardation of WS patients, is critically
      discussed. Future research avenues, including the identification of potential
      neurobiological markers in order to precociously diagnose this syndrome, are
      reviewed.

PMID- 10645655
TI  - [Prader-Willi syndrome].
AB  - Prader-Willi syndrome (PWS) is the most frequent cause of secondary obesity,
      characterized by neonatal hypotonia, dysmorphic facies, acromicria, hypogonadism,
      stunted growth, obesity, behavioural disturbances and cognitive impairment.
      Clinical diagnosis is confirmed by alteration of imprinted genes on the proximal
      long arm of chromosome 15 (15q11-13) for deletion, translocation, uniparental
      disomy for maternal chromosome 15 or imprinting center defect. Methylation test
      is the most reliable test for diagnosis. This issue explains diagnostic tests,
      clinical, metabolic, endocrinological features, and the most frequent
      complications observed in this syndrome. Precocious diagnosis and
      multidisciplinary approach allow in these patients to prevent the severe obesity
      and linked complications.

PMID- 10645656
TI  - [The Italian Fanconi Anemia Registry].
AB  - The Italian Registry of Fanconi's Anaemia (RIAF) was established in 1994 at the
      Cytogenetics Department of the Elena d'Aosta Hospital in Naples. Its aim is to
      collect data regarding Italian Fanconi's anaemia (FA) patients and their
      relatives. Since FA is a rare disease, the Registry is expected to benefit
      patients, improving the knowledge of this illness from the diagnostic, clinical,
      therapeutical and epidemiological viewpoint, and also supporting the laboratory
      and clinical research on FA aetiology, pathophysiology and therapy. Moreover, the
      Cytogenetics Department provides diagnosis through cytogenetic tests and collects
      blood samples of diagnosed patients, their parents and siblings for genetic tests
      and research. The RIAF is participating, through its coordinator and the
      physicians collaborating all over Italy, to some Italian and European research
      projects.

PMID- 10645657
TI  - [Rare diseases: general principles, specific problems, and health interventions].
AB  - Rare diseases are a large group of about 5000 diseases, 90% of which are
      genetically determined, which potentially involve all human organs and are
      characterized by a low prevalence in the population; this is frequently
      associated to problems in achieving a rapid and correct diagnosis and an adequate
      treatment. Up to now, a generally accepted definition or classification of rare
      diseases is not available. The Programme of Community Action 1999-2003 on rare
      diseases within the framework for action in the field of public health gives the
      following definition for rare diseases: diseases with a prevalence in the
      European Union (EU) population of less than 5 per 10,000. Notwithstanding the low
      prevalence of each disorder, rare diseases are very numerous and, when considered
      overall, they are a significant public health problem in many countries (e.g.
      Italy, Europe, USA); in fact rare diseases are often chronic and invalidating or
      cause early mortality. In this report, we illustrate some general concepts and
      specific problems regarding rare diseases as well as public health activities
      being undertaken in the USA, EU and Italy.

PMID- 10645658
TI  - [Genetic basis of endocrine-metabolic diseases].
AB  - Endocrine-metabolic diseases are very important because of either the variety of
      affected organs and the great social impact of at least some conditions, due to
      their high incidence and morbidity in the general population. A multifactorial
      origin has been recognized in many endocrine-metabolic diseases; in fact genetic
      and environmental risk factors contribute to the expression of pathologic
      phenotype. Recent progresses in molecular genetics allowed development of
      specific genetic tests which improved diagnosis of monogenic diseases and
      ascertainment of genetic susceptibility for some multifactorial pathologies.
      Therefore, management of the most important endocrine-metabolic diseases should
      take into account the interaction between improvement of the diagnosis and
      primary prevention actions through modification of environmental and lifestyle
      related risk factors.

PMID- 10645659
TI  - [IDDM-Sardinia Project: a study model on the etiopathogenesis of insulin
      dependent diabetes mellitus and other autoimmune pathologies. Gruppi di studio
      IDDM-Sardegna].
AB  - The "IDDM-Sardinia project" started in the beginning '90s and this main objective
      was, and still is, to clarify the epidemiological aspects of insulin-dependent
      diabetes mellitus in Sardinia, an island with a high incidence of the disease.
      Initially, the project included three main aims: 1) to continue monitoring the
      incidence of the disease and to design maps of geographical distribution of it in
      the island; 2) to study the pre-diabetes period, by assaying islet-related
      autoantibodies (ICA, GADA and IA-2icA), and to design models of prediction in a
      general population from a large cohort of 10,000 schoolchildren, and 3) to
      investigate the natural history of the disease by monitoring the appearance of
      islet-related autoantibodies in a cohort of 19,000 newborn. Most recently, new
      research lines branched from these main topics, and now the project is also
      investigating other autoimmune diseases, in particular coeliac disease and
      autoimmune thyroiditis. In this paper we still summarise and discuss the state-of
      the-art of the whole project.

PMID- 10645660
TI  - [Diabetes and pregnancy: physio-pathogenetic and epidemiologic aspects].
AB  - Diabetes mellitus is one of the most common maternal illnesses resulting in
      congenital malformations. All complications of pregnancy, either with diabetes
      pregestational or gestational, are directly or indirectly related to the degree
      of metabolic control. If it is not treated properly, diabetes in pregnancy causes
      major problems for both mother and fetus. The only way to reduce complications to
      the minimum and locate them near to those of the normal population, is to achieve
      a good metabolic control. Multi-disciplinary approach in which obstetricians,
      physicians, paediatricians are involved, combined with intensive monitoring and
      therapy throughout pregnancy, could achieve successful results in women with
      complicated diabetes. This objective is subordinate to early diagnosis for
      gestational diabetes and planning of pregnancy for diabetic women.

PMID- 10645661
TI  - [Congenital forms of hypothyroidism: study of risk factors and preventive
      interventions].
AB  - Maternal and child health represents one of the most relevant fields of interest
      in public health and particular attention is given to congenital pathologies. In
      Italy, the incidence of congenital hypothyroidism (CH) is 1:3200 live birth. CH
      is diagnosed at birth by neonatal thyroid screening. This allows a precocious
      onset of substitutive therapy which avoids severe psychomotor deficits in infants
      with CH. Moreover, the newborn screening program have permitted to identify
      transient disorders of thyroid function in newborns. These are essentially due to
      neonatal, maternal and environmental risk factors, especially iodine deficiency.
      The National Register (NR) of infants with CH was established in 1987. The aim of
      the NR is to provide disease surveillance and to monitor efficiency and
      effectiveness of neonatal screening. Furthermore, the NR represents an useful
      tool for developing epidemiological studies to identify possible environmental
      and/or familial risk factors of CH.

PMID- 10645662
TI  - [Functional status of intestinal t lymphocytes, regulatory mechanisms, and their
      variations in the course of Crohn disease and ulcerative colitis].
AB  - We analyzed the phenotype, proliferative responsiveness, cytokine production and
      apoptosis susceptibility of lamina propria lymphocytes to different activation
      pathways. Lamina propria lymphocytes is a population enriched of activated
      lymphocytes showing a "memory" phenotype. As opposite to peripheral blood
      lymphocytes, lamina propria lymphocytes show proliferative hyporesponsiveness
      when stimulated via TCR/CD3 pathway while proliferative response to the CD2
      activation pathway is relatively preserved. Under the latter activation pathway,
      cytokine production, especially IL-4 and IFN-gamma, is higher than that observed
      in peripheral lymphocytes. When compared to controls, lamina propria lymphocytes
      isolated from inflammatory bowel disease (Crohn's disease and ulcerative colitis)
      show distinctive variation in the cytokine production. In particular, Crohn's
      disease is characterized by an increased production of IFN-gamma, while in
      ulcerative colitis an increased production of IL-5 is observable. Among the
      different regulatory mechanisms contributing to maintain immunological
      homeostasis we analyzed the susceptibility to apoptosis of lamina propria
      lymphocytes. We found that CD2-activation pathway is regulated by Fas-mediated
      apoptosis, which regulates proliferation and cytokine production. In inflammatory
      bowel disease this apoptosis is defective thus contributing to the chronic
      inflammation and cytokine dysregulation.

PMID- 10645663
TI  - [Care in pregnancy, labor, and during the puerperium in Italy].
AB  - In 1995-96 a KAP (knowledge, attitude and practice) survey on care during
      pregnancy, delivery and in the post-natal period was carried out in Italy by the
      National Institute of Health (Istituto Superiore di Sanita). A sample of 9004
      women was interviewed in 13 regions within two months of the delivery. Care
      during pregnancy was generally at a good standard, but with an excessive use of
      some medical procedures. The level of knowledge was often low and some non
      invasive but effective methods for preventing negative outcomes were not widely
      adopted. Many women were ill informed about the procedures to which they were
      subjected and their degree of satisfaction was often low. In general, a wide
      geographic variability and a lack of continuity in pre- and post-natal care were
      observed.

PMID- 10645664
TI  - [Family health services and preventive strategies].
AB  - Health promotion is effective if it is based on the active offer of preventive
      measures to the target population. The active offer must be sustained by non
      standardised communication procedures, with the aim of producing empowerment of
      involved people. People, who are socially deprived and therefore at high risk,
      are hard to reach. They need special attention and resources. Prevention services
      and, in particular, those devoted to women, children and adolescents must be
      sufficiently diffused among the population. They must change from being dependent
      on demand to being based on active offer of preventive measures.

PMID- 10645665
TI  - [Researcher, physician, patient connection in information, communication, and
      relationship].
AB  - The change from the sociology of medicine to the sociology of health comes about
      in a post-modern social context characterized by a complex and ambiguous
      situation. This is particularly true in the case of maternity where communication
      between people of different knowledge is fundamental: the researcher, doctor and
      female patient tend to lean towards an auto-referential relationship based on an
      informative communication method (as emerged from a survey on how women patients
      received information in the cities of Bologna and Urbino). Adopting a relational
      type communication based on listening, the three subjects can create a common
      system which, thanks also to the support of modern technology, can help to easily
      overcome the difficulties encountered.

PMID- 10645666
TI  - [Evolution of voluntary interruption of pregnancy in Italy from its legalization
      until today].
AB  - Induced abortion was legalized in Italy in 1978. After an initial increase in the
      incidence, from 187,631 in 1979 to 234,801 in 1983, induced abortion has steadily
      decreased to 140,398 in 1996. Analysis of the abortion rates has shown that the
      main decrease has been among married women aged 25-35, while there has been an
      increase among unmarried women. Women with lower levels of education tend to have
      higher rates and housewives have higher rates than women in paid work. Programmes
      for the prevention of induced abortion should be directed at directed at easily
      accessible groups: women who have just delivered a baby, couples who marry,
      teenagers in school and women who have already had an induced abortion. In any
      case, the need for rationalisation of the procedure to obtain an induced abortion
      is urgent.

PMID- 10645668
TI  - [Control of congenital toxoplasmosis in Italy: The project of the Istituto
      Superiore di Sanita].
AB  - Toxoplasma gondii infection during pregnancy is a public health concern; many
      resources are used in diagnostic and therapeutic activities, sometime with a low
      benefit/cost due to lack of standardization in practices. In the lack of suitable
      epidemiological knowledge at national level regarding the congenital
      toxoplasmosis trend in Italy, an evaluation of the public health impact of this
      pathology is required. The Istituto Superiore di Sanita (ISS) has worked out a
      project on a prevalence-incidence study at national level, performing standard
      reference methods for diagnosis and both case definition and case management.
      Furthermore, the ISS urges all the involved centers on congenital toxoplasmosis
      to set up a network for an active collaboration to this project.

PMID- 10645667
TI  - [Prenatal and postnatal transplantation of hematopoietic stem cells in children
      with primary immunodeficiency].
AB  - Primary immunodeficiencies are inherited diseases characterized by impaired
      immune responses. In case of severe impairment of immunity bone marrow
      transplantation is the only therapeutic option. The molecular defect is known for
      several primary immunodeficiencies allowing prenatal diagnosis. This paper
      summarizes the clinical experience treating these pathologies by bone marrow
      transplantation.

PMID- 10645669
TI  - [Incidence of measles in Italy in the 1985-1994 period].
AB  - Measles notifications in Italy underestimate the actual incidence by a factor of
      ten, as it is ascertained by seroepidemiological investigation. In the decade
      1980-89, 45,000 measles cases were notified, on average, per year. Since 1988
      mass vaccination campaigns were implemented in several Italian regions. The
      strategy aimed to offer the prophylaxis actively to all children aged 13 months
      to 8-12 year for whom a sure recollection of measles was absent. The study has
      aimed to evaluate the impact of the strategy that worked in the period 1989-91,
      on the standardised average annual incidence of measles notification, comparing
      the periods 1985-89 and 1990-94. A reduction of 45% resulted all over Italy. On
      the contrary the incidence of chickenpox notifications has increased, indicating
      that the notification system did not worse.

PMID- 10645670
TI  - [Pilot study on compulsory vaccination coverage].
AB  - The disappearance of diphtheria and poliomyelitis is the best evidence of the
      efficacy of the vaccination strategies adopted in Italy. The active offer of the
      prophylaxis, reinforced by law, has characterised the operational aspects of the
      strategy. The active surveillance system is the main tool to take under control
      the effectiveness of health services responsible for vaccination. This system
      could be more easily implemented if the health services will be given a specific
      software aiming to handle and evaluate vaccination registers. The present pilot
      study, performed in the regions Marche and Sardegna, is an example of active
      surveillance and it is based on the ARVA software produced by the Istituto
      Superiore di Sanita. The results show a good level of coverage (> 95%) within the
      second year of life. Unsatisfactory results were obtained on the timing of
      vaccinations, as recommended by the vaccination schedule, mostly for the third
      doses.

PMID- 10645671
TI  - Should patients receive anticoagulation for paroxysmal atrial fibrillation?

PMID- 10645672
TI  - Heart failure: highlights from new consensus guidelines.
AB  - New guidelines for managing heart failure urge physicians to identify patients
      likely to benefit from therapy, obtain an echocardiogram to measure the ejection
      fraction, and, in patients with systolic dysfunction (i.e., an ejection fraction
      < or = 40%), institute therapy with an angiotensin-converting enzyme (ACE)
      inhibitor and a beta-blocker if at all possible. Digoxin and diuretics can
      relieve symptoms but do not affect the mortality rate. Spironolactone in low
      nondiuretic doses may reduce mortality when added to baseline drug regimens. The
      proper role of angiotensin II receptor blocking agents has yet to be determined.

PMID- 10645673
TI  - Gulf War syndrome: proposed causes.
AB  - Many veterans of the Persian Gulf War suffer from vague symptoms that have
      collectively become known as the Gulf War syndrome. Potential explanations
      include infectious disease, chemical exposure, and psychological stress. To date,
      no single etiology has been identified to explain Gulf War syndrome conclusively.
      It may be that multiple illnesses with overlapping symptoms and causes are
      responsible.

PMID- 10645674
TI  - Nonhealing cellulitis in a 54-year-old man with diabetes mellitus.

PMID- 10645675
TI  - The dilemma of nosocomial pneumonia: what primary care physicians should know.
AB  - Because nosocomial pneumonia is difficult to diagnose and the need to treat it is
      often urgent, particularly in patients on mechanical ventilation, therapy is
      often empiric. We review the pathogenesis, risk factors, microbiology, diagnosis,
      and treatment of this disease.

PMID- 10645677
TI  - Keeping your feet healthy.

PMID- 10645676
TI  - Recognizing, treating, and preventing common foot problems.
AB  - The incidence, prevalence, and severity of foot conditions increase with age.
      Teaching patients simple preventive techniques is crucial. Recognition,
      treatment, and prevention of common foot complaints--i.e., toenail problems,
      infections, corns and calluses, injuries, flat feet, bunions, arthritis of the
      toes, and toe and joint deformities--are reviewed.

PMID- 10645678
TI  - Unfractionated and low-molecular-weight heparins in acute coronary syndromes:
      current recommendations.
AB  - All patients with acute coronary syndromes and without obvious bleeding or acute
      cerebrovascular events are candidates for heparin therapy. This article is a
      review of the pharmacology of unfractionated and low-molecular-weight heparins,
      trials of heparin therapy in acute coronary syndromes, and recommendations for
      using these agents.

PMID- 10645679
TI  - COX-2 selective NSAIDs.

PMID- 10645680
TI  - Hypertension in the elderly.

PMID- 10645681
TI  - Improving access to NHS dentistry? Professionals complementary to dentistry: a
      consultation paper by the General Dental Council.

PMID- 10645682
TI  - A systematic review of the effectiveness of health promotion aimed at improving
      oral health.
AB  - OBJECTIVE: To examine the quality of oral health promotion research evidence and
      to assess the effectiveness of health promotion, aimed at improving oral health
      using a systematic and scientifically defensible methodology. BASIC RESEARCH
      DESIGN: Systematic review of oral health promotion research evidence using
      electronic searching, iterative hand-searching, critical appraisal and data
      synthesis. CLINICAL SETTING: The settings of the primary research reviewed were
      clinical, community, schools or other institutions. The participants were
      children, the elderly, adults and people with handicaps and disabilities.
      INTERVENTIONS: Only studies which reported an evaluative component were included.
      Theoretical and purely descriptive papers were excluded. MAIN OUTCOME MEASURES:
      The review examined the evidence of effectiveness of oral health promotion on
      caries, oral hygiene, oral health related knowledge, attitudes and behaviours.
      RESULTS: Very few definitive conclusions about the effectiveness of oral health
      promotion can be drawn from the currently available evidence. Caries and
      periodontal disease can be controlled by regular toothbrushing with a fluoride
      toothpaste but a cost-effective method for reliably promoting such behaviour has
      not yet been established. Knowledge levels can almost always be improved by oral
      health promotion initiatives but whether these shifts in knowledge and attitudes
      can be causally related to changes in behaviour or clinical indices of disease
      has also not been established. CONCLUSIONS: Oral health promotion which brings
      about the use of fluoride is effective for reducing caries. Chairside oral health
      promotion has been shown to be effective more consistently than other methods of
      health promotion. Mass media programmes have not been shown to be effective. The
      quality of oral health promotion evaluation research needs to be improved.

PMID- 10645683
TI  - Oral health systems in Europe. Part I: Finance and entitlement to care.
AB  - OBJECTIVE: To describe and compare the oral health systems in 18 European
      countries. BASIC RESEARCH DESIGN: Semi-structured, in-depth validation interviews
      were carried out with key informants from the main national dental associations
      of EU and associated countries. The interviews were structured around the
      responses to a previously completed questionnaire, the topics and terminology of
      which had been agreed in advance with the collaborating associations. The
      resulting descriptions of dental practice and the dental workforce in each
      country were returned for further validation and correction by the collaborating
      associations. Ultimate editorial control over the review of each country's oral
      health system rested with the authors. RESULTS AND CONCLUSIONS: Oral health care
      is mainly financed by government-regulated or compulsory social insurance in
      seven of the 18 countries examined here: Austria, Belgium, France, Germany,
      Luxembourg, The Netherlands and Switzerland. Providing universal or near
      universal coverage by membership of insurance institutions, these systems provide
      oral health care for about 180 million people across Europe, and almost half of
      all EU citizens. In the Nordic countries and the UK entitlement to care is
      typically based upon residence or citizenship, and apart from in Norway and
      Iceland is provided within a tax-funded and government-organised health service.
      In southern Europe, Norway, Ireland and Iceland oral health care is largely
      financed directly by the patient, with occasional support through private
      insurance. Some publicly-funded and organised services do exist in these
      countries but generally only for specific population groups (e.g. children,
      unemployed), or in particular regions.

PMID- 10645684
TI  - Household income in relation to dental health and dental health behaviours: the
      use of Super Profiles.
AB  - OBJECTIVE: To investigate the relationship between household income defined by
      Super Profiles, a socio-economic indicator, and dental health and dental health
      behaviours. BASIC RESEARCH DESIGN: Analytical survey involving a clinical
      examination and a questionnaire to parents. SETTING: Primary schools in Salford,
      UK. PARTICIPANTS: Two thousand five hundred and seventy eight 5-year-old children
      were examined; 1938 (75%) returned questionnaires. MAIN OUTCOME MEASURES: Mean
      caries experience and ages at first visit to dentist and when toothbrushing
      commenced. RESULTS: Children in the highest income group had a mean dmft of 1.83
      compared with 2.56 in the middle group and 3.43 in the lowest income group. The
      proportions who had visited a dentist by their second birthday were 71%, 64% and
      62% respectively. The corresponding proportions having their teeth brushed by
      their first birthday were 69%, 58% and 57%. CONCLUSIONS: The study showed a
      relationship between Super Profiles, and the dental health and dental health
      behaviours of 5-year-old children.

PMID- 10645686
TI  - Paediatric dental general anaesthesia rates and dental caries regionally and in
      districts in the former north western region.
AB  - OBJECTIVE: To chart paediatric dental general anaesthesia activity following
      implementation of the Poswillo Report recommendations and to characterise the
      relationship between dmft/DMFT and rates of paediatric dental general
      anaesthesia. DESIGN: An ecological study, using results of the NHS dental
      epidemiological surveys and routine NHS activity data. SETTING: The general,
      community and hospital dental services. SUBJECTS: Former regional and district
      health authorities' residents. OUTCOME MEASURES: Correlations between the
      regional and district rates of dental general anaesthesia and dmft/DMFT from the
      NHS dental epidemiology surveys. RESULTS: About half of all paediatric dental
      general anaesthetics are carried out in the General Dental Service. There were
      significant correlations between regional mean dmft/DMFT and under 18 combined
      dental general anaesthesia rates in 1991/2 and 1992/3. In the North West Region
      there were significant correlations between 0-4-year-old district dental general
      anaesthesia rates and dmft of 5-year-old children in 1989/90 (r = 0.45, P < 0.05)
      and 0-17-year-old district dental general anaesthesia rates and 12-year-old DMFT
      (r = 0.49, P < 0.05) in 1992/3. CONCLUSIONS: The number of paediatric dental
      general anaesthetics provided since the Poswillo Report was implemented (1991)
      has increased in the last two years (1993/4 and 1994/5). District rates of dental
      general anaesthesia bore little relation to dental need as measured by dmft/DMFT,
      except in 1989/90 for 5-year-old children and in 1992/3 for 12-year-old children.
      This suggests dental general anaesthesia is not provided in response to dental
      needs at a district health authority level.

PMID- 10645685
TI  - Explanatory models for oral health expressed as number of remaining teeth in an
      adult population.
AB  - OBJECTIVE: To develop explanatory models for oral health expressed as the number
      of remaining teeth. METHOD: Socio-economic attributes, health factors, dental
      attitudes and behaviours were used as explanatory variables in a logistic
      regression. Cross-sectional validated questionnaire data from all 50-year-old
      residents in two Swedish counties were collected from 8,888 persons, a response
      rate of 71.4% (n = 6,343). Adjusted number of teeth and three dichotomies of
      edentulousness and remaining teeth in various combinations were used as the
      dependent variables. RESULTS: Social class was unrelated to edentulousness, while
      individual and health factors were covariants. Individuals with < or = 8 teeth
      had a social class and education gradient, while those with > or = 25 teeth had
      class and education gradients as well as a relation to dental care utilisation.
      There were only three variables showing a consistent and stable relation to the
      various dependent variables, these were use of tobacco, having only junior high
      school education and satisfaction with dental care. The multiple and logistic
      regression models revealed different results. CONCLUSIONS: The main conclusions
      from this study were, first, that there were different mechanisms for different
      states of the dentition, interpreted as signs of disease and signs of health,
      corresponding to the ideas of patho- and salutogenesis, and secondly, that number
      of teeth present is not usable as a continuous variable, since it does not
      reflect the same mechanisms across the whole scale.

PMID- 10645687
TI  - Development of a classification and index of dental treatment experience for
      adults.
AB  - OBJECTIVE: To develop and evaluate a classification and index of dental treatment
      experience for adults. DESIGN: Twenty-four general dental practitioners recorded
      treatment experience at baseline on 4,211 regularly attending adults of whom
      3,878 were re-examined after one year and 3,698 patients completed a
      questionnaire on factors related to treatment. SETTING: Health authorities of
      Manchester and Salford. METHOD: Set theory was used to divide the baseline
      clinical data set into 7 mutually exclusive classes of dental treatment
      experience. Seven dental specialists used the nominal group technique to weight
      tooth status to form an index of dental treatment experience (DTE). The ability
      of the DTE classification and index to discriminate between groups of patients'
      responses to the questionnaire was compared with the THI and DMFT index. RESULTS:
      Ninety-nine per cent of the patients fell into 5 hierarchical classes ranging
      from fillings only to wearing a denture in addition to a crown and/or bridge.
      When calculated on the baseline data, the classification discriminated between 16
      of the 20 variables investigated in the questionnaire. Fifteen significant
      differences were found between mean scores for groups of patients on the DTE
      index, 14 on the THI and 8 on the DMFT index. Fifty-five (1%) patients moved
      their class as a consequence of the treatment carried out during the year. All
      three indices found significant differences for the same four variables of the 20
      tested. CONCLUSION: A classification of dental treatment experience together with
      an index to measure the severity of that experience has been successfully
      developed and tested. It appears to have advantages over the traditional DMFT
      index and is at least as discriminating as the THI.

PMID- 10645688
TI  - Adolescents' knowledge of common foods and drinks and the importance of the
      pattern of consumption: a study undertaken in an area of high dental needs.
AB  - OBJECTIVE: To assess the knowledge of adolescents concerning the cariogenic
      status of a range of foods and drinks. To determine the associations between this
      knowledge and their awareness of the importance of the ways sugars may be
      consumed in order to reduce tooth decay. DESIGN: Self-complete questionnaires
      assessing the above factors in a cross sectional study. PARTICIPANTS: Four
      hundred and fifteen 14-15-year-old young people attending second level schools.
      SETTING: North and West Belfast area, Northern Ireland. OUTCOME MEASURES:
      Students rated the dental safety of common foods and drinks, and their views on
      the necessity of reducing all sugars, and avoiding them between meals were
      recorded. RESULTS: Correct assessment of harmful items ranged from 96.9% for
      chocolate and 92.8% for cola to 39.0% for orange squash and 17.8% for plain
      biscuits. For non-harmful products there were high levels for most items and
      somewhat lower levels for crisps (57.6%). Significant links were established
      between this knowledge and children's awareness of the role of eating patterns,
      although the items involved varied. A majority recognised the importance of
      eating patterns in relation to dental caries. CONCLUSION: Health educators should
      be aware that many adolescents have poor knowledge of the cariogenic status of
      some of the foods and drinks they consume and some are unsure of the importance
      of eating patterns.

PMID- 10645689
TI  - The Community Dental Health homepage.

PMID- 10645690
TI  - Presidential address to the British Association for the Study of Community
      Dentistry, Manchester, May 1998.

PMID- 10645691
TI  - Hypertension in the next millennium.

PMID- 10645692
TI  - Serum and erythrocyte magnesium levels in hypertensives and their first degree
      relatives.
AB  - Essential hypertension is an arbitrarily defined disorder to which both genetic
      and environmental factors contribute. Magnesium and its interactions with other
      cations may play an important role in the pathogenesis of essential hypertension.
      Various studies have been carried out on the levels of serum and erythrocyte
      magnesium in hypertensives and the results are controversial and there is no
      systematic study in Indian population. In the present study serum and erythrocyte
      magnesium levels in 86 hypertensives and their 77 first degree relatives as well
      as in sex and age matched controls were studied. Serum and erythrocyte magnesium
      levels showed a significant decrease both in the hypertensives and their first
      degree relatives (p < 0.01). The significantly decreased levels of magnesium in
      the first degree relatives suggest genetic basis of essential hypertension and
      may be used as marker to identify those at risk.

PMID- 10645693
TI  - Behavioural parameters in hypertensives on atenolol therapy.
AB  - Behavioural responses which included psychological tests and cold pressor test as
      a stress test were studied in 20 mild to moderate hypertensives of both sexes,
      excluding smokers, alcoholics, secondary hypertensives and patients of chronic
      obstructive pulmonary diseases. Subjects were put on 2 weeks of placebo washout
      period followed by 6 weeks of treatment with atenolol. Following treatment with
      atenolol they showed no significant alteration in the scores of psychological
      tests which included Weschler adult intelligence scale for orientation, while
      showing significant depression in the rise of heart rate, systolic blood pressure
      and diastolic blood pressure following cold pressor test. On further analysis,
      the results showed that hypertensives on placebo had lower scores of memory and
      attention test as compared to normotensive controls. Besides this, hypertensives
      on placebo had higher rise of heart rate and systolic blood pressure as compared
      to normotensive controls after cold pressor test.

PMID- 10645694
TI  - Health awareness and treatment compliance of high blood pressure among women in a
      peri-urban colony of Chandigarh, India.
AB  - Health awareness is a central issue in the control of hypertension. In a cross
      sectional survey among 1727 women of > 30 years, 2 blood pressure recordings were
      done in 1686 cases. The prevalence of hypertension was found to be 13.1% (221 out
      of 1686 cases). A random sub sample of 72 hypertensive women above 30 years of
      age from a peri-urban colony of Chandigarh was selected to find out health
      awareness and treatment compliance of hypertension. Sixty-three (87.5%) of the
      selected women were aware of their high blood pressure. However, only 12 women
      (16.7%) who were on treatment had achieved control of blood pressure (< 140/90 mm
      Hg). Main reasons for discontinuing the treatment were ignorance about the need
      of regular treatment (33.3%), high cost of medicines (19.44%) and non
      availability of a family member who can go with the patient to hospital (9.72%).
      Twenty-six (36.1%) hypertensive women did not know the importance of weight
      reduction for controlling high blood pressure. Twenty-three (31.9%) hypertensive
      women were currently smoking. A comprehensive health education approach involving
      health care professionals, patients and general population should be launched to
      improve the care of hypertensives in the community.

PMID- 10645695
TI  - Non-pharmacological management of essential hypertension.
AB  - Lifestyle modifications are universally accepted, not only as the first step in
      the management of hypertension but also a way to prevent hypertension. The
      INTERSALT study of 52 communities worldwide showed that weight, among all
      measured characteristics except age, had the strongest, significant, most
      consistent and independent correlation with blood pressure. INTERSALT
      epidemiological data had demonstrated a positive association between sodium
      intake and level of blood pressure. A rigorous analysis of 23 randomly controlled
      trials showed that 100 mmol/day reduction in sodium intake was associated with a
      decline of 5-7 mm Hg (systolic)/2.7 mm Hg (diastolic) in hypertensive subjects.
      Excessive alcohol consumption is another important risk factor for hypertension
      and has been reported to account for 5-30% of all hypertension. Moderately
      intense exercise at 40 to 60% of maximum oxygen consumption e.g., 30 to 45
      minutes of brisk walking on 4-5 days a week, can lower blood pressure. The
      incidence of stroke and coronary artery disease in hypertensive patients who
      smoke is 2-3 times greater than in non-smoking patients with comparable blood
      pressure and stopping smoking rapidly reduces this risk. There have been several
      studies showing the stress reduction with various behavioural procedures, such as
      yoga, relaxation biofeedback, transcedental mediation and psychotherapy benefit
      hypertensive patients by lowering their blood pressure.

PMID- 10645696
TI  - Hypertension and cerebrovascular disease.
AB  - Cerebrovascular disease (CVD) is the third leading cause of death in United
      States and hypertension is a leading cause of both stroke and heart disease. It
      may cause headache, acute hypertensive encephalopathy, dementia and various types
      of strokes e.g., thrombotic, haemorrhagic, lacunar infarcts and transient
      ischaemic attacks. It remains the singlemost important treatable risk factor for
      stroke in all age groups and modern antihypertensive therapy has its documented
      prevention of stroke. Hypertension in acute phase of ischaemic stroke should not
      be treated. Hypertension in acute stroke should be treated. In advanced centres
      with specialised stroke units, the favoured drugs are short acting vasodilators
      e.g., sodium nitroprusside and labetalol. Nifedipine is the most popular drug
      followed by captopril, both sublingually and orally.

PMID- 10645697
TI  - Surgical treatment of endocrine hypertension experience in India.
AB  - Between 1980 and 1994, 162 cases of endocrine based hypertension were diagnosed
      and treated surgically. Seventy-nine cases (48.7%) of phaeochromocytoma, 63 cases
      (38.8%) of Cushing's syndrome, and 20 cases (12.3%) of Conn's syndrome were
      diagnosed. In phaeochromocytoma 75% of the tumours arose from the adrenal glands
      and 25% arose from the extra-adrenal sites. Cushing's syndrome was caused by
      adenoma (45%), diffuse bilateral adrenal hyperplasia (36%), pigmented
      macronodular hyperplasia (9%), and adrenal carcinoma (10%). The most common cause
      of Conn's syndrome was adenoma (95%) which arose mainly from the left adrenal
      gland (60%). In the present series the success rate of surgical treatment was
      100% for phaeochromocytoma, 90% for Cushing's syndrome and 96% for Conn's
      syndrome. Trucut biopsy of the kidneys of these patients showed hypertensive
      changes, the moderate hypertension could be due to renal damage.

PMID- 10645698
TI  - Patterns of cardiac disorders and epidemiology of coronary artery disease in
      urban population of Ahmedabad.
AB  - A hospital based study of coronary artery disease (CAD) was carried out in
      Gujaratis, admitted to Dr Jivraj Mehta Smarak Health Foundation, Ahmedabad. Total
      276 subjects were surveyed. CAD was diagnosed by ECG criteria. Prevalence of CAD
      in hospital admission was 29.6%. Highest incidence of CAD was seen in the age
      group of 51 to 60 years. Male/female ratio was 1.6:1. As a single risk factor
      hypertension was ranked first, next was obesity followed by hyperlipidaemia,
      diabetes, tobacco habits, and family history of CAD. Overall mortality of CAD was
      3.99%, being 1.83% for angina pectoris (AP) and 5.39% for myocardial infarction
      (MI). Mortality rate was higher in subjects having 2 or more risk factors.
      Incidence of CAD in young (age < 40 years) was very low (1.09%).

PMID- 10645699
TI  - Role of ACE inhibitors on pneumonia.

PMID- 10645700
TI  - Double blind, randomised, parallel, prospective, comparative, clinical evaluation
      of a combination of antispasmodic analgesic Diclofenac + Pitofenone +
      Fenpiverinium (Manyana vs Analgin + Pitofenone + Fenpiverinium (Baralgan) in
      biliary, ureteric and intestinal colic.
AB  - In this double blind, prospective study, the relative efficacy of Diclofenac +
      Pitofenone + Fenpiverinium (Manyana) and Analgin + Pitofenone + Fenpiverinium
      (Baralgan) in 200 patients of biliary, ureteric and intestinal colic was
      evaluated. Patients were given these coded drugs thrice daily for five days
      starting from day 0 to day 5. The results of the present clinical evaluation
      demonstrated that Manyana appeared to be superior to Baralgan in biliary and
      ureteric colic while it was therapeutically equivalent to Baralgan in reducing
      the pain intensity in intestinal colic. Both the medications were tolerated well
      and there were no side-effects reported.

PMID- 10645701
TI  - The impact of HIV-related neuropsychological dysfunction on driving behavior. The
      HNRC Group.
AB  - HIV infection often results in neuropsychological (NP) impairment. In order to
      assess the impact that HIV-related NP deficits may have on automobile driving, we
      evaluated 68 HIV-seropositive drivers using an NP battery and two PC-based
      driving simulations. Thirty-two participants were classified as NP impaired; most
      (72%) evidenced only mild impairment, and none met criteria for HIV-associated
      dementia. After controlling for degree of immunosuppression and disease stage, NP
      impaired participants failed a previously validated driving simulation at a much
      higher rate than cognitively intact participants [OR = 5.3, 95% CI (1.7, 17.0), p
      = .006]. Similarly, on a simulation of city driving, NP impaired participants
      were more likely to fail based upon the number of accidents [OR = 6.1, 95% CI
      (1.5, 24.6), p = .01]. Simulator performance was predicted by functioning in a
      number of NP domains, with NP tests accounting for 13-30% of the variance on the
      simulations. Although it would be premature to extrapolate these findings to
      impairment in on-the-road driving, they do argue for greater attention to the
      impact that even mild HIV-related NP deficits may have on driving skills.

PMID- 10645702
TI  - Polysubstance abuse and traumatic brain injury: quantitative magnetic resonance
      imaging and neuropsychological outcome in older adolescents and young adults.
AB  - Few studies have examined the consequences of alcohol and drug abuse on TBI
      though they commonly co-occur. Both TBI and substance abuse independently result
      in neuropathological changes in the brain such as ventricular enlargement and
      cortical atrophy, thus it is reasonable to hypothesize that the combination of
      the two would result in more significant cerebral damage. In this study, 3 groups
      of patients--traumatically brain injured (TBI) with substance abuse (N = 19), TBI
      without substance abuse (N = 19), and substance abuse with no TBI (N = 16)--were
      compared with normal controls (N = 20) on several quantitative MRI (QMRI)
      measures. Since TBI most frequently occurs in older adolescents and young men, we
      examined only male participants between 16 and 30 years of age. Comparing young
      substance abusers to controls resulted in no QMRI differences. When controlling
      for head injury severity, the effects of substance abuse in combination with TBI
      resulted in greater atrophic changes than seen in any other group. TBI and
      substance abuse patients' neuropsychological test performances also were
      examined, and no differences were found among patient groups on any measures.
      These findings have implications for the deleterious interaction of substance
      abuse combining with TBI to result in greater neuropathological changes that can
      be detected by QMRI techniques.

PMID- 10645703
TI  - Odor detection, learning, and memory in Huntington's disease.
AB  - We compared 7 mildly affected Huntington's disease (HD) patients to 7 age- and
      education-matched healthy controls (NC) on an odor detection test, the California
      Odor Learning Test, and the California Verbal Learning Test. Results demonstrated
      that odor detection sensitivity, but not group membership, accounted for
      significant variance in total olfactory learning. Both groups learned fewer items
      in the olfactory modality compared to the verbal modality, but retained a similar
      amount following a delay. No group differences were demonstrated for verbal
      recognition discriminability, but the HD group demonstrated significantly
      impaired odor recognition discriminability. Finally, odor detection provided
      excellent classification sensitivity and specificity between the patients and
      controls, suggesting that olfactory testing may provide a sensitive measure of
      the early disease process in HD.

PMID- 10645704
TI  - Neuropsychological patterns in right versus left frontotemporal dementia.
AB  - Patients with frontotemporal dementia (FTD) often present with an asymmetric left
      or right-sided anterior cerebral perfusion abnormality that is associated with
      differential behavioral symptoms. However, whether patients with primarily right
      versus left FTD also have unique neuropsychological characteristics has not been
      previously investigated. Comparisons of 11 patients with right-sided FTD and 11
      with left FTD indicated that the 2 patient groups showed relatively distinct
      cognitive profiles. Patients with right FTD exhibited relatively worse
      performance on PIQ than VIQ, and on select nonverbal executive tasks relative to
      their verbal analogs (e.g., design fluency < word generation; Picture Arrangement
      < word sequencing). In contrast, patients with left FTD showed the opposite
      pattern. In addition, the 2 patient groups differed on several absolute test
      scores; patients with right FTD demonstrated more errors and perseverative
      responses, and worse percent conceptual level responses, on the Wisconsin Card
      Sorting Test, while the left FTD patients obtained significantly worse scores on
      the Boston Naming Test, and Stroop word reading and color naming. Verbal and
      nonverbal memory, mental speed, visual perceptual-constructional skill, and IQ
      subtest scaled scores did not significantly differ between groups. These data
      indicate that FTD should not be viewed as a unitary disorder, and that
      neuropsychological testing holds promise for the differential diagnosis of right
      versus left FTD.

PMID- 10645705
TI  - Cross-modal semantic and homograph priming in healthy young, healthy old, and in
      Alzheimer's disease individuals.
AB  - Two experiments are reported that explore the influence of strength of the prime
      target relationship on the observed priming effects in young, healthy old, and
      individuals diagnosed with dementia of the Alzheimer type (DAT). In Experiment 1,
      participants were auditorily presented primes (FURNITURE) and after varying
      delays presented visual targets that were (1) high-strength related (e.g., SOFA),
      (2) low-strength related (e.g., RUG), or (3) unrelated control words (e.g., COW
      or DEER). The results indicated that the DAT individuals produced relatively
      larger priming effects that both the young and the healthy old, but these data
      could be accommodated by increases in effect size due to general slowing of
      response latencies. In Experiment 2, the same cross-modal priming paradigm was
      used with ambiguous words presented as primes (e.g., BANK) and either high
      dominant (e.g., MONEY) or low-dominant (e.g., RIVER) words as targets. The
      results of Experiment 2 produced a qualitatively distinct pattern of priming that
      indicated DAT individuals only produced priming for high-dominant targets and not
      for low-dominant targets, whereas, the healthy control groups produced equivalent
      priming for both high- and low-dominant targets. The discussion focuses on the
      implication that these results have for the interpretation of semantic priming
      effects, in general, along with implications for the apparent semantic memory
      loss in DAT individuals.

PMID- 10645706
TI  - Alterations in the dynamics of semantic activation in Alzheimer's disease:
      evidence for the Gain/Decay hypothesis of a disorder of semantic memory.
AB  - While it has been commonly assumed that a deficit in semantic memory underlies
      many of the clinical and cognitive features of early Alzheimer's disease (AD),
      there has been little agreement on what constitutes a proper theoretical
      description of this impaired system. Currently, most theories of this disorder
      fall into two categories: those that posit degraded semantic representations, and
      those that posit impaired retrieval operations with relatively intact semantic
      representations. It is argued that each position has both empirical and logical
      disadvantages that have prevented the development of a consensus on how to
      describe the pathology of semantic memory in AD. In this paper we present the
      details and supportive evidence for an alternative account of the semantic memory
      deficit of AD: the Gain/Decay hypothesis. The core claim of the Gain/Decay
      hypothesis is that a reduction in the time constant of spreading activation in AD
      produces dynamic changes in the availability of semantic representations that
      depend on the time frame in which this information must be accessed. The
      implications of this hypothesis for a range of experimental and clinical
      phenomena are discussed, as are possible biological correlates of the
      hypothesized alterations in the modulation of activation.

PMID- 10645707
TI  - Effects of structural similarity and name frequency on picture naming in
      Alzheimer's disease.
AB  - Impairments to either perceptual or word-retrieval processes have been
      hypothesized to explain confrontation naming impairments in patients with
      Alzheimer's disease (AD). This study measured the effects of structural
      similarity, which affects perceptual processing, and name frequency, which
      affects word retrieval, on naming latency and accuracy in 16 AD patients and 16
      age-matched controls. AD patients named pictures more slowly and made more errors
      than control participants. Their naming accuracy was disproportionately affected
      by name frequency, but not by structural similarity. The findings indicate that
      the processing of structural properties of objects is unaffected in early-stage
      AD, and suggest that word-retrieval impairments underlie the naming deficit in
      AD.

PMID- 10645708
TI  - Performance of Alzheimer's disease patients in judging word relatedness.
AB  - Sixty individuals with probable Alzheimer's disease (AD) and 48 normal elders
      were given a task in which they had to judge the relatedness of concepts as a
      means of evaluating semantic memory. Very mild AD patients performed similarly to
      normal elders. Mild AD patients were significantly inferior in performance to
      normals but the pattern of their performance did not suggest a loss of conceptual
      knowledge. Moderate AD patients were significantly inferior in performance to
      mild AD patients, and 8 moderate AD patients (compared to 1 mild AD patient) were
      unable to do the task. The pattern of performance of moderate patients suggests
      that conceptual knowledge may degrade and ultimately be lost.

PMID- 10645709
TI  - Well-organized conceptual domains in Alzheimer's disease.
AB  - We used a novel apparatus called the flags board to elicit similarity judgments
      from 32 Alzheimer's disease (AD) patients and 32 elderly normal (EN) controls for
      two 12-member conceptual domains, ANIMALS and (musical) INSTRUMENTS. Based on
      Pathfinder and multidimensional scaling (MDS) analyses, performance by AD
      patients was nearly identical to that of EN controls for ANIMALS. Performance
      differed for INSTRUMENTS, but the AD group's Pathfinder network was found to
      agree with the intuitions of a panel of 18 raters as well as the EN group's. MDS
      analysis showed no deficit on abstract dimensions for the AD group, for either
      domain. The results are discussed in the context of degradation versus
      preservation of semantic memory in AD.

PMID- 10645710
TI  - Instantiation of semantic categories in sentence comprehension by Alzheimer
      patients.
AB  - This study examined whether Alzheimer patients can make elaborative inferences
      based on the semantic context provided by a sentence. More specifically, if
      presented with the name of a category in a sentence do they, like normals, infer
      (instantiate) the particular member of that category most appropriate to the
      meaning of the sentence (e.g., if a sentence mentions a container of juice, do
      they infer it is a bottle). Patients were presented with a sentence containing
      the name of a concrete category. The sense of the sentence was consistent with a
      low-dominant member of that category. Patients were then shown drawings of four
      members of that category and asked to select the one appropriate to the sentence.
      They were later asked to name the drawings. If semantic information is degraded
      in Alzheimer patients for those objects Alzheimer patients cannot name (as has
      been claimed), then AD patients should be unable to carry out the type of
      elaborative semantic inference required to instantiate. Results showed that
      Alzheimer patients were highly accurate at instantiating even objects they could
      not name. This is consistent with a relative preservation of semantic knowledge
      about concrete objects in Alzheimer patients.

PMID- 10645711
TI  - Differential decline in word generation from phonemic and semantic categories
      during the course of Alzheimer's disease: implications for the integrity of
      semantic memory.
AB  - The ability to generate words from phonemic (i.e., words beginning with 'F,' 'A,'
      and 'S') and semantic (i.e., animals, fruits, and vegetables) categories was
      assessed longitudinally in patients with Alzheimer's disease (AD; N = 59) and
      normal controls (NC; N = 59). Patients with AD performed worse than NC
      participants on both tasks at each of 4 annual evaluations and exhibited greater
      impairment relative to controls on the semantic-category task than on the
      phonemic-category task. In addition, the performance of the patients with AD
      declined over time on both tasks, but the rate of decline was faster on the
      semantic-category than on the phonemic-category task. Examination of individual
      responses across the annual evaluations revealed that patients with AD were more
      consistent than NC participants in failing to generate previously produced
      semantic-category, but not phonemic-category, items in all years following the
      1st year in which the item was not produced. These results are consistent with
      the notion that patients with AD suffer a gradual deterioration of the
      organization and content of semantic memory as the disease progresses.

PMID- 10645712
TI  - [Current view on the etiology of childhood bronchial asthma].
AB  - In the last decades atopic diseases and among them the incidence of atopic asthma
      has increased significantly worldwide, first of all in countries of higher
      technical civilization. In many places the incidence has doubled in 10-20 years
      compared to the previous period. The investigations have provided a lot of new
      data about genetic alterations in the background of the disease but the
      modifications in the genetic material cannot be responsible for the increased
      frequency of the disease in such a short time. It has become clear that
      sensibilization in connection with allergens begins in the fetus and continues in
      the early period after birth. Environmental allergens, especially indoor ones,
      the allergen burden in extrauterine life, the nutrition factors and later airway
      inflammations caused by virus--all contribute to the spread of atopy. The harms
      of civilization contribute to the dominance of T helper 2 cells and therefore to
      atopy in our immunosystem. It seem, that otherwise useful components like the
      decrease of infective diseases, vaccinations, better hygienic conditions and
      "western" lifestyle also manipulate our immunosystem in the direction of atopy.
      Our existing knowledge can provide profilactic tasks against unfavourable
      processes only to a very small extent.

PMID- 10645713
TI  - [A brief review of recent achievements concerning biochemistry and physiology of
      prostaglandins in the eye].
AB  - Two prostaglandin molecules have important physiological and pathophysiological
      role in the tissues of the eye. Prostaglandin F2 alpha takes part in mediating
      intraocular pressure, prostaglandin E2 is the mediator of inflammation. In case
      of increased intraocular pressure, latanoprost a derivative of prostaglandin F2
      alpha can be applied. Numerous data are available on the favourable intraocular
      pressure lowering effect of latanoprost. It can be applied as a single
      hypotensive or it can be combined with eye-drops currently used in glaucoma. It
      exerts its therapeutic effect by increasing uveoscleral outflow. Inflammation in
      the eye can be diminished by nonsteroidal anti-inflammatory drugs similarly to
      inflammations in other tissues of the organism. Literature on nonsteroidal anti
      inflammatory drugs is enormous. Molecules of different structures inhibit the
      synthesis of prostaglandins. Primarily they are useful anti-inflammatory agents,
      reduce intraocular pressure in secundary glaucoma, inhibit intraocular miosis and
      prevent development of cystoid macula oedema. Nonsteroidal anti-inflammatory
      drugs do not exert their effects on prostaglandins themselves, but inhibit their
      synthesis. Hence the use of both, latanoprost and nonsteroidal anti-inflammatory
      drugs simultaneously, improves safety of therapy in case of patients prone to
      uveitis.

PMID- 10645714
TI  - [Dual fluorescence in situ hybridization analysis of synovial sarcoma].
AB  - Synovial sarcoma have (about in 95% of the cases) the specific and characteristic
      reciprocal chromosomal translocation t(X; 18) (p11.2; q 11.2). Application of
      dual-colour fluorescence in situ hybridization (FISH) on interphase nuclei to
      identify the specific translocation has a diagnostic importance for daily
      pathological practice. For visualisation of the translocated chromosomal
      fragments of synovial sarcoma cells on imprint smears, chromosome X painting
      probes and chromosome 18 centromeric probes were used. Our present study
      indicates that the precise preoperative diagnosis of synovial sarcoma using dual
      colour FISH is possible on smears and this possibility (to identify specific
      chromosomal translocations in soft tissue tumours) is a landmark in the
      preoperative diagnosis of soft tissue sarcomas.

PMID- 10645716
TI  - [The role of the 1909 International Medical Congress in Budapest in indicating
      adequate surgery for appendicitis].

PMID- 10645715
TI  - [Detection of antibodies against pancreatic islet cells in clinical practice].
AB  - Development of diabetes mellitus caused by pancreatic beta-cell destruction of
      autoimmune origin is the result of a long lasting process. The most easily
      examinable feature of this stage is the occurrence of the islet cell antibodies.
      The sera which are positive for islet cell cytoplasmic antibodies (ICA), examined
      by indirect immunofluorescence, contain a mixture of antibodies. The glutamic
      acid decarbocylase (GAD), the tyrosin phosphatase (IA2), the insulin, and the GM2
      1 glycolipid can be the targets of these antibodies. One can routinely examine
      the ICA, the GADA, the IA2 antibodies. The detection of antibodies against
      insulin (IAA) and GM-2-1 glycolipid is not invented in the routine laboratory
      work. The aim of the authors was the evaluation of clinical significance of
      occurrence of islet cell antibodies: one hundred and eighteen nondiabetic
      children an adult human being without known diabetic first degree relatives and
      366 type 1 diabetic children and adult patients served as controls. The authors
      evaluated the predictive value of the different islet cell antibodies to the
      development of type 1 diabetes mellitus in 596 nondiabetic children with type 1
      diabetic first degree relatives. The authors looked for markers of beta-cell
      destruction among sera of 320 diabetics manifested after 30 years of age with at
      least half a year of non-insulin-dependency and in the sera of 68 females
      suffered from gestational diabetes after 0-14 years of the index pregnancy.
      Finally the authors report 7 cases in which the examination of islet cell
      antibodies helped the diagnosis and classification of diabetes mellitus. Indirect
      immunofluorescence method was used for the detection of ICA, radioimmunoassay for
      that of GADA and IA2 antibodies. There was no positive reaction for ICA and GADA
      in the nondiabetic population without diabetic first degree relatives. Among the
      freshly diagnosed type 1 diabetic children 39% were positive for only ICA, 44%
      for only GADA and 80% for any antibodies. Among the freshly manifested type 1
      diabetic adults ICA positivity only was observed in 21%, GADA positivity only in
      7.1% and 93% for any antibodies. From the 595 nondiabetic children with type 1
      diabetic first degree relatives 23 were positive for ICA, from whom 5 became
      diabetic during a two years observation period. These diabetic children had
      multiplex autoantibodies besides ICA. One child from this group, who was negative
      for ICA became diabetic, too. Among type 2 diabetic patients 13% were positive
      for ICA alone, 17% were positive for GADA alone and 27% were positive for any
      antibodies. The insulin dependency manifested in a short time was associated with
      antibody positivity. Among the gestational diabetics 10 were found positive for
      ICA. From them, 7 were type 1 diabetics, and 3 were type 2 diabetics at the time
      of the detection of antibodies. The authors suggest the need of determination of
      islet cell antibodies in the group of nondiabetic first degree relatives of type
      1 diabetic patients (ICA, GADA, IA2 and IAA), in the group of non-insulin
      dependent diabetics (ICA and GADA) as a screening for later insulin dependency,
      and in gestational diabetes after delivery (ICA) as screening for type 1 diabetes
      mellitus.

PMID- 10645717
TI  - [Studies on the metabolism of group B vitamins. 1949].

PMID- 10645718
TI  - Multifunctionality and diversity within the plant MYB-gene family.
AB  - MYB proteins constitute a diverse class of DNA-binding proteins of particular
      importance in transcriptional regulation in plants. Members are characterised by
      having a structurally conserved DNA-binding domain, the MYB domain. Different
      categories of MYB proteins can be identified depending on the number of imperfect
      repeats of the MYB domain they contain. It is likely that single MYB-domain
      proteins, a class of expanding importance in plants, bind DNA in a different way
      than two-repeat or three-repeat MYB proteins, and these groups are therefore
      likely to have different functions. The two-repeat (R2R3) MYB family is the
      largest family characterised in plants, and there are estimated to be over 100
      members in Arabidopsis. Functions of MYB proteins in plants include regulation of
      secondary metabolism, control of cellular morphogenesis and regulation of
      meristem formation and the cell cycle. Although functional similarities exist
      between R2R3 MYB proteins that are closely related structurally, there are
      significant differences in the ways very similar proteins function in different
      species and also within the same organism. Therefore, despite the large number of
      R2R3 MYB proteins in plants, it is unlikely that many are precisely redundant in
      their functions, but more likely that they share overlapping functions.

PMID- 10645719
TI  - Identification of two chilling-regulated 1-aminocyclopropane-1-carboxylate
      synthase genes from citrus (Citrus sinensis Osbeck) fruit.
AB  - Diurnal change in the temperature below or above 12.5 degrees C hastens the
      degreening of citrus peel and elicits the phytohormone ethylene production in
      citrus fruit. Ethylene triggers the degradation of chlorophyll and synthesis of
      carotenoids in citrus peel. To investigate if ethylene is required for the
      degreening of citrus peel elicited by low temperatures, we studied the chilling
      regulated gene expression of ACC synthase, one of the key enzymes catalyzing
      ethylene biosynthesis. We isolated and characterized a chilling-inducible 1
      aminocyclopropane-1-carboxylate synthase (ACC synthase) gene, CS-ACS1, and a
      chilling-repressible gene, CS-ACS2, from citrus peel. The CS-ACS1 transcript 1.7
      kb in length encodes a polypeptide of 483 amino acids (Mr 54,115, pI 6.63),
      whereas the CS-ACS2 transcript of 1.8 kb encodes a polypeptide of 477 amino acids
      (Mr 53,291, pI 6.72). Both genes showed a rapid but transient induction (within
      2.4 h) of transcripts upon rewarming after the chilling (4 degrees C) treatment.
      After 24 h of incubation at room temperature, CS-ACS1 mRNA diminished to an
      undetectable level, whereas the CS-ACS2 mRNA regained its basal level of
      expression attained prior to the chilling treatment. Chilling-induced ethylene
      production and ACC accumulation were also observed upon rewarming. Both genes
      were also induced by the wound stress (excision). The protein synthesis inhibitor
      cycloheximide super-enhances the accumulation of both ACS transcripts at room
      temperature. Molecular analysis of the 3.3 kb genomic DNA of CS-ACS1 revealed
      that this gene consists of three introns and four exons. The intron 3 is
      exceptionally large ( 1.2 kb) and shares significant homology with mitochondrial
      DNA, supporting the intron-late theory.

PMID- 10645720
TI  - Expression of the pea (Pisum sativum L.) alpha-tubulin gene TubA1 is correlated
      with cell division activity.
AB  - Microtubules are thought to be major determinants of plant morphogenesis, through
      effects on planes of cell division and on directions of differential cell
      expansion. In differentiation and redifferentiation processes, tubulin expression
      may prove a useful early indicator of cell activity. We examined the expression
      and localization of the pea alpha-tubulin gene TubA1 in situ and in transgenic
      alfalfa (Medicago sativa) to explore its use as a probe for plant development,
      and as a test case for correct developmental expression between two legume
      species commonly compared for studies of symbiosis with Rhizobium. The TubA1 mRNA
      was more abundant in root tips and immature leaves than in other tissues of pea.
      The promoter of TubA1 was fused to beta-glucuronidase (GUS) to analyze alpha
      tubulin expression in transgenic alfalfa. Transient assays indicated that the
      TubA1 gene is transcribed at moderate levels compared to the cauliflower mosaic
      virus (CaMV) 35S promoter. Histochemical staining for GUS activity confirmed a
      correlation between TubA1 expression and cell division in nodules, roots and
      leaves. TubA1 promoter activity was first detected in the inner cortex of the
      root between 18 h and 24 h after spot inoculation with Rhizobium meliloti.
      Expression of a c-myc epitope fused to the carboxy-terminus of TubA1 resulted in
      an incorporation into the microtubular cytoskeleton, demonstrating the
      effectiveness of at least one epitope tag in creating functional tubulin fusions.

PMID- 10645721
TI  - Alternative splicing of two leading exons partitions promoter activity between
      the coding regions of the maize homeobox gene Zmhox1a and Trap (transposon
      associated protein).
AB  - Elucidation of the exon/intron structure of the maize Zmhox1a homeobox gene
      revealed two small introns in the homeodomain. Both intron positions are
      conserved in animal counterparts encoded in the metazoan homeobox gene clusters
      and thus may indicate a common ancestor. The transcription start of the Zmhox1a
      gene has been localized far from the protein-coding region. Two distal
      untranslated leading exons are alternatively spliced to either the Zmhox1a coding
      exons or an unrelated open reading frame comprising two exons located internally
      of the large second Zmhox1a intron. Due to significant homology to the C-terminus
      of the Mutator transposase this alternative gene product was named Trap
      (transposon-associated protein). Splice site selection may involve two sequence
      elements conserved at the splice acceptor sites in front of the Zmhox1a and Trap
      protein-coding regions. The translation of a mRNA species devoid of exon 3 which
      encodes the Zmhox1a transcription start codon may give rise to an N-terminal
      deletion polypeptide, deltaZmhox1a. Ectopic expression experiments in transgenic
      tobacco indicate a putative function distinct from the full-length Zmhox1a
      protein.

PMID- 10645722
TI  - Rubisco activase transcript (rca) abundance increases when the marine unicellular
      green alga Chlorococcum littorale is grown under high-CO2 stress.
AB  - cDNA and the corresponding genomic DNA region encoding Rubisco activase were
      isolated from the unicellular green alga Chlorococcum littorale. The deduced
      amino acid sequence encoded by the cDNA was 403 amino acids long and exhibited
      important homology with those of other known Rubisco activases. Its N-terminal
      sequence was similar to the chloroplastic transit peptides in Chlamydomonas
      reinhardtii. The mature protein had a predicted molecular mass of 42 kDa. Five
      introns were located inside the genomic gene encoding Rubisco activase (rca).
      Genomic Southern blots indicated that two copies of the rca gene were present in
      the genome of C. littorale. The level of rca messenger RNA increased when cells
      of C. littorale were subjected to high-CO2 stress (i.e. grown under at least 20%
      CO2). Hsp70 heat-shock protein was also induced under high-CO2 conditions and, as
      expected, was also induced at 35 degrees C. The rca gene, in contrast, was not
      induced at 35 degrees C, indicating that this gene was induced in response to the
      high CO2 concentration and not to general stress. A search of the promoter
      binding proteins by a gel retardation assay showed that, under the high-CO2
      conditions, a protein(s) which was probably an activator of the rca transcription
      was synthesized.

PMID- 10645723
TI  - Test of the combinatorial model of intron recognition in a native maize gene.
AB  - Previous studies have established that splice site selection and splicing
      efficiency in plants depend strongly on local compositional contrast consisting
      of high exon G+C content relative to high intron U content. The combinatorial
      model of plant intron recognition posits that splice site sequences as well as
      local intron and exon sequences contribute to splice site selection and splicing
      efficiency. Most of the previous studies used synthetic or chimeric constructs,
      often tested in heterologous hosts. To perform a more critical test of the
      combinatorial model in a native context, the single intron of the maize Bronze2
      gene and its flanking exons were modified by site-directed mutagenesis. Splicing
      efficiency was tested in maize protoplasts. Results show that a higher U content
      in the flanking 5' exon, whether close to or distant from the 5' splice site, did
      not modify splicing efficiency. Decreasing exon G+C content dramatically impaired
      splicing. Increasing intron G+C content or decreasing intron U content adversely
      impacted splicing. In all constructs splicing occurred exclusively at the
      original 5' and 3' splice sites. These results are consistent with the hypothesis
      that exon G+C content and intron U content contribute separate but complementary
      aspects of intron definition in the native Bz2 transcript.

PMID- 10645725
TI  - The involvement of ubiquitin in vegetative desiccation tolerance.
AB  - We have isolated a polyubiquitin cDNA from the modified desiccation-tolerant
      grass Sporobolus stapfianus. This cDNA, along with a commercially available
      polyclonal ubiquitin antibody, was used to characterize desiccation/rehydrated
      associated changes in ubiquitin-mediated protein degradation in S. stapfianus and
      the fully desiccation-tolerant moss Tortula ruralis. Northern analysis
      demonstrated that in S. stapfianus leaves two ubiquitin transcripts, of ca. 1.4
      and 1.2 kb, accumulated above control levels during drying and rehydration but
      were barely detectable in desiccated tissue. The peak in rehydration-associated
      transcript accumulation coincided with a depletion in ubiquitin monomer levels
      indicating an increase in protein degradation. Analysis of T. ruralis revealed
      three ubiquitin transcripts of ca. 1.9, 1.3 and 0.65 kb, with only the 1.3 kb
      transcript level varying in response to drying and rehydration and all
      transcripts being stable in dried tissue. Western analysis revealed that
      conjugated ubiquitin, indicative of proteins targeted for removal, was evident in
      all samples of Sporobolus but detectable only in slow-drying Tortula which also
      displayed reduced levels of ubiquitin monomer. These results demonstrate that
      desiccated T. ruralis gametophyte possesses stable ubiquitin transcripts which
      can be translated upon rehydration enabling rapid initiation of cellular repair
      through degradation of certain proteins. This is in contrast to S. stapfianus
      which requires several hours to replenish depleted ubiquitin transcripts. The
      ubiquitin response to drying and rehydration in evolutionarily diverse systems is
      characterized, and the role of repair mechanisms such as ubiquitin-mediated
      protein degradation in desiccation tolerance is assessed.

PMID- 10645724
TI  - A conserved His-Asp signal response regulator-like gene in Heterosigma akashiwo
      chloroplasts.
AB  - Regulation of gene expression in plastids may involve molecular components
      conserved from cyanobacteria-like ancestors. Among prokaryotes, genes are
      commonly regulated at the transcriptional level by 'two-component' or 'His-Asp'
      signal transducers, consisting of a 'sensor kinase', which autophosphorylates at
      a conserved histidine residue, and a cognate response regulator, which is
      phosphorylated by the sensor kinase at a conserved aspartate residue. A putative
      His-Asp response regulator gene (trg1: transcriptional regulatory gene 1) has
      been identified in the estuarine raphidophytic alga Heterosigma akashiwo. The
      chloroplast-encoded trg1 is 693 bp in length, contains no introns, and yields a
      conceptual translation product of 231 amino acids, with a predicted mass of 27
      kDa. Homology searches suggest that Heterosigma trgl has an omnpR-like identity
      within the DNA-binding His-Asp family of response regulators. trg1 contains both
      the phosphorylation and DNA-binding domains which are present in prokaryote
      response regulators. Quantitative competitive RT-PCR showed that Heterosigma trg1
      is expressed at low levels (5 microg per g total RNA). In contrast, psbA (a
      photosystem II component) transcript is abundant (60 mg per g total RNA). Cell
      cycle analysis showed that psbA abundance oscillates in response to light but
      trg1 mRNA levels are invariant. We hypothesize that a His-Asp phosphorelay
      mechanism may affect chloroplast genome transcription in a manner similar to
      bacterial signal transduction pathways in which 'sensor kinase' and cognate
      'response regulator' proteins interact.

PMID- 10645726
TI  - Comparative differential RNA display analysis of arbuscular mycorrhiza in Pisum
      sativum wild type and a mutant defective in late stage development.
AB  - In order to analyse gene expression associated with the late stages of arbuscular
      mycorrhizal development between Pisum sativum and Glomus mosseae, comparative
      differential RNA display was carried out using wild-type P. sativum and a mutant,
      RisNod24, where the fungal partner is not able to form functional arbuscules.
      Comparison of RNA accumulation patterns between controls, G. mosseae-colonized
      mutant and wild-type roots resulted in the identification of four differentially
      occurring cDNA fragments. One of the corresponding genes was from the fungus and
      three of plant origin. One plant gene, Psam4 (P. sativum arbuscular mycorrhiza
      regulated), was analysed in more detail. Sequencing of a cDNA clone showed that
      Psam4 encodes a proline-rich protein. Northern blot analysis and quantitative RT
      PCR revealed a higher basal level of Psam4 RNA accumulation in the mutant
      compared to the wild type. In both pea genotypes, RNA accumulation was reduced
      after inoculation with mycorrhiza- or nodule-forming symbiotic microorganisms,
      but enhanced after infection with a root pathogenic fungus.

PMID- 10645727
TI  - Bryophyte 5S rDNA was inserted into 45S rDNA repeat units after the divergence
      from higher land plants.
AB  - The 5S ribosomal RNA genes (5S rDNA) are located independently from the 45S rDNA
      repeats containing 18S, 5.8S and 26S ribosomal RNA genes in higher eukaryotes.
      Southern blot and fluorescence in situ hybridization analyses demonstrated that
      the 5S rDNAs are encoded in the 45S rDNA repeat unit of a liverwort, Marchantia
      polymorpha, in contrast to higher plants. Sequencing analyses revealed that a
      single-repeat unit of the M. polymorpha nuclear rDNA, which is 16,103 bp in
      length, contained a 5S rDNA downstream of 18S, 5.8S and 26S rDNA. To our
      knowledge, this is the first report on co-localization of the 5S and 45S rDNAs in
      the rDNA repeat of land plants. Furthermore, we detected a 5S rDNA in the rDNA
      repeat of a moss, Funaria hygrometrica, by a homology search in a database. These
      findings suggest that there has been structural re-organization of the rDNAs
      after divergence of the bryophytes from the other plant species in the course of
      evolution.

PMID- 10645729
TI  - Transcriptional regulation of the Nia1 gene encoding nitrate reductase in
      Chlamydomonas reinhardtii: effects of various environmental factors on the
      expression of a reporter gene under the control of the Nia1 promoter.
AB  - The NAD(P)H nitrate reductase (NR) from Chlamydomonas reinhardtii is encoded by
      the structural gene Nia1. Numerous data from the literature indicate that this
      enzyme is submitted to complex regulation mechanisms involving multiple controls
      at transcriptional and post-transcriptional levels. To specifically investigate
      the regulation of the Nia1 gene at the transcriptional level, NR+ and NR-
      transformed cells harbouring the Nia1:Ars construct (Nia1 promoter fused to the
      arylsulfatase (ARS)-encoding Ars reporter gene) were cultivated under various
      experimental conditions and the ARS activities were recorded. ARS levels were
      very low in cells grown in the presence of NH4Cl and dramatically increased on
      agar medium deprived of any nitrogen source or containing nitrate, nitrite, urea,
      arginine or glutamine. Compared to nitrogen-free medium, a slight positive effect
      of nitrate in the NR+ strain and a significant negative effect of nitrite in both
      NR+ and NR- strains were observed. The ARS activities were high in the light and
      very low in the dark or in the light in the presence of DCMU, indicating that
      Nia1 transcription is strikingly dependent on photosynthetic activity. Acetate
      used as a carbon source in the dark did not substitute for light in stimulating
      Nia1:Ars expression. Inactivation of NR by tungstate treatment of the NR+ strain
      resulted in a dramatic increase of ARS level suggesting that in Chlamydomonas,
      like in higher plants, active NR negatively regulates the transcription of the NR
      structural gene. Deleting the major part of the Nia1 leader sequence still
      present in the chimeric gene resulted in a decrease of ARS level but did not
      modify the regulation pattern.

PMID- 10645730
TI  - Neural substrates of orthographic lexical access as demonstrated by functional
      brain imaging.
AB  - OBJECTIVE: To delineate regions involved in visual word recognition. BACKGROUND:
      The processes and regions involved in visual word recognition have been somewhat
      controversial for over 100 years. METHODS: This study used regional cerebral
      blood flow as assessed by functional magnetic resonance imaging to study normal
      subjects (N = 9) on an individual within-subject basis while they were actively
      engaged on-line in a visual lexical decision task. Standard analysis techniques
      were used for identifying regions of activation. RESULTS: Across subjects, the
      task activated a number of regions, including the occipital pole, lateral and
      basal occipitotemporal (including lingual and fusiform) regions, superior and
      middle temporal gyri, and supramarginal and angular gyri. Typically, these
      regions were activated bilaterally; when activation was unilateral, it was on the
      left. Some of the areas activated (e.g., inferior parietal regions) have not been
      previously reported to be involved in such types of processing by activation
      studies but have been implicated in lesion studies. CONCLUSIONS: These results
      broaden the areas known to be involved in visual word recognition. The bilateral
      activation associated with visual word recognition is in some respects analogous
      to the "what" system in visual recognition described in subhuman primates. In
      addition, the study raises several methodologic issues. The within-subject
      analysis showed variability in the specific regions activated when subsequently
      comparing across individuals, raising implications for future functional imaging
      studies.

PMID- 10645728
TI  - Fine sequence analysis of 60 kb around the Arabidopsis thaliana AtEm1 locus on
      chromosome III.
AB  - The Arabidopsis thaliana Em1 gene has been mapped to the lower arm of chromosome
      III. Fine analysis of 60 kb around this gene, based largely on identification and
      sequencing of cognate cDNAs, has allowed us to identify 15 genes or putative
      genes. Cognate cDNAs exist for ten of these genes, indicating that they are
      effectively expressed. Analysis by sequence alignment and intracellular
      localization prediction programs allows attribution of a potential protein
      product to these genes which show no obvious functional relationship. Comparison
      of the true exon/intron structure based on cDNA sequences with that proposed by
      three commonly used prediction programs shows that, in the absence of further
      information, the results of these predictions on anonymous genomic sequences
      should be interpreted with caution. Examination of the non-coding sequence showed
      the presence of a novel repeated, palindromic element. The results of this
      detailed analysis show that in-depth studies will be necessary to exploit
      correctly the complete A. thaliana genome sequence.

PMID- 10645731
TI  - Perinatal complications and abnormal proton metabolite concentrations in frontal
      cortex of adolescents seen on magnetic resonance spectroscopy.
AB  - OBJECTIVE: The relation of perinatal complications to metabolism of orbitofrontal
      cortex was studied in 12 normal adolescents aged 13 to 17 years. BACKGROUND:
      Perinatal complications are associated with both (a) behavioral signs of frontal
      lobe dysfunction and (b) increased risk for mood disorders and schizophrenia.
      Perinatal complications are not usually sufficient to produce these disorders,
      however, suggesting an etiologic model in which perinatal complications interact
      with a second, familial, liability factor. The present study tested a key
      prediction of this "two-factor" model, namely, that perinatal complications will
      be associated with physiologic signs of frontal dysfunction, even in persons who
      have no personal or family history of these psychiatric disorders. METHODS:
      Subjects were screened by structured interviews with the Kiddie Schedule for
      Affective Disorders and Schizophrenia and had no personal or family history of
      psychiatric disorder. Ratios of choline and N-acetyl aspartate to creatine in
      orbitofrontal cortex were measured using proton magnetic resonance spectroscopy.
      Perinatal complications were scored with the examiners blinded to magnetic
      resonance spectroscopy data, applying published scales to hospital records on
      subjects' gestations and births. RESULTS: Perinatal complications were
      significantly correlated with reduced concentrations of choline and N-acetyl
      aspartate. CONCLUSIONS: Our results complement earlier findings of significant
      relations between perinatal complications and signs of frontal lobe dysfunction,
      as well as elevated rates of these two types of variables in mood disorders and
      schizophrenia.

PMID- 10645732
TI  - Auras, seizure focus, and psychiatric disorders.
AB  - OBJECTIVE: The goal of this study was to assess the types of auras and their
      associations with the focus of seizures in 144 consecutive adult patients with
      partial epilepsy refractory to medical treatment. The association of frequency
      and type of aura with a psychiatric disorder was also studied. BACKGROUND: The
      nature of the aura, its association with the seizure focus, and its relation with
      emotions and behavioral dysfunction have received relatively little attention,
      and remain controversial. METHODS: Patients were admitted to an epilepsy
      investigation unit for detailed observation of their seizures and type of aura.
      Patients underwent standard electroencephalographic telemetry, including
      implanted subdural electrodes, if necessary, to delineate the seizure focus. The
      auras were classified into nine categories. All patients had an independent
      clinical psychiatric interview for a Diagnostic and Statistical Manual, Third
      Edition-Revised (DSM-III-R)-based diagnosis. RESULTS: Of the 144 patients
      studied, 111 (77.1%) had one or more symptoms during the aura and 33 (22.9%) had
      no aura. The most frequent aura types were viscerosensory (47 cases [32.6%]),
      experiential (44 cases [30.6%]), and cephalic (21 cases [14.6%]). A temporal lobe
      focus was present in 116 (80.5%) patients. Only experiential auras were
      significantly associated with a temporal lobe seizure focus (33 of 44 cases). A
      DSM-III-R psychiatric diagnosis was present in 74 (51.4%) patients. Of the 116
      patients with a temporal lobe focus, 60 (50.2%) had a DSM-III-R psychiatric
      diagnosis. Patients with two or more auras were significantly more likely to have
      a psychiatric diagnosis (70.2%) compared with those with one aura (39.1%) or no
      aura (48.5%). A significant association between experiential auras and
      psychiatric morbidity was seen. CONCLUSIONS: Auras occurred in a majority of
      patients with a treatment-refractory partial epilepsy who were hospitalized for
      assessment of their seizure focus for possible surgical candidacy. Two or more
      auras were associated with a psychiatric diagnosis as was the presence of an
      experiential aura. Experiential auras were most common in temporal lobe epilepsy.
      Approximately half the patients, irrespective of seizure focus, had an associated
      psychiatric morbidity.

PMID- 10645733
TI  - A preliminary study of the relation of neuropsychological performance to
      neuroanatomic structures in bipolar disorder.
AB  - OBJECTIVE: To investigate the relation between neuropsychological dysfunction and
      volumetric measures of neuroanatomic structures in patients with bipolar
      disorder. BACKGROUND: Previous research suggests that neuropsychological deficits
      are associated with neuroanatomic changes in patients with bipolar disorder.
      METHOD: Twenty-six outpatients who met Diagnostic and Statistical Manual, Third
      Edition-Revised criteria for bipolar disorder were administered a battery of
      neuropsychological tests that assessed memory, abstracting ability, psychomotor
      performance, sustained attention, and intelligence. Patients also received a
      magnetic resonance imaging scan, from which volumes of the temporal lobes,
      hippocampus, third ventricle, and areas of the lateral ventricles were
      calculated. Using multiple regression analyses, neuroanatomic structures were
      compared with neuropsychological test variables. RESULTS: Data suggest that a
      larger right hippocampal volume is associated with poorer neuropsychological
      functioning. CONCLUSIONS: Further studies are needed to both replicate and
      examine the relation between potential mechanisms of neuroanatomic alterations
      and neuropsychological dysfunction in patients with bipolar disorder.

PMID- 10645735
TI  - Relation between informant-rated personality and clinician-rated depression in
      patients with memory disorders.
AB  - OBJECTIVE: The goal of this study was to examine the convergent validity of
      informant-rated changes in depressive and related personality traits with
      clinician-assessed depression in memory-disordered patients. BACKGROUND:
      Depressive symptoms are frequent complications in persons with dementias such as
      Alzheimer disease, and caregiver informants consistently report changes in
      depression and related neurotic traits on the NEO Personality Inventory (NEO-PI)
      in dementia patients. METHODS: In 78 patients undergoing evaluation of memory
      complaints at an Alzheimer disease clinic, depression was characterized by
      clinical diagnosis, a clinician-rated scale, and informant ratings of premorbid
      versus current depression, anxiety, vulnerability, and neuroticism on the NEO-PI.
      RESULTS: The diagnostic groups differed in meaningful patterns on the NEO-PI
      measures. Those with a diagnosis of major depression differed from never
      depressed patients in all personality areas, although those with depressed mood
      differed only on NEO-PI depression. The clinician-rated depression scale
      correlated modestly with current personality and change from baseline
      personality. CONCLUSIONS: The NEO-PI provides a useful measure of informants'
      perspectives on depressive personality changes in patients with memory disorders
      but does not correspond fully with a clinical syndrome of depression.

PMID- 10645734
TI  - Autistic savants. [correction of artistic].
AB  - OBJECTIVE: The objectives of this study were to examine common patterns in the
      lives and artwork of five artistic savants previously described and to report on
      the clinical, neuropsychological, and neuroimaging findings from one newly
      diagnosed artistic savant. BACKGROUND: The artistic savant syndrome has been
      recognized for centuries, although its neuroanatomic basis remains a mystery.
      METHODS: The cardinal features, strengths, and weaknesses of the work of these
      six savants were analyzed and compared with those of children with autism in whom
      artistic talent was absent. An anatomic substrate for these behaviors was
      considered in the context of newly emerging theories related to paradoxical
      functional facilitation, visual thinking, and multiple intelligences. RESULTS:
      The artists had features of "pervasive developmental disorder," including
      impairment in social interaction and communication as well as restricted
      repetitive and stereotyped patterns of behavior, interest, and activities. All
      six demonstrated a strong preference for a single art medium and showed a
      restricted variation in artistic themes. None understood art theory. Some
      autistic features contributed to their success, including attention to visual
      detail, a tendency toward ritualistic compulsive repetition, the ability to focus
      on one topic at the expense of other interests, and intact memory and
      visuospatial skills. CONCLUSIONS: The artistic savant syndrome remains rare and
      mysterious in origin. Savants exhibit extraordinary visual talents along with
      profound linguistic and social impairment. The intense focus on and ability to
      remember visual detail contributes to the artistic product of the savant. The
      anatomic substrate for the savant syndrome may involve loss of function in the
      left temporal lobe with enhanced function of the posterior neocortex.

PMID- 10645736
TI  - The relation between dopamine D2 receptor density and personality: preliminary
      evidence from the NEO personality inventory-revised.
AB  - OBJECTIVE: To examine the relation between dopamine (DA) D2 receptor-specific
      binding and personality, we assessed the relation between DA D2 binding and the
      NEO Personality Inventory-Revised (NEO PI-R). BACKGROUND: Previous studies have
      demonstrated a relation between DA D2 receptor-specific binding and a personality
      trait involving personal detachment as defined by the Karolinska Scales of
      Personality: A subsequent study using a different measure of personal detachment
      failed to replicate this finding, suggesting that metric properties of the
      personality scale may be important. To further examine this issue, we assessed
      the relation between DA D2 binding and a third personality measure, the NEO PI-R.
      METHODS: Eighteen adult subjects completed the NEO PI-R and participated in an
      11C-raclopride positron emission tomography study to quantify striatal DA D2
      receptor binding. RESULTS: We did not find a significant relation between binding
      and detachment-like traits on the NEO PI-R; however, we found a significant
      relation between DA D2 receptor binding and the NEO PI-R personality facet of
      Depression (r = 0.75, p <0.0001). CONCLUSIONS: The results fail to replicate the
      findings of previous studies reporting an association between DA D2 receptor
      density and personal detachment, suggesting that the relation is relatively
      specific to the trait defined by the Karolinska Scales of Personality. The
      relation between a nonclinical personality trait of depression and DA D2 binding,
      if replicated, may help to elucidate the role of dopamine in depression.

PMID- 10645737
TI  - Hypofrontality and negative symptoms in patients with dementia of Alzheimer type.
AB  - OBJECTIVE: The purpose of the current study was to examine the relation between
      regional cerebral blood flow (rCBF) and negative symptoms (NS) in patients with
      dementia of Alzheimer type (DAT). BACKGROUND: Negative symptoms in
      neuropsychiatric disorders were associated with altered rCBF in frontal cortex.
      METHODS: Twenty-five subjects with a diagnosis of DAT were administered the Scale
      for the Assessment of Negative Symptoms (SANS), the Positive and Negative Symptom
      Scale, the Hamilton Rating Scale for Depression, and the Mini-Mental State
      Examination. The subjects were divided into two groups by means of a median split
      with regard to NS severity (high NS group, N = 12; low NS group, N = 13). Each
      patient underwent a single photon emission tomography scan using 99mTc-HMPAO at
      rest. Cortical and subcortical regions of interest were symmetrically defined in
      each hemisphere. Cortical-to-cerebellar perfusion ratios were established
      quantitatively using ADAC software. RESULTS: High NS group subjects had a
      significantly lower rCBF than low NS group subjects in the frontal cortex and
      cingulate gyrus (MANOVA: p = 0.022) as a result of differences in the
      dorsolateral prefrontal cortex bilaterally (right: F = 12.12, p = 0.002; left: F
      = 6.55, p = 0.02) and in the frontal cortex, mainly in the right hemisphere
      (right: F = 6.33, p = 0.02; left: F = 3.26, p = 0.08). For all the subjects (N =
      25), there were negative correlations between the SANS total score and rCBF, most
      prominently in the dorsolateral prefrontal cortex bilaterally (right: r = -0.48,
      p <0.01; left: r = -0.49, p = 0.01). No significant correlation was found between
      rCBF in any of the regions of interest and either the Mini-Mental State
      Examination or the Hamilton Rating Scale for Depression scores. CONCLUSIONS: This
      study indicates that decreased perfusion in the frontal cortex is associated with
      NS severity but not with measures of cognitive impairment or depressive symptoms
      in DAT patients. These results support the hypothesis that the frontal lobes may
      be involved in the cause of NS in DAT, and they underscore the importance of NS
      evaluation in neuroimaging studies.

PMID- 10645738
TI  - Neuroimaging and behavioral correlates of recovery from mnestic block syndrome
      and other cognitive deteriorations.
AB  - OBJECTIVE: We conducted a follow-up study on a patient with enduring psychic
      shock-induced cognitive impairment to study by neuropsychological and functional
      imaging methods the degree of his recovery process on the brain and cognitive
      levels. BACKGROUND: Based on the assumption that trauma and stress conditions can
      alter the functions of the nervous systems, we report on a patient whom we
      studied 2 and 12 months after he suffered "mnestic block syndrome" and additional
      cognitive deterioration symptoms. METHODS: We report on a patient studied 2 and
      12 months after he suffered "mnestic block syndrome" and additional cognitive
      deterioration symptoms. Magnetic resonance imaging and fluorodeoxyglucose
      positron emission tomography were used for neural and detailed neuropsychological
      testing for cognitive deficits. RESULTS: The patient initially manifested severe
      intellectual decline, including severe anterograde and retrograde amnesia. His
      symptoms were correlated with major, although selective, reductions in his brain
      metabolism (2-3 SD below those of controls). Presently, he shows a normal brain
      metabolism and has regained parts of his memory and many of his other
      intellectual capabilities. Nevertheless, he still has long-term memory
      impairments. CONCLUSIONS: This case demonstrates a close relation between brain
      metabolism and cognitive performance, with major deficits of both at 2 months and
      major recovery of both at 12 months after a shocking event. It can serve as an
      example for possible stress-related deteriorations in certain brain regions,
      which can be partly corrected by psychotherapeutic interventions, passing time,
      and favorable environmental conditions.

PMID- 10645739
TI  - Marchiafava-Bignami disease: literature review and case report.
AB  - OBJECTIVE: We postulated that disruption of callosal pathways as occurs in
      Marchiafava-Bignami disease (MBD) is associated with marked impairment in brain
      functioning as measured by cognitive assessment and neuroimaging. BACKGROUND: MBD
      is considered to be a rare and severe complication of chronic alcoholism. It is
      characterized by necrosis and subsequent atrophy of the corpus callosum, which is
      the major brain structure connecting corresponding areas of both hemispheres.
      METHODS: We review the existing literature on MBD with respect to
      conceptualization, theories of pathogenesis, forms of the disease, and
      neuroimaging and neuropsychological findings. We then present the case of a
      middle-aged man with MBD who underwent extensive clinical, neuropsychological,
      and neuroimaging studies. RESULTS: Neuropsychological evaluation revealed a
      pattern of severe global dementia. Magnetic resonance imaging showed moderate
      atrophy of anterior callosal regions and severe atrophy of posterior callosal
      regions in the setting of cortical and subcortical atrophy. Resting metabolism
      positron emission tomography revealed decreased glucose metabolism most
      pronounced in subcortical and mesial frontal regions. The differential diagnosis,
      function of the corpus callosum, and potential limitations of our case study are
      discussed. CONCLUSIONS: On account of the history, clinical presentation, and
      results of magnetic resonance imaging of the brain, we diagnosed our patient with
      chronic MBD.

PMID- 10645740
TI  - Effects of marital conflict on subsequent triadic family interactions and
      parenting.
AB  - This study examined marital conflict's indirect effects on children through
      disruptions in family alliances and parenting. Forty married couples were
      observed interacting with their 6-8-year-old sons after pleasant and conflictual
      discussions. After conflictual discussion, fathers showed lower
      support/engagement toward sons, and coparenting styles were less democratic.
      Couple negativity was correlated with family negativity, regardless of the topic
      of discussion, which suggests continuity in the affective quality of the two
      family subsystems. Mothers' marital satisfaction moderated families' responses to
      the experimental manipulation. The results provide stronger evidence than
      previously available of a causal link between conflict and disrupted parenting.
      Further research is needed to identify which conflict-related disruptions in
      parenting influence the development of children's problems.

PMID- 10645741
TI  - Heterogeneity of popular boys: antisocial and prosocial configurations.
AB  - This study examined subtypes of popular 4th-6th grade boys (N = 452). Popular
      prosocial (model) and popular-antisocial (tough) configurations were identified
      by means of teacher ratings and compared with peer and self-assessments and
      social centrality measures. Peers perceived model boys as cool, athletic,
      leaders, cooperative, studious, not shy, and nonaggressive. Peers perceived tough
      boys as cool, athletic, and antisocial. Model boys saw themselves as
      nonaggressive and academically competent. Tough boys saw themselves as popular,
      aggressive, and physically competent. Tough boys were disproportionately African
      American, particularly when African Americans were a minority in their
      classrooms. Model and tough boys were overrepresented at nuclear social
      centrality levels. These findings suggest that highly aggressive boys can be
      among the most popular and socially connected children in elementary classrooms.

PMID- 10645742
TI  - Acquisition of mental state language in Mandarin- and Cantonese-speaking
      children.
AB  - Children's theory of mind appears to develop from a focus on desire to a focus on
      belief. However, it is not clear (a) whether this pattern is universal and (b)
      whether it could also be explained by linguistic and sociocultural factors. This
      study examined mental state language in 10 Mandarin-speaking (21-27 months) and 8
      Cantonese-speaking (18-44 months) toddlers. The results suggest a pattern of
      theory-of-mind development similar to that in English, with early use of desire
      terms followed by other mental state references. However, the Chinese-speaking
      children used desire terms much earlier, and the use of terms for thinking was
      very infrequent, even for Mandarin-speaking adults. This finding suggests a
      consistency in the overall sequence, but variation in the timing of beginning and
      end points, in children's theory-of-mind development across cultures.

PMID- 10645744
TI  - Child and mother cardiac vagal tone: continuity, stability, and concordance
      across the first 5 years.
AB  - In this prospective longitudinal study, vagal tone and heart period were measured
      at 2 months and at 5 years in children and their mothers to evaluate the
      development of vagal regulation at rest and during an environmental task. Child
      baseline vagal tone and heart period were discontinuous; mother baseline vagal
      tone was discontinuous, but heart period was continuous. Group mean baseline-to
      task change in vagal tone and heart period were continuous in both children and
      mothers. Children reached adult levels of baseline vagal tone by 5 years and did
      not differ from their mothers in baseline-to-task change in vagal tone or heart
      period. Baseline vagal tone tended to be stable, but baseline heart period and
      baseline-to-task change in vagal tone and heart period were unstable in children;
      both were stable in mothers. Baseline-to-task change in vagal tone showed
      consistent child-mother concordance. These findings contribute to understanding
      psychophysiological development, especially the ontogenesis of the vagal system
      and its regulatory capacity.

PMID- 10645743
TI  - Destructive sibling conflict and the development of conduct problems in young
      boys.
AB  - Little empirical work has explored the relation between destructive sibling
      conflict and conduct problems in children. This study used a measure of observed
      sibling conflict to examine its relations with maternal and teacher report of
      conduct problems in a low-income sample of 180 five-year-old boys and their close
      age siblings. Early report of behavior problems and rejecting parenting were
      added to the analyses to control for these predictors and to examine interactive
      effects. The interaction between destructive sibling conflict and rejecting
      parenting predicted aggressive behavior problems across time and informants such
      that a rise in aggression scores was evident for children who had high levels of
      both sibling conflict and rejecting parenting. Sibling conflict was also directly
      related longitudinally to the Child Behavior Checklist Delinquency factor.
      Results are discussed in terms of additive risk models and G. R. Patterson's
      (1984, 1986) theory of coercion.

PMID- 10645745
TI  - Languages, scripts, and the environment: factors in developing concepts of print.
AB  - Preschool children bilingual in English and Hebrew were investigated for their
      understanding of concepts of print by means of two tasks. In the first, children
      had to understand that a printed word did not change its meaning if it moved to a
      new location. In the second, children had to make judgments about word length and
      ignore the size of the named objects. Previous research had shown bilingual
      French-English and Chinese-English children to excel in the first task, but only
      older Chinese-English bilinguals had an advantage in the second. The present
      study extended those results by investigating the effect of writing system in
      more detail. The study also examined the effect of the language of the
      environment by conducting parallel studies in environments in which either
      English or Hebrew was the community language. The results show that the bilingual
      children in both settings were more advanced than the monolinguals in both tasks
      and in both settings.

PMID- 10645746
TI  - Young children's understanding of desire formation.
AB  - Two studies examined preschoolers' appreciation of how mental states arise. In
      Study 1, children aged 3 to 5 (24 at each age) better understood perception
      generated beliefs (e.g., that looking in a certain location generates a belief
      about the location's content) and attitude-generated desires (e.g., that positive
      experiences with an activity generate a desire to partake of the activity again)
      than physiology-generated desires (e.g., that not eating for a long time
      generates a desire for food). In Study 2, 4- and 5-year-olds (48 at each age)
      better understood the effects of quantity of experience (e.g., eating a lot vs. a
      little) than of time of experience (eating just now vs. a long time ago) on
      physiological states and desires. The findings suggest that whether children
      reason in more advanced fashion about desires or beliefs depends on which aspects
      of these mental states are considered.

PMID- 10645747
TI  - Localizing the development of covert attention in infants with scalp event
      related potentials.
AB  - This study examined covert shifts of attention in infants aged 14, 20, and 26
      weeks of age with scalp-recorded event-related potentials (ERPs). The infants
      were tested in a spatial cuing procedure. The reaction time to localize the
      target showed covert attention shifts (e.g., response facilitation or inhibition
      of return depending on cue-target stimulus onset asynchrony). There was a larger
      P1 ERP component on the valid trials than on the invalid trials or on the no-cue
      control trials. Presaccadic ERP potentials in response to the target were larger
      when it was in the cued location than when it was in uncued locations. There were
      increases from 14 to 26 weeks of age in the amount of inhibition of return, in
      the post-target-onset P1 effect, and in the presaccadic ERP potentials. These
      results suggest that cortical development parallels the development of covert
      orienting of attention and saccade planning in infants in this age range.

PMID- 10645748
TI  - Functional neuroanatomy of spatial working memory in children.
AB  - Functional magnetic resonance imaging (fMRI) was used to examine spatial working
      memory in 8- to 11-year-old children tested under three conditions. In the visual
      condition, children were asked to examine the location of a dot on a screen. In
      the motor condition, children were instructed to push a button that corresponded
      to the location of a dot presented on a screen. In the memory condition, children
      were asked to remember the location of a dot presented 1 or 2 trials previously.
      Subtracting the activation of the motor condition from the memory condition
      revealed activity in the dorsal aspects of the prefrontal cortex and in the
      posterior parietal and anterior cingulate cortex. These findings were also
      obtained in the analysis of the memory minus visual conditions except that motor
      cortex activation was also observed. These findings parallel those reported in
      comparable studies of adults and suggest that fMRI may be a useful means of
      examining function-structure relations in developmental populations.

PMID- 10645749
TI  - Goals as a mediator of gender differences in high-affiliation dyadic
      conversations.
AB  - The present study examined whether gender differences in affiliative aspects
      (collaboration and cooperation) of dyadic conversations occur because girls are
      more oriented than boys toward goals focused on others. Preadolescents (11-13
      years old; 51 boys, 53 girls) worked with a same- or an other-gender peer on a 4
      week-long creative-writing task at school. Dyadic conversations and goals were
      assessed twice. High-affiliation conversations and mutual-participation goals
      were more prevalent in female than in male and mixed-gender dyads. Mutual
      participation goals mediated gender differences in high-affiliation
      conversations. Control and task-performance goals did not differ by dyad gender.
      In mixed-gender dyads, conversation strategies and goals did not differ by
      gender. Implications of goals for understanding gender differences and
      similarities in conversations are discussed.

PMID- 10645750
TI  - Linking theory of mind and central coherence bias in autism and in the general
      population.
AB  - Three experiments investigated whether 2 characteristic aspects of the
      psychological profile of autism, theory-of-mind deficits and weak central
      coherence, might be functionally related. Experiment 1 showed that in the general
      population, performance on a proposed test of theory of mind was inversely
      related to speed on the Embedded Figures Test, a measure of central coherence
      bias. Experiments 2 and 3 confirmed that poor theory-of-mind performance was
      linked to weak central coherence among typically developing children and among
      children with autism; however, the correlations between these measures were
      reliable only after accounting for differences in individuals' verbal mental
      ages. This pattern of results is interpreted in terms of a relationship between
      individual differences in theory of mind and central coherence bias, a
      relationship that is separate from any developmental differences in these
      domains.

PMID- 10645751
TI  - Prokinetic activity of nizatidine: implications for the management of patients
      with gastroesophageal reflux disease.
AB  - Gastroesophageal reflux is a common condition caused mainly by motility disorders
      of the upper gastrointestinal tract. The most effective therapy combines acid
      suppression with a promotility agent. Nizatidine is a well-tolerated and
      effective histamine-2 (H2)-receptor antagonist used to suppress gastric acid
      secretion. Animal and human studies have conclusively demonstrated that
      nizatidine also has prokinetic activity comparable to that of cisapride, and its
      effect is evident <1 hour after administration of doses commonly used in clinical
      practice. This prokinetic activity occurs through noncompetitive inhibition of
      acetylcholine; this inhibition approximates the inhibition caused by neostigmine.
      Nizatidine appears to possess a prokinetic mechanism that may be helpful in
      treating patients with gastroesophageal reflux.

PMID- 10645752
TI  - Sex-related differences in response of plasma lipids to simvastatin: the Saitama
      Postmenopausal Lipid Intervention Study. S-POLIS Group.
AB  - The Saitama Postmenopausal Lipid Intervention Study was a multicenter,
      uncontrolled, collaborative study that investigated tolerability and sex-related
      differences in the response of serum lipids to simvastatin administered for 12
      months in 122 postmenopausal women and 55 men with serum total cholesterol (TC)
      levels > or =220 mg/dL. With simvastatin treatment, TC and low-density
      lipoprotein cholesterol (LDL-C) levels decreased significantly at 1 month in both
      groups, and these decreased levels were maintained throughout treatment (P <
      0.001). A significant decrease in triglyceride (TG) levels was also observed in
      both groups (P < 0.05). The mean percentage decreases in TC and LDL-C levels in
      women (20% and 28%, respectively) were significantly greater than those in men
      (15% and 20%, respectively) (P < 0.001). Mean percentage changes in TC and LDL-C
      levels in subgroups defined by stratification for baseline TC and LDL-C levels
      were also greater in women. There were no sex-related differences in the
      percentage changes in TG or high-density cholesterol levels, although the changes
      were influenced by baseline levels. Although the median dose of simvastatin
      (milligrams per kilogram of body weight) in women was significantly higher than
      in men (P < 0.001), the percentage changes in serum lipids were not correlated
      with the doses of simvastatin calibrated by body weight. Adverse reactions
      occurred in 8 men and 7 women, so there appeared to be no significant sex-related
      difference. Eleven patients had abnormal laboratory values. Simvastatin therapy
      for 12 months is well tolerated and effective for both women and men with
      hypercholesterolemia. Sex-related differences occurred in the response to
      simvastatin therapy of serum lipids, especially TC and LDL-C, with greater
      changes in lipid levels occurring in women.

PMID- 10645753
TI  - Dose linearity after oral administration of tacrolimus 1-mg capsules at doses of
      3, 7, and 10 mg.
AB  - Tacrolimus is an immunosuppressant drug used for the prophylaxis of organ
      rejection in patients who receive allogenic liver or kidney transplants. This
      study investigated the relationship between tacrolimus blood concentration-time
      profiles after 3-, 7-, and 10-mg single oral doses were given to 18 healthy, drug
      free, nonsmoking, institutionalized male volunteers. The protocol used a single
      dose, 3-period, 3-treatment, nonmasked, randomized-block, complete crossover
      design. The 90% CIs of the ratios of dose-adjusted, mean, log-transformed values
      of maximum blood concentration, area under the tacrolimus blood concentration
      time curve (0 to the last measurable concentration; lower limit of quantitation =
      0.5 ng/mL), and area under the blood concentration-time curve (0 to 0) fell
      within the range of 125%, indicating dose proportionality for these parameters
      under experimental conditions. Power to detect a 20% difference for the 3 doses
      tested was 82.2%, 66.7%, and 72.8%, respectively.

PMID- 10645754
TI  - Immunologic tolerability profile of celecoxib.
AB  - Celecoxib is primarily an inhibitor of cyclooxygenase (COX) 2 and, at therapeutic
      concentrations in humans, does not inhibit the COX-1 isoenzyme. The present meta
      analyses explore the incidence of allergic reactions with celecoxib in patients
      in the North American and international arthritis trials, in patients with a
      history of hypersensitivity reactions to sulfonamides, and in patients receiving
      medications containing sulfonamides. Data were obtained from 11,008 patients in
      14 double-masked trials of celecoxib in arthritis ranging from 4 to 24 weeks in
      duration. Results demonstrate that the incidence of allergic reactions with
      celecoxib was not statistically different from that seen with placebo or active
      comparators (nonsteroidal anti-inflammatory drugs [NSAIDs]) when data from the
      entire cohort were analyzed. The subset of patients with a history of sulfonamide
      hypersensitivity reactions had a 3-fold to 6-fold higher incidence of
      dermatologic reactions than did the entire arthritis trial cohort. Although
      dermatologic reactions occurred with greater frequency in patients with a history
      of sulfonamide hypersensitivity, the trend was consistent across all 3 treatment
      groups (celecoxib, NSAIDs, and placebo). According to these data and structural
      and metabolic differences between sulfonamides, the potential for cross
      allergenicity between celecoxib and other sulfonamide-containing medications
      appears comparable to that of placebo and nonsulfonamide-containing NSAIDs.
      Additionally, the risk of allergic reactions with celecoxib appears comparable to
      that of placebo and comparator NSAIDs. Prospective trials are needed to confirm
      these findings.

PMID- 10645755
TI  - Pharmacokinetics of intravenous glycyrrhizin after single and multiple doses in
      patients with chronic hepatitis C infection.
AB  - Intravenous glycyrrhizin has been used in Japan for the treatment of chronic
      hepatitis for >20 years, although only a few reports of its pharmacokinetic
      profile after multiple intravenous doses in small numbers of Japanese patients
      have been published. The present study compared these Japanese data against the
      pharmacokinetic characteristics of glycyrrhizin after single and multiple
      intravenous doses in 35 European patients with chronic hepatitis C infection. We
      administered 80, 160, or 240 mg glycyrrhizin 3 times/wk or 200 mg glycyrrhizin 6
      times/wk for 4 weeks. Twenty-four-hour pharmacokinetic assessments were performed
      on day 1 and on or around day 14. Glycyrrhizin levels were determined by high
      performance liquid chromatography. The mean (+/- SD) volume of distribution at
      steady state on day 1 in the 80-, 160-, 200-, and 240-mg groups were 67 +/- 11,
      62 +/- 13, 54 +/- 7, and 66 +/- 8 mL/kg, respectively. The respective terminal
      elimination half-lives on day 1 were 7.7 +/- 2.8, 10.1 +/- 1.4, 9.0 +/- 2.3, and
      8.6 +/- 2.1 hours. The area under the curve (AUC) increased linearly with doses <
      or =200 mg (r = 0.67; P < 0.001). No significant differences between day 1 and
      day 14 were found in any dose group, with the exception of AUC in the 200-mg
      group, which was significantly higher on day 14 compared with day 1 (P = 0.03).
      Comparing the European and Japanese data, the mean (+/- SD) AUC was 289 +/- 244
      microg/h per mL for the former and 402 +/- 372 microg/h per mL for the latter;
      the half-life was 8.2 +/- 2.6 versus 8.8 +/- 9.0 hours; and the total clearance
      was 7.6 +/- 3.6 versus 8.5 +/- 5.7 mL/h per kg. Thus our pharmacokinetic data are
      comparable to those from Japan. Glycyrrhizin's pharmacokinetics are linear up to
      200 mg. Drug accumulation is seen after 2 weeks of treatment with 200 mg
      administered 6 times/wk.

PMID- 10645756
TI  - Outcomes of prospective drug-use review of beta-agonist inhaler use in an elderly
      Medicaid population.
AB  - In 1990 Congress mandated that all state Medicaid programs implement both
      retrospective and prospective drug-use review (DUR). Nearly a decade later,
      implementation of prospective DUR (ProDUR) remains incomplete, and few of the
      implemented systems have been rigorously evaluated. This study was undertaken to
      analyze the impact of ProDUR screening of beta-agonist inhaler use in the
      Maryland Medicaid program from 1994 through 1996. The study used a
      pre/postcomparison series cohort design with data from Maryland, Georgia, and
      Iowa. Regression analysis was used to control for population differences between
      states in the year before the ProDUR intervention. The analysis used Medicaid and
      Medicare enrollment and claims data to select the study cohorts, assess exposure
      to the ProDUR intervention, develop patient risk profiles, and tabulate rates of
      adverse clinical outcomes for each subject. The study compared incidence rates
      for adverse outcomes for 2 1/2 years after implementation of the beta-agonist
      screens in Maryland, Georgia, and Iowa. Descriptive time plots and regression
      models were used to test the hypothesis that ProDUR screening reduces the
      incidence of adverse effects associated with misuse of beta-agonist inhalers. The
      study end points included 10 clinical outcomes related to therapeutic duplication
      and drug-drug interactions involving beta-agonist inhaler use by elderly
      individuals with chronic lung disease. No significant changes in the incidence of
      these outcomes could be linked to ProDur screening.

PMID- 10645757
TI  - Development of the Smoking Cessation Quality of Life questionnaire.
AB  - This paper describes the development of the Smoking Cessation Quality of Life
      (SCQoL) questionnaire, a self-reported measure designed to quantify the impact of
      smoking cessation on perceived functioning and well-being in adults. In addition
      to incorporating the Medical Outcomes Study 36-Item Short-Form Health Survey (SF
      36) as a generic core, the SCQoL contains 5 multi-item cessation-targeted scales:
      social interactions, self-control, sleep, cognitive functioning, and anxiety. The
      draft SCQoL was developed through a series of focus groups and was pilot-tested
      in a sample of 101 adults. Respondents were predominantly male (59.2%), with a
      mean (SD) age of (48.6) (12.7) years and a mean (SD) smoking history of 29.3
      (14.7) years. Of the respondents, 76.5% identified themselves as current smokers
      and 23.5% indicated that they were former smokers. The majority of former smokers
      (82.6%) reported being abstinent for > or =2 weeks. Multivariate analysis of
      variance was used to compare scale scores between smokers and former smokers who
      had been abstinent for > or =2 weeks. Former smokers reported significantly
      higher scores than did current smokers on 3 of 8 SF-36 scales and 3 of 5
      cessation-targeted scales (P < 0.05). In no case did current smokers report
      significantly higher scale scores than did former smokers. The internal
      consistency reliability of the SCQoL scales ranged from 0.68 to 0.96, exceeding
      0.70 on 12 of 13 scales. These findings provide preliminary evidence for the
      reliability and construct validity of the SCQoL.

PMID- 10645758
TI  - Medical costs of managed care in patients with type 2 diabetes mellitus.
AB  - The main objective of this study was to analyze the principal treatment cost
      drivers in patients with type 2 diabetes mellitus in a managed care setting. The
      study used retrospective integrated (linked) medical and pharmacy claims data for
      the calendar year 1995. The data were obtained from, and in cooperation with, the
      Hawaii Medical Service Association, Honolulu, Hawaii. The medical claims data
      included paid claims for services and procedures for diabetes and commonly
      associated comorbidities. Claims and associated costs for pharmacotherapy
      administered to the patient population were recorded in the pharmacy data.
      Patients aged > or =65 years were excluded because Medicare claims were
      unavailable for the type 2 diabetic population. The sample used in this study
      included 5171 patients. An ordinary least squares regression model was employed
      to identify principal cost drivers among the identified cohort to the managed
      care system. Independent variables in the analysis consisted of the presence or
      absence of a number of commonly observed comorbidities associated with diabetes
      mellitus (hypertension, hyperlipidemia, cardiovascular diseases, congestive heart
      failure, renal disorders, retinopathy, neurologic disorders, and any cardiac or
      noncardiac comorbidity combinations), pharmacologic therapy variables (insulin,
      oral medication, or both), a number of significant events (hospitalization,
      dialysis, hemoglobin A1c testing, and eye examination), patient enrollment
      category (fee-for-service vs a capitated system), and patient age and sex. The
      dependent variable was the natural logarithm of total medical costs of treatment
      for diabetes and commonly observed comorbidities. Results showed that among
      comorbidity variables, the 3 largest treatment cost drivers for patients with
      type 2 diabetes were the presence of neurologic disorders, renal disorders, and
      any comorbidity combination (cardiac or noncardiac or both), in decreasing order
      of significance. Similarly, higher costs of treatment were associated with
      episodes of hospitalization, use of antidiabetic medication, dialysis services,
      and hemoglobin A1c testing. Whether the patient was being treated under a
      capitated provider payment system or a fee-for-service system did not have any
      significant impact on the medical costs of diabetes-related treatment. Age was
      positively associated with these costs, indicating that older patients were more
      likely to incur higher costs to the system. The overall explanatory power of the
      model was 40%. In summary, unless diabetes is properly managed and glucose levels
      monitored, some component of an integrated health system (hospital vs pharmacy)
      necessarily bears financial risk. An understanding of the underlying cost
      distribution for a chronic disease could help in targeting interventions,
      integrating disease-management services, and managing the formal structure of the
      health plan being considered.

PMID- 10645759
TI  - Modeling the impact of treatment options in genital warts: patient-applied versus
      physician-administered therapies.
AB  - With the availability of new patient-applied treatments for genital and perianal
      warts, medical providers, physician groups, and health systems are reassessing
      the role of physician-administered therapies. Two key questions are: how cost
      effective are physician- versus patient-administered therapies and, given patient
      preferences for the convenience and privacy associated with the latter therapies,
      which of the 2 presently available treatments-imiquimod and podofilox-is most
      appropriate? The purpose of this article is to examine, from the perspective of
      the health care purchaser, these questions and to undertake a pharmacoeconomic
      analysis of the direct cost-effectiveness of therapy options, given targets being
      set for the outcomes of genital warts therapy. The analysis employs a synthetic,
      decision-modeling framework in which data on sustained clearance and the direct
      costs of treatment are drawn from both clinical studies and previous studies on
      the resources used to support treatment. Once targets are set-and it is proposed
      here that physicians should aim for at least a 50% sustained clearance rate for
      genital warts--it becomes clear that in cost per sustained clearance terms,
      imiquimod, as first-line therapy, is the most cost-effective intervention. If we
      compare imiquimod with podofilox as first-line therapy (with cryotherapy as the
      second-line option), the cost per sustained clearance for the imiquimod treatment
      sequence is $1367 compared with the podofilox-initiated sequence of $1508.

PMID- 10645760
TI  - Drug use and prescribing problems in the community-dwelling elderly: a study of
      three state Medicaid programs.
AB  - This paper describes a study of drug use and drug-related problems in community
      dwelling elderly (> or =65 years) Medicaid recipients in Maryland, Iowa, and
      Washington from 1989 through 1996. A claim-by-claim review of Medicaid
      prescriptions was conducted to detect 5 types of prescribing problems (dose,
      duration of therapy, duplicative therapy, drug-drug interactions, and
      contraindications or initial therapy). The study examined 8 drug categories:
      angiotensin-converting enzyme (ACE) inhibitors, antidepressant agents,
      antipsychotic agents, benzodiazepines, calcium channel blockers, digoxin,
      histamine2-receptor antagonists, and nonsteroidal anti-inflammatory drugs. The
      total number of persons with prescriptions in any of the 8 drug classes increased
      over the 8-year period, with the greatest growth in ACE inhibitors. Mean annual
      drug use per person declined in Maryland but increased in Washington and Iowa.
      Despite increasing use, the overall incidence of prescribing problems fell
      dramatically in all 3 states, particularly for dose- and duration-related
      criteria. Except in the area of drug-drug interactions, this elderly population
      was less likely to have received a prescription falling outside commonly accepted
      drug utilization review criteria for 8 major drug classes in 1996 than in 1989.

PMID- 10645761
TI  - Donepezil use in managed Medicare: effect on health care costs and utilization.
AB  - Donepezil is one of the first effective and well-tolerated medications approved
      for the treatment of Alzheimer's disease (AD). This study examined the impact of
      donepezil on the costs of AD in a multisite managed care organization between
      January 1, 1996, and March 31, 1998. A pretreatment/posttreatment study was
      conducted using retrospective medical and prescription claims data for 70
      individuals with AD and related dementias who were prescribed donepezil. The
      outcomes of interest were costs during the pretreatment and posttreatment phases,
      which were categorized as medical, prescription, and combined costs. Per diem
      costs were adjusted for differences in the duration of follow-up. We found that
      median per diem medical costs were $1.22 lower in the posttreatment phase than in
      the pretreatment phase (P = 0.02). Moreover, posttreatment costs were reduced in
      6 of 7 service settings, with median per diem savings of $0.77 in outpatient care
      (P = 0.002) and $0.65 in office visits (P < 0.001). In the posttreatment phase,
      the median per diem costs for prescriptions and all claims combined were higher
      by $2.59 (P < 0.001) and $2.11 (P = 0.04), respectively. Donepezil treatment was
      associated with a decrease in medical costs, particularly in the outpatient
      components of health care. However, overall costs were increased due to the
      higher costs of medication. Further pharmacoeconomic studies are needed to
      determine the exact impact of acetylcholinesterase-inhibitor therapy on the
      overall costs of care for individuals with dementia.

PMID- 10645762
TI  - Gene delivery to human hematopoietic progenitor cells to address inherited
      defects in the erythroid cellular lineage.

PMID- 10645763
TI  - Ex vivo expansion of hematopoietic stem cells.

PMID- 10645764
TI  - A comparative study of the generation of dendritic cells from mobilized
      peripheral blood progenitor cells of patients undergoing high-dose chemotherapy.
AB  - Immunization with ex vivo-generated, tumor antigen-loaded dendritic cells (DC)
      has been proposed as a strategy for reducing relapses following high-dose
      chemotherapy, but the ideal time and method for obtaining DC progenitors are
      unknown. We determined the percentage yield, phenotype, and function of DC
      generated over 7 days in GM-CSF and IL-4-supplemented, serum-free medium from
      PBMC obtained from breast cancer and lymphoma patients at the time of their
      initial presentation for transplant, cytokine or chemotherapy plus cytokine
      mobilized leukapheresis, and following granulocyte recovery from high-dose
      chemotherapy. The median yield of large dendritic-like cells as a percentage of
      the starting number of PBMC was similar for all the mobilization strategies
      (11.6%-13.8%) studied and at all time points (9.9%-12.7%), except the yield was
      lower from the pretherapy, unmobilized peripheral blood (6.3%). The phenotype of
      the generated cells was similar for the various mobilization procedures, and
      there were no differences in allostimulatory function of the DC from any of the
      groups. We conclude that functional DC may be generated equally well from
      mobilized PBPC and PBPC obtained after high-dose chemotherapy.

PMID- 10645765
TI  - Adeno-associated virus 2-mediated transduction and erythroid lineage-restricted
      expression from parvovirus B19p6 promoter in primary human hematopoietic
      progenitor cells.
AB  - Human parvovirus B19 gene expression from the viral p6 promoter (B19p6) is
      restricted to primary human hematopoietic cells undergoing erythroid
      differentiation. We have demonstrated that expression from this promoter does not
      occur in established human erythroid cell lines in the context of a recombinant
      parvovirus genome (Ponnazhagan et al. J Virol 69:8096-8101, 1995). However,
      abundant expression from this promoter can be readily detected in primary human
      bone marrow cells (Wang et al. Proc Natl Acad Sci USA 92:12416-12420, 1995;
      Ponnazhagan et al. J Gen Virol 77:1111-1122, 1996). In the present studies, we
      investigated the pattern of expression from the B19p6 promoter in primary human
      bone marrow-derived CD34+ HPC undergoing differentiation into myeloid and
      erythroid lineages. CD34+ cells were transduced with recombinant adeno-associated
      virus 2 (AAV) vectors containing the beta-galactosidase (lacZ) gene under the
      control of the following promoters/enhancers: the cytomegalovirus promoter (vCMVp
      lacZ), B19p6 promoter (vB19p6-lacZ), B19p6 promoter with an upstream erythroid
      cell-specific enhancer element (HS-2) from the locus control region (LCR) from
      the human beta-globin gene cluster (vHS2-B19p6-lacZ), and the human beta-globin
      gene promoter with the HS-2 enhancer (vHS2-beta p-lacZ). Transgene expression was
      evaluated either 48 h after infection or following erythroid differentiation in
      vitro for 3 weeks. Whereas high-level expression from the CMV promoter 48 h after
      infection diminished with time, low-level expression from the B19p6 and the beta
      globin promoters increased significantly following erythroid differentiation.
      Furthermore, in HPC assays, there was no significant difference in the level of
      expression from the CMV promoter in myeloid or erythroid cell-derived colonies.
      Expression from the B19p6 and the beta-globin promoters, on the other hand, was
      restricted to erythroid cell colonies. These data further corroborate that the
      B19p6 promoter is erythroid cell-specific and suggest that the recombinant AAV
      B19 hybrid vectors may prove useful in gene therapy of human hemoglobinopathies
      in general and sickle cell anemia and beta-thalassemia in particular.

PMID- 10645766
TI  - Expression of beta-globin in primary erythroid progenitors of beta-thalassemia
      patients using an SV40-based gene delivery system.
AB  - SV40-based vectors are very efficient in gene delivery into human hematopoietic
      cells. In the present work, we investigated the expression of constructs carrying
      the human beta-globin gene that were delivered as beta-globin pseudovirions.
      Expression studies were performed by RNA analysis of primary human erythroid
      progenitors cultivated from peripheral blood of beta(0)-thalassemia patients who
      are unable to produce normal beta-globin RNA. This erythroid culture system
      recapitulates in vitro the process of growth, differentiation, and maturation of
      authentic erythroid precursors. The progenitors were induced to differentiate by
      the addition of erythropoietin (EPO). Five days later, the cells were infected
      with pseudovirions containing the normal beta-globin gene, and RNA was harvested
      on day 8. The results showed significant levels of normal beta-globin gene mRNA.
      A small DNA fragment derived from the 5'-region of the HSII element of the human
      beta-globin locus control region (LCR) enhanced expression of the linked beta
      globin gene 20-30-fold. Normal beta-globin mRNA expression was in direct
      correlation to the multiplicity of infection. These studies suggest the potential
      feasibility of using the beta-globin delivery system for gene therapy of beta
      thalassemia.

PMID- 10645767
TI  - Endogenous erythroid and megakaryocytic colony formation in serum-free, cytokine
      free collagen gels.
AB  - We studied the suitability of collagen-based semisolid medium for assay of
      endogenous erythroid colony formation performed in myeloproliferative disorders.
      Bone marrow (BM) mononuclear cells (MNC) from 103 patients suspected of having
      polycythemia vera (PV, 76 patients) or essential thrombocythemia (ET, 27
      patients) were grown in collagen-based, serum-free, cytokine-free semisolid
      medium. Colony analysis at day 8 or 10 showed that this collagen assay is
      specific, as endogenous growth of erythroid colonies was never observed in
      cultures of 16 healthy donors and 6 chronic myelogenous leukemia (CML) patients.
      Endogenous erythroid colony formation was observed in 53.3% of patients suspected
      of PV, with only 15.4% of positive cultures for patients with 1 minor PV
      criterion and 72% (p = 0.009) of positive cultures for patients with > or =2
      minor or 1 major PV criterion. Similarly, endogenous growth of erythroid colonies
      was found in 44.4% of patients suspected of ET, with 31.6% of positive cultures
      for patients with 1 ET criterion versus 75% for patients with > or =2 ET
      criteria. In addition, we found that in collagen gels, tests of erythropoietin
      (EPO) hypersensitivity in the presence of 0.01 or 0.05 U/ml of EPO and tests of
      endogenous colony-forming units-megakaryocyte (CFU-MK) formation cannot be used
      to detect PV or ET, as these tests were positive for, respectively, 21.4% and 50%
      of healthy donors and 83% and 50% of CML patients. A retrospective analysis
      suggests that collagen assays are more sensitive than methylcellulose assays to
      assess endogenous growth of erythroid colonies. In summary, serum-free collagen
      based colony assays are simple and reliable assays of endogenous growth of
      erythroid colonies in myeloproliferative diseases. They also appear to be more
      sensitive than methylcellulose-based assays.

PMID- 10645768
TI  - Ex vivo expansion of CD34+ umbilical cord blood cells in a defined serum-free
      medium (QBSF-60) with early effect cytokines.
AB  - To investigate the clinically applicable conditions that support substantial
      expansion of both primitive and more mature hematopoietic cells of umbilical cord
      blood (UCB) for transplantation in adults, enriched CD34+ cells from 8 fresh UCB
      samples and 4 expanded UCB products were cultured in defined serum-free medium
      (QBSF-60) in the presence of a cytokine combination of SCF, Flt-3-ligand (FL),
      thrombopoietin (TPO), IL-3 for up to 2 weeks. Fresh medium with cytokines was
      supplemented or exchanged at day 4, day 7, and day 10. The proliferative response
      was assessed at day 7, day 10, and day 14 by evaluating the following parameters:
      nucleated cell (NC), clonogenic progenitors (colony-forming unit-granulocyte
      macrophage [CFU-GM], burst-forming unit-erythrocyte [BFU-E], CFU-GEMM, and high
      proliferative potential colony-forming cell [HPP-CFC]), immunophenotypes (CD34+
      cells and CD34+ subpopulations), and LTCIC. Simultaneously numerical expansion of
      various stem/progenitor cells, including primitive CD34+CD38-HLA-DR-
      subpopulation and LTCIC, CD34+ cells, and clonogenic progenitors to mature
      nucleated cells, were continuously observed during the culture. An average 103.32
      +/- 71.37 x 10(6) CD34+ cells (range 10.12 x 10(6)-317.9 x 10(6)) could be
      obtained from initial 1.72 +/- 1.13 x 10(6) UCB CD34+ cells after 10-14 days
      cultured under the described conditions. Sufficient CD34+ cells (>50.0 x 10(6))
      for transplantation in adults would be available in all but one UCB collections
      after 10-14 days expansion. The expanded CD34+ cells sustained most of the in
      vitro characteristics of initial unmanipulated CD34+ cells, including clonogenic
      efficiency (of both primitive and committed progenitors), the proportion of
      CD34+CD38-HLA-DR- subpopulation, and the expansion potential. Initial addition of
      IL-3 to the cocktail of SCF + FL + TPO had positive effects on the expansion of
      both primitive and, especially, the more mature hematopoietic cells. It
      accelerated the expansion speed and shortened the optimal culture time from 14
      days to 10 days. These results indicated that our proposed short-term culture
      system, consisting of QBSF-60 serum-free medium with a simple early acting
      cytokine combination of SCF + FL + TPO, could substantially support simultaneous
      expansion of various stem/progenitor cell populations involved in the different
      phases of engraftment. It would be a clinically applicable protocol for ex vivo
      expansion of CD34+ UCB cells.

PMID- 10645769
TI  - Stem cell transplantations in patients with malignant lymphoma: costs in a Dutch
      university hospital in the period 1984-1995.
AB  - In the past 15 years, perspectives on treatment of patients with relapsed non
      Hodgkin's lymphoma have changed. This has had important consequences for the
      costs of treatment. We conducted a retrospective study comparing the costs of
      four different treatment modalities in a university hospital in The Netherlands.
      The first group of patients received an autologous bone marrow transplantation
      (ABMT) and was kept in reverse barrier nursing. Their average total treatment
      costs amounted to US$26,539. Patients in the second group also received an ABMT
      but stayed on the normal hematology ward. The total average treatment costs for
      this group were US$20,806. In the third group, patients were transplanted with
      whole blood. Their average total treatment costs amounted to US$17,000. Patients
      in the fourth group received transplantation of autologous PBPC and their average
      total treatment costs were US$14,205. The decline in costs over time was mainly
      due to shorter hospitalization, less blood transfusions, and less parenteral
      nutrition. These factors also likely led to an improvement in patients' quality
      of life. The results of this study show that the progression in stem cell
      transplantation (SCT) techniques has been accompanied by significant benefits for
      patients and a decrease in costs.

PMID- 10645770
TI  - Induction of endothelial cell chemotaxis by sphingosine 1-phosphate and
      stabilization of endothelial monolayer barrier function by lysophosphatidic acid,
      potential mediators of hematopoietic angiogenesis.
AB  - Angiogenesis, the formation of new blood vessels, is an important component of
      restoration of hematopoiesis after BMT, but the mediators involved in
      hematopoietic angiogenesis have not been identified. We examined the influence of
      the lipid growth factors, phosphatidic acid (PA), lysophosphatidic acid (LPA),
      and sphingosine 1-phosphate (S1P), on several angiogenic properties of
      endothelial cells, including migration and stabilization of vascular barrier
      integrity. In a previous study, PA was found to disrupt the permeability of
      established endothelial monolayers, an early event in the angiogenic response
      that liberates cells for subsequent mobilization. In the present study, both PA
      and LPA weakly induced the chemotactic migration of endothelial cells from an
      established monolayer. The chemotactic response induced by PA and LPA was similar
      in intensity to that observed with optimal levels of the known protein
      endothelial cell chemoattractants, basic fibroblast growth factor (bFGF) and
      vascular endothelial growth factor (VEGF). A markedly greater chemotactic
      response was effected by nanomolar concentrations of S1P, indicating that this
      platelet-derived factor plays an important role in a key aspect of angiogenesis,
      chemotactic migration of endothelial cells. The chemotactic response to S1P was
      completely inhibited by preincubation of endothelial cells with antisense
      oligonucleotides to the high-affinity S1P receptor, Edg-1. In addition,
      chemotaxis of endothelial cells to S1P was inhibited by preincubation of cells
      with specific inhibitors of tyrosine kinases, but inhibitors of
      phosphatidylinositol 3' kinase had little effect. Finally, LPA effectively
      stabilized endothelial monolayer barrier function, a late event in angiogenesis.
      Thus, the phospholipid growth factors, PA, S1P, and LPA, display divergent and
      potent effects on angiogenic properties of endothelial cells and angiogenic
      differentiation of endothelial cells potentially act in tandem to effectively
      induce neovascularization. These mediators may thus exert important roles in
      restoration of hematopoiesis, as they facilitate blood vessel formation at sites
      of transplanted stem cells, allowing the progeny of engrafted progenitors to move
      from marrow sinusoids to the peripheral vasculature.

PMID- 10645771
TI  - Double immunoenzymatic APAAP staining for the detection of leukemia-associated
      immunophenotypes.
AB  - Detection of unusual or aberrant cell immunophenotype with flow cytometry is the
      basis for the immunologic recognition of minimal residual disease (MRD) in
      patients with acute leukemia (AL). In this study, we have shown that the double
      immunocytochemical alkaline phosphatase antialkaline phosphatase (APAAP) staining
      technique also makes possible the detection of leukemic cells with unusual
      (leukemic) combinations of antigens (ULCA) both at diagnosis and during follow-up
      of patients with ULCA+ AL. The applicability of double APAAP was analyzed on bone
      marrow (BM) samples obtained from 12 patients (8 with AML, 3 with ALL, and 1 with
      undifferentiated acute leukemia [AUL]) randomly chosen from a larger group of 22
      ULCA+ patients treated at our center in a 3-year period (22% observed ULCA+ AL
      frequency). The percentages of ULCA+ BM cells before chemotherapy were in the
      range of 5%-60%, which dropped to 0%-7% in 10 patients who achieved remission
      (range 0%-7%, p < 0.01). However, these cells could also be found 60 days after
      the initiation of therapy, ranging from 0%-2% of all nucleated cells. In 2 of 10
      patients who achieved remission, 2% ULCA+ BM cells were found on days 35 and 60
      after initiation of chemotherapy, and this finding was followed by relapse on
      days 110 and 270. However, the other 8 patients remained in remission despite
      positive finding of ULCA+ BM cells ranging from 0.2%-2% on at least one occasion.
      In 2 patients with AML FAB-M3 and cytomorphologic remission, the finding of ULCA+
      cells by double APAAP correlated with the molecular finding of PML/RARalpha
      junction. These results indicate that double APAAP staining can identify leukemic
      cells in samples with a cytomorphologic pattern consistent with remission, but
      its applicability in detection of MRD awaits additional studies on a larger
      number of patients with ULCA+ AL.

PMID- 10645772
TI  - T lymphocyte transduction with herpes simplex virus-thymidine kinase (HSV-tk)
      gene: comparison of four different infection protocols.
AB  - In this study, we assessed the efficiency of T lymphocyte transduction with a
      retroviral vector carrying the herpes simplex virus thymidine kinase (HSV-tk) and
      neomycin phosphotransferase (neo) genes by four different protocols: standard
      supernatant infection, supernatant infection plus centrifugation steps,
      supernatant infection on fibronectin fragment-coated wells, and cocultivation.
      After retrovirus-mediated gene transfer of tk-neo in PHA/IL-2-stimulated primary
      T lymphocytes and G418 selection, T cells retained their proliferative activity,
      alloresponsiveness, ability to produce and to respond to IL-2, and ganciclovir
      (gcv)-specific sensitivity. When the four different transduction techniques were
      compared, no significant differences were seen in terms of cellular viability,
      proliferation capacity, and immunophenotyping. tk gene expression was the same in
      all transduced selected populations, as indicated by gcv sensitivity.
      Transduction efficiency was evaluated by semiquantitative PCR. Using the standard
      supernatant infection method, the rate of infection was extremely low (<5%).
      After adding the centrifugation step or performing supernatant infection on
      fibronectin fragment-coated wells, PCR analysis showed a 30%-40% rate of
      transduced cells. After infection by cocultivation, the rate of transduced cells
      was 30%-40%. These results demonstrate that supernatant infection plus
      centrifugation, supernatant infection on fibronectin fragment-coated wells, and
      cocultivation methods provide equivalent rates of transduced cells. The lack of
      reproducibility and safety indicates that cocultivation is not suitable for
      clinical studies. In our view, supernatant infection plus centrifugation is
      easier to perform than using fibronectin fragments, and it is currently the
      optimal method for clinical studies when large quantities of T lymphocytes are
      being processed.

PMID- 10645773
TI  - The alterations of the activities of coagulation inhibitors and fibrinolytic
      factors in stored cord blood could affect the yield of progenitor cells during
      processing.
AB  - We assessed the changes in the activities of hemostatic variables by the storage
      temperature and time interval between collection and separation of cord blood
      (CB) and analyzed their relationship with the yield of progenitor cells during
      processing. Total nucleated cell (TNC) and CD34+ cell counts were significantly
      higher in the CB stored at ambient temperature than at 4 degrees C. The
      significant loss of TNC and CD34+ cells continued to 24 h after collection in CB
      stored at 4 degrees C, but loss of TNC began only after 24 h at ambient
      temperature. There were no changes in the plasma activities of antithrombin III
      (ATIII) and plasminogen. The activity of protein C was decreased significantly
      until 24 h after collection, particularly in CB stored at 4 degrees C. The
      activity of alpha2-antiplasmin was decreased until 24 h in CB stored at 4 degrees
      C and from 24 h in CB stored at ambient temperature. These data suggest that the
      alterations in the activities of coagulation inhibitors and fibrinolytic factors
      could be an important factor in coagulability, particularly in CB stored at 4
      degrees C compared to ambient temperature, and also affect the yield of
      progenitor cells in processed CB.

PMID- 10645774
TI  - Tissue factor assays as diagnostic tools for cancer? Correlation between urinary
      and monocyte tissue factor activity.
AB  - Monocyte and urinary tissue factors (mTF and uTF) are both elevated in a number
      of pathologic conditions, including cancer. This study validates the best
      available uTF and mTF assays as diagnostic tools for cancer and examines if uTF
      levels reflect monocyte activation. Using kinetic chromogenic assays for uTF and
      mTF (measured on fresh resting cells [baseline], unstimulated cells, and
      lipopolysaccharide [LPS]-stimulated cells), we assessed TF levels in normal
      individuals, surgical controls, and patients with benign and malignant diseases.
      Each benign disease group was stratified as inflammatory or noninflammatory.
      Controls and benign noninflammatory results were indistinguishable. The malignant
      and inflammatory groups showed raised uTF levels over controls (p < 0.001). mTF
      levels differ similarly. For mTF and uTF assays, there was no significant
      difference between the malignant and inflammatory groups. The relative operating
      characteristic (ROC) curve plots sensitivity against false positive rate (1
      specificity) for all possible cutoff values of a diagnostic test. Assay
      performance is assessed as the area under the curve (AUC). The ROC curve for the
      uTF assay displayed both sensitivity and specificity for cancer, the AUC being
      0.83. Of the three mTF levels, LPS-stimulated cells gave the optimum curve (AUC =
      0.71). uTF showed a weak to moderate association with mTF levels but correlated
      best and was statistically significant when compared with levels in the LPS
      stimulated cells. uTF represents an intrinsic, kidney-derived, physiologic
      concentration rather than that of preactivated or postactivated monocytes. In
      conclusion, both uTF and LPS-stimulated mTF levels showed sensitivity and
      specificity in detecting cancer and inflammatory diseases. However, the two forms
      of TF appear to be independently derived.

PMID- 10645775
TI  - Delivery of antisense oligonucleotides and plasmid DNA with various carrier
      agents.
AB  - A series of cationic nucleic acid carriers was evaluated for their ability to
      deliver pLuc plasmid DNA or a 2'-O-methyl-oligoribonucleoside phosphorothioate,
      ON-705. Oligonucleotide delivery and its antisense function were assayed by a
      recently developed assay based on alternative splicing of modified luciferase pre
      mRNA (Kang et al., 1998). This assay scores only the nuclear and sequence
      specific antisense activity of the oligonucleotides. The results show that the
      efficiencies of delivery of plasmid DNA and oligonucleotides by the tested
      carriers, with the exception of Exgene and Lipofectamine, differed markedly. The
      efficiency of the delivery of ON-705 oligonucleotide was reduced by 70%-90% for
      all carriers, except Effectene, in culture media containing 8% fetal bovine
      serum. Interestingly, the efficiency of delivery of the ON-705-Effectene complex
      increased with serum concentrations of up to 30%.

PMID- 10645776
TI  - Antisense oligodeoxynucleotide of glyceraldehyde-3-phosphate dehydrogenase gene
      inhibits cell proliferation and induces apoptosis in human cervical carcinoma
      cell lines.
AB  - Tumor cells characteristically exhibit an increased rate of glycolysis. A higher
      level of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA was found in human
      uterine cervical cancers. This study was designed using GAPDH antisense
      oligodeoxynucleotide (ODN) phosphorothioate (PS) to evaluate how alterations of
      GAPDH expression in human cervical carcinoma could influence growth inhibition
      and induction of apoptosis. Northern blot analyses revealed that the levels of
      GAPDH gene expression were strongly elevated in three cervical carcinoma cell
      lines (HeLa, CUMC-3, and CUMC-6) compared with normal cervical tissue. Reverse
      transcription-polymerase chain reaction (RT-PCR) showed that expression of the
      GAPDH gene was inhibited by 10 microM of GAPDH antisense ODN in all three cell
      lines. Western blot analysis showed that the levels of GAPDH protein were
      decreased or absent after GAPDH antisense ODN treatment for 12 days in cultured
      cervical carcinoma cell lines. Cervical carcinoma cell lines exposed to GAPDH
      antisense ODN showed reduced cellular proliferation, which was accompanied by
      reduced colony-forming efficiency. This effect of GAPDH antisense ODN on cultured
      carcinoma cells was associated with the apoptotic process, including increased
      DNA fragmentation. These results suggest that future gene therapy using antisense
      ODN directed against cervical cancer-specific GAPDH mRNA might be another
      therapeutic tool against human uterine cervical carcinomas.

PMID- 10645777
TI  - Polyethylenimine but not cationic lipid improves antisense activity of 3'-capped
      phosphodiester oligonucleotides.
AB  - Lipofectin, which is a mixture of neutral lipid with a cationic lipid, has been
      widely used to enhance cellular delivery of phosphorothioate, 2'-sugar-modified,
      and chimeric antisense oligonucleotides. Phosphodiester oligonucleotides
      delivered with Lipofectin usually do not elicit antisense activity probably
      because cationic lipid formulations do not sufficiently protect unmodified
      oligonucleotides from nuclease degradation. We show that a cationic polymer,
      polyethylenimine (PEI), improves the uptake and antisense activity of 3'-capped
      20-mer and 12-mer antisense phosphodiester oligonucleotides (PO-ODN) targeted to
      different regions of Ha-ras mRNA and to the 3'-untranslated region (3'-UTR) of C
      raf kinase. In contrast, PEI, which forms a very stable complex with the 20-mer
      phosphorothioate oligonucleotide (PS-ODN), does not enhance its antisense
      activity. Using fluorescently labeled carriers and ODN, we show that PEI-PS-ODN
      particles are very efficiently taken up by cells but PS-ODN is not dissociated
      from the carrier. Our results indicate that carrier-ODN particle size and
      stability and ODN release kinetics vary with the chemical nature of the ODN and
      the carrier being transfected into the cells. The very low cost of PEI compared
      with cytofectins and the increased affinity for target mRNA and decreased
      affinity for proteins of PO-ODN compared with PS-ODN make the use of PEI-PO-ODN
      very attractive.

PMID- 10645778
TI  - Triple helix formation inhibits DNA gyrase activity.
AB  - The goal of this work was to examine the effect of triple helix-forming
      oligonucleotides on a gyrase target region and on the activity of the enzyme.
      Using melting temperature measurements and gel mobility shift analysis, it was
      found that modified oligonucleotides can form a triple helix along the 29
      nucleotide region of a 32-bp duplex representing part of the gyrase DNA-target
      sequence of the 162-bp fragment from pBR322. Triplex formation with this target
      region has been achieved at pH 7.5 by using a synthetic oligonucleotide in which
      cytosine was replaced by the C-nucleoside of 2-aminopyridine. The results of the
      enzymic experiments in vitro with the 162-bp fragment demonstrated that the
      cleavage reaction mediated by gyrase can be efficiently inhibited by the triplex
      forming oligonucleotide modified with 2-aminopyridine. A possible inhibitory
      mechanism is discussed.

PMID- 10645779
TI  - Formation of nucleosomes does not suppress interaction of a DNA fragment with an
      alkylating derivative of a pyrimidine oligonucleotide.
AB  - Oligonucleotide derivatives capable of binding to specific nucleic acids are
      considered as potential therapeutic agents, exerting their action at the level of
      genome functioning (Helene, 1991; Knorre et al., 1993). A straightforward
      approach to targeting DNA is based on using oligonucleotides capable of binding
      to oligopurine-oligopyrimidine sequences by formation of triple-strand
      structures. We report results of experiments on sequence-specific chemical
      modification of a 490-bp fragment of pfosCAT plasmid, containing the promoter
      segment of the c-fos gene using 4-(N-2-chloroethyl-N-methylamino)
      benzylphosphamide derivatives of a homopyrimidine 14-mer oligonucleotide. It was
      shown that in both the free DNA and the DNA involved in nucleosome structure,
      reaction occurred with similar efficiency at the target guanosine residue G404.

PMID- 10645780
TI  - A mutation-independent therapeutic strategem for osteogenesis imperfecta.
AB  - Given the genetically heterogeneous nature of many dominantly inherited
      disorders, it will be imperative to design mutation-independent therapeutic
      strategies to circumvent such heterogeneity. Intragenic polymorphism represents a
      genomic resource that may be harnessed in the development of allele-specific
      mutation-independent therapeutics. A hammerhead ribozyme, Rzpol1a1, selectively
      cleaves a common single-nucleotide polymorphism (SNP) of the human COL1A1
      transcript (heterozygosity frequency of 2 pq = 0.4032, from Hardy-Weinberg
      equilibrium). One SNP variant contains a hammerhead ribozyme cleavage site, and
      the other does not. Kinetic evaluation shows Rzpol1a1 to be both specific and
      extremely efficient in vitro. Thus, a single efficient ribozyme has been
      characterized that should be valuable in the development of a gene therapy
      suitable for up to 1 in 5 dominant-negative osteogenesis imperfecta (OI)
      patients, where over 150 different mutations have been identified to date. Given
      the increasing characterization of intragenic SNP, it is predicted that such a
      mutation-independent strategy, based on selective silencing of mutant alleles at
      SNP, may become increasingly important in future genomics-driven drug development
      for many heterogeneous dominant disorders and complex traits.

PMID- 10645781
TI  - Antisense therapeutics in oncology: points to consider in their clinical
      evaluation.
AB  - Novel therapeutics in oncology stem from a rational design of drugs targeting
      selective pathways that stimulate and maintain tumor cell growth. Many of these
      agents are cytostatic in action and also have a limited toxicity profile.
      However, some can be cytotoxic if they successfully modulate molecular pathways
      of apoptosis, such as bcl-2. This article discusses points to consider in the
      design of one class of cytostatic agents, antisense therapy. Our purpose is to
      stimulate designs that answer the question specifically with regard to proof-of
      concept, and the concepts proposed should be viewed as ideas in development
      rather than firm recommendations.

PMID- 10645782
TI  - Porous balloon delivery of S-dC28 does not prevent restenosis in the porcine
      coronary artery model of balloon injury.
AB  - Phosphorothioate (PS) oligodeoxynucleotides (ODN) inhibit vascular smooth muscle
      cell proliferation through antisense and G-quartet aptameric mechanisms. PS-ODN
      such as the cytidine homopolymers, have been demonstrated to have non-G-quartet,
      nonsequence-specific inhibitory effects in a rat carotid balloon injury model of
      neointimal proliferation. We sought to test the efficacy of S-dC28, a cytidine
      homopolymer lacking G-quartets, on neointimal proliferation in the porcine
      coronary artery model of balloon injury. A total of 23 animals (11 controls, 12
      treated) were subjected to balloon injury in a coronary artery, followed by
      infusion of control solution or S-dC28 via porous balloon, the Scimed Dispatch
      Coronary Infusion Catheter. After a mean interval of 49 days, the animals were
      killed, and the target coronary segments were examined histologically. S-dC28 did
      not significantly inhibit neointimal formation. Fluorescein isothiocyanate (FITC)
      labeled S-dC28 was present in the intima and media immediately after
      administration but was present mainly within the adventitia 3 hours after
      administration. S-dC28, when delivered by a Scimed Dispatch Coronary Infusion
      Catheter (Maple Grove, MN), did not significantly affect neointimal proliferation
      after balloon injury in a porcine coronary artery model.

PMID- 10645783
TI  - 1998 Distinguished Lecture: biomechanics of the microcirculation, an integrative
      and therapeutic perspective.
AB  - The microcirculation, integratively speaking, is distensible and contains 40%-50%
      of the total blood volume. Other than the mission of mass transport, the
      microcirculation and its endothelial cells have the role of regulation, signal
      transduction, proliferation, and repair. In this article, the emphasis is on the
      integrative role of the microcirculation on circulatory control and its
      therapeutic role on blood volume compensation. To introduce this topic, I first
      summarize the morphometry data on the blood volume distribution in the coronary,
      pulmonary, and mesentery circulation and then review the methodology developed in
      my laboratory to assess the microvascular volume change or shift of blood volume
      from microcirculation to macrocirculation. Evidence obtained through these
      studies indicates that the microcirculation can play a more important role as a
      reservoir to compensate for blood volume loss than the venous system. Reanalysis
      of published data also indicates that microvascular pooling, not hypovolemia, is
      the likely factor causing endotoxin shock or hypotension for hemodialysis
      patients. Understanding of the role of the microcirculation could lead to more
      effective diagnosis of cardiovascular deficiency and therapy for hypotension or
      low cardiac output with intervention through the microcirculation.

PMID- 10645784
TI  - Generation of an anatomically based geometric coronary model.
AB  - A discrete anatomically accurate finite element model of the largest six
      generations of the coronary arterial network is developed. Using a previously
      developed anatomically accurate model of ventricular geometry the boundaries of
      the coronary mesh are defined from measured epicardial coronaries. Network
      topology is then generated stochastically from published anatomical data. Spatial
      information is added to this topological data using an avoidance algorithm
      accounting for global network geometry and optimal local branch angle properties.
      The generated vessel lengths, radii and connectivity are consistent with the
      published studies and a relativity even spatial distribution of vessels within
      the ventricular mesh is achieved. The local finite element coordinates of the
      coronary nodes within the ventricular mesh are calculated such that the coronary
      geometry can be recalculated within a deformed ventricular mesh.

PMID- 10645785
TI  - Numerical simulation of oxygen mass transfer in a compliant curved tube model of
      a coronary artery.
AB  - Arterial wall transport of blood-borne oxygen is essential for superficial
      arterial wall metabolism. The unique geometry and hemodynamics of coronary
      arteries curved over the heart surface may alter the O2 transport pattern and
      lead to abnormalities of O2 tension at the inner wall (epicardial surface) which
      may contribute to atherogenesis. This study focused on O2 transport in a
      compliant model of a curved coronary artery. A three-dimensional finite element
      model with moving boundaries was setup to simulate physiological flow and O2
      transport in coronary arteries. The full Navier-Stokes equations and the coupled
      conservation of species equation were solved simultaneously for typical coronary
      flow characteristics (aspect ratio=10, diameter variation=6%, mean Reynolds
      number= 150, unsteadiness parameter=3, Schmidt number=2,700). The results
      indicate a large difference in O2 wall flux (Sherwood number [Sh]) between the
      outside (Sh about 55) and inside (Sh about 2) walls and imply that O2 transport
      at the inner wall could be limited by the fluid phase.

PMID- 10645786
TI  - Experimental investigation of the steady flow downstream of the St. Jude
      bileaflet heart valve: a comparison between laser Doppler velocimetry and
      particle image velocimetry techniques.
AB  - This study investigates turbulent flow, based on high Reynolds number, downstream
      of a prosthetic heart valve using both laser Doppler velocimetry (LDV) and
      particle image velocimetry (PIV). Until now, LDV has been the more commonly used
      tool in investigating the flow characteristics associated with mechanical heart
      valves. The LDV technique allows point by point velocity measurements and
      provides enough statistical information to quantify turbulent structure. The main
      drawback of this technique is the time consuming nature of the data acquisition
      process in order to assess an entire flow field area. Another technique now used
      in fluid dynamics studies is the PIV measurement technique. This technique allows
      spatial and temporal measurement of the entire flow field. Using this technique,
      the instantaneous and average velocity flow fields can be investigated for
      different positions. This paper presents a comparison of PIV two-dimensional
      measurements to LDV measurements, performed under steady flow conditions, for a
      measurement plane parallel to the leaflets of a St. Jude Medical (SJM) bileaflet
      valve. Comparisons of mean velocity obtained by the two techniques are in good
      agreement except for where there is instability in the flow. For second moment
      quantities the comparisons were less agreeable. This suggests that the PIV
      technique has sufficient temporal and spatial resolution to estimate mean
      velocity depending on the degree of instability in the flow and also provides
      sufficient images needed to duplicate mean flow but not for higher moment
      turbulence quantities such as maximum turbulent shear stress.

PMID- 10645787
TI  - Microwave spectroscopy of myocardial ischemia and infarction. 1. Experimental
      study.
AB  - The purpose of this study was to assess whether physiologic changes in canine
      myocardium due to coronary blood flow reduction, ischemia, and infarction could
      be detected by changes in dielectrical properties. Measurements were made in the
      frequency range of 0.2-6.0 GHz. Percent coronary blood flow reduction was
      linearly related to the decrease in epsilon" at frequencies of 0.2 GHz(R =-0.997)
      and 1.1 GHz (R =- 0.9987). In 2 h occlusions, increased conduction time in the
      infarct area mirrored the temporal changes in dielectrical properties. In 2-week
      old infarctions differences, in epsilon' between normal and central infarct zones
      were statistically significant (P<0.05) for all frequencies. For epsilon" the
      differences between normal and central infarct zones were also significant for
      all frequencies (P<0.01). In conclusion, coronary blood flow reduction, ischemia,
      and infarction can be detected by microwave spectroscopy and potentially can form
      the basis for a physiologic microwave tomographic imaging system.

PMID- 10645788
TI  - Microwave spectroscopy of myocardial ischemia and infarction. 2. Biophysical
      reconstruction.
AB  - The proposed dielectrical relaxation model of the myocardium in the microwave
      spectrum has been verified both on test solutions and on normal canine
      myocardium. Furthermore, the model was utilized to reconstruct the changes in
      tissue properties (including myocardial bulk resistance and water content)
      following myocardial acute ischemia and chronic infarction. It was shown that the
      reconstructed myocardial resistance and water content correlate dynamically with
      the process of the development of acute myocardial ischemic injury. In chronic
      cases the reconstructed resistance and water content of infarcted myocardium are
      significantly different from that of normal myocardium: the resistance is lower
      and water content is higher than in normal myocardium.

PMID- 10645789
TI  - Recurrent patterns of atrial depolarization during atrial fibrillation assessed
      by recurrence plot quantification.
AB  - The aim of this study was to determine the presence of organization of atrial
      activation processes during atrial fibrillation (AF) by assessing whether the
      activation sequences are wholly random or are governed by deterministic
      mechanisms. We performed both linear and nonlinear analyses based on the cross
      correlation function (CCF) and recurrence plot quantification (RPQ),
      respectively. Recurrence plots were quantified by three variables: percent
      recurrence (PR), percent determinism (PD), and entropy of recurrences (ER). We
      recorded bipolar intra-atrial electrograms in two atrial sites during chronic AF
      in 19 informed subjects, following two protocols. In one, both recording sites
      were in the right atrium; in the other protocol, one site was in the right
      atrium, the other one in the left atrium. We extracted 19 episodes of type I AF
      (Wells' classification). RPQ detected transient recurrent patterns in all the
      episodes, while CCF was significant only in ten episodes. Surrogate data
      analysis, based on a cross-phase randomization procedure, decreased PR, PD, and
      ER values. The detection of spatiotemporal recurrent patterns together with the
      surrogate data results indicate that during AF a certain degree of local
      organization exists, likely caused by deterministic mechanisms of activation.

PMID- 10645790
TI  - Simultaneous regulation of hemodynamic and anesthetic states: a simulation study.
AB  - A model predictive control strategy to simultaneously regulate hemodynamic and
      anesthetic variables in critical care patients is presented. A nonlinear canine
      circulatory model, which has been used to study the effect of inotropic and
      vasoactive drugs on hemodynamic variables, has been extended to include propofol
      pharmacokinetics and pharmacodynamics. Propofol blood concentration is used as a
      measure for depth of anesthesia. The simulation model is used to design and test
      the control strategy. The optimization-based model predictive control strategy
      assures that constraints imposed on the drug infusion rates are met. The
      physician always remains "in the loop" and serves as the "primary controller" by
      making propofol blood concentration setpoint changes based on observations about
      anesthetic depth. Results are shown for three simulated cases: (i) congestive
      heart failure, (ii) postcoronary artery bypass, and (iii) acute changes in
      hemodynamic variables.

PMID- 10645791
TI  - Cyanide increases reduction but decreases sequestration of methylene blue by
      endothelial cells.
AB  - The mechanisms of endothelial cell transplasma membrane electron transport (TMET)
      have not been completely identified. Redox probes such as methylene blue (MB) can
      be useful tools, but the complexity of their disposition upon exposure to the
      cells can hinder interpretation. For example, MB is reduced on the cell surface
      by TMET, but after entering the cell in reduced form, it is reoxidized and
      sequestered within the cell. We developed a method to separately quantify the
      reduction and reoxidation rates such that it can be determined whether a
      metabolic inhibitor such as cyanide affects the reduction or oxidation process.
      MB was introduced at the inlet to a column filled with endothelial cell covered
      beads either as a short 12 s injection (bolus) or a long 45 min infusion (pulse),
      and its effluent concentration was measured as a function of time. The cells
      extracted 56% of the MB from the bolus, but only 41% during the pulse steady
      state. In the presence of cyanide, these extractions increased to 70% and
      decreased to 4%, respectively. Mathematical model results support the
      interpretation that these paradoxical effects on bolus and pulse extractions
      reflect the differential effects of cyanide on extracellular reduction and
      intracellular oxidation, i.e., cyanide increased the reduction rate from 7.3 to
      13.0 cm s-1 X 10(-5) and decreased the oxidation rate from 1.09 to 0.02 cm s-1 X
      10(-3). Cyanide also increased intracellular NADH by almost eight times,
      suggesting that TMET is sensitive to the cell redox status, i.e., NADH is a
      direct or indirect electron source. The cyanide-induced decrease in sequestration
      indicates a cyanide-sensitive intracellular oxidation mechanism. The results also
      demonstrate the potential utility of this approach for further evaluation of
      these endothelial redox mechanisms.

PMID- 10645792
TI  - Fractal characteristics of end-expiratory lung volume in anesthetized rats.
AB  - To test the possibility that the variations in end-expiratory lung volume (EEV)
      might exhibit long-term correlation, we calculated the Hurst exponent H for EEV
      in anesthetized rats during sustained positive and negative transrespiratory
      pressure (i.e., (PTRP) and (NTRP), correspondingly) using the dispersional
      analysis method. In nine vagi-intact rats, H for EEV was 0.551+/-0.051 (mean+/
      std) and 0.641 +/-0.076 (mean+/-std) with PTRP and NTRP, respectively. In both
      cases H was significantly different from those obtained after random shuffling of
      the original time series, indicating a positive long-term correlation in EEV.
      Also H with NTRP was significantly greater than that with PTRP (P=0.015). In six
      vagotomized rats, there was no significant difference in H for EEV between NTRP
      and PTRP. We demonstrated that long-term correlation is present in EEV. We
      inferred that the stimulation of vagal afferents could change the fractal
      property in EEV since different vagal pulmonary receptors are activated by PTRP
      and NTRP. Although the exact mechanisms for the fractal behavior are unknown, the
      results suggest that interaction of the pulmonary mechanoreceptor activity with
      the central respiratory pattern generator might contribute to the observed long
      term correlation.

PMID- 10645793
TI  - Nitric oxide, superoxide, and peroxynitrite effects on the insulin secretion and
      viability of betaTC3 cells.
AB  - The onset of insulin-dependent diabetes mellitus (IDDM) is often associated with
      the infiltration of pancreatic cells by macrophages. Upon activation, macrophages
      release nitric oxide (NO) and superoxide (O2). These species or their reactive
      intermediates can be cytoxic, mutagenic, or carcinogenic. Previous studies have
      reported both positive and negative effects of extracellularly generated NO on
      insulin secretion and viability of pancreatic cells. Inherent problems of several
      previous studies assessing the effects of NO on insulin secretion include
      unsteady state NO concentration exposures and the generation of other potentially
      damaging species. In this study, these problems were eliminated by using a
      modified experimental system in which NO delivery was achieved via diffusion
      across a gas-permeable tube and O2 delivery was maintained using an enzymatic
      reaction. The delivery rates were constant, leading to steady state
      concentrations of NO and O2 in the experimental system. Based on reaction
      kinetics, a model was developed to predict NO, O2, and peroxynitrite (ONOO-)
      concentrations during the experiment. This study showed that NO, O2, and ONOO- at
      predicted concentrations as high as 2.8 microM, 0.25 microM, and 0.1 nM,
      respectively, do not affect the insulin secretion rates of betaTC3 pancreatic
      cells over short times.

PMID- 10645794
TI  - Quantitative analysis of adhesion-mediated cell migration in three-dimensional
      gels of RGD-grafted collagen.
AB  - Adhesion-mediated migration is required in a number of physiological and
      pathological processes. A further quantitative understanding of the relationship
      between cell migration and cell-substratum adhesiveness may aid in therapeutic or
      tissue engineering applications. The aim of this work was to quantify three
      dimensional cell migration as a function of increasing cell-substratum
      adhesiveness within reconstituted collagen gels. Cell-substratum adhesiveness was
      controlled by grafting additional adhesive peptides containing the well
      characterized arginine-glycine-aspartic acid sequence to collagen. The three
      dimensional migration of multiple individual cells was tracked in real time in an
      automated fashion for extended periods. Cell displacements were statistically
      analyzed and fit to a correlated persistent random walk model to estimate root
      mean-square speed, directional persistence time, and random motility coefficient.
      Based on model parameter estimates, cell speed was found to be a monotonically
      decreasing function of increasing substratum adhesiveness, while the directional
      persistence time and random motility coefficient exhibited a biphasic dependence,
      with maximum values at approximately intermediate concentrations of grafted
      adhesive peptide and hence intermediate cell-substratum adhesiveness. In
      conclusion, these studies suggest an optimal adhesiveness for three-dimensional
      random migration, consistent with previous studies on two-dimensional surfaces.
      However, the maximum in random motility corresponded to a maximum in directional
      persistence, not in cell speed.

PMID- 10645795
TI  - A simple assay for evaluating inhibitors of proteoglycan-ligand binding.
AB  - Proteoglycans, once thought to primarily serve as structural components of
      extracellular matrix, are now being focused on for their role in tissue and cell
      regulation, particularly angiogenesis. Many growth factors, notably the
      fibroblast growth family (FGF) which now numbers 19 members, bind to heparin and
      heparan sulfate proteoglycans and this binding has been shown to have a
      significant impact on the availability and activity of these growth factors.
      Proteoglycans can serve as both temporal and spatial regulators and effective
      inhibitor design may depend on disruption of these interactions. We have
      developed a simple assay for evaluating small inhibitors of proteoglycan-ligand
      binding. The assay is based on cell-free incubation of the reactants and
      filtration across a cationic membrane. Conditions were established that allow one
      to semiquantitatively determine binding constants for both direct proteoglycan as
      well as soluble inhibitor affinity. The assay has been demonstrated using a model
      heparan sulfate proteoglycan preparation (perlecan from cultured bovine
      endothelial cells) and FGF-2. Protamine sulfate, sucrose octasulfate, and heparin
      were analyzed as model inhibitor molecules. This type of assay may have wide
      application as a fast and easy screening tool for small potential agonists and
      antagonists of proteoglycan-protein interactions.

PMID- 10645796
TI  - Modulation of paired-pulse responses in the dentate gyrus: effects of normal
      maturation and vigilance state.
AB  - This study examined the effect of normal development and vigilance state on the
      modulation of dentate granule cell activity in the freely moving rat at 15, 30,
      and 90 days of age across three vigilance states: quiet waking, slow-wave sleep,
      and rapid eye movement sleep. Using paired-pulse stimulation, the paired-pulse
      index (PPI) was obtained for the dentate evoked field potentials elicited by the
      stimulation of the medial perforant path. Although significant differences in PPI
      values were observed during development, no significant vigilance state related
      changes were obtained. Preweaning infant rats, i.e., 15-day old, exhibited
      significantly less early (interpulse intervals, IPI= 20-50 ms) and late (IPI =
      300-1,000 ms) inhibition, and less facilitation (IPI = 50-150 ms) when compared
      to the 90-day old adult rats during all three vigilance states. PPI values
      obtained from the 30-day old group fell intermediate between the 15- and 90-day
      old animals. These changes in PPI values provide a quantitative measure of
      changes in the modulation of dentate granule cell excitability during normal
      maturation. They can now can be used to evaluate the impact of various insults,
      such as prenatal protein malnutrition or neonatal stress, on hippocampal
      development.

PMID- 10645797
TI  - Introducing 'cancer genetics report' as a new section in JJCO: dawn of post
      sequencing age of human genome project.

PMID- 10645798
TI  - Non-traditional study designs in the analysis of gene-environment interactions.

PMID- 10645799
TI  - Prognosis after salvage chemotherapy for locally unresectable recurrent squamous
      cell carcinoma of the head and neck.
AB  - BACKGROUND: For locally unresectable recurrent squamous cell carcinoma of the
      head and neck, we investigated two salvage chemotherapy regimens as second-line
      chemotherapy. In our preliminary study, we observed that both regimens were
      active. In the present study we analyzed the prognosis of these patients.
      METHODS: Twenty-six patients with recurrent advanced head and neck cancer, were
      treated with one of two new regimens as second-line chemotherapy. The PEM regimen
      consisted of cisplatin 60 mg/m2 on day 1, etoposide 40 mg/m2 on days 1, 2 and 3
      and mitomycin-C 7 mg/m2 on day 1. The long CF regimen consisted of cisplatin 8
      mg/m2 on days 1-5, 8-12, 15-19 and 22-26 and 5-fluorouracil 300 mg/m2 as a 24 h
      infusion or oral administration of tegaful-uracil (UFT-E) 400 mg/m2 on days 1-28.
      Survival curves were calculated using the Kaplan-Meier method and compared by the
      log rank test. RESULTS: Of 24 patients evaluable for response, three complete
      responses (CR) and seven partial responses (PR) were achieved, with an overall
      response rate of 42%. Myelosuppression was the major side effect. One year
      survival was 100% for CR, 0% for PR and 20% for minor response (MR). All patients
      who failed to achieve a CR died within 12 months, except one patient with MR.
      CONCLUSION: Our data suggest that with these salvage regimens survival benefit
      was demonstrated only in CR patients.

PMID- 10645800
TI  - Local-regional control by conventional radiotherapy according to tumor volume in
      patients with squamous cell carcinoma of the pharyngolarynx.
AB  - BACKGROUND: To estimate the effect of tumor volume on local-regional control of
      pharyngolaryngeal cancer by radiotherapy (RT). METHODS: Definitive RT for 48
      patients with squamous cell carcinoma of the lateral wall of the oropharynx,
      pyriform sinus and supraglottic larynx was reviewed. Tumor volume was estimated
      from computed tomography and it was expressed as the diameter of a sphere the
      volume of which is equal to the primary tumor (Td) and sum of the volumes of
      metastatic adenopathies (Nd). All patients received > or =60 Gy (median 66 Gy) to
      the gross tumor by conventional fractionation with or without chemotherapy.
      RESULTS: A median period of follow-up for survivors was 32.7 months (range, 12.4
      68.6). The 2 year local control rate for T1/2 (n = 30) and T3/4 (n = 18) patients
      was 72 and 65%, respectively (P= 0.966), however, the rates for Td < 4 cm tumors
      (n = 37) and Td > or = 4 cm tumors (n = 11) were significantly different (80% vs
      27%, P < 0.001). The 2 year regional control rates for Nd < 3 cm lesions (n = 29)
      and Nd > or = 3 cm (n = 19) lesions were 85 and 42%, respectively (P < 0.001).
      The 2 year ultimate regional control rates for N2/3 disease with Nd < 4 cm (n =
      11) and Nd > or = 4 cm (n = 11) were 100 and 42%, respectively (P = 0.004).
      CONCLUSIONS: Conventional radiotherapy may allow organ preservation and ultimate
      local control in patients with Td < 4 cm and Nd < 4 cm disease, but larger volume
      tumors should be considered candidates for the most intensive chemoradiotherapy.

PMID- 10645801
TI  - Postoperative radiation therapy for completely resected invasive thymoma:
      prognostic value of pleural invasion for intrathoracic control.
AB  - BACKGROUND: Optimal management of postoperative radiation therapy for completely
      resected invasive thymoma remains controversial. This study was conducted to
      assess the efficacy of postoperative mediastinal irradiation in patients with
      completely resected invasive thymoma. METHODS: Between 1981 and 1996, 21 patients
      with completely resected invasive thymoma were referred for postoperative
      mediastinal irradiation. The distribution of Masaoka stages was stage II in 14
      patients and stage III in seven patients. Nine patients had pleural invasion by
      the tumor. Thirteen patients were treated with a localized field and eight were
      treated with the whole mediastinal field with boost. The total dose to the
      primary tumor was 40-61 Gy (median: 52 Gy). The median follow-up time of the 16
      living patients was 67 months (range: 29-202 months). RESULTS: The 5- and 10-year
      actuarial overall survival rates in all patients were both 77%. Relapses were
      observed in five patients, in all of whom the sites of the first relapse involved
      pleural dissemination. There were no relapses within the irradiated field in any
      of the 21 cases. Five of nine (56%) patients with pleural invasion had relapse of
      pleural dissemination, while 0 of 12 (0%) patients without pleural invasion had
      relapse. In univariate analysis, pleural invasion had a statistically significant
      impact on intrathoracic control (P = 0.01). CONCLUSIONS: The results indicated
      that pleural invasion might be predictive of pleural-based relapse for completely
      resected invasive thymoma. In patients with pleural invasion, mediastinal
      irradiation alone might be insufficient to avoid pleural-based relapse even after
      complete resection.

PMID- 10645802
TI  - Lower urinary tract function after intra-arterial chemotherapy with concurrent
      pelvic radiotherapy for invasive bladder cancer.
AB  - BACKGROUND: Intra-arterial chemotherapy with concurrent pelvic radiotherapy as a
      bladder-sparing regimen for invasive bladder cancer is highly promising for
      selected patients. However, lower urinary tract function after this treatment has
      not been fully investigated. METHODS: The urodynamic effects of intra-arterial
      chemotherapy with concurrent pelvic radiotherapy were retrospectively evaluated
      in 14 patients with organ-confined invasive bladder cancer. The post-treatment
      urodynamic findings were compared with the pretreatment ones (n = 7), and a
      comparison was made between the serial urodynamic findings after the treatment in
      another seven patients who were able to undergo the pretreatment urodynamic study
      (UDS). RESULTS: The median follow-up period up to the latest UDS was 34 months.
      Of the 14 patients, the latest UDS revealed some storage dysfunctions in 11 (79%)
      and some emptying dysfunctions in three (23%). Uninhibited detrusor contraction
      and decreased bladder compliance were recorded in 29 and 43% at the pretreatment
      UDS and approximately 50-60 and 20-60% in the serial follow-up studies,
      respectively (n = 7). Impaired detrusor contractility lasted in one patient. In
      the seven patients without the pretreatment UDS, decreased maximum cystometric
      capacity and decreased compliance were recorded in approximately 50-60 and 20-60%
      at the serial UDS, respectively. Detrusor contractility was aggravated in one
      patient and completely lost in one with time. CONCLUSIONS: The urodynamic
      findings indicate that the bladder-sparing regimen might result in perpetuating
      the lower urinary tract dysfunctions due to invasive bladder cancer itself and/or
      transurethral surgery and might injure the infrasacral autonomic nerves and the
      bladder itself.

PMID- 10645803
TI  - Alternating combination chemotherapy COP (cyclophosphamide, vincristine,
      prednisone) and MP (melphalan, prednisone) in multiple myeloma: a multicenter
      phase II study (JCOG8906). Lymphoma Study Group of the Japan Clinical Oncology
      Group.
AB  - BACKGROUND: The main form of cytotoxic treatment for multiple myeloma (MM) is
      conventional dose chemotherapy at present. METHOD: Between November 1989 and
      December 1991, a multicenter phase II study of alternating conventional dose
      combination chemotherapy (CCT) with COP (cyclophosphamide, vincristine,
      prednisone) and MP (melphalan and prednisone) to evaluate its clinical usefulness
      for overt MM patients was conducted by the Lymphoma Study Group of the Japan
      Clinical Oncology Group (JCOG). RESULTS: Eighty-one previously untreated patients
      were enrolled in the study. For 69 eligible patients, the response rate was 50.7%
      [95% confidence interval (CI) 38.4-63.0%]. The median survival time was 38.5 (95%
      CI 32.0-44.4) months. The survival rate at 3 and 5 years was 50.7 and 27.3%,
      respectively. Grade 4 toxicity by the criteria of the World Health Organization
      consisted of anemia in eight patients, leucocytopenia in three, cardiac in one
      and hepatic in two, but there was no treatment-related death. CONCLUSION: The COP
      MP regimen for overt MM is thought to be one of the effective CCTs according to
      the results of the present phase II study.

PMID- 10645804
TI  - Detection of gene-environment interaction by case-only studies.
AB  - BACKGROUND: The detection of gene-environment interaction can provide important
      clues not only for resolving biological mechanisms underlying diseases, but also
      for disease prevention. The newly introduced case-only study was compared with
      traditional case-control study in terms of statistical power to detect
      significant gene-environment interaction. METHODS: Odds ratios for interaction
      were calculated in the framework of case-control study and case-only study
      separately, by an unconditional logistic model. Hypothetical data with 200 cases
      and 200 or 400 controls and real published data derived from four cancer case
      control studies of genotype and smoking were used for the comparisons. RESULTS:
      Although odds ratio estimates for interaction were the same, 95% confidence
      intervals were narrower in case-only studies than in case-control studies.
      Similarly, there were no substantial differences in point estimates for
      interaction in four real cancer case-control studies between the two study
      designs, but the confidence intervals were narrower with the case-only study.
      CONCLUSIONS: Although the case-only study does not provide odds ratios for
      exposure or genotype alone, it is very useful for the detection of interaction,
      especially for screening purposes.

PMID- 10645805
TI  - Undifferentiated carcinoma with lymphoid infiltration of the esophagus: a case
      report.
AB  - This paper reports a surgically treated case of undifferentiated carcinoma with
      lymphoid infiltration of the esophagus. Histologically, most of the tumor
      consisted of undifferentiated carcinoma (non-small cell type) with lymphoid
      infiltration and a small portion showed features of poorly differentiated
      squamous cell carcinoma. Carcinoma with lymphoid infiltration in the stomach,
      breast or nasopharynx has a good prognosis, but in the esophagus this
      histological type is extremely rare and its characterization is unclear. This is
      only the sixth report to date of undifferentiated carcinoma with lymphoid
      infiltration of the esophagus.

PMID- 10645806
TI  - Palliative radiation therapy for brain metastases from endometrial carcinoma:
      report of two cases.
AB  - Although endometrial carcinoma is a common invasive neoplasm of the female
      genital tract, brain metastases are extremely rare and few reports exist of their
      treatment with radiation therapy. We report two patients with manifest clinical
      signs of brain metastases from endometrial carcinoma on computed tomography (CT)
      or magnetic resonance imaging (MRI). These two patients had multiple brain
      metastases, with widespread dissemination late in the course of the disease and
      received palliative whole-brain radiation therapy to a total dose of 50 Gy in 25
      fractions (case 1) and 30 Gy in 10 fractions (case 2). After radiation therapy,
      improvement of neurological function (NF) was observed in both patients. The
      duration of improvement of NF was 9 weeks in case 1 and 12 weeks in case 2. The
      patients died 5 months and 3 months after the diagnosis of brain metastases,
      respectively. In these two cases, palliative radiation therapy was effective in
      improving the quality of the remaining lifetime and appears to be the best
      treatment for brain metastases from endometrial carcinoma as well as those
      frequently seen from other primaries.

PMID- 10645807
TI  - Gestational choriocarcinoma whose responsible pregnancy was a complete
      hydatidiform mole identified by PCR analysis with new sequence tagged site
      primers.
AB  - We report a case where the pregnancy responsible for a gestational
      choriocarcinoma was not the antecedent pregnancy or the second normal term
      delivery, but a complete hydatidiform mole that had advanced to clinically
      invasive mole. This responsible pregnancy was identified by polymerase chain
      reaction analysis (PCR). PCR analysis was performed by using five new sets of
      sequence-tagged site (STS) primers on four chromosomes (chr. 1, D1S225; chr. 3,
      D3S1744; chr. 12, D12S1090; chr. 18, D18S849 and D18S877). The constitution of
      alleles of choriocarcinoma was shown to be almost identical with that of the
      husband on every marker. The allele patterns of choriocarcinoma on D3S1744 and
      D12S1090 were not observed with DNA from the patient. The band pattern
      originating from molar DNA was also identical with those of the husband and
      choriocarcinomas on D18S849 and D1S225.

PMID- 10645808
TI  - Hemoperitoneum is an initial presentation of recurrent granulosa cell tumors of
      the ovary.
AB  - Ovarian sex cord-stromal tumors account for less than 5% of all ovarian
      carcinoma, of which granulosa cell tumors account for 70%. These tumors have a
      propensity for indolent growth and late recurrence; they may even occur 25 years
      after initial treatment. We report a 44-year-old woman with hemoperitoneum (acute
      abdomen) after initial treatment 10 years earlier for granulosa cell tumor of the
      ovary. This case re-emphasizes the need for long-term follow-up in patients with
      stromal cell tumors of the ovary and considers the possibility of recurrence when
      presented with acute abdomen after conservative treatment.

PMID- 10645809
TI  - Germline p53 mutation in a case of Li-Fraumeni syndrome presenting gastric
      cancer.

PMID- 10645810
TI  - Japanese nerve-preserving techniques in surgery for cancer of the uterine cervix.

PMID- 10645811
TI  - Report of the sixth annual meeting of the Japan Society for Cancer Prevention.

PMID- 10645812
TI  - Prostatic levels of tocopherols, carotenoids, and retinol in relation to plasma
      levels and self-reported usual dietary intake.
AB  - This study evaluated how prostatic levels of antioxidants relate to plasma levels
      and self-reported usual dietary intake. Definition of these relations may aid in
      interpreting studies of antioxidant exposure and prostate cancer risk. Between
      July 1996 and April 1997, plasma and prostatic tissue levels of tocopherols,
      carotenoids, and retinol were measured in 47 men undergoing radical prostatectomy
      or transurethral prostatectomy at Loyola University Medical Center, Maywood,
      Illinois, and an affiliate hospital. Dietary intake was measured by using a 122
      item version of the Block Health Habits and History Questionnaire, and
      correlations were assessed with Pearson's coefficients. Prostatic levels of
      tocopherols and carotenoids (but not retinol) were significantly correlated with
      plasma levels (r= 0.31-0.56, p < 0.05-0.0001); the strongest correlations were
      associated with lycopene, beta-carotene, and gamma-tocopherol (0.56, 0.54, and
      0.52, respectively; p < 0.0001). Relative concentrations of tocopherols and
      carotenoids in prostate tissue were proportionate to those in plasma. No
      correlation between prostatic levels and reported dietary intake was observed (r
      = -0.09 to 0.16, p < not significant). Adjustment for energy intake, body mass
      index, and serum lipids did not impact these relations. These results suggest
      that plasma levels of tocopherols and carotenoids better reflect prostatic
      exposure than self-reported usual dietary intake.

PMID- 10645813
TI  - Prostate cancer and dietary carotenoids.
AB  - This population-based case-control study investigated associations between
      prostate cancer risk and dietary intake of the carotenoids beta-carotene and
      lycopene and their major plant food sources, including carrots, green leafy
      vegetables, and tomato-based foods. The study was carried out in Auckland, New
      Zealand, during 1996-1997 and recruited 317 prostate cancer cases and 480
      controls. The authors found that dietary intake of beta-carotene and its main
      vegetable sources was largely unassociated with prostate cancer risk, whereas
      intake of lycopene and tomato-based foods was weakly associated with a reduced
      risk. These results suggest that in contrast to the findings regarding many types
      of cancers, vegetables rich in beta-carotene are not protective against prostate
      cancer. However, lycopene from tomato-based foods was found to be associated with
      a small reduction in risk.

PMID- 10645814
TI  - Invited commentary: tomatoes, lycopene, and prostate cancer. How strong is the
      evidence?

PMID- 10645815
TI  - Prospective study of hepatitis B and C viral infections, cigarette smoking,
      alcohol consumption, and other factors associated with hepatocellular carcinoma
      risk in Japan.
AB  - This community-based prospective study examined the effects of viral infections
      and lifestyle habits on hepatocellular carcinoma (HCC) risk in Japan. A baseline
      survey was conducted for 981 males and 2,078 females in June 1992 and evaluated
      hepatitis B surface antigen, second-generation hepatitis C virus antibody, and
      history of cigarette smoking and habitual alcohol consumption. By March 1997, 14
      males and 8 females had been newly diagnosed with HCC. After controlling for
      gender and age by using the Cox model, the authors found that positivity for
      hepatitis B surface antigen (hazard ratio = 7.28, 95% confidence interval: 1.62,
      32.61; p < 0.01) and positivity for high-titer hepatitis C virus antibody (hazard
      ratio = 40.38, 95% confidence interval: 11.71, 139.21; p < 0.001) were
      significantly associated with HCC risk, although a history of smoking or alcohol
      consumption was not significantly related to risk. There was a significant
      interaction on an additive scale for the risk of HCC development between high
      titer hepatitis C virus antibody status and a history of smoking (p < 0.05) in
      spite of no significant interaction on a multiplicative scale. Although
      preventing the transmission of hepatitis viruses is most important for reducing
      the risk of HCC, intervention regarding lifestyle habits such as cigarette
      smoking should not go unheeded.

PMID- 10645816
TI  - Chinese food cooking and lung cancer in women nonsmokers.
AB  - Cigarette smoking cannot fully explain the epidemiologic characteristics of lung
      cancer in Taiwanese women, who smoke rarely but have lung cancer relatively
      often. In a previous study, the authors suspected that exposure to fumes from
      cooking oils was an important risk factor for lung cancer in Taiwanese women
      nonsmokers in the Republic of China. In a new case-control study conducted in
      1993-1996, they further explored the association of oil fumes with lung cancer in
      women. Two sets of controls were used concurrently. The subjects were 131
      nonsmoking incident cases with newly diagnosed and histologically confirmed
      primary carcinoma of the lung, 252 hospital controls hospitalized for causes
      unrelated to diseases of smoking, and 262 community controls; all controls were
      women nonsmokers matched by age and date of interview. Details on cooking
      conditions and habits were collected, in addition to other epidemiologic data.
      Lung cancer risk increased with the number of meals per day to about threefold
      for women who cooked these meals each day. The risk was also greater if women
      usually waited until fumes were emitted from the cooking oil before they began
      cooking (adjusted odds ratios = 2.0-2.6) and if they did not use a fume extractor
      (adjusted odds ratios = 3.2-12.2). These results suggest that a proportion of
      lung cancer may be attributable to the habit of waiting until the cooking oil has
      been heated to a high temperature before cooking the food.

PMID- 10645817
TI  - Health problems in teenage daily smokers versus nonsmokers, Norway, 1995-1997:
      the Nord-Trondelag Health Study.
AB  - Increased morbidity among teenage smokers has been reported, but specific current
      health problems and medication use other than of alcohol and narcotics have
      received less attention. The aim of this study was to examine the association
      between health problems and daily smoking in teenagers. Ninety percent of all
      teenagers attending junior high or high schools participated in a cross-sectional
      study conducted in Nord-Trondelag County, Norway, 1995-1997; included were 8,040
      students aged 13-18 years. Information on smoking habits, health problems,
      medication use, and use of health services was obtained in schools by self
      administered questionnaire and by interview. Fifty-five percent of boys and 57%
      of girls had tried smoking, and 9% and 11%, respectively, reported current daily
      smoking. When compared with boys and girls who had never smoked, daily smoking
      among both sexes and all age groups was associated with significantly poorer
      perceived health, respiratory symptoms, headache, neck and shoulder pain,
      stomachache, nausea, frequent heartbeats, nervousness/restlessness, and sleep
      problems. Daily smokers used more medications and health services. Daily smoking
      by adolescents is already associated with multiple somatic health problems.
      Whether or not the association is causal, daily smoking identifies a group of
      adolescents with health problems for whom preventive strategies should also
      include medical and social support.

PMID- 10645818
TI  - Population-based case-control study of amyotrophic lateral sclerosis in western
      Washington State. I. Cigarette smoking and alcohol consumption.
AB  - The associations of cigarette smoking and alcohol consumption with the risk of
      amyotrophic lateral sclerosis (ALS) were investigated in a population-based case
      control study conducted in three counties of western Washington State from 1990
      to 1994. Incident ALS cases (n = 161) were identified and were matched to
      population controls (n = 321) identified through random digit dialing and
      Medicare enrollment files. Conditional logistic regression analysis was used to
      compute odds ratios adjusted for age, gender, respondent type, and education. The
      authors found that alcohol consumption was not associated with the risk of ALS.
      Ever having smoked cigarettes was associated with a twofold increase in risk
      (alcohol-adjusted odds ratio (OR) = 2.0, 95% confidence interval (CI): 1.3, 3.2).
      A greater than threefold increased risk was observed for current smokers (alcohol
      adjusted OR = 3.5, 95% CI: 1.9, 6.4), with only a modestly increased risk for
      former smokers (alcohol-adjusted OR = 1.5, 95% CI: 0.9, 2.4). Significant trends
      in the risk of ALS were observed with duration of smoking (p for trend = 0.001)
      and number of cigarette pack-years (p for trend = 0.001). The finding that
      cigarette smoking is a risk factor for ALS is consistent with current etiologic
      theories that implicate environmental chemicals and oxidative stress in the
      pathogenesis of ALS.

PMID- 10645819
TI  - Population-based case-control study of amyotrophic lateral sclerosis in western
      Washington State. II. Diet.
AB  - The association of nutrient intake with the risk of amyotrophic lateral sclerosis
      (ALS) was investigated in a population-based case-control study conducted in
      three counties of western Washington State from 1990 to 1994. Incident ALS cases
      (n = 161) were identified and individually matched on age and gender to
      population controls (n = 321). A self-administered food frequency questionnaire
      was used to assess nutrient intake. Conditional logistic regression analysis was
      used to compute odds ratios adjusted for education, smoking, and total energy
      intake. The authors found that dietary fat intake was associated with an
      increased risk of ALS (highest vs. lowest quartile, fiber-adjusted odds ratio
      (OR) = 2.7, 95% confidence interval (CI): 0.9, 8.0; p for trend = 0.06), while
      dietary fiber intake was associated with a decreased risk of ALS (highest vs.
      lowest quartile, fat-adjusted OR = 0.3, 95% CI: 0.1, 0.7; p for trend = 0.02).
      Glutamate intake was associated with an increased risk of ALS (adjusted OR for
      highest vs. lowest quartile = 3.2, 95% CI: 1.2, 8.0; p for trend < 0.02).
      Consumption of antioxidant vitamins from diet or supplement sources did not alter
      the risk. The positive association with glutamate intake is consistent with the
      etiologic theory that implicates glutamate excitotoxicity in the pathogenesis of
      ALS, whereas the associations with fat and fiber intake warrant further study and
      biologic explanation.

PMID- 10645820
TI  - Does arsenic exposure increase the risk for circulatory disease?
AB  - Studies of residents in communities with high endemic concentrations of arsenic
      in drinking water suggest a deleterious effect on the circulatory system;
      however, studies among workers with high occupational exposures generally have
      shown either no or weak associations. This discrepancy could be a result of the
      healthy worker effect, including the healthy hire component and the healthy
      worker survivor effect (HWSE). Therefore, the authors conducted analyses of
      arsenic exposure in relation to circulatory disease mortality among 2,802 Tacoma,
      Washington, smelter workers by using 1) internal comparisons to control for the
      healthy hire effect and 2) the lagging method, adjustment for employment status,
      and the G-null test to control for the HWSE. Both lagging and adjustment for work
      status increased circulatory mortality rate ratios at all exposure levels, as
      compared with a baseline Poisson model. This excess mortality was limited to
      cardiovascular disease; no excess was observed for cerebrovascular disease. G
      null analyses suggested no adverse effect, but power was very limited for this
      analysis. Overall, these results may indicate that the HWSE obscures an effect of
      arsenic on circulatory disease. Since cardiovascular deaths constitute about one
      third of total mortality, small rate ratios translate into large numbers of
      excess deaths and, if causal, could be of wide public health significance.
      Further studies of arsenic exposure and cardiovascular disease are needed, and
      those conducted in occupational cohorts must control for the HWSE.

PMID- 10645821
TI  - Trends in epilepsy mortality in England and Wales and the United States, 1950
      1994.
AB  - The aim of this study was to analyze time trends in epilepsy mortality in England
      and Wales and the United States between 1950 and 1994. The authors calculated age
      and sex-specific epilepsy mortality rates for the nine quinquennia from 1950
      1954 to 1990-1994. Mortality rates were modeled as a function of age, period of
      death, and cohort of birth by using Poisson regression techniques. From 1950 to
      1994, there were more than 110,000 deaths from epilepsy in the two countries. The
      secular trends in mortality were similar for both sexes and in both countries.
      Among people younger than age 20 years, epilepsy mortality declined steeply after
      1950. For young and middle-aged adults, the rate of decline was lower. In the
      geriatric population, mortality declined between 1950 and 1974 but then
      increased. The Poisson model showed pronounced birth cohort effects. In the
      United States, epilepsy mortality fell with each successive birth cohort after
      1905. In England and Wales, there was a similar decline in birth cohort mortality
      after 1905 for women but not until after 1950 for men. The pronounced birth
      cohort effect supports explanations that focus on antenatal and developmental
      factors as the cause for the decline in epilepsy mortality in all but the oldest
      age groups between 1950 and 1994.

PMID- 10645822
TI  - Evaluation of simple indices of insulin sensitivity and insulin secretion for use
      in epidemiologic studies.
AB  - The metabolic characteristics of type 2 diabetes, insulin resistance, and
      diminished insulin secretion are costly to measure directly. To evaluate the
      utility of several simple indices derived from insulin and glucose measurements,
      the indices were examined from 1982 to 1997 with respect to correlation with more
      sophisticated measures of insulin sensitivity and secretion in Pima Indians in
      the Gila River Indian Community of Arizona. Ability to predict the incidence of
      diabetes in 1,731 persons was also examined. Indices were calculated from fasting
      and 2-hour glucose (G0, G120) and insulin (I0, I120) concentrations obtained
      during an oral glucose tolerance test. Fasting serum insulin concentration and
      the insulin sensitivity index (10(4)/(I0 x G0)) each showed a moderate
      correlation with the estimate of insulin sensitivity derived from the
      hyperinsulinemic-euglycemic clamp (absolute value r approximately 0.60). They
      also strongly predicted the incidence of diabetes (incidence rate ratio comparing
      the most and least insulin-resistant tertile groups approximately 3.0). Corrected
      insulin response (I120/(G120 x (G120 - 70))) was modestly correlated with insulin
      secretion as measured by an intravenous glucose tolerance test (r = 0.35).
      Impaired insulin secretion assessed by this index predicted incidence of
      diabetes, particularly after control for insulin sensitivity index (incidence
      rate ratio = 1.6). Thus, simple indices of insulin sensitivity and secretion may
      be reasonable surrogates for more sophisticated measures in epidemiologic
      studies.

PMID- 10645823
TI  - Self-collection of oral epithelial cell DNA under instruction from epidemiologic
      interviewers.
AB  - Oral epithelial cells provide an easily accessible source of germline DNA. Two
      methods for collection were compared in a 1992-1995 case-control study of oral
      cancer in Puerto Rico. One group of subjects (55 controls without oral cancer)
      collected oral rinse samples at home or work under the direction of a
      nonmedically trained interviewer ("self-collection"); the other group (94
      controls) participated in a clinic-based collection, which also included blood
      and urine samples, conducted by a medical technician ("clinic collection").
      Participation was higher for self-collection (98.2%) than for clinic collection
      (70.7%) (p < 0.001). DNA yields ranged from 2.0 to 204.5 microg (median, 25.9
      microg) and did not differ by collection method, although yields varied by
      interviewer among self-collected samples (p = 0.02). Success rates for polymerase
      chain reaction amplification of the ADH3, NAT1, and multiplex CYP1A1/GSTT1/GSTM1
      genotyping assays ranged from 76.4% (NAT1) to 98.2% (ADH3) for self-collected
      samples and were similar to those for clinic-collected samples (87.2-97.9%).
      Failure to amplify was associated with low DNA content (p = 0.015). Similar
      results were observed among cases (91 self-collected, 66 clinic collected),
      except that DNA yields did not vary by interviewer and a larger fraction (10.2%)
      of samples contained less than 5 microg of DNA, perhaps because of disease
      related oral impairment. Self-collection of oral epithelial DNA samples appears
      satisfactory and efficient for many epidemiologic studies.

PMID- 10645824
TI  - Re: "Epidemic hysteria: a review of the published literature".

PMID- 10645825
TI  - Re: "Syringe exchange and risk of infection with hepatitis B and C viruses".

PMID- 10645826
TI  - Re: "Attributable risk in practice".

PMID- 10645827
TI  - Variations in prudent laypersons' perceptions of the need for emergent medical
      care.
AB  - The objective of this study was to determine whether differences exist among
      distinct demographic groups' tendencies to view various medical symptoms as
      emergent in nature. A questionnaire containing six demographic questions and
      listing 29 common medical complaints was distributed to 306 respondents who
      agreed to participate; they were asked to indicate when (if at all) they would be
      likely to seek medical care for each problem. Overall, across the series of
      complaints, African American respondents desired statistically significantly more
      acute care than Caucasians. Those with a high school education or lower also
      wanted to be seen statistically significantly sooner for more symptoms than those
      with some college education or higher. We conclude that opinions as to the
      urgency of medical symptoms vary widely among demographic groups.

PMID- 10645828
TI  - The patient vs. caregiver perception of acute pain in the emergency department.
AB  - The assessment and management of acute pain is an essential part of care received
      in the emergency department (ED). This study was undertaken to measure how ED
      caregivers interpret and treat acute pain. A convenience cohort of 71 patients in
      a tertiary care teaching hospital were asked to rate their pain on arrival to the
      ED using a visual analog scale (VAS) and numerical rating scale (NRS). These
      ratings were compared with those given by their nurse and physician. Both
      physicians and nurses gave statistically significantly lower NRS and VAS pain
      ratings than those reported by the patients. Nurses' NRS pain ratings were found
      to be lower than physicians' ratings of the same patients. On chart review, no
      pain scale assessments were employed, and only one chart noted that a patient's
      pain had been relieved after treatment. Approximately half the patients (49%, n =
      35) felt on discharge from the ED that their pain had not been relieved. Pain
      assessment and treatment in the ED appears to be inadequate. The integration of
      pain assessment before and after treatment is essential in monitoring the
      effectiveness of pain management in the ED.

PMID- 10645829
TI  - A trial of etomidate for rapid sequence intubation in the emergency department.
AB  - A number of pharmacologic agents have been used for induction during rapid
      sequence intubation (RSI). Some of these agents may have adverse effects that can
      limit their use in certain clinical settings. This study was undertaken to
      determine the safety and utility of etomidate in patients with a range of
      underlying clinical conditions. Thirty-four patients underwent RSI in the
      emergency department (ED). Hemodynamic measurements and clinical assessments were
      recorded before and after intubation. The results suggest that etomidate is a
      safe and effective agent for use in a range of patients undergoing RSI in the ED.

PMID- 10645830
TI  - Emergency physician hiring practices: the effects of certain conditions on
      employability.
AB  - This study evaluated the impact of certain Emergency Physician (EP) conditions on
      hiring decisions by fellow EPs. An anonymous survey asked 255 Pennsylvania EPs to
      rate the likelihood of their voting to offer a position in each of six scenarios.
      Three scenarios consisted of EPs unable to work regular shifts because of
      periodic migraines, a sleep disorder, and periodic difficulty handling stress.
      The other scenarios involved an EP with a probable future pregnancy, a recovered
      alcoholic, and a healthy HIV-positive physician. Most respondents said they were
      unlikely to recommend hiring colleagues who disclose a disorder restricting their
      availability for regular shifts. EPs were generally tolerant of recovered
      alcoholics and plans for pregnancy leave, but nearly half had significant
      reservations regarding hiring HIV-positive peers. An understanding of which
      conditions negatively impact an EP's ability to obtain employment in Emergency
      Medicine may be useful in emergency medicine career counseling or in the process
      of obtaining disability coverage.

PMID- 10645831
TI  - Dorsal dislocation of the index carpometacarpal joint.
AB  - Dorsal dislocations of the index metacarpal are rare occurrences. A case is
      presented with an unusual mechanism of injury. Successful management included
      open reduction and internal temporary fixation of the involved joint.

PMID- 10645832
TI  - Central retinal vein occlusion due to hyperviscosity syndrome.
AB  - A 57-year-old man with no previous medical history entered the emergency
      department with 2 days of painless vision loss in the left eye. The patient was
      diagnosed with central retinal vein occlusion (CRVO) and admitted for treatment.
      Further work-up revealed that the cause of his CRVO was a hyperviscosity syndrome
      secondary to multiple myeloma. The patient received two rounds of plasmapheresis
      with slight recovery of vision and was discharged 28 days later.

PMID- 10645833
TI  - Electric injury, Part II: Specific injuries.
AB  - Electric injury can cause disruption of cardiac rhythm and breathing, burns,
      fractures, dislocations, rhabdomyolysis, eye and ear injury, oral and
      gastrointestinal injury, vascular damage, disseminated intravascular coagulation,
      peripheral and spinal cord injury, and Reflex Sympathetic Dystrophy. Secondary
      trauma from falls, fires, flying debris, and inhalation injury can complicate the
      clinical picture. Diagnostic and treatment considerations for electric injuries
      are described in this article, which is the second part of a three-part series on
      electric injuries.

PMID- 10645834
TI  - Acute tracheal rupture related to endotracheal intubation: case report.
AB  - Tracheal laceration is a rare complication of endotracheal intubation. We present
      a case of tracheal laceration after a simple prehospital tracheal intubation in a
      patient with severe tracheomalacia. The most likely cause of the tracheal injury
      was massive overinflation of the endotracheal tube cuff and the preexisting
      tracheal wall weakness. The case illustrates the classic radiologic signs of
      tracheal laceration, and we review the relevant literature.

PMID- 10645835
TI  - Hyponatremia and seizures in an ultradistance triathlete.
AB  - Hyponatremia is being increasingly recognized as a complication of participation
      in ultra-endurance sports. Reported is the case of an Ironman triathlete who
      collapsed at the end of the race, having gained 5% in body weight. His serum
      sodium concentration at the finish was 116 mmol/L. After an Intensive Care Unit
      course complicated by recurrent seizures, he eventually made a complete
      neurologic recovery. The pathogenesis of hyponatremia and its management in such
      cases is discussed.

PMID- 10645836
TI  - Peritonitis after gastrostomy tube replacement in the emergency department.
AB  - Peritonitis is a potentially fatal complication of the malpositioning of a
      gastrostomy feeding tube. We report a case of peritonitis that occurred
      subsequent to replacement of a gastrostomy tube in the emergency department.

PMID- 10645837
TI  - Ventricular flutter in a neonate--severe electrolyte imbalance caused by urinary
      tract infection in the presence of urinary tract malformation.
AB  - Male infants under the age of 3 months presenting with pyelonephritis in the
      presence of urinary tract malformation (UTM) are prone to transient
      pseudohypoaldosteronism. This may resemble congenital adrenal hyperplasia (CAH).
      Hyponatremia, hyperkalemia, dehydration, and metabolic acidosis are the primary
      findings that permit the diagnosis of CAH. We report a case of transient
      pseudohypoaldosteronism resulting from pyelonephritis and vesicouretric reflux.
      The 17-day-old boy presented with a salt-losing episode simulating adrenal
      insufficiency. An initial diagnosis of CAH was made. The severe metabolic
      imbalance resulted in ventricular flutter that resolved after correction of the
      metabolic acidosis and the electrolyte and volume depletion. Early diagnosis is
      essential because both conditions are potentially fatal and treatment differs
      significantly. Differential diagnosis may be achieved by urinalysis and abdominal
      ultrasound scan.

PMID- 10645838
TI  - Acute lindane poisoning in three children.
AB  - Lindane has been reported to cause central nervous system (CNS) toxicity
      including seizures after prolonged dermal contact and also after acute
      ingestions. Despite safer alternatives, lindane still remains a commonly used
      agent in the treatment of scabies and pediculosis. We present three cases of
      acute toxicity after the inadvertent oral administration of lindane in three
      siblings. A 17-month-old female suffered a single seizure. A 3-year-old male was
      listless, nauseated, pale, and had decreased responsiveness to verbal and tactile
      stimulation. A 4-year-old female became nauseated and required bag-valve-mask
      ventilation for hypoventilation. The three patients all recovered without
      sequelae.

PMID- 10645839
TI  - Myocardial infarction associated with phenylpropanolamine.
AB  - Phenylpropanolamine is a sympathomimetic agent widely used in over-the-counter
      and prescription decongestant medications. We describe a young woman without
      cardiac risk factors who sustained myocardial infarction after unintentional
      overuse of a nasal decongestant containing phenylpropanolamine. The
      pathophysiology of myocardial injury and current management strategies as related
      to this agent are discussed. Although serious adverse reactions to
      phenylpropanolamine are uncommon, potentially serious harm may be caused by this
      widely available drug in healthy individuals.

PMID- 10645840
TI  - Flumazenil reversal of carisoprodol (Soma) intoxication.
AB  - A 52-year-old woman presented with central nervous system depression and a
      Glasgow Coma Score of 9 secondary to ingestion of carisoprodol, a centrally
      acting muscle relaxant analgesic. After administration of i.v. flumazenil, the
      patient's neurologic status normalized and she required no further therapy.
      Carisoprodol and its active sedative-hypnotic metabolite, meprobamate, are gamma
      aminobutyric acid receptor indirect agonists with central nervous system chloride
      ion channel conduction effects similar to the benzodiazepines, thus making
      flumazenil a potentially useful antidote in toxic presentations.

PMID- 10645841
TI  - Severe gamma-hydroxybutyrate withdrawal: a case report and literature review.
AB  - We report a case of gamma-hydroxybutyrate (GHB) withdrawal resulting in severe
      agitation, mental status changes, elevated blood pressure, and tachycardia hours
      after stopping chronic use of GHB. The patient admitted to substantial GHB abuse
      on a daily basis for 2.5 years. Previous attempts at cessation reportedly
      resulted in diaphoresis, tremors, and agitation. The patient's symptoms, negative
      polypharmacy history, and negative urine and blood toxicological analysis for
      alcohol, benzodiazepines, sedative-hypnotics, or other substances suggested the
      diagnosis of GHB withdrawal. Later analysis of a patient drug sample confirmed
      the presence of GHB. The patient required 507 mg of lorazepam and 120 mg of
      diazepam over 90 h to control agitation. This is one of the few reported cases of
      GHB withdrawal and one of the most severe. Given the increasing use of GHB, more
      cases of severe GHB withdrawal should be anticipated.

PMID- 10645842
TI  - Electrocardiographic manifestations: patterns that confound the EKG diagnosis of
      acute myocardial infarction-left bundle branch block, ventricular paced rhythm,
      and left ventricular hypertrophy.
AB  - The 12-lead electrocardiogram (EKG), a powerful tool used in evaluating the chest
      pain patient, has its shortcomings. One such failing is encountered in a patient
      with one of the following electrocardiographic patterns: left bundle branch block
      (LBBB), ventricular paced rhythm (VPR), and left ventricular hypertrophy (LVH).
      These patterns reduce the ability of the EKG to detect acute coronary ischemic
      change and acute myocardial infarction (AMI). Several strategies are available to
      assist in the correct interpretation of these complicated electrocardiographic
      patterns, including a knowledge of the ST segment-T wave changes associated with
      these confounding patterns, performance of serial EKGs, and comparison with
      previous EKGs if available. This article suggests guidelines and interpretive
      tools for diagnosing AMI on EKG in patients with these confounding patterns.

PMID- 10645843
TI  - Serial abdominal ultrasound in the setting of trauma.
AB  - Ultrasound is gaining wide acceptance in Emergency Medicine as an inexpensive and
      accurate examination modality. One of the leading uses of this technology is in
      the initial assessment of the trauma patient, where the ultrasound examination is
      often used to determine the need for immediate laparotomy or further diagnostic
      study. We present a series of four patients, all of whom sustained blunt or
      penetrating abdominal trauma. In each case, the initial screening abdominal
      ultrasound was negative for free intraperitoneal (i.p.) fluid but, when repeated
      by the same practitioner, became positive. These cases demonstrate the need for
      serial ultrasounds in evaluating the patient with abdominal trauma. Future
      studies of trauma ultrasound should investigate the utility of serial sonographic
      examinations.

PMID- 10645844
TI  - Ultrasonography of flank pain in the emergency department: renal cell carcinoma
      as a diagnostic concern.
AB  - Acute flank pain is a common emergency department presenting symptom, and bedside
      ultrasound is being used increasingly in its evaluation. Emergency renal
      ultrasonography concentrates on the focused presence or absence of hydronephrosis
      as is often seen in patients with acute flank pain secondary to renal colic. We
      present three cases in which other abnormal sonographic signs not commonly taught
      prompted further investigation, revealing renal cell carcinoma. Baseline
      knowledge of sonographic characteristics of tumors will benefit the occasional
      emergency patient who has unsuspected renal carcinoma.

PMID- 10645845
TI  - An outbreak of carbon monoxide poisoning after a major ice storm in Maine.
AB  - Unintentional carbon monoxide (CO) exposure kills over 500 people in the U.S.
      annually. Outbreaks of CO poisoning have occurred after winter storms. The
      objective of this study was to describe clinical features and identify important
      risk factors of a CO poisoning outbreak occurring after a major ice storm. The
      study design included a case series of CO poisoning patients, a telephone survey
      of the general community, and a case-controlled study of households using
      specific CO sources. The setting was the primary service area of four hospital
      emergency departments located in the heavily storm-impacted interior region of
      Maine. Participants included all patients with a laboratory-confirmed diagnosis
      of CO poisoning during the 2 weeks after the storm onset, and a population-based
      comparison group of 522 households selected by random digit dialing. There were
      100 cases identified, involving 42 common-source exposure incidents, most of them
      during the first week. Though classic CO symptoms of headache, dizziness, and
      nausea predominated, 9 patients presented with chest pain and 10 were
      asymptomatic. One patient died and 5 were transferred for hyperbaric oxygen
      therapy. Gasoline-powered electric generators were a CO source in 30 incidents,
      kerosene heaters in 8, and propane heaters in 4. In the community, 31.4% of
      households used a generator after the ice storm. The strongest risk factor for
      poisoning was locating a generator in a basement or an attached structure such as
      a garage. Cases of CO poisoning with various presentations can be expected in the
      early aftermath of a severe ice storm. Generators are a major CO source and
      generator location an important risk factor for such disasters.

PMID- 10645846
TI  - Respiratory distress and leg pain.

PMID- 10645847
TI  - Classic helical CT scan findings of acute appendicitis.

PMID- 10645848
TI  - Dermoid tumor with ovarian torsion masking as appendicitis.

PMID- 10645849
TI  - Portal venous gas: an unusual finding in child abuse.

PMID- 10645850
TI  - Global epidemic of human T-cell lymphotropic virus type-I (HTLV-I).
AB  - Infection with human T-cell lymphotrophic virus-I (HTLV-I) is now a global
      epidemic, affecting 10 million to 20 million people. This virus has been linked
      to life-threatening, incurable diseases: adult T-cell leukemia/lymphoma (ATLL)
      and HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The
      cumulative lifetime risk of developing these incurable diseases is approximately
      5% in asymptomatic patients. For the emergency physician practicing among
      patients from high-risk groups, HTLV-I and its associated diseases are presenting
      an increasing challenge. This report describes its transmission, seroprevalence,
      treatment, and methods of controlling spread of this retrovirus. Coinfection with
      HTLV-I and HIV has been shown to accelerate the progression of acquired immune
      deficiency syndrome (AIDS).

PMID- 10645851
TI  - Re: Emergency Department management of occupational exposures to HIV-infected
      fluids.

PMID- 10645852
TI  - Re: Emergency Department management of occupational exposures to HIV-infected
      fluids

PMID- 10645853
TI  - Interaction of herbal medicine with Coumadin.

PMID- 10645854
TI  - Bayesian interpretation of trials: the example of intrapartum electronic fetal
      heart rate monitoring.

PMID- 10645855
TI  - Polycystic ovary syndrome: a risk factor for cardiovascular disease?

PMID- 10645856
TI  - The long learning curve of gynaecological cancer surgery: an argument for
      centralisation.
AB  - OBJECTIVE: To study the development of surgical performance of an unchanging
      surgical team over 13 years. DESIGN: Prospective, observational study. SETTING: A
      university hospital, The Netherlands. PARTICIPANTS: Three hundred and eight women
      who underwent surgical treatment for early cervical cancer. INTERVENTIONS:
      Radical hysterectomy and pelvic lymphadenectomy between 1 January 1984 and 31
      December 1996. RESULTS: The surgical procedure and indication for treatment
      remained unchanged during the study period. This applied also to the surgical
      team. The women's age increased significantly during the study years, as was the
      case with the number of nodes removed. The depth of infiltration by the tumour
      increased steadily throughout the study, but this failed to reach statistical
      significance. The distribution of FIGO stages, percentage of positive lymph
      nodes, radicality of the surgical margins and post-operative morbidity remained
      the same. Overall, the five year survival rate was 83%; for women with negative
      nodes 91%, and for women with positive nodes 53%. Survival tended to improve
      during the course of the study, but this was not statistically significant. Blood
      loss during surgery decreased consistently during the whole study period, from a
      mean of 1,515 mL at the beginning of the study to a mean of 1,071 mL at the end
      (P < 0.0001). The operating time also diminished significantly by 8 minutes per
      year (P < 0.0001). In 1985 the average operating time was 270 minutes, compared
      with 187 minutes in 1996. CONCLUSIONS: These findings indicate that it takes a
      long time to acquire skill in the surgical treatment of early cervical cancer.
      Centralisation of relatively infrequent operations for cancer should be
      encouraged.

PMID- 10645857
TI  - The role of laparoscopic surgery in the management of endometrial cancer.
AB  - OBJECTIVE: To assess the place of laparoscopically assisted vaginal hysterectomy
      in the treatment of endometrial cancer. DESIGN: A retrospective uncontrolled case
      series. SETTING: Gynaecological Oncology Department, Queen Elizabeth Hospital,
      Gateshead. POPULATION: Women with endometrial cancer referred to this centre from
      August 1992 to August 1997. MAIN OUTCOME MEASURES: Success of laparoscopically
      assisted vaginal hysterectomy, operative morbidity, and the length of hospital
      stay. RESULTS: Laparoscopically assisted vaginal hysterectomy was successful in
      35 of 40 women (88%). Five women required laparotomy. Two women sustained injury
      to the inferior epigastric vessels. One sustained injury to the small intestine
      requiring later laparotomy and three women required a blood transfusion. The mean
      hospital stay was 3 x 3 days (SD 1 x 5). Three women died of the disease within
      one year of their operation. CONCLUSION: Laparoscopically assisted vaginal
      hysterectomy is a feasible treatment for endometrial cancer. It can be performed
      successfully in high risk population who are medically unfit and overweight.
      However, a larger randomised study is required to assess the morbidity compared
      with the traditional open approach.

PMID- 10645858
TI  - A comparison of the side effects of prilocaine with felypressin and lignocaine
      with adrenaline in large loop excision of the transformation zone of the cervix:
      results of a randomised trial.
AB  - OBJECTIVE: To test the hypothesis that prilocaine with felypressin causes fewer
      side effects than lignocaine with adrenaline when performing large loop excision
      of the transformation zone of the cervix. DESIGN: Randomised trial. SETTING:
      Colposcopy clinic in a large district general hospital. PARTICIPANTS: Two hundred
      consecutive women undergoing large loop excision of the transformation zone of
      the cervix. METHODS: Two different local anaesthetic combinations (prilocaine
      with felypressin and lignocaine with adrenaline) were compared in women
      undergoing large loop excision of the transformation zone. Prospective collection
      of clinical and treatment data was undertaken with scoring using an ordinal scale
      of pain experienced by the women during the procedure. Peri-operative blood loss
      and any side effects were also recorded. MAIN OUTCOME MEASURES: Side effects
      associated with the local anaesthetic agents. RESULTS: Lignocaine with adrenaline
      resulted in less blood loss (P = 0.006) but was more likely to cause side
      effects, such as feeling faint (P = 0.017) and shaking (P < 0.001). CONCLUSION:
      Prilocaine with felypressin causes fewer side effects than lignocaine with
      adrenaline and is therefore the preferred local anaesthetic combination for large
      loop excision of the transformation zone.

PMID- 10645859
TI  - Evaluation of a human papillomavirus assay in cervical screening in Zimbabwe.
AB  - OBJECTIVE: To determine the utility of an assay for high risk genital human
      papillomavirus (HPV) in cervical screening in Zimbabwe, Africa. DESIGN: Cross
      sectional study. SETTING: Harare, Zimbabwe. POPULATION: Zimbabwe women (n =
      2,140), 25 to 55 years old, recruited in clinics in Chitungwiza and Greater
      Harare. METHODS: Genital specimens were assessed for HPV, using the HPV DNA test
      Hybrid Capture II (probe B). Further assessment of the women was conducted using
      colposcopy and biopsy as indicated. High grade squamous intraepithelial lesions
      were diagnosed in 215 women. Colposcopy and/or biopsy showed low grade lesions in
      346 women. RESULTS: The overall prevalences were: 42 x 7% for HPV, 10% for high
      grade squamous intraepithelial lesions and 16% for low grade lesions. Prevalence
      for HPV decreased significantly with increase in age (P for trend < 0 x 0001) and
      increased significantly with increasing disease severity, from 35% in normal
      women, to 53% in women with low grade lesions and 81% in women with high grade
      lesions (P for trend < 0 x 001). In specimens positive for HPV, the amount was 14
      fold higher in women with high grade lesions compared with normal women. In
      screening for high grade lesions the assay for HPV had a sensitivity of 81% (CI
      75%-86%); sensitivity for low grade lesions was 64% (CI 60%-68%). Specificity was
      62% (CI 59%-64%) for high grade lesions and 65% (CI 62%-67%) for low grade
      lesions. The positive predictive value was 19% (CI 17%-22%) for high grade
      lesions and 39% (CI 36%-42%) for low grade lesions. CONCLUSION: For high grade
      squamous intraepithelial lesions the sensitivity of the Hybrid Capture II HPV DNA
      test was high, but the specificity was relatively low. The test may therefore be
      most useful in conjunction with other screening tests.

PMID- 10645860
TI  - Quality of medical information about menorrhagia on the worldwide web.
AB  - OBJECTIVE: To evaluate the quality of medical information on the management of
      menorrhagia on the worldwide web. DESIGN AND PROCEDURES: An on-line search of the
      Internet, locating relevant web sites by using key phrases 'heavy periods' and
      'patient information' in seven search engines. Quality was defined as the extent
      to which the characteristics of a web page satisfied its stated and implied
      objectives. Assessment focused on credibility and content of each web page.
      Source, currency and editorial review process assessed credibility and hierarchy
      and accuracy of evidence assessed content of the web pages. MAIN OUTCOME
      MEASURES: Rate of compliance with preset criteria for quality of health
      information on the Internet. RESULTS: Nine relevant web pages were located, none
      of which complied with all of the criteria for quality. Seven of these pages
      displayed the source and five showed the currency of the information, while none
      described an editorial review process. Four web pages displayed a hierarchy of
      evidence and one web page depicted all the criteria for accuracy of its contents.
      CONCLUSION: None of the web pages provided complete information to women on heavy
      periods according to the quality criteria. This makes it difficult for the user
      without medical knowledge to determine which web page is credible and useable and
      which should be ignored or rejected. There is a need to be vigilant about the
      quality of information on the Internet.

PMID- 10645861
TI  - The effect of endometriosis and its radical laparoscopic excision on quality of
      life indicators.
AB  - OBJECTIVE: To assess the effect of endometriosis and radical laparoscopic
      excision on the quality of life of women with this condition. DESIGN: A
      prospective study. SETTING: The Northern Endometriosis Centre at South Cleveland
      Hospital, Middlesbrough and St. James's University Hospital, Leeds. POPULATION:
      Fifty-seven consecutive patients undergoing laparoscopic excision of invasive
      endometriosis. METHODS: Questionnaires, both pre-operatively and four-month post
      operatively, for a number of different symptoms associated with endometriosis
      were completed by patients. Details of fertility, previous treatments and quality
      of life as measured by SF12 and EuroQOL (EQ-5D) and sexual activity
      questionnaire, as well as linear pain scores for several symptoms, were recorded.
      Details of intra-operative findings was also collected. MAIN OUTCOME MEASURES:
      Effect of laparoscopic excision on pain scores and quality of life, operative
      findings, type of surgery, length of surgery and incidence of intra- and post
      operative complications. RESULTS: Patients with endometriosis were severely ill
      with significant pain and impairment of quality of life and sexual activity. Four
      months after radical laparoscopic excision for deep endometriosis there was
      significant improvement in all the parameters measured including their quality of
      life based on EuroQOL evaluation: EQ-5D (0 x 595:0 x 729, P = 0 x 002) and EQ
      thermometer (68 x 9:77 x 7, P = 0 x 008); SF12 physical score (44 x 8:51 x 9, P =
      0 x 015); sexual activity (habit P = 0 x 002, pleasure P = 0 x 002 and discomfort
      P < or = 0 x 001). Only the mental health score of SF12 failed to show any
      statistical improvement (47 x 1:48 x 4, P = 0 x 84). Symptomatically, there was a
      significant reduction in dysmenorrhoea (median 8 x 0:4 x 0, P < or = 0 x 001),
      pelvic pain (median 7 x 0:2 x 0, P < or = 0 x 001), dyspareunia (median 6 x 0:0 x
      0, P < 0 x 001) and rectal pain scores (median 4 x 0:0 x 0, P < 0 x 001).
      Complications were noted, but were deemed to be acceptable for the extent of the
      surgery. CONCLUSIONS: This is an early analysis of the first 57 cases studied,
      but structured evaluation suggests that meaningful improvements in clinical
      symptoms and quality of life can be obtained with this approach with acceptable
      levels of operative morbidity. Further follow up of this series is required, but
      early evidence would suggest that the technique should be further evaluated as
      part of a randomised trial.

PMID- 10645862
TI  - Factors associated with male infertility: a case-control study of 218 infertile
      and 240 fertile men.
AB  - OBJECTIVE: To determine the likely risk factors, such as smoking and drinking
      habits, and occupational groups, for infertility in a group of infertile men with
      no known cause, compared with a group of fertile men; and to examine the effects
      of the semen parameters, such as volume, density, motility, viability and normal
      morphology, on fertility. DESIGN: A case-control study. SETTING: The department
      of obstetric and gynaecology of a tertiary general hospital. PARTICIPANTS: Six
      hundred and forty consecutive male partners of couples trying to conceive were
      recruited from an infertility clinic. Of these, the cases comprised 218 men who
      had no known cause for their infertility. Two hundred and forty men whose wives
      were pregnant at the time of the study were recruited as controls. RESULTS: The
      semen parameters (e.g. density, total sperm counts, motility, viability and
      normal morphology) of all cases were significantly poorer than that of the
      controls. The risk of infertility is associated with smoking (crude OR 2 x 82,
      95% CI 1 x 93-4 x 13; adjusted OR 2 x 96; 95% CI 1 x 98-4 x 42). Technicians
      (adjusted OR 2 x 81; 95% CI 1 x 51-4 x 24) and professional, senior officials and
      managers were also at a greater risk of infertility (adjusted OR 2 x 36; 95% CI 1
      x 26-4 x 40), compared with service and clerical workers. The significant factors
      predicting infertility were smoking, density of sperm, and viability of sperm.
      Smoking increased the odds of being infertile. Higher sperm counts and larger
      percentage of viable sperm decrease the odds of infertility. Based on the
      multiple logistic regression model, the odds ratio for infertility = (94 x 70) x
      (2 x 88(smoking)) X (0 x 29(logdensity)) X (0 x 95(viability)). CONCLUSION:
      Smoking, density of sperm and the viability of sperm are significant predictors
      for infertility among men.

PMID- 10645863
TI  - Contraction kinetics of isolated human myometrium during menstrual cycle and
      pregnancy.
AB  - OBJECTIVE: To investigate the interaction between actin and myosin in the
      myometrium by studying the contraction kinetics of isolated samples of human
      myometrium. DESIGN: Experimental and observational cross-sectional study.
      SETTING: Eppendorf University Hospital, Hamburg. SAMPLES: Myometrium samples were
      taken from women in the follicular phase (n = 6) or luteal phase (n = 6) of the
      menstrual cycle and during pregnancy at term (n = 25). METHODS: The frequency,
      extent and rate of force development were determined in spontaneously active
      myometrial preparations. From a resting force of 2 mN, sustained tonic
      contractions were induced by K+-depolarisation (124 mM), or by protein kinase C
      activation (19 x 9 microM indolactam). The steady force was reversibly
      interrupted by rapid length changes (100 Hz sinus vibrations lasting 1 s, 5% of
      muscle length). Extent (steady plateau), as well as rate of force increase after
      cessation of vibrations, were derived from bi-exponential functions fitted to the
      time course of force recovery. RESULTS: Frequency of spontaneous contractions was
      higher in the follicular phase [mean (SD) 18 x 3 contractions/hour (1 x 0)] than
      in the luteal phase [13 x 4 contractions/hour (8 x 1)] or in pregnancy at term [8
      x 8 contractions/hour (7 x 6)]. During indolactam treatment, steady force in
      pregnancy at term was significantly increased [8 x 8 mN (4 x 0)], compared with
      the follicular phase [3 x 7 mN (0 x 9)]. Force recovery was distinctly slower in
      pregnancy at term during indolactam treatment [time constant 99 x 2 s (57 x 9); P
      < 0 x 005] than during K+-depolarisation [time constant 29 x 1 s (5 x 9)],
      whereas in the follicular phase the rate of force recovery was faster with
      indolactam [16 x 8 s (7 x 1)] than with K+ depolarisation [24 x 4 s (5 x 9); P <
      0 x 005]. CONCLUSIONS: The responses of human myometrium to contraction stimuli
      differ according to the reproductive state. Membrane depolarisation causes
      similar responses in all myometrial strips. In contrast, near term stimulation of
      protein kinase C generates a large tonic force and slow contraction kinetics,
      whereas early in the menstrual cycle contraction kinetics are fast.

PMID- 10645864
TI  - Maternal morbidity and mortality in two different populations of Senegal: a
      prospective study (MOMA survey).
AB  - OBJECTIVE: To compare maternal morbidity and mortality in two urban populations
      with contrasting availability of health care, and to test the hypothesis that
      differences in maternal outcome result mainly from the management of delivery in
      health facilities. DESIGN: A population-based study of a cohort of pregnant women
      which was part of a multicentre study of maternal morbidity in six countries of
      western Africa (MOMA). SETTING: Two different urban areas of Senegal (Saint-Louis
      and Kaolack). POPULATION: 3,777 pregnant women who were followed up throughout
      pregnancy, delivery and puerperium. MAIN OUTCOME MEASURES: Maternal morbidity and
      mortality: morbidity was assessed from women's recall at each visit by the
      investigator and from obstetric complications diagnosed by the birth attendant
      within health facilities. RESULTS: Maternal mortality was higher in the Kaolack
      area where women gave birth mainly in district health care centres, usually
      assisted by traditional birth attendants, than in Saint-Louis where women giving
      birth in health facilities went principally to the regional hospital and were
      usually assisted by midwives (874 and 151 maternal deaths per 100,000 live
      births, respectively, P < 0 x 01). Maternal morbidity, however, was higher in
      Saint-Louis than in Kaolack area, especially for births in health facilities (9 x
      50 and 4 x 84 episodes of obstetric complications per 100 live births,
      respectively, P < 0 x 01). Univariate and multivariate analyses showed that
      morbidity was mainly associated with the training of the birth attendant in
      facility deliveries and that antenatal care had no effect. CONCLUSION: Midwives
      in health facilities appear to detect more obstetric complications than
      traditional birth attendants. Immediate detection leads to immediate care and to
      low fatality rates. This could explain differences in maternal outcome between
      two urban centres with contrasting health care availability. These results
      suggest that one of the strongest weapons in the fight against maternal mortality
      is the employment of the most qualified personnel possible for monitoring labour.

PMID- 10645865
TI  - Risk factors for pre-eclampsia in a large cohort of Latin American and Caribbean
      women.
AB  - OBJECTIVE: To study risk factors for pre-eclampsia in a large cohort of Latin
      American and Caribbean women. DESIGN: Retrospective cross-sectional study from
      the Perinatal Information System, the database of the Latin American Center for
      Perinatology and Human Development, Montevideo, Uruguay. SETTING: Latin America
      and the Caribbean, 1985-1997. Population 878,680 pregnancies at 700 hospitals; of
      these 42,530 were complicated by pre-eclampsia and 1,872 by eclampsia. MAIN
      OUTCOME MEASURES: Crude and adjusted relative risks (RR) of risk factors for pre
      eclampsia. Adjusted relative risks were obtained after adjustment for potential
      confounding factors through multiple logistic regression models based on the
      method of generalised estimating equations. RESULTS: The following risk factors
      were significantly associated with increased risk of pre-eclampsia: nulliparity
      (RR 2 x 38; 95% CI 2 x 28-2 x 49); multiple pregnancy (RR 2 x 10; 95% CI 1 x 90-2
      x 32); history of chronic hypertension (RR 1 x 99; 95% CI 1 x 78-2 x 22);
      gestational diabetes mellitus (RR 1 x 93; 95% CI 1 x 66-2 x 25); maternal age >
      or = 35 years (RR 1 x 67; 95% CI 1 x 58-1 x 77); fetal malformation (RR 1 x 26;
      95% CI 1 x 16-1 x 37); and mother not living with infant's father (RR 1 x 21; 95%
      CI 1 x 15-1 x 26). Pre-eclampsia risk increased according to pre-pregnancy body
      mass index (BMI). In comparison with women with a normal pre-pregnancy BMI (19 x
      8 to 26 x 0), the RR estimates were 1 x 57 (95% CI 1 x 49-1 x 64) and 2 x 81 95%
      CI 2 x 69-2 x 94), respectively, for overweight women (pre-pregnancy BMI = 26 x 1
      to 29 x 0) and obese women (pre-pregnancy BMI > 29 x 0). Cigarette smoking during
      pregnancy and a pre-pregnancy BMI < 19 x 8 were significant protective factors
      against the development of pre-eclampsia. The pattern of risk factors among
      nulliparous and multiparous women was quite similar. CONCLUSIONS: Risk factors
      for pre-eclampsia observed among Latin American and Caribbean women are similar
      to those found among North American and European women.

PMID- 10645866
TI  - Prenatal diagnosis of fetal primary cytomegalovirus infection.
AB  - OBJECTIVE: To determine the reliability of prenatal diagnosis for congenital
      cytomegalovirus in women with primary infection. DESIGN: Retrospective analysis
      of case records between 1992 and 1997. SETTING: Fetal medicine unit of a large
      teaching hospital. POPULATION: Forty-two pregnant women with primary
      cytomegalovirus infection. METHODS: Fetal diagnosis was made by amniocentesis for
      viral culture and amplification of cytomegalovirus DNA by polymerase chain
      reaction (n = 37), or by cordocentesis for the detection of cytomegalovirus
      specific IgM antibodies (n = 13). All patients had serial ultrasonographic scans
      in order to detect those fetuses with abnormalities that could be associated with
      cytomegalovirus infection. RESULTS: Fourteen pregnancies (33 x 3%) had evidence
      of vertical transmission. Nine out of 14 (64 x 3%) had positive amniotic fluid
      culture, while 11 (78 x 6%) had positive polymerase chain reaction results. The
      combination of both tests allowed antenatal diagnosis in 12 of the 14 infected
      fetuses (sensitivity 85 x 7%). All women who underwent cordocentesis for the
      detection of cytomegalovirus-specific IgM antibodies had negative results, but in
      two cases cytomegalovirus infection was detected by amniotic fluid studies. In
      five of the infected fetuses there were abnormal ultrasonographic findings. All
      pregnancies with evidence of vertical transmission were terminated and the
      remainder proceeded normally to term. CONCLUSIONS: Our data showed that amniotic
      fluid studies, preferably polymerase chain reaction amplification of viral DNA,
      are the best diagnostic tools for the detection of vertical transmission in
      pregnancies with primary cytomegalovirus infection. For women with positive
      amniotic fluid studies who elect to continue their pregnancies, cordocentesis and
      serial ultrasound scans may be useful for assessment of fetal status.

PMID- 10645867
TI  - Association of a lack of psychosocial resources and the risk of giving birth to
      small for gestational age infants: a stress hypothesis.
AB  - OBJECTIVE: To test the stress hypothesis that women who give birth to small for
      gestational age infants lack important psychosocial coping resources, such as a
      sufficient social network, social support and control in daily life. DESIGN: A
      prospective cohort study of nulliparous pregnant women. SETTING: Antenatal care
      units in the city of Malmo, Sweden. POPULATION: All women (n = 994) during a one
      year period (1991-1992) were invited, and 872 (87 x 7%) participated. This study
      was restricted to pregnancies resulting in singleton live birth (n = 826); 6 x 7%
      of infants were classified as small for their gestational age. METHODS: Self
      administered questionnaires were given to all women at the time of their first
      antenatal visit. MAIN OUTCOME MEASURES: The classification of small for
      gestational age was based on a gender-specific intrauterine growth reference
      curve. Newborn babies were classified as being small for gestational age if their
      birthweight was > 2 SD below the mean weight for gestational age. RESULTS: Lack
      of psychosocial resources, such as social stability, social participation,
      emotional and instrumental support, all increased the likelihood of delivering an
      infant that was small for gestational age. The odds ratios when controlled for
      demographic background factors, lifestyle factors and anthropomorphic measures
      were: OR 1 x 7 (95% CI 0 x 9-3 x 3) for women with poor social stability; OR 2 x
      2 (95% CI 1 x 1-4 x 4) for women with poor social participation; OR 2 x 6 (95% CI
      1 x 2-5 x 7) for women with poor instrumental support; and OR 1 x 5 (95% CI 0 x 8
      2 x 8) for women with poor emotional support. Simultaneous exposure to a poor
      total network index, as well as a poor total support index showed a significantly
      increased odds ratio for having a small for gestational age baby: OR 3 x 3 (95%
      CI 1 x 6-6 x 7) and OR 2 x 7 (95% CI 1 x 3-5 x 6), respectively. A synergy index
      of 9 x 0 and 6 x 8 supported the assumption of an interaction between immigrant
      status and poor total network or poor total support, in a synergistic direction.
      CONCLUSIONS: The findings support the stress-hypothesis that a lack of
      psychosocial resources might increase the risk of giving birth to a baby that is
      small for gestational age.

PMID- 10645868
TI  - Attitudes toward clinical guidelines among obstetricians in Northern Ireland.
AB  - OBJECTIVES: To evaluate the attitudes of, and the influences on decisions made
      by, obstetricians in Northern Ireland in order to understand the feasibility of
      applying guidelines to obstetric practice. DESIGN: Cross-sectional postal survey.
      SETTING: Northern Ireland. POPULATION: Consultants, senior registrars,
      registrars, and senior house officers in obstetrics in Northern Ireland (n =
      170). Responses were received from 68 x 8% (n = 117), with complete data
      available for 67 x 1% (n = 114). MAIN OUTCOME MEASURES: An attitudes score was
      constructed by consolidating responses to a variety of statements about
      guidelines. Individual responses to guidelines statements and the standardised
      attitudes T-score were analysed by demographic and practice characteristics.
      RESULTS: Attitudes toward guidelines were generally positive, with women
      practitioners more likely to have positive attitudes toward guidelines than did
      their male counterparts. Younger obstetricians were more likely to report that
      practitioners should incorporate guidelines into their practices. Doctors who
      responded that their decisions were influenced by specific tools related to
      guidelines, such as computerised databases, during the previous three months had
      more positive attitudes toward guidelines than doctors who did not use such
      tools. Furthermore, doctors based in teaching hospitals were more likely than
      others to have been influenced by the guidelines of professional societies.
      CONCLUSIONS: Generally guidelines appear to be quite well received, with doctors
      reporting that their practice often is influenced by them. Doctors who reported
      that their decisions were influenced by guidelines had an especially positive
      attitude toward them. However, some tools which target the application of
      evidence-based methods (e.g. computerised databases) are used infrequently by
      obstetricians. The challenge remains to encourage the further development of
      guidelines and tools that are useful and appropriate for practitioners.

PMID- 10645869
TI  - Plasma from women with pre-eclampsia induces an in vitro alteration in the
      endothelium-dependent behaviour of myometrial resistance arteries.
AB  - OBJECTIVE: To compare the in vitro effect of plasma from normal pregnant women
      and women with pre-eclampsia on the endothelium-dependent behaviour of myometrial
      resistance arteries from normal pregnant women. DESIGN: An in vitro comparative
      study. SETTING: Nottingham City Hospital. SAMPLE: Uterine biopsy specimens were
      obtained from normal pregnant women delivered by elective caesarean section at
      term. Plasma was collected from nulliparous women with pre-eclampsia (n = 18),
      and from multiparous normal pregnant women (n = 18), all samples being matched
      for maternal age and gestation at venepuncture. Pools of plasma from women with
      pre-eclampsia and normal pregnant women were formed from these samples and were
      used in all the experiments. METHODS: Myometrial resistance vessels obtained from
      the uterine biopsies were incubated with normal pregnant plasma, plasma from
      women with pre-eclampsia, or without plasma. Wire myography was employed to study
      the effect of plasma on the endothelium-dependent behaviour of these vessels.
      RESULTS: Incubation of vessels from normal pregnant women with plasma from women
      with pre-eclampsia resulted in a significant reduction in endothelium-dependent
      relaxation, compared with vessels incubated either with plasma from normal
      pregnant women or without plasma. This alteration in endothelial function
      occurred after an incubation period of one hour and required a threshold
      concentration for its effect to become established. Removal of the vascular
      endothelium abolished these changes in vessel behaviour. There were no plasma
      induced alterations in the endothelium-independent behaviour of the vascular
      smooth muscle. CONCLUSIONS: This study supports the hypothesis that plasma from
      women with pre-eclampsia is capable of altering endothelium-dependent myometrial
      relaxation in vessels from pregnant women.

PMID- 10645870
TI  - Evidence of dysfunctional beta2-adrenoceptor signal system in pre-eclampsia.
AB  - OBJECTIVES: To determine how beta2-adrenoceptor binding and function differ
      between healthy women and those with pre-eclampsia. DESIGN: Case-control study.
      SETTING: Faculty of Medicine, University of Tromso, Norway. PARTICIPANTS: Two
      groups of pregnant women: eight cases with pre-eclampsia, matched with eight
      healthy controls. METHODS: Venous blood was drawn from women in both groups after
      an overnight rest. The two groups were matched for gestational age which was
      (mean (SD)) 36 x 4 (3 x 8) and 36 x 5 (4 x 4) weeks for the pre-eclamptic and
      control groups, respectively. Six weeks after delivery a second blood sample was
      obtained. The binding and function of beta2-adrenoceptors were determined in
      isolated human mononuclear leukocytes. The levels of adrenaline and noradrenaline
      were determined in plasma from venous blood. RESULTS: An elevated density of
      functional beta2-adrenoceptors was observed in normal pregnancy [mean (SD) 390
      (90) vs 270 (60) sites/cell postpartum], due to an increased fraction of
      receptors in high affinity state, with unaltered total receptor density. The
      number of functional beta2-adrenoceptors was reduced in pre-eclampsia [mean (SD)
      80 (40) vs 240 (30) sites/cell postpartum], due to a reduction in the total
      receptor number with an unaltered fraction of high affinity receptors. In
      pregnancy, both unstimulated and isoprenaline-stimulated cAMP levels were reduced
      in the women with pre-eclampsia (0 x 5 (0 x 2) and 1 x 7 (0 x 9) pmol/10(6)
      cells, respectively) compared with the normal pregnant controls (mean (SD) 1 x 2
      (0 x 3) and 4 x 7 (1 x 8) pmol/10(6) cells, respectively). Plasma catecholamine
      levels were not elevated in the women with pre-eclampsia. CONCLUSIONS: The
      increased number of functional beta2-adrenoceptors may contribute to the
      vasodilatation seen in normal pregnancy, while the reduced overall number of
      receptors may be one of several factors that account for increased peripheral
      vascular resistance in pre-eclampsia.

PMID- 10645871
TI  - The ultrasound diagnosis of retained fetal bones in West African patients
      complaining of infertility.
AB  - Prolonged retention of intrauterine bone is a recognised cause of secondary
      infertility. Between 1989 and 1995, eleven West African women had retained
      intrauterine bone as the cause of their infertility. All the women had had
      termination of pregnancies in their countries of origin. Transvaginal ultrasound
      scan detected bright intrauterine echoes suggestive of bone which was confirmed
      and removed at hysteroscopy. Subsequently eight women conceived spontaneously 12
      pregnancies. Doctors treating West African women with infertility should be aware
      of this condition and include transvaginal ultrasound scan in their
      investigations.

PMID- 10645872
TI  - Concurrent genital and rectal prolapse: two pathologies--one joint operation.
AB  - This study is a prospective assessment of a joint operation to repair concomitant
      genital and rectal prolapse, including 10 women treated for concomitant genital
      and rectal prolapse from 1991 to 1995. Joel-Cohen vaginal hysterectomy was used
      to correct the genital prolapse, followed by the Altemeier procedure
      (transperineal rectosigmoidectomy) to correct the rectal prolapse. The post
      operative course was uneventful in all cases and there were no recurrences of
      prolapse in the three year follow up period. Improvement of sphincteric tone was
      shown in all cases by transrectal manometry, and bladder and rectal continence
      was maintained. The combined surgical procedure for concurrent genital and rectal
      prolapse is easy to perform and safe and efficient in terms of recurrence and
      continence. It is hoped this report will increase multidisciplinary awareness of
      an effective solution for a potentially debilitating problem.

PMID- 10645873
TI  - Intimate examinations: use of chaperones in community-based family planning
      clinics.
AB  - We examined women's preferences regarding the use of chaperones during intimate
      examinations by a female doctor or nurse in community-based family planning
      clinics. An anonymous questionnaire was completed before consultation and
      examination by 126 women attending five family planning clinics selected to cover
      a range of social and ethnic groups. The questionnaire explored women's views
      regarding intimate examinations by a woman and the presence of a chaperone. A
      clear majority (107 vs 19) of our community clinic users preferred to be alone
      with the woman doctor or nurse during an internal examination. There was no
      significant difference in preference or strength of feeling when analysed by age,
      ethnicity or previous experience.

PMID- 10645874
TI  - B cell leukaemia/lymphoma-2 protein concentrations during normal pregnancy.
AB  - We evaluated bcl-2 protein levels in whole blood, and intraerythrocytic products
      of lipoperoxidation, in 65 healthy pregnant primiparous women at the end of the
      first, second and third trimesters of pregnancy. During pregnancy we found a
      progressive increase in concentrations of bcl-2 and intraerythrocytic products of
      lipoperoxidation. Moreover, a positive correlation was found between bcl-2
      concentrations and lipoperoxidation products, and between bcl-2 protein, E2 and
      progesterone. The results show that modifications occurring during pregnancy are
      accompanied by variations of bcl-2 protein.

PMID- 10645875
TI  - Mobile globules in benign cystic teratoma of the ovary.

PMID- 10645876
TI  - Pelvic tuberculosis: an uncommon gynaecological problem presenting as ovarian
      mass.

PMID- 10645877
TI  - Patient access to their records: rights or risks?

PMID- 10645878
TI  - The white coat effect in hypertensive pregnancy: much ado about nothing?

PMID- 10645879
TI  - Paracervical anaesthesia in outpatient hysteroscopy: a randomised double-blind
      placebo controlled trial.

PMID- 10645880
TI  - Information technology for postgraduate education: survey of facilities and
      skills in the South West Deanery.

PMID- 10645881
TI  - Information technology for postgraduate education: survey of facilities and
      skills in the South West Deanery.

PMID- 10645882
TI  - Comparison of vaginal misoprostol and gemeprost as pre-treatment in first
      trimester pregnancy interruption.

PMID- 10645883
TI  - January 2000!

PMID- 10645884
TI  - TNF-alpha stimulates alveolar liquid clearance during intestinal ischemia
      reperfusion in rats.
AB  - Intestinal ischemia-reperfusion commonly occurs in critically ill patients and
      may lead to the development of remote organ injury, frequently involving the
      lungs. In the present study, alveolar liquid clearance was studied in ventilated,
      anesthetized rats subjected to 45 min of intestinal ischemia followed by 3 h of
      reperfusion. An isosmolar 5% albumin solution was instilled into the lungs, and
      alveolar liquid clearance was measured from the increase in alveolar protein
      concentration as water was reabsorbed over 45 min. Intestinal ischemia
      reperfusion resulted in a 76% increase in alveolar liquid clearance compared with
      the control value (P < 0.05). The stimulated alveolar liquid clearance seen after
      intestinal ischemia-reperfusion was not inhibited by propranolol, indicating
      stimulation through a noncatecholamine-dependent pathway. Intestinal ischemia
      reperfusion did not result in increased intracellular cAMP levels. Amiloride
      inhibited similar fractions in animals subjected to ischemia-reperfusion and
      control animals. Administration of a neutralizing polyclonal anti-tumor necrosis
      factor-alpha antibody before induction of intestinal ischemia completely
      inhibited the increased alveolar liquid clearance observed after intestinal
      ischemia-reperfusion. In conclusion, our results suggest that intestinal ischemia
      reperfusion in rats leads to stimulation of alveolar liquid clearance and that
      this stimulation is mediated, at least in part, by a tumor necrosis factor-alpha
      dependent mechanism.

PMID- 10645885
TI  - Glucocorticoid-induced contractility and F-actin content of human lung
      fibroblasts in three-dimensional culture.
AB  - Fibroblast contractility plays a useful role in the wound healing process but
      contributes to architectural distortion in the lungs. Glucocorticoids (GCs) have
      been reported to reduce dermal fibroblast contractility, which may result in
      delaying wound healing, but the effects on lung fibroblasts are unknown. In this
      study, we examined how human lung fibroblast contractility is altered in the
      presence of GCs. Lung fibroblast cell lines (n = 5) were established from normal
      parts of surgically resected lung tissue. The effects of GCs on contractility
      were investigated with a type I collagen gel contraction assay. Filamentous actin
      (F-actin) content was detected by confocal microscopy and measured with a
      fluorescent phalloidin binding assay. GCs augmented fibroblast contraction in a
      concentration-dependent manner, with an approximate EC(50) of 1.8 x 10(-8) M,
      whereas other steroid derivatives had no effects. GC contractility needed de novo
      protein synthesis. The GC-induced increase in contractility was found to be
      consistent with an increase in F-actin content. In conclusion, lung fibroblast
      contractility was enhanced with GCs through an upregulation of lung fibroblast F
      actin.

PMID- 10645886
TI  - Is dipalmitoylphosphatidylcholine a substrate for convertase?
AB  - Convertase has homology with carboxylesterases, but its substrate(s) is not
      known. Accordingly, we determined whether dipalmitoylphosphatidylcholine (DPPC),
      the major phospholipid in surfactant, was a substrate for convertase. We measured
      [(3)H]choline release during cycling of the heavy subtype containing
      [(3)H]choline-labeled DPPC with convertase, phospholipases A(2), B, C, and D,
      liver esterase, and elastase. Cycling with liver esterase or peanut or cabbage
      phospholipase D produced the characteristic profile of heavy and light peaks
      observed on cycling with convertase. In contrast, phospholipases A(2), B, and C
      and yeast phospholipase D produced a broad band of radioactivity across the
      gradient without distinct peaks. [(3)H]choline was released when natural
      surfactant containing [(3)H]choline-labeled DPPC was cycled with yeast
      phospholipase D but not with convertase or peanut and cabbage phospholipases D.
      Similarly, yeast phospholipase D hydrolyzed [(3)H]choline from [(3)H]choline
      labeled DPPC after incubation in vitro, whereas convertase, liver esterase, or
      peanut and cabbage phospholipases D did not. Thus convertase, liver esterase, and
      plant phospholipases D did not hydrolyze choline from DPPC either on cycling or
      during incubation with enzyme in vitro. In conclusion, conversion of heavy to
      light subtype of surfactant by convertase may require a phospholipase D type
      hydrolysis of phospholipids, but the substrate in this reaction is not DPPC.

PMID- 10645887
TI  - Mechanisms of GM-CSF increase by diesel exhaust particles in human airway
      epithelial cells.
AB  - We have previously shown that exposure to diesel exhaust particles (DEPs)
      stimulates human airway epithelial cells to secrete the inflammatory cytokines
      interleukin-8, interleukin-1beta, and granulocyte-macrophage colony-stimulating
      factor (GM-CSF) involved in allergic diseases. In the present paper, we studied
      the mechanisms underlying the increase in GM-CSF release elicited by DEPs using
      the human bronchial epithelial cell line 16HBE14o-. RT-PCR analysis has shown an
      increase in GM-CSF mRNA levels after DEP treatments. Comparison of the effects of
      DEPs, extracted DEPs, or extracts of DEPs has shown that the increase in GM-CSF
      release is mainly due to the adsorbed organic compounds and not to the metals
      present on the DEP surface because the metal chelator desferrioxamine had no
      inhibitory effect. Furthermore, radical scavengers inhibited the DEP-induced GM
      CSF release, showing involvement of reactive oxygen species in this response.
      Moreover genistein, a tyrosine kinase inhibitor, abrogated the effects of DEPs on
      GM-CSF release, whereas protein kinase (PK) C, PKA, cyclooxygenase, or
      lipoxygenase inhibitors had no effect. PD-98059, an inhibitor of mitogen
      activated protein kinase, diminished the effects of DEPs, whereas SB-203580, an
      inhibitor of p38 mitogen-activated protein kinase, had a lower effect, and DEPs
      did actually increase the active, phosphorylated form of the extracellular signal
      regulated kinase as shown by Western blotting. In addition, cytochalasin D, which
      inhibits the phagocytosis of DEPs, reduced the increase in GM-CSF release after
      DEP treatment. Together, these data suggest that the increase in GM-CSF release
      is mainly due to the adsorbed organic compounds and that the effect of native
      DEPs requires endocytosis of the particles. Reactive oxygen species and tyrosine
      kinase(s) may be involved in the DEP-triggered signaling of the GM-CSF response.

PMID- 10645888
TI  - Increased elastase release by CF neutrophils is mediated by tumor necrosis factor
      alpha and interleukin-8.
AB  - Cystic fibrosis (CF) is a lethal, hereditary disorder characterized by a
      neutrophil-dominated inflammation of the lung. We sought to determine whether
      neutrophils from individuals with CF release more neutrophil elastase (NE) than
      neutrophils from normal subjects. Our results showed that peripheral blood
      neutrophils (PBNs) from normal subjects and individuals with CF contained similar
      amounts of NE, but after preincubation with CF bronchoalveolar lavage (BAL)
      fluid, significantly more NE was released by CF PBNs, a release that was
      amplified further by incubation with opsonized Escherichia coli. To determine
      which components of CF BAL fluid stimulated this excessive NE release from CF
      PBNs, we repeated the experiments after neutralization or immunoprecipitation of
      tumor necrosis factor (TNF)-alpha and interleukin (IL)-8 in CF BAL fluid. We
      found that subsequent NE release from CF PBNs was reduced significantly when TNF
      alpha and IL-8 were removed from CF BAL fluid. When TNF-alpha and IL-8 were used
      as activating stimuli, CF PBNs released significantly greater amounts of NE
      compared with PBNs from control subjects and individuals with bronchiectasis.
      These results indicate that CF PBNs respond abnormally to TNF-alpha and IL-8 in
      CF BAL fluid and react to opsonized bacteria by releasing more NE. This may help
      explain the increased NE burden seen in this condition.

PMID- 10645889
TI  - Retinoic acid-induced proliferation of lung alveolar epithelial cells is linked
      to p21(CIP1) downregulation.
AB  - Retinoids, including retinol and retinoic acid (RA) derivatives, have been shown
      to be involved in the processes of lung development as well as of lung repair
      after injury. Recently, we have provided evidence that RA could stimulate
      proliferation of lung alveolar type 2 epithelial cells (E. Nabeyrat, V. Besnard,
      S. Corroyer, V. Cazals, and A. Clement. Am. J. Physiol. Lung Cell. Mol. Physiol.
      275: L71-L79, 1998). To gain some insight into the mechanisms involved in the
      mitogenic action of RA, we focused in the present study on the effects of RA on
      the expression of G(1) phase cyclins and their cell cycle-dependent kinases
      (Cdks). Experiments were performed with serum-deprived cells cultured in the
      absence and presence of RA. The results showed no effects of RA on the expression
      of either cyclins or Cdks. In contrast, RA treatment was found to prevent the
      decrease in cyclin E-Cdk2 activity observed when cells were growth arrested by
      serum deprivation. The observation that changes in cyclin E-Cdk2 activity were
      not associated with modifications in the amount of complexes formed led to the
      suggestion that the Cdk inhibitory protein (CKI) was involved. Study of the CKI
      p21(CIP1) revealed marked differences in its expression in the absence and
      presence of RA, with a dramatic downregulation observed in RA-treated cells.
      Interestingly, immunoprecipitation experiments provided evidence that the
      decreased levels of p21(CIP1) were associated with a reduced interaction of this
      CKI with cyclin E-Cdk2 complexes. These data together with previous results
      obtained in various situations of type 2 cell growth arrest emphasize the role of
      p21(CIP1) in the control of lung alveolar epithelial cell proliferation.

PMID- 10645890
TI  - Regulation of SLPI and elafin release from bronchial epithelial cells by
      neutrophil defensins.
AB  - Secretory leukocyte proteinase inhibitor (SLPI) is a serine proteinase inhibitor
      that is produced locally in the lung by cells of the submucosal bronchial glands
      and by nonciliated epithelial cells. Its main function appears to be the
      inhibition of neutrophil elastase (NE). Recently, NE was found to enhance SLPI
      mRNA levels while decreasing SLPI protein release in airway epithelial cells.
      Furthermore, glucocorticoids were shown to increase both constitutive and NE
      induced SLPI mRNA levels. In addition to NE, stimulated neutrophils also release
      alpha-defensins. Defensins are small, antimicrobial polypeptides that are found
      in high concentrations in purulent secretions of patients with chronic airway
      inflammation. Like NE, defensins induce interleukin-8 production in airway
      epithelial cells. This induction is sensitive to inhibition by the glucocorticoid
      dexamethasone and is prevented in the presence of alpha(1)-proteinase inhibitor.
      The aim of the present study was to investigate the effect of defensins on the
      production of SLPI and the related NE inhibitor elafin/SKALP in primary bronchial
      epithelial cells (PBECs). Defensins significantly increase SLPI protein release
      by PBECs in a time- and dose-dependent fashion without affecting SLPI mRNA
      synthesis. In the presence of alpha(1)-proteinase inhibitor, the defensin-induced
      SLPI protein release is further enhanced, but no effect was observed on SLPI mRNA
      levels. Dexamethasone did not affect SLPI protein release from control or
      defensin-treated PBECs. In addition, we observed a constitutive release of
      elafin/SKALP by PBECs, but this was not affected by defensins. The present
      results suggest a role for defensins in the dynamic regulation of the
      antiproteinase screen in the lung at sites of inflammation.

PMID- 10645891
TI  - Protein kinase C is involved in enhanced airway smooth muscle cell growth in
      hyperresponsive rats.
AB  - Fischer rat airway smooth muscle (ASM) models two potential risk factors for
      asthma: hyperresponsiveness to contractile agonists and to growth stimuli. The
      aim of this study was to identify the mechanisms responsible for enhanced ASM
      mitogenic response in Fischer rats compared with the control Lewis strain. The
      enhanced Fischer ASM cell growth response to fetal bovine serum (FBS) could not
      be accounted for by phospholipase C, mitogen-activated protein kinases, or
      tyrosine kinase activities as assessed by pharmacological inhibition and Western
      blotting. In contrast, depletion of phorbol ester-sensitive isoforms of the
      serine/threonine kinase protein kinase C (PKC) removed the difference in growth
      response between the rat strains. Additionally, FBS selectively induced
      serine/threonine phosphorylation of a 115-kDa protein in Fischer ASM cells.
      Enhanced activation of PKC-betaI and decreased activation of PKC-delta in Fischer
      compared with Lewis cells following FBS stimulation were suggested by Western
      blotting of membrane and cytosolic fractions. The data are consistent with a role
      for PKC in the enhanced ASM cell growth of hyperresponsive rats.

PMID- 10645892
TI  - Lysosomes from rabbit type II cells catabolize surfactant lipids.
AB  - The role of a lysosome fraction from rabbit type II cells in surfactant
      dipalmitoylphosphatidylcholine (DPPC) catabolism was investigated in vivo using
      radiolabeled DPPC and dihexadecylphosphatidylcholine (1, 2-dihexadecyl-sn-glycero
      3-phosphocholine; DEPC), a phospholipase A(1)- and A(2)-resistant analog of DPPC.
      Freshly isolated type II cells were gently disrupted by shearing, and lysosomes
      were isolated with Percoll density gradients (density range 1.0591-1.1457 g/ml).
      The lysosome fractions were relatively free of contaminating organelles as
      determined by electron microscopy and organelle marker enzymes. After
      intratracheal injection of rabbits with [(3)H]DPPC and [(14)C]DEPC associated
      with a trace amount of natural rabbit surfactant, the degradation-resistant DEPC
      accumulated 16-fold compared with DPPC in lysosome fractions at 15 h. Lysosomes
      can be isolated from freshly isolated type II cells, and lysosomes from type II
      cells are the primary catabolic organelle for alveolar surfactant DPPC following
      reuptake by type II cells in vivo.

PMID- 10645894
TI  - Inhibition of NOS enhances pulmonary vascular changes in stroke-prone
      spontaneously hypertensive rats.
AB  - To determine the effects of chronic nitric oxide (NO) blockade on the pulmonary
      vasculature, 58-day-old spontaneously hypertensive rats of the stroke-prone
      substrain (SHRSP) and Wistar-Kyoto rats (WKY) received N(omega)-nitro-L-arginine
      (L-NNA; 15 mg. kg(-1). day(-1) orally for 8 days). Relaxation to acetylcholine
      (ACh) in hilar pulmonary arteries (PAs), the ratio of right ventricular (RV) to
      body weight (RV/BW) to assess RV hypertrophy (RVH), and the percent medial wall
      thickness (WT) of resistance PAs were examined. L-NNA did not alter the PA
      relaxation, RV/BW, or WT in WKY. Although the PA relaxation and RV/BW in control
      SHRSP were comparable to those in WKY, the WT was increased (31 +/- 2 vs. 19 +/-
      1%). L-NNA-treated SHRSP showed two patterns: in one group, the relaxation,
      RV/BW, and WT were comparable to those in the control SHRSP; in the other,
      impaired relaxation (36 +/- 7 vs. 88 +/- 4% for WKY) was associated with an
      increase in WT (37 +/- 1%) and RV/BW (0. 76 +/- 0.05). Thus the abnormal
      pulmonary vasculature in SHRSP at <10 wk of age is not accompanied by impaired
      relaxation in PAs or RVH; however, impaired relaxation is associated with
      increased WT and RVH.

PMID- 10645893
TI  - IL-4 increases surfactant and regulates metabolism in vivo.
AB  - Mice that express interleukin (IL)-4 in Clara cells (CCSP-IL-4) develop chronic
      airway inflammation and an alveolar proteinosis-like syndrome. To identify the
      role of IL-4 in surfactant homeostasis, we measured lipid and protein metabolism
      in the lungs of CCSP-IL-4 mice in vivo. Alveolar saturated phosphatidylcholine
      (Sat PC) pools were increased 6.5-fold and lung tissue Sat PC pools were
      increased 4. 8-fold in the IL-4 transgenic mice. Whereas surfactant protein (SP)
      A was increased proportionately to Sat PC, SP-D was increased approximately 90
      fold in the IL-4 mice compared with wild-type mice and was associated with 2.8
      fold increase in SP-D mRNA. The incorporation of palmitate and choline into Sat
      PC was increased about twofold in CCSP-IL-4 mice. Although trace doses of
      radiolabeled Sat PC were cleared from the air spaces and lungs of CCSP-IL-4 mice
      more slowly than in wild-type mice, net clearance of Sat PC from the lungs of
      CCSP-IL-4 mice was sixfold higher in the IL-4 mice than in wild-type mice because
      of the larger Sat PC pool sizes. Expression of IL-4 in Clara cells increased
      surfactant lipid synthesis and clearance, establishing a new equilibrium with
      increased surfactant pools and an alveolar proteinosis associated with a
      selective increase in SP-D protein, demonstrating a previously unexpected effect
      of IL-4 in pulmonary surfactant homeostasis.

PMID- 10645895
TI  - Enhanced anti-influenza activity of a surfactant protein D and serum conglutinin
      fusion protein.
AB  - We previously demonstrated that bovine serum conglutinin has markedly greater
      ability to inhibit influenza A virus (IAV) infectivity than other collectins. We
      now show that recombinant conglutinin and a chimeric protein containing the NH(2)
      terminus and collagen domain of rat pulmonary surfactant protein D (rSP-D) fused
      to the neck region and carbohydrate recognition domain (CRD) of conglutinin
      (termed SP-D/Cong(neck+CRD)) have markedly greater ability to inhibit infectivity
      of IAV than wild-type recombinant rSP-D, confirming that the potent IAV
      neutralizing activity of conglutinin resides in its neck region and CRD.
      Furthermore, by virtue of incorporation of the NH(2) terminus and collagen domain
      of SP-D, SP-D/Cong(neck+CRD) caused substantially greater aggregation of IAV
      particles and enhancement of neutrophil binding of, and H(2)O(2) responses to,
      IAV than recombinant conglutinin or recombinant rSP-D. Hence, SP-D/Cong(neck+CRD)
      combined favorable antiviral and opsonic properties of conglutinin and SP-D. This
      study demonstrates an association of specific structural domains of SP-D and
      conglutinin with specific functional properties and illustrates that
      antimicrobial activities of wild-type collectins can be enhanced through
      recombinant strategies.

PMID- 10645896
TI  - Curosurf modulates cAMP accumulation in human monocytes through a membrane
      controlled mechanism.
AB  - The cellular mechanisms by which pulmonary surfactant exerts its effects,
      including anti-inflammatory or proinflammatory effects, have remained elusive. To
      address the issue of whether plasma membrane modifications represent a target for
      these mechanisms, we designed an experimental protocol involving the
      determination of changes in cAMP levels under membrane-dependent or -independent
      stimulatory pathways. The effects of a modified natural porcine surfactant,
      Curosurf, and the major surfactant protein A were evaluated on resting and
      stimulated cAMP levels of human monocytes. We found that agents that elevate
      intracellular cAMP exhibit different susceptibilities toward a preexposure to
      Curosurf. The rise in cAMP induced by membrane-active agents such as cholera
      toxin or the diterpene forskolin was significantly inhibited by monocyte
      preexposure to Curosurf. In contrast, the rise in cAMP induced by the membrane
      permeant phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine or by the
      Bordetella pertussis toxin adenylate cyclase-hemolysin was unaffected by
      Curosurf. Surfactant protein A did not affect either cAMP levels or the
      inhibitory capacity of Curosurf. We suggest that a plasma membrane-associated
      event affecting the mechanism underlying the effects of cholera toxin or
      forskolin is involved in the inhibition of cAMP accumulation caused by Curosurf.

PMID- 10645897
TI  - Role of neuronal nitric oxide synthase in regulation of vascular and ductus
      arteriosus tone in the ovine fetus.
AB  - Nitric oxide (NO) is produced by NO synthase (NOS) and contributes to the
      regulation of vascular tone in the perinatal lung. Although the neuronal or type
      I NOS (NOS I) isoform has been identified in the fetal lung, it is not known
      whether NO produced by the NOS I isoform plays a role in fetal pulmonary
      vasoregulation. To study the potential contribution of NOS I in the regulation of
      basal fetal pulmonary vascular resistance (PVR), we studied the hemodynamic
      effects of a selective NOS I antagonist, 7-nitroindazole (7-NINA), and a
      nonselective NOS antagonist, N-nitro-L-arginine (L-NNA), in chronically prepared
      fetal lambs (mean age 128 +/- 3 days, term 147 days). Brief intrapulmonary
      infusions of 7-NINA (1 mg) increased basal PVR by 37% (P < 0.05). The maximum
      increase in PVR occurred within 20 min after infusion, and PVR remained elevated
      for up to 60 min. Treatment with 7-NINA also increased the pressure gradient
      between the pulmonary artery and aorta, suggesting constriction of the ductus
      arteriosus (DA). To test whether 7-NINA treatment selectively inhibits the NOS I
      isoform, we studied the effects of 7-NINA and L-NNA on acetylcholine-induced
      pulmonary vasodilation. The vasodilator response to acetylcholine remained intact
      after treatment with 7-NINA but was completely inhibited after L-NNA, suggesting
      minimal effects on endothelial or type III NOS after 7-NINA infusion. Western
      blot analysis detected NOS I protein in the fetal lung and great vessels
      including the DA. NOS I protein was detected in intact and endothelium-denuded
      vessels, suggesting that NOS I is present in the medial or adventitial layer. We
      conclude that 7-NINA, a selective NOS I antagonist, increases basal PVR, systemic
      arterial pressure, and DA tone in the late-gestation fetus and that NOS I protein
      is present in the fetal lung and great vessels. We speculate that NOS I may
      contribute to NO production in the regulation of basal vascular tone in the
      pulmonary and systemic circulations and the DA.

PMID- 10645898
TI  - Association of L-arginine transporters with fodrin: implications for hypoxic
      inhibition of arginine uptake.
AB  - In this study, we investigated the possible interaction between the cationic
      amino acid transporter (CAT)-1 arginine transporter and ankyrin or fodrin.
      Because ankyrin and fodrin are substrates for calpain and because hypoxia
      increases calpain expression and activity in pulmonary artery endothelial cells
      (PAEC), we also studied the effect of hypoxia on ankyrin, fodrin, and CAT-1
      contents in PAEC. Exposure to long-term hypoxia (24 h) inhibited L-arginine
      uptake by PAEC, and this inhibition was prevented by calpain inhibitor 1. The
      effects of hypoxia and calpain inhibitor 1 were not associated with changes in
      CAT-1 transporter content in PAEC plasma membranes. However, hypoxia stimulated
      the hydrolysis of ankyrin and fodrin in PAEC, and this could be prevented by
      calpain inhibitor 1. Incubation of solubilized plasma membrane proteins with anti
      fodrin antibodies resulted in a 70% depletion of CAT-1 immunoreactivity and in a
      60% decrease in L-arginine transport activity in reconstituted proteoliposomes
      (3,291 +/- 117 vs. 8,101 +/- 481 pmol. mg protein(-1). 3 min(-1) in control).
      Incubation with anti-ankyrin antibodies had no effect on CAT-1 content or L
      arginine transport in reconstituted proteoliposomes. These results demonstrate
      that CAT-1 arginine transporters in PAEC are associated with fodrin, but not with
      ankyrin, and that long-term hypoxia decreases L-arginine transport by a calpain
      mediated mechanism that may involve fodrin proteolysis.

PMID- 10645899
TI  - Capacitative Ca(2+) entry and tyrosine kinase activation in canine pulmonary
      arterial smooth muscle cells.
AB  - We investigated the role of capacitative Ca(2+) entry and tyrosine kinase
      activation in mediating phenylephrine (PE)-induced oscillations in intracellular
      free Ca(2+) concentration ([Ca(2+)](i)) in canine pulmonary arterial smooth
      muscle cells (PASMCs). [Ca(2+)](i) was measured as the 340- to 380-nm ratio in
      individual fura 2-loaded PASMCs. Resting [Ca(2+)](i) was 96 +/- 4 nmol/l. PE (10
      micromol/l) stimulated oscillations in [Ca(2+)](i), with a peak amplitude of 437
      +/- 22 nmol/l and a frequency of 1.01 +/- 0.12/min. Thapsigargin (1 micromol/l)
      was used to deplete sarcoplasmic reticulum (SR) Ca(2+) after extracellular Ca(2+)
      was removed. Under these conditions, a nifedipine-insensitive, sustained increase
      in [Ca(2+)](i) (140 +/- 7% of control value) was observed when the extracellular
      Ca(2+) concentration was restored; i.e., capacitative Ca(2+) entry was
      demonstrated. Capacitative Ca(2+) entry also refilled SR Ca(2+) stores.
      Capacitative Ca(2+) entry was attenuated (32 +/- 3% of control value) by 50
      micromol/l of SKF-96365 (a nonselective Ca(2+)-channel inhibitor). Tyrosine
      kinase inhibition with tyrphostin 23 (100 micromol/l) and genistein (100
      micromol/l) also inhibited capacitative Ca(2+) entry to 63 +/- 12 and 85 +/- 4%
      of control values, respectively. SKF-96365 (30 micromol/l) attenuated both the
      amplitude (15 +/- 7% of control value) and frequency (50 +/- 21% of control
      value) of PE-induced Ca(2+) oscillations. SKF-96365 (50 micromol/l) abolished the
      oscillations. Tyrphostin 23 (100 micromol/l) also inhibited the amplitude (17 +/-
      7% of control value) and frequency (45 +/- 9% of control value) of the
      oscillations. Genistein (30 micromol/l) had similar effects. Both SKF-96365 and
      tyrphostin 23 attenuated PE-induced contraction in isolated pulmonary arterial
      rings. These results demonstrate that capacitative Ca(2+) entry is present and
      capable of refilling SR Ca(2+) stores in canine PASMCs and may be involved in
      regulating PE-induced Ca(2+) oscillations. A tyrosine kinase is involved in the
      signal transduction pathway for alpha(1)-adrenoreceptor activation in PASMCs.

PMID- 10645900
TI  - Cell growth modulates nitric oxide synthase expression in fetal pulmonary artery
      endothelial cells.
AB  - Nitric oxide (NO), produced by endothelial (e) nitric oxide synthase (NOS), is a
      critical mediator of vascular function and growth in the developing lung.
      Pulmonary eNOS expression is diminished in conditions associated with altered
      pulmonary vascular development, suggesting that eNOS may be modulated by changes
      in pulmonary artery endothelial cell (PAEC) growth. We determined the effects of
      cell growth on eNOS expression in cultured ovine fetal PAEC studied at varying
      levels of confluence. NOS enzymatic activity was sixfold greater in quiescent
      PAEC at 100% confluence compared with more rapidly replicating cells at 50%
      confluence. To determine if there is a reciprocal effect of NO on PAEC growth,
      studies of NOS inhibition or the provision of exogenous NO from spermine NONOate
      were performed. Neither intervention had a discernable effect on PAEC growth. The
      influence of cell growth on NOS activity was unique to pulmonary endothelium,
      because varying confluence did not alter NOS activity in fetal systemic
      endothelial cells. The effects of cell growth induced by serum stimulation were
      also evaluated, and NOS enzymatic activity was threefold greater in quiescent,
      serum-deprived cells compared with that in serum-stimulated cells. The increase
      in NOS activity observed at full confluence was accompanied by parallel increases
      in eNOS protein and mRNA expression. These findings indicate that eNOS gene
      expression in fetal PAEC is upregulated during cell quiescence and downregulated
      during rapid cell growth. Furthermore, the interaction between cell growth and NO
      in the PAEC is unidirectional.

PMID- 10645901
TI  - beta-Adrenergic agonist modulation of monocyte adhesion to airway epithelial
      cells in vitro.
AB  - beta-Adrenergic agonists are commonly used in the treatment of obstructive airway
      diseases and are known to modulate cAMP-dependent processes of airway epithelial
      cells. However, little is known regarding the ability of cAMP-dependent
      mechanisms to influence cell-cell interactions within the airway. Thus we
      investigated the role of the beta-adrenergic agonist isoproterenol in modulating
      the ability of human bronchial epithelial cells to support the adhesion of THP-1
      cells, a monocyte/macrophage cell line, in vitro. We demonstrated that
      pretreatment of human bronchial epithelial cells (HBECs) with 10 microM
      isoproterenol or 100 microM salbutamol augments the adhesion of fluorescently
      labeled THP-1 cells to HBEC monolayers by approximately 40-60%. The increase in
      THP-1 cell adhesion occurred with 10 min of isoproterenol pretreatment of HBECs
      and gradually declined but persisted with up to 24 h of isoproterenol exposure.
      Exposure of THP-1 cells to isoproterenol or salbutamol before the adhesion assays
      did not result in an increase in adhesion to HBECs, suggesting that the
      isoproterenol modulation was primarily via changes in epithelial cells. A
      specific protein kinase A inhibitor, KT-5720, inhibited subsequent isoproterenol
      augmentation of THP-1 cell adhesion, further supporting the role of cAMP
      dependent mechanisms in modulating THP-1 cell adhesion to HBECs.

PMID- 10645902
TI  - Posttranscriptional regulation of plasminogen activator inhibitor-1 in human lung
      carcinoma cells in vitro.
AB  - Plasminogen activator inhibitor-1 (PAI-1), the major circulating inhibitor of
      urokinase [urokinase-type plasminogen activator (uPA)], has been linked to the
      pathogenesis of lung cancer. PAI-1 belongs to the serpin family of inhibitors and
      inhibits both free urokinase (uPA) and receptor-bound urokinase (uPA receptor).
      Although PAI-1 has been related to a poor prognosis in lung carcinoma, mechanisms
      that regulate its expression in human lung cancer cells are not well understood.
      We used cultured human small cell and non-small cell lung carcinoma cell lines as
      model systems to elucidate the regulatory mechanisms that control expression of
      PAI-1. Levels of PAI-1 protein were significantly increased in selected lung
      carcinoma cells compared with those in normal small-airway epithelial cells.
      Corresponding steady-state levels of PAI-1 mRNA were similarly increased in these
      cells. The half-life of PAI-1 mRNA was prolonged in these lung carcinoma cell
      lines after transcriptional or translational blockade. We identified a 60-kDa
      protein that binds the 3'-untranslated region of PAI-1, and complex formation of
      this binding protein with PAI-1 mRNA reciprocally correlates with mRNA stability.
      The findings demonstrate that expression of PAI-1 is regulated at the
      posttranscriptional level in small cell- and non-small cell-derived human lung
      carcinoma cell lines. Altered regulation of PAI-1 at the posttranscriptional
      level may contribute to relative overexpression by malignant lung epithelial
      cells. A newly identified regulatory protein that binds to the 3'-untranslated
      region of PAI-1 mRNA appears to be involved in the posttranscriptional regulation
      of PAI-1 gene expression by human lung carcinoma cells in vitro.

PMID- 10645903
TI  - Mobilization of intracellular Ca(2+) by endothelin-1 in rat intrapulmonary
      arterial smooth muscle cells.
AB  - Endothelin-1 (ET-1) increases intracellular Ca(2+) concentration ([Ca(2+)](i)) in
      pulmonary arterial smooth muscle cells (PASMCs); however, the mechanisms for
      Ca(2+) mobilization are not clear. We determined the contributions of
      extracellular influx and intracellular release to the ET-1-induced Ca(2+)
      response using Indo 1 fluorescence and electrophysiological techniques.
      Application of ET-1 (10(-10) to 10(-8) M) to transiently (24-48 h) cultured rat
      PASMCs caused concentration-dependent increases in [Ca(2+)](i). At 10(-8) M, ET-1
      caused a large, transient increase in [Ca(2+)](i) (>1 microM) followed by a
      sustained elevation in [Ca(2+)](i) (<200 nM). The ET-1-induced increase in
      [Ca(2+)](i) was attenuated (<80%) by extracellular Ca(2+) removal; by verapamil,
      a voltage-gated Ca(2+)-channel antagonist; and by ryanodine, an inhibitor of
      Ca(2+) release from caffeine-sensitive stores. Depleting intracellular stores
      with thapsigargin abolished the peak in [Ca(2+)](i), but the sustained phase was
      unaffected. Simultaneously measuring membrane potential and [Ca(2+)](i) indicated
      that depolarization preceded the rise in [Ca(2+)](i). These results suggest that
      ET-1 initiates depolarization in PASMCs, leading to Ca(2+) influx through voltage
      gated Ca(2+) channels and Ca(2+) release from ryanodine- and inositol 1,4,5
      trisphosphate-sensitive stores.

PMID- 10645904
TI  - Differentiated and functional human airway epithelium regeneration in tracheal
      xenografts.
AB  - To investigate the regeneration process of a well-differentiated and functional
      human airway epithelium, we adapted an in vivo xenograft model in which adult
      human nasal epithelial cells adhere and progressively repopulate denuded rat
      tracheae grafted in nude mice. The proliferating activity, the degree of
      differentiation, and the barrier integrity of the repopulated epithelium were
      studied during the regeneration process at optical and ultrastructural levels
      with immunocytochemistry and a permeability tracer. Three days after implantation
      in nude mice, tracheal xenografts were partially repopulated with a flattened
      nonciliated and poorly differentiated leaky epithelium. By the end of the first
      week after the graft, cell proliferation produced on the entire surface of the
      rat trachea an epithelium that was stratified into multiple layers and tightly
      sealed. During successive weeks, cell proliferation dramatically decreased.
      Moreover, the epithelium became progressively columnar, secretory, ciliated, and
      transiently leaky. At 4-5 wk, a fully differentiated pseudostratified functional
      epithelial barrier impermeable to a low-molecular-weight tracer was
      reconstituted. The regeneration of a well-differentiated and functional human
      airway epithelium in rat tracheae grafted in nude mice includes several steps
      that mimic the regeneration dynamics of airway epithelium after injury.

PMID- 10645905
TI  - Early expression of beta- and gamma-subunits of epithelial sodium channel during
      human airway development.
AB  - The amiloride-sensitive epithelial Na(+) channel (ENaC) is an apical membrane
      protein complex involved in active Na(+) absorption and in control of fluid
      composition in airways. There are no data reporting the distribution of its pore
      forming alpha-, beta-, and gamma-subunits in the developing human lung. With use
      of two different rabbit polyclonal antisera raised against beta- and gamma-ENaC,
      immunohistochemical localization of the channel was performed in fetal (10-35 wk)
      and in adult human airways. Both subunits were detected after 17 wk of gestation
      on the apical domain of bronchial ciliated cells, in glandular ducts, and in
      bronchiolar ciliated and Clara cells. After 30 wk, the distribution of beta- and
      gamma-subunits was similar in fetal and adult airways. In large airways, the two
      subunits were detected in ciliated cells, in cells lining glandular ducts, and in
      the serous gland cells. In the distal bronchioles, beta- and gamma-subunits were
      identified in ciliated and Clara cells. Ultrastructural immunogold labeling
      confirmed the identification of beta- and gamma-ENaC proteins in submucosal
      serous cells and bronchiolar Clara cells. Early expression of ENaC proteins in
      human fetal airways suggests that Na(+) absorption might begin significantly
      before birth, even if secretion is still dominant.

PMID- 10645906
TI  - Agarose plug instillation causes goblet cell metaplasia by activating EGF
      receptors in rat airways.
AB  - We hypothesized that foreign bodies in airways cause inflammation leading to
      goblet cell metaplasia. Instilled agarose plugs lodged in the bronchi of pathogen
      free rats caused a time-dependent increase in Alcian blue-periodic acid-Schiff
      staining that was detected within 24 h and markedly increased at 72 h. Control
      bronchi contained no pregoblet or goblet cells, but plugged bronchi contained
      many pregoblet and goblet cells and a decrease in nongranulated secretory cells.
      In situ hybridization showed no expression of MUC5AC in control airways, but
      plugged airways showed a marked expression. Control bronchi showed sparse
      staining for epidermal growth factor receptor (EGFR) protein, but plugged bronchi
      showed intense EGFR staining in the epithelium. Pretreatment with an EGFR
      tyrosine kinase inhibitor (BIBX1522) prevented Alcian blue-periodic acid-Schiff
      staining and MUC5AC gene expression in plugged bronchi. Pretreatment with tumor
      necrosis factor-alpha neutralizing antibody or pretreatment with cyclophosphamide
      abolished plug-induced EGFR protein expression and goblet cell metaplasia. Thus
      instillation of agarose plugs induces profound goblet cell metaplasia by causing
      EGFR expression and activation.

PMID- 10645907
TI  - Mast cell tryptase stimulates human lung fibroblast proliferation via protease
      activated receptor-2.
AB  - Mast cells play a potentially important role in fibroproliferative diseases,
      releasing mediators including tryptase that are capable of stimulating fibroblast
      proliferation and procollagen synthesis. The mechanism by which tryptase
      stimulates fibroblast proliferation is unclear, although recent studies suggest
      it can activate protease-activated receptor (PAR)-2. We therefore investigated
      the role of PAR-2 in tryptase-induced proliferation of human fetal lung and adult
      lung parenchymal and airway fibroblasts and, for comparative purposes, adult
      dermal fibroblasts. Tryptase (0.7-70 mU/ml) induced concentration-dependent
      increases in proliferation of all fibroblasts studied. Antipain, bis(5-amidino-2
      benzimidazolyl)methane, and benzamidine inhibited tryptase-induced fibroblast
      proliferation, demonstrating that proteolytic activity is required for the
      proliferative effects of tryptase. RT-PCR demonstrated the presence of PAR-2
      mRNA, and immunohistochemical staining localized PAR-2 to the cell surface of
      lung fibroblasts. In addition, specific PAR-2 activating peptides, SLIGKV and
      SLIGRL, mimicked the proliferative effects of tryptase. In contrast, human dermal
      fibroblasts only weakly stained with the PAR-2 antibody, PAR-2 mRNA was almost
      undetectable, and fibroblasts did not respond to PAR-2 activating peptides. These
      results suggest that tryptase induces lung, but not dermal, fibroblast
      proliferation via activation of PAR-2 and are consistent with the hypothesis that
      the release of tryptase from activated mast cells may play an important role in
      the fibroproliferative response observed in asthma, chronic obstructive pulmonary
      disease, and patients with pulmonary fibrosis.

PMID- 10645908
TI  - Developmental changes in endothelial nitric oxide synthase expression and
      activity in ovine fetal lung.
AB  - Endothelial nitric oxide (NO) synthase (eNOS) produces NO, which contributes to
      vascular reactivity in the fetal lung. Pulmonary vasoreactivity develops during
      late gestation in the ovine fetal lung, during the period of rapid capillary and
      alveolar growth. Although eNOS expression peaks near birth in the fetal rat, lung
      capillary and distal air space development occur much later than in the fetal
      lamb. To determine whether lung eNOS expression in the lamb differs from the
      timing and pattern reported in the rat, we measured eNOS mRNA and protein by
      Northern and Western blot analyses and NOS activity by the arginine-to-citrulline
      conversion assay in lung tissue from fetal, newborn, and maternal sheep. Cellular
      localization of eNOS expression was determined by immunohistochemistry. eNOS
      mRNA, protein, and activity were detected in samples from all ages, and eNOS was
      expressed predominantly in the vascular endothelium. Lung eNOS mRNA expression
      increases from low levels at 70 days gestation to peak at 113 days and remains
      high for the rest of fetal life. Newborn eNOS mRNA expression does not change
      from fetal levels but is lower in the adult ewe. Lung eNOS protein expression in
      the fetus rises and peaks at 118 days gestation but decreases before birth. eNOS
      protein expression rises in the newborn period but is lower in the adult. Lung
      NOS activity also peaks at 118 days gestation in the fetus before falling in late
      gestation and remaining low in the newborn and adult. We conclude that the
      pattern of lung eNOS expression in the sheep differs from that in the rat and may
      reflect species-related differences in lung development. We speculate that the
      rise in fetal lung eNOS may contribute to the marked lung growth and angiogenesis
      that occurs during the same period of time.

PMID- 10645909
TI  - Airway fibrosis in rats induced by vanadium pentoxide.
AB  - Vanadium pentoxide (V(2)O(5)) is a cause of occupational asthma and bronchitis.
      We previously reported that intratracheal instillation of rats with V(2)O(5)
      causes fibrosis of the lung parenchyma (J. C. Bonner, P. M. Lindroos, A. B. Rice,
      C. R. Moomaw, and D. L. Morgan. Am. J. Physiol. Lung Cell. Mol. Physiol. 274: L72
      L80, 1998). In this report, we show that intratracheal instillation of V(2)O(5)
      induces airway remodeling similar to that observed in individuals with asthma.
      These changes include airway smooth muscle cell thickening, mucous cell
      metaplasia, and airway fibrosis. The transient appearance of peribronchiolar
      myofibroblasts, which were desmin and vimentin positive, coincided with a twofold
      increase in the thickness of the airway smooth muscle layer at day 6 after
      instillation and preceded the development of airway fibrosis by day 15. The
      number of nuclear profiles within the smooth muscle layer also increased twofold
      after V(2)O(5) instillation, suggesting that hyperplasia accounted for thickening
      of the smooth muscle layer. The majority of cells incorporating bromodeoxyuridine
      at day 3 were located in the connective tissue surrounding the airway smooth
      muscle wall that was positive for vimentin and desmin. These data suggest that
      myofibroblasts are the principal proliferating cell type that contributes to the
      progression of airway fibrosis after V(2)O(5) injury.

PMID- 10645910
TI  - Vascular expression of the alpha(v)beta(3)-integrin in lung and other organs.
AB  - The expression of the alpha(v)beta(3)-integrin in nonproliferating vascular beds
      remains unclear. To determine possible organ-specific differences, we compared
      alpha(v)beta(3)-integrin expression in the lung and other organs. Paraffin
      embedded tissue sections of lung, liver, brain, muscle and skin obtained from
      rats were processed for immunohistochemistry with a monoclonal (LM609) and a
      polyclonal antibody (AB1903) against the alpha(v)beta(3)-integrin. Immunogold
      electron microscopy was used to localize alpha(v)beta(3)-integrin in rat lung
      microvasculature. With the use of custom-designed primers, lung sections were
      subjected to in situ PCR in a thermal cycler to amplify alpha(v) or beta(3) mRNA.
      To confirm specific amplification, PCR products were further hybridized in situ
      with an alpha(v) or beta(3) cDNA probe. In the lung, the alpha(v)beta(3)-integrin
      protein as well as alpha(v) and beta(3) mRNAs was extensively evident in the
      endothelium of extra-alveolar and alveolar microvessels, in vascular smooth
      muscle, and in large bronchial epithelium but not in the epithelium of alveolar
      ducts or alveoli. Ultrastructural immunogold labeling showed the presence of the
      integrin on the luminal and abluminal faces of the lung microvascular endothelium
      but not on the apical surface of the alveolar epithelium. Staining for the
      integrin was generally negative in blood vessels of several systemic organs,
      although weak staining was evident in branches of the hepatic portal vein. The
      constitutive presence of the alpha(v) and beta(3) mRNAs and the alpha(v)beta(3)
      integrin in the lung microvascular bed suggests that gene transcription for the
      integrin is ongoing in lung vessels. Because it binds vitronectin, the lung
      vascular alpha(v)beta(3)-integrin may play a role in ligation of bloodborne,
      vitronectin-containing macromolecular complexes formed in inflammation.

PMID- 10645911
TI  - Circulation online only : january 25, 2000

PMID- 10645912
TI  - Does hypertension confer a prothrombotic state? Virchow's triad revisited.

PMID- 10645913
TI  - Vascular matrix and vein graft failure. Is the message in the medium?

PMID- 10645914
TI  - Androgen receptor expression is greater in macrophages from male than from female
      donors. A sex difference with implications for atherogenesis.
AB  - BACKGROUND: Male sex is an independent risk factor for the extent and severity of
      atherosclerosis. The influence of androgens on foam cell formation, a key event
      in atherogenesis, has not yet been investigated. METHODS AND RESULTS: Primary
      human monocytes were allowed to differentiate into macrophages. RNA was then
      extracted from healthy male-donor (n=8) and premenopausal female-donor (n=8)
      macrophages, and message for the androgen receptor (AR) was examined by RT-PCR.
      There was a significantly higher level of AR mRNA in macrophages isolated from
      men than in those from women (0.64+/-0.06 versus 0.15+/-0.02 amol/microgram total
      RNA; P<0.001). AR mRNA levels were similar in macrophages from postmenopausal and
      premenopausal women (P=0.16). The functional consequence of this sex difference
      was then explored. Lipid-loading studies were performed on male (n=9) macrophages
      treated with the androgen dihydrotestosterone (DHT) and/or the AR antagonist
      hydroxyflutamide. These showed that DHT caused a dose-dependent and receptor
      mediated increase in macrophage cholesteryl ester content (109+/-10%, 117+/-3%,
      and 120+/-4% for 4, 40, and 400 nmol/L DHT, respectively, as a percentage of
      control, P=0.002; 95+/-8% for DHT with hydroxyflutamide, P=0.58 versus controls).
      By contrast, there was no significant effect of androgen on lipid loading in
      female-donor macrophages (P>0.2 versus controls). CONCLUSIONS: Sex differences in
      androgen-mediated macrophage lipid loading may contribute to the greater
      prevalence and severity of atherosclerosis in men.

PMID- 10645915
TI  - Accumulation of apolipoprotein C-I-rich and cholesterol-rich VLDL remnants during
      exaggerated postprandial triglyceridemia in normolipidemic patients with coronary
      artery disease.
AB  - BACKGROUND: Exaggerated postprandial triglyceridemia is common in normolipidemic
      patients with coronary artery disease (CAD). Alterations in the composition of
      triglyceride-rich lipoproteins (TRLs) are likely to underlie this metabolic
      disturbance. However, the composition of very-low-density lipoproteins (VLDLs),
      which are the most abundant postprandial TRLs, has never been defined in CAD
      patients. METHODS AND RESULTS: We examined postprandial changes in the number and
      composition of VLDLs in middle-aged, normolipidemic CAD patients and control
      subjects. TRLs from 14 patients and 14 control subjects aged 45 to 55 years were
      subfractionated by density gradient ultracentrifugation into Svedberg flotation
      rate (Sf) fractions >400, 60 to 400, and 20 to 60. The VLDLs were separated from
      chylomicron remnants by immunoaffinity chromatography. In CAD patients, the
      postprandial concentrations of triglycerides and large (Sf 60 to 400) VLDL
      particles were elevated. In addition, their postprandial large VLDLs were
      enriched in apolipoprotein (apo) C-I and their postprandial small (Sf 20 to 60)
      VLDL remnants were enriched with apo C-I and cholesterol. CONCLUSIONS: Perturbed
      handling of postprandial triglycerides in normolipidemic CAD patients involves
      the accumulation of apo C-I-rich large VLDL particles and the generation of
      small, apo C-I- and cholesterol-rich VLDL remnants.

PMID- 10645916
TI  - Enteroviral capsid protein VP1 is present in myocardial tissues from some
      patients with myocarditis or dilated cardiomyopathy.
AB  - BACKGROUND: There are still discrepancies in the association of enterovirus and
      myocardial disease, partially due to lack of data on the detection of virus
      antigens in tissues. It is desirable to localize enteroviral antigens so as to
      establish a link between the two and to study mechanisms of virus persistence.
      METHODS AND RESULTS: Nineteen fixed explanted or postmortem myocardial samples
      were obtained from patients with myocarditis or dilated cardiomyopathy (DCM).
      Control samples were collected from 11 subjects who had died accidentally or of
      noncardiovascular disease. Viral antigen was detected by an improved
      immunohistochemical technique using an enterovirus group-specific antibody to
      viral capsid protein VP1. Nine of 11 myocarditis cases (81.8%) and 6 of 8 DCM
      cases (75%) were positive. Signals were localized in the cytoplasm of myocytes.
      Intense immunostaining was observed in acute myocarditis, whereas VP1 was
      detected in scattered myocytes in chronic myocarditis or DCM. Enteroviral RNA was
      detected in 6 of 11 myocarditis samples (54.5%) and 3 of 8 DCM samples (37.5%) by
      the reverse transcription-nested polymerase chain reaction, correlating with
      antigen detection (kappa=0.6+/-0.21). Neither viral antigen nor RNA was detected
      in any controls. CONCLUSIONS: Our findings demonstrate a direct link between
      enterovirus infection and some myocarditis or DCM cases. The pattern of VP1
      detection may correlate with disease stage and severity. The data suggest that
      viral protein synthesis may be involved in persistent enterovirus infection in
      the pathogenesis of DCM.

PMID- 10645917
TI  - Modulation of vascular inflammation in vitro and in vivo by peroxisome
      proliferator-activated receptor-gamma activators.
AB  - BACKGROUND: Peroxisome proliferator-activated receptor-gamma (PPARgamma) is
      expressed in atherosclerotic plaques and in endothelial cells. The possible
      effects of PPARgamma activators on endothelial activation and inflammatory
      response within the plaque are currently unknown. METHODS AND RESULTS: We tested
      the hypothesis that PPARgamma activators inhibit vascular cell adhesion molecule
      (VCAM-1) and intercellular adhesion molecule (ICAM-1) expression in cultured
      endothelial cells (evaluated by flow cytometry) and homing of
      monocyte/macrophages to atherosclerotic plaques in vivo. In endothelial cells,
      the PPARgamma agonists troglitazone at 100 micromol/L and 15-deoxy-(Delta12,14)
      prostaglandin J(2) (15d-PGJ2) at 20 micromol/L markedly attenuated the tumor
      necrosis factor-induced expression of VCAM-1 and ICAM-1. A significant inhibition
      of VCAM-1 expression was also evident at 5 and 10 micromol/L 15d-PGJ2 and 20
      micromol/L troglitazone. Expression of E-selectin and PECAM-1 was not altered. To
      confirm the biological relevance of these results, we assessed the effects of
      troglitazone on monocyte/macrophage homing to atherosclerotic plaques in apoE
      deficient mice. A 7-day treatment with troglitazone (400 mg/kg) significantly
      reduced monocyte/macrophage homing to atherosclerotic plaques (236+/-77 versus
      177+/-43 macrophages, P=0.03); an even more striking inhibition was found at 3200
      mg/kg troglitazone (344+/-76 versus 172+/-83 macrophages, P=0.005). CONCLUSIONS:
      PPARgamma activators inhibit expression of VCAM-1 and ICAM-1 in activated
      endothelial cells and significantly reduce monocyte/macrophage homing to
      atherosclerotic plaques. These findings suggest that PPARgamma activators,
      currently used in treatment of type II diabetes, may have beneficial effects in
      modulating inflammatory response in atherosclerosis.

PMID- 10645919
TI  - Severity of coronary artery calcification by electron beam computed tomography
      predicts silent myocardial ischemia.
AB  - BACKGROUND: Detection of subclinical coronary artery disease (CAD) before the
      development of life-threatening cardiac complications has great potential
      clinical relevance. Electron beam computed tomography (EBCT) is currently the
      only noninvasive test that can detect CAD in all stages of its development and
      thus has the potential to be an excellent screening technique for identifying
      asymptomatic subjects with underlying myocardial ischemia. METHODS AND RESULTS:
      Over 2.5 years, we prospectively studied 3895 generally asymptomatic subjects
      with EBCT, 411 of whom had stress myocardial perfusion tomography (SPECT) within
      a close (median, 17 days) time period. SPECT and exercise treadmill results were
      compared with the coronary artery calcium score (CACS) as assessed by EBCT. The
      total CACS identified a population at high risk for having myocardial ischemia by
      SPECT although only a minority of subjects (22%) with an abnormal EBCT had an
      abnormal SPECT. No subject with CACS <10 had an abnormal SPECT compared with 2.6%
      of those with scores from 11 to 100, 11.3% of those with scores from 101 to 399,
      and 46% of those with scores >/=400 (P<0.0001). CACS predicted an abnormal SPECT
      regardless of subject age or sex. CONCLUSIONS: CACS identifies a high-risk group
      of asymptomatic subjects who have clinically important silent myocardial
      ischemia. Our results support the role of EBCT as the initial screening tool for
      identifying individuals at various stages of CAD development for whom therapeutic
      decision making may differ considerably.

PMID- 10645918
TI  - Abciximab improves both epicardial flow and myocardial reperfusion in ST
      elevation myocardial infarction. Observations from the TIMI 14 trial.
AB  - BACKGROUND: In the presence of ST-elevation myocardial infarction, patients with
      successful epicardial reperfusion (TIMI 3 flow) but persistent ST elevation on a
      12-lead ECG are at high risk for subsequent death and left ventricular
      dysfunction. In the TIMI 14 trial, a dose-ranging angiographic study, combined
      therapy with abciximab plus reduced-dose tPA enhanced the speed and efficacy of
      epicardial reperfusion. We determined whether the combination of abciximab plus
      reduced-dose tPA provided additional benefit in terms of myocardial reperfusion,
      as evidenced by greater resolution of ST elevation. METHODS AND RESULTS: All 346
      patients with interpretable baseline and 90-minute ECGs, treated with either tPA
      alone or abciximab plus reduced-dose tPA (combination therapy), were included.
      Patients receiving combination therapy (n=221) had a 59% rate of complete
      (>/=70%) ST resolution at 90 minutes versus 37% in those treated with tPA alone
      (n=125) (P<0.0001). When the analysis was limited to patients with TIMI 3 flow,
      patients treated with combination therapy (n=151) remained significantly more
      likely to achieve complete ST resolution than those receiving tPA alone (n=80)
      (69% versus 44%; P=0.0002). CONCLUSIONS: Combination therapy with abciximab and
      reduced-dose tPA improves myocardial (microvascular) reperfusion, as reflected in
      greater ST-segment resolution, in addition to epicardial flow. This finding may
      translate into improved clinical outcomes by enhancing myocardial salvage.

PMID- 10645920
TI  - Infections, inflammation, and the risk of coronary heart disease.
AB  - BACKGROUND: The role of infections and inflammation in the pathophysiology of
      coronary heart disease is emerging. We studied the independent and joint effects
      of these 2 components on coronary risk. METHODS AND RESULTS: We measured baseline
      levels of C-reactive protein (CRP) and antibodies to adenovirus, enterovirus,
      cytomegalovirus, and herpes simplex virus as well as to Chlamydia pneumoniae
      (Cpn) and Helicobacter pylori in 241 subjects who suffered either myocardial
      infarction or coronary death during the 8.5-year trial in the Helsinki Heart
      Study, a coronary primary prevention trial. The 241 controls in this nested case
      control study were subjects who completed the study without coronary events.
      Antibody levels to herpes simplex type I (HSV-1) and to Cpn were higher in cases
      than in controls, whereas the distributions of antibodies to other infectious
      agents were similar. Mean CRP was higher in cases (4.4 versus 2.0 mg/L; P<0.001),
      and high CRP increased the risks associated with smoking and with high
      antimicrobial antibody levels. The odds ratios in subjects with high antibody and
      high CRP levels were 25.4 (95% CI 2.9-220.3) for HSV-1 and 5.4 (95% CI 2.4-12.4)
      for Cpn compared with subjects with low antibody levels and low CRP. High
      antibody levels to either HSV-1 or to Cpn increased the risk independently of the
      other, and their joint effect was close to additive. CONCLUSIONS: Two chronic
      infections, HSV-1 and Cpn, increase the risk of coronary heart disease. The
      effect is emphasized in subjects with ongoing inflammation, denoted by increased
      CRP levels.

PMID- 10645921
TI  - Dobutamine-atropine stress echocardiography for the detection of coronary artery
      disease in patients with left ventricular hypertrophy. Importance of chamber size
      and systolic wall stress.
AB  - BACKGROUND: Left ventricular hypertrophy is a heterogeneous disorder with
      distinct morphologies. Changes in wall thickness, left ventricular chamber
      diameter, and mass alter systolic wall stress of the left ventricle and may
      influence ischemic threshold. Thus, the goal of this study was to investigate the
      effect of the different patterns of left ventricular hypertrophy on the accuracy
      of dobutamine-atropine stress echocardiography. METHODS AND RESULTS: Three
      hundred eighty-six patients underwent multistage dobutamine-atropine stress
      echocardiography and diagnostic angiography. Echocardiograms were measured for
      mean and relative wall thicknesses, chamber size, left ventricular mass, and end
      systolic wall stress. The patterns of ventricular hypertrophy were concentric
      hypertrophy (increased wall thickness and mass), eccentric hypertrophy (normal
      wall thickness and increased mass), and concentric remodeling (increased wall
      thickness and normal mass). The overall sensitivity, specificity, and accuracy of
      dobutamine-atropine stress echocardiography for the detection of coronary artery
      disease were 85%, 87%, and 86%, respectively. Increased left ventricular mass
      index alone did not affect accuracy. Sensitivity was markedly reduced (36%) only
      in those with concentric remodeling. The univariate predictors of false-negative
      studies were single-vessel left circumflex disease, increased wall thickness,
      small chamber size, hyperdynamic ejection fraction, and left ventricular
      concentric remodeling. Multivariate predictors were concentric remodeling
      (P<0.0001; odds ratio, 13.5), left ventricular ejection fraction >2 SD above
      normal (P<0.0001), and single-vessel left circumflex disease (P<0.0007; odds
      ratio, 7.6). Sensitivity was excellent in patients with small ventricles and
      normal wall thickness and in those with normal or large chambers regardless of
      wall thickness. CONCLUSIONS: Dobutamine-atropine stress echocardiography is an
      accurate test in most patients with left ventricular hypertrophy, but it is
      insensitive in the small subset with concentric remodeling.

PMID- 10645922
TI  - Association of blood pressure with fibrinolytic potential in the Framingham
      offspring population.
AB  - BACKGROUND: Hypertension is an established risk factor for acute coronary events.
      Because fibrinolytic and hemostatic factors are also associated with
      cardiovascular disease, we examined the relations of systolic and diastolic blood
      pressures (SBP and DBP) to levels of plasminogen activator inhibitor antigen,
      tissue plasminogen activator antigen, fibrinogen, factor VII, von Willebrand
      factor, fibrinogen, and plasma viscosity in subjects of the Framingham Offspring
      Study. METHODS AND RESULTS: We studied 1193 men and 1459 women after the
      exclusion of subjects with known cardiovascular disease and those receiving
      anticoagulant or antihypertensive therapy. Linear regression models were used to
      evaluate SBP and DBP as predictors of fibrinolytic and hemostatic factor levels
      in separate sex models, with adjustment for age, body mass index, smoking,
      diabetes, total cholesterol, HDL, triglycerides, alcohol intake, and estrogen use
      (in women). In both sexes, levels of plasminogen activator inhibitor and tissue
      plasminogen activator antigen were positively related to SBP and DBP (P<0.001).
      Plasma viscosity was positively related to SBP (P=0.008) and DBP (P=0.001) in
      women only. There was no association between SBP or DBP and fibrinogen, factor
      VII, or von Willebrand factor in either sex. CONCLUSIONS: These data suggest that
      impaired fibrinolysis may play an important role in the pathogenesis of
      cardiovascular disease in hypertensive patients.

PMID- 10645923
TI  - Atypical atrial flutter originating in the right atrial free wall.
AB  - BACKGROUND: Data from experimental models of atrial flutter indicate that macro
      reentrant circuits may be confined by anatomic and functional barriers remote
      from the tricuspid annulus-eustachian ridge atrial isthmus. Data characterizing
      the various forms of atypical atrial flutter in humans are limited. METHODS AND
      RESULTS: In 6 of 160 consecutive patients referred for ablation of
      counterclockwise and/or clockwise typical atrial flutter, an additional atypical
      atrial flutter was mapped to the right atrial free wall. Five patients had no
      prior cardiac surgery. Incisional atrial tachycardia was excluded in the
      remaining patient. High-density electroanatomic maps of the reentrant circuit
      were obtained in 3 patients. Radiofrequency energy application from a discrete
      midlateral right atrial central line of conduction block to the inferior vena
      cava terminated and prevented the reinduction of atypical atrial flutter in each
      patient. Atrial flutter has not recurred in any patient (follow-up, 18+/-17
      months; range, 3 to 40 months). CONCLUSIONS: Atrial flutter can arise in the
      right atrial free wall. This form of atypical atrial flutter could account for
      spontaneous or inducible atrial flutter observed in patients referred for
      ablation and is eliminated with linear ablation directed at the inferolateral
      right atrium.

PMID- 10645924
TI  - Cost-effectiveness of catheter ablation in patients with ventricular tachycardia.
AB  - BACKGROUND: This study evaluated the cost-effectiveness of catheter ablation
      therapy versus amiodarone for treating ventricular tachycardia (VT) in patients
      with structural heart disease. The analysis used a societal perspective for a
      hypothetical cohort of VT patients with implantable cardioverter-defibrillators,
      who were experiencing frequent shocks. METHODS AND RESULTS: We calculated
      incremental cost-effectiveness of ablation relative to amiodarone over 5 years
      after treatment initiation. Event probabilities were from the Chilli randomized
      clinical trial (Chilli Cooled Ablation System, Cardiac Pathways Corporation,
      Sunnyvale, Calif), the literature, and a consensus panel. Costs were from 1998
      national Medicare reimbursement schedules. Quality-of-life weights (utilities)
      were estimated using an established preference measurement technique. In a
      hypothetical cohort of 10 000 patients, 5-year costs were higher for patients
      undergoing ablation compared with amiodarone therapy ($21 795 versus $19 075).
      Ablation also produced a greater increase in quality of life (2.78 versus 2.65
      quality-adjusted life-years [QALYs]). This yielded a cost-effectiveness ratio of
      $20 923 per QALY gained for ablation compared with amiodarone. Results were
      relatively insensitive to assumptions about ablation success and durability. In
      less severe patients with good ejection fractions who suffer their first VT
      episode, the incremental cost-effectiveness ratio was $6028 per QALY gained.
      These cost-effectiveness ratios are within the range generally thought to warrant
      technology adoption. CONCLUSIONS: This study demonstrates that, from a societal
      perspective, catheter ablation appears to be a cost-effective alternative to
      amiodarone for treating VT patients.

PMID- 10645925
TI  - Thromboresistance of balloon-injured porcine carotid arteries after local gene
      transfer of human tissue factor pathway inhibitor.
AB  - BACKGROUND: Tissue factor pathway inhibitor (TFPI) is an endogenous inhibitor of
      factor Xa and the coagulant initiator complex tissue factor/factor VIIa. METHODS
      AND RESULTS: To study the effects of TFPI gene transfer on thrombus formation,
      balloon-injured porcine carotid arteries were treated locally with an adenovirus
      encoding human TFPI (Ad-TFPI) or control virus. Gene transfer of TFPI was
      confirmed by detection of human TFPI in the conditioned medium of porcine carotid
      arteries kept in culture after in vivo transduction. When carotid flow was
      measured with Doppler probe 5 days after surgery, cyclic flow variations (CFVs)
      developed in 7 of 8 control pigs after constriction of the injured carotid artery
      by 40%, and all control-treated arteries occluded after 70% constriction. In
      contrast, CFVs were observed in only 1 of 8 Ad-TFPI-treated pigs after 40%
      constriction, and only 3 of 8 occluded after constriction by 70% (P=0.0027 and
      P=0.007, respectively). None of the 5 TFPI-transduced arteries open after 70%
      constriction developed CFVs during an incremental epinephrine infusion.
      CONCLUSIONS: Compared with baseline, systemic hemostatic variables and platelet
      aggregation were unimpaired, suggesting that TFPI gene transfer can prevent
      arterial thrombosis in the presence of severe shear stress and without detectable
      hemostatic impairment.

PMID- 10645926
TI  - Inhibition of late vein graft neointima formation in human and porcine models by
      adenovirus-mediated overexpression of tissue inhibitor of metalloproteinase-3.
AB  - BACKGROUND: Autologous saphenous vein coronary artery bypass graft surgery is
      complicated by late graft failure due to neointima formation and subsequent
      atherosclerosis. Growth factors and metalloproteinases (MMPs) act in concert to
      promote neointima formation. Tissue inhibitor of metalloproteinase-3 (TIMP-3), an
      extracellular matrix-associated MMP inhibitor, uniquely promotes apoptosis of
      isolated vascular smooth muscle cells. Here, we overexpressed TIMP-3 at the
      luminal surface of human saphenous veins before organ culture and in pig
      saphenous veins before interposition grafting into carotid arteries in vivo to
      assess neointima formation. METHODS AND RESULTS: In both models, high TIMP-3
      immunoreactivity occurred in the luminal and upper medial extracellular matrix
      after adenovirus delivery. MMP activity measured by in situ zymography was
      reduced throughout the veins, confirming a bystander effect. By use of 3
      independent techniques, apoptosis levels in the neointima and medial layer were
      significantly elevated by TIMP-3 overexpression. Neointima formation was reduced
      by 84% in 14-day human organ cultures and by 58% in 28-day pig vein grafts (both
      P<0.05). In contrast, TIMP-2 overexpression had no effect on neointima formation
      in vivo. CONCLUSIONS: Our results highlight the potential therapeutic benefit for
      TIMP-3 overexpression to reduce neointima formation associated with late vein
      graft failure.

PMID- 10645927
TI  - Important role of local angiotensin II activity mediated via type 1 receptor in
      the pathogenesis of cardiovascular inflammatory changes induced by chronic
      blockade of nitric oxide synthesis in rats.
AB  - BACKGROUND: The chronic inhibition of NO synthesis by N(omega)-nitro-L-arginine
      methyl ester (L-NAME) upregulates the cardiovascular tissue angiotensin II (Ang
      II)-generating system and induces cardiovascular inflammatory changes in rats.
      METHODS AND RESULTS: We used a rat model to investigate the role of local Ang II
      activity in the pathogenesis of such inflammatory changes. Marked increases in
      monocyte infiltration into coronary vessels and myocardial interstitial areas,
      monocyte chemoattractant protein-1 (MCP-1) expression, and nuclear factor-kappaB
      (NF-kappaB, an important redox-sensitive transcriptional factor that induces MCP
      1) activity were observed on day 3 of L-NAME administration. Along with these
      changes, vascular superoxide anion production was also increased. Treatment with
      an Ang II type 1 receptor antagonist or with a thiol-containing antioxidant, N
      acetylcysteine, prevented all of these changes. CONCLUSIONS: Increased Ang II
      activity mediated via the type 1 receptor may thus be important in the
      pathogenesis of early cardiovascular inflammatory changes in this model.
      Endothelium-derived NO may decrease MCP-1 production and oxidative stress
      sensitive signals by suppressing localized activity of Ang II.

PMID- 10645928
TI  - Nifedipine-induced coronary vasodilation in ischemic hearts is attributable to
      bradykinin- and NO-dependent mechanisms in dogs.
AB  - BACKGROUND: Dihydropyridine calcium channel blockers protect endothelial cells
      against ischemia and reperfusion injury, suggesting that nifedipine may increase
      the in vivo cardiac NO level and thus coronary blood flow (CBF) in ischemic
      hearts. We tested this hypothesis. METHODS AND RESULTS: In open-chest dogs,
      coronary perfusion pressure (CPP) was reduced in the left anterior descending
      coronary artery so that CBF decreased to one third of the control level, and
      thereafter CPP was maintained constant (103+/-8 to 43+/-3 mm Hg, n=9). We
      obtained fractional shortening (FS) and lactate extraction ratio (LER) as indices
      of regional myocardial contraction and metabolism. Both FS (26.4+/-2.1% to 6.7+/
      2.0%, n=9, P<0.001) and LER (32+/-6% to -37+/-5%, n=9, P<0.001) showed a decrease
      when CPP was reduced. After intracoronary infusion of nifedipine (4 microgram.
      kg(-1). min(-1)), CBF increased from 30+/-1 to 48+/-4 mL. 100 g(-1). min(-1)
      (P<0.01) without a change of CPP (n=9). Both FS (14.0+/-1.9%, n=9) and LER (-9+/
      7%, n=9) also increased (P<0.01). Nifedipine increased the difference in the
      level of metabolites of NO (nitrate+nitrite; 9+/-3 to 25+/-5 nmol/mL, n=9,
      P<0.01) and bradykinin (22+/-5 to 58+/-4 pmol/mL, n=9, P<0.01) between coronary
      venous and arterial blood. L-NAME (an NO synthase inhibitor) or HOE-140 (a
      bradykinin receptor antagonist) attenuated (P<0.05) the increase in CBF (29+/-3
      and 35+/-2 mL. 100 g(-1). min(-1), n=5 each), FS (4.8+/-0.6% and 6.9+/-1.7%, n=5
      each), LER (-47+/-8% and -35+/-9%, n=5 each), and nitrate+nitrite (3+/-2 and 8+/
      4 nmol/mL, n=5 each) due to nifedipine infusion. CONCLUSIONS: These results
      indicate that the calcium channel blocker nifedipine mediates coronary
      vasodilation and improves myocardial ischemia through both bradykinin/NO
      dependent and -independent mechanisms.

PMID- 10645929
TI  - Effects of intravenous and intracoronary adenosine 5'-triphosphate as compared
      with adenosine on coronary flow and pressure dynamics.
AB  - BACKGROUND: Measurements of Doppler derived coronary flow reserve (CFR) and
      pressure derived fractional flow reserve (FFR) for coronary stenosis assessment
      depend on the induction of maximal hyperemia. Adenosine is the most widely used
      pharmacological agent but is expensive and poorly tolerated by some patients.
      METHODS AND RESULTS: The objective of this study was to test the equivalency of
      adenosine 5'-triphosphate (ATP) to adenosine in their ability to cause maximal
      hyperemia as compared with the hyperemic response of complete coronary occlusion
      in 6 canines. Intracoronary administration of either ATP or adenosine resulted in
      a significant increase in CFR (2.79+/-0.64 and 2.22+/-0.7 for 10 microgram versus
      4. 65+/-1.22 and 4.25+/-0.78 for 100 microgram for ATP and adenosine,
      respectively, P for trend <0.001) but not reaching the level of coronary
      occlusion (6.35+/-2.26). Additionally, FFR and CFR were measured in 35 different
      stenoses using ATP, adenosine, and coronary occlusion. There was an excellent
      linear correlation between ATP and adenosine for both CFR (R=0.934, P<0.001) and
      FFR (R=0.985, P<0.001). However, hyperemia with either ATP or adenosine was less
      than postocclusion hyperemia, resulting in significantly different reserve
      measurements (CFR: 1.93+/-0.66 and 2.08+/-0.81 versus 2.35+/-0.97, P<0.001; FFR:
      0.62+/-0.24 and 0.63+/-0.23 versus 0.58+/-0.2, P<0.001). CONCLUSIONS: 1) Step up
      in dosage of ATP and adenosine beyond currently recommended clinical doses
      resulted in a significant increase in coronary hyperemia; 2) ATP was equivalent
      to adenosine for both CFR and FFR; and 3) complete coronary occlusion yielded a
      better hyperemic response than either drug, indicating that maximal hyperemia was
      not achieved by either pharmacological stimulus.

PMID- 10645930
TI  - Flavone-8-acetic acid (Flavonoid) profoundly reduces platelet-dependent
      thrombosis and vasoconstriction after deep arterial injury In vivo.
AB  - BACKGROUND: Flavone-8-acetic acid (FAA; [Flavonoid]), an adjuvant antitumor drug,
      inhibits ristocetin-induced aggregation of human platelets. The effect of FAA on
      platelet-dependent thrombosis was studied in vivo in the porcine carotid artery
      after deep arterial injury by balloon angioplasty. METHODS AND RESULTS: (111)In
      labeled autologous platelet and (125)I-labeled porcine fibrin(ogen) deposition,
      and the incidence of macroscopic mural thrombosis onto deeply injured artery
      (tunica media) were compared in 20 pigs (40+/-1 kg [mean+/-SEM], body surface
      area=1.0+/-0.1 m(2)), randomized to FAA bolus (n=10) of 5.5g/m(2), followed by an
      infusion at 0.14g. m(-2). min(-1) or placebo (n=10). Vasoconstriction was
      measured immediately beyond the dilated segment using quantitative angiography.
      Platelet deposition (x10(6)/cm(2) of carotid artery) was reduced over 12-fold in
      pigs treated with FAA (13+/-3 versus 164+/-51, P=0.001) compared with placebo.
      Fibrin(ogen) deposition (x10(12) molecules/cm(2) of carotid artery) did not
      significantly differ in FAA-treated pigs versus placebo (40+/-8 versus 140+/-69,
      P=0.08). Large mural thrombi were present in 100% of placebo-treated pigs versus
      very small thrombi in 40% of FAA-treated pigs (P=0.005). Vasoconstriction was
      reduced from 46+/-6% in the placebo group to 15+/-3% in the FAA group (P<0.001).
      Plasma level of FAA before angioplasty was 515+/-23 microgram/mL. The activated
      partial thromboplastin time was unchanged. The bleeding time was >2SD above the
      normal mean in 4 of 5 treated pigs (increased from 157+/-29 to 522+/-123 s).
      CONCLUSIONS: FAA markedly reduced platelet deposition, mural thrombi, and injury
      induced vasoconstriction after deep arterial injury, suggesting that a major
      inhibition of platelet glycoprotein Ibalpha may be beneficial therapy.

PMID- 10645931
TI  - Essential hypertension. Part I: definition and etiology.

PMID- 10645932
TI  - The athlete's heart. A meta-analysis of cardiac structure and function.
AB  - BACKGROUND: It has been postulated that depending on the type of exercise
      performed, 2 different morphological forms of athlete's heart may be
      distinguished: a strength-trained heart and an endurance-trained heart.
      Individual studies have not tested this hypothesis satisfactorily. METHODS AND
      RESULTS: The hypothesis of divergent cardiac adaptations in endurance-trained and
      strength-trained athletes was tested by applying meta-analytical techniques with
      the assumption of a random study effects model incorporating all published
      echocardiographic data on structure and function of male athletes engaged in
      purely dynamic (running) or static (weight lifting, power lifting, bodybuilding,
      throwing, wrestling) sports and combined dynamic and static sports (cycling and
      rowing). The analysis encompassed 59 studies and 1451 athletes. The overall mean
      relative left ventricular wall thickness of control subjects (0.36 mm) was
      significantly smaller than that of endurance-trained athletes (0.39 mm, P=0.001),
      combined endurance- and strength-trained athletes (0.40 mm, P=0.001), or strength
      trained athletes (0.44 mm, P<0.001). There was a significant difference between
      the 3 groups of athletes and control subjects with respect to left ventricular
      internal diameter (P<0. 001), posterior wall thickness (P<0.001), and
      interventricular septum thickness (P<0.001). In addition, endurance-trained
      athletes and strength-trained athletes differed significantly with respect to
      mean relative wall thickness (0.39 versus 0.44, P=0.006) and interventricular
      septum thickness (10.5 versus 11.8 mm, P=0.005) and showed a trend toward a
      difference with respect to posterior wall thickness (10.3 versus 11.0 mm,
      P=0.078) and left ventricular internal diameter (53.7 versus 52.1 mm, P=0.055).
      With respect to cardiac function, there were no significant differences between
      athletes and control subjects in left ventricular ejection fraction, fractional
      shortening, and E/A ratio. CONCLUSIONS: Results of this meta-analysis regarding
      athlete's heart confirm the hypothesis of divergent cardiac adaptations in
      dynamic and static sports. Overall, athlete's heart demonstrated normal systolic
      and diastolic cardiac functions.

PMID- 10645933
TI  - Takayasu's arteritis : spiral CT angiography findings.

PMID- 10645934
TI  - Genetic drowning trigger.

PMID- 10645935
TI  - Health Care Financing Administration wants to make kidney transplant availability
      equal, regardless of race.

PMID- 10645936
TI  - Precautions advised to prevent needlestick injuries among US healthcare workers.

PMID- 10645937
TI  - Reducing the rate of medical errors in the United States.

PMID- 10645938
TI  - FDA approves new drug to reduce risk of stroke.

PMID- 10645939
TI  - Inverted left atrial appendage masquerading as myxoma.

PMID- 10645940
TI  - Natural statins and stroke.

PMID- 10645941
TI  - Safety and efficacy of ticlopidine after stent placement.

PMID- 10645942
TI  - Are there any associations among coagulation factor VII gene polymorphism, plasma
      activated factor VII levels, and cerebrovascular disease?

PMID- 10645943
TI  - The editors wish to recognize and thank these individuals for their help in
      reviewing manuscripts for circulation. Those listed returned manuscript reviews
      to circulation during the period from june 1, 1998 through june 30, 1999

PMID- 10645944
TI  - Making and using DNA microarrays: a short course at Cold Spring Harbor
      Laboratory.

PMID- 10645945
TI  - The bacterial replicative helicase DnaB evolved from a RecA duplication.
AB  - The RecA/Rad51/DCM1 family of ATP-dependent recombinases plays a crucial role in
      genetic recombination and double-stranded DNA break repair in Archaea, Bacteria,
      and Eukaryota. DnaB is the replication fork helicase in all Bacteria. We show
      here that DnaB shares significant sequence similarity with RecA and Rad51/DMC1
      and two other related families of ATPases, Sms and KaiC. The conserved region
      spans the entire ATP- and DNA-binding domain that consists of about 250 amino
      acid residues and includes 7 distinct motifs. Comparison with the three
      dimensional structure of Escherichia coli RecA and phage T7 DnaB (gp4) reveals
      that the area of sequence conservation includes the central parallel beta-sheet
      and most of the connecting helices and loops as well as a smaller domain that
      consists of a amino-terminal helix and a carboxy-terminal beta-meander.
      Additionally, we show that animals, plants, and the malarial Plasmodium but not
      Saccharomyces cerevisiae encode a previously undetected DnaB homolog that might
      function in the mitochondria. The DnaB homolog from Arabidopsis also contains a
      DnaG-primase domain and the DnaB homolog from the nematode seems to contain an
      inactivated version of the primase. This domain organization is reminiscent of
      bacteriophage primases-helicases and suggests that DnaB might have been
      horizontally introduced into the nuclear eukaryotic genome via a phage vector. We
      hypothesize that DnaB originated from a duplication of a RecA-like ancestor after
      the divergence of the bacteria from Archaea and eukaryotes, which indicates that
      the replication fork helicases in Bacteria and Archaea/Eukaryota have evolved
      independently.

PMID- 10645946
TI  - Spatially restricted hypopigmentation associated with an Ednrbs-modifying locus
      on mouse chromosome 10.
AB  - We have used the varied expressivity of white spotting (hypopigmentation)
      observed in intrasubspecific crosses of Ednrb(s) mice (Mayer Ednrb(s)/Ednrb(s)
      and C3HeB/FeJ Ednrb(s)/Ednrb(s)) to analyze the effects of modifier loci on the
      patterning of hypopigmentation. We have confirmed that an Ednrb(s) modifier locus
      is present on mouse Chromosome 10. This locus is now termed k10, using the
      nomenclature established by Dunn in 1920. The k10(Mayer) allele is a recessive
      modifier that accounts for almost all of the genetic variance of dorsal
      hypopigmentation. Using intercross analyses we identified a second allele of this
      locus or a closely linked gene termed k10(C3H). The k10(C3H) allele is
      semidominant and is associated with the penetrance and expressivity of a white
      forelock phenotype similar to that seen in Waardenburg syndrome. Molecular
      linkage analysis was used to determine that the k10 critical interval was flanked
      by D10Mit10 and D10Mit162/D10Mit122 and cosegregates with mast cell growth factor
      (Mgf). Complementation crosses with a Mgf(Sl) allele (a 3-5-cM deletion) confirm
      the semidominant white forelock feature of the k10(C3H) allele and the dorsal
      spotting feature of K10(Mayer) allele. MgF was assessed as a candidate gene for
      k10(Mayer) and k10(C3H) by sequence and genomic analyses. No molecular
      differences were observed between the Mayer and C57BL/6J alleles of MgF; however,
      extensive genomic differences were observed between the C3HeB/FeJ and C57BL/6J
      alleles. This suggests that alteration of MgF expression in C3H mice may account
      for the k10(C3H) action on white forelock hypopigmentation. Crosses of Ednrb(s)
      with Kit(WJ-2) (the receptor for MGF)-deficient mice confirmed the hypothesis
      that synergistic interaction between the Endothelin and MGF signaling pathways
      regulates proper neural crest-derived melanocyte development in vivo.

PMID- 10645947
TI  - Uterine dysfunction and genetic modifiers in centromere protein B-deficient mice.
AB  - Centromere protein B (CENP-B) binds constitutively to mammalian centromere repeat
      DNA and is highly conserved between humans and mouse. Cenpb null mice appear
      normal but have lower body and testis weights. We demonstrate here that testis
      weight reduction is seen in male null mice generated on three different genetic
      backgrounds (denoted R1, W9.5, and C57), whereas body-weight reduction is
      dependent on the genetic background as well as the gender of the animals. In
      addition, Cenpb null females show 31%, 33%, and 44% reduced uterine weights on
      the R1, W9.5, and C57 backgrounds, respectively. Production of "revertant" mice
      lacking the targeted frameshift mutation but not the other components of the
      targeting construct corrected these differences, indicating that the observed
      phenotype is attributable to Cenpb gene disruption rather than a neighbouring
      gene effect induced by the targeting construct. The R1 and W9.5 Cenpb null
      females are reproductively competent but show age-dependent reproductive
      deterioration leading to a complete breakdown at or before 9 months of age.
      Reproductive dysfunction is much more severe in the C57 background as Cenpb null
      females are totally incompetent or are capable of producing no more than one
      litter. These results implicate a further genetic modifier effect on female
      reproductive performance. Histology of the uterus reveals normal myometrium and
      endometrium but grossly disrupted luminal and glandular epithelium. Tissue in
      situ hybridization demonstrates high Cenpb expression in the uterine epithelium
      of wild-type animals. This study details the first significant phenotype of Cenpb
      gene disruption and suggests an important role of Cenpb in uterine morphogenesis
      and function that may have direct implications for human reproductive pathology.

PMID- 10645948
TI  - A major effect QTL determined by multiple genes in epileptic EL mice.
AB  - The EL mouse strain provides a polygenic model for epilepsy. Previous mapping
      experiments between EL and nonepileptic ABP mice identified, and a congenic
      strain confirmed, a quantitative trait locus (QTL), El2, which lowered the
      threshold to seizures induced by gentle rhythmic tossing. To narrow the map
      interval further we used a nested strategy to analyze a series of recombinants
      derived from the congenic strain. The recombinant strains revealed a complex
      pattern of inheritance, with at least two independent regions of Chromosome 2
      necessary for rhythmic tossing seizures and additional regions associated with
      unusual gender effects. Similar results obtained using a completely independent
      paradigm, pentylenetetrazole-induced tonic-clonic seizures, exclude the
      possibility that the genetic complexity was a unique property of the testing
      assay. Thus, although conventional QTL mapping efforts detected and appeared to
      confirm a trait locus with effects large enough for fine-structure mapping,
      subsequent dissection revealed multiple loci. Although at least one of these loci
      was mapped to a 1-cM interval, its individual effect is small, perhaps
      approaching the practical limits for further study. Our results in the EL mouse
      may be prophetic for similar assaults on other polygenic, composite neurological
      behaviors which vary among inbred strains, begging the consideration of
      alternative strategies toward gene identification in these models.

PMID- 10645949
TI  - Genetic localization of interacting modifiers affecting severity in a murine
      model of polycystic kidney disease.
AB  - Genetic analysis of mouse disease models provides a means to investigate how
      modifying loci cause variation in phenotypic expression. We have shown that
      polycystic kidney disease (PKD) progression in the juvenile cystic kidney (jck)
      mutation can be influenced by an epistatic interaction between alleles of
      different strain backgrounds and we localized one of these loci to chromosome 1.
      Using a chromosome 1 congenic strain, we improved the genetic analysis and mapped
      the interacting locus to proximal chromosome 4, with a highly significant lod
      association of 5.5. Re-analysis of the original F(2) cross reveals that in this
      cohort, while the lod association of the chromosome 4 locus alone is not
      significant, its effect is apparent when analyzed in combination with the
      chromosome 1 locus. This result suggests that correlation of paired genotype data
      with phenotype data will be an effective means to detect epistatic interactions
      contributing to complex traits, and that these associations can be tested using
      appropriate congenic lines.

PMID- 10645950
TI  - DNA profiling of B chromosomes from the yellow-necked mouse Apodemus flavicollis
      (Rodentia, Mammalia).
AB  - Using AP-PCR-based DNA profiling we examined some structural features of B
      chromosomes from yellow-necked mice Apodemus flavicollis. Mice harboring one,
      two, or three or lacking B chromosomes were examined. Chromosomal structure was
      scanned for variant bands by using a series of arbitrary primers and from these,
      informative bands were selected. The selection criteria used were the ability to
      differentiate between individuals of the species, to detect markers common for
      both A and B chromosomes, and, importantly, to differentiate between A- and B
      chromosome sets. In addition to primers, profiling conditions were found to be
      critical for meeting the selection criteria. Primers and analysis conditions that
      demonstrated structural characteristics unique to the B-chromosome set are
      described. These characteristics included variant bands as qualitative parameters
      and altered electrophoretic band intensities as quantitative distinctions
      estimated by integration of densitometric profiles of electrophoretograms. B
      chromosome-specific molecular markers are easy to detect by AP-PCR-based DNA
      profiling in the presence of a full set of A chromosomes. Models for the origin
      of yellow-necked mouse B chromosomes are discussed in the context of presented
      data.

PMID- 10645951
TI  - Simple sequence repeats in Escherichia coli: abundance, distribution,
      composition, and polymorphism.
AB  - Computer-based genome-wide screening of the DNA sequence of Escherichia coli
      strain K12 revealed tens of thousands of tandem simple sequence repeat (SSR)
      tracts, with motifs ranging from 1 to 6 nucleotides. SSRs were well distributed
      throughout the genome. Mononucleotide SSRs were over-represented in noncoding
      regions and under-represented in open reading frames (ORFs). Nucleotide
      composition of mono- and dinucleotide SSRs, both in ORFs and in noncoding
      regions, differed from that of the genomic region in which they occurred, with
      93% of all mononucleotide SSRs proving to be of A or T. Computer-based analysis
      of the fine position of every SSR locus in the noncoding portion of the genome
      relative to downstream ORFs showed SSRs located in areas that could affect gene
      regulation. DNA sequences at 14 arbitrarily chosen SSR tracts were compared among
      E. coli strains. Polymorphisms of SSR copy number were observed at four of seven
      mononucleotide SSR tracts screened, with all polymorphisms occurring in noncoding
      regions. SSR polymorphism could prove important as a genome-wide source of
      variation, both for practical applications (including rapid detection, strain
      identification, and detection of loci affecting key phenotypes) and for
      evolutionary adaptation of microbes.

PMID- 10645952
TI  - Selection against frameshift mutations limits microsatellite expansion in coding
      DNA.
AB  - Microsatellite enrichment is an excess of repetitive sequences characteristic to
      all studied eukaryotes. It is thought to result from the accumulated effects of
      replication slippage mutations. Enrichment is commonly measured as the ratio of
      the observed frequency of microsatellites to the frequency expected to result
      from random association of nucleotides. We have compared enrichment of specific
      types of microsatellites in coding sequences with those in noncoding sequences
      across seven eukaryotic clades. The results reveal consistent differences between
      coding and noncoding regions, in terms of both the quantity of repetitive DNA and
      the types present. In noncoding regions, all types of microsatellite (mono-, di-,
      tri-, tetra-, penta-, and hexanucleotide repeats) are found in excess, and in all
      cases, these excesses scale in a similar exponential fashion with the length of
      the microsatellite. This suggests that all types of noncoding repeats are subject
      to similar mutational and selective processes. Coding repeats, however, appear to
      be under much stronger and more specific constraints. Tri- and hexanucleotide
      repeats are found in consistent and significant excess over a wide range of
      lengths in both coding and noncoding sequences, but other repeat types are much
      less frequent in coding regions than in noncoding regions. These findings suggest
      that the differences between coding and noncoding microsatellite frequencies
      arise from specific selection against frameshift mutations in coding regions
      resulting from length changes in nontriplet repeats. Furthermore, the excesses of
      tri- and hexanucleotide coding repeats appear to be controlled primarily by
      mutation pressure.

PMID- 10645954
TI  - ACAPELLA-1K, a capillary-based submicroliter automated fluid handling system for
      genome analysis.
AB  - The Genomation Laboratory in the Electrical Engineering Department at the
      University of Washington has been developing an automated, high-throughput,
      submicroliter-scale fluid-handling system for use in molecular biology,
      especially as part of the Human Genome Project and other high-throughput DNA
      sequencing endeavors. Small glass capillaries enable the preparation, handling,
      and monitoring of 1-microliter reaction volumes. The Genomation Laboratory, with
      corporate partners Orca Photonic Systems, Inc. and Engineering Arts, has
      developed modules for aspiration, dispensing, mixing, transport, and rapid
      thermal processing of biological samples contained in glass capillaries. The
      ACAPELLA-1K is the first integration of these modules, designed to process 1000
      samples in an eight-hour day. It has served as a test bed for the technologies as
      well as for performing biological experiments in conjunction with the University
      of Washington Genome Center. This system and related results are presented in
      this paper. A video of the system in operation is provided at. The Genomation
      Laboratory is presently developing the next-stage ACAPELLA-5K system based on the
      results of the ACAPELLA-1K system.

PMID- 10645953
TI  - A preliminary gene map for the Van der Woude syndrome critical region derived
      from 900 kb of genomic sequence at 1q32-q41.
AB  - Van der Woude syndrome (VWS) is a common form of syndromic cleft lip and palate
      and accounts for approximately 2% of all cleft lip and palate cases.
      Distinguishing characteristics include cleft lip with or without cleft palate,
      isolated cleft palate, bilateral lip pits, hypodontia, normal intelligence, and
      an autosomal-dominant mode of transmission with a high degree of penetrance.
      Previously, the VWS locus was mapped to a 1.6-cM region in 1q32-q41 between
      D1S491 and D1S205, and a 4.4-Mb contig of YAC clones of this region was
      constructed. In the current investigation, gene-based and anonymous STSs were
      developed from the existing physical map and were then used to construct a contig
      of sequence-ready bacterial clones across the entire VWS critical region. All
      STSs and BAC clones were shared with the Sanger Centre, which developed a contig
      of PAC clones over the same region. A subset of 11 clones from both contigs was
      selected for high-throughput sequence analysis across the approximately 1.1-Mb
      region; all but two of these clones have been sequenced completely. Over 900 kb
      of genomic sequence, including the 350-kb VWS critical region, were analyzed and
      revealed novel polymorphisms, including an 8-kb deletion/insertion, and revealed
      4 known genes, 11 novel genes, 9 putative genes, and 3 psuedogenes. The
      positional candidates LAMB3, G0S2, HIRF6, and HSD11 were excluded as the VWS gene
      by mutation analysis. A preliminary gene map for the VWS critical region is as
      follows: [see text] 41-TEL. The data provided here will help lead to the
      identification of the VWS gene, and this study provides a model for how
      laboratories that have a regional interest in the human genome can contribute to
      the sequencing efforts of the entire human genome.

PMID- 10645955
TI  - Pooled genotyping of microsatellite markers in parent-offspring trios.
AB  - We studied the extent to which genotyping of simple sequence repeat polymorphisms
      (SSRs) in pooled DNA samples can be used to predict differences in allele
      frequencies between parents and their affected offspring. We also developed a
      simple method of correction for the effects of stutter and differential
      amplification on the analysis of SSRs in pooled DNA samples based on widely
      available software. We genotyped individually eight polymorphic microsatellite
      markers in 110 parent-offspring trios affected with bipolar affective disorder
      (BP). Analysis of pooled DNA samples predicted very accurately the differences in
      individual allele frequency distributions between children and their parents. The
      mean error was <1% (range 0%-3.2%) when marker-specific corrections for stutter
      and differential amplification were performed. We show that if an individual
      allele is significantly preferentially transmitted from parents to affected
      offspring, the difference in the frequency of that allele would be sufficiently
      large to be detected with pooling in most situations. We propose recommendations
      for disequilibrium mapping with pooling in which both case-control samples and
      trios are used in an initial screen and markers are genotyped individually only
      if they satisfy very relaxed criteria for statistical significance. The use of
      case-control samples should reduce the false-negative rate as the differences in
      allele frequencies between cases and controls are twice as high in the presence
      of the same genetic effect. The use of trios will confirm or reject any suggested
      differences, thus reducing the false-positive rate that can be created by hidden
      population stratification.

PMID- 10645956
TI  - Bacterial artificial chromosome libraries for mouse sequencing and functional
      analysis.
AB  - Bacterial artificial chromosome (BAC) and P1-derived artificial chromosome (PAC)
      libraries providing a combined 33-fold representation of the murine genome have
      been constructed using two different restriction enzymes for genomic digestion. A
      large-insert PAC library was prepared from the 129S6/SvEvTac strain in a
      bacterial/mammalian shuttle vector to facilitate functional gene studies. For
      genome mapping and sequencing, we prepared BAC libraries from the 129S6/SvEvTac
      and the C57BL/6J strains. The average insert sizes for the three libraries range
      between 130 kb and 200 kb. Based on the numbers of clones and the observed
      average insert sizes, we estimate each library to have slightly in excess of 10
      fold genome representation. The average number of clones found after
      hybridization screening with 28 probes was in the range of 9-14 clones per
      marker. To explore the fidelity of the genomic representation in the three
      libraries, we analyzed three contigs, each established after screening with a
      single unique marker. New markers were established from the end sequences and
      screened against all the contig members to determine if any of the BACs and PACs
      are chimeric or rearranged. Only one chimeric clone and six potential deletions
      have been observed after extensive analysis of 113 PAC and BAC clones. Seventy
      one of the 113 clones were conclusively nonchimeric because both end markers or
      sequences were mapped to the other confirmed contig members. We could not exclude
      chimerism for the remaining 41 clones because one or both of the insert termini
      did not contain unique sequence to design markers. The low rate of chimerism,
      approximately 1%, and the low level of detected rearrangements support the
      anticipated usefulness of the BAC libraries for genome research.

PMID- 10645957
TI  - A deep-coverage tomato BAC library and prospects toward development of an STC
      framework for genome sequencing.
AB  - Recently a new strategy using BAC end sequences as sequence-tagged connectors
      (STCs) was proposed for whole-genome sequencing projects. In this study, we
      present the construction and detailed characterization of a 15.0 haploid genome
      equivalent BAC library for the cultivated tomato, Lycopersicon esculentum cv.
      Heinz 1706. The library contains 129,024 clones with an average insert size of
      117.5 kb and a chloroplast content of 1.11%. BAC end sequences from 1490 ends
      were generated and analyzed as a preliminary evaluation for using this library to
      develop an STC framework to sequence the tomato genome. A total of 1205 BAC end
      sequences (80.9%) were obtained, with an average length of 360 high-quality
      bases, and were searched against the GenBank database. Using a cutoff expectation
      value of <10(-6), and combining the results from BLASTN, BLASTX, and TBLASTX
      searches, 24.3% of the BAC end sequences were similar to known sequences, of
      which almost half (48.7%) share sequence similarities to retrotransposons and 7%
      to known genes. Some of the transposable element sequences were the first
      reported in tomato, such as sequences similar to maize transposon Activator (Ac)
      ORF and tobacco pararetrovirus-like sequences. Interestingly, there were no BAC
      end sequences similar to the highly repeated TGRI and TGRII elements. However,
      the majority (70.3%) of STCs did not share significant sequence similarities to
      any sequences in GenBank at either the DNA or predicted protein levels,
      indicating that a large portion of the tomato genome is still unknown. Our data
      demonstrate that this BAC library is suitable for developing an STC database to
      sequence the tomato genome. The advantages of developing an STC framework for
      whole-genome sequencing of tomato are discussed.

PMID- 10645958
TI  - A consensus linkage map of the chicken genome.
AB  - A consensus linkage map has been developed in the chicken that combines all of
      the genotyping data from the three available chicken mapping populations.
      Genotyping data were contributed by the laboratories that have been using the
      East Lansing and Compton reference populations and from the Animal Breeding and
      Genetics Group of the Wageningen University using the Wageningen/Euribrid
      population. The resulting linkage map of the chicken genome contains 1889 loci. A
      framework map is presented that contains 480 loci ordered on 50 linkage groups.
      Framework loci are defined as loci whose order relative to one another is
      supported by odds greater then 3. The possible positions of the remaining 1409
      loci are indicated relative to these framework loci. The total map spans 3800 cM,
      which is considerably larger than previous estimates for the chicken genome.
      Furthermore, although the physical size of the chicken genome is threefold
      smaller then that of mammals, its genetic map is comparable in size to that of
      most mammals. The map contains 350 markers within expressed sequences, 235 of
      which represent identified genes or sequences that have significant sequence
      identity to known genes. This improves the contribution of the chicken linkage
      map to comparative gene mapping considerably and clearly shows the conservation
      of large syntenic regions between the human and chicken genomes. The compact
      physical size of the chicken genome, combined with the large size of its genetic
      map and the observed degree of conserved synteny, makes the chicken a valuable
      model organism in the genomics as well as the postgenomics era. The linkage maps,
      the two-point lod scores, and additional information about the loci are available
      at web sites in Wageningen (http://www.zod.wau.nl/vf/
      research/chicken/frame_chicken.html) and East Lansing
      (http://poultry.mph.msu.edu/).

PMID- 10645959
TI  - Mechanisms involved in valvuloseptal endocardial cushion formation in early
      cardiogenesis: roles of transforming growth factor (TGF)-beta and bone
      morphogenetic protein (BMP).
AB  - Endothelial-mesenchymal transformation (EMT) is a critical event in the
      generation of the endocardial cushion, the primordia of the valves and septa of
      the adult heart. This embryonic phenomenon occurs in the outflow tract (OT) and
      atrioventricular (AV) canal of the embryonic heart in a spatiotemporally
      restricted manner, and is initiated by putative myocardially derived inductive
      signals (adherons) which are transferred to the endocardium across the cardiac
      jelly. Abnormal development of endocardial cushion tissue is linked to many
      congenital heart diseases. At the onset of EMT in chick cardiogenesis,
      transforming growth factor (TGFbeta)-3 is expressed in transforming endothelial
      and invading mesenchymal cells, while bone morphogenetic protein (BMP)-2 is
      expressed in the subjacent myocardium. Three-dimensional collagen gel culture
      experiments of the AV endocardium show that 1) myocardially derived inductive
      signals upregulate the expression of AV endothelial TGFbeta3 at the onset of EMT,
      2) TGFbeta3 needs to be expressed by these endothelial cells to trigger the
      initial phenotypic changes of EMT, and 3) myocardial BMP2 acts synergistically
      with TGFbeta3 in the initiation of EMT.

PMID- 10645960
TI  - Quantitative analysis of the developing rat kidney: absolute and relative volumes
      and growth curves.
AB  - The development of the permanent kidney, or metanephros, is a complex process. In
      the present study, stereological methods were used at the light microscopic level
      to estimate the absolute volumes and volume densities of seven compartments in
      the developing rat metanephros, from embryonic day 14 (E14) to E21. Metanephroi
      from time-mated Sprague-Dawley rats were embedded whole in glycolmethacrylate,
      exhaustively sectioned at 2 microm and stained with PAS. The left metanephros
      from three embryos from each of three mothers were analysed at each of the ages
      (a total of 72 metanephroi). Relative volumes were multiplied by total
      metanephric volume to obtain absolute volumes. Total metanephric volume increased
      approximately 300-fold during the 7-day period studied. At E14, 92% of the
      metanephros was composed of undifferentiated mesenchyme, whilst the ureteric
      epithelium made up approximately 5% of the volume. By E21 the undifferentiated
      mesenchyme comprised 47% of the kidney, while the ureteric epithelium comprised
      9% and the various components of developing nephrons (epithelial vesicles, comma
      shaped bodies, S-shaped bodies, glomeruli, tubules) comprised 43%. Equations with
      prediction intervals describing the growth of the whole kidney as well as the
      absolute and relative growth of the seven kidney compartments were generated.
      These data provide a baseline for future studies on the roles of specific
      molecules in renal development.

PMID- 10645961
TI  - Apoptosis in the early developing periodontium of rat molars.
AB  - Development of the periodontium involves a series of complex steps that result in
      the formation of root dentine, cementum, bone and fibres of the ligament. These
      precisely controlled and timed events require the participation of the enamel
      organ derived epithelial cells of Hertwig's (HRS) and ectomesenchymal cells of
      the dental follicle. These events involve rapid turnover of the tissues and
      cells, including disappearance of epithelial cells of HRS. Thus, it seemed likely
      to us that programmed cell death (apoptosis) may play a role in the development
      of the periodontium. Fragments of first molars, obtained from 14- and 29-day-old
      rats, were fixed in glutaraldehyde-formaldehyde and processed for light and
      electron microscopy. For the TUNEL method for detection of apoptosis, specimens
      were fixed in 4% formaldehyde and embedded in paraffin. Results confirmed that
      epithelial cells of HRS maintain a close relationship with the forming dentine
      root, and that they may become trapped in the dentino-cemental junction. Some of
      the epithelial cells exhibited ultrastructural features which are consistent with
      the interpretation that they were undergoing programmed cell death, i.e.
      apoptosis. Periodontal fibroblast-like cells showed typical images of apoptosis
      and engulfed apoptotic bodies. TUNEL positive structures were present in all
      corresponding regions. It seems therefore that apoptosis of epithelial cells of
      HRS and fibroblast-like cells of the periodontal ligament constitutes an integral
      part of the developmental process of the tissues of the periodontium.

PMID- 10645962
TI  - Inherited retinal degeneration and apoptosis in mutant zebrafish.
AB  - The mechanism of retinal cell death was studied in mutant zebrafish (Danio rerio)
      which undergo inherited degeneration of the retina and the brain. The shrunken
      head (shr(m33)) mutation was isolated as part of a large scale mutagenesis
      screen. The yellow head (yhd) mutation arose spontaneously among inbred wild type
      zebrafish. Although the mutants share many morphological features, including
      small eyes, a small brain and an enlarged pericardial sac, crossing shr(m33) and
      yhd heterozygotes results in phenotypically normal fish. The retinae of both
      mutant lines of fish begin to develop normally and then undergo massive
      degenerative changes. Pyknotic cells first appear in the retina of the shr(m33)
      fish by 3 days post-fertilization and in the yhd fish by 1.5 days post
      fertilization. By 5 days post-fertilization the outer nuclear layer containing
      the photoreceptor cells has largely disappeared in both mutants. The inner
      nuclear layer and ganglion cell layer are also severely affected. By 6-7 days
      post-fertilization, the retina has been largely cleared of pyknotic cells by
      retinal pigment epithelial cells and by rare macrophage-like cells. Both
      mutations are lethal by 7-8 days post-fertilization. Two independent measures,
      TdT-mediated dUTP-biotin nick end label (TUNEL) and transmission electron
      microscopy, indicate that the pyknotic cells in the mutant retinae are apoptotic.
      Apoptosis is very rarely observed during normal development of the teleost retina
      and was not observed in age-matched wild type zebrafish retinae examined for
      comparison. Our results indicate that a genetic defect can induce massive
      apoptosis in cell populations that do not normally undergo apoptosis during
      development.

PMID- 10645963
TI  - Ultracytochemical study on the localization of superoxide producing sites in
      stimulated rat neutrophils.
AB  - Superoxide anion production in neutrophils plays an important role in the
      microbicidal defense system in the body. In this study, isolated rat neutrophils
      were stimulated experimentally and examined by electron microscopy to determine
      the site of superoxide production and its subsequent translocation during
      different cell stimulation time periods. Blood and peritoneal neutrophils were
      incubated for periods of 5, 10, and 15 min with phorbol 12-myristate 13-acetate
      (PMA), N-formyl-Met-Leu-Phe (fMLP), and combinations of PMA and cytochalasin B
      (CB) and fMLP and CB. Ultracytochemical detection of O(2)(-) was performed with
      the 3, 3'-diaminobenzidine-manganese (DAB/Mn) cytochemical method and cationized
      ferritin (CF) particles were added to stimulation media to monitor endocytotic
      events that occurred during neutrophil stimulation. Unstimulated neutrophils were
      devoid of O(2)(-) activity in cytoplasmic granules and at the plasma membrane
      surface. After 5 min stimulations with PMA, PMA + CB, or fMLP + CB, electron
      dense DAB/Mn reaction product was detected in small, centrally located tubular
      compartments within the neutrophils. CF particles which were added to the
      stimulation media became internalized in endocytotic vesicles after 5 min
      stimulation; these vesicles were devoid of O(2)(-) activity. At 10 min
      stimulation with PMA, O(2)(-)-positive granules subsequently fused with each
      other and translocated to sub-plasma membrane regions where they either contacted
      the plasma membrane or fused with CF-containing endocytotic vesicles. Little
      reaction product was observed on the surface of the neutrophils.
      Spectrophotometric comparison of the stimulatory effects of PMA, fMLP, and fMLP +
      CB revealed different rates and yields of O(2)(-) production. Results from this
      study suggest that the O(2)(-)-producing sites of rat neutrophils originate
      intracellularly and translocate to the plasma membrane surface following
      stimulation with PMA, PMA + CB, and fMLP + CB, but not with fMLP or CB alone.
      Furthermore, these compartments appear to possess the ability to fuse with
      endocytotic vesicles, a process that may be linked to intracellular microbicidal
      activity in circulating and tissue neutrophils.

PMID- 10645964
TI  - Development of the human elbow joint.
AB  - Many studies have been published on the development of the human elbow joint, but
      authors disagree on its morphogenetic timetable. Most discrepancies center on the
      cavitation of the elbow joint (including the humeroradial, humeroulnar, and
      superior radioulnar joints), and the organization of the tunnel of the ulnar
      nerve. We summarize our observations on the development of the elbow joint in 49
      serially sectioned human embryonic (n = 28) and fetal (n = 21) upper limbs.
      During week 12, ossification begins in the epiphyses of the elements comprising
      the elbow joint. At the end of the embryonic period, the shallow groove between
      the posterior aspect of the medial epicondyle and the olecranon process, begins
      to be visible. The elbow joint cavity appears in O'Rahilly stage 21 (51 days) at
      the level of the humeroulnar and humeroradial interzones. Formation of the cavity
      begins at the medialmost portion of the humeroradial interzone and the
      lateralmost portion of the humeroulnar interzone. The annular ligament begins to
      develop in O'Rahilly stage 21 (51 days), and the superior radioulnar joint cavity
      appears between this ligament and the lateral aspect of the head of the radius
      during O'Rahilly stage 23 (56 days). We established the morphogenetic timetable
      of the human elbow joint.

PMID- 10645965
TI  - Activity-induced fiber regeneration in rat soleus muscle.
AB  - In an attempt to understand why muscle recovery is limited following atrophy due
      to limb immobilization, satellite cell activity and muscle fiber regeneration
      were analyzed in rat soleus muscles. Adult rat hindlimbs were immobilized in
      plaster casts for a period of two to ten weeks. Soleus muscles were examined by
      electron microscopy for evidence of fiber degeneration or regeneration, and to
      quantify satellite cell nuclei. Immunocytochemical localization of embryonic
      myosin was used to identify regenerating myofibers. Soleus muscle wet weight to
      body weight ratios for the casted muscles significantly decreased over the 10
      week immobilization period. The casted muscles displayed ultrastructural evidence
      of minor fiber damage, including myofibrillar atrophy, Z-disc disruption, and
      abnormal triadic junctions. No ultrastructural evidence of regeneration was seen
      in the casted animals. The number of satellite cells in the casted muscles
      significantly decreased from 6.4% to 3. 3% by eight to 10 weeks of
      immobilization. Approximately 1.0% of extrafusal fibers in the control soleus
      muscles appeared to be regenerating since they expressed embryonic myosin and
      were of a small diameter, while in casted muscles, only 0.1% of the fibers were
      embryonic myosin-positive. Following release from immobilization, a reappearance
      of embryonic myosin-positive fibers was noted within four days of renewed
      activity. In contrast to control muscles, embryonic myosin-positive fibers in the
      recovery muscles included both small and large diameter fibers. Subtle changes in
      functional activity influence muscle damage and subsequent myofiber regeneration.
      Reduced activity reduces muscle fiber regeneration, while increased activity, as
      seen by increased hindlimb weight bearing and return to normal activity following
      immobilization, increase regenerating fibers and also the expression of embryonic
      myosin in adult fibers.

PMID- 10645966
TI  - Retinoic acid inhibition of cardiac mesenchyme formation in vitro correlates with
      changes in the secretion of particulate matrix from the myocardium.
AB  - Retinoic acid has been associated with a variety of cardiac defects. A percentage
      of these defects are related to changes in the endocardial cushions. Studies in
      mice and older chick embryos have shown a decrease in mesenchymal cell formation
      attributable to retinoic acid and have suggested that retinoic acid was affecting
      the extracellular matrix. In this study we have tested the effect of retinoic
      acid on cardiac mesenchyme formation in vitro and then tested retinoic acid
      treated myocyte cultures for changes in the expression of hLAMP-1, fibronectin
      and transferrin members of the particulate matrix that is required for mesenchyme
      formation. Initial experiments tested the effect of retinoic acid on mesenchymal
      cell formation first in atrioventricular canal and outflow tract explant cultures
      and then in AV endothelial monolayer cultures using myocyte conditioned media or
      the particulate matrix fraction from retinoic acid treated myocyte cultures. In
      all cases, mesenchymal cell formation was suppressed while no suppression was
      observed when MyoCM was included with retinoic acid. Protein analysis showed that
      retinoic acid had a stimulatory effect on protein synthesis. ELISA assays
      revealed that retinoic acid treated myocyte cultures contained significantly more
      hLAMP-1 and fibronectin than either normal or DMSO controls. However, transferrin
      was not affected by retinoic acid treatment in these experiments. Our results
      suggest that retinoic acid affects the expression of the particulate matrix and
      that these changes may be responsible for the observed decrease in mesenchymal
      cell formation.

PMID- 10645967
TI  - Changing distribution patterns of synaptophysin-immunoreactive structures in the
      human dorsal striatum of the fetal brain.
AB  - Within the striatum two compartments, matrix and patches, can be distinguished by
      differences in the expression of neuroactive substances, afferent and efferent
      connections and time of neurogenesis. The present study was done to demonstrate
      the pattern of synaptophysin (SYN) expression which is indicative of
      synaptogenesis in the human fetal striatum (15th-32nd weeks of gestation) with
      special reference to developmental changes. From the 15th to the 22nd gestational
      weeks an intense diffuse SYN immunolabelling of striatal patches is observed. In
      the matrix SYN-immunoreactive fiber bundles are seen until the 20th week.
      Thereafter, the matrix is nearly devoid of SYN-immunoreactive structures. From
      the 28th week of gestation the matrix contains diffuse SYN immunoreactivity which
      gradually becomes as intense as that of the patches. The latter, thus, can no
      longer be delineated in the 30th week. The results show that fibrous SYN
      immunolabelling most probably indicating intra-axonal transport of synaptic
      vesicles can only be observed during the first half of gestation. Moreover, it
      becomes obvious that the patch compartment can selectively be visualized by anti
      SYN until the 28th week. This pattern may correspond to the early dopaminergic
      innervation from the substantia nigra which is known to reach the developing
      patches. From the 28th week a transition from patchy to diffuse immunolabelling
      is seen. The increase in matrix labelling may be due to the occurrence of new
      neuronal contacts. The changeover from patchy to homogeneous SYN immunolabelling
      takes place distinctly earlier than changes in the distribution of other
      neuroactive substances described before.

PMID- 10645968
TI  - Reproliferation and relocation of mouse male germ cells (gonocytes) during
      prespermatogenesis.
AB  - In the prespermatogenesis period, male germ cells (gonocytes) begin to
      reproliferate and move to the basement membrane of the seminiferous tubule.
      Although these two events-reproliferation and relocation-are important for
      establishment of spermatogenesis, they have not been greatly analyzed both in a
      mechanical and in an endocrine or paracrine aspect. In this study, the
      relationship between reproliferation and relocation of gonocytes was examined,
      using the thymidine analog bromodeoxyuridine (BrdU) labeling method and
      transmission electron microscopy (TEM). BrdU was injected into the fetuses [day
      13.5 post coitus (dpc) to 18.5 dpc] and pups [day 0. 5 post partum (dpp) to 6.5
      dpp] of C57BL/6J mice. Two hours later, BrdU positive gonocytes were examined
      immunohistochemically and these data were analyzed. TEM and LM observation was
      carried out as well. Gonocytes began to relocate on the basement membrane from
      18.5 dpc (1.4%) while BrdU-labeled gonocytes were first detected on 1.5 dpp
      (13.6%). Relocated BrdU-negative gonocytes were recognized from 18.5 dpc (1.4%),
      and relocated BrdU-labeled gonocytes were recognized from 1.5 dpp (8.4%). On the
      other hand, non-relocated BrdU-labeled gonocytes were detected from 1.5 dpp
      (5.2%). Gonocyte relocation began 2 days earlier than reproliferation during the
      late fetal period. After birth, the two events occurred at random. These results
      indicate that the reproliferation of the gonocyte does not correlate with
      relocation. The two events may be regulated by different mechanisms.

PMID- 10645969
TI  - Critical and optimal Ig domains for promotion of neurite outgrowth by L1/Ng-CAM.
AB  - Mammalian L1 and avian Ng-CAM are homologous neural cell adhesion molecules
      (CAMs) that promote neurite outgrowth and cell adhesion in most neurons. Previous
      attempts to map these activities to discrete regions in the CAMs have suggested
      the involvement of a variety of different domains. However, these studies mainly
      used bacterially expressed proteins that were much less active on a molar basis
      than the native molecules. To define regions that are critical for maximal
      neurite outgrowth, we constructed and tested a panel of eukaryotically expressed
      proteins containing various extracellular segments of human L1 (hL1) or Ng-CAM.
      Our results indicate that Ig domains 1-4 of hL1 are critical for homophilic
      binding and neurite outgrowth; however this segment is less potent than the
      entire extracellular region. Optimal neurite outgrowth activity was seen with
      proteins containing all six Ig domains of hL1 or Ng-CAM. The adhesive properties
      of hL1 fragments correlated tightly with their neurite outgrowth activities,
      suggesting that these two processes are closely linked. These results suggest
      that Ig domains 1-4 form a structural cassette responsible for hL1 homophilic
      binding, while Ig domains 1-6 represent a functional region for optimal promotion
      of neurite outgrowth in vitro and possibly in vivo.

PMID- 10645970
TI  - MK801 increases retinotectal arbor size in developing zebrafish without affecting
      kinetics of branch elimination and addition.
AB  - Visual activity refines the retinotopic map formed on tectum during regeneration
      and development in goldfish through an N-methyl-D-aspartate (NMDA) receptor
      mediated mechanism. Retinal arbors are enlarged in fish with unrefined maps.
      Here, we examined the effect of NMDA receptor blockers on the development of
      retinotectal arbors in zebrafish. Since visual behaviors begin 68-79 h
      postfertilization, we blocked NMDA receptors by immersion of larvae in MK801,
      AP5, or CPP starting at either 48 or 72 h. We then labeled axons with DiI at 72
      or 96 h and examined them 5-9 h later. Arbors at 101-105 h (31 cases) were larger
      than at 77-79 h (11 cases): The average number of branches increased from 4.0 to
      7.6 and the area (convex polygon method) increased by 42%. Blocking NMDA
      receptors with MK801 from 72 to 101-105 h significantly enlarged arbor size, but
      the number of branches remained roughly the same. The length and area of the
      arbors were both significantly increased (21% and 36%), whereas the width
      increased by a smaller amount (6%). This increase was reflected in longer
      distances between branches within the arbor (interbranch segments, +13%) as well
      as in the summed length of all branches (+28%). This selective effect on the
      extent but not number of branches is in agreement with our previous report of
      strobe effects in both developing and regenerating projections in goldfish, and
      supports the role of NMDA receptors in the first 24 h of synaptic transmission.
      We also used DiO to label arbors in time-lapse images taken at hourly intervals
      from 77 to 112 h. These sequences confirmed that individual arbors grew during
      this time, but showed that rates of branch addition and deletion and branch
      lifetimes were unaltered by the MK801 treatment. This is consistent with a simple
      model of random insertion of new branches and selective activity-driven
      elimination of those at the periphery to keep the normal arbor focused. Blocking
      NMDA receptors is postulated to randomize the elimination allowing the periphery
      to expand, thus accounting for the enlarged areas, without change in branch
      numbers or branch dynamics.

PMID- 10645971
TI  - Developmental sex differences in calbindin-D(28K) and calretinin immunoreactivity
      in the neonatal rat hypothalamus.
AB  - The proteins calbindin-D(28K) and calretinin buffer intracellular calcium and are
      speculated to be involved in the integration of neuronal signaling. Using Western
      blot analysis, we compared the levels of calbindin-D(28K) and calretinin in the
      developing male and female rat hypothalamus on postnatal days (PN) 0, PN2, PN4,
      PN6, PN8, and PN10. Analysis of variance (ANOVA) of mean calbindin levels
      indicated a significant effect of sex (p </=.001) and age (p </=. 0001) and a
      significant interaction (p </=.02). Post-hoc Neuman-Keuls analysis revealed that
      PN0 and PN2 males had significantly elevated calbindin levels over PN0 and PN2
      females (p </=.05). ANOVA of mean calretinin levels from the same animals also
      indicated a significant effect of sex (p </=.002) and a significant interaction
      between sex and age (p </=.001). Post-hoc analysis indicated males had
      significantly elevated calretinin levels over PN0, PN4 (p </=.05) and PN6 (p
      </=.01) females. Immunocytochemical analyses indicated calbindin-immunopositive
      staining for cell bodies in the central subdivision of the medial preoptic
      nucleus, paraventricular nucleus, arcuate nucleus, and dorsomedial nucleus, and
      an area immediately surrounding the ventromedial nucleus (VMN). Calbindin
      immunoreactivity was absent from the ventrolateral VMN, but lightly stained cell
      bodies were observed in the dorsomedial VMN. The sex differences observed in
      calcium binding proteins parallel our previously observed sex differences in
      excitatory gamma-aminobutyric acid and glutamate early in development and may be
      related to mechanisms of sexual differentiation of the brain.

PMID- 10645972
TI  - Purkinje cell fate in staggerer mutants: agenesis versus cell death.
AB  - Staggerer (sg/sg) is an autosomal recessive mutation in an orphan nuclear hormone
      receptor gene, RORalpha, that causes a cell-autonomous, lineage-specific block in
      the development of the Purkinje cell. Purkinje cell number is reduced by about 75
      90% in adult mutants, and many of the surviving cells are small and ectopically
      positioned. To determine whether Purkinje cell numbers are reduced owing to
      either agenesis or cell death, cohorts of Purkinje cells were labeled with the
      birth-date marker bromodeoxyuridine (BrdU) at embryonic day (E) 10.5 or E11.5.
      The total number of BrdU-labeled profiles was then compared between cerebella
      from wild-type mice, heterozygous staggerer, and staggerer mutants at E17.5 and
      postnatal day (P)5. There was no significant difference between sg/sg mutants and
      +/sg or +/+ controls in the number of BrdU-labeled profiles or in cerebellar
      volumes in the E17 embryos. By P5, however, cerebellar volume was significantly
      reduced in the sg/sg mutants compared to controls (p <.005) and the number of
      BrdU-labeled profiles was reduced by 33% following E11.5 BrdU injections (p
      <.02). The results suggest that Purkinje cell genesis is not affected by the
      staggerer mutation and that Purkinje cell loss begins some time after E17.
      RORalpha is highly expressed in Purkinje cells by E14, so the delay between
      initial RORalpha expression and sg/sg Purkinje cell loss suggests that the
      staggerer mutation does not directly cause Purkinje cell death.

PMID- 10645973
TI  - A cell-survival factor (N-acetyl-L-cysteine) alters the in vivo fate of
      constitutively proliferating subependymal cells in the adult forebrain.
AB  - The adult mouse brain contains a population of constitutively proliferating
      subependymal cells that surround the lateral ventricle and are the direct progeny
      of the neural stem cell. Constitutively proliferating cells divide rapidly; 6
      days after labeling, 60% of their progeny undergo cell death, 25% migrate to the
      olfactory bulbs, and 15% continue to proliferate within the subependyma. We have
      intraventricularly infused a cell survival factor N-acetyl-L-cysteine (NAC),
      which is known to have survival effects without concomitant proliferative effects
      on cells in vitro, and examined the resulting fate of cells spared from the
      normally occurring cell death. NAC infusion for 5 days results in a five-fold
      increase in the number of retrovirally labeled subependymal cells compared to
      saline-infused controls. The increase in the number of subependymal cells is
      directly proportional to the amount of time during which NAC is present and is
      not due to increased proliferation. While NAC is able to keep all the normally
      dying progeny alive, the cells spared from death remain confined to the
      subependyma lining the lateral ventricles and do not migrate to the olfactory
      bulbs (one normal fate of constitutively proliferating progeny) or into the
      surrounding brain parenchyma. When animals survive for an additional 6 days
      following NAC infusion, the number of retrovirally labeled subependymal cells
      returns to control values, indicating that the continued presence of NAC is
      necessary for cell survival. These data suggest that preventing cell death is not
      sufficient to keep all of the progeny of these cells in a proliferative mode.

PMID- 10645974
TI  - Sustained upregulation in embryonic spinal neurons of a Kv3.1 potassium channel
      gene encoding a delayed rectifier current.
AB  - Differentiation of electrical excitability entails changes in the currents that
      generate action potentials in spinal neurons of Xenopus embryos, resulting in
      reduced calcium entry during impulses generated at later stages of development. A
      dramatic increase in delayed rectifier current (I(Kv)) during the first day of
      development plays the major role in this process. Identification of potassium
      channel genes responsible for the increase in I(Kv) is critical to understanding
      the molecular mechanisms involved. Several members of the Shaw Kv3 gene subfamily
      encode delayed rectifier currents, indicating that they could contribute to the
      upregulation of I(Kv) that reduces the duration of action potentials. We isolated
      a Xenopus (x) Kv3.1 gene whose expression is restricted to the central nervous
      system, which is upregulated throughout the period during which I(Kv) develops in
      vivo. The fraction of neurons in which transcripts of this gene are detected by
      single-cell RT-PCR increases to 40% with time in culture, paralleling the
      development of I(Kv) in neurons in vitro. Expression of xKv3.1 mRNA generates a
      delayed rectifier potassium current in oocytes, suggesting that xKv3. 1
      contributes to the maturation of I(Kv) and shortening of the action potential.

PMID- 10645975
TI  - Target cell contact suppresses neurite outgrowth from soma-soma paired Lymnaea
      neurons.
AB  - Neurite extension from developing and/or regenerating neurons is terminated on
      contact with their specific synaptic partner cells. However, a direct
      relationship between the effects of target cell contact on neurite outgrowth
      suppression and synapse formation has not yet been demonstrated. To determine
      whether physical/synaptic contacts affect neurite extension from cultured cells,
      we utilized soma-soma synapses between the identified Lymnaea neurons. A
      presynaptic cell (right pedal dorsal 1, RPeD1) was paired either with its
      postsynaptic partner cells (visceral dorsal 4, VD4, and Visceral dorsal 2, VD2)
      or with a non-target cell (visceral dorsal 1, VD1), and the interactions between
      their neurite outgrowth patterns and synapse formation were examined.
      Specifically, when cultured in brain conditioned medium (CM, contains growth
      promoting factors), RPeD1, VD4, and VD2 exhibited robust neurite outgrowth within
      12-24 h of their isolation. Synapses, similar to those seen in vivo, developed
      between the neurites of these cells. RPeD1 did not, however, synapse with its non
      target cell VD1, despite extensive neuritic overlap between the cells. When
      placed in a soma-soma configuration (somata juxtaposed against each other),
      appropriate synapses developed between the somata of RPeD1 and VD4 (inhibitory)
      and between RPeD1 and VD2 (excitatory). Interestingly, pairing RPeD1 with either
      of its synaptic partner (VD4 or VD2) resulted in a complete suppression of
      neurite outgrowth from both pre- and postsynaptic neurons, even though the cells
      were cultured in CM. A single cell in the same dish, however, extended elaborate
      neurites. Similarly, a postsynaptic cell (VD4) contact suppressed the rate of
      neurite extension from a previously sprouted RPeD1. This suppression of the
      presynaptic growth cone motility was also target cell contact specific. The
      neurite suppression from soma-soma paired cells was transient, and neuronal
      sprouting began after a delay of 48-72 h. In contrast, when paired with VD1, both
      RPeD1 and this non-target cell exhibited robust neurite outgrowth. We demonstrate
      that this neurite suppression from soma-soma paired cells was target cell
      contact/synapse specific and Ca(2+) dependent. Specifically, soma-soma pairing in
      CM containing either lower external Ca(2+) concentration (50% of its control
      level) or Cd(2+) resulted in robust neurite outgrowth from both cells; however,
      the incidence of synapse formation between the paired cells was significantly
      reduced. Taken together, our data show that contact (physical and/or synaptic)
      between synaptic partners strongly influence neurite outgrowth patterns of both
      pre- and postsynaptic neurons in a time-dependent and cell-specific manner.
      Moreover, our data also suggest that neurite outgrowth and synapse formation are
      differentially regulated by external Ca(2+) concentration.

PMID- 10645976
TI  - Localization of unconventional myosins V and VI in neuronal growth cones.
AB  - Class V and VI myosins, two of the six known classes of actin-based motor genes
      expressed in vertebrate brain (Class I, II, V, VI, IX, and XV), have been
      suggested to be organelle motors. In this report, the neuronal expression and
      subcellular localization of chicken brain myosin V and myosin VI is examined.
      Both myosins are expressed in brain during embryogenesis. In cultured dorsal root
      ganglion (DRG) neurons, immunolocalization of myosin V and myosin VI revealed a
      similar distribution for these two myosins. Both are present within cell bodies,
      neurites and growth cones. Both of these myosins exhibit punctate labeling
      patterns that are found in the same subcellular region as microtubules in growth
      cone central domains. In peripheral growth cone domains, where individual puncta
      are more readily resolved, we observe a similar number of myosin V and myosin VI
      puncta. However, less than 20% of myosin V and myosin VI puncta colocalize with
      each other in the peripheral domains. After live cell extraction, punctate
      staining of myosin V and myosin VI is reduced in peripheral domains. However, we
      do not detect such changes in the central domains, suggesting that these myosins
      are associated with cytoskeletal/organelle structures. In peripheral growth cone
      domains myosin VI exhibits a higher extractability than myosin V. This difference
      between myosin V and VI was also found in a biochemical growth cone particle
      preparation from brain, suggesting that a significant portion of these two motors
      has a distinct subcellular distribution.

PMID- 10645977
TI  - Gel test assay for IgG subclass detection by GM typing: application to hemolytic
      disease of the newborn.
AB  - The gel test assay was evaluated for IgG subclass detection by GM typing of
      antibodies and compared to the classical inhibition agglutination method on
      slides or microtiter plates. We used a panel of 5 murine monoclonal antibodies
      directed against G1M(1), G1M(3), G1M(17), G2M(23), and G3M(21) and 1 human
      polyclonal anti-G3M(5) antibody. Eleven polyclonal antisera (of immunized women)
      directed against red blood cells were tested for the GM allotypes carried by
      their alloantibodies. We controlled the specificity of the gel test reaction
      using a panel of anti-RH(D) monoclonal antibodies. All reagents exhibited a good
      reactivity and specificity. They can be used for routine typing. The gel test
      assay for IgG subclass detection is a specific, simple, and low-cost technique
      for the detection and management of severe forms of diseases in alloimmunized
      pregnancies.

PMID- 10645978
TI  - Detection of specific antibody isotypes and subtypes before and after treatment
      of American visceral leishmaniasis.
AB  - Sera from patients with American visceral leishmaniasis (AVL) were studied before
      and after treatment based on their antibody isotypes and subtypes. The study was
      comprised of 33 Brazilian patients with well-defined diagnosis of AVL and 39
      clinically healthy individuals. Antileishmanial antibody isotypes and subtypes
      were observed in almost all patients, except IgA that was detected in about 63%
      of them. The sensitivity and specificity of the immunofluorescence assay in the
      detection of antibody isotypes (IgG and IgM) and subtypes (IgG1, IgG2, IgG3, and
      IgG4) were high with no statistical difference, ranging from 0.937 to 1.000 and
      from 0.954 to 1.000, respectively. All IgG antibodies and its subtypes had their
      levels reduced after treatment. However, the IgG4 had an early decay and its
      conversion to negative was significantly high in children. Moreover, the profile
      of IgG4 before treatment corresponded to a unimodal curve that shifted to a
      patent bimodal curve after treatment, indicative of therapeutic success. Thus,
      the IgG4 shows to be a suitable immunological marker for the assessment of
      chemotherapy in AVL patients or communities. Our findings suggest that IgG4
      correlates with IL-4 that also decreases after therapy.

PMID- 10645979
TI  - Evaluation of an enzyme immunoassay system for measuring herpes simplex virus
      (HSV) type 1-specific and HSV type 2-specific IgG antibodies.
AB  - MRL Diagnostics has developed a dual enzyme immunoassay (EIA) system that employs
      the recombinant Herpes Simplex Virus (HSV) type-specific glycoproteins G1 (HSV1)
      and G2 (HSV2) to detect HSV type-specific IgG antibodies. This system was
      evaluated using 155 consecutive sera previously tested in a conventional dual EIA
      system (Zeus) that employs multiple HSV1 and HSV2 proteins to detect type-common
      as well as type-specific antibodies. Sera were also analyzed by Western blot to
      determine the true HSV type-specific IgG reactivity pattern. Of 110 sera giving
      concordant reactivity patterns in the MRL and Zeus EIA systems, 108 (98%) also
      displayed concordant Western blot patterns; two sera gave false positive HSV2
      reactivity in both EIA systems. Of 45 sera giving discordant MRL and Zeus EIA
      reactivity patterns, 41 (91%) displayed a Western blot reactivity pattern that
      matched the MRL reactivity pattern. Both the HSV1 IgG component and the HSV2 IgG
      component of the MRL EIA system were 100% sensitive and > 95% specific. In
      contrast, the Zeus HSV1 IgG EIA was 98% sensitive and 79% specific, and the Zeus
      HSV2 IgG EIA was 85% sensitive and 79% specific. An analysis of the distribution
      of index values in the MRL EIA system showed that low-positive values (1.0-3.0)
      were rare, but, when detected, often represented false positive results; only 11
      MRL low-positive results were observed, but all 6 MRL false positive results were
      found within this low-positive subgroup. These findings show that the MRL dual
      EIA system effectively detects HSV type-specific IgG antibodies.

PMID- 10645980
TI  - Automated chemiluminescent assay for C-peptide.
AB  - C-peptide is secreted in equimolar concentrations with insulin, and is often
      measured to assess pancreatic beta-cell function. C-peptide analysis is most
      often performed by radioimmunoassay (RIA) which has several disadvantages. We
      evaluated an automated, chemiluminescent immunoassay for C-peptide in terms of
      precision, linearity, interference, and correlation with a RIA method. The
      chemiluminescent assay demonstrated acceptable correlation with the RIA method
      (slope = 0.82, y-intercept = 0.88 ng/ml, r-value = 0.97). Between-run Cvs ranged
      from 8 to 9%, which compared well with the RIA method. Linearity extended beyond
      the manufacturer's recommendations and recovery ranged from 87 to 112% across the
      concentrations tested, with a slope of 1.007. No significant interference was
      noted with hemoglobin, bilirubin, or triglyceride. Overall this method compared
      favorably with the RIA method and offers an alternative to RIA for the analysis
      of C-peptide.

PMID- 10645981
TI  - Antibodies to Borrelia burgdorferi in European populations.
AB  - We compared the antibodies to B. burgdorferi in three different populations in
      order to evaluate the diagnostic reliability of Lyme borreliosis serologic
      analysis. The subjects included 25 patients with Lyme borreliosis (Group 1); 50
      patients with diseases of unknown cause, B. burgdorferi ELISA-positive in serum
      and without B. burgdorferi infection (Group 2); and 1,251 individuals without
      Lyme borreliosis (Group 3). All samples were tested for B. burgdorferi B31 and B.
      afzelii antigens using ELISA. The positive results of the ELISA B. burgdorferi
      B31 assay were confirmed with Western blot for the same strain. In Group 3, 162
      (12.9%) patients were ELISA positive for B. burgdorferi B31, while only 6 (0.6%)
      patients had IgG ELISA antibodies to B afzelii. Bands in WB were detected in 104
      (8.4%) of the Group 3 subjects. The bands found to be most reliable for the
      identification of strain B. burgdorferi B31 by IgG WB were those representing the
      93, 39, 34, and 23-kDa proteins. Our results show that serologic diagnosis of
      Lyme borreliosis is far from clearly established. To date, the only reliable
      criteria are clinical ones correlated with laboratory evidence.

PMID- 10645982
TI  - Novel assay for measuring serum conjugated bilirubin and its clinical relevance.
AB  - We have developed a new enzymatic assay for the determination of conjugated
      bilirubin (Bc) using stable liquid reagents. In this assay, only Bc is
      selectively oxidized by bilirubin oxidase at pH 5. 0 in the presence of
      nitrilotris (methylenephosphonic acid) trisodium salt, ethylenediaminetetraacetic
      acid disodium manganese (II) salt, and 4-hydroxy-2,2,6,6,-tetramethylpiperidine 1
      oxyl. Bc is quantitatively determined from a decrease in the absorbance at 450 nm
      caused by Bc oxidization. The reagent solutions of the assay were developed so
      that they could be stably stored for one year together with bilirubin oxidase, in
      order to eliminate the need to prepare working solutions every time they are
      required. The assay has good reactivity, differentiability, measurability, and
      precision. Neither ascorbic acid nor hemoglobin interfered with the measurement.
      Bc values determined by the assay reflected more clearly the pathophysiological
      condition of hepatobiliary disease patients with jaundice than the values of
      total bilirubin or direct bilirubin determined by conventional methods. From
      these observations, we concluded that this Bc assay is valuable for the
      evaluation of jaundice.

PMID- 10645983
TI  - Enhanced analytical sensitivity of a quantitative PCR for CMV using a modified
      nucleic-acid extraction procedure.
AB  - Accurate and rapid diagnosis of CMV disease in immunocompromised individuals
      remains a challenge. Quantitative polymerase chain reaction (QPCR) methods for
      detection of CMV in peripheral blood mononuclear cells (PBMC) have improved the
      positive and negative predictive value of PCR for diagnosis of CMV disease.
      However, detection of CMV in plasma has demonstrated a lower negative predictive
      value for plasma as compared with PBMC. To enhance the sensitivity of the QPCR
      assay for plasma specimens, plasma samples were centrifuged before nucleic-acid
      extraction and the extracted DNA resolubilized in reduced volume. Optimization of
      the nucleic-acid extraction focused on decreasing or eliminating the presence of
      inhibitors in the pelleted plasma. Quantitation was achieved by co-amplifying an
      internal quantitative standard (IS) with the same primer sequences as CMV. PCR
      products were detected by hybridization in a 96-well microtiter plate coated with
      a CMV or IS specific probe. The precision of the QPCR assay for samples prepared
      from untreated and from pelleted plasma was then assessed. The coefficient of
      variation for both types of samples was almost identical and the magnitude of the
      coefficient of variations was reduced by a factor of ten if the data were log
      transformed. Linearity of the QPCR assay extended over a 3.3-log range for both
      types of samples but the range of linearity for pelleted plasma was 20 to 40,000
      viral copies/ml (vc/ml) in contrast to 300 to 400,000 vc/ml for plasma. Thus,
      centrifugation of plasma before nucleic-acid extraction and resuspension of
      extracted CMV DNA in reduced volume enhanced the analytical sensitivity
      approximately tenfold over the dynamic range of the assay.

PMID- 10645984
TI  - Quantitative direct probe method for the detection of parvovirus B19.
AB  - Parvovirus B19 infection is associated with anemia and spontaneous abortions.
      While many qualitative assays are available, a few molecular-based quantitative
      methods have been described. This study reports the development and optimization
      of a quantitative direct-probe method for the detection of Parvovirus B19 DNA.
      Different concentrations of RNA probes were used to identify the optimal
      conditions for hybridizing to the target DNA. Detection of DNA was linear between
      concentrations of 2 ng/ml to 200 pg/ml. Because this method requires no enzymatic
      amplification, it is not susceptible to amplifier contamination or enzymatic
      inhibitors, and it can be applied to serum samples or paraffin-embedded tissue.

PMID- 10645985
TI  - Empowering the caregiver.

PMID- 10645986
TI  - Personality changes in an i.v. drug abuser.

PMID- 10645987
TI  - Acute chest pain with left bundle branch block.

PMID- 10645988
TI  - Food antigens and atherosclerosis.

PMID- 10645990
TI  - Cancer: the emerging molecular biology.
AB  - Discoveries at the molecular level have greatly increased our understanding of
      how a normal cell becomes a tumor cell, responsive only to growth signals. Cancer
      emerges as fundamentally genetic, representing mutations in protooncogenes and
      tumor suppressor genes arising from multiple "hits" over long spans of time. The
      knowledge portends abilities to interrupt the process at a precancerous stage.

PMID- 10645989
TI  - Managing urinary tract infections in men.
AB  - Despite the obvious genitourinary differences between the sexes, management of
      lower urinary tract infections in men is based largely on standards developed
      from studies in women. This has helped foster misconceptions that, among other
      problems, add needless complexity and expense to diagnosis and treatment of male
      patients.

PMID- 10645991
TI  - The many faces of Kawasaki syndrome.
AB  - The clinical challenge lies in recognizing cases not fully meeting the syndrome's
      diagnostic criteria and those that strongly resemble a variety of infectious and
      reactive disorders. Prompt treatment with high-dose intravenous immune globulin
      in combination with aspirin can significantly reduce the frequency and severity
      of cardiovascular complications.

PMID- 10645992
TI  - Hepatitis C: a challenge for the generalist.
AB  - Most cases of hepatitis C become chronic, and although many of those remain
      silent for decades, some eventually progress to cirrhosis or other complications.
      Since almost 2% of the U.S. population is already infected, clinicians are likely
      to encounter growing numbers of patients with progressive disease. Treatment has
      been modified; ribavirin can now be added to interferon therapy.

PMID- 10645993
TI  - Improving management of type 2 diabetes mellitus: 5. Thiazolidinediones.

PMID- 10645994
TI  - Coping with change: 3. Taking care of your needs.

PMID- 10645995
TI  - Episodic myalgia, weakness, and dark urine.

PMID- 10645996
TI  - Let dietitians, not physicians, write diet prescriptions in hospital settings.

PMID- 10645997
TI  - Congressional stalemate leaves future uncertain for managed-care reform.

PMID- 10645998
TI  - Is it wise to restrict fat in the diets of children?
AB  - The proponents of fat-restricted diets for children argue that low-fat diets
      given in childhood will prevent the development of atherosclerosis in adulthood,
      low-fat diets given a childhood will condition children to prefer low-fat diets
      in adulthood, and low-fat diets for children are safe. There is no evidence that
      low-fat diets in childhood will prevent atherosclerosis in adulthood. In fact,
      studies of migrating populations indicate that immigrants to the United States
      from Third World countries who consumed low-fat diets in childhood take on the
      character of their new environments, including higher serum cholesterol levels
      and more coronary disease. The prevalence of fatty streaks in childhood bears
      little relationship to the prevalence of atheromatous plaques in adulthood. In
      fact, girls have more aortic fatty streaks and higher serum cholesterol values in
      childhood than boys, but fewer plaques in adulthood and less coronary disease.
      From the PDAY study, it has also been learned that hypercholesterolemia in
      childhood enhances fatty streak formation, but not that of plaques. It now seems
      established from autopsy studies that the progression of atherosclerosis from
      fatty streaks to plaque is arrested in childhood and does not begin to a
      significant extent until after puberty in males and after menopause in females.
      So the oft-repeated statement that atherosclerosis begins in childhood is
      semantically true but very misleading. The particularly harmful form of
      atherosclerosis (the plaque) does not become significant until much beyond
      puberty. The effects of low-fat, low-cholesterol diets on serum lipids and
      lipoproteins are of a lesser magnitude in children than in adults. The 0.78
      mmol/L decrease in LDL cholesterol in the intervention group from controls
      (change 1.5%) in the DISC study was biologically insignificant and reflects the
      tighter control of lipoprotein and cholesterol synthesis in children compared
      with adults. It must be remembered that the human body synthesizes all of the
      cholesterol it needs from acetyl CoA. In general, the larger the amount of
      dietary cholesterol absorbed, the smaller the rate of biosynthesis of
      cholesterol. In some adults and most children this homeostatic control is nearly
      perfect, but in many adults the correction in biosynthesis of cholesterol with
      increased dietary input is imperfect and LDL cholesterol values increase. The
      second argument of the proponents of low-fat diets for children is that they are
      conditioned to continue low-fat diets in adulthood. From the studies of Birch and
      Fisher (51) this prediction seems unlikely. These investigators found that
      restricting access to palatable foods enhanced the interest of 3- to 5-year-old
      children in those foods and increased their desire to obtain and consume those
      foods. They concluded that "stringent parental controls can potentiate preference
      for high-fat energy-dense foods, limit children's acceptance of a variety of
      foods and disrupt children's regulation of energy intake." Brosin (52) has also
      observed that food restriction in childhood may lead to gluttony in adulthood.
      Finally, the claim that low-fat diets are safe in childhood is based on
      observations over too short a time to establish safety. It is true that growth
      and development of children studied in the DISC study was not changed from the
      expected increments, but that is not proof of long-term safety. In addition, the
      lower content of essential nutrients in low-fat, low-cholesterol diets (calcium,
      zinc, magnesium, phosphorus, vitamin E, vitamin B-12, thiamin, niacin, and
      riboflavin) must be considered along-term risk (53,54). Furthermore, the
      published studies of the safety of low-fat diets have been conducted under
      intensive surveillance in medical centers, conditions very different from those
      in the homes of free-living families.

PMID- 10645999
TI  - A moderate view on fat restriction for young children.
AB  - As dietetics professionals, rather than debating dietary prescriptions, we must
      make our priority evaluating whether those prescriptions can be reasonably and
      consistently translated into food selection and eating patterns. This is nothing
      new to us. We have long advised physicians about the practicality of diet
      prescriptions and often recommended that prescriptions be moderated. In my view,
      we are at our finest when we are advocates for people and their relationships
      with food rather than arbiters of diets. Rather than emphasizing what people
      should eat, we must emphasize what is possible and reasonable for them to eat. In
      my experience, the gap between knowing and doing will continue as long as the
      knowing is unrealistic. Clinical experience makes it clear that if a diet
      prescription is unrealistic, it will not do any good. In attempting to apply
      unrealistic dietary prescriptions, we do not help people. We just make them into
      dietary cripples. It has been extraordinarily difficult to lighten up on the
      particular diet prescription of the US Dietary Guidelines. Given the emphasis on
      preventive nutritional care and the urgency with which the messages are
      delivered, I and many other dietetics professionals believe our are hands tied:
      We must go along with the US Dietary Guidelines. If we relax our efforts to
      persuade people to eat in accordance with the prescription, we have been led to
      believe we will do them irreparable harm. The data do not support such a threat,
      either for children or for adults. There is enough inconsistency in the evidence
      linking dietary fat and heart disease to make prevention a hope, not a guarantee.
      Before we apply the formulas we love so well (yes, I love them too), we must
      consider what our attempts to apply a formula will do to people's eating
      attitudes and behaviors and to the feeding relationships between adults and
      children. People manage to feed themselves and their children, and they eat the
      way they do for reasons that grow out of their cultural traditions, preferences,
      and practicalities. Sweeping changes carry the risk of undermining serviceable
      foodways, so it is reasonable to recommend such changes only on an individual
      basis and, for the public, on the basis of compelling evidence. No such evidence
      exists. Because the scientific evidence for the connection between childhood diet
      and heart disease is debatable, it is legitimate for us to be advocates for
      children by recommending doing less, rather than more. "Less" in my view, does
      not mean doing nothing at all. It means helping families enjoy food and optimize
      normal eating patterns, rather than attempting to achieve a particular
      prescription for dietary fat.

PMID- 10646000
TI  - Should dietary fat recommendations for children be changed?

PMID- 10646001
TI  - Guidelines for healthy children: promoting eating, moving, and common sense.

PMID- 10646002
TI  - In defense of a low-fat diet for healthy children.

PMID- 10646003
TI  - Primary prevention of cardiovascular disease starts in childhood.

PMID- 10646004
TI  - Food sources of added sweeteners in the diets of Americans.
AB  - OBJECTIVE: To identify food sources of added sweeteners in the US diet. DESIGN: A
      descriptive study using data from the US Department of Agriculture (USDA) 1994
      1996 Continuing Survey of Food Intakes by Individuals. Each subject provided one
      24-hour dietary recall. Intake of added sweeteners was calculated using the USDA
      Food Guide Pyramid servings database. SUBJECTS/SETTING: A national sample of
      noninstitutionalized persons aged 2 years and older (N = 15,010). STATISTICAL
      ANALYSES: Mean intakes of added sweeteners from all food sources and from
      specific food categories; percentage contribution of added sweeteners to total
      energy intake; and percentage contribution of each food category to total intake
      of added sweeteners. All analyses were conducted for the total sample and for 12
      age-gender groups. RESULTS: During 1994 to 1996, Americans aged 2 years and older
      consumed the equivalent of 82 g carbohydrate per day from added sweeteners, which
      accounted for 16% of total energy intake. In absolute terms, adolescent males
      consumed the most; as a percentage of energy, male and female adolescents had the
      highest intakes (averaging 20% of total energy from added sweeteners). The
      largest source of added sweeteners was regular soft drinks, which accounted for
      one third of intake. Other sources were table sugars, syrups, and sweets;
      sweetened grains; regular fruitades/drinks; and milk products.
      APPLICATIONS/CONCLUSIONS: Intakes of added sweeteners exceed levels compatible
      with meeting current dietary recommendations. Knowing food sources of added
      sweeteners for the overall population and for specific age-gender groups can help
      dietitians provide appropriate nutrition education.

PMID- 10646005
TI  - Reported adoption of dietary fat and fiber recommendations among consumers.
AB  - OBJECTIVE: To identify constraints in adopting dietary fat and fiber
      recommendations. DESIGN: A questionnaire was mailed to a sample of the general
      population, a convenience sample of persons with heart disease and cancer in 11
      states, and registered dietitians in 5 states. The survey included questions on
      demographic and attitudinal factors that were correlated with specific practices
      to reduce fat intake and increase fiber intake. SETTING: From the general
      population sample of 6,206 eligible respondents (return rate of 51.5%), those
      selected were respondents who indicated that they would adopt a dietary
      recommendation if it were good for them (n = 2,682). Subsamples from the general
      population were matched to 362 registered dietitians and 147 persons with cancer
      or heart disease on selected demographic variables. Factors associated with
      adoption of specific behaviors were identified. STATISTICAL ANALYSIS PERFORMED:
      Statistical analysis included chi 2, factor analysis, and analysis of variance.
      RESULTS: The majority of persons who said they would adopt a fat-reducing
      behavior if it were good for their health reported practicing that behavior often
      or usually. More than 60% reported consuming whole grains; however, only 15%
      reported eating fruits and vegetables frequently. Among the general population
      sample, those more likely to practice a behavior had the following
      characteristics: female, college educated, older than 60 years, white, higher
      income, no children younger than 18 years, perceived health status as excellent,
      and absence of chronic disease. Registered dietitians and those with chronic
      disease were also more likely to follow dietary fat and fiber recommendations.
      APPLICATIONS: Nutrition education messages that lead to increased consumption of
      dietary fiber need to be developed. Nutrition educators should provide strategies
      for consumers for increasing use of fruits and vegetables in all meals. Good
      taste and convenience are critical components. The food industry may assist by
      providing a wider array of convenience entrees or side dishes that feature
      produce and whole grains.

PMID- 10646006
TI  - Descriptive anthropometric reference data for older Americans.
AB  - OBJECTIVE: To present selected anthropometric data derived from adults aged 60
      years and older examined in the third National Health and Nutrition Examination
      Survey (NHANES III). DESIGN: NHANES III used a complex, stratified, multistage,
      probability cluster sample design to obtain a nationally representative sample of
      the US civilian, noninstitutionalized population. Persons aged 60 years and
      older, Mexican-Americans, and African-Americans were oversampled to produce more
      reliable estimates for these groups. Trained technicians measured height, weight,
      skinfold thickness, and circumferences using standardized procedures. SUBJECTS: A
      total of 5,700 persons aged 60 years and older, and 1,861 persons aged 50 to 59
      years. STATISTICAL ANALYSES PERFORMED: Mean and selected percentiles for body
      weight, body mass index, triceps skinfold thickness, mid upper arm circumference,
      and arm muscle circumference were calculated by gender, race/ethnicity, and 3 age
      categories. Weight (lb) per height (in) tables were generated for men and women
      by age group. RESULTS: Mean body weight was lowest for persons aged 80 years and
      older. A decline in body mass index occurred that paralleled the direction and
      magnitude of the progressive decrease observed in weight. Muscle loss with
      increasing age, as indicated by arm muscle circumference, appeared to be greater
      among men than women. APPLICATIONS/CONCLUSIONS: In addition to being relatively
      simple, quick, and inexpensive, anthropometry is the most reliable and specific
      indicator of malnutrition in the older adult population. The cross-sectional
      reference data provided can be used by dietitians to interpret anthropometric
      measurements of persons aged 60 years and older.

PMID- 10646008
TI  - Current and future practices in hospital foodservice.
AB  - OBJECTIVES: To identify current operational practices and expectations for future
      practices in hospital foodservice; establish the probability that current
      practices will change; and determine whether differences in practices exist on
      the basis of profit status and hospital size. DESIGN: A questionnaire, to
      determine current practices, probability of change, and expectations for future
      practices, was mailed to foodservice directors. SUBJECTS: A random sample of 500
      foodservice directors in US hospitals with 200 or more beds. A total of 214
      questionnaires were returned for a response rate of 43%. STATISTICAL ANALYSIS:
      Descriptive statistics were used to report current practices, probability of
      change, and expectations for future practices. The Kruskal-Wallis test was
      conducted to examine whether the probability of change ratings differed on the
      basis of hospital profit status and size. chi 2 Analysis was used to examine
      whether expectations for future practices differed based on hospital profit
      status and size. RESULTS: Currently 81% of hospital foodservice departments have
      fewer than 100 employees; 73% have revenue budgets of less than $2 million; 49%
      have expense budgets greater than $2 million; 55% use a selective menu, often
      (43%) 1-week in length; 74% use conventional food production technology; 81% have
      a centralized, hot tray line; 91% operate a cafeteria; 96% do on-site catering;
      69% have differential pricing for employee meals; 58% have subsidized employee
      meals; and 19% have coffee kiosks. Changes in current practices are expected in
      several areas. Foodservice directors expect to serve meals to fewer inpatients
      (71%), employ less staff (73%), have smaller expense budgets (70%), and generate
      more revenue (61%). Kruskal-Wallis and chi 2 analyses indicated few differences
      on the basis of hospital profit status and size. There was little consensus among
      directors on how to best respond to these environmental changes. APPLICATIONS:
      Hospital foodservice practices will change in the future. Foodservice directors
      are using a variety of strategies (e.g., revenue-generating ventures, menu
      changes) to respond to current environmental changes. Increased emphasis will be
      placed on running a hospital foodservice department as a profit center rather
      than a cost center.

PMID- 10646007
TI  - Functional status and emotional well-being, dietary intake, and physical activity
      of severely obese subjects.
AB  - OBJECTIVE: Analyze functional status and emotional well-being, energy and
      nutrient intake, and physical activity in sibling pairs raised together in the
      same family. DESIGN: One sibling classified as severely obese (body mass index >
      or = 35) and the other sibling as normal weight (body mass index < or = 27).
      SUBJECTS: From January 1994 through December 1996 at the Cardiovascular Genetics
      Research Clinic of the University of Utah School of Medicine, 145 sibling pairs
      (n = 290) were selected from a population-based, family history database or a
      hospital-based, very-low-energy weight-loss program. STATISTICAL ANALYSIS
      PERFORMED: Repeated-measures analysis of variance tested for differences between
      severely obese and normal-weight siblings. RESULTS: All functional status and
      emotional well-being scores (poorer perceived health) were significantly lower in
      severely obese siblings compared with normal-weight siblings. The severely obese
      siblings had a higher percentage dietary fat intake (3% higher) and total energy
      intake (more than 350 kcal higher), and lower weight-adjusted total energy intake
      (almost 10 kcal/kg lower) and activity energy expenditure (3.5 kcal/kg lower),
      compared with normal-weight siblings. Thus, environmental influences such as
      energy and nutrient intake and physical activity are highly related to severe
      obesity. APPLICATIONS: Previously shared environment of severely obese and normal
      weight siblings raises questions about whether strong environmental influences or
      genetic predisposition account for the differences in sibling weight. When
      counseling individuals or families with a history of severe obesity, dietetics
      practitioners should be familiar with the potential for strong genetic factors
      and related environmental influences. In addition, dietitians should be prepared
      to offer a flexible approach to physical exercise as well as provide additional
      behavioral support.

PMID- 10646009
TI  - Preadmission nutrition screening: expanding hospital-based nutrition services by
      implementing earlier nutrition intervention.
AB  - The need to screen patients earlier than within the first 24 hours of hospital
      admission has resulted in the development of preadmission nutrition screening. At
      Providence Saint Joseph Medical Center (PSJMC), a 455-bed acute-care facility,
      this procedure has been used since 1994. The preadmission screening method was
      developed because of the use of critical pathways for patients in specific
      diagnosis-related groups. Critical pathways specified that registered dietitians
      must assess these patients within 24 hours of admission at PSJMC. However, at
      that time there was minimal data in the chart from which to assess the patient's
      nutritional status and the ability to interview the patient was often limited as
      a result of intubation or postoperative pain. Family members were not always
      available at the hospital to discuss a patient's preadmission nutritional status.
      To address this problem, we developed a system to call people at home before
      their admission to the hospital to obtain specific nutrition information. To
      analyze the effectiveness of the procedure, the Food and Nutrition Services
      Department developed a process to assess this method of screening and to improve
      the system. Patients were enrolled in a study over a 1-month period, demographics
      were identified for this sample population, and patient satisfaction was
      determined via an interview conducted by a dietetic technician after the patient
      was admitted. Most patients found this to be a very helpful process and an
      example is presented here on the role of preadmission nutrition screening in
      improving patient outcome. To better define the population of the case study
      presented, additional information was gathered on a second study group of
      patients screened before admission who were admitted for hip and knee surgery,
      one of the specific diagnosis-related groups with a critical pathway. Our
      findings indicate that preadmission nutrition screening has the potential to
      improve patient outcomes by increasing nutrient intake before their hospital
      admission, reducing hospitalization length, and enhancing patient satisfaction
      during their hospital stay.

PMID- 10646010
TI  - Dietary folate equivalents: interpretation and application.
AB  - The 1998 Dietary Reference Intakes express the new Recommended Dietary Allowances
      for folate in dietary folate equivalents ("DFEs"), which account for differences
      in the absorption of naturally occurring food folate and the more bioavailable
      synthetic folic acid. The quantity of dietary folate equivalents occurring
      naturally in food equals the micrograms of folate as reported, and the dietary
      folate equivalents provided by fortified foods equal the micrograms of food
      folate plus 1.7 times the micrograms of added folic acid. Currently, the use of
      dietary folate equivalents is recommended for planning and evaluating the
      adequacy of people's folate intake. As a result of new US Food and Drug
      Administration regulations, folic acid has been added to enriched cereal grains
      and thus affects hundreds of food products. To help dietetics professionals plan
      and evaluate diets that include enriched cereal grain products, we estimated the
      dietary folate equivalent content of a selection of foods using data supplied by
      the US Department of Agriculture and grouped the foods by dietary folate
      equivalent content.

PMID- 10646011
TI  - Use of computer-based patient records in dietetics supervised practice programs.

PMID- 10646012
TI  - Glycemic index of "energy" snack bars in normal volunteers.

PMID- 10646013
TI  - Top predictors of middle/junior high school students' satisfaction with school
      foodservice and nutrition programs.

PMID- 10646014
TI  - Family-style foodservice can meet US Dietary Guidelines for elementary school
      children.

PMID- 10646015
TI  - Flexible tape is an appropriate tool for knee height measurement and stature
      estimation of adults with developmental disabilities.

PMID- 10646016
TI  - Position of the American Dietetic Association: local support for nutrition
      integrity in schools.
AB  - It is the position of The American Dietetic Association that the school and
      community have a shared responsibility to provide all students with access to
      high-quality foods and nutrition services as an integral part of the total
      education program. Educational goals, including the nutrition goals of the
      National School Lunch Program and the School Breakfast Program, should be
      supported and extended through school district policies that create an overall
      school environment with learning experiences that enable students to develop
      lifelong, healthful eating habits. Local school policy, developed through a
      collaborative process that responds to community needs and priorities, should
      include the integration of the school nutrition program with education. Nutrition
      integrity policy provides a framework for the integration and coordination of all
      aspects of the school nutrition program. Nutrition integrity is defined as "a
      guaranteed level of performance that ensures that all foods available and
      consumed by children in schools are consistent with the Recommended Dietary
      Allowances and the Dietary Guidelines for Americans, and contribute to the
      development of lifelong, healthy eating habits." Achieving nutrition integrity
      means taking a comprehensive approach to program planning, management,
      operations, and integration of nutrition into the total education program of the
      school. The community is a valuable resource for this effort. Collaboration
      between key school- and community-based constituents, including children and
      other stakeholders, will result in the most effective and relevant plans for
      local school nutrition programs. However, competing and profit-making food and
      beverage sales may create a conflicting environment and can contradict lessons
      taught in health and nutrition education. This position provides direction for
      the dietetics profession for addressing this issue along with providing a
      suggested action plan for local schools and their communities.

PMID- 10646017
TI  - Report on the American Dietetic Association's Member Needs
      Assessment/Satisfaction Study.

PMID- 10646018
TI  - What has gone wrong in stroke research?

PMID- 10646019
TI  - Fish odor syndrome.
AB  - Fish odour syndrome (trimethylaminuria) is a metabolic syndrome caused by
      abnormal excretion of trimethylamine in the breath, urine, sweat, saliva and
      vaginal secretions. Trimethylamine is derived from the intestinal bacterial
      degradation of foods rich in choline and carnitine and is normally oxidised by
      the liver to odorless trimethylamine N-oxide which is then excreted in the urine.
      Impaired oxidation of trimethylamine is thought to be the cause of the fish odour
      syndrome and is responsible for the smell of rotting fish. Certain foods rich in
      choline exacerbate the condition and the patients have a variety of psychological
      problems. Recognition of the condition is important as dietary adjustments reduce
      the excretion of trimethylamine and may reduce the odour. Occasionally, a short
      course of metronidazole, neomycin and lactulose may suppress production of
      trimethylamine by reducing the activity of gut microflora.

PMID- 10646021
TI  - Methods of obtaining peripheral venous access in difficult situations.
AB  - Peripheral venous access is frequently required in the hospital environment. This
      can occasionally be difficult to obtain. We have reviewed the pertinent
      literature and propose a structured algorithmic approach to reduce patient
      discomfort and to minimise the time involved in securing venous access.

PMID- 10646022
TI  - Images in medicine. Hydatid disease of the liver.

PMID- 10646020
TI  - The role of exercise testing in the evaluation and management of heart failure.
AB  - The clinical syndrome of heart failure has been investigated so extensively that
      it may now almost be regarded as a metabolic disorder. Although an initial insult
      reduces cardiac pump efficacy, the resultant physiological response culminates in
      complex neurohormonal dysfunction. This has created confusion and prevented the
      acceptance of a universal definition of cardiac failure. With much current
      research concentrating on the pharmacological modification of neuroendocrine
      imbalance, it is easy to lose sight of the fundamental principles behind heart
      failure management, namely, to improve cardiac function. In attempting to achieve
      this, the issues of morbidity and mortality must be addressed jointly; they are
      not mutually exclusive entities. Discrepant results between mortality studies and
      changes in exercise capacity have undermined the value of exercise testing.
      Because a treatment enhances longevity we should not ignore its effect on
      symptomatic status, and likewise we should not discard a therapy, which improves
      function because adverse events result in occasional premature deaths. Informed
      patient choice must exist. Historically, exercise testing has been quintessential
      in our understanding and evaluation of heart failure. Peak oxygen consumption
      remains the best overall indicator of symptomatic status, exercise capacity,
      prognosis and hospitalisation. Unfortunately, muddling of surrogate and true end
      points has confused many of these issues. Improved comprehension may be gained by
      applying the concept of cardiac reserve which has been described in a variety of
      heart conditions and used in cardiac failure patients to provide an indication of
      prognosis and functional capacity.

PMID- 10646023
TI  - Do Indo-Asians have smaller coronary arteries?
AB  - There is a widespread belief that coronary arteries are smaller in Indo-Asians.
      The aim of the present study was to compare the size of atheroma-free proximal
      and distal epicardial coronary arteries of Indo-Asians and Caucasians. We
      analysed normal coronary angiograms from 77 Caucasians and 39 Indo-Asians. The
      two groups were comparable for dominance of the coronary arteries. Indo-Asian
      patients had generally smaller coronary arteries, with a statistically
      significant difference in the mean diameters of the left main coronary artery,
      proximal, mid and left anterior descending, and proximal and distal right
      coronary artery segments. There was a non-significant trend towards smaller
      coronary artery segment diameters for the distal left anterior descending,
      proximal and distal circumflex, and obtuse marginal artery segments. However,
      after correction for body surface area, none of these differences in size were
      statistically significant. Thus, the smaller coronary arteries in Indo-Asian
      patients were explained by body size alone and were not due to ethnic origin per
      se. This finding nevertheless has important therapeutic implications, since
      smaller coronary arteries may give rise to technical difficulties during bypass
      graft and intervention procedures such as percutaneous transluminal coronary
      angioplasty, stents and atherectomy. On smaller arteries, atheroma may also give
      an impression of more severe disease than on larger diameter arteries.

PMID- 10646024
TI  - Clinical presentation of thyroid dysfunction and Addison's disease in young
      adults with type 1 diabetes.
AB  - In a clinic population of 509 type 1 diabetic patients aged 16-45 years, 5.5% had
      received treatment for thyroid disorders (20 hypothyroid, three males; eight
      thyrotoxicosis, four males), and Addison's disease was present in four patients
      (0.8%, one male). In all patients, type 1 diabetes preceded the diagnosis of the
      other autoimmune disorder. The clinical presentation of hypothyroidism was
      usually insidious with few symptoms, although an increased frequency of
      hypoglycaemic symptoms and/or raised serum cholesterol levels often prompted
      thyroid function testing. In contrast, the patients with thyrotoxicosis had
      florid symptoms, weight loss (mean 8.12 kg), palpable goitres, increasing insulin
      requirements, and low cholesterol levels. Six patients did not achieve remission
      or had recurrent thyrotoxicosis after oral antithyroid treatment and required
      131I or thyroid surgery. A family history of autoimmune disease was present in
      25% of patients with thyroid disorders (seven thyrotoxic and one hypothyroid) and
      in three of the four patients with Addison's disease. In this population of young
      adult type 1 diabetic patients, appropriate tests for thyroid dysfunction and
      Addison's disease should be carried out if there is clinical suspicion and/or
      unexplained changes in diabetic metabolic control or serum cholesterol. Careful
      follow-up of patients with a family history of these conditions is recommended.

PMID- 10646025
TI  - Images in medicine. Spontaneous bilateral rupture of biceps tendons.

PMID- 10646026
TI  - A regional survey of chest drains: evidence-based practice?
AB  - Although the use of chest drains is common in medicine, there appear to be wide
      variations in practice. A survey was therefore conducted to establish the current
      status of chest drain management in the Northwest region. A questionnaire
      targeted consultants practising in the specialties of chest medicine, general
      surgery, accident & emergency and cardiothoracic surgery. The questionnaire
      consisted of five sections encompassing aspects of the insertion, day-to-day care
      and removal of chest drains. With an overall response rate of 75.3% (110/146),
      important variations in every major aspect of the practice of chest drains were
      found between the specialties and to a large extent within each specialty. We
      have made a number of recommendations which aim to encourage good practice and
      reduce unnecessary complications, including the adoption of standardised
      protocols for inserting and managing chest drains.

PMID- 10646027
TI  - Hypersensitivity pneumonitis associated with co-proxamol (paracetamol +
      dextropropoxyphene) therapy.
AB  - A 61-year-old man developed hypersensitivity pneumonitis and skin rash in close
      association with taking co-proxamol. These problems occurred in spite of being
      treated with prednisolone 40 mg daily (20 mg daily at the time of presentation)
      for assumed cranial arteritis. A therapeutic challenge with paracetamol was
      negative and the patient continues to take this drug. It seems likely that this
      patient's rash and hypersensitivity pneumonitis was caused by dextropropoxyphene.
      Dextropropoxyphene has not been reported previously as a cause of
      hypersensitivity pneumonitis.

PMID- 10646028
TI  - Reversible cerebellar involvement in the idiopathic hypereosinophilic syndrome.
AB  - We report a patient with cerebellar manifestations due to the idiopathic
      hypereosinophilic syndrome, in whom magnetic resonance imaging (MRI) showed hyper
      intense lesions in both cerebellar hemispheres. Following steroids and
      hydroxyurea administration, the lesions on MRI disappeared, suggesting that the
      pathogenetic mechanism was reversible and did not cause significant structural
      damage. To our knowledge, the resolution of the abnormal MRI findings have not
      been reported to date in the idiopathic hypereosinophilic syndrome.

PMID- 10646029
TI  - A patient with fever and an abdominal aortic aneurysm.
AB  - A 55-year-old man with an abdominal aortic aneurysm presented with fever and
      abdominal pain 3 weeks after an episode of Salmonella gastroenteritis. His
      symptoms persisted despite antimicrobial therapy. Two abdominal computed
      tomography (CT) scans showed no evidence of aortitis. His abdominal pain worsened
      and further investigation including a third CT scan demonstrated a leaking aortic
      aneurysm. The wall of the aorta was shown to contain Gram-negative bacilli. This
      case illustrates the difficulty in diagnosing bacterial aortitis.

PMID- 10646030
TI  - A lesson in the management of testicular cancer in a patient with a solitary
      testis.
AB  - Five per cent of patients with germ cell tumours of the testis will develop a
      further tumour in the contralateral testis. Standard treatment in such cases is a
      second orchidectomy, resulting in infertility, hormone replacement, and
      psychological morbidity. In this case report we explore the role of testis
      conservation in these patients and also show that there is a risk of removing a
      potentially normal testis if a histological diagnosis is not sought prior to
      orchidectomy.

PMID- 10646031
TI  - Extramedullary myeloid cell tumour: presentation as anterior chest wall mass
      during AML relapse.
AB  - Acute myeloid leukaemia is an uncommon but an important cause of soft tissue
      swellings. Such extrameningeal, extramedullary leukaemic infiltrates are called
      extramedullary myeloid cell tumours. Despite their large size they may respond
      well to chemotherapy and local radiotherapy, as is demonstrated in this case.

PMID- 10646032
TI  - Hereditary hypophosphataemic rickets: report of a family from the Indian
      subcontinent.
AB  - Nutritional deficiency continues to be an important cause of rickets in the
      underdeveloped and developing parts of the world. In the western hemisphere,
      predominantly non-nutritional forms of rickets and osteomalacia are now seen. In
      this report we discuss a family with X-linked hypophosphataemic rickets from the
      Kashmir region of the Indian subcontinent (which is an uncommon entity here).

PMID- 10646033
TI  - An unusual shoulder injury.

PMID- 10646034
TI  - Peri-articular 'hard tumours' in soft tissues.

PMID- 10646035
TI  - Fever of unknown origin.

PMID- 10646036
TI  - A young woman with fever of unknown origin.

PMID- 10646037
TI  - Intracerebral haemorrhage in previously healthy young adults.

PMID- 10646038
TI  - Hyperkalaemia following blood transfusion.

PMID- 10646039
TI  - A wheezy man with a bony abnormality.

PMID- 10646040
TI  - Electrocardiographic abnormalities in an elderly woman.

PMID- 10646041
TI  - A yellow patient with hepatomegaly.

PMID- 10646042
TI  - Drug-induced syndrome of inappropriate antidiuretic hormone secretion.

PMID- 10646043
TI  - Tuberculosis of the central nervous system.

PMID- 10646044
TI  - Introduction. Enkephalinase inhibition: a rational approach to antisecretory
      therapy for acute diarrhoea.

PMID- 10646045
TI  - Racecadotril demonstrates intestinal antisecretory activity in vivo.
AB  - BACKGROUND: Racecadotril (acetorphan), a potent enkephalinase inhibitor, protects
      endogenous enkephalins from degradation. Racecadotril exhibits experimental and
      clinical antidiarrhoeal activity without any effect on intestinal motility,
      suggesting selective antisecretory activity. The antisecretory effect of
      racecadotril was directly assessed in the present study. METHODS: A 1 m, jejunal,
      Thiry-Vella loop was created in six mongrel dogs, and water and ionic fluxes were
      evaluated during infusion (2 mL/min) of Tyrode solution labelled with 14C
      polyethylene glycol. Fluxes were determined both in the basal state and 5-6 h
      after commencement of a 2-h infusion of cholera toxin (0.4 microgram/mL).
      Racecadotril (10 mg/kg) or vehicle was given orally with and without prior
      intravenous administration of naloxone (0.1 mg/kg) or phentolamine (0.2 mg/kg).
      RESULTS: Basal absorption remained unchanged following racecadotril
      administration; however, racecadotril significantly decreased (P = 0.01) cholera
      toxin-induced water, sodium, and potassium hypersecretion, from 0.73 +/- 0.15 to
      0.37 +/- 0.13 mL/min; from 125.0 +/- 16.1 to 14.7 +/- 9.5 microMol/min; and from
      3.41 +/- 0.66 to 1.66 +/- 0.61 microMol/min, respectively. This antisecretory
      activity of racecadotril was suppressed by naloxone but not by phentolamine.
      CONCLUSIONS: This study directly demonstrates the antisecretory activity of
      racecadotril in relation to the protection of endogenous enkephalins.

PMID- 10646046
TI  - Effects of racecadotril and loperamide on bacterial proliferation and on the
      central nervous system of the newborn gnotobiotic piglet.
AB  - METHODS: The effects of 4 days of oral administration of different doses of two
      drugs, an enkephalinase inhibitor (the antisecretory agent, racecadotril) and a
      mu-receptor agonist (loperamide), on intestinal growth of a bacterial
      nonpathogenic strain (Escherichia coli E 404) and on the central nervous system
      (CNS) were compared in newborn gnotobiotic piglets. RESULTS: The E. coli content
      of the proximal jejunum (segment S1) and the E. coli ratio of stomach:segment S1
      were similar in the racecadotril (20 mg/kg b.d., n = 5) and control groups. In
      contrast, in the loperamide group (1 mg/kg b.d., n = 4), the E. coli content of
      segment S1 and the E. coli ratio stomach:S1 were both significantly higher than
      with racecadotril or control (P = 0.04 and 0.005, respectively, for E. coli
      content; P = 0.05 and 0.03, respectively, for stomach:S1). There were no clinical
      signs of neurotoxicity and no deaths with racecadotril given orally at a high
      dose of 130 mg/kg b.d. (n = 5)--nearly 60 times the paediatric dosage. In
      contrast, an equivalent high dose of loperamide (5 mg/kg b.d.) resulted in death
      in three out of four piglets. CONCLUSIONS: In contrast to loperamide,
      racecadotril did not induce bacterial overgrowth and did not produce central
      neurotoxicity.

PMID- 10646047
TI  - Racecadotril versus placebo in the treatment of acute diarrhoea in adults.
AB  - METHODS: A two-centre, double-blind, parallel-group, randomized study was carried
      out to compare the efficacy and tolerability of racecadotril (100 mg three times
      daily) and placebo in 70 adult patients with acute diarrhoea. An objective
      criterion of antisecretory activity, stool weight, was used. RESULTS:
      Racecadotril produced a significant (P = 0.025) decrease in stool weight during
      the first day of treatment compared with placebo, and was also associated with
      significantly fewer diarrhoeic stools than placebo after 1 day of treatment (p =
      0.027). Racecadotril and placebo were equally well tolerated, and the frequency
      of symptoms and signs was similar in both groups after 4 days of treatment. Fewer
      patients on racecadotril suffered from abdominal distension following treatment
      (5.6% vs. 18.2% on placebo). CONCLUSIONS: Racecadotril acts rapidly to resolve
      acute diarrhoea and has an incidence of adverse events similar to that of
      placebo.

PMID- 10646048
TI  - Comparison of racecadotril and loperamide in adults with acute diarrhoea.
AB  - METHODS: A multicentre, randomized, double-blind, double-placebo, parallel-group
      study was carried out to compare the efficacy, tolerability, and safety of
      racecadotril (100 mg three times daily) and loperamide (2 mg after each
      diarrhoeic stool) in 157 adults with acute diarrhoea. Patients were treated for 7
      days or until recovery, if this took place earlier. RESULTS: Both groups of
      patients passed similar numbers (mean +/- S.E.M.) of stools before recovery (3.5
      +/- 0.5 for racecadotril vs. 2.9 +/- 0.4 for loperamide), and the duration of
      diarrhoea (mean +/- S.E.M.) was similar in both groups (14.9 +/- 2.0 h for
      racecadotril and 13.7 +/- 2.2 h for loperamide). Both treatments reduced the
      incidence of associated symptoms and signs during the study, and both were
      similarly well tolerated. However, more patients on loperamide reported rebound
      constipation during treatment (18.7% vs. 9.8% with racecadotril). CONCLUSIONS:
      The enkephalinase inhibitor, racecadotril, and the intestinal transit inhibitor,
      loperamide, were similarly and rapidly effective in resolving the symptoms and
      associated signs of diarrhoea.

PMID- 10646049
TI  - Comparison of racecadotril and loperamide in children with acute diarrhoea.
AB  - METHODS: A multicentre, parallel-group, double-blind, double-placebo study was
      carried out to compare the efficacy, tolerability, and safety of racecadotril and
      loperamide in children aged 2 to 10 years who were suffering from acute
      diarrhoea. Patients received racecadotril (1.5 mg/kg) or loperamide (0.03 mg/kg)
      three times daily plus matching placebo until recovery. Fifty-two children
      received racecadotril and 50 loperamide. RESULTS: Patients on racecadotril passed
      a mean (+/- S.E.M.) of 2.7 +/- 0.4 stools before recovery compared with 2.1 +/-
      0.4 stools for loperamide. The duration of diarrhoea was similar with both
      treatments. The incidence of adverse events was lower with racecadotril than with
      loperamide (11.5% vs. 22%), and significantly more patients on loperamide
      suffered from constipation (58% vs. 36.5%; P = 0.03). Moreover, significantly
      more children receiving loperamide required concomitant medication during the
      study (38% v 19.2%; P = 0.047). Measurement of abdominal circumference at the
      final consultation, 6 days after entry to the study, revealed no significant
      differences between treatments. CONCLUSIONS: Racecadotril and loperamide were
      equally effective in treating acute diarrhoea in these children, and racecadotril
      had a superior tolerability and safety profile.

PMID- 10646050
TI  - Sandor Ferenczi today: reviving the broken dialectic.

PMID- 10646051
TI  - The countertransference in the work of Ferenczi.

PMID- 10646052
TI  - From Ferenczi to Kohut: from confusion of tongues to self-object.

PMID- 10646053
TI  - From Oedipus to Orpha: revisiting Ferenczi and Severn's landmark case.

PMID- 10646054
TI  - Contemporary application of Ferenczi: co-constructing past traumatic experiences
      through dream analysis.

PMID- 10646055
TI  - When trauma strikes the soul: shame, splitting, and psychic pain.

PMID- 10646056
TI  - Affect regulation, attachment and psychoanalysis.

PMID- 10646057
TI  - The analyst's mistakes: the aftermath: a panel discussion.

PMID- 10646058
TI  - Seeing ourselves as others see us.

PMID- 10646059
TI  - Acupuncture founded on magical and mystical musings about how the world works.

PMID- 10646060
TI  - An ethicist's commentary on an insurance policy requiring premature surgery.

PMID- 10646061
TI  - Veterinary informatics--why are we dragging our feet?

PMID- 10646062
TI  - The effect of opioid and acepromazine premedication on the anesthetic induction
      dose of propofol in cats.
AB  - The median effective dosage (ED50) for induction of anesthesia with propofol was
      determined by using the up-and-down method in 31 unpremedicated cats, in 30 cats
      premedicated with butorphanol, 0.4 mg/kg body weight (BW), and acepromazine, 0.1
      mg/kg BW, intramuscularly, and in 30 cats premedicated with morphine, 0.2 mg/kg
      BW, and acepromazine, 0.1 mg/kg BW, intramuscularly. The dose required for a
      satisfactory anesthetic induction in 50% of unpremedicated cats (ED50) was 7.22
      mg/kg BW and of premedicated cats was 5.00 mg/kg BW. The reduction in dose was
      statistically significant in both premedicated groups compared with no
      premedication. There was no significant difference in ED50 between premedication
      regimes. Cyanosis was the most common adverse effect observed in all groups
      following anesthetic induction with propofol.

PMID- 10646064
TI  - Osteochondrosis and epiphyseal bone abnormalities associated with copper
      deficiency in bison calves.
AB  - Two bison calves were submitted to the Western College of Veterinary Medicine to
      confirm suspected copper deficiency. In addition to clinical signs, there were
      pathologic changes in the cartilage and subchondral bone of several joints. Water
      analysis indicated high levels of sulfate in the drinking water, contributing to
      a secondary copper deficiency.

PMID- 10646063
TI  - [Control measures for contagious enteric diseases in a veterinary teaching
      hospital].
AB  - Instructions and control measures related to enteric contagious diseases at the
      Veterinary Medical Teaching Hospital (VMTH) of the Faculty of Veterinary Medicine
      of the University of Montreal are presented. These control measures, which have
      given satisfactory results within the past decade, are exemplified by a
      salmonellosis outbreak that occurred in spring 1996 in the large animal clinic of
      the VMTH. Emphasis was put on the importance of antigenic and/or genetic
      characterizations of Salmonella isolates, in order to detect an eventual source
      of contamination, but also to determine the incidence of nosocomial infections
      among hospitalized animals.

PMID- 10646065
TI  - Cutaneous mucinosis and mastocytosis in a shar-pei.
AB  - A 7-year-old shar-pei was presented because of a recurrent dermatologic
      condition. Skin biopsies revealed an idiopathic (primary) cutaneous mucinosis
      that initially responded to corticosteroids. The condition reappeared 2 years
      later and subsequent biopsies revealed a mast cell tumor in some of the skin
      sites previously diagnosed with mucinosis.

PMID- 10646066
TI  - Segmental aplasia of the left paramesonephric duct in the cow.
AB  - Segmental aplasia of the left uterine horn in a multiparous Holstein cow was
      diagnosed by palpation and ultrasonography. Treatment with prostaglandin was
      unsuccessful in eliminating the fluid from the distended uterine horn. Segmental
      aplasia should be included in the list of differential diagnoses for cows with
      nonresponsive uterine enlargement.

PMID- 10646067
TI  - Spinal cord compression secondary to hemangiosarcoma in a saddlebred stallion.
AB  - Hemangiosarcoma in the spinal canal was diagnosed in a 25-year-old stallion
      showing progressive and symmetrical 4-limb ataxia, proprioceptive deficits, and
      weakness. On necropsy, an extradural mass consisting of spindle-shaped cells and
      numerous free erythrocytes was found at the level of C7-T1. Immunohistochemical
      staining confirmed a neoplasm of endothelial origin.

PMID- 10646068
TI  - Mycotic (Candida sp.) enterocolitis of Atlantic salmon parr in a hatchery in
      British Columbia.

PMID- 10646069
TI  - H3N2 influenza A virus recovered from a neonatal pig in Ontario--1997.

PMID- 10646070
TI  - Veterinary phytotherapy: an overview.

PMID- 10646071
TI  - Diagnostic ophthalmology. Multifocal retinopathy of a Great Pyrenees.

PMID- 10646072
TI  - Guideline for the flow cytometric enumeration of CD34+ haematopoietic stem cells.
      Prepared by the CD34+ haematopoietic stem cell working party. General Haematology
      Task Force of the British Committee for Standards in Haematology.

PMID- 10646073
TI  - The classification and diagnostic criteria of the erythrocytoses (polycythaemias)
AB  - The term 'erythrocytosis' has advantages over 'polycythaemia' to describe
      patients with a raised haematocrit (PCV) and deserves to be more widely used.
      Measurement of red cell mass (RCM) and its relation to that expected for an
      individual's height and weight permits initial subdivision of erythrocytosis into
      absolute (increased RCM) or apparent normal RCM. Absolute erythrocytosis may be
      primary (intrinsically abnormal marrow erythropoiesis) or secondary (increased
      erythropoietin drive in response to pathological events outside the bone marrow).
      Both primary and secondary erythrocytosis may be either congenital or acquired.
      Idiopathic erythrocytosis is a third, probably heterogenous, group within the
      absolute erythrocytoses. Familial abnormalities of the erythropoietin receptor
      underlie the primary congenital subgroup. Polycythaemia vera (PV), the clonal
      myeloproliferative disorder, is so far, the only primary acquired disorder. Newer
      diagnostic investigations such as serum erythropoietin estimation, improved
      karyotypic analysis, in vitro culture of erythroid colonies and estimation of
      spleen size before splenomegaly is palpable, have permitted some modification of
      the traditional diagnostic criteria of polycythaemia vera. This may allow more
      confident diagnosis and, together with improved testing for causes of secondary
      erythrocytosis, may reduce the number of patients so far unsatisfactorily
      consigned to the idiopathic erythrocytosis group.

PMID- 10646074
TI  - Laboratory investigation of platelet function.
AB  - Advancement in the understanding of the mechanisms of platelet activation and the
      development of new techniques for studying platelet function have created the
      challenge of a wide range of options for investigating patients with suspected
      platelet disorders and for studying the effects of anti-platelet drugs. Novel
      classes of anti-platelet drug, such as adenosine diphosphate (ADP) receptor and
      glycoprotein IIb/IIIa receptor antagonists, are being developed and introduced
      into routine clinical practice. This review presents an overview of current
      techniques for laboratory investigation of platelet function in the light of
      these recent advances.

PMID- 10646075
TI  - The role of the Sysmex SE9000 immature myeloid index and Sysmex R2000
      reticulocyte parameters in optimizing the timing of peripheral blood stem cell
      harvesting in patients with lymphoma and myeloma.
AB  - Peripheral blood CD34/45+ cell (CD34/45) enumeration is an expensive and labour
      intensive investigation but remains the standard assay for optimizing yield and
      timing of peripheral blood stem cell harvesting (PBSCH). The present study
      examined the value of the Sysmex SE9000 parameters (WBC, neutrophil count, and
      immature myeloid index (IMI)) and Sysmex R2000 reticulocyte parameters (absolute,
      high and medium fluorescence reticulocytes) in predicting the optimum timing of
      PBSCH in comparison to peripheral blood CD34/45. Sixty-four PBSCH from 23
      patients with haematological malignancies were assessed with a variety of
      mobilization regimes used. Reticulocyte parameters showed high interpatient
      variability and did not prove clinically useful. IMI did not consistently predict
      satisfactory PBSCH yield except when > 1000 x 10(6)/l. Peripheral blood CD34/45
      was the most useful predictor of yield. IMI > 20 x 10(6)/l was, however, a useful
      surrogate for predicting a rise in peripheral blood CD34/45 from nadir and proved
      to be superior to WBC or neutrophil count. A rising IMI is a marker of early
      regeneration and has a role in determining when to initiate enumeration of
      peripheral blood CD34/45.

PMID- 10646076
TI  - Comparison of single and dual-platform assay formats for CD34+ haematopoietic
      progenitor cell enumeration.
AB  - Most techniques for CD34+ cell enumeration are dual platform assays. That is,
      they derive absolute numbers of CD34+ cells from either the flow cytometrically
      assessed per cent (%) CD34+ cells within the nucleated cells and/or the white
      blood cell count from a haematology cell analyser. Recently, so-called single
      platform assays have been developed, in which the absolute number of CD34+ cells
      is directly derived from a single flow cytometric measurement. The present study
      aims to compare the variation between eight laboratories in CD34+ cell counts
      from paired assays of 15 samples using a common single (ProCOUNT) and the local
      dual-platform method. Six laboratories used the 'SIHON' and two the 'ISHAGE'
      protocol for CD34+ cell enumeration. Use of the single-platform method reduced
      the inter-laboratory variation in per cent and absolute numbers of CD34+ cells,
      as measured by interquartile ranges, by half but did not lead to an appreciable
      reduction of the inter-laboratory variation in white blood cell counts. Thus,
      part of the reduced inter-laboratory variation obtained with ProCOUNT may have
      been a result of the use of standardized procedures and reagents to detect CD34+
      cells. In order to eliminate any variation arising from the use of different
      local protocols for percentage of CD34+ cell assessments, a comparison was made
      of the ProCOUNT-derived absolute CD34+ cell numbers (i.e. single platform) with
      the dual-platform absolute CD34+ cell numbers calculated by multiplying ProCOUNT
      derived percentage of CD34+ cells and with the corresponding haematology analyser
      derived white blood cell count. Regardless, the interquartile ranges of absolute
      CD34+ cell numbers remained almost a factor of two smaller with the use of the
      single platform method. Thus, these results suggest that single-platform
      methodology can reduce the variation in absolute CD34+ cell numbers between
      laboratories.

PMID- 10646077
TI  - Performance characteristics of blast flagging on the Cell Dyn 4000 haematology
      analyser.
AB  - This study investigated the performance characteristics of blast flagging on the
      Abbott Cell Dyn 4000 (CD4000) haematology analyser. Our special interest was
      focused on the usability and prognostic value of the confidence fraction (CF),
      accompanying blast flagging. From our routine patient samples, 100 with blast
      flagging on the CD4000 were selected and examined microscopically for the
      presence of blasts. Blast flagging on the CD4000 resulted in a high number of
      false positive events. The results indicate that the blast flag confidence
      fraction (CF) of the CD4000 can be useful as a parameter for the prediction of
      the presence of blasts in samples with normal and increased white blood cell
      count. A model with criteria for blood smear examination following blast flagging
      was developed, using the blast flag CF combined with the WBC count. The model was
      tested and validated in a new set of 100 samples with blast flagging.
      Implementation of the criteria of the model resulted in a total reduction of the
      number of microscopic smear examinations of 45%, without losing clinically
      significant sensitivity.

PMID- 10646078
TI  - Thrombosis, markers of thrombotic risk, indwelling central venous catheters and
      antithrombotic prophylaxis using low-dose warfarin in subjects with malignant
      disease.
AB  - Markers of thrombotic risk--fibrinogen, factor VIII and immunoglobulin G (IgG)
      anticardiolipin titres--were measured, and the presence of lupus anticoagulant
      and factor V Leiden were assessed in 84 patients with a solid or haematological
      malignancy. These patients were monitored, following the insertion of an
      indwelling venous catheter, for thrombosis. Fifty-five were given prophylactic
      low-dose warfarin. Over a mean of 15 weeks there were 10 (12%) thrombotic events
      in 10 patients. Seven were on warfarin. Haemorrhagic problems occurred in three
      (5%), all on warfarin. Of the 84 patients, 86% had raised fibrinogen levels, 37%
      elevated factor VIII and 44% raised anticardiolipin levels. Lupus anticoagulant
      was present in five and three were heterozygous for factor V Leiden. A high
      prevalence of a range of prothrombotic changes was confirmed and the frequent
      presence of low-titre anticardiolipin antibody in subjects with malignancy
      demonstrated. However, none of these parameters predicted the development of
      thrombosis (P > 0.05).

PMID- 10646079
TI  - D-dimer for the exclusion of venous thromboembolism: comparison of a new
      automated latex particle immunoassay (MDA D-dimer) with an established enzyme
      linked fluorescent assay (VIDAS D-dimer).
AB  - The use of D-dimer tests to exclude venous thromboembolism is an important
      advance in clinical practice and also has economic benefits. Ideally the test
      should be objective and a test that could be run on the routine coagulometer
      would obviate the need for additional investment in alternative hardware. A new
      automated latex particle immunoassay (MDA D-dimer) that can be run on a routine
      coagulometer was compared with a well established enzyme linked fluorescent assay
      (VIDAS D-dimer) on the basis of their ability to exclude venous thromboembolism.
      The assays were compared in 49 patients presenting to the emergency department
      with clinically suspected deep vein thrombosis or pulmonary embolism. After
      objective diagnostic imaging, 20 patients were confirmed to have venous
      thromboembolism. There was strong agreement between the assays in individual
      patients. Using a cut-off of 500 micrograms/l, both tests had a sensitivity of
      100% and therefore a negative predictive value of 100%, however the MDA test
      would have spared more patients (20% vs. 12%) from further testing if a negative
      D-dimer was used to rule-out the diagnosis. It was concluded that a rapid,
      objective latex D-dimer test run on a routine coagulometer (MDA D-dimer) can be
      used to exclude the diagnosis of venous thromboembolism.

PMID- 10646080
TI  - Plasma D-dimers: comparison of ELISA with a new, rapid, quantitative latex assay.

PMID- 10646081
TI  - Early diagnosis of septicaemia in preterm infants from examination of peripheral
      blood films.
AB  - Clinically significant staphylococcal septicaemia associated with the presence of
      bacteria in neutrophils in a routine peripheral blood film is described in four
      preterm infants. In all cases this allowed the diagnosis of infection prior to
      the result of microbiological cultures. It is likely that this finding is
      relatively common in this subgroup of patients resulting from a combination of
      severe infection associated with indwelling catheters and defective neutrophil
      bacteriacidal mechanisms. The findings in these cases suggest that careful blood
      film inspection in selected premature neonates may allow the early identification
      of sepsis.

PMID- 10646082
TI  - Ferritin and oral pathology.

PMID- 10646083
TI  - New millenium. The need for new vaccines.

PMID- 10646084
TI  - Conventional and non-conventional recognition of non-peptide antigens by T
      lymphocytes.

PMID- 10646085
TI  - Polyosides (encapsulated bacteria).
AB  - The polysaccharide capsule which surrounds bacterial species such as Haemophilus
      influenzae, Streptococcus pneumoniae, Neisseria meningitidis and Salmonella typhi
      is a potent virulence factor by protecting the bacteria from phagocytosis. The
      host responds with antibody production and specific antibodies plus complement
      binding to the capsule facilitate opsonization of the micro-organism, which is
      phagocytized and eliminated. Purified capsular polysaccharides elicit T
      independent antibody responses without a memory function, but are often poorly
      immunogenic in infants where much of the invasive H. influenzae type b (Hib) and
      pneumococcal infections is seen. Therefore purified polysaccharides have found
      limited use as vaccines. However, covalent linkage of the capsular
      polysaccharide, or fractions thereof, to immunogenic carrier proteins creates
      glycoconjugates which are T-dependent antigens and which elicit antibodies also
      in infants and which prime for boosting either with the glycoconjugate or the
      capsular polysaccharide. In the last decade Hib glycoconjugate vaccines have been
      successfully introduced and in countries with very high immunization coverage the
      disease has been virtually eliminated and a decline of over 95% has been seen in
      countries with slightly lower vaccine rates. World-wide use of Hib glycoconjugate
      vaccines offers the possibility of elimination of invasive Hib disease.
      Pneumococcal (11 serotypes with coverage of approximately 85% of invasive
      disease), meningococcal (A, C, W 135, Y but not B) and S. typhi glycoconjugates
      are in advanced development and offer the prospect of being as successful as the
      Hib glycoconjugates.

PMID- 10646086
TI  - Specific vaccines against autoimmune diseases.
AB  - Copolymer 1 (Cop 1, Copaxone) is a synthetic amino acid copolymer effective in
      suppression of experimental allergic encephalomyelitis (EAE). The suppressive
      effect of Cop 1 in EAE is not restricted to a certain species, disease type or
      encephalitogen used for EAE induction. In phase II and III clinical trials, Cop 1
      was found to slow the progression of disability and reduce the relapse rate in
      exacerbating-remitting multiple sclerosis (MS) patients. In vivo and in vitro
      studies suggest that the mechanism for Cop 1 activity in EAE and MS involves, as
      an initial step, the binding of Cop 1 to MHC class II molecules. This binding
      results in competition with myelin antigens for T-cell activation, both at the
      MHC and T-cell receptor levels and in induction of specific suppressor cells of
      the Th2 type. As an antigen-specific intervention, Cop 1 has the advantage of
      reduced probability for long-term damage to the immune system, and is thus a safe
      and effective novel therapeutic approach to MS. It also serves to illustrate the
      new concept of a drug/vaccine specific for a single autoimmune disease. Indeed,
      we have used a similar approach for myasthenia gravis. Myasthenia gravis (MG) and
      its experimental animal model, experimental autoimmune MG (EAMG), are immune
      disorders characterized by circulating antibodies and lymphocyte autoreactivity
      to nicotinic acetylcholine receptor (AChR). We utilized peptides representing
      different sequences of the human acetylcholine receptor alpha-subunit to study
      the role of T cells in the initiation, development and immunomodulation of
      myasthenia gravis. Here we summarize our studies over the last decade on T cells
      specific to 'myasthenogenic' epitopes of the alpha-subunit of the human
      acetylcholine receptor and their relevance for myasthenia gravis.

PMID- 10646087
TI  - [New vaccines and the prevention of infectious and degenerative disease].

PMID- 10646088
TI  - Vaccination against the major infectious diseases.
AB  - The reputation of vaccination rests on a 200-year-old history of success against
      major infectious diseases. That success has led to the doctrine of 'for each
      disease, a vaccine'. Although some diseases have proved frustrating, this
      doctrine carries considerable truth. However, when one reviews the vaccines now
      available it is apparent that most successes have been obtained when the microbe
      has a bacteremic or viremic phase during which it is susceptible to the action of
      neutralizing antibodies, and before replication in the particular organ to which
      it is tropic. Poliomyelitis and infections by capsulated bacteria are examples
      where vaccination has worked efficiently. However, some success has also been
      achieved against agents replicating on respiratory or gastrointestinal mucosae.
      Influenza, pertussis and rotavirus vaccines are examples of such agents, against
      which it has been possible to induce immune responses acting locally as well as
      systemically. In addition, when bacteria produce disease through exotoxins,
      purification and chemical or genetic inactivation of those toxins has yielded
      highly efficacious vaccines. Control of intracellular pathogens has not been
      achieved, except partly with the BCG vaccine against tuberculosis, and modern
      efforts are directed towards pathogens against which cellular immune responses
      are critical. In general, two achievements have been crucial to the success of
      vaccines: the induction of long-lasting immunological memory in individuals and
      the stimulation of a herd immunity that enhances control of infectious diseases
      in populations.

PMID- 10646089
TI  - Development of novel tuberculosis vaccines.
AB  - Efficacious control of tuberculosis (TB), one of the world's major health
      threats, is best achieved by a combination of chemotherapy and vaccination. The
      current vaccine, BCG, fails to prevent pulmonary TB in adults, which is the most
      prevalent form of this disease. Consequently, the design of novel vaccines
      against TB is urgently required. Because the acquired immune response is mediated
      by different T-cell sets, an optimal combination of these populations must be
      stimulated. As one third of the world's population is already infected with
      Mycobacterium tuberculosis, two types of vaccine may be required: one for
      eradication of already established infection and the other for prompt combat of
      invading microbes. A rational judgement on the efficacy of the different types of
      vaccine currently under development needs to await further evaluation.

PMID- 10646090
TI  - New prospects for the development of a vaccine against human immunodeficiency
      virus type 1. An overview.
AB  - During the past few years, definite progress has been made in the field of human
      immunodeficiency virus type 1 (HIV-1) vaccines. Initial attempts using envelope
      gp120 or gp140 from T-cell line-adapted (TCLA) HIV-1 strains to vaccinate
      chimpanzees showed that neutralizing antibody-based immune responses were
      protective against challenge with homologous TCLA virus strains or strains with
      low replicative capacity, but these neutralizing antibodies remained inactive
      when tested on primary HIV-1 isolates, casting doubts on the efficacy of gp120
      based vaccines in the natural setting. Development of a live attenuated simian
      immunodeficiency virus (SIV) vaccine was undertaken in the macaque model using
      whole live SIV bearing multiple deletions in the nef, vpr and vpx genes. This
      vaccine provided remarkable protective efficacy against wild-type SIV challenge,
      but the deletion mutants remain pathogenic, notably in neonate monkeys. Study of
      the mechanisms of protection in the SIV model unravelled the importance of the T
      cell responses, whether in the form of cytotoxic T-lymphocyte (CTL) killing
      activity, or in that of antiviral factor secretion of cytokines, beta-chemokines
      and other unidentified antiviral factors by CD8+ T-cells. Induction of such a
      response is being sought at this time using various live recombinant virus
      vaccines, either poxvirus or alphavirus vectors or DNA vectors, which can be
      combined together or with a gp120/gp140 boost in various prime-boost combination
      strategies. New vectors include attenuated vaccinia virus NYVAC, modified
      vaccinia strain Ankara (MVA), Semliki Forest virus, Venezuelan equine
      encephalitis virus, and Salmonellas. Recent DNA prime-poxvirus boost combination
      regimens have generated promising protection results against SIV or SIV/HIV
      (SHIV) challenge in macaque models. Emphasis is also put on the induction of a
      mucosal immune response, involving both a secretory IgA response and a mucosal
      CTL response which could constitute a 'first line of defence' in the vaccinated
      host. Finally, a totally novel vaccine approach based on the use of Tat or Tat
      and Rev antigens has been shown to induce efficient protection from challenge
      with pathogenic SIV or SHIV in vaccinated macaques. The only vaccine in phase 3
      clinical trials in human volunteers is a gp120-based vaccine, AIDSVAX. A prime
      boost combination of a recombinant canarypoxvirus and a subunit gp120 vaccine is
      in phase 2. Emphasis has been put recently on the necessity of testing prototype
      vaccines in developing countries using immunogens derived from local virus
      strains. Trial sites have thus been identified in Kenya, Uganda, Thailand and
      South Africa where phase I trials have begun or are expected to start presently.

PMID- 10646091
TI  - Veterinary vaccinology.
AB  - Veterinary vaccinology is a very interesting and rapidly developing field. In
      fact veterinary vaccines are not only used for the prevention of infectious
      diseases in the animal health sector, but also help to solve problems of public
      health, to reduce detrimental environmental impact of the use of some veterinary
      drugs and prevent the emergence of resistance of micro-organisms or parasites.
      After a short introduction, this paper will deal with the use of vaccines for
      animal health and welfare, including new developments in the veterinary field
      such as marker vaccines and vectored vaccines, the special case of equine
      influenza-inactivated vaccines and the use of veterinary vaccines in public
      health. The conclusions will analyse the reasons as to why develop veterinary
      vaccines and the obstacles to their development.

PMID- 10646092
TI  - Vaccination against infections by Chlamydia pneumoniae.
AB  - Chlamydia pneumoniae is an intracellularly growing bacterium that causes
      respiratory infections and is strongly associated with atherosclerosis.
      Antibodies against C. pneumoniae are frequently encountered in the adult
      population, indicating past exposure to the micro-organism. Immunity to
      reinfection is, however, only partial and does not prevent development of
      sequelae. Infections caused by and associated with C. pneumoniae are a major
      cause of morbidity and mortality world wide. Development of a vaccine capable of
      protecting against infections due to C. pneumoniae and their sequelae would
      prevent up to 10% of community-acquired pneumonias in adults and add a new
      dimension to the prevention of atherosclerosis and coronary heart disease.

PMID- 10646093
TI  - [Genetic vaccination. Perspectives for the prevention and treatment of hepatitis
      B].
AB  - Genetic vaccination by intramuscular injection of a plasmid vector encoding the
      hepatitis B virus surface antigen (HBsAg) induces antibodies in mice that are
      specific for the hepatitis B virus envelope proteins. The antibody titres were
      very high and remained constant for more than 6 months after a single injection.
      Transgenic (Tg) mice that constitutively express the HBsAg in the liver were used
      as a model for hepatitis B virus chronic carriers. Intramuscular injection of a
      plasmid encoding the HBsAg in Tg mice resulted in the complete clearance of
      circulating HBsAg and in the long-term control of transgene mRNA expression in
      hepatocytes. Genetic vaccination appears therefore as a promising method for both
      prevention and treatment of hepatitis B.

PMID- 10646094
TI  - [Societies and their vaccines].

PMID- 10646095
TI  - Economic aspects of vaccines and immunizations.
AB  - Several techniques are used to estimate whether investing in vaccines and
      immunization is worthwhile, including cost analysis, cost-benefit analysis, cost
      effectiveness analysis, and cost-utility analysis. At least 162 published
      economic evaluations of vaccines have been carried out from 1969 to 1998. They
      consistently show that immunization is an excellent investment--highly cost
      effective and usually cost-saving--for vaccines that are currently recommended
      for universal use. Although prices of newer vaccines are higher than prices of
      traditional vaccines, they are still highly cost-effective. The World Health
      Organization, UNICEF, and vaccine manufacturers have developed approaches to make
      newer vaccines available to developing countries at reduced prices.
      Sustainability of immunization programs (the ability of a country to continue its
      immunization program in the absence of external support) is an increasingly
      important goal. However, external assistance will be essential in the short term
      to ensure that all the world's people benefit fully from the new vaccines.

PMID- 10646096
TI  - Vaccination in the Third World. Contemporary issues.

PMID- 10646097
TI  - Introduction of vaccines into the Third World.

PMID- 10646098
TI  - [Vaccination in Africa. Performance and deficiencies].

PMID- 10646108
TI  - The roles of osteoprotegerin and osteoprotegerin ligand in the paracrine
      regulation of bone resorption.
AB  - Although multiple hormones and cytokines regulate various aspects of osteoclast
      formation, the final two effectors are osteoprotegerin ligand (OPG-L)/osteoclast
      differentiation factor (ODF), a recently cloned member of the tumor necrosis
      factor superfamily, and macrophage colony-stimulating factor. OPG-L/ODF is
      produced by osteoblast lineage cells and exerts its biological effects through
      binding to its receptor, osteoclast differentiation and activation receptor
      (ODAR)/receptor activator of NF-kappa B (RANK), on osteoclast lineage cells, in
      either a soluble or a membrane-bound form, the latter of which requires cell-to
      cell contact. Binding results in rapid differentiation of osteoclast precursors
      in bone marrow to mature osteoclasts and, at higher concentrations, in increased
      functional activity and reduced apoptosis of mature osteoclasts. The biological
      activity of OPG-L/ODF is neutralized by binding to osteoprotegerin
      (OPG)/osteoclastogenesis inhibitory factor (OCIF), a member of the TNF-receptor
      superfamily that also is secreted by osteoblast lineage cells. The biological
      importance of this system is underscored by the induction in mice of severe
      osteoporosis by targeted ablation of OPG/OCIF and by the induction of
      osteopetrosis by targeted ablation of OPG-L/ODF or overexpression of OPG/OCIF.
      Thus, osteoclast formation may be determined principally by the relative ratio of
      OPG-L/ODF to OPG/OCIF in the bone marrow microenvironment, and alterations in
      this ratio may be a major cause of bone loss in many metabolic disorders,
      including estrogen deficiency and glucocorticoid excess. That changes in but two
      downstream cytokines mediate the effects of large numbers of upstream hormones
      and cytokines suggests a regulatory mechanism for osteoclastogenesis of great
      efficiency and elegance.

PMID- 10646109
TI  - Trabecular bone microarchitecture, bone mineral density, and vertebral fractures
      in male osteoporosis.
AB  - Some studies have indicated that the risk of fragility fractures in men increases
      as bone mineral levels decrease, but there is an overlap in the bone mineral
      density (BMD) measurements between patients with or without fractures.
      Furthermore, it has been suggested that the biomechanical competence of
      trabecular bone is dependent not only on the absolute amount of bone present but
      also on the trabecular microarchitecture. In the present study, 108 men (mean age
      52.1 years) with lumbar osteopenia (T score < -2.5) were recruited to examine the
      relationships between BMD, architectural changes in trabecular bone, and the
      presence of vertebral fractures. Lumbar BMD was assessed from L2 to L4 in the
      anteroposterior view with dual-energy X-ray absorptiometry. At the upper left
      femur, hip BMD was measured at the transcervical site. Spinal X-ray films were
      analyzed independently by two trained investigators, and vertebral fracture was
      defined as a reduction of at least 20% in the anterior, middle, or posterior
      vertebral height. Transiliac bone biopsy specimens were obtained for all
      patients. Histomorphometric studies were performed on an image analyzer, and the
      following parameters were determined: trabecular bone volume (BV/TV), trabecular
      thickness (Tb.Th), number (Tb.N), and separation (Tb.Sp), interconnectivity index
      (ICI), characterization of the trabecular network (node count and strut
      analysis), and star volume of the marrow spaces. Spinal radiographs evidenced at
      least one vertebral crush fracture in 62 patients (group II) and none in 46
      patients (group I). After adjusting for age, body mass index, and BMD, there were
      no significant differences between the two groups in BV/TV, Tb.Th, or star
      volume. In contrast, the mean values of ICI, free end-to-free end struts
      (FF/TSL), and Tb.Sp were significantly higher, whereas Tb.N and node-to-node
      struts (NN/TSL) were lower in patients with at least one vertebral fracture.
      Logistic regression analysis showed that only ICI, FF/TSL, NN/TSL, and Tb.N were
      significant predictors of the presence of vertebral fracture: odds ratios for an
      alteration of 1 SD ranged from 1.7 (1.0-3.2) for NN/TSL to 3.2 (1.1-10.1) for
      ICI. Patients with at least three vertebral fractures (n = 23) were categorized
      as "multiple fractures." The results of logistic regression showed that spine
      BMD, BV/TV, and all architectural parameters were significant predictors of
      multiple vertebral fractures: odds ratios for an alteration of 1 SD ranged from
      2.2 (1.1-4.6) for star volume to 3.7 (1.4-9.7) for ICI. These results strongly
      suggest that bone trabecular microarchitecture is a major and independent
      determinant of vertebral fractures in middle-aged men with osteopenia.

PMID- 10646110
TI  - The contribution of trabecular architecture to cancellous bone quality.

PMID- 10646111
TI  - Determinants of bone loss from the femoral neck in women of different ages.
AB  - An age-stratified sample of 304 women from Rochester, Minnesota, aged 30-94 years
      (median 60 years) at baseline underwent measurement of femoral neck bone mineral
      density (BMD) over a follow-up period extending to 16 years. The average rate of
      change in femoral neck BMD was -1.0% per year (range -10.0% to +13.4%) and did
      not vary significantly with age. Because there was no marked increase in the rate
      of loss around the time of menopause, nor convincing evidence of there being a
      subset of fast losers, there was fairly good tracking of individual values over
      time; the correlation of baseline with femoral neck BMD values 16 years later was
      0.83. Although a large number of potential determinants was assessed, the only
      consistent predictor of femoral neck bone loss in women of different ages was
      baseline femoral neck BMD (r = -0.15; p = 0.023). Otherwise, different sets of
      risk factors were identified for premenopausal women, women within 20 years of
      menopause, and women 20 years or more postmenopausal, but the predictive power of
      these different multivariate models was modest. Nonetheless, these data indicate
      that femoral neck BMD is quite predictable for extended periods of time. This is
      reassuring with respect to the use of statistical models that incorporate such
      data to estimate future fracture risk.

PMID- 10646112
TI  - Variations in three-dimensional cancellous bone architecture of the proximal
      femur in female hip fractures and in controls.
AB  - Cubes of cancellous bone were obtained from proximal femora of women with hip
      fractures (n = 26) and from female cadaveric controls (n = 32) to compare
      architecture and mechanics between groups. Specimens were scanned on a
      microcomputed tomography system. Stereologic algorithms and model-based estimates
      were applied to the data to characterize the three-dimensional cancellous
      microstructure. Cubes were mechanically tested to failure to obtain mechanical
      properties. Specimens from control subjects had significantly higher bone volume
      fraction, trabecular number, and connectivity than specimens from patients with
      hip fractures; no difference in trabecular thickness was observed between groups.
      Both maximum modulus and ultimate stress were significantly higher in the control
      than in the fracture group, consistent with the higher bone volume found in the
      control group. No statistical differences in any of these architectural or
      mechanical variables were found when groups were matched for bone volume.
      Specimens from both patients with hip fractures and controls demonstrated strong
      relationships between trabecular number and bone volume fraction that were
      statistically equivalent, suggesting that for a given bone mass, both groups have
      the same overall number of trabeculae. However, there was an architectural
      difference between fracture and control groups in terms of the three-dimensional
      spatial arrangement of trabeculae. Fracture specimens had a significantly more
      anisotropic (oriented) structure than control specimens, with proportionately
      fewer trabecular elements transverse to the primary load axis, even when matched
      for bone volume. Relationships between mechanical and architectural parameters
      were significantly different between groups, suggesting that fracture and control
      groups have different structure-mechanics relationships, which we hypothesize may
      be a consequence of the altered three-dimensional structure between groups.

PMID- 10646113
TI  - In vitro and in vivo suppression of osteoclast function by adenovirus vector
      induced csk gene.
AB  - The proto-oncogene c-src, which encodes a non-receptor-type tyrosine kinase c
      Src, has been shown to be essential for osteoclastic bone resorption by the
      finding that the targeted disruption of the c-src gene induced osteopetrosis in
      mice. The csk (C-terminal Src family kinase) gene encodes a cytoplasmic protein
      tyrosine kinase that specifically phosphorylates the negative regulatory site of
      c-Src (Tyr-527), thereby inhibiting its kinase activity. To regulate osteoclast
      function by modulating the kinase activity of c-Src, we constructed an adenovirus
      vector that carries this gene. The recombinant adenovirus vector carrying csk
      cDNA induced Csk expression in mouse osteoclast-like cells formed in vitro and
      clearly reduced c-Src kinase activity in a dose-dependent manner. The expression
      of Csk caused cytoskeletal disorganization of osteoclast-like cells and strongly
      suppressed pit-forming activity of the cells in vitro. In addition, the viral
      vector carrying csk gene dramatically suppressed interleukin-1 alpha-induced bone
      resorption in vivo. Conversely, kinase-inactive Csk caused an increase in c-Src
      kinase activity and bone resorbing activity of the cells both in vitro and in
      vivo, acting as a dominant negative molecule against intrinsic Csk. These
      findings indicate that the inhibition of c-Src activity by adenovirus vector
      mediated csk expression offers an efficient means for inhibiting pathological
      bone resorption by suppressing osteoclast function.

PMID- 10646114
TI  - Cementum-forming cells are phenotypically distinct from bone-forming cells.
AB  - Normal human cementum-derived cells (HCDCs), expanded in vitro, formed
      mineralized matrix when attached to a ceramic carrier and transplanted
      subcutaneously into immunodeficient mice. The mineralized matrix elaborated by
      transplanted HCDC exhibited several features identical to cementum in situ and
      was significantly different from bone deposited by similarly transplanted human
      bone marrow stromal cells (BMSCs). No bone marrow formation and very few or no
      tartrate-resistant acid phosphatase (TRAP)-positive cells (osteoclasts and
      osteoclastic precursors) were found in HCDC transplants. In contrast, in BMSC
      transplants both hematopoiesis and TRAP-positive cells were routinely observed.
      Furthermore, compared with BMSC-derived matrix, HCDC-derived matrix was less
      cellular, numerous empty lacunae were present, and fewer cells were found on the
      cementum matrix/ceramic carrier interface. The organization of collagen fibers in
      HCDC-derived matrix, as visualized by using the Picrosirus red staining method,
      was similar to cementum, with typical unorganized bundles of collagen fibers. In
      contrast, bone matrix elaborated by transplanted BMSC had lamellar structure,
      identical to mature bone in situ. Finally, cementocytes embedded in the cementum
      like matrix were immunopositive for fibromodulin and lumican, whereas osteocytes
      within the bonelike matrix were negative. This pattern is consistent with the
      cementum and bone in situ, respectively. These results indicate that human
      cementum cells are phenotypically distinct from bone cells and provide further
      validation of the combined in vitro/in vivo model of human cementogenesis
      recently developed in our laboratory.

PMID- 10646115
TI  - Loss of osteocyte integrity in association with microdamage and bone remodeling
      after fatigue in vivo.
AB  - As a result of fatigue, bone sustains microdamage, which is then repaired by bone
      remodeling processes. How osteoclastic activity is targeted at the removal of
      microdamaged regions of bone matrix is unknown. In the current studies, we tested
      the hypothesis that changes in osteocyte integrity, through the initiation of
      regulated cell death (apoptosis), are associated with fatigue-related microdamage
      and bone resorption. Ulnae of adult rats were fatigue-loaded to produce a known
      degree of matrix damage. Osteocyte integrity was then assessed
      histomorphometrically from terminal deoxynucleotidyl transferase-mediated
      deoxyuridine triphosphate-nick end labeling (TUNEL)-stained sections to detect
      cells undergoing DNA fragmentation associated with apoptosis; toluidine blue
      stained sections were used for secondary morphological confirmation. Ten days
      after loading, large numbers of TUNEL-positive osteocytes were found in bone
      surrounding microcracks and in bone surrounding intracortical resorption spaces
      (approximately 300% increases over controls, p < 0.005). TUNEL labeling in loaded
      ulnae at sites distant from microcracks or resorption foci did not differ from
      that in control bone. Osteocytes in toluidine blue-stained sections showed
      equivalent trends to TUNEL-stained sections, with significant increases in
      pyknotic nuclei and empty lacunae associated with microcracks and intracortical
      resorption spaces. TUNEL-positive osteocytes were observed around bone
      microdamage by 1 day after loading (p < 0.01 relative to baseline), and their
      number remained elevated throughout the entire experimental period. Increases in
      empty lacunae and decreases in normal osteocyte numbers were observed over time
      as well. These studies show that (1) osteocyte apoptosis is induced by bone
      fatigue, (2) this apoptosis is localized to regions of bone that contain
      microcracks, and (3) osteoclastic resorption after fatigue also coincides with
      regions of osteocyte apoptosis. The strong associations between microdamage,
      osteocyte apoptosis, and subsequent bone remodeling support the hypothesis that
      osteocyte apoptosis provides a key part of the activation or signaling mechanisms
      by which osteoclasts target bone for removal after fatigue-induced matrix injury.

PMID- 10646116
TI  - Role of the latent transforming growth factor beta binding protein 1 in fibrillin
      containing microfibrils in bone cells in vitro and in vivo.
AB  - Latent transforming growth factor beta-binding proteins (LTBPs) are extracellular
      matrix (ECM) proteins that bind latent transforming growth factor beta (TGF-beta)
      and influence its availability in bone and other connective tissues. LTBPs have
      homology with fibrillins and may have related functions as microfibrillar
      proteins. However, at present little is known about their structural arrangement
      in the ECM. By using antibodies against purified LTBP1, against a short peptide
      in LTBP1, and against epitope-tagged LTBP1 constructs, we have shown
      colocalization of LTBP1 and fibrillin 1 in microfibrillar structures in the ECM
      of cultured primary osteoblasts. Immunoelectron microscopy confirmed localization
      of LTBP1 to 10- to 12-nm microfibrils and suggested an ordered aggregation of
      LTBP1 into these structures. Early colocalization of LTBP1 with fibronectin
      suggested a role for fibronectin in the initial assembly of LTBP1 into the
      matrix; however, in more differentiated osteoblast cultures, LTBP1 and
      fibronectin 1 were found in distinct fibrillar networks. Overexpression of LTBP1
      deletion constructs in osteoblast-like cells showed that N-terminal amino acids
      67-467 were sufficient for incorporation into fibrillin-containing microfibrils
      and suggested that LTBP1 can be produced by cells distant from the site of fibril
      formation. In embryonic long bones in vivo, LTBP1 and fibrillin 1 colocalized at
      the surface of newly forming osteoid and bone. However, LTBP1-positive fibrils,
      which did not contain fibrillin 1, were present in cartilage matrix. These
      studies show that in addition to regulating TGF beta 1, LTBP1 may function as a
      structural component of connective tissue microfibrils. LTBP1 may therefore be a
      candidate gene for Marfan-related connective tissue disorders in which linkage to
      fibrillins has been excluded.

PMID- 10646117
TI  - Different bone growth rates are associated with changes in the expression pattern
      of types II and X collagens and collagenase 3 in proximal growth plates of the
      rat tibia.
AB  - Skeletal growth depends on endochondral ossification in growth plate cartilage,
      where proliferation of chondrocytes, matrix synthesis, and increases in
      chondrocyte size all contribute to the final length of a bone. To learn more
      about the potential role of matrix synthesis/degradation dynamics in the
      determination of bone growth rate, we investigated the expression of matrix
      collagens and collagenase 3 in tibial growth plates in three age groups of rats
      (21, 35, and 80 days after birth), each characterized by specific growth rates.
      By combining stereological and in situ hybridization techniques, it was found
      that the expression of matrix collagens and collagenase 3 was specifically turned
      on or off at specific stages of the chondrocyte-differentiation cycle, and these
      changes occurred as a temporal sequence that varied depending of animal growth
      rate. Furthermore, the expression of these matrix proteins by a growth plate
      chondrocyte was found to be sped up or slowed down depending of the growth rate.
      In addition to expression of types II and X collagen, collagenase-3 expression
      was found to constitute a constant event in the series of changes in gene
      expression that takes place during the chondrocyte-differentiation process.
      Collagenase-3 expression was found to show a biphasic pattern: it was
      intermittently expressed at the proliferative phase and uniformly expressed at
      the hypertrophic stage. An intimate relationship between morphological and
      kinetic changes associated with chondrocyte hypertrophy and changes in the
      expression pattern of matrix collagens and collagenase 3 was observed. Present
      data prove that the matrix synthesis/degradation dynamics of the growth plate
      cartilage varied depending on growth rate; these results support the hypothesis
      that changes in matrix degradation and synthesis are a critical link in the
      sequence of tightly regulated events that lead to chondrocytic differentiation.

PMID- 10646118
TI  - Stimulation of sodium-dependent phosphate transport and signaling mechanisms
      induced by basic fibroblast growth factor in MC3T3-E1 osteoblast-like cells.
AB  - Physiological and pathological observations indicate that basic fibroblast growth
      factor (bFGF) is an important regulator of osteoblastic cell differentiation and
      in particular of cranial ossification. Experimental evidence suggests that
      inorganic phosphate (Pi) transport could be an important function of bone matrix
      calcification. In the present study, we address the influence of bFGF on Pi
      transport activity in MC3T3-E1 osteoblast-like cells derived from mouse calvaria.
      The results indicate that bFGF is a potent and selective stimulator of sodium
      dependent Pi transport in these cells. The change in Pi transport activity
      induced by bFGF depends on transcription and translation and corresponds to a
      change in the maximum velocity of the Pi transport system (Vmax). These
      observations suggest that enhanced Pi transport activity in response to bFGF may
      result from insertion of newly synthesized Pi transporters into the plasma
      membrane. A selective inhibitor of fibroblast growth factor receptor (FGFR)
      tyrosine kinase, SU5402, blunted the stimulation of Pi transport induced by bFGF.
      It also prevented the increase in protein tyrosine phosphorylation induced by
      bFGF, including phosphorylation of FGFR-1, FGFR-2, phospholipase C-gamma (PLC
      gamma), and Shc as well as the recruitment of the Grb2/Sos signaling complex. In
      addition, bFGF-induced the activation of the mitogen-activated protein (MAP)
      kinases extracellular signal-regulated kinase (ERK) and p38, effects that were
      prevented by SU5402. Both the protein kinase C (PKC) inhibitor calphostin C and
      PKC down-regulation suppressed the stimulatory effect of bFGF on Pi transport.
      Selective inhibitors of ERK and p38 MAP kinases slightly reduced this cellular
      response with a significant effect observed with the highest concentration of the
      p38 MAP kinase inhibitor. In conclusion, the results of this study indicate that
      bFGF selectively stimulates Pi transport in calvaria-derived osteoblastic cells.
      The main signaling mechanism responsible for this effect involves tyrosine
      phosphorylation of PLC-gamma and activation of PKC, with a possible contribution
      of the p38 MAP kinase pathway.

PMID- 10646119
TI  - Transgenic mice overexpressing tartrate-resistant acid phosphatase exhibit an
      increased rate of bone turnover.
AB  - Tartrate-resistant acid phosphatase (TRAP) is a secreted product of osteoclasts
      and a lysosomal hydrolase of some tissue macrophages. To determine whether TRAP
      expression is rate-limiting in bone resorption, we overexpressed TRAP in
      transgenic mice by introducing additional copies of the TRAP gene that contained
      the SV40 enhancer. In multiple independent mouse lines, the transgene gave a copy
      number-dependent increase in TRAP mRNA levels and TRAP activity in osteoclasts,
      macrophages, serum, and other sites of normal low-level expression (notably,
      liver parenchymal cells, kidney mesangial cells, and pancreatic secretory acinar
      cells). Transgenic mice had decreased trabecular bone consistent with mild
      osteoporosis. Measurements of the bone formation rate suggest that the animals
      compensate for the increased resorption by increasing bone synthesis, which
      partly ameliorates the phenotype. These mice provide evidence that inclusion of
      an irrelevant enhancer does not necessarily override a tissue-specific promoter.

PMID- 10646120
TI  - Altered postnatal expression of insulin-like growth factor-I (IGF-I) and type X
      collagen preceding the Perthes' disease-like lesion of a rat model.
AB  - The spontaneously hypertensive rat (SHR) is a widely used animal model for the
      study of hypertension. It also exhibits an osteonecrosis of the femoral epiphysis
      that resembles the clinical features of Perthes' disease in humans. In this rat
      model, occlusion of the epiphyseal vessels occurs as a result of a breakdown of
      the mechanically vulnerable epiphysis. The postnatal development of the epiphysis
      recapitulates the serial events of the endochondral ossification (i.e., cartilage
      formation), chondrocyte hypertrophy, cartilage mineralization, vascularization,
      and introduction of osteoblasts that form the secondary ossification center
      within the epiphysis. In the present study, a detailed radiographic and
      histological analysis demonstrates that the osteonecrosis is preceded by a
      disturbance of the cartilage mineralization and a disturbance of the
      ossification, despite a normal hypertrophy of the epiphyseal cartilage. These
      observations suggest that abnormal development of the femoral epiphysis occurs
      much earlier than manifestation of the osteonecrosis. They lead us to a
      hypothesis that yet-unclarified transitional events between the cartilage
      hypertrophy and the cartilage mineralization may be affected in SHRs. Type X
      collagen is a developmentally regulated matrix molecule that is implicated in the
      mineralization of the hypertrophied chondrocytes. We show that the expression of
      type X collagen during epiphyseal ossification is delayed in SHRs (vs. normal
      controls), suggesting disturbed growth and/or differentiation of the epiphyseal
      chondrocytes. Postnatal growth and differentiation of the chondrocytes at least
      partly depend on insulin-like growth factor-I (IGF-I), which is produced by the
      chondrocytes in response to the pituitary growth hormone and stimulates cartilage
      growth in situ. The present study demonstrates an altered IGF-I expression during
      early postnatal life in SHRs and suggests that the altered IGF-I expression as
      well as the following delay in upregulation of type X collagen may cause the
      mechanical vulnerability of the femoral epiphysis in SHRs.

PMID- 10646121
TI  - Mutations of the GNAS1 gene, stromal cell dysfunction, and osteomalacic changes
      in non-McCune-Albright fibrous dysplasia of bone.
AB  - Activating missense mutations of the GNAS1 gene, encoding the alpha subunit of
      the stimulatory G protein (Gs), have been identified in patients with the McCune
      Albright syndrome (MAS; characterized by polyostotic fibrous dysplasia, cafe au
      lait skin pigmentation, and endocrine disorders). Because fibrous dysplasia (FD)
      of bone also commonly occurs outside of the context of typical MAS, we asked
      whether the same mutations could be identified routinely in non-MAS FD lesions.
      We analyzed a series of 8 randomly obtained, consecutive cases of non-MAS FD and
      identified R201 mutations in the GNAS1 gene in all of them by sequencing cDNA
      generated by amplification of genomic DNA using a standard primer set and by
      using a novel, highly sensitive method that uses a protein nucleic acid (PNA)
      primer to block amplification of the normal allele. Histologic findings were not
      distinguishable from those observed in MAS-related FD and included subtle changes
      in cell shape and collagen texture putatively ascribed to excess endogenous
      cyclic adenosine monophosphate (cAMP). Osteomalacic changes (unmineralized
      osteoid) were prominent in lesional FD bone. In an in vivo transplantation assay,
      stromal cells isolated from FD failed to recapitulate a normal ossicle; instead,
      they generated a miniature replica of fibrous dysplasia. These data provide
      evidence that occurrence of GNAS1 mutations, previously noted in individual cases
      of FD, is a common and perhaps constant finding in non-MAS FD. These findings
      support the view that FD, MAS, and nonskeletal isolated endocrine lesions
      associated with GNAS1 mutations represent a spectrum of phenotypic expressions
      (likely reflecting different patterns of somatic mosaicism) of the same basic
      disorder. We conclude that mechanisms underlying the development of the FD
      lesions, and hopefully mechanism-targeted therapeutic approaches to be developed,
      must also be the same in MAS and non-MAS FD.

PMID- 10646122
TI  - The effect of pregnancy on bone density and bone turnover.
AB  - During pregnancy, the mother adapts to meet the calcium demands of the fetus. The
      effect of this adaptation on the maternal skeleton is not fully understood. Our
      objectives were to evaluate changes in bone mineral density (BMD) and bone
      turnover during pregnancy. We studied 16 women longitudinally, with baseline
      measurements before pregnancy; then at 16, 26, and 36 weeks of pregnancy; and
      postpartum. We measured total-body BMD and biochemical markers of bone resorption
      (urinary pyridinium crosslinks and telopeptides of type I collagen) and bone
      formation (serum bone alkaline phosphatase, propeptides of type I procollagen
      [PINP] and osteocalcin). We also measured parathyroid hormone (PTH), insulin-like
      growth factor I (IGF-I), and human placental lactogen. Postpartum, BMD increased
      in the arms (2.8%, P < 0.01) and legs (1.9%, P < 0.01) but decreased in the
      pelvis (-3.2%, P < 0.05) and spine (-4.6%, P < 0.01) compared with prepregnancy
      values. All biochemical markers, with the exception of osteocalcin concentration,
      increased during pregnancy. The change in IGF-I at 36 weeks was related to the
      change in biochemical markers (e.g., PINP, r = 0.72, P = 0.002). Pregnancy is a
      high-bone-turnover state. IGF-I levels may be an important determinant of bone
      turnover during pregnancy. Elevated bone turnover may explain trabecular bone
      loss during pregnancy.

PMID- 10646123
TI  - Analysis of ovariectomy and estrogen effects on body composition in rats by X-ray
      and magnetic resonance imaging techniques.
AB  - Resistance of bone to fracture--bone strength--has been shown to depend on both
      the amount of bone and its architectural spatial organization. In vivo magnetic
      resonance (MR) techniques have the capability of imaging bone tissue, including
      the trabecular microarchitecture and the marrow composition. We have applied in
      vivo and ex vivo MR methods to the tibia in an ovariectomized rat model of
      osteoporosis. Specifically, in vivo high-resolution three-dimensional MR imaging
      and localized MRS were facilitated by specialized coils and high field magnets,
      resulting in enhanced sensitivity of detection. As a result, in vivo and ex vivo
      differences in marrow composition were found between sham-ovariectomized,
      ovariectomized, and ovariectomized animals treated with 17-beta-estradiol.
      Estrogen effects were detected in vivo 7 days after surgery (3 days into
      treatment) as a decrease in the tibial fat signal level. The in vivo effects of
      ovariectomy were observed 56 days after surgery as an increase in MR image fat
      signal level and spectral fat/water ratio in the proximal tibia. Ex vivo
      measurements of tibial marrow water signal discriminated clearly between the sham
      and ovariectomized groups and showed increased individual variations in the
      treatment group. Imaging further showed that the highest fat content is observed
      in the epiphysis. Computed tomography confirmed ovariectomy-induced loss of bone
      in the proximal tibial metaphysis compared with the sham group. This loss of
      cancellous bone with ovariectomy is consistent with the MR observations of
      increases in both fat and water in the metaphysis. These data showed that MR
      techniques complement X-ray techniques in the bone, water, and fat compositional
      analysis of the appendicular skeleton in response to ovariectomy and
      pharmacological treatment.

PMID- 10646124
TI  - Effect of first treatment with aminobisphosphonates pamidronate and ibandronate
      on circulating lymphocyte subpopulations.
AB  - Up to 60% of patients receiving their first infusion of the bisphosphonate
      pamidronate experience an acute-phase reaction. In this study, we used flow
      cytometry to determine the effects of pamidronate treatment on circulating
      lymphocyte subpopulations, and we investigated whether pamidronate and
      ibandronate treatment affect lymphocyte subpopulations differently. Twenty
      patients received a pamidronate infusion, 20 patients received intravenously
      injected ibandronate, and 10 controls received a clodronate infusion. Pamidronate
      treatment was followed by a significant increase in median body temperature at
      the 10-hour measurement and a significant decrease in counts of circulating
      lymphocytes, natural killer cells, T cells, and CD4+ and CD8+ T-cell subsets.
      Ibandronate treatment did not affect median body temperature, and it was
      associated at the 10-hour measurement with maximum increases in total lymphocyte
      count, B cells, T cells, and CD4+ and CD8+ T-cell subsets. Thus, there is a
      substantial difference in the hematologic response to initial treatments with
      pamidronate and ibandronate. Clodronate treatment did not induce changes in body
      temperature or significantly affect the number of circulating T cells and NK
      cells. The reduction in lymphocyte subsets after initial pamidronate therapy
      might be mediated by the release of tumor necrosis factor alpha, whose source in
      the acute-phase reaction could be T cells.

PMID- 10646125
TI  - Expression of FGFR3 with the G380R achondroplasia mutation inhibits proliferation
      and maturation of CFK2 chondrocytic cells.
AB  - A G380R substitution in the transmembrane-spanning region of FGFR3 (FGFR3Ach)
      results in constitutive receptor kinase activity and is the most common cause of
      achondroplastic dwarfism in humans. The epiphyseal growth plates of affected
      individuals are disorganized and hypocellular and show aberrant chondrocyte
      maturation. To examine the molecular basis of these abnormalities, we used a
      chondrocytic cell line, CFK2, to stably express the b variant of wild-type FGFR3
      or the the constitutively active FGFR3Ach. Overexpression of FGFR3 had minimal
      effects on CFK2 proliferation and maturation compared with the severe growth
      retardation found in cells expressing FGFR3Ach. Cells expressing the mutant
      receptor also showed an abnormal apoptotic response to serum deprivation and
      failed to undergo differentiation under appropriate culture conditions. These
      changes were associated with altered expression of integrin subunits, which
      effectively led to a switch in substrate preference of the immature cell from
      fibronectin to type II collagen. These in vitro observations support those from
      in vivo studies indicating that FGFR3 mediates an inhibitory influence on
      chondrocyte proliferation. We now suggest that the mechanism is related to
      altered integrin expression.

PMID- 10646126
TI  - Phenotypic stability of articular chondrocytes in vitro: the effects of culture
      models, bone morphogenetic protein 2, and serum supplementation.
AB  - Numerous in vitro culture models have been developed for the investigation of
      chondrocyte and cartilage biology. In this study, we investigated the stability
      of the chondrocytic phenotype in monolayer, aggregate, pellet, and explant
      culture models and assessed the effects of recombinant human bone morphogenetic
      protein 2 (rhBMP-2) and serum supplementation on the phenotype in each model.
      Phenotypic effects were assessed by analyses of procollagen type II, aggrecan, (V
      + C)- fibronectin, and procollagen type I messenger RNA expression. In monolayer
      cultures, we noted a characteristic loss of procollagen type II and induction of
      procollagen type I expression. The aggregate and pellet culture models supported
      matrix protein gene expression profiles more reflective of in vivo levels. In
      explant cultures, expression of matrix protein genes was consistently depressed.
      Treatment with rhBMP-2 significantly increased the expression of procollagen type
      II and aggrecan in monolayer cultures; however, other models showed comparatively
      little response. Similarly, serum supplementation significantly down-regulated
      procollagen type II and aggrecan expression in monolayer cultures but had less
      effect on gene expression in the other models. Serum supplementation increased
      procollagen type I expression in monolayer and aggregate cultures. These results
      suggest that the influence of exogenous BMP-2 and serum on expression of
      chondrocyte-specific matrix protein genes is influenced by aspects of substrate
      attachments, cellular morphology, and/or cytoskeletal organization. Finally, the
      analyses of fibronectin expression suggest that V and C region alternative
      splicing in chondrocytes is linked to the establishment of a three-dimensional
      multicellular complex.

PMID- 10646127
TI  - 1,25-dihydroxyvitamin D3 as well as its analogue OCT lower blood calcium through
      inhibition of bone resorption in hypercalcemic rats with continuous parathyroid
      hormone-related peptide infusion.
AB  - The effects of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and its analogue 22-oxa
      1,25(OH)2D3 (22-oxacalcitriol) (OCT) on calcium and bone metabolism were examined
      in an animal model of hypercalcemia with continuous infusion of parathyroid
      hormone-related peptide (PTHrP), to determine whether active vitamin D could
      counteract the skeletal action of PTHrP in addition to its reported effect in
      suppressing the production of PTHrP in cancer cells. Parathyroid glands were
      removed from 8-week-old Sprague-Dawley rats to eliminate the confounding effects
      of endogenous PTH. Animals were then continuously infused with human PTHrP(1-34)
      at a constant rate via osmotic minipumps for 2 weeks, and at the same time
      treated orally or intravenously with OCT or 1,25(OH)2D3 four to nine times during
      the 2-week period. Under these conditions, OCT and, surprisingly, 1,25(OH)2D3
      alleviated hypercalcemia in a dose-dependent manner. 1,25(OH)2D3 and OCT
      suppressed the urinary excretion of deoxypyridinoline, although they did not
      affect renal calcium handling, suggesting that the antihypercalcemic effect is
      attributable to the inhibition of bone resorption. These active vitamin D
      compounds also counteracted the effects of PTHrP at the proximal renal tubules,
      as reflected by a decrease in phosphate excretion. Histomorphometric analysis of
      bone revealed a dose-related decrease in parameters of bone resorption. These
      results suggest that 1,25(OH)2D3 as well as OCT has the potential to alleviate
      hypercalcemia, at least in part, through the inhibition of bone resorption in
      hypercalcemic rats with constant PTHrP levels. We propose that the main function
      of active vitamin D in high bone-turnover states is to inhibit bone resorption,
      and this may have important implications for the understanding of the role of
      active vitamin D in the treatment of metabolic bone diseases, such as
      osteoporosis.

PMID- 10646128
TI  - Introduction of a new section: laboratory science.

PMID- 10646129
TI  - Bilensectomy: the implications of removing phakic intraocular lenses at the time
      of cataract extraction.

PMID- 10646130
TI  - Fibrinolysis of postcataract fibrin membranes in children.

PMID- 10646131
TI  - Fibrinolysis of postcataract fibrin membranes in children.

PMID- 10646132
TI  - Intraocular lens position after capsulotomy.

PMID- 10646133
TI  - Penetrating keratoplasty in eyes with low scleral rigidity.

PMID- 10646134
TI  - Hyaluronidase omission and diplopia.

PMID- 10646135
TI  - Laser in situ keratomileusis for hyperopia.

PMID- 10646136
TI  - Should ophthalmology practices be online?

PMID- 10646137
TI  - Ab externo 4-point scleral fixation.

PMID- 10646139
TI  - Visual acuity equivalents.

PMID- 10646138
TI  - Nuclear fragment in the scleral tunnel--an unusual cause of postoperative
      hypotony.

PMID- 10646140
TI  - Consultation section. Cataract surgical problem.

PMID- 10646141
TI  - Scleral corneal 1-plane incision cataract surgery.
AB  - The scleral corneal 1-plane incision for cataract surgery technique uses a single
      knife to perforate the anterior chamber from the sclera via the cornea by making
      a corneal valve that is 1.0 to 1.5 mm long. The technique is easy and
      reproducible. Even if incisions are widened to 6.0 mm, they readily self-seal
      with little surgically induced corneal topographic changes. Because surgical
      manipulations through a short scleral tunnel are easy and intraoperative mishaps
      can be dealt with smoothly, this incision technique can be used by those with
      relatively little surgical experience.

PMID- 10646142
TI  - Paired parallel locking forceps.
AB  - We describe an instrument used to prevent contact between an antimetabolite and
      the conjunctiva-Tenon's wound edge in filtering surgery. Paired parallel locking
      forceps were used to keep the everted conjunctival-Tenon's wound edge from
      touching the antimetabolite sponge during limbal-based filtering surgery while
      enabling manipulation of the antimetabolite sponge. This allows the surgeon to
      more easily avoid the conjunctival edge, making antimetabolite touch easier and
      safer.

PMID- 10646143
TI  - Ablation centration after active eye-tracker-assisted photorefractive keratectomy
      and laser in situ keratomileusis.
AB  - PURPOSE: To evaluate the ablation centration after active eye-tracker-assisted
      photorefractive keratectomy (PRK) and laser in situ keratomileusis (LASIK) and to
      investigate the effect of surgery, patient, and surgeon on the centration.
      SETTING: Department of Ophthalmology, China Medical College Hospital, Taichung,
      Taiwan, Republic of China. METHODS: This retrospective study comprised 177 eyes
      of 101 patients: 16 eyes had PRK and 161, LASIK. All laser treatments were
      performed with the aid of an eye tracker. The amount of decentration was analyzed
      by corneal topography. The factors influencing centration were divided into
      surgery related (PRK/LASIK), patient related (low/high myopia and effect of
      learning), and surgeon related (learning curve). RESULTS: The mean decentration
      was 0.33 mm in PRK eyes and 0.35 mm in LASIK eyes. For the surgery-related
      factor, there was no significant difference between the PRK and LASIK eyes. For
      the patient-related factors, centration was better in the second eye (effect of
      learning) and decentration was more severe in eyes with high myopia (low/high
      myopia). For the surgeon-related factor, there was no significant difference
      between eyes that had the first 50 LASIK procedures and those that had the last
      50 procedures. CONCLUSIONS: An eye tracker, which makes the laser beam follow the
      eye's movements, helps to avoid severe decentration. This study showed, however,
      that an active eye-tracking system alone cannot ensure good centration. Patient
      cooperation and fixation are important.

PMID- 10646144
TI  - Agreement and repeatability of pupillometry using videokeratography and infrared
      devices.
AB  - PURPOSE: To evaluate the accuracy and repeatability of the pupil-measuring
      modules of several corneal topography devices. SETTING: Department of
      Ophthalmology, Saint Louis University Eye Institute, St. Louis, Missouri, USA.
      METHODS: In 14 eyes of 7 healthy myopic patients, pupillometry was performed with
      3 corneal topography devices and with an infrared pupillometer under luminance
      matched conditions for the Placido projection of the topography devices. Pupils
      were also measured under a mesopic condition. Outcomes were pupil diameters,
      limits of agreement, and coefficient of repeatability of the topography devices.
      RESULTS: Mean pupil diameter measurements with the Technomed C-Scan, Humphrey
      Masterview, Alcon EyeMap, and under a mesopic condition were 3.35 mm, 2.96 mm,
      2.34 mm, and 5.94 mm, respectively. All pupil diameter measurements differed
      significantly from one another except those by the Masterview and C-Scan devices.
      The mean difference between the C-Scan and luminance-matched infrared
      measurements was 0.74 mm and between the Masterview and luminance-matched
      infrared measurements, 0.27 mm. The limits of agreement +/- 2 standard deviations
      was 4.12 mm and 1.56 mm for the C-Scan and Masterview devices, respectively.
      Coefficients of repeatability were 0.56 mm, 0.46 mm, and 0.44 mm for the C-Scan,
      Masterview, and EyeMap devices, respectively. CONCLUSIONS: Although topography
      pupillometry was repeatable, it underestimated the largest natural pupil diameter
      because of the luminance of the Placido rings. The difference in limits of
      agreement between the C-Scan and Masterview devices may be explained by pupil
      physiology and the static nature of videokeratoscopy. These results have
      implications when topography pupillometry is used to assess pupil diameters prior
      to refractive surgery. We do not recommend using pupil diameters measured by
      topography to preoperatively determine halo-related safety.

PMID- 10646145
TI  - Reoperations after myopic laser in situ keratomileusis.
AB  - PURPOSE: To evaluate the results after enhancement of myopic laser in situ
      keratomileusis (LASIK) using the VISX Star excimer laser. SETTING: The Buzard Eye
      Institute, Las Vegas, Nevada, USA. METHODS: In this prospective study, 52 eyes of
      40 patients had LASIK enhancement. The existing flap was lifted and the excimer
      laser treatment reapplied for the residual refractive error. The VISX Star
      excimer laser was used for the primary LASIK and the enhancement procedure.
      Retreatments for undercorrection, regression, and overcorrection were performed
      after 6 weeks and up to 40 weeks after the primary LASIK. Follow-up was 96% at 1
      month, 67% at 6 months, and 71% at 12 months. RESULTS: Mean pre-enhancement
      spherical equivalent was -0.77 diopters (D) +/- 0.94 (SD) and mean uncorrected
      visual acuity (UCVA), 20/60. One year after the enhancement, mean spherical
      equivalent was -0.13 +/- 0.33 D, and mean UCVA was 20/25. Refraction remained
      stable during the 1 year follow-up, with no treatment required. After the
      enhancement, all patients had a UCVA of 20/40 or better. At 1 year, 3% of
      patients had lost 1 line of best corrected visual acuity and 32% had gained 1
      line. No epithelial ingrowth was noted. CONCLUSION: Retreatment for LASIK
      beginning 6 weeks after the initial procedure proved to be effective with minimal
      complications and good results. The technique to raise and reposition the flap
      appeared safe, and complications were few.

PMID- 10646146
TI  - Epithelial ingrowth in a corneal graft treated by laser in situ keratomileusis:
      light and electron microscopy.
AB  - PURPOSE: To demonstrate progressive epithelial ingrowth histopathologically in a
      human cornea after laser in situ keratomileusis (LASIK) and review its
      pathophysiology. SETTING: Department of Ophthalmology, Medical College of
      Virginia Campus, Virginia Commonwealth University, and the Veterans Affairs
      Medical Center, Richmond, Virginia, USA. METHODS: Tissue from a corneal
      transplant specimen was examined 6 weeks after LASIK by light and transmission
      electron microscopy. RESULTS: Epithelial ingrowth in the flap interface with
      connection to the surface corneal epithelium was evident on light microscopy. In
      areas without epithelial ingrowth, the flap interface was imperceptible. Electron
      microscopy revealed minimal disruption of the stromal collagenous lamellae.
      CONCLUSION: Progressive epithelial ingrowth occurred with a continuous sheet of
      epithelium to the flap edge. Location of epithelial ingrowth and cytokine
      epithelial-stromal interaction appear to be important factors in this
      complication. Histopathological changes in the cornea after LASIK are difficult
      to detect in areas with normal wound healing.

PMID- 10646147
TI  - Digital retroilluminated photography to analyze posterior capsule opacification
      in eyes with intraocular lenses.
AB  - PURPOSE: To compare the formation and rates of posterior capsule opacification
      (PCO) in eyes with poly(methyl methacrylate) (PMMA) versus silicone intraocular
      lenses (IOLs) using an in vivo objective method. SETTING: Taipei Municipal Yang
      Ming Hospital, Taipei, Taiwan, Republic of China. METHODS: This prospective study
      comprised 40 eyes with senile cataract receiving phacoemulsification with
      capsular implantation of an IOL from March to April 1997. The uneventful
      surgeries were performed using the stop and chop method by the same surgeon.
      Twenty eyes received a PMMA IOL (Pharmacia 812A) and 20, a silicone IOL (AMO SI
      30NB). One year later, digital retroillumination images taken with the EAS-1000
      anterior segment analysis system (Nidek) were used to analyze posterior capsule
      transparency over the central 3.0 and 5.0 mm optic zones and evaluate the degree
      of PCO over the central and peripheral zones. RESULTS: Over the central 5.0 mm
      optic zone, mean transparency of the capsule was 87.71% +/- 11.35% (SD) in the
      silicone group and 79.22% +/- 21.10% in the PMMA group (P = .17). Over the
      central 3.0 mm optic zone, the means were 97.17% +/- 5.96% and 86.32% +/- 19.60%,
      respectively (P = .048). Mean opacity in the central zone was 75.18 +/- 13.22
      digital opacity units (OUs) in the silicone group and 80.24 +/- 7.93 OUs in the
      PMMA group (P = .18). The means in the peripheral zone were 88.49 +/- 18.47 OUs
      and 90.35 +/- 9.98 OUs, respectively (P = .71). CONCLUSION: The posterior capsule
      in the silicone IOL group was more transparent than in the PMMA IOL group over
      the central 3.0 mm optic zone after 1 year follow-up.

PMID- 10646148
TI  - Accuracy and accommodation capability of a handheld autorefractor.
AB  - PURPOSE: To determine the accuracy of measurement by the Nikon Retinomax handheld
      autorefractor and its ability to relax accommodation. SETTING: Pediatric Section,
      Department of Ophthalmology, University of Mainz, Germany. METHODS: To perform a
      series of comparative measurements, autorefractor readings were obtained on
      healthy young adults (students) and on children aged 2 to 12 years. The
      autorefractor readings were compared with subjective refractions of the young
      adults and with cycloplegic retinoscopy of the children. RESULTS: In adults, the
      accuracy of the handheld autorefractor measurements was comparable to that of
      conventional tabletop autorefractors. In children, the autorefractor measurements
      performed under cycloplegia were reliable; when cycloplegic agents were not
      administered, 24% were overcorrected by more than -2.0 diopters. CONCLUSION:
      Cycloplegia is often necessary to obtain accurate autorefractor results.

PMID- 10646149
TI  - Combined versus sequential phacotrabeculectomy with intraoperative 5
      fluorouracil.
AB  - PURPOSE: To determine and compare the intraocular pressure (IOP) lowering effects
      of single-incision combined phacoemulsification and trabeculectomy with
      phacoemulsification done after previous trabeculectomy, both with an
      intraoperative dose of 5-fluorouracil (5-FU). SETTING: Hospital Del Salvador
      Ophthalmology Service, Clinica Oftalmologica Pasteur, Santiago, Chile. METHODS:
      The effects on IOP after phacoemulsification in eyes with previous trabeculectomy
      using intraoperative 5-fluorouracil (5-FU) (Group 1, n = 18) were compared with
      those in a matched group of eyes having combined phacoemulsification and
      trabeculectomy, also with intraoperative 5-FU (Group 2, n = 22). The mean
      postoperative IOPs and survival curves for IOP values less than 20 mm Hg and 15
      mm Hg or less were determined in both groups. Data were retrospectively
      collected. Comparisons were made with the paired Student t test, and survival
      curves were compared using log-rank analysis. RESULTS: Mean postoperative IOP
      without medications was 12.6 mm Hg in Group 1 and 12.2 mm Hg in Group 2 (P =
      .64). Group 2 had a significant postoperative decrease in IOP (P = .0575); Group
      1 did not have a significant increase or decrease. There was no significant
      difference in the survival curves between groups using arbitrarily defined
      failure criteria: (1) IOP greater than 15 mm Hg or (2) IOP equal to or greater
      than 20 mm Hg, both without medication (log-rank analysis, P = .333 and P = 1.00,
      respectively). CONCLUSION: Combined cataract and glaucoma surgery with
      intraoperative 5-FU was associated with good long-term IOP control similar to
      that after phacoemulsification with intraoperative 5-FU in eyes with previous
      trabeculectomy.

PMID- 10646150
TI  - Effect of extracapsular cataract extraction and phacoemulsification performed
      after trabeculectomy on intraocular pressure.
AB  - PURPOSE: To determine whether there is a difference in intraocular pressure (IOP)
      control between extracapsular cataract extraction (ECCE) and phacoemulsification
      performed after successful trabeculectomy. SETTING: Eye Unit, St. Woolos
      Hospital, Newport, United Kingdom. METHODS: This retrospective study comprised 55
      patients with glaucoma who had had trabeculectomy and subsequently had cataract
      surgery. Extracapsular cataract extraction was performed in 34 eyes and
      phacoemulsification in 21. The IOP before cataract surgery was used as a baseline
      for comparison with the IOP at 6 and 12 months and at the last follow-up visit
      (mean 44.26 months in the ECCE group and 15.09 months in the phacoemulsification
      group). At the 3 postoperative examinations, the IOP was recorded before and
      after institution of medical treatment. RESULTS: In the ECCE group, the IOP
      exceeded the target pressure in 7 eyes and required medical treatment; it
      remained uncontrolled in 1 eye at the final visit. In the phacoemulsification
      group, the IOP was less than 18 mm Hg without any medication and within the
      target pressure in all 21 eyes. The IOP increase after ECCE was statistically
      significant (mean IOP was 13.61 mm Hg before and 15.53 mm Hg after ECCE; P =
      .0297). After treatment was instituted, there was no statistically significant
      difference in the IOP compared with the preoperative value (P = .0796 at 6
      months, .677 at 1 year, and .4419 at the final visit in the ECCE group and .0703,
      .2220, and .1035, respectively, in the phacoemulsification group). CONCLUSION:
      The findings indicated that IOP was better controlled by phacoemulsification than
      by ECCE in patients who had had filtration surgery.

PMID- 10646151
TI  - Induced corneal astigmatism using an asymmetric corneoscleral tunnel and a large
      optic intraocular lens.
AB  - PURPOSE: To prospectively evaluate the induction of corneal astigmatism using an
      asymmetric corneoscleral tunnel incision (J-incision) to implant large-optic (7.0
      mm) intraocular lenses (IOLs). SETTING: Department of Ophthalmology, University
      of Bonn, Germany. METHODS: Thirty-five patients had sutureless
      phacoemulsification with implantation of a 7.0 mm poly(methyl methacrylate)
      posterior chamber IOL using an inverse J-shaped asymmetric tunnel incision. The
      corneal astigmatism was measured by corneal keratometry and topography
      preoperatively and 1 day and 1 and 3 months postoperatively. Induced astigmatism
      was calculated by vector analysis. RESULTS: Mean induced changes in the corneal
      radii measured by keratometry were 0.17 mm +/- 0.14 (SD) on the first
      postoperative day, 0.18 +/- 0.14 mm after 1 month, and 0.17 +/- 0.14 mm after 3
      months. Mean postoperative induced astigmatism measured by corneal topography was
      1.08 +/- 0.66 diopters (D), 0.89 +/- 0.78 D, and 0.85 +/- 0.70 D, respectively.
      No signs of wound instability were detected. CONCLUSION: An asymmetric
      corneoscleral incision was suitable for implantation of large-optic IOLs,
      resulting in immediate stability of the induced cylindrical power in the central
      3.0 mm zone as measured by keratometry. A reduction in induced corneal
      astigmatism can be achieved using this technique versus using symmetrical wound
      constructions and large-optic IOLs.

PMID- 10646152
TI  - One year follow-up of astigmatism after 4.0 mm temporal clear corneal and
      superior scleral incisions.
AB  - PURPOSE: To compare the effect of 2 contemporary sutureless cataract surgery
      incisions on corneal astigmatism 1 year after surgery. SETTING: Outpatient
      Clinic, Department of Ophthalmology, Vejle Hospital, Denmark. METHODS: Sixty-nine
      patients who had cataract surgery in 1997 with a 4.0 mm temporal clear corneal (n
      = 32) or superior scleral (n = 37) incision were examined 1 year postoperatively.
      Surgically induced astigmatism was analyzed by vector analysis, vector
      decomposition, and polar values using preoperative and postoperative keratometric
      readings. RESULTS: Vector analysis revealed a slightly lower median induced
      cylinder in the clear corneal patients; 0.41 diopter (D) (95% confidence limits
      [CL] 0.24 to 0.67 D) versus 0.61 D (95% CL 0.49 to 0.73 D) (P < .05).
      Decomposition of the induced cylinder (against the rule/total) showed
      statistically significant differences in the direction of the cylinder; 0.21 (95%
      CL 0.03 to 0.41) versus 0.90 (95% CL 0.82 to 0.95) (P < .00001). The directional
      difference was confirmed by polar values. CONCLUSION: Both incisions induced low
      and comparable amounts of astigmatism. The directional differences were modest.
      Findings in previous studies of a poor outcome after clear corneal incisions were
      not confirmed in this long-term follow-up.

PMID- 10646154
TI  - AMO array multifocal lens versus monofocal correction in cataract surgery.
AB  - PURPOSE: To compare the functional capabilities of 15 patients (30 eyes) who had
      implantation of the Allergan Medical Optics (AMO) Array multifocal intraocular
      lens (IOL) with those of 13 patients (26 eyes) with an AMO monofocal IOL.
      SETTING: Department of Ophthalmology, The University of Western Ontario, Canada.
      METHODS: The objective capabilities of both groups were analyzed through visual
      acuity measurements for distance, near, and depth of focus. Subjective
      functionality was assessed through the use of a questionnaire that included the
      previously validated VF-14 index of visual function, a global measure of overall
      satisfaction with visual acuity, and questions related to the frequency of
      spectacle wear. RESULTS: Both groups had excellent corrected and uncorrected
      distance visual acuity postoperatively. The multifocal group had better acuity
      than the monofocal group at near with distance correction in place (70% versus
      43% achieved J3 or better). The multifocal group also had significantly better
      depth of focus. Subjectively, both groups indicated high levels of satisfaction
      with visual function. However, the multifocal group indicated higher levels of
      satisfaction during the day, at night, and overall without spectacles. This
      result translated into less spectacle wear for both near and distance in the
      multifocal group. CONCLUSIONS: The results of this study indicate high patient
      satisfaction with the Array multifocal IOL and greater functional independence
      from spectacle wear, by objective and subjective patient measures, than with the
      monofocal IOL.

PMID- 10646153
TI  - Silicone intraocular lens implantation in children: preliminary results.
AB  - PURPOSE: To evaluate the safety and outcome of foldable silicone intraocular lens
      (IOL) implantation in children. SETTING: Department of Ophthalmology, University
      of Giessen, Giessen, Germany. METHODS: The results of cataract extraction and
      silicone IOL implantation in children having surgery between 1992 and 1997 were
      retrospectively analyzed in 8 eyes (7 patients). All IOLs were implanted in the
      capsular bag through a 3.5 mm clear corneal incision. In 4 eyes, primary
      posterior capsulectomy and anterior vitrectomy were performed. RESULTS: Mean
      patient age at the time of surgery was 5.1 years (range 8 months to 15 years).
      The surgeries were uneventful. All IOLs remained anatomically stable and well
      centered during the mean follow-up of 29.6 months (range 18 to 46 months).
      Postoperative inflammatory reaction was minimal. Neither fibrinoid exudation nor
      posterior synechias occurred postoperatively. Postoperative best spectacle
      corrected visual acuity ranged from 20/800 to 20/20. All eyes with an intact
      posterior capsule developed posterior capsule opacification. In the 4 eyes that
      had primary posterior capsulectomy and anterior vitrectomy, the visual axis
      remained clear. CONCLUSIONS: These preliminary results suggest that silicone IOL
      implantation in children is a safe procedure with good and stable short-term
      anatomic results. Longer follow-up is necessary to answer questions about the
      long-term safety of silicone lens implantation in a child's eye.

PMID- 10646155
TI  - Impaired visual function after cataract surgery assessed using the Catquest
      questionnaire.
AB  - PURPOSE: To evaluate and explain why some patients report more difficulties
      performing everyday activities 6 months after a cataract extraction than they did
      before surgery. SETTING: Cataract surgeons from 4 departments of ophthalmology
      affiliated with the National Swedish Cataract Outcome Register. METHODS: Patients
      were recruited from those having cataract extraction during March 1995, 1996, or
      1997 at the participating units. Only patients who completed Catquest
      questionnaires before and after surgery and were evaluated to have a "no-benefit"
      outcome were included. The no-benefit outcomes were analyzed by using medical
      records and surgeon opinions. Possible and/or probable reasons for the outcome
      were identified. RESULTS: Several possible and/or probable reasons were
      identified as a single reason or combined with other reasons. The 5 most frequent
      reasons were ocular co-morbidity in the operative eye, anisometropia after
      surgery, problems with the nonoperative eye during follow-up, low disability
      score sum before surgery (no difficulties), and postoperative complications.
      CONCLUSION: In about a third of the cases, the no-benefit outcome could probably
      have been avoided by better planning for both eyes; that is, both eyes should
      have surgery within a short time and waiting for second-eye surgery in cases with
      anisometropia should be avoided.

PMID- 10646156
TI  - Combined sedation and topical anesthesia for cataract surgery.
AB  - PURPOSE: To determine whether lidocaine jelly is as efficacious as tetracaine
      drops for obtaining ocular anesthesia and to evaluate sublingual lorazepam as
      premedication for sedation in cataract surgery. SETTING: An ambulatory surgical
      center dedicated to ophthalmic surgery. METHODS: The study was divided into 2
      phases. In the first, 100 patients were divided into 2 groups of 50 each. The
      first group received tetracaine 0.5% drops for anesthesia. The second group
      received lidocaine 2% jelly for topical anesthesia. In the second stage, 100
      patients were divided into 2 groups of 50 each. The first 50 patients were given
      1 mg of sublingual lorazepam before surgery. The second group had cataract
      surgery without sublingual lorazepam. All patients were operated on by the same
      surgeon in an ambulatory surgical center. The technique was temporal clear
      corneal cataract surgery with foldable intraocular lens implantation. Exclusions
      from the study were the need to convert to peribulbar or retrobulbar anesthesia,
      intraocular complications, and altered mental status. RESULTS: In the first phase
      of the study, lidocaine 2% jelly was as efficacious as tetracaine 0.5% drops for
      topical anesthesia in cataract surgery. In the second phase of the study,
      overall, patients in the lorazepam group had less anxiety, greater amnesia, and
      lower blood pressure than those not receiving lorazepam as sedation for topical
      anesthesia. CONCLUSIONS: Lidocaine 2% jelly combined with sublingual lorazepam
      provided excellent cost-effective anesthesia and sedation for topical anesthesia
      in cataract surgery and enhanced patient satisfaction with the procedure.

PMID- 10646157
TI  - Detection of tumor necrosis factor alpha and interleukin 1 alpha gene expression
      in human lens epithelial cells.
AB  - PURPOSE: To analyze the gene expression of interleukin-1 alpha (IL-1 alpha) and
      tumor necrosis factor alpha (TNF alpha) in human lens epithelial cells (LECs) by
      in situ RNA hybridization. SETTING: Department of Ophthalmology and Laboratory
      for Molecular Biology, Charite, Humboldt University, Berlin, Germany. METHODS:
      Anterior lens capsules with attached LECs were collected in RNase-free conditions
      from 10 consecutive patients during cataract surgery. Samples were then
      systematically analyzed by an in situ RNA-hybridization technique using specific
      gene probes for IL-1 alpha and TNF alpha, which were previously labeled with
      digoxigenin (DIG). RESULTS: The LECs tested positive for DIG-labeled gene probes
      in the described conditions. One (10%) patient showed a clearly detectable IL-1
      alpha gene expression, and 7 (70%) showed a widely positive reaction for TNF
      alpha mRNA. CONCLUSION: The TNF alpha gene expression in LECs was more extended
      than that of IL-1 alpha in lens capsule samples from cataract surgery. Active
      synthesis of TNF alpha and IL-1 alpha may have consequences for postoperative
      inflammation and LEC proliferation.

PMID- 10646158
TI  - International Intraocular Lens & Implant Registry 2000.
AB  - This article updates the International Intraocular Lens Registry published in
      January 1999. A total of 936 intraocular lenses (IOLs) and nonoptical implants
      are available to surgeons in 2000. Sixty-seven new implants were added to the
      registry, and 25 existing IOLs required a change in the lens constant. The
      cooperation of the companies has been excellent, and comments from implant
      surgeons have been very gratifying.

PMID- 10646159
TI  - Traumatic partial unfolding of laser in situ keratomileusis flap with severe
      epithelial ingrowth.
AB  - We report an unusual flap-related complication that occurred 11 months after
      uneventful laser in situ keratomileusis (LASIK) performed in the eye of a 50-year
      old woman. She developed partial infolding of the LASIK flap in her left eye
      after blunt trauma. The initial diagnosis was partial flap loss and 4 weeks
      later, infolding of the flap was diagnosed after severe epithelial ingrowth.
      Surgical repositioning of the flap resulted in a best corrected visual acuity of
      20/20. Clinical features that assist in the diagnosis of this unusual
      complication and guidelines for its management are described.

PMID- 10646160
TI  - Infectious keratitis after photorefractive keratectomy in a comanaged setting.
AB  - A 48-year-old man had simultaneous bilateral photorefractive keratectomy (PRK).
      The surgeon who performed the PRK did not see the patient in follow-up, and there
      was confusion regarding the comanaging doctor. Therefore, the patient was not
      examined immediately postoperatively. Several days later, he was hospitalized for
      an unrelated, painful orthopedic problem and heavily sedated. Seven days after
      the PRK, an ophthalmologist was consulted for ocular irritation and discharge.
      Examination showed bilateral, purulent conjunctivitis and severe infectious
      keratitis in the left eye. The patient was treated with periocular and topical
      antibiotics. Corneal cultures yielded Staphylococcus aureus. The keratitis
      resolved slowly, leaving the patient with hand motion visual acuity. A corneal
      transplant and cataract extraction was performed 15 months later, resulting in a
      best corrected visual acuity of 20/400 because of glaucomatous optic nerve
      damage. Severe infectious keratitis may occur after PRK. Poor communication
      between the surgeon, comanaging doctor, and patient may result in treatment
      delay.

PMID- 10646161
TI  - Refractive error in cataract surgery after previous refractive surgery.
AB  - Bilateral cataract extraction with posterior chamber intraocular lens (IOL)
      implantation was performed in a patient after previous photorefractive
      keratectomy, radial keratotomy (RK) combined with astigmatic keratotomy, and
      retreatment of RK. Significant hyperopic error was observed after cataract
      surgery, and the IOLs were eventually exchanged in both eyes. A review of this
      case found that the refractive error was smaller when a refraction-derived
      keratometric value was selected for IOL power calculation. Nevertheless,
      hyperopic error still occurred.

PMID- 10646162
TI  - Truncated edge design, dysphotopsia, and inhibition of posterior capsule
      opacification.
AB  - A 73-year-old woman had implantation of a silicone intraocular lens (IOL) with a
      truncated edge design. Like some other patients with acrylic IOLs, she
      experienced long-term undesirable reflections and halos. However, the posterior
      capsule remained clear. The fellow eye had a different style silicone IOL, which
      induced no visual side effects but was associated with early posterior capsule
      opacification.

PMID- 10646163
TI  - Does sleep fragmentation impact recuperation? A review and reanalysis.
AB  - Studies have shown that next-day performance and alertness are impaired by sleep
      fragmentation procedures even when total sleep time (TST) is unaffected. Based on
      these studies it has been hypothesized that both the duration and continuity of
      sleep determine its recuperative value. This review of the literature suggests
      that when sleep fragmentation procedures increase the relative amount of stage 1
      sleep, next-day performance and alertness are impaired. Other studies suggest
      that stage 1 sleep has little or no recuperative value. Total sleep time,
      however, is typically defined as the sum of time spent in sleep stages 1, 2, 3,
      4, and REM. In the present paper it is shown that when stage 1 sleep is excluded
      from TST, a stronger relationship between TST and subsequent alertness and
      performance emerges--and the need to invoke 'sleep continuity' as a variable that
      contributes independently to recuperative sleep processes is obviated. In the
      same way that partial or total sleep deprivation impairs alertness and
      performance, it is proposed that sleep disruption also impairs alertness and
      performance by reducing true recuperative sleep time.

PMID- 10646164
TI  - Level of arousal and the ability to maintain wakefulness.
AB  - The ability to maintain wakefulness under baseline and sleep deprivation
      conditions was examined in a group of 14 normal young adults. Subjects
      participated in both standard and manipulation Maintenance of Wakefulness tests
      after being awake for 7, 19, and 31 h. In the manipulation Maintenance of
      Wakefulness tests, subjects performed varying degrees of physical activity at the
      onset of stage 1 to allow them to preserve wakefulness. As expected, ability to
      maintain wakefulness declined as time awake increased. With amount of time awake
      held constant, wakefulness was enhanced most after standing and doing knee bends,
      less after standing, less after sitting up, and least after subjects were spoken
      to. The improvement in alertness after doing knee bends as compared to being
      spoken to was of the same relative magnitude as the decrease in alertness after
      one night of total sleep deprivation. As expected, heart rate also increased
      consistently as activity increased. Each subject had a negative correlation
      between their EEG sleep latencies and their minimum r-r interval during the
      manipulation, i.e. the higher the heart rate, the longer the latency. These data
      were interpreted as a demonstration of the impact of discrete phasic arousal on
      the ability to maintain wakefulness.

PMID- 10646165
TI  - Quantifying the performance impairment associated with fatigue.
AB  - The present study systematically compared the effects of fatigue and alcohol
      intoxication on a range of neurobehavioural tasks. By doing so, it was possible
      to quantify the performance impairment associated with fatigue and express it as
      a blood alcohol impairment equivalent. Twenty-two healthy subjects aged 19-26
      years participated in three counterbalanced conditions. In the sustained
      wakefulness condition, subjects were kept awake for 28 h. In the alcohol and
      placebo conditions, subjects consumed either an alcoholic or non-alcoholic
      beverage at 30 min intervals, until their blood alcohol concentration reached
      0.10%. In each session, performance was measured at hourly intervals using four
      tasks from a standardised computer-based test battery. Analysis indicated that
      the placebo beverage did not significantly effect mean relative performance. In
      contrast, as blood alcohol concentration increased performance on all the tasks,
      except for one, significantly decreased. Similarly, as hours of wakefulness
      increased performance levels for four of the six parameters significantly
      decreased. More importantly, equating the performance impairment in the two
      conditions indicated that, depending on the task measured, approximately 20-25 h
      of wakefulness produced performance decrements equivalent to those observed at a
      blood alcohol concentration (BAC) of 0.10%. Overall, these results suggest that
      moderate levels of fatigue produce performance equivalent to or greater than
      those observed at levels of alcohol intoxication deemed unacceptable when
      driving, working and/or operating dangerous equipment.

PMID- 10646166
TI  - Scalp topography of the auditory evoked K-complex in stage 2 and slow wave sleep.
AB  - During NREM sleep a very large amplitude wave-form, known as the K-complex, may
      be elicited upon presentation of an external stimulus. The present study compared
      the scalp distribution of a prominent negative wave peaking at about 550 ms and a
      later positive wave peaking between 900 and 1300 ms in stage 2 and slow wave
      sleep (SWS). Nine subjects spent a single night in the laboratory. They were
      presented with an 80 dB SPL 2000 Hz auditory tone pip every 15 s. The EEG was
      recorded from 29 electrode sites and referenced to the nose. A K-complex was
      elicited on 34% of trials in stage 2 and on 46% of trials in SWS. A negative wave
      peaking at 330 ms was larger on trials in which the K-complex was elicited than
      on trials in which it was not. The large amplitude N550 was readily observable on
      trials in which the K-complex was elicited but could not be observed on trials in
      which it was not. The N550 was bilaterally symmetrical and was maximum over
      fronto-central areas of the scalp in both stage 2 and SWS. It inverted in
      polarity at the mastoid and inferior parietal regions. The scalp distribution of
      N550 significantly differed between stage 2 and SWS. It showed a sharper decline
      in amplitude over parietal and posterior-inferior areas of the scalp in stage 2
      compared to SWS. A later P900 was maximum over centro-frontal areas of the scalp
      and was also bilaterally symmetrical. It showed a significantly sharper decline
      in amplitude over widespread inferior areas during SWS. Because the scalp maps of
      the N550 and P900 are different in stage 2 and SWS, their intracranial sources
      must also be different.

PMID- 10646167
TI  - The N550 component of the evoked K-complex: a modality non-specific response?
AB  - A large amplitude late negative deflection peaking between 500 and 650 ms is
      observable in the averaged K-complex wave-form. This peak is thus often labelled
      the N550. 'N550' appears during stage 2 and is maintained into slow wave sleep
      but is not apparent during REM. Most studies have employed auditory stimuli to
      elicit the K-complex. Two experiments were run to examine the effects of stimulus
      modality on the topographical distribution of the N550. In the first experiment,
      the K-complexes were elicited in an auditory oddball procedure. In the second
      experiment, K-complexes were elicited by respiratory occlusions. Twenty-nine
      channel recordings were used to increase spatial resolution. N550 was
      substantially larger in the average of trials containing K-complexes than in
      trials in which a K-complex could not be identified. N550 varied inversely in
      amplitude with the probability of accordance of the stimulus. The topographic
      distribution of the N550 was consistent between experiments. It was bilaterally
      symmetrical and was maximal over fronto-central regions of the scalp. The results
      indicate that the N550 reflects the activity of a modality non-specific, sleep
      dependent generator that responds to both interoceptive and external stimulation.

PMID- 10646168
TI  - Carbachol microinjection into the caudal peribrachial area induces long-term
      enhancement of PGO wave activity but not REM sleep.
AB  - This study presents new findings of carbachol-induced long-term ponto-geniculo
      occipital (PGO) enhancement lasting five days, but without REM sleep enhancement.
      A quantitative analysis of the number and types of bilateral PGO wave events
      during slow wave sleep with PGO activity (SP) and REM was performed in each of
      four cats over a period of six days following a single unilateral microinjection
      of carbachol nanospheres into the caudolateral peribrachial area. The results
      demonstrate increases in the summed total of all PGO wave events to continue for
      five days postcarbachol reaching a peak sixfold increase on day three in SP and
      REM. The tendency of PGO waves to occur in clusters of greater than three waves
      increased sevenfold on day three in SP and fourfold during REM. These findings
      indicate a dissociation of long-term PGO enhancement from long-term REM
      enhancement, and suggest that even a sixfold increase in PGO activity alone is
      not, in itself, sufficient to produce the cholinergic orchestration of REM sleep
      enhancement.

PMID- 10646169
TI  - Morningness/eveningness and the need for sleep.
AB  - The purpose of this study was to determine, in a large sample of adults of all
      ages (17-80 years), the effect of morningness/eveningness on sleep/wake
      schedules, sleep needs, sleep hygiene and subjective daytime somnolence. A total
      of 617 subjects (219 subjects per chronotype group) matched for age, sex and
      employment status, completed an abridged morningness/eveningness questionnaire, a
      questionnaire on sleep habits and the quality of sleep, and the Epworth
      Sleepiness Scale. Eveningness was associated with a greater need for sleep, less
      time in bed during the week compared to ideal sleep needs, more time in bed at
      the weekend, a later bedtime and waking-up time especially at the weekend, more
      irregular sleep/wake habits and greater caffeine consumption. These subjects
      built up a sleep debt during the week and extended their duration of sleep at the
      weekend. They did not, however, rate themselves more sleepy than other types,
      despite the fact that our results showed a clear link between subjectively
      evaluated daytime somnolence and sleep debt. Why they were less affected by sleep
      deprivation is not clear. This raises the question of individual susceptibility
      to the modification of sleep parameters.

PMID- 10646170
TI  - Sleep, age, and shiftwork experience.
AB  - The effects of age and shiftwork experience (never, past, present) on sleep were
      studied in a sample of 3236 wage earners and retired workers by means of a
      questionnaire. The sample was composed of 32-, 42-, 52-, and 62-year-old
      subjects, and included both sexes and various occupational statuses. Age resulted
      in a continuously increasing frequency of sleep disturbances and hypnotic use,
      except for difficulty getting back to sleep and early awakening, which peaked at
      52 years and then decreased at 62 years, thus suggesting a 'retirement effect'.
      Current and past shiftworkers reported more problems with falling asleep and
      early awakening than subjects who had never worked on shifts. This is a likely
      explanation of why the effect of age was massive in the latter group and much
      less pronounced in the former groups. There were no clear effects of the length
      or recency of shiftwork experience. This finding does not support the
      hypothesized permanent effect of shiftwork experience on subsequent sleep.
      Females had higher complaint rates at every age. There was little interaction
      between age and sex, but women were affected more by shiftwork as they got older,
      particularly as to hypnotic consumption. Some of the results support the
      hypothesis that a selection process excludes workers who are no longer able to
      cope with the demands of shiftwork.

PMID- 10646171
TI  - The effect of clustered versus regular sleep fragmentation on daytime function.
AB  - Previously, we found that regular sleep fragmentation, similar to that found in
      patients with sleep apnoea/hypopnoea syndrome (SAHS), impairs daytime function.
      Apnoeas and hypopnoeas occur in groups in patients with REM or posture related
      SAHS. Thus, we hypothesised that clustered sleep fragmentation would have a
      similar impact on daytime function as regular sleep fragmentation. We studied 16
      subjects over two pairs of 2 nights and 2 days. The first night of each pair was
      for acclimatisation. On the second night, subjects either had their sleep
      fragmented regularly every 90 s, or fragmented every 30 s for 30 min every 90
      min, the remaining 60 min being undisturbed. We fragmented sleep with tones to
      produce a minimum 3 s increase in EEG frequency. During the days following each
      pair of nights we tested subjects daytime function. Total sleep time (TST) and
      microarousal frequency were similar no both study nights. We found significantly
      less stage 2 (55 SD 4, 62 +/- 7%; P = 0.001) and more slow wave sleep (21 SD 3,
      12 +/- 6%; P < 0.001) on the clustered night. Mean sleep onset latency was
      similar on MSLT (clustered 10 SD 5, regular 9 +/- 4 min; P = 0.7) and MWT
      (clustered 32 SD 7, regular 30 +/- 7 min; P = 0.2). There was no difference in
      subjects mood or cognitive function after either study night. These results
      suggest that although there is more slow wave sleep (SWS) on the clustered night,
      similar numbers of sleep fragmenting events produced similar daytime function
      whether the events were evenly spaced or clustered.

PMID- 10646172
TI  - Relations among hypnagogic and hypnopompic experiences associated with sleep
      paralysis.
AB  - The Waterloo Sleep Experiences Scale was developed to assess the prevalence of
      sleep paralysis and a variety of associated hypnagogic and hypnopompic
      hallucinoid experiences: sensed presence, felt pressure, floating sensations,
      auditory and visual hallucinations, and fear. Consistent with results of recent
      surveys, almost 30% of 870 university students reported at least one experience
      of sleep paralysis. Approximately three-quarters of those also reported at least
      one hallucinoid experience, and slightly more than 10% experienced three or more.
      Fear was positively associated with hallucinoid experiences, most clearly with
      sensed presence. Regression analyses lend support to the hypothesis that sensed
      presence and fear are primitive associates of sleep paralysis and contribute to
      the elaboration of further hallucinoid experiences, especially those involving
      visual experiences.

PMID- 10646173
TI  - Sleepiness in obstructive sleep apnea syndrome and simple snoring evaluated by
      the Epworth Sleepiness Scale.

PMID- 10646174
TI  - Obstructive sleep apnea syndrome induced by clonazepam in a narcoleptic patient
      with REM-sleep-behavior disorder.

PMID- 10646175
TI  - Treatment outcome in Australian veterans with combat-related posttraumatic stress
      disorder: a cause for cautious optimism?
AB  - This study investigated treatment outcome in combat-related posttraumatic stress
      disorder (PTSD). Participants were 419 Australian Vietnam veterans who completed
      a 12-week hospital-based program. A comprehensive protocol assessed PTSD,
      comorbidity, and social functioning at admission and at 3 and 9 months
      posttreatment. Overall, the group showed significant improvements in core PTSD
      symptoms, anxiety, depression, alcohol abuse, social dysfunction, and anger.
      Changes occurred mostly between admission and 3 months posttreatment, with gains
      maintained at 9 months. Ratings by patients and their partners indicated
      perceived improvement and strong satisfaction with treatment. Nevertheless,
      treatment gains were variable and, for most veterans, considerable pathology
      remained following the programs. The current study provides grounds for cautious
      optimism in the treatment of combat-related PTSD.

PMID- 10646176
TI  - Effects of guided imagery on memory distortion in women reporting recovered
      memories of childhood sexual abuse.
AB  - We tested whether having participants imagine unusual childhood events inflates
      their confidence that these events happened to them, and tested whether this
      effect is greater in women who report recovered memories of childhood sexual
      abuse than in women who do not. Participants were pretested on how confident they
      were that certain childhood events had happened to them before being asked to
      imagine some of these events in the laboratory. New confidence measures were
      readministered. Although guided imagery did not significantly inflate confidence
      that early childhood events had occurred in either group, the effect size of
      inflated confidence was more than twice as large in the control group as in the
      group with recovered memory. These data suggest that individuals can counteract
      memory distortions potentially associated with guided imagery, at least under
      some conditions.

PMID- 10646177
TI  - Cues, frequency, and the disturbing nature of intrusive thoughts: patterns seen
      in rescue workers after the crash of Flight 427.
AB  - Intrusive thoughts have been identified as key elements of chronic or traumatic
      stress, but many questions remain about how they operate and what causes
      persistence of disturbing intrusions. The present study considers these
      questions, examining the impact of having intrusive thoughts that are cued by
      stimuli in one's environment as opposed to uncued intrusions that seem to "come
      out of the blue." In addition, this research evaluates the extent to which
      distress accompanying intrusive thoughts shortly after a traumatic event predicts
      persistence of intrusions over time. Rescue workers who responded to the crash of
      Flight 427 were studied 4 to 8 weeks, and 6, 9, and 12 months after the disaster.
      Participants who reported crash-related thoughts that were not prompted by cues
      showed higher levels of distress than those reporting only cued thoughts or those
      reporting neither. The magnitude of distress that these thoughts caused in the
      first 2 months after the crash was important in predicting subsequent frequency
      of unwanted thoughts. The presence or absence of cues and their role in the
      maintenance of distress also is discussed.

PMID- 10646178
TI  - Reliability of reports of violent victimization and posttraumatic stress disorder
      among men and women with serious mental illness.
AB  - Although violent victimization is highly prevalent among men and women with
      serious mental illness (SMI; e.g., schizophrenia, bipolar disorder), future
      research in this area may be impeded by controversy concerning the ability of
      individuals with SMI to report traumatic events reliably. This article presents
      the results of a study exploring the temporal consistency of reports of childhood
      sexual abuse, adult sexual abuse, and adult physical abuse, as well as current
      symptoms of posttraumatic stress disorder (PTSD) among 50 people with SMI.
      Results show that trauma history and PTSD assessments can, for the most part,
      yield reliable information essential to further research in this area. The study
      also demonstrates the importance of using a variety of statistical methods to
      assess the reliability of self-reports of trauma history.

PMID- 10646179
TI  - Prevalence of depressive and alcohol abuse symptoms among women VA outpatients
      who report experiencing sexual assault while in the military.
AB  - Among a national sample of 3,632 women VA outpatients, we determined self
      reported prevalence of sexual assault experienced during military service and
      compared screening prevalence for current symptoms of depression and alcohol
      abuse between those who did and did not report this history. Data were obtained
      by mailed questionnaire. Military-related sexual assault was reported by 23%.
      Screening prevalence for symptoms of current depression was 3 times higher and
      for current alcohol abuse was 2 times higher among those who reported
      experiencing military-related sexual assault. Recent mental health treatment was
      reported by 50% of those who reported experiencing sexual assault during military
      service and screened positive for symptoms of depression, and by 40% of those who
      screened positive for symptoms of alcohol abuse.

PMID- 10646180
TI  - Similarities and differences between incestuous and nonincestuous rape in a
      French follow-up study.
AB  - Clinicians are familiar with the life and psychological difficulties of incest
      victims, but their observations often are refuted as being retrospective and
      unsystematic. We aimed to ascertain similarities and differences between
      incestuous rape and nonincestuous rape. One hundred and two victims consulting a
      French forensic center were interviewed in a systematic follow-up study over 6
      months using structured interview schedules. Stepwise logistic regression
      analysis adjusted for age, gender, and characteristics of the trauma showed that
      posttraumatic stress disorder, dissociative disorders, agoraphobia, and low self
      esteem were overrepresented in the incest-rape group compared to the nonincest
      rape group.

PMID- 10646181
TI  - Combat, dissociation, and posttraumatic stress disorder in Australian Vietnam
      veterans.
AB  - The specificity of various wartime stressors for different posttraumatic stress
      disorder (PTSD) symptoms is inconsistently reported in the literature. Combat,
      wounding, and peritraumatic dissociation have not been assessed together in their
      effects on each of the various PTSD symptom clusters. This cohort study of a
      random sample of male Australian Army Vietnam veterans yielded psychiatric
      assessments of 641 subjects. PTSD measures comprised symptom criteria for
      reexperiencing, numbing and avoidance, hyperarousal, and PTSD diagnosis both
      lifetime and current within the past month. Logistic regression is used to
      examine the effects of combat, wounding, and peritraumatic dissociation together
      on PTSD. Combat experiences comprised four components derived from a principal
      components analysis of combat experiences: direct combat exposure, exposure to
      death and injury, exposure to civilian death and injury, and exposure to
      mutilation. Each was differentially related to reexperiencing, avoidance,
      hyperarousal, and PTSD diagnosis. Being wounded was not related to lifetime or
      current PTSD and peritraumatic dissociation was related to all diagnostic
      components of PTSD in the presence of other variables.

PMID- 10646182
TI  - Hospitalized adolescents' reports of sexual and physical abuse: a comparison of
      two self-report measures.
AB  - This study assesses the consistency of adolescents' reports of sexual and
      physical abuse via two self-report questionnaires with different measurement
      approaches and examines demographic and psychopathological characteristics that
      influence abuse reporting. Seventy adolescent inpatients completed the Childhood
      Trauma Questionnaire (CTQ) (Likert-type items are summed to form dimensional
      scales, and cutoff scores determine abuse status), the Traumatic Events
      Questionnaire--Adolescents (multiple-choice items determine abuse status) and
      measures of depression, suicidal ideation, and dissociative symptoms. Consistent
      reports of physical and sexual abuse were given by 86% and 71% of youngsters,
      respectively. Discrepant reporters of sexual abuse were significantly more likely
      to be male, whereas consistent reporters were significantly more depressed and
      suicidal and reported higher levels of sexual abuse and emotional and physical
      neglect. Adolescents, for the most part, were consistent in their responses about
      sexual and physical abuse on both a Likert scale and a direct-answer-format
      questionnaire. The CTQ had a lower threshold for detection of sexual abuse,
      particularly for boys.

PMID- 10646183
TI  - Altruism and the Vietnam War veteran: the relationship of helping to
      symptomatology.
AB  - This study examines the relationships among demographic factors, combat
      experiences, personality characteristics, altruism, and posttraumatic stress
      disorder (PTSD) symptomatology. Participants were Vietnam War veterans currently
      undergoing treatment for PTSD. The developmental level of internalized schemas of
      interpersonal relations (object relatedness) and the altruistic intent to help
      were significant predictors of PTSD symptomatology, with lower levels of
      symptomatology associated with higher levels of altruism. Results indicated that
      predispositional variables and altruistic intentions may be important factors to
      consider in designing and implementing treatment programs for chronically
      impaired veterans with PTSD.

PMID- 10646184
TI  - Performance of children of adults with PTSD on the stroop color-naming task: a
      preliminary study.
AB  - Investigators have used various experimental paradigms to study how individuals
      with different emotional disorders process emotional information. However, little
      research has been done on relatives of individuals with emotional disorders,
      despite developments in the area of emotional contagion. In the current
      experiment, children of adults with posttraumatic stress disorder (PTSD) (n = 18)
      and control participants (n = 21), ages 9-17 years, participated in a modified
      Stroop color-naming task. The results indicated that the children of adults with
      PTSD showed increased Stroop interference for threat-related relative to neutral
      words and to the performance of the controls. These findings are discussed with
      respect to the literature on information processing in PTSD and emotional
      contagion in families.

PMID- 10646185
TI  - Dissociative symptoms in acute stress disorder.
AB  - This study provides a profile of symptoms, and particularly dissociative
      symptoms, in the diagnosis of acute stress disorder (ASD) following motor vehicle
      accidents (MVAs). Consecutive adult non-brain-injured admissions to a major
      trauma hospital (N = 92) were assessed between 2 days and 4 weeks following an
      MVA. Presence of ASD was determined by a structured clinical interview. The
      occurrence of full and subsyndromal ASD was approximately 13% and 21%,
      respectively. The majority of those who met criteria for subsyndromal ASD did not
      meet the ASD criteria for dissociation. At least 80% of individuals who reported
      derealization also reported reduced awareness and depersonalization. This
      significant overlap between dissociative symptoms questions the discriminatory
      power and conceptual independence of the dissociative criteria. These findings
      suggest the need for a more refined conceptual and operational understanding of
      dissociative symptoms in the acute trauma stage.

PMID- 10646186
TI  - Evaluation of dream content in combat-related PTSD.
AB  - Nightmares that replicate traumatic events are among the criteria that define
      posttraumatic stress disorder (PTSD); however, there has been limited systematic
      assessment of the content of dreams in PTSD. A PTSD dream rating instrument was
      developed to operationalize features attributed to dreams associated with combat
      related PTSD that incorporated dimensions from the dream content analysis
      literature, and its reliability was assessed. Then the instrument was used to
      characterize dream reports in 18 Vietnam combat veterans diagnosed with PTSD.
      Approximately half of the group's target dreams contained features characteristic
      of combat, and all but 3 (17%) were moderately to highly threatening. Fifty-three
      percent were set at least partially in the present and 79% contained distorted
      elements. We therefore conclude that target dreams of combat veterans with PTSD
      vary with regard to replication of trauma and elements normally associated with
      dreaming, but typically are threatening.

PMID- 10646187
TI  - Interpersonal friction and PTSD in female victims of sexual and nonsexual
      assault.
AB  - This study examines the relationship among features of social relationships, both
      negative and positive, and later posttrauma pathology. Using a prospective
      design, 142 female victims of sexual or nonsexual assault were assessed at both 2
      weeks and 3 months following the assault. We examined self-reported perceptions
      of how often the participant has been the recipient of socially supportive
      actions by others and how often the participant has been engaged in interpersonal
      friction with others. Degree of interpersonal friction shortly after the assault
      predicted PTSD severity 3 months later. On the contrary, positive social support
      did not predict later PTSD severity. These results are consistent with previous
      studies that underscore the association between negative features of social
      relationships and PTSD.

PMID- 10646188
TI  - Posttraumatic stress disorder and interpersonal functioning in Vietnam War
      veterans: a mediational model.
AB  - This study examines the association between posttraumatic stress disorder (PTSD)
      and interpersonal functioning in a New Zealand community sample of 756 Vietnam
      War veterans. The results support previous research findings showing that PTSD
      adversely affects veterans' interpersonal relationships, family functioning, and
      marital/dyadic adjustment and show that the effects of PTSD on family functioning
      and dyadic adjustment are mediated by severity of interpersonal problems. It is
      suggested that higher levels of PTSD affect the ability of veterans to initiate
      and maintain interpersonal relationships and that these interpersonal problems
      are evident in poorer levels of family functioning and poorer dyadic adjustment.

PMID- 10646189
TI  - Functional impairment and utilization of services associated with posttraumatic
      stress in the community.
AB  - This study describes social functioning and service utilization patterns
      associated with posttraumatic stress symptoms relative to nonpsychiatric controls
      and depressive disorder controls in a cross-sectional epidemiological survey.
      Data from 49 cases and 147 controls who participated in the North Carolina
      component of the Epidemiologic Catchment Area study were examined. Results
      indicate that symptoms of posttraumatic stress were associated with impairment
      along several domains of functioning: social, financial, physical, and
      psychological. Individuals with posttraumatic stress were found to have more
      socioeconomic disadvantages and impaired functioning. Despite this, individuals
      with posttraumatic stress are receiving relatively few mental health services.
      Further research assessing service use, treatment, and functional outcomes are
      indicated.

PMID- 10646190
TI  - Dissociative processes and symptoms of posttraumatic stress in Vietnam veterans.
AB  - The diagnostic taxonomy of posttraumatic stress disorder (PTSD) is a contentious
      issue. Commentators are divided as to whether PTSD should remain grouped with the
      anxiety disorders or conceptualized as a dissociative disorder. This study sought
      to clarify the issue by investigating the extent to which anxiety and
      dissociative processes differentially predict the severity of each of the three
      symptoms clusters in PTSD. Seventy-four Australian veterans of the Vietnam War
      were assessed on measures of dissociation, trait anxiety, and posttraumatic
      stress symptomatology. Multiple regression analyses showed that all three
      symptoms clusters were predicted by anxiety, but the clusters differed in the
      pattern of their relationship with dissociation variables. The failure of
      pathological dissociation to predict PTSD symptoms prompts a reconsideration of
      the point at which dissociative mechanisms may impact on this disorder. The
      findings are consistent with current classification of combat-related PTSD as an
      anxiety disorder.

PMID- 10646191
TI  - Parental perceptions of hearing loss classification in children.
AB  - Hearing loss classification scales are commonly used to explain audiometric
      findings to the parents of children with hearing loss. These scales, however,
      have little or no scientific basis. In this study, filtered auditory recordings
      were used to simulate three levels of childhood hearing loss, as defined by the
      commonly used terms--slight, mild, and moderate. Parents, after listening to each
      simulation, were asked to provide their impressions. Results demonstrated that:
      parents defined each simulated loss with terminology representing substantially
      greater magnitude than the commonly used terms; parents anticipated significantly
      greater difficulty (p < .05) for each of nine hearing-related tasks when hearing
      loss was defined by the simulations rather than the classification terms; and
      parents selected more aggressive management procedures in response to the
      simulations than to the classification terms. In an additional task, parents
      estimated degree of simulated hearing loss with percentage values, indicating
      about 40% greater hearing loss for the three levels of loss compared to values
      produced by the conventional American Academy of Otolaryngology-American Council
      of Otolaryngology (1979) percentage formula. The findings indicate that standard
      methods of classifying hearing loss in audiologic and medical clinics may
      undermine parents' understanding of their child's hearing loss, causing them to
      underestimate substantially the magnitude of the loss.

PMID- 10646192
TI  - Connexin 26 as a cause of hereditary hearing loss.
AB  - Connexin 26 (Cx26) is an inner ear protein that forms part of the potassium
      recycling pathway used to maintain the osmotic balance essential for normal
      auditory function. Mutations in the GJB2 gene, which encodes for the Cx26
      protein, recently have been implicated as the cause of up to 50% of hereditary
      prelingual severe-to-profound nonsyndromic hearing loss. A single mutation that
      results in the loss of a guanosine nucleotide at position 35, the 35delG
      mutation, is involved in approximately 97% of cases of Cx26-related deafness. In
      persons with prelingual severe-to-profound nonsyndromic hearing loss, genetic
      testing for Cx26-related deafness can establish a diagnosis and obviate the need
      for a more expensive evaluation. However, if this type of testing is considered,
      appropriate genetic counseling must be provided and the nuances and limitations
      of genetic testing must be understood.

PMID- 10646193
TI  - Head trauma and mid-frequency hearing loss.
AB  - Numerous reports in the literature associate head trauma with high-frequency
      hearing losses, often mimicking "4K notches" attributed to noise exposure. We
      have observed that some patients with a positive history for head trauma may show
      midfrequency notches in their audiometric configurations.

PMID- 10646194
TI  - Clinical masking in speech audiometry: a simplified approach.
AB  - The optimal masking level during speech audiometry is one that falls above the
      minimum and below the maximum masking levels. The goal is to select a masking
      level that falls at the middle of the masking plateau. This article presents a
      simplified approach to selecting an appropriate level of contralateral masking
      during suprathreshold speech audiometry. The underlying theoretical concepts and
      prerequisite conditions are reviewed. The advantages of insert earphones when
      using the simplified approach are discussed.

PMID- 10646195
TI  - Making sense of directional microphone hearing aids.
AB  - We have witnessed a large increase in the availability of directional microphone
      hearing aids over the past few years. Directional microphone technology is now
      available in analog, digitally controlled analog, and digital hearing aids, and
      has been implemented into both behind-the-ear and in-the-ear styles. This Short
      Course reviews basic design differences across directional microphone hearing
      aids. A number of different laboratory and clinical evaluation methods used for
      assessment of both electroacoustic and behavioral directivity are then reviewed.
      In addition, the potential impact of test conditions such as room reverberation
      and type and position of competing noise(s), on listener performance when fit
      with directional hearing aids are considered. Recommendations and suggestions
      relating to the clinical and laboratory assessment of directional hearing aids
      are provided.

PMID- 10646196
TI  - Effect of speech processor program modifications on cochlear implant recipients'
      threshold and maximum acceptable loudness levels.
AB  - This study's purpose was to determine whether or not modifications in speech
      processor electrical stimulation levels were associated with changes in five
      Nucleus 22 cochlear implant recipients' thresholds or maximum acceptable loudness
      levels (MALs). These modifications in minimum and maximum stimulation levels were
      made to optimize hearing in everyday life. One threshold and one MAL were
      obtained on each active electrode during six, weekly test sessions, three before
      and three after program modification. Only one participant had a significant
      change in threshold after program modification; this participant and four others
      had significant changes in MAL. Participants' threshold variability was the same,
      but MAL variability was higher than that observed in other studies. Because these
      participants had no experience making MAL judgments prior to this study, this
      result suggests that implant recipients should be given sufficient practice in
      making MAL judgments to provide a stable clinical estimate of the upper boundary
      of the electrical dynamic range.

PMID- 10646197
TI  - Implications from factor analysis for central auditory processing disorders.
AB  - Central auditory processing disorders among school-age children have been
      challenging to identify and treat. Many issues remain that need to be resolved.
      Here, we compare and contrast findings on 331 school-age children who were given
      two of the more common central auditory processing disorder tests (Staggered
      Spondaic Word [SSW] Test and the SCAN Screening Test for Auditory Processing
      Disorders). These results replicate and reinforce many of the psychometric
      findings reported earlier. The use of factor analysis with these test results was
      explored. Significantly, two factors emerged, including an auditory binaural
      separation from competition factor and a monaural low redundancy degradation
      factor. These findings help us define the nature of processes probed by the SCAN
      screening test and the SSW test. Furthermore, these findings clarify the use of
      SSW and SCAN because they showed both SSW Left Competing and Right Competing
      loading within the same factor, whereas the three subtests on SCAN sorted into
      two rather than three factors.

PMID- 10646198
TI  - Predictive validity of a procedure for pediatric hearing instrument fitting.
AB  - In 1994, Moodie, Seewald, & Sinclair described the development of a clinical
      procedure for predicting real-ear hearing instrument performance in young
      children. The purpose of the present study was to determine the validity of this
      procedure for predicting the real-ear aided gain (REAG) and real-ear saturation
      response (RESR) of hearing instruments worn by children. To this end, both the
      REAG and RESR were measured, through probe-microphone measures, and predicted,
      using the Moodie et al. procedure. The findings confirmed that the 2-cc coupler
      based procedure, with individualized acoustic transforms, described by Moodie et
      al., resulted in highly accurate predictions of real-ear hearing instrument
      performance for both REAG and RESR at five test frequencies. The implications of
      these findings for the clinical fitting of hearing instruments in infants and
      young children are discussed.

PMID- 10646199
TI  - Research on visual word recognition: from verbal learning to parallel distributed
      processing.

PMID- 10646200
TI  - Discrete threshold versus continuous strength models of perceptual recognition.
AB  - Two experiments were designed to test discrete-threshold models of letter and
      word recognition against models that assume that decision criteria are applied to
      measures of continuous strength. Although our goal is to adjudicate this matter
      with respect to broad classes of models, some of the specific predictions for
      discrete-threshold are generated from Grainger and Jacobs' (1994) Dual-Readout
      Model (DROM) and some of the predictions for continuous strength are generated
      from a revised version of the Activation-Verification Model (Paap, Newsome,
      McDonald, & Schvaneveldt, 1982). Experiment 1 uses a two-alternative forced
      choice task that is followed by an assessment of confidence and then a whole
      report if a word is recognized. Factors are manipulated to assess the presence or
      magnitude of a neighbourhood-frequency effect, a lexical-bias effect, a word
      superiority effect, and a pseudoword advantage. Several discrepancies between
      DROM's predictions and the obtained data are noted. Both types of models were
      also used to predict the distribution of responses across the levels of
      confidence for each individual participant. The predictions based on continuous
      strength were superior. Experiment 2 used a same-different task and confidence
      ratings to enable the generation of receiver operating characteristics (ROCs).
      The shapes of the ROCs are more consistent with the continuous strength
      assumption than with a discrete threshold.

PMID- 10646202
TI  - Modeling lexical decision and word naming as a retrieval process.
AB  - We argue that rule-like phenomena in naming and lexical decision reflect the
      collapsing of information that occurs during retrieval from the lexicon, and that
      complex patterns in performance reflect the pattern of correlation that exists in
      the reader's lexicon rather than mapping rules wired into, or learned by, the
      processing apparatus. By using a lexicon built to scale, we show that simple
      retrieval operations applied to a large corpus of words correctly predict an
      interaction of word frequency by spelling-to-sound regularity in naming, a
      frequency main effect in lexical decision, sensitivity to orthographically
      defined syllable-like structures in lexical decision, and an interaction of
      number of syllables with word frequency in naming.

PMID- 10646201
TI  - Reading speech and hearing print: constraining models of visual word recognition
      by exploring connections with speech perception.
AB  - Current models of reading and speech perception differ widely in their
      assumptions regarding the interaction of orthographic and phonological
      information during language perception. The present experiments examined this
      interaction through a two-alternative, forced-choice paradigm, and explored the
      nature of the connections between graphemic and phonemic processing subsystems.
      Experiments 1 and 2 demonstrated a facilitation-dominant influence (i.e.,
      benefits exceed costs) of graphemic contexts on phoneme discrimination, which is
      interpreted as a sensitivity effect. Experiments 3 and 4 demonstrated a
      symmetrical influence (i.e., benefits equal costs) of phonemic contexts on
      grapheme discrimination, which can be interpreted as either a bias effect, or an
      equally facilitative/inhibitory sensitivity effect. General implications for the
      functional architecture of language processing models are discussed, as well as
      specific implications for models of visual word recognition and speech
      perception.

PMID- 10646203
TI  - Word recognition and temporal order judgments: semantics turns back the clock.
AB  - This paper examines the consequences that codes activated during reading have on
      activities unrelated to reading by investigating the effects of semantics on
      temporal order judgments. Participants judged which of two word targets appeared
      first. Targets appeared either synchronously, or were separated by varying
      stimulus onset asynchronies (SOAs). For one group of participants, one target on
      each trial was related to a prime word shown at the beginning of the trial. This
      priming relation affected temporal order judgments such that participants
      sometimes reported related targets as having appeared first, even when they
      appeared second. It is suggested that this effect is best explained as showing
      that codes activated during word recognition affect the attentional selection
      aspects of the temporal order judgment task.

PMID- 10646204
TI  - Ambiguity and visual word recognition: can feedback explain both homophone and
      polysemy effects?
AB  - In a lexical-decision task (LDT), Hino and Lupker (1996) reported a polysemy
      effect (faster response times for polysemous words [e.g., BANK]), and attributed
      this effect to enhanced feedback from the semantic system to orthographic units,
      for polysemous words. Using the same task, Pexman, Lupker, and Jared (in review)
      reported a homophone effect (slower response times for homophonic words [e.g.,
      MAID]) and attributed this effect to inconsistent feedback from the phonological
      system to orthographic units, for homophones. In the present paper we test two
      predictions derived from this feedback explanation: Polysemy and homophone
      effects should (a) co-occur in a standard LDT (with pseudoword foils) and (b)
      both be larger with pseudohomophones (e.g., BRANE) as foils in LDT. The results
      supported both predictions.

PMID- 10646205
TI  - Context and homograph meaning resolution.
AB  - We describe an activation-based model of word recognition and apply it to the
      process of resolving the meaning of homographs presented in context. The
      interpretation of homographs was assessed by asking participants to decide
      whether a target word was related to the meaning of a sentence containing a
      homograph. These relatedness decisions varied systematically with the relative
      frequency of the homograph meanings, delay, and the nature of the sentence
      context. In the model, it was assumed that orthographic and contextual
      information combine additively to determine the activation of word meanings, and
      that the probability of a "related" response is determined by the activation
      level of the related meaning. The model accurately accounts for all observed
      effects, as well as their interaction. We conclude that the core process of
      lexical ambiguity resolution may be quite simple.

PMID- 10646206
TI  - Imageability effects in word naming: an individual differences analysis.
AB  - The present research was designed to extend research by Strain, Patterson, and
      Seidenberg (1995) who found that imageability facilitates naming of low-frequency
      irregular words. Experiment 1 shows that the impact of imageability on word
      naming varies with phonological coding skill. In Experiment 2, the effect of
      imageability on naming low-frequency irregular words was shown to occur across an
      extended set of items. Together, the present findings support the notion that
      semantics may play a role in phonological coding when the mappings between
      orthography and phonology are weak.

PMID- 10646207
TI  - Further evidence for feature correlations in semantic memory.
AB  - The role of feature correlations in semantic memory is a central issue in
      conceptual representation. In two versions of the feature verification task,
      participants were faster to verify that a feature (< is juicy >) is part of a
      concept (grapefruit) if it is strongly rather than weakly intercorrelated with
      the other features of that concept. Contrasting interactions between feature
      correlations and SOA were found when the concept versus the feature was presented
      first. An attractor network model of word meaning that naturally learns and uses
      feature correlations predicted those interactions. This research provides further
      evidence that semantic memory includes implicitly learned statistical knowledge
      of feature relationships, in contrast to theories such as spreading activation
      networks, in which feature correlations play no role.

PMID- 10646208
TI  - Context dependency in Stroop's paradigm: when are words treated as nonlinguistic
      objects?
AB  - The "memory" literature emphasizes the notion of encoding variability, whereas
      the "word recognition and attention" literature typically asserts that it is
      impossible to prevent immediate lexical and semantic activation when single words
      are presented to skilled readers. In the four experiments reported here, the
      presence/absence of a Stroop effect was associated with the nature of the between
      trial context. These data can be understood as an expression of contextually
      driven encoding variability, but are problematic for the decontextualized
      "automatic" processing account that has prevailed in the attention and
      performance literature for the last six decades.

PMID- 10646209
TI  - The influence of selection for response on repetition priming of word
      identification.
AB  - Repetition priming of word identification was examined using study tasks that
      required participants either to search for targets appearing in rapid serial
      visual presentation of word lists or to read aloud a list of target words.
      Nontarget words embedded in search lists produced a small amount of repetition
      priming on a masked word identification test, independent of presentation
      duration in the search list (200-1,000 ms), but no priming when they appeared as
      targets in a second search task used at test. For both test tasks, words that
      were originally encoded in a read-aloud task or served as detected targets during
      a search task generated more priming than nontarget words from search lists.
      These results suggest that priming effects are strongest when study tasks require
      an item to be selected as the basis for an overt response, even though the
      information on which study and test responses are based may be different.

PMID- 10646210
TI  - Current topics in Austrian anthropology.

PMID- 10646211
TI  - Thickness distribution of the occipital bone--a new approach based on CT-data of
      modern humans and OH 9 (H. ergaster).
AB  - A new approach for the analysis of cranial bone thickness is introduced. The
      study focuses on the occipital bone of modern humans and of a 1.25 Myr-old H.
      Ergaster/erectus specimen from Olduvai Gorge (OH 9). A semiautomatic algorithm
      detects a multitude of thicknesses from CT-data of the investigated bones. We
      find that every bone is characterized by its own distribution pattern of cranial
      thickness, which is then analyzed statistically. The results demonstrate that the
      thickness distribution of the occipital bone of OH 9 is within the normal range
      of the H. sapiens sample (which itself shows a remarkably high variance). This
      contributes to a further analysis of phyletic differences of hominid morphology
      by including distribution patterns of thickness combined with aspects of
      functional anatomy.

PMID- 10646212
TI  - The iceman under pressure (Part I): A description of skull deformations due to
      5100 years of glacial action.
AB  - Due to its long deposition in the glacier, the 'Iceman' (an ice-mummy from the
      Hauslabjoch) has been deformed, notably its skull. We introduce various
      comparative methods that describe these deformations, assuming they can be
      ascribed--to a large extent--to glacial action. While pressure is a scalar, the
      deformations must be described via a 2-tensor strain field (which can be
      represented by a matrix function value at every point throughout the skull). In
      this paper, we present the assumed deformations in numerous graphical forms and,
      furthermore, the limitations in interpretation--including an estimate of
      statistical variability--that can be revealed by this analysis. These methods,
      although describing the results of glacial action and implying a 2-tensor strain
      field (which will be presented in a subsequent paper), do not permit a
      straightforward reconstruction of the original, underformed skull. These methods
      have wider applications to the general problem of deformation.

PMID- 10646213
TI  - Human evolutionary aspects and urban dwelling features.
AB  - Planning and architecture of modern housing projects should take into account the
      fact that human well-being depends very much on needs derived from the natural
      history of human evolutionary aspects, which include territoriality, security,
      and a balance between privacy and communal activity. Although model housing
      projects should consider space, all to often the need for privacy and the
      importance of the residential environment has been neglected. Putative
      consequences are a loss of social coherence, resulting in anonymity, vandalism
      and an increase in crime rates. On a game theoretical basis, we predict that a
      tendency for cooperation grows with the increasing probability of future meetings
      among inhabitants. The higher the probability to re-meet co-residents, the more
      interactions are to be expected. Frequent meetings lead to reciprocal recognition
      and enable the inhabitants to control their environment by identifying straners.
      This mechanism results in the identification with a common territory. Friendly
      interactions between residents are a motor for and an indicator of satisfactory
      living conditions. For this study, six different Viennese residential apartment
      blocks were selected and their quality measured using a checklist. The behavior
      of the residents was recorded using ethological standard methods (N = 1653),
      their subjective evaluation was assessed by on-site interviews (N = 300), and the
      frequency of physical incivilities was counted. The results support the
      hypotheses. The classification of urban environments relating to the presence of
      the above-listed features indicates that high habitat quality covaries with
      differences in preference for the site, extent of friendly interactions and
      familiarity with other residents, and occurrences of incivilities. One may
      conclude that the importance of the quality of the habitat environment cannot be
      overestimated, as its socially integrative potential is a means to counteract
      anonymity and crime incidence in cities.

PMID- 10646214
TI  - Landscape and history: a multidisciplinary approach. Project Group Environmental
      History (P.G.E.H.).
AB  - Human societies have inhabited parts of the Central European country of Austria
      for thousands of years. The development process shopping the landscape by this
      long period of human impact remains poorly understood. The present study is an
      attempt to research landscape history on a local scale and compares an alpine,
      pre-alpine and midland-village area in Austria. We have developed an appropriate
      concept to describe the landscape ecology features of the study areas in several
      stages of the past from 1733 on. The landscape analysis is based on the
      interpretation of different kinds of historical data (e.g., documents, maps)
      going back to the pre-industrial epoch, which has--at least in terms of landscape
      ecology--hardly been accessible until now. An important aim of the study is to
      localize the historical information in the landscape. Individual plots can be
      traced back even to the early 14th century. Based on the quality of the available
      historical data, the historical landscape is analysed with regard to categories
      such as form and intensity of land use, distribution of nutrients and water as
      well as the pattern of landscape elements and their ecological functions. The
      comparison of present stages with former ones yields detailed knowledge on the
      dynamics and stability of landscape structure. This approach allows present-day
      land units to be identified as a result of long-term development going back to
      Medieval times. The primary aim of the study is to analyze factors that bring
      about change or resist it by creating stability. We therefore examine factors
      coupling landscape structure, agricultural production and population development.
      For this reason, we have studied the people and the evidence for their labor over
      a period of 400 years (1400-1800). Besides demographic data of the 18th and 19th
      century, historical registrar material has been collected; it enabled the land
      tenures to be reconstructed from the 15th to the 19th century. This type of data
      is a valuable source of information for investigating the socio-economic status
      of a local population or its farmsteads. The collected data reveal similarities
      in trends between time series of demography, land holding stability and landscape
      ecology features. A theoretical model shows how population, production and
      natural resources are connected in the investigated pre-modern communities.

PMID- 10646215
TI  - Re-evaluation of the endocranial volume of the Guattari 1 Neandertal specimen
      (Monte Circeo).
AB  - The endocranial capacity of Guattari 1 originally was estimated by Sergi as
      approximately 1.550 cm3. Using three different approaches, a physical endocast, a
      stereolithographic model, and a virtual endocast, we have estimated the
      endocranial capacity of Guattari 1 as approximately 1.350 cm3. This paper
      explains our revision of the estimated endocranial volume of Guattari 1, provides
      a cautionary case concerning other estimates of endocranial volume, and
      demonstrates and encourages the use of recent advances in imaging, modeling, and
      analysis of endocranial volume.

PMID- 10646216
TI  - Body composition characteristics, sex hormone levels and circadian gonadotropin
      fluctuations in infertile young women.
AB  - The present study dealt with the interaction between body composition estimated
      by means of dual energy x-ray absorptiometry, sex-specific fat distribution and
      sex hormone levels (LH, FSH, estradiol, prolactin, DHEA-S, androstendione,
      testosterone and SHBG) as well as LH and FSH fluctuations in infertile young
      women ageing between 18 and 30 years (x = 23.4 yr). Twenty patients suffered from
      polycystic ovaries (PCO), 15 women suffering from a mild anorexia nervosa were
      amenorrhoeic for more than one year. Marked associations between estradiol,
      testosterone, SHBG as well as the FSH output and body fat, bone mass and fat
      distribution were documented. PCO patients exhibited a high weight status and a
      typical android fat distribution which signals infertility comparable to
      postmenopausal women. In contrast, although anorexia patients had pathological
      decreased estrogen levels and were infertile at the time of investigation, their
      fat distribution was be classified as 'ypergynoid' and signals potential
      reproductive capability after a sufficient weight gain.

PMID- 10646217
TI  - Estimation of the onset of bone atrophy.
AB  - Disturbances of bone growth were investigated in the skeletal remains of two
      individuals. These two--unrelated--mature males possessed limbs with marked
      atrophy as a result of immobilization, while the non-affected limbs showed a
      massive hyper-robusticity of the bones. The atrophied bones were investigated
      metrically and histologically. We assessed the time of onset, the duration and
      the extent of the immobilization. Both males suffered from paralysis, whereby one
      was apparently paralyzed from the pelvis down, the other had both lower
      extremities and the right arm affected. It appears that the onset occurred during
      the juvenile period.

PMID- 10646218
TI  - Milk consumption, smoking and lead concentration in human hair.
AB  - Trace elements in hair samples were examined in 79 medical and sports students in
      Vienna and 77 biology students in Rome (ages 19-31 years). Lead concentration was
      determined by inductively coupled plasma mass spectrometry. The effect of smoking
      on lead levels is confirmed. Those who consume milk and dairy products daily show
      a lower lead concentration than those who consume them occasionally, both overall
      and in smokers and non-smokers. The effects of milk consumption and smoking
      appear to be independent. It seems that smokers may not enjoy the protective
      effect of milk consumption to the same extent as non smokers.

PMID- 10646219
TI  - Evidence of genocide 7000 BP--Neolithic paradigm and geo-climatic reality.
AB  - The early Neolithic fortified settlement of Schletz, Lower Austria is emerging as
      one of the most interesting sites of Linear Pottery culture excavation in
      Austria. In the course of systematic investigations carried out since 1983, a
      plethora of unexpected results have been obtained. Specifically, the human
      skeletal remains of 67 individuals have been found at the base of an oval trench
      system. Without exception, these remains are characterized by multiple traumatic
      lesions as well as carnivore gnaw marks. Demographic analysis presents the
      picture of the entire population of this early farming settlement having been
      extinguished. Further, the findings suggest that a genocide scenario may have
      been responsible for the final demise of this settlement. The age and sex
      distribution reveals a lack of young females, who are interpreted as having been
      abducted by aggressors. There is however no direct skeletal evidence of
      aggressors at the site; in fact, the uniformity of Strontium isotope ratios (HR
      ICP-MS analysis) implies that all 67 individuals, who were left unburied for
      months, were indigenous. Supporting evidence of increased levels of inter-human
      aggression--possibly caused by a broad wave of migration--comes from other
      contemporary end linear pottery sites in Germany. Such findings are here
      discussed in the context of a dramatic geological event in the region of the
      Black Sea shelf at this time (7.550 BP), which led to the submergence of some
      100.000 square kilometers of fertile land, and which might have been responsible
      for subsequent gradual population movements into the interior of Europe.

PMID- 10646220
TI  - Perineal swellings: a social and endocrine advantage for Barbary macaque females
      (Macaca sylvanus).
AB  - This study focuses the relationship between social rank, intersexual behavior,
      age, fecal cortisol equivalent excretion rates and perineal swelling size in
      contraceptive-treated Macaca sylvanus females. Behavioral data and fecal samples
      were collected during a twenty-week period from 24 females. Females were
      categorized with regard to perineal swelling (enlarged or reduced), and to their
      dominance rank (high or low); we found that swelling size was not associated with
      it. However, females with an enlarged perineum received more male grooming
      interactions, had closer spatial relations to males, and received significantly
      more interventions from males than did the others. Endocrinologically, females
      with enlarged swelling showed decreased fecal cortisol equivalent excretion
      rates. Multiple regression models showed a positive relationship between the
      extent of the swelling size and grooming, inspection and spatial relation. There
      was a negative relationship between the extent of swelling size and fecal
      cortisol equivalents. These results imply that enlarged perineal swellings among
      implanted Barbary macaque females have a greater impact on intersexual contact
      and adrenocortical activity than does social rank or age.

PMID- 10646221
TI  - A qualitative approach to assessing body compartments using bioelectrical
      variables.
AB  - A total of twelve subsamples of healthy European adults (207 males, 208 females)
      and Ecuadorian school children (300 males, 300 females) were studied with regard
      to their normal balance of body composition by calculating their bioelectrical
      values measured by a Phase-Sensitive Impedance Analyzer (BIA 101, Akern s.r.l.,
      Florence, Italy). The method involved bivariate analysis of reactance and phase
      angle and the associated Bioelectrical nomogram (i.e. 'Biagram') which gives
      valuable information on the ratio of extra-cellular to body cell masses and
      confirmed that the vast majority of the subjects were in good physical condition.
      The few cases of outliers were attributable to slight dehydration after excessive
      physical activity in the adult sample or to slight overhydration or malnutrition
      in the child sample. The results of the qualitative approach in various areas of
      assessment of body composition in healthy and diseased subjects implies its
      usefulness as a tool in epidemiological studies.

PMID- 10646222
TI  - Respirator triggering of electron beam computed tomography (EBCT): research on
      vital capacities.
AB  - In this project we evaluate the dynamic changes during expiration at different
      levels of positive-end-expiratory pressure (PEEP) in ventilated patients. We
      wanted to discriminate between normal lung function and acute respiratory
      distress syndrome (ARDS). After approval by the local Ethic Committee we studied
      two ventilated patients: (one with normal lung function and one with ARDS) We
      used the 50 ms scan mode of the EBCT. The beam was positioned 1 cm above the
      diaphragm while the table position remained unchanged. We developed an electronic
      trigger that utilizes the respirator's synchronizing signal to start the EBCT at
      the onset of expiration. During controlled mechanical expiration at two levels of
      PEEP (0 and 15 cm H2O), pulmonary aeration was rated as: well-aerated (-900HU to 
      500HU), poorly aerated (-500HU to -100HU) and non-aerated (-100HU to +100HU).
      Pathological and normal lung functions showed different dynamic changes. The
      different PEEP levels resulted in a significant change of pulmonary aeration in
      the same patient. Although we studied only two patients, respiratory triggered
      EBCT may be accurate in discriminating pathological changes due to the abnormal
      lung function in a mechanically ventilated patient.

PMID- 10646223
TI  - Differential diagnosis on ancient skeletal remains: conventional methods and
      novel application of the BSE-mode in SEM on a skull tumor of the early Bronze
      Age.
AB  - Tumor-like lesions on skeletal remains put relatively high demands on
      paleopathological diagnostic methods. In addition to conventional anthropological
      determination and non-invasive methods of macroscopical description and
      radiodiagnostic examination, bony lesions can be analyzed more accurately, but
      also more elaborately by light microscopy of invasive section preparations. In
      this study an irregular new bone formation on the excavated skull of a juvenile
      individual was also investigated by scanning electron microscopy (SEM). A cut-out
      block of the lesion was first observed in the secondary electron-mode (SE-mode),
      and then methylmethacrylate-embedded ground and polished sections were for the
      first time also evaluated in the back-scattered electron-mode (BSE-mode).
      Thereby, new insights into the bone structure and the development of this tumor
      like lesion could be obtained which led to the diagnosis of a meningioma.

PMID- 10646224
TI  - New methods and techniques in anthropology.
AB  - Since the discovery of the Tyrolean Iceman in 1991, advanced imaging and post
      processing techniques have been successfully applied to anthropological research.
      Among the specific techniques are spiral computed tomography and 3-dimensional
      reconstructions, which include stereolithographic and fused deposition modeling
      of volume data sets. The Iceman's skull was the first to be produced using
      stereolithography; subsequently, it has been successfully applied in preoperative
      planning. With the advent of high-end performance graphics workstations and
      biomedical image processing software packages, 3-dimensional reconstructions have
      become established as routine tools for analyzing volume data sets. These
      techniques enabled dramatically new insights to be gained in the field of
      physical anthropology. Computed tomography became the ideal research tool to
      access the internal structures of various precious fossils without even touching-
      let alone damaging--them. Among the most precious are specimens from the genus
      Australopithecus (1.8 Myr-3.5 Myr), as well as representatives of Homo
      heidelbergensis (200 kyr-600 kyr) and Homo neanderthalensis (40 kyr-100 kyr);
      such fossils have been CT-scanned during the last five years. The fossils often
      are filled with a stone matrix or other encrustations. During the post-processing
      routines, highly advanced algorithms were used to remove these encrustations
      virtually (the concrete fossils remain untouched). Thus it has been possible to
      visualize the morphological structures that are hidden by the matrix layer. Some
      specimens have been partially destroyed, but it has been possible for the missing
      parts were reconstructed on the computer screen in order to get estimations of
      brain volume and endocranial morphology, both major fields of interest in
      physical anthropology. Moreover, the data in computerized form allows new
      descriptions of morphological structures using geometric morphometrics. Some of
      the results may change aspects and interpretations in human evolution and
      approaches to long-standing questions in this field. We subsume the introduction
      of these new imaging and post-processing techniques into a new field of research:
      Virtual Anthropology.

PMID- 10646225
TI  - Anthropology and history: the revaluation of history in anthropological research.
AB  - The main premise of this paper is that the accepted view of history based on
      written documents (historiography) is marked by hierarchical ordering and
      evaluation implicit in it. The paper examines the context of the negation of
      history, and the revaluation of history in anthropological research. The lack of
      written documents concerning particular social groups on the internal plane, but
      also particular nations (ethnic groups) on the global plane, earned them the name
      of "nations (groups) without history". This criterion of historicity--the
      existence of a writing system and written documents--implies the hypothesis about
      the inferiority of those nations and groups. The attributes of history seen in
      this way are modernity, linearity and cumulativeness. This system implies
      ethnocentrism based on a twofold negation: a) the negation history, and b) the
      negation of otherness. What we must not forget is that the symbolic universes are
      social products with a history, and in order to understand their meaning, one
      must understand the history of their production. It is very important to pay
      close attention to the historical practice of projecting our cultural practices
      onto others. The question of who determines the history and which views are
      presented to a particular audience is a matter of power and contest. contemporary
      history-oriented sociocultural anthropology focuses on the total reconstruction
      of the way of life and thinking in particular periods of history: on the everyday
      life. This brought together the intellectual traditions of "new history",
      ethnology, sociocultural anthropology and the sociology of culture. While
      modernism stresses the present change versus the static past, postmodernism
      denies the past ever being static and hypostatises fluidity and change as
      permanent condition. Postmodernism strives to undermine the old, Euro-centric
      notion that "we" have a history but "they" do not; it has also lead to social
      scientists' renewed interest in history.

PMID- 10646226
TI  - The earliest islanders of the eastern Adriatic.
AB  - The introduction of farming into the Mediterranean was a complex process marked
      by regional variability. In the case of the Eastern Adriatic, the islands may
      have played a crucial role by providing footholds for seaborne travellers. The
      original islanders were bands of hunter-gatherers, who were pushed out of the
      north Adriatic plain by the marine transgression of the early Holocene. Farming
      was introduced around 6000 B.C. Several lines of evidence suggest that this
      involved at least some population movement from southern Italy, possibly along a
      chain of islands that span the central Adriatic. The details of interaction
      between the immigrant and the autochthonous population remain elusive, due to the
      patchy character of the currently available data.

PMID- 10646227
TI  - Genetic epidemiological studies of eastern Adriatic Island isolates, Croatia:
      objective and strategies.
AB  - In this paper, the authors discuss why isolate island populations represent a
      particularly helpful model for genetic epidemiological studies. A thorough
      previous anthropological research carried out in Eastern Adriatic island
      isolates, Croatia, in terms of ethnohistory, geography and current demography is
      reviewed. The major results of the studies of population genetic structure of
      those populations, including model-bound and model-free approaches, the analyses
      of serogenetic polymorphisms and most recent studies using HLA class II, VNTR and
      STR DNA polymorphisms, are briefly presented. The organization of health care on
      the islands is analyzed and some relevant details of specific medical problems
      and some autochtonous diseases in these island populations is noted. The authors
      present in outline four illustrative examples of research opportunities which are
      afforded by the unique circumstances found in these isolate communities. These
      relate to hereditary dwarfism on Krk island, Mal de Meleda on Mljet island,
      extreme inbreeding on Susak island and population genetics of cancer on the
      islands of Brac, Hvar, Korcula, Vis and Lastovo. Finally, the authors develop
      objectives and strategies for a long-term genetic epidemiological research of
      these populations and suggest that such a programme of investigation would
      further our understanding of the causes of (rare) diseases which are uniquely
      important to these communities but also of common diseases which are important
      contributors to the burden of disease both in these islands and throughout the
      world.

PMID- 10646228
TI  - Cancer incidence in eastern Adriatic isolates, Croatia: examples from the islands
      of Krk, Cres, Losinj, Rab and Pag.
AB  - As an extension of previous research this study investigates the incidence of
      cancer in five genetic isolate island populations of the Eastern Adriatic,
      Croatia. Thorough anthropological research over the past three decades has
      established some of those populations as outstanding examples of genetic
      isolates. A previous study which found higher cancer incidence in 5 Eastern
      Adriatic islands than in a control population supported a hypothesis that among
      the founders of these populations there were genetic variants (especially with
      recessive inheritance) responsible for genetic susceptibility to certain types of
      cancer. This study sought to investigate cancer incidence in 5 further island
      populations. All cancer cases in five island populations (Krk, Cres, Losinj, Rab
      and Pag) over the 20-year period (1971 to 1990) was extracted from the data of
      the Croatian Cancer Registry. The mainland populations of Istrian and Primorsko
      Goranska County, characterized by similar environmental factors but an outbred
      genetic structure, represented a control population. After standardization by by
      sex and age, cancer incidence was higher in the island populations than in the
      control population in both sexes. The cancer sites primarily responsible for the
      excess incidence were prostate, stomach and pancreatic cancer in males, and
      ovarian, breast, stomach, bowel, and brain cancer in females. The reasons for the
      increased cancer incidence are uncertain and may be due to different
      environmental exposure between the two populations. However, it is possible that
      genetic isolation and inbreeding are important factors. Further investigations of
      cancer in these isolate populations are warranted to explore these findings
      further.

PMID- 10646229
TI  - Surname as 'cancer risk' in extreme isolates: example from the island of Lastovo,
      Croatia.
AB  - The aim of this study was to analyze whether there are surnames which appear more
      frequently among the ancestors of cancer cases in a small isolate, in comparison
      to the ancestral surnames of the healthy controls, using the classic case-control
      design. The chosen setting was the island of Lastovo, Croatia, located more than
      100 kilometers from the nearest coastal region. The period of study was 1970
      1995, during which a total of 76 cancer cases were recorded in a population of
      approximately 800. The comparison of surname frequencies was performed in current
      and in five ancestral generations. The leading hypothesis was that, if inbreeding
      and common ancestry contributed to the development of the disease, then those
      phenomena should be reflected in increasing frequency of some surnames among
      ancestors, identifying the 'hidden' consanguinity, or 'following' cancer
      promoting genes on the Y-chromosome. The results imply that there are surnames
      representing a classic "risk" for cancer, but also those "protecting" from its
      development, which all underscores the importance of founder effect and genetic
      predisposition to the disease in a small, reproductively isolated population. All
      of the results become more evident and increasingly significant when analyzed in
      more distant ancestral generations.

PMID- 10646230
TI  - DNA-PCR system FGA (FIBRA)--genotype and allele frequencies in a sample of
      western Germany (Dusseldorf region).
AB  - Frequency data for the STR system FGA (HumFibra) were obtained from a Caucasoid
      German population sample (Dusseldorf area) of 424 unrelated individuals. PCR
      products were detected by horizontal polyacrylamid gel electrophoresis and a
      total of 16 alleles was identified by side-by-side comparison with a commercially
      available sequenced ladder. The observed genotype distribution showed no
      significant deviation from the Hardy-Weinberg equilibrium. The high information
      content (pooled German data: rate of heterozygosity = 0.8626; probability of
      match = 0.0344; mean exclusion chance = 0.7240) render this system a useful tool
      not only in forensic casework (criminal and paternity cases) but in population
      genetics too.

PMID- 10646231
TI  - High resolution molecular typing of HLA class II region in the population of the
      island of Krk, Croatia.
AB  - The HLA class II alleles (DRB1, DRB3, DRB5, DQA1, and DQB1) and haplotypic
      associations were studied in the population of the island of Krk using the PCR
      SSOP method and the 12th International Histocompatibility Workshop primers and
      probes. Allele and haplotypic frequencies were compared with the general Croatian
      population. Significant differences were observed between the population of the
      island of Krk and Croatians for: a) three broad specificities at DRB1 locus
      (DRB1*01, *15, and *07), b) one allele at DRB3 locus (DRB3*0301), c) one allele
      at DQA1 locus (DQA1*0201), d) one allele at DQB1 locus (DQB1*0303). Four unusual
      haplotypic associations, which have not yet been described in the Croatian
      population, DRB1*1301-DQA1*0103-DQB1*0607, DRB1*1302-DQA1*0102-DQB1*0605,
      DRB1*1305-DQA1*0102-DQB1*0605 and DRB1*1305-DQA1*0103-DQB1*0603 were observed in
      the population from the island of Krk.

PMID- 10646232
TI  - Dermatoglyphic analysis in bipolar affective disorder and schizophrenia-
      "continuum of psychosis" hypothesis corroborated?
AB  - Dermatoglyphic features are thought to be indicators of events in the early
      embryonal stages. They might also be associated with the developmental disorders
      of the central nervous system (CNS) including schizophrenia. Dermatoglyphic
      features of 92 male patients with bipolar affective disorder (BPAD) (unipolar
      depression and schizoaffective psychosis were excluded from the study) were
      compared with those of 195 males with schizophrenia (SCH) and both with those of
      200 male controls (control group-CG). DSM-III-R criteria were used for the
      diagnostic evaluation. Quantitative analysis showed only one statistically
      significant difference between BPAD and SCH patients groups, regarding the c-d
      ridge count of the left hand. The canonical discriminant analysis did not permit
      correct classification (only 59.23% of cases were correctly classified) between
      BPAD and SCH. Numerous quantitative dermatoglyphic features of both BPAD and SCH
      differed significantly from those of the control subjects. Finger ridge counts as
      well as palmar ridge counts were markedly lower in BPAD and SCH as compared to
      the controls. These findings are not in contradiction with the hypothesis
      claiming that psychoses are a set of diverse expressions (due also to
      noninherited factors) of a single underlying entity.

PMID- 10646233
TI  - Intellectual performance of chronic schizophrenic patients.
AB  - Intellectual characteristics of 116 male chronic schizophrenic patients were
      investigated by using the Quick's test of intelligence. Indirectly, by this test
      the thinking of examinees was analysed. The examinees were divided into age
      groups and differentially diagnostic groups. According to age, they were divided
      into three groups: from 25 to 40, from 41 to 50, and from 51 to 60 years. There
      were four differentially diagnostic groups: paranoid, catatonic, and hebephrenic
      patients and patients with schizophrenia simplex. The study has shown that the
      intelligence of chronic schizophrenic patients, divided into age groups, was
      significantly different. The average IQ of patients from 25 to 40 years was 82.9,
      from 41 to 50 years 67.4, and from 51 to 60 years 52.0. The intelligence of
      examinees divided into differentially-diagnostic groups was also significantly
      different. The average IQ of paranoid patients was 74.3, of catatonic patients
      64.8, of hebephrenic patients 59.2, and of those with schizophrenia simplex 57.4.
      Most cases with IQ = 0 related to the group with schizophrenia simplex. The
      willing-instinctive personality sphere and perceptual disturbances in chronic
      schizophrenic patients appear to exert a significant influence on their
      intellectual characteristics.

PMID- 10646235
TI  - PTSD and alcoholism.
AB  - PTSD is the development of symptoms after a distressful response. 52.20% of the
      respondents suffering from PTSD used to drink either moderately or excessively
      during the war. Some of their alcoholism stems from the pre-war period. According
      to our researches, more than one fifth (22.92%) of the respondents with PTSD
      consume alcohol more than they used to before the war. PTSD is frequently
      associated with chronic alcoholism as a kind of "self-healing". Alcoholism
      problem is particularly unfavourably reflected on the family of a PTSD patient,
      whose quality of life is already poor, due to their basic disease. Treatment of
      alcoholism with PTSD patients is rather demanding; emerging of PTSD is noticeable
      with a part of the staff who treat chronic alcoholism; what is noticed was the
      similarity in the intensity and frequency of the stressful responses, which is
      proportional to the one noticed with the staff treating AIDS patients. Chronic
      alcoholics are the source of strong and repetitive traumas for those who try to
      treat them. That is why the concern for the counter-transference responses is
      important while treating alcoholism.

PMID- 10646236
TI  - The potential role of hypocortisolism in the pathophysiology of PTSD and
      psoriasis.
AB  - Different physical, chemical and psychological stressors can provoke a unique but
      different endocrine response involving activation of the hypothalamo-pituitary
      adrenal (HPA) axis. Inability of adequate compensatory reaction can lead to many
      disorders. The aim of our study was comparison of cortisol values in diseases
      provoked by various stressors. Our investigation included 34 posttraumatic stress
      disorder (PTSD) patients, as an example of disorder caused by extremely strong,
      acute stressful stimulus, 19 psoriatic patients, as an example of chronic stress
      stimulus and 17 healthy volunteers. In each patient we determined 24-hour urinary
      cortisol, serum cortisol at 8 a.m. and 5 p.m., and cortisol in dexamethasone
      suppression test by the standard radioimmunoassay (RIA) method. PTSD patients
      showed lower urinary 24-hour cortisol values, (361 +/- 28 nmol/24 h), "stronger"
      circadian rhythm of serum cortisol (595 +/- 57 nmol/l at 8 a.m. and 242 +/- 23
      nmol/l at 5 p.m.) and attenuated suppression of cortisol in dexamethasone
      suppression test (197 +/- 45 nmol/l) in comparison to healthy volunteers (590 +/-
      87 nmol/24 h urine, 590 +/- 32 nmol/l at 8 a.m., 402 +/- 31 nmol/l, and < 86
      nmol/l in dexa test). Psoriatic patients showed markedly lower 24-hour cortisol
      values (150 +/- 98 nmol/24 h), even in comparison to PTSD patients, then serum
      cortisol values (404 +/- 138 nmol/l at 8 a.m., 187 +/- 80 nmol/l at 5 p.m.) and
      enhanced suppression of cortisol (23 +/- 5 nmol/l). The model of attenuated
      feedback inhibition in PTSD patients shows that they are unusually reactive to
      stress and represents an alternative model of acute stress reaction to extremely
      strong stressful stimulus. Unusually low cortisol values in psoriatic patients
      correlate to our hypothesis that in chronic stress-related disease, as psoriasis
      is, exists, by still undefined mechanism, altered HPA axis function, which is
      obviously incompetent to realise its immunoregulatory function, so
      consequentially, clinical signs of psoriasis persist.

PMID- 10646234
TI  - An integral approach to the victims of war.
AB  - Contemporary psychotherapy is of integral nature. It is a part of integral
      medicine and of the integral viewpoint in science. Integrity is the opposite of
      polarity. There can be no doubt about it, sub-specialisation deepens the insight,
      simultaneously narrowing the efficiency of any activity. Integration is mandatory
      if we are to approach the victims of the Patriotic war in Croatia. Biological,
      psychological, social, philosophical and religious standpoints of an individual
      and a group of facilitators make the appropriate form of that approach. This is
      why education of facilitators has been directed towards integral way of thinking.

PMID- 10646237
TI  - Epidemiology of coeliac disease in children in one Croatian county: the
      cumulative incidence over ten-year period and the way of clinical presentation
      (Part I).
AB  - Coeliac disease is a permanent intolerance to gluten, producing small-intestinal
      lesions. Its incidence in European countries varies from 1:400 to 1:2000, while
      there are no such epidemiological data for Croatia. Therefore, we investigated
      the incidence of coeliac disease for ten-year period in one well-defined region.
      Also, data concerning age at diagnosis and symptoms at the disease onset were
      collected. The cumulative incidence was 1.9:1000 life-births. The disease
      presented typically in more than 60% of cases. In 65% of patients, symptoms
      appeared during the first 2 years of life, while, when diagnosed, 45% were below
      2 years. Also, it was shown that coeliac disease presented significantly later in
      children diagnosed during the last five years (p < 0.05). In conclusion, coeliac
      disease in Croatia is more frequent than previously suspected. It presents early,
      mostly with classical symptoms, although a tendency towards later ages of
      diagnosis was observed during the last few years.

PMID- 10646238
TI  - Minimally invasive surgery in the field of gynecologic oncology.
AB  - The aim of this paper was to present the results in minimal invasive surgery in
      the field of gynecologic oncology at General hospital Zabok, Croatia. 381
      laparoscopic procedures were performed between 1994 and 1998. There were 263
      operations of the benign adnexal masses, and 107 operations due to benign tumors
      of corpus uteri (there were 18 LAVH, 12 LH and 77 TLH). There were 11
      laparoscopic operations due to carcinoma (1 ovary, 6 corpus and 4 cervix).
      Operations were: 3 LAVH (laparoscopically assisted vaginal hysterectomy), 5 TLH
      (total laparoscopic hysterectomy) with pelvic lymphadenectomy, 1 LAVH with pelvic
      lymphadenectomy, 1 coelio Shauta operation with laparoscopic pelvic
      lymphadenectomy and paraaortal lymphadenectomy, and 1 laparoscopic adnexectomy.
      Among laparoscopic procedures in 370 patients operations were successfully
      performed as planed, while in 11 patients it was necessary to switch to
      laprotomy. Among serious complications of laparscopic operations it is necessary
      to note 2 lesions of the ureter and 1 lesion of the bladder. Laparoscopic
      lymphadenectomies were performed successfully; there were no serious early or
      late postoperative complications. There was no operative mortality. Even though
      many authors claim that laparoscopic operations in the field of gynecologic
      oncology are safe and have the same results as in open surgery, patients benefit
      from shorter recovery and better quality of life during laparoscopic procedures.

PMID- 10646239
TI  - Ovarian cancer and ovulation induction drugs--is there a link?
AB  - Screening for ovarian cancer in a group of women with induced ovulations was
      encouraged by recently reported controversies about a possible association
      between the use of ovulation induction drugs and the increased risk of ovarian
      carcinoma. Transvaginal color Doppler ultrasonography was applied in screening
      for early stage ovarian malignoma in 110 asymptomatic women who received an
      ovulation induction therapy for infertility. Already reported standard parameters
      for discriminating malignant from benign flows, such as resistance index RI <
      0.40, pulsatility index PI < 1 and morphological score (borders, cyst quality,
      septate areas, papilla and ovarian tissue echogenicity) were used. Screening
      included 110 women and was carried out from April 1, 1198 to March 31, 1999.
      Seven examinees had abnormal ovarian findings. The finding spontaneously
      regressed in five of them, one underwent surgery for a persistent cyst with a
      benign pathohistologic diagnosis, and one was diagnosed with early stage ovarian
      malignoma. RI < 0.40 was reported in one patient (0.9%) with a morphologically
      suspect finding and a pathohistologically confirmed malignoma, PI < 1 was found
      in 40 subjects or 36.4%, while malignoma was demonstrated in one case alone. The
      results showed the advantage of RI over PI in discriminating malignant from
      benign structures. The association between the use of ovulation stimulation drugs
      and the increased risk of ovarian carcinoma remains unproved and also challenges
      new dilemmas. The paper cautions against undesirable, potentially serious long
      term effects of the use of ovulation induction agents. Additional trials should
      therefore be performed including a long-term prospective follow-up of women with
      induced ovulations.

PMID- 10646240
TI  - Qualitative dermatoglyphic traits in ovarian cancer patients: a case-control
      study.
AB  - The authors investigated the correlation between the occurrence of certain
      qualitative dermatoglyphic traits and the susceptibility to ovarian cancer, using
      the case-control design. A sample of 168 diseased cases, treated at the
      University Department of Gynecologic Oncology in Zagreb, Croatia between 1996
      1997 was compared to 200 healthy females, investigated at the Institute for
      Anthropological Research in Zagreb. The results showed significant differences
      between ovarian cancer cases and healthy controls regarding the frequency of
      arches on the fingers of both hands (10-11% vs. 4-5%, respectively, p < 0.05),
      and of characteristic patterns on the palms of right hand (33% vs. 54% in 3rd
      interdigital space (IS), p < 0.001; 39% vs. 47% in 4th IS, p < 0.05) and of the
      left hand (42% vs. 58% in 4th IS, p < 0.001; 24% vs. 34% in hypothenar, p <
      0.01). Although probably neither very sensitive nor specific, these findings
      could still be used in addition to other diagnostic procedures, as a rough
      screening method in early detecting of ovarian cancer.

PMID- 10646241
TI  - High frequencies and grade expressions of Carabelli's trait in a sample of the
      Croatian population.
AB  - Although it is generally accepted that Europeans exhibit the highest frequencies
      of Carabelli's trait (70-90%), these values represent the expression of all
      possible morphological grades. When only a well-defined trait expression is
      considered (grades 5th, 6th and 7th), the frequency is much lower, not more than
      19.2% for the 5th grade, and significantly less for the 6th and 7th grades. Our
      observations based on the study of the Croatian (Central European) populations
      show the highest frequencies for grade of the trait (exceeding 23%). Comparative
      data for European or European derived populations demonstrate significant
      variation in grade expression. While the previously published data suggest that
      the highest grade of the trait expression does not exceed 10%, our figures show
      the highest yet known frequency of a well-defined trait.

PMID- 10646242
TI  - The influence of tooth wear on root canal dimensions.
AB  - The objective was to investigate the relations between tooth wear and root canal
      dimensions. The experimental group comprised 100 cuspids (canines), 50 of which
      had advanced abrasion and 50 were without it The dimensions of root canal were
      investigated at the light microscope level in order to define their vestibulo
      oral and mesio-distal diameters in all three thirds. In the groups of teeth
      without abrasion the MD diameters of root canaliculi in their cervical thirds
      were greater than in the teeth with advanced abrasion. In the apical third the MD
      diameters of canaliculi were highly variable in teeth with no signs of abrasion.
      In the group of teeth with abrasion the MD and VO diameter values of the cervical
      thirds were significantly smaller than in the group of teeth without abrasion. In
      the mid-thirds the values of MD diameters were highly variable in the group of
      teeth with abrasion, whereas the VO diameter values were much greater than in the
      teeth without abrasion. As regards to the apical thirds, the VO diameter values
      were greater than in the control teeth. The data presented herewith contribute to
      better knowledge about tooth wear and are highly useful in restorative and
      reconstructive dental procedures.

PMID- 10646243
TI  - Chronology, dynamics and period of primary tooth eruption in children from
      Zagreb, Croatia.
AB  - The aim of the present paper is to determine the beginning, order, median time,
      termination, dynamics, continuity and intensity of the primary tooth eruption, as
      well as its calendar, in a sample of children from Zagreb, Croatia. The study
      included 1288 children. All subjects were classified in one-year age groups. In
      the examined group, the continuity of tooth eruption occurs from 4.2 months to
      41.5 months, i.e., for a period of 37.3 months. Each particular tooth has its own
      dynamics of eruption (V5-V95) which on the average amounts to 14.35 months (14.92
      months in boys and 13.79 months in girls). The continuity of eruption is 35.6
      months in boys and 38.9 months in girls. The dynamics of eruption is 14.82 months
      in boys and 13.79 in girls. The termination of tooth eruption is similar for both
      sexes.

PMID- 10646244
TI  - Influence of prolonged stress on cerebral hemodynamics.
AB  - The author has investigated the impact of psychological and socio-economic
      factors on cerebral hemodynamics and development of cerebrovascular disease
      (CVD). A group of 120 war sufferers with signs of post-traumatic stress disorder
      and adaptation disturbances, and 120 persons of the control group with no
      traumatic war experience have been studied. The blood flow velocity and various
      parameters of spectral frequency analysis have been measured, using the method of
      transcranial doppler sonography (TCD). A greater number of hemodynamical changes
      has been found in the group of subjects than in the control group (p < 0.05), in
      which increase of vasospasm is statistically significant probably as a result of
      predomination of the sympathetic system stimulation and nicotinic effect on the
      brain blood vessels. Flow disturbances are relatively more frequent in older
      subjects, which suggests the rapid development of the atherosclerotic process.
      The results suggest that exposure to prolonged stress and bad socio-economic
      factors, through different neurobiological mechanisms, increased the risk for
      stroke.

PMID- 10646245
TI  - Cytomegalovirus disease as a possible etiologic factor for early atherosclerosis.
AB  - A group of 284 patients who underwent orthotopic heart transplantation between
      April 1986 to June 1991 and who were followed up for at least five years was
      analyzed in this paper. Patients were divided into three groups according to the
      presence or absence of cytomegalovirus infection or disease: patients without
      infection, patients with serologycaly proven infection and patients with
      cytomegalovirus disease. The analysis of survival was performed with respect to
      all major factors that influence survival: age and sex of a donor and a
      recipient, number of rejection episodes, perioperative ischemic time and
      pulmonary vascular resistence. A recipient's age was shown to be a significant
      factor. Patients who experienced at least one episode of cytomegalovirus disease
      had significantly worse long-term survival compared to those with the infection
      only or without the infection. That difference was caused by the increased
      incidence of coronary atherosclerosis, which caused deaths in patients with a
      previous episode of cytomegalovirus disease. A possible mechanism responsible for
      this phenomenon is discussed.

PMID- 10646246
TI  - The corrected Q-T interval in the elderly with urban hypothermia.
AB  - During winter time in the period from 1993 to 1998, 18 elderly patients: 11
      female and 7 male aged 65-88 years, were treated because of hypothermia. Rectal
      temperature on admission was 20-34.5 degrees C. Ten patients suffered from
      moderate hypothermia (35-32 degrees C), and eight suffered of severe hypothermia
      (< 32 degrees C). Arterial hypotension was recorded in 7, and shock in 11
      patients. In all of them, and in 18 controls, an electrocardiogram was analyzed
      with the special reference to the corrected Q-T interval. Decompensated metabolic
      acidosis was observed in 7/8 patients with severe hypothermia and in 4/10 with
      moderate hypothermia. Among patients with moderate hypothermia, sinus tachycardia
      was present in 2, sinus bradycardia in 2, idioventricular rhythm in 2 and atrial
      fibrillation in 4/10 patients. In patients with severe hypothermia, sinus
      tachycardia was present in 2, sinus bradycardia in 3, idioventricular rhythm in
      one, and atrial fibrillation in 2/8 patients. In moderate hypothermia Osborn's or
      Tomaszewski's J wave was present in 7/10, and it only appeared in 3/10 patients;
      in severe hypothermia it was present in 6/8 and only appeared in 2/8 patients.
      The corrected Q-T interval in the group with hypothermia ranged 0.450-0.688 s, in
      the control group 0.343-0.444 s. The X minimum (s) in the group with hypothermia
      was 0.508 +/- 0.079, in the control group it was 0.371-0-139 s, and the
      difference was statistically significant (p < 0.001). The X maximum (s) in the
      group with hypothermia was 0.576 +/- 0.067 s, in the control group 0.390 +/-
      0.019 s, and the difference was also statistically significant (p < 0.0001). In
      both groups the most significant prolongation of the corrected Q-T interval in
      the majority of patients was found in anteroseptal leads. The dispersion of the
      corrected Q-T interval in the group with hypothermia was 87.19 +/- 28.44 ms, in
      the control group it was 32.06 +/- 8.94 ms, and the difference was statistically
      significant (p < 0.001).

PMID- 10646247
TI  - Analysis of changes in indicators of functional and motor readiness of female
      basketball players within one-year training cycles.
AB  - The basic goal of this work was the evaluation of functional and motor
      preparedness of 13 top female basketball players during a one-year training
      cycle. Across of the six time points the preparedness of subjects was measured by
      means of a twelve-test battery measuring the basic and specific motor and
      functional abilities. The experimental training program was the yearly training
      macrocycle with all its components and duration. The differences among individual
      measurements in the space of twelve basic and specific functional and motor
      variables were analyzed by the statistical procedures in the framework of
      discriminant analyses. In comparison to the first measurement, the players
      achieved better results in the second, third, fourth, fifth and sixth
      measurements. On the multivariate level, only the analysis of differences between
      the first and third measurements indicated statistically significant differences.
      It can be concluded that the training process executed during the course of the
      preparation and competition periods (the transitional period was excluded from
      the analysis) induced positive changes.

PMID- 10646248
TI  - Set of criteria for the actual quality evaluation of the elite basketball
      players.
AB  - The paper comprises a proposition of nineteen criteria for the actual quality
      (situation-related efficiency/performance) evaluation in the elite basketball
      players (seven criteria for the efficiency on defence and twelve for the
      efficiency on offence) regarding all the playing positions. Coaches and other
      practitioners connected to the domain of basketball could utilize this set of
      criteria for the individual and team aspects of the performance follow-up and
      assessment in players throughout their sports career, from the cadettes' to the
      senior selections. Proposed set of criteria is the pressumption for the exact
      scientific and expert approach to the basketball performance (situation-related
      efficiency) evaluation and prediction--criterion variable. Weighting factors
      (coefficients of significance) for each criterion in relation to the playing
      positions should be determined on the next stage of developing a system of the
      performance evaluation criteria.

PMID- 10646249
TI  - Development of aerobic endurance and repetitive strength in special army unit
      members.
AB  - A sample of 25 subjects, members of a Croatian Army special unit, mean age 22
      years, underwent a 4.5-month specially programmed kinesiologic training. The aim
      of the study was to determine the treatment effects on the development of aerobic
      endurance and repetitive strength as a basis for the development of the
      capacities needed for acting in urgent combat situations. A battery of nine
      variables for evaluation of aerobic endurance and repetitive strength was used on
      four occasions at 6-week intervals. Discriminant functions of differences in the
      variables between the measurements showed the changes in the capabilities to be
      ever more pronounced after each of the treatment phases. After the first phase of
      training, changes in the variables of aerobic endurance were more pronounced than
      in the repetitive strength variables. The second phase of training was followed
      by comparable changes in both aerobic endurance and repetitive strength
      variables, whereas the third phase of training entailed greater changes in the
      repetitive strength variables than in aerobic endurance.

PMID- 10646250
TI  - Endemic goitre and plasmatic levels of vitamins A and E in the school-children on
      the island of Krk, Croatia.
AB  - A total of 1975 school-children on the island of Krk aged 7-19 years of life were
      included in this study. The purpose was to establish the goitre status and
      plasmatic level of vitamins A and E in the examined children with the enlarged
      thyroid gland. The goitre prevalence was 29.8%. The average plasmatic values of
      vitamins A and E in the children with enlarged thyroids were statistically
      significantly lower from the reference values. Mentioned goitre prevalence at the
      level of moderate and heavier endemic goitre speaks on behalf of alimentary
      iodine deficiency. But the goiter examinations suggested the idoine deficiency
      not to be the only etiological factor of goitre on the island of Krk. Lower
      average plasmatic values of vitamins A and E in the examined with the enlarged
      thyroids referred to this fact to a certain degree.

PMID- 10646251
TI  - Anthropological measurements of the skeleton and parathyroid glands growth during
      fetal development.
AB  - The article presents the investigation of histomorphological differentiation and
      growth of parathyroid glands in human fetus from the second to the ninth lunar
      month. The longer and the shorter diameter of these glands were measured. The
      obtained values are compared with the development and the growth intensity of the
      skeleton (biparietal head diameter and femoral length of a fetus from lunar
      months 3 to 9) and with the role of the placenta in the mentioned processes. The
      results of our investigation show the concordance of the skeletal growth with the
      development and histomorphological differentiation of these glands. The factors
      involved in these processes point out the complex relationship between the mother
      and fetus during osteogenesis, expressed on the hormonal level, in mineral
      metabolism and placental activity.

PMID- 10646252
TI  - Development of acetabulum after closed reduction in developmental hip dysplasia.
AB  - The radiographic study of acetabulum development after closed reduction of 87
      congenitally dislocated hips in 64 patients who were treated between 1980 and
      1990 was conducted retrospectively. An average patient's age at the moment of
      closed hip reduction was 16 months (range between 6 to 24 months). On the
      average, patients were 16 months old (range between 6 to 24 months) at the moment
      of closed hip reduction. Development of bony acetabulum was followed for 8 years
      by measuring the AC angle. According to the age at the moment of closed reduction
      patients were sorted into three groups, the first group from 6 months to 12
      months old (39 hips), the second group from 12 to 24 months old (28 hips) and the
      third group from 24 to 36 months old (20 hips). At the beginning of the treatment
      mean values of the AC angle in the first group were 37.2 degrees +/- 3.31
      degrees; in the second group 39.7 degrees +/- 3.2 degrees; and in the third group
      43.8 degrees +/- 2.7 degrees. The final values of the AC angle in the first group
      were 14.7 degrees +/- 3.21 degrees, in the second group 21 degrees +/- 3.02
      degrees; and in the third group 24 degrees +/- 3.76 degrees. Normally and mildly
      dysplastic hips were achieved in 80.5% treated hips, while in 19.5% treated hips
      medium and serious dysplasia retarded. The acetabulum development in dysplastic
      hip after retained stable concentric reduction was the same as in the normal hip.
      The operative reconstruction of acetabulum should not be done before the third
      year of life.

PMID- 10646253
TI  - The use of scientometric parameters for the evaluation of scientific
      contributions.
AB  - This paper deals with the application of scientometric parameters in the
      evaluation of scientists, either as individuals or in small formal groups. The
      parameters are divided into two groups: parameters of scientific productivity and
      citation parameters. The scientific productivity was further subdivided into
      three types of parameters: (i) total productivity, (ii) partial productivity, and
      (iii) productivity in scientific fields and subfields. These citation parameters
      were considered: (i) impact factors of journals, (ii) impact factors of
      scientific fields and subfields, (iii) citations of individual papers, (iv)
      citations of individual authors, (v) expected citation rates and relative
      citation rates, and (vi) self-citations, independent citations and negative
      citations. Particular attention was payed to the time-dependence of the
      scientometric parameters. If available, numeric values of the world parameters
      were given and compared with the data about the scientific output of Croatian
      scientists.

PMID- 10646254
TI  - When school is out: analysis and recommendations.

PMID- 10646255
TI  - America's schoolchildren: past, present, and future.
AB  - To provide a context for the articles in this journal issue, which focus on
      programs for children in elementary and middle school, this article depicts the
      cohort of children who were between 5 and 14 years old in the 1990s and compares
      them with their counterparts earlier in the century. It reports their numbers,
      overall and by racial and ethnic heritage; the makeup, employment, and economic
      status of their parents; and the time they spend in school. The article examines
      changes in these demographics and characteristics of school-age children with an
      eye to the effect that these trends may have on public attitudes toward children
      and youths, and on support for government funding to keep young people safe and
      to promote their development.

PMID- 10646256
TI  - The development of children ages 6 to 14.
AB  - The years between 6 and 14--middle childhood and early adolescence--are a time of
      important developmental advances that establish children's sense of identity.
      During these years, children make strides toward adulthood by becoming competent,
      independent, self-aware, and involved in the world beyond their families.
      Biological and cognitive changes transform children's bodies and minds. Social
      relationships and roles change dramatically as children enter school, join
      programs, and become involved with peers and adults outside their families.
      During middle childhood, children develop a sense of self-esteem and
      individuality, comparing themselves with their peers. They come to expect they
      will succeed or fail at different tasks. They may develop an orientation toward
      achievement that will color their response to school and other challenges for
      many years. In early adolescence, the tumultuous physical and social changes that
      accompany puberty, the desire for autonomy and distance from the family, and the
      transition from elementary school to middle school or junior high can all cause
      problems for young people. When adolescents are in settings (in school, at home,
      or in community programs) that are not attuned to their needs and emerging
      independence, they can lose confidence in themselves and slip into negative
      behavior patterns such as truancy and school dropout. This article examines the
      developmental changes that characterize the years from 6 to 14, and it highlights
      ways in which the organization of programs, schools, and family life can better
      support positive outcomes for youths.

PMID- 10646257
TI  - Successful parenting in high-risk neighborhoods.
AB  - Impoverished inner-city neighborhoods in the United States are threatening
      contexts for the development of youngsters during middle childhood and
      adolescence. Nevertheless, some African-American families living in such
      neighborhoods succeed in protecting their children from the risks of "the
      streets" and launch them on paths toward achievement. Using quotes and
      ethnographic material from many studies, this article illustrates some of the
      parenting strategies that help inner-city African-American youths to overcome
      risks and achieve success.

PMID- 10646258
TI  - Cultural brokers: helping Latino children on pathways toward success.
AB  - Latino children in elementary and middle school not only experience developmental
      changes and confront the risks and adventures held by neighborhoods, they must
      also juggle the values and expectations of two cultures as they navigate their
      own pathways toward success. Integrating the results of a series of studies
      focused on the children of Mexican-American immigrants in California, this
      article discusses ways that teachers, parents, siblings, and program staff can
      help young Latino students succeed in U.S. schools and live according to their
      parents' values.

PMID- 10646259
TI  - Neighborhoods of southern California children and families.
AB  - Middle childhood is a time when children move beyond the boundaries of family to
      explore the neighborhood, forge their own relationships with friends and
      neighbors, and have experiences independent of their parents. Depending on the
      character of the surrounding community, parents are more or less comfortable
      allowing unfettered exploration by their children. This article reports a study
      of families with 9- and 10-year-olds in an array of southern California
      neighborhoods, showing close links between parent perceptions of their
      neighborhoods, the rules they impose on their children, and the children's
      experiences and social skills.

PMID- 10646260
TI  - After-school child care programs.
AB  - When the public, elected officials, and child advocates focus on the risks and
      opportunities inherent in after-school hours, discussions quickly hone in on the
      benefits that after-school programs might offer. This article points out,
      however, that parents and children consider a wide variety of options for the
      after-school hours. Children may be with a parent or relative, they may go to
      lessons or play sports, they may spend time alone or with friends. For many
      children, this pattern of activities is reflective of their families' resources
      and neighborhood surroundings as well as their own needs and interests. Drawing
      on recent studies, this article documents children's experiences in different
      settings, discusses the variable quality of after-school programs, and indicates
      how program participation and exposure to self-care can affect children's
      adjustment in elementary school.

PMID- 10646261
TI  - After-school programs for low-income children: promise and challenges.
AB  - Children's out-of-school time, long a low-level source of public concern, has
      recently emerged as a major social issue. This, in turn, has heightened interest
      in the heterogeneous field of after-school programs. This article provides a
      profile of after-school programs for low-income children, focusing on supply and
      demand, program emphases, and program sponsors and support organizations. It also
      discusses the major challenges facing the field in the areas of facilities,
      staffing, and financing. Details and examples are drawn from the ongoing
      evaluation of a specific after-school program initiative called MOST (Making the
      Most of Out-of-School Time), which seeks to strengthen after-school programs in
      Boston, Chicago, and Seattle. Looking ahead, the article highlights the pros and
      cons of options for increasing coverage to reach more low-income children,
      strengthening programs, expanding funding, and articulating an appropriate role
      for after-school programs to fill in the lives of low-income children.

PMID- 10646262
TI  - Where need meets opportunity: youth development programs for early teens.
AB  - Early adolescence is a time of burgeoning independence, autonomy, and focus on
      peers. It is also a time when individual interests, skills, and preferences
      become salient to young people. Not surprisingly, out-of-school programs designed
      to capture the interest of early teens are diverse in focus and varied in
      structure, ranging from sports teams to drop-in recreation centers, from museum
      apprenticeships to mentoring relationships between an individual teen and an
      adult. This article describes the array of various organizations that offer
      programs and services for youths in their early teens. It explains the philosophy
      of positive youth development that has emerged as a unifying theme in this long
      standing but newly self-conscious field. Principles of best practice are
      reviewed, as are five key implementation challenges: increasing participation by
      youths; expanding access to programs, especially in low-income communities;
      improving funding; evaluating program effectiveness; and coordination with other
      youth services. The article closes with a discussion anticipating the new
      opportunities that accompany the attention and funding now going toward positive
      youth development programs that enrich the lives of young people through informal
      learning.

PMID- 10646263
TI  - The role of the school in children's out-of-school time.
AB  - As the primary community institution in the lives of children, schools have much
      to contribute to plans for addressing the needs of today's youngsters during the
      time when classes are not being held. In recent years, demands have escalated for
      after-school child care, educational enrichment, and safe havens that also foster
      positive youth development. Many programs that respond to these needs are housed
      in school buildings. Some are operated by the schools, some by community-based
      organizations, and others by partnerships between schools and outside groups. New
      public funding for after-school programs often flows through the school system.
      This article reports the prevalence of school-based programs and discusses
      extracurricular activities, child care and extended-day programs, enrichment
      programs, and ambitious efforts to transform the schools into full-time community
      hubs offering something for residents of all ages. Implementation challenges
      accompany program expansion, and this article also examines major issues that
      arise in school-based programs: governance, space, program quality, funding, and
      accountability. If these programs fulfill their promise, the school of the future
      may, indeed, be open extended hours for the enrichment of the children and the
      sustenance of the family.

PMID- 10646264
TI  - The policy climate for school-age child care.

PMID- 10646265
TI  - The role of schools when school is out.

PMID- 10646266
TI  - Federal support for youth development.

PMID- 10646267
TI  - The policy climate for early adolescent initiatives.

PMID- 10646268
TI  - Children in self-care.

PMID- 10646269
TI  - When school is out. A selected bibliography.

PMID- 10646270
TI  - Special topic section on microtechniques, microsensors, microactuators, and
      microsystems.

PMID- 10646271
TI  - Integrating microfabricated fluidic systems and NMR spectroscopy.
AB  - The philosophy of miniature total analysis systems (mu-TAS) hinges on the
      integration of multiple chemical processing steps and the means of analyzing
      their results on the same miniaturized system. We have constructed chip-based
      capillary electrophoresis (CE) devices equipped with an integrated planar radio
      frequency detector coil used for nuclear magnetic resonance spectroscopy (NMR).
      Separations were accomplished in the devices, but satisfactory NMR spectra could
      only be obtained from samples of high concentration. The relative sensitivity is
      explained and the scaling law dichotomy of CE and NMR explored.

PMID- 10646272
TI  - Perspectives on MEMS in bioengineering: a novel capacitive position microsensor.
AB  - We describe a novel capacitive position sensor using micromachining to achieve
      high sensitivity and large range of motion. These sensors require a new
      theoretical framework to describe and optimize their performance. Employing a
      complete description of the electrical fields, the sensor should deviate from the
      standard geometries used for capacitive sensors. By this optimization, the sensor
      gains a twofold increase in sensitivity. Results on a PC board 10x model imply
      that the micromachined sensor should achieve a sensitivity of less than 10 nm
      over 500-micron range of travel. Some bioengineering applications are addressed,
      including positioning of micromirrors for laser surgery and dose control for
      implantable drug delivery systems.

PMID- 10646273
TI  - A portable microsystem-based telemetric pressure and temperature measurement
      unit.
AB  - This article shows how a fully implantable stand-by device for measuring
      intracorporal pressure and temperature under normal conditions can be
      implemented, consisting of a sensor element combined with a transcutaneous
      telemetric interface. One further point of interest is automatic event
      recognition in order to capture special signal components in an emergency
      situation. Therefore, signal processing and waveform analysis are exigent, first
      to observe the measured signal in realtime on a portable unit, and second to
      process the data offline on a stationary unit.

PMID- 10646275
TI  - Going into the next millennium.

PMID- 10646274
TI  - Aligned microcontact printing of micrometer-scale poly-L-lysine structures for
      controlled growth of cultured neurons on planar microelectrode arrays.
AB  - We describe a method for producing high-resolution chemical patterns on surfaces
      to control the attachment and growth of cultured neurons. Microcontact printing
      has been extended to allow the printing of micron-scale protein lines aligned to
      an underlying pattern of planar microelectrodes. Poly-L-lysine (PL) lines have
      been printed on the electrode array for electrical studies on cultured neural
      networks. Rat hippocampal neurons showed a high degree of attachment selectivity
      to the PL and produced neurites that faithfully grew onto the electrode recording
      sites.

PMID- 10646276
TI  - A new catheter design using needle electrode for subendocardial RF ablation of
      ventricular muscles: finite element analysis and in vitro experiments.
AB  - Radio-frequency (RF) cardiac ablation has been very successful for treating
      arrhythmias related with atrioventricular junction and accessory pathways with
      successful cure rates of more than 90%. Even though ventricular tachycardia (VT)
      is a more serious problem, it is known to be rather difficult to cure VT using RF
      ablation. In order to apply RF ablation to VT, we usually need to create a deeper
      and wider lesion. Conventional RF ablation electrodes often fail to produce such
      a lesion. We propose a catheter-electrode design including one or more needle
      electrodes with a diameter of 0.5-1.0 mm and length of 2.0-10 mm to create a
      lesion large enough to treat VT. One temperature sensor could be placed at the
      middle of the needle electrode for temperature-controlled RF ablation. From
      finite element analyses and in vitro experiments, we found that the depth of a
      lesion is 1-2 mm deeper than the insertion depth of the needle and the width
      increases as we increase the diameter of the needle and the time duration. We
      showed that a single needle electrode can produce a lesion with about 10-mm width
      and any required depth. If a wider lesion is required, more than one needle with
      suggested structures can be used. Or, repeated RF ablations around a certain area
      using one needle could produce a cluster of lesions. In some cases, a catheter
      with both conventional electrode and needle electrode at its tip may be
      beneficial to take advantage of both types of electrode.

PMID- 10646277
TI  - Finite element analyses of uniform current density electrodes for radio-frequency
      cardiac ablation.
AB  - The high current density at the edge of a metal electrode causes hot spots, which
      can lead to charring or blood coagulation formation during radio-frequency (RF)
      cardiac ablation. We used finite element analysis to predict the current density
      distribution created by several electrode designs for RF ablation. The numerical
      results demonstrated that there were hot spots at the edge of the conventional
      tip electrode and the insulating catheter. By modifying the shape of the edge of
      the 5-mm tip electrode, we could significantly reduce the high current density at
      the electrode-insulator interface. We also studied the current density
      distribution produced by a cylindrically shaped electrode. We modified the shape
      of a cylindrical electrode by recessing the edge and filled in a coating material
      so that the overall structure was still cylindrical. We analyzed the effects of
      depth of recess and the electrical conductivity of the added material. The
      results show that more uniform current density can be accomplished by recessing
      the electrode, adding a curvature to the electrode, and by coating the electrode
      with a resistive material.

PMID- 10646278
TI  - Dependence of apparent resistance of four-electrode probes on insertion depth.
AB  - The apparent resistance of a finite-thickness layer measured with a four
      electrode plunge probe depends on the electrode insertion depth, electrode
      spacing, and layer thickness, as well as the resistivity ratio of an underlying
      layer. A physical model consisting of air, a saline solution layer, and an agar
      layer simulates the real situation of resistivity measurement. The saline layer
      represents the finite-thickness layer whose resistivity is to be measured by a
      plunge electrode probe, and the agar layer represents an underlying perturbing
      layer. A micropositioner controls the insertion depth of the four electrodes into
      the saline solution. With the apparent resistance measured on a semi-infinite
      thickness layer of saline solution as standard, measurement results show
      decreasing apparent resistance and increasing error with increasing electrode
      insertion depth. This information is important for correct measurement of
      myocardial resistivity in vivo and in vitro.

PMID- 10646279
TI  - A multichannel continuously selectable multifrequency electrical impedance
      spectroscopy measurement system.
AB  - There is increasing evidence that alterations in the electrical property spectrum
      of tissues below 10 MHz is diagnostic for tissue pathology and/or
      pathophysiology. Yet, the complexity associated with constructing a high-fidelity
      multichannel, multifrequency data acquisition instrument has limited widespread
      development of spectroscopic electrical impedance imaging concepts. To contribute
      to the relatively sparse experience with multichannel spectroscopy systems this
      paper reports on the design, realization and evaluation of a prototype 32-channel
      instrument. The salient features of the system include a continuously selectable
      driving frequency up to 1 MHz, either voltage or current source modes of
      operation and simultaneous measurement of both voltage and current on each
      channel in either of these driving configurations. Comparisons of performance
      with recently reported fixed-frequency systems is favorable. Volts dc (VDC)
      signal-to-noise ratios of 75-80 dB are achieved and the noise floor for ac
      signals is near 100 dB below the signal strength of interest at 10 kHz and 60 dB
      down at 1 MHz. The added benefit of being able to record multispectral
      information on source and sense signal amplitudes and phases has also been
      realized. Phase-sensitive detection schemes and multiperiod undersampling
      techniques have been deployed to ensure measurement fidelity over the full
      bandwidth of system operation.

PMID- 10646280
TI  - Theoretical predictions of the optimal monophasic and biphasic defibrillation
      waveshapes.
AB  - The truncated decaying exponential waveshape has become the de facto standard for
      implantable cardiac defibrillators. However, the optimal defibrillation waveshape
      with respect to delivered energy remains unknown. To this end, this study has
      derived the theoretically optimal waveshapes for monophasic and biphasic
      defibrillation shocks as predicted from a lumped-component model of cardiac
      tissue in conjunction with the "charge-banking" and "charge-burping" hypotheses
      of defibrillation. These derivations predict that a truncated ascending
      exponential waveshape--with a shock time constant, tau s, always equal to the
      underlying tissue time constant, tau m--minimizes the delivered energy required
      for defibrillation. These predictions are qualitatively consistent with available
      experimental data. Thus, to the extent that "charge-banking" and "charge-burping"
      are assumed to be valid and accurate models of defibrillation, these derivations
      identify the theoretical "gold standards" of defibrillation waveshapes requiring
      minimum delivered energy.

PMID- 10646281
TI  - A new approach to uncover dynamic phase coordination and synchronization.
AB  - Phase attractive maps are an essential mechanism of multi-stable systems such as
      found in coupled neuronal oscillators. An essential feature of this type of
      dynamic nonlinear coordination is dynamic phase synchronization. The
      identification of dynamic phase synchronizations is complicated due to changing
      frequency ratios of synchronized intervals, other nonstationarities, and noise.
      In order to overcome these problems the momentary phase relations and their
      statistics were analyzed by several authors. In this way phase synchronizations
      also in chaotic and noisy oscillating systems could be uncovered. We propose a
      novel method which avoids one essential limitation of these approaches, namely
      the necessity of presetting particular frequency ratios of interest. The proposed
      novel method was validated by its application to a simulated driven neuronal
      generator during the transition period between different synchronization modes
      and to dynamically coupled components of sympathetic nerve discharges.

PMID- 10646282
TI  - Artifact reduction in magnetoneurography based on time-delayed second-order
      correlations.
AB  - Artifacts in magnetoneurography data due to endogenous biological noise sources,
      like the cardiac signal, can be four orders of magnitude higher than the signal
      of interest. Therefore, it is important to establish effective artifact reduction
      methods. We propose a blind source separation algorithm using only second-order
      temporal correlations for cleaning biomagnetic measurements of evoked responses
      in the peripheral nervous system. The algorithm showed its efficiency by
      eliminating disturbances originating from biological and technical noise sources
      and successfully extracting the signal of interest. This yields a significant
      improvement of the neuro-magnetic source analysis.

PMID- 10646283
TI  - Multiscale characterization of chronobiological signals based on the discrete
      wavelet transform.
AB  - To compensate for the deficiency of conventional frequency-domain or time-domain
      analysis, this paper presents a multiscale approach to characterize the
      chronobiological time series (CTS) based on a discrete wavelet transform (DWT).
      We have shown that the local modulus maxima and zero-crossings of the wavelet
      coefficients at different scales give a complete characterization of rhythmic
      activities. We further constructed a tree scheme to represent those interacting
      activities across scales. Using the bandpass filter property of the DWT in the
      frequency domain, we also characterized the band-related activities by
      calculating energy in respective rhythmic bands. Moreover, since there is a fast
      and easily implemented algorithm for the DWT, this new approach may simplify the
      signal processing and provide a more efficient and complete study of the temporal
      frequency dynamics of the CTS. Preliminary results are presented using the
      proposed method on the locomotion of mice under altered lighting conditions,
      verifying its competency for CTS analysis.

PMID- 10646284
TI  - Adaptive estimation of residue signal for voice pathology diagnosis.
AB  - The use of noninvasive techniques to evaluate the larynx and vocal tract helps
      the speech specialists to perform accurate diagnose of diseases. In this study, a
      method to distinguish among 21 different pathologies using speech signals was
      developed. Through inverse filtering (Kalman and Wiener filters) of the voice
      signal, the residue was estimated and seven acoustic features were extracted from
      it to evaluate the laryngeal diseases. As time-invariant inverse filtering was
      used, the nonstationary nature of dysphonic voices was also considered. Together
      with the estimation of the acoustic features using a robust statistical method,
      this technique also allowed us to discriminate among pathologies with very close
      perceptual characteristics. The results from a Mann-Whitney test indicated that
      the best measurement for pathological discrimination was JITTER with 54.79%
      ability to cluster the voice types and the worst one was spectral flatness of
      residue (SFR) with 36.41%.

PMID- 10646285
TI  - Microwave life-detection systems for searching human subjects under earthquake
      rubble or behind barrier.
AB  - A new sensitive microwave life-detection system which can be used to locate human
      subjects buried under earthquake rubble or hidden behind various barriers has
      been constructed. This system operating at 1150 MHz or 450 MHz can detect the
      breathing and heartbeat signals of human subjects through an earthquake rubble or
      a construction barrier of about 10-ft thickness. The basic physical principle for
      the operation of a microwave life-detection system is rather simple. When a
      microwave beam of appropriate frequency (L or S band) is aimed at a pile of
      earthquake rubble covering a human subject or illuminated through a barrier
      obstructing a human subject, the microwave beam can penetrate the rubble or the
      barrier to reach the human subject. When the human subject is illuminated by a
      microwave beam, the reflected wave from the human subject will be modulated by
      the subject's body movements, which include the breathing and the heartbeat. If
      the clutter consisting of the reflected wave from stationary background can be
      completely eliminated and the reflected wave from the human subject's body is
      properly modulated, the breathing and heartbeat signals of the subject can be
      extracted. Thus, a human subject buried under earthquake rubble or hidden behind
      barriers can be located. This system has been tested extensively in a simulated
      earthquake rubble in the laboratory and also in a field test using realistic
      earthquake rubble conducted by a Federal Emergency Management Agency (FEMA) Task
      Force.

PMID- 10646286
TI  - Hemodynamic management of congestive heart failure by means of a multiple mode
      rule-based control system using fuzzy logic.
AB  - A rule-based system was designed to control the mean arterial pressure (MAP) and
      the cardiac output (CO) of a patient with congestive heart failure (CHF), using
      two vasoactive drugs: sodium nitroprusside (SNP) and dopamine (DPM). The
      controller has three different modes, that engage according to the hemodynamic
      state. The critical conditions control mode (CCC) determines the initial infusion
      rates, and continues active if the MAP or the CO fall outside of the defined
      criticality thresholds: an upper and a lower boundary for the MAP and a lower
      boundary for the CO. Inside the boundaries the control is performed by
      noncritical conditions control modes (NCC's), which are fuzzy logic controllers.
      If the CO is within normal range and the MAP is close to the goal range, then the
      MAP is driven using only SNP, in a single-input-single-output mode (NCC-SISO).
      Otherwise the NCC multiple-input-multiple-output is active (NCC-MIMO). The goal
      values for the controlled variables are defined as a band of 5 mmHg for the MAP
      and 5 mL/kg/min for the CO, but there is little concern for this application if
      the CO is too high (i.e., in practical terms the CO only needs to achieve a
      necessary minimum rate). The NCC-MIMO includes a gain adaptation algorithm to
      cope with the wide variety in sensitivities to SNP. Supervisory capabilities to
      ensure adequate drug delivery complete the controller scheme. After extensive
      testing and tuning on a CHF-hemodynamics nonlinear model, the control system was
      applied in dog experiments, which led to further enhancements. The results show
      an adequate control, presenting a fast response to setpoint changes with an
      acceptable overshoot.

PMID- 10646287
TI  - A rule-based phonocardiographic method for long-term fetal heart rate monitoring.
AB  - A real-time method for fetal heart rate (FHR) monitoring based on signal
      processing of the fetal heart sounds is presented. The acoustic method, which
      utilizes an adaptive time pattern analysis to select and analyze those heartbeats
      that can be recorded without artefact, is guided by a number of rules involving
      an introduced confidence factor on the timing prediction. The algorithm was
      implemented in a low-power portable electronic instrument to enable long-term
      fetal surveillance. A large number of clinical tests have shown the very good
      performance of the phonocardiographic method in comparison with FHR curves
      simultaneously recorded with ultrasound cardiotocography. Indeed, approximately
      90% of the time, the acoustic FHR curve remained inside a +/- 3 beats/min
      tolerance limit of the reference ultrasound method. The confidence was typically
      CF > 0.85. The acoustic method exceeded a +/- 5 beats/min limit relative to the
      ultrasound method approximately 5% of the time. Finally, no relevant FHR data was
      measured approximately 5% of the time.

PMID- 10646288
TI  - Three-dimensional reconstruction of transillumination tomographic images of human
      breast phantoms by red and infrared lasers.
AB  - A laser transillumination tomographic system, using red and near infrared lasers,
      to obtain cross-sectional images of human breast phantoms and human hand is
      proposed. The scanning assembly is consisting of upward, downward, rotational and
      pitch movements. The phantoms, made of paraffin wax, agar gel, and milk placed in
      a glass model, are embedded with abnormalities like blood, water, solid objects,
      and tissues. By illuminating the phantoms at various heights by either red or
      infrared laser the projection data are collected. Based on 64 projections the
      tomogram of each section is constructed. By volume visualization procedure
      applied to the tomograms the objects of varying composition embedded within the
      phantoms are detected and their size, shape, and location depth are determined.
      The cross-sectional image of a human hand obtained by this procedure further
      shows the possibility of application of this technique for imaging of organs.

PMID- 10646289
TI  - The effect of nerve cuff geometry on interference reduction: a study by computer
      modeling.
AB  - The effect of nonlinearity in the extrafascicular field in tripolar electrode
      cuffs on interference pick-up was investigated. It was concluded that the
      interference is sensitive to electrode separation, especially in short cuffs.
      This suggests that significant improvements can be obtained by placing the end
      electrodes a few mm from the cuff ends.

PMID- 10646290
TI  - Method of reduction of the number of driving system channels for phased-array
      transducers using isolation transformers.
AB  - Phased-array technology offers an incredible advantage to therapeutic ultrasound
      due to the ability to electronically steer foci, create multiple foci, or to
      create an enlarged focal region by using phase cancellation. However, to take
      advantage of this flexibility, the phased-arrays generally consist of many
      elements. Each of these elements requires its own radio-frequency generator with
      independent amplitude and phase control, resulting in a large, complex, and
      expensive driving system. A method is presented here where in certain cases the
      number of amplifier channels can be reduced to a fraction of the number of
      transducer elements, thereby simplifying the driving system and reducing the
      overall system complexity and cost, by using isolation transformers to produce
      180 degrees phase shifts.

PMID- 10646291
TI  - Group therapy program development: clinician-administrator collaboration in new
      practice settings.
AB  - Despite being practiced widely and applied to many conditions, group therapy is
      underutilized in some segments of the market. One important reason for its
      underuse is the lack of a model for group program development. Program
      development requires an integrated effort involving many disciplines. Effective
      collaboration between clinicians and administrators is an essential but
      underappreciated component in the development of group programs in independent
      practice associations.

PMID- 10646292
TI  - Meta-analysis of medical self-help groups.
AB  - Self-help groups (SHGs) may rival all other forms of treatment sometime within
      the next century (see Goodman & Jacobs article in "The Handbook of Group
      Psychotherapy," Wiley, 1994), though the "purist" model of SHGs seems inaccurate
      because many professionals are actually involved. Although traditional forms of
      group treatment have kept pace with empirical research (Fuhriman & Burlingame,
      "The Handbook of Group Psychotherapy," 1994), SHGs have not. In particular,
      medical SHGs, often promoted by hospitals as viable treatment alternatives, have
      no systemized database from which to draw conclusions about overall effectiveness
      compared to traditional group therapies. A preliminary assessment of this area is
      presented using a meta-analysis of articles culled from a comprehensive review of
      the literature from 1970 to 1997. Results indicate that although the
      posttreatment analysis produced no significant differences between active and
      control conditions, pre to posttreatment scores indicated that SHGs produced
      higher patient improvement when compared to the control condition. Future
      implications for research and use of medical SHGs are explored.

PMID- 10646293
TI  - Silence in group psychotherapy: a powerful communication.
AB  - Silence in a psychotherapy group, including leader, member, subgroup, and whole
      group silence, is a common phenomenon with many possible forms, uses, and
      meanings. Five common sources of silence in group psychotherapy are described:
      situational factors, individual dynamics, member-to-member interactions, group
      dynamics, and leader-related dynamics. Silence can reflect defenses or indicate
      conditions favorable to intensified group work. Silence, sometimes mistaken for
      psychological inactivity, should be viewed as significant communication.

PMID- 10646294
TI  - Hope and the inclination to be troublesome: Winnicott and the treatment of
      character disorder in group therapy.
AB  - While some group participants communicate about the problems in their lives by
      patterns of troublesome behavior, others may accommodate superficially to the
      needs of the group but feel an inner sense of futility and quiet desperation.
      Through use of Winnicott's paradoxical emphasis on the hope that is expressed
      within the "antisocial inclination" in all character disorders, the group may
      negotiate an adequate alliance for the discovery, containment, and exploration of
      the inclination to be troublesome in group in all participants. It may also
      provide supportive holding during the experience of affects that formerly were
      overwhelming, such as shame and unresolved guilty anxiety. This approach is
      applicable to the group as a whole as well as to individuals.

PMID- 10646295
TI  - Evidence-based medicine hits group therapy.

PMID- 10646296
TI  - Nurses' perceptions of the reliability of an automated medication dispensing
      system.
AB  - Automated medication dispensing systems (AMDS) technology is increasingly being
      implemented in health care facilities to reduce the risk of medication errors.
      However, the case study evidence of their effectiveness has so far been mixed. It
      has been suggested that the attitudes of nursing staff toward AMDS can be an
      important factor in influencing whether or not the technology will be
      successfully implemented. Nurses' attitudes toward AMDS were examined at
      Riverview Health Centre, a long-term care facility where the Meditrol automated
      dispensing system had been installed the previous year. It was found that nurses
      were generally distrustful of AMDS and skeptical that it had reduced medication
      errors. A number of technological, organizational, and social factors has been
      put forward to explain this distrust. In addition, the efforts of hospital
      administrators to raise nurses' confidence in the system's reliability were also
      delineated.

PMID- 10646297
TI  - Patient education resource assessment: project management.
AB  - To thrive in today's health care environment, hospitals are constantly striving
      to exceed their customers' expectations in delivering quality care in a cost
      effective manner. Meeting the patient educational needs of the consumer is one
      well-recognized aspect of quality care. Delivering quality care does not happen
      by chance; rather, it requires intense planning. Our academic medical center
      formalized this process by empowering professional staff from Nursing Development
      to develop and implement a patient education strategic plan. This article
      outlines the project management for the assessment phase of this strategic
      planning process. The findings were instrumental in outlining the future
      direction for patient education initiatives that will benefit both the patient
      and the organization.

PMID- 10646299
TI  - Consumer contributions in developing clinical practice guidelines.
AB  - Clinical practice guidelines are designed for use with consumers. However,
      consumers are rarely consulted about their development. This paper describes a
      research project to develop clinical practice guidelines for a community meeting
      to prevent and intervene with assaultive behavior. The research included consumer
      input from psychiatric inpatients. The two-phase approach with the consumers
      included a focus group, followed by survey research. Results, problems, and
      recommendations are presented.

PMID- 10646298
TI  - Evaluating advanced practice nursing care through use of a heuristic framework.
AB  - In our modification of a quality of care framework, we blended the labels of both
      models with respect to structure, labeling it structure/inputs. We then specified
      the types of characteristics in each of the 12 cells that can guide the
      evaluation of the areas of interest in a primary care system. The identification
      of characteristics of this conceptual framework and its subsequent application
      are important for a number of reasons. Specifically, this framework
      systematically organizes standardized data elements that are critical to
      monitoring and subsequently improving quality of care, guiding research,
      influencing policy, and developing nurse-sensitive patient outcomes.

PMID- 10646300
TI  - Is altered nutritional status the root cause of your clients' negative outcomes?
AB  - The impact of altered nutritional status is costly. Surgical patients have 2-3
      times the risk of complications, length of stay is extended by 90%, and charges
      are 35-75% higher. Risk factors are numerous; therefore, collaboration among all
      members of the health care team is required to impact patient outcomes
      positively. The purpose of this article is to review the significance of
      alteration in nutrition and its impact on patient outcomes. The article
      demonstrates two approaches to improve the quality of care given to clients with
      an identified alteration in nutritional status: a clinical research project and a
      quality improvement project.

PMID- 10646301
TI  - Reevaluating practice changes: return to standard precautions after an outbreak
      of multidrug-resistant Klebsiella oxytoca.
AB  - Change in medical practice is usually made to solve immediate problems. The
      continued use of these changes should then be reevaluated. Following an outbreak
      of K. oxytoca in our Neonatal Intensive Care Unit (NICU), glove use for all
      patient contact was mandated. We evaluated the need for continued glove use after
      resolution of the outbreak. No change in colonization patterns was seen after
      returning to standard precautions, and, as a secondary benefit, financial savings
      resulting from decreased glove use was realized. Following implementation of any
      practice change, routine reevaluation will help to determine when that change is
      no longer needed or beneficial.

PMID- 10646302
TI  - Communication styles that promote perceptions of collaboration, quality, and
      nurse satisfaction.
AB  - Interdisciplinary collaboration has been identified as an essential element of
      quality health care. Often, however, the degree of interdisciplinary
      collaboration in health care settings is limited. This failure to collaborate is
      usually not due to ill intent, but rather to a lack of collaboration skills. This
      article notes the need for very tangible, behaviorally specific ways to describe
      collaboration. Norton's Theory of Communicator Styles was used as a framework to
      identify the effect of three specific communication behaviors (styles)--namely,
      dominant, contentious, and attentive styles--on nurses' perceptions of
      collaboration, quality of care, or satisfaction with the interaction. Suggestions
      for teaching these three styles to health care professionals are provided.

PMID- 10646303
TI  - Gender and racial differences in mathematical performance.
AB  - The authors examined gender and racial differences in mathematics performance
      among 5th- and 8th-grade students in the United States. Math performance was
      assessed by scores on the math-concepts and math-computation sections of the
      California Achievement Test (CTB/McGraw-Hill, 1986) given at the end of the
      previous year. There were no significant gender differences, but in both grades,
      the White students scored significantly higher than the Black students. The
      racial differences were more pronounced in the scores for concepts than in the
      scores for computation. Responses to a parent questionnaire showed significant
      relationships between parents' self-reported math anxiety, parents' most advanced
      math course, and parents' education level in relation to the child's math
      performance. Differences in these relationships suggest that, although parents'
      beliefs and attitudes about math influence their child's math performance, the
      relationship is complex and may vary with race.

PMID- 10646304
TI  - Assertiveness among Japanese, Malaysian, Filipino, and U.S. white-collar workers.
AB  - The author investigated modes of self-expression as they reflect the quality of
      assertiveness among Japanese, Malaysian, Filipino, and U.S. white-collar workers.
      The author collected respondents' answers to a questionnaire consisting of 33
      items involving assertiveness related to modes of expression typical of the
      Japanese people. Several modes of expression considered specific to the Japanese
      people--styles of group-oriented behavior, younger people's courtesy toward older
      people, and the deference of the individual to group consensus--were also found
      among the Malaysian and the Filipino respondents. These behaviors were in
      contrast to those observed among the U.S. respondents.

PMID- 10646305
TI  - Pre-employment screening and applicants' attitudes toward an employment
      opportunity.
AB  - In an experimental simulation with Israeli participants, the author examined the
      influence of two aspects of pre-employment screening (duration of screening and
      type of testing) on applicants' attitudes toward a recruitment effort and toward
      a potential job. Testing that lasted longer led to more favorable attitudes. The
      participants considered knowledge testing, compared with personality testing,
      more job related, less invasive of privacy, and less sensitive to the amount of
      time spent testing.

PMID- 10646306
TI  - Facets of loneliness and depression among Chinese children and adolescents.
AB  - The authors examined the relation among different facets of loneliness and
      depression in a sample of 6,356 Chinese children and adolescents from Grades 4-9.
      Loneliness and depression were closely related among the primary (Grades 4-6) and
      secondary (Grades 7-9) students, both boys and girls. Although the different
      facets of loneliness were predictive of the various facets of depression, peer
      related loneliness and aloneness were more predictive of depression in both
      groups than was parent-related loneliness. The students in Grades 5 and 6 scored
      lower for loneliness but a little higher for depression than did the students in
      Grade 4. The students in Grades 8 and 9 scored higher than the students in Grade
      7 for loneliness and depression. The primary boys scored higher than the primary
      girls for both loneliness and depression. Among the secondary students, there was
      no difference between the scores of the boys and those of the girls for
      loneliness, but the boys scored lower than the girls for depression.

PMID- 10646307
TI  - Pattern of social interaction in societies of the Asia-Pacific region.
AB  - The authors developed an 18-item Social Interaction Inventory that yielded a
      factorial structure based on the 3 domains of social interaction: interpersonal,
      personal, and extrapersonal. They administered the inventory to samples from 15
      countries of the Asia-Pacific region (N = 146). The participants in the different
      cultural groups preferred to interact more within the interpersonal (in-group)
      domain as compared with the personal (individual) and extrapersonal (out-group)
      domains. The findings reflect a collective pattern, rather than an
      individualistic pattern, of social interaction in the societies of the Asia
      Pacific region.

PMID- 10646308
TI  - Gendered personality disposition and gender role attitudes among Israeli
      students.
AB  - In a sample of 204 Israeli university students, the author examined the
      relationship between gendered personality dispositions and 2 aspects of gender
      role attitudes: occupational sex typing and gender role stereotypes. Evaluations
      of occupational gender attributes were the least sex typed among participants in
      the androgynous group. At the same time, contrary to expectations, the
      participants in the undifferentiated and sex-typed groups had relatively
      stereotyped perceptions of occupations. However, no relationship was found
      between gendered personality disposition and stereotyped perceptions of gender
      roles. Regardless of gendered personality disposition, the women, compared with
      the men, had more liberal attitudes toward gender roles.

PMID- 10646309
TI  - Variables affecting racial-identity salience among African Americans.
AB  - The author clarified the African American racial-group identification process by
      addressing the issue of salience and its relationship to racial-group attitudes.
      A sample of 409 African American adults responded to surveys pertaining to their
      racial-group salience, racial-group attitudes, racial socialization, racial-group
      interaction, political activism, experiences of discrimination, and demographic
      data (e.g., sex, age, and income). The author tested 3 hypotheses: (a) Racial
      socialization and interaction with other African Americans are predictive of
      African American racial-identity salience; (b) discriminatory experiences are
      predictive of African American racial-identity salience; and (c) racial-identity
      salience is a stronger predictor of African American racial-group identification
      than are previously identified predictive variables (D. H. Demo & H. Hughes,
      1990; V. L. Thompson Sanders, 1991, 1995). The results supported the 1st and 3rd
      hypotheses.

PMID- 10646310
TI  - Psychological health and change in closeness in platonic and romantic
      relationships.
AB  - The authors investigated (a) whether increased closeness and decreased closeness
      of a relationship are associated with better and poorer psychological health,
      respectively; and (b) whether poorer psychological health is related to
      perceiving oneself or to perceiving the other person as primarily responsible for
      decreased closeness. A sample of English undergraduate students (52 female, 52
      male; 16-23 years of age) completed M. Rosenberg's (1965) Self-Esteem Scale, D.
      P. Goldberg's (1972) 12-item General Health Questionnaire, and a 6-item scale
      developed for this study to measure change in closeness and to identify the
      initiator(s) of the change. Decreased closeness was related to poorer
      psychological health in male participants' platonic relationships and in female
      participants' romantic relationships. Poorer psychological health was associated
      with (a) perceiving the other person as responsible for decreased closeness in
      male participants' platonic relationships and (b) perceiving both parties as
      mutually responsible for decreased closeness in female participants' romantic
      relationships.

PMID- 10646311
TI  - Effects of in-group bias on planned encounters of Jewish and Arab youths.
AB  - In a sample of 9th-grade Jewish (n = 118) and Arab (n = 100) students in Israel
      who participated in planned binational encounters, the author examined in-group
      biases as a function of (a) their perceptions of the encounter between the groups
      as interpersonal or as intergroup contact and (b) their views of the status of
      their respective national groups in Israel as legitimate and stable. In
      comparisons of the 2 encounter groups (of equal status), both groups showed in
      group biases. In comparisons of the national groups at large (of unequal status),
      the Arab students considered their group similar to the Jewish group, whereas the
      Jewish students rated their group more favorably than they rated the Arab group.
      For the Jewish, but not the Arab, students, in-group bias was contingent on
      simultaneous ratings (legitimate-illegitimate; stable-unstable) of the binational
      situation in Israel. The data support a 2-dimensional model rather than a 1
      dimensional model of intergroup-interpersonal definition of the encounter.

PMID- 10646312
TI  - Identity styles and hypothesis-testing strategies.
AB  - The author investigated the manner in which individuals with different identity
      styles evaluate information relevant to a trait hypothesis-testing task. Identity
      style refers to how individuals seek, process, evaluate, and use self-relevant
      information. In a sample of U.S. college students, the participants with
      normative identity styles displayed confirmatory biases that served to protect
      and preserve the hypothesis being evaluated. The students with informational
      identity styles also used confirmation-biased hypothesis-testing strategies. The
      participants with diffuse-avoidant styles did not discriminate between
      confirmatory and disconfirmatory information.

PMID- 10646313
TI  - Gender differences in attitudes toward wife battering.

PMID- 10646314
TI  - Referral patterns of physicians requesting brain MRI procedures: a community
      based study.
AB  - The results of the brain MRI procedures (n = 490) performed in a medium-sized
      community with a single MRI unit were reviewed. The non-neurologic medical
      practitioners ordered nearly as many brain scans as the neurospecialists (40.8%
      and 59.2% of the total scans respectively). The incidence of abnormal scans was
      29.5% for the group of non-neurospecialists and 39.3% for the neurospecialists. A
      fairly large proportion (26.7%; n = 131) of the scans were requested to evaluate
      headaches. Twelve patients (9.2%) with headaches but without clear neurologic
      localizing features showed intracranial abnormalities in their MRI scans. Some of
      the abnormalities observed in the brain MRI scans could have been detected by a
      CT procedure.

PMID- 10646315
TI  - Twenty year primary care graduate survey at the University of Mississippi Medical
      Center.

PMID- 10646317
TI  - Medicare hospice benefit

PMID- 10646318
TI  - Hospice criteria for diseases (other than cancer)

PMID- 10646316
TI  - Hospice in Mississippi: an update.

PMID- 10646319
TI  - The burden of diabetes in Pakistan: the national diabetes survey.

PMID- 10646320
TI  - Pakistan National Diabetes Survey prevalence of glucose intolerance and
      associated factors in North West at Frontier Province (NWFP) of Pakistan.
AB  - AIM: To estimate the prevalence of non-insulin dependent diabetes mellitus
      (NIDDM) and impaired glucose tolerance (IGT) and their relationship with age and
      obesity in a population based survey in the rural areas of NWFP, Pakistan.
      SETTING: Three villages, Pawakai, Reghi and Jhagra in NWFP were the target areas.
      METHODS: Cluster sampling of 1035 adults aged 25 years and above (207 men, 828
      women) was done. Oral glucose tolerance tests were performed and the diagnosis of
      diabetes and IGT was made according to WHO criteria. Height, weight and waist hip
      ratio of the study population were recorded. The Chi Square test was used to
      measure the association among the different variables. Basic demographic
      information from the subjects was collected by a physician using a standard
      questionnaire. RESULTS: The overall prevalence of NIDDM and IGT in both sexes was
      11.1% and 9.4%. The sex-specific prevalence of diabetes was 9.2% in men and 11.6%
      in women. Advanced age, positive family history of diabetes and obesity were
      associated with higher rates of diabetes. In both sexes high Waist Hip Ratio
      (WHR) was more closely associated with diabetes than was high Body Mass Index
      (BMI). CONCLUSION: The prevalence of diabetes mellitus in rural areas of NWFP is
      high and almost similar to that of Sindh and Baluchistan.

PMID- 10646321
TI  - Spectrum of Hodgkin's disease in children and adults: impact of combined
      morphologic and phenotypic approach for exclusion of "look-alikes".
AB  - OBJECTIVE: To determine the prevalence of Hodgkin's disease (HD) and its various
      subtypes in children and adults and assess the use of immunohistochemical (IHC)
      studies in confirming HD cases and excluding its close mimicries/look-alikes.
      MATERIAL AND METHODS: All 265 Hodgkin's disease cases diagnosed at The Aga Khan
      University Hospital, Karachi over the last 6 years (July 1991-July 1997) were
      included. Of these 219 were diagnosed on routine H&E examination while in the
      remaining 46 cases, diagnosis was made after a thorough IHC workup. (This group
      initially included 161 cases labelled as lymphoproliferative disorder with HD as
      one of the differentials). RESULTS: Out of a total of 265 HD cases (206) 78% were
      males and (59) 22% were females in a ratio of 3.5:1.26% (69) cases were < 15
      years while 74% (196) were > 15 years old. In both age groups, the commonest
      subtype proved to be Mixed Cellularity (MC) (60% of < 15 years old and 40% of >
      15 years old) followed by Nodular Sclerosing (NS) (20% of < 15 years old and 27%
      of > 15 years old). Lymphocyte Predominant (LP) and Lymphocyte Depleted (LD) were
      seen less frequently. With the help of IHC studies performed on 161 cases in
      which HD was part of the differential diagnosis, 46 were conclusively diagnosed
      as HD. In the rest of the cases the main different was Non-Hodgkin's Lymphoma
      (NHL) that accounted for 72 of the cases. CONCLUSION: This study shows that the
      most common sub-type of HD in our series in MC followed by NS. This study also
      suggests reasons why the more aggressive sub-type MC is predominant in Third
      world countries like ours compared to the better prognostic NS seen more in
      developed countries and why LP and LD are less and less commonly diagnosed.

PMID- 10646322
TI  - Postprandial glucose response to mango, banana and sapota.
AB  - OBJECTIVE: Mango and Sapota are two fruits indigenous to Indian subcontinent. The
      objective of this study was to evaluate postprandial blood glucose response to
      mango and sapota in comparison to banana in patients with diabetes mellitus Type
      2. METHOD: The plasma glucose response to mango, sapota and banana were
      determined in ten diabetic patients. Blood was tested at 0, 30, 60, 120 and 180
      minutes following the ingestion of test meal. RESULTS: The results showed that
      the blood glucose response to these three fruits was not different in terms of
      area under the curve and postprandial change in blood glucose from baseline.
      CONCLUSION: We conclude that glucose response to mango and sapota (fruits
      indigenous to Indian subcontinent) is no different from banana.

PMID- 10646323
TI  - Dietary practices and beliefs of patients with chronic liver disease.
AB  - OBJECTIVE: To study of the dietary practices and beliefs of patients suffering
      from chronic liver disease. SETTING: Two private tertcary care hospitals. METHOD:
      Fifty patients presenting to the Gastroenterology Clinics at the Aga Khan
      University Hospital and Baqai Hospital, with compensated liver disease and no
      other co-morbid condition which required dietary modifications, were enrolled in
      the study. Patients were interviewed regarding their current dietary practices
      using an open-ended questionnaire. RESULTS: The mean age of the patients was 48
      years and the majority were in relatively poor nutritional status. Four had BMI's
      < 18; 58% had Hb < 12 g/dl and 36% had albumin levels < 3 gm/dl. The percentage
      of patients avoiding various foods is as follows: meats 72%, fats and oils 64%,
      salt 42%, spices 34%, milk and milk products 28%, rice 20%. CONCLUSION: The most
      commonly cited reason for avoiding a given food was the advice of the family
      doctor, followed by advice by gastroenterologists, family and friends. Concepts
      from alternative medicine and continuation of dietary restrictions imposed during
      a decompensated phase also influenced intake. Compromised nutritional status is a
      poor predictor of clinical outcome in liver disease therefore it is important
      that gastroenterologists be proactive regarding nutritional counseling and both
      patients and their primary care physicians understand the importance of not
      imposing unnecessary restrictions on dietary intake.

PMID- 10646324
TI  - Acute alcohol intoxication: prevalence, recognition and medicolegal importance.
AB  - OBJECTIVE: To highlight the clinical criteria of persons who are accused of being
      under the intoxicating effect of alcohol brought to medicolegal officer by the
      police. METHODS: Included cases of alcohol intoxication reported to the
      medicolegal sections of three major government hospitals of Karachi i.e., Jinnah
      Post Graduate Medical Centre, Civil Hospital and Abbasi Shaheed Hospital,
      Karachi, during the period January to December 1996. RESULTS: During one year of
      study, 338 persons were brought from police stations all over Karachi to the
      medicolegal sections of the above three hospitals. Out of these, 260 persons were
      disposed off by the medicolegal officers by use of their clinical judgement, 78
      persons were suspected to be under the effect of alcohol intoxication and were
      referred to the chemical examiner where urine and blood analysis for alcohol was
      positive in 40 and negative in 38 cases. Only one fatal case of alcohol
      intoxication was reported to the chemical examiner and the viscera sent for
      examination were positive for alcohol. CONCLUSION: The incidence of the positive
      cases of alcohol intoxication on laboratory analysis was 11.8% while negative
      results were obtained in 11.2% cases, out of 23% cases referred to the chemical
      examiner, indicating that the bulk of cases i.e. 76.9% were disposed off on
      clinical criteria only which is a crude method of assessment of cases of acute
      alcohol intoxication.

PMID- 10646325
TI  - Heterotropic pregnancy.

PMID- 10646326
TI  - A 3 year old girl with fibrodysplasia ossificans progressiva.

PMID- 10646327
TI  - Novalgin in pain and fever.
AB  - OBJECTIVE: Efficacy, tolerability and safety of Dipyrone (Novalgin) in the
      management of pain and fever in children. SETTING: Open, non-comparative study in
      Ganga Ram Hospital, Lahore. SUBJECTS: Children (of both sexes) aged 3 months to
      12 years with oral temperature of 38.5 degrees C or more/complaining of pain due
      to various reasons. RESULTS: Sixty-two (66.7%) out of 93 who had fever showed
      good response, 24 (25.8%) showed satisfactory response and 7 (7.5%) showed
      unsatisfactory response to Dipyrone (Novalgin). CONCLUSION: Dipyrone (Novalgin)
      in a dose of 10-15 mg/kg/dose every 6-8 hrs. is effective and safe in the
      treatment of pain and fever in children.

PMID- 10646328
TI  - Lessons learnt from problem based learning and community based education.

PMID- 10646329
TI  - Synthesis and conformational analysis of 3-substituted derivatives of 1H, 3H
      pyrido[2,3-d]pyrimidin-4-one of expected depressive activity on central nervous
      system. Part II.
AB  - Two series of new 1-aryl piperazinylacetyl derivatives of 1H, 3H-pyrido[2,3
      d]pyrimidyn-4-one were synthesized. The compounds were prepared by
      chloroacetylation; when made to react with respective arylpiperazine, then
      yielded VIa-o. The structures of compounds VIa-o were analyzed by 1H and 13C NMR
      spectroscopy. For selected compounds, acute toxicity and anticonvulsant activity
      were determined.

PMID- 10646330
TI  - Bone and joint infections. Prompt care is needed.

PMID- 10646331
TI  - Health tips. Ocean water safety.

PMID- 10646332
TI  - New skin patch calms pain following shingles.

PMID- 10646334
TI  - Blood donation. A much-needed gift.

PMID- 10646333
TI  - Getting enough calcium may reduce stroke risk in women.

PMID- 10646335
TI  - Outdated medications. Toss out expired drugs.

PMID- 10646336
TI  - Cruise safety. Keep health needs in mind.

PMID- 10646337
TI  - I'm nearing 60. Do I still need Pap smears?

PMID- 10646338
TI  - My doctor says I need to restrict my salt intake. Do I need to be concerned about
      the amount of salt I'm getting from softened water?

PMID- 10646339
TI  - Outcome focused home healthcare.

PMID- 10646340
TI  - Downsizing--remember to do it right.
AB  - Downsizing is always difficult even in the best of circumstances. The key to
      downsizing is treating people the way you would expect to be treated, and
      offering some understanding and compassion. The end result can be employees who
      adjust quickly to this momentary crisis in their lives verses angry, bitter,
      employees who voice their anger and bitterness against your agency publicly and
      perhaps even in a court of law.

PMID- 10646341
TI  - Avoiding claims of patient abandonment--terminating services appropriately.

PMID- 10646342
TI  - Home telehealthcare services: their role in home care today.

PMID- 10646343
TI  - Benchmarks.

PMID- 10646344
TI  - Preparing for the future: tips for using OASIS now.

PMID- 10646345
TI  - OASIS implementation: choosing and working with a software vendor.

PMID- 10646347
TI  - No time for education? Creative teaching tools for educators.
AB  - The creative teaching methods discussed in this paper have been successfully
      integrated into orientation, mandatory education, and continuing education
      programs. The response to all of the creative teaching methods discussed has been
      very positive. Nursing staff appreciates the effort educator's take to
      communicate information effectively and increase learner satisfaction.

PMID- 10646346
TI  - Are you getting your share of Medicare managed care referrals?

PMID- 10646348
TI  - The 5-minute inservice. Understanding the ABCs of hepatitis.

PMID- 10646349
TI  - The home care manager and agency employees: a brief look at the Department of
      Labor and the Fair Labor Standards Act.

PMID- 10646350
TI  - Facing the need for computerization of the patient record.

PMID- 10646351
TI  - The value and impact of violence prevention training in a home healthcare
      setting.

PMID- 10646352
TI  - "Two steps forward, one back".

PMID- 10646353
TI  - Health of lesbian, gay, bisexual, and transgender youth.

PMID- 10646354
TI  - Parenting and preschooler attachment among low-income urban African American
      families.

PMID- 10646355
TI  - Development of the cerebral cortex: XII. Stress and brain development: II.

PMID- 10646356
TI  - Alternate child care, history of hospitalization, and preschool child behavior.

PMID- 10646357
TI  - Elective delayed reduction and no anesthesia: "minimal intervention management"
      for gastroschisis.

PMID- 10646358
TI  - Pediatric day surgery outcomes management: the role of preoperative anxiety and a
      home pain management protocol.

PMID- 10646360
TI  - Parental self-efficacy and asthma self-management.

PMID- 10646359
TI  - Red flags in common pediatric symptoms.

PMID- 10646361
TI  - Measuring physiological variables in nursing research.
AB  - Physiological indicators of health status are recommended for observational and
      intervention research with children, adolescents, and families. Sources of
      measurement error including those relevant to participants, the research
      protocol, and the specific physiological indicator must be identified and
      minimized. To this end, information presented is this column is designed to
      enhance the collection of accurate, reliable, and reproducible data with the
      ultimate goal of informing and enhancing evidence-based practice.

PMID- 10646362
TI  - Pediatric medical and health journals: Part 4.

PMID- 10646363
TI  - Is doctoral education in your future?

PMID- 10646364
TI  - Program evaluation. Assessing resource impact.

PMID- 10646365
TI  - Principles of child healthcare financing. Committee on Child Health Financing
      Academy of Pediatrics.

PMID- 10646366
TI  - Good luck and good management: the miracle escape.
AB  - This case study illustrates the importance of education and training in the early
      management of reverse trauma in the rural setting. It clearly demonstrates the
      importance of ensuring a safe approach including an outline for the appropriate
      management of electrocution.

PMID- 10646367
TI  - Trauma during pregnancy.
AB  - Injury to the pregnant woman evokes a certain amount of anxiety because of its
      infrequent occurrence and the complex implications. By definition, it constitutes
      a multitrauma and, throughout the resuscitation and assessment of the woman, it
      is important to remember that there are two patients. Of particular importance is
      that one of these patients must be resuscitated aggressively to save the other
      and, very occasionally, the baby has to be delivered to save the mother. Early
      transfer to an urban environment should be considered. The aim of the present
      paper is to provide an overview of the current management and issues in relation
      to trauma in pregnancy.

PMID- 10646369
TI  - The emergency medicine training needs of rural general practitioners.
AB  - This study aimed to identify the emergency medicine training needs of rural
      general practitioners (GPs) in the catchment area of the Hunter Rural Division of
      General Practice. The GPs were surveyed using a questionnaire in which they were
      asked about their confidence levels in a number of specific emergency medicine
      skills, and about the areas of emergency medicine that they saw as priorities for
      upskilling. More than a third of GPs who were responsible for on-call work at the
      hospital indicated that they had low levels of confidence in a number of their
      emergency medicine skills, in particular skills relating to paediatric
      emergencies, cardiovascular emergencies, and respiratory emergencies. These
      emergency medicine domains were also seen as high priorities for upskilling by
      the majority of the respondents. The study shows that rural doctors need the
      opportunity to access emergency medicine training that provides upskilling not
      only in the management of clinical problems, but also in practical procedures.

PMID- 10646368
TI  - The role of ultrasound in the assessment of the trauma patient.
AB  - Ultrasound assessment of the patient with blunt abdominal trauma will enhance
      diagnostic accuracy and facilitate decision making about the need for urgent
      surgery. Numerous studies have reported the role of ultrasound in the assessment
      of the trauma patient. Focused ultrasound has been shown to compare in
      sensitivity to diagnostic peritoneal lavage and is helpful in assessing the need
      for a laparotomy. Ultrasound is safe, cheap and portable. The investigation is
      non-invasive and painless. The trauma ultrasound scan can be completed in under 3
      minutes and should be performed during the initial trauma assessment. The
      technique is not difficult to learn. Advances in technology are likely to make
      portable ultrasound increasingly appropriate to rural clinical practice.
      Detection of haemoperitoneum will be more accurate when ultrasound is available
      in the early care of trauma on a 24 hour basis and, to achieve this, clinicians
      managing trauma will need to become competent in the application of the focused
      ultrasound exam.

PMID- 10646370
TI  - Patient satisfaction with nursing care in a rural and an urban emergency
      department.
AB  - This descriptive study was designed to describe and compare the level of patient
      satisfaction and explore differences and relationships of demographic variables
      with patient satisfaction in two emergency department patient populations in
      Victoria, Australia. The sample consisted of 103 rural and urban emergency
      patients. Tests for differences demonstrated that urban patients were more
      satisfied with nurse teaching behaviours (P = 0.017), with female patients at the
      urban hospital more satisfied with nurse caring behaviours (P = 0.026). An item,
      'The nurse performed his/her duties with skill' scored highest and had the lowest
      variability. Qualitative analysis of two open-ended questions regarding what
      respondents liked best about the experience and what could have made the
      experience better, produced four and six themes, respectively. Conclusions
      indicated the need for more research comparing rural and urban emergency patients
      and patients of different cultures.

PMID- 10646372
TI  - Rural health information workshop report.

PMID- 10646371
TI  - GP-based emergency response in rural areas: is there a need?
AB  - Rural general practitioners (GPs) traditionally provide the initial care for the
      very ill and severely traumatised in small and medium-sized rural hospitals. It
      has been said that these patients would be better managed in a level 1 trauma
      centre. The present paper will test this hypothesis and shows that the benefits
      of the expertise available in the large centres may be outweighed by the loss of
      life in the prehospital phase, most of which occurs before the arrival of the
      ambulance. General practitioner involvement would enhance the current early
      retrieval system. Very ill and severe trauma should be assessed and stabilised in
      the most appropriate local facility. Routine bypassing of local emergency medical
      services should be avoided. A national standard for training rural GPs in
      emergency management skills is needed. Emergency facilities and equipment must be
      maintained and improved throughout rural Australia. These facilities and their
      staff must be accredited so that the ambulance service can more appropriately
      determine its transport priorities.

PMID- 10646373
TI  - Neonatal resuscitation in the isolated setting.
AB  - This review attempts a practical guide to unscheduled resuscitation of the
      newborn in the isolated setting, where high-risk cases have been screened for,
      identified and referred for delivery in the tertiary care. Regarding airway
      management in this emergency, there is for the most part consensus in Australia,
      but this is less so for cardiovascular aspects. Material from the 'Advanced
      Paediatric Life Support' course, which offers definitive instruction in necessary
      techniques, has been used as a framework, with added material based on the
      Australian experience. Internationally, specific aspects of resuscitation are
      under review.

PMID- 10646375
TI  - Collaborative approach to social inequalities in health.

PMID- 10646374
TI  - An overview of distal radial fractures.
AB  - Fractures of the distal radius include a wide spectrum of fracture patterns. As
      well as involving the distal radius, these injuries can involve the wrist, the
      distal radio-ulnar joint and the distal ulna. The management of these injuries is
      consequently diverse, ranging from a plaster cast to advanced surgery. The
      principles of treatment are to reduce and maintain the reduction by restoring the
      radial height, volar tilt and intra-articular step. The acceptable reduction is
      to have radial height to within 2 mm of the ulnar, volar tilt greater than 0
      degree and intra-articular step less than 1 mm. The present paper reviews the
      current concepts in the diagnosis, management and complications of distal radial
      fractures.

PMID- 10646376
TI  - Where's the caring?

PMID- 10646377
TI  - Ophthalmic nurse run services.

PMID- 10646378
TI  - Designing a career pathway.
AB  - The aim of this article is to examine the concept of a career pathway and to
      consider the benefits that career planning can offer the perioperative
      practitioner. The article will: consider definitions of the term 'career'
      highlight specific factors that demand that nurses take a proactive approach to
      managing their careers conclude with a step by step approach to career design.

PMID- 10646379
TI  - Let's get positive about postoperative nausea and vomiting.

PMID- 10646380
TI  - Anxiety and the preoperative patient.

PMID- 10646381
TI  - Introducing a music programme to reduce preoperative anxiety.

PMID- 10646382
TI  - Music in theatres.

PMID- 10646383
TI  - International partnerships in perioperative nursing.

PMID- 10646384
TI  - All pierced up: managing body piercing in perioperative practice.

PMID- 10646387
TI  - Cochlea implantation.

PMID- 10646386
TI  - Anaesthesia: airway management.
AB  - In this month's Back to Basics series, Rachelle Griffiths provides the first
      article pertaining to anaesthetic practice. The topic is airway management, which
      is a fundamental aspect of preserving life. The anaesthetic practitioner must
      ensure that all the necessary equipment for airway management is available.
      Reading this article will not only provide this knowledge but it will also
      identify some of the observational factors that are present when difficulties are
      occurring. The six articles of the previous Back to Basics series, which was much
      appreciated, were written by Claire Campbell and Marion Taylor. Claire Campbell
      is Senior Clinical Nurse at the Operating Department, Royal Lancaster Infirmary
      in Lancaster; Marion Taylor is Practice Development Nurse at the Operating
      Department, Royal Free Hospital, London.

PMID- 10646385
TI  - Preoperative visiting in Wales.
AB  - There is clear evidence in the nursing literature that preoperative visits
      conducted by theatre nurses have a therapeutic benefit for surgical patients.
      However, it would appear that the actual uptake of this practice is limited
      (Wicker 1995). The aim of this study is to investigate the prevalence of
      preoperative visiting in Wales and to identify factors associated with its
      occurrence or non-occurrence.

PMID- 10646388
TI  - Emergence delirium: a literature review.

PMID- 10646389
TI  - A personal triumph.

PMID- 10646390
TI  - Organ donation--a review of the literature.
AB  - Organ harvesting is part of the practice of many perioperative nurses in general
      hospitals. It is difficult to treat as just another case because the outcome is
      so different to other surgery, and brings a much more intense level of emotional
      involvement. Add to this the fact that organ harvesting often takes place outside
      'normal' working hours, and that the staff providing facilities for donation are
      left with the body and the mess, it is evident that both the issue and the
      perioperative nurse's part in this practice require some special attention. This
      is the first of three excellent articles by Janet Bothamley, based on her wide
      ranging review of the literature covering theatre nurses' perceptions of organ
      retrieval. Consent and patients' rights, and brain stem death, will be dealt with
      in the subsequent articles.

PMID- 10646391
TI  - Problem based learning: an opportunity for theatre nurse education.
AB  - In my experience theatre nurses are always saying that student nurses just don't
      know enough anatomy, even with compulsory regular teaching of the subject in pre
      registration nurse education. Boud and Feletti (1997) say anatomy and other
      subjects are forgotten because when they are taught students do not perceive
      their relevance. Problem based learning (PBL) seeks to overcome this difficulty
      by integrating theory and practice. This article will describe problem based
      learning and give an example of a scenario used in this educational process. The
      benefits of a PBL theatre nursing course and the implications for theatre nurse
      education will be discussed.

PMID- 10646392
TI  - Anaesthesia: breathing management.
AB  - It is our intention in this series to make the basic principles of anaesthesia
      more understandable--particularly to those who do not have a relevant, post
      basic, qualification in the subject. I hope that these articles will interest and
      maybe encourage you to research more deeply into the subject. In this month's
      piece Rachelle Griffiths, an ODP now working at Great Ormond Street, describes
      the basics of breathing management and provides a bibliography for you to pursue
      some further reading.

PMID- 10646393
TI  - Musings on nursing as a calling.

PMID- 10646394
TI  - Prescribing guidelines based on a flexible scope of practice.
AB  - Nurse practitioners (NPs) are in demand nationwide as primary care providers both
      in the inpatient and outpatient settings. Lack of prescriptive privileges and/or
      a narrow scope of practice can be practice limiting. This article provides a
      written template for prescribing authority, generic scope of practice, and
      furnishing policy, including evaluative process, for nurse practitioners who wish
      to obtain prescriptive privileges. Developed at the Palo Alto Veterans Affairs
      Health Care System, these documents can be used by NPs nationwide. They can be
      adapted to each provider's unique practice, whether in the hospital, clinic, or
      private practice setting.

PMID- 10646395
TI  - Utilization of the acute care nurse practitioner in lung transplantation.
AB  - Acute care nurse practitioners (ACNPs) are uniquely positioned to serve the
      inpatient population and provide continuation of care as the patient is
      reintegrated into the community. Currently, there are many well-defined roles
      that can be expanded upon to utilize the skills of an ACNP. The lung transplant
      coordinator role is one example of an advanced practice position that lends
      itself toward evolution. ACNPs have an educational and clinical focus in caring
      for the acutely ill patient within the hospital setting. In addition, ACNPs have
      a working knowledge base in preventive care and basic outpatient management. This
      combination creates a situation by which the ACNP can comfortably manage an acute
      population in the hospital or at home. There are many new and exciting
      opportunities for ACNPs, as they are becoming more visible to the rest of the
      healthcare community.

PMID- 10646396
TI  - Acute upper gastrointestinal bleed: a case study.
AB  - Upper gastrointestinal (UGI) bleeding on a presenting symptom is of major
      significance for nurse practitioners in any clinical setting. Bleeding in the
      upper gastric tract is a symptom of a disease process rather than a disease in
      itself. UGI bleeding accounts for 300,000 hospitalizations annually. An astute
      knowledge of the pathophysiology and clinical presentations of UGI bleeding
      enables swift intervention and a reduction in morbidity and mortality rates. This
      article presents a case report of a white male in his fifties diagnosed with
      metastatic colon cancer and acute UGI bleeding and emphasizes the need for early
      screening and detection, disease education, and prompt interventions to minimize
      associated complications.

PMID- 10646397
TI  - Evaluation and conservative management of chronic lower extremity arterial
      disease.
AB  - Aging of the population has made atherosclerotic cardiovascular disease one of
      the most significant health problems in the United States. Primary care providers
      are often the first contact for persons presenting with symptoms of chronic lower
      extremity arterial disease. Accurate assessment can prevent erroneous referrals,
      unnecessary diagnostic studies, and added time and medical expense for patients.
      Understanding of the natural history and risk factors associated with chronic
      lower extremity arterial disease provides the foundation for developing a
      knowledgeable, comprehensive plan of care for patients. Through multidisciplinary
      collaboration and a strong commitment to patient education and support, care
      providers can enhance the quality of life for individuals with chronic lower
      extremity arterial disease.

PMID- 10646398
TI  - Provider endorsement: the strongest cue in prompting high-risk adults to receive
      influenza and pneumococcal immunizations.
AB  - Vaccination against influenza and pneumococcal disease could decrease the
      sickness, suffering, and death from flu and pneumonia, yet immunization rates for
      adults at highest risk remain less than Healthy People 2000's goal of 60%. This
      study examined the effect of an educational cue on vaccination acceptance,
      ascertained the most influential reasons for receiving vaccination, and
      determined to what extent prior influenza immunization affected repeat
      vaccination. Two brochures, one each for influenza and pneumonia, were
      disseminated to 52% of 463 participants residing in two rural Maine counties.
      Information was sought from all participants via an anonymous written
      questionnaire. An educational cue did not increase vaccination coverage in this
      high-risk sample. Provider recommendation was the most important reason adults
      received immunization. Prior vaccination was a strong predictor of present
      immunization status. This study suggests that practitioner endorsement can
      significantly decrease the morbidity and mortality associated with flu and
      pneumonia by improving immunization rates.

PMID- 10646399
TI  - Actual and perceived risk for chronic illness in rural older women.
AB  - Little is known regarding the risk perceptions of older women for the chronic
      illnesses for which they are at highest risk. The purpose of this study was to
      explore the actual and perceived risk for six chronic illnesses: coronary heart
      disease, cerebrovascular disease (stroke), breast and colorectal cancer,
      osteoporosis, and depression. In addition, the relationship of demographic
      characteristics of the women and their perceived and functional health status to
      actual risk factors and risk perception was studied. A convenience sample of 102
      rural women aged 65-91 answered a questionnaire on their actual and perceived
      risk for the chronic illnesses. As in younger samples, these older women
      generally underestimated their risk of disease. There was no relationship between
      demographics and risk perception, but there was a significant correlation between
      perceived health and functional status and risk perception. Only those actual
      risk factors associated with life experience were associated with increased
      perceived risk, supporting earlier findings that life experience has more
      influence on risk perception than the presence of actual risk factors per se.
      Based on the results of this study, clinicians should assume that older women
      patients are likely to underestimate their risk for common health problems.
      Clinicians are advised, therefore, in addition to regular evaluation of actual
      risk based on epidemiologic data, to probe their patients for information
      regarding their perception of risk and the basis of that perception. Combining
      information regarding perceived risk with actual risk data, the clinician can
      work with the patient to develop and implement an effective personalized risk
      management program.

PMID- 10646400
TI  - The Expanded Care for Healthy Outcomes (ECHO) Project: addressing the spiritual
      care needs of homeless men in recovery.
AB  - As the nation's homeless population continues to rise, new practice models will
      need to address the specific health care needs of the homeless while providing
      cost-effective wellness-oriented quality care. This article describes the early
      development of one such model. The Expanded Care for Healthy Outcomes (ECHO)
      Project is an interdisciplinary curriculum/practice model that explores the vital
      intersection of spiritual and primary care in promoting health among homeless
      guests at the Pine Street Inn Nurses Clinics in Boston, Massachusetts. The
      authors describe the incorporation of spiritual assessment and care in clinical
      practice with homeless men to maximize patients' physical, psychosocial, and
      spiritual wellness.

PMID- 10646401
TI  - Implementing a nurse information system in a nurse-managed primary care practice:
      a process in progress.
AB  - As part of a larger project, a nurse-managed primary care clinic (Valencia
      Pediatric and Family Practice) sought to implement a nursing information system
      for the purposes of (1) patient record keeping, (2) capturing advanced practice
      nursing interventions and outcomes and transforming them into standardized
      language, (3) project data management, and (4) evaluating advanced practice
      nursing care thereby improving and standardizing quality of care. This article
      represents the background information for selection of a data management system
      and early experiences of implementation.

PMID- 10646402
TI  - Profiles of editorial board members: old England to new England.

PMID- 10646403
TI  - Is it heart attack or is it GERD?

PMID- 10646404
TI  - Injuries to children in the United States related to trampolines, 1990-1995: a
      national epidemic.

PMID- 10646405
TI  - Roles of nonphysician clinicians as autonomous providers of patient care.

PMID- 10646406
TI  - A salute to preceptors.

PMID- 10646408
TI  - Clinical assessment of a breast mass: a case study.
AB  - The estimated 180,300 new cases of breast cancer that were diagnosed in the
      United States during 1998 represent only a small percentage of the breast masses
      discovered by women and their healthcare providers during the same year. Almost
      half of women who have regular menstrual cycles will experience a breast mass
      during their reproductive years; and from 50% to 90% of all women will encounter
      fibrocystic breast changes. Imaging (ultrasound and mammography) and manual
      palpation have been demonstrated to be the most useful methods of breast mass
      detection and evaluation. A woman's age and reproductive status are factors to be
      considered in the selection of a protocol for the clinical assessment of a breast
      mass. While a suspicious lesion warrants immediate physician referral, nurse
      practitioners have important roles to play in the identification, documentation,
      and appropriate follow-up of breast masses.

PMID- 10646407
TI  - Topical treatment of acne vulgaris for the nurse practitioner.
AB  - Managed care has encouraged primary care providers to expand their management
      capabilities to include those diseases traditionally referred to specialists.
      Acne vulgaris is a common skin disorder that makes up 20% of a dermatology
      practice. Acne can have significant psychosocial ramifications that may improve
      with treatment. Most acne patients have a mild to moderate grade of acne that can
      be successfully treated with topical therapy. Tools are provided for the
      diagnosis and assessment of acne, and a practical approach to treatment is
      offered.

PMID- 10646409
TI  - Storytelling as a teaching tool.
AB  - This article discusses the revival of the ancient use of storytelling as a
      teaching tool and how it can be used in teaching values and in promoting learning
      for nurse practitioner students and for clients of all ages. Stories are better
      able to illustrate values and may therefore have a greater impact on learning.
      Differences between stories and case studies are examined. Examples of stories
      the reader can use with students and clients are given.

PMID- 10646410
TI  - Assessment and diagnosis of elderly depression.
AB  - Elderly depression is a common problem seen in primary care in the United States.
      Unfortunately, primary care practitioners often do not recognize or diagnosis
      depression in the older population. There are serious negative consequences for
      the elder whose depression remains untreated. Depression in the elderly has a
      unique presentation, different from that in the younger population. This article
      presents information on assessment and differential diagnosis of the depressed
      elder. The clinical interview is the key piece in the assessment process.
      Laboratory screening is one part of the diagnostic process that can detect
      physiologic changes related to depression. An overview of the Agency for Health
      Care Policy and Research guidelines on diagnosing depression in primary care is
      presented.

PMID- 10646411
TI  - Fibromyalgia syndrome: a comprehensive approach to identification and management.
AB  - Fibromyalgia syndrome (FMS) is a common, chronic musculoskeletal pain disorder of
      unknown etiology seen predominately in women. It is recognized as an important
      clinical problem associated with high levels of functional disability, emotional
      distress, and utilization of several types of medical services. While widespread
      pain and the presence of multiple tender points characterize the dominating
      features, there are a large number of nonrheumatic symptoms and associated
      conditions that occur in a high frequency in this disorder. When the
      characteristic pattern of symptoms is recognized, FMS can be successfully managed
      by nurse practitioners with expectation of some improvement. The mainstays of
      management include patient education, medication, aerobic exercise, and physical
      therapy. An ongoing relationship with the patient and periodic follow-up are
      mandatory.

PMID- 10646412
TI  - Factors that influence job satisfaction of nurses in urban and rural community
      health centers in Cameroon: implications for policy.
AB  - There has been a growing recognition of work-related stress among nurses in
      Cameroon that has contributed to job dissatisfaction and high turnover. This
      study, which was conducted with 158 nurses in three major hospitals and three
      rural health centers in the Northwest Province of Cameroon, examined whether
      there were significant differences in job satisfaction between nurses in urban
      hospitals and rural community health settings in the six major components of the
      job: work, pay, promotions, supervision, co-worker relationships, and the job in
      general. A convenience sample of 158 staff nurses grouped into three categories
      (nurses' aides, registered nurses, and state registered nurses), volunteered to
      participate in this study. These nurses differ by level of educational
      preparation of 1, 2, and 3 years, respectively. The Job Descriptive Index
      questionnaires and the Job In General scales were used to measure job
      satisfaction. These data were analyzed with inferential statistics. Focus group
      interviews with 10 nurses were also done, and content analysis was used to
      analyze the data. The major findings indicated significant differences between
      job satisfaction and type of healthcare work setting, level of professional
      education, gender, years of service, and age group. These results are useful for
      nurse educators, administrators, and researchers in the formulation and
      implementation of effective health policies for nurses and health care
      organizations. This study also provided the groundwork for a future cross
      cultural study of nurses in the United States and Cameroon.

PMID- 10646414
TI  - The Y2K leap and other ponderables to investigate using Internet resources.

PMID- 10646413
TI  - Antibiotic resistance and the new plagues for the 21st century.

PMID- 10646415
TI  - Profiles of editorial board members: Massachusetts to California.

PMID- 10646416
TI  - The role of the triage nurse practitioner in general medical practice: an
      analysis of the role.

PMID- 10646417
TI  - Care of the obstetric patient in the traditional intensive care unit.
AB  - Obstetric patients have long been a source of fear for nurses in the intensive
      care unit (ICU) setting. Several hospitals have moved toward having obstetric
      ICUs, but most do not have the volume to justify such units, leaving the care of
      these patients to nurses in traditional ICU settings. Collaboration of care may
      occur, but it is still imperative that ICU nurses have a basic understanding of
      the physiologic changes and care necessary to provide optimal outcomes for
      obstetric patients. Physiologic changes of pregnancy and basic care for pregnant
      and immediate postpartum patients are reviewed.

PMID- 10646418
TI  - New trends in thermometry for the patient in the ICU.
AB  - Modern engineering and space-age technology introduce innovations in thermometry
      at a crucial time in critical care history. Today's assessment and care decisions
      are based, in part, on emerging scientific evidence about thermoregulatory
      responses. Accurate body temperature measurements and the correct interpretation
      of their meaning are crucial for competent care. Confusion exists as to which
      instrument or site is "ideal." Interpretation of temperature correlations,
      between temperature sites or without consideration of linearity, has little
      meaning outside the clinical context. This article discusses hemodynamic and
      thermal conditions influencing regional body temperatures along with instrument
      accuracy, reliability, linearity, precision, safety, comfort, and need for staff
      training.

PMID- 10646419
TI  - Gastric tonometry: early warning of tissue hypoperfusion.
AB  - Perfusion status of the critically ill and injured has, in the past, been
      assessed by indices such as blood pressure (BP), heart rate, and urine output.
      These indices represent global perfusion and may not reflect regional blood-flow
      abnormalities. These hypoperfused regions may lead to organ failure and
      subsequent death. The gastrointestinal (GI) tract remains one of these tissue
      beds that is extremely sensitive to low-flow states. Gastric tonometry is a
      noninvasive means in which these early symptoms of low flow may be monitored with
      early interventions to optimize tissue perfusion and patient outcome.

PMID- 10646420
TI  - Nutritional assessment of the critically ill patient.
AB  - Nutritional assessment can be incorporated into the assessments performed daily
      by the critical care nurse for every patient. Identification of nutritional
      deficits will lead to timely interventions and will facilitate recovery and early
      discharge. The metabolic responses to starvation and stress are reviewed, and
      bedside techniques for nutritional assessment are outlined. General guidelines
      for nutritional support and parameters for monitoring the effectiveness of
      nutritional therapies are defined.

PMID- 10646421
TI  - Neurologic monitoring in the ICU.
AB  - While structure of the central nervous system (CNS) is evaluated through
      diagnostic tests such as computed tomography or magnetic resonance imaging, CNS
      function requires special monitoring techniques. These techniques are
      particularly useful adjuncts to the clinical examination, especially in the
      critically ill patient. Monitoring techniques include intracranial pressure
      monitoring, cerebral blood flow monitoring, cerebral hemodynamic assessment, and
      electrophysiologic monitoring. Rationale and specific applications are unique to
      each technique. Nursing considerations focus on knowledge of rationale for
      monitoring, providing safe patient care, validating appropriateness of
      interventions based on monitoring, and investigating the relationship of
      monitoring to outcome.

PMID- 10646422
TI  - Outcomes management of mechanically ventilated patients: utilizing informatics
      technology.
AB  - This article examines an informatics system developed for outcomes management of
      the mechanically ventilated adult population, focusing on weaning the patient
      from mechanical ventilation. The link between medical informatics and outcomes
      management is discussed, along with the development of methods, tools, and data
      sets for outcomes management of the mechanically ventilated adult population at
      an acute care academic institution. Pros and cons of this system are identified,
      and specific areas for improvement of future health care outcomes medical
      informatics systems are discussed.

PMID- 10646423
TI  - Invasive hemodynamic monitoring: applying advanced technologies.
AB  - Critical care practice has greatly changed over the last three decades. This is
      partly due to the advent of the pulmonary artery catheter and subsequent advances
      in technologies associated with it. The key determinants of cardiac performance,
      pressure, flow, and volume, are assessed either directly or indirectly.
      Parameters that were once only available on an intermittent basis can now be
      obtained continuously. Addition of mixed venous oxygen saturation to the
      cardiorespiratory profile and other derived parameters provides the bedside
      clinician with important variables to assess the cardiorespiratory status of the
      critically ill.

PMID- 10646424
TI  - Glucose monitoring in the acutely ill patient with diabetes mellitus.
AB  - The Diabetes Control and Complications Trial (DCCT) clearly demonstrated that
      improved blood-glucose control results in the decreased occurrence and
      progression of microvascular complications. The progression of acute medical
      conditions, commonly found in hospitalized diabetic patients, are also related to
      glycemic control. Glycemic control in the hospitalized setting is measured by
      point-of-care blood-glucose monitors. These monitors provide immediate feedback
      so that subcutaneous or infused insulin can be adjusted in a more timely and
      physiologic manner. The practitioner must become familiar with some of the
      limitations of these systems to ensure the accuracy of blood-glucose results.

PMID- 10646425
TI  - The view within: the emerging technology of thoracic electrical bioimpedance.
AB  - With the increasing incidence of catheter-related sepsis and recognition of
      increased mortality and cost of care with pulmonary artery catheters, the need
      for a safe, cost-effective, and clinically accurate means of obtaining
      hemodynamic data has become evident. Through the technology of thoracic
      electrical bioimpedance (TEB), non-invasive hemodynamic monitoring is now
      possible with the BioZ.com, manufactured by CardioDynamics International
      Corporation. The BioZ.com provides continuous hemodynamic readings safely,
      accurately, and inexpensively. TEB is proving to be a valuable adjunct to patient
      assessment and treatment across multiple health care settings.

PMID- 10646426
TI  - Advanced practice nursing for congestive heart failure.
AB  - Congestive heart failure (CHF) is an enormous burden on society and the health
      care system. The role of the advanced practice nurse (APN) in CHF is multifaceted
      and combines inpatient, outpatient, and community patient care skills. Case
      management and quality management have been traditional focuses, with a high
      level of practice impact on patient care. Outcomes management in the APN role for
      CHF care is the future for measurable outcomes and maximum impact on
      organizational values. Because outcomes management is an evolving field for the
      APN, focus on a chronic disease such as CHF is a very valuable tool for
      implementation.

PMID- 10646427
TI  - Evolving role descriptions of the acute care nurse practitioner.
AB  - Currently, more than 1,200 advanced practice nurses have sought certification as
      acute care nurse practitioners (ACNPs). Surveys of practicing ACNPs have shown
      that the role is expanding in terms of practice settings and role components.
      This article reports on the results of ongoing survey with ACNPs that portray the
      role of the ACNP as an evolving career opportunity for advanced practice nurses.

PMID- 10646428
TI  - Advanced practice nursing and the role of the pediatric critical care nurse
      practitioner.
AB  - Advanced practice nursing, since its inception in the early 1960s, has constantly
      changed in an effort to establish standardized core graduate education,
      specialization of practice, and autonomy, now common in the 1990s. Nurse
      practitioners, nurse midwives, and certified registered nurse anesthetists have
      followed in the footsteps of the clinical nurse specialist by enhancing their
      practice through advanced education. Nurses in these advanced areas are
      graduating from established programs with a master's of science in nursing and a
      specialty in their chosen field. The pediatric critical care nurse practitioner
      is one such specialty. This article highlights the results of a national survey
      that described pediatric critical care nurse practitioner practice over a broad
      geographic area. With change as a constant, nurses will look to the future of
      advanced practice roles, which are ever changing, and continue to provide safe,
      quality care to patients.

PMID- 10646429
TI  - The role of advanced practice in today's infectious diseases.
AB  - The importance of the role of an advanced practice nurse in infectious diseases
      has been heightened by the human immunodeficiency virus/acquired immunodeficiency
      syndrome (HIV/AIDS) epidemic. The unique abilities that are part of the expanded
      role enable the advanced practice nurse to utilize tools learned as a nurse and
      combine them with advanced clinical skills to be a comprehensive care provider.
      The clinical management of the patient with HIV is complex and requires up-to
      date knowledge regarding the constantly changing science of the virus.

PMID- 10646430
TI  - Collaborative practice in the acute care setting.
AB  - As acute care nurse practitioners (ACNPs) become increasingly visible in tertiary
      care centers, clinical nurse specialists (CNSs) have begun to re-evaluate their
      unique contributions to patient care. While CNSs continue to be involved in
      indirect care provision, their direct care role is encountering increasing
      competition for the same patients from ACNPs. This article reviews the evolution
      of the ACNP and CNS roles and offers practical advice to both professionals on
      working together successfully, compatibility, and cohesively in an acute care
      setting.

PMID- 10646431
TI  - Clinical nurse specialist: role restructuring to advanced practice registered
      nurse.
AB  - This article recognizes challenges facing the traditional clinical nurse
      specialist (CNS) role and supports the merger of the nurse practitioner (NP) and
      the CNS into a hybrid advanced practice registered nurse (APRN). A historical
      review of each role is presented, with justification for role merger. The focus
      of the article is to present a personal account of this author's successful
      reengineering of a traditional cardiovascular CNS role to conform to a new state
      and institutional APRN model and ultimately to better serve a population of post
      myocardial infarction patients.

PMID- 10646432
TI  - Leadership for coordinated care: role of a project manager.
AB  - The use of clinical pathways as a method to improve outcomes for specific
      populations within health care organizations has become widely adopted. This
      article focuses on the role of a project manager in facilitating a wide range of
      outcomes. Through a quality improvement framework, interdisciplinary
      collaboration, and data-driven decision making, organizational performance can be
      enhanced. An advanced practice nurse is well suited to lead organizational
      improvement efforts aimed at optimizing the care delivery system to effectively
      meet expectations of all constituents.

PMID- 10646433
TI  - Personal journal of a surgical intensive care unit nurse practitioner.
AB  - This article explores one nurse practitioner's personal observations and
      experiences associated with developing the nurse practitioner role in a surgical
      intensive care unit.

PMID- 10646434
TI  - The role of the transplant advanced practice nurse: a professional and personal
      evolution.
AB  - Rapid changes in health care toward cost-effective managed care have resulted in
      the evolution of the transplant advanced practice nurse to address the care needs
      of a specific patient population. This article describes the evolution of this
      role at one institution. The specific responsibilities of the transplant advanced
      practice nurse are delineated, and phases of development for the experienced
      clinical nurse specialist entering the role as a novice nurse practitioner are
      identified and discussed.

PMID- 10646435
TI  - The education of advanced practice nurses: a contemporary approach.
AB  - The Advanced Practice Nursing of Adults and the Elderly graduate program at San
      Diego State University School of Nursing prepares experienced professional nurses
      with primary and specialized care (acute or critical care) knowledge and skills
      to deliver health care to adults and elders across practice settings as nurse
      practitioners and clinical nurse specialists. Emphasis is placed on health care
      that is research based and congruent with national standards of practice. This
      approach to graduate education is congruent with recommendations of professional
      nursing organizations and responds to the educational needs of professional
      nurses and the health care needs of adult and elders.

PMID- 10646436
TI  - Psychosocial implications of spinal cord injury.
AB  - Spinal cord injury (SCI) is a devastating event that has not only physical but
      also social and psychological ramifications for both the injured person and the
      family. Within one brief moment, a person's world will be changed forever. Like a
      ripple on the water, one injured family member affects the entire family system.
      This article will identify the social and psychological forces that impact the
      injured person's quality of life along with that of his or her family and the
      interventions that can be instituted by acute care personnel.

PMID- 10646437
TI  - Pediatric spinal cord injuries: a case presentation.
AB  - Spinal cord injuries (SCIs) in the pediatric population present a unique
      challenge to the caregiver in that both the physical injury and the growth and
      development issues need to be addressed simultaneously. Different types of
      injuries are anticipated than those seen in adults because of the developmental
      phases of the pediatric spinal cord. This article will review the differences
      between the pediatric and adult spinal cords, growth and development, and the
      types of injuries incurred by this population, followed by a case presentation.

PMID- 10646438
TI  - Sports-related spinal cord injuries.
AB  - Although a relatively small number of all injuries sustained while participating
      in sports occur to the spinal cord, the impact that these injuries make on the
      U.S. health care system is enormous. Critical care nurses, who work in the field
      of trauma, should be aware of the epidemiology and etiology of these injuries
      while providing therapeutic interventions. Additionally, an understanding of the
      classification of these injuries will be beneficial when providing education to
      the patient and family.

PMID- 10646439
TI  - The older patient with a spinal cord injury.
AB  - The most common cause of spinal cord injury (SCI) in older persons is falls,
      followed by motor vehicle crashes and pedestrian/motor vehicle crashes. Upper
      cervical injuries, particularly central cord syndrome, are prominent in the
      geriatric patient population. In addition, the mortality is higher, the
      complications are life threatening, the hospital stay is longer, and the cost of
      care is significantly increased for the older trauma victim.

PMID- 10646440
TI  - Spinal cord injury pathophysiology.
AB  - This article reviews the mechanisms and pathophysiology of spinal cord injury
      (SCI). It is clear that there are two entwined phases of injury: one that occurs
      concurrently with the insult and the other that is initiated immediately after
      trauma and lasts for several days to weeks. The mechanisms of primary injury are
      described in terms of hyperflexion, hyperextension, axial loading, and rotation.
      Secondary injury processes are addressed at systemic and cellular levels.
      Diagnosis of SCI is discussed with respect to plain radiography, computed
      tomography (CT), and magnetic resonance imaging (MRI). Clinical motor and sensory
      patterns of complete and incomplete SCI are described.

PMID- 10646441
TI  - Prehospital management of spinal trauma: an evolution.
AB  - OBJECTIVE: To discuss the past, present, and future prehospital management of
      patients who sustain acute spinal cord injury (SCI). DISCUSSION: Prehospital
      management of SCI has evolved during the past two decades. Current standards
      emphasize the immediate treatment of life-threatening injuries while
      simultaneously preparing for transport to the nearest, appropriate facility.
      Rapid extrication techniques, pharmacological intervention, airway management,
      treatment controversies, and future areas of study are discussed.

PMID- 10646442
TI  - Promising pharmacological agents in the management of acute spinal cord injury.
AB  - The search for a pharmacologic treatment of acute spinal cord injury (SCI) dates
      back to the 1960s. It was not until 1990 that the pharmacologic agent
      methylprednisolone demonstrated improved outcomes in humans. Methylprednisolone
      has shown superiority to placebo in humans in two large, multicenter trials, and
      is the standard of care thus far. Other potentially useful agents include
      tirilazad, ganglioside (GM-1), and naloxone. Additional studies are needed for
      these agents to determine the optimal dose and timing of administration.

PMID- 10646443
TI  - Traumatic spinal cord injury: an acute care rehabilitation perspective.
AB  - Traumatic spinal cord injury (SCI) can have a devastating effect on the patient,
      family members, and acute care staff. A multidisciplinary team effort is
      essential for the psychosocial support of the patient and family through the
      injury process. SCI rehabilitation management in the acute care setting will be
      reviewed along with the process for selecting an appropriate rehabilitation
      facility.

PMID- 10646444
TI  - Acute care management of spinal cord injuries.
AB  - Meeting the health care needs of the spinal cord-injured patient is an immense
      challenge for the acute care multidisciplinary team. The critical care nurse
      clinician, as well as other members of the team, needs to maintain a
      comprehensive knowledge base to provide the care management that is essential to
      the care of the spinal cord-injured patient. With the active participation of the
      patient and family in care delivery decisions, the health care professionals can
      help to meet the psychosocial and physical needs of the patient/family unit. This
      article provides an evidence-based, comprehensive review of the needs of the
      spinal cord-injured patient in the acute care setting including optimal patient
      outcomes, methods to prevent complications, and a plan that provides an
      expeditious transition to rehabilitation.

PMID- 10646445
TI  - Spinal cord injury research: review and synthesis.
AB  - This article provides a substantive review and synthesis of major areas of
      emphasis in spinal cord injury (SCI) research. Comprehensive examination of the
      current status and future implications for SCI research includes consideration of
      investigations from the following arenas: epidemiology, functional classification
      and prediction, neurophysiologic testing, models of injury and recovery,
      psychosocial considerations, surgical strategies, animal laboratory research,
      economic implications, life expectancy, complication rates, gender differences,
      pharmacological management, and prevention. Synthesis of these research
      conclusions from a broad spectrum of laboratory, clinical, and scientific domains
      provides opportunity for improving SCI prevention, treatment, and adaptation.

PMID- 10646446
TI  - Adults with congenital heart disease: utilizing quality of life and Husted's
      nursing theory as a conceptual framework.
AB  - Adults with Congenital Heart Disease (CHD) are a new and growing population of
      clients who pose a challenge to both medicine and nursing. An analysis of the
      literature has resulted in the development of a new conceptual framework
      utilizing the concept analysis of Quality of Life and Husted and Husted's ethical
      decision making in nursing in the care of the adult with CHD. Additionally,
      application of Husted and Husted's theory will be explored with a critical care
      case study.

PMID- 10646447
TI  - Agreement: the origin of ethical action.
AB  - The health care setting is an interweaving of human concerns. What is needed in
      this arena is an ethic--a guidance system centered on, and relevant to, these
      concerns. Such an ethic must be derived from, and appropriate to, the health care
      setting and the practice of health care professionals. This is established by the
      health care professional/patient agreement. This article will describe how a
      practice-based, symphonological ethic--an ethic based on agreement--can be
      brought to bear on the adversities faced by nurses and any other health care
      professional in any setting.

PMID- 10646448
TI  - Religious perspectives on organ donation.
AB  - A donor's or family's religious beliefs are to be ascertained in discussions
      about organ donation. The positions of the major faith groups about donation are
      reviewed, leading to the conclusion that the large majority of faiths take a
      positive stance toward donation. Other factors such as the emotional response,
      the cultural values, and the spiritual issues may be even more compelling for
      family members than religious beliefs. Conflicts between one's personal beliefs
      and the position of one's faith group about donation are to be assessed and
      processed.

PMID- 10646449
TI  - Organ/tissue donation request: a multidisciplinary approach.
AB  - The need for solid organs suitable for transplantation is an ever growing one in
      the United States today. It is imperative that there is ongoing interaction
      between the local Organ Procurement Organization and the health care professional
      so that a trust and a spirit of collaboration can develop. The use of the
      Organ/Tissue Donation Algorithm and the multidisciplinary approach has produced
      both positive and negative outcomes.

PMID- 10646450
TI  - Neuromuscular blockade administration to end suffering: an ethical dilemma.
AB  - Critical care nurses face ethical issues every day in relation to end-of-life
      decisions. This article presents a case study involving the administration of a
      neuromuscular blocking agent prior to removing a patient from the respirator. The
      decision to use a paralyzing agent caused an ethical conflict between the nurse
      and physician. The article discusses ethical principles in relation to end-of
      life decisions from the nurse, physician, and family's perspective. Whatever the
      belief, critical care nurses must consider the belief's of the patient and family
      while trying to maintain their own convictions.

PMID- 10646451
TI  - Family intervention strategies when dealing with futility of treatment issues: a
      case study.
AB  - As multidisciplinary medical team members, we are sometimes confronted by cases
      that frustrate us because they do not proceed well, and our desired outcome goal
      of healing and restoration cannot be achieved. A case like this may stay in our
      memories due to our regrets regarding the inability to intervene in a manner that
      is effective. The following case is an example of this. This case is one that
      challenges health care professionals to revisit our thinking regarding
      intervention strategies for families confronted with terminal illness. The case
      also allows us to examine how systemic issues within a health care organization
      can sometimes impede the goal of achieving the most optimal outcome for the
      patient and family.

PMID- 10646452
TI  - Ethical dilemmas in critical care: nurse case managers' perspective.
AB  - Nurse case managers often face ethical dilemmas as they advocate for their
      critically ill and critically injured patients. They experience the tension that
      exists between advocating for the critically ill, the patient's right to self
      determination, and the payer source constraints. When there are no good
      alternatives for the patient or the list of options include none that are
      desirable, the nurse case manager may experience an ethical dilemma. Working with
      the critically ill and injured inherently presents a spectrum of biopsychosocial
      complexities, which present potential ethical dilemmas for the nurse case
      manager. The three case studies presented posed particular challenges to the
      nurse case managers and deal with the ethical principles of beneficence,
      autonomy, veracity, and justice.

PMID- 10646453
TI  - Compliance with advance directives: nursing's view.
AB  - The purpose for this article is to define the terms of the Advance Directive
      within the legal and medical community and then to explore the bioethical
      implications of the Advance Directive for the nurse. Over the last decade, a
      legal document has entered the arena of the health care facility: the Advance
      Directive. Today, not only is the critical care nurse responsible for technical
      handling of the ever-changing medical equipment, advances in medicine and
      nursing, and new pharmaceuticals, but this nurse is also responsible for being
      ever cognizant of a very important legal document called the Advance Directive.

PMID- 10646454
TI  - Compliance with advance directives: a legal view.
AB  - An Advance Medical Directive is a fairly new legal, medical, ethical, and social
      concept. Advances in modern medical technology have prompted more interest in
      ordinary citizens having such a document. Today life can be prolonged in
      situations which 50 years ago would have resulted in death. This provides an
      opportunity for citizens (patients) to face choices about measures to prolong
      life.

PMID- 10646455
TI  - Ethical issues in computerized medical records.
AB  - Greater use of computer technology has permitted rapid access to many forms of
      data. Hospitals have traditionally been slower to accept this technology for
      patient medical records. With the rapid approach of the new millennium, hospitals
      are being forced into re-evaluating many processes, including the volumes of data
      collected on paper. Electronic medical records are one approach to reducing
      storage and streamlining care across the health care continuum. This article
      examines the ethical impact of computerized medical records, including access to
      data, ownership of data, confidentiality, and medical record brokering.

PMID- 10646456
TI  - The medical futility controversy: bioethical implications for the critical care
      nurse.
AB  - Medical futility is a recent, complex bioethical issue. There is disagreement
      about how futility should be defined and who should be involved in futility
      decisions when an impasse exists between the patient/family and the physician.
      Bioethical discussions about Quinlan and Cruzan of the past have been replaced
      with the Wanglie, Baby K, and Linares cases--all of which involved critical care
      settings. Nurses often are involved in the debate and encounter ethical
      conflicts. Cost-containment, managed care, scarce resource allocation, and care
      due the elderly have fueled the debate. Key issues and their importance for
      critical care nurses will be reviewed.

PMID- 10646457
TI  - "Slow" code: perspectives of a physician and critical care nurse.
AB  - "Slow" codes are not conducted frequently, but even their limited use is
      controversial from an ethical point of view. Physicians and nurses may view the
      rationale for a "slow" code differently. A critical care nurse and a physician
      were interviewed regarding their experiences with and their views about "slow"
      codes.

PMID- 10646458
TI  - The suspiciousness factor: critical care nursing and forensics.
AB  - This conceptual article provides a guide for understanding the place of forensic
      nursing within the discipline of nursing. Ways of knowing in nursing and expert
      nursing practice are described to identify the role of intuition in nursing
      practice. The relationship between suspicion and intuition is explored.
      Strategies for developing forensic nursing expertise and increasing suspicion are
      described. Suspicion (intuition) is presented as a rapid, acquired, patient
      oriented perception that leads to decisive action.

PMID- 10646459
TI  - The role of the clinical forensic nurse in critical care.
AB  - Forensic nursing deals with the population of people whose lives have been
      affected by societal violence. The clinical forensic nurse (CFN) is seen as a
      means of coping with the resultant increased complexity of nursing practice,
      society, and the law. Critical care areas are clinical forensic domains where the
      CFN addresses the needs of living forensic patients through activities involving
      physical and non-physical evidence collection, crisis intervention, and
      documentation. Within a health care team, the CFN enhances patient care
      management, resulting in clinical service, legal order, and forensic protocol.

PMID- 10646460
TI  - Evidence recognition and collection in the clinical setting.
AB  - The critical care nurse encounters victims of violence and abuse in the clinical
      setting. From these patients or from their visitors, evidence can be collected
      that, when used in legal proceedings, may interrupt the cycle of violence if a
      perpetrator is identified and found guilty by a court of law. Evidence may be
      tangible or intangible, and includes what one hears, smells, sees, and touches.
      This article discusses proper evidence recognition, collection, and preservation.
      With an understanding of proper forensic techniques, the critical care nurse can
      be an outstanding patient advocate.

PMID- 10646461
TI  - Barriers to effective screening for domestic violence by registered nurses in the
      emergency department.
AB  - Triage nurses in the emergency department are in a unique position to screen for
      domestic violence. This study, using Orlando's theory with a focus on two of her
      five major concepts, identifies barriers that prevent effective screening for
      domestic violence. A quantitative survey was distributed to 101 registered nurses
      employed in a large emergency department. Results identified three major barriers
      and a relationship between age and inservice attendance on domestic violence.
      Education on abuse and resources should be essential in nursing school curricula.
      Policy development and review should be part of an annual, mandatory inservice
      for all emergency nurses.

PMID- 10646462
TI  - The real meaning of patient-nurse confidentiality.
AB  - Critical care nurses learn early in their careers that patient confidentiality is
      to be respected. Challenges to this belief come when public safety or justice
      seems to outweigh any individual's privacy. The resolution of the problem caused
      by such competing values may not be easy for a nurse and will necessarily demand
      examination of legal, ethical, and professional responsibilities.

PMID- 10646463
TI  - Munchausen by proxy syndrome: the forensic challenge of recognition, diagnosis,
      and reporting.
AB  - Munchausen by Proxy Syndrome (MBPS) is a rare form of abuse in which a caregiver
      fabricates or produces symptoms of an illness in a child, elder, or disabled
      person. The deception is usually repeated on numerous occasions, resulting in
      many hospitalizations, considerable morbidity, and sometimes death. MBPS is a
      factitious disorder in which caregivers injure their victims in order to gain
      sympathy or attention for themselves. It was named after Baron Karl von
      Munchausen, the 18th century cavalry officer who returned home from war and told
      embellished tales of his adventures. MBPS is a very horrifying circumstance of
      abuse. Unwillingness or the inability to recognize this abuse deprives the victim
      of the opportunity to be shielded from future harm. There is a need for strategic
      protocols and a multidisciplinary approach to this baffling problem. Discussing
      the clinical profile of the perpetrator, the victim, and the family may help
      nurses distinguish medical fact from fiction.

PMID- 10646464
TI  - Cameras in hospital rooms: the Fourth Amendment to the Constitution and
      Munchausen syndrome by proxy.
AB  - Does the Fourth Amendment to the Constitution protect the rights of children or
      the child abusers? Munchausen syndrome by proxy (MSBP): the mother, the child,
      and the nurse on convert video surveillance in hospitals.

PMID- 10646465
TI  - Mechanism of injury in gunshot wounds: myths and reality.
AB  - Despite technological advances, ballistic literature in the 20th century remains
      replete with errors, misconceptions, half truths, and false representations. In
      the majority of the literature, there has not been a deliberate attempt to
      distort or misrepresent the facts but rather a reliance on myth and
      misconception. It is this author's goal to impart a sound, scientifically
      supported overview of gunshot wounds and their mechanism of injury. In doing so,
      critical care nurses can care better for individuals suffering from gunshot
      wounds and more effectively assist the criminal justice system.

PMID- 10646466
TI  - Crime scene responders: the imperative sequential steps.
AB  - Investigation of the modern major crime scene is no longer an isolated endeavor
      confined to law enforcement. Recent advances in forensic science, especially
      forensic nursing, and the recognized need to include a broad range of
      professionals in the quest for justice and the quality of community life has
      demanded that the examination of major crimes requires a multidisciplinary team
      approach. This article documents the necessity for searching major crime scenes
      in a strictly sequential manner and outlines the procedures to be taken in each
      step. Emphasized in this article are the roles of a variety of professionals
      that, when acting in a coordinated and cooperative manner, may better serve the
      public.

PMID- 10646467
TI  - Changing the future as we prepare for a new millennium.

PMID- 10646468
TI  - Accessible diabetes education materials in low-vision format.

PMID- 10646469
TI  - Psychosocial self-efficacy and personal characteristics of veterans attending a
      diabetes education program.
AB  - PURPOSE: The purpose of this descriptive correlational study was to describe the
      perceived psychosocial self-efficacy, attitude toward having diabetes, baseline
      glucose level, and personal characteristics of male veterans with type 2
      diabetes. METHODS: The Diabetes Empowerment Scale (DES) was mailed to
      participants and collected on the day of the program. Percent ideal body weight
      and glycosylated hemoglobin were measured. Comparisons were made by educational
      level, racial origin, and type of medication regimen on the DES and its
      subscales. RESULTS: Participants on oral medication versus insulin had higher
      scores in the categories of Motivation to Change and Ability to Cope with
      Feelings. Participants with less education had greater scores in Ability to Cope
      with Feelings and Obtain Support. No racial differences were seen on the measured
      scores; a significant difference was seen between Caucasians and non-Caucasians
      in baseline glycemic control. CONCLUSIONS: Targeting intervention strategies
      early in the course of disease progression may positively affect outcome.
      Longitudinal studies are needed to demonstrate the impact of self-management
      training on psychosocial self-efficacy and clinical outcomes.

PMID- 10646470
TI  - Development of a community-based diabetes management program for Pacific
      Islanders.
AB  - PURPOSE: This study examined the perception of diabetes among a sample of Pacific
      Islanders in Honolulu, Hawaii. All 23 participants were diagnosed with type 2
      diabetes, ranged in age from 21 to 70 years, and had glycosylated hemoglobin
      levels of 5.8% to 13.9%. METHODS: Four focus groups were held in English and
      audiotaped. Outreach workers served as translators and comoderators. The content
      of transcripts was analyzed with Ethnograph software by investigators. The
      priority issues were confirmed by the comoderators and participants. RESULTS:
      Participants perceived diabetes as full of complications, emotions, symptoms, and
      behavior changes. Responses to hyperglycemia were fear, frustration, and
      uncertainty. Barriers to staying on the prescribed diet were habit, cultural
      ritual, ideal body image, and limited budget. CONCLUSIONS: Participants suggested
      that helpful activities would include walking/support group, cooking class,
      community healthy food store, translated material, and family participation. A
      community-based diabetes program has been developing as a result of the focus
      group findings.

PMID- 10646471
TI  - Diabetes education needs of family members caring for American Indian elders.
AB  - PURPOSE: This qualitative study investigated diabetes care management among
      family members of American Indian elders with self-care limitations. Focus groups
      were used to examine the reasons for and content of diabetes care management, the
      challenges faced, and the support services needed. METHODS: Five focus groups
      were conducted with family caregivers from six tribes. Caregivers' responses
      related to care management were identified and categorized into themes. RESULTS:
      Participants reported that they provided assistance with a wide range of diabetes
      care tasks (e.g., skin and wound care, in-home dialysis) depending on the elder's
      level of impairment. Caregivers described three major challenges related to
      diabetes care management: (1) anxiety about in-home care, (2) coping with
      psychosocial issues, and (3) decision making and communication problems with
      other family members. They emphasized the importance of developing a care routine
      for successful diabetes management. CONCLUSIONS: Based on these findings, we
      suggest areas where diabetes educators can assist American Indian family
      caregivers in meeting the needs of frail elders in the home.

PMID- 10646473
TI  - Making a case for the CDE's role in outsourcing diabetes services to a
      freestanding outpatient diabetes disease state management center.
AB  - Outsourcing of diabetes disease state management services by MCOs is a good thing
      for enrollees with diabetes. It is a good mechanism for MCOs that are striving to
      cut the costs of diabetes care, and it is a trend that the authors expect to see
      continue in an accelerated way, given the new diagnostic guidelines released by
      the American Diabetes Association and the epidemic of diabetes among older
      persons. Through a partnership with a quality, freestanding, outpatient diabetes
      disease state management center staffed by CDEs, MCOs with a vision can expect to
      profit now and pay less later for devastating, expensive diabetes complications
      that lead to increased hospitalizations.

PMID- 10646472
TI  - Diabetes care practices in primary care: results from two samples and three
      measurement sets.
AB  - PURPOSE: There has been substantial recent interest in diabetes disease
      management interventions, guidelines, and care practices. As the vast majority of
      diabetes care occurs in primary care settings, it makes sense to evaluate current
      levels of recommended practices in different primary care settings. METHODS: We
      report on two separate studies that included a combined total of 389 patients
      seen by over 30 different providers. Three different sets of recommended
      practices were assessed: (1) the ADA provider recognition measures, (2) the
      proposed Diabetes Quality Improvement Project measures, and (3) the state of
      Oregon Population-Based Guidelines for Diabetes. RESULTS: In general, there was
      only a moderate level of adherence to recommended practices, and adherence was
      much lower for behavioral or patient-focused practices as contrasted with
      laboratory tests. There was considerable variability across providers and across
      different guidelines activities. CONCLUSIONS: Policy and quality improvement
      implications and future research issues are discussed, including the need for
      studying different measurement approaches for evaluating guidelines adherence.

PMID- 10646474
TI  - Influence of the environmental context on diabetes self-management: a rationale
      for developing a new research paradigm in diabetes education.

PMID- 10646475
TI  - International education.

PMID- 10646476
TI  - Indonesia: an assessment of the health state, health care delivery system, and
      nursing education.
AB  - The purpose of the exploratory, descriptive study was fourfold: 1) to study the
      nursing education system in Indonesia, 2) to study the health state and health
      care delivery system, 3) to present various professional issues to nurses,
      physicians, and other health care professionals, and 4) to develop additional
      exchange programs between nursing faculty and students of Indonesia and the
      United States. Baccalaureate education in Indonesia is in the beginning stages of
      development. The type of hospital is dependent on the number of specialists and
      options for care. There is a high IMR and MMR, and a high incidence of infectious
      diseases. Educational exchange programs for faculty and students have been slow
      to develop.

PMID- 10646477
TI  - An international distance learning nursing course in the U.S. and Japan.
AB  - A distance learning nursing course is offered via two-way interactive video and
      the Internet from the University of North Carolina at Wilmington to nursing
      students at Mie Prefecture College of Nursing in Japan. The course was designed
      to teach Japanese students nursing practices and issues in the United States. The
      classroom environment used a combination of synchronous (two-way interactive
      video connections over an Integrated Services Digital Network) and asynchronous
      technologies (electronic mail, Internet-based discussion forums, and World Wide
      Web pages). Students' course evaluations highlighted areas of success, and
      pointed out some of the challenges that remain for effective implementation of
      international education courses.

PMID- 10646478
TI  - Mission to Honduras.
AB  - I have volunteered for many years for a woman's organization raising money to
      build trade and technical schools around the world, but I had never been asked to
      use my education as a nurse for this purpose. When the opportunity came for me
      and my classmates to join a volunteer mission to Honduras we jumped at the
      chance. Since we were all nurses we knew how to deliver patient care. This
      mission gave us the opportunity to use our newly acquired nurse practitioner
      skills. It also gave us the opportunity to see first hand how much need there is
      in other countries, as well as our own, for professional volunteers to help in
      multicultural settings.

PMID- 10646479
TI  - Transcultural healthcare: a phenomenological study of an educational experience.
AB  - This phenomenological study was undertaken for the purpose of describing the
      meaning of transcultural health care. A phenomenological approach was utilized to
      elicit the essence of meaning attached to the experience. Students in an upper
      midwestern university, enrolled in a transcultural health care course
      participated in the educational experience presented in this paper. While the
      course was multidisciplinary in nature, nursing represented the majority. The
      purpose was to identify and describe students' perception and definition of
      culture at the beginning and end of the course and to utilize an inductive
      process to formulate a descriptive structure depicting the meaning of
      transcultural health care. It was concluded that students' perception and
      definition of culture changed via the transformational process influenced by the
      passage of time and by the particular experiences students were exposed to.

PMID- 10646480
TI  - The American College of Radiology. ACR Appropriateness Criteria project.

PMID- 10646481
TI  - The role of cytokines in the pathogenesis of rheumatoid arthritis.
AB  - Recombinant DNA technology has made it possible to identify the cytokines
      expressed in the joints of people with active rheumatoid arthritis (RA). Because
      a large number of cytokines are expressed in the rheumatoid synovium and many of
      these cytokines may have redundant biological functions, it was necessary to
      study cytokine regulation to identify potential therapeutic targets. The
      regulation of interleukin 1, a proven inducer of bone and cartilage destruction
      in the rheumatoid synovium, was thus studied and anti-tumour necrosis factor
      alpha (anti-TNF-alpha) antibody was found to reduce its synthesis markedly, as
      well as that of other cytokines, leading to our proposal of TNF-alpha as a
      therapeutic target. The further study of clinical trials in RA verified that the
      mechanism of action of anti-TNF-alpha includes the down-regulation of several pro
      inflammatory agents, diminished leucocyte recruitment and possibly regulation of
      angiogenesis.

PMID- 10646482
TI  - Targeting of cells involved in the pathogenesis of rheumatoid arthritis.
AB  - The pathogenesis of rheumatoid arthritis (RA) is a consequence of the activation
      of T cells by as yet unknown antigens and the co-stimulatory molecules CD4 and
      CD28. A number of potential antigens have been proposed for this process,
      including type II collagen, heat shock proteins and the glycoprotein gp39.
      Following activation, T cells initiate the inflammatory cascade through secretion
      of either interleukin 2 (IL-2) or interferon gamma, or through direct cellular
      interaction with macrophages and synoviocytes. Targeted therapies in RA are
      predominantly directed against the T cell. Results of several trials of anti-CD4
      antibodies are being evaluated, including those of an anti-IL-6 receptor
      antibody, which showed short-term effectiveness but some toxicity, and an anti
      intercellular adhesion molecule 1 antibody that caused dramatic reduction in
      rheumatoid factor titres. Non-antibody therapies of RA being studied include
      nasal administration of gp39 and oral administration of type II articular
      collagen, but the results of these studies have been equivocal.

PMID- 10646483
TI  - Future trends in the treatment of rheumatoid arthritis: cytokine targets.
AB  - Recently, anti-inflammatory cytokines and cytokine-blocking agents such as
      monoclonal antibodies, soluble receptors and receptor antagonists have been
      explored as therapeutic agents for patients with rheumatoid arthritis. The anti
      inflammatory cytokines interleukin 10 (IL-10), which reverses the cartilage
      degradation induced by antigen-stimulated mononuclear cells, and IL-4, which
      reduces prostaglandin production by synoviocytes, are currently being tested for
      their clinical efficacy. Trials with the tumour necrosis factor alpha blocking
      agents infliximab (monoclonal antibody) and etanercept (the fusion protein of
      soluble tumour necrosis factor receptors linked to human immunoglobulin) have
      produced improvements in clinical and laboratory measures of inflammation with
      mild side-effects. Trials of IL-1 blockade with recombinant human IL-1 receptor
      antagonist produced significant improvement of clinical parameters with mild side
      effects. Blockade of IL-6, the cytokine that induces biosynthesis of acute-phase
      proteins, has been attempted with i.v. injections of anti-IL-6 monoclonal
      antibodies with improvement in clinical variables as well as reduced acute-phase
      proteins.

PMID- 10646484
TI  - Leflunomide, mycophenolic acid and matrix metalloproteinase inhibitors.
AB  - Leflunomide inhibits dihydro-orotate dehydrogenase with secondary effects on
      interleukin 2, transforming growth factor alpha and antibody production.
      Published data show that it is effective at 10-25 mg/day. Leflunomide's side
      effects include gastrointestinal toxicity, a low incidence of alopecia, elevated
      liver function test abnormalities and weight loss. Mycophenolate mofetil inhibits
      inosine monophosphate dehydrogenase with secondary decreases on guanine
      nucleotides, DNA synthesis and inhibition of natural killer cell activity. At 1
      or 2 g daily it is effective clinically, although it has little effect on
      erythrocyte sedimentation rate. Incidences of toxicity obtained from
      transplantation experience are principally gastrointestinal but also include a
      probable increase in viral infections, some myelosuppression and occasional
      cholestasis or pancreatitis. Matrix metalloproteinase inhibitors (MMPIs) are a
      diverse group of enzymes that are rapidly induced by inflammatory mediators. Some
      MMPIs are effective in rheumatoid arthritis. Their toxicities include
      gastrointestinal toxicity, sun sensitivity and rare systemic lupus erythematosus
      like syndromes.

PMID- 10646485
TI  - The role of current strategies in the future treatment of rheumatoid arthritis.
AB  - Rheumatoid arthritis (RA) is a serious, chronic, debilitating disease for which
      no cure is available. Therapeutic aims for patients with RA are to alleviate
      symptoms, slow disease progression and optimize quality of life. In recent years,
      measures to achieve these goals have changed, and the development of new drugs
      will probably result in new treatment regimens. Two drugs with an extensive
      record of clinical experience are methotrexate and cyclosporin. Methotrexate is
      widely used because of its efficacy and high therapy retention rate. Both drugs
      have been shown to slow the progression of RA, but not without side-effects that
      sometimes preclude their use. As neither drug generally induces remission,
      improved treatments are needed. Combination therapy using drugs with different
      mechanisms of action is beginning to be evaluated, as are biological response
      modifiers targeted to specific mediators of the immune response. The future
      treatment of RA should provide more effective relief with fewer side-effects.

PMID- 10646486
TI  - Rheumatoid arthritis: new developments in the use of existing therapies.
AB  - Combination therapy with methotrexate may be the newest standard to which future
      therapies for rheumatoid arthritis are compared. Many questions remain to be
      answered regarding the appropriateness of such combination therapies for specific
      patients and clinical situations, and the optimal therapeutic combinations. Other
      unanswered questions regarding combination therapy include the need for
      appropriate monitoring, long-term safety and cost-benefit implications. Future
      research is needed to clarify the role of biological response modifiers (e.g.
      anti-tumour necrosis factor therapies) and matrix metalloproteinase inhibitors,
      both as components of and alternatives to methotrexate combination regimens.

PMID- 10646487
TI  - Management of patients with newly diagnosed rheumatoid arthritis.
AB  - The traditional pyramidal approach to treatment of rheumatoid arthritis (RA) has
      the unfortunate effect of treating patients with early RA--those patients with
      the greatest potential for clinical response--with the least effective agents
      during the most prolonged and most damaging period of inflammation. Given the
      wide variety of therapies now available, and the fact that the disease itself can
      be more destructive than the toxicity of drug therapy, it is important to know
      the likely outcome for an individual patient so that therapy can be targeted
      accordingly. The rapid development of new imaging techniques has enabled joint
      damage to be assessed at a very early stage. The correlation of data obtained
      from these techniques with clinical data, such as the presence of rheumatoid
      factor and the shared epitope, may provide a basis on which therapies in the
      future can be tailored for individual patients.

PMID- 10646488
TI  - Management of refractory rheumatoid arthritis.
AB  - Based on the results of a MEDLINE search (1992-1997), the term 'refractory
      rheumatoid arthritis' (refractory RA) is ill-defined, in terms of both patient
      characterization and description of previous treatments. Current strategies of
      management of refractory RA include increasing disease-modifying anti-rheumatic
      drug dosage above standard dosage regimens, using combination therapy, and adding
      or increasing the dosage of corticosteroids. Options for further strategies
      include target-oriented biological agents (e.g. anti-tumour necrosis factor),
      gene therapy, stem-cell treatment and oral tolerance induction.

PMID- 10646489
TI  - How may quality of life for rheumatoid arthritis patients be enhanced by current
      and future treatments?
AB  - Health-related quality of life is best thought of simply as 'health'. Life
      quality in patients with rheumatoid arthritis (RA) is affected, for good or ill,
      by treatment effects. Health status now is readily and validly measurable, using
      the Health Assessment Questionnaire or other instruments. Disability and pain are
      reduced by disease-modifying anti-rheumatic drugs (DMARDs) much more than by non
      steroidal anti-inflammatory drugs (NSAIDs). Toxicity considerations vary among
      individual drugs but are roughly comparable between NSAIDs and DMARDs, mandating
      DMARD-based treatment strategies. Future therapies must accentuate the positives
      (reduction in pain and disability) while reducing the negatives (unwanted
      effects) if the health of RA patients is to be improved.

PMID- 10646490
TI  - The impact of pharmaco-economic considerations on the utilization of novel anti
      rheumatic therapies.
AB  - Rheumatoid arthritis exacts a tremendous cost, not only in physical suffering but
      also in economic terms. This economic burden arises both from the direct cost of
      treatment and the indirect cost to patients, their families and society, in
      decreased quality of life and loss of labour. Currently available therapies have
      not proven completely effective. Novel biological agents, although more expensive
      than standard therapies, may prove to be valuable when analysed on the basis of
      reduced long-term costs resulting from their superior efficacy, relative lack of
      toxicity and rapid effect.

PMID- 10646491
TI  - Workshop summary: the emerging role of biologicals in the treatment of patients
      with newly diagnosed rheumatoid arthritis.

PMID- 10646492
TI  - Workshop summary: the role of biologicals in the treatment of patients with
      refractory rheumatoid arthritis.

PMID- 10646493
TI  - Workshop summary: health outcomes and health economic issues surrounding the use
      of biological therapies in patients with rheumatoid arthritis.

PMID- 10646494
TI  - Recapitulation of the round-table discussion--assessing the role of anti-tumour
      necrosis factor therapy in the treatment of rheumatoid arthritis.
AB  - Clinical trials specifically targeting and neutralizing the cytokine, tumour
      necrosis factor (TNF), have recently provided evidence of efficacy and a promise
      of a novel approach for the treatment and management of rheumatoid arthritis
      (RA). With the evolving emergence of anti-TNF therapeutics, several unresolved
      issues have come to light, including the assessment of safety and efficacy of
      current therapies, study design for new agents and cost-benefit issues. During an
      international meeting of leading rheumatologists and specialists, the majority
      opinion regarding the use of anti-TNF therapy was that these agents are most
      appropriate in patients with active disease who have insufficient response to
      methotrexate, which is presently considered the standard for RA treatment. Anti
      TNF therapy was also recommended in patients with active disease unable to
      tolerate methotrexate therapy, or who have not responded to at least two other
      disease-modifying anti-rheumatic drugs (DMARDs). In patients with RA who have
      serious infection or malignancy, the use of anti-TNF therapies was not advised.
      Time, experience and clinical data from recently completed and currently ongoing
      studies of infliximab and etanercept, which will be available in the future, will
      help determine the ultimate role of such targeted therapeutics. Additional data
      on anti-TNF therapeutics as monotherapy or in various combinations are still
      needed to achieve maximum disease control safely with currently available DMARDs.

PMID- 10646495
TI  - Roles of nuclear factor kappaB in neuronal survival and plasticity.
AB  - The transcription factor nuclear factor kappaB (NF-kappaB) is moving to the
      forefront of the fields of apoptosis and neuronal plasticity because of recent
      findings showing that activation of NF-kappaB prevents neuronal apoptosis in
      various cell culture and in vivo models and because NF-kappaB is activated in
      association with synaptic plasticity. Activation of NF-kappaB was first shown to
      mediate antiapoptotic actions of tumor necrosis factor in cultured neurons and
      was subsequently shown to prevent death of various nonneuronal cells. NF-kappaB
      is activated by several cytokines and neurotrophic factors and in response to
      various cell stressors. Oxidative stress and elevation of intracellular calcium
      levels are particularly important inducers of NF-kappaB activation. Activation of
      NF-kappaB can interrupt apoptotic biochemical cascades at relatively early steps,
      before mitochondrial dysfunction and oxyradical production. Gene targets for NF
      kappaB that may mediate its antiapoptotic actions include the antioxidant enzyme
      manganese superoxide dismutase, members of the inhibitor of apoptosis family of
      proteins, and the calcium-binding protein calbindin D28k. NF-kappaB is activated
      by synaptic activity and may play important roles in the process of learning and
      memory. The available data identify NF-kappaB as an important regulator of
      evolutionarily conserved biochemical and molecular cascades designed to prevent
      cell death and promote neuronal plasticity. Because NF-kappaB may play roles in a
      range of neurological disorders that involve neuronal degeneration and/or
      perturbed synaptic function, pharmacological and genetic manipulations of NF
      kappaB signaling are being developed that may prove valuable in treating
      disorders ranging from Alzheimer's disease to schizophrenia.

PMID- 10646496
TI  - "Inflammatory" cytokines: neuromodulators in normal brain?
AB  - If cytokines are constitutively expressed by and act on neurons in normal adult
      brain, then we may have to modify our current view that they are predominantly
      inflammatory mediators. We critically reviewed the literature to determine
      whether we could find experimental basis for such a modification. We focused on
      two "proinflammatory" cytokines, interleukin (IL)-1 and tumor necrosis factor
      alpha (TNFalpha) because they have been most thoroughly investigated in shaping
      our current thinking. Evidence, although equivocal, indicates that the genes
      coding for these cytokines and their accessory proteins are expressed by neurons,
      in addition to glial cells, in normal brain. Their expression is region- and cell
      type-specific. Furthermore, bioactive cytokines have been extracted from various
      regions of normal brain. The cytokines' receptors selectively are present on all
      neural cell types, rendering them responsive to cytokine signaling. Blocking
      their action modifies multiple neural "housekeeping" functions. For example,
      blocking IL-1 or TNFalpha by several independent means alters regulation of
      sleep. This indicates that these cytokines likely modulate in the brain behavior
      of a normal organism. In addition, these cytokines are likely involved in
      synaptic plasticity, neural transmission, and Ca2+ signaling. Thus, the evidence
      strongly suggests that these cytokines perform neural functions in normal brain.
      We therefore propose that they should be thought of as neuromodulators in
      addition to inflammatory mediators.

PMID- 10646497
TI  - An allelic variation in the human prodynorphin gene promoter alters stimulus
      induced expression.
AB  - Prodynorphin, the precursor of the dynorphin opioid peptides, has been shown to
      play an important role in several aspects of human diseases and complex traits,
      e.g., drug abuse, epilepsy, and mood disorders. The objective of this study was
      to identify polymorphisms in the 5' control region of the human prodynorphin gene
      and to relate these polymorphisms to prodynorphin gene expression. Within the
      core promoter region, a 68-bp sequence was found to occur as a polymorphic
      element, either singular or as tandemly repeated element two, three, or four
      times. This 68-bp repeat element contains an AP-1 transcription factor binding
      site as demonstrated by electrophoretic mobility shift assay. Reporter gene
      assays were performed and provided evidence for allele dependent different
      promoter activity. Dynorphin was found to be involved in many pathophysiological
      processes so that the described prodynorphin alleles may correlate with the
      occurrence of several diseases, for example, drug addiction. However,
      prodynorphin allelic distributions were not significantly different in heroin
      addicts and control subjects.

PMID- 10646498
TI  - Structure of the human serotonin 5-HT4 receptor gene and cloning of a novel 5-HT4
      splice variant.
AB  - Several variants of the serotonin 5-HT4 receptor are known to be produced by
      alternative splicing. To survey the existence and usage of exons in humans, we
      cloned the human 5-HT4 gene. Based on sequence analysis seven C-terminal variants
      (a-g) and one internal splice variant (h) were found. We concentrated in this
      study on the functional characterization of the novel splice variant h, which
      leads to the insertion of 14 amino acids into the second extracellular loop of
      the receptor. The h variant was cloned as a splice combination with the C
      terminal b variant; therefore, we call this receptor 5-HT4(hb). This novel
      receptor variant was expressed transiently in COS-7 cells, and its
      pharmacological profile was compared with those of the previously cloned 5-HT4(a)
      and 5-HT4(b) isoforms, with the latter being the primary reference for the h
      variant. In competition binding experiments using reference 5-HT4 ligands, no
      significant differences were detected. However, the broadly used 5-HT4 antagonist
      GR113808 discriminated functionally among the receptor variants investigated. As
      expected, it was an antagonist on the 5-HT4(a) and 5-HT4(b) variant but showed
      partial agonistic activity on the 5-HT4(hb) variant. These data emphasize the
      importance of variations introduced by splicing for receptor pharmacology and may
      help in the understanding of conflicting results seen with 5-HT4 ligands in
      different model systems.

PMID- 10646499
TI  - Complex regulation of tau exon 10, whose missplicing causes frontotemporal
      dementia.
AB  - Tau is a microtubule-associated protein whose transcript undergoes complex
      regulated splicing in the mammalian nervous system. Exon 10 of the gene is an
      alternatively spliced cassette that is adult-specific and that codes for a
      microtubule binding domain. Recently, mutations that affect splicing of exon 10
      have been shown to cause inherited frontotemporal dementia (FTDP). In this study,
      we establish the endogenous expression patterns of exon 10 in human tissue; by
      reconstituting naturally occurring FTDP mutants in the homologous context of exon
      10, we show that the cis determinants of exon 10 splicing regulation include an
      exonic silencer within the exon, its 5' splice site, and the relative affinities
      of its flanking exons to it. By cotransfections in vivo, we demonstrate that
      several splicing regulators affect the ratio of tau isoforms by inhibiting exon
      10 inclusion.

PMID- 10646500
TI  - Synergistic induction of pituitary adenylate cyclase-activating polypeptide
      (PACAP) gene expression by nerve growth factor and PACAP in PC12 cells.
AB  - Pituitary adenylate cyclase-activating polypeptide (PACAP) gene expression was
      analyzed in PC12 cells. PC12 cells transfected with a PACAP promoter-luciferase
      reporter construct were utilized to investigate the effects of PACAP, either
      alone or in combination with nerve growth factor (NGF), on PACAP transcriptional
      response. PACAP induced transcription from the PACAP promoter through PACAP type
      I receptor (PAC1 receptor). PACAP gene transcription was also induced by NGF.
      Simultaneous treatment with PACAP and NGF resulted in a synergistic
      transcriptional response that was more than three times the predicted response,
      based on a simple additive effect of both agents. This synergism in
      transcriptional response paralleled the PACAP mRNA levels, as determined by RT
      PCR and northern blotting. The level of PACAP mRNA peaked 3 h after stimulation
      and gradually returned to basal levels by 48 h. PC12 cells are known to express
      predominantly the hop isoform of the PAC1 receptor, which positively couples to
      both adenylate cyclase and phospholipase C. To determine the role of the cyclic
      AMP and protein kinase C pathways in PACAP gene expression, the effects of
      forskolin and phorbol 12-myristate 13-acetate (PMA) were then examined. PMA did
      not alter PACAP mRNA levels but enhanced forskolin-induced PACAP mRNA expression.
      Down-regulation of protein kinase C blocked the ability of PACAP to stimulate
      PACAP mRNA expression. The mitogen-activated protein kinase extracellular signal
      regulated kinase (ERK) kinase 1/2 (MEK1/2) inhibitor PD98059 also blocked the
      PACAP mRNA expression induced by either PACAP or NGF but not that induced by a
      combination of PACAP and NGF. These results suggest that PACAP stimulates the
      PACAP gene expression in PC12 cells at least in part through activation of
      adenylate cyclase and protein kinase C signaling pathways and that the ERK1/2
      cascade is involved in PACAP and NGF-induced PACAP gene expression, although
      redundant signaling pathways may also be involved. The present finding showing
      that PACAP in combination with NGF causes a synergistic increase in PACAP gene
      expression in PC12 cells supports the idea that PACAP acts as an autocrine
      regulatory factor.

PMID- 10646501
TI  - Induction of matrix metalloproteinase MMP-9 (92-kDa gelatinase) by retinoic acid
      in human neuroblastoma SKNBE cells: relevance to neuronal differentiation.
AB  - Retinoic acid (RA) has been shown to induce human neuroblastoma SKNBE cell
      differentiation into a neuronal phenotype. Whether this neuronal differentiation
      is associated with modulation of matrix gelatinase [matrix metalloproteinase
      (MMP)-2 and MMP-9] expression was investigated in SKNBE cell cultures exposed to
      RA for 14 days. Their differentiation into a neuronal phenotype was typified by
      neural cell adhesion molecule and growth-associated protein-43 expression.
      Gelatinase expression was assessed by gel zymography, quantitative RT-PCR, and
      immunocytochemistry. Neuronal markers were located in neurites and ganglion-like
      clusters of neuronal cells induced upon RA exposure. MMP-2 expression was
      constitutive and remained unchanged at both the mRNA and protein levels in
      response to RA, tumor necrosis factor-alpha (TNFalpha), or phorbol 12-myristate
      13-acetate (PMA) treatment. In contrast, MMP-9 was inducible by RA, TNFalpha, or
      PMA. MMP-9 was progressively enhanced by RA as a function of time exposure until
      day 14. The addition of TNFalpha or PMA potentiated RA-induced MMP-9 expression
      with a synergic maximal effect at day 14 of RA exposure. Immunoreactive MMP-9 was
      located early in outgrowing neurites, but only at day 14 of RA exposure in
      extensive neuritic networks. Taken together, the correlation between the MMP-9
      expression by SKNBE cells and the time scale of their differentiation into a
      neuronal phenotype allowed us to propose that MMP-9 could participate in the
      neurite growth process and cell migration and organization into ganglion-like
      clusters.

PMID- 10646502
TI  - Synaptotagmin IV is present at the Golgi and distal parts of neurites.
AB  - Synaptotagmin IV (SytIV) is an immediate early gene induced by membrane
      depolarization in PC12 cells and in rat brain. However, little is known about the
      function of SytIV or the functional relationship between SytIV and SytI, because
      SytIV has yet to be localized. Here we show that SytIV was localized at the Golgi
      and distal part of neurites in nerve growth factor-differentiated PC12 cells and
      cultured hippocampal neurons by immunocytochemistry using an isoform-specific
      antibody (anti-SytIV). These SytIV signals were not colocalized well with SytI
      signals. Upon membrane depolarization, SytIV signals were increased at both the
      Golgi and distal part of neurites within several hours in both types of cells. We
      further show that the increase of SytIV protein levels results from protein
      kinase A-dependent gene up-regulation. In hippocampal neurons, SytIV was
      developmentally regulated. These results suggest that SytIV may play a role at
      the Golgi and tips of neurites during development and synaptic plasticity.

PMID- 10646503
TI  - Functional interplay between nuclear factor-kappaB and c-Jun integrated by
      coactivator p300 determines the survival of nerve growth factor-dependent PC12
      cells.
AB  - Nerve growth factor (NGF) activates the transcription factors nuclear factor
      kappaB (NF-kappaB) and activator protein-1 (AP-1) in sympathetic neurons. Whereas
      NGF-inducible NF-kappaB is required for the survival of neurons, c-Jun has the
      ability to promote neuronal death. In this report, we have examined the effect of
      NGF withdrawal on c-Jun and NF-kappaB transcription factors in PC12 cells
      differentiated to a neuronal phenotype. We show that the withdrawal of NGF from
      these cultures results in de novo synthesis of c-Jun, increase in AP-1 activity,
      and down-regulation of NF-kappaB activity. To investigate how the signal
      transduction pathways activating c-Jun and NF-kappaB are differentially regulated
      by NGF, we performed transcriptional analyses. Expression of ReIA (NF-kappaB)
      suppressed the c-Jun-dependent transcription of c-jun, and this effect was
      reversed by overexpression of the coactivator p300. RelA's effects on c-Jun
      transcription were mediated by competitive binding of the carboxy-terminal region
      of RelA to the CH1 domain of p300, which also binds to c-Jun; deletion of this
      region abrogated the ability of RelA to inhibit c-Jun activity. Furthermore, the
      inhibition of endogenous NF-kappaB in NGF-maintained neuronal PC12 cells led to
      the induction of c-Jun synthesis and a marked increase in cell death. Together,
      these studies demonstrate a functional interaction between NF-kappaB and c-Jun
      and suggest a novel mechanism of NF-kappaB-mediated neuroprotection.

PMID- 10646504
TI  - Selective synthesis of 2',3'-cyclic nucleotide 3'-phosphodiesterase isoform 2 and
      identification of specifically phosphorylated serine residues.
AB  - 2',3'-Cyclic nucleotide 3'-phosphodiesterase (CNP) is a protein found abundantly
      in the cytoplasmic compartments of CNS myelin. Two isoforms of this protein, CNP1
      and CNP2, are detectable. They differ by a 20-amino acid extension exclusive to
      CNP2. Additionally, CNP2 is essentially the only isoform to be phosphorylated in
      vivo. In this study, we examine the phosphorylation of CNP2 in transfected cells.
      CNP2 was selectively expressed ectopically in 293T cells and labeled with 32P.
      Immunoprecipitation of labeled CNP2 and tryptic phosphopeptide mapping analyses
      identified serines 9 and 22 as the major sites of phosphorylation. Only serine 22
      was phosphorylated initially in oligodendrocyte-enriched cultures of neonatal rat
      brain glial cells. However, 4beta-phorbol 12,13-dibutyrate (PDB) induced the
      phosphorylation of serine 9, thereby producing the same pattern seen in 293T
      cells. These results suggest that serine 9 is phosphorylated by a PDB-sensitive
      kinase, likely protein kinase C, and that serine 22 appears to be constitutively
      phosphorylated.

PMID- 10646505
TI  - Down-regulation of GD3 ganglioside and its O-acetylated derivative by stable
      transfection with antisense vector against GD3-synthase gene expression in
      hamster melanoma cells: effects on cellular growth, melanogenesis, and
      dendricity.
AB  - The expression of gangliosides in hamster melanoma cells is closely related to
      cellular growth and degree of differentiation, with slow-growing, highly
      differentiated melanotic melanoma cells expressing GM3 and fast-growing,
      undifferentiated amelanotic Ab melanoma cells having a preponderance of GD3 and O
      acetyl-GD3. We recently showed that down-regulation of O-acetyl-GD3 expression in
      hamster melanoma cells by introducing the influenza C virus O-acetylesterase cDNA
      into the cells resulted in induction of dendricity, with a concomitant increased
      expression of GD3. To examine the effect of the increased GD3 expression in the
      plasma membrane on the dendricity of the AbC-1 cells, we first established the
      cDNA coding for hamster GD3-synthase. We then targeted the sialyltransferase gene
      expression by the antisense knockdown experiment, and the results showed that
      inhibition of the expression of gangliosides GD3 and O-acetyl-GD3 induced
      dendricity in the hamster melanoma AbC-1 cell line. These GD3- and O-acetyl-GD3
      depleted cells also demonstrated a decreased rate of cell growth, but their
      melanogenic potential was not affected. These results rule out the possibility
      that GD3 may serve as an active molecule for dendrite outgrowth in this cell line
      and suggest that the enhanced expression of O-acetyl-GD3 ganglioside may
      stimulate cellular growth and suppress certain differentiated phenotypes such as
      dendrite formation, but not melanogenesis, in our system.

PMID- 10646506
TI  - Hippocampal astrocytes exhibit Ca2+-elevating muscarinic cholinergic and
      histaminergic receptors in situ.
AB  - Recent findings suggest that astrocytes respond to neuronally released
      neurotransmitters with Ca2+ elevations. These Ca2+ elevations may trigger
      astrocytes to release glutamate, affecting neuronal activity. Neuronal activity
      is also affected by modulatory neurotransmitters that stimulate G protein-coupled
      receptors. These neurotransmitters, including acetylcholine and histamine, might
      affect neuronal activity by triggering Ca2+-dependent release of
      neurotransmitters from astrocytes. However, there is no physiological evidence
      for histaminergic or cholinergic receptors on astrocytes in situ. We asked
      whether astrocytes have these receptors by imaging Ca2+-sensitive dyes
      sequestered by astrocytes in hippocampal slices. Our results show that
      immunocytochemically identified astrocytes respond to carbachol and histamine
      with increases in intracellular free Ca2+ concentration. The H1 histamine
      receptor antagonist chlorpheniramine inhibited responses to histamine. Similarly,
      atropine and the M1-selective muscarinic receptor antagonist pirenzepine
      inhibited carbachol-elicited responses. Astrocyte responses to histamine and
      carbachol were compared with responses elicited by alpha1-adrenergic and
      metabotropic glutamate receptor agonists. Individual astrocytes responded to
      different subsets of receptor agonists. Ca2+ oscillations were the prevalent
      response pattern only with metabotropic glutamate receptor stimulation. Finally,
      functional alpha1-adrenergic receptors and muscarinic receptors were not detected
      before postnatal day 8. Our data show that astrocytes have acetylcholine and
      histamine receptors coupled to Ca2+. Given that Ca2+ elevations in astrocytes
      trigger neurotransmitter release, it is possible that these astrocyte receptors
      modulate neuronal activity.

PMID- 10646507
TI  - Mitogenic signaling via endogenous kappa-opioid receptors in C6 glioma cells:
      evidence for the involvement of protein kinase C and the mitogen-activated
      protein kinase signaling cascade.
AB  - As reports on G protein-coupled receptor signal transduction mechanisms continue
      to emphasize potential differences in signaling due to relative receptor levels
      and cell type specificities, the need to study endogenously expressed receptors
      in appropriate model systems becomes increasingly important. Here we examine
      signal transduction mechanisms mediated by endogenous kappa-opioid receptors in
      C6 glioma cells, an astrocytic model system. We find that the kappa-opioid
      receptor-selective agonist U69,593 stimulates phospholipase C activity,
      extracellular signal-regulated kinase 1/2 phosphorylation, PYK2 phosphorylation,
      and DNA synthesis. U69,593-stimulated extracellular signal-regulated kinase 1/2
      phosphorylation is shown to be upstream of DNA synthesis as inhibition of
      signaling components such as pertussis toxin-sensitive G proteins, L-type Ca2+
      channels, phospholipase C, intracellular Ca2+ release, protein kinase C, and
      mitogen-activated protein or extracellular signal-regulated kinase kinase blocks
      both of these downstream events. In addition, by overexpressing dominant-negative
      or sequestering mutants, we provide evidence that extracellular signal-regulated
      kinase 1/2 phosphorylation is Ras-dependent and transduced by Gbetagamma
      subunits. In summary, we have delineated major features of the mechanism of the
      mitogenic action of an agonist of the endogenous kappa-opioid receptor in C6
      glioma cells.

PMID- 10646509
TI  - Brain-derived neurotrophic factor induces excitotoxic sensitivity in cultured
      embryonic rat spinal motor neurons through activation of the phosphatidylinositol
      3-kinase pathway.
AB  - Neurotrophic factors (NTFs) can protect against or sensitize neurons to
      excitotoxicity. We studied the role played by various NTFs in the excitotoxic
      death of purified embryonic rat motor neurons. Motor neurons cultured in brain
      derived neurotrophic factor, but not neurotrophin 3, glial-derived neurotrophic
      factor, or cardiotrophin 1, were sensitive to excitotoxic insult. BDNF also
      induces excitotoxic sensitivity (ES) in motor neurons when BDNF is combined with
      these other NTFs. The effect of BDNF depends on de novo protein and mRNA
      synthesis. Reagents that either activate or inhibit the 75-kDa NTF receptor
      p75NTR do not affect BDNF-induced ES. The low EC50 for BDNF-induced survival and
      ES suggests that TrkB mediates both of these biological activities. BDNF does not
      alter glutamate-evoked rises of intracellular Ca2+, suggesting BDNF acts
      downstream. Both wortmannin and LY294002, which specifically block the
      phosphatidylinositol 3-kinase (PI3K) intracellular signaling pathway in motor
      neurons, inhibit BDNF-induced ES. We confirm this finding using a herpes simplex
      virus (HSV) that expresses the dominant negative p85 subunit of PI3K. Infecting
      motor neurons with this HSV, but not a control HSV, blocks activation of the PI3K
      pathway and BDNF-induced ES. Through the activation of TrkB and the PI3K
      signaling pathway, BDNF renders developing motor neurons susceptible to glutamate
      receptor-mediated cell death.

PMID- 10646508
TI  - Mu-opioid agonist inhibition of kappa-opioid receptor-stimulated extracellular
      signal-regulated kinase phosphorylation is dynamin-dependent in C6 glioma cells.
AB  - In previous studies we found that mu-opioids, acting via mu-opioid receptors,
      inhibit endothelin-stimulated C6 glioma cell growth. In the preceding article we
      show that the kappa-selective opioid agonist U69,593 acts as a mitogen with a
      potency similar to that of endothelin in the same astrocytic model system. Here
      we report that C6 cell treatment with mu-opioid agonists for 1 h results in the
      inhibition of kappa-opioid mitogenic signaling. The mu-selective agonist
      endomorphin-1 attenuates kappa-opioid-stimulated DNA synthesis, phosphoinositide
      turnover, and extracellular signal-regulated kinase phosphorylation. To
      investigate the role of receptor endocytosis in signaling, we have examined the
      effects of dynamin-1 and its GTPase-defective, dominant suppressor mutant (K44A)
      on opioid modulation of extracellular signal-regulated kinase phosphorylation in
      C6 cells. Overexpression of dynamin K44A in C6 cells does not affect kappa-opioid
      phosphorylation of extracellular signal-regulated kinase. However, it does block
      the inhibitory action on kappa-opioid signaling mediated by the kappa-opioid
      receptor. Our results are consistent with a growing body of evidence of the
      opposing actions of mu- and kappa-opioids and provide new insight into the role
      of opioid receptor trafficking in signaling.

PMID- 10646510
TI  - Activation of nuclear factor-kappaB in C6 rat glioma cells after transfection
      with glia maturation factor.
AB  - The 17-kDa endogenous brain protein glia maturation factor (GMF) was transfected
      into C6 rat glioma cells using a replication-defective human adenovirus vector.
      The cells overexpressed GMF but did not secrete the protein into the medium.
      Transfection with GMF led to the activation of the transcription factor nuclear
      factor-kappaB (NF-kappaB), as evidenced by electrophoretic mobility shift assay
      of the nuclear extract, using a double-stranded oligonucleotide probe containing
      the consensus binding sequence for NF-kappaB. The specificity of binding was
      demonstrated by competition with unlabeled probe and by the nonbinding of the
      mutant probe. Binding was detectable as early as 3 h after transfection, peaked
      at 6 and 12 h, and gradually declined thereafter. The observed NF-kappaB
      activation was reduced by cotransfection with catalase and by the presence of
      high concentrations of pyruvate in the medium, suggesting the involvement of
      H2O2. The p38 mitogen-activated protein kinase inhibitor SB-203580 also
      suppressed the GMF-activated NF-kappaB, suggesting the involvement of the p38
      signal transduction cascade. On the other hand, the phorbol ester phorbol 12
      myristate 13-acetate activated NF-kappaB whether or not GMF was overexpressed.
      Along with NF-kappaB activation was an enhanced expression of superoxide
      dismutase (SOD), which was suppressed if NF-kappaB nuclear translocation was
      blocked by its specific decoy DNA, implicating NF-kappaB as an upstream mediator
      of this antioxidant enzyme. The p38 inhibitor SB-203580 also blocked the GMF
      activated SOD. As NF-kappaB and SOD are both pro-survival signals, the results
      suggest a cytoprotective role for endogenous GMF in glial cells.

PMID- 10646511
TI  - Stimulation of endothelin B receptor modulates the inflammatory activation of rat
      astrocytes.
AB  - Inside the brain tissue, endothelins play numerous important biological roles.
      One of the targets, astrocytes, predominantly display endothelin receptor subtype
      B (ET(B)). On cultured primary rat astroglial cells, we analyzed the effect of
      IRL1620, a selective ET(B) receptor agonist, on the production of nitric oxide
      (NO) and the synthesis of interleukin (IL)-6 and tumor necrosis factor (TNF)
      alpha. We performed these experiments in the presence or absence of interferon
      gamma (IFN-gamma) and/or lipopolysaccharide (LPS). IRL1620 decreases NO
      production under basal conditions and after IFN-gamma stimulation. However,
      during LPS-induced NO production, IRL1620 enhances this release. The basal IL-6
      secretion and especially the LPS-induced synthesis are enhanced by the IRL1620
      stimulation. The LPS-dependent TNF-alpha production is increased by the ET(B)
      stimulation. The IRL1620-induced decrease of basal NO production is not dependent
      on Ca2+ entry or on phospholipase C (PLC) activation, as shown by the use of
      LaCl3 and U73122, respectively. In the presence of LPS, the IRL1620 potentiation
      of NO production is inhibited by LaCl3 and U73122. The IRL1620-induced increase
      of IL-6 is dependent on PLC activation. These results suggest that endothelins
      can have dual effects depending on the costimulatory factors present. Endothelins
      thus have important immunomodulatory functions in the brain.

PMID- 10646512
TI  - Angiotensin II-induced decrease in expression of inducible nitric oxide synthase
      in rat astroglial cultures: role of protein kinase C.
AB  - Inducible nitric oxide synthase (iNOS) has been implicated as a mediator of
      cellular toxicity in a variety of neurodegenerative disorders. Nitric oxide,
      which is generated in high quantities following induction of iNOS, combines with
      other oxygen radicals to form highly reactive, death-inducing compounds. Given
      the frequency of neuronal death due to neurodegenerative diseases, cerebral
      trauma, and stroke, it is important to study the mechanisms of regulation of iNOS
      in the brain. We demonstrated previously that angiotensin II (Ang II) decreases
      the expression of iNOS produced by bacterial endotoxin or cytokines in cultured
      astroglia prepared from adult rat brain. Here, we have addressed the mechanisms
      by which Ang II negatively modulates iNOS. The inhibitory effects of Ang II on
      lipopolysaccharide-induced expression of iNOS mRNA and protein and nitrite
      accumulation were mimicked by the protein kinase C (PKC) activator phorbol 12
      myristate 13-acetate. Down-regulation of PKC produced by long-term treatment of
      astroglia with phorbol 12-myristate 13-acetate abolished the inhibitory effect of
      Ang II on lipopolysaccharide-stimulated expression of iNOS mRNA and nitrite
      accumulation. Finally, the reduction of lipopolysaccharide-induced nitrite
      accumulation by Ang II was attenuated by the selective PKC inhibitor
      chelerythrine. Collectively, these data indicate a role for PKC in the inhibitory
      actions of Ang II on iNOS expression in cultured astroglia.

PMID- 10646513
TI  - Chronic hypoxia enhances adenosine release in rat PC12 cells by altering
      adenosine metabolism and membrane transport.
AB  - Acute exposure to hypoxia causes a release of adenosine (ADO) that is inversely
      related to the O2 levels in oxygen-sensitive pheochromocytoma (PC12) cells. In
      the current study, chronic exposure (48 h) of PC12 cells to moderate hypoxia (5%
      O2) significantly enhanced the release of ADO during severe, acute hypoxia (1%
      O2). Investigation into the intra- and extracellular mechanisms underpinning the
      secretion of ADO in PC12 cells chronically exposed to hypoxia revealed changes in
      gene expression and activities of several key enzymes associated with ADO
      production and metabolism, as well as the down-regulation of a nucleoside
      transporter. Decreases in the enzymatic activities of ADO kinase and ADO
      deaminase accompanied by an increase in those of cytoplasmic and ecto-5'
      nucleotidases bring about an increased capacity to produce intra- and
      extracellular ADO. This increased potential to generate ADO and decreased
      capacity to metabolize ADO indicate that PC12 cells shift toward an ADO producer
      phenotype during hypoxia. The reduced function of the rat equilibrative
      nucleoside transporter rENT1 also plays a role in controlling extracellular ADO
      levels. The hypoxia-induced alterations in the ADO metabolic enzymes and the
      rENT1 transporter seem to increase the extracellular concentration of ADO. The
      biological significance of this regulation is unclear but is likely to be
      associated with modulating cellular activity during hypoxia.

PMID- 10646515
TI  - Localization of the heat-shock protein Hsp70 to the synapse following
      hyperthermic stress in the brain.
AB  - Heat-shock proteins are induced in response to cellular stress. Although heat
      shock proteins are known to function in repair and protective mechanisms, their
      relationship to critical neural processes, such as synaptic function, has
      received little attention. Here we investigate whether the major heat-shock
      protein Hsp70 localizes to the synapse following a physiologically relevant
      increase in temperature in the mammalian nervous system. Our results indicate
      that hyperthermia-induced Hsp70 is associated with pre- and postsynaptic
      elements, including the postsynaptic density. The positioning of Hsp70 at the
      synapse could facilitate the repair of stress-induced damage to synaptic proteins
      and also contribute to neuroprotective events at the synapse.

PMID- 10646514
TI  - Cyclic GMP/cyclic GMP-dependent protein kinase system prevents excitotoxicity in
      an immortalized oligodendroglial cell line.
AB  - Previously, we have demonstrated that excitotoxicity of oligodendrocyte-like
      cells (OLC), differentiated from immortalized rat O-2A progenitor cells (CG-4
      cells), is prevented by cyclic AMP-elevating agents. We now report that some
      agents that elevate cyclic GMP prevent OLC excitotoxicity. Kainate-induced injury
      was prevented by cyclic GMP analogues (8-bromo-cyclic GMP and dibutyryl cyclic
      GMP), a guanylate cyclase activator [atrial natriuretic peptide (ANP)], and
      phosphodiesterase inhibitors [3-isobutyl-1-methylxanthine (IBMX), ibudilast,
      propentofylline, and rolipram]. When both forskolin and 8-bromo-cyclic GMP were
      added, kainate-induced injury was additively prevented. There was a strong
      positive correlation between suppression of kainate-induced Ca2+ influx and
      prevention of injury by these chemicals. The measurement of intracellular cyclic
      AMP and cyclic GMP by radioimmunoassay demonstrated the following: an increase of
      cyclic GMP with treatment with 8-bromo-cyclic GMP, dibutyryl cyclic GMP, and ANP;
      an increase of cyclic AMP with treatment with ibudilast and rolipram; and an
      increase of both cyclic AMP and cyclic GMP with treatment with IBMX and
      propentofylline. Kainate-induced Ca2+ influx was decreased by 8-(4
      chlorophenylthiol)-guanosine-3',5'-monophosphate, an activator of cyclic GMP
      dependent protein kinase (PKG), or okadaic acid, an inhibitor of protein
      phosphatases 1 and 2A. RT-PCR and westem blotting of OLC demonstrated
      transcription of PKG II gene and translation of PKG Ibeta mRNA, but no
      translation of PKG Ialpha mRNA. Therefore, we concluded that the cyclic GMP/PKG
      system prevents OLC excitotoxicity.

PMID- 10646516
TI  - Kainic acid-induced apoptosis in rat striatum is associated with nuclear factor
      kappaB activation.
AB  - The present study evaluated whether nuclear factor-kappaB (NF-kappaB) activation
      contributes to the apoptotic-like death of striatal neurons induced by kainic
      acid (KA) receptor stimulation. Intrastriatally infused KA (1.25-5.0 nmol)
      produced substantial neuronal loss as indicated by an 8-73% decrease in 67-kDa
      glutamic acid decarboxylase (p<0.05). KA (1.25-5.0 nmol) elicited
      internucleosomal DNA fragmentation that was inhibited by the AMPA/KA receptor
      antagonist NBQX (1,2,3,4-tetrahydro-6-nitro-2,3-dibenzo[f]quinoxaline-7
      sulfonamide) but not by the NMDA receptor antagonist MK-801. A decrease in
      IkappaB-alpha protein levels, which was accompanied by an increase in NF-kappaB
      binding activity, was found from 6 to 72 h after KA (2.5 nmol) infusion. NF
      kappaB was composed mainly of p65 and c-Rel as revealed by supershift assay. In
      addition, c-Myc and p53 increased from five- to sevenfold from 24 to 72 h after
      KA (2.5 nmol) administration. Immunohistochemistry revealed high levels of c-Myc
      and p53 immunoreactivity, mainly in medium-sized striatal neurons. Pretreatment
      with the cell-permeable recombinant peptide NF-kappaB SN50 (5-20 microg) blocked
      NF-kappaB nuclear translocation, but had no effect on AP-1 binding. NF-kappaB
      SN50 also inhibited the KA-induced up-regulation of c-Myc and p53, as well as
      internucleosomal DNA fragmentation. The apoptotic-like destruction of rat
      striatal neurons induced by KA receptor stimulation thus appears to involve
      biochemical mechanisms similar to those mediating the excitotoxic response to
      NMDA receptor stimulation. The present results provide additional support for the
      view that NF-kappaB activation contributes to c-Myc and p53 induction and
      subsequent apoptosis in an excitotoxic model of Huntington's disease.

PMID- 10646517
TI  - Shp-2 specifically regulates several tyrosine-phosphorylated proteins in brain
      derived neurotrophic factor signaling in cultured cerebral cortical neurons.
AB  - Brain-derived neurotrophic factor (BDNF), a member of the neurotrophins, promotes
      differentiation and survival and regulates plasticity of various types of
      neurons. BDNF binds to TrkB, a receptor tyrosine kinase, which results in the
      activation of a variety of signaling molecules to exert the various functions of
      BDNF. Shp-2, a Src homology 2 domain-containing cytoplasmic tyrosine phosphatase,
      is involved in neurotrophin signaling in PC12 cells and cultured cerebral
      cortical neurons. To examine the roles of Shp-2 in BDNF signaling in cultured rat
      cerebral cortical neurons, the wild-type and phosphatase-inactive mutant (C/S
      mutant) forms of Shp-2 were ectopically expressed in cultured neurons using
      recombinant adenovirus vectors. We found that several proteins tyrosine
      phosphorylated in response to BDNF showed enhanced levels of tyrosine
      phosphorylation in cultured neurons infected with C/S mutant adenovirus in
      comparison with those infected with the wild-type Shp-2 adenovirus. In addition,
      in immunoprecipitates with anti-Shp-2 antibody, we also observed at least four
      proteins that displayed enhanced phosphorylation in response to BDNF in cultured
      neurons infected with the C/S mutant adenovirus. We found that the Shp-2-binding
      protein, brain immunoglobulin-like molecule with tyrosine-based activation motifs
      (BIT), was strongly tyrosine-phosphorylated in response to BDNF in cultured
      neurons expressing the C/S mutant of Shp-2. In contrast, the level of BDNF
      induced phosphorylation of mitogen-activated protein kinase and coprecipitated
      proteins with anti-Trk and Grb2 antibodies did not show any difference between
      neurons infected with these two types of Shp-2. Furthermore, the survival effect
      of BDNF was enhanced by the wild type of Shp-2, although it was not influenced by
      the C/S mutant of Shp-2. These results indicated that in cultured cerebral
      cortical neurons Shp-2 is specifically involved in the regulation of several
      tyrosine-phosphorylated proteins, including BIT, in the BDNF signaling pathway.
      In addition, the phosphatase Shp-2 may not influence the level of BDNF-induced
      activation of mitogen-activated protein kinase in cultured cortical neurons.
      Further, Shp-2 may have potential to positively regulate BDNF-promoting neuronal
      survival.

PMID- 10646518
TI  - Membrane-bound form of ADP-ribosyl cyclase in rat cortical astrocytes in culture.
AB  - ADP-ribosyl cyclase activities in cultured rat astrocytes were examined by using
      TLC for separation of enzymatic products. A relatively high rate of [3H]cyclic
      ADP-ribose production converted from [3H]NAD+ by ADP-ribosyl cyclase (2.015+/
      0.554 nmol/min/mg of protein) was detected in the crude membrane fraction of
      astrocytes, which contained approximately 50% of the total cyclase activity in
      astrocytes. The formation rate of [3H]ADP-ribose from cyclic ADP-ribose by cyclic
      ADP-ribose hydrolase and/or from NAD+ by NAD glycohydrolase was low and enriched
      in the cytosolic fraction. Although NAD+ in the extracellular medium was
      metabolized to cyclic ADP-ribose by incubating cultures of intact astrocytes, the
      presence of Triton X-100 in the medium for permeabilizing cells increased cyclic
      ADP-ribose production three times as much. Isoproterenol and GTP increased
      [3H]cyclic ADP-ribose formation in crude membrane-associated cyclase activity.
      This isoproterenol-induced stimulation of membrane-associated ADP-ribosyl cyclase
      activity was confirmed by cyclic GDP-ribose formation fluorometrically. This
      stimulatory action was blocked by prior treatment of cells with cholera toxin but
      not with pertussis toxin. These results suggest that ADP-ribosyl cyclase in
      astrocytes has both extracellular and intracellular actions and that signals of
      beta-adrenergic stimulation are transduced to membrane-bound ADP-ribosyl cyclase
      via G proteins within cell surface membranes of astrocytes.

PMID- 10646519
TI  - Signaling within a caveolae-like membrane microdomain in human neuroblastoma
      cells in response to fibroblast growth factor.
AB  - It is now clear that the plasma membrane is not homogeneous but contains specific
      subcompartments characterized by their unique lipid and protein composition.
      Based on their enrichment in various signaling molecules, these microcompartments
      are now recognized to be sites of localized signal transduction for several
      extracellular stimuli. At least two different types of microdomains can be
      identified, largely based on the presence or absence of the caveolin proteins.
      The generic name of caveolae-like domains is commonly used to refer to both
      domains indistinguishably. Although caveolin proteins were long thought to be
      absent from the brain, we have shown that the human neuroblastoma cell line LAN-1
      expresses both caveolin-1 and caveolin-2. Basic fibroblast growth factor (FGF)-2
      induced a specific signaling response within the caveolae-like domain of LAN-1
      cells, characterized by the tyrosine phosphorylation of a 75-80-kDa protein. This
      protein present in the caveolae-like domains has properties suggesting that it is
      a member of the SNT family of adapter proteins. The signaling event originating
      in the caveolae-like domains in response to FGF-2 appeared to require the
      activation of at least Fyn and Lyn, two members of the Src family of tyrosine
      kinases. This work suggests that compartmentalized signaling within caveolae-like
      domains may create a level of specificity for certain growth factors such as FGF.

PMID- 10646520
TI  - Feedback control of mesolimbic somatodendritic dopamine release in rat brain.
AB  - The objective of this study was to examine the role of dopamine (DA) receptors in
      the nucleus accumbens (ACB) in controlling feedback regulation of mesolimbic
      somatodendritic DA release in the ventral tegmental area (VTA) of Wistar rats
      using ipsilateral dual-probe in vivo microdialysis. Perfusion of the ACB for 60
      min with the DA uptake inhibitor GBR-12909 (10-1,000 microM) or nomifensine (10
      1,000 microM) dose-dependently increased the extracellular levels of DA in ACB
      and concomitantly reduced the extracellular levels of DA in the VTA. Coperfusion
      of 100 microM nomifensine with either 100 microM SCH-23390 (SCH), a D1
      antagonist, or 100 microM sulpiride (SUL), a D2 receptor antagonist, produced
      either an additive (for SCH) or a synergistic (for SUL) elevation in the
      extracellular levels of DA in the ACB, whereas the reduction in the extracellular
      levels of DA in the VTA produced by nomifensine alone was completely prevented by
      addition of either antagonist. Application of 100 microM SCH or SUL alone through
      the microdialysis probe in the ACB increased the extracellular levels of DA in
      the ACB, whereas the extracellular levels of DA in the VTA remained unchanged.
      Overall, the results suggest that (a) increasing the synaptic levels of DA in the
      ACB activates a long-loop negative feedback pathway to the VTA involving both D1
      and D2 postsynaptic receptors and (b) terminal DA release within the ACB is
      regulated directly by D2 autoreceptors and may be indirectly regulated by D1
      receptors, possibly on interneurons and/or through postsynaptic inhibition of the
      negative feedback loop.

PMID- 10646521
TI  - Role of striatal serotonin2A and serotonin2C receptor subtypes in the control of
      in vivo dopamine outflow in the rat striatum.
AB  - This study investigated, using in vivo microdialysis in the striatum of freely
      moving rats, the role of striatal serotonin2A (5-HT2A) and 5-HT2C receptor
      subtypes in the modulation of dopamine (DA) and 3, 4-dihydroxyphenylacetic acid
      (DOPAC) outflow, both in basal conditions and under activation induced by
      subcutaneous administration of 0.01 mg/kg haloperidol. The different 5-HT2 agents
      used were applied intrastriatally at a 1 microM concentration through the
      microdialysis probe. Basal DA efflux was enhanced (27%) by the 5-HT2A/2B/2C
      agonist 1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane (DOI) and reduced (-30%) by
      the 5-HT2B/2C antagonist SB 206553. It was unaffected by infusion of the 5-HT2A
      antagonist SR 46349B. The effect of DOI was abolished by SB 206553 but not
      modified by SR 46349B. Haloperidol-stimulated DA efflux (65-70%) was reduced by
      both SR 46349B (-32%) and the 5-HT2A/2B/2C antagonist ritanserin (-30%) but not
      affected by SB 206553. Conversely, the effect of haloperidol was potentiated
      (22%) when DOI was coperfused with SB 206553. Also, haloperidol-stimulated DOPAC
      outflow (40-45%) was reduced (-20%) by SR 46349B and potentiated (25%) by the
      combination of SB 206553 with DOI. These results indicate that striatal 5-HT2A
      receptors, probably through activation of DA synthesis, positively modulate DA
      outflow only under activated conditions. In contrast, striatal 5-HT2C receptors
      exert a facilitatory control on basal DA efflux, which appears to be both tonic
      and phasic.

PMID- 10646522
TI  - Sodium-calcium exchange affects local calcium signal decay and the rate of
      exocytotic secretion in single chromaffin cells.
AB  - The effects of Na+ deprivation on local calcium signal decay and the rate of
      exocytotic secretion were measured in single bovine chromaffin cells to determine
      whether Na-Ca exchange influences the local cytosolic Ca2+ signal for
      neurohormone release. Na+ replacement with N-methylglucamine caused a marked
      slowing of the decay of the local Ca2+ signal near points of its initiation, as
      measured by high-resolution fluorescent Ca2+ imaging in the confocal laser
      scanning microscope. Na+ replacement also resulted in a doubling of the rate and
      magnitude of exocytotic secretion measured in single cells by high-resolution
      microamperometry. Release rates provide an independent measure of local active
      zone Ca2+. Five repetitive stimulations of the same cell in Na+-free, but not in
      Na+-containing, medium resulted in a progressively increasing rate of
      catecholamine release, suggesting an increasing level of active zone Ca2+ and a
      role of Na-Ca exchange activity in Ca2+ clearance between stimulations. As
      secretory activity and its triggering Ca2+ signals are known to be co-localized
      in active zones along the plasma membrane, the results suggest that Na-Ca
      exchange may influence the decay of the local Ca2+ signal for exocytotic
      secretion. This would be consistent with a contribution to local Ca2+ clearance
      by a novel mechanism utilizing the insertion of secretory vesicle Na-Ca
      exchangers into the plasma membrane during exocytosis.

PMID- 10646523
TI  - Analysis of gap junction assembly using mutated connexins detected in Charcot
      Marie-Tooth X-linked disease.
AB  - The assembly of gap junction intercellular communication channels was studied by
      analysis of the molecular basis of the dysfunction of connexin 32 mutations
      associated with the X-linked form of Charcot-Marie-Tooth disease in which
      peripheral nervous transmission is impaired. A cell-free translation system
      showed that six recombinant connexin 32 mutated proteins-four point mutations at
      the cytoplasmic amino terminus, one at the membrane aspect of the cytoplasmic
      carboxyl terminus, and a deletion in the intracellular loop-were inserted into
      microsomal membranes and oligomerised into connexon hemichannels with varying
      efficiencies. The functionality of the connexons was determined by the ability of
      HeLa cells expressing the respective connexin cDNAs to transfer Lucifer yellow.
      The intracellular trafficking properties of the mutated connexins were determined
      by immunocytochemistry. The results show a relationship between intracellular
      interruption of connexin trafficking, the efficiency of intercellular
      communication, and the severity of the disease phenotype. Intracellular retention
      was explained either by deficiencies in the ability of connexins to oligomerise
      or by mutational changes at two targeting motifs. The results point to dominance
      of two specific targeting motifs: one at the amino terminus and one at the
      membrane aspect of the cytoplasmically located carboxyl tail. An intracellular
      loop deletion of six amino acids, associated with a mild phenotype, showed
      partial oligomerisation and low intercellular dye transfer compared with wild
      type connexin 32. The results show that modifications in trafficking and assembly
      of gap junction channels emerge as a major feature of Charcot-Marie-Tooth X
      linked disease.

PMID- 10646524
TI  - Alpha-synuclein up-regulation in substantia nigra dopaminergic neurons following
      administration of the parkinsonian toxin MPTP.
AB  - Mutations in alpha-synuclein cause a form of familial Parkinson's disease (PD),
      and wild-type alpha-synuclein is a major component of the intraneuronal
      inclusions called Lewy bodies, a pathological hallmark of PD. These observations
      suggest a pathogenic role for alpha-synuclein in PD. Thus far, however, little is
      known about the importance of alpha-synuclein in the nigral dopaminergic pathway
      in either normal or pathological situations. Herein, we studied this question by
      assessing the expression of synuclein-1, the rodent homologue of human alpha
      synuclein, in both normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)
      intoxicated mice. In normal mice, detectable levels of synuclein mRNA and protein
      were seen in all brain regions studied and especially in ventral midbrain. In the
      latter, there was a dense synuclein-positive nerve fiber network, which
      predominated over the substantia nigra, and only few scattered synuclein-positive
      neurons. After a regimen of MPTP that kills dopaminergic neurons by apoptosis,
      synuclein mRNA and protein levels were increased significantly in midbrain
      extracts; the time course of these changes paralleled that of MPTP-induced
      dopaminergic neurodegeneration. In these MPTP-injected mice, there was also a
      dramatic increase in the number of synuclein-immunoreactive neurons exclusively
      in the substantia nigra pars compacta; all synuclein-positive neurons were
      tyrosine hydroxylase-positive, but none coexpressed apoptotic features. These
      data indicate that synuclein is highly expressed in the nigrostriatal pathway of
      normal mice and that it is up-regulated following MPTP-induced injury. In light
      of the synuclein alterations, it can be suggested that, by targeting this
      protein, one may modulate MPTP neurotoxicity and, consequently, open new
      therapeutic avenues for PD.

PMID- 10646525
TI  - Nerve growth factor in glia and inflammatory cells of the injured rat spinal
      cord.
AB  - Nerve growth factor (NGF) is crucial for the development of sympathetic and small
      diameter sensory neurons and for maintenance of their mature phenotype. Its role
      in generating neuronal pathophysiology is less well understood. After spinal cord
      injury, central processes of primary afferent fibers sprout into the dorsal horn,
      contributing to the development of autonomic dysfunctions and pain. NGF may
      promote these states as it stimulates sprouting of small-diameter afferent fibers
      and its concentration in the spinal cord increases after cord injury. The cells
      responsible for this increase must be identified to develop a strategy to prevent
      the afferent sprouting. Using immunocytochemistry, we identified cells containing
      NGF in spinal cord sections from intact rats and from rats 1 and 2 weeks after
      high thoracic cord transection. In intact rats, this neurotrophin was present in
      a few ramified microglia and in putative Schwann cells in the dorsal root. Within
      and close to the lesion of cord-injured rats, NGF was in many activated, ramified
      microglia, in a subset of astrocytes, and in small, round cells that were neither
      glia nor macrophages. NGF-immunoreactive putative Schwann cells were prevalent
      throughout the thoracolumbar cord in the dorsal roots and the dorsal root entry
      zones. Oligodendrocytes were never immunoreactive for this protein. Therapeutic
      strategies targeting spinal cord cells that produce NGF may prevent primary
      afferent sprouting and resulting clinical disorders after cord injury.

PMID- 10646526
TI  - Caspase-3 mediated neuronal death after traumatic brain injury in rats.
AB  - During programmed cell death, activation of caspase-3 leads to proteolysis of DNA
      repair proteins, cytoskeletal proteins, and the inhibitor of caspase-activated
      deoxyribonuclease, culminating in morphologic changes and DNA damage defining
      apoptosis. The participation of caspase-3 activation in the evolution of neuronal
      death after traumatic brain injury in rats was examined. Cleavage of pro-caspase
      3 in cytosolic cellular fractions and an increase in caspase-3-like enzyme
      activity were seen in injured brain versus control. Cleavage of the caspase-3
      substrates DNA-dependent protein kinase and inhibitor of caspase-activated
      deoxyribonuclease and co-localization of cytosolic caspase-3 in neurons with
      evidence of DNA fragmentation were also identified. Intracerebral administration
      of the caspase-3 inhibitor N-benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethyl
      ketone (480 ng) after trauma reduced caspase-3-like activity and DNA
      fragmentation in injured brain versus vehicle at 24 h. Treatment with N
      benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethyl ketone for 72 h (480 ng/day)
      reduced contusion size and ipsilateral dorsal hippocampal tissue loss at 3 weeks
      but had no effect on functional outcome versus vehicle. These data demonstrate
      that caspase-3 activation contributes to brain tissue loss and downstream
      biochemical events that execute programmed cell death after traumatic brain
      injury. Caspase inhibition may prove efficacious in the treatment of certain
      types of brain injury where programmed cell death occurs.

PMID- 10646527
TI  - Effect of amphotericin B on wild-type and mutated prion proteins in cultured
      cells: putative mechanism of action in transmissible spongiform encephalopathies.
AB  - Transmissible spongiform encephalopathies form a group of fatal neurodegenerative
      disorders that have the unique property of being infectious, sporadic, or genetic
      in origin. Although some doubts remain on the nature of the responsible agent of
      these diseases, it is clear that a protein called PrP(Sc) [the scrapie isoform of
      prion protein (PrP)] plays a central role. PrP(Sc) represents a conformational
      variant of PrP(C) (the cellular isoform of PrP), the normal host protein. Polyene
      antibiotics, such as amphotericin B, have been shown to delay the accumulation of
      PrP(Sc) and to increase the incubation time of the disease after experimental
      transmission in laboratory animals. Unlike agents such as Congo red, the
      inhibitory effect of amphotericin B on PrP(Sc) generation has not been observed
      in infected cultures. Using transfected cells expressing wild-type or mutated
      mouse PrPs, we show here that amphotericin B is able to interfere with the
      generation of abnormal PrP isoforms in culture. Its action seems related to a
      modification of PrP trafficking through the association of this
      glycosylphosphatidylinositol-anchored protein with detergent-resistant
      microdomains. These results represent a first step toward the comprehension of
      the mechanism of action of amphotericin B in transmissible spongiform
      encephalopathies.

PMID- 10646528
TI  - Effect of alpha-phenyl-N-tert-butylnitrone on brain cell membrane function and
      energy metabolism in experimental Escherichia coli meningitis in the newborn
      piglet.
AB  - We evaluated the efficacy of alpha-phenyl-N-tertbutylnitrone as an adjunctive
      therapy in experimental bacterial meningitis in the newborn piglet. Meningitis
      was induced by intracisternal injection of 10(8) colony-forming units of
      Escherichia coli in 100 microl of saline. Alpha-Phenyl-N-tert-butylnitrone 100
      mg/kg was given as a bolus intravenous injection 30 min before induction of
      meningitis. Although it completely abolished the elevated CSF tumor necrosis
      factor-a level observed in the meningitis group, alpha-phenyl-N-tert-butylnitrone
      did not down-modulate parameters of inflammatory responses such as increased
      intracranial pressure, hypoglycorrhachia, elevated CSF lactate level, and CSF
      leukocytosis observed in this group. However, alpha-phenyl-N-tert-butylnitrone
      treatment mitigated alterations in brain cell membrane structure and function
      during meningitis, evidenced by amelioration of increased brain cell membrane
      lipid peroxidation products (conjugated dienes) and decreased Na+, K+-ATPase
      activity. Reduced mean arterial blood pressure, cerebral perfusion pressure,
      brain glucose concentration, and cerebral energy stores and marginally increased
      brain lactate level observed in the meningitis group were also ameliorated. These
      results suggest that although it failed to attenuate the inflammatory responses,
      alpha-phenyl-N-tert-butylnitrone was effective in ameliorating brain injury in
      neonatal bacterial meningitis.

PMID- 10646529
TI  - Acidic amino acid clearance from CSF in the neonatal versus adult rat using
      ventriculo-cisternal perfusion.
AB  - The acidic amino acids aspartate and glutamate are excitatory neurotransmitters
      in the CNS. The clearance of this group of amino acids from CSF of adult and
      neonatal (7-day-old) rats was investigated. Ventriculo-cisternal perfusions with
      14C-amino acids and 3H-dextran were carried out for up to 90 min. Uptake of the
      amino acids by the whole brain was measured, and the loss to blood was
      calculated. 3H-Dextran was included in the perfusate for measurement of CSF
      secretion rate. After 90-min perfusion, both aspartate and glutamate showed a
      similar uptake into the whole brain, and this did not change with age (p>0.05).
      However, clearance from CSF was greater in the adult, as was entry into blood
      from CSF. Addition of 5 mM excess unlabelled amino acid resulted in reduction in
      the brain uptake of both 14C-amino acids in the adult rat. In the neonate,
      addition of aspartate also reduced brain aspartate uptake, whereas addition of
      glutamate increased brain neonatal [14C]glutamate uptake. The rate of CSF
      secretion was significantly greater in the adult, 1.26+/-0.18 microl x min(-1) x
      g(-1), than in the neonate, 0.62+/-0.08 microl x min(-1) x g(-1), and the
      turnover of CSF was greater in adults (p<0.01). In summary, both aspartate and
      glutamate showed greater clearances from CSF in the adult than the neonate. This
      clearance was found to be by carrier-mediated mechanisms.

PMID- 10646530
TI  - Increased levels of tau protein in SH-SY5Y cells after treatment with
      cholinesterase inhibitors and nicotinic agonists.
AB  - Several cholinesterase inhibitors used in the treatment of Alzheimer's disease
      (AD) have been shown to interact with an allosteric site on the nicotinic
      acetylcholine receptor (nAChR). A possible linkage between the phosphorylation
      state of tau, the major component of paired helical filaments found in AD brain,
      and stimulation of nAChRs by cholinesterase inhibitors and nicotinic agonists was
      investigated. Western blot analysis showed that treatment of SH-SY5Y cells for 72
      h with the cholinesterase inhibitors tacrine (10(-5) M), donepezil (10(-5) M),
      and galanthamine (10(-5) M), nicotine (10(-5) M), and epibatidine (10(-7) M)
      increased tau levels as detected with Tau-1, AT 8, and AT 270 monoclonal
      antibodies and binding of [3H]epibatidine. The increase in tau immunoreactivity
      induced by nicotine, epibatidine, and tacrine, but not the up-regulation of
      nAChRs, was prevented by the antagonists d-tubocurarine and mecamylamine. Both
      antagonists were synergistic with the nicotinic agonists in causing up
      regulation, but only d-tubocurarine showed a synergistic effect with tacrine. The
      increased tau immunoreactivity induced by tacrine was not prevented by atropine,
      indicating that in terms of cholinergic receptors, tacrine modulates tau levels
      mainly through interactions with nAChRs and not with muscarinic receptors.
      Additional work is needed to determine the exact mechanism by which
      cholinesterase inhibitors and nicotinic agonists modulate phosphorylation and
      levels of tau protein.

PMID- 10646531
TI  - Chronic stress induces the expression of inducible nitric oxide synthase in rat
      brain cortex.
AB  - Long-term exposure to stress has detrimental effects on several brain functions
      in many species, including humans, and leads to neurodegenerative changes.
      However, the underlying neural mechanisms by which stress causes
      neurodegeneration are still unknown. We have investigated the role of
      endogenously released nitric oxide (NO) in this phenomenon and the possible
      induction of the inducible NO synthase (iNOS) isoform. In adult male rats, stress
      (immobilization for 6 h during 21 days) increases the activity of a calcium
      independent NO synthase and induces the expression of iNOS in cortical neurons as
      seen by immunohistochemical and western blot analysis. Three weeks of repeated
      immobilization increases immunoreactivity for nitrotyrosine, a nitration product
      of peroxynitrite. Repeated stress causes accumulation of the NO metabolites NO2+
      NO3- (NOx-) accumulation in cortex, and these changes occur in parallel with
      lactate dehydrogenase (LDH) release and impairment of glutamate uptake in
      synaptosomes. Administration of the selective iNOS inhibitor aminoguanidine (400
      mg/kg i.p. daily from days 7 to 21 of stress) prevents NOx- accumulation in
      cortex, LDH release, and impairment of glutamate uptake in synaptosomes. Taken
      together, these findings indicate that a sustained overproduction of NO via iNOS
      expression may be responsible, at least in part, for some of the
      neurodegenerative changes caused by stress and support a possible neuroprotective
      role for specific iNOS inhibitors in this situation.

PMID- 10646532
TI  - Involvement of nitric oxide in pentylenetetrazole-induced kindling in rats.
AB  - We investigated the role of nitric oxide (NO) and brain-derived neurotrophic
      factor (BDNF) in the pentylenetetrazole (PTZ)-induced kindling in rats. Seizures
      were induced by single administration of PTZ, which was associated with an
      increase in levels of NO metabolites (NOx) in the hippocampus. Pretreatment with
      a neuronal NO synthase inhibitor, 7-nitroindazole (7-NI), diminished the PTZ
      induced increase in NOx levels without affecting the seizure intensity. Repeated
      administration of PTZ produced a gradual increase in the seizure intensity,
      leading to the development of kindling. In the kindled rats, PTZ at a dose of 40
      mg/kg increased NOx levels in the hippocampus, whereas it had no effect in
      control animals. Cotreatment of 7-NI with PTZ blocked the development of kindling
      and attenuated the PTZ-induced increase in NOx levels. A significant increase in
      BDNF levels was observed in the hippocampus of the kindled rats, which returned
      to the control levels following seizures induced by PTZ. 7-NI reduced the
      hippocampal BDNF levels in control rats and suppressed the increase of BDNF
      levels in the kindled rats. Our findings suggest that NO plays a role in the
      development of PTZ-induced kindling and that BDNF may contribute to the NO
      dependent plastic changes in neuronal excitability.

PMID- 10646533
TI  - An investigation of noradrenaline uptake and release by the CATH.a cell line.
AB  - The cell bodies of ascending noradrenergic neurons in the brain are located
      predominantly in the locus coeruleus. An in vitro model of locus coeruleus
      neurons could prove to be a useful tool in the investigation of noradrenergic
      neural networks and their associated pathophysiologies. The CATH.a cell line
      demonstrates some of the properties expected of locus coeruleus neurons, and the
      present study investigated the neurotransmitter uptake and release properties of
      the CATH.a cells. It was surprising that the CATH.a cells failed to accumulate
      [3H]noradrenaline ([3H]NA), suggesting the lack of a functional NA transporter.
      RT-PCR supported this finding by demonstrating the absence of NA transporter
      mRNA. Treatment of CATH.a cells with various differentiating agents failed to
      increase the [3H]NA uptake. Endogenous NA release was studied using HPLC
      detection, which revealed a lack of depolarisation-induced increases in
      endogenous NA release. A human NA transporter-transfected CATH.a cell line was
      generated (termed RUNT), and a study of the [3H]NA uptake revealed that the RUNT
      cells displayed significant uptake that could be blocked by cocaine (10 microM).
      Furthermore, the uptake capacity could be dramatically increased by
      differentiation of the cells with dibutyryl cyclic AMP (1 mM) for 24 h. Using
      dibutyryl cyclic AMP-differentiated RUNT cells, high K+ concentrations (50 mM)
      significantly increased [3H]NA release above basal levels.

PMID- 10646534
TI  - Decreased protein phosphatase 2A activity in hippocampal long-term potentiation.
AB  - Using autophosphorylated Ca2+/calmodulin-dependent protein kinase II (CaM kinase
      II) as substrate, we now find that long-term potentian (LTP) induction and
      maintenance are also associated with a significant decrease in calyculin A
      sensitive protein phosphatase (protein phosphatase 2A) activity, without changes
      in Mg2+-dependent protein phosphatase (protein phosphatase 2C) activity. This
      decrease in protein phosphatase 2A activity was prevented when LTP induction was
      inhibited by treatment with calmidazolium or D-2-amino-5-phosphonopentanoic acid.
      In addition, the application of high-frequency stimulation to 32P-labeled
      hippocampal slices resulted in increases in the phosphorylation of a 55-kDa
      protein immunoprecipitated with anti-phosphatase 2A antibodies. Use of a specific
      antibody revealed that the 55-kDa protein is the B'alpha subunit of protein
      phosphatase 2A. Following purification of brain protein phosphatase 2A, the
      B'alpha subunit was phosphorylated by CaM kinase II, an event that led to the
      reduction of protein phosphatase 2A activity. These results suggest that the
      decreased activity in protein phosphatase 2A following LTP induction contributes
      to the maintenance of constitutively active CaM kinase II and to the long-lasting
      increase in phosphorylation of synaptic components implicated in LTP.

PMID- 10646535
TI  - Intracellular Ca2+ stores regulate muscarinic receptor stimulation of
      phospholipase C in cerebellar granule cells.
AB  - Muscarinic receptor activation of phosphoinositide phospholipase C (PLC) has been
      examined in rat cerebellar granule cells under conditions that modify
      intracellular Ca2+ stores. Exposure of cells to medium devoid of Ca2+ for various
      times reduced carbachol stimulation of PLC with a substantial loss (88%) seen at
      30 min. A progressive recovery of responses was observed following the reexposure
      of cells to Ca2+-containing medium (1.3 mM). However, these changes did not
      appear to result exclusively from changes in the cytosolic Ca2+ concentration
      ([Ca2+]i), which decreased to a lower steady level (approximately 25 nM decrease
      in 1-3 min after extracellular omission) and rapidly returned (within 1 min) to
      control values when extracellular Ca2+ was restored. Only after loading of the
      intracellular Ca2+ stores through a transient 1-min depolarization of cerebellar
      granule cells with 40 mM KCl, followed by washing in nondepolarizing buffer, was
      carbachol able to mobilize intracellular Ca2+. However, the same treatment
      resulted in an 80% enhancement of carbachol activation of PLC. In other
      experiments, partial depletion of the Ca2+ stores by pretreatment of cells with
      thapsigargin and caffeine resulted in an inhibition (18 and 52%, respectively) of
      the PLC response. Furthermore, chelation of cytosolic Ca2+ with BAPTA/AM did not
      influence muscarinic activation of PLC in either the control or predepolarized
      cells. These conditions, however, inhibited both the increase in [Ca2+]i and the
      PLC activation elicited by 40 mM KCl and abolished carbachol-induced
      intracellular Ca2+ release in predepolarized cells. Overall, these results
      suggest that muscarinic receptor activation of PLC in cerebellar granule cells
      can be modulated by changes in the loading state of the Ca2+ stores.

PMID- 10646536
TI  - Identification of an amino acid defining the distinct properties of murine beta1
      and beta3 subunit-containing GABA(A) receptors.
AB  - Murine gamma-aminobutyric acid (GABA) type A homomeric receptors made of beta1
      subunits are profoundly different, when expressed in Xenopus oocytes, from beta3
      homomeric receptors. Application of the intravenous general anesthetic
      pentobarbital, etomidate, or propofol to beta3 homomeric receptors allows current
      flow. In contrast, beta1 homomers do not respond to any of these agents. Through
      construction of chimeric beta1/beta3 receptors, we identified a single amino acid
      that determines the pharmacological difference between the two beta subunits.
      When the serine residue present in the wild-type nonresponsive beta1 subunit is
      replaced by an asparagine found in the same position in the beta3 subunit, the
      resulting point-mutated beta1S265N forms receptors responsive to intravenous
      general anesthetics, like the wild-type beta3 subunits. Conversely, after
      mutation of the wild-type beta3 to beta3N265S, the homomeric receptor loses its
      ability to respond to these same general anesthetics. Wild-type-to-mutant
      titration experiments showed that the nonresponsive phenotype is dominant: A
      single nonresponsive residue within a pentameric receptor is sufficient to render
      the receptor nonresponsive. In alpha1betax or alpha1betaxgamma2 heteromeric
      receptors, the same residue manifests as a partial determinant of the degree of
      potentiation of the GABA-induced current by some general anesthetics. The
      location of this amino acid at the extracellular end of the second transmembrane
      segment, its influence in both homomeric and heteromeric receptor function, and
      its dominant behavior suggest that this residue of the beta subunit is involved
      in an allosteric modulation of the receptor.

PMID- 10646537
TI  - Correlating physiology with gene expression in striatal cholinergic neurones.
AB  - The expression of 34 transmitter-related genes has been examined in the
      cholinergic neurones of rat striatal brain slices, with the aim of correlating
      gene expression with functional activity. The mRNAs encoding types I, II/IIA, and
      III alpha subunits of the voltage-sensitive sodium channels were detected,
      suggesting the presence of these three types of sodium channel. Similarly, mRNAs
      encoding all four alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)
      type glutamate receptor subunits and the NR1 and NR2A, 2B, and 2D subunits of the
      NMDA-type glutamate receptors were detected, suggesting that various combinations
      of these subunits mediate the cellular response to synaptically released
      glutamate. Other mRNAs detected included the NK1 and NK3 tachykinin receptors,
      all four known adenosine receptors, and the GABA-synthesising enzyme glutamate
      decarboxylase. Subpopulations of these cholinergic neurones have been identified
      on the basis of the expression of the NK3 tachykinin receptor in 5% and the trkC
      neurotrophin receptor in 12% of the cells investigated.

PMID- 10646539
TI  - Selective solubilization of high-molecular-mass neurofilament subunit during
      nerve regeneration.
AB  - A reduction in neurofilament (NF) protein synthesis and changes in their
      phosphorylation state are observed during nerve regeneration. To investigate how
      such metabolic changes are involved in the reorganization of the axonal
      cytoskeleton, we studied the injury-induced changes in the solubility and axonal
      transport of NF proteins as well as their phosphorylation states in the rat
      sciatic nerve. In the control nerve, 15-25% of high-molecular-mass NF subunit (NF
      H) was recovered in the 1% Triton-soluble fraction when fractionated in the
      presence of phosphatase inhibitors. After a complete loss of NF proteins distal
      to the injury site (70-75 mm from the spinal cord) 1 week after injury, NF-H
      detected in the regenerating sprouts at 2 weeks or later exhibited higher
      solubility (>50%) and lower C-terminal phosphorylation level than NF-H in the
      control nerve. Solubility increase was also apparent with L-[35S]methionine
      labeled NF-H that was in transit in the proximal axon at the time of injury. The
      low-molecular-mass subunit remained in the insoluble fraction in both the normal
      and the regenerating nerves, indicating that selective solubilization of NF-H
      rather than total filament disassembly occurs during regeneration.

PMID- 10646538
TI  - Pathways of neurosteroid biosynthesis in cell lines from human brain: regulation
      of dehydroepiandrosterone formation by oxidative stress and beta-amyloid peptide.
AB  - Neurosteroids in rodents can originate from peripheral tissues or be locally
      synthesized in specific brain areas. There is, as yet, no information about the
      synthesis and regulation of neurosteroids in human brain. We examined the ability
      of human brain cells to synthesize steroids from a radiolabeled precursor and the
      mRNA and protein expression of key components of peripheral steroidogenic
      machinery. Oligodendrocytes are the source of pregnenolone in human brain. Human
      astrocytes do not synthesize radiolabeled pregnenolone, nor do human neurons.
      There is potential for all three cell types to metabolize pregnenolone to other
      neurosteroids, including dehydroepiandrosterone. mRNA and protein for cytochrome
      P450 17alpha-hydroxylase were found in all cell types, although no activity could
      be demonstrated. We examined the ability of the cells to make
      dehydroepiandrosterone via an alternative pathway induced by treatment with Fe2+.
      Oligodendrocytes and astrocytes make dehydroepiandrosterone via this pathway, but
      neurons do not. In searching for a natural regulator of dehydroepiandrosterone
      formation, we observed that treating oligodendrocytes with beta-amyloid, which
      increases reactive oxygen species, also increased dehydroepiandrosterone
      formation. These effects of beta-amyloid were blocked by vitamin E. These results
      indicate that human brain makes steroids in a cell-specific manner and suggest
      that dehydroepiandrosterone synthesis can be regulated by intracellular free
      radicals.

PMID- 10646540
TI  - The butyrylcholinesterase K-variant shows similar cellular protein turnover and
      quaternary interaction to the wild-type enzyme.
AB  - A recent study has linked the butyrylcholinesterase (BChE) K-variant and the
      apolipoprotein epsilon4 isoform to late-onset Alzheimer's disease. These findings
      have been controversial and have led us to examine the differences between wild
      type and K-variant BChE in enzyme activity, protein stability, and quaternary
      structure. J-variant BChE (E497V/A539T) was also studied because it is associated
      with the K-variant mutation. The K-variant mutation (A539T) is located in the C
      terminal tetramerization domain. Wild-type, K-variant, and J-variant BChE were
      expressed in Chinese hamster ovary cells and purified. The purified enzymes had
      similar binding affinity (Km) values and catalytic rates for butyrylthiocholine
      and benzoylcholine. In pulse-chase studies the K-variant, J-variant, and wildtype
      BChE were degraded rapidly within the cell, with a half-time of approximately 1.5
      h. Less than 5% of the intracellular BChE was exported. The C-terminal peptide
      containing the K-variant mutation interacted with itself as strongly as did the
      wild-type peptide in the yeast two-hybrid system. Both K-variant and wild-type
      BChE assembled into tetramers in the presence of poly-L-proline or the proline
      rich attachment domain of the collagen tail. The native K-variant BChE in serum
      showed the same proportion of tetramers as the native serum wild-type BChE. We
      conclude that the K-variant BChE is similar to wild-type BChE in enzyme activity,
      protein turnover, and tetramer formation.

PMID- 10646541
TI  - Frontal lobe dysfunction in progressive supranuclear palsy: evidence for
      oxidative stress and mitochondrial impairment.
AB  - Recent data from our laboratory have shown a regionally specific increase in
      lipid peroxidation in postmortem progressive supranuclear palsy (PSP) brain. To
      extend this finding, we measured activities of mitochondrial enzymes as well as
      tissue malondialdehyde (MDA) levels in postmortem superior frontal cortex
      (Brodmann's area 9; SFC) from 14 pathologically confirmed cases of PSP and 13 age
      matched control brains. Significant decreases (-39%) in alpha-ketoglutarate
      dehydrogenase complex/glutamate dehydrogenase ratio and significant increases
      (+36%) in tissue MDA levels were observed in the SFC in PSP; no differences in
      complex I or complex IV activities were detected. Together, these results suggest
      that mitochondrial dysfunction and lipid peroxidation may underlie the frontal
      metabolic and functional deficits observed in PSP.

PMID- 10646543
TI  - Women's health issues and nuclear medicine, part III: women and osteoporosis.
AB  - OBJECTIVE: This article is the third in a 4-part series on women's health issues
      and nuclear medicine. After reading this article the technologist should be able
      to: (a) state potential risk factors for osteoporosis; (b) describe osteoporosis
      and its natural history; and (c) identify methods for detecting normal and
      abnormal bone mineral density results.

PMID- 10646542
TI  - Isolation and functional characterization of the chick M5 muscarinic
      acetylcholine receptor gene.
AB  - The chick is a widely used system for study of the actions of muscarinic
      acetylcholine receptors in the cardiovascular, visual, and nervous systems. We
      report the isolation and functional analysis of the gene encoding the chick M5
      muscarinic receptor. RT-PCR analysis indicates that the M5 receptor is expressed
      at low levels in embryonic chick brain and heart. When expressed in stably
      transfected Chinese hamster ovary cells, the M5 receptor exhibits high-affinity
      binding to muscarinic antagonists and mediates robust activation of phospholipase
      C activity.

PMID- 10646544
TI  - Optimizing images of acute deep-vein thrombosis using technetium-99m-apcitide.
AB  - OBJECTIVE: The purpose of this paper is to introduce the nuclear medicine
      technologist to a new radiopharmaceutical, 99mTc-apcitide, for imaging acute
      venous thrombosis. After reading this paper, the technologist should be able to:
      (a) describe patient preparation for imaging with 99mTc-apcitide; (b) state the
      amount of 99mTc-apcitide that is administered to patients for imaging acute
      venous thrombosis; (c) explain patient positioning for optimal image acquisition;
      and (d) discuss gamma camera acquisition parameters and their importance in
      obtaining high-quality images. Clinical cases illustrate both the whole-body
      distribution and diagnostic value of 99mTc-apcitide in detecting acute deep-vein
      thrombosis.

PMID- 10646545
TI  - The usefulness of iodine-123 whole-body scans in evaluating thyroid carcinoma and
      metastases.
AB  - OBJECTIVE: It is recognized that diagnostic doses of (131)I larger than 3 mCi
      will cause some cell injury to the tissue in which it concentrates and reduce
      subsequent uptake of (131)I administered therapeutically. Iodine-123 has been
      suggested as an alternate radiopharmaceutical to perform whole-body scans since
      its primary emissions are photons with minimal particulate radiation and it does
      not cause thyroid stunning and cell injury. The purpose of this study was to
      assess the effectiveness of (123)I for whole-body scans. METHODS: We examined 12
      patients who had (123)I whole-body scans for known papillary/follicular thyroid
      cancer and 1 patient with Hurthle cell carcinoma, all with suspected metastases.
      All patients had undergone neck surgery and were given 0.81-0 mCi (123)I. Twenty
      four hours later a whole-body image and static views of relevant areas were
      obtained. If abnormal uptake was noted, patients were treated with large doses of
      (131)I and then had whole-body (131)I scans 7-10 d post-therapy. These images
      were compared to (123)I whole-body scans. RESULTS: All 13 patients had abnormal
      (123)I scans and were treated with therapeutic doses of (123)I, followed by whole
      body scans 7-10 d later. In 11 patients the activity seen on the 123I scans
      correlated well with that seen on (131)I scans. In 1 patient, additional lesions
      were noted on the (131)I images. In another patient, neck activity was seen on
      the (123)I scan but not on the subsequent (131)I post-therapy scan. The (123)I
      activity was felt to represent esophageal lumen activity. CONCLUSION: We found
      (123)1 effective in demonstrating residual thyroid tissue, thyroid carcinoma and
      metastases, and recommend its use for whole-body iodine scans since it does not
      cause thyroid stunning.

PMID- 10646546
TI  - Congenital thyroid disease revisited: migrational anomalies and
      dyshormonogenesis.
AB  - Nuclear medicine scintigraphy, in conjunction with other diagnostic tools, plays
      a vital role in assessing patients with congenital migrational anomalies. We
      present 5 patients, 4 of whom were hypothyroid and 1 patient who was euthyroid.
      Scintigraphic and ultrasonographic images were examined and correlated with
      laboratory results. These patients demonstrate the spectrum of migrational
      anomalies of the thyroid. Nuclear medicine scintigraphy was a valuable aid in
      establishing the location of the ectopic thyroid as well as its function.

PMID- 10646547
TI  - Practical methods for reducing radioactive contamination incidents in the nuclear
      cardiology laboratory.
AB  - OBJECTIVE: The purpose of this study was to determine the extent and cause of
      radioactive contamination in our nuclear cardiology laboratory, and to develop
      possible solutions to minimize future occurrence. METHODS: We conducted a
      retrospective review to determine the underlying causes of the 15 minor
      radioactive contamination events that have occurred in the exercise areas of our
      laboratory since 1986. Of the 15 documented events, 8 were caused by failure of
      intravenous apparatus and 7 were due to syringe mishandling. Based on a staff
      questionnaire, we determined the most prevalent causes of radioactive
      contamination. Other than problems associated with intravenous setup, the causes
      were lack of experience by the individual performing the injection, followed
      closely by radioactive syringe disposal problems, injection technique, and
      unclear designation of duties during the exercise procedure. RESULTS: Based on
      these findings, we formulated a 4-part plan: a training program; a closely
      inspected intravenous apparatus; a mobile radioactive waste container; and a
      clear designation of duties for personnel to be included in the exercise
      procedure protocol. CONCLUSION: We have implemented a sensible and practical plan
      for reducing radioactive contamination, which is currently being evaluated.

PMID- 10646548
TI  - Sensible approaches to avoid needle stick accidents in nuclear medicine.
AB  - OBJECTIVE: Needle sticks are a continuous concern in the health care environment
      because of the prevalence of bloodborne pathogens in today's society. Radioactive
      contamination is another concern with needle sticks during nuclear medicine and
      nuclear pharmacy procedures. In our institution, substantial efforts have been
      made to prevent needle sticks, but they still occur occasionally. The purpose of
      this project was to analyze different practices and products to determine the
      best protocol in an effort to avoid further needle sticks. METHODS: The nuclear
      medicine technologists were surveyed to determine how many needle sticks have
      occurred and the situation behind each occurrence. Using our initial survey, the
      circumstances involved in each incident were reviewed, suggestions considered,
      and various means of protection analyzed. Five options were presented in a second
      survey. RESULTS: The results of the second survey showed that technologists
      favored the newly designed needle-capping blocks for preventing needle sticks in
      their daily routine procedures. CONCLUSION: The newly designed needle-capping
      block is best suited for both nuclear medicine and nuclear pharmacy laboratories.
      We will continue to monitor the effectiveness of this new approach in preventing
      needle sticks.

PMID- 10646549
TI  - The role of morphine-augmented cholescintigraphy and real-time ultrasound in
      detecting gallbladder disease.
AB  - OBJECTIVE: Rapid diagnosis of acute cholecystitis is essential to minimize
      morbidity and mortality. The purpose of this study was to assess the diagnostic
      utility of cholescintigraphy using morphine augmentation compared with
      ultrasound, in acute and chronic gallbladder disease. METHODS: Cholescintigrams
      were performed on 103 patients suspected of having acute cholecystitis. In 79
      patients (Group A) morphine sulfate was administered to reduce the scintigraphic
      imaging time if the gallbladder was not visualized during the first hour. In 24
      control patients (Group B) no morphine was administered. All patients were
      evaluated clinically and 93 patients had concurrent ultrasound examination.
      RESULTS: The clinical presentation was nonspecific. The ultrasound findings were
      sensitive in detecting gallbladder disease (100%), but had low specificity (24%).
      Only findings of sediments and pericholecystic fluid were specific for cystic
      duct obstruction. Morphine augmentation reduced the imaging time by 126 min in
      patients with chronic cholecystitis. CONCLUSION: Real-time ultrasound has low
      specificity for gallbladder disease. In the presence of an abnormal ultrasound,
      it is essential to perform a hepatobiliary scan, either to exclude gallbladder
      disease or distinguish acute from chronic cholecystitis. Low-dose morphine
      administration is a safe and useful adjunct to standard cholescintigraphy by
      substantially reducing the time required to obtain a diagnostic study.

PMID- 10646551
TI  - Hot spots observed on pulmonary perfusion imaging: a case report.
AB  - A case of hot spots observed on perfusion lung images is presented. This artifact
      is well known, however, it is rarely seen in our experience. Although this
      artifact can occur if a faulty injection technique is used, the artifact also may
      be caused by embolization of the MAA in the upper extremity venous blood after
      injection. This cause of the artifact is beyond the control of the nuclear
      medicine professional.

PMID- 10646550
TI  - Occult breast cancer detection with technetium-99m-sestamibi: a case report.
AB  - A 74-y-old woman with a 4-y history of left arm lymphedema and multiple negative
      mammography studies presented to her physician with a palpable subcutaneous
      nodule in the left upper arm. After biopsy the nodule was read pathologically as
      secondary breast carcinoma. We report a finding of a positive 99mTc-sestamibi
      scintimammography in the presence of an unremarkable mammogram. The study also
      revealed a positive uptake in a metastatic lesion in the manubrium of the
      sternum.

PMID- 10646553
TI  - Validation of a column method for technetium-99m exametazime quality control.
AB  - OBJECTIVE: The purpose of this study was to investigate if an octadecyl (18C)
      minicolumn could be applied successfully for quality control of 99mTc exametazime
      (HMPAO). METHODS: The 18C column system using saline eluent was validated against
      the Whatman 17 method in calculating the percent radiochemical purity of 99mTc
      HMPAO. The behavior of 99mTc-pertechnetate (99mTc04-) and hydrolyzed-reduced
      99mTc (99mTc02) on the column was examined, as well as method reproducibility.
      RESULTS: The column method is reproducible and yields results that are highly
      comparable to the Whatman 17 method. Technetium-99m-pertechnetate is associated
      with the eluent, and some 99mTc02 is retained by the column but this level is
      insignificant to the final patient dose. CONCLUSION: The minicolumn system is
      safe, simple, rapid and reliable for the quality control analysis of routine
      99mTCHMPAO preparations.

PMID- 10646552
TI  - Reverse mismatched ventilation-perfusion pulmonary imaging with accumulation of
      technetium-99m-DTPA in a mucous plug in a main bronchus: a case report.
AB  - The phenomenon of reverse mismatched ventilation-perfusion on pulmonary
      scintigraphy is a fairly common occurrence. We present a patient who was
      experiencing decreasing oxygen saturation and had a reverse mismatched
      ventilation-perfusion imaging pattern associated with radiotracer retention in a
      main bronchus. Technetium-99m-DTPA aerosol lung imaging showed tracer retention
      in the trachea and right main bronchus, absent ventilation in the right lung, and
      normal ventilation in the left lung. Technetium-99m-MAA perfusion lung images
      showed normal perfusion of the left lung and some perfusion in the right lung.
      These findings represented a reverse ventilation-perfusion mismatch. Reverse
      mismatched ventilation-perfusion, or totally absent ventilation with preservation
      of some perfusion in the right lung, resulted in functional intrapulmonary
      shunting, which explained the decreasing oxygen saturation observed in this
      patient. A concurrent portable chest radiograph showed elevation of the right
      hemidiaphragm, a shift of the mediastinum to the right, deviation of the
      endotracheal tube, narrowing of the intercostal space of the right thorax, and
      collapse of the right lower lobe. The radiographic findings of underventilation
      of the right lung with atelectasis of the right lower lobe were due to mucous
      plugging the right main bronchus.

PMID- 10646554
TI  - Lymphoscintigraphy and intraoperative lymphatic mapping of sentinel lymph nodes
      in melanoma patients.
AB  - Identification of sentinel lymph nodes (SLNs) using lymphoscintigraphy, the blue
      dye technique and intraoperative lymphatic mapping with a gamma-detecting probe
      has become the standard of care in diagnosing and treating melanoma. Numerous
      clinical studies have proven the reliability of predicting the histology of
      remaining lymph nodes in the lymphatic basin from the histologic evaluation of
      the SLNs. Technical and clinical factors presented in this paper have been shown
      to increase the accuracy of localization of SLNs. The nuclear medicine
      technologist shares a vital role in the radiopharmaceutical preparation and
      administration for preoperative lymphoscintigraphy and intraoperative lymphatic
      mapping in patients with melanoma.

PMID- 10646555
TI  - A distance-assisted training program for nuclear medicine technologists.
AB  - We have developed training materials for nuclear medicine technologists to be
      used in distance-assisted training programs. We have completed our first pilot
      project in Asia and report that there will be nearly 500 students around the
      world, in Asia, Africa, Central America and South America, using our materials
      during the coming year.

PMID- 10646556
TI  - Agglutinating activity of alcohol-soluble proteins from quinoa seed flour in
      celiac disease.
AB  - The edible seeds of the quinoa plant contain small quantities of alcohol-soluble
      protein which, after peptic-tryptic digestion, are unable to agglutinate K562(s)
      cells. When separated by affinity chromatography on sepharose-6B coupled with
      mannan, peptic-tryptic digest separated in two fractions. Fraction B peptides
      (about 1% of total protein) were shown to agglutinate K562(s) cells at a very low
      concentration, whereas peptides in fraction A and in the mixed fraction A+B were
      inactive, suggesting that fraction A contains protective peptides that interfere
      with the agglutinating activity of toxic peptides in fraction B.

PMID- 10646557
TI  - Chemical evaluation of waste from Thaumatococcus danielli (Benth) processing.
AB  - Three different batches of Thaumatococcus danielli (Benth) fruits were collected
      at different fruiting seasons. The proximate compositions of the pericarp and
      seeds were determined on a dry weight basis. Partial characterization of the
      lipid extract was carried out and tannin content determined. The average
      moisture, ash and lipid contents of the pericarp were higher (89.2+/-4.17%,
      20.7+/-1.10% and 11.6+/-1.23%, respectively) than those of the seed (31.2+/
      4.66%, 9.1+/-0.71% and 8.2+/-1.64%, respectively). Crude protein and total
      carbohydrate were, however, higher in the seed (9.5+/-4.38% and 69.4+/-11.52%,
      respectively) than in the pericarp (4.5+/-2.21% and 6.3+/-3.94%, respectively).
      The dietary fiber contents of both pericarp and seed were high. Starch content
      was very low in the pericarp (0.4+/-0.0%) compared to the seed (66.28+/-9.21%).
      Tannin content in the pericarp and seeds was 12.1+/-1.52 mg/g and 21.9+/-2.28
      mg/g, respectively. The oil extracted from both pericarp and seeds was light
      yellow in color and slightly solid at room temperature. Unsaturation level of T.
      danielli oil was low, while free fatty acids were high. The results obtained
      suggested that T. danielli waste could potentially be a raw material in livestock
      feed formulation.

PMID- 10646558
TI  - Biochemical changes in wheat during storage at three temperatures.
AB  - Biochemical changes in wheat grains stored at 10, 25 and 45 degrees C for six
      months were studied. A significant decrease in pH and an increase in titratable
      acidity was observed during storage of wheat grains at 25 degrees C and 45
      degrees C. Moisture contents of wheat grains decreased by 15% at 25 degrees C and
      26% at 45 degrees C during six months of storage. A significant decrease in water
      soluble amylose (20-28%) along with an increase in insoluble amylose contents
      (7.6-17%) were observed during storage at 25 and 45 degrees C. Amylase activity
      of the samples showed a decrease as the storage progressed. Total soluble sugars
      increased by 9% at 10 degrees C and 12% at 25 degrees C; a 37% decrease was
      observed after six months storage at 45 degrees C. Total available lysine
      decreased by 18.0% and 22.6% at 25 and 45 degrees C, respectively, after six
      months storage. In vitro protein digestibility of wheat grains decreased by 5.00%
      at 25 degrees C and 10.28% at 45 degrees C during six months of storage. However,
      no significant biochemical changes occurred during storage at 10 degrees C.

PMID- 10646559
TI  - Measurement of the relative sweetness of stevia extract, aspartame and
      cyclamate/saccharin blend as compared to sucrose at different concentrations.
AB  - Special diets are used to mitigate many human diseases. When these diets require
      changes in carbohydrate content, then sweetness becomes an important
      characteristic. The range of low-calorie sweeteners available to the food
      industry is expanding. It is essential to have an exact knowledge of the relative
      sweetness of various sweeteners in relation to different sucrose concentrations.
      The objective of this study was to determine the variation on the relative
      sweetness of aspartame (APM), stevia [Stevia rebaudiana (Bert.) Bertoni] leaf
      extract (SrB) and the mixture cyclamate/saccharin--two parts of cyclamate and one
      part of saccharin--(C/S) with the increase in their concentrations, and in
      neutral and acid pH in equisweet concentration to 10% sucrose, using magnitude
      estimation. Sweetness equivalence of SrB in relation to sucrose concentrations of
      20% or higher and of APM and C/S to sucrose concentrations of 40% or higher could
      not be determined, because a bitter taste predominated. The potency of all
      sweeteners decreased as the level of sweetner increased. In equi-sweet
      concentration of sucrose at 10%, with pH 7.0 and pH 3.0, the potency was
      practically the same for all sweeteners evaluated.

PMID- 10646560
TI  - Use of two varieties of hard-to-cook beans (Phaseolus vulgaris) and cowpeas
      (Vigna unguiculata) in the processing of koki (a steamed legume product).
AB  - Koki is a nutritious cowpea-based food product usually processed by steam cooking
      whipped cowpea (Vigna unguiculata) paste mixed with spices and palm oil. A study
      was carried out to investigate the effect of the partial replacement of cowpeas
      (CP) with hard-to-cook (HTC) beans on the chemical, nutritional and sensory
      characteristics of koki. Towards this objective, two varieties of beans-
      Phaseolus vulgaris (red kidney beans--RKB and mottled brown beans--MBB), each
      with the HTC defect, were separately incorporated into cowpea paste in the
      following Bean:CP ratios 0:100, 20:80, 30:70, 40:60, 50:50, 60:40 and processed
      into koki. Incorporation of dry HTC beans into cowpeas in the making of koki
      affected the bulking properties of the uncooked paste, the nutrient composition,
      essential amino acid content, antinutritional factors, digestibility as well as
      the sensory attributes of cooked koki. Sensory tests showed that a highly
      acceptable, nutritious and digestible koki can be processed from cowpeas
      partially replaced with dry HTC bean paste up to levels of about 40-50% depending
      on the variety of dry bean used.

PMID- 10646561
TI  - Quality attributes of fermented yam flour supplemented with processed soy flour.
AB  - Pretreated soy flour was used to replace 10, 20, 30 and 40% of fermented yam
      flour as a protein supplement. The effect of the supplementation on the
      physicochemical and sensory properties of 'amala', a popular West African food
      made from rehydrated yam flour, was investigated. Blanching (10 min in boiling
      water) and subsequent fermentation (24 h) as pretreatment methods produced flour
      that was lighter in color than the unfermented samples. Protein content of the
      yam-soy mixture increased from 3.5% in the control to 19.7% for 40% soy
      fortification. Water binding capacity increased from 212.6 g/100 g for the yam
      flour control to 257.3 g/100 g for the blend with 40% soy flour. However,
      swelling capacity and solubility were adversely affected with increased soy flour
      addition as dough became sticky and soft. There was no significant difference in
      color, taste, flavor or overall acceptability when compared with the control up
      to 20% soy substitution. Dough with 20% soy flour is a possibility for increasing
      the protein content of yam flour in human feeding.

PMID- 10646562
TI  - Calcium chloride sprays decrease physiological disorders following long-term cold
      storage of apple.
AB  - Field experiments were carried out at the Horticultural Research Institute, and
      in five commercial apple orchards, located in southwest Finland including the
      Aland Islands during 1994 and 1995. The experimental cultivars were Melba, Raike,
      Red Atlas, Akero, Aroma, and Lobo. The treatments were untreated control and
      preharvest calcium chloride (CaCl2) sprays at Ca 2.0 g/l. Fruit samples were
      stored for two to six months at 2-4 degrees C and 85-95% RH. The percentage of
      the incidence of physiological disorders of stored apples was scored. Fruit
      macronutrients, firmness, diameter and juice titratable acidity and percentage of
      soluble solids were determined. Only a few nutrient effects in the flesh of the
      apple cultivars were a result of CaCl2 sprayings. Preharvest CaCl2 sprays
      increased fruit firmness and the titratable acidity but decreased soluble solids,
      soluble solids/titratable acidity ratio, and the incidence of physiological
      storage disorders of some cultivars. When looking at the mean of all cultivars,
      CaCl2 sprayings increased titratable acidity and decreased soluble
      solids/titratable acidity ratio after four months of storage during 1995 and
      reduced the incidence of physiological disorders after three months of storage
      during 1994 and after four months of storage in 1995.

PMID- 10646563
TI  - Effect of Detarium microcarpum (Dm) and Mucuna flagellipes (Mf) gums on the
      quality of white bread.
AB  - Incorporation of Detarium Microcarpum (Dm) and Mucuna flagellipes (Mf) water
      soluble polysaccharides (gums) at 0.0 to 0.5% levels in wheat flour was studied
      to evaluate their effect on the rheological properties of wheat flour dough and
      white bread quality. At all levels of incorporation, there were increases (p < or
      = 0.05) in water absorption of the dough. Doughs containing gums had higher (p <
      or = 0.05) mixing tolerance index than the control. Set back viscosities
      decreased by 4.0 RVU and 9.0 RVU with increased levels of Dm and Mf gum
      incorporation, respectively. Significantly (p < or = 0.05) higher oven spring
      occurred in all the gum substituted white bread when compared to the control. The
      0.5% gum substituted breads had a significantly (p < or = 0.05) higher sensory
      score for crumb grain, texture but lower (p < 0.05) crumb firmness than the
      control as determined instrumentally. Textural analysis after 5 days storage
      revealed that Dm and Mf gums improved moisture retention properties of the bread
      and reduced crumb firming tendency.

PMID- 10646564
TI  - Private vs public genomics?

PMID- 10646565
TI  - Celera turns to public genome data to speed up endgame.

PMID- 10646566
TI  - Inadequate optics 'threat to US laser facility'

PMID- 10646568
TI  - Bell Labs win superconductivity patent

PMID- 10646567
TI  - UK discussed ban on foreign job ads in 1960s

PMID- 10646569
TI  - Genetics takes off in Naples as institute moves south.

PMID- 10646570
TI  - NIH seeks funding for neuroscience centre.

PMID- 10646571
TI  - Biologists flock to 'evo-devo' in a quest to read the recipes of life.

PMID- 10646572
TI  - Global bodies won't save the environment: it needs grass-roots efforts.

PMID- 10646573
TI  - Proteins and the naked truth about e-commerce

PMID- 10646574
TI  - EPA error risked halving India's rice harvest.

PMID- 10646575
TI  - Wherever HIV originated, polio vaccine is safe now.

PMID- 10646576
TI  - East German academics faced unfair hurdles

PMID- 10646577
TI  - Sowing nuclear misconceptions

PMID- 10646578
TI  - Positioning the goalposts.

PMID- 10646579
TI  - Deep ice and DNA languages.

PMID- 10646580
TI  - DNA computing on a chip.

PMID- 10646581
TI  - Aerodynamics: from insects to microvehicles.

PMID- 10646582
TI  - Astronomy: eyes wide shut.

PMID- 10646583
TI  - Gateway to the chloroplast.

PMID- 10646585
TI  - Phase transitions: jumping between liquid states

PMID- 10646584
TI  - Telomeres: a tale of ends.

PMID- 10646586
TI  - Fossil fish up for election.

PMID- 10646587
TI  - Neurobiology: internal model visualized.

PMID- 10646588
TI  - A pygostyle from a non-avian theropod

PMID- 10646589
TI  - Tall men have more reproductive success.

PMID- 10646590
TI  - Eel fat stores are enough to reach the Sargasso.

PMID- 10646591
TI  - Children learn an untaught rule of spelling.

PMID- 10646592
TI  - Rapid chromosomal evolution in island mice.

PMID- 10646593
TI  - MRT-2 checkpoint protein is required for germline immortality and telomere
      replication in C. elegans.
AB  - The germ line is an immortal cell lineage that is passed indefinitely from one
      generation to the next. To identify the genes that are required for germline
      immortality, we isolated Caenorhabditis elegans mutants with mortal germ lines-
      worms that can reproduce for several healthy generations but eventually become
      sterile. One of these mortal germline (mrt) mutants, mrt-2, exhibits progressive
      telomere shortening and accumulates end-to-end chromosome fusions in later
      generations, indicating that the MRT-2 protein is required for telomere
      replication. In addition, the germ line of mrt-2 is hypersensitive to X-rays and
      to transposon activity. Therefore, mrt-2 has defects in responding both to
      damaged DNA and to normal double-strand breaks present at telomeres. mrt-2
      encodes a homologue of a checkpoint gene that is required to sense DNA damage in
      yeast. These results indicate that telomeres may be identified as a type of DNA
      damage and then repaired by the telomere-replication enzyme telomerase.

PMID- 10646594
TI  - A reduced estimate of the number of kilometre-sized near-Earth asteroids.
AB  - Near-Earth asteroids are small (diameters < 10 km), rocky bodies with orbits that
      approach that of the Earth (they come within 1.3 AU of the Sun). Most have a
      chance of approximately 0.5% of colliding with the Earth in the next million
      years. The total number of such bodies with diameters > 1 km has been estimated
      to be in the range 1,000-2,000, which translates to an approximately 1% chance of
      a catastrophic collision with the Earth in the next millennium. These numbers
      are, however, poorly constrained because of the limitations of previous searches
      using photographic plates. (One kilometre is below the size of a body whose
      impact on the Earth would produce global effects.) Here we report an analysis of
      our survey for near-Earth asteroids that uses improved detection technologies. We
      find that the total number of asteroids with diameters > 1 km is about half the
      earlier estimates. At the current rate of discovery of near-Earth asteroids, 90%
      will probably have been detected within the next 20 years.

PMID- 10646595
TI  - Measurement of the spatial coherence of a trapped Bose gas at the phase
      transition
AB  - The experimental realization of Bose-Einstein condensates of dilute gases has
      allowed investigations of fundamental concepts in quantum mechanics at ultra-low
      temperatures, such as wave-like behaviour and interference phenomena. The
      formation of an interference pattern depends fundamentally on the phase coherence
      of a system; the latter may be quantified by the spatial correlation function.
      Phase coherence over a long range is the essential factor underlying Bose
      Einstein condensation and related macroscopic quantum phenomena, such as
      superconductivity and superfluidity. Here we report a direct measurement of the
      phase coherence properties of a weakly interacting Bose gas of rubidium atoms.
      Effectively, we create a double slit for magnetically trapped atoms using a radio
      wave field with two frequency components. The correlation function of the system
      is determined by evaluating the interference pattern of two matter waves
      originating from the spatially separated 'slit' regions of the trapped gas. Above
      the critical temperature for Bose-Einstein condensation, the correlation function
      shows a rapid gaussian decay, as expected for a thermal gas. Below the critical
      temperature, the correlation function has a different shape: a slow decay towards
      a plateau is observed, indicating the long-range phase coherence of the
      condensate fraction.

PMID- 10646596
TI  - A first-order liquid-liquid phase transition in phosphorus
AB  - First-order structural phase transitions are common in crystalline solids,
      whereas first-order liquid-liquid phase transitions (that is, transitions between
      two distinct liquid forms with different density and entropy) are exceedingly
      rare in pure substances. But recent theoretical and experimental studies have
      shown evidence for such a transition in several materials, including supercooled
      water and liquid carbon. Here we report an in situ X-ray diffraction observation
      of a liquid-liquid transition in phosphorus, involving an abrupt, pressure
      induced structural change between two distinct liquid forms. In addition to a
      known form of liquid phosphorus--a molecular liquid comprising tetrahedral P4
      molecules--we have found a polymeric form at pressures above 1 GPa. Changing the
      pressure results in a reversible transformation from the low-pressure molecular
      form into the high-pressure polymeric form. The transformation is sharp and
      rapid, occurring within a few minutes over a pressure range of less than 0.02
      GPa. During the transformation, the two forms of liquid coexist. These features
      are strongly suggestive of a first-order liquid-liquid phase transition.

PMID- 10646597
TI  - Nanoscopic channel lattices with controlled anisotropic wetting
AB  - Engineered microscopic surface structures allow local control of physical surface
      properties such as adhesion, friction and wettability. These properties are
      related both to molecular interactions and the surface topology--for example,
      selective adsorption and molecular recognition capabilities require controlled
      anisotropy in the surface properties. Chemistry with extremely small amounts of
      material has become possible using liquid-guiding channels of sub-micrometre
      dimensions. Laterally structured surfaces with differing wettabilities may be
      produced using various techniques, such as microcontact printing, micromachining,
      photolithography and vapour deposition. Another strategy for introducing
      anisotropic texture is based on the use of the intrinsic material properties of
      stretched ultrathin polymer coatings. Here we present a fast and simple method to
      generate extended patterned surfaces with controlled wetting properties on the
      nanometre scale, without any lithographic processes. The technique utilizes
      wetting instabilities that occur when monomolecular layers are transferred onto a
      solid substrate. The modified surfaces can be used as templates for patterning a
      wide variety of molecules and nanoclusters into approximately parallel channels,
      with a spatial density of up to 20,000 cm(-1). We demonstrate the transport
      properties of these channels for attolitre quantities of liquid.

PMID- 10646598
TI  - DNA computing on surfaces.
AB  - DNA computing was proposed as a means of solving a class of intractable
      computational problems in which the computing time can grow exponentially with
      problem size (the 'NP-complete' or non-deterministic polynomial time complete
      problems). The principle of the technique has been demonstrated experimentally
      for a simple example of the hamiltonian path problem (in this case, finding an
      airline flight path between several cities, such that each city is visited only
      once). DNA computational approaches to the solution of other problems have also
      been investigated. One technique involves the immobilization and manipulation of
      combinatorial mixtures of DNA on a support. A set of DNA molecules encoding all
      candidate solutions to the computational problem of interest is synthesized and
      attached to the surface. Successive cycles of hybridization operations and
      exonuclease digestion are used to identify and eliminate those members of the set
      that are not solutions. Upon completion of all the multistep cycles, the solution
      to the computational problem is identified using a polymerase chain reaction to
      amplify the remaining molecules, which are then hybridized to an addressed array.
      The advantages of this approach are its scalability and potential to be automated
      (the use of solid-phase formats simplifies the complex repetitive chemical
      processes, as has been demonstrated in DNA and protein synthesis). Here we report
      the use of this method to solve a NP-complete problem. We consider a small
      example of the satisfiability problem (SAT), in which the values of a set of
      boolean variables satisfying certain logical constraints are determined.

PMID- 10646599
TI  - Evidence for enhanced mixing over rough topography in the abyssal ocean
AB  - The overturning circulation of the ocean plays an important role in modulating
      the Earth's climate. But whereas the mechanisms for the vertical transport of
      water into the deep ocean--deep water formation at high latitudes--and horizontal
      transport in ocean currents have been largely identified, it is not clear how the
      compensating vertical transport of water from the depths to the surface is
      accomplished. Turbulent mixing across surfaces of constant density is the only
      viable mechanism for reducing the density of the water and enabling it to rise.
      However, measurements of the internal wave field, the main source of energy for
      mixing, and of turbulent dissipation rates, have typically implied diffusivities
      across surfaces of equal density of only approximately 0.1 cm2 s(-1), too small
      to account for the return flow. Here we report measurements of tracer dispersion
      and turbulent energy dissipation in the Brazil basin that reveal diffusivities of
      2-4 cm2 s(-1) at a depth of 500 m above abyssal hills on the flank of the Mid
      Atlantic Ridge, and approximately 10 cm2 s(-1) nearer the bottom. This amount of
      mixing, probably driven by breaking internal waves that are generated by tidal
      currents flowing over the rough bathymetry, may be large enough to close the
      buoyancy budget for the Brazil basin and suggests a mechanism for closing the
      global overturning circulation.

PMID- 10646600
TI  - Osmotic generation of 'anomalous' fluid pressures in geological environments
AB  - Osmotic pressures are generated by differences in chemical potential of a
      solution across a membrane. But whether osmosis can have a significant effect on
      the pressure of fluids in geological environments has been controversial, because
      the membrane properties of geological media are poorly understood. 'Anomalous'
      pressures--large departures from hydrostatic pressure that are not explicable in
      terms of topographic or fluid-density effects--are widely found in geological
      settings, and are commonly considered to result from processes that alter the
      pore or fluid volume, which in turn implies crustal changes happening at a rate
      too slow to observe directly. Yet if osmosis can explain some anomalies, there is
      no need to invoke such dynamic geological processes in those cases. Here I report
      results of a nine-year in situ measurement of fluid pressures and solute
      concentrations in shale that are consistent with the generation of large (up to
      20 MPa) osmotic-pressure anomalies which could persist for tens of millions of
      years. Osmotic pressures of this magnitude and duration can explain many of the
      pressure anomalies observed in geological settings. They require, however, small
      shale porosity and large contrasts in the amount of dissolved solids in the pore
      waters--criteria that may help to distinguish between osmotic and crustal-dynamic
      origins of anomalous pressures.

PMID- 10646601
TI  - The most primitive osteichthyan braincase?
AB  - Most living vertebrates, from teleosts to tetrapods, are osteichthyans (bony
      fishes), but the origin of this major group is poorly understood. The
      actinopterygians (ray-finned bony fishes) are the most successful living
      vertebrates in terms of diversity. They appear in the fossil record in the Late
      Silurian but are poorly known before the Late Devonian. Here we report the
      discovery of the oldest and most primitive actinopterygian-like osteichthyan
      braincase known, from 400-million-year-old limestone in southeastern Australia.
      This specimen displays previously unknown primitive conditions, in particular, an
      opening for a cartilaginous eyestalk. It provides an important and unique
      counterpart to the similarly aged and recently described Psarolepis from China
      and Vietnam. The contrasting features of these specimens, and the unusual anatomy
      of the new specimen in particular, provide new insights into anatomical
      conditions close to the evolutionary radiation of all modern osteichthyan groups.

PMID- 10646602
TI  - Molecular evidence regarding the origin of echolocation and flight in bats.
AB  - Bats (order Chiroptera) are one of the few orders of mammals that echolocate and
      the only group with the capacity for powered flight. The order is subdivided into
      Microchiroptera and Megachiroptera, with an array of characteristics defining
      each group, including complex laryngeal echolocation systems in microbats and
      enhanced visual acuity in megabats. The respective monophylies of the two
      suborders have been tacitly assumed, although microbat monophyly is
      uncorroborated by molecular data. Here we present a phylogenetic analysis of bat
      relationships using DNA sequence data from four nuclear genes and three
      mitochondrial genes (total of 8,230 base pairs), indicating that microbat
      families in the superfamily Rhinolophoidea are more closely related to megabats
      than they are to other microbats. This implies that echolocation systems either
      evolved independently in rhinolophoids and other microbats or were lost in the
      evolution of megabats. Our data also reject flying lemur (order Dermoptera) as
      the bat sister group, indicating that presumed shared derived characters for
      flying lemurs and bats are convergent features that evolved in association with
      gliding and flight, respectively.

PMID- 10646603
TI  - Human cerebellar activity reflecting an acquired internal model of a new tool.
AB  - Theories of motor control postulate that the brain uses internal models of the
      body to control movements accurately. Internal models are neural representations
      of how, for instance, the arm would respond to a neural command, given its
      current position and velocity. Previous studies have shown that the cerebellar
      cortex can acquire internal models through motor learning. Because the human
      cerebellum is involved in higher cognitive function as well as in motor control,
      we propose a coherent computational theory in which the phylogenetically newer
      part of the cerebellum similarly acquires internal models of objects in the
      external world. While human subjects learned to use a new tool (a computer mouse
      with a novel rotational transformation), cerebellar activity was measured by
      functional magnetic resonance imaging. As predicted by our theory, two types of
      activity were observed. One was spread over wide areas of the cerebellum and was
      precisely proportional to the error signal that guides the acquisition of
      internal models during learning. The other was confined to the area near the
      posterior superior fissure and remained even after learning, when the error
      levels had been equalized, thus probably reflecting an acquired internal model of
      the new tool.

PMID- 10646604
TI  - A constitutively open potassium channel formed by KCNQ1 and KCNE3.
AB  - Mutations in all four known KCNQ potassium channel alpha-subunit genes lead to
      human diseases. KCNQ1 (KvLQT1) interacts with the beta-subunit KCNE1 (IsK, minK)
      to form the slow, depolarization-activated potassium current I(Ks) that is
      affected in some forms of cardiac arrhythmia. Here we show that the novel beta
      subunit KCNE3 markedly changes KCNQ1 properties to yield currents that are nearly
      instantaneous and depend linearly on voltage. It also suppresses the currents of
      KCNQ4 and HERG potassium channels. In the intestine, KCNQ1 and KCNE3 messenger
      RNAs colocalized in crypt cells. This localization and the pharmacology, voltage
      dependence and stimulation by cyclic AMP of KCNQ1/KCNE3 currents indicate that
      these proteins may assemble to form the potassium channel that is important for
      cyclic AMP-stimulated intestinal chloride secretion and that is involved in
      secretory diarrhoea and cystic fibrosis.

PMID- 10646605
TI  - Uptake of apoptotic cells drives the growth of a pathogenic trypanosome in
      macrophages.
AB  - After apoptosis, phagocytes prevent inflammation and tissue damage by the uptake
      and removal of dead cells. In addition, apoptotic cells evoke an anti
      inflammatory response through macrophages. We have previously shown that there is
      intense lymphocyte apoptosis in an experimental model of Chagas' disease, a
      debilitating cardiac illness caused by the protozoan Trypanosoma cruzi. Here we
      show that the interaction of apoptotic, but not necrotic T lymphocytes with
      macrophages infected with T. cruzi fuels parasite growth in a manner dependent on
      prostaglandins, transforming growth factor-beta (TGF-beta) and polyamine
      biosynthesis. We show that the vitronectin receptor is critical, in both
      apoptotic-cell cytoadherence and the induction of prostaglandin E2/TGF-beta
      release and ornithine decarboxylase activity in macrophages. A single injection
      of apoptotic cells in infected mice increases parasitaemia, whereas treatment
      with cyclooxygenase inhibitors almost completely ablates it in vivo. These
      results suggest that continual lymphocyte apoptosis and phagocytosis of apoptotic
      cells by macrophages have a role in parasite persistence in the host, and that
      cyclooxygenase inhibitors have potential therapeutic application in the control
      of parasite replication and spread in Chagas' disease.

PMID- 10646606
TI  - The major protein import receptor of plastids is essential for chloroplast
      biogenesis.
AB  - Light triggers the developmental programme in plants that leads to the production
      of photosynthetically active chloroplasts from non-photosynthetic proplastids.
      During this chloroplast biogenesis, the photosynthetic apparatus is rapidly
      assembled, mostly from nuclear-encoded imported proteins, which are synthesized
      in the cytosol as precursors with cleavable amino-terminal targeting sequences
      called transit sequences. Protein translocon complexes at the outer (Toc complex)
      and inner (Tic complex) envelope membranes recognize these transit sequences,
      leading to the precursors being imported. The Toc complex in the pea consists of
      three major components, Toc75, Toc34 and Toc159 (formerly termed Toc86). Toc159,
      which is an integral membrane GTPase, functions as a transit-sequence receptor.
      Here we show that Arabidopsis thaliana Toc159 (atToc159) is essential for the
      biogenesis of chloroplasts. In an Arabidopsis mutant (ppi2) that lacks atToc159,
      photosynthetic proteins that are normally abundant are transcriptionally
      repressed, and are found in much smaller amounts in the plastids, although ppi2
      does not affect either the expression or the import of less abundant non
      photosynthetic plastid proteins. These findings indicate that atToc159 is
      required for the quantitative import of photosynthetic proteins. Two proteins
      that are related to atToc159 (atToc120 and atToc132) probably help to maintain
      basal protein import in ppi2, and so constitute components of alternative,
      atToc159-independent import pathways.

PMID- 10646607
TI  - Interferon-gamma elicits arteriosclerosis in the absence of leukocytes.
AB  - Atherosclerosis and post-transplant graft arteriosclerosis are both characterized
      by expansion of the arterial intima as a result of the infiltration of
      mononuclear leukocytes, the proliferation of vascular smooth muscle cells (VSMCs)
      and the accumulation of extracellular matrix. They are also associated with the
      presence of the immunomodulatory cytokine interferon-gamma (IFN-gamma). Moreover,
      in mouse models of atheroma formation or allogeneic transplantation, the
      serological neutralization or genetic absence of IFN-gamma markedly reduces the
      extent of intimal expansion. However, other studies have found that exogenous IFN
      gamma inhibits cultured VSMC proliferation and matrix synthesis, and reduces
      intimal expansion in response to mechanical injury. This discrepancy is generally
      explained by the idea that IFN-gamma either directly activates macrophages, or,
      by increasing antigen presentation, indirectly activates T cells within the
      lesions of atherosclerosis and graft arteriosclerosis. These activated leukocytes
      are thought to express the VSMC-activating cytokines and cell-surface molecules
      that cause the observed arteriosclerotic responses. Here we have inserted pig and
      human arteries into the aorta of immunodeficient mice, and we show that IFN-gamma
      can induce arteriosclerotic changes in the absence of detectable immunocytes by
      acting on VSMCs to potentiate growth-factor-induced mitogenesis.

PMID- 10646608
TI  - Negative regulation of lymphocyte activation and autoimmunity by the molecular
      adaptor Cbl-b.
AB  - The signalling thresholds of antigen receptors and co-stimulatory receptors
      determine immunity or tolerance to self molecules. Changes in co-stimulatory
      pathways can lead to enhanced activation of lymphocytes and autoimmunity, or the
      induction of clonal anergy. The molecular mechanisms that maintain
      immunotolerance in vivo and integrate co-stimulatory signals with antigen
      receptor signals in T and B lymphocytes are poorly understood. Members of the
      Cbl/Sli family of molecular adaptors function downstream from growth factor and
      antigen receptors. Here we show that gene-targeted mice lacking the adaptor Cbl-b
      develop spontaneous autoimmunity characterized by auto-antibody production,
      infiltration of activated T and B lymphocytes into multiple organs, and
      parenchymal damage. Resting cbl-b(-/-) lymphocytes hyperproliferate upon antigen
      receptor stimulation, and cbl-b(-/-) T cells display specific hyperproduction of
      the T-cell growth factor interleukin-2, but not interferon-gamma or tumour
      necrosis factor-alpha. Mutation of Cbl-b uncouples T-cell proliferation,
      interleukin-2 production and phosphorylation of the GDP/GTP exchange factor Vav1
      from the requirement for CD28 co-stimulation. Cbl-b is thus a key regulator of
      activation thresholds in mature lymphocytes and immunological tolerance and
      autoimmunity.

PMID- 10646609
TI  - Cbl-b regulates the CD28 dependence of T-cell activation.
AB  - Whereas co-stimulation of the T-cell antigen receptor (TCR) and CD28 triggers T
      cell activation, stimulation of the TCR alone may result in an anergic state or T
      cell deletion, both possible mechanisms of tolerance induction. Here we show that
      T cells that are deficient in the adaptor molecule Cbl-b (ref. 3) do not require
      CD28 engagement for interleukin-2 production, and that the Cbl-b-null mutation
      (Cbl-b(-/-)) fully restores T-cell-dependent antibody responses in CD28-/- mice.
      The main TCR signalling pathways, such as tyrosine kinases Zap-70 and Lck,
      Ras/mitogen-activated kinases, phospholipase Cgamma-1 and Ca2+ mobilization, were
      not affected in Cbl-b(-/-) T cells. In contrast, the activation of Vav, a guanine
      nucleotide exchange factor for Rac1/Rho/CDC42, was significantly enhanced. Our
      findings indicate that Cbl-b may influence the CD28 dependence of T-cell
      activation by selectively suppressing TCR-mediated Vav activation. Mice deficient
      in Cbl-b are highly susceptible to experimental autoimmune encephalomyelitis,
      suggesting that the dysregulation of signalling pathways modulated by Cbl-b may
      also contribute to human autoimmune diseases such as multiple sclerosis.

PMID- 10646610
TI  - Measurement of thermal contribution to photoreceptor sensitivity.
AB  - Activation of a visual pigment molecule to initiate phototransduction requires a
      minimum energy, Ea, that need not be wholly derived from a photon, but may be
      supplemented by heat. Theory predicts that absorbance at very long wavelengths
      declines with the fraction of molecules that have a sufficient complement of
      thermal energy, and that Ea is inversely related to the wavelength of maximum
      absorbance (lambda(max)) of the pigment. Consistent with the first of these
      predictions, warming increases relative visual sensitivity to long wavelengths.
      Here we measure this effect in amphibian photoreceptors with different pigments
      to estimate Ea (refs 2, 5-7) and test experimentally the predictions of an
      inverse relation between Ea and lambda(max). For rods and 'red' cones in the
      adult frog retina, we find no significant difference in Ea between the two
      pigments involved, although their lambda(max) values are very different. We also
      determined Ea for the rhodopsin in toad retinal rods--spectrally similar to frog
      rhodopsin but differing in amino-acid sequence--and found that it was
      significantly higher. In addition, we estimated Ea for two pigments whose
      lambda(max) difference was due only to a chromophore difference (A1 and A2
      pigment, in adult and larval frog cones). Here Ea for A2 was lower than for A1.
      Our results refute the idea of a necessary relation between lambda(max) and Ea,
      but show that the A1 --> A2 chromophore substitution decreases Ea.

PMID- 10646611
TI  - Bioorganic synthesis of lipid-modified proteins for the study of signal
      transduction.
AB  - Biological membranes define the boundaries of the cellular compartments in higher
      eukaryotes and are active in many processes such as signal transduction and
      vesicular transport. Although post-translational lipid modification of numerous
      proteins in signal transduction is crucial for biological function, analysis of
      protein-protein interactions has mainly focused on recombinant proteins in
      solution under defined in vitro conditions. Here we present a new strategy for
      the synthesis of such lipid-modified proteins. It involves the bacterial
      expression of a carboxy-terminally truncated non-lipidated protein, the chemical
      synthesis of differently lipidated peptides representing the C terminus of the
      proteins, and their covalent coupling. Our technique is demonstrated using Ras
      constructs, which exhibit properties very similar to fully processed Ras, but can
      be produced in high yields and are open for selective modifications. These
      constructs are operative in biophysical and cellular assay systems, showing
      specific recognition of effectors by Ras lipoproteins inserted into the membrane
      surface of biosensors and transforming activity of oncogenic variants after
      microinjection into cultured cells.

PMID- 10646612
TI  - Comorbid personality impairment in body dysmorphic disorder.
AB  - Personality impairment was evaluated in 17 body dysmorphic disorder (BDD)
      patients undergoing a treatment study of clomipramine versus desipramine.
      Semistructured interviews were administered using both categorical (Structured
      Clinical Interview for DSM [SCID II]) and dimensional (Dimensional Assessment of
      Personality Impairment [DAPI]) methods. Personality measures were also correlated
      with a range of clinical variables (severity of BDD and depressive symptoms, age,
      duration of illness, and response to treatment). A secondary aim of the study was
      to provide preliminary validation for the DAPI. Consistent with previous studies,
      BDD patients showed considerable personality pathology. By SCID II, patients met
      criteria for a mean of 2.53 personality disorder diagnoses; 87% of patients met
      criteria for at least 1 diagnosis and 53% for more than 1. Cluster C diagnoses
      were the most common. Mean scores for the DAPI were 2.63 (3 = mild impairment) to
      6.41 (7 = severe impairment), averaging 5.26 (5 = moderate). With regard to the
      DAPI, the results provided preliminary evidence of good reliability and validity.
      Moreover, both personality measures were highly intercorrelated. Although SCID II
      diagnoses correlated with baseline depression (Hamilton Rating Scale for
      Depression [HRSD]) scores, there were few other significant correlations between
      personality and other clinical variables. Of note, however, treatment responders
      demonstrated less personality impairment than nonresponders. The finding that
      personality measures were highly intercorrelated but, on the whole, not well
      correlated with other clinical measures supports the distinct and dissociable
      nature of personality phenomena in BDD. Despite the small sample size, these
      results suggest that personality impairment appears to be significant factor in
      BDD and may even play a role in treatment response.

PMID- 10646613
TI  - Polarity of the first episode, clinical characteristics, and course of manic
      depressive illness: a systematic retrospective investigation of 320 bipolar I
      patients.
AB  - In 320 patients with established bipolar I disorder, we examined the past course
      on the basis of polarity at onset (depressive, mixed, and manic). Despite the
      obvious limitations of retrospective methodology, information on course
      parameters in a large sample of affective disorders is most practically obtained
      by such methodology. We believe that our systematic interview of patients and
      their relatives--as well as the systematic study of their records--minimized
      potential biases. Depressive onsets were the most common, accounting for 50%,
      followed by mixed and manic onsets in about equal proportion. In general, the
      polarity of episodes over time reflected polarity at onset. Those with depressive
      onset had significantly higher levels of rapid cycling, as well as suicide
      attempts, but were significantly less likely to develop psychotic symptoms. Mixed
      onsets, too, had high rates of suicide attempts, but differed from depressive
      onsets in having significantly more chronicity yet negligible rates of rapid
      cycling at follow-up evaluation. Because cases with depressive onset had received
      significantly higher rates of psychopharmacologic treatment, our data are
      compatible with the hypothesis that antidepressants may play a role in the
      induction of rapid cycling. Overall, our data support the existence of distinct
      longitudinal patterns within bipolar I disorder, which in turn appear correlated
      with the polarity at onset. In particular, rapid cycling and mixed states emerge
      as distinct psychopathologic processes.

PMID- 10646614
TI  - The psychiatric sequelae of civilian trauma.
AB  - Much of the literature on the psychiatric consequences of stress has focused on
      wartime combat trauma. However, traumatic events also frequently occur in
      civilian life. Controlled studies on the psychiatric effects of noncombat trauma
      were reviewed and a meta-analysis of these data was conducted. Generalized
      anxiety disorder (GAD), posttraumatic stress disorder (PTSD), substance abuse,
      phobia, and major depressive disorder (MDD) were significantly elevated compared
      with a pooled control group, whereas panic disorder and dysthymic disorder were
      not significantly increased. These data suggest that the psychiatric effects of
      civilian trauma include both anxiety and depressive disorders. The results are
      strikingly similar to those reported in combat veterans, suggesting that severe
      trauma, even in very different populations, may be associated with similar
      psychopathology.

PMID- 10646615
TI  - Five-year follow-up study of eye movement desensitization and reprocessing
      therapy for combat-related posttraumatic stress disorder.
AB  - This study reports the results of a 5-year follow-up evaluation of 13 Vietnam
      combat veterans with chronic posttraumatic stress disorder (PTSD) who
      participated in a study of eye movement desensitization and reprocessing (EMDR)
      therapy previously reported in this journal. Pretreatment and follow-up
      psychometric outcome measures were compared with those of a demographically
      matched control group of 14 combat veterans with chronic PTSD who did not receive
      EMDR. Analysis of variance showed that the modest to moderate therapeutic
      benefits that were manifest immediately following EMDR were lost at the 5-year
      follow-up evaluation, and there was an overall worsening of PTSD symptomatology
      over the 5-year period in both EMDR-treated and nontreated control subjects.

PMID- 10646616
TI  - Predictors of comorbid personality disorders in patients with panic disorder with
      agoraphobia.
AB  - The aim of this study was to ascertain predictors of comorbid personality
      disorders in patients with panic disorder with agoraphobia (PDAG). Sixty
      consecutive outpatients with PDAG were administered the Structured Clinical
      Interview for DSM-IV Axis II Personality Disorders (SCID-II) for the purpose of
      diagnosing personality disorders. Logistic regressions were used to identify
      predictors of any comorbid personality disorder, any DSM-IV cluster A, cluster B,
      and cluster C personality disorder. Independent variables in these regressions
      were gender, age, duration of panic disorder (PD), severity of PDAG, and scores
      on self-report instruments that assess the patient's perception of their parents,
      childhood separation anxiety, and traumatic experiences. High levels of parental
      protection on the Parental Bonding Instrument (PBI), indicating a perception of
      the parents as overprotective and controlling, emerged as the only statistically
      significant predictor of any comorbid personality disorder. This finding was
      attributed to the association between parental overprotection and cluster B
      personality disorders, particularly borderline personality disorder. The duration
      of PD was a significant predictor of any cluster B and any cluster C personality
      disorder, suggesting that some of the cluster B and cluster C personality
      disorders may be a consequence of the long-lasting PDAG. Any cluster B
      personality disorder was also associated with younger age. In conclusion, despite
      a generally nonspecific nature of the relationship between parental
      overprotection in childhood and adult psychopathology, the findings of this study
      suggest some specificity for the association between parental overprotection in
      childhood and personality disturbance in PDAG patients, particularly cluster B
      personality disorders.

PMID- 10646617
TI  - Defense mechanisms, negative emotions, and psychopathology in adolescent
      inpatients.
AB  - Ego defense mechanisms were compared in adolescent psychiatric inpatients and
      healthy adolescents to determine their relationship to specific diagnoses and to
      negative emotions. Seventy-one patients with schizophrenia, 28 with major
      depressive disorder, and 24 with obsessive-compulsive disorder (OCD) and 87
      normal adolescents were assessed for defense mechanisms by the Life Style Index
      (LSI) and Ego Defense Scale (EDS). The Beck Depression Inventory (BDI), State
      Trait Anxiety Inventory (STAI), and Multidimensional Anger Inventory (MAI) were
      used to assess depression, anxiety, and anger. Several defenses distinguished all
      psychiatric patients from controls, and a few defenses characterized different
      patient groups, especially those with OCD. Projection (on the LSI), displacement,
      and regression correlated significantly with anger; displacement, reaction
      formation, and undoing on the EDS correlated with anxiety, and denial was
      negatively correlated with depression. These findings have some relevance for the
      evaluation of Plutchik's psychoevolutionary theory of emotions and for the
      further empirical study of defenses in psychopathology.

PMID- 10646618
TI  - Associations of self-reported past "psychotic" phenomena with features of
      personality disorders.
AB  - Patients with borderline personality disorder (BPD) may present with "psychotic"
      phenomena, which can be defined as a range of specified "altered experiences of
      reality." This study investigated the associations between self-reported past
      psychotic phenomena and features of DSM-III-R personality disorders (PDs) in 57
      inpatients without a previous diagnosis of the main disorders that involve
      delusions and hallucinations. The present findings include associations between
      past psychotic phenomena and features of BPD, between repeated self-harm and a
      report that "thoughts seemed put into head," and between psychotic phenomena and
      features of other PDs, particularly schizotypal PD. There was a high prevalence
      of BPD in the present sample. Dissociation, in the context of the features of
      BPD, may be a causal factor for the development of some of the psychotic
      phenomena presented by patients with PD.

PMID- 10646619
TI  - Sleep breathing and sleep movement disorders masquerading as insomnia in sexual
      assault survivors.
AB  - A descriptive, hypothesis-generating study was performed with 156 female sexual
      assault survivors who suffered from insomnia, nightmares, and posttraumatic
      stress disorder (PTSD). They completed 2 self-report sleep questionnaires to
      assess the potential presence of intrinsic sleep disorders. Seventy-seven percent
      of the sample (120 of 156) endorsed additional sleep complaints, besides their
      insomnia symptoms, that indicate the potential presence of sleep-disordered
      breathing ([SDB] 81 of 156, 52%) and sleep-related movement disorders ([SMD] 94
      of 156, 60%). The potential for SDB was strongly correlated with the body mass
      index (BMI), an increase in arousal symptoms, and greater total PTSD severity. In
      some sexual-assault survivors, the relationship between sleeplessness and
      posttraumatic stress may be caused or exacerbated by intrinsic sleep disorders,
      and not be solely a function of psychophysiological insomnia--the traditional
      diagnostic term usually offered to explain the sleep problems associated with
      PTSD. Prevalence studies that use objective diagnostic evaluations such as
      polysomnography (PSG) are needed to test these hypotheses.

PMID- 10646620
TI  - Summer and winter patterns of seasonality in Chinese college students: a
      replication.
AB  - The goal of this study is to replicate an earlier epidemiological finding of
      seasonal changes in mood and behavior among Chinese medical students using an
      independent study population. Three hundred nineteen college students were
      surveyed with a Chinese version of the Seasonal Pattern Assessment Questionnaire
      (SPAQ) and the Beck Depression Inventory (BDI) in Jining, China, during March of
      1996. The frequency of seasonal patterns and prevalence rates of seasonal
      affective disorder (SAD) were estimated and compared with data from the medical
      student survey conducted in the same city. The mean Global Seasonality Score
      (GSS) of this college student sample was 9.9 +/- 4.9; 84% of the subjects
      reported some problems with the changing seasons. Summer difficulties were more
      prevalent than winter difficulties by a ratio of 1.9 to 1 (38.9% v 20.1%). The
      estimated rates of summer SAD and subsyndromal-SAD (s-SAD) were 7.5% and 11.9%,
      respectively, as compared with the corresponding winter figures of 5.6% and 6.3%.
      In addition, the prevalence estimates of winter pattern or winter SADs were
      higher in males than in females, but the corresponding summer figures showed no
      gender difference. Compared with the data from the medical student survey, this
      college student sample had a higher GSS (P < .01) but comparable summer to winter
      and female to male ratios for the prevalence of SADs (P > .05). These results
      replicate our previous findings that seasonal problems are common in China, but
      the predominant problems are summer difficulties rather than winter difficulties,
      and there is no female preponderance in the prevalence estimates of such
      problems. Both findings stand in contrast to most Western studies but are
      consistent with the only other published study performed in the Orient.

PMID- 10646621
TI  - Assessment of social functioning in depression.
AB  - Impairment of social functioning is a significant aspect of depression distinct
      from the symptoms of depression. Social functioning defines an individual's
      interactions with their environment and the ability to fulfill their role within
      such environments as work, social activities, and relationships with partners and
      family. The analysis of social functioning has arisen from a growing interest in
      measuring the consequences of depression and antidepressant therapy. Impairment
      often persists long after the resolution of symptoms by pharmacotherapy, and is
      not extensively assessed by the traditional scales to measure the intensity of
      depressive symptoms. Assessment is influenced by the method used, and there is an
      increased awareness that the patient's perspective should be foremost. Several
      scales for the evaluation of social functioning have already been developed,
      ranging from those requiring a structured interview with a trained assessor to
      self-assessment scales. In constructing such tools, a balance must be found
      between the amount of detail required to produce a clear account of the patient's
      social functioning and the ease of use in large multicenter studies. The newest
      scale is the Social Adaptation Self-evaluation Scale (SASS), specifically for
      self-assessment of social functioning by patients with depression. It contains 21
      items covering the different aspects of social interactions, global social
      attitude, and self-perception. The SASS has been validated and found to be simple
      to use and sensitive to changes in the different areas of social functioning.
      Recently, the SASS was used to demonstrate the greater efficacy of reboxetine, a
      new selective noradrenaline reuptake inhibitor (selective NRI), compared with the
      selective serotonin reuptake inhibitor (SSRI) fluoxetine, in improving social
      functioning in patients with depression. Specifically, the SASS was able to show
      that reboxetine improved patient motivation and self-perception. The SASS is
      another tool for the evaluation of the extent and quality of the response to
      treatment and may also help to elucidate the roles of noradrenaline and serotonin
      in depressive illness.

PMID- 10646622
TI  - Pseudoakathisia: a review and two case reports.
AB  - Pseudoakathisia is a movement disorder associated with the use of neuroleptic
      medication. There has been disagreement on the precise nature of the condition
      and its relation to akathisia. The available literature on pseudoakathisia is
      reviewed. Two cases of pseudoakathisia are reported that demonstrate the
      reversibility of the diagnosis of pseudoakathisia.

PMID- 10646623
TI  - Catatonic signs in neuroleptic malignant syndrome.
AB  - The study assessed catatonic signs in neuroleptic malignant syndrome (NMS).
      Records of inpatients meeting both stringent research criteria and DSM-IV
      criteria (n = 11) or only DSM-IV criteria (n = 5) for NMS were identified. The
      records were systematically rated on a 23-item rating scale for the presence of
      catatonic signs. Scores for NMS severity were related to the number of catatonic
      signs. Fifteen patients met both research criteria for catatonia and DSM-IV motor
      criteria for organic catatonia. The severity scores of NMS correlated with the
      number of catatonic signs (Spearman rho = +.71, P < .005). We conclude that
      multiple catatonic signs are present in NMS and the severity of NMS predicts the
      number of catatonic signs.

PMID- 10646624
TI  - Effect of gamma irradiation on storability of apples (Malus domestica L.).
AB  - The aim of this study was to investigate the effect of gamma irradiation on
      storability of the two main apple varieties, Golden Delicious and Starking, in
      Syria. The experiments were performed in 1995 and 1996. Fruits were irradiated
      with 0, 0.5, 1.0 and 1.5 KGy. Irradiated and unirradiated fruits were stored at 1
      to 2 degrees C and under a relative humidity of 80 to 90%. Weight loss and
      spoilage due to physiological disorders and fungal diseases were evaluated
      throughout the different storage periods. Firmness, coloration and pH values were
      estimated immediately after irradiation. The results showed that, in both
      varieties, gamma irradiation increased the weight loss after 45 days of storage
      in apples gathered in 1995 but not in the 1996 season. After 180 days of storage,
      gamma irradiation had different effects on weight loss depending on the growing
      year and variety, and increased fungal spoilage. Application of gamma irradiation
      prevented the growth of Aspergillus niger and the formation of skin scald in
      'Golden Delicious' fruits. Immediately after treatment, gamma irradiation
      increased the softening of fruits, changed their color from green to yellow and
      decreased the pH value of the juice.

PMID- 10646625
TI  - Influence of temperature on the fermentation of bambara groundnut (Vigna
      subterranea) to produce a dawadawa-type product.
AB  - Bambara groundnut (Vigna subterranea) was fermented to produce a dawadawa-type
      product using a starter culture of Bacillus licheniformis isolated from naturally
      fermenting bambara groundnut beans. Fermentation was carried out at 30 and 37
      degrees C for four days and at 45 degrees C for two days. The pH of the substrate
      decreased after 24 hours and then rose at 30 and 37 degrees C but remained
      constant at 45 degrees C after the initial drop. Total titratable acidity of the
      fermenting beans mimicked the pH values. Proximate analyses for moisture, protein
      and fat of the cotyledons showed an increase in all three constituent at each of
      the three fermentation temperatures. At the end of fermentation, total available
      carbohydrate was 55%, 59% and 62% of the original value at 30, 37 and 45 degrees
      C, respectively. Fermentation of bambara groundnut at 45 degrees C for two days
      is recommended as the ideal fermentation temperature and time.

PMID- 10646626
TI  - Biscuit-making potential of millet/pigeon pea flour blends.
AB  - Biscuits were produced from millet flour (MF) and pigeon pea flour (PPF) blends.
      The various ratios of MF to PPF used were 100:0, 75:25, 65:35, and 50:50. The
      biscuits were analyzed for their nutritional composition. They all contained high
      proportions of protein (7.5-15.2%), fat (17.1-18.1%) and digestible carbohydrate
      (60.2-66.5%). The moisture content was in the range 5.0 to 6.6%, ash 1.5-2.3% and
      crude fiber 0-0.1%. Sensory evaluation results indicated that all the biscuits
      had high sensory ratings for all the selected attributes evaluated. The recipe
      with the 65% MF/35% PPF blend resulted in the highest scores for flavor, texture
      and general acceptability. There was no significant difference (p > 0.05) between
      all the biscuits and the familiar Nasco short cake biscuit (reference) in flavor,
      color, texture and general acceptability.

PMID- 10646627
TI  - Production and evaluation of weaning foods based on sorghum and legumes.
AB  - Five weaning formulations (F1-F5) based on sorghum, groundnuts, sesame seeds,
      chickpeas, and skim milk powder were processed by a twin-roller drum dryer and
      evaluated for composition, functional properties (bulk density, water absorption
      capacity, and apparent viscosity), in vitro indices (protein digestibility and
      available lysine), protein quality (PER, NPR, and NPU) and effects of feeding on
      rat livers. Composition and properties of the five formulations were compared to
      those of Cerelac. The results indicated that F3 (60% sorghum, 20% chickpeas, 5%
      sesame, 8.5% skim milk powder, 5% sugar, and 1.5% vitamins and minerals) and F2
      (55% sorghum, 15% chickpeas, 5% groundnuts, 10% sesame, 8.5% skim milk powder, 5%
      sugar, and 1.5% vitamins and minerals) formulations had compositions and
      properties comparable to those of Cerelac and hence have a good potential for use
      as weaning foods.

PMID- 10646628
TI  - Quality characteristics of Canarium schweinfurthii Engl. oil.
AB  - The oil content and quality characteristics of Canarium schweinfurthii Engl. oil
      are described. The oils were extracted from the mesocarp and endocarp using
      hexane to remove the free flowing lipid (FFL) and successive extraction with
      CHCl3-MeOH followed by water saturated butanol to remove bound lipid (BL). On a
      dry matter basis, the mesocarp contained 68.3% FFL and 13.7% BL while the
      endocarp contained 67.0% FFL and 13.0% BL. The quality characteristics of the
      mesocarp oil extracts were 151.9-195.3 mg KOH/g fat saponification value (SV), 20
      40 mEq peroxide/kg fat peroxide value (PV), 71.1-94.9 g iodine/100 g fat iodine
      value (IV) and 1.33-8.30 mg KOH acid value (AV). Characteristics for the endocarp
      oil extracts were 95.4-184.3 mg KOH/g fat SV, 4.0-8.0 mEq peroxide/kg fat PV,
      100.1-118.3 g iodine/100 g fat IV, and AV of 0.48-8.70 mg KOH. The fatty acid
      composition of the first hexane extracts indicated that the oils were primarily
      C16 and C18s. The mesocarp contained 31.7% hexadecanoic acid, 30.0% 9
      octadecenoic acid, 30.1% 6,9-octadecadienoic acid and 8.2% 9,12,15
      octadecatrienoic acid, while the endocarp, contained 31.2% hexadecanoic acid,
      28.9% 9-octadecenoic acid and 31.3% 6,9-octadecadienoic acid.

PMID- 10646629
TI  - Effects of malting on the milling performance and acceptability of bambara
      groundnut (Voandzeia subterranea Thouars) seeds and products.
AB  - Germinated bambara groundnut was dried by three methods--oven-drying at 50
      degrees C, in a solar drier at 38-42 degrees C, and sun drying at 28 +/- 2
      degrees C. The samples were milled into flour, and made into 'okpa', a steamed
      gel. Flour yield increased only in oven-dried malts. The quality of the 'okpa'
      based on appearance and taste decreased with malting time; solar drying resulted
      in the poorest product because of its dark color.

PMID- 10646630
TI  - Chemical composition, digestibility and antinutritional factors content of two
      wild legumes: Styphonolobium burseroides and Acacia bilimekii.
AB  - The chemical composition, digestibility and toxin contents of two wild legumes:
      Styphnolobium burseroides and Acacia bilimekii, collected in a semi-arid zone of
      Mexico, were determined. Both legumes had a high fiber content. The seeds of
      Styphnolobium burseroides had a low protein content (14%), and the pod a high
      content of reducing sugars. However the seeds of Acacia bilimekii had a high
      protein concentration (35%). The seed proteins were low in sulphur amino acids
      and tryptophan in both legumes but were rich in lysine. Trypsin inhibitors and
      lectins were present in low concentrations; alkaloids and cyanogenic glucosides
      were not detected. The in vitro digestibility for monogastric animals was low but
      the same test with ruminal juice showed a high digestibility for both legumes.
      Based on their chemical composition and digestibility, these legumes could be a
      good alternative source in the feeding of ruminants.

PMID- 10646631
TI  - Preparation and properties of flours and protein concentrates from raw, fermented
      and germinated fluted pumpkin (Telfairia occidentalis Hook) seeds.
AB  - In vitro protein digestibility, chemical composition and selected functional
      properties of flours and protein concentrates prepared from raw, fermented and
      germinated fluted pumpkin (Telfairia occidentalis Hook) seeds were studied.
      Protein concentrates prepared by an alkaline extraction process had increased
      crude protein contents (61.5-70.8%) compared to flour samples (46.4-52.7%). The
      yields of protein concentrates ranged from 24.5% to 29.4% while values for
      protein recoveries varied between 64.8% and 65.2%. Protein concentrates also had
      increased foam volume and decreased foam stability (100% decrease over a 2 h
      period), compared to flour samples. Fermentation and germination were observed to
      significantly (p < 0.05) lower polyphenol and phytic acid contents, but increased
      protein digestibility of fluted pumpkin seed flours and concentrates. Both raw
      flour and concentrate were significantly (p < 0.05) higher in water absorption
      capacity than germinated or fermented flours and concentrates. Protein
      concentrates had comparatively better fat absorption properties than the flour
      samples. Hence protein concentrates may prove to have useful applications in
      ground meat formulations.

PMID- 10646632
TI  - Nutritional parameters and yield evaluation of newly developed genotypes of
      lentil (Lens culinaris Medik.).
AB  - Among the commonly consumed food legumes, lentils occupy an important place in
      human nutrition in the Indian subcontinent. Twenty-one lentil genotypes were
      evaluated for such nutrition related parameters as moisture, protein, crude
      fiber, fat, ash (total mineral matter), carbohydrates, total energy and
      metabolizable energy. These genotypes were also analyzed for 100-seed weight and
      seed yield/plant. Protein content ranged between 22.1 and 27.4% with significant
      differences among genotypes. Considerable variations were observed among the
      genotypes for calcium, phosphorus, iron and tannin contents. Large variations
      existed in yield and 100-seed weight of these genotypes. Seed yield/plant was not
      significantly correlated with any of the principal seed constituents analyzed in
      the present study. The genotypes, LH 97 and LH 37 were found to be better and
      hence could be explored for further development and selection of desirable
      characteristics.

PMID- 10646633
TI  - Safflower petals: a source of gamma linolenic acid.
AB  - Safflower petals have been shown to have a lot of medicinal and therapeutic
      values. Indian safflower petal samples were analyzed for the red pigment
      carthamin, protein and oil contents. The petal oil (4.0-5.8%) was further
      analyzed for its fatty acids followed by alpha linolenic acid (15-19%) and
      palmitic acids (14-16%). Gamma linolenic acid, which has a lot of therapeutic
      value was present to an extent of 2-3%; decanoic and dodecanoic acids (2-5%) were
      also present.

PMID- 10646634
TI  - Inhibition of rabbit keratocyte and human fetal lens epithelial cell
      proliferation by retrovirus-mediated transfer of antisense cyclin G1 and
      antisense MAT1 constructs.
AB  - The aim of this study is to evaluate the potential of gene transfer of cell cycle
      control genes as treatment of corneal haze or secondary cataract formation. The
      guiding hypothesis is that strategic modulation of the cyclin G1 or MAT1 gene by
      retrovirus-mediated gene transfer will inhibit proliferation of rabbit
      keratocytes (RabK) and fetal human lens epithelial (FHLEpi) cells in vitro. RabK
      and FHLEpi cell cultures were transduced in triplicate with retroviral vectors
      bearing either a nuclear-targeted beta-galactosidase, an antisense cyclin G1
      (aG1), an antisense MAT1 (aMAT1) construct, or the neo(r) gene. The presence of
      beta-galactosidase activity in the transduced cultures was detected by
      immunohistochemical X-Gal staining, while cyclin G1 and MAT1 protein expression
      levels were evaluated by Western analysis. Proliferation of RabKs and FHLEpi
      cells was analyzed by counting the number of cells in the aG1 and aMAT1 vector
      transduced cultures over 5 days. The mean transduction efficiency was 34.4% (SD
      1.41) for RabKs and 19.7% (SD 1.83) for FHLEpi cells. Downregulation of cyclin G1
      and MAT1 protein expression was noted 24 hr after transduction of RabK cultures
      with the respective vectors. Cytostatic effects of the aG1 and aMAT1 vectors in
      both RabKs and FHLEpi cells were most pronounced on the fifth day (RabKs, p <
      0.0007; FHEpi cells, p < 0.001). An increased incidence of apoptosis was
      identified in both aG1 and MAT1-transduced FHLEpi cells. Taken together, these
      data suggest the potential utility of developing aG1 and aMAT1 retroviral vectors
      in gene therapy protocols for corneal haze and secondary cataract formation.

PMID- 10646635
TI  - Specific targeting of EGP-2+ tumor cells by primary lymphocytes modified with
      chimeric T cell receptors.
AB  - A promising strategy for cancer treatment is adoptive immunotherapy with gene
      modified lymphocytes expressing a chimeric T cell receptor (cTCR) that directs
      tumor targeting and stimulates T cell effector functions. In this study, the
      activities of two novel cTCR molecules (GAgamma and GAHgamma) were investigated.
      Both encode a single-chain variable fragment (scFv) derived from the monoclonal
      antibody (MAb) GA733.2, which binds the epithelial glycoprotein 2 (EGP-2)
      overexpressed on a variety of human carcinomas. In the GAgamma cTCR, the scFv is
      directly fused to the transmembrane/cytoplasmic portions of the immunoglobulin Fc
      receptor (Ig FcRI) gamma subunit, which mediates T cell signaling. GAHgamma
      possesses an extracellular spacer composed of the CD8alpha immunoglobulin
      hingelike domain inserted between the scFv and gamma chain. Activated T cells
      (ATCs), stimulated ex vivo using anti-CD3 MAb, were derived from either healthy
      donors or patients and transduced with recombinant retrovirus encoding the
      respective GA cTCR molecules. After culture expansion for 14 days, GAgamma
      modified ATCs demonstrated enhanced targeting and lysis of EGP-2+ colon cancer
      cells and increased cytokine secretion. Cells transduced with the GAHgamma cTCR
      displayed specific lytic activity that was about twofold greater than that of
      GAgamma-ATCs and produced significantly more cytokine. In addition, reactivation
      of GAHgamma-ATC with anti-CD3 MAb prior to addition to EGP-2+ tumor target
      induced a further increase in lytic activity. Because the activation status
      influences T cell antitumor functions, our data suggest that reactivation prior
      to adoptive transfer would improve the clinical efficacy of GAHgamma-modified
      ATCs.

PMID- 10646636
TI  - Phenotypic correction of feline lipoprotein lipase deficiency by adenoviral gene
      transfer.
AB  - Previous studies have revealed that adenovirus-mediated ectopic liver expression
      of human LPL (huLPL) can efficiently mediate plasma triacylglycerol (TG)
      catabolism in mice despite its native expression in adipose and muscle tissue. We
      aimed to explore the feasibility of liver-directed gene transfer and enzyme
      replacement for human LPL deficiency in a larger, naturally occurring feline
      animal model of complete LPL deficiency that is remarkably similar in phenotype
      to the human disorder. A cohort of LPL-deficient (LPL -/-) cats was given an
      intravenous injection of 8 x 10(9) PFU/kg of a CMV promoter/enhancer-driven,
      E1/E3-deleted adenoviral (Ad) vector containing a 1.36-kb huLPL cDNA (Ad-LPL) or
      reporter alkaline phosphatase gene (Ad-AP). After Ad-LPL administration, active,
      heparin-releasable huLPL was readily detected along with a 10-fold reduction in
      plasma TGs, disappearance of plasma TG-rich lipoproteins up to day 14, and
      enhanced clearance of an excess intravenous fat load on day 9. However, antibody
      against the huLPL protein was detected on day 14 in cats receiving Ad-LPL and
      adenovirus-specific neutralizing antibody was present 7 days after gene transfer
      in both cat cohorts. Tissue-specific expression of the huLPL transgene relative
      to controls was confirmed by RT-PCR. While huLPL expression was evident in the
      liver, other tissues including spleen and lung expressed huLPL message, in direct
      correlation with histological evidence of increased Oil red O (ORO)-positive
      neutral lipid influx. In contrast, intravenous LPL enzyme replacement therapy
      (ERT) led to rapid disappearance of 9000 mU/kg of active bovine LPL enzyme from
      the circulation, with t1/2 occurring at <10 min in two LPL-/- cats. Heparin
      injection 1 hr later released <10% of the original bovine LPL, further indicating
      its rapid systemic clearance, inactivation, or degradation as well as its
      ineffectiveness as a viable therapeutic alternative for complete LPL deficiency.
      Although LPL gene transfer and expression via this first-generation Ad vector was
      limited by the immune response against both the human LPL protein and adenovirus
      our results clearly provide a key advance supporting further development of LPL
      gene therapy as a viable therapeutic option for clinical LPL deficiency.

PMID- 10646637
TI  - A soluble transforming growth factor beta receptor expressed in muscle prevents
      liver fibrogenesis and dysfunction in rats.
AB  - We demonstrated that local expression of a dominant-negative type II TGF-beta
      receptor prevents live fibrogenesis and dysfunction in dimethylnitrosamine
      treated rats. Using the same model, we have now tested whether a soluble TGF-beta
      receptor expressed in skeletal muscle can effectively suppress TGF-beta signaling
      in a remote organ (the liver). We constructed an adenovirus expressing an entire
      ectodomain of human TGF-beta type II receptor fused to the Fc portion of human
      IgG (AdTbeta-ExR). This soluble receptor secreted from AdTbeta-ExR-infected cells
      bound TGF-beta and blocked TGF-beta-signaling in vitro. After intramuscular
      injection of AdTbeta-ExR in rats, the soluble receptor protein was detectable in
      the blood for at least 3 weeks. When such rats were treated with
      dimethylnitrosamine, liver fibrosis was markedly attenuated without apparent
      systemic or local side effects. The hepatic hydroxyproline content was reduced to
      a level indistinguishable from that achieved by local expression of the dominant
      negative TGF-beta receptor. Since a qualitatively and quantitatively similar
      suppression was achieved by the two methods, it may be concluded that the new
      strategy can achieve a complete inhibition of TGF-beta signaling under
      pathophysiological conditions in vivo. This strategy should facilitate
      clarification of the role of TGF-beta in vivo in various organs where direct gene
      transfer seems to be difficult.

PMID- 10646638
TI  - High-efficiency retroviral transduction of mammalian cells on positively charged
      surfaces.
AB  - The efficiency of retroviruses as transducing agents has been appreciated for
      many years, particularly for hematopoietic cell targets for which alternative
      strategies applicable to adherent cells are not effective. Advances in vector
      design, pseudotyping, and infection conditions have eliminated the need to
      cocultivate the target cells with virus-producing cells. Nevertheless,
      improvements are still needed for many applications, including those with a
      therapeutic or clinical cell-tracking objective. In this study we show that more
      positively charged surfaces, including those designed for the culture of
      anchorage-dependent cells, allow measurable levels of adhesion by different
      pseudotypes of retroviruses, which can result in increased gene transfer
      efficiencies to a variety of target cells including normal primary human
      hematopoietic cells as well as human leukemic cell lines and rat and murine
      fibroblasts. In the experiments with primary human cells, equal aliquots of
      enriched CD34+ cord blood cells were first stimulated for 2 days with cytokines
      (Flt3 ligand, Steel factor, IL-3, IL-6, and G-CSF) and then exposed for 4 days to
      a green fluorescent protein (GFP)- and Neo(r)-encoding retrovirus produced in
      PG13 cells. Both the final yield (approximately 300% relative to initial
      numbers), and the proportion (approximately 60%) of transduced CD34+ cells,
      colony-forming cells, and long-term culture-initiating cells were the same for
      cells infected either in tissue culture dishes or in fibronectin-coated petri
      dishes. Similar proportions (approximately 10%) and absolute yields of GFP+ human
      cells were also found in multilineage engrafted NOD/SCID mice assessed 6 to 8
      weeks after being transplanted with these two types of transduced, but
      unselected, cells. These findings suggest a new and simpler approach for
      achieving high gene transfer efficiencies to hematopoietic cells.

PMID- 10646639
TI  - Intratumoral administration of adenoviral interleukin 7 gene-modified dendritic
      cells augments specific antitumor immunity and achieves tumor eradication.
AB  - In two murine lung cancer models adenoviral interleukin 7-transduced dendritic
      cells (DC-AdIL-7) were administered intratumorally, resulting in complete tumor
      regression. Intratumoral DC-AdIL-7 therapy was as effective as DCs pulsed with
      specific tumor peptide antigens. Comparison with other intratumoral therapies
      including recombinant IL-7, AdIL-7 vector alone, unmodified DCs, IL-7-transduced
      fibroblasts, or DCs pulsed with tumor lysates revealed DC-AdIL-7 therapy to be
      superior in achieving antitumor responses and augmenting immunogenicity. Mice
      with complete tumor eradication as a result of either DC-AdIL-7 or AdIL-7 therapy
      were rechallenged with parental tumor cells 30 days or more after complete tumor
      eradication. All the DC-AdIL-7-treated mice completely rejected a secondary
      rechallenge, whereas the AdIL-7-treated mice had sustained antitumor effects in
      only 20-25% of the mice. DC-AdIL-7 therapy was more effective than AdIL-7 in
      achieving systemic antitumor responses and enhancing immunogenicity. After
      complete tumor eradication, those mice treated with DC-AdIL-7 evidenced
      significantly greater release of splenocyte GM-CSF and IFN-gamma than did
      controls or AdIL-7-treated mice. After intratumoral injection, gene-modified DCs
      trafficked from the tumor to lymph node sites and spleen. DCs were detected in
      nodal tissues for up to 7 days after intratumoral injection. We report that
      intratumoral DC-AdIL-7 leads to significant systemic immune responses and potent
      antitumor effects in murine lung cancer models.

PMID- 10646640
TI  - Double suicide gene therapy augments the antitumor activity of a replication
      competent lytic adenovirus through enhanced cytotoxicity and radiosensitization.
AB  - Replication-competent adenoviruses may provide a highly efficient means of
      delivering therapeutic genes to tumors. Previously, we evaluated in vitro a
      replication-competent adenovirus (Ad5-CD/TKrep) containing a cytosine deaminase
      (CD)/herpes simplex type 1 thymidine kinase (HSV-1 TK) fusion gene that allows
      lytic viral therapy to be combined with double suicide gene therapy. Both the
      CD/5-FC and HSV-1 TK/GCV enzyme/prodrug systems enhanced the tumor cell-specific
      cytopathic effects of the Ad5-CD/TKrep virus in vitro and sensitized cells to
      radiation. To extend these in vitro findings in vivo, we evaluated the antitumor
      activity of the Ad5-CD/TKrep virus in combination with double prodrug therapy and
      radiation therapy. The Ad5-CD/TKrep virus independently demonstrated significant
      antitumor activity against C33A cervical carcinoma xenografts. Therapeutic
      outcome was dramatically improved with systemic administration of double, but not
      single, prodrug (5-FC + GCV) therapy. When used in a neoadjuvant setting, Ad5
      CD/TKrep-mediated double suicide gene therapy dramatically potentiated the
      effectiveness of radiation therapy. The trimodal approach of Ad5-CD/TKrep viral,
      double suicide gene, and radiotherapies produced significant tumor regression and
      ultimately 100% tumor cure. The results demonstrate the high therapeutic
      potential of the trimodal approach and provide a solid foundation for future
      clinical trials.

PMID- 10646641
TI  - Experimental gene therapy for brain tumors using adenovirus-mediated transfer of
      cytosine deaminase gene and uracil phosphoribosyltransferase gene with 5
      fluorocytosine.
AB  - Transduction of the cytosine deaminase (CD) gene into tumor cells followed by
      administration of 5-fluorocytosine (5-FC), called 5-FC/CD gene therapy, was
      created as suicide gene therapy for various cancers. The uracil
      phosphoribosyltransferase (UPRT) gene, which is absent from mammalian cells,
      directly converts 5-fluorouracil (5-FU) to 5-fluorouridine 5'-monophosphate. We
      evaluated whether the coexpression of CD and UPRT genes could generate a
      synergistic antitumor effect on experimental brain tumors. In vitro study showed
      that 9L cells, transduced with the UPRT gene by an adenovirus, were 16 times more
      sensitive to 5-FU, and CD + UPRT-transduced cells were 6,000 times more sensitive
      to 5-FC than parent cells, indicating that the acquisition of CD and UPRT further
      increased the 5-FC sensitivity of 9L cells compared with cells transduced with CD
      alone. In a rat brain tumor model, decreased amounts of CD and UPRT vectors were
      inoculated into the tumors to detect any additional effect of UPRT. CD and UPRT
      coexpression followed by 5-FC administration showed an antitumor effect as
      detected by sequential magnetic resonance imaging. This therapy significantly
      prolonged animal survival. These results suggest that 5-FC/CD + UPRT gene therapy
      can enhance the antitumor effect of 5-FC/CD gene therapy. Consequently, this
      approach might be a more feasible modality for the treatment of malignant brain
      tumors.

PMID- 10646642
TI  - A defined window for efficient gene marking of severe combined immunodeficient
      repopulating cells using a gibbon ape leukemia virus-pseudotyped retroviral
      vector.
AB  - We have investigated the minimal time required for efficient transduction of
      human hematopoietic repopulating cells using a surrogate nonobese diabetic
      (NOD)/severe combined immunodeficient (SCID) xenoengraftment assay. Cord blood
      CD34+ cells were transduced to high levels over 24-48 hr in the presence of Flt-3
      ligand, stem cell factor, interleukin 3, and interleukin 6. Under these
      conditions, high levels of NOD/SCID repopulating activity were preserved, but the
      levels of gene marking in engrafting cell populations measured by expression of a
      reporter transgene were low. Extension of the transduction period by 24 hr (total
      culture period, 72 hr) under the same cytokine conditions resulted in high levels
      of gene marking, but on closer analysis expression was limited predominantly to
      the myeloid population. Efficient transduction of both lymphoid and myeloid
      lineages could be achieved only if the transduction protocol was extended by a
      further 24 hr (total culture period, 96 hr), suggesting that myeloid lineage
      committed precursors are capable of repopulation, and that over shorter time
      periods transduction is largely restricted to this population. This adds to the
      emerging evidence of heterogeneity within the SRC compartment, and has important
      implications for the interpretation of this assay in stem cell transplantation
      and gene transfer studies.

PMID- 10646643
TI  - Sustained expression of human apolipoprotein A-I after adenoviral gene transfer
      in C57BL/6 mice: role of apolipoprotein A-I promoter, apolipoprotein A-I introns,
      and human apolipoprotein E enhancer.
AB  - Elevation of HDL cholesterol, after adenoviral apolipoprotein A-I (apo A-I) gene
      transfer, may delay or revert ischemic cardiovascular disease, provided transgene
      expression is persistent. Previously, we observed transient human apo A-I
      expression after adenoviral gene transfer with a cytomegalovirus (CMV)-driven
      construct containing the human apo A-I cDNA. Therefore, the effects of promoters
      (CMV or 256 base pairs of the human apo A-I promoter), introns of the human apo A
      I gene, and the liver-specific human apolipoprotein E (apo E) enhancer on
      adenovirus-mediated human apo A-I expression were evaluated in C57BL/6 mice. In
      the presence of the CMV promoter, human apo A-I introns prolonged expression
      above 20 mg/dl from 14 to 35 days. Addition of one, two, or four copies of the
      human apo E enhancer in these constructs resulted in a copy-dependent but
      transient increase in expression for 14 days. The apo A-I promoter induced 3.2
      fold lower peak levels of human apo A-I than did the CMV promoter, but insertion
      of four apo E enhancers in the apo A-I promoter-driven construct resulted in
      human apo A-I levels above 20 mg/dl for 6 months. The decline between day 6 and
      day 35 of human apo A-I expression driven by the CMV promoter was due to (1) a
      2.5-fold decline in transgene DNA levels that is not observed with apo A-I
      promoter-driven constructs, and (2) CMV promoter attenuation as evidenced by a
      7.6-fold decline in the human apo A-I mRNA/human apo A-I DNA copy number ratio
      between day 6 and day 35. Hepatotoxicity, as evidenced by up to 10-fold higher
      serum levels of transaminases on day 6 after gene transfer with CMV promoter
      driven constructs than with apo A-I promoter-driven constructs, probably caused
      the accelerated decline of transgene DNA. In conclusion, gene transfer with an
      adenovirus comprising the 256-bp apo A-I promoter, the genomic apo A-I DNA, and
      four apo E enhancers, all of human origin, is associated with low hepatotoxicity
      and with the absence of promoter shutoff resulting in human apo A-I expression
      above 20 mg/dl for up to 6 months.

PMID- 10646644
TI  - Adenoviral gene transfer of interleukin 12 into tumors synergizes with adoptive T
      cell therapy both at the induction and effector level.
AB  - Tumors infected with a recombinant defective adenovirus expressing interleukin 12
      (IL-12) undergo regression, associated with a cytotoxic T lymphocyte (CTL)
      mediated antitumor immune response. In the present study we generated anti-CT26
      CTLs by short-term coculture of CT26 cells and lymph node cells obtained from
      mice harboring subcutaneous CT26 tumors injected with an adenoviral vector
      expressing IL-12 (AdCMVIL-12), control adenovirus (AdCMVlacZ), or saline.
      Regression of small intrahepatic CT26 tumors in unrelated syngeneic animals was
      achieved with CTLs derived from mice whose subcutaneous tumors had been injected
      with AdCMVIL-12 but not with CTLs from the other two control groups. The
      necessary and sufficient effector cell population for adoptive transfer consisted
      of CD8+ T cells that showed anti-CT26 specificity partly directed against the AH1
      epitope presented by H-2Ld. Interestingly, treatment of a subcutaneous tumor
      nodule with AdCMVIL-12, combined with intravenous adoptive T cell therapy with
      short-term CTL cultures, had a marked synergistic effect against large,
      concomitant live tumors. Expression of IL-12 in the liver in the vicinity of the
      hepatic tumor nodules, owing to spillover of the vector into the systemic
      circulation, appeared to be involved in the increased in vivo antitumor activity
      of injected CTLs. In addition, adoptive T cell therapy improved the outcome of
      tumor nodules transduced with suboptimal doses of AdCMVIL-12. Our data provide
      evidence of a strong synergy between gene transfer of IL-12 and adoptive T cell
      therapy. This synergy operates both at the induction and effector phases of the
      CTL response, thus providing a rationale for combined therapeutic strategies for
      human malignancies.

PMID- 10646645
TI  - Gene transfer to liver cancer cells of B7-1 plus interleukin 12 changes
      immunoeffector mechanisms and suppresses helper T cell type 1 cytokine production
      induced by interleukin 12 alone.
AB  - To investigate the cooperative effect of B7-1 and IL-12 in the induction of
      antitumor activity, we have developed retroviral vectors encoding human B7-1,
      murine IL-12, or both B7-1 and IL-12 coordinately. Murine transformed liver cells
      (BNL) were engineered to stably express B7-1, IL-12, or both by infection with
      corresponding retroviruses. No tumor was observed in 20, 75, and 95% of mice
      receiving, respectively, B7-1-, IL-12-, and B7-1/IL-12-modified tumor cells after
      250 days of inoculation. In contrast, injection of parental BNL or BNL/Neo cells
      resulted in lethal tumor progression in all mice. Protection against rechallenge
      with parental tumor cells was observed only in mice who had rejected BNL/IL-12,
      but not in animals that rejected BNL/B7-1 or BNL/B7-1-IL-12. Growth of parental
      tumor cells was significantly delayed by simultaneous injection in a distant site
      of irradiated tumor cells engineered to express IL-12 or both B7-1 and IL-12 but
      not B7-1 alone. BNL/B7-1 and BNL/B7-1-IL-12 showed similar efficacy in these
      experiments. Antitumor immunity induced by B7, with or without IL-12, was found
      to depend mainly on CD4+ T cells with a minor contribution of a non-T cell
      mechanism; whereas the effect of IL-12 was dependent on CD8+ T cells and on non-T
      cell effectors. Immunization of mice with IL-12-modified BNL cells induced
      secretion of a Thl pattern of cytokines while immunization with cells expressing
      both IL-12 and B7-1 resulted in inhibition of IFN-gamma production. Immunization
      with BNL/B7-1-IL-12 cells in the presence of anti-human B7-1 MAb resulted in
      restoration of IFN-gamma production to the levels found in animals injected with
      BNL/IL-12 cells. To summarize, in our model coexpression of B7-1 and IL-12 in
      tumor cells does not result in improved antitumoral activity as compared with
      expression of IL-12 alone. This may be related to the fact that B7-1 changes the
      mechanisms of antitumor immunity and inhibits IFN-gamma production induced by IL
      12 in vivo.

PMID- 10646646
TI  - Improved production of adenovirus vectors expressing apoptotic transgenes.
AB  - Adenovirus vectors expressing gene products that can induce apoptosis have
      potential utility in gene therapy applications ranging from the treatment of
      proliferative diseases to transplantation. However, adenovirus vectors carrying
      proapoptotic gene products are difficult to produce, as the apoptotic environment
      is not conducive to adenovirus gene expression and replication. Production of
      AdFasL/G, an adenovirus vector that expresses high levels of Fas ligand, was
      severely reduced in the 293 packaging cell line. Increased yields of AdFasL/G
      were achieved by inclusion of peptide-based caspase inhibitors in the growth
      medium. However, use of these inhibitors for large-scale production would be
      difficult and expensive. A screen for gene products that increase the yield of
      AdFasL/G in 293 cells revealed that the poxvirus serpin CrmA and the adenovirus
      14.7K product were able to increase virus yields significantly. Apoptosis induced
      by AdFasL/G was attenuated in 293CrmA cell lines and virus titers were increased
      dramatically. However, serial passage of AdFasL/G on 293CrmA cells resulted in
      the generation of replication-competent adenovirus. To resolve this problem, the
      CrmA gene was introduced into AE25 cells, an E1-complementing cell line that has
      limited sequence identity with the vectors. AdFasL/G titers were increased 100
      fold on AE25CrmA cells relative to the AE25 cells and RCA contamination was not
      detectable. In addition, adenovirus vectors that express FADD, caspase 8, and
      Fas/APO1 were produced efficiently in AE25CrmA and 293CrmA.

PMID- 10646647
TI  - Dynein- and microtubule-mediated translocation of adenovirus serotype 5 occurs
      after endosomal lysis.
AB  - Modified viruses are used as gene transfer vectors because of their ability to
      transfer genetic material efficiently to the nucleus of a target cell. To better
      understand intracellular translocation of adenovirus serotype 5 (Ad),
      fluorophores were covalently conjugated to Ad capsids, and movement of
      fluorescent Ad within the cytoplasm was observed during the first hour of
      infection of a human lung epithelial carcinoma cell line (A549). Ad translocation
      was characterized with respect to its ability to achieve nuclear envelope
      localization as well as directed movement in the cytoplasm. Whereas Ad achieved
      efficient nuclear localization 60 min after infection of A549 cells under control
      conditions, depolymerization of the microtubule cytoskeleton by addition of 25
      microM nocodazole reversibly inhibited development of nuclear localization. In
      contrast, depolymerization of microfilaments by addition of 1 microM cytochalasin
      D had no effect on nuclear localization. Direct video observation of Ad motility
      showed that nocodazole, but not cytochalasin D, caused a reversible decrease in
      rapid linear translocations of Ad in the cytoplasm of A549 cells. Microinjection
      of function-blocking antibodies against the microtubule-dependent motor protein,
      cytoplasmic dynein, but not kinesin, blocked nuclear localization of Ad,
      consistent with net minus end-directed motility indicated by accumulation of Ad
      at mitotic spindles. Fluorescence ratio imaging revealed a neutral pH in the
      environment of translocating Ad, leading to a model in which the interaction of
      Ad with an intact microtubule cytoskeleton and functional cytoplasmic dynein
      occurs after escape from endosomes and is a necessary prerequisite to nuclear
      localization of adenovirus serotype 5.

PMID- 10646648
TI  - Comparative in vivo approaches for selective adenovirus-mediated gene delivery to
      the placenta.
AB  - Gene delivery to the placenta is one potential way of specifically modifying
      placental biological processes and fetal development. The aim of this study was
      to determine the most efficient and least invasive route of placental adenovirus
      delivery. The feasibility of adenovirus-mediated gene transfer to the rat
      placenta was addressed by maternal intravenous or direct intraplacental injection
      of adenoviral vectors expressing the glucose transporter GLUT3, a noncirculating
      integral membrane protein. Both routes led to transgene expression in the
      placenta. However, direct intraplacental delivery on day 14 of gestation yielded
      a higher transduction efficiency than maternal intravenous administration, and
      markedly reduced transgene expression in maternal liver. Most importantly, the
      amount of the GLUT3 transgene and the adenovirus itself in fetal tissues was only
      1 to 3% of that found in the placenta. These results indicate that the nature of
      the transgene and the route of adenovirus administration are key parameters in
      selective placental somatic gene transfer. This novel strategy may prove useful
      for modifying a placental function without altering the fetal genome.

PMID- 10646649
TI  - Self-inactivating lentiviral vectors with enhanced transgene expression as
      potential gene transfer system in Parkinson's disease.
AB  - Glial cell line-derived neurotrophic factor (GDNF) is able to protect
      dopaminergic neurons against various insults and constitutes therefore a
      promising candidate for the treatment of Parkinson's disease. Lentiviral vectors
      that infect quiescent neuronal cells may allow the localized delivery of GDNF,
      thus avoiding potential side effects related to the activation of other brain
      structures. To test this hypothesis in a setting ensuring both maximal biosafety
      and optimal transgene expression, a self-inactivating (SIN) lentiviral vector was
      modified by insertion of the posttranscriptional regulatory element of the
      woodchuck hepatitis virus, and particles were produced with a multiply attenuated
      packaging system. After a single injection of 2 microl of a lacZ-expressing
      vector (SIN-W-LacZ) in the substantia nigra of adult rats, an average of 40.1 +/-
      6.0% of the tyrosine hydroxylase (TH)-positive neurons were transduced as
      compared with 5.0 +/- 2.1% with the first-generation lentiviral vector. Moreover,
      the SIN-W vector expressing GDNF under the control of the mouse phosphoglycerate
      kinase 1 (PGK) promoter was able to protect nigral dopaminergic neurons after
      medial forebrain bundle axotomy. Expression of hGDNF in the nanogram range was
      detected in extracts of mesencephalon of animals injected with an SIN-W-PGK-GDNF
      vector, whereas it was undetectable in animals injected with a control vector.
      Lentiviral vectors with enhanced expression and safety features further establish
      the potential use of these vectors for the local delivery of bioactive molecules
      into defined structures of the central nervous system.

PMID- 10646650
TI  - Fibroblast growth factor 2-retargeted adenoviral vectors exhibit a modified
      biolocalization pattern and display reduced toxicity relative to native
      adenoviral vectors.
AB  - Targeted vectors provide a number of advantages for systemic and local gene
      delivery strategies. Several groups have investigated the utility of using
      various ligands to alter the tropism of adenovirus (Ad) vectors. We have
      previously demonstrated that fibroblast growth factor (FGF) ligands can
      specifically target DNA transfection and Ad transduction through high-affinity
      FGF receptors (FGFRs). FGFRs are overexpressed in abnormally proliferating
      tissues, such as malignancies. The present studies explore the effects of
      retargeting with FGF2 on the tissue localization pattern and the systemic
      toxicity of Ad in mice. Results of semiquantitative PCR analyses indicate that
      the distribution of FGF2-Ad vector genome sequences after intravenous
      administration in mice is altered. Markedly lower amounts (10- to 20-fold) of
      FGF2-Ad localize to the liver when compared with native Ad. This decrease in
      liver deposition translates into a significant reduction in subsequent toxicity
      as measured by serum transaminases and histopathology in mice injected with FGF2
      AdHSV-thymidine kinase with and without ganciclovir administration. In an
      intraperitoneal model of ovarian cancer, FGF2-Ad generates increased transgene
      expression in tumor tissue when compared with Ad. Taken together, these results
      indicate that the retargeting of Ad with FGF2 results in a more efficient vector
      system for systemic and regional gene therapy applications, with concomitant
      lower levels of systemic toxicity.

PMID- 10646651
TI  - Transient production of bone morphogenetic protein 2 by allogeneic transplanted
      transduced cells induces bone formation.
AB  - The aim of this study was to evaluate the use of transplantation of genetically
      modified allogeneic cells as a method to induce bone formation. In this study, we
      infected a murine osteoprogenitor cell line with a retroviral vector containing
      the human bone morphogenic protein 2 (BMP2) gene. Transduced cells exhibited more
      alkaline phosphatase activity than cells treated with any of the tested doses of
      recombinant human BMP2 protein (rhBMP2). The transduced cells were suspended in a
      collagen solution and injected into the quadriceps muscle in immunocompetent
      outbred mice. Radiographic and histological examinations demonstrate abundant
      ectopic bone formation in 85% of the transplanted animals (n = 13). PCR and
      Southern blot analysis for the puromycin resistance gene revealed that the
      transplanted cells were detectable for up to 1 week, but not at later time
      points. None of the animals developed tumors. Our results suggest that allogeneic
      BMP2-expressing transduced cells may have therapeutic potential for enhancing new
      bone formation. This model also provides a simple, inexpensive, and sensitive
      assay for evaluating in vivo the osteoinductive potentials of secreted proteins
      without the requirement of protein purification or the use of immunodeficient
      animals.

PMID- 10646652
TI  - A cell line for high-yield production of E1-deleted adenovirus vectors without
      the emergence of replication-competent virus.
AB  - Production of E1-deleted adenovirus vectors for gene therapy has been plagued by
      the emergence of replication-competent adenovirus. A number of investigators have
      minimized homologous sequences between the vector and transfected E1 DNA in an
      attempt to avoid replication-competent adenovirus. We describe a HeLa-based cell
      line called GH329 that stably expresses the E1 locus from a promoter derived from
      the phosphoglycerate kinase gene. Overlap sequences with a standard E1-deleted
      vector that retains a full pIX transcriptional unit have been eliminated at the
      5' end and minimized at the 3' end. The GH329 cell line plaques and produces E1
      deleted adenovirus as well as 293 cells. Replication-competent virus has emerged
      after 5 passages of vector on 293 cells but was not detected after 20 passages on
      GH329 cells.

PMID- 10646653
TI  - Homocysteine, hypothyroidism, and effect of thyroid hormone replacement.
AB  - Elevation of total plasma concentration of homocysteine (t-Hcy) is an important
      and independent risk factor for cardiovascular disease. Hypothyroidism is
      possibly also associated with an increased risk for coronary artery disease,
      which may be related to atherogenic changes in lipid profile. Because
      hypothyroidism decreases hepatic levels of enzymes involved in the remethylation
      pathway of homocysteine, we prospectively evaluated fasting and postload t-Hcy in
      patients before and after recovery of euthyroidism. Fasting and postload t-Hcy
      levels were higher in 40 patients with peripheral hypothyroidism (14 with
      autoimmune thyroiditis and 26 treated for thyroid cancer) in comparison with
      those of 26 controls (13.0 +/- 7.5 vs. 8.5 +/- 2.6 micromol/L, p < .01,
      respectively, and 49.9 +/- 37.3 vs. 29.6 +/- 8.4 micromol/L p < .001,
      respectively). On univariate analysis, fasting Hcy was positively related to
      thyrotropin (TSH) and inversely related to folates. Multivariate analysis
      confirmed TSH as the strongest predictor of t-Hcy independent of age, folate,
      vitamin B12, and creatinine. Thyroid hormone replacement significantly decreased
      fasting but not postload t-Hcy. We conclude that t-Hcy is elevated in
      hypothyroidism. The association of hyperhomocysteinemia and lipid abnormalities
      occurring in hypothyroidism may represent a dynamic atherogenic state. Thyroid
      hormone failed to completely normalize t-Hcy. Potential benefit of treatment with
      folic acid in combination with thyroid hormone replacement has to be tested given
      that hypothyroid patients were found to have lower levels of folate.

PMID- 10646654
TI  - Factors associated with mortality of myxedema coma: report of eight cases and
      literature survey.
AB  - High-dose thyroid hormone replacement has been recommended for treatment of
      myxedema coma (MC) while questions of safety of the therapy and of efficacy of
      low-dose thyroid hormone replacement have not been systematically addressed. We
      treated 8 patients with MC in a period of 18 years, the first 3 with high-dose
      intravenous injections of levotriiodothyronine (LT3) and the other 5 patients
      with a smaller amount of either LT3 or levothyroxine (LT4). Two of the first 3
      patients died of pneumonia and the other 5 recovered despite pulmonary
      abnormalities at the outset. To find factors associated with fatal outcome after
      treatment, the MEDLINE database was searched for MC cases with data of thyroid
      hormone replacement and outcome within 1 month of therapy. Clinical data for our
      5 patients and 82 cases from the MEDLINE search were pooled and factors
      associated with mortality were sought among age, gender, presence of cardiac or
      pulmonary complications, and doses of thyroid hormone by multiple logistic
      regression analysis. It revealed that greater age, cardiac complications, and
      high-dose thyroid hormone replacement (LT4 > or = 500 microg/d or LT3 > or = 75
      microg/d) were significantly associated with a fatal outcome within 1 month of
      treatment. Elderly MC patients can be treated with low-dose hormone replacement.
      A bolus of 500 microg LT4, especially by mouth or via nasogastric tube, appears
      to be tolerated by younger patients (< 55 years) without cardiac complication.
      The conclusion remains to be confirmed in more patients.

PMID- 10646655
TI  - The combination of absent thyroid peroxidase antibodies and high thyroid
      stimulating immunoglobulin levels in Graves' disease identifies a group at
      markedly increased risk of ophthalmopathy.
AB  - Among Graves' Disease (GD) patients, we have observed an unexpectedly high
      prevalence of antithyroperoxidase antibody (TPOAb) and antithyroglobulin antibody
      (TgAb) negativity in those with severe ophthalmopathy. To study the possible role
      of thyroid autoantibodies in the pathogenesis of Graves' ophthalmopathy (GO),
      TPOAb, TgAb, thyroid-stimulating immunoglobulin (TSI), and thyrotropin-binding
      inhibitory immunoglobulin (TBII) levels were measured, and the presence or
      absence of GO was assessed by a single observer in 100 consecutive patients with
      newly diagnosed, untreated GD who were nonsmokers. Ophthalmopathy was present in
      43 patients. TSI levels (p = 0.001), and the prevalence of TPOAb-negativity (p =
      0.002) were significantly higher in patients with ophthalmopathy compared to
      those without. Logistic regression analysis showed that TSI levels (p = 0.005)
      and the absence of TPOAb (p = 0.0025) were independent predictors of GO. No
      correlation between TBII or TgAb and eye disease was found. The prevalence of GO
      increased with each quartile of TSI levels. The prevalence was 20%, 36%, 52%, and
      64% in the first, second, third and fourth quartiles of TSI, respectively. The
      odds ratio of GO (with 95% confidence intervals) when TSI levels were above the
      median level (1640%) was 3.6 (1.5-8.0), when TPOAb was negative it was 5.0 (1.7
      14.4), and with both risk factors it was 36.6 (4.3-313.5). The prevalence of
      ophthalmopathy in this last group was 92.9%. The combination of negative TPOAb
      and high TSI levels appears to be associated with a markedly increased risk of
      clinically evident ophthalmopathy.

PMID- 10646656
TI  - Radioiodine therapy in Graves' disease patients with large diffuse goiters
      treated with or without carbimazole at the time of radioiodine therapy.
AB  - We sought to ascertain how high the success rates of radioiodine therapy are for
      Graves' disease patients with large diffuse goiters when aiming for a constant
      absorbed dose of 250 Gy. Thirty-six patients with a thyroid volume of 50-110 mL
      were evaluated for changes in thyroid function and appearance 3, 6, and 12 months
      after radioiodine therapy. Success was defined as definitive elimination of
      hyperthyroidism following therapy (hypothyroidism corrected with thyroxine on
      diagnosis); failure as persistent/recurrent hyperthyroidism after 12 months.
      Overall success rate was 50%. However, a subgroup of 20 patients without
      simultaneous carbimazole (carbimazole-off) showed a highly significantly larger
      success rate (85%) than the 16 patients with simultaneous carbimazole
      (carbimazole-on) at the time of radioiodine therapy (6.3%, p < 0.000005).
      Successful cases showed a significantly higher volume reduction after radioiodine
      than failures (75.5% vs. 35.4%, p < 0.00005). Stepwise logistic regression showed
      that therapy failure was related to administration of carbimazole during
      radioiodine therapy (p < 0.0250 and absorbed dose (p < 0.05), but not thyroid
      function (free triiodothyronine [FT3] and free thyroxine [FT4]), initial thyroid
      volume or thyrotropin-receptor antibody (TRAb) value. However, a significant
      correlation of therapy success to absorbed dose (r = 0.69, p < 0.005) could be
      shown only for carbimazole-off patients, but not for the others. Finally,
      multivariate factor analysis consistently showed that therapy success was
      correlated only to absorbed dose and antithyroid drugs, not to initial thyroid
      volume, TRAb value, or thyroid function. Thyroid volume per se is not responsible
      for the lower success rate in Graves' disease patients with large goiters because
      even a comparable group of 32 Graves' disease patients with small thyroid glands
      (< or =20 mL) and without simultaneous carbimazole showed a success rate of
      87.5%. The high failure rate in the carbimazole-on patients (absorbed dose
      comparable to carbimazole-off) is due to the simultaneous administration of
      carbimazole. Therefore, if clinically feasible, we recommend discontinuing
      carbimazole at least one day before beginning radioiodine therapy.

PMID- 10646657
TI  - Color Doppler ultrasonography in patients with subacute thyroiditis.
AB  - We studied the utility of color Doppler ultrasonography in patients with subacute
      thyroiditis. Eighteen patients with subacute thyroiditis (SAT) with painful
      goiter and thyrotoxicosis underwent color Doppler ultrasonography during the
      acute and recovery stages of the disease. Thyroid vascularization in these
      patients was compared with that of 15 untreated patients with Graves' disease and
      17 control subjects. During the acute stage of subacute thyroiditis, color
      Doppler ultrasonography showed low echogenicity without increased tissue
      vascularity in the affected swollen thyroid. In the recovery stage, color Doppler
      ultrasonography showed isoechogenicity with slightly increased vascularization.
      Vascularization became normal at 1 year follow-up time. In contrast, marked by
      increased vascularization was observed in patients with untreated Graves'
      disease. Color Doppler ultrasonography showed clear differences between SAT and
      Graves' disease patients. Vascularity was significantly correlated with serum
      free thyroxine (FT4) and thyrotropin (TSH) concentrations in the recovery stage
      (3 months after the initial ultrasonography). Color Doppler ultrasonography
      accurately visualized lesions without increased vascularity in the acute stage of
      SAT and lesions of slightly increased vascularity in the recovery stage. Color
      Doppler ultrasonography may be a useful, noninvasive, and rapid method for
      differentiating SAT from Graves' disease and for evaluating and monitoring the
      location and activity of lesions in SAT.

PMID- 10646658
TI  - A novel point mutation in cluster 3 of the thyroid hormone receptor beta gene
      (P247L) causing mild resistance to thyroid hormone.
AB  - Resistance to thyroid hormone (RTH), a syndrome characterized by variable tissue
      hyposensitivity to thyroid hormone (TH), is linked to mutations in the thyroid
      hormone receptor (TR) beta gene. We report a new family with a heretofore
      unreported mutation, P247L. The proposita, a 31-year-old female, presented with
      goiter and palpitations. RTH was suspected because of elevated serum free
      thyroxine (FT4) level with a normal thyrotropin (TSH). Sequencing the TRbeta gene
      revealed a mutation causing replacement of a proline at position 247 with
      leucine. Seven family members were heterozygous for the mutation, two of whom
      also had evidence of autoimmune thyroid disease. The mutant TRbeta had a Ka for
      triiodothyronine (T3) 30% that of the wild-type TRbeta, approximately a threefold
      reduction in T3-induced transactivation and a low level dominant negative
      activity when tested with a positively regulated reporter gene. In vivo
      sensitivity to TH was evaluated in three affected subjects by measurement of the
      responses to graded doses of levotriiodothyronine (LT3). Peak TSH responses to
      TRH were reduced and were not completely suppressed at even the highest dose of
      LT3, (0.9, 0.2, and 0.2, compared to < 0.01 microU/mL in unaffected controls),
      confirming pituitary resistance to TH in all three subjects. In contrast,
      peripheral tissues responded variably to LT3: serum cholesterol decreased in all
      by 15%-25%, serum creatine kinase decreased by 15% in two subjects and increased
      35% in another, but serum ferritin and sex hormone-binding globulin increased in
      only one of the three affected individuals that were tested. Basal metabolic rate
      and sleeping pulse did not change in three and two individuals, respectively.
      Hyporesponsiveness to exogenous TH established the clinical diagnosis of RTH in
      one member of the family with a mutant TRbeta but normal tests of thyroid
      function at baseline. Three affected subjects had an axis I diagnosis of major
      depression but had Wechsler Intelligence Scale for Children, III (WISC-III) full
      scale IQs (FSIQs) in the normal range. This novel TRbeta mutation is associated
      with a realtively mild RTH. Results of responses to LT3 underscore the variable
      phenotype of RTH.

PMID- 10646660
TI  - Calcitonin reserve in different stages of atrophic autoimmune thyroiditis.
AB  - The objective of this study was to determine the calcitonin (CT) hormone reserve
      in different severity of atrophic autoimmune thyroiditis (AAT). Forty-eight
      female patients with AAT were divided into four groups based on basal and peak
      thyrotropin (TSH) values (after oral thyrotropin-releasing hormone [TRH], free
      triiodothyronine (FT3) and free thyroxine (FT4) ranging from normal in group 1 to
      overt hypothyroidism in group 4. All had thyroid antibodies. The control group
      comprised euthyroid females of comparable age, without thyroid antibodies. Basal
      CT and CT response to calcium infusion (area under the curve) were investigated
      as parameters of CT reserve. Basal CT was lower in groups 2 to 4 of patients with
      AAT (compared to controls), but the difference was not significant. Stimulated CT
      levels were lower (p < 0.05) in all groups of patients compared to controls, with
      markedly reduced CT-secretory reserve in group 4. Thyroid antibody concentrations
      and, basal and postinfusion calcium levels were not significantly different among
      the various groups. In conclusion CT deficiency (especially stimulated values)
      occurs in AAT and is more severe in hypothyroid patients than in earlier stages
      of AAT.

PMID- 10646659
TI  - Stimulation of Chinese hamster ovary cells expressing human thyrotropin receptors
      by serum human chorionic gonadotropin of patients with hydatidiform mole.
AB  - We evaluated the stimulation of Chinese hamster ovary cells expressing human
      thyrotropin receptors (CHO-hTSHR cell) by sera of five patients with hydatidiform
      mole before and after the evacuation of the mole, and compared the results with
      serum human chorionic gonadotropin (hCG) concentrations and serum free thyroid
      hormones in these patients. Significantly increased CHO-hTSHR cell stimulating
      activities were observed in sera from untreated patients, and the activity
      decreased promptly after the evacuation of the mole, concomitantly with the
      decrease in serum hCG and free thyroid hormones. CHO-hTSHR cell stimulating
      activity of sera of the untreated patients significantly correlated with serum
      hCG. Moreover, serum hCG stimulated CHO-hTSHR cells in a dose dependent manner
      similar to the dose-response curve of the stimulation by purified hCG. Sera of
      the patients and purified hCG did not stimulate nontransfected CHO-K1 cells.
      However, a significant correlation was not observed between serum-free thyroid
      hormones and serum hCG or between serum free thyroid hormones and CHO-hTSHR cell
      stimulating activities in untreated patients. These results indicate that serum
      hCG from patients with hydatidiform mole stimulates thyroid gland by interacting
      with TSH receptors, and suggest that the increase in thyroid hormones in patients
      may depend on both the increased serum hCG and the responsiveness of their
      thyroid glands to hCG.

PMID- 10646661
TI  - Telomerase activity in thyroid malignancy.
AB  - Telomerase activity seems to play a role in the development and pathogenesis of
      thyroid carcinoma. Its incidence of expression and its application as a tumor
      marker remain to be elucidated. Thyroid tissues obtained during thyroidectomy
      from 1996-1998 were rapidly frozen and stored at -80 degrees C until processed.
      Telomerase activity was determined using telomeric repeat amplification protocol
      (TRAP). Histology of the tissue examined (67 benign and 59 malignant) was
      reviewed. Telomerase activity was detected in 15 of 52 papillary carcinomas
      (29%); 1 of 1 thyroid lymphoma (100%); 1 of 2 anaplastic carcinomas (50%); and 2
      of 16 lymphocytic thyroiditis specimens (13%). Telomerase activity was not
      detectable in 35 normal thyroid, 9 follicular adenoma, 7 nodular hyperplasia, 2
      follicular carcinoma, and 2 medullary carcinoma. Lymphocytic thyroiditis was
      detected in 8 of 37 (22%) apparently normal thyroid tissues adjacent to papillary
      thyroid carcinoma and telomerase activity was present in 2 of these 8 specimens
      (25%). In conclusion, telomerase does not appear to be frequently activated in
      papillary thyroid carcinoma. The association of lymphocytic thyroiditis with
      papillary thyroid carcinoma may limit its clinical usefulness as a tumor marker.

PMID- 10646662
TI  - Invasion of human follicular thyroid carcinoma cells in an in vivo invasion
      model.
AB  - Models that demonstrate histological invasion of extracellular matrix barriers by
      tumor cell lines are useful for assessing new methods to treat or prevent tumor
      metastasis. An in vivo invasion model using acellular human dermal matrix has
      been described in a murine squamous cell carcinoma line. The present study
      examined the application of this tumor invasion model to another epithelial cell
      line derived from a different species. A human follicular thyroid carcinoma cell
      line, known to be invasive by other assays, was grown on the dermal-epidermal
      basement membrane surface of human acellular dermal matrix in culture and then
      grafted in athymic mice. Immunohistochemical staining of type IV collagen was
      used to identify the basement membrane and invasion was determined as penetration
      of the basement membrane by tumor cells. Identification of the human tumor cells
      in the in vivo grafts was done by in situ hybridization with species specific
      probes. FTC-133 tumor cells did not invade the matrix after 4 weeks of growth in
      in vitro culture, but there was extensive loss of the basement membrane and
      infiltration of the tumor cells into the dermis after 2 weeks growth in vivo.
      This study suggests that the in vivo dermal matrix model of invasion is
      applicable to a broad range of epithelial carcinoma cell lines to study their
      capability to penetrate basement membrane. A model such as this may be useful for
      studying the local effects of genetic manipulations of implanted tumor cell
      populations, leading to the development of therapeutic agents that block
      invasion.

PMID- 10646663
TI  - Factors related to the survival of papillary and follicular thyroid carcinoma
      patients with distant metastases.
AB  - There is limited clinical information comparing presentations and results of
      treatment of papillary and follicular thyroid carcinoma patients with distant
      metastases. We retrospectively analyzed data of 1,257 thyroid cancer patients who
      received their treatment and follow-up at Chang Gung Memorial Hospital. We found
      992 patients with papillary carcinoma and 205 patients with follicular thyroid
      carcinoma. Of these, 68 patients with papillary thyroid carcinoma (6.9%) had
      distant metastases at the time of diagnosis or during the follow-up period. Of
      the follicular thyroid carcinoma patients, 69 (33.7%) had distant metastases. Of
      the 68 patients with papillary carcinoma, only 33 were categorized as stage IV at
      the time of diagnosis. Nine of the patients were categorized as clinical stage I
      carcinoma, 10 as stage II, and 16 as stage III. Sixteen patients (23.5%) died
      during the study period, all but 2 of thyroid cancer. Twelve of the 68 patients
      were disease-free after treatment. Of the 69 patients with follicular thyroid
      carcinoma, 58 were categorized as stage IV at the time of diagnosis. Six of the
      patients were categorized as clinical stage I carcinoma, 2 as stage II, and 3 as
      stage III at the time of diagnosis; all of these patients deteriorated to stage
      IV during the follow-up period. Of the 42 patients with follicular thyroid
      carcinoma involving bone, 24 presented with bone metastases during the initial
      diagnosis. After treatment, 25 of 69 patients with follicular carcinoma died of
      follicular carcinoma. Only 3 patients were disease-free after the treatment. In
      patients with follicular carcinoma, only tumor size was an important prognostic
      factor. In this study, 8 patients categorized as clinical stages I to III at the
      time of operation had thyroglobulin (Tg) levels less than 5 ng/mL and developed
      distant metastases during the follow-up period. In conclusion, at diagnosis a
      large group of Asian patients with metastatic well-differentiated thyroid cancer
      was more likely to have follicular than papillary histology, and that, as
      expected, metastases from follicular cancer were present earlier and more
      frequently, were more likely to involve bone, were more likely to be associated
      with mortality, and were linked to tumor size but not gender. Also unlike some
      other reports, treatment producing a low Tg did not always produce a good
      outcome. More aggressive surgical procedures may be able to improve outcomes.

PMID- 10646664
TI  - Detection of RET/PTC oncogene rearrangements in Korean papillary thyroid
      carcinomas.
AB  - The prevalence of RET/PTC rearrangement in papillary thyroid carcinomas has been
      found to vary widely in different populations. Recent studies, however, have
      reported no significant geographical difference between Asian and Western
      countries. In addition, there are some disagreements about the correlation of
      RET/PTC expression with clinical aggressiveness. We have performed this study in
      order to examine the prevalence of RET/PTC-1, RET/PTC-2, and RET/PTC-3
      rearrangements in Korean papillary thyroid carcinomas, and to ascertain its
      clinical relevance. Thyroid tumors from 31 patients histologically confirmed to
      be papillary carcinomas were included in this study. To find rearrangements, we
      utilized reverse transcription-polymerase chain reaction (RT-PCR) and automated
      direct sequencing. Initial and follow-up clinical data were obtained from the
      patients' medical records. We identified two tumors containing RET/PTC-1 (2/31,
      6.5%) and two containing RET/PTC-2 (2/31, 6.5%). However, we could not find
      RET/PTC-3 rearrangement in any patients (0/31). In conclusion, we report RET/PTC
      rearrangements in 4 of 31, (12.9%) Korean patients with papillary thyroid
      carcinomas, a higher prevalence than previously reported in this population.

PMID- 10646665
TI  - Degree of thyrotropin suppression in differentiated thyroid cancer without
      recurrence or metastases.
AB  - Forty-eight patients with differentiated thyroid cancer (DTC), who had no
      evidence of tumor recurrence or metastases on studies such as radioiodine
      scanning, neck ultrasonography, and with thyrotropin (TSH) and thyroglobulin (Tg)
      levels less than 1 mU/L and 5 ng/mL, respectively, were included in the study.
      The mean age was 43 +/- 12 years (range 15-65) and all were receiving
      levothyroxine (LT4) treatment with a mean dose of 184 +/- 46 microg daily.
      Patients were divided into two groups; group A included patients that had
      baseline TSH levels of 0.4 mU/L or more, and group B patients had baseline TSH
      levels of less than 0.4 mU/L. LT4 doses for all patients were increased, and
      serum TSH and Tg measurements were reevaluated after 2 months of dose increments.
      The mean TSH of group A (patients with baseline TSH levels > or = 0.4 mU/L)
      decreased from 0.67 +/- 0.28 mU/L to 0.16 +/- 0.08 mU/L (p < 0.001), but mean
      serum Tg level showed no change after dose increments (2.92 +/- 1.36 ng/mL vs.
      3.59 +/- 0.93 ng/mL at the second month; p > 0.05). Similar results were also
      observed in group B (patients with baseline TSH levels < 0.4 mU/L). Mean TSH
      level decreased from 0.26 +/- 0.07 mU/L to 0.1 +/- 0.05 mU/L (p = 0.006), but no
      decrease occurred in mean Tg level (3.0 +/- 1.16 ng/mL vs. 3.3 +/- 1.03 ng/mL; p
      > 0.05). The patients' data were reevaluated according to second-month TSH
      levels. Patients with a TSH level between 0.11 to 0.4 mU/L were set as "final TSH
      > 0.1 group," and patients with a TSH level equal or less than 0.1 mU/L were set
      as "final TSH < or = 0.1 group," and baseline and second-month Tg levels were
      assessed. The mean second month Tg levels did not differ in these two patient
      groups (3.7 +/- 0.74 ng/mL for final TSH > 0.1 group vs. 3.3 +/- 1.2 ng/mL for
      final TSH < or = 0.1 group; p > 0.05). No difference could be found between
      initial and second-month Tg levels in both groups (2.8 +/- 1.4 ng/mL vs. 3.7 +/-
      0.74 ng/mL in final TSH > 0.1 group and 3.11 +/- 1.1 ng/mL vs. 3.3 +/- 1.2 in
      final TSH < or = 0.1 group; p > 0.05). In conclusion, these results indicate that
      serum Tg levels cannot be suppressed by maximal TSH suppression in tumor-free DTC
      patients. The suppression of TSH to less than 0.1 mU/L seems not to be necessary
      in most patients who have no evidence of active disease.

PMID- 10646666
TI  - Isolated thyrotropin deficiency secondary to primary empty sella in a patient
      with differentiated thyroid carcinoma: an indication for recombinant thyrotropin.
AB  - The primary empty sella syndrome is a common radiographic finding that is rarely
      associated with clinical pituitary dysfunction. Studies using dynamic endocrine
      testing, however, have shown altered pituitary reserve in some patients with the
      primary empty sella syndrome. We describe a patient with a primary empty sella
      and an isolated deficiency of thyrotropin reserve. This case is complicated by
      the presence of an aggressive metastatic papillary epithelial carcinoma of the
      thyroid. Standard treatment with radioactive iodine was unlikely to be effective
      in this patient due to the need for adequate thyrotropin (TSH) stimulation of the
      malignant tissue to optimize uptake of radioactive iodine by the tumor cells.
      Consequently, this patient was treated with human recombinant TSH before
      receiving radioactive iodine. The utility of this novel therapeutic agent and a
      review of hormonal abnormalities associated with the primary empty sella are also
      discussed.

PMID- 10646667
TI  - Recombinant human thyrotropin in thyroid cancer and hypopituitarism due to sella
      metastasis.
AB  - We present a patient with thyroid cancer and hypopituitarism who required
      recombinant human thyrotropin (rhTSH) for 131I scanning with respect to
      subsequent therapy. The thyroid cancer had been unknown until central
      neurological symptoms developed, leading to the diagnosis of a huge metastasis to
      the sella that was the only manifestation of metastatic spread. The failure to
      generate endogenous thyrotropin (TSH) was overcome by the use of rhTSH for
      performing a 131I test. Unfortunately, the 131I uptake was not sufficient for
      therapy. This subject is the first reported case who required the application of
      rhTSH due to a single thyroid cancer metastasis in the sella region with
      secondary failure to generate endogenous TSH.

PMID- 10646668
TI  - Exophthalmos, pretibial myxedema, osteoarthropathy syndrome associated with
      papillary fibroelastoma in the left ventricle.
AB  - EMO syndrome, a rare complication of Graves' disease, exhibits exophthalmos,
      pretibial myxedema, and osteoarthropathy. The presence of functional thyrotropin
      receptors (TSHR) in adipocytes and osteoblasts, both of which we have recently
      observed, may be related to these extrathyroidal manifestations of Graves'
      disease. In addition, the expression of TSHR in the heart has recently been
      reported. We describe here a patient with Graves' disease exhibiting EMO syndrome
      with a papillary fibroelastoma in the left ventricle. Pathological examinations
      showed that the fibroelastoma contained Alcian blue-stained mucinous materials
      that were also observed in the subcutaneous tissue of pretibial myxedema.

PMID- 10646669
TI  - Graves' disease and recurrent ectopic thyroid tissue.
AB  - Ectopic thyroid tissue is the result of abnormal migration of the gland as it
      travels from the floor of the primitive foregut to its destined pretracheal
      position. The prevalence of ectopic thyroid tissue ranges between 7%-10%.
      Patients with ectopic thyroid tissue are usually euthyroid, but can present with
      signs and symptoms of upper aerodigestive tract obstruction. We report a case in
      which ectopic mediastinal thyroid tissue was removed surgically because of
      substernal chest pain. It recurred 9 years later when the patient developed
      Graves' disease. We propose that the recurrence of the ectopic thyroid tissue was
      due to the influence of thyroid stimulating immunoglobulins (TSI).

PMID- 10646670
TI  - Improved radioimmunoassay for measurement of mouse thyrotropin in serum: strain
      differences in thyrotropin concentration and thyrotroph sensitivity to thyroid
      hormone.
AB  - We report an improved heterologous radioimmunoassay (RIA) for the measurement of
      thyrotropin (TSH) in mouse serum. The assay components are: antirat thyrotropin
      (rTSH) serum from the National Hormone and Pituitary Program, a commercial [125I]
      labeled rTSH and mouse thyrotropin (mTSH) serum standards produced by dilution of
      a serum pool from hypothyroid mice with high TSH with a serum pool from mice
      treated with excess levothyroxine (LT4) (mTSH-0). Sensitivity was increased by
      reducing the amount of antibody and tracer and by taking advantage of the
      disequilibrium technique. Accuracy was greatly improved by the preparation of
      mouse serum TSH standards. TSH in serial dilutions of individual mice with high
      TSH of different etiologies paralleled the mTSH standard curve but not that of
      rTSH or a crude mouse TSH/luteinizing hormone (LH) reference preparation. The
      high-mTSH-serum standard contained 20 mU TSH per milliliter, measured in a
      bioassay utilizing a cell line stably transfected with human TSH receptor cDNA,
      and a relative TSH concentration of 40 ng/mL. The sensitivity of the RIA is 0.01
      to 0.02 ng/mL, depending on the quality of the tracer and the preparation of mTSH
      0 serum. The intra-assay and interassay coefficients of variations were,
      respectively: 16% and 27% at 0.04 ng/mL; 6.3% and 8.2% at 0.4 ng/mL; 5.4% and
      9.8% at 1.7 ng/mL; 10% and 24% at 4.0 ng/mL. The mean TSH concentration in serum
      of 60-80-day-old male mice was four-fold higher than that in females of the same
      age. The assay was able to distinguish differences in serum TSH concentrations in
      five different strains of mice. Baseline serum TSH concentrations (mean +/- SD)
      of 70-day-old male mice were: 0.143 +/- 0.065 ng/mL in the CD-1 strain; 0.229 +/-
      0.042 ng/mL in C57BL/6 mice; 0.084 +/- 0.017 ng/mL in SWR/J mice; 0.133 +/- 0.057
      ng/mL in NOD SCID mice, and 0.266 +/- 0.122 ng/mL in FVB mice. Mean serum
      thyroxine (T4) concentrations were also significantly different among the mouse
      strains but did not correlate with the serum TSH level. Administration of
      levotriiodothyronine (LT3) suppressed the serum TSH to a greater degree in mice
      with higher baseline TSH values. Suppression of the thyroidal radioiodide uptake
      with LT3 correlated with that of serum TSH.

PMID- 10646671
TI  - Lymphoid lesions of the thyroid: review in light of the revised European-American
      lymphoma classification and upcoming World Health Organization classification.
AB  - Thyroid lymphomas are rare diseases and almost always rise in the background of
      chronic lymphocytic thyroiditis (Hashimoto's thyroiditis). Large cell lymphoma is
      an aggressive disease and usually is not a significant diagnostic challenge from
      the pathological point of view. Small cell lymphoma, however, can sometimes be
      difficult to distinguish from chronic lymphocytic thyroiditis. In the past, most
      thyroid lymphomas were considered to be of follicle center cell origin. Today,
      after the introduction of the mucosa-associated lymphoid tissue (MALT) and the
      extranodal lymphoid tissue (ELT) concepts, most of the lymphomas in the
      extranodal sites are thought to originate from the marginal zone of the lymphoid
      follicles. The distinction between the different types of lymphomas has
      significant impact on the patient's prognosis, treatment, and follow-up. It is
      imperative that clinicians (endocrinologists and surgeons) and pathologists are
      aware of these types of lymphomas in order for the most appropriate diagnostic
      procedures to be selected, specific staging principles to be applied, and
      appropriate disease-specific treatment to be implemented. It is also important
      that terms such as "lesion of uncertain malignant potential" as defined by
      ancillary studies be understood.

PMID- 10646672
TI  - A possible association between Graves' disease and Gluten-sensitive enteropathy.

PMID- 10646673
TI  - Piezoelectric shockwave lithotripsy of urinary calculi: comparative study of
      stone depth in kidney and ureter treatments.
AB  - PURPOSE: The aim of this prospective study was to assess the relation between
      stone depth and the efficiency of piezoelectric extracorporeal shockwave
      lithotripsy (SWL). PATIENTS AND METHODS: A total of 150 patients presenting with
      25 pelvic, 75 caliceal, and 25 upper and 25 lower ureteral calculi were treated
      using the EDAP LT02 lithotripter. All of the stones were easy to localize with
      sonographic and radiographic systems, and their largest diameter ranged from 4 to
      25 mm (mean 8.5 mm). Renal and upper ureteral calculi were treated with the
      patient in the supine position and lower ureteral stones in prone position. On
      the basis of a meticulous stone localization and focusing, depth measurements
      were carried out under real-time ultrasonic guidance, the minimal distance
      between the cutaneous plane and the focal point being recorded only for
      definitely localized calculi. RESULTS: Ureteral calculi were significantly deeper
      than renal stones (p < 0.0001), but the distance from the cutaneous plane was
      statistically similar for upper and lower ureteral calculi. Stone depth was
      statistically affected by body mass index (BMI), patients with a BMI >25 having
      significantly deeper renal and ureteral calculi than subjects with a BMI < or =25
      (p < 0.00001 and 0.01, respectively). Renal stones resisting SWL were
      significantly deeper than successfully treated calculi (p < 0.03). At the level
      of the ureter, the success rate after one SWL session was 85% for stones with a
      depth < or =110 mm and 57% for deeper stones, the difference being significant (p
      < 0.05). CONCLUSION: Stone depth has a significant influence on treatment outcome
      after piezoelectric SWL for both renal and ureteral calculi. We recommend
      particular attention be given to corpulent patients presenting with ureteral
      stones.

PMID- 10646674
TI  - Effect of vibration massage therapy after extracorporeal shockwave lithotripsy in
      patients with lower caliceal stones.
AB  - PURPOSE: To determine whether vibration massage influences the results of
      extracorporeal shockwave lithotripsy (SWL) in patients with lower caliceal
      stones. PATIENTS AND METHODS: One hundred three patients with lower caliceal
      stones were entered in the study. Patients were divided into two groups that
      received either SWL alone (Group A, N = 52) or with vibration massage (Group B, N
      = 51). There was no statistically significant difference between the two groups
      in stone size, duration of follow-up, or patient age. The complication, stone
      free, and stone recurrence rates of the groups were compared. RESULTS: There was
      no statistically significant difference between the groups in the number of
      shockwaves, number of SWL sessions, or shockwave energy. The renal colic rate was
      higher in Group B than in Group A (P = 0.03). The stone-free rates in Group A and
      Group B were 60% and 80%, respectively (P = 0.003). The stone recurrence rate was
      higher in Group A than in Group B (P = 0.0006). CONCLUSIONS: This retrospective
      study demonstrates that SWL with vibration massage appears to have a beneficial
      effect on the passage of fragments in patients with lower caliceal stones.

PMID- 10646675
TI  - Controversial cases in endourology.

PMID- 10646676
TI  - Retroperitoneoscopic approach to nephrectomy.
AB  - Laparoscopic management of a variety of renal diseases has assumed an
      increasingly important role as an alternative to open surgery. At many
      institutions, the transperitoneal approach has been the more commonly employed
      technique because it creates a larger working space and reveals easily recognized
      landmarks. At the Cleveland Clinic, however, laparoscopic simple nephrectomy for
      benign disease and laparoscopic radical nephrectomy for cancer are preferentially
      approached retroperitoneoscopically. Herein, we present our technique of
      retroperitoneal laparoscopic nephrectomy.

PMID- 10646677
TI  - Contemporary diagnosis of retrocaval ureter.
AB  - PURPOSE: We describe a noninvasive radiologic evaluation of a retrocaval ureter
      using currently available technology. MATERIALS AND METHODS: Three-dimensional
      volume-rendered CT and diuretic renography were performed for evaluation of a
      possible retrocaval ureter. RESULTS: The 3D CT scan definitively diagnosed the
      retrocaval ureter, while diuretic renography showed no evidence of clinically
      significant obstruction. No invasive procedures were required. CONCLUSION: A 3D
      volume-rendered CT scan in the excretory phase combined with diuretic renography
      is the radiologic evaluation of choice for patients with a suspected retrocaval
      ureter, as it is noninvasive yet highly accurate in its anatomic delineation.

PMID- 10646678
TI  - Retroperitoneoscopic technique for treating symptomatic caliceal diverticula.
AB  - Calculous disease in a caliceal diverticulum is a rare entity. The standard
      treatment currently is endoscopic surgery with marsupialization or fulguration or
      both with dilatation of the neck of the diverticulum. We present the fifth
      reported case of retroperitoneoscopic management of a caliceal diverticulum in a
      patient with a long history of flank pain and suggest that this treatment offers
      a stone-free rate comparable to that of open surgery with less morbidity than is
      associated with endoscopic treatments.

PMID- 10646679
TI  - Treatment for extended-mid and distal ureteral stones: SWL or ureteroscopy?
      Results of a multicenter study.
AB  - PURPOSE: In a randomized study, we analyzed the treatment results of
      ureterorenoscopy (URS) and shockwave lithotripsy (SWL) for extended-mid and
      distal ureteral stones. We investigated also, for reasons of cost effectiveness,
      the factors influencing the outcome, the complications, and the need for
      auxiliary procedures. PATIENTS AND METHODS: In three regional hospitals, we
      selected 156 patients with extended-mid and distal ureteral stones. After
      randomization, 87 were treated with URS, and 69 with SWL. The treatment results
      were studied in relation to complications, the need for auxiliary procedures and
      stone factors, urinary tract infection (UTI), dilatation, and kidney function.
      RESULTS: After retreatment of 45% of the patients, the stone-free rate after 12
      weeks in the SWL group was 51%. After a retreatment rate of 9% of the patients in
      the URS group, the stone-free rate was 91%. Including the number of auxiliary
      procedures, we calculated the Efficiency Quotient (EQ) as 0.50 for SWL and 0.38
      for URS. After correction and redefinition of auxiliary procedures, the EQ was
      0.66. The mean treatment time for SWL was 52 minutes and for URS 39 minutes.
      General anesthesia was more frequently needed in URS patients. Complications
      occurred more often in the URS group (22 v 3 and 24 v 13, respectively). These
      were mostly mild, and all could be treated with a double-J stent, antibiotics, or
      analgetics. A lower stone-free rate was achieved in patients with larger (> or
      =11 mm) stones (75% v 85% for smaller stones in the URS group and 17% v 73% in
      the SWL group. In the URS group, the stone-free rate of patients with extended
      mid ureteral stones was lower than that of patients with distal ureteral stones.
      Calculating the costs for URS and SWL appeared impossible because of the
      differences in available equipment. CONCLUSION: The stone-free rate after URS is
      much higher than after SWL, and the EQ in our series was strongly dependent on
      definitions. The decision about how to treat a patient with an extended-mid or
      distal ureteral stone therefore should not be made primarily on the basis of cost
      effectiveness but rather on the basis of the availability of proper equipment,
      the experience of the urologist, and the preference of the patient.

PMID- 10646680
TI  - Predictive value of urinary cultures in assessment of microbial colonization of
      ureteral stents.
AB  - BACKGROUND AND PURPOSE: Bacterial colonization of indwelling ureteral stents may
      serve as a nidus for bacteriuria in operations where stents are manipulated. The
      predictive value of urine cultures in the assessment of stent colonization was
      examined in 65 patients with indwelling ureteral stents. PATIENTS AND METHODS:
      Prophylactic antibiotic treatment was administered prior to stent insertion. All
      patients were ambulatory at the time of investigation and were examined in the
      outpatient clinic. Urine cultures were taken prior to stent removal after 8 to
      150 (mean 64) days. The stents were removed under aseptic conditions, and the
      proximal and distal ends were cut off and placed in a culture medium for
      evaluation. None of the patients was treated for urinary tract infection prior to
      stent removal. RESULTS: Bacteriuria was found in 15% of the patients. In 35
      patients (54%), urine and stent cultures were sterile. In 20 patients (31%), the
      urine culture was sterile but the stent was colonized (Enterococcus 9, E. coli 5,
      Staphylococcus aureus 2, S. epidermidis 2, Candida 1, Citrobacter diversus 1).
      One patient had a sterile stent culture with bacteriuria. In 9 patients (13.5%),
      urine and stent cultures were identical (E. coli 4, Pseudomonas 4, Candida 1).
      The incidence of stent colonization did not correlate with stent dwelling time.
      The sensitivity of urine cultures for the detection of stent colonization was
      poor, being 31% only. In a specific patient with negative urine culture, the
      probability of stent colonization was 36%. CONCLUSION: A sterile urine culture
      does not rule out the stent itself being colonized. Therefore, patients with
      indwelling ureteral stents and a sterile urine culture may benefit from
      prophylactic antibiotic treatment prior to endourologic procedures. The
      prophylactic regimen must provide coverage for common gram-negative uropathogens
      as well as gram-positive bacteria, including enterococci.

PMID- 10646681
TI  - Percutaneous suprapubic cystolithotripsy for treatment of large bladder calculi.
AB  - BACKGROUND AND PURPOSE: The treatment options available for managing bladder
      calculi include transurethral cystolithotripsy, open cystolithotomy, and
      shockwave lithotripsy. For larger calculi, transurethral treatment can be time
      consuming, and the manipulation has the potential to cause urethral injury.
      Percutaneous suprapubic cystolithotripsy represents another treatment option for
      bladder calculi which is effective and minimally invasive. PATIENTS AND METHODS:
      Fifteen patients had bladder calculi treated with percutaneous cystolithotripsy
      over a 3-year period. The mean stone size was 39 mm (range 10-64 mm). Stones were
      single in seven patients and multiple in eight patients. The indications for
      cystolithotripsy were stone size >3 cm, multiple stones >1 cm, and inability to
      perform transurethral cystolithotripsy because of patient anatomy. Percutaneous
      suprapubic cystolithotripsy was done through either a 30F or a 36F cystotomy
      tract. Fragmentation and removal was performed with a 26F rigid nephroscope and
      the pneumatic Swiss Lithoclast. Suprapubic and urethral catheters were placed
      postoperatively in all patients. RESULTS: Each patient was cleared of the stone
      burden with a single procedure, and there were no major complications. The mean
      duration of suprapubic catheterization was 2.6 (range 1-5) days. CONCLUSION:
      Percutaneous suprapubic cystolithotripsy is an effective and safe technique for
      treating large bladder calculi. It is minimally invasive, avoids urethral injury,
      and, in combination with the pneumatic Swiss Lithoclast, can be used to fragment
      and remove large and hard bladder calculi.

PMID- 10646682
TI  - Transurethral needle ablation of the prostate: outcome at 1 year.
AB  - BACKGROUND: Urologists continue to search for alternatives to transurethral
      prostatectomy that carry a lower potential for complications. PATIENTS AND
      METHODS: Twenty-five patients on the public waiting list for transurethral
      resection of the prostate, all spontaneously voiding, underwent transurethral
      needle ablation of the prostate (TUNA). Eight patients had a simultaneous bladder
      neck incision (BNI). Follow-up with International Prostate Symptom Scores and
      flow rate measurement was performed at 6 weeks, 7 months, and 1 year. RESULTS: A
      statistically significant increase in flow rate and fall in symptom scores
      occurred out to 1 year after TUNA. Despite this result, six patients (24%) were
      not satisfied with their outcome and underwent a second endoscopic operation.
      CONCLUSION: In our hands, TUNA produced an unsatisfactory clinical result.

PMID- 10646683
TI  - Nonoliguric renal failure after transurethral resection of prostate.
AB  - PURPOSE: To define the relation of nonoliguric renal failure to transurethral
      resection of the prostate (TURP), its clinical importance, and predictive
      factors. PATIENTS AND METHODS: The files of 439 patients who had undergone TURP
      at Hacettepe University School of Medicine, Department of Urology, between
      January 1991 and 1994 were analyzed. The patients were divided into three groups
      according to postoperative serum creatinine concentration and the presence of
      clinical signs and symptoms of TUR syndrome (Group I: patients with preoperative
      and postoperative creatinine in the normal range; Group II: patients suffering
      nonoliguric renal failure; and Group III: patients with TUR syndrome). The data
      of the groups were compared in terms of factors influencing nonoliguric renal
      failure. RESULTS: The mean postoperative concentrations of sodium, blood urea
      nitrogen, creatinine, and albumin in Groups II and III were statistically
      different from those in Group I (P < 0.001). There was a moderate relation
      between hyponatremia and the occurrence of nonoliguric renal failure (r(s) = 
      0.56). Capsule perforation increased the risk of nonoliguric renal failure 10.6
      fold. All of the patients were managed by a conservative approach, and none of
      the patients died or progressed to end-stage renal disease. They were all
      discharged with a mean hospitalization period of 7 days and normal renal function
      tests. CONCLUSION: Nonoliguric renal failure was thought to be an early step in
      the pathophysiology of TUR syndrome with acute renal failure. It is an
      asymptomatic clinical picture that is undiagnosed unless laboratory examinations
      are performed. A conservative therapeutic approach is enough.

PMID- 10646684
TI  - Fluorescence detection of bladder tumors with 5-amino-levulinic acid.
AB  - BACKGROUND: Preliminary data suggest that photodiagnosis by fluorescence
      detection of protoporphyrin IX, a biosynthetic product of the photosensitizer 5
      amino-levulinic acid (ALA), is superior to conventional cystoscopy in bladder
      tumor detection. PATIENTS AND METHODS: We instilled 1.5 g of ALA into the
      bladders of 52 patients with suspect bladder lesions 1 to 4 hours prior to
      transurethral resection or biopsy. Red fluorescence was induced by violet-blue
      light (wavelength 380-450 nm). RESULTS: In 13 patients (25%), significant tumors
      were detected by fluorescence that were missed on conventional cystoscopy. In the
      present series, ALA photodetection had a sensitivity of 94.6% (compared with 76%
      for cystoscopy) and a specificity of 43%. CONCLUSION: Fluorescence diagnosis with
      ALA may become a standard procedure for bladder tumor detection and resection,
      especially in endoscopically difficult situations (carcinoma in situ, multifocal
      tumors, multiple prior resections, or previous drug instillation therapy).

PMID- 10646685
TI  - Comprehensive review of the psychiatric uses of valproate.
AB  - The therapeutic effects of valproate in psychiatric conditions are most
      substantially recognized in bipolar disorder. However, this well-tolerated
      medication may be beneficial in the treatment of other mental illnesses. In this
      article, the authors comprehensively review studies of valproate as treatment for
      psychiatric conditions, including bipolar, depressive, anxiety, and psychotic
      disorders; alcohol withdrawal and dependence; tardive dyskinesia; agitation
      associated with dementia; and borderline personality disorder. Valproate shows
      the most promising efficacy in treating mood and anxiety disorders, with possible
      efficacy in the treatment of agitation and impulsive aggression, and less
      convincing therapeutic response in treating psychosis and alcohol withdrawal or
      dependence. The authors conclude with a brief summary of its mechanism of action
      and therapeutic spectrum.

PMID- 10646686
TI  - Lack of synchrony among multiple nuclei induces partial DNA fragmentation in V79
      cells polyploidized by demecolcine.
AB  - The nuclear morphology of polyploidized cells was examined in V79 Chinese hamster
      cells polyploidized by demecolcine or K-252a, inhibitors of spindle fibre
      formation and protein kinases, respectively. A variety of nuclear morphologies,
      including multinuclei, were observed in V79 cells polyploidized by demecolcine
      but not by K-252a, which produced mononuclear cells. A lack of synchrony in the
      nuclear cycle was observed among nuclei in multinuclear polyploidized cells.
      Partial DNA fragmentation, defined as DNA fragmentation of a nucleus in a
      multinuclear cell, was detected using the TUNEL method in V79 cells polyploidized
      by demecolcine but not by K-252a. Apoptosis occurred earlier in cell populations
      treated with demecolcine than in these treated with K-252a once the drugs were
      removed from the medium, suggesting that polyploidized cells with separate nuclei
      tend to apoptose earlier than those with mononuclei.

PMID- 10646687
TI  - Interactions between normal mammary epithelial cells and mammary tumour cells in
      a model system.
AB  - Normal mammary epithelial (NME) cells and MCF-7 cells aggregate and grow as
      spheroids when cultured on extracellular matrix derived from Engelbreth/
      Holmes/Swarth (EHS) tumour. NME cells stop dividing and differentiate but MCF-7
      cells continue to proliferate, although growth is counterbalanced by cell death.
      In mixed cultures of NME cells and MCF-7 cells, the two cell types form mixed
      aggregates but then segregate to form well separated domains, often joined by
      only a narrow neck of cells. In these mixed cultures the growth of MCF-7 cells is
      inhibited by a factor secreted by NME cells into the medium.

PMID- 10646688
TI  - Spontaneous apoptosis and expression of cell surface heat-shock proteins in
      cultured EL-4 lymphoma cells.
AB  - The expression of heat-shock proteins (HSPs) is enhanced in stressed cells and
      can protect cells from stress-induced injury. However, existing data about the
      relationship between apoptosis and HSP expression is contradictory. In this
      paper, a mouse lymphoma cell death model system is used to detect simultaneously
      both the process of apoptosis and the level of HSP expression. The model was
      established after discovering that spontaneous apoptosis and spontaneous cell
      surface HSP expression occurs in EL-4 mouse lymphoma cells during normal optimal
      culture conditions. The data show that apoptotic EL-4 cells had higher levels of
      hsp25, hsp60, hsp70 and hsp90 exposed on the plasma membrane surface than viable
      cells. The level of surface HSPs was found to increase through several stages of
      early and late apoptotic death as measured by flow cytometry, with the highest
      levels observed during the loss of cell membrane phospholipid asymmetry. Heat
      shock and actinomycin D significantly increased the proportion of apoptotic cells
      in culture. However, hyperthermia only stimulated a weak and temporary increase
      in surface HSP expression, whereas actinomycin D strongly elevated the level of
      surface and intracellular HSPs, particularly in live cells. These results show an
      associative relationship between apoptosis and HSP expression. The relationship
      between the progression of cell death and HSP expression suggests a role for
      membrane HSP expression in programmed cell death.

PMID- 10646689
TI  - The relationship between thiamine deficiency and performance of a learning task
      in rats.
AB  - We have been investigating the relationship between learning and thiamine.
      Electrical stimulation of mesencephalic periaqueductal gray matter (PAG) is known
      to have an aversive effect and elicits spontaneous instrumental escape behavior.
      We taught rats to press a lever to escape from the pain of electrical stimulation
      by learning to turn a switch off. Then we examined the relationship between
      learning and the thiamine concentration in various portions of the brain. (1) One
      group of rats was given a normal diet and another group was given a thiamine
      deficient diet which contained half of the amount of thiamine present in the
      normal diet. We measured the response time required for each rat to react by
      moving after an electrical impulse was applied, and the running time during which
      the rat was moving from the starting point to the end point to press a lever. The
      rats that were fed the thiamine-deficient diet showed a slower response time and
      a longer running time than the rats fed the normal diet. (2) We divided the rats
      fed the normal diet into two groups, one group trained to switch off a lever and
      the other group not trained for such a task. We found that the thiamine
      concentration in the blood of the rats in the trained group was significantly
      higher than that in the group without training.

PMID- 10646690
TI  - Effect of alcohol on energy storage of primary astrocytes and C6-glioma cells in
      vitro.
AB  - The present experiments were conducted to investigate the direct effects of
      ethanol on the energy metabolism of astrocytes and C6-glioma cells. Primary
      astrocytes were prepared from cerebral cortices of neonatal rats, and C6-glioma
      cells were purchased from American Type Culture Collection (ATCC). These cells
      were exposed to different concentrations of alcohol (100 mM, 200 mM, and 300 mM)
      for 15 minutes and 24 hours. The amount of ATP and PCr was measured by the method
      of Lowry and Passonneau (1972). Following 15 minutes treatment with different
      doses of ethanol the amount of ATP and PCr increased, in both cell types. Only
      the increase of ATP concentration with varying doses of ethanol (100 mM, 200 mM,
      and 300 mM) was statistically significant. Following 24 hours treatment of
      astrocytes with different doses of ethanol the concentration of ATP and PCr
      decreased. The decrease in concentration of ATP was significant with all three
      doses of ethanol, but the decrease of PCr concentration was only statistically
      significant with 300 mM ethanol. Following 24 hours treatment of C6-glioma cells
      to varying doses of ethanol, the concentration of PCr and ATP decreased. The
      decrease of PCr was statistically significant with all three doses of ethanol and
      the decrease of ATP concentration was only significant with 300 mM ethanol.

PMID- 10646691
TI  - Inhibition of rat brain lipid synthesis in vitro by 4-hydroxybutyric acid.
AB  - 4-Hydroxybutyric acid (4HB) is accumulated in succinic semialdehyde dehydrogenase
      deficiency, an inherited metabolic disease severely affecting the CNS during
      postnatal development. Thus, the present study was designed to evaluate the in
      vitro influence of 4HB on lipid synthesis and CO2 production from [U-14C] acetate
      in cerebral cortex of 30-day-old Wistar rats. In the presence of 4HB, there was
      an inhibition of lipid synthesis in cerebral cortex prisms and homogenates.
      However, no inhibition of lipid synthesis occurred in the homogenates free of
      nuclei and mitochondria. In addition, CO2 production was inhibited by 4HB in
      cerebral cortex prisms, and homogenates and in the mitochondrial fraction. These
      results might possibly be explained by an impairment of mitochondrial metabolism
      by 4HB which may secondarily inhibit lipid synthesis. The results reported here
      may help to better understand the neuropathophysiology of 4-hydroxybutyric
      aciduria.

PMID- 10646692
TI  - Melatonin reduces quinolinic acid-induced lipid peroxidation in rat brain
      homogenate.
AB  - The protective effects of melatonin against the neurotoxin, quinolinic acid, were
      investigated in rat brain homogenate using the thiobarbituric acid assay.
      Quinolinic acid increased lipid peroxidation in a dose dependent manner. When
      homogenate was cotreated with melatonin there was a significant decrease in lipid
      peroxidation. The results of the present report show that melatonin may play a
      protective role in the brain against the neurohormone quinolinic acid, which has
      been identified as a causative agent in Huntington's Disease.

PMID- 10646693
TI  - Behavioural deficits during the acute phase of mild renal failure in mice.
AB  - Partially nephrectomized (NX) and sham-operated mice were biochemically and
      behaviourally compared, 10 days, 1 month and 1 year post-surgery. Plasma urea and
      creatinine concentrations were mildly increased in all NX groups, but creatinine
      clearance was significantly decreased, 10 days post-surgery only. NX mice showed
      lower body weights and reduced growth. Wire suspension and rotarod indicated
      unaffected motor functions, but NX mice did show reduced ambulation and swimming
      velocity, 10 days post-surgery. Hidden-platform water maze indicated a spatial
      learning impairment in NX mice, 10 days post-surgery, which could not be entirely
      reduced to motor incapacity. The acute behavioural deficits in these mildly
      uremic mice may relate to analogous symptoms in uraemic encephalopathy, a poorly
      understood brain syndrome occurring in uraemic patients.

PMID- 10646694
TI  - Differentiation dependent activation of the myelin genes in purified
      oligodendrocytes is highly resistant to hypoglycemia.
AB  - We have previously demonstrated that the developmental upregulation of myelin
      specific genes in mixed glial cultures is strongly attenuated by hypoglycemia.
      The present study was designed to evaluate the effect of hypoglycemia on
      differentiation-dependent upregulation of myelin genes in purified
      oligodendrocyte cultures. The expression of major myelin protein genes, i.e.,
      proteolipid protein (PLP), basic protein (BP) and myelin associated glycoprotein
      (MAG) were monitored by Northern blot analysis. In control cultures maintained at
      6 mg/ml of glucose, the expression of all the genes upregulated rapidly, and
      plateaued at approximately day 4. A similar pattern of differentiation-dependent
      upregulation was observed for the gene encoding a lipogenic enzyme, i.e., malic
      enzyme (ME). In contrast to mixed glial cultures, however, this developmental
      gene upregulation was not significantly affected by severe hypoglycemia
      (approximately 0.02 mg/ml). The results indicate that the effect of glucose
      deprivation on oligodendrocyte genes observed in mixed glial cultures is mediated
      by other cells. The upregulation of the genes in differentiating oligodendrocytes
      was accompanied by the production of myelin-related membrane that was isolated by
      density gradient fractionation. In contrast to the effect on gene expression,
      this anabolic activity was highly dependent on glucose, as seen from a profound
      suppression by severe hypoglycemia.

PMID- 10646695
TI  - Antisense oligodeoxynucleotides targeted to MAG mRNA profoundly alter BP and PLP
      mRNA expression in differentiating oligodendrocytes: a caution.
AB  - The applicability of antisense technology to suppress the expression of myelin
      associated glycoprotein (MAG) in cultured oligodendrocytes was evaluated.
      Differentiating oligodendrocyte precursor cells obtained by the shake-off method
      were exposed to nine unmodified antisense oligodeoxynucleotides (ODNs) targeted
      to the first seven exons of MAG mRNA. After four days, steady-state levels of
      MAG, proteolipid protein (PLP) and basic protein (BP) mRNAs were determined by
      Northern blot analysis. Only ODN annealing to 599-618 nt of the MAG mRNA (the
      junction of exon 5 and 6) resulted in a significant, 75% decrease in the MAG mRNA
      level. Unexpectedly, six other anti-MAG ODNs which had no significant effect on
      the MAG message, greatly increased the level of BP mRNA. The highest upregulation
      of approximately 12 fold was observed with ODN annealing to 139-168 nt (junction
      of exon 3 and 4). On the other hand, the 997-1016 ODN decreased the levels of BP
      and PLP messages by 70-80%. The 599-618 ODN also decreased the PLP mRNA by 85%.
      The results demonstrate that antisense ODNs targeted to one gene may profoundly
      alter the expression of other genes, and hence, complicate functional analysis of
      the targeted protein.

PMID- 10646696
TI  - Nonprimate animal models of menopause: workshop report.

PMID- 10646697
TI  - Hot flashes revisited.

PMID- 10646698
TI  - Clinical challenges of perimenopause: consensus opinion of The North American
      Menopause Society.
AB  - OBJECTIVE: Perimenopause refers to the time period around menopause. The clinical
      goal of peri-menopause therapy is to optimize the woman's health during and after
      this transitional period. However, clinical trial data are insufficient to
      establish evidence-based treatment standards regarding the diagnosis and
      treatment for both acute and chronic symptoms and conditions of perimenopausal
      women. Accordingly, The North American Menopause Society (NAMS) sought to develop
      a consensus opinion on clinical approaches to perimenopause. DESIGN: NAMS held a
      closed conference of experts in the field to review the current literature, share
      clinical experience, and make recommendations about how to help women achieve
      optimal health throughout perimenopause. The proceedings of the conference were
      used to assist the NAMS Board of Trustees in developing this consensus opinion of
      the Society. RESULTS: On the basis of the conference proceedings, NAMS
      established the following recommendations for the treatment of perimenopausal
      women: (1) The annual health examination is valuable in the perimenopausal woman
      and should include comprehensive screening for physical and psychological
      problems as well as for appropriate lifestyle counseling. (2) Sufficient clinical
      data exist to provide recommendations for developing management plans for acute
      perimenopausal symptoms, as well as counseling for potential chronic diseases
      related to postmenopause. (3) The importance of individualized screening and
      management approaches for each woman is evident, as is the need for including the
      woman in the management decision-making process. (4) Because clinical research
      data on women in perimenopause are limited, healthcare providers may consider
      extrapolating data on postmenopausal women, as well as relying on clinical
      experience when considering management options. (5) Management of perimenopausal
      symptoms may include doing nothing (many symptoms may be self-limiting) or
      recommending a combination of treatments. CONCLUSIONS: Although perimenopause is
      largely unstudied, many therapeutic approaches to the management of perimenopause
      disturbances exist, both prescription and nonprescription. NAMS established these
      consensus opinions to be a resource for clinicians when designing a healthcare
      plan for a perimenopausal woman. The perimenopausal woman's health and quality of
      life can be maintained and improved through preventive care, lifestyle
      modifications, early diagnosis of disease or increased risk for disease, and
      interventions when appropriate. However, more research is needed in all areas
      concerning perimenopausal women.

PMID- 10646699
TI  - Nonprimate animal models of menopause: workshop report.
AB  - OBJECTIVE: Menopause, an understudied, normal biological process in middle-aged
      women, is associated with loss of fertility and increased risk for osteoporosis
      and cardiovascular disease. Appropriate animal models allow in-depth
      investigation of biological mechanisms that underlie the increased risk for
      adverse health events in menopausal women. Although some species of older female
      nonhuman primates experience a menopause-like condition, with cessation of
      reproductive cycles, decreased bone density, and perhaps an increased risk for
      atherosclerosis, several factors restrict their usefulness for research (e.g.,
      expense of purchase and care, relatively small numbers of animals available, risk
      for disease transmission to humans, limited facilities for experimentation).
      Thus, it may be useful to consider nonprimate animal species as potential models
      for pathophysiological changes associated with loss of reproductive function.
      DESIGN: A workshop was convened in June 1998 at the National Institutes of Health
      to explore the suitability of nonprimate animal species in this context. The
      focus of this workshop was on middle-aged, ovariectomized females of various
      laboratory animal species and the ability of exogenous estrogen to reverse
      pathophysiological changes in the skeleton, cardiovascular system, and
      thermoregulatory control mechanisms in these species. CONCLUSIONS: Of the species
      considered (mice, rats, dogs, rabbits, pigs, and sheep) and because of the
      limitations of relatively small amounts of research in ovariectomized, middle
      aged animals for most of these species, mice (largely because of transgenic
      technology) have the potential to be good models for the effect of ovariectomy
      and estrogen replacement on associated bone and cardiovascular changes. Rats are
      an excellent model for bone but a poor model for the cardiovascular system
      changes associated with loss of reproductive function. Usefulness of the pig,
      which is usually considered to be a good model for the human cardiovascular
      system, is limited by the dearth of information available on ovariectomized
      mature pigs in cardiovascular and bone studies, sensitivity of bone density to
      dietary calcium, the difficult-to-manage size of regular pigs, and the relatively
      high cost of minipigs. Rabbits show good potential as a cardiovascular model
      despite the limited numbers of studies and the difference from primates in
      coronary artery structure. Although rabbits are the smallest species known to
      have Haversian bone remodeling processes, the limited number of bone studies in
      ovariectomized rabbits is confounded by effects of dietary calcium. Although
      there are virtually no studies on the cardiovascular system of the ovariectomized
      dog, bone studies that have been conducted suggest that it is a poor model for
      the menopausal human. Furthermore, the role of estrogen in bone and
      cardiovascular physiology is difficult to interpret because of the limitation of
      two estrus cycles per year in the dog. The sheep seems to be a promising large
      animal model for the bone and cardiovascular systems, but more research is
      needed. Of the species examined for estrogen effects on vasomotor symptoms
      (guinea pig, mouse, rat, and monkey), only rats and monkeys show evidence of hot
      flashes associated with loss of reproductive function.

PMID- 10646700
TI  - Concentrations of calcitonin gene-related peptide and neuropeptide Y in plasma
      increase during flushes in postmenopausal women.
AB  - OBJECTIVE: To assess whether the plasma concentrations of calcitonin gene-related
      peptide (CGRP), neuropeptide Y (NPY), or neurokinin A (NKA) increase during hot
      flushes in postmenopausal women with vasomotor symptoms. DESIGN: Eight
      postmenopausal women (age range = 49-63 years) with vasomotor symptoms were
      included. During 1 day, repeated blood samples were taken between and during
      flushes; four samples were taken during each flush. The samples were analyzed for
      CGRP, NPY, and NKA using radioimmunoassay technique. RESULTS: The serum
      concentrations of CGRP and NPY increased significantly-73% and 34%, respectively
      during the flushes (p = 0.018; p = 0.028), whereas the concentrations of NKA did
      not change significantly. CONCLUSIONS: CGRP and NPY may be involved in the
      mechanisms that cause vasomotor symptoms.

PMID- 10646701
TI  - Hormone replacement therapy reduces mean 24-hour blood pressure and its
      variability in postmenopausal women with treated hypertension.
AB  - BACKGROUND: The rate and severity of hypertension increase dramatically after
      menopause. Complications seem to be more frequent and marked in hypertensive
      patients with greater blood pressure (BP) variability, and antihypertensive
      treatment does not easily reduce this variability. The effect of hormone
      replacement therapy (HRT) on BP and its variability is not well understood in
      moderate to severe hypertension, but estrogen may have calcium channel-blocking
      properties. Cardiovascular events occur more frequently in the morning, likely in
      part because of a rise in BP. DESIGN: We prospectively studied 34 postmenopausal
      women with treated hypertension (mean age = 53 years) and receiving a cyclic
      combination of estradiol and norgestrel for 19 weeks with 24-h ambulatory BP
      monitoring. RESULTS: Mean daily BP and its variability decreased significantly
      with HRT (149.3 +/- 6.1 mm Hg vs. 140.3 +/- 8.5 mm Hg [p < 0.001]; diastolic:
      95.4 +/- 4.7 mm Hg vs. 92.4 +/- 7.2 mm Hg [p < 0.05]). There was also a
      significant decrease in the early morning BP values after HRT (154.0 +/- 6.9 mm
      Hg vs. 145.6 +/- 11.0 mm Hg [p < 0.001]; diastolic: 98.0 +/- 4.8 mm Hg vs. 95.1
      +/- 10.0 mm Hg [p < 0.05]). Subjects who were taking calcium channel blockers (n
      = 11) had only half the reduction in 24-h systolic BP compared with those who
      were not taking calcium channel blockers (5.3 mm Hg vs. 10.5 mm Hg), and the
      reduction in those who were taking calcium channel blockers failed to reach
      statistical significance. CONCLUSIONS: Our results demonstrate that HRT may have
      a role in decreasing the severity of hypertension, and the mechanism of its
      action might be through calcium channels.

PMID- 10646702
TI  - Serum leptin levels in postmenopausal women: effects of transdermal hormone
      replacement therapy.
AB  - OBJECTIVE: To evaluate serum leptin levels in postmenopausal women who are
      receiving hormone replacement therapy (HRT) and postmenopausal women who are not
      receiving HRT with similar body mass index (BMI) to determine whether estrogens
      exert effects on leptin secretion. DESIGN: Cross-sectional, prospective study
      comparing serum leptin levels in premenopausal women, postmenopausal women who
      were not receiving HRT (group A), and postmenopausal women who were receiving HRT
      (group B). RESULTS: Serum leptin levels were significantly higher in group A in
      comparison to group B and control women (15.82 +/- 6.6 ng/ml, 8.14 +/- 4.17
      ng/ml, and 10.12 +/- 5.48 ng/ml, respectively; p < 0.05). Total fat mass (FM) was
      found to be significantly higher in untreated postmenopausal women in comparison
      to the other two groups (22.66 +/- 2.79 kg vs. 19.14 +/- 3.39 kg vs. 18.98 +/-
      3.82 kg; p < 0.05). No significant difference was observed in weight, height,
      BMI, blood pressure, or glucose levels among the three groups. A linear
      correlation between BMI and serum leptin levels as well as between total FM and
      serum leptin levels was observed in all groups. No correlation was found between
      serum leptin levels and months from menopause and months of HRT. CONCLUSIONS: Our
      results show that serum leptin is increased in untreated postmenopausal women,
      possibly as a consequence of the increase in FM, and that HRT reduces serum
      leptin levels to premenopausal values. These data need further investigation by a
      broader longitudinal study.

PMID- 10646703
TI  - Bone resorption levels by age and menopausal status in 5,157 women.
AB  - OBJECTIVE: The purpose of this study was to describe bone resorption activity
      using a biochemical marker according to the categories of age, menopausal status,
      and selected drug/supplement use in middle-aged and elderly community-based
      women. DESIGN: This was a cross-sectional study that assessed urinary cross
      linked N-telopeptide of type I collagen (NTx) and used self-report data to group
      women as premenopausal (Pre), perimenopausal (Peri), postmenopausal without
      hormone replacement therapy (Post), and postmenopausal with hormone replacement
      therapy (HRT). RESULTS: Mean NTx values were found to be significantly different
      by group and controlling for age (p = 0.001), with post hoc tests showing all
      pairwise group comparisons as significantly different (p = 0.001), except that
      the Pre and HRT groups were not significantly different. Both the Peri and the
      Post NTx levels were significantly higher than the Pre and the HRT groups'. NTx
      values in the Peri group varied with age-the youngest Peri women were similar to
      Pre women, and the oldest Peri women were similar to Post women. Significantly
      lower NTx levels were found only in the Post (p = 0.009) and HRT (p < 0.001)
      groups using diuretics compared with nonuse and only in the HRT group using
      calcium supplements compared with nonuse (p = 0.006). No differences by thyroid
      use were found. With a biochemical marker, the results showed that bone
      resorption activity differences could be demarcated in women according to age,
      estimated menopausal stage, and selected drug/supplement use. CONCLUSIONS: These
      results support the usefulness of NTx assessment for indicating bone resorption
      activity and therefore the potential for osteoporosis or for monitoring the
      efficacy of antiresorptive therapies.

PMID- 10646704
TI  - Ovarian volume and menopausal status.
AB  - OBJECTIVE: The purposes of this study were to (1) examine whether ovarian volume
      differs by age and menopausal status in healthy women; (2) evaluate whether
      ovarian volume could be a sensitive and specific predictor of menopausal status;
      and (3) assess whether ovarian volume is affected by cigarette smoke, oral
      contraceptives (OCs), and hormone replacement therapy (HRT). DESIGN: Each
      participant (527 women) completed an extensive in-home interview that assessed
      age, menopausal status, smoking history, OC use, and HRT use. Each participant
      also received a transvaginal ultrasound that measured ovarian volume. Geometric
      means for ovarian volume were compared between premenopausal and postmenopausal
      women using t tests. Tests for trends were conducted using linear regression
      analyses. RESULTS: Ovarian volume declined with age (p < or = 0.0001) and also
      differed by menopausal status; postmenopausal women had smaller ovarian volumes
      than premenopausal women of the same age (p < or = 0.0001). Ovarian volume was
      not associated with smoking history or HRT use. However, it was significantly
      smaller in current users of OCs compared with past users of or those who never
      used OCs (p < or = 0.0001). Ovarian volume was a sensitive and specific predictor
      of postmenopausal status. CONCLUSIONS: The data suggest that age, menopausal
      status, and OC use may be determinants of ovarian volume. They also suggest that
      ovarian volume may be useful for predicting menopausal status in women.

PMID- 10646705
TI  - Factors affecting access to menopause information.
AB  - OBJECTIVE: As female life expectancy increases, women spend a greater proportion
      of their life in menopause. Menopausal women may benefit from preventive
      treatments, such as hormone replacement therapy, and are more likely to use
      medical treatments if they have access to information about menopause. The
      purpose of this study was to identify women's needs with respect to learning
      about menopause. DESIGN: A 20-question survey was administered anonymously to 116
      women during outreach programs. Data were separated and evaluated by race and
      level of education. RESULTS: A significant association was found between access
      to information about menopause and both race and education level. Being African
      American or having less than a college education was associated with a twofold
      risk (p < 0.01) for not having a source of menopause information. A significant
      relationship was found between a woman's rating of her current knowledge of
      menopause and access to source of information (p = 0.03); women who did not have
      an information source felt the least knowledgeable about the subject. Women
      varied in the ways in which they are comfortable with learning about menopause.
      Different groups of women seemed to prefer different methods of learning about
      menopause. CONCLUSIONS: Both level of education and race are associated with a
      woman's ability to obtain information about menopause. To enhance women's
      understanding of health during menopause, information must be readily available.
      This information should be presented to women through educational programs that
      are designed to meet the needs of varied groups of adult women.

PMID- 10646706
TI  - Laryngeal cancer cost analysis: association of case-mix and treatment
      characteristics with medical charges.
AB  - OBJECTIVES: To examine the relationship of various pretreatment case-mix
      characteristics and treatment modalities with medical charges incurred during
      diagnosis, treatment, and 2-year follow-up for patients with laryngeal cancer.
      DESIGN: Retrospective chart review and billing record analysis. METHODS: The
      charts and billing records of patients diagnosed with laryngeal cancer at the
      University of Iowa Hospitals and Clinics (UIHC) between January 1, 1991 and
      December 31, 1994 were reviewed. The independent variables included various
      pretreatment patient-mix and tumor characteristics (age, AJCC TNM clinical stage,
      smoking history, ASA class, and comorbidity as defined by Kaplan-Feinstein grade)
      as well as type of treatment. The dependent variables included total physician,
      office, and university hospital-based charges incurred during the pretreatment
      evaluation and 0- to 3-, 3- to 12, and 12- to 24-month billing periods after the
      initiation of cancer-directed therapy. Total 1-year and 2-year charges were also
      evaluated. Univariate and multivariate analyses were used to investigate the
      relationships between dependent and independent variables and to develop models
      predictive of management charges during the individual and total billing periods.
      RESULTS: Pretreatment charges showed no significant associations (P < .05) with
      any of the independent variables. Multiple regression analyses indicated that
      comorbidity, stage, and initial treatment modality were significant variables in
      one or more of the models predicting charges incurred during the 0- to 3-month, 3
      to 12-month, total 1-year, and total 2-year billing periods. The models yielded
      R2 values for the total 1- and 2-year billing periods of 0.5246 and 0.5055,
      respectively. CONCLUSIONS: This work supports continued study of measures that
      may result in earlier detection of laryngeal cancer as a potential means of
      reducing management charges. These results also indicate that a more accurate
      method of stratifying the disease severity of laryngeal cancer patients for
      reimbursement purposes would include measurements of the severity of the index
      disease as well as comorbid diseases.

PMID- 10646707
TI  - Early wound complications in advanced head and neck cancer treated with surgery
      and Ir 192 brachytherapy.
AB  - OBJECTIVES: Brachytherapy, either as primary or adjuvant therapy, is increasingly
      used to treat head and neck cancer. Reports of complications from the use of
      brachytherapy as adjuvant therapy to surgical excision have been limited and
      primarily follow Iodine 125 (I125) therapy. Early complications include wound
      breakdown, infection, flap failure, and sepsis, and late complications may
      include osteoradionecrosis, bone marrow suppression, or carotid injuries. The
      authors sought to identify the early wound complications that follow adjuvant
      interstitial brachytherapy with iridium 192 (IrS92). STUDY DESIGN: A
      retrospective chart review of all patients receiving adjuvant brachytherapy at a
      tertiary medical center over a 4-year period. METHODS: Nine patients receiving
      Ir192 brachytherapy via afterloading catheters placed during surgical resection
      for close or microscopically positive margin control were evaluated. It was used
      during primary therapy in six patients and at salvage surgery in three. Early
      complications were defined as those occurring within 6 weeks of surgical therapy.
      RESULTS: The overall complication rate was 55% (5/9), and included significant
      wound breakdown in two patients, minor wound dehiscence in three, and wound
      infection, bacteremia, and local tissue erosion in one patient each. All
      complications occurred in patients receiving flap reconstruction and one patient
      required further surgery to manage the complication. Complication rates were not
      associated with patient age, site, prior radiotherapy, timing of therapy, number
      of catheters, or dosimetry. CONCLUSIONS: The relatively high complication rate is
      acceptable, given the minor nature of most and the potential benefit of
      radiotherapy. Further study should be undertaken to identify those patients who
      will achieve maximum therapeutic benefit without prohibitive local complications.

PMID- 10646708
TI  - Dendritic cells in precancerous lesions of the larynx.
AB  - OBJECTIVES: Hyperplastic lesions of the laryngeal mucosa can eventually develop
      into squamous cell carcinoma The relationship between dendritic cell infiltration
      of head and neck cancers and prognosis is well known. Surprisingly, data
      regarding dendritic cell infiltration in precancerous lesions are not available
      today. It was the purpose of our study to extend these observations and to
      investigate in more detail the density and distribution of dendritic cells in pre
      cancerous lesions. STUDY DESIGN: Retrospective survey by immunohistochemistry.
      METHODS: For this study we investigated paraffin-embedded tissue sections of 41
      specimens. Histological diagnosis disclosed precancerous lesions of the larynx in
      34 cases and in 7 cases, squamous cell carcinoma Immunohistochemical study was
      performed using antibodies against the cell surface markers S-100, HLA-DR, CD20,
      CD45 RO, CD45 RA, and Lag. Typical dendritic cell distributions of the
      immunostained specimens were photographed and measured on a quantitative basis.
      The medical histories of the patients were then analyzed retrospectively.
      RESULTS: HLA-DR+ cells could be detected in 14 of 16 cases in mild dysplastic
      lesions. The infiltration of the dysplastic lesions was sparse compared to cases
      with higher-graded dysplastic lesions. The distribution patterns of the dendritic
      cells in specimens with severe dysplastic lesions, but squamous cell carcinoma
      were extremely similar and markedly different from those in grades I and II
      specimens. Memory T lymphocytes (CD45 RO+) were detected more often in the group
      with severe dysplastic lesions (8 of 9 cases) than in the group with squamous
      cell carcinoma (3 of 8 cases). The inverse became evident for CD20 and CD45 RA
      immunolabeling. CONCLUSIONS: Few dendritic cells were found in the precancerous
      lesions. This may suggest that these early lesions (grades I and H) are not
      efficiently monitored by the immune system. Therefore they may develop into
      carcinomas unimpaired by cytotoxic T cells. As the degree of malignancy rises
      (grade III), more dendritic cells infiltrate the tumor.

PMID- 10646709
TI  - Compliance with anti-reflux therapy in patients with otolaryngologic
      manifestations of gastroesophageal reflux disease.
AB  - OBJECTIVES: The otolaryngologic manifestations of gastroesophageal reflux include
      sore throat, throat clearing, sensation of postnasal drip, hoarseness, and
      globus. This constellation of laryngeal and pharyngeal symptoms can be referred
      to as laryngopharyngeal reflux (LPR). Many patients with LPR are treated
      empirically and the results are often rewarding. The objective of this study is
      to evaluate compliance with antireflux therapy in this patient population. STUDY
      DESIGN: A prospective analysis of 30 patients referred to an otolaryngology
      clinic for the above symptoms. METHODS: The patients were treated for LPR using a
      standardized behavior modification form in combination with medical management.
      Patient compliance was followed with a patient questionnaire and evaluation of
      medication renewal from pharmacy records. RESULTS: The patients were followed for
      an average of 4 months and 80% reported an improvement of their symptoms.
      Evaluation of patient questionnaires revealed that 50% of patients reported
      taking their medications as prescribed. Compliance varied widely with regard to
      behavioral modifications. The degree of symptomatic improvement was significantly
      correlated with overall compliance with both medications and behavioral changes
      (Pearson correlation coefficient, P < .05). The individual behavioral changes
      that were significantly correlated with the reduction of symptoms were avoidance
      of food and liquid before sleep and elevation of the head of bed, but not food
      habits. CONCLUSIONS: The treatment plan for gastroesophageal reflux disease
      requires behavioral modifications and prescription medications that many patients
      may find difficult to follow. However, those patients who comply with the
      treatment plan can be expected to have an improvement of their symptoms.
      Furthermore, simplifying the treatment regimen including those elements most
      correlated with symptomatic improvement may increase patient compliance.

PMID- 10646710
TI  - Evaluation of airway obstruction using virtual endoscopy.
AB  - OBJECTIVES: This study examines the use of virtual endoscopy (VE) in the
      evaluation of patients with upper airway obstruction. The utility of VE compared
      with actual endoscopy was investigated with respect to accuracy of diagnosis and
      reproduction of endoscopic images. STUDY DESIGN: A random cohort of 30 patients
      with various causes of airway obstruction was examined. METHODS: The computed
      tomography (CT) data were reconstructed using a proprietary VE software program,
      FreeFlight, blind to the actual endoscopic findings. The cause of obstruction was
      identified and compared with actual endoscopic findings. This included 21
      patients with airway stenoses, 8 patients with laryngotracheomalacia, 3 tracheal
      tumors, 2 glottic webs, 5 patients with innominate artery compression, 2 tracheal
      granulomas, and 7 patients with impaired true vocal cord mobility. RESULTS:
      Virtual endoscopic evaluation was accurate in assessing stenosis width and length
      of fixed airway lesions. Correlation of stenosis shape and contour between actual
      endoscopy and VE was excellent. The stenosis-to-lumen ratios were compared
      between VE and actual endoscopy and were found to be within 10% (SD = 8).
      However, virtual endoscopic evaluation could not illustrate one of the glottic
      webs, half of the cases of tracheomalacia, or any of the cases of impaired true
      vocal cord mobility. CONCLUSIONS: Virtual endoscopy was not as sensitive as
      actual endoscopy in detecting the cause of airway obstruction that was based on
      dynamic movement. However, VE was excellent for the measurement and definition of
      fixed airway lesions.

PMID- 10646711
TI  - Polymerase chain reaction detection of Mycobacterium tuberculosis from fine
      needle aspirate for the diagnosis of cervical tuberculous lymphadenitis.
AB  - BACKGROUND: Despite its well-established usefulness in the diagnosis of cervical
      tuberculous lymphadenitis, fine-needle aspiration cytology (FNAC) has several
      limitations in its clinical applications, especially when the presence of acid
      fast bacilli is not proven. Furthermore, fine-needle aspirate is sometimes
      inadequate for diagnosis, and the sensitivity and specificity of this technique
      for cervical tuberculous lymphadenitis has not been firmly established.
      OBJECTIVE: The authors performed Mycobacterium tuberculosis polymerase chain
      reaction (PCR) for mycobacterial DNA sequences from the remainder of fine-needle
      aspirate after cytological examination and evaluated its diagnostic efficacy in
      clinical situations. METHODS: Conventional diagnostic procedures including FNAC
      and M tuberculosis PCR were performed simultaneously in 29 cases that had been
      suspected to be cervical tuberculous lymphadenitis on patients' first visit. The
      results of FNAC and M tuberculosis PCR were compared with the clinical outcomes
      after several months of follow-up and pathological results from open biopsy of
      some cases. RESULTS: Among the 17 cases of cervical tuberculous lymphadenitis
      diagnosed in clinical situations, M tuberculosis DNA was found by PCR in 13 cases
      (76.4%). Negative findings on PCR were achieved in 12 cases, which revealed non
      granulomatous lymphadenopathy. CONCLUSION: From these results, we conclude that M
      tuberculosis PCR using the remainder of aspirate for cytological examination is a
      very useful tool for the diagnosis of cervical tuberculous lymphadenitis, and its
      clinical application with FNAC could reduce the necessity for open biopsy.

PMID- 10646712
TI  - Stereotastic radiosurgery for glomus jugulare tumors.
AB  - OBJECTIVES/HYPOTHESIS: Surgery is considered to be the mainstay of treatment for
      glomus jugulare tumors. A subset of patients are poor surgical candidates based
      on age, medical problems, tumor size, or prior treatment failure. The purpose of
      this study was to review our results with stereotactic radiosurgery (gamma knife
      treatment) in this group of patients, with particular attention to adverse
      reactions and symptom relief. STUDY DESIGN: Retrospective review and phone
      survey. METHODS: Charts were reviewed for size and location of tumor, history of
      previous treatment, symptoms before and after treatment, amount of radiation
      received, acute and late complications, and functional level before and after
      treatment. Pre-treatment and posttreatment magnetic resonance imaging scans were
      also reviewed. Identified patients were then contacted for a phone interview.
      RESULTS: Eight patients were identified. Phone interviews were conducted with
      four patients. Four patients had failed previous treatment. Follow-up ranged from
      7 to 104 months. One patient experienced an acute complication: intractable
      vertigo requiring hospitalization. No patient experienced delayed cranial
      neuropathies. No patient reported worsening of any of the following symptoms:
      pulsatile tinnitus, hearing loss, facial weakness, hoarseness, or difficulty
      swallowing. Three patients reported improvement in their pulsatile tinnitus. Two
      patients reported improvement in hearing loss, and one patient each reported
      improvement in vertigo and difficulty swallowing. CONCLUSIONS: Preliminary
      results suggest that stereotactic radiosurgery is useful to control symptoms and
      may be delivered safely in patients with primary or recurrent glomus jugulare
      tumors who are poor surgical candidates.

PMID- 10646713
TI  - Endoscopic medial maxillectomy for inverted papillomas of the paranasal sinuses:
      value of the intraoperative endoscopic examination.
AB  - OBJECTIVE: The extent of paranasal sinus involvement by inverted papilloma and
      the degree of surgery are often determined before surgery by computer tomography
      (CT). The sensitivity and specificity of preoperative CT versus intraoperative
      endoscopic examination are unknown. STUDY DESIGN: Prospective. METHODS: Nineteen
      patients with inverted papilloma who underwent endoscopic medial maxillectomy
      were staged tomographically. Findings were compared with pathological and
      intraoperative endoscopic findings. RESULTS: Twenty sides were evaluated. The
      overall sensitivity and specificity for the preoperative CT evaluation were 69%
      and 20%, respectively. For intraoperative endoscopic evaluation they were 69% and
      68%, respectively. Excluding the sphenoid sinus, the overall sensitivity for CT
      scan and intraoperative endoscopic evaluation increased to 87%. Excluding the
      anterior ethmoids, the overall specificity for CT scan and intraoperative
      endoscopic evaluation increased to 25% and 79%, respectively. The overall cure
      rate was 94% (18 patients) with an average follow-up of 36 months (range, 16-80
      mo). CONCLUSION: Intraoperative endoscopic examination is comparable in
      sensitivity but better in specificity than preoperative CT analysis for
      differentiating between inverted papilloma and other disease. Both modalities of
      evaluation tend to overestimate the extent of disease (sensitivity). The presence
      of a normal intraoperative endoscopic examination may be a better way of
      determining the extent of mucosal removal during surgery. Endoscopic medial
      maxillectomy remains an effective surgical option for inverted papilloma removal.
      medial maxillectomy, computed tomography scan.

PMID- 10646714
TI  - Vocal fold paralysis after anterior cervical diskectomy and fusion.
AB  - OBJECTIVE: The anterior approach to the cervical spine now serves as the surgical
      access of choice for cervical spine disease. Vocal fold paralysis (VFP) may
      follow the procedure as a complication. The authors describe their experience
      with patients having VFP after anterior cervical diskectomy and fusion (ACDF),
      with an emphasis on outcome and prognosis. STUDY DESIGN: Retrospective. METHODS:
      Medical records of patients who underwent ACDF between January 1987 and February
      1998 were reviewed. Further detailed review of the patients with documented VFP
      after surgery was then performed. RESULTS: Over the given time period 411 ACDFs
      were performed and 21 patients with this complication were identified (5%). All
      21 patients had right-sided approaches. Eighteen patients had right VFP, 2 had
      left VFP, and 1 had bilateral VFP. Symptoms included hoarseness (18), persistent
      cough (7), aspiration (13), and dysphagia (7). The patient with bilateral VFP
      presented with stridor and respiratory distress requiring tracheotomy. The
      complete records of 17 patients with 18 VFPs were available for review. Fifteen
      of 18 VFPs (83.3%) had complete resolution within 12 months. One patient had
      recovery after 15 months. All patients were treated conservatively with speech
      and swallowing therapy. One patient required Gelfoam injection and another
      medialization thyroplasty, both for aspiration symptoms. CONCLUSIONS: The data
      suggest that at least 80% of VFP after ACDF will recover within 12 months of the
      procedure. The authors recommend regular follow-up and speech therapy for
      symptomatic patients. Medialization should be considered in patients with
      aspiration or persistent problems.

PMID- 10646715
TI  - Patency and flow of the internal jugular vein after functional neck dissection.
AB  - OBJECTIVES: To assess the patency and flow of the internal jugular vein after
      functional neck dissection. STUDY DESIGN: Prospective study of 54 internal
      jugular veins in 29 oncologic patients undergoing functional neck dissection
      between September 1994 and February 1997. METHODS: Patency, presence of
      thrombosis, characteristics of the vein wall, compressibility, area of the vein
      both in rest and during Valsalva maneuver, expiratory flow speed, Valsalva flow
      speed, jugular flow in each side, and total jugular flow were assessed in all
      veins before and after dissection. All patients were evaluated before and after
      the procedure by means of duplex Doppler ultrasonography. RESULTS: In no case was
      there thrombosis before or after the operation. Although total jugular flow
      decreases during the early postoperative period, it recovers to normal parameters
      within 3 months after surgery. CONCLUSIONS: According to these results, the
      patency of the internal jugular vein remains unaltered after functional neck
      dissection. Ultrasonographically there is no thrombosis after this procedure.

PMID- 10646716
TI  - Avoiding transfusion in head and neck surgery: feasibility study of
      erythropoietin.
AB  - OBJECTIVE: To determine the feasibility of perioperative erythropoietin to avoid
      blood transfusion in head and neck cancer surgery. STUDY DESIGN: Retrospective
      chart review. METHODS: Ninety-nine patients undergoing surgical resection of head
      and neck tumors at our institution were assessed for demographic data,
      nutritional parameters, tumor/surgical information, hematological/transfusion
      data, and contraindications to erythropoietin. Each transfusion was classified as
      to its appropriateness, and the potential benefit of erythropoietin was assessed
      in each patient. A cost analysis was also performed. RESULTS: Most transfused
      patients (63%) received too many units. A subgroup at high risk of transfusion
      was identified who would benefit most from perioperative erythropoietin. Assuming
      that perioperative erythropoietin therapy is equivalent to the transfusion of 4
      units, we estimate that the majority (741%) of transfused patients would not have
      required a transfusion if more stringent transfusion criteria were followed and
      those at high risk were given perioperative erythropoietin. Although the cost for
      transfusing 4 units is equivalent to that of a perioperative course of
      erythropoietin, the overall direct cost of erythropoietin treatment would
      actually have been more expensive. CONCLUSIONS: Perioperative erythropoietin
      therapy may be appropriate for a subgroup of head and neck cancer patients, but a
      prospective randomized controlled study in such a subgroup is needed to better
      define those most likely to benefit from it and to assess actual cost/benefit
      ratios.

PMID- 10646717
TI  - Second primary neoplasms in patients with laryngeal carcinoma.
AB  - OBJECTIVES: To better define the characteristics of second primary malignancies
      appearing in patients suffering from head and neck cancers, and more specifically
      laryngeal carcinoma, and to elicit those parameters that may be of assistance in
      better diagnosing, treating, and predicting outcome in such patients. STUDY
      DESIGN: Retrospective review of a group of 514 compliant subjects, examined and
      treated during an 8-year period until 1996. After initial diagnosis and
      subsequent treatment, rigorous follow-up ensured systematic screening of the
      subjects, who underwent standard examinations in outpatient clinics for periods
      of up to 56 months. RESULTS: Of 514 cases followed, presence of second primary
      neoplasms was established in 42 or 8.17%, 8 being synchronous and 34 metachronous
      of the original primary lesion. CONCLUSIONS: Respiratory and upper
      gastrointestinal localizations were primarily affected, incidence was highest in
      septuagenarians, and staging of the primary was found to be irrelevant to the
      incidence rates of second primaries. No statistical significance was attached to
      the fact that supraglottic primary tumors showed slightly higher second primary
      rates; the same applying for well-differentiated primary tumors compared with
      poorly differentiated ones. Modality of treatment surgery, and radiotherapy being
      the options in question-did not in the long run statistically influence incidence
      rates. Throughout, reference to current literature and this study's relevance in
      light of similar efforts were taken into account.

PMID- 10646718
TI  - Histological pattern of mandibular invasion by oral squamous cell carcinoma.
AB  - OBJECTIVE: Mandibular invasion by oral squamous cell carcinoma may progress by
      either an infiltrative or an erosive histological pattern. The infiltrative
      pattern is marked by nests and cords of tumor cells along an irregular tumor
      front, and the erosive pattern exhibits a broad, pushing tumor front. The
      objectives of this study were 1) to define the characteristics associated with
      each histological pattern of mandibular invasion, 2) to assess the relationship
      between pattern of invasion and clinical outcome as measured by death with
      disease and disease presence at last follow-up, and 3) to determine whether the
      cell cycle markers cyclin D1 and Ki-67 are associated with the histological
      pattern of invasion or are predictive of outcome. STUDY DESIGN: Retrospective
      study of 68 patients with mandibular invasion by oral cavity squamous cell
      carcinoma treated by mandibulectomy. METHODS: The clinical records, pathology
      reports, and original H&E-stained slides were reviewed for each patient.
      Immunohistochemical staining of cyclin D1 and Ki-67 was performed on slides cut
      from the paraffin blocks of these patients' specimens. RESULTS: The parameters
      found to be significantly associated with the infiltrative pattern of mandibular
      invasion included higher tumor grade, medullary space invasion, positive bone or
      soft tissue margins, history of previously failed treatment, and postoperative
      tumor recurrence. The infiltrative pattern had a positive bone margin rate of
      47.6% and a primary site recurrence rate of 52.6%. In contrast, the erosive
      pattern had a positive bone margin rate of 4.9% and a primary site recurrence
      rate of 16.7%. The infiltrative pattern of invasion gave a fourfold increased
      risk of death with disease and disease presence at last follow-up in univariate
      and multivariate analyses when compared with the erosive pattern of invasion. The
      3-year disease-free survival was 30% for the infiltrative pattern and 73% for the
      erosive pattern. The median disease-free survival was 1.5 years for the
      infiltrative pattern and 5.5 years for the erosive pattern. There was no
      correlation between cyclin D1 or Ki-67 staining and invasion pattern or clinical
      outcome. CONCLUSIONS: The infiltrative pattern of mandibular invasion by oral
      squamous cell carcinoma is correlated with a significantly worse prognosis when
      compared with the erosive pattern of invasion. The infiltrative pattern clearly
      exhibits a more aggressive behavior with an increased likelihood of positive
      margins, recurrence, death with disease, and shorter disease-free survival. We
      recommend that pathologists routinely comment on the histological pattern of
      invasion when reviewing oral squamous cell carcinoma with mandibular invasion.

PMID- 10646719
TI  - Accessory nerve function after modified radical and lateral neck dissections.
AB  - OBJECTIVES: Evaluate preoperative and postoperative electrophysiological changes
      related to the accessory nerve with reference to dissection technique, modified
      radical neck dissection, and lateral neck dissection. STUDY DESIGN: Prospective
      electrophysiological analysis of accessory nerve function in a total of 20
      laryngeal carcinoma patients after neck dissection, 12 being lateral neck
      dissection (4 bilateral) and 8 being modified radical neck dissection. METHODS:
      Distal latencies, compound muscle action potentials, and electromyography
      findings were investigated before surgery and, in early and late postoperative
      periods in 20 laryngeal carcinoma patients. Results were evaluated by Student t
      test and chi2 test for intragroup and intergroup differences. RESULTS: In the
      lateral neck dissection group, postoperative distal latencies were longer,
      without statistical significance, whereas in the modified radical neck dissection
      group postoperative latencies were statistically longer. Postoperative compound
      muscle action potentials were significantly lower in both groups.
      Electromyographic work-up showed deterioration in early postoperative periods and
      improvement in late postoperative periods. When intergroup differences were
      compared, both postoperative compound muscle action potential and
      electromyographic findings were worse in the lateral neck dissection group.
      CONCLUSIONS: The accessory nerve function after modified radical neck dissection
      is better than function after lateral neck dissection because of increased stress
      applied to the nerve during retraction of the sternocleidomastoid muscle for
      achievement of a better exposed surgical field in lateral neck dissection.

PMID- 10646720
TI  - Detection of squamous cell carcinoma of the oral cavity by imaging 5
      aminolevulinic acid-induced protoporphyrin IX fluorescence.
AB  - OBJECTIVES: Early cancer detection is the best way to improve the prognosis of
      patients with oral cancer. Therefore this study presents quantitative
      fluorescence measurements and results in the visualization of cancerous oral
      mucosa with 5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX (PPIX).
      METHODS: Time progression and type of porphyrin accumulation were analyzed in
      neoplastic and surrounding healthy tissue of 58 patients with a suspected cancer
      of the oral cavity by measuring emission spectra of 5-ALA-induced PPIX
      fluorescence. Fluorescence images in the red and green spectral range from the
      tumor tissue were recorded with a charge-coupled device camera. RESULTS: After
      topical application of 0.4% 5-ALA and incubation for 1 to 2.5 hours, all patients
      revealed higher intensities of red fluorescence in neoplastic tissue compared
      with the surrounding normal tissue. Maximum contrast was reached after 1.5 hours
      of incubation. In 13.8% (n = 8) of the patients, additional findings like
      dysplasia, carcinoma in situ, primary tumor, secondary carcinomas, and tumor
      branches were found by means of fluorescence marking in contrast to white light
      examination. An evaluation of the biopsy specimens resulted in a specificity of
      60% and a sensitivity of 99%. CONCLUSIONS: As a fluorescent marker, PPIX could
      represent a possible new diagnostic tool to detect early malignant and secondary
      lesions in the oral cavity. In addition, 5-ALA-induced PPIX fluorescence is
      promising as a useful intraoperative tool for determining adequate surgical
      margins of resection. Further investigations aim to assess this diagnostic
      procedure as a sensitive and clinically reliable method for patients with oral
      cancer.

PMID- 10646721
TI  - Characteristic distribution patterns of tenascin in laryngeal and hypopharyngeal
      cancers.
AB  - OBJECTIVES: Progression of malignant neoplasias is accompanied by alteration of
      the extracellular matrix (ECM) composition. Tenascin is known as a member of the
      adhesion-modulating family of ECM macromolecules; thus its expression and
      distribution may have significant influence on tumor cell proliferation and
      invasiveness. STUDY DESIGN: The present study was carried out to determine the
      distribution pattern of tenascin in laryngeal and hypopharyngeal cancer samples.
      METHODS: In double and triple immunofluorescent staining reactions the detection
      of tenascin was combined with labelings for cytokeratin (marker protein of
      epithelial cells), for CD-34 (endothelial cell surface glycoprotein), and for a
      reaction with Ki-67 monoclonal antibody (nuclear antigen in proliferating cells).
      RESULTS: In laryngeal cancers, in early stages of tumor growth a markedly
      enhanced production of tenascin at the tumor host interphase was observed. In the
      later stages of tumor progression, a high number of blood vessels located in the
      tumorous tissues were also strongly labeled for tenascin. Around these vessels a
      significant number of proliferating tumor cells could be detected. In contrast,
      in hypopharyngeal cancers this vasculature-associated staining pattern could be
      observed from the very early stage of tumor development. In laryngeal and in
      hypopharyngeal cancers, tenascin upregulation strongly correlated with metastasis
      formation, early tumor recurrence, and lethal outcome of the disease.
      CONCLUSIONS: Clinical and immunohistologic data indicate that the accumulation of
      tenascin in the tumor blood vessels is an unfavorable prognostic indicator in
      laryngeal and hypopharyngeal cancers.

PMID- 10646722
TI  - Absence of nuclear p16 from Epstein-Barr virus-associated undifferentiated
      nasopharyngeal carcinomas.
AB  - OBJECTIVE: Epstein-Barr virus (EBV) is detected in the majority of
      undifferentiated nasopharyngeal carcinomas (UNPCs, World Health Organization type
      III). However, the exact mechanism involved in the carcinogenesis of EBV
      associated UNPCs remains to be elucidated. An important unresolved question is:
      how is the normal cell cycle deregulated during EBV-associated UNPC development?
      The p16CDKN2 gene encodes a nuclear protein, p16, which inhibits the D-type
      cyclin/cyclin-dependent kinase complexes that phosphorylate the retinoblastoma
      gene product (pRb), thus blocking G1 cell cycle progression. The objective of
      this study was to determine whether p16 absence is involved in the development of
      EBV-associated UNPCs. METHODS: We performed immunohistochemistry to detect p16
      and pRb and in situ hybridization to detect EBV-encoded small RNA (EBER) in UNPCs
      from 28 patients. RESULTS: No p16 was detected in 23 of 28 UNPCs (82.1%), whereas
      pRb was expressed in all those examined and EBER was detected in 22 of 28
      (78.6%). The absence of p16 was associated with the presence of EBER in UNPCs (P
      < .0001): none of the 22 EBER+ UNPCs expressed p16, whereas 5 of 6 EBER- UNPCs
      did. CONCLUSION: Our data suggest that loss of p16-related cell cycle regulation
      plays an important role in the development of EBV-associated UNPCs.

PMID- 10646723
TI  - Long-term quality of life of patients with head and neck cancer.
AB  - OBJECTIVES: To describe prospectively the long-term changes of quality of life
      and mood in patients with squamous cell carcinoma of the head and neck treated
      with surgery and/or radiotherapy. PATIENTS AND METHODS: One hundred seven
      patients completed the European Organization for Research and Treatment of Cancer
      (EORTC) Core Questionnaire, the EORTC Head and Neck Cancer Module, and the Center
      for Epidemiological Studies Depression Scale before treatment, and 6, 12, 24, and
      36 months later. RESULTS: There was limited deterioration of physical and role
      functioning and of many head and neck symptoms at 6 months, with improvement
      thereafter. After 36 months only physical functioning, taste/ smell, dry mouth,
      and sticky saliva were significantly worse, compared with baseline. Female sex,
      higher cancer stage, and combination treatment were associated with more symptoms
      and worse functioning. Despite physical deterioration, there was a gradual
      improvement of depressive symptomatology and global quality of life. CONCLUSION:
      Treatment for head and neck cancer results in short-term morbidity, most of which
      resolves within 1 year. Despite an initially high level of depressive
      symptomatology, there is gradual improvement of psychological functioning and
      global quality of life over the course of 3 years. In this prospective study, the
      impact of the disease and its treatment in long-term survivors seems to be less
      severe than it is often assumed to be.

PMID- 10646724
TI  - Aspiration of nasal secretions into the lungs in patients with acute sinonasal
      infections.
AB  - OBJECTIVES: To compare the amounts of nasal secretions aspirated into the lower
      airway by patients with acute sinonasal infection with that aspirated by healthy
      adults during sleep. STUDY DESIGN: Sixteen patients who had received a diagnosis
      of acute sinonasal infections by accurate history, anterior rhinoscopic
      examination, and radiological assessment and 13 healthy volunteers, aged 14 to 45
      years. METHODS: A 10-mCi dose of technetium 99m-labeled macroaggregated albumin
      (Tc-99m MAA) with a concentration of 1 mCi/mL was prepared at midnight, just
      before sleep. Each subject was administered two puffs of this spray. At 8 AM the
      next morning transmission and emission views of the thorax were taken with a
      gamma camera. RESULTS: No significant difference between the two groups was
      observed in the amounts of nasal secretions aspirated into the lungs.
      CONCLUSIONS: The amount of nasal secretions aspirated does not increase during
      acute sinonasal infection. However, by irritating the mucosa of the lower
      respiratory tracts, bacteria, toxins, and inflammatory products existing in
      purulent secretions may play a major role in the pathophysiology of asthma and
      sinusitis.

PMID- 10646725
TI  - Apoptosis and phagocytosis of tissue-dwelling eosinophils in sinonasal polyps.
AB  - OBJECTIVE: Sinonasal polyps contain numerous tissue-dwelling eosinophils, but the
      mechanisms causing their accumulation, functional activities, and resolution are
      largely unknown. STUDY DESIGN: Nasal polyp tissue from 14 patients was evaluated
      for cellular expression of CD95, CD68, and annexin-V, for the degree of
      apoptosis, and for phagocytosis of eosinophils. MATERIAL AND METHODS:
      Histological sections were immunostained as single stains for CD95, CD68, and
      annexin-V, and as an immunostaining for CD68 combined with a modified Vital New
      Red staining. The latter staining is specific for eosinophils. Other sections
      were stained by terminal d-UTP nick end labeling (TUNEL) assay and routinely
      stained for H&E. Evaluation of the amount of stained cells was performed by
      counting the average number in 10 randomly chosen high-power fields. The TUNEL
      positivity was in all cases confirmed with apoptotic morphology. RESULTS: The
      inflammatory infiltrate consisted of numerous eosinophils but also a considerable
      amount of lymphocytes, mast cells, and macrophage-like CD68+ cells. CD95 was
      frequently expressed on eosinophils, on numerous other inflammatory cells, and
      also on morphologically apoptotic cells. annexin-V-positive eosinophils were not
      as frequent as CD95+ cells, but numerous annexin-V-positive eosinophils were
      found. CD68+ cells approximately equalled the number of eosinophils. The number
      of cells phagocytosing eosinophils varied between polyps. Apoptosis of
      eosinophils (as evaluated by TUNEL combined with apoptotic morphology) was a
      common finding in six of the polyps. CONCLUSIONS: Previous in vitro and ex vivo
      findings of CD95 on eosinophils are now supported by demonstration of CD95 on
      eosinophils in this in vivo study. This investigation revealed a switch of the
      membrane-bound phosphatidylserine of apoptotic cells, which is a novel
      observation. The study has demonstrated apoptosis of tissue-dwelling eosinophils,
      and that CD68+ macrophage-like cells phagocytose eosinophils within the sinonasal
      polyps.

PMID- 10646726
TI  - Saccharin test of maxillary sinus mucociliary function after endoscopic sinus
      surgery.
AB  - OBJECTIVES: To determine the usefulness of the saccharin time (ST) test for
      evaluating the mucociliary function of the maxillary sinus after endoscopic sinus
      surgery (ESS) for chronic sinusitis. STUDY DESIGN:  METHODS: This study was
      conducted on 88 maxillary sinuses of 74 patients after ESS. The maxillary sinus
      fontanel was broadly opened via the middle meatus using an endoscope, and a
      saccharin granule was adhered to the bottom of the maxillary sinus mucosa The
      time until the patient recognized the sweet taste was recorded. Before the ST
      test, the bilateral maxillary sinuses were classified into the following four
      groups on the basis of the post-ESS severity of mucosal edema and swelling as
      revealed by endoscopic observation: normal (45 sinuses), mild mucosal edema and
      swelling (24), moderate mucosal finding (14), and severe mucosal finding or
      filling of the sinus with a polyp(s) (5). RESULTS: The mean ST values in the
      normal group and the groups with mild, moderate, and severe mucosal edema and
      swelling were 35.7, 38.1, 63.6, and 88.0 minutes, respectively. Thus the ST
      increased with the post-ESS severity of the mucosal lesion. However, for the
      group with mild mucosal edema and swelling, scanning electron microscopic
      observation of three maxillary sinuses in which the ST exceeded 120 minutes and
      four sinuses in which the ST was 40 minutes revealed extensive cilia loss in the
      former sinuses, but not in the latter. A second post-ESS endoscopic observation
      was performed in 17 patients, revealing improvement in 11 sinuses, no change in 5
      sinuses, and aggravation in 1 sinus (compared with the initial test). The ST test
      was also repeated, revealing that the ST became shorter in most of the
      endoscopically improved sinus group. However, a few sinuses showed a discrepancy
      between the change in the endoscopic findings and the ciliary function (ST).
      CONCLUSION: Measurement of the maxillary sinus ST is a simple, accurate, and
      useful technique for assessing the post-ESS mucociliary function in conjunction
      with endoscopy, and the information gained can help in deciding subsequent
      therapy.

PMID- 10646727
TI  - The comet assay of nasal epithelia: measurement of DNA damage for the assessment
      of genotoxic air pollution.
AB  - OBJECTIVES: The alkaline single cell gel electrophoresis or "comet" assay allows
      measurement of DNA damage in single cells with a high degree of sensitivity,
      e.g., for investigations of the effect of environmental agents with DNA-damaging
      potential. This study aimed to adapt this test to respiratory cells of the human
      nasal mucosa to examine the genotoxic effect of air pollution (cigarette smoke).
      STUDY DESIGN: In a prospective study, nasal epithelia of 16 cigarette smokers
      were examined by the adapted comet assay and the results were correlated with the
      results of the Papanicolaou-stained nasal cytology, carried out in a blinded
      fashion. The control group comprised 20 non-smoking men. All subjects under
      investigation were healthy office workers. METHODS: Nasal epithelia were
      harvested from the maxilloturbinates. One part of cells was Papanicolaou stained
      and evaluated by cytopathologists. The comet assay was performed on the other
      part of the cells. The examiners were blinded to the study and control groups.
      RESULTS: Among cigarette smokers, a significant correlation between
      cytopathological cell nucleus changes (metaplasia and dysplasia) and the DNA
      migration (tail lengths) in the comet assay was found as a sign of DNA damage.
      This was not found in nonsmoking control persons. CONCLUSIONS: These results
      confirm the sensitivity of the comet assay and the hypothesis that cell nucleus
      changes in conventional nasal cytology are associated with DNA damage.

PMID- 10646728
TI  - Effects of clarithromycin on cultured human nasal epithelial cells and
      fibroblasts.
AB  - OBJECTIVE/METHODS: Long-term administration of clarithromycin has been reported
      to be effective in the treatment of chronic sinusitis. To investigate the
      mechanism underlying the anti-inflammatory activity of clarithromycin, the
      authors evaluated the effect of clarithromycin on the gene expression of
      proinflammatory cytokine and the DNA-binding activity of nuclear factor (NF)
      kappa B in cultured human nasal epithelial cells and fibroblasts. Cells were
      incubated with endotoxin purified from nontypable Haemophilus influenzae or
      interleukin (IL)-1 beta in the presence of clarithromycin. RESULTS: Northern blot
      analysis revealed that clarithromycin suppressed IL-1 beta gene expression in
      human nasal epithelial cells stimulated by H. influenzae endotoxin (HIE).
      Intercellular adhesion molecule-1 gene expression in nasal fibroblasts stimulated
      by IL-1 beta was also suppressed by clarithromycin. Furthermore, electrophoretic
      mobility shift assay demonstrated that clarithromycin reduced DNA-binding
      activity of NF-kappa B in both human nasal epithelial cells and fibroblasts
      stimulated by HIE or IL-1 beta, respectively. CONCLUSION: The present results
      suggest that clarithromycin may reduce gene expression of proinflammatory
      cytokines and adhesion molecules from nasal mucosa at the transcriptional factor
      level and exert an anti-inflammatory effect on nasal mucosa in chronic sinusitis.

PMID- 10646729
TI  - A multicenter trial of specific local nasal immunotherapy.
AB  - OBJECTIVE: To assess the efficacy and safety of specific local nasal
      immunotherapy (LNIT) in powder form in patients with allergic rhinitis, using
      subjective and objective parameters. STUDY DESIGN: A double-blind randomized
      multicenter trial of 102 patients with allergic rhinitis who were treated with
      specific LNIT for 8 consecutive months. METHODS: After identifying allergens with
      the skin prick test and sensitization threshold dose with the specific nasal
      provocation test, 102 patients were selected, of whom 55 were allergic to mites
      and 47 were allergic to Graminaceae or Parietaria pollen. The specific treatments
      were self-administered using an insufflator in two phases (phase 1: increasing
      doses; phase: 2, maintenance dose). Patients were evaluated before and after 32
      weeks of treatment by subjective analysis of their self-reported symptoms and by
      objective analysis of nasal provocation test, nasal resistance by anterior
      rhinomanometry, and mucociliary clearance time. RESULTS: Clinical efficacy of
      LNIT for allergy to mites and pollens was confirmed by the differences in the
      symptoms score between the active group and the placebo group. The nasal
      provocation test results confirmed that this difference was statistically
      significant. The rhinomanometric analysis gave positive results for the treated
      group mainly in LNIT for mites. No differences in mucociliary clearance time were
      found. CONCLUSIONS: Specific LNIT is effective for allergic rhinitis and appears
      to offer considerable advantages over other hyposensitization methods. It can be
      done at home, patient compliance is good, and the treatment is safe.

PMID- 10646730
TI  - Airway complication after thyroid surgery: minimally invasive management of
      bilateral recurrent nerve injury.
AB  - OBJECTIVES: After bilateral vocal cord paralysis, the consequent paramedian
      position usually necessitates tracheostomy for at least 6 months, when the
      paralysis is potentially reversible. In the present study a reversible endoscopic
      vocal cord laterofixation procedure was used instead of tracheotomy. STUDY
      DESIGN: Prospective study of 15 consecutive patients aged 33 to 73 years who
      suffered bilateral recurrent laryngeal nerve paralysis after thyroid surgery.
      METHODS: The operation was performed endoscopically with a special endo
      extralaryngeal needle carrier instrument. Two ends of a monofilament
      nonresorbable thread were passed above and under the posterior third of the vocal
      cord and knotted on the prelaryngeal muscles, permitting the creation of an
      abducted vocal cord position. If movement of one or both vocal cords recovered,
      the suture was removed. Regular spirometric measurements and radiological
      aspiration tests were conducted on the patients. RESULTS: During the follow-up
      period of 3 to 40 months, airway stability was demonstrated in all but one
      patient. After the repeated lateralization procedure, this patient's breathing
      improved. Partial or complete vocal cord recovery was observed in eight patients.
      In six patients further voice improvement was achieved when the threads were
      removed after vocal cord medialization or recovery. Mild postoperative
      aspirations ceased in the first postoperative days. CONCLUSIONS: This management
      approach offers an alternative to tracheostomy in the early period of paralysis,
      avoids terminal loss of voice quality, and provides a "one-stage" solution for
      permanent bilateral recurrent nerve injuries.

PMID- 10646731
TI  - Acuteness of preoperative factors to predict hearing preservation in acoustic
      neuroma surgery.
AB  - OBJECTIVES: To determine in patients with acoustic neuromas the predictive
      factors of hearing preservation according to clinical, radiological, and
      electrophysiological parameters and to evaluate, for each of these predictive
      factors, the percentage of patients with preserved hearing. STUDY DESIGN: The
      study involved 107 candidates for hearing preservation attempt. Mean age was 49.7
      +/- 11.4 years. Quantitative and qualitative parameters were prospectively
      studied. Quantitative parameters were age, duration of functional complaints,
      hearing loss assessed by pure tone and speech audiometry, and auditory brainstem
      responses (ABRs). Qualitative parameters (expressed in percentage of presence)
      were sex, functional complaints, vestibular deficit revealed by vestibular
      testings, well-shaped ABRs, wave I, III, or V of ABRs, and transient evoked
      otoacoustic emissions (TEOAEs). METHODS: Patients were divided into two groups
      according to whether their hearing was preserved (52.3%) or not preserved
      (47.7%). First, quantitative and qualitative factors were compared between both
      groups to identify predictive factors. Second, all patients were considered
      together and the percentage of hearing preservation was determined according to
      the presence of each predictive factor. RESULTS: The results confirmed the
      predictive value of classic parameters such as preoperative hearing level,
      radiological data, and trace of ABRs. They also emphasized the predictive role of
      other parameters such as short duration of hearing loss, presence of wave III in
      ABRs, and presence of TEOAEs. CONCLUSIONS: The size of the tumor and the
      preoperative hearing levels are longstanding predictive factors of hearing
      preservation in acoustic neuroma surgery, and candidates for hearing preservation
      are therefore now selected according to these factors. This study added more
      recent predictive factors and, among the 10 factors identified as predictive, the
      most relevant to hearing preservation were the presence of TEOAEs (69.7%), short
      duration of hearing loss (66.7%), and presence of wave III in ABRs (66.7%).

PMID- 10646732
TI  - Postoperative quality of life in vestibular schwannoma patients measured by the
      SF36 Health Questionnaire.
AB  - OBJECTIVE: To quantify the postoperative quality of life in patients following
      surgical treatment for vestibular schwannoma. STUDY DESIGN: Patient self
      assessment using the short form 36 (SF36) multidimensional quality of life health
      questionnaire. Sex- and age-matched normalized scores were calculated using a
      standardized process and accepted normative data. SETTING: Tertiary referral
      skull base unit. RESULTS: An 80% response rate (90 patients) was achieved. The
      postoperative quality of life in vestibular schwannoma patients, as quantified by
      seven of the eight SF36 health scales was less than the appropriate matched
      healthy standard. Comparison of a variety of preoperative patients and tumor
      factors-different operative approaches (translabyrinthine and retrosigmoid),
      tumor size (group cut of points of tumor diameter 1.5 mm and 2.5 mm), patient
      sex, and ranking of patient age-showed no statistically significant difference in
      measured quality of life outcomes for each of these traditional predictors.
      CONCLUSION: Reduced quality of life in patients after surgical treatment for
      vestibular schwannoma, coupled with the low tumor growth rates and minimal
      preoperative symptoms, supports a conservative approach to patient management.
      The advantages and disadvantages of a variety of approaches used to measure the
      quality of life after surgical treatment of vestibular schwannoma and their
      impact on clinical decision making for patients, are discussed.

PMID- 10646733
TI  - A cost-utility analysis of pediatric cochlear implantation.
AB  - OBJECTIVE/HYPOTHESIS: The aim of this study was to explore the cost-utility of
      pediatric cochlear implantation, incorporating savings associated with education
      into the analysis. METHODS: The costs of pediatric cochlear implantation were
      based on the full costs levied to purchasers, inclusive of complications and
      maintenance, by a large pediatric cochlear implant program in the United Kingdom.
      After implantation, profoundly hearing-impaired children have been found to
      develop hearing threshold levels equivalent to severely hearing-impaired children
      who wear hearing aids. An independent study calculated the educational costs for
      severely hearing-impaired and profoundly hearing-impaired children. From this
      study, savings in educational costs that would result from enabling the
      profoundly hearing-impaired to function as severely hearing-impaired were
      determined. Cost-utility was established conservatively by applying to children
      the known gains in utility reported by adults with cochlear implants. RESULTS:
      The discounted costs of creating a pediatric cochlear implant user and of
      maintaining the child over the first 12 years were 48,757 pound silver($78,011).
      The discounted difference in education costs associated with a profoundly hearing
      impaired child (HL >95 dB) as compared with a severely hearing-impaired child (HL
      70-95 dB) over the same period was 26,781 pound silver($42,850). These represent
      the potential savings in educational costs associated with pediatric cochlear
      implantation. Assuming implantation at age 4 years, the discounted net average
      cost of pediatric cochlear implantation over compulsory school years (ages 4-16)
      was 21,976 pound silver ($35,162). Cochlear implants have been shown to improve
      the quality of life in adults by 0.23 points per annum (where quality of life is
      rated on a scale from 0 to 1). Applying this weight to children receiving
      implantation at age 4 years, and assuming a life expectancy of 74 years, the
      quality-adjusted life-year (QALY) gain is calculated to be 16.33. The cost per
      undiscounted QALY gain was estimated to be 1,345.70 pound silver ($2153.12) and
      per discounted QALY gain to be 10,341 pound silver ($16,545.60). CONCLUSION: This
      study provides evidence, based on conservative assumptions, to support the view
      that pediatric cochlear implantation is a cost-effective health care intervention
      in profoundly hearing-impaired young children.

PMID- 10646734
TI  - Expression of angiogenic growth factors in paragangliomas.
AB  - OBJECTIVE/HYPOTHESIS: To determine if angiogenic growth factors including
      vascular endothelial growth factor (VEGF) and platelet-derived endothelial cell
      growth factor (PD-ECGF) are expressed in human paragangliomas. STUDY DESIGN: A
      histopathologic and molecular examination of paraganglioma specimens obtained
      from surgical cases or retrieved from the Pathology Department of the
      Massachusetts Eye and Ear Infirmary. METHODS: Fresh tumor or archival, paraffin
      embedded paraganglioma specimens were analyzed by immunohistochemistry, Western
      blotting, and ELISA. RESULTS: Positive immunohistochemical staining for VEGF was
      observed in five of nine surgical specimens and in six of eight archival
      specimens (11/17, or 65%). PD-ECGF immunoreactivity was detected in four of five
      surgical specimens and six of eight archival specimens (10/13, or 77%). The
      presence of PD-ECGF was confirmed by Western blot assay and ELISA confirmed the
      presence of VEGF in tumor extract. CONCLUSIONS: Both VEGF and PD-ECGF are
      expressed in paragangliomas and may contribute to the extreme vascularity of
      these tumors. Key Words. Vascular endothelial growth factor, platelet-derived,
      endothelial cell growth factor, hypoxia, tumor vasculature.

PMID- 10646735
TI  - A new drill for frontal sinus surgery.

PMID- 10646736
TI  - Surgical management of isolated malleus handle fractures.

PMID- 10646737
TI  - Transconjunctival blepharoplasty and the use of the "silent assistant".

PMID- 10646739
TI  - Practical use of total and partial ossicular replacement prosthesis in
      ossiculoplasty.

PMID- 10646740
TI  - Surgical causes of failure in endoscopic sinus surgery.

PMID- 10646741
TI  - Validation of objective measure of facial paralysis.

PMID- 10646742
TI  - Nasal dilator strips.

PMID- 10646743
TI  - Nasal dilator strips

PMID- 10646744
TI  - The Pediatric Eye Disease Investigator Group.

PMID- 10646745
TI  - Occlusion and levodopa-carbidopa treatment for childhood amblyopia.
AB  - PURPOSE: The purpose of the current study was to compare the effects of levodopa
      carbidopa with and without part-time occlusion on visual function in older
      amblyopic children. METHODS: Thirteen older amblyopic children were randomly
      assigned to receive or not receive part-time occlusion (3 h/day) combined with 7
      weeks of oral dosing with levodopa-carbidopa (1.02 mg/0.25 mg/kg body weight
      three times daily). Visual acuity, contrast sensitivity, and fusion were measured
      at baseline; 1, 3, 5, and 7 weeks during the treatment regimen; and 4 weeks after
      termination of all treatment. At these same times health status was assessed with
      standard laboratory blood tests, physical examination, and subjective
      questionnaire. RESULTS: From baseline to the follow-up test trial, both groups
      improved in visual acuity in the amblyopic eyes (occlusion group 20/116 to 20/76,
      P < .001; no occlusion group 20/90 to 20/73, P < .01) and dominant eyes
      (occlusion group 20/18 to 20/15, P > .05; no occlusion group 20/20 to 20/16, P <
      .01). The occlusion group exhibited a significant decrease in the difference in
      acuity between the dominant and amblyopic eyes of 1.3 lines (P < .02), whereas
      the no occlusion group revealed no significant effect. A comparison between
      groups revealed a significantly greater improvement in visual acuity in the
      amblyopic eye in the occlusion group compared with the no occlusion group (P =
      .01). In contrast, there was no significant difference between groups in terms of
      the change in visual acuity in the dominant eye (P = .15). Mean log contrast
      sensitivity in the amblyopic eye significantly improved in the occlusion group
      and did not significantly change in the no occlusion group. Fusion changed
      similarly in both groups. The improvements in visual function were maintained 4
      weeks after the termination of all treatment. Adverse side effects were minimal
      in both groups. CONCLUSION: The combination of levodopa-carbidopa and occlusion
      improves visual function more than levodopa-carbidopa alone in older amblyopic
      children.

PMID- 10646746
TI  - The natural history of acute traumatic sixth nerve palsy or paresis.
AB  - BACKGROUND: Spontaneous resolution of traumatic sixth nerve palsy or paresis has
      been reported to range between 12% and 54%. However, previous studies have been
      based in tertiary referral centers, have been retrospective in nature, have
      included a heterogeneous group of patients, and have included patients with long
      standing palsies. To provide a more accurate estimate of the true recovery rate,
      we performed a prospective natural history study. METHODS: All members of the
      American Association for Pediatric Ophthalmology and Strabismus and the North
      American Neuro-Ophthalmology Society were invited to enroll patients with acute
      traumatic sixth nerve palsy or paresis between March 1996-February 1997. Recovery
      at 6 months after injury was defined as absence of diplopia in primary position
      and less than or equal to 10 PD distance esotropia in primary position. Patients
      who had been treated with botulinum toxin (n = 8) within 6 months after injury
      and patients with <6 months of follow-up (n = 3) were excluded. RESULTS: Thirty
      three eligible patients were enrolled by 27 investigators. Twenty-five (76%) of
      the palsies were unilateral and 8 (24%) were bilateral. The overall spontaneous
      recovery rate was higher than previously reported (73%, 95% CI 54%-87%).
      Spontaneous recovery was more frequent in unilateral cases (84%, 95% CI 64%-95%)
      than in bilateral cases (38%, CI 9%-76%; P = .02). CONCLUSIONS: In this
      prospective multicenter study of acute traumatic sixth nerve palsy or paresis,
      the overall spontaneous recovery rate, particularly in unilateral cases, was much
      higher than previously reported. Our results have important sample size
      implications for the planning of any randomized treatment trial and may help
      guide early treatment decisions.

PMID- 10646747
TI  - Secondary posterior chamber intraocular lens implantation in children.
AB  - BACKGROUND: Primary intraocular lens (IOL) implantation after cataract aspiration
      is a widely accepted means of correcting pediatric aphakia. However, little is
      available in the literature on secondary IOL implantation in children. We present
      our experience over the past 6 years. METHODS: The charts of 57 aphakic children
      (61 eyes) who underwent secondary posterior chamber IOL implantation between
      January 1989 and April 1996 were reviewed. In general, these children were either
      intolerant of or noncompliant with their contact lenses. An attempt was made to
      correlate visual outcome with patient variables. Evaluation of the ciliary sulcus
      structure was made in selected patients by ultrasonographic biomicroscopy to
      reveal any changes resulting from the presence of the IOL haptic in the sulcus.
      RESULTS: The age range at the time of surgery was 2 to 16 years (mean 8 y). Mean
      follow-up was 14 months (range 6 to 48 months). Forty-two percent of the patients
      had a best-corrected visual acuity of 20/40 or better and 78% saw better than
      20/80. Posterior capsular opacification occurred in 10 eyes, 8 of which required
      neodymium:yttrium-aluminum-garnet laser capsulotomy. No major complications
      occurred. Ciliary sulcus evaluation by biomicroscopy did not reveal any
      significant ciliary body or scleral erosion. No changes were noted when the
      implanted sulcus was compared with the normal contralateral side. CONCLUSION:
      Although follow-up was short, this review suggests that secondary posterior
      chamber IOL implantation is a safe alternative when other methods of correcting
      pediatric aphakia fail.

PMID- 10646748
TI  - Early-onset refractive accommodative esotropia.
AB  - INTRODUCTION: We studied the natural history of pure refractive accommodative
      esotropia after spectacle correction in patients with onset before 1 year old to
      determine whether their outcomes and characteristics were different from those of
      patients with more typical age at onset of refractive accommodative esotropia.
      METHODS: We retrospectively reviewed the charts of 17 children with onset of
      refractive accommodative esotropia before 1 year old. Records of 26 children with
      onset after 2 years old were reviewed as controls. RESULTS: The mean ages at
      diagnosis were 9 months and 48 months for the study and control groups,
      respectively. All 17 study patients and all 26 control patients were initially
      well aligned with spectacles at distance and near. Follow-up averaged 34 months
      for study patients and 41 months for control patients. Three study patients
      (17.6%) and 1 control patient (3.8%) had eventual deterioration and required
      strabismus surgery (P = .28). None of the study patients developed amblyopia,
      whereas 42% of control patients did (P = .001). Seven of 15 (47%) of the study
      patients with known birth history were born prematurely, whereas only 3 of 24
      (12%) control patients were born prematurely (P = .03). CONCLUSIONS: Refractive
      accommodative esotropia was diagnosed at as early as and age 4 months.
      Prematurity appeared to be a risk factor. Amblyopia was not detected in any
      patient with early-onset refractive accommodative esotropia. Treatment with full
      hyperopic spectacle correction led to long-term stable alignment, with relatively
      few patients requiring surgery.

PMID- 10646749
TI  - Ocular torsion as a complication of scleral buckle procedures for retinal
      detachments.
AB  - BACKGROUND: Strabismus can occur in as many as 30% of patients after scleral
      buckle procedures for retinal detachments. Most previous case series have
      reported on horizontal and vertical deviations. This study examines the frequency
      of torsion after scleral buckle procedures, the abnormalities of extraocular
      muscles seen during strabismus surgery, and the surgical procedures effective in
      improving torsion. METHODS: A chart review examined the records of all patients
      coming to a strabismus referral practice with diplopia reported > or =6 months
      after scleral buckle procedures. RESULTS: Forty-six percent of patients with
      diplopia after scleral buckle operations had torsion (88% extorsion, 12%
      intorsion). The 2 mechanisms that caused extorsion most frequently were
      inadvertent production of a superior oblique muscle palsy and tightening of the
      inferior rectus muscle from the underlying scleral buckle. Other mechanisms of
      extorsion were also seen. The mechanism for production of intorsion was scarring
      of the superior oblique muscle to the nasal border of the insertion of the
      superior rectus muscle. Surgical procedures were successful in reducing torsion 4
      degrees or more in 59% of cases. CONCLUSION: In patients undergoing surgery for
      torsion after a scleral buckle procedure, exploration of the superior oblique
      muscle and the inferior rectus muscle may yield information about the mechanism
      involved in the production of the torsion.

PMID- 10646750
TI  - Ocular motility disturbances after surgery for retinal detachment.
AB  - PURPOSE: Relatively little has been published on the management of motility
      problems after surgery for retinal detachment. We report a large series with the
      aim of describing clinical features, management, and outcome. METHODS: The charts
      of 68 of 86 consecutive patients referred to one of us between 1989 and 1995 were
      retrieved and analyzed. Sixty-two had unilateral and 6 bilateral surgery for
      retinal detachment. In 45 cases the macula was detached at surgery. The visual
      acuity of the affected eyes ranged from hand motions to 6/6. Sensory testing
      suggested potential binocular function in 39.7%. Fifty-nine patients had combined
      vertical and horizontal strabismus, 8 horizontal alone, and 1 vertical only. The
      average vertical deviation measured 10.2 PD and the average horizontal 19 PD.
      RESULTS: Twelve patients underwent strabismus surgery, 26 were treated with
      botulinum toxin, 21 were managed conservatively with prisms or occlusion, and 8
      refused or did not require treatment. Forty-seven percent of the group regained
      binocularity (20.5% cured with surgery or botulinum toxin, 26.5% controlled with
      prisms or intermittent injection with botulinum toxin). A total of 20.7% gained
      improvement in appearance, 19.1% were managed with permanent occlusion, and 13.2%
      either refused or did not require treatment. CONCLUSION: Macula off retinal
      detachment, poor visual acuity plus or minus distortion, and multiple procedures
      for retinal reattachment are associated with a poor prognosis for restoration of
      binocular vision and a good outcome. In our hands, botulinum toxin treatment is
      the method of choice, with surgery used in selected cases.

PMID- 10646751
TI  - Etiology and surgical management of horizontal pontine gaze palsy with
      ipsilateral esotropia.
AB  - INTRODUCTION: An esotropia ipsilateral to a horizontal pontine gaze palsy has
      been infrequently reported. We discuss the etiology and review the surgical
      management of this ocular motility defect. METHODS: Four patients with
      radiographically documented dorsal pontine lesions and persistent horizontal gaze
      palsy with esotropia ipsilateral to the gaze palsy were treated. In each patient,
      the esotropia was present in attempted primary gaze, producing symptomatic
      diplopia. An anomalous face turn was required to attain single binocular vision.
      RESULTS: All 4 patients underwent surgical correction to alleviate the anomalous
      head position and diplopia. Bilateral, asymmetric surgery was required to achieve
      a long-term successful result. Single binocular vision in the primary position
      with elimination or marked improvement of the compensatory head posture was
      initially achieved in all 4 patients. One patient, who had not undergone
      asymmetric strabismus surgery to reconcile incomitance produced by the esotropia,
      rapidly developed a residual esotropia. CONCLUSIONS: Ophthalmologists should
      recognize that concurrent esotropia may occur in patients with horizontal pontine
      gaze palsy. Single binocular vision in the primary position, an expanded
      binocular visual field, and alleviation of a compensatory head position are
      achievable with strabismus surgery.

PMID- 10646752
TI  - Ocular status of boys with fragile X syndrome: a prospective study.
AB  - PURPOSE: The purpose of this study was to determine whether the high rates of
      ocular problems described in previous retrospective reports of individuals with
      fragile X syndrome were present in a prospective sample of young boys. Fragile X
      syndrome is currently considered the leading hereditary cause of mental
      retardation, with prevalence estimates of 1:2500 to 1:5000 males. METHODS: Forty
      eight boys with fragile X syndrome between the ages of 2.5 and 11 years were
      evaluated for ocular abnormalities. They received complete ophthalmic evaluations
      including assessment of visual acuity, cycloplegic refraction, ocular motility
      assessment, and dilated fundus examination. RESULTS: Approximately 25% of the
      children had clinically significant ocular findings that included refractive
      errors (17%, primarily hyperopia and astigmatism) and strabismus (8%). Of the 42
      children with quantifiable visual acuities, only 1 child, with diagnoses of
      nystagmus and hyperopia, had a Snellen visual acuity that was not within normal
      limits for his age. Three of the 5 children with gross measures of visual acuity
      had clinically significant findings: 2 had hyperopia greater than 3.5 diopters
      and 1 had esotropia. The other 2 children with gross measures of acuity and the 1
      child without visual acuity assessment had cycloplegic refractions of +1.25 to
      +1.5 and ocular motility appeared normal. CONCLUSIONS: These results suggest that
      previous reports of high rates of vision problems, particularly strabismus, in
      boys with fragile X syndrome may have resulted from selection bias. Although we
      did observe a higher prevalence of strabismus than that found in the general
      population (8% vs 0.5% to 1%), the proportion of children having strabismus in
      our sample was much smaller than that reported in other studies of children with
      fragile X syndrome (30% to 40%). However, 17% of the sample did have significant
      refractive errors. In addition to evaluating the ocular motility of children with
      fragile X syndrome, cycloplegic refraction should also be performed to determine
      whether refractive problems are present.

PMID- 10646753
TI  - Retinoblastoma in an eye with congenital uveal coloboma.
AB  - Retinoblastoma and congenital ocular abnormalities rarely coexist. The appearance
      of an intraocular tumor in a child with preexisting leukokoria may make the
      diagnosis of retinoblastoma more challenging. This report describes a unique case
      of unilateral congenital uveal coloboma and ipsilateral retinoblastoma in a
      patient with no family history of either abnormality and normal cytogenetic
      analysis.

PMID- 10646754
TI  - Superior oblique damage from the traction suture at cataract surgery.
AB  - A 41-year-old woman underwent uneventful phacoemulsification and posterior
      chamber lens implantation in the right eye. Approximately a month later similar
      surgery was performed in the left eye. The surgery was performed with the patient
      under retro-bulbar anesthesia with a combination of bupivacaine (Marcaine) 0.75%
      and lidocaine (Xylocaine) 4% administered through a lower lid injection.
      Immediately after the patch was removed, the patient was aware of constant
      vertical diplopia. Over the ensuing 6 months the symptom worsened. Orbital
      computed tomography showed no abnormalities.

PMID- 10646755
TI  - Absence of multiple extraocular muscles in craniosynostosis.
AB  - The absence of extraocular muscles, particularly the superior rectus1, 2 or
      superior oblique3, 4 has been recognized to cause strabismus among patients with
      craniosynostosis. Absence of multiple muscles is less common. In case 1 we note a
      patient with Pfieffer's syndrome and absent left superior rectus and inferior
      oblique, with the presence of only a vestigial left superior oblique and an
      underdeveloped and misinserted left inferior rectus. In case 2 we describe a
      patient with Apert's syndrome with bilateral absence of the superior rectus and
      superior oblique muscles. Unsuspected superior rectus absence led to a bilateral
      elevation deficit after inferior oblique weakening. Also, during the course of
      treatment, all 3 remaining recti muscles in 1 eye were disinserted. To our
      knowledge, this is the first report of absent extraocular muscles in Pfieffer's
      syndrome. Some evidence suggests that collateral anterior segment blood flow
      exists in cases of absent recti muscles. Further study is needed to determine
      whether all remaining muscles could be used for strabismus repair. Last, when
      patients with craniosynostosis require strabismus surgery, we feel that a limited
      exploration of all extraocular muscles should be carried out.

PMID- 10646756
TI  - Charles Bonnet syndrome in children.
AB  - Charles Bonnet syndrome (CBS) is characterized by the presence of complex visual
      hallucinations in psychologically healthy but visually impaired people. It has
      been well described in the adult population but has been less well characterized
      in children. This report describes CBS in 2 children, both of whom had diagnoses
      of cone-rod dystrophy. After previously normal visual experience, each underwent
      rapid visual deterioration between 6 and 8 years old. Formed visual
      hallucinations were noted shortly after loss of vision. The children's symptoms
      were identical to those described by adults with CBS. Formed visual phenomena
      included geometric shapes, people, and buildings. Images, which were both
      stationary and in motion, were described as interesting or entertaining and only
      rarely as frightening. No other senses were affected (no auditory component).
      Sixteen additional children with diseases of the eye or optic nerves were
      questioned about symptoms of CBS, including children with congenitally decreased
      vision, children with slowly progressive visual loss but current vision better
      than 20/200, and children with early normal vision who had profound vision loss
      before 4 years old; all these children denied hallucinations.

PMID- 10646757
TI  - Guiding systems for computer-assisted surgery: introducing synergistic devices
      and discussing the different approaches.
AB  - Computer-assisted surgery (CAS) or computer-assisted therapy (CAT) attempt
      primarily to optimize the performance of medical tasks. CAS systems include a
      guiding system to connect the information world of data and plans to the physical
      world of surgeons, patients and instruments, and to supplement the surgeon's
      perception and dexterity. Passive, semi-active and active systems have been
      proposed and implemented in various clinical applications. In this paper we
      introduce synergistic devices which are an extension of semi-active systems. We
      also discuss the advantages of the different categories of guiding systems on the
      basis of a list of task-oriented and user-oriented qualitative factors.

PMID- 10646758
TI  - Volumetric object modeling for surgical simulation.
AB  - Surgical simulation has many applications in medical education, surgical
      training, surgical planning and intra-operative assistance. However, extending
      current surface-based computer graphics methods to model phenomena such as the
      deformation, cutting, tearing or repairing of soft tissues poses significant
      challenges for real-time interactions. This paper discusses the use of volumetric
      methods for modeling complex anatomy and tissue interactions. New techniques are
      introduced that use volumetric methods for modeling soft-tissue deformation and
      tissue cutting at interactive rates. An initial prototype for simulating
      arthroscopic knee surgery is described which uses volumetric models of the knee
      derived from 3-D magnetic resonance imaging, visual feedback via real-time volume
      and polygon rendering, and haptic feedback provided by a force-feedback device.

PMID- 10646759
TI  - Experimentation with a transcranial magnetic stimulation system for functional
      brain mapping.
AB  - We describe functional brain mapping experiments using a transcranial magnetic
      stimulation (TMS) device. This device, when placed on a subject's scalp,
      stimulates the underlying neurons by generating focused magnetic field pulses. A
      brain mapping is then generated by measuring responses of different motor and
      sensory functions to this stimulation. The key process in generating this mapping
      is the association of the 3-D positions and orientations of the TMS probe on the
      scalp to a 3-D brain reconstruction such as is feasible with a magnetic resonance
      image (MRI). We have developed a registration system which not only generates
      functional brain maps using such a device, but also provides real-time feedback
      to guide the technician in placing the probe at appropriate points on the head to
      achieve the desired map resolution. Functional areas we have mapped are the motor
      and visual cortex. Validation experiments focus on repeatability tests for
      mapping the same subjects several times. Applications of the technique include
      neuroanatomy research, surgical planning and guidance, treatment and disease
      monitoring, and therapeutic procedures.

PMID- 10646760
TI  - Three-dimensional multi-scale line filter for segmentation and visualization of
      curvilinear structures in medical images.
AB  - This paper describes a method for the enhancement of curvilinear structures such
      as vessels and bronchi in three-dimensional (3-D) medical images. A 3-D line
      enhancement filter is developed with the aim of discriminating line structures
      from other structures and recovering line structures of various widths. The 3-D
      line filter is based on a combination of the eigenvalues of the 3-D Hessian
      matrix. Multi-scale integration is formulated by taking the maximum among single
      scale filter responses, and its characteristics are examined to derive criteria
      for the selection of parameters in the formulation. The resultant multi-scale
      line-filtered images provide significantly improved segmentation and
      visualization of curvilinear structures. The usefulness of the method is
      demonstrated by the segmentation and visualization of brain vessels from magnetic
      resonance imaging (MRI) and magnetic resonance angiography (MRA), bronchi from a
      chest CT, and liver vessels (portal veins) from an abdominal CT.

PMID- 10646761
TI  - A three-dimensional virtual environment for modeling mechanical cardiopulmonary
      interactions.
AB  - We have developed a real-time computer system for modeling mechanical
      physiological behavior in an interactive, 3-D virtual environment. Such an
      environment can be used to facilitate exploration of cardiopulmonary physiology,
      particularly in situations that are difficult to reproduce clinically. We
      integrate 3-D deformable body dynamics with new, formal models of (scalar)
      cardiorespiratory physiology, associating the scalar physiological variables and
      parameters with the corresponding 3-D anatomy. Our framework enables us to drive
      a high-dimensional system (the 3-D anatomical models) from one with fewer
      parameters (the scalar physiological models) because of the nature of the domain
      and our intended application. Our approach is amenable to modeling patient
      specific circumstances in two ways. First, using CT scan data, we apply semi
      automatic methods for extracting and reconstructing the anatomy to use in our
      simulations. Second, our scalar physiological models are defined in terms of
      clinically measurable, patient-specific parameters. This paper describes our
      approach, problems we have encountered and a sample of results showing normal
      breathing and acute effects of pneumothoraces.

PMID- 10646762
TI  - Definition of a four-dimensional continuous planispheric transformation for the
      tracking and the analysis of left-ventricle motion.
AB  - Cardiologists assume that analysis of the motion of the heart (especially the
      left ventricle) can provide useful information about the health of the
      myocardium. A 4-D polar transformation is defined to describe the left-ventricle
      (LV) motion and a method is presented to estimate it from sequences of 3-D
      images. The transformation is defined in 3-D planispheric coordinates (3PC) by a
      small number of parameters involved in a set of simple linear equations. It is
      continuous and regular in time and space, and periodicity in time can be imposed.
      The local motion can be easily decomposed into a few canonical motions (radial
      motion, rotation around the long-axis, elevation). To recover the motion from
      original data, the 4-D polar transformation is calculated using an adaptation of
      the iterative closest-point algorithm. We present the mathematical framework and
      a demonstration of its feasability on a series of gated SPECT sequences.

PMID- 10646763
TI  - Intraoperative pancreatoscopy for pancreatic duct stone debris distal to the
      common channel in choledochal cyst.
AB  - BACKGROUND/PURPOSE: Pancreatic duct stone debris is a recognised problem in
      patients with choledochal cyst (CC). The authors present the use of
      intraoperative pancreatoscopy (IP) in diagnosis and treatment of pancreatic duct
      stone debris distal to the common channel (distal PDSD). METHODS: Sixty-seven
      patients with CC treated over the past 12 years were reviewed retrospectively.
      Distal PDSD was detected in 8 of these 67 cases (11.9%) using cholangiography. IP
      of the common channel or pancreatic duct at the time of surgery for CC was
      performed using a pediatric cystoscope in 7 of these 8 cases. RESULTS: All 8
      patients had a long common channel. All presented with acute pancreatitis. In 7
      of these 8 patients, IP was efficient in detecting and for removing distal PDSD
      by irrigation. In the remaining case associated with annular pancreas, distal
      PDSD was identified in the proximal pancreatic duct and was removed directly
      after incision of the pancreatic duct. Postoperative pancreatitis occurred in
      only 1 case. All patients are well after a mean follow-up period of 7.3 years.
      CONCLUSION: Distal PDSD should not be ignored. IP allows direct examination of
      the pancreatic duct system and facilitates complete removal of distal PDSD, which
      may be the cause of relapsing pancreatitis or pancreatolithiasis after radical
      surgery for CC.

PMID- 10646764
TI  - Long-term survival expectancy after liver transplantation in children.
AB  - PURPOSE: The aim of this study was to assess the long-term survival rate in
      children who have undergone orthotopic liver transplantation (OLT) in the last 13
      years. METHODS: The records of 198 consecutive patients under 18 years of age who
      underwent 249 OLTs between 1986 and 1998 were reviewed. Actuarial patient
      survival rates were assessed at 1, 3, 5, and 10 years in the whole series, in the
      last 5 years, and in patients surviving more than 1 year. Age, weight, and
      indications were analyzed, as well as type and incidence of posttransplant
      complications. The median follow-up period was 41 months (0 to 154 months).
      RESULTS: Biliary atresia was the most common indication (41.9%) followed by alpha
      1 antitrypsin deficiency (8.1%), Alagille syndrome (7.6%), and fulminant hepatic
      failure (6.6%). One hundred forty-six patients (58.6%) were below 5 years, and 46
      patients were (18.5%) younger than 1 year at operation. Sixty-eight patients
      (27.3%) weighed less than 10 kg. One hundred seventy whole organs and 70 reduced,
      5 living-related donor, and 4 split-liver allografts were used. Hepatic artery
      thrombosis (n = 18), primary nonfunction (n = 15), and chronic rejection (n = 14)
      were the most common causes for allograft failure. Fourteen patients (7%) had
      posttransplant lymphoproliferative disorders (PTLD) at a median time of 28 months
      (4 to 124 months) postoperation (3 died). The 1-, 3-, 5-, and 10-year actuarial
      patient survival rates are 80%, 76%, 74%, and 74%, respectively; over the last 5
      years it is 88% at 1 year and 82% at 3 and 5 years. For patients surviving more
      than 1 year, 3-, 5-, and 10-year actuarial survival rates are 95%, 93%, and 93%,
      respectively. CONCLUSIONS: (1) Overall results of OLT improve with increasing
      experience. (2) Children who survive more than 1 year after OLT have an excellent
      prognosis, although long-term complications of immunosuppression can be expected.

PMID- 10646766
TI  - Experience with the Rex shunt (mesenterico-left portal bypass) in children with
      extrahepatic portal hypertension.
AB  - BACKGROUND/PURPOSE: Extrahepatic portal vein thrombosis (EPVT) in children can
      lead to severe bleeding from gastrointestinal varices, ascites, thrombocytopenia
      from hypersplenism, and other coagulation disorders. The authors have used the
      superior mesenteric vein to intrahepatic left portal vein (Rex) shunt in 5
      children with symptomatic EPVT and report their results with this novel
      technique. METHODS: Children with symptomatic portal hypertension were screened
      for the underlying cause. All children with essentially normal livers and
      obstruction of the extrahepatic portal vein were considered for the Rex shunt.
      Evaluation included liver function tests, liver biopsy, and radiological
      evaluation of the intrahepatic vascular anatomy. RESULTS: Five patients between
      the ages of 2.8 and 10.5 years underwent evaluation for portal hypertension
      secondary to extrahepatic portal vein obstruction. Three patients had idiopathic
      extra hepatic portal vein thrombosis with cavernous transformation, 1 had
      thrombosis after a living-related liver transplant, and 1 had compression and
      obstruction of the main portal vein from enlarged lymph nodes after treatment of
      systemic histoplasmosis. All patients were symptomatic. Three patients had
      intermittent bleeding from esophageal and gastric varices, and all 5 had relative
      degrees of hypersplenism with enlarged spleens and thrombocytopenia (11,000 to
      77,000). Three patients had significant leukopenia. Results of imaging studies
      suggested that 3 patients had inadequate intrahepatic portal veins for shunting,
      but all patients at exploration underwent successful shunting. There were no
      serious intraoperative complications. Postoperative complications included
      ascites in 2 patients that resolved within 1 month. There were no early shunt
      thromboses. The median postoperative length of stay was 7 days. Clinical follow
      up ranged from 7 to 21 months. Gastrointestinal bleeding did not recur in any
      patient, and ascites resolved in all. Spleen size decreased significantly (P <
      .01) from 9.4 +/- 4.0 cm to 5.0 +/- 3.7 cm below the left costal margin. Mean
      platelet count and white blood cell count rose after shunting from 79 +/- 42 to
      176 +/- 73 (P < .02) and 5.4 +/- 2.3 to 7.5 +/- 3.9 (P = .06), respectively. All
      shunts were studied at 1 and 7 days, and 3 and 6 months after the procedure.
      Shunt patency was documented in all cases. Subsequently, shunt blockage occurred
      in 2 patients. CONCLUSIONS: The Rex shunt has proven to be an effective method of
      resolving portal hypertension caused by EPVT including thrombosis after living
      donor transplantation. This shunt is preferable to other surgical procedures
      because it eliminates portal hypertension and its sequelae by restoring normal
      portal flow to the liver.

PMID- 10646765
TI  - Cumulative experience with pediatric living related liver transplantation.
AB  - PURPOSE: This study reports the authors' cumulative experience with pediatric
      living related orthotopic liver transplantation. METHODS: The charts of all
      patients who received living-related liver transplantation to study complications
      of transplant surgery, immunosuppression, rejection, and overall survival rate
      were reviewed retrospectively. RESULTS: Between November 1992 and October 1998,
      30 children underwent living-related liver transplantation. Patients were between
      the ages of 3 months and 7 years of age (mean, 28 months). All received left
      lateral segmental living-related transplants. At the time of transplant, 14 of 30
      patients were listed as United Network of Organ Sharing (UNOS) status 3, 11 were
      listed as UNOS status 2B, and 5 were listed as UNOS status 1. Indications for
      transplant included biliary atresia (n = 21), alpha-1-antitrypsin deficiency (n =
      2), hepatitis C (n = 2), giant cell hepatitis (n = 2), hepatoblastoma (n = 1),
      valproic acid toxicity (n = 1), and hemangioendothelioma (n = 1). All donors were
      parents except for one uncle. There were no major donor complications. Minor
      complications included wound infection (n = 4), ventral hernia (n = 2),
      postoperative gastric dysmotility (n = 2), and 1 case of central line-related
      pneumothorax (n = 1). All but 4 recipients received primary tacrolimus
      immunosuppressive regimens, and the other 4 underwent conversion from
      cyclosporine. Initial tacrolimus therapy was begun at 0.15 mg/kg/dose PO/NG every
      12 hours. Concomitant immunosuppression included methylprednisolone and
      mycophenolate mofetil. Fifty-three percent of patients experienced at least 1
      episode of rejection, and 27% experienced multiple episodes. Immediate
      postoperative complications included primary nonfunction (n = 2), vascular
      thrombosis (n = 3), biliary leaks (n = 3), and infections (n = 17). Two patients
      (n = 2) required retransplantation. Complications of immunosuppressive therapy
      included persistent systemic hypertension (n = 6), renal tubular acidosis (n =
      3), short-term hyperglycemia (n = 2), neurotoxicity (n = 2), nephrotoxicity (n =
      2), food allergies (n = 8), and posttransplant lymphoproliferative disease (n =
      4). All patients with PTLD were treated with immunosuppression reduction or
      withdrawal. Two of 4 had disease progression requiring chemotherapy. The majority
      of complications were treated with dose adjustments. There were 4 early deaths
      (13%): 1 of primary nonfunction, 2 of sepsis, and 1 of arrhythmia and renal
      failure. There was 1 late death of recurrent disease. Twenty-five patients (83%)
      are alive at 3 months to 6 years post-transplant. CONCLUSION: Living-related
      orthotopic liver transplantation is an effective intervention for pediatric
      patients with end-stage disease.

PMID- 10646767
TI  - The role of apoptosis during intestinal adaptation after small bowel resection.
AB  - BACKGROUND/PURPOSE: Adaptation after small bowel resection (SBR) is characterised
      by a new set point in the balance of enterocyte proliferation and apoptosis.
      Apoptosis is gene directed. The authors hypothesised that the adaptive response
      is influenced positively by antiapoptotic gene products (eg, bcl-2 gene-produced
      protein). The authors tested this hypothesis by studying the effect of bcl-2
      overexpression on intestinal adaptation after SBR. METHODS: Male bcl-2 transgenic
      mice, overexpressing bcl-2 in the small intestinal epithelium, and wild type
      control mice underwent either a 75% mid-SBR, or a sham operation. The 4
      experimental groups consisted of resection wild type (n = 8), transection wild
      type (n = 6), resection bcl-2 transgenic (n = 8), and transection bcl-2
      transgenic (n = 8). Seven days postoperatively small bowel was harvested; total
      weight, mucosal weight, and mucosal protein, DNA, and RNA content in jejunal and
      ileal tissue were determined to quantitate the hyperplastic response. RESULTS:
      Compared with sham-operated animals, SBR resulted in increased total jejunal
      weight; mucosal weight; and mucosal protein, DNA, and RNA content. Furthermore,
      in the SBR groups, the jejunal mucosal weight and mucosal protein and DNA content
      were significantly higher in the bcl-2 transgenic mice compared with the wild
      type mice. No differences were observed between any of these parameters in the
      transection wild-type and transgenic mice. In the ileum, similar changes were
      observed. The differences between resected and transected wild-type mice were
      less pronounced, and only total ileal weight and mucosal protein content reached
      statistical significance. In the transgenic animals, all ileal variables, with
      the exception of mucosal RNA content, were significantly higher in the SBR group
      than in the transected group. SBR in the transgenic mice resulted in higher ileal
      mucosal weight and mucosal protein, DNA, and RNA content compared with the wild
      type mice. CONCLUSIONS: The results show that the murine SBR model is a true
      representation of the process of adaptation after SBR. Furthermore, major
      components of the adaptive response, both in the jejunum and in the ileum, are
      significantly more pronounced in the bcl-2 transgenic mice than in the wild-type
      control animals. Thus, it can be concluded that intestinal hyperplasia after SBR
      is significantly enhanced by overexpression of the anti-apoptotic bcl-2 gene
      product. This finding should prompt further research on the effects of
      antiapoptotic interventions on adaptation after SBR.

PMID- 10646768
TI  - Time-dependent effects of endothelin-3 on enteric nervous system development in
      an organ culture model of Hirschsprung's disease.
AB  - BACKGROUND/PURPOSE: Terminal colonic aganglionosis (Hirschsprung disease) results
      from incomplete rostrocaudal colonisation of the embryonic gut by neural crest
      cells (NCC). Mutations in the genes encoding endothelin-3 (EDN3) or its receptor
      (EDNRB) have been shown to result in a similar aganglionosis. This article
      describes the development of an organ culture model using embryonic murine gut to
      determine how endothelin-3 regulates development of the enteric nervous system.
      METHODS: Gut explants from mice of different gestational ages were cultured for
      up to 3 days in the presence or absence of 5 micromol/L of the specific
      endothelin-B receptor antagonist BQ788. EDN3 and EDNRB mRNA expression were
      analysed by reverse-transcription polymerase chain reaction (RT-PCR) and whole
      mount in situ hybridisation. NCC were localised using immunoreactivity for PGP
      9.5, a specific neuronal marker. RESULTS: EDN3 mRNA continued to be expressed by
      caecal mesenchymal cells and EDNRB mRNA by the migrating NCC in culture.
      Embryonic day (E)11.5 explants were already colonised by NCC up to the terminal
      ileum. Complete colonisation occurred in organ culture over the next 72 hours
      (equivalent to E 14.5). Explants of E 12.5 and E 13.5 showed complete
      colonisation after 48 and 24 hours culture, respectively. Terminal aganglionosis
      resulted from treatment of E 11.5 and E 12.5 gut explants with 5 micromol/L
      BQ788, whereas there was no inhibitory effect on E 13.5 explants. CONCLUSIONS: An
      organ culture model has been developed in which NCC colonisation of embryonic gut
      mirrors that described in vivo. Blockade of the EDN3/EDNRB receptor pathway shows
      that the interaction of endothelin-3 with its receptor is only necessary for NCC
      colonisation at early time-points, despite the continued expression of endothelin
      3 mRNA in the gut.

PMID- 10646769
TI  - Anti-VEGF antibody suppresses primary tumor growth and metastasis in an
      experimental model of Wilms' tumor.
AB  - BACKGROUND/PURPOSE: Vascular endothelial growth factor (VEGF) has been shown
      previously to correlate with tumor growth and metastasis in an experimental model
      of anaplastic Wilms' tumor. The authors hypothesized that treatment with anti
      VEGF antibodies would suppress both primary tumor growth and metastasis in this
      model. METHODS: Tumors were induced in the right kidneys of nude mice by the
      injection of cultured Wilms' tumor cells. After 1 week, anti-VEGF treatment was
      begun with injection of either vehicle or an anti-VEGF antibody
      intraperitoneally. Mice were killed after 4.5 weeks of treatment and tumor
      weights and the incidence of metastases evaluated. RESULTS: Anti-VEGF treatment
      resulted in a greater than 95% reduction in tumor weight (P < .0001). Anti-VEGF
      treatment also abolished the establishment of lung metastases (40% in control
      animals, P < .003). Cessation of treatment resulted in rebound tumor growth.
      CONCLUSION: Anti-VEGF therapy can suppress both primary tumor growth and the
      establishment of metastases in experimental anaplastic Wilms' tumor.

PMID- 10646770
TI  - The effect of asphyxia on superior mesenteric artery blood flow in the premature
      sheep fetus.
AB  - BACKGROUND/PURPOSE: The aim of this study was to determine superior mesenteric
      artery blood flow changes during and after an asphyxial insult in utero in
      chronically instrumented unanaesthetised premature fetal sheep. METHODS: Fetal
      sheep at 0.7 gestation (103 to 104 days) underwent 25 minutes of complete
      umbilical cord occlusion (n = 6) or sham occlusion (n = 6). Fetal heart rate,
      blood pressure, superior mesenteric artery (SMA) blood flow and vascular
      resistance, electroencephalographic activity, and nuchal electromyographic
      activity were measured from 6 hours before occlusion until 3 days after
      occlusion. Fetal gastrointestinal tissue was taken for histological assessment.
      RESULTS: During occlusion, cardiovascular response was characterised by 3 phases:
      initial redistribution of blood flow away from the gut to maintain vital organ
      function, subsequently partial failure of this redistribution, and finally near
      terminal cardiovascular collapse with profound hypotension and gastrointestinal
      hypoperfusion. Postasphyxia there was a secondary period of hypoperfusion that
      was mediated by increased vascular resistance, not hypotension. There was no
      evidence of injury on standard histological assessment after 3 days of recovery.
      CONCLUSIONS: SMA blood flow is not only significantly reduced during asphyxia,
      but also for several hours after an asphyxial insult. The authors speculate that
      these perturbations of gastrointestinal blood flow could compromise gut wall
      integrity potentially leading to increased vulnerability to necrotising
      enterocolitis.

PMID- 10646771
TI  - Detection of intestinal bacterial translocation in subclinical ischemia
      reperfusion using the polymerase chain reaction technique.
AB  - BACKGROUND/PURPOSE: The purpose of this study was to evaluate the detection of
      bacterial translocation after subclinical ischemia reperfusion injuries in rats
      with the polymerase chain reaction (PCR) technique. METHODS: Six-week-old weaning
      rats were divided into 3 groups. (1) Experiment rats (n = 20) were gavaged with
      10(10) Escherichia coli followed by superior mesentery artery occluded for 10
      minutes, then reperfused for 30 minutes. (2) Control rats (n = 20) received
      bacterial gavage. (3) Group 3 were sham rats (n = 20). After the procedure, 3 mL
      of blood was obtained from the portal vein. The terminal ileum and mesenteric
      lymph node (MLN) near the terminal ileum were removed. E. coli DNA was detected
      in blood and MLN samples by PCR, and histological changes were examined. RESULTS:
      E. coli DNA detection in ischemia-reperfusion (I/R) group animals was 6 of 20
      (30%) in the MLN and 2 of 20 (10%) in the blood. PCR was negative in all the rats
      in the control group and in the sham group (P < .05). There were no significant
      differences in the histological examination of rat intestines. CONCLUSION: These
      data suggest that subclinical intestinal I/R injury results in bacterial
      translocation. Also, PCR is a highly sensitive and rapid method to detect the
      presence of microbial DNA.

PMID- 10646772
TI  - Nitric oxide inhibits neonatal hepatocyte oxidative metabolism.
AB  - BACKGROUND/PURPOSE: Liver function is frequently impaired in neonates with
      sepsis. Nitric oxide (NO) is thought to be a mediator of organ dysfunction and
      liver oxidative metabolism during sepsis. The authors developed an in vitro model
      to investigate the effect of NO and the combined effect of NO plus H2O2 on
      neonatal hepatocyte oxidative metabolism. METHODS: Hepatocytes were isolated from
      neonatal rats. Oxygen consumption was measured polarographically. In Study A,
      cells were exposed to S-Nitroso-N-acetylpenicillamine (SNAP), an NO donor, at
      various concentrations. In study B, myxothiazol and oligomycin, inhibitors of
      mitochondrial respiration, were added to investigate the site of action of NO. In
      study C, hepatocytes were incubated in the presence of both SNAP (300 micromol/L)
      and H2O2 (1.5 mmol/L). In study D, morphological alterations induced by NO and NO
      plus H2O2 were investigated by hepatocyte electron microscopy. RESULTS: In study
      A, SNAP caused a dose-dependent decrease in oxygen consumption. A significant
      inhibition was reached at 300 micromol/L SNAP. In study B, the lack of further
      inhibition when SNAP was given together with myxothiazol indicates that NO acts
      intramitochondrially. Similarly, no further inhibition occurred when the NO donor
      was given together with oligomycin, suggesting that the effect of NO is mainly at
      the level of ATP synthase. In study C, concomitant addition of 300 micromol/L
      SNAP and 1.5 mmol/L H2O2 to hepatocytes caused further inhibition of oxygen
      consumption compared with either SNAP or H2O2 alone. In study D, mild alterations
      in hepatocyte morphology were noted in the presence of SNAP or SNAP plus H2O2.
      CONCLUSIONS: In neonatal hepatocytes, NO significantly inhibits mitochondrial
      oxygen consumption, possibly at the level of ATP synthase. The effect of NO is
      additive to that of H2O2. Morphological findings were consistent with these
      biochemical effects and suggest that NO and H2O2 are important mediators of liver
      damage during sepsis.

PMID- 10646773
TI  - Effect of repetitive asphyxia on leukocyte-vessel wall interactions in the
      developing chick intestine.
AB  - BACKGROUND/PURPOSE: Information on leukocyte-vessel wall interactions (LVWI)
      during development of the immature intestine is scarce. The authors designed an
      experimental model for studying the microcirculation in the developing intestine
      of chick fetuses at days 13 (n = 12), 15 (n = 17), and 17 (n = 19) of incubation
      (0.6, 0.7, and 0.8 of the incubation time, respectively) using intravital
      microscopy. METHODS: The authors investigated whether episodes of asphyxia
      increase LVWI and induce tissue damage in the developing intestine. Asphyxia was
      induced by clamping of the chorioallantoic vein for 6 periods of 5 minutes each,
      with 5-minute intervals, whereas in sham groups a sham procedure was performed.
      Video recordings were made before as well as 10, 20, and 30 minutes after the end
      of the asphyxia or sham protocol. RESULTS: Baseline number of rolling leukocytes
      per minute significantly increased (P < .001) from 0 at 0.6 incubation to 1.5 and
      to 4 at 0.7 and 0.8 incubation time, respectively. At 0.6 and 0.7 incubation no
      adherent leukocytes were observed under baseline conditions, whereas at 0.8
      incubation single leukocytes adhered to the venular wall. LVWI variably increased
      during the course of the experiments. Asphyxia neither enhanced LVWI nor induced
      histological damage in the intestine. CONCLUSIONS: These findings indicate that
      (1) leukocyte-vessel wall interactions mature during fetal development, and (2)
      repetitive episodes of asphyxia induce neither an inflammatory response nor
      histological tissue injury in the developing intestine from 0.6 to 0.8
      incubation. The authors hypothesize that immaturity of leukocyte-vessel wall
      interactions, as part of the nonspecific host defense to invading bacteria, might
      play a role in the development of necrotizing enterocolitis in premature
      neonates.

PMID- 10646774
TI  - The management of oesophageal atresia in neonates with right-sided aortic arch.
AB  - BACKGROUND/PURPOSE: The management of oesophageal atresia (OA) in association
      with a right-sided aortic arch (RAA) is challenging. It is controversial whether
      right or left thoracotomy is the most appropriate surgical approach. The aim of
      this study was to determine the prevalence of RAA in patients with OA and the
      most appropriate surgical approach. METHODS: The case records of all the neonates
      with OA treated over an 18-year period (1980 through 1997) were reviewed.
      Patients with RAA were analysed with particular reference to the preoperative
      investigations, operative approach and findings, and postoperative complications.
      RESULTS: Of the 476 case notes reviewed, 12 (2.5%) had a RAA, and 5 of these
      infants had major cardiac anomalies. The diagnosis was not suspected on
      preoperative chest x-ray in any of these infants. In only 1 of the 5 neonates who
      had a preoperative echocardiogram was RAA suspected. A right thoracic approach
      was performed in the 11 infants in whom a RAA was not suspected. Immediate
      conversion to a left thoracotomy with primary anastomosis was carried out in 2
      infants. In 2 further infants, fistula ligation alone was performed because of a
      long gap atresia. Anastomosis via the right thoracotomy was performed in 7
      infants. There were 3 anastomotic leaks, 1 intractable stricture, and 1 recurrent
      fistula. Three patients (25%) had a double aortic arch, and, as a result, a left
      thoracotomy had to be abandoned in 2. There were 3 deaths, 2 as a result of major
      cardiac anomalies and 1 related to prematurity and sepsis. CONCLUSIONS: RAA
      occurs in 2.5% of infants with OA. Preoperative chest x-ray and echocardiogram
      are unreliable as diagnostic modalities. Anastomosis via a right thoracotomy is
      associated with a 42% leak rate. The presence of a double aortic arch can make
      the oesophageal anastomosis via a left thoracotomy as difficult as via a right
      thoracotomy.

PMID- 10646775
TI  - A longitudinal study of electrogastrography in normal neonates.
AB  - BACKGROUND/PURPOSE: Gastric motility is partly regulated by an inherent electric
      control activity (ECA). Electrogastrography (EGG) measures gastric ECA through
      cutaneous electrodes. Little is known about EGG in neonates. A slow wave
      frequency of 3 cycles per minute (cpm) accounts for 85% to 100% of gastric ECA in
      normal adults and children. However, the authors have shown previously a lower
      percentage of 3 cpm activity in neonates. Abnormal EGG patterns (tachygastria and
      bradygastria) have been described in adults and children with gastric motility
      disorders. In neonates, especially premature infants, disorders of
      gastrointestinal motility are common, especially after gastrointestinal
      operations. It is necessary to characterise normal ECA before the pathophysiology
      of these disorders can be studied. The aim of this study was to investigate the
      pattern of ECA in the developing neonate. METHODS: Nine healthy neonates born at
      34 weeks' gestation were studied using Synectics EGG sampling at 4 Hz. Each
      subject underwent 4 hourly EGG recordings at fortnightly intervals from birth
      until age 8 weeks, and then every 2 months until age 2 years. The paired sample t
      test (95% Confidence Interval [CI]) was used to compare recordings. RESULTS:
      Between birth and age 2 years, 3 cpm activity increased from 38% to 57% of
      recorded time. The mean percentage recorded time of tachygastria decreased from
      47% to 35%, and bradygastria decreased from 15% to 8%. Statistically significant
      differences were seen between birth, 6 months, and 2 years of age. CONCLUSIONS:
      The pattern of ECA in the normal neonatal stomach differs from that seen in adult
      studies. Tachygastria and bradygastria are seen more frequently, with fewer
      periods of 3 cpm. There is an increase in the percentage of 3 cpm activity over
      time, with statistically significant differences from the ECA pattern at birth
      first seen at the age of 6 months. The authors suggest that neonatal ECA
      undergoes a maturation process and that larger longitudinal and normal range
      studies are required to investigate this phenomenon.

PMID- 10646776
TI  - Is the 13C-acetate breath test a valid procedure to analyse gastric emptying in
      children?
AB  - BACKGROUND/PURPOSE: Scintigraphy is regarded as the "gold standard" procedure in
      measuring gastric emptying (GE) rates. 13C-acetate breath test (ABT), which
      already has been validated in adults, is a noninvasive and nonradioactive
      alternative method. The aim of the current study was to validate ABT against
      technetium Tc 99m scintigraphy in children affected by delayed GE. METHODS: Sixty
      children were recruited and divided into 2 groups: group A, 30 healthy controls;
      group B, 30 patients with gastroesophageal reflux, and scintigraphy-documented
      DGE (15 neurologically impaired). After an overnight fast, all of them underwent
      ABT using 25 to 150 mg 13C-acetate. Breath samples were obtained at baseline and
      then every 10 minutes for 2 hours. The 13CO2 to 12CO2 ratio in breath samples was
      analysed by isotope ratio mass spectrometry. Data are expressed as follows: time
      of peak 13C exhalation (tP13CO2b) and half emptying time in ABT (t(1/2b)), and
      scintigraphy half emptying time (t(1/2s)). RESULTS: In controls tP13CO2b was 37
      +/- 13 minutes and t(1/2b) 74 +/- 12 minutes. In patients tP13CO2b and t(1/2b)
      were, respectively, 65 +/- 26 minutes and 104 +/- 18 minutes t(1/2s) was 91 +/-
      21 minutes. In group B tP13CO2b and t(1/2b) were delayed significantly compared
      with controls, respectively, P < .03 and P < .01. In group B significant
      correlation between t(1/2s) and t(1/2b) was noted (r1 = 0.97). A close
      correlation was also observed between t(1/2s) and tP13CO2b (r2 = 0.95).
      CONCLUSION: The 13C ABT is an easy, reliable, and less expensive procedure for
      measuring GE, and its results closely correlate with those of scintigraphy in a
      paediatric population.

PMID- 10646777
TI  - Changing profile of abdominal wall defects in Japan: results of a national
      survey.
AB  - BACKGROUND/PURPOSE: The incidence of gastroschisis has increased over the past 3
      decades in a number of countries. To elucidate the Japanese status of anterior
      abdominal wall defects, the Japanese Society of Pediatric Surgeons conducted a
      national survey in Japan. METHODS: Information was obtained by sending out a
      questionnaire to 192 University Hospitals, Children's hospitals, and general
      hospitals that each had more than 200 beds. The characteristics of the patients
      including the birth date, birth weight, gestations, rate of associated anomalies,
      rate of antenatal diagnosis and prognosis, maternal age, gravidity, history of
      smoking, and drug use were analyzed. RESULTS: The authors obtained answers from
      149 institutions, including 1,785 cases of omphalocele and 970 cases of
      gastroschisis, which were treated between 1975 to 1997. There was a significant
      increase in the incidence of gastroschisis, from 0.131 in 1975 to 1980, 0.269 in
      1981 to 1985, 0.337 in 1986 to 1990, 0.461 in 1991 to 1995 to 0.467 per 10,000
      births in 1996 to 1997. The incidence of omphalocele was 0.322 in 1975 to 1980,
      0.567 in 1981 to 1985, 0.657 in 1986 to 1990, 0.741 in 1991 to 1995 to 0.626 per
      10,000 births in 1996 to 1997, respectively. In the omphalocele group, 43.1% of
      the mothers were between 25 to 29 years of age, whereas in the gastroschisis
      group 42.6% of the mothers were 20 to 24 years of age. In the gastroschisis
      group, the number of primipara mothers was larger than that of multipara mothers.
      In the omphalocele group, approximately 10% of the mothers smoked during each
      period, whereas in the gastroschisis group, the percentage of smoking mothers
      increased chronologically from 12.9% in 1981 to 1985, 18.7% in 1986 to 1990,
      23.5% in 1991 to 1995 and 29.3% in 1996 to 1997. A history of drug use by the
      mother was approximately 10% for both the omphalocele and gastroschisis groups.
      In the omphalocele group, 55.9% had associated anomalies against 21.8% in the
      gastroschisis group. Approximately 10% in the omphalocele group and less than 3%
      in the gastroschisis group showed chromosomal abnormalities. From 1986, a
      significant number of cases detected antenatally has been observed. CONCLUSIONS:
      There have been substantial changes in the incidence of anterior abdominal wall
      defects, particularly regarding gastroschisis in Japan. The reasons for such
      changes are most likely multifactorial, further epidemiological monitoring is
      thus called for.

PMID- 10646778
TI  - The management of exomphalos.
AB  - BACKGROUND/PURPOSE: The management of exomphalos in the authors' department over
      a 26-year period is reported together with a technique for delayed closure of the
      ventral hernia resulting from conservative treatment of exomphalos major.
      METHODS: Patients were classified into exomphalos minor and major. Exomphalos
      minor was treated by early surgical closure. Exomphalos major was treated
      preferentially conservatively with delayed repair of the ventral hernia. RESULTS:
      There were 104 patients (68 boys and 36 girls; exomphalos minor, 45; exomphalos
      major, 59). Forty-two patients with exomphalos minor underwent operation. Three
      patients died before surgery, and 9 others postoperatively of overwhelming
      sepsis. Fifteen babies with exomphalos major needed early operation (skin closure
      only in 3 and prolene mesh repair in 12), there were 2 preoperative and 4
      postoperative deaths. Forty-two patients were treated conservatively, among
      these, 8 died of sepsis. Thirty-four children had closure of the ventral hernia
      (prolene mesh, 7 and native tissue, 27); there was no morbidity. Two children
      died after laparotomy for adhesive intestinal obstruction. CONCLUSION: Mortality
      rate was related to sepsis, complications of delayed presentation, and severe
      congenital anomalies. There were no ill effects attributable to mercury or iodine
      absorption. Delayed ventral hernia repair by double breasting of the fibrous
      tissue sheet underlying the skin was found to be a reliable technique with low
      morbidity.

PMID- 10646779
TI  - Fusion of childhood inguinal hernia induced by HGF and CGRP via an epithelial
      transition.
AB  - BACKGROUND/PURPOSE: Recent evidence has suggested that calcitonin gene-related
      peptide (CGRP), which is released from the genitofemoral nerve, may trigger
      fusion of the patent processus vaginalis in children with inguinal hernia. The
      purpose of this study was to determine whether CGRP triggers the release of
      mesenchymal factors leading to subsequent fusion of the processus vaginalis.
      METHODS: The response of cultured epithelial cells derived from the patent
      processus vaginalis was analysed by a novel in vitro culture system. Epithelial
      cells lining fresh hernial sacs (removed at inguinal herniotomy) were detached
      enzymatically and cultured for 72 hours on Micropore filters, in the presence of
      either 100 ng/mL hepatocyte growth factor (HGF), 7.4 x 10(-6) mol/L CGRP (amino
      acids 1 to 37), 7.4 x 10(-6) mol/L CGRP (8 to 37) antagonist, 10% fetal calf
      serum (FCS), or serum-free medium (SFM) alone. Transformation from an epithelial
      cell morphology to motile mesenchymal fibroblast-like cells was assessed by an
      average migration score (AMS), ranging from 0 with no sign of migration, to 3
      with greater than 75% of cells migrating. Confocal microscopy was used to record
      changes in expression of epithelial (cytokeratin) and mesenchymal (vimentin)
      markers, as well as actin. Beta-catenin also was examined because it is part of
      the molecular complex that links cadherins to actin resulting in cell-cell
      adhesion. RESULTS: Epithelial and mesenchymal markers underwent either down
      regulation or up-regulation as epithelial cell sheets broke apart and individual
      cells commenced migration. The AMS after 72 hours of culture was 0.22 with SFM
      (control); with FCS the score was 1.4 (P < .01). The AMS score with CGRP (1 to
      37) was 0.55 (P = .165) and with its analogue, CGRP (8 to 37), which is a
      competitive inhibitor, 0.67 (P = .309). Neither was significant. HGF caused a
      significant increase in the AMS to 1.56 (P = .01). CONCLUSION: Both HGF and FCS
      (which contains various undefined peptides and growth factors) produced
      transformation of hernial sac epithelial cells, whereas CGRP and its inactive
      analogue did not. CGRP receptors are localised to mesenchymal fibroblasts within
      the processus vaginalis connective tissue, suggesting that CGRP could act
      indirectly via HGF, which, in turn, promotes fusion of the processus vaginalis.
      In the future, a nonsurgical treatment of inguinal herniae in children might be
      possible by the local administration of agents which promote fusion.

PMID- 10646780
TI  - Prehospital triage in the injured pediatric patient.
AB  - BACKGROUND/PURPOSE: Identifying major trauma patients in the prehospital setting
      is essential in determining management, destination, and best utilization of
      emergency department resources. Few methods of trauma triage have been accepted
      unanimously. This study prospectively evaluates the efficacy of comprehensive
      field triage using 12 criteria (simplified version of the American College of
      Surgeon's guidelines) in 1,285 pediatric trauma patients. METHODS: Major trauma
      was defined as occurring in those who died in the emergency room, had major
      surgery (penetrating injury involving surgery of the head, neck, chest, abdomen,
      or groin), or were admitted directly to the intensive care unit. The correlation
      between trauma triage criteria, hospital disposition, and triage accuracy were
      determined prospectively and compared in the pediatric patients (36 months) with
      an adult cohort of patients (12 months). RESULTS: A total of 1,285 pediatric
      trauma patients were evaluated and compared with 1,326 adult trauma patients. The
      most accurate trauma triage criterion for major injury was a blood pressure < or
      = 90 mmHg (systolic) with an accuracy of 86%. This was followed by burn greater
      than 15% total body surface area (79%), Glasgow Coma Scale score < or = 12 (78%),
      respiratory rate less than 10/min or greater than 29/min (73%), and paralysis
      (50%). Less accurate criteria included a fall from greater than 20 feet (33%);
      penetrating injury to head, neck, chest, abdomen, or groin (29%); ejection from
      vehicle (24%); pedestrian struck at greater than 20 mph (16%); paramedic
      judgement (12%); rollover (3%); and extrication (0%). The Glasgow Coma Scale
      score was a more accurate indicator of major injury in children than adults, and
      paramedic judgement was less accurate in children when compared with adults. Of
      the 379 major pediatric trauma victims, the Revised Trauma Score and Pediatric
      Trauma Score missed 36% and 45% of these major trauma victims, respectively. The
      overtriage rate for children was 71% with a sensitivity of 100% (no missed major
      trauma patients). CONCLUSIONS: Physiological variables, anatomic site, and
      mechanism of injury provide a sensitive and safe system of triage. Continued
      education of prehospital personnel regarding pediatric trauma and stratification
      of the current triage tools are necessary to minimize overtriage in an era of
      shrinking resources.

PMID- 10646781
TI  - Features and outcome of neuroblastoma detected before birth.
AB  - BACKGROUND/PURPOSE: The growing use of routine ultrasonography during pregnancy
      is leading to an increasing number of prenatally diagnosed neuroblastomas.
      Optimal strategy has not yet been defined for these patients, because knowledge
      on this particular neuroblastoma (NB) population is still limited. However,
      definite guidelines are needed to avoid inadequate treatment. The authors
      analyzed the cases of antenatally detected NB (ADNB) reported in the Italian
      Neuroblastoma Registry during the past 6 years to elucidate the features of this
      subset of NB. METHODS: The Italian Neuroblastoma Registry was reviewed for the
      period January 1993 to December 1998 to collect clinical, radiographic, surgical,
      and histopathological data on ADNB cases. NB stage was evaluated according to
      INSS criteria. All patients had undergone imaging (computed tomography or
      magnetic resonance imaging) of the primary tumor and bone marrow biopsy before
      surgical resection. RESULTS: Seventeen patients were identified. Primary tumour
      site was adrenal glands in 16 cases and retroperitoneal ganglia in 1. Stage
      distribution was stage I, 13 cases; stage II-A, 1 case; stage II-B, 1 case; stage
      IV-S, 2 cases. All cases underwent primary tumour resection. Mean age at surgery
      was 4 weeks. Resection of primary tumor was radical in 16 cases, partial in 1.
      All tumors were characterised by favourable histology according to Shimada
      classification. N-myc gene amplification was studied in 14 patients. N-myc
      amplification was detected only in a newborn with stage II-A NB, who died of
      massive bleeding 2 days after tumor resection. DNA index and 1p deletion were
      studied in 11 and 8 patients, respectively. Both diploidy and deletion of 1p were
      observed in a newborn who subsequently died of disease progression despite
      surgery, chemotherapy, and radiation therapy. Fourteen of 17 patients currently
      are alive and free of disease, and one with IV-S NB and short follow-up is alive
      with disease. CONCLUSIONS: Our data give evidence that in most cases infants with
      ADNB represent a subset of patients with excellent outcome. Aggressive treatment
      may not always be necessary. Infants with ADNB with unfavorable features should
      undergo early surgical excision, whereas patients with favourable features could
      be observed awaiting spontaneous regression of the mass, reserving delayed
      surgery for tumors that increase in size or do not regress.

PMID- 10646782
TI  - Analysis of the prognostic factors relating to better clinical outcome in
      ganglioneuroblastoma.
AB  - PURPOSE: To elucidate the precise reason for the better prognosis in
      ganglioneuroblastoma (GNB) than in neuroblastoma (NB), the prognostic factors
      (age at diagnosis, stage at diagnosis, primary site, N-myc amplification, Shimada
      classification, and ploidy) were analyzed. METHODS: A retrospective analysis of
      the 57 neuroblastoma cases (20 GNB cases and 37 NB cases), that had not been
      detected by mass screening over the past 19 years at the authors' institute, was
      carried out. RESULTS: A Kaplan-Meier analysis of the 5-year survival rates were
      67.2% and 35.1% in cases of GNB and NB, respectively, and these rates were
      significantly higher in GNB (logrank test; P = .04631). No significant
      differences were seen between GNB and NB regarding the rate in patients 1 year of
      age or older (95.0% v 78.4%; P = .1005), the rate of advanced cases (60.0% v
      78.4%, P = .1406), the rate of an unfavorable histology (Shimada classification,
      54.5% v 68.4%, P = .4473), or the diploid pattern rate (75.0% v 76.9%, P =
      .9200). However, N-myc amplification was found exclusively in NB (amplified cases
      per examined cases; 15/31), and all cases with N-myc amplification died. When the
      5-year survival rate was evaluated in the patient without N-myc amplification
      between GNB and NB, no significant difference was observed (logrank test; P =
      .8568). CONCLUSION: The better prognosis in patients with GNB was thus thought to
      be exclusively related to an absence of N-myc amplification.

PMID- 10646783
TI  - Does the sensory nucleus of the genitofemoral nerve have a role in testicular
      descent?
AB  - BACKGROUND/PURPOSE: A role for the genitofemoral nerve (GFN) and its
      neurotransmitter, CGRP, in testicular descent has been well established. The
      exact mechanism, however, by which circulating androgens act on the GFN is not
      yet known. The authors studied the sensory nucleus of the GFN (L1-L2 dorsal root
      ganglia [DRG]) to determine whether it is sexually dimorphic and able to be
      influenced by intrauterine antiandrogen treatment. METHODS: Sprague-Dawley rats
      were injected daily with 100 mg/kg/d of the antiandrogen flutamide on day 16 to
      19 of pregnancy. Control animals were treated with vehicle only. At the age of 2
      to 3 days the newborn rats underwent unilateral dissection of the GFN. The
      proximal end was labelled with fluorescent dye, diamidinophenyl indole. The rats
      were killed 48 hours later, and the relevant ganglia (L1,L2) were removed.
      Cryostat frozen serial sections were cut, and retrogradely labelled fluorescent
      cells were counted under an epifluorescence microscope. In 32 animals, the cells
      were double fluorescent labelled with antibody to CGRP and FITC. RESULTS: Of 75
      rats evaluated, the mean number of the DAPI-positive, retrogradely labelled cells
      in the control groups was 266 +/- 55 in the male, and 230 +/- 67 in the female as
      opposed to 186 +/- 45 and 161 +/- 35 in the flutamide-treated male and female
      groups, respectively. In 32 animals the DRG sections were double labelled for
      CGRP. The number of CGRP plus DAPI-positive cells were as follows: control males,
      60 +/-12; control females, 50 +/- 9; flutamide males, 36 +/- 8; flutamide
      females, 40 +/- 10. CONCLUSIONS: These findings show a sexual dimorphism in the
      number of GFN cell bodies in the DRG. Flutamide decreases the number of GFN cell
      bodies in the DRG of both males and females. Our results are consistent with a
      role for circulating androgens acting on the sensory nucleus of the GFN (DRG)
      instead of the motor nucleus as previously thought. The release of CGRP from the
      nerve endings may occur via the sensory branch of the GFN.

PMID- 10646784
TI  - The role of nitric oxide in testicular ischemia-reperfusion injury.
AB  - PURPOSE: This study was designed to determine the role of nitric oxide (NO) in
      the ischemia-reperfusion (I/R) injury process in testes. METHODS: Fifty
      prepubertal male rats were divided into 5 groups each containing 10 rats. After 4
      hour torsion and 4-hour detorsion, bilateral orchiectomies were performed for
      measurement of tissue malondialdehyde (MDA) level and histopathologic
      examination. The results were compared statistically. The groups were labeled as
      group 1, basal values of biochemical parameters in testes; group 2 (control
      group), torsion plus detorsion; group 3, torsion plus N-monomethyl-L-arginine (L
      NMMA) plus detorsion; group 4, torsion plus L-arginine plus detorsion; group 5,
      sham operation. RESULTS: The highest MDA values were determined in the L-arginin
      group in ipsilateral testes. Group 3 and group 4 were statistically different
      from control group. Histological examination showed that specimens from group 4
      had a significantly (P < .05) greater histological injury than group 3, and
      contralateral testes showed normal testicular architecture in all groups.
      CONCLUSIONS: These results suggest that NO plays an important role in damaging
      the testis with I/R. Although inhibition of NO synthesis with L-NMMA
      significantly improves I/R injury in testes, enhancing NO production by providing
      excess of L-arginine increases such damage. In the early periods of detorsion,
      there is no damage to contralateral testes after unilateral testicular torsion.

PMID- 10646785
TI  - Histology of the neobladder mucosa after sigmoidocolocystoplasty.
AB  - PURPOSE: The aim of this study was to examine the histopathology of neobladder
      mucosa biopsy specimens obtained routinely as part of postsigmoidocolocystoplasty
      (SCP) follow-up. METHODS: One hundred cases of SCP (mean age at surgery, 10.6
      years) performed by the authors were examined for the presence of dysplasia or
      malignant changes in the mucosa of the neobladder using H&E and proliferating
      cell nuclear antigen (PCNA) staining. RESULTS: No dysplastic or malignant changes
      were identified in any case. Metaplasia was found in 5 cases and hyperplasia in
      2. There were no major differences found on H&E and PCNA staining of specimens
      obtained after different periods of follow-up post-SCP; follow-up was short term
      (up to 5 years) in 44 cases, medium term (from 5 to 10 years) in 48 cases, and
      long term (over 10 years) in 8 cases. PCNA staining was significantly more
      intense in subjects who stopped regular bladder irrigations (BI) post-SCP and in
      subjects in whom bladder stones developed (P < .05; Welch's t test), compared
      with subjects who continued BI and subjects in whom bladder stones did not
      develop. CONCLUSIONS: After SCP, patients are advised to continue BI. Regular
      biopsies should be part of routine follow-up, especially in subjects with bladder
      stones.

PMID- 10646786
TI  - Administration of antenatal glucocorticoids upregulates peptide growth factor
      gene expression in nitrofen-induced congenital diaphragmatic hernia in rats.
AB  - BACKGROUND/PURPOSE: There is increasing evidence to suggest that various growth
      factors play a crucial role in fetal lung growth and morphogenesis. An array of
      peptide growth factors regulate cell proliferation, differentiation, and various
      other cell functions in the developing lung. The aim of this study was to
      investigate the effect of antenatal glucocorticoids administration on gene
      expression of basic fibroblast growth factor (bFGF), platelet-derived growth
      factor (PDGF) and transforming growth factor (TGF)-beta1 in nitrofen-induced
      congenital diaphragmatic hernia (CDH) in rats. METHODS: A CDH model was induced
      in pregnant rats after administration of nitrofen. Dexamethasone (Dex; 0.25
      mg/kg) was given intraperitoneally on day 18.5 and 19.5 of gestation (term, day
      22). Cesarean section was performed on day 21 of gestation. mRNA was extracted
      from left lung and reverse transcription-polymerase chain reaction (RT-PCR) was
      performed to evaluate mRNA expression of each growth factors. Relative levels of
      mRNA were expressed as a ratio of the band density divided by that of beta-actin,
      a housekeeping gene known to be expressed at a constant level. RESULTS: Relative
      mRNA levels of bFGF and TGF-beta1 were decreased significantly in CDH lung
      compared with controls. Antenatal Dex treatment up-regulated gene expression of
      bFGF, PDGF, and TGF-beta1 in the hypoplastic CDH lung. CONCLUSIONS: The authors'
      findings suggest that decreased gene expression of bFGF, PDGF, and TGF-beta1 in
      the CDH lung may suppress lung growth and development. Increased gene expression
      of bFGF, PDGF, and TGF-beta1 in Dex-treated lung suggests that antenatal
      glucocorticoid administration may accelerate fetal lung growth by up-regulating
      these growth factors.

PMID- 10646787
TI  - Fetal lung development: airway pressure enhances the expression of developmental
      genes.
AB  - BACKGROUND/PURPOSE: The mechanisms by which static airway pressures in the
      developing lung affect development are unknown. The in vitro murine fetal lung
      model with airway ligation reproduces the phenomenon of intraluminal airway
      pressure in developing lungs. We have applied the technique of differential
      display of mRNAs to fetal murine lungs that were maintained in organ culture with
      and without tracheal ligation. The goal of this investigation was to identify
      genes that are induced or enhanced by airway pressure during lung development.
      METHODS: Fetuses were harvested from CD-1 mice on gestational day (Gd) 14. The
      lungs were removed and trachea either transected or ligated and organ cultured
      for 7 days. Total RNA was extracted from cultured unligated controls and ligated
      lungs. Reverse transcription (RT) of the purified total RNA from each pooled
      sample was performed with anchor primer H-T11G or C and one of 24 arbitrary
      primers followed by polymerase chain reaction (PCR) of the RT mixtures. PCR
      products were electrophoresed on a DNA sequencing gel. Differentially expressed
      cDNA bands of interest were cut from the dried gel. Each cDNA was then
      reamplified. Reamplified cDNAs were extracted, PCR amplified, cloned, and
      sequenced for homology to existing sequences in the GenBank database. RESULTS:
      Sequencing identified 4 differentially expressed genes enhanced by tracheal
      ligation: hepatoma-derived growth factor (HDGF), ribosomal protein S24, stathmin,
      and parathyroid hormone (PTH). CONCLUSIONS: Genes enhanced by airway pressure or
      tracheal ligation are mitogenic for fibroblasts, correlate with cell
      proliferation, regulate cell proliferation and differentiation, and may play a
      role in growth in distal lung and type II cell differentiation. Further work is
      necessary to identify the mechanisms by which these genes influence lung
      maturational processes.

PMID- 10646788
TI  - Patch incorporation in diaphragmatic hernia.
AB  - BACKGROUND/PURPOSE: Biomaterial insertion often is required for closure of
      congenital diaphragmatic hernia (CDH). The optimal biomaterial remains uncertain.
      This study was designed to compare a commonly used patch
      (polytetrafluoroethylene) with a recently available fabric, fluorinated
      polyester. The aim of this study was to determine the clinical performance,
      histological tissue-polymer interaction, bacterial adhesion, and shrinkage rates
      of biomaterial inserted endoscopically into a CDH lamb model. METHODS:
      Polytetrafluoro-ethylene (PTFE) and fluorinated polyester (FP) were randomised
      for laparoscopic patch insertion into 12 lambs. All lambs (age <4 weeks)
      underwent 3-port laparoscopy, surgical creation of diaphragmatic hernia, and
      sutured patch placement. Two PTFE and 2 FP lambs were killed at 1-, 3-, and 6
      month intervals postoperatively. Postmortem examination histopathology, electron
      microscopy, and specific bacterial broth immersion (Escherichia coil,
      Staphylococcus aurens, and epidermidis) were performed. RESULTS: All 12 lambs
      completed the study with intact patches that were fully peritonised. One
      abdominal adhesion was noted in a FP lamb at 6 months. FP was comparatively
      easier to insert, manipulate, and suture endoscopically. Histopathology findings
      showed that PTFE patches created a strong peripheral foreign body reaction with
      dystrophic calcification, whereas FP was well incorporated with intrapatch
      fibroblastic activity and neovascularsation. No significant difference in
      resistance to bacterial adhesion of relevant organisms was noted between the
      materials. Graft shrinkage for FP was 7% in one direction only, evident by 3
      months. CONCLUSIONS: Fluorinated polyester has advantages in this laparoscopic
      lamb model. It shows rapid and sustained incorporation with intrapatch
      neovascularisation when compared with polytetrafluoro-ethylene's significant
      foreign body reaction. It was preferred for its endoscopic handling and suturing
      properties. The laparoscopic techniques used may contribute to the general lack
      of adhesions, and insufficient data are available to comment on the comparative
      effect of the materials on adhesion formation. No difference was demonstrated in
      resistance to bacterial adherence in the harvested materials.

PMID- 10646789
TI  - Early lung malformations in congenital diaphragmatic hernia.
AB  - BACKGROUND/PURPOSE: Lung hypoplasia, a leading contributor to the lethality of
      congenital diaphragmatic hernia (CDH), has been attributed to compression of the
      fetal lung by herniated abdominal viscera. Contested findings in experimental CDH
      suggest that lung malformation may precede diaphragmatic hernia. To address this
      unresolved question, we studied the pattern and progress of embryonic lung
      development in vivo and in vitro before diaphragmatic herniation in the nitrofen
      CDH model. METHODS: Sprague-Dawley rats were fed nitrofen on day 9.5 of pregnancy
      to induce pulmonary hypoplasia and CDH in newborns (term, day 22). Control rats
      received olive oil. Embryonic lungs were microdissected on day 13.5 gestation, 24
      hours after lung primordia bud from the foregut (normal diaphragmatic closure,
      day 16.5). In vivo airway branching was measured by counting terminal lung buds
      at this stage. Lungs were cultured for up to 78 hours and longitudinal in vitro
      development studied by serial measurements of terminal bud count, area, and
      perimeter. RESULTS: At 13.5 days of gestation in vivo, nearly 99% of normal lungs
      (n = 130) had > or = 6 terminal lung buds. In contrast, 36% of the nitrofen
      exposed lungs (n = 170) fell short of this developmental milestone with less than
      6 terminal buds (P < .001). In vitro, the nitrofen lungs had reduced area
      compared with controls after 6, 30, and 54 hours (P = .001, P < .001, and P =
      .001, respectively). Bud count and epithelial perimeter were reduced in the
      nitrofen lungs after 6 and 30 hours in vitro (P < .001 and P = .01 v normal
      terminal bud count; P < .001 and P= .002 v normal perimeter). CONCLUSIONS: Before
      diaphragmatic herniation, nitrofen-exposed embryos in vivo have a 36% frequency
      of reduced airway branching that strikingly parallels the 30% to 40% term
      incidence of CDH in this model. The authors propose that this early lung anomaly
      is restricted to a subset of nitrofen-exposed embryos in which it is integral to
      an emerging CDH phenotype. In vitro data confirm that nitrofen-induced pulmonary
      hypoplasia precedes visceral herniation and persists to allow experimental
      manipulation in culture. The developmental biology underlying lung hypoplasia in
      CDH may now be addressed using this organ culture system.

PMID- 10646790
TI  - Cell proliferation and apoptosis in experimental lung hypoplasia.
AB  - BACKGROUND/PURPOSE: Current treatment for lethal pulmonary hypoplasia in
      congenital diaphragmatic hernia (CDH) may be hampered by uncertainty over its
      origin. Herniation of abdominal organs into the chest was thought to produce lung
      hypoplasia by compression. Experimental CDH models suggest that disturbed lung
      growth precedes these events. Mammalian development comprises cell
      differentiation, proliferation and programmed cell death or apoptosis. Could lung
      hypoplasia in CDH result from alterations in these processes well before visceral
      herniation takes place? The aim of this study was to compare cell proliferation
      and apoptosis in normal and hypoplastic embryonic lungs before normal
      diaphragmatic closure using a CDH model. METHODS: Sprague-Dawley rats were given
      100 mg of nitrofen on day 9.5 of pregnancy to create lung hypoplasia and CDH in
      newborns (term, 22 days). Control rats received olive oil. Cell proliferation in
      embryonic lung specimens was measured by bromodeoxyuridine (BrdU) incorporation
      at 13.5 to 15.5 days' gestation, before normal diaphragmatic closure in this
      species (day 16.5). Apoptosis was measured by the in situ end-nick labelling
      (TUNEL) method in lung sections obtained from rat embryos of 13.5 to 16.5 days'
      gestation. RESULTS: High levels of cell proliferation were seen in both normal
      control and nitrofen-exposed lungs. However, 24 hours before normal diaphragmatic
      closure, nitrofen-exposed lungs had significant reductions in cell proliferation
      on day 15.5 of gestation (P = .009 v controls). Apoptosis occurred at low levels
      throughout the developmental stages examined (< 0.3%) without significant
      differences encountered between the study groups. CONCLUSIONS: These findings
      have shown high rates of cell division during normal lung development before
      diaphragmatic closure. Decreased levels over this critical period in gestation
      may contribute to early lung anomalies in the nitrofen CDH model. Strategies to
      promote cell proliferation in the fetal lung may therefore hold future promise in
      human CDH. Apoptosis appears not to play a major role in hypoplastic lung
      development. Therapies to inhibit apoptosis would seem unlikely to improve this
      early lung growth.

PMID- 10646791
TI  - Efficacy of primary and secondary video-assisted thoracic surgery in children.
AB  - BACKGROUND/PURPOSE: Video-assisted thoracic surgery (VATS) is used commonly for
      diagnostic and therapeutic procedures in children. The purpose of this study was
      to determine the accuracy, efficacy, and complications associated with primary
      and secondary VATS in children. METHODS: Eighty-seven infants, children, and
      adolescents underwent 104 VATS procedures between March 1993 and April 1999.
      There were 47 boys and 40 girls with an age range of 6 months to 19 years. VATS
      was performed for excision of pulmonary nodule (n = 51), biopsy of infiltrate (n
      = 14), excision or biopsy mediastinal mass (n = 12), decortication of empyema (n
      = 16), pleurodesis and bleb excision for pneumothorax (n = 5), pleurolysis for
      P32 administration (n = 3), esophageal myotomy (n = 2), and thymectomy (n = 1).
      In 6 children a contralateral thoracic procedure was performed along with VATS (3
      VATS, 3 thoracotomies). Secondary VATS was performed in 20 after prior thoracic
      procedures. RESULTS: VATS was efficacious for diagnostic or therapeutic purposes
      in 93 cases. Overall, 11 (11%) VATS required conversion to open thoracotomy.
      Average length of thoracostomy tube drainage (CTD) was 2.2 days, and average
      length of stay (LOS) was 3.7 days. Complications included prolonged air leak (> 7
      days) in 3 (2 empyema, 1 nodule). Two children with malignancy and pulmonary
      infiltrates died within 30 days of progressive respiratory failure. There were no
      bleeding complications or deaths related to VATS. CONCLUSIONS: VATS is a safe and
      effective primary and secondary procedure in children resulting in a short length
      of CTD and LOS. Duration of CTD and LOS are prolonged if empyema is associated
      with a bronchopleural fistula, and VATS may not be of value in this setting.

PMID- 10646793
TI  - Enterocolitis risk factors after pull-through for Hirschsprung's disease.

PMID- 10646792
TI  - Incidence of RET mutations in patients with Hirschsprung's disease.
AB  - BACKGROUND: RET mutations have been reported variously to affect 7% to 41% of
      Hirschsprung's disease (HSCR) patients depending on familial or sporadic
      occurrence of the disease, length of aganglionosis and possible association with
      other disease phenotypes. The authors report a study of the incidence of RET
      mutations in unselected HSCR patients from two regional centers and correlate
      their genotypes and phenotypes. METHODS: The records of HSCR patients treated in
      2 regional centers with a combined population of 5 million were reviewed, and
      blood samples were obtained from 57 patients. During the same period, 39 patients
      with similar demographic data refused or provided insufficient blood for study.
      DNA was extracted, and the 21 exons of the RET protooncogene were screened for
      mutations using denaturing gradient gel electrophoresis (DGGE). RESULTS: Of 57
      patients, 48 were sporadic, and 9 were familial. Lengths of aganglionosis were
      total colonic, 4; long, 11; short, 39; ultrashort, 1; unclassified, 2. Associated
      anomalies were present in 20. Causative mutations were identified in 4 (7%):
      missense or "silent" in 3 (exons 5, 11, 13) and deletion in 1. The silent
      mutation of exon 11 recently has been shown to have effects on correct RET mRNA
      splicing. One mutation occurred in total colonic aganglionosis (25%), 1 in long
      segment dysganglionosis (9%), and 2 in short segment aganglionosis (5%).
      Surprisingly, all these mutations occurred in sporadic cases (10%). Five patients
      (9%) had rare polymorphic alleles at exon 14 (n = 1) and exon 18 (n = 4). Fifty
      patients (88%) showed common polymorphic alleles (sequence variants) in 1 or more
      exons (> 4, n = 5). CONCLUSIONS: RET mutation as a primary cause for
      Hirschsprung's disease in the general surgical population is less frequent than
      previously thought. This observation is compatible with the hypothesis that HSCR
      could be a polygenic disease caused by additive subclinical effects of more than
      one gene, including RET.

PMID- 10646794
TI  - Molecular basis of left-right asymmetry.
AB  - In vertebrates visceral asymmetry is conserved along the left-right axis within
      the body. Only a small percentage of randomization (situs ambiguus), or complete
      reversal (situs inversus) of normal internal organ position and structural
      asymmetry is found in humans. A breakdown in left-right asymmetry is occasionally
      associated with severe malformations of the organs, clearly indicating that the
      regulated asymmetric patterning could have an evolutionary advantage over
      allowing random placement of visceral organs. Genetic, molecular and cell
      transplantation experiments in humans, mice, zebrafish, chick and Xenopus have
      advanced our understanding of how initiation and establishment of left-right
      asymmetry occurs in the vertebrate embryo. In particular, the chick embryo has
      served as an extraordinary animal model to manipulate genes, cells and tissues.
      This chick model system has enabled us to reveal the genetic pathways that occur
      during left-right development. Indeed, genes with asymmetric expression domains
      have been identified and well characterized using the chick as a model system.
      The present review summarizes the molecular and experimental studies employed to
      gain a better understanding of left-right asymmetry pattern formation from the
      first split of symmetry in embryos, to the exhibition of asymmetric morphologies
      in organs.

PMID- 10646795
TI  - Temporal expression patterns of 39 Brachyury-downstream genes associated with
      notochord formation in the Ciona intestinalis embryo.
AB  - Expression of the Brachyury (Ci-Bra) gene of the ascidian Ciona intestinalis is
      initiated at the 64-cell stage. Gene expression is restricted to notochord
      precursor cells, and Ci-Bra plays a key role in notochord differentiation. In a
      previous study, nearly 50 cDNA clones for potential Ci-Bra-downstream genes that
      are expressed in notochord cells were isolated. The present determination, by
      whole-mount in situ hybridization, of the temporal expression patterns of 19
      notochord-specific and 20 notochord-predominant genes demonstrated that the
      timings of initiation of the expression of various genes was not identical. The
      expression of several genes was initiated as early as the gastrula stage.
      However, the expression of most of the notochord-specific genes commenced at the
      neural plate stage. Partial nucleotide sequence data of these clones suggest that
      genes expressed earlier encode potential transcriptional factors and/or nuclear
      proteins, while those expressed later encode proteins implicated in cell
      adhesion, signal transduction, regulation of the cytoskeleton, and components of
      the extracellular matrix. These gene activities may be associated with changes in
      cell shape and adhesion during the intercalation and extension of the notochord
      cells.

PMID- 10646796
TI  - FGF10 can induce Fgf8 expression concomitantly with En1 and R-fng expression in
      chick limb ectoderm, independent of its dorsoventral specification.
AB  - The limb bud has a thickened epithelium at the dorsal-ventral boundary, the
      apical ectodermal ridge (AER), which sustains limb outgrowth and patterning. A
      secreted molecule fibroblast growth factor (FGF)10 is involved in inducing Fgf8
      expression in the prospective AER and mutual interaction between mesenchymal
      FGF10 and FGF8 in the AER is essential for limb outgrowth. A secreted factor
      Wnt7a and a homeobox protein Lmx1 are involved in the dorsal patterning of the
      limb, whereas a homeobox protein Engrailed 1 (En1) is involved in the dorsal
      ventral patterning as well as AER formation. Radical fringe (R-fng), a vertebrate
      homolog of Drosophila fringe was also found to elaborate AER formation in chicks.
      However, little is known about the molecular interactions between these factors
      during AER formation. The present study clarified the relationship between FGF10,
      Wnt7a, Lmx1, R-fng and En1 during limb development using a foil-barrier insertion
      experiment. It was found that a foil-barrier inserted into the chick prospective
      wing mesenchyme lateral to the mesonephric duct blocks AER induction. This
      experiment was expanded by implanting Fgf10-expressing cells lateral to the
      barrier and examined whether FGF10 could rescue the expression of the limb
      patterning genes reported in AER formation. It was found that FGF10 is sufficient
      to induce Fgf8 expression in the ectoderm of the foil-inserted limb bud,
      concomitantly with R-fng and En1 expression. However, FGF10 could not rescue the
      expression of the dorsal marker genes, Wnt7a or Lmx1. Thus, it is suggested that
      epithelial factors of En1 and R-fng can induce Fgf8 expression in the limb
      ectoderm in cooperation with a mesenchymal factor FGF10. Some factor(s) other
      than FGF10, possibly from the paraxial structures medial to the limb mesoderm, is
      responsible for the initial dorsal-ventral specification of the limb bud.

PMID- 10646797
TI  - Germline-specific expression of the Oct-4/green fluorescent protein (GFP)
      transgene in mice.
AB  - The Pic-1, Oct-1,2, Unc-86 (POU) transcription factor Oct-4 is specifically
      expressed in the germ cell line, and a previous study has indicated that the
      expression of the lacZ gene inserted into an 18 kb genomic fragment encompassing
      the Oct-4 gene can come close to mimicking the endogenous embryonic expression
      pattern of Oct-4 in transgenic mice. In the present study transgenic mice
      expressing green fluorescent protein (GFP) in the germ cell line were generated
      using the same Oct-4 genomic fragments and the expression pattern was analyzed in
      detail through all stages of germ cell development. The GFP expressing primordial
      germ cells were first detected as early as 8.0 days post-coitum (d.p.c.; early
      head fold stage) at the base of the allantois in living embryos. The GFP
      expression was thereafter found in both male and female germ cells at all
      developmental stages except in male germ cells after differentiating into type A
      spermatogonia in the postnatal testis. There was also a lower level of expression
      in female germ cells in the prophase of the first meiotic division. These
      transgenic mice therefore proved to be powerful tools for isolating living germ
      cells at various developmental stages to study their nature and to isolate new
      genes.

PMID- 10646798
TI  - Expression of Eph receptor tyrosine kinases and their ligands in chick embryonic
      motor neurons and hindlimb muscles.
AB  - Evidence is accumulating that Eph receptor tyrosine kinases and their ligands
      regulate cell migration and axonal guidance during development. It was previously
      found that one of the Eph receptors, EphA4, is transiently expressed in subsets
      of chick embryonic motor neurons. Here, the expression of EphA and ephrin-A
      subfamily members was further examined, and the dynamic patterns of expression in
      chick embryonic motor neurons found. EphA3, EphA4, ephrin-A2, and ephrin-A5 were
      also expressed in the connective tissues of limb muscles and EphA3 and EphA4
      expressing motor neurons innervated EphA3 and EphA4 expressing limb muscles,
      respectively. These spatiotemporal expression patterns suggest that EphA and
      ephrin-A proteins play important roles in muscle patterning and motor axonal
      guidance.

PMID- 10646799
TI  - Spatial expression of Drosophila glutathione S-transferase-D1 in the alimentary
      canal is regulated by the overlying visceral mesoderm.
AB  - Regional gene expression within Drosophila gut epithelium is regulated by the
      homeotic genes expressed in the overlying visceral mesoderm. Here it is reported
      that Glutathione S-transferase-D1 (Gst-D1) had three distinctive expression
      domains in the gut epithelia: the inner epithelium of the proventriculus, the
      anterior border of the hindgut epithelium, and the midgut epithelium. Gst-D1
      expression in the midgut epithelium became restricted to the region that later
      formed the third midgut constriction. This spatial restriction within the midgut
      epithelium required abdominal-A activity in the overlying visceral mesoderm,
      suggesting that Gst-D1 will be a useful marker to analyze the mechanism of gene
      regulation across the mesoderm and endoderm.

PMID- 10646800
TI  - Cell fate analysis of teloblasts in the Tubifex embryo by intracellular injection
      of HRP.
AB  - As in other clitellate annelids, embryonic development in the oligochaete Tubifex
      is characterized by the generation of five bilateral pairs of teloblasts
      (designated M, N, O, P and Q), which serve as embryonic stem cells to produce
      germ bands on either side of the embryo. A large part of the tissues comprising
      body segments has been assigned to the progenies of the teloblasts; however, the
      developmental fate of each teloblast has been inferred only from its initial
      position in the embryo. In the present study, the fate of the progenies of each
      teloblast was followed by means of intracellular injection of a tracer enzyme,
      horseradish peroxidase. Cell fate maps for teloblasts in the Tubifex embryo were
      constructed. M teloblasts gave rise to nearly all of the mesodermal tissues,
      which included circular and longitudinal muscles, coelomic walls, nephridia (in
      segments VII and VIII) and primordial germ cells (in segments X and XI). Although
      few in number, M teloblasts also contributed cells to the ventral ganglion.
      Similarly, each of the ectoteloblasts, N, O, P and Q, made a topographically
      characteristic contribution to the ectodermal tissues such as the nervous system
      (i.e. ganglionic cells and peripheral neurones) and epidermis, all of which
      exhibited a segmentally repeated distribution pattern. The P and Q teloblasts
      uniquely gave rise to additional ectodermal tissues, namely ventral and dorsal
      setal sacs, respectively. Furthermore, O teloblasts made a contribution to the
      nephridiopores in segments VII and VIII as well. These results confirm the
      previously held view that ectoteloblasts and mesoteloblasts are the main source
      of ectodermal and mesodermal segmental tissues, respectively, but also suggest
      that all of the teloblasts produce more types of tissue than has previously been
      thought.

PMID- 10646801
TI  - Expression pattern, subcellular localization and structure--function relationship
      of rat Tpx-1, a spermatogenic cell adhesion molecule responsible for association
      with Sertoli cells.
AB  - The gene for a testicular cell adhesion protein called Tpx-1, which mediates the
      binding of spermatogenic cells to Sertoli cells of the rat in primary culture,
      was previously cloned. Here the characterization of Tpx-1 is reported. Tpx-1
      messenger ribonucleic acid (mRNA) became detectable in pachytene spermatocytes
      and continued to be present throughout development into elongated spermatids,
      while the amount of Tpx-1 protein seemed to increase some time after the
      increment of mRNA. Tpx-1 protein was also present, although less abundantly, in
      spermatozoa prepared from the epididymis. Tpx-1 contains a cluster of hydrophobic
      amino acid residues near the amino terminus and a cysteine-rich region in the
      carboxyl-terminal half. Tpx-1 fused with green fluorescence protein was secreted
      into the medium when expressed in a cultured cell line, depending on the presence
      of the amino-terminal hydrophobic region. Moreover, Tpx-1 was present in the
      medium of testicular cell primary culture. Structure-function analysis revealed
      that the amino-terminal 101 amino acid residues were sufficient for cell adhesion
      activity, whereas the carboxyl-terminal cysteine-rich region was dispensable. In
      conclusion, Tpx-1 is produced and secreted from spermatogenic cells at various
      differentiation stages, and mediates the interaction of those cells with Sertoli
      cells.

PMID- 10646802
TI  - Pax-6 expression during retinal regeneration in the adult newt.
AB  - The present study examined the expression of Pax-6 during retinal regeneration in
      adult newts using in situ hybridization. In a normal retina, Pax-6 is expressed
      in the ciliary marginal zone, the inner part of the inner nuclear layer, and the
      ganglion cell layer. After surgical removal of the neural retina, retinal pigment
      epithelial cells proliferate into retinal precursor cells and regenerate a fully
      functional retina. At the beginning of retinal regeneration, Pax-6 was expressed
      in all retinal precursor cells. As regeneration proceeded, differentiating cells
      appeared at the scleral and vitreal margins of the regenerating retina, which had
      no distinct plexiform layers. In this stage, the expression of Pax-6 was
      localized in a strip of cells along the vitreal margin of the regenerating
      retina. In the late stage of regeneration, when the layer structure was
      completed, the expression pattern of Pax-6 became similar to that of a normal
      retina. It was found that Pax-6 is expressed in the retinal precursor cells in
      the early regenerating retina and that the expression pattern of Pax-6 changed as
      cell differentiation proceeded during retinal regeneration.

PMID- 10646803
TI  - Expression of helix-loop-helix type negative regulators of differentiation during
      limb regeneration in urodeles and anurans.
AB  - The urodele is capable of regenerating its limb by forming a blastema even in the
      adult. By contrast, the anuran, which is phylogenetically close to the urodele,
      loses this ability during metamorphosis and forms blastema-like tissues that
      develop only into a spike-like structure in the adult. In order to compare the
      molecular mechanism of the formation and maintenance of the blastema between the
      urodele and anuran, the genes encoding helix-loop-helix (HLH) type negative
      regulators of differentiation were characterized for both the Japanese newt,
      Cynops pyrrhogaster, and African clawed frog, Xenopus laevis. Cynops homologs of
      Id2, Id3, and HES1 and Xenopus Id2 were identified. To learn the roles of these
      genes in regeneration, their expression was examined. The expression of Id2 and
      Id3 was low in unamputated limbs, but was up-regulated in blastemas of both adult
      newt and Xenopus. Interestingly, transcripts of the two Id genes showed specific
      localizations in the blastema and the expression patterns were very similar in
      both species through the early to medium bud stage. Id2 was expressed
      predominantly in the blastemal epidermis, and Id3 was expressed equally in the
      blastemal epidermis and mesenchyme including cells in precartilage condensations.
      HES1 expression was up-regulated in the newt blastemal epidermis. It was thought
      that the up-regulation of these genes in the epidermis was related to the
      proliferation of the cells and that increased expression of these genes in the
      mesenchyme was related to the undifferentiated state of the blastemal cells.
      These results and considerations strongly suggested that the state of
      differentiation is similar in the early to medium bud blastema of both urodeles
      and anurans. The expression of Id3 remained high through to the digits stage in
      newts. In contrast, its expression in Xenopus decreased in spike-like
      regenerates, which correspond to palette-digits stage of newt regenerates. From
      these results, it was suggested that the blastema redifferentiates earlier in the
      frog than in the newt, and therefore the timing of redifferentiation of the
      cartilage is crucial for complete regeneration.

PMID- 10646804
TI  - Cause of the decreased number of PGC in albino Xenopus: analysis of the number
      and position of pPGC in albino embryos during and after cleavage.
AB  - In order to understand the cause for the decreased number of primordial germ
      cells (PGC) in Xenopus albino (a(p)/a(p)) tadpoles, the number of presumptive PGC
      (pPGC) in the albino and wild-type embryos at Nieuwkoop and Faber's stages 6
      37/38 were examined using the antibody specific to germ plasm. The positions of
      pPGC in the endodermal cell mass in embryos of both types at stages 28 and 33/34
      were also observed to learn the migratory behavior of pPGC. The number of pPGC in
      the albino increased up to stage 28 with development, but decreased thereafter.
      In contrast, the number in the wild-type increased to stage 33/34 as development
      proceeded, and the number of pPGC in stage 33/34 embryos reached nearly that of
      PGC of the feeding tadpoles in the same batches. Judging from the positions of
      pPGC, the migration of pPGC from the median part through the lateral to the
      dorsal part of the endodermal cell mass in the albino was suspected to be
      somewhat later than that in the wild-type. These results, together with the
      results in previous studies, suggest that the decreased number of PGC in the
      albino would be closely related to the sudden decrease in number of pPGC at stage
      33/34, as well as to the ectopic position of pPGC in endodermal cell mass, the
      latter of which had already been demonstrated to be responsible for the
      differentiation into PGC.

PMID- 10646805
TI  - Dorsoventral differential distribution of collagen type XIV around the spinal
      cord is regulated by the ectoderm.
AB  - Regional specification in the nervous system is a critical issue in nervous
      system morphogenesis. Along the dorsoventral axis of the spinal cord, ventral
      inductive signals of the notochord and floor plate, and dorsal ones of the
      epidermal ectoderm are essential. Collagen type XIV is uniquely distributed
      around the spinal cord with a gradient of dorsal high and ventral low at the
      early developmental stages of the chick embryo. In the present study it was found
      that collagen type XIV expression around the spinal cord was entirely regulated
      by the ectoderm and that even the ventralizing tissues, the notochord and floor
      plate, themselves could be influenced to express this molecule by the ectoderm.

PMID- 10646806
TI  - Differentiation of the gonad rudiment into ovary and testis in the solitary
      ascidian, Ciona intestinalis.
AB  - In the early juveniles of Ciona intestinalis, primordial germ cells arise on the
      degenerated mass of the resorbed tadpole tail, and assemble to form a discrete
      gonad rudiment. The present study elucidated the morphological sequences during
      differentiation of the gonad rudiment into the testis and ovary. In 11- to 12-day
      juveniles, the gonad rudiment, an elongate sac, divided into the testicular and
      ovarian rudiments. The testicular rudiment separated as a round vesicle from the
      thickened wall of the elongate sac. The original sac, after separation of the
      round vesicle, developed into the ovary. In the testicular rudiment, germ cells
      formed a continuous central mass without association of somatic cells, while in
      the ovarian rudiment, each germ cell was associated with somatic cells within the
      epithelium composing the wall of the rudiment. In 13- to 15-day juveniles the
      testicular rudiment changed into branched tubes ending in club-shaped follicles.
      Cells characterized by many flattened cisternae of rough endoplasmic reticulum
      (distal cells) constituted the distal wall of each follicle. Spermatogenic cells
      were freely present in the follicular lumen, but the largest spermatogonia were
      in contact with the distal cells. Both in the testicular and ovarian rudiments,
      germ cells entered meiosis in 18-day juveniles. A novel body (periesophageal
      body) was found just beneath the ventral margin of the esophageal opening. It
      comprised irregular follicles made up of one cell type whose cytoplasm, filled
      with round vesicles and Golgi complexes, was suggestive of an endocrine function.
      Fragments derived from the periesophageal body were present around the developing
      ovary.

PMID- 10646808
TI  - Fetal fibronectin as a predictor of term labor: a literature review.
AB  - OBJECTIVE: Accurately predicting the onset of delivery continues to be
      problematic notwithstanding the clinical relevance of this capability, especially
      with regard to the elective induction of labor. While the assessment of the
      cervix according to Bishop, to date, constitutes the single generally recognized
      method, the determination of fetal fibronectin (FFN) cervicovaginal secretions
      promises greater precision in this context. DESIGN: English-language medical
      literature was analyzed using the search parameter 'fetal fibronectin', 'term
      delivery', 'induction of labor', 'labor', and 'birth', respectively. All those
      original reports examining cervicovaginal FFN that were originally published in
      English and followed a prospective design were subsequently included in the study
      at hand. These reports were evaluated in regard to their findings on the
      predictive value of FFN for spontaneous delivery and induction of labor. RESULTS:
      A total of eight reports were included in the present study: five of these,
      covering a total of 480 patients, discussed the relationship between FFN and the
      spontaneous onset of labor; the other three addressed the subject of FFN and the
      induction of labor (300 patients). All reports clearly related the presence of
      FFN in cervicovaginal secretions to the imminent onset of delivery; three
      studies, furthermore, demonstrated a correlation with the spontaneous onset of
      labor, with a sensitivity greater than 90%. In case of the studies concerning
      induction of labor, a positive FFN result was accompanied by a significantly
      shorter interval until delivery than a negative FFN result. CONCLUSION:
      Determining the presence of FFN in cervicovaginal secretions promises to provide
      an indicator relating to the prediction of term labor, as well as to the
      prediction of successful labor induction.

PMID- 10646807
TI  - Phosphorylation-dependent regulation of skeletogenesis in sea urchin micromere
      derived cells and embryos.
AB  - Sea urchin embryo micromeres when isolated and cultured in vitro differentiate to
      produce spicules. Although several authors have used this model, almost nothing
      is known about the signaling pathways responsible for initiating skeletogenesis.
      In order to investigate the potential involvement of phosphorylation events in
      spiculogenesis, the effect of inhibitors of protein kinases and phosphatases on
      skeleton formation was studied. Results obtained using both cultured micromeres
      and embryos revealed that protein tyrosine kinase and phosphatase inhibitors
      blocked skeleton formation, but not serine/threonine phosphatase inhibitors. The
      inhibitors showed a dose-dependent effect and when removed from micromere or
      embryo culture, spicule formation resumed. Inhibition of tyrosine phosphatases
      resulted in an increase in the tyrosine phosphorylation level of two major
      proteins and a modest decrease in the expression of the mRNA coding for type I
      fibrillar collagen. These findings strongly suggest that tyrosine phosphorylation
      and dephosphorylation is required for micromere differentiation and for normal
      skeletogenesis during sea urchin embryo development.

PMID- 10646809
TI  - Rapid prenatal diagnosis of chromosome aneuploidies by interphase fluorescence in
      situ hybridization: a one-year clinical experience with high-risk and urgent
      fetal and postnatal samples.
AB  - OBJECTIVES: To evaluate the clinical utility of rapid prenatal and postnatal
      detection of common chromosome aneuploidies by interphase fluorescence in situ
      hybridization (FISH) analysis with DNA probes. DESIGN: Four hundred and seventy
      seven high-risk and/or urgent amniotic fluid, chorionic villus and fetal and
      postnatal blood samples were prospectively examined by FISH with probes specific
      for chromosomes 13, 18, 21, X, and Y and results were reported within 48 hours.
      All FISH results were followed by conventional chromosome analysis, if possible.
      SETTING: Cytogenetic service laboratory at the tertiary referral center,
      Rigshospitalet in Copenhagen. MAIN OUTCOME MEASURES: The fraction of clinically
      significant chromosome aneuploidies that was detected by FISH analysis, and the
      fraction of terminations that was based on FISH and ultrasound results rather
      than on conventional cytogenetic results. RESULTS: The FISH assay detected 76% of
      the clinically significant chromosome abnormalities as determined by subsequent
      cytogenetic analysis. Seventy-two percent of the terminations of the
      chromosomally abnormal pregnancies were based on FISH and ultrasound results
      rather than on conventional cytogenetic results. CONCLUSION: FISH analysis is a
      clinically useful adjunctive tool to conventional pre- and postnatal cytogenetic
      analysis. The assay rapidly detects the majority of clinically significant
      chromosome abnormalities, thus facilitating difficult pre- and postnatal clinical
      decisions.

PMID- 10646810
TI  - Etiology and outcome of second trimester non-immunologic fetal hydrops.
AB  - BACKGROUND: This investigation was undertaken to study the conditions resulting
      in midtrimester fetal hydrops and to evaluate its overall prognosis as regards
      counseling purposes. MATERIAL AND METHODS: The etiology of midtrimester non
      immune fetal hydrops was retrospectively evaluated as regards cases detected in
      singleton pregnancies (n=58) from January 1987 through December 1996. The
      condition was diagnosed by way of routine biochemical and ultrasonographic
      screening of a pregnant population. RESULTS: The rate of diagnosed midtrimester
      fetal hydrops was 1 in 1700 pregnancies and the overall survival rate in this
      usually unexpected condition was less than 10%. Various chromosomal and fetal
      structural abnormalities dominated as a cause of fetal hydrops, representing
      44.8% and 43.1% of the cases, respectively. Infection caused only 6.9%. The
      underlying etiology remained unknown in only three cases. However, in 78% the
      diagnosis was already known prenatally. DISCUSSION: Although the overall
      prognosis is poor, knowledge of the primary etiology is important to determine a
      rational therapeutic strategy. If the results of routine investigations rule out
      malformation and abnormal chromosomes, follow-up serial ultrasonographic
      assessment may indicate that the hydropic state is transient, carrying a somewhat
      better prognosis.

PMID- 10646811
TI  - Prediction of maternal and fetal complications in preeclampsia.
AB  - INTRODUCTION: Preeclampsia is associated with an increased risk for maternal and
      fetal morbidity. The aim of this study was to identify factors predicting for
      maternal or fetal complications. MATERIAL AND METHODS: One hundred and eleven
      patients with preeclampsia were included. Endpoint variables were maternal and
      fetal complications. Any of the diagnosis eclampsia, hemolysis elevated liver low
      platelet (HELLP) syndrome, oliguria or placental abruption was considered a
      maternal complication. Fetal complications were: small for gestational age (SGA)
      infant, umbilical artery pH<7.10 and admittance of the infant to a neonatal
      intensive care unit (NICU). Independent variables were maternal age, parity,
      gestational age, renal function, platelet count, liver enzymes and blood
      pressure. Logistic regression analysis was used for statistical evaluation.
      RESULTS: The following independent significant predictors were identified:
      Maternal complication (n=10) was predicted only by diastolic blood pressure; odds
      ratio (OR) 1.13 (95% confidence interval 1.01-1.25). SGA (n=21) was associated
      with maternal prepregnancy weight, OR 0.94 (0.89-0.99) and gestational age at
      debut of preeclampsia, OR 0.97 (0.94-0.99). NICU admittance (n=31) was only
      predicted by gestational age at delivery, OR 0.80 (0.67-0.96). No association was
      found between any of the independent variables and a low umbilical artery pH (n=
      10). CONCLUSIONS: In the surveillance of patients with established preeclampsia,
      the value of serial blood and urine sampling, which is common practice in many
      obstetrical units, might be questioned.

PMID- 10646812
TI  - Is pelvic pain in pregnancy a welfare complaint?
AB  - BACKGROUND: Pelvic pain in pregnancy has been suggested to be more common in
      Scandinavia than in the rest of the world, to be culturally specific for the
      region and to reflect a change in attitude among pregnant women. Little is known
      of the prevalence of pelvic pain in pregnancy in low-income countries. OBJECTIVE:
      To explore whether perceived pelvic pain among pregnant women differs between
      affluent and poor societies. SUBJECTS AND METHODS: Four observational studies,
      comprising a total of 752 women, were carried out in circumstances ranging from
      wealth to poverty, focusing on the reported prevalence, location and degree of
      pelvic pain in pregnancy. In Uppsala, Sweden, and in Rufiji, Tanzania, the women
      were interviewed in late pregnancy. In Jakobstad, Finland, and in Zanzibar Town,
      Zanzibar, the women were approached after delivery before discharge. RESULTS: The
      reported prevalence of pelvic pain in pregnancy was 49% in Uppsala and 66% in
      Rufiji, 77% in Jakobstad and 81% in Zanzibar, with an overall similarity of
      location and degree of pain. CONCLUSION: No geographical differences were found
      in perceived pelvic pain among pregnant women, irrespective of the socio-economy
      of the countries.

PMID- 10646813
TI  - Hydramnios and small for gestational age: prevalence and clinical significance.
AB  - OBJECTIVE: To investigate the clinical significance of combined obstetrical
      pathology of small for gestational age and hydramnios as a predictor of
      peripartum complications, intrapartum morbidity and poor neonatal outcome.
      METHODS: The study population consisted of 152 small for gestational age neonates
      with hydramnios out of 67,806 singleton deliveries during the study period
      (0.22%). We compared the 152 small for gestational age neonates with hydramnios
      (hydramnios/small for gestational age) to a sample of 1% of the appropriate for
      gestational age neonates with normal amniotic fluid (normal amniotic
      fluid/appropriate for gestational age) (582 cases). Analyses were conducted for
      the entire cohort as well as for the cohort in which all cases with congenital
      malformations were excluded. RESULTS: There was a significantly higher rate of
      congenital anomalies in the hydramnios/small for gestational age group compared
      with the normal amniotic fluid/appropriate for gestational age group (25% vs.
      2.4%, p<0.001). There were significantly more previous perinatal deaths,
      infertility treatments and diabetes type B-R among the hydramnios/small for
      gestational age group. These findings remained significant after exclusion of the
      neonates with congenital malformations. The rates of labor dystocia, placental
      abruptio, abnormal presentations, prolapse of cord and cesarean sections were
      significantly higher in the hydramnios/ small for gestational age group compared
      with normal amniotic fluid/appropriate for gestational age group (5.9/2.4%,
      p<0.05; 5.9/0.7%, p<0.001; 14.5/3.2%, p<0.001; 2/0.2%, p<0.01; 24.3/8.2%,p<0.001;
      respectively). Rates of ante partum death and post partum death as well as low 1
      and 5 minute Apgar scores were significantly higher in the hydramnios/small for
      gestational age group (9.9/0.3%; 14.5/0.3%; 12.8/2.1%; 11.7/0.6%, p<0.001,
      respectively). CONCLUSIONS: The combination of small for gestational age and
      hydramnios is a risk factor for peripartum complications and perinatal mortality
      even in the absence of congenital malformations.

PMID- 10646814
TI  - Addition of gonadotrophin-releasing hormone agonist and/or two inseminations with
      husband's sperm do not improve the pregnancy rate in superovulated cycles.
AB  - BACKGROUND: A prospective randomized study was performed to evaluate the addition
      of a gonadotropin releasing hormone agonist (GnRH-a) during treatment with human
      menopausal gonadotropins (hMG) in cycles with artificial inseminations with
      husband's washed sperm (AIH). We also compared the pregnancy rate per cycle after
      one versus two AIHs. METHODS: We designed a 22 factorial trial. A total of 172
      couples with unexplained infertility (n=88), endometriosis (n=39), or cervical
      (n=24) or male (n=21) factors were included, of whom 161 fulfilled the inclusion
      criteria and treatment. Eighty-one women were treated with GnRH-a/hMG and another
      80 with hMG only, respectively. RESULTS: The pregnancy rates did not differ
      between the two stimulation protocols (12% for GnRH-a/hMG and 9% for hMG). With
      GnRH-a/hMG more follicles >15 mm (3.4 and 2.4, respectively; p<0.01) and a higher
      multiple pregnancy rate after 20 weeks of gestation were observed (55% vs. 0%;
      p<0.05). Eighty-seven women were treated with one AIH, whereas 65 women received
      two AIHs on two consecutive days. The pregnancy rates were similar in these two
      groups (11% and 9% respectively; n.s.) CONCLUSION: It is concluded that neither
      addition of GnRH-a before and during controlled ovarian hyperstimulation nor two
      AIHs compared with one single AIH per cycle has a beneficial effect on the
      pregnancy rate. However, GnRH-a increases the risk for multiple pregnancies.

PMID- 10646815
TI  - Obesity is a risk factor for early pregnancy loss after IVF or ICSI.
AB  - BACKGROUND: Experience with polycystic ovary syndrome shows that insulin
      resistance is related to early pregnancy loss. This association was examined by
      comparing pregnancy outcome in obese and lean women. METHODS: A cohort of 383
      patients conceiving after in vitro fertilization (IVF) or intracytoplasmic sperm
      injection (ICSI) was studied. Ovarian stimulation was achieved by GnRHa and FSH
      or hMG (n=362), by FSH or hMG alone (n=16), or by clomiphene citrate and FSH or
      hMG (n=5). Luteal phase was supported with progesterone. Pregnancies were defined
      by >10 IU/l plasma beta-hCG on day 14. Ultrasound scan on week 6 and week 12
      confirmed fetal viability. RESULTS: Lean group (body mass index [BMI]<25 kg/m2;
      n=304) and obese group (BMI > or =25 kg/m2; n=79) were established. Obese
      patients had fewer oocytes collected (median: 8 vs 10 p=0.03), they had higher
      abortion rate during the first 6 weeks (22% vs 12%; p=0.03) and lower live-birth
      rate (63% vs 75%; p=0.04). The relative risk of abortion before week 6 was 1.77
      (95% CI: 1.05 to 2.97). Multivariate logistic regression analysis revealed that
      obesity and low oocyte count were independently associated with spontaneous
      abortion. In the obese group, low oocyte number was associated with a more
      profound increase in the risk of abortion than among lean patients. The effect of
      age, history of past pregnancies, or infertility diagnosis on the probability of
      miscarriage were not significant. CONCLUSIONS: Obesity is an independent risk
      factor for early pregnancy loss. This risk is, in part, related to the lower
      number of collected oocytes in obese women.

PMID- 10646816
TI  - Attitudes among health care professionals on the ethics of assisted reproductive
      technologies and legal abortion.
AB  - BACKGROUND: The purpose of the present study was to study the attitudes among
      Danish health care professionals likely to encounter ethical controversies of ART
      and related subjects. METHODS: Anonymous questionnaire study design. A total
      number of 993 were asked to participate from May-July 1994. RESULTS: There was a
      tendency towards a more liberal attitude among gynecologists than among nurses.
      There was a majority for legal abortion (before 12 weeks of gestation), for
      selective reduction in multiple pregnancies, and for donor anonymity. There was a
      majority against sex selection, artificial reproduction as to single women and
      lesbians, and against adoption by homosexuals. The multivariate analysis showed a
      strong correlation between attitude and background variables, especially as to
      religion and profession. CONCLUSION: Religion and profession are determinants for
      the attitude towards several of the ethical controversies of ART and related
      subjects asked for in this study. We found a discrepancy between recommendations
      by the Ethical Council of Denmark and the attitudes among health care
      professionals.

PMID- 10646817
TI  - Thermal endometrial ablation: a simple technique.
AB  - BACKGROUND: To evaluate the effectiveness and safety of a technique for thermal
      endometrial ablation. METHOD: The study was carried out in three steps; step I on
      10 fresh uterine specimens, step II on 14 intact uteri during hysterectomy and
      step III in five patients, two weeks prior to hysterectomy. A simple device
      comprising a Foley catheter No. 14F, a three way cannula and a 20 cc syringe was
      used for the procedure. The balloon of the catheter was inflated within the
      uterine cavity with boiling normal saline for 9 minutes. Uterine cavity and
      serosal temperature was recorded during the procedure. Thermal injury was
      assessed by gross and histological examination of the specimens. RESULTS: The
      mean maximum endometrial cavity temperature was 91 degrees C whereas serosal
      temperatures in steps I and II were 34 degrees C and 35.9 degrees C respectively.
      None of the balloons ruptured in any of the steps and there were no
      complications. In 13 of 14 specimens in step II, there was a zone of hyperemia
      with a depth of 3 to 7 mm. The corresponding histological picture was extensive
      hemorrhage and fragmentation of glands throughout the endometrium including the
      cornual regions. Consistent findings were noted in step III in which all but one
      showed extensive coagulative necrosis of the whole of endometrium with edema of
      the underlying myometrium. There was a statistically significant positive
      correlation between the volume of fluid injected and depth of hyperemia.
      CONCLUSION: This technique could be a simple, effective, inexpensive and safe
      alternative to hysteroscopic endometrial ablation.

PMID- 10646818
TI  - Comparison of transvaginal ultrasonography and vaginal sonohysterography in the
      detection of endometrial polyps.
AB  - BACKGROUND: The diagnostic accuracy of transvaginal ultrasonography and vaginal
      sonohysterography in detecting endometrial polyps in women suffering abnormal
      uterine bleeding are compared. METHODS: One hundred and six patients suffering
      from menometrorrhagia were studied. To detect whether there was endometrial polyp
      or not, these patients were subjected to transvaginal ultrasonographic
      examination as well as to sonohysterography. The final diagnosis was established
      by diagnostic hysteroscopy and its guided biopsy. RESULTS: Transvaginal
      ultrasonography resulted in false positive and false negative rates of 25% and
      36.2% respectively while the figures with sonohysterography were 5.4% and 8%
      respectively. Combining both techniques further improved such rates to 2.9% and
      2.8% respectively but not significantly (p>0.1). The sensitivity and specificity
      were 64.5%, 75.5% for transvaginal ultrasonography, and 93.1%, 93.9% for
      sonohysterography (significantly higher: p<0.001). CONCLUSIONS: Sonohysterography
      is significantly more accurate than transvaginal ultrasonography in the detection
      of endometrial polyps in cases with abnormal uterine bleeding. Combining both
      techniques did not significantly improve the diagnostic accuracy.
      Sonohysterography is an accurate and cost effective method which requires a
      little skill.

PMID- 10646819
TI  - Diagnosing fetal urinary tract abnormalities: benefits of MRI compared to
      ultrasonography.
AB  - BACKGROUND: To compare antepartum ultrasonography with magnetic resonance imaging
      for prenatal diagnosis of malformations in the fetal urinary tract in high risk
      patients during the last trimester. MATERIALS AND METHODS: The study involved 22
      women and 24 fetuses with either severe oligohydramnios or ultrasonographically
      or clinically suspected abnormality of urinary tract. Ultrasound examination was
      carried out with 5 MHz abdominal convex probe and magnetic resonance imaging with
      superconductive 1.5 T equipment. Postnatal findings were used as reference.
      RESULTS: Correct diagnosis of urinary tract anomaly was done in 15 fetuses on
      ultrasound and in 20 fetuses on magnetic resonance imaging. Both methods enabled
      correct diagnosis in 12, only ultrasound in three and only magnetic resonance
      imaging in eight fetuses. Both methods imaged equivocally in one case. The
      additional information by magnetic resonance imaging was gained from five fetuses
      out of 12 pregnancies with oligohydramnios and from three fetuses out of ten
      pregnancies with normal amount of amniotic fluid. CONCLUSIONS: MRI is a valuable
      additional method to ultrasonography of fetal urinary tract if resolution of
      ultrasound is impaired for reason of oligohydramnios or technical deterioration.

PMID- 10646820
TI  - The case for completing the lymphadenectomy when positive lymph nodes are found
      during radical hysterectomy for cervical carcinoma.
AB  - BACKGROUND: In the present study we report on the results of a retrospective
      study on the effect on survival of the pelvic lymphadenectomy in a group of 294
      patients with stage Ia2-IIa cervical carcinoma treated by radical hysterectomy
      from 1984 through 1996 at the Leiden University Medical Center. METHODS:
      Lymphadenectomy was called 'complete' when lymph node bearing tissue had been
      removed from 5 or 6 lymph node stations and 'not-complete' when this was the case
      in 1-4 stations. RESULTS: A radical hysterectomy was carried out in 294 patients.
      In 63 patients positive lymph nodes were found. Patients with positive nodes
      showed poorer 5 year survival: 64.5% compared to 90% in patients with negative
      nodes. In the univariate analysis the following factors were found to affect the
      presence of node metastases in a statistically significant way: age, tumor size,
      depth of infiltration, vaso-invasion, surgical margins, parametrial infiltration,
      stage and place of referral. In 63 patients with positive nodes, a complete
      lymphadenectomy was carried out in 23 patients, and in 40 patients the procedure
      was incomplete. All 63 patients were treated by adjuvant radiation therapy; those
      with complete lymphadenectomy had significantly less recurrences (25%) compared
      to those with incomplete lymphadenectomy (56%): the relative risk (RR) was 2.9
      (95% ci: 1.3-6.7), p=0.012. After adjustment for other prognostic factors
      including tumor size, depth of infiltration and parametrial involvement, the
      complete lymphadenectomy showed an independent effect on disease free survival:
      RR= 3.2 (95% ci: 1.3-7.7), p=0.011. Prognostic factors were not significantly
      different for patients with complete or incomplete lymphadenectomy. CONCLUSIONS:
      From the results of this study, although retrospective and non randomized, it can
      be concluded that to complete removal of lymph nodes in combination with radical
      hysterectomy seems to have a beneficial effect on prognosis in case of positive
      nodes. The policy of aborting the procedure when lymph node metastases are found
      in frozen section should be questioned.

PMID- 10646821
TI  - Vascular endothelial growth factor serum levels in pregnancy and preeclampsia.

PMID- 10646822
TI  - Primary ovarian leiomyoma in a postmenopausal woman.

PMID- 10646823
TI  - Bartter's syndrome and pregnancy.

PMID- 10646824
TI  - Severe maternal hypoxemia during a twin pregnancy.

PMID- 10646825
TI  - Thrombotic thrombocytopenic purpura: a difficult differential diagnosis in
      pregnancy.

PMID- 10646826
TI  - Fulminating gastric cancer in a pregnant woman, after 18 weeks of gestation,
      recipient of oocytes.

PMID- 10646827
TI  - Platelet alpha2A-adrenoceptor function in major depression: Gi coupling, effects
      of imipramine and relationship to treatment outcome.
AB  - Studies suggest alpha2A-adrenoceptors (alpha(2A)AR) dysregulation in major
      depressive disorder (MDD). Platelet alpha(2A)ARs exist in high- and low
      conformational states that are regulated by Gi protein. Although alpha(2A)AR
      coupling to Gi protein plays an important role in signal transduction and is
      modulated by antidepressants, it has not been previously investigated. Alpha2AR
      density in the high- and low-conformational states, agonist affinity and coupling
      efficiency were investigated in 27 healthy control subjects, 23 drug-free MDD
      patients and 16 patients after imipramine treatment using [3H]yohimbine
      saturation and norepinephrine displacement of [3H]yohimbine binding experiments.
      Coupling measures were derived from NE-displacement experiments. Patients had
      significantly higher alpha(2A)AR density, particularly in the high-conformational
      state, than control subjects. Coupling indices were normal in patients. High pre
      treatment agonist affinity to the receptor in the high-conformational state and
      normal coupling predicted positive treatment outcome. Decreased coupling to Gi
      predicted a negative treatment outcome. Imipramine induced uncoupling (-11%) and
      redistribution of receptor density in treatment responders only, but had no
      effect on alpha(2A)AR coupling or density in treatment non-responders. Increased
      alpha(2A)AR density may represent a trait marker in MDD. The results provide
      indirect evidence for abnormal protein kinase A (PKA) and protein kinase C (PKC)
      in MDD which may be pursued in future investigations.

PMID- 10646828
TI  - Severity of depression in abstinent alcoholics is associated with monoamine
      metabolites and dehydroepiandrosterone-sulfate concentrations.
AB  - Depressed mood increases the relapse risk of abstinent alcoholics; its
      neurobiological correlates may include reduced serotonin and norepinephrine
      turnover rates and increased cortisol concentrations during detoxification
      stress. Neurosteroids such as dehydroepiandrosterone and its sulfate (DHEA and
      DHEA-S) may antagonize cortisol action and may have mood-elevating effects on
      their own. We measured severity of depression with Beck's Depression Inventory
      (BDI) and Hamilton's Depression Rating Scale (HDRS), plasma concentrations of
      cortisol, DHEA and DHEA-S, and CSF concentrations of the serotonin metabolite 5
      hydroxyindoleacetic acid (5-HIAA), the norepinephrine metabolite 3-methoxy-4
      hydroxyphenylglycol (MHPG) and the dopamine metabolite homovanillic acid (HVA) in
      21 abstinent alcoholics after 4 weeks of abstinence and in 11 age-matched healthy
      control subjects. Only CSF MHPG concentrations were reduced in alcoholics
      compared to control subjects (41.4 +/- 6.6 vs. 53.3 +/- 8.6 pmol/ml). Self-rated
      depression was significantly correlated with CSF MHPG (Spearman's R = +0.57, P <
      0.01), CSF 5-HIAA (R = +0.51, P < 0.05) and plasma cortisol concentrations (R =
      +0.50, P < 0.05). Negative correlations were found between DHEA-S concentrations
      and both self-rated depression (R = -0.45, P < 0.05) and observer-rated
      depression (R = -0.55, P < 0.05). The ratio of DHEA-S to cortisol serum
      concentrations was also negatively correlated with depression (BDI: R = -0.55, P
      < 0.01; HDRS: R = -0.63, P < 0.005). Anxiety (Spielberger's State Anxiety Scale)
      was only associated with CSF MHPG concentrations (R = +0.58, P < 0.01). Our
      findings point to the importance of noradrenergic dysfunction in the pathogenesis
      of depression among abstinent alcoholics and indicate that their mood states may
      also be modulated by a low DHEA-S to cortisol ratio, hypothetically indicative of
      low stress protection capacities.

PMID- 10646829
TI  - Dopamine receptor D4 is not associated with antidepressant activity of sleep
      deprivation.
AB  - Total sleep deprivation (TSD) is an effective treatment for mood disorders which
      is thought to act through an enhancement in several neurotransmitter pathways
      including dopaminergic transmission. However, not all patients respond to TSD and
      genetic factors are likely to play a major role in determining TSD response. The
      aim of this study is to investigate the influence of dopamine receptor D4 exon 3
      (DRD4) variants on TSD antidepressant efficacy in bipolar disorder. One hundred
      and twenty-four depressed inpatients affected by bipolar disorder (DSM-IV) were
      treated with repeated cycles of TSD and were typed for DRD4 variants at the third
      exon using polymerase chain reaction (PCR) techniques. DRD4 variants were not
      associated with TSD outcome. Consideration of possible stratification effects
      such as gender, age at onset and duration of illness did not reveal any
      association either. DRD4 exon 3 variants are not a main factor influencing TSD
      outcome in bipolar disorder.

PMID- 10646830
TI  - Dopamine receptor responsivity in schizophrenic patients before and after switch
      from haloperidol to risperidone.
AB  - The increases that occur in plasma prolactin (PRL) levels after i.m.
      administration of 5 mg of haloperidol (the HAL test) provide information about
      the responsivity of D2 dopamine receptors in the hypothalamus-hypophysis, and may
      be a measure of their occupancy during the neuroleptic treatment of schizophrenic
      patients. We studied these responses during treatment with haloperidol (doses 7.5
      60 mg daily, mean = 20.6) in 12 male schizophrenic patients who did not have a
      satisfactory therapeutic response to the drug, and the test was repeated 6 weeks
      later, after the patients were switched to therapy with the atypical neuroleptic
      risperidone (8-16 mg daily, mean = 11.7). After the institution of risperidone
      treatment, the total score on the Brief Psychiatric Rating Scale (BPRS) fell by
      38% (from a mean score of 47.2 to 29.3). BPRS subscale scores for positive,
      negative, and general symptoms were reduced by 38, 35, and 40%, respectively.
      Moderate PRL responses to the HAL test were found during haloperidol treatment
      and no responses at all during treatment with risperidone. Baseline PRL increased
      significantly from a mean of 35.0 (S.D. = 16.0) to a mean of 55.7 ng/ml plasma
      (S.D. = 19.6). This high potency of risperidone to increase PRL levels cannot be
      explained by the serotonergic blocking activity of the drug, and seems not to be
      restricted to its D2 receptor blocking capacity.

PMID- 10646831
TI  - Evaluation of depression in schizophrenia: psychometric properties of a French
      version of the Calgary Depression Scale.
AB  - The aim of this study was to determine the psychometric properties (especially
      validity and reliability) of the French language version of the Calgary
      Depression Scale for Schizophrenia (CDSS) in schizophrenic patients. Ninety-five
      subjects who met DSM-IV criteria for schizophrenia were enrolled. The studies of
      the internal structural validity and of the reliability (internal consistency)
      showed that some items from the CDSS (early awakening and guilty ideas of
      reference) must be discussed in the constitution of this scale. The total score
      of the CDSS was significantly correlated with the MADRS total score, the HDRS
      total score, and the depression item (G6) on the PANSS, which suggests that the
      CDSS is a valid instrument for the assessment of depression in schizophrenia. The
      existence of a significant correlation between the CDSS total score and the PANSS
      positive sub-scale suggests a possible relationship between positive and
      depressive symptoms in schizophrenia.

PMID- 10646832
TI  - Screening for impaired cognitive function among the elderly in Spain: reducing
      the number of items in the Short Portable Mental Status Questionnaire.
AB  - The objectives of this work are to assess the agreement in classifying the 10th
      percentile of the population with impaired cognitive function resulting from
      different combinations of items in the Short Portable Mental Status
      Questionnaire, to evaluate the effect of literacy status on the new reduced
      versions, and to propose items less biased by education. Three data sets of
      representative samples of non-institutionalized elderly (65-year-olds and older)
      living in urban and rural communities in Spain were analyzed. Cognitive function
      was assessed using either the original or a modified Spanish version of the Short
      Portable Mental Status Questionnaire (SPMSQ). Different combinations of items
      were excluded from the scale and for each resulting reduced scale the lower 10th
      percentile of the distribution assessed a cut-off score. Cohen's kappa was used
      to test the agreement between the whole scale and the reduced scales in
      identifying the lowest 10th percentile of people with cognitive impairment. To
      test the effect of literacy status, the three samples were combined. New
      distributions were obtained for reduced versions of the scale including the items
      with the highest correlation with cognitive impairment controlling for literacy
      status. All three samples follow a similar distribution of errors. Most kappa
      values obtained when excluding one or more items from the original scales were
      between 0.80 and 0.95, while proportion of agreement varied between 94.2% and
      100%. Lack of agreement is highest when eliminating all items that represent one
      dimension. Shorter versions of the SPMSQ are as reliable as the complete 10-item
      version in identifying those at risk for cognitive dysfunction. Cut-off points
      differed by literacy status but remained stable regardless of the number of items
      included.

PMID- 10646833
TI  - Distribution of gonadotropin-releasing hormone immunoreactive systems in the
      brain of the Senegalese sole, Solea senegalensis.
AB  - The present paper reports the immunohistochemical distribution of the
      gonadotropin-releasing hormone (GnRH) structures in the brain of the Senegalese
      sole, Solea senegalensis. In this study, we have used two antibodies against the
      salmon GnRH and chicken GnRH-II forms and the streptavidin-biotin-peroxidase
      complex method. Immunoreactive cell bodies are observed at the junction between
      the olfactory bulbs and the telencephalon (terminal nerve ganglion cells), in the
      ventral telencephalon, in the preoptic parvocellular nucleus, and in the
      synencephalic nucleus of the medial longitudinal fasciculus. GnRH-immunoreactive
      fibres were found extensively throughout the brain, located in the telencephalon,
      preoptic area, hypothalamus, hypophysis, optic tectum, midbrain and
      rhombencephalon. The antisera used in this study against the two GnRH forms
      exhibited cross-reactivity on the same cell masses and did not allow cell
      populations expressing different GnRH forms to be discriminated clearly. However,
      anti-salmon GnRH immunostained the GnRH cells and fibres of the forebrain much
      more intensely, whereas the anti-chicken GnRH antiserum shows a higher
      immunoreactivity on synencephalic cells of the medial longitudinal fasciculus.

PMID- 10646834
TI  - A quantitative histochemical procedure for measurement of starch in apple fruits.
AB  - Measurements of starch (e.g. amyloplasts in stomatal guard cells, sieve elements,
      root tips or the starch sheath) is often very difficult using most analytical
      methods. An evaluation was made of interactive computer image analysis of starch
      measurements in apple fruits. The results obtained indicate that quantitative
      histochemistry can be an appropriate method to quantify starch. Correlations for
      starch values between the image analysis system and a colorimetric system were
      quantified. The thickness of plastic-embedded slices had no influence on the
      accuracy of the area occupied by image-quantified starch (starch/slice) or on its
      variance. The magnification of the objective also had no effect on measured
      starch-occupied areas (starch/slice), but there were big differences in variance.
      The number of replications required to establish statistically significant
      differences were calculated.

PMID- 10646835
TI  - Poly(ADP-ribose) immunostaining to detect apoptosis induced by a neurotoxic
      fragment of prion protein.
AB  - PrP106-126 is a synthetic peptide representing codons 106-126 of the prion
      protein, which spontaneously forms amyloid fibrils and exerts neurotoxic effects
      on primary mouse brain cell cultures. Neurotoxicity by this peptide is commonly
      used as a model for the neurotoxicity observed in prion diseases and involves the
      formation of reactive oxygen species which, in turn, can cause DNA damage,
      including DNA strand breaks. Strand breaks in nuclear DNA can activate poly(ADP
      ribose) polymerase to covalently modify nuclear proteins with poly(ADP-ribose).
      We, therefore, examined by immunofluorescence whether or not PrP106-126 triggers
      poly(ADP-ribose) formation. We observed strong poly(ADP-ribose)
      immunofluorescence signals in a fraction of cells, typically arranged in a
      clustered pattern, by 30-48 h after peptide addition. A few positive cells were
      also present in untreated cultures. Cell morphology was suggestive of apoptosis,
      and this was confirmed by positivity in the terminal deoxynucleotidyltransferase
      mediated dUTP nick-end labelling (TUNEL) assay. On the other hand, our
      immunofluorescence assay did not detect any 'early' activation of poly(ADP
      ribose) polymerase in morphologically normal cells that could have resulted from
      peptide-induced formation of reactive oxygen species. We conclude that poly(ADP
      ribose) immunostaining is a convenient and reliable method for visualizing cells
      undergoing apoptosis induced by PrP106-126.

PMID- 10646836
TI  - Immunohistochemical analysis of DNA 'mismatch-repair' enzyme human Mut-S
      Homologon-2 in ovarian carcinomas.
AB  - The human Mut-S-Homologon-2 (hMSH-2) gene product is a member of a highly
      conserved family of proteins involved in postreplication mismatch repair. We have
      analysed hMSH-2 expression in normal ovarian tissue (n = 15) and ovarian
      carcinomas (n = 40). hMSH-2 protein was investigated immunohistochemically on
      frozen sections using a highly sensitive streptavidin-peroxidase technique and a
      specific mouse monoclonal antibody (clone FE11). A hMSH-2-immunoreactivity score
      (hMSH-2-IRS) for semiquantitative analysis of hMSH-2 expression is presented. In
      normal ovarian tissue, we only found weak nuclear immunoreactivity for hMSH-2 in
      60%, while the remaining 40% were hMSH-2 negative (mean hMSH-2-IRS: 0.73; SD: +/
      0.70). All ovarian carcinomas analysed revealed moderate to strong nuclear
      immunoreactivity (mean hMSH-2-IRS: 8.05; SD: +/-3.65). hMSH-2 staining was
      heterogeneous, with visual differences between individual tumour cells.
      Expression of hMSH-2 protein was consistently and strongly upregulated in tumour
      cells of ovarian carcinomas as compared to normal ovarian tissue. No
      statistically significant correlation in comparing the labelling patterns for
      hMSH-2 with the labelling patterns for Ki-67 (mean percentage of Ki-67 positive
      tumour cells: 25.88%; SD: +/-18.43) was observed in ovarian carcinomas.
      Furthermore, no statistical significant correlations between hMSH-2-IRS and
      histological grading (p = 0.47), histological type of carcinoma (p = 0.706) or
      FIGO-classification (p = 0.054) were found. Our findings indicate that (a) hMSH-2
      is expressed in normal human ovarian tissue, (b) expression of hMSH-2 is
      increased in ovarian carcinomas, (c) expression of hMSH-2 may be of importance
      for the genetic stability of ovarian carcinomas in vivo, (d) hMSH-2 mutations may
      not cause microsatellite instability in ovarian carcinomas, (e) hMSH-2 may
      contribute to mechanisms responsible for resistance to anticancer drugs.

PMID- 10646837
TI  - Smoothelin and intermediate filament proteins in human aortocoronary saphenous
      vein by-pass grafts.
AB  - The aim of this immunohistochemical investigation was to study the distribution
      of the novel cytoskeletal protein smoothelin and the intermediate filament
      proteins vimentin and desmin in normal human great saphenous vein and in human
      aortocoronary by-pass vein grafts. Smoothelin was present in most smooth muscle
      cells in the media of the native vein. In the neointima of the vein grafts that
      had been in situ for three months or more, smoothelin was, in general, present
      only in few smooth muscle cells. Desmin was distributed in the same pattern as
      smoothelin in the native great saphenous vein. When desmin and smoothelin were
      present in the neointima, smoothelin was detected in more cells than desmin.
      Vimentin was present in most cells in all wall layers of both the native
      saphenous vein and the vein grafts. Vascular smooth muscle cells containing
      vimentin but not desmin or smoothelin are the principal cells in the neointima of
      human aortocoronary vein grafts. In some grafts, however, all three cytoskeletal
      proteins were detected in the neointima. The distribution of smoothelin and
      desmin in aortocoronary vein grafts support the postulate that these proteins are
      expressed mainly in the contractile smooth muscle cell phenotype.

PMID- 10646838
TI  - Expression profile of saccharide epitope CaMBr1 in normal and neoplastic tissue
      from dogs, cats, and rats: implication for the development of human-derived
      cancer vaccines.
AB  - CaMBr1 is a blood group-related tumour-associated antigen, whose pattern of
      expression provides a therapeutic window for passive or active immunotherapy and
      points to the promise of a vaccine against carcinomas overexpressing this
      antigen. In this context, an animal model that closely mimics the human situation
      would be extremely useful. We, therefore, utilised the murine monoclonal antibody
      MBr1, which defines CaMBr1, as a useful probe to detect the molecule targeted for
      vaccine development on canine and feline spontaneous breast and uterus tumours
      and on their normal counterparts, and on rat normal tissues and carcinoma cell
      lines. Immunoperoxidase staining of cryostat sections revealed homogeneous CaMBr1
      expression only in normal feline uterus and a uterus papilloma, whereas MBr1
      reactivity was very weak and heterogeneous in normal (1/3 and 1/3) and tumour
      (1/10 and 1/6) breast tissues from dogs and cats, respectively. In contrast, the
      data obtained in rat tissues were reproducible in the strains tested and showed
      that CaMBr1 was expressed in all epithelial tissues of the digestive tract,
      although with variable intensities. Monoclonal antibody staining appeared to
      correspond to membrane-bound structures as well as mucinous secretions.
      Similarly, secretion products of lactating mammary glands expressed CaMBr1. The
      spectrum of expression on rat digestive tract was broader than that in humans but
      the specificity of MBr1 reactivity was confirmed by competition assay with a
      synthetic tetrasaccharide that mimics the CaMBr1 antigen. On FACS analysis, only
      one of two clonal derivatives of the rat breast carcinoma line RAMA 25 expressed
      CaMBr1, and a negative cell subset was evident in repeated experiments. By
      contrast, both colon carcinoma lines, DHD/K12 and CC531, showed staining with
      MBr1, albeit at different levels of intensity, and no evidence of a negative
      subset. The cell line CC531 maintained or even increased CaMBr1 expression levels
      following transplantation in syngeneic immunocompetent animals. Our data suggest
      the usefulness of the rat as a test model for vaccines against human cancers
      overexpressing the CaMBr1 antigen.

PMID- 10646839
TI  - Lectin binding pattern and proteoglycan distribution in human eccrine sweat
      glands.
AB  - The distribution pattern of glycoconjugates in human eccrine sweat glands has
      been studied by the binding of newly discovered lectins and by antibodies against
      a chondroitin sulphate proteoglycan and chondroitin sulphate glycosaminoglycans.
      Mannose-specific lectins labelled large intracellular granules, part of which
      could be extended cisternae of the endoplasmic reticulum or Golgi apparatus. In
      contrast, lectins specific for terminal mannose/glucose residues predominantly
      labelled basement membranes and the glycocalyx. Lectins recognizing terminal N
      acetylgalactosamine groups left most parts of the glands unstained, but stained
      some dark cells intensely. These last cells were also intensively labelled by N
      acetylglucosamine-specific and by fucose-specific lectins. Sialic acid residues
      were preferentially located in luminal borders of secretory coils. No terminal
      galactose residues were detected. All antibodies against chondroitin
      glycoconjugates stained large granules similar to those revealed by the mannose
      specific lectins in the secretory cells. The basement membrane is only stained by
      the proteoglycan antibody and the chondroitin-6-sulphate antibody. Thus, a
      complex composition of glycoconjugates exists not only in matrix elements but
      also in the cells of eccrine glands of the human skin. A possible secretion of
      glycoconjugates is discussed.

PMID- 10646840
TI  - Detection of apoptotic DNA damage in prostate hyperplasia using tyramide
      amplified avidin-HRP.
AB  - Avidin binds to damaged DNA with high specificity. Avidin conjugated to
      horseradish peroxidase may therefore be used to label apoptotic DNA damage, using
      standard immunohistochemical protocols. However, the resulting label may be too
      weak to visualise. We used tyramide signal amplification to enhance the avidin
      peroxidase signal in a rat model of apoptotic damage in hyperplasic prostate
      tissue. After amplification, the difference between normal levels of apoptosis in
      the young rat prostate and the greatly reduced levels evident in aged rats was
      readily appreciated. The label was specific and the non-specific background was
      minimal. This method is particularly useful for the detection of weak apoptotic
      signals in tissue sections.

PMID- 10646841
TI  - Therapy of human pancreatic carcinoma implants by irinotecan and the oral
      immunomodulator JBT 3002 is associated with enhanced expression of inducible
      nitric oxide synthase in tumor-infiltrating macrophages.
AB  - We determined the therapeutic effect of irinotecan (CPT-11) combined with the
      immunomodulator JBT 3002, a synthetic bacterial lipopeptide (N-acylated
      derivative of psi-amino-C1-C3-alkane-sulfonic acid), against highly metastatic
      human pancreatic carcinoma cells injected into the pancreas of athymic nude mice.
      Mice received four courses consisting of three daily oral doses of JBT 3002,
      followed by once weekly i.p. injection of CPT-11. Control mice were treated with
      CPT-11 alone, JBT 3002 alone, or saline. Tumor growth and metastasis were
      assessed by gross pathology and confirmed by histological examination. Treatment
      with CPT-11 alone significantly decreased the median volume of pancreatic tumors
      and the incidence of metastasis, whereas treatment with only JBT 3002 did not.
      The combination therapy of CPT-11 plus JBT 3002 decreased tumor volume and
      incidence of metastasis significantly more than CPT-11 alone. The number of
      apoptotic cells (terminal deoxynucleotidyl transferase-mediated nick end labeling
      assay), the number of scavenger-receptor-positive macrophages, and expression
      level of inducible nitric oxide synthase (iNOS) within lesions directly
      correlated with therapeutic effects. Indeed, the in vitro incubation of tumor
      cells with macrophages activated by JBT 3002 plus IFN-gamma produced a
      significant lysis of tumor cells that could be blocked by a specific inhibitor of
      iNOS. Collectively, these data demonstrate that the oral administration of the
      immunomodulator JBT 3002 combined with i.p. injection of CPT-11 can decrease the
      growth of human pancreatic carcinoma and the incidence of metastasis in nude mice
      by both a direct antitumor effect and the activation of iNOS in infiltrating
      macrophages.

PMID- 10646842
TI  - Mutations in the retinoblastoma-related gene RB2/p130 in primary nasopharyngeal
      carcinoma.
AB  - Nasopharyngeal carcinoma (NPC) is an endemic cancer in southern China and
      northern Africa, and its pathogenesis is not yet well defined at the molecular
      level. Although the involvement of p53 and of the retinoblastoma gene (RB/p105)
      in NPC has been well studied, there is paucity of mutational data regarding the
      retinoblastoma-related gene RB2/p130 in primary tumors and particularly in NPC.
      We have shown previously that RB2/p130 could be rearranged in a nasopharyngeal
      cell line. In the present study, we screened by single-strand conformation
      polymorphism and sequence analysis the retinoblastoma-related gene RB2/p130 for
      mutations within exons 19-22. Mutations in the RB2/p130 gene were detected in 3
      of 10 primary human NPCs from Northern Africa (30%). These findings, along with
      previous data showing that genetic replacement of RB2/p130 restores a normal
      growth pathway in the nasopharyngeal cell line Hone-1, strengthen the hypothesis
      that genetic changes of RB2/p130 may be involved in the development and/or
      progression of nasopharyngeal cancer and suggest that RB2/p130 could be
      considered a tumor suppressor gene and may be a candidate for novel gene
      therapeutic approaches for NPC.

PMID- 10646843
TI  - Molecular cloning and characterization of human MAWD, a novel protein containing
      WD-40 repeats frequently overexpressed in breast cancer.
AB  - A full-length cDNA clone encoding a novel protein containing WD-40 repeats, which
      were frequently involved in protein-protein interactions, was isolated and
      sequenced. This clone had a predicted open reading frame (ORF) encoding 350 amino
      acids possessing six repeats of WD-40 motif. It was most closely homologous to
      TRIP-1, a phosphorylation substrate of the transforming growth factor-beta type
      II receptor. In the process of characterizing the function of the new gene
      product, we found that overexpression of the gene seemed to activate mitogen
      activated protein kinase and to promote anchorage-independent growth of the
      cells. Moreover, the gene product was frequently overexpressed in human tumor
      breast tissues compared with their normal breast tissues, suggesting that the
      gene might be involved in the tumor progression. Radiation hybrid mapping placed
      the gene into human chromosome 12q11-12 near the marker D12S1593.

PMID- 10646844
TI  - Loss of fragile histidine triad expression in colorectal carcinomas and
      premalignant lesions.
AB  - Abnormal expression of the fragile histidine triad (FHIT) candidate tumor
      suppressor gene has been observed in a variety of human tumors, but little is
      known about its expression during colorectal tumorigenesis. Sections of 70
      aberrant crypt foci (ACF), 55 adenomas, 84 primary colorectal carcinomas, and 13
      metastatic lesions were evaluated immunohistochemically for Fhit expression. All
      normal colonic epithelium showed a strong expression of Fhit; 44% of carcinomas
      showed a marked loss or absence of Fhit expression. The proportion of carcinomas
      with reduced expression showed an increasing trend (a) with decreasing
      differentiation and (b) in tumors with metastases (62%) compared with tumors
      without metastases (38%). The proportion of metastatic lesions (12 of 13) with
      reduced expression of Fhit was even greater. Although only a small proportion of
      ACF and adenomas showed a reduction of Fhit expression, the reduced expression of
      Fhit was strongly associated with the degree of dysplasia in both ACF (P =
      0.0002) and adenomas (P = 0.0085). The findings of reduced expression of Fhit in
      a small proportion of colonic precancerous lesions and in increased proportions
      of primary and metastatic colorectal cancers suggest that Fhit plays a role in
      the development and progression of some colon carcinomas.

PMID- 10646845
TI  - Increased p53-dependent apoptosis by the insulin-like growth factor binding
      protein IGFBP-3 in human colonic adenoma-derived cells.
AB  - We investigated the expression of insulin-like growth factor binding protein 3
      (IGFBP-3) in normal human colonic epithelium and whether IGFBP-3 is involved in
      the induction of apoptosis in colonic epithelial cells. A gradient of IGFBP-3
      protein expression was observed within the normal colonic crypt, and increased
      IGFBP-3 expression was coincident with the region of increased differentiation
      and apoptosis. Treatment of human colonic tumor cell lines with IGFBP-3 alone was
      shown to have no effect on growth. However, an increase in p53-dependent
      apoptosis was observed in the presence of 100 ng/ml IGFBP-3 24 h after the
      induction of DNA damage by gamma-irradiation. These results suggest that IGFBP-3
      enhances the p53-dependent apoptotic response of colorectal cells to DNA damage.

PMID- 10646846
TI  - Tumor progression is accompanied by significant changes in the levels of
      expression of polyamine metabolism regulatory genes and clusterin (sulfated
      glycoprotein 2) in human prostate cancer specimens.
AB  - Using Northern blotting, the expression levels of the genes for polyamine
      metabolism regulatory proteins and clusterin have been measured in a series of 23
      human prostate cancers (CaPs) dissected from radical prostatectomy specimens.
      Patient matched, nontumor tissue was dissected from benign areas of the gland.
      The results indicate that transcripts encoding ornithine decarboxylase (ODC), ODC
      antizyme, adenosylmethionine decarboxylase, and spermidine/spermine N1
      acetyltransferase (SSAT) were significantly higher, whereas clusterin (sulfated
      glycoprotein 2) mRNA was significantly lower in tumors compared with the benign
      tissue. All mRNA levels were compared with those of histone H3 and growth arrest
      specific gene 1, markers of cell proliferation and cell quiescence, respectively,
      and glyceraldehyde 3-phosphate dehydrogenase, a housekeeping gene. In poorly
      differentiated and locally invasive CaPs and in tumors with unfavorable prognosis
      or total prostate-specific antigen (PSA) levels > 10.0 ng/ml at diagnosis, an
      overall increase in the levels of H3 mRNA and a decrease in growth arrest
      specific gene 1 mRNA was detected, indicative of higher proliferation activity,
      whereas the differences in expression levels for the polyamine metabolism and
      clusterin genes were higher. ODC and SSAT changes were positively correlated in
      normal tissue but not in high-grade cancer, whereas ODC antizyme and SSAT changes
      were positively correlated in more malignant CaPs but not in normal tissue. Tumor
      classification based on the changes in expression levels of all of the genes
      studied could be correlated to differentiation grade and local invasiveness
      classification systems in 72.2 and 83.3% of the cases, respectively. In a 1-year
      follow-up period, three patients whose CaPs ranked as less aggressive according
      to clinical staging, but classified as advanced cancers with the proposed
      molecular classification, showed increases in total PSA levels, indicative of
      tumor relapse. Thus, molecular classification, based on gene expression, may
      enhance the available prognostic tools for prostate tumors.

PMID- 10646847
TI  - Threonine phosphorylation of the MMAC1/PTEN PDZ binding domain both inhibits and
      stimulates PDZ binding.
AB  - Two-hybrid searches with the tumor suppressor MMAC1/PTEN isolated the proteins
      hDLG and hMAST205. Further two-hybrid analysis and microtiter plate binding
      assays localized the sites of interaction to PDZ domains from hDLG and hMAST205
      and the PDZ binding domain at the COOH terminus of MMAC1/PTEN. A synthetic
      peptide derived from the MMAC1/PTEN PDZ binding domain (MMAC1/PTEN-PDZBD) was
      used to coprecipitate proteins from A431 human cell lysate. The recovered
      proteins were resolved by SDS-PAGE and immobilized on a nitrocellulose membrane.
      Treatment of this membrane with an anti-hDLG antibody identified a Mr 140,000
      band, consistent with the size of hDLG. Treatment of this membrane with the
      MMAC1/PTEN-PDZBD peptide identified a single prominent band of slightly larger
      than Mr 200,000 (Mr 200,000 kDa). Threonine phosphorylation of the MMAC1/ PTEN
      PDZBD peptide inhibited both microtiter plate binding to the hDLG and hMAST205
      PDZ domains and coprecipitation of the Mr 140,000 and > 200,000 proteins, but
      promoted coprecipitation of proteins of approximately Mr 90,000 and Mr 120,000
      from A431 cell lysate. This result suggests phosphorylation of the MMAC1/PTEN PDZ
      binding domain can both inhibit and promote PDZ interactions.

PMID- 10646848
TI  - Carcinogenic nickel induces genes involved with hypoxic stress.
AB  - Carcinogenic nickel compounds alter the program of gene expression in normal
      cells and induce a pattern of gene expression similar to that found in nickel
      induced cancers. Here we have demonstrated that nickel exposure induced hypoxic
      signaling pathways by inducing hypoxia-inducible transcription factor-1 (HIF-1),
      which mediated the induction of genes required by cells to survive hypoxia. We
      also show that a new gene, Cap43, is dependent upon HIF-1 because only HIF-1
      proficient cells induced Cap43 when exposed to either hypoxia or nickel. We also
      show that glyceraldehyde-3-phosphate dehydrogenase, a gene induced by hypoxia
      through HIF-1, was similar to Cap43 in that it required HIF-1-proficient cells to
      be induced by either nickel or hypoxia. These data demonstrate that nickel
      exposure turns on signaling for hypoxic stress, which may be important in its
      carcinogenesis.

PMID- 10646849
TI  - Tumor suppression and sensitization to tumor necrosis factor alpha-induced
      apoptosis by an interferon-inducible protein, p202, in breast cancer cells.
AB  - p202, an IFN-inducible protein, interacts with several important regulatory
      proteins, leading to growth arrest or differentiation. In this report, we
      demonstrate that, in addition to inhibiting in vitro cell growth, p202 can also
      suppress the tumorigenicity of breast cancer cells in vivo. Furthermore, we found
      that p202 expression could sensitize breast cancer cells to apoptosis induced by
      tumor necrosis factor alpha treatment. One possible mechanism contributing to
      this sensitization is the inactivation of nuclear factor-kappaB by its
      interaction with p202. These results provide a scientific basis for a novel
      therapeutic strategy that combines p202 and tumor necrosis factor alpha treatment
      against breast cancer.

PMID- 10646850
TI  - Fumitremorgin C reverses multidrug resistance in cells transfected with the
      breast cancer resistance protein.
AB  - Fumitremorgin C (FTC) is a potent and specific chemosensitizing agent in cell
      lines selected for resistance to mitoxantrone that do not overexpress P
      glycoprotein or multidrug resistance protein. The gene encoding a novel
      transporter, the breast cancer resistance protein (BCRP), was recently found to
      be overexpressed in a mitoxantrone-selected human colon cell line, S1-M1-3.2,
      which was used to identify FTC. Because the drug-selected cell line may contain
      multiple alterations contributing to the multidrug resistance phenotype, we
      examined the effect of FTC on MCF-7 cells transfected with the BCRP gene. We
      report that FTC almost completely reverses resistance mediated by BCRP in vitro
      and is a pharmacological probe for the expression and molecular action of this
      transporter.

PMID- 10646851
TI  - Enhancement of tumor-specific immune response with plasmid DNA replicon vectors.
AB  - To enhance the immunogenicity of nucleic acid vaccines, we used plasmid DNA
      vectors that contained replicons derived from the prototype alphavirus, Sindbis,
      and another alphavirus, Semliki Forest virus. When transfected into cells or
      injected directly into animal muscle, these plasmids launch a self-replicating
      RNA vector (replicon) which in turn directs the expression of a model tumor
      antigen. Immunization with plasmid DNA replicons elicited immune responses at
      doses 100 to 1000-fold lower than conventional DNA plasmids and effectively
      treated mice bearing an experimental tumor expressing the model antigen.
      Significantly, replicon-based DNA plasmids did not produce a greater quantity of
      antigen; instead, antigen production differed qualitatively. Plasmid DNA
      replicons mediated antigen production that was homogeneous in all transfected
      cells and associated with the apoptotic death of the host cells. Because of their
      safety and efficacy, plasmid DNA replicons may be useful in the development of
      recombinant vaccines for infectious diseases and cancer.

PMID- 10646852
TI  - A novel form of prostate-specific antigen transcript produced by alternative
      splicing.
AB  - Molecular characterization of prostate-specific antigen (PSA) has not been well
      elucidated, despite a great deal of clinical study. We examined the heterogeneity
      of PSA using reverse transcription-PCR and direct sequencing. A novel,
      alternatively spliced variant of the PSA transcript was found in prostate cancer
      (PC), as well as in benign prostatic tissue. This alternative splicing leads to
      the deletion of 44 amino acid residues (amino acids 45-88) from mature PSA,
      resulting in the loss of asparagine 45, which is a binding site for a
      carbohydrate chain. By these nested reverse transcription-PCR systems, this
      novel, alternatively spliced PSA gene was recognized in 13 of 18 (72.2%) cases
      with noncancerous prostate tissue, 4 of 5 (80.0%) PC cases, and 3 of 12 (25.0%)
      blood samples from PC patients (noncancerous prostate tissue group versus blood
      sample group, P = 0.011). At present, the biological significance of this
      alternative splicing remains to be established.

PMID- 10646853
TI  - Identical clonality of sporadic gastrinomas at multiple sites.
AB  - Gastrinomas are neuroendocrine neoplasms that occur sporadically and in patients
      with multiple endocrine neoplasia type 1 (MEN1). In MEN1, multiple gastrinomas
      have been shown to arise by independent clonal events (Debelenko, et al., Cancer
      Res., 57: 2238-2243, 1997). The purpose of the present study was to analyze
      clonality in 20 sporadic gastrinomas from eight patients in whom the tumor was
      present in at least two separate sites. A combination of methods was used to
      assess clonality, including MEN1 gene mutation analysis, loss of heterozygosity
      analysis of the MEN1 locus, and analysis of X-chromosome inactivation at the
      human androgen receptor locus (human androgen receptor analysis). In three
      patients, a somantic MEN1 gene mutation was detected in the tumor. Identical
      mutations were found in other tumors at different sites within the same patients.
      Human androgen receptor analysis in three informative patients and loss of
      heterozygosity analysis in five patients revealed identical clonal patterns in
      the tumors from multiple sites in each patient. We conclude that sporadic
      gastrinomas at multiple sites are monoclonal and that MEN1 gene alterations in
      gastrinomas occur before the development of tumor metastases.

PMID- 10646854
TI  - N-Myc induction stimulated by insulin-like growth factor I through mitogen
      activated protein kinase signaling pathway in human neuroblastoma cells.
AB  - Insulin-like growth factor I (IGF-I) stimulates proliferation, survival, and
      differentiation in many cell types, including pediatric neuroblastomas. The
      effect is mediated via the type I IGF-I receptor (IGF-IR), which is essential for
      growth in these cells. Several lines of evidence indicate that IGF-IR function
      may be particularly important in the pathogenesis of neuroblastoma. Amplification
      of the N-myc oncogene or overexpression of N-Myc oncoprotein has been reported to
      be associated with resistance to therapy and poor prognosis of neuroblastomas. It
      was therefore of interest to analyze whether IGF-I signaling regulated expression
      of N-myc in KP-N-RT human neuroblastoma cells as an experimental model that has
      amplified N-myc. We found that IGF-I induces N-myc mRNA and protein in the KP-N
      RT with maximums of four and six times more than the basal level at 2 and 3 h
      after stimulation, respectively. These effects of IGF-I were blocked by a
      neutralizing antibody against IGF-IR (alpha-IR3). Exogenous IGF-I induced
      phosphorylation and activation of extracellular signal-regulated kinases p44/42
      (ERK1 and ERK2), with a maximal level 30 min after the stimulation. The MEK1
      inhibitor PD98059 reduced IGF-I-mediated p44/42 MAPKs phosphorylation and
      produced a parallel reduction of IGF-I-stimulated N-Myc induction. Furthermore,
      both alpha-IR3 and PD98059 inhibited G1-S cell cycle progression stimulated by
      IGF-I. Our results demonstrate that IGF-I induces N-Myc in the KP-N-RT
      neuroblastoma cell line at the RNA level and establishes a clear correlation
      between N-Myc induction and activation of p44/42 MAPK signaling.

PMID- 10646856
TI  - Organ-specific, carcinogen-induced increases in cell proliferation in p53
      deficient mice.
AB  - Transgenic mice with germ-line p53 alleles disrupted by gene targeting are
      sensitive to the development of some spontaneous tumors and have provided
      researchers with much information with respect to cancer. In the present study,
      to cast light on the organ specificity of chemically induced carcinogenesis, we
      evaluated carcinogen-induced cell proliferation in target organs in heterozygote
      p53 knockout mice (p53-deficient mice). Groups of 9- or 10-week-old wild
      type(+/+) and p53-deficient mice were respectively treated with one of the
      following carcinogens for 4 weeks: N-butyl-N-(4-hydroxybutyl)nitrosamine (0.0075%
      in drinking water); dimethylnitrosamine (0.001% in drinking water); dihydroxy-di
      N-propylnitrosamine (0.1% in drinking water); 1,2-dimethylhydrazine (10 mg/kg
      body weight s.c. injection once a week); 4-nitroquinoline 1-oxide (4-NQO, 10
      mg/kg b.w. s.c. injection once a week); or 7,12-dimethylbenz(a)anthracene (25
      microg/kg body weight dermal application once a week). Cell proliferation was
      evaluated by measuring the 5-bromo-2'-deoxyuridine labeling indices in each
      target organ. The p53 and p21 statuses were evaluated by comparing the
      expressions of p53 protein, p21waf1/cip1 mRNA, and p21waf1/cip1 protein between
      the mice. 5-Bromo-2'-deoxyuridine labeling indices of the urinary bladder and the
      skin were significantly increased in p53-deficient mice as compared with the wild
      type(+/+) mice. In the all organs examined, carcinogen-induced p21waf1/cip1 mRNA
      overexpression was detected with levels obviously lower in the p53-deficient
      animals. These data suggest that p53-deficient mice have an organ-specific
      increased sensitivity to the induction of cell proliferation in the urinary
      bladder and the skin. These are the same organs for which sensitivity to
      carcinogenesis has been reported. Because a decrease of p21waf1/cip1 protein
      overexpression was also observed in the organs in which cell proliferation did
      not appreciably differ from the level in wild-type(+/+) mice, this decrease might
      have no effect on sensitivity to cell proliferation and carcinogenesis.
      Alternatively, it might play an important role in the cell cycle regulation of
      only the sensitive organs.

PMID- 10646855
TI  - A distinct tumor suppressor gene locus on chromosome 15q21.1 in sporadic form of
      colorectal cancer.
AB  - The SM1311 family is an Ashkenazi family with dominantly inherited predisposition
      to colorectal adenomas and carcinomas and has a high-penetrance locus in
      chromosome 15q, with a multipoint logarithm of the odds score of 3.06 at marker
      D15S118. In the present study, we performed a high-density loss of heterozygosity
      study with 13 polymorphic microsatellite markers, including D15S118, spanning
      15q15.3-q22.1, on 70 cases of the sporadic form of colorectal tumors. Our
      deletion mapping data showed a locus at D15S968 in chromosomal sub-band 15q21.1
      may harbor a tumor suppressor gene in an area <0.521 Mb in physical map distance
      defined by markers D15S514 and D15S222. THBS1, 0.185 Mb proximal to D15S968, is
      the nearest known gene to this specific narrow loss of heterozygosity region.
      Thus, we speculate that THBS1 might be the most probable candidate gene involved
      in colorectal cancer carcinogenesis.

PMID- 10646857
TI  - Polysialylated-neural cell adhesion molecule expression in rat pituitary
      transplantable tumors (spontaneous mammotropic transplantable tumor in Wistar
      Furth rats) is related to growth rate and malignancy.
AB  - Pituitary adenomas are usually benign neuroendocrine tumors. However, some of
      those that are histopathologically undistinguishable behave aggressively and
      metastasize. The polysialylated neural cell adhesion molecule (PSA-NCAM), which
      is highly expressed during the development of the brain and pituitary, is
      detected in some neuroendocrine tumors and might be relevant as a prognostic
      marker in pituitary tumors. In the present study, we have searched for PSA-NCAM
      expression in four lineages of rat pituitary transplantable tumors (SMtTW). Each
      lineage, maintained by serial tumor grafts under the kidney capsule and skin,
      differed in its GH/Prl secretion, growth rate, and malignant behavior. PSA-NCAM
      expression, detected by immunohistochemistry and Western blotting and quantified
      by ELISA, varied according to the SMtTW lineage. The benign tumors, SMtTW2, with
      a low growth rate never expressed PSA-NCAM. Another benign lineage, SMtTW3, with
      a high growth rate expressed a low amount of PSA-NCAM. The highest PSA-NCAM
      expression was seen in tumors that grew beneath the skin, invaded the kidney, and
      metastasized (SMtTW4). Tumors of the SMtTW10 lineage, which behaved as either
      benign or malignant tumors, were heterogeneous in terms of PSA-NCAM expression.
      In this rat transplantable pituitary tumor model, PSA-NCAM expression correlated
      in decreasing order with: (a) invasiveness (P < 0.0001), (b) metastases (P =
      0.004), (c) ability to grow under the skin (P = 0.006), and (d) growth rate under
      the kidney capsule (P < 0.01), but not with hormone secretion (r = 0.207). This
      model, which is very similar to the human pathology, suggests that PSA-NCAM
      evaluation is of interest in the diagnosis of malignancy and the prognosis of
      human pituitary tumors. In addition, the SMtTW tumors could be instrumental in
      evaluating the effects of new therapeutic agents modulating PSA-NCAM expression.

PMID- 10646858
TI  - Re-evaluating gadolinium(III) texaphyrin as a radiosensitizing agent.
AB  - Gadolinium(III) texaphyrin (Gd-tex) was recently proposed as a radiosensitizing
      agent that combines preferential tumor uptake with detection of drug localization
      by magnetic resonance imaging (S. W. Young et al., Proc. Natl. Acad. Sci. USA,
      93: 6610-6615, 1996). In view of the initial report on this compound, four
      radiobiology laboratories undertook independent efforts to further study
      radiosensitization by Gd-tex. In addition to repeating the previously reported
      studies on Gd-tex in HT-29 cells, we tested five other human tumor cell lines (U
      87 MG, U251-NCI, SW480, A549, and MCF-7). These studies included a Gd-tex
      treatment period of 24 h before irradiation (as in the original publication),
      with concentrations of Gd-tex ranging from 20-500 microM. In neither the HT-29
      cells nor any of the other five human cell lines did we see radiation
      sensitization by Gd-tex. Two cell lines (MCF-7 and U-87 MG) were further tested
      for radiosensitization by Gd-tex under hypoxic conditions. No radiosensitization
      was observed in either case. Finally, the radiation response of two tumor lines
      were assessed in vivo. Neither HT-29 xenografts in severe combined
      immunodeficient (SCID) mice nor RIF-1 tumors growing in C3H mice demonstrated
      radiosensitization after Gd-tex treatment before single or fractionated doses of
      radiation. Our results raise questions about the efficacy of Gd-tex as a
      radiosensitizing agent.

PMID- 10646859
TI  - Radiosensitivity of thymidylate synthase-deficient human tumor cells is affected
      by progression through the G1 restriction point into S-phase: implications for
      fluoropyrimidine radiosensitization.
AB  - Recent studies of fluoropyrimidine (FP)-mediated radiosensitization (RS) have
      focused on the molecular mechanisms underlying regulation of the cell cycle,
      particularly at the G1-S transition. Although thymidylate synthase (TS)
      inhibition by FP is necessary, we hypothesize that FP-RS is temporally dependent
      on progression of cells into S-phase under conditions of altered deoxynucleotide
      triphosphate pools, particularly an increased dATP:dTTP ratio, which subsequently
      results in enhanced DNA fragmentation and cell death. To better understand the
      mechanism of FP-RS, we characterized the cellular and biochemical responses to
      ionizing radiation (IR) alone, using different synchronization techniques in two
      isogenic, TS-deficient mutant cell lines, JH-1 (TS-) and JH-2 (Thy4), derived
      previously from a human colon cancer cell line. After G0 synchronization by
      leucine deprivation, these clones differ under subsequent growth conditions and
      dThd withdrawal: JH-2 cells have an intact G1 arrest (>72 h) and delayed cell
      death (>96 h), whereas JH-1 cells progress rapidly into early S-phase and undergo
      acute cell death (<24 h). No difference in the late S-phase and G2-M cell
      populations were noted between these growth-stimulated, G0-synchronized TS
      deficient cell lines with dThd withdrawal. Biochemically, the intracellular ratio
      of dATP:dTTP increased substantially in JH-1 cells as cells progressed into early
      S-phase compared with JH-2 cells, which remained in G1 phase. Synchronized JH-1
      cells showed significantly decreased clonogenic survival and an increase in DNA
      fragmentation after IR when compared with JH-2 cells. RS was demonstrated by an
      increase in alpha and decrease in beta, using linear quadratic analyses. An
      alternative synchronization technique used mimosine to induce a block in late G1,
      close to G1-S border. Both JH-1 and JH-2 cells, synchronized in late G1 and
      following growth stimulation, now progressed into S-phase identically (<24 h),
      with similarly increased dATP:dTTP ratios under dThd withdrawal conditions. These
      late G1-synchronized JH-1 and JH-2 cells also showed a comparable reduction in
      clonogenic survival and similar patterns of increased DNA fragmentation following
      IR. We suggest, based on the cellular and biochemical differences in response to
      IR between G0- and late G1-synchronized cells, that S-phase progression through
      the G1 restriction point under an altered (increased) dATP:dTTP ratio is a major
      determinant of FP-RS.

PMID- 10646860
TI  - APCL, a central nervous system-specific homologue of adenomatous polyposis coli
      tumor suppressor, binds to p53-binding protein 2 and translocates it to the
      perinucleus.
AB  - APCL, a central nervous system-specific sequence homologue of the adenomatous
      polyposis coli tumor suppressor, can regulate the cytoplasmic level of beta
      catenin as the adenomatous polyposis coli tumor suppressor does, but its overall
      biological function remains unclear. Using a yeast two-hybrid system, we
      attempted to isolate proteins that might associate with the unique COOH-terminus
      of APCL. Among 166 cDNA clones isolated from a human fetal-brain cDNA library as
      candidates for interaction with APCL, 32 encoded parts of p53-binding protein 2
      (53BP2), a molecule that interacts with p53 and Bcl2. An in vitro binding assay
      indicated that the Src-homology-3 domain and the ankyrin-repeat domain of 53BP2
      were both required for binding to the COOH-terminus of APCL. Confocal microscopy
      showed that APCL and 53BP2 proteins were localized together in the perinuclei of
      normal mammalian cells, but this was not the case in cells that expressed
      truncated APCL and 53BP2 proteins. These findings suggested that binding of the
      COOH-terminus of APCL to 53BP2 regulates the cytoplasmic location of 53BP2.
      Because 53BP2 also interacts with p53 and Bcl2 and regulates p53 function, our
      results suggest that APCL might be involved in the p53/Bcl2-linked pathway of
      cell-cycle progression and cell death.

PMID- 10646861
TI  - PLAG1, the main translocation target in pleomorphic adenoma of the salivary
      glands, is a positive regulator of IGF-II.
AB  - PLAG1, a novel developmentally regulated C2H2 zinc finger gene, is consistently
      rearranged and overexpressed in pleomorphic adenomas of the salivary glands with
      8q12 translocations. In this report, we show that PLAG1 is a nuclear protein that
      binds DNA in a specific manner. The consensus PLAG1 binding site is a bipartite
      element containing a core sequence, GRGGC, and a G-cluster, RGGK, separated by
      seven random nucleotides. DNA binding is mediated mainly via three of the seven
      zinc fingers, with fingers 6 and 7 interacting with the core and finger 3 with
      the G-cluster. In transient transactivation assays, PLAG1 specifically activates
      transcription from its consensus DNA binding site, indicating that PLAG1 is a
      genuine transcription factor. Potential PLAG1 binding sites were found in the
      promoter 3 of the human insulin-like growth factor II (IGF-II) gene. We show that
      PLAG1 binds IGF-II promoter 3 and stimulates its activity. Moreover, IGF-II
      transcripts derived from the P3 promoter are highly expressed in salivary gland
      adenomas overexpressing PLAG1. In contrast, they are not detectable in adenomas
      without abnormal PLAG1 expression nor in normal salivary gland tissue. This
      indicates a perfect correlation between PLAG1 and IGF-II expression. All of these
      results strongly suggest that IGF-II is one of the PLAG1 target genes, providing
      us with the first clue for understanding the role of PLAG1 in salivary gland
      tumor development.

PMID- 10646862
TI  - Frequent genetic heterogeneity in the clonal evolution of gynecological
      carcinosarcoma and its influence on phenotypic diversity.
AB  - Carcinosarcomas of the uterus, ovaries, and fallopian tubes are highly aggressive
      neoplasms with incompletely understood histogenesis. Although recent
      immunohistochemical, cell culture, and molecular genetic studies all favor these
      cancers to be monoclonal in origin, the extent of intratumoral genetic
      heterogeneity in these tumors with divergent histology has not been reported
      previously. For this study, we microdissected a total of 172 carcinomatous or
      sarcomatous foci from 17 gynecological carcinosarcomas and analyzed allelic
      status with 41 microsatellite markers on chromosomal arms 1p, 1q, 3p, 4q, 5q, 6q,
      8p, 9p, 10q, 11p, 11q, 13q, 16q, 17p, 17q, 18q, and 22q. With the exception of a
      single case with microsatellite instability, we found shared allelic losses and
      retentions among multiple individually dissected foci of each case, strongly
      supportive of the concept of a monoclonal origin for these neoplasms. In eight of
      these cases, we also found heterogeneous patterns of allelic loss at limited
      numbers of chromosomal loci in either the carcinomatous or sarcomatous components
      of the neoplasms. These heterogeneous patterns of allelic losses were consistent
      with either genetic progression or genetic diversion occurring during the clonal
      evolution of these neoplasms. In two cases, we found the specific patterns of
      genetic progression to be consistent with sarcomatous components of the neoplasms
      arising from carcinomatous components. We conclude that most of the gynecological
      carcinosarcomas have a monoclonal origin, and that genetic progression and
      diversion parallel the development of divergent phenotypes in these tumors.
      Because phenotypically divergent areas of the tumors share numerous genetic
      alterations, this divergence most likely occurs relatively late in the evolution
      of these tumors.

PMID- 10646864
TI  - Hypermethylation-associated inactivation of p14(ARF) is independent of p16(INK4a)
      methylation and p53 mutational status.
AB  - The INK4a/ARF locus encodes two cell cycle-regulatory proteins, p16INK4a
      andp14ARF, which share an exon using different reading frames. p14ARF antagonizes
      MDM2-dependent p53 degradation. However, no point mutations in p14ARF not
      altering p16INK4a have been described in primary tumors. We report that p14ARF is
      epigenetically inactivated in several colorectal cell lines, and its expression
      is restored by treatment with demethylating agents. In primary colorectal
      carcinomas, p14ARF promoter hypermethylation was found in 31 of 110 (28%) of the
      tumors and observed in 13 of 41 (32%) colorectal adenomas but was not present in
      any normal tissues. p14ARF methylation appears in the context of an adjacent
      unmethylated p16INK4a promoter in 16 of 31 (52%) of the carcinomas methylated at
      p14ARF. Although p14ARF hypermethylation was slightly overrepresented in tumors
      with wild-type p53 compared to tumors harboring p53 mutations [19 of 55 (34%)
      versus 12 of 55 (22%)], this difference did not reach statistical significance.
      p14ARF aberrant methylation was not related to the presence of K-ras mutations.
      Our results demonstrate that p14ARF promoter hypermethylation is frequent in
      colorectal cancer and occurs independently of the p16INK4a methylation status and
      only marginally in relation to the p53 mutational status.

PMID- 10646863
TI  - ICBP90, a novel human CCAAT binding protein, involved in the regulation of
      topoisomerase IIalpha expression.
AB  - The one-hybrid system with an inverted CCAAT box as the DNA target sequence was
      used to identify proteins acting on key DNA sequences of the promoter of the
      topoisomerase IIalpha gene. Screening of cDNA libraries from the leukemia Jurkat
      cell line and from the adult human thymus resulted in the isolation of a novel
      protein of 793 amino acids (89,758 Da). This protein has in vitro CCAAT binding
      properties and has been called ICBP90. Adult thymus, fetal thymus, fetal liver,
      and bone marrow, known as active tissues in terms of cell proliferation, are the
      tissues richest in ICBP90 mRNA. In contrast, highly differentiated tissues and
      cells such as the central nervous system and peripheral leukocytes are free of
      ICBP90 mRNA. Western blotting experiments showed a simultaneous expression of
      topoisomerase IIalpha and ICBP90 in proliferating human lung fibroblasts.
      Simultaneous expression of both proteins has also been observed in HeLa cells,
      but in both proliferating and confluent cells. Overexpression of ICBP90 in COS-1
      transfected cells induced an enhanced expression of endogenous topoisomerase
      IIalpha. Immunohistochemistry experiments showed that topoisomerase IIalpha and
      ICBP90 were coexpressed in proliferating areas of paraffin-embedded human
      appendix tissues and in high-grade breast carcinoma tissues. We have identified
      ICBP90, which is a novel CCAAT binding protein, and our results suggest that it
      may be involved in topoisomerase IIalpha expression. ICBP90 may also be useful as
      a new proliferation marker for cancer tissues.

PMID- 10646865
TI  - Beta1,6-N-acetylglucosamine-bearing N-glycans in human gliomas: implications for
      a role in regulating invasivity.
AB  - The metastatic potential of tumor cells has been shown to be correlated with the
      expression of tri- and tetra-antennary beta1,6-N-acetylglucosamine (beta1,6
      GlcNAc)-bearing N-glycans, which are recognized by Phaseolus vulgaris
      leukoagglutinating lectin (L-PHA). The expression of beta1,6-GlcNAc-bearing N
      glycans also has been used as a marker of tumor progression in human breast and
      colon cancers. In this report, the role of N-glycan branching in regulating
      glioma migration and invasion was examined. The expression of beta1,6-GlcNAc
      bearing N-glycans was found in human glioma specimens, whereas astrocytes from
      normal adult brain were negative. The expression of N
      acetylglucosaminyltransferase V (GnT-V) mRNA, which is responsible for the
      biosynthesis of beta1,6-GlcNAc-bearing N-glycans, was high in glioma cell lines
      with robust ets-1 expression. To study the molecular mechanism of GnT-V
      expression in human glioma cells, an inducible ets-1 gene was stably transfected
      into SNB-19 cells using a tetracycline repressor system. GnT-V mRNA expression
      was increased by the induction of c-ets-1, suggesting that the Ets-1
      transcription factor directly regulates the transcription of GnT-V. Stable
      transfection of GnT-V into human glioma U-373 MG cells resulted in changes in
      cell morphology and focal adhesions and a marked increase in glioma invasivity in
      vitro. L-PHA has little effect on cell migration. On the contrary, Phaseolus
      vulgaris erythroagglutinating lectin (E-PHA), which recognizes bisecting beta1,4
      GlcNAc-bearing N-glycans, strongly inhibits cell migration (haptotaxis) on a
      fibronectin substrate in U-373 MG transfectants and other glioma cell lines
      tested. These results suggest that the increased beta1,6-GlcNAc-bearing N-glycan
      expression found in malignant gliomas is modulated by GnT-V through the Ets-1
      transcription factor, and that the branching of complex type N-glycans plays a
      major role in glioma invasivity.

PMID- 10646866
TI  - c-Myc suppresses the tumorigenicity of lung cancer cells and down-regulates
      vascular endothelial growth factor expression.
AB  - The c-myc oncogene is frequently amplified in cells grown from lung tumors and
      has been linked to the malignancy of these cancers. In support of this, c-myc
      transfection enhances the in vitro proliferation and soft agar cloning of human
      small cell lung cancer (SCLC) cells. In this study, we surprisingly found that c
      myc expression suppressed the formation of tumors by SCLC cells in athymic nude
      mice. c-myc expression down-regulated the protein and transcript for vascular
      endothelial growth factor (VEGF) in these SCLC cells, as well as VEGF transcript
      in rat fibroblasts manipulated for c-myc expression and in liver cells of c-myc
      transgenic mice. Finally, bivariate and multivariate analyses demonstrated that
      the probability of tumor formation from lung cancer cell lines was negatively
      correlated with the relative expression of c-Myc, positively correlated with the
      relative expression of VEGF, and that the latent time to tumor formation was
      increased by the expression of c-Myc and decreased by the expression of VEGF. We
      hypothesize that, for lung cancer cells, c-Myc suppresses the formation of tumors
      in vivo by down-regulating VEGF, and that the amplification of c-myc seen in
      cells grown from lung tumors with a poor prognosis is an artifact of selection
      for growth in vitro.

PMID- 10646867
TI  - High levels of stromal hyaluronan predict poor disease outcome in epithelial
      ovarian cancer.
AB  - Several malignant tumors accumulate hyaluronan, a matrix component suggested to
      promote cancer cell migration and growth. To explore the potential clinical
      importance of this concept, we assessed the hyaluronan levels in epithelial
      ovarian cancer. A biotinylated affinity probe specific for hyaluronan was
      prepared and applied to histological sections of 309 epithelial ovarian cancers
      and 45 matched metastatic lesions. The staining was scored according to the
      percentage area of strong hyaluronan signal of total peri- and intratumoral
      stroma as low (<35%), moderate (35-75%), or high (>75%). Low, moderate, and high
      levels of stromal hyaluronan were observed in 95, 116, and 98 carcinomas,
      respectively. The high stromal hyaluronan level was significantly associated with
      poor differentiation, serous histological type, advanced stage, and large primary
      residual tumor, whereas it was not correlated with high CD44 expression on cancer
      cells. The 5-year outlook of the disease deteriorated with increasing stromal
      hyaluronan levels for both overall (45% versus 39% versus 26%; P = 0.002) and
      recurrence-free (66% versus 56% versus 40%; P = 0.008) survival. High levels of
      stromal hyaluronan were more frequent in metastatic lesions than in primary
      tumors (z = -3.9; P = 0.0001). In Cox's multivariate analyses, high level of
      stromal hyaluronan was an independent prognostic factor in all patients, as well
      as in stage-specific subgroups. These results suggest that stromal hyaluronan
      accumulation may be a powerful enhancer of tumor progression and, as such,
      provides a novel, independent prognostic marker and a potential target of
      therapy.

PMID- 10646868
TI  - p21WAF1 regulates anchorage-independent growth of HCT116 colon carcinoma cells
      via E-cadherin expression.
AB  - The cyclin-dependent kinase inhibitor p21WAF1 has been characterized as an
      important effector of the tumor suppressor p53 and has been linked to various
      growth-regulatory processes. To identify a potential role of p21 in anchorage
      dependent growth control, we analyzed a pair of HCT116 human colon carcinoma cell
      lines that differed only in their p21 status. We found that during suspension
      culture, HCT116 cells (which contain wildtype p53 and p21) continued to
      proliferate and formed compact multicellular spheroids (MCSs). In contrast,
      HCT116 cells engineered to lack functional p21 (HCTp21-/-) were unable to form
      MCSs in suspension culture, ceased proliferation, and eventually died through
      apoptosis. The parental HCT116 cells underwent the same fate when treated with
      hyaluronidase, indicating that cell-cell contact might be required for survival
      in suspension culture. We established that E-cadherin was induced in HCT116 but
      not in HCTp21-/- cells and accounted for the formation of MCSs. Forced expression
      of E-cadherin or p21 in HCTp21-/- cells restored the ability to form MCSs and to
      grow independently of anchorage. Moreover, HCTp21-/- cells exhibited a severely
      reduced transformed phenotype and demonstrated greatly enhanced chemosensitivity
      in suspension culture. Thus, our results link an important regulator of the cell
      cycle machinery to the expression of a cell-cell adhesion molecule involved in
      tumor formation. Because our results indicate that loss of p21 severely impairs
      the ability of HCT cells to grow independently of anchorage, it may not be
      coincidental that inactivating mutations of this gene are very rarely found in
      tumor cells.

PMID- 10646869
TI  - Source of oncofetal ED-B-containing fibronectin: implications of production by
      both tumor and endothelial cells.
AB  - ED-B fibronectin (FN) is a FN isoform derived from alternative splicing of the
      primary transcript of a single gene. Its expression on tumor stroma and neoformed
      tumor vasculature and its absence, with few exceptions, in normal adult tissues
      imply a prognostic and diagnostic value for ED-B FN. We investigated the location
      and source of ED-B FN because this will be of importance both in understanding
      its role in tumor development and in designing strategies to target this
      molecule. We have confirmed that ED-B FN is expressed in the majority of breast
      and colorectal carcinoma tissue samples, with strong immunohistochemical staining
      around the tumor cells and in the tumor stroma. No staining of tumor
      neovasculature was seen. ED-B FN is produced by a range of tumor and endothelial
      (both primary and transformed) cell lines, as detected by reverse transcription
      PCR, but is not expressed at the plasma membrane. Strong expression of human ED-B
      FN is seen in tumor xenografts. These data indicate that neoplastic cells can act
      as the source of ED-B FN in tumors. The lack of cell surface expression on tumor
      cell lines has clear implications for the design of therapeutic strategies which
      target this molecule.

PMID- 10646870
TI  - Testosterone-repressed prostate message-2 is an antiapoptotic gene involved in
      progression to androgen independence in prostate cancer.
AB  - Although initially reported as an androgen-repressed gene in the rat prostate,
      the functional role of testosterone-repressed prostate message-2 (TRPM-2) in
      apoptosis remains undefined. Inhibition of castration-induced apoptosis by
      calcium channel blocker treatment in androgen-dependent Shionogi tumors resulted
      in the prevention of TRPM-2 gene up-regulation, suggesting that TRPM-2 is not
      directly androgen-repressed, but is regulated by apoptotic stimuli. The
      overexpression of the TRPM-2 gene in human androgen-dependent LNCaP prostate
      cancer cells by stable transfection rendered them highly resistant to androgen
      ablation in vivo. We then tested the efficacy of antisense TRPM-2
      oligodeoxynucleotide (ODN) therapy in the Shionogi tumor model and demonstrated
      that the systemic administration of antisense TRPM-2 ODNs in mice bearing
      Shionogi tumors after castration resulted in a more rapid onset of apoptosis and
      time to complete regression, as well as a significant delay of emergence of
      androgen-independent recurrent tumors compared to control ODN treatment.
      Collectively, these findings illustrate that TRPM-2 is an antiapoptotic rather
      than an androgen-repressed gene that confers resistance to androgen ablation and
      thereby helps accelerate the progression to androgen independence.

PMID- 10646871
TI  - E-cadherin promotes intraepithelial expansion of bladder carcinoma cells in an in
      vitro model of carcinoma in situ.
AB  - High-grade transitional cell carcinomas (TCCs) of the urinary bladder are
      frequently associated with carcinoma in situ, which may replace large areas of
      the mucosa of the urinary tract. The invasive component of TCCs often reveals a
      loss of expression of the cell-cell adhesion molecule E-cadherin, but the role of
      E-cadherin in the development and expansion of intraepithelial neoplasia is
      unknown. To study the underlying mechanism of intraepithelial expansion (IEE), we
      have developed an IEE assay. Human TCC cell lines were investigated in this IEE
      assay for their capacity to replace the surrounding normal murine urothelial
      cells. In vitro IEE appeared to be prominent in three (SD, RT112, and 1207) of
      the four E-cadherin-positive cell lines. Although the two E-cadherin-negative
      cell lines (T24 and J82) were able to penetrate surrounding normal urothelium as
      single cells, they largely lacked the capacity of IEE. These results prompted us
      to investigate whether the cell-cell adhesion molecule E-cadherin is an important
      determinant for IEE. T24 cells that were transfected with full-length mouse E
      cadherin cDNA displayed an enhanced IEE rate. Transfection did not influence
      their proliferative capacity, their pattern and level of integrin expression, or
      their ability to expand in the absence of surrounding urothelium. The data
      suggest that E-cadherin-mediated cohesiveness is an important factor in the IEE
      of bladder carcinoma cells. These observations argue for a dual, paradoxical role
      of E-cadherin in bladder tumorigenesis. On the one hand, E-cadherin promotes the
      expansion of intraepithelial neoplasia; on the other hand, its loss correlates
      with invasive behavior.

PMID- 10646872
TI  - Inflammatory cytokines induce DNA damage and inhibit DNA repair in
      cholangiocarcinoma cells by a nitric oxide-dependent mechanism.
AB  - Chronic infection and inflammation are risk factors for the development of
      cholangiocarcinoma, a highly malignant, generally fatal adenocarcinoma
      originating from biliary epithelia. However, the link between inflammation and
      carcinogenesis in these disorders is obscure. Because nitric oxide (NO) is
      generated in inflamed tissues by inducible nitric oxide synthase (iNOS) and
      because DNA repair proteins are potentially susceptible to NO-mediated
      nitrosylation, we formulated the hypothesis that inflammatory cytokines induce
      iNOS and sufficient NO to inhibit DNA repair enzymes leading to the development
      and progression of cholangiocarcinoma. iNOS and nitrotyrosine were demonstrated
      in 18/18 cholangiocarcinoma specimens. Furthermore, iNOS and NO generation could
      be induced in vitro by inflammatory cytokines (mixture of interleukin-1beta, IFN
      gamma, and tumor necrosis factor alpha) in three human cholangiocarcinoma cell
      lines. NO-dependent DNA damage as assessed by the comet assay was demonstrated
      during exposure of the three cholangiocarcinoma cell lines to cytokines.
      Moreover, global DNA repair activity was inhibited by 70% by a NO-dependent
      process after exposure of cells to cytokines. Our data indicate that activation
      of iNOS and excess production of NO in response to inflammatory cytokines cause
      DNA damage and inhibit DNA repair proteins. NO inactivation of DNA repair enzymes
      may provide a link between inflammation and the initiation, promotion, and/or
      progression of cholangiocarcinoma.

PMID- 10646873
TI  - Psychotherapeutic practice in paediatric oncology: four examples.
AB  - Psychotherapy, often used with children treated for a solid tumour, is seldom
      described. We present four examples of such therapies: a mother who refused
      enucleation for her 7-month-old boy; a boy's jealousy towards his sister who was
      being treated for a brain tumour; a teenager troubled by his scar; a 7-year-old
      boy embarrassed by the unconscious memory of his treatment when he was 5 months
      old. All names have been changed, for reasons of privacy. Psychotherapies aim to
      help children and parents to cope with the violent experience of having cancer,
      to recover their freedom of thought and decision-making concerning their life,
      their place in the family, their body image, their self-esteem, their identity.
      These descriptions of brief psychotherapy could help paediatricians to gain a
      more thorough understanding of the child's experience, to improve collaboration
      with psychotherapists and to confront clinical skills of psychotherapists.

PMID- 10646874
TI  - Cognitive and academic outcome following cranial irradiation and chemotherapy in
      children: a longitudinal study.
AB  - Cranial irradiation therapy (CRT) and chemotherapy are associated with
      neurobehavioural deficits. Many studies have investigated late effects of these
      treatments, but few have evaluated changes in abilities over time. This study
      employed a longitudinal design to map abilities following these treatments. Three
      groups of children were studied: Group 1 (n = 35): children treated with CRT (18
      Gy) + chemotherapy, aged 5 years or less at time of diagnosis; Group 2 (n = 19):
      children treated with chemotherapy alone, aged 5 years or less at time of
      diagnosis; Group 3 (n = 35): healthy children. All children were aged 7-13 years
      at time of initial assessment, with no pre-diagnosis history of neurologic,
      developmental, or psychiatric disorder. Intellectual and educational abilities
      were evaluated twice: T1, not less than 2 years post-treatment, and T2, 3 years
      later. Group 1 achieved poorest results at T1, with comparison groups performing
      similarly. At T2 group differences were maintained. For verbal skills differences
      remained stable. Group 1 exhibited deterioration on non-verbal and processing
      tasks, while comparison groups showed improved abilities. Group 1 exhibited
      increases in literacy skills, with educational intervention predicting progress.
      Results suggest cumulative deficits in non-verbal and information processing
      skills for children treated with CRT + chemotherapy, with other deficits
      remaining relatively stable over time. Improved literacy skills suggest that
      gains can occur with remediation.

PMID- 10646875
TI  - Quality of life and home enteral tube feeding: a French prospective study in
      patients with head and neck or oesophageal cancer.
AB  - A prospective study was conducted to evaluate the impact of home enteral tube
      feeding on quality of life in 39 consecutive patients treated for head and neck
      or oesophageal cancer at the Centre Francois Baclesse in Caen, France. Patients
      were taken as their own controls. Quality of life was evaluated using the EORTC
      QLQ-C30 core questionnaire, and the EORTC H&N35 and OES24 specific
      questionnaires. The feeding technique tolerance was evaluated using a
      questionnaire specifically developed for this study. Two evaluations were made,
      the first a week after hospital discharge (n = 39) and the second 3 weeks later
      (n = 30). Overall, the global health status/quality of life scale score slightly
      improved; among symptoms, scale scores that significantly improved (P < 0.05)
      concerned constipation, coughing, social functioning and body image/sexuality.
      The physical feeding technique tolerance was acceptable while the technique was
      psychologically less tolerated with two-thirds of the patients longing to have
      the tube removed. One third of the patients was also uncomfortable about their
      body image. Home enteral tube feeding was responsible for not visiting family or
      close relations in 15% of patients, and not going out in public in 23%. We
      conclude that home enteral tube feeding is a physically well accepted technique
      although a substantial proportion of patients may experience psychosocial
      distress.

PMID- 10646876
TI  - Biomarkers and outcome after tamoxifen treatment in node-positive breast cancers
      from elderly women.
AB  - The predictive role of tumour proliferative rate and expression of p53, bcl-2 and
      bax proteins, alone and in association with tumour size, nodal involvement and
      oestrogen receptors (ER), was analysed on 145 elderly patients (> or =70 years of
      age) with histologically assessed node-positive breast cancers treated with
      radical or conservative surgery plus radiotherapy followed by adjuvant tamoxifen
      for at least 1 year. The 7-year probability of relapse was significantly higher
      for patients with tumours rapidly proliferating (hazard ratio (HR) = 2.0, P =
      0.01), overexpressing p53 (HR = 4.4, P = 0.0001), weakly or not exhibiting bcl-2
      (HR = 1.9, P = 0.02), without ERs (HR = 3.4, P = 0.0001) or with > or = 4
      positive lymph nodes (HR = 2.3, P = 0.003) than for patients with tumours
      expressing the opposite patho-biological profile. Conversely, tumour size and bax
      expression failed to influence relapse-free survival. Adjustment for the duration
      of tamoxifen treatment did not change these findings. Oestrogen receptors, cell
      proliferation, p53 accumulation and bcl-2 expression were also predictive for
      overall survival. Within ER-positive tumours, cell proliferation, p53
      accumulation, bcl-2 expression and lymph node involvement provided significant
      and independent information for relapse and, in association, identified subgroups
      of patients with relapse probabilities of 20% (low-risk group, exhibiting only
      one unfavourable factor) to 90% (high-risk group, exhibiting three unfavourable
      factors). Such data could represent the initial framework for a biologically
      tailored therapy even for elderly patients and highlight the importance of a
      patho-biological characterization of their breast cancers.

PMID- 10646877
TI  - ESHAP and G-CSF is a superior blood stem cell mobilizing regimen compared to
      cyclophosphamide 1.5 g m(-2) and G-CSF for pre-treated lymphoma patients: a
      matched pairs analysis of 78 patients.
AB  - Cyclophosphamide 1.5 g m(-2) followed by granulocyte colony-stimulating factor (G
      CSF) is an effective peripheral blood stem cell (PBSC) mobilizing regimen, but
      has limited anti-lymphoma activity. We therefore assessed the mobilizing
      potential of ESHAP (etoposide, ara-C, methylprednisolone and cisplatin), a potent
      second-line lymphoma regimen followed by G-CSF. The results were compared in 78
      patients with relapsed or resistant lymphomas with the use of cyclophosphamide
      1.5 g m(-2) followed by G-CSF in a matched pairs analysis, matching the ESHAP
      recipients (for predetermined prognostic factors) from a cohort of 178 lymphoma
      patients mobilized with cyclophosphamide and G-CSF. The total numbers of
      mononuclear cells collected at apheresis was similar with both regimens but ESHAP
      plus G-CSF resulted in a significantly higher percentage of CD34+ cells, absolute
      number of CD34+ cells and GM-CFC (all with P-values < 0.001). The number of
      patients requiring only one apheresis harvest to achieve a CD34+ cell yield of >
      2.0 x 10(6) kg(-1) was greatly increased in the ESHAP recipients (56/78 vs 17/78,
      P < 0.001). The total number of progenitor cells collected was not significantly
      different with the two mobilization regimens because of this higher number of
      apheresis in the cyclophosphamide group. The proportion of patients who failed to
      achieve a minimum CD34+ cell target of 1 x 10(6) kg(-1) with the pooled harvests
      was less in the ESHAP arm (four patients vs nine patients) despite an increased
      number of aphereses in the cyclophosphamide recipients. ESHAP plus G-CSF is well
      tolerated and is an excellent mobilization regimen in patients with pre treated
      lymphoma.

PMID- 10646878
TI  - Prostate cancer treated by anti-androgens: is sexual function preserved? EORTC
      Genitourinary Group. European Organization for Research and Treatment of Cancer.
AB  - This paper reports on results of the EORTC protocol 30892, an open, prospective,
      randomized study of 310 patients with previously untreated metastatic prostate
      cancer with favourable prognostic factors who were treated by either flutamide
      (FLU) or cyproterone acetate (CPA) monotherapy. The final analysis with regard to
      the main end points, time to progression and survival are still pending. Final
      results related to the evaluation of sexual functioning prior to and under
      treatment are reported here. Of 310 randomized patients 294 were eligible for
      evaluation within this side study. The median age was 71 years (range 48-85).
      Potential risk factors related to age, general health and prostate cancer were
      evaluated. For evaluation of sexual functions a five-item questionnaire was used
      which was administered by the investigator. The protocol allowed time dependent
      observations at 3-monthly follow-up visits. Sexual functioning was dependent on
      age but not on prostate cancer-related parameters. Sexual functions at entry were
      similar within the two treatment groups, spontaneous (nightly) erections and
      sexual activity were seen in 43-51% and 29-35% of cases. Under treatment, sexual
      functions under FLU and CPA declined slowly with median times of 12.9 and 5.8
      months versus 13.7 and 8.9 months respectively for spontaneous erections and
      sexual activity. Eventually, with an average observation time in excess of 2
      years, loss of spontaneous erections and of sexual activity occurred in 80%
      versus 92% and in 78% versus 88% of men under FLU versus CPA treatment
      respectively. None of these differences reached statistical significance.
      Maintenance of potency under treatment with FLU as reported in the literature is
      not confirmed in this study. However, loss of sexual functions under monotherapy
      with both antiandrogens is slow and 10-20% of men retain sexual activity after 2
      6 years of treatment. This observation can be exploited in new treatment schemes
      and is likely to lead to improved quality of life. The advantage of FLU in time
      and total preservation of sexual functions is statistically not significant and
      must be balanced against the side effects of FLU and other pure antiandrogens,
      which may exceed those of CPA especially with respect to gynaecomastia. Hepatic
      toxicity may limit the long-term use of both drugs.

PMID- 10646879
TI  - Methylene blue in the treatment and prevention of ifosfamide-induced
      encephalopathy: report of 12 cases and a review of the literature.
AB  - Ifosfamide is an alkylating agent used in the treatment of a variety of solid
      tumours. Ten to 15% of patients treated with ifosfamide develop an
      encephalopathy. Methylene blue (MB) may be used in the treatment of this
      encephalopathy. The purpose of this study was to evaluate the neuroprotective
      effect of MB in these patients and to review the literature. Between 1993 and
      1997, 52 patients (age 16-77 years) with solid tumours were treated with
      ifosfamide in dosages ranging from 3 to 5 g m(-2) q3w when given in combination
      schedules and up to 12 g m(-2) q4w when given as a single agent. Twelve patients
      developed central nervous system (CNS) depression, defined as National Cancer
      Institute Common Toxicity Criteria (NCI-CTC) neurocortical toxicity grade 2 or
      higher. Eight were treated with MB at a dose of 6 x 50 mg day(-1) intravenously
      (i.v.). Four recovered fully within 24 h, two recovered partially after 24 h and
      completely after 48 h while two recovered only after 72 h. Four patients did not
      receive MB and all recovered only after 48 h. Three patients received prophylaxis
      with MB at a dose of 4 x 50 mg day(-1) i.v. for the subsequent chemotherapy
      cycles. Two developed milder encephalopathy; one had no CNS depression at all. We
      conclude that MB is an effective treatment for ifosfamide-induced encephalopathy.
      Our findings suggest that it may also be used as a prophylactic agent.

PMID- 10646880
TI  - Sentinel node biopsy in early vulvar cancer.
AB  - Lymph node pathologic status is the most important prognostic factor in vulvar
      cancer; however, complete inguinofemoral node dissection is associated with
      significant morbidity. Lymphoscintigraphy associated with gamma-probe guided
      surgery reliably detects sentinel nodes in melanoma and breast cancer patients.
      This study evaluates the feasibility of the surgical identification of sentinel
      groin nodes using lymphoscintigraphy and a gamma-detecting probe in patients with
      early vulvar cancer. Technetium-99m-labelled colloid human albumin was
      administered perilesionally in 37 patients with invasive epidermoid vulvar cancer
      (T1-T2) and lymphoscintigraphy performed the day before surgery. An
      intraoperative gamma-detecting probe was used to identify sentinel nodes during
      surgery. A complete inguinofemoral node dissection was then performed. Sentinel
      nodes were submitted separately to pathologic evaluation. A total of 55 groins
      were dissected in 37 patients. Localization of the SN was successful in all
      cases. Eight cases had positive nodes: in all the sentinel node was positive; the
      sentinel node was the only positive node in five cases. Twenty-nine patients
      showed negative sentinel nodes: all of them were negative for lymph node
      metastases. Lymphoscintigraphy and sentinel-node biopsy under gamma-detecting
      probe guidance proved to be an easy and reliable method for the detection of
      sentinel node in early vulvar cancer. This technique may represent a true advance
      in the direction of less aggressive treatments in patients with vulvar cancer.

PMID- 10646881
TI  - Phase I study of dose-escalated paclitaxel, ifosfamide, and cisplatin (PIC)
      combination chemotherapy in advanced solid tumours.
AB  - Based on the already known in vitro synergy between paclitaxel (taxol), cisplatin
      and oxazophosphorine cytostatics and the broad spectrum of activity of the above
      drugs we sought to evaluate the paclitaxel (taxol)-ifosfamide-cisplatin (PIC)
      combination in the outpatient setting in individuals with a variety of advanced
      solid tumours. Cohorts of patients were entered into six successive dose levels
      (DLs) with drug doses ranging as follows: paclitaxel 135-215 mg m(-2) day 1 - (1
      h infusion), ifosfamide 4.5-6.0 g m(-2) (total dose) - divided over days 1 and 2,
      and cisplatin 80-100 mg m(-2) (total) - divided over days 1 and 2. Granulocyte
      colony-stimulating factor was given from day 5 to 14. Forty-two patients were
      entered. Eighteen patients had 2-8 cycles of prior chemotherapy with no taxanes
      or ifosfamide (cisplatin was allowed). The regimen was tolerated with outpatient
      administration in 36/42 patients. Toxicities included: grade 4 neutropenia for <
      or = 5 days in 27% of cycles; 5 episodes of febrile neutropenia in three patients
      at DL-III, -V and -VI. Grade 3/4 thrombocytopenia and cumulative grade 3 anaemia
      were seen in 7% and 13% of cycles respectively. Three cases of severe grade 3
      neuromotor/sensory neuropathy were recorded at DL-II, -III, and -V, all after
      cycle 3. The maximum tolerated dose was not formally reached at DL-V, but because
      of progressive anaemia and asthenia/fatigue, it was decided to test a new DL-VI
      with doses of paclitaxel 200 mg m(-2), ifosfamide 5.0 g m(-2) and cisplatin 100
      mg m(-2); this appeared to be tolerable and is recommended for further phase II
      testing. The response rate was 47.5% (complete response + partial response:
      20/42). The PIC regimen appears to be feasible and safe in the outpatient
      setting. Care should be paid to neurotoxicity. Phase II studies are starting in
      non-small-cell lung cancer, ovarian cancer and head and neck cancer at DL-VI.

PMID- 10646882
TI  - Search for NTRK1 proto-oncogene rearrangements in human thyroid tumours
      originated after therapeutic radiation.
AB  - Rearrangements of NTRK1 proto-oncogene were detected in 'spontaneous' papillary
      thyroid carcinomas with a frequency varying from 5 to 25% in different studies.
      These rearrangements result in the formation of chimaeric genes composed of the
      tyrosine kinase domain of NTRK1 fused to 5' sequences of different genes. To
      investigate if the NTRK1 gene plays a role in radiation-induced thyroid
      carcinogenesis, we looked for the presence of NTRK1-activating rearrangements in
      32 human thyroid tumours (16 follicular adenomas, 14 papillary carcinomas and two
      lymph-node metastases of papillary thyroid carcinomas) from patients who had
      received external radiation, using the reverse transcription polymerase chain
      reaction, Southern blot and direct sequencing techniques. These data were
      compared with those obtained in a series of 28 'spontaneous' benign and malignant
      thyroid tumours, collected from patients without a history of radiation exposure
      and four in vitro culture cell lines derived from 'spontaneous' thyroid cancers.
      Our results concerning the radiation-associated tumours showed that only
      rearrangements between NTRK1 and TPM3 genes (TRK oncogene) were detected in 2/14
      papillary carcinomas and in one lymph-node metastasis of one of these papillary
      thyroid carcinomas. All the radiation-associated adenomas were negative. In the
      'spontaneous' tumours, only one of the 14 papillary carcinomas and one of the
      four in vitro culture cell lines, derived from a papillary carcinoma, presented a
      NTRK1 rearrangement also with the TPM3 gene. Twenty-five of this series of
      radiation-associated tumours were previously studied for the ras and RET/PTC
      oncogenes. In conclusion, our data: (a) show that the overall frequency of NTRK1
      rearrangements is similar between radiation-associated (2/31: 6%) and
      'spontaneous' epithelial thyroid tumours (2/32: 6%). The frequency, if we
      consider exclusively the papillary carcinomas, is in both cases 12%; (b) show
      that the TRK oncogene plays a role in the development of a minority of radiation
      associated papillary thyroid carcinomas but not in adenomas; and (c) confirm that
      RET/PTC rearrangements are the major genetic alteration associated with ionizing
      radiation-induced thyroid tumorigenesis.

PMID- 10646883
TI  - Gene rearrangement and Chernobyl related thyroid cancers.
AB  - The increase in thyroid carcinoma post-Chernobyl has been largely confined to a
      specific subtype of papillary carcinoma (solid/follicular). This subtype is
      observed predominantly in children under 10 in unirradiated populations, but
      maintains a high frequency in those aged 10-15 from those areas exposed to
      fallout from the Chernobyl accident. The aim of this study was to link morphology
      with molecular biology. We examined 106 papillary carcinomas from children under
      the age of 15 at operation. All were examined for rearrangements of the RET
      oncogene by reverse transcription polymerase chain reaction (RT-PCR); a subset of
      these cases were also examined for mutations of the three ras oncogenes, exon 10
      of the thyroid stimulating hormone receptor, associated more usually with a
      follicular rather than papillary morphology, and exons 5, 6, 7 and 8 of the p53
      gene, commonly involved in undifferentiated thyroid carcinoma. Rearrangements of
      the REToncogene were found in 44% of papillary carcinomas in which we studied
      fresh material; none of the tumours examined showed mutation in any of the other
      genes. The two rearrangements resulting from inversion of part of chromosome 10
      (PTC1 and PTC3) accounted for the majority of RET rearrangements identified, with
      PTC1 being associated with papillary carcinomas of the classic and diffuse
      sclerosing variants and PTC3 with the solid/follicular variant.

PMID- 10646884
TI  - Loss of heterozygosity at 7p in Wilms' tumour development.
AB  - Chromosome 7p alterations have been implicated in the development of Wilms'
      tumour (WT) by previous studies of tumour cytogenetics, and by our analysis of a
      constitutional translocation (t(1;7)(q42;p15)) in a child with WT and radial
      aplasia. We therefore used polymorphic microsatellite markers on 7p for a loss of
      heterozygosity (LOH) study, and found LOH in seven out of 77 informative WTs
      (9%). The common region of LOH was 7p15-7p22, which contains the region disrupted
      by the t(1;7) breakpoint. Four WTs with 7p LOH had other genetic changes; a
      germline WT1 mutation with 11p LOH, LOH at 11p, LOH at 16q, and loss of
      imprinting of IGF2. Analysis of three tumour-associated lesions from 7p LOH cases
      revealed a cystic nephroma-like area also having 7p LOH. However, a nephrogenic
      rest and a contralateral WT from the two other cases showed no 7p LOH. No
      particular clinical phenotype was associated with the WTs which showed 7p LOH.
      The frequency and pattern of 7p LOH demonstrated in our studies indicate the
      presence of a tumour suppressor gene at 7p involved in the development of Wilms'
      tumour.

PMID- 10646885
TI  - Association of specific chromosome alterations with tumour phenotype in posterior
      uveal melanoma.
AB  - Posterior uveal melanomas have recurrent alterations of chromosomes 1, 3, 6 and
      8. In particular, changes of chromosomes 3 and 8 occur in association, appear to
      characterize those tumours with a ciliary body component, and have been shown to
      be of prognostic significance. The relevance of other chromosome alterations is
      less certain. We have performed cytogenetic analysis on 42 previously untreated
      primary posterior uveal melanomas. Of interest was the observation that as tumour
      size increased the involvement of specific chromosome changes, and the amount of
      chromosome abnormalities likewise increased. Loss, or partial deletions, of the
      short arm of chromosome 1 were found to associate with larger ciliary body
      melanomas; typically, loss of the short arm resulted from unbalanced
      translocations, the partners of which varied. Trisomy of chromosome 21 occurred
      more often in ciliary body melanomas, whilst rearrangements of chromosomes 6 and
      11 were primarily related to choroidal melanomas. Our results imply that
      alterations of chromosome 1 are important in the progression of some uveal
      melanomas, and that other chromosome abnormalities, besides those of chromosomes
      3 and 8, are associated with ocular tumours of particular locations.

PMID- 10646886
TI  - Vascular grading of angiogenesis: prognostic significance in breast cancer.
AB  - The study aimed to evaluate the prognostic value of angiogenesis by vascular
      grading of primary breast tumours, and to evaluate the prognostic impact of
      adding the vascular grade to the Nottingham Prognostic Index (NPI). The
      investigation included 836 patients. The median follow-up time was 11 years and 4
      months. The microvessels were immunohistochemically stained by antibodies against
      CD34. Angiogenesis was graded semiquantitatively by subjective scoring into three
      groups according to the expected number of microvessels in the most vascular
      tumour area. The vascular grading between observers was moderately reproduced
      (kappa = 0.59). Vascular grade was significantly associated with axillary node
      involvement, tumour size, malignancy grade, oestrogen receptor status and
      histological type. In univariate analyses vascular grade significantly predicted
      recurrence free survival and overall survival for all patients (P < 0.0001), node
      negative patients (P < 0.0001) and node-positive patients (P < 0.0001). Cox
      multivariate regression analysis showed that vascular grading contributed with
      independent prognostic value in all patients (P < 0.0001). A prognostic index
      including the vascular grade had clinical impact for 24% of the patients, who had
      a shift in prognostic group, as compared to NPI, and implied a better prognostic
      dissemination. We concluded that the angiogenesis determined by vascular grading
      has independent prognostic value of clinical relevance for patients with breast
      cancer.

PMID- 10646888
TI  - Hormonally-regulated proteins in breast secretions are markers of target organ
      sensitivity.
AB  - Anti-oestrogen therapy is being used in an attempt to prevent breast cancer but
      no intermediate end points of the effect of tamoxifen on the normal breast are
      available. Therefore, the purpose of this study was to develop a physiological
      measure of oestrogen action on the breast. We measured oestrogen-stimulated and 
      inhibited proteins in breast secretions from women on and off anti-oestrogen
      therapy. Two oestrogen-stimulated proteins (pS2 and cathepsin D) and oestrogen
      inhibited proteins (CP15, gross cystic disease fluid protein 15; Apo,:
      apolipoprotein D) were measured. Premenopausal women had significantly higher pS2
      and cathepsin D in association with lower Apo D and CP15 secretion levels
      compared to post-menopausal women. Sequential nipple aspirates from women treated
      with the luteinizing hormone releasing hormone agonist goserelin (n = 9),
      tamoxifen (n = 9) and hormone replacement therapy (HRT) (n = 26) were measured.
      Following treatment with goserelin, median nipple secretion levels of pS2 fell (P
      < 0.02) and Apo D and CP15 rose significantly (P < 0.03 and P < 0.05
      respectively). Similar changes were seen on tamoxifen therapy but not in
      untreated control women. Treatment with HRT resulted in a rise of pS2 (P < 0.001)
      and a fall in Apo D (P < 0.05). Measurement of pS2 and Apo D in nipple aspirates
      may prove useful intermediate end point of breast responsiveness to anti
      oestrogens.

PMID- 10646887
TI  - APC gene mutations and colorectal adenomatosis in familial adenomatous polyposis.
AB  - Correlations between germline APC mutation sites and colorectal pathophenotypes,
      as evaluated by the direct count of adenomas at colectomy, were investigated
      analysing colectomy specimens from 29 FAP patients carrying one mis-sense (codon
      208) and 14 frame-shift or non-sense APC mutations (codons 232, 367, 437, 623,
      876, 995, 1061, 1068, 1075, 1112, 1114, 1309, 1324, 1556). The mis-sense mutation
      at codon 208 was associated with a relatively mild colorectal pathophenotype. The
      mutation at codon 367, subject to alternative splicing, was associated with
      attenuated FAP. The mutation at codon 1309 was associated with the profuse
      colorectal adenomatosis. For 13 mutations, predicted to result in null alleles or
      truncated APC proteins, we correlated density and distribution of colorectal
      adenomas with the predicted functional effects of the mutation. The most severe
      colorectal pathophenotype was significantly associated with the truncating
      mutation at codon 1309, which is located downstream to the I beta-catenin binding
      domain but upstream II beta-catenin-binding domain. Mutations between codons 867
      and 1114, which affect the I beta-catenin binding domain, as well as mutations
      occurring in exons 6 and 9, predicted to result in null alleles, were associated
      with a less severe colorectal pathophenotype. Overall, the highest number of
      adenomas was detected in the right colon, followed by the left colon, transverse
      colon sigma and rectum. However, the highest density of adenomas was observed in
      the left colon, followed by the right colon, sigma, transverse colon and rectum.
      Colorectal carcinomas, observed in only five patients, were all in the left
      colon.

PMID- 10646889
TI  - Expression of a prostate-associated protein, human glandular kallikrein (hK2), in
      breast tumours and in normal breast secretions.
AB  - The recent demonstration of human glandular kallikrein (hK2) expression in a
      breast carcinoma cell line has suggested that this putatively prostate
      restricted, steroid hormone-regulated protease may also be expressed in breast
      epithelium in vivo and secreted into the mammary duct system. Given that the only
      substrate yet identified for hK2 activity is the precursor of prostate-specific
      antigen (PSA), the expression of which in breast carcinomas may be associated
      with favourable prognosis, our purpose was to examine the expression pattern of
      both hK2 and PSA in breast tumour tissues. Cytosolic extracts of 336 primary
      breast carcinomas prepared for routine oestrogen receptor (ER) and progesterone
      receptor (PR) analysis, as well as 31 nipple aspirates from six women with non
      diseased mammary glands, were assayed for hK2 and PSA using immunofluorometric
      assays developed by the authors. In the tumour extracts, measurable hK2 and PSA
      concentrations were detected in 53% and 73% of cases respectively, and were
      positively correlated to each other (r = 0.59, P = 0.0001). Higher concentrations
      of PSA and hK2 were found in tumours expressing steroid hormone receptors (P =
      0.0001 for PSA and P = 0.0001 for hK2, by Wilcoxon tests for both ER and PR), and
      both PSA (r = 0.25, P = 0.0001) and hK2 (r = 0.22, P = 0.0001) correlated
      directly with PR levels. A negative correlation between patient age and PSA (r = 
      0.12, P = 0.03) was also found. Both proteins were present in nipple aspirate
      fluid at relatively high concentrations which were positively correlated (r =
      0.53, P = 0.002). The molecular weights of the immunoreactive species quantified
      by the hK2 and PSA assays were established by high-performance liquid
      chromatography (HPLC) and were consistent with the known molecular weights of hK2
      and PSA. Together these data provide the first evidence, to our knowledge, that
      both malignant breast tissue and normal breast secretion contain measurable
      quantities of hK2, and that the degree of hK2 expression or secretion is directly
      proportional to the expression of PSA and steroid hormone receptors. hK2
      expression may therefore be a marker of steroid hormone action in breast tissue.

PMID- 10646890
TI  - Number of apoptotic cells as a prognostic marker in invasive breast cancer.
AB  - Apoptosis plays an important role in tumorigenesis. Tumour growth is determined
      by the rate of cell proliferation and cell death. We counted the number of
      apoptotic cells in haematoxylin and eosin (H&E)-stained tumour sections in series
      of 172 grade I and II invasive breast cancers with long-term follow-up. The
      number of apoptotic cells in ten high-power fields were converted to the number
      of apoptotic cells per mm2 to obtain the apoptotic index (AI). The AI showed a
      positive correlation to the mitotic activity index (MAI) (P = 0.0001),
      histological grade (P < 0.0001) and worse tumour differentiation. Patients with
      high AI showed shorter overall survival than patients with low AI in the total
      group as well as in the lymph node-positive group. Tumour size, MAI, lymph node
      status and AI were independent prognostic indicators in multivariate analysis.
      The AI was shown to be of additional prognostic value to the MAI in the total
      patients group as well as in the lymph node-positive group. The correlation
      between the AI and the MAI points to linked mechanisms of apoptosis and
      proliferation. Since apoptotic cells can be counted with good reproducibility in
      H&E-stained tumour sections, the AI may be used as an additional prognostic
      indicator in invasive breast cancer.

PMID- 10646891
TI  - p16 protein expression is associated with a poor prognosis in squamous cell
      carcinoma of the lung.
AB  - An immunohistochemical analysis for p16 protein was performed in 171 patients
      with non-small-cell lung cancer (NSCLC). Sixty-two carcinomas (36.3%) were
      classified as p16-negative. p16-negative tumours in squamous cell carcinomas
      (SCCs) were significantly more than those in adenocarcinomas (P = 0.039). There
      was no significant difference in survival according to tumour p16 status in
      patients with NSCLCs or in patients with adenocarcinomas. In contrast, of
      patients with SCCs, the 5-year survival rate of patients with p16-negative
      tumours was significantly lower than those with p16-positive tumours (P = 0.001).
      Especially, the survival of patients with p16-negative tumours was significantly
      worse than that of patients with p16-positive tumours in the early stage of the
      SCC, e.g. stage I (P = 0.005). Multivariate analysis showed that p16 status and
      nodal status were significant prognostic factors for the survival of patients
      with SCCs of the lung (P = 0.024 and P = 0.008 respectively). In conclusion, our
      study showed that alteration of p16 was one of the significant factors of a poor
      prognosis in SCCs of the lung, and that p16 might play an important role in some
      SCCs of the lung due to its high prevalence and prognostic value.

PMID- 10646892
TI  - Screen-detected breast cancers have a lower mitotic activity index.
AB  - We know that screening for breast cancer leads to detection of smaller tumours
      with less lymph node metastases. Could it be possible that the decrease in
      mortality after screening is not only caused by this earlier stage, but also by a
      different mitotic activity index (MAI) of the tumours that are detected by
      screening? Is MAI a prognostic factor for recurrence-free survival? A
      retrospective study was carried out of 387 patients with breast cancer, treated
      at the University Hospital Nijmegen between January 1992 and September 1997.
      Ninety patients had screen-detected breast cancer, 297 patients had breast
      cancers detected outside the screening programme. The MAI, other prognostic
      factors and recurrence-free survival were determined. In non-screen-detected
      tumours the MAI is twice as high as in screen-detected tumours, even after
      correction for age took place. The MAI correlated well with other tumour
      characteristics. The MAI in itself is a prognostic factor for recurrence-free
      survival. Favourable outcome in screen detected breast cancer is not entirely
      caused by detecting cancer in early stages: quantitative features such as the MAI
      indicate a less malignant character of screen detected breast cancer. The MAI is
      an independent prognostic factor for recurrence-free survival.

PMID- 10646893
TI  - Identification of angiogenic properties of insulin-like growth factor II in in
      vitro angiogenesis models.
AB  - Insulin-like growth factor II (IGF-II), highly expressed in a number of human
      tumours, has been recently known to promote neovascularization in vivo. Yet, the
      detailed mechanism by which IGF-II induces angiogenesis has not been well
      defined. In the present study, we explored an angiogenic activity of IGF-II in in
      vitro angiogenesis model. Human umbilical vein endothelial cells (HUVECs) treated
      with IGF-II rapidly aligned and formed a capillary-like network on Matrigel. In
      chemotaxis assay, IGF-II remarkably increased migration of HUVECs. A rapid and
      transient activation of p38 mitogen-activated protein kinase (p38 MAPK) and p125
      focal adhesion kinase (p125FAK) phosphorylation was detected in HUVECs exposed to
      IGF-II. IGF-II also stimulated invasion of HUVECs through a polycarbonate filter
      coated with Matrigel. Quantitative gelatin-based zymography identified that
      matrix metalloproteinase-2 (MMP-2) activity generated from HUVECs was increased
      by IGF-II. This induction of MMP-2 activity was correlated with Northern blot
      analysis, showing in HUVECs that IGF-II increased the expression of MMP-2 mRNA,
      while it did not affect that of TIMP-2, a tissue inhibitor of MMP-2. These
      results provide the evidence that IGF-II directly induces angiogenesis by
      stimulating migration and morphological differentiation of endothelial cells, and
      suggest that IGF-II may play a crucial role in the progression of tumorigenesis
      by promoting the deleterious neovascularization.

PMID- 10646894
TI  - p53 alterations in recurrent squamous cell cancer of the head and neck refractory
      to radiotherapy.
AB  - The aim of the study was to determine the incidence of p53 alterations by
      mutation, deletion or inactivation by mdm2 or human papillomavirus (HPV)
      infection in recurrent squamous cell cancer of the head and neck (SCCHN)
      refractory to radiotherapy. Twenty-two tumours were studied. The p53 status of
      each tumour was analysed by sequencing of exons 4-9 and by immunohistochemistry.
      Mdm2 expression was assessed by immunohistochemistry and HPV infection was
      assessed by polymerase chain reaction of tumour DNA for HPV 16, 18 and 33.
      Fifteen (68%) of the 22 tumours studied had p53 mutations, while seven had wild
      type p53 sequence. p53 immunohistochemistry correlated with the type of mutation.
      HPV DNA was detected in 8 (36%) tumours and all were of serotype HPV 16. Of
      these, five were in tumours with mutant p53 and three were in tumours with wild
      type p53. Mdm2 overexpression was detected in 11 (50%) tumours. Of these, seven
      were in tumours with mutant p53 and four were in tumours with wild-type p53.
      Overall, 21 of the 22 tumours had p53 alterations either by mutation, deletion or
      inactivation by mdm2 or HPV. In this study, the overall incidence of p53
      inactivation in recurrent head and neck cancer was very high at 95%. The main
      mechanism of inactivation was gene mutation or deletion which occurred in 15 of
      the 22 tumours studied. In addition, six of the seven tumours with wild-type p53
      sequence had either HPV 16 DNA, overexpression of mdm2 or both which suggested
      that these tumours had p53 inactivation by these mechanisms. This high incidence
      of p53 dysfunction is one factor which could account for the poor response of
      these tumours to radiotherapy and chemotherapy. Therefore, new therapies for
      recurrent SCCHN which either act in a p53 independent pathway, or which restore
      p53 function may be beneficial in this disease.

PMID- 10646895
TI  - Effect of carnitine on muscular glutamate uptake and intramuscular glutathione in
      malignant diseases.
AB  - Abnormally low intramuscular glutamate and glutathione (GSH) levels and/or a
      decreased muscular uptake of glutamate by the skeletal muscle tissue have
      previously been found in malignant diseases and simian immunodeficiency virus
      (SIV) infection and may contribute to the development of cachexia. We tested the
      hypothesis that an impaired mitochondrial energy metabolism may compromise the
      Na+-dependent glutamate transport. A randomized double-blind clinical trial was
      designed to study the effects of L-carnitine, i.e. an agent known to enhance
      mitochondrial integrity and function, on the glutamate transport and plasma
      glutamate level of cancer patients. The effect of carnitine on the intramuscular
      glutamate and GSH levels was examined in complementary experiments with tumour
      bearing mice. In the mice, L-carnitine treatment ameliorated indeed the tumour
      induced decrease in muscular glutamate and GSH levels and the increase in plasma
      glutamate levels. The carnitine-treated group in the randomized clinical study
      showed also a significant decrease in the plasma glutamate levels but only a
      moderate and statistically not significant increase in the relative glutamate
      uptake in the lower extremities. Further studies may be warranted to determine
      the effect of L-carnitine on the intramuscular GSH levels in cancer patients.

PMID- 10646896
TI  - Clinicopathologic study associated with long-term survival in Japanese patients
      with node-negative breast cancer.
AB  - This study was undertaken to determine the absolute and relative value of blood
      vessel invasion (BVI) using both factor VIII-related antigen and elastica van
      Gieson staining, proliferating cell nuclear antigen (PCNA), p53, c-erbB-2, and
      conventional prognostic factors in predicting relapse-free survival (RFS) and
      overall survival (OS) rates associated with long-term survival in Japanese
      patients with node-negative breast cancer. Two hundred patients with histological
      node-negative breast cancer were studied. We investigated nine
      clinicopathological factors, including PCNA, p53, c-erbB-2 using permanent
      section immunohistochemistry, clinical tumour size (T), histological grade (HG),
      mitotic index (MI), tumour necrosis (TN), lymphatic vessel invasion (LVI) and
      BVI, followed for a median of 10 years (range 1-20). Twenty-one patients (10.5%)
      had recurrence and 15 patients (7.5%) died of breast cancer. Univariate analysis
      showed that BVI, PCNA, T, HG, MI, p53, c-erbB-2 and LVI were significantly
      predictive of 20-year RFS or OS. Multivariate analysis showed that BVI (P =
      0.0159, P = 0.0368), proliferating cell nuclear antigen (PCNA) (P = 0.0165, P =
      0.0001), and T (P = 0.0190, P = 0.0399) were significantly independent prognostic
      factors for RFS or OS respectively. BVI, PCNA and T were independent prognostic
      indicators for RFS or OS in Japanese patients with node-negative breast cancer
      and are useful in selecting high-risk patients who may be eligible to receive
      strong adjuvant therapies.

PMID- 10646897
TI  - Detection of codon 12 K-ras mutations in non-neoplastic mucosa from bronchial
      carina in patients with lung adenocarcinomas.
AB  - K-ras activation by point mutation in codon 12 has been reported in lung
      adenocarcinomas in various models of experimental lung tumours induced by
      chemical carcinogens. The hypothesis of the presence of cells containing K-ras
      mutation in non neoplastic bronchial carina, the main site of impaction of
      airborne contaminants, was investigated by evaluating concurrent lung tumour and
      non-neoplastic proximal bronchial carinae from 19 patients with lung
      adenocarcinomas. The restriction fragment length polymorphism enriched PCR method
      used can detect one mutant allele among 10(3) normal alleles. A mutation was
      detected in 42% of lung adenocarcinoma samples. No mutation was detected in
      either tumour or bronchial carinae in nine patients (47%). K-ras mutation was
      detected in the lung tumour but not in bronchial carinae in four patients (21%),
      in both the lung tumour and bronchial carinae in four other patients (21%). In
      two patients (11%), K-ras mutation was detected in at least one bronchial carina,
      but not in the lung tumour. Mutations of codon 12, confirmed by sequencing
      analysis of ten samples, were G to T transversion, mostly TGT and GTT in
      bronchial carinae and lung tumours. Our data show that activated K-ras by point
      mutation can be present in non-neoplastic bronchial carina mucosa even when no
      mutation is detected in tumour samples.

PMID- 10646898
TI  - Immunohistochemical analysis of Bcl-2 protein in early squamous cell carcinoma of
      the bronchus treated with photodynamic therapy.
AB  - Photodynamic therapy (PDT) in early squamous cell carcinoma of the bronchus has
      been shown to result in complete response (CR) and cure. However, local
      recurrence after PDT develops frequently even after complete remission. Because
      the effect of PDT had been reported to depend on apoptosis, and apoptosis is
      inhibited by bcl-2 protein, the relationship between the expression of bcl-2
      protein and local recurrence after PDT was examined immunohistochemically. From
      1983 to 1997, 50 patients with 59 early squamous cell carcinoma of the bronchus
      received PDT, and a CR was obtained in 43 lesions (72.8%). As there was no
      recurrence among tumours that were disease-free for more than 2 years, in this
      study the tumours were defined as cured when recurrence did not occur 2 years
      subsequent to the receiving of PDT. Of these CR lesions, 31 carcinomas (53.4%)
      resulted in a cure. Bcl-2 immunoreactivity was detected in 23 tumours (46.9%) and
      p53 immunoreactivity was detected in 22 tumours (44.9%). When all tumours were
      divided into either a large tumour with a longitudinal tumour length of 10 mm or
      more, or a small tumour with a length of less than 10 mm, the large tumour
      expressed more bcl-2 protein than the small tumour (P = 0.0155). The degree of
      bcl-2 expression was significantly related with tumour size (P = 0.0155). The
      expression of bcl-2 and p53 protein was not associated with the cure rate due to
      PDT. Tumour length and T status in TNM staging were significantly related to the
      cure by univariate analysis. T status was the only predictor of the cure
      according to mutivariate analysis. Of 42 CR lesions, the expression of neither
      bcl-2 nor p53 protein was associated with local recurrence; only T status was
      significantly associated (P = 0.008). The relationship between the expression of
      oncoprotein and local recurrence after PDT was not documented in this study. The
      success of PDT may depend on the exact assessment of tumour size under optimized
      PDT illumination.

PMID- 10646899
TI  - Basal keratinocyte tetrasomy in low-grade squamous intra-epithelial lesions of
      the cervix is restricted to high and intermediate risk HPV infection but is not
      type-specific.
AB  - Human papillomavirus (HPV) infection appears to be an early event in cervical
      carcinogenesis with additional abnormalities being required for biological
      transformation. We have analysed 179 low-grade cervical squamous intra-epithelial
      lesions (SILs) and 15 normal cervices for the presence of HPV using both in situ
      hybridization and polymerase chain reaction (PCR). PCR was performed with
      GP5+/GP6+ primers followed by hybridization using probes for low (HPV 6, 11, 40,
      42, 43, 44), intermediate (HPV 31, 33, 35, 39, 51, 52, 58, 59, 66 and 68) and
      high-risk HPVs (HPV 16, 18, 45 and 56). Interphase cytogenetic analysis using
      pericentromeric probes for chromosomes 1, 3, 4, 6, 10, 11, 17, 18 and X was also
      performed to identify numerical chromosomal abnormalities. Tetrasomy of all nine
      chromosomes was identified within basal keratinocytes, was restricted to
      epithelia infected with high risk (17 of 46) or intermediate risk (23 of 83) HPVs
      but was not HPV type-specific. Tetrasomy was not identified in any of the
      epithelia infected with low risk HPVs (n = 62). These numbers include multiple
      infection. These findings indicate that the induction of tetrasomy is a property
      restricted to high and intermediate-risk HPV types but that it is not type
      specific. The factors governing which lesions will develop this abnormality are
      as yet unclear.

PMID- 10646900
TI  - Detection of lymph node metastasis of oesophageal cancer by RT-nested PCR for SCC
      antigen gene mRNA.
AB  - With recent development in molecular biology, reverse transcriptase polymerase
      chain reaction (RT-PCR) has been applied to detect occult lymph node metastasis,
      but there have been few reports concerning oesophageal cancer. The objective of
      this study is to investigate the usefulness of the squamous cell carcinoma (SCC)
      antigen gene as a marker with RT-nested PCR to detect occult lymph node
      metastases of oesophageal cancer. The SCC antigen has been widely used as a serum
      tumour marker and was reported as a target gene to detect tumour cells in
      peripheral blood in cervical cancer. In this study, 620 lymph nodes from 14
      oesophageal cancer patients were analysed. The results of RT-nested PCR were
      compared with that of pathological and immunohistochemical examinations. In the
      test of sensitivity, the RT-nested PCR detected 10(1) of SCC antigen producing
      cells in 10(7) peripheral blood mononucleocytes and was not found in 43 control
      lymph nodes. The pathological examination, immunohistochemical examination and
      the RT-nested PCR detected 36, 45 and 65 nodes respectively. The RT-nested PCR
      detected statistically more lymph nodes than the pathological or
      immunohistochemical examination. The sensitivity and specificity seem higher in
      squamous cell carcinoma cases. The SCC antigen gene is one of the more useful
      markers for RT-nested PCR to detect occult lymph node metastases of oesophageal
      cancer.

PMID- 10646901
TI  - BCL-2 family protein expression and platinum drug resistance in ovarian
      carcinoma.
AB  - The expression of the BCL-2 family proteins, BCL-2, BAX, BCL(XL) and BAK have
      been determined in a panel of 12 human ovarian carcinoma cell lines encompassing
      a wide range in sensitivity to cisplatin. Whereas BAX, BCL(XL) and BAK levels did
      not correlate with sensitivity, there was a statistically significant inverse
      correlation (r = -0.81; P = 0.002) between growth inhibition by cisplatin and BCL
      2 levels. In sublines possessing acquired resistance to various platinum-based
      drugs or across a panel of human ovarian carcinoma xenografts, there was no
      consistent pattern of BCL-2 expression. Two relatively sensitive lines (A2780 and
      CH1) have been stably transfected with bcl-2 and bcl(XL) respectively and two
      relatively resistant lines (A2780cisR and SKOV-3) stably transfected with bax.
      Overexpression of BCL-2 in A2780 cells led to resistance to cisplatin compared to
      the vector control when assayed at 48 h post-drug incubation but a significant
      increase in sensitivity at 96 h. Relative rates of apoptosis at 48- and 96-h post
      cisplatin exposure mirrored the growth inhibition. There was no significant
      difference in sensitivity of the pair of lines by clonogenic assay. No
      significant changes in chemosensitivity to a variety of DNA-damaging or tubulin
      interactive agents were observed in the remaining transfected lines. Taken
      together, these results suggest that, in human ovarian carcinoma cells, high BCL
      2 levels (either naturally occurring or through gene transfection) confers a
      trend towards sensitivity not resistance to platinum drugs.

PMID- 10646902
TI  - Different types of FCgamma-receptors are involved in anti-Lewis Y antibody
      induced effector functions in vitro.
AB  - Stimulation of monocytes by interaction of monoclonal antibodies (mAbs) with Fc
      gamma receptors (FcgammaRs) results in the activation of various monocyte
      effector functions. In the present investigation we show that the anti-Lewis Y
      (LeY) anti-tumour mAb ABL 364 and its mouse/human IgG1 chimaera induce both
      antibody-dependent cellular cytotoxicity (ADCC) and the release of tumour
      necrosis factor alpha (TNF-alpha) during mixed culture of monocytes with LeY+
      SKBR5 breast cancer cells in vitro. Although anti-LeY mAb-mediated TNF-alpha
      release paralleled ADCC activity, cytokine release required a higher
      concentration of sensitizing mAb than the induction of cytolysis. The
      determination of the FcgammaR classes involved in the induction of the distinct
      effector functions showed that anti-LeY mAb-induced cytolysis was triggered by
      interaction between anti-LeY mAbs and FcgammaRI. In contrast, mAb-induced TNF
      alpha release mainly depended on the activation of monocyte FcgammaRII.
      Neutralization of TNF-alpha showed no influence on monocyte ADCC activity towards
      SKBR5 target cells. Our data indicate an independent regulation of anti-LeY mAb
      induced effector functions of ADCC and TNF-alpha release which seemed to be
      triggered by activation of different types of FcgammaR.

PMID- 10646903
TI  - Breast cancer incidence highest in the range of one species of house mouse, Mus
      domesticus.
AB  - Incidence of human breast cancer (HBC) varies geographically, but to date no
      environmental factor has explained this variation. Previously, we reported a 44%
      reduction in the incidence of breast cancer in women fully immunosuppressed
      following organ transplantation (Stewart et al (1995) Lancet 346: 796-798). In
      mice infected with the mouse mammary tumour virus (MMTV), immunosuppression also
      reduces the incidence of mammary tumours. DNA with 95% identity to MMTV is
      detected in 40% of human breast tumours (Wang et al (1995) Cancer Res 55: 5173
      5179). These findings led us to ask whether the incidence of HBC could be
      correlated with the natural ranges of different species of wild mice. We found
      that the highest incidence of HBC worldwide occurs in lands where Mus domesticus
      is the resident native or introduced species of house mouse. Given the similar
      responses of humans and mice to immunosuppression, the near identity between
      human and mouse MTV DNA sequences, and the close association between HBC
      incidence and mouse ranges, we propose that humans acquire MMTV from mice. This
      zoonotic theory for a mouse-viral cause of HBC allows testable predictions and
      has potential importance in prevention.

PMID- 10646904
TI  - Novel therapeutic approach: organic arsenical melarsoprol) alone or with all
      trans-retinoic acid markedly inhibit growth of human breast and prostate cancer
      cells in vitro and in vivo.
AB  - The organic arsenical known as melarsoprol (Mel-B) is used to treat African
      trypanosomiasis. Recently, another arsenical, As2O3 was shown to be effective in
      treatment of acute promyelocytic leukaemia. We have investigated the anti-tumour
      activities of Mel-B either with or without all-trans-retinoic acid (ATRA) using
      the MCF-7 human breast cancer cells, as well as the PC-3 and DU 145 human
      prostate cancer cells both in vitro and in vivo. The antiproliferative effects of
      Mel-B and/or ATRA against breast and prostate cancer were tested in vitro using
      clonogenic assays and in vivo in triple immunodeficient mice. Furthermore, the
      mechanism of action of these compounds was studied by examining the cell cycle,
      levels of bcl-2, apoptosis and antiproliferative potency using a pulse-exposure
      assay. Clonogenic assays showed that the cancer cell lines were sensitive to the
      inhibitory effect of Mel-B (effective dose that inhibited 50% clonal growth
      [ED50]: 7 x 10(-9) M for MCF-7, 2 x 10(-7) M for PC-3, 3 x 10(-7) M for DU145
      cells. Remarkably, the combination of Mel-B and ATRA had an enhanced
      antiproliferative activity against all three cancer cell lines. Furthermore, the
      combination of Mel-B and ATRA induced a high level of apoptosis in all three cell
      lines. Treatment of PC-3 and MCF-7 tumours growing in triple immunodeficient mice
      with Mel-B and ATRA either alone or in combination markedly retarded tumour size
      and weight of the tumours without major side-effects. In conclusion, our results
      suggest that either Mel-B alone or with ATRA may be a useful, novel therapy for
      breast and prostate cancers.

PMID- 10646905
TI  - Suppressed tumorigenicity of human endometrial cancer cells by the restored
      expression of the DCC gene.
AB  - To obtain functional evidence for DCC as a tumour suppressor associated with
      endometrial cancer, the human DCC cDNA encoding a complete open reading frame
      (ORF) was transfected into highly tumorigenic human endometrial carcinoma cells,
      HHUA and Ishikawa in which DCC expression was completely deleted. Reconstituted
      expression of DCC in HHUA had little effect on in vitro growth, but suppressed
      tumour formation in mice completely. The clones from Ishikawa had abundant DCC
      expression similar to that in normal endometrium. Their growth in vitro was
      suppressed and showed apoptotic phenotype. Lower levels of DCC expression in the
      prolonged passaged clones did not induce apoptosis, but still had the potential
      to suppress tumorigenicity. These observations imply a role of DCC in regulation
      of normal endometrial cell growth, and categorize DCC as the tumour suppressor
      gene for endometrial cancer.

PMID- 10646906
TI  - Effects of Fas-mediated liver cell apoptosis on diethylnitrosamine-induced
      hepatocarcinogenesis in mice.
AB  - The present study was designed to investigate the effect of Fas-mediated liver
      cell apoptosis, induced by a hamster monoclonal antibody against mouse Fas
      antigen, on diethylnitrosamine (DEN)-induced hepatocarcinogenesis in mice. DEN
      (10 microg g(-1), intraperitoneally (i.p.)) was given to 15-day-old male C3H/HeJ
      mice. Three weeks after DEN treatment, Fas-mediated liver cell apoptosis induced
      by anti-Fas antibody resulted in a biphasic effect on induction of liver cell
      tumours, depending on dosage and time of antibody administration. Single or
      multiple treatment with high dose anti-Fas antibody (5 microg animal(-1)),
      induced gross liver cell damage and decreased the incidence of liver cell tumours
      in DEN-treated mice. In contrast, five treatments with low dose anti-Fas antibody
      (2 microg animal(-1)), induced dispersed localized liver cell damage and promoted
      the number of large-sized liver cell adenomas and hepatocellular carcinomas.
      These findings suggest that high dose anti-Fas antibody has a marked effect on
      the clearance of DEN-initiated liver cells, whereas repeated administration of
      low dose anti-Fas antibody promotes hepatocarcinogenesis. It is concluded that
      Fas-mediated liver cell apoptosis has a biphasic effect on hepatocarcinogenesis.

PMID- 10646907
TI  - CD3 directed bispecific antibodies induce increased lymphocyte-endothelial cell
      interactions in vitro.
AB  - Bispecific antibody (BsMAb) BIS-1 has been developed to redirect the cytolytic
      activity of cytotoxic T lymphocytes (CTL) to epithelial glycoprotein-2 (EGP-2)
      expressing tumour cells. Intravenous administration of BIS-1 F(ab')2 to carcinoma
      patients in a phase I/II clinical trial, caused immunomodulation as demonstrated
      by a rapid lymphopenia prior to a rise in plasma tumour necrosis factor-alpha and
      interferon-gamma levels. Yet, no lymphocyte accumulation in the tumour tissue and
      no anti-tumour effect could be observed. These data suggest a BsMAb-induced
      lymphocyte adhesion to blood vessel walls and/or generalized redistribution of
      the lymphocytes into tissues. In this study, we describe the effects of BIS-1
      F(ab')2 binding to peripheral blood mononuclear cells (PBMC) on their capacity to
      interact with resting endothelial cells in vitro. Resting and pre-activated PBMC
      exhibited a significant increase in adhesive interaction with endothelial cells
      when preincubated with BIS-1 F(ab')2, followed by an increase in transendothelial
      migration (tem). Binding of BIS-1 F(ab')2 to PBMC affected the expression of a
      number of adhesion molecules involved in lymphocyte adhesion/migration.
      Furthermore, PBMC preincubated with BIS-1 F(ab')2 induced the expression of
      endothelial cell adhesion molecules E-selectin, VCAM-1 and ICAM-1 during
      adhesion/tem. These phenomena were related to the CD3 recognizing antibody
      fragment of the BsMAb and dependent on lymphocyte-endothelial cell contact.
      Possibly, in patients, the BIS-1 F(ab')2 infusion induced lymphopenia is a result
      of generalized activation of endothelial cells, leading to the formation of a
      temporary sink for lymphocytes. This process may distract the lymphocytes from
      homing to the tumour cells, and hence prevent the occurrence of BIS-1 F(ab')2 -
      CTL-mediated tumour cell lysis.

PMID- 10646908
TI  - Anti-tumour activity of tachykinin NK1 receptor antagonists on human glioma U373
      MG xenograft.
AB  - Astrocytes harbour functional receptors to many neurotransmitters, including
      substance P (SP), an undecapeptide belonging to the tachykinin family of peptide
      transmitters. SP activates malignant glial cells to induce cytokine release and
      proliferation, both responses being relevant for tumour progression. In tumours
      developed in nude mice transplanted subcutaneously (s.c.) to U373 MG human glioma
      cells, the presence of SP was observed at immunohistochemistry. Although the
      administration of exogenous SP did not significantly affect the size or
      development of U373 MG xenograft, a role of SP in supporting glioma progression
      in vivo was highlighted by the tumour growth inhibition induced by highly
      specific and selective human tachykinin NK1 receptor antagonists (MEN 11467 and
      MEN 11149). The anti-tumour activity of MEN 11467 was observed both with s.c. or
      intravenous treatments and was partially reverted by the concomitant
      administration of exogenous SP. Doxorubicin did not show any activity in
      controlling U373 MG growth in this in vivo model. A novel therapeutic approach to
      treat malignant gliomas with tachykinin NK1 receptor antagonists is suggested by
      these findings.

PMID- 10646909
TI  - Modulation of DNA topoisomerase II activity and expression in melanoma cells with
      acquired drug resistance.
AB  - The role of DNA topoisomerases (Topo) IIalpha and IIbeta was investigated in
      various drug-resistant melanoma cells. Melanoma cells resistant to etoposide,
      exhibited an up to tenfold reduced Topo II activity corresponding to an
      increasing degree of drug resistance indicating that modulation of Topo II
      activity contribute to the drug-resistant phenotype. The reduction of Topo II
      activity was reflected by decreased nuclear amounts of both Topo II isoforms.

PMID- 10646910
TI  - Modulation of oestrone sulphate formation and hydrolysis in breast cancer cells
      by breast cyst fluid from British and Hungarian women.
AB  - Women with gross cystic breast disease may have an increased risk of breast
      cancer. In this study the ability of breast cyst fluid (BCF), obtained from
      British or Hungarian women, to modulate oestrone sulphate (E1S) formation or
      hydrolysis, has been examined. For this, oestrogen receptor-positive (ER+) MCF-7
      or MDA-MB-231 (ER-) breast cancer cells were employed. The formation and
      hydrolysis of E1S was measured using radiometric techniques. BCF from British and
      Hungarian women mainly inhibited E1S hydrolysis in MCF-7 cells while stimulating
      hydrolysis in MDA-MB-231 cells. The extent of inhibition or stimulation of E1S
      hydrolysis in these cells was related to the Na+/K+ ratio of the BCF. There was a
      significant inverse relationship between the extent to which BCF samples
      inhibited hydrolysis in MCF-7 cells and stimulated it in MDA-MB-231 cells. BCF
      stimulated E1S formation in MCF-7 cells while inhibiting formation in MDA-MB-231
      cells. No difference in the ability of BCF from British or Hungarian women to
      inhibit or stimulate E1S hydrolysis was detected in ER+ or ER- breast cancer
      cells. In contrast, BCF from British women stimulated E1S formation in ER+ cells
      (median 82%) to a significantly greater extent (P < 0.01) than BCF from Hungarian
      women (median 33%). The role that E1S has in breast cancer development remains
      unclear. The greater stimulation of E1S formation by BCF from British women, who
      have a higher risk of breast cancer than Hungarian women, suggests that it may
      act as a storage form of oestrogen within cells that can be activated by oestrone
      sulphatase.

PMID- 10646911
TI  - Possible metabolic interaction between docetaxel and ifosfamide.

PMID- 10646912
TI  - In vitro assessment of Lipiodol-targeted radiotherapy for liver and colorectal
      cancer cell lines.

PMID- 10646913
TI  - Benchmarking in trauma care: the dilemma of choosing between improved outcome
      measures and widely used indicators.

PMID- 10646914
TI  - Road traffic accidents with vehicular entrapment: incidence of major injuries and
      need for advanced life support.
AB  - Road traffic accidents (RTAs) with entrapment are perceived as a challenge to
      emergency systems because of the severity of the ensuing traumas and the inherent
      complexity of the rescue procedures. To clarify these two aspects this
      prospective cohort study enrolling 244 entrapped trauma patients was conducted by
      a Regional Medical Helicopter Service. Forty-six victims (18.9%) were found dead,
      101 (51%) of the 198 patients who reached the hospital alive had an injury
      severity score (ISS) > or = 16. The use of seat belts was associated with lower
      trauma severity. Out of the 101 severely traumatized patients (ISS > or = 16), 46
      (42.6%) were intubated at road side, 12 required decompression of a tension
      pneumothorax on the scene and in 15 cases a pneumothorax was drained during the
      early intrahospital phase. Thirty-six (34.7%) patients had the first systolic
      blood pressure (SBP) < or = 90 mmHg and were then aggressively infused: in 75% of
      these cases, the SBP on arrival at the emergency department increased. The first
      SBP was significantly correlated with mortality. There was no correlation of
      extrication time, total rescue time and mortality. Fourteen patients (13.9%) died
      during hospitalization. These data demonstrate that a high percentage of
      entrapped patients require advanced life support (ALS), including on scene
      intubation and chest decompression. Aggressive field resuscitation and immediate
      transport to a level 1 trauma centre is associated with a mortality lower than
      that predicted by TRISS in spite of the prolonged prehospital time.

PMID- 10646915
TI  - Myocardial contusion as a result of isolated sternal fractures: a fact or a myth?
AB  - Isolated sternal fractures are seen with an increasing frequency in traffic road
      accidents especially after the introduction of the seatbelt legislation. In most
      cases, the victims are young, otherwise healthy individuals. The medical records
      of all patients who were treated with a diagnosis of sternal fracture over the
      past 10 years were retrospectively reviewed. All patients with a radiologic
      diagnosis of sternal fracture were admitted for cardiac monitoring for at least
      24 hours. ECG, determinations of cardiac enzyme levels CK (creatinephosphokinase)
      and CK-MB and evaluation by a cardiologist were routinely performed. An
      echocardiography was performed when indicated by the cardiologist. A total of 86
      patients had sustained a sternal fracture during the 10-year study period. There
      were 39 males and 47 females with a mean age of 50 years (range 15-97 years).
      Serial 12-lead electrocardiograms, which were performed in 83 (97%) patients,
      revealed no information about myocardial contusion or cardiac arrhythmias with
      consequent therapy. In eight patients, a significant elevation in cardiac enzyme
      levels (elevation of CK-MB fraction above 10% of CK) was observed. All were
      normalized within 24 hours without development of any arrhythmias.
      Echocardiography was performed in 31 patients. In two patients, dyskinesia of the
      right ventricle (without enzyme elevations or arrhythmias) was observed. Within
      24 hours these abnormalities resolved. The cardiac rhythm was monitored in 61
      (71%) patients for a total of 1550 hours. No arrhythmias were observed. The
      cardiac enzyme studies, ECG and echocardiography revealed no consequent
      information about arrhythmias. In case of a sternal fracture, we recommend a
      chest X-ray to exclude other associated intrathoracic injuries. If no
      abnormalities are identified, admission to hospital is not necessary.

PMID- 10646916
TI  - How good are accident and emergency doctors in the evaluation of psychiatric
      patients?
AB  - The aim of this study was to find out the agreement between psychiatrists and
      emergency department (ED) doctors in the diagnosis and treatment of psychiatric
      emergencies. All patients presenting with a psychiatric complaint and who were
      subsequently referred to the psychiatrist were included. A standard form was used
      to collect demographic data, provisional diagnoses and initial treatment by ED
      doctors, diagnoses by psychiatrists, and compatibility of ED diagnoses and
      treatment as judged by consulting psychiatrists. The mean age of the 223 patients
      enrolled was 36.5 years and the distribution between males and females was
      roughly equal. The most frequent presentations were aggressive behaviour (27.9%),
      depressive mood (13.5%) and suicidal idea (12.1%). Schizophrenia (39%) was the
      most common diagnosis followed by depression (20%) and adjustment disorders
      (9.5%). The agreements between psychiatrists and ED doctors in diagnosis and
      treatment were 61.4% and 89.5% respectively. Schizophrenia and bipolar disorders
      were least likely to be mis-classified. It is concluded that ED doctors were
      deficient in the diagnosis of psychiatric conditions especially in the less
      common diagnostic categories.

PMID- 10646917
TI  - Violence against doctors: 1. A study of violence against doctors in accident and
      emergency departments.
AB  - The risk of violence directed at health care professionals in their working
      environment has aroused widespread concern in recent years. Clinical areas most
      associated with violence are accident and emergency departments, psychiatry, and
      general practice. Surveyed physicians reported rates of violence against them to
      vary from 54% to 79%. Violence, however, is difficult to quantify and there is
      wide variation between the severity of incidents recorded by different workers.
      This study was an attempt to measure the incidence and the severity of violence
      against doctors in accident and emergency departments in Kuwait. Eighty-seven
      (86%) out of 101 of our doctors reported having experienced verbal insults or
      imminent threat of violence; in addition, 28% had also experienced physical
      attacks, and 7% had experienced physical assaults likely to have caused serious
      or fatal injury. Similarly, out of a total of 781 violent incidents reported by
      our doctors, 73 involved physical attacks, and eight involved physical assaults
      likely to have caused serious or fatal injury.

PMID- 10646919
TI  - Is there a gender difference in aetiology of chest pain and symptoms associated
      with acute myocardial infarction?
AB  - Many previous studies have shown that there is a gender difference in terms of
      the use of diagnostic procedures and the treatment of patients with chest pain.
      The mechanisms behind these observations are less well described. This survey
      describes gender differences in the aetiology of chest pain and symptoms
      associated with acute myocardial infarction (AMI). Among the patients with
      symptoms of acute chest pain, in the emergency medical department women less
      frequently develop an AMI and are less frequently given a diagnosis of ischaemic
      heart disease. Among patients developing an AMI, women differ from men by less
      frequently reporting chest pain, more frequently reporting nausea, vomiting,
      abdominal complaints, fatigue and dyspnoea and less frequently reporting
      sweating. With regard to the localization of pain in AMI, women differ from men
      by more frequently reporting pain in the back, neck and jaw. In terms of
      electrocardiographic changes, women seem to have less marked ST deviations than
      men. However, we do not believe that these differences between women and men are
      substantial enough and, as a result, we do not recommend that the initial medical
      care of patients seeking medical attention with chest pain or other symptoms
      raising a suspicion of AMI should be differentiated with regard to gender. The
      differences described here might partly explain the prolonged delay until
      hospital admission in women suffering from AMI.

PMID- 10646918
TI  - Violence against doctors: 2. Effects of violence on doctors working in accident
      and emergency departments.
AB  - There is abundant evidence to suggest that doctors are increasingly being exposed
      to violent incidents at their workplace. The possible effects of aggression on an
      individual are varied and likely to depend on the severity and frequency of
      episodes and the perceived vulnerability to further episodes. The reported
      sequaelae of violent incidents towards doctors include varied psychological
      disturbances, and changes in behaviour, such as increasing prescribing, ongoing
      fear of violence at work, and poor staff morale. We investigated the effects of
      violence against doctors in the accident and emergency departments in Kuwait.
      Seventy-five (86%) out of 87 doctors exposed to violent incidents reported one or
      more of the symptoms consisting of: depression, reliving experience (flashbacks),
      insomnia, and taking 'time off'. The effects lasted for more than 4 weeks in 25,
      for 3-4 weeks in 17, and for 2-3 weeks in 21. The duration of symptoms was longer
      in doctors exposed to verbal insults or threats of imminent violence coupled with
      incidents involving single acts of violence. Out of a total of 101 doctors; 90
      (89%) remained worried about violence at work and 72 (71%) thought training to
      deal with potentially violent situations would be useful.

PMID- 10646920
TI  - Treatment of self-referred patients with abdominal complaints by emergency
      physicians. A prospective observational study in an emergency department in The
      Netherlands.
AB  - The quality of the treatment by emergency physicians of patients with abdominal
      complaints, who visited the emergency department (ED) of a city hospital (OLVG),
      Amsterdam, The Netherlands, was evaluated in a prospective observational study.
      During 6 months 1853 patients with abdominal complaints visited the emergency
      department of the OLVG hospital, 1221 patients (66%) without referral by a
      general practitioner (GP). Of these 1221 patients, 933 (76%) were treated by the
      emergency physician without consulting a specialist. Of these 933 patients, 814
      were included in our follow-up study. A questionnaire was sent to them 1 week
      after visiting the ED. The response rate was 81% (663 patients). Of these 633
      patients 48 patients sought medical help within 2 weeks after being discharged
      from the ED (38 patients in the same hospital and 10 patients in another
      hospital). Of these 48 patients, 17 were admitted to the hospital and 14 of them
      were operated on. After evaluation of these 17 patients we could conclude that
      seven patients were initially misdiagnosed by the emergency physician (1.1%). It
      is concluded that most patients with abdominal complaints visit the ED of this
      hospital without referral by their GP. Of these patients, the emergency physician
      can treat 76% without further specialist consultation. In seven patients (1.1%)
      the diagnosis was missed.

PMID- 10646921
TI  - Out-of-hospital cardiopulmonary resuscitation: a population-based Norwegian study
      of incidence and survival.
AB  - The Trondheim region's (315 km2, population 154,000) emergency medical service
      (EMS) provides advanced cardiac life support (ACLS) with combined paramedic and
      physician response. This EMS system is commonly employed in Norway, yet no
      population based study of outcome in cardiac arrest has been published to date.
      This retrospective study reports incidence and outcome from every attempted out
      of-hospital cardiopulmonary resuscitation (CPR) during 1990 through 1994
      according to the Utstein template. Information on the patient's pre-morbid
      conditions and final outcome was obtained from hospital records. The incidence of
      cardiac arrest and CPR from all causes was 68 per 100,000 per year, with 83%
      primary cardiac aetiology. The median alarm to patient arrival interval for
      ambulance and emergency physician was 8 minutes and 11 minutes, respectively. The
      presenting rhythm was ventricular fibrillation or tachycardia in 51%, asystole in
      34%, pulseless electrical activity in 8% and undetermined in 8%. Definite return
      of spontaneous circulation occurred in 211 patients (40%, 27 per 100,000 per
      year) and 57 patients (11%, 7.4 per 100,000 per year) survived to discharge. Most
      patients made a favourable cerebral outcome, although nine were severely
      disabled. This is the first population-based Norwegian study of outcome from out
      of-hospital cardiac arrest in this combined paramedic/physician staffed EMS.
      Incidence, survival and neurological outcome are comparable with results obtained
      in other EMS systems.

PMID- 10646922
TI  - Is there an evolution in the epidemiology and follow-up of carbon monoxide
      poisoning victims?
AB  - A retrospective study was conducted to investigate for potential changes in the
      epidemiology of acute carbon monoxide (CO) poisoning and to evaluate the
      recommendations within the emergency department (ED) on therapy and neurological
      and social follow-up of these patients. One hundred and sixty-seven patients with
      a non-intentional CO poisoning in the time period from 1995 to 1997 were reviewed
      and compared with data of a similar patient population between 1988 and 1990.
      Both patient groups were matched for age, sex and comorbidity. Comparing the
      epidemiological data of the two groups, three main evolutions were observed: (1)
      there is a global reduction in ED admissions for CO poisoning; (2) the number of
      young victims has a tendency to decrease; (3) the most common CO source has
      become an insufficiently functioning stove instead of a defective gas water
      heater. Regarding treatment and follow-up strategies three conclusions could be
      drawn: (1) the recommendations for hyperbaric-oxygen therapy were strictly
      followed; (2) the neurological follow-up was poor and has to be ameliorated and
      revisited; (3) the systematic follow-up by the social worker on the other hand
      resulted in immediate actions to prevent a second CO poisoning. This recently
      elaborated protocol for social evaluation emphasizes the important function of
      the social worker in the ED and the importance of transmural follow-up organized
      by the ED.

PMID- 10646923
TI  - Delayed mobilization of the emergency physician in prehospital missions.
AB  - A retrospective analysis of 118 prehospital missions involving vitally important
      therapy (anaesthesia or resuscitation with admission) was carried out. Primary
      mobilization of the emergency physician (EP) (i.e. before arrival of the rescue
      ambulance) was carried out by the alarm dispatch centre in only 36% of these
      missions. In the 74 missions utilizing secondary alarm (i.e. request for the EP
      after the arrival of the ambulance), detrimental delay of 8 minutes or more was
      found in 30%. In two of the 27 missions of cardiopulmonary resuscitation with
      subsequent admission, the physician was only mobilized after the patient
      developed cardiac arrest during unescorted transport although acute myocardial
      infarction had been suspected prior to transport. The observations suggest that
      an improved assessment of possible involvement of an EP is necessary, both at the
      alarm central and the emergency site. Moreover, continued monitoring (quality
      control) of this delay is necessary.

PMID- 10646924
TI  - Extrication of entrapped victims from motor vehicle accidents: the crew concept.
AB  - During the extrication process the trauma victim is at high risk for additional
      injuries or aggravation of existing lesions. Improper handling during extrication
      with poor concern and knowledge of the ongoing resuscitation process may increase
      the time spent at the scene and expose the patient to unnecessary risks. Earlier
      studies report a significant number of neurological injuries that appear to be a
      result of the extrication process, or of inadequate immobilization during
      transport. Recent work also underlines the need for appropriate and situation
      adapted Advanced Life Support (ALS) procedures to improve outcome after
      prehospital trauma resuscitation. In this paper we present a method for training
      advanced extrication of trauma victims and the results obtained after five
      consecutive courses. The training focuses on enhanced liaison between medical and
      technical team members to optimize synchronization of operations. The course
      consists of both theoretical lectures and practical training in different crash
      scenarios. The complexity of the scenarios increases throughout the course and
      different extrication techniques and strategies are practised. Both the times to
      extrication and on-scene times were reduced during the 3-day course. Therapeutic
      interventions and handling of the patient were also improved, in terms of early
      recognition of medical and technical risks and reduction of the time of no
      therapy.

PMID- 10646925
TI  - Collisions involving mobile intensive care unit vehicles in Flanders, Belgium.
AB  - In order to evaluate the risk of collision during emergency responses of mobile
      intensive care units (MICUs) in Flanders, Belgium, a questionnaire was sent to 37
      MICU services. The response rate was 84%. During the study period (1992-96) the
      incident rates for collision, collision with significant physical harm, and
      collision leading to a wrecked MICU vehicle were 1 per 52,000 km, 1 per 214,000
      km and 1 per 250,000 km, respectively. Most collisions occurred during use of
      'lights and siren' (66%), and involved other motor vehicles (72%). About 50%
      occurred during daylight with clear weather conditions and on dry roadways.
      Drivers had attended a course for safe and defensive driving in only four
      services (13%). The use of seat belts was imposed by the hospital authorities in
      21 services (72%). Vehicles equipped with airbags and an ABS-braking system were
      used in eight (28%) and 13 (45%) services, respectively. Our data confirm that
      the collision rate for MICUs is high and that measures to reduce the risk of
      collisions and resulting injuries and damage are at present not optimal.

PMID- 10646926
TI  - Costing of an ambulance system in a developing country, Turkey: costs of Ankara
      Emergency Aid and Rescue Services' (EARS) ambulance system.
AB  - The purposes of the study were to determine the total cost of Ankara Emergency
      Aid and Rescue Services (EARS), to calculate the cost of a single ambulance
      response and the cost per patient responded to. A descriptive study was planned
      to find out the cost of Ankara EARS, conducted between 1 October 1995 and 30
      September 1996. The main variables of the study were the capital and recurrent
      costs of the system. The data relating to the costs were obtained from financial
      registries of various health institutes and personnel working in the system. The
      data was collected by two of the researchers. The total and average costs--cost
      per one ambulance run and cost per one patient--were determined. The total cost
      of Ankara EARS ambulance system in the period between 1 October 1995 and 30
      September 1996 was US$918,877.90. The total capital costs of Ankara EARS was
      US$85,171.10 (9.3% of the total cost). The total recurrent costs of Ankara EARS
      was US$833,706.80 (90.7% of the total cost). The cost per one ambulance run was
      US$163.00. On the other hand the cost per patient or injured person was
      US$180.50. In Ankara, Turkey, the costs of such ambulance services could not be
      afforded by the private sector. The ambulance service activities should continue
      to be a part of primary health care services and the Ministry of Health should
      continue to serve in this field.

PMID- 10646927
TI  - The puzzle of neuronal death and life: is mannitol the right drug for the
      treatment of brain oedema associated with ischaemic stroke?
AB  - Brain oedema is a major factor contributing to the poor outcome of subjects with
      acute ischaemic stroke but the use of mannitol and other hyperosmolar agents in
      this setting is controversial and hardly debated. Recent data have demonstrated
      that mannitol at concentrations which may be achieved in clinical conditions and
      hyperosmotic stress itself can activate the process of apoptotic cell death. This
      could have important clinical implications as apoptosis is involved in the more
      gradual loss of neurons in the penumbra zone surrounding the core of ischaemic
      stroke where neurons die immediately from oxygen starvation. Mannitol has the
      potential to activate inflammatory mediators, induce oxidant stress and produce
      rebound cell swelling and, through these mechanisms, can further aggravate the
      neuronal injury due to ischaemia. Furthermore, apoptosis in ischaemic areas
      closely parallels the timing of brain oedema and this suggests that a cause
      effect relationship links the two phenomena rather than simply a temporal
      correlation. On this basis, it is crucial that emergency-physicians critically
      rethink the management strategy of brain oedema associated with ischaemic stroke.

PMID- 10646928
TI  - Recommendations for uniform reporting of data following major trauma--the Utstein
      Style. An International Trauma Anaesthesia and Critical Care Society (ITACCS)
      initiative.

PMID- 10646929
TI  - Injuries in The Netherlands: results of surveillance-based public health
      research.
AB  - Public health is the scientific field which aims to study, preserve and improve
      the health of populations. Its primary diagnostic tool is public health
      surveillance. In this paper the methodology and results are presented of three
      surveillance-based studies on injury patients in The Netherlands. With the help
      of national registration data the economic burden of injury was assessed, and
      both time trends and regional differences in injury mortality were analysed. The
      results show that the societal burden of injury is high on the one hand, but that
      there seems large potential for reducing health damage by prevention and improved
      emergency care on the other. It was also shown that surveillance-based studies
      may reveal differences in patient outcome by time period or geographic region. In
      this way they provide valuable information for an assessment of the quality of
      individual patient care, including the care by emergency clinicians. A basic
      condition, however, is the availability of valid surveillance data. A central
      issue is the recording of information on the injury diagnosis, including
      information on injury severity. This can only be obtained if clinicians are
      willing to collect data. Public health surveillance therefore highly relies on
      the co-operation of clinicians.

PMID- 10646930
TI  - Frightening dreams and spells: a case of ventricular asystole from Lyme disease.
AB  - We present a case of a 20-year-old woman who presented with a febrile illness,
      frightening dreams and repeated short episodes of apparent seizure activity.
      Third degree heart block and ventricular asystole were noted on the monitor when
      the patient experienced a spell during conscious sedation for a lumbar puncture.
      The combination of heart block and a predominantly lymphocytic cerebrospinal
      fluid led to the diagnosis of Lyme disease. Lyme titres were strongly positive
      and subsequently confirmed by Western Blot analysis. Cardiac aetiologies and
      specifically heart block associated with Lyme disease should be considered in
      patients from endemic areas presenting with fever and unexplained spells or
      seizure-like activity.

PMID- 10646931
TI  - Acute myocardial infarction induced by alcohol ingestion in an asymptomatic
      individual.
AB  - This case report deals with a 47-year-old asymptomatic man without risk factors
      for coronary artery disease. He developed acute myocardial infarction 6 hours
      after ingestion of 0.5 litre of whisky within 30-60 minutes. The acute myocardial
      infarction was proved by a typical and prolonged angina pectoris, elevated
      enzymes typical for myocardial necrosis and ECG signs of acute anteroseptal and
      anterolateral myocardial infarction. A coronary angiography 3 months later
      revealed normal coronary arteries but marked hypokinesia of the anteroseptal and
      anterolateral segments of left ventricular wall. The sequence of events and
      objective data support our hypothesis that disturbance of coronary flow could be
      induced by an excessive ingestion of alcohol. The article discusses possible
      mechanisms of alcohol effects on arteries.

PMID- 10646932
TI  - Arm wrestler's fracture.

PMID- 10646933
TI  - Evaluation of scoring systems in acute meningococcaemia.

PMID- 10646934
TI  - Acute presentation of abdominal aortic aneurysm.

PMID- 10646935
TI  - Management of ingested foreign bodies in childhood--response.

PMID- 10646936
TI  - Report from Turkey.

PMID- 10646937
TI  - A study of the correlation between organic matrices and nanocomposite materials
      in oyster shell formation.
AB  - Calcium carbonate minerals are an integral part of many organisms. These biogenic
      minerals are all of original size, shape and high strength, and they are quite
      different from those found in their abiotic precipitates. It has been accepted
      that the formation, morphological development and crystallography of the
      biocomposites are controlled by the intrinsic molecular recognition of
      macromolecules. In this study, with the analyses of X-ray diffraction and
      scanning electron microscopy of the texture of biogenic minerals in oyster
      shells, we noted that the intracrystalline proteins deliberately reduce the
      coherence lengths of biogenic crystals compared to synthetic ones, leading to
      more isotropy. In order to understand the exact nature of the controlled
      nucleation and growth, we investigated the changes in protein conformation in
      vivo from the mineral-specific layers using Fourier self-deconvolution and
      Gaussian curve-fitting techniques. And via in vitro assays, we studied the
      relation of such changes to biomineral phase and morphology. We showed that the
      shell proteins in vivo are in the higher structural ordered state, and beta
      antiparallel structure was predominant in each shell layer. Also, as the shell
      undergoes a change of calcium carbonate polymorphs from aragonite to calcite,
      significant alterations of the protein conformation with the denaturing of alpha
      helix and beta-structure in the aragonitic layer is induced. These results
      provide a relationship between the effects of conformational changes on the
      nanostructure of biocomposites and the necessity of new synthetic strategies.

PMID- 10646938
TI  - The phase diagram of the monoolein/water system: metastability and equilibrium
      aspects.
AB  - Interest in the liquid crystal structure, transport and membrane protein
      crystallizing properties of the monoolein/water system has grown in the recent
      past. Monoolein is also an important homolog in a series of monoacylglycerols
      used to decipher how lipid molecular structure relates to liquid crystal phase
      behavior--information needed for rational design applications and for
      understanding the origin of membrane lipid diversity. To make intelligent use of
      the monoolein/water system, a reliable and detailed temperature-composition phase
      diagram is needed. The phase diagram of Briggs et al. (J Phys II France
      1996;6:723-51) was constructed for this purpose. However, we have established
      that the liquid crystal phases in the latter below ca. 20 degrees C are
      metastable. By implementing a sub-zero degree (degrees C) sample incubation prior
      to data collection in the heating direction, we can reset the system into the
      lamellar crystal phase which we assume represents equilibrium behavior. We have
      re-examined the low-temperature part of the phase diagram and characterized
      structurally the new 'equilibrium' phases by static and time-resolved low- and
      wide-angle X-ray diffraction and by differential scanning calorimetry. A more
      complete phase diagram that incorporates the new equilibrium behavior at low
      temperatures is reported.

PMID- 10646939
TI  - Integration of dense HA rods into cortical bone.
AB  - HA ceramics are daily used in human surgery for bone healing partly due to their
      ability to integrate into bone. They are generally used under a macroporous form.
      The behaviour of dense HA after implantation is not so well known. We implanted
      within cortical sheep femurs dense pure HA-ceramics cylinders for periods from 2
      weeks to 18 months. The samples were then sectioned and examined using back
      scattered and secondary SEM and the interface was analysed using EDS.
      Histomorphometry measurement was also performed using an image analysis device
      coupled to a light microscope. It appeared that the cylinders were in direct
      contact with immature bone after three weeks. The bone maturated within three
      months. The implant surface showed moderate signs of resorption and some grains
      were released from the surface. The resorption zone was only a few microm thick
      after 18 months. The bulk ceramic contained default zones of increased porosity.
      They can constitute fragile zone when located close to the surface in which the
      resorption rate is increased. We conclude that dense pure HA is poorly degraded
      when implanted in cortical bone. Degradation depends on the defaults found on the
      ceramic structure and the remodelling of bone surrounding the material.

PMID- 10646940
TI  - Isostatic compression, a new process for incorporating vancomycin into biphasic
      calcium phosphate: comparison with a classical method.
AB  - Isostatic compression has rarely been used to load calcium-phosphate biomaterials
      with therapeutic agents. This report, concerning four processes associating
      vancomycin, compares isostatic compression with wet granulation, a classical
      method. In the wet granulation study, vancomycin was associated with biphasic
      calcium-phosphate (BCP) granules either by adsorption or incorporation with a new
      granulation. In the isostatic compression study, BCP powder was compressed at
      100, 140 and 200 MPa. The blocks obtained were crushed and 200-500 microm,
      sieved; thus, the vancomycin solution was absorbed on these granules. Compaction
      of BCP and vancomycin powders gave, after crushing and sieving, granules loaded
      with vancomycin. In each study, 5% vancomycin was associated with BCP. Vancomycin
      release profiles were assessed by an in vitro culture chamber dissolution test.
      Physicochemical studies of BCP and vancomycin showed their structural integrity
      after isostatic compression. Isostatic compression prolonged vancomycin release
      time from 3 to 7 days and the release time became greater as isostatic pressure
      increased, probably because of the porosity decrease of the granules during
      compression.

PMID- 10646941
TI  - In vitro bioactivity of glass and glass-ceramics of the 3CaO x P2O5-CaO x SiO2
      CaO x MgO x 2SiO2 system.
AB  - A glass of nominal composition (wt%) 40.0 CaO-34.5 SiO2-16.5 P2O5-8.5 MgO-0.5
      CaF2 has been obtained (G13). The glass showed in vitro bioactivity evidenced by
      the formation on its surface of a calcium phosphate-rich layer when soaked in a
      solution with ionic composition analogous to human plasma. By thermal treatments
      of G13, a glass-ceramic (GC13) containing apatite, diopside, althausite and
      akermanite as crystalline phases was developed. GC13 as-made did not show in
      vitro bioactivity. However, after chemical treatment of GC13 with 1 M HCl (GC13
      HCl), the in vitro studies showed the formation of an apatite-like layer covering
      certain areas of the material surface. The influence of both chemical and
      morphological factors on the in vitro bioactivity has been studied.

PMID- 10646942
TI  - Biodegradable photo-crosslinked poly(ether-ester) networks for lubricious
      coatings.
AB  - Biodegradable poly(ether-ester) networks were synthesized by UV
      photopolymerization and their lubrication performances were evaluated. Polyethers
      such as poly(ethylene glycol) (PEG), poly(propylene glycol) (PPG), and
      poly(tetramethylene glycol) (PTMG) were copolymerized with oligomers of D,L
      lactic acid and terminated with acrylate groups to form photopolymerizable
      macromers. 1H NMR and IR spectra confirmed the chemical structures of copolymers
      and diacrylated macromers. Crosslinked polymer networks were formed upon UV
      initiated free-radical polymerization. Gel contents, water contents, and contact
      angles were measured to characterize the crosslinked networks. In vitro
      degradation times of the crosslinked networks at 37 degrees C in 1 N NaOH varied
      from 20 min to 7 days depending on the crosslinking density (molecular weight of
      macromer) and the hydrophilic susceptibility (types of polyethers). The
      crosslinked polymers were coated on stainless-steel needles to investigate the
      lubrication properties by measuring penetration and drag forces through rubber
      stoppers. The maximum improvement in penetration force over control was 41% in
      the needle coated with PPG-based polymer networks (molecular weight of PPG =
      4000). These materials can potentially be used as biodegradable lubricants for
      coating various medical products to replace the existing non-degradable silicone
      based materials currently used.

PMID- 10646943
TI  - Hepatocyte adhesion, growth and differentiated function on RGD-containing
      proteins.
AB  - There is currently much interest in designing synthetic substrates incorporating
      the cell binding motif RGD for tissue engineering. In this paper, hepatocyte
      function was examined on two synthetic RGD substrates and compared to that on
      fibronectin (Fn). One is a 2.3 kD RGD peptide (P-2) containing a single RGD, a
      short spacer in the middle and an end basic sequence to enhance adsorption. On
      bacteriological plastic, P-2 induced a rounded cell shape, enhanced
      differentiated function, and inhibited DNA synthesis. The other, a 73 kD
      synthetic RGD protein Pronectin F (PnF), contains repeating RGD units
      interspersed with a structural peptide. PnF induced cell spreading,
      dedifferentiation, and enhanced DNA synthesis, similar to Fn. In addition, only P
      2 showed distinct differences in cell shape and DNA synthesis when coated on
      bacteriological plastic, or on Immulon II plastic, both intrinsically non
      adhesive to cells. On bacteriologic plates coated with P-2, cells were round and
      showed diminished DNA synthesis while on Immulon II plates, they were spread and
      showed enhanced DNA synthesis. These results demonstrate that synthetic RGD
      peptides can induce very different hepatocyte function depending on the context
      in which they are presented to cells. It is likely that the RGD peptide
      conformation determines the specificity of cellular response.

PMID- 10646944
TI  - Bacterial colonization of functionalized polyurethanes.
AB  - A protocol was developed for studying the growth of bacteria upon polyurethanes
      subsequent to the establishment of an adherent bacterial population. An inocula
      of approximately 10(5) cfu S. aureus were spread on functionalized polyurethanes
      which included Pellethane, sulfonated Pellethane, phosphonated Pellethane,
      quaternized amine polyurethanes, and a zwitterionic phosphonated polyurethane.
      After 24 h incubation, Pellethane, sulfonated Pellethane, and phosphonated
      Pellethane showed bacterial growth by at least a factor of 10. In contrast, the
      zwitterionic phosphonated polyurethane showed a factor of 10 decrease in bacteria
      after 24 h and the quaternized amine polyurethanes reduced the bacteria to only a
      few hundred after only 1 h. When treated with bovine serum albumin, Pellethane,
      sulfonated Pellethane, and phosphonated Pellethane again showed bacterial growth
      by as much as a factor of 10 over 24 h. The quaternized amine polyurethanes and
      the zwitterionic phosphonated polyurethane still exhibited bactericidal abilities
      even when coated with bovine serum albumin, with the zwitterionic material
      reducing bacteria by more than a factor of 10 over 24 h and the quaternized amine
      polyurethane reducing the bacteria to only a few hundred after only 1 h. A zone
      of inhibition study suggested that the bactericidal activity of the zwitterionic
      phosphonated polyurethane was due to the leaching of cadmium ions. A quaternized
      amine polyurethane which contained chloride instead of iodide as the counterion
      to the amine moiety was less bactericidal than the iodide-containing polymer when
      treated with albumin. Thus, bacteria were able to colonize Pellethane,
      phosphonated sulfonated Pellethane, and phosphonated Pellethane, but the iodide
      containing quaternized amine polyurethane and the zwitterionic polyurethane
      prevented colonization.

PMID- 10646945
TI  - The relationship between the clinical performance and large deformation
      mechanical behavior of retrieved UHMWPE tibial inserts.
AB  - Many aspects of the proposed relationship between material properties and
      clinical performance of UHMWPE components remain unclear. In this study, we
      explored the hypothesis that the clinical performance of tibial inserts is
      directly related to its large-deformation mechanical behavior measured near the
      articulating surface. Retrieval analysis was performed on three conventional
      UHMWPE and three Hylamer-M tibial components of the same design and manufacturer.
      Samples of material were then obtained from the worn regions of each implant and
      subjected to mechanical characterization using the small punch test.
      Statistically significant relationships were observed between the metrics of the
      small punch test and the total damage score and the burnishing damage score of
      the implants. We also examined the near-surface morphology of the retrievals
      using transmission electron microscopy. TEM analysis revealed lamellar alignment
      at and below the wear surfaces of the conventional UHMWPE retrievals up to a
      maximum depth of approximately 8 microm, consistent with large-deformation
      crystalline plasticity. The depth of the plasticity-induced damage layer varied
      not only between the retrievals, but also between the conventional UHMWPE and
      Hylamer-M components. Thus, the results of this study support the hypothesis that
      the clinical performance of UHMWPE tibial inserts is related to the large
      deformation mechanical behavior measured near the articulating surface.

PMID- 10646946
TI  - Osteoconductivity of an injectable and bioresorbable poly(propylene glycol-co
      fumaric acid) bone cement.
AB  - We have investigated an injectable form of a resorbable bone cement based on in
      situ crosslinking of the unsaturated polyester, poly(propylene glycol-co-fumaric
      acid) (PPF). This material, filled with calcium gluconate/hydroxyapatite (CG/HA),
      cures to a hard cement degradable by hydrolysis. The purpose of this study was to
      evaluate the osteoconductive properties of this injectable cement. The cement was
      used as an adjunct to fixation with an intramedullary rod in the rat femoral
      osteotomy model. Ingrowth of new bone into the cement was examined in vivo.
      Negative and positive controls with rigid and loose internal fixation were
      included for comparison. Animals were evaluated histologically and
      histomorphometrically at 4 weeks postoperatively. Results of this study showed
      osteoblastic activity and new bone formation at the interface between the femoral
      bone and the cement in the experimental group. However, there was little bone
      remodeling at the endosteal surface in positive and negative controls. Histologic
      evaluation of the cement revealed the formation of cavitations, which likely
      resulted from leaching of the highly soluble calcium gluconate portion of the
      filler from the cement. These cavitations were sites of ingrowth of vascular and
      bony tissues. Intimate contact between the bone cement and the endosteal surface
      of the cortex was found. Quantitative histomorphometric analysis corroborated
      these observations. Findings of this study demonstrated the osteoconductivity of
      this type of injectable PPF-based bone cement.

PMID- 10646948
TI  - Polyurethane surfaces modified by amphiphilic polymers: effects on protein
      adsorption.
AB  - Surface modification of polyurethane (PUR) surfaces was carried out by using
      three different amphiphilic polymers. Two of the polymers were graft copolymers,
      having backbones consisting of poly(methyl methacrylate-co-ethylhexyl acrylate)
      and poly(styrene-co-acrylamide), respectively, and poly(ethylene oxide) PEO 2000
      grafts. The third polymer was a commercially available poly(ethylene oxide-b
      propylene oxide-b-ethylene oxide) block copolymer, Pluronic 9400. The polymers
      were designated ACRY, STY2, and PE94, respectively. Surface modification was
      achieved by adsorption of the amphiphilic polymers at PUR surfaces from an
      aqueous solution, or by blending the amphiphiles into a PUR solution, followed by
      solution casting of films. The accumulation of the amphiphilic polymers at the
      PUR surfaces was observed by XPS and contact angle measurements. The ACRY and
      PE94 polymers were shown to adsorb poorly at the PUR surface, but gave strong
      surface effects when present in the PUR matrix. Protein adsorption was measured
      under static as well as under flow conditions. The modified surfaces had
      generally lower adsorption of blood proteins (HSA, Fg and IgG) than the
      unmodified PUR surfaces. ACRY blend modified surfaces had the lowest adsorption.

PMID- 10646947
TI  - Effect of protein on the dissolution of HA coatings.
AB  - The dissolution behavior of hydroxyapatite (HA) in the presence and absence of
      protein needs to be investigated in order to fully understand the initial
      cellular response to HA surfaces. In this study, HA coatings were characterized
      using X-ray diffraction, X-ray photoelectron spectroscopy, and Fourier transform
      infrared spectroscopy (FTIR) prior to protein study. Fibronectin and albumin
      adsorption study were also performed. Calcium and phosphorus released in the
      presence and absence of albumin were measured. pH of the solution was measured
      daily. From the materials characterization, it was observed that the coatings
      exhibit a HA-type structure, with traces of sodium on the surface. FTIR indicated
      the possible presence of carbonates on the coatings. From the adsorption study,
      the amount of albumin adsorbed (0.052+/-0.005 microg/mm2) was statistically
      higher than the amount of fibronectin adsorbed on HA surfaces (0.035+/-0.002
      microg/mm2). Flame atomic absorption indicated a significantly higher calcium
      ions released initially for HA coatings incubated with proteins as compared to
      coatings in the absence of proteins. However, after 7 days incubation, no
      significant difference in calcium ions release was observed between the HA
      coatings in the presence and absence of proteins. Phosphorus dissolution on HA
      coatings was not significantly affected by the presence of proteins. Thus, it was
      suggested from this study that the initial dissolution properties of calcium ions
      from HA coatings was dependent on the media.

PMID- 10646949
TI  - Clinical investigation of the role of membrane structure on blood contact and
      solute transport characteristics of a cellulose membrane.
AB  - Regenerated cellulose membranes contain cellulose chains with crystalline and
      amorphous regions in the direction of extrusion. A study was undertaken to
      investigate if reduced contact surface arising from alteration of pore size
      alters biocompatibility (complement activation (C3a and C5a) and neutropenia) and
      solute transport. The average pore size for the membrane studied (RC HP400A) was
      7.23 compared to 2.76 nm for the standard membrane (Cuprophan). C3a levels rose
      to 6861+/-1595 compared to 2723+/-1228 ng/ml for Cuprophan at 15 min after
      initial blood contact (P < 0.0001). C5a levels also rose to 30.1+/-11.9 compared
      to 21.3+/-6.6 ng/ml for Cuprophan (P = 0.18). Both fractions gradually returned
      to baseline levels thereafter. Circulating white cell count fell rapidly over the
      same time period to 39+/-17% of the baseline value by 15 min and was similar to
      Cuprophan (27.5+/-11.2%) (P = 0.25). A small (< 10%) change in platelet numbers
      was noted for both membranes. Removal of urea (60 Da) was independent of pore
      size; however, the RC HP400A removed r2 microglobulin (11818 Da). These findings
      indicate that pore distribution fails to influence material-induced complement
      activation but influences large solute transport.

PMID- 10646950
TI  - Chest pain centers: moving toward proactive acute coronary care.
AB  - Ischemic heart disease is the major cause of death, disability and lost
      productivity in the developed countries of the world. The evolution of cardiac
      care units has improved patient survival from myocardial infarctions, but
      requires a high-tech, very expensive treatment facility. Chest pain centers,
      located in emergency departments, present an efficient alternative to triage
      patients with chest pain, providing prompt and accurate diagnosis, risk
      evaluation and appropriate treatments. Hospitals benefit from this cost-effective
      approach as resources are used more efficiently, and patients benefit from a
      supportive treatment facility that focuses on early intervention. Early
      recognition of prodromal unstable angina symptoms and intercession with newly
      developed treatment can help move the cardiologist toward a more proactive role
      that minimizes or avoids myocardial infarctions rather than reacting to the acute
      event.

PMID- 10646951
TI  - Relation between spatial distribution of late potentials and location of origin
      of premature ventricular complexes on body surface map in patients with
      postinfarction ventricular tachycardia.
AB  - We studied the relationship between the spatial distribution of late potentials
      (LPs) and the origin of premature ventricular complexes (PVCs) using body surface
      maps in 55 patients with postinfarction sustained ventricular tachycardia (VT).
      Body surface maps were recorded from 87 leads to construct departure maps during
      sinus rhythm and signal-averaged ECGs were recorded from 32 unipolar leads to
      construct a LP map. The root-mean-square values during 40 ms intervals behind the
      QRS end were computed as LPs. The PVC map was recorded simultaneously in 14
      patients presenting PVC with similar morphology to VT during LP detection. The
      origin of PVC was localized at the site of isopotential minimum when the
      potential exceeded -0.5 mV during the early QRS period. The LP area and the
      departure area showed a similar distribution. However, the PVC origin was closer
      to the site of LP maximum than the departure minimum in 11 (79%) patients, and
      the spatial correlation between the LP maximum and the PVC origin was good in 12
      (86%) patients. LP and PVC mapping from the body surface is feasible and of worth
      to predict noninvasively the site of origin of ventricular arrhythmias in
      patients with remote myocardial infarction and sustained VT.

PMID- 10646952
TI  - Comparison of the risk factors for coronary artery spasm with those for organic
      stenosis in a Japanese population: role of cigarette smoking.
AB  - We compared the risk factors for coronary spasm with those for coronary
      atherosclerosis in 183 patients with coronary spasm, 132 patients with coronary
      organic stenosis, and 224 control subjects with chest pain syndrome. Our findings
      confirmed that, when compared with controls, age, gender, total cholesterol, LDL
      cholesterol, hypertension, diabetes mellitus, and cigarette smoking are all
      significant risk factors for coronary organic stenosis. On the other hand, only
      cigarette smoking proved to be a significant risk factor for coronary spasm.
      Also, when compared between coronary spasm group and coronary organic stenosis
      group, the incidence of cigarette smoking in males was significantly higher in
      the coronary spasm group than in the coronary organic stenosis group. We conclude
      that cigarette smoking is a crucial risk factor for coronary spasm. On the other
      hand, serum lipid levels and the incidence of hypertension and diabetes mellitus
      were within the normal ranges in the coronary spasm patients and were thus poorly
      associated with coronary spasm. These results showed that the risk factors for
      coronary spasm differ significantly from those for atherosclerosis-based coronary
      stenosis in the Japanese. Among the risk factors for coronary atherosclerosis
      (organic stenosis) smoking alone was a significant preventable risk factor for
      coronary artery spasm.

PMID- 10646953
TI  - Pedicled omental transfer for limb salvage in Buerger's disease.
AB  - We performed pedicled omental transfer in 62 patients with Buerger's disease at
      the Department of Surgery, J.L.N. Hospital, Ajmer between January 1990 and
      December 1996. All were male and had evidence of limb ischaemia. Post-operative
      results in these patients consisted of relief of intermittent claudication in
      92%, disappearance of rest pain in 94%, disappearance of limb coldness in 83%,
      disappearance of discolouration in 82%, and healing of ischaemic ulcers in 83%.
      Tissue oxygen saturation in the affected limb improved from a mean of 84.8+/-3.6%
      in the preoperative period, to 89+/-1.5% at 12 h, 93.1+/-1.8% at 72 h and 96+/
      1.2% at the end of 2 months of follow-up. Claudication distance improved from a
      mean of 75+/-20 m in the pre-operative period to 1000+/-110 m at 2 months of
      follow-up in 57 of 62 patients. Major amputations were not required in any
      patient, thus conserving the limb. We conclude that pedicled omental transfer
      offers promising results in patients with limb ischaemia due to Buerger's
      disease.

PMID- 10646954
TI  - Atrial fibrillation in coronary artery disease.
AB  - To answer whether atrial ischemia plays an important role in the genesis of
      atrial fibrillation in patients with coronary artery disease, we analyzed the
      electrocardiograms obtained at the time of coronary angiography and left
      ventriculography in 3220 consecutive patients. Atrial fibrillation was found in
      74 (2.3%). Among those with significant coronary artery disease were 49 (66.2%)
      patients with atrial fibrillation and 88.5% with sinus rhythm (P<0.02).
      Angiograms of patients with atrial fibrillation and significant (>50%) coronary
      stenosis were re-evaluated and results compared to the control group which
      consisted of 108 consecutive patients who were in sinus rhythm at the time of
      coronary angiography. There were no differences between groups with respect to
      either frequency of injury to the right coronary artery and circumflex branch of
      left coronary artery or localization of the injury to this region (before or
      after atrial branch take-off). But patients with atrial fibrillation
      significantly more often had heart failure (55.1% versus 18.5%, P<0.001) and
      three vessel disease (30.5% versus 20.4%, P=0.05) as well as mitral valve
      insufficiency (20.4% versus 10.2%, P<0.05). In conclusion, in patients with
      coronary disease, systolic heart failure may be more important than atrial
      ischemia in causing atrial fibrillation.

PMID- 10646955
TI  - Beta-adrenoceptor density in chronic infarcted myocardium: a subtype specific
      decrease of beta1-adrenoceptor density.
AB  - Beta-adrenoceptor density is altered in different cardiac diseases. In heart
      failure beta-adrenoceptor density is down regulated but in acute myocardial
      ischemia beta-adrenoceptor density is up regulated. In hearts with myocardial
      infarction total beta-adrenoceptor density is decreased shortly after myocardial
      infarction. AIMS AND METHODS: To investigate whether total beta-adrenoceptor
      number is altered in the chronic phase after myocardial infarction, and to
      identify the specificity of alteration, we studied male Wistar rats (n = 18)
      which underwent a ligation of the left coronary artery or a sham operation.
      Twelve weeks after coronary ligation, rats were sacrificed and hearts were
      excised, perfused to obtain blood-free myocardium and frozen in liquid nitrogen.
      Infarcted myocardium was identified visually and separated from non-infarcted
      myocardium. Total beta-adrenoceptor number was calculated in fmol (-)
      [125I]iodocyanopindolol specifically bound/mg protein and the relative amount of
      beta1- and beta2-adrenoceptor density was measured by inhibition of (-)
      [125I]iodocyanopindolol binding with CGP 20712 A. RESULTS: Total beta
      adrenoceptor number in infarcted myocardium was significantly decreased (25.7+/
      1.4 vs. 24.9+/-2.2 vs. 20.1+/-3.2 fmol/mg protein (P=0.03) resp. Sham vs. Non
      infarcted vs. Infarcted myocardium), due to a decrease of only beta1-adrenoceptor
      density (14.7+/-0.61 vs. 12.7+/-1.09 vs. 4.84+/-0.96 fmol/mg protein (P=0.004)
      resp.), whereas the beta2-adrenoceptor density and the dissociation constant (Kd)
      were not significantly decreased. CONCLUSION: In the infarcted myocardium total
      beta-adrenoceptor density is decreased due to a decreased beta1-adrenoceptor
      density at 12 weeks after myocardial infarction.

PMID- 10646956
TI  - Left ventricular remodelling and dysfunction. Can the process be prevented?
AB  - Due to continuous remodelling myocardial dysfunction is a progressive condition.
      Even if the initial event is so mild that it causes no immediate cardiac
      dysfunction (e.g. a small myocardial infarction), the remodelling process is
      triggered. Although the remodelling process can be adaptive, the process becomes
      maladaptive when the stimuli are continuous and pathological. A similar
      remodelling process is seen in most primary myocardial disorders, suggesting
      common mechanisms for the development of heart failure. Although clinical heart
      failure may develop acutely, for example, after an acute myocardial infarction,
      the progressive changes in myocardial structure and deterioration of myocardial
      function can go on silently for a very long time and overt heart failure may
      develop several years after an initial insult, even if there are no further
      events. In order to fundamentally improve prognosis in cardiac failure it is
      necessary to identify patients with an ongoing remodelling process and to
      effectively counteract this process as early as possible.

PMID- 10646957
TI  - Synergistic effect of angiotensin-converting enzyme and angiotensinogen gene on
      cardiac hypertrophy.
AB  - AIMS: There are controversies concerning the association of angiotensin
      converting enzyme (ACE) insertion/deletion (I/D) polymorphism with left
      ventricular hypertrophy (LVH), and the unclear association between
      angiotensinogen (ATG) M235T polymorphism and LVH. We investigated both the
      separate and interactive effects of these two genes on LVH in patients (N=396)
      with cardiovascular disease and normal healthy volunteers (N=133). RESULTS:
      Frequency of DD genotype of ACE gene was significantly (P<0.05) higher in
      patients with LVH than patients without LVH or normal controls. Frequency of IT
      genotype of ATG gene in patients with LVH was significantly (P<0.01) greater than
      that in normal controls or marginally (P=0.1) higher than that in patients
      without LVH. These findings were also observed in normotensive patients and
      normal controls after excluding hypertensive patients. Only in patient group, the
      frequency of DD genotype in the highest quartile of LVMI was significantly
      greater than that in the lowest quartile (P<0.05). The higher tendency of TT
      genotype in the highest quartile patients compared with that in the lowest, did
      not reach statistical significance. In combined genotype analysis, there was a
      remarkable difference in LVMI between the two extreme double homozygotes only in
      patient group (156+/-25 versus 109+/-25 g/m2 for TT+DD versus MM+II) (P<0.01). In
      ANCOVA, the interaction term composed of ACE and ATG genotype was a significant
      independent variable for LVMI only in the male patient group (P<0.01).
      CONCLUSION: The D-allele of ACE and T-allele of ATG gene exert a synergistic
      effect on cardiac hypertrophy in male patients with cardiovascular diseases, but
      not in normal healthy population.

PMID- 10646958
TI  - Long term prognosis after CABG in relation to preoperative left ventricular
      ejection fraction.
AB  - AIM: To evaluate the mortality rate, risk indicators for death, mode of death and
      symptoms of angina pectoris during 5 years after coronary artery by pass grafting
      (CABG) in relation to the preoperative left ventricular ejection fraction (LVEF).
      PATIENTS: All patients in western Sweden who underwent CABG without concomitant
      valve surgery and without previously performed CABG between June 1988 and June
      1991. RESULTS: In all 1904 patients were included in the analysis, of whom 173
      (9%) had a LVEF < 40%. Patients with LVEF > or = 40% had a 5-year mortality of
      12.5%. LVEF < 40% was associated with an increased risk of death (RR 2.3; 95% cl
      1.7-3.1). There was no significant interaction between age, sex or any other
      factor in terms of clinical history and LVEF. However, left main stenosis was a
      strong independent predictor of death among patients with LVEF < 40% but not in
      those with a higher LVEF. Patients with a low LVEF more frequently died a cardiac
      death and a death associated with myocardial infarction (AMI). Furthermore they
      more frequently died in association with congestive heart failure and ventricular
      fibrillation. Among survivors, symptoms of angina pectoris were similar
      regardless of the preoperative LVEF. CONCLUSION: Patients with a low preoperative
      LVEF have a more than two-fold increased risk of death during 5 years after CABG.
      Their increased risk of death includes cardiac death, death associated with AMI,
      congestive heart failure and ventricular fibrillation.

PMID- 10646960
TI  - Ergonomics, gerontechnology and well-being in older patients with cardiovascular
      disease.

PMID- 10646959
TI  - The role of inflammatory mediators in chronic heart failure: cytokines, nitric
      oxide, and endothelin-1.
AB  - There is now considerable evidence to suggest that neurohormonal and immune
      mechanisms may play a central role in the pathogenesis of chronic heart failure
      (CHF), which is likely to have important implications for the management of this
      condition. It has been proposed that CHF is a state of immune activation with
      inflammatory cytokines contributing to both the central and the peripheral
      manifestations of this syndrome. The immune system is the body's natural defence
      mechanism against infection and other stresses, which has several different
      components that interact with each other in a complex manner. The main components
      which are thought to be relevant to the pathogenesis of CHF are: cytokines,
      adhesion molecules, autoantibodies, nitric oxide, and endothelin-1, and this
      review will concentrate on these factors. This article will also discuss the
      potential role of anti-cytokine therapies in the treatment of CHF.

PMID- 10646961
TI  - Vegetation due to Streptococcus viridans in the pulmonary artery in a child with
      patent ductus arteriosus.

PMID- 10646962
TI  - Usefulness of a rapid cardiac troponin I test kit in patients with non-diagnostic
      chest pain or elevated CK enzyme in a Coronary Care Unit.

PMID- 10646963
TI  - Desmin-storage disease and third degree atrioventricular block.

PMID- 10646964
TI  - Circadian variation of oxidant stress in myocardial ischaemic syndromes.

PMID- 10646965
TI  - Vitellogenin of the cicada Graptopsaltria nigrofuscata (Homoptera): analysis of
      its primary structure.
AB  - We cloned and sequenced the cDNA of vitellogenin (Vg) from the cicada
      Graptopsaltria nigrofuscata (Homoptera). The deduced amino acid sequence of 1987
      residues (including 16 residues for a putative signal peptide) was obtained. The
      pro-Vg was cleaved into two subunits between residues 379 and 380 following a
      consensus RXXR cleavage site sequence, secreted as S-Vg (apparent molecular
      weight 43 kDa) and L-Vg (200 kDa), sequestered, and stored in the egg as two
      vitellins (Vns), S-Vn and L-Vn, with similar respective molecular weights. There
      was a single long serine-rich stretch closely following the cleavage site. The
      entire amino acid sequences of the Vgs from the eight insects so far reported
      could be aligned confidently. The presence of subdomains I-V (areas of relatively
      high amino acid conservation) and of 10 cysteines at conserved locations at the C
      terminus, noted previously among insect Vgs, were confirmed. Antisera raised
      against G. nigrofuscata S- and L-Vn cross-reacted with the S- and L-Vg/Vn,
      respectively, of all three other cicada species examined. Another major egg
      protein (170 kDa) unrelated to Vg/Vn, was also detected in all species examined.

PMID- 10646966
TI  - The intrinsic peritrophic matrix protein peritrophin-95 from larvae of Lucilia
      cuprina is synthesised in the cardia and regurgitated or excreted as a highly
      immunogenic protein.
AB  - The intrinsic peritrophic matrix glycoprotein, peritrophin-95, from the midgut of
      larvae of Lucilia cuprina can only be solubilized from the matrix using strong
      denaturants. This suggests that the protein has a structural role in the matrix.
      Consistent with this is the finding that immuno-gold and immuno-fluorescence
      localizations of the protein showed a uniform distribution within the peritrophic
      matrix. RT-PCR demonstrated that expression of peritrophin-95 mRNA was restricted
      to the larval cardia, a small organ located in the anterior midgut from which the
      type 2 peritrophic matrix originates. Immuno-blots and ELISAs demonstrated that
      the sera from sheep infested naturally or artificially with these larvae
      recognised peritrophin-95. This indicates that peritrophin-95 stimulates the
      ovine immune system during larval infestation even though the protein is firmly
      attached to the peritrophic matrix in the larval midgut and seemingly "concealed"
      from the ovine immune surveillance system. Analyses of larval regurgitated or
      excreted material by immuno-blots, immuno-affinity purification and amino
      terminal sequencing demonstrated the presence of soluble monomeric peritrophin
      95. These results indicate that peritrophin-95, a candidate vaccine antigen for
      use in sheep is not a "concealed" antigen as previously thought. The presence of
      soluble peritrophin-95 in the regurgitated/excreted material from larvae suggests
      that this protein may be involved in a maturation phase of peritrophic matrix
      production, a by-product of which is the excretion or regurgitation of soluble
      peritrophin-95.

PMID- 10646967
TI  - Pupal cuticle proteins of Manduca sexta: characterization and profiles during
      sclerotization.
AB  - Proteins in pupal abdominal cuticle of the tobacco hornworm, Manduca sexta, were
      characterized during the pre-ecdysial and post-ecdysial periods of sclerotization
      and endocuticle formation. Protein extractability decreased dramatically as the
      cuticle became sclerotized through 6 h post-ecdysis, but increased rapidly from 9
      to 48 h as endocuticular layers were secreted. Nearly 100 proteins that were
      extracted from pre-ecdysial cuticle became largely insoluble during
      sclerotization. Three major proteins in this group destined to become exocuticle
      had apparent molecular masses (Mapp) of 20, 27 and 36 kDa, and were designated MS
      PCP20, MS-PCP27, and MS-PCP36. Amino acid analysis revealed glycine to
      predominate in all three proteins, and alanine, aspartate, glutamate, proline and
      serine were also relatively abundant. Histidine residues, which provide sites for
      adduct and cross-link formation with quinone metabolites of N-beta-alanyldopamine
      during sclerotization of pupal cuticle, ranged from 2 to 3 mol %. N-Terminal
      amino acid analysis of MSPC-20 and MSPC-36 also revealed some sequence
      similarities indicating they may be related. An almost entirely new group of
      proteins appeared by 9 h as endocuticule secretion began, and these increased in
      abundance through 48 h post-ecdysis. Two of these were major proteins with Mapps
      of 33 and 34 kDa, and they also had close similarities in their N-terminal amino
      acid sequences. This study showed that the large number of proteins secreted into
      the presumptive exocuticle of the pupa before ecdysis are involved in
      sclerotization reactions and as a consequence become largely insoluble. The
      epidermis then switches to the secretion of an entirely new group of proteins
      that are involved in formation of the endocuticle.

PMID- 10646968
TI  - Cyclic nucleotide-dependent protein phosphorylation in vitellogenic follicles of
      Hyalophora cecropia.
AB  - (1) In homogenates of vitellogenic follicles from Hyalophora cecropia, cyclic
      nucleotides promoted the transfer of label from [gamma32P]-ATP to at least four
      polypeptides. PKI (6-20) amide, an inhibitor of PKA (cAMP-dependent protein
      kinase), prevented all four reactions. Quantitative tests using kemptide as a
      substrate indicated that 80% of the total follicular PKA activity was localized
      in the follicle cells; labeling at 45, 32, and 27 kDa was particle-associated and
      also restricted to the follicle cells, while a 58 kDa substrate was labeled only
      in homogenates of the oocyte. (2) When intact follicles were incubated in [32P]
      phosphate and okadaic acid, a protein phosphatase inhibitor, the 32 kDa substrate
      again exhibited cAMP-dependent labeling. There was thus a physiological
      relationship between PKA activation and 32 kDa protein phosphorylation, while
      exposure of at least two of the other three substrates to appropriate kinases
      required homogenization. The latter was illustrated by phosphorylation of the 42
      kDa small subunit of vitellogenin, which occurred only when homogenization mixed
      the proteins of the yolk bodies with cytoplasmic kinases. (3) PKA activation is
      known to promote the termination of vitellogenesis, even in the absence of
      detectable labeling of the 32 kDa substrate. The possibility remains that
      phosphorylation at 32 kDa concerns later aspects of postvellogenic development
      that were not tested by the assay system used here.

PMID- 10646969
TI  - Molecular characterization of five serine protease genes cloned from Anopheles
      gambiae hemolymph.
AB  - We identified five new serine protease cDNAs from the hemolymph of the malaria
      vector, Anopheles gambiae. All five show sequence similarity to genes thought to
      be involved in vertebrate or invertebrate defense responses. Sp14A, Sp14D2 and
      Sp22D demonstrate changes in transcript abundance in response to bacteria
      injections. Sp14A and Sp14D2, as well as the previously characterized Sp14D1, are
      induced by infection with the malaria parasite, Plasmodium berghei. These three
      proteases, along with Sp18D, are related to a group of secreted proteases that
      have amino-terminal clip domains and trypsin-like substrate specificity. BLAST
      results and phylogenetic analyses group Sp14A, Sp14D1 and Sp14D2 with the
      Drosophila protease EASTER, and three prophenoloxidase activating enzymes from
      other insects. EASTER's substrate is SPAETZLE, a ligand involved in embryogenesis
      but also in activating anti-microbial peptide synthesis. Their similarity to
      EASTER and immune inducibility suggest that one of these proteases may activate a
      SPAETZLE-like ligand during anti-parasite responses in mosquitoes. Alternatively,
      as potential prophenoloxidase activators, Sp14A, Sp14D1 or Sp14D2 may play a role
      in melanotic encapsulation of Plasmodium.

PMID- 10646970
TI  - Characterization of cuticular proteins in the red flour beetle, Tribolium
      castaneum.
AB  - We are characterizing the cuticular proteins of Tribolium castaneum (Herbst)
      (Coleoptera:Tenebrionidae) to determine their role in the function of the
      exoskeleton. Based on qualitative analyses of cuticles, we focused on the sodium
      dodecyl sulfate (SDS)-extractable proteins. A small-scale cuticle "mini-prep"
      procedure was devised that yields preparations virtually free of contaminating
      cellular material compared to hand-dissected preparations, as assessed by
      fluorescent microscopy using DAPI to stain nuclei. Proteins extracted in 1% SDS
      from various developmental stages (last larval instar, pupal, adult) were
      analyzed by one-dimensional denaturing polyacrylamide gel electrophoresis and by
      two-dimensional gel electrophoresis. The cuticular protein profiles show both
      similarities and differences among the stages examined. The amino acid
      composition, glycosylation, and partial amino acid sequence of several abundant
      cuticular proteins indicate similarity to cuticular proteins of other insects.

PMID- 10646971
TI  - Identification of novel serine proteinase gene transcripts in the midguts of two
      tropical insect pests, Scirpophaga incertulas (Wk.) and Helicoverpa armigera
      (Hb.).
AB  - We have used RT PCR and 3'RACE to identify diverse serine proteinase genes
      expressed in the midguts of the rice yellow stem borer (Scirpophaga incertulas)
      and Asian corn borer (Helicoverpa armigera). The RT-PCR primers encoded the
      conserved regions around the active site histidine57 and serine195 of Drosophila
      melanogaster alpha trypsin, including aspartate189 of the specificity pocket.
      These primers amplified three transcripts (SiP1-3) from midguts of S. incertulas,
      and two transcripts (HaP1-2) from midguts of H. armigera. The five RT PCR
      products were sequenced to permit design of gene-specific forward primers for use
      with anchored oligo dT primers in 3'RACE. Sequencing of the 3'RACE products
      indicated that SiP1, SiP2 and HaP1 encoded trypsin-like serine proteinases, while
      HaP2 encoded a chymotrypsin-like serine proteinases. The SiP3 transcript proved
      to be an abundant 960 nt mRNA encoding a trypsin-like protein in which the active
      site serine195 was replaced by aspartate. The possible functions of this unusual
      protein are discussed.

PMID- 10646972
TI  - Secreted proteases from Photorhabdus luminescens: separation of the extracellular
      proteases from the insecticidal Tc toxin complexes.
AB  - Photorhabdus luminescens secretes both high molecular weight insecticidal toxin
      complexes and also a range of extracellular proteases into culture broth.
      Previous studies by others have suggested that insecticidal activity of the broth
      is associated with these proteases. However, by gene cloning and targeted knock
      out, we have previously shown that oral insecticidal activity is associated with
      high molecular weight 'toxin complexes' (Tc) encoded by toxin complex or tc
      genes. Here we further clarify this distinction by biochemically separating the
      protease fractions away from the oral insecticidal activity of the Tc proteins.
      We purified three distinct protease fractions from the broth: one consisting of a
      single species of 55 kDa and two of several putatively related species of
      approximately 40 kDa. All of these clearly separate from the oral insecticidal
      activity associated with the high molecular weight Tc proteins and also show no
      effect on insect weight gain following injection into the haemocoel. Here we
      examine the substrate preferences and inhibitor profiles of these protease
      fractions and discuss their relationship with those previously described from
      other P. luminescens strains and phase variants.

PMID- 10646973
TI  - Molecular cloning and expression of CYP6B8: a xanthotoxin-inducible cytochrome
      P450 cDNA from Helicoverpa zea.
AB  - Xanthotoxin, a plant allelochemical, induces alpha-cypermethrin insecticide
      tolerance in Helicoverpa zea (corn earworm); inhibition of tolerance by piperonyl
      butoxide implicates cytochrome P450 monooxygenases (P450s) in the detoxification
      of this insecticide. To characterize the xanthotoxin-inducible P450 that might
      mediate alpha-cypermethrin tolerance in this species, a cDNA library prepared
      from xanthotoxin-induced H. zea fifth instar larvae was screened with cDNAs
      encoding furanocoumarin-metabolizing P450s from Papilio polyxenes (CYP6B1v2) and
      P. glaucus (CYP6B4v2) as well as a sequence-related P450 from Helicoverpa
      armigera (CYP6B2). One full-length cDNA isolated in this screening shares 51-99%
      amino acid identity with the CYP6B subfamily of P450s isolated from Papilio and
      Helicoverpa species and, thus, has been designated CYP6B8. All of these CYP6B
      subfamily members share a number of highly conserved domains, including substrate
      recognition site 1 (SRS 1) that is critical for xanthotoxin metabolism by
      CYP6B1v2 from Papilio polyxenes and coumarin metabolism by CYP2a5 from Mus
      musculus. Northern and RT-PCR analyses indicate that CYP6B8 expression is
      strongly induced by xanthotoxin and phenobarbital and negligibly induced by alpha
      cypermethrin.

PMID- 10646974
TI  - Characterisation of multiple trypsins from the midgut of Locusta migratoria.
AB  - Three isoforms of trypsin were identified in midgut preparations from Locusta
      migratoria. Ammonium-sulphate-fractionated luminal contents of midguts were
      subjected to benzamidine affinity chromatography; proteins eluted by benzamidine
      were then separated by anion-exchange chromatography. Cationic (TRY 1) and
      anionic (TRY 2) trypsin activities were eluted from the DEAE column. TRY 1 was
      homogeneous, producing a single band of Mr 23,000 on SDS-PAGE. TRY 2 comprised
      two trypsins, TRY 2A (Mr 27,000) and TRY 2B (Mr 29,000). Following a subsequent
      chromatography step using a Bio-Rad UNO Q column, TRY 2A and TRY 2B were resolved
      to homogeneity. When homogenates of midgut caecae were the starting material for
      chromatography, SDS-PAGE of benzamidine-eluted proteins revealed an additional
      putative trypsin of Mr 17,000 (termed SERP 17) which had been absent from luminal
      enzyme preparations. Determination of the N-terminal 11 amino acid residues of
      each protein revealed unique, but similar sequences. The four sequences all began
      with IVGG, a motif which signifies all four proteins are serine proteases. TRY 1,
      TRY 2A and TRY 2B were shown to contain only trypsin activity and the
      preparations were sensitive to inhibition by AEBSF, PMSF, TLCK, benzamidine,
      leupeptin, SBTI, BPTI and E64.

PMID- 10646975
TI  - MR imaging of Pellegrini-Stieda disease.
AB  - OBJECTIVE: To describe the MR imaging of Pellegrini-Stieda disease, a post
      traumatic ossification of the medial collateral ligament with typical
      radiographic findings. METHODS: Coronal and/or axial T2*-weighted field echo and
      T1-weighted conventional spin echo MR images were obtained with 1.5-Tesla or 0.5
      Tesla units. Four patients with radiographic and clinical diagnoses of Pellegrini
      Stieda disease were examined. Surgery was performed on one patient, and
      histopathologic correlation was obtained. RESULTS AND CONCLUSION: Delineating it
      as a signal void, T2*-weighted MR imaging indicated the precise extent of the
      osseous fragment in relation to the medial collateral ligament. T1-weighted
      imaging showed the presence of fatty marrow as a high signal region within the
      fragment, indicating maturity of the fragment. These findings may help to
      determine preoperative planning for resection of massive fragments around the
      ligament. Pellegrini-Stieda disease cannot be considered rare, since it is often
      encountered in daily MRI examinations.

PMID- 10646977
TI  - Small cell carcinoma of the lung: CT findings of parenchymal lesions.
AB  - PURPOSE: The purpose of this study was to describe the CT findings of small cell
      carcinoma of the lung. MATERIALS AND METHODS: CT findings were retrospectively
      reviewed in 38 patients (34 men, 4 women; aged 46-73 years) with pathologically
      proven small cell carcinoma. RESULTS: Tumors were located centrally in 23 cases
      (61%) and peripherally in 15 cases (39%). Twenty-seven patients had a bulky
      central mass with encasement of the great vessels or extrinsic compression of the
      airway (22 central tumors, 5 peripheral tumors). Six patients had peripheral
      lesions without adenopathy. Five peripheral small cell carcinomas demonstrated
      peribronchial thickening adjacent to the primary tumor. CONCLUSION: The first
      sign of small cell carcinoma most typically is a bulky central mass that
      represents metastasis to the hilar and/or mediastinal lymph nodes. Although no
      findings specific to peripheral small cell carcinoma are available, small cell
      carcinoma originating from the peripheral lung parenchyma should be included in
      the differential diagnosis when peribronchial thickening is associated with the
      tumor.

PMID- 10646976
TI  - Multi-fractionated wide-field radiation therapy for palliation of multiple
      symptomatic bone metastases from solid tumors.
AB  - PURPOSE: This was a pilot study to explore the toxicity and response of multi
      fractionated wide-field radiation therapy (MF-WFRT) in patients with multiple
      symptomatic osseous metastases. PATIENTS AND METHODS: From February 1997 to April
      1998, a total of nine patients (5 lung cancer, 3 breast cancer, 1 prostate
      cancer) were treated with MF-WFRT. The patients received 1.5 Gy per fraction
      (twice a day) to a total dose of 7 Gy in 3 days for the upper body and a total
      dose of 9 Gy in 3 days for the lower body. Ten treatments in nine patients were
      carried out with this technique (2 upper half-body, 5 lower half-body, 3 mid
      body; one patient had both upper mid-body and lower-half body treatments).
      RESULTS: Pain relief was complete in two patients (20%) and eight (80%) achieved
      better than 50% pain relief. Seventy-five percent of pain responders achieved
      pain relief within one week of MF-WFRT. The pain relief was long-lasting and
      continued without need of reirradiation for 45% of the remainder of the patients'
      lives. The incidence of gastrointestinal complications was low, basically Grade 1
      2 toxicity. Four patients (40%) experienced Grade 3-4 hematological toxicity.
      Hematological toxicity was treated with blood transfusion or G-CSF. General
      tolerance was excellent, and no pneumonitis or radiation-related deaths occurred.
      CONCLUSION: This treatment modality appears to be well tolerated and effective.
      The optimal indications, dose, and fractionation for MF-WFRT should be further
      explored in randomized studies.

PMID- 10646978
TI  - Unilateral renal cystic disease.
AB  - Unilateral renal cystic disease (URCD) is a distinct entity that is one of the
      renal cystic diseases. URCD consists of a cluster of multiple cysts in part or
      most of one kidney with no association of cystic disease in the contralateral
      kidney. URCD is a nonfamilial, nonprogressive disorder and is not related with
      autosomal dominant polycystic kidney disease (ADPKD). We report a case of URCD
      with six-year CT follow-up. Confinement of the cystic disease to one kidney with
      an absence of cysts in other organs such as liver or pancreas distinguish URCD
      from ADPKD. Absence of an encapsulated mass and intervening normal renal
      parenchyma between the cysts can differentiate URCD from cystic renal tumors.

PMID- 10646979
TI  - Placental site trophoblastic tumor: imaging findings.
AB  - Placental site trophoblastic tumor (PSTT) is the least common form of gestational
      trophoblastic disease, with only about 100 cases having been reported. Although
      the imaging findings of PSTT have seldom been reported, previous findings of the
      tumor indicate that it can be divided into two types, a hypervascular type and a
      relatively hypovascular type. We reported the imaging findings of these two
      representative types of PSTT. In the hypervascular type, massive bleeding
      following dilatation and curettage have been reported. When prominent vascularity
      of the tumor is indicated by imaging findings, dilatation and curettage should be
      avoided. On the other hand, uterine conservative surgery may be possible in
      patients with the localized hypovascular type. The main role of imaging diagnosis
      of PSTT is to clarify the vascularity of the tumor.

PMID- 10646980
TI  - A case of ganglioneuroma with fatty replacement: CT and MRI findings.
AB  - We report a rare case of posterior mediastinal ganglioneuroma with fatty
      replacement together with its appearance on CT and MRI and suggest adding this
      entity to the differential diagnosis of fat-containing posterior mediastinal
      masses.

PMID- 10646981
TI  - Gastric toxicity related to perfusion of the stomach via the left inferior
      phrenic artery during hepatic arterial infusion chemotherapy: report of two
      cases.
AB  - We present two cases of gastric toxicity related to hepatic arterial infusion
      chemotherapy (HAIC) for liver metastases. The gastric toxicity was caused by the
      inflow of infused drugs into the stomach via the left inferior phrenic artery
      arising from the celiac arterial trunk. The catheter hole was placed in the
      celiac arterial trunk with occlusion of the splenic and many gastric arteries. It
      must be kept in mind that perfusion of the stomach may occur through the left
      inferior phrenic artery in HAIC.

PMID- 10646982
TI  - False positive appearance of subarachnoid hemorrhage on CT with bilateral
      subdural hematomas.
AB  - We describe a patient with bilateral traumatic subdural hematomas in whom CT
      findings of hyperattenuation in the basal cisterns and subarachnoid spaces
      falsely suggested superimposed acute subarachnoid hemorrhage.

PMID- 10646983
TI  - Squamous cell carcinoma of the external auditory canal: two cases treated with
      high dose rate 192Ir remote afterloading system (RALS).
AB  - We report two cases of early-stage external auditory canal cancer treated by
      intracavitary irradiation with a high dose rate (HDR) 192Ir remote afterloading
      system (RALS) for preoperative treatment. A 6-Fr catheter for the HDR 192Ir
      remote afterloader, fixed by a plastic earplug, was inserted into the external
      auditory canal in two cases (case 1, T2N0M0; case 2, T1N0M0). The total
      intracavitary radiation dosages were 50 Gy (10 Gy/2 Fr/wk for 5 wks) for case 1,
      and 42 Gy (15 Gy/5 Fr/wk for 3 wks) for case 2. No external irradiation was given
      in either case. Surgical resection was performed in both cases, three to four
      weeks after irradiation. Histopathological examination confirmed the post
      irradiation changes of necrosis, hyalinosis, and calcification, although vivid
      cancer cells remained. In preoperative irradiation of external auditory cancer,
      this method, although limited to treating early-stage cancers, may be a modality
      of choice for its efficacy and less severe side effects.

PMID- 10646984
TI  - MR images of ovarian carcinosarcoma.
AB  - The MR imaging of an ovarian carcinosarcoma is described. The tumor was
      heterogeneous and showed very high-intensity on T2-weighted images and iso
      intensity on T1-weighted images, with visible enhancement. Even though signal
      intensities were somewhat different from those of ovarian adenocarcinoma, the
      preoperative diagnosis of ovarian carcinosarcoma is still difficult.

PMID- 10646985
TI  - Ewing's sarcoma of the sacrum.
AB  - Radiological findings in a case of spinal Ewing' s sarcoma are reported. A lytic
      lesion with soft tissue component in the sacrum was identified. Ewing's sarcoma
      should be included in the differential diagnosis, especially when a child has a
      lytic lesion with soft tissue extension in the spine.

PMID- 10646986
TI  - Three-dimensional CT imaging of aneurysm of aberrant right subclavian artery.
AB  - We report a case of an aneurysm originating from an aberrant right subclavian
      artery, which was incidentally found as a compression deformity of the upper
      esophagus on a barium study in a 46-year-old man. Computed tomography (CT)
      clearly demonstrated the aneurysm of the aberrant right subclavian artery. In
      particular, reconstructed three-dimensional CT (3D-CT) was valuable in evaluating
      the positional relationships between the anomalous vessel with aneurysm and other
      structures.

PMID- 10646988
TI  - Sickle-tip sheath for percutaneous implantation of hepatic arterial catheter with
      subclavian arterial access.
AB  - We used a new type of sheath-introducer to facilitate the percutaneous procedure
      of hepatic arterial catheter implantation with left subclavian arterial access.
      Insertion into the descending aorta was easy without any additional catheters
      because the sheath could be manipulated to the aortic arch. After hepatic
      arterial catheterization, the sheath was slid safely away by fitting a 5 F
      catheter to the end of the indwelling catheter. The procedures of sheath
      insertion and removal were successful in all 29 cases, without any complications.
      The sickle-tip sheath is a useful optional device for trans-subclavian
      catheterization to the hepatic artery.

PMID- 10646987
TI  - Case report of 14-year survival after radiotherapy for clinical T3 esophageal
      carcinoma, with local recurrence finally rescued by surgery.
AB  - A 51-year-old man with increasing dysphasia was admitted to our hospital on March
      18, 1985. Several examinations revealed thoracic esophageal squamous cell
      carcinoma 11 cm in length staged T3N0M0 (stage IIA) by UICC 1987. As he rejected
      our proposal of surgery, definitive radiotherapy (60 Gy) was delivered, and
      complete response was obtained. The patient had been doing well for 5 years after
      radiotherapy until superficial local recurrence was discovered at a periodic
      endoscopic examination. High-dose-rate intraluminal brachytherapy (10 Gy/2 Fr)
      was administered. After a 3-year disease-free interval, superficial recurrence
      developed in the same location, and early gastric cancer was detected as a
      secondary cancer. Radical salvage surgery was performed. The patient was alive
      and disease free 5 years and 5 months after surgery. We present this rare case of
      a patient who survived 14 years after the initial radiotherapy. The present case
      demonstrated the importance of long-term follow-up after radiotherapy, long-term
      local controllability of relatively low doses of intraluminal brachytherapy after
      superficial recurrence, and the feasibility of salvage surgery as long as local
      recurrence is limited to within the mucosal layer.

PMID- 10646989
TI  - The increasing opacity of gene therapy.

PMID- 10646990
TI  - US universities find that demand for botanists exceeds supply.

PMID- 10646991
TI  - Publishing group offers peer review on PubMed Central.

PMID- 10646992
TI  - Ukraine denies arresting biologist.

PMID- 10646993
TI  - Race is on to find successor to Varmus at NIH.

PMID- 10646994
TI  - Surprise boost for stem-cell work.

PMID- 10646995
TI  - German scientists must repay fees.

PMID- 10646996
TI  - Publishers map out a way forward in response to free online archives.

PMID- 10646997
TI  - Survey confirms fears about licensing of genetic tests.

PMID- 10646998
TI  - Homo sapiens declared extinct.

PMID- 10646999
TI  - RNA interference. Policing rogue genes.

PMID- 10647000
TI  - Distorting sex ratios.

PMID- 10647001
TI  - Dual control of mitotic exit.

PMID- 10647002
TI  - Plant genetics. Knocking out nodules.

PMID- 10647003
TI  - Motherhood improves learning and memory.

PMID- 10647004
TI  - Dichromatism in macaque monkeys.

PMID- 10647005
TI  - A protein kinase encoded by the t complex responder gene causes non-mendelian
      inheritance.
AB  - Males heterozygous for the t-haplotype form of mouse chromosome 17 preferentially
      transmit the t-chromosome to their progeny. Several distorter/sterility loci
      carried on the t-haplotype together impair flagellar function in all spermatozoa
      whereas the responder, Tcr, rescues t-sperm but not wild-type sperm. Thus, t
      sperm have an advantage over wild-type sperm in fertilizing egg cells. We have
      isolated Tcr by positional cloning and show that it is a member of a novel
      protein kinase gene family, designated Smok, which is expressed late during
      spermiogenesis. Smok kinases are components of a signal cascade which may control
      sperm motility. Tcr has a reduced kinase activity, which may allow it to
      counterbalance a signalling impairment caused by the distorter/sterility loci.
      Tcr transgene constructs cause non-mendelian transmission of chromosomes on which
      they are carried, which leads to sex-ratio distortion when Tcr cosegregates with
      the Y chromosome.

PMID- 10647006
TI  - Identification of in vivo substrates of the chaperonin GroEL.
AB  - The chaperonin GroEL has an essential role in mediating protein folding in the
      cytosol of Escherichia coli. Here we show that GroEL interacts strongly with a
      well-defined set of approximately 300 newly translated polypeptides, including
      essential components of the transcription/translation machinery and metabolic
      enzymes. About one third of these proteins are structurally unstable and
      repeatedly return to GroEL for conformational maintenance. GroEL substrates
      consist preferentially of two or more domains with alphabeta-folds, which contain
      alpha-helices and buried beta-sheets with extensive hydrophobic surfaces. These
      proteins are expected to fold slowly and be prone to aggregation. The hydrophobic
      binding regions of GroEL may be well adapted to interact with the non-native
      states of alphabeta-domain proteins.

PMID- 10647007
TI  - Signal but not noise changes with perceptual learning.
AB  - Perceptual discrimination improves with practice. This 'perceptual learning' is
      often specific to the stimuli presented during training, indicating that practice
      may alter the response characteristics of cortical sensory neurons. Although much
      is known about how learning modifies cortical circuits, it remains unclear how
      these changes relate to behaviour. Different theories assume that practice
      improves discrimination by enhancing the signal, diminishing internal noise or
      both. Here, to distinguish among these alternatives, we fashioned sets of faces
      and textures whose signal strength could be varied, and we trained observers to
      identify these patterns embedded in noise. Performance increased by up to 400%
      across several sessions over several days. Comparisons of human performance to
      that of an ideal discriminator showed that learning increased the efficiency with
      which observers encoded task-relevant information. Observer response consistency,
      measured by a double-pass technique in which identical stimuli are shown twice in
      each experimental session, did not change during training, showing that learning
      had no effect on internal noise. These results indicate that perceptual learning
      may enhance signal strength, and provide important constraints for theories of
      learning.

PMID- 10647008
TI  - Conflict monitoring versus selection-for-action in anterior cingulate cortex.
AB  - The anterior cingulate cortex (ACC), on the medial surface of the frontal lobes
      of the brain, is widely believed to be involved in the regulation of attention.
      Beyond this, however, its specific contribution to cognition remains uncertain.
      One influential theory has interpreted activation within the ACC as reflecting
      'selection-for-action', a set of processes that guide the selection of
      environmental objects as triggers of or targets for action. We have proposed an
      alternative hypothesis, in which the ACC serves not to exert top-down attentional
      control but instead to detect and signal the occurrence of conflicts in
      information processing. Here, to test this theory against the selection-for
      action theory, we used functional magnetic resonance imaging to measure brain
      activation during performance of a task where, for a particular subset of trials,
      the strength of selection-for-action is inversely related to the degree of
      response conflict. Activity within the ACC was greater during trials featuring
      high levels of conflict (and weak selection-for-action) than during trials with
      low levels of conflict (and strong selection-for-action), providing evidence in
      favour of the conflict-monitoring account of ACC function.

PMID- 10647009
TI  - Two functionally distinct alpha2-adrenergic receptors regulate sympathetic
      neurotransmission.
AB  - The sympathetic nervous system regulates cardiovascular function by activating
      adrenergic receptors in the heart, blood vessels and kidney. Alpha2-adrenergic
      receptors are known to have a critical role in regulating neurotransmitter
      release from sympathetic nerves and from adrenergic neurons in the central
      nervous system; however, the individual roles of the three highly homologous
      alpha2-adrenergic-receptor subtypes (alpha2A, alpha2B, alpha2C) in this process
      are not known. We have now studied neurotransmitter release in mice in which the
      genes encoding the three alpha2-adrenergic-receptor subtypes were disrupted. Here
      we show that both the alpha2A- and alpha2C-subtypes are required for normal
      presynaptic control of transmitter release from sympathetic nerves in the heart
      and from central noradrenergic neurons. Alpha2A-adrenergic receptors inhibit
      transmitter release at high stimulation frequencies, whereas the alpha2C-subtype
      modulates neurotransmission at lower levels of nerve activity. Both low- and high
      frequency regulation seem to be physiologically important, as mice lacking both
      alpha2A- and alpha2C-receptor subtypes have elevated plasma noradrenaline
      concentrations and develop cardiac hypertrophy with decreased left ventricular
      contractility by four months of age.

PMID- 10647010
TI  - Rapid gating and anion permeability of an intracellular aquaporin.
AB  - Aquaporin (AQP) water-channel proteins are freely permeated by water but not by
      ions or charged solutes. Although mammalian aquaporins were believed to be
      located in plasma membranes, rat AQP6 is restricted to intracellular vesicles in
      renal epithelia. Here we show that AQP6 is functionally distinct from other known
      aquaporins. When expressed in Xenopus laevis oocytes, AQP6 exhibits low basal
      water permeability; however, when treated with the known water channel inhibitor,
      Hg2+, the water permeability of AQP6 oocytes rapidly rises up to tenfold and is
      accompanied by ion conductance. AQP6 colocalizes with H+-ATPase in intracellular
      vesicles of acid-secreting alpha-intercalated cells in renal collecting duct. At
      pH less than 5.5, anion conductance is rapidly and reversibly activated in AQP6
      oocytes. Site-directed mutation of lysine to glutamate at position 72 in the
      cytoplasmic mouth of the pore changes the cation/anion selectivity, but leaves
      low pH activation intact. Our results demonstrate unusual biophysical properties
      of an aquaporin, and indicate that anion-channel function may now be explored in
      a protein with known structure.

PMID- 10647011
TI  - Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA
      methyltransferase gene.
AB  - The recessive autosomal disorder known as ICF syndrome (for immunodeficiency,
      centromere instability and facial anomalies; Mendelian Inheritance in Man number
      242860) is characterized by variable reductions in serum immunoglobulin levels
      which cause most ICF patients to succumb to infectious diseases before adulthood.
      Mild facial anomalies include hypertelorism, low-set ears, epicanthal folds and
      macroglossia. The cytogenetic abnormalities in lymphocytes are exuberant:
      juxtacentromeric heterochromatin is greatly elongated and thread-like in
      metaphase chromosomes, which is associated with the formation of complex
      multiradiate chromosomes. The same juxtacentromeric regions are subject to
      persistent interphase self-associations and are extruded into nuclear blebs or
      micronuclei. Abnormalities are largely confined to tracts of classical satellites
      2 and 3 at juxtacentromeric regions of chromosomes 1, 9 and 16. Classical
      satellite DNA is normally heavily methylated at cytosine residues, but in ICF
      syndrome it is almost completely unmethylated in all tissues. ICF syndrome is the
      only genetic disorder known to involve constitutive abnormalities of genomic
      methylation patterns. Here we show that five unrelated ICF patients have
      mutations in both alleles of the gene that encodes DNA methyltransferase 3B (refs
      5, 6). Cytosine methylation is essential for the organization and stabilization
      of a specific type of heterochromatin, and this methylation appears to be carried
      out by an enzyme specialized for the purpose.

PMID- 10647012
TI  - A plant regulator controlling development of symbiotic root nodules.
AB  - Symbiotic nitrogen-fixing root nodules on legumes are founded by root cortical
      cells that de-differentiate and restart cell division to establish nodule
      primordia. Bacterial microsymbionts invade these primordia through infection
      threads laid down by the plant and, after endocytosis, membrane-enclosed
      bacteroids occupy cells in the nitrogen-fixing tissue of functional nodules. The
      bacteria excrete lipochitin oligosaccharides, triggering a developmental process
      that is controlled by the plant and can be suppressed. Nodule inception initially
      relies on cell competence in a narrow infection zone located just behind the
      growing root tip. Older nodules then regulate the number of nodules on a root
      system by suppressing the development of nodule primordia. To identify the
      regulatory components that act early in nodule induction, we characterized a
      transposon-tagged Lotus japonicus mutant, nin (for nodule inception), arrested at
      the stage of bacterial recognition. We show that nin is required for the
      formation of infection threads and the initiation of primordia. NIN protein has
      regional similarity to transcription factors, and the predicted DNA
      binding/dimerization domain identifies and typifies a consensus motif conserved
      in plant proteins with a function in nitrogen-controlled development.

PMID- 10647013
TI  - CaMKII regulates the density of central glutamatergic synapses in vivo.
AB  - Synaptic connections undergo a dynamic process of stabilization or elimination
      during development, and this process is thought to be critical in memory and
      learning and in establishing the specificity of synaptic connections. The type II
      calcium- and calmodulin-dependent protein kinase (CaMKII) has been proposed to be
      pivotal in regulating synaptic strength and in maturation of synapses during
      development. Here we describe how CaMKII regulates the formation of central
      glutamatergic synapses in Caenorhabditis elegans. During larval development, the
      density of ventral nerve cord synapses containing the GLR-1 glutamate receptor is
      held constant despite marked changes in neurite length. The coupling of synapse
      number to neurite length requires both CaMKII and voltage-gated calcium channels.
      CaMKII regulates GLR-1 by at least two distinct mechanisms: regulating transport
      of GLR-1 from cell bodies to neurites; and regulating the addition or maintenance
      of GLR-1 to postsynaptic elements.

PMID- 10647014
TI  - Diverse behavioural defects caused by mutations in Caenorhabditis elegans unc-43
      CaM kinase II.
AB  - Calcium/calmodulin-dependent serine/threonine kinase type II (CaMKII) is one of
      the most abundant proteins in the mammalian brain, where it is thought to
      regulate synaptic plasticity and other processes. Activation of the multisubunit
      kinase by calcium is effectively cooperative and can persist long after transient
      calcium rises. Despite extensive biochemical characterization of CaMKII and
      identification of numerous in vitro kinase targets, little is known about its
      function in vivo. Here we report that unc-43 encodes the only Caenorhabditis
      elegans CaMKII. A gain-of-function unc-43 mutation reduces locomotory activity,
      alters excitation of three muscle types and lengthens the period of the motor
      output of a behavioural clock. Null unc-43 mutations cause phenotypes generally
      opposite to those of the gain-of-function mutation. Mutations in the unc-103
      potassium channel gene suppress a gain-of-function phenotype of unc-43 in one
      tissue without affecting other tissues; thus, UNC-103 may be a tissue-specific
      target of CaMKII in vivo.

PMID- 10647015
TI  - APC(Cdc20) promotes exit from mitosis by destroying the anaphase inhibitor Pds1
      and cyclin Clb5.
AB  - Ubiquitin-mediated proteolysis due to the anaphase-promoting complex/cyclosome
      (APC/C) is essential for separation of sister chromatids, requiring degradation
      of the anaphase inhibitor Pds1, and for exit from mitosis, requiring inactivation
      of cyclin B Cdk1 kinases. Exit from mitosis in yeast involves accumulation of the
      cyclin kinase inhibitor Sic1 as well as cyclin proteolysis mediated by APC/C
      bound by the activating subunit Cdh1/Hct1 (APC(Cdh1)). Both processes require the
      Cdc14 phosphatase, whose release from the nucleolus during anaphase causes
      dephosphorylation and thereby activation of Cdh1 and accumulation of another
      protein, Sic1 (refs 4-7). We do not know what determines the release of Cdc14 and
      enables it to promote Cdk1 inactivation, but it is known to be dependent on APC/C
      bound by Cdc20 (APC(Cdc20)) (ref. 4). Here we show that APC(Cdc20) allows
      activation of Cdc14 and promotes exit from mitosis by mediating proteolysis of
      Pds1 and the S phase cyclin Clb5 in the yeast Saccharomyces cerevisiae.
      Degradation of Pds1 is necessary for release of Cdc14 from the nucleolus, whereas
      degradation of Clb5 is crucial if Cdc14 is to overwhelm Cdk1 and activate its
      foes (Cdh1 and Sic1). Remarkably, cells lacking both Pds1 and Clb5 can
      proliferate in the complete absence of Cdc20.

PMID- 10647016
TI  - The RNA splicing factor hSlu7 is required for correct 3' splice-site choice.
AB  - The production of correctly spliced messenger RNA requires two catalytic splicing
      steps. During step II, exon 1 attacks an adenine-guanine (AG) dinucleotide at the
      3' splice site. This AG is usually located between 18 and 40 nucleotides
      downstream from the branch site, and closer AGs are skipped in favour of AGs
      located more optimally downstream. At present, little is understood about how the
      correct AG is distinguished from other AGs. Here we describe a metazoan splicing
      factor (hSlu7) that is required for selection of the correct AG. In the absence
      of hSlu7, use of the correct AG is suppressed and incorrect AGs are activated. We
      investigated this loss of fidelity by analysing spliceosomes assembled in the
      absence of hSlu7. These studies reveal that exon 1 is loosely associated with
      these spliceosomes. Thus, the improperly held exon cannot access the correct AG,
      but can attack other AGs indiscriminately. We conclude that hSlu7 is required to
      hold exon 1 tightly within the spliceosome for attack on a prespecified AG.

PMID- 10647018
TI  - Improving the plight of the physician-scientist in the US.

PMID- 10647017
TI  - From bench to bedside... research makes the translational transition.

PMID- 10647019
TI  - The future of nursing education.
AB  - Market-driven economic policy, dramatic technology developments, changing
      demographics, and the knowledge explosion are rapidly changing health care and
      educational institutions as well as creating a climate of continuous rapid
      change. Nursings' contract with society requires the profession to be responsive
      to these changes. Four views of changes in nursing practice and therefore nursing
      education are presented. Changes in the role of faculty and in the nature of the
      curriculum are described. Twelve strategies for facilitating change are listed.

PMID- 10647020
TI  - Professional nursing practice in an HMO: the future is now.
AB  - Managed care forms of service delivery now dominate the nursing practice
      environment. Nursing is potentially a key resource for helping the system to meet
      the increased and evolving demands, maintaining quality while decreasing costs.
      However, nurses need additional competencies to function effectively in this
      environment. Nurse educators need to prepare nurses for these new roles. This
      paper describes trends influencing nursing roles and identifies the nine
      categories of competencies needed by professional nurses practicing in HMO
      settings. Cost-reduction pressures have driven profound changes in the health
      care system in recent years. Countering these demands for cost-reduction are
      increases in costs driven by new, more expensive treatments and higher patient
      expectations. While the future of health care is anything but clear, certain
      features of the health care system seem relatively certain: major changes will
      continue to be cost-driven; more hospitals will close, or consolidate or
      collaborate to compete; and inpatient acuity will continue to increase. In
      addition, corporate America will increasingly influence how care is delivered and
      demands for information on health plan performance, such as the Health Employers
      Data Information System (HEDIS) (National Committee for Quality Assurance, 1997)
      will increase. These forces will inevitably redirect use of resources within
      health care organizations. Other external forces that will continue to influence
      how care is delivered are discussed below.

PMID- 10647021
TI  - Advocating healthy public policy: implications for baccalaureate nursing
      education.
AB  - Advocating healthy public policy is increasingly recognized as an essential
      strategy for enhancing the health of populations. The purpose of this paper is to
      discuss the implications this priority area portends for the educational
      preparation of public health nurses (PHNs). Population health is central to
      public health nursing, and as such, it is imperative that PHNs employ policy
      advocacy strategies to influence positively the determinants that affect the
      health of populations. In this paper, we introduce the concept of healthy public
      policy and its relevance for public health nursing and baccalaureate nursing
      education. We outline substantive content areas that are fundamental to policy
      advocacy, such as determinants of health and their interrelationships, the policy
      process, and theoretical frameworks consistent with a socioenvironmental approach
      to health. In addition, we detail examples of specific learning experiences that
      provide students with opportunities to apply the content. Some of these
      activities include analysis of a population health issue, developing a position
      paper or resolution, writing letters to policy makers and the media, and working
      with lobbyists and policy makers.

PMID- 10647022
TI  - Nursing and health care reform: implications for curriculum development.
AB  - The health care system is undergoing profound changes. Cost containment efforts
      and restructuring have resulted in cutbacks in registered nurse (RN) positions.
      These changes are often related to the increased market penetration by managed
      care companies. To determine how RN graduates perceive these changes and their
      impact on the delivery of patient care, Healthcare Environment Surveys were
      mailed to graduates of the classes of 1986 and 1991. Using the Survey's 5-point
      Likert Scale, we measured the graduates' satisfaction with their salary, quality
      of supervision they received, opportunities for advancement, recognition for
      their job, working conditions, the overall job and the changes in their careers
      over the previous five year period. Our study suggests that the changes in the
      health care system are having an impact on how health care is being delivered and
      the way nurses view their jobs. Respondents reported that insurance companies are
      exerting increased control over patient care and perceive that the quality of
      patient care is declining. Increased workloads and an increase in the amount of
      paperwork were reported. Participants perceived that there were fewer jobs
      available and that job security was decreasing. The percentage of nurses who see
      job satisfaction as remaining the same or increasing are a majority. However, the
      relatively high percent of nurses who see job satisfaction as declining should
      provide a note of warning. The major implications of this study are that the
      professional nursing curriculum must be modified to include content on
      communication, organization, legislative/policy skills, and leadership. The
      nation's health care system is undergoing profound changes. There are numerous
      forces at work that are effecting the delivery of care and, consequently, the
      work of health professionals. These forces include significant efforts at cost
      containment, restructuring and downsizing of hospitals, and the movement of
      health care delivery out of acute care centers and into the community. Even
      though cutbacks in registered nurse (RN) positions appear to have leveled off in
      sections of the country that have gone through restructuring and reengineering of
      the work place, there still remains a heavy emphasis on lowering costs by
      decreasing employee benefits and increasing productivity through the substitution
      of part-time RNs for full-time RNs and the substitution of unlicensed assistive
      personnel (UAP) for RNs. These changes are often related to the increased market
      penetration by managed care companies, which are not expected to abate any time
      soon. It is important to determine what impact these changes are having on the
      delivery of patient care since there is some evidence to suggest that reduction
      in nursing staff below certain levels is related to poor patient outcomes
      (Fridken et al, 1996). It is also important to assess the effect of system
      changes on the satisfaction level health professionals have in their jobs. This
      is particularly important since some researchers suggest that job
      dissatisfaction, over a period of time, can result in burnout and eventually,
      turnover (Cameron, Horsburgh, & Armstrong-Stassen, 1994; Cotterman, 1991).
      Finally, understanding the impact of these health care delivery system changes
      has significant implications for baccalaureate nursing education and the
      preparation needed by future nurses to help them adjust to the changed
      environment.

PMID- 10647023
TI  - Incorporating a political action framework into a BSN program.

PMID- 10647024
TI  - The effect of health policy education on self-perceived political competence of
      graduate nursing students.

PMID- 10647025
TI  - Exploring commonality of professional values among nurse educators in the United
      States and England.

PMID- 10647026
TI  - Resources in genetics for nursing education.

PMID- 10647027
TI  - Presidential address. The cure for all diseases.

PMID- 10647028
TI  - Introduction of Professor Peter J. Hotez as the Henry Baldwin Ward Medalist for
      1999.

PMID- 10647029
TI  - Acceptance of the 1999 Henry Baldwin Ward Medal.

PMID- 10647030
TI  - Presentation of the 1999 recipient of the American Society of Parasitologists'
      Mentor Award, Dr. Gerald W. Esch.

PMID- 10647031
TI  - Acceptance of the American Society of Parasitologists' Mentor Award: musings of a
      mentor.

PMID- 10647032
TI  - Sporogonic development of Hepatozoon americanum (Apicomplexa) in its definitive
      host, Amblyomma maculatum (Acarina).
AB  - Light microscopic observations of the sporogonic development of Hepatozoon
      americanum are described in its acarine host, Amblyomma maculatum. Laboratory
      reared nymphal ticks were fed on 2 dogs infected with H. americanum. Nymphal
      ticks were sampled daily, starting 3 days after being placed on a parasitemic
      dog, until 18 days after infestation (PI), and then every 3 or 4 days until
      replete nymphs molted. Ticks were examined as unstained wet mounts and
      hematoxylin-eosin-stained paraffin sections. Gametes were found within the gut
      cells of nymphs 4 and 6 days PI. Although differentiation of gamonts into gametes
      was not detected, syngamy and sporogony were observed. Sporogony appears to occur
      wholly within tick gut cells, followed by release of mature oocysts into the
      hemocoel. The earliest evidence of sporoblast formation was observed 23 days PI
      and of sporozoite formation, 10 days later. Mature oocysts were first found 42
      days PI in newly molted adult ticks. Most adult ticks (>98%) that were dissected
      contained mature oocysts. Oocysts were multisporocystic, and sporocysts contained
      a variable number of sporozoites. Oocysts in various stages of development were
      often seen within the same tick, and the number of mature oocysts ranged from 4
      to 573.

PMID- 10647033
TI  - Influencing random transmission is a neutral character in hosts.
AB  - This study introduces an individual-based model on a host-parasite assemblage to
      investigate whether hosts are necessarily selected for obstructing the
      transmission of virulent parasites to conspecifics. Contrary to the widespread
      notion, a host's ability to influence parasite transmission within the host
      population is a neutral character provided that parasite transmission routes are
      random, with no reference to genetic relatedness. Due to a lack of selection
      pressure under such circumstances, hosts may fail to evolve counteradaptations
      against manipulations by parasites to enhance transmission. However, vertically
      biased transmission (biased toward kin) selects hosts for a decrease of parasite
      transmission, while it is also known to select parasites to decrease virulence.
      Horizontally biased transmission routes (biased toward nonrelated conspecifics)
      select hosts to increase parasite transmission. In this case, their interests
      coincide with that of their virulent parasites in enhancing transmission to
      conspecifics. This finding yields the predictions that hosts infected by virulent
      pathogens, but unable to recover from disease, should be prone to emigrate from
      their natal territories and also to enhance transmission at a distance from their
      natal ranges. These results may considerably improve our understanding of the
      epidemiology of contagious pathogens and the evolution of social and sexual
      behavior in host species.

PMID- 10647034
TI  - Nerocila benrosei n. sp. (Isopoda: Cymothoidae), an external parasite of
      hogfishes from the northern Bahamas.
AB  - Nerocila benrosei n. sp. is described from the hogfish, Lachnolaimus maximus
      (Walbaum), and the Spanish hogfish, Bodianus rufus (Linnaeus), (Perciformes:
      Labridae) from the northern Bahamas. Nerocila benrosei differs from all species
      of Nerocila by having the body of females 1.4-1.9 times as wide as long, instead
      of 2.0-3.0 times, and pleopods 1 and 2 lacking accessory lamellae. It differs
      from the only species of Nerocila with which it overlaps geographically, N.
      lanceolata (Say, 1818), by having the lateral margins of pleonites 1-5 strongly
      produced ventrally, coxae 5-7 manifestly shorter than the posterolateral
      projection of the respective pereonite, and a vaulted dorsal surface. The species
      of Nerocila in the northwestern Atlantic have almost mutually exclusive
      geographic ranges: New England to Panama, including Bermuda and the northern
      coast of Cuba (Nerocila lanceolata); Brazil to Trinidad and Tobago (Nerocila
      fluviatilis Schiodte and Meinert, 1881); and the northern Bahamas and Bermuda
      (Nerocila benrosei). No species of Nerocila have been reported from the insular
      Caribbean. Nerocila benrosei appears to be highly host and site specific.

PMID- 10647035
TI  - Localization of Toxoplasma gondii in feline intestinal tissue using PCR.
AB  - Gametogony of Toxoplasma gondii occurs only in the epithelial cell layers within
      the intestine of the definitive feline host. Infected feline intestine is
      required in order to study the physiology, histology, and molecular biology of
      the gametogenic stages. Therefore, we set out to devise a rapid, conservative,
      and reproducible technique to determine which portions of the intestine were
      infected. Several methods of collecting and processing infected material were
      assessed for their ability to detect T. gondii. Infected and uninfected
      intestines from domestic cats were used to produce nitrocellulose lift
      impressions along the entire small intestine. The nitrocellulose was analyzed for
      the presence of T. gondii DNA using polymerase chain reaction (PCR) primers
      specific for the T. gondii alpha-tubulin gene. In addition, mucosal tissue
      scrapings, derived from segments of intestinal tissue, were used to isolate DNA
      and RNA for subsequent PCR and reverse transcriptase PCR analysis, respectively.
      The nitrocellulose impression lift method demonstrated distribution of parasite
      throughout the intestine. Histological staining and indirect immunofluorescence
      antibody analysis of sections obtained from the same infected tissue confirmed
      the presence of T. gondii intraepithelial stages. Comparison among the different
      techniques indicates that the nitrocellulose impression lift technique proved to
      be effective for easily and quickly assessing presence of T. gondii in infected
      tissue. This technique does not require a significant amount of the experimental
      material.

PMID- 10647036
TI  - Structure of the tegument and ectocommensal microorganisms of Gyliauchen
      nahaensis (Digenea: Gyliauchenidae), an inhabitant of herbivorous fish of the
      Great Barrier Reef, Australia.
AB  - The ultrastructure of the tegument and tegument-associated microorganisms of the
      gyliauchenid digenean Gyliauchen nahaensis is described by transmission and
      scanning electron microscopy. The tegument is devoid of surface spines and is
      characterized by a moderately folded apical membrane, abundant vesicles, basal
      mitochondria, a folded basal plasma membrane, and a thick basal matrix.
      Microorganisms form a dense biofilm on the tegument of the posterodorsal surface
      and the excretory papilla. At least 7 microbial morphotypes were identified,
      including eubacteria, spirochaetes, and nanobacteria.

PMID- 10647037
TI  - Morphological, molecular and biological characterization of Mehdinema alii
      (Nematoda: Diplogasterida) from the decorated cricket (Gryllodes sigillatus).
AB  - The nematode Mehdinema alii was recovered from the decorated cricket Gryllodes
      sigillatus (Walker). Morphometric comparisons are presented from 3 populations.
      The nematode is characterized by dense arrays of spines on the cuticle of the
      anterior half of the body and a highly elongate, tubular stoma with a dorsal
      denticle in the glottoid region. Females have a protruding vulva. Young females
      are amphidelphic, but the anterior ovary disappears in older females bearing
      multiple developing juveniles. The male is monorchic with asymmetrically placed
      genital papillae, distally fused spicules, and a highly complex gubernaculum
      bearing 2 cuticularized thorns that protrude through a separate, postcloacal
      opening. Adult nematodes are located primarily in the hindgut, whereas juveniles
      or dauers occur mainly in the genital chamber of both male and female crickets.
      Male crickets are significantly more likely to be infected than females. This
      male-biased infection may be linked to the venereal transmission mechanism of the
      dauers. Although morphologically unusual in many respects, placement of M. alii
      in Diplogasterida is supported by both the morphology of the anterior digestive
      tract as well as analysis of its 18S rDNA sequence. These sequence data suggest
      that M. alii groups most closely with members of the Cylindrocorporidae.

PMID- 10647038
TI  - Factors affecting adoptive transfer of resistance to Schistosoma mansoni in the
      snail intermediate host, Biomphalaria glabrata.
AB  - We examined potential variables affecting adoptive transfer of resistance to
      Schistosoma mansoni in Biomphalaria glabrata implanted with amebocyte-producing
      organs (APOs) from resistant snails. Transplants of 7 tissues other than the APO
      (heart, kidney, mantle, albumin gland, brain, digestive gland, and gonad) did not
      transfer resistance, suggesting a unique property of this structure. Only APOs
      from donors previously exposed to miracidia transferred resistance, although
      whether this is evidence for a priming effect or merely the elimination of
      susceptible donors is not known. Variability in the donor and in the implant
      itself apparently was unimportant, inasmuch as implants from small or large
      snails or from 2 separate donors all conferred similar levels of resistance.
      Recipients of APOs from 2 additional resistant strains of B. glabrata, 10-R2 and
      Salvador, also displayed resistance. However, no resistance was transferred by
      APOs from schistosome-refractory B. obstructa. Histological examination of
      implants removed from recipients that either did or did not show transferred
      resistance revealed no differences in mitotic activity. Furthermore, implanted
      APOs from B. obstructa displayed no mitotic activity. Finally, reexposure of
      snails with transferred resistance to a large dose of miracidia caused infection
      in 70%, suggesting that either transferred resistance is transitory or it can be
      overwhelmed.

PMID- 10647039
TI  - Prevention of vertical transfer of Neospora caninum in BALB/c mice by
      vaccination.
AB  - Neosporosis is an important cause of abortion and neonatal morbidity in dairy
      cattle. The disease is caused by Neospora caninum, an intracellular protozoan
      parasite. In this report, we describe the use of a mouse model in the preliminary
      evaluation of vaccination as a means to prevent vertical transfer of N. caninum.
      Parasites present in the tissues of the offspring were detected using an N.
      caninum-specific polymerase chain reaction assay. Immunization of dams with a
      single inoculation of a crude lysate of N. caninum tachyzoites appeared to induce
      complete protection against infection of the offspring.

PMID- 10647040
TI  - Humoral immune responses among mucosal and cutaneous leishmaniasis patients
      caused by Leishmania braziliensis.
AB  - Mucosal leishmaniasis is arguably the most morbid sequelae of cutaneous
      leishmaniasis. The importance of early diagnosis for effective therapy, coupled
      with the difficulty of diagnosing the disease parasitologically, prompted this
      investigation of humoral immune markers of mucosal disease. Promastigote soluble
      antigens of Leishmania braziliensis, isolated from cutaneous and mucosal lesions,
      were separated by sodium dodecyl sulfate polyacrylamide gel electrophoresis;
      antigens were identified by immunoblotting with parasite-specific IgG antibody
      positive sera of patients with mucosal disease (n = 18) and cutaneous disease (n
      = 23). For antigens of the cutaneous parasite WR 2095, mucosal sera generally
      reacted intensely to antigens of 75, 66, and 45 kDa and weakly to 48-50-kDa
      antigens, whereas cutaneous sera generally detected weakly the first 3 antigens
      and intensely the latter doublet. The data suggest that the transition from the
      cutaneous antigenic profile to a mucosal antigenic profile could be used to
      predict mucosal disease in approximately half of mucosal patients. An additional
      finding was that antibodies present in the sera of patients with mucosal disease
      labeled a 66-kDa peptide of normal human lip mucosa more intensely than did
      cutaneous sera. Autoimmune processes stimulated by the reaction of IgG,
      originally directed against the 66-kDa of L. braziliensis, to the 66-kDa antigen
      of mucosal tissue may contribute to the clinical presentation of mucosal
      leishmaniasis.

PMID- 10647041
TI  - Cryptosporidium sp. and Giardia sp. infections in mountain gorillas (Gorilla
      gorilla beringei) of the Bwindi Impenetrable National Park, Uganda.
AB  - For conservation purposes and because of growing ecotourism, some mountain
      gorilla (Gorilla gorilla beringei) populations have been habituated to humans.
      Fecal specimens (n = 100) of nonhabituated and human-habituated gorillas (5
      populations; 6 age classes) were tested for Cryptosporidium sp. oocysts and
      Giardia sp. cysts by conventional staining and immunofluorescent antibody (IFA).
      Cryptosporidium sp. infections (prevalence 11%) were not restricted to very young
      gorillas but were observed in 3-yr-old to >12-yr-old gorillas; most of the
      infections (73%) occurred in human-habituated gorillas. The prevalence of Giardia
      sp. infections was 2%; 1 nonhabituated gorilla was concomitantly infected.
      Oocysts of Cryptosporidium sp. in the gorilla stools were morphologically,
      morphometrically, and immunologically undistinguishable from a bovine isolate of
      Cryptosporidium parvum oocysts. Mean concentration of Cryptosporidium sp. oocysts
      and Giardia sp. cysts in gorilla stools was 9.39x10(4)/g, and 2.49x10(4)/g,
      respectively. There was no apparent relationship between oocyst concentration and
      gorilla age, sex, or habituation status. Most Cryptosporidium sp. infections
      found in gorillas with closest proximity to people may be a result of the
      habituation process and ecotourism. This study constitutes the first report of
      Cryptosporidium sp. infections in the family Pongidae, in the free-ranging great
      apes, and in the species of gorilla.

PMID- 10647042
TI  - Antibody response to heat shock proteins and histopathology in mice infected with
      Trypanosoma cruzi and maintained at elevated temperature.
AB  - Highly susceptible C3HeB/FeJ mice survive an otherwise lethal infection with a
      Brazil strain of Trypanosoma cruzi when held at an elevated environmental
      temperature of 36 C. The body temperature of these mice has been shown to
      increase 3-4 C to levels typical of a febrile response. In the present study, the
      synthesis of parasite heat shock proteins (hsp60, hsp70, and hsp90) was shown to
      be enhanced at a temperature of 39 C and the results of immunoprecipitation
      analysis indicated that parasite HSPs are highly immunogenic in T. cruzi-infected
      mice maintained at 36 C or room temperature (RT). Differences in the
      histopathology of cardiac and skeletal muscle in C3HeB/FeJ mice maintained at RT
      or 36 C at different times postinfection also were investigated in this study.
      The lower numbers of circulating parasites observed in mice maintained at 36 C
      were correlated with lower levels of tissue parasitism, inflammation, and tissue
      destruction. Finally, the transfer of infected mice from RT to an environment of
      36 C at various times during infection was shown to increase the survival rate of
      infected mice and also resulted in a dramatic reduction in parasitemia levels. In
      light of the growing evidence for a beneficial effect of elevated temperature
      during experimental Chagas' disease, further studies seem warranted to determine
      if hyperthermia or fever therapy might also be beneficial in the treatment of
      humans infected with T. cruzi.

PMID- 10647043
TI  - Cryptosporidium parvum-induced inflammatory bowel disease of TCR-beta- x TCR
      delta-deficient mice.
AB  - Experimental inoculation of neonatal immunocompetent strains of mice with
      Cryptosporidium parvum results in a transient, noninflammatory enteric infection.
      In the present study, we show that inoculation of mice deficient in alphabeta and
      gammadelta T cells (TCR-beta- x TCR-delta-deficient mice) with C. parvum results
      in persistent infection and severe inflammatory bowel disease-like lesions. The
      most severe lesions in these mice were in the cecum with similar yet less severe
      lesions in the ileum and proximal colon. The most notable aspect of the
      histopathology was glandular hyperplasia with abscess formation, extensive
      fibrosis of the lamina propria with infiltrates of predominately
      polymorphonuclear cells and macrophages, and a few small aggregates of B cells.
      Persistently infected mice also developed extensive hepatic periportal fibrosis
      in association with C. parvum colonization of bile ducts. Lesions observed in TCR
      beta- x TCR-delta-deficient mice were markedly different than previously
      described lesions detected in C. parvum-infected TCR-alpha-deficient mice.
      Cryptosporidium parvum-infected TCR-alpha-deficient mice have extensive
      infiltrations of B cells, whereas TCR-beta- x TCR-delta-deficient mice had only a
      few small aggregates of B cells. These findings indicate that although gammadelta
      T cells are not necessary for induction of intestinal inflammation in C. parvum
      infected alphabeta T-cell-deficient mice, their presence does alter the
      morphology of the ensuing lesion.

PMID- 10647044
TI  - Acanthamoeba strains isolated from organs of freshwater fishes.
AB  - Contrary to data on Acanthamoeba infections in humans, little is known about
      infections in fishes. The present study combines the description of strains
      isolated from fishes with presentation of an improved method for subgeneric
      classification. Acanthamoeba spp. were isolated aseptically from tissues of 14
      (1.7%) of 833 asymptomatic fishes collected in rivers and streams in the Czech
      Republic. Acanthamoebae successfully cloned from 10 of the 14 isolated strains
      were examined here. Morphology of these isolates was evaluated using light optics
      plus scanning and transmission electron microscopy. Cyst morphology, which varied
      extensively within and among clones, was most like morphological group II, but
      species-level classification was considered impossible. A distance analysis based
      on 442 bases in an 18S rDNA polymerase chain reaction fragment of about 460 bp
      placed the isolates in a clade composed of sequence types T3, T4, and T11, the 3
      subdivisions of morphological group II. Fluorescent in situ hybridization (FISH)
      using oligonucleotide probes indicated that all isolates belong to a single
      subdivision of group II, the T4 sequence type. It has been concluded that the
      fish isolates are most closely related to strains commonly isolated from human
      infections, especially Acanthamoeba keratitis. The shorter diagnostic fragment
      sequences have proved nearly as useful as complete 18S rDNA sequences for
      identification of Acanthamoeba isolates.

PMID- 10647045
TI  - A new Microsporidium sp. (microsporidia) from the musculature of the mountain
      whitefish Prosopium williamsoni from British Columbia: morphology and phylogeny.
AB  - Few microsporidia have been reported from whitefish species (subfamily
      Coregoninae). For the most part, these microsporidia have been incompletely
      described. In a survey of parasites of mountain whitefish Prosopium williamsoni
      collected from Kootenay Lake, British Columbia, we encountered an unusual
      microsporidium infecting the endomysium of the skeletal musculature. Spores were
      uninucleate, ovoid to pyriform, and were 5.6 (5-7) microm x 3.2 (3-4) microm with
      13-16 coils in the polar filament. We describe here this organism as a new
      species based on its site of development and its relationship among fish
      microsporidia based on small subunit ribosomal DNA sequence data, i.e., our
      analysis showed that it is not closely related to other microsporidia for which
      ribosomal DNA sequence is available thus far.

PMID- 10647046
TI  - Descriptions of two new species of coccidia (Protozoa: Eimeriidae) and
      redescriptions of Eimeria ivensae and Eimeria odocoilei from captive white-tailed
      deer, Odocoileus virginianus.
AB  - Two new species of Eimeria were observed in the feces of captive white-tailed
      deer fawns, Odocoileus virginianus, from Alabama. The first new species was
      easily recognized because of its small size. Sporulated oocysts are spherical,
      average 10.2 by 10.0 microm, and lack a micropyle and oocyst residuum. Oocysts
      contain a polar granule and elongate-ellipsoidal sporocysts that measure 6.7 by
      3.1 microm. A Stieda body is present on the sporocysts. Oocysts were observed in
      the feces, and gamonts and oocysts were observed in the jejunum of a month-old
      fawn from Minnesota that died from enteritis due to this species. Oocysts of this
      small species were present in 5 of the 6 white-tailed deer fawns examined.
      Oocysts of a second new species are ellipsoidal and average 29.5 by 24.6 microm.
      The oocyst encloses an oocyst residuum, polar granule, and elongate-ellipsoidal
      sporocysts that average 16.0 by 9.0 microm. A Stieda body and substieda body are
      present on the sporocysts. Oocysts of the second new species were present in 4 of
      the 6 white-tailed deer fawns examined. Oocysts of E. ivensae are ovoid or flask
      like and average 32.0 by 20.8 microm. The oocyst wall is rough, contains a
      micropyle, and encloses elongate-ellipsoidal sporocysts that average 16.5 by 7.8
      microm. A Stieda body is present on the sporocysts. Oocysts of E. ivensae were
      present in 4 of the 6 white-tailed deer fawns. Oocysts of E. odocoilei are
      spherical or slightly subspherical and measure 24.7 by 21.5 microm. They enclose
      ovoid sporocysts that average 12.7 by 8.8 microm. A Stieda and substieda body are
      present on the sporocyst. Oocysts of E. odocoilei were present in 4 of the 6
      white-tailed deer fawns.

PMID- 10647047
TI  - Phylogenetic relationships among isolates of Cryptosporidium: evidence for
      several new species.
AB  - Isolates of Cryptosporidium were characterized using nucleotide sequence analysis
      of the 18S rRNA and dihydrofolate reductase genes and also random-amplified
      polymorphic DNA analysis. Phylogenetic analysis confirmed the validity of the
      species of Cryptosporidium examined in this study such as Cryptospordium muris
      and Cryptosporidium baileyi, and also reinforced evidence from numerous
      researchers worldwide suggesting that Cryptosporidium parvum is not a single
      uniform species. The data obtained provided strong support for the validity of
      Cryptosporidium felis. Evidence suggests that the newly identified marsupial and
      pig genotypes may also be distinct and valid species, but biological studies are
      required for confirmation.

PMID- 10647049
TI  - Cicesetrema unami n. gen., n. sp. (Digenea: Cryptogonimidae: Cryptogoniminae)
      from Paralichthys californicus (Ayres, 1859) (Osteichthyes: Pleuronectiformes:
      Paralichthydae) in San Quintin Bay, Baja California, Mexico.
AB  - Cicesetrema unami n. gen., n. sp. (Digenea: Cryptogonimidae) is described from
      the intestine of the California halibut, Paralichthys californicus, from San
      Quintin Bay, Baja California, Mexico. The new genus is distinguished from other
      members of the Cryptogoniminae in having vitellaria that form asymmetric bunches
      of follicles and extend in lateral fields from the level of the ovary posteriad
      beyond the testes. In addition, the species in the new genus possess a
      subterminal, funnel-shaped oral sucker that is prominent when protruded but
      usually retracted in a fold at the anterior end.

PMID- 10647048
TI  - Evolution of the major lineages of tapeworms (Platyhelminthes: Cestoidea)
      inferred from 18S ribosomal DNA and elongation factor-1alpha.
AB  - The interrelationships of the tapeworms (Platyhelminthes: Cestoidea) were
      inferred by analysis of complete gene sequences (approximately 2,200 bp) of 18S
      small subunit ribosomal DNA (18S) and partial gene sequences (approximately 900
      bp) of elongation factor-1alpha (Ef-1alpha). New collections were made of 23
      species representing each of the 14 currently recognized orders of tapeworms,
      including the Amphilinidea, Gyrocotylidea, and the 12 orders of the Eucestoda.
      Sequences were determined directly from polymerase chain reaction (PCR) products
      by either manual or automated methods. Nucleotide sequences of platyhelminth
      species outside of the Cestoidea were obtained for rooting the resulting trees.
      The 18S sequences were aligned with reference to the secondary structural
      features of the gene and the Ef-1alpha sequences were aligned with reference to
      their corresponding amino acid residues. Significant length variation among taxa
      was observed in the V2, V4, and V7 variable regions of the 18S gene. Such
      positions where sequences could not be aligned confidently were excluded from the
      analyses. Third codon positions of the Ef-1alpha gene were inferred to be
      saturated at an ordinal level of comparison. In addition, a short (approximately
      35 bp) intron region of the Ef-1alpha gene was found to be shared only among the
      eucestode taxa, with the exception of Spathebothrium simplex (Spathebothriidea),
      which lacked the intron. Complete alignments showing structural features of the
      genes and sites excluded from analysis are provided as appendices. The sequence
      data were partitioned into 7 data sets in order to examine the effects of
      analyses on different subsets of the data. Analyses were conducted on the 2 genes
      independently, different codon positions of Ef-1alpha, amino acid sequences of Ef
      1alpha, and combinations thereof. All subsets of the data were analyzed under the
      criterion of maximum parsimony as well as minimum evolution using both maximum
      likelihood estimated, and LogDet-transformed distances. Results varied among the
      different data partitions and methods of analysis. Nodes with strong character
      support, however, were consistently recovered, and a general pattern of evolution
      was observed. Monophyly of the Cestoidea (Amphilinidea + Gyrocotylidea +
      Eucestoda) and Eucestoda and the traditionally accepted positions of the
      Amphilinidea and Gyrocotylidea as sister lineages to the Eucestoda were
      supported. Within the Eucestoda, the Spathebothriidea was found to be the sister
      of all other eucestodes. The remaining orders generally formed a diphyletic
      pattern of evolution consisting of separate difossate and tetrafossate lineages.
      This pattern was not universally observed among the analyses, primarily because
      the trypanorhynch and diphyllidean taxa showed instability in their phylogenetic
      position. Additional relationships that showed high levels of nodal support
      included a sister relationship between the Pseudophyllidea and Haplobothriidea
      and a clade uniting the Cyclophyllidea, Nippotaeniidea, and Tetrabothriidea. The
      Tetraphyllidea, as currently defined, was found to be paraphyletic without the
      inclusion of the orders Proteocephalidea and, possibly, Lecanicephalidea. Ordinal
      status of a monophyletic Litobothriidea, currently classified within the
      Tetraphyllidea, was found to be supported from a phylogenetic perspective.

PMID- 10647050
TI  - A comparison of enumeration techniques for Cryptosporidium parvum oocysts.
AB  - A variety of methods have been used to enumerate Cryptosporidium parvum oocysts
      from source or drinking waters. The reliability of these counting methods varies,
      in part, with suspension density, sample purity, and other factors. Frequently,
      the method of determination of suspension density is not reported by authors. To
      confound the problem, each method of counting has large inherent variation. There
      is a relationship between suspension density, overall number of organisms
      counted, and counting mechanism accuracy that should be accounted for when
      selecting a counting mechanism. This study selected a maximum acceptable
      coefficient of variation (CV) to be 10%. A method was considered unreliable if
      this standard was not achieved. Flow cytometry achieved this standard at 486
      oocysts/ml. Counting with a Coulter counter achieved this level of reliability at
      about 1,230 oocysts/ml. Neither chamber slides nor fluorescent antibody-stained
      well slides ever demonstrated less than 10% CV. However, estimates of the minimum
      required concentrations were 5,100 oocysts/ml and approximately 6,500 oocysts/ml,
      respectively. The hemacytometer provided counts accurate to a 10% CV at a
      concentration of at least 60,000 organisms/ml. Of the methods tested, flow
      cytometry provided the least amount of variability at low suspension densities.

PMID- 10647051
TI  - Capillaria hepatica (Nematoda) infections in human-habituated mountain gorillas
      (Gorilla gorilla beringei) of the Parc National de Volcans, Rwanda.
AB  - Habituation to humans of free-ranging populations of endangered mountain gorillas
      (Gorilla gorilla beringei) raised concern of anthropozoonotic transmission of
      parasitic helminths and protozoans. Examinations of liver tissue of 19 gorillas
      found dead in the Parc National de Volcans, Rwanda, revealed 10 cases of hepatic
      nematodiasis due to Capillaria hepatica. Identifiable C. hepatica eggs were
      present in the liver of 4 gorillas (3 juveniles, 1 adult), and nematode cross
      sections were found in 1 juvenile gorilla. Six other adult gorillas had areas of
      periportal and subcapsular fibrosis with calcified eggs. Histologically, the
      lesions surrounded by the areas of mild inflammatory reaction were characterized
      by subcapsular, periportal foci of fibrosis in which were embedded numerous C.
      hepatica eggs. Control of hepatic capillariasis in the remaining populations of
      mountain gorillas should be focused on eradication or control of populations of
      rodent pests (i.e., mice and rats) that sustain the reservoir of C. hepatica in
      habitats shared by gorillas and humans.

PMID- 10647052
TI  - Isolation of Angiostrongylus costaricensis first-stage larvae from rodent feces
      on a Percoll gradient.
AB  - Several density gradients were tested for the isolation of parasitic nematode,
      Angiostrongylus costaricensis, first-stage larvae from rodent feces. With a
      45/72% Percoll gradient, 83-99% (89.56+/-6.57%) of the larvae were recovered in a
      clean preparation.

PMID- 10647053
TI  - A retrospective histopathological survey of capillariasis in raccoons (Procyon
      lotor) from Oregon.
AB  - A 2-yr retrospective survey (1995-1998) of 63 adult raccoons (Procyon lotor) from
      Oregon, northwestern United States, was conducted by histopathological
      examination of various tissues. An overall prevalence of capillariasis was
      recorded in 52% of the raccoons. Highest prevalence of nematodes (29/30, 97.7%)
      was present in the anal sacs, where variable numbers of nematodes, their ova, and
      extensive diffuse inflammatory cellular infiltrate were evident. Lesser numbers
      of nematodes were also seen in the mucosa of the anterior alimentary tract (mouth
      2/63, tongue 10/62, esophagus 2/63) and in the urinary bladder (7/63). However,
      at these sites, there was a paucity of inflammatory infiltrate. The findings of
      this study indicate that capillariasis of the anal sacs is commonly seen in free
      ranging raccoons in Oregon, and the infection is essentially subclinical because
      only 1 case of anal sac impaction has been reported. Measurements of the nematode
      and their ova from the anal sacs indicate that it is most likely a new
      capillariid species, which to date has not been fully described in raccoons. It
      is speculated that the high prevalence of anal sac infection by a Capillaria sp.
      in Oregon raccoons may also be true for raccoons in other parts of North America
      and in parts of Europe and Asia where this species has been introduced.

PMID- 10647054
TI  - Fatal cysticercosis by Taenia crassiceps (Cyclophyllidea: Taeniidae) in a
      presumed immunocompromised canine host.
AB  - Cysticercosis in a canine host (Canis familiaris) attributable to the taeniid
      cestode Taenia crassiceps is reported for the first time in North America.
      Numerous parent and daughter cysticerci occurred in a massive intrapleural and
      intraperitoneal infection in an apparently immunocompromised host. The largest
      cysticerci were ovoid to elongate, 5-9 mm in maximum length, and armed with 32-34
      rostellar hooks in 2 rows; small hooks measured 114-143 microm long (x = 124+/
      8.2 microm), and large hooks were 156-180 microm (x = 163+/-7.4 microm). Taenia
      crassiceps is widespread in boreal North America and, like a number of other
      taeniids, constitutes a potential risk as a zoonotic parasite. The immunological
      status of the host may be important in determining the outcome of infections for
      this and other taeniids in atypical hosts.

PMID- 10647055
TI  - Mating rendezvous in monogenean gill parasites of the humbug Dascyllus aruanus
      (Pisces: Pomacentridae).
AB  - The gills of the humbug, Dascyllus aruanus (Pomacentridae), were infected by a
      monogenean genus Haliotrema at a high prevalence (83%) but with a low mean
      intensity (5.6 worms/fish). All the gill arches of 365 fish, caught on the
      fringing reef of Moorea Island (French Polynesia), were examined for parasites.
      Each hemibranch was divided into 12 subequal sections. Monogeneans showing
      microhabitat overlap were defined as couples. Hosts with low intensity of
      infection (fewer than 5 monogeneans per gill) were selected and couples were
      recorded. Among the 37 hosts harboring 2 worms on their gills, 18 fish were
      infected with these 2 monogeneans on the same gill side of the body; 50% (n = 9)
      of these harbored monogeneans within the same gill arch and 55% (n = 5) of these
      last fish showed individual parasites within the same section of the gill. In the
      case of hosts with few monogeneans (3 and 4 individuals; n = 37) on the same
      arch, more than 40% (n = 16) harbored worms in couples. There may be some
      chemical communication that allowed these monogeneans to migrate toward each
      other and thus enhance mating success. Mating rendezvous appears to be a more
      important factor than site location for these gill monogeneans.

PMID- 10647056
TI  - Insulin sensitivity predicts glycemia after a protein load.
AB  - Protein ingestion results in small but distinct changes in plasma glucose and
      insulin. We hypothesized that the glycemic and/or insulin response to protein
      might be related to the degree of insulin sensitivity. Our aim was to determine
      the relationships between insulin sensitivity (assessed by euglycemic
      hyperinsulinemic clamp) and postprandial glucose, insulin, C-peptide, and
      glucagon responses to a 75-g protein meal and a 75-g glucose load. Sixteen lean
      healthy Caucasian subjects (mean +/- SD age, 25 +/- 6 years; body mass index
      [BMI], 23.1 +/- 1.7 kg/m2) participated in the study. After the protein meal, the
      mean plasma glucose declined gradually below fasting levels to a nadir of -0.36
      +/- 0.46 mmol/L from 60 to 120 minutes, showing wide intraindividual variation.
      Insulin sensitivity (M value) was 1.1 to 3.9 mmol/L/m2 min in the subjects and
      correlated inversely with the plasma glucose response to the protein meal (r = 
      .58, P = .03), ie, the most insulin-sensitive subjects showed the greatest
      decline in plasma glucose. In contrast, there was no correlation between insulin
      sensitivity and the insulin or glucagon response to the protein load, or between
      the M value and the metabolic responses (glucose, insulin, C-peptide, and
      glucagon) to the glucose load. Our study suggests that the net effect of insulin
      and glucagon secretion on postprandial glucose levels after a protein meal might
      depend on the individual's degree of insulin sensitivity. Gluconeogenesis in the
      liver may be less susceptible to inhibition by insulin in the more highly
      resistant subjects, thereby counteracting a decline in plasma glucose.

PMID- 10647057
TI  - Postabsorptive resting metabolic rate and thermic effect of food in relation to
      body composition and adipose tissue distribution.
AB  - One hundred thirty subjects were studied to investigate relationships between the
      body composition and fat distribution as evaluated by computed tomography and the
      resting metabolic rate (RMR) as evaluated by indirect calorimetry: 82
      premenopausal women (age, 18 to 52 years; body mass index [BMI], 27 to 52 kg/m2),
      27 postmenopausal women (46 to 71 years; 28 to 49 kg/m2), and 21 men (18 to 70
      years; 31 to 43 kg/m2). The thermic effect of food (TEF) was evaluated in all men
      and in 2 subgroups of 55 and 19 women. The best-fitting equations for predicting
      RMR, obtained by multiple regression, included the following as covariates: fat
      free mass and both subcutaneous and visceral adipose tissue in premenopausal
      women (R2 = .55, P = .0001), fat-free mass and visceral adipose tissue in
      postmenopausal women (R2 = .58, P = .001), and age, with minus sign, and visceral
      adipose tissue in men (R2 = .44, P = .0051). Fasting insulin and fat-free mass,
      with minus sign, and both visceral and subcutaneous adipose tissue were the
      predictors of the TEF (R2 = .25, P = .0055) in premenopausal women. This study
      demonstrates that visceral fat distribution is important in determining the RMR
      in postmenopausal women and men. In premenopausal women, total adipose tissue is
      a main determinant of both the RMR and TEF This last effect could be
      counterbalanced by insulin resistance.

PMID- 10647058
TI  - Important role of the hepatic vagus nerve in glucose uptake and production by the
      liver.
AB  - We examined the role of the hepatic vagus nerve in hepatic and peripheral glucose
      metabolism. To assess endogenous glucose production (EGP), hepatic uptake of
      first-pass glucose infused intraportally (HGU), and the metabolic clearance rate
      of glucose (MCR), rats were subjected to hepatic vagotomy (HV, n = 7) or sham
      operation (SH, n = 8), after 10 days, they were then subjected to a euglycemic
      hyperinsulinemic clamp together with a portal glucose load in the 24-hour fasting
      state. Metabolic parameters were determined by the dual-tracer method using
      stable isotopes. During the experiment, [6,6-2H2]glucose was continuously infused
      into the peripheral vein. To maintain euglycemia (4.5 mmol/L), insulin (54 pmol x
      kg(-1) x min(-1)) and glucose were infused peripherally after the 90-minute
      tracer equilibration and 30-minute basal periods, and glucose containing 5%
      enriched [U-13C]glucose was infused intraportally (50 micromol x kg(-1) x min(
      1)) for 120 minutes (clamp period). EGP was significantly higher in HV rats
      versus SH rats during the basal period (64.3 +/- 7.6 v 43.6 +/- 5.3 micromol x
      kg(-1) x min(-1), P < .005)) and was comparable to EGP in SH rats during the
      clamp period (9.3 +/- 21.5 v 1.1 +/- 11.7 micromol x kg(-1) x min(-1)). HGU was
      reduced in HV rats compared with SH rats during portal glucose infusion (5.9 +/-
      2.4 v 10.1 +/- 3.2 micromol x kg(-1) x min(-1)). The MCR in HV rats was
      significantly higher than in SH rats in the basal period (11.0 +/- 2.0 v 7.9 +/-
      0.8 mL x kg(-1) x min(-1), P < .01)) and was comparable to the MCR in SH rats
      during the clamp period (41.9 +/- 10.0 and 36.6 +/- 5.7 mL x kg(-1) x min(-1)).
      We conclude that innervation of the hepatic vagus nerve is important for the
      regulation of hepatic glucose production in the postabsorptive state and HGU in
      the postprandial state.

PMID- 10647059
TI  - Effects of hydrochlorothiazide and furosemide diuretics on human bone marrow
      stromal osteoprogenitor cells.
AB  - Thiazide diuretics have been shown to decrease bone loss and improve bone mineral
      density, while long-term furosemide therapy has been suggested to decrease bone
      mineral content. However, the direct effects of these diuretics on osteoblastic
      cells are not well established. Some investigators have reported direct effects
      of thiazides on osteoblastic cells but the results remain controversial, and
      there are few data about the direct effect of furosemide on osteoblastic cells.
      We investigated the effects of hydrochlorothiazide (HCTZ) and furosemide on
      proliferation, alkaline phosphatase activity, osteocalcin, and interleukin
      6/interleukin-11 (IL-6/IL-11) secretion in cultured normal human bone marrow
      stromal osteoprogenitor cells (hBMSCs). Treatment with HCTZ or furosemide for 24
      hours in the concentration range of 10(-6) to 10(-4) mol/L did not affect 3H
      thymidine incorporation in hBMSCs. Cellular alkaline phosphatase activity and
      osteocalcin production were not changed significantly by treatment with HCTZ or
      furosemide (up to 10(-4) mol/L) during culture. There was also no significant
      difference in IL-6 and IL-11 production in hBMSCs. These results suggested that
      HCTZ or furosemide had no significant direct effect on proliferation, alkaline
      phosphatase activity, osteocalcin, and IL-6/IL-11 production in hBMSCs, and the
      effects of these diuretics on bone mass may be related to the indirect action on
      calcium balance.

PMID- 10647060
TI  - The db/db mouse, a model for diabetic dyslipidemia: molecular characterization
      and effects of Western diet feeding.
AB  - Diabetic dyslipidemia is a major factor contributing to the accelerated
      atherosclerosis in type 2 diabetes mellitus. Although several mouse models are
      available, the plasma lipoproteins in response to diet have not been fully
      characterized in these animals. In this study, we have characterized the plasma
      lipoproteins and related apolipoproteins, as well as the vascular lipases, in
      diabetes (db/db) mice and their nondiabetic controls (+/?) in the C57BL/KsJ
      strain. Within 6 weeks of age, db/db mice developed significant obesity, fasting
      hyperglycemia, and hyperinsulinemia. By FPLC analysis, db/db mice showed a
      prominent peak in the low-density lipoprotein (LDL) range that was absent in +/?
      mice, although high-density lipoprotein (HDL) was the predominant species in both
      groups of animals. Postheparin lipoprotein lipase (LPL) activity in db/db mice
      was 28% of the level in +/? mice. Upon feeding a human-like 0.15% (wt/wt)
      cholesterol and 21% (wt/wt) fat "Western" diet, db/db mice developed elevated
      plasma cholesterol, accompanied by an exaggerated apolipoprotein E (apoE)
      response compared with +/? mice. FPLC analysis showed that the marked
      hypercholesterolemic response in db/db mice was the result of a massive increase
      in the LDL region, which overshadowed a moderate increase in HDL. We next
      isolated lipoproteins by ultracentrifugation and characterized them by
      nondenaturing gradient gel electrophoresis. With regular chow, db/db mice had
      almost exclusively small dense LDL with a peak size at 21.4 nm, as compared with
      26.6 nm in nondiabetic controls. On the Western diet, the small dense LDLs
      persisted but larger particles also appeared in db/db mice, whereas the size
      distribution in +/? mice was unchanged by the diet. Our results suggest that
      db/db mice fed a Western diet have a plasma lipoprotein phenotype that shows some
      similarities to that in patients with type 2 diabetes mellitus, and that db/db
      mice are a useful model to study the pathogenesis and treatment of diabetic
      dyslipidemia.

PMID- 10647061
TI  - No seasonal variation of insulin sensitivity and glucose effectiveness in men.
AB  - Insulin resistance is of pathogenetic importance for the development of non
      insulin-dependent diabetes mellitus (NIDDM). However, not much is known about the
      variation in insulin sensitivity in the individual over longer periods.
      Consequently, we measured insulin sensitivity (Si) and glucose effectiveness (Sg)
      in healthy young men (N = 10) 5 times over a period of 15 months using a
      frequently sampled intravenous glucose tolerance test (FSIVGTT) with minimal
      model analysis (study of seasonality). The maximal aerobic capacity (V(O2)max),
      fat-free mass, body mass index (BMI), and 24-hour ambulatory blood pressure (BP)
      were also assessed. Furthermore, we performed a study designed to evaluate the
      day-to-day variation in Si and Sg (study of day-to-day variation). Here, we
      studied Si and Sg in healthy young men (n = 8) within 2 weeks. In the study of
      seasonality, the coefficient of variation (CV) for Si was 24.0%, whereas the CV
      for Sg was 26.0%. Anticipating a seasonal variation in Si following a sine curve
      with a cycle length of 1 year and an unknown phase and amplitude, we tested this
      hypothesis with a multiple linear regression model that allows for different
      levels of Si between individuals, and failed to detect any impact due to this. Si
      (mean +/- SD, 1.17 +/- 0.28 x 10(-4) x min(-1) x pmol/L(-1), P = .38), Sg (0.023
      +/- 0.006 min(-1), P= .71), fasting insulin (21.2 +/- 7.3 pmol/L, P= .98),
      V(O2)max (3.8 +/- 0.6 L/min, P= .13), and fat-free mass (64.9 +/- 2.5 kg, P =
      .92) were constant over time. In the study of day-to-day variation, we found a CV
      for Si of 17.3% and a CV for Sg of 23.3%. In conclusion, we found that the
      variations in Si and Sg were slightly higher than those found in studies
      performed to establish the day-to-day variation. However, no significant seasonal
      variation in Si and Sg was evident in this group of healthy young lean caucasian
      men. Consequently, indices of Si and Sg obtained at different times of the year
      appear comparable.

PMID- 10647062
TI  - Effects of low-dose and high-dose glucagon on glucose production and
      gluconeogenesis in humans.
AB  - The analysis of mass isotopomers in blood glucose and lactate can be used to
      estimate gluconeogenesis (Gneo), glucose production (GP), and, by subtraction,
      nongluconeogenic glucose release by the liver. At 6 AM, 18 normal subjects
      received a 7-hour primed constant infusion of [U-13C6] glucose. After a 3-hour
      baseline period (12 hours of fasting), somatostatin, insulin, hydrocortisone,
      growth hormone (GH), and glucagon were infused for 4 hours. Glucagon was infused
      at a low-dose (n = 6) or high-dose (n = 6) concentration for 4 hours and was
      compared with fasting alone (n = 6). Low-dose glucagon infusion increased plasma
      glucagon (64 +/- 3 v 44 +/- 7 ng/L, low glucagon v baseline). GP increased above
      baseline (15.5 +/- 0.5 v 13.8 +/- 0.5 micromol/kg/min, P < .05), which was also
      greater than fasting alone (11 .5 +/- 0.6 micromol/kg/min, P < .05). The
      elevation in GP was due to a near doubling of nongluconeogenic glucose release
      compared with fasting alone (8.3 +/- 0.6 v 4.7 +/- 0.5 micromol/kg/min, P < .01).
      High-dose glucagon infusion (125 +/- 25 ng/L) increased GP above baseline (15.8
      +/- 0.6 v 13.5 +/- 0.5 micromol/kg/min, P < .05), which was also greater than
      fasting alone (11.5 +/- 0.6 micromol/kg/min, P < .05). The increase in GP was due
      to an increase in Gneo (8.5 +/- 0.5 v 6.8 +/- 0.7 micromol/kg/min, P < .05) and
      nongluconeogenic glucose release (7.4 +/- 0.5 v 4.7 +/- 0.4 micromol/kg/min, P <
      .05) compared with fasting. Low-dose glucagon increases GP only by stimulation of
      nongluconeogenic glucose release. High-dose glucagon increases GP by an increase
      in both Gneo and nongluconeogenic glucose release.

PMID- 10647063
TI  - Increased circulating calcitonin in cirrhosis. Relation to severity of disease
      and calcitonin gene-related peptide.
AB  - Increased circulating levels of the neuropeptide calcitonin gene-related peptide
      (CGRP) have recently been described in cirrhosis. CGRP is formed by alternative
      transcription of the calcitonin/alpha-CGRP gene, which also gives rise to
      calcitonin (CT). This study was undertaken to determine circulating plasma
      concentrations of CT in patients with cirrhosis in relation to the severity of
      disease and the plasma level of CGRP. Moreover, the kinetics of CT was evaluated
      for different organ systems by determination of arteriovenous extraction. Thirty
      nine patients with cirrhosis (Child-Turcotte classes A/B/C, n = 10/22/7) were
      studied under a hemodynamic investigation and compared with 13 control subjects
      without liver disease. CT and CGRP in arterial and organ venous plasma were
      determined by radioimmunoassays. In patients with cirrhosis, circulating CT was
      significantly increased versus control (12.1 v 6.9 pmol/L, P < .001) and a direct
      relation to the Child-Turcotte score was found (P < .005). The increased
      circulating CT was directly correlated with increased CGRP (r = .29, P < .05). No
      significant arteriovenous extraction of circulating CT was observed in the
      kidneys, hepatosplanchnic system, lower extremities, or peripheral circulation,
      but there was a substantial rate of pulmonary disposal and clearance (P < .005).
      It is concluded that in addition to thyroid production, increased circulating CT
      in cirrhosis is most likely due to overexpression of the calcitonin/alpha-CGRP
      gene, with relation to the severity of disease and possibly to an accompanying
      pulmonary dysfunction.

PMID- 10647064
TI  - Influence of triglyceride concentration on the relationship between lipoprotein
      cholesterol and apolipoprotein B and A-I levels.
AB  - A sample of 2,103 men aged 47 to 76 years from the Quebec Cardiovascular Study
      cohort was examined to quantify the influence of plasma triglyceride (TG) levels
      on the relationship between plasma lipoprotein cholesterol and either
      apolipoprotein A-I (apo A-I) or apo B concentrations. Regression analyses between
      high-density lipoprotein cholesterol (HDL-C) and apo A-I through TG tertiles
      showed highly significant correlations (.62 < or = r < or = .75, P < .0001) in
      all TG tertiles between these 2 variables. The associations for plasma apo B
      versus low-density lipoprotein cholesterol (LDL-C) and non-HDL-C levels were also
      studied on the basis of TG concentrations, and correlation coefficients between
      either LDL-C or non-HDL-C and apo B were essentially similar among TG tertiles
      (.78 < or = r < or = .85 and .83 < or = r < or = .86 for LDL-C and non-HDL-C,
      respectively, P < .0001). Regression analyses also showed that lower HDL-C levels
      were found for any given apo A-I concentration among men in the 2 upper TG
      tertiles, whereas lower LDL-C concentrations were observed at any given apo B
      level among subjects in the upper TG tertile. We further investigated whether
      there were synergistic alterations in the HDL-C/apo A-I and LDL-C/apo B ratios as
      a function of increasing plasma TG. A significant association was noted between
      these 2 ratios (r = .37; P < .0001). Mean HDL-C/apo A-I and LDL-C/apo B ratios
      were then calculated across quintiles of plasma TG concentrations. Increased TG
      concentrations were first associated with a reduced HDL-C/apo A-I ratio, followed
      by a decreased LDL-C/apo B ratio. These results suggest that a relatively modest
      increase in TG may rapidly alter the relative cholesterol content of HDL
      particles. Finally, the cholesterol content of the non-HDL fraction appears to be
      influenced less by TG levels than HDL-C and LDL-C fractions. Thus, the plasma apo
      B-containing lipoprotein cholesterol level may provide a better index of number
      of atherogenic particles than the LDL-C concentration, particularly in the
      presence of hypertriglyceridemia (HTG).

PMID- 10647065
TI  - Urinary excretion and serum concentration of mevalonic acid during acute intake
      of alcohol.
AB  - The influence of 2 different alcoholic beverages containing an equal amount of
      alcohol (48 g), 1 with mevalonic acid (beer) and 1 without (vodka), on the
      urinary excretion and serum concentration of mevalonic acid was investigated in 7
      healthy subjects. Drinking 1 L of beer at night containing 608 microg/L mevalonic
      acid more than doubled the urinary excretion of mevalonic acid the following 12
      hours, on average from 103 +/- 15 microg/12 h to 211 +/- 17 microg/12 h (P <
      .001; 18% of the administered dose). Drinking the same amount of alcohol as vodka
      had no effect, but urinary mevalonic acid output increased slightly the following
      day (7 AM to 7 PM) after ingestion of both alcoholic beverages. Serum
      concentrations of mevalonic acid were significantly increased the following
      morning after ingestion of beer (from 3.22 +/- 0.20 ng/mL to 6.79 +/- 0.58 ng/mL)
      or vodka (from 3.23 +/- 0.37 ng/mL to 5.36 +/- 0.55 ng/mL, P < .002 for both). An
      increase in the ratio of lathosterol to cholesterol in serum, another indicator
      of 3beta-hydroxy-3beta-methylglutaryl coenzyme A reductase activity in the liver,
      was also observed (+18% and +25%, respectively). After oral administration of
      [13C2] mevalonic acid at night, 20% +/- 0.7% of the dose was excreted in urine
      the following 12 hours, and only trace amounts thereafter. No [13C2] mevalonic
      acid could be detected in serum the following morning. We conclude that the
      absorption of dietary mevalonic acid and alcohol-induced mevalonic acid synthesis
      affects the urinary excretion and serum concentration of this cholesterol
      precursor. Therefore, studies using mevalonic acid as a marker of cholesterol
      synthesis must be carefully monitored regarding dietary mevalonic acid intake and
      alcohol consumption.

PMID- 10647066
TI  - The effect on serum lipids and oxidized low-density lipoprotein of supplementing
      self-selected low-fat diets with soluble-fiber, soy, and vegetable protein foods.
AB  - An increased intake of soluble fiber and soy protein may improve the blood lipid
      profile. To assess any additional benefit on serum lipids of providing soy
      protein and soluble-fiber foods to hyperlipidemic subjects already consuming low
      fat, low-cholesterol therapeutic diets, 20 hyperlipidemic men and postmenopausal
      women completed 8-week test and control dietary treatments in a randomized
      crossover design as part of an ad libitum National Cholesterol Education Program
      (NCEP) step 2 therapeutic diet (<7% saturated fat and <200 mg/d cholesterol).
      During the test phase, foods high in soy, other vegetable proteins, and soluble
      fiber were provided. During the control phase, low-fat dairy and low-soluble
      fiber foods were provided. Fasting blood lipid and apolipoprotein levels were
      measured at 4 and 8 weeks of each phase. On the test diet, 12 +/- 2 g/d soy
      protein was selected from the foods chosen. Direct comparison of test and control
      treatments indicated an elevated high-density lipoprotein (HDL) cholesterol
      concentration on the test diet (6.4% +/- 2.4%, P = .013) and a significantly
      reduced total to HDL cholesterol ratio (-5.9% +/- 2.3%, P = .020). The proportion
      of conjugated dienes in the low-density lipoprotein (LDL) cholesterol fraction
      was significantly reduced (8.5% +/- 3.3%, P = .020) as a marker of oxidized LDL.
      A combination of acceptable amounts of soy, vegetable protein, and soluble-fiber
      foods as part of a conventional low-fat, low-cholesterol therapeutic diet is
      effective in further reducing serum lipid risk factors for cardiovascular
      disease.

PMID- 10647067
TI  - Effects of endothelin-1 and nitric oxide on glucokinase activity in isolated rat
      hepatocytes.
AB  - To test the hypothesis that endothelin-1 (ET-1) and nitric oxide (NO) influence
      glucokinase (GK) activity in an opposite manner, we evaluated the effects of ET
      1, L-NAME, an inhibitor of NO synthase, and L-arginine, a substrate for NO
      synthase, on GK activity and glycogen content in isolated rat hepatocytes.
      Moreover, to understand the receptor involved in the process, the effects of BQ
      788, a specific antagonist of ETB receptor, and PD 142893, an antagonist of ETA
      ETB receptors, were also evaluated. GK activity, cyclic guanosine monophosphate
      (cGMP), and glycogen intracellular content were measured on isolated hepatocytes,
      while glucose levels and NO as NO2-/NO3- were determined in the medium. High ET-1
      levels induced a 20% decrease of NO2-/NO3- levels and cGMP intracellular content,
      followed by a 49% reduction of GK activity and a 15% decrease of glycogen. In
      parallel, a 10% increase of glucose in the medium was observed. In the presence
      of L-NAME, GK activity and glycogen levels showed analogous decrements as
      observed with ET-1. Also in this case, a significant decrease of the
      intracellular content of cGMP was observed. No synergistic effects of ET-1 and L
      NAME were observed. L-Arginine was able to counteract the inhibitory effect of ET
      1 on cGMP and GK activity. Glycogen content was slightly but not significantly
      reduced, and under those conditions, a significant decrease of glucose in the
      medium was observed. When hepatocytes were incubated with ET-1 plus BQ 788 or ET
      1 plus PD 142893, GK activity was unchanged. Interestingly, no changes were
      observed in NO2-/NO3- levels and the intracellular content of cGMP was not
      modified when the antagonists of ET-1 receptors were added to the medium. In
      conclusion, the present study shows that the NO pathway seems to be an important
      regulator of GK activity and glycogen content through cGMP activity. In addition,
      ET-1 seems to be not active per se, but its activity seems mediated by a
      simultaneous decrease of NO levels.

PMID- 10647068
TI  - Hypertension and its treatment influence changes in fasting nonesterified fatty
      acid concentrations: a link between the sympathetic nervous system and the
      metabolic syndrome?
AB  - In previous studies, a cross-sectional association has been described between
      blood pressure (BP) and nonesterified fatty acid (NEFA) concentrations. The
      direction of causality, and thus, the mechanism explaining this relationship,
      remains uncertain. Therefore, we analyzed a prospective population-based cohort
      of 937 subjects who underwent an oral glucose tolerance test (OGTT) on two
      occasions separated by 4.5 years. In cross-sectional analysis, NEFA measures were
      correlated with systolic and diastolic BP, both at baseline and at follow-up
      study. In longitudinal analysis, baseline systolic and diastolic BP predicted
      changes in fasting NEFA levels (both P < .01). However, baseline NEFA levels did
      not predict change in BR In multivariate analysis, the relationship between
      baseline BP and change in fasting NEFA was independent of age and sex. Obesity
      and its interaction with BP did not explain this association. Absolute changes in
      NEFA concentrations were greater among subjects who were hypertensive at baseline
      compared with the normotensive individuals. This change was greater in subjects
      treated with diuretics compared with those treated with beta-adrenergic
      antagonists (P < .01), an observation that provides support for a role of
      sympathetic nervous system (SNS) activity in explaining the relationship between
      BP and NEFA concentration.

PMID- 10647069
TI  - Improved glycemic control and platelet function abnormalities in diabetic
      patients with microvascular disease.
AB  - Patients with diabetes mellitus have a variety of platelet and coagulation system
      dysfunctions. At least theoretically, these can contribute to microvascular
      complications. Intensive glycemic control has been demonstrated to decrease
      microvascular complications in type 1 diabetics. We studied 16 patients with type
      1 diabetes mellitus (11 men and five women; mean age, 39 years) with albuminuria
      greater than 0.1 g/d and/or proteinuria greater than 0.3 g/d and a creatinine
      clearance rate higher than 30 mL/min. They received a regimen including three to
      four injections of insulin per day with or without a weekly infusion of
      intravenous insulin, and were evaluated for 6 months. We compared the plasma
      level of von Willebrand factor, platelet aggregation responses to adenosine
      diphosphate (ADP), epinephrine, and collagen, and platelet adhesion at the
      beginning of the study and at follow-up intervals. Glycemic control improved
      significantly. There were no significant differences in the platelet aggregation
      responses to ADP (1.59 +/- 0.34 v 1.88 +/- 0.23 mmol/L, P = .3; normal, 4.6 +/-
      0.2), epinephrine (0.50 +/- 0.20 v 1.11 +/- 0.31 mmol/L, P = .06; normal, 7.6 +/-
      1.5), or collagen (92.4 +/- 6.61 v 82.60 +/- 3.78 seconds, P = .6; normal, 79.1
      +/- 3.1) or in platelet adhesion (126.31 +/- 16.95 v 195.08 +/- 30.2 platelets, P
      = .34; normal, 68.6 +/- 1.4). Baseline von Willebrand factor increased, but not
      significantly (166.38% +/- 10.6% v 142.72% +/- 14.73%, P = .21; normal, 102.0% +/
      6.0%). In type 1 diabetic patients with established microvascular complications
      of nephropathy, a statistically significant improvement in glycemic control did
      not improve the in vitro platelet function abnormalities. Improved glycemic
      control delays the progression of microvascular disease through mechanisms not
      measured by tests of platelet function.

PMID- 10647070
TI  - Evidence of enhancement of malate-aspartate shuttle activity in beta cells of
      streptozotocin-induced non-insulin-dependent diabetic rats.
AB  - Glucose-induced insulin secretion is selectively impaired in beta cells from
      animals with non-insulin-dependent diabetes mellitus (NIDDM). This study was
      performed to clarify whether the malate-aspartate shuttle among the glucose
      metabolic pathways is intact in beta cells of NIDDM rats. The insulin secretory
      capacity of the islets and the K(ATP) channel activity in single beta cells were
      measured in control and NIDDM rats injected with streptozotocin (STZ) during the
      neonatal period, using a radioimmunoassay and patch-clamp technique. The increase
      of insulin secretion induced by 11.1 mmol/L glucose or 10 mmol/L dihydroxyacetone
      (DHA) was significantly reduced in NIDDM islets, suggesting an impaired glycerol
      phosphate shuttle. The application of glyceraldehyde (10 mmol/L) in NIDDM or
      control islets elicited an increase in insulin secretion, but the difference
      between the 2 groups was indistinguishable. On the contrary, the increase of
      insulin secretion and the inhibition of K(ATP) channel activity induced by
      aspartate, which preferentially participates in the malate-aspartate shuttle,
      were significantly greater in NIDDM versus the control. However, intracellularly
      applied aspartate in the inside-out mode did not inhibit K(ATP) channel activity.
      These findings show that malate-aspartate shuttle activity is potentiated in
      pancreatic beta cells of NIDDM rats, suggesting the development of a compensatory
      mechanism for the reduced activity of the glycerol-phosphate shuttle in NIDDM.

PMID- 10647071
TI  - Effect of branched-chain amino acids on the plasma concentration of uridine does
      not occur via the action of glucagon or insulin.
AB  - To examine whether branched-chain amino acids affect the plasma concentration of
      uridine, we administered branched-chain amino acids (L-isoleucine, 2.85 g, L
      leucine 5.71 g, and L-valine, 3.43 g) orally to 6 healthy subjects. Plasma
      uridine and glucose decreased by 44% and 12%, respectively, together with an
      increase in plasma isoleucine, leucine, and valine 90 minutes after
      administration. However, branched-chain amino acids did not affect the plasma
      concentration and urinary excretion of purine bases (hypoxanthine, xanthine, and
      uric acid) and uridine or the plasma concentration of insulin, glucagon, and
      cyclic adenosine monophosphate (cAMP). Since small amounts of regular insulin,
      which were found to decrease plasma glucose more than the amino acids, did not
      decrease the plasma concentration of uridine, these results suggest that plasma
      uridine was decreased by a direct effect of the branched-chain amino acids on the
      cellular uptake and/or release of uridine.

PMID- 10647072
TI  - Influence of age on the thermic response to caffeine in women.
AB  - The purpose of this study was to examine age-related differences in the magnitude
      of caffeine-induced thermogenesis and the relationship of aerobic fitness, body
      composition, and hormone and substrate concentrations to the thermic effect of
      caffeine in younger and older women. Using a placebo-controlled, double-blind
      study design, 10 older (50 to 67 years) and 10 younger (21 to 31 years) healthy
      women who were moderate consumers of caffeine (self-reported intake: younger, 139
      +/- 152 mg/d; older, 204 +/- 101 mg/d, NS, mean +/- SD) were characterized for
      fasting plasma glucose, insulin, free fatty acid (FFA), and caffeine levels,
      energy expenditure, body composition, anthropometry, aerobic fitness, physical
      activity, and energy intake. Before and after placebo and caffeine ingestion (5
      mg/kg fat-free mass [FFM]), the following variables were measured: fasting plasma
      glucose, insulin, FFA, and energy expenditure, plasma glucose, insulin, and FFA,
      and energy expenditure in response to placebo and caffeine ingestion. Caffeine
      ingestion resulted in similar increases in younger and older women for plasma
      caffeine (younger, 80 +/- 34 to 5,604 +/- 528 ng/mL, P < .01; older, 154 +/- 134
      to 5,971 +/- 867 ng/mL, P < .01) and fatty acids (younger, 294 +/- 118 to 798 +/-
      248 micromol/L, P < .01; older, 360 +/- 180 to 727 +/- 310 micromol/L, P < .01),
      whereas plasma insulin and glucose levels remained unchanged from baseline.
      Energy expenditure increased following caffeine ingestion in both groups
      (younger, 15.4%, 1.09 +/- 0.14 to 1.24 +/- 0.13 kcal/min, P < .05; older, 7.8%,
      0.98 +/- 0.14 to 1.06 +/- 0.12 kcal/min, P < .05), although there was a blunted
      thermic response in the older versus younger women (older, 6.9 +/- 5 kcal/90 min;
      younger, 15.5 +/- 7 kcal/90 min, P < .05). In younger women, the thermic response
      to caffeine was positively correlated with the waist circumference (r = .70, P <
      .05) and body weight (r = .91; P < .01), whereas aerobic fitness (r = .77; P <
      .05) was the only significant correlate in older women. In conclusion, older and
      younger women increase energy expenditure significantly following caffeine
      ingestion, but older women have a blunted thermic response compared with younger
      women. Second, the thermic response to caffeine is positively associated with the
      body weight and waist circumference in younger women, whereas a positive
      association with aerobic fitness was observed in older women. Thus, the
      physiologic determinants of the thermic response to caffeine differ among women
      of different age groups.

PMID- 10647073
TI  - Decrease in triglyceride accumulation in tissues by restricted diet and
      improvement of diabetes in Otsuka Long-Evans Tokushima fatty rats, a non-insulin
      dependent diabetes model.
AB  - With respect to the connection between triglyceride (TG) and non-insulin
      dependent diabetes mellitus (NIDDM), previous reports have shown that TG
      accumulation in the liver and muscle is one of the causes of insulin resistance,
      and TG accumulation in pancreatic islets induces impairment of pancreatic beta
      cell function. This experiment examined the relationship between an amelioration
      of hypertriglyceridemia (HTG), a decrease in TG accumulation in tissues, and an
      improvement of NIDDM by food restriction. In this experiment using Otsuka Long
      Evans Tokushima fatty (OLETF) rats developing NIDDM and Long-Evans Tokushima
      Otsuka (LETO) rats as controls, sequential changes in body weight and TG content
      in tissue were measured and biochemical blood tests, an insulin euglycemic clamp
      test, and histopathologic examination of the pancreas and liver were performed.
      OLETF rats were allocated to a food-satiated group (satiated) or 30% food
      restricted group (restricted). As a result, several findings were more evident in
      the restricted group than in the satiated group: (1) reductions in body weight
      and intraabdominal fat weight, decreases in plasma TG, insulin, and glucose
      levels, a decrease in the TG secretion rate, and an increase in plasma
      lipoprotein lipase (LPL) activity, (2) decreases in the TG content in the liver,
      pancreas, and muscle, (3) improvement of the glucose infusion rate (GIR), and (4)
      a marked reduction of TG accumulation in the liver and pancreatic islets on
      histopathologic examination. These results indicate that the improved HTG caused
      a reduction in TG accumulation in the liver and muscle, thereby improving insulin
      resistance. Moreover, the decrease in TG accumulation in pancreatic islets
      suggests an improvement of pancreatic beta-cell function.

PMID- 10647074
TI  - Effects of simvastatin and pravastatin on gonadal function in male
      hypercholesterolemic patients.
AB  - Inhibition of cholesterol biosynthesis by hydroxymethyl glutaryl coenzyme A (HMG
      CoA) reductase inhibitors could, in theory, adversely affect male gonadal
      function because cholesterol is a precursor of steroid hormones. The objective of
      this randomized double-blind trial was to compare the effects of simvastatin,
      pravastatin, and placebo on gonadal testosterone production and spermatogenesis.
      After a 6-week placebo and lipid-lowering diet run-in period, 159 male patients
      aged 21 to 55 years with type IIa or IIb hypercholesterolemia, low-density
      lipoprotein (LDL) cholesterol between 145 and 240 mg/dL, and normal basal levels
      of testosterone were randomly assigned to treatment with simvastatin 20 mg (n =
      40), simvastatin 40 mg (n = 41), pravastatin 40 mg (n = 39), or placebo (n = 39)
      once daily. After 24 weeks of treatment, mean total cholesterol levels were
      decreased 24% to 27% and mean LDL cholesterol was decreased 30% to 34% in the 3
      active-treatment groups (P < .001 for all comparisons to placebo). At 24 weeks,
      there were no statistically significant differences between the placebo group and
      any of the active-treatment groups for the change from baseline in testosterone,
      human chorionic gonadotropin (hCG)stimulated testosterone, free testosterone
      index, follicle-stimulating hormone (FSH), luteinizing hormone (LH), or sex
      hormone-binding globulin (SHBG). Moreover, there were no statistically
      significant differences at week 12 or week 24 for the change from baseline in
      sperm concentration, ejaculate volume, or sperm motility for any active treatment
      relative to placebo. Both simvastatin and pravastatin were well tolerated. In
      summary, we found no evidence for clinically meaningful effects of simvastatin or
      pravastatin on gonadal testosterone production, testosterone reserve, or multiple
      parameters of semen quality.

PMID- 10647075
TI  - Fat metabolism during high-intensity exercise in endurance-trained and untrained
      men.
AB  - To determine whether trained individuals rely more on fat than untrained persons
      during high-intensity exercise, six endurance-trained men and six untrained men
      were studied during 30 minutes of exercise at 75% to 80% maximal oxygen
      consumption (VO2max). The rates of appearance (Ra) and disappearance (Rd) of
      glycerol and free fatty acids (FFAs) were determined using [1,1,2,3,3-2H]glycerol
      and [1-13C]palmitate, respectively, whereas the overall rate of fatty acid
      oxidation was determined using indirect calorimetry. During exercise, the whole
      body rate of lipolysis (ie, glycerol Ra) was higher in the trained group (7.1 +/-
      1.2 v 4.5 +/- 0.7 micromol x min(-1) x kg(-1), P < .05), as was the Ra
      (approximately Rd) of FFA (9.0 +/- 0.9 v 5.0 +/- 1.0 micromol x min(-1) x kg(-1),
      P < .001). FFA utilization was higher in trained subjects even when expressed as
      a percentage of total energy expenditure (10% +/- 1% v 7% +/- 1%, P < .05).
      However, this difference in plasma FFA flux could not account for all of the
      difference in fatty acid oxidation between trained and untrained subjects (20.8
      +/- 3.3 v 7.9 +/- 1.6 micromol x min(-1) x kg(-1), or 23% +/- 3% v 13% +/- 2% of
      total energy expenditure, both P < .05). Thus, the oxidation of fatty acids
      derived from some other source also must have been greater in the trained men. We
      conclude that trained athletes use more fat than untrained individuals even
      during intense exercise performed at the same percentage of VO2max. The
      additional fatty acids appear to be derived from both adipose tissue and,
      presumably, intramuscular triglyceride stores.

PMID- 10647076
TI  - Intermittent administration of brain-derived neurotrophic factor ameliorates
      glucose metabolism in obese diabetic mice.
AB  - We have previously shown that brain-derived neurotrophic factor (BDNF), a member
      of the neurotrophin family, interacts with the endocrine system in obese diabetic
      mice, and systemic peripheral administration of BDNF regulates glucose metabolism
      in this model. Results from the present study show that the hypoglycemic effect
      induced by 2 weeks' daily administration of BDNF (20 mg/kg/d) to db/db mice lasts
      for several weeks after treatment cessation, irrespective of food reduction. On
      the other hand, the antidiabetic agent, metformin had no lasting effect. This
      duration of the BDNF hypoglycemic action prompted us to examine the efficacy of
      BDNF intermittent administration on glucose metabolism. BDNF administered once or
      twice per week (70 mg/kg/wk) to db/db mice for 3 weeks significantly reduced
      blood glucose concentrations and hemoglobin A(1c), (HbA(1c)) as compared with ad
      libitum-fed phosphate-buffered saline (PBS)-treated and pair-fed PBS-treated
      groups. This suggests that BDNF not only temporarily reduced blood glucose
      concentrations but also ameliorated systemic glucose balance in this obese
      diabetic mouse model during the experimental period. Our results indicate that
      BDNF could be a novel hypoglycemic agent with an exceptional ability to normalize
      glucose metabolism even with treatment as infrequently as once per week.

PMID- 10647077
TI  - Contribution of hyperinsulinemia to modulation of lipoprotein lipase activity in
      the obese Zucker rat.
AB  - This study was designed to assess the contribution of hyperinsulinemia to the
      maintenance of high adipose and low muscle lipoprotein lipase (LPL) activity in
      the obese Zucker fa/fa rat. Insulinemia in obese Zucker rats was reduced for 4
      days with a single injection of low-dose streptozotocin (STZ). Saline-injected
      intact obese (obese-INT) and STZ-injected obese (obese-STZ) rats were compared
      with a lean Fa/? reference group. LPL activity was assessed after a 12-hour fast,
      with or without a 1-hour refeeding period. Fasting serum insulin levels were 17
      fold higher in obese-INT versus lean rats and were reduced to 60% of obese-INT
      levels in obese-STZ animals. In the postprandial state, serum insulin levels
      remained low in obese-STZ rats and were similar to the values in lean animals,
      whereas insulinemia increased in the obese-INT group to 18-fold the levels in
      lean rats. Serum glucose, nonesterified fatty acid (NEFA), and triglyceride
      levels, which were higher in obese-INT versus lean rats, were further increased
      in the obese-STZ group. Tissue weights of obese rats were unaffected by STZ
      treatment. Fasting LPL specific activity was higher in white adipose tissue
      ([WAT] +87%) and brown adipose tissue ([BAT] +167%) of obese-INT versus lean
      rats. Reducing the insulinemia in obese-STZ rats reduced fasting enzyme activity
      to the levels in lean animals in both WAT and BAT. Insulinemia and adipose LPL
      activity were positively correlated in the fasted state. Acute food intake
      increased WAT LPL activity in lean animals, but not in obese animals. Soleus LPL
      activity was lower in obese-INT compared with lean rats and was further decreased
      in obese-STZ animals. Heart LPL was decreased only in obese-STZ rats compared
      with the lean group. LPL in muscle tissue was not correlated with insulinemia,
      but an inverse relationship was found between serum NEFA levels and enzyme
      activity. It is concluded that in the obese Zucker rat, hyperinsulinemia is
      responsible for the maintenance of elevated basal LPL activity in adipose tissue
      independently of fat mass, whereas muscle enzyme activity appears to be more
      strongly and inversely related to the availability or tissue utilization of lipid
      substrates.

PMID- 10647078
TI  - Dietary glutamine suppresses endogenous glutamine turnover in the rat.
AB  - Plasma glutamine turnover was determined using 1-14C-labeled glutamine in rats
      that consumed crystalline amino acid diets containing the equivalent of 16%
      protein with 25% of the amino acids as glutamine or a control diet containing no
      glutamine (or glutamate) for 10 days. Glutamine turnover in glutamine-fed animals
      was 66% of the rate in the control group. Glutamine feeding caused 20% higher
      levels of arterial plasma glutamine. Arterial-portal differences across the
      portal-drained viscera showed net glutamine uptake in control animals but no net
      uptake or release in the glutamine-fed group. Skeletal muscle glutamine
      synthetase activity was similar in both groups. The results indicate that long
      term consumption of relatively large amounts of dietary glutamine decreases the
      turnover of plasma glutamine and thus reduces the need for endogenous glutamine
      synthesis.

PMID- 10647079
TI  - Decreased production of AmpC-type beta-lactamases associated with the development
      of resistance to quinolones in Citrobacter freundii strains.
AB  - The effect of fluoroquinolones in Citrobacter freundii strains that results in a
      decreased expression of cephalosporin-hydrolysing beta-lactamases was studied.
      Resistance to broad-spectrum cephalosporins and penicillins in two C. freundii
      clinical isolates was associated with moderate production of chromosomal AmpC
      type-beta-lactamase in addition to changes in the outer membrane proteins profile
      with respect to wild-type C. freundii strains. Ten quinolone-resistant mutants
      were derived from the two clinical isolates using increasing fluoroquinolone
      concentrations. The level of susceptibility to cephalosporins and meropenem of
      these 10 mutants was increased and was associated with a 3.6-32% diminution in
      the hydrolyzing activity of their periplasmic extracts containing beta-lactamases
      on cephaloridine as compared with those from their parent strains. Susceptibility
      to cephalosporins and meropenem, as well as the expression of chromosomal AmpC
      type-beta-lactamase in C. freundii strains, was influenced by the exposure to
      quinolones.

PMID- 10647080
TI  - Acquisition of new capsular genes among clinical isolates of antibiotic-resistant
      Streptococcus pneumoniae.
AB  - Antibiotic-resistant clones of Streptococcus pneumoniae are recognizable through
      a combination of unique molecular, microbiological, and serological properties.
      In the course of surveillance of epidemic clones of S. pneumoniae, several
      isolates were identified that shared the clone-specific pulsed-field gel
      electrophoretic (PFGE) pattern and antibiotype but expressed serotypes atypical
      for the particular clone. A selected group of isolates belonging to the
      Spanish/USA clone but expressing serotypes 19, 14, or 3, instead of the expected
      serotype 23F, were tested using DNA probes for each of the 18 open reading frames
      (ORFs) of the 23F capsular locus. In no case were there any 23F-specific genes
      retained, with the possible exception of genes already known to be common to the
      capsular loci involved. Analysis of the sequence of the capsular locus of a
      penicillin-resistant serotype 23F isolate from Mexico showed that part of the
      cpsA gene of this strain, as well as genes cpsQ and cpsR, had high degrees of
      identity to the sequence of the homologous genes in isolates expressing serotype
      19F. The capsular locus of this Mexican strain may have originated from an in
      vivo capsular switch event in which the original 19F locus was replaced by 23F
      specific capsular genes.

PMID- 10647081
TI  - Calcium signaling in Streptococcus pneumoniae: implication of the kinetics of
      calcium transport.
AB  - The kinetics and pharmacological characterization of a Na+/Ca2+ exchange system,
      essential for the growth of the extracellular pathogen Streptococcus pneumoniae
      in high-calcium media, demonstrated that calcium transport, in addition to its
      role in calcium homeostasis, is involved in the induction of autolysis and of
      competence for genetic transformation. These responses are expressed respectively
      in cultures entering the stationary phase and growing with exponential rates.
      Experimental virulence also appears to be modulated by the kinetics of calcium
      transport. Calcium transport in S. pneumoniae is electrogenic and shows
      sigmoidicity, indicating a cooperative mechanism with an inflexion point at 1 mM
      Ca2+. Mutant strains with Hill number values of 4 and 1, compared to 2 in the
      wild-type strain, were isolated. These changes were associated with altered
      regulation of competence and autolysis, and also with reduced experimental
      virulence. By contrast, they could not be related to a specific calcium
      requirement for growth. This indicates that the cooperativity of Ca2+ transport
      is not involved in vegetative growth, but rather regulates competence and
      autolysis. Competence and autolysis represent two growth-phase-dependent
      responses to an oligopeptide-activator exported to the medium, the competence
      stimulating peptide. Addition of this activator to noncompetent cells, triggers
      net and transient 45Ca2+ influx. One effect of the activator might be to activate
      a calcium transporter by enhancing its cooperativity. In addition to an increase
      in intracellular calcium, a transient membrane depolarization induced by
      electrogenic calcium influx may be part of the signaling mechanism. The
      competence activator is a quorum-sensing molecule whose synthesis is
      autoregulated. This regulation might involve calcium-mediated signaling. As an
      extracellular pathogen, S. pneumoniae probably develops in niches with variable
      calcium concentration. Interestingly, virulence depends strongly upon the
      kinetics of Ca2+ transport. Regulation of calcium influx may represent a common
      mechanism of sensing the environment, if the Na+/Ca2+ exchanger is the target for
      external mediators including the competence activator.

PMID- 10647082
TI  - Inactivation of the methicillin resistance gene mecA in vancomycin-resistant
      Staphylococcus aureus.
AB  - Acquisition of high-level resistance to vancomycin in the laboratory mutant VM50
      (vancomycin MIC increased from 1.5 to 100 microg/ml) was accompanied by the
      appearance of a heterogeneous phenotype and a virtual loss in methicillin
      resistance: in most cells of cultures of VM50 the methicillin MIC of the parental
      strain was reduced from 800 to 1.5 microg/ml with only a subpopulation (10(-5))
      retaining methicillin resistance at near the parental level (MIC of 400
      microg/ml). Interestingly, the vancomycin MIC of this subpopulation was less (25
      microg/ml) than that of VM50 (100 microg/ml). A similar antagonism between
      methicillin and vancomycin resistance levels was observed upon introduction of an
      intact mecA into VM50 on a plasmid vector: methicillin resistance of the majority
      of cells increased from 1.5 to 100 microg/ml while the vancomycin MIC declined
      from 100 to 12/25 microg/ml. Membrane preparations from mutant VM50 showed no
      detectable penicillin-binding protein (PBP) 2A by the fluorographic assay.
      Sequencing of the mecA gene resident in mutant VM50 indicated the presence of a
      19-bp duplication between nucleotide residues 280-298, leading to the generation
      of a stop codon TAA starting at nucleotide position 286.

PMID- 10647083
TI  - Identification and characterization of a new intermediate in the ribosylative
      inactivation pathway of rifampin by Mycobacterium smegmatis.
AB  - Mycobacterium smegmatis DSM 43756 inactivates rifampin by ribosylation. To study
      this process of rifampicin, all possible inactivated forms of the antibiotic were
      extracted and purified. Structural studies showed the presence of a new
      inactivation product, designated RIP-TAp(23-phosphoribosyl-rifampin). Formation
      of 23-(O-ADP-ribosyl)rifampin (RIP-TAs) is the first step, followed by removal of
      AMP to give rise to the newly identified compound. Lastly, dephosphorylation
      leads to formation of 23-ribosyl-rifampin (RIP-Mb). Feeding experiments with the
      ADP-ribosylated antibiotic obtained from the cell homogenates of an Escherichia
      coli strain carrying the cloned M. smegmatis gene confirmed this rifampin
      inactivation process.

PMID- 10647084
TI  - Activity of 16 antimicrobial agents against drug-resistant strains of
      Mycobacterium tuberculosis.
AB  - The in vitro activity of 16 antimicrobial agents against 46 drug-resistant
      strains of Mycobacterium tuberculosis recently isolated from Italian patients was
      determined. As for first-line antituberculosis drugs, while isoniazid was
      ineffective against all the strains tested, resistance to streptomycin,
      rifampicin, pyrazinamide, and ethambutol was 80.4%, 71.7%, 39.1%, and 8.7%,
      respectively. Among second-line antituberculous drugs, resistance to
      ciprofloxacin, ofloxacin, and sparfloxacin and to amikacin and kanamycin was
      around 20%. About 10% of the strains were resistant to capreomycin and
      cycloserine and 4.3% were resistant to ethionamide; no strain was found to be
      resistant to thiacetazone, para-aminosalicylic acid, and viomycin. Although all
      strains displayed a rather continuous distribution of minimal inhibitory
      concentrations (MICs), a bimodal distribution was observed for rifampicin,
      amikacin, and kanamicin, with very high MIC values for resistant strains;
      relatively low MICs were found for fluoroquinolone-resistant strains. Among the
      small number of strains resistant to second-line agents, low resistant levels
      were observed. Restriction fragment length polymorphism analysis showed few
      strain clusters with resistance to first-line antituberculous drugs and
      aminoglycosides, fluoroquinolones, or both. Altogether, these results showed that
      second-line agents were still active against the isoniazid-resistant and multiply
      first-line resistant strains tested, with none or low resistance levels; these
      observations can be of importance for the treatment of multidrug-resistant
      tuberculosis in Italy.

PMID- 10647085
TI  - Prevalence and patterns of resistance of Streptococcus pneumoniae strains
      isolated from carriers attending day care centers in the area of Athens.
AB  - The prevalence and patterns of Streptococcus pneumoniae resistance to antibiotics
      was examined in 146 nasopharyngeal carrier strains obtained during April and May,
      1997, from 382 healthy children attending eight day care centers (DCCs) in the
      area of Athens. Reduced susceptibility to at least one antibiotic was found in
      32.6% as follows: penicillin 11.4% (intermediate), cefotaxime 0.8%
      (intermediate), trimethoprim-sulfamethoxazole 22.7%, erythromycin 13.6%,
      tetracycline 11.4%, chloramphenicol 8.3%. Most of the nonsusceptible to
      penicillin isolates belonged to serogroups 23, 9, and 19. Multidrug resistance
      was detected in 11.4% of S. pneumoniae isolates including five penicillin
      nonsusceptible serogroup 23 strains. More than half of the multidrug resistant
      strains were susceptible to penicillin and belonged to serogroups 6 (4), 23 (1),
      19 (1), and 1(1). Strains that belonged to the same serogroup/serotype and had
      identical resistance patterns appeared to cluster in some DCCs. Antibiotic use in
      the previous month was associated with reduced susceptibility to penicillin (p =
      0.007) and multidrug resistance (p = 0.012). In conclusion, a moderate prevalence
      of reduced susceptibility to penicillin in pneumococcal carrier strains was found
      in our community. Multidrug resistance was common and was often associated with
      susceptibility to penicillin. Several distinct patterns of resistance were
      observed, suggesting the spread of resistant clones to our country.

PMID- 10647086
TI  - Characterization of integrons in Escherichia coli of the normal intestinal flora
      of swine.
AB  - Multiresistant Escherichia coli isolates of the normal intestinal flora of
      healthy fattening pigs were examined for the presence of integron class 1 by XL
      (extra long) PCR. The class 1 integron was detected in 17 isolates originating
      from 14 healthy animals on seven different farms. One isolate contained two class
      1 integrons. The inserted gene cassettes were characterized by DNA sequencing and
      PCR. The ant(3")-Ia gene responsible for resistance to streptomycin/spectinomycin
      was inserted in all integrons detected. Fifteen isolates contained this gene
      cassette as the only inserted cassette. Three isolates contained integrons with
      two gene cassettes. Two isolates contained integrons with the trimethoprim
      resistance gene dfr1 and one isolate contained the oxa1 beta-lactamase gene
      upstream to the ant(3")-Ia gene. Detection of these three different resistance
      gene cassettes in bacteria from swine shows that cassettes occurring in integrons
      in human clinical isolates also appear in bacteria of the normal intestinal flora
      of healthy swine. Two integron-harboring strains were obtained from each of three
      different animals. These strains were probably not clonal derivatives of each
      other, suggesting the existence of different multiresistance clones within the
      intestinal normal flora of one specific animal. The oxa1 nucleotide sequence
      found in E. coli from swine differ by seven nucleotides from the oxa1 nucleotide
      sequence of the gene from the R-plasmid RGN238. The fact that these two sequences
      are not identical might indicate that the two genes have evolved separately in
      different surroundings from the common ancestor. Transmissible plasmids of
      approximately 200 kb containing integron class I were detected in eight of the
      isolates when conjugation experiments were performed with E. coli DH5 as
      recipient strain. The transfer frequency ranged from 4x10(-4) to 6x10(-2)
      transconjugants per recipient cell. This study shows that the enteric commensals
      of domestic animals may be considered as a reservoir of integron-containing
      transmissible plasmids and gene cassettes that might be transferable to the
      pathogens of swine and to important zoonotic bacteria associated with the enteric
      flora of swine such as Salmonella typhimurium DT104.

PMID- 10647087
TI  - Antimicrobial susceptibility of equine isolates of Actinobacillus spp. and
      identification of beta-lactamases in some strains.
AB  - A total number of 149 Actinobacillus strains isolated from clinical samples (73
      strains) and from the oral cavity of healthy horses (76 strains) were tested for
      their susceptibility to 17 antimicrobial substances. The antibiograms were
      generally very similar between the various strains and no differences could be
      clearly correlated to either phenotype or source of isolates. However, when
      tested against penicillin, ampicillin, trimethoprim-sulfa, and streptomycin,
      small groups of strains with what appeared to be acquired resistance could be
      identified. Eight of the penicillin-resistant strains were found to produce beta
      lactamase. The beta-lactamases appeared to be bound tightly to the cell wall,
      thereby frustrating further characterization by isoelectric focusing. Plasmids of
      approximately 3 kb were found in four out of seven beta-lactamase-producing
      strains submitted to plasmid analysis.

PMID- 10647088
TI  - Pneumococcal meningitis: current pathophysiologic concepts.

PMID- 10647089
TI  - HPA axis and cytokines dysregulation in schizophrenia: potential implications for
      the antipsychotic treatment.
AB  - The authors discuss literature evidence on the possible dysfunctioning of HPA
      axis and the inflammatory response system (IRS) in schizophrenia in relation to a
      more comprehensive bio-pathogenetic hypothesis of the disorder and to the
      development of specific clinical patterns or 'core' schizophrenic symptoms, like
      those included in the so called negative/depressive dimension. The dysfunctions
      of HPA axis and IRS could be linked to some neurodevelopmental damage in relevant
      brain areas like hippocampus and it could involve mainly the glutamatergic
      pathways (e.g. NMDA receptors). Moreover, these changes could have some
      predictive value for response to typical antipsychotics (specifically for
      negative symptoms and drug resistance) in schizophrenia. Finally, the
      differential activity of typical versus atypical antipsychotic compounds on the
      basic HPA axis and IRS dysregulations in schizophrenia could account, at least
      partly, for the better clinical stabilization achieved in patients treated with
      the latter drugs compared to those receiving conventional neuroleptics.

PMID- 10647090
TI  - Chronic mild unpredictable stress after noradrenergic denervation: attenuation of
      behavioural and biochemical effects of DSP-4 treatment.
AB  - Chronic mild unpredictable stress, which reduces rewarded behaviour in rats, is
      becoming increasingly popular as an animal model of depression. The effect of
      chronic mild stress (applied to animals housed five per cage for 15 days) on
      forced swimming and open field behaviour, and on beta-adrenoceptor binding was
      studied in naive rats and after the denervation of the locus coeruleus
      projections by DSP-4 (50 mg kg(-1)) treatment. In the forced swimming test,
      chronic mild stress reduced the immobility time on the second day of testing in
      both vehicle- and DSP-4-treated rats, indicating rather an antidepressant-like
      effect. This antidepressant-like effect of chronic mild stress in the forced
      swimming test was not present in individually housed rats which suggests that
      this paradigm is sensitive to housing conditions. Stress had no clear effect on
      the open field locomotion in naive animals (but caused a reduction in
      defecations), but completely blocked the DSP-4-induced decrease in the
      exploratory activity. As measured by 3H-dihydroalprenolol binding, DSP-4
      treatment increased the beta-adrenoceptor affinity in the frontal cortex and the
      number of binding sites in the hippocampus and in the cerebral cortex (total
      frontal cortex). Stress had no effect on the beta-adrenoceptor binding in the
      frontal cortex and cerebral cortex, but prevented the increase in affinity caused
      by DSP-4 treatment in the frontal cortex. In the hippocampus, chronic mild stress
      and DSP-4 treatment increased the number of beta-adrenoceptor binding sites.
      Neither chronic mild stress nor DSP-4 treatment had any effect on CCK(B) receptor
      binding in the cerebral cortex and striatum. These results show that chronic mild
      stress applied to group-housed rats can prevent the development of certain
      behavioural and biochemical changes caused by the denervation of the locus
      coeruleus projection areas.

PMID- 10647091
TI  - Dopamine D3 receptor gene polymorphism and response to clozapine in schizophrenic
      Pakastani patients.
AB  - The dopamine D3 receptor (DRD3) appears to play an important role in the
      mediation of antipsychotic drug action. Genetic association of treatment response
      to the atypical antipsychotic drug clozapine with the DRD3 polymorphism Ser9Gly
      was investigated in a sample of 32 schizophrenic patients. We found association
      of treatment response with allele Gly-9 (P=0.0058) and with genotypes consisting
      of Gly-9 (P=0.033) by this pharmacogenetic approach. A combined analysis with two
      previous studies (Shaikh et al., Hum. Genet. 97 (1996) 714-719; Malhotra et al.,
      Mol. Psychiatry 3 (1998) 72-75) further substantiates these results (P=0.0041).

PMID- 10647093
TI  - Rat brain monoamines after acute and chronic myo-inositol treatment.
AB  - Inositol was reported to have effects in depression, panic disorder and OCD, and
      in animal models of depression and anxiety. The present study tested whether
      inositol treatment alters monoamine systems. Brain areas of rats pre-treated with
      acute or chronic inositol were analysed by HPLC for monoamines and their
      metabolites and compared to control animals. Inositol treatment had no
      significant effect on levels of monoamines, their metabolites, or turnover rates
      compared to controls.

PMID- 10647092
TI  - Distribution and characterization of [3H]mesulergine binding in human brain
      postmortem.
AB  - Much interest is currently being directed towards serotonin (5-HT) receptors of
      type 2C (5-HT2C) because of their possible involvement in the control of
      different activities, such as the composition of the cerebrospinal fluid,
      locomotion, feeding, neuronal excitability and anxiety. The limited information
      regarding their distribution in the human brain prompted us to investigate, and
      to characterize the binding of [3H]mesulergine, a HT2C antagonist, in autopsy
      samples from 24 subjects. The results showed that the [3H]mesulergine binding
      represented 95% of the total binding and equilibrium saturation binding
      experiments resulted in a single straight line, consistent with the presence of
      one site only. The area with the highest density of [3H]mesulergine binding was
      the choroid plexus, followed at a significantly lower level by the hippocampus,
      substantia nigra, basal ganglia, amygdala, hypothalamus and prefrontal cortex.
      The pharmacological profile of the [3H]mesulergine binding was consistent with
      that of 5-HT2C receptors, since the most effective displacers were ritanserin,
      mesulergine and mianserine, followed by clozapine, ketanserine and m-CPP, while
      other compounds had a negligible or no effect. These findings, showing a wide
      distribution of [3H]mesulergine binding sites in the human brain, could provide
      anatomical bases for the different functions attributable to 5-HT2C receptors in
      humans.

PMID- 10647094
TI  - Differential changes in brain and platelet 5-HT concentrations after steady-state
      achievement and repeated administration of antidepressant drugs in mice.
AB  - The aim of the study was to compare in male NMRI mice the simultaneous evolution
      of blood serotonin (5-HT) concentrations, which correspond to 99% of platelet 5
      HT content, and 5-HT parameters in the dorsal raphe, caudate nucleus and frontal
      cortex after clomipramine, fluoxetine and moclobemide treatments. After steady
      state concentrations of the three compounds were reached, the 5-HT levels were
      significantly enhanced vs. saline-treated mice in the three brain areas studied.
      Tryptophan (TRP) levels in the three brain areas were significantly increased
      with clomipramine and fluoxetine but not with moclobemide. A significant decrease
      in the metabolite 5-hydroxyindoleacetic acid (5-HIAA) levels was observed only
      with moclobemide. After 14 days of treatment, 5-HT levels in all areas studied
      were found to be enhanced only with moclobemide while TRP and 5-HIAA levels were
      not different under the three drug regimes from those of controls. After 21 days
      of treatment, 5-HT levels were found enhanced only with moclobemide in the nerve
      terminal regions. An important depletion in platelet 5-HT content was observed
      after clomipramine and fluoxetine treatments at day 14 and day 21 and a
      significant increase was observed after moclobemide treatment at day 14 with a
      return to initial values after 21 days. Our results show significantly different
      effects between central and peripheral indices of 5-HT metabolism according to
      time and to the antidepressant assessed: (i) an enhancement of total tissue 5-HT
      levels in the three brain areas studied after steady-state achievement of the 3
      antidepressants, (ii) the return to initial values of brain 5-HT levels after
      repeated administration of the two 5-HT re-uptake inhibitors, consistent with the
      presence of brain adaptative mechanisms, with a concomitant dramatic decrease of
      platelet 5-HT content and (iii) an apparent gradual attenuation of the brain and
      periphery MAOI-A effect induced by moclobemide with 5-HT levels remaining
      elevated only in 5-HT nerve terminal regions.

PMID- 10647095
TI  - Effects of the 5-HT1A receptor agonist ipsapirone on operant self-administration
      of ethanol in the rat.
AB  - Although the serotonin (5-HT)1A receptor agonist ipsapirone reduces ethanol
      intake in a variety of animal models of alcoholism, such effects have only been
      reported in models based on nonoperant behavior (e.g., two-bottle choice
      procedures). It was the aim of the present study to characterize the effects of
      ipsapirone in an operant model of alcohol self-administration. Rats were trained
      during daily 30-min sessions to respond for oral delivery of an ethanol solution
      (10% w/v) or water in a two-lever, fixed-ratio:1, saccharin-fading procedure.
      After establishment of stable responding, ipsapirone (0, 2.5-20 mg/kg,
      intraperitoneal) was tested in combination with different ethanol unit doses (0,
      1.25-20%). Ethanol-reinforced responding was related to the ethanol unit dose in
      an inverted U-shaped manner. Ipsapirone dose-dependently decreased the number of
      ethanol- and water-reinforced lever responses, irrespective of the ethanol unit
      dose, and failed to affect ethanol preference. As there was only a minor
      difference between the minimal effective dose which reduced operant responding
      for ethanol and water (i.e., 10 and 20 mg/kg, respectively), and there was no
      evidence for a drug-induced left- or rightward shift of the ethanol unit dose
      response curve, the effects of ipsapirone are considered to be nonselective. It
      is suggested that the ethanol intake-reducing effects of ipsapirone are not the
      result of a drug-induced interference (either of an attenuating, or potentiating,
      nature) with the positive reinforcing stimulus properties of alcohol.

PMID- 10647096
TI  - Clozapine blocks dopamine, 5-HT2 and 5-HT3 responses in the medial prefrontal
      cortex: an in vivo microiontophoretic study.
AB  - Clozapine is an atypical antipsychotic drug active on both positive and negative
      symptoms of schizophrenia which has a unique serotonergic and dopaminergic
      profile. Given the putative role of the medial prefrontal cortex (mPFC) in
      negative symptoms of schizophrenia, the aim of this study was to assess the
      effects of clozapine on the dopamine- and serotonin-responsive neurons in that
      particular brain structure. D1 and D2 agonists (SKF 38393 and quinpirole) as well
      as 5-HT2 and 5-HT3 agonists (1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane, DOI,
      and phenylbiguanide) were applied by microiontophoresis alone and concurrently
      with clozapine while recording extracellularly mPFC neurons. Dopamine ejections
      inhibited firing activity while D1 and D2 agonists were ineffective. Clozapine
      did not change basal firing by itself, but was able to suppress the inhibition
      produced by dopamine and by the 5-HT2/5-HT3 receptor agonists. It is concluded
      that clozapine at the mPFC level exerts a complex modulatory activity on dopamine
      receptors, that is directly at the dopaminergic receptors and through 5-HT
      receptors on the same neurons.

PMID- 10647097
TI  - Lack of drug interactions between mirtazapine and risperidone in psychiatric
      patients: a pilot study.
AB  - An open-label, non-randomized, pilot study has been performed in inpatients in
      need of treatment with an antipsychotic (risperidone) and an antidepressant
      (mirtazapine) with the objective to preliminarily assess a possible
      pharmacokinetic interaction and the tolerability of this combination. A 1-4-week
      single drug treatment phase (risperidone 1-3 mg bid or mirtazapine 30 mg nocte)
      was followed by a 2-4-week combined drug treatment phase at unchanged doses.
      Twelve patients were enrolled, nine of whom were treated with risperidone in the
      single drug phase. Results of plasma level measurements are available for six
      patients and indicate that adding mirtazapine to risperidone does not alter
      steady-state plasma concentrations of risperidone and its 9-hydroxy metabolite.
      Data from one patient suggest that adding risperidone to mirtazapine does not
      result in clinically relevant changes in plasma concentrations of either
      compound. The combination was well tolerated and no major or relevant adverse
      events were observed. Adding risperidone to mirtazapine probably does not
      necessitate a change of the dosage of either drug, but more extensive
      investigations are needed.

PMID- 10647098
TI  - Differential tissue distribution of the enantiomers of racemic pindolol in the
      rat.
AB  - Racemic pindolol, a beta-adrenoceptor and a 5-HT1A/1B receptor antagonist, has
      been reported to augment and accelerate the clinical efficacy of antidepressants.
      The (S)-enantiomer is more potent than the (R)-enantiomer both at the beta
      adrenergic and at the 5-HT1A/1B receptors. A chiral HPLC column was used for
      determination of tissue concentrations of the enantiomers of pindolol at 90 min
      after 8 mg/kg s.c. of the racemate. The (S)/(R) ratio was found to vary between
      tissues from 1.74 in brain to 0.82 in plasma. The present findings may be
      important for understanding the pharmacodynamic actions of racemic pindolol.

PMID- 10647099
TI  - Effect of flibanserin (BIMT 17), fluoxetine, 8-OH-DPAT and buspirone on serotonin
      synthesis in rat brain.
AB  - In male rats, the effects of the administration of the novel serotonergic agent
      flibanserin on the synthesis of 5-HT were evaluated in the frontal cortex (FC),
      hippocampus (Hip) and brainstem (Br). The selective serotonergic uptake blocker,
      fluoxetine, and two serotonin1A (5-HT1A) agonists, 8-hydroxy-2-(di-n
      propylamino)tetraline (8-OH-DPAT) and buspirone, were used as reference
      compounds. The synthesis of 5-HT was assessed by measuring the accumulation of 5
      hydroxytryptophan (5-HTP) after blockade of aromatic amino acid decarboxylase
      induced by m-hydroxybenzylhydrazine (NSD-1015), at 100 mg/kg i.p., 30 min before
      sacrifice. Flibanserin, 8-OH-DPAT and buspirone were given 15 min before NSD
      1015, while fluoxetine 120 min before NSD-1015. In our experimental conditions, a
      different efficacy, expressed as percentage of maximal inhibition (Max) of 5-HTP
      accumulation, and a different potency, expressed in terms of minimal effective
      dose (MED), were observed in different brain areas with tested compounds.
      Flibanserin (1-32 mg/kg) decreased 5-HT synthesis with preferential activity in
      the FC, compared to the Hip and Br, both in terms of potency (MED=2 mg/kg in FC,
      16 mg/kg in Hip and Br) and efficacy (Max=65% in FC, 44% in Hip and 29% in Br).
      Fluoxetine (1-30 mg/kg) decreased 5-HT synthesis with preferential activity in FC
      than in Hip and Br, only in terms of potency (MED=3 mg/kg in FC, 10 mg/kg in Hip
      and Br), this result being similar to that observed for flibanserin. In contrast,
      it showed greater efficacy both in FC and Hip (Max about 60%), than in Br
      (Max=49%). On the contrary, 8-OH-DPAT (0.3-3 mg/kg) decreased 5-HT synthesis with
      the same potency in all brain regions (MED=3 mg/kg) and showed the greatest
      efficacy in FC than in Hip and Br (Max=56% in FC, 49% in Hip and 40% in Br).
      Furthermore, buspirone (3-30 mg/kg), while inhibiting 5-HTP accumulation in all
      areas with the same efficacy (Max about 30%), seemed to have higher potency in Br
      than in FC and Hip (MED=3 mg/kg in Br, 10 mg/kg in FC and Hip). The results in
      terms of regional differences are discussed.

PMID- 10647100
TI  - Subchronically applied phencyclidine fails to disrupt prepulse inhibition in
      rats.
AB  - To simulate psychosis in rats, the psychotomimetic agent phencyclidine (PCP, 5.0
      mg/kg) was administered either by daily pulsatile injections or by continuous
      delivery with subcutaneously implanted, PCP-loaded controlled release polymers
      for a 5 day period. The acoustic startle response (ASR) and the prepulse
      inhibition (PPI) were then assessed 15 and 60 min as well as 24 h after the PCP
      application was discontinued. An impaired PPI occurred only under the acute
      influence of the last PCP injection, i.e. 15 and 60 min after last PCP treatment
      when it had previously been given in a pulsatile manner but not when it was
      administered continuously. The ASR to unpaired stimuli after PCP was not
      modified. These findings suggest that disruption of PPI occurs only under the
      acute influence of PCP and that PPI deficits are not primarily the consequence of
      structural brain damage which PCP produces.

PMID- 10647101
TI  - Congenital pseudarthrosis of the tibia: Part 1. European Pediatric Orthopaedic
      Society multicenter study of congenital pseudoarthrosis.

PMID- 10647102
TI  - Pathology of bone lesions associated with congenital pseudarthrosis of the leg.
AB  - Congenital pseudarthrosis of the leg remains one of the most controversial
      pediatric entities in terms of etiopathogenesis, pathology, treatment, and
      prognosis. The authors reviewed the pathologic material of 24 patients with
      congenital pseudarthrosis of the leg along with clinical and radiographic data.
      The tibia was affected in 22 patients; in two patients the disease was limited to
      the fibula. Fifteen patients were male and nine were female. Age at surgery
      ranged from 1 to 26 years. Nineteen patients were classified as having dysplastic
      type, one cystic, and four mixed. Clinical evidence of neurofibromatosis type I
      (NF-I) was found in 17 patients. The main histopathologic change observed was the
      growth of a highly cellular, fibromatosis-like tissue. In the dysplastic type,
      such tissue was associated with the periosteum. In the cystic type, a closely
      similar tissue occupied the lytic area. In case classified as of mixed type, the
      coexistence of endosteal/medullary and periosteal involvement by the fibromatosis
      like tissue was observed. In the cystic lesion, evidence of de novo bone
      formation within the lesional tissue was obvious. Overall, the histologic
      features of the cystic lesion were similar to those of osteofibrous dysplasia. In
      the dysplastic type, the proliferation of the fibrovascular tissue was associated
      with active osteoclastic resorption of the cortex, which remodeled into a
      trabecular rather than a compact type of structure. Histologic comparison of the
      pathologic samples of patients with and without NF-I revealed no significant
      differences. The pseudarthrosis gap was continuous with periosteal soft tissues
      and filled by fibrous tissue, fibrocartilage, and hyaline cartilage with features
      of enchondral ossification. The authors suggest that the clinical diversity of
      congenital pseudarthrosis of the leg results from the diverse location of a
      single pathologic process--namely the growth of an abnormal, fibromatosis-like
      tissue either within the periosteum or within the endosteal/marrow tissues. It is
      tempting to suggest that such an "osteofibromatosis" represent a skeletal
      expression of neurofibromatosis, either within the fully expressed syndrome
      (patients with known neurofibromatosis) or as isolated lesion (patients with
      unknown/cryptic neurofibromatosis).

PMID- 10647103
TI  - Congenital pseudarthrosis of the tibia: history, etiology, classification, and
      epidemiologic data.
AB  - Congenital pseudarthrosis of the tibia is a rare disease with a variable history.
      The pseudarthrosis is usually not present at birth (and therefore is not truly
      congenital) but occurs during the first decade of life. Paget in 1891 was the
      first to describe a case. The etiology is unknown. Neurofibromatosis plays a role
      in approximately 50% of patients. In the others, hereditary and mechanical
      factors are debated. Various (morphologic) classification systems have been
      proposed (Andersen, Boyd, Crawford). Because the appearance changes during the
      course of the disease, all classification systems have limited value: the
      determining factor is the stage of the disease at which it was classified.
      Because of the rarity of the disease and the variability of its history, the
      European Pediatric Orthopaedic Society decided to carry out a multicenter study
      on this disease. This paper presents the epidemiologic data on the patients
      involved. Data have been gathered on 340 patients from 13 countries. Two hundred
      patients were male (58.8%), 140 were female (41.2%). The right side was affected
      in 165 patients (48.5%) and the left side in 172 (50.6%); 3 patients had
      bilateral disease. Symptoms of neurofibromatosis were present in 54.7%.
      Histologic examinations in 192 patients showed a nonspecific appearance in 45.3%;
      in 15.6% the ultrastructure resembled fibrous dysplasia, and in 39% there was
      histologic evidence of neurofibromatosis. Most of the lesions were initially
      localized in the middle or distal third of the tibia. In 29% the localization
      changed during the course of the disease.

PMID- 10647104
TI  - Management of congenital pseudarthrosis of the tibia by excision of the
      pseudarthrosis, onlay grafting, and intramedullary nailing.
AB  - Fourteen skeletally immature children with congenital pseudarthrosis of the tibia
      were treated by excision of the pseudarthrosis, double onlay autogenous cortical
      bone grafting, and intramedullary nailing. Union was achieved in 12 patients, and
      no refractures occurred at the site of the original pseudarthrosis. In three
      patients, a fresh pseudarthrosis developed at a different site; these united
      after repeat onlay grafting. Five skeletally mature patients were treated by
      excision of the pseudarthrosis, compression at the site, and limb lengthening by
      callotasis. Union was achieved in three. Gain in tibial length ranged from 6 to
      13 cm, with no significant complications during lengthening. The authors conclude
      that union can be achieved and refractures prevented in a significant proportion
      of skeletally immature children with congenital pseudarthrosis of the tibia by
      excision of the pseudarthrosis, dual onlay bone grafting, and intramedullary
      nailing. Any residual shortening of the limb can be treated at skeletal maturity.

PMID- 10647105
TI  - Absence of congenital prethrombotic disorders in children with Legg-Perthes
      disease.
AB  - Resistance to activated protein C (RPCA) and other congenital prethrombotic
      disorders have been recently reported to be strongly associated with Legg-Perthes
      disease. RPCA and deficiencies of protein C, protein S, and antithrombin III were
      sought in 22 children with Legg-Perthes disease. Detection of the factor V Leiden
      mutation was found in children with RPCA. Twenty-two healthy children paired by
      age and sex served as controls. The prevalence of congenital prethrombotic
      disorders was not found to differ significantly among patients with Legg-Perthes
      disease and among control subjects. Only one patient had RPCA; this patient was
      heterozygous for the factor V Leiden mutation. Twenty patients and all the
      control subjects had entirely normal coagulation results. The authors conclude
      that unless more data become available, RPCA and deficiencies of protein C,
      protein S, and antithrombin III should not be considered associated with Legg
      Perthes disease.

PMID- 10647106
TI  - Combined salter innominate osteotomy with femoral shortening versus other methods
      of treatment for Legg-Calve-Perthes disease.
AB  - The results of treatment of Legg-Calve-Perthes disease in 357 patients at the
      Institute for Orthopaedic Surgery "Banjica," Belgrade, from January 1963 to
      December 1987 with > or = 10 years of follow-up are summarized. The advantages of
      combined Salter innominate osteotomy with femoral shortening, as a one-step
      operation, are emphasized. Male predominance was found in a ratio of 4.75:1, and
      bilateral involvement was present in 21% of the patients. Disease onset was
      usually between ages 4 and 7 years (mean 6.5 years). Catterall criteria for the
      classification of the disease were used; patients in groups I and II were treated
      nonsurgically and those in groups III and IV were treated surgically. Most of the
      surgically treated patients (64.4%) had one or more head risk factors. The most
      frequently used surgical procedure was a Salter innominate osteotomy with or
      without femoral shortening. Assessment of treatment was made by measuring the
      final center-edge angle and by using criteria developed by Catterall, Mose,
      Harrison, and Stulberg. Final functional status of the operated hips was recorded
      as well. The greatest final center-edge angle of 34.27 degrees was found in the
      patients treated with combined Salter innominate osteotomy and femoral
      shortening, showing improvement of 14.98 degrees. Surgical treatment, except for
      revascularization procedures, showed good and fair results in > 90% of patients.
      The range of hip motion was improved in most patients. The earliest weight
      bearing allowance was found in patients who underwent Salter innominate osteotomy
      and femoral shortening; it averaged 3.1 months. The duration of immobilization
      was also the shortest in this group. The average femoral shortening was 1.38 cm
      (range 0.9-1.9 cm). The proposed combined Salter osteotomy with femoral
      shortening is recommended for the treatment of more severe cases of Legg-Calve
      Perthes disease, thus preventing establishment of early secondary hip arthrosis.

PMID- 10647107
TI  - Neuromuscular function and radioanatomical form of the myelomeningocele hip.
AB  - The aim of this study was to describe variants in neuromuscular function and
      radioanatomical form of the myelomeningocele hip based on the level of spinal
      paralysis. For this purpose, 84 hip joints of 44 children with myelomeningocele
      age 1 to 10.75 years were classified into five spinal paralysis groups. Using
      anteroposterior pelvic radiographs, the position of the capital epiphysis,
      represented by the epiphyseal angle, and the position of the greater trochanter
      apophysis, represented by the apophyseal angle, were evaluated. The epiphyseal
      angle of the five paralysis groups showed three categories of average values. The
      thoracic/thoracolumbar group had an average of 0 degree, groups 2 (distal L1/L2)
      and 3 (distal L3/L4) had average values of 5 degrees to 6 degrees, and groups 4
      (distal L5) and 5 (distal S1) had average values of 13 degrees to 14 degrees. The
      average values of the apophyseal angle showed a characteristic curve: the values
      dropped from group 1 (67 degrees) to groups 2 (45 degrees) and 3 (34 degrees) and
      then rose in groups 4 (44 degrees) and 5 (52 degrees). The authors concluded that
      the insufficiency of the hip abductors leads to a reduction of the epiphysis
      angle, and the relative insufficiency of the small glutei compared with the knee
      extensors leads to a reduction of the apophysis angle.

PMID- 10647108
TI  - Distal tibial and fibular epiphyseal fractures in children: prognostic criteria
      and long-term results in 158 patients.
AB  - From 1974 to 1993, 158 injuries of the ankle joint were treated at the Department
      of Orthopedics and Traumatology of Santobono Children's Hospital. One hundred
      thirty-two patients were treated conservatively; 26 patients underwent surgical
      treatment. Fibular fractures of the malleolus without epiphyseal separation or
      dislocation (68 patients) were excluded from this review. Of the 158 patients,
      113 (70%) were available for follow-up. The mean age of patients was 11 years.
      The mean follow-up was 6 years (range 3-15 years). In this review, the authors
      compare, based on the degree of epiphyseal separation or dislocation, the
      Carothers-Crenshaw classification, which is based on the mechanism of trauma,
      with the Salter-Harris classification, which is based on anatomical-radiographic
      criteria. The aim is to review the authors' patients based on these
      classifications, to verify the prognostic ability of these criteria and thus to
      establish a better and more viable treatment for these injuries. Therefore, two
      fundamental factors should be considered for the prognosis: the mechanism of
      trauma and damage to the epiphyseal plate. Compressive trauma and adduction
      supination trauma are the most dangerous types of injury, and any damage or gap
      in the physis should be perfectly reduced, by open means if necessary, to prevent
      a bone bridge from forming.

PMID- 10647110
TI  - Idiopathic toe-walking: does treatment alter the natural history?
AB  - Outcomes from observation or cast or surgical treatment of idiopathic toe-walking
      were determined in 136 children. With patient-determined outcomes, for the
      observation group, gait was normal in 6%, improved in 45%, and unchanged in 49%.
      Physician-determined outcomes demonstrated normal gait in 12% of children.
      Outcomes were similar in the cast group. With patient-determined outcomes in the
      surgical group, 22% walked normally, 50% had improved, 26% were unchanged, and 2%
      had deteriorated; with physician-determined outcomes, 37% walked normally. The
      natural history, determined from the observation group, was for idiopathic toe
      walking to persist, albeit with improvement in 50%. Cast treatment did not alter
      the natural history. Surgical treatment may influence the outcome, but
      indications for surgery need to be clarified.

PMID- 10647109
TI  - Anterior interosseous nerve palsy associated with Galeazzi fracture.
AB  - Galeazzi fracture is more common in adults than in children. Associated
      neurologic deficits are rare and easily missed at the first clinical examination.
      The authors describe a case of anterior interosseous nerve palsy after closed
      Galeazzi fracture. Conservative treatment resulted in complete return of normal
      nerve function, suggesting that this is a neurapraxia type of injury.

PMID- 10647111
TI  - Avascular necrosis of the talus after Dennyson-Fulford subtalar arthrodesis.
AB  - The authors report avascular necrosis of the talus, after a Dennyson-Fulford
      subtalar arthrodesis. Vascular and neuropathic causes are discussed.

PMID- 10647112
TI  - Cytogenetic studies in patients with hemophilic hemarthrosis treated by 198Au,
      186Rh, and 90Y radioactive synoviorthesis.
AB  - This study assesses chromosomal structural changes (CSCs) studied by conventional
      lymphocyte cultures and banding techniques in 79 hemophilic patients with
      hemarthrosis treated with radioactive synoviorthesis, 31 hemophilic patients with
      hemarthrosis not treated by this procedure, and 110 nonhemophilic patients
      matched by age and sex (control group). In 14 patients treated with 198Au (group
      A), premalignant CSCs and nonspecific CSCs were found, respectively, in 1.69% and
      17.23% of metaphases. The former disappeared, but 1.7% of the nonspecific changes
      persisted 2 years after injection. In 31 patients treated with 186Rh (group B),
      CSCs were not found previous to radioactive synoviorthesis but were present as
      nonspecific changes in 1.25% of metaphases 6 months later; they disappeared 1
      year after injection. In 34 patients treated with 90Y (group C), CSCs were not
      found previous to radioactive synoviorthesis but were present as nonspecific
      changes in 0.89% of metaphases 6 months later; they disappeared 1 year after
      injection. Only nonspecific CSCs were found in 0.79% of metaphases in patients
      not treated with radioactive synoviorthesis (group D). CSCs were not present in
      control subjects. The authors conclude that in some hemophilic patients with
      hemarthosis treated with radioactive synoviorthesis using 198Au, 186Rh, or 90Y,
      reversible premalignant or nonspecific CSCs could be present; nonspecific CSCs
      may persist in a low proportion of metaphases up to 2 years after injection when
      198Au is used as the radioactive agent. Radioactive synoviorthesis seems to be
      from a cytogenetic point of view a safe alternative for these patients.

PMID- 10647113
TI  - Vertebral collapse and normal peripheral blood cell count at the onset of acute
      lymphatic leukemia in childhood.
AB  - Acute lymphatic leukemia presenting with bone pain and spine involvement is a
      recognized clinicopathologic complex that can mimic a wide range of orthopaedic
      conditions. Bone pain as the presenting complaint is common, with a reported
      incidence of 27% to 50%. Radiologic abnormalities associated with leukemia in
      children has been described previously. In the literature, the incidence of
      spinal involvement is controversial, but there is agreement that the spine is
      less commonly involved than are the long bones. At the onset of the disease, only
      10% of children have normal peripheral blood counts. If the patient has spinal
      involvement and a normal leukocyte count, the diagnosis is often unclear. Only
      three of these patients have been described in the literature; this article adds
      one more patient with acute lymphatic leukemia with back pain as the main
      symptom, vertebral collapse, and a normal peripheral blood cell count at the time
      of initial presentation. It illustrates that delay in diagnosis frequently
      occurs, with the classic features of the disease being uniformly absent.

PMID- 10647114
TI  - Orthopaedic manifestations of mucolipidosis III: an illustrative case.
AB  - The musculoskeletal manifestations of mucolipidosis III include short stature,
      claw hands, carpal tunnel syndrome, and limited joint mobility. This article
      presents a series of complex orthopaedic problems, including avascular necrosis
      of the talus, encountered in one such patient whose presentation had initially
      given the impression of a mild form of the disease.

PMID- 10647115
TI  - Long-term follow-up of conservatively treated popliteal cysts in children.
AB  - This study was undertaken to determine the long-term outcome of conservatively
      treated popliteal cysts in children. It was based on a review of 20 cysts, none
      of which were initially treated surgically. The records of children with
      popliteal cysts between 1986 and 1992 were studied, and a group of patients
      without other diseases or other physical abnormality in the knee region was
      selected. Twenty-one patients were included and were subjected to a clinical and
      ultrasound investigation. Three were lost to follow-up, leaving 18 patients with
      20 cysts available for analysis. In the follow-up period, which ranged from 5 to
      10 years, 14 cysts were treated conservatively with a mean follow-up of 7 years,
      whereas 6 cysts were operated on after a mean period of 2 years. Of the
      conservatively treated cysts, eight had disappeared and six had shrunk. Although
      spontaneous remission is not to be expected in all cases, asymptomatic popliteal
      cysts in children can be treated conservatively with good results.

PMID- 10647116
TI  - Slipped capital femoral epiphysis.

PMID- 10647117
TI  - The future of pediatric education II. Organizing pediatric education to meet the
      needs of infants, children, adolescents, and young adults in the 21st century. A
      collaborative project of the pediatric community. Task Force on the Future of
      Pediatric Education.

PMID- 10647118
TI  - Antioxidant systems in the pathogenic fungi of man and their role in virulence.
AB  - In the last two decades, a variety of fungal antioxidants have attracted
      considerable interest, largely arising from their hypothetical role as virulence
      determinants. Melanin is a potent free radical scavenger and in Cryptococcus
      neoformans, there is now good evidence that the production of melanin is a
      significant virulence determinant. There is also recent evidence linking melanin
      biosynthesis to the virulence of Aspergillus fumigatus conidia. Superoxide
      dismutases are important housekeeping antioxidants and have an additional
      hypothetical role in virulence; however, although these enzymes have been
      biochemically characterized from Aspergillus and Cryptococcus, there is as yet no
      firm evidence that these enzymes are involved in pathogenicity. Catalase
      production may play some role in the virulence of Candida albicans but this
      enzyme has not been shown, as yet, to influence the virulence of A. fumigatus.
      There are some data supporting an antioxidant function for the acyclic hexitol
      mannitol in C. neoformans, but further investigations are required in this area.
      Research into the putative antioxidant activities of a range of other fungal
      enzymes, such as acid phosphatases, remains limited at this time.

PMID- 10647119
TI  - D-arabinitol--a marker for invasive candidiasis.
AB  - The five-carbon sugar alcohol D-arabinitol (DA) is a metabolite of most
      pathogenic Candida species, in vitro as well as in vivo, and can be determined by
      gas chromatography or enzymatic analysis. Endogenous DA and L-arabinitol (LA) are
      present in human body fluids, and serum DA and LA increase in renal dysfunction.
      In prospective clinical studies, elevated DA/LA or DA/creatine ratios in serum or
      urine have been found in immunocompromised, usually neutropenic, patients with
      invasive candidiasis. In addition, positive DA results have been obtained several
      days to weeks before positive blood cultures, and the normalization of DA levels
      has been correlated with therapeutic response in both humans and animals.
      However, to date, only a few prospective studies have been conducted in which
      adequate analytical methods were used. Thus, further investigation of various
      patient groups is needed to establish the applicability of the 'arabinitol
      method' in the diagnostic battery for invasive Candida infections.

PMID- 10647120
TI  - Involvement of CD4+ T cells and macrophages in acquired protection against
      infection with Sporothrix schenckii in mice.
AB  - The cell-mediated immune response against infection with Sporothrix schenckii was
      investigated in vivo and in vitro. Following primary infection, mice were
      protected against a secondary subcutaneous inoculation with S. schenckii as
      determined by the local growth of fungi, and subcutaneously immunized mice were
      able to survive a lethal intravenous infection. Protection could be transferred
      to naive congenitally athymic nude mice using lymph node cells taken from immune
      mice. When immune lymph node cells had CD4+ cells depleted by antibody plus
      complement, the ability to transfer protection was significantly reduced.
      Treatment of mice with carrageenan, a macrophage blocker, before and after
      secondary inoculation abolished protection. An in vitro system, using either
      immune lymph node cells alone or macrophages alone, failed to kill the organism.
      However, inhibition of fungal growth was observed when both immune lymph node
      cells and macrophages were combined. Growth inhibition in vitro was reduced after
      depletion of CD4+ cells but not CD8+ cells. Addition of anti-interferon (IFN)
      gamma monoclonal antibodies (MAb) also reduced growth inhibition. By using
      reverse transcription-polymerase chain reaction (RT-PCR) analysis, it was shown
      that immune lymph node cells expressed message for IFN-gamma, tumour necrosis
      factor (TNF)-alpha and interleukin (IL)-10 after stimulation with heat-killed S.
      schenckii. These results suggest that acquired immunity against S. schenckii is
      expressed mainly by macrophages activated by CD4+ T cells.

PMID- 10647121
TI  - In vitro susceptibility of chromoblastomycosis and phaeohyphomycosis agents to
      antifungal drugs.
AB  - The in vitro susceptibility of chromoblastomycosis and phaeohyphomycosis agents
      to antifungal drugs was appraised using the reference macrodilution method
      proposed by the National Committee for Clinical Laboratory Standards (NCCLS) for
      yeasts modified for filamentous fungi. The antifungal drugs amphotericin B, 5
      fluorocytosine, itraconazole and fluconazole were tested against one
      environmental and 18 clinical isolates. This work amended the macrodilution
      methods proposed by NCCLS and suggests that a conidial suspension free of hyphae
      leads to a more reliable assay and provides for better reproducibility. The
      macrodilution method was performed with 10(4) conidia ml-1. The MIC values ranged
      from 1.0 to 16.0 micrograms ml-1 for amphotericin B and 3.12 to 25.0 micrograms
      ml-1 for 5-fluorocytosine. A MIC range of 0.06 to 1.95 micrograms ml-1 was
      determined for itraconazole while 2.0 to 64.0 micrograms ml-1 was detected for
      fluconazole.

PMID- 10647122
TI  - Characterization of a double gene disruption in the LYS2 locus of the pathogenic
      yeast, Candida albicans.
AB  - The 4.2 kbp LYS2 gene of Candida albicans encodes the 150 kDa subunit of the 180
      kDa heterodimeric enzyme alpha-aminoadipate reductase. To facilitate structural
      and functional studies of the LYS2 gene, in this investigation both alleles were
      sequentially disrupted in C. albicans CAI4. The disruptions were performed using
      a targeting vector that contained a 2.2 kbp portion of LYS2 from which a 600-bp
      fragment had been deleted and replaced with a hisG-URA3-hisG cassette. Disruption
      of both alleles of the LYS2 locus was confirmed by Southern hybridization with
      appropriate probes. To determine the physiological effect of the LYS2 disruption,
      cell extracts were assayed for the LYS2-encoded alpha-aminoadipate reductase
      activity. The parent, heterozygote and LYS2-disrupted strains exhibited
      significant, partial and no activity, respectively. Transformation of the LYS2
      disrupted strain with the LYS2 gene reversed the mutant phenotype as shown by
      growth on selective media and restored alpha-aminoadipate reductase activity.
      These results demonstrated that the LYS2 gene of C. albicans is responsible for
      the synthesis of functional alpha-aminoadipate reductase.

PMID- 10647123
TI  - Increased susceptibility to systemic candidiasis in interleukin-6 deficient mice.
AB  - Interleukin-6 (IL-6) is a multifunctional cytokine that regulates multiple
      aspects of the innate immune response. It has been recently shown that endogenous
      IL-6 is crucial for an efficient defence against severe infections with Gram
      negative and Gram-positive bacteria. The aim of the present study was to
      investigate the role of endogenous IL-6 in the defence against infection with the
      yeast Candida albicans. During experimental candidemia, IL-6 deficient mice (IL-6
      /-) had a decreased survival and an increased fungal load in their organs when
      compared with IL-6+/+ controls, despite increased plasma concentrations of tumour
      necrosis factor-alpha (TNF), interleukin-1 alpha (IL-1 alpha) and IL-1 beta, IL-6
      /- mice were not able to mount an efficient neutrophil response during the
      infection. When mice were rendered neutropenic by cyclophosphamide, neutropenic
      IL-6-/- mice were equally susceptible to C. albicans when compared to neutropenic
      IL-6+/+ mice, implying that neutrophils mediate the beneficial effect of
      endogenous IL-6. In conclusion, IL-6-/- mice are more susceptible to disseminated
      candidiasis, and the effect of IL-6 is most likely mediated by neutrophils.

PMID- 10647124
TI  - A description of cutaneous-subcutaneous pythiosis in fifteen dogs.
AB  - Information regarding signalment, duration of clinical signs, history of
      swimming, results of CBC and serum biochemical analyses, biopsy findings and
      mycological results, together with treatments and outcome, was retrieved from the
      medical records of 15 dogs with a diagnosis of pythiosis made between 1985 and
      1995 at the Colleges of Veterinary Medicine, North Carolina State University and
      the University of Florida. Most of the dogs were young (median age 22 months) and
      represented larger breeds (> 20 kg). Lesions were characteristically chronic,
      ulcerated, and nodular with multiple draining tracts on the limbs, thoracic wall
      or perineal regions. The median duration of these lesions was 3 months with a
      range of 2 weeks-6 months. Seven dogs had a history of swimming. Peripheral
      eosinophilia was observed in 14 of the dogs. Cytological evaluation of discharge,
      aspirates, or impression smears made from biopsy specimens revealed hyphae in
      five of 11 dogs (45%). Histopathological evaluation using the Gomori Methenamine
      Silver (GMS) stain was the most useful test for providing presumptive evidence of
      cutaneous pythiosis. Immunotherapy or antifungal therapy using either
      amphotericin B, liposomal nystatin, itraconazole, or ketoconazole were all
      unsuccessful. The only dog to survive underwent amputation of the affected limb;
      thus, the prognosis for cutaneous pythiosis in the dog is poor.

PMID- 10647125
TI  - Molecular epidemiology of Fonsecaea pedrosoi using mitochondrial DNA analysis.
AB  - Restriction fragment length polymorphism (RFLP) of mitochondrial DNA (mtDNA) from
      49 clinical Fonsecaea pedrosoi isolates (18 isolates from Japan, 17 from
      Madagascar, 7 from Argentina, 5 from Venezuela, 1 from Costa Rica and 1 unknown)
      was studied. The 49 isolates were composed of 20 isolates of Type 1, 16 of Type
      2, 12 of Type 4 and 1 of a new mtDNA type, Type 7, which was closely related to
      Type 2. On the bases of the results of 120 isolates of the present (49 isolates)
      and previous (71 isolates) studies, F. pedrosoi was classified into seven mtDNA
      types and according to the relationship between mtDNA types and geographic
      origins: in Japan and probably in China, Type 1 isolates; in Zaire and
      Madagascar, Type 2; in Central and South America, Type 4 and Type 1. These
      results indicated that the geographical origin of F. pedrosoi isolate could be
      roughly inferred from its mtDNA type.

PMID- 10647126
TI  - Evaluation of the susceptibility of Coccidioides immitis to lufenuron, a chitin
      synthase inhibitor.
AB  - The activity of the chitin synthase inhibitor lufenuron was evaluated in vitro
      using the spherule-endospore (SE) phase of Coccidioides immitis. The lufenuron
      was also used to treat mice infected with C. immitis by the respiratory route. In
      vitro, lufenuron had no effect upon fungal cell growth. Two formulations of
      lufenuron were evaluated in vivo. Neither the oral nor the injectable lufenuron
      extended the survival of mice infected with C. immitis when compared with placebo
      treated mice.

PMID- 10647127
TI  - Analysis of the enzymatic activity of mycelial and yeast phases of Penicillium
      marneffei.
AB  - The cell-associated and extracellular enzymatic activities were examined in a
      total of 10 Penicillium marneffei isolates. Both mycelia and yeast expressed
      alkaline phosphatase, acid phosphatase and naphthol-AS-BI-phosphohydrolase
      activities, whereas a variety of other enzyme activities, including trypsin,
      chymotrypsin and alpha-fucosidase were absent. There was some inter-isolate
      variation in both mycelia and yeast in the activities of other enzymes such as
      esterases and galactosidases. Enzyme activities did not change significantly over
      the course of culturing in three representative isolates.

PMID- 10647128
TI  - The immune system versus cancer: can the immune system win? IBC's 4th
      International Conference on Immunotherapy for Cancer, Coronado, CA, USA, 16-17
      August 1999.

PMID- 10647129
TI  - UFD1L is not the monogenic basis for heart defects associated with the CATCH
      phenotype.

PMID- 10647130
TI  - Patients' responsibility for their suicidal behavior.

PMID- 10647131
TI  - The human factor in mergers and acquisitions: a personal story.

PMID- 10647133
TI  - Association between week of the month and hospitalization for substance abuse.

PMID- 10647132
TI  - Two case studies of cognitive adaptation training for outpatients with
      schizophrenia.

PMID- 10647134
TI  - Highlights of the 1999 Institute on Psychiatric Services. Integrating research
      advances with clinical wisdom.

PMID- 10647135
TI  - The last half-century of psychiatric services as reflected in psychiatric
      services.
AB  - The last half-century of psychiatric services in the United States is examined
      through developments and trends reported in the 50 years of publication of
      Psychiatric Services. The journal, earlier named Mental Hospitals and then
      Hospital and Community Psychiatry, was launched by the American Psychiatric
      Association in January 1950 and marks its 50th anniversary this year. The author
      organizes his review of psychiatric services largely around the locus of care and
      treatment because the location of treatment--institution versus community--has
      been the battleground for the ideology of care and for the crystallization of
      policy and legal reform. He uses "dehospitalization" to describe the movement of
      patients out of state hospitals, rejecting the widely used term
      "deinstitutionalization" as inappropriate; one reason is that the term wrongly
      implies that many settings where patients ended up were not institutional. Also
      covered in detail, as reflected in the journal, are community care and treatment,
      economics, patient empowerment, and the interface issues of general hospitals,
      outpatient commitment, and psychosocial rehabilitation. The author notes that
      some concepts, such as outpatient commitment and patient empowerment, emerged
      earlier than now assumed, and that others, like psychosocial rehabilitation,
      recurred in slightly different forms over time. He concludes that even after 50
      years of moving patients out of state hospitals and putting them somewhere else,
      mental health policymakers and practitioners remain too myopically focused on the
      locus of care and treatment instead of on the humaneness, effectiveness, and
      quality of care.

PMID- 10647136
TI  - Overcoming social amnesia: the role for a social perspective in psychiatric
      research and practice.
AB  - Psychiatry's reliance on biological models has resulted increasingly in the
      social realm's being dismissed or trivialized. The author examines the adverse
      consequences of this situation for psychiatric research and practice and suggests
      methods for addressing the problem. He describes how the social perspective has
      been extruded from discussions about the definition, future, and accomplishments
      of psychiatry, and he reviews four areas in which the biological model has
      produced unvalidated assumptions about the etiology, course, and prevention of
      mental disorders. The author shows how the social realm is intrinsic to concepts
      of mind and mental illness, and he describes seven ways in which a social
      perspective can provide a complement or a corrective to the prevailing
      assumptions of biological models, indicate new points of departure, and suggest
      methods for psychiatry's expansion.

PMID- 10647137
TI  - Characteristics of participants and nonparticipants in medication trials for
      treatment of schizophrenia.
AB  - OBJECTIVE: The study compared the characteristics of patients who participated in
      efficacy trials of medications for treatment of schizophrenia with those of the
      other patients in the clinical population from which the trial participants had
      been selected. METHODS: Study participants from ten trials of treatment efficacy
      conducted at a community mental health center in the early and mid-1990s were
      compared with nonparticipants using data on demographic and diagnostic
      characteristics and service utilization from the center's administrative
      database. Six of the trials selected patients with schizophrenia and no
      concurrent substance use disorder, and four selected patients with dual diagnoses
      of schizophrenia and a substance use disorder. RESULTS: Compared with
      nonparticipants, participants in both types of trial were about six to eight
      years younger, were two to four times less likely to have ever married, and used
      more services. Participants in trials that selected patients with no substance
      use disorder were more likely to be high school graduates and were four times
      more likely to work full time, compared with nonparticipants. Participants in
      trials that selected patients with dual diagnoses were likely to be minorities
      and less likely to have medical comorbidities, compared with nonparticipants.
      CONCLUSIONS: Participants in treatment efficacy trials differed substantially
      from nonparticipants. Some characteristics of the trial participants, including
      reduced likelihood of ever having been married and male gender, have been
      associated with poorer treatment outcomes in earlier studies. Other
      characteristics, such as younger age and greater likelihood of having graduated
      from high school and of working full time, have been associated with better
      outcomes.

PMID- 10647138
TI  - Routine outcome monitoring in a public mental health system: the impact of
      patients who leave care.
AB  - OBJECTIVE: An interest exists in using patient outcome data to evaluate the
      performance of publicly financed mental health organizations. Because patients
      leave these organizations at a high rate, the impact of patient attrition on
      routinely collected outcome data was examined. METHODS: In one county mental
      health system, routinely collected data on a wide range of outcomes were
      examined, and a random sample of patients who left treatment was interviewed.
      RESULTS: Of the 1,769 patients in ongoing treatment during a one-year period, 554
      (31 percent) were lost to follow-up. Among a random sample of 102 patients who
      left treatment, two had died and 47 were interviewed. Compared with patients who
      left treatment, patients who stayed were older, more likely to have
      schizophrenia, less likely to be married, more likely to be living in an
      institution, more satisfied with their relationships with friends and family, and
      less likely to have legal problems. Average outcomes improved both for patients
      who stayed and for patients who left. Patients who left and could be located for
      follow-up were less severely ill and showed the greatest improvement and the best
      outcomes. Patients who left and could not be located may have been more severely
      ill at baseline. CONCLUSIONS: Outcomes appear to vary substantially by whether
      patients stay in care and whether they can be located after leaving care. Public
      mental health systems that wish to evaluate treatment quality using outcome data
      should attend carefully to which patients are being assessed. Biases can result
      from convenience sampling and from patients leaving care.

PMID- 10647139
TI  - Utilization and outcome in an overnight psychiatric observation program at a
      Veterans Affairs Medical Center.
AB  - OBJECTIVE: The effectiveness of an overnight psychiatric observation program was
      evaluated. The program was designed to avoid unnecessary hospitalization of
      patients experiencing acute psychiatric crises. METHODS: Of 110 patients admitted
      to the observation unit at a Veterans Affairs medical center over a six-month
      period in 1996, the charts of 92 patients were retrospectively reviewed.
      Characteristics of patients referred to the program were documented, inpatient
      hospitalization rates and suicide rates in the six-month periods before and after
      admission to the observation unit were examined, and variables related to the
      need for hospitalization immediately after observation were explored. RESULTS:
      Most of the 92 patients (98 percent) were referred from the medical center's
      emergency room. At the time of observation, 80 percent of the patients were
      unemployed, 55 percent expressed suicidal or homicidal ideation, 49 percent were
      intoxicated or at risk for alcohol withdrawal, and 41 percent were homeless. The
      most frequent psychiatric diagnosis was substance abuse or dependence (77
      percent). The large majority of patients (88 percent) were referred the next day
      to other outpatient programs for follow-up and treatment, which avoided costly
      inpatient treatment. In the six months before admission to the observation
      program, the mean number of inpatient psychiatric bed days was 9.8, compared with
      2.7 days in the six-month period after discharge from the observation program. No
      increase in suicide gestures or attempts was noted among the patients. No
      variables significantly predicted admission to inpatient care after the
      observation period. CONCLUSIONS: Overnight observation programs may provide a
      cost-effective alternative to traditional inpatient treatment for some
      individuals with psychiatric disorders.

PMID- 10647140
TI  - Gambling behavior of Louisiana students in grades 6 through 12.
AB  - OBJECTIVES: The prevalence of problem and gambling behavior, the average age of
      onset of gambling behavior, and the co-occurrence of gambling disorder with
      substance use were determined in the Louisiana student population grades 6
      through 12. METHODS: A stratified randomized sample of 12,066 students in
      Louisiana schools during the 1996-1997 school year was surveyed about gambling
      behavior using the South Oaks Gambling Screen--Revised for Adolescents (SOGS-RA).
      RESULTS: Fourteen percent of the students never gambled, 70.1 percent gambled
      without problems, 10.1 percent indicated problem gambling in the past year (level
      2 according to the SOGS-RA), and 5.8 percent indicated pathological gambling
      behavior in the past year (level 3). Weekly or more frequent lottery play was
      reported by 16.5 percent. The average age of onset of gambling behavior was 11.2
      years. Fifty-nine percent of the students with problem and pathological gambling
      behavior reported frequent alcohol and illicit drug use. CONCLUSIONS: A
      significant minority of Louisiana students in grades 6 through 12-15.9 percent-
      acknowledged gambling-related symptoms and life problems. The association of
      problem and pathological gambling with use of alcohol, tobacco, and marijuana
      provides preliminary support for the inclusion of gambling among other adolescent
      risk behaviors.

PMID- 10647141
TI  - Similarities and differences in homelessness in Amsterdam and New York City.
AB  - Differences and similarities in homelessness in Amsterdam and New York City were
      examined, particularly in regard to persons most at risk for homelessness--those
      with mental illness and with substance abuse problems. The Netherlands is a
      welfare state where rents are controlled by the national government and more than
      half of the housing is public housing. Virtually all homeless people in Amsterdam
      are unemployed and receive some sort of social security benefit. Direct
      comparisons of the results of American and Dutch studies on homelessness are
      impossible, mainly because the estimates are uncertain. Because of the Dutch
      welfare system, Amsterdam has a smaller proportion of homeless people than New
      York City, although more people are homeless in Amsterdam today than 15 years
      ago. Neither a lack of affordable housing or sufficient income nor unemployment
      has been a direct cause of the increase of homelessness. As in New York City,
      many of the homeless in Amsterdam are mentally ill or have substance use
      disorders. The increase in the number of homeless people in Amsterdam consists
      largely of mentally ill people who would have been admitted to a mental hospital
      20 years ago and of older, long-term heroin abusers who can no longer live
      independently. Thus institutional factors such as fragmentation of services and
      lack of community programs for difficult-to-serve people are a likely explanation
      of the growing number of homeless people in Amsterdam.

PMID- 10647142
TI  - Pregnancy of the early-career psychiatrist.
AB  - OBJECTIVE: Since the 1970s the number of women physicians has steadily increased
      and is expected to continue to climb into the next century. Psychiatry is a
      medical specialty that has been successful in attracting women. As more young
      women enter psychiatry, more colleagues will be pregnant in the workplace. This
      paper explores some of the practical issues that pregnancy poses for the early
      career psychiatrist, her colleagues, and her patients. METHODS: A MEDLINE search
      was conducted. Literature on the pregnant physician, the pregnant therapist, and
      the pregnant resident was reviewed. Recommendations found in these resources were
      combined with the author's observations to create a single resource paper that
      outlines common problems and practical strategies for the psychiatrist who is
      pregnant. RESULTS: The integration of the psychiatrist's maternal identity with
      her professional identity is a task that often begins during pregnancy. The fear
      of abandonment is a common theme for patients under her care. Relationships with
      colleagues are sometimes strained. The medical workplace has been slow to
      accommodate the needs of women, who make up a growing percentage of professional
      employees. CONCLUSIONS: The reproductive years and the early years of practice
      overlap for a growing number of women in psychiatry. The life experience of
      motherhood can be an important part of one's growth as a psychiatrist.
      Relationships with coworkers and patients can be eased if potential problems are
      recognized and dealt with early on. Employers and medical organizations are
      challenged to make an investment in women professionals through the development
      of family-oriented policies.

PMID- 10647143
TI  - Assaults on staff by psychiatric patients in community residences.
AB  - The study examined assaultive behavior directed toward staff of community-based
      residential facilities by patients who had been discharged to these facilities
      from Massachusetts state psychiatric hospitals in the early 1990s. Observed rates
      of assault declined by 61 percent over a six-and-a-half-year period. Early in the
      study period, male patients were more likely than female patients to be
      assaultive, but men and women had similar rates of assaultiveness later in the
      study period, after they had been in residential placements for several years.
      The most common diagnosis among assaultive patients was schizophrenia.

PMID- 10647144
TI  - Patterns of substance use among patients in an urban psychiatric emergency
      service.
AB  - Data from patients visiting an urban psychiatric emergency service in California
      were examined to document incidence and patterns of substance use and ethnic
      differences among users. A total of 392 patients were randomly assigned to
      receive a drug screen (N = 198) or to receive usual care (N = 194). Forty-four
      percent of the mandatorily screened patients had positive screens for any
      substances: 37 percent were positive for any drugs, and 7 percent were positive
      for alcohol only. Cocaine was present in 62 percent of the drug-positive screens.
      Blacks were two and a half times more likely than whites to have positive screens
      for drugs and five times more likely to have positive screens for cocaine.

PMID- 10647145
TI  - Correlates of improvement in quality of life among homeless persons with serious
      mental illness.
AB  - Longitudinal data from 4,331 homeless mentally ill clients at 18 sites
      participating in the Access to Community Care and Effective Services and Supports
      program were used to assess participants' quality of life over a one-year period.
      At baseline higher quality of life was associated with less severe depressive and
      psychotic symptoms, less use of alcohol and drugs, and more social support. At 12
      months improved quality of life was associated with decreased psychotic and
      depressive symptoms, reduced substance abuse, fewer days of homelessness, and
      increased social support, income, employment, and service use.

PMID- 10647146
TI  - Legislation extending Medicaid, Medicare coverage to disabled people who work
      wins approval in congress.

PMID- 10647147
TI  - Research funds for mental illness and substance abuse are increased by 14
      percent.

PMID- 10647148
TI  - Computer validation in toxicology: historical review for FDA and EPA good
      laboratory practice.
AB  - The application of computer validation principles to Good Laboratory Practice is
      a fairly recent phenomenon. As automated data collection systems have become more
      common in toxicology facilities, the U.S. Food and Drug Administration and the
      U.S. Environmental Protection Agency have begun to focus inspections in this
      area. This historical review documents the development of regulatory guidance on
      computer validation in toxicology over the past several decades. An overview of
      the components of a computer life cycle is presented, including the development
      of systems descriptions, validation plans, validation testing, system
      maintenance, SOPs, change control, security considerations, and system
      retirement. Examples are provided for implementation of computer validation
      principles on laboratory computer systems in a toxicology facility.

PMID- 10647149
TI  - Using benchmarking to improve organizational communication.
AB  - Best practice refers to those practices that lead to superior performance in a
      company or enterprise relative to industry or international leaders. Benchmarking
      of those activities that are critical to organizational performance is an
      important part of the identification and implementation of best-practice
      approaches. This article looks at communication as one aspect in the development
      of best practice in the management of safety, environment, and quality. A number
      of barriers to effective communication are identified, and benchmarks for the
      evaluation of organizational communication are suggested.

PMID- 10647150
TI  - Assessment of uncertainty in mechanical testing of dental materials.
AB  - A generally valid and commonly accepted model for assessing the reliability of
      measurements in the field of medical and dental materials is hard to establish.
      The results obtained in different laboratories sometimes are difficult to
      compare. We therefore discuss different assessors of the quality of measurements
      from both conceptual and operational perspectives. Especially addressed are the
      customary terms accuracy, error and uncertainty, these terms that often are mixed
      rather confusingly in expressing the quality of experiments. The aim of this work
      is to present the advantages of choosing uncertainty rather than error as the
      appropriate assessor of the reliability of measurements. The transverse
      deflection testing of four denture-base acrylic resins served as an experimental
      basis for the analysis.

PMID- 10647151
TI  - Auditing of chromatographic data.
AB  - During a data audit, it is important to ensure that there is clear documentation
      and an audit trail. The Quality Assurance Unit should review all areas, including
      the laboratory, during the conduct of the sample analyses. The analytical
      methodology that is developed should be documented prior to sample analyses. This
      is an important document for the auditor, as it is the instrumental piece used by
      the laboratory personnel to maintain integrity throughout the process. It is
      expected that this document will give insight into the sample analysis, run
      controls, run sequencing, instrument parameters, and acceptance criteria for the
      samples. The sample analysis and all supporting documentation should be audited
      in conjunction with this written analytical method and any supporting Standard
      Operating Procedures to ensure the quality and integrity of the data.

PMID- 10647152
TI  - The missing piece: embracing shared decision making to reform health care.

PMID- 10647153
TI  - The fine connective tissue architecture of the human ligamentum nuchae.
AB  - STUDY DESIGN: An anatomic study of the posterior midline structures of the
      cervical spine was performed using a new sheet-plastination (E12) technique in
      conjunction with gross anatomic dissection. OBJECTIVES: To clarify the structural
      status of the human ligamentum nuchae. SUMMARY OF BACKGROUND DATA: Little is
      known about the arrangement of connective tissue attachments of the neighboring
      neck muscles to the ligamentum nuchae. In addition, it is not clear whether the
      cervical supraspinous ligaments form part of the ligamentum nuchae. METHODS: This
      study used a combined approach of a detailed gross anatomic study on eight
      cadavers and a macroscopic and microscopic study of the connective tissue
      organization of the posterior midline structures on serial horizontal thin (2.5
      mm) plastinated slices of the cervical spine (occiput-T1) from an adult female
      cadaver. RESULTS: The dorsal and ventral portions of the ligamentum nuchae are a
      single entity formed by the aponeurotic fibers of the trapezius, splenius
      capitis, rhomboideus minor, and serratus posterior superior muscles. CONCLUSIONS:
      The regional differences in the connective tissue organization of the ligamentum
      nuchae and its well-defined attachments to the C6 and C7 vertebrae suggest that
      it is designed to function in the lower cervical spine.

PMID- 10647154
TI  - Plaster of Paris as an osteoconductive material for interbody vertebral fusion in
      mature sheep.
AB  - STUDY DESIGN: In adult female sheep, histologic and biomechanical criteria were
      used to determine whether the osteoconductive performance of plaster of paris
      would promote the incorporation of the tubular titanium mesh implants used for
      interbody vertebral fusions. OBJECTIVES: To compare the osteogenicity of plaster
      of paris with that of autogenous iliac crest bone and bone marrow 6 months after
      they were loaded into tubular titanium mesh cages and implanted as L3-L5 bridges
      after L4 corpectomies. SUMMARY OF BACKGROUND DATA: One of the aims of surgery for
      vertebral pathology is to stabilize the spine by interbody fusions. The morbidity
      associated with the use of iliac crest autograft bone for fusion grafts prompted
      trials using plaster of paris as an osteoconductive substrate. METHODS: The total
      volume of bone that invested the L3-L5 mesh cages after 6 months was quantitated
      by computed tomography scans. All specimens subsequently were cut into fusion
      mass segments for biomechanical testing in flexion, extension, compression, and
      torsion, and then embedded in plastic for sectioning and histomorphometry to
      determine the trabecular bone volume within the titanium mesh. RESULTS: In each
      experimental model, implants of plaster of paris were the osteoconductive equal
      of autogenous iliac crest bone/marrow preparations. The volumes of bone formed
      around and within the titanium mesh were identical, and the tissues were
      biomechanically indistinguishable. A partial mechanism was determined by
      modifying the system for midshaft femoral defects. CONCLUSIONS: In the sheep, a
      tubular titanium mesh packed with plaster of paris forms an osteoconductive
      conduit to achieve a biomechanically stable interbody lumbar vertebral fusion.

PMID- 10647155
TI  - Sensitivity of anulus fibrosus cells to interleukin 1 beta. Comparison with
      articular chondrocytes.
AB  - STUDY DESIGN: Anulus fibrosus cells from rabbits were grown in primary culture 1)
      to study their ability to produce prostaglandin E2 and Type II phospholipase A2,
      and to express stromelysin-1 messenger ribonucleic acid; and 2) to study the
      effect of interleukin 1 beta on this production and on proteoglycan aggregation.
      OBJECTIVES: To investigate the potency of anulus fibrosus cells to respond to
      interleukin 1 beta by producing degradative and inflammatory agents as compared
      with the potency of articular chondrocytes in the same animal. SUMMARY OF
      BACKGROUND DATA: Interleukin 1 beta has been implicated in the degradation of
      intervertebral discs. The way anulus fibrosus cells differ from articular
      chondrocytes in their responses to interleukin 1 beta remains to be established.
      METHODS: Anulus fibrosus cells and articular chondrocytes were obtained from
      young rabbits, grown in primary culture, and incubated with interleukin 1 beta.
      The newly synthesized proteoglycan was measured by labeling with [35S]-sulfate.
      Proteoglycan aggregation was analyzed by the elution profile on Sepharose 2B
      columns. The contents of collagen Type II and stromelysin-1 messenger ribonucleic
      acid were assessed by Northern blot analysis. The Type II phospholipase A2
      activity was measured using a fluorometric substrate. Prostaglandin E2 production
      was evaluated by radioimmunoassay. RESULTS: Anulus fibrosus cells had 2.5-fold
      less Type II collagen messenger ribonucleic acid than articular chondrocytes, and
      interleukin 1 beta had no significant effect on this. Anulus fibrosus cells
      synthesized and secreted four-fold less proteoglycan than articular chondrocytes.
      Interleukin 1 beta reduced the anulus fibrosus content of total [35S]-sulfated
      proteoglycan by 35% (P < 0.01), and that of articular cells by 41% and decreased
      proteoglycan aggregation. Interleukin 1 beta induced the production of
      stromelysin-1 messenger ribonucleic acid in both cell types. The stromelysin-1
      messenger ribonucleic acid content of anulus fibrosus cells was one half that of
      articular cells. Interleukin 1 beta increased the production of prostaglandin E2
      and caused a dose-dependent secretion of Type II phospholipase A2 activity in
      both cell types. Its effect was 2.5-fold lower in anulus fibrosus cells than in
      articular chondrocytes. CONCLUSION: Anulus fibrosus cells can be stimulated by
      interleukin 1 beta to produce factors implicated in local degradative and
      inflammatory processes. This production is associated with decreased proteoglycan
      aggregation. Anulus fibrosus cells respond slightly less well to interleukin 1
      beta in vitro than do articular cells.

PMID- 10647157
TI  - Stopping nicotine exposure before surgery. The effect on spinal fusion in a
      rabbit model.
AB  - STUDY DESIGN: A double-blind, prospective, randomized study using a validated
      rabbit model of intertransverse process fusion. OBJECTIVES: To determine the
      effect of stopping prolonged nicotine exposure on autogenous bone graft
      incorporation in a rabbit lumbar spinal fusion model. SUMMARY OF BACKGROUND DATA:
      There is a growing body of evidence that systemic nicotine impairs healing of
      spinal fusions and fractures. However, it remains to be determined whether, if
      nicotine increases the nonunion rate of spinal fusion surgery, stopping nicotine
      exposure before surgery will negate this inhibitory effect. METHODS: Forty-seven
      rabbits were divided into two experimental groups and one control group. The two
      experimental groups were exposed to systemic nicotine for 8 weeks. Nicotine
      exposure was stopped in one group 1 week before surgery; nicotine exposure was
      continued in the other group throughout the study. All rabbits underwent an L5-L6
      intertransverse process fusion with autogenous iliac crest bone graft. All
      rabbits were killed 35 days after surgery. Forty rabbits completed the study and
      underwent radiographic, biomechanical, and histologic testing. RESULTS: Fusion,
      as determined by a blinded examiner palpating the spine, occurred in 7 of 13
      control rabbits, 4 of 13 rabbits that "quit" nicotine, and none of the 14 rabbits
      exposed to continuous nicotine. There was a statistically significant difference
      between the control and continuous nicotine (P = 0.0015) and between the
      discontinued nicotine and continuous nicotine groups (P = 0.025). Biomechanical
      testing showed no significant differences between groups (P = 0.11). A blinded
      musculoskeletal pathologist was unable to detect a difference between groups
      based on histologic analysis. CONCLUSIONS: Chronic nicotine exposure was shown to
      decrease spinal fusion rates. Discontinuing nicotine before surgery improved
      fusion rates.

PMID- 10647156
TI  - Effects of EPC-K1 on lipid peroxidation in experimental spinal cord injury.
AB  - STUDY DESIGN: A study in which levels of lipid peroxidation were measured, the
      thiobarbituric acid-reactive substances were estimated in an experimental rat
      model, and the recovery was assessed. OBJECTIVE: To ascertain the occurrence of
      thiobarbituric acid-reactive substances in the damaged spinal cord, and to
      investigate the effectiveness of a hydroxyl radical scavenger EPC-K1, a phosphate
      diester linkage of vitamins E and C, in attenuating the severity of spinal cord
      injury. SUMMARY OF BACKGROUND DATA: Lipid peroxidation has been reported to play
      an important role in spinal cord injury. There is no report on the use of EPC-K1
      to attenuate the severity of spinal cord injury in either animal or human
      studies. METHODS: Spinal cord injury was induced by placing a 25-g weight on T12,
      and the animals were divided into six groups. Group 1 (sham) received only
      laminectomy. Group 2 (control) received spinal cord injury. Group 3 received EPC
      K1 5 minutes before injury. Group 4 received it 5 minutes after injury. Group 5
      received it 3 hours after injury. Group 6 received it five times, respectively:
      at 5 minutes, then 1, 2, 3, and 4 hours after injury. The levels of
      thiobarbituric acid-reactive substances were measured in the spinal cord, and the
      recovery was assessed. RESULTS: The thiobarbituric acid-reactive substances
      content increased after injury, with two peaks, at 1 and 4 hours. Concentration
      at the 4-hour peak was lower in nitrogen mustard-induced leukocytopenia rats than
      in the control rats. The EPC-K1 injection reduced thiobarbituric acid-reactive
      substances content at 1 and 4 hours after injury in Group 3 (respectively, 34.3%
      and 42.7% vs. control) and only that at 4 hours in Group 6 (24.9% vs. control).
      Motor function recovery and histologic findings were better in these two groups
      than in Group 2. CONCLUSION: Repeated injection of EPC-K1 attenuated the severity
      of spinal cord injury.

PMID- 10647158
TI  - Influence of PLIF cage size on lumbar spine stability.
AB  - STUDY DESIGN: In vitro biomechanical testing on functional spine units with
      posterior lumbar interbody fusion cage implants of progressively larger sizes.
      OBJECTIVES: To determine the influence of increasing cage size on the restoration
      of spine stability after total facetectomy. SUMMARY OF BACKGROUND DATA: Bilateral
      insertion of cages in posterior lumbar interbody fusion commonly involves
      facetectomy. To restore stability with no additional instrumentation, the cages
      must provide sufficient distraction of the vertebrae and adequate tension in the
      anulus. The size of cages is therefore an important consideration in posterior
      lumbar interbody fusion. METHODS: Eight human lumbar functional spine units were
      obtained and divided into two equal groups; one group underwent bending tests and
      the other twisting. The functional spinal units were tested intact, after total
      bilateral facetectomy and with three sets of cages that were progressively larger
      in size. RESULTS: After facetectomy, the functional spine unit's stiffness
      reduced significantly from that of the intact spine in extension (48% of intact),
      lateral bending (25%), and torsion (39%). With the posterior insertion of small
      cages into the facetectomized functional spine units, only extension stiffness
      was restored to the intact level, whereas flexion stiffness reduced significantly
      (41% of intact). The medium cages restored the lateral bending stiffness of the
      facetectomized functional spine units; only the large cages managed to restore
      the torsional stiffness. Flexion stiffness of the facetectomized functional spine
      units with cages remained significantly less than that of the intact spine,
      regardless of cage size. CONCLUSION: In the facetectomized lumbar spine unit,
      cage size influences lateral bending and torsional stability.

PMID- 10647159
TI  - Increased fusion rates with cervical plating for two-level anterior cervical
      discectomy and fusion.
AB  - STUDY DESIGN: A retrospective review of all patients surgically treated with a
      two-level anterior cervical discectomy and fusion with and without anterior plate
      fixation by a single surgeon. OBJECTIVES: To compare the clinical and
      radiographic success of two-level discectomy and the effect of anterior cervical
      plate fixation. SUMMARY OF BACKGROUND DATA: Prior studies of multisegment fusions
      have shown decreased fusion rates correlating with the number of increased
      levels. The use of anterior plates for single-level cervical fusions is
      controversial. However, their use in multilevel fusions may be warranted because
      of the increased pseudarthrosis rates. METHODS: Over a 6-year period, 60 patients
      were treated surgically with a two-level anterior cervical discectomy and fusion
      by the senior author. Thirty-two patients had cervical plates, and 28 underwent
      fusions without plates. These patients were followed for an average of 2.7 years.
      Clinical and radiographic follow-up evaluations were performed. RESULTS: Of the
      60 patients, 7 had a pseudarthrosis. The pseudarthrosis rates were 0% for
      patients with plating and 25% for those with no plating. This difference was
      statistically significant (P = 0.003). No correlation of pseudarthrosis with
      gender, age, level of surgery, history of tobacco use, or the presence of prior
      anterior surgery was found. There was significantly less graft collapse (P =
      0.0001) in the patients without plates in whom pseudarthrosis developed (1.4 mm)
      than in those who had fusions with plates (0.3 mm). The amount of kyphotic
      deformity of the fused segment was 0.4 degree in patients with plating compared
      with 4.9 degrees in those without plating who developed a pseudarthrosis (P =
      0.0001). CONCLUSIONS: The addition of plate fixation for two-level anterior
      cervical discectomy and fusion is a safe procedure with no significant increase
      in complication rates. The pseudarthrosis rates are significantly higher in
      patients treated without plate fixation. No nonunions occurred in the patients
      treated with plate fixation. There was significantly less disc space collapse and
      kyphotic deformity with the plated fusions than with the nonplated fusions, in
      which a pseudarthrosis developed. The complication rates for plated fusions are
      extremely low and do not differ from those for nonplated fusions.

PMID- 10647160
TI  - Canal geometry changes associated with axial compressive cervical spine fracture.
AB  - STUDY DESIGN: A laboratory study using isolated ligamentous human cadaveric
      cervical spines to investigate canal occlusion during (transient) and after
      (steady-state) axial compressive fracture. OBJECTIVES: To determine whether
      differences exist between transient and postinjury canal occlusion under axial
      compressive loading, and to examine the effect of loading rate on canal
      occlusion. SUMMARY OF BACKGROUND DATA: Prior studies have shown no correlation
      between neurologic deficit and canal occlusion measurements made on radiographs
      and computed tomography scans. The authors hypothesized that postinjury
      radiographic assessment does not provide an appreciation for the transient
      occlusion that occurs during the traumatic fracture event, which may
      significantly affect the neurologic outcome. METHODS: Twelve human cervical
      spines were instrumented with a specially designed canal occlusion transducer,
      which dynamically monitored canal occlusion during axial compressive impact. Six
      specimens were subjected to a fast-loading rate (time to peak load, approximately
      20 msec), and the other six were subjected to a slow-loading rate (time to peak
      load, approximately 250 msec). After impact, two different postinjury canal
      occlusion measurements were performed. RESULTS: Each of the six specimens
      subjected to the fast-loading rate incurred burst fractures, whereas the slow
      loading rate produced six wedge-compression fractures. For the fast-rate group,
      the postinjury occlusion-measurements were significantly smaller than the
      transient occlusion. In contrast, transient occlusion was not found to be
      significantly different from postinjury occlusion in the slow-rate group. All of
      the comparisons between loading rate groups showed significant differences, with
      the fast-rate fractures producing larger amounts of canal occlusion in every
      category. CONCLUSIONS: The findings indicate that even if canal occlusion could
      be measured immediately after axial compressive trauma, the measurement would
      underestimate the maximal amount of transient canal occlusion. Therefore,
      postinjury measurement of canal occlusion may indicate a smaller degree of
      neurologic deficit than what might be expected if the transient occlusion could
      be measured.

PMID- 10647161
TI  - The effect of polytrauma in persons with traumatic spine injury. A prospective
      database of spine fractures.
AB  - STUDY DESIGN: A mixed cross-sectional survey and cohort study using a
      prospectively gathered database of persons with traumatic spine injury.
      OBJECTIVES: To identify demographic and injury mechanism factors that predict
      greater injury severity, and to determine the effect of injury severity on
      outcomes in traumatic spine fracture. SUMMARY OF BACKGROUND DATA: Traumatic spine
      fracture outcome studies have focused on defining type and level of vertebral
      fracture without considering the severity of associated injuries. In the trauma
      population, greater injury severity has been shown to be related to worse
      outcome. No studies have been reported on the effect of injury severity on
      outcome in the traumatic spine fracture population. METHODS: Prospectively
      collected data on 830 persons with traumatic spine injury who were admitted to a
      trauma hospital were reviewed. Patient demographics; injury mechanism; hospital
      events; and disability, employment, and pain status at discharge, 1 year, and 2
      years after injury were recorded. Associations between these factors and trauma
      severity (Injury Severity Score) were explored using Pearson's correlation and
      analysis of variance. RESULTS: Trauma was more severe in patients who had been
      married previously, who were involved in a motor vehicle accident, were ejected
      from the vehicle, had loss of consciousness, had higher-level and multiple
      complicated vertebral fractures, or had neurologic deficit. Those more severely
      injured had longer lengths of stay, more surgery, more complications, higher
      mortality, more disability, and less return to work. CONCLUSIONS: Persons with
      traumatic spine injury and polytrauma have poorer short- and long-term outcomes.
      This high-risk group may require aggressive interventions, more hospital
      resources, and close follow-up observation after discharge from hospital to
      optimize outcome.

PMID- 10647162
TI  - Scoliosis correction maintenance in skeletally immature patients with idiopathic
      scoliosis. Is anterior fusion really necessary?
AB  - STUDY DESIGN: A retrospective evaluation of the occurrence of the crankshaft
      phenomenon in skeletally immature patients with idiopathic scoliosis. OBJECTIVE:
      To determine what factors, if any, contribute to a decreased occurrence of
      crankshaft phenomenon in patients treated with posterior surgery only. SUMMARY OF
      BACKGROUND DATA: Reports have described the progression of scoliotic deformity,
      termed the crankshaft phenomenon, in a region of solid posterior arthrodesis in
      skeletally immature patients. This has led some authors to advocate the use of
      concomitant anterior discectomy and fusion to prevent crankshaft. METHODS: From
      1989 through 1994, 18 Risser 0 patients with thoracic or thoracolumbar idiopathic
      scoliosis underwent Isola (De Puy-Acromed, Raynham, MA) posterior instrumentation
      and fusion. They were assessed for evidence of the crankshaft phenomenon,
      identified by coronal plane deformity progression of 10 degrees or more, or a rib
      vertebra angle difference of 10 degrees or more. The average age of the patients
      was 12.5 years (range, 10.5-15.5 years), and the average follow-up period was 39
      months (range, 24-68 months). RESULTS: Eleven patients (10 girls and 1 boy) had
      closed triradiate cartilage at the time of surgery. Their average Cobb angle was
      62 degrees before surgery, 21 degrees after surgery, and 22 degrees at follow-up
      assessment. No patients in this group met the criteria for crankshaft. Seven
      patients (6 girls and 1 boy) had open triradiate cartilage at the time of
      surgery. Their average Cobb angle was 62 degrees before surgery, 18 degrees after
      surgery, and 20 degrees at follow-up evaluation. No patient had a 10 degrees or
      more increase in rib vertebra angle difference. One patient had more than a 10
      degrees increase in her Cobb angle (11 degrees) from postoperative to latest
      follow-up assessment. Her instrumentation construct, performed in 1989, used
      sublaminar wires as the caudal anchors. Hooks and pedicle screws are now used.
      Two of the seven patients with open triradiate cartilage underwent surgery during
      or before their peak height velocity and displayed no evidence of crankshaft. No
      deaths, neurologic complications, or infections occurred in either group.
      CONCLUSIONS: These findings suggest that scoliotic deformity progression can be
      prevented in skeletally immature patients with idiopathic scoliosis as young as
      10 years of age with the use of stiff segmental posterior instrumentation,
      without the necessity of concomitant anterior arthrodesis.

PMID- 10647163
TI  - Modulation of spinal deformities in patients with neurofibromatosis type 1.
AB  - STUDY DESIGN: A consecutive case retrospective chart and radiographic review.
      OBJECTIVES: To determine the incidence of nine radiographic dystrophic features
      acquired during the process of modulation, and to analyze the statistical
      correlation of these acquired dystrophic features with clinical progression of a
      spinal deformity. SUMMARY OF BACKGROUND DATA: In patients with neurofibromatosis,
      spinal deformities with seemingly few initial dystrophic features have shown a
      tendency to acquire dystrophic changes during long-term follow-up periods.
      Similarly, deformities with dystrophic changes can acquire further dystrophic
      features. This phenomenon is termed "modulation," a feature unique to spinal
      deformities in neurofibromatosis. These dystrophic changes may evolve slowly or
      aggressively, and may spread to other regions as well. METHODS: A review was done
      of the clinical records, photographs, radiographs, and other imaging studies of
      457 patients referred between 1982 and 1995 with the diagnosis of
      neurofibromatosis Type 1. One hundred twenty-eight patients were diagnosed with a
      spinal deformity. Ninety-one patients who had a complete set of clinical and
      radiographic data were included in the study. Location and type of curve as well
      as the extent of spinal deformity were studied for their effect on the tendency
      for modulation. Initial spinal radiographs were analyzed for nine radiographic
      dystrophic features: rib penciling, vertebral rotation, posterior vertebral
      scalloping, anterior vertebral scalloping, lateral vertebral scalloping,
      vertebral wedging, spindling of the transverse process, widened interpedicular
      distance, and enlarged intervertebral foramina. Subsequent radiographs were
      analyzed critically for evolution, progression, or spread of these features.
      Correlation of acquisition in these dystrophic features with clinical progression
      in the spinal deformity, as measured in increments of scoliosis and kyphosis, was
      analyzed. RESULTS: In 81% of patients with spinal deformity diagnosed before 7
      years of age and in 25% of patients with such a diagnosis after 7 years of age,
      evidence of modulation was observed. Location, side, and extent of the deformity
      and patient gender did not influence the propensity of the deformity to modulate.
      Correlation of modulation with clinical progression of the deformity showed rib
      penciling to be the only singular factor statistically influencing risk of
      progression. Of the deformities that acquired three or more penciled ribs, 87%
      showed significant clinical progression. No other radiographic dystrophic feature
      individually influenced progression. However, when three or more of the
      dystrophic skeletal features were acquired, the risk of progression reached
      statistical significance in 85% of patients. CONCLUSIONS: Spinal deformities in
      patients with neurofibromatosis 1 should be regarded as deformities in evolution.
      One should resist assigning these evolving deformities to either the dystrophic
      or nondystrophic end of the spectrum without considering the possibility of
      modulation across the spectrum. A spinal deformity that develops before 7 years
      of age should be followed closely for evolving dystrophic features (i.e.,
      modulation). When a curve acquires either three penciled ribs or a combination of
      three dystrophic features, clinical progression is almost a certainty.

PMID- 10647164
TI  - Comparison of push-prone and lateral-bending radiographs for predicting
      postoperative coronal alignment in thoracolumbar and lumbar scoliotic curves.
AB  - STUDY DESIGN: A comparative evaluation of supine right and left lateral-bending
      radiographs and push-prone radiographs in patients with thoracolumbar and lumbar
      scoliosis to determine postoperative correction of the curve. OBJECTIVES: To
      determine the difference in the ability of the push-prone radiograph and the
      supine lateral-bending radiograph to predict postoperative coronal alignment for
      primary thoracolumbar and lumbar curves managed with an anterior spinal
      instrumentation and fusion. SUMMARY OF BACKGROUND DATA: Right and left supine
      side-bending radiographs are the standard means of evaluating curve flexibility
      before surgery in idiopathic scoliosis. A push-prone radiograph also has been
      obtained at the authors' institution as a single dynamic radiographic assessment
      of forced correction of the primary curve and resultant effects on compensatory
      curves above and below the fusion. METHODS: Preoperative standing, supine right
      and left lateral-bending, and push-prone radiographs were performed in 40
      patients who underwent anterior spinal instrumentation and fusion. Postoperative
      standing radiographs of the spine were obtained at 3 months after surgery.
      Measurements on all the radiographs included the coronal Cobb angle, the angle of
      the lowest instrumented vertebra to the horizontal, the rotation of the lowest
      instrumented vertebra, and the distance of the midpoint of the lowest
      instrumented vertebra from the center sacral line. RESULTS: The lateral-bending
      and the push-prone radiographs predicted less correction of the Cobb angle and
      the angle of the lowest instrumented vertebra to the horizontal than was achieved
      after surgery. However, the push-prone radiograph was superior to the lateral
      bending radiograph in accurately predicting the postoperative correction of the
      rotation of the lowest instrumented vertebra as well as the translation of the
      lowest instrumented vertebra from the center sacral line. CONCLUSIONS: The push
      prone and lateral-bending radiographs are similar in predicting less correction
      of the Cobb angle after anterior spinal surgery. The push-prone radiograph helps
      in determining the effects that correction of the primary curve has on the curves
      above and below the level of fusion by better predicting the translational
      correction of the lowest instrumented vertebra and the rotation of the lowest
      instrumented vertebra.

PMID- 10647165
TI  - A prospective evaluation of pulmonary function in patients with adolescent
      idiopathic scoliosis relative to the surgical approach used for spinal
      arthrodesis.
AB  - STUDY DESIGN: A prospective evaluation of pulmonary function in patients with
      adolescent idiopathic scoliosis undergoing surgical correction. OBJECTIVES: 1) To
      evaluate prospectively, at regular intervals, the changes in pulmonary function
      after surgical arthrodesis of primary thoracic and double primary thoracic-lumbar
      (double major) types of adolescent idiopathic scoliosis in a homogeneous
      population; 2) to compare the changes in pulmonary function after surgical
      correction relative to the surgical approach used for spinal arthrodesis; and 3)
      to determine if short- to midterm morbidity with respect to pulmonary function is
      associated with the type of surgical approach used for spinal arthrodesis.
      SUMMARY OF BACKGROUND DATA: The effect of surgical correction on the pulmonary
      function of patients with adolescent idiopathic scoliosis is controversial.
      Studies have shown improvement, decline, or no change in pulmonary function after
      surgical correction of idiopathic scoliosis. METHODS: Ninety-eight patients with
      adolescent idiopathic scoliosis undergoing surgical treatment at the authors'
      institution were prospectively evaluated with pulmonary function tests assessing
      volume (forced vital capacity and total lung capacity) and flow (forced
      expiratory volume in 1 second). Pulmonary functions were evaluated before surgery
      and after surgery at 3 months, 1 year, 2 years, and at the final follow-up visit.
      All patients were divided into four groups depending on the surgical approach
      used for spinal fusion: Group 1 (n = 47) underwent a posterior spinal fusion with
      iliac crest bone graft; Group 2 (n = 33) underwent a posterior spinal fusion with
      rib resection thoracoplasty; Group 3 (n = 7) underwent an anterior spinal fusion
      with a rib resection thoracotomy; and Group 4 (n = 11) underwent a combined
      anterior and posterior spinal fusion with autogenous rib and iliac crest graft
      used, respectively. RESULTS: Patients in Group 1 had improved pulmonary function
      values at 3 months after surgery, whereas patients in Groups 2, 3, and 4 showed a
      decline at 3 months after surgery. Two years after surgery, Group 1 had
      significantly improved pulmonary function values (P < 0.0001), whereas the
      pulmonary function values of patients in Groups 2, 3, and 4 had returned to
      preoperative values. CONCLUSIONS: 1) Patients with chest cage disruption during
      surgical treatment showed a decline in pulmonary function at 3 months after
      surgery. 2) In contrast, patients without chest cage disruption showed an
      improvement in pulmonary function at 3 months after surgery. 3) Irrespective of
      the surgical approach used for spinal arthrodesis, postoperative pulmonary
      function tests (absolute values) returned to preoperative values at 2 years after
      surgery. 4) Patients who had no chest cage disruption experienced a significantly
      greater improvement in two of their pulmonary function values at 2 years after
      surgery than patients with chest cage disruption.

PMID- 10647166
TI  - Consistency of history taking and physical examination in patients with suspected
      lumbar nerve root involvement.
AB  - STUDY DESIGN: A cross-sectional study of interobserver variability in primary
      care patients. OBJECTIVE: To investigate the consistency of signs and symptoms of
      nerve root compression in primary care patients with pain irradiating pain into
      the leg (sciatica). SUMMARY OF BACKGROUND DATA: The literature does not report on
      all the clinical tests for nerve root compression. In previous studies, most
      patients had low back pain with no irradiation. Often, little information on
      examination technique, proportion of positive test results, or clinical patient
      characteristics was provided. METHODS: A random selection of 91 patients was
      investigated by a neurologist-resident couple. Agreement percentages, proportions
      of positive test results, and kappas were calculated. RESULTS: The kappa of the
      overall conclusion after the history taking was 0.40, increasing to 0.66 after
      physical examination. Kappas were good for decreased muscle strength and sensory
      loss (0.57-0.82), intermediate for reflex changes (0.42-0.53), and poor for the
      examination of the lumbar spine (0.16-0.33). The straight leg raising, crossed
      straight leg raising, Bragard's sign, and Naffziger's sign were the most
      consistent nerve root tension signs (> 0.66). CONCLUSIONS: Two clinicians
      disagreed on the presence of nerve root involvement in one of four patients after
      history taking, and in one of five patients after physical examination. For a
      more consistent overall diagnosis, the physician probably should put more
      emphasis on the history of pain on coughing-straining-sneezing, a feeling of
      coldness in the legs, and urinary incontinence. The investigation of paresis,
      sensory loss, reflex changes, straight leg raising, and Bragard's sign provide
      the most consistent results.

PMID- 10647167
TI  - Spinal position sense is independent of the magnitude of movement.
AB  - STUDY DESIGN: Position sense in the spine was recorded at T1, T7, L1, and S2 in
      three incremental angular ranges of flexion and on return to upright standing
      from these movements. OBJECTIVES: To determine the effect of angular range of
      movement on position sense. The main purpose was to establish a protocol for
      whole spine assessment of position sense in healthy and pathologic spines.
      SUMMARY OF BACKGROUND DATA: Position sense is one dimension of proprioception,
      classically assessed by the ability to reproduce preselected target positions.
      This approach was used in the current study to determine whether spinal position
      sense is affected by the magnitude of movement traversed in repositioning tasks.
      METHODS: Spinal position sense was assessed in 20 healthy subjects during
      repeated flexion movements carried out in one-third, half, and two thirds of the
      full range of movement in the sagittal and coronal planes. During each movement,
      the 3-Space Fastrak (Polhemus Inc., Colchester, VT) was used to record angular
      movement of the spine at four sensor locations (T1, T7, L1, and S2). The absolute
      difference in the sensor angles between repeated trials was calculated for each
      flexed position and on return to upright standing from these. These absolute
      differences were used as a measure of position sense. RESULTS: Absolute position
      sense after one-third angular movements was accurate to within 4.30 degrees +/-
      2.84 degrees in flexed positions and 2.70 degrees +/- 2.20 degrees in upright
      postures. Corresponding results for two-thirds movements were 4.75 degrees +/-
      2.63 degrees and 3.33 degrees +/- 2.60 degrees, respectively. Range of movement
      had no significant influence on the accuracy of position sense. CONCLUSIONS: 1)
      Healthy individuals are able to reposition their spine accurately under
      conditions of incremental increases in angular range. 2) Range-related variations
      in position sense are small and unlikely to be of clinical significance.

PMID- 10647168
TI  - The use of a classification approach to identify subgroups of patients with acute
      low back pain. Interrater reliability and short-term treatment outcomes.
AB  - STUDY DESIGN: A prospective, consecutive, cohort study of patients with acute low
      back pain classified into subgroups based on examination data and treated with a
      specific treatment approach. OBJECTIVE: To calculated the interrater reliability
      of a classification system, and to compare initial patient characteristics and
      outcomes of physical therapy treatment when a classification approach is used.
      SUMMARY OF BACKGROUND DATA: Classification of patients with low back pain into
      homogeneous subgroups has been identified as a research priority. Identifying
      relevant subgroups of patients could improve clinical outcomes and research
      efficiency. METHODS: Consecutive patients referred to physical therapy for
      treatment of acute low back pain were evaluated and classified into one of four
      subgroups (immobilization, mobilization, specific exercise, or traction) before
      treatment. Physical therapy treatment was based on the patient's classification.
      The classifications were compared for initial patient characteristics, frequency
      and duration of physical therapy, and improvement in Oswestry scores. RESULTS: In
      this study, 120 patients were evaluated and classified. Analysis of interrater
      reliability showed a kappa value of 0.56. Differences were found among the
      classifications for age, initial Oswestry score, history of low back pain,
      symptom distribution, and average change in Oswestry score with treatment.
      CONCLUSIONS: Reaching a consensus regarding relevant patient subgroups requires
      data on the reliability and validity of existing classification systems. Further
      work is required to validate improvement in treatment outcomes using a
      classification approach.

PMID- 10647169
TI  - Beyond the good prognosis. Examination of an inception cohort of patients with
      chronic low back pain.
AB  - STUDY DESIGN: A 22-month prospective cohort study. OBJECTIVES: To describe the
      course of an inception cohort of patients with chronic low back pain. SUMMARY OF
      BACKGROUND DATA: Chronic low back pain is a debilitating condition with great
      medical and social cost. METHODS: A cohort of 1246 patients with acute low back
      pain who sought treatment from 208 North Carolina providers was observed.
      Patients who developed chronic low back pain were identified. Entry criteria were
      back pain of less than 10 weeks' duration, no previous care for this episode of
      low back pain, no previous spine surgery, not pregnant, no nonskin malignancy,
      and access to a telephone. The providers were of four types: primary care medical
      doctors, doctors of Chiropractic, orthopedic surgeons, and health maintenance
      organization-based primary care providers. Patients were contacted by telephone
      shortly after enrollment and at 2, 4, 8, 12, and 24 weeks, with a final interview
      at 22 months. Patient functional status, care-seeking, and satisfaction were
      evaluated. RESULTS: Ninety-six patients had chronic, continuous symptoms for 3
      months, forming the inception cohort of chronic low back pain. A valid, reliable
      measure of back-specific functional disability also was used. Predictors of the
      development of chronicity were poor baseline functional status and sciatica. A
      more powerful predictor of chronicity was poor functional status at 4 weeks. Two
      thirds of patients with chronic low back pain at 3 months had functionally
      disabling symptoms at 22 months, and a majority of these were employed.
      Satisfaction with care was low. Forty-six patients (2.6% of the entire cohort)
      underwent surgery, with no statistically significant difference in surgical rates
      among initial provider strata. Patients who underwent surgery after 3 months had
      a Roland disability score at 22 months of 10 (7.7, 12.3). Forty-one percent of
      patients with chronic low back pain see an orthopedic or neurologic surgeon.
      Chronic low back pain occurs in 7.7% of patients who seek care for acute low back
      pain, with unremitting pain for 22 months in 4.7%. CONCLUSION: Once established,
      chronic low back pain is persistent. Most patients with chronic low back pain
      seek little care, and a majority are employed. Future research should emphasize
      maintenance of employment and function.

PMID- 10647170
TI  - Management of symptomatic lumbar pseudarthrosis with anteroposterior fusion. A
      functional and radiographic outcome study.
AB  - STUDY DESIGN: An independent retrospective review of 37 patients undergoing 39
      anteroposterior lumbar fusions for lumbar pseudarthrosis repair between 1984 and
      1990. OBJECTIVES: To evaluate radiographically and functionally the results of
      the combined anteroposterior fusion for the management of symptomatic lumbar
      pseudarthrosis, and to assess risk factors for functional failure after the
      procedure. SUMMARY OF BACKGROUND DATA: Most reported techniques of pseudarthrosis
      repair involve posterior fusion with no instrumentation, posterior fusion with
      instrumentation, or anterior fusion alone. The results of lumbar pseudarthrosis
      repair are poor. Fusion rates range from 30% to 70%, with only a 30% to 50% rate
      of functional success. METHODS: Thirty-nine procedures were assessed in 37
      patients. The outcomes were assessed radiographically (solid fusion vs.
      pseudarthrosis) and functionally (success vs. failure). Radiographs were assessed
      at follow-up examination for consolidation of fusion anteriorly and posteriorly.
      Functional outcome was graded by using multiple instruments, including data from
      chart review and the follow-up outcome questionnaire. A functional failure score
      that took into account 10 items was developed. RESULTS: In this patient
      population (37 patients, 59% with a smoking history, 71% with compensation or
      legal claims), there was a 10% pseudarthrosis rate. Pseudarthrosis was defined
      when one or more levels were involved and when it occurred anteriorly and
      posteriorly. In 12 patients (35%), the outcome was rated as functional failure.
      The presence of one or more abnormal neurologic findings and significant narcotic
      use before surgery significantly increased the chance of a patient's outcome
      being functional failure. Workmen's Compensation or legal status before surgery
      also increased the chance of functional failure, though this correlation was not
      statistically significant. CONCLUSIONS: A combined anterior and posterior
      approach for the management of symptomatic lumbar pseudarthrosis is a viable
      alternative to posterior fusion alone. In fact, this procedure affords a higher
      fusion rate based on radiographic assessment. Functional failure rates may be
      decreased by using caution for those patients using narcotics regularly before
      surgery or in those with unexplained preoperative neurologic abnormal findings.

PMID- 10647171
TI  - Giovanni Alfonso Borelli: "Father of spinal biomechanics".
AB  - The first modern textbook on spinal biomechanics was written by Giovanni Alfonso
      Borelli in 1680. A mathematician, astronomer, and physicist by trade, Borelli
      became consumed in the physical laws of nature and the human body. His work
      served as a monumental contribution to ascertain, in depth and with undiminished
      accuracy, the basic biomechanical principles of the human body.

PMID- 10647172
TI  - The pain of Sognsvann walks.

PMID- 10647173
TI  - Wet and dry interfaces: the role of solvent in protein-protein and protein-DNA
      recognition.
AB  - Water molecules are found in abundance in protein-protein and protein-DNA
      interfaces. Although interface solvent molecules exchange quickly with the bulk
      solvent, structural and biochemical data suggest that water-mediated interactions
      are as important as direct hydrogen bonds in the stability and specificity of
      recognition.

PMID- 10647174
TI  - Still a puzzle: why is haem covalently attached in c-type cytochromes?
AB  - c-Type cytochromes are a group of proteins with diverse structures and functions.
      Their common feature is covalent attachment of haem to one or more CXXCH motifs.
      There does not seem to be a single advantageous reason for this covalent
      attachment.

PMID- 10647175
TI  - Leaving no element of doubt: analysis of proteins using microPIXE.

PMID- 10647176
TI  - Solution structure of a pair of modules from the gelatin-binding domain of
      fibronectin.
AB  - BACKGROUND: Fibronectin has a role in vital physiological processes such as cell
      migration during embryogenesis and wound healing. It mediates the attachment of
      cells to extracellular matrices that contain fibrous collagens. The affinity of
      fibronectin for native collagen and denatured collagen (gelatin) is located
      within a 42 kDa domain that contains four type 1 (F1) and two type 2 (F2)
      modules. A putative ligand-binding site has been located on an isolated F2
      module, but the accessibility of this site in the intact domain is unknown. Thus,
      structural studies of module pairs and larger fragments are required for a better
      understanding of the interaction between fibronectin and collagen. RESULTS: The
      solution structure of the 101-residue 6F1 1F2 module pair, which has a weak
      affinity for gelatin, has been determined by multidimensional NMR spectroscopy.
      The tertiary structures determined for each module conform to the F1 and F2
      consensus folds established previously. The experimental data suggest that the
      two modules interact via a small hydrophobic interface but may not be tightly
      associated. Near-random-coil 1H NMR chemical shifts and fast dynamics for
      backbone atoms in the linker indicate that this region is unlikely to be involved
      in the overall stabilisation of the module pair. CONCLUSIONS: The modules in the
      6F1 1F2 module pair interact with each other via a flexible linker and a
      hydrophobic patch, which lies on the opposite side of the 1F2 module to the
      putative collagen-binding site. The intermodule interaction is relatively weak
      and transient.

PMID- 10647177
TI  - Anchoring an extended HTLV-1 Rex peptide within an RNA major groove containing
      junctional base triples.
AB  - BACKGROUND: The Rex protein of the human T cell leukemia virus type 1 (HTLV-1)
      belongs to a family of proteins that use arginine-rich motifs (ARMs) to recognize
      their RNA targets. Previously, an in vitro selected RNA aptamer sequence was
      identified that mediates mRNA transport in vivo when placed in the primary
      binding site on stem-loop IID of the Rex response element. We present the
      solution structure of the HTLV-1 arginine-rich Rex peptide bound to its RNA
      aptamer target determined by multidimensional heteronuclear NMR spectroscopy.
      RESULTS: The Rex peptide in a predominantly extended conformation threads through
      a channel formed by the shallow and widened RNA major groove and a looped out
      guanine. The RNA aptamer contains three stems separated by a pair of two-base
      bulges, and adopts an unanticipated fold in which both junctional sites are
      anchored through base triple formation. Binding specificity is associated with
      intermolecular hydrogen bonding between guanidinium groups of three non-adjacent
      arginines and the guanine base edges of three adjacent G.C pairs. CONCLUSIONS:
      The extended S-shaped conformation of the Rex peptide, together with previous
      demonstrations of a beta-hairpin conformation for the bovine immunodeficiency
      virus (BIV) Tat peptide and an alpha-helical conformation for the human
      immunodeficiency virus (HIV) Rev peptide in complex with their respective RNA
      targets, expands our understanding of the strategies employed by ARMs for
      adaptive recognition and highlights the importance of RNA tertiary structure in
      accommodating minimalist elements of protein secondary structure.

PMID- 10647178
TI  - Helianthus tuberosus lectin reveals a widespread scaffold for mannose-binding
      lectins.
AB  - BACKGROUND: Heltuba, a tuber lectin from the Jerusalem artichoke Helianthus
      tuberosus, belongs to the mannose-binding subgroup of the family of jacalin
      related plant lectins. Heltuba is highly specific for the disaccharides Man alpha
      1-3Man or Man alpha 1-2Man, two carbohydrates that are particularly abundant in
      the glycoconjugates exposed on the surface of viruses, bacteria and fungi, and on
      the epithelial cells along the gastrointestinal tract of lower animals. Heltuba
      is therefore a good candidate as a defense protein against plant pathogens or
      predators. RESULTS: The 2.0 A resolution structure of Heltuba exhibits a
      threefold symmetric beta-prism fold made up of three four-stranded beta sheets.
      The crystal structures of Heltuba in complex with Man alpha 1-3Man and Man alpha
      1-2Man, solved at 2.35 A and 2.45 A resolution respectively, reveal the
      carbohydrate-binding site and the residues required for the specificity towards
      alpha 1-3 or alpha 1-2 mannose linkages. In addition, the crystal packing reveals
      a remarkable, donut-shaped, octahedral assembly of subunits with the mannose
      moieties at the periphery, suggesting possible cross-linking interactions with
      branched oligomannosides. CONCLUSIONS: The structure of Heltuba, which is the
      prototype for an extended family of mannose-binding agglutinins, shares the
      carbohydrate-binding site and beta-prism topology of its galactose-binding
      counterparts jacalin and Maclura pomifera lectin. However, the beta-prism
      elements recruited to form the octameric interface of Heltuba, and the strategy
      used to forge the mannose-binding site, are unique and markedly dissimilar to
      those described for jacalin. The present structure highlights a hitherto
      unrecognized adaptability of the beta-prism building block in the evolution of
      plant proteins.

PMID- 10647179
TI  - The solution structure of Lac repressor headpiece 62 complexed to a symmetrical
      lac operator.
AB  - BACKGROUND: Lactose repressor protein (Lac) controls the expression of the
      lactose metabolic genes in Escherichia coli by binding to an operator sequence in
      the promoter of the lac operon. Binding of inducer molecules to the Lac core
      domain induces changes in tertiary structure that are propagated to the DNA
      binding domain through the connecting hinge region, thereby reducing the affinity
      for the operator. Protein-protein and protein-DNA interactions involving the
      hinge region play a crucial role in the allosteric changes occurring upon
      induction, but have not, as yet, been analyzed in atomic detail. RESULTS: We have
      used nuclear magnetic resonance (NMR) spectroscopy and restrained molecular
      dynamics (rMD) to determine the structure of the Lac repressor DNA-binding domain
      (headpeice 62; HP62) in complex with a symmetrized lac operator. Analysis of the
      structures reveals specific interactions between Lac repressor and DNA that were
      not found in previously investigated Lac repressor-DNA complexes. Important
      differences with the previously reported structures of the HP56-DNA complex were
      found in the loop following the helix-turn-helix (HTH) motif. The protein-protein
      and protein-DNA interactions involving the hinge region and the deformations in
      the DNA structure could be delineated in atomic detail. The structures were also
      used for comparison with the available crystallographic data on the Lac and Pur
      repressor-DNA complexes. CONCLUSIONS: The structures of the HP62-DNA complex
      provide the basis for a better understanding of the specific recognition in the
      Lac repressor-operator complex. In addition, the structural features of the hinge
      region provide detailed insight into the protein-protein and protein-DNA
      interactions responsible for the high affinity of the repressor for operator DNA.

PMID- 10647180
TI  - Crystal structure of a transcriptionally active Smad4 fragment.
AB  - BACKGROUND: Smad4 functions as a common mediator of transforming growth factor
      beta (TGF-beta) signaling by forming complexes with the phosphorylated state of
      pathway-restricted SMAD proteins that act in specific signaling pathways to
      activate transcription. SMAD proteins comprise two domains, the MH1 and MH2
      domain, separated by a linker region. The transcriptional activity and
      synergistic effect of Smad4 require a stretch of proline-rich sequence, the SMAD
      activation domain (SAD), located N-terminal of the MH2 domain. To understand how
      the SAD contributes to Smad4 function, the crystal structure of a fragment
      including the SAD and MH2 domain (S4AF) was determined. RESULTS: The structure of
      the S4AF trimer reveals novel features important for Smad4 function. A Smad4
      specific sequence insertion within the MH2 domain interacts with the C-terminal
      tail to form a structural extension from the core. This extension (the TOWER)
      contains a solvent-accessible glutamine-rich helix. The SAD reinforces the TOWER
      and the structural core through interactions; two residues involved in these
      interactions are targets of tumorigenic mutation. The solvent-accessible proline
      residues of the SAD are located on the same face as the glutamine-rich helix of
      the TOWER, forming a potential transcription activation surface. A tandem sulfate
      ion-binding site was identified within the subunit interface, which may interact
      with the phosphorylated C-terminal sequence of pathway-restricted SMAD proteins.
      CONCLUSIONS: The structure suggests that the SAD provides transcriptional
      capability by reinforcing the structural core and coordinating with the TOWER to
      present the proline-rich and glutamine-rich surfaces for interaction with
      transcription partners. The sulfate-ion-binding sites are potential 'receptors'
      for the phosphorylated sequence of pathway-restricted SMAD proteins in forming a
      heteromeric complex. The structure thus provides a new model that can be tested
      using biochemical and cellular approaches.

PMID- 10647181
TI  - Conformational changes induced by phosphorylation of the FixJ receiver domain.
AB  - BACKGROUND: A variety of bacterial adaptative cellular responses to environmental
      stimuli are mediated by two-component signal transduction pathways. In these
      phosphorelay cascades, histidine kinases transphosphorylate a conserved aspartate
      in the receiver domain, a conserved module in the response regulator superfamily.
      The main effect of this phosphorylation is to alter the conformation of the
      response regulator in order to modulate its biological function. The response
      regulator FixJ displays a typical modular arrangement, with a phosphorylatable N
      terminal receiver domain and a C-terminal DNA-binding domain. In the symbiotic
      bacterium Sinorhizobium meliloti, phosphorylation of this response regulator
      activates transcription of nitrogen-fixation genes. RESULTS: The crystal
      structures of the phosphorylated and of the unphosphorylated N-terminal receiver
      domain of FixJ (FixJN) were solved at 2.3 A and 2.4 A resolution, respectively.
      They reveal the environment of the phosphoaspartate in the active site and the
      specific conformational changes leading to activation of the response regulator.
      Phosphorylation of the conserved aspartate induces major structural changes in
      the beta 4-alpha 4 loop, and in the signaling surface alpha 4-beta 5 that
      mediates dimerization of the phosphorylated full-length response regulator. A
      site-directed mutant at this protein-protein interface decreases the affinity of
      the phosphorylated response regulator for the fixK promoter tenfold. CONCLUSIONS:
      The cascade of phosphorylation-induced conformational changes in FixJN
      illustrates the role of conserved residues in stabilizing the phosphoryl group in
      the active site, triggering the structural transition and achieving the post
      phosphorylation signaling events. We propose that these phosphorylation-induced
      conformational changes underly the activation of response regulators in general.

PMID- 10647182
TI  - Structural transitions in the FixJ receiver domain.
AB  - BACKGROUND: Two-component signal transduction pathways are sophisticated
      phosphorelay cascades widespread in prokaryotes and also found in fungi, molds
      and plants. FixL/FixJ is a prototypical system responsible for the regulation of
      nitrogen fixation in the symbiotic bacterium Sinorhizobium meliloti. In
      microaerobic conditions the membrane-bound kinase FixL uses ATP to
      transphosphorylate a histidine residue, and the response regulator FixJ transfers
      the phosphoryl group from the phosphohistidine to one of its own aspartate
      residues in a Mg(2+)-dependent mechanism. RESULTS: Seven X-ray structures of the
      unphosphorylated N-terminal receiver domain of FixJ (FixJN) have been solved from
      two crystal forms soaked in different conditions. Three conformations of the
      protein were found. In the first case, the protein fold impairs metal binding in
      the active site and the structure reveals a receiver domain that is self
      inhibited for catalysis. In the second conformation, the canonical geometry of
      the active site is attained, and subsequent metal binding to the protein induces
      minimal conformational changes. The third conformation illustrates a non
      catalytic form of the protein where unwinding of the N terminus of helix alpha 1
      has occurred. Interconversion of the canonical and self-inhibited conformations
      requires a large conformational change of the beta 3-alpha 3 loop region.
      CONCLUSIONS: These unphosphorylated structures of FixJN stress the importance of
      flexible peptide segments that delineate the active site. Their movements may act
      as molecular switches that define the functional status of the protein. Such
      observations are in line with structural and biochemical results obtained on
      other response regulator proteins and may illustrate general features that
      account for the specificity of protein-protein interactions.

PMID- 10647183
TI  - The crystal structure of coxsackievirus A9: new insights into the uncoating
      mechanisms of enteroviruses.
AB  - BACKGROUND: Coxsackievirus A9 (CAV9), a human pathogen causing symptoms ranging
      from common colds to fatal infections of the central nervous system, is an
      icosahedral single-stranded RNA virus that belongs to the genus Enterovirus of
      the family Picornaviridae. One of the four capsid proteins, VP1, includes the
      arginine-glycine-aspartate (RGD) motif within its C-terminal extension. This
      region binds to integrin alpha v beta 3, the only receptor for CAV9 to be
      conclusively identified to date. RESULTS: The crystal structure of CAV9 in
      complex with the antiviral compound WIN 51711 has been solved to 2.9 A
      resolution. The structures of the four capsid proteins, VP1 to VP4, resemble
      those of other picornaviruses. The antiviral compound is bound in the VP1
      hydrophobic pocket, and it is possible that the pocket entrance contains a second
      WIN 51711 molecule. Continuous electron density for the VP1 N terminus provides a
      complete picture of the structure close to the fivefold axis. The VP1 C-terminal
      portion is on the outer surface of the virus and becomes disordered five-residues
      N-terminal to the RGD motif. CONCLUSIONS: The RGD motif is exposed and flexible
      in common with other known integrin ligands. Although CAV9 resembles coxsackie B
      viruses (CBVs), several substitutions in the areas implicated in CBV receptor
      attachment suggest it may recognise a different receptor. The structure along the
      fivefold axis provides new information on the uncoating mechanism of
      enteroviruses. CAV9 might bind a larger natural pocket factor than other
      picornaviruses, an observation of particular relevance to the design of new
      antiviral compounds.

PMID- 10647184
TI  - Crystal structure of the actin-binding region of utrophin reveals a head-to-tail
      dimer.
AB  - BACKGROUND: Utrophin is a large multidomain protein that belongs to a superfamily
      of actin-binding proteins, which includes dystrophin, alpha-actinin, beta
      spectrin, fimbrin, filamin and plectin. All the members of this family contain a
      common actin-binding region at their N termini and perform a wide variety of
      roles associated with the actin cytoskeleton. Utrophin is the autosomal homologue
      of dystrophin, the protein defective in the X-linked Duchenne and Becker muscular
      dystrophies, and upregulation of utrophin has been suggested as a potential
      therapy for muscular dystrophy patients. RESULTS: The structure of the actin
      binding region of utrophin, consisting of two calponin-homology (CH) domains, has
      been solved at 3.0 A resolution. It is composed of an antiparallel dimer with
      each of the monomers being present in an extended dumbell shape and the two CH
      domains being separated by a long central helix. This extended conformation is in
      sharp contrast to the compact monomer structure of the N-terminal actin-binding
      region of fimbrin. CONCLUSIONS: The crystal structure of the actin-binding region
      of utrophin suggests that these actin-binding domains may be more flexible than
      was previously thought and that this flexibility may allow domain reorganisation
      and play a role in the actin-binding mechanism. Thus utrophin could possibly bind
      to actin in an extended conformation so that the sites previously identified as
      being important for actin binding may be directly involved in this interaction.

PMID- 10647185
TI  - The structure of the signal receiver domain of the Arabidopsis thaliana ethylene
      receptor ETR1.
AB  - BACKGROUND: In Arabidopsis thaliana, ethylene perception and signal transduction
      into the cell are carried out by a family of membrane-bound receptors, one of
      which is ethylene resistant 1 (ETR1). The large cytoplasmic domain of the
      receptor showed significant sequence homology to the proteins of a common
      bacterial regulatory pathway, the two-component system. This system consists of a
      transmitter histidine kinase and a response regulator (or signal receiver). We
      present the crystal structures of the first plant receiver domain ETRRD (residues
      604-738) of ETR1 in two conformations. RESULTS: The monomeric form of ETRRD
      resembles the known structure of the bacterial receiver domain. ETRRD forms a
      homodimer in solution and in the crystal, an interaction that has not been
      described previously. Dimerization is mediated by the C terminus, which forms an
      extended beta sheet with the dimer-related beta-strand core. Furthermore, the
      loop immediately following the active site adopts an exceptional conformation.
      CONCLUSIONS: The three-dimensional structure of ETRRD shows the expected
      conformational conservation to prokaryotic receiver proteins, such as CheY and
      CheB, both of which are part of the chemotaxis signaling pathway. ETRRD provides
      the first detailed example of a dimerized receiver domain. Given that the dimer
      interface of ETRRD coincides with the phosphorylation-dependent interfaces of
      CheY and CheB, we suggest that the monomerization of ETRRD is phosphorylation
      dependent too. In the Mg(2+)-free form of ETRRD, the gamma-loop conformation does
      not allow a comparable interaction as observed in the active-site architectures
      of Mg(2+)-bound CheY from Escherichia coli and Salmonella typhimurium.

PMID- 10647186
TI  - The three-dimensional structure of the HRDC domain and implications for the
      Werner and Bloom syndrome proteins.
AB  - BACKGROUND: The HRDC (helicase and RNaseD C-terminal) domain is found at the C
      terminus of many RecQ helicases, including the human Werner and Bloom syndrome
      proteins. RecQ helicases have been shown to unwind DNA in an ATP-dependent
      manner. However, the specific functional roles of these proteins in DNA
      recombination and replication are not known. An HRDC domain exists in both of the
      human RecQ homologues that are implicated in human disease and may have an
      important role in their function. RESULTS: We have determined the three
      dimensional structure of the HRDC domain in the Saccharomyces cerevisiae RecQ
      helicase Sgs1p by nuclear magnetic resonance (NMR) spectroscopy. The structure
      resembles auxiliary domains in bacterial DNA helicases and other proteins that
      interact with nucleic acids. We show that a positively charged region on the
      surface of the Sgs1p HRDC domain can interact with DNA. Structural similarities
      to bacterial DNA helicases suggest that the HRDC domain functions as an auxiliary
      domain in RecQ helicases. Homology models of the Werner and Bloom HRDC domains
      show different surface properties when compared with Sgs1p. CONCLUSIONS: The HRDC
      domain represents a structural scaffold that resembles auxiliary domains in
      proteins that are involved in nucleic acid metabolism. In Sgs1p, the HRDC domain
      could modulate the helicase function via auxiliary contacts to DNA. However, in
      the Werner and Bloom syndrome helicases the HRDC domain may have a role in their
      functional differences by mediating diverse molecular interactions.

PMID- 10647188
TI  - The Escherichia coli large ribosomal subunit at 7.5 A resolution.
AB  - BACKGROUND: In recent years, the three-dimensional structure of the ribosome has
      been visualised in different functional states by single-particle cryo-electron
      microscopy (cryo-EM) at 13-25 A resolution. Even more recently, X-ray
      crystallography has achieved resolution levels better than 10 A for the ribosomal
      structures of thermophilic and halophilic organisms. We present here the 7.5 A
      solution structure of the 50S large subunit of the Escherichia coli ribosome, as
      determined by cryo-EM and angular reconstitution. RESULTS: The reconstruction
      reveals a host of new details including the long alpha helix connecting the N-
      and C-terminal domains of the L9 protein, which is found wrapped like a collar
      around the base of the L1 stalk. A second L7/L12 dimer is now visible below the
      classical L7/L12 'stalk', thus revealing the position of the entire L8 complex.
      Extensive conformational changes occur in the 50S subunit upon 30S binding; for
      example, the L9 protein moves by some 50 A. Various rRNA stem-loops are found to
      be involved in subunit binding: helix h38, located in the A-site finger; h69, on
      the rim of the peptidyl transferase centre cleft; and h34, in the principal
      interface protrusion. CONCLUSIONS: Single-particle cryo-EM is rapidly evolving
      towards the resolution levels required for the direct atomic interpretation of
      the structure of the ribosome. Structural details such as the minor and major
      grooves in rRNA double helices and alpha helices of the ribosomal proteins can
      already be visualised directly in cryo-EM reconstructions of ribosomes frozen in
      different functional states.

PMID- 10647187
TI  - Direct three-dimensional localization and positive identification of RNA helices
      within the ribosome by means of genetic tagging and cryo-electron microscopy.
AB  - BACKGROUND: Ribosomes are complex macromolecular machines that perform the
      translation of the genetic message. Cryo-electron microscopic (cryo-EM) maps of
      the Escherichia coli 70S ribosome are approaching a resolution of 10 A and X-ray
      maps of the 30S and 50S subunits are now available at 5 A. These maps show a lot
      of details about the inner architecture of the ribosome and ribosomal RNA helices
      are clearly visible. However, in the absence of further biological information,
      even at the higher resolution of the X-ray maps many rRNA helices can be placed
      only tentatively. Here we show that genetic tagging in combination with cryo-EM
      can place and orient double-stranded RNA helices with high accuracy. RESULTS: A
      tRNA sequence inserted into the E. coli 23S ribosomal RNA gene, at one of the
      points of sequence expansion in eukaryotic ribosomes, is visible in the cryo-EM
      map as a peripheral 'foot' structure. By tracing its acceptor-stem end, the
      location of helix 63 in domain IV and helix 98 in domain VI of the 50S subunit
      could be precisely determined. CONCLUSIONS: Our study demonstrates for the first
      time that features of a three-dimensional cryo-EM map of an asymmetric
      macromolecular complex can be interpreted in terms of secondary and primary
      structure. Using the identified helices as a starting point, it is possible to
      model and interpret, in molecular terms, a larger portion of the ribosome. Our
      results might be also useful in interpreting and refining the current X-ray maps.

PMID- 10647189
TI  - [Acute coronary syndrome].

PMID- 10647190
TI  - [Pathogenetic significance of cholesterol-containing immune complexes and lipid
      peroxidation in ischemic heart disease].
AB  - AIM: To ascertain a relationship between cholesterol content in circulating
      immune complexes (CIC) and plasm lipid peroxidation (LPO) in patients with
      ischemic heart disease (IHD). MATERIALS AND METHODS: Blood samples from 33 IHD
      patients 23 of which had a history of myocardial infarction and from 8 healthy
      subjects were examined for total cholesterol, high and low density lipoproteins
      cholesterol, CIC, the ability of blood serum to induce free radicals, superoxide
      dismutase. RESULTS: A statistically significant positive correlation was found
      between CIC cholesterol level and content of free radicals while a negative
      correlation existed between superoxide dismutase activity and high density
      lipoprotein cholesterol level in blood plasm of healthy individuals and patients
      with IHD. After myocardial infarction an inversion of the above parameters was
      seen as a result of disorders in both antioxidant and immune systems. CONCLUSION:
      The level of both LPO and CIC cholesterol, their interaction are important
      atherogenic factors in development of IHD.

PMID- 10647191
TI  - [Symptomless myocardial ischemia: feasibility of diagnostic mistakes].
AB  - AIM: To examine feasibility of ST segment depression on ECG in treadmill exercise
      test and 24-h ECG monitoring in subjects with coronarographically intact coronary
      arteries. MATERIALS AND METHODS: 9 males aged 41 to 52 years with chest pains
      unrelated to muscular load. They had neither stenosis of coronary arteries, nor
      arterial hypertension, valvular defects, disturbance of electrolyte metabolism.
      All of them have undergone treadmill exercise test and 24-h ECG monitoring.
      RESULTS: The exercise test provoked chest pain in none of the examinees. ST
      segment was depressed in one patient. 24-h monitoring registered depression of ST
      segment in one more patient. The rest 7 patients showed no changes in ST segment
      either in exercise test or 24-h ECG monitoring. CONCLUSION: It is confirmed that
      typical ischemic ECG changes (horizontal depression of ST segment) in healthy
      persons can occur and may be mistaken for silent myocardial ischemia.

PMID- 10647192
TI  - [Thrombolytic therapy for acute myocardial infarction: circadian sensitivity].
AB  - AIM: To identify additional factors which may influence the results of
      thrombolytic therapy (TT) with streptokinase in acute myocardial infarction
      (AMI). MATERIALS AND METHODS: 122 case histories of males treated with
      streptokinase for AMI were analyzed. The patients were subdivided into 3 groups
      according to TT effectiveness: effective (74 patients-60.7%, age 61.3 +/- 11.9
      years, group 1); probably successful (13 patients-10.7%, age 68.9 +/- 9.3, group
      2), unsuccessful (35 patients-28.6%, age 64.9 +/- 13.6, group 3). RESULTS:
      Between groups 1 and 3 there were no differences by age, AMI location, coronary
      risk factors (smoking, hypertension, diabetes mellitus, hyperlipidemia, family
      history of coronary disease), previous MI, Q and non-Q-wave MI prevalence.
      Significant differences were, on the contrary, obtained for the Killip class
      (1.82 +/- 0.46 vs 2.26 +/- 0.74, p = 0.0001), fibrinogen level before TT (314.6
      +/- 87.2 vs 215.5 +/- 121.9 mg%, p = 0.003), LVEF% (by echo) 24 hours after the
      treatment (41.9 +/- 6.3 vs 36.5 +/- 7.8, p = 0.0001), time delay of TT from AMI
      symptoms onset (2.45 +/- 1.14 vs 3.08 +/- 1.73 hours, p = 0.014). Circadian
      variation has been discovered for efficacy of streptokinase: in the evening (from
      16 to 24 pm) the effectiveness of TT was highest--38.0% vs 14.7% (p = 0.005) and
      at night (from 24 pm to 08 am) the effect was the lowest--22.5% vs 41.2% (p =
      0.024). Smoking was not an independent factor for TT success. CONCLUSION:
      Multiple regression analysis (step by step) has shown that the main independent
      determinants for TT success in males were: Killip class (p = 0.002), time delay
      of TT (p = 0.014), day time of TT beginning (p = 0.023) and MI location (p =
      0.123). These findings may have several clinical implications, for example: dose
      adjustment of streptokinase for the time of day or preference for primary
      coronary angioplasty in the morning.

PMID- 10647193
TI  - [Pilot experience with skeletal muscles electrostimulation in rehabilitation of
      patients with complicated myocardial infarction].
AB  - AIM: To test electric stimulation of the skeletal muscles in rehabilitation of
      patients with complicated myocardial infarction. MATERIALS AND METHODS: 27
      patients with macrofocal myocardial infarction (age 67 +/- 2.4 years) with
      persisting left ventricular insufficiency in the beginning of the subacute
      period. From day 3-4 all the patients were subjected to electrostimulation of
      large skeletal muscles (ESSM). The procedures were made daily for 2 hours using
      the Mioritm-040 unit. In the course of the first session the study was made of
      the changes in the intracardiac hemodynamics and doppler parameters of
      circulation in the popliteal artery. RESULTS: In the course of ESSM of 10-15
      sessions none of the patients had anginal attacks, aggravation of dyspnea,
      arrhythmia episodes. After the course there was a marked increase in left
      ventricular ejection fraction and stroke volume. CONCLUSION: ESSM is safe in
      complicated myocardial infarction, prevent unwanted effects of long-term stay in
      bed, improves intracardiac hemodynamics.

PMID- 10647194
TI  - [Effects of melatonin alone and in combination with aceten on chronostructure of
      diurnal hemodynamic rhythms in patients with hypertension stage II].
AB  - AIM: To study effects of monotherapy with melatonin and combination melatonin +
      aceten on circadian pattern of hemodynamics in patients with essential
      hypertension stage II. MATERIALS AND METHODS: 20 EH patients were randomized into
      2 groups, 10 patients each. Group 1 patients were given melatonin alone (6 mg at
      22.00). Group 2 received aceten (25 mg at 18.00) and melatonin (6 mg at 22.00).
      Before treatment and after 10 days of it, hemodynamic parameters were measured
      each 3 hours for 24 hours. Arterial pressure was measured by Korotkov method,
      heart rate--by ECG R-R interval, stroke volume--by tetrapolar chest rheography
      according to Kubichek. Cardiac index, total and specific peripheral resistance,
      double product were estimated routinely. RESULTS: Internal and external
      dyssynchronism was registered in hemodynamic parameters of EH patients. Melatonin
      normalized circadian hemodynamic rhythms. It produced a hypotensive effect,
      reduced energy requirements of the myocardium. Combination of melatonin with
      aceten had a hypotensive and vasodilating effects but failed to restore circadian
      hemodynamic rhythms. CONCLUSION: Melatonin, epiphysial neurohormone, and its
      combination with aceten have hypotensive and vasodilating effects but melatonin
      monotherapy normalizes circadian hemodynamic rhythms while the combination was
      uneffective in this respect. This may be explained by interaction of melatonin
      and aceten actions.

PMID- 10647195
TI  - [24-hour ECG monitoring in cardiac fibrillation].
AB  - AIM: To elucidate clinical value of 24-h ECG monitoring followed by analysis of
      cardiac rhythm structure in patients with perpetual cardiac fibrillation (CF).
      MATERIALS AND METHODS: 24-h ECG monitoring has been performed 163 times in 142
      patients aged 33-82 years. Interval histograms and cardiointervalograms of R-R
      intervals were performed. RESULTS: 24-h ECG monitoring has shown the phenomena
      which can be used for perfection of the diagnosis and treatment: features of 24-h
      changes in heart rate; features of ventricular ectopy; periods of asystole;
      preclinical signs of hyperdigitalization; frequency-related shift of ST segment.
      CONCLUSION: 24-h ECG monitoring in patients with perpetual CF provides valuable
      diagnostic information. Therefore, it should be conducted in all of them
      irrespective of subjective state and routine ECG data, especially in deciding on
      antiarrhythmic therapy.

PMID- 10647196
TI  - [Role of staphylococcus aureus hemolytic toxin-alpha in pathogenesis of
      infectious endocarditis: studies in vitro].
AB  - AIM: To study effects of alpha-toxin (AT) Staphylococcus aureus on human
      platelets and endothelial cells. MATERIALS AND METHODS: Concentrations of
      intracellular calcium in human platelets and endothelial cells were estimated by
      fluorescence, phosphoinositide metabolism in the endothelial cells was studied
      using 3H-myoinositole. RESULTS: AT induced a dose-dependent increase of
      intracellular calcium in blood and vascular cells, stimulates dose-dependent
      formation of inositol phosphates in endothelial cells. CONCLUSION: AT action on
      the platelets and endothelial cells results in a significant receptor-independent
      rise in concentration of intracellular calcium, activation of phosphoinositide
      metabolism, death of cells. These data support the hypothesis that the platelet
      and endothelial cell damage is mostly due to the passive Ca2+ influxvia pores
      formed by AT in cellular membrane.

PMID- 10647197
TI  - [Diagnosis of chronic abdominal ischemia due to compressive celiac trunk
      stenosis].
AB  - AIM: Elucidation of clinical symptoms of compressive celiac trunk stenosis (CCTS)
      and development of diagnostic programs and the disease classification. MATERIALS
      AND METHODS: Clinical signs of CCTS and results of device examinations have been
      analyzed in 511 patients operated for CCTS. The diagnostic program is proposed
      which simplifies CCTS identification. How to use methods of auscultation and
      phonoangiography of the abdomen, sonography and angiography of the visceral
      aortic branches, endoscopy and kinesography in this disease is shown. Three
      symptom complexes are most noticeable in CCTS clinical picture: abdominal pain
      after meals (100%), digestive tract dysfunctions (78.4%), neurovegetative
      disorders (84.38%). 67.44% of patients noted meteorological dependence of the
      disease exacerbation. Objective investigation revealed tenderness to palpation in
      the epigastrium (100%), systolic murmur in the epigastrium on an empty stomach
      after full expiration (98.67%). CONCLUSION: Sonographic and endoscopic
      investigations are recommended for screening of patients to reveal stenotic
      injury of the celiac trunk. Timely detection of the disease and surgical
      treatment produce a positive effect in most cases.

PMID- 10647198
TI  - [Melatonin effects on functional activity of platelets in patients with bronchial
      asthma].
AB  - AIM: To assess effects of epiphysial hormone melatonin in various dose regimens
      on ADP-induced aggregation of platelets in patients with bronchial asthma (BA).
      Correlations with urine levels of 6-sulphatoxymelatonin (6-SOMT), basic melatonin
      metabolite, were made. MATERIALS AND METHODS: Melatonin was given to 17 patients
      with mild or moderate BA and 16 healthy controls. RESULTS: BA patients were found
      to have disorders in circadian rhythm of urine 6-SOMT excretion, lack of
      correlation between platelet functional activity and elevated nocturnal excretion
      of 6-SOMT, in vitro platelet activation in response to low-dose melatonin and
      absence of this reaction to high-dose melatonin. CONCLUSION: It is suggested that
      melatonin may be involved in genesis of bronchoobstructive syndrome in BA.

PMID- 10647199
TI  - [Prognosis of nosocomial pneumonia outcome].
AB  - AIM: To assess frequency of occurrence of factors registered before or in the
      course of nosocomial pneumonia (NP) and implications of these factors for the
      risk of NP lethal outcome. MATERIALS AND METHODS: 70 NP patients entered the
      study. They were admitted to hospital with diagnosis of chronic nonspecific
      pulmonary disease, severe trauma, hemoblastosis, other tumors, etc. 26 of them
      recovered and were discharged from hospital, 44 patients died. RESULTS: The risk
      of lethal outcome in NP was higher in hepatic disturbances, high levels of urea
      in the blood, hemorrhagic syndrome, antibiotic treatment prior to NP,
      administration of glucocorticosteroids. St. aureus as the etiologic agent of
      nosocomial pneumonia was registered more frequently in patients with a lethal
      outcome. CONCLUSION: Further studies are needed for more precise evaluation of
      pathophysiological links between NP and lesions of other organs.

PMID- 10647200
TI  - [Cardiolipin antibodies dependents on beta2-glycoprotein-1 in antiphospholipid
      syndrome].
AB  - AIM: To study beta2-GP-I-dependent binding of phospholipid antibodies (PAb) to
      phospholipids and this process participation in pathogenesis of antiphospholipid
      syndrome (APS). MATERIALS AND METHODS: IgG-fractions and sera from 20 patients
      with APS. Cofactor activity of beta2-GP-I isolated from serum of healthy donors
      was examined with modified immunoassay. RESULTS: Contrary to donor IgG, binding
      of IgG fractions isolated from sera of APS patients with cardiolipin grows dose
      dependently in the presence of beta2-GP-I. Cofactor activity of beta2-GP-I is
      confirmed in the study of sera of APS patients. Sera containing beta2-GP-I
      dependent antibodies to cardiolipin (aCL), unlike aCL-negative sera, react with
      solid-phase immobilized beta2-GP-I. CONCLUSION: It is confirmed that beta2-GP-I
      participates in interaction of PAb with cardiolipin. Pathogenetic implication of
      beta2-GP-I-dependent PAb for onset of APS is discussed.

PMID- 10647201
TI  - [Osteodystrophy in systemic lupus erythematosis: it due to SLE or steroids?].

PMID- 10647202
TI  - [Drug-induced hepatitis].
AB  - AIM: To improve diagnosis and treatment of drug-induced hepatitis: to specify
      drugs with hepatotoxic effect, clinical variants of drug-induced hepatic
      diseases, management of drug-induced hepatitis (DIH). MATERIALS AND METHODS: Of
      2300 examinees with hepatic lesions, 62 were diagnosed to have DIH. Measurements
      were made of serum levels of bilirubin and its fractions, total protein, some
      protein fractions, markers of hepatitis A, B, C, activity of aminotransferases
      (AlAT and AsAT), alkaline phosphatase (AP), glutamate dehydrogenase (GlDG),
      sorbitol dehydrogenase (SDG), gamma-glutamate transpeptidase (GGTP), choline
      esterase (CE). Timolveronal test was made. On demand, tests were made for CEA,
      AFP; device examinations were made: ultrasound investigation, computed tomography
      of the abdominal organs, endoscopic retrograde pancreatography, laparoscopy with
      hepatic biopsy, transcutaneous hepatic biopsy, laparotomy with
      cholecystocholangiography. RESULTS: A direct relationship of hepatitis with drugs
      intake was revealed in all the patients. Development of drug-induced intrahepatic
      cholestasis in patients on long-term treatment with anticancer drugs was
      accompanied with affection of cellular organellas and progressive destruction of
      small interlobular ducts provoking intrahepatic cholestasis and depletion of
      natural glutathione. CONCLUSION: Correction of intrahepatic cholestasis and
      deficiency of endogenic glutathione is successfully carried out with heptral.

PMID- 10647203
TI  - [Heterogeneity of diabetes mellitus].
AB  - AIM: To define a criterium for differentiation of different types of diabetes
      mellitus (DM). MATERIALS AND METHODS: The condition of immunity, antibodies to
      the pancreatic island cells, proliferative activity of peripheral blood
      lymphocytes in response to human immunoglobulin were studied in 152 patients with
      DM. RESULTS: Sensitization of lymphocytes to insulin is associated with DM type
      I. Latent sensitization of lymphocytes to insulin detectable in inhibition of
      functional activity of prostaglandin-synthesizing cells is encountered in classic
      course of DM type II, while detectable in inhibition of functional activity of
      the cells carrying receptors to histamine is observed in patients with symptoms
      of either DM type I or DM type II. Lack of either apparent or latent lymphocyte
      sensitization to insulin in chronic hyperglycemia is associated with secondary
      DM. CONCLUSION: How lymphocytes are sensitized to insulin is important for
      differential diagnosis not only of DM type but also of DM forms within the same
      type. Groups of the DM patients were different not only by immunological indices
      but also by clinical course, treatment and prognosis.

PMID- 10647204
TI  - [Antianginal effectiveness of regular isosorbide-5-mononitrate (monochinkwe
      retard) intake].

PMID- 10647205
TI  - [Secondary amyloidosis in patient with Kaposi's sarcoma].

PMID- 10647206
TI  - [Myocarditis, polymyositis and Raynaud's syndrome in female patient with chronic
      hepatitis C].

PMID- 10647207
TI  - [Peripheral beta-adrenoreceptors in arterial hypertension].

PMID- 10647208
TI  - [Clinico-morphological features of dilated and ischemic cardiomyopathy].

PMID- 10647209
TI  - [Role of magnesium in pathogenesis and treatment of arterial hypertension].

PMID- 10647210
TI  - [Autoimmune lesions of thyroid as complications of interferon treatment of
      chronic viral hepatitis].

PMID- 10647211
TI  - [Role of aldosterone block in combined therapy of heart failure].

PMID- 10647212
TI  - [Chronic obstructive pulmonary disease (lecture)].

PMID- 10647213
TI  - Effectiveness of ascorbate and ascorbate peroxidase in promoting nitrogen
      fixation in model systems.
AB  - Ascorbate and ascorbate peroxidase are important antioxidants that are abundant
      in N2-fixing legume root nodules. Antioxidants are especially critical in root
      nodules because leghemoglobin, which is present at high concentrations in
      nodules, is prone to autoxidation and production of activated oxygen species such
      as O2.- and H2O2. The merits of ascorbate and ascorbate peroxidase for
      maintaining conditions favorable for N2 fixation were examined in two model
      systems containing oxygen-binding proteins (purified myoglobin or leghemoglobin)
      and N2-fixing microorganisms (free-living Azorhizobium or bacteroids of
      Bradyrhizobium japonicum) in sealed vials. The inclusion of ascorbate alone to
      these systems led to enhanced oxygenation of hemeproteins, as well as to
      increases in nitrogenase (acetylene reduction) activity. The inclusion of both
      ascorbate and ascorbate peroxidase resulted in even greater positive responses,
      including increases of up to 4.5-fold in nitrogenase activity. In contrast,
      superoxide dismutase did not provide beneficial antioxidant action and catalase
      alone provided only very marginal benefit. Optimal concentrations were 2 mM for
      ascorbate and 200 micrograms/ml for ascorbate peroxidase. These concentrations
      are similar to those found in intact soybean nodules. These results support the
      conclusion that ascorbate and ascorbate peroxidase are beneficial for maintaining
      conditions favorable for N2 fixation in nodules.

PMID- 10647214
TI  - Microbial transformation of delta 9(15)-africanene.
AB  - Incubation of delta 9(15)-africanene with fungi Aspergillus niger and Rhizopus
      oryzae for 8 days yielded two oxidized derivatives, 10 alpha-hydroxy-delta 9(15)
      africanene and 9 alpha,15-epoxyafricanane. The structure of the two products were
      assigned by interpretation of their spectral data.

PMID- 10647215
TI  - The microbiological hydroxylation of 3 alpha,5-cycloandrostanes by Cephalosporium
      aphidicola.
AB  - The microbiological hydroxylation of some 3 alpha,5-cycloandrostanes by the
      fungus, Cephalosporium aphidicola has been shown to take place at C-2 alpha and C
      14 alpha and a 6 beta-alcohol was oxidized to the 6-ketone.

PMID- 10647216
TI  - Pentacyclic triterpenes from Chuquiraga ulicina.
AB  - Four taraxastane triterpenes, 3 beta-acetoxy-6 beta-hydroxytaraxasta-20-ene, 6
      beta-hydroxytaraxasta-20-en-3-one, 6 beta-hydroxytaraxasta-20-ene 3 beta
      palmitate and 3 beta,6 beta-dihydroxytaraxasta-20-ene were isolated from the
      dichloromethane-methanol extract of Chuquiraga ulicina ssp. ulicina together with
      the known triterpenes lupeol, lupenyl acetate, lupenone, friedelinol, 3 beta
      acetoxy-30-nor-lupan-20-one, and 30-nor-lupan-3 beta-ol-20-one.

PMID- 10647217
TI  - Two C21-steroidal glycosides isolated from Cynanchum stauntoi.
AB  - Studies on the roots of Cynanchum stauntoi led to the isolation of two C21
      steroidal glycosides, formally named stauntosides A and B. Their structures were
      elucidated on the basis of spectroscopic evidence, especially that from analysis
      of 2D-NMR spectra. They were found to possess an unusual skeleton and were
      identified as stauntogenin 3-O-alpha-L-diginopyranosyl-(1-4)-beta-L
      cymaropyranosyl-(1- 4)-beta-D- digitoxopyranosyl-(1-4)-beta-D-thevetopyranoside
      and stauntogenin 3-O-alpha-L-cymaropyranosyl-(1-4)-beta-D-digitoxopyranosyl-( 1
      4)-beta-D-3- demethyl-2-deoxy-thevetopyranoside.

PMID- 10647218
TI  - Identification of the bright-greenish-yellow-fluorescence (BGY-F) compound on
      cotton lint associated with aflatoxin contamination in cottonseed.
AB  - In order to characterize the structure of the bright-greenish-yellow-fluorescence
      (BGY-F) compound on cotton lint associated with aflatoxin contamination in cotton
      seed, various in vitro and in vivo natural BGY-F reaction products were prepared.
      Under similar high pressure liquid chromatography separation with variable
      wavelength and programmable fluorescence detection (HPLC-UV/FL), combined with
      atmospheric pressure ionization and mass spectral determinations it was found
      that the BGY-F reaction products prepared from three preparations: (a) kojic acid
      (KA) + peroxidase (soybean peroxide or horseradish type VI and type II) + H2O2,
      or (b) detached fresh cotton locules + KA + H2O2, or (c) attached field cotton
      locules that were treated with a spore suspension of aflatoxigenic Aspergillus
      flavus, all resulted in identical chromatographic characteristics, and all
      exhibited a molecular weight of 282. Further characterization of the BGY-F
      reaction product with 1H- and 13C-NMR spectroscopic analysis revealed that it was
      a dehydrogenator dimer of 2 KA, linked through the C-6 positions.

PMID- 10647219
TI  - Antibacterial and antifungal flavanones from Eysenhardtia texana.
AB  - An activity-guided fractionation of a methanol-dichloromethane extract obtained
      from the aerial parts of Eysenhardtia texana led to the isolation of two novel
      antibacterial and antifungal flavanones together with a known flavanone. Their
      structures were established as 4',5,7-trihydroxy-8-methyl-6-(3-methyl-[2
      butenyl])-(2S)-flavanone, 4',5,7-trihydroxy-6-methyl-8-(3-methyl-[2-butenyl])
      (2S)-flavanone and 4',5-dihydroxy-7-methoxy-6-(3-methyl-[2-butenyl])-(2S)
      flavanone on the basis of their UV, 1D and 2D-NMR spectra.

PMID- 10647220
TI  - Antibacterial activity of pure flavonoids isolated from mosses.
AB  - Seven pure flavonoids were isolated and identified from five moss species. The
      flavonoids were the flavones apigenin, apigenin-7-O-triglycoside, lucenin-2,
      luteolin-7-O-neohesperidoside, saponarine and vitexin; and the biflavonoid
      bartramiaflavone. Some of these flavonoids were shown to have pronounced
      antibacterial effects against Enterobacter cloaceae, E. aerogenes and Pseudomonas
      aeruginosa (minimal bacteriostatic concentration MIC in the range of 4-2048
      micrograms/ml). Because of their antibacterial spectrum mainly active against
      Gram negative bacterial strains, responsible for severe opportunistic infections
      and resistant to common antibacterial therapy, these flavonoids may be important
      tools in antibacterial strategies.

PMID- 10647221
TI  - Taxane diterpenoids from the seeds of Chinese yew Taxus chinensis.
AB  - The taxoid chinentaxunine has been isolated from the seeds of Chinese yew Taxus
      chinensis, and its structure determined on the basis of spectral and chemical
      methods. In addition, the known taxol C, paclitaxel, 10-deacetyl taxol A, 10
      deacetyl-7-epitaxol, 10-deacetyl-10-oxo-7-epi-taxol, taxinine M, taxchinin A, 10
      deacetyl taxinine B and taxuspine X were also isolated and identified from this
      source.

PMID- 10647222
TI  - Oligomeric hydrolysable tannins from Tibouchina multiflora.
AB  - Two hydrolysable tannins, nobotanin O and nobotanin P, were isolated from the
      leaf extract of Tibouchina multiflora (Melastomataceae) and their dimeric and
      tetrameric structures elucidated on the basis of spectral data and chemical
      correlations with nobotanin B and K, respectively. Thirteen known hydrolysable
      tannins including nobotanins A, B, C and J, which are oligomers characteristic of
      the Melastomataceae, were also isolated.

PMID- 10647223
TI  - Megistosarcimine and megistosarconine, two alkaloids from Sarcomelicope
      megistophylla.
AB  - Two new alkaloids, megistosarcimine and megistosarconine, were isolated from the
      aerial parts of Sarcomelicope megistophylla. Their structures have been
      elucidated on the basis of their spectral data and molecular modeling.

PMID- 10647224
TI  - Importance of differentiation of Entamoeba histolytica from entamoeba dispar.

PMID- 10647225
TI  - Prenatal diagnosis of haemophilia-A: a basis for the Pakistani families.
AB  - OBJECTIVE: To determine the feasibility of a PCR based strategy for prenatal
      diagnosis of Haemophilia-A in Pakistani Families. DESIGN: Prospective. SETTING:
      Department of Haematology, Armed Forces Institute of Pathology, Rawalpindi.
      SUBJECTS: Five families with at least one child affected with Haemophilia-A. Each
      family comprised of father, mother, affected child and fetus when present. MAIN
      OUTCOME MEASURES: Short Tandem Repeat (STR) analysis in the Intron 22 of factor
      VIII gene. RESULTS: PCR based analysis of the STR in intron 22 of factor VIII
      gene showed that the marker was informative in 4/5 study families and could be
      used in these families for the prenatal diagnosis of Haemophilia-A. In two
      families prenatal diagnosis was carried out by Chorionic Villus Sampling at 10-13
      weeks gestation and the results in both the cases showed a carrier female fetus.
      CONCLUSION: Linkage based prenatal diagnosis of Haemophilia-A by an intragenic
      STR marker is feasible in most of the Pakistani families. The long term response
      of the Haemophiliac families to the availability of prenatal diagnosis remains to
      be seen. The STR marker can also be used for carrier detection of female subjects
      in the affected families.

PMID- 10647226
TI  - Clinicopathological features and management of Pakistani patients with multiple
      myeloma.
AB  - OBJECTIVE: Purpose of the study was to evaluate the clinicopathological features
      of multiple myeloma in Pakistan and to study the influence of therapeutic
      management in these cases. METHODS: We retrospectively analyzed 99 newly
      diagnosed patients with multiple myeloma seen from 1988 to 1996. Diagnostic
      criteria included bone marrow plasmacytosis, monoclonal gammopathy in serum or
      urine and radiological evidence of skeletal lesions. RESULTS: There were 57 males
      and 42 females. Mean age of the patients was 58 years with a range of 23 to 86
      years. One-third of the patients were bed ridden at the time of presentation.
      Common presenting symptoms included bone pain (82%), fatigue (78%) and backache
      (73%). Physical findings, laboratory features and radiologic assessment revealed
      pallor (56%), severe anaemia with hemoglobin < 8.5 gm/dl (39%), creatinine > or =
      2 2 mg/dl (57%), serum calcium > or = 12 gm/dl (23%), uric acid > or = 8 gm/dl
      (47%) and albumin < or = 3.5 gm/dl (63%). Commonest monoclonal gammopathy was igG
      kappa. Majority (71%) of the patients presented with stage III disease. Commonest
      chemotherapeutic regimen utilized was melphalan and prednisolone which was
      administered to 88% of the patients. Complete remission was observed in 25% and
      partial remission in 36% of the evaluated patients. Commonest complication during
      the course of disease was related to skeletal involvement followed by renal
      failure and bone marrow suppression. Median survival of the patients was 34
      months. CONCLUSION: Multiple myeloma patients in Pakistan are younger, more
      frequently have poor performance status and more often present with advanced
      stage of disease. Response to therapy, however, is adequate and survival is
      comparable to Western patients.

PMID- 10647227
TI  - Bacteriological quality of drinking water in Punjab: evaluation of H2S strip
      test.
AB  - OBJECTIVE: To assess bacteriological quality of drinking water in Punjab and to
      evaluate usefulness of H2S strip test in comparison with multiple tube test.
      METHOD: Samples of water were tested using H2S strips and multiple tube test.
      RESULTS: Maximum bacterial contamination was observed in water from domestic
      pumps (95.83%). Followed by tap water in rural areas of Punjab (91.30%) and tap
      water in Lahore (42.85%). Bacterial contamination was significantly higher (p <
      0.001) in rural areas as compared to urban areas. Comparison of results of
      testing water samples by H2S strip test and multiple tube test revealed that H2S
      strip is 87.24% sensitive and 100% specific for detection of bacterial
      contamination with a positive predictive value of 100%. It was also observed that
      100% water samples negative for total coliforms were also negative by H2S strip
      method. Moreover, with increase in number of total coliforms in the water
      samples, positivity by H2S strip method also increased (samples with more than 10
      total coliforms/100 ml were 100% positive by H2S strip method). Therefore, H2S
      strip test can be used as alternative to multiple tube test for detection of
      bacterial contamination of water supplies. CONCLUSION: It is concluded that
      bacterial contamination of water is a significant problem in Punjab. It can be
      improved by regular monitoring of water supplies. For this purpose use of H2S
      strip test is advocated at house hold level.

PMID- 10647228
TI  - p53 and PCNA expression in benign, atypical and malignant meningiomas.
AB  - OBJECTIVE: Alterations: p53 genes are turning out to be the most common genetic
      alterations in human cancers. Due to long half-life of mutated p53, its detection
      is possible by immunohistochemistry. Proliferating cell nuclear antigen (PCNA) is
      expressed by dividing cells, hence has been shown to correlate with prognosis. We
      have used monoclonal antibodies protein DO-7 (p53) and PC10 (PCNA) to see whether
      their expression correlates with histological grading in meningethelial tumour.
      MATERIAL AND METHODS: Twenty nine meningiomas (20 benign, 7 atypical and 2
      malignant) were selected from the records of our laboratory. p53 and PCNA
      expression was sought by immunohistochemistry using Peroxidase Anti Peroxidase
      (PAP) technique. RESULTS: Four benign and 2 atypical meningiomas showed weak
      staining for p53. Both malignant meningiomas showed strong positivity for p53.
      Six benign meningiomas had less than 5% PCNA positivity, one 10% positivity and
      three showed 20% positivity. PCNA positivity ranged for 10-80% in atypical
      meningiomas. In two malignant meningiomas PCNA positivity was 70% and 90%.
      CONCLUSION: It is worthwhile to include p53 and PCNA expression along with
      histologic assessment in predicting outcome of meningiomas. A larger series with
      complete follow-up is essential in assessing value of these markers which
      unfortunately remains a dream in our country.

PMID- 10647229
TI  - Pneumothorax: a review of 146 adult cases admitted at a university teaching
      hospital in Pakistan.
AB  - OBJECTIVE: There is a lack of data on the etiology and outcome of pneumothorax
      among the Pakistani population. Our aim was to review the etiology, clinical
      course, management and outcome of patients presenting with pneumothorax. PATIENTS
      AND METHODS: All adult cases with pneumothorax admitted to a University Teaching
      Hospital in Karachi, between January 1992 and June 1996, were reviewed and
      analyzed. RESULTS: A total of 146 patients were reviewed. Their mean age was 46.3
      years (SD +/- 17.8 years) with a male to female ratio of 3.7:1. Secondary
      pneumothorax was the commonest type seen (45%), followed by traumatic (21%),
      iatrogenic (18%) and primary (16%). Tuberculosis (47%) and COPD (45%) were most
      common lung diseases associated with secondary pneumothorax. Pneumothorax
      secondary to TB presented at an earlier age than that with COPD (49.6 vs. 60.1
      years). Similarly, patients with primary pneumothorax were significantly younger
      than patients with secondary pneumothorax (42.3 vs. 51.7 years). Rib fracture was
      the most common cause of traumatic pneumothorax. Coronary artery bypass grafting,
      transthoracic fine needle aspiration and neck vein cannulations were the leading
      iatrogenic causes. The commonest symptoms of pneumothorax were dyspnea (68%) and
      chest pain (40%). Most cases (81%) were successfully managed by intercostal tube
      drainage. CONCLUSION: In our study population, secondary pneumothorax was the
      commonest variety seen. TB was the commonest cause of secondary pneumothorax,
      closely followed by COPD. Nearly 40% of pneumothorax were either traumatic or
      iatrogenic. Intercostal tube drainage remains the treatment of choice for
      pneumothorax.

PMID- 10647230
TI  - A case for comprehensive antenatal screening for blood group antibodies.
AB  - OBJECTIVES: To determine the frequency of various blood group antibodies
      responsible for haemolytic disease of the new born (HDN). DESIGN: A prospective
      study of all neonates and still born foetuses suspected to have haemolytic
      disease of the new born and their mothers. SUBJECTS: Neonates suspected to have
      HDN as per study criteria along with their mothers and mothers of still born
      foetuses with hydrops foetalis. METHODS: Pertinent serological tests, serum
      bilirubin estimation, haemoglobin estimation and reticulocyte count on neonate's
      blood samples and demonstration/titration of blood group specific antibodies in
      maternal blood samples. RESULTS: Six cases of HDN due to blood group antibodies
      were detected so far. Four were due to anti-D and all were of mild severity as
      per study criteria. Two cases were of severe haemolytic disease (hydrops
      foetalis). Both were due to anti Kell. Both women had history of previous blood
      transfusion and abortions. CONCLUSION: Comprehensive antibody screening should be
      performed during antenatal period in women who have received blood transfusion
      and/or have history of un-explained abortions.

PMID- 10647231
TI  - Spinal cord compression caused by metastatic epithelial myoepithelial carcinoma
      of the parotid gland.

PMID- 10647232
TI  - Sexual knowledge and practice in Pakistani young men.
AB  - BACKGROUND: There is a shortage of scientific data on the subject of sexuality
      from Pakistan. We decided to document misconceptions among Pakistani young men,
      regarding masturbation and nocturnal emissions and to make a case for sex
      education in the country. OBJECTIVE: To study the knowledge, attitude and
      practice of Pakistani young men as regards masturbation and nocturnal emissions
      and to see any associations with demographic factors like age, marital status,
      occupation, level of education and socio economic status. METHOD: A questionnaire
      was developed, based on the objectives of the study. It was administered to 188
      men between the age's 18-30 years, who presented to the outpatient department of
      the Aga Khan University Hospital. There was double entry of the data from
      questionnaires and the demographic form into the computer program, using the Fox
      Pro for windows and the SPSS for windows. RESULTS: We found a high prevalence of
      misconceptions and guilt associated with both these acts. Eighty percent of the
      respondents had masturbated while a 94% had experienced nocturnal emissions.
      31.4% and 62.8% of the respondents reported association of physical illness and
      weakness with masturbation. Responses were 14.9% and 42.6% for nocturnal
      emissions. Association of guilt with masturbation and nocturnal emissions was
      68.6% and 32% respectively. We also studied the association of demographic
      variables with these prevalence figures, in order to point out areas for future
      studies and interventions. CONCLUSION: We have documented the misconceptions
      regarding masturbation and nocturnal emissions among Pakistani young men and have
      made a case for sex education of our youth.

PMID- 10647233
TI  - Clinical scoring system: a valuable tool for decision making in cases of acute
      appendicitis.
AB  - OBJECTIVE: Decision making in cases of acute appendicitis poses a clinical
      challenge specially in developing countries where advanced radiological
      investigations do not appear cost effective and so clinical parameters remain the
      mainstay of diagnosis. The aim of our study was to devise a scoring system from
      our local database and test its accuracy in the preoperative diagnosis of acute
      appendicitis. METHODS: Clinical data from 401 patients having undergone
      appendectomy were collected to identify predictive factors that distinguished
      those with appendicitis from those who had a negative appendectomy. Ten such
      factors were identified and using Bayesian probability a weight was assigned to
      each and the results summated to get an overall score. A cut-off point was
      identified to separate patients for surgery and those for observation. The
      scoring system was then retrospectively applied to a second population of 99
      patients in order to compare suggested actions (derived from the scoring system)
      to those actually taken by surgeons. The sensitivity, specificity and accuracy
      for the level of decision was then calculated. RESULTS: Of the 99 patients, the
      method suggested immediate surgery for 65 patients, 63 of whom had acute
      appendicitis (3.1% diagnostic error rate). Of the 33 patients in whom the score
      suggested active observation, 18 had appendicitis. The accuracy of our scoring
      system was 82%. The method had a sensitivity of 78%, specificity 89% and a
      positive predictive value of 97%. The negative appendectomy rate determined by
      our study was 7% and the perforation rate 13%. CONCLUSION: Scoring system
      developed from a local database can work effectively in routine practice as an
      adjunct to surgical decision making in questionable cases of appendicitis.

PMID- 10647234
TI  - H. pylori: isolation and sensitivity from biopsy specimen of CLO positive
      patients.

PMID- 10647235
TI  - Use of herbal medicine in liver disease.

PMID- 10647236
TI  - Drug resistance in Mycobacterium tuberculosis: a four years experience.
AB  - OBJECTIVE: To assess the prevalence of drug resistance amongst the clinical
      isolates of M. tuberculosis. SETTING: Armed Forces Institute of Pathology,
      Rawalpindi. METHOD: Four first line anti-tuberculosis drugs, isoniazid (INH),
      rifampicin (RIF), ethambutol (ETH) and streptomycin (STR) were tested on 300
      isolates from clinical samples, by agar dilution method on Lowenstein Jensen
      medium. The sensitivities were interpreted by the resistance ratio method.
      RESULTS: One hundred and fifty eight (52.66%) isolates were found resistant to
      one drug at least. Among the resistant isolates, 79 (26.33%) were resistant to
      INH, 72 (24.0%) to RIF, 84 (28.0%) to STR and 70 (23.33%) to ETH with or without
      resistance to other drugs. Multi-drug resistance (MDR) was found in 41 isolates
      (13.66%). CONCLUSION: To overcome this problem there is a need to establish
      centres at a number of places all over the country with professionals trained to
      handle the emerging problem of MDR. Each centre must be equipped with adequate
      facilities for susceptibility testing so that the resistance pattern can be
      ascertained and treatment regimens tailored accordingly.

PMID- 10647237
TI  - Anxiety, depression and stress among the husbands of obstetric cases at Karachi.
AB  - OBJECTIVE: To determine the level of Anxiety, Depression and Stress among the
      Husbands of Obstetric Cases. SUBJECTS AND METHODS: This hospital-based
      prospective study was conducted at Karachi, during the year 1998. A semi
      structured proforma along with Hospital Anxiety Depression Scale (HAD) and Life
      Events Scale were administered to the consenting spouses of obstetric cases.
      RESULTS: Only 23% of lower socio-economic group husbands accompanied their wives
      to the hospital compared to 70% of the higher socio-economic group. Out of the
      56% of husbands of 82 consecutive obstetric cases interviewed, 13% of those whose
      wives were NVD showed anxiety and depression as compared to 25% of those with
      Cesarean Section (C/S). Life Events Scale showed 50% of lower socio-economic
      group having stress compared to only 10% in higher socio-economic group.
      CONCLUSION: Contrary to the West, where majority of the Obstetric cases are
      accompanied by their spouses, in our study only 23% of the cases had their
      husbands present within the obstetric facility. There is a need of such a study,
      based on a larger sample in order to address this critical period/issue,
      considering the concept of 'paternity leaves'. Surprisingly, majority of husbands
      did not have Anxiety or Depression during the Obstetric period (a critical period
      needing appropriate attention) of their wives.

PMID- 10647238
TI  - Risk behaviours associated with urethritis in prison inmates, Sindh.
AB  - OBJECTIVE: To identify sexual risk behaviours associated with lifetime risk of
      urethritis in prison inmates. DESIGN: A cross-sectional study using a pre
      designed questionnaire. SETTING: Fourteen prisons throughout the Sindh Province,
      Pakistan. SUBJECTS: Three thousand three hundred ninety-five prison inmates
      incarcerated during July, 1994. MAIN OUTCOME MEASURE: Lifetime risk of urethritis
      occurrence (whether or not the subject was ever affected with urethritis up to
      his present age) RESULTS: Lifetime risk of urethritis occurrence in the study
      population was 20.8% (706/3395). The final multivariate logistic regression model
      indicated that risk behaviours associated with lifetime risk of urethritis in
      this population were 'sexual intercourse with a female' (adjusted OR = 2.18; 95%
      CI 1.60, 2.95), 'multiple female sexual partners' (adjusted OR = 1.67; 95% CI
      1.28, 2.18) and 'sexual intercourse with man' (adjusted OR = 2.75; 95% CI 2.29,
      3.31). CONCLUSION: The prevalence of urethritis in this population was very high.
      High prevalence of various risky sexual behaviours among inmates indicates, their
      unawareness as to what precautions they might take to avoid risk of acquiring
      STDs including HIV. The study subjects meet the characteristics of a core group
      of STDs transmitters and provides short window of opportunity for STD/HIV control
      programs to intervene, while they are in detention to reduce the risk not only
      for this group but also for general population.

PMID- 10647239
TI  - Study of the mechanisms of killing of Mycobacterium bovis BCG by apoptosis in
      J774 murine macrophages.
AB  - OBJECTIVE: To determine the relationship between the mechanism of apoptosis and
      intracellular killing of Mycobacterium bovis BCG. Apoptosis, "programmed cell
      death"--a physiologically beneficial and distinct form of cell death. SETTING: In
      vitro study was carried out in murine macrophage cell line J774 that was infected
      with Mycobacterium bovis BCG in different set of conditions. Percentage of
      surviving BCG and apoptotic cells was determined. METHODS: IFN-g and/or LPS
      activated and non-activated J774 mouse macrophage cells were infected with BCG in
      a ratio of 1:5. The morphology of the host cells was studied after 4 hours, 24
      hours and 48 hours of infection in cytospins stained with Jenner-Giemsa.
      Surviving bacteria were counted by incorporation of radiolabelled-uridine after
      cell lysis. RESULTS: Both in the activated and non-activted J774 cultures some
      cells undergo apoptosis. In cells activated with IFN-g or LPS without BCG, less
      than 10% of cells were found to be apoptotic. More apoptosis was seen when LPS
      activated cells were infected with BCG. In the cells activated with IFN-g or LPS
      activated cells the percentage of apoptotic cells was much higher than in non
      activated cells or cells activated with either INF-g or LPS alone. After 24 hours
      culture, without BCG, about 15% of the cells were found to be apoptotic and with
      BCG infection this increased to 23% (p < 0.01). The level further increased after
      48 hours of infection. BCG growth inhibition was observed in both non-activated
      J774 cells and cells activated with LPS, INF-g or both and was sustained to 48
      hours of co-culture. CONCLUSION: It is evident that BCG-infected J774 cells
      undergo apoptosis in the presence of a high concentration of RNI and/or ROI.
      During this process the cells shrink considerably in volume with the removal of
      water that may concentrate toxic products in the cell. The increased
      concentration of toxic species and the disorganisation of the phagocytic vacuoles
      may account for the enhanced stasis and/or death of the intracellular micro
      organisms. We conclude that host cell apoptosis may arrest the growth and account
      for the death of the intracellular mycobacterial pathogen.

PMID- 10647240
TI  - Comparison of five different treatment regimens for H. pylori eradication.
AB  - AIM: Treatment response to five different H. Pylori eradication regimens were
      evaluated to see which is the best regimen in our setup. METHODS: Patients
      presenting with upper GI symptoms of acid peptic disease underwent upper GI
      endoscopy and an antral CLO test. All those with a positive CLO test were
      included in the study. The study was carried out over a year and one trial was
      followed by another. The treatment regimens comprised of (1) Omeprazole 20 mg
      once a day, colloidal bismuth subcitrate 120 mg three times a day, Metronidazole
      200 mg three times a day (18 cases). (2) Colloidal bismuth subcitrate three times
      a day, furazolidone 100 mg three times a day, metronidazole 200 mg three times a
      day (28 cases). (3) Omeprazole 20 mg once a day, Clarithromycin 500 mg twice a
      day (21 cases). (4) Lansoprazole 30 mg once a day, Amoxycillin 500 mg three times
      a day (21 cases). (5) Lansoprazole once a day, Amoxycillin 500 mg three times a
      day and Roxithromycin 150 mg twice a day (14 cases). Therapy for all 5 groups
      comprised of 14 days. Endoscopy and CLO test were done prior to the entry in the
      trial and at 28 days to see the response. RESULTS: Meta analysis was done for all
      the 5 regimens. For the purpose of analysis patients were divided into 2 groups,
      i.e., those with peptic ulcer and positive CLO (peptic ulcer disease (PUD) and
      those without peptic ulcer but positive CLO test (Non ulcer dyspepsia (NUD). PUD
      was seen in 14 of 18 cases in group 1, 18 of 28 cases in group 2, 16 of 21 cases
      in group 3, 6 of 21 cases in group 4 and 3 of 14 cases in group 5. In PUD after
      14 days of therapy, lesions healed and CLO became negative in 50% cases each in
      group 1 and 2, 56% in group 3, 83% in group 4 and all in group 5, while in NUD,
      25%, 60%, 80%, 47% and 82% respectively showed H. Pylori eradication. CONCLUSION:
      Of the different therapies one proton pump inhibitor with two antibiotics gave
      best results in ulcer healing and H. pylori eradication in ulcer and non ulcer
      dyspepsia.

PMID- 10647241
TI  - Arthritis and Rosai-Dorfman disease of the skin: a diagnostic dilemma.

PMID- 10647242
TI  - Evaluation and management of gout.

PMID- 10647243
TI  - The Commonwealth Foundation Medical Electives Bursary--1999.

PMID- 10647244
TI  - Emergence of nalidixic acid resistant Vibrio cholerae O-1 in Karachi.

PMID- 10647245
TI  - The New Jersey medicine interview.

PMID- 10647246
TI  - Doctors know best.

PMID- 10647247
TI  - Polypharmacy. Reducing adverse events among the elderly in NJ.
AB  - This is the second of a two-part series that focuses on reducing polypharmacy and
      adverse drug events in the community-dwelling elderly. Part 2 focuses on the
      medical exception process (MEP), explains information flow relevant to the
      physician's practice, and provides clinical examples illustrating the potential
      of computer technology in improving outcomes of care. A combined approach, which
      employs computer-based technology, values physician judgment, and stresses
      patient and provider education, is described.

PMID- 10647248
TI  - Health care issues for specific populations of employees.
AB  - Formulation of a medical treatment plan by a physician can be influenced by an
      individual's current and past medical conditions, gender, and socioeconomic,
      racial, and genetic background. This applies equally to treating work-related
      injuries and illnesses. Experienced workers' compensation clinicians know that
      treatment guidelines developed to treat one group of workers may not be effective
      for other populations of employees.

PMID- 10647250
TI  - Tools for the practice manager.
AB  - Managers must ensure that financial and human resources are used efficiently and
      effectively in the accomplishment of an organization's objectives. This involves
      establishing plans and performance standards and correcting deviations from those
      plans and standards.

PMID- 10647249
TI  - Disclosing genetic information to family members. Do old paradigms fit the new
      medicine?
AB  - Launched in 1990, the Human Genome Project (HGP), an ambitious, international,
      federally funded project to map and sequence all human genes, has rapidly
      expanded our genetic knowledge. Not only does the HGP promise to arm physicians
      with impressive diagnostic tools, its ultimate target is radical improvement in
      therapeutic and preventive interventions in a new era of genetic medicine. At the
      same time, however, the genetic revolution poses momentous ethical, legal, and
      social questions. During the past decade, a substantial--and unresolved-
      discourse has emerged about such matters as genetic privacy, genetic
      discrimination, research with stored tissue samples, ownership of genetic
      material and information, gene patenting, and the genomic challenge to time
      honored concepts of health and disease.

PMID- 10647251
TI  - What's right to do? New Jersey malpractice cases reflect clinical quandaries.
AB  - There's no formula for making the right clinical decision in the face of
      competing factors of personal values, cost-quality trade-offs, insufficient
      information, and social environments that lie beyond the clinician's reach.

PMID- 10647252
TI  - Expectant management of prostate cancer--the author replies.

PMID- 10647253
TI  - Do growth hormones retard aging? Hopeful patients want to find out.

PMID- 10647254
TI  - Organized medicine's response to Hurricane Floyd.

PMID- 10647255
TI  - Hurricane Floyd. Response of the Pitt County Medical Community.
AB  - The financial impact of Hurricane Floyd on the medical community is still being
      tabulated. Initial estimates indicate a $5.8 million loss to UHS in operating
      revenue. Additional hospital costs include $568,000 for overtime pay, $310,000
      for special equipment including helicopters and general supplies, and $1.2
      million in "bonus pay" to the hospital's 6000 employees. The ECU School of
      Medicine suffered losses estimated at $3.6 million, including lost revenue,
      overtime, and salaries paid when clinics and services were shut down. Most
      private offices suffered from lost revenues and occasionally from flood damage to
      property. Hurricane Floyd was the most costly disaster to hit Eastern North
      Carolina and the Mid-Atlantic United States. The medical community and its
      patients were severely challenged from the terrible effects of flooding, but the
      collaborative efforts of a great number of individuals and a spirit of teamwork
      came together to provide continued health care to the region. It is very likely
      that the preventive measures enacted both before and after the storm averted
      illness and injury, and saved lives. Ingenuity, innovation, and optimal use of
      available resources allowed Pitt County Memorial Hospital and its surrounding
      medical community to stay in operation. We have learned a great deal from these
      experiences that will help us plan for future natural disasters.

PMID- 10647257
TI  - Non-remembrance of things past. Ginkgo biloba for memory loss.

PMID- 10647258
TI  - Fouling our nest. Geographic and temporal patterns of toxic industrial chemicals
      released in North Carolina, 1988-1994.

PMID- 10647256
TI  - A seizure in the tobacco field. Green tobacco sickness.

PMID- 10647259
TI  - Ephraim McDowell, Jane Todd Crawford, and the origins of oophorectomy.

PMID- 10647260
TI  - Smoking cessation. "It's the right time".

PMID- 10647261
TI  - Did this pregnancy end with a live birth or a fetal death? Reporting definitions
      for vital statistics.

PMID- 10647262
TI  - Endoscopic ultrasound. State of the art.

PMID- 10647263
TI  - A woman with low energy and high calcium.

PMID- 10647264
TI  - Project IDEAL. Improving Diabetes Education, Access to care and Living. A plan to
      reduce the burden of diabetes in North Carolina.

PMID- 10647265
TI  - Whatever happened to psychotherapy?

PMID- 10647266
TI  - [Surgical management of reflux disease--laparoscopy: renaissance of
      fundoplication?].
AB  - The importance of the surgical treatment of the gastroesophageal reflux disease
      have been increased in recent years. After the medical treatment has spread, the
      minimally invasive procedures were developed. Testing these procedures clinically
      and applying them on several numbers of patients, the surgical solution has
      become conspicuous again and the good results proved reason for the existence of
      the surgical methods that are effective, safe, cost-effective and load to limited
      complications. The goal of this article is to sum up the advance of the
      antireflux-surgery, to give a summary about the tendencies of surgical therapies
      and representating the new results on this topic.

PMID- 10647267
TI  - [The effect of a one-year alendronate therapy on postmenopausal osteoporosis.
      (Results in Hungary of an international multicenter clinical study)].
AB  - The FOSIT (Fosamax International Trial) was a placebo-controlled, double blind
      trial, to determine the effects of daily oral dose of 10 mg alendronate-sodium
      (Fosamax) or placebo, for one year in postmenopausal osteoporotic women. It was
      an international, multicenter study; the 153 centers distributed over 34
      countries. The number of patients was 1908. Authors report the data of the only
      Hungarian study site, Debrecen. Twenty women [age (mean +/- SD) 62 +/- 8 years
      with bone mineral density--BMD--< or = 0.98 g/cm2 at the lumbar spine by LUNAR
      DPX densitometer] were enrolled into the study and randomly assigned to oral
      alendronate 10 mg daily or placebo (10 patients in each group). Patients in both
      groups received 500 mg of calcium. Bone density measurements were performed by
      dual x-ray absorptiometry (DXA) at months 0, 3, 6, and 12 at the lumbar spine and
      at the femoral neck. Biochemical indices of bone turnover [bone specific alkaline
      phosphatase (bAP) and urinary N-telopeptide/creatinine ratio (NTx/crea] were also
      measured every three months. Percent change of the BMD measurements from baseline
      at one-year in the alendronate group was +6% and in the placebo group -0.7% on
      the lumbar spine (p < 0.001). Alendronate treatment increased the bone mineral
      density in the femoral neck, the trochanter, the Ward's triangle and the total
      hip by +3.2, +1.6, +3.5, +2.2% respectively, meanwhile the changes in the placebo
      group were -1.2%; -0.7%; -0.9%; -0.8%, respectively, the difference was not
      significant. Urinary NTx/crea decreased by 70.6% in the alendronate group and by
      9.4% in the placebo group, while bAP decreased by 47.4% in the alendronate group
      and 15.2% in the placebo group (p < 0.001). In conclusion, after one year of
      treatment with alendronate induced increase of bone mineral density at the lumbar
      spine and decreased the bone turnover as compared to the placebo group.

PMID- 10647268
TI  - [Speech activation SPECT measurements in the determination of hemispheric
      dominance].
AB  - Cognitive activity leads to an increased regional cerebral blood flow (rCBF) and
      energy metabolism in both cerebral hemispheres. In order to assess the
      reliability of rCBF-SPECT measurements in hemispheric dominance (Broca's area)
      speech activation SPECT studies were performed in nine patients. Patients (men, n
      = 6; women, n = 3, mean age: 33.8 +/- 13.8 years) with diagnosis of epilepsy (n =
      7) and AVM (n = 2) participated in the preoperative study. Two SPECT studies were
      performed in each case, one in rest, and one during speech activation. 740 MBq of
      99mTc-HMPAO/ECD was injected and stereo TCD monitoring was performed during the
      three minutes of speech activation. The acquisition was performed by a dual-head
      ADAC Solus Epic Atlas SPECT camera (ADAC Laboratories, Milpitas, USA). RCBF SPECT
      measurements were analyzed visually and by a special region-of-interest (ROI)
      program. The hemispheric dominance profiles were established on the basis of the
      respective blood flow velocity values obtained by fTCD and cortical
      hyperperfusion measured by SPECT. The neuropsychological test battery, used in
      the present study, was developed in our institute. The results of rCBF-SPECT
      studies highly correlated with the lateralization of hemispheric dominance
      measured by fTCD. There was a significant increase of rCBF in the inferior
      posterior frontal cortex (Broca's area, p < 0.0003). The non-invasive speech
      activation rCBF-SPECT measurement is a highly reliable and useful method in the
      determination of hemispheric dominance. SPECT studies are especially useful in
      cases where the performance of fTCD measurements are impossible due to the lack
      of temporal bone window or occlusive cerebral arterial disease.

PMID- 10647269
TI  - [Atrial fibrillation provoked by Valsalva maneuver].
AB  - The connection between certain arrhythmias and the autonomic nervous system is
      well known. Authors report a patient, whose paroxysmal atrial fibrillation was
      induced by increased vagal tone.

PMID- 10647270
TI  - [Evidence-based medicine from the viewpoint of the clinician].

PMID- 10647272
TI  - [Chosen or outcast?].

PMID- 10647271
TI  - [Professor Ferenc Herzog, among the neglected ones].

PMID- 10647273
TI  - [Trauma: epidemic of our age. 1974].

PMID- 10647274
TI  - [The principles of pharmacotherapy for arrhythmia at the turn of the millenium].
AB  - A review is presented at the main causes of the change in paradigm that has
      occurred in the past 10 years in antiarrhythmic pharmacotherapy. The new attitude
      is ascribed to (1) the advances made in the application of non-pharmacological
      therapeutic modalities (radiofrequency catheter ablation, implantable
      antiarrhythmic devices), (2) the modification of therapeutic practice in response
      to the results of large-scale prospective randomized clinical trials, and (3) the
      proper recognition and appropriate appreciation of the frequently life
      threatening proarrhythmic action of antiarrhythmic drugs. The current state of
      knowledge is discussed as concerns the anti- and proarrhythmic effects of the
      drugs available at present, and also their safe clinical use.

PMID- 10647275
TI  - [Hydranencephaly. (Severe cerebral malformations in three newborn infants)].
AB  - Three neonatal cases of hydranencephaly are reported. Clinical and radiological
      characteristics of this disease are also described. Factors which can have any
      role in the development of hydranencephaly are reviewed. The importance of
      intrauterine ultrasonography and the quick, early diagnosis is emphasized.
      Therapeutic approaches are also discussed.

PMID- 10647276
TI  - [Plastic facial reconstruction in forensic medicine].
AB  - Plastic facial reconstruction is the field of personal identification where the
      limitations of science are augmented by the intuition of an artist. In this
      field, success requires the cooperation of an anthropologist and a sculptor--and
      sometimes a little luck. Authors summarize the applications and limitations of
      this method. For the first time in the history of their institute, University
      Medical School of Pecs, the face of a victim in an actual crime case have been
      reconstructed. In this situation, the victim was in advanced stages of
      decomposition. The features of the man's face were unrecognizable. Using thirty
      craniometric measuring points, the soft tissues on the victims macerated scull
      was reconstructed, based on known soft tissue thickness of the middle-European
      population. After the reconstruction was complete, police circulated a photograph
      of the victim's face. The victim's son recognized her missing father from the
      photograph and notified the police. These efforts were noted as the first success
      of its kind in our region.

PMID- 10647277
TI  - [The effect of trace elements--especially zinc--on metastasizing of Lewis lung
      tumor].
AB  - The effect of a widely used trace element preparation (Beres-Drop Plus, BDP) on
      the liver metastasis forming potential of 3LL-HH tumor was studied. The daily,
      oral administration of BDP caused a decrease in the number of liver metastases,
      irrespective of the presence or absence of the primary spleen tumor. It is
      suggested, that the zinc component of BDP is responsible, at least partly--for
      the inhibitory action.

PMID- 10647278
TI  - [Effective demeclocycline therapy in a patient with over-secretion of
      antidiuretic hormone following head trauma].
AB  - The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is a
      common cause of hyponatremia. In this study a case of SIADH caused by head trauma
      is reported, in which severe hyponatraemia, escorted by life-threatening
      neurological symptoms was observed that could only be managed by parenteral
      sodium chloride infusions. Severe hyponatraemia was accompanied by elevated
      urinary sodium excretion, a characteristic sign of SIADH. After introducing the
      therapy with demeclocycline, a tetracycline type antibiotic that inhibits the
      renal action of antidiuretic hormone, serum sodium levels began to rise
      gradually, and the urinary sodium excretion slowly decreased. These observations
      show the effectiveness of demeclocycline in the treatment of SIADH.

PMID- 10647279
TI  - [Use of Bronchoalveolar lavage fluid for diagnosing and monitoring interstitial
      lung diseases].

PMID- 10647280
TI  - [Usefulness of analyzing ANCA changes for diagnosis of Wegener's granulomatosis].
AB  - ANCA were described in 1982 as sensitive and specific markers for active
      Wegener's granulomatosis (WG). We analysed the results of ANCA test performed in
      298 patients hospitalized in Institute of Tuberculosis and Lung Diseases in the
      period 1990-1998 because of different symptoms and syndromes of respiratory
      system which could be symptoms of WG. Presence of c-ANCA, p-ANCA and other not
      well defined types of ANCA in the titer greater than 1:40 in the serum was
      regarded as positive result of test. We found it in 60 patients. In 47 WG pts
      ANCA were present in 40 of 42 pts with active disease and 1 of 5 in remission.
      Further 19 positive results were found in a group of 251 patients with other
      diseases: 1 of 4 pts with Churg-Strauss syndrome, 1 of 2 with pulmonary renal
      syndrome, 5 of 28 with connective tissue diseases, 1 of 21 with tuberculosis, 1
      of 23 with sarcoidosis, 1 of 6 with histiocytosis, 3 of 11 with hypersensitivity
      pneumonitis, 1 (lymphoma) of 34 with neoplasms, 1 of 20 with pulmonary fibrosis,
      1 of 8 with cardiac failure, 1 of 5 with pleural fluid, 1 of 10 pneumoconiosis
      and toxic reactions (after furagin), 1 of 6 with BOOP. Sensitivity of ANCA test
      in our material is 87%, specificity = 95%, and positive prevalence accuracy is
      68%. It means that 32% of the patients with positive results could be
      inappropriate treated as WG. CONCLUSION: ANCA test could be not used as a
      screening test. Results of ANCA test alone cannot be used as basis for treatment.
      ANCA test is a helpful tool in diagnosing of WG.

PMID- 10647281
TI  - [Predisposing factors for bronchiectasis--analysis of 69 patients treated in the
      years 1995-1999].
AB  - The aim of this study was to analyze the predisposing factors for bronchiectasis
      in 69 patients hospitalized in the 3rd Dept. of the Institute of TB and Lung
      Diseases in Warsaw in years 1995-1999. Bronchiectasis was diagnosed on the basis
      of the high resolution computed tomography (HRCT) scan. Among 69 patients at the
      age of 15-72 years there were 45 women (65%) and 24 men (35%). Fifty patients
      were nonsmokers. The most frequent predisposing factors of bronchiectasis in that
      group of patients were as follows: pneumonia (30.1%, in it recurrent pneumonia-
      19.3%, a single pneumonia--10.8%), sinobronchial syndrome (19.3%), pulmonary
      tuberculosis (12.1%), nontuberculous mycobacterial lung infections (7.2%),
      recurrent pneumonia and bronchitis in childhood (7.2%) and connective-tissue
      diseases (3.6%). Among other predisposing factors there were allergic
      bronchopulmonary aspergillosis, foreign body in bronchus, hypogammaglobulinemia
      and colitis ulcerosa.

PMID- 10647282
TI  - [Usefulness of CD1 expression on surfaces of cells in bronchoalveolar fluid for
      diagnosis of histiocytosis X--our experience].
AB  - Histiocytosis X (HX), also referred as Langerhans cell granulomatosis is a
      disorder characterized by the presence of destructive granulomas containing
      Langerhans cells, lymphocytes, eosinophils and fibroblastes in the involved
      organs. Three presentations are commonly observed: 1) nonproductive cough or
      effort dyspnea, 2) spontaneous pneumothorax 3) incidental pulmonary infiltrates
      on chest X-ray in asymptomatic patients. HRCT may be helpful in the initial
      diagnosis of pulmonary HX. HRCT scans show nodules, cysts and estimate the extent
      of disease. But the final diagnosis of histiocytosis X requires the histologic
      demonstration of specific histiocytosis X cell in biopsy specimens of the lung.
      The aim of this study was to define the importance of the detection of Langerhans
      cells in bronchoalveolar lavage fluid (BALF) for the diagnosis of HX. The
      searched cells express a specific CD1 antigen, recognized by the monoclonal
      antibody OKT-6. In our study the demonstration of more than 5% of CD1 positive
      cells was defined to confirm HX. We have studied the BALF in 21 patients with
      suspected histiocytosis X. In BALF of 4 patients more than 5% of CD1 positive
      cells were found. In 1 of them HX was confirmed with open lung biopsy. Two
      patients displayed 5% of CD1 positive cells. The final diagnosis of the first
      patient was hypersensitivity pneumonitis and of the second one was bronchitis
      chronica. In 5 patients out of 15 patients in whom less than 5% of CD1 positive
      cells were found histiocytosis X was histologically proven. In other 10 patients
      the following disorders were histologically recognised: pulmonary emphysema 3
      cases, pneumoconiosis-3, LMA-BOOP-1, sarcoidosis-1 and pleuritis eosinophilica-1.
      The estimation of Langerhans cells in BALF can be a useful method among the
      diagnostic procedures for histiocytosis X. It is necessary to remember that
      demonstration of less than 5% of CD1 positive cells do not exclude histiocytosis
      X.

PMID- 10647284
TI  - [Relationship between the clinical course of bronchial asthma from childhood to
      adulthood (deterioration/improvement), bronchial hyperreactivity and incidence of
      house dust mite allergens in households of persons treated for atopic bronchial
      asthma as children].
AB  - The aim of the study was to determine the impact of the exposition to house dust
      mite allergens or its lack on clinical state of asthma in young adults treated in
      their childhood for atopic bronchial asthma. The concentration of house mite
      allergen was studied with the method of Acarex test (detection of guanine-
      excretory product of house dust mites) in the flats of 55 persons treated for
      atopic asthma before adolescence. There was significant difference (p < 0.006)
      between the clinical course of asthma (improvement) in persons living in flats
      free of house dust mite allergens and those living in flats infested with mites.
      House dust mite allergens were present significantly more frequently in flats of
      persons with a low histamine threshold (19 of 20 examined flats) than in flats of
      persons with a high histamine threshold or without hyperreactivity to histamine
      (6 of 20 examined flats).

PMID- 10647283
TI  - [The effect of sputum induction on spirometry parameters in patients with
      bronchial asthma].
AB  - Evaluation of differential cell count and biochemical parameters in sputum seems
      to be a valuable method in asthma studies. The purpose of the paper was to
      evaluate the effects of sputum induction alone and after fenoterol and salmeterol
      premedication, on spirometry in asthma patients. The another aim of the study was
      to observe the correlation between bronchial hyperreactivity and decreases in
      FEV1 and MEF50 in asthmatics during sputum induction. The studies were carried
      out on 20 mild to moderate asthma patients (FEV1 baseline 79 +/- 16% of the
      predicted values) who inhaled an increasing concentration of hypertonic saline
      (3%, 4% and 5%), using an ultrasonic nebuliser. The forced expiratory volume in
      one second and MEF50, as the good indicators of bronchial obturation, were
      evaluated. During the sputum induction significant decreases in FEV1 and MEF50
      were observed, which were proportional to the concentration of NaCl. After
      inhalation of 3% of NaCl the mean of FEV1 was 87.2 +/- 12.7% of the baseline,
      after 4%--84.3 +/- 16.9% and 5%--77.4 +/- 19.8%. No significant correlation
      between bronchial hyperreactivity and the induced decreases in FEV1 and MEF50
      were found. Fenoterol and salmeterol fully prevented bronchial obturation during
      sputum induction.

PMID- 10647285
TI  - [Treatment results of patients with bacteriologically confirmed tuberculosis
      registered in Poland in 1996].
AB  - Basing on the data from the Central Tuberculosis Register (existing since 1985),
      an analysis on the treatment regimens and outcomes was made in 7.919 (6.538 new
      cases and 1.010 recurrents) patients with active confirmed bacteriologically
      tuberculosis in 1996. After one year follow-up, among 7.919 patients: 371 were
      untreated (2.3%), 6.551 were cured (82.7%) (3 x 3 negative smears and culture
      examinations in the period of 6 months after last positive examination; and 386
      were doubtful (4.9%)--i.e. patients in whom 1 x 3 or 2 x 3 negative smears and
      culture examinations were obtained after last positive examination. 676 patients
      (8.5%) died of which 418--(4.0%) due to TB; 121 patients--1.5% were still
      positive. In summary--87.6% of patients were cured or considered as completed
      treatment. In 1996 year 77.1% patients received four--drug regimens (INH, RMP,
      PZA, SM/EMB), 18.6% of patients received--3 drugs (in the majority INH, RMP, PZA)
      in the initial phase of the treatment. The treatment in this phase is, in the
      majority of cases, performed in hospital under supervision. In spite of the high
      efficacy of applied regimens, the duration of treatment was too long: 55.9%
      patients was treated longer than 6 months (32.8% > 9 months).

PMID- 10647286
TI  - [Infection as a main or additional cause of death in patients treated for small
      cell lung cancer].
AB  - The aim of this study was to analyse the frequency of infection as a cause of
      death in small cell lung cancer (SCLC) patients. Our material consisted of 845
      unselected SCLC patients, 246 women and 599 men, aged 29-78 years, treated
      between 1980-1994 in the Institute of Tuberculosis in Warsaw. 479 patients had
      limited and 366 extensive disease. 530 were in good (0-2) and 315 in bad (3-4)
      performance status. 784 patients died. Autopsy was done in 211 patients.
      Infection was regarded as a main cause of death in 39 patients (4.6%) and as a
      coexistent cause in 77 (9.1%). At the time of death from and/or with infection in
      16 patients complete remission and in 27 partial remission of cancer was
      confirmed. The risk of death from and/or with infection was not related to the
      age and sex or to the performance status of patients and to extension of cancer.
      The risk of death from and/or with infection in the first 3 months of treatment
      was however greater for patients in bad performance status and with extensive
      disease and later (after 3rd months) for patients in good performance status and
      with limited disease.

PMID- 10647288
TI  - [Mobility of the diaphragm and lung perfusion following decortication due to
      chronic pleural empyema].
AB  - Mobility of the diaphragm and lung perfusion after decortication, due to chronic
      pleural empyema in the group of 31 patients is analysed. In our group amplitude
      of 8 cm diaphragm mobility at PA radiological examination was confirmed and it is
      accepted as normal range. Scintigraphic assessment of the lung perfusion with
      human macroalbumin-Technet complex was made. In 10 patients after left side
      decortication perfusion was lower than normal range. There was no statistical
      correlation between worsering of the mobility of the diaphragm and reduction of
      the lung perfusion in the examined group.

PMID- 10647287
TI  - [The cause of infection as the main or additional cause of death in patients
      treated for small cell lung cancer].
AB  - In 116 out of 845 patients treated for small cell lung cancer (SCLC) in the
      Institute of Tuberculosis and Chest Disease in Warsaw in the years 1980-1994
      infection was the main or coexistent cause of death. In 4.1% infection was proved
      of bacterial origin and in further 6.5% of probable bacterial origin (in the
      later group cultures were negative or not done but fungal infection,
      pneumocystosis pneumonia and tuberculosis were excluded on autopsy). In 1.54%
      infection was of fungal origin, 1.2% patients died of Pneumocystis carinii
      pneumonia and 0.35% of tuberculosis. The majority of patients who died with
      and/or from infection had treatment-related leukopenia and 99 of them were
      treated with corticosteroids. Fungal infection, pneumocytosis and tuberculosis
      were found more frequently than bacterial infection in patients treated with
      cumulative dose of prednisone above 2000 mg. 33.62% patients had no symptoms or
      signs of infection. No connection was found between the absence of symptoms and
      treatment with steroids or the grade of leukopenia. In all cases infection was
      recognised very late, in 58 only at autopsy.

PMID- 10647289
TI  - [Pulmonary tuberculosis in families of patients with bacteriologically positive
      pulmonary tuberculosis].
AB  - The aim of the study was to carry out analysis of pulmonary tuberculosis
      occurrence in multimember families in which at least one person was suffering
      from pulmonary tuberculosis bacteriologically confirmed (BK+). The study was
      based on clinical examination, chest-X-rays analysis and outpatients clinic
      files. The initial number of patients suffering from tuberculosis BK(+) was 70,
      therefore 268 people from 70 families were included in the study. In 48 (70%) of
      families there was only one case of pulmonary tuberculosis BK+ throughout 5 years
      of observation. In the remaining 22 (30%) of families at least one more case of
      pulmonary tuberculosis was recorded. 60% of those cases concerned a spouse. In
      10% of families where one person had relapses of tuberculosis BK+, within one
      year an another case of pulmonary tuberculosis bacteriologically positive or
      negative was confirmed.

PMID- 10647290
TI  - [Aspergilloma of the lung imitating lung cancer].
AB  - 75-year old woman admitted to Institute of TB due to the opacity in middle lobe
      of the right lung is described. The chest X-ray might suggest possibility of the
      lung cancer. The examination of the patient did not revealed any abnormalities.
      At the admission the nature of the lesion was not recognised by the accessible
      methods. Therefore, the thoracotomy was performed, and the aspergilloma was
      confirmed by intraoperative histopathologic methods. The middle lobe with the
      lesion was totally resected. The postoperative period was uneventful. The six
      months follow-up revealed that patient was cured.

PMID- 10647291
TI  - [Progress and new perspective treatments of systemic fungal infections].

PMID- 10647292
TI  - [Chronic necrotizing pulmonary aspergillosis].

PMID- 10647293
TI  - The hows and whys of imprinting.

PMID- 10647294
TI  - Bridging the gap between sequence and function.

PMID- 10647295
TI  - Consolidating motor neuron identity.

PMID- 10647296
TI  - RNA polymerase comes into focus.

PMID- 10647297
TI  - MBDs mediate methylation, deacetylation and transcriptional repression.

PMID- 10647298
TI  - [Changes in the millenium: even the eyes should be adapted to the year 2000!].

PMID- 10647299
TI  - [Hand-fireworks has been created by the Devil himself!].

PMID- 10647300
TI  - [Two cases of severe eye and cranial injuries due to firework explosions].
AB  - Two patients who sustained serious facial, cranial and eye trauma secondary to
      recreational fireworks injuries are reported. Initial assessment included axial
      and coronary computerized tomography, control of haemorrhage, debridement of
      wound and brain, and in one patient bilateral excenteration of the globe. Both
      patients suffered from intracranial haemorrhage, but both recovered without
      severe neurological sequelae.

PMID- 10647301
TI  - [Gunter Blobel, the 1999 Nobel Prize winner in physiology or medicine. Proteins
      in the cell are directed by built-in "zip codes"].

PMID- 10647302
TI  - [A jubilee, that cannot be celebrated].

PMID- 10647303
TI  - [The girl with blueberries--use of the "concept of clearance" in everyday life].

PMID- 10647304
TI  - ["And it happened during those days". Birth of the Danish model].

PMID- 10647305
TI  - [Age-related growth of the ears and problems with ear-wax].

PMID- 10647307
TI  - [Politics, war between tribes or science?].

PMID- 10647306
TI  - [About the seven little devils who changed physiology. August and Marie Krogh on
      pulmonary gas exchange].

PMID- 10647308
TI  - [Audiometry in otologic practice, cooperation or...].

PMID- 10647309
TI  - [A letter to Agneta Parving].

PMID- 10647310
TI  - [Acute otitis media and antibiotics].

PMID- 10647311
TI  - [Etiology of migraine].

PMID- 10647312
TI  - [Mutation of the plasma cholinesterase gene and anesthesia. Information from the
      Danish Cholinesterase Registry].

PMID- 10647313
TI  - [Methadone as an analgesic].
AB  - Methadone is a synthetic opioid agonist which has been available for more than 40
      years. Although its main use has been in the maintenance therapy of opioid
      addicts, it has a number of unique characteristics including excellent analgesic
      effect, a high bioavailability, no known active metabolites, long duration of
      action during long-term treatment, high potency, and low cost. However, its use
      is limited by the complexity of the pharmacokinetics, with a risk of drug
      accumulation with toxic effects. Recent findings suggest that standard
      equianalgesic tables are unreliable, because methadone is much more potent when
      used for long-term treatment. Therefore methadone should be titrated carefully
      and increases in dosage should be performed every third or fourth day.

PMID- 10647314
TI  - [The significance of genetic and environmental factors for migraine with aura. A
      genetic epidemiologic study of Danish twins].
AB  - We studied the genetic and environmental influence on migraine with aura (MA) by
      analysing a twin population. The twin sample consisted of 2,026 monozygotic (MZ)
      pairs and 3,334 same-gender dizygotic (DZ) pairs recruited from the population
      based Danish Twin Register. A total of 211 pairs were identified, of whom 77 were
      MZ and 134 were DZ. The pairwise concordance rate was significantly higher in MZ
      than in DZ-pairs, i.e. 34% and 12%, respectively, emphasizing the importance of
      genetic factors in MA. However, environmental factors are also important, as the
      pair wise concordance rate was less than 100% in MZ-pairs. Similarly, the
      recurrence risk of MA was 50% in MZ- and 21% in DZ-pairs which was a significant
      difference. In non-twin siblings, the recurrence risk of MA is 27%, which is
      similar to the recurrence risk in DZ-pairs. This indicates that MA is not
      developed due to specific environmental factors shared by the twins.

PMID- 10647315
TI  - [Inhibition of nitric oxide synthase has an analgesic effect in chronic pain].
AB  - The efficacy of the inhibitor of nitric oxide synthase, NG-monomethyl-L-arginine
      hydrochloride (L-NMMA), was tested in 16 patients with chronic tension-type
      chronic headache. The study was designed as a randomized double-blind, crossover
      trial. Patients were assigned intravenous infusion of 6 mg/kg L-NMMA or placebo
      on two days separated by at least one week in a randomized order. Headache
      intensity was measured on a 100 mm visual analogue scale at baseline and at 30
      min, 60 min, and 120 min after start of treatment. L-NMMA reduced pain intensity
      significantly more than placebo: 120 min after start of treatment, the mean pain
      score was decreased from 49 to 33 with L-NMMA and from 44 to 40 with placebo (p =
      0.01). The present study demonstrates that inhibition of NOS has an analgesic
      effect in chronic tension-type headache.

PMID- 10647316
TI  - [Therapeutic manipulation of episodic tension type headache. A randomized,
      controlled clinical trial].
AB  - In a randomized controlled clinical trial, 75 subjects fulfilling the IHS
      criteria for episodic tension-type headache were treated for four weeks. One
      group received spinal manipulation plus soft tissue therapy in the neck, the
      other received soft tissue therapy plus low-power laser therapy to the same
      region. In the three month follow-up period both groups showed significant
      improvement, but there were no differences between the groups. Thus, spinal
      manipulation had no effect on episodic tension-type headache, in contrast to the
      significant effect of spinal manipulation which has previously been demonstrated
      in cases of cervicogenic headache. These two headaches should therefore be
      diagnostically differentiated in the future.

PMID- 10647317
TI  - [Prolonged neck pain following automobile accidents. Gender and age related risk
      calculated on basis of data from an emergency department].
AB  - Whiplash injuries following road traffic accidents seem to be an increasing
      problem in many countries. Many studies are based on biased material from
      specialized departments or data from insurance companies. The aim of this study
      was to calculate the risk of longer lasting neck pain for persons involved in
      road traffic accidents and treated in the emergency room. We found that 49% of
      the patients treated following road traffic accidents in motor vehicles reported
      problems with neck pain. Thirteen percent had neck pain with more than six months
      of duration. The highest risk of neck pain was recorded in women aged 20-59
      years. Accidents with front to back collisions presented the highest risk. The
      conclusion was that whiplash associated disorders following road traffic
      accidents in motor vehicles apparently is a large problem. The treatment and
      rehabilitation must be centralized at the level of the general practitioners.

PMID- 10647318
TI  - [Predictive factors of the effect of multidisciplinary, intensive rehabilitation
      of back pain. Demographic, socioeconomic and physical factors].
AB  - In order to identify possible predictive factors for success from rehabilitation
      in a functional restoration (FR) program for patients with chronic low back pain,
      pre-treatment baseline variables were correlated to different outcome parameters
      following treatment in either a FR program or control programs. A prospective
      clinical trial involving 816 patients was carried out. Of the total cohort 621
      patients participated in a FR program and 195 in control groups. The results
      showed that different factors could be identified as useful in predicting outcome
      from a FR program, but most of these factors were also shown to predict success
      for controls of shorter outpatient programs or of no treatment.

PMID- 10647319
TI  - [Syndrome of headache, transitory neurological deficits and lymphocytosis in the
      cerebrospinal fluid].
AB  - The authors report three case stories of patients who experienced a transient
      syndrome consisting of headache with neurologic al deficits and CSF lymphocytic
      pleocytosis (HaNDL). The diagnostic criteria for this benign syndrome are
      presented and differential diagnoses are discussed.

PMID- 10647321
TI  - [Hypercalcemic crisis--is simple rehydration an acceptable alternative?].

PMID- 10647320
TI  - [Herceptin (trastuzumab). A new exciting therapeutic principle in breast cancer].

PMID- 10647322
TI  - [How to treat uncomplicated cystitis?].

PMID- 10647323
TI  - [Ruptured aneurysms can be treated by assisted surgery in local hospitals when
      the patient's condition doesn't allow transportation].

PMID- 10647324
TI  - [Virus on the vestibular nerve].

PMID- 10647325
TI  - Measles. Progress towards global control and regional elimination, 1998-1999.

PMID- 10647326
TI  - Progress towards measles elimination, WHO Eastern Mediterranean Region, 1980
      1998.

PMID- 10647327
TI  - Influenza.

PMID- 10647328
TI  - Performance of AFP surveillance and incidence of poliomyelitis, 1998-1999.

PMID- 10647329
TI  - Outbreak news. Japanese encephalitis, India.

PMID- 10647330
TI  - Low-calorie sweeteners--from molecules to mass markets.

PMID- 10647331
TI  - Factors affecting sweetness.

PMID- 10647332
TI  - The evolution of taste perception.

PMID- 10647333
TI  - Double functionality of sweeteners: a case of study.

PMID- 10647334
TI  - New developments in low-calorie sweeteners.

PMID- 10647335
TI  - Discovery and development of neotame.

PMID- 10647336
TI  - Effect of storage on the flavours of cola drinks sweetened with different
      sweetener systems.

PMID- 10647337
TI  - Sweetness, appetite, and energy intake: physiological aspects.

PMID- 10647338
TI  - Sweeteners and weight control.

PMID- 10647339
TI  - Role of intense sweeteners in diabetes management.

PMID- 10647341
TI  - Erythritol: a novel noncaloric sweetener ingredient.

PMID- 10647340
TI  - D-tagatose--a novel low-calorie bulk sweetener with prebiotic properties.

PMID- 10647342
TI  - Natural versus 'artificial' sweeteners: regulatory aspects.

PMID- 10647343
TI  - An estimation of the detection and quantitation limits of neohesperidine DC by
      high-performance liquid chromatography.

PMID- 10647344
TI  - Thaumatin: a natural flavour ingredient.

PMID- 10647345
TI  - Improved powder mix quality with Twinsweet.

PMID- 10647346
TI  - Consumer perceptions of products containing sweeteners: USA.

PMID- 10647347
TI  - Consumer behaviour and attitudes towards low-calorie products in Europe.
AB  - A number of observations and conclusions can be made based on the data we have
      just seen: (1) There are large differences across the countries in terms of
      penetration of 'light' products. (2) The penetration of low-fat products is
      higher than that of low-sugar products. (3) Penetration of both low fat and low
      sugar products is higher among women than among men. (4) Penetration of both low
      fat and low-sugar products is not dependent on age. (5) Consumption relates to
      penetration. (6) Consumer concerns about fat are greater than about sugar. (7)
      Consumer concerns about fat are at approximately the same level across Europe.
      (8) Concern about fat and sugar seems to increase with age. (9) Overweight is a
      problem for a third of the population across Europe. (10) Overweight is higher
      among men than among women. (11) Overweight increases with age.

PMID- 10647348
TI  - Consumer perceptions of products containing sweeteners: Latin America.

PMID- 10647349
TI  - Consumer perceptions of products containing sweeteners in Asian countries.

PMID- 10647350
TI  - Use of intense sweeteners in Africa and nutrition.

PMID- 10647351
TI  - Intake of intense sweeteners.

PMID- 10647352
TI  - The world market for intense sweeteners.

PMID- 10647353
TI  - Regulators and industry: priorities compared.

PMID- 10647354
TI  - The role of Codex alimentarius.

PMID- 10647355
TI  - Vaginal infections--common but misunderstood.

PMID- 10647356
TI  - Your continuing education topic(s) 3 & 4--1999. "Pharmacology update".

PMID- 10647357
TI  - Some of the most devastating pressure ulcers nowadays occur...in younger patients
      with neurological damage or disease.

PMID- 10647358
TI  - The Scottish Leg Ulcer Project.
AB  - National and international guidelines on many topics have been introduced in
      recent years. It is unlikely that the implementation of few, or any, has been
      evaluated by randomized trial, nor have the impacts of guidelines when combined
      with training been evaluated. A national guideline produced by the Scottish
      Intercollegiate Guideline Network (SIGN) entitled 'Management of Chronic Leg
      Ulcer' was published in July 1998 and this may have influence on care and
      ultimately healing rates of leg ulcers. The purpose of this paper is to describe
      the design of a Scottish multi-centre trial and to present baseline data. The
      Scottish Leg Ulcer Project is a randomized controlled trial which commenced in
      July 1997 and is designed to compare the impact of the SIGN guideline with the
      impact of the SIGN guideline reinforced by a formal training programme, on
      healing rates of leg ulcers. Participants include 16 Scottish community
      healthcare trusts or health boards, with a population of approximately 2.7
      million. Localities have been randomized into control (SIGN guidelines alone) and
      intervention (SIGN guideline plus a formal training programme). In the
      intervention localities, link nurses, after intensive training, cascaded similar
      training to all community staff involved in leg ulcer care. Data are provided by
      district nurse caseload managers in censuses every three months throughout a six
      month baseline and 24-month trial period. The principal endpoint is an ulcer-free
      leg. The data collection is due to be completed in December 1999, and the project
      analysed and reported by June 2000.

PMID- 10647359
TI  - 'Putting the pressure on': a study of compression sleeves used in breast cancer
      related lymphoedema.
AB  - Breast cancer-related lymphoedema is a chronic, progressive condition
      characterized by swelling in the arm and adjacent trunk, with changes to the skin
      and underlying tissues. The application of compression garments is an essential
      component in the long-term management of lymphoedema. A wide range of garments is
      available in the UK; however, there is limited literature to guide therapists in
      their appropriate selection. This paper reviews the effects of compression
      therapy, outlines the components of lymphoedema treatment, and discusses features
      of lymphoedema compression sleeves. A small study of nine women with breast
      cancer-related lymphoedema is reported. The study investigates the interface
      pressure profiles of a selection of commonly used compression sleeves as measured
      by the Oxford Pressure Monitor. The results showed a wide variation in the
      interface pressures for all sleeves. A graduated profile along the length of the
      arm was not always present, Two layers of garments led to markedly increased
      pressures at the top of the arm but the pressures along the arm did not double.
      The possible implications for clinical practice are discussed.

PMID- 10647360
TI  - Clinical governance and the potential implications for tissue viability.
AB  - This article explores how clinical governance can and will impact on tissue
      viability specialists. It highlights the principles of governance and what it
      means for healthcare organizations, and the different processes of application,
      including responsibilities, that will be adopted. The dimensions of clinical
      governance have been applied to the quality of care expected and given by staff
      as well as ways of assessing performance and ensuring that quality is everybody's
      business. It is up to us all as healthcare practitioners to ensure that we keep
      professionally up-to-date, enhance our education, research and development, and
      have a mechanism for monitoring and safeguarding our performance. The paper
      should promote discussion and provide food for thought regarding the application
      and full utilization of clinical governance.

PMID- 10647361
TI  - The importance of becoming or staying independent: bucking the consolidation
      trend.

PMID- 10647362
TI  - The hospital-based outpatient dialysis provider: dinosaur or strategic partner of
      the future?

PMID- 10647363
TI  - IPAs: practicing independence in nephrology.
AB  - I would like to share some comments that have been made by the nephrologists who
      have decided to form IPAs. I consider them the risk takers. "Bite off only what
      you can chew ..." (and swallow) Speak loudly "and carry a big stick" "...and you
      will have to change your behavior."

PMID- 10647364
TI  - Strength in numbers: setting up a multi-state IPA.

PMID- 10647365
TI  - Consolidation: how do you measure its impact?

PMID- 10647366
TI  - Has consolidation improved renal care?

PMID- 10647367
TI  - A buying slowdown? TRC continues expansion, but some providers slow acquisition
      efforts.

PMID- 10647368
TI  - Will the doors to managed care open soon for ESRD patients?

PMID- 10647369
TI  - A nephrologist's guide to managed care contracting.

PMID- 10647370
TI  - Building a dialysis facility within the confines of a skilled nursing facility.
AB  - Creating a dialysis facility within an existing SNF will cost more money then
      building an independent dialysis facility. If a new building is created and is
      physically attached to the existing SNF, it will have to meet the regulations
      that apply to the SNF. It is possible to build a new building adjacent to but not
      connected with the SNF without having to meet SNF requirements. If this is an
      option, then it is imperative to determine with the local authorities how much
      space must be between the structures. If the decision is made to build within the
      physical confines of the existing SNF, the SNF may no longer meet current
      regulations. In some cases I have seen, the SNF facility was older and had been
      grandfathered under current regulations. When the building inspector and fire
      marshall inspected the new dialysis unit, they made the determination that the
      SNF had to be upgraded to meet some of the current regulations. This was a very
      costly situation for the SNF. If the organization is considering creating a
      dialysis unit in conjunction with a SNF, I would recommend the dialysis unit be
      constructed as a new, separate building on the campus rather then within the
      existing building. The combination of these two types of care can be very
      positive both for the patients and the organizations.

PMID- 10647371
TI  - Nutritional guidance for the ESRD patient in long-term care facilities.
AB  - The health care teams dealing with the long-term care resident with ESRD need to
      develop and implement ethical, humanistic and practical guidelines which enhance
      the continuity of comprehensive medical, psychosocial, and nutrition care.
      Increased quality of life, heightened satisfaction, improved nutritional status,
      and decreased feelings of isolation are important potential benefits to these
      patients.

PMID- 10647372
TI  - Techniques to improve compliance in hemo- and peritoneal dialysis patients.
AB  - "I would like some input on how other technicians effectively deal with non
      compliancy among some of our more stubborn patients," wrote a technician recently
      in an e-mail note to NN&I. "... Any strategies that may enable us to show that
      compliancy is for (the patient's) own good, and not just because we are trying to
      be hard on them." In this article, the second in a two-part series, authors
      Batson and Schwartz suggest some practical interventions that renal staff can use
      for both hemo- and peritoneal dialysis patients. The authors cover theories of
      compliance in Part I (6/99, NN&I).

PMID- 10647373
TI  - They also serve.

PMID- 10647374
TI  - Preparation for practice.

PMID- 10647375
TI  - Continuity of clinical instruction: the effect on freshman nursing students.

PMID- 10647376
TI  - Clinical leadership experience for the beginning nursing student.

PMID- 10647377
TI  - From tasks to caring: analysis of the changes in baccalaureate nursing students'
      attitudes toward the profession.

PMID- 10647378
TI  - Role conception of RN-BSN students.

PMID- 10647379
TI  - A care plan for the student.

PMID- 10647380
TI  - Nursing students elect to pursue wellness.

PMID- 10647381
TI  - Preparing a testing blueprint from levels of course objectives.

PMID- 10647382
TI  - Preparing students to practice in the home.

PMID- 10647383
TI  - Clinical learning for advanced practice nurses in managed care environments.

PMID- 10647384
TI  - Using benchmarking practices for the learning resource center.
AB  - Structured ongoing and systematic evaluation is required to ensure up-to-date
      resources and continuous quality improvement plans to meet the learning needs of
      the diverse student population and the complex needs of patients. Using
      benchmarking to achieve evaluation goals in the learning resource center has
      great merit as schools of nursing respond to consumer demand for improvement,
      rapid changes resulting from changing patient needs, and the technology
      explosion.

PMID- 10647385
TI  - Perceptions of leadership competence between interns and mentors in a cooperative
      nurse internship.
AB  - The ongoing nature of leadership development and a marketplace that requires
      strong clinical competence call for programs that enhance leadership and clinical
      skills for new nurses. The author describes an internship designed and
      implemented by baccalaureate and associate degree faculty and nurse
      administrators at a local community hospital. Ten new graduates, employed full
      time, were mentored by nurse managers and taught leadership and clinical skills
      by nursing faculty during the one-year program. Perceptions of leadership
      competence between interns and mentors improved in the six categories measured.

PMID- 10647386
TI  - Integrating patterns of knowing in an undergraduate nursing course.
AB  - A complex and changing contemporary healthcare system and holistic consideration
      of patients create a need for nurses who have a sophisticated, broad knowledge
      base. Empirical, ethical, personal, and aesthetic patterns of knowing provide a
      meaningful background for course development and offer students the opportunity
      to understand themselves and their patients through multiple modes of awareness.
      In this article, the author describes the integration of patterns of knowing into
      an undergraduate nursing course. Course objectives, content, assignments, and
      evaluation are discussed. A course such as this one that incorporates scientific
      knowledge of humans in health and illness, aesthetic perception of human
      experiences, personal understanding of self and others, and the capacity to make
      ethical choices enriches student learning about the art and science of nursing.

PMID- 10647387
TI  - Teaching nursing management using popular movies.

PMID- 10647388
TI  - Nursing education as cognitive apprenticeship. A framework for clinical
      education.
AB  - The cognitive apprenticeship model is an effective tool in planning,
      implementing, and evaluating clinical learning experiences for nursing students.
      The goal of this model is to develop not only the explicit knowledge, psychomotor
      skills, and critical thinking processes of nursing students but also the usually
      covert processes of cognition, metacognition, and culture in the profession. The
      authors use a clinical case study to illustrate how the cognitive apprenticeship
      model can be applied to optimize clinical learning experiences.

PMID- 10647389
TI  - Do anxiety, math self-efficacy, and gender affect nursing students' drug dosage
      calculations?

PMID- 10647390
TI  - Addressing social, political, and health issues. The student congress strategy.
AB  - The authors describe a classroom instructional strategy used to resolve current
      social, political, and health issues. The strategy includes participation in
      group work and database searching in the preparation of proposed resolutions. The
      class serves as a Student Congress, voting for or against the resolutions
      presented. This instructional model could be used in any university classroom if
      the goal is to enhance critical-thinking skills and to heighten a sense of social
      and personal responsibility.

PMID- 10647391
TI  - Teaching critical thinking through a health-promotion contract.
AB  - Critical thinking is an important topic in nursing education today. The authors
      describe an assignment, based on the steps of the nursing process, in which
      students use critical-thinking skills to develop, implement, and evaluate a
      personal health-promotion contract. The assignment allows students to integrate
      health promotion, behavioral contracting, and critical-thinking concepts from the
      dual perspective of the nurse and the patient.

PMID- 10647392
TI  - Ambulatory care nursing courses.
AB  - As healthcare delivery moves into ambulatory and community-based settings, nurses
      need preparation for professional-level practice in these new environments. The
      University of Arkansas for Medical Sciences (UAMS) College of Nursing has
      designed and implemented its own ambulatory care nursing course to educate nurses
      for this growing practice setting. The author discusses the design and
      implementation of the courses.

PMID- 10647393
TI  - She is Melissa.

PMID- 10647394
TI  - Towards a society for all ages.

PMID- 10647395
TI  - Older men in contemporary discourses on ageing: absent bodies and invisible
      lives.
AB  - Contemporary discourses on ageing are essentially 'feminized', and as such report
      little on the experiences of older men. Living into late old age has become, and
      will continue to be, a normal phenomenon in our social worlds for both men and
      women. As a disadvantaged group, older women have attracted more attention than
      their older male counterparts. Yet this 'advantaged' older man may well be
      shackled by his gender role, and male gender socialization does impact upon men
      in later life. Older single men often have poorly developed social and family
      networks leaving them at a disadvantage. However, the masculinities of older men
      are conspicuously absent from most male gender studies. Rather than omitted, it
      is more that the dominant discourses of younger and middle-aged men are
      preserved. In turn, disability and disease do accompany old age yet disability
      has remained in the background and is, consequently, underdeveloped. This is not
      to say that disability represents the whole experience of health for older
      people, but it is clearly not an ageist fantasy. The phenomena of ageing, gender
      (including masculinity), and disability can be connected and consequently
      interpreted and understood by studying embodiment in old age.

PMID- 10647396
TI  - Searching for new possibilities to care: a qualitative analysis of family caring
      involvement in nursing homes.
AB  - This paper explores families' experience of searching for new possibilities to
      continue caring which emerged as a significant aspect of a larger hermeneutic
      phenomenological study of family caring in nursing homes. Hermeneutic analysis of
      in-depth interview transcripts and observation field notes of 14 family carers'
      experiences of caring uncovered eight shared meanings: feeling duty-bound;
      setting up possibilities for human connection; possessing special knowledge and
      skills; providing the personal approach; acting as an advocate; living with hope
      of improvement and recovery; feeling satisfied when care experienced was deemed
      to be quality care; and possessing a sense of worth through making a useful and
      positive contribution. Being engaged in new caring activities and relationships
      in the nursing home context assisted family members in coping with the changes in
      their situation. This paper highlights how finding new ways of caring for their
      relatives was important as everyday involvement in care set up possibilities
      through which meaning could be attributed to their existence.

PMID- 10647397
TI  - Reading Heidegger and interpretive phenomenology: a response to the work of
      Michael Crotty.
AB  - In a recent paper in Nursing Inquiry and in his other work, Michael Crotty was
      severely critical of much interpretive nursing scholarship and especially of some
      nurse scholars' interpretations of the work of Martin Heidegger. In this paper we
      respond to Crotty's attempt to set out what Heidegger 'actually says' [sic] in
      relation to tradition, culture, destruction, das Man and everydayness. We suggest
      that Crotty took a narrow, existentialist view of Heidegger's work and that this
      view was often misguided and poorly informed. We show not only that an
      alternative understanding of Heidegger's work in these important areas is
      possible, but that this interpretation is strongly supported by a deeper and
      wider reading of Heidegger's own work and of the secondary literature of
      Heideggerian scholarship.

PMID- 10647398
TI  - Mad talk: attending to the language of distress.
AB  - This paper will examine how the narrative of one woman, Madeleine, can be
      constructed as symptomatic of the diagnosis of schizophrenia, and how it can also
      be read from other perspectives, particularly a poststructural feminist one. The
      readings are presented as possibilities for understanding the woman's experiences
      and the implications of this for mental health nursing practice. A poststructural
      feminist reading acknowledges the gendered experiences of subjectivity and how
      those experiences are constructed in language. The purpose of this paper is to
      identify for mental health nursing practice an approach which recognizes the
      figurative and literal characteristics of language in order to provide nursing
      care which positions the individual's experience of mental distress as central.
      This requires an acknowledgement of Madeleine's path into mental distress rather
      than simply a categorization of what is observed in a clinical setting.
      Intervention may need to include a range of strategies: medical and nonmedical,
      psychotherapeutic and social, physical and environmental. It may also require the
      provision of sanctuary and security whilst these options are explored.

PMID- 10647399
TI  - Practical skill development in new nurses.
AB  - This paper reports the results of an empirical study of new nurses' development
      of practical skill. Actual practice and clinical learning of new nurses has
      received minor attention in nursing research. This may build on the assumption
      that practical skill naturally improve as a result of working in the clinical
      setting. In the present study nurses were videotaped several times as they
      performed in the clinical setting, and interviewed after each filming. Analysis
      of skill development was rendered possible by comparing characteristics of
      performance over time. A model of practical skill performance was developed
      during the analysis. This model advances a broader understanding of practical
      skill by incorporating the following constructs: substance and sequence,
      accuracy, fluency, integration and caring comportment. The nurses' trajectories
      of practical skill development are presented on the basis of this model.
      Individual and common trends in practical skill development are discussed, and
      the idea of development of practical skill as a natural happening in the clinical
      setting is critiqued.

PMID- 10647400
TI  - Constructions of self-neglect: a multiple case study design.
AB  - Patients who neglect personal hygiene, household cleanliness and their own health
      are familiar to most nurses. Despite this familiarity, self-neglect is a poorly
      conceptualized and little researched phenomenon. This multiple case study design
      uncovers the perceptions of self-neglect held by professionals, patients and
      relatives. The assumptions which underpin Orem's Theory of Self-Care and the
      medical model construction of self-neglect are explored and it will be suggested
      that there are limitations in understanding self-neglect using these theoretical
      frameworks.

PMID- 10647401
TI  - Theorizing about nurses' work lives: the personal and professional aftermath of
      living with healthcare 'reform'.
AB  - In this paper we discuss the impact of healthcare 'reform' on nurses' personal
      and professional lives. Using a thematic analysis, we interviewed 38 nurses in
      Nova Scotia, Canada regarding their experiences of job displacement, inability to
      find full-time employment and job losses. Their stories reflect how they lived
      day by day and the effects this had on their children, partners, friends and
      leisure, as well as their financial burdens. We theorize about the relationship
      between nurses' work and women's work, and particularly about women working in
      unstable conditions and the impact on their lives and that of the clients with
      whom they work.

PMID- 10647402
TI  - A voice for people with disabilities in the prenatal screening debate.

PMID- 10647403
TI  - The myth that nursing can yield megabucks.

PMID- 10647404
TI  - In the line of fire.

PMID- 10647405
TI  - Cultural evolution. Interview by Esther Leach.

PMID- 10647406
TI  - Midwife with a mission. Interview by Rebecca Coombes.

PMID- 10647407
TI  - Meningitis: a village holds its breath.

PMID- 10647408
TI  - Heard the one about the nurse and the engineer?

PMID- 10647409
TI  - Killing them softly.

PMID- 10647410
TI  - Seeing the funny side of things can do more than just help you survive your job:
      it can make you a better nurse.

PMID- 10647411
TI  - For anyone thinking of modernizing the NHS Niall Dickson has a lesson in policy
      making.

PMID- 10647412
TI  - Seat of the motions.

PMID- 10647413
TI  - The heat is on.

PMID- 10647414
TI  - Dousing the flames.

PMID- 10647415
TI  - It's so easy to get into hot water.

PMID- 10647416
TI  - Nurse heroes of the century. Interview by Jeannette Davidson.

PMID- 10647417
TI  - War wounds.

PMID- 10647418
TI  - Darkness visible.

PMID- 10647419
TI  - A gender for change.

PMID- 10647420
TI  - Making a will.

PMID- 10647421
TI  - A third way in which training and education in nursing are given equal status.

PMID- 10647422
TI  - The heart, Part Two: Anatomy and physiology.

PMID- 10647423
TI  - Asthma care in general practice.

PMID- 10647424
TI  - Drug interactions can make it worse.

PMID- 10647425
TI  - Fitness to practise in community mental health.

PMID- 10647426
TI  - Preventing injuries at work.

PMID- 10647427
TI  - Wound care. Conflict or diplomacy?

PMID- 10647428
TI  - Wound care. Discharged but not forgotten.
AB  - A pilot study assessed a methodology for establishing the incidence of post
      discharge surgical wound infections. An infection rate of 13% was recorded. The
      eight patients who developed infections generated 35 clinical episodes. This
      could have resource implications for early discharge after surgery.

PMID- 10647429
TI  - Wound care. Points of friction.
AB  - This article aims to identify optimum management strategies for hypergranulation
      of gastrostomy, tracheostomy and suprapubic catheter sites. It discusses the
      aetiology of hypergranulation and gives an overview of the available literature
      on existing treatments. It concludes that the optimum choice of management may be
      to tape the tube to the body to prevent friction and to use a polyurethane foam
      dressing with a high moisture vapour transmission rate.

PMID- 10647430
TI  - [A study on professionalism].

PMID- 10647431
TI  - [Austrian Nurse's Association and International Council of Nurses--a worthwhile
      relationship?].

PMID- 10647432
TI  - [EU-Project--public health in nursing. An interim report by Monika Klampfl].

PMID- 10647433
TI  - [Equality of opportunity and top jobs ... completed studies of the nursing
      sciences].

PMID- 10647434
TI  - [Attach your chariot to the stars. Lecture by Sister Liliane Juchli, given at the
      occasion of her farewell from the "public nursing scene" on February 28, 1998 in
      Baunatal].

PMID- 10647435
TI  - [Nursing diagnoses and professionalization].

PMID- 10647436
TI  - [No "old person", only old people].

PMID- 10647437
TI  - [Using the resources of age by conscious living. Sleeping away life or living
      consciously?].

PMID- 10647438
TI  - [Transitional care--accompanying patients into their home. After discharge
      problems arise, particularly for the aged, in dealing with activities of daily
      living].

PMID- 10647439
TI  - [The aged and society].

PMID- 10647440
TI  - [Sexuality in old age--a taboo?].

PMID- 10647441
TI  - [Tasks of the DRGS in geriatric care].

PMID- 10647442
TI  - [Teaching methods--pathways to success].

PMID- 10647443
TI  - [Hygiene: evaporators--steamers--nebulizers].

PMID- 10647444
TI  - [Applied hygiene in health facilities. "Between demand and behavior!"].

PMID- 10647445
TI  - [Student training and introduction to the wards].

PMID- 10647446
TI  - [The nursing process in the operating room].

PMID- 10647447
TI  - [Laughter in the hospital--taboo or chance].

PMID- 10647448
TI  - [Fair? Pay--or loss?].

PMID- 10647449
TI  - [Hygiene is not everything--but without hygiene nothing is anything].

PMID- 10647451
TI  - [Central venous catheter--infection control during insertion and care].

PMID- 10647450
TI  - [Psychological health--only a slogan?].

PMID- 10647452
TI  - [Teaching methods--pathways to success].

PMID- 10647453
TI  - [Studying during clinical practice].

PMID- 10647454
TI  - [Centennial of the International Council of Nurses].

PMID- 10647455
TI  - [A backward glance with a future. Interview by Harald Verworner].

PMID- 10647456
TI  - [Bandages and compresses--formerly and today].

PMID- 10647457
TI  - [Basal stimulation in nursing--heard about it?].

PMID- 10647458
TI  - [The art of nursing: effective love. Health care and nursing based on
      anthroposophy].

PMID- 10647459
TI  - [End of the didactics series in the Austrian Nursing Journal by Ingrid Bruckler
      and Ina Huppmann, teachers for health care and nursing].

PMID- 10647460
TI  - [Changes in the concept of instruction on the basis of current policy. Report on
      a charitable project at the School for General Health Care and Nursing at the
      Vienna General Hospital].

PMID- 10647461
TI  - [Nursing school, Bad Ischl: instruction in nursing research. The 1. class of the
      Ischl nursing school reports...].

PMID- 10647462
TI  - [Touch and perception in nursing].

PMID- 10647463
TI  - [The hospital scandal in upper Austria. Objective dangers or the dynamics of a
      case].

PMID- 10647464
TI  - [Basis of nursing science and nursing research in teaching of general health care
      and nursing].

PMID- 10647465
TI  - [Empirical study of the care of patients with abdominal aortic aneurysm].

PMID- 10647466
TI  - [Projects in nursing research and their relevant preparation].

PMID- 10647467
TI  - [Health promotion in nursing].

PMID- 10647468
TI  - Valuing diversity--a foundation stone of advanced wound caring.

PMID- 10647469
TI  - It doesn't have to be 1-800-TUF-LUCK: the clinician's role in appealing denied
      claims.

PMID- 10647470
TI  - Unusual leg ulcers.

PMID- 10647471
TI  - The beneficent nature of chronic wound care.
AB  - The principle of beneficence is one of four bioethical principles, which also
      include non-maleficence, autonomy, and justice. Beneficence is a moral term; it
      is the obligation to act for the benefit of others. Social policy is developed
      from informed choices with regard to a balance between costs, risks, and
      beneficence. Wound care clinicians conduct clinical and economic outcome studies
      to guide those responsible for making reimbursement decisions for patients with
      costly complications of chronic illness. This column discusses the balance of
      benefits, costs, and risks in the face of the principle of beneficence.
      Prevention, as an alternative to costly treatment of recurrent wounds, is
      presented as a strategy to balance cost, risk, and beneficence.

PMID- 10647472
TI  - Pressure ulcers in an age of managed care: a nursing perspective.
AB  - Successful competition for acquisition of capitated groups and maintenance of
      existing managed care contracts require demonstrations of cost controls, positive
      clinical outcomes, and customer satisfaction. In preparation for, and in response
      to managed care, healthcare providers must assure equality in their supply and
      demand equation if they are to survive and prosper. Iatrogenic pressure ulcers
      represent a major healthcare problem illustrative of this point. Successful
      pressure ulcer prevention and treatment programs in all practice settings demand:
      1) administrative support, 2) access to staffing and supplies, 3)
      multidisciplinary ownership, 4) integration of science-based knowledge of risk
      factors, risk assessment tools, pathophysiology, and appropriate management into
      clinical practice, and 5) dissemination of knowledge.

PMID- 10647473
TI  - Pressure ulcer assessment instruments: a critical appraisal.
AB  - Numerous evaluation tools have been developed to document various aspects of
      wound status or appearance of pressure ulcers. These include the Pressure Sore
      Status Tool (PSST), Pressure Ulcer Scale for Healing (PUSH Tool), Sussman Wound
      Healing Tool (SWHT), Sessing scale, and the Wound Healing Scale (WHS). A critical
      appraisal of the literature was undertaken to examine the purpose and methods for
      the development of each instrument, the extent to which the instruments have been
      validated to date, the practicality of their use, and the work that remains to be
      done to establish their suitability for clinical and/or research purposes. All of
      these instruments have been developed to describe and evaluate change in pressure
      ulcer status over time with the exception of the WHS, which was developed as an
      alternative to reverse staging. More of the validation parameters have been
      addressed for the PSST and the Sessing scale than for the PUSH Tool, the SWHT,
      and the WHS. All of the instruments can be completed within approximately 5
      minutes except the PSST, which requires 10 to 15 minutes to complete. For all
      instruments, experience with wounds and training in the use of the instrument are
      required to improve reliability. For each of the measurement instruments,
      suggestions are made that would complete necessary validation procedures and thus
      prepare the instruments for clinical and/or research purposes.

PMID- 10647475
TI  - The 1999 O/WM buyers guide.

PMID- 10647474
TI  - Clean versus sterile: a review of the literature.
AB  - To use clean or to use sterile is a question that is posed every day in clinical
      practice. While this review of the literature can not definitively answer the
      question, it does provide insight for ET nurses and other specialists who include
      wound care or urinary continence in their clinical practice.

PMID- 10647476
TI  - Lessons learned over 25 years.

PMID- 10647477
TI  - ASPRSN: celebrating 25 years of excellence in our specialty.

PMID- 10647478
TI  - History of breast prostheses.
AB  - What material was available for breast augmentation 25 to 75 years ago? How has
      the development of today's breast implants evolved? These and other related
      issues are discussed in this article on the history of breast prostheses.

PMID- 10647480
TI  - A glimpse at the specialty of wound care.
AB  - Many lessons have been learned over the course of the history of wound care. The
      answers to many questions still lie in the future. With this glimpse of where
      wound care has been and where it is headed in the future, certain trends were
      found. These trends are, in and of themselves, lessons that will be incorporated
      into this article as an act of reflection.

PMID- 10647479
TI  - Flaps and grafts revisited: cross-leg and thigh flaps for lower extremity wounds.
AB  - Soft tissue reconstruction of the lower extremity has evolved considerably over
      the last 25 years. We no longer have to rely only on awkward pedicle flaps, or
      ultimately, amputation in order to heal a leg wound. The following is a brief
      history of the flaps prior to the development and use of the operating microscope
      and an increased knowledge of the circulation distal to the knee.

PMID- 10647481
TI  - The good old days: a look back at cosmetic surgery.
AB  - During the 25-year, history of the American Society of Plastic and Reconstructive
      Surgical Nurses (ASPRSN), cosmetic surgery procedures and nursing care have
      undergone constant change. Lessons learned over the past quarter-century will be
      discussed as we live and learn from our past experiences.

PMID- 10647482
TI  - The history of ASPRSN: a look back.
AB  - This article takes a look back at the 25-year history of the American Society of
      Plastic and Reconstructive Surgical Nurses (ASPRSN). Alice Davis, a founding
      member of the Society, examines ASPRSN's history from the beginning in 1975
      through the present day in 1999.

PMID- 10647483
TI  - Insurance and patient rights: an ethical approach.

PMID- 10647484
TI  - Patient education: then and now.

PMID- 10647485
TI  - Do we need more regulation in health care?

PMID- 10647486
TI  - President's message. Nursing: a career measured in moments, not in years.

PMID- 10647487
TI  - A comparative analysis of individuals with spinal cord injury who differ in
      unplanned utilization of health services.
AB  - The purpose of this descriptive study is to describe the profile of individuals
      with spinal cord injuries (SCI) who frequently use health care services in an
      unplanned manner so that nursing interventions could be designed to decrease
      utilization. The medical records of 78 subjects with SCI were reviewed for
      demographic and injury-related variables, comorbid health conditions, discharge
      disposition, and health care utilization for five years. Based on the rate of
      unplanned utilization of health care services, three groups of users were
      identified: non-user, low-user, and high-user groups. Results indicated that high
      users, compared to non-users and low users, had a higher substance-use rate, a
      higher unemployment rate at the time of the most recent health care visit, and
      more violent causes of their SCI. Findings suggest four clinically meaningful
      trends that have practical implications for nurses related to marital status,
      substance use, employment status, and etiology of injury. Results of this study
      laid the foundation for future research aimed at devising a more in-depth risk
      profile of high users of health care services in the SCI population.

PMID- 10647488
TI  - The development of a nurse-directed computerized functional electrical
      stimulation program.
AB  - Today's spinal-cord-injured (SCI) person is discharged from the inpatient
      clinical setting very early in his or her recovery process. Faced with the
      tremendous challenges of relearning the skills of daily living and
      psychologically adjusting to a catastrophic injury, the newly injured person is
      thrust into an overwhelming environment. As early as 1994, when inpatient stays
      were longer, concern was expressed about the impact of early discharge on the
      health and well-being of persons with SCI (Ditunno & Formal, 1994). For over 10
      years, the Medical Illness Counseling Center (MICC) has offered a community
      based, nurse-directed program of Computerized Functional Electrical Stimulation
      (CFES) for persons with SCI. The program is founded on the belief that when multi
      system deterioration associated with paralysis is avoided and a behavioral
      approach is used, the person with SCI will have a renewed sense of well-being
      that enables him or her to overcome the challenges of daily living. Over time,
      the need for expansion of the program became apparent; it evolved into a
      comprehensive package of medical, nursing, and psychological care. This article
      describes the essential elements that comprised a successful program design, the
      benefits of participation in CFES, and the significance of this technology in a
      nurse-managed setting.

PMID- 10647489
TI  - The efficacy of nursing education as an intervention in the treatment of
      recurrent urinary tract infections in individuals with spinal cord injury.
AB  - Urinary tract infection (UTI) continues to be the most frequent secondary medical
      complication experienced by persons with spinal cord injury (SCI). We developed a
      carepath designed to minimize recurrent UTIs in patients identified as at risk.
      Data were collected in a prospective fashion for 1,000 consecutive days at an
      outpatient SCI clinic. The number of UTIs decreased to below threshold in 65
      percent of the patients when the nurse clinician counseled them regarding proper
      technique and hygiene related to clean intermittent catheterization. Of the
      patients who responded to this intervention, 73 percent required multiple
      counseling sessions. We conclude that educational intervention by a clinic nurse
      is a simple, cost-effective means of decreasing the risk of UTIs in individuals
      with SCI who are identified as at risk.

PMID- 10647490
TI  - My furry friends.

PMID- 10647492
TI  - Client resources online.

PMID- 10647491
TI  - Team jeopardy! Learning about living with spinal cord injury.

PMID- 10647493
TI  - Research corner. Developing an instrument.

PMID- 10647494
TI  - Cross-resistance of topoisomerase I and II inhibitors in neuroblastoma cell
      lines.
AB  - PURPOSE: We have previously shown that neuroblastomal cell lines established from
      patients after intensive chemotherapy show sustained resistance to various drugs
      and especially high resistance to etoposide (up to 51 times higher than a
      clinically achievable level). To determine whether topoisomerase I inhibitors
      (topotecan and CPT- 11) are effective against etoposide-resistant neuroblastomas,
      we studied the response to topotecan and the active metabolite of CPT-11 (SN-38)
      in 19 cell lines with a spectrum of sensitivities to etoposide. MATERIALS AND
      METHODS: The panel included cell lines established at diagnosis and after disease
      progression either during induction chemotherapy or after myeloablative therapy
      supported with bone marrow transplantation. Cytotoxicities of topotecan, SN-38,
      and etoposide were determined using a microplate digital image microscopy
      (DIMSCAN) assay with a 4-log dynamic range. RESULTS: All six etoposide-resistant
      cell lines were resistant to topotecan and SN-38 (resistance defined as LC90
      higher then clinically achievable levels for the drug). Significant cross
      resistance by Pearson's correlation analysis (r > or = 0.6) occurred between
      topotecan + etoposide, topotecan + SN-38, and etoposide + SN-38. CONCLUSIONS:
      Topotecan and CPT-11 do not have significant activity against most etoposide
      resistant neuroblastoma cell lines and this suggests that agents other than
      topoisomerase inhibitors should be explored for the treatment of recurrent
      neuroblastomas.

PMID- 10647495
TI  - Clinical pharmacokinetics of the irinotecan metabolite 4-piperidinopiperidine and
      its possible clinical importance.
AB  - PURPOSE: To investigate the clinical relevance of 4-piperidinopiperidine (4PP) in
      the activity of irinotecan (CPT-11), a high-performance liquid chromatography
      turboionspray-tandem mass spectrometry assay for plasma 4PP was developed.
      METHODS: Plasma samples were prepared for analysis following C18 solid-phase
      extraction. Chromatography was performed on a Waters Nova-Pak Phenyl column.
      Selected reaction monitoring with the mass transitions m/z 169.2 --> 84.2 and
      139.2 --> 98.1 was used for the detection of 4PP and the internal standard (IS),
      1-piperidineproprionitrile, respectively. RESULTS: The assay was linear from 14.8
      to 591.0 nM with absolute recoveries of 4PP (59.1 nM) and IS (143.7 nM) of 85.7%
      (n = 10) and 86.7% (n = 10), respectively. The accuracy and imprecision of the
      method (total) was > or = 96.8% and < or = 8.5% over the concentration range
      studied, respectively. 4PP was detectable in plasma following the administration
      of 125, 350, 500 mg/m2 and 600 mg/m2 CPT-11 to patients, with AUC(4PP) correlated
      with the dose (r2 = 0.66). Plasma concentrations of 4PP declined slowly with a
      long terminal half-life (33.4 +/- 17.1 h). CONCLUSIONS: Overall, the
      concentrations of 4PP in plasma were in the sub-micromolar range (< 206.9 nM) and
      substantially lower than those capable of inducing apoptosis of cancer cells.

PMID- 10647496
TI  - Four-hourly scheduling of temozolomide improves tumour growth delay but not
      therapeutic index in A375M melanoma xenografts.
AB  - PURPOSE: To establish whether temozolomide is more effective against A375M human
      melanoma xenografts if given every 4 h rather than every 24 h, in order to
      exploit depletion of the DNA repair protein O6-alkylguanine-DNA alkyltransferase
      (ATase) by prior doses of the drug. METHODS: ATase depletion in A375M human
      melanoma xenografts was determined over 24 h after a single dose of temozolomide.
      The effect of different drug schedules (all of total dose 500 mg/kg) in delaying
      the growth of the xenografts was tested, and ATase depletion and DNA methylation
      damage assessed in tumour and normal tissue. RESULTS: Maximal depletion of ATase
      in tumour, to 2.52 +/- 0.23% of pretreatment levels, occurred 4-8 h after a
      single 100 mg/kg i.p. dose of temozolomide, with 23.0% recovery of protein levels
      at 24 h. Scheduling of temozolomide every 4 h increased tumour growth delay (33.6
      +/- 1.39 days with temozolomide 100 mg/kg 4-hourly x versus 23.2 +/- 1.43 days
      with temozolomide 100 mg/kg once daily x 5; P < 0.0001) at the expense of
      increased toxicity (17.4 +/- 1.55% animal weight loss versus 10.6 +/- 1.27%.
      respectively). Temozolomide every 4 h did not increase ATase depletion compared
      with the 5-day schedule, but resulted in greater DNA 06-guanine methylation
      (29.0% more in tumour, 20.8% in liver and 56.0% in brain, comparing areas under
      the methylation-time curve). CONCLUSIONS: The 4-hourly schedule of temozolomide
      delayed tumour growth significantly more than the once-daily and 12-hourly
      schedules, probably as a result of greater DNA damage inflicted, but also
      increased toxicity. It remains to be seen if this regimen confers a net benefit
      over the standard schedule.

PMID- 10647497
TI  - The influence of recombinant human insulin-like growth factor-I (rhIGF-I) on cell
      growth and cytotoxicity of drugs in childhood rhabdomyosarcoma cell lines and
      xenograft models.
AB  - PURPOSE: Recombinant human insulin-like growth factor I (rhIGF-I) has been
      reported to ameliorate vincristine-induced neuropathy, the dose-limiting side
      effect of this antimitotic anticancer drug. However, rhIGF-I also might have
      adverse effects, as has been shown in vitro, where it stimulates growth of cancer
      cells and protects them from cytotoxicity of anticancer drugs. The influence of
      rhIGF-I on the cytotoxicity of vincristine has not yet been studied. Furthermore,
      studies performed have been done under serum-free conditions, which are far from
      physiological. METHODS: We studied the influence of rhIGF-I on the growth of two
      rhabdomyosarcoma cell lines (Rh30 and Rh1) and on the antitumor effects of
      vincristine, cisplatin, etoposide, doxorubicin, and topotecan under serum-free
      and serum-containing conditions. To extend the in vitro data, we grew Rh30 cells
      as xenografts in mice and determined the effects of vincristine. rhIGF-I or their
      combination on tumor growth. RESULTS: In vitro, both cell lines demonstrated a
      functional type I IGF receptor, as shown by the rapid activation of ribosomal p70
      S6 kinase after stimulation with rhIGF-I. Under serum-free conditions, rhIGF-I
      stimulated growth of both cell lines. Exposure to cytotoxic drugs with and
      without rhIGF-I resulted in higher cell numbers in cultures exposed to rhIGF-I.
      However, relative to the appropriate control, fractional growth inhibition and or
      cell kill of the cytotoxic drugs was identical with and without rhIGF-I. Under
      serum-containing conditions, rhIGF-I had no effect on cell growth or drug
      cytotoxicity. In vivo we did not find a significant influence of rhIGF-I on
      HxRh30 cell growth, or on the antitumor activity of vincristine. CONCLUSIONS:
      These studies show that rhIGF-I has no adverse effects on human rhabdomyosarcoma
      growth or on the antitumor effect of cytotoxic drugs under serum-containing
      conditions in vitro or in tumor-bearing mice. Potentially, therefore, rhIGF-I may
      ameliorate vincristine-induced neuropathy without adversely influencing tumor
      growth or vincristine cytotoxicity in children.

PMID- 10647498
TI  - Combined treatment of Dunning R3327 rat prostatic tumor with the 5alpha-reductase
      inhibitor PNU 157706 and the antiandrogen bicalutamide.
AB  - PNU 157706 [N-(1,1,1,3,3,3-hexafluorophenyl-propyl)-3-oxo-4-aza- 5alpha-androst-1
      ene-17beta-carboxamide], a novel, potent and selective dual 5alpha-reductase
      inhibitor, was reported to be effective in inhibiting the growth of established
      tumors in the Dunning R3327 rat prostatic carcinoma model. PURPOSE: We
      investigated the efficacy of treatment with PNU 157706 in combination with the
      antiandrogen bicalutamide in this prostatic tumor model. METHODS: Rats with tumor
      diameters of about 1 cm were treated orally 6 days a week for 9 weeks with PNU
      157706 (10 mg/kg per day) alone or in combination with bicalutamide (0.2 and 1 mg
      kg per day). Animals were killed 24 h after the last treatment, and ventral
      prostates were removed for testosterone (T) and dihydrotestosterone (DHT)
      determination. RESULTS: PNU 157706 reduced the growth of established tumors by
      39%; bicalutamide proved ineffective at 0.2 mg/kg per day, but reduced tumor
      growth by 45% at a dose of 1 mg/kg per day. The combination of PNU 157706 with
      both doses of bicalutamide caused an additive tumor growth inhibition (50% and
      64%). Castration resulted in marked tumor growth inhibition (72%). Ventral
      prostate weight was markedly reduced by PNU 157706 (78%) treatment and by
      bicalutamide (59% and 77%); combined treatment was as effective as castration.
      Prostatic DHT content was markedly reduced by PNU 157706 (88%), whereas prostatic
      T increased slightly (60%). Concomitant treatment with bicalutamide antagonized
      the T increase induced by PNU 157706 and did not modify the already remarkable
      suppression of DHT. CONCLUSIONS: These data show that the inhibitory effect of
      PNU 157706 and bicalutamide on Dunning prostatic tumor growth is additive, thus
      suggesting a possible role of PNU 157706 in the therapy of advanced prostate
      cancer, in combination with antiandrogens, to provide an effective peripheral
      androgen ablation therapy with minimal side effects.

PMID- 10647500
TI  - Sulfur-containing amino acids decrease cisplatin cytotoxicity and uptake in renal
      tubule epithelial cell lines.
AB  - PURPOSE: Nephrotoxicity is one of the major dose-limiting side-effects of
      cisplatin (DDP). The disproportionate accumulation of cisplatin in kidney tissue
      may play an important role, however, therapeutic measures to prevent this prime
      cause of nephrotoxicity are not available. Because certain amino acids (AAs) have
      been reported to modulate DDP nephrotoxicity in vivo, we explored the potential
      of all 20 protein AAs, N-acetylcysteine and DL-homocysteine to reduce DDP
      cytotoxicity and uptake in S1, S3 (proximal tubule), and DCT (distal convoluted
      tubule) cell lines. METHODS: Immortalized but non-transformed renal tubule
      epithelial cell lines, derived from specific portions of the nephron of an SV40
      transgenic mouse. were grown to confluency and exposed to various concentrations
      of DDP for 1 h with or without concurrent exposure to AAs in an otherwise AA-free
      Krebs-Ringer buffer (KRB). After 1 h, cell layers were washed and replenished
      with medium for cytotoxicity assays, or processed immediately for the
      determination of DDP accumulation. Cytotoxicity was assessed 48 h later by an MTT
      assay, and DDP uptake after 1 h was determined by atomic absorption spectroscopy.
      RESULTS: In an initial screening where the cells were concurrently incubated with
      0.25 mM DDP and 1 mM AA for 1 h in KRB, only cysteine (Cys), methionine (Met), N
      acetylcysteine and DL-homocysteine reduced DDP toxicity. This effect was enhanced
      at 5 mM AA and most potent for Cys, which reduced DDP cytotoxicity by 79 +/- 3%
      in S3 cells, by 78 +/- 12.2% in DCT cells, and by 19 +/- 3.6% in S1 cells (P <
      0.05). Reduction of cytotoxicity was less for Met, DL-homocysteine, and N
      acetylcysteine, in decreasing order. All four AAs also inhibited DDP uptake in
      renal cells, with Cys as the strongest inhibitor. Inhibition of DDP accumulation
      by 1 mM Cys after 1 h was 39% in S3 cells, 38% in DCT cells, and 28% in S1 cells.
      Again, reduction of uptake was less for the three other AAs. Pre-complexing of
      DDP with Cys for 16 h increased its uptake by 8- to 30-fold compared with native
      DDP, but markedly inhibited its toxicity. Thus, pre-complexing of DDP with Cys
      could not explain the reduced uptake of DDP, but could partly account for the
      reduction in cytotoxicity. Double-reciprocal Lineweaver-Burk plots of DDP
      concentration-versus-uptake rates at a constant concentration of Cys suggested
      that Cys competitively inhibited DDP uptake in S1 and DCT cells, and in a more
      complex fashion in S3 cells. CONCLUSIONS: We conclude that Cys, Met, N
      acetylcysteine, and DL-homocysteine differentially inhibit DDP toxicity and
      uptake in cultured S1, S3, and DCT cells, and that the inhibition of uptake, as
      well as the complexation of DDP with Cys within the cell, may prevent toxicity.
      The structural element R-CH(NH2)-[CH2]1 2-S-R, which is common to all four
      molecules, may play a crucial role in blocking the transport of DDP, and could
      have future clinical applications.

PMID- 10647499
TI  - Interaction between gemcitabine and mitomycin-C in vitro.
AB  - Both gemcitabine (2',2'-difluorodeoxycytidine; dFdCyd) and mitomycin-C (MMC) are
      active against several solid malignancies. dFdCyd is an attractive agent for use
      in combination with drugs which damage DNA and with radiation therapy because of
      its ability to inhibit DNA replication and repair as well as its radiosensitizing
      effect. We hypothesized that the repair of MMC adducts in DNA might be inhibited
      by dFdCyd leading to a synergistic effect. To test this possibility, we studied
      the effect of combining dFdCyd and MMC in HT29 human colon carcinoma cells in
      vitro. The cells were exposed to a variety of drug concentration ratios and
      schedules, then assessed for clonogenic survival. D50 values (drug concentration
      at which clonogenicity is inhibited by 50%) were calculated, and the interactive
      effects of the two drugs were evaluated using median effect analysis. In this
      approach, if the calculated combination index (CI) is < 1, 1, or > 1, it
      indicates synergism, additivity, or antagonism, respectively (Chou and Talalay
      1984). We found that marked synergy (CI of 0.5-0.7) was produced by concurrent
      exposure to mitomycin and gemcitabine. In contrast, sequential treatment led only
      to additivity. These findings suggest that, when combined in an appropriate
      schedule, the chemosensitizing effect of gemcitabine may be beneficial in the
      treatment of malignancies which are sensitive to MMC.

PMID- 10647501
TI  - Metabolism of camptothecin, a potent topoisomerase I inhibitor, in the isolated
      perfused rat liver.
AB  - PURPOSE: Camptothecin (CPT) is a potent topoisomerase I inhibitor that has
      recently been undergoing phase I clinical trials. Though CPT shows high activity
      against various tumor cells, its biotransformation is still unknown. To
      investigate the metabolism and biliary excretion of CPT, an isolated perfused rat
      liver system was used. METHODS: CPT was added to the perfusion medium at a
      concentration of 20 microM, and bile and perfusate samples were collected for 90
      min. CPT (lacton and carboxylate) and three novel metabolites were identified by
      mass spectroscopy and quantified by reversed-phase high-performance liquid
      chromatography (HPLC). Kinetic parameters of CPT and its biotransformation
      products were then estimated in bile and effluent perfusate. RESULTS: Biliary
      secretion of CPT and its three metabolites reached a peak secretion of 37.6 +/-
      16.3, 0.94 +/- 0.29, 0.19 +/- 0.023 and 0.302 +/- 0.076 nmol/g liver/min,
      respectively, after 20 min. The total amount of CPT and M1-M3 excreted into bile
      during 90 min of perfusion was 63.5 +/- 15.4%, 1.8 +/- 0.37%, 0.43 +/- 0.06%, and
      0.72 +/- 0.15% of CPT cleared from the perfusate during 90 min, respectively. In
      the perfusate, only one metabolite (M3) could be detected (cumulative release
      into the perfusion medium: 0.37 +/- 0.026 micromol/liver). Analysis of the
      biliary metabolites by mass spectroscopy supported the existence of dihydroxy-CPT
      derivatives (M1 and M2), whereas M3 appears to be a monohydroxy-analog.
      CONCLUSION: CPT is biotransformed to three novel metabolites, mainly excreted
      into bile. The possible pharmacological effects of these new metabolites need to
      be considered.

PMID- 10647502
TI  - A pharmacokinetic and phase II study of gallium nitrate in patients with non
      small cell lung cancer.
AB  - This study investigated the pharmacokinetics and activity of gallium nitrate in
      non-small cell lung cancer when 700 mg/m2 was given as a 30-min infusion with
      prehydration every 2 weeks. Gallium was measured in plasma and urine using
      flameless atomic absorption spectrophotometry, and pharmacokinetics of total and
      ultrafilterable gallium were calculated. Twenty-five patients with non-small cell
      lung cancer received 1-12 (median 2) courses of gallium nitrate every 2 weeks. Of
      21 patients evaluable for response, 1 partial response was recorded, 4 patients
      had stable disease. and 16 had progressed. The most serious toxicities were renal
      impairment and optic neuritis. Hypocalcaemia was recorded in 3 patients. The mean
      C(max) was 15.2 +/- 3.1 microg/ ml (range 9.5-21.2). Most gallium remained
      ultrafilterable for the first 10 h, after which plasma protein binding increased,
      and at 48 h only 11% was present as ultrafilterable gallium. The elimination
      profiles of both total and ultrafilterable gallium were biphasic, and the
      distribution phase consisted of ultrafilterable gallium, with a distribution half
      life of 1.4 h. Total gallium plateaued at 1.9 microg/ml at between 8 and 12 h,
      and the estimated elimination half-life was 63 h. The elimination half-life of
      ultrafilterable gallium was 16.5 h. Inter- and intra-patient variability in
      pharmacokinetics was minimal. A mean of 50 +/- 14% of the gallium dose was
      excreted in the urine within 48 h. A short infusion of gallium nitrate achieving
      high peak plasma concentrations results in little efficacy in non-small cell lung
      cancer.

PMID- 10647503
TI  - DNA guanine-guanine crosslinking sequence specificity of isophosphoramide
      mustard, the alkylating metabolite of the clinical antitumor agent ifosfamide.
AB  - PURPOSE: The purpose of this investigation was to determine the base sequence
      specificity of isophosphoramide mustard (IPM), the alkylating metabolite of
      ifosfamide, by crosslinking of designed DNA oligomers in comparison with the
      clinical alkylating agents mechlorethamine (ME) (nitrogen mustard) and
      phosphoramide mustard (PM), the alkylating metabolite of cyclophosphamide.
      METHODS: IPM, as well as PM and ME were each reacted with three dodecameric
      duplexes, which were designed to detect interstrand crosslinking between guanines
      in 5'-GC-3' (I), 5'-GNC-3' (II) or 5'-GNNC-3' (III) sequences (N = A or T).
      RESULTS: All three agents preferentially react with 5'-GNC-3' target sequences.
      The 5'-GNNC-3' target sequence is less reactive by a factor of approximately 2.5-
      to 10-fold, while 5'-GC-3' is of even lower reactivity. CONCLUSION: These results
      indicate that all three agents show approximately equal preference for reaction
      with a 5'-GNC-3' target sequence in spite of the fact that IPM yields a 7-atom
      crosslink, while the other two agents yield 5-atom crosslinks.

PMID- 10647504
TI  - Variability of cyclophosphamide uptake into human bronchial carcinoma:
      consequences for local bioactivation.
AB  - PURPOSE: The alkylating cytostatic prodrug cyclophosphamide is bioactivated by
      the human cytochrome P450 enzyme system. Since these enzymes are not only
      expressed in human liver, but also in extrahepatic tissue, local bioactivation of
      this drug may play an important role in its antineoplastic effects, e.g.,
      chemotherapy of lung tumors. This would require uptake of significant amounts of
      cyclophosphamide into tumor tissue, which has not yet been demonstrated. METHODS:
      We used a recently developed, ex vivo isolated, ventilated and perfused human
      lung model to study cyclophosphamide uptake into bronchial carcinoma and healthy
      lung tissue. Following a standard lobectomy, lung samples containing the tumor
      were perfused with buffer containing 2 mM cyclophosphamide for 2 h.
      Cyclophosphamide concentrations in perfusate and healthy peripheral tissue were
      measured during the perfusion and in tumors at the end of perfusion. RESULTS: In
      all tissue samples, cyclophosphamide uptake was relatively poor, indicated by a
      tissue to perfusate ratio of 0.021. Moreover, in tumor samples, cyclophosphamide
      concentrations were significantly lower (P < 0.05) than in healthy lung tissue
      and showed pronounced interindividual variability. Median concentrations were
      36.8 microg/g (26.9 44.2 microg/g) in healthy tissue and 5.1 microg/g (0.0-26.8
      microg/g) in tumor samples. Tumor cyclophosphamide concentrations varied between
      0 and 75% of those reached in healthy tissue. CONCLUSIONS: Our results indicate
      that CP tumor concentrations are modulated by factors different from dose and
      that expression of bioactivating enzymes in human lung or transfection of genes
      encoding these enzymes into tumor cells does not necessarily lead to local
      bioactivation of cyclophosphamide.

PMID- 10647505
TI  - Potentiation of BCNU antitumor efficacy by 9-substituted O6-benzylguanines.
      Effect of metabolism.
AB  - PURPOSE: O6-Benzylguanine (BG), an O6-methylguanine-DNA methyltransferase (MGMT)
      inactivator, potentiates the efficacy of 1,3-bis(2-chloroethyl)-1-nitrosourea
      (BCNU) and of other DNA chloroethylating and methylating anticancer drugs and is
      currently undergoing clinical trials. O6-Benzyl-2'-deoxyguanosine (dBG), a less
      effective MGMT inactivator than BG in vitro, is at least as effective as BG in
      combination with BCNU against tumor xenografts in athymic mice. In order to
      identify the mechanism of dBG activation in in vivo systems we tested the
      metabolism, ability to inactivate MGMT, and efficacy to potentiate BCNU in vivo
      of two additional 9-substituted derivatives of BG, namely O6-benzyl-9
      cyanomethylguanine (CMBG) and O6-benzylguanosine (BGS). METHODS: Metabolism and
      disposition of these drugs was examined in athymic mice and Sprague-Dawley rats.
      MGMT suppression was determined in human medulloblastoma (Daoy) tumor xenografts
      in athymic mice following treatment with BGS, dBG, and CMBG and was compared with
      the loss of resistance to BCNU as determined by tumor growth delays. RESULTS:
      Growth delays at 25 mg/m2 BCNU and 133 mg/m2 BG or equimolar doses of CMBG, BGS
      or dBG were 23.0, 2.5, 21.3 days. and 30.4 days, respectively. The above
      differences did not correlate with the ED50S of 0.2, 13, 11 microM, and 2 microM
      determined for the above compounds, respectively, in cell free extracts.
      Differences in the efficacies of the 9-substituted compounds did correlate,
      however, with the extent of their metabolic conversion to BG. The maximum
      concentrations of BG in blood achieved after the administration of equimolar (250
      micromol/kg) doses of CMBG, BGS and dBG were 10, 30 microM, and 55 microM,
      respectively. Although such levels were lower than those achieved in circulation
      by administration of an equimolar amount of BG, BG levels persisted longer
      following treatments with BGS or dBG than after treatment with BG itself.
      Formation of BG was required for continuous and prolonged (> 16 h) suppression of
      MGMT activity to non-detectable levels (< 5 fmol/mg protein). CONCLUSION:
      Metabolism of BGS and dBG to BG explains the unexpected high efficacy of these
      compounds in potentiating the antitumor activity of BCNU in the athymic mouse
      model. The faster and more effective suppression of tumor MGMT by dBG and its
      greater efficacy, as compared with BGS, also correlates with a more rapid
      accumulation of BG in blood after dBG than after BGS administration, which
      results in faster and complete suppression of MGMT in Daov xenografts. Thus,
      metabolism of dBG and BGS to BG appears to be the determining factor for
      continuous and prolonged suppression of MGMT activity, and that near complete
      suppression of such activity during and following BCNU administration is required
      for the higher efficacy of treatments. Similarly, the failure of CMBG to suppress
      tumor MGMT to the same extent as BGS, in spite of their similar ED50 values,
      could be attributed to the metabolism of this compound mainly by pathways other
      than conversion to BG.

PMID- 10647506
TI  - Mechanism of action of the dual topoisomerase-I and -II inhibitor TAS-103 and
      activity against (multi)drug resistant cells.
AB  - TAS-103 is a recently developed dual inhibitor of topoisomerase-I (topo-I) and
      topoisomerase-II (topoII). TAS-103 has documented cytotoxicity in vitro and
      antitumor activity against a variety of mouse, rat, and human xenografts in vivo.
      PURPOSE: To determine TAS-103 activity against (multi)drug resistant cells in
      vitro and to delineate its mechanism of action. METHODS: TAS-103 was evaluated
      for activity against three human multidrug-resistant cell lines representing
      resistance mediated by P-glycoprotein (Pgp)-, multidrug resistance protein (MRP),
      and lung resistance protein (LRP) as well as one camptothecin-resistant cell line
      associated with a mutated topo-I enzyme. Drug sensitivity following short (2 h),
      intermediate (6-8 h) and long term (24 h) exposures were compared. The mechanism
      of action was studied by evaluating inhibition of topoisomerase-I and -II
      specific DNA relaxation assays, drug-induced DNA/protein cross-link formation,
      and competitive DNA intercalation with ethidium bromide. RESULTS: Increasing the
      exposure time only modestly potentiated TAS-103 cytotoxicity (3-5 fold)
      demonstrating a lack of strong exposure duration dependency. TAS-103 cytotoxicity
      was not affected by the presence of any of the drug resistance mechanisms
      studied. TAS-103 inhibits topo-I and -II activity in DNA relaxation assays, but
      in our assay system TAS-103 was found to have only a weak ability to induce DNA
      protein crosslinks. DNA migration patterns in agarose gel electrophoresis
      indicate that TAS-103 can interact directly with DNA. Also its ability to
      displace ethidium bromide which has intercalated into the DNA provides an
      indication on the nature of drug-DNA interaction. CONCLUSIONS: TAS-103
      cytotoxicity is not affected by the presence of Pgp, MRP, LRP or mutations in the
      CAM binding region of the topo-I enzyme and its growth-inhibitory effect appears
      to be weakly dependent on exposure duration. The presented evidence suggest that
      the inhibitory effects of TAS-103 on topo-I and -II may in part be related to its
      DNA binding rather than primarily through stabilization of topo-I or -II
      intermediates with DNA through specific binding to the enzymes.

PMID- 10647507
TI  - Phase I trial with weekly EO9, a novel bioreductive alkylating indoloquinone, by
      the EORTC Early Clinical Study Group (ECSG).
AB  - PURPOSE: EO9 is a new synthetic bioreductive alkylating indoloquinone, with
      preferential activity against solid tumors and higher antitumor activity under
      anaerobic conditions compared with aerobic conditions. In preclinical models EO9
      demonstrated no major organ toxicity. The aim of the present phase I study was to
      determine the toxicities and the maximal tolerated dose (MTD) of EO9 administered
      as a 5-min i.v. infusion weekly to patients with solid cancers. METHODS: Twenty
      eight patients entered the study. The dose was escalated from 2.7 mg/m2 according
      to a Fibonacci-like schedule. RESULTS AND CONCLUSION: The dose-limiting toxicity
      was proteinuria. No other major toxicities were detected and in particular there
      was no significant increase in serum creatinine. This was in contrast to findings
      in a previous phase I trial using EO9 in a 3-weekly schedule, where a number of
      patients experienced severely decreased kidney function. The MTD in the present
      study was 15.0 mg/m2 weekly and the recommended dose for phase II studies was
      12.0 mg/m2 weekly. Compared with 3-weekly EO9, the dose intensity could be
      increased from 22 mg/m2 to 36 mg/m2 with the weekly administration. Phase II
      studies have been performed by the EORTC Early Clinical Study Group in advanced
      breast, gastric, colorectal, pancreatic, and non-small-cell lung cancer.

PMID- 10647508
TI  - Lack of nephrotoxicity of new oral platinum drug JM216 in lung cancer patients.
AB  - PURPOSE: The purpose of this study was to assess renal function in patients
      treated with the oral platinum drug JM216 [bisacetato-ammine-dichloro
      cyclohexylamine-platinum(IV)], since the effects of JM216 on renal function have
      only partly been investigated using serum parameters or 51Cr-EDTA clearance. We
      used a sensitive method that assessed glomerular filtration rate (GFR), effective
      renal plasma flow (ERPF), and indicators of tubular and glomerular damage.
      METHODS: A group of 24 patients with either non-small-cell lung cancer (NSCLC)
      stage IIIb/IV or small-cell lung cancer (SCLC), limited disease (LD) or extensive
      disease (ED), treated with JM216 were studied. All patients had no prior
      chemotherapy, a performance score < 2, a life expectancy of more than 3 months
      and normal liver, renal and bone marrow functions before treatment. All patients
      received oral JM216 120 mg/m2 per day for 5 consecutive days, repeated every 21
      days with a maximum of six cycles. In six SCLC patients the dose was escalated to
      140 mg/m2 per day after the first cycle. Prior to treatment, after the first
      cycle and after the end of treatment renal function was assessed by 125I-sodium
      thalamate and 131-hippurate clearances to determine acute and cumulative changes
      in GFR and ERPF, respectively. Furthermore, tubular and glomerular damage were
      assessed by urinary excretion of beta2-microglobulin, lactic dehydrogenase (LDH),
      alkaline phosphatase (ALP), gamma-glutamyltransferase (GT) and albumin. RESULTS:
      In 20 evaluable patients no significant acute impairment of renal function was
      observed. Median (range) GFR, ERPF and filtration fraction (FF) before treatment
      were 101 ml/min (53-164 ml/min), 417 ml/min (227-719 ml/min), and 0.25 (0.19
      0.33), respectively. After the first cycle values were 117 ml/min (71-189
      ml/min), 418 ml/min (228-709 ml/ min) and 0.28 (0.21-0.33), respectively. Also,
      no indications of tubular or glomerular damage were found. In four patients renal
      function was evaluated at the end of treatment (one after three cycles, one after
      five cycles and two after six cycles). Median (range) GFR, ERPF and FF were 99
      ml/min (74-139 ml/min), 401 ml/min (277-496 ml/min) and 0.26 (0.23-0.30),
      respectively, revealing no delayed nephrotoxicity. CONCLUSION: We conclude that
      oral JM216 shows no nephrotoxicity.

PMID- 10647509
TI  - Detection of domoic acid in northern anchovies and California sea lions
      associated with an unusual mortality event.
AB  - The occurrence of an unusual mortality event involving California sea lions
      (Zalophus californianus) along the central California coast in May 1998 was
      recently reported. The potent neurotoxin domoic acid (DA), produced naturally by
      the diatom Pseudo-nitzschia australis and transmitted to the sea lions via
      planktivorous northern anchovies (Engraulis mordax), was identified as the
      probable causative agent. Details of DA analyses for anchovy tissues and sea lion
      feces are described. Domoic acid levels were estimated in anchovy samples by HPLC
      UV, and in sea lion feces using the same method as well as a microplate receptor
      binding assay, with absolute confirmation by tandem mass spectrometry. The
      highest DA concentrations in anchovies occurred in the viscera (223 +/- 5 microg
      DA g(-1)), exceeding values in the body tissues by seven-fold and suggesting
      minimal bioaccumulation of DA in anchovy tissue. HPLC values for DA in sea lion
      fecal material (ranging from 152 to 136.5 microg DA g(-1)) required correction
      for interference from an unidentified compound. Inter-laboratory comparisons of
      HPLC data showed close quantitative agreement. Fecal DA activity determined using
      the receptor binding assay corresponded with HPLC values to within a factor of
      two. Finally, our detection of P. australis frustules, via scanning electron
      microscopy, in both anchovy viscera and fecal material from sea lions exhibiting
      seizures provides corroborating evidence that this toxic algal species was
      involved in this unusual sea lion mortality event.

PMID- 10647510
TI  - Mycotoxins (trichothecenes, zearalenone and fumonisins) in cereals associated
      with human red-mold intoxications stored since 1989 and 1991 in China.
AB  - Two corn powder samples implicated in the human food poisoning that occurred in
      Guangxi province in 1989, and eight wheat and two barley samples linked to an
      episode that involved about 130,000 people in gastrointestinal disorders in Anhui
      province in 1991 were analyzed for trichothecenes including deoxynivalenol (DON),
      nivalenol (NIV) and their esters, zearalenone (ZEA) and fumonisins (FMs) by gas
      chromatography/mass spectroscopy and high performance liquid chromatography, and
      T-2 toxin by enzyme-linked immunosorbent assays. DON was detected in all samples
      as a major trichothecene (16-51,450 microg kg(-1)), and NIV was in one corn, one
      barley and all wheat at relatively low levels (10-6935 microg kg(-1)). ZEA was
      found in all corn and barley, and six wheat samples (46-3079 microg kg(-1)). In
      addition, 3-acetyl-DON (2544 microg kg(-1)) and 15-acetyl-DON (2537 microg kg(
      1)) were detected separately in one corn and one wheat sample. The highest levels
      of these mycotoxins were found in one wheat sample associated with the human
      intoxication in Anhui province. FMs in corn were below 1000 microg kg(-1). Risks
      of DON and ZEA on the people who consumed the causative cereals were assessed.

PMID- 10647511
TI  - Two analogs of azaspiracid isolated from mussels, Mytilus edulis, involved in
      human intoxication in Ireland.
AB  - Two new analogs of azaspiracid, azaspiracid-2 and azaspiracid-3, were isolated
      from mussels collected at Arranmore Island, Ireland in 1997 as additional causes
      of human intoxication. Their structures were determined to be 8-methylazaspiracid
      and 22-demethylazaspiracid, respectively by NMR and negative ion FAB CID MS/MS
      experiments.

PMID- 10647512
TI  - Survey of microcystins in water between 1995 and 1996 in Parana, Brazil using
      ELISA.
AB  - An enzyme-linked immunosorbent assay (ELISA) based on a monoclonal antibody was
      used to determine microcystin (MC) concentrations in water supplies and water
      plant samples collected between November 1995 and October 1996, from five regions
      of Parana, Brazil. In addition, the presence of Microcystis sp. was monitored. Of
      the 50 samples obtained, 12 were from an urban lake, 8 from human water supplies,
      10 from recreational lakes, 13 from farm waters used for animal pasture and 7
      from aquaculture facilities. M. aeruginosa was positive in all locations. MCs
      were positive (>50 pg ml(-1)) in 9 samples (2 samples from human water supplies,
      5 from recreational lakes and 2 from animal pasture). Heavy contamination with
      MCs was observed in water samples collected in May 1996 from 2 recreation
      (swimming-fishing sites at Itaipu dam, 6380 and 10,000 pg ml(-1)) and human
      supplies (6627 pg ml(-1)) samples. At these sites, a large bloom of Microcystis
      sp. was detected. Treatment with 1 ppm Cl- reduced MCs levels, although 267 pg
      ml(-1) remained in the water plant samples. Our data showed frequent occurrence
      of Microcystis sp., which may be a hazard to humans and animals in the state of
      Parana. More detailed investigations are required to evaluate the risk of natural
      MC contamination in the water supplied in this region.

PMID- 10647513
TI  - Isolation and characterization of 3-methoxy-2(5H)-furanone as the principal
      nephrotoxin from Narthecium ossifragum (L.) Huds.
AB  - The principal substance in Narthecium ossifragum (L.) Huds, responsible for the
      nephrotoxic effects on cattle, moose, goats and other ruminants has been isolated
      and identified by X-ray crystallography as 3-methoxy-2(5H)-furanone. The Fourier
      transform infra-red, 1H and 13C nuclear magnetic resonance, and mass spectra are
      also given. The concentration in four different batches of plant material varied
      from 113 to 344 microg g(-1) (wet weight). Extracts of N. ossifragum and
      fractions derived from them, including purified 3-methoxy-2(5H)-furanone, were
      each dosed intraruminally, to young goats. 3-Methoxy-2(5H)-furanone of 99.9%
      purity (15 mg kg(-1) live weight) caused increased concentration of creatinine in
      serum within 2-3 days, typical of kidney damage caused by N. ossifragum, while
      toxic effect was obtained down to 4 mg kg(-1) live weight with less purified
      material (> or = 95%). Toxic effect was also obtained with synthesized 3-methoxy
      2(5H)-furanone (30 mg kg(-1) live weight). The isomer 4-methoxy-2(5H)-furanone,
      detected in some of the batches of the plant material, was not toxic when dosed
      at 60 mg kg(-1) live weight.

PMID- 10647514
TI  - Isolation and characterization of phytotoxic compounds produced by Phomopsis
      helianthi.
AB  - The isolation, chemical characterization and biological activity of two
      phytotoxic metabolites of Phomopsis helianthi Munt-Cvet et al. is reported. These
      compounds were identified by spectroscopic methods (UV, IR, 1H and 13C NMR, and
      MS) as trans-4,6-dihydroxymellein (trans-3-methyl-4,6,8-trihydroxy-3,4
      dihyroisocoumarin) and cis-4,6-dihydroxymellein (cis-3-methyl-4,6,8-trihydroxy
      3,4-dihydroisocoumarin). This is the first report of the isolation of trans-4,6
      dihydroxymellein from fungal cultures and of the production of cis- and trans-4,6
      dihydroxymelleins by P. helianthi. Rice was found to be a good substrate for the
      production of the dihydroxymelleins. Culture extracts of some Italian and French
      strains of P. helianthi showed different degrees of phytotoxicity towards
      sunflower leaves and seedlings. The minimum effective doses of trans- and cis-4,6
      dihydroxymelleins with different bioassays were 76 and 135 microg per spot (leaf
      puncture bioassay), 3 and 5 micromol g(-1) fresh tissue (absorption by leaf
      cutting) and 5 and 2 micromol g(-1) fresh tissue (absorption by cut seedlings),
      respectively. These compounds may contribute to the severity of the sunflower
      disease caused by P. helianthi.

PMID- 10647515
TI  - Intra-articular corticosteroids: an updated overview.
AB  - Intra-articular corticosteroids are widely used in the management of arthritic
      conditions. In the present article, literature concerning intraarticular
      corticosteroid preparations, administration, effects in different clinical uses,
      and adverse reactions is reviewed to identify areas of potential future study.
      There is little consensus in the literature on the appropriate technique of
      administration, and no clinical studies have been performed comparing various
      preparations for safety and effectiveness. The small number of reported
      complications, however, suggests that low intermittent doses pose little risk of
      significant adverse effects.

PMID- 10647516
TI  - Spinal anesthesia versus general anesthesia for hip fracture repair: a
      longitudinal observation of 741 elderly patients during 2-year follow-up.
AB  - The Baltimore Hip Studies, a multicenter, noninterventional, observational trial,
      provided an opportunity to investigate the effects of anesthetic technique on the
      long-term outcome of elderly patients after hip fracture repair. Detailed
      interviews assessing functional status and pain were conducted during the
      hospital stay. Out-of-hospital evaluations were repeated after the procedure at
      2, 6, 12, 18, and 24 months with a portable gait and balance laboratory.
      Multivariate analysis was done to determine the effects of anesthetic technique
      on functional and other outcomes, after controlling for multiple baseline
      variables. Of 741 enrolled patients who completed the study, 430 and 311 patients
      received spinal anesthesia or general anesthesia, respectively. Subgroup analysis
      of three spinal anesthetics, tetracaine, lidocaine, and epinephrine, was also
      done. In the present large observational study, general anesthesia was at least
      as efficacious as spinal anesthesia, and possibly better, in affording good long
      term outcome.

PMID- 10647517
TI  - Anatomic considerations of a modified anterior approach to the cervicothoracic
      junction.
AB  - The results of a study on 30 adult human cadavers showed that the anterior aspect
      of T-3 can be easily exposed through a modified anterior approach to the
      cervicothoracic spinal junction. Anterior exposure of T-4 caused significant
      tension on the brachiocephalic vein in 57%; in 7% the vein actually tore. The
      location of the vital structures is as follows: the left brachiocephalic vein is
      at T-1 and T-2 in 80%; the aortic arch is at T-2 and T-3 in 90%; the right
      recurrent laryngeal nerve reaches the tracheoesophageal groove at the level of C
      6 in 50%; the thoracic duct empties into the systemic venous system from C-7 to T
      2. Adequate exposure of the low cervical to the upper thoracic spine can be
      obtained with this approach. Preoperative computed tomographic evaluation of the
      location of the left brachiocephalic vein with respect to the vertebral levels is
      recommended.

PMID- 10647518
TI  - Traumatic rupture of the tibialis posterior tendon after ankle fracture: a case
      report.
AB  - Degenerative tears of the posterior tibial tendon associated with chronic disease
      are well documented in the literature. Traumatic ruptures of this tendon,
      however, are much less common and consequently have received little attention. An
      association has been shown between pronation-external rotation ankle fractures
      and tears of the tendons that cross the medial aspect of the ankle, most commonly
      the posterior tibial tendon. In the present case report, we share our unique
      experience of an open-ankle fracture associated with the traumatic rupture of the
      posterior tibial tendon. This injury illustrates that soft-tissue injury must
      always be suspected concomitantly in the treatment of certain fractures on the
      basis of both mechanism of injury and fracture pattern.

PMID- 10647519
TI  - Humeral shaft nonunions treated with fibular allograft and compression plating.
AB  - The present study is a retrospective review of the treatment of 12 humeral shaft
      nonunions by using an intramedullary allograft with compression plating. The
      average age of the patients was 61 years (range, 36-82 years). Eight cases
      involved the proximal shaft, 3 cases were at the mid-diaphyseal level, and 1 case
      was at the distal one third. Follow-up averaged 30 months (range, 12-96 months).
      Ten patients (83%) went on to uneventful healing at an average of 3 months after
      surgery. Two failures involving patients with multiple medical conditions
      occurred secondary to reinjury. Two cases of postoperative radial nerve
      neuropraxia involved the posterior approach to the humerus. Each resolved with no
      long-term residual morbidity. One patient developed postoperative adhesive
      capsulitis of the shoulder that resolved with nonoperative treatment. We feel
      that a fibular allograft, along with compression plating, can give satisfactory
      results for humeral shaft nonunions. This technique can be especially helpful in
      proximal humeral nonunions and in nonunions involving osteoporotic bone. Patients
      with multiple medical problems at risk for refalls should be protected until
      complete healing has occurred.

PMID- 10647520
TI  - Ligament reconstruction tendon interposition arthroplasty for basal joint
      arthritis: simplifying flexor carpi radialis tendon passage through the thumb
      metacarpal.
AB  - During the ligament reconstruction tendon interposition arthroplasty for basal
      joint arthritis, the flexor carpi radialis tendon is passed through the base of
      the thumb and out an exit hole on its dorsum. When the entire width of the tendon
      is harvested, this aspect of the procedure can be difficult. Tapering the width
      of the proximal tendon and using a Carroll tendon retriever simplify the
      procedure and eliminate the need for enlarging the transosseous hole in the thumb
      metacarpal.

PMID- 10647521
TI  - Primary bone tumor.

PMID- 10647522
TI  - Hemodynamic during a postexertional asystolia in a healthy athlete: a case study.
AB  - Hemodynamic events leading to spontaneous postexertional vasovagal syncope are
      not completely understood because of the lack of beat-to-beat data. We report a
      case study of a young athlete who undergoes a syncopal episode during the
      recovery period following a maximal cycle-ergometer test. The episode was
      monitored by an impedance cardiograph which can gather noninvasively beat-to-beat
      the flow of heart rate (HR), stroke volume (SV), cardiac output (CO), diastolic
      filling rate (SV/DT), and myocardial contractility index (PEP/LVET). The most
      important findings of this report are the dramatic reduction of SV/DT preceding
      the syncope, the increment of SV together with the reduction of HR preceding and
      following the syncope, the prompt recovery of CO values after the syncopal
      episode despite the bradycardia, and the reduction of PEP/LVET after the syncope.
      This report confirms the importance of active recovery immediately after
      strenuous exercise and supports the hypothesis that the reduction of SV/DT in the
      presence of an inotropic stimulation can trigger the vasovagal reaction.

PMID- 10647523
TI  - The effect of recurrent ankle inversion sprain and taping on proprioception at
      the ankle.
AB  - PURPOSE: A common explanation for the tendency for ankle inversion sprains to
      recur is that proprioception is impaired by the initial sprain. It is further
      hypothesized that the application of tape prevents further sprains by enhancing
      proprioceptive acuity. The purpose of this study was to determine whether
      proprioception was impaired in people with recurrent ankle inversion sprain, and
      whether taping the ankle provided enhanced proprioceptive ability. METHODS: We
      compared the ability to perceive passive plantarflexion and dorsiflexion
      movements imposed at the relaxed ankle in 25 subjects with recurrent ankle
      inversion sprain, with a group of 18 healthy control subjects, matched for age,
      height, weight, and activity level. Subjects were tested with the ankle both
      taped and untaped. Detection thresholds were determined at three velocities, 0.1
      degrees x s(-1), 0.5 degrees x s(-1), and 2.5 degrees x s(-1). Velocity of the
      imposed movements and testing of the taped and untaped conditions were
      randomized. RESULTS: There was no significant difference in the ability to
      perceive ankle movements between subjects with sprains and healthy controls at
      any velocity of movement tested. In addition, there was no significant difference
      in movement perception between the taped and untaped conditions for either
      subject group at any velocity. CONCLUSION: The ability to detect passive
      plantarflexion and dorsiflexion movements is not impaired in subjects with
      recurrent ankle inversion sprain. Furthermore, the protective effect of taping
      was shown not to arise from enhanced proprioception in the dorsiflexion
      plantarflexion plane.

PMID- 10647524
TI  - The strength of percutaneous methods of repair of the Achilles tendon: a
      biomechanical study.
AB  - PURPOSE: A study on 36 cadaveric Achilles tendons was undertaken to compare
      different Achilles tendon repairs. METHODS: The strength of the repair and the
      gapping resistance were tested under different standardized experimental
      conditions. Each matched pair of cadaveric Achilles tendons was randomly repaired
      in the original Ma-Griffith configuration and in the new modified configuration
      and loaded to failure. Using a special equipment, the force displacement curve
      was measured. RESULTS: Under different experimental conditions, the new modified
      technique presented in the paper provided significantly greater tensile strength
      and gapping resistance than the original Ma-Griffith repair configuration.
      CONCLUSION: The results of this study may be clinically relevant in terms of
      choice of the percutaneous method used for the repair of the ruptured Achilles
      tendon.

PMID- 10647525
TI  - Shoulder impingement in front-crawl swimming: I. A method to identify
      impingement.
AB  - PURPOSE: The impingement of subacromial structures has been proposed as a major
      cause of the shoulder problems experienced by athletes who use repetitive
      overhead actions. The purpose of this study was to develop a noninvasive method
      to identify instances at which the shoulder was experiencing impingement during
      front-crawl swimming. METHODS: Shoulder impingement has been reported to occur
      when an arm is: (a) elevated above shoulder height while being rotated
      internally; and (b) forcibly elevated at, or beyond, the maximum active elevation
      angle. In this study shoulder configurations that satisfied the above two
      conditions were sought throughout the functional range of each shoulder; and a
      boundary that distinguished configurations that would cause shoulder impingement
      was defined. The shoulder movements exhibited during performance of the front
      crawl stroke were measured using three-dimensional videography and compared with
      the boundary defined for each shoulder. The shoulder was considered to experience
      impingement if the shoulder configuration observed exceeded the boundary defined
      for that shoulder. RESULTS: For a male collegiate swimmer, impingement occurred
      for 12% of the stroke time for each shoulder. CONCLUSIONS: The analysis permitted
      the identification of the instances at which the shoulders were experiencing
      impingement during the front-crawl swimming. In this study, the measurement of
      the boundary was based entirely upon the mechanism of impingement described in
      the literature. Further studies are needed to confirm the occurrence of
      impingement by means of advanced visualization techniques, such as magnetic
      resonance imaging (MRI) and ultrasonogram.

PMID- 10647526
TI  - Shoulder impingement in front-crawl swimming: II. Analysis of stroking technique.
AB  - PURPOSE: The purpose of this study was to determine the technical causes of
      shoulder impingement experienced by front-crawl swimmers. METHODS: The shoulder
      movements exhibited during performance of the front-crawl stroke were measured
      using three-dimensional videography, and the instances at which each shoulder was
      experiencing impingement were identified. RESULTS: On average, impingement
      occurred 24.8% of the stroke time (%ST). In one or more phases of the stroke
      cycle, each subject experienced impingement in some trials and not in other
      trials. This suggests that stroke technique, and not just anatomical differences,
      accounted for individual susceptibility to shoulder impingement. No significant
      difference was found between the mean values for %ST for slow and fast stroking
      speeds and for trials with and without hand paddles. Use of a unilateral
      breathing technique was often associated with a small magnitude of tilt angle (an
      effect of the scapular elevation/abduction on one side and depression/adduction
      on the other side) on the breathing side; in such cases a high incidence of
      shoulder impingement was observed for the shoulder on the ipsilateral side.
      Swimmers at high risk of experiencing shoulder impingement had three
      characteristics in their stroking techniques: (a) a large amount of internal
      rotation of the arm during the pull phase, (b) a late initiation of external
      rotation of the arm during the recovery phase, and (c) a small amount of tilt
      angle. CONCLUSIONS: A swimmer should be able to reduce the risk of developing
      shoulder impingement by altering the technique to eliminate the three
      characteristics.

PMID- 10647527
TI  - Effects of exercise training on gallbladder function in an obese female
      population.
AB  - PURPOSE: Aerobic exercise may influence gallstone disease pathogenesis through
      its effect on gallbladder motility. The purpose of this investigation was to
      examine the effects of exercise training on gallbladder emptying in obese women.
      METHODS: Twenty-seven obese subjects were randomized into one of two groups:
      exercise (E) (five 45-min brisk walking sessions per week at 75.2 +/- 0.5% of
      maximum heart rate) and controls (C). Gallbladder function via cholescintigraphy,
      cardiorespiratory fitness, and body composition were measured in all subjects
      before and after a 12-wk intervention period. In each cholescintigraphy trial
      subjects ingested an 8-oz liquid meal 45 min after injection of 99mTc disofenin
      to promote gallbladder emptying. Gallbladder areas were then scanned for 60 s and
      then every 5 min for 60 min. RESULTS: VO2max increased significantly by 9% for E
      when compared with that for C (P < 0.001). Within E postprandial gallbladder
      ejection fraction (EF) increased significantly after training (39.5 +/- 4.9% to
      54.7 +/- 6.5%, P < 0.05); however, this 15.2% increase in EF was not
      significantly greater than the change reported in the controls. CONCLUSIONS:
      Results indicate that 12 wk of moderate exercise training does improve
      cardiorespiratory fitness but does not significantly effect gallbladder emptying
      in obese women.

PMID- 10647528
TI  - The symptomatology of upper respiratory tract infections and exercise in elderly
      people.
AB  - PURPOSE: To analyze, both by a retrospective and prospective study design, the
      relationship of maximal oxygen consumption (VO2max) and physical activity (PA) to
      upper respiratory tract infections (URTI) symptomatology in elderly subjects.
      METHODS: 61 (33 men and 28 women) healthy and weight-stable active elderly
      volunteers aged 66-84 yr participated in the study. PA was evaluated by a
      questionnaire QAPSE (Questionnaire d'Activite Physique Saint-Etienne) and
      expressed by two QAPSE activity indices: MHDEE (mean habitual daily energy
      expenditure) and sports activity (daily energy expenditure corresponding to
      leisure time sports activities). Log books for daily recording of URTI
      symptomatology were used in prospective design. RESULTS: In a 1-yr retrospective
      study a significant correlation was found between number of weeks with URTI per
      year and Sports activity index (r = -0.27, P = 0.037). In a prospective 12-month
      follow-up, the number of episodes per year and number of days with URTI per year
      were significantly negatively associated with sports activity index (r = -0.29, P
      = 0.022 and r = -0.26, P = 0.041, respectively). CONCLUSIONS: In healthy active
      elderly subjects the symptomatology of URTI over long periods of time is inversly
      related to energy expenditure utilized during moderately intensive physical
      exercise.

PMID- 10647529
TI  - Anaerobic power and muscle strength in young hemophilia patients.
AB  - PURPOSE: The purpose of this study was to evaluate muscle strength and anaerobic
      power in young boys with hemophilia compared with healthy boys. METHODS: Thirteen
      boys with severe hemophilia (H) (mean (+/- SD) age = 12.0 +/- 3.17 yr) and 16
      control (C) boys (age = 11.9 +/- 2.8 yr) performed elbow and knee flexion and
      extension on the Biodex System II dynamometer at two angular velocities. They
      also performed a Wingate Anaerobic Test (WAnT) for the legs and for the arms. All
      H subjects received prophylactic factor VIII treatment in the 24 h pretesting,
      and no test was performed in the presence of hemorrhage. RESULTS: C were
      consistently stronger than H in all dynamic strength measures (e.g., elbow
      flexors: 0.47 +/- 0.15 vs 0.36 +/- 0.08 N x m x kg(-1) for C and H, respectively,
      P < 0.05). Anaerobic mean power was also higher in C compared with H in both
      upper and lower extremities (arms: 3.08 +/- 0.99 vs 2.22 +/- 0.46 W x kg(-1) for
      C and H, respectively; legs: 6.94 +/- 1.62 vs 5.54 +/- 1.03 W x kg(-1) for C and
      H, respectively, P < 0.05). Upper and lower extremity strength, as well as
      anaerobic power, increased with age in C but not in H. By using the Godin Leisure
      Time Exercise Questionnaire, H were found to be much less active, especially in
      intense activities, compared with C. CONCLUSION: Children and adolescents with
      hemophilia are characterized by lower muscle strength and anaerobic power
      compared with age-matched controls. This may be related to their lower leisure
      time activity.

PMID- 10647530
TI  - Physical and psychological changes with vigorous exercise in sedentary
      primigravidae.
AB  - PURPOSE: The present study examined the effects of exercise on physical and
      psychological variables in sedentary primigravidae (PRA). METHODS: A total of
      nine women randomly assigned to an exercise (E) (mean age = 31.3 +/- 3.1 yr) and
      six subjects randomly assigned to a control (C) group (mean age = 27.8 +/- 3.1
      yr) fulfilled all requirements for the study. Exercise included a variety of
      exercise activities performed to a target heart rate of 150-156 beats x min(-1),
      three times per week for 15 wk. RESULTS: Results showed no significant
      differences between E and C groups in physical characteristics initially. A
      repeated measures ANOVA showed a significant group effect (P < 0.05) and a
      significant group by time interaction (P = 0.001) with the E group showing a
      significantly longer amount of time on the PWC150 test than the C group. There
      was no significant group, time, or group by time interaction for lactate
      accumulation. This occurred, despite the fact that the E group spent 56% longer
      on the PWC150 test and the C group spent 30% less time on the same test at the
      conclusion of the study. Finally, the E group in comparison to the C group showed
      more favorable improvements in several items related to health and well-being on
      the Body Cathexis Scale. There were no significant differences between E and C
      groups in any pregnancy outcome measures. All babies were delivered healthy at
      term. CONCLUSIONS: These data suggest that a vigorous exercise program can lead
      to significant improvements in aerobic fitness at similar lactate concentrations
      compared to a control group and can be well tolerated by low risk sedentary PRA
      without any deleterious effects occurring to herself or unborn child.

PMID- 10647531
TI  - Premenarcheal gymnasts possess higher bone mineral density than controls.
AB  - PURPOSE: The purpose of this study was to examine bone mineral density (BMD),
      body composition, dietary intake, physical activity, and energy expenditure (EE)
      in premenarcheal gymnasts (N = 16; age = 10.5 +/- 1.5 yr) in comparison to age-
      (+/- 0.35 yr), height- (+/- 2.6 cm), and weight- (+/- 1.5 kg) matched controls (N
      = 16; age = 10.5 +/- 1.3 yr). It was hypothesized that premenarcheal gymnasts
      would have higher BMD, fat-free soft tissue (FFST) mass, physical activity, and
      EE, but lower fat mass, percent body fat, and dietary intake than controls.
      METHODS: Dual energy x-ray absorptiometry was used to measure whole body, femur,
      and lumbar spine (L1-4) BMD, FFST, and fat mass. Three-day diet records were used
      to estimate mean daily dietary energy, macronutrient, and calcium intakes.
      Physical activity and EE were estimated by the Seven-Day Physical Activity
      Recall. RESULTS: The BMD means of the gymnasts were significantly higher (P <
      0.05) than controls at all sites, except whole body, as were lumbar spine and
      femoral neck bone mineral apparent densities, despite lower protein intake
      expressed per kg FFST mass. Fat mass was significantly lower in gymnasts versus
      controls (P < 0.01) as was percent body fat (P < 0.001). Very hard physical
      activity during weekdays (P < 0.0001) and estimated EE (P < 0.01) were
      significantly higher in gymnasts compared with controls. CONCLUSION:
      Premenarcheal gymnasts have higher BMD than age-, height-, and weight-matched
      controls.

PMID- 10647532
TI  - Limiting factors for maximum oxygen uptake and determinants of endurance
      performance.
AB  - In the exercising human, maximal oxygen uptake (VO2max) is limited by the ability
      of the cardiorespiratory system to deliver oxygen to the exercising muscles. This
      is shown by three major lines of evidence: 1) when oxygen delivery is altered (by
      blood doping, hypoxia, or beta-blockade), VO2max changes accordingly; 2) the
      increase in VO2max with training results primarily from an increase in maximal
      cardiac output (not an increase in the a-v O2 difference); and 3) when a small
      muscle mass is overperfused during exercise, it has an extremely high capacity
      for consuming oxygen. Thus, O2 delivery, not skeletal muscle O2 extraction, is
      viewed as the primary limiting factor for VO2max in exercising humans. Metabolic
      adaptations in skeletal muscle are, however, critical for improving submaximal
      endurance performance. Endurance training causes an increase in mitochondrial
      enzyme activities, which improves performance by enhancing fat oxidation and
      decreasing lactic acid accumulation at a given VO2. VO2max is an important
      variable that sets the upper limit for endurance performance (an athlete cannot
      operate above 100% VO2max, for extended periods). Running economy and fractional
      utilization of VO2max also affect endurance performance. The speed at lactate
      threshold (LT) integrates all three of these variables and is the best
      physiological predictor of distance running performance.

PMID- 10647533
TI  - Maximal oxygen uptake "classical" versus "contemporary" viewpoints.
AB  - In two articles Timothy Noakes proposes a new physiological model in which
      skeletal muscle recruitment is regulated by a central "govenor," specifically to
      prevent the development of a progressive myocardial ischemia that would precede
      the development of skeletal muscle anaerobiosis during maximal exercise. In this
      rebuttal to the Noakes' papers, we argue that Noakes has ignored data supporting
      the existing hypothesis that under normal conditions cardiac output is limiting
      maximal aerobic power during dynamic exercise engaging large muscle groups.

PMID- 10647534
TI  - Skeletal muscle: master or slave of the cardiovascular system?
AB  - Skeletal muscle and cardiovascular system responses to exercise are so closely
      entwined that it is often difficult to determine the effector from the affector.
      The purpose of this manuscript and its companion papers is to highlight (and
      perhaps assist in unraveling) the interdependency between skeletal muscle and the
      cardiovascular system in both chronic and acute exercise. Specifically, we
      elucidate four main areas: 1) how a finite cardiac output is allocated to a large
      and demanding mass of skeletal muscle, 2) whether maximal muscle oxygen uptake is
      determined peripherally or centrally, 3) whether blood flow or muscle metabolism
      set the kinetic response to the start of exercise, and 4) the matching of
      structural adaptations in muscle and the microcirculation in response to
      exercise. This manuscript, the product of an American College of Sports Medicine
      Symposium, unites the thoughts and findings of four researchers, each with
      different interests and perspectives, but with the common intent to better
      understand the interaction between oxygen supply and metabolic demand during
      exercise.

PMID- 10647535
TI  - Effect of skeletal muscle demand on cardiovascular function.
AB  - Cardiac output is directed primarily to skeletal muscle during exercise. Recent
      investigations have examined how different groups of skeletal muscle compete for
      the cardiac output during exercise. To date, there is a lack of consistent
      findings on a blood flow steal effect of arm versus leg exercise, although the
      majority of data suggest that leg blood flow is not compromised when arm exercise
      is added to leg exercise. A recent set of experiments have demonstrated that
      respiratory muscles compete favorably for blood flow with the legs during maximal
      exercise. Decreased work of breathing leads to: 1) a decrease in cardiac output,
      due primarily to reduced stroke volume; and 2) increased leg blood flow and leg
      vascular conductance. An increased work of breathing leads to the converse.
      Exercise performance may also be affected by the work of breathing during heavy
      exercise due to redistribution of blood flow between the chest wall and the
      locomotor muscles. It appears that in contrast to arm exercise, respiratory
      muscles demand a significant portion of the cardiac output during maximal
      exercise, and the work of breathing normally experienced during heavy exercise
      compromises leg blood flow.

PMID- 10647536
TI  - What governs skeletal muscle VO2max? New evidence.
AB  - Recent investigations into the determinants of skeletal muscle maximal oxygen
      consumption (VO2) have provided further evidence regarding the role of O2 supply
      and demand in governing exercise metabolism. Specifically, four studies utilizing
      both animal and human exercise models are highlighted here: 1) the role of the
      diffusive O2 component was examined in the exercising canine gastrocnemius muscle
      by a rightward shift in the O2 dissociation curve while maintaining O2 delivery
      constant; 2) the role of peripheral and central components was examined by
      studying the human quadriceps muscle, already recognized to have a very high mass
      specific O2 delivery, under conditions of increased (hyperoxia) and reduced O2
      availability (hypoxia); 3) the role of intracellular PO2 in the progressive
      increase in lactate efflux from skeletal muscle from submaximal to maximal
      effort; and finally 4) the role of intracellular PO2 itself as a determinant of
      maximal mitochondrial O2 consumption. In summary, these investigations illustrate
      1) the importance of the diffusion gradient from blood to muscle cell; 2)
      illustrate that even in functionally isolated trained skeletal muscle the highest
      recorded metabolic rates can be increased by increasing O2 supply; 3) that a
      constant intracellular PO2 during graded exercise is therefore unrelated to
      increasing lactate efflux; and 4) that only in hyperoxia does trained human
      skeletal muscle approaching very high mitochondrial metabolic limits, as shown by
      a disproportionate increase in intracellular PO2 for the recorded change in
      VO2max.

PMID- 10647537
TI  - Skeletal muscle VO2 on-kinetics: set by O2 delivery or by O2 utilization? New
      insights into an old issue.
AB  - Recent work conducted by our group has expanded knowledge on some basic issues
      related to pulmonary and skeletal muscle O2 uptake (VO2) on-kinetics. We
      demonstrated that, in exercising humans during transitions from unloaded pedaling
      to loaded pedaling below the ventilatory threshold, alveolar VO2 on-kinetics can
      be taken as a rather close approximation of skeletal muscle VO2 on-kinetics.
      Experiments conducted on the isolated in situ dog gastrocnemius preparation have
      shown that, during transitions from rest to contractions corresponding to
      approximately 70% of the muscle peak VO2, convective O2 delivery to muscle,
      intramuscular blood flow (Q) versus VO2 maldistribution, and peripheral O2
      diffusion are not limiting factors for skeletal muscle VO2 on-kinetics. The
      latter, therefore, appears to be mainly determined by an intrinsic inertia of
      skeletal muscle oxidative metabolism, possibly related to acetyl group
      availability within mitochondria, to regulatory effects on intracellular
      respiration related to phosphocreatine splitting, and/or to other still not
      precisely identified control mechanism(s). Evidence from the literature suggests
      that the limiting factors for skeletal muscle VO2 on-kinetics may vary according
      to the intensity of muscular contractions or of exercise.

PMID- 10647538
TI  - Skeletal muscle: microcirculatory adaptation to metabolic demand.
AB  - The issue of whether skeletal muscle is master or slave of the cardiovascular
      system depends on frame of reference. Acute manipulations of convective O2
      delivery clearly show that O2 supply sets the upper limit of muscle VO2max.
      However, studies of adaptation to chronic conditions such as training and hypoxia
      show that skeletal muscle has a remarkable capacity to meet changes in metabolic
      demand. Moreover, there are several lines of evidence that these adaptations are
      essential to changes in VO2max. Studies show that with training, electrical
      stimulation, and chronic hypoxia, the ratio of capillary surface per fiber
      surface and fiber mitochondrial volume/fiber length is preserved, suggesting a
      primary regulated feature in skeletal muscle is matching the structural capacity
      for O2 flux to mitochondrial metabolic demand. Adaptations in both capillarity
      and mitochondrial respiratory capacity have also been shown to be important
      components in the adaptive increase in VO2max with training. Collectively, this
      evidence argues against skeletal muscle being simply a slave to the
      cardiovascular system.

PMID- 10647539
TI  - Intravenous versus oral rehydration during a brief period: responses to
      subsequent exercise in the heat.
AB  - PURPOSE: The purpose of this study was to assess whether a brief period (20 min)
      of intravenous (i.v.) fluid rehydration versus oral rehydration differentially
      affects cardiovascular, thermoregulatory, and performance factors during
      exhaustive exercise in the heat. METHODS: Following dehydration (-4% of body
      weight), eight nonacclimated highly trained cyclists (age = 23.5 +/- 1.2 yr;
      VO2peak = 61.4 +/- 0.8 mL x kg x min(-1); body fat = 13.5 +/- 0.6%) rehydrated
      and then cycled at 70% VO2peak to exhaustion in 37 degrees C. Rehydration
      (randomized, cross-over design) included: 1) CONTROL (no fluid), 2) DRINK (oral
      rehydration, 0.45% NaCl) equal to 50% of prior dehydration, and 3) IV
      (intravenous rehydration, 0.45% NaCl), equal to 50% of prior dehydration. Thus,
      in the DRINK and IV treatments subjects began exercise (EX) at -2% of body
      weight. RESULTS: Exercise time to exhaustion was not different (P = 0.07) between
      DRINK (34.9 +/- 4 min) and IV (29.5 +/- 3.5 min), but both were significantly (P
      < 0.05) longer than CONTROL (18.9 +/- 2.7 min). Plasma volume was better (P <
      0.05) restored during IV than CONTROL and DRINK at pre-exercise and 5 min EX, but
      different (P < 0.05) from only CONTROL at 15 min EX. Plasma lactate during DRINK
      was lower (P < 0.05) than IV at 15 min EX and postexercise. Heart rate during
      CONTROL was greater (P < 0.05) than DRINK and IV from 0-8 min EX, and greater (P
      < 0.05) than DRINK from 10-14 min EX. Rectal temperature during DRINK was less (P
      < 0.05) than IV from 0-24 min EX. Mean weighted skin temperature during DRINK was
      less (P < 0.05) than IV from 4-12 min EX. CONCLUSIONS: Thus, despite no
      statistically significant performance differences between DRINK and IV, it
      appears that certain physiological parameters were better maintained in the DRINK
      trial, and the trend toward performance differences may be important to elite
      athletes.

PMID- 10647540
TI  - Gastrointestinal mucosal integrity after prolonged exercise with fluid
      supplementation.
AB  - PURPOSE: Studies on the effect of exercise on gastrointestinal (GI) mucosal
      integrity have been limited to occult-blood tests, which were often nonspecific
      for human blood. The aim of our study was to investigate more aspects of this
      integrity. METHODS: We examined the effect of prolonged exercise and carbohydrate
      (CHO) supplementation on mucosal integrity in 22 male triathletes by measuring
      fecal lysozyme, alpha1-antitrypsin, and occult-blood loss, which was examined by
      two tests specific for human blood (Colon-Albumin and Monohaem test). Exercise
      consisted of two 150-min tests (alternately running, cycling, and running at 70
      75% VO2max), either with a 7.0% CHO drink or water (W). Furthermore, GI symptoms
      during exercise were registered by questionnaire. RESULTS: Three subjects showed
      human albumin only in the first stool after exercise: twice with W and once with
      CHO. However, human hemoglobin (Hb) could not be detected in these samples. Four
      other subjects showed an elevated lysozyme concentration after exercise with CHO
      but not with W. Elevated alpha1-antitrypsin values were found in three of seven
      specimens in which either positive albumin tests and/or an elevated lysozyme
      concentration were demonstrated. Twenty-one subjects (95%) reported one or more
      GI symptoms during exercise. Incidence rates of different GI symptoms varied from
      5 to 68%. Most symptoms were more frequent and lasted longer during running than
      during cycling but did not differ significantly between supplements and were not
      related to any mucosal integrity parameter. CONCLUSIONS: GI blood loss during
      exercise is of no clinical importance, at least in our study design with a group
      of well-trained male subjects who consumed a relatively high amount of fluid (up
      to 2.3 L). Nevertheless, an increased alpha1-antitrypsin and lysozyme
      concentration may indicate a transient local mucosal damage with an inflammatory
      response.

PMID- 10647541
TI  - Swimming training prevents generation of suppressor macrophages during acute cold
      stress.
AB  - PURPOSE: Acute cold stress induces suppressor macrophages expressing large
      numbers of receptors to Fc portion of immunoglobulin G (MAC-1+ Fc
      gammaRII/IIIbright cells), resulting in suppression of splenocyte mitogenesis.
      The generation of MAC-1+ Fc gammaRII/IIIbright cells is partly mediated by
      increased glucocorticoid levels during acute cold stress. The aim of the current
      study was to investigate the effect of swimming training on the generation of the
      MAC-1+ Fc gammaRII/IIIbright suppressor macrophages by acute cold stress.
      METHODS: The trained mice underwent a 6-wk endurance swimming training (5
      times/wk) in water at 35-36 degrees C for 90 min. The swimming training
      significantly increased brown adipose tissue mass, suggesting improved cold
      tolerance. Actually, when the swimming-trained mice were exposed to 5 degrees C
      for 3 h (acute cold stress), the rectal temperature was not decreased. The
      proportion of MAC-1+ Fc gammaRII/IIIbright cells in peritoneal exudate cells from
      swimming-trained mice was significantly lower than that from control mice. In
      addition, the proportion of MAC-1+ Fc gammaRII/IIIbright cells in peritoneal
      exudate cell population from swimming-trained mice was unaffected by the acute
      cold stress. The swimming training significantly attenuated the increases in
      serum corticosterone levels in response to acute cold stress. These results
      suggested that swimming training not only improves cold tolerance but also
      inhibits the generation of suppressor macrophages under acute cold stress as well
      as under normal conditions.

PMID- 10647542
TI  - Self-report measures and scoring protocols affect prevalence estimates of meeting
      physical activity guidelines.
AB  - PURPOSE: Prevalence estimates of meeting the guidelines for physical activity
      based on various self-report measures were compared, and the effects of various
      scoring protocols on the estimates were evaluated. METHOD: A sample of 575
      university students aged 24.5 +/- 1.9 yr (56% women, 54% Euro-American) completed
      the Seven-Day Physical Activity Recall interview (PAR), Youth Risk Behavior
      Survey (YRBS), and National Health Interview Survey 1991 (NHIS). To determine the
      prevalence of meeting the ACSM (1990) fitness and the CDC/ACSM (1995) health
      related guidelines, various scoring protocols were employed that closely
      approximated the recommendations. Protocols varied by whether frequency and
      duration or duration only were considered. For the health-related guidelines,
      scoring protocols also varied depending on the intensity of activities
      considered. RESULTS: Depending on the scoring protocol and instrument used, the
      proportion meeting the fitness guidelines ranged from 32 to 59%. The NHIS, YRBS,
      and PAR resulted in significantly different proportions of those meeting the
      health-related guideline, ranging from 4 to 70%. CONCLUSION: The type of measure
      as well as the scoring protocol affected prevalence estimates of meeting the
      physical activity guidelines. This study indicates the difficulty of comparing
      prevalence rates across studies using different measures.

PMID- 10647543
TI  - Adaptation to a standardized training program and changes in fitness in a large,
      heterogeneous population: the HERITAGE Family Study.
AB  - PURPOSE: This paper describes the variations in response to a standardized,
      computer-controlled training program. METHODS: Steady-state heart rate (HR) and
      oxygen intake (VO2) of 614 healthy, sedentary men and women aged 16-65 yr were
      measured during three cycle ergometer exercise tests. The HR associated with 55,
      65, 70, and 75% of each subject's pretraining VO2max was used to prescribe
      exercise intensity. Subjects exercised three times a week, beginning at a HR
      associated with 55% VO2max for 30 min. Duration and intensity was gradually
      increased over 20 wk of training. The duration and HR of each training session
      were controlled by a computer. RESULTS: Using the linear relationship between HR,
      VO2 and power output (PO), PO were predicted for each of 60 training sessions at
      the respective programmed HR. The average ratio of the actual training HR to
      programmed HR was 0.99. It was hypothesized that participants whose actual
      training PO exceeded their predicted PO would improve VO2max more than those
      whose actual PO was less than their predicted PO. Using the ratio of
      actual/predicted PO determined after the training was over, participants were
      arbitrarily assigned to three groups: 128 participants had low (LO) ratios (0.65
      0.84), 408 had average (AV) ratios (0.85-1.14), and 78 had high (HI) ratios (1.15
      1.34). Secondary analysis showed that the training program significantly
      increased mean VO2max of all three groups. Those who had a smaller increase in
      training PO (LO) had significantly less increase in VO2max than those with larger
      increases in PO (HI). CONCLUSION: People who exercise at a HR associated with the
      same %VO2max can vary substantially in their training PO, in their rate of
      increase in PO over a 20-wk training program, and in improvement of their VO2max.

PMID- 10647544
TI  - Resting heart rate definition and its effect on apparent levels of physical
      activity in young children.
AB  - PURPOSE: Heart rate monitoring is widely used to measure physical activity in
      children, but it may be dependent on the definition of resting heart rate used
      and the protocol used to measure or derive resting heart rate (RHR). The aim of
      this study was to determine the effect of RHR definition on activity levels
      assessed by PAHR-25 (% time at >25% of RHR), PAHR-50 (% time at >50% of RHR), and
      activity heart rate (AHR; mean HR minus RHR). METHODS: Minute-to-minute heart
      rates were measured over 3 d in 20 healthy preschool children aged 3-4 yr.
      Resting heart rate was measured for 5 min after a 10-min rest and was also
      derived from the following different but commonly used protocols: 1) mean of
      lowest heart rate plus all heart rates within three beats; 2) mean of lowest 5;
      3) lowest 10; 4) lowest 50. This gave five different definitions of RHR.
      Differences in RHR and in the derived indices of activity among definitions were
      tested for agreement using a Bland-Altman analysis, and by rank order
      correlation. RESULTS: Differences in RHR among all definitions were statistically
      significant. These resulted in significant differences in apparent physical
      activity levels: PAHR-25 varied 10-50% depending on the protocol used to define
      RHR; PAHR-50 varied by 16-65% as a function of the protocol used to define RHR.
      However, the different definitions of RHR had no significant influence on
      physical activity level when children were rank ordered. CONCLUSION: Choice of
      method for defining RHR has a profound effect on the apparent level of activity
      of children. This does not alter the relative assessment of activity by rank
      order. A consensus definition of RHR is desirable if comparisons of activity
      levels between samples or populations are to be made and if the adequacy of
      physical activity levels is to be assessed using heart rate.

PMID- 10647545
TI  - Perceived exertion with glucose ingestion in adolescent males with IDDM.
AB  - PURPOSE: The rating of perceived exertion (RPE) is an indicator of exercise
      effort in adolescents that may be influenced by certain pediatric conditions. The
      purpose of this study was to determine the influence of insulin-dependent
      diabetes mellitus (IDDM) and glucose intake on RPE. METHODS: Eight male
      adolescents with IDDM and eight healthy controls of similar age, weight, and
      VO2peak cycled for 60 min at 60%VO2peak on two occasions spaced 1-4 wk apart.
      During a control trial (CT), subjects drank water, and in a glucose trial (GT),
      glucose at a rate of approximately 1.5 g x kg(-1) x h(-1). Heart rate,
      ventilation, and RPE (Borg 6-20 scale) were assessed at 5, 25, 35, and 55 min and
      blood glucose and lactate levels before and at 30 and 60 min. RESULTS: RPE in
      both trials was 15-25% higher in IDDM versus healthy subjects (F = 8.83; df =
      1,14; eta-squared = 0.39; P = 0.01). In CT, it increased from 10.6 +/- 0.4 at 5
      min to 15.2 +/- 0.6 at 55 min in IDDM and from 9.3 +/- 0.9 at 5 min to 13.0 +/-
      0.8 at 55 min in healthy adolescents. In GT, RPE increased similarly to CT in the
      IDDM group but was 1-2 points lower in the healthy group. Blood glucose levels
      were 4.8 +/- 1.8 mmol x L(-1) and 1.8 +/- 0.4 mmol x L(-1) higher by the end of
      exercise in GT than in CT for the IDDM and healthy groups, respectively. There
      were no differences in heart rate, ventilation, or lactate levels between the
      groups or trials. CONCLUSIONS: For exercise performed at a similar moderate
      intensity, RPE in IDDM is higher by 2-3 points than in controls. Compared with
      water, glucose intake is associated with lower RPE in healthy, but not in IDDM,
      adolescents.

PMID- 10647546
TI  - Effect of push frequency on the economy of wheelchair racers.
AB  - PURPOSE: The aim of the study was to examine the effect of varying push frequency
      on pushing economy (oxygen uptake at a given speed). METHODS: Eight male
      wheelchair racers completed a series of exercise bouts on a wheelchair ergometer
      (Bromking Turbo Trainer, Bromakin, UK) at 6.58 m x s(-1). Initially, subjects
      self-selected their freely chosen push frequency (FCF); this was followed by 4
      random trials pushing at 60, 80, 120, and 140% of this FCF. Steady state VO2 was
      determined using Douglas bags, and heart rate was recorded by telemetry. After
      each condition, a small capillary blood sample was obtained and analyzed for
      blood lactate concentration (BLa) and a rating of perceived exertion (RPE) was
      recorded. RESULTS: At 6.58 m x s(-1) oxygen uptake, RPE, and gross mechanical
      efficiency were nonlinearly related to push frequency. Analysis of variance
      showed a significant effect (P < 0.05) of cycle frequency on VO2. VO2 was 11%
      higher at the 140% FCF compared with the 100% FCF condition. Changes in push
      frequency had little effect on HR although BLa increased linearly and was higher
      at the 140% FCF condition compared with 60% FCF (P < 0.05). A two-dimensional
      sagittal plane video analysis showed large interindividual differences in
      propulsion style. Both cycle time and the propulsion phase (%) decreased as the
      push frequency increased. The start angle and end angle of hand contact were
      similar for conditions, whereas the range of trunk motion decreased with push
      frequency (P < 0.05). CONCLUSION: The results of this study showed that the push
      frequency had an effect on pushing economy, and that the athletes' FCF was the
      most economical.

PMID- 10647547
TI  - A new bilateral closed chain assessment technique: methods and error analysis.
AB  - PURPOSE: The purpose of this paper is to present the Omnikinetic methodology for
      clinical evaluation of lower extremity function, to characterize its sensitivity
      to errors, and to present typical data for an assessment protocol. METHODS: A 5
      bar, 2-degree of freedom linkage was used to model the geometry of the crank,
      pedal, and lower extremity. Two-degree force transducers at the pedal were used
      to calculate center of pressure and force applied at the foot. A Newton-Euler
      inverse dynamic model was used to calculate net joint torques and powers
      bilaterally of the ankle, knee, and hip. Ten subjects performed a high velocity
      evaluation protocol which served as the control. Error sensitivity was determined
      by adding instrumental error, hip translation, and segmental length errors to the
      collected data and comparing the outcome to the control. RESULTS: All variables
      associated with instrumental error had mean errors under 4%. Mean errors
      associated with violations of the fixed hip assumption were under 15% for all
      variables. Mean errors associated with anthropometric measures were divided into
      two types: relative error (overall length unchanged, ratios of segments changed)
      and absolute (overall length changed, ratios of segment lengths unchanged).
      Relative anthropometric mean errors were under 5%. Absolute anthropometric mean
      errors were under 12%. CONCLUSION: The Omnikinetic is a new tool for bilateral
      lower extremity evaluation that enables the whole lower extremity to be evaluated
      at the joint level. Instrumental accuracy was excellent. The instrument was most
      sensitive to violations of the fixed hip position assumption over the last 20
      degrees of knee extension.

PMID- 10647548
TI  - Submaximal motor unit firing rates after 8 wk of isometric resistance training.
AB  - PURPOSE: The purpose of this study was to test the hypothesis that average motor
      unit firing rates change in parallel with the contractile properties of vastus
      lateralis following 8 wk of isometric resistance training. METHODS: The firing
      rates from more than 400 motor units of vastus lateralis were obtained during
      voluntary isometric contractions of 50% MVC, before and again after training in
      male subjects (N = 10) and their untrained controls (N = 10). Single motor unit
      spike trains were recorded with tungsten microelectrodes. RESULTS: Training
      resulted in a 36% (P < 0.05) increase in MVC. We also found significant increases
      (P < 0.05) in maximal twitch amplitude (+17%), time to peak tension (+9%) and the
      maximal instantaneous rate of contraction (+20%) in the trained leg of the
      experimental group. Neither the maximal integrated EMG nor the rate of increase
      of integrated EMG was different after training. There were no significant changes
      in any of these measures from the untrained leg or the control group. Average
      firing rates were not different after training despite the increase in twitch
      contractile speed. CONCLUSION: These findings suggest that the control properties
      of the nervous system are not altered despite sizable changes in the contractile
      properties of muscle following 8 wk of resistance training.

PMID- 10647549
TI  - Considering body mass differences, who are the world's strongest women?
AB  - PURPOSE: Allometric modeling (AM) has been used to determine the world's
      strongest body mass-adjusted man. Recently, however, AM was shown to demonstrate
      body mass bias in elite Olympic weightlifting performance. A second order
      polynomial (2OP) provided a better fit than AM with no body mass bias for men and
      women. The purpose of this study was to apply both AM and 2OP models to women's
      world powerlifting records (more a function of pure strength and less power than
      Olympic lifts) to determine the optimal model approach as well as the strongest
      body mass-adjusted woman in each event. METHODS: Subjects were the 36 (9 per
      event) current women world record holders (as of Nov., 1997) for bench press
      (BP), deadlift (DL), squat (SQ), and total (TOT) lift (BP + DL + SQ) according to
      the International Powerlifting Federation (IPF). RESULTS: The 2OP model
      demonstrated the superior fit and no body mass bias as indicated by the
      coefficient of variation and residuals scatterplot inspection, respectively, for
      DL, SQ, and TOT. The AM for these three lifts, however, showed favorable bias
      toward the middle weight classes. The 2OP and AM yielded an essentially identical
      fit for BP. CONCLUSIONS: Although body mass-adjusted world records were dependent
      on the model used, Carrie Boudreau (U.S., 56-kg weight class), who received top
      scores in TOT and DL with both models, is arguably the world's strongest woman
      overall. Furthermore, although the 2OP model provides a better fit than AM for
      this elite population, a case can still be made for AM use, particularly in light
      of theoretical superiority.

PMID- 10647550
TI  - Monitoring strength training: neuromuscular and hormonal profile.
AB  - PURPOSE: This study investigated changes induced by a single heavy resistance
      training session on neuromuscular and endocrine systems in trained athletes,
      using the same exercises for training and testing. METHODS: Five different groups
      volunteered: track and field male sprinters (MS, N = 6), track and field female
      sprinters (FS, N = 6), body builders (BB, N = 6), and weight lifters performing
      low-repetition exercise (WLL, N = 4) and high-repetition exercise (WLH, N = 4).
      In training, the work performed during half and full squat exercise was monitored
      for mechanical power output as well as EMG analysis on leg extensor muscles of
      the subjects belonging to the MS, FS, and BB groups. Just before and immediately
      after the training session, venous blood samples were obtained for RIA
      determination of testosterone (T), cortisol (C), lutropin (LH), human prolactin
      (PRL), and follitropin (FSH) in FS and MS. In the other three groups (BB, WLH,
      and WLL), the hormonal profile was limited to T and human growth hormone (hGH)
      only. RESULTS: After training the power developed in full squat demonstrated a
      statistically significant decrease (P < 0.01) in MS and no changes in FS. The EMG
      activity remained constant during the training session. Consequently, the
      EMG/Power ratio increased in both MS and FS, although only in MS a statistical
      significance was noted (P < 0.05). In MS immediately after the session the levels
      of C, T, and LH were significantly lower (P < 0.05). No changes were found in FS.
      In both groups and in BB significant negative correlation was found between
      changes in T level and EMG/Power ratio in half squat performance. CONCLUSIONS: It
      is likely that adequate T level may compensate the effect of fatigue in FT fibers
      by ensuring a better neuromuscular efficiency.

PMID- 10647551
TI  - Training and overtraining markers in selected sport events.
AB  - PURPOSE: Varieties of symptoms are supposed to detect overtraining (OT). Besides
      the problems of diagnosis and analysis in elite athletes, a daily monitoring of
      training status takes place with measurement of the parameters serum urea (SU)
      and serum creatine kinase (CK); therefore, their meaningfulness will be examined,
      with special respect inter- and intra-individually. METHODS: Data were obtained
      from determinations during training from athletes in rowing and athletes of
      international level. RESULTS: For 6981 SU determinations (male, N = 717; female,
      N = 285), a slightly asymmetric normal distribution was found (male, 80%, 5-7
      mmol x L(-1); female, 75%, 4-6 mmol x L(-1)). Values for women were approximately
      1.5 mmol x L(-1) lower. Individual variability was enormous; there seems little
      point in setting fixed value as 8.3 mmol x L(-1) for men and 7.0 mmol x L(-1) for
      women as a critical limit for OT. CK has also been measured and evaluated in
      sports as an essential parameter for determination of muscular stress. Frequency
      distributions of CK in 2790 samples (male, N = 497; female, N = 350) presented an
      asymmetric normal distribution with distinct trend toward higher values being
      evident for the range between 100 and 250 U x L(-1). Conspicuously elevated
      values occurred in the ranges 250-350 U x L(-1) and 1000-2000 U x L(-1). Men's
      maximal values were 3000 U x L(-1) and 1150 U x L(-1) for women. Individual
      variability was enormous. Athletes with chronically low CK exhibited mainly low
      variability; those with chronically higher values exhibited considerable
      variability. CONCLUSIONS: Establishment of both parameters should be useful to
      determine individual baselines from a large number of samples. Determinations
      should be made at least every 3 d in standardized conditions. If a large increase
      is observed in combination with reduced exercise tolerance after a phase of
      exertion (2-4 d), then the possibility of a catabolic/metabolic activity or
      insufficient exercise tolerance becomes much more likely.

PMID- 10647552
TI  - Specific fitness training and testing in competitive sports.
AB  - Improvements of athletic capacity in high-performance sport are mainly achieved
      through an increase of the quality of training. In physical preparation, the
      quality of training can be improved by developing highly specific means of
      training. The aim of this paper is to present three examples of how highly
      specific means of fitness training of world class athletes can be developed. The
      first example presents a test profile of specific motor abilities of top class
      tennis players, the second one deals with the improvement of specific strength
      training methods for ski jumpers, and the third deals with the development of
      specific training devices of Alpine ski racers.

PMID- 10647553
TI  - Skin temperature and skin blood flow affect bioelectric impedance study of female
      fat-free mass.
AB  - PURPOSE: This study examined the effects of skin temperature (Ts) and skin blood
      flow (SKBF) on bioelectrical impedance (BIA) measurements of body composition in
      healthy young females. METHODS: The Lukaski (FFM(LUK)) and Guo (FFM(GUO)) BIA
      equations for measuring female fat-free mass (FFM) were used. All subjects (N =
      20, age = 18-22 yr) underwent the following measurements under three ambient
      temperatures (T(amb)): Ts and SKBF for the calf, thigh, biceps, and chest; oral
      temperature (T(OR)); and the BIA measures of resistance (R) and reactance (Xc).
      The three T(amb) were 17, 25, and 35 degrees C which were considered as cold
      (CT), neutral (NT), and hot (HT) conditions, respectively. Their underwater
      weighing (UWW), lung residual volume, and skinfold thickness were measured in the
      NT. Data were analyzed using repeated measures of ANOVA and Tukey post-hoc test.
      RESULTS: We observed that in the CT mean SKBF and Ts decreased (P < 0.05) and R
      and Xc increased (P < 0.05), compared with those in both NT and HT. However, in
      the HT both SKBF and Ts increased and R deceased, but Xc remained unchanged
      relative to the NT. In these subjects, a net change in Ts of 17 degrees C
      resulted in a net change in the BIA measure of R of 46 ohms or 2.5 ohms per
      degree C. These changes affected the estimate of FFM(LUK) between CT, NT, and HT,
      but not the estimate of FFM(GUO) Regarding the two BIA equations for estimating
      FFM, the Guo equation underestimated FFM(UWW) (P < 0.05) in the CT, NT, and HT,
      and the Lukaski equation underestimated FFM(UWW) (P < 0.05) only in the CT,
      compared with that in the UWW technique. CONCLUSIONS: Ambient temperature affects
      Ts and SKBF which in turn influence the BIA measures of R and Xc, especially in
      the cold ambient temperature; the Guo BIA equation consistently underestimated
      FFM of young nonobese Chinese women in all temperatures; and the Lukaski equation
      closely approximates the FFM in the neutral and hot conditions compared with the
      FFM(UWW).

PMID- 10647554
TI  - Body composition in dancers: the bioelectrical impedance method.
AB  - PURPOSE: The aim of this study was to generate and validate a prediction equation
      for estimating the body composition in dancers using the bioelectrical impedance
      analysis (BIA) as a method of assessment. METHODS: The fat-free mass (FFM) of 42
      young female professional dance students was estimated by four different methods:
      dual x-ray absorptiometry (DXA), BIA, simple anthropometry, and skinfold
      thickness; DXA was used as a criterion method. RESULTS: The dancers' FFM was 42.6
      kg (SD: 3.3) and, on the average, body fat represented the 19.4% (SD: 4.3) of
      their body weight. Two dancer-specific BIA equations for the prediction of FFM
      (E(BIA)) were developed by multiple regression analysis using weight, height,
      resistance index, and triceps as predictor variables (E(BIA) and E(BIA-TRICEPS)).
      The validity of these equations as well as of those previously reported was
      assessed in two randomly selected subgroups of the initial study group, as
      described by the Bland-Altman analysis. The bias and the limits of agreement of
      the equations developed in the present study were lower than those resulting from
      the application of the previously used equations of Segal et al. and Hergenroeder
      et al. It was also found that, when validated against DXA, skinfolds measurements
      did not accurately predict body fatness in this group of young females.
      CONCLUSION: The new equations allow for an accurate routine assessment of body
      composition in young female dancers by using the method of BIA. Further studies
      are needed for the cross-validation of the equations in various groups of
      dancers.

PMID- 10647555
TI  - Single versus multiple sets in long-term recreational weightlifters.
AB  - PURPOSE: The purpose of this study was to determine the effects of increasing
      training volume from one set to three sets on muscular strength, muscular
      endurance, and body composition in adult recreational weight lifters. METHODS:
      Forty-two adults (age 39.7 +/- 6.2 yr; 6.2 +/- 4.6 yr weight training experience)
      who had been performing one set using a nine-exercise resistance training circuit
      (RTC) for a minimum of 1 yr participated in this study. Subjects continued to
      perform one set (EX-1; N = 21) or performed three sets (EX-3; N = 21) of 8-12
      repetitions to muscular failure 3 d x wk(-1) for 13 wk using RTC. One repetition
      maximums (1-RM) were measured for leg extension (LE), leg curl (LC), chest press
      (CP), overhead press (OP), and biceps curl (BC). Muscular endurance was evaluated
      for the CP and LE as the number of repetitions to failure using 75% of
      pretraining 1-RM. Body composition was estimated using the sum of seven skinfold
      measures. RESULTS: Both groups significantly improved muscular endurance and 1 RM
      strength (EX-1 by: 13.6% LE; 9.2% LC; 11.9% CP; 8.7% OP; 8.3% BC; and EX-3 by:
      12.8% LE; 12.0% LC; 13.5% CP; 12.4% OP; 10.3% BC) (P < 0.05). Both groups
      significantly improved lean body mass (P < 0.05). No significant differences
      between groups were found for any of the test variables (P > 0.05). CONCLUSION:
      Both groups significantly improved muscular fitness and body composition as a
      result of the 13 wk of training. The results show that one-set programs are still
      effective even after a year of training and that increasing training volume over
      13 wk does not lead to significantly greater improvements in fitness for adult
      recreational weight lifters.

PMID- 10647557
TI  - Re: Long-term oral creatine supplementation does not impair renal function in
      healthy athletes.

PMID- 10647556
TI  - Assessment of blood lactate: practical evaluation of the Biosen 5030 lactate
      analyzer.
AB  - PURPOSE: The aim of this study was to assess the validity and reliability of the
      Biosen 5030 lactate analyzer compared with a YSI 2300 lactate analyzer and a
      Kodak Ektachem DTII in a practical laboratory study context. METHODS: To assess
      validity, 144 triplicate capillarized blood samples, across a range of values,
      were analyzed using the three analyzers. To assess reliability a further 665
      samples were repeat analyzed. Temporal stability was determined by the reanalysis
      of resting and maximal exercise blood samples, after a period of storage ranging
      from 7 to 20 h, at room temperature. To measure inter- and intra-investigator
      reliability, 20 resting samples were taken from three different subjects by
      different investigators and a coefficient of variation was determined. RESULTS:
      There were strong relationships between the Biosen, the YSI (r2 = 0.97), and the
      Kodak Ektachem (r2 = 0.91). An analysis of Biosen compared with YSI revealed a
      positive bias of 0.37 mmol x L(-1) (95% limits of agreement, -0.85 to 1.59 mmol x
      L(-1)). The test-retest reliability correlation was significant (r2 = 0.99, P <
      0.05), but a paired t-test revealed a small (0.03 mmol x L(-1), P < 0.05)
      significant difference. The coefficient of variation from the three investigators
      across the 20 samples ranged from 1.3 to 3%. Blood lactate concentration in
      resting blood samples did significantly increase in value (0.2 mmol x L(-1), P <
      0.05) after 7-h exposure to the air, whereas there was no change in maximal
      exercise blood lactate values after 20-h exposure to the air. CONCLUSIONS: In a
      practical context, the Biosen 5030 lactate analyzer was comparable to the other
      analyzers giving fast reliable measures of blood lactate concentrations over the
      full range of values, which remained stable over extended periods at room
      temperature.

PMID- 10647558
TI  - Trauma centers and trauma surgeons: have we become too specialized?

PMID- 10647559
TI  - Persistent occult hypoperfusion is associated with a significant increase in
      infection rate and mortality in major trauma patients.
AB  - OBJECTIVE: To investigate the hypothesis that occult hypoperfusion (OH) is
      associated with infectious episodes in major trauma patients. METHODS: Data were
      collected prospectively on all adult trauma patients admitted to the
      Surgical/Trauma Intensive Care Unit from November of 1996 to December of 1998.
      Treatment was managed by a single physician according to a defined resuscitation
      protocol directed at correcting OH (lactic acid [LA] > 2.4 mmol/L). RESULTS: Of a
      total of 381 consecutive patients, 118 never developed OH and 263 patients
      exhibited OH. Seventeen patients were excluded because their LA never corrected,
      and they all subsequently died. One hundred seventy-six infectious episodes
      occurred in 97 of the 364 patients remaining. The infection rate in patients with
      no elevation of LA was 13.6% (n = 118) compared with 12.7% (n = 110) in patients
      whose LA corrected by 12 hours, 40.5% (n = 79; p < 0.01 compared with all other
      groups) in patients whose LA corrected between 12 and 24 hours, and 65.9% (n =
      57; p < 0.01 compared with all other groups) in patients who corrected after 24
      hours. Among the patients with infections, there were 276 infection sites with
      42% of infections involving the lung and 21% involving bacteremia. There was no
      difference in proportion of infections occurring at each site between groups. The
      mortality rate of patients who developed infections was 7.9% versus 1.9% in
      patients without infections (p < 0.05). Of the patients who developed infections,
      69.8% versus 25.8% (p < 0.001) did not have their lactate levels normalized
      within 12 hours of emergency room admission. Logistic regression demonstrated
      that both the Injury Severity Score and OH > 12 hours were independently
      predictive of infection. CONCLUSION: A clear increase in infections occurred in
      patients with OH whose lactate levels did not correct by 12 hours, with an
      associated increase in length of stay, days in surgical/trauma intensive care
      unit, hospital charges, and mortality.

PMID- 10647560
TI  - An examination of the volume-mortality relationship for New York State trauma
      centers.
AB  - OBJECTIVES: New York State Trauma Registry data were analyzed to determine
      whether there is a significant relationship between the volume of trauma patients
      treated by a trauma center and its risk-adjusted inpatient mortality rate.
      METHODS: Stepwise logistic regression was used to identify significant
      independent predictors of mortality, their weights, and the probability of in
      hospital mortality for each patient. These data were then used to calculate risk
      adjusted mortality rates for various ranges of hospital volume. Ranges were
      identified on the basis of homogeneity of mortality rates, the number of
      hospitals in each range, and the number of patients in each range. Three volume
      measures were used: (1) total annual volume of trauma cases > or = 1200 and total
      annual volume > or = 240 for patients with Injury Severity Score (ISS) > or = 15
      (equivalent to American College of Surgeons [ACS] criteria), (2) total annual
      volume of patients with ISS > or = 15, and (3) total annual volume of cases in
      the Registry (approximately, inpatients with ISS > or = 9). RESULTS: Results show
      that the 35 New York State trauma centers not meeting the ACS criteria had lower,
      but not significantly lower, observed and risk-adjusted mortality rates (7.62%
      and 8.25%, respectively) than the corresponding rates for the 8 New York State
      trauma centers that met the ACS criteria (9.36% and 8.83%, respectively).
      Regarding the other two criteria, hospital ranges representing lower annual
      volumes tended to have somewhat lower, although not significantly lower, observed
      and risk-adjusted mortality rates. For example, using a total annual volume for
      patients with ISS > or = 15, the risk-adjusted mortality rates for the volume
      ranges 1-150, 151-250, and 251+ were 7.78%, 9.23%, and 8.70%, respectively.
      CONCLUSIONS: We were unable to document an inverse relationship between hospital
      volume and inpatient mortality rate for trauma centers in New York State. Volume
      criteria should not be considered indicators of the quality of trauma care.

PMID- 10647561
TI  - Effectiveness of state trauma systems in reducing injury-related mortality: a
      national evaluation.
AB  - BACKGROUND: Regional trauma systems were proposed 2 decades ago to reduce injury
      mortality rates. Because of the difficulties in evaluating their effectiveness
      and the methodologic limitations of previously published studies, the relative
      benefits of establishing an organized system of trauma care remains
      controversial. METHODS: Data on trauma systems were obtained from a survey of
      state emergency medical service directors, review of state statutes and a
      previously published trauma system inventory. Injury mortality rates were
      obtained from national vital statistics data, whereas motor vehicle crash (MVC)
      mortality rates were obtained from the Fatality Analysis Reporting System.
      Mortality rates were compared between states with and without trauma systems.
      RESULTS: As of 1995, 22 states had regional trauma systems. States with trauma
      systems had a 9% lower crude injury mortality rate than those without. When MVC
      related mortality was evaluated separately, there was a 17% reduction in deaths.
      After controlling for age, state speed laws, restraint laws, and population
      distribution, there remained a 9% reduction in MVC-related mortality rate in
      states with a trauma system. CONCLUSION: These data demonstrate that a state
      trauma system is associated with a reduction in the risk of death caused by
      injury. The effect is most evident on analysis of MVC deaths.

PMID- 10647563
TI  - Impact of burn injury on hepatic TGF-beta1 expression and plasma TGF-beta1
      levels.
AB  - BACKGROUND: The liver plays a critical regulatory role in the acute inflammatory
      response to injury, although the mechanisms of this regulation are not well
      understood. transforming growth factor-beta1 (TGF-beta1) is induced after burn
      injury and may contribute to an inhibitory or fatal effect on hepatocytes. We
      investigated the association over time between plasma concentration of TGF-beta1,
      expression of TGF-beta1 m-RNA in liver tissue, and histologic analysis of liver
      apoptosis after burn injury. METHODS: Male BALB/c mice were anesthetized and
      randomized to receive 0% (sham), moderate (approximately 25%) (M), or large
      (approximately 50%) (L) body surface area full-thickness contact burn, followed
      by resuscitation and analgesia. Animals were killed over a time course from 15
      minutes to 24 hours after burn injury, and liver tissue and peripheral blood were
      collected. Plasma levels of TGF-beta1 (nanograms per milliliter) were measured by
      enzyme-linked immunosorbent assay. TGF-beta1 m-RNA was extracted from liver and
      measured by reverse transcription-polymerase chain reaction. Histology of liver
      apoptosis was examined after fixation and staining with TdT-mediated dUTP nick
      end labeling (TUNEL) method. RESULTS: The plasma concentration of TGF-beta in
      burn group L was significantly increased at 4 hours after burn when compared with
      sham and M burn groups. This rise in plasma TGF-beta1 was preceded by an increase
      in hepatic TGF-beta1 m-RNA expression at 30 minutes, 1, 2, and 4 hours after burn
      in the L group. Histologic analysis found greater hepatocyte death in the L group
      than in the M group at 8 hours after burn. CONCLUSION: The levels of induced TGF
      beta1 and TGF-beta1 m-RNA after L burn injury are higher and peak earlier than
      after M burn injury. Elevated TGF-beta1 may be associated with cell death in
      hepatocytes. The TGF-beta1 rise may be associated with hepatocyte injury and
      systemic response to massive burn.

PMID- 10647562
TI  - Neutrophil mediated remote organ injury after lower torso ischemia and
      reperfusion is selectin and complement dependent.
AB  - BACKGROUND: Lower torso ischemia and reperfusion leads to remote organ
      leukosequestration and injury. We now examine the intermediary role of selectins
      and complement in mediating lung and liver injury after hindlimb ischemia.
      METHODS: Mice underwent a 2-hour bilateral tourniquet hind-limb ischemia followed
      by 3 hours of reperfusion. RESULTS: Neutrophil depletion significantly decreased
      lung vascular permeability index (PI), measured by the extravasation of 125I
      albumin, and liver injury as assessed by serum alanine aminotransferse levels.
      Lung PI and serum alanine aminotransferse levels were also reduced in mice
      treated with recombinant soluble P-selectin glycoprotein ligand-immunoglobulin
      fusion protein. Complement inhibition with soluble complement receptor type 1
      decreased lung PI and serum alanine aminotransferse levels. C5-deficient mice
      exhibited a similar decrease in lung PI and liver injury. Lung and liver injury
      were restored in C5-deficient mice reconstituted with wild-type serum.
      CONCLUSION: Remote organ injury after lower torso reperfusion is selectin and
      complement dependent.

PMID- 10647564
TI  - Hypertonic saline resuscitation abrogates neutrophil priming by mesenteric lymph.
AB  - OBJECTIVE: Neutrophil (PMN) priming after hemorrhagic shock is predictive of the
      subsequent development of multiple organ failure, but the mechanism remains
      unknown. Recently, we and others have demonstrated that mesenteric lymph from
      shock animals resuscitated with lactated Ringer's solution (LR) is not only a
      potent PMN priming agent but also causes lung injury. Work by others has shown
      that resuscitation with hypertonic saline (HTS) protects animals from lung injury
      after hemorrhagic shock. Therefore, we hypothesize that resuscitation with HTS
      will abolish PMN priming by postshock mesenteric lymph. METHODS: After mesenteric
      lymph duct catheterization, male rats underwent hemorrhagic shock (mean arterial
      pressure of 40 mm Hg for 90 minutes) and resuscitation with shed blood plus
      either LR (2x volume of shed blood) or 4 mL/kg of 7% HTS (isonatremic). Priming
      for superoxide by PMN was measured after fMLP (1 microM) activation. RESULTS:
      Shock significantly decreased mesenteric lymph flow from preshock levels in both
      groups. LR resuscitation produced significantly more mesenteric lymph than HTS
      resuscitation. Mesenteric lymph from LR animals primed PMN for superoxide
      production, whereas, HTS eliminated this priming. CONCLUSION: HTS not only
      decreases postshock mesenteric lymph production, it eliminates PMN priming by
      mesenteric lymph, suggesting a mechanism for the beneficial effects of HTS
      resuscitation.

PMID- 10647565
TI  - Age-related differences in the metabolic response to injury.
AB  - OBJECTIVE: To investigate the effect of age on the metabolic response to injury.
      METHODS: Fifty-two trauma patients meeting entrance criteria were prospectively
      enrolled. Patients were grouped by age: elderly, >60 years; and young, < or =60
      years. After 4 days of nutrition support, physiologic and laboratory data were
      collected. Energy and nitrogen metabolism, and body composition were evaluated.
      RESULTS: Elderly patients demonstrated a reduced incidence of fever (48% vs.
      77%,p = 0.027). Independent of body composition, temperature, and injury
      severity, oxygen consumption was 8% lower in the elderly (p = 0.0032). However,
      nitrogen loss and myofibrillar catabolic rate was not altered by age. Elderly
      subjects were more often hyperglycemic (38% vs. 0%, p < 0.0001) and azotemic (62%
      vs. 22%, p = 0.004), despite similar carbohydrate and protein intake. CONCLUSION:
      Fever is less common and oxygen consumption lower in elderly trauma patients.
      Postinjury myofibrillar protein catabolism and nitrogen loss are not influenced
      by aging. Metabolic complications of nutrition support (hyperglycemia, azotemia)
      are more common in elderly trauma patients.

PMID- 10647566
TI  - Should normothermia be restored and maintained during resuscitation after trauma
      and hemorrhage?
AB  - BACKGROUND: Although hypothermia often occurs after trauma and has protective
      effects during ischemia and organ preservation, it remains unknown whether
      maintenance of hypothermia or restoring the body temperature to normothermia
      during resuscitation has any deleterious or beneficial effects on heart
      performance and organ blood flow after trauma-hemorrhage. METHODS: Male rats
      underwent laparotomy (i.e., induced trauma) and were exsanguinated to and
      maintained at a mean arterial pressure of 40 mm Hg until 40% of the maximum shed
      volume was returned in the form of Ringer's lactate. Body temperature decreased
      from approximately 36.5 degrees C to below 32 degrees C. The animals were then
      resuscitated with four times the volume of maximal bleedout with Ringer's
      lactate. In one group, body temperature was rewarmed to 37 degrees C during
      resuscitation. In another group, body temperature was maintained at hypothermia
      (32 degrees C) for 4 hours after resuscitation. In an additional group, the body
      temperature was kept at 37 degrees C during hemorrhage as well as during
      resuscitation. Left ventricle performance parameters such as maximal rate of left
      ventricular pressure increase and decrease (+/-dP/dt(max)) were measured up to 4
      hours. Cardiac output and regional blood flow were determined by radioactive
      microspheres at 4 hours after the completion of resuscitation. RESULTS: The
      maintenance of normothermia during hemor. rhage or prolonged hypothermia after
      resuscitation depressed the left ventricular performance parameters, cardiac
      output, and regional blood flow in various organs. Rewarming the body to
      normothermia during resuscitation, however, significantly increased heart
      performance, cardiac output (from hypothermia 16.2 +/- 1.4 to 22.3 +/- 1.4 mL/min
      per 100 g body weight,p < 0.05) and total hepatic blood flow (from hypothermia
      117.5 +/- 5.3 to 166.0 +/- 9.3 mL/min per 100 g tissue, p < .05). CONCLUSION: Our
      data indicate that restoration of normothermia during resuscitation improves
      cardiac function and hepatic blood flow compared with hypothermia.

PMID- 10647567
TI  - Approach to the management of complex hepatic injuries.
AB  - BACKGROUND: Complex hepatic injuries American Association for the Surgery of
      Trauma Organ Injury Scale grades IV and V incur high mortality rate ranging from
      40 to 80%, respectively. The objective of this study is to assess the clinical
      experience with an aggressive approach to the management of these, the most
      complex of hepatic injuries. METHODS: This is a retrospective 6-year study (1992
      1997) at an American College of Surgeons urban Level I trauma center of patients
      sustaining complex hepatic injuries whose interventions included surgery,
      angiographic embolization, endoscopic retrograde cholangiopancreatography plus
      biliary stenting and percutaneous computed tomographic-guided drainage. The main
      outcome measure was survival. RESULTS: A total of 22 patients sustaining complex
      hepatic injuries; mean age of 26 years (range, 10-52 years), mean Revised Trauma
      Scale score of 9.9, mean Injury Severity Score of 32 (range, 16-75), American
      Association for the Surgery of Trauma - Organ Injury Scale grade IV (13 cases);
      grade V (9 cases). Mean estimated blood loss was 4,600 mL; mean number of units
      of blood transfused was 15. The patients underwent the following interventions:
      surgery (n = 22), re-operated (n = 13), mean number of operations 1.6 (range, 1
      4), extensive hepatotomy and hepatorrhaphy (n = 17), nonanatomic resection (n =
      7), formal hepatectomy (n = 4), packing (n = 10), direct approach to hepatic
      veins (n = 3); angiographic embolization (n = 15); endoscopic retrograde
      cholangiopancreatography and stenting (n = 5); computed tomographic guided
      drainage (n = 6). Mean length of stay in the intensive care unit was 21 days
      (range, 2-134 days), mean hospital length of stay was 40 days (range, 2-147
      days). Overall mortality rate was 14% (3 of 22 cases), hepatic mortality rate was
      9% (2 of 22 cases), mortality rate by injury grade was 8% grade IV (1 of 13
      cases) and 22% grade V (2 of 9 cases). CONCLUSION: In this select patient
      population, improvements in mortality rates can be achieved with an aggressive
      approach to the management of complex hepatic injuries, including surgery, early
      packing, angiographic embolization, endoscopic retrograde
      cholangiopancreatography and stenting of biliary leaks, and drainage of hepatic
      abscesses.

PMID- 10647568
TI  - Use of the capture-recapture method to estimate severe traumatic brain injury
      rates.
AB  - OBJECTIVE: This study assessed the applicability of using three different data
      sources (hospital discharge data, Traumatic Brain Injury Registry data, and death
      certificates) to identify high-risk groups for traumatic brain injuries (TBI).
      Reporting biases were also addressed. METHODS: Linkage of the data sources and
      log-linear modelling in conjunction with the capture-recapture method was used to
      estimate the number of missing TBI. Biased reporting to each data source was
      assessed by using the total number of estimated TBI by age and sex. RESULTS: An
      estimated 2% of TBI that occurred in Iowa were not reported to any of the data
      sources. Overall, women 85 years old and older were more likely to be missed by
      the combined data sources. Males and those of advanced age were less likely to be
      reported to the Registry. By using the capture-recapture method, falls among the
      elderly were found to be a significant public health problem in Iowa. CONCLUSION:
      Despite biased reporting to the three data sources, the capture-recapture method
      can be used to identify high-risk groups for TBI in Iowa.

PMID- 10647569
TI  - Accounting for intubation status in predicting mortality for victims of motor
      vehicle crashes.
AB  - BACKGROUND: Two of the important predictors of mortality for trauma patients are
      the Glasgow Coma Scale and the respiratory rate. However, for intubated patients,
      the verbal response component of the Glasgow Coma Scale and the respiratory rate
      cannot be accurately obtained. This study extends previous work that attempts to
      predict mortality accurately for intubated patients without using verbal response
      and respiratory rate. METHODS: The New York State Trauma Registry was used to
      identify 1994 and 1995 victims of motor vehicle crashes (MVCs). For the subset of
      patients who were not intubated, we developed two statistical models to predict
      mortality: one did not contain verbal response or respiratory rate, and the other
      contained a predicted verbal response. These were compared with a model that did
      include verbal response and respiratory rate. We also compared the predictive
      abilities of the first two models for all MVC patients (intubated and
      nonintubated) and determined the extent to which intubated patients were at
      increased risk of dying in the hospital after having adjusted for other
      predictors of mortality. RESULTS: For nonintubated patients, the statistical
      model without verbal response and the model with predicted verbal response had
      slightly better discrimination and worse calibration than the model that included
      verbal response and respiratory rate. Predicted verbal response did not improve
      the strength of the model without verbal response. For all MVC patients
      (intubated and nonintubated), predicted verbal response was not a significant
      predictor of mortality when used in combination with the other predictors.
      Intubation status was a significant predictor, with intubated patients having a
      higher probability of dying in the hospital than patients with otherwise
      identical risk factors. CONCLUSION: Inpatient mortality for intubated MVC
      patients can be accurately predicted without respiratory rate or verbal response.
      There appears to be no need for predicted verbal response to be part of the
      prediction formula, but intubation status is an important independent predictor
      of mortality and should be used in statistical models that predict mortality for
      MVC patients.

PMID- 10647570
TI  - Anatomic basis of safe percutaneous subclavian venous catheterization.
AB  - BACKGROUND: The technique of percutaneous catheterization of the subclavian vein
      by the infraclavicular approach is dependent on the location of the subclavian
      vein in relation to the clavicle. The purpose of this study was to analyze the
      anatomic relationship between these two structures and how it is influenced by
      changes in shoulder positioning. METHODS: Dissections of the infraclavicular
      region were performed in seven fresh cadavers and linear measurements made to
      determine the extent of overlap between the vein and the clavicle in different
      shoulder positions. RESULTS: When the shoulder was in neutral position, the
      subclavian vein was overlapped by the medial third or more of the clavicle and
      this segment of bone was able to serve as a landmark for the vein. However,
      shoulder elevation displaced the clavicle cephalad and reduced the degree of
      overlap. Mild shoulder retraction increased the area of contact between the vein
      and the undersurface of the clavicle, whereas protraction lifted the clavicle off
      the vein. CONCLUSION: Infraclavicular subclavian venipuncture should be performed
      with shoulders in a neutral position and also in slight retraction. An
      appreciation of the anatomic relationship between the clavicle and the subclavian
      vein is the key to successful execution of this technique.

PMID- 10647572
TI  - Biomechanical analysis of the Medoff sliding plate.
AB  - BACKGROUND: A new device for fixation of hip fractures the Medoff plate was
      biomechanically tested and compared with the Ambi plate and Gamma nail. METHODS:
      Six pairs of human cadaveric femurs were used. The characteristics evaluated were
      structural stiffness, strain distribution, and modes of failure. Results were
      compared with the Ambi plate and Gamma nail biomechanical studies from a previous
      study that used the same methods. RESULTS: The Medoff plate was stiffer than the
      other two implants for intertrochanteric fractures, and for segmental
      subtrochanteric fracture. The Medoff plate was more load sharing than the other
      implants in these fracture configurations. The mean load to failure was lower
      than for the Ambi plate or the Gamma nail. CONCLUSION: The Medoff plate is a
      better load-sharing device than the Ambi (DHS) or Gamma nail systems. The main
      concern is its structural weakness. The implant failed at loads 50% less than
      other devices. The greatest risk of implant failure is with unstable
      subtrochanteric fractures.

PMID- 10647571
TI  - New technique for treatment of unstable distal femur fractures by locked double
      plating: case report and biomechanical evaluation.
AB  - BACKGROUND: A comminuted, intra-articular distal femur fracture was surgically
      treated by the authors with a locked, double-plating technique because fixation
      stability could not be initially achieved by using a standard double-plating
      technique. The purpose of this study was to determine biomechanically whether a
      locked double-plate construct would enhance fixation stability compared with a
      nonlocked double-plate construct. METHODS: Six matched pairs of mildly osteopenic
      femurs were selected and all had a reproducible intra-articular fracture pattern
      created. Each pair underwent fixation with either a double-plating construct or a
      locked, double-plating construct that was randomly assigned. The instrumented
      femurs were then mechanically tested in several loading modes to determine
      fixation stability. After initial testing, specimens were cyclically loaded and
      retested for stability. RESULTS: The locked, double-plating construct provided
      significantly greater fixation stability than the standard double-plating
      construct in precycling and postcycling biomechanical testing. CONCLUSION: The
      technique described is particularly applicable for severely comminuted fractures
      of the distal femur and fractures in osteopenic bone with poor screw purchase. It
      offers a simple alternative for enhancing fixation stability, which avoids the
      potential complications of methylmethacrylate-enhanced screw fixation.

PMID- 10647573
TI  - Effects of inhalation of corticosteroids immediately after experimental chlorine
      gas lung injury.
AB  - BACKGROUND: To assess the effects of treatment with nebulized corticosteroids
      immediately after chlorine gas injury. METHODS: Eighteen anesthetized and
      mechanically ventilated pigs were exposed to chlorine gas (140 ppm for 10
      minutes) and observed for 6 hours. Nine pigs were treated with nebulized
      beclomethasone-dipropionate 20 microg/kg (BDP group), and nine pigs were given no
      treatment (control group). RESULTS: All animals developed severe pulmonary
      dysfunction. The initial decrease in PaO2 was similar in both groups, but BDP
      treated animals improved whereas control animals deteriorated (p < 0.005;
      analysis of variance). Pulmonary vascular resistance increased in both groups but
      less in the BDP group (p < 0.01). Lung-thorax compliance was better preserved in
      the BDP group (p < 0.01), and oxygen delivery was significantly better in the BDP
      group (p < 0.01). One animal died in the BDP group, as did three animals in the
      control group. CONCLUSION: Immediate treatment with nebulized BDP improved
      pulmonary and cardiovascular function after experimental chlorine gas injury.

PMID- 10647574
TI  - Alcohol problems in women admitted to a level I trauma center: a gender-based
      comparison.
AB  - BACKGROUND: Male patients constitute such a large proportion of trauma patients
      that most studies of alcohol problems in trauma patients have been carried out
      with clinical data largely or totally contributed by male patients. It may be
      incorrect to assume that the nature of alcoholism in women and men is identical,
      or that the size of the problem among women is small, eliminating the need to
      specifically study female patients. The purpose of this study was to perform a
      gender-based comparison of alcohol problems in trauma patients. METHODS: Admitted
      injured patients underwent routine screening, including a blood alcohol
      concentration, serum gamma-glutamyl transpeptidase, and the Short Michigan
      Alcohol Screening Test. A random sample of screen positive women and men
      underwent a comprehensive alcohol use and psychosocial assessment, and the
      results were compared by gender. RESULTS: The screen-positive rate was higher for
      men, 51% versus 34% (p < 0.01). However, screen-positive women and men had
      similar problem severity as reflected by mean blood alcohol concentration (162
      mg/dL vs. 142 mg/dL, p = 0.16) and Short Michigan Alcohol Screening Test scores
      (4.6 vs. 5.0, p = 0.32). The Alcohol Use Disorders Identification Test, NIMH-DIS,
      and Severity of Alcohol Dependence Data form showed that female trauma patients
      with alcohol problems have the same severity of dependence symptoms as men.
      However, women were significantly more likely to have liver dysfunction,
      depression, psychological distress, and recent physical, emotional, or sexual
      abuse. CONCLUSION: Alcohol problems are more common in male trauma patients, but
      women with alcohol problems are just as severely impaired, have at least as many
      adverse consequences of alcohol use as their male counterparts, and have more
      evidence of alcohol-related physical and psychological harm.

PMID- 10647575
TI  - Screening trauma patients for alcohol problems: are insurance companies barriers?
AB  - BACKGROUND: Impairment caused by alcohol is the leading risk factor for trauma.
      However, many physicians do not screen for alcohol use because of concerns about
      confidentiality and denial of insurance coverage. The purpose of this study was
      to examine objectively the confidentiality issues and insurance statutes
      affecting alcohol screening in trauma centers. METHODS: We conducted a survey of
      insurance commissioners in all 50 states to determine the prevalence of statutes
      allowing denial of coverage for injuries sustained while impaired due to alcohol,
      reviewed state insurance laws, and reviewed federal regulations protecting the
      confidentiality of alcohol information in patients seeking alcohol treatment.
      RESULTS: Special federal regulations protecting confidentiality of alcohol
      screening data depend on how such information is acquired and do not routinely
      cover trauma patients. Concerns about screening on insurance coverage are valid
      in 38 states. CONCLUSION: Segregating information about alcohol use in the
      medical record and assigning designated chemical dependency counselors to screen
      all trauma patients would provide confidentiality of alcohol information under
      current federal regulations, allowing denial of release of such information,
      except under subpoena.

PMID- 10647576
TI  - Low-cost improvements in prehospital trauma care in a Latin American city.
AB  - OBJECTIVE: Prehospital care is a critical component of efforts to lower trauma
      mortality. In less-developed countries, scarce resources dictate that any
      improvements in prehospital care must be low in cost. In one Latin American city,
      recent efforts to improve prehospital care have included an increase in the
      number of sites of ambulance dispatch from two to four and introduction of the
      Prehospital Trauma Life Support (PHTLS) course. METHODS: The effect of increased
      dispatch sites was evaluated by comparing response times before and after
      completion of the change. The effect of PHTLS was evaluated by comparing
      prehospital treatment for the 3 months before initiation of the course (n = 361
      trauma patients) and the 6 months after (n = 505). RESULTS: Response time
      decreased from a mean of 15.5 +/- 5.1 minutes, when there were two sites of
      dispatch, to 9.5 +/- 2.7 minutes, when there were four sites. Prehospital trauma
      care improved after initiation of the PHTLS course. For all trauma patients, use
      of cervical immobilization increased from 39 to 67%. For patients in respiratory
      distress, there were increases in the use of oropharyngeal airways (16-39%), in
      the use of suction (10-38%), and in the administration of oxygen (64-87%). For
      hypotensive patients, there was an increase in use of large-bore intravenous
      lines from 26 to 58%. The improved prehospital treatment did not increase the
      mean scene time (5.7 +/- 4.4 minutes before vs. 5.9 +/- 6.8 minutes after). The
      percent of patients transported who died in route decreased from 8.2% before the
      course to 4.7% after. These improvements required a minimal increase (16%) in the
      ambulance service budget. CONCLUSION: Increase in sites of dispatch and increased
      training in the form of the PHTLS course improved the process of pre-hospital
      care in this Latin American city and resulted in a decrease in prehospital
      deaths. These improvements were low cost and should be considered for use in
      other less developed countries.

PMID- 10647577
TI  - Taking care of the "good guys:" a trauma center-based model of medical support
      for tactical law enforcement.
AB  - The potential need for rapid medical intervention and access to a trauma center
      after major injury is crucial to the safety and success of SWAT team operations.
      This manuscript describes the genesis and development of a unique model for which
      advanced medical care is rendered by trained health care professionals within a
      regional trauma system in the support of a SWAT team. The model was developed
      jointly by the Newark, New Jersey, Division of the Federal Bureau of
      Investigation and The New Jersey Trauma Center-University Hospital, an academic,
      urban Level I trauma center. After the signing of a Memorandum of Understanding
      between the two agencies in 1995, the program became operational. The medical
      team is composed of physicians, nurses, and paramedics. Since inception, the
      medical team has provided medical support for 33 tactical missions and 99
      training days. Ten patients were treated: 7 agents (syncope, fractured foot,
      blunt head/neck trauma, lacerations), 2 bystanders (chest pain, asthma), and 1
      suspect (chest pain). The advantages of the Newark model in contrast to other
      programs of tactical medical support, are the operational activities of the team
      and the cost of the program was outlined.

PMID- 10647578
TI  - Medical care solicitation by criminals with gunshot wound injuries: a survey of
      Washington, DC, jail detainees.
AB  - BACKGROUND: The best estimates of nonfatal gunshot wounds in the United States
      come from hospital emergency room data and may miss, among other things, wounded
      individuals who do not seek medical treatment. Criminals may be those least
      likely to rely on professional care for their wounds. This study provides
      evidence of whether medical care is solicited by criminals after gunshot wounds.
      In addition, the circumstances of the injury events are described. METHODS: A
      case series of 79 detainees at a Washington, DC, jail who had previously been
      shot in 93 separate incidents were interviewed using a standardized
      questionnaire. Data were obtained concerning the age and race of the victim, the
      location of the wound, and the length of hospital stay. RESULTS: In 92% of the
      incidents, respondents reported going to the hospital; one-third of those shot
      were hospitalized for more than 1 week. More than half (54%) had been hit in the
      head or torso, and 40% had a current disability attributable to the wound.
      CONCLUSION: Among these "criminals," the vast majority reported that they
      obtained professional care for their gunshot wounds. Such evidence suggests that
      individuals previously thought unlikely to enter the medical care system after a
      firearm injury usually do so. Statistics on medically treated nonfatal gunshot
      wounds probably do not substantially underestimate the actual number of nonfatal
      shootings.

PMID- 10647579
TI  - Urologic complications of diastasis of the public symphysis: a trauma case report
      and review of world literature.

PMID- 10647580
TI  - Choledochocaval fistula as a result of a right flank stab wound: case report.

PMID- 10647581
TI  - Dislodgment of inferior vena cava filters during central line placement: case
      report.

PMID- 10647582
TI  - Endovascular treatment of a ruptured intracranial dissecting vertebral aneurysm
      in a kickboxer.

PMID- 10647583
TI  - Immediate pulmonary embolism after trauma: case report.

PMID- 10647584
TI  - Visceral pleural lung graft for myocardial injury: case report.

PMID- 10647585
TI  - Review of tricuspid valve injury after airbag deployment: presentation of a case
      and discussion of mechanism of injury.

PMID- 10647586
TI  - Acute mediastinal tamponade secondary to blunt sternal fracture.

PMID- 10647587
TI  - Intra-articular dislocation of the patella.

PMID- 10647588
TI  - Comminuted pelvic ring disruption in toddlers: management of a rare injury.
AB  - Pediatric pelvic fractures are rare injuries. The clinical management,
      classification, and operative treatment of this type of injury was presented in
      two toddlers ranging in age from 1 to 3 years. The CT examination proved to be
      the most reliable diagnostic tool for the assessment of the fracture morphology.
      The findings of the CT examination provide the possibility for an exact
      classification and operative planning. The surgical treatment was performed with
      the AO instrumentation for small fragments by using the approved standard
      approaches of adult surgery. The postoperative management has to be adapted to
      the physiology of the children. It is important to remove the osteosynthesis
      material in due time to avoid the risk of epiphysiodesis at the pelvis. To detect
      late sequelae of the trauma, follow-up should be performed regularly until growth
      is completed.

PMID- 10647590
TI  - Delayed small bowel injury as a result of penetrating extraperitoneal high
      velocity ballistic trauma to the abdomen.

PMID- 10647589
TI  - Granulocytes, including neutrophils, synthesize IL-10 after traumatic
      pancreatitis: case report.

PMID- 10647591
TI  - Frostbite: pathogenesis and treatment.
AB  - Frostbite, once almost exclusively a military problem, is becoming more prevalent
      among the general population and should now be considered to be within the scope
      of the civilian physician's practice. Studies into the epidemiology of civilian
      frostbite have identified several risk factors that may aid the clinician in the
      diagnosis and management of cold injuries. Research into the pathophysiology has
      revealed marked similarities in inflammatory processes to those seen in thermal
      burns and ischemia/reperfusion injury. Evidence of the role of thromboxanes and
      prostaglandins has resulted in more active approaches to the medical treatment of
      frostbite wounds. Although the surgical management of frostbite involves delayed
      debridement 1 to 3 months after demarcation, recent improvements in radiologic
      assessment of tissue viability have led to the possibility of earlier surgical
      intervention. In addition, several adjunctive therapies, including vasodilators,
      thrombolysis, hyperbaric oxygen, and sympathectomy, are discussed.

PMID- 10647593
TI  - The image of trauma: left thoracoabdominal incision with medial visceral
      rotation.

PMID- 10647592
TI  - Properties of calcium phosphate ceramics in relation to their in vivo behavior.

PMID- 10647594
TI  - Advancing the concept of two distinct ARDSs.

PMID- 10647596
TI  - Decade of the brain: nuclear medicine contributions.

PMID- 10647597
TI  - Nuclear medicine in the new millennium.

PMID- 10647595
TI  - Guidelines for osteoporosis in coeliac disease and inflammatory bowel disease.
      British Society of Gastroenterology.

PMID- 10647598
TI  - Clinical application of 201Tl SPECT imaging of brain tumors.
AB  - This study investigated the clinical usefulness of evaluating the histologic
      grade of brain tumors by 201Tl SPECT brain imaging. METHODS: Early and delayed
      SPECT brain images were obtained about 10 min and 3 h, respectively, after
      intravenous injection of 111MBq (3 mCi) 201Tl in 9 healthy subjects (control
      subjects), 3 patients with brain hematomas, and 41 patients with brain tumors.
      Semiquantitative data were obtained for early and delayed 201Tl uptake indices
      and 201Tl retained index in all patients and healthy subjects. RESULTS: In 9
      healthy subjects, there was little radioactivity in brain substance. In all
      patients with brain hematomas or tumors, a high tracer uptake was visible in
      lesions on early images, but the radioactivity in lesions varied with the
      histologic nature of the lesion on delayed images. The radioactivity decreased
      remarkably in brain hematomas (average retained index, 0.61 +/- 0.04). The
      radioactivity was stable or decreased slightly in benign or low-grade tumors
      (average retained index, 0.96 +/- 0.24). The radioactivity was increased in high
      grade or metastatic tumors (average retained index, 1.26 +/- 0.28). CONCLUSION:
      This study indicates that 201Tl brain SPECT early and delayed imaging is very
      useful in brain tumor localization, in distinguishing low-grade from high-grade
      brain tumors, in predicting histologic grades of brain tumors, and in detecting
      residual or recurrence of brain tumors postoperatively. 201Tl brain SPECT may
      also offer the most accurate assessment of response to therapy.

PMID- 10647599
TI  - Effect of mental stress on myocardial blood flow and vasomotion in patients with
      coronary artery disease.
AB  - In patients with coronary artery disease (CAD), mental stress may provoke
      ischemic electrocardiograph changes and abnormalities in regional and global left
      ventricular function. However, little is known about the underlying myocardial
      blood flow response (MBF) in these patients. METHODS: We investigated the
      hemodynamic, neurohumoral, and myocardial blood flow responses to mental stress
      in 17 patients with CAD and 17 healthy volunteers of similar age. Mental stress
      was induced by asking individuals to solve mathematic subtractions in a
      progressively challenging sequence; MBF was quantified at rest and during mental
      stress using 13N ammonia PET. RESULTS: Mental stress induced significant (P <
      0.01) and comparable increases in rate-pressure product, measured in beats per
      minute x mm Hg, in both patients (from 7826 +/- 2006 to 10586 +/- 2800) and
      healthy volunteers (from 8227 +/- 1272 to 10618 +/- 2468). Comparable increases
      also occurred in serum epinephrine (58% in patients versus 52% in healthy
      volunteers) and norepinephrine (22% in patients versus 27% in healthy
      volunteers). Although MBF increased in patients (from 0.67 +/- 0.15 to 0.77 +/-
      0.18 mL/min/g, P < 0.05) and healthy volunteers (from 0.73 +/- 0.13 to 0.95 +/-
      0.22 mL/min/g, P < 0.001), the magnitude of flow increase was smaller in patients
      (14% +/- 17%) than in healthy volunteers (29% +/- 14%) (P = 0.01). The increase
      in MBF during mental stress correlated significantly with changes in cardiac work
      in healthy volunteers (r = 0.77; P < 0.001) but not in patients. CONCLUSION:
      Despite similar increases in cardiac work and comparable sympathetic stimulation
      in CAD patients and healthy volunteers, CAD patients exhibit an attenuated blood
      flow response to mental stress that may contribute to mental stress-induced
      ischemic episodes in daily life.

PMID- 10647600
TI  - Adaptive response in patients treated with 131I.
AB  - The aim of this study was to investigate whether an adaptive response (defined as
      the induction of radiation tolerance after a small dose of radiation) could be
      observed in peripheral blood lymphocytes of patients treated with 1311 for
      thyroid disease. METHODS: For each patient, blood samples were taken immediately
      before and 1 wk after 131I administration. Each blood sample was divided into 3
      fractions and the fractions were subsequently irradiated in vitro with 0, 0.5,
      and 1.0 Gy 60Co gamma-rays. After blood culture for 70 h, cells were harvested
      and stained with Romanowsky-Giemsa and micronuclei were counted in 1000
      binucleated cells. The increase in micronuclei by the in vitro irradiation of the
      blood samples taken before and after therapy was compared. In this setup, an
      adaptive response is represented by a significant decrease of the in vitro
      induced micronucleus yield after therapy compared with that before therapy. The
      iodine therapy can be considered as an in vivo adaptation dose, after which the
      subsequent in vitro irradiation acts as a challenge dose. To investigate the
      reproducibility of the method, 2 subsequent blood samples of healthy volunteers
      were taken 7 d apart. Irradiation and cell culture were performed as described.
      RESULTS: In 8 of 20 patients, a significant (P = 0.0002) decrease was found in
      the in vitro induced micronucleus yield in the blood sample taken 1 wk after 1311
      administration compared with that of the blood sample taken before therapy. No
      significant (P > 0.1) differences were observed between these 8 patients and the
      other patients when the number of micronuclei induced in vivo by the iodine
      treatment and the resulting equivalent total body dose were compared. None of the
      control subjects showed a significant change in micronucleus yield after in vitro
      irradiation between both blood samples taken 1 wk apart. CONCLUSION: The iodine
      treatment can act as an in vivo adaptation dose and can induce an adaptive
      response that is observed by a decrease of the cytogenetic damage in peripheral
      blood lymphocytes after in vitro irradiation as a challenge dose. A large
      interindividual difference was observed.

PMID- 10647601
TI  - A multicenter trial on interobserver reproducibility in reporting on 99mTc-DMSA
      planar scintigraphy: a Belgian survey.
AB  - Conflicting opinions have been expressed regarding reproducibility in 99mTc
      dimercaptosuccinic acid (DMSA) planar renal image interpretation. The purpose of
      this investigation was to determine the level of interobserver variability among
      a large group of Belgian nuclear medicine physicians who evaluated a randomly
      selected series of DMSA planar scintigraphic examinations performed on children
      and adults. METHODS: All Belgian nuclear medicine centers (n = 82) were invited
      to participate in a reproducibility study on 99mTc-DMSA scintigraphy. 99mTc-DMSA
      scans obtained on 10 adults and 40 children were randomly selected from the
      databases of 2 hospitals. Those participating in this investigation (65 centers =
      79%) received a series of computer disks containing 50 99mTc-DMSA studies. To
      avoid potential problems related to unfamiliar display, the disks were formatted
      to be interpretable using the participants' own computer systems. Each
      participant was then free to use his or her usual display (hard copies, contrast
      enhancement, color scale, gray scale, and so forth). For each kidney, the
      observers had to choose between the following answers: normal, abnormal,
      equivocal, and lack of quality. RESULTS: Forty-two responses were obtained from a
      wide variety of institutions and from observers with different levels of
      experience in interpreting 99mTc-DMSA scintigraphy. Altogether, the following
      data were obtained: 60.8% normal, 25.2% abnormal, 7.0% equivocal, and 3.2% lack
      of quality. The median percentage of agreement (overall reproducibility) for the
      42 observers was 92%. When the results of all 42 observers were compared, the
      median agreements on normality and abnormality were 93.5% and 90.5%,
      respectively. In a small number (n = 4) of kidneys, reproducibility was poor and
      ranged from 51% to 70%. Except for 2 outliers, all observers had almost the same
      level of performance. CONCLUSION: A large number of Belgian nuclear medicine
      physicians participated in evaluating a large randomly selected sample of 99mTc
      DMSA studies, and excellent interobserver agreement was found.

PMID- 10647602
TI  - Transient prolonged stunning induced by dipyridamole and shown on 1- and 24-hour
      poststress 99mTc-MIBI gated SPECT.
AB  - We investigated whether poststress gated SPECT, which was believed to show
      resting wall motion, revealed stunning induced by dipyridamole stress. METHODS:
      In 62 patients with coronary artery disease (n = 57) or chest pain (n = 5),
      dipyridamole stress gated 99mTc-hexakis-2-methoxyisobutyl isonitrile (MIBI) SPECT
      and rest 201Tl SPECT were performed on the first day; 24-h delayed 201Tl SPECT
      and rest gated 99mTc-MIBI SPECT were performed on the second day. Stress and rest
      gated 99mTc-MIBI SPECT was performed 1 h after injection. The myocardium was
      divided into 17 segments, and perfusion was scored on a 4-point scoring system
      (scores, 0-3 for normal to defect); wall motion during first-day poststress gated
      and second-day rest gated SPECT was also scored on another 4-point scale (scores,
      0-3 for normal to dyskinesia). RESULTS: Thirty-one of 62 patients showed wall
      motion abnormality that was worse after stress than during resting. Three hundred
      eight (29%) of the total 1054 segments showed wall motion abnormality on
      poststress gated SPECT. In 198 of these segments, wall motion abnormality was the
      same on poststress and rest gated SPECT, and 106 segments showed wall motion that
      was worse on 1-h poststress than on rest gated SPECT. Perfusion was normal either
      during rest (n = 113) or after a 24-h delay (n = 18) in 131 segments with the
      poststress wall motion abnormality. Of these 131 segments, 69 showed the same
      wall motion abnormality between poststress and resting periods (persistent
      stunning). However, in 40 segments, abnormal wall motion on 1-h poststress gated
      SPECT normalized on rest gated SPECT (transient prolonged stunning). The other 20
      segments showed improvement of wall motion during rest compared with the
      poststress period but still showed abnormal wall motion during the resting period
      (between transient prolonged stunning and persistent stunning). Stress perfusion
      decrease was more severe in transient prolonged stunning than in persistent
      stunning. Poststress wall motion abnormality was more severe in persistent
      stunning. CONCLUSION: Using gated 99mTc-MIBI SPECT, stunned myocardium was found
      on 1-h poststress SPECT compared with normal resting wall motion found on rest
      gated SPECT on the next day. We conclude that some myocardial walls did not show
      true resting wall motion on 1-h poststress gated SPECT; hence, caution is
      necessary when using wall motion on 1-h poststress gated SPECT to assess resting
      wall motion.

PMID- 10647603
TI  - Imaging serotonin and dopamine transporters with 123I-beta-CIT SPECT: binding
      kinetics and effects of normal aging.
AB  - [123I]beta-carbomethoxy-3-beta-(4-iodophenyl)-tropane (CIT) is a useful ligand
      for dopamine transporters (DATs) and serotonin transporters (5-HTTs). Previous
      SPECT studies have shown a state of sustained equilibrium in the striatum on day
      2 after injection that allows quantification of striatal DATs using a simple
      ratio of specific-to-nondisplaceable binding. The aim of this study was to
      investigate the kinetics of [123I]beta-CIT uptake in the thalamus, hypothalamus,
      and midbrain, areas known to contain 5-HTTs in high densities. METHODS: SPECT
      with a triple-head camera was performed on 16 healthy volunteers (13 women, 3
      men; mean age [+/-SD], 32 +/- 11 y) after intravenous bolus injection of 130 +/-
      20 MBq (3.5 +/- 0.5 mCi) [123I]beta-CIT. Two individuals were scanned 1, 2, 4, 7,
      10, 13, 16, and 24 h after injection, and the remaining 14 were scanned 4, 7, 10,
      20, and 24 h after injection. Values from 19 previously examined healthy
      volunteers (8 women, 11 men; mean age, 52 +/- 20 y) were included in the analysis
      to study the age dependency of beta-CIT binding in striatal and 5-HTT-rich brain
      areas in a larger control sample. RESULTS: Peak uptake 4 h after injection,
      followed by stable uptake until 10 h and a slow decrease until 24 h, was observed
      in the thalamus-hypothalamus region. Activity in the midbrain-pons region peaked
      2 h after injection. Because of a concomitant slow but steady decline of uptake
      in reference regions starting 4 h after injection, a higher stability of binding
      ratios for 5-HTT-rich brain areas was observed on day 2, suggesting that a state
      of transient equilibrium is reached between 20 and 24 h but that conditions are
      only close to transient equilibrium between 4 and 10 h after injection for 5-HTT
      rich brain areas. In addition to an age-related decline of striatal [123I]beta
      CIT binding of 6.6% per decade, a significant age-associated decrease of beta-CIT
      binding of 3-4% per decade was found in 5-HTT-rich brain areas. The decline of
      beta-CIT binding in these regions may be explained, at least in part, by a loss
      of monoamine transporters with age but may also be related to age-associated
      morphologic changes. CONCLUSION: [123I]beta-CIT appears to be a suitable ligand
      for imaging serotonin transporters with SPECT. However, careful age matching is
      warranted for [123I]beta-CIT SPECT studies of 5-HTT changes in patients with
      neuropsychiatric disorders.

PMID- 10647604
TI  - Three brain SPECT region-of-interest templates in elderly people: normative
      values, hemispheric asymmetries, and a comparison of single- and multihead
      cameras.
AB  - The purpose of this study was to generate anatomically guided region-of-interest
      (ROI) brain SPECT templates based on scans of elderly healthy volunteers. We
      describe normal tracer uptake and hemispheric asymmetries for each of 3 camera
      systems and compare these characteristics among systems. METHODS: 99mTc
      hexamethyl propyleneamine oxime SPECT scans were acquired from 28 elderly healthy
      volunteers (mean age [+/-SD], 70.3 +/- 6.5 y) on a single-head rotating gamma
      camera (n = 15) or on dual- (n = 18) or triple-head (n = 13) cameras. The average
      number of counts in each ROI was calculated and referenced to counts in a
      cerebellar ROI, providing semiquantitative regional cerebral blood flow (rCBF)
      ratios. For the templates and ROI map, base images of a healthy volunteer were
      obtained with each camera. Data from individuals scanned with 2 cameras on the
      same day (n = 15) were used to evaluate rCBF differences across cameras. For each
      camera, averaged SPECT templates were made using automated image registration.
      The base volunteer's T1-weighted MR image was converted to stereotactic space
      with dimensions similar to those of the SPECT templates, and 79 bilateral ROIs
      were defined. To obtain ROI rCBF ratios, we aligned individual images to their
      appropriate template and then to this modified MR image. RESULTS: The ROI
      coefficients of variation indicated that the fit of the ROIs was acceptable (0.07
      0.35). Mean rCBF ratios ranged from 0.57 to 1.0, 0.67 to 1.01, and 0.63 to 1.00
      for single-, dual-, and triple-head cameras, respectively. The cuneus, occipital
      cortex, occipital pole, middle temporal gyrus, and posterior middle frontal gyrus
      showed consistent hemispheric asymmetry (right side greater than left side in 83%
      100% of individuals). Mean rCBF ratios did not differ between dual- and triple
      head cameras, whereas the ratios for single- and dual-head cameras differed
      significantly (39 ROIs differed), even after smoothing and filtering the dual
      head images to the level of the single-head images. CONCLUSION: The use of SPECT
      templates based on elderly healthy volunteers is an important feature of this
      technique because most available templates have used young individuals. Another
      important feature is the use of MR image-based ROIs. These procedures are
      versatile because they use more than 1 camera. They can easily be implemented in
      clinical and research settings to detect camera-specific, abnormal deviations in
      rCBF ROI ratios and asymmetry magnitudes in diseases associated with aging, such
      as stroke and dementia.

PMID- 10647605
TI  - Single SPECT measures of cerebral cortical perfusion reflect time-index
      estimation of dementia severity in Alzheimer's disease.
AB  - To determine the relationship between cerebral cortical blood flow loss and the
      temporal development of the dementia in Alzheimer's disease (AD), SPECT was
      studied in a cross section of AD patients with a broad range of impairment.
      METHODS: Thirty patients with a diagnosis of probable AD had their mini-mental
      state examination scores transformed into time-index values to give an estimation
      of dementia severity relative to the developmental time course. SPECT images were
      obtained using 99mTc-ethyl cysteinate dimer and a 3-head camera. Cortical surface
      perfusion was analyzed, including modified Talairach standardization, to obtain
      cortical elements from the convexity (each representing about 0.25 cm2 at the
      surface, 6.6-mm cortical depth) referenced to the mean perfusion of the full
      greater cerebellar hemisphere. These element ratios were analyzed (individually
      and by averages of estimated Brodmann's areas and brain regions) using linear
      regression with the time-index value. RESULTS: For individual posterotemporal and
      inferoparietal Brodmann's areas (21, 22 and 39, 40, respectively) the correlation
      coefficients between cortical perfusion ratios and dementia severity ranged
      between -0.67 and -0.78 (P < 0.001). Perfusion ratios from these regions declined
      2.5%-4.2% for each estimated year of progression. Prefrontal area perfusion
      showed less association with severity. Perfusion in primary cortical regions had
      no significant association with dementia severity. CONCLUSION: Cerebral cortical
      perfusion loss is temporally related to development of dementia. The spatial
      pattern of high, significant correlations between cortical perfusion and dementia
      severity shows a regional distribution that corresponds closely to the
      distribution of AD pathology described in autopsy studies.

PMID- 10647606
TI  - Upregulation of putaminal dopamine D2 receptors in early Parkinson's disease: a
      comparative PET study with [11C] raclopride and [11C]N-methylspiperone.
AB  - Dopamine D2 receptor function was assessed in a PET study with 2 dopamine D2
      receptor PET ligands, [11C]raclopride (RAC) and [11C]N-methylspiperone (NMSP), in
      early Parkinson's disease. METHODS: Seven patients with early Parkinson's disease
      and 5 healthy volunteers were studied. Each underwent PET both with reversible
      [11C]RAC and with irreversible [11C]NMSP. RESULTS: Upregulation of dopamine D2
      receptors in the putamen contralateral to the predominant symptoms of Parkinson's
      disease was confirmed using both [11C]RAC and [11C]NMSP. Uptake of [11C]RAC in
      the contralateral putamen was 105% of uptake in the opposite putamen (P = 0.020).
      For [11C]NMSP, uptake in the contralateral putamen was 105% of uptake in the
      ipsilateral putamen (P = 0.011). No significant differences between Parkinson's
      disease patients and healthy volunteers were detected in any of the studied brain
      regions using either [11C]RAC or [11C]NMSP. No significant differences between
      [11C]RAC and [11C]NMSP uptake were detected in the striatum, whereas in the
      extrastriatal regions, [11C]NMSP showed significantly higher uptake than [11C]RAC
      both in healthy volunteers and in Parkinson's disease patients. CONCLUSION: This
      study confirms an increase in dopamine D2 receptors in the putamen contralateral
      to the predominant symptoms, compared with the ipsilateral putamen, in early
      Parkinson's disease. This increase was seen both with reversible ligand [11C]RAC
      and with irreversible ligand [11C]NMSP and thus does not seem a consequence of
      depleted endogenous dopamine.

PMID- 10647607
TI  - Cardiac sympathetic denervation from the early stage of Parkinson's disease:
      clinical and experimental studies with radiolabeled MIBG.
AB  - Autonomic disorder is not infrequent in patients with akinetic-rigid syndromes,
      including idiopathic Parkinson's disease. In the advanced stage of Parkinson's
      disease, abnormal blood pressure responses, such as orthostatic hypotension and
      abnormal circadian blood pressure rhythm, may occur. Few cases of reduced 123I
      metaiodobenzylguanidine (MIBG) accumulation in the heart or limbs of Parkinson's
      disease patients have been reported. However, whether reduced accumulation is
      caused by damage to the postganglionic sympathetic nervous system or by central
      autonomic failure corresponding to abnormalities in blood pressure regulation is
      unknown. METHODS: We evaluated sympathetic denervation in 32 Parkinson's disease
      patients using 123I-MIBG cardiac scintigraphy and compared the findings with
      those for autonomic dysfunction detected by orthostatic hypotension and diurnal
      blood pressure variation. Cardiac 125I-MIBG accumulation was also determined in
      an experimental model of Parkinson's disease using mice pretreated with 1-methyl
      4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). RESULTS: Cardiac 123I-MIBG
      accumulation 15 min after injection and 4 h after injection was markedly reduced
      in the Parkinson's disease patients (heart-to-mediastinum ratio: 1.58 +/- 0.37
      and 1.33 +/- 0.28, respectively) compared with 7 healthy volunteers (2.42 +/-
      0.27 and 2.60 +/- 0.15, respectively). This reduction was observed even at the
      earlier stages of physical activity or disease duration and also in patients with
      normal blood pressure response and variation, indicating that the marked decrease
      in cardiac 123I-MIBG accumulation may be a special feature of Parkinson's
      disease. Pretreatment with a total dose of 100 mg/kg MPTP, which is the standard
      dose used to destroy the dopaminergic neurons in models of Parkinson's disease,
      significantly reduced cardiac 125I-MIBG accumulation in C57BL/6 mice.
      Interestingly, the reduction of 125I-MIBG accumulation was still significant when
      MPTP was reduced to 5 mg/kg. These findings indicated that the postganglionic
      sympathetic nerves may be damaged by MPTP or unknown toxic substrates in
      experimental or human Parkinson's disease during the early stage, because
      dopaminergic neurons and sympathetic nerves are substantially similar in their
      plasma membrane transporters. CONCLUSION: Cardiac scintigraphy with 123I-MIBG may
      be used as a new imaging approach in the diagnosis and characterization of
      akinetic-rigid syndromes, especially Parkinson's disease.

PMID- 10647608
TI  - Evaluation of FDG uptake by renal malignancies (primary tumor or metastases)
      using a coincidence detection gamma camera.
AB  - The aim of this study was to evaluate the usefulness of FDG scanning using an
      ordinary gamma camera equipped with coincidence detection (CDET) for 2 renal
      cancer indications: characterization and staging of renal masses before
      nephrectomy and search for recurrence after nephrectomy. METHODS: Between
      September 1997 and June 1998, a whole-body scan and at least 1 tomoscintigram
      were obtained on 23 occasions in 22 patients (fasting for at least 6 h) using a
      Prism XP 2000 CDET gamma camera; scanning was begun 45 min after intravenous
      injection of 150-250 MBq FDG. RESULTS: Postoperative histologic evidence was
      obtained from 13 of 16 patients who underwent FDG using a CDET gamma camera
      before renal surgery; 4 renal masses did not accumulate FDG (3 true-negatives, 1
      false-negative), whereas 9 renal tumors accumulated FDG (8 true-positives, 1
      false-positive). In the other 3 patients, only 1 extrarenal site of FDG uptake
      was checked and confirmed on histologic examination: a bone metastasis from renal
      cell carcinoma in 2 cases and lymph node metastasis from a squamous cell
      carcinoma (3 true-positives). The primary local and regional staging of the
      malignant renal tumors was accurate in the 9 patients who underwent nephrectomy
      (8 true-negatives, 1 true-positive). The primary distant staging was positive in
      1 case (focus in the chest corresponding to a probable true-positive on follow
      up). In the 7 examinations performed because of suspected recurrence of renal
      cell carcinoma several months after nephrectomy, metastases were visualized by
      FDG in 4 patients, confirmed by biopsy in 2 patients, and confirmed by
      conventional imaging or follow-up (or both) in 2 patients. The other 3 patients
      had negative FDG scans, corresponding to probable true-negative results on follow
      up. CONCLUSION: FDG using a CDET gamma camera can be used effectively for the
      staging and restaging of renal tumors and might be useful for characterization of
      the primary renal tumor in doubtful cases.

PMID- 10647609
TI  - FDG PET measurement of the proliferative potential of non-small cell lung cancer.
AB  - The goals of this study were to correlate FDG uptake with cell proliferation and
      cellular density in non-small cell lung cancer. METHODS: Thirty-one patients with
      32 non-small cell lung cancers were examined with FDG PET. For semiquantitative
      analysis, standardized uptake values (SUVs) were calculated. All patients
      underwent thoracotomy within 4 wk after the FDG PET study. Cell proliferation was
      immunohistochemically assessed as the relative number of cells expressing the
      proliferating cell nuclear antigen ([PCNA] labeling index). Cellular density was
      also evaluated using light microscopy. RESULTS: SUVs correlated significantly
      with PCNA labeling index (r = 0.740; P < 0.0001) but only weakly with cellular
      density (r = 0.392; P = 0.0266). High FDG uptake correlated with high PCNA
      expression. The PCNA labeling index and SUVs were significantly lower in
      bronchioloalveolar carcinomas (n = 8) (12.3 +/- 9.45% and 1.45 +/- 0.76,
      respectively) than in nonbronchioloalveolar carcinomas (n = 19) (33.5 +/- 21.8%,
      P = 0.015, and 3.75 +/- 1.93, P = 0.003, respectively). However, no significant
      differences in cellular density were seen between bronchioloalveolar carcinomas
      and nonbronchioloalveolar carcinomas. CONCLUSION: FDG uptake is related to cell
      proliferation rather than to the cellular density of non-small cell lung cancer.

PMID- 10647610
TI  - Initial experience with high-dose radioimmunotherapy of metastatic medullary
      thyroid cancer using 131I-MN-14 F(ab)2 anti-carcinoembryonic antigen MAb and
      AHSCR.
AB  - This phase I study was initiated to determine the toxicity and therapeutic
      potential of high-dose 131I-MN-14 F(ab)2 anti-carcinoembryonic antigen monoclonal
      antibody (MAb) combined with autologous hematopoietic stem cell rescue (AHSCR) in
      patients with rapidly progressing metastatic medullary thyroid cancer. METHODS:
      Twelve patients were entered into the study. Dose escalation was based on
      prescribed radiation doses to critical organs (i.e., kidney, lung, and liver).
      Starting doses were 900 cGy to the kidney and no more than 1200 cGy to the lung
      and liver, with dose increments of 300 cGy until the maximum tolerable dose is
      determined. Tumor targeting was assessed by external scintigraphy, toxicity was
      assessed according to the common toxicity criteria of the National Cancer
      Institute, and therapy responses were assessed by CT, serum carcinoembryonic
      antigen, and calcitonin. RESULTS: One patient received 9.95 GBq 131I-MN-14
      F(ab)2, for an initial dose of 656 cGy to critical organs, 8 received 900 cGy
      (8.69-17.98 GBq), and 3 received 1200 cGy (15.17-17.69 GBq). The MAb scans of all
      patients showed positive findings. Autologous hematopoietic stem cells were given
      to all patients 1-2 wk after therapy, when the total body radiation exposure was
      less than 5.2 x 10(-7) C/kg/h. Dose-limiting toxicity, defined as grade 3 or 4
      nonhematologic toxicity, was not seen in the patient who received the 656-cGy
      dose, and only 1 of the 8 patients treated at the 900-cGy dose level had grade 3
      toxicity, which was gastrointestinal and reversible. No dose-limiting toxicity
      was seen in the 3 patients treated at the 1200-cGy dose level. Except for the
      instance of grade 3 gastrointestinal toxicity, nonhematologic toxicity was
      relatively mild, with only grade 1 or 2 toxicity observed in 9 patients. No renal
      toxicity was seen. Of the 12 patients, 1 had partial remission for 1 y, another
      had a minor response for 3 mo, and 10 had stabilization of disease lasting
      between 1 and 16 months. CONCLUSION: The results show the safety of administering
      high myeloablative doses of 131I-MN-14 F(ab)2 with AHSCR in patients with
      metastatic medullary thyroid cancer. The antitumor responses in patients with
      aggressive, rapidly progressing disease are encouraging and warrant further
      research to optimize the effectiveness of this new treatment.

PMID- 10647611
TI  - Tumor-targeted radionuclide therapy: trial design driven by patient dosimetry.

PMID- 10647612
TI  - 99mTc-labeled vasoactive intestinal peptide analog for rapid localization of
      tumors in humans.
AB  - In recent years, imaging tumors with receptor-specific biomolecules has been the
      focus of increasing interest. Vasoactive intestinal peptide (VIP) has a high
      affinity for specific receptors that are expressed in high density on a large
      number of malignant tumors. VIP was modified (TP 3654) without compromising its
      biologic activity and labeled with 99mTc. Pharmacokinetics and feasibility
      studies were performed in 3 healthy volunteers and 11 patients with a history of
      cancer. Imaging was performed for up to 2 h after injection. Within 24 h after
      injection of 99mTc-TP 3654 (370-555 MBq/5 microg), approximately 70% of the
      tracer cleared through the kidneys and 20% through the liver. Blood clearance was
      rapid. No adverse reaction was noted in any subject. All known tumors were
      clearly delineated within 20 min. Findings were compared with the results of
      99mTc-methoxyisobutyl isonitrile, CT, MRI, or histology. There was concordance in
      9 patients. In the other 2 patients, only the VIP scan was positive for tumors
      known to express VIP receptors. The early results of imaging tumors with 99mTc
      VIP are promising and warrant further study.

PMID- 10647613
TI  - Java-based remote viewing and processing of nuclear medicine images: toward "the
      imaging department without walls".
AB  - In nuclear medicine practice, images often need to be reviewed and reports
      prepared from locations outside the department, usually in the form of hard copy.
      Although hard-copy images are simple and portable, they do not offer electronic
      data search and image manipulation capabilities. On the other hand, picture
      archiving and communication systems or dedicated workstations cannot be easily
      deployed at numerous locations. To solve this problem, we propose a Java-based
      remote viewing station (JaRViS) for the reading and reporting of nuclear medicine
      images using Internet browser technology. METHODS: JaRViS interfaces to the
      clinical patient database of a nuclear medicine workstation. All JaRViS software
      resides on a nuclear medicine department server. The contents of the clinical
      database can be searched by a browser interface after providing a password.
      Compressed images with the Java applet and color lookup tables are downloaded on
      the client side. This paradigm does not require nuclear medicine software to
      reside on remote computers, which simplifies support and deployment of such a
      system. To enable versatile reporting of the images, color tables and thresholds
      can be interactively manipulated and images can be displayed in a variety of
      layouts. Image filtering, frame grouping (adding frames), and movie display are
      available. Tomographic mode displays are supported, including gated SPECT.
      RESULTS: The time to display 14 lung perfusion images in 128 x 128 matrix
      together with the Java applet and color lookup tables over a V.90 modem is <1
      min. SPECT and PET slice reorientation is interactive (<1 s). JaRViS could run on
      a Windows 95/98/NT or a Macintosh platform with Netscape Communicator or
      Microsoft Intemet Explorer. The performance of Java code for bilinear
      interpolation, cine display, and filtering approaches that of a standard imaging
      workstation. CONCLUSION: It is feasible to set up a remote nuclear medicine
      viewing station using Java and an Internet or intranet browser. Images can be
      made easily and cost-effectively available to referring physicians and ambulatory
      clinics within and outside of the hospital, providing a convenient alternative to
      film media. We also find this system useful in home reporting of emergency
      procedures such as lung ventilation-perfusion scans or dynamic studies.

PMID- 10647614
TI  - Java and teleradiology.

PMID- 10647615
TI  - Characterization of scatter and penetration using Monte Carlo simulation in 131I
      imaging.
AB  - In 131I SPECT, image quality and quantification accuracy are degraded by object
      scatter as well as scatter and penetration in the collimator. The
      characterization of energy and spatial distributions of scatter and penetration
      performed in this study by Monte Carlo simulation will be useful for the
      development and evaluation of techniques that compensate for such events in 131I
      imaging. METHODS: First, to test the accuracy of the Monte Carlo model, simulated
      and measured data were compared for both a point source and a phantom. Next,
      simulations to investigate scatter and penetration were performed for four
      geometries: point source in air, point source in a water-filled cylinder, hot
      sphere in a cylinder filled with nonradioactive water, and hot sphere in a
      cylinder filled with radioactive water. Energy spectra were separated according
      to order of scatter, type of interaction, and gamma-ray emission energy. A
      preliminary evaluation of the triple-energy window (TEW) scatter correction
      method was performed. RESULTS: The accuracy of the Monte Carlo model was verified
      by the good agreement between measured and simulated energy spectra and radial
      point spread functions. For a point source in air, simulations show that 73% of
      events in the photopeak window had either scattered in or penetrated the
      collimator, indicating the significance of collimator interactions. For a point
      source in a water-filled phantom, the separated energy spectra showed that a 20%
      photopeak window can be used to eliminate events that scatter more than two times
      in the phantom. For the hot sphere phantoms, it was shown that in the photopeak
      region the spectrum shape of penetration events is very similar to that of
      primary (no scatter and no penetration) events. For the hot sphere regions of
      interest, the percentage difference between true scatter counts and the TEW
      estimate of scatter counts was <12%. CONCLUSION: In 131I SPECT, object scatter as
      well as collimator scatter and penetration are significant. The TEW method
      provides a reasonable correction for scatter, but the similarity between the 364
      keV primary and penetration energy spectra makes it difficult to compensate for
      these penetration events using techniques that are based on spectral analysis.

PMID- 10647616
TI  - Clinical optimization of pretargeted radioimmunotherapy with antibody
      streptavidin conjugate and 90Y-DOTA-biotin.
AB  - Pretargeted radioimmunotherapy (PRIT) was evaluated using an antibody
      streptavidin conjugate, followed by a biotin-galactose-human serum albumin
      clearing agent and 90Y-dodecane tetraacetic acid (DOTA)-biotin as the final step
      for therapy. The objective was to develop a clinical protocol that could show an
      improved tumor-to-red marrow therapeutic ratio compared with conventional
      radioimmunotherapy (RIT) and at the same time preserve the efficiency of tumor
      targeting. METHOD: Forty-three patients with adenocarcinomas reactive to NR-LU-10
      murine monoclonal antibody received the 3 components. Doses and timing parameters
      were varied to develop an optimized schema. In some patients, the conjugate was
      radiolabeled with 186Re as an imaging tracer to assess biodistribution of the
      conjugate and effectiveness of the clearing agent. 111In-DOTA-biotin was
      coinjected with 90Y-DOTA-biotin for quantitative imaging. Safety,
      biodistribution, pharmacokinetics, dosimetry, and antiglobulin formation were
      evaluated. RESULTS: The optimal schema was defined as a conjugate dose of 125
      microg/mL plasma volume followed at 48 h by a clearing agent in a 10:1 molar
      ratio of clearing agent to serum conjugate. The therapeutic third step was 0.5 mg
      radiobiotin administered 24 h later. No significant adverse events were observed
      after administration of any of the components. The mean tumor-to-marrow absorbed
      dose ratio when using the optimized PRIT schema was 63:1, compared with a 6:1
      ratio reported previously for conventional RIT. Antiglobulin to murine antibody
      and to streptavidin developed in most patients. CONCLUSION: This initial study
      confirmed that the PRIT approach is safe and feasible and achieved a higher
      therapeutic ratio than that achieved with conventional RIT using the same
      antibody.

PMID- 10647617
TI  - Biodistribution, dosimetry, and safety of myocardial perfusion imaging agent
      99mTcN-NOET in healthy volunteers.
AB  - 99mTcN-NOET (bis[N-ethoxy,N-ethyl]dithiocarbamato nitrido technetium (V)) has
      been proposed for myocardial perfusion imaging. Biodistribution, safety, and
      dosimetry were studied in 10 healthy volunteers (5 at rest and 5 during
      exercise). METHODS: Biodistribution was studied by acquiring dynamic images up to
      60 min after injection and whole-body images up to 24 h after injection. The
      MIRDOSE3 analysis program was used for radiation dosimetry calculations. RESULTS:
      Safety parameters measured to 48 h after injection revealed no clinically
      significant changes. Cardiac uptake of 99mTcN-NOET was high (2.9%-3%), with
      biologic half-life of 210-257 min on average. Lung uptake of 99mTcN-NOET was
      higher (10%-20%) but, on average, biologic half-life was shorter (1-77 min).
      Clearance from the blood was rapid (5% by 5 min). Radiation dosimetry
      calculations indicated an effective absorbed dose of 5.11 x 10(-3) mSv/MBq at
      rest and 5.38 x 10(-3) mSv/MBq after exercise. CONCLUSION: 99mTcN-NOET exhibits
      high cardiac uptake and an estimated effective absorbed dose comparable with that
      of the other 99mTc-labeled compounds used in myocardial perfusion imaging.

PMID- 10647618
TI  - Re-evaluation of absorbed fractions for photons and electrons in spheres of
      various sizes.
AB  - Absorbed fractions for unit density spheres in an infinite unit density medium,
      previously calculated for photon emitters and electron emitters, were reevaluated
      with the Monte Carlo codes EGS4 and MCNP4B. METHODS: Activity was assumed to be
      distributed uniformly throughout the spheres, and absorbed fractions for self
      irradiation were calculated at discrete photon and electron energies. RESULTS:
      For electrons, the codes were in very good agreement with each other (+/-5%) and
      with published values, except at higher energies in the very smallest spheres,
      where some differences exceeded 10%. For photons, the codes were again in good
      agreement with each other but produced results that varied considerably from
      published MIRD values. For energies <1 MeV and sphere sizes <50 g, the absorbed
      fractions determined using the Monte Carlo codes were typically 20%-40% higher
      than values in MIRD 3 and 8. For energies >1 MeV, the Monte Carlo values were
      sometimes lower than those in the MIRD documents. Recommended values, generally
      the average results from the 2 Monte Carlo codes, are given for all sphere sizes
      and energies for both electrons and photons. CONCLUSION: The absorbed fractions
      calculated using the Monte Carlo codes should replace the older values and are
      helpful in evaluating tumor doses, doses to small organs, and other situations in
      which a uniform distribution of activity throughout a spherical structure of unit
      density can be assumed.

PMID- 10647619
TI  - Imaging vascular thrombosis with 99mTc-labeled fibrin alpha-chain peptide.
AB  - An agent that permits scintigraphic detection of chronic deep venous thrombosis
      (DVT) or pulmonary embolism (PE) would be a welcome addition to the armamentarium
      of nuclear medicine. Because fibrin is the integral part of each clot, old or
      fresh, we hypothesized that a 99mTc-labeled fibrin alpha-chain N-terminal
      peptide, Gly-Pro-Arg-Pro-Pro, that binds to the C-terminal portion of the gamma
      chain of fibrin can detect DVT and PE. METHODS: The peptide was modified to Gly
      Pro-Arg-Pro-Pro-Aba-Gly-Gly-(D)-Ala-Gly to permit efficient binding of 99mTc
      (99mTc-TP 850). The stability of the peptide was examined in vitro as well as in
      vivo. The ability of the agent to bind to rabbit, dog, and human fibrin and to
      inhibit adenosine diphosphate-induced platelet aggregation was examined. Blood
      clearance and 3-h tissue distribution were studied. DVT was induced in 8 rabbits
      using a stimulating electrode and in 2 rabbits by inserting a thrombin-soaked
      suture. PE was induced in 6 additional rabbits by introducing tantalum
      impregnated blood clots into the right atrium, and the rabbits were radiographed
      to locate the emboli. 99mTc-TP 850 was then injected through a lateral ear vein,
      and each rabbit was imaged for up to 3 h. The rabbits were then killed, the heart
      and lungs were dissected and radiographed and the clots were harvested so that
      clot-to-blood radioactivity ratios could be determined. RESULTS: The peptide
      analog permitted efficient incorporation of 99mTc, which was stable in vitro and
      in vivo. The blood clearance was biphasic, with an alpha phase half-life of
      approximately 4 min (20%) and a beta phase half-life of approximately 13 min
      (88%). The mean binding of 99mTc-TP 850 to human, dog, and rabbit fibrin was 46%
      +/- 2%, 60% +/- 3%, and 56% +/- 2.5%, respectively, and the inhibitory
      concentration of 50% for dog and rabbit platelet aggregation was 236 pm and 167
      pm, respectively. All clots, including 24-h-old pulmonary emboli, were
      delineated. The radioactivity associated with clots varied from 0.01 to 0.09
      %ID/g, with clot-to-blood radioactivity ratios ranging from 1.2 to 12.0. However,
      48-h-old pulmonary emboli had lysed and were seen neither by radiography nor by
      scintigraphy. CONCLUSION: A fibrin alpha-chain, N-terminal peptide that binds to
      the C-terminal portion of the gamma-chain of fibrin has been modified and labeled
      with 99mTc. The resultant peptide is stable in vitro and in vivo; binds to human,
      dog, and rabbit fibrin in large quantities; and inhibits platelet aggregation.
      The peptide clears rapidly from the blood and delineates experimental DVT and PE
      in rabbits. This agent is worthy of further investigation.

PMID- 10647620
TI  - BRU59-21, a second-generation 99mTc-labeled 2-nitroimidazole for imaging hypoxia
      in tumors.
AB  - Hypoxia in tumors is believed to be an important cause of local failure of
      radiotherapy in certain types of cancer. BRU59-21 (BMS194796) is a second
      generation 99mTc-labeled 2-nitroimidazole that has been shown to offer improved
      characteristics for imaging myocardial ischemia. It has now been evaluated in
      models of tumor hypoxia. METHODS: Accumulation of BRU59-21 was compared with that
      of BMS181321 in Chinese hamster ovary cells incubated under aerobic or hypoxic
      conditions. The effects of competition with unlabeled nitroimidazoles and oxygen
      were studied. Biodistribution studies were performed in mice bearing transplanted
      KHT-C tumors in the leg. RESULTS: Within 5 min, BRU59-21 partitioned into aerobic
      cells in vitro at a level 10 times higher than external medium with no further
      increase over time. In hypoxic cells this initial partitioning was followed by
      selective accumulation to levels 5 times higher than in aerobic cells by 4 h. Low
      levels of oxygen (approximately 40 ppm) inhibited the maximal accumulation rate
      by 50%. Unlabeled misonidazole, a 2-nitroimidazole, inhibited accumulation of
      radioactivity, whereas tinidazole, a 5-nitroimidazole, enhanced accumulation;
      similar effects had been reported with BMS181321. Biodistribution studies in mice
      showed rapid clearance of radioactivity from the blood, resulting in enhanced
      tumor-to-blood ratios compared with BMS181321. Increasing the hypoxic fraction in
      the tumor by injection of nitro-L-arginine resulted in increased retention of
      tracer in the tumor without affecting other tissues. CONCLUSION: These results
      suggest that BRU59-21 warrants further investigation as an agent for imaging
      tumor hypoxia in the clinic.

PMID- 10647621
TI  - Pharmacokinetics and renal handling of 99mTc-labeled peptides.
AB  - 99mTc-labeled peptides, particularly those of a lipophilic nature, are often
      excreted through the hepatobiliary system, and the subsequent accumulation in the
      intestine may obscure receptor-mediated uptake in tumor sites in the pelvis. We
      have therefore explored the route and rate of excretion of a small series of Tc
      labeled peptides to shed some light on the mechanisms that influence the
      clearance of these agents. METHODS: Pharmacokinetic parameters, biodistribution,
      routes of elimination of 99mTc-complexes of 3 model tetrapeptides--namely, acetyl
      N-Gly-Gly-Cys-Gly (AGGCG), acetyl-N-Ser-Ser-Cys-Gly (ASSCG), and acetyl-N-Gly-Gly
      Cys-Lys (AGGCL)--were determined in rats in vivo. Renal handling of the complexes
      was studied in the perfused rat kidney. RESULTS: After intravenous injection, a
      relatively fast disappearance of the complexes from blood was found. Although the
      parameters of distribution in all 3 chelates were very similar, the elimination
      rate of 99mTc-AGGCG was higher than those of 99mTc-ASSCG and 99mTc-AGGCL. The Tc
      complexes under study were distributed mainly to the excretory organs (kidneys
      and liver), and no specific accumulation in other organs or tissues was found.
      Most of the radioactivity after intravenous administration of the chelates was
      rapidly eliminated through the urine, but a significant amount was also excreted
      through the feces, in the following order among the 3 chelates: 99mTc-AGGCL <
      99mTc-ASSCG < 99mTc-AGGCG. Different proportions of glomerular filtration and
      secretion in renal tubules of the complexes were found in the perfused rat
      kidney. Elimination by glomerular filtration was dominant only in the case of
      99mTc-AGGCL, whereas the rate of filtration of 99mTc-AGGCG was very low because
      of its high protein binding. Various rates of secretion into renal tubules were
      shown for all 3 agents. This renal excretion pathway was decisive in 99mTc-AGGCG
      and lowest in 99mTc-AGGCL. 99mTc-ASSCG was eliminated by both mechanisms at
      similar rates. CONCLUSION: These studies show that increasing the hydrophilic
      nature or reducing the negative charge of the peptides will reduce their
      hepatobiliary excretion, whereas the incorporation of suitable peptide sequences
      permits them to exploit efficient routes of renal excretion, such as tubular
      secretion, thereby optimizing the pattern of biodistribution of these
      radiopharmaceuticals.

PMID- 10647622
TI  - Biologic mechanisms of 89SrCl2 incorporation into type I collagen during bone
      mineralization.
AB  - 89SrCl2 is currently used as a palliative treatment for painful osseous
      metastases associated with an osteoblastic reaction in bone. However, the
      underlying biologic mechanism by which 89SrCl2 accumulates at these lesions and
      mediates palliation remains unclear. The aim of this study was therefore to
      elucidate this mechanism. METHODS: An in vitro cell biologic model, incorporating
      the MC3T3-E1 murine osteoblast cell line, was established to replicate the
      process of collagen production and mineralization. Experiments were performed to
      investigate the cellular association of 89SrCl2 and 45CaCl2 with both MC3T3-E1
      cells and the PC-3 human prostate adenocarcinoma cell line. RESULTS: No evidence
      of intracellular localization of 89SrCl2 or 45CaCl2 was found for either cell
      line. Localization of radiolabel was seen to be associated with MC3T3-E1 cells
      but only in cultures that had undergone both differentiation and mineralization.
      The association of 89SrCl2 was inhibited by the alkaline phosphatase inhibitor
      levamisole, and extracellular localization of 89SrCl2 was confirmed by
      microautoradiography. CONCLUSION: 89SrCl2 acts as a calcium mimic and, as such,
      becomes associated with the collagen matrix produced by the MC3T3-E1 cells during
      collagen mineralization.

PMID- 10647623
TI  - S values for radionuclides localized within the skeleton.
AB  - Calculations of radiation absorbed dose to the active marrow are important to
      radionuclide therapies such as radioimmunotherapy and bone pain palliation. In
      diagnostic nuclear medicine, calculations of the effective dose for
      radiopharmaceutical procedures also require the assessment of radiation dose to
      the skeletal endosteum. We have previously reported the development of 2 3
      dimensional electron transport models for assessing absorbed fractions to both
      marrow and endosteum in trabecular and cortical bone, respectively. Here, we
      extend these calculations to the assignment of radionuclide S values. METHODS:
      Data published in International Commission on Radiological Protection Publication
      70 were used to develop tables of masses for total marrow space, active and
      inactive marrow, endosteum, and bone matrix within 22 skeletal sites in the
      adult. Using our site-specific tissue masses, along with electron absorbed
      fractions given by our 3-dimensional transport models, radionuclide S values
      (electron and beta particle components only) were subsequently calculated using
      the MIRD schema for 32P, 33P, 89Sr, 90Sr, 90Y, 117mSn, 153Sm, 169Er, 177Lu, and
      186Re. Specific consideration was given to the trabecular active marrow as both a
      source and a target region. RESULTS: Site-specific radionuclide S values are
      reported for 22 skeletal sites, for 9 source-target tissue combinations within
      trabecular bone, and for 6 source-target tissue combinations within cortical
      bone. Skeletal-averaged S values are also provided. CONCLUSION: A fully
      documented model is presented for the adult for use in radionuclide dosimetry of
      the skeleton. The model is based on both the latest international recommendations
      for skeletal tissue masses and results from three-dimensional electron transport
      calculations within the skeleton. Comparisons are additionally made against the
      radionuclide S values published in MIRD Pamphlet No. 11 and those calculated
      using the MIRDOSE2 and MIRDOSE3 computer codes. Differences in these datasets
      vary with the source-target combination considered and may be attributed to 1 of
      3 causes: (a) assumptions on reference target masses, (b) transport models used
      to assign absorbed fractions, and (c) implicit assumptions made in considering
      the trabecular active marrow as both a source and a target tissue.

PMID- 10647624
TI  - Effect of methodology on mismatch.

PMID- 10647625
TI  - Clinical research in gastrointestinal surgery and in gastroenterology: where are
      the obstacles?

PMID- 10647626
TI  - Hereditary colorectal cancer: clinical consequences of predictive molecular
      testing.
AB  - The continuing increase in knowledge about the genetic basis of carcinogenesis
      has led to diverse efforts to exploit this knowledge clinically, primarily in the
      form of predictive genetic testing. In conjunction with family history, gene
      tests are intended to improve individual cancer risk assessment. The objectives
      of predictive molecular testing are to identify the disease-causing germline
      mutation in an index person who has already developed the disease and to
      distinguish asymptomatic mutation carriers from non-mutation carriers within a
      given cancer-prone family. At present, genetic testing for colorectal cancer
      risk, primarily in form of DNA sequencing, is applied in familial adenomatous
      polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC). In these
      inherited colorectal tumor syndromes determining the genetic status may result in
      an individually tailored surveillance program and prophylactic treatment. The
      implications of genetic testing for the clinical management of disease, both of
      mutation and non-mutation carriers, in familial adenomatous polyposis and
      hereditary nonpolyposis colorectal cancer families are discussed.

PMID- 10647627
TI  - Towards a molecular classification of colorectal cancer.
AB  - The basic mechanisms driving genetic instability underlie a new molecular
      classification of colorectal cancer that is assuming diagnostic and prognostic
      importance. These mechanisms and the criteria for stratifying colorectal cancer
      as microsatellite stable (MSS), microsatellite instability-low (MSI-L) and
      microsatellite instability-high (MSI-H) are presented. This molecular
      classification is discussed in relation to morphogenesis, histopathology,
      behaviour and investigation of prognostic biomarkers in colorectal cancer.
      Clinical applications are considered, emphasising the role of the pathologist in
      identifying and working up cases of suspected hereditary non-polyposis colorectal
      cancer. The principal value of microsatellite instability testing is in relation
      to the diagnosis of hereditary non-polyposis colorectal cancer. Demonstration of
      loss of DNA mismatch repair genes, notably hMLH1 and hMSH2, by
      immunohistochemistry provides additional diagnostic information and may reduce
      the requirement for microsatellite instability testing. It is likely that testing
      for DNA mismatch repair will be adopted as a routine for colorectal cancer as
      more is learned of the distinctive pathobiology and behaviour of MSS, MSI-L and
      MSI-H cancers.

PMID- 10647628
TI  - Dietary resistant starch and chronic inflammatory bowel diseases.
AB  - These studies were performed to test the benefit of resistant starch on
      ulcerative colitis via prebiotic and butyrate effects. Butyrate, propionate, and
      acetate are produced in the colon of mammals as a result of microbial
      fermentation of resistant starch and other dietary fibers. Butyrate plays an
      important role in the colonic mucosal growth and epithelial proliferation. A
      reduction in the colonic butyrate level induces chronic mucosal atrophy. Short
      chain fatty acid enemas increase mucosal generation, crypt length, and DNA
      content of the colonocytes. They also ameliorate symptoms of ulcerative colitis
      in human patients and rats injected with trinitrobenzene sulfonic acid (TNBS).
      Butyrate, and also to a lesser degree propionate, are substrates for the aerobic
      energy metabolism, and trophic factors of the colonocytes. Adverse butyrate
      effects occur in normal and neoplastic colonic cells. In normal cells, butyrate
      induces proliferation at the crypt base, while inhibiting proliferation at the
      crypt surface. In neoplastic cells, butyrate inhibits DNA synthesis and arrests
      cell growth in the G1 phase of the cell cycle. The improvement of the TNBS
      induced colonic inflammation occurred earlier in the resistant starch (RS)-fed
      rats than in the RS-free group. This benefit coincided with activation of colonic
      epithelial cell proliferation and the subsequent restoration of apoptosis. The
      noncollagenous basement membrane protein laminin was regenerated initially in the
      RS-fed group, demonstrating what could be a considered lower damage to the
      intestinal barrier function. The calculation of intestinal short-chain fatty acid
      absorption confirmed this conclusion. The uptake of short-chain fatty acids in
      the colon is strongly inhibited in the RS-free group, but only slightly reduced
      in the animals fed with RS. Additionally, RS enhanced the growth of intestinal
      bacteria assumed to promote health. Further studies involving patients suffering
      from ulcerative colitis are necessary to determine the importance of RS in the
      therapy of a number of intestinal diseases and the maintenance of health.

PMID- 10647629
TI  - Cellular localization of cyclo-oxygenase isozymes in Crohn's disease and
      colorectal cancer.
AB  - Deregulation of cyclo-oxygenase isozyme expression has been shown to be a
      consistent feature of inflammatory bowel diseases and colorectal cancer in
      humans. This study investigated the cellular localization of aberrant cyclo
      oxygenase expression in normal and diseased colon. Biopsies of seven normal
      colonic tissues, eight tissue samples from patients suffering from Crohn's
      disease, five polyps from patients with familiar adenomatous polyposis coli, and
      ten sporadic adenocarcinomas were analyzed using isozyme-selective
      immunoprecipitation, western blotting, and immunohistochemistry. Cyclo-oxygenase
      1 expression was demonstrated in normal human colon, Crohn's disease, and
      colorectal tumors. In normal colon and also in adenomatous polyps, cyclo
      oxygenase-1 specific immunosignals were localized to epithelial cells of the
      upper part of the crypts and endocrine cells of the lower part. In Crohn's
      disease cyclo-oxygenase-1 expression was restricted to cells of the inflammatory
      infiltrate. While barely detectable in normal colon, cyclo-oxygenase-2 protein
      was strongly increased in epithelial cells located in the uppermost part of the
      crypts, in surface epithelial cells, and in mononuclear cells of the lamina
      propria of Crohn's disease. The constitutive overexpression of cyclo-oxygenase-2
      protein observed in the majority of the adenomatous polyps and all
      adenocarcinomas was attributed to both epithelial and interstitial cells in that
      the latter predominated in adenomas, and epithelial cells were the prevailing
      cyclo-oxygenase-2 expressing cell type in adenocarcinomas. In conclusion, both
      autocrine and paracrine effects of aberrant cyclooxygenase-2 expression may
      contribute to the development of Crohn's disease and colonic tumor development.

PMID- 10647630
TI  - Effect of anti-CD11b (alphaM-MAC-1) and anti-CD54 (ICAM-1) monoclonal antibodies
      on indomethacin induced chronic ileitis in rats.
AB  - Leukocyte emigration from blood to sites of inflammation involves sequential
      interaction of specific adhesion molecules expressed by both leukocytes and
      endothelial cells. The central steps in leukocyte-endothelial adhesive
      interactions are leukocyte rolling, sticking, and transmigration. This study
      investigated the effect of monoclonal antibodies against CD54 (ICAM-1) and CD11b
      (alphaM-chain of MAC-1) on intestinal inflammation. Anti-CD54 and anti-CD11b were
      tested in rats with indomethacin-induced chronic ileitis. Macroscopic changes
      were assessed by a modified version of the Wallace et al. score. Leukocyte
      rolling and sticking were investigated by intravital microscopy. Results show
      that indomethacin administration led to a chronic inflammatory response
      characterized by significant increase (P<0.05) in rolling (from 5.41+/-2.87 to
      32.41+/-15.03 100 microm(-1) s(-1)) and sticking (from 0.16+/-0.18 to 9.11+/-5.3
      100 microm(-1) s(-1)) leukocytes. After antibody treatment only the anti-CD11b
      group showed significant (P<0.05) reduction in rolling (from 32.41+/-15.03 to
      6.6+/-2.7 100 microm(-1) s-1) and sticking (from 9.11+/-5.3 to 0.07+/-0.09 100
      microm(-1) s-1) leukocytes. This was also the case for macroscopic changes.
      Indomethacin led to a rise in the Wallace score from 0 to 4.29+/-0.76 points
      (P<0.05) and anti-CD11b to a reduction from 4.29+/-0.76 to 1.29+/-1.11 points
      (P<0.05). Anti-CD54 and combined anti-CD11b/CD54 administration was not followed
      by significant changes. Therefore we suggest that leukocyte-based CD11b but not
      endothelial-based CD54 contributes most to leukocyte adhesion in the setting of
      indomethacin-induced ileitis in rats.

PMID- 10647631
TI  - Operative and environmental risk factors for recurrence of Crohn's disease.
AB  - This retrospective study determined whether a hand-sewn or stapled anastomosis
      leads to a greater recurrence rate in patients undergoing ileocecal resection for
      terminal ileal Crohn's disease. The effects of oral contraceptive use, smoking,
      and age at onset of disease were also examined. Ninety-two patients with Crohn's
      disease of the terminal ileum whose first operation was an ileocecal resection
      (terminal ileum and right colon up to but not including the hepatic flexure) were
      studied for symptomatic and operative recurrence. The symptomatic recurrence
      rates were 15% at 1 year, 31% at 2 years, and 45% at 3 years. The operative
      recurrence rates were 6% at 1 year, 14% at 2 years, and 22% at 3 years. The type
      of anastomosis, whether hand-sewn or stapled, did not affect the rates of
      symptomatic (P = 0.3) or operative (P = 0.6) recurrence. After the initial
      resection smoking affected both symptomatic (P = 0.03, risk ratio = 2.380) and
      operative (P = 0.041, risk ratio = 3.13) recurrence, but there was no effect of
      age at onset of disease or use of the birth control pill.

PMID- 10647632
TI  - Causes of arterial hypertension and splachnic ischemia during acute elevations in
      intra-abdominal pressure with CO2 pneumoperitoneum: a complex central nervous
      system mediated response.
AB  - The application of laparoscopic technique has gained popularity in the past
      decade. Numerous studies have qualified and quantified the systemic impact of
      acutely elevated intra-abdominal pressure during pneumoperitoneum at time of
      laparoscopy. The major hemodynamic effects are increased central venous pressure,
      increased systemic vascular resistance and systemic hypertension. Reductions in
      splanchnic and renal blood flow have also been documented, but the clinical
      significance of these observations is not clear and required further
      investigation. In our previous work we demonstrated intracranial hypertension
      secondary to acute elevation in intra-abdominal pressure and described the
      pathophysiology. Elevated intra-abdominal pressure during induced
      pneumoperitomeum can serve as a basic model for other disease processes which are
      characterized by acute or chronic abdominal hypertension. Here we review the
      current literature and describe our own experience to suggest a unifying model,
      with emphasis on the key role of the central nervous system in mediating the
      systemic response to increased intra-abdominal pressure.

PMID- 10647633
TI  - Rectosigmoid junction: anatomical, histological, and radiological studies with
      special reference to a sphincteric function.
AB  - The existence of a sphincter at the rectosigmoid junction (RSJ) is controversial.
      Recent studies have demonstrated a high-pressure zone within the RSJ which
      responds to sigmoid colon or rectal contractions by relaxation or contraction,
      respectively. These findings suggest the presence of a "physiological" sphincter
      at the RSJ. The current study investigated the anatomical and histological
      structure and the radiological picture of the RSJ in view of the possible
      existence of an anatomical sphincter at the RSJ and elucidating its function. The
      RSJ was studied in 28 cadavers (18 adults and 10 fully mature neonates) by
      dissection. A histological study of the RSJ was performed in 5 cadavers.
      Radiological examination using double-contrast barium enema was carried out in 50
      healthy volunteers (mean age 44.2+/-14.4 years; 32 men, 18 women). The mucous
      membrane of the RSJ was found in folds forming a "mucosal rosette" of a mean
      length of 2.8+/-0.9 cm in adult specimens and 0.7+/-0.2 cm in neonates. The
      distal end of the mucosal rosette was sharply delineated and in some specimens
      protruded into the rectal lumen as a small nipple, which was surrounded by a
      "rectal fornix" on either side. The histological examination of the RSJ showed
      mucosal foldings with deep crypts surrounded by lymphocytic aggregates and
      marginated by muscularis mucosa. The circular muscle coat showed gradually
      increasing thickness towards the rectum. Nerve cells in the submucosa were
      located at three levels: in the vicinity of the muscularis mucosa, in the middle
      of the submucosa, and in the proximity of the circular muscle. Radiologically the
      opening of the sigmoid colon into the RSJ presented as a ring or crescent.
      Radiological striations representing the mucosal rosette were demonstrated. The
      RSJ appeared as a narrow contractile segment. The anatomical, histological, and
      radiological findings thus indicate that the RSJ is a segment which can be
      identified by its interior rather than outer aspect. The study suggests the
      presence of an anatomical sphincter at the RSJ which seems to regulate the
      passage of stools from the sigmoid colon to the rectum.

PMID- 10647634
TI  - A new grading of rectal internal mucosal prolapse and its correlation with
      diagnosis and treatment.
AB  - The management of rectal internal mucosal prolapse (RIMP) is not based on an
      accepted classification of the lesion which helps to choose the appropriate
      treatment. The aim of this prospective study was to report a new endoscopic
      grading of RIMP and to evaluate its clinical value. Thirty-two patients (7 men,
      25 women; mean age 56 years, range 28-72) affected by symptomatic RIMP were
      prospectively classified as follows: RIMP was defined as first degree when
      detectable below the anorectal ring on straining, as second degree when it
      reached the dentate line, and as third degree when it reached the anal verge.
      Anal manometry was carried out in 26 patients, and anal ultrasound and
      defecography in 6 prior to surgery. A correlation was found between the
      occurrence and severity of symptoms and the degree of the prolapse as obstructed
      defecation, bleeding and fecal soiling affected mainly patients with third-degree
      RIMP. At manometry the maximal resting tone was 60+/-23 mm Hg and voluntary
      contraction 96+/-41 mm Hg (mean+/-SEM). At anal ultrasound the mean internal
      sphincter thickness was 2.1+/-0.2 mm, and external sphincter thickness was 7.0+/
      0.8 mm. A significant rectocele and rectal intussusception (n = 2) and a
      nonrelaxing puborectalis muscle on straining (n = 2) were observed at
      defecography in cases with third-degree RIMP. The anorectal angle was 100+/-75
      degrees at rest, 63+/-20 degrees on squeezing, and 115+/-9 degrees on straining.
      A conservative treatment with high-fiber diet and/or rubber band ligation was
      carried out in all cases of first and in most patients with second-degree RIMP (n
      = 26). Those who required surgery, i.e., stapled transanal excision of the
      prolapse (n = 6), had either severely symptomatic third-degree RIMP with solitary
      ulcer syndrome (n = 4) or second-degree RIMP (n = 2). A positive outcome was
      achieved in 71% of cases. The proposed classification evaluated by the present
      study may be of clinical value in managing rectal internal mucosal prolapse.

PMID- 10647635
TI  - Diverticulitis: the effect of age and location on the course of disease.
AB  - To examine the effect of patient's age and the location of diverticular disease
      on the course of the acute disease we retrospectively collected demographic data,
      symptoms, laboratory findings, imaging techniques, type of treatment
      (conservative vs. surgical), early and late complications, and follow-up data on
      119 patients with acute diverticulitis (74 women, 45 men; mean age 64+/-14 years;
      follow-up 7-102 months, median 40). Patients were divided by their age into two
      groups (42 aged 60 years or younger, 77 aged over 60) and on the location of
      their disease (108 to the left of the middle transverse, 11 to the right). Lower
      abdominal pain, abdominal tenderness, and fever were the most common complaints
      (70-97%). In the younger patients we found a significantly greater preponderance
      in the right colon (P = 0.02) than in older patients. Abdominal abscesses and
      fistulas were more common in right-sided diverticulitis (P = 0.01). Patients with
      right-sided colon diverticulitis were treated surgically (82%) and on an
      emergency basis more often than patients with left-side colon diverticulitis
      (25%; P = 0.001). Older patients treated conservatively suffered more than
      younger patients (61% and 33% respectively; P = 0.04) from recurrent abdominal
      pain but not from recurrent, confirmed diverticulitis. Patients with right-sided
      diverticulitis treated conservatively suffered more from recurrent diverticulitis
      episodes than patients with left-sided diverticulitis (P = 0.05). Younger
      patients thus do not have a more aggressive form of diverticulitis than older
      patients. Patients with acute diverticulitis in the right colon are likely to be
      operated earlier and for mistaken diagnoses than patients with left-sided
      diverticulitis.

PMID- 10647636
TI  - Gains and losses with stapling and omission of loop ileostomy in pelvic pouch
      surgery: a matched control study.
AB  - After 10 years experience of pelvic pouch surgery with handsewn pouch and
      ileoanal anastomosis, mucosectomy, and covering loop ileostomy, the surgical
      technique was altered. Twenty patients were operated on with staple technique in
      pouch and ileoanal anastomosis but without mucosal proctectomy and loop
      ileostomy. This study group was compared with a matched control group of patients
      from our previous series with respect to duration of surgery, blood loss,
      hospital stay, complications, and functional outcome after 2 months, 12 months,
      and 60 months. It was found that staple technique significantly reduced the
      duration of surgery and the need of blood transfusions. Length of hospital stay
      after pouch surgery did not differ between the two groups, but omitting loop
      ileostomy reduced total hospital stay by about 2 weeks. Ileoanal anastomotic
      insufficiency occurred in two patients in the study group. Treatment by
      establishment of a defunctioning loop ileostomy, local saline perfusion, and
      administration of antibiotics was successful; the anastomosis healed within 2
      weeks, and the longterm functional outcome did not differ from the average.
      Increased temperature persisted postoperatively in seven patients in the study
      group. Transient peroneal paresis occurred in three patients in the control
      group. Only in the control group was there stenosis in the ileoanal anastomosis
      requiring dilatation and fibrosis at the levator plane demanding emptying by a
      catheter. Concerning functional outcome, nighttime continence was significantly
      better in the study group than in the control group. The evacuation rate per 24 h
      was significantly higher in the study group after 2 and 12 months but not after
      60 months. The outcome concerning other functional parameters such as urgency to
      evacuate, capacity to discriminate between gas and stool, deferral time, and
      perianal symptoms, did not differ significantly. Staple technique without mucosal
      proctectomy and loop ileostomy thus results in shorter duration of surgery and
      shorter hospital stay. In patients with increased risk of insufficiency of the
      anastomosis, however, covering loop ileostomy may be justified because of the
      risk for more serious consequences if anastomotic leakage occurs.

PMID- 10647637
TI  - Long-term effects of a single course of nicotine treatment in acute ulcerative
      colitis: remission maintenance in a 12-month follow-up study.
AB  - Patients with mild to moderate active colitis who are treated with mesalazine
      plus transdermal nicotine reportedly suffer fewer relapses than patients treated
      with mesalazine plus oral prednisone. A long-term follow-up period was carried
      out to confirm this. Thirty patients with remission of distal colitis after
      therapy with the above treatment schedules were monitored for 12 months
      (Rachmilewitz' activity index plus endoscopy). Relapsed patients were retreated
      in a cross-over fashion. After 12 months recurrences were observed in 14 of 15
      patients initially treated with steroids and in 7 of 15 subjects who were had
      received transdermal nicotine (P = 0.007, Fisher's test). A higher proportion of
      relapsed patients from the prednisone group, after successful retreatment with
      nicotine patches, remained in remission after 6 months (20%) than relapsed
      patients who switched to steroid treatment (57%). Our present results confirm the
      concept that nicotine-induced remission of ulcerative colitis lasts longer than
      that obtained by oral corticosteroids.

PMID- 10647638
TI  - A stone within an anal fistula tract.

PMID- 10647639
TI  - Hyaluronidase in the reduction of incarcerated rectal prolapse: a novel use.

PMID- 10647640
TI  - Microcirculation in inflammatory bowel diseases.

PMID- 10647641
TI  - This month in investigative urology. Myogenic versus neurogenic mechanism of
      detrusor instability.

PMID- 10647642
TI  - Diagnosis and management of adrenal incidentalomas.
AB  - PURPOSE: The incidental discovery of adrenal masses has become a common clinical
      problem. We address current trends in clinical, endocrine, radiological and
      scintigraphic evaluation, and strategies for management of adrenal masses. A
      diagnostic and therapeutic algorithm is suggested. MATERIALS AND METHODS: A
      comprehensive review of the literature was performed using MEDLINE,
      bibliographies of select articles, current issues of peer reviewed general
      medicine, endocrinology, diagnostic imaging and surgical journals, and meeting
      abstracts of recent international congresses. RESULTS: Most adrenal
      incidentalomas are benign and nonhypersecreting but all should be evaluated to
      exclude from diagnosis hypersecretory syndromes or malignancy. In all cases
      hormonal screening for pheochromocytoma, hyperaldosteronism and subclinical
      hypercortisolism should be performed. Attenuation values on computerized
      tomography, chemical shift magnetic resonance imaging and scintigraphy reveal the
      nature of the mass in most cases. Fine needle aspiration biopsy should be
      reserved for cases suspected of extra-adrenal malignancy. CONCLUSIONS: A
      multidisciplinary approach, including hormonal screening, radiological evaluation
      and scintigraphy, is required to identify and remove adrenal masses with
      endocrine and oncological morbidity. Long-term morphofunctional followup is
      suggested for nonoperated cases.

PMID- 10647643
TI  - Systemic therapy for renal cell carcinoma.
AB  - PURPOSE: We review the status of systemic therapy for patients with advanced
      renal cell carcinoma. MATERIALS AND METHODS: A literature search was performed on
      MEDLINE and CANCERLIT to identify results of systemic therapy for patients with
      renal cell carcinoma published from January 1990 through December 1998. Treatment
      results of chemotherapy agents, immunotherapy, combination programs and adjuvant
      therapy were reviewed. RESULTS: No chemotherapy agent has produced response rates
      that justify its use as a single agent. Interferon-alpha and interleukin (IL)-2
      demonstrated low response rates ranging from 10% to 20%. The results of 2
      randomized trials suggest that treatment with interferon-alpha compared to
      vinblastine or medroxyprogesterone achieves a small improvement in survival.
      Response rates in patients treated with low dose IL-2 are similar to those
      achieved with a high dose bolus schedule but whether the responses are as durable
      is being addressed in an ongoing randomized trial. A randomized trial of
      interferon-alpha plus IL-2 compared to monotherapy with either agent showed
      increased toxicity but no improvement in survival. In 3 randomized trials no
      survival benefit was associated with adjuvant interferon-alpha therapy following
      complete resection of locally advanced renal cell carcinoma. CONCLUSIONS: Despite
      extensive evaluation of many different treatment modalities, metastatic renal
      cell carcinoma remains highly resistant to systemic therapy. A few patients
      exhibit complete or partial responses to interferon and/or IL-2 but most do not
      respond, and there are few long-term survivors. Preclinical research, and
      clinical evaluation of new agents and treatment programs to identify improved
      antitumor activity against metastases remain the highest priorities in this
      refractory disease.

PMID- 10647644
TI  - Laparoscopic radical prostatectomy: the Montsouris experience.
AB  - PURPOSE: We evaluate our experience with laparoscopic radical prostatectomy.
      MATERIALS AND METHODS: Between February 1, 1998 and May 1, 1999, 120 consecutive
      patients underwent laparoscopic radical prostatectomy. Morbidity of the first 40
      (group 1), next 40 (group 2) and last 40 (group 3) procedures was compared.
      Oncological data were assessed by pathological examination and postoperative
      prostate specific antigen (PSA). Functional results were assessed by a self
      administered questionnaire for the first 60 patients and potency was assessed in
      the last 40. RESULTS: Mean operating time plus or minus standard deviation was
      239+/-59 minutes (range 150 to 450) for the series, and 282, 247 and 231,
      respectively, for groups 1, 2 and 3. Surgical conversion was necessary in 7 cases
      (5.8%) overall, including 10% (4) in group 1, 7.5% (3) in group 2 and 0% in group
      3. Mean intraoperative bleeding was 402+/-293 ml. (range 50 to 1,500) in the
      series, and 534, 517 and 277, respectively, for groups 1, 2 and 3. The
      transfusion rate was 10% overall, and 15%, 12.5% and 2.5%, respectively, in
      groups 1, 2 and 3. The reoperation rate was 1.7%. Mean postoperative bladder
      catheterization time was 6.6+/-2.4 days. The positive and questionable surgical
      margin rate was 15%. Pathological tumor stage was pT2a in 4 specimens (11%), pT2b
      in 11 (16%), pT3a in 0 and pT3b in 3 (50%) with positive surgical margins. PSA
      assays were available in 94 patients with a mean postoperative followup of 2.2
      months (range 1 to 12). Serum PSA was 0.1 ng./ml. or less in 89 men (94.7%). The
      continence rate at 6 months postoperatively was 72% among the first 60 patients.
      Of 20 group 3 patients who were sexually active preoperatively 9 (45%) reported
      postoperative spontaneous erections. The overall cost of retropubic radical
      prostatectomy was about $1,237 more than that for laparoscopy. CONCLUSIONS:
      Laparoscopic radical prostatectomy is feasible and perioperative morbidity is
      low. Based on our postoperative followup, oncological results are identical to
      those of conventional surgery and functional results are encouraging.

PMID- 10647645
TI  - Double renal transplants from marginal donors: 2-year results.
AB  - PURPOSE: Marginal cadaveric renal transplant donors represent a potential source
      for expansion of the donor pool but these kidneys have generally demonstrated
      significantly poorer survival compared to those from conventional donors. A
      strategy to provide sufficient renal mass for adequate nephron dosing and
      subsequent improved survival is the use of both kidneys for a single recipient.
      We present our 2-year experience with double renal transplants from marginal
      donors. MATERIALS AND METHODS: During an 8-year period 28 patients received
      double renal transplants (group 1) and 31 received a single transplant (group 2)
      from marginal donors. Donors were older than 55 years, or had diabetes mellitus,
      hypertension, greater than 15% glomerulosclerosis on biopsy, increasing
      creatinine or intrinsic renal parenchymal disease. RESULTS: Both groups were of
      similar age and the number of rejection episodes per year was similar but
      followup time differed (22.4+/-14.6 months for group 1 versus 43.7+/-20.5 for
      group 2). Male-to-female ratio, cold ischemia time, terminal creatinine and pre
      transplant biopsy rates were similar for donors in both groups. Average donor age
      was younger in group 1 (48.9+/-15.8 versus 57.5+/-8.2 years, p = 0.01), and
      incidence of intrinsic renal disease and increasing donor creatinine was greater
      (12 versus 2, p = 0.002 and 4 versus 0, p = 0.04, respectively). Incidence of
      primary nonfunction (1 group 1 versus 5 group 2 patients) and delayed graft
      function (6 versus 7) was similar. The 1 and 2-year graft survival rates of 96%
      and 96%, respectively, for group 1 were significantly higher than those for group
      2 (77% and 73%, p = 0.02). CONCLUSIONS: Our experience to date with double kidney
      transplants from marginal donors demonstrates acceptable 1 and 2-year survival
      rates significantly superior to the outcome using only 1 marginal kidney. This
      finding has important implications in the decision to use marginal donors in
      regard to cost-effectiveness and patient survival compared to the alternative of
      continued hemodialysis until an ideal donor organ becomes available.

PMID- 10647646
TI  - Renal cell carcinoma: prognostic significance of incidentally detected tumors.
AB  - PURPOSE: We determined the prognostic significance of incidentally discovered
      renal cell carcinoma in the era of increased incidental detection. MATERIALS AND
      METHODS: We reviewed the records of 633 consecutive patients who underwent
      radical or partial nephrectomy for renal cell carcinoma at our institution
      between 1987 and 1998. Patients were divided into those who were asymptomatic and
      tumor was diagnosed incidentally and those diagnosed after presenting with any of
      the classic symptoms of renal cell carcinoma or subsequent metastasis. All renal
      cell carcinoma lesions were assigned a stage and grade according to 1997 TNM
      criteria. All patients were followed postoperatively to assess survival rates,
      and monitor recurrence and metastasis. RESULTS: Of the 633 patients 95 (15%) were
      treated for incidentally discovered renal cell carcinoma and 538 (85%) presented
      with symptoms secondary to renal cell carcinoma at diagnosis. Patient age and sex
      distribution were similar in the 2 groups. Stage I lesions were observed in 62.1%
      of patients with incidental renal cell carcinoma and in 23% with symptomatic
      renal cell carcinoma. In contrast, stage IV lesions were present in 27.4% of
      patients with incidental versus 54% with symptomatic renal cell carcinoma. Thus,
      incidental lesions were of significantly lower stage than those causing symptoms
      (p <0.001). Similarly 15.8% of incidental but 42.4% of symptomatic lesions were
      grade 3 or 4 (p = 0.006). Patients were followed postoperatively for a mean of 47
      months plus or minus 40 months. The 5-year cancer specific survival rate was
      significantly higher for incidental than for symptomatic tumors (85.3% versus
      62.5%). Likewise, the local and distal recurrence rates were higher for
      symptomatic lesions. When adjusted for stage, no difference in survival was noted
      in the 2 groups for stages I to III disease and a minimally significant
      difference was noted for stage IV cancer. Multivariate analysis of stage and
      grade attributed the survival difference in stage IV disease to the significantly
      higher grade of symptomatic lesions. CONCLUSIONS: At presentation incidental
      tumors are of significantly lower stage and grade than tumors producing symptoms.
      Subsequently these clinically and histologically less aggressive lesions lead to
      better patient survival and decreased recurrence. Thus, the detection of renal
      cell carcinoma before symptom onset enables treatment of less aggressive tumors
      and provides a better prognosis for patients. Given these data efforts should be
      directed toward the development of a screening protocol to detect these lesions
      early, so that they may be prevented from progressing to the point when symptoms
      are apparent and prognosis becomes worse. In addition, the significant
      correlation of tumor grade with survival in our study further demonstrates the
      prognostic value of tumor grade and molecular markers for the future evaluation
      and treatment of renal cell carcinoma.

PMID- 10647647
TI  - Prevalence of microscopic tumors in normal appearing renal parenchyma of patients
      with hereditary papillary renal cancer.
AB  - PURPOSE: We describe the earliest renal lesions associated with hereditary
      papillary renal cancer and estimate the prevalence of microscopic papillary renal
      tumors. MATERIALS AND METHODS: Grossly normal tissue was obtained from 12 kidneys
      during renal surgery in 9 patients with hereditary papillary renal cancer. Tissue
      was examined microscopically and findings were compared to those previously
      reported to be associated with von Hippel-Lindau disease and sporadic renal cell
      carcinoma. RESULTS: A total of 92 microscopic papillary renal cell carcinoma
      lesions were identified on 46 of 88 slides (53%). No other lesions were
      identified. All tumors were solid and displayed the basophilic papillary
      histology characteristic of hereditary papillary renal cancer. Extrapolation of
      the data predicted the prevalence of 1,100 to 3,400 microscopic papillary tumors
      in a single kidney in a patient with hereditary papillary renal cancer.
      CONCLUSIONS: The basophilic papillary histology characteristic of clinically
      apparent renal tumors in patients with hereditary papillary renal cancer also
      characterizes the multiple microscopic lesions seen in the kidneys. These
      findings suggest that the earliest renal tumor in patients with an activating
      hereditary mutation of the met gene is papillary basophilic renal cancer. The
      large number of microscopic tumors in patients with hereditary papillary renal
      cancer was comparable to or greater than that seen in those with von Hippel
      Lindau disease.

PMID- 10647648
TI  - Complete radical nephrectomy and vena caval thrombectomy during circulatory
      arrest.
AB  - PURPOSE: A modification of radical nephrectomy for renal carcinoma and vena caval
      tumor thrombectomy for supradiaphragmatic tumor extension under hypothermic
      circulatory arrest is presented. MATERIALS AND METHODS: Nephrectomy was performed
      during the circulatory arrest time in 16 consecutive patients during the last 4
      years. RESULTS: Average hypothermic circulatory arrest time increased by 6
      minutes. By elimination of manipulation of tumor and thrombus before circulatory
      arrest potential thrombus fragmentation and embolization were minimized. There
      were no significant differences in blood loss or complications compared to a
      prior series of 10 patients undergoing the procedure using conventional
      techniques. CONCLUSIONS: Performance of complete radical nephrectomy along with
      venal caval embolectomy during circulatory arrest increases the safety of the
      procedure without significant morbidity.

PMID- 10647649
TI  - Is adrenalectomy a necessary component of radical nephrectomy? UCLA experience
      with 511 radical nephrectomies.
AB  - PURPOSE: We determine the incidence and characteristics of adrenal involvement in
      localized and advanced renal cell carcinoma, and evaluate the role of
      adrenalectomy as part of radical nephrectomy. MATERIALS AND METHODS: The records
      of 511 patients undergoing radical nephrectomy with ipsilateral adrenalectomy for
      renal cell carcinoma at our medical center between 1986 and 1998 were reviewed.
      Mean patient age was 63.2 years (range 38 to 85), and 78% of the subjects were
      males and 22% were females. Patients were divided into subgroups of 164 with
      localized (stage T1-2 tumor, group 1) and 347 with advanced (stage T3-4N01M01,
      group 2) renal cell carcinoma. Staging of tumors was performed according to the
      1997 TNM guidelines. A retrospective review of preoperative computerized
      tomography (CT) of the abdomen was performed. Radiographic findings were
      subsequently compared to postoperative histopathological findings to assess the
      predictive value of tumor characteristics and imaging in determining adrenal
      metastasis. RESULTS: Of the 511 patients 29 (5.7%) had adrenal involvement.
      Average size of the adrenal tumor was 3.86 cm. (standard deviation 1.89). Tumor
      stage correlated with probability of adrenal spread, with T4, T3 and T1-2 tumors
      accounting for 40%, 7.8% and 0.6% of cases, respectively. Upper pole intrarenal
      renal cell carcinoma most likely to spread was local extension to the adrenal
      glands, representing 58.6% of adrenal involvement. In contrast, multifocal, lower
      pole and mid region renal cell carcinoma tumors metastasized hematogenously,
      representing 32%, 7% and 4% of adrenal metastasis, respectively. The relationship
      between intrarenal tumor size (mean 8.9 cm., range 3 to 17) and adrenal
      involvement (independent of stage) was not statistically significant. Renal vein
      thrombus involvement was demonstrated in 8 of 12 cases (67%) with left and 2 of 9
      (22%) with right adrenal involvement. Preoperative CT demonstrated 99.6%
      specificity, 99.4% negative predictive value, 89.6% sensitivity and 92.8%
      positive predictive value for adrenal involvement by renal cell carcinoma.
      CONCLUSIONS: With a low incidence of 0.6%, adrenal involvement is not likely in
      patients with localized, early stage renal cell carcinoma and adrenalectomy is
      unnecessary, particularly when CT is negative. In contrast, the 8.1% incidence of
      adrenal involvement with advanced renal cell carcinoma supports the need for
      adrenalectomy. Careful review of preoperative imaging is required to determine
      the need for adrenalectomy in patients at increased risk with high stage lesions,
      renal vein thrombus and upper pole or multifocal intrarenal tumors. With a
      negative predictive value of 99.4%, negative CT should decrease the need for
      adrenalectomy. In contrast, positive findings are less reliable given the
      relatively lower positive predictive value of this imaging modality. Although
      such positive findings may raise suspicion of adrenal involvement, they may not
      necessarily indicate adrenalectomy given the low incidence, unless renal cell
      carcinoma with risk factors, such as high stage, upper pole location,
      multifocality and renal vein thrombus, is present.

PMID- 10647650
TI  - Long-term results of nephron sparing surgery for localized renal cell carcinoma:
      10-year followup.
AB  - PURPOSE: Partial nephrectomy is effective for renal cell carcinoma when
      preservation of renal function is a concern. We present the 10-year followup of
      patients treated with nephron sparing surgery at our institution. MATERIALS AND
      METHODS: Partial nephrectomy was performed in 107 patients with localized
      sporadic renal cell carcinoma before December 1988. Tumors were symptomatic in 73
      patients (68%) and indications for surgery were imperative in 96 (90%). Of the
      patients 42 (39%) had renal insufficiency preoperatively. All patients were
      followed a minimum of 10 years or until death. RESULTS: At the end of the
      followup interval 32 patients (30%) had no evidence of recurrence, 28 (26%) died
      of metastatic renal cell carcinoma and 46 (42%) died of unrelated causes. Cancer
      specific survival was 88.2% at 5 and 73% at 10 years, and was significantly
      affected by tumor stage, symptoms, tumor laterality and tumor size. Long-term
      renal function was stable in 52 patients (49%). CONCLUSIONS: Partial nephrectomy
      is effective for localized renal cell carcinoma, providing long-term tumor
      control with preservation of renal function.

PMID- 10647651
TI  - Successful long-term outcome using existing native cutaneous ureterostomy for
      renal transplant drainage.
AB  - PURPOSE: We report our long-term experience with a preexisting native cutaneous
      ureterostomy via an ipsilateral transplant ureteral native ureterostomy for
      transplant drainage without native nephrectomy. MATERIALS AND METHODS: Between
      1993 and 1998, 5 patients without a usable bladder had undergone previously
      urinary diversion via cutaneous ureterostomy. All patients had a well functioning
      cutaneous ureterostomy for a mean plus or minus standard deviation of 18+/-12
      years before renal transplantation. No patient had a history of stomal stenosis,
      recent urinary tract infection or pyelonephritis. RESULTS: All 5 patients
      continued to have a functioning renal transplant at last mean followup of 36+/
      6.6 months. Complications included stomal retraction due to postoperative weight
      gain requiring revision in 2 cases and ureteroureteral anastomotic stenosis
      treated with endopyelotomy in 1. Mean serum creatinine at last followup was 1.5+/
      0.6 mg./dl. CONCLUSIONS: Of the complications that we present only 1 may be
      attributed to the singularity of our procedure. Our experience suggests that a
      preexisting native cutaneous ureterostomy may serve as a receptacle for
      transplant ureteral drainage in select patients with excellent long-term
      function.

PMID- 10647652
TI  - Ureteroenteric anastomosis in continent urinary diversion: long-term results and
      complications of direct versus nonrefluxing techniques.
AB  - PURPOSE: Controversy exists over the importance of antireflux mechanisms in large
      volume, low pressure intestinal bladder substitutions. Despite the theoretical
      benefits of reflux prevention, antirefluxing ureteral reimplantations may have a
      greater risk of anastomotic stricture. We hypothesize that this inherent
      stricture rate may outweigh the potential benefits associated with reflux
      prevention. To assess this question critically we compare our results to those of
      direct and nonrefluxing techniques of ureterointestinal anastomosis during
      continent diversion. MATERIALS AND METHODS: Between 1990 and 1998, 58 patients
      underwent continent urinary diversion using an Indiana pouch or ileal orthotopic
      neobladder following cystectomy for muscle invasive bladder cancer. A total of 56
      renal units were implanted using an end-to-side Nesbit direct anastomosis and 60
      were implanted in a nonrefluxing manner. Clinical end points included anastomotic
      stricture formation, hydronephrosis, pyelonephritis, upper tract stone formation
      and renal deterioration, and were assessed with a mean followup of 41 months.
      RESULTS: Of 60 nonrefluxing ureteroenteric anastomoses 8 (13%) resulted in
      nonneoplastic stricture formation compared to 1 of 56 (1.7%) direct anastomoses,
      which was statistically significant (Fisher's exact test p <0.05). Strictures
      occurred up to 6 years following the original surgery. There was no significant
      difference between the 2 groups in regard to hydronephrosis, pyelonephritis,
      upper tract stone formation or azotemia. CONCLUSIONS: Nonrefluxing methods of
      ureterointestinal reimplantation resulted in a statistically significant higher
      rate of anastomotic stricture than the end-to-side direct anastomosis. This
      finding appears to outweigh any theoretical benefits of preventing
      pyelonephritis, stones or azotemia. For patients undergoing large volume, low
      pressure continent diversion the refluxing ureterointestinal anastomosis may be
      the technique of choice since it preserves renal function as well as the
      nonrefluxing method, is technically easier to perform and poses less risk of
      stricture. Delayed stricture formation years after surgery underscores the
      necessity for long-term radiological followup in patients following continent
      diversion.

PMID- 10647653
TI  - Effect of functional continuous magnetic stimulation for urinary incontinence.
AB  - PURPOSE: We evaluated the therapeutic efficacy of continuous magnetic stimulation
      on urinary incontinence by studying the urodynamic effect on urethral closure and
      bladder inhibition. MATERIALS AND METHODS: A total of 11 patients with stress
      incontinence and 12 with urge incontinence (7 males and 16 females, mean age 55.8
      years) were evaluated. In the pilot study urethral pressure profile was performed
      before and after 20 Hz. 15-minute (with 1-minute on/30-second off cycles)
      stimulation, and maximum intraurethral pressure was recorded during stimulation
      in stress incontinence cases. Cystometry was performed before and during 15
      minute stimulation at 10 Hz. in urge incontinence cases. In the therapeutic study
      8 females with stress incontinence, and 3 males and 5 females with urge
      incontinence were treated with magnetic stimulation twice a week for 5 weeks.
      RESULTS: In the pilot study maximum intraurethral pressure increased by 34%
      during stimulation and maximum urethral closure pressure increased by 20.9% (p =
      0.0409) after stimulation in stress incontinence cases. In urge incontinence
      cases significant increases in bladder capacities at first and maximum desire to
      void during stimulation were noted (p = 0.0164 and 0.0208, respectively). In the
      therapeutic study 86% of 7 patients with stress incontinence and 75% of 8 with
      urge incontinence were improved, and 1 dropped out of the study. CONCLUSIONS:
      Continuous magnetic stimulation was effective on urethral closure and bladder
      inhibition, and as treatment of urinary incontinence.

PMID- 10647654
TI  - Incidence of erectile dysfunction in men 40 to 69 years old: longitudinal results
      from the Massachusetts male aging study.
AB  - PURPOSE: We estimated the incidence of erectile dysfunction in men 40 to 69 years
      old at study entry during an average 8.8-year followup, and determined how risk
      varied with age, socioeconomic status and medical conditions. MATERIALS AND
      METHODS: Data from a randomly sampled population based longitudinal study of
      Massachusetts men were analyzed. A total of 1,709 men completed the baseline
      interview during 1987 to 1989 and 1,156 survivors completed followup from 1995 to
      1997. The analysis sample consisted of 847 men without erectile dysfunction at
      baseline and with complete followup information. Erectile dysfunction was
      assessed by discriminant analysis of 13 questions from a self-administered sexual
      function questionnaire and a single global self-rating question. RESULTS: The
      crude incidence rate for erectile dysfunction was 25.9 cases per 1,000 man-years
      (95% confidence interval [CI] 22.5 to 29.9). The annual incidence rate increased
      with each decade of age and was 12.4 cases per 1,000 man-years (95% CI 9.0 to
      16.9), 29.8 (24.0 to 37.0) and 46.4 (36.9 to 58.4) for men 40 to 49, 50 to 59 and
      60 to 69 years old, respectively. The age adjusted risk of erectile dysfunction
      was higher for men with lower education, diabetes, heart disease and
      hypertension. Population projections for men 40 to 69 years old suggest that
      17,781 new cases of erectile dysfunction in Massachusetts and 617,715 in the
      United States (white males only) are expected annually. CONCLUSIONS: Although
      prevalence estimates and cross-sectional correlates of erectile dysfunction have
      recently been established, incidence estimates were lacking. Incidence is
      necessary to assess risk, and plan treatment and prevention strategies. The risk
      of erectile dysfunction was about 26 cases per 1,000 men annually, and increased
      with age, lower education, diabetes, heart disease and hypertension.

PMID- 10647655
TI  - Does prostaglandin E1 therapy modify the intracavernous musculature?
AB  - PURPOSE: Intracavernous injection of prostaglandin E1 in patients with erectile
      dysfunction has become widespread. However, to our knowledge long-term side
      effects on the penile smooth muscles in man have not been documented. We
      evaluated the histological changes of intracavernous smooth muscle after long
      term treatment with prostaglandin E1. MATERIALS AND METHODS: A total of 10
      patients with a mean age of 56.5 years (range 46 to 69) underwent biopsy of the
      corpora before (5) and after (10 in both corpora) prostaglandin E1 treatment.
      Between 150 and 250 injections during 3 years were performed, and the dosage
      varied from 5 to 20 microg. Only 1 patient injected prostaglandin E1 on both
      sides. Staining with hematoxylin and eosin, and immunohistochemical staining with
      actin anti-actin of intracavernous smooth muscle and its quantification with
      computerized image analysis were performed. RESULTS: No histological difference
      was observed with classic staining. A reduction was noted in the percentage of
      intracavernous smooth muscle after treatment in 2 of 5 patients on the side of
      injection (before 35% and 41%, and after 19% and 30%, respectively) but there was
      no difference with the other corpus cavernosum. No difference was observed in the
      percentage of intracavernous smooth muscle between both corpora in the 5 patients
      with biopsies performed only after treatment. CONCLUSIONS: Prostaglandin E1 does
      not seem to alter intracavernous structures.

PMID- 10647656
TI  - Logistic regression and survival analysis of 450 impotent patients treated with
      injection therapy: long-term dropout parameters.
AB  - PURPOSE: We report the dropout rate associated with intracavernosal self
      injection for erectile dysfunction at long-term followup, and determine
      parameters related to dropout. MATERIALS AND METHODS: Of 2,252 impotent patients
      evaluated during 9 years 450 (20%) enrolled in our self-injection program.
      Papaverine and phentolamine were given in 53% (initial treatment), prostaglandin
      E1 in 21%, and papaverine, phentolamine and prostaglandin E1 (triple mixture) in
      26% of cases. Average injection volume for the 3 injection types was 0.52 cc.
      Data were retrospectively reviewed for patient dropout versus nondropout,
      specifically for type of drug, volume injected, changing treatment (from 1 drug
      and/or dosage to another), patient age, marital status, ethnic group, impotence
      duration and diabetes. RESULTS: Patient age ranged from 23 to 79 years (mean age
      55). Of the patients treated at least 4 months 155 (35%) dropped out of the
      study. Mean treatment duration was 3.5 years. Logistic regression suggested that
      type of drug, changing treatment during the course of therapy and dosage (volume
      injected) were the only significant (p <0.05) parameters influencing dropout.
      Papaverine and phentolamine were twice as likely to lead to dropout as triple
      mixture or prostaglandin E1, and injection greater than 0.5 cc was more than
      twice as likely to lead to dropout. Demographic, ethnic, age and etiological
      factors had no significant effect on the overall dropout rate. CONCLUSIONS: The
      effectiveness of injection therapy was an underlying factor determining the long
      term dropout rate for patients with erectile dysfunction. Other parameters or
      combinations of parameters that may influence patient dropout remain to be
      explored.

PMID- 10647657
TI  - Erectile dysfunction--is the incidence increasing?

PMID- 10647658
TI  - Embolization of the deep dorsal vein for the treatment of erectile impotence due
      to veno-occlusive dysfunction.
AB  - PURPOSE: We evaluate the effectiveness of deep dorsal vein embolization for the
      treatment of venous impotence. MATERIALS AND METHODS: A total of 32 impotent
      patients with veno-occlusive dysfunction underwent deep dorsal vein embolization.
      The condition was suspected based on findings of penile Doppler ultrasonography
      and cavernosometry. The diagnosis was confirmed with pharmacocavernosography that
      appeared to delineate venous leakage. During the procedure we isolated and
      cannulated the deep dorsal vein through a small dorsal penile incision with the
      patient under local anesthesia. We used a mixture of the tissue glue, N-butyl
      cyanoacrylate, and lipodol for embolization, with a total volume of 5 ml.
      injected antegrade into the previously catheterized dorsal vein under
      fluoroscopic control. As soon as we observed the occluded veins we performed
      repeat pharmacocavernosography. At 3-month followup patients were reassessed with
      history and cavernosometry. Followup ranged from 12 to 36 months (median 25).
      RESULTS: Of 32 patients 22 (68.7%) regained sexual activity, which was confirmed
      by cavernosometry. The remaining 10 patients (31.3%) experienced little if any
      clinical response, which correlated with cavernosometry. There were no
      significant side effects. CONCLUSIONS: Deep dorsal vein embolization for
      venogenic impotence is simple, effective and safe, and appears to be cost
      effective. The results obtained in this limited number of patients are promising
      and justify trials in larger groups.

PMID- 10647659
TI  - 10 years of experience with penile prosthesis implantation in Taiwanese patients.
AB  - PURPOSE: We evaluated the long-term results of penile prosthesis implantation
      during the last 10 years. Special considerations were examined concerning Asian
      corporeal diameter, device survival and sociocultural factors influencing patient
      partner satisfaction. MATERIALS AND METHODS: We followed 331 patients who
      underwent penile prosthesis implantation from December 1985 to May 1996. Surgical
      data, postoperative complications and information from a survey on satisfaction
      are reported. RESULTS: The most prevalent corporeal diameter in our patients was
      11.0 to 11.5 cm. Postoperatively wound infection was the most serious surgical
      complication. The 5-year device survival was similar in the malleable and
      inflatable types except for a poorer outcome with the self-contained inflatable
      Hydroflex penile prosthesis. Overall patient satisfaction with surgery was 86.6%.
      CONCLUSIONS: Penile prosthesis implantation still has its place as definitive
      therapy in some patients with uncorrectable erectile dysfunction. In Taiwanese
      society more consideration of prosthesis selection, surgical preparation and
      patient-partner counseling is the basis for further success in the future.

PMID- 10647660
TI  - Long-term experience with salvage of infected penile implants.
AB  - PURPOSE: The effectiveness of treating patients with an infected penile implant
      by removing the device, cleansing the wound with a series of antiseptic solutions
      and placing a new device at the same procedure was assessed. MATERIALS AND
      METHODS: A total of 65 patients were included in the study. All foreign material
      was removed from the infected wound followed by copious wound irrigations with a
      protocol of 7 antibacterial solutions. A new prosthesis was inserted and the
      patient was placed on antibiotics. RESULTS: Followup ranged from 6 to 93 months.
      Recent status was determined in 85% of cases (55 of 65). Of the 55 patients 45
      (82%) showed no sign of infection. In 5 patients recurrent infection was
      documented and in 5 others erosion of parts to the exterior possibly related to
      infection was noted. CONCLUSIONS: Salvage of an infected penile implant has been
      successful and is gaining in popularity among urologists to reduce morbidity
      associated with infection.

PMID- 10647661
TI  - Modified vasoepididymostomy with simultaneous double needle placement, tubulotomy
      and tubular invagination.
AB  - PURPOSE: Recently a new technique for vasoepididymostomy was described which
      included tubular invagination by the triangulation method with a patency rate of
      92%. Although these early data were encouraging, some technical problems were
      noted with the technique. After placing the first suture there was often tubular
      leakage and collapse. The tubulotomy was difficult and in some cases a suture was
      inadvertently cut. A modified technique is presented for vasoepididymostomy with
      tubular invagination, including some methods described in rat models. Only 2
      sutures are used with simultaneous double needle placement. MATERIALS AND
      METHODS: The 2-suture technique was used on 19 men who had undergone at least 1
      vasoepididymostomy during vasectomy reversal procedures. RESULTS: Patency was
      demonstrated in 7 of 9 men (77.7%) who underwent modified bilateral
      vasoepididymostomy and 6 of 7 (85.7%) who underwent unilateral vasoepididymostomy
      and unilateral vasovasostomy. Pregnancies were reported in both groups. The
      overall operating time for the modified technique was about 35 to 45 minutes per
      side. CONCLUSIONS: Modified vasoepididymostomy with simultaneous needle
      placement, tubulotomy and invagination resulted in early patency in a high
      percentage of patients. Tubular invagination may have advantages compared to
      other conventional methods of vasoepididymostomy but more followup is needed.

PMID- 10647662
TI  - Recurrent epididymo-orchitis in patients with Behcet's disease.
AB  - PURPOSE: We study the clinical features of epididymo-orchitis in patients with
      Behcet's disease. MATERIALS AND METHODS: Of 57 men with Behcet's disease 7 had
      epididymo-orchitis during the course of disease. A questionnaire was applied to
      all cases and the clinical features were recorded. HLA class 1 was determined and
      a pathergy test was performed. RESULTS: All 7 patients fulfilled the
      international study group criteria for Behcet's disease. All patients had
      recurrent oral ulcers, skin lesions (folliculitis, erythema nodosum-like lesions)
      and uveitis, and 6 had recurrent genital ulcers, 2 arthritis, 1 vasculitis and 4
      central nervous system involvement. The pathergy test was positive in 4 patients
      and all had B5(51). The allele B5101 was present in 6 patients and 1 had B5102.
      Recurrences were observed in 5 patients. Concurrent symptoms with epididymo
      orchitis consisted of oral ulcers, fever, uveitis, arthritis and penile ulcer.
      Colchicine, glucocorticoids, nonsteroidal anti-inflammatory drugs and
      cyclosporine were administered. CONCLUSIONS: Epididymo-orchitis in patients with
      Behcet's disease is not as infrequent as believed. It was not the first
      manifestation of the disease but developed during followup. In any patient with
      epididymo-orchitis Behcet's disease should be considered, particularly in regions
      with a high prevalence of the disease.

PMID- 10647663
TI  - Race, ethnicity and benign prostatic hyperplasia in the health professionals
      follow-up study.
AB  - PURPOSE: We examined whether the prevalence of benign prostatic hyperplasia (BPH)
      varies by racial or ethnic origin in a large cohort of American male health
      professionals. MATERIALS AND METHODS: Included in our study were 1,508 men who
      underwent surgery for BPH between 1986 and 1994, and 1,837 with high moderate to
      severe lower urinary tract symptoms assessed by the American Urological
      Association symptom index in 1992 or 1994. "Noncases" comprised 23,246
      asymptomatic participants. Self-reported major ancestry was black in 201 men,
      Asian in 413, other origin in 604 and white in 25,373. White heritage was further
      classified as southern European in 6,408 men, Scandinavian in 2,951 and other
      white in 16,014. The relative risk of BPH and 95% confidence intervals (CI)
      adjusted for age, body mass index, alcohol consumption, smoking and physical
      activity were calculated by logistic regression. RESULTS: Black men were not at
      increased risk for BPH (relative risk 0.85, 95% CI 0.55 to 1.31) compared with
      white men. Asian men were less likely to have undergone BPH surgery (relative
      risk 0.41, 95% CI 0.21 to 0.82), although the relative risk for symptoms was
      similar to that of white men. White men whose major ancestry was southern
      European were at modestly higher risk for BPH surgery (relative risk 1.28, 95% CI
      1.12 to 1.46) and symptoms (relative risk 1.34, 95% CI 1.20 to 1.50), whereas men
      of Scandinavian heritage were at slightly decreased risk for symptoms than those
      of other white heritages. CONCLUSIONS: Racial and ethnic variation is evident in
      the incidence of BPH surgery and symptom severity. Whether this observed
      variation reflects underlying biological phenomena rather than differences in
      symptom tolerance requires further exploration.

PMID- 10647664
TI  - A prospective study of the natural history of hematuria associated with benign
      prostatic hyperplasia and the effect of finasteride.
AB  - PURPOSE: We prospectively studied the effect of finasteride on chronic hematuria
      associated with benign prostatic hyperplasia. MATERIALS AND METHODS: We
      prospectively evaluated 57 patients with chronic intermittent hematuria who were
      randomized to a finasteride treated or a control arm. RESULTS: In the untreated
      control group hematuria recurred in 17 patients (63%) within a year but in only 4
      (14%) in the finasteride group, which was a statistically significant difference
      (p <0.05). Surgery was required for bleeding in 7 controls (26%), while no
      patient on finasteride required surgery. CONCLUSIONS: Hematuria secondary to
      prostatic bleeding may be significant if not treated. Finasteride appears to be
      effective for suppressing hematuria caused by benign prostatic hyperplasia and
      should be considered as treatment.

PMID- 10647665
TI  - Practice patterns of Canadian urologists in benign prostatic hyperplasia and
      prostate cancer. Canadian Prostate Health Council.
AB  - PURPOSE: We reviewed the practice patterns of Canadian urologists in benign
      prostatic hyperplasia (BPH) and prostate cancer, and assessed the changes that
      occurred between 1995 and 1998. MATERIALS AND METHODS: In 1995 and 1998
      questionnaires were mailed to all active members of the Canadian Urological
      Association who practiced adult urology in Canada. Many questions were similar,
      allowing for the assessment of changes in practice patterns. RESULTS: A number of
      changes were observed between 1995 and 1998. Cystoscopy and imaging of the upper
      urinary tract were used less often to evaluate uncomplicated cases of BPH.
      However, 39% of respondents continued to perform cystoscopy routinely.
      Finasteride was no longer administered in men with a smaller prostate. In 1998
      before radical prostatectomy 28% of respondents routinely performed a bone scan,
      29% cystoscopy and 57% chest x-ray. The number believing that maximal androgen
      blockade is the most effective hormonal therapy decreased from 90% to 62%, while
      24% reported in the 1998 survey that they frequently administered intermittent
      hormonal therapy. Comparison with an American study from 1995 indicated that
      American urologists used the American Urological Association symptom score and
      performed a prostate specific antigen test more frequently than Canadian
      urologists. However, Canadian urologists performed cystoscopy more frequently.
      CONCLUSIONS: These surveys provide a useful insight into the variations in
      clinical practice of Canadian urologists and help to determine whether changes
      are occurring in regard to the development of practice guidelines. They also
      indicate the need to develop further guidelines, and ensure that these guidelines
      are widely promoted and accepted by the urological community.

PMID- 10647666
TI  - Trends in mortality rates in patients with prostate cancer during the era of
      prostate specific antigen screening.
AB  - PURPOSE: We assess the influence of prostate specific antigen screening on trends
      in mortality rates in patients with prostate cancer. MATERIALS AND METHODS: The
      incidence based mortality method was applied to prostate cancer data from the
      Surveillance, Epidemiology, and End Results Program. This method links data on
      patients diagnosed with cancer to vital status and cause of death, such that
      mortality can be evaluated by factors associated with disease at diagnosis.
      Prostate and nonprostate cancer mortality rates were evaluated according to
      patient age at death, disease stage and grade at diagnosis, race and whether
      additional cancers involving other sites were present. RESULTS: Mortality due to
      prostate cancer decreased from 37% in 1988 to 30% in 1995 largely as a result of
      a sharp increase in nonprostate cancer mortality rates. The overall trend in
      prostate cancer mortality rates increased from 1988 through 1992 and then
      decreased. The increase and decrease in rates occurred across categories of age,
      race, grade and number of cancer primaries. However, the increase in rates did
      not occur in distant staged cases, nor did the subsequent decrease in rates occur
      in nondistant staged cases. CONCLUSIONS: Prostate specific antigen screening
      influenced the increase and decrease in prostate cancer mortality rates.

PMID- 10647667
TI  - The perioperative charge equivalence of interstitial brachytherapy and radical
      prostatectomy with 1-year followup.
AB  - PURPOSE: We compare the comprehensive 1-year charges in a consecutive group of
      patients undergoing radical prostatectomy and transperineal interstitial
      brachytherapy for clinically localized prostate cancer at a single urban
      institution. MATERIALS AND METHODS: A total of 60 consecutive men with clinically
      localized prostate cancer (T1-T2, N0, M0) were treated during a 15-month period
      with radical prostatectomy or interstitial brachytherapy. Hospital and outpatient
      records were analyzed for each patient in regard to preoperative, operative and
      postoperative charges. Parameters included number of encounters, diagnostic and
      therapeutic interventions, hospitalization and operative charges, and followup
      visits, diagnostic tests and interventions for 1 year. All charge calculations
      were based arbitrarily on the 1996 Medicare fee schedule, factoring in the
      mandated global charge reimbursement period of 90 days for both procedures.
      RESULTS: Of the patients 38 underwent radical prostatectomy (prostatectomy group)
      and 22 underwent interstitial brachytherapy (brachytherapy group). The
      brachytherapy group was older with higher pretreatment serum prostate specific
      antigen and clinical stage disease, and more frequently received neoadjuvant
      hormonal therapy compared to the prostatectomy group. The 2 groups were similar
      in Gleason score and, when applicable, duration of neoadjuvant hormonal therapy.
      Preoperative charges were 15.3% lower for prostatectomy than for brachytherapy
      (not statistically significant). Conversely, operative charges for prostatectomy
      were 13.5% higher (p = 0.04). The major difference among preoperative, operative
      and postoperative charges was for those incurred postoperatively by the
      brachytherapy group, which were 56.0% higher than those for the prostatectomy
      group ($2,285.20 versus $1,007.20, p = 0.0004). CONCLUSIONS: Transperineal
      interstitial seed implantation is perceived by many as more cost-effective than
      radical prostatectomy for patients with clinically localized prostate cancer. We
      demonstrated that when such patients were followed for 1 year, the comprehensive
      charges for radical prostatectomy and interstitial brachytherapy were equivalent.

PMID- 10647668
TI  - Transurethral holmium laser resection of the prostate.
AB  - PURPOSE: We evaluated the efficacy of the holmium:YAG laser for transurethral
      endoscopic prostatectomy for benign prostatic hyperplasia (BPH). MATERIALS AND
      METHODS: We treated 103 patients with BPH with holmium:YAG laser resection of the
      prostate. A high power holmium laser generating a maximum of 60 or 81 W. was used
      in a pulsed mode, applying energy directly to prostatic tissue via a forward
      firing 550 micron. fiber transurethrally under direct vision. Treatment outcome
      was evaluated by the International Prostate Symptom Score, quality of life score,
      maximum flow rate and post-void residual urine volume. We also compared holmium
      laser surgery and transurethral resection of the prostate for operative factors,
      such as surgical duration, bleeding volume and catheterization time. RESULTS:
      Average symptom score, quality of life score, peak flow rate and post-void
      residual significantly improved at 1 week, 1 month and 3 months postoperatively,
      with improvement maintained up to 36 months postoperatively in the holmium:YAG
      group. Intraoperative bleeding volume was significantly lower and catheterization
      time was significantly shorter for holmium:YAG than for transurethral prostatic
      resection. Use of the holmium laser caused no complications. CONCLUSIONS: Because
      of its effectiveness and safety holmium:YAG resection is a viable potential
      surgical alternative for symptomatic BPH. The holmium:YAG laser has been verified
      to be useful for many purposes in urology.

PMID- 10647669
TI  - A comparison of cause of death determination in men previously diagnosed with
      prostate cancer who died in 1985 or 1995.
AB  - PURPOSE: We quantified the agreement between the underlying cause of death
      determination from information in hospital medical records and on death
      certificates, and determined whether the frequency of assigning death from
      prostate cancer had changed since the introduction of testing for prostate
      specific antigen. MATERIALS AND METHODS: We retrospectively reviewed and analyzed
      the information in hospital medical records and on death certificates for men
      previously diagnosed with prostate cancer who died in 1985 or 1995. RESULTS: The
      underlying cause of death determinations from a review of 201 hospital medical
      records agreed with those from information on part 1 of the death certificate in
      87% of cases and with those using the International Classification of Diseases-9
      system coding rules in 80%. Agreement was higher in men who were older than those
      who were younger at the time of death, and higher in those diagnosed with
      prostate cancer several years before death than in those diagnosed shortly before
      death. CONCLUSIONS: There was a high level of agreement concerning the underlying
      cause of death after a review of the information in hospital medical records and
      on death certificates for men with prostate cancer when cause of death was viewed
      as a dichotomous variable. The International Classification of Diseases-9 coding
      rules concerning the underlying cause of death favor overreporting rather than
      underreporting prostate cancer deaths compared with a review of hospital medical
      records. Cause of death determination does not appear to have changed after the
      introduction of prostate specific antigen testing.

PMID- 10647670
TI  - A prospective analysis of 1,930 patients with hematuria to evaluate current
      diagnostic practice.
AB  - PURPOSE: The commonly accepted diagnostic algorithm for hematuria includes
      excretory urography (IVP) and cystoscopy. Some have suggested that ultrasound of
      the upper urinary tract is adequate and that cystoscopy is not necessary in
      younger patients with microscopic hematuria. We ascertain whether a less
      intensive algorithm could be adopted while retaining diagnostic efficacy.
      MATERIALS AND METHODS: A total of 1,930 patients were enrolled prospectively in
      the study at a hematuria clinic between October 1994 and March 1997. Evaluation
      consisted of basic demographics, history and examination, routine blood tests,
      urinalysis and cytology. All patients underwent plain abdominal radiography,
      renal ultrasound, IVP and flexible cystoscopy. RESULTS: A total of 1,194 males
      and 736 females with a mean age of 58 years (range 17 to 96) were included in the
      study. Overall, 61% of patients had no basis found for hematuria, 12% had bladder
      cancer, 13% had urinary tract infection and 2% had stones. Kidney and upper tract
      tumors were noted in 14 patients (0.7%), including 4 who presented with
      microscopic hematuria. If only ultrasound or IVP had been performed 4 of these
      cases would have been missed. Of 982 patients presenting with microscopic
      hematuria 51 had cancer. Bladder cancer was found in 7 patients younger than 40
      years. CONCLUSIONS: Our findings suggest that cystoscopy cannot be safely avoided
      even in younger patients with microscopic hematuria. Only a combination of
      ultrasound and IVP detected all upper tract tumors.

PMID- 10647672
TI  - Predicting the need for anti-incontinence surgery in continent women undergoing
      repair of severe urogenital prolapse.
AB  - PURPOSE: We determined the indications for anti-incontinence surgery in continent
      women undergoing surgical repair of severe urogenital prolapse. MATERIALS AND
      METHODS: We prospectively evaluated 24 continent women referred for evaluation of
      severe urogenital prolapse. All patients underwent a meticulous clinical
      evaluation, including a complete history and physical examination, urinary
      questionnaire, voiding diary, pad test, cotton swab test, video urodynamics and
      cystoscopy. The urodynamic evaluation was repeated with prolapse repositioning by
      a fitted vaginal pessary. Surgical intervention was tailored according to
      urodynamic findings. RESULTS: Reduction of prolpase with a pessary unmasked
      sphincteric incontinence in 14 women (58%). Ten women with no urodynamic evidence
      of sphincteric incontinence underwent anterior colporrhaphy and no additional
      anti-incontinence procedure was performed. Mean followup was 44 months (range 12
      to 96). None had postoperative stress incontinence but 1 (10%) had a recurrent
      grade 2 cystocele. The 14 remaining women with sphincteric incontinence after
      prolapse reduction underwent anterior colporrhaphy with a pubovaginal sling
      procedure. Mean followup in these cases was 47 months (range 12 to 108). In 2
      patients (14%) stress incontinence developed postoperatively and 1 (7%) had a
      recurrent grade 3 cystocele. The incidence of urge incontinence did not appear to
      be significantly influenced by either surgical intervention. Overall 12 patients
      had preoperative urge incontinence, of whom 9 (75%) had persistent urge
      incontinence postoperatively. In another woman new onset urge incontinence
      developed. CONCLUSIONS: Preoperative urodynamic evaluation with and without
      prolapse reduction is essential for making the correct diagnosis of masked stress
      incontinence in women with urogenital prolapse. The decision to perform a
      concomitant prophylactic anti-incontinence procedure should be tailored to
      individual urodynamic findings. Larger series and longer followup are needed to
      establish the most effective preventive procedure for this troublesome clinical
      problem.

PMID- 10647671
TI  - Nephrovesical subcutaneous stent: an alternative to permanent nephrostomy.
AB  - PURPOSE: We studied whether a subcutaneous ureteral bypass may be an alternative
      to a permanent nephrostomy tube in patients with ureteral obstruction caused by
      pelvic malignancy. MATERIALS AND METHODS: Using local anesthesia we inserted an
      especially designed nephrovesical stent into subcutaneous tissue. The stent
      consists of 2 J stents that are joined by a connector after insertion into the
      renal pelvis and bladder. RESULTS: In 8 patients 10 subcutaneous stents were
      inserted instead of a permanent nephrostomy tube. Nephrostomy was required
      because of obstructed ureters caused by metastatic prostate or invasive bladder
      cancer. Attempted Double-J stent insertion into the obstructed ureter had
      previously failed. The bypass has functioned well in all cases during 6 weeks to
      18 months of followup (mean 5.5 months). CONCLUSIONS: The high complication rate
      of a permanent nephrostomy tube and frequent rehospitalization render the
      subcutaneous stent an important alternative to nephrostomy. The subcutaneous
      stent eliminates external devices for urine drainage and improves patient quality
      of life.

PMID- 10647673
TI  - The application of ultrastructural studies in the diagnosis of bladder
      dysfunction in a clinical setting.
AB  - PURPOSE: We examine the ultrastructural changes reported to be present in
      dysfunctional bladders and determine whether they can be used as a predictor of
      urodynamic diagnosis in a clinical setting. MATERIALS AND METHODS: Subjects who
      required urodynamic diagnosis and cystoscopy as part of clinical management were
      recruited for this study. After urodynamic diagnosis cases were classified into 1
      of 5 dysfunction groups as normal bladder outflow obstruction, idiopathic sensory
      urgency, obstruction with detrusor instability and pure detrusor instability. A
      detrusor muscle biopsy was taken from the lateral wall of the bladder at
      cystoscopy for subsequent electron microscopy. RESULTS: Of the 27 cases 6 were
      normal, 9 had bladder outflow obstruction and detrusor instability, 8 had pure
      detrusor instability and 4 had idiopathic sensory urgency. The obstructed group
      showed the myohypertrophy pattern previously reported. In contrast to previous
      reports, abnormal junctions were found in all patients. For each patient the
      ratios of abnormal-to-normal junctions were calculated. Mean and standard error
      ratios were 1.1+/-0.1, 2.7+/-0.2, 6.1+/-1.2, 13.3+/-4.4 for normal, idiopathic
      sensory urgency, obstruction with detrusor instability and pure detrusor
      instability, respectively (p = 0.0003, 0.0042 and 0.04). CONCLUSIONS: There are
      distinct morphological changes in the detrusor associated with bladder
      dysfunction. The ratio of abnormal-to-normal junctions is a novel measurement and
      can be used to predict urodynamic dysfunction. Ultrastructural studies may be
      useful as an adjunct in the diagnosis of bladder dysfunction.

PMID- 10647674
TI  - Liesegang bodies in a solid renal mass: misdiagnosis as parasitic ova.

PMID- 10647675
TI  - Right atrial embolus after percutaneous decompression of obstructing cysts in
      autosomal dominant polycystic kidney disease.

PMID- 10647676
TI  - Transitional cell carcinoma in a multicystic dysplastic kidney.

PMID- 10647677
TI  - Gastroparesis after retroperitoneal surgery successfully treated with
      erythromycin.

PMID- 10647678
TI  - Ureteroduodenal fistula: a rare complication of duodenal ulcer.

PMID- 10647679
TI  - Alpha-fetoprotein producing urachal tumor.

PMID- 10647680
TI  - Osteosarcoma of the bladder successfully treated with partial cystectomy.

PMID- 10647681
TI  - Epididymal lymphangioma.

PMID- 10647682
TI  - Re: The significance of the open bladder neck associated with pelvic fracture
      urethral distraction defects.

PMID- 10647683
TI  - Re: Ethanol injection therapy of the prostate for benign prostatic hyperplasia:
      preliminary report on application of a new technique.

PMID- 10647684
TI  - Renal glomerular response to the inhibition of prostaglandin E2 synthesis and
      protein loading after the relief of unilateral ureteropelvic junction
      obstruction.
AB  - PURPOSE: We investigated glomerular filtration rate and renal function reserve
      after the surgical relief of partial obstruction. MATERIALS AND METHODS: We
      evaluated 4 boys and 1 girl 9 to 14 years old who underwent pyeloplasty because
      of unilateral ureteropelvic junction obstruction. Contralateral normal kidneys
      served as controls. The glomerular filtration rate (inulin clearance), and
      urinary excretion of prostaglandin E2, thromboxane B2 and endothelin were
      determined at baseline and after a meal of 4 gm./kg. cooked unsalted red meat on
      day 4 postoperatively. Tests were repeated the following day 1 hour after the
      oral administration of 20 mg./kg. aspirin, an inhibitor of prostaglandin E2
      synthesis. Urine was collected separately through a bladder catheter and another
      catheter placed in the upper renal pelvis at surgery. RESULTS: Glomerular
      filtration rate at baseline was significantly greater in normal than in
      surgically treated kidneys (77.2 ml. per minute, range 60 to 98 versus 63.6,
      range 43 to 78, p = 0.04). Aspirin did not change baseline inulin clearance in
      normal kidneys but it significantly decreased the glomerular filtration rate in
      operated renal units (-4% versus -26.4%, p = 0.04). The concentration of all
      vasoactive compounds was not significantly different in the urine specimens of
      normal and operated kidneys. The administration of aspirin resulted in a
      significant decrease in mean urinary prostaglandin E2 excretion plus or minus
      standard error in operated but not in normal renal units (0.64+/-0.12 ng. per
      minute versus 0.27+/-0.06, p = 0.04). When expressed as mean versus baseline
      values, protein induced glomerular hyperfiltration seemed lower in operated than
      in contralateral intact kidneys (6.9% and 12.4%, respectively). CONCLUSIONS: In
      the immediate postoperative period previously obstructed kidneys maintain renal
      function via mechanisms that depend on the activation of prostaglandin, mimicking
      normal renal function. This effect is decreased by drugs that inhibit
      prostaglandin E2 production. Therefore, renal damage may be present when the
      glomerular filtration rate appears normal.

PMID- 10647685
TI  - Cost analysis of the treatment of vesicoureteral reflux: a computer model.
AB  - PURPOSE: Surgical intervention for vesicoureteral reflux is generally limited to
      children who have recurrent infection despite adequate antimicrobial prophylaxis
      or in whom compliance with followup cannot be ensured. In addition, surgical
      therapy is considered in children with persistent reflux after a reasonable
      period of surveillance. We used a model based on the management of a theoretical
      population of girls with various grades of reflux and followed the costs incurred
      during a 5-year management period. MATERIALS AND METHODS: The literature on
      vesicoureteral reflux was used to create a set of assumptions regarding
      epidemiology, likelihood of resolution, need for operative intervention, risk of
      infection and appropriate regimen for nonoperative surveillance. These parameters
      were evaluated in infants and children as noted in the literature. A 5-year
      management period was considered. Patients in whom reflux did not resolve with
      medical management at the end of 5 years were assumed to have undergone surgical
      correction. Costs were calculated based on the amounts billed, managed care
      reimbursement and Medicaid reimbursement in Maryland. The costs of up front
      surgical management were calculated and compared to those of 5 years of standard
      management. All costs were discounted at a rate of 10%. RESULTS: Calculated costs
      of standard management were lower for lower grades than those for higher grades
      of reflux. The costs of surgical management were lower than those of standard
      management for higher reflux grades using nondiscounted costs. However, when
      costs were discounted to present value, the costs of standard management were
      significantly lower than those of up-front surgery for all scenarios studied.
      CONCLUSIONS: The cost of vesicoureteral reflux is considerable when whole patient
      groups are considered. Using cost as the only parameter the standard management
      of reflux is less costly than up-front surgery. In the individual surgical
      intervention usually is predicated by patient and family factors which were not
      considered in this model. This computer based construct allows data from
      different institutions to be analyzed to project costs of the management of
      reflux.

PMID- 10647686
TI  - Urinary diversion and orthotopic bladder substitution in children and young
      adults with neurogenic bladder: a safe option for treatment?
AB  - PURPOSE: Combined pharmacotherapy, clean intermittent catheterization and
      infection prophylaxis is currently the gold standard of treatment for neurogenic
      bladder. However, as the adolescent gains independence from parental supervision,
      the intervals of clean intermittent catheterization compliance with medical
      treatment and regularity of followup examinations may decrease, and neurological
      and/or orthopedic status may change. This situation sometimes leads to failure of
      conservative treatment, resulting in incontinence and/or deterioration of the
      upper urinary tract. A multidisciplinary team was established at our institution
      30 years ago to assess all aspects of care for patients with neurogenic bladder,
      of which urological function is just 1 aspect of the complex problem. Patient
      desires and essential medical goals, such as preservation of renal function, are
      considered by this team. An adequate compromise is sought and achieved in some
      cases by urinary diversion. We investigated the long-term safety of urinary
      diversion in these patients and its ability to protect the upper urinary tract.
      MATERIALS AND METHODS: Between 1967 and 1997 urinary diversion was performed in
      149 patients with neurogenic bladder. Mean followup was 11.8 years (range 0.8 to
      28.5) in 129 cases. Mean patient age at surgery was 12.1 years (range 0.8 to 20).
      A colonic conduit was created in 59 patients, mainly before the era of clean
      intermittent catheterization and continent diversion, while orthotopic bladder
      substitution was performed in 12 and continent urinary diversion (Mainz pouch I)
      in 58, of whom 50% were wheelchair bound. RESULTS: The upper urinary tract
      improved or remained stable in 97% of the renal units in patients with a colonic
      conduit or Mainz pouch I, and in 95% of the renal units in those with orthotopic
      bladder substitution. All patients with bladder substitution were continent
      during the day, 1 required occasional pads at night and 7 of 12 performed clean
      intermittent catheterization. Complete continence was achieved in 98% of those
      with a continent stoma. CONCLUSIONS: After failure of conservative treatment in
      patients with neurogenic bladder urinary diversion represents a safe long-term
      compromise. Daytime and nighttime continence is provided by the Mainz pouch
      bladder substitution and urinary diversion, while the upper urinary tract is
      protected by antireflux ureteral implantation.

PMID- 10647687
TI  - The overactive bladder in childhood: long-term results with conservative
      management.
AB  - PURPOSE: Idiopathic detrusor overactivity has not been thoroughly investigated
      and its natural history remains largely anecdotal. Bladder overactivity resulting
      from a neurogenic, anatomical or medical condition has been well described.
      Therefore, we assessed the long-term results of conservative treatment of
      children with idiopathic symptomatic refractory detrusor instability. MATERIALS
      AND METHODS: We reviewed the records of 58 patients who had an isolated finding
      of uninhibited contractions on urodynamics performed for refractory enuresis and
      daytime wetting between 1988 and 1994. Study exclusion criteria were chronic
      urinary tract infection, neurological lesion, anatomical abnormality of the lower
      urinary tract and less than 12 months of followup. RESULTS: Of the 30 children
      who met our study inclusion criteria 26 (87%) had complete (21) or significant
      (5) symptom resolution. Average time to resolution was 2.7 years (range 0.2 to
      6.6). Patients with a 50% to 90% bladder capacity expected for age were more
      likely to benefit from therapy than those with a bladder capacity outside of this
      range. Age and gender were not significant predictors of resolution although
      girls were more likely to have resolution than boys. CONCLUSIONS: Idiopathic
      detrusor instability is amenable to conservative management in the majority of
      patients during a prolonged period. We advocate thorough urological and
      urodynamic evaluation to identify idiopathic detrusor instability as an etiology
      of enuresis and daytime wetting in complicated cases.

PMID- 10647688
TI  - The overactive bladder in childhood.

PMID- 10647689
TI  - A nontoxic diphtheria toxin analogue inhibits neonatal bladder smooth muscle cell
      proliferation.
AB  - PURPOSE: The response of the neonatal bladder to infravesical obstruction, such
      as posterior urethral valves or detrusor-sphincter dyssynergia, may result in
      structural and functional changes that persist well after obstruction is treated.
      A pharmacological means of inhibiting smooth muscle cell proliferation would
      likely serve to halt or reverse this deleterious process. Heparin binding (HB)
      epidermal growth factor (EGF) is a known smooth muscle cell mitogen, while its
      membrane bound precursor serves as the diphtheria toxin receptor. We report the
      effects of the nontoxic diphtheria toxin analogue cross reacting material (CRM)
      197 on neonatal sheep bladder smooth muscle cell proliferation. MATERIALS AND
      METHODS: Neonatal sheep smooth muscle cell cultures were obtained from whole
      bladder explants. Immunohistochemical staining was performed for desmin and alpha
      smooth muscle actin. HB-EGF messenger RNA was detected by reverse transcriptase
      polymerase chain reaction using primers to the human sequence, while pro-HB-EGF
      peptide was confirmed using a diphtheria toxin sensitivity assay with
      incorporation of tritiated leucine. Cells grown in 96 well plates were exposed to
      1, 10 and 100 microg./ml. CRM 197 for 5 days, after which relative cell number
      was determined using an 3-[4,5-dimethylthiazol-2-yl] -2,5-diphenyltetrazolium
      bromide; thiazolyl blue based assay read at a wavelength of 550 nm. Statistical
      analysis was performed using Student's t test. RESULTS: Primary cell cultures
      stained positive for desmin and alpha-smooth muscle actin, confirming a smooth
      muscle origin. Reverse transcriptase polymerase chain reaction yielded a 453 bp
      product with 88% homology to human HB-EGF. Total protein synthesis significantly
      decreased when cells were incubated with diphtheria toxin, confirming the
      presence of membrane bound pro-HB-EGF. CRM 197 inhibited bladder smooth muscle
      cell growth in a dose dependent fashion at a concentration of 10 microg./ml.,
      resulting in a 40% decrease in proliferation (p <0.0001). CONCLUSION: CRM 197
      inhibits bladder smooth muscle cell proliferation in a dose dependent, nontoxic
      fashion through its interaction with HB-EGF. These data suggest that molecular
      strategies designed to inhibit HB-EGF mediated cell growth may prove beneficial
      for the prevention and/or treatment of detrusor hypertrophy secondary to
      anatomical or functional bladder outlet obstruction.

PMID- 10647690
TI  - Urethral instability as an important element of dysfunctional voiding.
AB  - PURPOSE: We monitored detrusor and urethral behavior during bladder filling in
      girls with dysfunctional voiding (incomplete perineal relaxation) to determine
      the causes of this pathological condition. MATERIALS AND METHODS: In 15 girls
      without neuropathy but with a staccato voiding pattern in whom symptoms of
      urinary tract infection and urge incontinence were refractory to treatment we
      recorded urethral and bladder pressure, and anal sphincter needle
      electromyography throughout slow bladder filling. RESULTS: Urethral instability
      was observed in 8 of the 15 girls as urethral pressure decreases with short
      periods of electromyography silence (6) or as intermittent urethral pressure
      increases with short perineal spasms (2). Detrusor instability was noted in 12
      girls, while bladder pressure was normal in 1 and hypoactive in 2. In 6 cases of
      an unstable bladder urethral pressure decreases with silent electromyography
      periods were also noted. In 1 case low basic urethral pressure had short periods
      of increased pressure with electromyography bursts. In another case high
      compliance bladder uninhibited sphincter contractions were noted throughout
      filling. CONCLUSIONS: Dysfunctional voiding is a misleading term since a
      pathological condition is also present during the bladder filling phase.
      Frequently observed detrusor and urethral instability may explain the urge
      sensation during filling and the staccato voiding phase.

PMID- 10647691
TI  - Modified technique of antegrade continence enema using a stapling device.
AB  - PURPOSE: We present a stapling technique for constructing an antegrade continence
      enema (ACE) conduit that is helpful in cases of insufficient appendiceal luminal
      length or when a concomitant appendiceal Mitrofanoff stoma is required. MATERIALS
      AND METHODS: In 6 patients with a mean age of 9.5 years who required an ACE
      procedure the cecum was tubularized in continuation with the orthotopic appendix
      at its base, using a stapling device to construct an ACE conduit. The tubularized
      segment was imbricated with permanent suture material. In 3 cases appendiceal
      length after tubularization was sufficient to allow splitting for the concomitant
      creation of an appendiceal Mitrofanoff stoma. RESULTS: Patients have been
      followed an average of 16.5 months. Stomal continence was achieved in all cases
      as well as reliable catheterization of the appendiceal cecostomy in 6 and the
      Mitrofanoff conduit in 3. CONCLUSIONS: This modification of the ACE procedure
      with cecal tubularization in continuation with the appendix using a stapling
      device is an excellent approach in cases of inadequate appendiceal length. It
      successfully creates a catheterizable stoma with a reliable flap valve continence
      mechanism. The complex reconstructive procedure is simplified by eliminating the
      need to use tapered small intestine, while allowing the creation of a concomitant
      appendiceal Mitrofanoff stoma as necessary.

PMID- 10647692
TI  - Inadvertent concentrated epinephrine injection at newborn circumcision: effect
      and treatment.

PMID- 10647693
TI  - Testicular volume does not predict germ cell count in patients with
      cryptorchidism.
AB  - PURPOSE: A germ cell count of less than 0.2 germ cell per tubule on the
      prepubertal biopsy of cryptorchid testes predicts abnormal spermiograms and
      decreased fertility in adulthood, and may be used to select patients for post
      orchiopexy hormonal therapy. Testicular volume directly correlates with
      testicular function and spermiogenesis. We determined whether testicular volume
      would predict the total germ cell count accurately enough to replace testicular
      biopsy in the modern management of cryptorchidism. MATERIALS AND METHODS: At our
      hospital 723 patients younger than 9 years with cryptorchidism (unilateral in 619
      and bilateral in 104) underwent orchiopexy and bilateral testicular biopsies.
      These patients had not undergone groin surgery or hormonal therapy previously and
      had at least 50 tubules in each testicular biopsy. Testicular volume and
      position, patient age and germ cell counts were analyzed. The generalized
      estimating equation was used to determine whether a correlation existed between
      testicular volume and germ cell count. RESULTS: The generalized estimating
      equation demonstrated a direct correlation between testicular volume and germ
      cell count. However, germ cell counts predicted from testicular volume varied
      widely within the 95% confidence intervals. Testes with less than 0.2 germ cell
      per tubule cannot be reliably distinguished from those with greater than 0.2 germ
      cell per tubule. CONCLUSIONS: Testicular volume does not accurately predict the
      germ cell count in patients with undescended testes, cannot be used to select
      patients for post-orchiopexy hormonal therapy and cannot replace testicular
      biopsy in the modern management of cryptorchidism.

PMID- 10647694
TI  - An in vivo endoluminal ultrasonographic study of peristaltic activity in the
      distal porcine ureter.
AB  - PURPOSE: Experiments were performed to quantify the duration and frequency of
      ureteric peristaltic activity in the laparotomized and non-laparotomized pig in
      its virgin and postinstrumented states. MATERIALS AND METHODS: Pigs (n = 10) in a
      steady state of hydration were studied under halothane anesthesia in two groups.
      The study was undertaken in two separate sessions at a week's interval. In group
      I laparotomy and vesicotomy were undertaken to obtain ELUS images. In group II,
      peristalsis was studied using an ELUS probe introduced through the working
      channel of a 22F rigid cystoscope. Peristalsis was visualized as a periodic
      diameter-change of ureter and recorded (for approx. 30 minutes) on videotape
      after an initial period of adaptation of approx. 30 minutes. RESULTS: The ureter
      acts like a pump discharging urine into the bladder through peristaltic activity.
      ELUS imaging of ureteric peristalsis correlated well with "eyeballing" of the
      passage of peristalsis through a ureter (group I). The shortest peristaltic
      activity in group I was 6.0+/-2.0 seconds in the non-instrumented- and 5.1+/-1.4
      seconds in the instrumented ureter. In group II it was 6.8+/-1.5 seconds in the
      non-instrumented- and 6.4+/-1.5 seconds in the instrumented ureter. Chronic
      dilatation of ureter led to decrease in peristalsis frequency. Interestingly,
      acute dilatation caused an increase in ureteric peristalsis frequency.
      CONCLUSIONS: Ureteric peristalsis acts as a pump discharging urinary boluses
      (intraluminal fluid load) unidirectionally into the bladder. ELUS provides us an
      opportunity to quantify and study ureteric peristalsis.

PMID- 10647695
TI  - Selective cyclooxygenase-2 inhibitors reduce ureteral contraction in vitro: a
      better alternative for renal colic?
AB  - PURPOSE: To quantitate the effects of a selective cyclooxygenase (COX)-2
      inhibitor, NS-398, on porcine and human ureteral contractility in vitro.
      MATERIALS AND METHODS: This study was performed in 3 distinct groups. In group 1,
      segments of ureter were obtained from freshly sacrificed domestic swine. Sections
      were isolated and suspended longitudinally. Twenty-four ureteral segments were
      treated with either indomethacin (a nonselective COX inhibitor), NS-398
      (selective COX-2 inhibitor), or DMSO (control). Spontaneous contractions were
      then recorded in each group. In group 2, fifteen segments of human ureter were
      obtained from patients undergoing donor nephrectomy or ureteral reimplantation.
      Segments were isolated and suspended as above, and treated with either
      indomethacin, NS-398, or DMSO. In group 3, eighteen sections of human ureter
      obtained from donor nephrectomy patients were passively sensitized for 20 hours
      in ragweed allergic donor serum. Ureteral segments were then treated with either
      indomethacin, NS-398 or DMSO, and then the segments were subsequently exposed to
      ragweed antigen and contractions were subsequently recorded. RESULTS: In group 1,
      the average time to 100% inhibition of spontaneous contraction was 48.8 minutes
      (S.E.M. = 7.9) for indomethacin, 65.7 minutes (S.E.M. 6.7) for NS-398, and beyond
      150 minutes for DMSO. The percent reduction was 100% for indomethacin (S.E.M. =
      0), 92.5% for NS-398 (S.E.M. 4.9%), and 52.9% for DMSO (s.e.m. = 10.8%). In group
      2, the average time to 100% inhibition was 29 minutes (S.E.M. = 10.4) for
      indomethacin, 21 minutes (S.E.M. 4.8) for NS-398, and beyond 150 minutes for
      DMSO. The percent reduction was 100% for indomethacin (S.E.M. = 0), 100% (S.E.M.
      = 0) for NS-398, and 20% (S.E.M. = 12%) for DMSO. In group 3, ragweed sensitized
      ureters treated with DMSO (control group) contracted an average maximum of 10
      times per 5 minutes. Antigen failed to induce contractions of sensitized tissues
      treated with indomethacin or NS-398. CONCLUSION: A selective COX-2 inhibitor (NS
      398) reduces ureteral contractility as effectively as indomethacin (a
      nonselective COX inhibitor) in both porcine and human ureteral segments in vitro
      (p <0.05). Selective COX-2 inhibitors may have significant clinical potential in
      treating renal colic as they cause less gastric ulceration.

PMID- 10647696
TI  - Quality of nucleic acids extracted from fresh prostatic tissue obtained from TURP
      procedures.
AB  - PURPOSE: The molecular genetic study of benign prostatic hyperplasia (BPH)
      requires high quality nucleic acids from BPH tissue. It has been generally
      assumed, but not experimentally proven, that the diathermy used in trans-urethral
      resection of the prostate (TURP) damages nucleic acids. MATERIALS AND METHODS:
      Total RNA, polyA+ RNA and genomic DNA isolated from fresh tissue obtained from
      TURP procedures were compared with those isolated from tissue obtained from open
      prostatectomy. RESULTS: On a formaldehyde agarose gel, there was an increase in
      low molecular weight RNA in the TURP derived samples, in comparison to that in
      the open prostatectomy derived samples. The 28S and 18S rRNA were present in all
      TURP specimens and although the two bands were reduced in some samples, there
      were samples in which the 2 bands were indistinguishable from the open
      prostatectomy derived samples. Low molecular weight fragments seen in total RNA
      were reduced greatly in polyA+ RNA and the difference in polyA+ RNA between the
      TURP and open prostatectomy derived samples was significantly diminished. RT-PCR
      of two ubiquitously expressed gene transcripts (Galpha11, 256 bp and HPRT, 847
      bp) yielded products of similar size and intensity between TURP and open
      prostatectomy derived samples. Genomic DNA obtained from TURP derived specimens
      showed no difference in size or enzyme digestibility in comparison to that from
      open prostatectomy. CONCLUSIONS: Nucleic acids extracted from fresh prostatic
      tissue derived from TURP procedures can be used as readily as any other fresh
      tissue for RT-PCR based molecular genetic studies, although polyA+ RNA isolation
      is recommended if degradation-free RNA is required.

PMID- 10647697
TI  - Characterization of an immortalized human vaginal epithelial cell line.
AB  - PURPOSE: Adherence of type 1 piliated Escherichia coli to vaginal mucosa plays a
      major role in the pathogenesis of ascending urinary tract infections (UTIs) in
      women. Progress in understanding the mechanism of adherence to the vaginal
      surface could be enhanced by the utilization of well-characterized vaginal
      epithelial cells. The objective of this study was to immortalize vaginal
      epithelial cells and study their bacterial adherence properties. MATERIALS AND
      METHODS: Primary vaginal cells were obtained from a normal post-menopausal woman,
      immortalized by infection with E6/E7 genes from human papillomavirus 16 (HPV 16)
      and cultured in serum free keratinocyte growth factor medium. RESULTS: Positive
      immunostaining with a pool of antibodies to cytokeratins 1, 5, 10 and 14 (K1, K5,
      K10 and K14) and to K13 confirmed the epithelial origin of these cells. The
      immortalized cells showed binding of type 1 piliated E. coli in a pili specific
      and mannose sensitive manner. CONCLUSION: This model system should facilitate
      studies on the interaction of pathogens with vaginal mucosal cells, an essential
      step in the progression of ascending UTIs in women.

PMID- 10647698
TI  - High incidence of receptors for luteinizing hormone-releasing hormone (LHRH) and
      LHRH receptor gene expression in human prostate cancers.
AB  - PURPOSE: Agonistic analogs of luteinizing hormone-releasing hormone (LHRH) are
      widely used for therapy of advanced prostate cancer based upon their ability to
      suppress testosterone secretion in patients. Various studies also indicate that
      LHRH analogs might have direct inhibitory effects on prostate tumors mediated by
      specific LHRH receptors. In this study we investigated the presence and
      characteristics of receptors for LHRH and their messenger (m) ribonucleic acid
      (RNA) expression in specimens of human prostate adenocarcinomas and benign
      prostatic tissue. MATERIALS AND METHODS: In vitro ligand competition assays as
      well as reverse transcriptase polymerase chain reaction (RT-PCR) were performed
      to investigate the expression of receptors for LHRH in surgical specimens of
      human prostate cancers and benign prostatic tissue. RESULTS: Sixty-nine of 80
      (86%) cancers exhibited specific, medium to high-affinity binding for [D
      Trp6]LHRH with a dissociation constant (Kd) of 6.55+/-0.4 nM and a maximal
      binding capacity (Bmax) of 483.6+/-25.4 fmol./mg. membrane protein. Two prostate
      cancer patients who were treated with the LHRH agonist goserelin prior to
      prostatectomy did not show tumor LHRH receptors. The expression of mRNA for LHRH
      receptors was observed in 19 of 22 (86%) prostate cancers. Benign prostatic
      tissue also displayed LHRH receptor gene expression, but exhibited lower Bmax
      value. There was a negative correlation (p <0.001) between LHRH receptor binding
      capacity and cancer grade (Gleason score); higher Gleason scores were associated
      with significantly lower binding capacity but an increased binding affinity.
      CONCLUSIONS: The expression of specific receptor proteins for LHRH in human
      prostate cancer provides a rationale for the improvement in methods for therapy
      of this malignancy based on LHRH analogs.

PMID- 10647699
TI  - Neural network analysis of clinicopathological and molecular markers in bladder
      cancer.
AB  - PURPOSE: To evaluate retrospectively the ability of an artificial neural network
      (ANN) to predict bladder cancer recurrence within 6 months of diagnosis and stage
      progression in patients with Ta/T1 bladder cancer, and 12-month cancer-specific
      survival in patients with T2-T4 bladder cancer. MATERIALS AND METHODS: Data were
      analyzed using a NeuralWorks Professional II/Plus software package. The input
      neural data consisted of clinicopathological and molecular characteristics.
      Distinct patient groups were used for the prediction of stage progression and
      tumor recurrence in Ta/T1 bladder cancers, and 12-month cancer-specific survival
      for patients with T2-T4 tumors. ANN predictions were compared with those of four
      consultant urologists. RESULTS: The accuracy of the neural network in predicting
      stage progression and recurrence within 6 months for Ta/T1 tumors and 12-month
      cancer-specific survival for T2-T4 cancers was 80%, 75% and 82% respectively;
      with corresponding figures for clinicians being 74%, 79% and 65%. On restricting
      the validation subset to patients with T1G3 tumors in relation to stage
      progression, the sensitivity of the ANN analysis increased to 100% with a
      specificity of 78% and an overall accuracy of 82%. The performance of the ANN in
      predicting stage progression in T1G3 tumors was significantly higher than that of
      clinicians (p = 0.25 for the ANN and p = 0.008 for clinicians, McNemar test).
      CONCLUSIONS: Data analysis using an ANN has been shown to be a useful adjunct in
      predicting outcomes in patients with bladder cancer and out-performs clinicians'
      predictions of stage progression in the high risk group of patients with T1G3
      disease.

PMID- 10647700
TI  - Assessment of the degradation of denatured albumin solder by human urine.
AB  - PURPOSE: Several studies have been undertaken to evaluate the efficacy of human
      serum albumin (HSA) as a solder in urologic procedures. The purpose of this study
      was to evaluate whether albumin solder undergoes significant degradation in
      urine. MATERIALS AND METHODS: Laser denatured 25% HSA pellets were incubated at
      37C for varying times with 1 ml. of either pooled human urine or control diluent
      solution adjusted to the same pH and osmolality as urine. To assess the
      contribution of enzymatic degradation, aliquots of urine were boiled and compared
      with non-boiled urine and diluent. The amount of solubilized HSA in solution was
      measured using the Bradford assay, while the degradation of albumin was detected
      by SDS-PAGE electrophoresis. RESULTS: Approximately 5% of the albumin was
      degraded over a period of 7 days following incubation at 37C, regardless of
      treatment. SDS-PAGE revealed only minor traces of degradation in urine and
      controls. The very slight degradation of denatured HSA appears to be non
      enzymatic, as it was observed in both urine and diluent samples. CONCLUSIONS: HSA
      solder appears to be appropriate for use in urologic reconstructive surgery since
      it is not appreciably degraded in the presence of urine.

PMID- 10647701
TI  - Multiple sites of action in the inhibitory effect of nociceptin on the
      micturition reflex.
AB  - PURPOSE: Nociceptin, the endogenous peptide ligand for the opioid receptor-like1
      (ORL1) receptors, exerts a naloxone-resistant suppressant effect on micturition
      reflex after intravenous administration. This work aims to elucidate the
      mechanism and the site of action of the inhibitory effect of nociceptin on the
      micturition reflex. MATERIALS AND METHODS: The bladder of urethane-anesthetized
      rats was cannulated through the dome (cystometries) or the urethra in
      isovolumetric conditions (distension-induced reflex contractions, DIRCs). In this
      latter model, the effect of the application of nociceptin onto the serosal
      surface of the urinary bladder was determined. The effect of intravenous,
      intrathecal and intracerebroventricular administration of nociceptin on ongoing
      cystometries at two different infusion rates (50 and 250 microL/min.) was
      assessed. The effect of the intravenous administration of nociceptin on
      cystometries was also studied in capsaicin-pretreated animals. RESULTS: When
      cystometric recordings were obtained at a low infusion-rate (50 microL/min.), the
      intravenous administration of nociceptin (10 to 100 nmol./kg.) induced a dose
      dependent reduction in the micturition frequency associated to an increase of the
      pressure threshold for activating the micturition reflex, whereas the amplitude
      of micturition contractions was unaffected. These effects faded within 60
      minutes. The intracerebroventricular administration of nociceptin (0.3 nmol./rat)
      produced urodynamic changes similar to those observed after the intravenous route
      and, in addition, also reduced the amplitude of micturition contractions. The
      intrathecal administration of nociceptin up to 1 nmol./rat was ineffective.
      Capsaicin pretreatment (164 micromol./kg., s.c. 5 to 6 days before) significantly
      reduced the micturition frequency as compared with controls. In capsaicin
      pretreated animals intravenous nociceptin was ineffective. When cystometries were
      recorded at a high infusion-rate (250 microL/min.) either intravenous (100
      nmol./kg.), i.t. (1 nmol./rat) nociceptin or capsaicin pretreatment had no
      effect. In contrast, intracerebroventricular nociceptin (0.3 and 1 nmol./rat)
      inhibited the micturition reflex by reducing both the frequency and the amplitude
      of micturition contractions: these effect were not modified by naloxone (0.5
      micromol./kg., i.v.). The topical application of nociceptin (5 and 50 nmol./rat)
      caused a dose-dependent inhibition of DIRCs. CONCLUSION: Nociceptin inhibits the
      micturition reflex at a peripheral and at a supraspinal site. The effects
      observed after the intravenous administration of nociceptin indicate that the
      functional integrity of capsaicin-sensitive bladder afferents is required for
      exerting its inhibitory activity at the peripheral level. In contrast, the
      supraspinal effect of nociceptin involves both the afferent and the efferent
      pathways of the micturition reflex, possibly through a direct effect on ORL1
      receptors located in the pontine micturition center.

PMID- 10647702
TI  - Studies of the pathophysiology of idiopathic detrusor instability: the
      physiological properties of the detrusor smooth muscle and its pattern of
      innervation.
AB  - PURPOSE: Idiopathic detrusor instability (IDI) is a common cause of lower urinary
      tract storage symptoms, such as urgency, frequency and urge incontinence. We have
      investigated the in vitro properties and pattern of innervation of the detrusor
      from patients with this condition. MATERIALS AND METHODS: Full thickness bladder
      specimens were obtained perioperatively from 14 patients with IDI and from 14
      cadaveric controls undergoing transplant organ retrieval. Isolated detrusor
      smooth muscle strips were mounted in organ baths for isometric tension recording.
      Frequency-response curves to electrical field stimulation (EFS) (1 Hz to 50 Hz)
      and concentration response curves for carbachol (10(-7) M to 5 x 10(-4) M) and
      potassium (12 mM to 120 mM) were constructed. Acetylcholinesterase histochemistry
      and immunohistochemistry for both phosphorylated and non-phosphorylated
      neurofilaments was carried out on frozen sections of control and IDI bladders.
      RESULTS: IDI strips developed greater spontaneous tone (0.25 gm./mg. versus 0.12
      gm./mg.; p <0.0001) and more spontaneous fused tetanic contractions (16.8% versus
      6.8%; p <0.005) during an initial 90 minutes equilibration period. The IDI strips
      were less responsive than controls to nerve stimulation (max. response to EFS
      0.79 gm./mg. versus 1.23 gm./mg.; p <0.0001) and were supersensitive to potassium
      (EC50 39.7 mM versus 45.7 mM; p = 0.003) but not to carbachol (EC50 7.3 x 10(-6)
      M versus 6.6 x 10(-6) M; p = 0.48). Morphometric studies revealed reduced
      staining of presumed cholinergic nerves, with 34.7% of IDI smooth muscle bundles
      appearing denervated compared with 1.5% of controls (p <0.0001). CONCLUSIONS: Our
      study supports the notion that there is a fundamental abnormality in IDI at the
      level of the bladder wall, with evidence of altered spontaneous contractile
      activity consistent with an increased electrical coupling of cells, a patchy
      denervation of the detrusor and a potassium supersensitivity.

PMID- 10647703
TI  - The mechanism of contraction by 2-chloroadenosine in cat detrusor muscle cells.
AB  - PURPOSE: Four adenosine receptors (ARs), designated A1AR (A1 adenosine receptor),
      A2aAR (A2a adenosine receptor), A2bAR (A2b adenosine receptor), and A3AR (A3
      adenosine receptor), have been cloned from various species, but the contraction
      mechanism via A1ARs in cat detrusor muscle cell is not well known. MATERIALS AND
      METHODS: We examined the cellular mechanism using an A1AR agonist 2
      chloroadenosine (2-CA) in cat detrusor cell isolated by enzymatic digestion. To
      examine which phospholipase mediates the contraction, we used phospholipase
      inhibitors. RESULTS: The adenosine analog potency order is R-N6
      phenylisopropyladenosine (R-PIA) > 5'-N-ethylcarbosamine adenosine (NECA) > 2
      chloroadenosine (2-CA) > S-N6-phenylisopropyladenosine (S-PIA). The ratio of equi
      effective concentrations of R-PIA/S-PIA was 58.2. 8-cyclopentyl-1,3
      dipropylxanthine (DPCPX, 300 nM) shifted to the right the concentration-response
      curves of 2-CA. These results indicate A1ARs mediate 2-CA induced contraction in
      cat detrusor muscle. G proteins (Gi1, Gi2, Gi3, Go, Gs, and Gq) in cat detrusor
      muscle were detected by immunoblot analysis. Pertussis toxin (PTX) inhibited 2-CA
      induced contraction. In permeabilized cells, antibodies against Galphai3
      antagonized 2-CA induced contraction, suggesting that the contraction is mediated
      by Gi3 protein. A phosphatidylinositol-specific phospholipase C (PLC) inhibitor,
      neomycin, reduced 2-CA induced contraction, but a phospholipase D (PLD)
      inhibitor, p-chloromercuribenzoic acid, and a phospholipase A2 (PLA2) inhibitor,
      dimethyl-eicosa-dienoic acid (DEDA), had no effect. We found the presence of the
      main PLC isozymes, PLC-beta1, PLC-beta3, and PLC-gamma1. 2-CA induced contraction
      in permeabilized cells was inhibited by PLC-beta3 but not by PLC-beta1 or PLC
      gamma1 antibody. These results imply that A1ARs are coupled to PLC-beta3 via PTX
      sensitive Gi3 protein. Sr2+ medium and thapsigargin, which replaces intracellular
      Ca2+ and deplete intracellular calcium stores respectively, inhibited 2-CA
      induced contraction. CONCLUSIONS: These results suggest that A1ARs mediating 2-CA
      induced contraction exist in cat detrusor muscle and the contraction depends on a
      PTX-sensitive Gi3 protein, PLC-beta3 and the release of intracellular Ca2+.

PMID- 10647704
TI  - Tumor size predicts the survival of patients with pathologic stage T2 bladder
      carcinoma: a critical evaluation of the depth of muscle invasion.

PMID- 10647705
TI  - Klinefelter's syndrome in the male infertility clinic.

PMID- 10647706
TI  - Silicone oil tamponade for macular holes.

PMID- 10647707
TI  - Screening for amblyopia in preverbal children.

PMID- 10647708
TI  - Success rate of endoscopic laser-assisted dacryocystorhinostomy.

PMID- 10647709
TI  - Schizophrenia, psychotropic medication, and cataract.

PMID- 10647710
TI  - Excimer laser photorefractive keratectomy.

PMID- 10647711
TI  - Excimer laser photorefractive keratectomy.

PMID- 10647712
TI  - Evidence-based analysis of prophylactic treatment of asymptomatic retinal breaks
      and lattice degeneration.
AB  - PURPOSE: To assess the quality of information in the literature regarding the
      benefits of prophylactic treatment of asymptomatic retinal tears and lattice
      degeneration. CLINICAL RELEVANCE: Asymptomatic retinal breaks occur in
      approximately 7% of patients over age 40, and lattice degeneration is present in
      approximately 8% of the general population. Because retinal breaks cause retinal
      detachment and lattice degeneration is associated with approximately 30% of
      retinal detachments, prophylactic treatment of these lesions has sometimes been
      recommended. LITERATURE REVIEWED: A panel of vitreoretinal experts performed a
      literature review of all publications regarding prevention of retinal detachment
      that have been published in English. These articles were then used to prepare
      recommendations for patient care in an American Academy of Ophthalmology
      Preferred Practice Pattern (PPP). Each recommendation was rated according to: (1)
      its importance in the care process and (2) the strength of evidence supporting
      the given recommendation. RESULTS: Most recommendations were rated as A (most
      important to patient care). Only a single publication was graded as I (providing
      strong evidence in support of a recommendation), and this was not a prospective
      trial. Of the few publications rated as II (substantial evidence), most were
      studies documenting a lack of treatment benefit. Because of an absence of level I
      and level II studies in the literature, level III (consensus of expert opinion)
      was the basis for most recommendations in the PPP. CONCLUSIONS: The current
      literature regarding prevention of retinal detachment does not provide sufficient
      information to support strongly prophylactic treatment of lesions other than
      symptomatic flap tears. Prospective randomized trials of prophylactic therapy are
      indicated. Eyes highly predisposed to retinal detachment should be considered for
      such studies.

PMID- 10647713
TI  - A screening approach to the surveillance of patients with diabetes for the
      presence of vision-threatening retinopathy.
AB  - OBJECTIVE: To provide scientifically based screening rules for the primary care
      setting designed to identify, through evaluation of a prescribed and limited
      portion of the posterior fundus, those patients with diabetes who have
      retinopathy severe enough to need referral to eye care specialists. DESIGN:
      Retrospective analysis of the Early Treatment Diabetic Retinopathy Study (ETDRS)
      photographic data base. PARTICIPANTS: The fundus photographic grading data from
      3711 patients with diabetes enrolled in the ETDRS. METHODS: Multivariate
      regression techniques were used to identify retinopathy lesions in photographic
      fields 1, 2, 3, or a combination thereof that predict proliferative diabetic
      retinopathy (PDR) or clinically significant macular edema (CSME) within the seven
      standard fields. These were used to construct a family of screening rules with
      optimal combined sensitivity and specificity on which to base referrals to eye
      care specialists. MAIN OUTCOME MEASURES: Presence of moderate to severe
      nonproliferative diabetic retinopathy (NPDR), PDR, or CSME in graded fundus
      photographs. RESULTS: Hemorrhages and microaneurysms (h/ma) temporal to the
      macula (photographic field 3), as severe as or more severe than ETDRS standard
      photograph 1 (h/ma 3 > or = 3), identified 87% to 89% of eyes with PDR and 92% to
      93% of eyes with moderately severe to severe NPDR, which are at high risk for
      developing PDR. Extrapolating the results using retinopathy prevalence data from
      epidemiologic studies for the general older onset diabetic population, the
      calculated sensitivity for detecting PDR on a single examination is 87%, the
      specificity 80%; for moderate NPDR or worse, the sensitivity is 81 %, specificity
      93%. Applying the presence of h/ma 3 > or = 3 as a screening rule to the older
      onset population, 26.5% of patients would be referred and 73.5% would not be
      referred. Any hard exudate within one disc diameter of the macular center detects
      CSME with sensitivity 94%, specificity 54%. Hard exudate of moderate or worse
      severity anywhere in the macular region (field 2) predicts CSME with sensitivity
      89%, specificity 58%. CONCLUSIONS: Screening protocols based on assessing
      retinopathy lesion severity in the posterior fundus have the potential to
      identify most diabetic patients with vision-threatening retinopathy. If the
      protocols can be implemented effectively in a primary care setting, patients
      requiring referral for specialty care could be reliably identified, and the total
      number of patients needing specialty referral could be substantially reduced from
      current guidelines.

PMID- 10647714
TI  - Telemedical evaluation and management of retinopathy of prematurity using a
      fiberoptic digital fundus camera.
AB  - OBJECTIVE: We sought to determine whether retinopathy of prematurity (ROP) can be
      evaluated and managed telemedically. DESIGN: Multicenter noncomparative case
      series. PARTICIPANTS: Ten patients (19 eyes) with ROP were evaluated and treated
      per standard of care and imaged with the RetCam 120 digital fundus camera (Massie
      Research Laboratories, Inc., Dublin, CA). INTERVENTION: Images were transmitted
      to a remote site for evaluation and management recommendations. MAIN OUTCOME
      MEASURES: Telemedical evaluations and management recommendations were compared
      with traditional on-site standard of care evaluations and treatments. RESULTS:
      The identification of Plus disease at the remote site was accurately identified
      in 95% of eyes. Prethreshold, threshold, and stage 4 or 5 ROP were correctly
      detected in 17 of 19 (89%) eyes. CONCLUSIONS: Results indicate ROP can be
      evaluated and treatment recommendations made at remote sites with telemedicine
      strategies.

PMID- 10647715
TI  - Problems with and pitfalls of photodynamic therapy.
AB  - OBJECTIVE: To delineate the various factors that may influence the outcome of
      photodynamic therapy of the retina and choroid. DESIGN: Experimental animal
      study. ANIMALS: Pigmented and nonpigmented rabbits; rhesus monkeys. INTERVENTION:
      The hydrophilic photosensitizer, mono-L-aspartyl chlorin e6, which is maximally
      activated at 664 nm, was studied after intravenous injection into pigmented and
      nonpigmented rabbits and rhesus monkeys. Laser light was supplied by a red diode
      laser coupled to a modified slit-lamp biomicroscope and delivered to the ocular
      fundus after passing through a standard fundus contact lens. Standard
      photodynamic parameters were used. The effects of fundus pigmentation,
      intraocular pressure, spot focus and defocus, region of fundus treated,
      equivalent fluence, and retreatment were observed in the different animal
      species. MAIN OUTCOME MEASURES: Slit-lamp biomicroscopy, fluorescein angiography,
      light and transmission electron microscopy. RESULTS: Fundus pigmentation appeared
      to be a factor only at the lowest fluence level tested, where only 4 of 12
      lesions attempted in pigmented fundi were noted on fluorescein angiography,
      compared with 12 of 12 lesions in albino rabbits. At normal intraocular pressures
      and a given fluence, 10 of 10 lesions were fully manifested on fluorescein
      angiography, compared with 4 of 10 at 30 mmHg and 0 of 10 at pressures sufficient
      to blanch the optic nerve (>60 mmHg). For laser spots either focused or
      defocused, there were 6 of 6 lesions that were fully manifested on fluorescein
      angiography for each of the parameters. Lesions treated in the fovea resulted in
      larger spots on fluorescein angiography. The fluence of 5 mW for 10 seconds
      resulted in a larger lesion on angiography than the equivalent fluence of 10 mW
      for 5 seconds. Areas of retreatment in rabbits demonstrated more thinning of the
      neurosensory retina and loss of photoreceptor outer segments and nuclei than
      corresponding areas receiving one treatment. CONCLUSIONS: Photodynamic therapy
      results varied, depending on intraocular pressure, region of fundus treated,
      ocular pigmentation, and the total time of exposure to the photosensitizer.
      Retreatment resulted in progressive thinning of the neurosensory retina with loss
      of photoreceptor outer segments and nuclei in the rabbit eye.

PMID- 10647716
TI  - Retinal detachment in ocular toxoplasmosis.
AB  - PURPOSE: To report on the clinical course and prognosis of retinal breaks and
      detachment occurring in patients with ocular toxoplasmosis. DESIGN: Retrospective
      cross-sectional observational study. PARTICIPANTS: One hundred fifty consecutive
      patients with ocular toxoplasmosis. INTERVENTION: A review of all records of
      patients with ocular toxoplasmosis who had consulted our department from 1990
      through 1997 was performed. MAIN OUTCOME MEASURES: The presence of retinal
      detachment or breaks and possible risk factors, such as age, myopia, the interval
      between the last recurrence of inflammation and the onset of retinal detachment,
      severity of vitritis, previous treatment methods, and the location of the retinal
      abnormalities, were analyzed. RESULTS: We found a frequency of 6% (9/150) for
      retinal detachment and an additional 5% (7/150) for retinal breaks among our
      patients with ocular toxoplasmosis. Attacks of active ocular toxoplasmosis
      preceding the retinal detachment or retinal breaks were characterized by severe
      intraocular inflammation. The frequency of myopia in our patients with retinal
      detachment or retinal breaks was significantly higher than in patients with
      ocular toxoplasmosis without retinal detachment or retinal breaks. The functional
      prognosis for the patients with retinal detachment was poor; legal blindness
      (visual acuity < or = 20/200) resulting from retinal detachment occurred in five
      of the nine patients. CONCLUSIONS: Careful retinal examination in ocular
      toxoplasmosis is warranted, especially in patients with myopia and severe
      intraocular inflammation.

PMID- 10647717
TI  - Sub-Tenon's injection for local anesthesia in posterior segment surgery.
AB  - OBJECTIVE: To determine whether the sub-Tenon's parabulbar approach for local
      anesthesia is a safe and effective choice for posterior segment surgery. DESIGN:
      Prospective, noncomparative case series. PARTICIPANTS: Two hundred seventy-six
      consecutive patients underwent posterior segment surgery at the University of
      Texas Medical Branch. INTERVENTION: Two hundred patients received sub-Tenon's
      parabulbar anesthesia containing an 11 -ml mixture of 5-ml 2% lidocaine
      (Xylocaine), 5-ml 0.5% bupivacaine (Marcaine), and 1 ml of 150 hyaluronidase
      (Wydase) units as primary anesthesia. The method did not involve a separate
      transcutaneous lid nerve or subconjunctival injection. MAIN OUTCOME MEASURES: The
      proportion of cases receiving supplementation (significant intravenous
      anesthesia, intraoperative local anesthesia, or both) was estimated. Its
      relationship to duration of surgery and surgical procedures deemed painful was
      assessed. Surgery lasting 3 hours or more was considered a long duration. Both
      scleral buckle and cryotherapy were considered painful procedures. The proportion
      of cases receiving additional local anesthesia preoperatively was also evaluated.
      Complications associated with sub-Tenon's parabulbar injection were monitored.
      RESULTS: There were 101 instances of patients receiving additional anesthesia.
      Nineteen received additional preoperative sub-Tenon's anesthesia, 12 received
      intraoperative local anesthesia supplementation, and 70 received intravenous
      medication. Of these 70, 19 required what the authors defined as a significant
      amount of intravenous medication, three of whom also received intraoperative
      local anesthesia supplementation. Consequently, 28 of 200 patients (14%; 95%
      confidence interval: 9.5, 19.6) received supplementation (significant intravenous
      anesthesia, intraoperative local anesthesia, or both). The proportion of cases
      receiving supplementation was directly related to duration of surgery. Patients
      involved in longer cases (51.7% vs. 7.6%; P < 0.001) and those involved in more
      painful procedures (48.2% vs. 8.7%; P < 0.001) were more likely to receive
      supplementation. Adjusting for surgery duration, a greater proportion of patients
      undergoing painful procedures required supplementation (31.3% vs. 0.5% for
      surgery < 3 hours, P = 0.003; 72.7% vs. 38.9% for surgery > or = 3 hours, P =
      0.13). No associated ocular or systemic complications were observed. CONCLUSIONS:
      The results of this large study demonstrate that a single injection of sub
      Tenon's anesthesia is relatively safe and effective for achieving local
      anesthesia during vitrectomies, with or without other intraocular procedures,
      lasting less than 3 hours. Other types of posterior segment surgery may require
      supplementation if they are more painful procedures, such as scleral buckle or
      cryotherapy, or last longer than 3 hours.

PMID- 10647718
TI  - Therapeutic options for capillary papillary hemangiomas.
AB  - PURPOSE: To describe the results and therapeutic complications of treatment of
      papillary capillary hemangiomas over the last 13 years. DESIGN: Retrospective,
      noncomparative, interventional case series. PARTICIPANTS: Five cases of
      unilateral capillary papillary hemangiomas were reviewed. Three patients had von
      Hippel-Lindau disease, and two had no associated familial or systemic disease.
      METHODS: Two patients were treated with argon green laser, one patient received
      argon green and diode photocoagulation, and two patients underwent argon green
      photocoagulation and diode transpupillary thermotherapy (TTT); two eyes also
      underwent vitreoretinal surgery. Follow-up ranged from 1 to 13 years. MAIN
      OUTCOME MEASURES: The presence of exudative retinal detachment associated with
      the activity of the hemangioma and the visual acuity were the two main
      parameters. RESULTS: Prompt argon green laser treatment was the most effective
      therapy; -II was ineffective. Vitreoretinal surgery, transscleral drainage, and
      argon endolaser photocoagulation in one case resolved bullous retinal detachment
      secondary to tumor exudation. Pretreatment visual acuity (VA) levels ranged from
      20/25 to counting fingers; posttreatment VA levels ranged from 20/25 to light
      perception. CONCLUSIONS: If left untreated, papillary hemangiomas may evolve to
      exudative retinal detachment and marked VA decreases. Although we have not
      established an ideal therapy, we recommend appropriate treatment on diagnosis.
      Close follow-up and multiple treatments with argon laser are likely the best
      therapeutic course.

PMID- 10647720
TI  - Surgical management and outcomes of dislocated intraocular lenses.
AB  - OBJECTIVE: To evaluate the surgical management and visual acuity outcomes in a
      large series of patients with dislocated intraocular lenses (IOLs). DESIGN:
      Retrospective consecutive noncomparative case series. PARTICIPANTS: All patients
      who underwent surgical management of dislocated IOLs by two vitreoretinal
      surgeons at one institution between January 1, 1991, and March 31, 1998. METHODS:
      Demographic and clinical data were abstracted from patients' medical records.
      MAIN OUTCOME MEASURES: Visual acuity at final follow-up and surgical
      complications. RESULTS: The study population consisted of 110 patients, with a
      median follow-up interval of 50 weeks after dislocated IOL management. Surgical
      techniques included IOL repositioning in 93 (84.5%) eyes, IOL exchange in 16
      (14.5%) eyes, and IOL removal in 1 (1 %) eye. Final visual acuity was > or =20/40
      in 63 patients (57%) patients, 20/50-20/200 in 34 (31%) patients, and <20/200 in
      13 (12%) patients. Ninety-nine (90%) patients had stable or improved final
      vision. Observed complications included postoperative retinal detachment in 7
      (6.3%) eyes, chronic cystoid macular edema in 19 (17%) eyes, and suprachoroidal
      hemorrhage in 1 (1%) eye. CONCLUSIONS: Surgical management of dislocated IOLs
      usually results in satisfactory visual outcomes. Pre-existing ocular pathology
      and postoperative complications may limit final vision.

PMID- 10647719
TI  - Autosomal dominant cone-rod retinal dystrophy (CORD6) from heterozygous mutation
      of GUCY2D, which encodes retinal guanylate cyclase.
AB  - OBJECTIVE: To describe the clinical features of autosomal dominant cone-rod
      retinal dystrophy (CRD) in a British family mapping to chromosome 17p12-p13
      (CORD6), with a heterozygous mutation (Glu837Asp/ Arg838Ser) of GUCY2D. DESIGN: A
      prospective, clinical family survey. PATIENTS: Ten affected members of a family
      with autosomal dominant CRD. METHODS: Full clinical examinations were undertaken.
      Selected affected family members underwent electrophysiologic evaluation,
      scotopic static perimetry, dark adaptometry, and color vision assessment. MAIN
      OUTCOME MEASURES: Clinical appearance and electroretinographic responses.
      RESULTS: Typical clinical and electroretinographic features of childhood-onset
      CRD were recorded. In addition, moderate myopia and pendular nystagmus were seen
      in affected individuals. Color vision assessment in the youngest affected
      individual showed no color discrimination on a tritan axis, but retention of
      significant red-green discrimination. Electronegative electroretinogram responses
      were seen on electrophysiology in the only young family member examined.
      CONCLUSIONS: The phenotype associated with GUCY2D CRD is clinically distinct from
      that associated with other dominant CRD loci. Unusual electroretinographic
      responses may indicate that this mutation of GUCY2D is associated with early
      defects in photoreceptor synaptic transmission to second-order neurons.

PMID- 10647721
TI  - A randomized controlled trial of intracameral lidocaine during
      phacoemulsification under topical anesthesia.
AB  - OBJECTIVE: To test the hypothesis that adjunctive intracameral 1% lidocaine
      reduces intraoperative pain during phacoemulsification using topical anesthesia.
      DESIGN: Prospective, double-masked, randomized, controlled trial. PARTICIPANTS: A
      total of 200 patients undergoing routine phacoemulsification under topical 1%
      tetracaine were studied. INTERVENTION: Randomization to 0.5 ml intracameral,
      unpreserved, epinephrine-free 1% lidocaine or placebo was conducted. MAIN OUTCOME
      MEASURE: Intraoperative pain was quantified by the patients using a 0-10 visual
      analog pain scale. RESULTS: Intraoperative pain scores (+/- standard deviation)
      for the lidocaine and control groups were 1.29 +/-1.24 and 1.44 +/- 1.33,
      respectively (P > 0.35). CONCLUSIONS: In a rigorously double-masked, prospective,
      randomized, controlled trial there was no significant reduction in intraoperative
      pain when intracameral 1% lidocaine was used during phacoemulsification under
      topical anesthesia.

PMID- 10647722
TI  - One-year results of laser vision correction for low to moderate hyperopia.
AB  - OBJECTIVE: To assess the efficacy and safety of hyperopic laser vision correction
      using a refined ablation architecture and the VISX STAR Excimer Laser. DESIGN:
      Prospective noncomparative case series. PARTICIPANTS: Fifty-two eyes with
      hyperopia from +1 to +6 diopters (D) spherical equivalent (SE) with or without
      cylinder < or =1.5 D based on cycloplegic refraction. Hyperopia was primary or
      caused by prior overcorrection of myopia. INTERVENTION: Hyperopic laser vision
      correction using a 9 mm/5 mm ablation profile and a pulse rate of 10 Hz. We
      prescribed ciprofloxacin and fluorometholone four times a day for 1 week. MAIN
      OUTCOME MEASURES: SE; uncorrected visual acuity (UCVA); predictability within +/-
      0.5 D, +/- 1.0 D, and +/- 2.0 D of target refraction (emmetropia); loss of best
      corrected visual acuity (BCVA); haze, and all complications at 1, 3, 6, and 12
      months. RESULTS: We treated 52 eyes (mean preoperative SE; +3.03 D). Forty-one
      eyes (78.8%) had primary hyperopia. At 3, 6, and 12 months, 66%, 67%, and 79% of
      all eyes had refraction within +/-0.5 D of emmetropia. At these same intervals,
      83%, 88%, and 79% were within +/-1.0 D of emmetropia. At 12 months, all eyes were
      within +/-2.0 D. At 3 months, 85.4% of eyes had UCVA of 20/40 or better, with
      95.3% achieving 20/40 or better at 6 months. At 1 year, all eyes (n = 19) had
      gained from 1 to 8 Snellen lines of UCVA, with most (n = 16) gaining between 3
      and 7 lines. At 12 months, all eyes maintained preoperative BCVA or gained 1 to 4
      lines. There was some early, transient haze < or = grade 1.5. There were no
      corneal infiltrates, decentered ablations, or infections. CONCLUSIONS: These data
      suggest that the 9 mm/5 mm hyperopic ablation profile of the VISX STAR can
      produce accurate corrections without significant, progressive regression.
      Refractive stability was achieved 3 months after surgery. We did not observe any
      differences in outcomes between eyes treated for primary hyperopia and eyes
      treated for prior myopic overcorrections. We believe the quicker ablation time
      (10 Hz pulse rate) helped patients maintain fixation and reduced the risk of
      decentration. There was a high degree of satisfaction among all patients,
      especially those with presbyopia.

PMID- 10647723
TI  - Fluid lamellar keratoplasty in keratoconus.
AB  - OBJECTIVE: The authors evaluated the efficacy of the modified technique of fluid
      deep lamellar keratoplasty in keratoconus. DESIGN: Noncomparative case series.
      PARTICIPANTS: Twenty-six eyes of 25 patients with moderate to advanced
      keratoconus were included. Fourteen males and 11 females with age range of 16 to
      37 years. INTERVENTION: Deep lamellar keratoplasty aided by intrastromal
      injection of balanced salt solution to facilitate corneal dissection down to
      Descemet's membrane. Full-thickness graft devoid of endothelium and Descemet's
      membrane was then sutured in place. MAIN OUTCOME MEASURES: Spectacle-corrected
      visual acuity, slit-lamp biomicroscopy, corneal topography, and ocular tension.
      RESULTS: Two cases (8.4%) were converted to penetrating keratoplasty because of
      intraoperative perforation. Of the 24 successful cases, 19 eyes (79%) achieved
      >20/50 at 3 months and 21 (87.5%) achieved >20/40 at 6 months. Twenty-three eyes
      (95.8%) were 20/30 or better 1 year after suture removal. Only one eye (4.2%) had
      interface irregular astigmatism corrected by contact lens to 20/40. CONCLUSIONS:
      Fluid deep lamellar keratoplasty is a safe and effective procedure, especially in
      bilateral keratoconus, because it has no rejection complication. However, it is
      technically difficult with slow visual rehabilitation.

PMID- 10647724
TI  - Optical coherence tomography evaluation of the corneal cap and stromal bed
      features after laser in situ keratomileusis for high myopia and astigmatism.
AB  - OBJECTIVE: To study the corneal microstructure by optical coherence tomography
      (OCT) after laser in situ keratomileusis (LASIK) for high myopia with and without
      astigmatism. DESIGN: Nonrandomized self-controlled comparative trial.
      PARTICIPANTS: Sixty-three consecutive LASIK eyes with spherical equivalent
      refraction between -6.0 and -17.0 diopters (D) and astigmatism between 0.0 and 
      5.0 D were prospectively recruited for examination. INTERVENTION: LASIK was
      performed with the Chiron Hansatome microkeratome (160-microm fixed plate) and
      Summit Apex Plus excimer laser using a 5.5/6.0/6.5-mm multizone pattern. Proper
      preoperative calculations were performed to ensure stromal beds thicker than 250
      microm. MAIN OUTCOME MEASURES: OCT imaging and measurement of corneal thickness
      was performed preoperatively. In addition, corneal cap and stromal bed thickness
      measurements were performed 1 day, 1 month, and 3 months postoperatively.
      RESULTS: The average central corneal pachymetry was 538.9 +/- 26.2 microm
      preoperatively. Mean corneal cap thickness measured 124.8 +/- 18.5 microm 1-day
      postoperatively. Mean stromal bed thickness was 295.2 +/- 37.1 microm on the
      first postoperative day. Compared with the 1-day postoperative examination, the
      average stromal bed thickness increased significantly by 5.9 microm (P = 0.001)
      and 7.2 microm (P = 0.001) at the 1-month and 3-month postoperative examinations,
      respectively. Mean difference between actual (118.7 +/- 27.8 microm) and
      predicted (104.1 +/- 20.8 microm) central ablation depths was 14.6 +/- 16.7
      microm (P = 0.0001). A weak but statistically significant positive association
      was found between preoperative refraction and the difference between expected and
      real ablation depth values (R = 0.26; P = 0.042). Posterior stromal beds were
      more than 250-microm thick in 58 eyes (89.9%) 1 day postoperatively. This safety
      requirement improved at the 1-month postoperative examination, when the partial
      regression accounted for slightly thicker stromal beds and only two cases (3.2%)
      exhibited posterior stromal tissue thinner than 250 microm. These two cases were
      seen only for corrections exceeding 12 D (P = 0.04). CONCLUSIONS: OCT appears to
      be a useful tool for the evaluation of both the qualitative and quantitative
      anatomic outcome of LASIK. Corrections of higher degrees of ametropia run a
      higher risk of producing a thinner than expected central cornea. Particularly,
      corrections greater than 12 D may lead eventually to stromal beds thinner than
      250 microm, despite proper preoperative calculations. Because corneal flaps are
      usually thinner than expected with the microkeratome used herein, adequate
      posterior corneal stroma is preserved in most instances.

PMID- 10647726
TI  - A new concept for the correction of astigmatism: full-arc, depth-dependent
      astigmatic keratotomy.
AB  - OBJECTIVE: The purpose of this study is to introduce and evaluate a new concept
      in astigmatic keratotomy (AK) named full-arc, depth-dependent AK (FDAK). DESIGN:
      Noncomparative interventional case series. PARTICIPANTS: FDAK was performed on a
      total of 37 eyes with regular astigmatism; of these, 16 eyes received FDAK alone,
      and 21 eyes received FDAK combined with cataract surgery. METHODS: Corneal
      topography was used to divide the cornea into two discreet regions of "steep" and
      "flat." Then, paired arcuate incisions, 90 degrees in length, were placed along
      the full arc of the steep area. The level of astigmatic correction was controlled
      by varying the incision depth from 40% to 80% on the basis of a provisional
      nomogram developed by the authors. MAIN OUTCOME MEASURES: Keratometries, corneal
      topographies, and visual acuities were measured. RESULTS: The FDAK alone group
      showed a significant improvement from a preoperative corneal astigmatism of 2.90
      +/- 0.78 diopters (D) to a postoperative value of 0.89 +/- 0.52 D. The "combined"
      group also showed significant improvement from a preoperative corneal astigmatism
      of 2.97 +/- 1.01 D, to a postoperative value of 1.02 +/- 0.45 D. The deviation of
      achieved correction from attempted correction using vector analysis was between
      1.37 D of undercorrection and 0.98 D of overcorrection, with 91.9% of cases
      within the range of +/- 1.0 D. Slight oblique change caused by axis deviation was
      observed in seven cases. Both uncorrected and corrected visual acuity showed
      statistically significant improvement. No serious complications were encountered.
      CONCLUSIONS: Controlling the level of correction by varying the incision depth
      allowed the surgeon to use long incisions (90 degrees in length in regular
      astigmatism) covering the entire steep area, minimizing the undesirable changes
      induced by conventional deep and narrow incision AK and resulting in an ideal
      corneal sphericity after surgery. FDAK enabled the surgeon to accurately control
      the level of astigmatic correction with minimal risk of corneal perforation.

PMID- 10647725
TI  - Topical mitomycin-C for subepithelial fibrosis after refractive corneal surgery.
AB  - OBJECTIVE: To determine the effectiveness of mitomycin-C (MMC), 0.02%, in
      preventing recurrence of corneal subepithelial fibrosis after debridement and/or
      keratectomy in patients who have undergone refractive corneal surgery. DESIGN:
      Noncomparative case series. PARTICIPANTS: Eight eyes of five patients with
      corneal subepithelial fibrosis who had previously undergone radial keratotomy (n
      = 4) or photorefractive keratectomy (n = 4). INTERVENTION: All eyes underwent
      epithelial debridement followed by a single intraoperative application of MMC
      (0.02%) for 2 minutes followed by saline irrigation. The eyes were then patched,
      or a bandage contact lens placed until epithelial healing was complete. MAIN
      OUTCOME MEASURES: Corneal clarity and best-corrected visual acuity (BCVA).
      RESULTS: In all cases, the cornea remained clear with no recurrence throughout
      the follow-up period (6-25 mos., mean, 13.8 mos). No adverse reactions were
      reported. BCVA improved in all cases. CONCLUSIONS: Subepithelial fibrosis can be
      a visually disabling condition after refractive corneal surgery. Topical
      application of MMC (0.02%) may be a successful method of preventing recurrence of
      subepithelial fibrosis after debridement.

PMID- 10647727
TI  - The effects of long-term contact lens wear on corneal thickness, curvature, and
      surface regularity.
AB  - PURPOSE: To evaluate the effect of long-term contact lens wear on corneal
      thickness, curvature, and surface regularity. DESIGN: A prospective, clinic
      based, case-control study. PARTICIPANTS: A total of 40 eyes of 20 normal subjects
      and 64 eyes of 35 subjects wearing contact lenses for more than 5 years were
      evaluated. METHODS: The Orbscan Corneal Topography System was used to evaluate
      the entire corneal thickness and curvature, anterior curvature and the anterior
      and posterior elevation topographic patterns in normal eyes and subjects wearing
      contact lenses on a regular basis for more than 5 years. Indices of TMS-1 Corneal
      Topography System were used to determine corneal surface regularity in subjects
      wearing contact lenses and normal eyes. All topographic examinations were
      performed after contact lenses had been removed for at least 2 weeks. MAIN
      OUTCOME MEASURES: The entire corneal thickness, curvature, surface regularity
      index (SRI), surface asymmetry index (SAI), potential visual acuity (PVA) and
      topographic patterns were compared between normal eyes and subjects wearing
      contact lenses for more than 5 years. RESULTS: The 64 eyes of 35 subjects
      evaluated by the Orbscan instrument had an average of 13.45 +/- 6.42 years of
      contact lens wear. The mean corneal thickness in the center and in eight
      peripheral areas measured in contact lens wearing subjects was significantly
      reduced by about 30 to 50 microm compared to normal subjects (P < 0.001 for
      central and peripheral sites). No correlation was noted between central corneal
      thickness and degree of myopia in diopters (r = 0.15, 0.10 < P < 0.25). The
      corneal curvature, maximum keratometry (Max K) and minimum keratometry (Min K)
      readings, were significantly steeper in eyes wearing contact lenses than normal
      eyes (P < 0.01 for Max K and Min K measured by both instruments). No difference
      in the mean corneal astigmatism was noted between groups. The SRI and SAI, but
      not the PVA index, of the TMS-1 were significantly greater in contact lens
      wearers than in the control group (P < 0.01 for both SRI and SAI, P = 0.15 for
      PVA). The color-coded patterns of all curvature and elevation maps made with both
      instruments showed no significant difference between subjects wearing contact
      lenses and the control group. There was no significant difference between corneal
      curvature measurements taken with the Orbscan System or the TMS-1 System in both
      normal and contact lens groups. CONCLUSIONS: Long-term contact lens wear appears
      to decrease the entire corneal thickness and increase the corneal curvature and
      surface irregularity.

PMID- 10647728
TI  - Salicylate inhibition of Acanthamoeba attachment to contact lenses: a model to
      reduce risk of infection.
AB  - PURPOSE: Acanthamoeba attachment (adsorption) to hydrogel contact lenses is
      enhanced by Pseudomonas aeruginosa biofilm. The effect of sodium salicylate on
      Acanthamoeba attachment to biofilm-coated and uncoated hydrogel lenses was
      investigated. DESIGN: Experimental study. PARTICIPANTS AND CONTROLS: A minimum of
      16 replicates were used for each test condition; a control condition using clean
      lenses without biofilm was included. METHODS: Four groups of hydrogel contact
      lenses (etafilcon A) were pretreated with P. aeruginosa to form a biofilm. In
      addition, two more groups remained untreated. Quartered lenses of all six groups
      were then incubated in a suspension of A. castellanii trophozoites. Two batches
      of lenses had either 3 or 30 mM sodium salicylate added to the bacterial
      suspension (stage 1 intervention). Two other batches of lenses had salicylate
      added to the amoebal suspension (stage 2 intervention). One of the batches, which
      had a stage 1 intervention, had salicylate added at the second stage as well. The
      remaining batches received no salicylate exposure and included lenses with and
      without biofilm coating. MAIN OUTCOME MEASURE: The outcome measure in this study
      was the number of Acanthamoeba trophozoites attached, per square centimeter, to
      the hydrogel surfaces. RESULTS: Biofilm coating from P. aeruginosa gave a
      significantly increased attachment of A. castellanii trophozoites to the contact
      lens. When introduced at a first (biofilm) stage, second (trophozoite attachment)
      stage, or with intervention at both stages, 30 mM sodium salicylate reduced
      amoebal attachment to the hydrogel lens. When applied to both stages and when
      applied at stage 2 to the biofilm coated contact lenses, 3 mM sodium salicylate
      reduced amoebal attachment. The 3 mM concentration was not effective for the
      lower level of amoebae attachment to uncoated (nonbiofilm) lenses. CONCLUSIONS:
      Sodium salicylate successfully reduced amoebal trophozoite attachment to hydrogel
      lenses. This was the result of one of the following possibilities or a
      combination thereof: inhibition of biofilm formation; a direct effect on the
      amoebae; an alteration in the biofilm-amoebal attachment and resulting
      modification of the hydrogel lens surface. The results of this study suggest the
      major action is at stage 2 (on amoebal attachment to lenses) and favors
      alteration of the biofilm-amoebal attachment mechanism. This study demonstrates
      salicylate's potential benefit as a component of contact lens care solutions,
      designed to reduce microbial attachment and the risk of infection.

PMID- 10647729
TI  - A comparison of the rate of refractive growth in pediatric aphakic and
      pseudophakic eyes.
AB  - OBJECTIVE: To compare the rate of refractive growth in pseudophakic children's
      eyes to that of aphakic eyes. DESIGN: Multicenter, retrospective observational
      case series. PARTICIPANTS: 83 patients with pseudophakic eyes (100 eyes) and 74
      patients with aphakic eyes (106 eyes), with an age of surgery between 3 months
      and 10 years and a minimum follow-up time of 3 years or more, depending on the
      age at surgery. METHODS: A logarithmic model was used to analyze the rate of
      refractive growth for each eye. MAIN OUTCOME MEASURES: Age at surgery,
      intraocular lens power, intraocular lens A-constant, initial postoperative
      refraction, final refraction, and final age. RESULTS: Overall, pseudophakic eyes
      showed a lesser rate of refractive growth than aphakic eyes (-4.6 diopter vs. 
      5.7 diopter, P = 0.03). This trend was also present but less significant when the
      eyes were grouped into those less than 6 months of age at surgery (-3.3 diopter
      vs. -4.6 diopter, P = 0.09) and older patients (-5.0 diopter vs. -6.1 diopter, P
      = 0.07). However, the mean quantity of myopic shift was greater in pseudophakic
      eyes than in aphakic eyes (-5.26 diopter vs. -4.54 diopter), despite shorter
      follow-up times in the pseudophakic eyes. This is due to the optical effects of a
      constant intraocular lens power in a growing eye. CONCLUSIONS: Pediatric
      pseudophakic eyes have a slightly lesser rate of refractive growth than aphakic
      eyes. The new rate values should be used for predicting future refractions in
      these eyes.

PMID- 10647730
TI  - Bilateral consecutive central corneal perforations associated with
      hypogammaglobulinemia.
AB  - OBJECTIVE: To describe the presentation and the clinical course of a patient with
      consecutive central sterile corneal perforations associated with common variable
      immunodeficiency. DESIGN: Case report. METHODS: Multiple corneal cultures and
      scrapings were performed in an effort to identify an infectious cause and all
      were negative. Corneal biopsy did not demonstrate any evidence of micro
      organisms. An extended investigation failed to uncover a collagen vascular cause
      or atopy. RESULTS: Progressive sterile stromal thinning with intact epithelium in
      the left eye proceeded to perforation despite topical treatment, and
      cyanoacrylate gluing was performed. However, a secondary Haemophilus influenza
      endophthalmitis developed, and the eye was eventually lost. The fellow eye
      proceeded along the same clinical course with sterile stromal thinning. A
      lamellar patch graft was performed when the central ulceration progressed to a
      descemetocele. The eye remained quiet with 20/25 vision for 2 years, until the
      patient died from complications of a liver transplant. CONCLUSIONS: Devastating
      central sterile corneal thinning leading to perforation may occur in patients
      with hypogammaglobulinemia.

PMID- 10647731
TI  - Increased intraocular pressure and visual field defects in high resistance wind
      instrument players.
AB  - OBJECTIVE: In this twofold study, part 1 aimed to determine whether the playing
      of high resistance wind instruments elevates intraocular pressure (IOP) and if
      so, to investigate the mechanism of IOP elevation and whether its magnitude
      differs while playing high resistance versus low resistance instruments. The
      purpose of part 2 was to evaluate whether high resistance players have a greater
      incidence of glaucomatous changes than other musicians. DESIGN: Three case
      reports and a cross-sectional study. PARTICIPANTS: Two players of high resistance
      instruments and one player of high and low resistance wind instruments
      participated in part 1 of the study. Nine high resistance wind players, 12 low
      resistance wind players, and 24 nonwind players were recruited among professional
      musicians in the Boston area to participate in part 2. INTERVENTION: In part 1,
      IOP and uveal thickness changes were measured by pneumatonometry and ultrasound
      biomicroscopy in two participants playing their high resistance wind instruments
      (trumpet and oboe) and in a third participant playing both high (trumpet) and low
      (clarinet and saxaphone) resistance instruments. Each musician in part 2
      underwent medical and musical history, measurement of IOP, Humphrey visual field
      testing, slit-lamp examination, gonioscopy, and dilated examination. MAIN OUTCOME
      MEASURES: Intraocular pressure and uveal thickness changes, and visual field loss
      and optic nerve head appearance were the main parameters measured in part 1 and
      part 2, respectively. RESULTS: In part 1, pneumatonometry showed IOP elevation
      dependent on the force of blowing, and ultrasound biomicroscopy revealed uveal
      thickening associated with IOP elevation. The magnitude of IOP elevation was
      dependent on the amount of expiratory resistance provided by the particular
      instrument. Part 2 showed that life hours of high resistance wind instrument
      playing had a significant relationship to abnormal visual field (P = 0.03) and
      corrected pattern standard deviation (CPSD) scores (P = 0.007) in univariate
      logistic regression and univariate linear regression, respectively. A 0.011-unit
      increase in CPSD for each 1000 life hours of high resistance wind playing was
      found. CONCLUSIONS: High and low resistance wind musicians experience a transient
      rise in their IOP while playing their instruments as a result least in part of
      uveal engorgement. The magnitude of IOP increase is greater in high resistance
      wind players versus low resistance wind players. High resistance wind musicians
      had a small but significantly greater incidence of visual field loss (abnormal
      fields and increased CPSD scores) than other musicians, which was related to life
      hours of playing. The cumulative effects of long-term intermittent IOP elevation
      during high resistance wind instrument playing may result in glaucomatous damage,
      which could be misdiagnosed as normal-tension glaucoma.

PMID- 10647732
TI  - Comparison between Tendency-Oriented Perimetry (TOP) and octopus threshold
      perimetry.
AB  - OBJECTIVE: To compare the results obtained by a new ultra-short automated
      perimetry test known as Tendency-Oriented Perimetry (TOP), which is an algorithm
      based on estimation of thresholds from information gathered from adjacent points
      with those obtained by a standard bracketing approach. TOP is designed to save up
      to 1/5 of the time taken by standard strategy by presenting each stimulus once on
      each location (instead of 4 to 6 times per location with the standard technique)
      and reaching a final threshold estimate by gathering information from responses
      to adjacent locations. DESIGN: Prospective, multicenter, observational
      comparative case series. PARTICIPANTS/METHODS: Four academic institutions
      provided data from testing 57 subjects, 15 with a normal ocular exam and 42 with
      a variety of visual field abnormalities. A total of 228 visual fields were
      analyzed. Two examinations of standard thresholding testing (Octopus program 32)
      and two examinations of the TOP program were obtained in each subject the same
      day. MAIN OUTCOME MEASURES: Comparison of global indices such as mean deviation
      (MD), square root of loss of variance (sLV), topographical defects, point by
      point differences, reproducibility, sensitivity/specificity, and time required to
      complete the test. RESULTS: Correlation coefficient of global indices between
      both tests was high, with mean deviation of r = 0.97 (SE[YX] +/- 1.65 decibels)
      and square root of loss variance of r = 0.93 (SE[YX] +/- 1.10 dB). Mean
      sensitivity tended to be 1 dB higher while MD tended to be 1 dB lower with TOP
      strategy. Reproducibility was equally good between both tests for threshold
      determination as well as for all global indices (MS, MD per quadrant, and LV).
      Cluster criteria for abnormality demonstrated TOP versus 32: sensitivity of
      89/87; specificity of 90/77; positive predictive value of 96/91; negative
      predictive value of 75/68; and accuracy of 89/84. Mean time taken by this beta
      version of TOP was 4.05 minutes standard deviation +/- 0.55 versus the standard
      32 version taking 14.65 minutes standard deviation +/- 3.75. CONCLUSIONS: TOP was
      four times faster than the traditional full-threshold technique and was
      successful in detecting visual field abnormalities. Defects with TOP tended to be
      smaller, shallower, and with softer edges than with standard approach. TOP could
      prove an alternative to traditional perimetric techniques.

PMID- 10647733
TI  - Initial experience with pneumatically stented baerveldt implant modified for pars
      plana insertion for complicated glaucoma.
AB  - OBJECTIVE: To assess the efficacy of pneumatically stented drainage tube implants
      specially modified for pars plana insertion in the treatment of complicated
      glaucoma. DESIGN: Retrospective, non-comparative case series. PARTICIPANTS: 50
      consecutive patients with refractory complicated glaucoma nonresponsive to
      medical treatment. INTERVENTION: Baerveldt glaucoma implants modified by Hofmann
      for pars plana insertion were placed following pars plana vitrectomy and gas
      fluid exchange (pneumatically stented implant, or PSI procedure). MAIN OUTCOME
      MEASURE: Reduction of intraocular pressure (IOP) to 21 mmHg or less. RESULTS: 31
      neovascular and 19 complicated non-neovascular glaucoma eyes in 48 patients
      referred to a vitreoretinal subspecialty practice, average age 69 years (range 29
      91), were followed an average of 18 months (range 3-41). The average preoperative
      IOP was 44 mmHg (14-78) on an average 3.2 glaucoma medications (range 2-6). The
      average final postoperative IOP was 14 mmHg (range 5-31) on an average 0.6
      glaucoma medications (range 0-3, median 0). The final intraocular pressure was 21
      mmHg or less in 47 of 50 (94%) operated eyes. Serious complications related to
      the procedure occurred in five eyes (10%). CONCLUSIONS: Pneumatically stented
      Baerveldt glaucoma implants modified with the Hofmann elbow to facilitate pars
      plana insertion are effective in the treatment of complicated glaucoma.

PMID- 10647734
TI  - Re-evaluation of "reactive lymphoid hyperplasia of the uvea": an
      immunohistochemical and molecular analysis of 10 cases.
AB  - OBJECTIVE: Cases of uveal lymphoid proliferation previously classified as
      reactive lymphoid hyperplasia (RLH) were studied to correlate pathologic features
      with clinical outcome. DESIGN: Retrospective case series. PARTICIPANTS: Ten cases
      of RLH of the uvea on file at the Armed Forces Institute of Pathology with
      sufficient formalin-fixed, paraffin-embedded tissue for analysis. METHODS:
      Clinical, histologic, immunohistochemical, and molecular (polymerase chain
      reaction [PCR]) characteristics of uveal lymphoid proliferations were studied.
      MAIN OUTCOME MEASURES: Morphologic, immunohistochemical, and PCR characteristics
      of study cases. RESULTS: Patient age ranged from 40 to 73 years at time of
      enucleation, with a mean age of 55 years. Retinal detachment was noted clinically
      in nine patients and glaucoma in eight. All patients were treated with
      enucleation, and three received radiotherapy. Histologically, two cases were
      interpreted as RLH and eight were well-differentiated small-cell lymphoma
      (WDSCL). Systemic lymphoid infiltrate developed in two patients, but there were
      no deaths with a mean follow-up of 9.9 years. Mature lymphocytes were noted in
      the iris and angle structures; the atypical cells of uveal lymphoma were found in
      the choroid and ciliary body. Eight cases were monoclonal by B-cell and T-cell
      markers and/or immunoglobulin light chain restriction. Amplifiable DNA was
      present in 6 of 10 cases by PCR. Three cases monoclonal by cell markers were also
      monoclonal by PCR, but two cases monoclonal by cell markers could not be
      confirmed by PCR. Lymphoid follicles with germinal centers were found in two
      cases of RLH and five cases of WDSCL. Nine specimens demonstrated extraocular
      lymphoid involvement of the episclera and orbit; most appeared more benign
      morphologically than the choroidal infiltrates. Extraocular infiltrates of WDSCL
      were monoclonal by immunohistochemistry in five cases, polyclonal in one case,
      and indeterminate in two cases. CONCLUSIONS: Most cases (8 of 10) previously
      described as RLH were low-grade B-cell lymphomas histologically and by
      immunohistochemistry. PCR results agreed with histologic diagnosis in four of six
      cases. Open-angle glaucoma was common and related mostly to lymphocytic
      infiltration of the angle structures. Extraocular involvement is common but may
      not be representative of the choroidal lesion. Prognosis is excellent in low
      grade uveal lymphoid neoplasia.

PMID- 10647735
TI  - Conjunctival lymphocytic infiltrates associated with Epstein-Barr virus.
AB  - PURPOSE: To describe the clinicopathologic features of two patients with Epstein
      Barr virus (EBV) associated conjunctival lymphocytic infiltrates. DESIGN: Two
      case reports. METHODS: The clinical histories and pathologic findings of two
      patients with salmon-colored conjunctival infiltrates are described. MAIN OUTCOME
      MEASUREMENTS: Clinical observation and pathologic examination of conjunctival
      biopsy specimens with accompanying immunohistochemical staining, flow cytometric
      immunophenotyping, and polymerase chain reaction analysis when appropriate.
      RESULTS: One patient had ipsilateral preauricular lymphadenopathy, elevated serum
      EBV titers, and a unilateral reactive lymphocytic infiltrate resulting in a
      conjunctival mass. The other patient had bilateral conjunctival lymphocytic
      infiltrates causing conjunctival masses. There was an expanded clonal population
      of B lymphocytes in the conjunctival mass in the second patient. Both patients
      had EBV antigen in their conjunctival lymphocytic infiltrates. CONCLUSIONS:
      Conjunctival lymphocytic lesions associated with EBV represent a spectrum of
      reactive infiltrates to monoclonal populations.

PMID- 10647736
TI  - Basal cell adenocarcinoma of the lacrimal gland.
AB  - PURPOSE: Basal cell adenocarcinoma is a recently recognized entity among
      malignant tumors of the salivary glands. This entity has not received enough
      attention among ophthalmologists and ophthalmic pathologists. We recommend that
      basal cell adenocarcinoma be included in the differential diagnosis of lacrimal
      gland tumors. DESIGN: Case report. METHODS: In 1988 a lacrimal gland tumor was
      incompletely removed from the left orbit of a 36-year-old woman and diagnosed as
      "solid basaloid adenoid cystic carcinoma". Soon after, an exenteration of the
      orbit was performed. In 1998, upon review of the initial histopathology, the
      diagnosis of solid adenoid cystic carcinoma was changed to basal cell
      adenocarcinoma. RESULTS AND MAIN OUTCOME MEASURE: The pathologic findings
      included nests of basaloid cells with minimal atypia and incomplete palisading
      around the periphery. The cells were of two types. The first type were large,
      pale cells with round or oval nuclei, scanty cytoplasm, and ill-defined borders.
      The other type were smaller cells with hyperchromatic nuclei situated mainly near
      the periphery of the nests. There was no necrosis or perineural invasion. Mitotic
      figures were present. Cysts within the nests showed Alcian blue negative
      contents. Immunohistochemistry showed a positive reaction to cytokeratin and a
      negative reaction with smooth muscle actin (SMA). CONCLUSIONS: The Alcian blue
      negative stain, the negative reaction to SMA, and the fact that the patient is
      still alive 10 years after exenteration favored the diagnosis of basal cell
      adenocarcinoma. It is essential to differentiate a basal cell adenocarcinoma of
      the lacrimal gland from the solid basaloid type of adenoid cystic carcinoma,
      because the former has a better prognosis. Patients with basal cell
      adenocarcinomas of the lacrimal gland should be closely monitored for local
      recurrences because this tumor has the tendency to show perineural invasion.

PMID- 10647737
TI  - South American cutaneous leishmaniasis of the eyelids: report of five cases in
      Rio de Janeiro State, Brazil.
AB  - PURPOSE: To describe American cutaneous leishmaniasis of the eyelids and
      highlight the main clinical and diagnostic features of lesions, which are rare in
      this location. DESIGN: Retrospective, noncomparative case series METHODS:
      Leishmanin skin test, touch preparations, histopathologic analysis, and culture
      in appropriate media were used for clinical confirmation and parasitologic
      diagnosis. Positive cultures were identified by the iso-enzymes technique. All
      patients were treated with pentavalent antimony applied intramuscularly. RESULTS:
      Leishmanin skin test was positive in all five patients. Touch preparations,
      histopathologic analysis, and culture were performed in four patients. Touch
      preparations were positive (presence of Leishman's bodies) in two patients;
      histopathologic analysis showed a granulomatous infiltrate in four patients and
      parasite was present in two patients; culture was positive in three patients, and
      in two the parasite was identified as Leishmania (Viannia) braziliensis. Therapy
      was effective for all patients. CONCLUSIONS: Cutaneous leishmaniasis of the
      eyelids is uncommon in the Americas. The disease may present diagnostic
      difficulties when appearing in nonendemic areas. The clues for diagnosis are the
      clinical aspect of lesions, the epidemiologic data, and a positive Leishmanin
      skin test. Demonstration of parasite is not always possible. Pentavalent
      antimonial compounds are the therapy of choice. Formerly, transmission of
      leishmaniasis occurred only when humans penetrated forested areas and became an
      incidental host. Now, eyelid lesions are part of the changing pattern in the
      transmission of the disease. With the increase in ecotourism, these lesions may
      begin to be seen in air travelers returning to other parts of the world.

PMID- 10647738
TI  - Ocular plagiocephaly: ocular torticollis with skull and facial asymmetry.
AB  - PURPOSE: To observe facial asymmetry in patients with ocular torticollis to
      better understand its cause. DESIGN: Observational case series. PARTICIPANTS:
      Forty-four consecutive patients with ocular torticollis in one author's (MFG)
      private practice were examined for facial asymmetry from January 1998 to August
      1998. Some of these, as well as selective others before January 1998 were
      photographed for a total of 53 photos. METHODS: One author (MFG) examined the
      frontal, maxillary, and mandibular facial areas of 44 consecutive torticollis
      patients for appearance of unilateral compression or reduced mass. The laterality
      of such findings was compared with the side of the head turn or tilt. Photographs
      of 53 selected ocular torticollis patients were inspected and the direction of
      nasal tip and columella deviation compared with the direction of head tilt or
      turn. MAIN OUTCOME MEASURES: Subjective clinical determination of appearance of
      unilateral facial compression or reduced facial mass. Subjective photographic
      determination of nasal tip and columella deviation. RESULTS: Forty-three patients
      with 10 types of ocular torticollis examined were included. Forty-one of 43
      showed compression or reduced mass on the same side as the head turn or tilt,
      including 3 with adult-onset strabismus. Eight nonsuperior oblique palsy patients
      had nasal deviation to the same side as the torticollis. Six of the eight had
      head tilts. Seventeen nonsuperior oblique palsy patients had nasal tip deviation
      to the opposite side of the torticollis. All were pure head turns. Eight superior
      oblique palsy patients had nasal tip deviation to the same side as the
      torticollis; nine had deviation opposite. CONCLUSIONS: Patients with multiple
      types of ocular torticollis, including face turns, show similar appearance of
      facial compression on the side of the torticollis, suggesting that the tilt or
      turn itself may cause the asymmetry. This includes face turn strabismus, in which
      facial asymmetry has not previously been described. Head tilts are frequently
      associated with nasal tip deviation to the side of the torticollis, head turns
      with deviation opposite. We refer to such asymmetric facial changes associated
      with ocular torticollis as "ocular plagiocephaly."

PMID- 10647739
TI  - Immunohistochemical evidence for estrogen receptors in meibomian glands.
AB  - PURPOSE: To look for sex hormone receptor distribution in three structures
      contributing to the normal human tear film: the conjunctiva, the accessory
      lacrimal glands, and the meibomian glands. DESIGN: An immunohistochemical study.
      TISSUES AND CONTROLS: Forty-one upper eyelid specimens were collected from 15
      male and 26 female patients (age range, 1.5-85 years) during blepharoptosis
      surgery via posterior tarsoconjunctival mullerectomy (Fasanella-Servat or
      Gavaris). In addition, control sections of histologically normal breast,
      prostate, and skin tissue were obtained. METHODS: Immunohistochemical staining
      using mouse monoclonal antibodies against estrogen, progesterone, and androgen
      receptors was performed on all tissues and controls. Quantitation of the
      receptors was performed and expressed as percentage nuclear positivity. Specimens
      were divided into three groups based on the age of the patient: <12 years (n =
      9); 18-55 years (n = 1); >55 years (n = 12). RESULTS: Forty-one specimens
      contained conjunctiva. All were negative for estrogen, progesterone, and androgen
      receptors. Twenty-four specimens contained accessory lacrimal glands of Wolfring.
      All were negative for the three receptors. Twenty-two specimens contained
      meibomian glands. All were positive for estrogen receptors; one was positive for
      progesterone receptors and one for androgen receptors. Using Minitab statistical
      software (Minitab Inc. State College, PA), analysis of variation revealed no
      statistical difference between sexes or between age groups studied. The sebaceous
      glands of skin were uniformly positive for androgen receptors. Sebaceous glands
      of the face and scalp (3 of the 15 skin samples) were also positive for estrogen
      receptors. CONCLUSIONS: Estrogen receptors are present in the meibomian glands of
      the upper eyelid. Unlike sebaceous glands elsewhere on the skin, the meibomian
      glands lack androgen receptors. Estrogen receptors may play a role in modulation
      of the lipid layer of the tear film, and their activity may be linked to
      meibomian gland dysfunction and dry eye syndrome.

PMID- 10647741
TI  - Nasolacrimal duct obstruction secondary to ectopic teeth.
AB  - OBJECTIVE: To describe two patients with nasolacrimal duct obstruction (NLDO)
      caused by ectopic eruption of teeth. The literature concerning nasal and other
      unusual ectopic sites of tooth eruption is reviewed. DESIGN: Two interventional
      case reports and literature review. PARTICIPANTS: A 3-year-old girl with epiphora
      and recurrent dacryocystitis of the right eye. Previous medical and surgical
      management was unsuccessful. A 32-year-old female with a long history of right
      eye discomfort and epiphora. Previous examinations and workup were negative.
      INTERVENTION: A computed tomographic (CT) scan of the orbits and sinuses was
      performed in both patients. The ectopic teeth were surgically removed. MAIN
      OUTCOME MEASURES: Nasolacrimal system function and response to treatment at the
      last follow-up were recorded. RESULTS: In the first patient, CT imaging disclosed
      two teeth within the right inferior meatus compressing the nasolacrimal duct. In
      the second patient, CT revealed a large dental structure in the maxillary sinus
      compressing the nasolacrimal duct. Endoscopic tooth extraction and nasolacrimal
      duct probing in the first patient and surgical removal of the dental structure in
      the second patient effected complete resolution of symptoms. Both patients were
      symptom free at last follow-up. CONCLUSIONS: These cases suggest that ectopic
      eruption of teeth should be added to the differential diagnosis of NLDO. Surgical
      removal of the ectopic teeth compressing the nasolacrimal duct results in
      resolution of the lacrimal drainage obstruction.

PMID- 10647740
TI  - Congenital Horner's syndrome resulting from agenesis of the internal carotid
      artery.
AB  - OBJECTIVE: To report a patient with agenesis of the right internal carotid artery
      associated with ipsilateral, congenital Homer's syndrome. DESIGN: Case report.
      METHODS: A 30-year-old woman, with a past history of migraine headaches,
      underwent neuro-ophthalmologic and neuroradiologic evaluation for transient
      visual obscurations and congenital Horner's syndrome. RESULTS: A right, third
      order neuron Horner's syndrome was confirmed with 1% hydroxyamphetamine topical
      drops. Cranial magnetic resonance imaging revealed an absent right internal
      carotid artery flow void, computed tomography demonstrated absence of the right
      carotid canal, and cerebral angiography confirmed absence of the right internal
      carotid artery. No atheromatous lesions were found and the results of coagulation
      studies were normal. CONCLUSIONS: Agenesis of the internal carotid artery is a
      rare cause of congenital Horner's syndrome. The cause of transient visual
      blurring in the current patient remains unproven.

PMID- 10647742
TI  - Optic neuropathy occurring after bee and wasp sting.
AB  - OBJECTIVE: To inform ophthalmologists about bee and wasp sting-related optic
      neuropathy. DESIGN: Two case reports and literature review. METHODS: Review of
      two cases, clinical history, laboratory testing, and follow-up. RESULTS: Two
      cases of bee and wasp sting optic neuritis are described and five additional
      cases of optic neuritis occurring after Hymenoptera sting are reviewed from the
      English language literature. These cases share certain characteristics, including
      acute to subacute onset of symptoms; moderate to severe visual loss followed by
      significant visual recovery; edematous and hemorrhagic optic discs; and central
      or cecocentral scotomas. CONCLUSIONS: Acute optic neuropathy may follow
      Hymenoptera sting to the face.

PMID- 10647743
TI  - Transplantation tolerance: a look at the nonhuman primate literature in the light
      of modern tolerance theories.
AB  - Ever since the beginning of clinical transplantation, investigators have searched
      for a way to transplant tissues from one person to another without chronic
      immunosuppression. That goal, known as allograft tolerance, has remained
      clinically elusive. In the past decade, however, many of the fundamental
      principles of tolerance have been redefined, and biological agents capable of
      exploiting them in vivo have been developed. Accordingly, experimental methods
      for tolerance induction have rapidly evolved in concert with a growing
      understanding of physiological tolerance to self and the development of novel
      immunoreactive reagents. In general, old world monkeys have become the pre
      clinical testing ground for methods that have shown reasonable promise for
      clinical application, particularly antibodies or other biological agents with
      limited cross-species reactivity. As such, a survey of the nonhuman primate
      experience in transplantation is representative of all reasonably successful
      experimental attempts to develop clinically applicable tolerance regimens. This
      article summarizes many of the concepts currently unfolding in the tolerance
      literature. It also reviews the techniques for tolerance induction that have been
      and are currently being investigated in nonhuman primates. The validity of these
      models is summarized, and the older literature is reinterpreted in light of
      recent changes in our understanding of tolerance.

PMID- 10647744
TI  - Cell adhesion molecules: selectins and integrins.
AB  - Cell adhesion molecules play a key role in different physiological and
      pathological phenomena. Selectins comprise a family of three members (E-, P-, and
      L-selectin) that are differentially expressed by leukocytes and endothelial
      cells, and are involved in the early steps of leukocyte extravasation. Although
      many different putative ligands of selectins have been described, their
      physiological relevance has not been elucidated in all cases. Selectins and some
      of their counter-receptors function also as signal-transducing receptors,
      significantly contributing to leukocyte and endothelial cell activation.
      Integrins represent a large family of adhesion receptors that are widely
      expressed and mainly interact with extracellular matrix components. The affinity
      and avidity of integrins can be modulated by different mechanisms triggered
      either from the extracellular milieu or through intracellular signals. Integrins
      show a close relationship with cytoskeleton and exert an important role as signal
      transducing receptors, activating different biochemical pathways, mainly the
      mitogen-activated protein (MAP) kinase cascade. In addition to their adhesive
      function, these receptors modulate key intracellular phenomena, including cell
      activation, proliferation, and apoptosis. Because selectins and integrins are
      involved in leukocyte extravasation and the inflammatory response, different
      strategies are in progress for the blockade of these molecules and, therefore,
      for therapy of inflammatory diseases.

PMID- 10647745
TI  - Generation of human gammadelta T-cell repertoires.
AB  - The nature of how the human gammadelta T-cell repertoire is generated during
      normal development is poorly understood. Unlike TCR -alphabeta+ cells that are
      almost exclusively dependent upon the thymus for their development and
      maturation, gammadelta T cells can be generated in extrathymic sites. The focus
      of this article is to understand how the human gammadelta T-cell repertoire is
      generated during normal human development before and after birth. The expressed
      repertoire is a reflection of many mechanisms operating at both the DNA and
      protein levels, and we describe the features of the observed repertoires in
      various tissues in fetal and postnatal development and in the adult, and the
      potential mechanisms that account for them. Identifying the site(s) of origin and
      understanding how the various subsets of gammadelta T cells are generated is
      important for understanding their function. In addition, understanding how the
      gammadelta T-cell repertoire is modulated during life by infection, inflammation,
      and cancer should also bring us closer to understanding its function.

PMID- 10647746
TI  - The fetus and the maternal immune system: pregnancy as a model to study
      peripheral T-cell tolerance.
AB  - In this article, we discuss recent findings that describe how maternal T cells
      respond upon encountering fetal antigens. Many earlier studies have characterized
      changes in the maternal T-cell repertoire of both humans and mice, yet it has
      been difficult to understand the significance of these findings since there has
      been no way to decipher if the alterations were the result of encounters with
      fetal antigens or were nonspecific changes related to pregnancy itself. Now, in
      the mouse, the availability of TCR transgenic mice and other technological
      advances allow direct visualization of the fate of maternal T cells that are
      reactive to the fetus and provide a means to probe the mechanisms by which
      tolerance to the fetus is maintained. This article focuses on how the fetus more
      closely resembles "developmental self' than a true allograft and how the study of
      maternal T-cell interactions with fetally derived antigens can be useful as a
      model for the study of peripheral T-cell tolerance.

PMID- 10647747
TI  - Regulation of the formation and external transport of secretory immunoglobulins.
AB  - Secretory IgA (SIgA) is the best defined effector component of the mucosal immune
      system. Generation of SIgA and secretory IgM (SIgM) in exocrine glands and mucous
      membranes depends on a fascinating cooperation between local plasma cells that
      produce polymeric IgA (pIgA, mainly dimers and some larger polymers) and
      pentameric IgM, and secretory epithelial cells that express the polymeric Ig
      receptor (pIgR)--also known as transmembrane secretory component. After release
      from the local plasma cells and diffusion through the stroma, pIgA and pentameric
      IgM become readily bound to pIgR, and are then actively transported across
      secretory epithelial cells for extrusion into external secretions after cleavage
      of pIgR. Much knowledge has recently been obtained at the molecular level about
      the regulation of pIgR-mediated transport of antibodies. This mechanism is of
      considerable biological interest because SIgA and SIgM form the first line of
      specific immunological defense against infectious agents and other harmful
      substances that may enter the body through the mucosae.

PMID- 10647748
TI  - Hard science versus phenomenology in reproductive immunology.
AB  - It has been suggested that studies of immunological aspects of reproduction have
      recently changed from the phenomenological (e.g., speculative/descriptive) to
      hard science (e.g., precise molecular description/ explanation). The significance
      of this development is explored by analysis of the contribution made by hard
      science that has led to a number of assertions. Does HLA-G determine maternal
      tolerance of her semi-allogeneic fetus? Do differences in placentation between
      humans, rodents, and other species make direct comparisons largely meaningless?
      Does membrane cofactor protein (CD46) contribute to pregnancy success by
      protecting sperm and fetal trophoblast from complement-mediated lysis? Does a low
      frequency in mice of maternal T cells specific for paternal alloantigens occur,
      and if so, does phenomenon explain specific maternal tolerance in pregnancy? Do
      placental and decidual macrophage components provide an important immediate
      antigen-nonspecific host defense to infection? Does the mix of bioactive
      molecules make the uterus an immunologically privileged site, and does the
      molecular melange have a pivotal role in promoting growth and development of the
      placenta and embryo? Does prolactin acting on receptors on lymphocytes suppress
      function and thereby account for remission of autoimmune disease in pregnant
      women? Is the efficacy and safety of immunotherapy for recurrent spontaneous
      abortion a thorny issue that will be resolved by an ongoing funded national
      trial? What is a scientifically correct timeline of important discoveries and
      developments in reproductive immunology? It is argued that it is unprofitable to
      divorce phenomenology from hard science and that the timeline for developments in
      reproductive immunology begin with Darwin. Irrespective of whether one is dealing
      with phenomena or hard science data, Hippocrates was correct in his aphorism that
      "description is infinite and easy; explanation is limited and difficult".

PMID- 10647749
TI  - Diabetes and change in cognitive function.

PMID- 10647750
TI  - Silent pulmonary embolism.

PMID- 10647751
TI  - Benefits of antihypertensive therapy in older patients with hypertension.

PMID- 10647752
TI  - St John's wort for depression: a systematic review.
AB  - To address whether St John's wort is useful for the treatment of depression we
      attempted to retrieve all English-language articles with data on the efficacy,
      safety, and availability of St John's wort. Randomized, controlled, double-blind
      trials were selected and assessed for methodological quality using a standardized
      checklist, and data on pharmacology, cost, regulation, and safety were extracted.
      Eight studies were identified, found to be of generally good methodological
      quality, and determined to provide a modest amount of data to suggest that St
      John's wort is more effective than placebo in the treatment of mild to moderate
      depression. The absolute increased response rate with the use of St John's wort
      ranged from 23% to 55% higher than with placebo, but ranged from 6% to 18% lower
      compared with tricyclic antidepressants. More data are required to assess both
      its use in severe depression and its efficacy compared with other
      antidepressants. Rates of side effects were low. As a dietary supplement, St
      John's wort is currently largely unregulated, but the Food and Drug
      Administration is reviewing plans to tighten its regulatory oversight.

PMID- 10647753
TI  - Systematic lung scans reveal a high frequency of silent pulmonary embolism in
      patients with proximal deep venous thrombosis.
AB  - BACKGROUND: A high frequency of asymptomatic pulmonary embolism (PE) has been
      reported in patients with deep venous thrombosis (DVT) in studies of a limited
      number of patients using varying criteria for lung scan assessment. OBJECTIVES:
      To estimate the frequency of PE using systematic lung scans in a large group of
      outpatients with DVT and to compare the results using varying lung scan
      assessment criteria. METHODS: An international multicenter study comparing 2
      different regimens of low-molecular-weight heparin nadroparin in DVT: perfusion
      lung scans were performed in 622 outpatients with no clinical indication of PE
      and with proximal DVT confirmed by venography. Three hundred seventy-nine of
      these patients underwent ventilation lung scans. High-probability (HP) scans for
      PE were assessed separately using either ventilation scans or chest radiographs
      to define mismatched perfusion defects. RESULTS: Perfusion scans showed
      abnormalities in 82% of the patients; 59% had segmental defects and 30% had
      normal scans or scans with a very low probability of PE. Depending on the
      criteria used, 32% to 45% had HP scans for PE; these percentages were higher in
      young patients. No relationship was found between extent of thrombosis and HP
      scans. The estimated frequency of silent PE was 39.5% to 49.5%. During a 3-month
      follow-up period during which the patients received therapy, the rate of PE
      recurrence was low (1.3%) and did not differ between patients with baseline HP
      scans and those with normal scans. CONCLUSIONS: Regardless of what interpretative
      criteria are used for assessing lung scans in PE, the frequency of silent PE is
      40% to 50% in patients with DVT. A baseline lung scan may easily detect PE in
      these patients but is not useful for predicting early thromboembolic recurrences
      that may occur during therapy.

PMID- 10647754
TI  - Male pattern baldness and coronary heart disease: the Physicians' Health Study.
AB  - OBJECTIVE: To examine the association between male pattern baldness and the risk
      of coronary heart disease (CHD) events. DESIGN, SETTING, AND PARTICIPANTS:
      Retrospective cohort study among 22,071 US male physicians aged 40 to 84 years
      enrolled in the Physicians' Health Study. Of these, 19,112 were free of CHD at
      baseline and completed a questionnaire at the 11-year follow-up concerning their
      pattern of hair loss at age 45 years. Response options included no hair loss,
      frontal baldness only, or frontal baldness with mild, moderate, or severe vertex
      baldness. MAIN OUTCOME MEASURES: Coronary heart disease events defined as
      nonfatal myocardial infarction (MI), angina pectoris, and/or coronary
      revascularization. RESULTS: During 11 years of follow-up, we documented 1446 CHD
      events in this cohort. Compared with men with no hair loss, those with frontal
      baldness had an age-adjusted relative risk (RR) of CHD of 1.09 (95% confidence
      interval [CI], 0.94-1.25), while those with mild, moderate, or severe vertex
      baldness had RRs of 1.23 (95% CI, 1.05-1.43), 1.32 (95% CI, 1.10-1.59), and 1.36
      (95% CI, 1.11-1.67), respectively (P for trend, <.001). Multivariate adjustment
      for age, parental history of MI, height, body mass index (weight in kilograms
      divided by the square of the height in meters as a continuous variable), smoking,
      history of hypertension, diabetes, high cholesterol level, physical activity, and
      alcohol intake did not materially alter these associations. Results were similar
      when nonfatal MI, angina, and coronary revascularization were examined
      separately, and when events were analyzed among men older and younger than 55
      years at baseline. Vertex baldness was more strongly associated with CHD risk
      among men with hypertension (multivariate RR, 1.79; 95% CI, 1.31-2.44) or high
      cholesterol levels (multivariate RR, 2.78; 95% CI, 1.09-7.12). CONCLUSION: Vertex
      pattern baldness appears to be a marker for increased risk of CHD events,
      especially among men with hypertension or high cholesterol levels.

PMID- 10647755
TI  - Is diabetes associated with cognitive impairment and cognitive decline among
      older women? Study of Osteoporotic Fractures Research Group.
AB  - BACKGROUND: The long-term effect of type 2 diabetes on cognitive function is
      uncertain. OBJECTIVE: To determine whether older women with diabetes have an
      increased risk of cognitive impairment and cognitive decline. DESIGN: Prospective
      cohort study. SETTING: Four research centers in the United States (Baltimore, Md;
      Portland, Ore; Minneapolis, Minn; and the Monongahela Valley, Pennsylvania).
      PARTICIPANTS: Community-dwelling white women 65 years and older (n = 9679).
      MEASUREMENTS: Physician-diagnosed diabetes and other aspects of health history
      were assessed by interview. Three tests of cognitive function, the Digit Symbol
      test, the Trails B test, and a modified version of the Mini-Mental State
      Examination (m-MMSE), were administered at baseline and 3 to 6 years later.
      Change in cognitive function was defined by the change in the score for each
      test. Major cognitive decline was defined as the worst 10th percentile change in
      the score for each test. RESULTS: Women with diabetes (n = 682 [7.0%]) had lower
      baseline scores than those without diabetes on all 3 tests of cognitive function
      (Digit Symbol and Trials B tests, P<.01; m-MMSE, P = .03) and experienced an
      accelerated cognitive decline as measured by the Digit Symbol test (P<.01) and m
      MMSE (P = .03). Diabetes was also associated with increased odds of major
      cognitive decline as determined by scores on the Digit Symbol (odds ratio = 1.63;
      95% confidence interval, 1.20-2.23) and Trails B (odds ratio, 1.74; 95%
      confidence interval, 1.27-2.39) tests when controlled for age, education,
      depression, stroke, visual impairment, heart disease, hypertension, physical
      activity, estrogen use, and smoking. Women who had diabetes for more than 15
      years had a 57% to 114% greater risk of major cognitive decline than women
      without diabetes. CONCLUSION: Diabetes is associated with lower levels of
      cognitive function and greater cognitive decline among older women.

PMID- 10647756
TI  - A meta-analysis comparing low-molecular-weight heparins with unfractionated
      heparin in the treatment of venous thromboembolism: examining some unanswered
      questions regarding location of treatment, product type, and dosing frequency.
AB  - OBJECTIVES: To compare the efficacy and safety of unfractionated heparin (UFH)
      and low-molecular-weight heparins (LMWHs) and to examine current controversies in
      the treatment of venous thromboembolism (VTE) (ie, setting, product type, and
      frequency of administration). METHODS: Data were abstracted from MEDLINE, HEALTH,
      previous reviews, personal files, clinical experts, and conference abstracts.
      Randomized controlled trials of patients diagnosed with acute VTE that compared
      LMWHs with UFH were included. Independent duplicate assessment was done for
      methodological quality and data extraction. Data are reported as pooled relative
      risks (RRs) and 95% confidence intervals (CIs) comparing LMWHs with UFH as
      determined by the random effects model. RESULTS: Thirteen studies were included.
      There was no statistically significant difference in risk between UFH and LMWHs
      for recurrent VTE (RR, 0.85 [95% CI, 0.65-1.12]), pulmonary embolism (RR, 1.02
      [95% CI, 0.64-1.62]), major bleeding (RR, 0.63 [95% CI, 0.37-1.05]), minor
      bleeding (RR, 1.18 [95% CI, 0.87-1.61]), and thrombocytopenia (RR, 0.85 [95% CI,
      0.45-1.62]). There was a statistically significant difference for risk of total
      mortality (RR, 0.76 [95% CI, 0.59-0.98]) in favor of LMWHs. Inpatient treatment
      may reduce the risk of major bleeding vs outpatient therapy. Once-daily therapy
      is as safe and effective as twice-daily therapy when compared indirectly.
      Different products could not be statistically compared, but qualitative analysis
      shows that there are no apparent differences in efficacy and safety. CONCLUSIONS:
      Low-molecular-weight heparins are at least as effective as UFH in preventing
      recurrent VTE. It is unlikely that LMWHs are superior in the treatment of VTE,
      but they do show a statistically significant decrease in total mortality. No
      differences were seen in the development of recurrent VTE dependent on treatment
      setting. There were no apparent differences between once-daily and twice-daily
      therapy or among products. Inpatient therapy may be associated with less major
      bleeding; therefore, if LMWHs are given in the outpatient setting, patients
      should be rigorously monitored.

PMID- 10647757
TI  - Anticoagulation of pregnant women with mechanical heart valves: a systematic
      review of the literature.
AB  - BACKGROUND: The management of women with prosthetic heart valves during pregnancy
      poses a particular challenge as there are no available controlled clinical trials
      to provide guidelines for effective antithrombotic therapy. Oral anticoagulants
      such as warfarin sodium cause fetal embryopathy; subcutaneous administration of
      heparin sodium has been reported to be ineffective in preventing thromboembolic
      complications. OBJECTIVE: To identify the risks of maternal and fetal
      complications in women with mechanical heart valves treated with different
      anticoagulation regimens during pregnancy. METHODS: We performed a systematic
      review of the literature to determine pooled estimates of maternal and fetal
      risks associated with the 3 commonly used approaches: (1) oral anticoagulants
      (OA) throughout pregnancy, (2) replacing OA with heparin in the first trimester
      (from 6-12 weeks' gestation), and (3) heparin use throughout pregnancy. Fetal
      outcomes included spontaneous abortions and fetopathic effects, and maternal
      outcomes were major bleeding, thromboembolic complications, and death. RESULTS:
      The use of OA throughout pregnancy is associated with warfarin embryopathy in
      6.4% (95% confidence interval [CI], 4.6%-8.9%) of livebirths. The substitution of
      heparin at or prior to 6 weeks, and continued until 12 weeks, eliminated this
      risk. Overall risks for fetal wastage (spontaneous abortion, stillbirths, and
      neonatal deaths) were similar in women treated with OA throughout, compared with
      women treated with heparin in the first trimester. Maternal mortality was 2.9%
      (95% CI, 1.9%-4.2%). Maj or bleeding events occurred in 2.5% (95% CI, 1.7%-3.5%)
      of all pregnancies, most at the time of delivery. The regimen associated with the
      lowest risk of valve thrombosis (3.9%; 95% CI, 2.9-5.9%) was the use of OA
      throughout; using heparin only between 6 and 12 weeks' gestation was associated
      with an increased risk of valve thrombosis (9.2%; 95% CI, 5.9%-13.9%).
      CONCLUSIONS: Thromboembolic prophylaxis of women with mechanical heart valves
      during pregnancy is best achieved with OA; however, this increases the risk of
      fetal embryopathy. Substituting OA with heparin between 6 and 12 weeks reduces
      the risk of fetopathic effects, but with an increased risk of thromboembolic
      complications. The use of low-dose heparin is definitely inadequate; the use of
      adjusted-dose heparin warrants aggressive monitoring and appropriate dose
      adjustment. Large prospective trials to determine the best regimen for these
      women are needed.

PMID- 10647758
TI  - Congestive heart failure in the United States: is there more than meets the I(CD
      code)? The Corpus Christi Heart Project.
AB  - BACKGROUND: Congestive heart failure (CHF) is increasing as a public health
      problem in the United States. The ability to quantify this problem has been
      limited by a lack of data regarding the validity of CHF identification.
      OBJECTIVE: To assess the validity of the use of International Classification of
      Diseases, Ninth Revision, Clinical Modification (ICD) codes to identify
      hospitalizations with clinical evidence of an episode of acute CHF in data of The
      Corpus Christi Heart Project, a population-based surveillance program for
      hospitalized coronary heart disease. METHODS: The validation standard was a
      composite variable including the presence of physician diagnosed acute CHF or
      radiographic evidence of pulmonary edema. Data were abstracted from the medical
      records of 5083 patients identified as hospitalized for possible acute myocardial
      infarction, aortocoronary bypass surgery, percutaneous transluminal coronary
      angioplasty, and related revascularization procedures in the Corpus Christi Heart
      Project. Discharge diagnoses, a secondary source of data, were used to apply 3
      computer algorithms to assess the assignment of ICD codes. RESULTS: The
      prevalence of clinically documented CHF was 27.1% (1376/5083). The ICD code 428
      (CHF), assigned as the primary or a secondary discharge diagnosis, was associated
      with 62.8% sensitivity, 95.4% specificity, 83.5% positive predictive value, 87.4%
      negative predictive value, and a 24.8% underenumeration of CHF-related
      hospitalizations. An algorithm based on a series of ICD codes was associated with
      67.1% sensitivity, 92.6% specificity, 77.1% positive predictive value, 88.3%
      negative predictive value, and a 13.0% underenumeration of CHF-related
      hospitalizations. CONCLUSIONS: Reliance on ICD codes results in the exclusion of
      one third of the patients with clinical evidence of acute CHF. This
      underenumeration is compounded by the typical reliance on the first listed
      diagnosis. Congestive heart failure may be a greater public health problem than
      currently recognized. The allocation of resources for relevant surveillance,
      research, medical care, and preventive efforts should be reevaluated.

PMID- 10647759
TI  - Physician practice variation in assignment of return interval.
AB  - BACKGROUND: Recent shifts in reimbursement toward capitation makes appointment
      availability a significant resource and stimulates us to understand primary care
      physician (hereafter referred to as "provider") behavior concerning appointment
      assignment. The results of prior studies suggest significant provider variability
      in this area. OBJECTIVE: To examine the influences on assigning patient revisit
      intervals in the ambulatory setting. METHODS: Survey regarding general care
      issues of hypothetical diabetic and hypertensive patients seen in an ambulatory
      setting was given to 62 providers in the Internal Medicine Program at the Tulane
      University Internal Medicine Residency Program and outpatient clinics, New
      Orleans, La. Measurements evaluated included survey responses for demographics
      (sex, year of birth, year of graduation from medical school, and level of
      training) and practice style (decision to change therapy, order tests, and
      recommended return appointment interval in weeks) variables. RESULTS: The
      response rate was 89% (56 providers). Most respondents were men (n = 39). Wide
      variation was noted in assignment of reappointment interval with mean return
      intervals for the scenarios ranging from 2.2 to 20.5 weeks. Significant
      influences on provider practice included patient stability (P<.001), the decision
      to change therapy (P = .001), and the decision to order tests (P = .001). All
      correlated with an earlier return appointment. Some providers exhibited test
      ordering tendencies across scenarios. Sex was a significant provider independent
      variable and was not influenced by other study variables. Female providers
      assigned earlier reappointment intervals for their patients. CONCLUSIONS: Wide
      variation exists among practitioners with similar training background and
      practice setting. As expected, patient stability was a major determinant of
      assigned return interval. Test-ordering behaviors may consume appointments
      inappropriately and may be a productive area for efforts to reduce provider
      variability. The influence of the provider's sex on scheduling follow-up
      appointments warrants further investigation.

PMID- 10647761
TI  - Overlapping conditions among patients with chronic fatigue syndrome,
      fibromyalgia, and temporomandibular disorder.
AB  - BACKGROUND: Patients with chronic fatigue syndrome (CFS), fibromyalgia (FM), and
      temporomandibular disorder (TMD) share many clinical illness features such as
      myalgia, fatigue, sleep disturbances, and impairment in ability to perform
      activities of daily living as a consequence of these symptoms. A growing
      literature suggests that a variety of comorbid illnesses also may commonly
      coexist in these patients, including irritable bowel syndrome, chronic tension
      type headache, and interstitial cystitis. OBJECTIVE: To describe the frequency of
      10 clinical conditions among patients with CFS, FM, and TMD compared with healthy
      controls with respect to past diagnoses, degree to which they manifested symptoms
      for each condition as determined by expert-based criteria, and published
      diagnostic criteria. METHODS: Patients diagnosed as having CFS, FM, and TMD by
      their physicians were recruited from hospital-based clinics. Healthy control
      subjects from a dermatology clinic were enrolled as a comparison group. All
      subjects completed a 138-item symptom checklist and underwent a brief physical
      examination performed by the project physicians. RESULTS: With little exception,
      patients reported few past diagnoses of the 10 clinical conditions beyond their
      referring diagnosis of CFS, FM, or TMD. In contrast, patients were more likely
      than controls to meet lifetime symptom and diagnostic criteria for many of the
      conditions, including CFS, FM, irritable bowel syndrome, multiple chemical
      sensitivities, and headache. Lifetime rates of irritable bowel syndrome were
      particularly striking in the patient groups (CFS, 92%; FM, 77%; TMD, 64%)
      compared with controls (18%) (P<.001). Individual symptom analysis revealed that
      patients with CFS, FM, and TMD share common symptoms, including generalized pain
      sensitivity, sleep and concentration difficulties, bowel complaints, and
      headache. However, several symptoms also distinguished the patient groups.
      CONCLUSIONS: This study provides preliminary evidence that patients with CFS, FM,
      and TMD share key symptoms. It also is apparent that other localized and systemic
      conditions may frequently co-occur with CFS, FM, and TMD. Future research that
      seeks to identify the temporal relationships and other pathophysiologic
      mechanism(s) linking CFS, FM, and TMD will likely advance our understanding and
      treatment of these chronic, recurrent conditions.

PMID- 10647760
TI  - Chinese trial on isolated systolic hypertension in the elderly. Systolic
      Hypertension in China (Syst-China) Collaborative Group.
AB  - BACKGROUND: In 1988, the Systolic Hypertension in China (Syst-China)
      Collaborative Group initiated the placebo-controlled Syst-China trial to
      investigate whether antihypertensive drug treatment could reduce the incidence of
      fatal and nonfatal stroke in older Chinese patients with isolated systolic
      hypertension. OBJECTIVES: To explore (1) whether the benefits of active treatment
      were evenly distributed across 4 strata, prospectively defined according to sex
      and previous cardiovascular complications, and (2) whether the morbidity and
      mortality results were influenced by age, level of systolic or diastolic blood
      pressure (BP), smoking or drinking habits, or diabetes mellitus at enrollment.
      METHODS: Eligible patients had to be 60 years or older with a sitting systolic BP
      of 160 to 219 mm Hg and diastolic BP less than 95 mm Hg. After stratification for
      center, sex, and previous cardiovascular complications, 1253 patients were
      assigned to active treatment starting with nitrendipine (10-40 mg/d), with the
      possible addition of captopril (12.5-50.0 mg/d), and/or hydrochlorothiazide (12.5
      50 mg/d). In the 1141 control patients, matching placebos were used similarly.
      RESULTS: Male sex, previous cardiovascular complications, older age, higher
      systolic BP or lower diastolic BP, living in northern China, smoking, and
      diabetes mellitus significantly and independently increased the risk of 1 or more
      of the following end points: total or cardiovascular mortality, all fatal and
      nonfatal cardiovascular end points, all strokes, and all cardiac end points. In
      the placebo-control group diabetes raised the risk of all end points 2- to 3-fold
      (P< or =.05). However, active treatment reduced the excess risk associated with
      diabetes to a nonsignificant level (P values ranging from .12-.86) except for
      cardiovascular mortality (P = .04). Cox regression with adjustments applied for
      significant covariates suggested that active treatment may reduce total mortality
      more (P = .06) in women and stroke more (P = .07) in men and that it may provide
      better protection against cardiac end points in nonsmokers than smokers (P =
      .04). Otherwise, the benefits of active treatment were equally manifest,
      regardless of the enrollment characteristics of the patients, and regardless of
      whether active treatment consisted of only nitrendipine or of nitrendipine
      associated with other active drugs. CONCLUSIONS: In elderly Chinese patients with
      isolated systolic hypertension, stepwise antihypertensive drug treatment,
      starting with the dihydropyridine calcium channel blocker nitrendipine, improved
      prognosis. The benefit was particularly evident in diabetic patients; for cardiac
      end points it tended to be larger in nonsmokers. Otherwise, the benefit of active
      treatment was not significantly influenced by the characteristics of the patients
      at enrollment in the trial.

PMID- 10647762
TI  - Low-molecular-weight heparin vs heparin in the treatment of patients with
      pulmonary embolism. American-Canadian Thrombosis Study Group.
AB  - BACKGROUND: Pulmonary embolism (PE) occurs in 50% or more of patients with
      proximal deep-vein thrombosis. Low-molecular-weight heparin treatment is
      effective and safe in patients with deep vein thrombosis and may also be so in
      patients with PE. Recent rigorous clinical trials have established objective
      criteria for determining a high probability of PE by perfusion lung scanning.
      OBJECTIVE: To compare low-molecular-weight heparin with intravenous heparin for
      the treatment of patients with objectively documented PE and underlying proximal
      deep vein thrombosis. METHODS: In a multicenter, double-blind, randomized trial,
      we compared fixed-dose subcutaneous low-molecular-weight heparin (tinzaparin
      sodium) given once daily with dose-adjusted intravenous heparin given by
      continuous infusion using objective documentation of clinical outcomes. Pulmonary
      embolism at study entry was documented by the presence of high-probability lung
      scan findings. RESULTS: Of 200 patients with high-probability lung scan findings
      at study entry, none of the 97 who received low-molecular-weight heparin had new
      episodes of venous thromboembolism compared with 7 (6.8%) of 103 patients who
      received intravenous heparin (95% confidence interval for the difference, 1.9%
      11.7%; P = .01). Major bleeding associated with initial therapy occurred in 1
      patient (1.0%) who was given low-molecular-weight heparin and in 2 patients
      (1.9%) given intravenous heparin (95% confidence interval for the difference, 
      2.4% to 4.3%). CONCLUSIONS: Low-molecular-weight heparin administered once daily
      subcutaneously was no less effective and probably more effective than use of dose
      adjusted intravenous unfractionated heparin for preventing recurrent venous
      thromboembolism in patients with PE and associated proximal deep vein thrombosis.
      Our findings extend the use of low-molecular-weight heparin without anticoagulant
      monitoring to patients with submassive PE.

PMID- 10647763
TI  - Intraspinal hemorrhage complicating oral anticoagulant therapy: an unusual case
      of cervical hematomyelia and a review of the literature.
AB  - Intraspinal hemorrhage is a rare but dangerous complication of anticoagulant
      therapy. It must be suspected in any patient taking anticoagulant agents who
      complains of local or referred spinal pain associated with limb weakness, sensory
      deficits, or urinary retention. We describe a patient with hematomyelia, review
      the literature on hematomyelia and other intraspinal hemorrhage syndromes, and
      summarize intraspinal hemorrhage associated with oral anticoagulant therapy. The
      patient (a 62-year-old man) resembled previously described patients with
      hematomyelia in age and sex. However, he was unusual in having cervical rather
      than thoracic localization. As with intracranial bleeding, the incidence of
      intraspinal hemorrhage associated with anticoagulant therapy might be minimized
      by close monitoring and tight control of the intensity of anticoagulation.
      However, it is noteworthy that many of the reported cases were anticoagulated in
      the therapeutic range. If intraspinal hemorrhage is suspected, anticoagulation
      must be reversed immediately. Emergency laminectomy and decompression of the
      spinal cord appear mandatory if permanent neurologic sequelae are to be
      minimized. A high index of suspicion, prompt recognition, and immediate
      intervention are essential to prevent major morbidity and mortality from
      intraspinal hemorrhage.

PMID- 10647764
TI  - Iron and ischemic heart disease in the African setting.

PMID- 10647765
TI  - Moses Maimonides.

PMID- 10647766
TI  - Does treatment with antenatal glucocorticoids for the risk of premature delivery
      contribute to ketoacidosis in pregnant women with diabetes who receive continuous
      subcutaneous insulin infusion (CSII)?

PMID- 10647767
TI  - Do anticoagulation clinics treat patients more effectively than physicians?

PMID- 10647768
TI  - Treatment of human immunodeficiency virus enteropathy with a gluten-free diet.

PMID- 10647769
TI  - Is functional upregulation of the 5-HT2B receptor in deoxycorticosterone acetate
      salt-treated rats blood pressure dependent?
AB  - This study tests the hypothesis that the functional upregulation of the arterial
      5-hydroxytryptamine (5-HT)2B receptor in arteries of deoxycorticosterone acetate
      (DOCA)-salt hypertensive rats depends on the development of high blood pressure.
      Wistar-Furth and Wistar rats were given sham or DOCA-salt treatment (200 mg/kg
      DOCA, SC; 1.0% NaCl and 0.2% KCI in drinking water). Systolic blood pressures (4
      week; mm Hg) were: Wistar Sham (120+/-3), Wistar DOCA (176+/-6), Wistar-Furth
      Sham (112+/-3) and Wistar-Furth DOCA (136+/-4). Isolated mesenteric arteries from
      Wistar DOCA and Wistar-Furth DOCA rats displayed a three- to fivefold leftward
      shift in contraction to 5-HT that was insensitive to blockade by the 5-HT2A
      receptor antagonist ketanserin (10 nM) and a significantly increased maximal
      contraction to the 5-HT2B receptor agonist BW723C86 [Wistar DOCA = 90+/-17%
      phenylephrine contraction; Wistar Sham = 1+/-1%; Wistar-Furth DOCA = 33+/-8%;
      Wistar-Furth Sham = 0%]. Arteries from Sprague-Dawley rats receiving salt or DOCA
      alone displayed similar systolic blood pressures (151+/-11 mm Hg and 144+/-5 mm
      Hg, respectively), but only tissues from rats receiving DOCA displayed an
      increased contraction to BW723C86 (DOCA alone = 60.7+/-16% vs. sham = 13+/-5.3%).
      These data suggest that upregulation of the arterial 5-HT2B receptor is largely
      independent of an increase in blood pressure.

PMID- 10647770
TI  - Synergistic centrally mediated cardiovascular effects of a kappa opioid agonist
      and an alpha2-adrenoceptor agonist.
AB  - In this study, we determined possible additive and synergistic centrally mediated
      hypotensive and bradycardic effects of U-62,066E, a nonpeptide kappa opioid
      agonist acting on the hippocampal formation (HF), and guanabenz, an alpha2
      adrenoceptor agonist acting on the rostral ventrolateral medulla (RVLM), the
      nucleus tractus solitarius (NTS), or the locus coeruleus (LC). The drugs were
      microinjected at various doses into these areas of alpha-chloralose-anesthetized
      Sprague-Dawley rats. There were synergistic hypotensive and bradycardic effects
      between low, noneffective doses of U-62,066E acting on the HF and guanabenz
      acting simultaneously on the RVLM. Higher doses of each agent, which themselves
      caused hypotension and bradycardia acting on each brain area alone, did not lead
      to synergistic effects when the drugs were injected simultaneously into those
      areas. There were no synergistic effects between U-62,066E acting on the HF and
      guanabenz acting on the NTS or the LC.

PMID- 10647771
TI  - Contribution of sarcoplasmic reticulum calcium uptake and L-type calcium channels
      to altered vascular responsiveness in the aorta of renal hypertensive rats.
AB  - This study examined whether alterations in intracellular or extracellular Ca2+
      mobilization were related to differences in caffeine and phenylephrine (PHE)
      induced contractions between two-kidney. one-clip hypertensive (2K-1C) and
      normotensive (2K) rat aortas. After depletion and reloading of intracellular Ca2+
      stores, caffeine and PHE-induced contractions in Ca2+-free solution were
      increased in 2K-1C. Thapsigargin reduced the contraction to caffeine in 2K-1C and
      2K with similar sensitivity. PHE-induced contraction in 1.6-mM Ca2+ solution was
      decreased in 2K-1C, and nifedipine was less effective in lowering this response.
      The responsiveness to extracellular Ca2+ was decreased in 2K-1C hypertensive rat
      aortas. Our results indicate an increased intracellular Ca2+ stores that are not
      related to alteration in Ca2+-ATPase function and a lower contribution of L-type
      channels to the contraction of 2K-1C aortas.

PMID- 10647772
TI  - Beneficial effects of ACE-inhibition with zofenopril on plaque formation and low
      density lipoprotein oxidation in watanabe heritable hyperlipidemic rabbits.
AB  - The effects of angiotensin-converting enzyme (ACE)-inhibition with zofenopril on
      the development of atherosclerosis and low-density lipoprotein (LDL) oxidation
      were determined in Watanabe Heritable Hyperlipidemic (WHHL) rabbits. Rabbits
      received either placebo (n = 6) or 0.5 mg/kg/day of zofenopril (n = 6). After 6
      weeks of treatment, the computer-assisted analysis revealed that zofenopril
      reduced the aortic and common carotid corrected cumulative lesion area by 34% and
      39%, respectively (p < 0.05 vs placebo-treated group). The intimal/medial ratio
      of the largest fatty streaks was 0.426+/-0.158 in the zofenopril-treated group
      and 0.875+/-0.238 in the placebo-treated group (p < 0.05). Furthermore, we found
      in the zofenopril-treated group smaller lesions with an intimal/medial ratio of
      zofenopril also reduced plasmatic LDL oxidation, as shown by significant
      reduction of malondialdehyde content (p < 0.01) and relative agarose gel mobility
      (p < 0.05), as well as by the prolongation of the lag-time (p < 0.05). Compared
      to zofenopril-treated rabbits, arterial sections of the placebo-group had
      significant increase in the intimal presence of macrophages-derived foam cells (p
      < 0.05), ox-LDL (p < 0.01), and native LDL (p < 0.01) detected by
      immunocytochemistry with RAM-11, MDA2 and NP1533975 monoclonal antibodies,
      respectively. To investigate the amount of platelet accumulation in the
      atherosclerotic plaque we also measured platelet-associated radioactivity.
      Autologous platelets were labeled with 111Indiumoxine and injected intravenously.
      After 2 hours, WHHL were sacrificed and arterial sections were counted for
      platelet-associated radioactivity. In the placebo-treated group, platelet
      radioactivity was 0.52+/-0.12 equivalent of radioactivity per mg of tissue in the
      common carotid and 0.25+/-0.18 in the abdominal aorta; in contrast, rabbits
      treated by zofenopril had 0.20+/-0.12 in the common carotid and 0.06+/-0.01 in
      the abdominal aorta. These data indicate that ACE-inhibition with zofenopril has
      antiatherosclerotic and antioxidant effects in WHHL-rabbits. Our results also
      shows that these effects could be linked to a reduced wall-associated platelet
      deposition at the site of atherosclerotic lesions.

PMID- 10647773
TI  - Possible involvement of nitric oxide in pilocarpine induced seminal emission in
      rats.
AB  - Intraperitoneal injection of pilocarpine (0.75-3.0 mg/kg) caused a dose-related
      seminal emission in adult male rats. The seminal emission response to 3 mg/kg of
      pilocarpine was greatly reduced in atropinized (5 and 10 mg/kg, SC) animals,
      suggesting a cholinomimetic effect. Nw-nitro-L-arginine methyl ester (5, 10, and
      20 mg/kg, SC), a nitric oxide synthesis inhibitor, also inhibited the pilocarpine
      induced seminal emission, which was reversed by L-arginine (600 mg/kg, SC) or by
      coinjection of sodium nitroprusside (0.5 mg/kg, SC). Urine analysis for levels of
      nitric oxide metabolites, nitrate/nitrite (NO3-/NO2-), showed marked alterations
      in accordance with the drug treatments. The results suggest that nitric oxide
      mediates the inhibitory neurotransmission responsible for seminal emission in
      pilocarpine stimulated rats.

PMID- 10647774
TI  - Homocysteine provokes leukocyte-endothelium interaction by downregulation of
      nitric oxide.
AB  - Recent evidence indicates that chronic hyperhomocysteinemia, which is found in
      from 9 to 15% of the general population, is an independent risk factor for the
      development of atherosclerosis. We sought to elucidate the mechanism by which
      exposure of the vascular wall to high levels of homocysteine initiates this
      inflammatory reaction. We examined the acute effect of homocysteine on
      endothelial dysfunction in isolated rat arteries and on microcirculatory
      leukocyte-endothelium interaction in vivo. Intravital microscopy of rat
      mesenteric venules was performed by superfusing the mesentery with increasing
      concentrations of homocysteine (1-5 mmol/l). There was a significant
      concentration- and time-dependent increase in leukocyte rolling, adherence, and
      extravasation compared with control rats superfused with Krebs-Henseleit solution
      (p < 0.01). Moreover, immunohistochemical staining demonstrated significantly
      increased P-selectin and intercellular adhesion molecule-1 (ICAM-1) expression on
      intestinal venules after homocysteine superfusion. In contrast, mesenteric
      superfusion with the nitric oxide donor 4-hydroxymethyl-furazan-3-carboxylic acid
      oxide (CAS1609, 1 micromol/l) significantly attenuated homocysteine-induced
      leukocyte rolling, adherence, and transmigration to control levels (p < 0.01).
      CAS1609 also attenuated both P-selectin and ICAM-1 expression on mesenteric
      venules and decreased CD18 expression on isolated leukocytes. Superior mesenteric
      arteries incubated with 5 mmol/l homocysteine developed significant (p < 0.01)
      endothelial dysfunction (i.e., impaired relaxation to endothelium-dependent
      dilators). Acute hyperhomocysteinemia induces endothelial dysfunction,
      characterized by a loss of endothelium-derived nitric oxide, leading to an
      inflammatory state. This state results in increased leukocyte rolling, adherence,
      and transmigration by upregulation of cell adhesion molecules. Our data suggest
      that hyperhomocysteinemia inhibits the important homeostatic role of nitric oxide
      in preventing endothelial dysfunction.

PMID- 10647775
TI  - Genetic approaches to TGFbeta signaling pathways.

PMID- 10647776
TI  - Remarkable versatility of Smad proteins in the nucleus of transforming growth
      factor-beta activated cells.
AB  - Smad proteins were identified three years ago as intracellular mediators of
      signaling by Transforming Growth Factor-beta (TGF-beta) family members. Two
      subclasses of the Smad proteins, the receptor-regulated Smads and common mediator
      Smads, transduce signals from the cell surface to the nucleus, where they
      participate in the regulation of gene expression. Meanwhile, it has become
      evident that Smads should be envisaged as very versatile proteins, which
      integrate multiple signaling pathways and can directly affect target gene
      expression in many ways. Indeed, their direct binding to DNA and their
      interaction in the nucleus with non-Smad proteins, many of which are DNA-binding
      activators or repressors of transcription uncover a unique but complex mode of
      action. We summarize some of the most recent data with regard to this aspect in
      this rapidly advancing field.

PMID- 10647777
TI  - The insulin-like growth factor (IGF) system and gonadotropin regulation: actions
      and interactions.
AB  - Insulin-like growth factors (IGF) are polypeptides that regulate growth,
      differentiation and survival in a multitude of cells and tissues. The IGF system
      consists of ligands, receptors, binding proteins and binding protein proteases.
      The influence of the IGF system on reproductive parameters, specifically
      gonadotropin release and interactions between the IGF system and other effectors
      of gonadotropin release will be examined in this review.

PMID- 10647778
TI  - Evasion and exploitation of chemokines by viruses.
AB  - Chemokines and chemokine receptors play a critical role in the host defense
      against viruses by mobilizing leukocytes to sites of infection, injury and
      inflammation. In order to replicate successfully within their host organisms,
      viruses have devised novel strategies for exploiting or subverting chemokine
      networks. This review summarizes various mechanisms that are currently known to
      be used by viruses for modulating chemokine activities including viral homologs
      of chemokines and chemokine receptors and soluble viral chemokine binding
      proteins. Insight into these strategies is providing a wealth of information on
      viral-host interactions, the function of chemokines in host defense and may help
      to generate novel anti-chemokine agents for treating against viral diseases or
      inflammatory disorders.

PMID- 10647779
TI  - NF-kappaB activation and HIV-1 induced apoptosis.
AB  - HIV infection leads to the progressive loss of CD4+ T cells and the near complete
      destruction of the immune system in the majority of infected individuals. High
      levels of viral gene expression and replication result in part from the
      activation of NF-kappaB transcription factors, which in addition to orchestrating
      the host inflammatory response also activate the HIV-1 long terminal repeat. NF
      kappaB induces the expression of numerous cytokine, chemokine, growth factor and
      immunoregulatory genes, many of which promote HIV-1 replication. Thus, NF-kappaB
      activation represents a double edged sword in HIV-1 infected cells, since stimuli
      that induce an NF-kappaB mediated immune response will also lead to enhanced HIV
      1 transcription. NF-kappaB has also been implicated in apoptotic signaling,
      protecting cells from programmed cell death under most circumstances and
      accelerating apoptosis in others. Therefore, activation of NF-kappaB can impact
      upon HIV-1 replication and pathogenesis at many levels, making the relationship
      between HIV-1 expression and NF-kappaB activation multi-faceted. This review will
      attempt to analyse the many faces and functions of NF-kappaB in the HIV-1
      lifecycle.

PMID- 10647780
TI  - Modulation of Wnt signaling by Axin and Axil.
AB  - The Wnt signaling pathway is conserved in various species from worms to mammals,
      and plays important roles in development, cellular proliferation, and
      differentiation. The molecular mechanisms by which the Wnt signal regulates
      cellular functions are becoming increasingly well understood. Wnt stabilizes
      cytoplasmic beta-catenin, which stimulates the expression of genes including c
      myc, c-jun, fra-1, and cyclin D1. Axin and its homolog Axil, newly recognized as
      components of the Wnt signaling pathway, negatively regulate this pathway. Other
      components of the Wnt signaling pathway, including Dvl, glycogen synthase kinase
      3beta (GSK-3beta), beta-catenin, and adenomatous polyposis coli (APC), interact
      with Axin, and the phosphorylation and stability of beta-catenin are regulated in
      the Axin complex. Axil has similar functions to Axin. Thus, Axin and Axil act as
      scaffold proteins in the Wnt signaling pathway, thereby modulating the Wnt
      dependent cellular functions.

PMID- 10647781
TI  - Tec family of protein-tyrosine kinases: an overview of their structure and
      function.
AB  - The Tec family is a recently emerging subfamily of non-receptor protein-tyrosine
      kinases (PTKs) represented by its first member, Tec. This family is composed of
      five members, namely Tec, Btk. Itk/Emt/Tsk, Bmx and Txk/Rlk. The most
      characteristic feature of this family is the presence of a pleckstrin homology
      (PH) domain in their protein structure. The PH domain is known to bind
      phosphoinositides; on this basis, Tec family PTKs may act as merge points of
      phosphotyrosine-mediated and phospholipid-mediated signaling systems. Many Tec
      family proteins are abundantly expressed in hematopoietic tissues, and are
      presumed to play important roles in the growth and differentiation processes of
      blood cells. Supporting this, mutations in the Btk gene cause X chromosome-linked
      agammaglobulinemia (XLA) in humans and X chromosome-linked immunodeficiency (Xid)
      in mice, indicating that Btk activity is indispensable for B-cell ontogeny. In
      addition, Tec family kinases have been shown to be involved in the intracellular
      signaling mechanisms of cytokine receptors, lymphocyte surface antigens,
      heterotrimeric G-protein-coupled receptors and integrin molecules. Efforts are
      being made to identify molecules which interact with Tec kinases to transfer Tec
      mediated signals in vivo. Candidates for such second messengers include PLC
      gamma2, guanine nucleotide exchange factors for RhoA and TFII-I/BAP-135. This
      review summarizes current knowledge concerning the input and output factors
      affecting the Tec kinases.

PMID- 10647782
TI  - A piece of my mind. A fragile commodity.

PMID- 10647783
TI  - Chimpanzees as original source for HIV.

PMID- 10647784
TI  - Researchers buoyed by promise of targeted leukemia therapy.

PMID- 10647785
TI  - Increase in global access to essential drugs sought.

PMID- 10647786
TI  - From the Centers for Disease Control and Prevention. Achievements in public
      health, 1900-1999: family planning.

PMID- 10647787
TI  - From the Centers for Disease Control and Prevention. Carbon monoxide poisoning
      associated with use of LPG-powered (propane) forklifts in industrial settings-
      Iowa, 1998.

PMID- 10647788
TI  - Editors and owners of scientific journals.

PMID- 10647789
TI  - Editors and owners of scientific journals.

PMID- 10647790
TI  - The hospitalist's role in advance-care directives.

PMID- 10647791
TI  - Accurate ascertainment of child-abuse mortality.

PMID- 10647792
TI  - Estrogen-receptor status in breast cancer.

PMID- 10647794
TI  - Pressure to publish in the premedical years.

PMID- 10647793
TI  - Prescribing for elderly persons.

PMID- 10647795
TI  - Human papillomavirus antibody and risk of prostate cancer.

PMID- 10647796
TI  - Measles history and atopic diseases: a population-based cross-sectional study.
AB  - CONTEXT: Many recent cross-sectional studies have suggested that lack of early
      exposure to communicable diseases, including measles, in affluent countries may
      have increased rates of atopic disease. OBJECTIVE: To study the association
      between natural measles infection and atopy. DESIGN AND SETTING: Cross-sectional
      nationwide study in Finland using data gathered between November 1, 1982, and
      June 30, 1986. SUBJECTS: A total of 547910 individuals aged 14 months to 19 years
      who at the time of measles-mumps-rubella (MMR) vaccination had relevant
      information collected on the occurrence of measles and allergic rhinitis, eczema,
      and asthma. MAIN OUTCOME MEASURES: Lifetime occurrence of atopic manifestations
      in subjects who had had measles compared with those who had not, expressed as age
      specific and age-adjusted prevalence ratios. RESULTS: The age-adjusted prevalence
      ratio of atopic manifestations among those who had had measles (n = 20 690)
      compared with those who had not (n = 527 220) was 1.32 (95% confidence interval
      [CI], 1.27-1.36) for eczema, 1.41 (95% CI, 1.33-1.49) for rhinitis, and 1.67 (95%
      CI, 1.54-1.79) for asthma. The positive association between measles and atopy was
      evident at all ages, in both urban and rural dwellers, and among subjects with
      many or few contacts at home or in day care. CONCLUSIONS: Based on our data,
      measles and atopy occur more frequently together than expected, which does not
      support the hypothesis that experiencing natural measles infection offers
      protection against atopic disease.

PMID- 10647797
TI  - Association between minor elevations of creatine kinase-MB level and mortality in
      patients with acute coronary syndromes without ST-segment elevation. PURSUIT
      Steering Committee. Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor
      Suppression Using Integrilin Therapy.
AB  - CONTEXT: Controversy surrounds the diagnostic and prognostic importance of
      slightly elevated cardiac markers in patients with acute coronary syndromes
      without ST-segment elevation. OBJECTIVES: To investigate the relationship between
      peak creatine kinase (CK)-MB level and outcome and to determine whether a
      threshold CK-MB level exists below which risk is not increased. DESIGN AND
      SETTING: Retrospective observational analysis of data from the international
      Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using
      Integrilin Therapy (PURSUIT) trial, conducted from November 1995 to January 1997.
      PATIENTS: A total of 8250 patients with acute coronary syndromes without ST
      segment elevation who had at least 1 CK-MB sample collected during their index
      hospitalization. MAIN OUTCOME MEASURE: Mortality at 30 days and 6 months, was
      assessed by category of index-hospitalization peak CK-MB level (0-1, >1-2, >2-3,
      >3-5, >5-10, or >10 times the upper limit of normal). Multivariable logistic
      regression was used to determine the independent prognostic significance of peak
      CK-MB level after adjustment for baseline predictors of 30-day and 6-month
      mortality. RESULTS: Mortality at 30 days and 6 months increased from 1.8% and
      4.0%, respectively, in patients with normal peak CK-MB levels, to 3.3% and 6.2 %
      at peak CK-MB levels 1 to 2 times normal, to 5.1% and 7.5% at peak CK-MB levels 3
      to 5 times normal, and to 8.3% and 11.0% at peak CK-MB levels greater than 10
      times normal. Log-transformed peak CK-MB levels were predictive of adjusted 30
      day and 6-month mortality (P<.001 for both). CONCLUSIONS: Our data show that
      elevation of CK-MB level is strongly related to mortality in patients with acute
      coronary syndromes without ST-segment elevation, and that the increased risk
      begins with CK-MB levels just above normal. In the appropriate clinical context,
      even minor CK-MB elevations should be considered indicative of myocardial
      infarction.

PMID- 10647798
TI  - Urinary and sexual function after radical prostatectomy for clinically localized
      prostate cancer: the Prostate Cancer Outcomes Study.
AB  - CONTEXT: Patients with prostate cancer and their physicians need knowledge of
      treatment options and their potential complications, but limited data on
      complications are available in unselected population-based cohorts of patients.
      OBJECTIVE: To measure changes in urinary and sexual function in men who have
      undergone radical prostatectomy for clinically localized prostate cancer. DESIGN:
      The Prostate Cancer Outcomes Study, a population-based longitudinal cohort study
      with up to 24 months of follow-up. SETTING: Population-based cancer registries in
      6 geographic regions of the United States. PARTICIPANTS: A total of 1291 black,
      white, and Hispanic men aged 39 to 79 years who were diagnosed as having primary
      prostate cancer between October 1, 1994, and October 31, 1995, and who underwent
      radical prostatectomy within 6 months of diagnosis for clinically localized
      disease. MAIN OUTCOME MEASURES: Distribution of and change in urinary and sexual
      function measures reported by patients at baseline and 6, 12, and 24 months after
      diagnosis. RESULTS: At 18 or more months following radical prostatectomy, 8.4% of
      men were incontinent and 59.9% were impotent. Among men who were potent before
      surgery, the proportion of men reporting impotence at 18 or more months after
      surgery varied according to whether the procedure was nerve sparing (65.6% of non
      nerve-sparing, 58.6% of unilateral, and 56.0% of bilateral nerve-sparing). At 18
      or more months after surgery, 41.9% reported that their sexual performance was a
      moderate-to-large problem. Both sexual and urinary function varied by age (39.0%
      of men aged <60 years vs 15.3 %-21.7% of older men were potent at > or =18 months
      [P<.001]; 13.8% of men aged 75-79 years vs 0.7%-3.6% of younger men experienced
      the highest level of incontinence at > or =18 months [P = .03]), and sexual
      function also varied by race (38.4% of black men reported firm erections at > or
      =18 months vs 25.9% of Hispanic and 21.3% of white men; P = .001). CONCLUSIONS:
      Our study suggests that radical prostatectomy is associated with significant
      erectile dysfunction and some decline in urinary function. These results may be
      particularly helpful to community-based physicians and their patients with
      prostate cancer who face difficult treatment decisions.

PMID- 10647799
TI  - Trends in pregnancy-related smoking rates in the United States, 1987-1996.
AB  - CONTEXT: Rates of smoking are increasing among adolescents and young adults, but
      trends in smoking among pregnant women have not been studied. OBJECTIVE: To
      assess pregnancy-related variations in smoking behaviors and their determinants
      among women of childbearing age in the United States. DESIGN: Analysis of data
      collected between 1987-1996 from the Behavioral Risk Factor Surveillance System
      survey. SETTING AND SUBJECTS: A total of 187302 (178499 nonpregnant and 8803
      pregnant) noninstitutionalized women aged 18 to 44 years from 33 states. MAIN
      OUTCOME MEASURES: Prevalence rates of smoking initiation and current smoking,
      median number of cigarettes smoked, and adjusted odds ratios for smoking
      stratified by pregnancy status; prevalence rate ratio for current smoking
      comparing pregnant with nonpregnant women. RESULTS: The overall percentage of
      women who had ever initiated smoking decreased significantly from 44.1% in 1987
      to 38.2% in 1996. During that 10-year period, the prevalence of current smoking
      also decreased significantly among both pregnant women (16.3% to 11.8%) and
      nonpregnant women (26.7% to 23.6%). Overall, pregnant women were about half (54%)
      as likely as nonpregnant women to be current smokers during 1987-1996. Over time,
      the median number of cigarettes smoked per day by pregnant smokers remained at
      10, whereas among nonpregnant smokers it decreased from 19 to 15 (P<.05 for
      trend). In the same period, among young women (aged 18-20 years), prevalence
      rates of smoking initiation and current smoking increased slightly.
      Sociodemographic subgroups of women at increased risk for current smoking were
      the same for pregnant and nonpregnant women (ie, those with a completed high
      school education or less, whites, and those who were unmarried). CONCLUSIONS: In
      this analysis, the decline in smoking over time among pregnant women was
      primarily due to the overall decline in smoking initiation rates among women of
      childbearing age, not to an increased rate of smoking cessation related to
      pregnancy. To foster effective perinatal tobacco control, efforts are needed to
      further reduce the number of young women who begin smoking. Clinicians should
      query all pregnant women and women of childbearing age about smoking and provide
      cessation and relapse interventions to each smoker.

PMID- 10647800
TI  - Methylnaltrexone for reversal of constipation due to chronic methadone use: a
      randomized controlled trial.
AB  - CONTEXT: Constipation is the most common chronic adverse effect of opioid pain
      medications in patients who require long-term opioid administration, such as
      patients with advanced cancer, but conventional measures for ameliorating
      constipation often are insufficient. OBJECTIVE: To evaluate the efficacy of
      methylnaltrexone, the first peripheral opioid receptor antagonist, in treating
      chronic methadone-induced constipation. DESIGN: Double-blind, randomized, placebo
      controlled trial conducted between May 1997 and December 1998. SETTING: Clinical
      research center of a university hospital. PARTICIPANTS: Twenty-two subjects (9
      men and 13 women; mean [SD] age, 43.2 [5.5] years) enrolled in a methadone
      maintenance program and having methadone-induced constipation. MAIN OUTCOME
      MEASURES: Laxation response, oral-cecal transit time, and central opioid
      withdrawal symptoms were compared between the 2 groups. RESULTS: The 11 subjects
      in the placebo group showed no laxation response, and all 11 subjects in the
      intervention group had laxation response after intravenous methylnaltrexone
      administration (P<.001). The oral-cecal transit times at baseline for subjects in
      the methylnaltrexone and placebo groups averaged 132.3 and 126.8 minutes,
      respectively. The average (SD) change in the methylnaltrexone-treated group was 
      77.7 (37.2) minutes, significantly greater than the average change in the placebo
      group (-1.4 [12.0] minutes; P<.001). No opioid withdrawal was observed in any
      subject, and no significant adverse effects were reported by the subjects during
      the study. CONCLUSIONS: Our data demonstrate that intravenous methylnaltrexone
      can induce laxation and reverse slowing of oral cecal-transit time in subjects
      taking high opioid dosages. Low-dosage methylnaltrexone may have clinical utility
      in managing opioid-induced constipation.

PMID- 10647801
TI  - Physicians and the pharmaceutical industry: is a gift ever just a gift?
AB  - CONTEXT: Controversy exists over the fact that physicians have regular contact
      with the pharmaceutical industry and its sales representatives, who spend a large
      sum of money each year promoting to them by way of gifts, free meals, travel
      subsidies, sponsored teachings, and symposia. OBJECTIVE: To identify the extent
      of and attitudes toward the relationship between physicians and the
      pharmaceutical industry and its representatives and its impact on the knowledge,
      attitudes, and behavior of physicians. DATA SOURCES: A MEDLINE search was
      conducted for English-language articles published from 1994 to present, with
      review of reference lists from retrieved articles; in addition, an Internet
      database was searched and 5 key informants were interviewed. STUDY SELECTION: A
      total of 538 studies that provided data on any of the study questions were
      targeted for retrieval, 29 of which were included in the analysis. DATA
      EXTRACTION: Data were extracted by 1 author. Articles using an analytic design
      were considered to be of higher methodological quality. DATA SYNTHESIS: Physician
      interactions with pharmaceutical representatives were generally endorsed, began
      in medical school, and continued at a rate of about 4 times per month. Meetings
      with pharmaceutical representatives were associated with requests by physicians
      for adding the drugs to the hospital formulary and changes in prescribing
      practice. Drug company-sponsored continuing medical education (CME)
      preferentially highlighted the sponsor's drug(s) compared with other CME
      programs. Attending sponsored CME events and accepting funding for travel or
      lodging for educational symposia were associated with increased prescription
      rates of the sponsor's medication. Attending presentations given by
      pharmaceutical representative speakers was also associated with nonrational
      prescribing. CONCLUSION: The present extent of physician-industry interactions
      appears to affect prescribing and professional behavior and should be further
      addressed at the level of policy and education.

PMID- 10647802
TI  - Antiretroviral therapy in adults: updated recommendations of the International
      AIDS Society-USA Panel.
AB  - OBJECTIVE: To update recommendations for antiretroviral therapy for adult human
      immunodeficiency virus type 1 (HIV-1) infection, based on new information and
      drugs that are available. PARTICIPANTS: A 17-member international physician panel
      with antiretroviral research and HIV patient care experience initially convened
      by the International AIDS Society-USA in December 1995. EVIDENCE: Available
      clinical and basic science data including phase 3 controlled trials; data on
      clinical, virologic, and immunologic end points; research conference reports; HIV
      pathogenesis data; and panel expert opinion. Recommendations were limited to
      therapies available (US Food and Drug Administration approved) in 1999. CONSENSUS
      PROCESS: The panel assesses new research reports and interim results and
      regularly meets to consider how the new data affect therapy recommendations.
      Recommendations are updated via full-panel consensus. Guidelines are presented as
      recommendations if the supporting evidence warrants routine use in the particular
      situation and as considerations if data are preliminary or incomplete but
      suggestive. CONCLUSIONS: The availability of new antiretroviral drugs has
      expanded treatment choices. The importance of adherence, emerging long-term
      complications of therapy, recognition and management of antiretroviral failure,
      and new monitoring tools are addressed. Optimal care requires individualized
      management and ongoing attention to relevant scientific and clinical information
      in the field.

PMID- 10647803
TI  - Interactions between physicians and the health care technology industry.

PMID- 10647804
TI  - Protection against atopic diseases by measles--a rash conclusion?

PMID- 10647806
TI  - JAMA Patient Page: allergies.

PMID- 10647805
TI  - An evaluation of poor pregnancy outcomes among Burundian refugees in Tanzania.
AB  - CONTEXT: Little is known about pregnancy outcomes among the approximately 11
      million refugees worldwide, 25% of whom are women of reproductive age. OBJECTIVE:
      To estimate incidence of and determine risk factors for poor pregnancy outcomes
      and to calculate the contribution of mortality from neonatal and maternal deaths
      to overall mortality in a refugee camp. DESIGN: Cross-sectional review of records
      and survey, conducted in February and March 1998. SETTING: Mtendeli refugee camp,
      Tanzania. PARTICIPANTS: For the overall assessment, 664 Burundi women who had a
      pregnancy outcome during a recent 5-month period (September 1, 1997-January 31,
      1998) and their 679 infants; 538 women (81%) completed the survey. MAIN OUTCOME
      MEASURES: Incidence of fetal death (fetus born > or =500 g or > or =22 weeks'
      gestation with no signs of life), low birth weight (<2500 g), neonatal death
      (death <28 days of life), and maternal death (deaths during or within 42 days of
      pregnancy from any cause related to or aggravated by the pregnancy or its
      management). RESULTS: The fetal death rate was 45.6 per 1000 births, the neonatal
      mortality rate was 29.3 per 1000 live births, and 22.4% of all live births were
      low birth weight. Compared with women without poor pregnancy outcome, those with
      poor pregnancy outcome were more likely to report prior high socioeconomic status
      (adjusted odds ratio [OR], 1.6; 95% confidence interval [CI], 1.1-2.4), having a
      first or second pregnancy (OR, 2.2; 95% CI, 1.4-3.4), and having 3 or more
      episodes of malaria during pregnancy (OR, 2.0; 95% CI, 1.4-3.1). Neonatal and
      maternal deaths accounted for 16% of all deaths during the period studied.
      CONCLUSIONS: Poor pregnancy outcomes were common in this refugee setting, and
      neonatal and maternal deaths, 2 important components of reproductive health
      related deaths, contributed substantially to overall mortality.

PMID- 10647807
TI  - Effects of papain on isolation of single smooth muscle cells from the guinea pig
      longitudinal ileum.
AB  - The methods for isolation of single cells from the guinea pig longitudinal ileum
      were investigated with focussing on the papain concentration for the digestion of
      the ileum. The ileal muscle was minced. The minced muscle was loaded with
      fluorescent probes of calcein or fura 2, and treated with papain for 30 min at
      various concentrations. Papain at concentrations more than 1 U/ml reduced both
      calcein fluorescence and fura-2-signal evoked by carbachol. Carbachol-induced
      fura-2-signal was more sensitive to papain than calcein fluorescence, suggesting
      that proteins related to the formation of receptors are more vulnerable than
      membrane lipids or proteins limiting the membrane permeability upon the exposure
      to papain. The resultant yield of single cells was highest at 0.56 U/ml of papain
      without affecting calcein and fura-2 fluorescence responses, thus this
      concentration appeared to be appropriate for the isolation of single cells from
      the ileum. Single cells alive contracted dose dependently by the exposure to
      carbachol (0.1-10 microM) under the microscopic measurement, and were appeared to
      grow confluent in culture for approximately 15 days. These results suggest that
      the low concentration, 0.56 U/ml, of papain in the isolation medium is better to
      obtain functional cells from the guinea pig ileum.

PMID- 10647808
TI  - Interaction between platelet-aggregating response and vasoconstrictive response
      to platelet activating factor.
AB  - It is very important to know under medical treatment which kinds of platelet
      agonists participate in abnormal platelet-blood vessel interactions. The present
      study, focusing on platelet activating factor (PAF) was undertaken in an attempt
      to investigate its action on platelet aggregating response and vasocontractile
      response to noradrenaline (NA-R). We used autologous platelets and isolated
      perfused arterial segments from Japanese white rabbits. Firstly, typical tracings
      of platelet aggregating response to PAF were increased in a dose-dependent
      fashion, which remained constant and long-lasting. Secondly, noradrenaline (NA)
      at 5 to 25 ng elicited an initially augmented response in the presence of
      platelet rich plasma (PRP) with PAF, followed by gradually attenuated responses.
      Based on the light transmission intensity, platelet aggregation did not seem to
      be directly or strictly linked to vasocontractile response. Pretreatment with
      either dibutyryl cyclic AMP (DBcAMP) or indomethacin (IM, a cyclo-oxygenase
      inhibitor) clearly caused reductions in NA-R as well as platelet aggregation in
      the presence of PRP with collagen, whereas platelet aggregation and NA-R in the
      presence of PRP with PAF were scarcely influenced by pretreatment with either
      DBcAMP or IM. Thus, it seems reasonable to conclude that, in contrast to the
      response to collagen, platelet aggregation response to PAF was almost indifferent
      to the adenylate cyclase-cyclic AMP system and the cyclo-oxygenase metabolic
      pathway.

PMID- 10647809
TI  - Reactivity of intrarenal arteries to vasoconstrictor and vasorelaxant
      polypeptides in adult stroke-prone spontaneously hypertensive rats.
AB  - The reactivity of intrarenal arteries to vasoconstrictor and vasodilator
      polypeptides was examined in adult stroke-prone spontaneously hypertensive rats
      (SHRSP). The contraction response to endothelin-1 (ET-1) was greater in SHRSP
      than in age-matched Wistar-Kyoto rats (WKY), and so was the pD2 estimate (8.05+/
      0.03 in SHRSP, and 7.73+/-0.06 in WKY; n=5, P < 0.05). The contraction response
      to, and the pD2 estimate of, vasopressin were comparable in SHRSP and WKY.
      Neuropeptide Y did not contract the intrarenal arteries. In norepinephrine
      precontracted arteries with intact endothelium, substance P and neurokinin A did
      not relax the arteries of either SHRSP or WKY, while calcitonin gene-related
      peptide (CGRP) induced a profound relaxation response. Relaxation response to
      CGRP was significantly greater in SHRSP than in WKY. Atrial, brain, and C-type
      natriuretic peptides (ANP, BNP, CNP), vasoactive intestinal polypeptide (VIP),
      and peptide histidine isoleucine (PHI) all caused relaxation responses, with a
      greater extent of relaxation to ANP, BNP, and VIP and a less extent to CNP and
      PHI. However, there were no significant differences in these relaxation responses
      between SHRSP and WKY. The current results revealed the character of
      heterogeneity of rat intrarenal arteries in response to vasoconstrictor and
      vasodilator peptides, and showed an enhanced reactivity to ET-1 and to CGRP in
      SHRSP.

PMID- 10647810
TI  - The effect of mutations in EF-Tu on its affinity for tRNA as measured by two
      novel and independent methods of general applicability.
AB  - Elongation factor Tu is essential for binding and a correct delivery of aminoacyl
      tRNA during protein biosynthesis. For a good characterization of its interaction
      with tRNA in terms of structure-function relationship, determinations of kinetic
      equilibrium parameters are of great value. We describe two novel methods for that
      purpose. One method is based on EF-Tu protection of the tRNA 3' acceptor end
      against RNase A cleavage and yields the Kd value together with the corresponding
      dissociation and association rate constants from one single set of experiments.
      The other is a rapid method for screening relative affinities of mutant EF-Tus
      for tRNA. It is based on competition between EF-Tu species with and without a
      (His)6 extension for the same aminoacyl-tRNA and yields a relative Kd value. The
      method can be of general importance for the measuring of ligand affinities of all
      sorts of His-tagged proteins. Both methods are illustrated by their application
      in the analysis of mutant EF-Tus with changed interactions with tRNA and
      antibiotics. Raising the assay temperature from 4 to 37 degrees C causes a 30
      fold increase of Kd for EF-Tu x GTP x Phe-tRNA complexes. The mutation K237E
      leads to rapid inactivation at the latter temperature. A parallel is found
      between the order of increasing Kd values for EF-Tus with mutation G316D, A375T
      and Q124K, respectively, and their order of increasing resistance to kirromycin.

PMID- 10647811
TI  - Effects of ethidium bromide and SYBR Green I on different polymerase chain
      reaction systems.
AB  - In an in-gel polymerase chain reaction (PCR), the generation of a 1750-bp yeast
      DNA fragment was inhibited when yeast DNA gel-stabs or gel-slices stained with
      ethidium bromide (EtBr) or SYBR Green I were used. Similar inhibition occurred to
      a varying degree in the reamplification of PCR fragments in prokaryotic systems.
      Inclusion of the dyes in PCR resulted in an inhibition at about 10 microg/ml EtBr
      and at 10,000-20,000-fold dilution of SYBR Green I in all systems. The effect
      remained unchanged despite increasing the PCR cycles to 40. However, increasing
      the magnesium chloride concentration did reverse the inhibitory actions, although
      the PCR specificity was lost. In an unusual observation, we find that, at higher
      dye concentrations (50 microg/ml EtBr, or thousand fold dilution of SYBR Green
      I), the input yeast DNA electrophoretic profile is maintained following 25 PCR
      cycles (despite a denaturation temperature of 94 degrees C). It varied
      significantly in different DNA systems and was readily reversed by high Mg++
      concentrations. It is concluded that, at low Mg++ concentrations, different PCR
      systems are inhibited to varying extents by intercalating dyes and, in some PCR
      systems, intercalating dyes at unusually high concentrations maintain input DNA
      electrophoretic profile.

PMID- 10647812
TI  - Detection of peptide nucleic acids in tissue extracts of treated animals by gel
      mobility shift assay.
AB  - We have developed a sensitive and reproducible gel mobility shift assay to detect
      PNA oligomers in tissue of treated animals. PNA present in purified tissue
      extracts of treated animals is hybridized to a 33P-labelled DNA oligomer probe,
      and analyzed by polyacrylamide gel electrophoresis. The PNA-DNA hybrid migrates
      more slowly than the DNA probe alone and can be quantified relative to a standard
      curve. This detection method is useful for detecting PNAs in many different
      tissues, including brain, heart, kidney, liver, spleen, and serum, as well as
      cells in culture.

PMID- 10647813
TI  - An advantage for use of isotope labeling and NMR chemical shifts to analyze the
      structure of four homologous IgG-binding domains of staphylococcal protein A.
AB  - Because of the complexity arising from the large molecular size and the amino
      acid sequence homologies of IgG-binding domains of Staphylococcal Protein A
      (SpA), we have introduced, a combination of stable isotope labeling and both
      qualitative and quantitative investigations of the structural dependence of the
      NMR chemical shifts for its structure analysis. In order to enable selective
      isotope labeling with high efficiency, a mutated low molecular weight Protein A
      (LPA; MWt = 27 kDa) which consists of E, D, A, B and 13 residues of the C-domain
      was used in this study. Amide proton chemical shifts, measured using uniformly
      15N-labeled LPA and LPA labeled selectively with 15N-alanine, show that the turn
      between helices 1 and 2, and its tertiary interactions with helix 3, are very
      similar in all domains. This contradicts previous results obtained using
      independent structure calculations on isolated domains. The close similarity in
      NH and 15N chemical shifts of alanine residues in the interdomain linker suggests
      that the linker maintains a similar structure both in isolated domains and in the
      intact protein. We show that the high-field shifted methyl signal of Ala 48 is
      affected by the ring-current effect arising from Phe 30, and has a very similar
      helical environment in all four domains. Thus, helix 3 is present in all domains,
      as we previously reported [Kikuchi et al., J Biochem Biophys Method, 1999:38:203
      208], even though it is not observed in the crystal structure [Deisenhofer J.
      Biochemistry 1981;20:2361-2370].

PMID- 10647814
TI  - Determination the rate constants of some biexponential reactions.
AB  - Reactions that are described by biexponential functions are typical for many
      biological processes. The kinetics of these reactions is described by
      transcendental irrational equations interconnecting the reagent concentrations,
      time and rate constants. Meantime, their graphical representation in the semi
      logarithmic coordinates can be decomposed into two straight lines that intercept
      at some angle. New simple methods for asymptotic numerical solution of the
      equations describing these reactions are suggested. These methods permit
      determining the rate constants using the kinetic data of initial substance
      concentration, which transform into final product according to a two-component
      model, a sequential model or a competitive model.

PMID- 10647815
TI  - Transfer of SDS-proteins from gel electrophoretic zones into mass spectrometry,
      using electroelution of the band into buffer without sectioning of the gel.
AB  - Five SDS-proteins, ranging in molecular weight from 14 to 66 kDa, were detected
      without covalent fluorescent labeling by the automated gel electrophoresis
      apparatus with intermittent fluorescence scanning (HPGE apparatus,
      LabIntelligence) during electrophoresis in barbiturate buffer in the presence of
      Cascade Blue. The SDS-proteins were electroeluted from the gel into 220 microl of
      buffer by a modification of the procedure of Gombocz and Cortez. The
      electroeluate was freed of SDS, ultrafiltered and subjected to MALDI-TOF mass
      spectrometry. The masses of the five native proteins were found to be maintained
      after electrophoresis and electroelution in the presence of the potential
      contaminants SDS, barbituric acid and Cascade Blue. The procedure of protein
      transfer from SDS-PAGE into mass spectrometry, without excision of bands, gel
      maceration and protein recovery by diffusion, therefore is shown to be suitable
      for the identification by mass of intact proteins derived from gel
      electrophoretic bands.

PMID- 10647816
TI  - High-throughput DNA sequencing: a genomic data manufacturing process.
AB  - The progress trends in automated DNA sequencing operation are reviewed.
      Technological development in sequencing instruments, enzymatic chemistry and
      robotic stations has resulted in ever-increasing capacity of sequence data
      production. This progress leads to a higher demand on laboratory information
      management and data quality assessment. High-throughput laboratories face the
      challenge of organizational management, as well as technology management.
      Engineering principles of process control should be adopted in this biological
      data manufacturing procedure. While various systems attempt to provide solutions
      to automate different parts of, or even the entire process, new technical
      advances will continue to change the paradigm and provide new challenges.

PMID- 10647817
TI  - Isolation of cDNAs encoding gibbon and monkey platelet and T cell activation
      antigen 1 (PTA1).
AB  - Human platelet and T cell activation antigen 1 (PTA1) is a 67kDa type I
      transmembrane glycoprotein mainly expressed on the surface of activated T cells
      and platelets, and is involved in the development of human cytotoxic T cell (CTL)
      as well as platelet activation and aggregation. We have cloned and sequenced
      gibbon PTA1 (gPTA1) and monkey PTA1 (mPTA1) cDNAs by RT-PCR from gibbon leukemic
      cell line MLA 144 and PHA-induced Rhesus monkey PBMC respectively. The mature
      proteins of gPTA1, mPTA1 and human PTA1 (hPTA1) share 93-95% amino acid
      similarity with the highest similarity in domain 1 of extracellular region. All
      the important features of PTA1 molecule are conserved among these Primates: (1)
      the ORF encoding 336 amino acid residues including signal sequence (18aa),
      extracellular region (232aa), transmembrane sequence (25aa) and cytoplasmic
      region (61aa); (2) two conserved pairs of Cys (Cys19 to Cys90 and Cys134 to
      Cys204) forming disulfide bonds stabilizing the two immunoglobulin superfamily V
      like domains; (3) eight putative N-linked glycosylation sites (except gPTA1 with
      nine sites) and three O-linked glycosylation sites in extracellular region; and
      (4) predicated protein kinase C phosphorylation sites (Thr275 and Ser311), casein
      kinase II sites (Ser295 and The299) and the potential tyrosine phosphorylation
      site (Tyr304). These data indicate that PTA1 molecule is highly conserved among
      the Primates and may play important roles in immune response.

PMID- 10647818
TI  - Cloning, DNA sequence analysis, and deletion of a gene encoding diacetyl-acetoin
      reductase from Lactococcus lactis.
AB  - Diacetyl is produced by strains of lactic acid bacteria used in the dairy
      industry. Production of this important flavour compound could be increased by
      genetic manipulation of genes encoding enzymes involved in diacetyl metabolism.
      This paper reports the cloning and sequencing of the gene (dar) encoding diacetyl
      acetoin reductase from Lactococcus lactis. Analysis of the DNA sequence of the
      dar gene and surrounding area revealed the presence of a putative operon with
      similarity to the family of ABC transporter systems. The dar gene has been
      deleted from the chromosome by double cross-over homologous recombination.

PMID- 10647819
TI  - The fortuitous cloning of retroelement-like sequences from wheat and rye as by
      products of a specific polymerase chain reaction.
AB  - Cloning of by-products of a specific PCR reaction, directed to the Em genes of
      wheat and rye, has resulted in the identification of ten sequences with homology
      to the known Tyl-copia-like retroelements WIS 2-1A from wheat and BARE-1 from
      barley. These sequences were amplified by only one of the primers due to the
      presence of an inverted repeat. Nine sequences are ca. 740 bp long and contain
      part of the left LTR, the adjacent primer-binding site and part of the leader
      sequence, whereas one shorter sequence (535 bp) consists of part of the leader
      sequence only. The dendrogram, constructed from the multiple sequence alignment,
      classified the isolated sequences into two narrowly related groups that belong to
      the WIS-2 family of cereal retroelements.

PMID- 10647820
TI  - Cloning and sequencing of mouse glutaredoxin (grx) cDNA.
AB  - Glutaredoxins are small proteins (12 kDa) with a conserved active sequence Cys
      Pro-Tyr(-Phe)-Cys that catalyse GSH-disulfide oxidoreduction reactions in the
      presence of NADPH and glutathione reductase. Many mammalian glutaredoxins have
      been characterized and human and pig cDNA sequence determined. However, no mouse
      glutaredoxin cDNA or protein sequence has yet been reported. We have cloned a
      cDNA from a mouse liver library that encodes the putative mouse glutaredoxin
      homologue. The deduced polypeptide sequence encodes a 107 amino acid protein
      displaying a high degree of homology with other members of the glutaredoxin
      family.

PMID- 10647821
TI  - The isolation and sequence of canine interleukin-8 receptor.
AB  - A cDNA corresponding to canine IL-8 receptor has been cloned and sequenced. The
      cDNA was synthesized using RT-PCR, with oligonucleotide primers designed from
      conserved regions of published IL-8 receptors. The 5'-end was cloned by 5'-RACE
      and the 3'-end was cloned by 3'-RACE. The cDNA encodes a predicted full length IL
      8r protein of 356 amino acids. At the nucleic acid level, the canine cDNA shows
      83.9%, 82.4%/78.8%, 81.5%/78%, 81.4%/77.7%, 77.8% and 77.3%/71.9% identity to
      published sequences of bovine, human, gorilla, rabbit, mouse and rat IL8RB/IL8RA,
      respectively. The derived protein from the cDNA sequences shows 75.3%/70.3%,
      75.3%/70.1%, 74.8%/69.4%, 70%/59%, and 69.7% identity to that of human, rabbit,
      gorilla, rat and mouse IL8RB/IL8RA homolog.

PMID- 10647822
TI  - Rubisco small subunit gene family in cassava.
AB  - Cassava leaves of two different cultivars, Brazil and Buloh, were used to isolate
      mRNA. The mRNA isolated was successfully used in the construction of cDNA
      libraries for each of the cultivars. The cDNA libraries were screened for members
      of ribulose-1,5-bisphosphate carboxylase/oxygenase small subunit gene family and
      positive clones were sequenced. A total of seven different SSU genes, of which
      five were from cultivar Brazil and two were from cultivar Buloh, were isolated.
      Comparison results show that even though all the sequences are highly similar,
      they can be classified into three subfamilies. Homology between members of the
      same subfamily is higher than homology between members from the same cultivar.

PMID- 10647823
TI  - Cloning and characterization of the human novel gene encoding 6.2 kDa protein
      highly expressed upon ultraviolet irradiation in DNA-PK-deleted human glioma
      M059J cells.
AB  - The full length of a gene isolated using a methylated DNA binding column as
      previously reported (Cross et al., 1994) has been cloned. The gene encodes 55
      amino acids (6.2 kDa), and has a transcript of approximately 0.45 kb. It has 2
      exons in the genome. After searching for sequence homology (BLAST), a homology to
      hypothetically 6.3 kDa protein located at cosmid ZK652 (protein P34660; EMBL
      Accession No. L14429) of C. elegans chromosome 3 was noted (51.9% amino acid
      homology). It has 1 site (-SQ-) for DNA-dependent protein kinase (DNA-PK)
      phosphorylation and 2 sites of myristilation. This novel gene is very strongly
      expressed (about 25.6 times) in DNA-PK-deleted human glioma cell line (M059J) 2
      hrs after ultraviolet (UV) irradiation compared to the DNA-PK +/+ cell line
      (M059K) which expresses the gene at a relatively low level (about 7.5 times).
      Therefore, this result suggests that DNA-PK may negatively regulate the
      transcriptional level of this gene in M059K cells upon UV damage (50 J/m2),
      associated with cell toxicity.

PMID- 10647824
TI  - Molecular characterization and classification of Stylosanthes mexicana, S.
      macrocarpa, S. seabrana and S. fruticosa by DNA sequence analysis of two
      chloroplast regions.
AB  - The trnL (UAA) intron and trnL (UAA) - trnF (GAA) intergenic spacer region from
      the diploid species Stylosanthes mexicana, S. macrocarpa and S. seabrana and the
      tetraploid species S. fruticosa were amplified by polymerase chain reaction and
      subjected to direct DNA sequencing. Comparison of these chloroplast regions with
      previously determined DNA sequences of 19 Stylosanthes species revealed a close
      relationship with a clade containing the diploid species S. hamata, S. calcicola,
      and the tetraploid species S. scabra. The results were used to infer
      relationships between the diploid species of this clade, in relation to the
      alloploid species S. scabra and S. fruticosa.

PMID- 10647825
TI  - cDNA sequence of bovine thioredoxin.
AB  - In this paper, we report the cDNA sequence of bovine thioredoxin. We determined
      the full-length cDNA sequence of bovine thioredoxin by RT-PCR, 5'-RACE and 3'
      RACE methods. Currently, the thioredoxin cDNA sequences of only five mammalian
      species (human, macaca, mouse, ovine and rat) are registered in the GenBank
      database. We performed sequence comparisons on the total cDNA sequence and the
      coding region, and produced a multialignment between the amino acid sequences of
      bovine and other mammalian thioredoxins. The amino acid sequences of thioredoxins
      are highly conserved among mammalian species, for example, only one difference
      exists between the amino acid sequences of bovine and ovine thioredoxin.

PMID- 10647826
TI  - Cardiothoracic surgery in Europe: politics, pressures and practice.

PMID- 10647827
TI  - Combined approach for internal carotid artery stenosis and cardiovascular disease
      in septuagenarians--a comparative study.
AB  - OBJECTIVE: The best surgical approach for concomitant carotid artery and cardiac
      disease remains controversial. Many studies proved the safety and efficiency of
      simultaneous surgery. We aimed to demonstrate the same benefits for patients > or
      = 70 years. METHODS: We retrospectively evaluated 205 patients simultaneously
      operated upon between 1988 and 1998. Group A comprised patients < 70 years (n =
      110), group B > or = 70 years, (n = 95). Risk factors, neurologic and cardiac
      history, angiographic findings, operative data, morbidity and mortality (30-day
      postoperatively) were analysed. The mean age was 62 years in group A and 75 years
      in group B. All patients with symptomatic carotid artery disease, stenosis > 70%
      or ulcerative carotid disease had simultaneous surgery. Always, the carotid
      artery was addressed first. RESULTS: Patients in group B had a higher prevalence
      of peripheral vascular disease (P = 0.0005), renal insufficiency (P = 0.0011) and
      COPD (P = 0.03). Urgent operation was indicated in 19% of group A patients vs.
      37% in group B. In group A 70% were asymptomatic regarding the carotid vs. 48% in
      group B. Left ventricular dysfunction was present in 45% (group A) and 58% (group
      B). In the present study 4% in group A and 7% in group B suffered a perioperative
      myocardial infarction. Pathologic changes of the contralateral carotid were found
      in 42 vs. 57% (A vs. B). Mortality due to cardiac causes was 1 and 5%,
      respectively. The combination of persistent neurologic deficit and neurologic
      death occurred in 3% in group A (n = 3) and 5% in group B (n = 5). Postoperative
      neuro-cognitive dysfunction was more common in group B (35 vs. 16%; P = 0.01).
      CONCLUSIONS: The incidence of persistent neurologic deficits and neurologic
      mortality in patients > or = 70 years is acceptable, and low in patients < 70
      years. Preoperative risk factors are increasing with age and are related to the
      higher mortality in elderly patients. Due to our results we will conclude that
      the combined approach for carotid stenosis and cardiovascular disease is the
      method of choice in this high-risk population.

PMID- 10647828
TI  - Twenty-four year experience with reoperations after ascending aortic or aortic
      root replacement.
AB  - OBJECTIVE: A retrospective analysis of early and late outcome for late (>4 weeks)
      reoperations on the ascending aorta or aortic root. MATERIALS AND METHODS: During
      a 24-year interval, starting in 1974, 834 patients underwent replacement of the
      ascending aorta (39.2%) or aortic root (60.8%). During the same period, 56
      patients with a mean age of 51.1 +/- 14.4 years underwent reoperation after
      ascending aortic or aortic root replacement. Predominant indications for
      reoperation were false aneurysm in 25 (44.6%) patients and true aneurysm in 18
      (32.1%) patients. Most frequent surgical procedures were redo aortic root
      replacement in 30 (53.6%) patients and closure of a false aneurysm in 14 (25.0%)
      patients. Median interval between the operations was 51 months. Eighteen (32.2%)
      patients underwent concomitant partial or total aortic arch replacement. RESULTS:
      Hospital mortality was 5.4% (n = 3; 70% CL: 2.4-8.4%). Cause of death was low
      cardiac output in two patients and rupture of the aorta at the distal suture line
      in one patient. Univariate analysis identified two or more previous operations (P
      = 0.038) and the interval between initial operation and reoperation for
      complication of less than 8 months (P = 0.005) as risk factors for hospital
      death. Multivariate analysis indicated operation for active endocarditis or
      vascular graft infection as an independent risk factor for hospital death (P =
      0.038, odds 14.6). Follow-up was complete, median 3.1 years. Nine (16.9%; 70% CL:
      11.7-22.1%) patients died during that period. Estimated survival at 1, 5 and 10
      years was 91.2, 84.0 and 76.4%. One patient underwent another reoperation.
      Estimated event-free survival at 1, 5 and 10 year is 84.3, 72.2 and 65.6%.
      CONCLUSION: False aneurysm formation and progression of aneurysmatic disease are
      the predominant causes for late reoperations after aortic root or ascending
      aortic replacement. Reoperations can be performed with low hospital mortality and
      good late results.

PMID- 10647829
TI  - Does focal destruction of the thoracic aorta wall by Staphylococcus aureus lead
      to the development of infected aneurysms? An experimental study.
AB  - OBJECTIVE: The infrequency of infected aneurysms suggests that either infection
      of segments of the aortic wall is uncommon, or that infections do not always lead
      top infected aneurysm formation. The purpose of the study was to determine
      whether focal Staphylococcus aureus infection of aortic wall segments leads
      consistently to the development of infected aneurysms and to evaluate the
      segments in which infection did not lead to the infected aneurysm formation.
      METHODS: Twenty pigs were inoculated with 0.1 ml of a Staphylococcus aureus
      inoculum in three segments of the thoracic aorta wall (study group). In another
      10 pigs, 0.1 ml of saline solution was injected in three segments of the thoracic
      aorta wall (control group). STUDY GROUP: histological abnormalities and bacterial
      culture of the inoculation sites were evaluated at 10 days (n = 5 pigs), 30 days
      (n = 5 pigs), and 90 days (n = 10 pigs). CONTROL GROUP: histological
      abnormalities were evaluated at 10 days (n = 5 pigs) and 90 days (n = 5 pigs).
      RESULTS:  STUDY GROUP: infected aneurysms developed in only two animals killed at
      30 days. At 90 days, destruction of the elastic tissue, scar tissue and neointima
      formation were found in all the aortic segments studied. CONTROL GROUP: no
      significant changes were found in any of the segments evaluated. CONCLUSION: In
      our experimental model, acute local infection by S. aureus caused the development
      of infected aortic aneurysm in only 10% of the animals. In the remaining 90%,
      healing of the site of infection followed resolution of the infection.

PMID- 10647830
TI  - Mesothelioma--VATS biopsy and lung mobilization improves diagnosis and
      palliation.
AB  - OBJECTIVES: Mesothelioma is an increasingly frequent malignancy in which
      diagnosis is often delayed and disease diagnosed at an advanced stage. Earlier
      diagnosis and therapeutic intervention that can control recurrent pleural
      effusion may improve outlook and survival. METHODS: A prospective series of 25
      patients in whom mesothelioma was suspected was referred for histological
      diagnosis by video assisted-thoracoscopy (VAT) after failure of other methods. At
      the same operative procedure drainage of pleural effusion, cytoreductive
      pleurectomy and lung mobilization was performed where possible. Complete follow
      up was obtained. RESULTS: All patients had a histological diagnosis (100%) from
      the material sent for biopsy. In 23 patients this was mesothelioma, in two
      patients chronic empyema. All patients undergoing drainage of effusion,
      cytoreductive pleurectomy and lung mobilization subsequently were diagnosed of
      having mesothelioma stages III to IV. Fifteen out of 21 who underwent lung
      mobilization had closure of the pleural space. Post operative air leak in this
      group was a mean of 5 days (2-12 days). Recurrent effusion occurred in only one
      patient. Eleven patients remain alive at 1-2 years post operation with no
      hospital admissions for recurrent pleural effusion. In the six out of 21 who did
      not have closure of the pleural space, one remained alive 9 months post surgery.
      Five died within 1-6 months of the procedure. The average number of further
      hospital admissions for repeat drainage of effusion was 3 (1-6). CONCLUSIONS:
      VATs provides adequate tissue for histological diagnosis where other methods
      fail. At the same operative sitting it provides a therapeutic intervention that
      allows drainage of effusion cytoreductive pleurectomy and lung mobilization in a
      significant number of cases. Where the pleural space can be closed this results
      in significantly fewer hospital admissions and appears to improve quality of life
      and length of survival. The price is a longer hospital stay due to prolonged air
      leak.

PMID- 10647831
TI  - Videothoracoscopic lung biopsy in the diagnosis of interstitial lung disease.
AB  - OBJECTIVE: Interstitial lung diseases (ILD) require lung biopsy for the diagnosis
      in more than 30% of patients. Open lung biopsy (OLB) was generally considered the
      most reliable method of biopsy and tissue diagnosis. This study tests the
      diagnostic accuracy and safety of the videothoracoscopic lung biopsy (VTLB) in
      the diagnosis of ILD. METHODS: During the last 5 years, 58 patients were
      submitted to VTLB under general anesthesia. The mean age was 49.6 +/- 12.0 years
      (range 21-69). All the biopsies were performed by an endostapler EndoPath 30 or
      45. Conversion to minithoracotomy was necessary in only one patient because of
      extensive pleural sinfisis. All the specimens were sent to the microbiology and
      pathology department for microbiological and histopathological diagnosis. One
      chest-tube (28F) was positioned and connected to a drainage-system and placed on
      suction. RESULTS: The histopathological diagnosis was obtained for all patients
      and therefore the diagnostic accuracy of the procedure was 100%. No postoperative
      haemothorax occurred and only two patients experienced a prolonged air-leakage
      (3.4%). The median duration of the chest-drain was 3 days (range 1-7) and the
      median hospital stay was 4 days (range 2-7). CONCLUSION: VTLB provides adequate
      specimen volume for histopathologic diagnosis and achieves a very high diagnostic
      accuracy (100% in our series). The postoperative morbidity and mortality rates
      are lower than those related to OLB. We conclude that VTLB is an effective and
      safe procedure in the diagnosis of ILD.

PMID- 10647833
TI  - One-stage pedicled omentum majus transplantation into thoracic cavity for
      treatment of chronic persistent empyema with or without bronchopleural fistula.
AB  - OBJECTIVE: Assessment of the present results of surgical treatment for chronic
      persistent empyema with or without bronchopleural fistula (BPF) using one-stage
      pedicled omentum majus transplantation into the thoracic cavity. METHODS: From
      November 1979 to December 1996, 50 patients with chronic persistent empyema were
      treated by pedicled omentum majus transplanted into the thoracic cavity. There
      were 35 men and 15 women, and the age range was 15-58 years. Empyema had been
      present for 0.5-18 years. Twenty-six of 35 cases with chronic tuberculous empyema
      and six of 15 cases with chronic bacterial empyema suffered from concomitant BPF
      (n = 32). In the latter, the most common organisms were Staphylococcus aureus,
      Pseudomonas aeruginosa and Escherichia coli. RESULTS: There were no perioperative
      deaths. Two cases had a significant air leak on the first postoperative day. One
      of them underwent rethoractomy 30 h after the initial operation to stop the
      fistula using intrathoracic omentum. Thoracic dead space disappeared in most of
      the operated cases and a sterilized dry cavity remained in some cases.
      CONCLUSIONS: One-stage pedicled omentum majus transposition is a safe and easy
      procedure for chronic persistent empyema and BPF, it breaks down residual or
      recurrent inflammatory foci mechanically and closes the BPF effectively with
      minimal deformity of the chest wall.

PMID- 10647832
TI  - Pulmonary hydatidosis: surgical treatment and follow-up of 240 cases.
AB  - OBJECTIVE: We review a series of 240 patients treated surgically for pulmonary
      hydatid cyst in our center between 1966 and 1988, assessing the results with our
      surgical technique, which involves a novel needle aspiration device designed by
      Professor D. Figuera, and postoperative treatment protocol. PATIENTS AND METHODS:
      The majority (60.4%) of the patients were from areas endemic for hydatid disease.
      The mean age of the patients at the time of the surgical procedure was 31.5 +/-
      7.2 years (range: 4-70 years). A trocar-suction device was used for the needle
      aspiration of 276 (92%) of the 300 cysts encountered in the 240 patients. The
      remaining 24 cysts were removed integrally by means of different surgical
      techniques such as cyst enucleation, lobectomy, segmentectomy and atypical
      pulmonary resection. The residual cavity was treated by pericystectomy and
      eversion to the pleural surface in 238 cases (86.2%) and by capitonnage in 38
      (13.7%). High vacuum suction (-30 cm H2O) was employed in every case. Depending
      on when the procedure was performed, the patients were treated with mebendazole
      or albendazole according to the protocol designed by Bekhti. RESULTS: Clinical
      assessment of the symptoms and plain chest X-ray led to the correct diagnosis in
      228 cases (95%). In six (2.5%), imaging studies such as ultrasonography, computed
      tomography and nuclear magnetic resonance were required, and in the remaining six
      cases (2.5%), the diagnosis was established intraoperatively or in the subsequent
      histopathological study. One hundred and seventy patients (70.8%) presented a
      solitary lung cyst, while the remaining 70 (29.2%) were found to have multiple
      cysts in one or more lobes of one or both lungs. In addition, 45 patients (18.7%)
      presented hepatic cysts and 25 (10.4%) had cysts in other locations. After 18
      years of follow-up, the survival rate was 94.6%. Of the surviving patients, 98.3%
      were free of pulmonary hydatid disease and 95.1% were free of hydatid disease.
      CONCLUSIONS: The trocar-suction device employed here for needle aspiration of
      hydatid cysts has demonstrated its efficacy in preventing the rupture of the cyst
      and its possible dissemination. With its use, the parasite is eradicated and the
      residual cavity can be excised.

PMID- 10647834
TI  - Ischemic preconditioning enhances donor lung preservation in the rabbit.
AB  - OBJECTIVE: Ischemic preconditioning achieved by brief periods of ischemia
      followed by reperfusion before a prolonged period of ischemia, is well known to
      reduce myocardial damage. We investigated whether ischemic preconditioning of the
      lung could also attenuate ischemia-reperfusion injury following pulmonary
      preservation. METHODS: Transient ischemia of the right lung was achieved in
      rabbits (n = 4 in each group) by occluding the main bronchus and pulmonary
      artery, followed by reperfusion according to a protocol that differed between
      study groups: group 1 (control), 45 min ventilation; group 2, 30 min ventilation,
      5 min ischemia and 10 min reperfusion; group 3, three periods of 5 min ischemia
      and 10 min reperfusion; group 4, five periods of 3 min ischemia and 6 min
      reperfusion. Donor lungs were then flushed with a crystalloid solution followed
      by inflated storage at 37 degrees C for 2 h. The function of the right lung was
      assessed during reperfusion for 2 h with homologous, diluted and deoxygenated
      blood in an isolated, pressure-limited, and room-air ventilated model. RESULTS:
      Significant differences (P < 0.0001) were observed between groups 1 and 2 vs.
      groups 3 and 4 in veno-arterial oxygen pressure gradient (29 +/- 6 and 24 +/- 6
      mmHg vs. 124 +/- 24 and 132 +/- 14 mmHg, respectively), and in weight gain (88 +/
      13 and 98 +/- 13% vs. 44 +/- 9 and 29 +/- 3%, respectively) after 1 h of
      reperfusion, and in wet-to-dry weight ratio (15.5 +/- 1.5 and 14.3 +/- 0.4 vs.
      10.1 +/- 1.6 and 9.0 +/- 0.8, respectively) at the end of reperfusion. No
      significant differences in any of these parameters were observed between group 1
      vs. group 2 neither between group 3 vs. group 4. CONCLUSIONS: These data suggest:
      (1) That 15 min, but not 5 min of transient ischemia prior to pulmonary
      preservation can significantly reduce edema in the lung graft upon reperfusion,
      thus improving oxygenation capacity and (2) although not significant, this
      beneficial effect seems to be slightly better with more repetitive periods of
      transient ischemia. Further research is warranted to investigate whether ischemic
      preconditioning in the human organ donor may become a new strategy to protect
      lung tissue during a planned ischemic event as in pulmonary transplantation.

PMID- 10647835
TI  - Minimally-invasive versus conventional aortic valve replacement--perioperative
      course and mid-term results.
AB  - OBJECTIVE: We performed a case-control-study to compare perioperative and mid
      term results of minimally invasive with conventional aortic valve replacement.
      METHODS: Between 8/96 and 7/97, 113 patients underwent isolated aortic valve
      replacement (minimally invasive: 29, conventional: 84) in our Department.
      Diagnosis, ejection fraction, pressure gradient/regurgitation fraction, age,
      gender and body-mass-index were used as matching criteria for the case-control
      study. For qualitative data correspondence was requested, for quantitative data
      deviations up to 10% were accepted. With these criteria 25 patients of the
      minimally invasive group were matched to 25 patients of conventional group. All
      patients were reexplored 1 year after aortic valve replacement. Statistical
      analysis was done by the Fisher's exact test for qualitative data and the Mann
      Whitney test for quantitative data. RESULTS: We implanted 15 (20) bioprosthesis'
      and 10 (five) mechanical prosthesis' in the minimally invasive, respectively,
      conventional group. There were no statistically significant differences between
      both groups with respect to the perioperative course, only duration of surgery
      (mean 201.6 vs. 143.9 min, P < 0.01) and extracorporeal circulation (mean 116.1
      vs. 71.3 min, P < 0.01) as well as aortic-cross-clamp-time (mean 77.9 vs. 46.9
      min, P < 0.01) were significantly longer in the minimally invasive group.
      Postoperative complications occurred in one patient of the minimally invasive
      group (dissection of the right coronary artery) and four patients of the
      conventional group (third degree AV block, pneumothorax, grand mal convulsion,
      cardiopulmonary resuscitation). Two patients, one of each group, died during
      follow-up for unknown reasons. Follow-up revealed no significant differences with
      respect to clinical and echocardiographic data, but the shorter skin incision was
      cosmetically more accepted by patients of the minimally invasive group. Minor
      paravalvular leaks occurred in four patients of the minimally invasive and three
      patients of the conventional group as diagnosed by transthoracic
      echocardiography. CONCLUSIONS: Both surgical techniques may be performed with
      comparable perioperative and mid-term results, but the better cosmetic result in
      the minimally invasive group is paid by a longer duration of surgery.

PMID- 10647836
TI  - Surgery for infective valve endocarditis in children.
AB  - OBJECTIVE: Surgery for endocarditis in children is relatively uncommon. Our aim
      is to assess operative mortality, recurrent infection, re-operation and long-term
      survival rates following surgery for infective valve endocarditis in children.
      PATIENTS: Sixteen consecutive children (ten female, six male, mean age 11.8
      years, range 25 days-16 years) undergoing surgery between 1972 and 1999 in
      Southampton were studied. The aortic valve was affected in five, mitral in four,
      aortic and mitral in one, tricuspid in five and a pulmonary homograft in one
      patient. Prosthetic valve endocarditis was present in three. Twelve surgical
      interventions were emergency and four urgent. Indications for operation included
      cardiac failure in five, severe valvular dysfunction in nine, vegetations in
      nine, persistent sepsis in four and embolization in four patients. The offending
      micro-organism was identified in 13. Valve replacement was performed in 11 and
      excision of vegetations in two and excision of vegetations and repair in three.
      Follow-up was complete (mean 11.2 years, range 2 months to 26.3 years, total
      179.5 patient years). RESULTS: There was one operative death (6.2%) in a 25-day
      old neonate who presented in a moribund condition. Endocarditis recurred in one
      patient (6.25%). Freedom from recurrent infection at 10 and 20 years was 100.0
      and 87.5%. Seven surgical re-interventions were required in four (25.0%) patients
      with no operative mortality. Freedom from re-operation at 1, 5, 10 and 20 years,
      was 84.6, 76.1, 76.1 and 60.9%, respectively. Two patients died 15 and 23 years
      after their first operation. The cause of the late deaths was non-cardiac in the
      first and unknown in the other. Actuarial survival, including operative
      mortality, at 1, 15 and 20 years was 93.7, 93.7 and 78.1%. CONCLUSIONS: Surgery
      in children with infective valve endocarditis can be performed with low operative
      mortality. Although some patients may require re-operation, freedom from
      recurrent infection and long-term survival are satisfactory.

PMID- 10647837
TI  - The fate of antibiotic sterilized aortic allografts in Fontan circulation:
      results of the long-term follow-up.
AB  - OBJECTIVE: Between 1977 and 1988, 27 patients, mean age 8.9 (range 4-22) received
      an antibiotic sterilised aortic allograft in the setting of the Fontan procedure.
      This study describes the long-term follow-up of these patients. METHODS: Fifteen
      patients had tricuspid atresia, nine double inlet ventricles and three others.
      The connection with the allograft was made to the pulmonary artery on the right
      side of the aorta in ten and to a left-sided main pulmonary artery in eight. In
      nine patients the allograft was anastomosed between the right atrium and the
      right ventricle. RESULTS: There were five early and five late deaths. One late
      death may have been allograft related. Survival was 81, 74 and 68% at 5, 10 and
      15 years, respectively. Conduit calcification was universal. Twelve patients
      underwent reoperation, freedom from reoperation was 100, 88 and 54% at 5, 10 and
      15 years following the initial Fontan procedure. At reoperation the gradient
      across the allograft was never more than 3 mmHg. The allograft was explanted with
      conversion to atriopulmonary or cavopulmonary connection in nine and a second
      allograft was inserted between the right atrium and right ventricle in two. No
      mortality occurred at reoperation. 41.1% of survivors still have their original
      allograft. CONCLUSIONS: Although there is a significant attrition rate allograft
      inclusion in the Fontan circulation does not change survival, but results in an
      increased reoperation rate. Inclusion of a valved conduit between the right
      atrium and ventricle does not usually enhance the growth potential of the
      rudimentary ventricle. All patients are in a good functional class which may
      represent the strict original selection criteria. The inclusion of a valve in the
      Fontan circulation is not recommended.

PMID- 10647838
TI  - Images in cardio-thoracic surgery. Fatal ischemic multiorgan damage with
      intraaortic balloon pumping in a patient with small aorta syndrome.

PMID- 10647839
TI  - Images in cardio-thoracic surgery. Spontaneous esophageal dissection.

PMID- 10647840
TI  - Congenital bronchoesophageal fistula in the adult.
AB  - Congenital bronchoesophageal fistulas, when not associated with esophageal
      atresia, are compatible with life and may persist until adulthood before
      diagnosis has been established. We report such a rare case of a 55-year-old
      Caucasian female with a history of repeated pulmonary infections, suffering from
      cough during the last 12 months due to a mass in the right lung. A
      bronchoesophageal fistula (type III according to Braimbridge and Keith
      classification) was incidentally discovered during thoracotomy which was resected
      and end-sutured. Following that, a right lower lobectomy was performed. The
      patient had an uneventful recovery. The final diagnosis of congenital
      bronchoesophageal fistula was established excluding all the reasons that lead to
      the acquired disease. The diagnostic and therapeutic procedures are analyzed and
      the relevant literature is reviewed.

PMID- 10647841
TI  - Inflammatory pseudotumor: a controversial entity.
AB  - Inflammatory pseudotumor of the lung is considered to be a rare, benign,
      neoplastic lesion, consisting mainly of spindle mesenchymal cells, sometimes in
      such a way that its histological appearance mimics that of a spindle cell
      sarcoma, fibrous histiocytoma or fibrosarcoma. On the occasion of a case managed
      in our department, the literature is reviewed, in an attempt to clarify some
      issues concerning this tumor. Emphasis is given to complete resection of the
      tumor for both diagnostic and therapeutic purposes. Malignant behavior may occur
      and recurrence is possible.

PMID- 10647842
TI  - Spontaneous hemorrhage of thymus and thymoma in adults.
AB  - Spontaneous hemorrhage from the thymus is extremely rare. In adults, it may occur
      in patients without underlying coagulopathy and mimic aortic dissection. To the
      best of our knowledge, only three previous adult cases have been reported in the
      English literature. This report presents two additional adult patients who were
      admitted in our institution with different clinical presentations of spontaneous
      thymic hemorrhage.

PMID- 10647843
TI  - Video-assisted cardioscopy for removal of primary left ventricular myxoma.
AB  - Left ventricular myxoma is a rare benign cardiac tumor. Surgical excision is the
      treatment of choice and completeness of removal is mandatory to avoid late
      recurrence. A case is presented in which aortic transvalvular video-assisted
      cardioscopy was used to facilitate removal.

PMID- 10647844
TI  - Atrioventricular septal defect following blunt chest trauma.
AB  - The authors describe an acquired atrioventricular septal defect that has resulted
      from a blunt chest trauma. Besides being an uncommon traumatic heart injury, this
      case has the particularities of the non-involvement of other adjacent anatomical
      structures and the long delay between the accident and the occurrence of the
      myocardial rupture.

PMID- 10647845
TI  - Modified approach to close multiple apical ventricular septal defects.
AB  - The fish-mouth incision of the left ventricular apex is the established incision
      to access and close apical ventricular septum defect. A long diagonal branch may
      render this incision dangerous. In such a case, we performed a more anterior
      incision on the left ventricle, and fashioned a patch to exclude the whole
      defective area.

PMID- 10647846
TI  - Esophageal perforation after transesophageal echocardiography.

PMID- 10647847
TI  - Aromatic residues mediate the pressure-induced association of digoxigenin and
      antibody 26-10.
AB  - We have previously found that the complex between fluorescently labeled
      digoxigenin and the monoclonal antibody 26-10 forms with a decrease in volume of
      approximately 30 ml/mol, leading to increased association of these species under
      applied hydrostatic pressure. In the present study, we have utilized a panel of
      mutant antibodies and Fab fragments, previously characterized for their
      importance in the binding affinity of digoxin:26-10, to probe the molecular basis
      of pressure sensitivity in this complex, as measured by fluorescence polarization
      spectroscopy. Several mutations that result in marked decreases in affinity
      exerted little or no significant effect on the association volume. Mutation at
      any of several key aromatic residues of the 26-10 Fab heavy chain led to a
      decrease in the pressure-induced association, and two mutants with Trp-->Arg
      mutations at heavy chain residue 100 exhibited pressure-induced dissociation. The
      effect of charged groups was found to depend on their proximity to contacting
      aromatic groups. The ability to understand and control the pressure sensitivity
      of antigen-antibody complexes has numerous potential applications in
      immunoseparations and immunosensors.

PMID- 10647848
TI  - Why is the human visual system sensitive only to light of wavelengths from
      approximately 760 to 380 nm? An answer from thermochemistry and chemical
      kinetics.
AB  - The range of visible light has been explained by the knowledge available of gas
      phase thermochemistry and chemical kinetics. The C, C-pi bond dissociation energy
      at the 11 and 12 positions of the rhodopsin complex is estimated to be
      approximately 37.4+/-1.5 kcal/mol. This energy is just equivalent to wavelength
      of the red limit of the visible light. The photons of the violet limit (approx.
      75.2 kcal/mol) can break the weakest C-C and H-C bonds in important species
      involved in the photo-induced cis-trans isomerization cycle and can stop the
      visual cycle.

PMID- 10647849
TI  - Discrete reduction of type I collagen thermal stability upon oxidation.
AB  - The oxidation of acid-soluble calf skin collagen type I caused by metal-dependent
      free radical generating systems, Fe(II)/H2O2 and Cu(II)/H2O2, was found to bring
      down in a specific, discrete way the collagen thermal stability, as determined by
      microcalorimetry and scanning densitometry. Initial oxidation results in
      splitting of the collagen denaturational transition into two components. Along
      with the endotherm at 41 degrees C typical for non-oxidized collagen, a second,
      similarly cooperative endotherm appears at 35 degrees C and increases in enthalpy
      with the oxidant concentration and exposure time, while the first peak
      correspondingly decreases. The two transitions at 35 and 41 degrees C were
      registered by densitometry as stepwise increases of the collagen-specific volume.
      Further oxidation results in massive collagen destruction manifested as
      abolishment of both denaturational transitions. The two oxidative systems used
      produce identical effects on the collagen stability but at higher concentrations
      of Cu(II) in comparison to Fe(II). The discrete reduction of the protein thermal
      stability is accompanied by a decrease of the free amino groups, suggestive of an
      oxidation attack of the side chains of lysine residues. Since the denaturation
      temperature of collagen shifts from above to below body temperature (41 degrees C
      35 degrees C) upon oxidation, it appears important to account for this effect in
      a context of the possible physiological implications of collagen oxidation.

PMID- 10647850
TI  - Small angle X-ray scattering studies on local structure of tobacco mosaic virus
      RNA in solution.
AB  - Effects of temperature and ionic strength (S) on the local structure of tobacco
      mosaic virus RNA in phosphate buffer solution are studied by analyzing the small
      angle X-ray scattering (SAXS) curves. The root-mean-square radius of a cross
      section of RNA chain was kept at 0.845+/-0.005 nm over a wide range of S from 0.2
      to 0.003 at 20 degrees C, whereas it gradually diminished from 0.85 to 0.61 nm
      when the temperature is raised from 20 to 50 degrees C at S = 0.2. Nevertheless,
      all of SAXS curves reflecting the backbone structures were equally mimicked by
      theoretical ones of freely hinged rod (FHR) models, i.e. several straight rods
      joined with freely hinged joints in the form of a combination of the letter Y, if
      the constituent rod lengths in the models are adjusted. From these facts, it is
      suggested that the local structure of the RNA chain in aqueous solution is
      characterized by an essential feature that unpaired bases in the partially double
      stranded helix are constantly far isolated from each other along the helix and
      the rod-like structure of the helix is preserved over a range of helical
      contents. Such a characteristic local structure of the chain is entirely
      collapsed in the formamide solution at 50 degrees C.

PMID- 10647851
TI  - A proposal for the structuring of water.
AB  - In spite of much work, many of the properties of water remain puzzling. A
      fluctuating network of water molecules, with localised icosahedral symmetry, is
      proposed to exist derived from clusters containing, if complete, 280 fully
      hydrogen-bonded molecules. These are formed by the regular arrangement of
      identical units of 14 water molecules that can tessellate locally, by changing
      centres, in three-dimensions and interconvert between lower and higher density
      forms. The structure allows explanation of many of the anomalous properties of
      water including its temperature-density and pressure-viscosity behaviour, the
      radial distribution pattern, the presence of both pentamers and hexamers, the
      change in properties and 'two-state' model on supercooling and the solvation
      properties of ions, hydrophobic molecules, carbohydrates and macromolecules. The
      model described here offers a structure on to which large molecules can be mapped
      in order to offer insights into their interactions.

PMID- 10647852
TI  - The main role of the sequence-dependent DNA elasticity in determining the free
      energy of nucleosome formation on telomeric DNAs.
AB  - Using a competitive reconstitution assay, we measured the free energy spent in
      nucleosome formation of eight telomeric DNAs, differing in sequence and/or in
      length. The obtained values are in satisfactorily good agreement with those
      derived from a theoretical model that allows the calculation of the free energy
      of nucleosome formation on the basis of sequence-dependent DNA elasticity, using
      a statistical thermodynamic approach. Both theoretical and experimental
      evaluations show that telomeres are characterized by the highest free energies of
      nucleosome formation among all the DNA sequences so far studied. The free energy
      of nucleosome formation varies according to the different telomeric sequences and
      the length of the fragments. Theoretical analysis and experimental mapping by
      lambda exonuclease show that telomeric nucleosomes occupy multiple positions
      spaced every telomeric repeat. Sequence-dependent DNA elasticity appears as the
      main determinant of the stability of telomeric nucleosomes and their multiple
      translational positioning.

PMID- 10647853
TI  - Physiology and pathology of tracheobronchial glands.
AB  - The tracheobronchial glands, composed of mucous and serous secretory cells,
      provide a mucin-rich, antimicrobial-rich secretion for the conducting airways.
      The secretory processes of these cells are under complex neurohumoral control.
      Several diseases demonstrate considerable increases in the volume of secretory
      glands, the amount of glandular secretions or the character of the secretory
      product. The role of the tracheobronchial glands in the pathophysiology of
      chronic bronchitis, asthma and cystic fibrosis is discussed.

PMID- 10647854
TI  - Understanding the limitation of O2 supply through comparative physiology.
AB  - Comparative physiology and morphometry are used to explore the role of the lung
      in the limitation of oxygen supply to working muscle as it is experienced at
      aerobic capacity and in hypoxia such as at high altitude or in subterraneous
      burrows. In the human lung, as in that of most mammals, the pulmonary diffusing
      capacity is about 1.5 times larger than what is needed at aerobic capacity. In
      athletic species (horse, dog) there is no such excess diffusing capacity. As an
      exception the pronghorn antelope from the Rocky Mountains is a high performance
      athletic mammal whose lung shows an excess diffusing capacity. This is
      interpreted as a means to develop hypoxia tolerance as this animal performs its
      vigorous runs at high altitude. Information on the fossorial mole rat
      demonstrates that the lung's diffusing capacity is important in developing
      hypoxia tolerance. It is concluded that the lung is designed in relation to both
      internal and external constraints.

PMID- 10647855
TI  - Modeling oxygen availability to exercising muscle.
AB  - To quantify the role of factors determining O2 availability to exercising muscle,
      a model previously devised for the analysis of O2 uptake in lungs is used. With
      the variables: (1) blood flow (Q); (2) slope of the blood O2 equilibrium curve
      (betaO2); and (3) muscle blood-tissue O2 diffusing capacity (D(O2)), the extent
      of diffusion and perfusion limitations are determined by the 'equilibration
      index', Y(O2) = D(O2)/(Q x betaO2). Application to recent literature values on
      maximal O2 uptake in humans reveals diffusion limitation to be less important
      than perfusion limitation in normoxia, but to be predominant in deep hypoxia. The
      validity of the model is restricted by several factors whose disregard leads to
      an underestimation of muscle D(O2), i.e. an overestimation of diffusion
      limitation.

PMID- 10647856
TI  - The energetics of anaerobic muscle metabolism: a reappraisal of older and recent
      concepts.
AB  - This paper discusses under an energetic perspective the recent and older evidence
      supporting the classical notion that the 'oxygen debt', as originally defined by
      Margaria et al. (1933) [Am. J. Physiol. 106, 689-714], consists of two major
      components: the alactic oxygen debt, with a half-time of the order of 30 sec, and
      the lactic oxygen debt, with a much longer half-time, similar to that of lactic
      acid removal from blood after exercise (approximately 15 min). In particular, two
      ensuing concepts are treated, namely (i) the energetic equivalent of blood
      lactate accumulation in blood, whence the notions of lactic power and lactic
      capacity, and (ii) the energy sources allowing contraction of the oxygen deficit
      at the onset of square-wave exercise. The notion of alactic oxygen deficit is
      rediscussed on the basis of recent evidence in humans. The analogies between
      lactate accumulation during supramaximal exercise and during exercise transients
      are discussed under an energetic perspective.

PMID- 10647857
TI  - Brainstem amino acid neurotransmitters and hypoxic ventilatory response.
AB  - The ventilatory response to acute hypoxia in mammalian species is biphasic, an
      initial hyperventilatory response is followed by a reduction in ventilation
      within 2-3 min below the peak level (roll-off). Brain amino acid
      neurotransmitters also change during hypoxia. This study explores the role of
      neurotransmitters in anesthetized adult Sprague Dawley rats mechanically
      ventilated during 20 min of 10% O2 breathing. Phrenic nerve activity was
      recorded, and microdialysate concentrations of selected amino acids were
      determined at 3- to 5-min intervals in respiratory chemosensitive areas of the
      ventrolateral medulla (VMS) 1.25-2.00 mm below the surface. Phrenic nerve output
      was biphasic during hypoxia, concurrent with a rapid glutamate and gradual GABA
      increase. Taurine first decreased, then increased. In both intact and
      chemodenervated animals, time-dependent change in phrenic nerve activity during
      hypoxia was associated with corresponding changes in glutamate, GABA, and taurine
      concentrations, suggesting that cumulative effects of changes in the
      concentration of these three amino acids could account for response of the
      phrenic nerve to hypoxia.

PMID- 10647858
TI  - Locus coeruleus neurones in vitro: pH-sensitive oscillations of membrane
      potential in an electrically coupled network.
AB  - The response to hypercapnic acidosis (2-8% CO2, bath pH 7.8-7.2) was examined in
      whole cell recordings from neonatal (P1 to P5) rat Locus coeruleus (LC) neurones
      in the in vitro brainstem-spinal cord preparation exposed to low Ca2+ (0.2 mM)
      high Mg2+ (5 mM). This medium suppressed chemical synaptic transmission and
      resulted in a pattern of subthreshold oscillations of membrane potential and
      rhythmic burst discharge which was synchronized throughout the network. The
      oscillation was suppressed, and the discharge of individual neurones
      desynchronized, by the gap junction uncoupler, carbenoxolone, indicating that in
      low Ca2+-high Mg2+ LC neurones form an electrically coupled network. Switching
      from 2 to 8% CO2 decreased the oscillation amplitude and increased its frequency.
      The oscillation was suppressed by external Cd2+ and by TTX. but persisted during
      injection into the cell soma of QX-314. We conclude that in LC neurones acidosis
      increases the frequency of a Ca2+- and Na+-dependent dendritic oscillator which
      is synchronized by gap junction coupling throughout the network. This coupling is
      retained during acidosis.

PMID- 10647859
TI  - Diaphragm inhibition with positive pressure ventilation: quantification of
      mechanical effects.
AB  - To quantify any mechanical inhibitory effect of nasal intermittent positive
      pressure ventilation (IPPV) on inspiratory activity of the diaphragm we
      ventilated five conscious relaxed subjects on two occasions at respiratory rates
      similar to quiet breathing (QB) and at three levels of applied pressure (Pappl)-
      6, 9 and 12 cmH2O, each during hypocapnia (P(CO2) allowed to decrease) and
      eucapnia (CO2 added to inspired gas). Diaphragm activity was assessed from
      transdiaphragmatic pressure (esophageal and gastric balloons) and diaphragm EMG
      (surface electrodes) both integrated with time (integral(Pdi x dt) and
      integral(EMGdi x dt), respectively). Neural inspiratory time (Tin) was measured
      as onset to peak of the integral(EMGdi x dt) signal. Relative to QB, integral(Pdi
      x dt) was 50-69% less during eucapnic IPPV 6-12 cmH2O (P < 0.005) and 67-85% less
      during hypocapnic IPPV (P < 0.005). Tin decreased (P < 0.05) with IPPV and, on
      ceasing IPPV, there was apnoea (prolonged expiratory time) on 23 of 27 occasions;
      these changes were independent of P(CO2). Integral(EMGdi x dt) decreased (P <
      0.05) at Pappl 12 cmH2O during eucapnia and at all Pappl during hypocapnia. The
      repeatability of integral(EMGdi x dt) was substantially less than integral(Pdi x
      dt) (F = 42, P << 0.01). We conclude that, during non-invasive IPPV in awake
      healthy subjects mechanical factors are of major importance in inhibiting
      inspiratory activity of the diaphragm.

PMID- 10647860
TI  - Breathing pattern in patients with Parkinson's disease.
AB  - The improvement in motor performance resulting from levodopa administration in
      patients with Parkinson's disease (PD) provides the opportunity to investigate
      ventilatory changes brought about by the disease. The aim of this study has been
      to investigate these changes in order to specify the mechanisms of the impairment
      in breathing in PD. Breathing patterns at rest were investigated in 11 patients
      with idiopathic PD both before (OFF) and after (ON) administration of levodopa at
      a dose improving their motor performance by at least 30%. Airflow (Fleisch head
      mounted on a mask), rib cage and abdomen movements (inductance plethysmography)
      were recorded in the OFF condition 1 h after subjects woke up. Subjects then
      received levodopa and a new set of recordings was obtained 1 h later, in the ON
      condition. Breath-by-breath processing of recordings was carried out, and tidal
      volume (VT), inspiratory (TI) and expiratory (TE) durations were measured. The
      main finding was a lengthening of TI resulting in a decrease in ventilation and
      in VT/TI, and an increase in TI/TTOT in the ON compared to the OFF condition. In
      the ON condition abnormal rib cage-abdomen plots patterns were found in four out
      of six subjects. A hypothesis on the effect of PD on breathing is proposed on
      grounds of normal diaphragmatic activity but impaired activity of the other
      respiratory muscles and more specifically the intercostal muscles.

PMID- 10647861
TI  - Age-related changes in the ventilatory response to inspired CO2 in neonatal rats.
AB  - The objective of this study was to determine whether there is an age-related
      ventilatory response to transient increases in inspired CO2 in unanesthetized rat
      pups. Using plethysmography, ventilatory responses to 30 sec of 0, 2, 4, 6, and
      8% inspired CO2 were measured in 21 rat pups from two litters. Recordings were
      made 1, 2, 3, 5, 7, 9 and 12 days after the day of birth (day 0). On day 1 there
      was a significant dose-related decrease in mean ventilatory frequency in response
      to each of the inspired CO2 concentrations. On day 2 there was no significant
      change in breathing frequency in response to 2 or 4% CO2 and a significant
      increase in frequency in response to 6 and 8% CO2. On days 3, 5, 7, 9 and 12
      there was generally a significant increase in frequency in response to each of
      the inspired CO2 concentrations. Tidal volume was not significantly affected by
      the CO2 stimuli on any of the test days. Minute ventilation exhibited a
      significant decrease, on day 1, in response to 6 and 8% CO2. Litter, sex or
      weight of the rat pups was not correlated with the ventilatory depressions
      observed on day 1. These results show that in neonatal rats the ventilatory
      response to inspired CO2 is age-related and indicates a possible link between
      upper airway CO2 chemoreceptors, an inhibition of breathing, and SIDS.

PMID- 10647862
TI  - Lung deflation stimulates fictive ventilation in decerebrated and
      unidirectionally ventilated toads.
AB  - We describe how the degree of lung inflation and hypercapnia influenced fictive
      ventilation in five toads (Bufo marinus) that were decerebrated and paralysed
      with roccuronium. Both lungs were unidirectionally ventilated and the degree of
      lung inflation was determined by controlling the outflow resistance of these
      catheters, while ventilatory motor output was assessed on the basis of nervous
      activity in the mandibular branch of the Vth cranial nerve. The pattern of the
      recorded activity ('fictive ventilation') resembled the ventilatory patterns
      previously described for conscious toads. Increasing the fraction of CO2 in the
      gas mixture used for unidirectional ventilation from 0.00 to 0.05 stimulated
      fictive breathing. Fictive ventilation was also greatly stimulated, at all CO2
      levels, by reduced lung volume, while complete inflation of the lungs abated
      fictive ventilation at all levels of CO2. Stimulation of CO2 sensitive
      chemoreceptors and pulmonary stretch receptors appear to have interactive effects
      on the central generation of ventilatory output in toads.

PMID- 10647863
TI  - In vivo blood oxygen binding in hypoxic lesser spear-nosed bats: relationship to
      control of breathing.
AB  - The hypoxic ventilatory threshold of many mammals correlates with their
      hemoglobin-oxygen affinity (P50). Yet, in some small mammals ventilation actually
      declines, rather than increases, with exposure to decreasing PaO2; their air
      convection requirement (V(E)/V(O2)), however, is elevated in hypoxia. We propose
      that the threshold of the hypoxic V(E)/V(O2) of small mammals coincides with the
      inflection ('knee') of their in vivo O2 equilibrium curve (O2EC). In vivo blood
      gas and pH data were obtained from normoxic and hypoxic lesser-spear nosed bats,
      Phyllostomus discolor; in vitro blood O2EC were also generated for normoxic bats
      at 32 and 37 degrees C and at three P(CO2)'s. The hypoxic V(E)/V(O2) threshold of
      P. discolor occurs at PaO2 = 39 Torr; the corresponding in vivo O2 saturation is
      0.70, approximating the inflection of the O2EC. This animal has a high blood O2
      affinity (P50 = 27.5 Torr at pH 7.40 and 37 degrees C; P50 = 30.8 Torr at in vivo
      pH of 7.31 and TB of 37.4 degrees C). As PaO2 is reduced, a pronounced hypoxia
      induced respiratory alkalosis and hypothermia help maintain SaO2 near the O2EC
      inflection (0.64-0.70 S(O2)).

PMID- 10647864
TI  - Chronic resistive loading induces diaphragm injury and ventilatory failure in the
      hamster.
AB  - The purpose of this study was to examine the effects of tracheal banding for 30
      days on arterial blood gases, and diaphragm structure and function. Hamsters were
      tracheal banded (TB) or underwent a sham procedure (C) (n = 16 and 18,
      respectively). After 30 days, arterial blood gases from awake TB hamsters showed
      hypoxemia and a respiratory acidosis. Histochemical analysis of diaphragm cross
      sections showed a five-fold greater area fraction of abnormal muscle; a greater
      variation in fiber size; and a 3% higher proportion of type 1 fibers in TB than C
      hamsters. In vitro physiologic studies of costal strips from TB hamsters showed
      lower stress (45-70% over 10-100 Hz) than C values. Maximal esophageal pressure
      during occlusion was 45% higher and normalized diaphragm mass was 10% higher in
      TB hamsters than C hamsters. We conclude that the lower stress in vitro was
      attributable, at least in part, to diaphragm injury. Hypercapnea was present in
      spite of the higher diaphragm mass and maximal esophageal pressures in banded
      hamsters.

PMID- 10647866
TI  - How does positive end-expiratory pressure decrease pulmonary CO2 elimination in
      anesthetized patients?
AB  - In anesthetized, mechanically ventilated patients, 10 cm H2O positive end
      expiratory pressure (PEEP10) immediately decreased the CO2 volume exhaled per
      breath (V(CO2,br)) by 96%, as exhaled tidal volume (VT) decreased to expand
      functional residual capacity during the first 8 breaths after PEEP10 began. Then,
      the sustained decrease in V(CO2,br) for over 10 min was due to the 19% decrease
      in cardiac output (QT, decreased CO2 delivery from tissues to lung) and to the
      decrease in alveolar ventilation (VA). In turn, decreased VA resulted from
      decreased VT (loss of inspired volume into the compressible volume of the
      ventilating circuit) and possibly from increased physiological dead space, due to
      the potential for new high alveolar ventilation-to-perfusion (VA/Q) lung regions.
      V(CO2,br) increased and recovered to baseline by 20 min of PEEP10 ventilation
      because QT increased to augment the CO2 delivery to the lung and alveolar P(CO2)
      increased (increased mixed venous P(CO2) and tissue CO2 retention) to increase
      V(CO2,br) while alveolar VT remained depressed. End-tidal P(CO2) (PET(CO2)
      progressively increased during PEEP10 and did not detect the decrease in
      V(CO2,br) during PEEP10 ventilation because PET(CO2) does not account for exhaled
      volume.

PMID- 10647865
TI  - Respiratory pattern after wet and dry chamber dives to 0.6 MPa ambient pressure
      in healthy males.
AB  - The purpose of this study was to evaluate respiratory effects of wet and dry
      hyperbaric chamber dives to 0.6 MPa ambient pressure in healthy males. There were
      19 and 22 subjects who participated in two series of dives with a bottom time of
      15 min and decompression times of 28 and 17 min, respectively. Airways
      conductance, residual volume, forced vital capacity, forced expiratory volume in
      1 sec, mid expiratory flow at 25, 50 and 75% of FVC, and diffusion capacity for
      CO were measured before the dives, after 3 h, and after 24 h. Multivariate
      analysis of covariance revealed no statistically significant effects of time or
      the interaction between time and dry or wet environment on the measured lung
      function parameters. These findings suggest first that even deep air dives may
      not necessarily affect pulmonary function, and second, that factors related to
      the particular wet environment do not seem to contribute to lung function changes
      after dives.

PMID- 10647867
TI  - Regulation of intracellular calcium by extracellular nucleotides in pig tracheal
      submucosal gland cells.
AB  - The mechanisms by which extracellular nucleotides (ATP and UTP) regulate
      intracellular Ca2+ in cultured pig tracheal gland cells were studied. The calcium
      response induced by ATP or UTP was composed of a peak response and a steady
      plateau. In the absence of extracellular Ca2+, the peak response of the cells to
      both ATP and UTP was smaller, and no subsequent plateau was observed. After
      treatment of the cells with pertussis toxin, the peak response to UTP was
      significantly smaller and no plateau was seen even in the presence of
      extracellular Ca2+, but pertussis toxin did not change the effect of ATP.
      Pretreatment with U107, a phospholipase C inhibitor, almost abolished the calcium
      response to both ATP and UTP. Immunocytochemistry showed that in these cells, the
      IP3 receptor was localized in the cytoplasm (including the endoplasmic reticulum)
      of the cells. Our results indicate that both release of calcium from the
      intracellular store and Ca2+ influx across the cell membrane contribute to the
      mobilization of [Ca2+]i upon stimulation with nucleotides, that ATP and UTP
      regulate intracellular Ca2+ predominantly via the G protein-phospholipase C-IP3
      pathway, and that ATP and UTP may act via distinct subtypes of P2Y receptors.

PMID- 10647868
TI  - Impact of periodic breathing on V(O2) and V(CO2): a quantitative approach by
      Fourier analysis.
AB  - Oscillations in oxygen uptake (V(O2)) and carbon dioxide production (V(CO2)) in
      patients with chronic heart failure differ in amplitude and phase from the
      oscillations in ventilation (periodic breathing, PB), leading some to doubt
      whether they result from PB. We applied Fourier transforms to a pulmonary gas
      exchange model to quantify the effects of fluctuations in alveolar ventilation
      (V(A)). We found that PB causes oscillations in V(O2) and V(CO2), but their
      amplitude and phase are complex, and vary with workload. At low workloads, the
      relative oscillations in V(O2) and V(CO2) closely mirror the relative
      oscillations in V(A). But at high workloads, the metabolic oscillations are
      attenuated (V(O2) most severely), and the V(O2) peaks precede the ventilatory
      peaks significantly. This study also explains why normal controls simulating PB
      at higher workloads fail to reproduce the V(O2) and V(CO2) oscillations seen in
      spontaneous PB of heart failure.

PMID- 10647869
TI  - Drugs toxic to the bone marrow that target the stromal cells.
AB  - Drugs that cause toxicity to the bone marrow are a heterogeneous group of
      compounds that act by various mechanisms. The etiology of this pathology is
      poorly understood but the highly proliferative nature of the hematopoietic cells
      is assumed to make the bone marrow more sensitive to toxicity. Recent evidence
      suggests that drugs can also affect specific aspects of stromal cells and the
      extracellular matrix that they establish. The data support the view that
      characteristics other than a high proliferation rate could confer susceptibility
      of the bone marrow to the toxic effects of drugs. This article discusses those
      drugs that have been shown to have direct effects on the bone marrow stromal
      cells.

PMID- 10647870
TI  - Fucogalactan isolated from Sarcodon aspratus elicits release of tumor necrosis
      factor-alpha and nitric oxide from murine macrophages.
AB  - Eight species of mushrooms were evaluated for mitogenic activity by the
      tetrazolium salt 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide
      (MTT) method using spleen cells of C3H/HeN female mice. The hot water-soluble
      (HWS) fraction extracted from Sarcodon aspratus showed the highest activity. The
      mitogen in Sa. aspratus was isolated by Sepharose 6B and DEAE-Sepharose CL-6B
      column chromatography. Preliminary structural analyses indicated that the mitogen
      was a fucogalactan. Fucogalactan elicited the release of tumor necrosis factor
      alpha (TNF-alpha) and nitric oxide (NO) in macrophages of mice in vitro. TNF
      alpha production induced with 50 microg/ml of fucogalactan was significantly
      higher than that induced by lentinan (500 microg/ml) by approximately 4.3-fold.
      Also, fucogalactan showed dose dependence at concentrations from 5 to 500
      microg/ml in NO production. Thus, fucogalactan does elicit the release of
      cytokines such as TNF-alpha and NO.

PMID- 10647871
TI  - Trichloroethylene accelerates an autoimmune response by Th1 T cell activation in
      MRL +/+ mice.
AB  - Trichloroethylene (1,1,2-trichloroethene) is a major environmental contaminant.
      There is increasing evidence relating exposure to trichloroethylene with
      autoimmunity. To investigate potential mechanisms, we treated the autoimmune
      prone MRL +/+ mice with trichloroethylene in the drinking water at 0, 2.5 or 5.0
      mg/ml and sacrificed them at 4, 8 and 22 weeks. As early as 4 weeks of treatment,
      Western blot analysis showed a dose-dependent increase in the level of
      trichloroethylene-modified proteins, indicating that a reactive metabolite of
      trichloroethylene was formed. Significant increases in antinuclear antibodies
      (ANA) and total serum immunoglobulins were found following 4-8 weeks of
      trichloroethylene treatment, indicating that trichloroethylene was accelerating
      an autoimmune response. Investigation into possible mechanisms of this autoimmune
      response revealed that trichloroethylene treatment dramatically increased the
      expression of the activation marker CD44 on splenic CD4+ T cells at 4 weeks. In
      addition, splenic T cells from mice treated for 4 weeks with trichloroethylene
      secreted more IFN-gamma and less IL-4 than control T cells, consistent of a T
      helper type 1 (Th1) type immune or inflammatory response. A specific immune
      response directed against dichloroacetylated proteins was found at 22 weeks of
      trichloroethylene treatment. Taken collectively, the results suggest that
      trichloroethylene treatment accelerated an autoimmune response characteristic of
      MRL +/+ mice in association with nonspecific activation of Th1 cells. In
      addition, long-term treatment with trichloroethylene led to the initiation of a
      trichloroethylene-specific immune response.

PMID- 10647872
TI  - Inflammatory hyperalgesia induced by zymosan in the plantar tissue of the rat:
      effect of kinin receptor antagonists.
AB  - The Randall-Selitto paradigm (maximal tolerated pressure externally applied by a
      mechanical device) was used to develop a rat model of localized inflammatory
      hyperalgesia in order to compare the analgesic effects of bradykinin (BK) B1 and
      B2 receptor antagonists and of a non-steroidal anti-inflammatory drug (NSAID).
      Intra-plantar injection of zymosan (12.5 mg per paw) induced a considerable
      inflammation as evidenced from gross and histological evaluation and a mechanical
      hyperalgesia at 6 h. The contra-lateral paw of zymosan-treated animals or saline
      vehicle-injected paws did not exhibit a decreased pressure tolerance, relative to
      pre-injection measurements. Since the B1 receptor may be induced under
      inflammatory situations, we examined the amount of corresponding mRNA using
      quantitative RT-PCR. We found a significant increase of B1 receptor mRNA in the
      zymosan--but not the saline-injected paw at 6 h. Drugs were given subcutaneously
      2 h before the 6 h readings to test their analgesic potential. The kinin B1
      receptor antagonists [Leu8]des-Arg9-BK (3-30 nmol/kg) and R-715 (100 nmol/kg),
      the B2 receptor antagonists Hoe 140 (15 nmol/kg) and LF 16.0687 (3 and 10 mg/kg),
      as well as the NSAID diclofenac sodium (1 and 3 mg/kg) significantly reversed
      zymosan-induced hyperalgesia. We conclude that zymosan-induced hyperalgesia is a
      model suitable for the rapid evaluation of analgesic drugs with a peripheral site
      of action interfering either with kinin receptors or with prostanoid formation.
      In this regard, results of the present study confirm that blocking kinin B1
      receptors is a novel approach for treatment of inflammatory pain.

PMID- 10647873
TI  - Orally administered decoction of Kampo (Japanese herbal) medicine, "Juzen-Taiho
      To" modulates cytokine secretion and induces NKT cells in mouse liver.
AB  - The effects of orally administered decoction of Juzen-Taiho-To (JTT; Si-Quan-Da
      Bu-Tang in Chinese) on cytokine production in hepatic lymphocytes were studied in
      mice. JTT was found to increase interferon gamma (IFN-gamma), as well as
      interleukin-4 (IL-4), IL-5 and IL-6 secretion from stimulated hepatic
      lymphocytes, whereas IL-2 secretion was reduced. The number of IFN-gamma- and IL
      4-spot forming cells (SFC) were not changed by administration of JTT. These
      results suggest that modulation of cytokine secretion by JTT might not be due to
      changes in the number of cytokine secreting cells within liver lymphocytes.
      CD4/CD8 ratio and alphabeta/gammadelta T cell receptor (TCR) ratio in hepatic
      lymphocytes were not changed. However, flow cytometric analysis revealed that the
      population of CD3 positive intermediate cells in NK positive cells (NKT cells)
      was increased after oral administration of JTT. The population of CD3int IL
      2Rbeta+ cells was also increased. The induction of NKT cells by JTT was reduced
      by injection of 2-chloroadenosine. JTT enhanced transcription of IL-12 mRNA in
      liver. From these results, it may be concluded that a rise in NKT cell population
      contributes, at least partially, to the modulating effect of JTT on cytokine
      production in liver lymphocytes, and macrophages. The production of IL-12 in
      liver may also contribute to this NKT induction.

PMID- 10647874
TI  - Plasma C3a and C4a levels in liver transplant recipients: a longitudinal study.
AB  - Liver transplant patients were enrolled in a study designed to investigate
      correlations between plasma complement C3a or C4a levels and various
      postoperative complications. Longitudinal EDTA-plasma levels of C3a and C4a were
      measured by quantitative radioimmunoassay. Acute rejection gave a characteristic
      and marked increase in blood C3a, C4a and gamma-glutamyl transferase (gammaGT)
      levels, which rapidly resolved after high dose steroid treatment. Cytomegalovirus
      (CMV) infections in two of three patients gave an initial small increase only in
      C3a levels (i.e., alternative pathway activation) followed approximately 6 weeks
      later by a marked increase in C4a levels (i.e., classical or lectin pathway
      activation). In a third patient diagnosed for CMV infection, the complement
      activation profile was complicated by a coincident minor rejection episode.
      However, a late stage elevation in C4a was also noted. Two patients experiencing
      biopsy proven recurrent hepatitis C infections following transplantation
      exhibited increases in both gammaGT and C4a levels, without a significant
      increase in the level of C3a. Several hepatitis C and one hepatitis B patient had
      multiple late activation episodes involving marked elevation in both plasma C3a
      and C4a levels without detectable increases in the liver enzymes conventionally
      used to monitor organ function. We also showed that ex vivo activation of
      complement in EDTA plasma from all transplant patients was abnormally high. The
      classical or lectin pathway is believed to be responsible for this excessive ex
      vivo complement activation in the plasma of these patients. Therefore,
      subclinical rejection episodes and/or viral infections may be effectively
      detected or monitored by measuring C3a and C4a levels in plasma samples from
      liver transplant patients. Routine measurement of plasma complement products may
      provide an early non-invasive mode for detecting infections and also serve to
      monitor chronic or acute changes in the patient's immune system.

PMID- 10647875
TI  - Thalidomide's ability to augment the synthesis of IL-2 in vitro in HIV-infected
      patients is associated with the percentage of CD4+ cells in their blood.
AB  - Thalidomide is used for treating erythema nodosum leprosum. It is also used to
      treat aphthous ulcers in HIV-infected patients. The mechanism of action of this
      drug is yet to be fully understood, but modulation of inflammatory cytokines like
      IL-2 and TNF-alpha may play a role. We investigated the effect of thalidomide on
      the production of IL-2 and TNF-alpha by staphylococcal enterotoxin A (SEA)
      stimulated peripheral blood mononuclear cells (PBMC) from HIV-infected patients.
      The PBMC from 20 patients was incubated in the presence of 4.0 microg/ml of
      thalidomide and 50 ng/ml of SEA. After 18 h, the culture supernatant was assayed
      for IL-2 and TNF-alpha. The PBMC incubated with thalidomide and SEA produced
      significantly more IL-2 than those incubated with SEA alone. The TNF-alpha
      secreted by the same cells incubated with thalidomide and SEA was not
      significantly different from that secreted by the cells incubated with SEA alone.
      The amount of IL-2 produced in the thalidomide and SEA treated cultures was
      directly correlated with the percentage of CD4+ cells in blood, and inversely
      correlated with the percentage of CD8+ cells in blood. No statistically
      significant correlations were found when comparing the amount of TNF-alpha
      produced in the thalidomide and SEA treated cultures with the percentage of CD4+
      or CD8+ cells in the blood. Thalidomide can act, in vitro, as an additional
      stimulant to augment the synthesis of IL-2 in HIV-infected patients. Increased
      production of IL-2 by activated T-cells may be a mechanism through which it
      exerts its immunomodulatory effects.

PMID- 10647876
TI  - The role of interferon-alpha in the treatment of idiopathic myelofibrosis.
AB  - Idiopathic myelofibrosis (IMF) is a chronic myeloproliferative disorder
      characterized by fibrosis of the bone marrow, varying degrees of extramedullary
      hematopoiesis, splenomegaly, anemia, and a leukoerythroblastic peripheral blood
      smear. Bone marrow fibrosis develops as a secondary phenomenon and is caused by
      increased intramedullary activity of mitogens such as platelet-derived growth
      factor (PDGF), transforming growth factor-beta (TGF-beta), basic fibroblast
      growth factor (bFGF), epidermal growth factor (EGF), and calmodulin. Because of
      the variable clinical course of IMF, attempts have been made to define prognostic
      parameters that can be helpful in detecting patients with a shortened life
      expectancy. The most important adverse prognostic parameters that have been
      reported are hemoglobin concentration, age, leukocyte count, number of
      thrombocytes, and cytogenetic abnormalities. However, no standardized prognostic
      score for IMF has yet been established. Therapeutic strategies in IMF remain
      predominantly supportive. The most common are blood transfusions, androgens, and
      cytoreductive agents such as hydroxyurea. Bone marrow transplantation is
      increasingly being taken into consideration, but it still has to be regarded as
      an experimental approach. Interferon-alpha (IFN-alpha) has shown promising
      results in early hyperproliferative stages of IMF but has no or only very little
      effect in more advanced stages of the disease. Whether IFN-alpha is able to
      postpone marrow fibrosis if administered in early disease stages remains to be
      determined in future clinical trials.

PMID- 10647877
TI  - Thrombosis-free survival and life expectancy in 187 consecutive patients with
      essential thrombocythemia.
AB  - A total of 187 consecutive patients with essential thrombocythemia (ET) were
      diagnosed and followed by our Hematology Department in the period October 1980
      November 1994. The overall follow-up was 773 patient-years. Thrombosis-free
      survival and overall survival were calculated for the whole cohort; the same
      parameters were then calculated after arbitrary division of the cohort into two
      groups, according to the median age at diagnosis (55 years). Fifty percent of the
      patients had at least one thrombotic episode within 9 years after diagnosis. The
      thrombosis-free survival curves calculated for patients younger or older than 55
      years at diagnosis were comparable. About 85% of the patients were alive 10 years
      after diagnosis. The survival curves for patients younger and older than 55 years
      at diagnosis were not significantly different in the observation period, and the
      observed mortality (seven patients) among patients younger than 55 years at
      diagnosis was significantly higher than expected (1.68 cases). The relative risk
      of death was four times greater (SMR = 4.17, 95% C.I. 1.6-8.6, p<0.01) than for
      healthy, age-matched people living in the same area. Age at diagnosis, smoking,
      sex, hypercholesterolemia, peak number of platelets, hypertension, and diabetes
      were not significant prognostic cardiovascular risk factors in our cohort. In
      conclusion, our data show that ET has to be considered a serious disease that
      significantly decreases both quality of life (expected life without thrombosis)
      and life expectancy for younger patients.

PMID- 10647878
TI  - Second malignancies after Hodgkin's disease: the Munich experience.
AB  - The occurrence of second malignancies (SM) is an important late event following
      the treatment of Hodgkin's disease (HD). We sought to determine the incidence,
      the risk factors, and the prognosis of SM in our population of patients with HD.
      A total of 1120 patients diagnosed with HD were registered at six participating
      institutions in Munich (calendar period 1974-1994). The mean follow-up for the
      development of SM was 9.1 years. A cumulative treatment score was calculated for
      both radio- and chemotherapy. The relative and absolute risks of SM were
      established. All SM were investigated for response to treatment and outcome. We
      observed 85 SM [eight leukemias, 22 non-Hodgkin's lymphomas (NHL), two plasma
      cell neoplasias, and 53 solid tumors]. Five patients developed third
      malignancies. The relative risk of developing a second neoplasm was compared with
      that within the normal population and was 3.1-fold. The risk varied according to
      the category of SM. Higher relative risks (20.5 and 25.9-fold), but lower
      absolute risks were observed for leukemias and non-Hodgkin's lymphomas. Solid
      tumors had lower relative risks (1.8-fold). Splenectomy increased the risk of SM
      (relative risk 4.4-fold versus 2.7-fold). The risk of SM did not correlate with
      the initial treatment (radio- or chemotherapy) and did not decrease with
      prolonged follow-up. The cumulative intensity of radiotherapy, chemotherapy, or
      the two modalities combined correlated with the risk of SM. Since some cases
      occurred early after diagnosis, not all second neoplasms can be considered
      treatment-associated. After 15 years, an actuarial risk of 11.7% was calculated
      for all SM, of 1.0% for leukemias, of 3.0% for NHL, and of 7.7% for solid tumors.
      The prognosis of SM varied between good (thyroid cancer, melanoma: median
      survival 5+ years), average (breast cancer, NHL), and poor (acute myeloid
      leukemias, lung cancers: median survival 9 months). With the exception of NHL,
      second cancers often occurred in topographic relation to the field of previous
      radiotherapy. Taken together, in our patient population, we observed all three
      categories of SM (solid tumors, leukemias, NHL). The risk for second leukemias is
      lower than in previous studies, whereas the risk of second NHL is somewhat
      higher. We confirm that splenectomy is a possible risk factor for SM. Even after
      correction for the age-specific cancer incidence, treatment intensity is
      associated with the development of second malignant tumors. Continued follow-up
      is mandatory after treatment for HD. Since the prognosis of most SM is
      unfavorable, early recognition and prevention are of the utmost importance.

PMID- 10647879
TI  - Cryohemolysis test as a diagnostic tool for hereditary spherocytosis.
AB  - The cryohemolysis test has been proposed as a new method of identifying
      hereditary spherocytosis. The purpose of the present study was to analyze the
      sensitivity and specificity of this method in comparison to the measurement of
      osmotic fragility. The examination included 61 patients suffering from hereditary
      spherocytosis and 58 patients with other hemolytic and nonhemolytic anemias.
      Hereditary spherocytosis patients showed significantly higher cryohemolysis
      values (median 29.7%, range 12.3-50.2%) than both normal subjects (median 3%,
      range 0.5-27%) and all other anemic patients excepting those with immune
      hemolytic anemia (median 4%, range 0.5-10.1%). Analysis of immune hemolytic
      anemia revealed broadly scattered values ranging from 1.4% to 53.5% (median
      8.6%). Taking 15% as the threshold value, the sensitivity and specificity of the
      cryohemolysis test for hereditary spherocytosis were 95% and 96%, respectively.
      It is concluded that the simple-to-perform cryohemolysis test is quite comparable
      to the estimation of red cell osmotic fragility and therefore very useful as a
      diagnostic measure of hereditary spherocytosis.

PMID- 10647880
TI  - Thrombotic thrombocytopenic purpura in a patient with sickle cell crisis.
AB  - The combination of sickle cell disease crisis and thrombotic thrombocytopenic
      purpura has been described only a few times. Here we present the case of a
      patient with a hemolytic crisis due to sickle cell disease complicated by
      thrombotic thrombocytopenic purpura. We also review the cases previously reported
      and compare and contrast them, highlighting diagnostic challenges.

PMID- 10647881
TI  - Inflammatory pseudotumor of the spleen: a case report and review of the
      literature.
AB  - Inflammatory pseudotumor of the spleen is a benign tumorous lesion of unknown
      etiology and pathogenesis that has been described in only a few cases in the
      literature. Recognition of this rare entity is important, as the clinical
      manifestations and imaging features could be indistinguishable from a
      lymphoproliferative disorder or another malignancy of the spleen. We report a new
      case and review the clinical presentation, laboratory findings, pathological and
      immunohistochemical studies, treatment, and prognosis of the previously reported
      cases of inflammatory pseudotumor of the spleen.

PMID- 10647882
TI  - A magnetic resonance abnormality correlating with permeability of the blood-brain
      barrier in a child with chemical meningitis during central nervous system
      prophylaxis for acute leukemia.
AB  - Chemical meningitis developed in a boy with acute lymphoblastic leukemia during
      central nervous system (CNS) prophylaxis. Cerebrospinal fluid examination showed
      pleocytosis and a high protein level. There were no malignant cytological
      findings. Calculated permeability of albumin across the blood-brain barrier (BBB)
      was more elevated than that of immunoglobulin or alfa2-macroglobulin. Magnetic
      resonance imaging (MRI) revealed diffuse pachymeningeal enhancement without any
      intracerebral lesion. Subsequent CNS prophylaxis was postponed. CSF findings and
      BBB permeability returned to normal, correlating well with the decrease of MRI
      abnormality.

PMID- 10647883
TI  - A case of juvenile myelomonocytic leukemia with ocular infiltration.
AB  - We present a case of juvenile myelomonocytic leukemia (JMML) with ocular
      infiltration. A 1-month-old boy presented with myeloid precursors in peripheral
      blood and a white blood cell count >10x10(9)/l. His peripheral blood monocyte
      count was >1x10(9)/l, bone marrow blasts were <20%, and no Ph chromosome was
      identified. The boy also presented with hepatosplenomegaly, pallor, fever, and
      skin rash. We diagnosed this case as JMML, although hemoglobin F was within the
      normal range and no spontaneous colony growth was observed from peripheral blood
      mononuclear cells. Neither Epstein-Barr (EB) virus nor cytomegalovirus was
      detected by PCR in bone marrow aspirate or peripheral blood. The patient had
      several lesions into which JMML cells might have infiltrated, including skin,
      liver, spleen, oral cavity, right lung, sigmoid colon, and both eyes. To our
      knowledge, this is the first reported case of JMML with ocular involvement. Since
      infiltration of JMML cells into both eyes causes blindness, further consideration
      of the timing of bone marrow transplantation (BMT) in JMML is necessary.

PMID- 10647884
TI  - The behavior of diabetic red cells in microcirculation examined by a new
      microcapillary method.

PMID- 10647885
TI  - A genome-wide search for genes predisposing to familial psoriasis by using a
      stratification approach.
AB  - We have performed a genome scan, using markers spaced by 10 cM, in the search for
      psoriasis-susceptibility loci. The family material of 134 affected sibling pairs
      was ascertained on the basis of a population genetic study in which 65% of the
      probands had two healthy parents. Genotyping results were analyzed for non-random
      excessive allele-sharing between sib pairs by using GENEHUNTER ver 1.1. A
      stratification approach was applied to increase the homogeneity of the material
      by means of an operational definition of joint complaints among affected
      individuals. Significant linkage to the human leukocyte antigen region on
      chromosome 6p in a cohort including 42 families without joint complaints
      (nonparametric linkage score of 2.83, P=0.002) strongly supported the validity of
      this operational definition as it replicated results from an earlier linkage
      report with similar stratification criteria. New candidate regions on chromosomes
      3 and 15 were identified. The highest non-parametric linkage values in this
      study, 2.96 (P=0.0017) and 2.89 (P=0.0020), were reached on chromosome 15 in a
      subgroup with joint complaints and on chromosome 3 in a subgroup without joint
      complaints. In addition, confirmation of previously reported loci was established
      on chromosomes 4q, 6p, and 17q. This study indicates that distinct disease loci
      might be involved in psoriasis etiology for various phenotypes.

PMID- 10647886
TI  - BamHI-SacI RFLP and Gm analysis of the immunoglobulin IGHG genes in the Northern
      Selkups (west Siberia): new haplotypes with deletion, duplication and
      triplication.
AB  - Gm immunoglobulin allotypes have been studied in 1157 individuals of seven
      Northern Selkup populations, which account for 80% of the entire population of
      this west Siberian tribe. This study confirms that the northern Selkup
      populations are a Caucasoid-Mongoloid hybrid. Restriction fragment length
      polymorphism (RFLP) analysis of the IGHG genes using double BamHI-SacI digests,
      performed on 475 DNA samples, allowed us to describe nine new BamHI-SacI
      haplotypes (BS47 to BS55), eight of them being characterized by IGHG gene
      deletion or duplication: G1 (BS49) or G4 (BS55) deletion, G4 duplication (BS51),
      GP-G2-G4 multigene deletion (BS50), duplication (BS48, BS53 and BS54) or
      triplication (BS52). A new rare Gm haplotype 15,16*;1,17;23 has been found
      associated with BS52. The BS51 haplotype characterized by a duplicated G4 gene
      (additional 7.85 kb G4 band identifying a new G4*C5 allele) was always found
      associated with the Gm 5*;3;23 haplotype. A high RFLP diversity has been observed
      for the Northern-Mongoloid haplotype Gm 15,16*;1,17;.. which was found (1) with
      the BS27 haplotype characterized by a 3-exon hinge G3 gene, (2) with two
      different GP-G2-G4 multigene duplications, BS53 and BS54 haplotypes, which differ
      by the size of the duplicated G4 genes, and (3) with the BS55 haplotype
      characterized by a G4 deletion. In the Northern Selkups, haplotypes with
      duplicated genes were observed at a higher frequency (24%) than haplotypes with
      deleted genes (6%).

PMID- 10647887
TI  - Association between monoamine oxidase A activity in human male skin fibroblasts
      and genotype of the MAOA promoter-associated variable number tandem repeat.
AB  - Among fifteen male skin fibroblast cultures from eleven donors ranging in age
      from less than 1 year to 90 years old, the specific activity of monoamine oxidase
      A (MAO-A) differed 515-fold. Each culture had one of the two most common alleles
      (three or four 30-bp repeats) at the variable number tandem repeat locus
      positioned 1.2 kb upstream from MAOA exon 1 (uVNTR). The mean MAO-A activity in
      cultures with three uVNTR repeats was significantly lower than that in cultures
      with four repeats (1.6 +/- 1.1 and 13 +/- 12 nmol/h per milligram, respectively;
      P=0.032). MAO-A expression was confined to a cell sub-population varying from
      0.5% to 90% of cells in different cultures. The mean specific activity in MAO-A+
      cells (whole culture specific activity divided by the proportion of
      immunopositive cells) was lower for cultures with three repeats than for those
      with four (7.2 +/- 3.1 and 23.9 +/- 9.5 nmol/h per milligram protein,
      respectively; P=0.0013), with no overlap in activity between genotypes. Finding
      lower MAO-A activity in cultures with three uVNTR repeats compared to those with
      four is consistent with published evidence that MAO-A promoter constructs bearing
      three repeats have lower transcriptional activity in transfected neuroblastoma
      and choriocarcinoma cells. The uVNTR genotype may be a common genetic determinant
      of significant individual differences in oxidizing capacity for critical MAO-A
      substrates, which include serotonin, norepinephrine, and tyramine.

PMID- 10647888
TI  - A novel gene containing LIM domains (LIMD1) is located within the common
      eliminated region 1 (C3CER1) in 3p21.3.
AB  - Chromosomal deletions on 3p have been described in a large number of human
      tumors, suggesting the presence of a tumor suppressor gene(s). Using an
      experimental system, called the elimination test, we previously identified a 1 Mb
      segment, the common eliminated region 1 (C3CER1). C3CER1 was also covered by a
      PAC contig. Using the sequence of two overlapping PACs from C3CER1, we localized
      the human KIAA0028 cDNA, encoding the precursor of mitochondrial leucyl-tRNA
      synthetase. We also characterized a novel human LIM domain-containing gene
      (LIMD1) and its mouse ortholog (Limd1). LIM domains consist of a cysteine-rich
      consensus sequence containing two distinct zinc-binding subdomains, which mediate
      protein-protein interactions. The predicted protein sequences of the human and
      mouse genes reveal three LIM domains located at the C-terminal end, which
      indicates that they belong to the group 3 of the gene family encoding LIM motifs.
      We characterized the genomic structure of the human LIMD1 gene and assigned the
      mouse Limd1 gene to the chromosome 9F subtelomeric region. Both genes are
      ubiquitously expressed at the mRNA level. The LIM motif has been previously
      identified in many developmentally important factors from various eukaryotes.
      These factors have been shown to play a role in intracellular signaling,
      transcriptional regulation and cellular differentiation during development. The
      human C3CER1-located LIMD1 gene should therefore be further studied for its
      possible role in tumor suppression.

PMID- 10647889
TI  - Two novel mutations of SURF1 in Leigh syndrome with cytochrome c oxidase
      deficiency.
AB  - Cytochrome c oxidase (COX) deficiency is the most common cause of Leigh syndrome
      (LS). COX consists of ten nuclear-encoded and three mtDNA-encoded structural
      subunits. Although the nucleotide sequences of all 13 genes are known, no
      mutation was found in nuclear-encoded subunit genes of COX-deficiency patients.
      Zhu et al. (1998) and Tiranti et al. (1998) found nine mutations in the surfeit 1
      (SURF1) gene in LS families with COX deficiency. The mouse surfeit gene cluster
      consists of six closely spaced housekeeping genes unrelated by sequence homology.
      Except for the Surf3 gene, the function is still not known. The juxtaposition of
      at least five of the surfeit genes is conserved between birds and mammals. We
      identified two novel mutations of SURF1 in a Japanese LS patient with COX
      deficiency using direct sequencing analysis. Firstly, a 2-bp deletion at
      nucleotide position 790 (790delAG) in exon 8 was found, which shifts the reading
      frame such that the mutant protein has a completely different amino acid sequence
      from codon 264 to the premature stop codon at 290. Secondly, we found a T-to-G
      transversion at nucleotide 820, resulting in the substitution of tyrosine by
      aspartic acid at codon 274 (Y274D). We also studied the parents' genes, and found
      that the Y274D mutation was in his father and the 790delAG mutation was in his
      mother heterozygously. Therefore, we concluded that the patient was a compound
      heterozygote with these mutations. These are the first pathogenetic SURF1
      mutations identified in a Japanese family.

PMID- 10647890
TI  - Correlation between human papillomavirus-associated cervical cancer and p53 codon
      72 arginine/proline polymorphism.
AB  - High-risk mucosal human papillomaviruses encode an E6 oncoprotein, which binds
      the cellular p53 tumor suppressor protein, thereby marking it for degradation
      through the ubiquitin-mediated pathway. A common p53 polymorphism at codon-72 of
      exon 4 results in translation to either arginine or proline. Recently reported
      data suggested an increased susceptibility to E6/ubiquitin-mediated degradation
      of the Arg72-p53 isoform and an over-representation of the homozygous Arg72-p53
      genotype in cervical cancer patients. We have analyzed this polymorphism in a
      larger series of patients with cervical cancer and in controls in the Czech
      Republic. We found no statistically significant differences between the codon-72
      p53 genotypes of cervical cancer patients and the control women. Based on these
      results, it is unlikely that Arg72-p53 is associated with an increased risk for
      human papillomavirus-associated cervical tumor development in Czech women.

PMID- 10647892
TI  - High throughput analysis of 10 microsatellite and 11 diallelic polymorphisms on
      the human Y-chromosome.
AB  - We describe an integrated approach to the determination of complex Y chromosome
      haplotypes that is both fast and relatively inexpensive. The method employs
      GeneScan technology to enable a researcher to assay repeat number variation at
      ten microsatellite loci and determine the status of 11 diallelic polymorphisms.
      The method requires only four PCRs and four GeneScan runs per sample and is
      relatively insensitive to sample DNA concentration.

PMID- 10647891
TI  - Minisatellite mutational processes reduce F(st) estimates.
AB  - We have used a new method for binning minisatellite alleles (semi-automated
      allele aggregation) and report the extent of population diversity detectable by
      eleven minisatellite loci in 2,689 individuals from 19 human populations
      distributed widely throughout the world. Whereas population relationships are
      consistent with those found in other studies, our estimate of genetic
      differentiation (F(st)) between populations is less than 8%, which is lower than
      comparative estimates of between 10%-15% obtained by using other sources of
      polymorphism data. We infer that mutational processes are involved in reducing
      F(st) estimates from minisatellite data because, first, the lowest F(st)
      estimates are found at loci showing autocorrelated frequencies among alleles of
      similar size and, second, F(st) declines with heterozygosity but by more than
      predicted assuming simple models of mutation. These conclusions are consistent
      with the view that minisatellites are subject to selective or mutational
      constraints in addition to those expected under simple step-wise mutation models.

PMID- 10647893
TI  - Genomic characterization of the human peptidyl-prolyl-cis-trans-isomerase,
      mitochondrial precursor gene: assessment of its role in familial dilated
      cardiomyopathy.
AB  - Dilated cardiomyopathy (DCM) is a common cause of morbidity and mortality, with
      >30% of cases being inherited. In one family with autosomal dominant familial
      dilated cardiomyopathy (FDCM), we localized the gene to the region of 10q21-10q23
      and have performed candidate positional gene cloning. The peptidyl-prolyl-cis
      trans-isomerase, mitochondrial precursor (PPIF: previously known as cyclophilin
      3) is a protein that is part of the mitochondrial permeability transition pore,
      the activation of which is involved in the induction of necrotic and apoptotic
      cell death. Since it is encoded by a gene located within this FDCM critical
      region, PPIF was considered a potential candidate gene for FDCM. In order to
      screen patient genomes for evidence of disease-associated mutations, the genomic
      organization of this gene was determined. BAC libraries were screened by PCR,
      using primers designed from the published cDNA sequence, and positive clones were
      identified. This enabled the gene to be further localized to between the CEPH
      markers D10S1777 and D10S201. The DNA from a BAC clone was digested and subcloned
      into pUC18. Following identification of a subclone by whole-cell PCR, the gene
      was characterized by DNA sequencing; five introns were identified, and the
      sequences of the intron-exon boundaries were characterized. Additionally, 450 bp
      of DNA sequence upstream of the published cDNA were obtained and a potential
      transcription initiation site and promoter sequence were identified. DNA analysis
      of the entire PPIF coding region (including the intron-exon boundaries) of two
      affected and one unaffected family member revealed no mutations, therefore
      excluding this gene as the cause of FDCM in this family.

PMID- 10647894
TI  - Molecular analysis of eight mutations in FBN1.
AB  - Mutations in the gene encoding extracellular glycoprotein fibrillin-1 (FBN1)
      cause Marfan syndrome (MFS) and other related connective tissue disorders. In
      this study, eight mutations have been detected in MFS patients by heteroduplex
      analysis. These comprise two missense mutations, C1835Y and C2258Y in calcium
      binding epidermal growth factor-like domains, two nonsense mutations, R1541X and
      R2394X in transforming growth factor beta1-binding protein-like domains, one
      splice site mutation, which has been detected previously, and three small
      insertions or deletions resulting in a frameshift. Fibroblast cells have been
      established from seven of the MFS patients and the biochemical effects of the
      mutations on fibrillin-1 synthesis and secretion assessed by pulse-chase
      analysis. Each cysteine mutation resulted in the delayed secretion of fibrillin-1
      and both nonsense and frameshift mutations caused reduced levels of synthesis
      and/or deposition of fibrillin-1. Indirect immunofluorescence and rotary
      shadowing electron microscopy analysis of fibrillin microfibrils revealed no
      major differences between normal and patient samples. We discuss the relative
      merits of the biochemical techniques used in this study.

PMID- 10647895
TI  - Screening for UBE3A gene mutations in a group of Angelman syndrome patients
      selected according to non-stringent clinical criteria.
AB  - The Angelman syndrome (AS) is caused by genetic abnormalities affecting the
      maternal copy of chromosome region 15q12. Until recently, the molecular diagnosis
      of AS relied on the detection of either a deletion at 15q11-13, a paternal
      uniparental disomy (UPD) for chromosome 15 or imprinting mutations. A fourth
      class of genetic defects underlying AS was recently described and consists of
      mutations of the UBE3A gene. The vast majority of mutations reported so far are
      predicted to cause major disruptions at the protein level. It is unclear whether
      mutations with less drastic consequences for the gene product could lead to
      milder forms of AS. We report on our results obtained by screening 101 clinically
      diagnosed AS patients for mutations in the UBE3A gene. Non-stringent clinical
      criteria were purposely applied for inclusion of AS patients in this study. The
      mutation search was carried out by single-strand conformation polymorphism
      (SSCP), and SSCP/restriction fragment length polymorphism (RFLP) analyses and
      revealed five novel UBE3A gene mutations as well as three different
      polymorphisms. All five mutations were detected in patients with typical features
      of AS and are predicted to cause frameshifts in four cases and the substitution
      of a highly conserved residue in the fifth. The results we obtained add to the as
      yet limited number of reports concerning UBE3A gene mutations. Important aspects
      that emerge from the data available to date is that the four classes of genetic
      defects known to underlie AS do not appear to cover all cases. The genetic defect
      underlying approximately 10% of AS cases, including some familial cases, remains
      unknown.

PMID- 10647896
TI  - MEN I gene mutations in sporadic adrenal adenomas.
AB  - Loss of heterozygosity (LOH) on chromosome 11q13 occurs in about 20% of sporadic
      adrenal neoplasms. Adrenal lesions, mostly benign, occur in up to 40% of patients
      from MEN I kindreds. The MEN I gene, positioned on 11q13, has been considered a
      primary candidate gene in these lesions. We studied a group of 15 patients with
      sporadic adrenal adenoma, and 1 patient with multinodular hyperplasia. Of the 16
      patients, 4 had incidentally discovered masses, 5 had Conn's syndrome, 6 suffered
      from Cushing's syndrome, and 9 had high sex hormone production. Studies with the
      markers D11S480, PYGM, D11S449, and D11S987 in 13 patients (12 of whom were from
      our group of 16) revealed 4 losses of heterozygosity on D11 S480 on 11q13, but
      the deletion did not affect the MEN I gene in any case. We present complete
      direct DNA sequencing data of the menin gene in 14 sporadic adrenal adenomas and
      one with adrenal hyperplasia. We identified one heterozygous missense mutation,
      T552S, in a hormonally inactive adrenal adenoma. One base exchange was identified
      close to the intron-exon boundary in intron 9 of a nodular adrenal hyperplasia.
      mRNA expression studies found that MEN I was transcribed in all 13 samples
      analyzed. In summary, our study identified the second patient with sporadic
      benign adrenal tumor presenting a menin gene mutation. Our complete direct
      sequencing approach adds evidence that menin gene mutations may account only for
      a minority of benign adrenal tumors if at all. Another tumor-suppressor gene
      inactivated in sporadic adrenal neoplasms may be located on chromosome 11q13.

PMID- 10647897
TI  - Multiple small accessory marker chromosomes from different centromeric origin in
      a moderately mentally retarded male.
AB  - The occurrence of more than two small accessory chromosomes (SACs) in a single
      individual is extremely rare. Here, we characterize six SACs found in the cells
      of two different tissues of a moderately mentally retarded male. Microdissection
      combined with regular FISH demonstrates that the SACs are ring chromosomes
      derived from the centromeres of different chromosomes. The SACs are often
      associated with the centromeres of other chromosomes. Immunofluorescence with an
      anti-CENP-C antibody demonstrates that the SACs contain an active centromere. A
      possible mechanism by which the SACs originated and their clinical relevance are
      discussed.

PMID- 10647898
TI  - Genes and chromosomal breakpoints in the Langer-Giedion syndrome region on human
      chromosome 8.
AB  - The tricho-rhino-phalangeal syndrome type II (TRPS II, or Langer-Giedion
      syndrome) is an example of contiguous gene syndromes, as it comprises the
      clinical features of two autosomal dominant diseases, TRPS I and a form of
      multiple cartilaginous exostoses caused by mutations in the EXT1 gene. We have
      constructed a contig of cosmid, lambda-phage, PAC, and YAC clones, which covers
      the entire TRPS I critical region. Using these clones we identified a novel
      submicroscopic deletion in a TRPS I patient and refined the proximal border of
      the minimal TRPS1 gene region by precisely mapping the inversion breakpoint of
      another patient. As a first step towards a complete inventory of genes in the
      Langer-Giedion syndrome chromosome region (LGCR) with the ultimate aim to
      identify the TRPS1 gene, we analyzed 23 human expressed sequence tags (ESTs) and
      four genes (EIF3S3, RAD21, OPG, CXIV) which had been assigned to human 8q24.1.
      Our analyses indicate that the LGCR is gene-poor, because none of the ESTs and
      genes map to the minimal TRPS1 gene region and only two of these genes, RAD21 and
      EIF3S3, are located within the shortest region of deletion overlap of TRPS II
      patients. Two genes, OPG and CXIV, which are deleted only in some patients with
      TRPS II may contribute to the clinical variability of this syndrome.

PMID- 10647899
TI  - Germline origins in the human F9 gene: frequent G:C-->A:T mosaicism and increased
      mutations with advanced maternal age.
AB  - The factor IX gene (F9) is an advantageous system for analyzing recent
      spontaneous germline mutation in humans. Herein, the male:female ratio of
      mutation ("r") in F9 have been estimated by Bayesian analysis from 59 germline
      origin families. The overall "r" in F9 was estimated at 3.75. The "r"s varied
      with the type of mutation. The "r"s ranged from 6.65 and 6.10 for transitions at
      CpG and A:T to G:C transitions at non-CpG dinucleotides, respectively, to 0.57
      and 0.42 for microdeletions/microinsertions and large deletions (>1 kb),
      respectively. The "r" for the two subtypes of non-CpG transitions differed (6.10
      for A:T to G:C vs 0.80 for G:C to A:T). Somatic mosaicism was detected in 11% of
      the 45 origin individuals for whom the causative mutation was visualized directly
      by genomic sequencing of leukocyte DNA (estimated sensitivity of approximately
      one part in 20). Four of the five defined somatic mosaics had G:C to A:T
      transitions at non-CpG dinucleotides, hinting that this mutation subtype may
      occur commonly early in embryogenesis. The age at conception was analyzed for 41
      US Caucasian families in which the age of the origin parent and the year of
      conception for the first carrier/hemophiliac were available. No evidence for a
      paternal age effect was seen. However, an advanced maternal age effect was
      observed (P=0.03) and was particularly prominent for transversions (average of
      the 79th percentile when maternal age was normalized for the year of conception).
      This suggests that an increased maternal age results in a higher rate of
      transmitted mutation, whereas the increased number of mitotic replications
      associated with advanced paternal age has little, if any, effect on the rate of
      transmitted mutation.

PMID- 10647900
TI  - Genetic susceptibility to pre-eclampsia and chromosome 7q36.
AB  - Pre-eclampsia is the most common serious medical disorder of human pregnancy. The
      human endothelial cell nitric oxide synthase (eNOS) gene is a candidate for pre
      eclampsia/eclampsia (PE/E) susceptibility. A linkage study was performed on
      Australian PE/E families using 25 microsatellite markers from chromosome 7, one
      of which (eNOS-CA) resides within the eNOS gene. No significant linkage was found
      for the eNOS-CA marker using either parametric or non-parametric analysis.
      However, D7S 1805 from the eNOS gene region on 7q36, gave a suggestion of linkage
      using parametric analysis (maximum LOD score =2.143 at theta=0.14) and non
      parametric APM analysis (T1/sqrt(p)=3.53; P=0.002). Further, an association study
      was performed on unrelated PE/E cases and controls from both Chinese and
      Australian populations to test for a relationship between the eNOS gene and PE/E.
      No association was found between the eNOS-CA marker and PE/E in either
      population. However, there was a significant difference in the allelic
      distribution of eNOS-CA between the two ethnic groups. The linkage results
      support the possibility that a susceptibility locus for pre-eclampsia resides in
      the 7q36 region, however, there is no definitive evidence to support the notion
      that the eNOS gene itself is responsible for susceptibility to pre-eclampsia.

PMID- 10647901
TI  - Novel mutations in the 3 region of the polycystic kidney disease 1 (PKD1) gene.
AB  - Mutation screening in 90 unrelated ADPKD1 patients was carried out on some of the
      exons in the single copy area (37, 38, 39, 44, 45) using genomic PCR and SSCP.
      Four novel mutations were found: a 15 bp in-frame deletion in exon 39 [nt11449
      (del 15)], a 2 bp deletion in exon 44 [nt12252 (del 2)], a G insertion in exon 44
      [nt12290 (Ins G)], and a GTT in-frame deletion in exon 45 [nt12601 (del 3)].

PMID- 10647902
TI  - Inheritance of heart rate variability: the kibbutzim family study.
AB  - Heart rate variability (HRV) measures are associated with coronary heart disease
      incidence and mortality. Therefore insight into the genetic and environmental
      determinants of these measures may have clinical relevance. We assessed the role
      of genetic and environmental factors of time domain and frequency domain HRV
      indices. Participants were 451 kibbutz members, aged 15 and up, belonging to 80
      families. HRV indices were calculated from Holter recordings measured over 5 min.
      Our data indicate that for the two time- and four frequency domain indices, a
      mixture of two normal distributions fit the data significantly better than a
      single normal distribution (P<0.05). We used complex segregation analysis to
      infer the modes of inheritance of these HRV measures. We found evidence for
      possible involvement of a recessive major gene in the inheritance of the root
      mean square of successive differences in RR intervals (RMSSD), which is
      predominantly vagally mediated. A putative major gene explains 28%-34% of the
      adjusted inter-individual variability. The SD, determined by a mixture of
      mechanisms, is influenced by environmental and polygenic effects, but not by a
      major gene. The findings regarding the heritability of the frequency domain
      indices were not conclusive. However, the involvement of genetic factors was not
      rejected. Additional studies in extended families are needed to confirm the
      involvement of major genes in the determination of the autonomic activity.

PMID- 10647903
TI  - The EIF3S3 gene encoding the p40 subunit of the translation initiation factor
      eIF3 has eight exons and maps to the Langer-Giedion syndrome chromosome region on
      8q24, but is not the TRPS1 gene.
AB  - We have mapped the gene encoding the p40 subunit of the eukaryotic translation
      initiation factor eIF3 (EIF3S3) close to the distal border of the minimal
      critical region for tricho-rhino-phalangeal syndrome type I (TRPS I) on human
      chromosome 8q24. Because this location makes EIF3S3 a candidate for the TRPS1
      gene, we have determined the genomic structure of the EIF3S3 gene and searched
      for gene deletions and mutations in patients with TRPS I. The gene has eight
      exons and is transcribed from telomere to centromere. No deletion could be
      detected in 32 unrelated patients with an apparently normal karyotype. Sequence
      analysis of all exons in 15 unrelated patients did not reveal any point mutation
      either. Our data exclude EIF3S3 as the TRPS1 gene.

PMID- 10647905
TI  - Letter to human genetics journals.

PMID- 10647904
TI  - A 5-kb imprinting center deletion in a family with Angelman syndrome reduces the
      shortest region of deletion overlap to 880 bp.
AB  - Imprinting on human chromosome 15q11-q13 is controlled by a bipartite imprinting
      center (IC) that maps to the SNRPN locus. Deletions of the IC result in an
      imprinting defect and Prader-Willi syndrome or Angelman syndrome (AS). We have
      now identified a 5-kb IC deletion in an English AS patient (AS-LO); this
      represents the smallest microdeletion found in AS and narrows down the shortest
      region of deletion overlap to 880 bp.

PMID- 10647906
TI  - Isoform selective inhibition and inactivation of human cytochrome P450s by
      methylenedioxyphenyl compounds.
AB  - 1. A series of methylenedioxyphenyl compounds were evaluated for their inhibitory
      and inactivation effects on nine human cytochrome P450 (CYP) activities using
      microsomes from human B-lymphoblast cells expressing specific human CYP isoforms.
      2. Methylenedioxyphenyl compounds which possess a bulky structure such as 1,4
      benzothiazine showed substantial inhibition of S-warfarin 7-hydroxylation
      catalysed by CYP2C9, S-mephenytoin 4'-hydroxylation by CYP2C19, bufuralol 1'
      hydroxylation by CYP2D6, and testosterone 6beta-hydroxylation by CYP3A4.
      Regarding ethoxyresorufin O-deethylation catalysed by CYP1A1 and
      benzyloxyresorufin O-dealkylation by CYP2B6, the subtle change of a substitution
      of the 1,4-benzothiazine structure affected the inhibition selectivity.
      Ethoxyresorufin O-deethylation by CYP1A2, coumarin 7-hydroxylation by CYP2A6, and
      chlorzoxazone 6-hydroxylation by CYP2E1 were not inhibited by almost any of the
      methylenedioxyphenyl compounds. The inhibitory effects of methylenedioxyphenyl
      compounds that possess a short chain amino group on the human CYP isoforms were
      not significant. 3. The methylenedioxyphenyl compounds inactivated CYP1A1
      (k(inact) = 0.034 min(-1) and K(i) = 0.81 microM), CYP2C9 (k(inact) = 0.041 and
      0.042 min(-1) and K(i) = 0.56 and 0.15 microM), CYP2D6 (k(inact) = 0.044-0.339
      min(-1) and K(i) = 0.21-19.88 microM), and CYP3A4 (k(inact) = 0.076-0.251 min(-1)
      and K(i) = 0.25-0.69 microM). These results suggested that the
      methylenedioxyphenyl compounds investigated in this study would be potent
      mechanism-based inactivators of these human CYP isoforms. In contrast, CYP2B6 and
      CYP2C19 were not inactivated. 4. The present study suggested that the selectivity
      of inhibition or inactivation of human CYP isoforms by methylenedioxyphenyl
      compounds may vary according to the structure of the side chain.

PMID- 10647907
TI  - Characterization of hepatic cytochrome P450 isozyme composition in the transgenic
      rat expressing low level human growth hormone.
AB  - 1. The present authors have previously developed a transgenic rat carrying a
      chimeric gene of the mouse whey acidic protein promoter and the structural
      portion of human growth hormone (GH) gene. Among this (hGH-TG) rat, a line (low
      GH rat) missing a male-specific pulsatile GH secretary pattern due to suppression
      of endogenous GH secretion and having a continuous low GH (hGH and rat GH) level
      in the peripheral circulation was identified. The latter rat was also
      characterized as having severe obesity with age. This strain (low Gh rat) was
      used to correlate the sex-specific secretory pattern of GH with the sex-specific
      expression of cytochrome P450 (CYP) in rat. 2. Comparisons were made between the
      low GH rat and the non-transgenic rat as to the expression of liver microsomal
      CYP isozymes. The following enzyme activities were assessed: testosterone (T)
      hydroxylation and oxidation; ethoxyresorufin O-dealkylation (EROD); bunitrolol
      (BTL) 4-hydroxylation and T5 alpha-reduction. Protein expression of CYP1A,
      CYP2C11, CYP2D, CYP2E1, CYP3A2 and CYP4A1 were also assessed by Western blot
      analysis. 3. Enzyme activities and protein expression of CYP2C11 (T16 alpha and
      2alpha-hydroxylase and 17-oxidase activities) and CYP3A2 (T6beta and 2beta
      hydroxylase activities) levels, which are known to be higher in the male than in
      the female rat, were significantly lower in the adult male low GH rat than in the
      control male rat. In contrast, CYP2A1 (T7 alpha-hydroxylase) and T5-alpha
      reductase activities, which are known to be specifically elevated in the female,
      were significantly higher in the adult male low GH rat than in the control male
      rat. Thus, the loss of male-specific secretory pattern of GH results in
      feminization of the pattern of expression of CYP and T5 alpha-reductase activity
      in the liver. 4. In contrast to other GH-deficient models so far studied, an
      increase in CYP4A1 and a decrease in CYP2E1 protein expression were observed in
      the low GH rat. These trends are consistent with the characteristic phenotype of
      obesity in the transgenic rat because CYP4A1 and CYP2E1 enhance fatty acid
      excretion and glyconeogenesis from fatty acids respectively.

PMID- 10647908
TI  - In vitro metabolism of simazine, atrazine and propazine by hepatic cytochrome
      P450 enzymes of rat, mouse and guinea pig, and oestrogenic activity of
      chlorotriazines and their main metabolites.
AB  - 1. The in vitro metabolism of chlorotriazines, simazine (SIZ), atrazine (ATZ) and
      propazine (PRZ) in liver microsomes from rat, mouse and guinea pig and the
      oestrogenic activity of chlorotriazines and their main metabolites have been
      studied. 2. The formation rates of products in chlorotriazine metabolism were
      determined by HPLC. The principal reactions catalysed by the cytochrome P450
      (P450) system were N-monodealkylation and isopropylhydroxylation in all liver
      microsomes. As a result, 2-chloro-4-ethylamino-6-amino-1,3,5-triazine (M1) (SIZ
      M1 for SIZ and ATZ-M1 for ATZ) and 2-chloro-4-amino-6-isopropylamino-1,3,5
      triazine (M2) (ATZ-M2 for ATZ and PRZ-M2 for PRZ), and 2-chloro-4-ethylamino-6-(1
      hydroxyisopropylamino)-1,3,5-triazine (M3) (ATZ-M3 for ATZ) and 2-chloro-4
      isopropylamino-6-(1-hydroxyisopropylamino)-1,3,5-triazi ne (M4) (PRZ-M4 for PRZ)
      were detected as the metabolites. N-bidealkylation was not found in this system.
      3. The formation rates of N-deethylated metabolites (SIZ-M1 and ATZ-M2) were
      generally higher in mouse than in rat and guinea pig. The formation rates of N
      deisopropylated metabolites (ATZ-M1 and PRZ-M2) in guinea pig were the lowest
      among the three animal species. The formation rates of isopropylhydroxylated
      metabolites (ATZ-M3 and PRZ-M4) were remarkably low in mouse compared with rat
      and guinea pig. 4. The enzyme kinetics of chlorotriazine metabolism were examined
      by Eadie-Hofstee analyses. Some species differences in Michaelis-Menten
      parameters for each metabolite were observed, and the ranking orders were varied
      among the metabolites. 5. The binding affinity of chlorotriazines (SIZ, ATZ and
      PRZ) and their metabolites (M1-4) for recombinant human oestrogen receptor-alpha
      was assayed using the fluorescence polarization method. The binding affinity of
      M2 was significantly higher than those of parent compounds and other metabolites,
      although the oestrogenic activity was remarkably low compared with that of 17beta
      oestradiol (E2). 6. These results suggest that the pattern of metabolism of SIZ,
      ATZ and PRZ by the P450 system differs extensively among rat, mouse and guinea
      pig, and that M2 may be an activated metabolite of chlorotriazines.

PMID- 10647909
TI  - Differential effects of dietary flavonoids on drug metabolizing and antioxidant
      enzymes in female rat.
AB  - 1. Gavage administration of the natural flavonoids tangeretin, chrysin, apigenin,
      naringenin, genistein and quercetin for 2 consecutive weeks to the female rat
      resulted in differential effects on selected phase 1 and 2 enzymes in liver,
      colon and heart as well as antioxidant enzymes in red blood cells (RBC). 2.
      Glutathione transferase (GST) activity assayed by use of the substrate 1-chloro
      2,4-dinitrobenzene was significantly induced by apigenin, genistein and
      tangeretin in the heart but not in colon or liver. 3. In RBC chrysin, quercetin
      and genistein significantly decreased the activity of glutathione reductase (GR),
      catalase (CAT) and glutathione peroxidase (GPx), whereas superoxide dismutase
      (SOD) was only significantly decreased by genistein. 4. The oxidative status of
      the animal, measured as plasma malondialdehyde, revealed that chrysin, quercetin,
      genistein, and beta-naphthoflavone (BNF) significantly protected against, 2-amino
      1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP)-induced oxidative stress. Hepatic
      PhIP-DNA adduct formation was not affected by any of the administered flavonoids,
      whereas PhIP-DNA adduct formation in colon was slightly, but significantly,
      inhibited by quercetin, genistein, tangeretin and BNF. 5. The observed effects of
      chrysin, quercetin and genistein on antioxidant enzymes, concurrently with a
      protection against oxidative stress, suggest a feedback mechanism on the
      antioxidant enzymes triggered by the flavonoid antioxidants. 6. Despite the use
      of high flavonoid doses, which by far exceed the human exposure levels, the
      effect on drug metabolizing and antioxidant enzymes was still very minor. The
      role of singly administered flavonoids in the protection against cancer and heart
      disease is thus expected to be limited.

PMID- 10647910
TI  - Extensive metabolism of the flavonoid chrysin by human Caco-2 and Hep G2 cells.
AB  - 1. Chrysin is one of many bioflavonoids with chemopreventive properties in
      cardiovascular disease and cancer. In an effort better to understand factors that
      may affect the oral bioavailability of the bioflavonoids from dietary sources,
      the metabolism of chrysin by cultured intestinal Caco-2 cells and hepatic Hep G2
      cells was studied, together modelling human presystemic metabolism. 2. At
      concentrations that may be achieved in the diet, chrysin was extensively
      metabolized to two conjugated metabolites, M1 and M2, with no CYP-mediated
      oxidation. M1 was identified as a glucuronide, and M2 as a sulphate conjugate by
      LC/MS and other spectroscopic and biochemical techniques. Sulphate conjugation
      occurred at a rate twice that of glucuronic acid conjugation in both cell types.
      3. M1 was catalyzed by UGT1A6 with a Km = 12 microM. M2 was catalyzed both by M-
      and P-form phenolsulphotransferases (SULT 1A3 and SULT 1A1) with very low Km of
      3.1 and 0.05 microM respectively. 4. Pretreatment with 3-methylcholanthrene,
      interestingly, did not result in oxidation of chrysin but rather in increased
      glucuronidation. 5. Also, M1 and M2 were the only metabolites formed from chrysin
      in fresh rat hepatocytes. The metabolism of another flavonoid, apigenin, was very
      similar to that of chrysin. 6. These observations suggest that both sulphation
      and glucuronidation are critical determinants of the oral bioavailability of
      bioflavonoids in humans, although a contribution from CYP-mediated oxidation can
      not be excluded.

PMID- 10647911
TI  - Characterization of metabolites of benz(j)aceanthrylene in faeces, urine and bile
      from rat.
AB  - 1. The excretion of benz[j]aceanthrylene (B[j]A) and the biotransformation
      products found in faeces, urine and bile of rat exposed to [3H]-labelled B[j]A
      have been studied. 2. About 95% of the administered radioactivity was excreted
      within 7 days, 79% via faeces and 16% via urine, and most of the radioactivity in
      urine and faeces was excreted within 2 days. 3. The B[j]A metabolites excreted
      between days 1 and 2, including those excreted in bile during the first 5.5 h in
      a separate experiment, were further characterized by HPLC, UV and
      electrospray/atmospheric pressure chemical ionization mass spectrometry. 4. In
      faeces, bile and urine, hydroxylated B[j]A metabolites predominated. The major
      metabolites in faeces were B[j]A-1,2-dihydrodiol-8-hydroxy and B[j]A-1,2
      dihydrodiol-10-hydroxy. These metabolites were found as conjugated metabolites in
      the bile. The glucuronide conjugate of B[j]A-1,2-dihydrodiol-10-hydroxy was also
      a major metabolite in urine. Two sulphate conjugates of oxidized B[j]A were
      detected in bile, a sulphate conjugate of a B[j]A-dihydrodiol-phenol and B[j]A
      1,2-dihydrodiol-10-sulphate. Trans-B[j]A-1,2-dihydrodiol was detected in urine,
      faeces and bile. 5. These findings support the hypothesis that epoxidation at the
      cyclopenta ring is an important biotransformation pathway for B[j]A in vivo. In
      addition to the characterized metabolites, a large fraction of polar compounds,
      possibly glutathione conjugates, was also excreted in urine and bile.

PMID- 10647912
TI  - Identification of cytochromes P450 involved in human liver microsomal metabolism
      of ecabapide, a prokinetic agent.
AB  - 1. In vitro studies identified the hepatic cytochrome P450 (CYP) enzyme(s)
      involved in the major metabolism of ecabapide in human. 2. Ecabapide mainly
      underwent N-dealkylation to form M1 and 6-hydroxylation of the benzamide moiety
      to form M6. 3. The rates of formation of the major metabolites M1 and M6 were
      significantly correlated with CYP3A-selective testosterone 6beta-hydroxylase
      activities in 14 different human liver microsomes. The formation of both
      metabolites was markedly decreased by ketoconazole, miconazole or troleandomycin
      (TAO), CYP3A-selective inhibitors, and also was inhibited by anti-CYP3A
      antibodies. 4. These results strongly indicate that CYP3A is the predominant
      isozyme responsible for the major metabolism of ecabapide in human liver
      microsomes. 5. Marginal inhibition of the formation of M1 and M6 by nifedipine, a
      substrate of CYP3A with a Ki > 100 microM, suggested that nifedipne has a limited
      potential to inhibit the major metabolic pathways of ecabapide.

PMID- 10647913
TI  - Pharmacokinetics of oligodeoxynucleotides encapsulated in liposomes: effect of
      lipid composition and preparation method.
AB  - 1. The effect of the method employed to prepare liposomes and their lipid
      composition were evaluated in terms of the encapsulation efficiency and
      pharmacokinetic features of two oligodeoxynucleotides of a 21 mer: the normal (N
      Odn) and the phosphorothioate (S-Odn) oligodeoxynucleotide. 2. Liposomes were
      prepared by the classical method of multilamellar vesicles (MV) and by the
      dehydration-rehydration method (DR). Two lipid mixtures were used to prepare
      liposomes--the predominant lipid being phosphatidylcholine (PC) and sphingomyelin
      (SM) respectively. 3. The DR method for liposome preparation provided the highest
      encapsulation efficiency, regardless of liposome lipid composition and the type
      of oligodeoxynucleotide involved (N-Odn or S-Odn). 4. The pharmacokinetics of
      free and liposome encapsulated oligodeoxynucleotides was studied in mouse
      following i.v. administration. Liposome encapsulated oligodeoxynucleotides
      exhibited a significantly lower plasma clearance and longer half-life and
      residence time than free oligodeoxynucleotides. The method used to obtain the
      liposomes affected plasma clearance, which was lower for liposomes elaborated by
      the DR method than for liposomes prepared with the MV method. The use of S-Odn in
      place of N-Odn decreased the plasma clearance of oligodeoxynucleotide when
      administered encapsulated in liposomes, regardless of the lipid composition and
      method used to obtain the liposomes.

PMID- 10647914
TI  - Cadmium-induced apoptosis and changes in expression of p53, c-jun and MT-I genes
      in testes and ventral prostate of rats.
AB  - Apoptosis and a change in the expression of p53, c-jun and MT-I genes occurred in
      rats exposed to cadmium in a way known to cause carcinogenesis in testes and
      ventral prostate. In situ end labelling (ISEL), DNA electrophoresis, and RT-PCR
      methods were used in present study. Adult male Wistar rats were given a single
      (s.c.) injection of 0, 5, 10, or 20 micromol/kg CdCl2. Then 12, 48 or 96 h after
      administration of cadmium, animals were sacrificed. It was observed that cadmium
      markedly induced apoptosis in the testes at the dose of 5 micromol/kg while 10
      and 20 micromol/kg cadmium caused more necrosis than apoptosis. Apoptosis in the
      ventral prostate was markedly induced by all the doses of cadmium and there was
      an obvious time- and dose-dependent relationship between apoptotic index (AI) and
      cadmium treatment. Far fewer apoptotic cells appeared in liver, compared to the
      testes and ventral prostate. p53 mRNA expression was clearly enhanced in the
      ventral prostate but clearly suppressed in the testes by cadmium exposure, and
      the time- and dose-effect was very clear. The expression level of p53 in the
      liver was not affected by cadmium treatment. Cadmium-induced overexpression of c
      jun gene appeared at 12 h in the liver, but not until 96 h in the testes and
      ventral prostate. Although the MT-I gene was found to be expressed in all
      tissues, marked induction by cadmium of the expression of MT-I gene was only
      observed in the liver. These results indicate: (1) that apoptosis is an early
      mechanism of acute tissue damage by cadmium in the testes and ventral prostate;
      (2) that p53 and c-jun genes may be involved in cadmium-induced cytotoxicity
      (apoptosis) and related carcinogenicity in male reproductive tissues; and (3)
      that the enhanced expression of MT-I in the liver could protect this organ from
      cadmium-induced cytotoxicity (apoptosis) and carcinogenicity.

PMID- 10647915
TI  - Effect of central and peripheral cholinergic antagonists on chlorpyrifos-induced
      changes in body temperature in the rat.
AB  - Exposure to the organophosphate (OP)-based pesticide chlorpyrifos (CHP) in the
      rat results in an initial period of hypothermia lasting < 24 h, followed by a
      fever lasting 48-72 h. The purpose of this study was to determine how cholinergic
      pathways participate in the mediation of the thermoregulatory effects of CHP. The
      corn oil (CO) vehicle or CHP (25 mg/kg; p.o.) was administered to female rats
      while core temperature (Tc) and motor activity (MA) were monitored by
      radiotelemetry. The peripheral muscarinic antagonist, methyl scopolamine (MS) and
      central antagonist, scopolamine (S) were administered during the period of CHP
      induced hypothermia and fever. The hypothermia was attenuated by scopolamine but
      not by methyl scopolamine. The delayed fever was augmented by scopolamine but
      blocked by methyl scopolamine. The results indicate that CHP-induced hypothermia
      is mediated by cholinergic stimulation of heat loss pathways in CNS
      thermoregulatory centers. Peripheral cholinergic pathways appear to have a
      minimal role in mediating chlorpyrifos-induced hypothermia. On the other hand,
      the chlorpyrifos-induced fever appears to be mediated by a peripheral pathway
      that is blocked by methyl scopolamine. The data provides a possible explanation
      for the persistent fever in humans exposed to OP pesticides and treated with
      atropine. Methyl atropine or methyl scopolamine may be a more effective therapy
      in the treatment of the fever.

PMID- 10647916
TI  - Carcinogenicity testing in the CD-1 mouse of a prospective insect repellent (KBR
      3023) using the dermal route of exposure.
AB  - The carcinogenic potential of 1-(1-methyl-propoxycarbonyl)-2-(2-hydroxyethyl)
      piperidine (KBR 3023), a prospective new insect repellent intended for human use,
      was studied in mice using the dermal route of application. Relying upon the
      toxicology profile that emerged in the subchronic rat bioassay that was conducted
      using dermally applied dosages of 0, 80, 200, 500, and 1000 mg KBR 3023/kg body
      weight per day, it was determined, in concert with the EPA, that dermally applied
      dosages of 0, 50, 100, or 200 mg KBR 3023/kg body weight per day would be used in
      the conduct of all definitive forms of subchronic, chronic, and lifetime
      descriptive testing performed with the chemical. Using this testing approach, the
      specific results of this 18-month study are as follows. All in-life parameters,
      which included body weight, food consumption, clinical observations, survival,
      and hematology were unaffected by exposure to KBR 3023. Similarly, postmortem
      analyses, which included organ weights and gross pathology, and histopathology
      were also unchanged following exposure to KBR 3023. No evidence of a compound
      induced neoplasia was suggested in this bioassay.

PMID- 10647917
TI  - Chronic toxicity and carcinogenicity testing in the Sprague-Dawley rat of a
      prospective insect repellant (KBR 3023) using the dermal route of exposure.
AB  - The chronic toxicology and carcinogenic potential of 1-(1-methyl-propoxycarbonyl)
      2-(2-hydroxyethyl)-piperidine (KBR 3023), a prospective new insect repellent
      intended for human use, was studied in rats using the dermal route of
      application. Relying upon the toxicology profile that emerged in the subchronic
      rat bioassay that was conducted using dermally applied dosages of 0, 80, 200, 500
      and 1000 mg KBR 3023/kg body wt/day, it was determined, in concert with the
      Environmental Protection Agency (EPA), that dermally applied dosages of 0, 50,
      100 or 200 mg KBR 3023/kg body wt/day would be used in the conduction of all
      definitive forms of subchronic, chronic, and lifetime descriptive testing
      performed with the chemical. Using this testing approach, the specific results of
      this 2-year study are as follows. All in-life parameters, which included body
      weight, food consumption, clinical observations, survival, ophthalmology,
      clinical chemistry, hematology, and urinalysis, were unaffected by exposure to
      KBR 3023. Similarly, postmortem analyses, which included organ weights and gross
      pathology, were also unchanged following exposure to KBR 3023. Histopathology at
      the dose site/skin was characterized by a pattern of acanthosis and/or
      hyperkeratosis across all doses in 1- and 2-year rats. Beyond the dosing site,
      cystic degeneration of the liver was described in 2-year 200-mg KBR 3023/kg body
      wt/day males. No other compound-related non-dosing site lesion was identified at
      any dose tested. No evidence of a compound-induced neoplasia was suggested in
      this bioassay.

PMID- 10647918
TI  - Effects of the chlorotriazine herbicide, cyanazine, on GABA(A) receptors in
      cortical tissue from rat brain.
AB  - Chlorotriazine herbicides disrupt luteinizing hormone (LH) release in female rats
      following in vivo exposure. Although the mechanism of action is unknown,
      significant evidence suggests that inhibition of LH release by chlorotriazines
      may be mediated by effects in the central nervous system. GABA(A) receptors are
      important for neuronal regulation of gonadotropin releasing hormone and LH
      release. The ability of chlorotriazine herbicides to interact with GABA(A)
      receptors was examined by measuring their effects on [3H]muscimol, [3H]Ro15-4513
      and [35S]tert-butylbicyclophosphorothionate (TBPS) binding to rat cortical
      membranes. Cyanazine (1-400 microM) inhibited [3H]Ro15-4513 binding with an IC50
      of approximately 105 microM (n=4). Atrazine (1-400 microM) also inhibited
      [3H]Ro15-4513 binding, but was less potent than cyanazine (IC50 = 305 microM).
      However, the chlorotriazine metabolites diaminochlorotriazine, 2-amino-4-chloro-6
      ethylamino-s-triazine and 2-amino-4-chloro-6-isopropylamino-s-triazine were
      without significant effect on [3H]Ro15-4513 binding. Cyanazine and the other
      chlorotriazines were without effect on [3H]muscimol or [35S]TBPS binding. To
      examine whether cyanazine altered GABA(A) receptor function, GABA-stimulated 36Cl
      flux into synaptoneurosomes was examined. Cyanazine (50-100 microM) alone did
      not significantly decrease GABA-stimulated 36Cl- flux. Diazepam (10 microM) and
      pentobarbital (100 microM) potentiated GABA-stimulated 36Cl- flux to 126 and 166%
      of control, respectively. At concentrations of 50 and 100 microM, cyanazine
      decreased potentiation by diazepam to 112 and 97% of control, respectively, and
      decreased potentiation by pentobarbital to 158 and 137% of control (n = 6).
      Interestingly, at lower concentrations (5 microM), cyanazine shifted the EC50 for
      GABA-stimulated 36Cl- flux into synaptoneurosomes from 28.9 to 19.4 microM,
      respectively (n = 5). These results suggest that cyanazine modulates
      benzodiazepine, but not the muscimol (GABA receptor site) or TBPS (Cl- channel),
      binding sites on GABA(A) receptors. Furthermore, at low concentrations, cyanazine
      may slightly enhance function of GABA(A) receptors, but at higher concentrations,
      cyanazine antagonizes GABA(A) receptor function and in particular antagonizes the
      positive modulatory effects of diazepam and pentobarbital.

PMID- 10647919
TI  - The susceptibility to nephrotoxicity of streptozotocin-induced diabetic rats
      subchronically exposed to cadmium chloride in drinking water.
AB  - Streptozotocin-induced diabetic rats and normal non-diabetic (ND) rats were
      exposed to cadmium chloride in drinking water in doses of 0, 50 and 100 ppm for
      90 days. There was a dose-related increase in urinary protein and enzymes in the
      diabetic group, but an increase in proteinuria only in the high exposure subgroup
      of the ND group. It is suggested that diabetic rats induced by streptozotocin are
      more susceptible to cadmium nephrotoxicity than normal (ND) rats. Metallothionein
      synthesis in liver was estimated to be similar in both the diabetic and non
      diabetic groups after exposure to cadmium. Less excretion of cadmium in urine and
      greater accumulation of cadmium in kidney were observed in the diabetic group,
      and this may be one of the mechanisms underlying the susceptibility of diabetic
      animals to the effects of cadmium. Further biochemical and histological studies
      are required in order to explain the detailed events involved in inducing such
      changes in the toxicokinetics of cadmium.

PMID- 10647920
TI  - Toluene inhalation induced epididymal sperm dysfunction in rats.
AB  - Toluene is a widely abused inhaled solvent. This study was designed to determine
      whether toluene abuse affects the reproductive functions or general health of
      males. Seven-week-old male Sprague-Dawley rats were exposed to toluene vapor
      inhalation (0, 4000, or 6000 ppm; 2 h/day) daily for 5 weeks. Exposure-related
      suppression of body weight gain and food consumption were observed. Salivation
      and lacrimation were observed during exposure periods and intensified with
      repeated exposure. Rats exposed to 6000 ppm toluene had decreased spleen and
      thymus weights, as well as suppressed lymphocyte counts. In 6000 ppm group, the
      epididymal sperm counts, sperm motility, sperm quality and in vitro penetrating
      ability to zona-free hamster eggs were significantly reduced, while no exposure
      related changes in the testes weight or spermatogenesis within testes were
      detected. Tail-less sperm heads were seen within zona-free eggs incubated with
      sperm from rats exposed to 6000 ppm toluene, but not control rats. No significant
      changes were observed in serum luteinizing hormone, follicle-stimulating hormone,
      or testosterone levels following 1 month of exposure to 6000 ppm toluene. These
      results indicate that high concentrations of toluene may directly target sperm in
      the epididymis and disrupt sperm maturation.

PMID- 10647921
TI  - Species comparison of hepatic and pulmonary metabolism of benzene.
AB  - Benzene is an occupational hazard and environmental toxicant found in cigarette
      smoke, gasoline, and the chemical industry. The major health concern associated
      with benzene exposure is leukemia. Studies using microsomal preparations from
      human, mouse, rabbit, and rat to determine species differences in the metabolism
      of benzene to phenol, hydroquinone and catechol, indicate that the rat is most
      similar, both quantitatively and qualitatively, to the human in pulmonary
      microsomal metabolism of benzene. With hepatic microsomes, rat is most similar to
      human in metabolite formation at the two lower concentrations examined (24 and
      200 microM), while at the two higher concentrations (700 and 1000 microM) mouse
      is most similar in phenol formation. In all species, the enzyme system
      responsible for benzene metabolism approached saturation in hepatic microsomes
      but not in pulmonary microsomes. In pulmonary microsomes from mouse, rat, and
      human, phenol appeared to competitively inhibit benzene metabolism resulting in a
      greater proportion of phenol being converted to hydroquinone when the benzene
      concentration increased. The opposite effect was seen in hepatic microsomes.
      These findings support the hypothesis that the lung plays an important role in
      benzene metabolism, and therefore, toxicity.

PMID- 10647922
TI  - Effects of some probable antioxidants on selenite-induced cataract formation and
      oxidative stress-related parameters in rats.
AB  - The effect of several natural and synthetic compounds on selenite-induced
      cataract was investigated in rat pups. Simultaneous determination of glutathione
      S-transferase (GST), selenium dependent glutathione peroxidase (Se-GPx), catalase
      (CAT), superoxide dismutase (SOD) activities and malondialdehyde (MDA) levels
      were carried out in the lens, erythrocyte and plasma. The results showed that
      propolis, diclofenac, vitamin C (Vit-C) and quercetin prevented cataract
      formation to the extent of 70, 60, 58.4, and 40%, respectively. Standardized
      extract of Ginkgo biloba (Egb 761) did not affect the cataract formation.
      Selenite treatment caused a significant decrease in the activity of erythrocyte
      SOD. This was accompanied by a simultaneous increase in the levels of MDA either
      in lens and in plasma. A significant increase was shown in erythrocyte GST
      (substrate ethacrynic acid; eaa), and GPx activities and lens GST (substrate
      chlorodinitro benzene; cdnb) activity. Antioxidant treatment caused significant
      changes in enzyme activities and MDA levels. There was no effect of selenite and
      antioxidants on total body weight increase during the course of the study. Blood
      parameters did not correlate to lens parameters following selenite treatment. Our
      results suggest that antioxidant supplementation following selenite exposure may
      prevent the cataract formation and may enhance antioxidant defence of blood and
      lens.

PMID- 10647923
TI  - Protection of mice against soman by pretreatment with eptastigmine and
      physostigmine.
AB  - Organophosphate (OP) compounds such as the nerve agents sarin, soman and VX are
      powerful inhibitors of acetylcholinesterases (AChEs), butyrylcholinesterases
      (BChEs), and carboxylesterases (CaEs) The acute toxicity of OPs is the result of
      their irreversible binding with AChEs in the nervous system, which elevates the
      acetylcholine (ACh) levels. In this study the protective actions of intravenously
      (i.v.), administered eptastigmine and physostigmine in acute soman intoxication
      were studied in mice. The mice received eptastigmine (0.9 mg/kg body weight) or
      physostigmine (0.1 mg/kg body weight) 10 min prior to the intraperitoneal (i.p.)
      administration of soman. To avoid possible signs of poisoning, the animals
      received atropine 37.5 mg/kg body weight subcutaneously (s.c.) in saline
      immediately after soman injection. Eptastigmine was the most effective carbamate
      against soman intoxication. The LD50 value of soman was 0.44 mg/kg, and the
      protective ratios of eptastigmine and physostigmine were 2.1- and 1.3-fold,
      respectively. Both eptastigmine and physostigmine had protected AChEs when
      measured 24 h after soman exposure. In this study, there was no inhibition of
      microsomal CaEs in soman treated mice. Nonetheless, the role of microsomal CaEs
      might be more important with prophylaxis at multiple LD50s of soman. In
      conclusion, these results indicate that eptastigmine treatment given i.v.
      protects better than physostigmine against soman exposure.

PMID- 10647924
TI  - Effects of phenolic antioxidants and flavonoids on DNA synthesis in rat liver,
      spleen, and testis in vitro.
AB  - Paracetamol (acetaminophen) and hydroxyurea were found to inhibit DNA synthesis
      in a dose-dependent manner in tissue slices in vitro, with little effect on
      protein synthesis. Considerable variation in the sensitivity of the different
      tissues was also observed with an order of least sensitive to most sensitive
      tissue of liver < testis < spleen. The phenolic antioxidant properties of
      paracetamol are thought to be the mechanism by which paracetamol inhibits DNA
      synthesis, which led us to study other phenolic antioxidant molecules and
      flavonoids for specific inhibition of DNA synthesis. (+)-catechin, m-aminophenol,
      p-aminophenol and p-cresol all displayed a highly specific inhibition of DNA
      synthesis. Quercetin displayed a preferential inhibition of DNA synthesis but a
      significant level of inhibition of protein synthesis was also seen.
      Nordihydroguaiaretic acid (NDGA) and n-propyl gallate showed preferential
      inhibition of DNA synthesis at the lower doses tested, but at higher doses showed
      significant inhibition of protein synthesis, presumably because of cytotoxicity.
      Caffeic acid and naringenin did not display any specific inhibition of DNA
      synthesis as protein synthesis was equally inhibited at all doses tested. This
      study demonstrates that certain phenolic antioxidants can inhibit DNA synthesis
      specifically but this is not a property shared by all phenolic antioxidants; and
      that these inhibitors show considerable variation in effectiveness between
      different tissues.

PMID- 10647925
TI  - Lead intoxication impairs the generation of a delayed type hypersensitivity
      response.
AB  - The effect of oral administration of lead, as Pb-acetate, via the drinking water
      on the murine delayed type hypersensitivity (DTH) response was investigated. The
      DTH response of BALB/c mice sensitized intravenously with sheep red blood cells
      (SRBC) was found to be suppressed markedly in lead-intoxicated mice. Suppression
      of the DTH correlated with increasing blood Pb concentration. Suppression of the
      DTH response by Pb intoxication depended on the route of administration of the
      sensitizing antigen, as Pb intoxication did not impair the DTH reaction when mice
      were sensitized to SRBC via intraperitoneal injection. Since DTH reactions are
      regulated in large part by Th1 cells, these data establish an in vivo model
      system based on a rational route of Pb exposure in which to study further the
      modulation of Th1-mediated immune effector function by Pb.

PMID- 10647926
TI  - Change in hepatic antioxidant defense system with liver injury development in
      rats with a single alpha-naphthylisothiocyanate intoxication.
AB  - The change in hepatic antioxidant defense system with the development of alpha
      naphthylisothiocyanate (ANIT)-induced liver injury was examined in rats injected
      once with the toxicant (75 mg/kg body weight). Liver injury with cholestasis did
      not occur 12 h after ANIT injection, but appeared at 24 h, progressed at 48 h,
      and recovered at 72 h, judging from the serum levels of marker enzymes and
      components. Liver lipid peroxide content increased 12 h after ANIT injection and
      further increased 24 and 48 h, but this increase was attenuated at 72 h. Liver
      superoxide dismutase and catalase activities decreased 24 and 48 h, respectively,
      after ANIT injection, although the catalase activity increased at 12 h, but these
      decreases were attenuated at 72 h. Liver Se-glutathione peroxidase activity
      remained unchanged 24, 48, and 72 h after ANIT injection, although the activity
      increased at 12 h. Liver reduced glutathione content increased 24 h after ANIT
      injection, but the increase was reduced time dependently thereafter. Liver
      ascorbic acid content increased 12 h after ANIT injection and further increased
      at 24 h, but the increase was reduced time dependently thereafter. These results
      indicate that the change in hepatic antioxidant defense system occurs before and
      with the development of ANIT-induced liver injury in rats, and suggest that the
      reduction of hepatic antioxidant defense system mediated by SOD and catalase
      could contribute to the liver injury development through an enhancement of
      hepatic lipid peroxidation.

PMID- 10647927
TI  - Evolution: bringing molecules into the fold.

PMID- 10647928
TI  - The twentieth century trajectory of plant biology.

PMID- 10647929
TI  - Development: the natural history of genes.

PMID- 10647930
TI  - The molecular metamorphosis of experimental embryology.

PMID- 10647931
TI  - The hallmarks of cancer.

PMID- 10647932
TI  - A long twentieth century of the cell cycle and beyond.

PMID- 10647933
TI  - Molecular "vitalism".

PMID- 10647934
TI  - Dynamic spatial regulation in the bacterial cell.

PMID- 10647935
TI  - The road taken: past and future foundations of membrane traffic.

PMID- 10647936
TI  - Signaling--2000 and beyond.

PMID- 10647937
TI  - Immunology: improving on nature in the twenty-first century.

PMID- 10647938
TI  - Virology in the next millennium.

PMID- 10647939
TI  - Stem cells: a new lease on life.

PMID- 10647940
TI  - Stem cells: units of development, units of regeneration, and units in evolution.

PMID- 10647941
TI  - Genomic biology.

PMID- 10647942
TI  - Introduction: exploring the relationships among aging, ethnicity, and family
      dementia caregiving.

PMID- 10647943
TI  - Decision-making within the social course of dementia: accounts by Chinese
      American caregivers.
AB  - The goal of this retrospective pilot study was to provide a naturalistic
      description of the decision-making process regarding dementia, a chronic illness.
      The hypothesis was that in-depth descriptions by caregivers in a community
      setting would provide a more comprehensive and realistic representation of
      decision-making in the case of chronic illness than has been provided by most
      models. Data were gathered from in-depth, qualitative interviews with seven
      Chinese-American families living in the Boston area and caring for an elderly
      family member with dementia. These were supplemented with interviews with medical
      professionals and ethnography done in the community regarding the care of elders
      with dementia. Based on the findings, this paper proposes a dynamic, more
      comprehensive model for the social process of decision-making which is
      particularly applicable to clinical and life situations of decision-making in the
      case of chronic illness. The model describes: 1) the decision-maker
      constellation, including multiple family members, professionals and service
      systems; 2) relationships between decision-makers as "allies" or "competitors";
      3) variations in the nature of the decision-making process; and 4) the
      interaction of decision-making with larger social, economic and cultural forces.
      Decision-making in the case of dementia is placed within the conceptual framework
      of the "social course" of chronic illness.

PMID- 10647944
TI  - Constructing Alzheimer's: narratives of lost identities, confusion and loneliness
      in old age.
AB  - This paper is a qualitative study based on retrospective, unstructured,
      qualitative interviews with Mrs. Jones and other African-American, Chinese
      American, Irish-American and Latino family caregivers in the Boston area. A
      narrative approach is used to show how family caregivers draw on their cultural
      and personal resources to create stories about the nature and meaning of illness
      and to ask how ethnic identity may influence the kinds of stories family
      caregivers tell. Three different story types are identified and described, each
      with a distinctive configuration of illness meanings and overarching theme, or
      storyline: a subset of African-American, Irish-American, and Chinese-American
      caregivers told us stories about Alzheimer's as a disease that erodes the core
      identity of a loved one and deteriorates their minds; a subset of Chinese
      caregivers narrated stories that emphasized how families managed confusion and
      disabilities, changes ultimately construed as an expected part of growing old; a
      subset of Puerto Rican and Dominican families, while using the biomedical label
      of Alzheimer's disease or dementia, placed the elder's illness in stories about
      tragic losses, loneliness, and family responsibility. To construct their stories,
      caregivers drew upon both biomedical explanations and other cultural meanings of
      behavioral and cognitive changes in old age. Their stories challenge us to move
      beyond the sharp contrast between ethnic minority and non-ethnic minority views
      of dementia-related changes, to local clinics and hospitals as sites where
      biomedical knowledge is interpreted, communicated, discussed, and adapted to the
      perspectives and lived realities of families.

PMID- 10647945
TI  - Locations of remorse and homelands of resilience: notes on grief and sense of
      loss of place of Latino and Irish-American caregivers of demented elders.
AB  - In this essay, based on qualitative research with Latino and Irish-American
      caregivers of demented elders, we argue that spatially and culturally constituted
      definitions of personhood, the moral life, and justice shape perceptions of
      normative aging, the agency of the demented persons and their place in the
      community, the appropriate care of the aged and demented, as well as partially
      determine the concrete resources which will be available to elders and their
      families. We review how ties to homelands and neighborhood institutions act as
      mediators and shapers of anticipatory grief, caregiver burdens, and caregiver
      resources, serving as a buffer against exhaustion and despair for some families
      (primarily the Irish-American sample), and as an additional site of loss or
      stress for others (primarily the Latino sample).

PMID- 10647947
TI  - Vasculitis at the millennium.

PMID- 10647946
TI  - Take up the caregiver's burden: stories of care for urban African American elders
      with dementia.
AB  - This pilot study uses an anthropological gaze to analyze transcripts of extended
      in-home interviews among a set of ten caregivers of African-American elders with
      dementia. How are race and ethnicity made to matter in the recognition of, the
      meaning-making around and the responses to dementing illness among a sample of
      African-American caregivers? The essay contrasts prevailing cultural
      representations of African-American caregiver burden with caregiver interview
      data. What we find is that current constructs which consistently demonstrate
      "lesser burden" among African-American caregivers compared with Whites may not
      adequately capture these caregivers' experiences. Interpretations of experiences,
      meanings of "burden" and the logic of symptoms in the illness narratives
      generated by these African-American caregivers of elders with dementia require
      attention to the embodiment of large scale sociopolitical and historical forces
      like residential, educational and occupational segregation, institutional racism,
      and economic exploitation over the life course.

PMID- 10647948
TI  - Is Wegener's granulomatosis an autoimmune disease?
AB  - Wegener's granulomatosis is a multisystem disease characterized by granulomata of
      the respiratory tract and systemic necrotising vasculitis. There is a strong and
      specific association with autoantibodies directed against proteinase 3, a
      constituent of neutrophril azurophilic granules. Antibody titers correlate with
      clinical disease activity and predict relapses. The disease responds favorably to
      immunosuppressive therapy. The pathogenicity of antineutrophil cytoplasmic
      antibodies (ANCA), however, remains unproven. In vitro, the expression of
      proteinase-3 and other ANCA antigens on the surface of neutrophils and monocytes
      can be induced by priming with proinflammatory cytokines. Antineutrophil
      cytoplasmic antibodies are then able to activate these leukocytes, stimulating
      degranulation, the production of reactive oxygen species, and the secretion of
      further cytokines. Neutrophils activated by ANCA, and possibly ANCA alone,
      directly damage endothelial cells in vitro. An animal model of proteinase 3-ANCA
      induced vasculitis has not been found. Antineutrophil cytoplasmic antibodies
      directed against another antigen, myeloperoxidase, are not sufficient to cause
      vasculitis but they promote damage in certain animal models. Thus, a considerable
      amount of evidence supports the notion that Wegener's granulomatosis is an
      autoimmune disease.

PMID- 10647949
TI  - Are animal models of vasculitis suitable tools?
AB  - Several rodent models have been proposed for various forms of systemic
      vasculitis. The MRL-lpr mouse has been studied extensively as a model for
      systemic lupus erythematosus. Backcross experiments in combination with genetic
      linkage studies have firmly established that the phenotype of autoimmune disease
      is dependent on the combination of various background genes. It has also become
      apparent that environmental factors, particularly infections, modulate the
      disease phenotype. Specific interventions, such as the treatment of Brown Norway
      rats with agents resulting in polyclonal B cell stimulation or immunization with
      human myeloperoxidase and subsequent localized perfusion with neutrophil
      lysosomal extract and H2O2, have provided substantial insights into the cellular
      and molecular mechanisms leading to the development of vasculitis and
      glomerulonephritis. Even though the existing models may not exactly mirror any
      specific human disease, they offer reproducible, highly controlled conditions to
      answer specific questions about pathogenesis and novel therapeutic approaches.

PMID- 10647950
TI  - The socioeconomic impact of vasculitis.
AB  - Information detailing the socioeconomic impact of the vasculitides on society has
      been difficult to obtain. Recent published studies provide preliminary
      information suggesting that the impact of systemic vasculitis may be significant
      and far greater than previously anticipated. A rough estimate of expenditures for
      vasculitis-related hospitalizations for polyarteritis nodosa, hypersensitivity
      vasculitis, Wegener's granulomatosis, giant cell arteritis and Takayasu's
      arteritis in the US amounted to $150 million per year. Costs associated with
      outpatient care, disability, and death were not calculated. A more comprehensive
      investigation into the economic and social burden of these conditions is
      necessary. Aspects to consider include quantifying the incidence and prevalence
      of disease, estimating the direct, indirect, and intangible costs of care,
      assessing long-term clinical outcomes, and measuring quality of life from the
      patient perspective.

PMID- 10647951
TI  - Urticarial vasculitis.
AB  - Chronic or recurrent urticarial lesions are common in both primary care and
      referral medicine. Diagnosis and treatment are usually a challenge for both the
      patient and the medical practitioner. Most patients are eventually diagnosed with
      chronic idiopathic urticaria. IgG autoantibody to IgE receptor or IgE itself
      causes urticarial lesions in 30% of these patients. Only a minority
      (approximately 10%) of patients with chronic urticarial lesions have urticarial
      vasculitis. Although some cases are benign, urticarial vasculitis by itself can
      cause significant morbidity, and it is often a manifestation of a serious
      illness. Successful diagnosis and treatment of urticarial vasculitis requires
      careful assessment over time for underlying diseases like systemic lupus
      erythematosus, hypocomplementemic urticarial vasculitis syndrome, Sjogren's
      syndrome, and mixed cryoglobulinemia.

PMID- 10647952
TI  - Immune-mediated inner ear disease.
AB  - Immune-mediated inner ear disease (IMIED) is a syndrome that includes the
      subacute onset of sensorineural hearing loss, often accompanied by vertigo and
      tinnitus. This constellation of symptoms may occur as a primary disorder in which
      no other organ involvement is evident, or it may complicate certain systemic
      conditions, including Wegener's granulomatosis, Cogan's syndrome, polyarteritis
      nodosa, and systemic lupus erythematosus. The precise disease mechanisms remain
      undefined, largely because of the difficulty obtaining relevant tissue specimens
      in untreated patients. However, if treated promptly with aggressive
      immunosuppression, the devastating sequelae of IMIED may be avoided. In this
      article, we review the pathophysiology, clinical evaluation, diagnostic testing,
      and therapy of IMIED.

PMID- 10647953
TI  - Fibromuscular dysplasia.
AB  - Fibromuscular dysplasia is an uncommon angiopathy that occurs in young to middle
      aged, predominately female individuals. The disease consists of a heterogeneous
      group of histologic changes, which ultimately lead to arterial narrowing.
      Clinical manifestations reflect the arterial bed involved, most commonly
      hypertension (renal) and stroke (carotid). Fibromuscular dysplasia is a
      pathologic diagnosis, but the characteristic changes seen on an angiogram can be
      used to make the diagnosis in the appropriate clinical setting. This
      noninflammatory disease is a common mimic of vasculitis. A very limited amount of
      new literature has been published in the past year about this relatively uncommon
      condition.

PMID- 10647954
TI  - Musculoskeletal and systemic reactions to biological therapeutic agents.
AB  - Autoimmune disease, in particular systemic lupus erythematosus (SLE), can be
      induced by drugs. Over the past couple of years biologic agents have become
      available for the treatment of inflammatory disease; simultaneously, researchers
      have realized that these drugs can not only suppress autoimmune disease but may
      also potentiate it. Interferon-alpha and interferon-beta both may induce
      autoimmune disease, but this is more frequent with interferon-alpha. Therapy to
      block tumor necrosis factor-alpha, either with monoclonal antibodies or fusion
      proteins, has been associated with the development of antinuclear antibodies, but
      only rarely with clinical development of SLE. None of the three reported cases of
      SLE occuring after anti-tumor necrosis factor-alpha therapy has developed major
      organ involvement. The continued use of biologic agents will provide interesting
      insights into the pathogenesis of autoimmune disease.

PMID- 10647955
TI  - Relation between infection and autoimmunity in mixed cryoglobulinemia.
AB  - Mixed cryoglobulinemia (MC) is a systemic vasculitis of small to medium-sized
      vessels due to the vascular deposition of circulating immune-complexes (CIC) and
      complement. A leukocytoclastic vasculitis is the histologic hallmark of cutaneous
      manifestations of the disease, while a clonal B lymphocyte expansion in blood,
      bone marrow, liver, and spleen represents the underlying pathologic alteration
      responsible for the production of cryo-CIC and non-cryo CIC with rheumatoid
      factor activity. A causative role of hepatitis C virus (HCV) infection has been
      demonstrated in the large majority of MC patients. Hepatitis C virus is both a
      hepatotropic and a lymphotropic virus; due to this latter biological peculiarity,
      HCV may trigger a constellation of autoimmune-lymphoproliferative disorders.
      Besides MC, other important HCV-related diseases are porphyria cutanea tarda,
      autoimmune hepatitis, membranoproliferative glomerulonephritis, and B cell
      neoplasias. Hepatitis C virus-related MC represents a link between autoimmune and
      lymphoproliferative disorders; moreover, MC is an important model to study the
      complex relation between infections and immune system alterations in humans.
      During the last years many other autoimmune manifestations have been correlated
      with HCV infection; namely, sicca syndrome, chronic polyarthritis,
      polydermatomyositis, fibromyalgia, autoimmune thyroiditis, lung fibrosis, and
      diabetes mellitus. It is often difficult to verify whether the above associations
      are coincidental or a pathogenetic link actually exists. At least for particular
      patients' subsets and in some geographic areas, a causative role of HCV seems to
      be likely. The geographically heterogeneous distribution of HCV-related
      autoimmune diseases suggests the contribution of important environmental and
      genetic factors in the pathogenesis of such conditions. In clinical practice,
      patients with recent-onset, atypical rheumatic and autoimmune disorders should be
      carefully investigated for possible HCV infection; this is particularly advisable
      for correct diagnosis and adequate therapeutic strategy.

PMID- 10647956
TI  - The relation between familial Mediterranean fever and amyloidosis.
AB  - Familial Mediterranean fever (FMF) is the most prevalent type of hereditary
      recurrent fever. Although the inflammatory attacks that characterize the disease
      may sometimes be debilitating, reactive amyloidosis remains the most serious
      manifestation of FMF. Daily treatment with colchicine can prevent both the
      attacks and amyloid deposition, but FMF-associated amyloidosis has not been
      eradicated and is still a cause of chronic renal failure in children and adults.
      The discovery of the gene responsible for FMF, Mediterranean fever gene (MEFV),
      and of associated mutations represents a major advance that now allows
      researchers to establish a strong, although nonexclusive association between one
      specific mutation, M694V, and the amyloid phenotype.

PMID- 10647957
TI  - Is there a pathogenic link between gamma heavy chain disease and chronic
      arthritis?
AB  - In 1991, gamma heavy chain disease was diagnosed in a 43-year-old female, who 3
      years earlier had contracted an erosive seronegative chronic arthropathy. In
      1996, her lymphoproliferative disorder required treatment with melphalan and
      prednisolone. Laboratory studies revealed a gamma3 heavy chain monoclonal
      component in serum and urine. Massive localization of plasma cells and blasts
      with cytoplasmic or cell membrane staining for gamma3 chains, but no staining for
      light chains, was observed by immunohistochemical studies of bone marrow as well
      as affected synovial tissue. Large amounts of extracellular gamma3-chains were
      also deposited in the synovial membrane. This is the first documentation of gamma
      heavy chain deposition disease directly affecting articular structures. Whether
      it represents the primary pathogenic event followed by reactive inflammatory
      changes in the joints, or another example of gamma heavy chain disease preceded
      by chronic arthritis, remains elusive. Regardless, several common cellular and
      molecular mechanisms discussed here suggest a pathogenic link between the two
      disease processes.

PMID- 10647958
TI  - New pathogenetic insights into the sarcoid granuloma.
AB  - Although the most important enigma of sarcoidosis, ie, its etiology, remains an
      unsolved problem, the past few years have seen remarkable advances in
      understanding general immunologic and molecular aspects of the mechanisms leading
      to granuloma formation in sarcoidosis. It is now clear that during the sarcoid
      inflammatory process several cytokines are secreted at sites of disease activity;
      in addition, high affinity receptors for cytokines participating in the granuloma
      development have been recently identified. This article provides a detailed
      description of recent data that have clarified cellular interactions governing
      the dynamics of granuloma formation in sarcoidosis. Together, these new results
      provide important insights that can refocus efforts at developing
      immunotherapeutic methods of inhibiting cytokine production at sites of granuloma
      formation.

PMID- 10647960
TI  - Bibliography. Current world literature. Vasculitis syndromes.

PMID- 10647959
TI  - An update of diagnostic strategies using molecular genetic and magnetic resonance
      imaging techniques for musculoskeletal tumors.
AB  - Rheumatologists may be incidentally confronted by bone and soft tissue lesions
      presenting in and around joints that require early recognition and appropriate
      referral. The diagnostic and therapeutic management of patients with
      musculoskeletal tumors is critically dependent on a multidisciplinary approach.
      Advances, particularly in the fields of histopathology, molecular (cyto)genetics
      and radiologic imaging techniques, have resulted in significant improvements in
      reaching a correct (differential) diagnosis, essential for implementing optimal
      treatment modalities. Magnetic resonance imaging is becoming increasingly
      important in planning preoperative and postoperative management strategies, and
      should precede all invasive procedures. Improvements in the fields of
      immunohistochemistry, together with the realization that certain tumor groups may
      be associated with specific genetic alterations, has significantly improved
      diagnostic accuracy. Additionally, the presence of certain genetic alterations
      within the tumoral genome have been found to be of prognostic value, and the
      hereditary context recognized for a number of specific bone and soft tissue
      tumors should be taken into account in the management of a patient with such a
      neoplasm. It is envisaged that an increasing understanding of the molecular
      biology and histogenesis of individual musculoskeletal tumor types will lead to
      tailor-made therapeutic options and consequently prognostic improvements. This
      update serves to highlight some important recent developments in fundamental and
      diagnostic aspects of musculoskeletal tumors.

PMID- 10647961
TI  - Bibliography. Current world literature. Systemic disorders with rheumatic
      manifestations.

PMID- 10647962
TI  - Pleiotropic effects of growth hormone and insulin-like growth factor (IGF)-1 on
      biological aging: inferences from moderate caloric-restricted animals.
AB  - Moderate caloric restriction (60% of ad libitum intake) is an important model to
      investigate potential mechanisms of biological aging. This regimen has been
      reported to decrease the number of pathologies and increase life span in all
      species tested to date. Although moderate caloric restriction induces a wide
      range of physiological changes within the organism, adaptive changes within the
      endocrine system are evident and serve to maintain blood levels of glucose. These
      alterations include an increase in growth hormone secretory dynamics and a
      decline in plasma levels of IGF-1. These endocrine compensatory mechanisms can be
      induced at any age, and we have proposed that these alterations mediate some of
      the beneficial aspects of moderate caloric restriction. Numerous studies indicate
      that growth hormone and IGF-1 decrease with age and that administration of these
      hormones ameliorates the deterioration of tissue function evident in aged ad
      libitum-fed animals, suggesting that the absence of these hormones contributes to
      the phenotype of aging. Nevertheless, IGF-1 is an important risk factor in age
      related pathologies including lung, breast, and prostate cancer. From these
      studies, we propose that endocrine compensatory mechanisms induced by moderate
      caloric restriction (including increased growth hormone and decreased IGF-1)
      decrease the stimulus for cellular replication, resulting in a decline in
      pathologies and increased life span observed in these animals. These findings
      have important implications for potential mechanisms of moderate caloric
      restriction and suggest that neuroendocrine compensatory mechanisms exert a key
      role on the actions of moderate caloric restriction on life span.

PMID- 10647963
TI  - Age-associated impairment in brain MAPK signal pathways and the effect of caloric
      restriction in Fischer 344 rats.
AB  - Mitogen-activated protein kinases (MAPKs) play important roles in cell
      proliferation, differentiation, and apoptosis. Important functional roles for
      MAPKs in postmitotic cells have recently been suggested. In the present study, we
      investigated the effect of aging on the brain ERK (extracellular signal-regulated
      kinase) and p38 MAPK signaling pathways of Fischer 344 rats. The results show
      that basal tyrosine-phosphorylated ERK1/ERK2 in cortex of 24-month-old rats was
      reduced by 36%-59%, compared to 6- and 12-month-old rats (p<.05, 24- vs. 12- or 6
      month-old rats). Similarly, the phosphotransferase activities of ERK and p38
      MAPK, measured by in vitro immunocomplex kinase assays using myelin basic protein
      (MBP) as substrate, were shown to be reduced approximately 50% and 59%
      respectively, in the cerebrocortex of 24-month-old rats (p<.01, 24- vs. 12- or 6
      month-old rats). The reductions in basal ERK and p38 MAPK activities are not due
      to altered protein levels of these kinases as assessed by Western analysis.
      Immunohistochemically, no age-related differences in ERK expression and cellular
      distribution were observed However, cytosolic ERK tended to aggregate in brain
      neurons of aged rats. In contrast brain tyrosine-phosphorylated PLCgamma1 did not
      change with age. Activation of ERK in response to EGF or PMA was also reduced in
      cortical brain slices of 24-month-old rats. These results demonstrate an age
      associated selective impairment in the MAPK signaling pathways. Moreover,
      lifelong caloric restriction completely prevented the age-related decrease in
      basal brain ERK activity and diminished the age-related reduction of p38 MAPK
      activity. Taken together, these data indicate that ERK and p38 MAPK signaling
      pathways are impaired in the aged brain and that lifelong caloric restriction
      modulates these defects in brain intracellular signaling pathways.

PMID- 10647964
TI  - Behavioral biomarkers of aging: illustration of a multivariate approach for
      detecting age-related behavioral changes.
AB  - The goal of the current project is to develop a multivariate statistical strategy
      for the formation of behavioral indices of performance and, further, to apply
      this strategy to establish the relationship between age and important
      characteristics of performance. The strategy was to begin with a large set of
      measures that span a broad range of behaviors. The behavioral effects of the
      following variables were examined: Age (4, 12, 24, and 30 months), genotype
      [Fischer 344 and a hybrid (F1) of Fischer 344 and Brown Norway (F344xBN)], gender
      (Fischer 344 males and Fischer 344 females), long-term diet (ad lib diet or
      dietary restriction beginning at 4 months of age), and short-term diet (ad lib
      diet or dietary restriction during testing). The behavioral measures were grouped
      into conceptually related indicators. The indicators within a set were submitted
      to a principal component analysis to help identify the summary indices of
      performance, which were formed with the assumption that these component scores
      would offer more reliable and valid measures of relevant aspects of behavioral
      performance than would individual measures taken alone. In summary, this approach
      has made a number of important contributions. It has provided sensitive and
      selective measures of performance that indicated contributions of all variables:
      psychological process, age, genotype, gender, long-term and short-term diet and
      has increased the sensitivity of behavioral measures to age-related behavioral
      impairment. It has also improved task-manageability by decreasing the number of
      meaningful variables without losing important information, consequently providing
      a simplification of the pattern of changes.

PMID- 10647965
TI  - Effect of age on plasma membrane asymmetry and membrane fluidity in human
      leukocytes and platelets.
AB  - BACKGROUND: We determined whether ageing changes in plasma membrane phospholipid
      asymmetry were related to changes in membrane physical characteristics. METHODS:
      Plasma membrane asymmetry was determined in polymorphonuclear leukocytes (PMN),
      lymphocytes, and platelets from 45 healthy young (mean 29 years, 26 male) and 28
      healthy elderly (mean 70 years, 15 male) subjects by flow cytometric measurement
      of annexin V binding to cell surface phosphatidylserine. Membrane fluidity in
      lymphocytes and platelets from young and elderly subjects was determined by
      fluorescence polarization of 1,6-diphenyl- 1,3,5-hexatriene (DPH) and (4
      trimethylammonium)-DPH (TMA). RESULTS: In elderly subjects, a higher proportion
      of lymphocytes had specific annexin V binding to phosphatidylserine (PS) than in
      young subjects (young: median percentage of cells with specific annexin V binding
      to PS 5.3 [second to fourth quintiles range 3.8-8.7]; elderly: 8.5 [5.2-17.2]; p
      = .028). No ageing change in annexin V binding to PMN was observed (young: 35.0%
      [21.8-53.5]; elderly: 39.6% [27.4-69.8]; p = .42). Platelets had no specific
      annexin V binding (young: median molecules of annexin V specific binding 3.8 [0.4
      11.3]; elderly: -1.4 [-4.8-1.7]; p = .23). Superficial membrane fluidity was
      increased in lymphocytes (TMA anisotropy, young: 0.271 [0.259-0.289]; elderly:
      0.262 [0.242-0.279];p = .004), but not in platelets (young: 0.273 [0.259-0.293];
      elderly: 0.269 [0.248-0.284]; p = .12). Lymphocyte annexin V binding correlated
      with TMA (r = -.65, p = .022), but not DPH anisotropy (r = -.39, p = .18).
      CONCLUSIONS: Plasma membrane asymmetry is decreased with age in human
      lymphocytes, but not in human PMN or platelets. The increased proportion of
      lymphocytes with loss of plasma membrane asymmetry corresponds to the ageing
      changes in superficial membrane fluidity observed in lymphocytes. Such
      alterations in lymphocyte plasma membrane structure with age could account for
      changes in membrane-bound receptor function described with ageing, and may
      contribute to alterations in immune responsiveness and vascular thrombosis seen
      in older humans.

PMID- 10647966
TI  - Geropsychological problems in medical rehabilitation: dementia and depression
      among stroke and lower extremity fracture patients.
AB  - BACKGROUND: Although stroke and lower extremity fracture are often viewed as
      distinct medical rehabilitation conditions, they share similarities in that they
      are both experienced primarily among older adults, and are often accompanied by
      gero-psychological problems such as dementia and depression. In spite of these
      similarities, actual comparisons of these prevalence rates have been rare in the
      previous literature, most likely due to obvious differences in the nature of the
      injuries involved (neurological vs. peripheral injury). METHODS: One hundred and
      one stroke and 198 lower extremity fracture patients were assessed with
      neuropsychological tests from the Normative Studies Research Project test
      battery. The prevalence rates of dementia and depression were then compared
      between these two patient groups. RESULTS: Overall, 34.7% of stroke and 27.8% of
      lower extremity fracture patients met the criteria for dementia. In addition,
      33.3% of stroke and 25.1% of lower extremity fracture patients scored in the
      depressed range on the Geriatric Depression Scale. The prevalence rates for
      dementia and depression did not differ significantly between these two patient
      groups. CONCLUSIONS: Although rehabilitation efforts focus mainly upon the
      primary diagnoses of geriatric patients, these findings suggest that stroke and
      lower extremity fracture should be considered within the context of the geriatric
      issues (e.g., dementia, depression, and comorbid medical illness) which accompany
      them.

PMID- 10647967
TI  - Disability fingerprints: patterns of disability in spinal cord injury and
      multiple sclerosis differ.
AB  - BACKGROUND: Models for causation of functional disability differ as to whether
      different diseases lead to common expressions of disability versus producing
      unique "disability fingerprints." Multiple sclerosis (MS) and Spinal Cord Injury
      (SCI) both affect the spinal cord; however, their pathophysiologies differ
      (progressive vs. nonprogressive; multifocal vs. unifocal). METHODS: Patterns of
      disability were compared among veterans who reported in a national survey that
      they had MS (n = 1789) or SCI (n = 6361) as the sole cause of their spinal cord
      dysfunction. The study used self-reported information on disease duration,
      physical impairments, and self-care skills to compare the two samples for
      differences in disability overall and after stratification according to (a)
      disease duration, and (b) specific physical impairments. RESULTS: Patterns of
      disability differed significantly among persons with MS compared to SCI (p =
      .001). Differences in level of disability between the two samples remained
      statistically significant after stratification on disease duration. There were
      substantial, statistically significant differences between the two samples in the
      amount and kinds of physical impairment. However, differences in level of
      disability between the two conditions remained highly significant after
      stratifying on number of affected limbs (p = .003), amount of useful movement (p
      = .001), overall motor impairment (p = .003), amount of sensation (p = .001),
      impairment in memory and thinking (p = .001), and visual impairment (p = .001).
      CONCLUSIONS: This study shows differing diseases indeed have unique disability
      fingerprints, which remain unique after controlling for disease duration and for
      population-specific differences in physical impairment. These findings point out
      the need to explain the disablement process more fully.

PMID- 10647968
TI  - A randomized outcome evaluation of group exercise programs in long-term care
      institutions.
AB  - BACKGROUND: Physical activity programs in nursing homes typically consist of
      seated, range of motion (ROM) exercises, regardless of resident abilities. The
      Functional Fitness for Long-Term Care (FFLTC) Program was designed not only to
      maintain ROM, but also to improve strength, balance, flexibility, mobility, and
      function. In addition, it was tailored to meet the needs of both high and low
      mobility residents. METHODS: The feasibility and efficacy of the FFLTC Program
      were evaluated with 68 residents (mean age 80) from five institutions. Persons
      were classified as low or high mobility and randomized into either the FFLTC
      program or a seated ROM program. Classes were conducted in groups of 4 to 10
      residents by trained facility staff for 45 minutes, three times per week.
      Assessments at baseline and 4 months consisted of mobility, balance, gait,
      flexibility, functional capacity, and several upper and lower extremity strength
      measures. RESULTS: Attendance averaged 86% for the FFLTC and 79% for the ROM
      classes. Four months of exercise led to significant improvements in mobility
      (16%), balance (9%), flexibility (36%), knee (55%), and hip (12%) strength for
      the FFLTC group. Shoulder strength was the only improvement found for the ROM
      group. The ROM group significantly deteriorated in some areas, particularly hip
      strength, mobility, and functional ability. CONCLUSIONS: Institutionalized
      seniors, even those who are physically frail, incontinent and/or have mild
      dementia, can respond positively to a challenging exercise program. The FFLTC
      program demonstrated clear benefits over typical, seated ROM exercises. Moreover,
      with minimal training, the program can be safely delivered at low cost by
      institutional staff and volunteers.

PMID- 10647969
TI  - Tai chi practice reduces movement force variability for seniors.
AB  - BACKGROUND: The purpose of this study was to examine whether Tai Chi practice can
      reduce the inconsistency of arm movement force output in older adults. METHODS:
      Twenty seniors took part in the 8-week-long exercise intervention program (12 in
      Tai Chi practice, M = 79.3 years, SD = 2.4; and 8 in a locomotor activity group,
      walking or jogging, M = 79.5 years, SD = 1.9). Linear and curvilinear manual
      aiming movements were tested at the beginning (pretest), during 4th week
      (retest), and the end of the exercise program (post-test). The measure of
      vertical pressure on the surface of a tablet served as the dependent variable.
      RESULTS: The findings suggest that the Tai Chi participants significantly reduce
      more pressure variability than the participants in locomotor activity group after
      8 weeks of practice. Additionally, seniors produced higher pressure variability
      in the curvilinear task than in the linear task. CONCLUSIONS: Evidence from this
      study proposes that Tai Chi practice may serve as a better real world exercise
      for reducing force variability in older adults' manual performance.

PMID- 10647970
TI  - Intertrochanteric versus femoral neck hip fractures: differential
      characteristics, treatment, and sequelae.
AB  - BACKGROUND: More than 220,000 persons 65 years and older fracture a hip every
      year in the United States. Although hip fractures have been considered as a
      single, homogeneous condition, there are two major anatomic types of proximal
      femoral fractures: intertrochanteric and femoral neck. The present study's
      objective was to determine if the two types of hip fracture have different
      patient characteristics and sequelae. METHODS: A prospective study of 923 elderly
      patients admitted to seven Baltimore hospitals for a hip fracture between 1984
      and 1986. RESULTS: Patients with intertrochanteric fractures were slightly older,
      sicker on hospital admission, had longer hospital stays, and were less likely at
      2 months postfracture to have recovered activities of daily living than femoral
      neck fracture patients. Intertrochanteric fracture patients also had higher
      mortality rates at 2 and 6 months after fracturing. Long-term recovery (1 year)
      did not differ between fracture type. CONCLUSIONS: It appears that
      intertrochanteric fracture patients have intrinsic factors (older age, poor
      health) impacting upon their risk of fracture and ability to recover. Differences
      in patient characteristics and sequelae do exist between femoral neck and
      intertrochanteric hip fracture patients that impact upon recovery.

PMID- 10647971
TI  - An individualized approach to outcome measurement in geriatric rehabilitation.
AB  - BACKGROUND: The heterogeneity of health problems experienced by frail elderly
      patients makes it difficult to use a single standard measure to evaluate multiple
      outcomes of geriatric rehabilitation. Commonly, several measures are used, but an
      alternative is to use an individualized measure such as Goal Attainment Scaling
      (GAS). This study investigated the reliability, validity, and responsiveness of
      GAS as an outcome measure in geriatric rehabilitation. METHODS: We studied 173
      consecutive admissions (mean age 81; 77% female; mean length of stay 33 days) to
      a geriatric rehabilitation unit. Assessment instruments were completed at
      admission and discharge. Individualized treatment goals were identified for each
      patient by using GAS; standardized measures included self-rated health, a global
      clinical assessment, the Barthel Index, the OARS IADL scale, the Folstein Mini
      Mental State Examination (MMSE), and the Nottingham Health Profile (NHP).
      RESULTS: Mobility, future care arrangements, and functional impairment were the
      most commonly identified GAS goal areas. The interrater reliability of the GAS
      discharge score was 0.93. The GAS discharge score correlated strongly (r> or
      =0.50) with the standardized measures, except for self-rated health, the MMSE,
      and the NHP (r> or =0.31). GAS was more responsive to change than any of the
      standardized measures. The GAS score was used to derive receiver operating
      characteristic curves for other measures; this can provide insight into the
      interpretation of clinically important outcomes. CONCLUSIONS: GAS appears to be a
      feasible, reliable, valid, and responsive approach to outcome measurement in
      geriatric rehabilitation.

PMID- 10647973
TI  - Should antihypertensive therapies be given to patients with acute ischemic
      stroke?
AB  - Hypertension is a major risk factor for stroke and many patients with acute
      stroke have elevated blood pressures. The management of hypertension in the
      setting of acute ischaemic stroke remains a source of confusion and controversy.
      Lowering blood pressure in this setting may be hazardous because of impaired
      cerebral autoregulation. Treatment may be considered in patients who are
      otherwise candidates for thrombolytic therapy, patients who have severe
      hypertension or patients who have specific concomitant medical conditions
      including acute myocardial infarction, aortic dissection, hypertensive
      encephalopathy, or severe left ventricular failure. In choosing an agent for
      acute treatment, drugs that can produce a precipitous decline in blood pressure
      (e.g. sublingual calcium antagonists) should be avoided. Drugs with the capacity
      to dilate cerebral vessels should be used with caution as they have the potential
      to increase intracranial pressure. Long term management of hypertension in
      poststroke patients is often required. The potential for certain classes of drugs
      (e.g. alpha2-adrenergic receptor agonists and alpha1-adrenergic receptor
      antagonists) to impair the recovery process should be considered when choosing an
      antihypertensive for treatment of these patients.

PMID- 10647972
TI  - Guidelines for monitoring patients taking tamoxifen treatment.
AB  - Tamoxifen is the most important anti-breast cancer drug in clinical use and has
      the potential to be used as a chemopreventive breast cancer agent. Using
      outpatient hysteroscopy and based on 2 case control and 2 cohort follow-up
      studies in our department, we were able to demonstrate that 50% of women
      receiving long term tamoxifen experienced some sort of adverse endometrial
      effects. Although many women retain an atrophic endometrial layer, tamoxifen
      intake can lead to extensive senile cystic atrophia of the human endometrium, to
      endometrial hyperplasia and to endometrial polyp formation. Based on a critical
      review of the literature, we have shown that tamoxifen doubles the risk for
      developing endometrial cancer in postmenopausal women, although this increased
      risk may be higher and is duration (i.e. time of use)-dependent. Screening
      patients with breast cancer for endometrial abnormalities while they are taking
      tamoxifen is feasible and uterine morbidity related to tamoxifen intake is
      preventable. Although screening may increase drug compliance it may not be cost
      beneficial. However, uterine safety becomes important when only a small benefit
      of the treatment is to be expected as in the use of tamoxifen in healthy women
      for breast cancer prevention. The aim of this report is to discuss methods and
      guidelines for detecting endometrial adverse effects of tamoxifen and to provide
      the clinician with a current opinion on timing and frequency of screening
      patients taking tamoxifen for the development of endometrial cancer. In summary,
      those who advocate screening should start with pretreatment uterine assessment
      using transvaginal ultrasonography or outpatient hysteroscopy. Symptom-free women
      with a normal pretreatment uterine cavity can be screened annually with
      transvaginal sonography from 2 to 3 years after the start of tamoxifen.
      Hysteroscopy or saline infusion sonography will be required if there is
      endometrial thickening because the only value of transvaginal ultrasonography is
      a normal finding being a thin rectilinear endometrium.

PMID- 10647974
TI  - A risk-benefit assessment of interleukin-2 as an adjunct to antiviral therapy in
      HIV infection.
AB  - Immunomodulation has become a major focus of HIV research in an effort to
      augment, boost or restore the patient's damaged immune system. Recombinant
      interleukin-2 is currently being studied in phase II/III trials in HIV-infected
      patients. Several clinical studies have demonstrated that intermittent regimens
      are associated with marked rises in CD4+ cell counts without an increase in viral
      load. Most of these studies employ 5 consecutive days of interleukin-2 therapy by
      continuous intravenous infusion or subcutaneous injection, repeated every 8
      weeks. An alternative strategy is the daily administration of low doses of
      interleukin-2, but clinical experience with this regimen is limited. Interleukin
      2 administration can adversely affect virtually every organ system, requiring
      aggressive supportive care. A variety of administration strategies and
      interventions are being evaluated to minimise toxicity. Currently, no clinical
      end-point data are available for interleukin-2 in HIV-infected patients. Until
      phase III studies are completed, interleukin-2 can be used in the research
      setting as an immunomodulator and adjunct to antiretroviral therapy. Its
      potential to activate latently infected cells and promote HIV eradication from
      reservoir sites is also an important area for further study. If clinical benefit
      can be demonstrated, interleukin-2 could be useful as an adjunct to
      antiretroviral therapy if adverse effects can be minimised and therapy can be
      given infrequently on an outpatient basis.

PMID- 10647975
TI  - A risk-benefit assessment of the newer oral antifungal agents used to treat
      onychomycosis.
AB  - The newer antifungal agents itraconazole, terbinafine and fluconazole have become
      available to treat onychomycosis over the last 10 years. During this time period
      these agents have superseded griseofulvin as the agent of choice for
      onychomycosis. Unlike griseofulvin, the new agents have a broad spectrum of
      action that includes dermatophytes, Candida species and nondermatophyte moulds.
      Each of the 3 oral antifungal agents, terbinafine, itraconazole and fluconazole,
      is effective against dermatophytes with relatively fewer data being available for
      the treatment of Candida species and nondermatophyte moulds. Itraconazole is
      effective against Candida onychomycosis. Terbinafine may be more effective
      against C. parapsilosis compared with C. albicans; furthermore with Candida
      species a higher dose of terbinafine or a longer duration of therapy may be
      required compared with the regimen for dermatophytes. The least amount of
      experience in treating onychomycosis is with fluconazole. Griseofulvin is not
      effective against Candida species or the nondermatophyte moulds. The main use of
      griseo-fulvin currently is to treat tinea capitis. Ketoconazole may be used by
      some to treat tinea versicolor with the dosage regimens being short and requiring
      the use of only a few doses. The preferred regimens for the 3 oral antimycotic
      agents are as follows: itraconazole - pulse therapy with the drug being
      administered for 1 week with 3 weeks off treatment between successive pulses;
      terbinafine - continuous once daily therapy; and fluconazole - once weekly
      treatment. The regimen for the treatment of dermatophyte onychomycosis is:
      itraconazole - 200mg twice daily for I week per month x 3 pulses; terbinafine -
      250 mg/day for 12 weeks; or, fluconazole - 150 mg/wk until the abnormal-appearing
      nail plate has grown out, typically over a period of 9 to 18 months. For the 3
      oral antifungal agents the more common adverse reactions pertain to the following
      systems, gastrointestinal (for example, nausea, gastrointestinal distress,
      diarrhoea, abdominal pain), cutaneous eruption, and CNS (for example, headache
      and malaise). Each of the new antifungal agents is more cost-effective than
      griseofulvin for the treatment of onychomycosis and is associated with high
      compliance, in part because of the shorter duration of therapy. The newer
      antifungal agents are generally well tolerated with drug interactions that are
      usually predictable.

PMID- 10647978
TI  - Assessment of infant development during an 18-month follow-up after treatment of
      infections in pregnant women with cefuroxime axetil.
AB  - BACKGROUND: Choices of antibacterial for infections in pregnancy are limited
      because of potential risks to the fetus, particularly in the early months.
      However, infections may result in preterm labour or other problems and so
      treatment is needed. Increasingly, resistance is reported among common pathogens
      to older agents, such as ampicillin or amoxicillin, that have been widely used in
      pregnancy. OBJECTIVE: To assess the safety and efficacy of cefuroxime axetil in
      the treatment of infections during pregnancy. DESIGN: This was a retrospective
      analysis of case records for women who were treated with cefuroxime axetil at
      some point during pregnancy. SETTING: Patients were treated at one centre in
      Lubliniec, Poland in 1996 and 1997. PATIENTS AND PARTICIPANTS: The study included
      78 women aged 19 to 38 years (mean 26 years) and their 80 infants. MAIN OUTCOME
      MEASURES AND RESULTS: Efficacy in treating maternal infections was assessed, and
      the physical and mental development of children born to treated mothers was
      evaluated for at least 18 months after birth. 13 women were treated in the first
      trimester, 19 in the second trimester and 46 in the third trimester. There were
      no abnormalities causing concern in terms of physical or mental development in
      any of the children, and no abnormality that was attributable to the treatment
      the mother had received. CONCLUSIONS: The results add clinical support for the
      use of cefuroxime axetil in pregnancy if an antibacterial is needed, thus
      offering an alternative if antibacterial resistance to older agents is an issue
      for the pregnant mother.

PMID- 10647977
TI  - Managing antipsychotic-induced acute and chronic akathisia.
AB  - Akathisia is a frequent and common adverse effect of treatment with antipsychotic
      (neuroleptic) drugs. This syndrome consists of subjective (feeling of inner
      restlessness and the urge to move) as well as objective components (rocking while
      standing or sitting, lifting feet as if marching on the spot and crossing and
      uncrossing the legs while sitting). Antipsychotic-induced akathisia can be
      classified according to the time of onset in the course of antipsychotic
      treatment (acute, tardive, withdrawal and chronic akathisia). Reported prevalence
      rates vary widely between 5 and 36.8%. Numerous risk factors for acute akathisia
      have been described and the exact pathophysiology of akathisia is still unknown.
      Since akathisia is a drug-induced adverse effect, optimal management involves its
      prevention rather than treatment. Standardised titration and the use of novel
      antipsychotics are successful measures of prevention. This paper reviews
      different forms of therapeutic approaches for the treatment of akathisia. Based
      on the available literature, propranolol or other lipophilic beta-blockers seem
      to be the most consistently effective treatment for acute akathisia. There is
      nothing in the literature to guide a clinician when treatment with beta-blockers
      fails. Addition of benzodiazepines would appear to be a sensible next choice,
      especially if subjective distress persists. If all of these drugs are
      unsuccessful, amantadine or clonidine can be tried. Other agents that have been
      investigated include ritanserin, piracetam, valproic acid (sodium valproate) and
      tricyclic antidepressants. Evidence on the treatment of tardive akathisia is
      unsatisfactory.

PMID- 10647980
TI  - Determination of the isotopic composition of uranium in urine by inductively
      coupled plasma mass spectrometry.
AB  - A simple method based on inductively coupled plasma mass spectrometry (ICP-MS)
      was developed to identify exposure to depleted uranium by measuring the isotopic
      composition of uranium in urine. Exposure to depleted uranium results in a
      decreased percentage of 235U in urine samples causing measurements to vary
      between natural uranium's 0.72% and depleted uranium's 0.2%. Urine samples from a
      non-depleted uranium exposed group and a suspected depleted uranium exposed group
      were processed and analyzed by ICP-MS to determine whether depleted uranium was
      present in the urine. Sample preparation involved dry-ashing the urine at 450
      degrees C followed by wet-ashing with a series of additions of concentrated
      nitric acid and 30% hydrogen peroxide. The ash from the urine was dissolved in 1
      M nitric acid, and the intensity of 235U and 238U ions were measured by ICP-MS.
      After the samples were ashed, the ICP-MS measurements required less than 5 min.
      The 235U percentage in individuals from the depleted uranium exposed group with
      urine uranium concentrations greater than 150 ng L(-1) was between 0.20%-0.33%,
      correctly identifying depleted uranium exposure. Samples from the non-depleted
      uranium exposed individuals had urine uranium concentration less than 50 ng L(-1)
      and 235U percentages consistent with natural uranium (0.7%-1.0%). A minimum
      concentration of 14 ng L(-1) uranium was required to obtain sufficient 235U to
      allow calculating a valid isotopic ratio. Therefore, the percent 235U in urine
      samples measured by this method can be used to identify low-level exposure to
      depleted uranium.

PMID- 10647979
TI  - Retinal image motion during deliberate fixation: implications to laser safety for
      long duration viewing.
AB  - With the easy attainability of hand-held laser devices and the burgeoning light
      emitting diode (LED) technology, safety standards for long-term viewing of
      continuous light sources are being scrutinized. One concern is with quantifying
      the effect of head and eye movements on the distribution of energy over the
      retina. This experiment describes target motion over the retina as a result of
      head and eye movements during a deliberate fixation task. Volunteers deliberately
      fixated, with (fettered) and without (unfettered) head and chin rest support, on
      LEDs that subtended a 0.1 min of arc visual angle. A Dual Purkinje Image
      Eyetracker measured eye position during each 100-s fixation trial. The data
      showed an elliptical retinal energy distribution, oriented on the temporal/ nasal
      retinal axis, with a major axis 1.5 times greater than the minor. The average
      half-maximum diameter for the major axis was 40 microm for the fettered and 107
      microm for the unfettered condition. The retinal area illuminated from head and
      eye movements showed a positive linear relationship with time. Peak retinal
      radiant exposure at 100 s was reduced by a factor of 10 as a result of eye
      movements and by a factor of 30 as a result of head and eye movements. Although
      the net result was a reduction in radiant exposure from a "no-movement" baseline,
      the distribution of energy over the retina was well within the 200 microm foveal
      boundary. The data suggest that the laser permissible exposure limits for long
      term viewing of a small continuous wave source include a factor that adjusts for
      this reduction in retinal radiant exposure with time.

PMID- 10647981
TI  - Quantification of local deposition patterns of inhaled radon decay products in
      human bronchial airway bifurcations.
AB  - Aerosol deposition studies with tracheobronchial casts and models have
      demonstrated that inhaled particles are preferentially deposited within
      transitional bifurcation zones, exhibiting hot spots in the vicinity of carinal
      ridges. The goal of the present study is to quantify the inhomogeneity of
      theoretically predicted deposition patterns by local deposition enhancement
      factors. First, inspiratory particle deposition patterns of unattached (1 nm),
      ultrafine (10 nm and 20 nm), and attached (100 nm and 200 nm) radon progeny
      within three-dimensional models of segmental bronchial airway bifurcations were
      simulated by a numerical fluid dynamics and particle trajectory model. Second,
      local deposition enhancement factors were computed by scanning along the surface
      of the bifurcation models with prespecified surface area elements. Maximum values
      and frequency distributions of local deposition enhancement factors of inhaled
      radon progeny were derived for different sizes of the scanning element in a
      "narrow" and a "physiologically realistic" bifurcation model and for two
      different flow rates (10 L min(-1) and 60 L min(-1) in the trachea). Computed
      enhancement factors indicate that cells located at carinal ridges may receive
      localized doses which are 20-40 times (1 nm) and 50-115 times higher (10 nm-200
      nm), respectively, than the corresponding average doses. This may have important
      implications for the microdosimetry of inhaled radon progeny and the resulting
      lung cancer risk.

PMID- 10647976
TI  - Drug-induced diarrhoea.
AB  - Diarrhoea is a relatively frequent adverse event, accounting for about 7% of all
      drug adverse effects. More than 700 drugs have been implicated in causing
      diarrhoea; those most frequently involved are antimicrobials, laxatives,
      magnesium-containing antacids, lactose- or sorbitol-containing products,
      nonsteroidal anti-inflammatory drugs, prostaglandins, colchicine,
      antineoplastics, antiarrhythmic drugs and cholinergic agents. Certain new drugs
      are likely to induce diarrhoea because of their pharmacodynamic properties;
      examples include anthraquinone-related agents, alpha-glucosidase inhibitors,
      lipase inhibitors and cholinesterase inhibitors. Antimicrobials are responsible
      for 25% of drug-induced diarrhoea. The disease spectrum of antimicrobial
      associated diarrhoea ranges from benign diarrhoea to pseudomembranous colitis.
      Several pathophysiological mechanisms are involved in drug-induced diarrhoea:
      osmotic diarrhoea, secretory diarrhoea, shortened transit time, exudative
      diarrhoea and protein-losing enteropathy, and malabsorption or maldigestion of
      fat and carbohydrates. Often 2 or more mechanisms are present simultaneously. In
      clinical practice, 2 major types of diarrhoea are seen: acute diarrhoea, which
      usually appears during the first few days of treatment, and chronic diarrhoea,
      lasting more than 3 or 4 weeks and which can appear a long time after the start
      of drug therapy. Both can be severe and poorly tolerated. In a patient presenting
      with diarrhoea, the medical history is very important, especially the drug
      history, as it can suggest a diagnosis of drug-induced diarrhoea and thereby
      avoid multiple diagnostic tests. The clinical examination should cover severity
      criteria such as fever, rectal emission of blood and mucus, dehydration and
      bodyweight loss. Establishing a relationship between drug consumption and
      diarrhoea or colitis can be difficult when the time elapsed between the start of
      the drug and the onset of symptoms is long, sometimes up to several months or
      years.

PMID- 10647982
TI  - A new anthropometric phantom for calibrating in vivo measurements of stable lead
      in the human leg using x-ray fluorescence.
AB  - A new anthropometric phantom has been developed for calibrating in vivo
      measurements of stable lead deposited in bone using x-ray fluorescence. The
      phantom reproduces the shape of the mid shaft of the adult human leg and is
      fabricated using polyurethanes and calcium carbonate to produce materials that
      exhibit the same density, energy transmission, and calcium content as cortical
      bone, bone marrow, and muscle. The phantom includes a removable tibia fabricated
      using simulants for cortical bone and bone marrow to which a precise amount of
      stable lead has been added to cortical bone. The formulations used in fabricating
      the new anthropometric phantom are much more uniform in density and composition
      than the conventional phantom made from Plexiglas cylinders filled with plaster
      of-Paris. The energy spectrum from an x-ray fluorescence measurement of the
      phantom using a 109Cd source is indistinguishable from an in vivo x-ray
      fluorescence measurement of the human leg, demonstrating that the materials used
      in the phantom exhibit the same radiological properties as human tissue.
      Likewise, results from x-ray fluorescence measurements of the phantom exhibit the
      same positional dependency as the human leg and vary by approximately 36% when,
      for example, the phantom containing 54 ppm of stable lead in the tibia was
      rotated by only 15 degrees. The detection limit for a 30 min 109Cd K shell x-ray
      fluorescence in vivo measurement is approximately 20 ppm determined from a
      background measurement using the new phantom containing no added lead in the
      muscle, bone, or bone marrow. The new anthropometric phantom significantly
      improves in vivo x-ray fluorescence calibration measurements by (1) faithfully
      reproducing the anatomy of the human leg, (2) having components that exhibit
      radiological properties similar to that of human tissue, and (3) providing a
      realistic calibration standard that can be used for in vivo x-ray fluorescence
      intercomparison measurements.

PMID- 10647983
TI  - Radio frequency radiation of millimeter wave length: potential occupational
      safety issues relating to surface heating.
AB  - Currently, technology is being developed that makes use of the millimeter wave
      (MMW) range (30-300 GHz) of the radio frequency region of the electromagnetic
      spectrum. As more and more systems come on line and are used in everyday
      applications, the possibility of inadvertent exposure of personnel to MMWs
      increases. To date, there has been no published discussion regarding the health
      effects of MMWs; this review attempts to fill that void. Because of the shallow
      depth of penetration, the energy and, therefore, heat associated with MMWs will
      be deposited within the first 1-2 mm of human skin. MMWs have been used in states
      of the former Soviet Union to provide therapeutic benefit in a number of diverse
      disease states, including skin disorders, gastric ulcers, heart disease and
      cancer. Conversely, the possibility exists that hazards might be associated with
      accidental overexposure to MMWs. This review attempts to critically analyze the
      likelihood of such acute effects as burn and eye damage, as well as potential
      long-term effects, including cancer.

PMID- 10647984
TI  - Biokinetic and dosimetric model of plutonium in the dog.
AB  - A biokinetic model of the systemic distribution and dosimetry of 239Pu in the
      beagle dog is presented. To achieve maximum consistency with experimental data,
      known histomorphometric parameters and results of autoradiographic studies were
      adopted directly. The remaining parameters were determined from retention and
      excretion measurements by optimization procedures. The beagle model attempts to
      parallel the human model as much as possible, but only one liver compartment and
      one compartment representing other soft tissues were needed to describe the data
      adequately. The salient features and differences of the biokinetic behavior of
      239Pu beagles and humans are compared. Generally the organ retention of the
      beagle in relation to the lifetime is longer than in humans. This is particularly
      pronounced in the skeleton. Trabecular deposits of plutonium are gradually
      shifted to cortical sites. For the dosimetric model some additional features
      disregarded in the human model were employed. These relate to bone volume labels,
      a gradation of concentrations in marrow, the energy-dependence of absorbed
      fractions, and the self-absorption in marrow. The model predicts that the
      contribution of surface deposits to the endosteal dose still exceeds the
      contributions from bone volume and marrow labels. The average endosteal dose is
      about eight times and the marrow dose about two times larger than the average
      skeletal dose. The model provides the basis for the analysis of survival and
      relative risks.

PMID- 10647985
TI  - Effect of leachability on environmental risk assessment for naturally occurring
      radioactive materials in petroleum oil fields.
AB  - Elevated concentrations of naturally occurring radioactive material (NORM),
      including 238U, 232Th, and their progeny found in underground geologic deposits,
      are often encountered during crude oil recovery. Radium, the predominant
      radionuclide brought to the surface with the crude oil and produced water, co
      precipitates with barium in the form of complex compounds of sulfates,
      carbonates, and silicates found in sludge and scale. These NORM deposits are
      highly stable and very insoluble under ambient conditions at the earth's surface.
      However, the co-precipitated radium matrix is not thermodynamically stable at
      reducing conditions which may enable a fraction of the radium to eventually be
      released to the environment. Although the fate of radium in uranium mill tailings
      has been studied extensively, the leachability of radium from crude oil NORM
      deposits exposed to acid-rain and other aging processes is generally unknown. The
      leachability of radium from NORM contaminated soil collected at a contaminated
      oil field in eastern Kentucky was determined using extraction fluids having wide
      range of pH reflecting different extreme environmental conditions. The average
      226Ra concentration in the samples of soil subjected to leachability testing was
      32.56 Bq g(-1) +/- 0.34 Bq g(-1). The average leaching potential of 226Ra
      observed in these NORM contaminated soil samples was 1.3% +/- 0.46% and was
      independent of the extraction fluid. Risk assessment calculations using the
      family farm scenario show that the annual dose to a person living and working on
      this NORM contaminated soil is mainly due to external gamma exposure and radon
      inhalation. However, waterborne pathways make a non-negligible contribution to
      the dose for the actual resident families living on farmland with the type of
      residual NORM contamination due to crude oil recovery operations.

PMID- 10647986
TI  - Electron absorbed fractions and dose conversion factors for marrow and bone by
      skeletal regions.
AB  - The possible inductions of bone cancer and leukemia are the two health effects of
      primary concern in the irradiation of the skeleton. The relevant target tissues
      to consider in the dosimetric evaluation have been the cells on or near endosteal
      surfaces of bone, from which osteosarcomas are thought to arise, and
      hematopoietic bone marrow, which is associated with leukemia. The complex
      geometry of the soft tissue-bone intermixture makes calculations of absorbed
      doses to these target regions a difficult problem. In the case of photon or
      neutron radiations, charged particle equilibrium may not exist in the vicinity of
      a soft tissue-bone mineral interface. In this paper, absorbed fraction data are
      developed for calculations of the dose in the target tissues from electron
      emitters deposited within the volume or on the surfaces of trabecular bone. The
      skeletal average absorbed fractions presented are consistent with usage of this
      quantity in the contemporary dosimetric formulations of the International
      Commission on Radiological Protection (ICRP). Implementation of the new bone and
      marrow model is then developed within the context of the calculational schema of
      the Medical Internal Radiation Dose (MIRD) Committee. Model parameters relevant
      to the calculation of dose conversion factors (S values) for different regions of
      the skeleton of individuals of various age are described, and an example
      calculation is performed for a monoclonal antibody which localizes in the marrow.
      The utility of these calculations for radiation dose calculations in nuclear
      medicine is discussed.

PMID- 10647987
TI  - Effective half-lives for patients administered radiolabeled antibodies and
      calculated dose to the public in close proximity to patients.
AB  - Effective half-lives (T(e)) for radiolabeled antibodies can be much longer than
      that of traditional radiopharmaceuticals, potentially resulting in larger doses
      to members of the public. Clearance-rate data from patients treated with radio
      labeled antibodies (RABs) were obtained from ten institutions. Calculations were
      made to determine if a single- or bi-exponential clearance-rate model was
      statistically justified; the results indicated that the former model was
      justified for more than 95% of the data. Values of T(e) for the different RABs
      are summarized. To plan actions to limit doses to less than 5 mSv annually for
      individuals continuously close to the patient (at 1 m), dose rates from patients
      at the time of release also are given as a function of T(e).

PMID- 10647988
TI  - Poor design of local exhaust hood leads to radioactive release in the work area.
AB  - At a U.S. Department of Energy (DOE) waste handling facility, transuranic waste
      contained in standard 208-L (55-gallon) drums was being prepared to meet the
      DOE's Waste Isolation Pilot Project Waste Acceptance Criteria. During a
      particular waste handling operation, it was necessary for the workers to open
      several 208-L drums with TRU waste and prepare the waste to meet the WIPP Waste
      Acceptance Criteria. This operation was performed while the waste drums where
      positioned adjacent to a drum ventilator, which was designed to capture emissions
      generated from the drums during waste handling activities. During this activity,
      the continuous air monitor alarmed and reached an instantaneous air concentration
      of 0.1 Bq m(-3), or a factor of 300 times higher than the derived air
      concentration for inhalation class W 239Pu. The DOE conducted an investigation to
      determine why the drum ventilator did not control the transuranic emissions and
      to evaluate possible improvements to the drum ventilator and exposure controls.
      By adding upper and lower flanges to the drum ventilator, the capture velocity
      was increased by 88% without increasing the fan's speed. Adding flanges is a
      simple and inexpensive modification that enhances the performance of the drum
      ventilator. In addition to a poor design, the drum ventilator's capture velocity
      was compromised by competing air velocities that were generated by waste handling
      activities.

PMID- 10647989
TI  - Anomalous dose assessment associated with film badge storage in a controlled
      area.
AB  - Higher than expected film badge readings were obtained for radiologic
      technologists operating computed tomography scanners. The cause of the erroneous
      dose assignments was determined to be improper storage of the film packet in the
      console area. Since the filter holder was absent during exposure, the
      overestimation of photon energy resulted in an incorrect conversion from optical
      density to dose. Film badges and particularly the film packet should not be
      stored in controlled areas where the radiation levels are expected to be above
      background.

PMID- 10647990
TI  - Performance of E-PERM electret ion chamber radon monitors at very high humidity,
      high temperature in the presence of microbial activity.

PMID- 10647991
TI  - IAEA reports on Tokaimura accident. International Atomic Energy Agency.

PMID- 10647993
TI  - Synergistic action of pro-inflammatory agents: cellular and molecular aspects.
AB  - Generation of an inflammatory response is a complex process involving multiple
      factors acting in parallel and in concert. Viruses, parasites, and bacteria,
      particularly lipopolysaccharide (LPS), a component of the cell wall of gram
      negative bacteria, act cooperatively with the cytokine interferon (IFN)-gamma to
      induce many of the genes involved in inflammation. In addition, these components
      synergistically induce secretion of tumor necrosis factor alpha (TNF-alpha),
      which also synergizes strongly with IFN-gamma. The molecular mechanisms
      underlying the synergistic gene induction discussed in this review involve
      cooperative activation of transcription factors. IFN-gamma-activated signal
      transducer and activator of transcription 1 and interferon regulatory factor-1
      function synergistically with nuclear factor kappaB activated by LPS and TNF
      alpha. In addition, cross-talk between the signal transduction pathways upstream
      of the activation of the transcription factors contributes to generation of the
      synergistic action. Cooperative activity of proinflammatory agents profoundly
      influences the immune response to infections and the efficiency of cellular
      clearance mechanisms.

PMID- 10647992
TI  - CD40-CD40 ligand.
AB  - CD40 is a cell surface receptor that belongs to the tumor necrosis factor-R (TNF
      R) family, and that was first identified and functionally characterized on B
      lymphocytes. Its critical role in T cell-dependent humoral immune responses was
      demonstrated by patients with the hyper-IgM syndrome, as well as by gene
      targeting in mice. However, in recent years it has become clear that CD40 is
      expressed much more broadly, including expression on monocytes, dendritic cells,
      endothelial cells, and epithelial cells. In addition, the CD40-ligand (CD40
      L/CD154), a member of the TNF family, is also expressed more widely than
      activated CD4+ T cells only. Therefore it is now thought that CD40-CD40-L
      interactions play a more general role in immune regulation. Collectively these
      studies have culminated in pre-clinical and clinical studies that are in
      progress. This article reviews recent developments in this field of research,
      with main emphasis on (1) structure and expression of CD40 and its ligand; (2)
      CD40 signal transduction; (3) in vitro function of CD40 on different cell types;
      and (4) in vivo functions of CD40/CD40-L interactions.

PMID- 10647994
TI  - A novel lysophosphatidic acid analog, LXR-1035, inhibits leukocyte-endothelium
      interaction via inhibition of cell adhesion molecules.
AB  - A novel synthetic phosphorothioate analog of oleoyl lysophosphatidic acid LXR
      1035 was studied for its ability to modulate leukocyte-endothelial cell
      interactions using intravital microscopy of the rat mesentery. Superfusion of the
      rat mesentery with 50 microM L-NAME elicited a significant, time-dependent
      increase in leukocyte rolling, adherence, and transmigration compared to control
      rats superfused with Krebs-Henseleit solution. However, superfusion of the rat
      mesentery with 300 nM LXR-1035 consistently attenuated 65-87% of the L-NAME
      induced leukocyte rolling, adherence, and transmigration, without altering
      systemic blood pressure or mesenteric venular shear rate. Similar results were
      also obtained in rats subjected to 90 min of hemorrhage followed by 90 min of
      reperfusion. Resuscitation from hemorrhage increased significantly the number of
      rolling, adherent, and transmigrated leukocytes in the rat mesenteric
      microcirculation. However, superfusion of the rat mesentery with LXR-1035
      markedly attenuated the leukocyte-endothelium interaction occurring after
      hemorrhage and reinfusion by 75+/-12%. Immunohistochemical localization of P
      selectin expression on mesenteric venular endothelium was significantly increased
      after exposure to L-NAME and after hemorrhage-reinfusion, which was significantly
      attenuated by LXR-1035 (P<0.05). In addition, treatment of isolated rat
      neutrophils with 300 nM LXR-1035 significantly attenuated leukotriene B4-induced
      up-regulation of CD18 (P<0.05). Our data clearly demonstrate that LXR-1035 can
      potently inhibit the recruitment of leukocytes in the mesenteric rat
      microvasculature by attenuating cell-surface expression of adhesion molecules.

PMID- 10647995
TI  - Human monocytic U937 cells transfected with human hepatic inducible nitric oxide
      synthase exhibit leishmanicidal activity.
AB  - In mice, the high inducible synthesis of nitric oxide (NO) resulting from
      inducible NO synthase (iNOS, NOS2) expression by macrophages (Mphi) is considered
      an essential component of the protective immune response against infection by
      intracellular pathogens. Conversely, in humans, the question of a role for NO as
      an antimicrobial defense mechanism has been the subject of much debate. Recently,
      however, iNOS expression by human Mphi and formation of NO or its derivatives
      have been reported both in vivo and in vitro, strongly suggesting that human Mphi
      are indeed capable of inducible NO synthesis. However, the conditions allowing NO
      production by human Mphi in culture remain poorly defined, rendering more
      difficult the study of the effector functions of NO in these cells. To alleviate
      this problem, cells of the U937 monocytoid line were engineered to express iNOS
      by transfection with human hepatic iNOS (DFGiNOS), leading to production of NO on
      supplementation with the cofactor tetrahydrobiopterin. We report that U937 cells,
      when differentiated with 1,25-dihydroxyvitamin D3 and retinoic acid, acquire a
      phenotype allowing infection by Leishmania parasites and maintain viable
      intracellular microorganisms up to 72 h post-infection. Leishmania survival in
      DFGiNOS cells is strongly decreased when the cells are treated with
      tetrahydrobiopterin. Intracellular killing is evident by 24 h and increases up to
      72 h post-infection, and is inhibited by L-N5-(1-iminoethyl)ornithine, an
      inhibitor of NO synthesis. In contrast, superoxide anion does not appear to play
      a role in the killing of Leishmania by DGFiNOS U937 cells. The relevance of this
      model to the study of the mechanisms of intracellular killing by human
      macrophages is discussed.

PMID- 10647996
TI  - Effect of age on human neutrophil function.
AB  - Neutrophil phagocytosis, reactive oxygen intermediate production (intra- and
      extracellular), neutrophil bactericidal activity, and chemotaxis/chemokinesis
      were assessed in three age groups: 21-36, 38-56, and 62-83 years. A significant
      age-dependent reduction in the number of phagocytized Escherichia coli per
      neutrophil (measured by acridine orange staining) and Staphylococcus aureus
      phagocytosis (measured by flow cytometry) was seen (r = 0.669 and r = 0.684,
      P<0.001 for both). These findings correlated with an age-dependent increase in
      intracellular calcium concentrations in resting neutrophils (r = 0.698, P<0.001)
      and a reduced hexose uptake (r = 0.591, P<0.01). In addition, a significant
      reduction in the intracellular reactive oxygen production was seen after
      stimulation with S. aureus (P<0.001) with increasing age. In contrast, no
      differences between the groups in reactive oxygen production was seen after
      stimulation with E. coli. The neutrophil bactericidal activity was impaired with
      increasing age (64+/-4% of the phagocytized bacteria were killed in group 1; 66+/
      2 in group 2, and 59+/-6 in group 3; P<0.01). In addition, a trend toward a
      reduced neutrophil chemotaxis was seen with increasing age (P = 0.022). The
      findings suggest that increased intracellular calcium concentrations in resting
      neutrophils and/or a reduced hexose uptake result in reduced phagocytic ability
      and decreased bactericidal activity of neutrophils in the elderly.

PMID- 10647997
TI  - Monochloramine enhances Fas (APO-1/CD95)-induced apoptosis in Jurkat T cells.
AB  - Monochloramine derivatives are physiological oxidants produced by activated
      neutrophils. We report the effects of chemically prepared monochloramine (NH2Cl)
      on Fas-induced apoptosis in Jurkat T cells. When the cells were pretreated with
      NH2Cl (20-70 microM), subsequent addition of apoptosis-inducing anti-Fas antibody
      resulted in a synergistic enhancement of apoptosis. Treatment of NH2Cl (50-70
      microM) alone resulted in a slight but definite apoptosis. Caspase activities, as
      measured by DEVD and IETD cleavage activities, were also elevated synergistically
      by NH2Cl + anti-Fas antibody stimulation. Moreover, a broad caspase inhibitor, Z
      VAD-fmk, almost completely inhibited the apoptosis induced by NH2Cl and/or anti
      Fas antibody. Fas expression on the Jurkat cell surface was not affected by the
      NH2Cl treatment. After 3 h of NH2Cl treatment, when the apoptosis was beginning
      to increase, the cells showed cytochrome c release from mitochondria, proteolytic
      activation of caspase 9, and poly (ADP-ribose) polymerase cleavage, regardless of
      Fas stimulation. Z-VAD-fmk almost completely inhibited this poly (ADP-ribose)
      polymerase cleavage, but not cytochrome c release. By contrast, Fas stimulation
      alone resulted in neither cytochrome c release nor caspase 9 activation at 3 h,
      and the increase in the DEVD cleavage activity and apoptosis became evident at
      later time points. These results suggested that NH2Cl enhanced Fas-induced
      apoptosis through the cytochrome c release and caspase 9 activation at the early
      stage of apoptosis. Chloramines derived from acute inflammation may modify immune
      reactions, such as cell-mediated cytotoxicity and some autoimmune diseases, by
      the enhancement of Fas-induced apoptosis.

PMID- 10647999
TI  - Cloning and expression of bovine p47-phox and p67-phox: comparison with the human
      and murine homologs.
AB  - Neutrophils play an essential role in bovine cellular host defense, and
      compromised leukocyte function has been linked to the development of respiratory
      and mucosal infections. During the host defense process, neutrophils migrate into
      infected tissues where they become activated, resulting in the assembly of
      neutrophil membrane and cytosolic proteins to form a superoxide anion-generating
      complex known as the NADPH oxidase. Two of the essential cytosolic components of
      the NADPH oxidase are p47-phox and p67-phox. Currently, only the human and murine
      homologs of these proteins have been sequenced. Because of the important role
      neutrophils play in bovine host defense, we carried out studies to clone,
      sequence, and express bovine p47-phox and p67-phox. Using polymerase chain
      reaction (PCR) cloning techniques and a bovine bone marrow cDNA library, we have
      cloned both of these bovine NADPH oxidase cytosolic components. Comparison of the
      bovine sequences with those of the human and murine homologs showed that they
      were highly conserved, but also revealed important information regarding key
      structural features of p47-phox and p67-phox, including location of putative
      phosphorylation sites. Functional expression of bovine p47-phox and p67-phox
      showed that these proteins could substitute for the human proteins in
      reconstituting NADPH oxidase activity in a cell-free assay system, again
      demonstrating the high degree of conservation between human and bovine homologs.
      This study greatly contributes to our understanding of the potential
      structural/functional regions of p47-phox and p67-phox as well as providing
      information that can be used to study the role of neutrophils in bovine
      inflammatory diseases.

PMID- 10647998
TI  - The tumorigenic and angiogenic effects of MGSA/GRO proteins in melanoma.
AB  - Continuous expression of the MGSA/GROalpha, beta, or gamma chemokine bestows
      tumor-forming capacity to the immortalized murine melanocyte cell line, melan-a.
      The mechanism for this transformation is unclear, although both autocrine and
      paracrine processes are possible because melan-a cells as well as endothelial
      cells express a low level of the receptor for this ligand. To further define the
      role of MGSA/GRO proteins in melanocyte transformation, two types of experiments
      were designed to neutralize the biological effects of MGSA/GRO in the transfected
      melan-a clones: (1) the effect of neutralizing antiserum to MGSA/GRO proteins on
      melan-a tumor growth was assessed; (2) the tumor-forming capacity of melan-a
      clones expressing ELR motif-mutated forms of MGSA/GRO with compromised receptor
      affinity was compared to the tumor-forming capacity of clones expressing wild
      type MGSA/GRO. These experiments revealed that SCID mice inoculated with
      MGSA/GROalpha- or gamma-expressing melan-a cells and subsequently treated with
      antiserum to the respective chemokine exhibited decreased tumor growth. This
      reduction in tumor growth was accompanied by declining angiogenic activity in
      MGSA/GROgamma-expressing tumors. Moreover, athymic nude mice injected with melan
      a cells expressing ELR-mutant forms of MGSA/GROalpha exhibited markedly impaired
      tumor-forming capacity compared with those mice injected with melan-a clones
      expressing wild-type MGSA/GRO. These data suggest that continuous expression of
      MGSA/GRO proteins may facilitate tumor growth by stimulating the growth of
      microvessels into the tumor (paracrine) and by affecting melanocyte growth
      (autocrine).

PMID- 10648000
TI  - Neonatal neutrophil interaction with P-selectin: contribution of P-selectin
      glycoprotein ligand-1 and sialic acid.
AB  - Previously we had determined that neonatal neutrophils had decreased interaction
      with monolayers expressing P-selectin compared to adult cells. In this study we
      examined the function of neonatal P-selectin glycoprotein ligand-1 (PSGL-1). A
      rabbit polyclonal antibody directed against the amino terminus of human PSGL-1
      was produced and purified (3RB-PSGL-1). Neonatal neutrophils expressed the
      epitope recognized by 3RB-PSGL-1 and expression was decreased compared with adult
      neutrophils (20%, P<0.05). In addition neonatal neutrophils had decreased
      interaction with Chinese hamster ovary (CHO)-P-selectin under both shear
      conditions and static adhesion (P<0.05). Treatment of both neonatal and adult
      neutrophils with 3RB-PSGL-1 similarly inhibited the interaction with P-selectin
      monolayers under shear conditions, effects similar to treatment with O
      sialoglycoprotein endopeptidase (OSGE). Neuraminidase treatment of neonatal and
      adult cells also markedly inhibited the interaction. In a detachment assay marked
      differences were noted between neonatal and adult cells treated with either 3RB
      PSGL-1 or neuraminidase. Such treatments had little effect on adult neutrophils
      until shear stress exceeded 2.8 dynes/cm2. Treated neonatal neutrophils were
      exquisitely sensitive to shear stress with a marked decrease in interaction noted
      at a shear stress as low as 0.6 dynes/cm2. Thus the adhesive mechanisms that
      remain after treatment with neuraminidase or 3RB-PSGL-1 have a relatively low
      avidity and function less well in neonatal neutrophils compared to adult
      neutrophils. We speculate that this may account for the less efficient adhesion
      of neonatal neutrophils to P-selectin under conditions of flow.

PMID- 10648001
TI  - TNF-alpha release by monocytic THP-1 cells through cross-linking of the extended
      V-region of the oral streptococcal protein I/II.
AB  - We tested the hypothesis of a conserved activation mode of monocytic THP-1 cells
      by proteins I/II expressed by several species of oral streptococci through the
      specific role of the extended V-region. We studied the binding and modulating
      activities of six proteins I/II purified from strains representing four different
      species of oral streptococci, and of expression products of polymerase chain
      reaction-amplified sequences encoding corresponding extended V-regions. We found
      that the different proteins I/II bound to THP-1 cells in a sugar-dependent mode
      involving the extended V-region. Furthermore, all the proteins I/II stimulated
      THP-1 cells to produce tumor necrosis factor alpha, indicating that these
      properties are not strain- or species-specific. Despite the weak stimulation of
      THP-1 cells by the extended V-region alone, we obtained evidence that cross
      linking of this region can be one of the mechanisms involved in monocytic cell
      activation by proteins I/II.

PMID- 10648002
TI  - Bimodal role of endogenous interleukin-6 in concanavalin A-induced hepatitis in
      mice.
AB  - Acute concanavalin A (Con A)-induced hepatitis in mice is an animal model for
      hepatic injury induced by activated T cells. The evolution of hepatic involvement
      can be followed from hour to hour by measuring serum transaminase levels. We
      investigated the possible role of endogenous interleukin-6 (IL-6) in this model.
      We found serum IL-6 levels and splenic IL-6 mRNA during Con A-induced hepatitis
      to be significantly lower in interferon-gamma (IFN-gamma)-deficient mice, which
      are resistant against the Con A-induced syndrome, than in wild-type ones,
      suggesting that systemic IL-6 production favors development of hepatic injury.
      However, IL-6-deficient mice proved to be more susceptible to the disease than
      wild-type mice, indicating that endogenous IL-6 plays a predominantly
      hepatoprotective role. Experiments in which wild-type mice were treated with anti
      IL-6 antibodies, before or after Con A challenge, allowed us to reconcile these
      contrasting observations. The antibody injections resulted in a biphasic
      alteration of serum IL-6 levels, initial neutralization being followed by rebound
      increased levels due to accumulation of IL-6 in the form of antigen-antibody
      complexes. The effect of antibody on disease severity differed depending on the
      time of injection. Antibody injection at 2.5 h post Con A resulted in delayed
      disease manifestation, whereas treatment initiated before Con A resulted in
      accelerated disease. We conclude that endogenous IL-6 plays a bimodal role. IL-6
      present before Con A challenge as well as that induced in the very early phase
      after Con A injection triggers hepatoprotective pathways. Continuation of IL-6
      production beyond this early phase, by some other pathway, seems to be harmful to
      hepatocytes.

PMID- 10648003
TI  - Regulation of scavenger receptor CD163 expression in human monocytes and
      macrophages by pro- and antiinflammatory stimuli.
AB  - CD163, also referred to as M130, a member of the scavenger receptor cysteine-rich
      family (SRCR) is exclusively expressed on cells of the monocyte lineage. In
      freshly isolated monocytes the CD14bright CD16+ monocyte subset revealed the
      highest expression of CD163 among all monocyte subsets. CD163 mRNA and protein
      expression is up-regulated during macrophage colony-stimulating factor (M-CSF)
      dependent phagocytic differentiation of human blood monocytes. In contrast,
      monocytic cells treated with GM-CSF and interleukin-4 (IL-4) for dendritic
      differentiation down-regulate this antigen. CD163 expression is also suppressed
      by proinflammatory mediators like lipopolysaccharide (LPS), interferon-gamma (IFN
      gamma), and tumor necrosis factor alpha, whereas IL-6 and the antiinflammatory
      cytokine interleukin-10 (IL-10) strongly up-regulate CD163 mRNA in monocytes and
      macrophages. The effects of the immunosuppressants dexamethasone, cyclosporin A
      (CA), and cortisol differ in their capacity to influence CD163 mRNA levels. Our
      results demonstrate that CD163 expression in monocytes/macrophages is regulated
      by proinflammatory and antiinflammatory mediators. This expression pattern
      implies a functional role of CD 163 in the antiinflammatory response of
      monocytes.

PMID- 10648004
TI  - Surface expression and rapid internalization of macrosialin (mouse CD68) on
      elicited mouse peritoneal macrophages.
AB  - Macrosialin, the mouse homolog of human CD68, is a heavily glycosylated
      transmembrane protein found almost exclusively in macrophages. Its function
      remains uncertain. It has a high affinity for oxidized low-density lipoprotein
      (LDL) in ligand blots and antibodies against the human homolog, CD68, inhibit the
      binding of oxidized LDL to a human monocyte-derived cell line (THP-1). However,
      there is still controversy as to whether macrosialin, found predominantly in late
      endosomes, is expressed at all on the plasma membrane. The present studies, done
      in thioglycollate-elicited peritoneal macrophages, confirm that macrosialin is
      predominantly intracellular but show clearly that 10-15% of it is expressed on
      the cell surface. Exchange with intracellular pools occurs at an extremely high
      rate. The results are compatible with a surface function, including
      internalization of bound ligands or adhesion to surfaces.

PMID- 10648005
TI  - Structural and functional evidence for microglial expression of C1qR(P), the C1q
      receptor that enhances phagocytosis.
AB  - Microglial activation has been associated with several degenerative diseases of
      the central nervous system (CNS). One consequence of activation is the induction
      of a more efficient phagocytic response, and it is therefore important to
      determine what factors regulate microglial phagocytosis and whether this capacity
      influences the progression of neurodegenerative changes. Previous studies have
      demonstrated that complement component C1q enhances Fc receptor- and CR1-mediated
      phagocytosis in cells of the myeloid lineage via a cell surface receptor, C1qRp.
      Because C1q has been found in the area of lesions in several degenerative CNS
      diseases, the current investigations were carried out to characterize the effects
      of C1q on microglial phagocytosis. Neonatal rat microglia were shown to express
      C1qRp, as assessed by flow cytometry and immunocytochemistry. Interaction of
      these cells with substrate-bound C1q was shown to enhance both FcR-and CR1
      mediated phagocytosis two- to fourfold. In addition, introduction of an antibody
      raised against the carboxy-terminal, cytoplasmic domain of C1qRp into microglia
      by electroporation markedly diminished the ability of C1q to enhance uptake of
      IgG-coated targets, whereas nonspecific IgG had no such effect. These results
      suggest that C1q in areas of active degeneration may promote the phagocytic
      capacity of microglia via interaction with microglial C1qRp.

PMID- 10648006
TI  - Platelet-activating factor activates mitogen-activated protein kinases through
      the activation of phosphatidylinositol 3-kinase and tyrosine kinase in human
      eosinophils.
AB  - We determined whether platelet-activating factor (PAF) activates mitogen
      activated protein (MAP) kinases in human eosinophils, and if so, which signaling
      pathways are utilized for the MAP kinase activation. PAF activated 42-and 44-kDa
      MAP kinases (ERK1/ERK2) in eosinophils, which became maximal at 1 min after
      stimulation. The PAF receptor antagonist E6123 and pertussis toxin inhibited the
      PAF-induced MAP kinase activation in eosinophils. The phosphatidylinositol 3
      kinase (PI 3-kinase) inhibitor wortmannin, tyrosine kinase inhibitors herbimycin
      A and genistein, and an intracellular Ca2+ chelator BAPTA/AM inhibited PAF
      induced MAP kinase activation in eosinophils, whereas protein kinase C inhibitors
      staurosporine and calphostin C had no effect. Furthermore, wortmannin as well as
      herbimycin A and genistein, but not BAPTA/AM, prevented PAF-induced tyrosine
      phosphorylation of Shc adapter protein in eosinophils. Finally, the specific MEK
      inhibitor PD98059 inhibited PAF-induced chemotaxis in eosinophils. Taken
      together, these results indicate that PAF activates MAP kinases in eosinophils
      through the activation of PI 3-kinase and a tyrosine kinase and the increase in
      intracellular Ca2+ and that PAF-induced MAP kinase activation mediates chemotaxis
      in eosinophils.

PMID- 10648007
TI  - Interaction of various intracellular signaling mechanisms involved in mononuclear
      phagocyte toxicity toward neuronal cells.
AB  - Microglia become activated in a wide range of neurodegenerative disorders,
      including Alzheimer's disease. Such activation may lead to autodestruction of
      neurons. It is demonstrated here that activation of both human microglia and
      monocytic THP-1 cells by a combination of lipopolysaccharide and interferon-gamma
      results in secretion of neurotoxins that kill human neuronal SH-SY5Y cells. This
      neurotoxicity can be partially blocked by inhibitors of cytosolic phospholipase
      A2, cGMP-selective phosphodiesterases, or protein kinase C. When combinations of
      these inhibitors, or combinations of an inhibitor plus nordihydroguaiaretic acid,
      or the nonsteroidal anti-inflammatory drug diclofenac were tried, additive
      reductions in neurotoxicity were observed. It is concluded that the stimulants
      activated multiple intracellular pathways, and that combination therapies
      inhibiting these pathways might be beneficial for treating neurodegenerative
      disorders.

PMID- 10648008
TI  - The bone and joint decade 2000-2010.

PMID- 10648009
TI  - Evidence based rheumatology.

PMID- 10648010
TI  - Whose life is it anyway? Understanding quality of life in children with rheumatic
      diseases.

PMID- 10648011
TI  - The role of infection in the pathogenesis of catastrophic antiphospholipid
      syndrome--molecular mimicry?

PMID- 10648012
TI  - Polymorphonuclear elastase-alpha1-proteinase inhibitor (elastase-alpha1
      antitrypsin) in patients with rheumatic diseases: influence of disease activity.
AB  - OBJECTIVE: To determine whether elastase-alpha1-proteinase inhibitor (E-alpha1PI)
      complex behaves as an acute phase reactant in inflammatory arthritis. METHODS: E
      alpha1PI complex was measured in the plasma of 89 patients with different
      rheumatic diseases and 28 healthy controls. Correlations were sought between
      standard indices of disease activity as patients went into remission with the use
      of disease modifying antirheumatic drugs (DMARD). RESULTS: Compared with levels
      in 28 healthy controls, E-alpha1PI was significantly higher in 58 patients with
      rheumatoid arthritis (RA), 14 with ankylosing spondylitis, and 17 with
      noninflammatory rheumatoid disease. No significant correlations were found
      between E-alpha1PI and various laboratory and clinical variables of disease
      activity in RA before introduction of a DMARD. There was a slight decrease in E
      alpha1PI over 24 weeks of treatment as other acute phase reactants fell
      significantly, although this did not reach significant levels. No correlations
      were found between intra-individual change of E-alpha1PI and different indices of
      disease activity from Week 0 to Week 24. CONCLUSION: E-alpha1PI complex levels,
      measured as an index of neutrophil activation, did not correlate with improvement
      in disease activity in inflammatory arthritis afforded by DMARD.

PMID- 10648013
TI  - A citrus flavonoid, nobiletin, suppresses production and gene expression of
      matrix metalloproteinase 9/gelatinase B in rabbit synovial fibroblasts.
AB  - OBJECTIVE: Flavonoids including nobiletin are known to exert many biological
      actions in vitro. We investigated the chondroprotective effect of citrus
      flavonoids, especially nobiletin, using cultured rabbit synovial fibroblasts and
      articular chondrocytes. METHODS: We examined the effects of citrus flavonoids on
      the production and gene expression of matrix metalloproteinases (MMP) and
      prostaglandin E2 (PGE2)production in rabbit synovial fibroblasts. RESULTS: Six
      flavonoids isolated from Citrus depressa Rutaceae including tangeretin, 6
      demethoxytangeretin, nobiletin, 5-demethylnobiletin, 6-demethoxynobiletin, and
      sinensetin suppressed the interleukin 1 (IL-1) induced production of proMMP
      9/progelatinase B in rabbit synovial cells in a dose dependent manner (<64
      microM); nobiletin most effectively suppressed proMMP-9 production along with the
      decrease in its mRNA. Nobiletin also reduced IL-1 induced production of PGE2 in
      the synovial cells, but did not modify the synthesis of total protein. These
      suppressive effects of nobiletin were also observed in rabbit articular
      chondrocytes. Nobiletin inhibited proliferation of rabbit synovial fibroblasts in
      the growth phase. CONCLUSION: These results suggest nobiletin is a novel
      antiinflammatory candidate that has the potential to inhibit PGE2 production,
      matrix degradation of the articular cartilage, and pannus formation in
      osteoarthritis and rheumatoid arthritis.

PMID- 10648014
TI  - Two edged role of mannose binding lectin in rheumatoid arthritis: a cross
      sectional study.
AB  - OBJECTIVE: We investigated whether polymorphisms in the gene of mannose binding
      lectin (MBL) may be associated with onset of rheumatoid arthritis (RA), and
      whether MBL in conjunction with aggregated agalactosyl IgG (IgG-G0) may be
      associated with clinical and paraclinical variables. METHODS: MBL genotypes and
      serum concentrations were measured by polymerase chain reaction and ELISA in 189
      patients with established RA. Binding of purified MBL to IgG-G0 in serum was
      assessed and clinical and paraclinical variables were recorded. RESULTS: The
      median age at onset of RA in the 3 genotypes (normal: A/A, hetero: A/0, and
      homozygous: 0/0 for variant alleles) was 54.1 (n = 108), 47.0 (n = 68), and 38.4
      years (n = 13), respectively (p = 0.01). The frequency of variant alleles in
      patients with onset below the median age (50.8 yrs) was 0.32, but was 0.17 in
      patients with onset above 50.8 years (p = 0.003) and 0.20 in 250 controls (p =
      0.001). Stratification according to erosion score (no, small, large) revealed an
      increasing tendency among the different groups in binding of MBL to IgG-G0,
      increased Health Assessment Questionnaire score, and acute phase reactants in A/A
      individuals, while no difference was seen among carriers of variant alleles. This
      effect was most pronounced in those with late onset RA. CONCLUSION: Presence of
      MBL variant alleles was associated with early onset of RA. MBL deficiency may,
      therefore, accelerate the disease. However, in patients with late onset and
      advanced disease our results indicate that the A/A type may be associated with
      additional inflammation different from that seen in carriers of variant alleles.

PMID- 10648015
TI  - Influence of blood and synovial fluid immune complexes of patients with
      rheumatoid arthritis on production of nitric oxide and growth and viability of
      chondrocytes.
AB  - OBJECTIVE: To determine whether blood and synovial fluid (SF) immune complexes
      (IC) of patients with rheumatoid arthritis (RA) influence the production of
      nitric oxide (NO) and growth and viability of chondrocytes. METHODS: IC were
      precipitated and IgM and IgG were determined in the precipitates by ELISA and
      nephelometry, respectively. Primary cultures of bovine articular chondrocytes
      were incubated with the IC precipitates. After 48 h NO was determined as nitrite.
      After 7 days, growth was determined by incorporation of tritiated thymidine and
      viability was detected by neutral red uptake. RESULTS: Patient sera were positive
      in 8/12 for IgM IC and 9/12 for IgG IC, and 1/8 control sera was slightly
      positive for IgM IC. Seven of 12 SF samples were IgM IC and 10/12 IgG IC
      positive. With and without additional interleukin 1alpha (IL-1alpha) stimulation,
      NO production by chondrocytes was significantly higher with SF IC precipitates
      than with control serum precipitates (p = 0.03, p = 0.04, respectively). NO
      production by chondrocytes that were not stimulated with IL-1alpha was
      significantly increased with SF IC precipitates compared to RA serum IC
      precipitates (p = 0.03). SF IC significantly inhibited growth compared to control
      serum precipitates (p = 0.04) and RA serum IC (p = 0.012). Neutral red uptake by
      chondrocytes was significantly decreased when incubated with RA serum IC in
      comparison with control serum IC (p = 0.012) and SF IC (p = 0.006). With and
      without additional IL-1alpha stimulation, NO production by chondrocytes after
      incubation with SF derived IC was positively correlated to the Ritchie score (r =
      0.8, r = 0.7, respectively) and the number of swollen joints (r = 0.8, r = 0.6,
      respectively). CONCLUSION: These results support the hypothesis that, especially
      in active RA, SF derived IC stimulate NO production and inhibit chondrocyte
      growth.

PMID- 10648016
TI  - Decreased progression to rheumatoid arthritis or other connective tissue diseases
      in patients with palindromic rheumatism treated with antimalarials.
AB  - OBJECTIVE: To determine whether the use of antimalarials is associated with a
      reduction in the risk of developing rheumatoid arthritis (RA) or other connective
      tissue diseases in patients with palindromic rheumatism. METHODS: We conducted a
      retrospective cohort study based on a review of medical records to evaluate the
      outcome of patients with palindromic rheumatism referred to an academic center
      from 1986 to 1996: 113 patients complied with the selection criteria, including
      diagnostic criteria for palindromic rheumatism and onset of disease since 1980.
      After adjusting for potential confounders, Kaplan-Meier methods and Cox
      regression models were used to estimate the risk of developing RA or other
      connective tissue disease in patients who had received antimalarials compared to
      those who had not. RESULTS: Age of disease onset was 40+/-12 yrs, and mean
      disease duration 4.8+/-4 yrs; two-thirds of the patients were female. Sixty-two
      (55%) patients received antimalarials, for a mean duration of therapy of 28 mo.
      Thirty-three (29%) patients developed RA, 3 developed systemic lupus, and 4
      developed other connective tissue diseases. Twenty (32%) patients in the
      antimalarial group developed a secondary disease, compared to 20 (39%) who did
      not receive therapy. Statistically significant differences were observed
      comparing time to event in both groups. The estimated median time to development
      of a chronic disease was 162 months in treated and 56 months in untreated
      patients. After adjusting for other variables in the Cox regression models,
      significant risk reduction in the development of a secondary disease was observed
      for antimalarial use (hazard ratio = 0.24; 95% CI 0.09-0.61). For RA, the risk
      reduction was 0.19 (95% CI 0.07-0.57). We conducted a sensitivity analysis around
      our censoring estimates. The risk reduction remained statistically significant,
      with 0.36 for RA and 0.41 for RA or other connective tissue disease. CONCLUSION:
      Use of antimalarials in patients with palindromic rheumatism is associated with a
      reduction in the risk of developing subsequent RA or other connective tissue
      disease.

PMID- 10648017
TI  - Inflammatory patterns in rheumatoid arthritis estimated by the number of swollen
      and tender joints, the erythrocyte sedimentation rate, and hemoglobin: longterm
      course and association to radiographic progression.
AB  - OBJECTIVE: To investigate the association of individual plots and time-integrated
      values of repeated measures of inflammatory variables with radiographic outcome
      in rheumatoid arthritis (RA). METHODS: In 112 patients with RA, examinations of
      joint swelling and joint tenderness of 68 joints, and measurement of hemoglobin
      (Hb) and erythrocyte sedimentation rate (ESR) were performed each year for up to
      22 years after the first visit. For each of these 4 variables, the patients were
      divided arbitrarily into 5 characteristic subgroups by means of inspection of
      individual plots of longitudinal observations of the variables and divided into 5
      other subgroups according to 20% percentiles of the cumulative mean values of the
      variables. The outcome of the subgroups was evaluated by varying degrees of
      radiographic events estimated by Larsen scoring of consecutive radiographs of 46
      joints. RESULTS: An increasing number of radiographic events in subgroups with
      increasing severity (increasing values of joint swelling, joint tenderness, and
      ESR, decreasing values of Hb) was seen for both the arbitrary subgroups and the
      percentile subgroups of joint swelling, Hb, and ESR, whereas the association of
      joint tenderness to radiographic progression was weak. CONCLUSION: A highly
      significant association between inflammatory variables and radiographic outcome
      could be observed, indicating that the degree of inflammation is important for
      the development of destructive joint damage in RA.

PMID- 10648018
TI  - Serum amyloid A in the assessment of early inflammatory arthritis.
AB  - OBJECTIVE: Acute phase serum amyloid A (A-SAA) has been reported to be more
      sensitive than C-reactive protein (CRP) as a marker of disease activity. It may
      function in immune regulation and is linked to the development of secondary
      amyloidosis. We investigated the profile of A-SAA in early inflammatory arthritis
      and compared A-SAA with CRP and erythrocyte sedimentation rate (ESR) in relation
      to diagnosis and disease activity. METHODS: Using a sensitive and specific ELISA,
      A-SAA was measured in the serum of 140 patients with early arthritis (disease
      duration 2 weeks to 24 mo, mean 6 mo). CRP was determined using a standard ELISA;
      ESR and clinical disease activity variables were also recorded. RESULTS: Sixty
      four patients had rheumatoid arthritis (RA), 19 psoriatic arthritis (PsA), 28
      undifferentiated arthritis (UA), and 29 other forms of arthritis. A-SAA levels
      correlated with both CRP (r = 0.73, p = 0.0001) and ESR (r = 0.6, p = 0.0001).
      The magnitude of the A-SAA response was greater than either the CRP or ESR, and
      very high A-SAA levels were observed in disease as early as 2 weeks. Highest A
      SAA concentrations occurred in RA (median 70.3 mg/l, maximum 1542) compared with
      the other groups (medians, PsA: 33 mg/l; UA: 12.3 mg/l; other arthritis: 11.2
      mg/l), with values > 520 mg/l observed exclusively in RA. A-SAA, unlike CRP or
      ESR, could distinguish patients with a final diagnosis of RA from those who had
      persistent UA. In RA, A-SAA provided the strongest correlations with clinical
      measurements of disease activity. Clinical improvement was also best represented
      by A-SAA, while disease deterioration was associated with a significant increase
      in A-SAA values, but not CRP or ESR. CONCLUSION: Compared with ESR or CRP, A-SAA
      correlates best with markers of disease activity, and in patients with recent
      onset arthritis, very high levels of SAA occur exclusively in RA. As A-SAA is
      sensitive to change and accurately reflects alterations in disease status, it is
      the best marker available for the assessment of inflammatory joint disease.

PMID- 10648019
TI  - Levels of serum and synovial fluid pyridinium crosslinks in patients with
      rheumatoid arthritis.
AB  - OBJECTIVE: To elucidate the major source of pyridinium crosslinks in rheumatoid
      arthritis (RA). METHODS: Serum samples were collected from 75 patients with RA
      and 41 healthy controls, and synovial fluid (SF) samples were collected from 20
      patients with RA and 13 with osteoarthritis (OA). Paired samples of serum and SF
      were collected at the same time from 26 patients with RA. Levels of pyridinium
      crosslinks were determined by a recently developed high sensitivity assay method
      using high pressure liquid chromatography. RESULTS: The levels of serum
      pyridinoline (PYD) and serum deoxypyridinoline (DPD) were significantly higher in
      patients with RA than in healthy controls, and significantly correlated with
      laboratory variables indicating disease activity and severity. The levels of SF
      DPD, but not SF PYD, were significantly higher in patients with RA than in
      patients with OA. The levels of SF PYD and SF DPD both showed a significantly
      positive correlation with those of either SF interleukin 1beta or SF interleukin
      6 in patients with RA. Finally, the levels of PYD, but not DPD, were higher in SF
      than in serum in all paired RA samples collected at the same time, with
      significant correlation between the members of each pair. CONCLUSION: These
      observations suggest than an increase of PYD in RA serum may originate mostly
      from affected joints and that an increase of DPD in RA serum may be influenced
      more by systemic bone resorption.

PMID- 10648020
TI  - Hemostatic factors and cardiovascular disease in active rheumatoid arthritis: an
      8 year followup study.
AB  - OBJECTIVE: To investigate the prospective effect of hemostatic factors and
      inflammatory variables on the progression of cardiovascular disease in rheumatoid
      arthritis (RA). METHODS: Von Willebrand factor (vWF) and the fibrinolytic factors
      tissue plasminogen activator (tPA), measured as tPA capacity, and plasminogen
      activator inhibitor 1 (PAI-1), platelets, fibrinogen, and inflammatory markers
      were measured in 74 patients with active seropositive RA. Lipid levels,
      lipoprotein(a), and cardiolipin antibodies were also analyzed. Cardiovascular
      disease, measured by past cardiovascular events including thrombotic events, was
      registered in an 8 year followup. RESULTS: Patients with a cardiovascular event
      during the followup period (n = 26) had significantly higher levels of vWF, PAI
      1, erythrocyte sedimentation rate (ESR), and haptoglobin at entry to the study.
      In a multiple logistic regression model controlling for several conventional
      cardiovascular risk factors and pharmacological treatment at sampling, PAI-1 and
      tPA were significantly associated with cardiovascular disease progression.
      CONCLUSION: The altered levels of vWF, PAI-1, and, in logistic regression, tPA in
      RA patients with cardiovascular disease progression indicates a status of
      hypofibrinolysis in these patients. Higher levels of ESR and haptoglobin may
      reflect the importance of the inflammatory process for the development of
      cardiovascular disease in RA.

PMID- 10648021
TI  - The effect of rheumatoid arthritis on the quality of life of primary caregivers.
AB  - OBJECTIVE: Rheumatoid arthritis (RA) is a chronic and disabling disease
      frequently leading to physical and psychological dependence, with considerable
      economic consequences. Responsibility for care of the patient is taken on by a
      member of the family called the primary caregiver. Studies of caregivers of
      patients with RA are scarce. A better understanding of the caregiver's situation
      could provide interventions that reduce the burden and postpone
      institutionalization of people with arthritis disability. Our objective was to
      assess the effect of RA on the quality of life of primary caregivers. METHODS:
      Sixty-two patients from the rheumatic disease outpatient clinic and their
      respective caregivers were interviewed. Demographic and clinical data were
      recorded. Health and psychological status were measured using the Health
      Assessment Questionnaire (HAQ), Medical Outcomes Survey Short Form 36 (SF-36),
      Self-Reporting Questionnaire (SRQ-20), and a numerical pain rating scale. Burden
      of disease on the caregiver was assessed by the Caregiver Burden scale (CB
      scale). RESULTS: The majority of caregivers were women (82.3%), married (59.7%),
      mean (SD) age of 39.7 (15.7) years, with children/son (32.7%) or spouse (24.2%),
      with low education level and low income. Thirty-seven percent displayed
      psychoemotional disturbance measured by SRQ-20. Emotional aspect and mental
      health (by SF-36) were the most affected. The mean (SD) score of total burden
      experienced was 1.82 (0.59). The quality of relationship between caregivers and
      patients and SF-36 mental health of caregivers were important predictors of
      burden. CONCLUSION: Caregivers of patients with RA show high prevalence of
      psychological disturbance. The quality of the relationship between caregivers and
      patients and the mental health of the caregiver are important predictors of the
      burden of disease.

PMID- 10648022
TI  - Foot deformities in rheumatoid arthritis and relevance of disease severity.
AB  - OBJECTIVE: To investigate foot deformities in rheumatoid arthritis (RA) in
      relation to the disease severity. METHODS: Radiographs of 100 weight bearing feet
      of 50 patients who had had RA for >10 years (mean 13.5 years) were studied. The
      patients were classified into 2 study groups according to the severity of
      disease. We measured hallux valgus angle (HVA), intermetatarsal angle between
      first and 2nd (M1/2), and intermetatarsal angle between first and 5th (M1/5) on
      anteroposterior (AP) radiographs, as well as calcaneal pitch (CP) and first
      metatarsal pitch (MP) on lateral radiographs. The differences in these angles
      between the 2 groups (Inter-group study) and the correlations among angles within
      each group (Intra-group study) were examined. RESULTS: Inter-group study showed
      significant differences between the 2 groups for all variables. Intra-group
      study, on the other hand, showed no correlation between variables of the 2
      deformities, i.e., splaying of forefoot (M1/2 and M1/5) and flattening of
      longitudinal arch (CP and MP). Only HVA correlated with the splaying (M1/2 and
      M1/5) in both study groups. CONCLUSION: Disease severity is related to the
      progression of foot deformities in RA, but the flattening and the splaying are
      not correlated with each other. We believe that foot deformities should be
      treated properly and early, especially for patients who are expected to have
      severe disease.

PMID- 10648023
TI  - Prevalence of radiological changes in the cervical spine--a cross sectional study
      after 20 years from presentation of rheumatoid arthritis.
AB  - OBJECTIVE: To evaluate the prevalence of cervical spine changes in patients with
      rheumatoid factor (RF) positive rheumatoid arthritis (RA) followed prospectively
      for 20 years. METHODS: An inception cohort of 103 patients with RF positive RA
      have been followed at the Rheumatism Foundation Hospital, Heinola. A total of 68
      patients attended for the 20 year followup. An additional 28 patients died and 7
      were not able to attend due to severe disease or old age. The plain cervical
      spine radiographs of 69 patients (68 and one received from another hospital)
      taken after 20 years of RA were evaluated. RESULTS: Anterior atlantoaxial
      subluxation was found in 16 cases (23%), while 18 patients (26%) had atlantoaxial
      impaction as judged by the Sakaguchi-Kauppi method. Subaxial subluxations and
      lateral atlantoaxial subluxations were found in 13 cases (19%) and 3/52 cases
      (6%), respectively, while 45 patients (65%) had subaxial disc space narrowing.
      CONCLUSION: Cervical spine changes are common in patients with long lasting RA.
      They should be diagnosed and treated early to avoid complications. In our patient
      group no cervical spine surgery was performed, but at least 7 patients (10%)
      required further evaluation for possible surgery.

PMID- 10648024
TI  - Incidence of chronic inflammatory joint diseases in Finland in 1995.
AB  - OBJECTIVE: To investigate trends in the incidence of chronic inflammatory joint
      diseases. METHODS: Subjects entitled to receive drug reimbursement for chronic
      inflammatory joint diseases in 5/21 central hospital districts (population base
      about 1 million adults) in Finland during 1995 were studied. The mean age at
      disease onset was compared with figures from 1975, 1980, 1985, and 1990.
      Incidence rates were compared with those from 1980, 1985, and 1990. RESULTS: A
      total of 710 subjects were entitled to drug reimbursement for chronic
      inflammatory joint disease that had started at the age of 16 or over. The total
      incidence was 65/100,000 (95% confidence interval 60.7-70.4); the figures for
      rheumatoid arthritis (RA), ankylosing spondylitis, psoriatic arthritis, and
      undifferentiated chronic poly/oligoarthritis were 34, 6, 7, and 13/100,000,
      respectively. In RA, the mean age at diagnosis was 59.0 years and was the same in
      rheumatoid factor (RF) positive and RF negative disease. The mean age at
      diagnosis had increased by 8.8 years from 1975 to 1995 (p<0.001). A 14% decline
      was evident in the incidence of RA in 1990 and 1995 compared with the earlier
      years (p = 0.013). In the younger age groups (35-54 years), the incidence
      declined by 50% compared with the year 1980. The incidence of
      spondyloarthropathies remained similar during 1980-95. CONCLUSION: Continuous
      monitoring of sickness insurance data provides information on the epidemiology of
      inflammatory joint diseases that will be useful in assessing demand for and
      supply of health services.

PMID- 10648025
TI  - Recent onset arthritis in the elderly: a 5 year longitudinal observational study.
AB  - OBJECTIVE: To study the spectrum of diagnoses, course, and outcome of recent
      onset arthritis after the age of 60, presenting as rheumatoid arthritis (RA)-like
      disease. METHODS: A 5 year longitudinal observational study enrolled 92
      consecutive patients (median age 73 yrs, 54/38 women/men, median duration of
      arthritis 12 weeks at inclusion). RESULTS: Forty-eight percent were classified as
      having RA according to the 1987 American Rheumatism Association criteria, 52% as
      non-RA (41.4% undifferentiated seronegative polyarthritis, 10.8% oligoarthritis
      with polymyalgic symptoms). Symmetrical involvement of small and medium size
      joints was more predominant in the RA (91 and 84%, respectively) than the non-RA
      patients (58 and 52%). The patients with RA compared to non-RA had more active
      and serious disease at onset, reflected by significant differences in number of
      swollen joints (median values 18 and 9, respectively), duration of morning
      stiffness (75 and 10 min), physician's global assessment of disease activity (45
      and 28 mm on visual analog scale), and Health Assessment Questionnaire (HAQ)
      score for functional disability (1.8 and 1.0). Improvement during the course was
      observed in disease process variables as well as in HAQ disability score for both
      RA and non-RA patients. Risk factors for a poor 5 year functional outcome were
      female sex (OR 4.24), diagnosis of RA (OR 3.28), and baseline HAQ score > or =1.4
      (OR 3.52). The median change in radiological progression (Larsen-Dale index) was
      zero. Twenty patients died during followup, the majority from cardiovascular
      diseases, infections, and malignancies. Mortality compared to the age and sex
      matched general population was increased for rheumatoid factor (RF) positive
      patients (standardized mortality ratio 272). Mortality risk factors within the
      patient cohort were male sex (OR 4.35), age (OR 1.17), and having RF+ RA (OR
      11.93). CONCLUSION: Arthritis in the elderly is a heterogeneous group of
      arthritides with an overall favorable functional prognosis. The subgroup of women
      with elderly onset RA with functional disability at onset is at risk for a less
      favorable functional outcome. Mortality was increased for the patients with RF+
      elderly onset RA only.

PMID- 10648026
TI  - Autoantibodies specific for alpha-enolase in systemic autoimmune disorders.
AB  - OBJECTIVE: To analyze the presence and specificity of anti-alpha-enolase
      antibodies in various systemic autoimmune diseases. METHODS: Sera from patients
      with systemic lupus erythematosus (SLE), mixed cryoglobulinemia (MC), systemic
      sclerosis (SSc), and rheumatoid arthritis (RA) were tested by immunoblot on
      partially purified a-enolase from human kidney and on beta- and gamma-enolase.
      The isotype of anti-enolase antibodies was determined by means of isotype
      specific monoclonal antibodies. RESULTS: IgG anti-alpha-enolase antibodies were
      detected in 9/33 (27%) SLE sera (6/9 patients had active renal disease), in 6/19
      sera from patients with MC and nephritis, in 0/15 sera from MC patients without
      renal involvement, in 6/20 (30%) SSc sera, in 2/35 (6%) disease controls with RA,
      and in 2/32 (6%) healthy controls. The antibodies were not species-specific, but
      in most cases were specific for the alpha isoform of enolase. The anti-enolase
      immune response was not isotypically restricted. In half of the patients with SLE
      the anti-alpha-enolase and anti-DNA antibodies constituted distinct antibody
      populations, while in the other half a partial overlap of the 2 antibody
      specificities was observed. CONCLUSION: Anti-alpha-enolase antibodies can
      frequently be detected in systemic autoimmune disorders. In SLE and MC they are
      associated with nephritis and in SSc they are associated with severe endothelial
      damage. Alpha-enolase is ubiquitous, but is highly expressed in the kidney and
      also on the membrane of several cell types including endothelial cells. Thus,
      anti-alpha-enolase antibodies could contribute to renal injury not only by the
      local formation of immune complexes, but also by direct damage to endothelial
      cells.

PMID- 10648027
TI  - Increased expression of c-rel, from the NF-kappaB/Rel family, in T cells from
      patients with systemic lupus erythematosus.
AB  - OBJECTIVE: To explore the role of the NF-kappaB/Rel transcription factor family
      in autoimmunity, we investigated whether peripheral blood mononuclear cells
      (PBMC) and T cells from the blood of patients with systemic lupus erythematosus
      (SLE) exhibit abnormal expression of c-rel, both when recently isolated and/or
      during in vitro activation. METHODS: Total RNA and protein extracts were prepared
      from PBMC and T cells isolated by immunoadsorption with magnetic beads. The
      relative concentrations of c-rel mRNA and of c-Rel protein were determined by
      semiquantitative assays of competitive reverse transcriptase-polymerase chain
      reaction and chemiluminescent immunoblots, respectively. Activity of NF
      kappaB/Rel was studied by electrophoretic mobility shift assay of nuclear
      extracts. RESULTS: Significantly increased levels of c-rel mRNA were found (1) in
      PBMC from SLE patients (n = 48; p<0.0000001), even during inactive disease (n =
      11; p<0.001), compared to controls (n = 54), and (2) in T cells isolated from a
      subgroup of these patients (n = 11; p<0.00002) and controls (n = 12). c-Rel
      protein was found increased in the cytosol but not in the nucleus of PBMC of
      patients with SLE (n = 12; p<0.02) compared to controls (n = 12). No evidence of
      NF-kappaB/Rel nuclear activity was detected. In vitro stimulation of T cells by
      incubating PBMC with concanavalin A showed that less c-Rel entered the nucleus in
      lupus cells than healthy cells, correlating with lower interleukin 2 production.
      However, the same stimulating conditions provoked an increase in c-rel mRNA to
      higher levels in lupus cells from 2 patients compared with 2 controls. Increased
      levels of both IkappaB alpha and IkappaB beta could account for c-Rel cytosolic
      retention. CONCLUSION: Our data suggest that T cells from patients with SLE
      possess altered regulatory mechanisms of c-rel expression and nuclear import that
      might potentially determine conditions for developing autoimmunity. Other cells
      present in the PBMC could also be affected.

PMID- 10648028
TI  - Anti-calreticulin segregates anti-Ro sera in systemic lupus erythematosus: anti
      calreticulin is present in sera with anti-Ro alone but not in anti-Ro sera with
      anti-La or anti-ribonucleoprotein.
AB  - OBJECTIVE: To examine a well characterized group of patients with systemic lupus
      erythematosus (SLE) for anti-calreticulin. METHODS: The sera of 77 patients with
      SLE were studied by immunodiffusion, solid phase immunoassay, and immunoblot for
      antibodies against ribonucleoprotein (RNP) autoantigens and calreticulin.
      RESULTS: Thirty-five had anti-calreticulin and 40 had anti-60 kDa Ro. There was
      no association of anti-60 kDa Ro and anti-calreticulin. However, among anti-60
      kDa Ro positive sera that also contained either anti-La or anti-RNP, none of 18
      had anti-calreticulin. All the remaining sera with anti-60 kDa Ro had anti
      calreticulin and anti-52 kDa Ro. CONCLUSION: Anti-60 kDa Ro patients with SLE can
      be divided into those with anti-60 kDa Ro and either anti-La or anti-RNP or those
      with anti-60 kDa Ro, anti-52 kDa Ro, and anti-calreticulin.

PMID- 10648029
TI  - Anti-ganglioside antibodies in a large cohort of European patients with systemic
      lupus erythematosus: clinical, serological, and HLA class II gene associations.
      European Concerted Action on the Immunogenetics of SLE.
AB  - OBJECTIVE: To assay anti-ganglioside antibodies (aGM1) in sera of a large cohort
      of European patients with systemic lupus erythematosus (SLE) to define the
      prevalence of these autoantibodies in SLE; to evaluate the association of aGM1
      with clinical manifestations and other autoantibodies found in SLE; and to search
      for aGM1 association with HLA class II alleles. METHODS: Four hundred forty-eight
      patients with SLE were consecutively enrolled in 8 centers from 6 European
      countries. All sera were tested for antinuclear antibodies by immunofluorescence
      on HEp-2 cells as substrate, anti-dsDNA, aGM1, aCL, abeta2-glycoprotein I (abeta2
      GPI) antibodies by ELISA, and antineutrophil cytoplasmic antibodies (ANCA) by
      immunofluorescence and by ELISA. Genomic typing for HLA class II loci was
      performed by polymerase chain reaction-sequence specific oligonucleotide probe
      method. Clinical assessment was done at the time of enrolment. RESULTS: We found
      41.9% of patients with clinical signs of neuropsychiatric involvement; 15.5% of
      patients were positive for aGM1, 8% of the IgG isotype and 8.6% of the IgM
      isotype; aGM1-IgG were associated with neuropsychiatric manifestations (NPM) (RR
      = 3.7), with migraine (RR = 2.4), with OBS (RR = 7.3), and with peripheral
      neuropathy (RR = 8.5). aGM1-IgM were associated with NPM (RR = 4) and with
      depression (RR = 3.4). Furthermore, the genetic study showed that aGM1-IgG were
      associated with HLA-DQB1*0404 (RR = 7.2) while aGM1-IgM were associated with HLA
      DQB1*0605 (RR = 33.3). No associations were found between aGM1 and anti-dsDNA,
      aCL, abeta2GP1, or ANCA. CONCLUSION: Our results show aGM1 can be found in
      patients with SLE. aGM1 may play a pathogenetic role for some NPM in this
      condition.

PMID- 10648030
TI  - Circulating anticentromere CENP-A and CENP-B antibodies in patients with diffuse
      and limited systemic sclerosis, systemic lupus erythematosus, and rheumatoid
      arthritis.
AB  - OBJECTIVE: To determine the disease sensitivity and specificity of testing for
      autoantibodies against 2 of the 3 main human centromere antigenic components,
      CENP-A and CENP-B (recombinant, expressed in baculovirus). METHODS: ELISA with
      CENP-A and CENP-B antigens were used to test 45 sera showing a centromere pattern
      by immunofluorescence (IFA) and sera from 96 patients with systemic sclerosis
      (SSc), subdivided into diffuse (dSSc) and limited (lSSc) forms. For controls, the
      same tests were performed on sera from 100 patients with rheumatoid arthritis
      (RA), 100 with systemic lupus erythematosus (SLE), and 50 random blood donors.
      Sera from all the patients with SSc were also tested for the presence of anti
      Scl70 antibody by ELISA (bovine antigen), and for pattern and titer by IFA (HEp-2
      cells). RESULTS: Of the 45 IFA positive sera, 93% were positive for anti-CENP-A
      and 91% for anti-CENP-B. There was a very good quantitative correlation between
      the antibody levels against these 2 centromere components (r = 0.597; p<0.001).
      Anti-CENP-A and B were found in 48% of patients with lSSc, and in 11% and 9%,
      respectively, of those with dSSc. The difference in the frequency of anti-CENP-A
      between the 2 patient groups was significant (chi-squared, p<0.001). Similar
      levels of anticentromere staining pattern by IFA were observed for these 2
      groups. Anti-Scl70 was elevated in 8% of lSSc and 25% of dSSc patients; this
      difference was also significant (chi-squared, p = 0.02). Neither CENP-A nor CENP
      B reacted with IgG from SSc patients containing anti-Scl70. The frequency of
      abnormal levels in patients with SLE and RA was, respectively, 11% and 3% for
      anti-CENP-A and 4% and 3% for anti-CENP-B. The reaction of IgG from SLE and RA
      patients with CENP-A was not inhibited by histone H3, i.e., it was not due to
      recognition of the histone-like domain in CENP-A. Thus, when 96 SSc patients were
      compared to 200 patients with RA and SLE, the disease specificity of anti-CENP-A
      and B was 93% and 96.5%, respectively. CONCLUSION: In addition to IFA, ELISA
      tests for CENP-A and CENP-B yield results with similar sensitivity and
      specificity for the diagnosis of SSc. CENP-A and CENP-B are primarily associated
      with lSSc. In SSc the autoantibody response is directed simultaneously and with
      similar amplitude against these 2 components of the centromere structure, whereas
      in other autoimmune diseases the response is directed mainly against one of the 2
      components.

PMID- 10648031
TI  - Serum levels of connective tissue growth factor are elevated in patients with
      systemic sclerosis: association with extent of skin sclerosis and severity of
      pulmonary fibrosis.
AB  - OBJECTIVE: To determine the serum levels and clinical correlation of connective
      tissue growth factors (CTGF) in patients with systemic sclerosis (SSc). METHODS:
      Serum samples from patients with limited cutaneous SSc (lSSc, n = 32), diffuse
      cutaneous SSc (dSSc, n = 28), systemic lupus erythematosus (SLE, n = 30),
      polymyositis/dermatomyositis (PM/DM, n = 20), and healthy control subjects (n =
      30) were examined by ELISA for detection of CTGF. RESULTS: Serum CTGF levels in
      patients with SSc were significantly higher than those in patients with SLE or
      PM/DM, and in controls. CTGF levels in patients with dSSc were significantly
      higher than those in patients with lSSc. As for clinical correlation of CTGF, SSc
      patients with elevated CTGF had pulmonary fibrosis, decreased DLCO, and decreased
      vital capacity more frequently than those with normal CTGF levels. Further, DLCO
      and vital capacity were inversely and directly correlated with serum CTGF levels
      in patients with SSc. The dSSc patients with disease duration of 1-3 years had
      significantly elevated levels of CTGF compared with dSSc patients with duration <
      1 year or more than 3 years. CONCLUSION: Serum CTGF levels were increased in
      patients with SSc, and correlated with the extent of skin sclerosis and the
      severity of pulmonary fibrosis. In addition, it appears that production of CTGF
      is involved in the development or maintenance of fibrosis rather than in
      initiation of fibrosis in SSc. These data suggest that CTGF plays a critical role
      in the development of fibrosis in SSc.

PMID- 10648032
TI  - Nailfold videocapillaroscopy assessment of microvascular damage in systemic
      sclerosis.
AB  - OBJECTIVE: To correlate microvascular abnormalities, evaluated by nailfold
      videocapillaroscopy (NVC), with the duration of both Raynaud's phenomenon (RP)
      and systemic sclerosis (SSc) from the date of diagnosis, in a large number of
      patients with SSc. METHODS: Ninety-seven consecutive patients were recruited and
      distributed into 3 groups on the basis of the morphological NVC patterns
      observed: "early" (E), "active" (A), and "late" (L). In each group the age of
      patients, age at onset, and the duration of RP as well as of overt SSc were
      investigated and correlated with the different NVC pattern variables. RESULTS:
      The early appearance of giant capillaries and hemorrhages (E pattern) is of great
      relevance for the early diagnosis of SSc. Therefore, these alterations are more
      evident in the active phase of the disease (A pattern). Conversely, the NVC
      observation of loss of capillaries and vascular architectural disorganization and
      the presence of ramified/bushy capillaries (L pattern) represents the clearest
      aspect of advanced SSc microvascular damage. These morphological alterations were
      found to correlate significantly with the duration of both RP and SSc, as well as
      with age of patients (p = 0.0001). No significant differences were observed when
      the variables were analyzed in the patients classified as having limited
      cutaneous SSc or diffuse cutaneous SSc. CONCLUSION: Classification of defined
      major nailfold patterns may be useful in assessing the appearance and progression
      of sclerodermic microangiopathy. As well, nailfold changes might represent a
      morphological reproduction of the evolution of SSc.

PMID- 10648033
TI  - Antiendothelial cell antibodies in inflammatory myopathies: distribution among
      clinical and serologic groups and association with interstitial lung disease.
AB  - OBJECTIVE: To determine the prevalence and associations of antiendothelial cell
      antibodies (AECA) in a well characterized cohort of patients with idiopathic
      inflammatory myopathies (IIM). METHODS: Clinical characteristics, AECA, and
      myositis-specific autoantibodies were assessed by standard methods in 56 subjects
      with IIM. RESULTS: AECA were found in 20/56 patients with IIM, were seen in all
      the major clinical and serologic IIM groups, and were found in 10/15 patients
      with interstitial lung disease (ILD) (chi squared 6.5, p<0.01 with Yates'
      correction, relative risk 2.7, specificity 86% and sensitivity 50%).
      Antisynthetase antibodies, also associated with ILD as described (chi squared =
      26.5, p<0.001 with Yates' correction, relative risk 8.7, specificity 95%,
      sensitivity 77%), did not correlate with the presence of AECA. CONCLUSION: AECA
      appear to be present in all forms of IIM and are markers for ILD that are
      independent of anti-synthetase autoantibodies. AECA may be a useful serologic
      marker for ILD in IIM.

PMID- 10648034
TI  - Anxiety and depression in patients with primary Sjogren's syndrome.
AB  - OBJECTIVE: To examine the degree of anxiety and depression and to assess well
      being and general symptoms in patients with primary Sjogren's syndrome (SS).
      METHODS: A standardized questionnaire, the Hospital Anxiety and Depression Scale,
      was used to examine the degree of anxiety and depression in patients with primary
      SS (n = 62) and in age matched healthy female controls. The Gothenburg quality of
      life instrument (GQOL) was used to assess well being and general symptoms.
      Patients with rheumatoid arthritis (RA; n = 38) were used as patient controls.
      RESULTS: The patients with primary SS had significantly higher scoring rate for
      "possible" clinical anxiety (48%) and for "possible" clinical depression (32%)
      compared with reference groups (p<0.05). The physical and mental well being of
      the patients with primary SS were significantly reduced compared with controls.
      Furthermore, patients with primary SS complained more commonly of low mood,
      irritability, headache, gastrointestinal symptoms, and impaired concentration and
      memory than the patients with RA. CONCLUSION: The results indicate that patients
      with primary SS often have psychiatric symptoms and worse well being, which may
      affect their quality of life.

PMID- 10648035
TI  - Spondyloarthropathy in the community: differences in severity and disease
      expression in Alaskan Eskimo men and women.
AB  - OBJECTIVES: To determine the relative severity and compare the clinical
      expression of spondyloarthropathy (SpA) in men and women. METHODS: A clinical
      study was conducted in 43 women and 40 men who made up 80% of all individuals
      identified as having SpA in a community-wide epidemiologic study of Alaskan
      Eskimos. The study included interviews, physical, laboratory, radiographic and
      electrocardiographic examinations, record reviews, and functional assessments. A
      measure of relative severity was developed to evaluate disease impact in
      individual patients. The results in men and women were compared. RESULTS: No
      significant differences between men and women were found in many features,
      including the age of onset, frequency of inflammatory joint swelling or
      inflammatory back pain, physical signs of sacroiliitis, presence of skin changes,
      or positive family history of SpA. Women were less likely to have sacroiliac
      joint fusion, advanced spinal changes, uveitis, severe cardiac conduction and
      valvular abnormalities, and elevated erythrocyte sedimentation rates. According
      to our relative severity measure, a smaller proportion of women had severe
      disease than men. CONCLUSION: Although as many women as men were affected by SpA
      in the communities studied, severe disease was seen more often in men and a
      number of disease manifestations were more frequent or more marked in men. These
      discrepancies in disease severity and expression may contribute to the
      underdiagnosis of SpA in women and the long standing impression that SpA is a
      disease predominantly of men.

PMID- 10648036
TI  - Ankylosing spondylitis and the shoulder: commonly involved but infrequently
      disabling.
AB  - OBJECTIVE: To undertake 2 independent studies of shoulder involvement in patients
      with ankylosing spondylitis (AS) and assess the frequency of shoulder pain,
      stiffness, and loss of movement and function. To evaluate and correlate shoulder
      symptoms, function, range of movement, and radiology. METHODS: A cross sectional
      design was used in both studies. In Study A, a self-administered questionnaire
      was sent to members of the National Ankylosing Spondylitis Society of the UK and
      patients attending the Royal National Hospital for Rheumatic Diseases. In Study
      B, a clinical assessment of 88 patients with AS was undertaken that included a
      radiological assessment of 26 consecutive patients. RESULTS: In Study A, 15.2%
      and 13.8% of subjects had severe/very severe shoulder pain or stiffness,
      respectively. In Study B the corresponding findings were 9.6% and 17.6%. Patient
      reported disability associated with shoulder involvement was uncommon. Study A
      revealed that patients with severe/very severe shoulder pain were more likely to
      have significant hip and knee involvement. Significant shoulder involvement
      appears to be as common as involvement of the hip joint. In Study B radiological
      changes were common, being present in 31% of patients, but were often minor.
      There was a significant correlation between the sum of the stiffness, abduction,
      and flexion scores for both shoulders and the total radiological score (r = 0.87;
      p<0.001). CONCLUSION: The results suggest that shoulder symptoms and loss of
      shoulder mobility are common in patients with AS, and correlate with higher pain
      scores and influence of AS on their lives as assessed by the Arthritis Impact
      Measurement Scale, but are rarely disabling. Involvement of the shoulder joint in
      AS correlates with involvement of other peripheral joints as well as the extent
      of radiographic change on shoulder radiographs.

PMID- 10648037
TI  - LMP2 polymorphism is associated with extraspinal disease in HLA-B27 negative
      Caucasian and Mexican Mestizo patients with ankylosing spondylitis.
AB  - OBJECTIVE: To determine the effects of HLA Class II genes, particularly LMP2 and
      previously implicated Class I genes, on susceptibility and disease expression in
      HLA-B27 negative ankylosing spondylitis (AS). METHODS: Patients included 41 HLA
      B27 negative Caucasians from a total AS population of 546 and 17 HLA-B27 negative
      Mexican Mestizo. Controls included 4352 random HLA-B27 negative Caucasians. LMP2
      genotype assignments were made on all patients and 282 random Caucasian controls
      by polymerase chain reaction-restriction fragment length polymorphism with the
      Cfo I restriction enzyme while HLA typing was performed on patients and controls
      using microcytotoxicity assays for Class I, and sequence specific probe-PCR for
      HLA-B60, B39, B38, and DR. RESULTS: The LMP2BB genotype was significantly
      decreased in Caucasian AS patients without extraspinal (ES) disease (25%)
      compared to AS patients with ES (64.7%) (p = 0.01) and random Caucasian controls
      (53.9%) (p = 0.007), even when those with colitis and psoriasis were excluded
      from analysis (ES+ 55.6% versus ES- 22.2%). This finding remained significant
      after stratification by HLA-DR. Similar trends were noted in the Mexican
      population. A potential role for HLA-DR8 and DR2 in susceptibility to disease was
      observed in Caucasian patients, although this observation requires confirmation.
      We could not confirm reported associations with HLA-B60 or B39. Peripheral
      arthritis was significantly more commonly observed in those who had had acute
      anterior uveitis (AAU) (75%) than in those who had not developed AAU (27.3%) (p =
      0.04). CONCLUSION: HLA Class II encoded genes may have effects on disease
      susceptibility and/or phenotype in HLA-B27 negative individuals similar to those
      noted in HLA-B27 positive AS. Eccentric and axial phenotypes of disease may be
      immunogenetically determined.

PMID- 10648038
TI  - FK506 attenuates developing and established joint inflammation and suppresses
      interleukin 6 and nitric oxide expression in bacterial cell wall induced
      polyarthritis.
AB  - OBJECTIVE: To determine the efficacy of therapeutic administration of FK506
      (Tacrolimus) in suppressing developing and established joint inflammation,
      proinflammatory cytokine expression, and nitric oxide (NO) production in
      peptidoglycan-polysaccharide (PG/PS) induced experimental polyarthritis in rats.
      METHODS: Chronic joint inflammation was induced by intraperitoneal injection of
      PG/PS, and joint inflammation was quantified using arthritis index and paw
      volume. Serum and joint levels of interleukin 6 (IL-6) were measured by bioassay
      and Western blot analysis respectively, and serum levels of NO production were
      determined by the Griess procedure and the expression of the inducible isoform of
      nitric oxide synthase (i-NOS) in the joints was determined by Western blot
      analysis. RESULTS: Arthritis induced by PG/PS is biphasic, progressing through an
      initial acute phase and a remission phase, which is followed by a persistent
      chronic phase. Daily administration of FK506 initiated during the remission phase
      significantly attenuated the onset and development of chronic joint inflammation.
      We observed a significant reduction in joint inflammation and swelling, an
      apparent suppression of pannus development, and minimal erosive damage to the
      articular cartilage and subchondral bone. Fully established chronic joint
      inflammation was also ameliorated by daily administration of FK506. Joint
      swelling and inflammation was significantly reduced by 5 days post-treatment with
      FK506 and the erosive activity associated with the pannus appeared diminished.
      The elevated expression of IL-6 and NO characteristic of chronic joint
      inflammation in the serum and in joint tissue was significantly reduced by FK506
      treatment. CONCLUSION: Therapeutic administration of FK506 has a profound
      antiinflammatory effect on the development of the chronic, erosive arthritis
      induced by PG/PS. This attenuation in joint inflammation was associated with
      suppression of IL-6 and NO production systemically and locally in the joints. Our
      data suggest that FK506 may be effective in the treatment of chronic joint
      inflammation associated with rheumatoid arthritis.

PMID- 10648039
TI  - Improving the selective use of plain radiographs in the initial evaluation of
      shoulder pain.
AB  - OBJECTIVE: In a previous retrospective study, we had found that shoulder
      radiographs were overused in the initial evaluation of patients presenting to the
      emergency department with shoulder pain. Our objective was to prospectively
      define clinical criteria that identify patients who have a low risk of
      radiographic findings that influence the management of the initial evaluation of
      shoulder pain in the emergency department. METHODS: All adult patients presenting
      to the emergency department of a university teaching hospital with shoulder pain
      were eligible to participate. Patients with deformities, penetrating wounds,
      referred pain, and those presenting for followup were excluded. Data were
      recorded prospectively using a standardized form. All radiographs were classified
      as therapeutically uninformative (TU) except fracture, acromioclavicular joint
      separation (> or =Grade 3), infection, or malignancy. A classification tree was
      used for analysis. RESULTS: Two hundred six patients had shoulder radiographs, of
      which 88% were TU. The model yielded 3 sets of low risk patients with a high
      percentage of TU radiographs: (1) no fall, no swelling (99% TU: 106 TU, 1
      radiograph with lytic lesions in a cancer patient); (2) a fall, but no swelling,
      and no pain at rest (100% TU, n = 18); (3) a fall and pain at rest, but no
      swelling and normal range of motion (100% TU, n = 10). Not performing radiographs
      on these low risk patients would have decreased radiograph utilization from 52 to
      18% of all shoulder patients seen. CONCLUSION: Our findings suggest that specific
      clinical criteria are able to identify patients who do not need radiographs as
      part of the initial management of shoulder pain. Prospective validation of these
      criteria are needed to confirm that these low risk patients can be safely
      evaluated without radiographs.

PMID- 10648040
TI  - A metaanalysis of chondroitin sulfate in the treatment of osteoarthritis.
AB  - OBJECTIVE: To examine the efficacy of chondroitin sulfate (CS) in the treatment
      of osteoarthritis (OA) on the basis of a metaanalysis of controlled clinical
      trials. METHODS: After personal, Medline, and Embase searches, a decision tree
      analysis of the available publications was performed, with respect to types of
      joint involvement studied, study designs, numbers of patients enrolled, and
      variables analyzed. The Lequesne index and pain rating on visual analog scale
      (VAS) were considered the main variables. Of a total of 16 publications found, 7
      trials of 372 patients taking CS could be enrolled into the metaanalysis.
      Although all selected studies claimed to be randomized, double blind designs in
      parallel groups, it should be noted that CS was given along with analgesics or
      nonsteroidal antiiflammatory drugs, making required dosage of comedication an
      important factor. RESULTS: Following patients to 120 or more days, CS was shown
      to be significantly superior to placebo with respect to the Lequesne index and
      pain VAS. Pooled data confirmed these results and showed at least 50% improvement
      in the study variables in the CS group compared to placebo. CONCLUSION: CS may be
      useful in OA, but further investigations in larger cohorts of patients for longer
      time periods are needed to prove its usefulness as a symptom modifying drug in
      OA.

PMID- 10648041
TI  - Evaluation of the relationship between depression and fibromyalgia syndrome: why
      aren't all patients depressed?
AB  - OBJECTIVE: To examine the relationship between fibromyalgia syndrome (FM) and
      depression by determining the set of factors that differentiate FM patients with
      and without depressive disorders. METHODS: A sample of 69 patients with FM
      underwent a standardized tender point examination and a semistructured
      psychological interview and completed a set of self-report inventories. RESULTS:
      Of the sample, 39 met criteria for depressive disorder and 30 did not. Depressed
      patients with FM were significantly more likely to live alone, report elevated
      functional limitations, and display maladaptive thoughts than nondepressed
      patients. Nondepressed patients were significantly more likely to have received
      prior physical therapy than depressed patients. Pain severity, numbers of
      positive tender points, and pain intensity of tender points and control points
      did not differentiate the depressed and nondepressed patients. Discriminant
      analysis revealed that living status, the perception of functional limitations,
      maladaptive thoughts, and physical therapy treatment together identified
      diagnoses of depressive disorders for 78% of the patients. CONCLUSION: Concurrent
      depressive disorders are prevalent in FM and may be independent of the cardinal
      features of FM, namely, pain severity and hypersensitivity to pressure pain, but
      are related to the cognitive appraisals of the effects of symptoms on daily life
      and functional activities.

PMID- 10648043
TI  - Distinction of quality of life, health related quality of life, and health status
      in children referred for rheumatologic care.
AB  - OBJECTIVE: Current health status measures [sometimes called quality of life (QOL)
      measures] are based on the values of their designers. QOL, though, reflects the
      idiosyncratic values of each individual. We investigated whether children
      referred for rheumatologic care differentiate between the concepts of health
      related quality of life (HRQOL), overall QOL, and health status. METHODS: One
      hundred twenty-two consecutive children seen at a pediatric rheumatology referral
      clinic completed a new global self-report quality of life scale (Quality of My
      Life), a functional impairment scale (Childhood Health Assessment Questionnaire),
      and a disease severity visual analog scale. Sixty children were seen for a
      followup assessment. RESULTS: HRQOL was somewhat lower than overall QOL (median
      6.6 vs 8.6 out of 10; respectively) in this sample of patients. Our subjects did
      differentiate between overall QOL and HRQOL and health status. Health status, as
      measured by disease severity, accounted for only a moderate amount of variability
      in HRQOL (R2 = 0.25, p< or =0.0001). Health status measured by functional
      disability accounted for even less of the variability in HRQOL (R2 = 0.047, p =
      0.013). Similarly, HRQOL accounted for only a moderate amount of the variability
      seen in overall QOL (R2 = 0.31, p< or =0.0001). CONCLUSION: The goal of most
      health professionals is to improve their patients' overall QOL. QOL, though,
      appears to be a broad and idiosyncratic construct affected only moderately by
      health. Health status, global HRQOL, and overall QOL all provide independent
      information. All 3 measures should be considered for use in research studies.
      HRQOL and overall QOL reflect patients' own values, and therefore may offer
      important information for clinicians in addition to health status.

PMID- 10648042
TI  - Prevalence of back symptoms in elders.
AB  - OBJECTIVE: The prevalence of back pain has not been well studied in elders in the
      US. We describe the prevalence of back symptoms in a cohort of elderly subjects
      residing in the US by age, sex, examination site, and location of pain. METHODS:
      Data from this study are based on 1037 surviving members of the original
      Framingham Heart Study cohort aged 68-100 years who participated in the 22nd
      biennial examination in 1992-93. Subjects were questioned about back pain and
      timing and location of pain. RESULTS: Prevalence estimates varied, depending on
      the question used to assess back symptoms and the manner in which the question
      was asked. For example, back symptoms on most days occurred in 22.3 of 100
      elders. Low back symptoms were more prevalent than those in the mid or upper
      back. Prevalence was higher among women than men, especially for symptoms in the
      mid or upper back area. Age did not affect the prevalence of back symptoms in
      this elderly cohort. Back symptoms were also more prevalent among subjects who
      were examined in their residence than among those who were examined at the
      examination site. Most subjects who were examined at their residence chose this
      location for health reasons. CONCLUSION: Back symptoms are highly prevalent in
      the elderly, although, among elders, they do not increase in prevalence with age.
      They are more common in women than men. Elders confined mostly to their homes
      have an especially high prevalence of back symptoms.

PMID- 10648044
TI  - A 92-year-old man with systemic lupus erythematosus who developed acute lupus
      pneumonitis.
AB  - We describe a 92-year-old male patient with systemic lupus erythematosus (SLE)
      who had sudden onset of thrombocytopenia and developed acute lupus pneumonitis
      (ALP). Although steroid pulse therapy was effective for ALP, he developed
      complicated bacterial pulmonary disease. This patient is the oldest ever reported
      to have contracted SLE.

PMID- 10648045
TI  - Catastrophic antiphospholipid syndrome: clinical description and triggering
      factors in 8 patients.
AB  - In 1992, an attempt to single out a different and important group of patients was
      adopted by introducing the term "catastrophic" antiphospholipid syndrome (APS) to
      describe their potentially life threatening clinical course, characterized by
      acute multiorgan failure (3 or more organ systems damaged). Patients previously
      described in the literature showed certain differences that appear to distinguish
      this minority group of patients with catastrophic APS from the majority of APS
      patients. We describe 8 patients with catastrophic APS, focusing especially on
      the possible extrinsic factors (mainly infections) that might trigger this
      "catastrophic" situation.

PMID- 10648046
TI  - Imaging characteristics in a case of diffuse cystic angiomatosis.

PMID- 10648047
TI  - Multifocal dactylitis as the sole clinical expression of sarcoidosis.

PMID- 10648048
TI  - Heterogeneity in rheumatoid arthritis radiographic trials. Issues to consider in
      a metaanalysis: an OMERACT Imaging Task Force Workshop, San Diego, California,
      USA. November 7, 1998.

PMID- 10648049
TI  - Principles of metaanalysis.
AB  - Metaanalysis is a relatively new tool to help make evidence based decisions. This
      technique involves the systematic examination of available evidence on a given
      clinical topic, and the summary of that evidence using statistical techniques
      that pool data from multiple studies to yield a single result. We briefly discuss
      the principal steps in a metaanalysis: identifying all the studies; assessing the
      studies for quality; organizing the studies into subgroups; and summarizing the
      results.

PMID- 10648050
TI  - An overview of radiographic analysis of joint damage in rheumatoid arthritis and
      its use in metaanalysis.
AB  - A brief history of the development of scoring methods to represent the extent of
      radiographic abnormalities in rheumatoid arthritis shows that grading systems
      have become more detailed with time. Taken together with the observation that
      physicians continue to modify scoring methods it is clear that we have not yet
      arrived at the ideal method. Issues to be considered in evaluating scoring
      methods include which abnormalities and which joints to score and what scale to
      use. Data from one early trial indicate that erosion and joint space narrowing
      scores do not progress in lockstep and progression in one does not predict
      progression in the other; this leads to the conclusion that including both
      features in a scoring method is important. Data from the same trial raise the
      possibility that joint space narrowing scores for the proximal interphalangeal
      finger joints may not be helpful in detecting treatment differences, illustrating
      that further investigation of which joints to include in scoring is needed. The
      possibility that an expanded scoring scale might be more sensitive to recording a
      change in radiographic damage also was raised. A simple method of determining
      which patients show progression of damage was proposed based on assessing the
      distribution of negative progression scores (baseline erosion scores subtracted
      from followup scores adjusted for time). It was pointed out that radiographic
      assessment has established that a few drugs slow the progression of joint damage.
      Radiographic evaluation of disease progression should continue to be utilized as
      an outcome measure in evaluating new therapies.

PMID- 10648051
TI  - How to read radiographs according to the Sharp/van der Heijde method.
AB  - This article is a short overview of the development of the Sharp/van der Heijde
      methods for scoring radiographs of hands and feet in rheumatoid arthritis, in
      addition to a detailed description on how to use the scoring method.

PMID- 10648052
TI  - Using the Larsen index to assess radiographic progression in rheumatoid
      arthritis.
AB  - To describe the Larsen index and its strengths and weaknesses. I reviewed the
      original publication, a number of published modifications, tests of
      reproducibility, and some clinical studies that have used the index. The Larsen
      index is essentially a grading of erosion severity that has satisfactory
      reproducibility for use in groups of patients. The Larsen index can clearly
      distinguish different rates of erosive progression in groups of patients with
      different characteristics or treatments. Recent studies using the Larsen index
      have identified clear treatment effects. Difficulty in measuring the success of
      previous treatments designed to hold back the progression of erosions relates to
      the inefficacy of those treatments, not insensitivity of the Larsen index.

PMID- 10648053
TI  - Pooled metaanalysis of radiographic progression: comparison of Sharp and Larsen
      methods.
AB  - Metaanalysis refers to the statistical analysis of results from individual
      studies for the purpose of integrating the findings. However, numerous biases can
      threaten the internal validity of metaanalyses. This paper specifically addresses
      the issue of study heterogeneity in metaanalyses of radiographic progression. It
      considers the validity of pooling studies that have used either the Sharp score
      (or its variants) or the Larsen score (or its variants) by examining whether the
      2 scoring methods are sufficiently concordant for pooling in terms of content of
      items, scaling and measurement properties. Despite differences between the Sharp
      and Larsen methods, they essentially measure the construct of radiographic
      damage, and as long as the spectrum of radiographic damage in the pooled series
      is similar, then the scoring methods are robust to pooling. However, where the
      spectrum of damage is not similar, for example, studies of radiographic
      progression of early disease compared with late disease, pooling should be
      exercised with caution.

PMID- 10648054
TI  - Safety of self-injection of gold and methotrexate.

PMID- 10648055
TI  - Environmental factors in myositis.

PMID- 10648056
TI  - Large coronary aneurysms in a child with suspected Behcet's disease.

PMID- 10648057
TI  - Adult onset Still's disease [corrected].

PMID- 10648058
TI  - Adult onset Still's disease in Catalonia, Spain.

PMID- 10648059
TI  - Phalangeal metastases indicating relapse of non-Hodgkin's lymphoma.

PMID- 10648060
TI  - Cryptococcal tenosynovitis in the setting of disseminated cryptococcosis.

PMID- 10648061
TI  - Embryonic and postnatal accumulation of homogeneous substance in the
      endolymphatic sac in the guinea pig.
AB  - OBJECTIVE: The endolymphatic sac (ES) of vertebrates contains varying amounts of
      a homogeneous substance (HS) that stains deeply with basic aniline dyes.
      Histochemically, HS is characterized as a carbohydrate-protein complex, being
      both neutral and acidic in nature. In the present study, deposition of HS in the
      ES was studied in the guinea pig from the 3rd week of gestation to 104 weeks
      postnatally in order to find out if HS accumulates with age, at which point
      during embryonic development this substance appears, if its presence is
      correlated to the sense of hearing and if the amount of substance in the left
      versus right ear of one and the same animal is correlated to any degree. METHODS:
      Sixty-nine endolymphatic sacs were evaluated in 38 guinea pigs. The ES specimens
      were sectioned for light and transmission electron microscopy and the amount of
      HS filling was categorized in four groups: none, low, medium and a high level of
      substance. RESULTS: The substance was not discerned until after 7 weeks of
      gestation, when it filled only a minor part of the distal ES lumen. At 9 weeks
      gestation the nature of the substance altered, becoming homogeneous, as
      visualized by osmium-toluidine blue staining and approximately filling the distal
      half of the luminal space. In the postnatal period, 65% of ES specimens were
      filled with HS to the intermediate or proximal ES, whereas only 6.5% of the ES
      specimens were devoid of the substance. The extent of filling of the ES in the
      prenatal temporal bones was significantly less than postnatally (P < 0.0001, chi2
      test). The extent of postnatal filling was not correlated with age. Left and
      right ears were closely correlated in one and the same animal. Phagocytic cells
      were often found at the border between clear endolymph and stainable substance.
      CONCLUSION: The appearance of HS seemed to coincide temporally with the onset of
      hearing during the prenatal period indicating that it could play a part in normal
      inner ear functioning in the guinea pig. The close correlation regarding the
      level of the HS in the left and right ear, both pre- and postnatally could
      reflect a general symmetry in endolymph pressure-volume conditions within the
      inner ear fluid systems, as well as in the environmental hydrostatic pressure in
      the posterior cranial fossa.

PMID- 10648062
TI  - The long-term outcome of hearing preservation following vestibular schwannoma
      surgery.
AB  - OBJECTIVE: The aim of this study is to describe the long-term outcome of
      preserved hearing after vestibular schwannoma surgery. METHODS: Subjects are 20
      unilateral vestibular schwannoma patients whose class A hearing of the AAO-HNS
      classification was preserved successfully after tumor removal. Hearing
      preservation surgery was attempted via the middle cranial fossa (MCF) or the
      extended MCF approach. The follow-up periods ranged from 2 to 16 years. The
      outcome measures included the pure tone average (PTA) and speech discrimination
      score (SDS). RESULTS: PTA was maintained in less than 30 dB in 11 out of 20
      patients within 2 years follow-up, six out of 13 patients within 4 years follow
      up, and two out of five patients within 6 years follow-up, respectively. SDS was
      maintained in more than 70% in 17 out of 20 patients within 2 years follow-up,
      ten out of 13 patients within 4 years follow-up, and three out of five patients
      within 6 years follow-up, respectively. CONCLUSIONS: The preserved hearing
      maintained about more than 40% of the patients with the class A hearing in every
      2 years follow-up. From this result, we can conclude that the hearing
      preservation surgery could be one of the best treatments for vestibular
      schwannoma patients with class A hearing. However, further study will be needed
      to clarify the mechanism of the deterioration in hearing after hearing
      preservation surgery.

PMID- 10648063
TI  - Optical recording of membrane potential in dissociated mouse vestibular ganglion
      cells using a voltage-sensitive dye.
AB  - We investigated membrane electrophysiological features of dissociated vestibular
      ganglion neurons, using a voltage-sensitive dye and a multiple site optical
      imaging system. The neuronal nature of the cultured vestibular ganglion cells was
      confirmed by positive staining with the anti-neurofilament 200 kDa antibody,
      using immunocytochemical methods. Optical absorption of the dye which binds to
      the external surface of neuron membranes increased while the cells were
      depolarized during perfusion with 150 mM potassium solution. The relative ratio
      (deltaI/I) of optical absorption change was 0.23 +/- 0.08% (means +/- S.D., n =
      16). These optical responses were wavelength dependent, therefore, the optical
      response apparently originated from the voltage-sensitive dye. Under our
      experimental conditions, photodynamic damage and pharmacological effects of the
      dye were either absent or insignificant. We therefore concluded that optical
      recording is a new, practical and non-invasive method to simultaneously monitor
      changes in membrane potential from cultured vestibular ganglion cells. Optical
      recording is expected to provide further insight into mechanisms of information
      processing by vestibular ganglion neurons.

PMID- 10648064
TI  - Decreased vestibulo-ocular reflex gain of vestibular schwannoma patients.
AB  - OBJECTIVE: The vestibulo-ocular reflex (VOR) stabilizes gaze during head
      movements by producing compensatory eye movements. Gain of the VOR can be defined
      as the difference between the eye and corresponding head movement amplitudes. The
      objective of the study was to compare the gain of postoperative vestibular
      schwannoma (VS) patients with that of healthy controls. METHODS: The gain of 19
      vestibular schwannoma (VS) patients and 100 healthy controls was measured with a
      head autorotation test (HART) in the five frequency bands of 1-5 Hz. It was
      computed as the ratio of the amplitude of the eye position signal to the
      amplitude of the head position signal. The mean gain was compared between the VS
      patients and healthy subjects in each frequency band by using an analysis of
      variance with statistical significance pre-defined as P < 0.05. RESULTS: The HART
      was abnormal in 58% of the VS patients, whose mean gains in the five frequency
      bands of 1-5 Hz were 0.85, 0.79, 0.72, 0.64 and 0.60, respectively. The mean
      gains of the VS patients were significantly (P < 0.05) smaller than those of the
      controls in all the frequency bands. CONCLUSIONS: The deficit of the VOR gain
      seems to prevail in more than a half of postoperative VS patients, although this
      inaccuracy of compensatory eye movements may not lead to the occurrence of any
      symptoms. However, in these patients a potential threat to gaze stability exists.

PMID- 10648065
TI  - A clinical study on temporomandibular joint ankylosis.
AB  - OBJECTIVE: Temporomandibular joint (TMJ) ankylosis results from trauma, infection
      and inadequate surgical treatment of the condylary area. Many techniques for
      treatment have been described so far. However, none of them gave uniformly
      successful results. A limited range of intrinsical opening due to relapse, loss
      of vertical height of the affected ramus, foreign body reactions and reankylosis
      are expected complications. However, wide bone resection, the use of
      interpositional spacer, insensitive and aggressive physiotherapy immediately
      after the operation are the basic principles as agreed by many authors. In this
      article, a review of the historical background of the treatment has been
      discussed. METHODS: A clinical and retrospective evaluation of 42 patients
      treated for this disorder showed that 89% of all patients had unilaterally and
      11% had bilateral ankylosis. From the viewpoint of the techniques we used,
      patients fell into three groups. In two groups, two different type of spacers
      were used, and in the third group gap arthroplasty were performed for the
      treatment of TMJ ankylosis. RESULTS: Our results revealed a predominance of
      traumatic aetiology. The highest incidence was between the ages of 11 and 20. A
      total of 45.24% of the patients were treated by interpositional arthroplasty by
      using acrylic spacer, 11.90% of the patients by sylastic sheet used as an
      interpositional material and the rest of the cases (42.86%) were treated only by
      gap arthroplasty. CONCLUSION: The advantages of the spherical acrylic spacer and
      gap arthroplasty were discussed. The advantages of the techniques are, shorter
      operating time, and more importantly its very low cost.

PMID- 10648066
TI  - Bilateral same day surgery for bilateral perforated chronic otitis media.
AB  - OBJECTIVE: Bilateral same day surgery has been performed rarely because of the
      risk of postoperative sensorineural hearing loss following conventional
      myringoplasty or tympanoplasty (CMT). Simple underlay myringoplasty (SUM) through
      the ear canal has been developed by Yuasa R, Saijo S, Tomioka Y, et al. Office
      closure of eardrum perforation with fibrin glue (in Japanese), Otolaryngol Head
      Neck Surg (Tokyo) 1989;61:1117-1122, which has little risk of sensorineural
      hearing loss. We tried bilateral same day surgery using this technique and
      evaluated its outcome. METHODS: Of 86 cases with bilateral perforated chronic
      otitis media that we treated between 1995-1997, 25 cases underwent bilateral same
      day surgery. Bilateral SUMs was performed on seven patients, SUM and CMT on 16
      patients, and bilateral CMTs on two patients. RESULTS: Closure of perforation was
      successful in 18 patients (72%) on both sides and in seven patients (28%) on one
      side. Postoperative air-bone gap of less than 20 dB was achieved in 15 cases
      (60%) on both sides and in 23 cases (92%) on one side. CONCLUSION: Bilateral same
      day surgery for bilateral perforated chronic otitis media is possible if the
      operative indications are considered.

PMID- 10648067
TI  - A guinea pig model of adhesive otitis media and the effect of tympanostomy.
AB  - OBJECTIVE: The pathophysiology and prevention strategies of adhesive otitis media
      were investigated using two animal otitis media models induced by the inoculation
      of a corrosive agent into the tympanic clefts of guinea pigs. METHODS: In the
      first experiment, KANSUI (consisting of potassium carbonate and sodium carbonate)
      solution was injected into the left tympanic cleft of the guinea pigs. Five
      groups of five animals were sacrificed at 2 weeks, and at 1, 3, 6, and 12 months
      after inoculation to observe the pathological changes with time. In the second
      experiment, a similar otitis media model was induced in 18 guinea pigs.
      Tympanostomy was performed at 1 and 2 weeks after induction of the otitis media
      to eliminate inflammatory exudate from the tympanic cleft. Three groups of six
      animals were sacrificed at 1, 3, and 6 months after the tympanostomy to compare
      the differences in pathological changes between the groups with and without
      tympanostomy. RESULTS: In the first experiment, severe mucosal injury to the
      middle ear mucosa was observed at 2 weeks, and at 1 and 3 months after
      inoculation, and the tympanic membrane (TM) had adhered to the promontorium at 3,
      6 and 12 months after inoculation. In the second experiment, TM adhesion
      decreased following the tympanostomy. CONCLUSION: It is suggested that severe
      injury to the middle ear mucosa caused TM adhesion during the process of wound
      healing, and that tympanostomy is effective in preventing adhesive otitis media.

PMID- 10648068
TI  - The attachment structure of the guinea pig tympanic membrane.
AB  - OBJECTIVE: The attachment structure between the tympanic membrane and the
      surrounding structures, the annular ring and the manubrial part, has not been
      described fully. We examined the relationship between the tympanic membrane and
      the tympanic annulus or the handle of the malleus in guinea pigs using light
      microscopy as well as transmission and scanning electron microscopy (SEM).
      METHODS: We used the temporal bone of the guinea pig and examined the
      relationship between the tympanic membrane and the surrounding structures using
      light microscopy and transmission electron microscopy. In the examination of
      scanning electron microscopy, we used the special method such as alkali-water
      maceration/SEM method. RESULTS: The results showed that the radial fibers of the
      tympanic membrane continued directly into the annular ring and the manubrial
      part. The histological structure of the annular ring was amorphous and collagen
      fibers were seen in the amorphous matrix. The manubrial part histologically
      resembled the annular ring. These structures were associated with the cartilage
      structure. Our observations indicated that the collagen fibers of the tympanic
      membrane are a special type of cartilage collagen fibers. CONCLUSION: In
      conclusion, we propose that the surrounding structures of the tympanic membrane
      such as the tympanic annulus and manubrial part play an important role in the
      maintenance and the vibration of the tympanic membrane.

PMID- 10648069
TI  - Immunohistochemical localization of cytokines and cell adhesion molecules in
      maxillary sinus mucosa in chronic sinusitis.
AB  - OBJECTIVE: Chronic sinusitis is a common disease characterized by persistent
      inflammation of the nasal and paranasal sinus mucosa. Accumulating evidence
      supports the importance of proinflammatory cytokines and endothelial cell
      adhesion molecule (CAM) expression as an initiating process in tissue
      inflammation. This study was conducted to investigate the localization of major
      cytokines and CAMs in the maxillary sinus mucosa from patients with chronic
      sinusitis and from normal subjects. METHODS: Maxillary sinus mucosal specimens
      from patients with chronic sinusitis (n = 10) and from normal subjects (n = 6)
      were immunostained with specific antibodies directed against the cytokines (IL
      1alpha, IL-1beta, IL-6, IL-8 and TNF-alpha) and the CAMs (intercellular adhesion
      molecule-1, ICAM-1 and vascular CAM-1, VCAM-1). RESULTS: The number of
      immunoreactive cells for IL-1alpha, IL-1beta, IL-6, IL-8, and TNF-alpha was
      increased significantly in patients with chronic sinusitis compared with normal
      controls. Immunoreactivity for ICAM-1 was also increased significantly in
      patients with chronic sinusitis compared with normal controls, whereas VCAM-1 is
      only minimally expressed or is absent in both groups. CONCLUSION: These findings
      indicate that bacterial and/or viral infection may induce functional and
      morphologic changes in the maxillary sinus mucosa in chronic sinusitis through
      enhanced generation of specific cytokines in conjunction with CAMs.

PMID- 10648071
TI  - Endoscopic dacryocystorhinostomy without stents.
AB  - OBJECTIVE: The aim of this study is to present our endoscopic DCR operation
      method without the use of silicone tubing and our results on the patients
      suffering from chronic epiphora with postsaccal stenosis. METHODS: Endoscopic
      dacryocystorhinostomy operations were performed to 21 sides of 18 patients who
      had chronic epiphora. No silicone tubing was used in any of the cases. In the
      postoperative healing period, the rhinostomy opening was maintained with frequent
      removal of nasal debris and using eyedrops. The patients were evaluated by
      fluoresceine test and endoscopic controls. RESULTS: Symptomatic improvement was
      achieved in 19 out of 21 sides of the patients (90.5%) and the results were
      confirmed by the fluoresceine test under endoscopic control. CONCLUSION: Our
      results of 21 sides of 18 cases underwent primary DCR without stents are as
      successful as those reported in the literature and the technique seems to be
      promising.

PMID- 10648070
TI  - Inflammatory cells in nasal mucosa and nasal polyps.
AB  - OBJECTIVE: Since some controversy exists concerning the frequency of inflammatory
      cells in nasal polyps, we have compared the frequency of tissue inflammatory
      cells (lymphocytes, neutrophils, eosinophils and plasma cells) including 11 kinds
      of lymphocyte subsets in the same specimens of nasal mucosa and nasal polyps.
      METHODS: Histopathological observations and flow cytometric analyses were
      performed on eight mucosal specimens of the inferior turbinates of patients with
      nasal polyps and on 13 polyp specimens. RESULTS: Nasal polyps contained
      significantly more eosinophils, neutrophils and plasma cells than nasal mucosa,
      and EG2+ cells (activated eosinophils) were significantly more frequent in nasal
      polyps than in nasal mucosa. Flow cytometric analysis showed that there were no
      significant differences in the frequencies of lymphocytes and lymphocyte subsets
      (CD1+, CD2+, CD3+, CD5+, CD7+, CD4+, CD8+, CD10+, CD19+, CD20+ and HLA-DR+ cells)
      including CD4/8 ratios between nasal mucosa and polyps, though, both nasal mucosa
      and polyps contained significantly more lymphocytes than eosinophils, neutrophils
      or plasma cells. The T cell lineage (CD2+, CD3+, CD5+ and CD7+ cells) was found
      in high frequency and B cell lineage (CD10+, CD19+ and CD20+ cells) in low
      frequency in both nasal mucosa and polyps. The frequency of HLA-DR+ cells (most
      of which were activated T cells) was not significantly different between nasal
      mucosa and nasal polyps. CONCLUSION: Histopathological and flow cytometric
      analyses were performed on the composition of inflammatory cells in nasal mucosa
      of the inferior turbinates and in polyps from the same patients. The elevated
      numbers of activated eosinophils, neutrophils and plasma cells in nasal polyps
      compared with nasal mucosa suggest that inflammatory processes play important
      roles in the pathophysiology of nasal polyps. The frequencies of lymphocytes and
      lymphocyte subsets were not significantly different between these two tissues.

PMID- 10648072
TI  - Middle ear adenoma with neuroendocrine differentiation.
AB  - The lining of the middle ear cleft is normally a thin modified respiratory type
      mucosa. Normal mucosa of the middle ear is devoid of salivary type seromucous
      glands. Middle ear adenoma is a rare tumor that seems to be derived from the
      middle ear mucosa. This tumor has been previously described under a variety of
      names because of its different nature and biological behavior. We herein report a
      case of middle ear tumor that shows adenomatous and neuroendocrine features. A 64
      year-old woman presented with a history of hearing loss, tinnitus and stuffy
      feeling of the right ear. The patient was treated two times for ear polyp. She
      finally underwent a tympanomastoidectomy and there was no evidence of recurrence
      18 months after the procedure. Histopathological examination displayed cuboidal
      and columnar cells, arranged as glands, trabeculae and solid sheets.
      Neuroendocrine differentiation was revealed by immunohistochemical staining with
      polyclonal antibodies against neuron specific enolase and chromogranin antigens.

PMID- 10648073
TI  - Acute otalgia: a case report of mature termite in the middle ear.
AB  - Acute otalgia during childhood is one of the most common complaints in general
      ENT practice. It may occur as a result of acute otitis externa, otitis media or a
      foreign body. Animate foreign body in the ear canal or in the middle ear usually
      results in otalgia and hearing loss. We present a rare case of a living mature
      termite in the middle ear of a 9-year-old girl complaining of intermittent
      attacks of otalgia associated with a loud cracking sound in the left ear. In this
      case, a small perforation of the tympanic membrane without a history of previous
      trauma, infection, or evidence of a foreign body in the external ear raises a
      suspicion. A careful, time-consumed microscopic examination could show the living
      creature in the middle ear. Immediate immobilization and removal of the living
      foreign body are imperative. In conclusion, tympanic membrane perforation and
      intermittent severe otalgia without history of otitis may lead to a suspicion of
      any insects in the middle ear.

PMID- 10648074
TI  - Treatment of malignant melanoma of the lower eyelid using anterolateral thigh
      flap.
AB  - Malignant melanoma is a poor prognostic disease with the potential for high
      mortality despite early diagnosis and currently available treatment. Surgical
      judgment pertaining to the extent of primary resection and regional node
      dissections must be tempered by cosmetic considerations and by the anatomically
      diffuse pathways for lymphatic spread in certain lesions. We reported a case of
      malignant melanoma of the left lower eyelid, and presented the surgical excision
      and reconstruction using anterolateral thigh flap for skin defect. It is evident
      that comprehensive treatment using radical surgery and adjuvant chemotherapy is
      necessary for cutaneous malignant melanoma of head and neck areas.

PMID- 10648075
TI  - Assessment of in vivo glucose kinetics using stable isotope tracers to determine
      their alteration in humans during critical illness.
AB  - Glucose plays a central role in energy metabolism, and alterations in its
      utilization have been reported under a variety of physiological and pathological
      conditions. The extent and direction of its changes provide useful information to
      promote the understanding of pathophysiology. The regulation of in vivo glucose
      kinetics is important because it is closely linked to energy production and the
      control of amino acid and protein metabolism. Although alterations in glucose
      kinetics have been demonstrated in critically ill patients, the mechanisms
      responsible are not well understood. The measurement of glucose kinetics in
      humans using stable isotopic glucose tracers provides a better understanding of
      the responses to nutritional support in these patients. While tracer methods have
      been used to quantitatively measure in vivo kinetics in patients with a variety
      of critical illnesses as well as in normal volunteers during fasting and exercise
      in European countries and the United States, they have not received the same
      attention in Japan. Stable isotopic glucose tracers can be safely given to humans
      since they are themselves naturally occurring substances, accounting for a small
      percentage of the total, depending on the isotopic species. The intravenous
      administration of a glucose tracer allows quantitative assessment of in vivo
      glucose kinetics under a variety of conditions. This method has wide potential
      for obtaining kinetic data on all aspects of in vivo glucose metabolism, with
      major advantages for conducting metabolic studies in humans.

PMID- 10648076
TI  - Does central venous pressure reflect the circulating blood volume for the
      decrement of compliance just after esophagectomy?
AB  - This study investigates whether the pressure parameters obtained from the Swan
      Ganz catheter (SGC) accurately reflect the circulating blood volume just after en
      bloc resection of the thoracic esophagus with regional lymph node dissection. It
      is well known that this operation induces severe hemodynamic changes and although
      the pressure parameters obtained from the SGC are an accepted means of monitoring
      circulating blood volume, we have often experienced a discrepancy between the SGC
      data and the clinical state. We examined the pressure parameters and diameter of
      the inferior vena cava (IVC) and left ventricle (LV), and the central venous
      compliance using SGC and echocardiography in ten patients who underwent
      esophagectomy for esophageal cancer. The central venous pressure, pulmonary
      arterial mean pressure, and pulmonary artery wedged pressure were significantly
      increased just after the operation compared with the preoperative levels, while
      the diameters of the IVC and LV decreased just after the operation. The
      compliances of the IVC decreased significantly just after the operation. The
      hemodynamic shift to the third space after esophagectomy induces decrement of the
      compliances of IVC. As the CVP does not always reflect the circulating blood
      volume, measuring the diameter of the IVC using echocardiography is extremely
      useful for monitoring circulating blood volume just after esophagectomy.

PMID- 10648077
TI  - Preoperative intranasal mupirocin ointment significantly reduces postoperative
      infection with Staphylococcus aureus in patients undergoing upper
      gastrointestinal surgery.
AB  - Nasal carriage of Staphylococcus aureus including methicillin-resistant S. aureus
      (MRSA) is associated with an increased risk for postoperative staphylococcal
      infection. This study was conducted to investigate the effect of preoperative
      nasal mupirocin treatment on the postoperative infections in patients undergoing
      upper gastrointestinal surgery. The intervention group consisted of 141
      consecutive patients who underwent upper gastrointestinal surgery between March
      1, 1997, and February 28, 1998. The patients in the intervention group were
      treated with intranasal mupirocin three times a day for 3 consecutive days before
      surgery. The incidence of postoperative staphylococcal infections in the
      intervention group was then compared with that of the historical control group.
      The control group consisted of 128 consecutive patients who underwent upper
      gastrointestinal surgery without mupirocin treatment between January 1, 1996 and
      December 31, 1996. The postoperative staphylococcal infection rate in the control
      group (11.7%) was significantly higher (P < 0.001) than in the intervention group
      (0.71%). The postoperative MRSA infection rate was significantly reduced by the
      intervention (control group 7.0% and intervention group 0%; P < 0.01). These
      results suggest that preoperative nasal eradication of S. aureus with mupirocin
      thus appears to be an effective measure to prevent postoperative staphylococcal
      infection in patients undergoing upper gastrointestinal surgery.

PMID- 10648078
TI  - Emergency abdominal surgery in patients aged 80 years and older.
AB  - The outcome of emergency abdominal surgery in elderly patients remains
      unsatisfactory. We studied factors contributing to the outcome of abdominal
      emergency surgery in elderly patients, particularly in those aged 80 years and
      older. Subjects were 61 patients aged 80 years and older (group A) and 108
      patients aged from 65 to 79 years (group B) who underwent emergency abdominal
      surgery between 1983 and 1997. Complications were significantly higher in group A
      than in group B, with respiratory failure the most common postoperative
      complication. Mortality rate within 30 days after surgery was also higher in
      group A (9.8%) than in group B (3.3%). Complications and mortality did not differ
      significantly between those with and without preexisting concomitant disease in
      group A. Systemic inflammatory response syndrome (SIRS) was seen in 35 patients
      in group A and 50 in group B. Severe complications occurred in 62.5% of group A
      with preoperative SIRS. Mortality in those with SIRS was significantly higher
      than those without. SIRS is thus a feasible predictor of poor outcome in patients
      aged 80 years and older who have emergency abdominal surgery and in those aged
      from 65 to 79 years. Patients with SIRS should initially receive minimal
      treatment whenever possible, rather than be overtreated, until their conditions
      stabilize.

PMID- 10648080
TI  - Postoperative renal function after an abdominal aortic aneurysm repair requiring
      a suprarenal aortic cross-clamp.
AB  - We describe herein the postoperative renal functions of patients who required a
      suprarenal aortic cross-clamp during abdominal aortic surgery. Seven patients
      required a unilateral suprarenal aortic cross-clamp (group A) and six patients
      required a bilateral suprarenal clamp (group B). Eighty-three patients who
      required an infrarenal aortic clamp were assigned to group C. Renal hypothermia
      with renal perfusion or topical cooling during suprarenal clamp was not
      performed. No hospital deaths were encountered. In group B, the postoperative
      creatinine and blood urea nitrogen (BUN) levels remained statistically
      significantly higher than that of group C until the seventh postoperative day.
      The postoperative renal dysfunction (serum creatinine level >2.0 mg/dl) was 28.6%
      in group A and 50% in group B, while it was only 8.4% in group C, although no
      patient required either temporary or permanent hemodialysis. The postoperative
      peak BUN over 30 min suprarenal clamp was significantly higher than that within
      30 min. In summary, the postoperative renal function was impaired after an
      extended bilateral suprarenal clamp. These findings suggest that if prolonged
      renal ischemia is thus expected, then renal preservation should be considered.

PMID- 10648079
TI  - Immunohistochemical expression of the CD44 variant 6 in colorectal
      adenocarcinoma.
AB  - The CD44 variant 6 (CD44 v6) has been postulated to be involved in both
      carcinogenesis and tumor progression. In the present study, CD44 v6 was stained
      immunohistochemically in 63 colorectal cancer tissues to assess significance of
      CD44 v6 in the carcinogenesis and progression of colorectal carcinoma. None of
      the normal colonocytes showed an expression of CD44 v6. CD44 v6 expression was
      very strong in 24, moderate in 13, and negative in 26 tumor tissues. A negative
      or moderate expression of CD44 v6 was significantly associated with a larger
      tumor size (P < 0.05) and invasion through the bowel wall (P < 0.01). There was
      no correlation between the expression of CD44 v6 and gross type, histologic
      differentiation, lymph node involvement, liver metastasis, and clinical stage of
      the disease. The present study showed that the expression of CD44 v6 was
      characteristic of neoplastic changes in the colonocytes and that a diminished
      expression of CD44 v6 was associated with the penetration of colorectal cancer
      through the bowel wall, but not with either lymph node or distant metastasis.

PMID- 10648081
TI  - The relationship between the angiographic findings and the clinical features of
      carotid artery plaque.
AB  - The purpose of this study was to investigate the histological characteristics of
      atheromatous carotid plaque, and to analyze the relationship between the
      angiographic findings and the clinical features. We retrospectively reviewed 55
      cases of carotid endarterectomy for extracranial internal carotid artery
      stenosis, who were treated at our institute from January 1995 to December 1997.
      The histological examination included hematoxylin-eosin staining, Masson
      trichrome staining, and immunostaining for antismooth muscle antibody and anti
      CD68 antibody. The main compositions of the carotid plaque included synthetic
      type vascular smooth muscle cells and extracellular matrix. The histological
      findings showed ulceration in 49 (89.1%) cases, calcium deposits in 42 (76.4%)
      cases, and an inflammatory reaction in 44 (80.0%) cases. Neurological
      abnormalities were strongly associated with plaque ulceration (P = 0.045) and an
      inflammatory reaction (P = 0.013), whereas no correlation existed regarding
      calcium deposits (P = 0.173). The angiographic findings showed ulceration in 46
      (83.6%) cases. Plaque ulceration in the angiography findings showed no
      statistically significant correlation with the histologic findings (P = 0.410)
      and preoperative neurologic abnormalities (P = 0.059). All of the atherosclerotic
      risk factors such as hypertension, smoking, diabetes mellitus, hyperlipidemia,
      and myocardial infarction had no statistically significant correlation with the
      histological features of the carotid plaque. In conclusion, the main compositions
      of carotid plaque were synthetic-type vascular smooth muscle cells and
      extracellular matrix. The histological ulceration and inflammatory reaction of
      the plaque showed a statistically significant correlation with the preoperative
      neurologic symptoms, whereas no correlation was seen in the calcium deposits.
      Angiographic ulceration showed no correlation with the histological findings or
      preoperative neurologic abnormalities. In addition, the histological findings
      showed no correlation with the atherosclerotic risk factors.

PMID- 10648082
TI  - Evaluation of the malignant grade of thymic epithelial tumors according to the
      epithelial subclassification.
AB  - We investigated the clinicopathological correlations among 49 surgically resected
      thymic epithelial tumors (TET), which were subclassified according to the six
      subtypes established by the Marino, Kirchner, and Muller-Hermelink system, which
      were renamed as follows: spindle cell type (medullary thymoma), mixed spindle and
      polygonal cell type (mixed medullary and cortical thymoma), small polygonal cell
      type (predominantly cortical thymoma), large polygonal cell type (cortical
      thymoma), atypical type (well differentiated thymic carcinoma), and cytologically
      malignant type (high-grade thymic carcinoma). The related categories were grouped
      for statistical analysis as follows: group 1, spindle cell type and mixed type;
      group 2, small polygonal cell type and large polygonal cell type; group 3,
      atypical type; group 4, cytologically malignant type. The association of each
      group with the presence of myasthenia gravis, tumor stage, and the length of
      survival was studied. Myasthenia gravis was significantly present in patients
      with small polygonal type, large polygonal type, and atypical type tumors (groups
      2 and 3) (P = 0.003). The tumors in group 1 showed the lowest tumor stage while
      those of group 4 had the most advanced tumor stage (P = 0.002). The patients in
      group 4 had the worst prognosis, followed by those in group 3, 2, and 1, in that
      order. The differences among these groups were statistically significant (P =
      0.0003). From our results, we determined that TET can be separated into an
      extremely low-grade malignancy group (group 1), a low-grade malignancy group
      (group 2), an intermediate malignancy group (group 3), and a high-grade
      malignancy group (group 4).

PMID- 10648083
TI  - The role of lipid peroxidation on gastric mucosal lesions induced by water
      immersion-restraint stress in rats.
AB  - This study was designed to determine the effect of water-immersion-restraint
      stress (WIRS) and pretreatment by reduced glutathione on both the production of
      gastric mucosal lesions and the content of gastric mucosal phosphatidylcholine
      hydroperoxide (PCOOH). Sprague-Dawley rats were divided into control and
      treatment groups (treated with reduced glutathione before stress). After graded
      durations of WIRS, the macroscopic ulcer index (UI) was measured and the PCOOH
      content was examined by a chemiluminescence-high performance liquid
      chromatography assay. The UI in the control group increased significantly in a
      time-dependent fashion. Elevation of the PCOOH level was observed in combination
      with the UI for up to 2h of WIRS, but then showed a declining tendency.
      Pretreatment with reduced glutathione significantly lowered both the UI and the
      PCOOH level. Lipid peroxidation is probably involved in the pathogenesis of
      gastric injury induced by WIRS at least in the early phases. However, in the late
      phases, other mechanisms causing gastric mucosal lesions may also be involved. We
      therefore believe this study to be the first to accurately and quantitatively
      assess the degree of lipid peroxidation in the gastric mucosa as a result of
      stress.

PMID- 10648084
TI  - The facilitation of peritoneal dissemination of a tumor by laparotomy in a rabbit
      model.
AB  - The effects of conventional laparotomy and laparoscopic surgery on the peritoneal
      dissemination of VX2 tumors were evaluated in a rabbit model. Either 5 x 10(3) or
      5 x 10(4) of VX2 tumor cells were inoculated into the peritoneal cavities of
      rabbits which were divided into three groups according to the procedure
      performed, namely, a conventional laparotomy group (group 1), a laparoscopy group
      (group 2), and a control group (group 3). All the animals were killed 2 weeks
      after the treatment to examine the spread of the VX2 tumor in the omentum. In the
      experiment in which 5 x 10(3) tumor cells were inoculated, no significant
      difference was found in the number of metastases among the three groups.
      Conversely, after inoculating 5 x 10(4) tumor cells, the mean numbers of
      metastatic colonies greater than 1 mm in diameter in the greater omentum were
      14.4+/-4.7 in group 1, 9.9+/-2.4 in group 2, and 3.3+/-1.1 in group 3, with a
      significant difference between groups 1 and 3, and between groups 2 and 3, but
      not between groups 1 and 2. In conclusion, conventional laparotomy facilitated
      the greatest peritoneal dissemination of a VX2 tumor in this animal model when 5
      x 10(4) tumor cells were inoculated. Furthermore, laparoscopic surgery influences
      tumor growth to almost the same degree as conventional laparotomy.

PMID- 10648085
TI  - Benign schwannoma of the esophagus removed by enucleation: report of a case.
AB  - A submucosal tumor of the esophagus was enucleated by a thoracotomy. A
      microscopic examination showed the tumor to be composed of spindle-shaped cells
      showing mild nuclear atypia with vague nuclear palisading and scarce mitotic
      figures. The tumor was surrounded by peripheral lymphoid cuffs. An
      immunohistochemical study demonstrated diffuse positive staining for S-100
      protein in the tumor cells. The lesion was diagnosed to be an esophageal
      schwannoma based on these pathological features. Benign schwannoma of the
      esophagus has been described in five cases in four reports in the English
      literature. This is the sixth case diagnosed by immunohistochemical studies.

PMID- 10648086
TI  - Left diaphragmatic hernia complicated by perforation of an intrathoracic gastric
      ulcer into the aorta: report of a case.
AB  - We describe herein a rare but fatal complication of diaphragmatic hernia that
      occurred in a 51-year-old man 3 years after his diaphragm had been repaired by a
      polytetrafluoroethylene sheet following resection during pleuropneumonectomy for
      a left pleural mesothelioma. He was admitted to our hospital in shock status, and
      was found to have massive bleeding from the nasogastric tube. An emergency
      operation revealed that an ulcer of the stomach, which had been displaced into
      the left thorax, had perforated directly into the descending aorta.

PMID- 10648087
TI  - Ileal perforation due to a Richter hernia at the drain insertion site following
      an operation for idiopathic rectal perforation: report of a case.
AB  - A case of a Richter hernia at the insertion site of the drainage tube following
      open abdominal surgery is reported. A 54-year-old man underwent an emergency
      operation for an idiopathic rectal perforation. A partial resection of the rectum
      and drainage using four 10-mm (outer diameter) drainage tubes with round cross
      sections was performed. Despite an uneventful early postoperative course, an
      emergency reoperation was required for peritonitis due to a bowel perforation 14
      days after removing the drain inserted into the rectosacral space. A laparotomy
      revealed an incarcerated Richter hernia with ileal perforation through the 10-mm
      drainage site. The postoperative course after a partial resection of the ileum
      and drainage with Penrose drains was uneventful. This is the first report of a
      Richter hernia through the insertion site of a drainage tube in abdominal
      surgery. The possible occurrence of a Richter hernia in cases with postoperative
      drainage using large-size round drainage tubes should thus be considered in such
      patients.

PMID- 10648088
TI  - The development of an elevated lesion associated with colitis cystica profunda in
      the transverse colonic mucosa during the course of ulcerative colitis: report of
      a case.
AB  - We report the case of a 53-year-old man with a long history of ulcerative colitis
      in whom an elevated lesion in the epithelium of the affected transverse colon was
      initially diagnosed as a benign inflammatory polyp by endoscopic biopsies. After
      4 years of follow-up, because the tumor had enlarged and villous components were
      endoscopically observed on the surface, a colonic resection was performed. The
      tumor was found to consist of hyperplastic colonic epithelium associated with
      multiple mucinous cysts lined with dysplastic colonic epithelial cells. Moreover,
      the mucinous cysts were primarily located beneath the submucosal layer and
      appeared to intrude into the muscularis propria of the colonic wall. This lesion
      had a unique pathological feature, presumably indicating neither benign
      inflammatory epithelium nor a neoplastic lesion of the colonic epithelium.
      Mucinous cysts lined with colonic epithelial components in the muscularis propria
      suggest a loss of normal integrity of the colonic wall. Areas of the epithelial
      cell lining of the mucinous cysts showed apparent structural and nuclear atypia
      and positive expression for p53, suggesting that this portion of the specimen was
      dysplastic epithelium. These pathological findings may indicate one longitudinal
      aspect of tumor development which could provide evidence of premalignant change
      or initial pathological features during the long-standing course of ulcerative
      colitis.

PMID- 10648089
TI  - Metastatic colon carcinoma found within an inguinal hernia sac: report of a case.
AB  - We report herein the case of a patient in whom metastatic colon carcinoma was
      found within an inguinal hernia sac. According to Lejar's classification, colon
      carcinomas within inguinal hernias are categorized as intrasaccular- and saccular
      type tumors. In our patient, asymptomatic transverse colon carcinoma was the
      primary lesion, and to the best of our knowledge, this is only the fourth case of
      such a saccular-type tumor to be reported in the literature. To date, 21 cases of
      intrasaccular tumors have been reported, and saccular-type tumors are considered
      to be an even rarer entity, unless the patients have obvious ascites, indicating
      peritonitis carcinomatosa. Histologic examination of the hernia sac is
      recommended for male patients of advanced age with an inguinal hernia, especially
      those who have previously undergone surgery for colorectal carcinoma.

PMID- 10648090
TI  - Adenocarcinoid of the appendix presenting as a disseminated ovarian carcinoma:
      report of a case.
AB  - The occurrence of disseminated tumors of the appendix is a rare event. Usually
      appendix tumors are very small, located on the inside of the appendix, and can be
      pathologically diagnosed. Adenocarcinoid is an uncommon variant of carcinoid
      tumors that usually arises in the appendix. This report describes a case of a
      primary adenocarcinoid of the appendix in a patient who was preoperatively
      diagnosed to have uterus myomatosus but was intraoperatively found to instead
      have disseminated ovarian carcinoma. This case demonstrates that the clinical
      picture can be misleading, and that surgeons therefore always have to wait for
      the final pathological report before making a final diagnosis.

PMID- 10648091
TI  - Spontaneous regression of a large hepatocellular carcinoma with portal vein tumor
      thrombi: report of a case.
AB  - A 65-year-old man with chronic hepatitis C showed a markedly elevated serum alpha
      fetoprotein concentration. Computed tomography revealed a huge tumor occupying
      the entire right hepatic lobe. Three months later, the tumor regressed
      spontaneously from 12 cm to 7 cm in diameter without any medical treatment. A
      right hepatic lobectomy was performed 4 months after the initial diagnosis. The
      main tumor, located in the posterior inferior segment, was completely necrotic,
      and had a thick fibrous capsule. Many inflammatory cells had also infiltrated
      into the tumor. Only a small portion of a tumor thrombus in the portal vein and
      one of three intrahepatic metastases contained viable cancer cells. The tumor was
      found to be poorly differentiated hepatocellular carcinoma. Tumor regression may
      have been caused by a disturbance in hepatic circulation associated with the
      portal vein thrombus.

PMID- 10648092
TI  - Capillary hemangioma of the liver with Kasabach-Merritt syndrome in a neonate:
      report of a case.
AB  - Hepatic hemangiomas are benign tumors, and therefore minimally invasive treatment
      such as irradiation or steroid therapy is often recommended. However, in patients
      who have a hemangioma complicated by Kasabach-Merritt syndrome, surgical
      intervention should also be considered because of its confirmative therapeutic
      effect. We present herein the case of a 32-day-old male infant in whom a huge
      hepatic hemangioma associated with Kasabach-Merritt syndrome was treated by
      surgical intervention together with strong antidisseminated intravascular
      coagulation therapy.

PMID- 10648093
TI  - Small-cell carcinoma of the gallbladder: report of a case.
AB  - We report herein the case of an 81-year-old woman in whom a mass in the
      gallbladder was revealed by an ultrasound examination conducted as part of a
      follow-up study for a silent gallstone. The mass showed evidence of invasion into
      the adjacent liver parenchyma. Under the tentative diagnosis of malignant
      neoplastic disease originating in the gallbladder, a cholecystectomy with partial
      hepatectomy was performed. Histological examination of the tumor confirmed a
      diagnosis of small-cell carcinoma of the gallbladder, which is considered to be a
      rare type of neoplasm.

PMID- 10648094
TI  - Pancreaticoduodenectomy for metastatic renal cell carcinoma: report of a case.
AB  - Metastasis to the pancreas from a distant primary cancer is uncommon, most cases
      being detected in the advanced stages of disease, often multiple in number, and
      diffusely displayed beyond surgical salvage. A solitary metastasis in the head of
      the pancreas is rarely encountered and although potentially amenable to surgical
      resection, surgeons are hesitant to perform pancreaticoduodenectomy for
      metastatic disease. Renal cell carcinoma is one malignancy with a propensity to
      metastasize to the pancreas. We report herein the case of a solitary pancreatic
      metastasis from renal cell carcinoma successfully treated by
      pancreaticoduodenectomy in a middle-aged man. A discussion on the indications and
      effectiveness of performing pancreaticoduodenectomy for metastatic renal cell
      carcinoma is also presented.

PMID- 10648095
TI  - Cystic peritoneal mesothelioma: report of a case.
AB  - Peritoneal mesothelioma is a rare disease, especially when it arises in a cystic
      form with tardive and often nonspecific symptoms. While diffuse neoplasms have an
      unfavorable prognosis, cystic forms are usually benign. An accurate diagnosis can
      only be made only with electron microscopy and immunohistochemical studies. A 92
      year-old woman with an ultrastructurally ascertained cystic peritoneal
      mesothelioma was admitted to the hospital's emergency ward, and was considered to
      be unusual because of the size of the mass and the patient's age. A review of the
      literature is made, and the clinical and diagnostic aspects of this disease are
      also discussed.

PMID- 10648097
TI  - An improved technique for temporary diverting ileostomy.
AB  - A modification of the Turnbull technique for a temporary diverting ileostomy,
      which may be also applied to diverting colostomies, is described herein.
      According to the technical modification described, a totally diverting ileostomy
      is performed with the help of a Foley catheter secured in the subcutaneous
      tissue, and pulled upward and to the right like a sling around the efferent loop.
      This simple modification allows for better protection of distal anastomosis and
      an optimal diversion of enteric transit. Furthermore, this technique also permits
      an easier postoperative handling of the stoma, an easier application of the
      stomal bags and at the same time, it also more efficiently prevents the eventual
      subcutaneous infiltration with enteric contaminated fluid. In the authors'
      preliminary experience with ten cases the procedure was shown to offer advantages
      in reducing local discomfort and also in achieving the objectives of a totally
      diverting ileostomy.

PMID- 10648096
TI  - Urinary bladder injury during inguinal herniorrhaphy in a renal transplant
      patient: report of a case.
AB  - The urinary bladder was injured in a renal transplant patient during inguinal
      herniorrhaphy. The bladder was mistakenly identified as an internal inguinal
      hernia. The protuberant bladder from the thin muscle layers was caused by a
      previous renal transplantation. The defect in the bladder was sutured by
      absorbable suture material, and the posterior wall of the inguinal canal was
      reinforced by artificial mesh. Surgeons performing inguinal herniorrhaphy on the
      grafted side in a renal transplant patient should thus be warned not to injure
      the bladder during the operation.

PMID- 10648098
TI  - Nickel transport systems in microorganisms.
AB  - The transition metal Ni is an essential cofactor for a number of enzymatic
      reactions in both prokaryotes and eukaryotes. Molecular analyses have revealed
      the existence of two major types of high-affinity Ni2+ transporters in bacteria.
      The Nik system of Escherichia coli is a member of the ABC transporter family and
      provides Ni2+ ion for the anaerobic biosynthesis of hydrogenases. The periplasmic
      binding protein of the transporter, NikA, is likely to play a dual role. It acts
      as the primary binder in the uptake process and is also involved in negative
      chemotaxis to escape Ni overload. Expression of the nik operon is controlled by
      the Ni-responsive repressor NikR, which shows functional similarity to the ferric
      ion uptake regulator Fur. The second type of Ni2+ transporter is represented by
      HoxN of Ralstonia eutropha, the prototype of a novel family of transition metal
      permeases. Members of this family have been identified in gram-negative and gram
      positive bacteria and recently also in a fission yeast. They transport Ni2+ with
      very high affinity, but differ with regard to specificity. Site-directed
      mutagenesis experiments have identified residues that are essential for
      transport. Besides these uptake systems, different types of metal export systems,
      which prevent microorganisms from the toxic effects of Ni2+ at elevated
      intracellular concentrations, have also been described.

PMID- 10648099
TI  - Characterization of the ftsZ cell division gene of Neisseria gonorrhoeae:
      expression in Escherichia coli and N. gonorrhoeae.
AB  - We cloned the cell division gene ftsZ of the gram-negative coccus Neisseria
      gonorrhoeae (Ng) strain CH811, characterized it genetically and phenotypically,
      and studied its localization in N. gonorrhoeae and Escherichia coli (Ec). The
      1,179-bp ORF of ftsZ(Ng) encodes a protein with a predicted molecular mass of
      41.5 kDa. Protein sequence alignments indicate that FtsZ(Ng) is similar to other
      FtsZ proteins and contains the conserved GTP binding motif. FtsZ homologues were
      identified in several N. gonorrhoeae strains and in Neisseria lactamica,
      Neisseria sicca, Neisseria polysaccharae and Neisseria cinerea either by Western
      blot or by PCR-Southern blot analysis. Attempts to inactivate the ftsZ(Ng) on the
      chromosome failed, indicating that it is essential for gonococcal growth.
      FtsZ(Ng) was synthesized in an in vitro transcription/translation system and was
      shown to be 43 kDa, the same size as in Western blots. Expression of the ftsZ(Ng)
      gene from nongonococcal promoters resulted in a filamentous phenotype in E. coli.
      Under controlled expression, the FtsZ(Ng)-GFP fusion protein localized at the mid
      cell division site in E. coli. E. coli expressing high levels of the FtsZ(Ng)-GFP
      fusion protein formed filaments and exhibited different fluorescent structures
      including helices, spiral tubules extending from pole to pole, and regularly
      spaced dots or bands that did not localize at the middle of the cell. Expression
      of the FtsZ(Ng)-GFP fusion protein in N. gonorrhoeae resulted in abnormal cell
      division as shown by electron microscopy. FtsZ(Ng)-GFP fusions were also
      expressed in a gonococcal background using a unique shuttle vector.

PMID- 10648100
TI  - P45, an extracellular 45 kDa protein of Listeria monocytogenes with similarity to
      protein p60 and exhibiting peptidoglycan lytic activity.
AB  - A monoclonal antibody obtained by immunization of mice with heat-killed cells of
      Listeria monocytogenes serotype 4d showed reactivity towards a protein (P45) from
      L. monocytogenes with an apparent molecular mass of 45 kDa. This protein was
      detected in the culture supernatant and at the cell surface of L. monocytogenes.
      Proteins cross-reacting with the monoclonal antibody were present in all Listeria
      strains investigated, except L. grayi. The structural gene was cloned in
      Escherichia coli and sequenced. Translation of the gene starts at a TTG
      initiation codon. The gene was found to code for a protein of 402 amino acid
      residues with a predicted molecular mass of 42.7 kDa. It has a signal peptide of
      27 amino acid residues, resulting in a molecular mass for the mature polypeptide
      of 39.9 kDa. Protein database searches showed that this protein has 55%
      similarity and 38% identity to protein p60 of L. monocytogenes and exhibits
      significant sequence similarities to p54 from Enterococcus faecium and Usp45 from
      Lactococcus lactis. P45 was shown to have peptidoglycan lytic activity and the
      encoding gene was named spl (secreted protein with lytic property).

PMID- 10648101
TI  - Primary structure of cytochrome c' of Methylococcus capsulatus Bath: evidence of
      a phylogenetic link between P460 and c'-type cytochromes.
AB  - Cytochrome c' of Methylococcus capsulatus Bath is involved in electron flow from
      the enzyme responsible for hydroxylamine oxidation, cytochrome P460, to
      cytochrome C555. This cytochrome is spectrally similar to other cytochromes c'
      but is larger (16,000 Da) and has a lower midpoint potential (-205 mV). By a
      combination of Edman degradation, mass spectroscopy, and gene sequencing, we have
      obtained the primary structure of cytochrome c' from M. capsulatus Bath. The
      cytochrome shows low sequence similarity to other cytochromes c', only residues
      R12, Y53, G56, and the C-terminal heme-binding region (GXXCXXCHXXXK) being
      conserved. In contrast, cytochrome c' from M. capsulatus Bath shows considerable
      sequence similarity to cytochromes P460 from M. capsulatus Bath (31% identity)
      and from Nitrosomonas europaea (18% identity). This suggests that P460-type
      cytochromes may have originated from a c'-type cytochrome which developed a
      covalent cross-link between a lysine residue and the c'-heme.

PMID- 10648102
TI  - Initial in vitro characterisation of phosphonopyruvate hydrolase, a novel
      phosphate starvation-independent, carbon-phosphorus bond cleavage enzyme in
      Burkholderia cepacia Pal6.
AB  - A novel, inducible carbon-phosphorus bond cleavage enzyme, phosphonopyruvate
      hydrolase, was detected in cell-free extracts of Burkholderia cepacia Pal6, an
      environmental isolate capable of mineralising L-phosphonoalanine as carbon,
      nitrogen and phosphorus source. The activity was induced only in the presence of
      phosphonoalanine, did not require phosphate starvation for induction and was
      uniquely specific for phosphonopyruvate, producing equimolar quantities of
      pyruvate and inorganic phosphate. The native enzyme had a molecular mass of some
      232 kDa and showed activation by metal ions in the order Co2+ > Ni2+ > Mg2+ >
      Zn2+ > Fe2+ > Cu2+. Temperature and pH optima in crude cell extracts were 50
      degrees C and 7.5, respectively, and activity was inhibited by EDTA, phosphite,
      sulfite, mercaptoethanol and sodium azide. Phosphonopyruvate hydrolase is the
      third bacterial C-P bond cleavage enzyme reported to date that proceeds via a
      hydrolytic mechanism.

PMID- 10648103
TI  - Biochemical controls of citrate synthase in chickpea bacteroids.
AB  - Bacteroids formed by Mesorhizobium ciceri CC 1192 in symbiosis with chickpea
      plants (Cicer arietinum L.) contained a single form of citrate synthase [citrate
      oxaloacetate-lyase (CoA-acetylating) enzyme; EC 4.1.3.7], which had the same
      electrophoretic mobility as the enzyme from the free-living cells. The citrate
      synthase from CC 1192 bacteroids had a native molecular mass of 228 +/- 32 kDa
      and was activated by KCl, which also enhanced stability. Double reciprocal plots
      of initial velocity against acetyl-CoA concentration were linear, whereas the
      corresponding plots with oxaloacetate were nonlinear. The Km value for acetyl-CoA
      was 174 microM in the absence of added KCl, and 88 microM when the concentration
      of KCl in reaction mixtures was 100 mM. The concentrations of oxaloacetate for
      50% of maximal activity were 27 microM without added KCl and 14 microM in the
      presence of 100 mM KCl. Activity of citrate synthase was inhibited 50% by 80
      microM NADH and more than 90% by 200 microM NADH. Inhibition by NADH was linear
      competitive with respect to acetyl-CoA (Kis = 23.1 +/- 3 microM) and linear
      noncompetitive with respect to oxaloacetate (Kis = 56 +/- 3.8 microM and Kii =
      115 +/- 15.4 microM). NADH inhibition was relieved by NAD+ and by micromolar
      concentrations of 5'-AMP. In the presence of 50 or 100 mM KCl, inhibition by NADH
      was apparent only when the proportion of NADH in the nicotinamide adenine
      dinucleotide pool was greater than 0.6. In the microaerobic environment of
      bacteroids, NADH may be at concentrations that are inhibitory for citrate
      synthase. However, this inhibition is likely to be relieved by NAD+ and 5'-AMP,
      allowing carbon to enter the tricarboxylic acid cycle.

PMID- 10648104
TI  - Two new arsenate/sulfate-reducing bacteria: mechanisms of arsenate reduction.
AB  - Two sulfate-reducing bacteria, which also reduce arsenate, were isolated; both
      organisms oxidized lactate incompletely to acetate. When using lactate as the
      electron donor, one of these organisms, Desulfomicrobium strain Ben-RB, rapidly
      reduced (doubling time = 8 h) 5.1 mM arsenate at the same time it reduced sulfate
      (9.6 mM). Sulfate reduction was not inhibited by the presence of arsenate.
      Arsenate could act as the terminal electron acceptor in minimal medium (doubling
      time = 9 h) in the absence of sulfate. Arsenate was reduced by a membrane-bound
      enzyme that is either a c-type cytochrome or is associated with such a
      cytochrome; benzyl-viologen-dependent arsenate reductase activity was greater in
      cells grown with arsenate/sulfate than in cells grown with sulfate only. The
      second organism, Desulfovibrio strain Ben-RA, also grew (doubling time = 8 h)
      while reducing arsenate (3.1 mM) and sulfate (8.3 mM) concomitantly. No evidence
      was found, however, that this organism is able to grow using arsenate as the
      terminal electron acceptor. Instead, it appears that arsenate reduction by the
      Desulfovibrio strain Ben-RA is catalyzed by an arsenate reductase that is encoded
      by a chromosomally-borne gene shown to be homologous to the arsC gene of the
      Escherichia coli plasmid, R773 ars system.

PMID- 10648105
TI  - Anaerobic oxidation of alkanes by newly isolated denitrifying bacteria.
AB  - The capacity of denitrifying bacteria for anaerobic utilization of saturated
      hydrocarbons (alkanes) was investigated with n-alkanes of various chain lengths
      and with crude oil in enrichment cultures containing nitrate as electron
      acceptor. Three distinct types of denitrifying bacteria were isolated in pure
      culture. A strain (HxN1) with oval-shaped, nonmotile cells originated from a
      denitrifying enrichment culture with crude oil and was isolated with n-hexane
      (C6H14). Another strain (OcN1) with slender, rod-shaped, motile cells was
      isolated from an enrichment culture with n-octane (C8H18). A third strain (HdN1)
      with oval, somewhat pleomorphic, partly motile cells originated from an
      enrichment culture with aliphatic mineral oil and was isolated with n-hexadecane
      (C16H34). Cells of hexane-utilizing strain HxN1 grew homogeneously in the growth
      medium and did not adhere to the alkane phase, in contrast to the two other
      strains. Quantification of substrate consumption and cell growth revealed the
      capacity for complete oxidation of alkanes under strictly anoxic conditions, with
      nitrate being reduced to dinitrogen.

PMID- 10648106
TI  - Purification and characterization of intracellular alpha-L-rhamnosidase from
      Pseudomonas paucimobilis FP2001.
AB  - alpha-L-Rhamnosidase was extracted and purified from the cells of Pseudomonas
      paucimobilis FP2001 with a 19.5% yield. The purified enzyme, which was
      homogeneous as shown by SDS-PAGE and isoelectric focusing, had a molecular weight
      of 112,000 and an isoelectric point of 7.1. The enzyme activity was accelerated
      by Ca2+ and remained stable for several months when stored at -20 C. The optimum
      pH was 7.8; the optimum temperature was 45 degrees C. The Km, V(max) and k(cat)
      for p-nitrophenyl alpha-L-rhamnopyranoside were 1.18 mM, 92.4 microM x min(-1)
      and 117,000 x min(-1), respectively. Examination of the substrate specificity
      using various synthetic and natural L-rhamnosyl glycosides showed that this
      enzyme had a relatively broader substrate specificity than those reported so far.

PMID- 10648107
TI  - Anaerobic degradation of flavonoids by Eubacterium ramulus.
AB  - Eubacterium ramulus, a quercetin-3-glucoside-degrading anaerobic microorganism
      that occurs at numbers of approximately 10(8)/g dry feces in humans, was tested
      for its ability to transform other flavonoids. The organism degraded luteolin-7
      glucoside, rutin, quercetin, kaempferol, luteolin, eriodictyol, naringenin,
      taxifolin, and phloretin to phenolic acids. It hydrolyzed kaempferol-3
      sorphoroside-7-glucoside to kaempferol-3-sorphoroside and transformed 3,4
      dihydroxyphenylacetic acid, a product of anaerobic quercetin degradation, very
      slowly to non-aromatic fermentation products. Luteolin-5-glucoside, diosmetin-7
      rutinoside, naringenin-7-neohesperidoside, (+)-catechin, and (-)-epicatechin were
      not degraded. Cell extracts of E. ramulus contained alpha- and beta-D-glucosidase
      activities, but were devoid of alpha-L-rhamnosidase activity. Based on the
      degradation patterns of these substrates, a pathway for the degradation of
      flavonoids by E. ramulus is proposed.

PMID- 10648108
TI  - Salmonella typhimurium forms adenylcobamide and 2-methyladenylcobamide, but no
      detectable cobalamin during strictly anaerobic growth.
AB  - Under microaerophilic conditions Salmonella typhimurium LT2 synthesizes
      cobalamin, during which 5,6-dimethylbenzimidazole is formed from riboflavin. We
      report here that in an anoxic environment S. typhimurium did not form cobalamin,
      but rather adenylcobamide, 2-methyladenylcobamide, and cobyric acid. This
      indicated that S. typhimurium, like other microorganisms that synthesize 5,6
      dimethylbenzimidazole from riboflavin, requires oxygen for the formation of the
      cobalamin base.

PMID- 10648109
TI  - Indole-inducible proteins in bacteria suggest membrane and oxidant toxicity.
AB  - Oxidant toxicity of indole was demonstrated by the induction of
      alkylhydroperoxide reductase subunit C (AhpC) in Escherichia coli K12 and by the
      constitutive overproduction of AhpC in a variant of E. coli JM109 with enhanced
      resistance to indole. Oxidant toxicity was also indicated in an indole-adapted
      variant of Brevibacterium flavum by the indole-inducible overproduction of a
      novel 36-kDa protein with N-terminal sequence similarity to proteins involved in
      superoxide and singlet oxygen resistance. It is proposed that indole dissolved in
      membrane lipids, which caused membrane derangement and enabled direct interaction
      of redox-cycling isoprenoid quinones and dioxygen, resulting in the generation of
      superoxide. A direct indication of membrane derangement in E. coli may be the
      indole-inducible overproduction of spheroplast protein y (Spy).

PMID- 10648110
TI  - Vaccination and autoimmunity-'vaccinosis': a dangerous liaison?
AB  - The question of a connection between vaccination and autoimmune illness (or
      phenomena) is surrounded by controversy. A heated debate is going on regarding
      the causality between vaccines, such as measles and anti-hepatitis B virus (HBV),
      and multiple sclerosis (MS). Brain antibodies as well as clinical symptoms have
      been found in patients vaccinated against those diseases. Other autoimmune
      illnesses have been associated with vaccinations. Tetanus toxoid, influenza
      vaccines, polio vaccine, and others, have been related to phenomena ranging from
      autoantibodies production to full-blown illness (such as rheumatoid arthritis
      (RA)). Conflicting data exists regarding also the connection between autism and
      vaccination with measles vaccine. So far only one controlled study of an
      experimental animal model has been published, in which the possible causal
      relation between vaccines and autoimmune findings has been examined: in healthy
      puppies immunized with a variety of commonly given vaccines, a variety of
      autoantibodies have been documented but no frank autoimmune illness was recorded.
      The findings could also represent a polyclonal activation (adjuvant reaction).
      The mechanism (or mechanisms) of autoimmune reactions following immunization has
      not yet been elucidated. One of the possibilities is molecular mimicry; when a
      structural similarity exists between some viral antigen (or other component of
      the vaccine) and a self-antigen. This similarity may be the trigger to the
      autoimmune reaction. Other possible mechanisms are discussed. Even though the
      data regarding the relation between vaccination and autoimmune disease is
      conflicting, it seems that some autoimmune phenomena are clearly related to
      immunization (e.g. Guillain-Barre syndrome). The issue of the risk of vaccination
      remains a philosophical one, since to date the advantages of this policy have not
      been refuted, while the risk for autoimmune disease has not been irrevocably
      proved. We discuss the pros and cons of this issue (although the temporal
      relationship (i.e. always 2-3 months following immunization) is impressive).

PMID- 10648111
TI  - Immunologic hazards associated with vaccination of humans.
AB  - Universal vaccination remains the most effective measure for preventing the
      spread of many infectious diseases. Since vaccination is one of the few medical
      interventions applied to healthy individuals, its safety must be as absolute as
      human efforts can make it. Questions have been raised recently about the
      possibility that particular vaccines can trigger or promote autoimmune disease,
      although controlled, population-based studies have not supported this notion. In
      collaboration with the World Health Organization, we investigated a subunit
      vaccine of human chorionic gonadotropin, and found evidence of benign, but not
      pathologic, autoimmunity. We propose an algorithm for systematic study of
      possible immunologic hazards of vaccines in animals and human subjects.

PMID- 10648112
TI  - Vaccination and autoimmunity.

PMID- 10648113
TI  - Stimulation of the developing immune system can prevent autoimmunity.
AB  - Both genetic and environmental factors contribute to the development of
      autoimmunity. Animals and humans exposed to natural infections have a reduced
      rate of autoimmune diseases. There is increasing evidence that immune stimulation
      prevents autoimmune diseases. Our hypothesis is that the process of the
      development of pathogenic cells involved in autoimmunity can be modulated by
      early stimulation of the immune system in autoimmunity prone individuals This
      allows for the upregulation of cytokines and growth factors that influence the
      generation of regulatory cells involved in autoimmunity. As we live in a 'cleaner
      environment' the decreasing chances of natural infection in the general
      population may contribute to the induction of autoimmunity because the developing
      immune system is not exposed to stimulation that may be necessary to generate
      regulatory cells involved in the modulation and prevention of autoimmunity.
      Immunization with certain vaccines may provide an alternative approach to
      stimulate the immune system to modulate or prevent the generation of pathogenic
      cells involved in autoimmunity by induction of regulatory cells.

PMID- 10648114
TI  - The inhibitory effects of transforming growth factor-beta-1 (TGF-beta1) in
      autoimmune diseases.
AB  - The importance of transforming growth factor-beta-1 (TGF-beta1) in
      immunoregulation and tolerance has been increasingly recognized. It is now
      proposed that there are populations of regulatory T cells (T-reg), some
      designated T-helper type 3 (Th3), that exert their action primarily by secreting
      this cytokine. Here, we emphasize the following concepts: (1) TGF-beta1 has
      multiple suppressive actions on T cells, B cells, macrophages, and other cells,
      and increased TGF-beta1 production correlates with protection and/or recovery
      from autoimmune diseases; (2) TGF-beta1 and CTLA-4 are molecules that work
      together to terminate immune responses; (3) Th0, Th1 and Th2 clones can all
      secrete TGF-beta1 upon cross-linking of CTLA-4 (the functional significance of
      this in autoimmune diseases has not been reported, but TGF-beta1-producing
      regulatory T-cell clones can produce type 1 inflammatory cytokines); (4) TGF
      beta1 may play a role in the passage from effector to memory T cells; (5) TGF
      beta1 acts with some other inhibitory molecules to maintain a state of tolerance,
      which is most evident in immunologically privileged sites, but may also be
      important in other organs; (6) TGF-beta1 is produced by many cell types, is
      always present in the plasma (in its latent form) and permeates all organs,
      binding to matrix components and creating a reservoir of this immunosuppressive
      molecule; and (7) TGF-beta1 downregulates adhesion molecules and inhibits
      adhesion of leukocytes to endothelial cells. We propose that rather than being
      passive targets of autoimmunity, tissues and organs actively suppress
      autoreactive lymphocytes. We review the beneficial effects of administering TGF
      beta1 in several autoimmune diseases, and show that it can be effectively
      administered by a somatic gene therapy approach, which results in depressed
      inflammatory cytokine production and increased endogenous regulatory cytokine
      production.

PMID- 10648115
TI  - Adjuvant effects of cholera toxin b subunit on immune response to recombinant
      thyrotropin receptor in mice.
AB  - We had previously shown that BALB/c mice immunized with the extracellular domain
      of human thyrotropin receptor (ETSHR) developed moderate hyperthyroxinemia. The
      antibody responses in these mice were predominantly of the IgG1 subclass. Since
      cholera toxin B subunit (CT-B) has direct effects on the thyroid, and is known to
      activate B lymphocytes and cause enhanced IgG1 production, we tested the ability
      of CT-B to modulate the antibody response to ETSHR. CT-B is unique in that it not
      only elicits a strong immune response to itself, but more importantly, when given
      with other antigens acts as a potent adjuvant. In the present study, BALB/c mice
      given ETSHR with CFA or CT-B via ip route showed higher titers of antibodies to
      ETSHR when compared to mice similarly immunized with ETSHR alone, or with IFA.
      Antibodies in ETSHR+CT-B immunized mice were mostly of the IgG1 subclass and
      reacted predominantly with ETSHR peptides 1 (aa 22-41), 21 (aa 322-341), and 23
      (352-371). In contrast, animals immunized with ETSHR+CFA showed IgG1, IgG2a and
      IgG2b responses and reacted with peptides 1 and 21. Furthermore, mice immunized
      with ETSHR along with CT-B showed significantly higher levels of thyrotropin
      (TSH) binding inhibitory immunoglobulins (TBII) compared to those that did not
      receive CT-B. None of the mice immunized with a control antigen showed antibody
      response to ETSHR. These results suggested that CT-B could enhance and modulate
      immune response to ETSHR.

PMID- 10648116
TI  - No evidence of epitope spreading after immunization with the major Sm epitope P-P
      G-M-R-P-P anchored to sequential oligopeptide carriers (SOCs).
AB  - The sequence Pro-Pro-Gly-Meth-Arg-Pro-Pro (PPGMRPP) is the major B-cell epitope
      of the Sm autoantigen. The aim of the present study was to evaluate the immune
      response against the native forms of Sm and U1RNP and immune mediated tissue
      injury after immunization with the sequence PPGMRPP anchored in five copies to a
      new type helicoid sequential oligopeptide carrier (SOC) formed by the repetitive
      Lys-Aib-Gly moiety, [(PPGMRPP)(5)SOC(5)]. Rabbits (n=3) were immunized with 0.5
      mg of (PPGMRPP)(5)SOC(5)in complete Freud's adjuvant and boosted at days 26, 53,
      99; control rabbits were immunized with the PPGMRPP alone (n=3), phosphate
      buffered saline (PBS) (n=1), SOC(5)alone (n=1), a peptide at aminoacid (aa)
      position 158-177 of myelin basic protein (MBP aa 158-147) (n=1) and three La/SSB
      autoantigen B-cell epitopes (n=3). Antibodies to (PPGMRPP)(5)SOC(5)were
      determined by enzyme linked immunosorbent assay (ELISA); precipitating anti-Sm
      and anti-U1RNP antibodies were detected by RNA precipitation and western blot on
      HeLa total cellular and nuclear extract and 12s sucrose gradient fraction of rat
      liver extracts. High titres of anti-(PPGMRPP)(5)SOC(5)antibodies not recognizing
      the native forms of Sm or U1RNP antigens were detected in the
      (PPGMRPP)(5)SOC(5)immunized but not in the control animals. The sera of two
      (PPGMRPP)(5)SOC(5)immunized but not of the control rabbits recognized a 67 kDa
      protein in HeLa nuclear extract, distinct from the 70 kDa U1RNP antigen. Diffuse
      and segmental increase of mesangeal matrix and cells, crescent formation,
      segmental glomerular necrosis, rarely massive subendothelial deposits occluding
      the lumen and C3 complement component in the mesangeal area were seen in the
      kidneys of one (PPGMRPP)(5)SOC(5)immunized, but not of the remaining animals. In
      conclusion, the immune response induced by (PPGMRPP)(5)SOC(5)was specific for the
      immunizing epitope but not for the native forms of Sm and U1RNP antigens, but it
      was associated with immune mediated kidney injury.

PMID- 10648118
TI  - Association of KM genotype with bullous pemphigoid.
AB  - Association of kappa light chain immunoglobulin allotypes with bullous pemphigoid
      was examined in 101 Caucasian patients. Km alleles were determined by polymerase
      chain reaction amplification followed by restriction enzyme digestion. The
      frequency of Km(3)/Km(1,2)kappa light-chain genotype was found to be
      significantly associated with the disease, while that of the Km(3)homozygous
      genotype was significantly higher in patients with both anti-BPAG1 and anti-BPAG2
      autoantibodies.

PMID- 10648117
TI  - CD69, HLA-DR and the IL-2R identify persistently activated T cells in psoriasis
      vulgaris lesional skin: blood and skin comparisons by flow cytometry.
AB  - Many lymphocyte-activation-associated molecules are observed by
      immunohistochemistry in psoriasis vulgaris lesional skin. Non-T cells in lesional
      skin also express these molecules. We quantitatively measured the number of T
      cells expressing cell surface activation-associated molecules (CD69, CD25, CD122,
      HLA-DR) and co-stimulatory molecules (CD28, CTLA-4, CD80, CD86), including a Type
      2 T cell marker (CD30) and CD11b, by flow cytometry of skin and peripheral blood.
      T cells in single cell suspensions of psoriatic lesional-epidermis-expressed HLA
      DR (86%), CD69 (59%), CD25 (55%), CD122 (44%), and CD28 (91%). Dermal T cells
      showed similar percentages except for CD69 (17%). CD69 was found directly in
      lesional skin biopsies by immunohistochemistry. Both CD4 and CD8 subsets from
      lesional skin contained large populations of CD25+ cells with a bias towards CD8
      activation in the epidermis and towards CD4 activation in the dermis. CD86, CD80,
      CTLA-4, CD30 and CD11b were expressed by less than 23% of the T cell populations
      from both the epidermis and dermis. CD30+CD4+ cells were found two-fold over CD8+
      T cells. These results show that the majority of lesional lymphocytes are
      persistently activated. We also found the majority of Type 2 associated markers
      primarily on the CD4+ epidermal T cell population. Psoriatic blood contained
      elevated levels of T cells expressing CD25, primarily within the CD8+ subset.
      Thus the majority of lesional T cells expressed the three primary activation
      markers, while psoriatic blood T cells were distinguished by an increase in CD25,
      specifically within the CTL population.

PMID- 10648119
TI  - Identification of histone H1 as a cognate antigen of the ulcerative colitis
      associated marker antibody pANCA.
AB  - Perinuclear anti-neutrophil cytoplasmic antibody (pANCA)(4)is a predominant serum
      marker of ulcerative colitis (UC), and a familial trait associated with disease
      susceptibility and disease associated MHC haplotypes. This study characterizes
      the pANCA antigen defined by representative UC-pANCA human monoclonal antibodies,
      Fab 5-3 and 5-2. Western blot analysis probed with Fab 5-3 revealed specific
      binding to a nuclear protein doublet (apparent MW=32-33 kDa) expressed in several
      cell types. Purification and tryptic peptide sequencing identified the protein as
      histone H1, and this specificity was confirmed by Fab 5-3 binding to purified H1.
      Rabbit anti-histone H1 immunostaining and Western blot analysis confirmed that
      the pANCA epitope is preferentially immunoaccessible in polymorphonuclear
      neutrophils (PMN). The epitope was localized to the COOH-terminal region by site
      specific proteolysis, and recombinant deletants further localized binding
      activity for both Fab 5-2 and 5-3 to two non-overlapping segments (AA 69-171 and
      172-226) associated with a recurring PKKAK motif. Serum IgG binding was
      detectable to these segments, but was not significantly correlated with pANCA
      titer or disease status. These findings indicate that histone H1 bears a
      recurring COOH-terminal epitope recognized by monoclonal ulcerative colitis
      associated pANCA marker antibodies, but this epitope is not a predominant
      specificity of serum pANCA.

PMID- 10648120
TI  - Immune potentiation of ultrafine dietary particles in normal subjects and
      patients with inflammatory bowel disease.
AB  - Various specific and non-specific environmental factors have been associated with
      the induction and/or exacerbation of disease activity in patients with Crohn's
      disease and ulcerative colitis. One such factor is the potential role of ingested
      ultrafine particles. In fact, based on a Western diet, recent data suggest that
      more than 10(12)ultrafine particles are ingested per person every day. These
      microparticles have been considered inert although they adsorb endogenous
      constituents of the intestinal lumen and are taken up by human intestinal
      lymphoid aggregates. Based on these observations, we determined whether one such
      dietary microparticle, titanium dioxide (TiO(2)), alters intestinal cell
      responsiveness to lipopolysaccharide (LPS) using colonic biopsy specimens from 28
      patients with ulcerative colitis, 21 with Crohn's disease, and 36 healthy
      controls. These samples, as well as peripheral blood mononuclear cells when
      available, were incubated alone (control), or with either (a) LPS (1-2,000
      ng/ml), (b) TiO(2)(5 microg/ml) or (c) LPS (1 ng/ml) adsorbed to TiO(2)(5
      microg/ml). In each case, the levels of interleukin 1 (IL-1) produced in these
      assays were quantitated by bioassay and by ELISA. Interestingly, there was
      dramatic stimulation of peripheral blood mononuclear cells using the TiO(2)-LPS
      conjugate, with values 30-60-fold above controls and only minor stimulation with
      LPS or TiO(2)alone. In intestinal organ cultures there was no increase in IL-1
      secretion when challenged with TiO(2)alone or with up to 2,000 ng/ml LPS.
      However, the TiO(2)-LPS conjugate produced a two-to-three-fold, significant
      increase in the intestinal secretion of IL-1. Our data demonstrate that ultrafine
      dietary particles are not immunologically inert and may be important adjuncts in
      overcoming normal gut cell hyporesponsiveness to endogenous luminal molecules.
      This may be particularly relevant to patients with inflammatory bowel disease
      where there is abnormal intestinal permeability.

PMID- 10648121
TI  - Induction of a germinal center phenotype in B cells in vitro by a Th2 cell line.
AB  - We have investigated the contribution of various stimuli for generating in vitro
      the changes in surface phenotype characteristic of B cells responding to a T
      dependent antigen in a germinal center (GC). We show that, unlike many other
      stimuli such as B cell mitogens, cytokines, and surrogate antigen, alone or in
      combination, an alloreactive Th2 clonal line induces splenic B cells to become
      cell surface peanut agglutinin (PNA)(hi), Ig(lo), CD62L(lo), and CD44(hi) to
      produce mRNA for M17 and to express a GC-specific transgene even without B cell
      receptor ligation. Neither proliferation nor prior activation of responding B
      cells is needed, but B cells from CD45-null mice show reduced efficiency of this
      induction. These findings open up possibilities for separation and dissection of
      the various components of the GC response.

PMID- 10648122
TI  - CD154 (CD40L) induces human endothelial cell chemokine production and migration
      of leukocyte subsets.
AB  - CD154-CD40 interactions play key roles in humoral and cellular immune responses.
      With regard to the latter, ligation of CD40 on endothelial cells upregulates
      important intercellular adhesion molecules. Activated endothelial cells also
      regulate leukocyte trafficking into inflammatory sites by secreting chemokines.
      In this study we asked whether CD154 mediated signals induce human umbilical vein
      endothelial cells (HUVEC) to secrete neutrophil or peripheral blood mononuclear
      cell (PBMC) chemoattractants. HUVEC were cocultured with CD154(+) Jurkat D1.1
      cells in the presence or in the absence of anti-CD154 mAb or control mAb.
      Additionally, HUVEC were cocultured with control CD154(-) Jurkat B2.7 cells.
      Supernatants were harvested after 24 h and chemotaxis assays performed.
      Supernatants derived from Jurkat cells did not induce either neutrophil or PBMC
      chemotaxis. Resting endothelial cells produce at baseline some neutrophil and
      PBMC chemoattractants. However, there was significantly enhanced neutrophil and
      PBMC chemoattractant activity in supernatants derived from CD154 stimulated
      HUVEC. The enhanced leukocyte migration was specifically inhibited by anti-CD154
      mAb. Anti-chemokine mAbs were used to identify specific chemokines mediating the
      enhanced leukocyte chemotaxis activity in CD154 stimulated HUVEC supernatants.
      There was complete or near complete inhibition of enhanced neutrophil and PBMC
      migration by anti-IL-8 and anti-monocyte chemoattractant protein-1 (MCP-1) mAbs,
      respectively. Anti-RANTES mAb partially blocked the enhanced PBMC migration,
      whereas anti-macrophage inflammatory protein-1alpha (MIP-1alpha) mAb had no
      effect. Utilizing specific ELISAs, we confirmed that CD40 ligation induces HUVEC
      to secrete IL-8, MCP-1, and RANTES, but not MIP-1alpha. Finally, we present
      evidence that the effects of CD154-CD40 interactions on HUVEC chemokine
      production are independent of IL-1beta production. These findings demonstrate
      that CD154-CD40 interactions induce endothelial cells to produce specific
      neutrophil and mononuclear cell chemoattractants.

PMID- 10648123
TI  - Suppression of experimental autoimmune encephalomyelitis by dermatan sulfate.
AB  - The effect of dermatan sulfate (DS) on the treatment of Lewis rats with
      experimental autoimmune encephalomyelitis (EAE) was examined. DS, a sulfated
      glycosaminoglycan, has been reported to exhibit anticoagulant and fibrinolytic
      activities. DS treatment (50 mg/kg/day) facilitates recovery from the clinical
      manifestations of EAE. In this study, the fibrinolytic activity was higher in DS
      treated rats than in saline-treated rats. Although the degree of perivascular
      mononuclear cell infiltration in the spinal cord was not suppressed in DS-treated
      rats compared to that in saline-treated rats, perivascular fibrin deposition was
      markedly suppressed in DS-treated rats. These findings suggest that DS would act
      as an effective therapeutic agent for EAE by preventing fibrin deposition.

PMID- 10648124
TI  - Interleukin-10 reduces natural killer (NK) sensitivity of tumor cells by
      downregulating NK target structure expression.
AB  - We examined the effect of exogenous IL-10 on the sensitivity of rat W14 and W31
      tumor cells to natural killer (NK) cell-mediated cytotoxicity in relation to
      previously identified NK target structure (NKTS) expressed on these cells. We
      also examined the effect of endogenous interleukin-10 (IL-10) on rat IL-10 cDNA
      introduced W31 cells (W31T-H, a high-IL-10-producer clone; W31T-L, a low-IL-10
      producer clone). Both exogenous and endogenous IL-10 had no effect on the
      proliferative activity of these cells, but incubation of cells with recombinant
      human (rh) IL-10 resulted in a dose-dependent decrease in the expression of NKTS
      recognized by mAb 109. The expression level of NKTS on W31T-H cells was
      dramatically decreased compared with that on W31T-L cells and parental W31 cells.
      In addition, treatment of W31 cells with the culture supernatants of W31T-H cells
      could downregulate the expression of the NKTS. Moreover, NK sensitivity of W31T-H
      was suppressed down to a level equivalent to that of W31 cells pretreated with
      exogenous rhIL-10, and cytolysis could no longer be inhibited by mAb 109. We
      previously demonstrated that IL-10 downregulated MHC class I expression in this
      model. Nevertheless, NK susceptibility was also decreased. Taken together, these
      results suggest that the IL-10-mediated decrease in NKTS expression has a larger
      effect than decreased MHC class I expression on NK sensitivity. Thus, our data
      reveal a novel mechanism for an IL-10-mediated escape of tumor cells from host
      immune surveillance by downregulation of NKTS expression.

PMID- 10648125
TI  - Identification of IFN-gamma-producing cells in IL-12/IL-18-treated mice.
AB  - Both IL-12 and IL-18 have been characterized as effective IFN-gamma-inducing
      cytokines. Concomitant treatment with IL-12 and IL-18 has been shown to
      synergistically induce IFN-gamma and may be an effective therapy for treating
      cancer, allergy, and infectious diseases. To understand the mechanisms underlying
      the strong induction of IFN-gamma by IL-12/IL-18 in mice, we focused our studies
      on the IFN-gamma-producing cells in various lymphoid organs and tissues and
      utilized the intracellular cytokine staining method to detect such cells in situ.
      After combined treatment with IL-12 and IL-18, IFN-gamma-positive cells in
      C57BL/6 mice were detected in the liver (12.18%), spleen (0.68%), bone marrow
      (1.80%), and peritoneum (2.12%), but not in the thymus or lymph nodes (<0.05 and
      <0.08%, respectively). A two-color staining method revealed that the majority of
      IFN-gamma-producing cells in the liver were NK1.1(+) cells, while those in the
      spleen were mostly CD3(+) cells, and to a lesser degree NK1.1(+) cells. Both
      CD4(+) and CD8(+) cells in the liver and in the spleen produced IFN-gamma. The
      CD19(+) B cell population was not definitely shown to produce IFN-gamma in our
      induction experiments. NKT cells, which are a subpopulation of NK1. 1(+) CD3(+)
      cells, were diminished in the liver and did not seem to contribute to IFN-gamma
      production arising from IL-12/IL-18 treatment. Further in vitro experiments
      confirmed the responsiveness of hepatic mononuclear cells to IL-12/IL-18
      stimulation. This study is the first to show the IFN-gamma-producing mechanisms
      of IL-12/IL-18 treatment at the phenotypic level.

PMID- 10648126
TI  - Heterogeneous cytokine production by acutely stimulated bronchoalveolar T
      lymphocytes in reovirus 1/Lang-infected mice.
AB  - While the in vitro properties of CD4(+) and CD8(+) cytokine-producing lymphocytes
      have been well studied, the in vivo cytokine production patterns and relative
      roles of CD4(+) and CD8(+) T lymphocytes during a primary in vivo immune response
      remain unclear. In this study, mice were inoculated intranasally with reovirus
      1/L, and respiratory T lymphocyte populations were analyzed using multicolor flow
      cytometric analysis for the production of cytokine within and between classical
      type 1/type 2 patterns. Cytokine production observed in vivo following infection
      did not correlate with classical T cell cytokine expression patterns; instead,
      multiple types of lymphocyte populations that produced one of several possible
      cytokine combinations were present. Cytokine production by CD4(+) lymphocytes
      appears in the early and middle stages of the immune response, while CD8(+)
      lymphocytes produce more cytokine in the later stages. Early cytokine responses
      occurred predominantly in the whole lung and lung-associated lymph node
      populations. The complex patterns of cytokine expression seen in this study
      likely influence local cell-mediated immunity as well as the complex interaction
      of T cell subsets and the interaction of T cells with B cells which are necessary
      for the generation of cell-mediated and humoral immune responses required for
      effective broad-spectrum immunity.

PMID- 10648127
TI  - Enhanced immune response to the melanoma antigen gp100 using recombinant
      adenovirus-transduced dendritic cells.
AB  - Glycoprotein 100 (gp100) is one of a series of well-characterized human melanoma
      associated antigens expressed by most melanoma cells. Immunization of C57BL/6
      mice with an adenovirus (Ad) vector encoding human gp100 (Adhgp100) has been
      shown to induce limited protective immunity against challenge with murine
      melanoma B16 cells. In the current study we determined whether gp100-specific
      immunity can be enhanced using bone-marrow-derived dendritic cells (DCs)
      transduced with Adhgp100 ex vivo. Subcutaneous injection of Adhgp100-infected DCs
      resulted in potent T-cell-mediated protective immunity and a greater than 80%
      reduction of established tumors when administered to B16 tumor-bearing hosts.
      Compared to direct injection of Adhgp100 vector alone, immunization with Adhgp100
      infected DCs induced markedly greater antitumor activity. In vitro CTL analysis
      demonstrated that DC-Adhgp100 immunization activated both CD4(+) and CD8(+) CTLs,
      while no lytic activity was generated by vaccination with Adhgp100 alone. In vivo
      depletion of CD4(+) T cells, but not CD8(+) T cells, completely abrogated CTL
      activity, suggesting that Adhgp100-transduced DCs result in activation of both
      CD4(+) and CD8(+) CTLs via a CD4(+)-dependent mechanism. We speculate that this
      improved efficacy of Adhgp100-transduced DCs compared to direct immunization with
      Adhgp100 may be the result of direct DC-mediated CD4(+) T cell activation. These
      results emphasize the importance of CD4(+) T cells in the development of
      therapeutic antigen-specific cancer vaccines.

PMID- 10648128
TI  - B1 B cell numbers and antibodies against phosphorylcholine and LPS are increased
      in IL-6 gene knockout mice.
AB  - Peritoneal cavity cells were isolated from IL6-gene knockout (IL6(-/-)) and wild
      type mice and stained for expression of IgM, CD5, and CD23. B1 cell (IgM(+)/CD23(
      ), CD5(+)/IgM(+)) numbers were increased twofold in IL6(-/-) mice compared to
      normals while IgM(+)/CD23(+) (B2) cell numbers were reduced threefold. Intestinal
      antibody levels were also determined for both total immunoglobulin and
      phosphorylcholine (PC)-specific and LPS-specific antibody following oral
      challenge with attenuated Salmonella typhimurium. Total immunoglobulin levels
      (IgM, IgG, and IgA) were reduced 60-80% in intestinal secretions of IL6(-/-) mice
      compared to wild-type controls; however, PC-specific antibody was significantly
      higher in IL6(-/-) mice. Anti-LPS antibodies were also three- to sevenfold higher
      in IL6(-/-) mice compared to controls following Salmonella challenge. These data
      suggest that in IL6(-/-) mice the development of mucosal B2 cells is impaired but
      that intestinal B1 cells responding to microbial antigens such as PC and LPS
      develop normally and are fully functional.

PMID- 10648129
TI  - An evaluation of endocrine modulators: implications for human health.
AB  - The potential health risk of a group of chemicals, popularly known as "endocrine
      disrupters," has generated considerable scientific debate and media attention.
      The endocrine disrupter hypothesis asserts that exogenous substances with
      estrogenic or other hormonally active properties may adversely affect human
      health. Proponents of this hypothesis have associated endocrine modulators with
      negative outcomes such as cancer in hormonally sensitive tissues and declining
      sperm counts in men. However, the available laboratory, wildlife, and
      epidemiological data do not provide consistent or convincing evidence that
      industrial chemicals suspected of modulating estrogenic pathways are related to
      adverse health effects in humans. Both public and private initiatives are
      investigating chemicals labeled as endocrine disrupters for their relative
      hormonal activity. Screening assays aimed at assessing the endocrine activity or
      potential of a variety of substances should not be confused with assessment of
      risk to humans, however. The latter entails not only hazard identification (the
      type of information that screening assays are designed to provide), but also
      critical factors such as exposure analysis, potency assessment, and dose-response
      for individual chemicals.

PMID- 10648130
TI  - Antioxidant biomarkers in freshwater bivalves, Unio tumidus, in response to
      different contamination profiles of aquatic sediments.
AB  - Antioxidant systems were studied in the freshwater bivalve Unio tumidus
      transplanted from a control site to four different contaminated areas, in order
      to study the biological response according to the contamination characteristics.
      Reduced and oxidized glutathione (GSH, GSSG), the activities of antioxidant
      enzymes such as selenium-dependent and non-selenium-dependent glutathione
      peroxidases (SeGPx and non-SeGPx), and glutathione reductase (GRd) were measured
      in the gills and the digestive gland of the mussels after 15 days of exposure at
      different sites. Lipid peroxidation (LPO) was evaluated by means of
      malondialdehyde measurements (MDA). The four sites investigated were located in
      the valleys of Fensch (F), Moselle (M), Lot et Garonne (LG), and Sarthe (S). At
      each site, the bivalves were placed upstream (Up) from an identified pollution
      source (a cokery, a laundry, or a foundry) and downstream (Do), close to the
      effluent outfall (Do(1)) or farther (Do(2)). The goal was to study the
      antioxidant response in relation to the pollution gradient. Metals and congeners
      of PAHs, PCBs, and organochlorinated pesticides were analyzed in the river
      sediments of each station. The exposure of the bivalves at the most highly
      polluted sites or close to the pollution source led to a sharp depletion in some
      antioxidant parameters, namely GRd, SeGPx, and GSH. The decrease in enzyme
      activities could reach 80% for GRd and 70% for SeGPx, while GSH depletion could
      yield 70%, leading then in an induction of lipid peroxidation, either in the
      digestive gland or in the gills. The higher the MDA concentrations, the lower the
      activity of these three antioxidant parameters, suggesting that they could be
      biomarkers for toxicity. Yet, a depletion in these parameters was sometimes
      insufficient for cytotoxicity to be induced, since lipid peroxidation failed to
      appear in some cases where antioxidant depletion was clear, although not so
      severe. The response of the gills and the digestive gland was not always
      paralleled, which can be explained by differences in the bioavailability of
      pollutants. In some cases, a relationship was not found between the antioxidant
      response and the degree and the type of contamination in sediments, suggesting
      that the effects could result from nonidentified pollutants or/and be indicators
      of bio-availability.

PMID- 10648131
TI  - Uptake, toxicity, and effects on detoxication enzymes of atrazine and
      trifluoroacetate in embryos of zebrafish.
AB  - The uptake, toxicity, and elimination of atrazine and trifluoroacetate (TFA) were
      studied in early life stages of the zebrafish (Danio rerio). Furthermore, the
      effects of these xenobiotics on soluble (s) and microsomal (m) glutathione S
      transferases (GST) of zebrafish embryos were investigated using 1-chloro-2,4
      dinitrobenzene (CDNB), 1,2-dichloro-4-nitrobenzene (DCNB), and [(14)C]atrazine.
      [(14)C]Atrazine was taken up by the embryos within seconds, unhindered by the
      chorions. It accumulated in the embryos by a factor of 19 after 24 h of exposure
      time. LC(50) (48 h) was determined at 36.8 mg/L. At a level of 5 mg/L atrazine,
      activities of s and m GSTs were elevated in most stages, especially in prim 6 and
      long pec stage (24, 48 h after fertilization, respectively). GST activity toward
      atrazine was detectable only in untreated D. rerio eggs, increasing with
      developmental time. [(14)C]Atrazine was eliminated from the embryos between 24
      and 48 h, indicating a possible metabolism to a more hydrophilic GSH conjugate.
      [(14)C]TFA was taken up by embryos, reaching at maximum fivefold the
      concentration of the incubation medium after 10 h. The chorions served no
      physiological protection. TFA (1 g/L) caused low elevation of the GST activity.
      No acute toxic effects (48 h) were observed up to 4 g/L TFA.

PMID- 10648132
TI  - Hazard assessment of selenium and other trace elements in wild larval razorback
      sucker from the Green River, Utah.
AB  - Contaminant investigations of the Green River in northeastern Utah have
      documented selenium contamination at sites receiving irrigation drainage. The
      Green River provides critical habitat for four endangered fishes including the
      largest extant riverine population of endangered razorback sucker. Although 2175
      larval razorback suckers were collected from the river between 1992 and 1996,
      very few juveniles have been captured within recent decades. Selenium
      concentrations were measured in larval razorback suckers collected from five
      sites in the Green River (Cliff Creek, Stewart Lake Drain, Sportsman's Drain,
      Greasewood Corral, and Old Charlie Wash) to assess the potential for adverse
      effects on recruitment of larvae to the juvenile stage and the adult population.
      Larvae from all sites contained mean selenium concentrations ranging from 4.3 to
      5.8 microg/g. These values were at or above the proposed toxic threshold of 4
      microg/g for adverse biological effects in fish, which was derived from several
      laboratory and field studies with a wide range of fish species. At two sites,
      Cliff Creek and Stewart Lake Drain, selenium concentrations in larvae increased
      over time as fish grew, whereas selenium concentrations decreased as fish grew at
      Sportsman's Drain. Evaluation of a 279-larvae composite analyzed for 61 elements
      demonstrated that selenium and, to a lesser extent, vanadium were elevated to
      concentrations reported to be toxic to a wide range of fish species. Elevated
      selenium concentrations in larval razorback suckers from the five sites suggest
      that selenium contamination may be widespread in the Green River, and that
      survival and recruitment of larvae to the juvenile stage may be limited due to
      adverse biological effects. Selenium contamination may be adversely affecting the
      reproductive success and recruitment of endangered razorback sucker.

PMID- 10648134
TI  - Intraspecific variation in gamma-radiation resistance and genomic structure in
      the filamentous fungus Alternaria alternata: a case study of strains inhabiting
      Chernobyl reactor no. 4.
AB  - This is probably the first report on intraspecific variation in radiation
      resistance for filamentous fungi. It was revealed that natural ("field") strains
      of the filamentous fungus Alternaria alternata are extremely variable in response
      to gamma-irradiation ranging from supersensitive to highly resistant to
      radiation. At the same time nearly all strains originating from the highly
      radiation-polluted reactor of the Chernobyl (Ukraine) Nuclear Power Plant
      possessed high radiation resistance. The genome structure of strains studied by
      universally primed polymerase chain reaction (UP-PCR) was found to be well
      conserved in "reactor" but not in "control" strains. The "reactor" strains appear
      to be genetically adapted to this high radiation habitat by means of selection,
      thus providing a natural source of genetically homogeneous fungal lineages.

PMID- 10648135
TI  - Using constructed wetlands to treat biochemical oxygen demand and ammonia
      associated with a refinery effluent.
AB  - This study evaluated the effectiveness of constructed wetlands for tertiary
      treatment of a petroleum refinery effluent. Specific performance objectives were
      to decrease 5-day biochemical oxygen demand (BOD(5)) and ammonia by at least 50%
      and to reduce toxicity associated with this effluent. Two bench-scale wetlands
      (replicates) were constructed in a greenhouse to provide tertiary treatment of
      effluent samples shipped from the refinery to the study site. Integrated wetland
      features included Typha latifolia Linnaeus planted in low organic (0.2%), sandy
      sediment, 48-h nominal hydraulic retention time, and 15-cm overlying water depth.
      Targeted constituents and aqueous toxicity were monitored in wetland inflows and
      outflows for 3 months. Following a 2 to 3-week stabilization period, effective
      and consistent removal of BOD(5) and ammonia (as NH(3)-N) from the effluent was
      observed. Average BOD(5) removal was 80%, while NH(3)-N decreased by an average
      of 95%. Survival of Pimephales promelas Rafinesque and Ceriodaphnia dubia Richard
      (7-day, static, renewal exposures) increased by more than 50% and 20%,
      respectively. Reproduction of C. dubia increased from zero in undiluted wetland
      inflow to 50% of controls in undiluted wetland outflow. This study demonstrated
      the potential for constructed wetlands to decrease BOD(5), ammonia, and toxicity
      in this refinery effluent.

PMID- 10648133
TI  - Development of methods for evaluating toxicity to freshwater ecosystems.
AB  - This article presents a summary of a collaborative research program involving
      five European research groups, that was partly funded by the European Commission
      under its Environmental Research Program. The objective of the program was to
      develop aquatic toxicity tests that could be used to obtain data for inclusion at
      Level 2 of the Risk Evaluation Scheme for the Notification of Substances as
      required by the 7th Amendment to EC Directive 79/831/EEC. Currently only a very
      limited number of test methods have been described that can be used for this
      purpose and these are based on an even smaller number of test species. Tests
      based upon algae (Chlamydomonas reinhardi, Scenedesmus subspicatus, and Euglena
      gracilis), protozoa (Tetrahymena pyriformis), rotifera (Brachionus calyciflorus),
      crustacea (Gammarus pulex), and diptera (Chironomus riparius) were developed. The
      tests encompassed a range of end points and were evaluated against four reference
      chemicals: lindane, 3, 4-dichloroaniline (DCA), atrazine, and copper. The
      capacity of the tests to identify concentrations that are chronically toxic in
      the field was addressed by comparing the effects threshold concentrations
      determined in the laboratory tests with those determined for similar and/or
      related species and end points in stream and pond mesocosm studies. The lowest no
      observed-effect concentrations (NOEC), EC(x), or LC(x) values obtained for
      lindane, atrazine, and copper were comparable with the lowest values obtained in
      the mesocosms. The lowest chronic NOEC determined for DCA using the laboratory
      tests was approximately 200 times higher than the lowest NOEC in the mesocosms.

PMID- 10648136
TI  - Environmental research section A

PMID- 10648137
TI  - Microscopic displacement imaging with pulsed field gradient turbo spin-echo NMR.
AB  - We present a pulse sequence that enables the accurate and spatially resolved
      measurements of the displacements of spins in a variety of (biological) systems.
      The pulse sequence combines pulsed field gradient (PFG) NMR with turbo spin-echo
      (TSE) imaging. It is shown here that by ensuring that the phase of the echoes
      within a normal spin-echo train is constant, displacement propagators can be
      generated on a pixel-by-pixel basis. These propagators accurately describe the
      distribution of displacements, while imaging time is decreased by using separate
      phase encoding for every echo in a TSE train. Measurements at 0.47 T on two
      phantoms and the stem of an intact tomato plant demonstrate the capability of the
      sequence to measure complete and accurate propagators, encoded with 16 PFG steps,
      for each pixel in a 128 x 128 image (resolution 117 x 117 x 3,000 microm) within
      17 min. Dynamic displacement studies on a physiologically relevant time
      resolution for plants are now within reach.

PMID- 10648138
TI  - The NMR spectra of samples dissolved in liquid-crystalline phases: automatic
      analysis with the aid of multiple quantum spectra--the case of flexible
      molecules.
AB  - Homonuclear N(S) = 0 and heteronuclear N(S) not equal 0 multiple quantum spectra,
      involving changes in the magnetic number m(I) by (N(I)-1), (N(I) - 2), and (N(I)
      3), with N(I) and N(S) the number of interacting nuclei of magnetogyric ratio
      gamma(I) and gamma(S), are used for the automatic analysis of (1)H NMR spectra of
      flexible molecules dissolved in liquid-crystalline phases. The automatic
      procedure has been applied to study molecules of general formula Ph-CH(2)-X
      starting from a parameter set having all the spectral parameters set to zero. The
      results of such an analysis are then used as starting parameters for analysis of
      the single quantum spectrum. The method was first tested when X = Br and X = H in
      order to compare strategies differing for the types of parameters used and was
      then applied to the analysis of 3-phenylprop-1-yne.

PMID- 10648139
TI  - Characterization of molecular motion in the solid state by carbon-13 spin-lattice
      relaxation times.
AB  - Relaxation calculations for rapidly spinning samples show that spin-lattice
      relaxation time (T(1Z)) anisotropy varies with the angle between the rotor
      spinning axis and the external field. When the rate of molecular motion is in the
      extreme narrowing limit, the measurement of T(1Z) anisotropies for two different
      values of the spinning angle allows the determination of two linear combinations
      of the three static spectral densities, J(0)(0), J(1)(0), and J(2)(0). These
      functions are sensitive to molecular geometry and the rate and trajectory of
      motion. The utility of these linear combinations in the investigation of
      molecular dynamics in solids has been demonstrated with natural abundance (13)C
      NMR experiments on ferrocene. In an isolated (13)C-(1,2)H group, the dipole
      dipole interaction has the same orientational dependence as the quadrupole
      interaction. Thus, the spectral densities that are responsible for dipolar
      relaxation of (13)C are the same as those responsible for deuteron quadrupolar
      relaxation. For ferrocene-d(10), deuteron T(1Z) and T(1Q) anisotropies and the
      relaxation time of the (13)C magic angle spinning peak provide sufficient
      information to determine the orientation dependence of all three individual
      spectral densities.

PMID- 10648140
TI  - A fast variant of (1)H spectroscopic U-FLARE imaging using adjusted chemical
      shift phase encoding.
AB  - So far, fast spectroscopic imaging (SI) using the U-FLARE sequence has provided
      metabolic maps indirectly via Fourier transformation (FT) along the chemical
      shift (CS) dimension and subsequent peak integration. However, a large number of
      CS encoding steps N(omega) is needed to cover the spectral bandwidth and to
      achieve sufficient spectral resolution for peak integration even if the number of
      resonance lines is small compared to N(omega) and even if only metabolic images
      are of interest and not the spectra in each voxel. Other reconstruction
      algorithms require extensive prior knowledge, starting values, and/or model
      functions. An adjusted CS phase encoding scheme (APE) can be used to overcome
      these drawbacks. It incorporates prior knowledge only about the resonance
      frequencies present in the sample. Thus, N(omega) can be reduced by a factor of 4
      for many (1)H in vivo studies while no spectra have to be reconstructed, and no
      additional user interaction, prior knowledge, starting values, or model function
      are required. Phantom measurements and in vivo experiments on rat brain have been
      performed at 4.7 T to test the feasibility of the method for proton SI.

PMID- 10648141
TI  - Fast and accurate characterization of biological membranes by EPR spectral
      simulations of nitroxides.
AB  - A method by which it is possible to characterize the membranes of biological
      samples on the basis of the EPR spectral lineshape simulation of membrane
      dissolved nitroxide spin probes is described. The presented simulation procedure
      allows the determination of the heterogeneous structure of biological membranes
      and fluidity characteristics of individual membrane domains. The method can deal
      with isotropic and anisotropic orientations of nitroxides introduced into the
      biological samples described by restricted fast motion with a correlation time
      between 0.01 and 10 ns. The linewidths of the Lorentzian lineshapes are
      calculated in a restricted fast-motion approximation. In the special case of
      samples with high concentrations of nitroxides or in the presence of paramagnetic
      ions, the lineshapes are calculated directly from the exchange-coupled Bloch
      equations. The parameters describing ordering, relaxation, polarity, and the
      portions of the individual spectral components are extracted by optimizing the
      simulated spectra to the experimental spectrum with either a Simplex or a Monte
      Carlo algorithm. To improve the algorithm's efficiency, a new way of
      characterizing the goodness of fits is introduced. The new criterion is based on
      the standard least-squares function, but with special weighting of the partial
      sums. Its benefits are confirmed with membrane spectral simulation. Two classes
      of examples-simulation and optimizations of synthetic spectra to evaluate the
      accuracy of the optimization algorithms and simulation and optimization of EPR
      spectra of nitroxides in liposome suspensions in the presence of a broadening
      agent and in human leukocytes are shown.

PMID- 10648142
TI  - A new method for quantitation of spin concentration by EPR spectroscopy:
      application to methemoglobin and metmyoglobin.
AB  - A new method of EPR spectral analysis is developed to quantitate overlapping
      signals. The method requires double integration of a number of spectra containing
      the signals in different proportions and the subsequent solution of a system of
      linear equations. The result gives the double integral values of the individual
      lines, which can then be further used to find the concentrations of all the
      paramagnetic species present. There is no requirement to deconvolute the whole
      spectrum into its individual components. The method is employed to quantify
      different heme species in methemoglobin and metmyoglobin preparations. A
      significantly greater intensity of the high-spin signal in metmyoglobin, compared
      to methemoglobin at the same heme concentration, is shown to be due to larger
      amounts of low-spin forms in methemoglobin. Three low-spin types in methemoglobin
      and two in metmyoglobin are present in these samples. When their calculated
      concentrations are added to those of the high-spin forms, the results correspond
      to the total heme concentrations obtained by optical spectroscopy.

PMID- 10648143
TI  - New (15)N NMR exchange experiments for the unambiguous assignment of
      (1)H(N)/(15)N resonances of proteins in complexes in slow chemical exchange with
      free form.
AB  - The potentialities of a 2D proton-detected heteronuclear exchange experiment to
      assign the nitrogen and amide proton resonances in a uniformly (15)N-enriched
      macromolecule involved in a complex, starting from the free form assignments, are
      demonstrated on a protein-DNA complex. This 2D experiment is further extended to
      a 3D experiment in the case of severe superpositions.

PMID- 10648144
TI  - Analytical polarization and coherence transfer functions for three dipolar
      coupled spins 12.
AB  - Analytical polarization and coherence transfer functions are presented for a spin
      system consisting of three dipolar coupled homonuclear spins 12 under energy
      matched conditions. Based on these transfer functions, optimal durations of
      Hartmann-Hahn mixing periods can be determined for arbitrary dipolar coupling
      constants D(12), D(13), and D(23). In addition, the dependence of the transfer
      efficiency on the relative size of the dipolar coupling constants is illustrated.

PMID- 10648145
TI  - 3D HCCH(3)-TOCSY for resonance assignment of methyl-containing side chains in
      (13)C-labeled proteins.
AB  - Two 3D experiments, (H)CCH(3)-TOCSY and H(C)CH(3)-TOCSY, are proposed for
      resonance assignment of methyl-containing amino acid side chains. After the
      initial proton-carbon INEPT step, during which either carbon or proton chemical
      shift labeling is achieved (t(1)), the magnetization is spread along the amino
      acid side chains by a carbon spin lock. The chemical shifts of methyl carbons are
      labeled (t(2)) during the following constant time interval. Finally the
      magnetization is transferred, in a reversed INEPT step, to methyl protons for
      detection (t(3)). The proposed experiments are characterized by high digital
      resolution in the methyl carbon dimension (t(2max) = 28.6 ms), optimum
      sensitivity due to the use of proton decoupling during the long constant time
      interval, and an optional removal of CH(2), or CH(2) and CH, resonances from the
      F(2)F(3) planes. The building blocks used in these experiments can be implemented
      in a range of heteronuclear experiments focusing on methyl resonances in
      proteins. The techniques are illustrated using a (15)N, (13)C-labeled E93D mutant
      of Schizosacharomyces pombe phosphoglycerate mutase (23.7 kDa).

PMID- 10648146
TI  - Sensitivity improvement and new acquisition scheme of heteronuclear active
      coupling-pattern-tilting spectroscopy.
AB  - A simplified phase-cycling scheme for heteronuclear active-coupling-pattern
      tilting (ACT) spectroscopy is presented. It is demonstrated that the
      theoretically expected twofold sensitivity gain over earlier implementations can
      be experimentally realized. A further intensity increase by a factor of 2 is
      obtained with standard sensitivity-enhancement pulse-sequence elements. The HSQC
      HECADE sequence presented is designed for an accurate determination of
      heteronuclear one-bond and, with subsequent I-spin isotropic mixing, long-range
      coupling constants. As an exemplary application, the determination of the
      (3)J(N,Hbeta) coupling constants in a peptide at natural isotope abundance is
      demonstrated. Additionally, a new polarization-transfer step for the long-range
      HSQC-HECADE experiment is proposed which avoids a fixed delay tuned to a specific
      coupling-constant value. Thus, the long-range correlation experiment does not
      require prior knowledge of the coupling constants to be measured and yields more
      uniform cross-peak intensity for a broad range of active coupling constants.

PMID- 10648147
TI  - Ultrawide band multifrequency high-field EMR technique: A methodology for
      increasing spectroscopic information.
AB  - We report methodology that combines an ultrawide band multifrequency microwave
      system with technology of high magnetic fields for solving challenging problems
      in electron magnetic resonance (EMR) spectroscopy. This strategy has been made
      possible due to a novel EMR facility operating in an exceptionally wide range of
      microwave frequencies of 24 GHz to 3 THz, at magnetic fields up to 17 T, and in
      the temperature range of 1.6 to 330 K. The basic configuration of the
      multifrequency system works in a transmission mode and employs oversized
      cylindrical waveguides for routing the microwave power. A wide-band, low-noise,
      liquid helium cooled (4.2 K) InSb bolometer is used for signal detection. This
      approach results in an extremely wide-band performance, thus making it possible
      to employ a variety of solid-state millimeter and submillimeter microwave sources
      in combination with a far infrared laser microwave source for performing
      multifrequency EMR experiments. A complexity of resonant structures and related
      technical problems such as microphonics at high magnetic fields is virtually
      eliminated. The system is simple, yet sensitive, and has been revealed to be
      extremely advantageous while solving such problems as observation of AFMR
      transitions in spin-ordered systems, g-factor resolution enhancement in complex
      organic radicals, and resonance signal detection in EMR-silent spin systems
      having integer spin and large zero field splitting. A technical description of
      the multifrequency high-field EMR facility is presented and results of its
      performance tests are given. The potential utility of using the multifrequency
      high-field methodology in EMR studies is illustrated with selected examples of
      its recent applications.

PMID- 10648148
TI  - A k-space analysis of MR tagging.
AB  - We present a k-space approximation that directly relates a pulse sequence to its
      residual pattern of z-directed magnetization M(z), in a manner akin to the k
      space approximation for small tip-angle excitation. Our approximation is
      particularly useful for the analysis and design of tagging sequences, in which
      M(z) is the important quantity-as opposed to the transverse magnetization
      components M(x) and M(y) considered in selective excitation. We demonstrate that
      our approximation provides new insights into tagging, can be used to design novel
      tag patterns, and, more generally, may be applied to selective presaturation
      sequences for purposes other than tagging.

PMID- 10648149
TI  - Improved convection compensating pulsed field gradient spin-echo and stimulated
      echo methods.
AB  - The need for convection compensating methods in NMR has been manifested through
      an increasing number of publications related to the subject over the past few
      years (J. Magn. Reson. 125, 372 (1997); 132, 13 (1998); 131, 126 (1998); 118, 50
      (1996); 133, 379 (1998)). When performing measurements at elevated temperature,
      small convection currents may give rise to erroneous values of the diffusion
      coefficient. In work with high resolution NMR spectroscopy, the application of
      magnetic field gradients also introduces an eddy-current magnetic field which may
      result in errors in phase and baseline in the FFT-spectra. The eddy current field
      has been greatly suppressed by the application of bipolar magnetic field
      gradients. However, when introducing bipolar magnetic field gradients, the pulse
      sequence is lengthened significantly. This has recently been pointed out as a
      major drawback because of the loss of coherence and of NMR-signal due to
      transverse relaxation processes. Here we present modified convection compensating
      pulsed field gradient double spin echo and double stimulated echo sequences which
      suppress the eddy-current magnetic field without increasing the duration of the
      pulse sequences.

PMID- 10648151
TI  - Dead-time free measurement of dipole-dipole interactions between electron spins.
AB  - A four-pulse version of the pulse double electron-electron resonance (DEER)
      experiment is presented, which is designed for the determination of interradical
      distances on a nanoscopic length-scale. With the new pulse sequence electron
      electron couplings can be studied without dead-time artifacts, so that even broad
      distributions of electron-electron distances can be characterized. A version of
      the experiment that uses a pulse train in the detection period exhibits improved
      signal-to-noise ratio. Tests on two nitroxide biradicals with known length
      indicate that the accessible range of distances extends from about 1.5 to 8 nm.
      The four-pulse DEER spectra of an ionic spin probe in an ionomer exhibit features
      due to probe molecules situated both on the same and on different ion clusters.
      The former feature provides information on the cluster size and is inaccessible
      with previous methods.

PMID- 10648150
TI  - Modified spectral editing methods for (13)C CP/MAS experiments in solids.
AB  - The spectral editing approach of Zilm and coworkers utilizes polarization,
      polarization inversion, and spin depolarization methods for enhancing or
      suppressing NMR spectral lines in solids. The proposed pulse sequences allow
      nonprotonated C, CH, CH(2), and CH(3) types of carbon resonances to be separated
      from one another and identified accordingly. The former method tentatively
      separates the nonprotonated C and CH(3) peaks with a cutoff shift of 35 ppm. This
      shift is a reasonable demarcation shift for a preponderance of organic molecules,
      but exceptions do exist that could constitute a serious drawback in a few
      instances. The new approach separates the nonprotonated C and CH(3) carbon peaks
      unequivocally using modified pulse sequences similar to those of Zilm. Further,
      both the CH only and CH(2) only spectra, respectively, can be acquired directly
      from combining so called (+) and (-) sequences using different spectral delay
      periods and pulse parameters. The (+) and the (-) pulse sequences produce signals
      for the nonprotonated and methyl carbons that have essentially the same amplitude
      but opposite phases. These spectra, combined with the previously reported CH(3)
      and nonprontonated C only spectra, offer a complete spectral editing technique
      for solid samples. Examples of these spectral editing methods are provided for 3
      methylglutaric acid, fumaric acid monoethyl ester, and two complex natural
      products: methyl o-methylpodocarpate and 10-deacetylbaccatin III.

PMID- 10648152
TI  - Time-domain quantification of multiple-quantum-filtered (23)Na signal using
      continuous wavelet transform analysis.
AB  - The application of continuous wavelet transform (CWT) analysis technique is
      presented to analyze multiple-quantum-filtered (MQF) (23)Na magnetic resonance
      spectroscopy (MRS) data. CWT acts on the free-induction-decay (FID) signal as a
      time-frequency variable filter. The signal-to-noise ratio (SNR) and frequency
      resolution of the output filter are locally increased. As a result, MQF
      equilibrium longitudinal magnetization and the apparent fast and slow transverse
      relaxation times are accurately estimated. A developed iterative algorithm based
      on frequency signal detection and components extraction, already proposed, was
      used to estimate the values of the signal parameters by analyzing simulated time
      domain MQF signals and data from an agarose gel. The results obtained were
      compared to those obtained by measurement of signal height in frequency domain as
      a function of MQF preparation time and those obtained by a simple time-domain
      curve fitting. The comparison indicates that the CWT approach provides better
      results than the other tested methods that are generally used for MQF (23)Na MRS
      data analysis, especially when the SNR is low. The mean error on the estimated
      values of the amplitude signal and the apparent fast and slow transverse
      relaxation times for the simulated data were 2.19, 6. 63, and 16.17% for CWT,
      signal height in frequency domain, and time-domain curve fitting methods,
      respectively. Another major advantage of the proposed technique is that it allows
      quantification of MQF (23)Na signal from a single FID and, thus, reduces the
      experiment time dramatically.

PMID- 10648153
TI  - Toroid cavity detectors for high-resolution NMR spectroscopy and rotating frame
      imaging: capabilities and limitations.
AB  - The capabilities of toroid cavity detectors for simultaneous rotating frame
      imaging and NMR spectroscopy have been investigated by means of experiments and
      computer simulations. The following problems are described: (a) magnetic field
      inhomogeneity and subsequent loss of chemical shift resolution resulting from
      bulk magnetic susceptibility effects, (b) image distortions resulting from off
      resonance excitation and saturation effects, and (c) distortion of lineshapes and
      images resulting from radiation damping. Also, special features of signal
      analysis including truncation effects and the propagation of noise are discussed.
      B(0) inhomogeneity resulting from susceptibility mismatch is a serious problem
      for applications requiring high spectral resolution. Image distortions resulting
      from off-resonance excitation are not serious within the rather narrow spectral
      range permitted by the RF pulse lengths required to read out the image.
      Incomplete relaxation effects are easily recognized and can be avoided. Also,
      radiation damping produces unexpectedly small effects because of self
      cancellation of magnetization and short free induction decay times. The results
      are encouraging, but with present designs only modest spectral resolution can be
      achieved.

PMID- 10648154
TI  - Improved reduction of motion artifacts in diffusion imaging using navigator
      echoes and velocity compensation.
AB  - Navigator echoes provide a means with which to remove motion artifacts from
      diffusion-weighted images obtained using any multishot imaging technique.
      However, residual motion artifact is often present in the corrected images
      rendering the technique unreliable. It is shown that velocity-compensated
      diffusion sensitization when used in tandem with a navigator echo further reduces
      the degree of residual motion artifacts present in the corrected images and
      improves the reliability and clinical utility of the technique. This is
      demonstrated by applying a method for quantification of motion artifact to brain
      images of healthy volunteers scanned using both conventional (Stejskal-Tanner)
      and velocity-compensated gradient sensitization. Other factors affecting the
      efficacy of the navigator echo technique, such as brain pulsatile motion,
      gradient b factor, and navigator echo signal-to-noise ratio, are also discussed.

PMID- 10648155
TI  - Pulsed EPR spin-probe study of intracellular glasses in seed and pollen.
AB  - EPR spectra of 3-carboxy-proxyl (CP) in dry biological tissues exhibited a
      temperature-dependent change in the principal value A'(zz) of the hyperfine
      interaction tensor. The A'(zz) value changed sharply at a particular temperature
      that was dependent on water content. At elevated water contents, the break
      occurred at lower temperatures and appeared to be associated with the melting of
      the cytoplasmic glassy state. To investigate the reason for the change in A'(zz),
      we employed echo-detected EPR (ED EPR) spectroscopy. The shape of the ED EPR
      spectrum revealed the presence of librational motion of the spin probe, a motion
      typically present in glassy materials. The similarities in temperature dependency
      of A'(zz) and librational motion of CP in pea seed axes indicated that the change
      in A'(zz) arose from librational motion. ED EPR measurements of CP as a function
      of water content in Typha latifolia pollen showed that librational motion
      decreased with decreasing water contents until a plateau or minimum was reached.
      ED EPR spectroscopy is a valuable technique for characterizing the relation
      between molecular motion and storage kinetics of dry seed and pollen.

PMID- 10648156
TI  - Broadband heteronuclear Hartmann-Hahn sequences with short cycle times.
AB  - For some applications, broadband heteronuclear Hartmann-Hahn sequences with very
      short cycle times are required. A quality factor is presented that makes it
      possible to assess the relative sizes of cycle time, bandwidth, and maximum RF
      amplitude for any given multiple-pulse sequence. This quality factor is
      determined for multiple-pulse sequences that are commonly used in HEHAHA
      experiments and for some favorable sequences that were so far only discussed in
      the context of heteronuclear decoupling.

PMID- 10648157
TI  - Low-frequency molecular dynamics studied by spin-lock field cycling imaging.
AB  - Spin-lock adiabatic field cycling imaging (SLOAFI) relaxometry was shown to be a
      useful technique for obtaining a fast study of spin-lattice relaxation dispersion
      in the rotating frame. The aim of the present article is to describe some
      technical aspects of the experiment in more detail, while showing simple examples
      that can be compared with laboratory frame relaxation. We also present here a
      general discussion of the equations for an off-resonance experiment used to
      analyze low-frequency molecular dynamics.

PMID- 10648158
TI  - Small crystals and small coils in variable-temperature single-crystal NMR.
AB  - Time savings by a factor of between 20 and 30 in the acquisition of multinuclear
      single-crystal (SC) NMR spectra have been obtained for submillimeter-size (0.01
      to 0.03 mm(3)) single crystals when compared to recent results for (31)P and
      (87)Rb SC NMR. This gain in sensitivity is achieved by optimizing the filling
      factor using the smallest possible rf coil (2.0 mm inner diameter) for the
      specific SC probe design. Furthermore, this small coil is particularly useful for
      variable-temperature SC NMR studies. A probe design for such studies is presented
      and demonstrated experimentally.

PMID- 10648159
TI  - Three-dimensional pulsed ESR Fourier imaging.
AB  - Three-dimensional pulsed ESR imaging was performed on a (FA)(2)PF(6) crystal
      using a three-dimensional Fourier imaging sequence. The best resolution achieved
      was of 20 microm(3). Comparison with images obtained using the filtered back
      projection method shows the superiority of this method under the given
      conditions.

PMID- 10648160
TI  - A simple method for measuring the Q value of an NMR sample coil.
AB  - A simple method for measuring the Q (quality factor) value of an NMR sample coil
      based on an impedance matching principle is described. This method has the
      advantage of utilizing a signal generator and reflection coefficient bridge
      rather than an expensive high-frequency Q meter and offers an alternative means
      of measuring the Q value of an NMR sample coil or any other radio frequency coil.

PMID- 10648161
TI  - In-phase selective excitation of overlapping multiplets.
AB  - An editing experiment is presented that selects for a peak on the basis of its
      chemical shift and that of one of its scalar coupling partners. The selected
      multiplet is pure in-phase. The editing procedure can be used in conjunction with
      1D TOCSY/HOHAHA and NOE measurements. The pulse sequence described is
      particularly suitable for small molecules; data is presented for Gramicidin S and
      dehydrotestosterone.

PMID- 10648162
TI  - Direct refinement against proton-proton dipolar couplings in NMR structure
      determination of macromolecules.
AB  - The computational tools necessary for making use of (1)H-(1)H dipolar couplings
      in macromolecular structure refinement are presented. Potentials are described
      for direct refinement against (1)H-(1)H dipolar couplings of known sign as well
      as of unknown sign. In addition, a multiple potential is developed for prochiral
      protons whose stereospecific assignments are unknown. The utility of direct (1)H
      (1)H dipolar coupling refinement is illustrated using the small protein
      ubiquitin. It is shown that direct (1)H-(1)H dipolar coupling refinement leads to
      improvements in the precision, accuracy, and quality of the resulting structures.

PMID- 10648163
TI  - Improved expression characteristics of single-chain Fv fragments when fused
      downstream of the Escherichia coli maltose-binding protein or upstream of a
      single immunoglobulin-constant domain.
AB  - The expression of single-chain Fv fragments (scFv) targeted to the periplasm of
      Escherichia coli often results in very low yields of soluble protein frequently
      accompanied by host cell growth arrest and sometimes lysis. Single-chain antibody
      fragments (scAb) are scFv with a human kappa light chain constant (HuCkappa)
      domain attached C-terminally and share similar problems of expression. By fusing
      the E. coli maltose-binding protein (mbp) gene either 3' or 5' to a scAb specific
      for the herbicide atrazine, a reduction in growth arrest was observed that was
      dependent on the order of gene fusion. The scAb-mbp fusion delayed the onset of
      growth arrest following induction while the mbp-scAb fusion appeared to ablate
      growth arrest completely. Cell fractionation revealed barely detectable levels of
      scAb-mbp in the periplasm while mbp-scAb was detected at equivalent levels as
      scAb in the periplasmic compartment, indicating that periplasmic scAb solubility
      is unrelated to propensity to cause growth arrest. IMAC purification of scAb and
      mbp-scAb proteins followed by liquid competition ELISA revealed the IC(50) for
      atrazine to be approximately 1 nM for both proteins demonstrating that 5'-mbp
      fusion does not alter antigen binding. The equivalent scFv and mbp-scFv vectors
      expressed far less material in both periplasmic and insoluble fractions
      indicating that the HuCkappa domain can have a positive effect on scFv expression
      when expressed either alone or as a mbp fusion. The ablation of growth arrest by
      a 5'-mbp fusion and enhancement of expression by a 3'-HuCkappa domain fusion were
      extended to a second scFv specific for the herbicide diuron. Therefore, by
      expressing scFv as tripartite fusions (mbp-scFv-HuCkappa) enhanced levels of
      soluble periplasmic expression can be achieved without causing growth arrest of
      the host cell, realizing the potential for constitutive expression of hapten
      binding scFv in the E. coli periplasm.

PMID- 10648164
TI  - In vitro refolding of heterodimeric CapZ expressed in E. coli as inclusion body
      protein.
AB  - CapZ is a heterodimeric Ca(2+)-independent actin binding protein which plays an
      important role in organizing the actin filament lattice of cross-striated muscle
      cells. It caps the barbed end of actin filaments and promotes nucleation of actin
      polymerization, thereby regulating actin filament length. Here we report the
      expression of the two muscle-specific isoforms alpha2 and beta1, from chicken in
      Escherichia coli as individual subunits using the pQE60 expression vector and the
      subsequent renaturation of the functional CapZ heterodimer from inclusion bodies.
      Optimal renaturation conditions were obtained both by simultaneous refolding of
      urea-solubilized subunits and by rapid dilution into a buffer containing 20%
      glycerol, 5 mM EGTA, 2 mM DTT, 1 mM PMSF, and 100 mM Tris, pH 7.4. The refolding
      mixture was incubated for 24 h at 15 degrees C and the protein was concentrated
      by ultrafiltration. Biochemical characterization of the recombinant heterodimer
      revealed actin binding activities indistinguishable from those of native CapZ as
      purified from chicken skeletal muscle. Using the same protocol, we were able to
      refold the beta1, but not the alpha2 isoform as a single polypeptide, indicating
      a role for beta1 as a molecular template for the folding of alpha2. The reported
      recombinant approach leads to high yields of active heterodimer and allows the
      renaturation and characterization of the beta subunit.

PMID- 10648165
TI  - Overexpression, purification, and characterization of a barley alpha-glucosidase
      secreted by Pichia pastoris.
AB  - alpha-Glucosidases (EC 3.2.1.20) are recognized as important in starch
      degradation during cereal seed germination. A barley (Hordeum vulgare) alpha
      glucosidase expressed in Pichia pastoris was cultured in flasks; however, the
      yield was low necessitating the use of multiple batches. Problems arose because
      of significant variation between batches. We solved these problems by switching
      to a fermentation system producing a sufficient quantity of a uniform sample.
      Here we present the expression and purification of a recombinant alpha
      glucosidase grown under fermentation conditions. We also present the results of
      experiments to characterize the thermostability, pH optimum, and substrate
      specificity of the recombinant enzyme. The optimal pH for the hydrolysis of
      maltose by recombinant alpha-glucosidase is between 3.5 and 4.5. The
      thermostability of recombinant alpha-glucosidase was determined at pH 4, where
      activity is optimal, and at pH 5 and 6, which better mimic the conditions used to
      convert barley starch to fermentable sugars during industrial processing. The
      results indicate the enzyme is most thermolabile at pH 4. However, the enzyme is
      protected from heat inactivation at pH 4 by high concentrations of sucrose. The
      purified enzyme hydrolyzed maltose three times more rapidly than nigerose and 20
      times more rapidly than trehalose and isomaltose. Concentrations of maltose
      greater than 20 mM inhibited maltose hydrolysis. This is the first report of
      substrate inhibition for any alpha-glucosidase. The results indicate that the
      only significant difference between the recombinant enzyme and the previously
      characterized barley isoforms was the V(max) for maltose hydrolysis.

PMID- 10648166
TI  - Expression, purification, and characterization of recombinant S
      adenosylhomocysteine hydrolase from the thermophilic archaeon Sulfolobus
      solfataricus.
AB  - S-Adenosylhomocysteine hydrolase from Sulfolobus solfataricus was expressed in
      Escherichia coli by inserting the genomic fragment containing the gene encoding
      for S-adenosylhomocysteine hydrolase downstream the isopropyl-beta-d
      thiogalactoside-inducible promoter of pTrc99A expression vector. An ATG
      positioned 25 bp upstream of the gene which is in frame with a stop codon was
      utilized as the initiation codon. This construct was used to transform E. coli
      RB791 and E. coli JM105 strains. The recombinant protein, purified by a fast and
      efficient two-step procedure (yield of 0.4 mg of enzyme per gram of cells), does
      not appear homogeneous on SDS-PAGE because of the presence of a protein
      contaminant corresponding to a "truncated" S-adenosylhomocysteine hydrolase
      subunit lacking the first 24 amino acid residues. The recombinant enzyme shows
      the same molecular mass, optimum temperature, and kinetic features of S
      adenosylhomocysteine hydrolase isolated from S. solfataricus but it is less
      thermostable. To construct a vector which presents a correct distance between the
      ribosome-binding site and the start codon of S-adenosylhomocysteine hydrolase
      gene, a NcoI site was created at the translation initiation codon using site
      directed mutagenesis. The expression of the homogeneous mutant S
      adenosylhomocysteine hydrolase was achieved at high level (1.7 mg of mutant
      protein per gram of cells). The mutant S-adenosylhomocysteine hydrolase and the
      native one were indistinguishable in all physicochemical and kinetic properties
      including thermostability, indicating that the interactions involving the NH(2)
      terminal sequence of the protein play a role in the thermal stability of S.
      solfataricus S-adenosylhomocysteine hydrolase.

PMID- 10648167
TI  - Purification and characteristics of recombinant human folylpoly-gamma-glutamate
      synthetase expressed at high levels in insect cells.
AB  - Folylpoly-gamma-glutamate synthetase activity is central to the operation of
      folate metabolism and is essential for the survival of mammalian stem cell
      populations but the very low levels of endogenous expression of this enzyme have
      greatly limited its study. We now report the expression of cytosolic folylpoly
      gamma-glutamate synthetase (FPGS) cloned from human leukemic cells in baculovirus
      infected insect cells at levels of 4-5% of the total soluble protein of the
      cells. As was the case with endogenously expressed mammalian FPGS, recombinant
      enzyme was quantitatively blocked at the amino terminus in spite of the large
      scale production in insect cells. A three-step purification procedure resulted in
      an overall yield of 7-35 mg per liter of culture with a recovery of about 50% and
      purity approximately 95%; pure enzyme was stable to storage for extended periods.
      Pure protein had a specific activity of 25 micromol h(-1)mg(-1) with aminopterin
      as a substrate and used a broad spectrum of folates as substrates. The pure
      enzyme also carried out ATP hydrolysis in the absence of a folate substrate or
      glutamic acid; this partial reaction occurred at a k(cat) about 0.4% that of the
      full reaction. In vitro, this single protein added several (1-8) moles of
      glutamic acid per mole of folate analog, the same spectrum of folate
      polyglutamates as seen in vivo. The quantities of pure enzyme achievable in
      insect cells should allow functional and structural studies on this enzyme.

PMID- 10648168
TI  - Purification and characterization of a unique alkaline elastase from Micrococcus
      luteus.
AB  - Micrococcus luteus isolated from human skin secretes an alkaline protease which
      degrades elastin. M. luteus protease (MLP) was produced in the late logarithmic
      and stationary phases of growth. MLP, purified to homogeneity by a three-step
      process, had a molecular mass of 32,812 Da and an isoelectric point of 9.3. MLP
      was active and highly stable in solution for 24 h from pH 6.0 to 10.5; it had
      maximal activity at temperatures between 57 and 59 degrees C. The presence of
      calcium in the solution was essential for enzyme activity and to prevent
      autolysis. Optimal activity occurred between pH 9.0 and 9.5, with 60% maximal
      activity from pH 6.5 to 11.0. The enzyme was inhibited by the serine enzyme
      inhibitors phenylmethylsulfonyl fluoride and chymostatin but not by the
      metalloenzyme inhibitor 1,10-phenanthroline or sulfhydryl enzyme inhibitors.
      Casein, bovine serum albumin, ovalbumin, beta-lactoglobulin, and elastin were
      digested by the protease while collagen and keratin were resistant to digestion.
      MLP demonstrated both esterase and amidase activity on synthetic peptide
      substrates. MLP preferentially cleaved the Leu(15)-Tyr(16) and Phe(24)-Phe(25)
      bonds of the oxidized beta-chain of insulin. Longer digests of insulin and the
      pattern of activity against synthetic substrates suggest that MLP has a cleavage
      specificity for bulky, hydrophobic, or aromatic amino acids in the P(1) or P(1)'
      positions. Amino acid sequences from the N-terminus and internal peptides of MLP
      were unique.

PMID- 10648169
TI  - High-level secretion of biologically active recombinant human macrophage
      inflammatory protein-1alpha by the methylotrophic yeast Pichia pastoris.
AB  - The human CC chemokine macrophage inflammatory protein-1alpha (MIP-1alpha) was
      produced at a high level in Pichia pastoris under transcriptional control of the
      highly inducible alcohol oxidase 1 promoter. To ensure proper folding and
      secretion of the recombinant polypeptide, the MIP-1alpha gene had been fused to
      the Saccharomyces cerevisiae alpha-factor prepropeptide. As was revealed by
      analysis of the cell culture supernatant of recombinant Pichia pastoris, MIP
      1alpha was efficiently secreted. Immunoblot analysis of secreted proteins from
      recombinant clones using a polyclonal antibody directed against MIP-1alpha
      revealed an apparent molecular mass of 8 kDa for the recombinant polypeptide. Up
      to 70 mg of MIP-1alpha was purified from 1 liter of yeast culture supernatant by
      a single chromatography step. Biological activity of recombinant MIP-1alpha was
      shown in a chemotaxis assay. Here, the polypeptide specifically induced migration
      of U937 cells expressing the CCR1 (MIP-1alpha receptor). Also, in competition
      binding assays the recombinant MIP-1alpha displayed high affinity binding.

PMID- 10648170
TI  - Cloning, overexpression, and purification of Escherichia coli quinolinate
      synthetase.
AB  - Quinolinate synthetase catalyzes the second step of the de novo biosynthetic
      pathway of pyridine nucleotide formation. In particular, quinolinate synthetase
      is involved in the condensation of dihydroxyacetone phosphate and iminoaspartate
      to form quinolinic acid. To study the mechanism of action, the specificity of the
      enzyme and the interaction with l-aspartate oxidase, the other component of the
      so-called "quinolinate synthetase complex," the cloning, the overexpression, and
      the purification to homogeneity of Escherichia coli quinolinate synthetase were
      undertaken. The results are presented in this paper. Since the overexpression of
      the enzyme resulted in the formation of inclusion bodies, a procedure of
      renaturation and refolding had to be set up. The overexpression and purification
      procedure reported in this paper allowed the isolation of 12 mg of
      electrophoretically homogeneous quinolinate synthetase from 1 liter of E. coli
      culture. A new, continuous, method for the evaluation of quinolinate synthetase
      activity was also devised and is presented. Finally, our data definitely exclude
      the possibility that other enzymes are involved in the biosynthesis of quinolinic
      acid in E. coli, since it is possible to synthesize quinolinic acid from l
      aspartate, dihydroxyacetone phosphate, and O(2) by using only nadA and nadB gene
      overexpressed products.

PMID- 10648171
TI  - Overproduction in Escherichia coli and purification of the hemolytic protein
      sticholysin II from the sea anemone Stichodactyla helianthus.
AB  - The cDNA coding for the cytolytic toxins sticholysin I and sticholysin II from
      the sea anemone Stichodactyla helianthus has been isolated, cloned in pUC18, and
      sequenced. A 6His-tagged version of sticholysin II has been overproduced in
      Escherichia coli and purified to homogeneity in milligram amounts. Conformational
      and functional analyses of recombinant sticholysin II do not reveal any
      significant difference when compared to the natural cytolysin.

PMID- 10648172
TI  - Inclusion of S-sepharose beads in the culture medium significantly improves
      recovery of secreted rBPI(21) from transfected CHO-K1 cells.
AB  - rBPI(23), a recombinant N-terminal fragment of human bactericidal/permeability
      increasing protein (BPI), kills gram-negative bacteria and binds endotoxin.
      rBPI(21), a variant, in which cysteine 132 is changed to alanine, retains the
      activities of rBPI(23). Initial attempts using conventional ion-exchange
      chromatography to purify rBPI(23) from culture supernatants of transfected CHO-K1
      cells resulted in lower than expected yields. Also, ELISA of supernatants from
      CHO-K1 transfectants expressing rBPI(23) or rBPI(21) yielded variable signals.
      Results from pulse-chase experiments using [(35)S]methionine had indicated that
      rBPI(23) could not be detected in the culture medium by 7 h of chase, suggesting
      that these proteins were degraded and/or bound to cells, media components, or
      vessel surfaces. To address these issues, we developed a novel process whereby
      sterile S-Sepharose beads were added directly to the cell culture medium. For
      attached cells, the beads were added to confluent cultures with serum-free medium
      for the expression phase, while for suspension-adapted cells, beads were added at
      the beginning of culture growth. The S-Sepharose was then separated from cells
      and media and washed, and BPI was eluted with high-salt buffer. This approach
      yielded up to a 50-fold improvement in recovery of rBPI(23) and rBPI(21) from
      roller bottles, shake flasks, and 2-liter fermenters. It also resulted in
      improved detection and quantitation of secreted rBPI(23) and rBPI(21) by ELISA.
      Results of competition binding studies with iodinated rBPI(21) in conjunction
      with unlabeled rBPI(21) and rBPI(23) or with heparin demonstrated that these
      proteins bound specifically and with high affinity to heparan-containing sites on
      the surface of the CHO-K1 cells. We conclude that the S-Sepharose included in the
      culture medium captures the BPI protein products as they are secreted and
      protects them from degradation and/or irreversible binding to cell surfaces. This
      method has been scaled up to a manufacturing process in large (2750 liter)
      fermenters for pharmaceutical production.

PMID- 10648173
TI  - Purification and characterization of human Syk produced using a baculovirus
      expression system.
AB  - The cytoplasmic tyrosine kinase p72syk (Syk) plays an essential role in signaling
      via a variety of immune and nonimmune cell receptors. Syk is activated in
      response to the engagement of the appropriate cell surface receptors and can
      phosphorylate downstream targets and recruit additional SH2-domain-containing
      proteins. In order to study the characteristics of Syk in vitro, we have
      overexpressed untagged, full-length human Syk in a recombinant baculovirus
      expression system. The enzyme was purified to 95% purity using a novel two-step
      affinity chromatography process using reactive yellow and phosphotyrosine
      columns. Yields of 3-10 mg purified Syk were obtained from 1 liter of infected
      insect cells. Western blotting, internal protein sequencing, and the specific
      tyrosine phosphorylation of a Syk peptide substrate indicated authenticity of the
      purified protein. The enzymatic properties of Syk were in good agreement with
      published data for the human enzyme, as the apparent K(m) of Syk for ATP was 10
      microM and the peptide substrate was 3 microM. The recombinant protein also
      showed similar biochemical characteristics to the native protein isolated from B
      cells such as autophosphorylation. Proteolytic cleavage of purified recombinant
      Syk was used to generate the kinase domain by micro-calpain. We therefore
      describe an efficient expression system and purification methodology to produce
      biologically active human Syk.

PMID- 10648174
TI  - Purification of his-tagged proteins by immobilized chelate affinity
      chromatography: the benefits from the use of organic solvent.
AB  - Recombinant proteins overexpressed in and purified from Escherichia coli contain
      impurities that are toxic in biological assays. The application of affinity
      purification procedures is often not sufficient to remove these toxic components.
      We here describe a simple and fast, one-step protocol to remove these impurities
      highly efficiently. Four recombinant proteins were overexpressed in E. coli as
      His-tagged fusion proteins and purified by immobilized metal chelate affinity
      chromatography on Ni-NTA beads. Depending on the protein, the composition of the
      lysis buffer, and the washing protocol, various impurities appeared to be present
      in the purified protein preparations. Here we show how the use of 60% isopropanol
      during washing steps removed most of these contaminants from the end products. In
      addition to the removal of proteins that aspecifically adhere to the beads or to
      the tagged protein, this procedure was particularly useful in removing
      endotoxins. Moreover, we show that detergents such as NP-40, that are necessarily
      employed during lysis, are also efficiently removed. Finally, we show that
      proteins are able to refold correctly after isopropanol treatment. Thus, the
      resulting end products contain significantly less contaminating E. coli proteins,
      endotoxins, and detergents.

PMID- 10648175
TI  - Molecular cloning and high-level expression of human polymerase beta cDNA and
      comparison of the purified recombinant human and rat enzymes.
AB  - The cDNA encoding the human polymerase beta from HeLa cells was PCR amplified and
      cloned, and its nucleotide sequence determined. The DNA sequence is identical to
      the polymerase beta cDNA sequence from Tera-2 cells. Three expression strategies
      were employed that were designed to maximize translation initiation of the
      polymerase beta mRNA in Escherichia coli and all yielded a high level of human
      polymerase beta. The recombinant protein was purified and its properties were
      compared with those of the recombinant rat enzyme. The domain structure and
      kinetic parameters (k(cat) and K(m)) were nearly identical. A mouse IgG
      monoclonal antibody to the rat enzyme (mAb-10S) was approximately 10-fold less
      reactive with the human enzyme than with the rat enzyme as determined by ELISA.

PMID- 10648176
TI  - Purification of wheat germ amylase by precipitation.
AB  - alpha-Amylase from various sources was found to bind alginate in free solution.
      The alginate-enzyme complex could be precipitated with Ca(2+). The enzyme
      activity could be recovered by dissolving the precipitate in 1 M maltose and
      precipitating alginate alone by addition of Ca(2+). Based upon these
      observations, alpha-amylase from wheat germ was purified with 68-fold
      purification and 72% recovery. The molecular weight estimated by SDS-PAGE was 18
      kDa. The method also worked equally well with alpha-amylase for the whole wheat
      seed. The latter enzyme could be purified 54-fold with 70% activity recovery. The
      molecular weight of this second enzyme was estimated to be 45 kDa by SDS-PAGE.

PMID- 10648177
TI  - The human polyomaviruses, BKV and JCV: molecular pathogenesis of acute disease
      and potential role in cancer.

PMID- 10648178
TI  - Oral DNA vaccination promotes mucosal and systemic immune responses to HIV
      envelope glycoprotein.
AB  - In this report, we described induction of HIV envelope (env)-specific systemic
      and mucosal immune responses by oral vaccination of BALB/c mice with env-encoded
      plasmid DNA encapsulated in poly(dl-lactide-co-glycolide) (PLG) microparticles.
      We demonstrated that intragastric administration of the encapsulated plasmid DNA
      resulted in transduced expression of the env glycoprotein in the intestinal
      epithelium. Mice immunized orally exhibited env-specific type 1 and cytotoxic T
      lymphocyte (CTL) responses in spleen and the inductive (Peyer's patches) and
      effector (lamina propria) mucosal tissues of gut. Oral administration of PLG
      encapsulated plasmid DNA encoding gp160 also induced env-specific serum
      antibodies, and an increased level of IgA directed to gp160 was detected in fecal
      washes of the immunized mice. In contrast, intramuscular (i.m.) administration of
      naked or PLG-encapsulated DNA vaccine induced only systemic cellular and humoral
      responses to the env glycoprotein. Using an HIV env-expressing recombinant
      vaccinia viral intrarectal murine challenge system, we observed higher resistance
      to mucosal viral transmission in mice immunized orally than in animals injected
      i.m. with PLG-encapsulated plasmid DNA encoding gp160. Results of these studies
      demonstrate the feasibility of using orally delivered PLG microparticles
      containing plasmid DNA-encoded HIV gp160 for induction of env-specific systemic
      and mucosal immune responses and protection against recombinant HIV env vaccinia
      virus challenge.

PMID- 10648179
TI  - Early stages of influenza virus entry into Mv-1 lung cells: involvement of
      dynamin.
AB  - Viruses generally have one of two mechanisms for entry and uncoating. They can
      enter the cell either by endocytosis or by direct fusion at the plasma membrane.
      We have established a novel mink lung (Mv-1) cell line that expresses a dominant
      interfering form of dynamin-1 (K44A) under the control of a tetracycline
      responsive element and studied the early events in influenza infection using
      these cells. We found that influenza virus binds equally to both induced and
      uninduced cells, but in K44A-expressing cells, electron microscopy showed viruses
      trapped in deep coated pits and irregular-shaped tubular structures that contain
      discrete coated regions. We also show by immunofluorescence and confocal
      microscopy that entry of incoming virus into the nucleus is blocked in K44A
      expressing cells. Virus replication was assayed by immunofluorescence microscopy
      and was strongly inhibited at both early and late times postinfection in K44A
      expressing cells. Virus infectivity was inhibited by approximately 2 log units in
      cells expressing K44A dynamin when analyzed by influenza plaque assay. Overall
      these data show that dynamin is required for efficient influenza virus entry,
      presumably due to its function in release of vesicles from coated pits.

PMID- 10648180
TI  - Efficient expression of foreign proteins in roots from tobravirus vectors.
AB  - Viral vectors were constructed from infectious cDNA clones of each of the three
      tobraviruses, tobacco rattle virus (TRV), pea early-browning virus (PEBV), and
      pepper ringspot virus (PepRSV). RNA2 of each of the three viruses was modified to
      carry an additional coat protein subgenomic promoter and was used to express
      green fluorescent protein (GFP) when inoculated to plants. The tobravirus
      expression vectors have a wide host range and were able to express GFP in, for
      example, Nicotiana species, tomato, pea, arabidopsis, and sugar beet. The TRV
      vector was able to invade and express GFP very efficiently in roots, whereas the
      widely used PVX vector was not.

PMID- 10648181
TI  - Coevolution of host and virus: the pathogenesis of virulent and attenuated
      strains of myxoma virus in resistant and susceptible European rabbits.
AB  - Myxoma virus was introduced into the European rabbit population of Australia in
      1950. Although the virus was initially highly lethal in rabbits, there was rapid
      selection for less virulent strains of virus and innately resistant rabbits. To
      investigate the basis of resistance to myxoma virus, we have compared the
      pathogensis of the virulent strain of myxoma virus originally released into
      Australia and an attenuated, naturally derived field strain of myxoma virus. This
      was done in laboratory rabbits, which have not been selected for resistance, and
      in wild rabbits that have developed significant resistance. Wild rabbits were
      able to recover from infection with virus that was always lethal in laboratory
      rabbits. Laboratory rabbits were able to control and recover from infection with
      attenuated virus. This virus caused a trivial disease in wild rabbits. There was
      little difference between laboratory and wild rabbits in titers of either
      virulent or attenuated virus in the skin at the inoculation site. However,
      resistant wild rabbits had a 10- to 100-fold lower titer of virulent virus within
      the lymph node draining the inoculation site and controlled virus replication in
      tissues distal to the draining lymph node. Replication of virus in lymphocytes or
      fibroblasts cultured from wild and laboratory rabbits demonstrated that
      resistance was not due to altered cellular permissivity for replication.
      Neutralizing antibodies were present in both susceptible and resistant rabbits,
      suggesting that these have no significant role in resistance. We hypothesise that
      resistance is due to an enhanced innate immune response that allows the rabbit to
      mount an effective cellular immune response.

PMID- 10648182
TI  - Incorporation of simian virus 5 fusion protein into murine leukemia virus
      particles and its effect on the co-incorporation of retroviral envelope
      glycoproteins.
AB  - We describe the generation of murine leukemia virus (MLV) virus particles
      carrying the paramyxovirus fusion protein F from simian virus 5 (SV5-F). This
      glycoprotein was expressed in cells providing Moloney MLV (MoMLV) Gag and Pol
      proteins and a lacZ retroviral vector. SV5-F was correctly expressed, processed,
      and efficiently incorporated into retroviral particles. SV5-F-bearing
      retroviruses were not infectious although a weak binding to primate and rodent
      cells could be detected and SV5-F could mediate cell to cell fusion. We then co
      expressed the SV5-F glycoprotein in retroviral particles with chimeric and wild
      type MoMLV envelope glycoproteins. Our results show that F strongly inhibited
      infection via the retroviral envelopes although the mechanism of inhibition was
      different depending on the retroviral envelope used.

PMID- 10648183
TI  - Full-genome sequence analyses of hepatitis B virus (HBV) strains recovered from
      chimpanzees infected in the wild: implications for an origin of HBV.
AB  - Hepatitis B virus (HBV) belongs to the genus Orthohepadnavirus of the family
      Hepadnaviridae. Having been found in various animals (duck, heron, woodchuck,
      ground squirrel, and primates), hepadnaviruses must have undergone a long history
      of evolution and may comprise more members than currently recognized. Chimpanzees
      may also have their own hepadnavirus, even if it might be very close to HBV. We
      analyzed HBV-like sequences from three chimpanzees (Pan troglodytes) that were
      most likely infected during their life in Africa in the wild. Two chimpanzees
      (Ch256 and Ch258) possessed a viral genome of 3182 nt in length with a 33-nt
      deletion in the preS1 region, which could not be classified into any of the six
      genotypes (A-F) of human HBV but was very homologous to a previously reported
      isolate from a London Zoo chimpanzee. Phylogenetically distinct from the HBV-like
      sequences from gibbons, orangutans, and a gorilla so far reported, the Ch256 and
      Ch258 isolates would represent an indigenous chimpanzee HBV (tentatively ChHBV).
      A third chimpanzee (Ch195) had a 3212-nt genome, classifiable into the genotype E
      of HBV. Because HBV-E has been found mostly in Africans, Ch195 may have been
      infected from a human source in Africa. However, an inverse scenario is also
      possible: a spread of HBV-E might have occurred from chimpanzees to humans a long
      time ago in Africa. Analysis of the arginine-rich C-terminal region of the core
      protein, which is well conserved among mammalian hepadnaviruses, indicated that
      HBV-E/F and nonhuman primate hepadnaviruses are much closer than HBV-A/B/C/D to
      the hepadnaviruses of woodchuck and ground squirrel. Our results support an "ex
      nonhuman primate" hypothesis for the origin of HBV.

PMID- 10648184
TI  - Vaccinia virus gene B7R encodes an 18-kDa protein that is resident in the
      endoplasmic reticulum and affects virus virulence.
AB  - This paper presents a characterisation of vaccinia virus (VV) gene B7R that was
      predicted to encode a polypeptide of 182 amino acids with an N-terminal signal
      peptide. In vitro transcription and translation analysis showed the B7R gene
      product was a 21-kDa protein that, in the presence of microsomes, was processed
      into an 18-kDa mature form. The 18-kDa form associated with the microsomal
      membranes and was within the lumen of the vesicle where it was inaccessible to
      exogenous protease or an antibody raised against the B7R C terminus. Within VV
      infected cells, the 18-kDa form of B7R was detected late during infection in the
      endoplasmic reticulum where it colocalised with protein disulphide isomerase. The
      B7R protein was detected neither in the culture supernatant nor associated with
      virus particles. A virus deletion mutant lacking the B7R gene and a revertant
      virus were constructed. Compared to wild-type and revertant viruses, the deletion
      mutant replicated normally in cell culture and had unaltered virulence in a
      murine intranasal model of infection. However, the deletion mutant was attenuated
      in a murine intradermal model where it induced a smaller lesion than the control
      viruses.

PMID- 10648185
TI  - V and C proteins of measles virus function as virulence factors in vivo.
AB  - The measles virus (MV) P gene encodes three proteins: the P protein and two
      nonstructural proteins, C and V. Because the functions of both the C and V
      protein are unknown, we used MV C (C-) and V (V-) deletion recombinants generated
      by the MV reverse genetics system (F. Radecke, P. Spielhofer, H. Schnieder, K.
      Kaelin, M. Huber, C. Dotsch, G. Christiansen, and M. A. Billeter 1995. EMBO J.
      14, 5773-5784). Compared to parental vaccine strain, Edmonston (Ed) MV, both had
      normal growth and cytopathic effects in Vero cells and showed similar growth
      kinetics in human neuroblastoma SK-N-MC cells and in primary mouse neurons
      expressing the MV receptor, CD46. However, in vivo, using YAC-CD46 transgenic
      mice as a model for MV induced CNS disease (M. B. A. Oldstone, H. Lewicki, D.
      Thomas, A. Tishon, S. Dales, J. Patterson, M. Manchester, D. Homann, D. Naniche,
      and A. Holz 1999. Cell 98, 629-640), C- and V- viruses differed markedly from wt
      Ed(V(+)C(+)) virus. Newborn mice inoculated with as little as 10(3) PFU of Ed
      strain became ill and died after 10-15 days. In contrast, those inoculated with
      10(3) or 10(4) PFU of MV C- or MV V- showed significantly fewer and milder
      clinical symptoms and had a lower mortality. A total of 10(5) PFU V- virus were
      required to kill most YAC-CD46 mice, and less than half (44%) were killed with a
      corresponding dose of MV C-. Immunohistochemical staining for MV antigens showed
      similar extents of spread for MV C- and MV Ed but restricted spread for MV V-
      throughout the brain. Viral load and transcription were markedly reduced for V-
      but not for C-. Multiple cytokines and chemokines were equivalently upregulated
      for all three viruses. Therefore, MV C and V proteins encode virulence functions
      in vivo and likely operate via separate mechanisms.

PMID- 10648186
TI  - Maize chlorotic mottle machlomovirus expresses its coat protein from a 1.47-kb
      subgenomic RNA and makes a 0.34-kb subgenomic RNA.
AB  - Analysis of double-stranded RNAs produced in maize plants infected with maize
      chlorotic mottle machlomovirus (MCMV) and Northern blots of total RNA from
      infected plants or protoplasts showed two subgenomic RNAs (sgRNAs). Primer
      extension was used to map these sgRNAs, which are 1.47 and 0.34 kb long. The
      transcription start sites are nucleotide (nt) 2970 or 2971 for sgRNA1 and nt 4101
      for sgRNA2. The 5' ends of the sgRNAs are similar to one another and to the 5'
      end of genomic RNA, and 11 nt sequences immediately upstream of their
      transcription start sites are similar. The location of the sgRNA1 transcription
      start site indicates that MCMV expresses a 7-kDa open reading frame (ORF) from nt
      2995 to 3202 instead of the predicted 9-kDa ORF from nt 2959 to 3202. In
      protoplast inoculation experiments, a silent mutation at nt 2965 and a 4-nt
      change at nt 2959-2962 stopped the synthesis of sgRNA1 and expression of the coat
      protein ORF, which begins more than 400 nt downstream. Replication of MCMV does
      not require the expression of any of the ORFs encoded on sgRNA1. SgRNA2 has the
      potential to encode 2.3-, 2.7-, and 4. 6-kDa peptides, but the function, if any,
      of sgRNA2 is unknown.

PMID- 10648187
TI  - Genetic engineering of herpes simplex virus and vector genomes carrying loxP
      sites in cells expressing Cre recombinase.
AB  - The prokaryotic Cre-loxP recombination system is a powerful tool that enables in
      vitro and in vivo site-specific manipulations of the genome of eukaryotic cells
      as well as of DNA viruses and their derived vectors. This system, however, has
      not yet been exploited in the context of herpes simplex virus type 1 (HSV-1)
      infected cells, perhaps because this virus encodes several functions that induce
      a strong shutoff of cellular protein synthesis, a fact that could preclude
      expression of cellular-encoded Cre recombinase. In the present study, we show
      that efficient site-specific recombination can take place in cell lines
      expressing Cre, even in the context of HSV-1 infection, as evidenced by the
      engineering of an HSV-1 recombinant virus and several viral vectors carrying one
      or two loxP sequences. More precisely, we have used this system to induce an
      irreversible switch in the expression of a viral complex transcription unit
      encoding two different open reading frames and allowing consecutive expression of
      two reporter genes. Furthermore Cre recombinations were also used to induce the
      decatenation of the genomic concatemers harbored by amplicon particles upon
      infection of cells under nonreplicative conditions, thus enabling the rescue of
      many independent plasmids corresponding to the original amplicon plasmid used to
      generate the vectors. Thus the Cre-loxP recombination system can successfully be
      used for engineering the genome of HSV-1 or HSV-1-based vectors in cultured
      cells.

PMID- 10648188
TI  - Capsid-targeted viral inactivation can eliminate the production of infectious
      murine leukemia virus in vitro.
AB  - Capsid-targeted viral inactivation (CTVI), a promising gene-based antiviral
      strategy against retroviruses, was designed to disrupt the retroviral life cycle
      by incorporating a degradative enzyme (e.g., nuclease) into viral particles
      during assembly, thereby reducing or eliminating the production of infectious
      virus. The experimental system used to develop the CTVI strategy for retroviruses
      is designed to block the production of infectious Moloney murine leukemia virus
      (Mo-MLV). Two nucleases, Escherichia coli ribonulease HI and Staphylococcus
      nuclease, have been shown to be tolerated by the cell as Mo-MLV Gag-nuclease
      fusion polyproteins and still be active in the viral particles. The goal of this
      study was to determine what cellular and viral factors limit CTVI in cultured
      cells. The avian DF-1 cell line greatly expanded our ability to test the
      antiviral efficacy of CTVI in long-term assays and to determine the mechanism(s)
      of CTVI action. The CTVI antiviral effect is dependent on the level of Mo-MLV Gag
      nuclease fusion polyprotein expressed. The Mo-MLV Gag-nuclease polyproteins
      produce a long-term prophylactic antiviral effect after a low- or high-dose Mo
      MLV challenge. The Mo-MLV Gag-nuclease fusions have a significant therapeutic
      effect ( approximately 1000-fold) on the production of infectious Mo-MLV. The
      therapeutic CTVI effect can be improved by a second delivery of the CTVI fusion
      gene. Both the prophylactic and the therapeutic CTVI antiviral approaches can
      virtually eliminate the production of infectious Mo-MLV in vitro and are only
      limited by the number of cells in the population that do not express adequate
      levels of the CTVI fusion polyprotein.

PMID- 10648190
TI  - Diplospory and Parthenogenesis in Sexual x Agamospermous (Apomictic ) Erigeron
      (Asteraceae) Hybrids.
AB  - Segregation for asexual seed production was evaluated for 130 experimental F1
      hybrids resulting from a cross between diploid (2n=18) sexual Erigeron strigosus
      and triploid (2n=27) agamospermous Erigeron annuus. Paternity of hybrids was
      documented using 13 RAPD markers. The distribution of F1 chromosome numbers is
      bimodal, centering on diploid and triploid ploidal levels but with
      underrepresentation of diploids. Diplosporous versus meiotic megagametophyte
      development was ascertained microscopically for >/=100 ovules per plant.
      Diplospory ranges from 0% to 100% among all progeny but is uniformly low (0%-3%)
      for 17 diploid hybrids. The inheritance of diplospory in Erigeron appears to be
      best explained by a one-locus-two-allele polysomic model with selection against
      gametes homozygous for diplospory. Parthenogenesis, estimated via seed counts,
      ranges from 0% to 60% and apparently is contingent upon diplospory, as seed
      production was absent or very low in predominantly meiotic hybrids. However, the
      absence of parthenogenesis in many highly diplosporous hybrids indicates that
      these two aspects of agamospermous development are not strictly associated. The
      segregation of both diplospory and parthenogenesis in this population will permit
      further genetic dissection of these traits with molecular marker-based analyses.

PMID- 10648189
TI  - Changes in a murine leukemia virus (MLV) receptor encoded by an alphavirus vector
      during passage in cells expressing the MLV envelope.
AB  - We constructed alphavirus vectors encoding the ecotropic murine leukemia virus
      (MLV) receptor mCAT1. Cells electroporated with these vector RNAs expressed mCAT1
      protein and fused with cells that expressed a fusogenic form of the MLV envelope
      on the cell surface. Electroporated cells also released submicron particles that
      were infectious in envelope-expressing cells. Infection resulted in giant
      syncytia that could be enumerated by plaque assay. Cell-free supernatants could
      be serially passaged and contained up to 10(4) infectious units/ml. To determine
      whether repeated passage would select for functional variants of the receptor, we
      analyzed mCAT1 amplified by RT-PCR after 12 serial passages. Several amino acid
      substitutions were identified that encoded functional receptor variants. In
      independent experiments, variants containing an isoleucine or a leucine instead
      of a phenylalanine at position 224 in the third extracellular domain of the
      receptor arose spontaneously and outgrew the parental vector, indicating that
      mutations at this site are highly selected in this system. This region of the
      receptor has previously been implicated in the envelope-receptor interaction.
      This alphavirus vector system provides a novel method for generating and
      selecting functional variants of viral receptors

PMID- 10648191
TI  - Epiphylly in a Variant of Helianthus Annuus x H. Tuberosus Induced by In vitro
      Tissue culture.
AB  - A variant clone (EMB-2) derived by in vitro tissue culture of the interspecific
      hybrid Helianthus annuus x Helianthus tuberosus shows a particular deviation from
      the usual pattern of plant development in that it produces, both in vitro and in
      vivo, epiphyllous embryos and/or shootlike structures. Ectopic structures, which
      are usually arranged in clusters or rows along preexisting veins, originate
      asynchronously from epidermal cells of the adaxial surface of the leaf blade.
      Sometimes embryos and buds are also detected on the adaxial plane of the petioles
      and at the nodes of the stem. EMB-2 individual plants differ greatly in terms of
      the timing and extent of phenotypic expression of epiphylly. Leaves precociously
      affected by ectopic structures show a more drastic alteration in the
      differentiation process. Growth is arrested, the spongy parenchyma and air spaces
      are absent, and the mesophyll cells do not enlarge. Excluding the veins and
      epidermis, the leaves are wholly composed of isodiametric cells that are
      regularly arranged in parallel rows that have dense cytoplasm and prominent
      nuclei. Ectopic structures isolated from leaves and cultured in vitro mostly
      produce plantlets with the same phenotype as the original clones. In vivo, the
      EMB-2 plants are propagated by tubers. Often, the shoot-meristems that originate
      from tubers exhibit a teratological appearance and die without further
      development. However, several normal shoots grow and produce plants that display
      epiphyllous structures like those of the parent plants. Alterations of the
      endogenous hormonal levels or mutations in genes involved in the switch from
      indeterminate to determinate cell fate may be responsible for the ectopic
      development of shoots and embryos on leaves of EMB-2 variant.

PMID- 10648192
TI  - Floral structure and development of Acoraceae and its systematic relationships
      with basal angiosperms.
AB  - Flower development and anatomy of Acorus calamus and flower anatomy of A.
      gramineus were studied. Findings were compared with published reports on
      paleoherbs. Important developmental features include an abaxially median tepal
      that is initiated first and is similar to a flower-subtending bract and
      unidirectional flower development with an inversion of organ initiation sequence
      in the second tepal whorl. The mature gynoecium is largely synascidiate, but
      early development of carpels is plicate, and the apocarpous portion persists up
      to anthesis. The carpels form dorsal bulges on the style, enclosing longitudinal
      intercarpellary slits. The dominance of the synascidiate portion and the apical
      position of the placenta result from a late and distinct basal elongation of the
      gynoecium. Stigma, pollen transmitting tract, and ovary are filled with
      secretion. Secretory papillae are present from the stigma to the placenta;
      papillae also occur on the rims of the integuments of the ovules. In the
      uppermost part of the inflorescence, the adaxial floral sectors are reduced in
      number and structure, and at the apex of the inflorescence, a peloria-like
      structure is formed. Developmental and morphological similarities seem to be
      closer between Acorus and Piperales than between Acorus and other magnoliids.

PMID- 10648193
TI  - Floral Morphology and Relationships of Clusia gundlachii with a Discussion of
      Floral Organ Identity and Diversity in the Genus Clusia.
AB  - The genus Clusia L. is highly variable in many floral features. Several Clusia
      species have floral organs of mixed or uncertain identity, such as organs that
      are transitional between bracteoles and sepals, petaloid sepals, and partly
      petaloid stamen rings. Unique in Clusia is the "corona" of Clusia gundlachii
      Stahl, a thick, urn-shaped structure that is initiated as a ring primordium. In
      male flowers it surrounds a synandrium, and in female flowers it surrounds the
      ovary and a row of staminodes. The corona combines features typical of both
      petals and stamens of other Clusia species. It is hypothesized that this corona
      may be the result of the altered expression patterns of the genes that determine
      floral organ identity. Clusia gundlachii has many floral features in common with
      two small genera that are sometimes included in Clusia: Havetiopsis and
      Oedematopus. These genera have four thick connivent petals. Their apparent close
      relationship makes it seem likely that the corona of C. gundlachii evolved via
      congenital fusion of such petals. The corona is also somewhat similar to the
      staminodial rings present in many Clusia species, but taxa in which such organs
      occur show little similarity to C. gundlachii in terms of other floral
      characters.

PMID- 10648195
TI  - An Assessment of alphaalpha-Tubulin Isotype Modification in Developing Cotton
      Fiber.
AB  - Multiple isoforms of alpha- and beta-tubulin accumulate in higher plant cells,
      including cotton (Gossypium hirsutum L.) fiber. Isotypes may originate either by
      transcription of distinct genes or by posttranslational modification of gene
      products. The existence of two types of posttranslational modification in cotton
      fiber alpha-tubulin has been examined by immunoblotting cotton fiber proteins
      from two developmental stages and by probing with specific monoclonal antibodies
      to acetylated (6-11B-1) or tyrosinated (YL 1/2 ) alpha-tubulin. Control
      experiments were conducted with an antibody (YOL 1/34) that recognizes a
      conserved region in plant and animal alpha-tubulins. No acetylated forms of alpha
      tubulin were found in either of two varieties of cotton fiber at 10 or 20 d
      postanthesis. One isotype of alpha-tubulin, isotype 6, failed to cross-react with
      YL 1/2 at 10 d postanthesis, which indicated that the protein was detyrosinated,
      and isotype 8 appeared to be detyrosinated at 20 d postanthesis. Since the
      carboxyl terminus of higher plant alpha-tubulin is exposed on the surface of
      microtubules, removal of the carboxyl-terminal amino acid may lead to some of the
      changes in the structure and organization of microtubules that are associated
      with fiber development.

PMID- 10648196
TI  - Floral Display in Narcissus: Variation in Flower Size and Number at the Species,
      Population, and Individual Levels.
AB  - Floral display (the size, number, and arrangement of open flowers) influences
      pollinator visitation to animal-pollinated plants and should be an important
      determinant of reproductive success. We examined variation in the size and number
      of open flowers in wild daffodils (Narcissus). Our analysis of published data on
      45 taxa showed that flower number varied negatively with flower diameter among
      Narcissus species, which supports the widespread assumption that there is a trade
      off between these traits. In contrast, field measurements indicated a positive
      relation between flower number and diameter within two populations of Narcissus
      dubius, and no relation was evident after we controlled for variation in bulb
      size. The discrepancy between inter- and intraspecific patterns may have occurred
      because variable resource levels obscure trade-offs when variation in flower size
      is low (e.g., within species). Size-related increases in floral tube length were
      half as great as corresponding increases in flower diameter, a result that is
      consistent with stronger stabilizing selection on tube length. Staggered
      flowering within N. dubius inflorescences limited the mean number of open flowers
      to <66% of total flower number, and slow expansion by later opening flowers
      resulted in significant differences in flower size throughout flowering. Although
      pollinators preferred large flowers, experimental reductions in flower diameter
      did not affect seed production. Our results illustrate how the relative
      importance of the factors influencing floral display can vary among levels of
      biological organization. Interspecific variation in flower size and number
      appeared to be constrained by allocation trade-offs, but intraspecific variation
      in both traits was more greatly influenced by plant resource status. Within
      plants, the size and number of open flowers reflected the relative age of
      individual flowers and floral longevity.

PMID- 10648194
TI  - Development and growth of several strains of Arabidopsis seedlings in
      microgravity.
AB  - Growth and development of dark-grown Arabidopsis thaliana seedlings were studied
      in microgravity during space shuttle mission STS-84. The major purpose of this
      project was to determine if there were developmental differences among the four
      ecotypes studied--Wassilewskija (Ws), Columbia (Col), Landsberg erecta (Ler), and
      C24--and to evaluate whether particular ecotypes are better suited for
      spaceflight experimentation compared with others. A secondary goal was to study
      the growth of three starch-deficient strains of Arabidopsis by extending the
      observations made in a previously published report. For all strains, seed
      germination was not affected by microgravity, but seedlings were smaller in the
      spaceflight samples compared with the ground controls. The starch-deficient
      strains continued to exhibit vigorous growth until the termination of the
      experiment at 121 h after imbibition of seeds. However, ethylene effects, i.e.,
      reduced growth and exaggerated hypocotyl hooks, were observed in all strains
      studied. Nevertheless, the Ler and C24 ecotypes seem to be more suitable for
      spaceflight research, compared with the other two ecotypes, based on measurements
      of their relative and absolute growth. This type of information should aid in the
      design of plant experiments for the International Space Station.

PMID- 10648197
TI  - Flowering Phenology and Gender Variation in Pennisetum typhoides.
AB  - Because of the modular structure of pearl millet (an annual grass crop, Poaceae),
      different tillers of a plant share the same genotype but are subjected to
      different environmental conditions during their maturation. This allows
      investigation of the effects of tiller flowering phenology on allocation to
      resource-producing photosynthetic biomass, sexual functions, and thus tiller
      gender. All tillers of plants of two families collected from individual maternal
      plants (represented by 33 and 31 plants each) were analyzed. In both families,
      allocation to aboveground vegetative biomass decreased as flowering was delayed.
      On average, late-flowering tillers were 65% smaller than the first ones to
      flower. The proportion of biomass allocated to reproduction significantly
      increased with the flowering rank of the tillers, suggesting that translocations
      of assimilates occurred between early- and late-flowering tillers. In both
      families, late-flowering tillers produced significantly fewer pollen grains per
      stamen than early-flowering ones, and female reproductive allocation (expressed
      as seed mass per tiller) was also affected by flowering phenology. Tillers became
      increasingly female as flowering phenology progressed. This gender variation is
      possibly adaptive because pollination efficiency is maximized by plant height.
      Natural selection may favor a shift toward femaleness to maximize reproductive
      fitness in small, late-developing tillers.

PMID- 10648198
TI  - Phenotypic Integration and the Plasticity of Integration in an Amphicarpic
      Annual.
AB  - In annual plants, including amphicarpic annuals, variation in light availability
      can evoke phenotypic plasticity in multiple traits. We examined plasticity to
      light availability of vegetative and reproductive performance traits in
      Amphicarpaea bracteata (Fabaceae) by developing and evaluating three path
      analysis models using data from a greenhouse study. To assess whether light
      availability altered the phenotypic integration of these performance traits, we
      examined the models' fit to data collected within a high- or a low-light
      treatment. We also examined whether a single model or alternate models were
      required to fit data from the two contrasting light treatments. Using our path
      analysis approach, we also made comparisons among three population types: shade-
      and sun-native populations of the widespread variety A. bracteata var. bracteata
      and sun-native populations of the variety A. bracteata var. comosa. Although each
      type of population was somewhat distinctive in patterns of integration and in the
      plasticity of integration, patterns did not correspond to contrasting ecological
      affinity, i.e., shade- and sun-native population types or to genetic relatedness
      of the two varieties. Counter to the prediction that selection regimes involving
      variation in one or more environmental factor favor intermediate levels of
      integration, phenotypic integration in A. bracteata was very flexible, with
      plasticity occurring in a trait-by-trait manner. In particular, there was an
      inverse relationship between aerial and subterranean reproductive modes in low
      but not high light. Previous studies of amphicarpic annuals have not observed
      this type of environment-specific life history trade-off.

PMID- 10648199
TI  - Morphological and Physiological Responses of Hawaiian Hibiscus tiliaceus
      Populations to Light and Salinity.
AB  - Hibiscus tiliaceus (Hau) is a pantropical mangrove associate that usually occurs
      in coastal ecosystems where substrate salinity is relatively high, but it also
      inhabits upland habitats in Hawaii. Cuttings from three populations on the island
      of Oahu, Hawaii, were collected and grown in the glasshouse under two levels of
      substrate salinity (0 and 335 mOsm kg-1) and three light treatments (0%, 50%, and
      90% shade). Photosynthetic gas exchange, biomass allocation, and accumulation
      were studied in relation to salinity and light. Salinity reduced net CO2
      assimilation in the upland population but had no effect or stimulated
      photosynthesis in the coastal populations, whereas increasing salinity decreased
      stomatal conductance in all populations and therefore increased water-use
      efficiency. The degree to which photosynthesis was inhibited by salinity was
      inversely proportional to the salinity of the source population, indicating a
      loss of salinity tolerance in upland plants. Light had a stronger effect on leaf
      area ratio (LAR) and leaf mass per area (LMA), whereas salinity had a stronger
      effect on leaf water content, internode length, and plant biomass. Salinity
      reduced total new biomass by 58%, 50%, and 34% in full sun, 50% shade, and 90%
      shade, respectively, but this response did not differ between populations.
      Salinity reduced the photosynthesis, but not growth, of upland plants because
      increased allocation to photosynthetic tissue increased LAR to compensate for
      inhibition of photosynthesis by salinity.

PMID- 10648200
TI  - Responses to Light and Water Availability of Four Invasive Melastomataceae in the
      Hawaiian Islands.
AB  - Plant invasion by Neotropical Melastomataceae is prominent in Hawaii. To
      understand life history traits of four successful invasive Melastomataceae, two
      shade-intolerant herbs (Arthrostema ciliatum and Tibouchina herbacea) and two
      shade-tolerant woody species (Clidemia hirta, a shrub, and Miconia calvescens, a
      tree) were subjected to three light levels and two watering regimes in a
      greenhouse. Plant height, leaf number and area, biomass allocation, relative
      growth rate (RGR), carbon assimilation (A), leaf nutrient content, leaf
      construction costs (CC), specific leaf mass (SLM), and leaf spectral properties
      were determined at the end of the experimental period. Plant size, total biomass,
      RGR, A, CC, and SLM decreased, whereas leaf light transmittance and leaf N
      increased under low light in all species. The effects of water stress were weaker
      than light-stress effects. Relative growth rate of herbs grown in sun and partial
      shade (0.046 and 0.033 g g-1 d-1, respectively) was higher than in the woody
      species (0.027 and 0.020 g g-1 d-1). Woody species allocated more biomass to leaf
      production than herbs, which allocated more biomass to stem production. Shade
      increased allocation of biomass to leaves, and water stress increased the root
      shoot ratio in all species. Partial shade increased leaf area ratios more in the
      herbs (140%) than in woody species (68%). Miconia calvescens and C. hirta had
      higher leaf absorbance (92%) than both herbs (79%). Maximum A under all light
      treatments was similar in all species, and there was substantial acclimation to
      the different light levels. Leaf construction cost was higher in the apparently
      long-lived leaves of the woody species. Relative growth rate, carbon allocation,
      and SLM showed larger changes to light and water stress than A and related
      photosynthetic parameters. All species showed responses qualitatively similar to
      those of other tropical species including the high acclimation potential to
      light, but the herbs exhibited the largest quantitative responses. When compared
      with a large group of native species, the four melastomes appear to be better
      suited to capture and use light, which is consistent with their rapid spread in
      mesic and disturbed Hawaiian environments.

PMID- 10648201
TI  - Effects of Resource Availability on Carbon Allocation and Developmental
      Instability in Cloned Birch Seedlings.
AB  - Abundant nitrogen improves seedling growth and establishment. Vigorous growth
      brings about changes in rates and patterns of plant development and changes in
      the relationship between primary and secondary metabolism, which may make
      seedlings more susceptible to herbivores and pathogens than are slow-growing
      seedlings. We studied how nitrogen fertilization and manual defoliation of source
      leaves affect growth, carbon allocation, and developmental instability in cloned
      seedlings of white birch (Betula pubescens Ehrh.). Biomass was higher, whereas
      concentrations of most classes of phenolic compounds were lower in the nitrogen
      rich environment. Interestingly, fertilization did not change the concentrations
      of cell wall-bound proanthocyanidins, which represent an important fraction of
      the group of phenolic compounds. Nitrogen enrichment increased levels of
      fluctuating asymmetry, an index of developmental instability. This result
      confirms that not only stress but also any deviation from normal resource
      availability may increase leaf developmental instability in birches. In contrast
      to fertilization, a one-time defoliation of source leaves did not shape seedling
      growth, development, or carbon allocation. This could be the result of
      compensatory growth or of the fact that the defoliation treatment was not strong
      enough to induce detectable effects until the end of the growing season.

PMID- 10648202
TI  - Morphology and Stomatal Function of Douglas Fir Needles Exposed to Climate
      Change: Elevated CO2 and Temperature.
AB  - Climate change may have an impact on the productivity of conifer trees by
      influencing the morphology (size and surface characteristics) and function
      (capacity for gas exchange) of conifer needles. In order to test the responses of
      needles to climatic variables, Douglas fir (Pseudotsuga menziesii [Mirb.]
      Franco), saplings were grown in sunlit controlled environment chambers at ambient
      or elevated (+200 parts per million above ambient) CO2 and at ambient or elevated
      temperature (+4 degrees C above ambient). Needle characteristics, including
      length, width, area, stomatal density (stomata per mm2), percentage of stomatal
      occlusion, and the morphology of epicuticular wax, were evaluated. Needle
      function was evaluated as stomatal conductance to water vapor and transpiration.
      Needle length increased significantly with elevated temperature but not with
      elevated CO2. Neither elevated CO2 nor elevated temperature affected stomatal
      density or stomatal number in these hypostomatous needles. Epicuticular wax was
      less finely granular at elevated than at ambient temperature and was similar in
      appearance at elevated and ambient CO2. Stomatal conductance and transpiration
      increased with elevated temperature and associated increased vapor pressure
      deficit; however, neither conductance nor transpiration was affected by elevated
      CO2. These results indicate that simulated climate change influences Douglas fir
      needle structure and function.

PMID- 10648203
TI  - Twinned Raphides of Calcium Oxalate in Grape (Vitis): Implications for Crystal
      Stability and Function.
AB  - Among the higher plants that accumulate crystalline calcium oxalate, many taxa
      characteristically produce raphides, or needle-shaped crystals. Substantial
      evidence has accumulated indicating that raphides function in plant defenses
      against herbivory and that their acicular shape is a critical component in
      proposed mechanisms for these defenses. Previous observations have shown that
      raphides in members of the Vitaceae are twinned crystals. In this study, the fine
      structure of raphides in Vitis was examined in order to determine the nature of
      twinning. Rotation of isolated raphides under cross-polarized light revealed
      extinction patterns that indicated that raphides are twinned along their length.
      In cross sections of raphides, the twin plane extends across the raphides,
      parallel to their surfaces. The dissolution patterns observed in etched crystals
      indicate that the type of twinning is rotational. Parallels in other
      biomineralization systems indicate that the rotational nature of the twinning may
      increase mechanical strength. In addition, because twinning may affect crystal
      growth or enhance stability and persistence of crystals, it could be an important
      factor in allowing plant cells to produce the raphide morphology.

PMID- 10648204
TI  - Direct Access to Plant Epicuticular Wax Crystals by a New Mechanical Isolation
      Method.
AB  - A new method for the isolation of wax crystals from plant surfaces is presented.
      The wax-covered plant surface, e.g., a piece of a leaf or fruit, is brought into
      contact with a preparation liquid, e.g., glycerol or triethylene glycol, and
      cooled to ca. -100 degrees C. When the plant specimen is removed, the
      epicuticular wax remains embedded in the frozen liquid. After it warms up, the
      wax layer can be captured on appropriate carriers for further studies. This
      isolation method causes very little stress on the wax crystals; thus the shape
      and crystal structure are well preserved. In many cases it is possible, by
      choosing a preparation liquid with appropriate wettability, to isolate either the
      entire epicuticular wax layer or only discrete wax crystals without the
      underlying wax film. These crystals are well suited for electron diffraction
      studies by transmission electron microscopy and high resolution imaging by atomic
      force microscopy. The absence of intracuticular components and other impurities
      and the feasibility of the selective isolation of wax crystals enable improved
      chemical analysis and a more detailed study of their properties.

PMID- 10648205
TI  - The Stomatal Ontogeny and Structure of the Liassic Pteridosperm Sagenopteris
      (Caytoniales) from Hungary.
AB  - Stomatal ontogeny is often inferred but rarely documented for extinct fossil
      plants because it requires observations from young leaves that are rarely
      preserved as fossils. The discovery of several very young leaves of the Jurassic
      plant Sagenopteris (Caytoniales) in the Mecsek Mountains (southern Hungary) in a
      good state of preservation provides the opportunity for studying the stomatal
      ontogenesis of this genus. The specimens show perigenous anomocytic stomata. This
      feature confirms the evolutionarily high position of Sagenopteris among fossil
      gymnosperms and supports the opinion that the ancestors of angiosperms and some
      groups of pteridosperms might be closely related. Such clear examples of stomatal
      development have not previously been documented for fossil material.

PMID- 10648206
TI  - A New Species of Millerocaulis (Osmundaceae) from the Lower Cretaceous of
      California.
AB  - A small permineralized osmundaceous stem has been collected from marine sediments
      of the Early Cretaceous (Aptian), Upper Chickabally Member of the Budden Canyon
      Formation near Ono, California. The specimen, 8.5 cm long and 5.4 cm wide,
      represents a stem surrounded by a mantle of stipular leaf bases and adventitious
      roots. A large number of sections were studied through the use of the cellulose
      acetate peel technique. The stem was erect, 11x13 mm in diameter, with a
      parenchymatous pith and two-layered cortex. The stele is an ectophloic
      siphonostele with 65-79 leaf traces in the stem per cross section. Leaf gaps are
      only produced in 13% of the departing traces. Most leaf traces have "delayed"
      gaps or completely lack leaf gaps. Leaf traces are C-shaped, endarch, with one
      protoxylem strand, and have sclerenchyma lining the adaxial concavity. Leaf bases
      have stipular wings with large patches of heterogeneous sclerenchyma and a few
      scattered strands outside of the heterogeneous sclerotic ring. Patches of
      sclerenchyma occur inside the ring and outside of the vascular tissues. Numerous
      diarch roots arise singly or doubly from the leaf traces as they depart the axis
      stele. Although the stem compares fairly closely to both Ashicaulis Tidwell and
      Millerocaulis Erasmus ex Tidwell emend. Tidwell, it is most similar to
      Millerocaulis. However, the combination of characters observed in our specimen
      differs from that of the seven known species of Millerocaulis. This stem is
      described as Millerocaulis embreei sp. nov. and is the youngest known species of
      the genus and the first to be found in the Northern Hemisphere.

PMID- 10648207
TI  - Chaneya, a New Genus of Winged Fruit from the Tertiary of North America and
      Eastern Asia.
AB  - A new genus is recognized on the basis of wind-dispersed fruits from the Eocene
      of western North America and Miocene of eastern Asia. The fruits consist of an
      accrescent hypogynous calyx of five obovate sepals and one or more globose fruit
      bodies. Although the fossils were formerly placed in the extant genera Porana
      (Convolvulaceae) and Astronium (Anacardiaceae), our investigation of numerous
      specimens from several floras in the western United States (e.g., Florissant,
      Green River, Clarno) and Canada (Whipsaw Creek, British Columbia) and the Yilan
      and Shanwang floras of China reveals unique characters that indicate that the
      fossils are a distinct genus, which we name Chaneya. Unlike Porana and Astronium,
      the fossil calyces have stomata that are longitudinally aligned, and early stages
      of fruit development show a gynoecium of five apocarpous carpels, of which only
      one or two usually enlarge at maturity. Precise systematic placement of the
      fossil genus is uncertain, but similarities to the extant Picrasma of the
      Simaroubaceae are suggestive of possible affinities. Two species are recognized:
      Chaneya tenuis (Lesq.) comb. nov., from the Eocene of western North America and
      northeastern China, and Chaneya kokangensis (Endo) comb. nov., from the Miocene
      of eastern Asia.

PMID- 10648208
TI  - Revision of Lyonothamnus A. Gray (Rosaceae) from the Neogene of Western North
      America.
AB  - Lyonothamnus Gray is a monotypic genus of evergreen trees endemic to California's
      Channel Islands. There is one species, L. floribundus, with two subspecies, ssp.
      floribundus and ssp. asplenifolius. Subspecies floribundus has simple and entire
      margined leaves, while leaves of ssp. asplenifolius are pinnate and composed of
      three to seven primary segments. Despite its restricted modern occurrence, three
      fossil species have been described from Neogene paleofloras in the far western
      United States. Lyonothamnus mohavensis Axelrod is known from California; L.
      parvifolius (Axelrod) Wolfe and L. cedrusensis Axelrod, from Nevada. However, the
      size ranges used to segregate these species were all found to fall within the
      range of L. parvifolius from Stewart Valley, Nevada. Study of intact leaves
      reveals that the combination of (1) number of primary segments, (2) length of
      primary segments, (3) number of medial secondary segments per primary segment,
      and (4) lengths and widths of medial secondary segments is important in
      segregating species. Using these characters, L. parvifolius and L. wolfei Erwin
      et Schorn sp. nov. are recognized from Nevada and Oregon, and two species, L.
      mohavensis and L. axelrodii Erwin et Schorn sp. nov., from California. This
      renewed taxonomy within an updated temporal framework provides an important first
      step toward understanding the evolution, diversity, paleoecology, and
      paleobiogeographic history of this unusual member of the Rosaceae.

PMID- 10648209
TI  - Molecular systematics of the African electric fishes (Mormyroidea: teleostei) and
      a model for the evolution of their electric organs.
AB  - We present a new molecular phylogeny for 41 species of African mormyroid electric
      fishes derived from the 12S, 16S and cytochrome b genes and the nuclear RAG2
      gene. From this, we reconstruct the evolution of the complex electric organs of
      these fishes. Phylogenetic results are generally concordant with earlier
      preliminary molecular studies of a smaller group of species and with the
      osteology-based classification of Taverne, which divides the group into the
      Gymnarchidae and the Mormyridae, with the latter including the subfamilies
      Petrocephalinae (Petrocephalus) and Mormyrinae (all remaining taxa). However, we
      find that several genera previously recognized by Taverne are non-monophyletic.
      Within the Mormyrinae, the genus Myomyrus is the sister group to all the
      remaining taxa. Other well-supported clades within this group are recovered. A
      reconstruction of electrocyte evolution on the basis of our best-supported
      topology suggests that electrocytes with penetrating stalks evolved once early in
      the history of the mormyrids followed by multiple paedomorphic reversals to
      electrocytes with non-penetrating stalks.

PMID- 10648210
TI  - Temperature-induced pupil movements in insect superposition eyes.
AB  - In this paper, we describe the hitherto largely overlooked effect of temperature
      on the pupil of insect compound eyes. In the turnip moth Agrotis segetum and in
      two other nocturnal insects with superposition eyes, the lacewing Euroleon
      nostras and the codling moth Cydia pomonella, the pupil not only opens and closes
      with changes in the ambient light level, as expected, but also with changes in
      temperature in the absence of light. In complete darkness, the pupil of A.
      segetum responds over a wide range of temperatures, with the pupillary pigments
      migrating to a light-adapted position when the animal is exposed to either low or
      high temperatures. At temperatures between 21.0 and 22.7 C, the pigments migrate
      to the fully dark-adapted position, resulting in an open pupil and maximal eye
      glow. Pupil closure at high temperatures shows two distinct thresholds: the first
      at 23.8+/-0.7 C and a second some degrees higher at 25.7+/-1.2 C (means +/- s.d.,
      N=10). Temperatures exceeding the first threshold (the activation temperature,
      T(a)) initiate a closure of the pupil that is completed when the temperature
      exceeds the second threshold (the closure temperature, T(c)), which causes rapid
      and complete migration of pigment to the light-adapted position. All temperatures
      above T(a) affect the pupil, but only temperatures exceeding T(c) result in
      complete closure. Temperatures between T(a) and T(c) cause a slow, partial and
      rather unpredictable closure. The lacewing and the codling moth both show very
      similar responses to those of A. segetum, suggesting that this response to
      temperature is widespread in superposition eyes. The possibility that the ambient
      temperature could be used to pre-adapt the eye to different light intensities is
      discussed.

PMID- 10648211
TI  - Transcriptional control of Ca(2+)-activated K(+) channel expression:
      identification of a second, evolutionarily conserved, neuronal promoter.
AB  - Neuronal signaling properties are largely determined by the quantity and
      combination of ion channels expressed. The Drosophila slowpoke gene encodes a
      Ca(2+)-activated K(+) channel used throughout the nervous system. The slowpoke
      transcriptional control region is large and complex. To simplify the search for
      sequences responsible for tissue-specific expression, we relied on evolutionary
      conservation of functionally important sequences. A number of conserved segments
      were found between two Drosophila species. One led us to a new 5' exon and a new
      transcriptional promoter: Promoter C0. In larvae and adults, Promoter C0 was
      demonstrated to be neural-specific using flies transformed with reporter genes
      that either contain or lack the promoter. The transcription start site of
      Promoter C0 was mapped, and the exon it appends to the 5' end of the mRNA was
      sequenced. This is the second neural-specific slowpoke promoter to be identified,
      the first being Promoter C1. Promoter choice does not alter the encoded
      polypeptide sequence. RNAase protection assays indicate that Promoter C0
      transcripts are approximately 12 times more abundant that Promoter C1
      transcripts. Taken together, these facts suggest that promoter choice may be a
      means for cells to control channel density.

PMID- 10648212
TI  - The distribution of NADPH-diaphorase-labelled interneurons and the role of nitric
      oxide in the swimming system of Xenopus laevis larvae.
AB  - The possible involvement of the free radical gas nitric oxide (NO) in the
      modulation of spinal rhythm-generating networks has been studied using Xenopus
      laevis larvae. Using NADPH-diaphorase histochemistry, three putative populations
      of nitric oxide synthase (NOS)-containing cells were identified in the brainstem.
      The position and morphology of the largest and most caudal population suggested
      that a proportion of these neurons is reticulospinal. The possible contribution
      of nitrergic neurons to the control of swimming activity was examined by
      manipulating exogenous and endogenous NO concentrations in vivo with an NO donor
      (SNAP, 100-500 micromol l(-)(1)) and NOS inhibitors (l-NAME and l-NNA, 0.5-5 mmol
      l(-)(1)), respectively. In the presence of SNAP, swim episode duration decreased
      and cycle period increased, whereas the NOS inhibitors had the opposite effects.
      We conclude from these data that the endogenous release of NO from brainstem
      neurons extrinsic to the spinal cord of Xenopus laevis larvae exerts a continuous
      modulatory influence on swimming activity, functioning like a 'brake'. Although
      the exact level at which NO impinges upon the swimming rhythm generator has yet
      to be determined, the predominantly inhibitory effect of NO suggests that the
      underlying mechanisms of NO action could involve modulation of synaptic
      transmission and/or direct effects on neuronal membrane properties.

PMID- 10648213
TI  - Serotonin activates a Ca(2+)-dependent K(+) current in identified peptidergic
      neurons from the crayfish.
AB  - The effects of 5-hydroxytryptamine (5-HT) were investigated in red pigment
      concentrating hormone (RPCH)-containing neurons isolated from the X-organ of the
      crayfish (Procambarus clarkii). Under current-clamp conditions and using the
      gramicidin-perforated-patch configuration, 5-HT elicited a prolonged
      hyperpolarization that suppressed neuronal firing concomitant with an increase in
      membrane conductance. Under voltage-clamp conditions, 5-HT evoked an outward
      current at a holding potential of -50 mV. This current reversed at an E(K) of -90
      mV, which shifted by 30 mV when the extracellular K(+) concentration was
      increased from 5.4 to 19 mmol l(-1). The effect of 5-HT was dose-dependent within
      the range 1-100 micromol l(-1) and followed simple Michaelis-Menten kinetics,
      with a half-maximal response being elicited at 10 micromol l(-1). Preincubation
      with charybdotoxin (100 nmol l(-1)), tetraethylammonium (500 micromol l(-1)) or
      methysergide (100 micromol l(-1)) was effective in blocking the response to 5-HT.
      These results suggest that 5-HT is an inhibitory mediator of the release of red
      pigment concentrating hormone by acting on a Ca(2+)-dependent K(+) current.

PMID- 10648214
TI  - Kinematics and mechanics of ground take-off in the starling Sturnis vulgaris and
      the quail Coturnix coturnix.
AB  - The mechanics of avian take-off are central to hypotheses about flight evolution,
      but have not been quantified in terms of whole-body movements for any species. In
      this study, I use a combination of high-speed video analysis and force plate
      recording to measure the kinematics and mechanics of ground take-off in the
      European starling Sturnis vulgaris and the European migratory quail Coturnix
      coturnix. Counter to hypotheses based on the habits and morphology of each
      species, S. vulgaris and C. coturnix both produce 80-90 % of the velocity of take
      off with the hindlimbs. S. vulgaris performs a countermovement jump (peak
      vertical force four times body weight) followed by wing movement, while C.
      coturnix performs a squat jump (peak vertical force 7.8 times body weight) with
      simultaneous wing movement. The wings, while necessary for continuing the
      movement initiated by the hindlimbs and thereafter supporting the body weight,
      are not the primary take-off accelerator. Comparison with one other avian species
      in which take-off kinematics have been recorded (Columba livia) suggests that
      this could be a common pattern for living birds. Given these data and the fact
      that running take-offs such as those suggested for an evolving proto-flier are
      limited to large or highly specialized living taxa, a jumping model of take-off
      is proposed as a more logical starting point for the evolution of avian powered
      flight.

PMID- 10648215
TI  - Optimum take-off techniques and muscle design for long jump.
AB  - A two-segment model based on Alexander (1990; Phil. Trans. R. Soc. Lond. B 329, 3
      10) was used to investigate the action of knee extensor muscles during long
      jumps. A more realistic representation of the muscle and tendon properties than
      implemented previously was necessary to demonstrate the advantages of eccentric
      force enhancement and non-linear tendon properties. During the take-off phase of
      the long jump, highly stretched leg extensor muscles are able to generate the
      required vertical momentum. Thereby, serially arranged elastic structures may
      increase the duration of muscle lengthening and dissipative operation, resulting
      in an enhanced force generation of the muscle-tendon complex. To obtain maximum
      performance, athletes run at maximum speed and have a net loss in mechanical
      energy during the take-off phase. The positive work done by the concentrically
      operating muscle is clearly less than the work done by the surrounding system on
      the muscle during the eccentric phase. Jumping performance was insensitive to
      changes in tendon compliance and muscle speed, but was greatly influenced by
      muscle strength and eccentric force enhancement. In agreement with a variety of
      experimental jumping performances, the optimal jumping technique (angle of
      attack) was insensitive to the approach speed and to muscle properties (muscle
      mass, the ratio of muscle fibre to tendon cross-sectional area, relative length
      of fibres and tendon). The muscle properties also restrict the predicted range of
      the angle of the velocity vector at take-off.

PMID- 10648216
TI  - Load-elongation characteristics of in vivo human tendon and aponeurosis.
AB  - In the present study, we measured the in vivo load-elongation characteristics of
      the human tibialis anterior tendon and its central aponeurosis. Measurements were
      taken in five men using dynamometry, muscle electrical stimulation and
      ultrasonography. Percutaneous tetanic stimulation of the muscle at successive
      voltages corresponding to 20, 40, 60, 80 and 100 % of maximum isometric
      dorsiflexion moment was applied. During electrical stimulation, we recorded the
      displacements of the tibialis anterior tendon origin and its aponeurosis proximal
      end using B-mode ultrasonography. Aponeurosis displacement was calculated by
      subtracting tendon displacement from the displacement of the aponeurosis proximal
      end. Tendon and aponeurosis displacements increased curvilinearly from 1.3 to 4
      mm and from 3.7 to 12 mm, respectively, as a function of dorsiflexion load.
      Scaling of the displacements recorded to the resting lengths (measured over the
      skin) yielded strain values that increased curvilinearly with load, from 0.8 to
      2.5% in the tendon and from 2.1 to 7% in the aponeurosis. Tendon strain was
      smaller by between 61 and 64% compared with aponeurosis strain at any given
      contraction level. These findings are in line with reports from in vitro isolated
      material testing and have important implications for muscle modelling.

PMID- 10648217
TI  - Bistable membrane potential of the ciliate Coleps hirtus.
AB  - In normal recording solution, the swimming pattern of the freshwater ciliate
      Coleps hirtus, belonging to the class Prostomatea, consists of alternating
      periods of nearly linear forward swimming and circular swimming within a small
      area. Current-clamp recordings were performed to elucidate the mechanism for this
      behaviour. No members of this class have previously been studied using
      electrophysiological techniques. The ciliates were maintained in culture and fed
      on the planctonic alga Rhodomonas minuta. The membrane potential showed
      spontaneous shifts between a more negative (deep) level of approximately -50 mV
      and a less negative (shallow) level of approximately -30 mV. The input resistance
      and capacitance at the more negative level were approximately 400 M capomega and
      120 pF respectively. C. hirtus displayed a pronounced inward rectification, which
      was virtually insensitive to 1 mmol l(-1) Cs(+) and almost completely blocked by
      1 mmol l(-1) Ba(2+). Depolarising current injections failed to evoke graded,
      regenerative Ca(2+) spikes. However, current-induced depolarisations from the
      more negative potential level (-50 mV) showed a pronounced shoulder during the
      repolarising phase. Increased current injections prolonged the shoulder, which
      occasionally stabilised at the shallow membrane potential (-30 mV). The membrane
      potential could be shifted to the deep level by brief hyperpolarising current
      injections. Similar biphasic membrane properties have not been reported
      previously in any ciliate. The bistability of the membrane potential was
      abolished in Ca(2+)-free solution containing Co(2+) or Mg(2+). In Ca(2+)-free
      solution containing 1 mmol l(-1) Ba(2+), brief depolarising current injections at
      the deep potential level evoked all-or-nothing action potentials with a prolonged
      plateau coinciding with the shallow potential. We conclude that the deep membrane
      potential in C. hirtus corresponds to the traditional resting potential, whereas
      the shallow level is a Ca(2+)-dependent plateau potential. In normal solution,
      the direction of the ciliary beat was backwards at the deep potential level and
      forwards at the shallow membrane potential, probably reflecting the two main
      phases of the swimming pattern.

PMID- 10648218
TI  - Urine as a source of conspecific disturbance signals in the crayfish Procambarus
      clarkii.
AB  - Chemical signals are an important aspect of ecological interactions in crustacean
      systems. Repellent chemical signals can be classified into three context-specific
      categories: chemicals released directly from a repellent stimulus (avoidance
      chemicals), chemicals released from damaged conspecifics (alarm chemicals) and
      chemicals released from stressed but undamaged conspecifics (stress chemicals).
      Our study examines the existence and putative source of the stress signals in
      crayfish. We hypothesize that Procambarus clarkii can recognize stressed
      individuals through chemical signals and also that the source of the signal that
      provides P. clarkii with information on the behavioral state of the sender is the
      urine. We collected urine and gill water from stressed and non-stressed animals,
      and chemicals from damaged conspecifics. Chemical cues were introduced into a
      test arena while several behavior patterns of P. clarkii were recorded. Stressed
      crayfish produce significantly more urine than non-stressed crayfish, and this
      urine caused crayfish to walk significantly faster and farther and away from the
      source of the signal. These results demonstrate that predator-stressed crayfish
      release urine that causes other crayfish to move away from the source of the
      signal. Responses to stress chemical signals may allow receiving organisms to
      avoid the fate of the signal sender.

PMID- 10648219
TI  - Prevalence of cutaneous evaporation in Merriam's kangaroo rat and its adaptive
      variation at the subspecific level.
AB  - Previous estimates suggested that ventilatory evaporation constitutes the major
      source of water loss in kangaroo rats (Dipodomys spp.). We quantified rates of
      water loss in Merriam's kangaroo rat (Dipodomys merriami) and demonstrate the
      degree to which acclimation to a particular thermal and hydric environment plays
      a role in the intraspecific variation in water loss evident in this species. We
      draw the following conclusions: (1) that water loss varies intraspecifically in
      Merriam's kangaroo rat, in association with habitats of contrasting aridity and
      temperature; (2) that animals from more xeric locations have lower water loss
      rates than those from more mesic sites; (3) that most water loss is cutaneous,
      with ventilatory evaporative water loss contributing, at most, only 44% to total
      evaporative water loss; and (4) that intraspecific differences in rates of water
      loss are not acclimatory, but fixed. After acclimating under the same conditions,
      xeric-site animals still show a 33% lower rate of evaporative water loss than
      mesic-site animals.

PMID- 10648220
TI  - Extreme resistance to desiccation in overwintering larvae of the gall fly Eurosta
      solidaginis (Diptera, tephritidae).
AB  - During winter, larvae of the goldenrod gall fly Eurosta solidaginis are exposed
      for extended periods to severe low ambient temperatures and low humidities within
      plant galls. The resistance of these larvae to desiccation at various
      temperatures and humidities, the transition (critical) temperature, and the
      effects of treatment with organic solvents on the larval rates of water loss and
      on changes in osmolality during desiccation were examined. The water loss rates
      of the flesh fly Sarcophaga crassipalpis under desiccating conditions were also
      measured. The water permeability of the cuticle of E. solidaginis larvae was very
      low (0.038 microgram h(-1 )cm(-2 )Pa(-1) at 20 C and 4% relative humidity)
      compared with that of larvae of other species. The value for E. solidaginis is
      equivalent to that of the very drought-resistant larvae of the tenebrionid beetle
      Tenebrio molitor (0.038 microgram h(-1)cm(-2)Pa(-1) at 30 C). In contrast, the
      permeability of larvae of the flesh fly Sarcophaga crassipalpis at 20 C and 4 %
      relative humidity was 0.331 microgram h(-1) cm(-2)Pa(-1). The thermal dependence
      of the cuticular permeability increased with temperature by approximately 0.0010
      +microgram h(-1) cm(-2)Pa(-1) C(-1) in the interval between 4 and 40 C. At the
      transition temperature of 40 C, the thermal dependence of the permeability
      increased abruptly to 0.0400 microgram h(-1)cm(-2)Pa(-1) C(-1). Larvae treated
      with hexane and acetone remained remarkably resistant to water loss. However,
      treatment with chloroform:methanol increased the water loss rate approximately 25
      fold. During desiccation at 4 C and 4% relative humidity for 21 days, E.
      solidaginis larvae showed a mass loss of 18.5+/-4.4 % (mean +/- s.e.m., N=6).
      Animals dried under the same conditions over the same period showed a haemolymph
      osmolality of 851+/-75 mosmol kg(-1) (N=4). Larvae freshly removed from the galls
      showed a haemolymph osmolality of 918+/-67 mosmol kg(-1)(N=3). A higher
      osmolality in the dried compared with the fresh larvae would have been expected.
      The present observation suggests that important ions in the haemolymph may have
      been excreted or rendered osmotically inactive during desiccation.

PMID- 10648221
TI  - Prey transport kinematics in Tupinambis teguixin and Varanus exanthematicus:
      conservation of feeding behavior in 'chemosensory-tongued' lizards.
AB  - Although lizards have been predicted to show extensive intraoral prey-processing
      behaviors, quantitative analyses of the types of prey-processing behavior they
      demonstrate and of their kinematics have been limited. The more basal lizard
      lineages (Iguanians) have undergone some study, but the prey-processing
      repertoires of crown taxa have not been thoroughly examined and quantitative
      comparisons of behaviors within or among species have not been made. In this
      study, the prey transport behavior of the savannah monitor (Varanus
      exanthematicus) and gold tegu (Tupinambis teguixin) are described. Although these
      two lineages have independently evolved tongues that are highly specialized for
      chemoreception, we found that they share the same three distinct types of
      transport behavior. These behavior patterns are (i) a purely inertial transport,
      (ii) an inertial transport with use of the tongue, and (iii) a non-inertial
      lingual transport. The tongue is used extensively in both the inertial and the
      purely lingual transport behaviors. More than 75 % of all transport behaviors
      involved tongue movements. These species appear to exhibit a conservation of
      feeding kinematics compared with patterns known for basal lizards. A hypothesis
      for the evolution of inertial feeding is proposed.

PMID- 10648222
TI  - Effects of complex radiative and convective environments on the thermal biology
      of the white-crowned sparrow (Zonotrichia leucophrys gambelii).
AB  - The energy budgets of small endotherms are profoundly affected by characteristics
      of the physical environment such as wind speed, air temperature and solar
      radiation. Among these, solar radiation represents a potentially very large heat
      load to small animals and may have an important influence on their
      thermoregulatory metabolism and heat balance. In this investigation, we examined
      the interactive effects of wind speed and irradiance on body temperature,
      thermoregulatory metabolism and heat balance in the white-crowned sparrow
      (Zonotrichia leucophrys gambelii). We measured changes in metabolic heat
      production by exposing birds to different wind speeds (0.25, 0.5, 1.0 and 2.0 m
      s(-1)) and irradiance combinations (<3 W m(-2) and 936+/-11 W m(-2); mean +/-
      s.d.) at an air temperature of 10 degrees C. Body temperature was not affected by
      wind speed, but was significantly higher in animals not exposed to simulated
      solar radiation compared with those exposed at most wind speeds. In the absence
      of solar radiation, metabolic heat production was strongly affected by wind speed
      and increased by 30 % from 122 to 159 W m(-2) as wind speed increased from 0.25
      to 2.0 m s(-1). Metabolic heat production was even more strongly influenced by
      wind speed in the presence of simulated solar radiation and increased by 51% from
      94 to 142 W m(-2) as wind speed increased from 0.25 to 2. 0 m s(-1). Solar heat
      gain was negatively correlated with wind speed and declined from 28 to 12 W m(-2)
      as wind speed increased from 0.25 to 2.0 m s(-1) and, at its maximum, equaled 11%
      of the radiation intercepted by the animal. The overall thermal impact of the
      various wind speed and irradiance combinations on the animal's heat balance was
      examined for each treatment. Under cold conditions, with no solar radiation
      present, an increase in wind speed from 0.25 to 2.0 m s(-1) was equivalent to a
      decrease in chamber air temperature of 12.7 degrees C. With simulated solar
      radiation present, a similar increase in wind speed was equivalent to a decrease
      in chamber air temperature of 16 degrees C. Overall, shifting environmental
      conditions from a wind speed of 0.25 m s(-1) and irradiance of 936 W m(-2) to a
      wind speed of 2.0 m s(-1) with no short-wave radiation present was equivalent to
      decreasing chamber air temperature by approximately 20 degrees C. The sensitivity
      to changes in the convective environment, combined with the complex effects of
      changes in irradiance levels revealed by re-analyzing data published previously,
      significantly complicates the task of estimating the heat balance of animals in
      nature.

PMID- 10648223
TI  - Effects of fin size on swimming performance, swimming behaviour and routine
      activity of zebrafish Danio rerio.
AB  - The zebrafish Danio rerio exhibits substantial morphological variability in the
      sizes and shapes of the body and the caudal fin. The present study describes
      swimming performance, swimming behaviour and routine locomotor activity patterns
      in three of the major morphotypes: wild-type, long-finned and no-tail. Wild-type
      and long-finned differ in total length (TL), fork length (FL), caudal fin length
      (CFL) and caudal fin height (CFH). No-tail has no caudal fin and is significantly
      smaller in standard length (SL) than the other types. Critical swimming speeds
      (U(crit)) were measured at 28 degrees C in a modified Brett-type water tunnel.
      U(crit) of wild-type fish was 56.0+/-4.8 cm s(-1) or 15.5 SL s(-)(1) (mean +/-
      s.d., N=21), significantly faster than the U(crit) of long-finned fish (43.7+/
      6.8 cm s(-1) or 12.5 SL s(-1), N=17); both were significantly faster than the
      U(crit) of no-tail fish (19. 8+/-4.7 cm s(-1) or 6.9 SL s(-1), N=15). When forced
      to swim in the water tunnel, zebrafish tended to turn and swim downstream for
      short periods at slow water velocities. Turning frequencies (turns per minute,
      f(T)) at the slowest velocity (4 cm s(-1)) were 10. 1+/-6.5 min(-)(1) (N=63) and
      8.6+/-4.7 min(-1) (N=51) for wild-type and long-finned, respectively,
      significantly different from that of the no-tail fish, 4.7+/-2.8 min(-1) (N=45).
      These frequencies decreased below 1 min(-1) at 56%, 64% and 61% of U(crit) in
      wild-type, long-finned and no-tail fish, respectively. Activity levels of wild
      type fish were generally significantly higher than those of long-finned fish, and
      the levels of both were significantly higher than those of no-tail fish. The
      pattern of differences in relative activity levels between types was similar to
      that for U(crit). The results show that the wild-type fish, on a size-scaled
      basis, is one of the fastest-swimming fishes ever measured, reaching the maximum
      predicted theoretical sustained swimming speed. U(crit) of long-finned fish was
      22% lower than that of wild-type fish, and U(crit) of no-tail fish was 65% lower.
      Similar differences were found in turning frequencies and routine activity level.

PMID- 10648224
TI  - The physiology of salinity tolerance in larvae of two species of Culex
      mosquitoes: the role of compatible solutes.
AB  - We investigated the physiological basis for differences in salinity tolerance
      ranges in mosquito larvae of the genus Culex. We examined the response of larvae
      of C. quinquefasciatus, a freshwater obligate, and C. tarsalis, a euryhaline
      osmoconformer, following transfer from fresh water to 34% sea water. Hemolymph
      Na(+) and Cl(-) levels increased similarly in both species, indicating that ion
      regulation does not differ under these conditions. C. quinquefasciatus responded
      to increased environmental salinity with increased hemolymph levels of serine,
      but suffered a significant reduction in levels of trehalose. C. tarsalis
      responded to increased environmental salinity with increased hemolymph levels of
      both proline and trehalose. When C. tarsalis larvae were held in 64% sea water,
      which C. quinquefasciatus larvae cannot tolerate, hemolymph proline and trehalose
      were accumulated approximately 50-fold and twofold, respectively, relative to
      freshwater values. We found that proline serves as both an intra- and
      extracellular compatible solute in C. tarsalis, the first such circumstance
      documented in an animal in response to increased environmental salinity. Analyses
      of the acute responses of the two species to an increase in salinity (from 30% to
      50% sea water) indicate that larvae of C. tarsalis are able to volume-regulate
      via drinking and to attenuate increases in hemolymph NaCl concentration using
      unknown mechanisms during large, rapid increases in salinity.

PMID- 10648225
TI  - Regulation of compatible solute accumulation in larvae of the mosquito Culex
      tarsalis: osmolarity versus salinity.
AB  - In this study, we demonstrate that two of the osmolytes utilized in the
      osmoconforming strategy of larval Culex tarsalis are regulated by two
      fundamentally different signals. When the external osmolality was increased using
      salinity (sea salts), hemolymph NaCl, proline and trehalose concentrations
      increased significantly. When sorbitol was used to increase the external
      osmolality without an elevation in salt concentration, hemolymph NaCl and proline
      concentrations decreased, whereas hemolymph trehalose concentration increased.
      The results suggest that proline accumulation was cued by increases in salinity,
      whereas trehalose levels followed increases in osmolality. Interestingly, we
      found that C. tarsalis larvae accumulated the exogenous sorbitol in the hemolymph
      in an osmoconforming manner. We conducted further studies in which changes in
      hemolymph NaCl concentrations were manipulated using changes in environmental
      salinity. The results suggested that hemolymph proline accumulation was cued by
      the proximal signal of hemolymph NaCl levels. Regardless of which solute (sea
      salts, sorbitol or mixtures thereof) was used to raise the external osmolality,
      trehalose accumulation tracked the increase in total osmolality of the medium.
      These findings indicate that the synthesis and accumulation of these two
      osmolytes are regulated by two independent signals.

PMID- 10648226
TI  - Structure, function and evolution of sex-determining systems in Dipteran insects.
AB  - Nature has evolved an astonishing variety of genetic and epigenetic sex
      determining systems which all achieve the same result, the generation of two
      sexes. Genetic and molecular analyses, mainly performed during the last 20 years,
      have gradually revealed the mechanisms that govern sexual differentiation in a
      few model organisms. In this review, we will introduce the sex-determining system
      of Drosophila and compare the fruitfly to the housefly Musca domestica and other
      Dipteran insects. Despite the ostensible variety, all these insects use the same
      basic strategy: a primary genetic signal that is different in males and females,
      a key gene that responds to the primary signal, and a double-switch gene that
      eventually selects between two alternative sexual programmes. These parallels,
      however, do not extend to the molecular level. Except for the double-switch gene
      doublesex at the end of the cascade, no functional homologies were found between
      more distantly related insects. In particular, Sex-lethal, the key gene that
      controls sexual differentiation in Drosophila, does not have a sex-determining
      function in any other genus studied so far. These results show that sex
      determining cascades, in comparison to other regulatory pathways, evolve much
      more rapidly.

PMID- 10648227
TI  - Organ shape in the Drosophila salivary gland is controlled by regulated,
      sequential internalization of the primordia.
AB  - During Drosophila development, the salivary primordia are internalized to form
      the salivary gland tubes. By analyzing immuno-stained histological sections and
      scanning electron micrographs of multiple stages of salivary gland development,
      we show that internalization occurs in a defined series of steps, involves
      coordinated cell shape changes and begins with the dorsal-posterior cells of the
      primordia. The ordered pattern of internalization is critical for the final shape
      of the salivary gland. In embryos mutant for huckebein (hkb), which encodes a
      transcription factor, or faint sausage (fas), which encodes a cell adhesion
      molecule, internalization begins in the center of the primordia, and completely
      aberrant tubes are formed. The sequential expression of hkb in selected cells of
      the primordia presages the sequence of cell movements. We propose that hkb
      dictates the initial site of internalization, the order in which invagination
      progresses and, consequently, the final shape of the organ. We propose that fas
      is required for hkb-dependent signaling events that coordinate internalization.

PMID- 10648228
TI  - Generation of neurons by transient expression of neural bHLH proteins in
      mammalian cells.
AB  - Basic helix-loop-helix (bHLH) transcription factors are known to function during
      mammalian neurogenesis. Here we show that transient transfection of vectors
      expressing neuroD2, MASH1, ngn1 or related neural bHLH proteins, with their
      putative dimerization partner E12, can convert mouse P19 embryonal carcinoma
      cells into differentiated neurons. Transfected cells express numerous neuron
      specific proteins, adopt a neuronal morphology and are electrically excitable.
      Thus, the expression of neural bHLH proteins is sufficient to confer a neuronal
      fate on uncommitted mammalian cells. Neuronal differentiation of transfected
      cells is preceded by elevated expression of the cyclin-dependent kinase inhibitor
      p27(Kip1) and cell cycle withdrawal. This demonstrates that the bHLH proteins can
      link neuronal differentiation to withdrawal from the cell cycle, possibly by
      activating the expression of p27(Kip1). The ability to generate mammalian neurons
      by transient expression of neural bHLH proteins should create new opportunities
      for studying neurogenesis and devising neural repair strategies.

PMID- 10648229
TI  - The fax-1 nuclear hormone receptor regulates axon pathfinding and
      neurotransmitter expression.
AB  - Specification of neuron identity requires the activation of a number of discrete
      developmental programs. Among these is pathway selection by growth cones: in
      order for a neuron's growth cone to respond appropriately to guidance cues
      presented by other cells or the extracellular matrix, the neuron must express
      genes to mediate the response. The fax-1 gene of C. elegans is required for
      pathfinding of axons that extend along the ventral nerve cord. We show that fax-1
      is also required for pathfinding of axons in the nerve ring, the largest nerve
      bundle in the nematode, and for normal expression of FMRFamide-like
      neurotransmitters in the AVK interneurons. The fax-1 gene encodes a member of the
      superfamily of nuclear hormone receptors and has a DNA-binding domain related to
      the human PNR and Drosophila Tailless proteins. We observe fax-1 expression in
      embryonic neurons, including the AVK interneurons, just prior to axon extension,
      but after neurogenesis. These data suggest that fax-1 coordinately regulates the
      transcription of genes that function in the selection of axon pathways,
      neurotransmitter expression and, perhaps, other aspects of the specification of
      neuron identity.

PMID- 10648230
TI  - The bromodomain protein LIN-49 and trithorax-related protein LIN-59 affect
      development and gene expression in Caenorhabditis elegans.
AB  - We have molecularly characterized the lin-49 and lin-59 genes in C. elegans, and
      found their products are related to Drosophila trithorax group (trx-G) proteins
      and other proteins implicated in chromatin remodelling. LIN-49 is structurally
      most similar to the human bromodomain protein BR140, and LIN-59 is most similar
      to the Drosophila trx-G protein ASH1. In C. elegans, lin-49 and lin-59 are
      required for the normal development of the mating structures of the adult male
      tail, for the normal morphology and function of hindgut (rectum) cells in both
      males and hermaphrodites and for the maintenance of structural integrity in the
      hindgut and egg-laying system in adults. Expression of the Hox genes egl-5 and
      mab-5 is reduced in lin-49 and lin-59 mutants, suggesting lin-49 and lin-59
      regulate HOM-C gene expression in C. elegans as the trx-G genes do in Drosophila.
      lin-49 and lin-59 transgenes are expressed widely throughout C. elegans animals.
      Thus, in contrast to the C. elegans Polycomb group (Pc-G)-related genes mes-2 and
      mes-6 that function primarily in the germline, we propose lin-49 and lin-59
      function in somatic development similar to the Drosophila trx-G genes.

PMID- 10648231
TI  - Redundant regulation of meristem identity and plant architecture by FRUITFULL,
      APETALA1 and CAULIFLOWER.
AB  - The transition from vegetative to reproductive phases during Arabidopsis
      development is the result of a complex interaction of environmental and
      endogenous factors. One of the key regulators of this transition is LEAFY (LFY),
      whose threshold levels of activity are proposed to mediate the initiation of
      flowers. The closely related APETALA1 (AP1) and CAULIFLOWER (CAL) meristem
      identity genes are also important for flower initiation, in part because of their
      roles in upregulating LFY expression. We have found that mutations in the
      FRUITFULL (FUL) MADS-box gene, when combined with mutations in AP1 and CAL, lead
      to a dramatic non-flowering phenotype in which plants continuously elaborate
      leafy shoots in place of flowers. We demonstrate that this phenotype is caused
      both by the lack of LFY upregulation and by the ectopic expression of the
      TERMINAL FLOWER1 (TFL1) gene. Our results suggest that the FUL, AP1 and CAL genes
      act redundantly to control inflorescence architecture by affecting the domains of
      LFY and TFL1 expression as well as the relative levels of their activities.

PMID- 10648232
TI  - Segmentation of the central nervous system in leech.
AB  - Central nervous system (CNS) in leech comprises segmentally iterated progeny
      derived from five embryonic lineages (M, N, O, P and Q). Segmentation of the
      leech CNS is characterized by the formation of a series of transverse fissures
      that subdivide initially continuous columns of segmental founder cells in the N
      lineage into distinct ganglionic primordia. We have examined the relationship
      between the N lineage cells that separate to form the fissures and lateral
      ectodermal and mesodermal derivatives by differentially labeling cells with
      intracellular lineage tracers and antibodies. Although subsets of both lateral
      ectoderm and muscle fibers contact N lineage cells at or near the time of fissure
      formation, ablation experiments suggest that these contacts are not required for
      initiating fissure formation. It appears, therefore, that this aspect of
      segmentation occurs autonomously within the N lineage. To support this idea, we
      present evidence that fundamental differences exist between alternating
      ganglionic precursor cells (nf and ns primary blast cells) within the N lineage.
      Specifically, ablation of an nf primary blast cell sometimes resulted in the
      fusion of ipsilateral hemi-ganglia, while ablation of an ns primary blast cell
      often caused a 'slippage' of blast cells posterior to the lesion. Also,
      differences in cell behavior were observed in biochemically arrested nf and ns
      primary blast cells. Collectively, these results lead to a model of segmentation
      in the leech CNS that is based upon differences in cell adhesion and/or cell
      motility between the alternating nf and ns primary blast cells. We note that the
      segmentation processes described here occur well prior to the expression of the
      leech engrailed-class gene in the N lineage.

PMID- 10648233
TI  - Drosophila bunched integrates opposing DPP and EGF signals to set the operculum
      boundary.
AB  - The Drosophila BMP homolog DPP can function as a morphogen, inducing multiple
      cell fates across a developmental field. However, it is unknown how graded levels
      of extracellular DPP are interpreted to organize a sharp boundary between
      different fates. Here we show that opposing DPP and EGF signals set the boundary
      for an ovarian follicle cell fate. First, DPP regulates gene expression in the
      follicle cells that will create the operculum of the eggshell. DPP induces
      expression of the enhancer trap reporter A359 and represses expression of
      bunched, which encodes a protein similar to the mammalian transcription factor
      TSC-22. Second, DPP signaling indirectly regulates A359 expression in these cells
      by downregulating expression of bunched. Reduced bunched function restores A359
      expression in cells that lack the Smad protein MAD; ectopic expression of BUNCHED
      suppresses A359 expression in this region. Importantly, reduction of bunched
      function leads to an expansion of the operculum and loss of the collar at its
      boundary. Third, EGF signaling upregulates expression of bunched. We previously
      demonstrated that the bunched expression pattern requires the EGF receptor ligand
      GURKEN. Here we show that activated EGF receptor is sufficient to induce ectopic
      bunched expression. Thus, the balance of DPP and EGF signals sets the boundary of
      bunched expression. We propose that the juxtaposition of cells with high and low
      BUNCHED activity organizes a sharp boundary for the operculum fate.

PMID- 10648234
TI  - mab-20 encodes Semaphorin-2a and is required to prevent ectopic cell contacts
      during epidermal morphogenesis in Caenorhabditis elegans.
AB  - The Semaphorins are a family of secreted and transmembrane proteins known to
      elicit growth cone repulsion and collapse. We made and characterized a putative
      null mutant of the C. elegans gene semaphorin-2a (Ce-sema-2a). This mutant failed
      to complement mutants of mab-20 (Baird, S. E., Fitch, D. H., Kassem, I. A. A. and
      Emmons, S. W. (1991) Development 113, 515-526). In addition to low-frequency axon
      guidance errors, mab-20 mutants have unexpected defects in epidermal
      morphogenesis. Errant epidermal cell migrations affect epidermal enclosure of the
      embryo, body shape and sensory rays of the male tail. These phenotypic traits are
      explained by the formation of inappropriate contacts between cells of similar
      type and suggest that Ce-Sema-2a may normally prevent formation or stabilization
      of ectopic adhesive contacts between these cells.

PMID- 10648235
TI  - Formation and specification of distal leg segments in Drosophila by dual Bar
      homeobox genes, BarH1 and BarH2.
AB  - Here, we show that BarH1 and BarH2, a pair of Bar homeobox genes, play essential
      roles in the formation and specification of the distal leg segments of
      Drosophila. In early third instar, juxtaposition of Bar-positive and Bar-negative
      tissues causes central folding that may separate future tarsal segments 2 from 3,
      while juxtaposition of tissues differentially expressing Bar homeobox genes at
      later stages gives rise to segmental boundaries of distal tarsi including the
      tarsus/pretarsus boundary. Tarsus/pretarsus boundary formation requires at least
      two different Bar functions, early antagonistic interactions with a pretarsus
      specific homeobox gene, aristaless, and the subsequent induction of Fas II
      expression in pretarsus cells abutting tarsal segment 5. Bar homeobox genes are
      also required for specification of distal tarsi. Bar expression requires Distal
      less but not dachshund, while early circular dachshund expression is delimited
      interiorly by BarH1 and BarH2.

PMID- 10648236
TI  - The Fab-8 boundary defines the distal limit of the bithorax complex iab-7 domain
      and insulates iab-7 from initiation elements and a PRE in the adjacent iab-8
      domain.
AB  - The Drosophila bithorax complex Abdominal-B (Abd-B) gene specifies parasegmental
      identity at the posterior end of the fly. The specific pattern of Abd-B
      expression in each parasegment (PS) determines its identity and, in PS10-13, Abd
      B expression is controlled by four parasegment-specific cis-regulatory domains,
      iab-5 to iab-8, respectively. In order to properly determine parasegmental
      identity, these four cis-regulatory domains must function autonomously during
      both the initiation and maintenance phases of BX-C regulation. The studies
      reported here demonstrate that the (centromere) distal end of iab-7 domain is
      delimited by the Fab-8 boundary. Initiators that specify PS12 identity are
      located on the proximal iab-7 side of Fab-8, while initiators that specify PS13
      identity are located on the distal side of Fab-8, in iab-8. We use transgene
      assays to demonstrate that Fab-8 has enhancer blocking activity and that it can
      insulate reporter constructs from the regulatory action of the iab-7 and iab-8
      initiators. We also show that the Fab-8 boundary defines the realm of action of a
      nearby iab-8 Polycomb Response Element, preventing this element from ectopically
      silencing the adjacent domain. Finally, we demonstrate that the insulating
      activity of the Fab-8 boundary in BX-C is absolutely essential for the proper
      specification of parasegmental identity by the iab-7 and iab-8 cis-regulatory
      domains. Fab-8 together with the previously identified Fab-7 boundary delimit the
      first genetically defined higher order domain in a multicellular eukaryote.

PMID- 10648237
TI  - Requirement of Sox2-mediated signaling for differentiation of early Xenopus
      neuroectoderm.
AB  - From early stages of development, Sox2-class transcription factors (Sox1, Sox2
      and Sox3) are expressed in neural tissues and sensory epithelia. In this report,
      we show that Sox2 function is required for neural differentiation of early
      Xenopus ectoderm. Microinjection of dominant-negative forms of Sox2 (dnSox2) mRNA
      inhibits neural differentiation of animal caps caused by attenuation of BMP
      signals. Expression of dnSox2 in developing embryos suppresses expression of N
      CAM and regional neural markers. We have analyzed temporal requirement of Sox2
      mediated signaling by using an inducible dnSox2 construct fused to the ligand
      binding domain of the glucocorticoid receptor. Attenuation of Sox2 function both
      from the late blastula stage and from the late gastrula stage onwards causes an
      inhibition of neural differentiation in animal caps and in whole embryos.
      Additionally, dnSox2-injected cells that fail to differentiate into neural
      tissues are not able to adopt epidermal cell fate. These data suggest that Sox2
      class genes are essential for early neuroectoderm cells to consolidate their
      neural identity during secondary steps of neural differentiation.

PMID- 10648238
TI  - Receptor tyrosine phosphatases regulate axon guidance across the midline of the
      Drosophila embryo.
AB  - Neural receptor-linked protein tyrosine phosphatases (RPTPs) are required for
      guidance of motoneuron and photoreceptor growth cones in Drosophila. These
      phosphatases have not been implicated in growth cone responses to specific
      guidance cues, however, so it is unknown which aspects of axonal pathfinding are
      controlled by their activities. Three RPTPs, known as DLAR, DPTP69D, and DPTP99A,
      have been genetically characterized thus far. Here we report the isolation of
      mutations in the fourth neural RPTP, DPTP10D. The analysis of double mutant
      phenotypes shows that DPTP10D and DPTP69D are necessary for repulsion of growth
      cones from the midline of the embryonic central nervous system. Repulsion is
      thought to be triggered by binding of the secreted protein Slit, which is
      expressed by midline glia, to Roundabout (Robo) receptors on growth cones. Robo
      repulsion is downregulated by the Commissureless (Comm) protein, allowing axons
      to cross the midline. Here we show that the Rptp mutations genetically interact
      with robo, slit and comm. The nature of these interactions suggests that DPTP10D
      and DPTP69D are positive regulators of Slit/Roundabout repulsive signaling. We
      also show that elimination of all four neural RPTPs converts most noncrossing
      longitudinal pathways into commissures that cross the midline, indicating that
      tyrosine phosphorylation controls the manner in which growth cones respond to
      midline signals.

PMID- 10648239
TI  - The Arabidopsis embryonic shoot fate map.
AB  - A fate map has been constructed for the shoot apical region of the embryo of the
      dicotyledonous plant Arabidopsis thaliana using spontaneously arising clonal
      albino sectors caused by the chloroplast mutator 1-2 mutation. Chimeric seedlings
      exhibiting albino sectors shared between the cotyledons and first true leaves
      revealed patterns of organ inclusion and exclusion. Frequencies of clone sharing
      were used to calculate developmental distances between organs based on the
      frequency of clonal sectors failing to extend between different organs. The
      resulting fate map shows asymmetry in the developmental distances between the
      cotyledons (embryonic leaves) which in turn predicts the location of the first
      post-germination leaf and the handedness of the spiral of leaf placement around
      the central stem axis in later development. The map suggests that embryonic leaf
      fate specification in the cotyledons may represent a developmental ground state
      necessary for the formation of the shoot apical meristem.

PMID- 10648241
TI  - Post-translational control of occludin membrane assembly in mouse trophectoderm:
      a mechanism to regulate timing of tight junction biogenesis and blastocyst
      formation.
AB  - The mouse blastocyst forms during the 32-cell stage with the emergence of the
      blastocoelic cavity. This developmental transition is dependent upon the
      differentiation and transport function of the trophectoderm epithelium which
      forms the wall of the blastocyst and exhibits functional intercellular tight
      junctions (TJs) to maintain epithelial integrity during blastocoele expansion. To
      investigate mechanisms regulating the timing of blastocyst formation, we have
      examined the dynamics of expression of occludin, an integral membrane protein of
      the TJ. Confocal microscopy of intact embryos and synchronised cell clusters
      revealed that occludin first assembles at the apicolateral membrane contact site
      between nascent trophectoderm cells usually during the early 32-cell stage, just
      prior to the time of blastocoele cavitation. This is a late event in the assembly
      of TJ-associated proteins within trophectoderm which, from our previous data,
      spans from 8- to 32-cell stages. Occludin membrane assembly is dependent upon
      prior E-cadherin-mediated cell-cell adhesion and is sensitive to brefeldin A, an
      inhibitor of Golgi-to-membrane transport. Occludin is delivered to the TJ site in
      association with the TJ plaque protein, ZO-1(&agr;)+, which we have shown
      previously is newly transcribed and translated during late cleavage. Immediately
      after assembly and before cavitation, occludin localised at the TJ site switches
      from a Triton X-100-soluble to -insoluble form indicative of actin cytoskeletal
      and/or membrane anchorage. Occludin mRNA and protein are detectable throughout
      cleavage by RT-PCR and immunoblotting, respectively, indicating that timing of
      membrane assembly is not controlled by expression alone. Rather, we have
      identified changes in the pattern of different occludin forms expressed during
      cleavage which, using phosphatase treatment of embryo lysates, include post
      translational modifications. We propose that the phosphorylation of one form of
      occludin (band 2, 65-67 kDa) during late cleavage, which leads to its exclusive
      conversion from a Triton X-100-soluble to -insoluble pool, may regulate occludin
      association with ZO-1(&agr;)+ and membrane assembly, and thereby act to control
      completion of TJ biogenesis and the timing of blastocyst formation.

PMID- 10648240
TI  - BMP-binding modules in chordin: a model for signalling regulation in the
      extracellular space.
AB  - A number of genetic and molecular studies have implicated Chordin in the
      regulation of dorsoventral patterning during gastrulation. Chordin, a BMP
      antagonist of 120 kDa, contains four small (about 70 amino acids each) cysteine
      rich domains (CRs) of unknown function. In this study, we show that the Chordin
      CRs define a novel protein module for the binding and regulation of BMPs. The
      biological activity of Chordin resides in the CRs, especially in CR1 and CR3,
      which have dorsalizing activity in Xenopus embryo assays and bind BMP4 with
      dissociation constants in the nanomolar range. The activity of individual CRs,
      however, is 5- to 10-fold lower than that of full-length Chordin. These results
      shed light on the molecular mechanism by which Chordin/BMP complexes are
      regulated by the metalloprotease Xolloid, which cleaves in the vicinity of CR1
      and CR3 and would release CR/BMP complexes with lower anti-BMP activity than
      intact Chordin. CR domains are found in other extracellular proteins such as
      procollagens. Full-length Xenopus procollagen IIA mRNA has dorsalizing activity
      in embryo microinjection assays and the CR domain is required for this activity.
      Similarly, a C. elegans cDNA containing five CR domains induces secondary axes in
      injected Xenopus embryos. These results suggest that CR modules may function in a
      number of extracellular proteins to regulate growth factor signalling.

PMID- 10648242
TI  - Combined activities of Gurken and decapentaplegic specify dorsal chorion
      structures of the Drosophila egg.
AB  - During Drosophila oogenesis Gurken, associated with the oocyte nucleus, activates
      the Drosophila EGF receptor in the follicular epithelium. Gurken first specifies
      posterior follicle cells, which in turn signal back to the oocyte to induce the
      migration of the oocyte nucleus from a posterior to an anterior-dorsal position.
      Here, Gurken signals again to specify dorsal follicle cells, which give rise to
      dorsal chorion structures including the dorsal appendages. If Gurken signaling is
      delayed and starts after stage 6 of oogenesis the nucleus remains at the
      posterior pole of the oocyte. Eggs develop with a posterior ring of dorsal
      appendage material that is produced by main-body follicle cells expressing the
      gene Broad-Complex. They encircle terminal follicle cells expressing variable
      amounts of the TGFbeta homologue, decapentaplegic. By ectopically expressing
      decapentaplegic and clonal analysis with Mothers against dpp we show that
      Decapentaplegic signaling is required for Broad-Complex expression. Thus, the
      specification and positioning of dorsal appendages along the anterior-posterior
      axis depends on the intersection of both Gurken and Decapentaplegic signaling.
      This intersection also induces rhomboid expression and thereby initiates the
      positive feedback loop of EGF receptor activation, which positions the dorsal
      appendages along the dorsal-ventral egg axis.

PMID- 10648243
TI  - Analysis of Drosophila photoreceptor axon guidance in eye-specific mosaics.
AB  - During development of the adult Drosophila visual system, axons of the eight
      photoreceptors in each ommatidium fasciculate together and project as a single
      bundle towards the optic lobes of the brain. Within the brain, individual
      photoreceptor axons from each bundle then seek specific targets in distinct
      layers of the optic lobes. The axons of photoreceptors R1-R6 terminate in the
      lamina, while R7 and R8 axons pass through the lamina to terminate in separate
      layers of the medulla. To identify genes required for photoreceptor axon
      guidance, including those with essential functions during early development, we
      have devised a strategy for the simple and efficient generation of genetic
      mosaics in which mutant photoreceptor axons innervate a predominantly wild-type
      brain. In a large-scale saturation mutagenesis performed using this system, we
      recovered new alleles of the gene encoding the receptor tyrosine phosphatase
      PTP69D. PTP69D has previously been shown to function in the correct targeting of
      motor axons in the embryo and R1-R6 axons in the visual system. Here, we show
      that PTP69D is also required for correct targeting of R7 axons. Whereas mutant R1
      R6 axons occasionally extend beyond their normal targets in the lamina, mutant R7
      axons often fail to reach their targets in the medulla, stopping instead at the
      same level as the R8 axon. These targeting errors are difficult to reconcile with
      models in which PTP69D plays an instructive role in photoreceptor axon targeting,
      as previously proposed. Rather, we suggest that PTP69D plays a permissive role,
      perhaps reducing the adhesion of R1-R6 and R7 growth cones to the pioneer R8 axon
      so that they can respond independently to their specific targeting cues.

PMID- 10648244
TI  - Dorsal downregulation of GSK3beta by a non-Wnt-like mechanism is an early
      molecular consequence of cortical rotation in early Xenopus embryos.
AB  - Cortical rotation and concomitant dorsal translocation of cytoplasmic
      determinants are the earliest events known to be necessary for dorsoventral
      patterning in Xenopus embryos. The earliest known molecular target is beta
      catenin, which is essential for dorsal development and becomes dorsally enriched
      shortly after cortical rotation. In mammalian cells cytoplasmic accumulation of
      beta-catenin follows reduction of the specific activity of glycogen synthase
      kinase 3-beta (GSK3beta). In Xenopus embryos, exogenous GSK3beta) suppresses
      dorsal development as predicted and GSK3beta dominant negative (kinase dead)
      mutants cause ectopic axis formation. However, endogenous GSK3beta regulation is
      poorly characterized. Here we demonstrate two modes of GSK3beta regulation in
      Xenopus. Endogenous mechanisms cause depletion of GSK3beta protein on the dorsal
      side of the embryo. The timing, location and magnitude of the depletion
      correspond to those of endogenous beta-catenin accumulation. UV and D(2)O
      treatments that abolish and enhance dorsal character of the embryo, respectively,
      correspondingly abolish and enhance GSK3beta depletion. A candidate regulator of
      GSK3beta, GSK3-binding protein (GBP), known to be essential for axis formation,
      also induces depletion of GSK3beta. Depletion of GSK3beta is a previously
      undescribed mode of regulation of this signal transducer. The other mode of
      regulation is observed in response to Wnt and dishevelled expression. Neither Wnt
      nor dishevelled causes depletion but instead they reduce GSK3beta-specific
      activity. Thus, Wnt/Dsh and GBP appear to effect two biochemically distinct modes
      of GSK3beta regulation.

PMID- 10648245
TI  - Endoderm patterning by the notochord: development of the hypochord in Xenopus.
AB  - The patterning and differentiation of the vertebrate endoderm requires signaling
      from adjacent tissues. In this report, we demonstrate that signals from the
      notochord are critical for the development of the hypochord, which is a
      transient, endodermally derived structure that lies immediately ventral to the
      notochord in the amphibian and fish embryo. It appears likely that the hypochord
      is required for the formation of the dorsal aorta in these organisms. We show
      that removal of the notochord during early neurulation leads to the complete
      failure of hypochord development and to the elimination of expression of the
      hypochord marker, VEGF. Removal of the notochord during late neurulation,
      however, does not interfere with hypochord formation. These results suggest that
      signals arising in the notochord instruct cells in the underlying endoderm to
      take on a hypochord fate during early neural stages, and that the hypochord does
      not depend on further notochord signals for maintenance. In reciprocal
      experiments, when the endoderm receives excess notochord signaling, a
      significantly enlarged hypochord develops. Overall, these results demonstrate
      that, in addition to patterning neural and mesodermal tissues, the notochord
      plays an important role in patterning of the endoderm.

PMID- 10648246
TI  - OVO transcription factors function antagonistically in the Drosophila female
      germline.
AB  - OVO controls germline and epidermis differentiation in flies and mice. In the
      Drosophila germline, alternative OVO-B and OVO-A isoforms have a common DNA
      binding domain, but different N-termini. We show that these isoforms are
      transcription factors with opposite regulatory activities. Using yeast one-hybrid
      assays, we identified a strong activation domain within a common region and a
      counteracting repression domain within the OVO-A-specific region. In flies, OVO-B
      positively regulated the ovarian tumor promoter, while OVO-A was a negative
      regulator of the ovarian tumor and ovo promoters. OVO-B isoforms supplied ovo(+)
      function in the female germline and epidermis, while OVO-A isoforms had dominant
      negative activity in both tissues. Moreover, elevated expression of OVO-A
      resulted in maternal-effect lethality while the absence of OVO-A resulted in
      maternal-effect sterility. Our data indicate that tight regulation of
      antagonistic OVO-B and OVO-A isoforms is critical for germline formation and
      differentiation.

PMID- 10648247
TI  - The growth of the dermomyotome and formation of early myotome lineages in
      thoracolumbar somites of chicken embryos.
AB  - Myotome formation in the epaxial and hypaxial domains of thoraco-lumbar somites
      was analyzed using fluorescent vital dye labeling of dermomyotome cells and cell
      fate assessment by confocal microscopy. Muscle precursor cells for the epaxial
      and hypaxial myotomes are predominantly located in the dorsomedial and
      ventrolateral dermomyotome lips, respectively, and expansion of the dermomyotome
      is greatest along its mediolateral axis coincident with the dorsalward and
      ventralward growth directions of the epaxial and hypaxial myotomes. Measurements
      of the dermomyotome at different stages of development shows that myotome growth
      begins earlier in the epaxial than in the hypaxial domain, but that after an
      initial lag phase, both progress at the same rate. A combination of dye injection
      and/or antibody labeling of early and late-expressed muscle contractile proteins
      confirms the myotome mediolateral growth directions, and shows that the myotome
      thickness increases in a superficial (near dermis) to deep (near sclerotome)
      growth direction. These findings also provide a basis for predicting the
      following gene expression sequence program for the earliest muscle precursor
      lineages in mouse embryos: Pax-3 (stem cells), myf-5 (myoblast cells) and myoD
      (myocytes). The movements and mitotic activity of early muscle precursor cells
      lead to the conclusion that patterning and growth in the myotome specifically,
      and in the epaxial and hypaxial domains of the body generally, are governed by
      morphogenetic cell movements.

PMID- 10648249
TI  - Dietary supplements and the american journal of clinical nutrition(1)

PMID- 10648248
TI  - A novel hydra matrix metalloproteinase (HMMP) functions in extracellular matrix
      degradation, morphogenesis and the maintenance of differentiated cells in the
      foot process.
AB  - As a member of Cnidaria, the body wall of hydra is structurally reduced to an
      epithelial bilayer with an intervening extracellular matrix (ECM). Biochemical
      and cloning studies have shown that the molecular composition of hydra ECM is
      similar to that seen in vertebrates and functional studies have demonstrated that
      cell-ECM interactions are important to developmental processes in hydra. Because
      vertebrate matrix metalloproteinases (MMPs) have been shown to have an important
      role in cell-ECM interactions, the current study was designed to determine
      whether hydra has homologues of these proteinases and, if so, what function these
      enzymes have in morphogenesis and cell differentiation in this simple metazoan.
      Utilizing a PCR approach, a single hydra matrix metalloproteinase, named HMMP was
      identified and cloned. The structure of HMMP was similar to that of vertebrate
      MMPs with an overall identity of about 35%. Detailed structural analysis
      indicated some unique features in (1) the cysteine-switch region of the
      prodomain, (2) the hinge region preceding the hemopexin domain, and (3) the
      hemopexin domain. Using a bacterial system, HMMP protein was expressed and folded
      to obtain an active enzyme. Substrate analysis studies indicated that recombinant
      HMMP could digest a number of hydra ECM components such as hydra laminin. Using a
      fluorogenic MMP substrate assay, it was determined that HMMP was inhibited by
      peptidyl hydroxamate MMP inhibitors, GM6001 and matlistatin, and by human
      recombinant TIMP-1. Whole-mount in situ studies indicated that HMMP mRNA was
      expressed in the endoderm along the entire longitudinal axis of hydra, but at
      relatively high levels at regions where cell-transdifferentiation occurred
      (apical and basal poles). Functional studies using GM6001 and TIMP-1 indicated
      that these MMP inhibitors could reversibly block foot regeneration. Blockage of
      foot regeneration was also observed using antisense thio-oligo nucleotides to
      HMMP introduced into the endoderm of the basal pole using a localized
      electroporation technique. Studies with adult intact hydra found that GM6001
      could also cause the reversible de-differentiation or inhibition of
      transdifferentiation of basal disk cells of the foot process. Basal disk cells
      are adjacent to those endoderm cells of the foot process that express high levels
      of HMMP mRNA. In summary, these studies indicate that hydra has at least one MMP
      that is functionally tied to morphogenesis and cell transdifferentiation in this
      simple metazoan.

PMID- 10648250
TI  - Viscous fibers, health claims, and strategies to reduce cardiovascular disease
      risk.

PMID- 10648251
TI  - Coffee and homocysteine.

PMID- 10648252
TI  - Effects of probiotic bacteria on diarrhea, lipid metabolism, and carcinogenesis:
      a review of papers published between 1988 and 1998.
AB  - We reviewed the evidence from human intervention studies for the health effects
      of probiotic bacteria, ie, live bacteria that survive passage through the
      gastrointestinal tract and have beneficial effects on the host. Of the 49 studies
      reviewed, 26 dealt with the prevention or treatment of diarrheal disease, 9 with
      the prevention of cancer or of the formation of carcinogens, 7 with the lowering
      of serum cholesterol, and 7 with the stimulation of the immune system. The most
      widely studied probiotic bacteria were Lactobacillus GG (22 studies),
      Lactobacillus acidophilus (16 studies), Bifidobacterium bifidum (6 studies), and
      Enterococcus faecium (7 studies). Intake of Lactobacillus GG consistently
      shortened the diarrheal phase of rotavirus infection by 1 d. However, evidence
      for the prevention by Lactobacillus GG and other probiotics of diarrhea due to
      viral or bacterial infections was less strong. Effects of probiotics on the
      immune system are inconclusive because of the variety of outcome variables
      reported. Cholesterol lowering by L. acidophilus was shown in some but not all
      studies; cholesterol lowering by E. faecium seems to be transient. Two studies of
      one research group showed a smaller recurrence of bladder tumors in patients
      after treatment with Lactobacillus casei; these results await confirmation. The
      production of mutagens after a meal might be reduced by the concomitant intake of
      probiotics, but the relevance of this finding is unclear. In conclusion,
      consumption of foods containing Lactobacillus GG may shorten the course of
      rotavirus infection. Other health effects of probiotic bacteria have not been
      well established. Well-designed placebo-controlled studies with validated outcome
      variables are needed to determine the health effects of probiotics.

PMID- 10648253
TI  - Carbohydrate-induced hypertriacylglycerolemia: historical perspective and review
      of biological mechanisms.
AB  - Current trends in health promotion emphasize the importance of reducing dietary
      fat intake. However, as dietary fat is reduced, the dietary carbohydrate content
      typically rises and the desired reduction in plasma cholesterol concentrations is
      frequently accompanied by an elevation of plasma triacylglycerol. We review the
      phenomenon of carbohydrate-induced hypertriacylglycerolemia, the health effects
      of which are among the most controversial and important issues in public health
      nutrition today. We first focus on how seminal observations made in the late
      1950s and early 1960s became the basis for subsequent important research
      questions and areas of scientific study. The second focus of this paper is on the
      current knowledge of biological mechanisms that contribute to carbohydrate
      induced hypertriacylglycerolemia. The clinical rationale behind mechanistic
      studies is this: if carbohydrate-induced hypertriacylglycerolemia shares a
      metabolic basis with endogenous hypertriacylglycerolemia (that observed in
      subjects consuming high-fat diets), then a similar atherogenic risk may be more
      likely than if the underlying metabolic mechanisms differ. The third focus of the
      paper is on both the positive metabolic changes that occur when high-carbohydrate
      diets are consumed and the potentially negative health effects of such diets. The
      review concludes with a summary of some important research questions that remain
      to be addressed. These issues include the level of dietary carbohydrate that
      induces carbohydrate-induced hypertriacylglycerolemia, whether the phenomenon is
      transient or can be avoided, whether de novo lipogenesis contributes to the
      phenomenon, and what magnitude of triacylglycerol elevation represents an
      increase in disease risk.

PMID- 10648254
TI  - The revolution in microanalytic chemistry: a macro-opportunity for clinical
      nutrition.

PMID- 10648255
TI  - Short-term, high-fat diets lower circulating leptin concentrations in rats.
AB  - BACKGROUND: Leptin is produced in proportion to body fat mass and can act on the
      brain to induce satiety and regulate adipose tissue mass; factors other than
      adipose tissue mass may influence circulating leptin concentrations. OBJECTIVE:
      We explored the possibility that short-term, moderately high-fat diets induce
      weight gain by producing inappropriately low circulating leptin concentrations.
      DESIGN: Female Hooded Wistar rats were fed either a moderately high-fat diet or
      control diet. Body weight, energy intake, body composition, and fasting plasma
      leptin were compared after 4 and 14 wk of dietary treatment. RESULTS: After 4 wk,
      abdominal fat mass was 38% greater in rats fed the high-fat diet than in those
      fed the control diet (P < 0.01). However, plasma leptin concentrations were 24%
      lower in animals fed the high-fat diet (P < 0.05), resulting in significantly
      lower plasma leptin concentrations per unit abdominal fat mass than in control
      animals (P < 0.005). From 4 to 14 wk, animals fed the high-fat diet gained twice
      as much weight and consumed 32 kJ/d more than controls (both P < 0.05). At 14 wk,
      plasma leptin concentrations per unit abdominal fat mass were 27% lower in rats
      fed the high-fat diet (P = 0.058) and there was a significant negative
      association between leptin concentrations per unit abdominal fat mass and body
      weight (r = 0.44, P < 0.05). CONCLUSIONS: In the short term, a moderately high
      fat diet is associated with lower than expected circulating leptin
      concentrations, which correlate with a higher body weight. A high-fat diet may
      therefore contribute to weight gain by reducing leptin secretion in adipose
      tissue.

PMID- 10648256
TI  - Acute hyperinsulinemia and very-low-density and low-density lipoprotein
      subfractions in obese subjects.
AB  - BACKGROUND: The influence of hyperinsulinemia on concentrations of lipoprotein
      subfractions in obese, nondiabetic persons has not been clarified. OBJECTIVE: We
      analyzed VLDL and LDL subfractions before and after a euglycemic,
      hyperinsulinemic clamp. DESIGN: Lipoprotein subfractions were isolated from
      plasma samples obtained in the basal state and after a 4-h clamp from obese
      patients, obese patients with type 2 diabetes, and nonobese control subjects.
      RESULTS: Hyperinsulinemia tended to reduce concentrations (&xmacr;: 20%) of
      large, triacylglycerol-rich VLDL(1) in obese patients but had a minor effect on
      VLDL(2) and VLDL(3). Placing obese patients into insulin-sensitive and insulin
      resistant subgroups revealed distinct effects of the degree of insulin
      sensitivity on VLDL. VLDL(1) concentrations decreased by a mean of 38% (P < 0.05)
      in insulin-sensitive patients after the clamp, similar to but less marked than
      the decrease observed in control subjects (&xmacr;: 62%; P < 0.01). VLDL(1)
      concentrations did not change significantly after the clamp in insulin-resistant
      patients (and patients with type 2 diabetes), whereas VLDL(3) concentrations
      decreased in both groups, in contrast with the changes seen in the insulin
      sensitive patients and control subjects. Acute hyperinsulinemia modified the LDL
      subfraction profile toward a greater prevalence of small, dense LDLs in insulin
      resistant patients and patients with type 2 diabetes. CONCLUSIONS: Insulin
      resistance appears to be the primary determinant of the modifications to VLDL
      subfraction concentrations. Our results suggest a continuum of impaired insulin
      action on VLDL, ranging from that in healthy persons to that in patients with
      type 2 diabetes, in which obese patients occupy a transition state. Insulin
      resistance may also play a role in detrimental modifications to the LDL profile
      by allowing the development of hypertriglyceridemia.

PMID- 10648257
TI  - Fat and carbohydrate balances during adaptation to a high-fat.
AB  - BACKGROUND: Dietary fat contents are highly variable. Failure to compensate for
      the positive fat balance that occurs during the shift to a high-fat, low
      carbohydrate diet by increasing energy expenditure or by decreasing food intake
      may result in the gain of fat mass. OBJECTIVE: The objective of this study was to
      investigate the time course of fat oxidation during adaptation to an isoenergetic
      high-fat, low-carbohydrate diet. DESIGN: After a 5-d control diet, dietary fat
      was increased from 37% of energy to 50% of energy for 4 d in 6 healthy, young
      lean men. Respiratory quotient and substrate macronutrient oxidation and balance
      were measured in a respiratory chamber. Fasting concentrations of insulin,
      glucose, and triacylglycerol; maximal oxygen consumption (f1.gif"
      BORDER="0">O(2)max) during treadmill exercise; and free-living energy expenditure
      were determined. Body fat was measured by dual-energy X-ray absorptiometry and
      visceral adipose tissue by computerized tomography. RESULTS: Compared with the
      baseline diet, the high-fat, low-carbohydrate diet resulted in positive fat and
      protein balances and a negative carbohydrate balance. Insulin concentration and
      the postabsorptive respiratory quotient were positively correlated with the fat
      balance during the high-fat, low-carbohydrate diet, whereas f1.gif"
      BORDER="0">O(2)max during treadmill exercise was negatively related to fat
      balance. With use of stepwise regression, f1.gif" BORDER="0">O(2)max was the best
      predictor of fat balance. There was a negative correlation between fat balance
      and carbohydrate balance (r(2) = 0.88). CONCLUSION: Both baseline insulin
      concentration and f1.gif" BORDER="0">O(2)max during treadmill exercise predict
      fat balance during the shift to a high-fat diet under isoenergetic conditions.

PMID- 10648258
TI  - alpha-tocopherol supplementation decreases production of superoxide and cytokines
      by leukocytes ex vivo in both normolipidemic and hypertriglyceridemic
      individuals.
AB  - BACKGROUND: alpha-Tocopherol plays an important role in protecting LDL against
      oxidation. However, additional effects of alpha-tocopherol at the intracellular
      level may contribute to the clinical outcome of intervention studies. OBJECTIVE:
      We investigated whether alpha-tocopherol influences the inflammatory responses of
      immune cells in normolipidemic and hypertriglyceridemic subjects. DESIGN: RRR
      alpha-Tocopherol was administered for 6 wk at a dose of 600 IU (402 mg)/d to 12
      primary hypertriglyceridemic and 8 normolipidemic (fasting triacylglycerol >3.0
      and <2.0 mmol/L, respectively) subjects. Cytokine production [tumor necrosis
      factor alpha (TNF-alpha), interleukin (IL)-1beta, and IL-8] by mononuclear cells
      and superoxide production by polymorphonuclear cells and in diluted whole blood
      were determined before and after the intervention. RESULTS: Cytokine and
      superoxide production did not differ significantly between hypertriglyceridemic
      and normolipidemic subjects. alpha-Tocopherol supplementation resulted in a 2- to
      3-fold increase in the concentration of alpha-tocopherol in plasma and LDL.
      Whereas superoxide production in response to phorbol 12-myristate 13-acetate
      decreased in all subjects, response to oxidized LDL increased in 19 of 20
      subjects. Response to opsonized zymosan before alpha-tocopherol supplementation
      was not significantly different from that after supplementation.
      Lipopolysaccharide-induced cytokine production by mononuclear cells decreased
      after supplementation with alpha-tocopherol. CONCLUSIONS: alpha-Tocopherol
      differentially influences inflammatory responses of immune cells. These effects
      of alpha-tocopherol may be relevant in chronic inflammatory processes such as
      atherogenesis.

PMID- 10648259
TI  - Postprandial lipemia: effects of exercise and restriction of energy intake
      compared.
AB  - BACKGROUND: The mitigating effect of exercise on postprandial lipemia may be
      attributable to the energy deficit incurred. OBJECTIVE: We aimed to compare the
      effects of prior exercise and an equivalent energy intake deficit on postprandial
      lipemia. DESIGN: Eleven postmenopausal women participated in 3 oral-fat-tolerance
      tests after undergoing different treatments on the preceding day: control
      (subjects refrained from exercise and consumed a prescribed diet), exercise
      (subjects consumed the same diet but walked briskly for 90 min), and intake
      restriction (subjects' food intake was restricted to induce the same energy
      deficit, relative to control, as brought about by the 90-min walk). Venous blood
      samples were obtained after subjects fasted overnight, 30 min after they ate a
      mixed, high-fat meal (1.70 g fat, 1.65 g carbohydrate, and 99 kJ/kg fat-free body
      mass), and hourly for the next 6 h. RESULTS: In the exercise trial, the mean
      fasting triacylglycerol concentration was 19% and 17% lower than the control and
      intake restriction values, respectively (P < 0.05 for both). Compared with the
      control trial, exercise reduced postprandial lipemia by a mean of 20% (P < 0.05),
      whereas intake restriction reduced it by 7% (NS). In the exercise trial, fasting
      and postprandial fatty acid concentrations were higher than control values (P <
      0.05). Exercise, but not intake restriction, reduced postprandial insulin
      concentrations. CONCLUSIONS: The results suggest that the effect of exercise on
      postprandial lipid metabolism was greater than and different from that
      attributable to the energy deficit incurred.

PMID- 10648260
TI  - Cholesterol-lowering effects of psyllium intake adjunctive to diet therapy in men
      and women with hypercholesterolemia: meta-analysis of 8 controlled trials.
AB  - BACKGROUND: Soluble fibers, including those from psyllium husk, have been shown
      to augment the cholesterol-lowering effects of a low-fat diet in persons with
      hypercholesterolemia. As evidence of this, the US Food and Drug Administration
      recently authorized the use of health claims on food products containing soluble
      fiber from psyllium that state that they are associated with a decreased risk of
      coronary heart disease. OBJECTIVE: This meta-analysis was conducted to more
      precisely define the hypolipidemic effects and safety of psyllium when used
      adjunctive to a low-fat diet in men and women with hypercholesterolemia. DESIGN:
      The 8 studies in the meta-analysis included a total of 384 and 272 subjects
      receiving psyllium or cellulose placebo, respectively. All studies evaluated the
      hypocholesterolemic effects of 10.2 g psyllium/d adjunctive to a low-fat diet for
      >/=8 wk in individuals with mild-to-moderate hypercholesterolemia after a low-fat
      diet lead-in phase lasting >/=8 wk. The safety and adverse events associated with
      psyllium consumption were summarized from pooled data of 19 clinical studies
      ranging from 6 wk to 6 mo in duration. RESULTS: Consumption of 10.2 g psyllium/d
      lowered serum total cholesterol by 4% (P < 0.0001), LDL cholesterol by 7% (P <
      0.0001), and the ratio of apolipoprotein (apo) B to apo A-I by 6% (P < 0.05)
      relative to placebo in subjects already consuming a low-fat diet, with no effect
      on serum HDL or triacylglycerol concentrations. CONCLUSIONS: Psyllium
      supplementation significantly lowered serum total and LDL-cholesterol
      concentrations in subjects consuming a low-fat diet. Psyllium is well tolerated
      and safe when used adjunctive to a low-fat diet in individuals with mild-to
      moderate hypercholesterolemia.

PMID- 10648261
TI  - Unfiltered coffee increases plasma homocysteine concentrations in healthy
      volunteers: a randomized trial.
AB  - BACKGROUND: An elevated plasma homocysteine concentration is a putative risk
      factor for cardiovascular disease. Observational studies have reported an
      association between coffee consumption and plasma homocysteine concentrations.
      OBJECTIVE: We studied the effect of coffee consumption on plasma homocysteine in
      a crossover trial. We used unfiltered coffee so as to include the possible
      effects of coffee diterpenes, which are removed by filtering. DESIGN: Sixty-four
      healthy volunteers (31 men and 33 women) with a mean (+/-SD) age of 43 +/- 11 y
      were randomly assigned to 2 groups. One group (n = 30) drank 1 L unfiltered
      cafetiere (French press) coffee daily for 2 wk. Such coffee is rich in the
      cholesterol-raising diterpenes kahweol and cafestol. The other group (n = 34)
      received water, milk, broth, tea, and chocolate drinks instead of coffee. After a
      washout period of 8 wk, both groups received the alternate intervention for
      another 2 wk. RESULTS: Consumption of 1 L unfiltered coffee/d for 2 wk
      significantly raised fasting plasma homocysteine concentrations by 10%, from 12.8
      to 14.0 micromol/L. CONCLUSIONS: Unfiltered coffee increases plasma homocysteine
      concentrations in volunteers with normal initial concentrations. It is unclear
      whether the effect is caused by the cholesterol-raising diterpenes present
      exclusively in unfiltered coffee or by factors that are also present in filtered
      coffee.

PMID- 10648262
TI  - Standardized thigh muscle area measured by computed axial tomography as an
      alternate muscle mass index for nutritional assessment of hemodialysis patients.
AB  - BACKGROUND: Quantification of muscle mass, which represents the largest protein
      pool in the body, is important for nutritional assessment but is difficult to
      achieve with conventional methods in hemodialysis patients. OBJECTIVE: We
      measured the cross-sectional area of the thigh occupied by muscle by using
      computed tomography and compared this with other muscle mass indicators. DESIGN:
      Thigh muscle area (TMA) was examined and correlated with creatinine production
      and various nutritional indexes in 163 patients undergoing hemodialysis. Where
      appropriate, TMA was expressed relative to bone area in the thigh (TBA) to avoid
      the influence of body size. RESULTS: TMA was highly correlated with creatinine
      production as measured in the spent dialysate (r = 0.85, P < 0.001), indicating
      that TMA substantially reflects total-body muscle mass. TMA standardized for TBA
      was negatively correlated with age and positively correlated with other
      nutritional indicators including body weight, body mass index, serum albumin,
      serum transthyretin, and protein catabolic rate. Multiple regression analysis
      revealed that of these variables, age, serum albumin, and protein catabolic rate
      independently predicted TMA standardized for TBA. By using correlations with
      various nutritional indicators, we concluded that patients with a value <10.0 for
      TMA standardized for TBA were likely to be malnourished whereas those with a
      value >13.0 were likely to be well nourished. CONCLUSIONS: These results indicate
      that TMA standardized for TBA, measured by computed tomography, is a reliable
      indicator of muscle mass that could be used for nutritional assessment of
      hemodialysis patients.

PMID- 10648263
TI  - Cysteine kinetics and oxidation at different intakes of methionine and cystine in
      young adults.
AB  - BACKGROUND: We previously studied methionine kinetics and oxidation with the
      tracer L-[1-(13)C, methyl-(2)H(3)]methionine. OBJECTIVES: We sought to explore
      methionine-cysteine interrelations in adults by using L-[1-(13)C]cysteine under
      different dietary conditions. DESIGN: In experiment 1, 12 adults consumed a
      protein-free diet for 6 d. On day 7, methionine (n = 6) or cysteine (n = 6)
      oxidation rates were measured during an 8-h continuous infusion of L-[1-(13)C,
      methyl-(2)H(3)]methionine or L-[1-(13)C]cysteine, respectively. In experiment 2,
      6 young men consumed 3 diets for 6 d each before a tracer study on day 7 with L
      [1-(13)C]cysteine. The amounts (in mg*kg(-)(1)*d(-)(1)) of methionine and
      cysteine, respectively, were: high-methionine (HM) diet, 13 and 0; low-methionine
      (LM) diet, 6.5 and 0; and methionine-plus-cystine (MC) diet, 6.5 and 5.6.
      Cysteine flux and oxidation rates were determined and sulfur amino acid (SAA,
      methionine plus cysteine) balances were estimated. RESULTS: In experiment 1,
      rates of methionine and cysteine oxidation were similar to losses predicted from
      obligatory nitrogen losses. In experiment 2, SAA balance was less negative when
      subjects consumed the HM diet than the LM and MC diets (interaction, P = 0.034),
      largely because of a difference in fed-state balance (HM compared with LM, P <
      0.01; HM compared with MC, P < 0.05). There was no evidence of a sparing effect
      of dietary cystine on the methionine requirement. CONCLUSION: These studies
      support use of [1-(13)C]cysteine for studying whole-body SAA oxidation and
      conclusions that maintenance of SAA balance is best achieved by supplying
      methionine at approximately the FAO/WHO/UNU recommendations for total SAA intake
      (13 mg*kg(-)(1)*d(-)(1)).

PMID- 10648264
TI  - Racial differences in energy expenditure and aerobic fitness in premenopausal
      women.
AB  - BACKGROUND: Aerobic fitness, or maximal oxygen uptake (f1.gif"
      BORDER="0">O(2)max), and energy expenditure (EE) may be lower in African
      Americans than in whites. OBJECTIVE: The objective of this study was to compare
      sleeping EE (SEE), resting EE (REE), free-living total EE (TEE), and f1.gif"
      BORDER="0">O(2)max in African American and white women after adjustment for body
      composition and free-living activity-related energy expenditure (AEE). DESIGN:
      Eighteen African American and 17 white premenopausal women were matched for
      weight, percentage body fat, and age. SEE and REE were measured in a room
      calorimeter and f1.gif" BORDER="0">O(2)max was measured on a treadmill. Fat-free
      mass (FFM) and fat mass (FM) (4-compartment model), AEE (doubly labeled water and
      SEE), and regional lean tissue (dual-energy X-ray absorptiometry) were used as
      adjustment variables in SEE, REE, TEE, and f1.gif" BORDER="0">O(2)max
      comparisons. RESULTS: The African American women had significantly more limb lean
      tissue and significantly less trunk lean tissue than did the white women. The
      African American women also had significantly lower SEE (6.9%), REE (7.5%), TEE
      (9.6%), and f1.gif" BORDER="0">O(2)max (13.4%) than did the white women. Racial
      differences persisted after adjustment for f1.gif" BORDER="0">O(2)max, AEE, FFM,
      and limb lean tissue but disappeared after adjustment for trunk lean tissue. The
      f1.gif" BORDER="0">O(2)max difference was independent of all body-composition
      variables and of AEE. CONCLUSIONS: African American women had lower aerobic
      fitness than did white women, independent of differences in lean tissue or AEE.
      Diminished racial differences in SEE, REE, and TEE after adjustment for trunk
      lean tissue suggest that low EE in African American women is mediated by low
      volumes of metabolically active organ mass.

PMID- 10648265
TI  - Vitamin A supplementation selectively improves the linear growth of indonesian
      preschool children: results from a randomized controlled trial.
AB  - BACKGROUND: Vitamin A deficiency is associated with stunting and wasting in
      preschool children, but vitamin A supplementation trials have not shown a
      consistent effect on growth. OBJECTIVE: We examined the effect of vitamin A
      supplementation on height and weight increments among Indonesian preschool
      children. DESIGN: Data were obtained from a randomized, double-masked, placebo
      controlled trial of rural Javanese children aged 6-48 mo. Children received
      206000 IU vitamin A (103000 IU if aged <12 mo) or placebo every 4 mo. RESULTS:
      High-dose vitamin A supplementation modestly improved the linear growth of the
      children by 0.16 cm/4 mo. The effect was modified by age, initial vitamin A
      status, and breast-feeding status. Vitamin A supplementation improved height by
      0.10 cm/4 mo in children aged <24 mo and by 0.22 cm/4 mo in children aged >/=24
      mo. The vitamin A-supplemented children with an initial serum retinol
      concentration <0.35 micromol/L gained 0.39 cm/4 mo more in height and 152 g/4 mo
      more in weight than did the placebo group. No growth response to vitamin A was
      found among children with an initial serum retinol concentration >/=0.35
      micromol/L. In non-breast-fed children, vitamin A supplementation improved height
      by 0.21 cm/4 mo regardless of age. In breast-fed children, vitamin A
      supplementation improved linear growth by approximately 0.21 cm/4 mo among
      children aged >/=24 mo, but had no significant effect on the growth of children
      aged <24 mo. CONCLUSION: High-dose vitamin A supplementation improves the linear
      growth of children with very low serum retinol and the effect is modified by age
      and breast-feeding.

PMID- 10648266
TI  - Plasma vitamin B-12 concentrations relate to intake source in the Framingham
      Offspring study.
AB  - BACKGROUND: Low vitamin B-12 status is prevalent among the elderly, but few
      studies have examined the association between vitamin B-12 status and intake.
      OBJECTIVE: We hypothesized that vitamin B-12 concentrations vary according to
      intake source. DESIGN: Plasma concentrations and dietary intakes were assessed
      cross-sectionally for 2999 subjects in the Framingham Offspring Study. The
      prevalence of vitamin B-12 concentrations <148, 185, and 258 pmol/L was examined
      by age group (26-49, 50-64, and 65-83 y), supplement use, and the following food
      intake sources: fortified breakfast cereal, dairy products, and meat. RESULTS:
      Thirty-nine percent of subjects had plasma vitamin B-12 concentrations <258
      pmol/L, 17% had concentrations <185 pmol/L, and 9% had concentrations <148
      pmol/L, with little difference between age groups. Supplement users were
      significantly less likely than non-supplement-users to have concentrations <185
      pmol/L (8% compared with 20%, respectively). Among non-supplement-users, there
      were significant differences between those who consumed fortified cereal >4
      times/wk (12%) and those who consumed no fortified cereal (23%) and between those
      in the highest and those in the lowest tertile of dairy intake (13% compared with
      24%, respectively), but no significant differences by meat tertile. Regression of
      plasma vitamin B-12 on log of intake, by source, yielded significant slopes for
      each contributor adjusted for the others. For the total group, b = 40.6 for
      vitamin B-12 from vitamin supplements. Among non-supplement-users, b = 56.4 for
      dairy products, 35.2 for cereal, and 16.7 for meat. Only the meat slope differed
      significantly from the others. CONCLUSIONS: In contrast with previous reports,
      plasma vitamin B-12 concentrations were associated with vitamin B-12 intake. Use
      of supplements, fortified cereal, and milk appears to protect against lower
      concentrations. Further research is needed to investigate possible differences in
      bioavailability.

PMID- 10648267
TI  - Comparison of estimates of zinc absorption in humans by using 4 stable isotopic
      tracer methods and compartmental analysis.
AB  - BACKGROUND: Adjustment of gastrointestinal absorption is the primary means of
      maintaining zinc homeostasis; however, a precise, accurate method for measuring
      zinc absorption in humans has not been identified. OBJECTIVE: The purpose of this
      study was to compare the estimates of the fraction of dietary zinc absorbed (FZA)
      by using 4 stable isotopic tracer methods: mass balance (MB) corrected for
      endogenous secretion, fecal monitoring (FM), deconvolution analysis (DA), and the
      double isotopic tracer ratio (DITR) method. DESIGN: All 4 methods were applied to
      a single data set for each of 6 women. FZA was also determined for each subject
      by using a detailed compartmental model of zinc metabolism, and that value was
      used as the reference with which the simpler methods were compared. RESULTS: The
      estimates of FZA (&xmacr; +/- SD) determined by DA (0.27 +/- 0. 08) and the DITR
      technique in plasma (0.30 +/- 0.10), 24-h urine samples (0.29 +/- 0.09), and spot
      urine samples (0.291 +/- 0.089) all compared well with the FZA reference value
      from the compartmental model (0.30 +/- 0.10). The MB and FM methods tended to
      overestimate FZA compared with the reference value. CONCLUSIONS: The
      determination of FZA by MB or FM is laborious, is sensitive to subject
      compliance, and may result in an overestimate. DA, although relatively accurate,
      has the disadvantage of requiring multiple blood drawings over several days. In
      contrast, the DITR technique applied to a spot urine specimen obtained >/=3 d
      after tracer administration provides an accurate measure of FZA and is easy to
      implement; therefore, it is the recommended method for determination of FZA.

PMID- 10648268
TI  - Ascorbate is depleted by smoking and repleted by moderate supplementation: a
      study in male smokers and nonsmokers with matched dietary antioxidant intakes.
AB  - BACKGROUND: Lack of reliable dietary data has hampered the ability to effectively
      distinguish between effects of smoking and diet on plasma antioxidant status. As
      confirmed by analyses of comprehensive food-frequency questionnaires, the total
      dietary intakes of fruit and vegetables and of dietary antioxidants were not
      significantly different between the study groups in the present study, thereby
      enabling isolation of the effect of smoking. OBJECTIVE: Our objective was to
      investigate the effect of smoking on plasma antioxidant status by measuring
      ascorbic acid, alpha-tocopherol, gamma-tocopherol, beta-carotene, and lycopene,
      and subsequently, to test the effect of a 3-mo dietary supplementation with a
      moderate-dose vitamin cocktail. DESIGN: In a double-blind, placebo-controlled
      design, the effect of a vitamin cocktail containing 272 mg vitamin C, 31 mg all
      rac-alpha-tocopheryl acetate, and 400 microg folic acid on plasma antioxidants
      was determined in a population of smokers (n = 37) and nonsmokers (n = 38). The
      population was selected for a low intake of fruit and vegetables and recruited
      from the San Francisco Bay area. RESULTS: Only ascorbic acid was significantly
      depleted by smoking per se (P < 0.01). After the 3-mo supplementation period,
      ascorbic acid was efficiently repleted in smokers (P < 0.001). Plasma alpha
      tocopherol and the ratio of alpha- to gamma-tocopherol increased significantly in
      both supplemented groups (P < 0.05). CONCLUSIONS: Our data suggest that previous
      reports of lower concentrations of plasma vitamin E and carotenoids in smokers
      than in nonsmokers may primarily have been caused by differences in dietary
      habits between study groups. Plasma ascorbic acid was depleted by smoking and
      repleted by moderate supplementation.

PMID- 10648269
TI  - Effect of vitamin A status at the end of term pregnancy on the saturation of
      retinol binding protein with retinol.
AB  - BACKGROUND: Vitamin A (retinol), which is required for normal fetal development
      and successful gestation, circulates in the blood bound to a specific protein,
      the retinol binding protein (RBP). Little is known about the transport and
      metabolism of this complex protein or about retinol status during normal human
      pregnancy. OBJECTIVE: The aim of this study was to assess retinol status and
      transport modalities of retinol in well-nourished women with normal pregnancies,
      a population poorly investigated compared with pathologic and malnourished
      pregnant women. DESIGN: The maternal blood and cord blood concentrations of
      retinol, vitamin E, beta-carotene, RBP, and transthyretin of pregnant French
      women at term (n = 27) were measured and compared with values from a nonpregnant
      control group (n = 27). In addition, holo-RBP (retinol bound), apo-RBP (retinol
      free), and total protein were assessed in both groups to enable the hemodilution
      occurring during pregnancy to be taken into consideration and to evaluate the
      extent of saturation of RBP with retinol. RESULTS: Healthy pregnant women at term
      had normal serum circulatory amounts of retinol, vitamin E, binding proteins, and
      beta-carotene. However, they had less binding of retinol to RBP (holo-RBP: 49.9%
      in pregnant women, 54.0% in cord blood, and 77.5% in the control group).
      CONCLUSION: The results of this study suggest that retinol homeostasis and
      transport are modified during normal human pregnancy.

PMID- 10648270
TI  - Effect of calcium supplementation on bone mineral accretion in gambian children
      accustomed to a low-calcium diet.
AB  - BACKGROUND: Rural Gambian children have poor growth, delayed puberty, a low bone
      mineral content, and a low calcium intake. OBJECTIVE: We investigated the effect
      of a calcium supplement on bone mineral accretion in rural Gambian children.
      DESIGN: A randomized, double-blind, placebo-controlled study was conducted in 160
      children (80 boys, 80 girls) aged 8.3-11.9 y. Bone mineral content (BMC), bone
      mineral density (BMD), and BMC adjusted for bone width, body weight, and height
      (size-adjusted BMC) were measured at the midshaft and distal radius. Each child
      received either 1000 mg Ca/d (as calcium carbonate) or a placebo 5 d/wk for 12
      mo. Supplementation increased calcium intake from 342 to 1056 mg/d (8.6 to 26.4
      mmol/d). RESULTS: Calcium supplementation resulted in a higher BMC, BMD, and size
      adjusted BMC (&xmacr; difference +/- SE): midshaft radius-BMC (3.0 +/- 1.4%; P =
      0.034), BMD (4.5 +/- 0.9%; P </= 0.0001), and size-adjusted BMC (4.6 +/- 0.9%; P
      </= 0.0001); distal radius-BMC (8. 4 +/- 3.2%; P = 0.009), BMD (7.0 +/- 2.7%; P =
      0.011), and size-adjusted BMC (5.5 +/- 2.7%; P = 0.042). Supplementation had no
      significant effect on height, weight, or bone width at the midshaft radius or
      distal radius. At the end of the study, the calcium group had a significantly
      lower mean plasma osteocalcin concentration than the placebo group after
      adjustment for baseline concentration, sex, and pubertal status (-21.9 +/- 6.5%;
      P = 0.001). CONCLUSIONS: Increased calcium intake resulted in increased bone
      mineral status, possibly in association with a decreased bone remodeling space.
      Further studies are needed to determine whether an increased calcium intake has
      long-term benefits in Gambian children.

PMID- 10648271
TI  - Severe linear growth retardation in rural Zambian children: the influence of
      biological variables.
AB  - BACKGROUND: The prevalence of stunting in preschool children in Zambia is high;
      stunting has detrimental effects on concurrent psychomotor development and later
      working capacity. OBJECTIVE: Our objective was to investigate biological
      variables that may contribute to linear growth retardation in preschool children
      in Samfya District, Zambia. DESIGN: Children aged 6-9 mo (n = 108) and 14-20 mo
      (n = 102) attending mother-and-child health clinics were included. With a mixed
      longitudinal design, they were followed up 9 and 21 mo later. Height and weight
      of children and their mothers were measured. Biochemical measures (eg, serum
      zinc, retinol, thyrotropin, iron, and acute phase protein concentrations),
      malaria parasitemia, and intestinal parasitosis were assessed. RESULTS: Height
      for-age z scores (HAZ) were low, indicating a high prevalence of stunting (36
      79%). Ninety percent of the children were anemic, 53-71% had elevated acute phase
      proteins, and 80% had malaria parasitemia. Regression analyses showed that
      maternal height predicted the children's height at 6-9 mo (regression coefficient
      = 0.05; 95% CI: 0.02, 0.08). The children's height at an early age (6-9 and 14-20
      mo) showed a strong relation with their height at later ages (22-30 and 34-41
      mo). Serum micronutrient status did not show a significant relation with later
      HAZ. CONCLUSION: Unlike other studies, we did not identify specific biological
      factors, such as health and micronutrient status, which contribute to the
      retardation of linear growth. The normal zinc and iodine statuses of the children
      suggest that at least these factors are not causal.

PMID- 10648272
TI  - Altered diurnal regulation of blood ionized calcium and serum parathyroid hormone
      concentrations during parenteral nutrition.
AB  - BACKGROUND: Little is known about parathyroid gland function in patients
      receiving total parenteral nutrition (TPN). OBJECTIVE: Our objective was to
      determine whether parathyroid gland function is abnormal in TPN recipients.
      DESIGN: Six patients with a mean (+/-1 SD) age of 45.5 +/- 8.0 y who had been
      receiving TPN for 18.7 +/- 2. 8 y underwent bone biopsy, bone mass measurements
      with dual-energy X-ray absorptiometry, and dynamic tests of parathyroid gland
      function. Diurnal variations in blood ionized calcium (iCa(2+)) and serum
      parathyroid hormone (PTH) concentrations were also assessed. Results were
      compared with those of healthy volunteers. RESULTS: Bone mass and bone formation
      were subnormal in all patients. Basal serum PTH concentrations were moderately
      higher in the TPN recipients than in healthy volunteers, and values obtained
      every 30 min over 24 h were significantly higher (P < 0.001) in TPN recipients
      (5.0 +/- 0.9 pmol/L) than in healthy volunteers (2.6 +/- 0.6 pmol/L). The
      percentage increase in serum PTH during citrate-induced hypocalcemia was lower in
      the TPN recipients, consistent with secondary hyperparathyroidism. Evening
      infusions of calcium-containing TPN eliminated the nocturnal rise in serum PTH,
      increased the amplitude of change for iCa(2+) and PTH over 24 h, increased the
      orderliness of change for iCa(2+) and PTH as measured by approximate entropy
      (ApEn), and enhanced the synchrony of change between iCa(2+) and PTH. Treatment
      for 10 d with calcium-free TPN restored the nocturnal rise in serum PTH and
      increased ApEn for PTH. ApEn for iCa(2+) remained low, suggesting that a
      component of nutrient solutions, but not calcium per se, enhances the regularity
      of PTH release in TPN recipients. CONCLUSION: Parathyroid gland function is
      abnormal in long-term TPN recipients, which may contribute to disturbances in
      bone metabolism.

PMID- 10648273
TI  - Association of low plasma cholesterol with mortality for cancer at various sites
      in men: 17-y follow-up of the prospective Basel study.
AB  - BACKGROUND: Low serum cholesterol has been associated with an increased risk of
      cancer mortality in various studies, which has led to uncertainty regarding the
      benefit of lower blood cholesterol. OBJECTIVE: The aim of our study was to
      evaluate the association between low blood cholesterol (<5.16 mmol/L) and cancer
      at sites that have rarely been evaluated. We placed special emphasis on the
      potential confounding effect of antioxidant vitamins. DESIGN: Plasma
      concentrations of cholesterol and antioxidant vitamins were measured in 1971-1973
      in 2974 men working in Basel, Switzerland. In 1990, the vital status of all
      participants was assessed. RESULTS: Two hundred ninety of the participants had
      died from cancer, 87 from lung, 30 from prostate, 28 from stomach, and 22 from
      colon cancer. Group means for plasma cholesterol concentrations did not differ
      significantly between survivors and those who died from cancer at any of the
      studied sites. With plasma cholesterol, vitamins C and E, retinol, carotene,
      smoking, and age accounted for in a Cox model, an increase in total cancer
      mortality in lung, prostate, and colon but not in stomach cancer mortality was
      observed in men >60 y of age with low plasma cholesterol. When data from the
      first 2 y of follow-up were excluded from the analysis, the relative risk
      estimates remained practically unchanged with regard to lung cancer but decreased
      for colon, prostate, and overall cancer. CONCLUSIONS: Increased cancer mortality
      risks associated with low plasma cholesterol were not explained by the
      confounding effect of antioxidant vitamins, but were attributed in part to the
      effect of preexisting cancer.

PMID- 10648274
TI  - Carotenoids and colon cancer.
AB  - BACKGROUND: Carotenoids have numerous biological properties that may underpin a
      role for them as chemopreventive agents. However, except for beta-carotene,
      little is known about how dietary carotenoids are associated with common cancers,
      including colon cancer. OBJECTIVE: The objective of this study was to evaluate
      associations between dietary alpha-carotene, beta-carotene, lycopene, lutein,
      zeaxanthin, and beta-cryptoxanthin and the risk of colon cancer. DESIGN: Data
      were collected from 1993 case subjects with first primary incident adenocarcinoma
      of the colon and from 2410 population-based control subjects. Dietary data were
      collected from a detailed diet-history questionnaire and nutrient values for
      dietary carotenoids were obtained from the US Department of Agriculture-Nutrition
      Coordinating Center carotenoid database (1998 updated version). RESULTS: Lutein
      was inversely associated with colon cancer in both men and women [odds ratio (OR)
      for upper quintile of intake relative to lowest quintile of intake: 0.83; 95% CI:
      0.66, 1.04; P = 0.04 for linear trend]. The greatest inverse association was
      observed among subjects in whom colon cancer was diagnosed when they were young
      (OR: 0.66; 95% CI: 0.48, 0.92; P = 0.02 for linear trend) and among those with
      tumors located in the proximal segment of the colon (OR: 0.65; 95% CI: 0.51,
      0.91; P < 0.01 for linear trend). The associations with other carotenoids were
      unremarkable. CONCLUSION: The major dietary sources of lutein in subjects with
      colon cancer and in control subjects were spinach, broccoli, lettuce, tomatoes,
      oranges and orange juice, carrots, celery, and greens. These data suggest that
      incorporating these foods into the diet may help reduce the risk of developing
      colon cancer.

PMID- 10648275
TI  - Weight loss and elevated gluconeogenesis from alanine in lung cancer patients.
AB  - BACKGROUND: The role of gluconeogenesis from protein in the pathogenesis of
      weight loss in lung cancer is unclear. OBJECTIVE: Our aim was to study
      gluconeogenesis from alanine in lung cancer patients and to analyze its relation
      to the degree of weight loss. DESIGN: In this cross-sectional study, we used
      primed-constant infusions of [6,6-(2)H(2)]-D-glucose and [3-(13)C]-L-alanine to
      assess whole-body glucose and alanine turnover and gluconeogenesis from alanine
      in weight-losing (WL, n = 9) and weight-stable (WS, n = 10) lung cancer patients
      and healthy control (n = 15) subjects. RESULTS: Energy intake and plasma alanine
      concentrations did not differ significantly among the subject groups. Mean (+/
      SEM) whole-body glucose production was significantly higher in WL than in WS and
      control subjects (0.74 +/- 0.06 compared with 0.55 +/- 0.04 and 0.51 +/- 0.04
      mmol*kg(-)(1)*h(-)(1), respectively, P < 0.01). Alanine turnover was
      significantly elevated in WL compared with WS and control subjects (0.57 +/- 0.04
      compared with 0.42 +/- 0.05 and 0.40 +/- 0.03 mmol*kg(-)(1)*h(-)(1),
      respectively, P < 0.01). Gluconeogenesis from alanine was significantly higher in
      WL than in WS and control subjects (0.47 +/- 0.04 compared with 0.31 +/- 0.04 and
      0.29 +/- 0.04 mmol*kg(-)(1)*h(-)(1), respectively, P < 0.01). The degree of
      weight loss was positively correlated with glucose and alanine turnover and with
      gluconeogenesis from alanine (r = 0.45 for all, P < 0.01). CONCLUSIONS: Aberrant
      glucose and alanine metabolism occurred in WL lung cancer patients. These changes
      were related to the degree of weight loss and not to the presence of lung cancer
      per se.

PMID- 10648276
TI  - Effect of micronutrient status on natural killer cell immune function in healthy
      free-living subjects aged >/=90 y.
AB  - BACKGROUND: Natural killer (NK) cells play a role in natural immunity against
      tumor and infected cells. Advanced aging is associated with functional impairment
      of NK cells and increased susceptibility to nutritional deficiencies. OBJECTIVE:
      Our objective was to test whether micronutrient status affects NK cell activity
      in an older population. DESIGN: The relations between NK cell variables
      (percentage of leukocytes and cytotoxicity) and blood concentrations of selected
      micronutrients were studied in 62 healthy, free-living northern Italian subjects
      (25 men, 37 women) aged 90-106 y. Anthropometric measurements were also made.
      RESULTS: All subjects were well nourished according to age-specific
      anthropometric norms but many of them had micronutrient deficiencies. The
      prevalence of micronutrient deficiency was highest for selenium (in approximately
      50% of both sexes), zinc (in 52% of men and 41% of women), and vitamin B-6 (in
      40% of men and 59% of women), followed by vitamin A (in 16% of men and 27% of
      women) and vitamin E, vitamin B-12, and folate (each in <10% of both sexes).
      Ubiquinone-10 status was inadequate in 40% of women and 24% of men (P = 0.02).
      The percentage of NK cells was associated with serum zinc (men: r = 0.573, P = 0.
      007; women: r = 0.373, P = 0.031) and selenium (women: r = 0.409, P = 0.018)
      concentrations. In women only, NK cell cytotoxicity at different effector-target
      cell ratios was positively associated with plasma vitamin E and ubiquinone-10
      concentrations (P < 0.05). No significant associations with NK cell variables
      were found for the other measured nutrients. CONCLUSIONS: The results of this
      study strengthen the hypothesis that individual micronutrients may affect the
      number and function of NK cells in old age. The study also confirms the high
      prevalence of micronutrient deficiencies in healthy and apparently well-nourished
      persons aged >/=90 y.

PMID- 10648277
TI  - Fish consumption, cancer, and Alzheimer disease.

PMID- 10648279
TI  - Lactose intolerance-a confusing clinical diagnosis.

PMID- 10648289
TI  - Aging at a Turning Point in the 21st Century.

PMID- 10648281
TI  - Programming not metabolic imprinting.

PMID- 10648290
TI  - Personality disorders in late life. Understanding and overcoming the gap in
      research.
AB  - A review of the literature on personality disorders (PD) in late life reveals
      fewer research papers than those found for PD in younger adults and for other
      major late-life psychiatric diagnoses. The authors suggest that this gap is
      largely due to the difficult and inconsistent diagnostic process for late-life
      PDs. Diagnosis is complicated by the frequent unavailability and/or unreliability
      of longitudinal data, lack of age-adjusted diagnostic instruments, and failure of
      the current Axis II nosology to account for age-related issues, including changes
      in social functioning, and the effects of comorbid illness and cognitive
      impairment. They propose that the development of a geriatric subclassification
      for PD, along with improved clinical documentation of personality and data from
      dimensional instruments for both normal and pathologic personalities, would
      provide a more reliable, valid, and geriatric-friendly diagnostic process.

PMID- 10648291
TI  - Schizophrenia and older adults. An overview: directions for research and policy.
AB  - The Group for the Advancement of Psychiatry, Committee on Aging, believes that a
      crisis has emerged with respect to the understanding of the nature and treatment
      of schizophrenia in older persons. Moreover, critical gaps exist in clinical
      services for this population. In this article, we examine the epidemiology of
      aging and schizophrenia; life-course changes in psychopathology, cognitive
      function, social functioning, and physical health; and various concerns regarding
      treatment, services, and financing. Finally, we propose six research and policy
      recommendations and suggest methods for addressing the research questions that we
      have posed.

PMID- 10648292
TI  - Psychosis of Alzheimer's disease and related dementias. Diagnostic criteria for a
      distinct syndrome.

PMID- 10648293
TI  - Beyond morbidity and mortality. When older persons undergo anesthesia and
      elective surgery.

PMID- 10648294
TI  - Mental status change in older surgical patients. Cognition, depression, and other
      comorbidity.
AB  - The authors studied patients age 60 and over to assess the effect of elective
      surgery as a precipitating factor for cognitive decline over the postoperative
      year. They found an association between change in test performance and age,
      physical disability, and number of depressive symptoms. However, persistent
      decline in Mini-Mental State Exam scores was associated with identifiable factors
      related to the initial surgery in only 3/ 251 (1 percent of cases). Depression
      and new onset of acute illness were confounding factors in the assessment of
      cognitive decline.

PMID- 10648295
TI  - Monitoring Alzheimer's patients for acute changes in cognitive functioning.
AB  - To develop and evaluate the use of cognitive monitoring for detecting episodes of
      acute, excess cognitive decline in individual Alzheimer's disease (AD) patients,
      the authors conducted six repeated cognitive assessments over 11 weeks on 41
      otherwise healthy people with mild-to-moderate AD. Patients demonstrated stable
      cognitive performance over 11 weeks on seven standard neuropsychological tests.
      Prediction intervals quantitatively defined the expected limits of cognitive
      decline. They indicated with 90% certainty that over the 11-week period, healthy
      mild-to-moderate AD patients should not decline more than 4 points on the Word
      List Recall test, 3 points on the Digit Span test, or 8 items on the Digit Symbol
      or Verbal Fluency tests. The cognitive stability of healthy AD patients indicates
      that it is possible to monitor them for acute, excess cognitive decline.

PMID- 10648296
TI  - Executive functions and P300 latency in elderly depressed patients and control
      subjects.
AB  - The authors asked whether impaired executive functioning and long P300 latency
      are related dysfunctions and whether they are associated with geriatric
      depression. A group of 25 elderly depressed patients without dementia and 20
      control subjects were assessed on tasks of fluency, initiation and perseveration,
      the Stroop task, the Wisconsin Card Sorting Test (WCST) perseverative error
      score, and P300 latency. The groups' performance differed significantly on these
      tasks and in P300 latency. Longer latency was associated with poorer performance
      in both groups on all measures except WCST perseverative errors. Regardless of
      patients' depression status, increased P300 latency predicts poorer performance
      on executive function tasks requiring speeded performance.

PMID- 10648297
TI  - A controlled clinical trial of sertraline in the treatment of depression in
      nursing home patients with late-stage Alzheimer's disease.
AB  - A sample of 31 female nursing home patients with late-stage Alzheimer's disease
      participated in a double-blind clinical trial of the antidepressant medication
      sertraline. Measures of depression included various objective scales and two
      measures of facial expressions of emotion coded during a semistructured interview
      using a facial affect coding system. Repeated-measures ANOVAs at baseline and at
      the 8-week endpoint indicated that on all measures, both the treatment and
      placebo groups improved over time, with three of six measures showing a
      significant time effect. The "knit-brow" facial measure approached significance
      for a Treatment x Time effect. Thus, sertraline had no significant benefits over
      placebo. However, if, as we hypothesize, the knit-brow response is more sensitive
      to signs of depression in advanced dementia, our study justifies the further
      investigation of the use of sertraline in this population.

PMID- 10648298
TI  - The use of the neuropsychiatric inventory in nursing home residents.
      Characterization and measurement.
AB  - The authors assessed the validity of the nursing home version of the
      Neuropsychiatric Inventory-Nursing Home Version (NPI-NH), comparing the responses
      of certified nurses' aides (CNAs) and licensed vocational nurses (LVNs) with
      research observations. Correlations were significant but moderate for all of the
      domains of the NPI-NH (delusions, hallucinations, agitation/aggression,
      depression, apathy, disinhibition, euphoria, irritability/lability, and aberrant
      motor disturbances) except anxiety and appetite disturbance. The LVNs' ratings
      showed consistently higher correlations with the researchers' behavioral
      observations than did the CNAs', but were moderate and generally better for
      residents with high levels of neuropsychiatric symptoms, thus, caution should be
      used with any untrained rater in the nursing home setting. The NPI-NH used by non
      research staff can be useful in identifying residents with significant
      neuropsychiatric disturbances, but may be limited as an instrument for tracking
      behavioral changes.

PMID- 10648299
TI  - Depressive symptoms in Alzheimer's disease. An examination among community
      dwelling Cuban American patients.
AB  - The authors examined the prevalence and clinical correlates of mood disturbance
      in 96 Cuban American (CA) Alzheimer's disease (AD) patients. Depression (Cornell
      Scale for Depression in Dementia score > or = 7) was evident in 39.6% of the
      participants and showed associations with comorbid psychosis, lower education,
      and decreased length of residence in the United States, a measure of
      acculturation. Mood disturbance was not related to age, gender, marital status,
      cognitive dysfunction, functional impairment, history of significant alcohol use,
      or coexisting medical conditions. The results of this investigation suggest that
      signs and symptoms of depression are common neuropsychiatric disturbances in CA
      AD patients residing in the community.

PMID- 10648300
TI  - Cannabis: time for scientific evaluation of this ancient remedy?

PMID- 10648301
TI  - Small-dose neuraxial block: heading toward the new millennium.

PMID- 10648302
TI  - Modeling of asynchronous myocardial contraction by effective stroke volume
      analysis.
AB  - Left ventricular (LV) regional wall motion abnormalities (RWMA) are not easily
      quantified. We describe a model for quantifying RWMA by referencing regional
      amplitude and phase angle changes to global LV systole in eight anesthetized,
      open-chest dogs. Regional and total LV volumes (conductance catheter), regional
      shortening (epicardial piezoelectric crystals), and LV pressure were measured
      before, during, and after transient esmolol-induced apical RWMA. Regional phase
      angle (alpha) was defined as the relative distance, measured in degrees, that
      regional minimal volume differs from global end-systole. We compared maximal
      stroke volume (SV) with effective SV (that portion of regional SV contributing to
      total LV SV). Regional effective SV was also calculated from our model as the
      product of cosine alpha and regional maximal SV. Esmolol delayed apical end
      systolic alpha (14.3 degrees +/- 11.4 degrees versus 35.7 degrees +/- 8.0 degrees
      baseline versus esmolol, P < 0.05) and decreased apical effective SV (2.4 +/- 0.3
      versus 1.7 +/- 0.3 mL, P < 0.05), while apical maximal SV and total LV SV were
      not altered. Piezoelectric crystal dimension changes mirrored regional SV
      changes. We conclude that effective SV and phase angle analysis are more
      sensitive measures of regional myocardial dysfunction when RWMA exist than are
      measures of maximal regional SV. IMPLICATIONS: In a dog model of regional
      myocardial dyskinesis induced by esmolol, effective regional stroke volume and
      phase angle analyses are more sensitive measures of regional myocardial
      dysfunction than measures of maximal regional stroke volume that do not account
      for phase shifts.

PMID- 10648303
TI  - Esmolol-induced regional wall motion abnormalities do not affect regional
      ventricular elastances.
AB  - The effect of regional wall motion abnormalities (RWMA) on regional and global
      left ventricular (LV) elastances has not been defined. To induce RWMA, we infused
      esmolol (9 mg) into the left anterior descending coronary artery in eight
      anesthetized open-chest canine preparations. Global and regional stroke volumes
      and end-systolic pressure-volume relationships (LV conductance catheter) and
      pressure-length relationships (sonomicrometer crystals) were measured in
      dysfunctional (apical) and normal (basilar) LV regions at baseline, during
      esmolol infusion, and after treatment with a systemic dobutamine infusion (4
      microg. kg(-1). min(-1)) and combined dobutamine-esmolol. Esmolol induced apical
      dyskinesis, as evidenced by reduced effective apical stroke volumes and stroke
      work, a parallel right-shift of the apical regional, global end-systolic pressure
      volume relationships, and increased regional and global LV volumes (P < 0.05).
      However, global and regional elastances remained unchanged. Dobutamine increased
      global and apical regional elastances, but did not increase regional volumes.
      During the infusion of combined esmolol-dobutamine, apical elastance and volumes
      increased compared with baseline (P < 0.05), but apical regional stroke work
      decreased. Thus, esmolol-induced RWMA were associated with cardiac dilation but
      not with decreased regional or global elastances. IMPLICATIONS: Regional and
      global elastances and maximal stroke volumes may not identify esmolol-induced
      left ventricular regional dysfunction in dogs. The primary effect of asynchrony
      of regional contraction is global cardiac dilation. Systemic dobutamine infusion
      increases regional and global left ventricular elastances but does not reverse
      regional wall motion abnormality-induced cardiac dilation.

PMID- 10648304
TI  - The significance of preformed aprotinin-specific antibodies in cardiosurgical
      patients.
AB  - Acute hypersensitivity reactions are serious complications of reexposure to
      aprotinin. Previous contact via infusions or fibrin tissue adhesives can induce
      specific antibodies. In this study, we aimed to elucidate the preoperative
      prevalence of aprotinin-specific antibodies in patients scheduled for cardiac
      operations. Sera of 520 consecutive cardiosurgical patients were collected
      preoperatively and screened retrospectively for aprotinin-specific IgG using a
      standard enzyme-linked immunosorbent assay (ELISA). Positive sera were analyzed
      also for aprotinin-specific IgA (ELISA) and IgE (fluorescence enzyme
      immunoassay). The histories of all patients were reviewed with focus on aprotinin
      preexposure. Of 520 patients, 22 (4%) had specific IgG. Only three of these had a
      documented aprotinin preexposure. Of 448 patients exposed to aprotinin
      intraoperatively, 15 had preformed specific antibodies. The only patient
      presenting with severe anaphylaxis was positive for both IgG and IgE, and had a
      recent IV preexposure in cardiovascular surgery. The presence of aprotinin
      specific IgG alone seems not to induce adverse reactions on exposure. Exposure
      history alone is not sensitive enough to identify patients with aprotinin
      specific antibodies. IMPLICATIONS: Anaphylaxis on IV reexposure to aprotinin is a
      medical emergency. The clinical significance of preformed aprotinin-specific IgG
      remains questionable, whereas preformed IgE was present in the only patient who
      suffered from severe anaphylaxis on reexposure to aprotinin. Preformed antibodies
      are not reliably predicted by exposure history.

PMID- 10648305
TI  - Pulmonary artery thromboendarterectomy: a comparison of two different
      postoperative treatment strategies.
AB  - Pulmonary artery thromboendarterectomy (PTE) is a potentially curative surgical
      procedure for chronic thromboembolic pulmonary hypertension. It is, nevertheless,
      associated with considerable mortality caused by postoperative complications,
      such as reperfusion pulmonary edema (RPE) (i.e., pulmonary infiltrates in regions
      distal to vessels subjected to endarterectomy) and right heart failure (RHF).
      However, there are no reports about the influence of different postoperative
      treatment strategies on complications and mortality. Therefore, we compared two
      different treatment strategies. In Group I (n = 33), positive inotropic
      catecholamines and vasodilators were avoided during termination of
      cardiopulmonary bypass (CPB) and thereafter, and mechanical ventilation was
      performed with low tidal volumes < 8 mL/kg, duration of inspiration:duration of
      expiration = 3:1, and peak inspiratory pressures < 18 cm H(2)O. In Group II (n =
      14), positive inotropic catecholamines and vasodilators were regularly used for
      termination of CPB and thereafter, and ventilation was performed with high tidal
      volumes (10-15 mL/kg) and peak inspiratory pressures up to 50 cm H(2)O.
      Hemodynamics, the incidence of RPE and RHF, duration of ventilation, morbidity,
      and mortality were recorded. Cardiac index was comparable before surgery (2.11 +/
      0.09 vs 2.08 +/- 0.09 L. min(-1). m(-2)) and 20 min after CPB (2.26 +/- 0.09 vs
      2.60 +/- 0.20 L. min(-1). m(-2)). RPE occurred in 6.1% (Group I) versus 14.3%
      (Group II), and RHF was observed in 9.1% (Group I) versus 21.4% (Group II).
      Mortality was 9.1% (Group I) versus 21.4% (Group II). Thus, the avoidance of
      positive inotropic catecholamines and vasodilators in combination with
      nonaggressive mechanical ventilation after PTE was associated with a low
      incidence of RPE, RHF, duration of ventilation, and mortality after PTE.
      IMPLICATIONS: The avoidance of positive inotropic catecholamines and vasodilators
      in combination with nonaggressive mechanical ventilation was associated with a
      low incidence of reperfusion pulmonary edema and/or right heart failure after
      pulmonary artery thromboendarterectomy.

PMID- 10648306
TI  - In vitro effects of different medium molecular hydroxyethyl starch solutions and
      lactated Ringer's solution on coagulation using SONOCLOT.
AB  - Hydroxyethyl starch (HES) solutions are widely used to replace intravascular
      volume. HES solutions differ from each other with regard to molecular weight and
      mode of hydroxyl substitution (degree of hydroxylation, C2:C6 hydroxyethyl ratio,
      concentration), factors which may have varying effects on coagulation. We
      studied, in vitro, three different HES preparations (molecular weight/degree of
      hydroxylation/concentration/C2:C6 ratio of substitution 70.000/0. 5/6%/3.2;
      Pharmacia & Upjohn Co., Erlangen, Germany; 130.000/0. 4/6%/11.2 and
      200.000/0.5/6%/4.6; Fresenius Co., Bad Homburg, Germany) and, for comparison,
      lactated Ringer's solution (RL) at 33% and 66% dilution with whole blood. The
      influence of hemodilution was measured by using routine laboratory variables and
      SONOCLOT (Sonoclot II Coagulation and Platelet Function Analyzer, Sienco Co.)
      analysis, using a viscoelastic test, on the cellular as well as on the plasmatic
      hemostatic system. For statistical analysis of quantitative data, we used
      nonparametric analysis of variance and adequate post hoc tests. Qualitative data
      were analyzed by using the nonparametric Kruskal-Wallis test. A P value below
      0.05 was considered significant. In contrast to the control group with RL, the
      liquid phase of coagulation (activated clotting time) was slightly affected by
      the 33% diluted HES solutions. HES 70.000, 130. 000, and 200.000 interfered
      significantly with the early stage of coagulation as expressed by the clot rate
      (gel/fibrin formation). Clot maturation and speed of maturation (time to peak)
      were strongly affected by HES 70.000 at all grades of dilution. HES 130.000
      showed a faster clot formation process compared with the other HES solutions. HES
      130.000 diluted 33% showed a better clot retraction as compared with the other
      HES solutions. In conclusion, in vitro hemodilution comparing different medium
      molecular weight HES solutions reveals that HES 130.000 seems preferable
      regarding some aspects of clot formation and retraction. RL affected clot
      formation only minimally, except for the early activation of clotting, which was
      measured by a shortened activated clotting time. IMPLICATIONS: We investigated
      the effect of different hydroxyethyl starch (HES) solutions (70.000, 130.000,
      200.000) on coagulation. Regarding clot formation and retraction, HES 130.000 had
      some advantages over the other tested HES solutions. Lactated Ringer's solution
      affected coagulation only minimally, except for the early stage of clot
      formation.

PMID- 10648307
TI  - The use of esmolol, nicardipine, or their combination to blunt hemodynamic
      changes after laryngoscopy and tracheal intubation.
AB  - Laryngoscopy and tracheal intubation (LTI) often provoke an undesirable increase
      in blood pressure (BP) and/or heart rate (HR). We tested the premise that
      nicardipine (NIC) and esmolol (ESM) in combination (COMB) would oppose both.
      Adult surgical patients received pretreatment (randomized) with IV bolus NIC 30
      microg/kg (n = 31), ESM 1.0 mg/kg (n = 34), or COMB (one-half dose each, n = 32).
      Peak BP and HR after LTI were compared with controls (CONT; n = 35) with no
      pretreatment. Anesthetic induction was standardized: IV thiopental (5-7 mg/kg),
      fentanyl (1-2 microg/kg), and succinylcholine (1.5 mg/kg). Systolic (S),
      diastolic (D), and mean (M) BP and HR awake before pretreatment (baseline) were
      similar in all test groups. No patient was treated for hypotension, bradycardia,
      or tachycardia after pretreatment or anesthetic induction. Peak HR after LTI was
      increased versus baseline in CONT and all test groups, but did not differ from
      CONT among the test groups. Peak SBP and DBP increased versus baseline in CONT,
      and with ESM and NIC, but not COMB. Peak SBP, DBP, and MBP were increased with
      ESM versus COMB, and peak DBP with ESM versus NIC. Compared with no pretreatment
      before the IV induction of general anesthesia, the peak increase in BP after LTI
      is best blunted by the combination of nicardipine and ESM, compared with either
      drug alone. No single drug or combination in the doses tested opposed increased
      HR. IMPLICATIONS: Compared with no pretreatment before the IV induction of
      general anesthesia, the peak increase in blood pressure after laryngoscopy and
      tracheal intubation is best blunted by the combination of nicardipine and
      esmolol, compared with either drug alone. No single drug or combination in the
      doses tested opposed increased heart rate.

PMID- 10648308
TI  - Forced-air warming decreases vasodilator requirement after coronary artery bypass
      surgery.
AB  - Postoperative hypothermia is common and associated with adverse hemodynamic
      consequences, including adrenergically mediated systemic vasoconstriction and
      hypertension. Hypothermia is also a known predictor of dysrhythmias and
      myocardial ischemia in high-risk patients. We describe a prospective, randomized
      trial designed to test the hypothesis that forced-air warming (FAW) provides
      improved hemodynamic variables after coronary artery bypass graft. After
      institutional review board approval and written informed consent, 149 patients
      undergoing coronary artery bypass graft were randomized to receive postoperative
      warming with either FAW (n = 81) or a circulating water mattress (n = 68). Core
      temperature was measured at the tympanic membrane. A weighted mean skin
      temperature was calculated. Heart rate, mean arterial blood pressure, central
      venous pressure, cardiac output, and systemic vascular resistance were monitored
      for 22 h postoperatively. Mean arterial blood pressure was maintained by protocol
      between 70 and 80 mm Hg by titration of nitroglycerin and sodium nitroprusside.
      The two groups had similar demographic characteristics. Tympanic and mean skin
      temperatures were similar between groups on intensive care unit admission. During
      postoperative rewarming, tympanic temperature was similar between groups, but
      mean skin temperature was significantly greater in the FAW group (P < 0.05).
      Heart rate, mean arterial pressure, central venous pressure, cardiac output, and
      systemic vascular resistance were similar for the two groups. The percent of
      patients requiring nitroprusside to achieve the hemodynamic goals was less (P <
      0.05) in the FAW group. In conclusion, aggressive cutaneous warming with FAW
      results in a higher mean skin temperature and a decreased requirement for
      vasodilator therapy in hypothermic patients after cardiac surgery. This most
      likely reflects attenuation of the adrenergic response or opening of cutaneous
      vascular beds as a result of surface warming. IMPLICATIONS Forced-air warming
      after cardiac surgery decreases the requirement for vasodilator drugs and may be
      beneficial in maintaining hemodynamic variables within predefined limits.

PMID- 10648309
TI  - Cardiovascular surgery without cardiopulmonary bypass in patients with heparin
      induced thrombocytopenia type II using anticoagulation with recombinant hirudin.

PMID- 10648310
TI  - Oral ketamine/midazolam is superior to intramuscular meperidine, promethazine,
      and chlorpromazine for pediatric cardiac catheterization.
AB  - An IM combination of meperidine, promethazine, and chlorpromazine (DPT) has been
      given as sedation for pediatric procedures for more than 40 years. We compared
      this IM combination to oral (PO) ketamine/midazolam in children having cardiac
      catheterization. A total of 51 children, ages 9 mo to 10 yr, were enrolled and
      randomized in this double-blinded study. All children received an IM injection at
      time zero and PO fluid 15 minutes later. We observed acceptance of medication,
      onset of sedation and sleep, and sedative efficacy. The cardiorespiratory changes
      were evaluated. Sedation was supplemented with IV propofol as required. Recovery
      time, parental satisfaction, and patient amnesia were assessed.
      Ketamine/midazolam given PO was better tolerated (P < 0.0005), had more rapid
      onset (P < 0.001), and provided superior sedation (P < 0.005). Respiratory rate
      decreased after IM DPT only. Heart rate and shortening fraction were stable.
      Oxygen saturation and mean blood pressure decreased minimally in both groups.
      Supplemental propofol was more frequently required (P < or = 0.02) and in larger
      doses (P < 0.05) after IM DPT. Parental satisfaction ratings were higher (P <
      0.005) and amnesia was more reliably obtained (P = 0.007) with PO
      ketamine/midazolam. Two patients needed airway support after the PO medication,
      as did two other patients when PO ketamine/midazolam was supplemented with IV
      propofol. Although PO ketamine/midazolam provided superior sedation and amnesia
      compared to IM DPT, this regimen may require the supervision of an
      anesthesiologist for safe use. IMPLICATIONS: Oral medication can be superior to
      IM injections for sedating children with congenital heart disease; however, the
      safety of all medications remains an issue.

PMID- 10648311
TI  - A comparison of the incidence of the oculocardiac and oculorespiratory reflexes
      during sevoflurane or halothane anesthesia for strabismus surgery in children.
AB  - We examined changes in the cardiorespiratory system of small children during
      surgical correction of strabismus with a laryngeal mask airway and spontaneous
      respiration with sevoflurane or halothane inhaled anesthesia. Fifty-one children,
      1-7 yr old, having outpatient strabismus correction were randomized to
      sevoflurane (S) or halothane (H) in 66% nitrous oxide at 1.3 minimum alveolar
      concentration. Children breathed spontaneously through a laryngeal mask airway
      and were not pretreated with anticholinergics. The oculocardiac reflex (OCR),
      defined as a 20% decrease in heart rate (HR) from baseline, dysrhythmias, or
      sinoatrial arrest concomitant with ocular muscle traction occurred less
      frequently with sevoflurane than with halothane (S 38%, H79%, P = 0.009). The
      baseline HR was higher with sevoflurane (S 114 +/- 13 bpm, H 101 +/- 15 bpm, P =
      0.002). The lowest HR occurred with halothane (S 95 +/- 22 bpm, H 73 +/- 19 bpm,
      P = 0.001). The incidence of dysrhythmias was higher in the halothane group (S
      4%, H 42%, P = 0.004). Reductions in minute ventilation and PETCO(2) accompanied
      OCRs. Airway irritability was present with halothane only (S 0, H 3). Eleven
      children, of whom the majority had received halothane, required measures to
      correct SpO(2) < 95% or PETCO(2) > 60 mm Hg during maintenance anesthesia (S 11%,
      H 32%). Sevoflurane may be a more suitable anesthetic than halothane for
      operations involving traction on the ocular muscles with spontaneous respiration
      in children because of reduced incidence of OCR, airway irritability, and
      ventilatory disturbances. IMPLICATIONS: Some children experience a sudden slowing
      of the heart and impaired breathing when the surgeon pulls on the eye muscles
      during squint operations under anesthesia. Sevoflurane, a recently developed
      anesthetic vapor, may reduce this problem when compared with the established
      vapor halothane.

PMID- 10648312
TI  - Reduction of postoperative nausea and vomiting by dimenhydrinate suppositories
      after strabismus surgery in children.
AB  - Although dimenhydrinate has been used for treatment and prevention of
      postoperative nausea and vomiting (PONV) since the fifties, there have been few
      controlled studies about its efficacy. We performed a double-blinded study of 301
      children aged 4 to 10 yr who underwent strabismus surgery. Preanesthetic
      medication with midazolam (0.5 mg/kg) as well as application of either
      dimenhydrinate suppositories or a placebo preparation was performed 30 min before
      the induction of anesthesia. Anesthesia was induced with thiopentone (5-10 mg/kg)
      and vecuronium (0.1 mg/kg) and maintained with halothane (1%-2%) in N(2)O/O(2)
      (65%/35%). The incidence of PONV, requirements for rescue dimenhydrinate, and
      time to recovery were recorded. The overall incidence of PONV was 60.1% in the
      placebo group and 30.7% in the dimenhydrinate group. In the dimenhydrinate group,
      children had to be observed in the recovery room significantly longer than those
      in the placebo group. Children having received dimenhydrinate were discharged
      from the recovery room with lower arousal scores. We conclude that the rectal
      administration of dimenhydrinate is effective for the prevention of PONV,
      although the sedative effect may require longer postoperative monitoring.
      IMPLICATIONS: We performed a double-blinded, randomized study to investigate the
      effects of prophylactic rectal dimenhydrinate application on postoperative nausea
      and vomiting in children undergoing strabismus surgery. In comparison with
      placebo, dimenhydrinate reduced the incidence of postoperative vomiting from
      60.1% to 30.7%.

PMID- 10648313
TI  - Comparison of NAD 6000 and servo 900C ventilators in an infant lung model.
AB  - We compared the ability of the NAD 6000 (North American Drager, Telford, PA) and
      the Servo 900C (Siemens-Elema AB, Solna, Sweden) anesthesia ventilators to
      maintain precise delivery of small tidal volumes (V(t)) and positive end
      expiratory pressure using an infant test lung model. A variety of ventilator and
      lung model settings were selected to test clinical conditions simulating normal
      and extremely compromised lung function. Differences in ventilator output were
      analyzed by using an independent t-test with P <0.05 considered significant. With
      the ventilators set to deliver a V(t) of 30 mL, the actual delivered V(t) was
      significantly better for the NAD 6000 (25 +/- 2 mL) compared with the Servo 900C
      (18 +/- 3 mL), P <0.001. When the ventilators were set to deliver 100 mL V(t),
      their delivered V(t) were not significantly different, NAD 6000 (66 +/- 19 mL)
      and Servo 900C (60 +/- 12 mL), P = 0.09. The exhaled V(t) read by the anesthesia
      machines was significantly closer to the delivered V(t) for the NAD 6000 (11 +/-
      9 mL) compared with the Servo 900C (37 +/- 11 mL), P < 0.001. Both ventilators
      maintained the end expiratory pressure delivered to the test lung within 2 cm
      H(2)O of the set positive end-expiratory pressure on average. As the conditions
      changed requiring the ventilator to develop a higher peak inflating pressure,
      both ventilators showed a decrease in V(t) delivered, which was proportionate to
      the tubing compression volume loss. IMPLICATIONS: The NAD 6000 (North American
      Drager, Telford, PA) and Servo 900C (Siemens-Elema AB, Solna, Sweden) are able to
      precisely deliver small Tidal Volumes. They both decreased in performance when
      tested under extreme conditions. Earlier studies of traditional anesthesia
      ventilators suggest that the NAD 6000 and Servo 900C are superior pediatric
      ventilators.

PMID- 10648314
TI  - A massive pulmonary tumor embolism after surgical manipulation and biopsy of a
      pelvic mass.

PMID- 10648315
TI  - Prevention of hypotension by a single 5-mg dose of ephedrine during small-dose
      spinal anesthesia in prehydrated cesarean delivery patients.
AB  - To evaluate the effectiveness of prophylactic ephedrine for the prevention of
      hypotension associated with spinal anesthesia, 50 parturients undergoing cesarean
      delivery received either ephedrine 5 mg or saline IV in a double-blinded fashion
      immediately after the induction of spinal anesthesia. Spinal anesthesia was
      performed with hyperbaric bupivacaine 6.6 mg combined with sufentanil 3.3 microg
      as part of a combined spinal-epidural technique. All patients received 1000 mL of
      lactated Ringer's solution and 500 mL of hydroxyethylstarch 6% before the spinal
      injection. Additional ephedrine boluses (5 mg) were administered IV when the
      systolic blood pressure or heart rate decreased by more than 30% from baseline
      values, when systolic blood pressure became <100 mm Hg, or when patients
      complained of nausea or feeling faint. The height of the block was equal in the
      groups; however, more patients in the placebo group were found to develop
      hypotension (58% vs 25%, P < 0. 05). Only 2 (8%) patients in the ephedrine group
      developed hypotension with systolic blood pressure values <90 mm Hg, whereas 10
      patients (42%) in the saline group experienced hypotension of this severity (P <
      0.05). In addition, there was a higher incidence of nausea in the placebo-treated
      patients. The total amount of ephedrine administered did not differ between
      groups. These findings suggest that the incidence and severity of hypotension are
      significantly reduced by the IV administration of a prophylactic dose of 5 mg
      ephedrine in patients receiving small-dose spinal anesthesia for cesarean
      delivery. IMPLICATIONS: Ephedrine is the drug most often used to correct
      hypotension during spinal anesthesia for cesarean delivery in healthy patients. A
      single IV dose of 5 mg decreases the occurrence and limits the severity of
      hypotension in prehydrated subjects receiving a small-dose spinal local
      anesthetic-opioid combination.

PMID- 10648316
TI  - Patient-controlled epidural analgesia during labor: the effects of the increase
      in bolus and lockout interval.
AB  - Most studies use a bolus size of <6 mL of 0.125% bu- pivacaine for patient
      controlled epidural analgesia (PCEA) during labor. In this double-blinded,
      randomized study, we compared the efficacy of a larger bolus injected via a PCEA
      pump to a conventional PCEA setting. By using a combination of 0.125% bupivacaine
      with 1:800,000 epinephrine and 0.625 microg/mL sufentanil, the first PCEA setting
      was typical (4 mL/8 min), whereas the other combined a 12-mL bolus dose and a 25
      min lockout interval, i.e., similar maximal hourly dose. Rescue analgesia was
      provided with 6 mL of 0.25% bupivacaine. Patient satisfaction and pain were
      scored on verbal and visual analog scales. Data were analyzed from 103
      parturients in the 12-mL/25-min group and 100 in the 4-mL/8-min group. In the 12
      mL/25-min group, the median pain score on a 0- to 10-cm visual analog scale was
      lower at 6-cm cervical dilation (1 [range = 0-8] vs 3 [0-8]) and at delivery (1
      [0-10] vs 2 [0-10]). Satisfaction was also better (70% vs 38% "excellent"
      opinions, at 6-cm cervical dilation). Use of the pump (ratio of successful and
      total demands) was high and similar in both groups. Rescue analgesia was
      comparable. Doses of analgesics were greater in the 12-mL/25-min group (hourly
      bupivacaine dose = 13.9 +/- 5.3 [mean+/- SD] vs 9.4 +/- 4.1 mg). No differences
      were noted between groups for the severity of hypotension, ephedrine requirement,
      outcome of the delivery, and Apgar scores. IMPLICATIONS: A patient-controlled
      epidural analgesia setting that allows a parturient to receive an increased
      analgesic dose improves satisfaction with patient-controlled epidural analgesia
      during labor.

PMID- 10648317
TI  - An assessment of the effects on coagulation of midtrimester and final-trimester
      amniotic fluid on whole blood by Thrombelastograph analysis.
AB  - The Thrombelastograph((R)) test (TEG; Haemoscope Corporation, Skokie, IL) was
      used to assess the effects of midtrimester and final-trimester amniotic fluid
      (AF) on whole blood coagulation. Different volumes of midtrimester and final
      trimester AF were added to whole blood from nonpregnant volunteers in a series of
      TEG tests. The addition of both midtrimester and final-trimester AF resulted in
      significant decreases in reaction time (P < 0.001) and time from reaction to a
      fixed level of clot firmness (P < 0.05) and significant increases in angle (P <
      0.05) and coagulation index (P < 0.05) values. This reflects accelerated clot
      initiation and propagation. There was no significant change in the maximal
      amplitude or % lysis at 30 and 60 min with the addition of either midtrimester or
      final-trimester AF. There was no significant difference between the effects of
      midtrimester and final-trimester AF on whole blood TEG. TEG may be an additional
      useful tool in the treatment of coagulopathy in AF embolism. IMPLICATIONS: We
      used the Thrombelastograph((R)) test (Haemoscope Corporation, Skokie, IL) to
      assess the effects of midtrimester and final-trimester amniotic fluid (AF) on
      whole blood coagulation. Results demonstrate that AF accelerates clot initiation
      and propagation. The Thrombelastograph((R)) test may be useful in assessing
      coagulopathy in patients with AF embolism.

PMID- 10648318
TI  - The effect of nitroglycerin on the gravid uterus in sheep and rabbits.
AB  - Clinical reports suggest that nitroglycerin (TNG) has an effect on the uterus
      that is detected by the obstetrician on palpation, but not obvious by measurement
      of uterine pressure. This study was designed to compare the effects of TNG on
      uterine compliance and tension. We used three sets of experiments to evaluate the
      effect of TNG on the uterus. In vivo experiments were conducted on laboring ewes
      and rabbits 2 h postpartum to measure the effect of TNG on active uterine
      tension. An in vitro experiment was also conducted by using isolated uterine
      strips from term pregnant rabbits to evaluate the effect of TNG on uterine
      compliance. TNG had no discernible effect on uterine intracavitary pressure or
      frequency of contraction in either laboring ewes or postpartum rabbits at doses
      that were sufficient to reduce the mean arterial pressure. TNG did, however,
      increase the compliance of uterine tissue from rabbits at term, whereas S-nitroso
      N-acetylpenicillamine failed to produce a similar effect. Thus, the perceived
      relaxant effects of TNG may be caused by an increase in uterine compliance, which
      may facilitate efforts by the obstetrician to manipulate the uterus. While the
      mechanism of action remains unclear, it appears to be independent of nitric
      oxide. IMPLICATIONS: The administration of nitroglycerin may have a relaxant
      effect on the uterus. These experiments were conducted to elucidate the effect of
      nitroglycerin on the peripartum uterus by measuring active tension and
      compliance.

PMID- 10648319
TI  - Factors influencing the reporting of adverse perioperative outcomes to a quality
      management program.
AB  - Quality management programs have used several data reporting sources to identify
      adverse perioperative outcomes. We compared reporting sources and identified
      factors that might improve data capture. Adverse perioperative outcomes between
      January 1, 1992, and December 31, 1994, were reported to the Department of
      Anesthesiology Quality Management program by anesthesiologists, hospital chart
      reviewers, and other hospital personnel using incident reports. The reports were
      compared for preoperative health status, severity of outcome, and associated
      human error. Subsequently, personnel representing the various sources were
      surveyed regarding factors that might affect their reporting of adverse outcomes.
      Of 37,924 anesthetics, 734 (1. 9%) adverse outcomes were reported, 519 (71%) of
      which were identified by anesthesiologists, 282 (38%) by chart reviewers, and 67
      (9.1%) by incident report. There was no statistically significant difference in
      reporting rates by anesthesiologists according to preexisting disease, severity
      of outcome, or presence of human error. Thirteen cases involving human error,
      however, resulted in disabling patient injury, with a higher rate of self
      reporting for these cases (92%, P < 0.05). Rates of reporting by chart reviewers
      varied (P < 0.05) according to severity of patient illness and severity of
      outcome. Incident reports identified only 67 adverse outcomes (9.1%), but
      included a significantly higher percentage of the adverse outcomes involving
      human error (23.3%, P < 0.05). Twenty attending anesthesiologists, 15 resident
      anesthesiologists, 29 operating room nurses, 19 postanesthesia care unit nurses,
      and 6 hospital chart reviewers responded to the survey. Only the potential to
      improve quality of patient care influenced or strongly influenced a decision by
      all groups to report an adverse outcome to a peer review process. Physician self
      reporting is a more reliable method of identifying adverse outcomes than either
      medical chart review or incident reporting. IMPLICATIONS: Physician self
      reporting is a more reliable method of identifying adverse outcomes than either
      medical chart review or incident reporting. Reporting by chart reviewers is
      biased both by the severity of outcome and severity of patient illness, whereas
      incident reports tend to focus on human error. All groups feel compelled to
      report adverse outcomes when the data may result in improved patient care.

PMID- 10648320
TI  - The use of transesophageal echocardiography for preload assessment in critically
      ill patients.
AB  - IV volume is often administered to patients in an intensive care unit (ICU) to
      improve cardiovascular function. We investigated the relationship between stroke
      volume (SV) and left ventricular (LV) size by using transesophageal
      echocardiography (TEE) in a population of 20 ICU patients and 21 postoperative
      cardiac surgical patients. We also examined whether LV end diastolic area (EDA),
      by TEE, could identify patients who increased SV by 20% or more (responders)
      after 500 mL of pentastarch administration. There was only a modest relationship
      (r = 0.60) between the EDA and the SV in all patients. No relationship could be
      found between the pulmonary capillary wedge pressure (PCWP) and the EDA in all
      patients. Both responder and nonresponder PCWP increased significantly after
      volume administration. Only responder EDA increased significantly after volume
      administration. Responders had significantly lower EDA (15.3 +/- 5.4 cm(2)) and
      PCWP (12.2 +/- 2.2 mm Hg) when compared with nonresponders (20.2 +/- 4.8 cm(2))
      and 15.9 +/- 3.1 mm Hg, respectively). Few ICU patients and only those with a
      small EDA responded to volume administration. It was not possible to identify an
      overall optimal LV EDA below which most patients demonstrate volume-recruitable
      increases in SV. IMPLICATIONS: In a ventilated intensive care unit and cardiac
      surgical population, transesophageal echocardiography and pulmonary artery
      catheter are sensitive in detecting changes in preload after volume
      administration. Few patients demonstrate volume-recruitable increases in stroke
      volume when compared to cardiac surgical patients. It is not possible to
      establish an overall end diastolic threshold below which a large proportion of
      ventilated patients respond to volume administration.

PMID- 10648321
TI  - Systemic perfluorocarbons suppress the acute lung inflammation after gastric acid
      aspiration in rats.
AB  - Perflurocarbons (PFCs) are used during liquid ventilation and as hemoglobin
      substitutes. PFCs reduce free radical generation and damage to the lung during
      liquid ventilation. Thus, we examined the effects of parenteral administration of
      PFCs on lung injury after acid aspiration. Rats were treated with intraperitoneal
      injection of either FC-77 or IV injection of Fluosol. Controls received
      intraperitoneal or IV normal saline (NS) before or at the time of injury and then
      were injured by instillation of NS + HCl (pH = 1.25) into their lungs via a
      tracheotomy. The animals were exposed to air or 98% oxygen, breathing
      spontaneously. The rats were injected with 0.05 microCi of (125)I-albumin (bovine
      serum albumin) before injury. The extent of lung injury was assessed 5 h
      postinjury by compliance and lung albumin permeability index measurement.
      Myeloperoxidase (MPO) activity and histologic examination were used to assess
      neutrophilic infiltration. Both FC-77 and Fluosol decreased the permeability
      index compared with controls (1.05 +/- 0.08; 1.08 +/- 0. 12, respectively, versus
      1.34 +/- 0.21) and improved lung compliance after intratracheal instillation of
      1.2 mL/kg of HCl/NS, pH = 1.25 + hyperoxia injury (P < 0.05). Lung MPO activity
      decreased in the FC-77 group and was associated with a concomitant decrease in
      neutrophil infiltration. MPO activity of the spleen increased after FC-77
      treatment. The administration of FC-77 decreased the severity of lung
      permeability changes associated with acid in the presence or absence of hyperoxia
      exposure. These data suggest that attenuation of neutrophilic infiltration by
      PFCs decreases lung injury. IMPLICATIONS: Intraperitoneally administered
      perfluorocarbons in rats attenuate the neutrophilic infiltration in the lung
      after acid aspiration, thereby decreasing the alveolar protein leakage and
      improving pulmonary compliance.

PMID- 10648322
TI  - S-Nitroso-N-acetylpenicillamine (SNAP) during hemorrhagic shock improves
      mortality as a result of recovery from vascular hyporeactivity.
AB  - Nitric oxide donors are protective against hemorrhagic shock (HS). However, no
      detailed investigation has been performed. We investigated this mechanism using S
      nitroso-N-acetylpenicillamine (SNAP). HS (mean arterial pressure: 40 mm Hg) was
      induced in 20 dogs. Sixty min after HS, the animals were treated with saline
      (Cont-Gr: n = 7) or SNAP; 5 microg. kg(-1). 10 min(-1) followed by 5 microg. kg(
      1). h(-1) (SNAP-Gr: n = 7). After another 60 min, the shed blood was reinfused.
      Reactivities to noradrenalin (NA), changes in hemodynamics, the plasma
      catecholamines, and nitric oxide derivatives were determined. In Cont-Gr, 3 dogs
      died at 90, 98, and 102 min after HS. In Cont-Gr, % changes of systolic arterial
      blood pressure to 1 and 2.5 microg/kg of NA after the recovery from HS decreased
      from 23.7% +/- 4.1% (before HS) to 6.5% +/- 0.6% and from 50.1% +/- 7.7% (before
      HS) to 14.5% +/- 2.6%, respectively (P < 0. 01). In SNAP-Gr, reactivity to NA was
      maintained. At 120 min after HS, mean arterial pressure and cardiac output in
      SNAP-Gr increased but not in Cont-Gr. Plasma catecholamine levels in SNAP-Gr were
      suppressed compared with those of Cont-Gr. In conclusion, a small dose of SNAP
      during HS decreased the mortality of the dogs. This might have been caused in
      part by residual vascular hyporeactivity. IMPLICATIONS: The administration of a
      small dose of S-nitroso-N-acetylpenicillamine (a nitric oxide donor), a dose
      which did not exert a significant vasodilator effect, was administered during
      hemorrhagic shock in dogs. S-nitroso-N-acetylpenicillamine improved the vascular
      hyporeactivity to noradrenaline and decreased the mortality rate.

PMID- 10648323
TI  - Benzocaine-induced methemoglobinemia.

PMID- 10648324
TI  - Changes in cerebral blood volume with changes in position in awake and
      anesthetized subjects.
AB  - Changes in posture affect cerebral blood volume (CBV), and moderate head-up tilt
      is used as a therapeutic maneuver to reduce CBV and intracranial pressure.
      However, CBV is rarely measured in the clinical setting. Near-infrared
      spectroscopy allows real-time bedside monitoring of cerebral hemodynamics, and we
      have used this technique to measure changes in CBV with changes in posture in 10
      normal subjects and 10 propofol-anesthetized patients. In the awake subjects,
      changes in CBV were correlated with the degree of table tilt. CBV decreased with
      18 degrees head-up tilt and increased with 18 degrees head-down tilt (P < 0.0001,
      r = -0.924). In anesthetized patients, there were differences between head-up and
      head-down tilt. In the head-down position, CBV was also correlated with the
      degree of table tilt (P < 0.001, r = -0.782), whereas there was a clinically
      insignificant reduction in CBV in the head-up position. Near-infrared
      spectroscopy allows continuous, real time measurement of changes in CBV at the
      bedside. IMPLICATIONS: Near-infrared spectroscopy, a bedside technique, has been
      used to measure changes in cerebral blood volume in normal subjects. We have used
      the same technique in anesthetized patients and have shown that, when a patient
      is placed in the head up position, the decrease in cerebral blood volume is
      attenuated, relative to normal subjects.

PMID- 10648325
TI  - The effects of propofol with and without ketamine on human cerebral blood flow
      velocity and CO(2) response.
AB  - The combination of propofol and ketamine has been used for total IV anesthesia.
      This study was designed to clarify the effects of propofol-ketamine anesthesia on
      cerebral circulation by using transcranial Doppler ultrasonography. In Study 1,
      we examined the time course of time-mean middle cerebral artery blood flow
      velocity (Vmca) after ketamine (n = 10) or saline (n = 6) administration during
      propofol anesthesia. In Study 2, CO(2) responses were measured under the
      following conditions: awake (Group C, n = 7), propofol anesthesia (Group D, n =
      7), and propofol-ketamine anesthesia (Group E, n = 8). Ketamine administration
      during propofol anesthesia administration did not affect Vmca, mean arterial
      pressure, or heart rate. Vmca under normocapnia in Groups D and E were 36 +/- 3
      and 37 +/- 3 cm/s (mean +/- SE), respectively. The values were significantly
      lower than that of Group C (70 +/- 3 cm/s). The CO(2) response slopes of Groups D
      and E were significantly lower than that of Group C, although there was no
      significant difference between Groups D and E. These results suggest that
      ketamine does not influence Vmca or the cerebrovascular CO(2) response during
      propofol anesthesia administration, although the sample size in each group was
      small. IMPLICATIONS: Our study suggests that ketamine does not influence middle
      cerebral artery blood flow velocity or the cerebrovascular CO(2) response
      assessed by transcranial Doppler ultrasonography during propofol anesthesia
      administration in patients without neurological complications.

PMID- 10648326
TI  - Sufentanil does not prolong the duration of analgesia in a mepivacaine brachial
      plexus block: a dose response study.
AB  - To date, results of studies evaluating the efficacy of opioids and local
      anesthetic combinations in the brachial plexus are inconclusive. We examined
      whether increasing sufentanil in doses of 5, 10, and 20 microg decreased onset
      time or increased duration of an axillary brachial plexus block. Ninety-two
      patients scheduled for carpal tunnel release under axillary brachial plexus block
      were enrolled in the study. Patients were randomized to receive axillary plexus
      block with 40 mL 1.5% mepivacaine and saline (Group 1), sufentanil 5 microg
      (Group 2), 10 microg (Group 3), or 20 microg (Group 4). Onset and duration of
      sensory and motor block were measured. Opioid-related side effects were recorded.
      The addition of sufentanil did not improve speed of onset or increase the
      duration of sensory or motor block. Paradoxically, duration of sensory and motor
      block was longest in the control group: sensory, 241 min (188-284) and motor, 234
      min (128-305), and decreased with increasing doses of sufentanil in Group 4:
      sensory, 216 min (115-315) and motor, 172 min (115-260) (P < 0.05). Side effects
      occurred in 55% of patients belonging to Groups 2 and 4, and in 60% of the
      patients in Group 3. In contrast, only 10% of the patients reported side effects
      in the control group. We conclude that sufentanil added to mepivacaine does not
      increase the onset or prolong the duration of an axillary plexus block.
      Furthermore, the addition of sufentanil was associated with a frequent incidence
      of side effects. IMPLICATIONS: This study demonstrates that the addition of
      sufentanil in a dose-dependent manner to 1.5% mepivacaine in the axillary plexus
      does not improve onset or duration of blockade, and that this admixture is
      associated with an increased incidence of side effects.

PMID- 10648327
TI  - Small-dose dopamine increases epidural lidocaine requirements during peripheral
      vascular surgery in elderly patients.
AB  - We studied 20 patients over the age of 65 yr undergoing prolonged peripheral
      vascular surgery under continuous lidocaine epidural anesthesia, anticipating
      that the increased hepatic metabolism caused by small-dose IV dopamine would
      lower plasma lidocaine concentrations. Subjects were assigned (random, double
      blinded) to receive either a placebo IV infusion or dopamine, 2 microg. kg(-1).
      min(-1) during and for 5 h after surgery. Five minutes after the IV infusion was
      started, 20 mL of 2% lidocaine was injected through the epidural catheter. One
      half hour later, a continuous epidural infusion of 2% lidocaine at 10 mL/h was
      begun. The epidural infusion was temporarily decreased to 5 mL/h or 5 mL boluses
      were added to maintain a T8 analgesic level. Arterial blood samples were analyzed
      for plasma lidocaine concentrations regularly during and for 5 h after surgery.
      Plasma lidocaine concentrations increased continuously during the epidural
      infusion and, despite wide individual variation, were similar for the two groups
      throughout the observation period. During the observation period, the mean
      maximal plasma lidocaine concentration was 5.8 +/- 2.3 microg/mL in the control
      group and 5.7 +/- 1.2 microg/mL in the dopamine group. However, the mean hourly
      lidocaine requirement during surgery was significantly different, 242 +/- 72 mg/h
      for control and 312 +/- 60 mg/h for dopamine patients (P < 0.03). At the end of
      Hour 4, the last period when all 20 patients were still receiving the epidural
      lidocaine infusion, the total lidocaine requirement was significantly different,
      1088 +/- 191 mg for the control group and 1228 +/- 168 mg for the dopamine group
      (P < 0.05). Despite very large total doses of epidural lidocaine (1650 +/- 740
      mg, control patients, and 1940 +/- 400, dopamine patients) mean maximal plasma
      concentrations remained below 6 microg/mL, and no patient exhibited signs or
      symptoms of toxicity. We conclude that small-dose IV dopamine increased epidural
      lidocaine requirements, presumably as a consequence of increased metabolism.
      IMPLICATIONS: We tested dopamine, a drug that increases liver metabolism of the
      local anesthetic lidocaine to determine if it would prevent excessively large
      amounts of lidocaine in the blood during prolonged epidural anesthesia in elderly
      patients. Dopamine did not alter the blood levels of lidocaine, but it did
      increase the lidocaine dose requirement to maintain adequate epidural anesthesia.

PMID- 10648328
TI  - The mechanical properties of intact and traumatized epidural catheters.
AB  - Comparative data on the mechanical properties of epidural catheters used
      clinically are not available. We performed a controlled laboratory investigation
      to assess the mechanical performance of three different intact or traumatized
      catheter types (Polyurethane, clear nylon, and radiopaque nylon catheters,
      designed for 18-gauge Tuohy needles). We studied a control (intact) and two
      trauma groups (needle bevel and surgical blade). Catheters were loaded to their
      breaking points by using a Lloyd LS500 material testing machine (Lloyd,
      Southampton, UK). Maximal load and extension values before breakage were
      measured, and modulus of elasticity and toughness values were calculated. Intact
      polyurethane catheters did not break within the limits of the experimental study
      (extension up to 3 times the original length of a specimen). The toughness values
      obtained from polyurethane and clear nylon catheters were significantly higher
      than those for the radiopaque catheters in intact specimens (P < 0.05). In the
      traumatized groups, polyurethane catheters had the highest toughness values (P <
      0.05). Modulus of elasticity values were higher in both control and trauma groups
      of the radiopaque catheters when compared with the polyurethane and clear nylon
      catheters, which indicates a higher stiffness to elastic deformation (P < 0.05).
      In conclusion, polyurethane catheters are the most durable catheter type to
      tensile loading, either intact or traumatized. Mechanical properties can be used
      to predict complications related to the clinical use of these catheters.
      IMPLICATIONS: Using a computer-assisted material testing machine, we studied the
      mechanical properties of three different types of epidural catheters, either
      intact or traumatized, in a blinded, controlled study. This information may be
      vital to clinicians who implant epidural catheters by helping them choose a
      catheter that has the lowest probability of failure.

PMID- 10648329
TI  - Antinociception by epidural and systemic alpha(2)-adrenoceptor agonists and their
      binding affinity in rat spinal cord and brain.
AB  - This study was designed primarily to relate the antinociceptive and hemodynamic
      effects of clinically available alpha(2)-adrenoceptor agonists to their binding
      affinity for alpha(2)-adrenoceptors in the spinal cord and brain. In rats with
      chronic indwelling epidural catheters, the percentage maximal possible effect on
      tail-flick latency was measured after epidural or IM dexmedetomidine (DXM),
      clonidine (CL), or tizanidine (TZ) administration. To examine their binding
      affinities, isolated spinal cord and brain membranes with an alpha(2) agonist
      were incubated with (3)H-UK14304, a selective alpha(2) agonist, and the
      radioactivity in the reaction mixtures was measured by liquid scintillation
      spectrometry. Epidural DXM (0.5-10 microg), CL (10-500 microg), and TZ (5-500
      microg) all produced dose-dependent antinociceptive effects; the rank order of
      potencies was DXM > CL > TZ, the same as for their systemic administration. The
      antinociceptive effects were blocked by epidural yohimbine. The receptor binding
      affinities expressed as the concentration that inhibits 50% for spinal cord and
      brain, respectively, were 0.25 and 1.3 nM (DXM), 10.8 and 12.5 nM (CL), and 48.2
      and 96.8 nM (TZ). The changes in arterial blood pressure and heart rate evoked by
      antinociceptive doses did not correlate with the rank order of antinociceptive
      potencies. The relative antinociceptive potencies of epidural alpha(2) agonists
      may depend on their binding affinities to alpha(2)-adrenoceptors in the spinal
      cord, but their cardiovascular effects may result from actions both inside and
      outside the central nervous system. IMPLICATIONS: Spinal antinociception caused
      by the epidural administration of alpha(2) agonists is well correlated with their
      binding affinity to spinal alpha(2)-adrenoceptors.

PMID- 10648330
TI  - The effects of ketamine on the temporal summation (wind-up) of the R(III)
      nociceptive flexion reflex and pain in humans.
AB  - Animal studies have suggested that the temporal summation of nociceptive inputs
      might play a significant role in the development of central sensitization (i.e.,
      hyperexcitability of central nociceptive neurons) and hyperalgesia via the
      activation of N-methyl-D-aspartate receptors. To further analyze these processes
      in humans, we evaluated the effects of small systemic doses of ketamine on the
      temporal summation (i.e., wind-up) of both the nociceptive flexion (R(III))
      reflex and sensations of pain in six healthy volunteers. The R(III) reflex was
      recorded from the biceps femoris and was elicited by electrical stimulation of
      the sural nerve. First, the recruitment (stimulus/response) curve for the reflex
      was built using stimuli up to the pain tolerance threshold (applied once every 6
      s). A series of 15 stimuli was then applied once a second at an intensity of 1.2
      times the reflex threshold. These procedures were performed both before and after
      the randomized IV injection of either 0.15 mg/kg ketamine or a placebo. The
      R(III) reflex threshold and its recruitment curve were not significantly altered
      after the injection of ketamine or placebo. By contrast, the significant
      increases (i.e., wind-up) in both the reflex responses and the sensations of pain
      observed during the higher frequency stimulation were significantly reduced after
      the administration of ketamine, but not placebo. This method might be useful for
      quantifying and analyzing the wind-up phenomenon and, thus, for studying the
      neurophysiological and pharmacological mechanisms underlying hyperalgesia in
      humans. IMPLICATIONS: The wind-up phenomenon (i.e., the progressive increase of
      the responses induced by repetitive nociceptive stimuli) was characterized in
      humans by using electrophysiological recordings of the nociceptive flexion
      reflex. We showed that, as in animals, this phenomenon, which might represent an
      elementary form of the central sensitization involved in various painful
      syndromes, depends on the activation of N-methyl-D-aspartate receptors, because
      it was selectively reduced after the administration of ketamine.

PMID- 10648331
TI  - Comparisons of the anesthetic potency and intracellular concentrations of S(-)
      and R() bupivacaine and ropivacaine in crayfish giant axon in vitro.
AB  - Levobupivacaine and ropivacaine are both single S(-) enantiomers that have less
      severe cardiotoxic and convulsant effects than racemic bupivacaine. We compared
      the anesthetic actions of S(-) bupivacaine, R(+) bupivacaine, and ropivacaine in
      vitro by studying their effects on action potential amplitude and the maximal
      rate of rise of action potential in crayfish giant axon. To clarify the
      difference of intracellular anesthetic concentration, the intracellular ionized
      anesthetic concentration was measured. Desheathed crayfish axons were stimulated
      at a frequency of either 0. 1 or 5 Hz and perfused with 1 mM of each anesthetic
      at pH 7.0. Intracellular anesthetic concentration was measured by us- ing local
      anesthetic-sensitive glass microelectrodes. At 0.1-Hz stimulation, no differences
      were observed in their potency. At 5-Hz stimulation, the order of magnitude of
      the mean percentage decrease in maximal rate of rise of action potential was S(-)
      bupivacaine > R(+) bupivacaine > ropivacaine. Intracellular local anesthetic
      concentration did not differ among the three anesthetics at 0.1 Hz and 5 Hz. We
      conclude that, compared with ropivacaine, S(-) bupivacaine has a more potent
      phasic blocking effect in crayfish giant axon. The intracellular local anesthetic
      concentrations of S(-), R(+) bupivacaine and ropivacaine were not significantly
      different, regardless of differences in blocking effect and stimulation
      frequency. IMPLICATIONS: S(-) bupivacaine has a more potent phasic blocking
      effect than ropivacaine or R(+) bupivacaine in crayfish giant axons in vitro. An
      equivalent intracellular local anesthetic concentration for the three anesthetics
      was found, suggesting that the intracellular cationic local anesthetic
      concentration is not directly correlated with the intensity of block.

PMID- 10648332
TI  - An analysis of drug interaction between morphine and neostigmine in rats with
      nerve-ligation injury.
AB  - Intrathecal neostigmine reverses mechanical allodynia in humans and animals. The
      efficacy of morphine in a neuropathic pain state is still controversial. This
      study examines the antiallodynic interaction between morphine and neostigmine in
      a rat model of neuropathic pain. Rats were prepared with tight ligation of left
      L5-6 (fifth and sixth lumbar) spinal nerves and chronic intrathecal catheter
      implantation. Mechanical allodynia was measured by using application of von Frey
      hairs to the left hindpaw. Morphine (1, 3, 10, and 30 microg) and neostigmine
      (0.3, 1, 3, and 10 microg) were administered intrathecally to obtain the dose
      response curves and the 50% effective dose (ED(50)) for each drug. ED(50) values
      and fractions of the ED(50) values (1/2, 1/4, and 1/8) were administered
      intrathecally in an equal dose ratio to establish the ED(50). Isobolographic and
      fractional analyses for the drug interaction were performed. Intrathecal morphine
      produced a moderate antagonism of the tactile allodynia. A morphine-neostigmine
      combination produced a dose-dependent increase in withdrawal threshold of the
      lesioned hind paw with reduced side effects. Both analyses revealed a synergistic
      interaction after the coadministration of morphine and neostigmine. These
      experiments suggest that the antiallodynic action of a morphine-neostigmine
      combination is synergistic at the spinal level. IMPLICATIONS: This study
      indicates that, by using both isobolographic and fractional analyses, the
      antiallodynic effect of intrathecal morphine and neostigmine is synergistic when
      coadministered intrathecally. In a rat model of neuropathic pain, the intrathecal
      morphine produced a moderate antagonism on touch-evoked allodynia at the spinal
      level.

PMID- 10648333
TI  - A comparison of regularly administered sustained release oral morphine with
      intramuscular morphine for control of postoperative pain.
AB  - We studied the efficacy and side effect profile of regularly administered, oral
      sustained-release morphine sulfate tablets (MST) and IM morphine in patients
      undergoing total hip arthroplasty under lumbar spinal anesthesia. Patients in
      Group I received MST 20 mg 12 hourly and a placebo IM injection 6 hourly
      regularly. Group II patients received an oral placebo 12 hourly and morphine
      sulfate 10 mg IM 6 hourly regularly. Rescue analgesia was provided with regular
      diclofenac suppositories and patient-controlled analgesia. Pain scores assessed
      by using visual analog scale and verbal pain scoring at rest and with movement
      were low in both groups, with no statistical difference between groups. Mean
      patient-controlled analgesia morphine consumption during the 48-h study was 16.7
      mg in the IM group and 25.9 mg in the MST group. The difference between the
      groups was significant at 36 h postoperatively (0.03). Side effects of sedation
      and respiratory depression were not problematic in either group, with a maximal
      sedation score of 2 occurring once in a patient in Group II. Nausea and vomiting
      occurred more often in Group II, but this was not statistically significant, with
      a mean nausea/vomiting score for Group II of 1.7. We conclude that oral,
      sustained-release morphine is an attractive alternative to IM opiates in patients
      undergoing body surface surgery under regional anesthesia. IMPLICATIONS: Each
      postoperative analgesic has its own limitations for route of administration,
      dosage, and potential side effects. Using the oral route for drug administration
      seems more attractive than other methods but may not be suitable in all
      postoperative patients. We studied the efficacy and side effect profile of
      sustained-release, oral morphine compared with standard IM morphine for the
      treatment of pain after hip replacement surgery. We concluded that use of the
      oral preparation is a suitable alternative to the IM route in this population
      undergoing surgery under spinal anesthesia.

PMID- 10648334
TI  - The pharmacokinetics and analgesic efficacy of larger dose rectal acetaminophen
      (40 mg/kg) in adults: a double-blinded, randomized study.
AB  - Analgesic acetaminophen plasma concentrations are not known. We investigated in a
      randomized, double-blinded study the pharmacokinetics and analgesic efficacy of
      small- (AS; 20 mg. kg(-1)) and larger- (AL; 40 mg/kg) dose rectal acetaminophen
      and compared it with the combination (C) of rectal diclofenac (100 mg) and
      acetaminophen (20 mg/kg) in 65 women undergoing hysterectomy. Suppositories were
      administered after the induction of a standardized general anesthesia. Pain
      (measured by using a 10-cm visual analog scale) and morphine consumption (patient
      controlled analgesia) were repeatedly assessed for 24 h. Acetaminophen plasma
      concentrations were measured by using a fluorescence polarization immunoassay.
      Antipyretic plasma concentrations (10-20 mg/L) after 40 mg/kg acetaminophen were
      not associated with improved analgesia or decreased opioid requirements; 20 mg/kg
      acetaminophen produced subtherapeutic plasma levels (<10 mg/L). Maximal plasma
      concentrations of 17.2 and 10.4 mg/L (P < 0.01, analysis of variance) were
      achieved after 4.2 and 3.6 h for the AL and AS groups, respectively. The only
      difference in clinical outcome was lower visual analog scale scores after
      acetaminophen/diclofenac (C 2.0 versus AS 3.2 and AL 3.4) 4 h after the induction
      (P < 0.05, analysis of variance). Acetaminophen pharmacokinetics in adults were
      similar to those observed in children. Analgesic plasma concentrations are likely
      to be higher than antipyretic plasma levels, which were only attained after twice
      the recommended rectal dose was administered. Analgesic plasma concentrations
      have yet to be determined but may be higher than those associated with
      antipyresis. IMPLICATIONS: Acetaminophen pharmacokinetics were comparable in
      adults and children. Plasma concentrations known to reduce fever did not produce
      better pain relief and were only achieved after twice the conventional dose was
      administered. Analgesic plasma concentrations have yet to be determined but may
      be higher than those associated with antipyresis.

PMID- 10648335
TI  - Transient neurologic symptoms after epidural analgesia.

PMID- 10648336
TI  - A pilot study of pharyngeal pulse oximetry with the laryngeal mask airway: a
      comparison with finger oximetry and arterial saturation measurements in healthy
      anesthetized patients.
AB  - We compared pharyngeal SpO(2) by using the laryngeal mask airway (LMA) to finger
      SpO(2) and oxygen saturation from arterial blood samples (SaO(2)). We studied 20
      hemodynamically stable, well oxygenated, anesthetized patients (ASA physical
      status I-III, aged 18-80 yr). A single-use pediatric pulse oximeter was attached
      to the back plate of a size 5 LMA. Pharyngeal and finger SpO(2) (dominant index
      finger) and SaO(2) (nondominant radial artery) were measured with the cuff volume
      at 0-40 mL in the neutral position. The intracuff pressure was then set at 60 cm
      H(2)O in the neutral position, and readings were taken with the head-neck flexed,
      extended, and rotated. SaO(2) was the same as pharyngeal SpO(2) at 20 and 30 mL
      cuff volume, but higher than pharyngeal SpO(2) at all other cuff volumes and head
      neck positions (P < 0.04). SaO(2) was always higher than finger SpO(2) (P <
      0.01). Pharyngeal SpO(2) was higher than finger SpO(2) at cuff volumes 10-40 mL
      and in the flexed and rotated head-neck positions (all: P < 0.007), but was lower
      at 0 cuff volume (P < 0.0001) and similar in the extended head-neck position.
      There was an increase in pharyngeal SpO(2) between 0 and 10 mL cuff volume (P <
      0.0001), but no changes thereafter. Pharyngeal SpO(2) was similar in the flexed,
      rotated and extended head-neck positions. Pharyngeal SpO(2) agrees more closely
      with SaO(2) (mean difference < 0.7%) than finger SpO(2) (mean difference > 1.1%)
      at 10-40 mL cuff volume and in head-neck flexion. The standard error of limits
      was identical (0.09) for both finger SpO(2) and pharyngeal SpO(2) if data at 0
      cuff volume are excluded. We conclude that pharyngeal SpO(2) with the LMA is
      feasible and generally provides more accurate readings than finger SpO(2) in
      hemodynamically stable, well oxygenated, anesthetized patients. IMPLICATIONS:
      Pharyngeal oximetry with the laryngeal mask airway is feasible and generally
      provides more accurate readings than finger oximetry in hemodynamically stable,
      well oxygenated, anesthetized patients.

PMID- 10648337
TI  - Nimodipine premedication and induction dose of propofol.
AB  - Antagonists at the L-type voltage sensitive calcium channel (L-VSCC) potentiate
      anesthetic potency in experimental models, suggesting that it may be a target
      site for IV anesthetics. Nimodipine is a 1, 4-dihydro- pyridine antagonist of L
      VSCC which crosses the blood-brain barrier. We tested the hypothesis that
      premedication with oral nimodipine in healthy patients would reduce the induction
      dose of propofol, independently of its effects on the cerebral circulation. Sixty
      ASA physical status I or II patients (18-60 yr), undergoing knee arthroscopy or
      minor urological surgery, were randomized to receive either nimodipine 60 mg or
      placebo, orally 1-2 h before induction. Noninvasive mean blood pressure, heart
      rate, and time-averaged mean velocity in the middle cerebral artery by using
      transcranial Doppler ultrasonography were obtained before and 5 min after the
      induction of anesthesia. Propofol 1% was administered by an infusion pump at a
      rate of 10 mL/min. Both groups of patients had a reduction in mean blood pressure
      after the induction (P < 0.01), but there were no significant differences between
      the groups. The induction dose of propofol was 2.19 mg/kg (95% confidence
      interval [CI]: 1.97-2.42) in the nimodipine group, compared with 2.16 mg/kg (95%
      CI 1.98-2.34) in the control group, P = 0.8. Time-averaged mean velocity remained
      unchanged after the induction of anesthesia in both patients receiving nimodipine
      premedication (51% CI 43-59 cm/s to 52% CI 46-58 cm/s, P = 0.6) and those
      receiving placebo (50% CI 43-58 cm/s to 53% CI 45-59 cm/s, P = 0.3).
      Premedication with oral nimodipine 60 mg does not reduce the induction dose of
      propofol compared with placebo, casting doubt on the hypothesis that propofol has
      an anesthetic action at L-VSCC. IMPLICATIONS: Premedication with oral nimodipine
      60 mg does not reduce the induction dose of propofol compared with placebo,
      casting doubt on the hypothesis that propofol has an anesthetic action at L-type
      voltage sensitive calcium channels.

PMID- 10648338
TI  - Propofol/sufentanil anesthesia suppresses the metabolic and endocrine response
      during, not after, lower abdominal surgery.
AB  - We investigated the influence of propofol/sufentanil anesthesia on metabolic and
      endocrine responses during, and immediately after, lower abdominal surgery.
      Twenty otherwise healthy patients undergoing abdominal hysterectomy for benign
      myoma received either continuous infusions of propofol supplemented with
      sufentanil (0.01 microg. kg(-1). min(-1), n = 10) or enflurane anesthesia
      (enflurane, n = 10). Plasma concentrations of glucose, lactate, free fatty acids,
      triglycerides, insulin, glucagon, cortisol, epinephrine, and norepinephrine were
      measured before, during, and 2 h after surgery. Pre- and postoperative endogenous
      glucose production (R(a) glucose) was analyzed by an isotope dilution technique
      by using [6,6-(2)H(2)] glucose. Propofol/sufentanil anesthesia prevented the
      increase in plasma cortisol and catecholamine concentrations and attenuated the
      hyperglycemic response during surgery without showing any difference after the
      operation. Mediated through a higher glucagon/insulin quotient
      (propofol/sufentanil 15 +/- 7 versus enflurane 8 +/- 4 pg/microU, P < 0.05), the
      R(a) glucose postoperatively increased more in the propofol/sufentanil than in
      the enflurane group (propofol/sufentanil 15.6 +/- 2.0 versus enflurane 13.4 +/-
      2.2 micromol. kg(-1). min(-1), P < 0.05). IMPLICATIONS: The concept of stress
      free anesthesia using propofol combined with sufentanil is valid only during
      surgery. The metabolic endocrine stress response 2 h after the operation is more
      pronounced than after inhaled anesthesia.

PMID- 10648339
TI  - Predictive variables of hypothermia in the early phase of general anesthesia.
AB  - Core temperature decreases precipitously for 1 h and then decreases slowly for 2
      3 h after the induction of general anesthesia. We investigated the predictive
      variables of hypothermia by measuring peripheral skin temperature and total body
      fat (TBF). We studied 60 adult patients who required general anesthesia with
      isoflurane. The following variables were measured preoperatively: right palmar
      skin temperature by using an infrared thermometer and skin thickness at arm and
      scapula by using a standard caliper. TBF was calculated by using the regression
      equation of Durnin and Womersley. Rectal temperature, taken to represent core
      temperature, was measured during the operation. The gradient of hypothermia
      induced by general anesthesia was divided into two parts: 1) a precipitous
      decrease for the first hour and 2) a slow decrease for the following 2-3 h.
      Preoperative palmar skin temperature had a significant linear relationship with
      the precipitous decrease in temperature over the first hour (r = 0.69, P <
      0.0001), and TBF had a significant linear relationship with the subsequent slow
      decrease in temperature (r = 0. 63, P < 0.0001). By simple measurements, we can
      predict the extent of hypothermia in the early phase of general anesthesia and
      prevent its onset by using body-warming techniques. IMPLICATIONS: After the
      induction of general anesthesia, palmar skin temperature had a linear
      relationship with the precipitous decrease in rectal temperature over the first
      hour, and total body fat had a linear relationship with the subsequent decrease
      in temperature. Thus, by simple measurements, we can predict the extent of
      hypothermia in the early phase of general anesthesia.

PMID- 10648340
TI  - Supraglottic combined frequency jet ventilation versus subglottic monofrequent
      jet ventilation in patients undergoing microlaryngeal surgery.
AB  - We compared the efficacy of gas exchange during supraglottic combined-frequency
      jet ventilation via a jet ventilation laryngoscope and during monofrequent jet
      ventilation via the Mon-Jet catheter (Xomed, Jacksonville, FL). Twenty-three
      anesthetized (propofol, fentanyl, vecuronium) patients undergoing microlaryngeal
      surgery were prospectively studied and randomly assigned to one of two groups.
      The patients' lungs were ventilated with combined-frequency jet ventilation (10
      min, 15 and 600 breaths/min, inspiration/expiration time ratio = 1, driving
      pressure 750-1500 mm Hg), monofrequent (low-frequency group: 15 breaths/min; high
      frequency group: 600 breaths/min) jet ventilation (20 min), and again combined
      frequency jet ventilation (15 min). PaO(2), PaCO(2), and the inspiratory oxygen
      fraction (FIO(2)) were measured. Wilcoxon's signed rank test was applied. During
      monofrequent jet ventilation, PaCO(2) increased and the PaO(2)/FIO(2) decreased
      significantly (P < 0.05) as compared with combined-frequency jet ventilation (low
      frequency group: PaCO(2) from 39.4 +/- 3.3 to 50. 8 +/- 8.0 mm Hg, PaO(2)/FIO(2)
      from 306 +/- 100 to 225 +/- 94 mm Hg; high-frequency group: PaCO(2) from 36.7 +/-
      7.2 to 60.3 +/- 6.1 mm Hg, PaO(2)/FIO(2) from 429 +/- 87 to 190 +/- 51 mm Hg;
      mean +/- SD). After switching back to combined-frequency jet ventilation, PaCO(2)
      decreased and PaO(2)/FIO(2) increased to baseline levels. We conclude that gas
      exchange during microlaryngeal surgery can be more easily maintained with
      supraglottic combined-frequency jet ventilation than with subglottic monofrequent
      jet ventilation via the Mon-Jet catheter. IMPLICATIONS: This study demonstrates
      that the combination of high- and low-frequency supraglottic jet ventilation via
      a jet ventilation laryngoscope provides a better pulmonary gas exchange and
      allows more accurate airway pressure monitoring during microlaryngeal surgery
      than subglottic monofrequent jet ventilation via an endotracheal catheter.

PMID- 10648341
TI  - Inert gas exchange during pneumoperitoneum at incremental values of positive end
      expiratory pressure.
AB  - Laparoscopy is a surgical technique for a growing variety of abdominal
      operations. In patients undergoing this procedure, arterial blood oxygenation and
      hemodynamics are frequently depressed. This study evaluated the effect of
      different levels of positive end-expiratory pressure (PEEP) during
      intraperitoneal CO(2) insufflation on the lung's ventilation-perfusion
      distribution in a porcine model. We studied 13 anesthetized pigs with an
      intraperitoneal pressure of 15 cm H(2)O applied at either incremental values of
      PEEP (5-20 cm H(2)O, increments of 5 cm H(2)O) or a constant PEEP of 5 cm H(2)O.
      The effects of CO(2) pneumoperitoneum on inert gas exchange and hemodynamics were
      examined with the multiple inert gas elimination technique. During
      pneumoperitoneum, gas exchange was most augmented by 15 and 20 cm H(2)O of PEEP.
      Although the differences in hemodynamics between the individual settings were
      insignificant, 10 cm H(2)O of PEEP provided the smallest impairment of
      hemodynamics. We conclude that PEEP of 15 H(2)O during pneumoperitoneum resulted
      in a modest hemodynamic depression but significant gas exchange augmentation in
      our experiment. IMPLICATIONS: Anesthetized pigs, with a pneumoperitoneum of 15 cm
      H(2)O, were treated either with incremental values of positive end-expiratory
      pressure (5-20 cm H(2)O, increments of 5 cm H(2)O) or with a constant positive
      end-expiratory pressure of 5 cm H(2)O. Fifteen and 20 cm H(2)O resulted in
      significantly improved pulmonary gas exchange compared with 5 cm H(2)O.

PMID- 10648342
TI  - Ramosetron for preventing postoperative nausea and vomiting in women undergoing
      gynecological surgery.
AB  - In a prospective, randomized, double-blinded, placebo-controlled trial, we
      evaluated the efficacy of ramosetron at three different doses (0.15, 0.3, and 0.6
      mg) for the prevention of postoperative nausea and vomiting (PONV) after
      gynecological surgery. One hundred twenty women, ASA physical status I or II,
      aged 21-63 yr, received IV either placebo or ramosetron 0.15, 0.3, or 0.6 mg (n =
      30 of each) at the completion of surgery. A standard general anesthetic technique
      and postoperative analgesia were used. A complete response, defined as no PONV
      and no need for another rescue antiemetic, during 0-3 h after anesthesia occurred
      in 40%, 47%, 87%, and 90% of patients who had received placebo and ramosetron
      0.15, 0.3, and 0.6 mg, respectively. Corresponding results during 3-24 h after
      anesthesia were 43%, 50%, 87%, and 90%, and 24-48 h after anesthesia were 50%,
      53%, 90%, and 93% (P < 0.05). Patients who had received ramosetron 0.3 or 0.6 mg
      were satisfied compared with those who had received placebo (P < 0.05). There
      were no serious clinical adverse events caused by the study drug in any of the
      groups. In conclusion, ramosetron 0.3 mg is an effective antiemetic for
      preventing PONV during 0-48 h after anesthesia in female patients undergoing
      gynecological surgery. Increasing the dose to 0.6 mg provided no further benefit.
      IMPLICATIONS: This randomized, double-blinded, placebo-controlled trial in 120
      women found the effective dose of ramosetron for preventing postoperative nausea
      and vomiting after gynecological surgery to be 0.3 mg.

PMID- 10648343
TI  - Nondepolarizing neuromuscular blockers inhibit the serotonin-type 3A receptor
      expressed in Xenopus oocytes.
AB  - Molecular cloning and sequence comparison indicates a high degree of structural
      homology between muscle nicotinic acetylcholine (nACh) and serotonin-type 3 (5
      HT(3A)) receptors, both members of the direct ligand-gated family of ion
      channels. Because of the structural similarities and common evolutionary origin
      of these receptors, neuromuscular blockers (competitive nACh antagonists) may
      demonstrate pharmacologic cross talk and exhibit attributes of 5-HT(3A) receptor
      antagonists. We examined six clinically-used neuromuscular blockers for their
      ability to antagonize currents flowing through the 5-HT(3A) receptors in voltage
      clamped Xenopus oocytes. The neuromuscular blockers reversibly inhibited the 5
      HT(3A) receptor-gated current in the rank order potency of (IC50 mean +/- SEM): d
      tubocurarine (0.046 +/- 0.003 microM), atracurium (0.40 +/- 0.03 microM),
      mivacurium (15.1 +/- 2.93 microM), vecuronium (16.3 +/- 2.24 microM), and
      rocuronium (19.5 +/- 2.31 microM). Gallamine was essentially inactive as a 5
      HT(3A) receptor antagonist with an extrapolated IC50 of 1170 microM. We
      demonstrate that drugs classically known as competitive nACh receptor antagonists
      also block 5-HT(3A) receptors. It is likely that certain neuromuscular blockers
      share pharmacological properties with 5-HT(3A) receptor antagonists, such as a
      reduction in postoperative nausea and vomiting. With careful drug selection,
      pharmacological cross talk could potentially be used to minimize polypharmacy and
      optimize patient management. IMPLICATIONS: Muscle nicotinic acetylcholine and
      serotonin-type 3A (5-HT(3A)) receptors are similar. Therefore neuromuscular
      relaxants may block 5-HT(3A) receptors. Our pharmacological study demonstrates
      that neuromuscular relaxants, as with ondansetron, are 5-HT(3A) receptor
      antagonists. It is likely that certain neuromuscular relaxants exhibit
      ondansetron-like clinical properties, such as reduction in postoperative nausea
      and vomiting.

PMID- 10648344
TI  - Inhaled nitric oxide delivery by anesthesia machines.
AB  - Inhaled nitric oxide (NO) is a selective pulmonary vasodilator used to treat
      intraoperative pulmonary hypertension and hypoxemia. In contrast to NO delivered
      by critical care ventilators, NO delivered by anesthesia machines can be
      complicated by rebreathing. We evaluated two methods of administering NO
      intraoperatively: via the nitrous oxide (N(2)O) flowmeter and via the INOvent
      (Datex-Ohmeda, Madison, WI). We hypothesized that both systems would deliver NO
      accurately when the fresh gas flow (FGF) rate was higher than the minute
      ventilation (VE). Each system was set to deliver NO to a lung model. Rebreathing
      of NO was obtained by decreasing FGF and by simulating partial NO uptake by the
      lung. At FGF > or = VE (6 L/min), both systems delivered an inspired NO
      concentration ([NO]) within approximately 10% of the [NO] set. At FGF < VE and
      complete NO uptake, the N(2)O flowmeter delivered a lower [NO] (70 and 40% of the
      [NO] set at 4 and 2 L/min, respectively) and the INOvent delivered a higher [NO]
      (10 and 23% higher than the [NO] set at 4 and 2 L/min, respectively). Decreasing
      the NO uptake increased the inspired [NO] similarly with both systems. At 4 L/min
      FGF, [NO] increased by 10%-20% with 60% uptake and by 18%-23% with 30% uptake. At
      2 L/min, [NO] increased by 30%-33% with 60% uptake and by 60%-69% with 30%
      uptake. We conclude that intraoperative NO inhalation is accurate when
      administered either by the N(2)O flowmeter of an anesthesia machine or by the
      INOvent when FGF > or = VE. IMPLICATIONS: Inhaled nitric oxide (NO) is a
      selective pulmonary vasodilator. In a lung model, we demonstrated that NO can be
      delivered accurately by a N(2)O flowmeter or by a commercial device. We provide
      guidelines for intraoperative NO delivery.

PMID- 10648345
TI  - Interference of cerebral near-infrared oximetry in patients with icterus.
AB  - Near-infrared spectrophotometry assesses cerebral oxygen saturation (ScO(2))
      based on the absorption spectra of oxygenated and deoxygenated hemoglobin and the
      translucency of biological tissue in the near-infrared band. In patients with
      icterus, however, bilirubin can potentially hinder cerebral oximetry. In 48
      patients undergoing orthotopic liver transplantation, we related total plasma
      bilirubin to ScO(2) as determined from spectrophotometry with wavelengths of 733
      and 809 nm. Before surgery, ScO(2) was 59% (15%-78%) (median with range) and
      bilirubin was 71 (6-619) micromol/L with a negative correlation (r = -0.72; P <
      0.05). The 95% prediction interval included the lowest measurable ScO(2) of 15%
      at a bilirubin level of 370 micromol/L. During reperfusion of the grafted liver,
      the ScO(2) increased by 7% (-8% to 17%) (P < 0.05), and bilirubin did not
      influence this increase. In one patient, the ScO(2) remained below 15% despite a
      decrease in bilirubin from 619 to 125 micromol/L, suggesting that tissue
      pigmentation deposits also absorb light. In conclusion, bilirubin dampens the
      spectrophotometry-determined cerebral oxygen saturation at 733 and 809 nm. A
      bilirubin level of 370 micromol/L, tissue pigment deposits, or both, may render
      determination of cerebral oxygen saturation impossible. Even at high bilirubin
      values, changes in cerebral perfusion may be visible. IMPLICATIONS: In 48
      patients undergoing liver transplantation, the interference of icterus on
      cerebral oximetry by near-infrared light was investigated. Bilirubin absorbed the
      near-infrared light and lowered the measured cerebral oxygen saturation. Even at
      high bilirubin values, changes in cerebral oxygenation, as seen during
      reperfusion of the grafted liver, may be visible.

PMID- 10648346
TI  - A new method of monitoring the effect of muscle relaxants on laryngeal muscles
      using surface laryngeal electromyography.

PMID- 10648348
TI  - Premedication with midazolam in pediatric anesthesia

PMID- 10648347
TI  - Mivacurium administration in children with Duchenne muscular dystrophy.

PMID- 10648349
TI  - Defining the anatomy of Freudian psychiatry.

PMID- 10648350
TI  - A new clinical application of nitroglycerin as an aid to venipuncture in
      nitroglycerin tape users.

PMID- 10648351
TI  - Streptococcus mitis-induced meningitis after spinal anesthesia.

PMID- 10648352
TI  - How long should an internal jugular catheter be?

PMID- 10648353
TI  - Cannulating the internal jugular vein: two for one technique.

PMID- 10648354
TI  - Use of level 1(R) warmer for lavage fluid during bilateral pulmonary lavage.

PMID- 10648356
TI  - Epidural analgesia after dural puncture.

PMID- 10648355
TI  - Math made simple.

PMID- 10648357
TI  - Clinical guidelines.

PMID- 10648358
TI  - MMR vaccine and allergy.

PMID- 10648359
TI  - Public health: Sustainable development, human induced global climate change, and
      the health of children.

PMID- 10648360
TI  - Stamps in paediatrics: Breast feeding.

PMID- 10648361
TI  - A clinical comparison of SIDS and explained sudden infant deaths: how healthy and
      how normal? CESDI SUDI Research Group. Confidential Inquiry into Stillbirths and
      Deaths in Infancy study.
AB  - OBJECTIVES: To compare the clinical characteristics associated with sudden infant
      death syndrome (SIDS) and explained sudden unexpected deaths in infancy (SUDI).
      DESIGN: Three year population based, case control study with parental interviews
      for each death and four age matched controls. SETTING: Five regions in England
      (population, > 17 million; live births, > 470,000). SUBJECTS: SIDS: 325 infants;
      explained SUDI: 72 infants; controls: 1,588 infants. RESULTS: In the univariate
      analysis, all the clinical features and health markers at birth, after discharge
      from hospital, during life, and shortly before death, significant among the
      infants with SIDS were in the same direction among the infants who died of
      explained SUDI. In the multivariate analysis, at least one apparent life
      threatening event had been experienced by more of the infants who died than in
      controls (SIDS: 12% v 3% controls; odds ratio (OR) = 2.55; 95% confidence
      interval (CI), 1.02 to 6.41; explained SUDI: 15% v 4% controls; OR = 16.81; 95%
      CI, 2.52 to 112.30). Using a retrospective illness scoring system based on "Baby
      Check", both index groups showed significant markers of illness in the last 24
      hours (SIDS: 22% v 8% controls; OR = 4.17; 95% CI, 1.88 to 9.24; explained SUDI:
      49% v 8% controls; OR = 31.20; 95% CI, 6.93 to 140.5). CONCLUSIONS: The clinical
      characteristics of SIDS and explained SUDI are similar. Baby Check might help
      identify seriously ill babies at risk of sudden death, particularly in high risk
      infants.

PMID- 10648362
TI  - Body index measurements in 1996-7 compared with 1980.
AB  - OBJECTIVES: To compare the distribution of body mass index (BMI) in a national
      representative study in The Netherlands in 1996-7 with that from a study in 1980.
      METHODS: Cross sectional data on height, weight, and demographics of 14 500 boys
      and girls of Dutch origin, aged 0-21 years, were collected from 1996 to 1997. BMI
      references were derived using the LMS method. The 90th, 50th, and 10th BMI
      centiles of the 1980 study were used as baseline. Association of demographic
      variables with BMI-SDS was assessed by ANOVA. RESULTS: BMI age reference charts
      were constructed. From 3 years of age onwards 14-22% of the children exceeded the
      90th centile of 1980, 52-60% the 50th centile, and 92-95% the 10th centile. BMI
      was related to region, educational level of parents (negatively) and family size
      (negatively). The -0.9, +1.1, and +2.3 SD lines in 1996-7 corresponded to the
      adult cut off points of 20, 25, and 30 kg/m(2) recommended by the World Health
      Organisation/European childhood obesity group. CONCLUSION: BMI age references
      have increased in the past 17 years. Therefore, strategies to prevent obesity in
      childhood should be a priority in child public health.

PMID- 10648363
TI  - Social, economic, and political context of parenting.

PMID- 10648364
TI  - Genetics of childhood epilepsy.

PMID- 10648365
TI  - Randomised placebo controlled trial of nebulised corticosteroids in acute
      respiratory syncytial viral bronchiolitis.
AB  - OBJECTIVE: To evaluate short and long term effects of giving nebulised budesonide
      early in respiratory syncytial viral (RSV) bronchiolitis. DESIGN: A multicentre
      randomised double blind placebo controlled trial. SUBJECTS: Infants admitted to
      hospital with their first episode of RSV positive bronchiolitis. INTERVENTION:
      Randomisation to receive either 1 mg of nebulised budesonide (Bud) or placebo
      (Pla) twice daily from admission until 2 weeks after discharge. Follow up was for
      12 months. MAIN OUTCOME MEASURES: Duration of hospital admission, time taken to
      become symptom free, re-admission rates, general practitioner consultation rates,
      and use of anti-wheeze medication during follow up. RESULTS: 161 infants were
      studied. Both arms were similar with respect to initial clinical severity, age,
      sex, socioeconomic class, and tobacco exposure. Median time from first
      nebulisation to discharge: Bud and Pla, 2 days. Median number of days for 50% of
      infants to be symptom free for 48 hours: Bud, 10 days; Pla, 12 days. Respiratory
      re-admission rates in the 12 month follow up: Bud, 16%; Pla, 18%; median
      difference (95% confidence interval (CI)), -2 (-14 to 10). Median respiratory
      related general practitioner attendances: Bud, 4.0; Pla, 4.5; median difference
      (95% CI), -1 (-2 to 0). Percentage of infants receiving at least one prescription
      for anti-wheeze medication during follow up, corticosteroids: Bud, 50%; Pla, 60%;
      difference (95% CI), -10 (-26 to 6); bronchodilators: Bud, 60%; Pla, 67%;
      difference (95% CI), -7 (-22 to 8). CONCLUSIONS: There are no short or long term
      clinical benefits from the administration of nebulised corticosteroids in the
      acute phase of RSV bronchiolitis.

PMID- 10648366
TI  - Gastrointestinal symptoms in patients with asthma.
AB  - AIMS: Minor gastrointestinal abnormalities have been reported in children with
      asthma, but the prevalence of gastrointestinal symptoms in these children has not
      been studied. METHODS: 75 children with bronchial asthma and an age and sex
      matched control group were recruited. Parents completed a questionnaire on
      gastrointestinal symptoms and on asthma. Weight and height were measured; a
      clinical evaluation of asthma was undertaken and skin prick tests were performed.
      RESULTS: Children with asthma had a significantly greater frequency of
      gastrointestinal symptoms, particularly diarrhoea, vomiting, and abdominal pain,
      than did controls. Gastrointestinal symptoms were slightly more common in
      children with atopic symptoms other than asthma, or with positive skin prick
      tests to foods. There was no association between current gastrointestinal
      symptoms and medications or attacks of asthma. CONCLUSIONS: The occurrence of
      gastrointestinal symptoms appears to be common in children with asthma. These
      symptoms might be caused by an atopic gastroenteropathy, which might play a part
      in the pathogenesis of asthma in some cases.

PMID- 10648367
TI  - Helicobacter pylori infection with iron deficiency anaemia and subnormal growth
      at puberty.
AB  - The purpose of this study was to determine whether Helicobacter pylori infection
      can contribute to growth deficit, especially in pubescent children who need large
      amounts of iron for growth. A structured questionnaire was sent to the parents of
      532 healthy children aged 10 to 15 years (mean 12.9) to obtain demographic
      information on the parents and the environment. Of the 532 questionnaires sent
      out, 375 (70.5%; 170 girls and 205 boys) were returned. After collecting blood
      samples from participants, haemoglobin, serum iron, total iron binding capacity,
      serum ferritin, and serum IgG antibodies to H pylori were measured. The effects
      of risk factors such as H pylori infection, iron deficiency anaemia, sex,
      socioeconomic status, type of house, and crowding index on growth were analysed
      using multiple regression analysis. Of 63 H pylori positive children, 18 (28.6%)
      were below the 25th centile values for height, compared with 63 of 312 (20.2%) H
      pylori negative children. The prevalence rate of H pylori infection was 15.5% (53
      of 343) in children without iron deficiency anaemia and 31.3% (10 of 32) in those
      affected. The relative risk of short stature was 2.2 (95% confidence interval
      (CI), 1.0 to 4.8) for iron deficiency anaemia, and 1.4 (95% CI, 0.8 to 2.4) for H
      pylori infection. The mean height was significantly lower in the group having
      both H pylori infection and iron deficiency anaemia. Therefore, H pylori
      infection accompanied by iron deficiency anaemia, rather than H pylori infection
      per se, might delay pubertal growth.

PMID- 10648368
TI  - Periodic fever syndrome

PMID- 10648369
TI  - Immunisation against varicella in end stage and pre-end stage renal failure.
      Trans-Pennine Paediatric Nephrology Study Group.
AB  - OBJECTIVES: To investigate the seroconversion rate and duration of persistence of
      protective antibody titres after varicella immunisation in children with renal
      failure. DESIGN: 32 children (25 end stage and 7 pre-end stage renal failure)
      were immunised using 2 x 2,000 plaque forming unit doses of varicella vaccine 3
      months apart. Varicella antibody titres were measured by enzyme linked
      immunosorbent assay. RESULTS: All children initially seroconverted after
      immunisation. At a mean follow up of 20.3 months, 23 of 28 had protective
      antibody titres, 4 children having died of unrelated causes. Two children
      required a third booster dose. 11 children underwent renal transplantation; 10
      had protective titres at the time of transplantation and, at a mean of 23.4
      months after immunisation, 6 currently have protective titres. Minor side effects
      occurred after 11 vaccine doses in 9 children. No child developed varicella,
      despite 10 clear episodes of exposure to the wild-type virus. CONCLUSIONS:
      Varicella immunisation in children with end stage and pre-end stage renal failure
      results in a high rate of seroconversion and persistence of protective antibody
      titres. More widespread use of the vaccine before renal transplantation is
      recommended.

PMID- 10648370
TI  - Unsuspected Pneumocystis carinii pneumonia at presentation of severe primary
      immunodeficiency.
AB  - BACKGROUND: Pneumocystis carinii is an important pathogen in immunodeficiency but
      may be an unrecognised cause of respiratory compromise. OBJECTIVES: To ascertain
      the incidence of P carinii pneumonia (PCP) at presentation of severe combined
      immunodeficiency (SCID), whether it had been diagnosed, and the effect of
      treatment on outcome. SETTING: The supraregional paediatric bone marrow
      transplant unit for primary immunodeficiencies at Newcastle General Hospital.
      METHODS: Retrospective case note review of infants referred with a diagnosis of
      SCID from 1992 to 1998. RESULTS: Ten of 50 infants had PCP at presentation; only
      one was diagnosed before transfer. Eight were diagnosed by bronchoalveolar lavage
      and two by lung biopsy. In only one was P carinii identified in nasopharyngeal
      secretions. Five required ventilation for respiratory failure but all were
      successfully treated with co-trimoxazole and methylprednisolone with or without
      nebulised budesonide. Nine survived to bone marrow transplantation and four are
      long term survivors after bone marrow transplantation; no deaths were related to
      PCP. CONCLUSIONS: PCP is a common presenting feature of SCID but is rarely
      recognised. Bronchoalveolar lavage or lung biopsy are needed for diagnosis.
      Treatment with co-trimoxazole is highly successful.

PMID- 10648371
TI  - A familial case of pulmonary arterial sequestration.
AB  - The cases of a mother and infant son are reported, both with a rare type of
      pulmonary sequestration where the arterial supply to the lung arises from the
      systemic circulation. This is a familial case of arterial sequestration. In both
      patients, the lung parenchyma was radiologically normal.

PMID- 10648372
TI  - Controversy: Sedation of children for magnetic resonance imaging.

PMID- 10648373
TI  - Cerebral blood flow during vasovagal syncope induced by active standing or head
      up tilt.
AB  - BACKGROUND: Vasovagal syncope is usually associated with a sudden drop of blood
      pressure and/or heart rate. However, occasionally the symptoms of syncope induced
      by orthostatic stress testing are not associated with obvious haemodynamic
      changes. The mechanisms of syncope in these patients are not clear. AIM: To
      evaluate changes in cerebral blood flow velocities during orthostatic stress
      testing in children and adolescents with vasovagal syncope. METHODS:
      Electrocardiogram, instantaneous arterial blood pressure, and right middle
      cerebral artery blood flow velocity were recorded at rest, during active
      standing, and 80 degrees head up tilt. 32 children and adolescents aged between 7
      and 18 years with a history of repeated vasovagal syncope and 23 healthy control
      subjects were studied. RESULTS: Presyncope occurred in 10 patients during
      standing, and 13 patients during head up tilt. None of the controls had symptoms
      during the test. The transcranial Doppler study showed that the symptoms were
      associated with significant decreases of diastolic cerebral blood flow velocity
      and an increase of pulsatility. There was no significant change of the systolic
      cerebral blood flow velocity. The changes of cerebral blood flow velocities
      occurred in all episodes of presyncope, including those not associated with
      severe drop of blood pressure or heart rate. CONCLUSIONS: Diastolic cerebral
      blood flow velocity decreased significantly during episodes of presyncope induced
      by orthostatic stress. Impairment of autoregulation of cerebral blood flow might
      play an important role in the pathophysiology of syncope.

PMID- 10648374
TI  - Making human cells make tumours

PMID- 10648375
TI  - Whole body air displacement plethysmography compared with hydrodensitometry for
      body composition analysis.
AB  - AIMS: To assess the acceptability and feasibility of whole body air displacement
      plethysmography in children and to determine its precision and agreement with
      hydrodensitometry, an appropriate reference method. METHODS: Age specific two
      component model equations were used to predict fat mass from body density in 22
      children aged 8-12 years and in 10 adults for comparison of methods. Precision
      for each method was established from duplicate measurements. RESULTS:
      Plethysmography was accepted more readily than hydrodensitometry (100% v 69%
      provided duplicate measurements). Precision for fat mass in children was 0.38 kg
      by plethysmography and 0.68 kg by hydrodensitometry, and results were similar in
      adults. The mean (SD) fat mass in children was 6.9 kg (4.0) and 6.7 kg (4. 2) by
      plethysmography and hydrodensitometry, respectively, but 95% limits of agreement
      between methods were large (-4.1 kg to 3.5 kg fat). CONCLUSION: Plethysmography
      was more readily accepted and had better precision than hydrodensitometry. It
      also provided similar body composition results for the group but not for all
      individual children.

PMID- 10648376
TI  - Interleukin 8 in middle ear fluid during acute otitis media: correlation with
      aetiology and bacterial eradication.
AB  - OBJECTIVES: To study the concentration of interleukin 8 (IL-8) in the middle ear
      fluid of children with acute otitis media and the association between IL-8
      concentrations, aetiology of acute otitis media, and bacteriological
      sterilisation. STUDY DESIGN: Middle ear fluid was obtained by tympanocentesis at
      enrollment (day 1) and on day 4-5 in 81 children aged 3-36 months with acute
      otitis media who received antibiotic treatment. IL-8 concentrations were measured
      by enzyme linked immunosorbent assay. RESULTS: 101 samples were obtained on day 1
      and 47 samples on day 4-5. 94 pathogens were isolated in 79 of 101 samples
      obtained on day 1: 56 Haemophilus influenzae, 35 Streptococcus pneumoniae, 2
      Moraxella catarrhalis, and 1 Streptococcus pyogenes. Among 40 paired, initially
      culture positive samples, sterilisation was achieved on day 4-5 in 22 but not in
      18 (13 H influenzae, 2 S pneumoniae, and 3 H influenzae and S pneumoniae
      concomitantly). IL-8 was detected in 96 of 101 and 46 of 47 samples obtained on
      days 1 and 4-5, respectively. Mean (SD) IL-8 concentration on day 1 was
      significantly higher in culture positive than in negative samples (12,636
      (23,317) v 5,920 (7,080) pg/ml). In paired samples, IL-8 concentration fell in 12
      of 22 ears in which sterilisation was achieved and in 9 of 21 ears with
      persistent or new infection. Mean (SD) IL-8 concentrations on day 4-5 were
      significantly higher in culture positive than in negative samples (15,420
      (15,418) v 6,695 (5,092) pg/ml). CONCLUSIONS: Higher IL-8 concentrations are
      found in culture positive middle ear fluid in acute otitis media. Bacterial
      eradication is associated with a fall in these concentrations.

PMID- 10648377
TI  - Effect of oral antibiotics on intestinal production of propionic acid.
AB  - BACKGROUND: Propionic acid derived from colonic bacterial fermentation
      contributes substantially to overall propionate load in children with disorders
      of propionate metabolism, and its reduction is important for adequate metabolic
      control. AIMS: To evaluate the in vitro and in vivo effects of antibiotic
      treatment on propionate production by colonic bacteria, and plasma propionate
      concentrations in a child with propionic acidaemia. METHODS: In vitro
      fermentation techniques were used to study the effects of addition of antibiotics
      (metronidazole, clindamycin, erythromycin, and vancomycin) on net faecal
      production of short chain fatty acids including propionic acid. Courses of oral
      antibiotics of 7 days duration were used to assess the in vivo effects on faecal
      propionate production and metabolic control including plasma propionate
      concentrations. RESULTS: Metronidazole produced the largest and most consistent
      reduction (77-84%) in the production in vitro of propionate from faecal
      homogenates. Oral administration of metronidazole reduced faecal propionate
      production by 43% within 24 hours of treatment; a 7 day course virtually
      eliminated it for the next 3 weeks. These reductions were accompanied by
      substantially lowered plasma propionate concentrations during the same period.
      CONCLUSIONS: Intermittent courses of oral metronidazole might be as effective as
      continuous treatment in reducing gut propionate production in children with
      disorders of propionate metabolism.

PMID- 10648378
TI  - A simple chart to identify non-familial short stature.
AB  - OBJECTIVE: To develop a chart to identify non-familial short stature. DESIGN: A
      height chart that adjusts for maternal, paternal, midparental, or sibling height
      based on the British 1990 height reference. MAIN OUTCOME MEASURE: Height between
      2 and 9 years of age. RESULTS: The chart identifies children whose height is
      below the familially adjusted 0.4th centile, assuming a correlation of 0.4
      between child height standard deviation score (SDS) and familial height SDS. The
      adjustment can be for parents, either alone or together, or for a sibling aged 2
      9 years. The chart identifies about 2 children/1,000 over and above the 4/1,000
      identified by the unconditional 0.4th centile. CONCLUSION: The chart should be a
      useful addition to screening programmes for short stature.

PMID- 10648379
TI  - Guidelines for the ethical conduct of medical research involving children. Royal
      College of Paediatrics, Child Health: Ethics Advisory Committee.

PMID- 10648380
TI  - In vivo inhibition by a site-specific catalytic RNA subunit of RNase P designed
      against the BCR-ABL oncogenic products: a novel approach for cancer treatment.
AB  - One major obstacle to the effective treatment of cancer is to distinguish between
      tumor cells and normal cells. The chimeric molecules created by cancer-associated
      chromosomal abnormalities are ideal therapeutic targets because they are unique
      to the disease. We describe the use of a novel approach based on the catalytic
      RNA subunit of RNase P to destroy specifically the tumor-specific fusion genes
      created as a result of chromosome abnormalities. Using as a target model the
      abnormal BCR-ABL p190 and p210 products, we constructed M1-RNA with guide
      sequences that recognized the oncogenic messengers at the fusion point (M1-p190
      GS and M1-p210-GS). To test the effectiveness and the specificity of M1-p190-GS
      and M1-p210-GS, we studied in vitro and in vivo effects of these RNA enzymes
      against BCR-ABL(p190) and BCR-ABL(p210), bearing in mind that both fusion genes
      share the ABL sequence but differ in the sequence coming from the BCR gene. We
      showed that M1-p190-GS and M1-p210-GS can act as sequence-specific endonucleases
      and can exclusively cleave target RNA that forms a base pair with the guide
      sequence (GS). We also demonstrated that when M1-p190-GS and M1-p210-GS were
      expressed in proper mammalian cell models, they abolished the effect of BCR-ABL
      by specifically decreasing the amount of the target BCR-ABL mRNA and preventing
      the function of the BCR-ABL oncogenes. These data clearly demonstrate the
      usefulness of the catalytic activity of M1-GS RNA to cleave specifically the
      chimeric molecules created by chromosomal abnormalities in human cancer and to
      represent a novel approach to cancer treatment.

PMID- 10648381
TI  - Large deletions at the t(9;22) breakpoint are common and may identify a poor
      prognosis subgroup of patients with chronic myeloid leukemia.
AB  - The hallmark of chronic myeloid leukemia (CML) is the BCR-ABL fusion gene, which
      is usually formed as a result of the t(9;22) translocation. Patients with CML
      show considerable heterogeneity both in their presenting clinical features and in
      the time taken for evolution to blast crisis. In this study, metaphase
      fluorescence in situ hybridization showed that a substantial minority of patients
      with CML had large deletions adjacent to the translocation breakpoint on the
      derivative 9 chromosome, on the additional partner chromosome in variant
      translocations, or on both. The deletions spanned up to several megabases, had
      variable breakpoints, and could be detected by microsatellite polymerase chain
      reaction in unfractionated bone marrow and purified peripheral blood
      granulocytes. The deletions were likely to occur early and possibly at the time
      of the Philadelphia (Ph) chromosome translocation: deletions were detected at
      diagnosis in 11 patients, were found in all Ph-positive metaphases, and were more
      prevalent in patients with variant Ph chromosomes. Kaplan-Meier analysis showed a
      median survival time of 36 months in patients with a deletion; patients without a
      detectable deletion survived > 90 months. The survival-time difference was
      significant on log-rank analysis (P =. 006). Multivariate analysis demonstrated
      that the prognostic importance of deletion status was independent of age, sex,
      percentage of peripheral blood blasts, and platelet count. Our data therefore
      suggest that an apparently simple, balanced translocation may result not only in
      the generation of a dominantly acting fusion oncogene but also in the loss of one
      or more genes that influence disease progression. (Blood. 2000;95:738-743)

PMID- 10648382
TI  - CREB-binding protein and p300: molecular integrators of hematopoietic
      transcription.

PMID- 10648383
TI  - Chemokine SDF-1 enhances circulating CD34(+) cell proliferation in synergy with
      cytokines: possible role in progenitor survival.
AB  - The chemokine stromal cell-derived factor-1 (SDF-1), and its receptor, CXCR-4,
      have been implicated in the homing and mobilization of human CD34(+) cells. We
      show here that SDF-1 may also be involved in hematopoiesis, promoting the
      proliferation of human CD34(+) cells purified from normal adult peripheral blood
      (PB). CXCR-4 was expressed on PB CD34(+) cells. The amount of CXCR-4 on PB
      CD34(+) cells was 10 times higher when CD34(+) cells were purified following
      overnight incubation. CXCR-4 overexpression was correlated with a primitive PB
      CD34(+) cell subset defined by a CD34(high) CD38(low)CD71(low)c-Kit(low)Thy-1(+)
      antigenic profile. The functional significance of CXCR-4 expression was
      ascertained by assessing the promoting effect of SDF-1alpha on cell cycle,
      proliferation, and colony formation. SDF-1 alone increased the percentage of
      CD34(+) cells in the S+G(2)/M phases and sustained their survival. In synergy
      with cytokines, SDF-1 increased PB CD34(+) and CD34(high)CD38(low) cell expansion
      and colony formation. SDF-1 also stimulated the growth of colonies derived from
      primitive progenitors released from quiescence by anti-TGF-beta treatment. Thus,
      our results shed new light on the potential role of this chemokine in the stem
      cell engraftment process, which involves migration, adhesion, and proliferation.
      Furthermore, both adhesion-induced CXCR-4 overexpression and SDF-1 stimulating
      activity may be of clinical relevance for improving cell therapy settings in stem
      cell transplantation.

PMID- 10648384
TI  - Stromal cell-derived factor-1 (SDF-1) acts together with thrombopoietin to
      enhance the development of megakaryocytic progenitor cells (CFU-MK).
AB  - Stromal cell-derived factor-1 (SDF-1) is a CXC chemokine that acts as a
      stimulator of pre-B lymphocyte cell growth and as a chemoattractant for T cells,
      monocytes, and hematopoietic stem cells. More recent studies also suggest that
      megakaryocytes migrate in response to SDF-1. Because genetic elimination of SDF-1
      or its receptor lead to marrow aplasia, we investigated the effect of SDF-1 on
      megakaryocyte progenitors (colony-forming units-megakaryocyte [CFU-MK]). We
      report that SDF-1 augments the growth of CFU-MK from whole murine bone marrow
      cells when combined with thrombopoietin (TPO). The addition of SDF-1 to
      interleukin-3 (IL-3) or stem cell factor (SCF) had no effect. Specific
      antagonists for CXCR4 (the sole receptor for SDF-1), T22, and 1-9 (P2G) SDF-1
      reduced megakaryocyte colony growth induced by TPO alone, suggesting that many
      culture systems contain endogenous levels of the chemokine that contributes to
      the TPO effect. To examine whether SDF-1 has direct effects on CFU-MK, we
      developed a new protocol to purify megakaryocyte progenitors. CFU-MK were highly
      enriched in CD41(high) c-kit(high) cells generated from lineage-depleted TPO
      primed marrow cells. Because the growth-promoting effects of SDF-1 were also
      observed when highly purified populations of CFU-MK were tested in serum-free
      cultures, these results suggest that SDF-1 directly promotes the proliferation of
      megakaryocytic progenitors in the presence of TPO, and in this way contributes to
      the favorable effects of the bone marrow microenvironment on megakaryocyte
      development.

PMID- 10648385
TI  - Adaptor proteins CRK and CRKL associate with the serine/threonine protein kinase
      GCKR promoting GCKR and SAPK activation.
AB  - STE20-related kinases play significant regulatory roles in a range of cellular
      responses to environmental stimuli. GCKR (also referred to as KHS1) is a
      serine/threonine protein kinase that has an STE20-like protein kinase domain and
      that stimulates the stress-activated protein kinase (SAPK, also referred to as
      Jun kinase or JNK) pathway. GCKR has a large C-terminal regulatory domain that
      provides sites for interactions with other proteins. Adaptor proteins mediate the
      interactions between signaling molecules. In this study we showed that the
      adaptor proteins Crk and CrkL associated with GCKR. When Crk-I, Crk-II, or CrkL
      was transiently expressed in HEK 293T cells along with GCKR, each
      coimmunoprecipitated with GCKR. Furthermore, in the Bcr-Abl transformed cell
      line, K562 endogenous GCKR and CrkL coimmunoprecipitated, indicating a
      constitutive association. Detection of the CrkL-GCKR interaction required the SH3
      domains of CrkL and 2 regions in GCKR-1 between amino acids 387 and 395 that
      contains a consensus SH3 binding motif and the other between amino acids 599 and
      696. Crk or CrkL overexpression increased GCKR catalytic activity. A dominant
      negative form of Ras abolished Crk- or CrkL-induced GCKR activation, suggesting a
      dependence on Ras activation for their activation of GCKR. Finally, we showed
      impairment of the known ability of CrkL to activate the SAPK pathway by a
      catalytically inactive form of GCKR or by a GCKR antisense construct. Thus, GCKR
      associates with other proteins through interactions mediated by SH2/SH3 adaptor
      proteins, which can lead to GCKR and SAPK activation.

PMID- 10648386
TI  - Prognosis of follicular lymphoma: a predictive model based on a retrospective
      analysis of 987 cases. Intergruppo Italiano Linfomi.
AB  - Patients (n-987) with a histologically confirmed diagnosis of follicular lymphoma
      were studied with the aim of developing a prognostic model specifically devised
      for this type of lymphoma. We collected information on age, sex, Ann Arbor stage,
      number of extranodal disease sites, bone marrow (BM) involvement, bulky disease,
      B symptom criteria (fever, night sweats, and weight loss), performance status
      (PS), serum lactate dehydrogenase (LDH) level, serum albumin level, hemoglobin
      level, and erythrocyte sedimentation rate (ESR). In the training sample of 429
      patients with complete data, multivariate analysis showed that age, sex, number
      of extranodal sites, B symptoms, serum LDH level, and ESR were factors predictive
      for overall survival. Using these 6 variables, a prognostic model was devised to
      identify 3 groups at different risk. The 5- and 10-year survival rate was 90% and
      65% for patients at low risk, respectively; 75% and 54% for patients at
      intermediate risk; and 38% and 11% for those at high risk (log-rank test, 86.62;
      P <. 0001). The model was also predictive (P =.0001) in the validation sample of
      265 patients with complete data only for the 6 variables used in the development
      of the model and even in the group of 210 patients from the validation sample
      uniformly treated with doxorubicin-containing regimens (P =.0001). The prognostic
      model appears to be very useful in identifying patients with follicular lymphoma
      at low, intermediate, or high risk.

PMID- 10648387
TI  - Rapid molecular response during early induction chemotherapy predicts a good
      outcome in childhood acute lymphoblastic leukemia.
AB  - Early response to therapy is an independent prognostic factor in childhood acute
      lymphoblastic leukemia. Although most patients have rapid early responses, as
      detected by morphology, 15% to 20% of patients have relapses. The authors
      evaluated residual disease by molecular methods on day 15 of minimal residual
      disease (MRD) therapy and compared these data with their recently established MRD
      based risk stratification, defined by MRD levels 5 weeks after induction
      treatment and before consolidation. All 68 children treated according to current
      Berlin-Frankfurt-Munster (BFM) protocols went into morphologically complete
      remission after induction. There was a significant difference in outcome between
      children with rapid disease clearance and those with high levels of day-15 MRD (P
      =.035). Among patients with high levels of day-15 MRD, only the MRD-based risk
      stratification was predictive of the outcome. All patients with negative or low
      day-15 MRD had excellent prognoses and were in the MRD-based low-risk group.
      Thus, after only 2 weeks of treatment, the authors were able to identify a
      patient population of 20% who may benefit from the least intensive treatment.

PMID- 10648388
TI  - Thrombopoietin induces rapid resolution of thrombocytopenia after orthotopic
      liver transplantation through increased platelet production.
AB  - Thrombopoietin (TPO) deficiency has been proposed as an important etiologic
      factor for thrombocytopenia in advanced-stage liver disease. To clarify the
      contributions of platelet production, platelet consumption, coagulation
      activation, and splenic sequestration to thrombocytopenia in liver disease, we
      studied TPO serum levels and markers of platelet production, platelet activation,
      and coagulation activation before and 14 days after orthotopic liver
      transplantation (OLT) in 18 patients with advanced liver cirrhosis.
      Thrombocytopenia before transplantation occurred with low-normal serum levels of
      TPO, normal levels of platelet and coagulation activation markers, and no
      increase in bone marrow production of platelets. TPO serum levels increased
      significantly on the first day after OLT, preceding the increase of reticulated
      platelets by 3 days and peripheral platelets by 5 days. Normalization of the
      peripheral platelet count occurred in most patients within 14 days of OLT,
      irrespective of the change in spleen size assessed by computed tomography
      volumetry. Normalization of platelet counts was not hampered by a certain degree
      of platelet activation observed during the steepest increase in the peripheral
      platelet count. Bone marrow production of platelets increased significantly
      within 2 weeks of transplantation. Low TPO serum levels with low platelet counts
      and without platelet consumption suggests low TPO production in end-stage liver
      disease. The rapid increase in TPO serum levels after transplantation induces an
      increase in the bone marrow production of platelets. Decreased TPO production in
      the cirrhotic liver is an important etiologic factor for thrombocytopenia in
      liver disease that is rapidly reversed by transplantation.

PMID- 10648389
TI  - Mucosa-associated lymphoid tissue lymphoma is a disseminated disease in one third
      of 158 patients analyzed.
AB  - Mucosa-associated lymphoid tissue-derived lymphoma (MALT lymphoma) is usually a
      very indolent lymphoma, described as localized at diagnosis and remaining
      localized for a prolonged period; dissemination occurs only after a long course
      of evolution. In our database, out of 158 patients with MALT lymphoma, 54
      patients presented with a disseminated disease at diagnosis. Of these 54
      patients, 17 patients (30%) presented with multiple involved mucosal sites; 37
      patients (70%) presented with 1 involved mucosal site, but in 23 of these
      patients (44%), dissemination of the disease was due to bone marrow involvement;
      12 patients (22%) had multiple lymph node involvement; and 2 patients (4%) had
      nonmucosal site involvement. No significant difference in clinical
      characteristics (sex, age, performance status, B symptoms) and biological
      parameters (hemoglobin [Hb] and lactate dehydrogenase levels) was observed
      between localized or disseminated MALT-lymphoma patients. Only beta2
      microglobulin level was significantly more elevated in disseminated disease
      patients than in localized disease patients. Complete response after the first
      treatment was achieved in 74% of the patients, and there was no difference
      between the 2 groups. With a median follow-up of 4 years, the estimated 5- and 10
      year overall survival rates were similar in the 2 groups, 86% and 80%,
      respectively. The median freedom-from-progression survival was 5.6 years for all
      patients, surprisingly without any difference between localized and disseminated
      MALT-lymphoma patients. In conclusion, MALT lymphoma is an indolent disease but
      presents as a disseminated disease in one-third of the cases at diagnosis. The
      dissemination does not change the outcome of the patients.

PMID- 10648390
TI  - Epstein-Barr virus (EBV) load in bone marrow transplant recipients at risk to
      develop posttransplant lymphoproliferative disease: prophylactic infusion of EBV
      specific cytotoxic T cells.
AB  - A semiquantitative polymerase chain reaction assay was used to monitor the blood
      levels of Epstein-Barr virus (EBV)-DNA in 9 patients receiving allogeneic bone
      marrow transplants (BMT). Four of 5 recipients of HLA-mismatched T-cell-depleted
      grafts showed a 4- to 5-log increase of EBV-DNA within 1 to 3 months after BMT.
      Administration of 2 to 4 infusions of 10(7) EBV-specific cytotoxic T-lymphocytes
      (CTLs)/m(2) starting from the time of maximal virus load resulted in a 2- to 3
      log decrease of virus titers in 3 patients. One patient, who received a T-cell
      culture lacking a major EBV-specific component, progressed to fatal EBV-positive
      lymphoma. Administration of EBV-CTLs before the onset of the EBV-DNA peak
      resulted in stabilization of the virus titers within 2 to 3 logs above the normal
      levels in the fifth patient. A moderate increase of virus titers was also
      detected in 3 of 4 patients receiving unmanipulated HLA-matched grafts, whereas 1
      patient with Wiskott-Aldrich syndrome reached a 5-log increase of EBV-DNA load
      within 70 days after BMT. Our results suggest that a rapid increase of
      circulating EBV-DNA occurs in the absence of EBV-specific T-cell precursors or in
      the presence of congenital immune defects that prevent the reestablishment of
      virus-specific immunity. Prophylactic administration of EBV-CTLs early after BMT
      appears to provide the most effective protection against the development of EBV
      associated lymphoproliferative disease.

PMID- 10648391
TI  - Molecular quantitation of minimal residual disease in acute myeloid leukemia with
      t(8;21) can identify patients in durable remission and predict clinical relapse.
AB  - One of the most common translocations in acute myeloid leukemia (AML) is the
      t(8;21), which produces the fusion gene AML1-MTG8. We have developed a sensitive
      competitive reverse transcriptase-polymerase chain reaction (RT-PCR) assay for
      AML1-MTG8 transcripts, coupled with a competitive RT-PCR for the ABL transcript
      as a control to accurately estimate the level of amplifiable RNA. We have shown
      that AML1-MTG8 and ABL transcripts have equal degradation rates. Thus, this
      method is useful for multicenter studies. We studied 25 patients with t(8;21) AML
      by means of serial analysis done on bone marrow (BM) and peripheral blood (PB)
      samples from 21 patients. Our analysis showed that, in general, a successful
      induction chemotherapy produces a reduction of 2 to 3 log in the level of AML1
      MTG8, followed by a further 2 to 3 log after consolidation/intensification
      chemotherapy. Levels up to 1 x 10(3) and 1 x 10(2) molecules/microg of RNA in BM
      and PB, respectively, were compatible with durable remission. On the other hand,
      5 patients with levels of 0.71 x 10(5) to 2.27 x 10(5) molecules/microg of RNA in
      BM and 2.27 x 10(3) to 2.27 x 10(4) molecules/microg of RNA in PB had hematologic
      relapse within 3 to 6 months. Our data indicate that serial quantitation of AML1
      MTG8 transcripts is useful in identifying patients at high risk of relapse and
      may offer an opportunity for clinical intervention to prevent hematologic
      relapse. This approach was applied successfully in a patient who had an
      allogeneic BM transplantation. We also suggest that PB may be used an alternative
      to BM for quantitating AML1-MTG8 transcripts.

PMID- 10648392
TI  - Sustained high-level expression of full-length human factor VIII and restoration
      of clotting activity in hemophilic mice using a minimal adenovirus vector.
AB  - The successful prophylactic treatment of hemophilia A by frequent infusions of
      plasma concentrates or recombinant factor VIII (hFVIII) indicates that gene
      therapy may be a potential alternative for the treatment of the disease. For
      efficient delivery and long-term expression of the hFVIII gene, a novel minimal
      adenovirus (mini-Ad) vector, MiniAdFVIII, has been developed. The vector is
      devoid of all viral genes and carries the full-length hFVIII cDNA under the
      control of the human 12.5-kb albumin promoter. The MiniAdFVIII vector was
      propagated with the assistance of an ancillary vector in 293 cells and was
      purified by CsCl banding. Sustained expression of hFVIII at physiologic levels
      (100-800 ng/mL) was achieved in mice after a single intravenous injection of
      MiniAdFVIII. The expressed hFVIII had a structure identical to that of
      recombinant hFVIII, as determined by Western blot analysis. The functionality of
      the protein was confirmed by the restoration of blood coagulation capacity in
      MiniAdFVIII-treated hemophilic mice, as determined by tail clipping observations.
      Although antivector or antihuman FVIII antibodies at various levels were
      detected, long-term expression of the transgene was observed in the mice that did
      not generate antibodies against the transgene product. The vector DNA persisted
      in the liver tissues of the mice with long-term expression. No significant
      histopathologic findings or toxicities were observed to be associated with the
      vector in the MiniAdFVIII-treated C57BL/6 mice. These results support the further
      development of MiniAdFVIII for clinical trials toward the treatment of hemophilia
      A.

PMID- 10648393
TI  - Long-term multilineage expression in peripheral blood from a Moloney murine
      leukemia virus vector after serial transplantation of transduced bone marrow
      cells.
AB  - Using a mouse bone marrow transplantation model, the authors evaluated a Moloney
      murine leukemia virus (MMLV)-based vector encoding 2 anti-human immunodeficiency
      virus genes for long-term expression in blood cells. The vector also encoded the
      human nerve growth factor receptor (NGFR) to serve as a cell-surface marker for
      in vivo tracking of transduced cells. NGFR(+) cells were detected in blood
      leukocytes of all mice (n=16; range 16%-45%) 4 to 5 weeks after transplantation
      and were repeatedly detected in blood erythrocytes, platelets, monocytes,
      granulocytes, T cells, and B cells of all mice for up to 8 months. Transgene
      expression in individual mice was not blocked in the various cell lineages of the
      peripheral blood and spleen, in several stages of T-cell maturation in the
      thymus, or in the Lin(-/lo)Sca-1(+) and c-kit(+)Sca-1(+) subsets of bone marrow
      cells highly enriched for long-term multilineage-reconstituting activity. Serial
      transplantation of purified NGFR(+)c-kit(+)Sca-1(+) bone marrow cells resulted in
      the reconstitution of multilineage hematopoiesis by donor type NGFR(+) cells in
      all engrafted mice. The authors concluded that MMLV-based vectors were capable of
      efficient and sustained transgene expression in multiple lineages of peripheral
      blood cells and hematopoietic organs and in hematopoietic stem cell (HSC)
      populations. Differentiation of engrafting HSC to peripheral blood cells is not
      necessarily associated with dramatic suppression of retroviral gene expression.
      In light of earlier studies showing that vector elements other than the long
      terminal repeat enhancer, promoter, and primer binding site can have an impact on
      long-term transgene expression, these findings accentuate the importance of
      empirically testing retroviral vectors to determine lasting in vivo expression.

PMID- 10648394
TI  - Myelopoietin, an engineered chimeric IL-3 and G-CSF receptor agonist, stimulates
      multilineage hematopoietic recovery in a nonhuman primate model of radiation
      induced myelosuppression.
AB  - Myelopoietins (MPOs) constitute a family of engineered, chimeric molecules that
      bind and activate the IL-3 and G-CSF receptors on hematopoietic cells. This study
      investigated the in vivo hematopoietic response of rhesus monkeys administered
      MPO after radiation-induced myelosuppression. Animals were total body irradiated
      (TBI) in 2 series, with biologically equivalent doses consisting of either a 700
      cGy dose of Cobalt-60 ((60)Co) gamma-radiation or 600 cGy, 250 kVp x-irradiation.
      First series: On day 1 after 700 cGy irradiation, cohorts of animals were
      subcutaneously (SC) administered MPO at 200 microg/kg/d (n = 4), or 50
      microg/kg/d (n = 2), twice daily, or human serum albumin (HSA) (n = 10). Second
      series: The 600 cGy x-irradiated cohorts of animals were administered either MPO
      at 200 microg/kg/d, in a daily schedule (n = 4) or 0.1% autologous serum (AS),
      daily, SC (n = 11) for 23 days. MPO regardless of administration schedule (twice
      a day or every day) significantly reduced the mean durations of neutropenia
      (absolute neutrophil count [ANC] < 500/microL) and thrombocytopenia (platelet <
      20,000/microL) versus respective control-treated cohorts. Mean neutrophil and
      platelet nadirs were significantly improved and time to recovery for neutrophils
      (ANC to < 500/microL) and platelets (PLT < 20,000/microL) were significantly
      enhanced in the MPO-treated cohorts versus controls. Red cell recovery was
      further improved relative to control-treated cohorts that received whole blood
      transfusions. Significant increases in bone marrow-derived clonogenic activity
      was observed by day 14 after TBI in MPO-treated cohorts versus respective time
      matched controls. Thus, MPO, administered daily was as effective as a twice daily
      schedule for multilineage recovery in nonhuman primates after high-dose,
      radiation-induced myelosuppression.

PMID- 10648395
TI  - Opposing effects of engagement of integrins and stimulation of cytokine receptors
      on cell cycle progression of normal human hematopoietic progenitors.
AB  - We evaluated the effect of beta1-integrin receptor engagement on the expression
      and activity of cell cycle regulatory proteins in CD34(+) cells under conditions
      that mimic the steady-state marrow microenvironment and in the presence of
      supraphysiological concentrations of interleukin-3 (IL3) and stem cell factor
      (SCF). Adhesion of CD34(+) progenitors to fibronectin (FN) was similar whether
      IL3 or SCF was present or absent. Engagement of beta1-integrins blocked S-phase
      entry of CD34(+) cells in the absence of IL3 or SCF, whereas addition of 10 ng/mL
      IL3 or SCF prevented such a block in S-phase entry. In the absence of IL3 or SCF,
      cyclin-E levels were significantly lower and p27(KIP1) levels significantly
      higher in FN-adherent than in FN-nonadherent cells, or than in poly-L-lysine
      (PLL)-adherent or (PLL)-nonadherent cells. Cyclin-dependent-kinase (cdk)-2
      activity was decreased and levels of cyclin-E-cdk2 complexes were lower in FN
      adherent than in PLL-adherent cells. In contrast, cyclin-E and p27(KIP1) protein
      levels and cdk2 activity in cells adherent to FN in the presence of IL3 or SCF
      were similar to those in PLL-adherent and FN-nonadherent or PLL-nonadherent
      cells. In conclusion, under physiological cytokine conditions, integrin
      engagement prevents S-phase entrance of CD34(+) cells, which is associated with
      elevated levels of the contact-dependent cyclin kinase inhibitor p27(KIP1).
      Supraphysiological concentrations of IL3 or SCF prevent p27(KIP1) elevation and
      override the integrin-mediated inhibition of entry into S phase.

PMID- 10648396
TI  - High-resolution tracking of cell division suggests similar cell cycle kinetics of
      hematopoietic stem cells stimulated in vitro and in vivo.
AB  - The kinetics of proliferation of primitive murine bone marrow (BM) cells
      stimulated either in vitro with growth factors (fetal liver tyrosine kinase
      ligand 3 [FL], Steel factor [SF], and interleukin-11 [IL-11], or hyper-IL-6) or
      in vivo by factors active in myeloablated recipients were examined. Cells were
      first labeled with 5- and 6-carboxyfluorescein diacetate succinimidyl ester
      (CFSE) and then incubated overnight prior to isolating CFSE(+) cells. After 2
      more days in culture, more than 90% of the in vivo lymphomyeloid repopulating
      activity was associated with the most fluorescent CFSE(+) cells (ie, cells that
      had not yet divided), although this accounted for only 25% of the repopulating
      stem cells measured in the CFSE(+) "start" population. After a total of 4 days in
      culture (1 day later), 15-fold more stem cells were detected (ie, 4-fold more
      than the day 1 input number), and these had become (and thereafter remained)
      exclusively associated with cells that had divided at least once in vitro. Flow
      cytometric analysis of CFSE(+) cells recovered from the BM of transplanted mice
      indicated that these cells proliferated slightly faster (up to 5 divisions
      completed within 2 days and up to 8 divisions completed within 3 days in vivo
      versus 5 and 7 divisions, respectively, in vitro). FL, SF, and ligands which
      activate gp130 are thus efficient stimulators of transplantable stem cell self
      renewal divisions in vitro. The accompanying failure of these cells to accumulate
      rapidly indicates important changes in their engraftment potential independent of
      accompanying changes in their differentiation status.

PMID- 10648397
TI  - Quantitative PCR analysis of HbF inducers in primary human adult erythroid cells.
AB  - The development and evaluation of drugs to elevate fetal hemoglobin in the
      treatment of the genetic diseases of hemoglobin would be facilitated by the
      availability of reliable cell assays. We have used real-time, quantitative
      polymerase chain reaction (PCR) analyses of globin messenger RNA (mRNA) levels in
      a biphasic, erythropoietin-dependent primary culture system for human adult
      erythroid cells in order to assay compounds for their ability to modulate levels
      of adult (beta) and fetal (gamma) globin mRNA. Complementary DNA synthesized from
      total RNA extracted at timed intervals from aliquots of cells were assayed
      throughout the period that the culture was studied. gamma-globin mRNA levels were
      found to be much lower (less than 1%) than beta-globin mRNA levels. At
      concentrations of agents chosen for minimal effect on cell division, we find that
      the 3 drugs studied, 5-azacytidine (5 micromol/L), hydroxyurea (40 micromol/L),
      and butyric acid (0.5 mmol/L), significantly increase gamma-globin mRNA levels.
      Interestingly, hydroxyurea also had a small stimulatory effect on beta-globin
      mRNA levels, while butyric acid caused a twofold inhibition of beta-globin mRNA
      levels, and 5-azacytidine had little effect on beta-globin mRNA levels. The net
      result of all 3 drugs was to increase the gamma/(gamma + beta) mRNA ratios by
      threefold to fivefold. These data suggest that the mechanism is distinct for each
      drug. The profile of butyric-acid-induced changes on globin gene expression is
      also quite distinct from changes produced by trichostatin A, a known histone
      deacetylase inhibitor. Quantitative PCR analyses of human erythroid cells should
      prove useful for studying the mechanism(s) of action of known inducers of gamma
      globin and identifying new drug candidates.

PMID- 10648398
TI  - Characterization of hematopoietic lineage-specific gene expression by ES cell in
      vitro differentiation induction system.
AB  - The continuous generation of mature blood cells from hematopoietic progenitor
      cells requires a highly complex series of molecular events. To examine lineage
      specific gene expression during the differentiation process, we developed a novel
      method combining LacZ reporter gene analysis with in vitro hematopoietic
      differentiation induction from mouse embryonic stem cells. For a model system
      using this method, we chose the erythroid and megakaryocytic differentiation
      pathways. Although erythroid and megakaryocytic cells possess distinct functional
      and morphologic features, these 2 lineages originate from bipotential erythro
      megakaryocytic progenitors and share common lineage-restricted transcription
      factors. A portion of the 5' flanking region of the human glycoprotein IIb
      (alphaIIb) integrin gene extending from base -598 to base +33 was examined in
      detail. As reported previously, this region is sufficient for megakaryocyte
      specific gene expression. However, previous reports that used human erythro
      megakaryocytic cell lines suggested that one or more negative regulatory regions
      were necessary for megakaryocyte-specific gene expression. Our data clearly
      showed that an approximately 200-base enhancer region extending from -598 to -400
      was sufficient for megakaryocyte-specific gene expression. This experimental
      system has advantages over those using erythro-megakaryocytic cell lines because
      it recapitulates normal hematopoietic cell development and differentiation.
      Furthermore, this system is more efficient than transgenic analysis and can
      easily examine gene expression with null mutations of specific genes.

PMID- 10648399
TI  - PU.1 is required for myeloid-derived but not lymphoid-derived dendritic cells.
AB  - The ets-family transcription factor PU.1 is required for the proper development
      of both myeloid and lymphoid progenitors. We used PU. 1-deficient animals to
      examine the role of PU.1 during dendritic cell development. PU.1(-/-)animals
      produce lymphoid-derived dendritic cells (DC): low-density class II major
      histocompatibility complex [MHC-II(+)] CD11c(+) CD8alpha(+) DEC-205(+). But they
      lack myeloid-derived DC: low-density MHC-II(+) CD11c(+) CD8alpha(-) DEC-205(-).
      PU.1(-/-) embryos also lack progenitors capable of differentiating into myeloid
      DC in response to granulocyte-macrophage colony-stimulating factor plus
      interleukin-4. The appearance of lymphoid DC in developing PU.1(-/-)thymus was
      initially delayed, but this population recovered to wild type (WT) levels upon
      organ culture of isolated thymic lobes. PU. 1(-/-)lymphoid DC were functionally
      equivalent to WT DC for stimulating T-cell proliferation in mixed lymphocyte
      reactions. These results demonstrate that PU.1 is required for the development of
      myeloid DC but not lymphoid DC.

PMID- 10648400
TI  - Structural and functional characterization of the mouse von Willebrand factor
      receptor GPIb-IX with novel monoclonal antibodies.
AB  - Five novel monoclonal antibodies (mAbs; p0p 1-5) were used to characterize the
      structural and functional properties and the in vivo expression of the murine
      GPIb-IX complex (von Willebrand factor receptor). The molecular weights of the
      subunits are similar to the human homologs: GPIbalpha (150 kd), GPIbbeta (25 kd),
      and GPIX (25 kd). Activation of platelets with thrombin or PMA predominantly
      induced shedding of glycocalicin (GC; 130 kd) but only low levels of receptor
      internalization. The GC concentration in normal mouse plasma was found to be at
      least 10 times higher than that described for human plasma (approximately 25
      microg/mL versus 1-2 microg/mL). Two additional cleavage sites for unidentified
      platelet-derived proteases were found on GPIbalpha, as demonstrated by the
      generation of 3 N-terminal fragments during in vitro incubation of washed
      platelets (GC, 60 kd, 45 kd). Occupancy of GPIbalpha with p0p mAbs or F(ab)(2)
      fragments resulted in aggregate formation in vitro and rapid irreversible
      thrombocytopenia in vivo, irrespective of the exact binding epitopes of the
      individual antibodies. GPIb-IX was not detectable immunohistochemically on
      endothelial cells in the major organs under normal or inflammatory conditions.
      The authors conclude that the mouse system might become an interesting model for
      studies on GPIb-IX function and regulation.

PMID- 10648401
TI  - Platelet secretion induced by phorbol esters stimulation is mediated through
      phosphorylation of MARCKS: a MARCKS-derived peptide blocks MARCKS phosphorylation
      and serotonin release without affecting pleckstrin phosphorylation.
AB  - Previous experiments suggest that actin disassembly, perhaps at a specific site,
      is required for platelet secretion. Platelet stimulation by phorbol 12-myristate
      13-acetate (PMA) induced pleckstrin phosphorylation, platelet aggregation, and
      secretion. Inhibition of protein kinase C (PKC) is accompanied by inhibition of
      pleckstrin phosphorylation and serotonin secretion. Here, we demonstrate the
      presence of myristoylated alanine-rich C kinase substrate (MARCKS), another PKC
      substrate, in platelets and its phosphorylation during PMA stimulation. MARCKS is
      known to bind actin and to cross-link actin filaments; the latter is inhibited by
      PKC-induced MARCKS phosphorylation. MARCKS phosphorylation and serotonin release
      from permeabilized platelets have the same time course and were blocked by a
      peptide (MPSD) with the amino acid sequence corresponding to the phosphorylation
      site domain of MARCKS. Pleckstrin and myosin light chain phosphorylation was not
      modified. A peptide (Ala-MPSD) in which the four serine residues of MPSD were
      substituted by alanines was ineffective. These results provide the first evidence
      that MARCKS may play a role in platelet secretion. Moreover, pleckstrin
      phosphorylation has a different time course than that of MARCKS or serotonin
      release and was not modified when MARCKS phosphorylation and serotonin release
      were inhibited, suggesting that pleckstrin is either not directly involved in
      secretion or that it might only be involved upstream in the cascade of events
      leading to exocytosis.

PMID- 10648402
TI  - Requirement of leucine-rich repeats of glycoprotein (GP) Ibalpha for shear
      dependent and static binding of von Willebrand factor to the platelet membrane GP
      Ib-IX-V complex.
AB  - The platelet glycoprotein (GP) Ib-IX-V complex mediates adhesion to von
      Willebrand factor (vWf) in (patho)physiologic thrombus formation. The vWf-binding
      site on GP Ib-IX-V is within the N-terminal 282 residues of GP Ibalpha, which
      consist of an N-terminal flanking sequence (His-1-Ile-35), 7 leucine-rich repeats
      (Leu-36-Ala-200), a C-terminal flank (Phe-201-Gly-268), and a sulfated tyrosine
      sequence (Asp-269-Glu-282). We have used mammalian cell expression of canine
      human chimeras of GP Ibalpha, corresponding to precise structural boundaries, to
      demonstrate the first specific requirement for individual leucine-rich repeats
      for binding of vWf either induced by a modulator, ristocetin, or under
      hydrodynamic flow. Implicit in this approach was that the GP Ibalpha chimeras
      retained a functional conformation, a supposition confirmed by analyzing
      restoration of function to reversed human-canine chimeras and demonstrating that
      all chimeras bound vWf activated by botrocetin, a modulator that is
      indiscriminate between species. Leucine-rich repeats 2, 3, and 4 of GP Ibalpha
      were identified as being critical for vWf adhesion to GP Ib-IX-V.

PMID- 10648403
TI  - Sequential binding of CD11a/CD18 and CD11b/CD18 defines neutrophil capture and
      stable adhesion to intercellular adhesion molecule-1.
AB  - The relative contributions of CD11a/CD18 and CD11b/CD18 to the dynamics and
      strength of neutrophil adhesion to intercellular adhesion molecule (ICAM)-1
      transfected cells were examined over the time course of chemotactic stimulation.
      Suspensions of neutrophils and transfectants were sheared in a cone-plate
      viscometer, and formation of heterotypic aggregates was measured by 2-color flow
      cytometry. The 2-body collision theory was used to compute adhesion efficiency,
      defined as the proportion of collisions between neutrophils and target cells that
      resulted in capture. ICAM-1 surface density and shear rate both regulated
      adhesion efficiency. Target cells expressing approximately 1000 ICAM-1
      sites/microm(2) (I(low)) were captured with an efficiency of 0.15 at 100 s(-1),
      which decreased to zero at 300 s(-1). At 8-fold higher ICAM-1 expression
      (I(high)) corresponding to levels measured on interleukin-1-stimulated
      endothelium, efficiency was 0.3 at 100 s(-1) and remained above background to 900
      s(-1). Shear alone was sufficient for CD11a/CD18-mediated adhesion to ICAM-1, and
      stimulation with formyl-methionyl-leucyl-phenylalanine boosted capture efficiency
      through CD11a/CD18 by 4-fold. In comparison, CD11b/CD18 supported one third of
      this efficiency, but was necessary for aggregate stability over several minutes
      of shear and at shear stresses exceeding 5 dyne/cm(2). Hydrodynamics influenced
      capture efficiency predominantly through the collisional contact duration,
      predicted to be approximately 9 milliseconds for successful capture of I(low) and
      4 milliseconds for I(high). The implication is that an increase in ICAM-1 from
      resting levels to those on inflamed endothelium effectively increases the
      permissible shear in which capture through beta(2)-integrins may occur.
      Neutrophil adhesion to ICAM-1 appears to be a cooperative and sequential process
      of CD11a-dependent capture followed by CD11b-mediated stabilization.

PMID- 10648404
TI  - Molecular mechanisms of platelet exocytosis: role of SNAP-23 and syntaxin 2 in
      dense core granule release.
AB  - To characterize the molecular mechanisms of platelet secretion, we focused on the
      calcium-induced exocytosis of dense core granules. Platelets contain several
      known t-SNAREs (soluble N-ethylmaleimide sensitive factor [NSF] attachment
      protein receptors) such as syntaxins 2, 4, and 7 and SNAP-23 (synaptosomal
      associated protein 23). By using an in vitro exocytosis assay, we have been able
      to assign roles for some of these t-SNAREs in dense core granule release. This
      calcium-induced secretion relies on the SNARE proteins because it is stimulated
      by the addition of recombinant alpha-SNAP and inhibited by a dominant negative
      alpha-SNAP-L294A mutant or by anti-alpha-SNAP and anti-NSF antibodies. SNAP-23
      antibodies and an inhibitory C-terminal SNAP-23 peptide both blocked dense core
      granule release, demonstrating a role for SNAP-23. Unlike other cell types,
      platelets contain a significant pool of soluble SNAP-23, which does not partition
      into Triton X-114. Of the anti-syntaxin antibodies tested, only anti-syntaxin 2
      antibody inhibited dense core granule release. Immunoprecipitation studies showed
      that the 2 t-SNAREs syntaxin 2 and SNAP-23 do form a complex in vivo. These data
      clearly show that SNAPs, NSF, and specific t-SNAREs are used for dense core
      granule release; these data provide a greater understanding of regulated
      exocytosis in platelets.

PMID- 10648405
TI  - Cellular origin and procoagulant properties of microparticles in meningococcal
      sepsis.
AB  - Patients with meningococcal sepsis generally suffer from disseminated
      intravascular coagulation (DIC). The aim of this study was to address whether
      these patients have elevated numbers of circulating microparticles that
      contribute to the development of DIC. Plasma samples from 5 survivors, 2
      nonsurvivors, and 5 healthy volunteers were analyzed for the presence of
      microparticles by flow cytometry. Ongoing coagulation activation in vivo was
      quantified by enzyme-linked immunosorbent assay of plasma prothrombin fragment
      F(1 + 2), and procoagulant properties of microparticles in vitro were estimated
      by thrombin-generation assay. On admission, all patients had increased numbers of
      microparticles originating from platelets or granulocytes when compared with
      controls (P =.004 and P =.008, respectively). Patients had elevated levels of F(1
      + 2) (P =.004), and their microparticles supported thrombin generation more
      strongly in vitro (P =.003) than those of controls. Plasma from the patient with
      the most fulminant disease course and severe DIC contained microparticles that
      expressed both CD14 and tissue factor, and these microparticles demonstrated
      extreme thrombin generation in vitro. We conclude that patients with
      meningococcal sepsis have elevated numbers of circulating microparticles that are
      procoagulant. These findings may suggest a novel therapeutic approach to combat
      clinical conditions with excessive coagulation activation.

PMID- 10648406
TI  - Pharmacokinetic and thrombolytic properties of cysteine-linked polyethylene
      glycol derivatives of staphylokinase.
AB  - Recombinant staphylokinase (SakSTAR) variants obtained by site-directed
      substitution with cysteine, in the core (lysine 96 [Lys96], Lys102, Lys109,
      and/or Lys135) or the NH(2)-terminal region that is released during activation of
      SakSTAR (serine 2 [Ser2] and/or Ser3), were derivatized with thiol-specific
      (ortho-pyridyl-disulfide or maleimide) polyethylene glycol (PEG) molecules with
      molecular weights of 5,000 (P5), 10,000 (P10), or 20,000 (P20). The specific
      activities and thrombolytic potencies in human plasma were unaltered for most
      variants derivatized with PEG (PEGylates), but maleimide PEG derivatives had a
      better temperature stability profile. In hamsters, SakSTAR was cleared at 2.2
      mL/min; variants with 1 P5 molecule were cleared 2-to 5-fold; variants with 2 P5
      or 1 P10 molecules were cleared 10-to 30-fold; and variants with 1 P20 molecule
      were cleared 35-fold slower. A bolus injection induced dose-related lysis of a
      plasma clot, fibrin labeled with 125 iodine ((125)I-fibrin plasma clot), and
      injected into the jugular vein. A 50% clot lysis at 90 minutes required 110
      microg/kg SakSTAR; 50 to 110 microg/kg of core-substitution derivatives with 1
      P5; 25 microg/kg for NH(2)-terminal derivatives with 1 P5; 5 to 25 microg/kg with
      derivatives with 2 P5 or 1 P10; and 7 microg/kg with P20 derivatives. Core
      substitution with 1 or 2 P5 molecules did not significantly reduce the
      immunogenicity of SakSTAR in rabbits. Derivatization of staphylokinase with a
      single PEG molecule allows controllable reduction of the clearance while
      maintaining thrombolytic potency at a reduced dose. This indicates that mono
      PEGylated staphylokinase variants may be used for single intravenous bolus
      injection.

PMID- 10648407
TI  - Proteolytic processing of human coagulation factor IX by plasmin.
AB  - Previous studies have shown that thrombin generation in vivo caused a 92%
      decrease in factor IX (F.IX) activity and the appearance of a cleavage product
      after immunoblotting that comigrated with activated F.IX (F.IXa). Under these
      conditions, the fibrinolytic system was clearly activated, suggesting plasmin may
      have altered F.IX. Thus, the effect(s) of plasmin on human F.IX was determined in
      vitro. Plasmin (50 nM) decreased the 1-stage clotting activity of F.IX (4 microM)
      by 80% and the activity of F.IXa (4 microM) by 50% after 30 minutes at 37 degrees
      C. Plasmin hydrolysis of F.IX yields products of 45, 30, 20, and 14 kd on
      reducing sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and
      2 products of 52 and 14 kd under nonreducing conditions. Plasmin-treated F.IX did
      not bind the active site probe, p-aminobenzamidine, or form an SDS-stable complex
      with antithrombin. It only marginally activated human factor X in the presence of
      phospholipid and activated factor VIII. Although dansyl-Glu-Gly-Arg-chloromethyl
      ketone inactivated-F. IXa inhibited the clotting activity of F.IXa, plasmin
      treated F.IX did not. Plasmin cleaves F.IX after Lys43, Arg145, Arg180, Lys316,
      and Arg318, but F.IXa is not appreciably generated despite cleavage at the 2
      normal activation sites (Arg145 and Arg180). Tissue plasminogen activator
      catalyzed lysis of fibrin formed in human plasma results in generation of the 45-
      and 30-kd fragments of F.IX and decreased F.IX clotting activity. Collectively,
      the results suggest that plasmin is able to down-regulate coagulation by
      inactivating F.IX.

PMID- 10648408
TI  - Expression of VEGFR-2 and AC133 by circulating human CD34(+) cells identifies a
      population of functional endothelial precursors.
AB  - Emerging data suggest that a subset of circulating human CD34(+) cells have
      phenotypic features of endothelial cells. Whether these cells are sloughed mature
      endothelial cells or functional circulating endothelial precursors (CEPs) is not
      known. Using monoclonal antibodies (MoAbs) to the extracellular domain of the
      human vascular endothelial receptor-2 (VEGFR-2), we have shown that 1.2 +/- 0.3%
      of CD34(+) cells isolated from fetal liver (FL), 2 +/- 0.5% from mobilized
      peripheral blood, and 1.4 +/- 0.5% from cord blood were VEGFR-2(+). In addition,
      most CD34(+)VEGFR-2(+) cells express hematopoietic stem cell marker AC133.
      Because mature endothelial cells do not express AC133, coexpression of VEGFR-2
      and AC133 on CD34(+) cells phenotypically identifies a unique population of CEPs.
      CD34(+)VEGFR-2(+) cells express endothelial-specific markers, including VE
      cadherin and E-selectin. Also, virtually all CD34(+)VEGFR-2(+) cells express the
      chemokine receptor CXCR4 and migrate in response to stromal-derived factor (SDF)
      1 or VEGF. To quantitate the plating efficiency of CD34(+) cells that give rise
      to endothelial colonies, CD34(+) cells derived from FL were incubated with VEGF
      and fibroblast growth factor (FGF)-2. Subsequent isolation and plating of
      nonadherent FL-derived VEGFR-2(+) cells with VEGF and FGF-2 resulted in
      differentiation of AC133(+ )VEGFR-2(+) cells into adherent AC133(-)VEGFR-2(+)Ac
      LDL(+ )(acetylated low-density lipoprotein) colonies (plating efficiency of 3%).
      In an in vivo human model, we have found that the neo-intima formed on the
      surface of left ventricular assist devices is colonized with AC133(+)VEGFR-2(+)
      cells. These data suggest that circulating CD34(+) cells expressing VEGFR-2 and
      AC133 constitute a phenotypically and functionally distinct population of
      circulating endothelial cells that may play a role in neo-angiogenesis.

PMID- 10648409
TI  - Activation of the small GTPases, rac and cdc42, after ligation of the platelet
      PAR-1 receptor.
AB  - Stimulation of platelet PAR-1 receptors results in the rapid (10 to 30 seconds)
      and extensive (30% to 40% of total) guanosine triphosphate (GTP) charging of
      endogenous platelet rac, previously identified as a possible key intermediate in
      the signal pathway between PAR-1 and actin filament barbed-end uncapping, leading
      to actin assembly. During PAR-1-mediated platelet activation, rac distributes
      from the cell interior to the cell periphery, and this reorganization is
      resistant to the inhibition of PI-3-kinase activity. Rac, in resting or activated
      platelets, is Triton X-100 soluble, suggesting that it does not form tight
      complexes with actin cytoskeletal proteins, though its retention in octyl
      glucoside-treated platelets and ultrastructural observations of activated
      platelets implies that rac binds to plasma membranes, where it can interact with
      phosphoinositide kinases implicated in actin assembly reactions. PAR-1
      stimulation also rapidly and extensively activates cdc42, though, in contrast to
      rac, some cdc42 associates with the actin cytoskeleton in resting platelets, and
      the bound fraction increases during stimulation. The differences in subcellular
      distribution and previous evidence showing quantitatively divergent effects of
      rac and cdc42 on actin nucleation in permeabilized platelets indicate different
      signaling roles for these GTPases.

PMID- 10648410
TI  - Switch in the protein tyrosine phosphatase associated with human CD100 semaphorin
      at terminal B-cell differentiation stage.
AB  - Human CD100, the first semaphorin identified in the immune system, is a
      transmembrane protein involved in T-cell activation. In the present study, we
      showed that activation of peripheral blood or tonsillar B lymphocytes induced the
      expression of CD100 in CD38(+)CD138(-) cell populations, including in CD148(+)
      subpopulations, thus expressing a memory B-cell-like phenotype. Using an in vitro
      enzymatic assay, we found that protein tyrosine phosphatase (PTP) activities were
      immunoprecipitated with CD100 in these cell populations, which were isolated by
      cell sorting, as well as in most B-cell lines representing various stages of B
      cell differentiation. Immunodepletion and Western blotting experiments
      demonstrated that CD45 was the PTP associated with CD100 in cell lines displaying
      pre-B, activated B, and pre-plasma cell phenotypes. CD45 also accounted for PTP
      activity immunoprecipitated with CD100 in CD38(+)CD138(-) cells sorted after
      activation of peripheral blood or tonsillar B lymphocytes. In contrast, no CD100
      CD45 association was observed in plasma cell lines corresponding to the terminal
      B-cell differentiation stage. CD148, the other transmembrane PTP known to be
      implicated in lymphocyte signaling pathways, was either only partly involved in
      the CD100-associated PTP activity or not expressed in plasma cell lines,
      indicating the association of CD100 with another main PTP. Our data show that
      CD100 is differentially expressed and can functionally associate with distinct
      PTPs in B cells depending on their activation and maturation state. They also
      provide evidence for a switch in the CD100-associated PTP at terminal stage of B
      cell differentiation.

PMID- 10648411
TI  - Adenosine triphosphate-induced oxygen radical production and CD11b up-regulation:
      Ca(++) mobilization and actin reorganization in human eosinophils.
AB  - Eosinophils are major effector cells in cellular inflammatory conditions such as
      parasitic infections, atopic diseases, bullous dermatoses, and vasculitis.
      Biological activities of adenosine triphosphate (ATP) were characterized in human
      eosinophils and compared with those of other eosinophil activators such as
      complement fragment product C5a, platelet-activating factor (PAF), and eotaxin.
      ATP initiated production of reactive oxygen metabolites, as demonstrated by
      lucigenin-dependent chemiluminescence. Furthermore, ATP caused up-regulation of
      the integrin CD11b. In addition, fluorescence microscope measurements labeled
      with fura-2 (1-[2-(5-carboxy-oxazol-2-yl)-6-aminobenzofuran-5-oxy]-2-(2' -amino
      5' -methyl-phenoxy)-ethane-N, N, N, N'-tetraacetic acid, pentaacetoxymethyl
      ester) eosinophils in the presence or absence of ethyleneglycotetraacetic acid
      (EGTA) indicated that there was Ca(++) mobilization from intracellular stores by
      ATP. Flow cytometric studies showed transient actin polymerization upon
      stimulation with ATP and its stable analogues adenosine 5'-0-(3-thiotriphosphate)
      and 2-methylthioadenosine triphosphate tetrasodium (met-ATP). The reactions
      induced by ATP were comparable to those obtained by C5a, PAF, and eotaxin.
      Production of reactive oxygen metabolites and actin polymerization after
      stimulation with ATP was inhibited by pertussis toxin, which indicated
      involvement of receptor-coupled guanine nucleotide-binding proteins (G(i)
      proteins). In addition, experiments with oxidized ATP also suggest involvement of
      P2X receptors in this activation process. The results show that ATP is a strong
      activator of eosinophils and has biological activity comparable to those of the
      eosinophil chemotaxins C5a, PAF, and eotaxin. The findings strongly suggest a
      role of ATP in the pathogenesis of eosinophilic inflammation as an activator of
      proinflammatory effector functions.

PMID- 10648412
TI  - Protein truncation test of LYST reveals heterogenous mutations in patients with
      Chediak-Higashi syndrome.
AB  - Chediak-Higashi syndrome (CHS) is a rare autosomal recessive disorder in which an
      immune deficiency occurs in association with pigmentation abnormalities. Most
      patients who do not undergo bone marrow transplantation die of a
      lymphoproliferative syndrome, though some patients with CHS have a relatively
      milder clinical course of the disease. The large size of the LYST gene, defective
      in CHS, has made it difficult to screen for mutations in a large number of
      patients. Only 8 mutations have been identified so far, and all lead to a
      truncated LYST protein. We conducted protein truncation tests on this gene in 8
      patients with CHS. Different LYST mutations were identified in all subjects
      through this approach, strengthening the observation of a high frequency of
      truncated LYST proteins as the genetic cause of CHS.

PMID- 10648413
TI  - The receptor tyrosine kinase c-kit provides a critical signal for survival,
      expansion, and maturation of mouse natural killer cells.
AB  - Fetal liver kinase ligands (flk2L/flt3L) and stem cell factor (SCF) have been
      shown to promote natural killer (NK) cell differentiation from hematopoietic stem
      cell (HSC) precursors in vitro. However, the contribution of signaling through
      the receptors for these growth factors for in vivo NK cell development remains
      ill-defined. We have analyzed the role of the SCF receptor c-kit in NK cell
      differentiation by reconstituting NK-deficient mice with fetal liver (FL) HSCs of
      c-kit(-/-) (W/W) mice. Although c-kit(-/-)NK cells were generated in W/W
      chimeras, they were reduced in number, contained a lower percentage of CD45R
      (B220)(+) cells, and were poorly cytolytic. In vitro experiments showed that
      generation of NK cells from FL precursors was reduced in the absence of c-kit
      signaling and that SCF promoted the survival of peripheral c-kit(+) NK cells. We
      conclude that c-kit/SCF interactions in vivo are dispensable for the commitment
      of HSC to the NK lineage, but they provide essential signals for generating
      normal numbers of fully mature NK cells.

PMID- 10648414
TI  - Ectopic expression of fibroblast growth factor receptor 3 promotes myeloma cell
      proliferation and prevents apoptosis.
AB  - The t(4;14) translocation occurs in 25% of multiple myeloma (MM) and results in
      both the ectopic expression of fibroblast growth factor receptor 3 (FGFR3) from
      der4 and immunoglobulin heavy chain-MMSET hybrid messenger RNA transcripts from
      der14. The subsequent selection of activating mutations of the translocated FGFR3
      by MM cells indicates an important role for this signaling pathway in tumor
      development and progression. To investigate the mechanism by which FGFR3
      overexpression promotes MM development, interleukin-6 (IL-6)-dependent murine B9
      cells were transduced with retroviruses expressing functional wild-type or
      constitutively activated mutant FGFR3. Overexpression of mutant FGFR3 resulted in
      IL-6 independence, decreased apoptosis, and an enhanced proliferative response to
      IL-6. In the presence of ligand, wild-type FGFR3-expressing cells also exhibited
      enhanced proliferation and survival in comparison to controls. B9 clones
      expressing either wild-type FGFR3 at high levels or mutant FGFR3 displayed
      increased phosphorylation of STAT3 and higher levels of bcl-x(L) expression than
      did parental B9 cells after cytokine withdrawal. The mechanism of the enhanced
      cell responsiveness to IL-6 is unknown at this time, but does not appear to be
      mediated by the mitogen-activated protein kinases SAPK, p38, or ERK. These
      findings provide a rational explanation for the mechanism by which FGFR3
      contributes to both the viability and propagation of the myeloma clone and
      provide a basis for the development of therapies targeting this pathway.

PMID- 10648415
TI  - Immunostimulatory CpG-oligonucleotides cause proliferation, cytokine production,
      and an immunogenic phenotype in chronic lymphocytic leukemia B cells.
AB  - Bacterial DNA and synthetic CpG-oligodeoxynucleotides (ODNs) derived thereof have
      attracted attention because they activate cells of the immune system in a
      sequence-dependent manner. Here we investigated the potential of CpG-ODNs to
      cause proliferation, cytokine production, and regulation of surface molecules in
      human B-chronic lymphocytic leukemia (CLL) cells. CpG-ODN induced proliferation
      in both B-CLL cells and normal B cells; however, only B-CLL cells increased
      proliferative responses when CpG-ODN was added to co-cultures of CD40-ligand
      transfected mouse fibroblasts (CD40LF) and B cells. Production of interleukin-6
      and tumor necrosis factor alpha was detectable at borderline levels, using CpG
      ODN as the only stimulus. In contrast, when CpG-ODN was added to co-cultures of B
      cells and CD40LF, a strong increase in cytokine production occurred in B-CLL
      cells as well as in normal B cells. The surface molecules CD40, CD58, CD80, CD86,
      CD54, and MHC class I molecules were up-regulated in B-CLL cells, whereas CD95
      expression was not influenced by CpG-ODN stimulation. The same pattern of surface
      molecule regulation was observed in normal B cells, but up-regulation of CD40 was
      significantly stronger in B-CLL cells. Costimulation with CpG-ODN and CD40LF
      resulted in further up-regulation of CD58, CD80, CD86, and MHC class I molecules.
      In contrast, CD95 expression induced by CD40-ligation was inhibited by CpG-ODN.
      CpG-ODN activated B-CLL cells acquired a strong stimulatory capacity toward T
      cells in allogeneic mixed lymphocyte reaction. This effect was completely
      inhibited by a combination of anti-CD80 and anti-CD86 monoclonal antibody. Taken
      together, these findings suggest the possible use of CpG-ODN for
      immunotherapeutic strategies in patients with B-CLL.

PMID- 10648416
TI  - A primitive hematopoietic cell is the target for the leukemic transformation in
      human philadelphia-positive acute lymphoblastic leukemia.
AB  - BCR-ABL is a chimeric oncogene generated by translocation of sequences from the
      chromosomal counterpart (c-ABL gene) on chromosome 9 into the BCR gene on
      chromosome 22. Alternative chimeric proteins, BCR-ABL(p190) and BCR-ABL(p210),
      are produced that are characteristic of chronic myelogenous leukemia (CML) and
      Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(1)-ALL). In
      CML, the transformation occurs at the level of pluripotent stem cells. However,
      Ph(1)-ALL is thought to affect progenitor cells with lymphoid differentiation.
      Here we demonstrate that the cell capable of initiating human Ph(1)-ALL in non
      obese diabetic mice with severe combined immunodeficiency disease (NOD/SCID),
      termed SCID leukemia-initiating cell (SL-IC), possesses the differentiative and
      proliferative capacities and the potential for self-renewal expected of a
      leukemic stem cell. The SL-ICs from all Ph(1)-ALL analyzed, regardless of the
      heterogeneity in maturation characteristics of the leukemic blasts, were
      exclusively CD34(+ )CD38(-), which is similar to the cell-surface phenotype of
      normal SCID-repopulating cells. This indicates that normal primitive cells,
      rather than committed progenitor cells, are the target for leukemic
      transformation in Ph(1)-ALL.

PMID- 10648418
TI  - Hodgkin and Reed-Sternberg-like cells in B-cell chronic lymphocytic leukemia
      represent the outgrowth of single germinal-center B-cell-derived clones:
      potential precursors of Hodgkin and Reed-Sternberg cells in Hodgkin's disease.
AB  - In rare cases of B-cell chronic lymphocytic leukemia (B-CLL), large cells
      morphologically similar to or indistinguishable from Hodgkin/Reed-Sternberg (HRS)
      cells of Hodgkin's disease (HD) can be found in a background of otherwise typical
      B-CLL. To test these HRS-like cells for a potential clonal relationship to the B
      CLL cells, single cells were micromanipulated from immunostained tissue sections,
      and rearranged immunoglobulin genes were amplified from HRS-like cells and B-CLL
      cells and sequenced. The same variable (V) gene rearrangements with shared and
      distinct somatic mutations were found in HRS-like and B-CLL cells from 1 patient,
      which indicates derivation of these cells from 2 distinct members of a germinal
      center B-cell clone. Separate clonal V gene rearrangements were amplified from
      HRS-like and B-CLL cells from 2 other patients, showing concomitant presence of 2
      distinct expanded B-cell clones. Epstein-Barr virus (EBV) was detected in the HRS
      like cells of these 2 latter cases, indicating clonal expansion of an EBV
      harboring B cell in the setting of B-CLL. There is evidence that HRS-like cells
      in B-CLL, like HRS cells in HD, derive from germinal-center B cells. In all
      cases, somatic mutations have been detected in the rearranged V genes of the HRS
      like cells, and in 1 of the EBV-positive HRS-like cell clones, somatic mutations
      rendered an originally functional V gene rearrangement nonfunctional. We
      speculate that the HRS-like cells in B-CLL represent potential precursors for HRS
      cells causing HD.

PMID- 10648417
TI  - Arsenic induces apoptosis of multidrug-resistant human myeloid leukemia cells
      that express Bcr-Abl or overexpress MDR, MRP, Bcl-2, or Bcl-x(L).
AB  - We investigated the in vitro growth inhibitory and apoptotic effects of
      clinically achievable concentrations of As(2)O(3) (0.5 to 2.0 micromol/L) against
      human myeloid leukemia cells known to be resistant to a number of apoptotic
      stimuli. These included chronic myelocytic leukemia (CML) blast crisis K562 and
      HL-60/Bcr-Abl cells, which contain p210 and p185 Bcr-Abl, respectively, and HL-60
      cell types that overexpress Bcl-2 (HL-60/Bcl-2), Bcl-x(L) (HL-60/Bcl-x(L)), MDR
      (HL-60/VCR), or MRP (HL-60/AR) protein. The growth-inhibitory IC(50) values for
      As(2)O(3) treatment for 7 days against all these cell types ranged from 0.8 to
      1.5 micromol/L. Exposure to 2 micromol/L As(2)O(3) for 7 days induced apoptosis
      of all cell types, including HL-60/Bcr-Abl and K562 cells. This was associated
      with the cytosolic accumulation of cyt c and preapoptotic mitochondrial events,
      such as the loss of inner membrane potential (DeltaPsim) and the increase in
      reactive oxygen species (ROS). Treatment with As(2)O(3) (2 micromol/L) generated
      the activities of caspases, which produced the cleavage of the BH3 domain
      containing proapoptotic Bid protein and poly (ADP-ribose) polymerase.
      Significantly, As(2)O(3)-induced apoptosis of HL-60/Bcr-Abl and K562 cells was
      associated with a decline in Bcr-Abl protein levels, without any significant
      alterations in the levels of Bcl-x(L), Bax, Apaf-1, Fas, and FasL. Although
      As(2)O(3 )treatment caused a marked increase in the expression of the myeloid
      differentiation marker CD11b, it did not affect Hb levels in HL-60/Bcr-Abl, K562,
      or HL-60/neo cells. However, in these cells, As(2)O(3 )potently induced hyper
      acetylation of the histones H3 and H4. These findings characterize As(2)O(3) as a
      growth inhibiting and apoptosis-inducing agent against a variety of myeloid
      leukemia cells resistant to multiple apoptotic stimuli.

PMID- 10648419
TI  - Detection of aberrant isotype switch recombination in low-grade and high-grade
      gastric MALT lymphomas.
AB  - Gastric mucosa-associated lymphoid tissue (MALT) lymphoma originates from
      reactive lymphocytic infiltrates during chronic gastritis, closely associated
      with Helicobacter pylori infection. MALT lymphomas may be either "low grade" or
      "high grade," and transformation from low grade to high grade can occur. To
      obtain information on the maturational state of MALT lymphoma cells, we
      investigated their ability to undergo isotype switch recombination, which
      together with immunoglobulin variable gene somatic mutation, contributes to
      normal B-cell maturation. Using specific probes for the immunoglobulin heavy
      chain (IgH) switch regions, we found by Southern blot that 3 out of 5 low-grade
      cases and 2 out of 2 high-grade cases showed rearrangements within IgH switch
      regions, which appeared aberrant in 4 of the 5 cases. The cloning of two
      rearranged fragments from one low-grade and one high-grade case confirmed the
      aberrant nature of the rearranged fragments. A deletion from the switch mu region
      (S mu) to the first constant mu exon (C mu 1) and a second deletion from the
      second constant mu exon (C mu 2) to the gamma 3 region (gamma 3) was detected in
      the low-grade case. In the high-grade case, there was a deletion of the IgH
      intronic enhancer (E mu) and a 336-base pair (bp) insertion into the S mu region
      of a gene (KIAA0307) normally located at 15q24. These data demonstrate for the
      first time the ability of MALT lymphoma cells to undergo aberrant isotype switch
      recombinations, which might be directly involved in the development or
      progression of malignancy.

PMID- 10648420
TI  - CD40 activation mediates p53-dependent cell cycle regulation in human multiple
      myeloma cell lines.
AB  - It has been reported that the activation of multiple myeloma (MM) cells by CD40
      induces proliferation, growth arrest, and apoptosis. To determine whether the
      biologic sequelae of CD40 activation in MM cells depends on p53 function, we
      identified temperature-sensitive p53 mutations in the RPMI 8226 (tsp53E285K) and
      the HS Sultan (tsp53Y163H) MM cell lines. These cells were then used as a model
      system of inducible wtp53-like function because wild-type-like p53 is induced at
      permissive (30 degrees C) but not at restrictive (37 degrees C) temperatures.
      Using p21-luciferase reporter assays, we confirmed that CD40 induces p53
      transactivation in RPMI 8226 and HS Sultan cells cultured under permissive, but
      not restrictive, conditions. Furthermore, CD40 activation of these MM cells under
      permissive, but not restrictive, temperatures increased the expression of p53 and
      p21 mRNA and protein. Importantly, CD40 activation induced the proliferation of
      RPMI 8226 and HS Sultan cells at restrictive temperatures and growth arrest and
      increased subG1 phase cells at permissive temperatures. These data confirmed that
      CD40 activation might have distinct biologic sequelae in MM cells, depending on
      their p53 status.

PMID- 10648421
TI  - Regulation of drug sensitivity by ribosomal protein S3a.
AB  - When bcl-2 is immunoprecipitated from (32)P-labeled cell extracts of all-trans
      retinoic acid (ATRA)-treated acute myeloblastic leukemia (AML) blasts, a
      phosphorylated protein of approximately 30 kd is coprecipitated. This protein has
      been identified as ribosomal protein S3a. The biologic effects of S3a include
      favoring apoptosis and enhancing the malignant phenotype. We sought to determine
      whether S3a, like bcl-2, influenced the response of cells to chemotherapeutic
      drugs and ATRA. Cell lines were studied in which S3a was genetically increased or
      disrupted; increased S3a was regularly associated with increased plating
      efficiency and increased sensitivity to either cytosine arabinoside (ara-C) or
      doxorubicin (DNR). S3a did not affect the sensitivity of cells to paclitaxel.
      Pulse exposures to either (3)HTdR or ara-C showed a greater percentage of
      clonogenic cells in the S phase of the cell cycle in cells with increased S3a
      than in controls. Cells with increased S3a responded to ATRA by increased ara-C
      or DNR sensitivity, whereas cells with reduced S3a protein were either protected
      by ATRA or not affected. We studied cryopreserved blast cells from patients with
      AML or chronic myelomonocytic leukemia (CMML). S3a protein levels were
      heterogeneous in these populations. In 32 cryopreserved blast populations, S3a
      levels were significantly correlated with both bcl-2 and with cell growth in
      culture. As in cell lines, high S3a in cryopreserved blasts was associated with
      ATRA-induced sensitization to ara-C. No significant association was seen between
      S3a levels and response to treatment.

PMID- 10648422
TI  - Myeloma progenitors in the blood of patients with aggressive or minimal disease:
      engraftment and self-renewal of primary human myeloma in the bone marrow of NOD
      SCID mice.
AB  - The myelomagenic capacity of clonotypic myeloma cells in G-CSF mobilized blood
      was tested by xenotransplant. Intracardiac (IC) injection of NOD SCID mice with
      peripheral cells from 5 patients who had aggressive myeloma led to lytic bone
      lesions, human Ig in the serum, human plasma cells, and a high frequency of
      clonotypic cells in the murine bone marrow (BM). Human B and plasma cells were
      detected in BM, spleen, and blood. Injection of ex vivo multiple myeloma cells
      directly into the murine sternal BM (intraosseus injection [IO]) leads to lytic
      bone lesions, BM plasma cells, and a high frequency of clonotypic cells in the
      femoral BM. This shows that myeloma has spread from the primary injection site to
      distant BM locations. By using a cellular limiting dilution PCR assay to quantify
      clonotypic B lineage cells, we confirmed that peripheral myeloma cells homed to
      the murine BM after IC and IO injection. The myeloma progenitor undergoes self
      renewal in murine BM, as demonstrated by the transfer of human myeloma to a
      secondary recipient mouse. For 6 of 7 patients, G-CSF mobilized cells from
      patients who have minimal disease, taken at the time of mobilization or after
      cryopreservation, included myeloma progenitors as identified by engraftment of
      clonotypic cells and/or lytic bone disease in mice. This indicates that myeloma
      progenitors are mobilized into the blood by cyclophosphamide/G-CSF. Their ability
      to generate myeloma in a xenotransplant model implies that such progenitors are
      also myelomagenic when reinfused into patients, and suggests the need for an
      effective strategy to purge them before transplant.

PMID- 10648423
TI  - Novel SH3 protein encoded by the AF3p21 gene is fused to the mixed lineage
      leukemia protein in a therapy-related leukemia with t(3;11) (p21;q23).
AB  - The mixed lineage leukemia (MLL) gene located at chromosome band 11q23 is
      frequently rearranged in patients with therapy-related acute monocytic leukemia
      who received topoisomerase II inhibitors. We have identified a novel fusion
      partner of MLL (FAB M5b) in a patient who developed t-AML 9 years after treatment
      for acute lymphoblastic leukemia (ALL). The leukemic cells had a sole karyotypic
      abnormality of t(3;11) (p21;q23). Screening of a genomic DNA library, prepared
      from leukemic cell DNA, identified rearranged clones composed of MLL and a novel
      gene on chromosome 3p21 (AF3p21). The AF3p21 gene encodes a protein of 722 amino
      acids, which contains an Src homology 3 (SH3) domain, a proline-rich domain, and
      a bipartite nuclear localizing signal (NLS). RNA analysis demonstrated that exon
      6 of the MLL gene fused to exon 2 of the AF3p21 gene. The resulting chimeric
      protein consists of AT-hooks, methyltransferase, and transcription repressor
      domains of MLL in addition to the AF3p21 proline-rich domain and NLS but not the
      AF3p21 SH3 domain.

PMID- 10648425
TI  - Phosphatidylinositide 3-kinase localizes to cytoplasmic lipid bodies in human
      polymorphonuclear leukocytes and other myeloid-derived cells.
AB  - Phosphatidylinositide 3-kinase (PI3K) is a key enzyme implicated in intracellular
      signaling of diverse cellular responses including receptor-mediated responses and
      neutrophil activation. Several PI3K subunits have been cloned and shown to be
      localized to plasma membrane receptors, the cytosol, or intracellular vesicles or
      caveolae. We report the localization of PI3K to a distinct intracellular site,
      cytoplasmic lipid bodies, in leukocytes. In U937 monocyte cells, PI3K p85
      regulatory and p110beta catalytic subunits were localized to lipid bodies by
      immunocytochemistry and/or immunoblotting and enzyme assays of subcellular
      fractions. In RAW murine macrophages, p55, p85alpha, and p85beta PI3K subunits
      were present at isolated lipid bodies. PI3K p85 was also shown to colocalize and,
      by co-immunoprecipitation, to be physically associated with phosphorylated Lyn
      kinase in lipid bodies induced to form in human polymorphonuclear leukocytes.
      These findings, therefore, indicate a novel site for PI3K compartmentalization
      and suggest that PI3K-mediated signaling is active within cytoplasmic lipid
      bodies in leukocytes.

PMID- 10648424
TI  - Cell-specific, activation-dependent regulation of neutrophil CD32A ligand-binding
      function.
AB  - Neutrophils express 2 low-affinity FcgammaR, FcgammaRIIIB (CD16B), and
      FcgammaRIIA (CD32A). CD16B is a glycosyl-phosphatidyl inositol-anchored molecule,
      whereas CD32A is a polypeptide-anchored molecule. These 2 receptors also differ
      in their signaling. The biological significance of coexpression of 2 FcgammaRs
      with distinct membrane anchors and signaling capacities is not clearly
      understood. Using neutrophils from a CD16B-deficient donor and normal neutrophils
      treated with anti-CD16 monoclonal antibodies, the authors demonstrated that
      affinity modulation of CD32A is one of the mechanisms by which neutrophils
      regulate their FcgammaR-dependent functions. Neutrophils isolated from a CD16B(-
      )donor rosetted poorly with sheep erythrocytes opsonized with rabbit IgG (EA)
      (12% +/- 2% versus 80% +/- 6% for control) and were unable to mediate
      immunophagocytosis. However, activation of CD16B(-) neutrophils with fMLP, a
      bacterial chemotactic peptide, increased the CD32A-dependent EA rosetting to 58%.
      The CD32A-dependent rosetting of fMLP-activated normal neutrophils also increased
      nearly 5-fold, but there was no increase in CD32A expression. The CD32A-dependent
      immune complex (IC) binding was also increased in activated neutrophils. This
      affinity regulation was not observed with CD32A expressed on Chinese hamster
      ovary cells. These results suggest that in resting neutrophils CD32A is in a low
      affinity state and that these cells primarily engage CD16B for IC binding.
      However, once the neutrophils are activated, the CD32A is converted to a high
      affinity state that leads to CD32A-dependent ligand binding and signaling. These
      results suggest that neutrophils adopt a novel strategy to engage the 2 different
      FcgammaR selectively during physiologic and pathologic conditions to carry out
      their functions efficiently.

PMID- 10648426
TI  - Polytrauma induces increased expression of pyruvate kinase in neutrophils.
AB  - Polytrauma (PT) leads to systemic activation of polymorphonuclear neutrophils
      (PMNs). Organ damage commonly found in these patients is ascribed to respiratory
      bursts of activated PMNs. With the use of sodium dodecyl sulfate-polyacrylamide
      gel electrophoresis, PMN extracts from PT patients were found to contain a clear
      protein band not seen in control PMNs from healthy volunteers. This band was
      identified by amino acid sequencing and Western blotting as pyruvate kinase (PK).
      Enzymatic assays revealed a 600-fold increase in PK activity in PMNs of PT
      patients, with the highest levels occurring between the fifth and seventh
      posttraumatic day. In lymphocytes, no such increase was detectable. As PK is a
      major regulatory enzyme in glycolysis, glucose-dependent lactate production in
      PMNs from PT patients was assayed. These cells showed a higher glycolytic lactate
      production than controls. It was additionally demonstrated that acute activation
      of respiratory burst activity depends mainly on breakdown of glucose to lactate
      via the pentose-phosphate pathway and glycolysis. In PMNs from PT patients, this
      glucose-dependent respiratory burst activity was more than twofold higher than in
      controls. The increase in expression and activity of PK in PMNs from PT patients
      may contribute to the high glucose-dependent respiratory burst activity seen in
      these cells.

PMID- 10648427
TI  - Cloning of the cellular receptor for feline leukemia virus subgroup C (FeLV-C), a
      retrovirus that induces red cell aplasia.
AB  - Feline leukemia virus-C (FeLV-C) causes red cell aplasia in cats, likely through
      its interaction with its cell surface receptor. We identified this receptor by
      the functional screening of a library of complementary DNAs (cDNA) from feline T
      cells. The library, which was cloned into a retroviral vector, was introduced
      into FeLV-C-resistant murine (NIH 3T3) cells. The gene conferring susceptibility
      to FeLV-C was isolated and reintroduced into the same cell type, as well as into
      FeLV-C-resistant rat (NRK 52E) cells, to verify its role in viral infection. The
      receptor cDNA is predicted to encode a protein of 560 amino acids with 12
      membrane-spanning domains, termed FLVCR. FLVCR has significant amino acid
      sequence homology with members of the major facilitator superfamily and
      especially D-glucarate transporters described in bacteria and in C. elegans. As
      FeLV-C impairs the in vivo differentiation of burst-forming unit-erythroid to
      colony-forming unit-erythroid, we hypothesize that this transporter system could
      have an essential role in early erythropoiesis. In further studies, a 6-kb
      fragment of the human FLVCR gene was amplified by polymerase chain reaction from
      genomic DNA, using homologous cDNA sequences identified in the human Expressed
      Sequence Tags database. By radiation hybrid mapping, the human gene was localized
      to a 0.5-centiMorgan region on the long arm of chromosome 1 at q31.3.

PMID- 10648428
TI  - DFFRY codes for a new human male-specific minor transplantation antigen involved
      in bone marrow graft rejection.
AB  - Graft rejection after histocompatibility locus antigen (HLA)-identical stem cell
      transplantation results from the recognition of minor histocompatibility antigens
      on donor stem cells by immunocompetent T lymphocytes of recipient origin. T
      lymphocyte clones that specifically recognize H-Y epitopes on male target cells
      have been generated during graft rejection after sex-mismatched transplantation.
      Previously, 2 human H-Y epitopes derived from the same SMCY gene have been
      identified that were involved in bone marrow graft rejection. We report the
      identification of a new male-specific transplantation antigen encoded by the Y
      chromosome-specific gene DFFRY. The DFFRY-derived peptide was recognized by an
      HLA-A1 restricted CTL clone, generated during graft rejection from a female
      patient with acute myeloid leukemia who rejected HLA-phenotypically identical
      bone marrow from her father. The identification of this gene demonstrates that at
      least 2 genes present on the human Y-chromosome code for male-specific
      transplantation antigens.

PMID- 10648429
TI  - Axonal lesions in multiple sclerosis: an old story revisited.

PMID- 10648430
TI  - The detection and management of unruptured intracranial aneurysms.
AB  - The incidence of subarachnoid haemorrhage (SAH) is 6-8 per 100 000 person years,
      peaking in the sixth decade. SAH, mostly due to rupture of an intracranial
      aneurysm, accounts for a quarter of cerebrovascular deaths. Aneurysms increase in
      frequency with age beyond the third decade, are 1.6 times more common in women
      and are associated with a number of genetic conditions. Prospective autopsy and
      angiographic studies indicate that between 3.6 and 6% of the population harbour
      an intracranial aneurysm. Studies have found an increased rate of SAH in first
      degree relatives of SAH patients (relative risk 3.7-6.6). In affected families,
      the most frequent relationship between sufferers is sibling to sibling. The
      rupture rate of asymptomatic aneurysms was thought to be 1-2% per annum, but the
      recent International Study of Unruptured Intracranial Aneurysms found that the
      rupture rate of small aneurysms was only 0.05% per annum in patients with no
      prior SAH, and 0.5% per annum for large (>10 mm diameter) aneurysms and for all
      aneurysms in patients with previous SAH. Non-invasive tests such as magnetic
      resonance angiography (MRA), computed tomographic angiography (CTA) and
      transcranial Doppler (TCD) have been advocated as alternatives to intra-arterial
      digital subtraction angiography to screen for aneurysms. Although all are
      promising techniques, the quality of data testing their accuracy is limited.
      Overall reported sensitivity for CTA and MRA (TCD is poorer) was 76-98% and
      specificity was 85-100%, but many subjects had an aneurysm or recent SAH, which
      could overestimate accuracy. CTA and MRA are much poorer methods for the
      detection of aneurysms <5 mm diameter, which account for up to one-third of
      unruptured aneurysms. Elective surgical clipping of asymptomatic aneurysms has a
      morbidity of 10.9% and mortality of 3. 8%. Treatment of aneurysms by Guglielmi
      coils, for which there is less long-term follow-up available, has a 4% morbidity
      and 1% mortality, but only achieves complete aneurysm occlusion in 52-78% of
      cases. There has been interest in screening for aneurysms, but the indication
      for, and cost effectiveness of screening are unclear because aneurysm prevalence
      varies, rupture rate is low, non-invasive imaging tests are not yet accurate
      enough to exclude small aneurysms and the morbidity and mortality for elective
      surgical treatment of unruptured aneurysms is high. There may be a limited role
      for investigation of high risk subgroups. Ideally, screening in such subgroups
      should be tested in a randomized trial. The avoidance of risk factors for
      aneurysms such as smoking, hypertension and hypercholesterolaemia should be part
      of the management of at-risk subjects.

PMID- 10648431
TI  - Charcot-Marie-Tooth disease type 1: molecular pathogenesis to gene therapy.
AB  - Charcot-Marie-Tooth disease type 1 (CMT1) is caused by mutations in the
      peripheral myelin protein, 22 kDa (PMP22) gene, protein zero (P0) gene, early
      growth response gene 2 (EGR-2) and connexin-32 gene, which are expressed in
      Schwann cells, the myelinating cells of the peripheral nervous system. Although
      the clinical and pathological phenotypes of the various forms of CMT1 are
      similar, including distal muscle weakness and sensory loss, their molecular
      pathogenesis is likely to be quite distinct. In addition, while demyelination is
      the hallmark of CMT1, the clinical signs and symptoms of the disease are probably
      produced by axonal degeneration, not demyelination itself. In this review we
      discuss the molecular pathogenesis of CMT1, as well as approaches to an effective
      gene therapy for this disease.

PMID- 10648432
TI  - Affective aggression in patients with temporal lobe epilepsy: a quantitative MRI
      study of the amygdala.
AB  - Recurrent episodes with interictal affective aggression are a rare but well
      recognized problem in patients with temporal lobe epilepsy. They are referred to
      as episodic dyscontrol or, more precisely, as intermittent explosive disorder
      (IED). The amygdala play a crucial role in the affective evaluation of multimodal
      sensory input and the neurobiological mediation of aggressive behaviour. With
      hippocampal sclerosis, in the context of mesial temporal lobe sclerosis, being
      the most common cause of temporal lobe epilepsy, we hypothesized that the
      amygdala might be affected by the same pathogenic process in aggressive patients.
      We investigated 50 patients with temporal lobe epilepsy: 25 with and 25 without a
      history of IED. Data from clinical, electrophysiological, neuropsychological and
      psychometric investigations were obtained, as well as MRI scans for the
      quantitative assessment of possible amygdala pathology. We found no evidence of a
      higher prevalence of amygdala sclerosis in the aggressive patients. Hippocampal
      sclerosis was significantly less common in patients with temporal lobe epilepsy
      and IED. However, a significant subgroup of patients (20%) with temporal lobe
      epilepsy and aggressive behaviour had severe amygdala atrophy in the context of a
      history of encephalitis. Another subgroup of aggressive patients (28%) had
      different left temporal lesions affecting either the amygdala or periamygdaloid
      structures. IED was associated with left-sided or bilateral EEG and MRI
      abnormalities, low IQ and high scores in depression and anxiety.

PMID- 10648433
TI  - Localizing value of epileptic visual auras.
AB  - It is difficult to differentiate between seizures of occipital or temporal lobe
      origin in patients with focal epileptic seizures associated with visual aura.
      These are often suspected to originate from the visual cortex, which causes
      reluctance to propose resection as treatment for the affected patient. To
      determine the value of localizing different types of visual auras, we report on
      20 patients experiencing visual aura from a series of 878 surgically treated
      patients suffering from intractable focal seizures. In all of these patients, a
      morphological abnormality was identified on MRI (n = 18) or cranial CT (n = 2).
      These abnormalities were shown to represent the morphological correlate of the
      epileptogenic zone in each case, as demonstrated by intracranial ictal EEG
      recordings and/or seizure freedom after focal resective surgery. Elementary
      hallucinations, illusions and visual loss were reported not only by all patients
      with occipital lobe epilepsy, but also by patients with occipitotemporal and
      anteromedial temporal seizure onset. Complex hallucinations never occurred in
      occipital lobe seizures but were present in the two other groups. The same
      correlation was found for concentric changes of visual field (tunnel vision), a
      newly described ictal phenomenon. We conclude that elementary hallucinations,
      illusions and visual loss, although typical for occipital lobe epilepsy, can also
      occur in anteromedial temporal or occipitotemporal seizures and are therefore not
      a discordant feature in presurgical evaluation of patients with suspected
      temporal lobe epilepsy. Complex hallucinations and tunnel vision, however, should
      be considered concordant only with the assumption of an anteromedial temporal or
      occipitotemporal seizure onset.

PMID- 10648434
TI  - The timing of primary orthostatic tremor bursts has a task-specific plasticity.
AB  - Primary orthostatic tremor is characterized by unsteadiness and shakiness of the
      legs while standing. It is due to a remarkably strong and regular EMG modulation
      at approximately 16 Hz that is thought to be of CNS origin. Previous studies have
      shown that the tremor frequency is the same in all involved muscles and that the
      time relation between bursts of activity in different muscles may be fixed (e.g.
      always co-contracting or always contracting in an alternating pattern). Here we
      have used frequency domain analysis of postural muscle EMG signals in five
      primary orthostatic tremor patients and in two normal controls to explore the
      nature of such fixed timing patterns. The timing is found not to relate simply to
      the relative conduction times for passage of rhythmic bursts from a central
      oscillation to different muscles. Indeed, although the timing pattern (expressed
      as phase) of the 16-Hz EMG bursts in different postural muscles remains constant
      while the subject adopts a certain steady posture, it is different for different
      subjects and also changes when the same subject adopts a different posture. It
      seems unlikely that such complex task-dependent timing relations of rhythmic
      postural muscle activity are due to the primary pathology of primary orthostatic
      tremor. Instead, we suggest that the abnormally strong peripheral manifestation
      of a 16-Hz CNS oscillation merely unmasks normal central processes so that the
      timing patterns may provide a clue to the nature of postural motor control.

PMID- 10648435
TI  - Semantic dementia with ubiquitin-positive tau-negative inclusion bodies.
AB  - Three cases are reported with dementia and ubiquitin-positive but tau-negative
      inclusion bodies. All patients had a semantic dementia and the clinical details
      of two of these have been published as the first description of a selective
      semantic memory impairment. The original diagnosis had been of Pick's disease
      based on frontotemporal atrophy, but re-examination has revealed ubiquitin
      positive but tau-negative inclusions as well as neurites in the frontotemporal
      cortices and ubiquitin-positive, intracytoplasmic inclusions in the granule cells
      of the dentate fascia. These inclusions are identical to those reported in
      association with amyotrophic lateral sclerosis (motor neuron disease), but none
      were seen in brainstem or spinal cord motor neurons.

PMID- 10648436
TI  - Adaptation to oscillopsia: a psychophysical and questionnaire investigation.
AB  - In this study we explore the reasons why patients with bilateral vestibular
      failure report disparate degrees of oscillopsia. Twelve bilateral labyrinthine
      defective (LD) subjects and twelve normal healthy controls were tested using a
      self- versus visual-motion psychophysical experiment. The LD subjects also
      completed a questionnaire designed to quantify the severity of handicap caused by
      oscillopsia. Additional standardized questionnaires were completed to identify
      the role of personality, personal beliefs and affective factors in adaptation to
      oscillopsia. During the psychophysical experiment subjects sat on a motorized
      Barany chair whilst viewing a large-field projected video image displayed on a
      screen in front of them. The chair and video image oscillated sinusoidally at 1
      Hz in counter-phase at variable amplitudes which were controlled by the subject
      but constrained, so that the net relative motion of the chair and video image
      always resulted in a sinusoid with a peak velocity of 50 degrees /s. The
      subject's task was to find the ratio of chair versus video image motion that
      subjectively produced the 'most comfortable visual image'. Eye movements were
      recorded during the experiment in order that the net retinal image slip at the
      point of maximum visual comfort could be measured. The main findings in the LD
      subjects were that, as a group, they selected lower chair motion amplitude
      settings to obtain visual comfort than did the normal control subjects. Responses
      to the questionnaires highlighted considerable variation in reported handicap due
      to oscillopsia. Greater oscillopsia handicap scores were significantly correlated
      with a greater external locus of control (i.e. the perception of having little
      control over one's health). Retinal slip speed was negatively correlated with
      oscillopsia handicap score so that patients who suffered the greatest retinal
      slip were those least handicapped by oscillopsia. The results suggest that
      adaptation to oscillopsia is partly related to the patient's personal attitude to
      the recovery process and partly associated with the development of tolerance to
      the movement of images on the retina during self-motion. The latter is likely to
      be related to previously described changes in visual motion sensitivity in these
      patients.

PMID- 10648437
TI  - The visual word form area: spatial and temporal characterization of an initial
      stage of reading in normal subjects and posterior split-brain patients.
AB  - A standard model of word reading postulates that visual information is initially
      processed by occipitotemporal areas contralateral to the stimulated hemifield,
      from whence it is subsequently transferred to the visual word form (VWF) system,
      a left inferior temporal region specifically devoted to the processing of letter
      strings. For stimuli displayed in the left visual field, this transfer proceeds
      from the right to the left hemisphere through the posterior portion of the corpus
      callosum. In order to characterize the spatial and temporal organization of these
      processes, reading tasks with split-field presentation were performed by five
      control subjects and by two patients suffering from left hemialexia following
      posterior callosal lesions. The subjects' responses were studied using
      behavioural measures and functional brain imaging techniques, providing both high
      spatial resolution (functional MRI, fMRI) and high temporal resolution (high
      density event-related potentials, ERPs). Early visual processing was revealed as
      activations contralateral to stimulation, located by fMRI in the inferior
      occipitotemporal region and presumably coincident with area V4. A negative wave
      occurring 150-160 ms post-stimulus, also strictly contralateral to stimulation,
      was recorded over posterior electrodes. In contrast with these hemifield
      dependent effects, the VWF system was revealed as a strictly left-hemispheric
      activation which, in control subjects, was identical for stimuli presented in the
      left or in the right hemifield and was located in the middle portion of the left
      fusiform gyrus. The electrical signature of the VWF system consisted of a
      unilateral sharp negativity, recorded 180-200 ms post-stimulus over left inferior
      temporal electrodes. In callosal patients, due to the inability of visual
      information to pass across the posterior part of the corpus callosum, the VWF
      system was activated only by stimuli presented in the right visual field.
      Similarly, a significant influence of the word/non-word status on ERPs recorded
      over the left hemisphere was discernible for either hemifield in controls, while
      it affected only right-hemifield stimuli in callosal patients. These findings
      provide direct support for the main components of the classical model of reading
      and help specify their timing and cerebral substrates.

PMID- 10648438
TI  - Axonal changes in chronic demyelinated cervical spinal cord plaques.
AB  - Imaging and pathomorphological studies in multiple sclerosis suggest that axonal
      injury and axonal loss are playing a crucial role in those with persistent
      disability and long-standing disease. Although the existence of axonal injury in
      multiple sclerosis is proven, especially in the zone of active inflammation, the
      effect of chronic inflammation on the axons remains elusive. The aim of this
      study was to perform a quantitative morphometrical analysis, estimating axonal
      loss and evaluating axonal degenerative changes in cervical spinal cord samples
      of patients suffering from secondary progressive multiple sclerosis. Completely
      demyelinated plaques, normal appearing white matter (NAWM) and control material
      from anatomically identical regions of the cord have been compared. Neurofilament
      immunostaining was used for identification of the axons. We observed a
      significant reduction of axonal density (number of axons/mm(2)) in multiple
      sclerosis, both in the plaque and in the NAWM compared with the control cases.
      Axons under approximately 3.3 microm diameter seemed to be more affected. The
      intensity of the immunostaining was significantly reduced in the plaque compared
      with either NAWM or control. Our results on the cervical cord combined with other
      observations support the concept of slow axonal degeneration rather than acute
      damage as a cause of chronic disability in multiple sclerosis.

PMID- 10648439
TI  - Neuropsychological EEG activation in patients with epilepsy.
AB  - To examine the effects of higher mental activity on the EEG, 480 Japanese
      patients with different types of epilepsy were subjected to potentially
      provocative cognitive tasking, termed 'neuropsychological EEG activation' (NPA),
      during standard EEG recordings. NPA tasks consisted of reading, speaking,
      writing, written arithmetic calculation, mental arithmetic calculation and
      spatial construction. The NPA tasks provoked epileptic discharges in 38 patients
      (7.9%) and were accompanied by myoclonic seizures in 15 patients, absence
      seizures in eight and simple partial seizures in one. Among the cognitive tasks,
      mental activities mainly associated with use of the hands, i.e. writing (68.4%),
      written calculation (55. 3%) and spatial conction (63.2%), provoked the most
      discharges, followed by mental calculation (7.9%) and reading (5.3%). Detailed
      examination of the precipitating events revealed action-programming type
      activities to be the most crucial in 32 out of the 38 patients (84.2%), followed
      by thinking type activities in four patients (10. 5%). Regarding the
      classification of epilepsies proposed by the International League Against
      Epilepsy, seizure-precipitating mental activities in our series were almost
      exclusively (in 36 out of the 38 patients) related to idiopathic generalized
      epilepsies (IGEs) including juvenile myoclonic epilepsy, juvenile absence
      epilepsy, grand mal epilepsy on awakening and childhood absence epilepsy, and
      were rarely (in only two out of the 38 patients) related to temporal lobe
      epilepsy. In our IGE patients, the provocative effects of NPA were related to
      myoclonic seizures rather than absence or generalized tonic-clonic seizures.
      These results suggest that NPA is a useful tool for examining the relationship
      between cognitive function and epileptic seizures, and that the IGE patients with
      myoclonic seizures are vulnerable to higher mental activities requiring action
      programming or thinking.

PMID- 10648441
TI  - Cortical dysfunction in non-demented Parkinson's disease patients: a combined
      (31)P-MRS and (18)FDG-PET study.
AB  - Regional cerebral phosphorus-31 magnetic resonance spectroscopy ((31)P-MRS) was
      performed in 10 non- demented Parkinson's disease patients and nine age-matched
      control subjects. Five of the patients undergoing (31)P-MRS and four additional
      Parkinson's disease patients had cerebral 2-[(18)F]fluoro-2-deoxy-D-glucose PET
      ((18)FDG-PET), the results of which were compared with those of eight age-matched
      control subjects. All Parkinson's disease patients underwent neuropsychological
      testing including performance and verbal subtests of the Wechsler Adult
      Intelligence Scale-Revised, Boston Naming Test, Controlled Oral Word Association
      test (FAS Test) and California Learning Test to exclude clinical dementia. (31)P
      MR spectra from right and left temporo-parietal cortex, occipital cortex and a
      central voxel incorporating basal ganglia and brainstem were obtained. (31)P MR
      peak area ratios of signals from phosphomonoesters (PMEs), inorganic phosphate
      (P(i)), phosphodiesters (PDEs), alpha-ATP, gamma-ATP and phosphocreatine (PCr)
      relative to beta-ATP were measured. Relative percentage peak areas of PMEs, P(i),
      PDEs, PCr, and alpha-, beta- and gamma-ATP signals were also measured with
      respect to the total (31)P-MRS signal. Significant bilateral increases in the
      P(i)/beta-ATP ratio were found in temporoparietal cortex (P = 0.002 right and P =
      0.014 left cortex) for the non-demented Parkinson's disease patients compared
      with controls. In the right temporoparietal cortex, there was also a significant
      increase in the mean relative percentage P(i) (P = 0.001). (18)FDG-PET revealed
      absolute bilateral reductions in glucose metabolism after partial volume effect
      correction in posterior parietal and temporal cortical grey matter (P < 0.01 and
      P < 0.05, respectively) for the Parkinson's disease group, using both volume of
      interest analysis and statistical parametric mapping. There were significant
      correlations between right temporoparietal P(i)/beta-ATP ratios and estimated
      reductions in performance IQ (r = 0.96, P < 0.001). Left temporoparietal
      P(i)/beta-ATP ratios correlated with full scale IQ and verbal IQ (r = -0.82, P =
      0.006, r = -0.86, P = 0.003, respectively). In summary, temporoparietal cortical
      hypometabolism was seen in non-demented Parkinson's disease patients with both
      (31)P-MRS and (18)FDG-PET, suggesting that both glycolytic and oxidative pathways
      are impaired. This dysfunction may reflect either the presence of primary
      cortical pathology or deafferentation of striato-cortical projections. (31)P-MRS
      and (18)FDG-PET may both provide useful predictors of future cognitive impairment
      in a subset of Parkinson's disease patients who go on to develop dementia.

PMID- 10648440
TI  - Rapid eye movement sleep behaviour disorder: demographic, clinical and laboratory
      findings in 93 cases.
AB  - We describe demographic, clinical, laboratory and aetiological findings in 93
      consecutive patients with rapid eye movement (REM) sleep behaviour disorder
      (RBD), which consists of excessive motor activity during dreaming in association
      with loss of skeletal muscle atonia of REM sleep. The patients were seen at the
      Mayo Sleep Disorders Center between January 1, 1991 and July 31, 1995. Eighty-one
      patients (87%) were male. The mean age of RBD onset was 60.9 years (range 36-84
      years) and the mean age at presentation was 64.4 years (37-85 years). Thirty-two
      per cent of patients had injured themselves and 64% had assaulted their spouses.
      Subdural haematomas occurred in two patients. Dream content was altered and
      involved defence of the sleeper against attack in 87%. The frequency of nocturnal
      events decreased with time in seven untreated patients with neurodegenerative
      disease. MRI or CT head scans were performed in 56% of patients. Although four
      scans showed brainstem pathology, all of these patients had apparently unrelated
      neurodegenerative diseases known to be associated with RBD. Neurological
      disorders were present in 57% of patients; Parkinson's disease, dementia without
      parkinsonism and multiple system atrophy accounted for all but 14% of these. RBD
      developed before parkinsonism in 52% of the patients with Parkinson's disease.
      Five of the 14 patients with multiple system atrophy were female, and thus the
      strong male predominance in RBD is less evident in this condition. Psychiatric
      disorders, drug use or drug withdrawal were rarely causally related to RBD.
      Clonazepam treatment of RBD was completely or partially successful in 87% of the
      patients who used the drug. We conclude that RBD is a well-defined condition and
      that descriptions from different centres are fairly consistent. It is commonest
      in elderly males and may result in serious morbidity to patients and bed
      partners. There is a strong relationship to neurodegenerative disease, especially
      Parkinson's disease, multiple system atrophy and dementia, and neurologists
      should explore the possibility of RBD in patients with these conditions. RBD
      symptoms may be the first manifestations of these disorders and careful follow-up
      is needed. Neuroimaging is unlikely to reveal underlying disorders not suspected
      clinically. We confirm the effectiveness of clonazepam, but note that attention
      to the safety of the bed environment may be sufficient for patients with
      contraindications to the drug.

PMID- 10648442
TI  - Electrophysiological evidence for an early(pre-attentive) information processing
      deficit in patients with right hemisphere damage and unilateral neglect.
AB  - Patients with right hemisphere damage and contralesional neglect are often
      unaware of visual, auditory or tactile stimuli occurring on their left side. In
      an effort to understand the contribution of pre-attentive processes to this
      phenomenon, we examined the processing of the pitch, duration and spatial
      location of auditory stimuli using an electrophysiological probe, the mismatch
      negativity (MMN). This event-related brain potential indexes the integrity of
      cerebral processes that respond automatically to deviations from regularity in
      the acoustic environment. We compared the MMN elicited by right- and left-sided
      deviant stimuli in 10 patients with left unilateral neglect and 10 age-matched
      healthy volunteers, exploring an anticipated dissociation between the processing
      of spatial localization of sounds and the processing of the other auditory
      dimensions. Across dimensions, the MMN elicited by deviance occurring to the left
      of the patients was reduced relative to that elicited by deviance occurring to
      the right. This effect was robust for spatial location, and less so for pitch,
      whereas the processing of stimulus duration was not significantly affected by the
      side of stimulation. In healthy subjects, deviance in either side elicited
      similar MMN. We suggest that an early deficit in detecting changes in the
      environment hampers the involuntary triggering of attention in those patients and
      discuss the specific role of encoding spatial location in the establishment of
      conscious awareness.

PMID- 10648443
TI  - Preservation of midbrain catecholaminergic neurons in very old human subjects.
AB  - Parkinson's disease is characterized by a progressive degeneration of
      dopaminergic neurons in the midbrain, yet the cause of this neuronal loss is
      still unknown. It has been hypothesized that Parkinson's disease could be the
      consequence of accelerated ageing. In order to reveal a possible common process
      during ageing and Parkinson's disease neurodegeneration, catecholaminergic
      neurons of five anatomical regions of the brainstem (substantia nigra, central
      grey substance, ventral tegmental area, peri- and retrorubral area, and locus
      coeruleus) have been quantified using immunohistochemical staining for tyrosine
      hydroxylase (TH) on regularly spaced sections, between the rostral and caudal
      poles of the mesencephalon and in the rostral pole of the pons, in post-mortem
      samples of 21 control subjects who died at ages 44-110 years. No statistically
      significant loss of TH positive neurons was observed in the older subjects,
      either in the substantia nigra or in the other midbrain regions that are known to
      degenerate to a lesser degree in Parkinson's disease. Furthermore, in the later
      regions no neuronal loss was observed from age 44 to 80 years, indicating that
      this result is not dependent on the inclusion of 'supernormal' very old people.
      These results suggest that from age 44 to 110 years, ageing in control adults is
      not, or is scarcely, accompanied by catecholaminergic cell loss in the midbrain
      and hence Parkinson's disease is probably not caused by an acceleration of a
      degenerative process during ageing.

PMID- 10648444
TI  - Synergistic effect of beta-amyloid protein and interferon gamma on nitric oxide
      production by C2C12 muscle cells.
AB  - Nitric oxide (NO) is an important mediator of diverse physiological and
      pathological responses. NO-induced oxidative stress has been proposed in the
      pathogenesis of muscle tissue damage in inclusion-body myositis (IBM), which is
      characterized by deposition of beta-amyloid protein (Abeta) in vacuolated muscle
      fibres. To determine whether Abeta can induce NO production in skeletal muscle,
      we stimulated C2C12 mouse skeletal muscle cells in vitro with Abeta[1-42] or
      Abeta[25-35] peptides in the presence or absence of interferon gamma (IFN-gamma).
      Neither Abeta peptides nor IFN-gamma were able to stimulate nitrite (NO(2)(-))
      production by C2C12 cells when given alone. However, combination of IFN-gamma
      with either Abeta[1-42] or Abeta[25-35] resulted in significant NO(2)(-) release
      into cell-free supernatants. Northern blot analysis of RNA obtained from
      Abeta/IFN-gamma-stimulated C2C12 cells revealed increased mRNA accumulation of
      inducible nitric oxide synthase (iNOS). Moreover, approximately 4% of muscle
      cells incubated with Abeta peptides and IFN-gamma showed ultrastructural features
      of DNA fragmentation. These findings, taken together, indicate that the
      association of Abeta with IFN-gamma stimulates NO(2)(-) production via induction
      of iNOS gene expression in skeletal muscle cells, with occasional evidence for
      nuclear changes suggesting apoptotic morphology. These data further support a
      role for Abeta deposition in the pathogenesis of postulated oxidative damage in
      IBM.

PMID- 10648445
TI  - The coordination of bimanual prehension movements in a centrally deafferented
      patient.
AB  - Many everyday tasks require that we use our hands co-operatively, for example,
      when unscrewing a jar. For tasks where both hands are required to perform the
      same action, a common motor programme can be used. However, where each hand needs
      to perform a different action, some degree of independent control of each hand is
      required. We examined the coordination of bimanual movement kinematics in a
      female patient recovering from a cerebrovascular accident involving anterior
      regions of the parietal lobe of the right hemisphere, which resulted in a dense
      hemianaesthesia of her left arm. Our results indicate that unimanual movements
      executed by our patient using her non-sensate hand are relatively unimpaired. In
      contrast, during bimanual movements, reaches executed by our patient using her
      non-sensate hand show gross directional errors and spatiotemporal irregularities,
      including the inappropriate coupling of movement velocities. These data are
      discussed with reference to the role played by limb proprioception in the
      planning and control of prehension movements.

PMID- 10648446
TI  - Cortical motor reorganization in akinetic patients with Parkinson's disease: a
      functional MRI study.
AB  - Using functional MRI (fMRI), we have studied the changes induced by the
      performance of a complex sequential motor task in the cortical areas of six
      akinetic patients with Parkinson's disease and six normal subjects. Compared with
      the normal subjects, the patients with Parkinson's disease exhibited a relatively
      decreased fMRI signal in the rostral part of the supplementary motor area (SMA)
      and in the right dorsolateral prefrontal cortex, as previously shown in PET
      studies. Concomitantly, the same patients exhibited a significant bilateral
      relative increase in fMRI signal in the primary sensorimotor cortex, lateral
      premotor cortex, inferior parietal cortex, caudal part of the SMA and anterior
      cingulate cortex. These fMRI data confirm that the frontal hypoactivation
      observed in patients with Parkinson's disease is restricted to the rostral part
      of the SMA and to the dorsolateral prefrontal cortex. These results also show
      that, apart from the lateral premotor and parietal cortices, increased fMRI
      signals can be found in other cortical motor areas of these patients, including
      the posterior SMA, the anterior cingulate cortex and the primary sensorimotor
      cortices, which are then likely to participate in the same putative attempt by
      the dopamine-denervated brain to recruit parallel motor circuits in order to
      overcome the functional deficit of the striatocortical motor loops.

PMID- 10648448
TI  - The neural systems sustaining face and proper-name processing

PMID- 10648447
TI  - Language processing in both sexes: evidence from brain studies.

PMID- 10648449
TI  - Clinical genetics of familial progressive supranuclear palsy

PMID- 10648450
TI  - Status dystonicus: the syndrome and its management

PMID- 10648451
TI  - The genomic era: from DNA to patient and back to DNA.

PMID- 10648452
TI  - Effects of sildenafil on esophageal motility of patients with idiopathic
      achalasia.
AB  - BACKGROUND & AIMS: Sildenafil shows an intense and prolonged inhibitory effect on
      the smooth muscle cells of the human corpus cavernosum by blocking
      phosphodiesterase type 5 that destroys nitric oxide-stimulated cyclic guanosine
      monophosphate. We investigated if sildenafil possesses a similar effect on the
      esophageal musculature of patients with achalasia, where there is an impairment
      of nitric oxide production similar to that of functional impotence. METHODS: In
      14 patients affected by achalasia with an esophageal diameter of </=5 cm,
      esophageal motility was recorded with a low-compliance manometric system. After a
      basal period of 30 minutes, a 50-mg tablet of sildenafil dissolved in water was
      infused in the stomach in 7 patients and one of placebo in the other 7 patients,
      randomly and in double-blind manner, continuing the recording for 60 minutes.
      RESULTS: Lower esophageal sphincter tone, residual pressure, and wave amplitude
      after sildenafil showed a significant decrease compared with both the basal
      period and the placebo group, with a marked interpatient variability. The
      inhibitory effect reached its maximum (about -50%) 15-20 minutes after the
      infusion and lasted <1 hour. Propagation of pressure waves was not modified by
      sildenafil. CONCLUSIONS: Sildenafil inhibits the contractile activity of the
      esophageal musculature of patients with achalasia, decreasing lower esophageal
      sphincter tone and residual pressure as well as contraction amplitude.

PMID- 10648453
TI  - Microprocessor-controlled movement of solid gastric content using sequential
      neural electrical stimulation.
AB  - BACKGROUND & AIMS: Gastric electrical stimulation has been attempted for years
      without much success. The aim of this study was to determine if movement of solid
      gastric content could be achieved using microprocessor-controlled sequential
      electrical stimulation. METHODS: The study was performed on 9 anesthetized dogs.
      The dogs underwent laparotomy, pyloroplasty, and implantation of 4-6 sets of
      bipolar stainless-steel wire electrodes. Each set consisted of 2-6 electrodes (10
      x 0.25 mm, 3 cm apart) implanted circumferentially. The stomach was filled with
      solid food mixed with plastic pellets, and the process of gastric emptying was
      monitored. Artificial contractions were produced using microprocessor-controlled
      phase-locked bipolar trains of 50-Hz rectangular voltage with flexible
      amplitudes. RESULTS: Using the above stimulating parameters, we were able to
      produce circumferential gastric contractions that were artificially propagated
      distally by embedding and phase-locking the stimulating voltage. The number of
      expelled pellets after the stimulation sessions was significantly higher than the
      number of pellets emptied during the nonstimulation sessions (P < 0.01).
      CONCLUSIONS: Microprocessor-controlled electrical stimulation produced artificial
      peristalsis and markedly accelerated the movement of solid gastric content.

PMID- 10648454
TI  - Prophylaxis of postoperative relapse in Crohn's disease with mesalamine: European
      Cooperative Crohn's Disease Study VI.
AB  - BACKGROUND & AIMS: This study investigated if long-term treatment with high-dose
      mesalamine reduces the risk of clinical relapse of Crohn's disease after surgical
      resection. METHODS: In a prospective, randomized, double-blind, multicenter
      study, 4 g of mesalamine (Pentasa; Ferring A/S, Vanlose, Denmark) daily was
      compared with placebo in 318 patients. Treatment was started within 10 days after
      resective surgery and continued for 18 months. Primary outcome parameter was
      clinical relapse as defined by an increase in Crohn's Disease Activity Index,
      reoperation, septic complication, or newly developed fistula. Risk factors for
      recurrence were prospectively defined to be analyzed in a stepwise proportional
      hazards model. RESULTS: Cumulative relapse rates (+/-SE) after 18 months were
      24.5% +/- 3.6% and 31.4% +/- 3.7% in the mesalamine (n = 152) and placebo (n =
      166) groups, respectively (P = 0.10, log-rank test, 1-sided). Retrospective
      analysis showed a significantly reduced relapse rate with mesalamine only in a
      subgroup of patients with isolated small bowel disease (n = 124; 21.8% +/- 5.6%
      vs. 39.7% +/- 6.1%; P = 0.02, log-rank test). Probability of relapse was
      predominantly influenced by the duration of disease (P = 0.0006) and steroid
      intake before surgery (additional risk, P = 0.0003). CONCLUSIONS: Eighteen months
      of mesalamine, 4 g daily, did not significantly affect the postoperative course
      of Crohn's disease. Some relapse-preventing effect was found in patients with
      isolated small bowel disease.

PMID- 10648455
TI  - Clinical phenotype is related to HLA genotype in the peripheral arthropathies of
      inflammatory bowel disease.
AB  - BACKGROUND & AIMS: The detection of phenotype-determining genes as opposed to
      disease susceptibility genes requires precise phenotypic characterization of
      patients. Peripheral arthropathies in inflammatory bowel disease (IBD) are well
      recognized and are classified with the HLA-B*27-related spondyloarthropathies by
      the European Spondyloarthropathy Study Group. However, previous HLA studies in
      IBD have only shown this association with axial disease rather than peripheral
      arthropathy. We recently reported a clinical classification that describes 2
      types of peripheral arthropathy, distinguished by their natural history and
      articular distribution. We now report the results of immunogenetic studies in
      these patients and compare them with other spondyloarthropathies. METHODS: IBD
      patients with type 1 (n = 57) and type 2 (n = 45) peripheral arthropathy were
      identified by case note review and questionnaire. Patients and 603 controls from
      Oxfordshire were assigned HLA-A, -B, -C, -DR, and -DQ genotypes by sequence
      specific primer polymerase chain reaction. Patient results were compared with
      controls (corrected for multiple comparisons), then with each other in light of
      existing hypotheses. The results were compared with those of a cohort of 30
      patients with postenteric reactive arthritis (ReA) and 16 patients with IBD
      associated ankylosing spondylitis (IBD-AS). RESULTS: Type 1 arthropathy was
      associated with HLA-DRB1*0103 (DR103; a rare subtype of DR1) in 33% (P < 0.0001;
      relative risk [RR], 12.1), B*35 in 30% (P = 0.01; RR, 2.2), and B*27 in 26% (P =
      0. 001; RR, 4.0). In contrast, type 2 was associated with HLA-B*44 in 62% (P =
      0.01; RR, 2.1). Similar significant associations to type 1 arthropathy were found
      in ReA, except that the HLA-B*27 association was significantly stronger and an
      association was found with DRB1*0101 (DR1) in 43% (P = 0.001; RR, 2.2). IBD-AS
      was associated only with HLA-B*27 and DRB1*0101. CONCLUSIONS: These data suggest
      that the clinical classification into type 1 and type 2 arthropathies describes
      immunogenetically distinct entities and establish that in polygenic disorders,
      genes may determine clinical phenotype without conferring overall disease
      susceptibility (in this case, HLA genes). Type 1 arthropathy is clinically and
      immunogenetically similar to the spondyloarthropathies, but different HLA
      associations may define phenotypically distinct groups. Type 2 arthropathy has
      different HLA associations and may have a different etiology. Further studies are
      now required to confirm these associations and to elucidate the different
      pathogenetic mechanisms.

PMID- 10648456
TI  - High multidrug resistance (P-glycoprotein 170) expression in inflammatory bowel
      disease patients who fail medical therapy.
AB  - BACKGROUND & AIMS: The multidrug resistance (MDR) gene codes for a drug efflux
      pump P-glycoprotein 170 (Pgp-170) expressed on the surface of lymphocytes and
      intestinal epithelial cells. Inflammatory bowel disease (IBD) poorly responsive
      to medical therapy may relate to MDR expression because glucocorticoids are known
      Pgp-170 substrates. METHODS: Using flow cytometry, we measured peripheral blood
      lymphocyte (PBL) MDR in 153 IBD patients and 50 healthy volunteers, and assessed
      the relationship between PBL, mucosal intraepithelial lymphocyte (IEL), and
      mucosal epithelial cell (EC) MDR expression in a further 20 IBD patients and 19
      controls. RESULTS: Compared with controls, PBL MDR was significantly elevated in
      patients with Crohn's disease who required bowel resection for failed medical
      therapy (mean +/- SEM, 26.7 +/- 2.8 vs. 11.9 +/- 1.0; P <0.0001) and patients
      with ulcerative colitis who required proctocolectomy for failed medical therapy
      (20.3 +/- 2.5 vs. 11.9 +/- 1.0; P = 0.001). PBL MDR remained stable over time and
      was not influenced by disease activity or glucocorticoid therapy. Both PBL and
      mucosal MDR expression appeared independent of disease activity, and there was a
      significant correlation between PBL MDR expression and both IEL expression (r =
      0.92; P < 0.0001) and EC expression (r = 0.54; P < 0.001). CONCLUSIONS: PBL and
      mucosal MDR expression may play an important role in determining the response of
      IBD patients to glucocorticoid therapy.

PMID- 10648457
TI  - Adhesion molecules expressed on homing lymphocytes in model intestinal epithelia.
AB  - BACKGROUND & AIMS: The development of intestinal intraepithelial lymphocytes
      (IELs) requires the movement of lymphocytes into the epithelial compartment
      (i.e., IEL homing). The rules governing and the biologic consequences of IEL
      homing are poorly understood. The aims of this study were to examine the adhesion
      molecules involved in IEL homing and the phenotypic alteration of lymphocytes as
      a consequence of homing. METHODS: We previously developed an in vitro IEL homing
      model consisting of human IEL cell lines and a polarized monolayer of human
      intestinal epithelial T84 cells. Homing capacity of lymphocytes was assessed by
      measuring their migration into epithelial monolayers, and phenotypic analysis was
      performed by flow cytometry. RESULTS: In this model, approximately 30% of
      lymphocytes moved into the epithelial monolayer, regardless of the lymphocyte
      concentration. Flow cytometric screening of adhesion molecules revealed that
      homed lymphocytes expressed high levels of integrin alphaXbeta2 and alphaEbeta7
      and low levels of alpha4beta7 compared with non-homed lymphocytes. In addition,
      subpopulations sorted as alphaXbeta2(high) or alphaEbeta7(high) independently
      showed greater homing capacities. After homing, alphaEbeta7 and intercellular
      adhesion molecule 1 (ICAM-1) on homed lymphocytes were significantly up
      regulated, which was consistent with their high expression observed on freshly
      isolated human IELs. The up-regulation of alphaEbeta7 (but not ICAM-1) was
      completely dependent on epithelial-derived transforming growth factor beta1 (TGF
      beta1). The expression of alphaXbeta2 was observed on a small population of
      freshly isolated human IELs, and was markedly induced by stimulation. Also,
      epithelial-derived TGF-beta1 down-regulated the alphaXbeta2 expression (an event
      likely to occur after homing). CONCLUSIONS: Our findings indicate a relationship
      between IEL alphaXbeta2 and alphaEbeta7 expression and homing into intestinal
      epithelia. We also show that phenotypic alteration of IELs is induced by close
      interaction with intestinal epithelia as a consequence of homing.

PMID- 10648458
TI  - The effect of insulin on human small intestinal mucosal protein synthesis.
AB  - BACKGROUND & AIMS: Insulin deficiency was recently shown to stimulate splanchnic
      protein synthesis in vivo, whereas insulin enhances small intestinal mucosal cell
      proliferation in vitro. Because insulin is a postprandial hormone, it was
      hypothesized that it has an important role in regulating small intestinal protein
      synthesis in humans. METHODS: Small intestinal mucosal protein synthesis was
      measured in C-peptide-negative patients with type 1 diabetes mellitus during
      insulin deprivation (n = 6) and during insulin treatment (n = 6) and in
      nondiabetic control subjects (n = 6). Mucosal protein synthesis was measured from
      the increment of [(13)C]leucine enrichment in endoscopically obtained duodenal
      mucosa samples during a primed continuous infusion of L-[1-(13)C]leucine.
      RESULTS: During insulin treatment, the rate of mucosal protein synthesis in
      patients with type 1 diabetes was similar (1.32% +/- 0.05%/h) to that of
      nondiabetic controls (1.33% +/- 0.06%/h). However, during insulin deprivation,
      the mucosal protein synthesis rate in patients with type 1 diabetes was
      significantly lower (1.15% +/- 0.33%/h) than during either insulin treatment (P =
      0.01) or in nondiabetic controls (P = 0.04). CONCLUSIONS: These studies show that
      insulin is required for the maintenance of normal rates of protein synthesis in
      small intestinal mucosa. Because protein synthesis is an essential component of
      the remodeling process of this fast turning over tissue, the decline in the
      synthesis rate of small intestinal mucosa during insulin deprivation may be a
      contributing factor in the development of gastrointestinal complications that
      occur in poorly controlled type 1 diabetic patients.

PMID- 10648459
TI  - A predominant Th1 type of immune response is induced early during acute
      Helicobacter pylori infection in rhesus macaques.
AB  - BACKGROUND & AIMS: The immune response of gastric T cells during acute
      Helicobacter pylori infection has not been previously characterized. The aim of
      this study was to delineate the phenotypic and functional responses of gastric T
      cells during acute H. pylori infection of rhesus macaques. METHODS: Four monkeys
      were experimentally infected with H. pylori. Gastric biopsy specimens and
      peripheral blood samples were obtained 1 and 12 weeks after inoculation. Samples
      from 3 animals uninfected with H. pylori served as controls. The immunophenotypic
      changes and functional potential of CD4(+) and CD8(+) T cells in gastric mucosa
      and peripheral blood to produce cytokines (interleukin [IL]-2, IL-4, IL-13,
      interferon [IFN]-gamma, MIP-1beta, and tumor necrosis factor [TNF]-alpha) were
      determined at a single cell level using flow cytometry. RESULTS: An increase in
      CD4(+) T cells occurred in the gastric mucosa during acute H. pylori infection as
      early as 1 week after infection. Acute infection was characterized by a
      predominantly T helper (Th)1 (IL-2 and IFN-gamma) and proinflammatory (TNF-alpha
      and MIP-1beta) type of cytokine response and the absence of a Th2 type of
      response. CONCLUSIONS: A predominant Th1 type response was induced early during
      acute H. pylori infection and may contribute to the development of gastric
      disease.

PMID- 10648461
TI  - Distal and deglutitive inhibition in the rat esophagus: role of inhibitory
      neurotransmission in the nucleus tractus solitarii.
AB  - BACKGROUND & AIMS: This study aimed to show the presence of deglutitive and
      distal inhibition in the rat esophagus and to differentiate the underlying neural
      mechanisms. METHODS: Under urethane anesthesia, the pharyngoesophageal tract was
      fitted with water-filled balloons for luminal distention and pressure recording.
      Neural activity was recorded in the nucleus tractus solitarii subnucleus
      centralis and rostral nucleus ambiguous. RESULTS: Distal esophageal distention
      evoked both rhythmic local contractions and burst discharges of ambiguous neurons
      that were simultaneously inhibited by a swallow or proximal esophageal
      distention. In subnucleus centralis interneurons, type I rhythmic burst
      discharges correlated with distal esophageal pressure waves and were suppressed
      by midthoracic esophageal distention; type II non-rhythmic excitatory responses,
      like type III inhibitory responses, were evoked by distention of either the
      thoracic or distal esophagus. When applied to the surface of the solitarius
      complex, bicuculline and, less effectively, strychnine suppressed distal
      inhibition, and 2-(OH)-saclofen and 3-aminopropylphosphonic acid were
      ineffective. None of the drugs tested, including systemic picrotoxin, affected
      deglutitive inhibition. CONCLUSIONS: Distal and deglutitive inhibition are
      present in the rat esophagus. The former, unlike the latter, depends on
      activation of ligand-gated chloride channels associated with subnucleus centralis
      premotor neurons. Inhibitory aminoacidergic local interneurons are a probable
      source of type II responses.

PMID- 10648460
TI  - Role of inducible nitric oxide synthase in postoperative intestinal smooth muscle
      dysfunction in rodents.
AB  - BACKGROUND & AIMS: We have shown that intestinal manipulation leads to a
      significant inhibition of circular muscle contraction. We hypothesized that the
      inflammatory mediator inducible nitric oxide (NO) plays a role in surgically
      induced ileus. METHODS: Rats and inducible NO synthase (iNOS) knockout and wild
      type mice underwent a simple intestinal manipulation. Reverse-transcription
      polymerase chain reaction and immunohistochemistry were used to detect and
      localize iNOS expression. Nitrite and NO production were measured in muscularis
      cultures. Spontaneous and bethanechol-stimulated jejunal circular muscle
      contractions were measured in an organ bath. RESULTS: Intestinal manipulation
      resulted in significant iNOS messenger RNA induction in mucosa and muscularis.
      Immunohistochemistry localized iNOS in phagocytes within the muscularis. Nitrite
      and NO production increased 59.8-fold 24 hours after manipulation. L-n(6)-(1
      iminoethyl) lysine (L-NIL) inhibited this response. In control rats, selective
      iNOS inhibition did not increase spontaneous muscle activity, but after
      manipulation L-NIL significantly improved spontaneous activity. iNOS knockout
      mice showed a significant 81% decrease in neutrophil infiltration into the
      muscularis after intestinal manipulation compared with wild-types. Contractile
      activity was normal in knockout mice after intestinal manipulation. CONCLUSIONS:
      These results show that leukocyte-derived inducible NO inhibits gastrointestinal
      motility after manipulation and plays an essential role in the initiation of
      intestinal inflammation.

PMID- 10648462
TI  - Cyclooxygenase 2 expression is increased in the stroma of colon carcinomas from
      IL-10(-/-) mice.
AB  - BACKGROUND & AIMS: The pathological and molecular changes associated with colitis
      associated colorectal cancer and sporadic colorectal cancer are considered to be
      distinct. Therefore, we have used a mouse model of ulcerative colitis to
      determine if expression of the enzyme cyclooxygenase (COX)-2 is increased in
      colitis-associated tumors. METHODS: Reverse-transcription polymerase chain
      reaction and Western analysis were used to determine if COX-2 expression is
      increased in these tumors; in situ hybridization and immunohistochemistry were
      used to determine the localization of COX-2. RESULTS: Increased levels of COX-2
      messenger RNA and protein were detected in interleukin (IL)-10 (-/-) tumors and
      in an inflamed region of the colon that contained no macroscopically detected
      tumors. This expression was localized to the inflammatory cells associated with
      ulcerated regions of the tumor by in situ hybridization and immunohistochemistry.
      Increased COX-2 expression was also associated with the areas of the tumor
      expressing alpha-smooth muscle actin, which is a molecular marker for
      subepithelial myofibroblasts. The association between COX-2 expression and
      subepithelial myofibroblasts was also noted in tumors derived from the multiple
      intestinal neoplasia mice (Min/+) and from carcinogen-induced tumors.
      CONCLUSIONS: These results indicate that COX-2 is expressed very early in the
      pathogenesis of colitis-associated tumors, and that the expression pattern is
      similar to that seen in tumors from azoxymethane-treated and Min/+ mice.

PMID- 10648463
TI  - Hepatitis C virus-specific T-cell reactivity during interferon and ribavirin
      treatment in chronic hepatitis C.
AB  - BACKGROUND & AIMS: The role of virus-specific T-helper lymphocyte reactivity in
      determining the therapeutic response in chronic hepatitis C virus (HCV) infection
      is not fully understood. METHODS: We studied CD4(+) T lymphocyte proliferation
      together with interferon (IFN)-gamma and interleukin (IL)-10 production from
      peripheral blood mononuclear cells in response to 4 HCV antigens (core, NS3, NS4,
      and NS5) in 25 patients with chronic hepatitis C undergoing antiviral therapy
      with IFN alone or in combination with ribavirin, prospectively, before, during,
      and after treatment. RESULTS: HCV-specific T-cell reactivity was uncommon at
      baseline but increased markedly during antiviral therapy, peaking around
      treatment weeks 4-8. Resolution of hepatitis C viremia was significantly more
      likely in patients who developed HCV-specific T-cell proliferation with increased
      IFN-gamma production. The main difference in T-cell reactivity of patients
      treated with IFN plus ribavirin was a significantly lower production of IL-10,
      whereas lymphocyte proliferation was similar to that in patients receiving IFN
      monotherapy. CONCLUSIONS: Treatment-induced control of hepatitis C viremia is
      associated with the development of HCV-specific T-cell responses with enhanced
      IFN-gamma and low IL-10 production. The greater efficacy of combination therapy
      with IFN-alpha plus ribavirin may be related to its ability to suppress HCV
      specific IL-10 production.

PMID- 10648464
TI  - Differential expression of chemokines in normal pancreas and in chronic
      pancreatitis.
AB  - BACKGROUND & AIMS: Cellular infiltrates are present already in early stages of
      chronic pancreatitis. The mechanisms responsible for their recruitment are
      unknown. Hence, we determined the differential expression of chemokine genes and
      their cellular sources in normal and affected pancreatic tissues. METHODS:
      Pancreatic tissues from 23 patients with chronic pancreatitis and from 4 normal
      controls were subjected to in situ hybridization for detecting messenger RNA
      (mRNA) of the chemokine genes interleukin 8, ENA-78, MIG, MCP-1, and I-309.
      RESULTS: Normal pancreatic tissues lack cells expressing mRNA for IL-8, ENA-78,
      MIG, and MCP-1. In contrast, pancreatic lobuli with mild to moderate signs of
      tissue alterations strongly expressed MCP-1 mRNA in centroacinar ducts,
      endothelia, fibroblasts, macrophages, T cells, and occasionally in nerves.
      Interleukin 8 and ENA-78 mRNA is preferentially detected in centroacinar ducts of
      pancreatic lobuli with more advanced alterations. Variable numbers of pancreas
      infiltrating T cells express MIG mRNA. I-309 mRNA, however, is consistently
      observed in normal acini and in tissue with mild to moderate signs of tissue
      alterations. CONCLUSIONS: The observed differential expression of distinct
      chemokine genes in pancreatic parenchyma and infiltrates from patients with
      chronic pancreatitis strongly suggests an involvement of distinct chemokines in
      the initiation and perpetuation of disease.

PMID- 10648465
TI  - Mechanisms of attachment and internalization of Cryptosporidium parvum to biliary
      and intestinal epithelial cells.
AB  - BACKGROUND & AIMS: Although infection of the intestinal and biliary tracts by
      Cryptosporidium parvum is a major problem in patients with the acquired
      immunodeficiency syndrome, the specific microbial and host molecules involved in
      C. parvum infection are unknown. We tested the hypothesis that lectin
      carbohydrate interactions and cytoskeleton reorganization are involved in the
      infection of biliary and intestinal epithelia by C. parvum. METHODS: In vitro
      models of cryptosporidial infection using human biliary and intestinal epithelial
      cell lines were used to assay C. parvum attachment and invasion. RESULTS:
      Exposure of C. parvum sporozoites to the sugar, galactose-N-acetylgalactosamine
      (Gal/GalNAc), and to bovine mucin reduced C. parvum attachment to biliary and
      intestinal epithelia up to 70%. Preincubation of cell monolayers with either
      lectins specific to Gal/GalNAc, or glycosidases that specifically release
      Gal/GalNAc oligosaccharides from glycoproteins, decreased attachment up to 80%.
      Cytochalasin B and cytochalasin D, but not nocodazole, decreased invasion of
      cells by C. parvum up to 70% without affecting attachment. During cell invasion
      (but not attachment), confocal microscopy showed recruitment of actin (but not
      tubulin) in biliary and intestinal epithelia directly adjacent to C. parvum.
      CONCLUSIONS: Gal/GalNAc epitopes of glycoproteins on the epithelial apical
      membrane and Gal/GalNAc-specific sporozoite surface lectins are involved in the
      mechanism(s) of C. parvum attachment to intestinal and biliary epithelial cells,
      and actin remodeling in host cells is required for C. parvum invasion.

PMID- 10648466
TI  - Genipin, a metabolite derived from the herbal medicine Inchin-ko-to, and
      suppression of Fas-induced lethal liver apoptosis in mice.
AB  - BACKGROUND & AIMS: We showed previously that a Kampo (Chinese/Japanese herbal)
      medicine, Inchin-ko-to (ICKT), inhibits hepatocyte apoptosis induced by
      transforming growth factor beta1 in vitro. The present study investigated whether
      ICKT or its ingredients inhibit Fas-mediated liver apoptosis in vivo. METHODS:
      Acute liver injury was induced by an intravenous injection of anti-Fas antibody,
      Jo2. The effects of ICKT and its ingredients on lethality, histology, apoptotic
      index, serum transaminase levels, caspase activation, mitochondrial membrane
      potential (Deltapsi(m)), and mitochondrial permeability transition (MPT) were
      analyzed. Apoptosis in mouse hepatocytes in vitro was also evaluated. RESULTS:
      Pretreatment with ICKT rescued 75% of Jo2-treated mice and markedly suppressed
      liver apoptosis/injury. Genipin, an intestinal bacterial metabolite of geniposide
      that is a major ingredient of ICKT, was found to be an active principle of ICKT.
      Genipin also suppressed in vitro Fas-mediated apoptosis in primary-cultured
      murine hepatocytes. Activation of caspase 3 and 8 in the liver homogenate and
      rapid reduction of triangle uppsi(m) of hepatocytes isolated from Jo2-treated
      mice were inhibited by genipin preadministration. The resistance to Ca(2+)
      induced MPT was enhanced in liver mitochondria of genipin-treated mice.
      CONCLUSIONS: These results suggest that the antiapoptotic activity of genipin via
      the interference with MPT is a possible mechanism for therapeutic effects of
      ICKT.

PMID- 10648467
TI  - Cryopreserved mouse hepatocytes retain regenerative capacity in vivo.
AB  - BACKGROUND & AIMS: Substitution of hepatocyte transplantation for whole liver
      transplants in selected individuals with liver disease could significantly expand
      the number of patients to benefit from use of scarce donor livers. However,
      successful hepatocyte transplantation may require that donor cells retain normal
      functional and proliferative capabilities and that they be readily available.
      Banking of cryopreserved hepatocytes would fulfill the latter requirement.
      Cryopreservation protocols have been developed that minimize hepatocyte injury
      and allow preservation of metabolic activity. The aim of this study was to assess
      cryopreserved hepatocyte proliferative capacity in vivo after thawing. METHODS:
      Fresh and frozen/thawed mouse hepatocytes were transferred separately into the
      livers of recipient mice with transgene-induced liver disease, an environment
      that is permissive for clonal expansion of donor cell populations. Fresh and
      cryopreserved donor cells were compared for their ability to proliferate and
      replace damaged parenchyma. RESULTS: Although cryopreservation decreased
      hepatocyte viability, individual viable frozen/thawed hepatocytes demonstrated
      clonal replicative potential identical to that of fresh hepatocytes. Even after
      storage for 32 months in liquid nitrogen, transplanted hepatocytes constituting
      0.1% of total adult hepatocyte number could repopulate a mean of 32% of recipient
      liver parenchyma. CONCLUSIONS: These findings suggest that cryopreserved
      hepatocytes represent an appropriate source of cells for therapeutic hepatocyte
      transplantation.

PMID- 10648468
TI  - Functional interactions between oxidative stress, membrane Na(+) permeability,
      and cell volume in rat hepatoma cells.
AB  - BACKGROUND & AIMS: Oxidative stress leads to a rapid initial loss of liver cell
      volume, but the adaptive mechanisms that serve to restore volume have not been
      defined. This study aimed to evaluate the functional interactions between
      oxidative stress, cell volume recovery, and membrane ion permeability. METHODS:
      In HTC rat hepatoma cells, oxidative stress was produced by exposure to H(2)O(2)
      or D-alanine plus D-amino acid oxidase (40 U/mL). RESULTS: Oxidative stress
      resulted in a rapid decrease in relative cell volume to 0.85 +/- 0.06. This was
      followed by an approximately 100-fold increase in membrane cation permeability
      and partial volume recovery to 0.97 +/- 0.05 of original values. The volume
      sensitive conductance was permeable to Na(+) approximately K(+) >> Tris(+), and
      whole-cell current density at -80 mV increased from -1.2 pA/pF at 10(-5) mol/L
      H(2)O(2) to -95.1 pA/pF at 10(-2) mol/L H(2)O(2). The effects of H(2)O(2) were
      completely inhibited by dialysis of the cell interior with reduced glutathione,
      and were markedly enhanced by inhibition of glutathione synthase. CONCLUSIONS:
      These findings support the presence of dynamic functional interactions between
      cell volume, oxidative stress, and membrane Na(+) permeability. Stress-induced
      Na(+) influx may represent a beneficial adaptive response that partially restores
      cell volume over short periods, but sustained cation influx could contribute to
      the increase in intracellular [Na(+)] and [Ca(2+)] associated with cell injury
      and necrosis.

PMID- 10648470
TI  - Drug- and estrogen-induced cholestasis through inhibition of the hepatocellular
      bile salt export pump (Bsep) of rat liver.
AB  - BACKGROUND & AIMS: Drug-induced cholestasis is a frequent form of acquired liver
      disease. To elucidate the molecular pathogenesis of drug-induced cholestasis, we
      investigated the effects of prototypic cholestatic drugs on the canalicular bile
      salt export pump (Bsep) of rat liver. METHODS: Vesicles were isolated from Bsep-,
      Mrp2-, and Bsep/Mrp2-expressing Sf9 cells. Canalicular plasma membrane (cLPM)
      vesicles from rat liver and Sf9 cell vesicles were used to study adenosine
      triphosphate (ATP)-dependent solute uptake by a rapid filtration technique.
      RESULTS: Bsep-expressing Sf9 cell vesicles showed ATP-dependent transport of
      numerous monoanionic bile salts with similar Michaelis constant values as in cLPM
      vesicles, whereas several known substrates of the multispecific organic anion
      transporter Mrp2 were not transported by Bsep. Cyclosporin A, rifamycin SV,
      rifampicin, and glibenclamide cis-inhibited Bsep-mediated bile salt transport to
      similar extents as ATP-dependent taurocholate transport in cLPM vesicles. In
      contrast, the cholestatic estrogen metabolite estradiol-17beta-glucuronide
      inhibited ATP-dependent taurocholate transport only in normal cLPM and in
      Bsep/Mrp2-coexpressing Sf9 cell vesicles, but not in Mrp2-deficient cLPM or in
      selectively Bsep-expressing Sf9 cell vesicles, indicating that it trans-inhibits
      Bsep only after its secretion into bile canaliculi by Mrp2. CONCLUSIONS: These
      results provide a molecular basis for previous in vivo observations and identify
      Bsep as an important target for induction of drug- and estrogen-induced
      cholestasis in mammalian liver.

PMID- 10648469
TI  - NO-aspirin protects from T cell-mediated liver injury by inhibiting caspase
      dependent processing of Th1-like cytokines.
AB  - BACKGROUND & AIMS: Concanavalin A (con A)-induced hepatitis is an immunomediated
      disease in which assembly of CD4(+) T cells and T helper (Th)1-like cytokines
      causes Fas-mediated liver cell death. Nitric oxide (NO) modulates Th1 response in
      vitro. NCX-4016 is an NO-aspirin derivative that spares the gastrointestinal
      tract and shares molecular targets with NO. The aim of this study was to
      investigate whether this NO-aspirin modulates Th1-like response induced by con A.
      METHODS: BALB/c mice were injected with 0.3 mg con A per mouse alone or in
      combination with NO-aspirin (18-100 mg/kg) or aspirin (10-55 mg/kg). RESULTS: NO
      aspirin, but not aspirin, caused a dose-dependent protection against liver damage
      induced by con A. At a dose of 100 mg/kg, NO-aspirin caused a 40%-80% reduction
      of interleukin (IL)-1beta, IL-12, IL-18, interferon (IFN)-gamma, and tumor
      necrosis factor alpha production without affecting cytokine messenger RNA
      expression. NO-aspirin prevented Fas, Fas ligand, and IL-2 receptor up-regulation
      on spleen lymphocytes and Fas ligand on hepatocytes and caused the S
      nitrosylation/inhibition of IL-1beta-converting enzyme-like cysteine proteases
      (caspases) involved in the processing and maturation of IL-1beta and IL-18. IL-18
      immunoneutralization prevented IFN-gamma release and protected from liver injury
      induced by con A. In contrast to a selective caspase 1 inhibitor, zVAD.FMK, a
      pancaspase inhibitor, prevented IFN-gamma release and protected the liver from
      injury. CONCLUSIONS: Th1-like response induced by con A is mediated by IL-18 and
      requires activation of multiple caspases. NCX-4016 causes the S
      nitrosylation/inhibition of caspases involved in cytokine production. Inhibition
      of Th1-like response is a new anti-inflammatory mechanism of action of NO
      aspirin.

PMID- 10648471
TI  - Florid opioid withdrawal-like reaction precipitated by naltrexone in a patient
      with chronic cholestasis.
AB  - Findings consistent with the hypothesis that increased central opioidergic tone
      contributes to the pruritus of cholestasis provide a rationale for treating this
      form of pruritus with opiate antagonists. However, initiation of therapy with an
      opiate antagonist in a cholestatic patient may precipitate a transient opioid
      withdrawal-like reaction. A woman with chronic cholestasis and disabling pruritus
      experienced severe transient opioid withdrawal-like reactions after oral
      administration of 12.5 and 2 mg naltrexone. Subsequently, naloxone was
      administered by intravenous infusion. Initially, the infusion rate was low and
      subtherapeutic. It was gradually increased to a rate known to be effective in
      inducing opioid antagonism. Oral naltrexone was then reintroduced without any
      reaction occurring. During the ensuing 12 months, while taking naltrexone, 25 mg
      daily, the patient has been completely free from pruritus. These observations
      strongly support the hypothesis that increased central opioidergic tone is a
      component of the pathophysiology of cholestasis.

PMID- 10648472
TI  - The brute force approach to electrical stimulation of gastric emptying: A future
      treatment for refractory gastroparesis?

PMID- 10648473
TI  - Mesalamine for the prevention of postoperative recurrence: is nearly there the
      same as being there?

PMID- 10648475
TI  - Neostigmine for acute colonic pseudo-obstruction: new use for an old drug?

PMID- 10648474
TI  - Alternatives to liver transplantation: from hepatocyte transplantation to tissue
      engineered organs.

PMID- 10648476
TI  - How do intestinal T cells sense the dietary and microbial environment?

PMID- 10648477
TI  - Interferon therapy prevents hepatocellular carcinoma in some patients with
      chronic HCV: the role of fibrosis.

PMID- 10648478
TI  - The oxford textbook of clinical hepatology

PMID- 10648479
TI  - Homocysteine, B vitamins, and risk of cardiovascular disease.

PMID- 10648481
TI  - Second harmonic imaging: a new tune for an old fiddle?

PMID- 10648482
TI  - Non-contrast second harmonic imaging improves interobserver agreement and
      accuracy of dobutamine stress echocardiography in patients with impaired image
      quality.
AB  - OBJECTIVE: To examine the influence of second harmonic imaging during dobutamine
      echocardiography on regional endocardial visibility, interobserver agreement in
      the interpretation of wall motion abnormalities, and diagnostic accuracy in
      patients with reduced image quality. DESIGN: Blinded comparison. SETTING:
      Tertiary care centre. PATIENTS: 103 consecutive patients with suspected coronary
      artery disease and impaired transthoracic image quality (>/= 2 segments with poor
      endocardial delineation). METHODS: Fundamental and second harmonic imaging were
      performed at each stage of a dobutamine stress echocardiography. Coronary
      angiography was undertaken within three weeks of dobutamine echocardiography in
      75 patients. MAIN OUTCOME MEASURES: Evaluation of regional endocardial visibility
      (scoring from 0 = poor to 2 = good) and of segmental wall motion abnormalities
      for both modalities separately. A second blinded examiner analysed 70 studies to
      determine interobserver agreement. RESULTS: Mean (SD) visibility score for all
      segments was 1.2 (0.4) using fundamental imaging and 1.7 (0.2) using second
      harmonic imaging at rest (p < 0.001), and 1.1 (0.4) v 1.6 (0.3), respectively, at
      peak dobutamine dose (p < 0.001). The average number of segments with poor
      endocardial visibility was lower for second harmonic than for fundamental imaging
      (0.6 (1.1) v 3.8 (2.6) at rest, p < 0.001; 0.9 (1.3) v 4.3 (2.9) at peak dose, p
      < 0.001). Improvement was most pronounced in all lateral and anterior segments.
      The kappa value for identical study interpretation increased from 0. 40 to 0.69
      (p < 0.05). Sensitivity for the diagnosis of coronary artery disease was 64%
      using fundamental imaging versus 92% using harmonic imaging (p < 0.001), while
      specificity remained unchanged at 75% for both imaging modalities. CONCLUSIONS:
      Second harmonic imaging enhances endocardial visibility during dobutamine
      echocardiography. Consequently, interobserver agreement on stress
      echocardiography interpretation and diagnostic accuracy are significantly
      improved compared to fundamental imaging. Thus, in difficult to image patients,
      dobutamine echocardiography should be performed using second harmonic imaging.

PMID- 10648483
TI  - Negative stress echocardiographic responses in normotensive and hypertensive
      patients with angina pectoris, positive exercise stress testing, and normal
      coronary arteriograms.
AB  - OBJECTIVES: To systematically compare the results of dobutamine stress
      echocardiography in matched groups of hypertensive and normotensive patients with
      anginal chest pain and normal coronary arteriograms (CPNA). SETTING: University
      hospital. SUBJECTS: 33 patients with exertional anginal chest pain, a positive
      exercise stress ECG, and a completely normal coronary arteriogram; 17 had a
      history of systemic hypertension (14 women; mean (SD) age 57 (6) years), and 16
      had no hypertensive history (12 women; age 54 (9) years). METHODS: Ambulatory ECG
      monitoring, dobutamine stress echocardiography, and thallium-201 single photon
      emission computed tomography (SPECT) were performed in all subjects. RESULTS: All
      patients had normal left ventricular systolic function at rest and none fulfilled
      the criteria for ventricular hypertrophy. Eight normotensive patients and 10
      hypertensive patients had perfusion abnormalities on thallium SPECT (p = 0.61).
      Dobutamine infusion reproduced anginal pain in seven normotensive and seven
      hypertensive patients (p = 0.88). ST segment depression was also recorded in
      eight normotensive patients and seven hypertensive patients (p = 0. 61). No
      patient in either group developed regional wall motion abnormalities during
      dobutamine stress echocardiography. CONCLUSIONS: Neither hypertensive nor
      normotensive CPNA patients developed regional wall motion abnormalities during
      dobutamine stress echocardiography, despite the high prevalence of scintigraphic
      perfusion defects in both groups and the presence of chest pain and ST segment
      depression. Thus myocardial ischaemia was not present in either group, or else
      dobutamine stress echocardiography is insensitive to ischaemia caused by
      microvascular dysfunction.

PMID- 10648484
TI  - A pre-excitation growing up over the time.

PMID- 10648485
TI  - Chronic heart failure in the elderly: value of cardiopulmonary exercise testing
      in risk stratification.
AB  - OBJECTIVE: To assess the value of cardiopulmonary exercise testing in predicting
      prognosis in a cohort of elderly patients with chronic heart failure (CHF).
      DESIGN: A retrospective cohort study of all patients with CHF over the age of 70
      years assessed between January 1992 and May 1997. SETTING: Tertiary centre.
      PATIENTS: 50 patients (mean (SD) age 75.9 (4.5) years, 8 women) with CHF New York
      Heart Association (NYHA) class I (3 patients), II (25 patients), III (20
      patients), and IV (2 patients). Follow up was complete for two years in all
      patients. RESULTS: The patients underwent cardiopulmonary exercise testing (peak
      oxygen consumption 15.2 (4.5) ml/kg/min, minute ventilation/carbon dioxide
      production (VE/VCO(2)) slope 38.7 (11.8)); radionucleide ventriculography (left
      ventricular ejection fraction 32.8 (14.3)%); serum sodium measurement (139 (2.8)
      mmol/l); and echocardiography (left ventricular end diastolic dimension 6.1 (1.1)
      cm, left ventricular end systolic dimension 4.7 (1.5) cm). At the end of follow
      up in May 1999, 26 patients had died. The median follow up of the survivors was
      47.7 months (interquartile range 31. 5-53.5 months). On univariate analysis
      VE/VCO(2) slope (p < 0.0001), NYHA class (p < 0.001), peak oxygen uptake (VO(2))
      (p < 0.01), left ventricular end systolic dimension (p < 0.05), and serum sodium
      concentration (p < 0.05) had significant predictive power. Stepwise multivariate
      analysis identified only VE/VCO(2) slope (p < 0.01), NYHA class (p < 0.05), and
      peak VO(2) (p< 0.05) as conveying significant independent prognostic information.
      CONCLUSION: Elderly patients with CHF have a high mortality, with the majority
      dead within two years. Cardiopulmonary exercise testing provides important
      information for risk stratification within this group and its use should not be
      neglected.

PMID- 10648486
TI  - "Apparent" heart failure: a syndrome caused by renal artery stenoses.
AB  - OBJECTIVE: To report on renal artery stenosis presenting as congestive heart
      failure. DESIGN: Case series. SETTING: Tertiary referral centre. PATIENTS: Nine
      hypertensive subjects (five male, four female) seen in the blood pressure unit,
      St George's Hospital, between 1991 and 1997 with clinical signs and symptoms of
      congestive cardiac failure but without overt coronary or valvar heart disease.
      Mean (SEM) age was 67 (3) years. Eight patients had renal artery
      revascularisation with percutaneous angioplasty and one had surgery. RESULTS:
      Renal revascularisation was followed by a large fall in blood pressure from
      191/94 (7/3) to 150/75 (8/5) mm Hg two days after intervention (p < 0.01). There
      was also a large natriuresis and weight reduction. One week after
      revascularisation there was a mean loss in weight of 3.8 (0.6) kg. The largest
      fall in weight was seen in those patients with stenosis in a single functioning
      kidney. Furthermore, plasma atrial natriuretic factor fell from 120 (28) to 48
      (9) pg/ml (p < 0.05; n = 6; normal value = 8.6 (0.8) pg/ml), and serum creatinine
      fell from 200 (37) to 140 (11) micromol/l (p < 0. 025). The clinical signs and
      symptoms of heart failure resolved and the diuretics were then withdrawn in all
      patients. On long term follow up, patients remained free from symptoms and signs
      of heart failure and the blood pressure was better controlled. CONCLUSIONS: In
      hypertensive patients with symptoms and signs of congestive heart failure who do
      not have obvious ischaemic or valvar heart disease, renal artery stenosis should
      be considered as a possible underlying cause. Relief of the stenosis can result
      in resolution of the apparent heart failure.

PMID- 10648487
TI  - The alveolar-capillary membrane diffusing capacity and the pulmonary capillary
      blood volume in heart transplant candidates.
AB  - OBJECTIVES: To determine the mechanism of impairment of pulmonary transfer factor
      for carbon monoxide (TL(CO)) in heart transplant candidates, as this is the most
      common lung function abnormality. SETTING: Regional cardiopulmonary transplant
      centre. METHODS: TL(CO) and its components (the diffusing capacity of the
      alveolar-capillary membrane (D(M)) and the pulmonary capillary blood volume
      (V(C))) were measured using the Roughton and Forster method and the single breath
      technique in 38 patients with severe chronic heart failure awaiting heart
      transplantation (mean age 51 years, range 19 to 61; mean left ventricular
      ejection fraction 12.8%). Results were compared with data from 26 normal subjects
      (mean age 47 years, range 27 to 62). RESULTS: Mean per cent predicted TL(CO),
      D(M), and V(C) were significantly reduced in patients (69.9%, 81.4%, and 80.2% of
      predicted, respectively) compared with controls (97.7%, 100.1%, and 102.3% of
      predicted, respectively, p < 0.001). The relative contribution of the two
      components of TL(CO) in patients was similar to that of normal subjects, with
      each component accounting for approximately 50% of the total resistance to
      diffusion (1/TL(CO)). CONCLUSIONS: TL(CO) impairment in patients with severe
      chronic heart failure awaiting heart transplantation results from a proportionate
      reduction in both D(M) and V(C), suggesting a significant disturbance of the
      pulmonary vascular bed.

PMID- 10648488
TI  - Dissociation between muscle metabolism and oxygen kinetics during recovery from
      exercise in patients with chronic heart failure.
AB  - OBJECTIVE: To estimate muscle metabolism and oxygen delivery to skeletal muscle
      in patients with chronic heart failure. METHODS: 13 patients with chronic heart
      failure and 15 controls performed calf plantar flexion for six minutes at a
      constant workload of 50% of one repetition maximum. During recovery from
      exercise, skeletal muscle content of oxygenated haemoglobin (oxy-Hb) and the
      level of phosphocreatine (PCr) were measured by near-infrared spectroscopy and
      (31)P-magnetic resonance spectroscopy, respectively. RESULTS: The mean (SD) time
      constants of PCr and oxy-Hb during recovery from exercise were significantly
      greater in patients with chronic heart failure than in normal subjects (tau PCr:
      76.3 (30.2) s v 36.5 (5.8) s; tau oxy-Hb: 48.3 (7.3) s v 30.1 (7.7) s; p < 0.01).
      Both time constants were similar in normal subjects, while the tau PCr was
      significantly greater than the tau oxy-Hb in patients with chronic heart failure.
      CONCLUSIONS: The slower recovery of PCr compared with oxy-Hb in patients with
      chronic heart failure indicates that haemoglobin resaturation is not a major rate
      limiting factor of PCr resynthesis. It is suggested that muscle metabolic
      recovery may depend more on oxygen utilisation than on haemoglobin resaturation
      or oxygen delivery in patients with chronic heart failure.

PMID- 10648489
TI  - Antianginal and anti-ischaemic efficacy of tedisamil, a potassium channel
      blocker.
AB  - OBJECTIVE: To determine the efficacy and safety of the potassium channel blocker
      tedisamil versus placebo in the treatment of patients with stable angina. DESIGN:
      Prospective, double blind, placebo controlled study. 203 patients first completed
      a seven day placebo run in. They were then randomised to receive 50 mg, 100 mg or
      150 mg tedisamil twice daily, or placebo. Treadmill exercise testing was carried
      out at baseline and after 14 days of double blind treatment. MAIN OUTCOME
      MEASURES: Primary efficacy parameters were an increase in total exercise duration
      and a reduction of the sum of ST segment depression using six ECG leads at
      maximum workload at trough (12 hours after last medication). Secondary aims
      included increase in exercise time to onset of 0.1 mV ST segment depression,
      increase in exercise time to onset of any anginal pain, and reduction in ST
      segment depression in any of the six specified leads at maximum workload. These
      were all at trough. The same parameters were also assessed at peak concentrations
      (two hours after administration). Overall attacks of angina and the use of short
      acting nitrates were assessed from patient diaries. RESULTS: Tedisamil led to a
      dose dependent prolongation of exercise duration (significant at all
      concentrations), an effect that was greater at peak than at trough. Treatment
      also led to a significant dose dependent reduction in the sum of ST segment
      depression at both trough and peak concentrations. Tedisamil also decreased (in a
      dose dependent way) the frequency of anginal attacks and the consumption of short
      acting nitrates, an improvement that became significant for all doses in the
      second treatment week. Adverse events with tedisamil were few. There was a
      pronounced rise in the incidence of diarrhoea with the 150 mg twice daily
      regimen. Bradycardic effects and increases in QT interval were dose dependent,
      but were no more evident at exercise than at rest. CONCLUSIONS: Tedisamil, at
      doses of 50-100 mg twice daily, was found to be an effective antianginal and anti
      ischaemic agent. At doses above 100 mg twice daily its main side effect,
      diarrhoea, becomes pronounced; therefore the 50-100 mg twice daily regimen
      appears to be appropriate.

PMID- 10648490
TI  - Is there a synergic effect of propafenone associated with atrial overdrive pacing
      for atrial arrhythmia prevention? A randomised crossover study.
AB  - OBJECTIVE: To assess the effect of adding propafenone to atrial overdrive for the
      prevention of atrial arrhythmia episodes in patients with DDD pacemakers. DESIGN:
      22 patients (8 female, 14 male, mean (SD) age 67 (9) years, range 48 to 77) with
      DDD pacemakers and frequent paroxysmal atrial arrhythmia episodes were evaluated
      in a randomised crossover study. SETTING: University hospital. METHODS: Atrial
      overdrive was defined as a paced rate of 10 paced beats/min above the mean
      ventricular rate stored for the last 24 hours in the pacemaker memory function.
      The protocol consisted of two phases of one month each. The first phase consisted
      of atrial overdrive alone, while in the second phase, propafenone (600 mg/day)
      was added to atrial overdrive (atrial overdrive + propafenone). All 22 patients
      underwent the two phases in random order. RESULTS: Mean ventricular rate was 72
      (8) beats/min with atrial overdrive v 73 (6) with atrial overdrive + propafenone
      (NS). With atrial overdrive, 14 patients (64. 6%) had no recorded atrial
      arrhythmia v 15 (68.2%) with atrial overdrive + propafenone (NS). There was no
      statistical difference between the atrial overdrive and atrial overdrive +
      propafenone phases with regard to the number of atrial arrhythmia episodes (14
      (27) v 13 (28)), their total duration (30 (78) v 29 (63) h), and their maximum
      duration (41 (72) v 31 (58) min). However, in the brady-tachy subgroup with
      persistent atrial arrhythmias, atrial overdrive + propafenone produced a shorter
      mean cumulative duration of atrial arrhythmia than atrial overdrive (104 (115) v
      178 (149) h, p = 0.04), with a significant decrease in the number of atrial
      arrhythmia episodes (134 (98) v 102 (83), p = 0.05). The proportion of
      asymptomatic atrial arrhythmia episodes increased only in the AV block group
      during atrial overdrive + propafenone (p = 0.03). Three patients had atrial
      arrhythmias during atrial overdrive + propafenone but not with atrial overdrive
      alone. CONCLUSIONS: In DDD paced patients, the overall effect of propafenone
      during atrial overdrive is variable. Propafenone may increase the proportion of
      asymptomatic atrial arrhythmia episodes. A proarrhythmic effect of propafenone
      was documented (aggravation of atrial arrhythmias). These results need to be
      confirmed by further larger randomised studies.

PMID- 10648491
TI  - Induction of atrial fibrillation with rapid high voltage ventricular pacing for
      ventricular fibrillation conversion testing. The Ventak AV II DR Study.
AB  - OBJECTIVE: To assess whether rapid high voltage ventricular pacing can also
      induce atrial fibrillation, and whether the induction of atrial fibrillation
      during ventricular fibrillation conversion testing is related to the patient's
      heart disease. DESIGN: Prospective study of 50 patients who received the dual
      chamber implantable cardioverter-defibrillator (ICD) Ventak AV II DR (Guidant) as
      a first implant. This device can record atrial activity even during a ventricular
      fibrillation episode and can induce atrial fibrillation by rapid atrial bursts.
      MAIN OUTCOME MEASURES: Frequency of atrial fibrillation after induction of
      ventricular fibrillation; clinical characteristics of patients with and without
      induced atrial fibrillation; frequency of atrial fibrillation induced by rapid
      atrial bursts during predischarge testing. RESULTS: Atrial fibrillation was
      observed in 40 of the 217 ventricular fibrillation episodes (18%) that could be
      detected immediately after delivery of high voltage pacing. The biphasic ICD
      shock for termination of ventricular fibrillation also terminated the atrial
      fibrillation in all cases. The 40 episodes of simultaneous atrial and ventricular
      fibrillation occurred in 18 patients (36%). The distribution of the clinical
      characteristics of the patients and the inducibility of atrial fibrillation
      during predischarge testing were similar in those with and without induced atrial
      fibrillation. CONCLUSIONS: Rapid high voltage ventricular pacing frequently
      induces atrial fibrillation, which was terminated by the subsequent biphasic ICD
      shock. The induction of atrial fibrillation seems to be a non-specific
      phenomenon, unrelated to the clinical status of the patient.

PMID- 10648493
TI  - Aortic valve tumour trapped in the right coronary ostium.

PMID- 10648492
TI  - Haemodynamic effects of increasing angle of head up tilt.
AB  - OBJECTIVE: To investigate the haemodynamic effects of varying the angle of head
      up tilt. METHODS: 20 healthy subjects (12 female, eight male; mean (SD) age 33.6
      (8.4) years) underwent head up tilt for five minutes to each of four angles of
      tilt in random order, with a five minute rest period at the horizontal between
      each angle. Forearm blood flow was measured using intermittent occlusion mercury
      strain gauge plethysmography at two and five minutes. Subjects underwent
      continuous monitoring of heart rate, systolic blood pressure (SBP), and diastolic
      blood pressure (DBP) by Finapres and cardiac output and stroke volume by
      impedance cardiography. Each variable was measured at two and five minutes,
      averaged over the period of blood flow measurement. RESULTS: Every haemodynamic
      variable at each angle was significantly different from supine values. Head up
      tilt produced progressive increases in heart rate (11-21%), SBP (12-21%), and DBP
      (20-33%) with increasing tilt angle. However, although 45 degrees produced
      significantly less haemodynamic effect, there were no significant differences for
      angles between 60 degrees and 90 degrees. Cardiac output fell on head up tilt by
      17-20% and stroke volume by 28-34%, but increasing tilt angle produced no
      significant additional reduction in cardiac output and stroke volume because of
      increases in heart rate and vasoconstriction. CONCLUSIONS: Angles < 60 degrees
      produce significantly less haemodynamic effects than steeper angles. Increasing
      tilt angle beyond 60 degrees produces no apparent additional effect on cardiac
      output or sympathetic tone. Increasing tilt angle beyond 60 degrees confers no
      additional orthostatic stress and may not affect the sensitivity and specificity
      of head up tilt testing as previously thought. Sixty degrees of tilt is a more
      practical angle for support of a syncopal patient and is recommended.

PMID- 10648494
TI  - Left sided valvar regurgitation in normal children and adolescents.
AB  - OBJECTIVE: To determine the prevalence and characteristics of left sided valvar
      regurgitation in normal children and adolescents. DESIGN: Prospective
      observational study. SETTING: Tertiary paediatric referral centre. PATIENTS: 329
      volunteers (194 male, 135 female, age range 3-18 years). MAIN OUTCOME MEASURES:
      Detection of regurgitation with colour flow mapping after valve closure.
      Measurement of jet area, maximal velocity, and duration. RESULTS: Mitral
      regurgitation was present in six subjects (1.82%, 95% confidence interval (CI)
      0.38% to 3.3%) and was not seen before 7 years of age. The jets ranged from 1.1
      to 1.9 cm(2) (mean 1.4 cm(2)) in area and were confined to the proximal half of
      the left atrium. All of the detectable jets were pansystolic and five of six
      arose from the posteriomedial aspect of the mitral valve. Aortic regurgitation
      was seen in one girl aged 11 years (0.3%, 95% CI 0% to 0.9%). The signal was
      pandiastolic and 0.44 cm(2) in area. CONCLUSIONS: True mitral regurgitation
      occurring after rather than during mitral valve closure was detected in < 2% of
      subjects. These data support previous work in adult patients suggesting that
      trivial degrees of mitral regurgitation may be related to the process of aging.
      Aortic regurgitation is very rare in normal children and adolescents and should
      not be considered as a normal finding.

PMID- 10648495
TI  - High resolution magnetic resonance imaging of atherosclerosis and the response to
      balloon angioplasty.
AB  - OBJECTIVE: To explore the use of high resolution magnetic resonance imaging (MRI)
      of the popliteal artery in defining atheroscelerotic lesions and to monitor the
      remodelling response to balloon angioplasty. METHODS: Four patients (aged 49-67)
      with symptomatic discrete popliteal artery stenoses, as demonstrated by
      conventional angiography, underwent balloon angioplasty. MRI of the diseased
      vessel was performed before and one week, one month, three months, and six months
      after therapeutic balloon angioplasty. Cine phase contrast MRI was used to
      estimate blood flow just proximal to the lesion before and after angioplasty.
      RESULTS: In all patients the extent of the atherosclerotic plaque could be
      defined, such that even in segments of vessel which were angiographically
      "normal", atherosclerotic lesions with cross sectional areas ranging from 49% to
      76% of potential lumen area were identified. Following angioplasty, plaque
      fissuring and local dissection were easily identified and serial changes in lumen
      diameter, blood flow. and lesion size could be documented. CONCLUSIONS: High
      resolution MRI can define the extent of atherosclerotic plaque in the peripheral
      vasculature and demonstrate the changes that occur with remodelling and
      restenosis following angioplasty. As a safe, reproducible technique MRI is ideal
      for assessing plaque and monitoring intervention, but further technological
      developments will be needed if similar or better images are to be achieved in
      other vascular beds.

PMID- 10648496
TI  - Preintervention lesion remodelling affects operative mechanisms of balloon
      optimised directional coronary atherectomy procedures: a volumetric study with
      three dimensional intravascular ultrasound.
AB  - AIMS: To classify atherosclerotic coronary lesions on the basis of adequate or
      inadequate compensatory vascular enlargement, and to examine changes in lumen,
      plaque, and vessel volumes during balloon optimised directional coronary
      atherectomy procedures in relation to the state of adaptive remodelling before
      the intervention. DESIGN: 29 lesion segments in 29 patients were examined with
      intravascular ultrasound before and after successful balloon optimised
      directional coronary atherectomy procedures, and a validated volumetric
      intravascular ultrasound analysis was performed off-line to assess the
      atherosclerotic lesion remodelling and changes in plaque and vessel volumes that
      occurred during the intervention. Based on the intravascular ultrasound data,
      lesions were classified according to whether there was inadequate (group I) or
      adequate (group II) compensatory enlargement. RESULTS: There was no significant
      difference in patient and lesion characteristics between groups I and II (n = 10
      and 19), including lesion length and details of the intervention. Quantitative
      coronary angiographic data were similar for both groups. However, plaque and
      vessel volumes were significantly smaller in group I than in II. In group I, 9
      (4)% (mean (SD)) of the plaque volume was ablated, while in group II 16 (11)% was
      ablated (p = 0.01). This difference was reflected in a lower lumen volume gain in
      group I than in group II (46 (18) mm(3) v 80 (49) mm(3) (p < 0.02)). CONCLUSIONS:
      Preintervention lesion remodelling has an impact on the operative mechanisms of
      balloon optimised directional coronary atherectomy procedures. Plaque ablation
      was found to be particularly low in lesions with inadequate compensatory vascular
      enlargement.

PMID- 10648497
TI  - Preoperative evaluation and surgery in isolated ventricular septal defects: a 21
      year perspective.
AB  - OBJECTIVE: To study short and long term results after surgical closure of
      isolated ventricular septal defects (VSDs) from 1976 to 1996, especially in
      relation to changes in preoperative evaluation during this period. DESIGN:
      Retrospective study. SETTING: Tertiary referral centre for paediatric cardiac
      care. PATIENTS: All children under 18 years of age who had corrective surgery for
      VSD between 1976 and 1996. MAIN OUTCOME MEASURES: Preoperative evaluation,
      indications for surgery, diagnostic errors, and early and late results. RESULTS:
      A significant decrease in the use of invasive preoperative studies in favour of
      non-invasive methods was found; from 1976 to 1990, a total of 109/110 patients
      had preoperative invasive study as compared to 43/167 from 1991 to 1996 (p <
      0.001). Pulmonary hypertension in small children, without detailed information on
      Qp:Qs ratio, as well as small or modest shunts without pulmonary hypertension,
      were more frequent indications for surgery in recent years. Early mortality after
      surgery occurred in 10 patients, with a significantly lower mortality rate found
      between 1991 and 1996 than between 1976 and 1990 (0.6% v 8.2%, p < 0.001).
      Children with large VSDs experienced perioperative complications significantly
      less often between 1991 and 1996 than between 1976 and 1990 (16/105 v 28/96, p <
      0.05). Diagnostic errors showed a tendency to decrease between the two time
      periods. No late deaths occurred. CONCLUSIONS: Significant reductions in early
      mortality, perioperative complications, and diagnostic mistakes were seen during
      the study period, even though less invasive diagnostic procedures were being
      performed.

PMID- 10648498
TI  - Abnormalities of endothelial function in patients with predialysis renal failure.
AB  - BACKGROUND: Endothelial dysfunction plays an important role in the development of
      atherosclerotic vascular disease, which is the leading cause of mortality in
      patients with chronic renal failure. OBJECTIVE: To examine the relation between
      predialysis renal failure and endothelial function. DESIGN: Two groups were
      studied: 80 patients with non-diabetic chronic renal failure and 26 healthy
      controls, with similar age and sex distributions. Two indices of endothelial
      function were assessed: high resolution ultrasonography to measure flow mediated
      endothelium dependent dilatation of the brachial artery following reactive
      hyperaemia, and plasma concentration of von Willebrand factor. Endothelium
      independent dilatation was also assessed following sublingual glyceryl
      trinitrate. The patients were divided into those with and without overt
      atherosclerotic vascular disease. RESULTS: Although patients with chronic renal
      failure had significantly impaired endothelium dependent dilatation compared with
      controls (median (interquartile range), 2.6% (0.7% to 4.8%) v 6.5% (4.8% to
      8.3%); p < 0.001) and increased von Willebrand factor (254 (207 to 294) v 106 (87
      to 138) iu/dl; p < 0.001), there was no difference between renal failure patients
      with and without atherosclerotic vascular disease. Within the chronic renal
      failure group, endothelium dependent dilatation and von Willebrand factor were
      similar in patients in the upper and lower quartiles of glomerular filtration
      rate (2.7% (0.7% to 6.7%) v 2.8% (1.1% to 5.0%); and 255 (205 to 291) v 254 (209
      to 292) iu/dl, respectively). Endothelium independent dilatation did not differ
      between the renal failure or control groups and was also similar in patients with
      renal failure irrespective of the degree of renal failure or the presence of
      atherosclerotic vascular disease. CONCLUSIONS: Endothelial function is abnormal
      in chronic renal failure, even in patients with mild renal insufficiency and
      those without atherosclerotic vascular disease, suggesting that uraemia may
      directly promote the development of atherosclerosis early in the progression of
      chronic renal failure.

PMID- 10648500
TI  - ST segment elevation in the precordial leads mimicking Brugada syndrome.

PMID- 10648499
TI  - Autonomic dysfunction is related to impaired pancreatic beta cell function in
      patients with coronary artery disease.
AB  - OBJECTIVE: To assess the role of beta cell failure in the development of
      autonomic dysfunction in patients with coronary artery disease. DESIGN: Autonomic
      function was measured by standard clinical methods and by heart rate variability
      in 24 type II diabetic and 24 non-diabetic subjects with coronary artery disease.
      Quantitative estimates of pancreatic beta cell function (%beta) and insulin
      resistance were made from basal plasma glucose and insulin concentrations using a
      computer solved model. Fasting proinsulin levels provided an independent measure
      of beta cell function. RESULTS: The circadian rhythm of sympathovagal balance
      (ratio of low to high frequency spectral components of heart rate variability)
      was significantly attenuated in patients with below median (%beta </= 63. 3)
      compared with above median pancreatic beta cell function. Multiple measures of
      autonomic function showed positive associations with %beta (low frequency: r =
      0.41, p = 0.004; high frequency: r = 0.27, p = 0.07; lying/standing fall in
      systolic pressure: r = -0.30, p = 0.04) and negative associations with proinsulin
      (low frequency: r = -0.35, p = 0.03; high frequency: r = -0.36, p = 0.02;
      standard deviation of RR intervals: r = -0.43, p = 0.007). Associations tended to
      be stronger in non-diabetic than diabetic patients. In contrast, there was no
      association between insulin resistance and either autonomic function or the
      circadian rhythm of sympathovagal balance, regardless of diabetes status.
      CONCLUSIONS: The data are consistent with the hypothesis that beta cell failure
      plays a pathogenic role in the development of autonomic dysfunction in patients
      with coronary artery disease.

PMID- 10648502
TI  - Platypnoea-orthodeoxia syndrome.
AB  - PLATYPNOEA: orthodeoxia is a rare syndrome of postural hypoxaemia accompanied by
      breathlessness. The predominant symptom, dyspnoea induced by upright posture, can
      be debilitating and difficult to discern without thorough evaluation of the
      patient's pattern of dyspnoea. The precise cause of the syndrome is unclear but
      patients develop right to left intracardiac shunting in the presence of normal
      right sided cardiac pressures. Initially, patients should have confirmation of
      orthostatic desaturation by erect and supine pulse oximetry. However, definitive
      diagnosis of an orthostatic intracardiac shunt is most readily established by
      echocardiography. The use of echocontrast with postural manoeuvres may facilitate
      the diagnosis. The treatment of choice is surgical closure of the intracardiac
      (usually interatrial) communication, which may result in dramatic symptomatic and
      haemodynamic improvement. Three cases (a 27 year old man and two women aged 63
      and 72 years) are described that exemplify the presentation of this syndrome, and
      reflect the varied management strategies and outcomes of this condition.

PMID- 10648501
TI  - Neurostimulation treatment for angina pectoris.

PMID- 10648503
TI  - Coronary angioplasty: guidelines for good practice and training. Joint Working
      Group on Coronary Angioplasty of the British Cardiac Society and British
      Cardiovascular Intervention Society.

PMID- 10648504
TI  - Interventional catheterisation. Opening up II: venous return, the atrial septum,
      the arterial duct, aortopulmonary shunts, and aortopulmonary collaterals.

PMID- 10648505
TI  - Acute coronary syndromes: risk stratification.

PMID- 10648506
TI  - Atherogenesis: current understanding of the causes of atheroma.

PMID- 10648508
TI  - Genetic and biochemical characterization of Salmonella enterica serovar typhi
      deoxyribokinase.
AB  - We identified in the genome of Salmonella enterica serovar Typhi the gene
      encoding deoxyribokinase, deoK. Two other genes, vicinal to deoK, were determined
      to encode the putative deoxyribose transporter (deoP) and a repressor protein
      (deoQ). This locus, located between the uhpA and ilvN genes, is absent in
      Escherichia coli. The deoK gene inserted on a plasmid provides a selectable
      marker in E. coli for growth on deoxyribose-containing medium. Deoxyribokinase is
      a 306-amino-acid protein which exhibits about 35% identity with ribokinase from
      serovar Typhi, S. enterica serovar Typhimurium, or E. coli. The catalytic
      properties of the recombinant deoxyribokinase overproduced in E. coli correspond
      to those previously described for the enzyme isolated from serovar Typhimurium.
      From a sequence comparison between serovar Typhi deoxyribokinase and E. coli
      ribokinase, whose crystal structure was recently solved, we deduced that a key
      residue differentiating ribose and deoxyribose is Met10, which in ribokinase is
      replaced by Asn14. Replacement by site-directed mutagenesis of Met10 with Asn
      decreased the V(max) of deoxyribokinase by a factor of 2.5 and increased the K(m)
      for deoxyribose by a factor of 70, compared to the parent enzyme.

PMID- 10648509
TI  - WdCHS3, a gene that encodes a class III chitin synthase in Wangiella (Exophiala)
      dermatitidis, is expressed differentially under stress conditions.
AB  - Class III chitin synthases are important for hyphal growth in some filamentous
      fungi but are not found in yeasts. Using a specific PCR product that encodes a
      portion of the class III chitin synthase of W. dermatitidis as a probe, we
      isolated the chitin synthase gene, WdCHS3, from this polymorphic melanized
      pathogen of humans. Northern blotting showed that WdCHS3 was highly expressed
      under stress conditions, such as the shift of cells to temperatures commensurate
      with infection, or to conditions that induce cellular morphogenesis in this
      fungus. Analysis of the 5' upstream sequence of WdCHS3 provided evidence for a
      negative regulatory element at between -780 and -1600 bp. Western blotting
      indicated that the production of the WdChs3p was temperature dependent and
      temporally regulated. Disruption of WdCHS3 in a wild-type strain and in two
      temperature-sensitive morphological mutants resulted in significantly reduced
      chitin synthase activities but did not obviously affect their morphologies,
      growth rates, chitin contents, or virulence. This paradox suggested that the
      contributions of the high levels of WdCHS3 gene expression and WdChs3p production
      in strains subjected to stress reside in unknown or unexamined parts of the life
      cycle of this ecologically poorly known member of the Fungi Imperfecti.
      Nonetheless, this report presents the first evidence that transcription of a
      chitin synthase gene is regulated by a negative regulatory element in its 5'
      upstream sequence.

PMID- 10648507
TI  - S-Layer proteins.

PMID- 10648510
TI  - Production of an endo-beta-N-acetylglucosaminidase activity mediates growth of
      Enterococcus faecalis on a high-mannose-type glycoprotein.
AB  - Enterococcus faecalis is associated with a high proportion of nosocomial
      infections; however, little is known of the ability of this organism to
      proliferate in vivo. The ability of RNase B, a model glycoprotein with a single N
      glycosylation site occupied by a family of high-mannose-type glycans (Man(5)- to
      Man(9)-GlcNAc(2)), to support growth of E. faecalis was investigated. Sodium
      dodecyl sulfate-polyacrylamide gel electrophoresis of RNase B demonstrated a
      reduction in the molecular mass of this glycoprotein during bacterial growth.
      Further analysis by matrix-assisted laser desorption ionization-time of flight
      (MALDI-TOF) mass spectrometry revealed that this mass shift was due to the
      degradation of all high-mannose-type glycoforms to a single N-linked N
      acetylglucosamine residue. High-pH anion-exchange chromatography analysis during
      exponential growth demonstrated the presence of RNase B-derived glycans in the
      culture supernatant, indicating the presence of an endoglycosidase activity. The
      free glycans were eluted with the same retention times as those generated by the
      action of Streptomyces plicatus endo-beta-N-acetylglucosaminidase H on RNase B.
      The cleavage specificity was confirmed by MALDI-TOF analysis of the free glycans,
      which showed glycan species containing only one N-acetylglucosamine residue. No
      free glycans were detectable after 5 h of bacterial growth, and we have
      subsequently demonstrated the presence of mannosidase activity in E. faecalis,
      which releases free mannose from RNase B-derived glycans. We propose that this
      deglycosylation of glycoproteins containing high-mannose-type glycans and the
      subsequent degradation of the released glycans by E. faecalis may play a role in
      the survival and persistence of this nosocomial pathogen in vivo.

PMID- 10648511
TI  - Cloning and characterization of 1-deoxy-D-xylulose 5-phosphate synthase from
      Streptomyces sp. Strain CL190, which uses both the mevalonate and nonmevalonate
      pathways for isopentenyl diphosphate biosynthesis.
AB  - In addition to the ubiquitous mevalonate pathway, Streptomyces sp. strain CL190
      utilizes the nonmevalonate pathway for isopentenyl diphosphate biosynthesis. The
      initial step of this nonmevalonate pathway is the formation of 1-deoxy-D-xylulose
      5-phosphate (DXP) by condensation of pyruvate and glyceraldehyde 3-phosphate
      catalyzed by DXP synthase. The corresponding gene, dxs, was cloned from CL190 by
      using PCR with two oligonucleotide primers synthesized on the basis of two highly
      conserved regions among dxs homologs from six genera. The dxs gene of CL190
      encodes 631 amino acid residues with a predicted molecular mass of 68 kDa. The
      recombinant enzyme overexpressed in Escherichia coli was purified as a soluble
      protein and characterized. The molecular mass of the enzyme was estimated to be
      70 kDa by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and 130 kDa
      by gel filtration chromatography, suggesting that the enzyme is most likely to be
      a dimer. The enzyme showed a pH optimum of 9.0, with a V(max) of 370 U per mg of
      protein and K(m)s of 65 microM for pyruvate and 120 microM for D-glyceraldehyde 3
      phosphate. The purified enzyme catalyzed the formation of 1-deoxyxylulose by
      condensation of pyruvate and glyceraldehyde as well, with a K(m) value of 35 mM
      for D-glyceraldehyde. To compare the enzymatic properties of CL190 and E. coli
      DXP synthases, the latter enzyme was also overexpressed and purified. Although
      these two enzymes had different origins, they showed the same enzymatic
      properties.

PMID- 10648512
TI  - Function of a principal Na(+)/H(+) antiporter, ShaA, is required for initiation
      of sporulation in Bacillus subtilis.
AB  - ShaA (sodium/hydrogen antiporter, previously termed YufT [or NtrA]), which is
      responsible for Na(+)/H(+) antiporter activity, is considered to be the major
      Na(+) excretion system in Bacillus subtilis. We found that a shaA-disrupted
      mutant of B. subtilis shows impaired sporulation but normal vegetative growth
      when the external Na(+) concentration was increased in a low range. In the shaA
      mutant, sigma(H)-dependent expression of spo0A (P(S)) and spoVG at an early stage
      of sporulation was sensitive to external NaCl. The level of sigma(H) protein was
      reduced by the addition of NaCl, while the expression of spo0H, which encodes
      sigma(H), was little affected, indicating that posttranscriptional control of
      sigma(H) rather than spo0H transcription is affected by the addition of NaCl in
      the shaA mutant. Since this mutant is considered to have a diminished ability to
      maintain a low internal Na(+) concentration, an increased level of internal Na(+)
      may affect posttranscriptional control of sigma(H). Bypassing the phosphorelay by
      introducing the sof-1 mutation into this mutant did not restore spo0A (P(S))
      expression, suggesting that disruption of shaA affects sigma(H) accumulation, but
      does not interfere with the phosphorylation and phosphotransfer reactions of the
      phosphorelay. These results suggest that ShaA plays a significant role at an
      early stage of sporulation and not only during vegetative growth. Our findings
      raise the possibility that fine control of cytoplasmic ion levels, including
      control of the internal Na(+) concentration, may be important for the progression
      of the sporulation process.

PMID- 10648513
TI  - prpR, ntrA, and ihf functions are required for expression of the prpBCDE operon,
      encoding enzymes that catabolize propionate in Salmonella enterica serovar
      typhimurium LT2.
AB  - The genes required for the catabolism of propionate in Salmonella enterica
      serovar Typhimurium are organized as two transcriptional units (prpR and prpBCDE)
      that are divergently transcribed from one another. Sequence homology to genes
      encoding members of the sigma-54 family of transcriptional activators and the
      identification of a consensus sigma-54 promoter 5' to the prpBCDE operon
      suggested that PrpR was required to activate expression of this operon. We
      isolated insertions in prpR and showed that prpR function was needed for growth
      on propionate as a carbon and energy source. A medium-copy-number plasmid
      carrying the lacZ gene under the control of the native sigma-54 promoter of
      prpBCDE was used to study prpBCDE operon expression. Transcription of the lacZ
      reporter in prpR, ntrA, and ihfB mutants was 85-, 83-, and 15-fold lower than the
      level of transcription measured in strains carrying the wild-type allele of the
      gene tested. These data indicated that PrpR, IHF, and transcription sigma factor
      RpoN were required for the expression of the prpBCDE operon. Further analysis of
      the involvement of the integration host factor (IHF) protein in the expression of
      this operon is required due to the well-documented pleiotropic effect the lack of
      this global regulator has on gene expression. Deletion of the 5' 615-bp portion
      of the prpR gene resulted in a PrpR(c) mutant protein that activated prpBCDE
      transcription regardless of the ability of the strain to synthesize 2
      methylcitrate, the putative coactivator of PrpR. These results indicate that the
      N terminus of PrpR is the coactivator-sensing domain of the protein. When placed
      under the control of the arabinose-inducible promoter P(araBAD), expression of
      prpR(c) allele by arabinose had a strong negative effect on growth of the cell.
      It is proposed that this deleterious effect of PrpR(c) may be due to an
      uncontrolled ATPase activity of PrpR or to cross-activation of genes whose
      functions negatively affect cell growth under the conditions tested.

PMID- 10648514
TI  - Cloning and characterization of the Flavobacterium johnsoniae gliding-motility
      genes gldB and gldC.
AB  - The mechanism of bacterial gliding motility (active movement over surfaces
      without the aid of flagella) is not known. A large number of mutants of the
      gliding bacterium Flavobacterium johnsoniae (Cytophaga johnsonae) with defects in
      gliding motility have been previously isolated, and genetic techniques to analyze
      these mutants have recently been developed. We complemented a nongliding mutant
      of F. johnsoniae (UW102-99) with a library of wild-type DNA by using the shuttle
      cosmid pCP26. The complementing plasmid (pCP200) contained an insert of 26 kb and
      restored gliding motility to 4 of 50 independently isolated nongliding mutants. A
      1.9-kb fragment which encompassed two genes, gldB and gldC, complemented all four
      mutants. An insertion mutation in gldB was polar on gldC, suggesting that the two
      genes form an operon. Disruption of the chromosomal copy of gldB in wild-type F.
      johnsoniae UW101 eliminated gliding motility. Introduction of the gldBC operon,
      or gldB alone, restored motility. gldB appears to be essential for F. johnsoniae
      gliding motility. It codes for a membrane protein that does not exhibit strong
      sequence similarity to other proteins in the databases. gldC is not absolutely
      required for gliding motility, but cells that do not produce GldC form colonies
      that spread less well than those of the wild type. GldC is a soluble protein and
      has weak sequence similarity to the fungal lectin AOL.

PMID- 10648515
TI  - Amino acid transport and metabolism in mycobacteria: cloning, interruption, and
      characterization of an L-Arginine/gamma-aminobutyric acid permease in
      Mycobacterium bovis BCG.
AB  - Genes encoding L-arginine biosynthetic and transport proteins have been shown in
      a number of pathogenic organisms to be important for metabolism within the host.
      In this study we describe the cloning of a gene (Rv0522) encoding an amino acid
      transporter from Mycobacterium bovis BCG and the effects of its deletion on L
      arginine transport and metabolism. The Rv0522 gene of BCG was cloned from a
      cosmid library by using primers homologous to the rocE gene of Bacillus subtilis,
      a putative arginine transporter. A deletion mutant strain was constructed by
      homologous recombination with the Rv0522 gene interrupted by a selectable marker.
      The mutant strain was complemented with the wild-type gene in single copy.
      Transport analysis of these strains was conducted using (14)C-labeled substrates.
      Greatly reduced uptake of L-arginine and gamma-aminobutyric acid (GABA) but not
      of lysine, ornithine, proline, or alanine was observed in the mutant strain
      compared to the wild type, grown in Middlebrook 7H9 medium. However, when the
      strains were starved for 24 h or incubated in a minimal salts medium containing
      20 mM arginine (in which even the parent strain does not grow), L-[(14)C]arginine
      uptake by the mutant but not the wild-type strain increased strongly. Exogenous L
      arginine but not GABA, lysine, ornithine, or alanine was shown to be toxic at
      concentrations of 20 mM and above to wild-type cells growing in optimal carbon
      and nitrogen sources such as glycerol and ammonium. L-Arginine supplied in the
      form of dipeptides showed no toxicity at concentrations as high as 30 mM.
      Finally, the permease mutant strain showed no defect in survival in unactivated
      cultured murine macrophages compared with wild-type BCG.

PMID- 10648516
TI  - Multiple gene products and sequences required for excision of the mobilizable
      integrated Bacteroides element NBU1.
AB  - NBU1 is an integrated 10.3-kbp Bacteroides element, which can excise and transfer
      to Bacteroides or Escherichia coli recipients, where it integrates into the
      recipient genome. NBU1 relies on large, >60-kbp, conjugative transposons for
      factors that trigger excision and for mobilization of the circular form to
      recipients. Previously, we showed that a single integrase gene, intN1, was
      necessary and sufficient for integration of NBU1 into its target site on the
      Bacteroides or E. coli genome. We now show that an unexpectedly large region of
      NBU1 is required for excision. This region includes, in addition to intN1, four
      open reading frames plus a large region downstream of the fourth gene, prmN1.
      This downstream sequence was designated XRS, for "excision-required sequence."
      XRS contains the oriT of the circular form of NBU1 and about two-thirds of the
      adjacent mobilization gene, mobN1. This is the first time an oriT, which is
      involved in conjugal transfer of the circular form, has been implicated in
      excision. Disruption of the gene immediately downstream of intN1, orf2,
      completely abolished excision. The next open reading frame, orf2x, was too small
      to be disrupted, so we still do not know whether it plays a role in the excision
      reaction. Deletions were made in each of two open reading frames downstream of
      orf2x, orf3 and prmN1. Both of these deletions abolished excision, indicating
      that these genes are also essential for excision. Attempts to complement various
      mutations in the excision region led us to realize that a portion of the excision
      region carrying prmN1 and part of the XRS (XRS(HIII)) inhibited excision when
      provided in trans on a multicopy plasmid (8 to 10 copies per cell). However, a
      fragment carrying prmN1, XRS, and the entire mobilization gene, mobN1, did not
      have this effect. The smaller fragment may be interfering with excision by
      attracting proteins made by the intact NBU1 and thus removing them from the
      excision complex. Our results show clearly that excision is a complex process
      that involves several proteins and a cis-acting region (XRS) which includes the
      oriT. We suggest that this complex excision machinery may be necessary to allow
      NBU1 to coordinate nicking at the ends during excision and nicking at the oriT
      during conjugal transfer, to prevent premature nicking at the oriT before NBU1
      has excised and circularized.

PMID- 10648517
TI  - A set of genes encoding a second toluene efflux system in Pseudomonas putida DOT
      T1E is linked to the tod genes for toluene metabolism.
AB  - Sequence analysis in Pseudomonas putida DOT-T1E revealed a second toluene efflux
      system for toluene metabolism encoded by the ttgDEF genes, which are adjacent to
      the tod genes. The ttgDEF genes were expressed in response to the presence of
      aromatic hydrocarbons such as toluene and styrene in the culture medium. To
      characterize the contribution of the TtgDEF system to toluene tolerance in P.
      putida, site-directed mutagenesis was used to knock out the gene in the wild-type
      DOT-T1E strain and in a mutant derivative, DOT-T1E-18. This mutant carried a Tn5
      insertion in the ttgABC gene cluster, which encodes a toluene efflux pump that is
      synthesized constitutively. For site-directed mutagenesis, a cassette to knock
      out the ttgD gene and encoding resistance to tellurite was constructed in vitro
      and transferred to the corresponding host chromosome via the suicide plasmid
      pKNG101. Successful replacement of the wild-type sequences with the mutant
      cassette was confirmed by Southern hybridization. A single ttgD mutant, DOT-T1E
      1, and a double mutant with knock outs in the ttgD and ttgA genes, DOT-T1E-82,
      were obtained and characterized for toluene tolerance. This was assayed by the
      sudden addition of toluene (0.3% [vol/vol]) to the liquid culture medium of cells
      growing on Luria-Bertani (LB) medium (noninduced) or on LB medium with toluene
      supplied via the gas phase (induced). Induced cells of the single ttgD mutant
      were more sensitive to sudden toluene shock than were the wild-type cells;
      however, noninduced wild-type and ttgD mutant cells were equally tolerant to
      toluene shock. Noninduced cells of the double DOT-T1E-82 mutant did not survive
      upon sudden toluene shock; however, they still remained viable upon sudden
      toluene shock if they had been previously induced. These results are discussed in
      the context of the use of multiple efflux pumps involved in solvent tolerance in
      P. putida DOT-T1E.

PMID- 10648518
TI  - A novel operon encoding formaldehyde fixation: the ribulose monophosphate pathway
      in the gram-positive facultative methylotrophic bacterium Mycobacterium gastri
      MB19.
AB  - A 4.2-kb PstI fragment harboring the gene cluster of the ribulose monophosphate
      (RuMP) pathway for formaldehyde fixation was identified in the chromosome of a
      gram-positive, facultative methylotroph, Mycobacterium gastri MB19, by using the
      coding region of 3-hexulose-6-phosphate synthase (HPS) as the hybridization
      probe. The PstI fragment contained three complete open reading frames (ORFs)
      which encoded from the 5' end, a DNA-binding regulatory protein (rmpR), 6-phospho
      3-hexuloisomerase (PHI; rmpB), and HPS (rmpA). Sequence analysis suggested that
      rmpA and rmpB constitute an operon, and Northern blot analysis of RNA extracted
      from bacteria grown under various conditions suggested that the expression of the
      two genes is similarly regulated at the transcriptional level. A similarity
      search revealed that the proteins encoded by rmpA and rmpB in M. gastri MB19 show
      high similarity to the unidentified proteins of nonmethylotrophic prokaryotes,
      including bacteria and anaerobic archaea. The clusters in the phylogenetic tree
      of the HPS protein of M. gastri MB19 and those in the phylogenetic tree of the
      PHI protein were nearly identical, which implies that these two formaldehyde
      fixing genes evolved as a pair. These findings give new insight into the
      acquisition of the formaldehyde fixation pathway during the evolution of diverse
      microorganisms.

PMID- 10648519
TI  - Cloning, expression, and purification of a thermostable nonhomodimeric
      restriction enzyme, BslI.
AB  - BslI is a thermostable type II restriction endonuclease with interrupted
      recognition sequence CCNNNNN/NNGG (/, cleavage position). The BslI restriction
      modification system from Bacillus species was cloned and expressed in Escherichia
      coli. The system is encoded by three genes: the 2,739-bp BslI methylase gene
      (bslIM), the bslIRalpha gene, and the bslIRbeta gene. The alpha and beta subunits
      of BslI can be expressed independently in E. coli in the absence of BslI
      methylase (M.BslI) protection. BslI endonuclease activity can be reconstituted in
      vitro by mixing the two subunits together. Gel filtration chromatography and
      native polyacrylamide gel electrophoresis indicated that BslI forms heterodimers
      (alphabeta), heterotetramers (alpha(2)beta(2)), and possibly oligomers in
      solution. Two beta subunits can be cross-linked by a chemical cross-linking
      agent, indicating formation of heterotetramer BslI complex (alpha(2)beta(2)). In
      DNA mobility shift assays, neither subunit alone can bind DNA. DNA mobility shift
      activity was detected after mixing the two subunits together. Because of the
      symmetric recognition sequence of the BslI endonuclease, we propose that its
      active form is alpha(2)beta(2). M.BslI contains nine conserved motifs of N-4
      cytosine DNA methylases within the beta group of aminomethyltransferase.
      Synthetic duplex deoxyoligonucleotides containing cytosine hemimethylated or
      fully methylated at N-4 in BslI sites in the first or second cytosine are
      resistant to BslI digestion. C-5 methylation of the second cytosine on both
      strands within the recognition sequence also renders the site refractory to BslI
      digestion. Two putative zinc fingers are found in the alpha subunit of BslI
      endonuclease.

PMID- 10648520
TI  - Genetic evidence of distinct physiological regulation mechanisms in the sigma(54)
      Pu promoter of Pseudomonas putida.
AB  - The activity of the toluene-responsive sigma(54) Pu promoter of the pWW0 TOL
      plasmid of Pseudomonas putida is down-regulated in vivo during exponential growth
      in rich medium and also by the presence of glucose in the culture. Although the
      Pu promoter already performs poorly during log growth in minimal medium when
      amended with casamino acids, the addition of glucose further decreased by two- to
      threefold the accumulation of beta-galactosidase in a Pu-lacZ reporter P. putida
      strain. Since Pu was still down-regulated during exponential growth regardless of
      glucose addition, it appeared that the carbohydrate separately influenced
      promoter activity. This notion was supported by the growth-dependent induction
      pattern of Pu in a ptsN mutant of P. putida, the loss of which makes Pu no longer
      responsive to repression by glucose. On the other hand, overexpression of the
      sigma factor sigma(54), known to partially alleviate the exponential silencing of
      the promoter, did not affect glucose inhibition of Pu. These data indicated that
      exponential silencing and carbon source-dependent repression are two overlapping
      but genetically distinguishable mechanisms that adapt Pu to the physiological
      status of the cells and nutrient availability.

PMID- 10648521
TI  - The TorR high-affinity binding site plays a key role in both torR autoregulation
      and torCAD operon expression in Escherichia coli.
AB  - In the presence of trimethylamine N-oxide (TMAO), the TorS-TorR two-component
      regulatory system induces the torCAD operon, which encodes the TMAO respiratory
      system of Escherichia coli. The sensor protein TorS detects TMAO and
      transphosphorylates the response regulator TorR which, in turn, activates
      transcription of torCAD. The torR gene and the torCAD operon are divergently
      transcribed, and the short torR-torC intergenic region contains four direct
      repeats (the tor boxes) which proved to be TorR binding sites. The tor box 1-box
      2 region covers the torR transcription start site and constitutes a TorR high
      affinity binding site, whereas box 3 and box 4 correspond to low-affinity binding
      sites. By using torR-lacZ operon fusions in different genetic backgrounds, we
      showed that the torR gene is negatively autoregulated. Surprisingly, TorR
      autoregulation is TMAO independent and still occurs in a torS mutant. In
      addition, this negative regulation involves only the TorR high-affinity binding
      site. Together, these data suggest that phosphorylated as well as
      unphosphorylated TorR binds the box 1-box 2 region in vivo, thus preventing RNA
      polymerase from binding to the torR promoter whatever the growth conditions. By
      changing the spacing between box 2 and box 3, we demonstrated that the DNA motifs
      of the high- and low-affinity binding sites must be close to each other and
      located on the same side of the DNA helix to allow induction of the torCAD
      operon. Thus, prior TorR binding to the box 1-box 2 region seems to allow
      cooperative binding of phosphorylated TorR to box 3 and box 4.

PMID- 10648522
TI  - Polar clustering of the chemoreceptor complex in Escherichia coli occurs in the
      absence of complete CheA function.
AB  - Bacterial chemotaxis requires a phosphorelay system initiated by the interaction
      of a ligand with its chemoreceptor and culminating in a change in the directional
      bias of flagellar rotation. Chemoreceptor-CheA-CheW ternary complexes mediate
      transduction of the chemotactic signal. In vivo, these complexes cluster
      predominantly in large groups at the cell poles. The function of chemoreceptor
      clustering is currently unknown. To gain insight into the relationship between
      signaling and chemoreceptor clustering, we examined these properties in several
      Escherichia coli mutant strains that produce CheA variants altered in their
      ability to mediate chemotaxis, autophosphorylate, or bind ATP. We show here that
      polar clustering of chemoreceptor complexes does not require functional CheA
      protein, although maximal clustering occurred only in chemotactically competent
      cells. Surprisingly, in cells containing a minimum of 13 gold particles at the
      cell pole, a significant level of clustering was observed in the absence of CheA,
      demonstrating that CheA is not absolutely essential for chemoreceptor clustering.
      Nonchemotactic cells expressing only CheA(S), a C-terminal CheA deletion, or CheA
      bearing a mutation in the ATP-binding site mediated slightly less than maximal
      chemoreceptor clustering. Cells expressing only full-length CheA (CheA(L)) from
      either a chromosomal or a plasmid-encoded allele displayed a methyl-accepting
      chemotaxis protein localization pattern indistinguishable from that of strains
      carrying both CheA(L) and CheA(S), demonstrating that CheA(L) alone can mediate
      polar clustering.

PMID- 10648523
TI  - Structural characterization of the released polysaccharide of desiccation
      tolerant Nostoc commune DRH-1.
AB  - The structure of the viscous extracellular polysaccharide (glycan) of desiccation
      tolerant Nostoc commune DRH-1 was determined through chromatographic and
      spectroscopic methods. The polysaccharide is novel in that it possesses a 1-4
      linked xylogalactoglucan backbone with D-ribofuranose and 3-O-[(R)-1
      carboxyethyl]-D-glucuronic acid (nosturonic acid) pendant groups. The presence of
      D-ribose and nosturonic acid as peripheral groups is unusual, and their potential
      roles in modulating the rheological properties of the glycan are discussed.
      Nosturonic acid was present in the glycans of N. commune from diverse geographic
      locations, suggesting that this uronic acid is an integral component of this
      cosmopolitan anhydrophile.

PMID- 10648524
TI  - Mutagenesis and functional characterization of the glnB, glnA, and nifA genes
      from the photosynthetic bacterium Rhodospirillum rubrum.
AB  - Nitrogen fixation is tightly regulated in Rhodospirillum rubrum at two different
      levels: transcriptional regulation of nif expression and posttranslational
      regulation of dinitrogenase reductase by reversible ADP-ribosylation catalyzed by
      the DRAT-DRAG (dinitrogenase reductase ADP-ribosyltransferase-dinitrogenase
      reductase-activating glycohydrolase) system. We report here the characterization
      of glnB, glnA, and nifA mutants and studies of their relationship to the
      regulation of nitrogen fixation. Two mutants which affect glnB (structural gene
      for P(II)) were constructed. While P(II)-Y51F showed a lower nitrogenase activity
      than that of wild type, a P(II) deletion mutant showed very little nif
      expression. This effect of P(II) on nif expression is apparently the result of a
      requirement of P(II) for NifA activation, whose activity is regulated by NH(4)(+)
      in R. rubrum. The modification of glutamine synthetase (GS) in these glnB mutants
      appears to be similar to that seen in wild type, suggesting that a paralog of
      P(II) might exist in R. rubrum and regulate the modification of GS. P(II) also
      appears to be involved in the regulation of DRAT activity, since an altered
      response to NH(4)(+) was found in a mutant expressing P(II)-Y51F. The
      adenylylation of GS plays no significant role in nif expression or the ADP
      ribosylation of dinitrogenase reductase, since a mutant expressing GS-Y398F
      showed normal nitrogenase activity and normal modification of dinitrogenase
      reductase in response to NH(4)(+) and darkness treatments.

PMID- 10648525
TI  - The detergent-soluble maltose transporter is activated by maltose binding protein
      and verapamil.
AB  - The maltose transporter FGK2 complex of Escherichia coli was purified with the
      aid of a glutathione S-transferase molecular tag. In contrast to the membrane
      associated form of the complex, which requires liganded maltose binding protein
      (MBP) for ATPase activity, the purified detergent-soluble complex exhibited a
      very high level of ATPase activity. This uncoupled activity was not due to
      dissociation of the MalK ATPase subunit from the integral membrane protein MalF
      and MalG subunits. The detergent-soluble ATPase activity of the complex could be
      further stimulated by wild-type MBP but not by a signaling-defective mutant MBP.
      Wild-type MBP increased the V(max) of the ATPase 2.7-fold but had no effect on
      the K(m) of the enzyme for ATP. When the detergent-soluble complex was
      reconstituted in proteoliposomes, it returned to being dependent on MBP for
      activation of ATPase, consistent with the idea that the structural changes
      induced in the complex by detergent that result in activation of the ATPase are
      reversible. The uncoupled ATPase activity resembled the membrane-bound activity
      of the complex also with respect to sensitivity to NaN(3), as well as a
      mercurial, p-chloromercuribenzosulfonic acid. Verapamil, a compound that
      activates the ATPase activity of the multiple drug resistance P-glycoprotein,
      activated the maltose transporter ATPase as well. The activation of this
      bacterial transporter by verapamil suggests that a structural feature that is
      conserved among both eukaryotic and prokaryotic ATP binding cassette transporters
      is responsible for this activation.

PMID- 10648526
TI  - Cysteine-scanning mutagenesis of the periplasmic loop regions of PomA, a putative
      channel component of the sodium-driven flagellar motor in Vibrio alginolyticus.
AB  - The sodium-driven motor consists of the products of at least four genes, pomA,
      pomB, motX, and motY, in Vibrio alginolyticus. PomA and PomB, which are
      homologous to the MotA and MotB components of proton-driven motors, have four
      transmembrane segments and one transmembrane segment, respectively, and are
      thought to form an ion channel. In PomA, two periplasmic loops were predicted at
      positions 21 to 36 between membrane segments 1 and 2 (loop(1-2)) and at positions
      167 to 180 between membrane segments 3 and 4 (loop(3-4)). To characterize the two
      periplasmic loop regions, which may have a role as an ion entrance for the
      channel, we carried out cysteine-scanning mutagenesis. The T186 residue in the
      fourth transmembrane segment and the D71, D148, and D202 residues in the
      predicted cytoplasmic portion of PomA were also replaced with Cys. Only two
      mutations, M179C and T186C, conferred a nonmotile phenotype. Many mutations in
      the periplasmic loops and all of the cytoplasmic mutations did not abolish
      motility, though the five successive substitutions from M169C to K173C of loop(3
      4) impaired motility. In some mutants that retained substantial motility,
      motility was inhibited by the thiol-modifying reagents dithionitrobenzoic acid
      and N-ethylmaleimide. The profiles of inhibition by the reagents were consistent
      with the membrane topology predicted from the hydrophobicity profiles.
      Furthermore, from the profiles of labeling by biotin maleimide, we predicted more
      directly the membrane topology of loop(3-4). None of the loop(1-2) residues were
      labeled, suggesting that the environments around the two loops are very
      different. A few of the mutations were characterized further. The structure and
      function of the loop regions are discussed.

PMID- 10648527
TI  - Arginine catabolism in the cyanobacterium Synechocystis sp. Strain PCC 6803
      involves the urea cycle and arginase pathway.
AB  - Cells of the unicellular cyanobacterium Synechocystis sp. strain PCC 6803
      supplemented with micromolar concentrations of L-[(14)C]arginine took up,
      concentrated, and catabolized this amino acid. Metabolism of L-[(14)C]arginine
      generated a set of labeled amino acids that included argininosuccinate,
      citrulline, glutamate, glutamine, ornithine, and proline. Production of
      [(14)C]ornithine preceded that of [(14)C]citrulline, and the patterns of labeled
      amino acids were similar in cells incubated with L-[(14)C]ornithine, suggesting
      that the reaction of arginase, rendering ornithine and urea, is the main initial
      step in arginine catabolism. Ornithine followed two metabolic pathways: (i)
      conversion into citrulline, catalyzed by ornithine carbamoyltransferase, and
      then, with incorporation of aspartate, conversion into argininosuccinate, in a
      sort of urea cycle, and (ii) a sort of arginase pathway rendering glutamate (and
      glutamine) via Delta(1)pyrroline-5-carboxylate and proline. Consistently with the
      proposed metabolic scheme (i) an argF (ornithine carbamoyltransferase)
      insertional mutant was impaired in the production of [(14)C]citrulline from
      [(14)C]arginine; (ii) a proC (Delta(1)pyrroline-5-carboxylate reductase)
      insertional mutant was impaired in the production of [(14)C]proline,
      [(14)C]glutamate, and [(14)C]glutamine from [(14)C]arginine or [(14)C]ornithine;
      and (iii) a putA (proline oxidase) insertional mutant did not produce
      [(14)C]glutamate from L-[(14)C]arginine, L-[(14)C]ornithine, or L-[(14)C]proline.
      Mutation of two open reading frames (sll0228 and sll1077) putatively encoding
      proteins homologous to arginase indicated, however, that none of these proteins
      was responsible for the arginase activity detected in this cyanobacterium, and
      mutation of argD (N-acetylornithine aminotransferase) suggested that this
      transaminase is not important in the production of Delta(1)pyrroline-5
      carboxylate from ornithine. The metabolic pathways proposed to explain
      [(14)C]arginine catabolism also provide a rationale for understanding how
      nitrogen is made available to the cell after mobilization of cyanophycin [multi-L
      arginyl-poly(L-aspartic acid)], a reserve material unique to cyanobacteria.

PMID- 10648528
TI  - Barriers to genetic exchange between bacterial species: Streptococcus pneumoniae
      transformation.
AB  - Interspecies genetic exchange is an important evolutionary mechanism in bacteria.
      It allows rapid acquisition of novel functions by transmission of adaptive genes
      between related species. However, the frequency of homologous recombination
      between bacterial species decreases sharply with the extent of DNA sequence
      divergence between the donor and the recipient. In Bacillus and Escherichia, this
      sexual isolation has been shown to be an exponential function of sequence
      divergence. Here we demonstrate that sexual isolation in transformation between
      Streptococcus pneumoniae recipient strains and donor DNA from related strains and
      species follows the described exponential relationship. We show that the Hex
      mismatch repair system poses a significant barrier to recombination over the
      entire range of sequence divergence (0.6 to 27%) investigated. Although mismatch
      repair becomes partially saturated, it is responsible for 34% of the observed
      sexual isolation. This is greater than the role of mismatch repair in Bacillus
      but less than that in Escherichia. The remaining non-Hex-mediated barrier to
      recombination can be provided by a variety of mechanisms. We discuss the possible
      additional mechanisms of sexual isolation, in view of earlier findings from
      Bacillus, Escherichia, and Streptococcus.

PMID- 10648529
TI  - The amino terminus of bacteriophage lambda integrase is involved in protein
      protein interactions during recombination.
AB  - Bacteriophage lambda integrase (Int) catalyzes at least four site-specific
      recombination pathways between pairs of attachment (att) sites. Protein-protein
      contacts between monomers of Int are presumed to be important for these site
      specific recombination events for several reasons: Int binds to the att sites
      cooperatively, catalytic Int mutants can complement each other for strand
      cleavage, and crystal structures for two other recombinases in the Int family
      (Cre from phage P1 and Int from Haemophilus influenzae phage HP1) show extensive
      protein-protein contacts between monomers. We have begun to investigate
      interactions between Int monomers by three approaches. First, using a genetic
      assay, we show that regions of protein-protein interactions occur throughout Int,
      including in the amino-terminal domain. This domain was previously thought to be
      important only for high-affinity protein-DNA interactions. Second, we have found
      that an amino-terminal His tag reduces cooperative binding to DNA. This
      disruption in cooperativity decreases the stable interaction of Int with core
      sites, where catalysis occurs. Third, using protein-protein cross-linking to
      investigate the multimerization of Int during recombination, we show that Int
      predominantly forms dimers, trimers, and tetramers. Moreover, we show that the
      cysteine at position 25 is present at or near the interface between monomers that
      is involved in the formation of dimers and tetramers. Our evidence indicates that
      the amino-terminal domain of Int is involved in protein-protein interactions that
      are likely to be important for recombination.

PMID- 10648530
TI  - Insertional inactivation of genes encoding components of the sodium-type
      flagellar motor and switch of Vibrio parahaemolyticus.
AB  - Vibrio parahaemolyticus possesses two types of flagella, polar and lateral,
      powered by distinct energy sources, which are derived from the sodium and proton
      motive forces, respectively. Although proton-powered flagella in Escherichia coli
      and Salmonella enterica serovar Typhimurium have been extensively studied, the
      mechanism of torque generation is still not understood. Molecular knowledge of
      the structure of the sodium-driven motor is only now being developed. In this
      work, we identify the switch components, FliG, FliM, and FliN, of the sodium-type
      motor. This brings the total number of genes identified as pertinent to polar
      motor function to seven. Both FliM and FliN possess charged domains not found in
      proton-type homologs; however, they can interact with the proton-type motor of E.
      coli to a limited extent. Residues known to be critical for torque generation in
      the proton-type motor are conserved in the sodium-type motor, suggesting a common
      mechanism for energy transfer at the rotor-stator interface regardless of the
      driving force powering rotation. Mutants representing a complete panel of
      insertionally inactivated switch and motor genes were constructed. All of these
      mutants were defective in sodium-driven swimming motility. Alkaline phosphatase
      could be fused to the C termini of MotB and MotY without abolishing motility,
      whereas deletion of the unusual, highly charged C-terminal domain of FliM
      disrupted motor function. All of the mutants retained proton-driven, lateral
      motility over surfaces. Thus, although central chemotaxis genes are shared by the
      polar and lateral systems, genes encoding the switch components, as well as the
      motor genes, are distinct for each motility system.

PMID- 10648531
TI  - Molecular analysis of the tagF gene, encoding CDP-Glycerol:Poly(glycerophosphate)
      glycerophosphotransferase of Staphylococcus epidermidis ATCC 14990.
AB  - Staphylococcus epidermidis ATCC 14990 produces a wall-associated glycerol
      teichoic acid which is chemically identical to the major wall-associated teichoic
      acid of Bacillus subtilis 168. The S. epidermidis tagF gene was cloned from
      genomic DNA and sequenced. When introduced on a plasmid vector into B. subtilis
      1A486 carrying the conditionally lethal temperature-sensitive mutation tagF1
      (rodC1), it expressed an 85-kDa protein which allowed colonies to grow at the
      restrictive temperature. This showed that the cloned S. epidermidis gene encodes
      a functional CDP-glycerol:poly(glycerophosphate) glycerophosphotransferase. An
      amino acid substitution at residue 616 in the recombinant TagF protein eliminated
      complementation. Unlike B. subtilis, where the tagF gene is part of the tagDEF
      operon, the tagF gene of S. epidermidis is not linked to any other tag genes. We
      attempted to disrupt the chromosomal tagF gene in S. epidermidis TU3298 by
      directed integration of a temperature-sensitive plasmid but this failed, whereas
      a control plasmid containing the 5' end of tagF on a similarly sized DNA fragment
      was able to integrate. This suggests that the tagF gene is essential and that the
      TagF and other enzymes involved in teichoic acid biosynthesis could be targets
      for new antistaphylococcal drugs.

PMID- 10648532
TI  - The sigma(70) transcription factor TyrR has zinc-stimulated phosphatase activity
      that is inhibited by ATP and tyrosine.
AB  - The TyrR protein of Escherichia coli (513 amino acid residues) is the chief
      transcriptional regulator of a group of genes that are essential for aromatic
      amino acid biosynthesis and transport. The TyrR protein can function either as a
      repressor or as an activator. The central region of the TyrR protein (residues
      207 to 425) is similar to corresponding polypeptide segments of the NtrC protein
      superfamily. Like the NtrC protein, TyrR has intrinsic ATPase activity. Here, we
      report that TyrR possesses phosphatase activity. This activity is subject to
      inhibition by L-tyrosine and its analogues and by ATP and ATP analogues. Zinc ion
      (2 mM) stimulated the phosphatase activity of the TyrR protein by a factor of 57.
      The phosphatase-active site of TyrR was localized to a 31-kDa domain (residues
      191 to 467) of the protein. However, mutational alteration of distant amino acid
      residues at both the N terminus and the C terminus of TyrR altered the
      phosphatase activity. Haemophilus influenzae TyrR (318 amino acid residues), a
      protein with a high degree of sequence similarity to the C terminus of the E.
      coli TyrR protein, exhibited a phosphatase activity similar to that of E. coli
      TyrR.

PMID- 10648533
TI  - A pAD1-encoded small RNA molecule, mD, negatively regulates Enterococcus faecalis
      pheromone response by enhancing transcription termination.
AB  - pAD1 is a 60-kb hemolysin-bacteriocin plasmid in Enterococcus faecalis that
      encodes a conjugative mating response to a peptide sex pheromone, cAD1, secreted
      by plasmid-free bacteria. The pheromone response is regulated by two proteins:
      TraE1, which positively regulates all or most conjugative structural genes, and
      TraA, which negatively regulates traE1. TraA binds to pAD1 DNA at the iad
      (encoding the inhibitor peptide iAD1) promoter but is released upon binding to
      imported pheromone. This leads to enhanced transcription through two closely
      spaced downstream terminators (t1 and t2) into traE1. TraE1 is believed to then
      upregulate itself from a site located within t2; thus, a small amount of
      transcription through t1-t2 could lead to overall induction. It is important
      therefore that the t1-t2 terminators be tightly controlled to keep the response
      shut down in the absence of pheromone. A small (200-nucleotide) RNA molecule
      designated mD is encoded just upstream of t1 by a determinant (traD) oriented in
      the direction opposite to that of transcripts utilizing t1. mD is expressed at
      high levels in the uninduced state, but it decreases significantly upon
      induction. Here we present results of genetic studies relating to the activity of
      t1-t2 and show that mD strongly enhances transcriptional termination at t1. The
      mD activity is shown to influence transcription well downstream and can affect
      the determinant for aggregation substance asa1. The phenomenon is specific in
      that there is no effect of mD on the unrelated pheromone-responding plasmids pPD1
      and pCF10.

PMID- 10648534
TI  - Cloning, characterization, and inactivation of the gene pbpC, encoding penicillin
      binding protein 3 of Staphylococcus aureus.
AB  - The gene pbpC from Staphylococcus aureus was sequenced: it encodes a 691-amino
      acid protein with all of the conserved motifs of a class B high-molecular-weight
      penicillin-binding protein (PBP), including the transpeptidase conserved motifs
      SXXK, SXN, and KTG. Insertional inactivation of pbpC and introduction of the
      intact gene in a laboratory mutant missing PBP 3 showed that the pbpC gene
      encodes the staphylococcal PBP 3. Inactivation of pbpC caused no detectable
      change in the muropeptide composition of cell wall peptidoglycan and had only
      minimum, if any, effect on growth rates, but caused a small but significant
      decrease in rates of autolysis. Cells of abnormal size and shape and disoriented
      septa were produced when bacteria with inactivated pbpC were grown in the
      presence of a sub-MIC of methicillin.

PMID- 10648535
TI  - Quorum sensing but not autoinduction of Ti plasmid conjugal transfer requires
      control by the opine regulon and the antiactivator TraM.
AB  - Conjugal transfer of the Ti plasmids from Agrobacterium tumefaciens is controlled
      by autoinduction via the transcriptional activator TraR and the acyl-homoserine
      lactone ligand, Agrobacterium autoinducer (AAI). This control process is itself
      regulated by opines, which are small carbon compounds produced by the crown gall
      tumors that are induced by the bacteria. Opines control autoinduction by
      regulating the expression of traR. Transfer of pTiC58 from donors grown with
      agrocinopines A and B, the conjugal opines for this Ti plasmid, was detected only
      after the donors had reached a population level of 10(7) cells per cm(2). Donors
      incubated with the opines and AAI transferred their Ti plasmids at population
      levels about 10-fold lower than those incubated with opines only. Transcription
      of the tra regulon, as assessed by monitoring a traA::lacZ reporter, showed a
      similar dependence on the density of the donor population. However, even in
      cultures at low population densities that were induced with opines and AAI, there
      was a temporal lag of between 15 and 20 h in the development of conjugal
      competence. Moreover, even after this latent period, maximal transfer frequencies
      required several hours to develop. This lag period was independent of the
      population density of the donors but could be reduced somewhat by addition of
      exogenous AAI. Quorum-dependent development of conjugal competence required
      control by the opine regulon; donors harboring a mutant of pTiC58 deleted for the
      master opine responsive repressor accR transferred the Ti plasmid at maximum
      frequencies at very low population densities. Similarly, an otherwise wild-type
      derivative of pTiC58 lacking traM, which codes for an antiactivator that inhibits
      TraR activity, transferred at high frequency in a population-independent manner
      in the absence of the conjugal opines. Thus, while quorum sensing is dependent
      upon autoinduction, the two phenomena are not synonymous. We conclude that
      conjugal transfer of pTiC58 is regulated in a quorum-dependent fashion but that
      supercontrol of the TraR-AAI system by opines and by TraM results in a complex
      control process that requires not only the accumulation of AAI but also the
      expression of TraR and the synthesis of this protein at levels that overcome the
      inhibitory activity of TraM.

PMID- 10648536
TI  - Antigen 43 and type 1 fimbriae determine colony morphology of Escherichia coli K
      12.
AB  - Colony morphology has been used as an important identification and
      characterization criterion in bacteriology for many decades. However, the
      molecular mechanisms underlying the appearance of different colony types have
      been given little attention. The synthesis of O antigen is defunct in Escherichia
      coli K-12, and colonies should accordingly only appear to be rough. However,
      previous reports have noted the presence of different interchangeable colony
      morphology types. In this study we have addressed the influence of two phase
      variable surface structures, antigen 43 and type 1 fimbriae, on colony
      morphology. Due to differential expression of these structures, four different
      colony phenotypes could be distinguished. By creating and studying defined
      mutants of the respective loci, i.e. , flu and fim, we conclude that the presence
      or absence of the corresponding gene products on the cells correlates with the
      observed colony morphology forms. Interestingly, the habitat specificity of
      bacteria under static liquid conditions seems to correlate with the colony
      phenotypes.

PMID- 10648537
TI  - SpoIIB localizes to active sites of septal biogenesis and spatially regulates
      septal thinning during engulfment in bacillus subtilis.
AB  - A key step in the Bacillus subtilis spore formation pathway is the engulfment of
      the forespore by the mother cell, a phagocytosis-like process normally
      accompanied by the loss of peptidoglycan within the sporulation septum. We have
      reinvestigated the role of SpoIIB in engulfment by using the fluorescent membrane
      stain FM 4-64 and deconvolution microscopy. We have found that spoIIB mutant
      sporangia display a transient engulfment defect in which the forespore pushes
      through the septum and bulges into the mother cell, similar to the situation in
      spoIID, spoIIM, and spoIIP mutants. However, unlike the sporangia of those three
      mutants, spoIIB mutant sporangia are able to complete engulfment; indeed, by time
      lapse microscopy, sporangia with prominent bulges were found to complete
      engulfment. Electron micrographs showed that in spoIIB mutant sporangia the
      dissolution of septal peptidoglycan is delayed and spatially unregulated and that
      the engulfing membranes migrate around the remaining septal peptidoglycan. These
      results demonstrate that mother cell membranes will move around septal
      peptidoglycan that has not been completely degraded and suggest that SpoIIB
      facilitates the rapid and spatially regulated dissolution of septal
      peptidoglycan. In keeping with this proposal, a SpoIIB-myc fusion protein
      localized to the sporulation septum during its biogenesis, discriminating between
      the site of active septal biogenesis and the unused potential division site
      within the same cell.

PMID- 10648538
TI  - Fragmentation of 23S rRNA in strains of Proteus and Providencia results from
      intervening sequences in the rrn (rRNA) genes.
AB  - Intervening sequences (IVSs) were originally identified in the rrl genes for 23S
      rRNA (rrl genes, for large ribosomal subunit, part of rrn operon encoding rRNA)
      of Salmonella enterica serovars Typhimurium LT2 and Arizonae. These sequences are
      transcribed but later removed during RNase III processing of the rRNA, resulting
      in fragmentation of the 23S species; IVSs are uncommon, but have been reported in
      at least 10 bacterial genera. Through PCR amplification of IVS-containing regions
      of the rrl genes we showed that most Proteus and Providencia strains contain IVSs
      similar to those of serovar Typhimurium in distribution and location in rrl
      genes. By extraction and Northern blotting of rRNA, we also found that these IVSs
      result in rRNA fragmentation. We report the first finding of two very different
      sizes of IVS (113 bp and 183 to 187 bp) in different rrl genes in the same
      strain, in helix 25 of Proteus and Providencia spp.; IVSs from helix 45 are 113
      to 123 bp in size. Analysis of IVS sequence and postulated secondary structure
      reveals striking similarities of Proteus and Providencia IVSs to those of serovar
      Typhimurium, with the stems of the smaller IVSs from helix 25 being similar to
      those of Salmonella helix 25 IVSs and with both the stem and the central loop
      domain of helix 45 IVSs being similar. Thus, IVSs of related sequences are widely
      distributed throughout the Enterobacteriaceae, in Salmonella, Yersinia, Proteus,
      and Providencia spp., but we did not find them in Escherichia coli, Citrobacter,
      Enterobacter, Klebsiella, or Morganella spp.; the sporadic distribution of IVSs
      of related sequence indicates that lateral genetic transfer has occurred.

PMID- 10648539
TI  - Functional domains of the TOL plasmid transcription factor XylS.
AB  - The alkylbenzoate degradation genes of Pseudomonas putida TOL plasmid are
      positively regulated by XylS, an AraC family protein, in a benzoate-dependent
      manner. In this study, we used deletion mutants and hybrid proteins to identify
      which parts of XylS are responsible for the DNA binding, transcriptional
      activation, and benzoate inducibility. We found that a 112-residue C-terminal
      fragment of XylS binds specifically to the Pm operator in vitro, protects this
      sequence from DNase I digestion identically to the wild-type (wt) protein, and
      activates the Pm promoter in vivo. When overexpressed, that C-terminal fragment
      could activate transcription as efficiently as wt XylS. All the truncations,
      which incorporated these 112 C-terminal residues, were able to activate
      transcription at least to some extent when overproduced. Intactness of the 210
      residue N-terminal portion was found to be necessary for benzoate responsiveness
      of XylS. Deletions in the N-terminal and central regions seriously reduced the
      activity of XylS and caused the loss of effector control, whereas insertions into
      the putative interdomain region did not change the basic features of the XylS
      protein. Our results confirm that XylS consists of two parts which probably
      interact with each other. The C-terminal domain carries DNA-binding and
      transcriptional activation abilities, while the N-terminal region carries
      effector-binding and regulatory functions.

PMID- 10648541
TI  - The metabolic network of Lactococcus lactis: distribution of (14)C-labeled
      substrates between catabolic and anabolic pathways.
AB  - Lactococcus lactis NCDO 2118 was grown in a simple synthetic medium containing
      only six essential amino acids and glucose as carbon substrates to determine
      qualitatively and quantitatively the carbon fluxes into the metabolic network.
      The specific rates of substrate consumption, product formation, and biomass
      synthesis, calculated during the exponential growth phase, represented the carbon
      fluxes within the catabolic and anabolic pathways. The macromolecular composition
      of the biomass was measured to distribute the global anabolic flux into the
      specific anabolic pathways. Finally, the distribution of radiolabeled substrates,
      both into the excreted fermentation end products and into the different
      macromolecular fractions of biomass, was monitored. The classical end products of
      lactic acid metabolism (lactate, formate, and acetate) were labeled with glucose,
      which did not label other excreted products, and to a lesser extent with serine,
      which was deaminated to pyruvate and represented approximately 10% of the
      pyruvate flux. Other minor products, keto and hydroxy acids, were produced from
      glutamate and branched-chain amino acids via deamination and subsequent
      decarboxylation and/or reduction. Glucose labeled all biomass fractions and
      accounted for 66% of the cellular carbon, although this represented only 5% of
      the consumed glucose.

PMID- 10648540
TI  - A role for the umuDC gene products of Escherichia coli in increasing resistance
      to DNA damage in stationary phase by inhibiting the transition to exponential
      growth.
AB  - The umuDC gene products, whose expression is induced by DNA-damaging treatments,
      have been extensively characterized for their role in SOS mutagenesis. We have
      recently presented evidence that supports a role for the umuDC gene products in
      the regulation of growth after DNA damage in exponentially growing cells,
      analogous to a prokaryotic DNA damage checkpoint. Our further characterization of
      the growth inhibition at 30 degrees C associated with constitutive expression of
      the umuDC gene products from a multicopy plasmid has shown that the umuDC gene
      products specifically inhibit the transition from stationary phase to exponential
      growth at the restrictive temperature of 30 degrees C and that this is correlated
      with a rapid inhibition of DNA synthesis. These observations led to the finding
      that physiologically relevant levels of the umuDC gene products, expressed from a
      single, SOS-regulated chromosomal copy of the operon, modulate the transition to
      rapid growth in E. coli cells that have experienced DNA damage while in
      stationary phase. This activity of the umuDC gene products is correlated with an
      increase in survival after UV irradiation. In a distinction from SOS mutagenesis,
      uncleaved UmuD together with UmuC is responsible for this activity. The umuDC
      dependent increase in resistance in UV-irradiated stationary-phase cells appears
      to involve, at least in part, counteracting a Fis-dependent activity and thereby
      regulating the transition to rapid growth in cells that have experienced DNA
      damage. Thus, the umuDC gene products appear to increase DNA damage tolerance at
      least partially by regulating growth after DNA damage in both exponentially
      growing and stationary-phase cells.

PMID- 10648542
TI  - Crc is involved in catabolite repression control of the bkd operons of
      Pseudomonas putida and Pseudomonas aeruginosa.
AB  - Crc (catabolite repression control) protein of Pseudomonas aeruginosa has shown
      to be involved in carbon regulation of several pathways. In this study, the role
      of Crc in catabolite repression control has been studied in Pseudomonas putida.
      The bkd operons of P. putida and P. aeruginosa encode the inducible multienzyme
      complex branched-chain keto acid dehydrogenase, which is regulated in both
      species by catabolite repression. We report here that this effect is mediated in
      both species by Crc. A 13-kb cloned DNA fragment containing the P. putida crc
      gene region was sequenced. Crc regulates the expression of branched-chain keto
      acid dehydrogenase, glucose-6-phosphate dehydrogenase, and amidase in both
      species but not urocanase, although the carbon sources responsible for catabolite
      repression in the two species differ. Transposon mutants affected in their
      expression of BkdR, the transcriptional activator of the bkd operon, were
      isolated and identified as crc and vacB (rnr) mutants. These mutants suggested
      that catabolite repression in pseudomonads might, in part, involve control of
      BkdR levels.

PMID- 10648544
TI  - Covalent linkage of polyamines to peptidoglycan in Anaerovibrio lipolytica.
AB  - Spermidine and cadaverine were found to be constituents of the cell wall
      peptidoglycan of Anaerovibrio lipolytica, a strictly anaerobic bacterium. The
      peptidoglycan was degraded with the N-acetylmuramyl-L-alanine amidase and
      endopeptidase into two peptide fragments, peptide I and peptide II, at a molar
      ratio of 4:1. Peptides I and II were identified as L-alanine-D-glutamic
      acid(alphacadaverine)gammameso-diaminopimelic acid (DAP)-D-alanine and L-alanine
      D-glutamic acid(alphaspermidine)gammameso-DAP-D-alanine, respectively. The N(1)
      amino group of spermidine was linked to the alpha-carboxyl group of the D
      glutamic acid residue of peptide II.

PMID- 10648545
TI  - Cell cycle arrest in archaea by the hypusination inhibitor N(1)-guanyl-1,7
      diaminoheptane.
AB  - Hypusination is an essential posttranslational modification unique to archaeal
      and eukaryotic protein synthesis initiation factor 5A (aIF5A and eIF5A,
      respectively). We have investigated the effect of the efficient hypusination
      inhibitor N(1)-guanyl-1,7-diaminoheptane (GC(7)) on four archaeal and one
      bacterial species. We found that (i) archaea are sensitive to GC(7), whereas the
      bacterium Escherichia coli is not, (ii) GC(7) causes rapid and reversible arrest
      of growth of the archaeon Sulfolobus acidocaldarius, and (iii) the growth arrest
      is accompanied by a specific reversible arrest of the cell cycle prior to cell
      division. Our findings establish a link between hypusination and sustained growth
      of archaea and thereby provide the framework to study molecular details of
      archaeal cell cycle in connection with in vivo functions of hypusine and of aIF5A
      and eIF5A.

PMID- 10648543
TI  - Catabolite repression control by crc in 2xYT medium is mediated by
      posttranscriptional regulation of bkdR expression in Pseudomonas putida.
AB  - The effect of growth in 2xYT medium on catabolite repression control in
      Pseudomonas putida has been investigated using the bkd operon, encoding branched
      chain keto acid dehydrogenase. Crc (catabolite repression control protein) was
      shown to be responsible for repression of bkd operon transcription in 2xYT. BkdR
      levels were elevated in a P. putida crc mutant, but bkdR transcript levels were
      the same in both wild type and crc mutant. This suggests that the mechanism of
      catabolite repression control in rich media by Crc involves posttranscriptional
      regulation of the bkdR message.

PMID- 10648546
TI  - Single-molecule imaging of interaction between dextran and glucosyltransferase
      from Streptococcus sobrinus.
AB  - Using total internal reflection fluorescence microscopy, we directly observed the
      interaction between dextran and glucosyltransferase I (GTF) of Streptococcus
      sobrinus. Tetramethylrhodamine (TMR)-labeled GTF molecules were individually
      imaged as they were associating with and then dissociating from the dextran fixed
      on the glass surface in the evanescent field. Similarly dynamic behavior of TMR
      labeled dextran molecules was also observed on the GTF-fixed surface. The
      duration of the stay on the surface (dwell time) was measured for each of these
      molecules by counting the number of video frames that had recorded the image. A
      histogram of dwell time for a population of several hundred molecules indicated
      that the GTF-dextran interaction obeyed an apparent first-order kinetics. The
      rate constraints estimated for TMR-labeled GTF at pH 6.8 and 25 degrees C in the
      absence and presence of sucrose were 9.2 and 13.3 s(-1), respectively, indicating
      that sucrose accelerated the dissociation of GTF from dextran. However, the
      accelerated rate was still much lower than the catalytic center activity of GTF
      (> or = 25 s(-1)) under comparable conditions.

PMID- 10648547
TI  - Increase of external osmolarity reduces morphogenetic defects and accumulation of
      chitin in a gas1 mutant of Saccharomyces cerevisiae.
AB  - We have performed a physiological analysis of the effects of high-osmolarity
      media on gas1Delta cells. The reductions in the duplication time, number of
      pluribudded cells, hypersensitivity to Calcofluor and sodium dodecyl sulfate, and
      chitin level indicate a partial suppression of the mutant phenotype. GAS1
      deletion was found to be lethal in the absence of the Bck1 and Slt2 (Mpk1)
      proteins of the cell integrity pathway.

PMID- 10648548
TI  - Visualization of phospholipid domains in Escherichia coli by using the
      cardiolipin-specific fluorescent dye 10-N-nonyl acridine orange.
AB  - Cardiolipin (CL)-specific fluorescent dye 10-N-nonyl-acridine orange (NAO) was
      used to visualize CL distribution in Escherichia coli cells of different
      phospholipid compositions. In a filamentous mutant containing only anionic
      phospholipids, green fluorescent spots were observed along the filaments at
      approximately regular intervals. Three-dimensional image reconstruction obtained
      by optical sectioning and a deconvolution algorithm revealed NAO-binding domains
      in the plane of the cell membrane. Substantial red fluorescence emission of bound
      NAO supported labeling of CL-containing domains. These structures were not found
      in mutants deficient in CL biosynthesis. The domains were also observed mostly in
      the septal region and on the poles in cells of normal size with wild-type
      phospholipid composition.

PMID- 10648549
TI  - Native plasmids of Fusobacterium nucleatum: characterization and use in
      development of genetic systems.
AB  - Three native plasmids of Fusobacterium nucleatum were characterized, including
      DNA sequence analysis of one plasmid, pFN1. A shuttle plasmid, pHS17, capable of
      transforming Escherichia coli and F. nucleatum ATCC 10953 was constructed with
      pFN1. pHS17 was stably maintained in the F. nucleatum transformants, and
      differences in the transformation efficiencies suggested the presence of a
      restriction-modification system in F. nucleatum.

PMID- 10648550
TI  - Two extracytoplasmic function sigma subunits, sigma(E) and sigma(FecI), of
      Escherichia coli: promoter selectivity and intracellular levels.
AB  - The promoter selectivity of two extracytoplasmic function (ECF) subfamily sigma
      subunits, sigma(E) (sigma(24)) and sigma(FecI) (sigma(18)), of Escherichia coli
      RNA polymerase was analyzed by using an in vitro transcription system and various
      promoters. The Esigma(E) holoenzyme recognized only the known cognate promoters,
      rpoEP2, rpoHP3, and degP, and the Esigma(FecI) recognized only one known cognate
      promoter, fecA. The strict promoter recognition properties of sigma(E) and
      sigma(FecI) are similar to those of other minor sigma subunits. Transcription by
      Esigma(E) and Esigma(FecI) was enhanced by high concentrations of glutamate, as
      in the case of other minor sigma subunits. The optimum temperature for
      transcription by Esigma(FecI) was low, around 25 degrees C, apparently in
      agreement with the high rate of iron sequestration by E. coli at low
      temperatures. By quantitative Western blot analysis, the intracellular levels of
      sigma(E) and sigma(FecI) in the uninduced steady-state culture of E. coli W3110
      (type A) were determined to be 0.7 to 2.0 and 0.1 to 0.2 fmol per microg of total
      proteins (or 3 to 9 and 0.4 to 0.9 molecules per cell), respectively, and less
      than 1% of the level of the major sigma(70) subunit.

PMID- 10648551
TI  - High-resolution physical map of the Sinorhizobium meliloti 1021 pSyma
      megaplasmid.
AB  - To facilitate sequencing of the Sinorhizobium meliloti 1021 pSyma megaplasmid, a
      high-resolution map was constructed by ordering 113 overlapping bacterial
      artificial chromosome clones with 192 markers. The 157 anonymous sequence tagged
      site markers (81,072 bases) reveal hypothetical functions encoded by the
      replicon.

PMID- 10648552
TI  - The tails of two myosins.

PMID- 10648553
TI  - Nuclear factor-kappaB to the rescue of cytokine-induced neuronal survival.

PMID- 10648555
TI  - Polyploidy induces centromere association.
AB  - Many species exhibit polyploidy. The presence of more than one diploid set of
      similar chromosomes in polyploids can affect the assortment of homologous
      chromosomes, resulting in unbalanced gametes. Therefore, a mechanism is required
      to ensure the correct assortment and segregation of chromosomes for gamete
      formation. Ploidy has been shown to affect gene expression. We present in this
      study an example of a major effect on a phenotype induced by ploidy within the
      Triticeae. We demonstrate that centromeres associate early during anther
      development in polyploid species. In contrast, centromeres in diploid species
      only associate at the onset of meiotic prophase. We propose that this mechanism
      provides a potential route by which chromosomes can start to be sorted before
      meiosis in polyploids. This explains previous reports indicating that meiotic
      prophase is shorter in polyploids than in their diploid progenitors. Even
      artificial polyploids exhibit this phenotype, suggesting that the mechanism must
      be present in diploids, but only expressed in the presence of more than one
      diploid set of chromosomes.

PMID- 10648554
TI  - The elusive functions of proteoglycans: in vivo veritas.

PMID- 10648556
TI  - Nuclear eukaryotic initiation factor 4E (eIF4E) colocalizes with splicing factors
      in speckles.
AB  - The eukaryotic initiation factor 4E (eIF4E) plays a pivotal role in the control
      of protein synthesis. eIF4E binds to the mRNA 5' cap structure, m(7)GpppN (where
      N is any nucleotide) and promotes ribosome binding to the mRNA. It was previously
      shown that a fraction of eIF4E localizes to the nucleus (Lejbkowicz, F., C.
      Goyer, A. Darveau, S. Neron, R. Lemieux, and N. Sonenberg. 1992. Proc. Natl.
      Acad. Sci. USA. 89:9612-9616). Here, we show that the nuclear eIF4E is present
      throughout the nucleoplasm, but is concentrated in speckled regions. Double label
      immunofluorescence confocal microscopy shows that eIF4E colocalizes with Sm and
      U1snRNP. We also demonstrate that eIF4E is specifically released from the
      speckles by the cap analogue m(7)GpppG in a cell permeabilization assay. However,
      eIF4E is not released from the speckles by RNase A treatment, suggesting that
      retention of eIF4E in the speckles is not RNA-mediated. 5,6-dichloro-1-beta-d
      ribofuranosylbenzimidazole (DRB) treatment of cells causes the condensation of
      eIF4E nuclear speckles. In addition, overexpression of the dual specificity
      kinase, Clk/Sty, but not of the catalytically inactive form, results in the
      dispersion of eIF4E nuclear speckles.

PMID- 10648557
TI  - nSec1 binds a closed conformation of syntaxin1A.
AB  - The Sec1 family of proteins is proposed to function in vesicle trafficking by
      forming complexes with target membrane SNAREs (soluble N-ethylmaleimide-sensitive
      factor [NSF] attachment protein [SNAP] receptors) of the syntaxin family. Here,
      we demonstrate, by using in vitro binding assays, nondenaturing gel
      electrophoresis, and specific neurotoxin treatment, that the interaction of
      syntaxin1A with the core SNARE components, SNAP-25 (synaptosome-associated
      protein of 25 kD) and VAMP2 (vesicle-associated membrane protein 2), precludes
      the interaction with nSec1 (also called Munc18 and rbSec1). Inversely,
      association of nSec1 and syntaxin1A prevents assembly of the ternary SNARE
      complex. Furthermore, using chemical cross-linking of rat brain membranes, we
      identified nSec1 complexes containing syntaxin1A, but not SNAP-25 or VAMP2. These
      results support the hypothesis that Sec1 proteins function as syntaxin chaperons
      during vesicle docking, priming, and membrane fusion.

PMID- 10648558
TI  - RhoA function in lamellae formation and migration is regulated by the alpha6beta4
      integrin and cAMP metabolism.
AB  - Clone A colon carcinoma cells develop fan-shaped lamellae and exhibit random
      migration when plated on laminin, processes that depend on the ligation of the
      alpha6beta4 integrin. Here, we report that expression of a dominant negative RhoA
      (N19RhoA) in clone A cells inhibited alpha6beta4-dependent membrane ruffling,
      lamellae formation, and migration. In contrast, expression of a dominant negative
      Rac (N17Rac1) had no effect on these processes. Using the Rhotekin binding assay
      to assess RhoA activation, we observed that engagement of alpha6beta4 by either
      antibody-mediated clustering or laminin attachment resulted in a two- to
      threefold increase in RhoA activation, compared with cells maintained in
      suspension or plated on collagen. Antibody-mediated clustering of beta1
      integrins, however, actually suppressed Rho A activation. The alpha6beta4
      mediated interaction of clone A cells with laminin promoted the translocation of
      RhoA from the cytosol to membrane ruffles at the edges of lamellae and promoted
      its colocalization with beta1 integrins, as assessed by immunofluorescence
      microscopy. In addition, RhoA translocation was blocked by inhibiting
      phosphodiesterase activity and enhanced by inhibiting the activity of cAMP
      dependent protein kinase. Together, these results establish a specific integrin
      mediated pathway of RhoA activation that is regulated by cAMP and that functions
      in lamellae formation and migration.

PMID- 10648559
TI  - In vivo release of mitotic silencing of ribosomal gene transcription does not
      give rise to precursor ribosomal RNA processing.
AB  - Nuclear RNA transcription is repressed when eukaryotic cells enter mitosis. Here,
      we found that the derepression of ribosomal gene (rDNA) transcription that
      normally takes place in telophase may be induced in prometaphase, metaphase, and
      anaphase mitotic HeLa cells, and therefore appears not to be dependent on
      completion of mitosis. We demonstrate for the first time that in vivo inhibition
      of the cdc2- cyclin B kinase activity is sufficient to give rise to okadaic acid
      sensitive dephosphorylation of the mitotically phosphorylated forms of components
      of the rDNA transcription machinery, and consequently to restore rDNA
      transcription in mitotic cells. These results, showing that during mitosis the
      rDNA transcription machinery is maintained repressed by the cdc2-cyclin B kinase
      activity, provide an in vivo demonstration of the cell cycle-dependent regulation
      of rDNA transcription. Interestingly in mitotic cells, the newly synthesized 47S
      precursor ribosomal RNA (pre-rRNA) is not processed into the mature rRNAs,
      indicating that rDNA transcription and pre-rRNA processing may be uncoupled.
      Moreover this suggests that inhibition of the cdc2- cyclin B kinase is not
      sufficient to activate the 47S pre-rRNA processing machinery and/or to induce its
      relocalization at the level of newly synthesized 47S pre-rRNA. This in vivo
      approach provides new possibilities to investigate the correlation between pre
      rRNA synthesis and pre-rRNA processing when the nucleolus reforms.

PMID- 10648560
TI  - Electron tomography reveals posttranscriptional binding of pre-mRNPs to specific
      fibers in the nucleoplasm.
AB  - Using electron tomography, we have analyzed whether the Balbiani ring (BR) pre
      mRNP particles in transit from the gene to the nuclear pore complex (NPC) are
      bound to any structure that could impair free diffusion through the nucleoplasm.
      We show that one-third of the BR particles are in contact with thin connecting
      fibers (CFs), which in some cases merge into large fibrogranular clusters. The
      CFs have a specific protein composition different from that of BR particles, as
      shown by immuno-EM. Moreover, we have identified hrp65 as one of the protein
      components of the CFs. The sequencing of hrp65 cDNA reveals similarities with
      hnRNP proteins and splicing factors. However, hrp65 is likely to have a different
      function because it does not bind to nascent pre-mRNA and is not part of the pre
      mRNP itself. Taken together, our observations indicate that pre-mRNPs are not
      always freely diffusible in the nucleoplasm but interact with fibers of specific
      structure and composition, which implies that some of the posttranscriptional
      events that the pre-mRNPs undergo before reaching the NPC occur in a bound state.

PMID- 10648561
TI  - Promyelocytic leukemia (PML) nuclear bodies are protein structures that do not
      accumulate RNA.
AB  - The promyelocytic leukemia (PML) nuclear body (also referred to as ND10, POD, and
      Kr body) is involved in oncogenesis and viral infection. This subnuclear domain
      has been reported to be rich in RNA and a site of nascent RNA synthesis,
      implicating its direct involvement in the regulation of gene expression. We used
      an analytical transmission electron microscopic method to determine the structure
      and composition of PML nuclear bodies and the surrounding nucleoplasm. Electron
      spectroscopic imaging (ESI) demonstrates that the core of the PML nuclear body is
      a dense, protein-based structure, 250 nm in diameter, which does not contain
      detectable nucleic acid. Although PML nuclear bodies contain neither chromatin
      nor nascent RNA, newly synthesized RNA is associated with the periphery of the
      PML nuclear body, and is found within the chromatin-depleted region of the
      nucleoplasm immediately surrounding the core of the PML nuclear body. We further
      show that the RNA does not accumulate in the protein core of the structure. Our
      results dismiss the hypothesis that the PML nuclear body is a site of
      transcription, but support the model in which the PML nuclear body may contribute
      to the formation of a favorable nuclear environment for the expression of
      specific genes.

PMID- 10648562
TI  - An ATP-dependent, Ran-independent mechanism for nuclear import of the U1A and
      U2B" spliceosome proteins.
AB  - Nuclear import of the two uracil-rich small nuclear ribonucleoprotein (U snRNP)
      components U1A and U2B" is mediated by unusually long and complex nuclear
      localization signals (NLSs). Here we investigate nuclear import of U1A and U2B"
      in vitro and demonstrate that it occurs by an active, saturable process. Several
      lines of evidence suggest that import of the two proteins occurs by an import
      mechanism different to those characterized previously. No cross competition is
      seen with a variety of previously studied NLSs. In contrast to import mediated by
      members of the importin-beta family of nucleocytoplasmic transport receptors,
      U1A/U2B" import is not inhibited by either nonhydrolyzable guanosine triphosphate
      (GTP) analogues or by a mutant of the GTPase Ran that is incapable of GTP
      hydrolysis. Adenosine triphosphate is capable of supporting U1A and U2B" import,
      whereas neither nonhydrolyzable adenosine triphosphate analogues nor GTP can do
      so. U1A and U2B" import in vitro does not require the addition of soluble
      cytosolic proteins, but a factor or factors required for U1A and U2B" import
      remains tightly associated with the nuclear fraction of conventionally
      permeabilized cells. This activity can be solubilized in the presence of elevated
      MgCl(2). These data suggest that U1A and U2B" import into the nucleus occurs by a
      hitherto uncharacterized mechanism.

PMID- 10648563
TI  - Golgi alkalinization by the papillomavirus E5 oncoprotein.
AB  - The E5 oncoprotein of bovine papillomavirus type I is a small, hydrophobic
      polypeptide localized predominantly in the Golgi complex. E5-mediated
      transformation is often associated with activation of the PDGF receptor (PDGF-R).
      However, some E5 mutants fail to induce PDGF-R phosphorylation yet retain
      transforming activity, suggesting an additional mechanism of action. Since E5
      also interacts with the 16-kD pore-forming subunit of the vacuolar H(+)-ATPase (V
      ATPase), the oncoprotein could conceivably interfere with the pH homeostasis of
      the Golgi complex. A pH-sensitive, fluorescent bacterial toxin was used to label
      this organelle and Golgi pH (pH(G)) was measured by ratio imaging. Whereas pH(G)
      of untreated cells was acidic (6.5), no acidification was detected in E5
      transfected cells (pH approximately 7.0). The Golgi buffering power and the rate
      of H(+) leakage were found to be comparable in control and transfected cells.
      Instead, the E5-induced pH differential was attributed to impairment of V-ATPase
      activity, even though the amount of ATPase present in the Golgi complex was
      unaltered. Mutations that abolished binding of E5 to the 16-kD subunit or that
      targeted the oncoprotein to the endoplasmic reticulum abrogated Golgi
      alkalinization and cellular transformation. Moreover, transformation-competent E5
      mutants that were defective for PDGF-R activation alkalinized the Golgi lumen.
      Neither transformation by sis nor src, two oncoproteins in the PDGF-R signaling
      pathway, affected pH(G). We conclude that alkalinization of the Golgi complex
      represents a new biological activity of the E5 oncoprotein that correlates with
      cellular transformation.

PMID- 10648564
TI  - A cell-free system for regulated exocytosis in PC12 cells.
AB  - We have developed a cell-free system for regulated exocytosis in the PC12
      neuroendocrine cell line. Secretory vesicles were preloaded with acridine orange
      in intact cells, and the cells were sonicated to produce flat, carrier-supported
      plasma membrane patches with attached vesicles. Exocytosis resulted in the
      release of acridine orange which was visible as a disappearance of labeled
      vesicles and, under optimal conditions, produced light flashes by fluorescence
      dequenching. Exocytosis in vitro requires cytosol and Ca(2+) at concentrations in
      the micromolar range, and is sensitive to Tetanus toxin. Imaging of membrane
      patches at diffraction- limited resolution revealed that 42% of docked granules
      were released in a Ca(2+)-dependent manner during 1 min of stimulation. Electron
      microscopy of membrane patches confirmed the presence of dense-core vesicles.
      Imaging of membrane patches by atomic force microscopy revealed the presence of
      numerous particles attached to the membrane patches which decreased in number
      upon stimulation. Thus, exocytotic membrane fusion of single vesicles can be
      monitored with high temporal and spatial resolution, while providing access to
      the site of exocytosis for biochemical and molecular tools.

PMID- 10648565
TI  - Cytokine-induced nuclear factor kappa B activation promotes the survival of
      developing neurons.
AB  - Ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF),
      cardiotrophin-1 (CT-1), and interleukin 6 (IL-6) comprise a group of structurally
      related cytokines that promote the survival of subsets of neurons in the
      developing peripheral nervous system, but the signaling pathways activated by
      these cytokines that prevent neuronal apoptosis are unclear. Here, we show that
      these cytokines activate NF-kappaB in cytokine-dependent developing sensory
      neurons. Preventing NF-kappaB activation with a super-repressor IkappaB-alpha
      protein markedly reduces the number of neurons that survive in the presence of
      cytokines, but has no effect on the survival response of the same neurons to
      brain-derived neurotrophic factors (BDNF), an unrelated neurotrophic factor that
      binds to a different class of receptors. Cytokine-dependent sensory neurons
      cultured from embryos that lack p65, a transcriptionally active subunit of NF
      kappaB, have a markedly impaired ability to survive in response to cytokines, but
      respond normally to BDNF. There is increased apoptosis of cytokine- dependent
      neurons in p65(-/)- embryos in vivo, resulting in a reduction in the total number
      of these neurons compared with their numbers in wild-type embryos. These results
      demonstrate that NF-kappaB plays a key role in mediating the survival response of
      developing neurons to cytokines.

PMID- 10648566
TI  - Reciprocal role of ERK and NF-kappaB pathways in survival and activation of
      osteoclasts.
AB  - To examine the role of mitogen-activated protein kinase and nuclear factor kappa
      B (NF-kappaB) pathways on osteoclast survival and activation, we constructed
      adenovirus vectors carrying various mutants of signaling molecules: dominant
      negative Ras (Ras(DN)), constitutively active MEK1 (MEK(CA)), dominant negative
      IkappaB kinase 2 (IKK(DN)), and constitutively active IKK2 (IKK(CA)). Inhibiting
      ERK activity by Ras(DN) overexpression rapidly induced the apoptosis of
      osteoclast-like cells (OCLs) formed in vitro, whereas ERK activation after the
      introduction of MEK(CA) remarkably lengthened their survival by preventing
      spontaneous apoptosis. Neither inhibition nor activation of ERK affected the bone
      resorbing activity of OCLs. Inhibition of NF-kappaB pathway with IKK(DN) virus
      suppressed the pit-forming activity of OCLs and NF-kappaB activation by IKK(CA)
      expression upregulated it without affecting their survival. Interleukin 1alpha
      (IL-1alpha) strongly induced ERK activation as well as NF-kappaB activation.
      Ras(DN) virus partially inhibited ERK activation, and OCL survival promoted by IL
      1alpha. Inhibiting NF-kappaB activation by IKK(DN) virus significantly suppressed
      the pit-forming activity enhanced by IL-1alpha. These results indicate that ERK
      and NF-kappaB regulate different aspects of osteoclast activation: ERK is
      responsible for osteoclast survival, whereas NF-kappaB regulates osteoclast
      activation for bone resorption.

PMID- 10648567
TI  - Homeobox B3 promotes capillary morphogenesis and angiogenesis.
AB  - Endothelial cells (EC) express several members of the Homeobox (Hox) gene family,
      suggesting a role for these morphoregulatory mediators during angiogenesis. We
      have previously established that Hox D3 is required for expression of integrin
      alphavbeta3 and urokinase plasminogen activator (uPA), which contribute to EC
      adhesion, invasion, and migration during angiogenesis. We now report that the
      paralogous gene, Hox B3, influences angiogenic behavior in a manner that is
      distinct from Hox D3. Antisense against Hox B3 impaired capillary morphogenesis
      of dermal microvascular EC cultured on basement membrane extracellular matrices.
      Although levels of Hox D3-dependent genes were maintained in these cells, levels
      of the ephrin A1 ligand were markedly attenuated. Capillary morphogenesis could
      be restored, however, by addition of recombinant ephrin A1/Fc fusion proteins. To
      test the impact of Hox B3 on angiogenesis in vivo, we constitutively expressed
      Hox B3 in the chick chorioallantoic membrane using avian retroviruses that
      resulted in an increase in vascular density and angiogenesis. Thus, while Hox D3
      promotes the invasive or migratory behavior of EC, Hox B3 is required for the
      subsequent capillary morphogenesis of these new vascular sprouts and, together,
      these results support the hypothesis that paralogous Hox genes perform
      complementary functions within a particular tissue type.

PMID- 10648568
TI  - A role for myosin-I in actin assembly through interactions with Vrp1p, Bee1p, and
      the Arp2/3 complex.
AB  - Type I myosins are highly conserved actin-based molecular motors that localize to
      the actin-rich cortex and participate in motility functions such as endocytosis,
      polarized morphogenesis, and cell migration. The COOH-terminal tail of yeast
      myosin-I proteins, Myo3p and Myo5p, contains an Src homology domain 3 (SH3)
      followed by an acidic domain. The myosin-I SH3 domain interacted with both Bee1p
      and Vrp1p, yeast homologues of human WASP and WIP, adapter proteins that link
      actin assembly and signaling molecules. The myosin-I acidic domain interacted
      with Arp2/3 complex subunits, Arc40p and Arc19p, and showed both sequence
      similarity and genetic redundancy with the COOH-terminal acidic domain of Bee1p
      (Las17p), which controls Arp2/3-mediated actin nucleation. These findings suggest
      that myosin-I proteins may participate in a diverse set of motility functions
      through a role in actin assembly.

PMID- 10648570
TI  - Caenorhabditis elegans UNC-45 is a component of muscle thick filaments and
      colocalizes with myosin heavy chain B, but not myosin heavy chain A.
AB  - In the nematode Caenorhabditis elegans, animals mutant in the gene encoding the
      protein product of the unc-45 gene (UNC-45) have disorganized muscle thick
      filaments in body wall muscles. Although UNC-45 contains tetratricopeptide
      repeats (TPR) as well as limited similarity to fungal proteins, no biochemical
      role has yet been found. UNC-45 reporters are expressed exclusively in muscle
      cells, and a functional reporter fusion is localized in the body wall muscles in
      a pattern identical to thick filament A-bands. UNC-45 colocalizes with myosin
      heavy chain (MHC) B in wild-type worms as well as in temperature-sensitive (ts)
      unc-45 mutants, but not in a mutant in which MHC B is absent. Surprisingly, UNC
      45 localization is also not seen in MHC B mutants, in which the level of MHC A is
      increased, resulting in near-normal muscle thick filament structure. Thus,
      filament assembly can be independent of UNC-45. UNC-45 shows a localization
      pattern identical to and dependent on MHC B and a function that appears to be MHC
      B-dependent. We propose that UNC-45 is a peripheral component of muscle thick
      filaments due to its localization with MHC B. The role of UNC-45 in thick
      filament assembly seems restricted to a cofactor for assembly or stabilization of
      MHC B.

PMID- 10648569
TI  - Direct involvement of yeast type I myosins in Cdc42-dependent actin
      polymerization.
AB  - The generation of cortical actin filaments is necessary for processes such as
      cell motility and cell polarization. Several recent studies have demonstrated
      that Wiskott-Aldrich syndrome protein (WASP) family proteins and the actin
      related protein (Arp) 2/3 complex are key factors in the nucleation of actin
      filaments in diverse eukaryotic organisms. To identify other factors involved in
      this process, we have isolated proteins that bind to Bee1p/Las17p, the yeast WASP
      like protein, by affinity chromatography and mass spectroscopic analysis. The
      yeast type I myosins, Myo3p and Myo5p, have both been identified as Bee1p
      interacting proteins. Like Bee1p, these myosins are essential for cortical actin
      assembly as assayed by in vitro reconstitution of actin nucleation sites in
      permeabilized yeast cells. Analysis using this assay further demonstrated that
      the motor activity of these myosins is required for the polymerization step, and
      that actin polymerization depends on phosphorylation of myosin motor domain by
      p21-activated kinases (PAKs), downstream effectors of the small guanosine
      triphosphatase, Cdc42p. The type I myosins also interact with the Arp2/3 complex
      through a sequence at the end of the tail domain homologous to the Arp2/3
      activating region of WASP-like proteins. Combined deletions of the Arp2/3
      interacting domains of Bee1p and the type I myosins abolish actin nucleation
      sites at the cortex, suggesting that these proteins function redundantly in the
      activation of the Arp2/3 complex.

PMID- 10648572
TI  - The Changing of the Guard: A New Editorial Team.

PMID- 10648573
TI  - Right lobe living donor liver transplantation: a review.
AB  - The continuing shortage of organs for adult transplant recipients has generated
      enthusiasm for adult-to-adult living donor liver transplantation (LDLT). The
      major concern has been the ability to resect a graft of adequate size without
      subjecting the donor to undue risk. The right hepatic lobe is generally large
      enough for adult recipients, but because of the real and perceived risks of right
      lobe (RL) resection, surgeons have been hesitant to offer this option to their
      patients. The first series of RL resections that included a significant number of
      patients was reported in 1999, and the results were encouraging. Only minor
      complications occurred in donors, and the recipients fared quite well. Enthusiasm
      for these donor resections is growing, and more centers are beginning to perform
      them. There is a good deal of global experience with pediatric LDLT but little
      with adults, and there are unique considerations in this population. This review
      examines donor selection criteria for adult recipients, highlights technical
      points critical for good outcome, and examines the early results and
      complications in both donors and recipients. If the preliminary results continue
      to be reproduced, RL LDLT could have significant impact on the worsening organ
      shortage.

PMID- 10648574
TI  - Animal models of fulminant hepatic failure: a critical evaluation.
AB  - Few conditions in medicine are more dramatic or more devastating than acute liver
      failure. Our understanding and treatment of this condition have been limited by
      the lack of satisfactory animal models. The most widely used models consist of
      surgical anhepatic and devascularization procedures and hepatotoxins, such as
      galactosamine and acetaminophen. Potential disadvantages with surgical models are
      their inability to recreate the inflammatory milieu that exists in acute liver
      failure and their reliance on surgical expertise. Models using hepatotoxins are
      free of such constraints. Galactosamine-induced hepatotoxicity is more
      predictable than acetaminophen, but its cost and lack of a human equivalent
      clinical syndrome has restricted its use. Acetaminophen-based models offer the
      greatest potential but have proven the most difficult to develop because of
      difficulties with reproducibility and refractory anemia. Although progress has
      been made, research must continue in this area to establish an animal model with
      minimal disadvantages that would accurately reflect the clinical syndrome seen in
      humans.

PMID- 10648575
TI  - Hepatocyte transplantation in acute liver failure.
AB  - The majority of patients with acute liver failure (ALF) die waiting for
      orthotopic liver transplantation (OLT). No other treatment modality is shown to
      improve survival. This study was conducted to assess the safety and feasibility
      of hepatocyte transplantation (HT) and subsequent engraftment and function of
      donor cells. Functional and structural integrity of cryopreserved and thawed
      human hepatocytes were assessed by their morphological characteristics, induction
      of P-4501A1 transcription, and survival in vivo by xenotransplantation into rats.
      Five patients with severe ALF underwent intrasplenic (4 patients) and/or
      intrahepatic (2 patients) HT through angiography under cyclosporine
      immunosuppression. All patients had grade III to IV encephalopathy and factor V
      levels less than 0.5 U/mL, were ventilator and dialysis dependent, and were not
      OLT candidates. Three of the 5 patients who survived 48 hours after HT had
      substantial improvement in encephalopathy scores, arterial ammonia levels, and
      prothrombin times. Clinical improvement was paralleled by an increase in
      aminopyrine and caffeine clearances. All 3 patients lived substantially longer
      than expected based on clinical experience after HT (12, 28, and 52 days) but
      eventually died. Postmortem examination showed the presence of transplanted
      hepatocytes in liver and spleen by light microscopy and fluorescent in situ
      hybridization (FISH). Cryopreserved and thawed human hepatocytes can be
      transplanted into recipients with ALF with some acceptable but definite
      complications. Engraftment of donor hepatocytes was proven by histological
      examination and FISH by both transjugular biopsy and at autopsy. Improvement in
      brain edema, encephalopathy grade, and clearance of antipyrine and caffeine
      suggested function, albeit with a 24- to 72-hour delay posttransplantation.

PMID- 10648571
TI  - ErbB2 is necessary for induction of carcinoma cell invasion by ErbB family
      receptor tyrosine kinases.
AB  - The epidermal growth factor (EGF) family of tyrosine kinase receptors (ErbB1, -2,
      -3, and -4) and their ligands are involved in cell differentiation,
      proliferation, migration, and carcinogenesis. However, it has proven difficult to
      link a given ErbB receptor to a specific biological process since most cells
      express multiple ErbB members that heterodimerize, leading to receptor cross
      activation. In this study, we utilize carcinoma cells depleted of ErbB2, but not
      other ErbB receptor members, to specifically examine the role of ErbB2 in
      carcinoma cell migration and invasion. Cells stimulated with EGF-related peptides
      show increased invasion of the extracellular matrix, whereas cells devoid of
      functional ErbB2 receptors do not. ErbB2 facilitates cell invasion through
      extracellular regulated kinase (ERK) activation and coupling of the adaptor
      proteins, p130CAS and c-CrkII, which regulate the actin-myosin cytoskeleton of
      migratory cells. Overexpression of ErbB2 in cells devoid of other ErbB receptor
      members is sufficient to promote ERK activation and CAS/Crk coupling, leading to
      cell migration. Thus, ErbB2 serves as a critical component that couples ErbB
      receptor tyrosine kinases to the migration/invasion machinery of carcinoma cells.

PMID- 10648576
TI  - Hepatocyte transplantation in acute liver failure: a new therapeutic option for
      the next millennium?

PMID- 10648577
TI  - Prediction of liver allograft fibrosis after transplantation for hepatitis C
      virus: persistent elevation of serum transaminase levels versus necroinflammatory
      activity.
AB  - Recurrence of hepatitis C virus (HCV) after orthotopic liver transplantation
      (OLT) remains a significant source of morbidity and mortality. Factors that
      reliably predict allograft injury from HCV have not been identified.
      Demographics, clinical data, and histopathological characteristics of recipients
      with and without persistently elevated serum transaminase levels (PEST) were
      compared. Twenty-four patients with HCV-induced end-stage liver disease who
      underwent OLT between October 1995 and December 1998 were entered into a
      longitudinal, prospective evaluation for identification of parameters associated
      with graft injury. Liver biopsies were performed preoperatively and between
      posttransplantation days 1 to 28, 29 to 60, 61 to 180, 181 to 360, and then every
      6 to 12 months thereafter. Biopsy specimens were reviewed in a blinded fashion
      and scored for rejection, necroinflammatory activity, extent of fibrosis, and
      infiltrating cell type, location, and magnitude. Transplant recipients with PEST
      (alanine transaminase level >1.5 times normal for 3 consecutive months) and
      cholestatic hepatitis showed an increased viral load compared with their own
      preoperative values (16-fold and 256-fold, respectively). Compared with control
      transplant recipients, PEST was associated with macrovesicular steatosis within
      28 days after OLT (P <.05) and showed an increased rate of fibrosis (P <.003)
      despite similar degrees of rejection and necroinflammatory activity. There was no
      difference in demographics or immunosuppression. Macrovesicular steatosis may be
      the earliest predictor of graft fibrosis. Despite similar degrees of
      necroinflammatory activity, transplant recipients with PEST had an increased rate
      of fibrosis that could be predicted on average within 6 months
      posttransplantation.

PMID- 10648578
TI  - Predicting bacteremia and bacteremic mortality in liver transplant recipients.
AB  - Predictors of bacteremia and mortality in bacteremic liver transplant recipients
      were prospectively assessed. One hundred eleven consecutive episodes of fever or
      infections were documented in 59 patients over a 4-year period. Forty-nine
      percent (29 of 59 patients) of the patients had bacteremia, 39% (23 of 59
      patients) had nonbacteremic infections, and 12% (7 of 59 patients) had fever of
      noninfectious cause. Primary (catheter-related) bacteremia (31%; 9 of 29
      patients), pneumonia (24%; 7 of 29 patients), abdominal and/or biliary infections
      (14%; 4 of 29 patients), and wound infections (10%; 3 of 29 patients) were the
      predominant sources of bacteremia. Diabetes mellitus (odds ratio, 6.9; P =.03)
      and serum albumin level less than 3.0 mg/dL (odds ratio, 0.14; P =.02) were
      independently significant predictors of bacteremia compared with nonbacteremic
      infections. Mortality at 14 days was 28% (8 of 29 patients) in those with
      bacteremia compared with 4% (1 of 23 patients) in those with nonbacteremic
      infections and 0% (0 of 7) in patients with fever of noninfectious cause (P
      =.03). Intensive care unit stay at the time of bacteremia (100% v 47%; P =.005),
      absence of chills (0% v 53%; P =.005), lower temperature at the onset of
      bacteremia (99.2 degrees F v 101.5 degrees F; P =.009), lower maximum temperature
      during the course of bacteremia (99.3 degrees F v 102 degrees F, P =.008),
      greater serum bilirubin level (7.6 v 1.5 mg/dL; P =.024), presence of abnormal
      blood pressure (80% v 16%; P =. 0013), and greater prothrombin time (15.6 v 13.3
      seconds; P =.013) were significantly predictive of greater mortality in the
      bacteremic patients. These data have implications for discerning the likelihood
      of bacteremia and initiation of empiric antibiotics pending cultures. Lack of
      febrile response in bacteremic liver transplant recipients portended a poorer
      outcome.

PMID- 10648579
TI  - Significance of detecting Epstein-Barr-specific sequences in the peripheral blood
      of asymptomatic pediatric liver transplant recipients.
AB  - Pediatric allograft recipients are at increased risk for Epstein-Barr virus (EBV)
      associated illnesses. The early identification and diagnosis of EBV-associated
      disorders is critical because disease progression can often be curtailed by
      modification of immunosuppression. We have previously shown that detection of EBV
      specific sequences in the circulation by polymerase chain reaction (PCR)
      correlated well with the clinical symptoms of EBV infection. The purpose of the
      current study is to determine the significance of detecting EBV-specific
      sequences by PCR in asymptomatic pediatric liver transplant recipients.
      Peripheral-blood DNA was analyzed for the EBV genes, coding from the nuclear
      antigen 1 (EBNA-1) and the viral capsid antigen (gp220) by PCR. Samples from
      asymptomatic pediatric liver transplant recipients were analyzed from the
      immediate postoperative period and at 2- to 4-month intervals thereafter. We
      followed up 13 of these asymptomatic recipients who tested positive for EBV
      compared with 7 asymptomatic recipients who tested negative for EBV during the
      early posttransplantation period. Follow-up ranged from 1.5 to 4 years
      posttransplantation. Nine patients (69%) initially positive for EBV and
      asymptomatic ultimately developed symptoms of EBV infection, including fever,
      lymphadenopathy, rash, respiratory and gastrointestinal symptoms, and/or
      hepatitis. Five of these patients (56%) went on to develop posttransplant
      lymphoproliferative disorder based on histological examination of biopsied tissue
      and immunohistochemical identification of the EBV antigen/DNA in tissue. This is
      the first report suggesting that detection of EBV-specific sequences in the
      absence of symptoms may herald impending EBV-associated disorders. Thus, routine
      monitoring for circulating EBV sequences in asymptomatic recipients may be useful
      in the early identification of those at risk for developing EBV-associated
      disease and its ultimate prevention.

PMID- 10648580
TI  - Needle-tract implantation from hepatocellular cancer: is needle biopsy of the
      liver always necessary?
AB  - Percutaneous needle biopsies are frequently used to evaluate focal lesions of the
      liver. Needle-tract implantation of hepatocellular cancer has been described in
      case reports, but the true risk for this problem has not been clearly defined. We
      retrospectively reviewed 91 cases of hepatocellular cancer during a 4-year period
      from 1994 to 1997. Data on diagnostic studies, therapy, and outcome were noted.
      Of 91 patients with hepatocellular cancer, 59 patients underwent percutaneous
      needle biopsy as part of their diagnostic workup for a liver mass. Three patients
      (5.1%) were identified with needle-tract implantation of tumor. Two patients
      required en bloc chest wall resections for implantation of hepatocellular cancer
      in the soft tissues and rib area. The third patient, who also received
      percutaneous ethanol injection of his tumor, required a thoracotomy and lung
      resection for implanted hepatocellular cancer. Percutaneous needle biopsy of
      suspicious hepatic lesions should not be performed indiscriminately because there
      is a significant risk for needle-tract implantation. These biopsies should be
      reserved for those lesions in which no definitive surgical intervention is
      planned and pathological confirmation is necessary for a nonsurgical therapy.

PMID- 10648581
TI  - When should a liver mass suspected of being a hepatocellular carcinoma be
      biopsied?

PMID- 10648582
TI  - Influence of human fulminant hepatic failure sera on endogenous retroviral
      expression in pig hepatocytes.
AB  - A porcine endogenous retrovirus (PERV) has been shown to infect human embryonic
      kidney 293 (HEK293) cells in vitro. The PERV proviral sequence exists in the
      genome of all porcine cells, including hepatocytes used in a bioartificial liver
      (BAL). We examined the possibility of PERV infection in HEK293 cells during
      exposure to supernatant from cultured pig hepatocytes. Pig hepatocytes were
      cultured in media supplemented with serum from patients in fulminant hepatic
      failure (FHF) to simulate conditions of an extracorporeal BAL. Pig hepatocytes
      were cultured in serum-free media for 24 hours and then exposed to fresh medium
      containing serum from a patient with FHF (22 patients tested). Twenty-four hours
      later, supernatant was collected and analyzed by polymerase chain reaction (PCR),
      with and without reverse transcriptase. Primers targeting the pol gene of PERV
      were used for PCR. Products of amplification were detected by an enzyme-linked
      immunosorbent assay-based technique using an internal capture probe also
      targeting the pol gene. Levels of PERV sequences were estimated by serial
      dilution. All positive samples were tested for infectivity in HEK293 cells.
      Porcine kidney 15 cell supernatant and fresh culture media were studied as
      positive and negative controls, respectively. Pig hepatocytes were also studied
      in the absence of FHF sera and in the presence of mitogenic stimulation with
      phytohemagglutinin (PHA) and phorbol 12-myristate-13-acetate (PMA). PERV DNA and
      PERV RNA were detected in all supernatants of cultured pig hepatocytes. The level
      of PERV RNA in the supernatant of pig hepatocytes was not altered by exposure to
      human FHF serum or stimulation with PHA and PMA. In addition, PERV RNA was
      undetectable in the supernatant of HEK293 cells for up to 50 days after exposure
      to pig hepatocyte supernatant (with or without FHF sera). These findings show
      that production of PERV by cultured pig hepatocytes was unaffected by exposure to
      growth factors and cytokines present in human FHF sera.

PMID- 10648583
TI  - Clinical predictors of pulmonary hypertension in patients undergoing liver
      transplant evaluation.
AB  - Clinical prediction of portopulmonary hypertension (PPHTN) is critical in the
      preoperative evaluation of candidates for orthotopic liver transplantation (OLT)
      because of its association with significant morbidity and mortality. To determine
      the clinical, laboratory, and echocardiographic predictors of PPHTN, we
      retrospectively evaluated 55 candidates before OLT. From those, 8 candidates had
      pulmonary hypertension ([HTN] group A) and 47 candidates did not (group B).
      Pulmonary HTN was defined as a mean pulmonary artery pressure (PAP) of 25 mm Hg
      or greater and either elevated pulmonary vascular resistance or normal pulmonary
      artery wedge pressure. The significant predictors of PPHTN were (1) systemic
      arterial HTN (63% in group A v 9% in group B; P <.001), (2) loud pulmonary
      component of the second heart sound (38% v 2%; P =. 001), (3) right ventricular
      (RV) heave (38% v 4%; P =.002), (4) RV dilatation by echocardiogram (63% v 0%; P
      <.001), (5) RV hypertrophy by echocardiogram (38% v 0%; P =.001), and (6)
      echocardiogram-estimated systolic PAP (SPAP) greater than 40 mm Hg (63% v 2%; P
      <.001). The sensitivity of these variables for the detection of pulmonary HTN
      ranges from 37% to 63%, and their specificity from 91% to 100%. We conclude that
      several clinical and echocardiographic features are significantly associated with
      pulmonary HTN in patients with cirrhosis. In particular, echocardiogram-estimated
      SPAP greater than 40 mm Hg is strongly associated with pulmonary HTN and is
      specific. These predictors, however, are not sensitive enough to identify all the
      patients with PPHTN. Therefore, the evaluation of a combination of these
      variables may be useful for the preoperative identification of pulmonary HTN in
      liver transplant candidates.

PMID- 10648584
TI  - Clinical and virologic outcomes of hepatitis B and C viral coinfection after
      liver transplantation: effect of viral hepatitis D.
AB  - Hepatitis B (HBV) and C viral (HCV) dual-infection-associated liver disease is an
      uncommon indication for liver transplantation. The clinical and virologic
      outcomes in such patients have not been well studied. We retrospectively studied
      13 patients with hepatitis B surface antigen (HBsAg) and antibody to HCV
      positivity who underwent orthotopic liver transplantation (OLT) and survived at
      least 30 days post-OLT. Antibody to hepatitis delta virus (HDV) was negative in 8
      patients (group I) and positive in 5 patients (group II). Eleven of the 13
      patients received standard hepatitis B immune prophylaxis, and they all remained
      HBsAg negative. All group I patients were HCV RNA positive after transplantation;
      in contrast, all group II patients were HCV RNA negative. Serum alanine
      aminotransferase levels were elevated in 88% (7 of 8) of the patients in group I
      compared with 20% (1 of 5 patients) in group II. None of the patients had graft
      loss from chronic rejection or recurrent hepatitis. Three patients had
      unsuspected hepatocellular carcinoma in the explant. We conclude that among liver
      transplant recipients with HBV and HCV coinfection, HDV infection is associated
      with the suppression of HCV replication and mild inflammatory activity after OLT.

PMID- 10648585
TI  - Hepatic resection of noncolorectal nonneuroendocrine metastases.
AB  - Because hepatic resection is generally a safe procedure, the indications for
      resection of noncolorectal nonneuroendocrine (NCNNE) hepatic metastases have
      broadened. The prognostic features of NCNNE metastases treated surgically were
      reviewed to define better the value of resection. A retrospective review of
      patients undergoing liver resection for NCNNE metastases between 1978 and 1998
      was undertaken. Thirty-seven patients were identified. Mean age was 56 years,
      with a median follow-up of 22 months. Primary tumor sites were grouped into
      gastrointestinal (GI) adenocarcinoma (small bowel, n = 4; pancreas, n = 2;
      esophagus, n = 1) and other (renal cell, n = 7; sarcoma, n = 7; melanoma, n = 5;
      adrenal, n = 3; unknown adenocarcinoma, n = 3; thyroid, n = 2; testicular, n = 1;
      ovarian, n = 1; breast, n = 1). All patients underwent surgery for cure.
      Metastases were synchronous in 14 patients. There was no surgical mortality.
      Overall 5-year survival rate was 45%. Five-year survival rates were better for
      patients with non-GI-origin metastases (60% v 0%; P =.01). Long-term survival was
      seen only in patients with non-GI-origin metastases. The extent of resection,
      presence of synchronous metastases, or disease-free interval from time of
      original disease to presentation with liver metastases were not predictive of
      outcome. We conclude that patients with NCNNE hepatic metastases can undergo
      liver resection with an expectation of prolonged survival. However, patients with
      liver metastases from GI primary tumors other than the colorectum are unlikely to
      show extended survival.

PMID- 10648586
TI  - Spectrum of chronic hepatic allograft rejection and arteriopathy and the
      controversy of centrilobular necrosis.

PMID- 10648587
TI  - Laparoscopic surgery after orthotopic liver transplantation.
AB  - Laparoscopic surgery is currently a widely accepted approach to several surgical
      fields because of its advantages in terms of postoperative pain reduction and
      easy patient recovery. This approach may be useful even in solid-organ
      transplantation surgery as a diagnostic or treatment procedure in some surgical
      complications. From July 1991 to December 1998, we performed 142 liver
      transplantations on 129 patients. During the postoperative period, many
      complications occurred. Here we report two cases of intestinal occlusion caused
      by adhesions and three cases of lymphocele, all approached with laparoscopic
      surgery. In all cases but one, we were able to complete the surgery by
      laparoscopic means; in one of the two occlusions, the procedure was switched to
      laparotomy because of a choledochojejunal anastomosis lesion. The three cases of
      lymphocele must be considered in a particular manner because such cases, to our
      knowledge, have never been described in the literature. They always presented
      with a late-onset right pleural effusion and were located in the retrohepatic,
      retrogastric, and left paracaval areas, close to the esophageal hiatus. In
      conclusion, we believe a laparoscopic approach is a useful strategy to solve some
      surgical complications in patients who underwent orthotopic liver
      transplantation; however, the use of laparoscopic surgery in this field is
      strictly connected to the surgeon's experience and versatility.

PMID- 10648588
TI  - Partial left lateral segment transplant from a living donor.
AB  - A shortage of liver donors for low-weight transplant recipients has prompted the
      development of procedures for liver-reduction, split-liver, and living related
      donor transplantations. For pediatric recipients weighing less than 10 kg, the
      left lateral segment is often still too large. We describe the procedure of
      monosegmental transplantation using segment II after segment III was resected in
      situ from a living related donor. Successful monosegmental transplantation is
      technically feasible and is a valid alternative to be considered for cases of
      size discrepancy between the recipient's volume and the donor's left lateral
      segment.

PMID- 10648589
TI  - Hepatopulmonary Syndrome and Liver Transplantation.

PMID- 10648590
TI  - Cross-Species Transmission of PERV Appears Unlikely.

PMID- 10648591
TI  - Transforming Power of Immunosuppression: Experimental Mirage or Clinical Mirror
      to the Future.

PMID- 10648592
TI  - Discount Pricing and the "Cost" of Liver Transplantation.

PMID- 10648593
TI  - Liver transplantation. American Association for the Study of Liver Diseases.
AB  - Liver transplantation has revolutionized the care of patients with end-stage
      liver disease. Liver transplantation is indicated for acute or chronic liver
      failure from any cause. Because there are no randomized controlled trials of
      liver transplantation versus no therapy, the efficacy of this surgery is best
      assessed by carefully comparing postoperative survival with the known natural
      history of the disease in question. The best examples of this are in primary
      biliary cirrhosis and primary sclerosing cholangitis, for which well-validated
      disease-specific models of natural history are available. There are currently
      relatively few absolute contraindications to liver transplantation. These include
      severe cardiopulmonary disease, uncontrolled systemic infection, extrahepatic
      malignancy, severe psychiatric or neurological disorders, and absence of a viable
      splanchnic venous inflow system. One of the most frequently encountered
      contraindications to transplantation is ongoing destructive behavior caused by
      drug and alcohol addiction. The timing of the surgery can have a profound impact
      on the mortality and morbidity of patients undergoing liver transplantation.
      Because of the long waiting lists for donor organs, the need to project far in
      advance when transplantation might be required has proven to be one of the
      greatest challenges to those treating patients with end-stage liver disease.
      Three important questions must be addressed in a patient being considered for
      liver transplantation: (1) when should the patient be referred for possible
      transplantation? (2) when should the patient be listed for transplantation? and
      (3) when is the patient too sick to have a reasonable chance of surviving the
      perioperative period?

PMID- 10648594
TI  - Kinetics of ribosomal pausing during programmed -1 translational frameshifting.
AB  - In the Saccharomyces cerevisiae double-stranded RNA virus, programmed -1
      ribosomal frameshifting is responsible for translation of the second open reading
      frame of the essential viral RNA. A typical slippery site and downstream
      pseudoknot are necessary for this frameshifting event, and previous work has
      demonstrated that ribosomes pause over the slippery site. The translational
      intermediate associated with a ribosome paused at this position is detected, and,
      using in vitro translation and quantitative heelprinting, the rates of synthesis,
      the ribosomal pause time, the proportion of ribosomes paused at the slippery
      site, and the fraction of paused ribosomes that frameshift are estimated. About
      10% of ribosomes pause at the slippery site in vitro, and some 60% of these
      continue in the -1 frame. Ribosomes that continue in the -1 frame pause about 10
      times longer than it takes to complete a peptide bond in vitro. Altering the rate
      of translational initiation alters the rate of frameshifting in vivo. Our in
      vitro and in vivo experiments can best be interpreted to mean that there are
      three methods by which ribosomes pass the frameshift site, only one of which
      results in frameshifting.

PMID- 10648595
TI  - The N-terminal domain that distinguishes yeast from bacterial RNase III contains
      a dimerization signal required for efficient double-stranded RNA cleavage.
AB  - Yeast Rnt1 is a member of the double-stranded RNA (dsRNA)-specific RNase III
      family identified by conserved dsRNA binding (dsRBD) and nuclease domains.
      Comparative sequence analyses have revealed an additional N-terminal domain
      unique to the eukaryotic homologues of RNase III. The deletion of this domain
      from Rnt1 slowed growth and led to mild accumulation of unprocessed 25S pre-rRNA.
      In vitro, deletion of the N-terminal domain reduced the rate of RNA cleavage
      under physiological salt concentration. Size exclusion chromatography and cross
      linking assays indicated that the N-terminal domain and the dsRBD self-interact
      to stabilize the Rnt1 homodimer. In addition, an interaction between the N
      terminal domain and the dsRBD was identified by a two-hybrid assay. The results
      suggest that the eukaryotic N-terminal domain of Rnt1 ensures efficient dsRNA
      cleavage by mediating the assembly of optimum Rnt1-RNA ribonucleoprotein complex.

PMID- 10648596
TI  - Translation of chloroplast psbA mRNA is modulated in the light by counteracting
      oxidizing and reducing activities.
AB  - Light has been proposed to stimulate the translation of Chlamydomonas reinhardtii
      chloroplast psbA mRNA by activating a protein complex associated with the 5'
      untranslated region of this mRNA. The protein complex contains a redox-active
      regulatory site responsive to thioredoxin. We identified RB60, a protein
      disulfide isomerase-like member of the protein complex, as carrying the redox
      active regulatory site composed of vicinal dithiol. We assayed in parallel the
      redox state of RB60 and translation of psbA mRNA in intact chloroplasts. Light
      activated the specific oxidation of RB60, on the one hand, and reduced RB60,
      probably via the ferredoxin-thioredoxin system, on the other. Higher light
      intensities increased the pool of reduced RB60 and the rate of psbA mRNA
      translation, suggesting that a counterbalanced action of reducing and oxidizing
      activities modulates the translation of psbA mRNA in parallel with fluctuating
      light intensities. In the dark, chemical reduction of the vicinal dithiol site
      did not activate translation. These results suggest a mechanism by which light
      primes redox-regulated translation by an unknown mechanism and then the rate of
      translation is determined by the reduction-oxidation of a sensor protein located
      in a complex bound to the 5' untranslated region of the chloroplast mRNA.

PMID- 10648597
TI  - The orphan nuclear receptor SHP utilizes conserved LXXLL-related motifs for
      interactions with ligand-activated estrogen receptors.
AB  - SHP (short heterodimer partner) is an unusual orphan nuclear receptor consisting
      only of a ligand-binding domain, and it exhibits unique features of interaction
      with conventional nuclear receptors. While the mechanistic basis of these
      interactions has remained enigmatic, SHP has been suggested to inhibit nuclear
      receptor activation by at least three alternatives; inhibition of DNA binding via
      dimerization, direct antagonism of coactivator function via competition, and
      possibly transrepression via recruitment of putative corepressors. We now show
      that SHP binds directly to estrogen receptors via LXXLL-related motifs. Similar
      motifs, referred to as NR (nuclear receptor) boxes, are usually critical for the
      binding of coactivators to the ligand-regulated activation domain AF-2 within
      nuclear receptors. In concordance with the NR box dependency, SHP requires the
      intact AF-2 domain of agonist-bound estrogen receptors for interaction. Mutations
      within the ligand-binding domain helix 12, or binding of antagonistic ligands,
      which are known to result in an incomplete AF-2 surface, abolish interactions
      with SHP. Supporting the idea that SHP directly antagonizes receptor activation
      via AF-2 binding, we demonstrate that SHP variants, carrying either interaction
      defective NR box mutations or a deletion of the repressor domain, have lost the
      capacity to inhibit agonist-dependent transcriptional estrogen receptor
      activation. Furthermore, our studies indicate that SHP may function as a cofactor
      via the formation of ternary complexes with dimeric receptors on DNA. These novel
      insights provide a mechanistic explanation for the inhibitory role of SHP in
      nuclear receptor signaling, and they may explain how SHP functions as a negative
      coregulator or corepressor for ligand-activated receptors, a novel and unique
      function for an orphan nuclear receptor.

PMID- 10648598
TI  - Requirement for TAF(II)250 acetyltransferase activity in cell cycle progression.
AB  - The TATA-binding protein (TBP)-associated factor TAF(II)250 is the largest
      component of the basal transcription factor IID (TFIID). A missense mutation that
      maps to the acetyltransferase domain of TAF(II)250 induces the temperature
      sensitive (ts) mutant hamster cell lines ts13 and tsBN462 to arrest in late G(1).
      At the nonpermissive temperature (39.5 degrees C), transcription from only a
      subset of protein encoding genes, including the G(1) cyclins, is dramatically
      reduced in the mutant cells. Here we demonstrate that the ability of the ts13
      allele of TAF(II)250 to acetylate histones in vitro is temperature sensitive
      suggesting that this enzymatic activity is compromised at 39.5 degrees C in the
      mutant cells. Mutagenesis of a putative acetyl coenzyme A binding site produced a
      TAF(II)250 protein that displayed significantly reduced histone acetyltransferase
      activity but retained TBP and TAF(II)150 binding. Expression of this mutant in
      ts13 cells was unable to complement the cell cycle arrest or transcriptional
      defect observed at 39.5 degrees C. These data suggest that TAF(II)250
      acetyltransferase activity is required for cell cycle progression and regulates
      the expression of essential proliferative control genes.

PMID- 10648599
TI  - Extracellular signal-regulated kinase binds to TFII-I and regulates its
      activation of the c-fos promoter.
AB  - We have previously shown that TFII-I enhances transcriptional activation of the c
      fos promoter through interactions with upstream elements in a signal-dependent
      manner. Here we demonstrate that activated Ras and RhoA synergize with TFII-I for
      c-fos promoter activation, whereas dominant-negative Ras and RhoA inhibit these
      effects of TFII-I. The Mek1 inhibitor, PD98059 abrogates the enhancement of the c
      fos promoter by TFII-I, indicating that TFII-I function is dependent on an active
      mitogen-activated protein (MAP) kinase pathway. Analysis of the TFII-I protein
      sequence revealed that TFII-I contains a consensus MAP kinase interaction domain
      (D box). Consistent with this, we have found that TFII-I forms an in vivo complex
      with extracellular signal-related kinase (ERK). Point mutations within the
      consensus MAP kinase binding motif of TFII-I inhibit its ability to bind ERK and
      its ability to enhance the c-fos promoter. Therefore, the D box of TFII-I is
      required for its activity on the c-fos promoter. Moreover, the interaction
      between TFII-I and ERK can be regulated. Serum stimulation enhances complex
      formation between TFII-I and ERK, and dominant-negative Ras abrogates this
      interaction. In addition, TFII-I can be phosphorylated in vitro by ERK and
      mutation of consensus MAP kinase substrate sites at serines 627 and 633 impairs
      the phosphorylation of TFII-I by ERK and its activity on the c-fos promoter.
      These results suggest that ERK regulates the activity of TFII-I by direct
      phosphorylation.

PMID- 10648600
TI  - Expression of interferon consensus sequence binding protein (ICSBP) is
      downregulated in Bcr-Abl-induced murine chronic myelogenous leukemia-like
      disease, and forced coexpression of ICSBP inhibits Bcr-Abl-induced
      myeloproliferative disorder.
AB  - Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disorder
      resulting from the neoplastic transformation of a hematopoietic stem cell. The
      majority of cases of CML are associated with the (9;22) chromosome translocation
      that generates the bcr-abl chimeric gene. Alpha interferon (IFN-alpha) treatment
      induces hematological remission and prolongs life in 75% of CML patients in the
      chronic phase. It has been shown that mice deficient in interferon consensus
      sequence binding protein (ICSBP), a member of the interferon regulatory factor
      family, manifest a CML-like syndrome. We have shown that expression of Bcr-Abl in
      bone marrow (BM) cells from 5-fluorouracil (5-FU)-treated mice by retroviral
      transduction efficiently induces a myeloproliferative disease in mice resembling
      human CML. To directly test whether icsbp can function as a tumor suppressor
      gene, we examined the effect of ICSBP on Bcr-Abl-induced CML-like disease using
      this murine model for CML. We found that expression of the ICSBP protein was
      significantly decreased in Bcr-Abl-induced CML-like disease. Forced coexpression
      of ICSBP inhibited the Bcr-Abl-induced colony formation of BM cells from 5-FU
      treated mice in vitro and Bcr-Abl-induced CML-like disease in vivo.
      Interestingly, coexpression of ICSBP and Bcr-Abl induced a transient B
      lymphoproliferative disorder in the murine model of Bcr-Abl-induced CML-like
      disease. Overexpression of ICSBP consistently promotes rather than inhibits Bcr
      Abl-induced B lymphoproliferation in a murine model where BM cells from non-5-FU
      treated donors were used, indicating that ICSBP has a specific antitumor activity
      toward myeloid neoplasms. We also found that overexpression of ICSBP negatively
      regulated normal hematopoiesis. These data provide direct evidence that ICSBP can
      act as a tumor suppressor that regulates normal and neoplastic proliferation of
      hematopoietic cells.

PMID- 10648601
TI  - c-Myc protein synthesis is initiated from the internal ribosome entry segment
      during apoptosis.
AB  - Recent studies have shown that during apoptosis protein synthesis is inhibited
      and that this is in part due to the proteolytic cleavage of eukaryotic initiation
      factor 4G (eIF4G). Initiation of translation can occur either by a cap-dependent
      mechanism or by internal ribosome entry. The latter mechanism is dependent on a
      complex structural element located in the 5' untranslated region of the mRNA
      which is termed an internal ribosome entry segment (IRES). In general, IRES
      mediated translation does not require eIF4E or full-length eIF4G. In order to
      investigate whether cap-dependent and cap-independent translation are reduced
      during apoptosis, we examined the expression of c-Myc during this process, since
      we have shown previously that the 5' untranslated region of the c-myc proto
      oncogene contains an IRES. c-Myc expression was determined in HeLa cells during
      apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand. We
      have demonstrated that the c-Myc protein is still expressed when more than 90% of
      the cells are apoptotic. The presence of the protein in apoptotic cells does not
      result from either an increase in protein stability or an increase in expression
      of c-myc mRNA. Furthermore, we show that during apoptosis initiation of c-myc
      translation occurs by internal ribosome entry. We have investigated the signaling
      pathways that are involved in this response, and cotransfection with plasmids
      which harbor either wild-type or constitutively active MKK6, a specific immediate
      upstream activator of p38 mitogen-activated protein kinase (MAPK), increases IRES
      mediated translation. In addition, the c-myc IRES is inhibited by SB203580, a
      specific inhibitor of p38 MAPK. Our data, therefore, strongly suggest that the
      initiation of translation via the c-myc IRES during apoptosis is mediated by the
      p38 MAPK pathway.

PMID- 10648602
TI  - Activation of the heterodimeric IkappaB kinase alpha (IKKalpha)-IKKbeta complex
      is directional: IKKalpha regulates IKKbeta under both basal and stimulated
      conditions.
AB  - Signal-induced nuclear expression of the eukaryotic NF-kappaB transcription
      factor involves the stimulatory action of select mitogen-activated protein kinase
      kinase kinases on the IkappaB kinases (IKKalpha and IKKbeta) which reside in a
      macromolecular signaling complex termed the signalsome. While genetic studies
      indicate that IKKbeta is the principal kinase involved in proinflammatory
      cytokine-induced IkappaB phosphorylation, the function of the equivalently
      expressed IKKalpha is less clear. Here we demonstrate that assembly of IKKalpha
      with IKKbeta in the heterodimeric signalsome serves two important functions: (i)
      in unstimulated cells, IKKalpha inhibits the constitutive IkappaB kinase activity
      of IKKbeta; (ii) in activated cells, IKKalpha kinase activity is required for the
      induction of IKKbeta. The introduction of kinase-inactive IKKalpha, activation
      loop mutants of IKKalpha, or IKKalpha antisense RNA into 293 or HeLa cells blocks
      NIK (NF-kappaB-inducing kinase)-induced phosphorylation of the IKKbeta activation
      loop occurring in functional signalsomes. In contrast, catalytically inactive
      mutants of IKKbeta do not block NIK-mediated phosphorylation of IKKalpha in these
      macromolecular signaling complexes. This requirement for kinase-proficient
      IKKalpha to activate IKKbeta in heterodimeric IKK signalsomes is also observed
      with other NF-kappaB inducers, including tumor necrosis factor alpha, human T
      cell leukemia virus type 1 Tax, Cot, and MEKK1. Conversely, the theta isoform of
      protein kinase C, which also induces NF-kappaB/Rel, directly targets IKKbeta for
      phosphorylation and activation, possibly acting through homodimeric IKKbeta
      complexes. Together, our findings indicate that activation of the heterodimeric
      IKK complex by a variety of different inducers proceeds in a directional manner
      and is dependent on the kinase activity of IKKalpha to activate IKKbeta.

PMID- 10648603
TI  - The survival function of the Bcr-Abl oncogene is mediated by Bad-dependent and 
      independent pathways: roles for phosphatidylinositol 3-kinase and Raf.
AB  - The Bcr-Abl tyrosine kinase constitutively activates cytokine signal transduction
      pathways that stimulate growth and prevent apoptosis in hematopoietic cells. The
      antiapoptotic action of interleukin-3 (IL-3) has been linked to a signaling
      pathway which inactivates the proapoptotic protein Bad by phosphorylation through
      kinases such as Akt and Raf. Here we report also that expression of Bcr-Abl leads
      to phosphorylation of Bad in hematopoietic cells. Bad phosphorylation induced by
      Bcr-Abl is kinase dependent, requires phosphatidylinositol 3-kinase (PI3-kinase),
      and mitochondrial targeting of Raf, and occurs independently of Erk. The ability
      of Bcr-Abl to confer cytokine-independent survival to hematopoietic cells was
      compromised by inhibitors of PI3-kinase, as well as by a dominant negative form
      of Raf targeted to the mitochondria. Furthermore, when the capacity of Bcr-Abl to
      phosphorylate Bad was completely blocked by dominant negative Raf, a
      subpopulation of cells remained viable, providing evidence for Bad-independent
      survival pathways. This alternative survival pathway remained PI3-kinase
      dependent. Finally, Bcr-Abl, but not IL-3, inhibited the proapoptotic activity of
      overexpressed Bad. We conclude that the antiapoptotic function of Bcr-Abl is
      mediated through pathways involving PI3-kinase and Raf and that survival can
      occur in the absence of Bad phosphorylation.

PMID- 10648604
TI  - Tim18p, a new subunit of the TIM22 complex that mediates insertion of imported
      proteins into the yeast mitochondrial inner membrane.
AB  - Import of carrier proteins from the cytoplasm into the mitochondrial inner
      membrane of yeast is mediated by a distinct system consisting of two soluble 70
      kDa protein complexes in the intermembrane space and a 300-kDa complex in the
      inner membrane, the TIM22 complex. The TIM22 complex contains the peripheral
      subunits Tim9p, Tim10p, and Tim12p and the integral membrane subunits Tim22p and
      Tim54p. We identify here an additional subunit, an 18-kDa integral membrane
      protein termed Tim18p. This protein is made as a 21.9-kDa precursor which is
      imported into mitochondria and processed to its mature form. When mitochondria
      are gently solubilized, Tim18p comigrates with the other subunits of the TIM22
      complex on nondenaturing gels and is coimmunoprecipitated with Tim54p and Tim12p.
      Tim18p does not cofractionate with the TIM23 complex upon immunoprecipitation or
      nondenaturing gel electrophoresis. Deletion of Tim18p decreases the growth rate
      of yeast cells by a factor of two and is synthetically lethal with temperature
      sensitive mutations in Tim9p or Tim10p. It also impairs the import of several
      precursor proteins into isolated mitochondria, and lowers the apparent mass of
      the TIM22 complex. We suggest that Tim18p functions in the assembly and
      stabilization of the TIM22 complex but does not directly participate in protein
      insertion into the inner membrane.

PMID- 10648605
TI  - RAD51 is required for the repair of plasmid double-stranded DNA gaps from either
      plasmid or chromosomal templates.
AB  - DNA double-strand breaks may be induced by endonucleases, ionizing radiation,
      chemical agents, and mechanical forces or by replication of single-stranded
      nicked chromosomes. Repair of double-strand breaks can occur by homologous
      recombination or by nonhomologous end joining. A system was developed to measure
      the efficiency of plasmid gap repair by homologous recombination using either
      chromosomal or plasmid templates. Gap repair was biased toward gene conversion
      events unassociated with crossing over using either donor sequence. The
      dependence of recombinational gap repair on genes belonging to the RAD52
      epistasis group was tested in this system. RAD51, RAD52, RAD57, and RAD59 were
      required for efficient gap repair using either chromosomal or plasmid donors. No
      homologous recombination products were recovered from rad52 mutants, whereas a
      low level of repair occurred in the absence of RAD51, RAD57, or RAD59. These
      results suggest a minor pathway of strand invasion that is dependent on RAD52 but
      not on RAD51. The residual repair events in rad51 mutants were more frequently
      associated with crossing over than was observed in the wild-type strain,
      suggesting that the mechanisms for RAD51-dependent and RAD51-independent events
      are different. Plasmid gap repair was reduced synergistically in rad51 rad59
      double mutants, indicating an important role for RAD59 in RAD51-independent
      repair.

PMID- 10648607
TI  - Target specificity of the endonuclease from the Xenopus laevis non-long terminal
      repeat retrotransposon, Tx1L.
AB  - Elements of the Tx1L family are non-long terminal repeat retrotransposons (NLRs)
      that are dispersed in the genome of Xenopus laevis. Essentially all genomic
      copies of Tx1L are found inserted at a specific site within another family of
      transposable elements (Tx1D). This suggests that Tx1L is a site-specific
      retrotransposon. Like many (but not all) other NLRs, the Xenopus element encodes
      an apparent endonuclease that is related in sequence to the apurinic-apyrimidinic
      endonucleases that participate in DNA repair. This enzyme is thought to introduce
      the single-strand break in target DNA that initiates transposition by the target
      primed reverse transcription (TPRT) mechanism. To explore the issue of target
      specificity more fully, we expressed the polypeptide encoded by the endonuclease
      domain of open reading frame 2 from Tx1L (Tx1L EN) and characterized its cleavage
      capabilities. This endonuclease makes a specific nick in the bottom strand
      precisely at one end of the presumed Tx1L target duplication. Because this
      activity leaves a 5'-phosphate and 3'-hydroxyl at the nick, it has the location
      and chemistry required to initiate new insertion events by TPRT. Tx1L EN does not
      make a specific cut at a preferred target site for Tx1D elements, ruling out the
      alternative possibility that the composite Tx1L-Tx1D element moves as a unit
      under the control of functions encoded by Tx1L. Further characterization revealed
      that the endonuclease remains active for many hours at room temperature and that
      it is capable of enzymatic turnover. Scanning substitution mutagenesis located
      the recognition site for Tx1L EN within 10 bp surrounding the primary nick site.
      Implications of these features for natural transposition events are discussed.

PMID- 10648606
TI  - A CAF-1-PCNA-mediated chromatin assembly pathway triggered by sensing DNA damage.
AB  - Sensing DNA damage is crucial for the maintenance of genomic integrity and cell
      cycle progression. The participation of chromatin in these events is becoming of
      increasing interest. We show that the presence of single-strand breaks and gaps,
      formed either directly or during DNA damage processing, can trigger the
      propagation of nucleosomal arrays. This nucleosome assembly pathway involves the
      histone chaperone chromatin assembly factor 1 (CAF-1). The largest subunit (p150)
      of this factor interacts directly with proliferating cell nuclear antigen (PCNA),
      and critical regions for this interaction on both proteins have been mapped. To
      isolate proteins specifically recruited during DNA repair, damaged DNA linked to
      magnetic beads was used. The binding of both PCNA and CAF-1 to this damaged DNA
      was dependent on the number of DNA lesions and required ATP. Chromatin assembly
      linked to the repair of single-strand breaks was disrupted by depletion of PCNA
      from a cell-free system. This defect was rescued by complementation with
      recombinant PCNA, arguing for role of PCNA in mediating chromatin assembly linked
      to DNA repair. We discuss the importance of the PCNA-CAF-1 interaction in the
      context of DNA damage processing and checkpoint control.

PMID- 10648608
TI  - The B-cell-specific Src-family kinase Blk is dispensable for B-cell development
      and activation.
AB  - The B-cell lymphocyte kinase (Blk) is a src-family protein tyrosine kinase
      specifically expressed in B-lineage cells of mice. The early onset of Blk
      expression during B-cell development in the bone marrow and the high expression
      levels of Blk in mature B cells suggest a possible important role of Blk in B
      cell physiology. To study the in vivo function of Blk, mice homozygous for the
      targeted disruption of the blk gene were generated. In homozygous mutant mice,
      neither blk mRNA nor Blk protein is expressed. Despite the absence of Blk, the
      development, in vitro activation, and humoral immune responses of B cells to T
      cell-dependent and -independent antigens are unaltered. These data are consistent
      with functional redundancy of Blk in B-cell development and immune responses.

PMID- 10648609
TI  - Novel WD-repeat protein Mip1p facilitates function of the meiotic regulator Mei2p
      in fission yeast.
AB  - In fission yeast, the onset of meiosis is triggered by activation of the RNA
      binding protein Mei2p. We screened for a high-copy-number suppressor of the
      ectopic meiosis induced by expression of an active form of Mei2p. Consequently we
      isolated a truncated form of a novel gene, named mip1, from a fission yeast
      genomic library. The mip1 gene encoded a protein of 1,313 amino acids which
      carried a WD-repeat motif in the C-terminal region and was apparently conserved
      among eukaryotes. Mip1p was cytoplasmic, and two-hybrid and immunoprecipitation
      analyses demonstrated that Mip1p was bound to Mei2p in vivo. Genetic evidence
      indicated that wild-type Mip1p was required for the function of Mei2p to induce
      meiosis and that the truncated form of it (Mip1-15p) dominantly interfered with
      Mei2p. Mip1p appeared to be involved also in conjugation, associating with
      Ste11p, which is a key transcription factor for sexual development. Furthermore,
      Mip1p was essential for cell growth, to which neither Mei2p nor Ste11p is
      relevant. These results suggest that Mip1p assists functional expression of a
      number of proteins required for proliferation and sexual development in fission
      yeast.

PMID- 10648610
TI  - Identification of a sequence element from p53 that signals for Mdm2-targeted
      degradation.
AB  - The binding of Mdm2 to p53 is required for targeting p53 for degradation. p73,
      however, binds to Mdm2 but is refractory to Mdm2-mediated degradation, indicating
      that binding to Mdm2 is not sufficient for degradation. By utilizing the
      structural homology between p53 and p73, we generated p53-p73 chimeras to
      determine the sequence element unique to p53 essential for regulation of its
      stability. We found that replacing an element consisting of amino acids 92 to 112
      of p53 with the corresponding region of p73 results in a protein that is not
      degradable by Mdm2. Removal of amino acids 92 to 112 of p53 by deletion also
      results in a non-Mdm2-degradable protein. Significantly, the finding that
      swapping this fragment converts p73 from refractory to sensitive to Mdm2-mediated
      degradation supports the conclusion that the amino acids 92 to 112 of p53
      function as a degradation signal. We propose that the presence of an additional
      protein recognizes the degradation signal and coordinates with Mdm2 to target p53
      for degradation. Our finding opens the possibility of searching for the
      additional protein, which most likely plays a critical role in the regulation of
      p53 stability and therefore function.

PMID- 10648611
TI  - Characterization of Schizosaccharomyces pombe Hus1: a PCNA-related protein that
      associates with Rad1 and Rad9.
AB  - Hus1 is one of six checkpoint Rad proteins required for all Schizosaccharomyces
      pombe DNA integrity checkpoints. MYC-tagged Hus1 reveals four discrete forms. The
      main form, Hus1-B, participates in a protein complex with Rad9 and Rad1,
      consistent with reports that Rad1-Hus1 immunoprecipitation is dependent on the
      rad9(+) locus. A small proportion of Hus1-B is intrinsically phosphorylated in
      undamaged cells and more becomes phosphorylated after irradiation. Hus1-B
      phosphorylation is not increased in cells blocked in early S phase with
      hydroxyurea unless exposure is prolonged. The Rad1-Rad9-Hus1-B complex is readily
      detectable, but upon cofractionation of soluble extracts, the majority of each
      protein is not present in this complex. Indirect immunofluorescence demonstrates
      that Hus1 is nuclear and that this localization depends on Rad17. We show that
      Rad17 defines a distinct protein complex in soluble extracts that is separate
      from Rad1, Rad9, and Hus1. However, two-hybrid interaction, in vitro association
      and in vivo overexpression experiments suggest a transient interaction between
      Rad1 and Rad17.

PMID- 10648612
TI  - The Rpb6 subunit of fission yeast RNA polymerase II is a contact target of the
      transcription elongation factor TFIIS.
AB  - The Rpb6 subunit of RNA polymerase II is one of the five subunits common to three
      forms of eukaryotic RNA polymerase. Deletion and truncation analyses of the rpb6
      gene in the fission yeast Schizosaccharomyces pombe indicated that Rpb6,
      consisting of 142 amino acid residues, is an essential protein for cell
      viability, and the essential region is located in the C-terminal half between
      residues 61 and 139. After random mutagenesis, a total of 14 temperature
      sensitive mutants were isolated, each carrying a single (or double in three cases
      and triple in one) mutation. Four mutants each carrying a single mutation in the
      essential region were sensitive to 6-azauracil (6AU), which inhibits
      transcription elongation by depleting the intracellular pool of GTP and UTP. Both
      6AU sensitivity and temperature-sensitive phenotypes of these rpb6 mutants were
      suppressed by overexpression of TFIIS, a transcription elongation factor. In
      agreement with the genetic studies, the mutant RNA polymerases containing the
      mutant Rpb6 subunits showed reduced affinity for TFIIS, as measured by a pull
      down assay of TFIIS-RNA polymerase II complexes using a fusion form of TFIIS with
      glutathione S-transferase. Moreover, the direct interaction between TFIIS and RNA
      polymerase II was competed by the addition of Rpb6. Taken together, the results
      lead us to propose that Rpb6 plays a role in the interaction between RNA
      polymerase II and the transcription elongation factor TFIIS.

PMID- 10648613
TI  - Poliovirus 2A protease induces apoptotic cell death.
AB  - A cell line was generated that expresses the poliovirus 2A protease in an
      inducible manner. Tightly controlled expression was achieved by utilizing the
      muristerone A-regulated expression system. Upon induction, cleavage of the
      eukaryotic translation initiation factor 4GI (eIF4GI) and eIF4GII is observed,
      with the latter being cleaved in a somewhat slower kinetics. eIF4G cleavage was
      accompanied by a severe inhibition of protein synthesis activity. Upon induction
      of the poliovirus 2A protease, the cells displayed fragmented nuclei, chromatin
      condensation, oligonucleosome-size DNA ladder, and positive TUNEL (terminal
      deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling) staining;
      hence, their death can be characterized as apoptosis. These results indicate that
      the expression of the 2A protease in mammalian cells is sufficient to induce
      apoptosis. We suggest that the poliovirus 2A protease induces apoptosis either by
      arresting cap-dependent translation of some cellular mRNAs that encode proteins
      required for cell viability, by preferential cap-independent translation of
      cellular mRNAs encoding apoptosis inducing proteins, or by cleaving other, yet
      unidentified cellular target proteins.

PMID- 10648615
TI  - The p21(WAF1/CIP1) promoter is methylated in Rat-1 cells: stable restoration of
      p53-dependent p21(WAF1/CIP1) expression after transfection of a genomic clone
      containing the p21(WAF1/CIP1) gene.
AB  - Rat-1 cells are used in many studies on transformation, cell cycle, and
      apoptosis. Whereas UV treatment of Rat-1 cells results in apoptosis, X-ray
      treatment does not induce either apoptosis or a cell cycle block. X-ray treatment
      of Rat-1 cells results in both an increase of p53 protein and expression of the
      p53-inducible gene MDM2 but not the protein or mRNA of the p53-inducible
      p21(WAF1/CIP1) gene, which in other cells plays an important role in p53-mediated
      cell cycle block. The lack of p21(WAF1/CIP1) expression appears to be the result
      of hypermethylation of the p21(WAF1/CIP1) promoter region, as p21(WAF1/CIP1)
      protein expression could be induced by growth of Rat-1 cells in the presence of 5
      aza-2-deoxycytidine. Furthermore, sequence analysis of bisulfite-treated DNA
      demonstrated extensive methylation of cytosine residues in CpG dinucleotides in a
      CpG-rich island in the promoter region of the p21(WAF1/CIP1) gene. Stable X-ray
      induced p53-dependent p21(WAF1/CIP1) expression and cell cycle block were
      restored to a Rat-1 clone after transfection with a P1 artificial chromosome
      (PAC) DNA clone containing a rat genomic copy of the p21(WAF1/CIP1) gene. The
      absence of expression of the p21(WAF1/CIP1) gene may contribute to the
      suitability of Rat-1 cells for transformation, cell cycle, and apoptosis studies.

PMID- 10648614
TI  - NF-kappaB activation by double-stranded-RNA-activated protein kinase (PKR) is
      mediated through NF-kappaB-inducing kinase and IkappaB kinase.
AB  - The interferon (IFN)-inducible double-stranded-RNA (dsRNA)-activated serine
      threonine protein kinase (PKR) is a major mediator of the antiviral and
      antiproliferative activities of IFNs. PKR has been implicated in different stress
      induced signaling pathways including dsRNA signaling to nuclear factor kappa B
      (NF-kappaB). The mechanism by which PKR mediates activation of NF-kappaB is
      unknown. Here we show that in response to poly(rI). poly(rC) (pIC), PKR activates
      IkappaB kinase (IKK), leading to the degradation of the inhibitors IkappaBalpha
      and IkappaBbeta and the concomitant release of NF-kappaB. The results of kinetic
      studies revealed that pIC induced a slow and prolonged activation of IKK, which
      was preceded by PKR activation. In PKR null cell lines, pIC failed to stimulate
      IKK activity compared to cells from an isogenic background wild type for PKR in
      accord with the inability of PKR null cells to induce NF-kappaB in response to
      pIC. Moreover, PKR was required to establish a sustained response to tumor
      necrosis factor alpha (TNF-alpha) and to potentiate activation of NF-kappaB by
      cotreatment with TNF-alpha and IFN-gamma. By coimmunoprecipitation, PKR was shown
      to be physically associated with the IKK complex. Transient expression of a
      dominant negative mutant of IKKbeta or the NF-kappaB-inducing kinase (NIK)
      inhibited pIC-induced gene expression from an NF-kappaB-dependent reporter
      construct. Taken together, these results demonstrate that PKR-dependent dsRNA
      induction of NF-kappaB is mediated by NIK and IKK activation.

PMID- 10648616
TI  - The N-terminal domain of p73 interacts with the CH1 domain of p300/CREB binding
      protein and mediates transcriptional activation and apoptosis.
AB  - The newly identified p53 homolog p73 mimics the transcriptional function of p53.
      We have investigated the regulation of p73's transcriptional activity by
      p300/CREB binding protein (CBP). p73-p300 complexes were identified in HeLa cell
      extracts by cofractionation and coimmunoprecipitation assays. The p73-p300
      interaction was confirmed in vitro by glutathione S-transferase-protein
      association assays and in vivo by coimmunoprecipitating the overexpressed p300
      and p73 in human p53-free small-cell lung carcinoma H1299 or osteosarcoma Saos-2
      cells. The N terminus but not the N-terminal truncation of p73 bound to the CH1
      domain (amino acids [aa] 350 to 450) of p300/CBP. Accordingly, this p73 N
      terminal deletion was unable to activate transcription or to induce apoptosis.
      Overexpression of either p300 or CBP stimulated transcription mediated by p73 but
      not its N-terminally deleted mutant in vivo. The N-terminal fragment from aa 19
      to 597, but not the truncated fragment from aa 242 to 1700 of p300, reduced p73
      mediated transcription markedly. p73-dependent transcription or apoptosis was
      partially impaired in either p300- or CBP-deficient human breast carcinoma MCF-7
      or H1299 cells, suggesting that both coactivators mediate transcription by p73 in
      cells. These results demonstrate that the N terminus of p73 directly interacts
      with the N-terminal CH1 domain of p300/CBP to activate transcription.

PMID- 10648617
TI  - Identification of a novel element required for processing of intron-encoded box
      C/D small nucleolar RNAs in Saccharomyces cerevisiae.
AB  - Processing of intron-encoded box C/D small nucleolar RNAs (snoRNAs) in metazoans
      through both the splicing-dependent and -independent pathways requires the
      conserved core motif formed by boxes C and D and the adjoining 5'-3'-terminal
      stem. By comparative analysis, we found that five out of six intron-encoded box
      C/D snoRNAs in yeast do not possess a canonical terminal stem. Instead,
      complementary regions within the flanking host intron sequences have been
      identified in all these cases. Here we show that these sequences are essential
      for processing of U18 and snR38 snoRNAs and that they compensate for the lack of
      a canonical terminal stem. We also show that the Rnt1p endonuclease, previously
      shown to be required for the processing of many snoRNAs encoded by monocistronic
      or polycistronic transcriptional units, is not required for U18 processing. Our
      results suggest a role of the complementary sequences in the early recognition of
      intronic snoRNA substrates and point out the importance of base pairing in
      favoring the communication between boxes C and D at the level of pre-snoRNA
      molecules for efficient assembly with snoRNP-specific factors.

PMID- 10648618
TI  - Regulatory interactions between the Reg1-Glc7 protein phosphatase and the Snf1
      protein kinase.
AB  - Protein phosphatase 1, comprising the regulatory subunit Reg1 and the catalytic
      subunit Glc7, has a role in glucose repression in Saccharomyces cerevisiae.
      Previous studies showed that Reg1 regulates the Snf1 protein kinase in response
      to glucose. Here, we explore the functional relationships between Reg1, Glc7, and
      Snf1. We show that different sequences of Reg1 interact with Glc7 and Snf1. We
      use a mutant Reg1 altered in the Glc7-binding motif to demonstrate that Reg1
      facilitates the return of the activated Snf1 kinase complex to the autoinhibited
      state by targeting Glc7 to the complex. Genetic evidence indicated that the
      catalytic activity of Snf1 negatively regulates its interaction with Reg1. We
      show that Reg1 is phosphorylated in response to glucose limitation and that this
      phosphorylation requires Snf1; moreover, Reg1 is dephosphorylated by Glc7 when
      glucose is added. Finally, we show that hexokinase PII (Hxk2) has a role in
      regulating the phosphorylation state of Reg1, which may account for the effect of
      Hxk2 on Snf1 function. These findings suggest that the phosphorylation of Reg1 by
      Snf1 is required for the release of Reg1-Glc7 from the kinase complex and also
      stimulates the activity of Glc7 in promoting closure of the complex.

PMID- 10648620
TI  - Epstein-Barr virus suppresses a G(2)/M checkpoint activated by genotoxins.
AB  - Several Epstein-Barr virus (EBV)-negative Burkitt lymphoma-derived cell lines
      (for example, BL41 and Ramos) are extremely sensitive to genotoxic drugs despite
      being functionally null for the tumor suppressor p53. They rapidly undergo
      apoptosis, largely from G(2)/M of the cell cycle. 5-bromo-2'-deoxyuridine
      labeling experiments showed that although the treated cells can pass through S
      phase, they are unable to complete cell division, suggesting that a G(2)/M
      checkpoint is activated. Surprisingly, latent infection of these genotoxin
      sensitive cells with EBV protects them from both apoptosis and cell cycle arrest,
      allowing them to complete the division cycle. However, a comparison with EBV
      immortalized B-lymphoblastoid cell lines (which have functional p53) showed that
      EBV does not block apoptosis per se but rather abrogates the activation of, or
      signalling from, the checkpoint in G(2)/M. Furthermore, analyses of BL41 and
      Ramos cells latently infected with P3HR1 mutant virus, which expresses only a
      subset of the latent viral genes, showed that LMP-1, the main antiapoptotic
      latent protein encoded by EBV, is not involved in the protection afforded here by
      viral infection. This conclusion was confirmed by analysis of clones of BL41
      stably expressing LMP-1 from a transfected plasmid, which respond like the
      parental cell line. Although steady-state levels of Bcl-2 and related proteins
      varied between BL41 lines and clones, they did not change significantly during
      apoptosis, nor was the level of any of these anti- or proapoptotic proteins
      predictive of the outcome of treatment. We have demonstrated that a subset of EBV
      latent gene products can inactivate a cell cycle checkpoint for monitoring the
      fidelity and timing of cell division and therefore genomic integrity. This is
      likely to be important in EBV-associated growth transformation of B cells and
      perhaps tumorigenesis. Furthermore, this study suggests that EBV will be a unique
      tool for investigating the intimate relationship between cell cycle regulation
      and apoptosis.

PMID- 10648619
TI  - TATA-Binding protein-TATA interaction is a key determinant of differential
      transcription of silkworm constitutive and silk gland-specific tRNA(Ala) genes.
AB  - We have investigated the contribution of specific TATA-binding protein (TBP)-TATA
      interactions to the promoter activity of a constitutively expressed silkworm
      tRNA(C)(Ala) gene and have also asked whether the lack of similar interactions
      accounts for the low promoter activity of a silk gland-specific tRNA(SG)(Ala)
      gene. We compared TBP binding, TFIIIB-promoter complex stability (measured by
      heparin resistance), and in vitro transcriptional activity in a series of mutant
      tRNA(C)(Ala) promoters and found that specific TBP-TATA contacts are important
      for TFIIIB-promoter interaction and for transcriptional activity. Although the
      wild-type tRNA(C)(Ala) promoter contains two functional TBP binding sequences
      that overlap, the tRNA(SG)(Ala) promoter lacks any TBP binding site in the
      corresponding region. This feature appears to account for the inefficiency of the
      tRNA(SG)(Ala) promoter since provision of either of the wild-type TATA sequences
      derived from the tRNA(C)(Ala) promoter confers robust transcriptional activity.
      Transcriptional impairment of the wild-type tRNA(SG)(Ala) gene is not due to
      reduced incorporation of TBP into transcription complexes since both the
      tRNA(C)(Ala) and tRNA(SG)(Ala) promoters form transcription complexes that
      contain the same amount of TBP. Thus, the deleterious consequences of the lack of
      appropriate TBP-TATA contacts in the tRNA(SG)(Ala) promoter must come from
      failure to incorporate some other essential transcription factor(s) or to
      stabilize the complete complex in an active conformation.

PMID- 10648621
TI  - Yeast meiosis-specific protein Hop1 binds to G4 DNA and promotes its formation.
AB  - DNA molecules containing stretches of contiguous guanine residues can assume a
      stable configuration in which planar quartets of guanine residues joined by
      Hoogsteen pairing appear in a stacked array. This conformation, called G4 DNA,
      has been implicated in several aspects of chromosome behavior including
      immunoglobulin gene rearrangements, promoter activation, and telomere
      maintenance. Moreover, the ability of the yeast SEP1 gene product to cleave DNA
      in a G4-DNA-dependent fashion, as well as that of the SGS1 gene product to unwind
      G4 DNA, has suggested a crucial role for this structure in meiotic synapsis and
      recombination. Here, we demonstrate that the HOP1 gene product, which plays a
      crucial role in the formation of synaptonemal complex in Saccharomyces
      cerevisiae, binds robustly to G4 DNA. The apparent dissociation constant for
      interaction with G4 DNA is 2 x 10(-10), indicative of binding that is about 1,000
      fold stronger than to normal duplex DNA. Oligonucleotides of appropriate sequence
      bound Hop1 protein maximally if the DNA was first subjected to conditions
      favoring the formation of G4 DNA. Furthermore, incubation of unfolded
      oligonucleotides with Hop1 led to their transformation into G4 DNA. Methylation
      interference experiments confirmed that modifications blocking G4 DNA formation
      inhibit Hop1 binding. In contrast, neither bacterial RecA proteins that
      preferentially interact with GT-rich DNA nor histone H1 bound strongly to G4 DNA
      or induced its formation. These findings implicate specific interactions of Hop1
      protein with G4 DNA in the pathway to chromosomal synapsis and recombination in
      meiosis.

PMID- 10648622
TI  - Spb1p is a yeast nucleolar protein associated with Nop1p and Nop58p that is able
      to bind S-adenosyl-L-methionine in vitro.
AB  - We present here the characterization of SPB1, an essential yeast gene that is
      required for ribosome synthesis. A cold-sensitive allele for that gene (referred
      to here as spb1-1) had been previously isolated as a suppressor of a mutation
      affecting the poly(A)-binding protein gene (PAB1) and a thermosensitive allele
      (referred to here as spb1-2) was isolated in a search for essential genes
      required for gene silencing in Saccharomyces cerevisiae. The two mutants are able
      to suppress the deletion of PAB1, and they both present a strong reduction in
      their 60S ribosomal subunit content. In an spb1-2 strain grown at the restrictive
      temperature, processing of the 27S pre-rRNA into mature 25S rRNA and 5.8S is
      completely abolished and production of mature 18S is reduced, while the abnormal
      23S species is accumulated. Spb1p is a 96.5-kDa protein that is localized to the
      nucleolus. Coimmunoprecipitation experiments show that Spb1p is associated in
      vivo with the nucleolar proteins Nop1p and Nop5/58p. Protein sequence analysis
      reveals that Spb1p possesses a putative S-adenosyl-L-methionine (AdoMet)-binding
      domain, which is common to the AdoMet-dependent methyltransferases. We show here
      that Spb1p is able to bind [(3)H]AdoMet in vitro, suggesting that it is a novel
      methylase, whose possible substrates will be discussed.

PMID- 10648623
TI  - The SCF(HOS/beta-TRCP)-ROC1 E3 ubiquitin ligase utilizes two distinct domains
      within CUL1 for substrate targeting and ubiquitin ligation.
AB  - We describe a purified ubiquitination system capable of rapidly catalyzing the
      covalent linkage of polyubiquitin chains onto a model substrate, phosphorylated
      IkappaBalpha. The initial ubiquitin transfer and subsequent polymerization steps
      of this reaction require the coordinated action of Cdc34 and the SCF(HOS/beta
      TRCP)-ROC1 E3 ligase complex, comprised of four subunits (Skp1, cullin 1 [CUL1],
      HOS/beta-TRCP, and ROC1). Deletion analysis reveals that the N terminus of CUL1
      is both necessary and sufficient for binding Skp1 but is devoid of ROC1-binding
      activity and, hence, is inactive in catalyzing ubiquitin ligation. Consistent
      with this, introduction of the N-terminal CUL1 polypeptide into cells blocks the
      tumor necrosis factor alpha-induced and SCF-mediated degradation of IkappaB by
      forming catalytically inactive complexes lacking ROC1. In contrast, the C
      terminus of CUL1 alone interacts with ROC1 through a region containing the cullin
      consensus domain, to form a complex fully active in supporting ubiquitin
      polymerization. These results suggest the mode of action of SCF-ROC1, where CUL1
      serves as a dual-function molecule that recruits an F-box protein for substrate
      targeting through Skp1 at its N terminus, while the C terminus of CUL1 binds ROC1
      to assemble a core ubiquitin ligase.

PMID- 10648624
TI  - Active repression of methylated genes by the chromosomal protein MBD1.
AB  - MBD1 belongs to a family of mammalian proteins that share a methyl-CpG binding
      domain. Previous work has shown that MBD1 binds to methylated sites in vivo and
      in vitro and can repress transcription from methylated templates in transcription
      extracts and in cultured cells. In the present study we established by several
      experimental criteria that, contrary to a previous report, MBD1 is not a
      component of the MeCP1 repressor complex. We identified a powerful
      transcriptional repression domain (TRD) at the C terminus of MBD1 that can
      actively repress transcription at a distance. Methylation-dependent repression in
      vivo depends on the presence of both the TRD and the methyl-CpG binding domain.
      The mechanism is likely to involve deacetylation, since the deacetylase inhibitor
      trichostatin A can overcome MBD1-mediated repression. Accordingly, we found that
      endogenous MBD1 is particularly concentrated at sites of centromeric
      heterochromatin, where acetylated histone H4 is deficient. Unlike MBD2 and MeCP2,
      MBD1 is not depleted by antibodies to the histone deacetylase HDAC1. Thus, the
      deacetylase-dependent pathway by which MBD1 actively silences methylated genes is
      likely to be different from that utilized by the methylation-dependent repressors
      MeCP1 and MeCP2.

PMID- 10648626
TI  - Minimal phenotype of mice homozygous for a null mutation in the forkhead/winged
      helix gene, Mf2.
AB  - Mf2 (mesoderm/mesenchyme forkhead 2) encodes a forkhead/winged helix
      transcription factor expressed in numerous tissues of the mouse embryo, including
      paraxial mesoderm, somites, branchial arches, vibrissae, developing central
      nervous system, and developing kidney. We have generated mice homozygous for a
      null mutation in the Mf2 gene (Mf2(lacZ)) to examine its role during embryonic
      development. The lacZ allele also allows monitoring of Mf2 gene expression.
      Homozygous null mutants are viable and fertile and have no major developmental
      defects. Some mutants show renal abnormalities, including kidney hypoplasia and
      hydroureter, but the penetrance of this phenotype is only 40% or lower, depending
      on the genetic background. These data suggest that Mf2 can play a unique role in
      kidney development, but there is functional redundancy in this organ and other
      tissues with other forkhead/winged helix genes.

PMID- 10648625
TI  - A novel TATA-binding protein-binding protein, ABT1, activates basal transcription
      and has a yeast homolog that is essential for growth.
AB  - Identification of a novel mouse nuclear protein termed activator of basal
      transcription 1 (mABT1) that associates with the TATA-binding protein (TBP) and
      enhances basal transcription activity of class II promoters is described. We also
      identify mABT1 homologous counterparts in Caenorhabditis elegans and
      Saccharomyces cerevisiae and show the homologous yeast gene to be essential for
      growth. The mABT1 associated with TBP in HeLa nuclear extracts and with purified
      mouse TBP in vitro. In addition, ectopically expressed mABT1 was
      coimmunoprecipitated with endogenous TBP in transfected cells. More importantly,
      mABT1 significantly enhanced transcription from an adenovirus major late promoter
      in a reconstituted cell-free system. We furthermore demonstrate that mABT1
      consistently enhanced transcription from a reporter gene with a minimal core
      promoter as well as from reporter genes with various enhancer elements in a
      cotransfection assay. Taken together, these results suggest that mABT1 is a novel
      TBP-binding protein which can function as a basal transcription activator.

PMID- 10648627
TI  - Differential T-cell antigen receptor signaling mediated by the Src family kinases
      Lck and Fyn.
AB  - Src family tyrosine kinases play a key role in T-cell antigen receptor (TCR)
      signaling. They are responsible for the initial tyrosine phosphorylation of the
      receptor, leading to the recruitment of the ZAP-70 tyrosine kinase, as well as
      the subsequent phosphorylation and activation of ZAP-70. Molecular and genetic
      evidence indicates that both the Fyn and Lck members of the Src family can
      participate in TCR signal transduction; however, it is unclear to what extent
      they utilize the same signal transduction pathways and activate the same
      downstream events. We have addressed this issue by examining the ability of Fyn
      to mediate TCR signal transduction in an Lck-deficient T-cell line (JCaM1). Fyn
      was able to induce tyrosine phosphorylation of the TCR and recruitment of the ZAP
      70 kinase, but the pattern of TCR phosphorylation was altered and activation of
      ZAP-70 was defective. Despite this, the SLP-76 adapter protein was inducibly
      tyrosine phosphorylated, and both the Ras-mitogen-activated protein kinase and
      the phosphatidylinositol 4, 5-biphosphate signaling pathways were activated. TCR
      stimulation of JCaM1/Fyn cells induced the expression of the CD69 activation
      marker and inhibited cell growth, but NFAT activation and the production of
      interleukin-2 were markedly reduced. These results indicate that Fyn mediates an
      alternative form of TCR signaling which is independent of ZAP-70 activation and
      generates a distinct cellular phenotype. Furthermore, these findings imply that
      the outcome of TCR signal transduction may be determined by which Src family
      kinase is used to initiate signaling.

PMID- 10648628
TI  - Human keratinocytes that express hTERT and also bypass a p16(INK4a)-enforced
      mechanism that limits life span become immortal yet retain normal growth and
      differentiation characteristics.
AB  - Normal human cells exhibit a limited replicative life span in culture, eventually
      arresting growth by a process termed senescence. Progressive telomere shortening
      appears to trigger senescence in normal human fibroblasts and retinal pigment
      epithelial cells, as ectopic expression of the telomerase catalytic subunit,
      hTERT, immortalizes these cell types directly. Telomerase expression alone is
      insufficient to enable certain other cell types to evade senescence, however.
      Such cells, including keratinocytes and mammary epithelial cells, appear to
      require loss of the pRB/p16(INK4a) cell cycle control mechanism in addition to
      hTERT expression to achieve immortality. To investigate the relationships among
      telomerase activity, cell cycle control, senescence, and differentiation, we
      expressed hTERT in two epithelial cell types, keratinocytes and mesothelial
      cells, and determined the effect on proliferation potential and on the function
      of cell-type-specific growth control and differentiation systems. Ectopic hTERT
      expression immortalized normal mesothelial cells and a premalignant, p16(INK4a)
      negative keratinocyte line. In contrast, when four keratinocyte strains cultured
      from normal tissue were transduced to express hTERT, they were incompletely
      rescued from senescence. After reaching the population doubling limit of their
      parent cell strains, hTERT(+) keratinocytes entered a slow growth phase of
      indefinite length, from which rare, rapidly dividing immortal cells emerged.
      These immortal cell lines frequently had sustained deletions of the CDK2NA/INK4A
      locus or otherwise were deficient in p16(INK4a) expression. They nevertheless
      typically retained other keratinocyte growth controls and differentiated normally
      in culture and in xenografts. Thus, keratinocyte replicative potential is limited
      by a p16(INK4a)-dependent mechanism, the activation of which can occur
      independent of telomere length. Abrogation of this mechanism together with
      telomerase expression immortalizes keratinocytes without affecting other major
      growth control or differentiation systems.

PMID- 10648629
TI  - A novel positive feedback loop mediated by the docking protein Gab1 and
      phosphatidylinositol 3-kinase in epidermal growth factor receptor signaling.
AB  - The Gab1 protein is tyrosine phosphorylated in response to various growth factors
      and serves as a docking protein that recruits a number of downstream signaling
      proteins, including phosphatidylinositol 3-kinase (PI-3 kinase). To determine the
      role of Gab1 in signaling via the epidermal growth factor (EGF) receptor (EGFR)
      we tested the ability of Gab1 to associate with and modulate signaling by this
      receptor. We show that Gab1 associates with the EGFR in vivo and in vitro via
      pTyr sites 1068 and 1086 in the carboxy-terminal tail of the receptor and that
      overexpression of Gab1 potentiates EGF-induced activation of the mitogen
      activated protein kinase and Jun kinase signaling pathways. A mutant of Gab1
      unable to bind the p85 subunit of PI-3 kinase is defective in potentiating EGFR
      signaling, confirming a role for PI-3 kinase as a downstream effector of Gab1.
      Inhibition of PI-3 kinase by a dominant-interfering mutant of p85 or by
      Wortmannin treatment similarly impairs Gab1-induced enhancement of signaling via
      the EGFR. The PH domain of Gab1 was shown to bind specifically to
      phosphatidylinositol 3,4,5-triphosphate [PtdIns(3,4,5)P3], a product of PI-3
      kinase, and is required for activation of Gab1-mediated enhancement of EGFR
      signaling. Moreover, the PH domain mediates Gab1 translocation to the plasma
      membrane in response to EGF and is required for efficient tyrosine
      phosphorylation of Gab1 upon EGF stimulation. In addition, overexpression of Gab1
      PH domain blocks Gab1 potentiation of EGFR signaling. Finally, expression of the
      gene for the lipid phosphatase PTEN, which dephosphorylates PtdIns(3,4, 5)P3,
      inhibits EGF signaling and translocation of Gab1 to the plasma membrane. These
      results reveal a novel positive feedback loop, modulated by PTEN, in which PI-3
      kinase functions as both an upstream regulator and a downstream effector of Gab1
      in signaling via the EGFR.

PMID- 10648630
TI  - Accommodating protein flexibility in computational drug design.

PMID- 10648631
TI  - Mutational analysis of the highly conserved arginine within the Glu/Asp-Arg-Tyr
      motif of the alpha(1b)-adrenergic receptor: effects on receptor isomerization and
      activation.
AB  - We have suggested previously that both the negatively and positively charged
      residues of the highly conserved Glu/Asp-Arg-Tyr (E/DRY) motif play an important
      role in the activation process of the alpha(1b)-adreneric receptor (AR). In this
      study, R143 of the E/DRY sequence in the alpha(1b)-AR was mutated into several
      amino acids (Lys, His, Glu, Asp, Ala, Asn, and Ile). The charge-conserving
      mutation of R143 into lysine not only preserved the maximal agonist-induced
      response of the alpha(1b)-AR, but it also conferred high degree of constitutive
      activity to the receptor. Both basal and agonist-induced phosphorylation levels
      were significantly increased for the R143K mutant compared with those of the wild
      type receptor. Other substitutions of R143 resulted in receptor mutants with
      either a small increase in constitutive activity (R143H and R143D), impairment
      (R143H, R143D), or complete loss of receptor-mediated response (R143E, R143A,
      R143N, R143I). The R413E mutant displayed a small, but significant increase in
      basal phosphorylation despite being severely impaired in receptor-mediated
      response. Interestingly, all the arginine mutants displayed increased affinity
      for agonist binding compared with the wild-type alpha(1b)-AR. A correlation was
      found between the extent of the affinity shift and the intrinsic activity of the
      agonists. The analysis of the receptor mutants using the allosteric ternary
      complex model in conjunction with the results of molecular dynamics simulations
      on the receptor models support the hypothesis that mutations of R143 can drive
      the isomerization of the alpha(1b)-AR into different states, highlighting the
      crucial role of this residue in the activation process of the receptor.

PMID- 10648632
TI  - Molecular and conformational features of a transport-relevant domain in the C
      terminal tail of the vasopressin V(2) receptor.
AB  - We have previously shown a conserved glutamate/dileucine motif ((335)ELRSLL(340))
      in the intracellular C terminus of the vasopressin V(2) receptor (V(2) receptor)
      to be essential for receptor transport from the endoplasmic reticulum (ER) to the
      Golgi apparatus. The motif may represent a transport signal that is recognized by
      a component of ER to Golgi vesicles. Alternatively, it may be necessary for
      transport-competent receptor folding to pass the quality-control system of the
      ER. To assess these two possibilities, we constructed a receptor fragment that
      allows transport studies independent of full-length receptor folding.
      Transmembrane domains II-VII were deleted, thereby fusing the intracellular C
      terminus to the first cytoplasmic loop. The mutations that impaired transport of
      the full-length receptor were introduced, and receptor fragments were localized
      in transiently transfected HEK 293 cells. All mutant receptor fragments were
      detectable at the plasma membrane, demonstrating that the glutamate/dileucine
      motif does not function as a small, linear vesicular transport signal. Instead,
      our data strongly suggest that this motif is required for transport-competent
      folding of the full-length receptor. To assess the underlying conformational
      features, a three-dimensional homology model of the V(2) receptor was computed.
      Our model predicts that the glutamate/dileucine motif contributes to a U-like
      loop within the intracellular C terminus. Residue Leu(339) may be required for
      folding back the intracellular C terminus to residue Leu(62) of the first
      cytoplasmic loop. We characterized the naturally occurring L62P and DeltaL62-R64
      mutations in the first cytoplasmic loop and show that they lead to transport
      defective full-length V(2) receptors that are retained in the ER, consistent with
      the structure model.

PMID- 10648633
TI  - 7- and 10-substituted camptothecins: dependence of topoisomerase I-DNA cleavable
      complex formation and stability on the 7- and 10-substituents.
AB  - 7-Alkyl, 7-alkyl-10-hydroxy, 7-alkyl-10-methoxy, and 7-alkyl-10, 11
      methylenedioxy analogs of camptothecin have been synthesized and evaluated for
      their ability to trap human DNA topoisomerase I in cleavable complexes. The 7
      alkyl chain lengths varied linearly from methyl to butyl. The concentration
      required to produce cleavable complexes with purified topoisomerase I in 50% of
      the plasmid DNA (EC(50)) was reduced by 1 order of magnitude by the introduction
      of a 10-methoxy or 7-alkyl group compared with camptothecin. The EC(50) values
      were reduced by 2 orders of magnitude with a 10-hydroxy or 10, 11-methylenedioxy
      moiety compared with camptothecin. The steady-state EC(50) concentrations for all
      of the analogs tested were slightly dependent on substitution at the 7-position,
      but this dependence was least with the 10-methoxy series. The kinetics of the
      reversibility of the complexes formed with all analogs was only slightly
      influenced by the length of the 7-substitution, with the trend that ethyl or
      greater lengths led to slightly reduced rate constants for cleavable complex
      reversal. These results were also observed for DNA-protein cross-link formation
      by the analogs in isolated CEM cell nuclei. Our data indicate that in vitro
      cleavable complex stability, as determined by the apparent rate constants for
      complex dissociation, does not reflect the in vitro biological activity of these
      camptothecin analogs. However, complex stability in vivo may be important for the
      antitumor activity of the compounds.

PMID- 10648634
TI  - beta1-adrenergic receptors mediate beta3-adrenergic-independent effects of CGP
      12177 in brown adipose tissue.
AB  - CGP 12177 is a beta-adrenergic receptor (AR) ligand that has been used to
      characterize the beta3-AR and the putative beta4-AR. The ability of CGP 12177 to
      activate beta1-AR when overexpressed in vitro and the presence of beta1-AR in
      tissues expressing putative beta4-AR prompted us to investigate the actions of
      CGP 12177 at recombinant and natively-expressed beta-AR. CGP 12177 potently
      activated recombinant rat and human beta1-AR expressed in Chinese hamster ovary
      cells. This activation, like that of putative beta4-AR, was resistant to blockade
      by selective and nonselective beta-AR antagonists. Brown fat has been proposed to
      contain beta4-AR, as evidenced by the presence of CGP 12177-mediated
      thermogenesis in mice lacking beta3-AR. Therefore, the identity of the receptors
      mediating CGP 12177 responses in brown fat was examined using wild-type mice and
      mice lacking beta1-AR or beta3-AR. In wild-type mice, CGP 12177 activated
      adenylyl cyclase via high- and low-affinity sites. The high-affinity site, but
      not the low-affinity site, was blocked by CGP 20712 with potency indicating an
      interaction with beta1-AR. Moreover, the high-affinity site was absent in mice
      lacking beta1-AR. In contrast, the low-affinity, CGP 20712-resistant activation
      by CGP 12177 was absent in mice lacking beta3-AR. Rather, activation occurred
      exclusively through the high-affinity, CGP 20712-sensitive site. These data
      indicate that the actions of CGP 12177 in brown fat that have been attributed to
      novel beta-AR (i.e., beta4-AR) are mediated via an atypical interaction with
      beta1-AR.

PMID- 10648635
TI  - Functional domains and expression of truncated atrial natriuretic peptide
      receptor-A: the carboxyl-terminal regions direct the receptor internalization and
      sequestration in COS-7 cells.
AB  - The objective of this study was to determine the role of cytoplasmic (protein
      kinase-like homology and guanylyl cyclase catalytic) domains of atrial
      natriuretic peptide (ANP) receptor-A (Npra) in postbinding events and metabolic
      turnover of ligand-receptor complexes. Using deletion mutagenesis, the specific
      regions in the intracellular domains of Npra relevant to the receptor function,
      namely ligand-binding, cGMP production, and internalization and sequestration of
      ligand-receptor complexes, have been determined in transiently expressing COS-7
      cells. Deletion of 12 aa (aa) at the carboxyl-terminal end of receptor (Delta1045
      Npra) affected neither ligand-binding efficiency nor cGMP production. However,
      deletion of 120 to 170 aa residues (Delta937-Npra, Delta916-Npra, Delta902-Npra,
      and Delta887-Npra) decreased ligand binding by 16 to 20% and cGMP production by
      50 to 90%. Further deletion of 422 aa and 569 aa (Delta635-Npra and Delta488
      Npra) reduced ligand binding efficiency by 40% and 90%, respectively. The
      deletion of 12 aa (Delta1045-Npra) did not affect the internalization of Npra;
      however, deletions up to 170 aa (Delta937-Npra, Delta916-Npra, Delta887-Npra)
      reduced the internalization of ligand-receptor complexes by 60%. Cells expressing
      either full-length (wild-type) Npra or 120 aa deleted receptor (Delta937-Npra)
      released 40 to 45% (125)I-ANP radioactivity into culture medium, but only 10 to
      15% radioactivity was released from the cells that expressed Delta635-Npra.
      Furthermore, 35 to 40% (125)I-ANP radioactivity was detected into the
      intracellular compartments of cells that expressed the wild-type Npra, and only 5
      to 10% (125)I-ANP radioactivity was observed in cells expressing the Delta635
      Npra (-422 aa) or Delta488-Npra (-569 aa) mutant receptors. These results show
      that specific regions within the intracellular domains of Npra determine the
      extent of ligand-binding efficiency, cGMP production, endocytosis, and
      intracellular sequestration of ligand-receptor complexes in cDNA expressing COS-7
      cells.

PMID- 10648636
TI  - Molecular determinants of mexiletine structure for potent and use-dependent block
      of skeletal muscle sodium channels.
AB  - On the basis of the information about drug receptor on voltage-gated sodium
      channels, mexiletine (Mex) analogs with substitutions at either the asymmetric
      carbon atom or the aromatic ring were synthesized as pure enantiomers. The
      compounds were tested in vitro for their ability to produce voltage- and use
      dependent block of sodium currents (I(Na)) of frog muscle fibers by the vaseline
      gap voltage-clamp method. In all experimental conditions, the drug potency was
      highly correlated with the lipophilicity of the group on the asymmetric center,
      the derivative with a benzyl moiety (Me6) having IC(50) values more than 10 times
      lower than those of Mex, followed by the phenyl (Me4) and the isopropyl (Me5)
      derivative. All of the compounds showed a further reduction of IC(50) values at
      depolarized membrane potentials and at high frequency of stimulation (10 Hz). Mex
      and Me5, but not Me4, produced a stereoselective tonic block of I(Na), the R-(-)
      isomers being 2-fold more potent than the S-(+) ones. The removal of both methyl
      groups from the aromatic ring of Mex (Me3) caused a 7-fold reduction of the
      potency, whereas similar substitutions on the phenyl derivative Me4 (Me7 and Me8)
      produced opposite effects. In fact, the IC(50) of R-(-) Me7 for use-dependent
      block of I(Na) was 30 times lower than that of R-(-) Mex. Me8 and Me7 were
      stereoselective during both tonic and use-dependent blockade. All of the
      compounds left-shifted the steady-state inactivation curves in relation to their
      potency and to the duration of the inactivating prepulse. Finally, the presence
      of apolar groups on the asymmetric center of mexiletine is pivotal to reinforce
      hydrophobic interactions with the proposed aromatic residues at the receptor, and
      lead to potent and therapeutically interesting inactivated channel blockers.

PMID- 10648637
TI  - Mechanisms of impaired beta-adrenergic receptor signaling in G(alphaq)-mediated
      cardiac hypertrophy and ventricular dysfunction.
AB  - Targeted cardiac overexpression of the alpha-subunit of the heterotrimeric G
      protein G(q) in transgenic mice evokes hypertrophy and depressed stimulation of
      cardiac inotropy and chronotropy by beta-adrenergic receptor (betaAR) agonists in
      vivo, which is a hallmark of many forms of experimental and human heart failure.
      The molecular basis of this betaAR dysfunction was explored in transgenic mice
      overexpressing G(alphaq) approximately 5-fold over background. Isoproterenol
      stimulated adenylyl cyclase activities in myocardial membranes were significantly
      depressed in G(alphaq) mice compared with nontransgenic controls (19.7 +/- 2.6
      versus 43.7 +/- 5. 6 pmol/min/mg) without a decrease in betaAR expression levels.
      Functional coupling of both betaAR subtypes was impaired. Similarly, in whole
      cell patch-clamp studies, betaAR stimulation of L-type Ca(2+) channel currents
      was depressed approximately 75% in the G(alphaq) mice. Cardiac betaAR from these
      mice showed decreased formation of the active high-affinity conformation (R(H) =
      29% versus 62% for nontransgenic littermates), confirming a receptor-G(s)
      coupling defect. Of the three candidate kinases that might impose this uncoupling
      by receptor phosphorylation (protein kinase A, betaAR kinase, protein kinase C),
      only protein kinase C activity was elevated in G(alphaq) mouse hearts. Type V
      adenylyl cyclase was decreased approximately 45% in these mice, consistent with
      decreased basal, NaF, and forskolin-stimulated enzyme activities. Although
      cellular G(s) levels were unaltered, G(i2) and G(i3) were increased in G(alphaq)
      mice. Pertussis toxin treatment of isolated G(alphaq) myocytes resulted in an
      improvement in betaAR, but not that of forskolin or NaF, stimulation of adenylyl
      cyclase. Thus three distinct mechanisms contribute to impaired betaAR function by
      in vivo G(q) signaling cross-talk in myocytes. Because many elements of
      hypertrophy and/or failure in cellular and animal models can be initiated by
      increased G(alphaq) signaling, the current work may be broadly applicable to
      interfaces whereby modification of heart failure might be considered.

PMID- 10648638
TI  - Actions of cannabinoids on membrane properties and synaptic transmission in rat
      periaqueductal gray neurons in vitro.
AB  - The midbrain periaqueductal gray (PAG) is a major site of cannabinoid-mediated
      analgesia in the central nervous system. In the present study, we examined the
      actions of cannabinoids on rat PAG neurons in vitro. In brain slices, superfusion
      of the cannabinoid receptor agonist WIN55,212-2 inhibited electrically evoked
      inhibitory and excitatory postsynaptic currents in all PAG neurons. The
      endogenous cannabinoid anandamide inhibited evoked inhibitory postsynaptic
      currents in the presence of the anandamide transport inhibitor AM404, but not in
      its absence. The stable anandamide analog R1-methanandamide also inhibited evoked
      inhibitory postsynaptic currents. WIN55,212-2 reduced the rate of spontaneous
      miniature inhibitory postsynaptic currents in normal and Ca(2+)-free solutions,
      but had no effect on their amplitude distributions or kinetics. The WIN55,212-2
      induced decrease in miniature inhibitory postsynaptic current rate was
      concentration dependent (EC(50) = 520 nM). The effects of cannabinoids were
      reversed by the CB(1) receptor antagonist SR141716. WIN55,212-2 produced no
      change in membrane current or conductance in PAG neurons in brain slices and had
      no effect on Ca(2+)-channel currents in acutely isolated PAG neurons. These
      findings suggest that cannabinoids act via CB(1) receptors to inhibit GABAergic
      and glutamatergic synaptic transmission in rat PAG, although the efficacy of
      endogenous cannabinoids is likely to be limited by uptake and breakdown. Like mu
      opioids, cannabinoids act to reduce the probability of transmitter release from
      presynaptic terminals via a Ca(2+)-independent mechanism. In contrast to mu
      opioids, cannabinoids have no direct postsynaptic actions on PAG neurons. Thus,
      cannabinoids and mu-opioids are likely to produce analgesia within PAG in part by
      different mechanisms.

PMID- 10648639
TI  - Selection of human leukemic CEM cells for resistance to the DNA topoisomerase II
      catalytic inhibitor ICRF-187 results in increased levels of topoisomerase IIalpha
      and altered G(2)/M checkpoint and apoptotic responses.
AB  - ICRF-187 is a bisdioxopiperazine anticancer drug that inhibits the catalytic
      activity of DNA topoisomerase (topo) II without stabilizing DNA-topoII cleavable
      complexes. To better understand the mechanisms of action of and resistance to
      topoII catalytic inhibitors, human leukemic CEM cells were selected for
      resistance to ICRF-187. The clones CEM/ICRF-8 and CEM/ICRF-18 are approximately
      40- and 69-fold resistant to ICRF-187, and 12- and 67-fold cross-resistant to
      ICRF-193, respectively, but are sensitive to other topoII catalytic inhibitors
      (merbarone and aclarubicin), as well as collaterally sensitive to the DNA-topoII
      complex-stabilizing drug etoposide (VP-16). Both the number of VP-16- induced DNA
      topoII complexes formed and the amount of in vitro topoII catalytic activity are
      enhanced in the drug-resistant cells. The ICRF-187-resistant clones contain
      approximately 5-fold increase in topoIIalpha protein levels and approximately 2.2
      fold increase in topoIIalpha mRNA levels. Furthermore, CEM/ICRF-8 expresses
      approximately 3.5-fold increase in topoIIalpha promoter activity, suggesting that
      up-regulation of topoIIalpha in this clone occurs at the transcriptional level.
      Treatment of the drug-resistant or -sensitive cells with equitoxic doses of
      merbarone or teniposide results in a G(2)/M arrest. In marked contrast, when
      treated with equitoxic ICRF-187 doses, the drug-resistant clones exhibit either a
      transient arrest or completely lack the G(2)/M checkpoint compared with the drug
      sensitive cells. This aberrant cell cycle profile is associated with a 48-h delay
      in drug-induced apoptotic cell death, as revealed by fluorescent-end labeling of
      DNA and poly (ADP-ribose) polymerase cleavage. In summary, resistance to ICRF-187
      in CEM cells is associated with increased levels of catalytically active
      topoIIalpha and altered G(2)/M checkpoint and apoptotic responses.

PMID- 10648640
TI  - Photoaffinity labeling and purification of ZG-16p, a high-affinity
      dihydropyridine binding protein of rat pancreatic zymogen granule membranes that
      regulates a K(+)-selective conductance.
AB  - In rat pancreatic zymogen granules (ZG), an ATP-sensitive K(+) conductance and a
      Cl(-) conductance have been characterized that are inversely regulated by an
      approximately 65-kDa multidrug resistance P-glycoprotein (mdr1) gene product. In
      search of a label for purification of this protein, we found that the
      dihydropyridine derivative (-)-[(3)H]BZDC-DHP, a recently developed high-affinity
      ligand for Mdr1, binds with similar affinity to ZG membranes (ZGM) (K(d) = 6.2
      nM). Binding was inhibited by nanomolar concentrations of the L-type Ca(2+)
      channel blockers azidopine and verapamil and by micromolar concentrations of the
      K(+) channel blockers glibenclamide and quinidine. Inhibition by glibenclamide
      was noncompetitive. The Mdr1 modulators cyclosporin A and vinblastine did not
      inhibit binding, which is different from Mdr1. In addition, only (+/-)-BZDC-DHP,
      azidopine, and verapamil selectively inhibited the K(+) conductance in ZGs,
      whereas the Cl(-) conductance was not affected. In photoaffinity labeling
      experiments, (-)-[(3)H]BZDC-DHP surprisingly specifically and selectively labeled
      a approximately 19-kDa protein in ZGM with a pharmacological profile identical
      with the high-affinity binding site but did not label a 65-kDa protein. The 19
      kDa protein was purified by ion exchange chromatography and SDS-polyacrylamide
      gel electrophoresis and sequenced. The sequence obtained corresponds to ZG-16p, a
      recently cloned ZG protein with no apparent homology to Mdr1. The identity of the
      19-kDa protein was confirmed by immunoprecipitation of (-)-[(3)H]BZDC-DHP-labeled
      ZGM with an anti-ZG-16p antibody. Furthermore, it is shown that ZG-16p is
      associated with the ZGM. We propose that ZG-16p, as part of the submembranous
      granule matrix, regulates the ATP-sensitive K(+) conductance of ZGs.

PMID- 10648641
TI  - Role of the amino acid 45 residue in reduced folate carrier function and ion
      dependent transport as characterized by site-directed mutagenesis.
AB  - In previous reports, an E45K mutation in reduced folate carrier (RFC1) resulted
      in marked substrate-specific changes in folate binding and the induction of an
      obligatory inorganic anion requirement for carrier function. In this study, site
      directed mutagenesis was employed to further characterize the role of glutamate
      45 in carrier function by replacement with glutamine, arginine, aspartate,
      leucine, or tryptophan followed by tranfection of the mutated cDNAs into the
      MTX(r)A line, which lacks a functional endogenous carrier. Alterations in
      transport function with amino acid substitutions at this residue were not charge
      related. Hence, E45Q, E45R, and E45K all 1) increased carrier affinity for 5
      formyltetrahydrofolate approximately 4-fold, 2) increased affinity for folic acid
      approximately 6- to 10-fold, 3) did not change affinity for 5
      methyltetrahydrofolate, and 4) except for E45R decreased affinity for
      methotrexate (2- to 3-fold). In contrast, mutations E45D, E45L, and E45W
      generally reduced affinity for all these folates except for folic acid. Finally,
      chloride-dependent influx was only noted in the E45R mutant. These data further
      substantiate the important role that glutamate-45 plays in the selectivity of
      binding of folates to RFC1 and establish that it is the addition of a positive
      charge at this site and not the loss of a negative charge that results in the
      induced anion dependence. These and other studies indicate that mutations in the
      first transmembrane domain can have a markedly selective impact on the affinity
      of RFC1 for folate compounds and in particularly a highly salutary effect on
      binding of the oxidized folate, folic acid.

PMID- 10648642
TI  - Basic fibroblast growth factor sensitizes NIH 3T3 cells to apoptosis induced by
      cisplatin.
AB  - One mechanism by which chemotherapeutic agents kill tumor cells is by induction
      of apoptosis. Basic fibroblast growth factor (bFGF/FGF-2) has been reported to
      inhibit apoptosis in NIH 3T3 cells treated with chemotherapy drugs. We have
      investigated how bFGF modulates apoptosis induced by cisplatin in NIH 3T3 cells.
      Treatment with 10 microgram/ml cisplatin for 12 h induced apoptosis in 2 to 13%
      of the cells at 24 h post-treatment. Preincubation with 10 ng/ml bFGF for 24 h
      led to cisplatin-induced apoptosis in 20% to 50% of the cells. Preincubation with
      lower concentrations of bFGF (0.1-1 ng/ml) or simultaneous addition of bFGF and
      cisplatin had no effect on the amount of apoptosis. Pretreatment with bFGF also
      significantly decreased the dose-dependent survival of NIH 3T3 cells exposed to
      cisplatin, as determined by colony formation. Cells treated with 10 ng/ml bFGF
      showed a distinct morphology, appearing smaller and more refractile, before
      cisplatin exposure. The enhancement of cisplatin-induced apoptosis and the
      morphology shift demonstrated the same dose response to bFGF, and both effects
      were reversible if bFGF was removed from the medium for 24 h before cisplatin
      treatment. Mitogenic response to bFGF by NIH 3T3 cells saturated at 0.5 ng/ml, as
      measured by (3)H-thymidine uptake, and this response was blocked by coaddition of
      suramin, an inhibitor of FGF ligand-receptor interactions. Suramin did not
      reverse the enhancement of cisplatin-induced apoptosis by bFGF. Therefore, bFGF
      sensitized NIH 3T3 cells to cisplatin, and this effect might be mediated through
      a pathway separate from that used for mitogenic signaling.

PMID- 10648643
TI  - Eosine-induced blockade of N-methyl-D-aspartate channels in acutely isolated rat
      hippocampal neurons.
AB  - Acutely isolated rat hippocampal neurons were voltage-clamped in the whole-cell
      configuration. The currents through N-methyl-D-aspartate (NMDA) channels were
      elicited by fast application of aspartate in a Mg(2+)-free 3 microM glycine
      containing solution. Eosine, known as a potent reversible inhibitor of the plasma
      membrane Ca(2+) pump, proved to be able to induce a blockade of NMDA channels.
      The eosine-induced inhibition of NMDA-mediated currents enhanced with eosine
      concentration (IC(50) = 248 microM) but did not depend on the membrane potential,
      agonist (aspartate) or coagonist (glycine) concentrations, pH, or the presence of
      spermine, ethanol, and the disulfide-reducing agents dithiothreitol and
      glutathione. Zn(2+) inhibited NMDA channels with equal efficiency both in the
      presence and absence of eosine. These results suggest that eosine interacts with
      a new, previously unknown NMDA receptor regulatory site.

PMID- 10648644
TI  - Alterations in subunit expression, composition, and phosphorylation of striatal N
      methyl-D-aspartate glutamate receptors in a rat 6-hydroxydopamine model of
      Parkinson's disease.
AB  - Recent evidence has linked striatal N-methyl-D-aspartate (NMDA) receptor function
      to the adverse effects of long-term dopaminergic treatment in Parkinson's
      disease. We have studied the abundance, composition, and phosphorylation of NMDA
      receptor subunits (NRs) in the rat 6-hydroxydopamine lesion model of
      parkinsonism. In lesioned striatum, the abundance of NR1 and NR2B in striatal
      membranes was decreased to 68 +/- 3.2 and 62 +/- 4.4%, respectively, relative to
      the unlesioned striata, whereas the abundance of NR2A was unchanged.
      Coimmunoprecipitation of NMDA receptors under nondenaturing conditions revealed
      that these changes reflected a selective depletion of receptors composed of
      NR1/NR2B, without alteration in receptors composed of NR1/NR2A. However, the
      abundance and composition of striatal NMDA receptors in extracts containing both
      cytoplasmic and membrane proteins were not altered in lesioned rats, suggesting
      that the changes in the membrane fraction resulted from intracellular
      redistribution of receptors. The phosphorylation of NR1 protein at serine 890 and
      serine 896, but not at serine 897, and the tyrosine phosphorylation of NR2B but
      not NR2A were decreased in the membrane fraction of the lesioned striatum.
      Chronic treatment of lesioned rats with L-dopa normalized the alterations in the
      abundance and subunit composition of the NMDA receptors in striatal membranes,
      and produced striking hyperphosphorylation, both of NR1 at serine residues, and
      NR2A and NR2B at tyrosine residues. These findings suggest that the adverse motor
      effects of chronic L-dopa therapy may result from alterations in regulatory
      phosphorylation sites on NMDA receptors.

PMID- 10648645
TI  - Differential regulation of prostaglandin F(2alpha) receptor isoforms by protein
      kinase C.
AB  - Prostaglandin F(2alpha) receptors (FP) are G protein-coupled receptors that bind
      prostaglandin F(2alpha) (PGF(2alpha)), resulting in the activation of an inositol
      phosphate (IP) second messenger pathway. Alternative mRNA splicing generates two
      FP receptor isoforms. These isoforms, designated FP(A) and FP(B), are otherwise
      identical except for their carboxyl termini. FP(B) is essentially a truncated
      version of FP(A) that lacks the 46 carboxyl-terminal amino acids, including four
      putative protein kinase C (PKC) phosphorylation sites. Until now, functional
      differences between these FP receptor isoforms have not been identified. We now
      report that pretreatment with the PKC inhibitor bisindolylmaleimide I enhanced
      PGF(2alpha)-stimulated IP accumulation in transfected cells stably expressing the
      FP(A) isoform but not in cells stably expressing the FP(B) isoform. Whole-cell
      phosphorylation experiments showed a strong agonist-dependent phosphorylation of
      the FP(A) isoform but little or no phosphorylation of the FP(B). Pretreatment of
      cells with bisindolylmaleimide I decreased PGF(2alpha)-stimulated phosphorylation
      of the FP(A) isoform consistent with a PKC-dependent phosphorylation. In vitro
      phosphorylation of an FP(A) carboxyl-terminal fusion protein by recombinant
      PKCalpha showed that the carboxyl terminus of the FP(A) is a substrate for PKC.
      These results suggest that PKC-dependent phosphorylation is responsible for
      differential regulation of second messenger signaling by FP prostanoid receptor
      isoforms.

PMID- 10648646
TI  - Drug-resistant variants of Escherichia coli thymidylate synthase: effects of
      substitutions at Pro-254.
AB  - Drug-resistant variants of thymidylate synthase (TS) can potentially be used in
      gene therapy applications to decrease the myelosuppressive side effects of TS
      directed anticancer agents or to select genetically modified cells in vivo.
      Mutations of proline 303 of human TS confer resistance to TS-directed
      fluoropyrimidines and antifolates (). We generated the corresponding variants in
      Escherichia coli TS (ecTS), position 254, to better understand the mechanism by
      which mutations at this residue confer resistance. In addition, because ecTS is
      intrinsically resistant to several antifolates when compared with human TS, we
      suspected that greater resistance could be achieved with the bacterial enzyme.
      The P254L enzyme conferred >100-fold resistance to both raltitrexed and 5-fluoro
      2'-deoxyuridine (FdUrd) compared with wild-type ecTS. Four additional mutants
      (P254F, P254S, P254G, and P254D), each of which complemented growth of a TS
      deficient cell line, were generated, isolated, and characterized. Steady-state
      values of K(m) for dUMP and k(cat) were not substantially different among the
      variants and were comparable with the wild-type values, but K(m) for
      methylenetetrahydrofolate (CH(2)H(4)PteGlu) was >10-fold higher for P254D. Values
      of k(on) and k(off) for nucleotide binding, which were obtained by stopped-flow
      spectroscopy, were virtually unchanged among the mutants. Drastic differences
      were observed for CH(2)H(4)PteGlu binding, with K(d) values >15-fold higher than
      observed with the wild-type enzyme; surprisingly, the proposed isomerization
      reaction that is very evident for the wild-type enzyme is not observed with
      P254S. The decrease in affinity for CH(2)H(4)PteGlu correlates well with K(i)
      values obtained for three TS-directed inhibitors. These results show that
      mutations at Pro-254 specifically affect the initial binding interactions between
      enzyme and cofactor and also alter the ability of the mutant enzymes to undergo
      conformational changes that occur on ternary complex formation. The crystal
      structure of P254S was determined at 1.5 A resolution and is the most precise
      structure of TS available. When compared with wild-type TS, the structure shows
      local conformational changes affecting mostly Asp-253; its carbonyl is rotated
      approximately 40 degrees, and the side chain forms an ion pair with Arg-225.

PMID- 10648647
TI  - Molecular determinant of high-affinity dofetilide binding to HERG1 expressed in
      Xenopus oocytes: involvement of S6 sites.
AB  - This study reports that the affinity of HERG1 A for dofetilide is decreased from
      0.125 +/- 0.003 microM for wild-type (WT) channels to 15 +/- 3 microM for F656V,
      a mutation in the COOH-terminal half of the S6. Similarly, the IC(50) for
      quinidine was increased from 8 +/- 4 microM for WT to 219 +/- 65 microM for the
      F656V mutation, whereas affinity for external tetraethylammonium was similar for
      WT (51 +/- 10 mM) and F656V (36 +/- 10 mM, NS). Kinetics of onset of inactivation
      of F656V was similar to WT but kinetics of deactivation, activation, and recovery
      from inactivation differed from WT. However, mutations in nearby amino acids in
      the S6 more strikingly altered deactivation, activation, and recovery from
      inactivation but had little effect on affinity for dofetilide. To assess the
      effects of disruption of inactivation, the S631A mutation was made. The S631A
      mutation altered the IC(50) for dofetilide to 20 +/- 3 microM, but the IC(50) for
      quinidine was unchanged at 8 +/- 4 microM for WT and 10 +/- 1 microM for S631A.
      To address whether the F656V mutation alters the IC(50) for dofetilide in a
      channel that does not inactivate, the double mutation S631A/F656V was made. The
      IC(50) for dofetilide of the double mutation was 32 +/- 3 microM, which is not
      substantially different than that of S631A. These data support the notion that
      allosteric changes occurring during the process of inactivation are necessary for
      high-affinity dofetilide binding. In conclusion, the Phe-656 residue of HERG is a
      molecular determinant of high-affinity dofetilide binding.

PMID- 10648648
TI  - The impact of functional vitamin D(3) receptor conformations on DNA-dependent
      vitamin D(3) signaling.
AB  - The vitamin D(3) receptor (VDR) is the nuclear receptor for 1alpha, 25
      dihydroxyvitamin D(3) (VD) that acts primarily as a heterodimer with the retinoid
      X receptor (RXR) on different types of VD response elements, i.e., DNA-bound VDR
      RXR heterodimers are the molecular switches in nuclear VD signaling pathways. In
      this study, DNA-dependent limited protease digestion assays and gel shift
      clipping assays were used for the analysis of VDR conformations and showed the
      same high ligand sensitivity for VD response element-bound VDR-RXR heterodimers
      (EC(50) of 0.1 nM for VD). In contrast, DNA-independent limited protease
      digestion assays clearly demonstrated a reduced ligand sensitivity for monomeric
      VDR in solution. Interestingly, the relative amount of reduction was found to be
      specific for each VDR agonist. Moreover, complex formation of the VDR on DNA
      resulted in a shift from the receptor's low-affinity ligand binding conformation
      (c3(LPD)) to its high affinity conformation (c1(LPD)). Finally, the
      characterization of the conformations of N- and C-terminally truncated VDR
      proteins defined the high-affinity ligand binding domain of the VDR as being
      positioned between amino acids 128 and 427. Taken together, the analysis of VDR
      conformations in solution in comparison to those of DNA-complexed VDR-RXR
      heterodimers allows a differentiation to be drawn between DNA-dependent and DNA
      independent VD signaling pathways that can in turn be used for the identification
      of pathway selective VDR agonists.

PMID- 10648649
TI  - A designed peptidomimetic agonistic ligand of TrkA nerve growth factor receptors.
AB  - A proteolytically stable small molecule beta-turn peptidomimetic, termed D3, was
      identified as an agonist of the TrkA neurotrophin receptor. D3 binds the Ig-like
      C2 region of the extracellular domain of TrkA, competes the binding of another
      TrkA agonist, affords selective trophic protection to TrkA-expressing cell lines
      and neuronal primary cultures, and induces the differentiation of primary
      neuronal cultures. These results indicate that a small beta-turn peptidomimetic
      can activate a tyrosine kinase neurotrophin receptor that normally binds a
      relatively large protein ligand. Agents such as D3 that bind the extracellular
      domain of Trk receptors will be useful pharmacological agents to address
      disorders where Trk receptors play a role, by targeting populations selectively.

PMID- 10648650
TI  - Selective block of late currents in the DeltaKPQ Na(+) channel mutant by
      pilsicainide and lidocaine with distinct mechanisms.
AB  - The congenital long QT syndrome is an inherited disorder characterized by a delay
      in cardiac repolarization, leading to lethal cardiac arrhythmias such as torsade
      de pointes. One form of this disease involves mutations in the voltage-dependent
      cardiac Na(+) channel, which includes an in-frame deletion of three amino acids
      (Lys-1505, Pro-1506, and Gln-1507; DeltaKPQ). The potential for selective
      suppression of the mutant was examined by heterologous expression of DeltaKPQ
      Na(+) channels in Chinese hamster fibroblast cells via single-channel recording.
      In a single-channel cell-attached patch study, DeltaKPQ-Na(+) channels yielded
      currents that peaked at approximately 1 ms after voltage steps to 0 mV with
      aberrant late currents, which were composed of burst and isolated openings. The
      affinity of certain anesthetics (pilsicainide and lidocaine) to the late currents
      of the mutant channels was examined. It was revealed that 1) pilsicainide (1
      microM), an open channel blocker of voltage-dependent Na(+) channels, remarkably
      decreased the late currents primarily by the shortening of burst duration without
      suppressing the initial peak current; and 2) lidocaine (1 microM), an inactivated
      channel blocker, decreased the late currents primarily by the suppression of
      isolated channel openings. Because the late currents in DeltaKPQ mutants are
      mainly composed of the burst openings, we conclude that pilsicainide is capable
      of selectively blocking the late currents in the mutant Na(+) channels that show
      dominant abnormal burst openings such as in DeltaKPQ mutants.

PMID- 10648651
TI  - Post-transcriptional regulation of mouse kappa-opioid receptor expression.
AB  - Three mRNA variants are generated from the mouse kappa-opioid receptor (KOR)
      gene. The expression patterns of these KOR mRNA variants in adult animal tissues
      and during developmental stages are examined. Furthermore, the biological
      significance of generating these variants is demonstrated with respect to two
      post-transcriptional mechanisms, i.e., mRNA stability and translation efficiency.
      Variants A and B are both transcribed from promoter 1 of the KOR gene and
      expressed from early developmental stages through adult life. Although their
      sequences differ only at a 30-nucleotide insertion for variant B, these two
      variants are distinct with regard to their expression patterns, mRNA stability,
      and translation efficiency. Variant A is expressed ubiquitously in all the
      tissues examined and has a longer t(1/2) (12 h), whereas variant B is more
      specific to the central nervous system both pre- and postnatally and has a t(1/2)
      of approximately 8 h. Variant C is transcribed from promoter 2 of the KOR gene
      and is most specifically expressed, being detected only in the brain stem, spinal
      cord, and thalamic/hypothalamic areas of postnatal animals. With regard to
      protein translation, variants B and C are significantly more efficient than
      variant A. This study provides the evidence for multiple levels of KOR
      regulation. The biological implication of the generation of KOR mRNA variants is
      discussed.

PMID- 10648652
TI  - Huprine X is a novel high-affinity inhibitor of acetylcholinesterase that is of
      interest for treatment of Alzheimer's disease.
AB  - Inhibitors of the enzyme acetylcholinesterase (AChE) slow and sometimes reverse
      the cognitive decline experienced by individuals with Alzheimer's disease.
      Huperzine A, a natural product used in traditional Chinese herbal medicine, and
      tacrine (Cognex) are among the potent AChE inhibitors used in this treatment, but
      the search for more selective inhibitors continues. We report herein the
      synthesis and characterization of (-)-12-amino-3-chloro-9-ethyl-6,7, 10,11
      tetrahydro-7,11-methanocycloocta[b]quinoline hydrochloride (huprine X), a hybrid
      that combines the carbobicyclic substructure of huperzine A with the 4
      aminoquinoline substructure of tacrine. Huprine X inhibited human AChE with an
      inhibition constant K(I) of 26 pM, indicating that it binds to this enzyme with
      one of the highest affinities yet reported. Under equivalent assay conditions,
      this affinity was 180 times that of huperzine A, 1200 times that of tacrine, and
      40 times that of E2020 (donepezil, Aricept), the most selective AChE inhibitor
      currently approved for therapeutic use. The association and dissociation rate
      constants for huprine X with AChE were determined, and the location of its
      binding site on the enzyme was probed in competition studies with the peripheral
      site inhibitor propidium and the acylation site inhibitor edrophonium. Huprine X
      showed no detectable affinity for the edrophonium-AChE complex. In contrast,
      huprine X did form a ternary complex with propidium and AChE, although its
      affinity for the free enzyme was found to be 17 times its affinity for the
      propidium-AChE complex. These data indicated that huprine X binds to the enzyme
      acylation site in the active site gorge but interferes slightly with the binding
      of peripheral site ligands.

PMID- 10648653
TI  - Functional genomics in nephrology.

PMID- 10648654
TI  - Calcium-mediated proximal tubular injury-what is the role of cysteine proteases?

PMID- 10648655
TI  - When insufficient arterial inflow becomes the Achilles heel of the av-fistula
      what are the surgical approaches?

PMID- 10648656
TI  - Early referral and selection of peritoneal dialysis as a treatment modality.

PMID- 10648657
TI  - Chronic allograft nephropathy-a model of impaired repair from injury?

PMID- 10648658
TI  - Acute renal failure in Central Anatolia.
AB  - BACKGROUND: The aetiological spectrum of acute renal failure (ARF) has changed in
      developed countries. It was the purpose of the study to evaluate whether similar
      changes have occurred in this part of the world as well. METHODS: In a
      prospective study a total of 439 patients with ARF were evaluated. They had been
      admitted to one hospital during two successive periods, i.e. 1983-1990 and 1991
      1997. RESULTS: Of 439 patients with ARF, 116 were admitted in 1983-1990 (first
      period) and 323 in 1991-1997 (second period). The age of presentation increased
      from 49.8+/-6.2 years in the first period to 58.8+/-16.4 years in the second.
      Medical causes were present in 259 cases (59%), surgical causes in 110 cases
      (25%), and obstetric causes in 70 cases (16%). The frequency of surgical cases
      decreased from 28.4% in the first period to 23.8% in the second period. The
      respective figures for obstetric cases were 18.9% and 14.8%. Mortality did not
      change with time (33.6% in the first and 31.0% in the second period); the overall
      mortality was 31.7%. The mortality was higher for surgical (45.5%) than for
      obstetric (27.8%) and medical ARF (24.3%). CONCLUSION: In the mid-1970s, the most
      common causes of ARF in Turkey were obstetric complications and septic abortion.
      The aetiological spectrum of ARF has changed and today medical causes
      predominate. ARF resulting from septic abortion has become rare, possibly because
      of liberalization of abortion in 1983 in Turkey.

PMID- 10648659
TI  - Changing pattern of end-stage renal disease in central and eastern Europe.
AB  - BACKGROUND: The epidemiology of end-stage renal disease (ESRD) is changing all
      over the world. Particularly dramatic changes of the epidemiology of ESRD have
      occurred in central and eastern Europe (CEE). The aim of the present study was
      (i) to document the further expansion of renal replacement therapy (RRT) noted in
      recent years in CEE and (ii) to analyse in some detail treatment modalities and
      underlying renal conditions. METHODS: Three independent surveys were performed in
      1995, 1997 and 1998. Fifteen CEE countries participated. The data were mainly
      obtained from national registries which are based on centre and patient
      questionnaires. RESULTS: The data collected from 15 CEE countries document
      further expansion of RRT in this region. The report includes data on the
      availability of RRT in Byelorussia, Estonia, and Russia which have become
      available for the first time. The epidemiology of dialysed patients has changed
      remarkably. In the majority of countries the number of diabetic patients has
      increased, most dramatically so in the Czech Republic (31% of all dialysed
      patients), in the majority of the other countries 10-14%. The number of ESRD
      patients with the diagnosis of hypertensive nephropathy has also increased and
      this was accompanied by an increase in proportion of elderly (>65 years)
      patients, i.e. 46% in the Czech Republic and 12-25% in most other countries.
      CONCLUSION: Dramatic changes of the availability of RRT treatment have occurred
      in central and eastern Europe. The proportion of diabetic nephropathy and elderly
      patients has risen. Large differences in RRT exist between individual CEE
      countries and this appears mainly dependent on the level of economic development.

PMID- 10648660
TI  - Cholesterol feeding activates macrophages to upregulate rat mesangial cell
      fibronectin production.
AB  - BACKGROUND: Cholesterol feeding has been shown to accelerate the development of
      glomerulosclerosis in many experimental renal diseases, possibly by promoting the
      infiltration of macrophages into the glomerulus. METHODS: In order to assess
      whether hyperlipidaemia could directly modulate macrophage function to promote
      glomerulosclerosis, confluent quiescent mesangial cells were exposed to resident
      (r) or elicited (e) macrophages, from either control (C) or cholesterol-fed (HC)
      rats or the conditioned media derived from the various macrophage preparations.
      RESULTS: All macrophage preparations stimulated mesangial cell fibronectin
      accumulation over medium alone, but eHC macrophages stimulated significantly
      greater fibronectin levels. Similarly, all macrophage conditioned media (MPCM)
      stimulated mesangial cell fibronectin production over medium alone and again the
      effect was greatest with MPCM derived from eHC macrophages. Proliferation studies
      using [(3)H]thymidine incorporation demonstrated that all conditioned media, with
      the exception of rC, stimulated significant mesangial cell proliferation over
      control levels. TGF-beta and PDGF, pro-fibrogenic growth factors known to be
      associated with macrophage infiltration, could not be detected in the MPCMs per
      se. However, they were detected in the culture supernatants of mesangial cells
      exposed to MPCMs and again secretion was greatest from mesangial cells exposed to
      eHC-MCPM. CONCLUSION: Monocytes are systemically activated by high serum
      cholesterol levels so that following maturation to macrophages they elaborate
      soluble factors that can stimulate mesangial cell fibronectin production, cell
      proliferation, and growth factor secretion. Hypercholesterolaemia may therefore
      accelerate glomerulosclerosis not only by increasing macrophage number, but also
      by upregulating the ability of macrophages to induce pro-sclerotic responses in
      glomerular mesangial cells.

PMID- 10648661
TI  - Low-density lipoprotein stimulates mesangial cell proteoglycan and hyaluronan
      synthesis.
AB  - BACKGROUND: Hyperlipidaemia leads to glomerulosclerosis in small mammals and may
      contribute to progressive renal disease in man. One prominent feature of lipid
      induced glomerular injury in animal models is the accumulation of mesangial
      matrix. These studies were designed to investigate whether low-density
      lipoprotein (LDL) enhanced mesangial cell (MC) matrix deposition by modulating
      the production of proteoglycans (PG) and hyaluronan (HA). METHODS: Growth
      arrested human MC were metabolically labelled with either 50 microCi/ml
      Na(2)[(35)S]sulphate or 25 microCi/ml [(3)H]glucosamine and stimulated with LDL
      (10-100 microg/ml). The radiolabelled PG and HA extracted from the cell layer and
      the culture medium were isolated, quantified and characterized. Comparison of the
      PG core proteins synthesized by MC was carried out using Western blot analysis.
      RESULTS: LDL stimulation led to a dose- and time-dependent increase in
      [(35)S]sulphate incorporation into PG in the culture medium and to a lesser
      extent in the cell layer. Analysis of the glycosaminoglycan (GAG) chains showed
      no difference in either their size or charge. Enzyme digestion studies
      demonstrated that the synthesis of both chondroitin sulphate PG (CSPG) and
      heparan sulphate PG (HSPG) was enhanced as was the production of the core
      proteins of versican (a large CSPG), perlecan (a basement membrane HSPG) and to a
      lesser extent decorin (a small dermatan sulphate PG (DSPG)). An increase in HA
      synthesis was also demonstrated in [(3)H]glucosamine labelled cells following LDL
      stimulation. CONCLUSION: LDL selectively enhances the synthesis of specific PG
      and HA by mesangial cells. Such effects may contribute to the expansion of the
      mesangial matrix and modify cell-matrix interactions in lipid-induced renal
      damage.

PMID- 10648664
TI  - Immunoelectron microscopic study on type I, II and III TGF-beta receptors on
      visceral glomerular epithelial cells in relation to glomerular basement membrane
      alterations in proteinuric rats.
AB  - BACKGROUND: Transforming growth factor (TGF)-beta is a regulator of extracellular
      matrix accumulation. Both TGF-beta receptors, type I (TbetaRI) and type II
      (TbetaRII), may be required for signal transduction in the TGF-beta pathway. The
      aim of this study was to investigate the relationship between the TGF-beta
      pathways and glomerular basement membrane (GBM) accumulation in vivo. METHODS: We
      examined TbetaRI, II, and III protein expression on visceral glomerular
      epithelial cells (GEP) in relation to GBM alterations in passive Heymann
      nephritis (PHN), anti-GBM nephritis and anti-thymocyte serum (ATS) nephritis.
      Renal tissues were examined by pre-embedding immunoelectron microscopy 3, 7 and
      14 days after induction of nephritis in rats. RESULTS: In normal control rats
      TbetaRI was not detected on GEP, TbetaRII expression was very occasionally found
      on GEP and TbetaRIII was seen in the cytoplasm of the GEP. TbetaRI, TbetaRII, and
      TbetaRIII were constitutively expressed on glomerular endothelial cells. By day 3
      of anti-GBM nephritis and PHN, expression of TbetaRI, TbetaRII, and TbetaRIII was
      still similar to that of normal control rats, and GBM alterations in both models
      were not prominent except for deposit formation in PHN. From day 7 onwards, in
      both models, expression of TbetaRI and TbetaRII on GEP increased in association
      with GBM thickening. Expression of TbetaRIII in the cytoplasm of the GEP was
      increased, with occasional positive staining being seen on the urinary surface of
      the GEP from day 7 onwards. On the other hand, at day 3 of ATS nephritis,
      increased expression of TbetaRI and TbetaRII on GEP was noted, but from day 7
      onwards, expression of TbetaR II on GEP dramatically decreased. Expression of
      TbetaRIII in the cytoplasm of the GEP also transiently increased at day 3. GBM
      thickening was not noted in ATS nephritis. CONCLUSIONS: The results suggest that
      persistent upregulation of expression of TbetaRI, TbetaRII and possibly TbetaRIII
      on GEP may contribute to GBM matrix accumulation in vivo.

PMID- 10648663
TI  - Effects of mycophenolic acid on human renal proximal and distal tubular cells in
      vitro.
AB  - BACKGROUND: Mycophenolic acid has been shown to be effective for the prevention
      and treatment of renal allograft rejection. Rejection episodes were found to be
      associated with an infiltration of lymphocytes and macrophages/monocytes into the
      diseased kidney. Expression of RANTES, HLA-DR and ICAM-1 may be important for the
      pathogenesis of this leukocyte infiltration. Therefore the aim of this study was
      to evaluate the effect of the antiproliferative and immunosuppressive agent
      mycophenolic acid (MPA) on cell growth and cytokine-induced expression of RANTES,
      HLA-DR and ICAM-1 of highly purified proximal (PTC) and distal tubular cells
      (DTC) from human kidney. METHODS: Human PTC and DTC were cultured in the presence
      of different concentrations of MPA (0.25-50 microM) or MPA plus guanosine (100
      microM). Total cell number (DNA content) was determined after 4 days of cell
      culture by a non-radioactive fluorescence assay. Cells were stimulated by a
      combination of cytokines (IL1beta+gammaIFN+TNFalpha=cytomix) or cytomix plus MPA.
      Secretion of RANTES protein was evaluated with an enzyme-linked-immunosorbent
      assay. Cell surface expression of HLA-DR and ICAM-1 was assessed by flow
      cytometric analysis. RESULTS: MPA inhibited cell growth of PTC and DTC in a dose
      dependent manner. This effect was totally abolished by the addition of guanosine.
      Cytokine-induced RANTES expression was synergistically increased in the presence
      of MPA, an effect that was partially prevented by the addition of guanosine.
      Cytokine stimulation resulted in de novo expression of HLA-DR and a marked
      increase of ICAM-1 expression, which was partially inhibited by dexamethasone.
      Addition of MPA did not influence this stimulated expression. CONCLUSIONS: We
      demonstrate that MPA has an effect on cell growth and chemokine release of
      tubular epithelial cells, and that these effects are dependent on the inhibition
      of cellular guanosine production. The clinical consequences of this possible pro
      inflammatory effect of MPA on RANTES release may be abolished by a concomitant
      treatment with steroids.

PMID- 10648662
TI  - Inflammatory mediators in human renal dysplasia.
AB  - BACKGROUND: Cytokines regulate many processes in the immune system and have
      recently been implicated in normal organogenesis. We previously demonstrated that
      the archetypal inflammatory cytokine tumour necrosis factor-alpha (TNF-alpha) is
      expressed in the murine metanephros, and exogenous TNF-alpha inhibits
      nephrogenesis and increases macrophage numbers in vitro (Cale et al., Int J Dev
      Biol 1998; 42: 663-674). The phenotype seen, with an arrest of ureteric bud
      branching and failure of mesenchymal to epithelial conversion, is similar to
      human renal dysplasia. Methods and results. In normal human fetal kidneys we
      demonstrated the presence of macrophages and T cells and also documented TNF
      receptor expression on ureteric bud derivatives. In contrast to normal tissues,
      TNF-alpha protein was detected in dysplastic kidneys. This factor was also
      detected in the urine of fetuses with obstructive uropathy and TNF receptors were
      expressed in dysplastic tubules. Furthermore, we noted a fetal distribution of
      macrophages and T cells in dysplastic tissues and persistent expression of the
      adhesion molecules neural cell adhesion molecule and intercellular adhesion
      molecule. CONCLUSIONS: We suggest that abnormal expression of cytokines early in
      renal development dysregulates normal patterns of adhesion molecule expression
      and inflammatory cells, and may contribute to the pathogenesis of renal
      dysplasia.

PMID- 10648665
TI  - The diagnostic yield of intravenous urography.
AB  - BACKGROUND: Intravenous urography (IVU) is considered an integral imaging
      component of the nephro-urological work-up in a wide array of clinical settings.
      At our institution there is an open-access policy with regard to requesting IVU
      studies. METHODS: In a prospective, blinded observational study we undertook to
      assess the diagnostic yield of IVU with respect to the source of referral (i.e.
      Urology, Nephrology, GP, A & E, other speciality) and the presenting features,
      such as renal colic, haematuria, bladder outflow obstruction, recurrent urinary
      tract infection (UTI) etc. Two hundred consecutive patients were evaluated.
      RESULTS: Overall, 23% of tests were positive. There was a highly significant
      difference in diagnostic yield between the groups (P<0.001 for both referral
      source and test indication). A positive result was most likely after referral by
      a kidney specialist (37.1%) and when the test indication was renal colic (42%) or
      haematuria (32%). The yield was <15% in all other circumstances, with 94.9% and
      92.1% of GP- and other hospital speciality-initiated IVUs being negative. When
      investigating recurrent UTI, 91.7% of tests were negative and 86.2% were negative
      when the indication was bladder outflow obstruction. CONCLUSIONS: It is suggested
      that an open access policy for IVU is not justified, especially when cost and the
      risk associated with contrast media and radiation exposure are taken into
      account. Our study supports the abandonment of routine IVU in the investigation
      of UTI and bladder outflow obstruction.

PMID- 10648666
TI  - Autosomal dominant polycystic kidney disease-type 2. Ultrasound, genetic and
      clinical correlations.
AB  - BACKGROUND: Ultrasound, genetic and clinical correlations are available for ADPKD
      1, but lacking for ADPKD-2. The present study was carried out to address: (i) the
      age-related diagnostic usefulness of ultrasound compared with genetic linkage
      studies; (ii) the age-related incidence and prevalence of relevant symptoms and
      complications; and (iii) the age and causes of death in patients with ADPKD-2.
      METHODS: Two hundred and eleven alive subjects, from three ADPKD-2 families at
      50% risk, were evaluated by physical examination, consultation of hospital
      records, biochemical parameters, ultrasound and with genetic linkage and DNA
      mutation analyses. Nineteen deceased and affected family members were also
      included in the study. RESULTS: Of the 211 alive members, DNA linkage studies and
      direct mutation analyses showed that 106 were affected and 105 were not.
      Ultrasound indicated 94 affected, 108 not affected and nine equivocal results in
      nine children under the age of 15. For all ages, the false-positive diagnostic
      rate for ultrasound was 7.5% and the false-negative rate was 12.9%. The
      difference between ultrasound and DNA findings was most evident in children aged
      5-14 years where the ultrasound was correct in only 50% and wrong or inconclusive
      in the remaining 50%. The mean age of the 106 alive, ADPKD-2 genetically affected
      patients was 37.9 years (range: 6-66 years). Among them, 23.5% had experienced
      episodes of renal pain, 22.6% were treated for hypertension, 22.6% had
      experienced at least one urinary tract infection, 19.8% had nephrolithiasis,
      11.3% had at least one episode of haematuria, 9.4% had asymptomatic liver cysts,
      7.5% had developed chronic renal failure and 0.9% had reached end-stage renal
      failure. Of the 19 deceased members, nine died before reaching end-stage renal
      failure at a mean age of 58.7 years (range: 40-68 years), mainly due to vascular
      complications, while the remaining 10 died on haemodialysis at a mean age of 71.4
      years (range: 66-82 years). CONCLUSIONS: DNA analysis is the gold standard for
      the diagnosis of ADPKD-2, especially in young people. Ultrasound diagnosis is
      highly dependent on age. Under the age of 14, ultrasound is not recommended as a
      routine diagnostic procedure, but ultrasound becomes 100% reliable in excluding
      ADPKD-2 in family members at 50% risk, over the age of 30. ADPKD-2 represents a
      mild variant of polycystic kidney disease with a low prevalence of symptoms and a
      late onset of end-stage renal failure.

PMID- 10648667
TI  - Treatment-related acute renal failure in the elderly: a hospital-based
      prospective study.
AB  - BACKGROUND: Elderly individuals need a host of diagnostic procedures and
      therapeutic interventions to take care of ailments. This prospective study was
      carried out to determine the magnitude of treatment-related acute renal failure
      (ARF) in the elderly in a hospital setting, to know about pathogenetic factors
      and to study the factors that could predict an adverse outcome. METHODS: All
      elderly patients (>60 years) admitted over a 12-month period were screened
      prospectively throughout their hospital stay for the development of ARF. RESULTS:
      Of 31860 patients admitted, 4176 (13%) were elderly. Of these 59 (1.4%) developed
      ARF in the hospital. Nephrotoxic drugs contributed towards development of ARF in
      39 (66%), sepsis and hypoperfusion in 27 (45.7%) each, contrast medium in 10
      (16.9%) and postoperative ARF occurred in 15 (25.4%) patients. These pathogenetic
      factors were responsible for ARF in different combinations. Amongst these
      combination of pathogenetic factors, radiocontrast administration (partial chi(2)
      28.1, P<0.0001), surgery (partial chi(2) 14.89, P=0.001), and drugs (partial
      chi(2) 6. 22, P=0.0126) predicted ARF on their own. Nine patients (15.23%) needed
      dialytic support. Of 59 patients, 15 (25.4%) died, of those who survived, 38
      (86.3%) recovered renal function completely and six (13.6%) partially. Mortality
      in the elderly with ARF was significantly higher than in those without ARF (25.4
      vs 12.5%; chi(2) 8.3, P=0.03). Sepsis (odds ratio 43), oliguria (odds ratio 64),
      and hypotension (odds ratio 15) were independent predictors of poor patient
      outcome on logistic regression analysis. CONCLUSION: Incidence of treatment
      related ARF in the elderly was 1.4%, with more than one pathogenetic factor
      playing a role in the development of ARF in the majority. Sepsis, hypotension,
      and oliguria were the independent predictors of poor patient outcome.

PMID- 10648668
TI  - Morphology of coronary atherosclerotic lesions in patients with end-stage renal
      failure.
AB  - BACKGROUND: An excessive rate of cardiac death is a well-known feature of renal
      failure. Coronary heart disease is frequent and the possibility has been raised
      that the natural history of the coronary plaque is different in uraemic patients.
      We assessed the morphology of coronary arteries in patients with end-stage renal
      failure and compared them with coronary arteries of matched non-uraemic control
      patients. METHODS: Fifty-four cases were identified at autopsy who met the
      inclusion criteria: cases, end-stage renal disease (n=27); controls, non-renal
      patients with coronary artery disease (n=27). At autopsy all three coronary
      arteries were prepared at corresponding sites for investigations: (i) qualitative
      analysis (after Stary), (ii) quantitative measurements of intima and media
      thickness (by planimetry), (iii) immunohistochemical analysis of the coronary
      plaques and (iv) X-ray diffraction of selected calcified plaques. RESULTS:
      Qualitative analysis of the coronary arteries showed significantly more calcified
      plaques of coronary arteries in patients with end-stage renal failure. Plaques of
      non-uraemic patients were mostly fibroatheromatous. Media thickness of coronary
      arteries was significantly higher in uraemic patients (187+/-53 microm vs 135+/
      29 microm in controls) and intima thickness tended to be higher (158+/-38 microm
      vs 142+/-31 microm) but this difference was not statistically significant. Plaque
      area (4.09+/-1. 50 mm(2) vs 4.39+/-0.88 mm(2)) was comparable in both groups.
      Lumen area, however, was significantly lower in end-stage renal patients.
      Immunohistochemical analysis of the cellular infiltrate in coronary arteries
      showed no major differences in these advanced plaques of uraemic and non-uraemic
      subjects. CONCLUSION: Coronary plaques in patients with end-stage renal failure
      are characterized by increased media thickness and marked calcification. In
      contrast to the previous opinion the most marked difference compared to non
      uraemic controls does not concern the size, but the composition of the plaque.
      Deposition of calcium within the plaques may contribute to the high complication
      rate in uraemic patients.

PMID- 10648669
TI  - Comparison of cellulose diacetate and polysulfone membranes in the outcome of
      acute renal failure. A prospective randomized study.
AB  - BACKGROUND: Whether the nature of haemodialysis (HD) membranes can influence the
      outcome of acute renal failure (ARF) remains debatable. Recent studies have
      suggested that dialysis with bioincompatible unsubstituted cellulosic membranes
      is associated with a less favourable patient outcome than dialysis with
      biocompatible synthetic membranes. Since we generally use a modified cellulosic
      membrane with substantially lower complement- and leukocyte-activating potential
      than cuprophane, for dialysis of patients with ARF, and because there are no data
      in the literature regarding the influence of modified cellulosic membranes on the
      outcome of patients with ARF, we compared the outcome of ARF patients dialysed
      either with cellulose diacetate or with a synthetic polysulfone membrane. We also
      investigated the potential role of permeability by comparing membranes with high
      flux versus low-flux characteristics. METHODS: This prospective, randomized,
      single centre study included 159 patients with ARF requiring HD. Patients were
      stratified according to age, gender, and APACHE II score and then randomized in
      chronological order to one of three dialysis membranes: low-flux polysulfone,
      high-flux polysulfone and meltspun cellulose diacetate. RESULTS: Aetiologies of
      ARF and the prevalence of oliguria were similarly distributed among the three
      groups. There was no significant difference between the three groups for survival
      (multivariate Cox's proportional hazards model, P=0.57), time necessary to
      recover renal function (P=0.82), and number of dialysis sessions required before
      recovery (P=0.86). Multivariate analysis showed that survival was significantly
      influenced only by the severity of the disease state (APACHE III score,
      P<0.0001), but not by the nature of the dialysis membrane (P=0.57) or the
      presence of oliguria (P=0.24). CONCLUSIONS: Among patients with ARF requiring HD
      survival and recovery time are not significantly influenced by the use of either
      meltspun cellulose diacetate or the more biocompatible high-flux or low-flux
      polysulfone. Dialysis using modified cellulose membranes is just as effective as
      dialysis using synthetic polysulfone membranes, but at a lower cost. In addition,
      the flux of the membrane did not influence patient outcome.

PMID- 10648670
TI  - Outpatient CAPD catheter salvage for persistent exit-site/tunnel infection.
AB  - BACKGROUND: Partial replantation (i.e. replacement of the extraperitoneal portion
      of the catheter with creation of a new subcutaneous tunnel) has been suggested to
      avoid catheter removal in patients with persistent exit-site/tunnel infection
      (ESTI). However, published experience with this technique is limited. METHODS:
      Partial replantation was performed on an outpatient basis under local anesthesia
      for seven patients with persistent ESTI of >3 months duration. All patients
      resumed CAPD immediately following surgery. RESULTS: One patient had dialysate
      leakage less than 1 week after surgery that required catheter removal. The other
      patients had no complications and mean catheter survival following surgery was 7.
      7 months (range 3.5-13 months). There was no recurrence of ESTI after surgery,
      although two patients presented with exit-site infection unrelated to the initial
      episode (i.e. different organism, long latency). Three other patients presented
      with episodes of peritonitis unrelated to surgery (i.e. delay >1 month) or ESTI
      (i.e. different organism). CONCLUSIONS: Partial replantation allows significant
      prolongation of catheter survival without major complications or interruption of
      CAPD. This novel procedure appears to be an appropriate alternative to catheter
      removal for the management of persistent ESTI. However, further studies are
      needed to prospectively compare partial replantation with catheter removal.

PMID- 10648671
TI  - Dextran sulphate cellulose columns for the treatment of nephrotic syndrome due to
      inactive lupus nephritis.

PMID- 10648672
TI  - Measurement of glomerular volume in needle biopsy specimens. The ESPRIT Study
      Group (European Study of the Progression of Renal Disease in Type 1 Diabetes).
AB  - BACKGROUND: Various methods have been used to determine mean glomerular volume,
      some requiring measurement of over 30 glomerular profiles for a satisfactory
      estimate. Needle biopsies are useful diagnostically, but if small, provide
      insufficient tissue for the use of such methods. METHODS: We performed glomerular
      volume measurements on renal biopsies from 10 normotensive, non-uraemic patients
      with Type 1 diabetes. Sections were taken at 10 microm intervals through 10
      glomeruli per biopsy and points landing on glomerular tuft counted under light
      microscopy. Volume was calculated from the measured cross-sectional area and
      known section thickness using the Cavalieri principle. RESULTS: Estimating the
      volume of 10 glomeruli per biopsy gave an overall mean glomerular volume of
      4.21x10(6) microm(3) and standard deviation between patient means 1.23x10(6)
      microm(3.) Using a sample size of five glomeruli per biopsy only increased the
      standard deviation between patient mean values by 3%. Using sections taken at 20
      microm intervals made little difference to the mean glomerular volume and
      standard deviation estimates (MGV 4.20x10(6) microm(3)+/-1.24). Further increases
      in the sectioning interval resulted in an appreciable increase in the variance of
      the estimate. CONCLUSIONS: The results suggest that a satisfactory estimate of
      mean glomerular volume can be obtained from a sample size of five glomeruli per
      biopsy using a sectioning interval of 20 microm. This represents a great saving
      in analysis time and effort, making widespread use of this method of glomerular
      volume measurement in renal disease more practicable, in both research and
      clinical settings.

PMID- 10648673
TI  - The deep circumflex iliac vein for secondary central venous access and
      haemodialysis.

PMID- 10648674
TI  - Cerebral vasculitis in Henoch-Schonlein purpura.

PMID- 10648675
TI  - A patient with hypertension was cured after resection of a renal AV fistula.

PMID- 10648676
TI  - Haemoperitoneum originating in renal cyst in a patient with ADPKD not treated by
      dialysis.

PMID- 10648677
TI  - A malnourished haemodialysis patient-a diagnostic surprise.

PMID- 10648678
TI  - Renal myelofibrosis: an unusual cause of renal impairment.

PMID- 10648679
TI  - Concealed by veils.

PMID- 10648680
TI  - Hyponatraemia in a neurosurgical patient: syndrome of inappropriate antidiuretic
      hormone secretion versus cerebral salt wasting.

PMID- 10648681
TI  - Ischaemic heart disease following renal transplantation.

PMID- 10648682
TI  - Curs educational de nefrologie bucuresti, 30 october 1999

PMID- 10648683
TI  - Professor F. Kokot, katowice, poland

PMID- 10648684
TI  - Physical symptoms and quality of life in patients on chronic dialysis: results of
      the netherlands cooperative study on adequacy of dialysis (NECOSAD)

PMID- 10648685
TI  - Regression of nephrotic syndrome due to amyloidosis secondary to familial
      mediterranean fever following colchicine treatment.

PMID- 10648686
TI  - Tuberculostatic treatment-an unusual case of renal failure.

PMID- 10648687
TI  - Increased incidence of tuberculosis in patients on renal replacement therapy in
      the last decade.

PMID- 10648688
TI  - A swollen face in a girl on haemodialysis.

PMID- 10648689
TI  - Extrapulmonary tuberculous infection manifested as peritoneal fluid eosinophilia
      in a continuous ambulatory peritoneal dialysis patient.

PMID- 10648690
TI  - Procurement of a cadaveric liver transplant from a chronically haemodialysed
      patient.

PMID- 10648691
TI  - Monitoring sialyl lewis x (CD15s) on peripheral lymphocytes for the diagnosis of
      acute rejection.

PMID- 10648692
TI  - Restoration of renal function after prolonged allograft artery occlusion by
      thrombolysis.

PMID- 10648693
TI  - Relief of G-protein inhibition of calcium channels and short-term synaptic
      facilitation in cultured hippocampal neurons.
AB  - G-protein inhibition of voltage-gated calcium channels can be transiently
      relieved by repetitive physiological stimuli. Here, we provide evidence that such
      relief of inhibition contributes to short-term synaptic plasticity in microisland
      cultured hippocampal neurons. With G-protein inhibition induced by the GABA(B)
      receptor agonist baclofen or the adenosine A1 receptor agonist 2-chloroadenosine,
      short-term synaptic facilitation emerged during action potential trains. The
      facilitation decayed with a time constant of approximately 100 msec. However,
      addition of the calcium channel inhibitor Cd(2+) at 2-3 microM had no such effect
      and did not alter baseline synaptic depression. As expected of facilitation from
      relief of channel inhibition, analysis of miniature EPSCs implicated presynaptic
      modulation, and elevating presynaptic Ca(2+) entry blunted the facilitation. Most
      telling was the near occlusion of synaptic facilitation after selective blockade
      of P/Q- but not N-type calcium channels. This was as predicted from experiments
      using recombinant calcium channels expressed in human embryonic kidney (HEK) 293
      cells; we found significantly stronger relief of G-protein inhibition in
      recombinant P/Q- versus N-type channels during action potential trains. G-protein
      inhibition in HEK 293 cells was induced via recombinant M2 muscarinic
      acetylcholine receptors activated by carbachol, an acetylcholine analog. Thus,
      relief of G-protein inhibition appears to produce a novel form of short-term
      synaptic facilitation in cultured neurons. Similar short-term synaptic plasticity
      may be present at a wide variety of synapses, as it could occur during
      autoreceptor inhibition by glutamate or GABA, heterosynaptic inhibition by GABA,
      tonic adenosine inhibition, and in many other instances.

PMID- 10648694
TI  - Effects of halothane on GABA(A) receptor kinetics: evidence for slowed agonist
      unbinding.
AB  - Many anesthetics, including the volatile agent halothane, prolong the decay of
      GABA(A) receptor-mediated IPSCs at central synapses. This effect is thought to be
      a major factor in the production of anesthesia. A variety of different kinetic
      mechanisms have been proposed for several intravenous agents, but for volatile
      agents the kinetic mechanisms underlying this change remain unknown. To address
      this question, we used rapid solution exchange techniques to apply GABA to
      recombinant GABA(A) receptors (alpha(1)beta(2)gamma(2s)) expressed in HEK 293
      cells, in the absence and presence of halothane. To differentiate between
      different microscopic kinetic steps that may be altered by the anesthetic, we
      studied a variety of measures, including peak concentration-response
      characteristics, macroscopic desensitization, recovery from desensitization,
      maximal current activation rates, and responses to the low-affinity agonist
      taurine. Experimentally observed alterations were compared with predictions based
      on a kinetic scheme that incorporated two agonist binding steps, and open and
      desensitized states. We found that, in addition to slowing deactivation after a
      brief pulse of GABA, halothane increased agonist sensitivity and slowed recovery
      from desensitization but did not alter macroscopic desensitization or maximal
      activation rate and only slightly slowed rapid deactivation after taurine
      application. This pattern of responses was found to be consistent with a
      reduction in the microscopic agonist unbinding rate (k(off)) but not with changes
      in channel gating steps, such as the channel opening rate (beta), closing rate
      (alpha), or microscopic desensitization. We conclude that halothane slows IPSC
      decay by slowing dissociation of agonist from the receptor.

PMID- 10648695
TI  - Secondary nicotinic synapses on sympathetic B neurons and their putative role in
      ganglionic amplification of activity.
AB  - The strength and number of nicotinic synapses that converge on secretomotor B
      neurons were assessed in the bullfrog by recording intracellularly from isolated
      preparations of paravertebral sympathetic ganglia 9 and 10. One input to every B
      neuron invariably produced a suprathreshold EPSP and was defined as the primary
      nicotinic synapse. In addition, 93% of the cells received one to four
      subthreshold inputs that were defined as secondary nicotinic synapses. This
      contradicts the prevailing view, which has long held that amphibian B neurons are
      singly innervated. More important, the results revealed that B cells provide the
      simplest possible experimental system for examining the role of secondary
      nicotinic synapses on sympathetic neurons. Combining the convergence data with
      previous estimates of divergence indicates that the average preganglionic B
      neuron forms connections with 50 ganglionic B neurons and that the majority of
      these nicotinic synapses are secondary in strength. Secondary EPSPs evoked by low
      frequency stimulation ranged from 0.5 to 10 mV in amplitude and had an average
      quantal content of 1. Nonetheless, secondary synapses could trigger action
      potentials via four mechanisms: spontaneous fluctuations of EPSP amplitude, two
      pulse facilitation, coactivation with other secondary synapses, and coactivation
      with a slow peptidergic EPSP. The data were used to formulate a stochastic theory
      of integration, which predicts that ganglia function as amplifiers of the
      sympathetic outflow. In this two-component scheme, primary nicotinic synapses
      mediate invariant synaptic gain, and secondary nicotinic synapses mediate
      activity-dependent synaptic gain. The model also provides a common framework for
      considering how facilitation, metabotropic mechanisms, and preganglionic
      oscillators regulate synaptic amplification in sympathetic ganglia.

PMID- 10648696
TI  - Local control of acetylcholinesterase gene expression in multinucleated skeletal
      muscle fibers: individual nuclei respond to signals from the overlying plasma
      membrane.
AB  - Nuclei in multinucleated skeletal muscle fibers are capable of expressing
      different sets of muscle-specific genes depending on their locations within the
      fiber. Here we test the hypothesis that each nucleus can behave autonomously and
      responds to signals generated locally on the plasma membrane. We used
      acetylcholinesterase (AChE) as a marker because its transcripts and protein are
      concentrated at the neuromuscular and myotendenous junctions. First, we show that
      tetrodotoxin (TTX) reversibly suppresses accumulation of cell surface AChE
      clusters, whereas veratridine or scorpion venom (ScVn) increase them. AChE mRNA
      levels are also regulated by membrane depolarization. We then designed chambered
      cultures that allow application of sodium channel agonists or antagonists to
      restricted regions of the myotube surface. When a segment of myotube is exposed
      to TTX, AChE cluster formation is suppressed only on that region. Conversely,
      ScVn increases AChE cluster formation only where in contact with the muscle
      surface. Likewise, both the synthesis and secretion of AChE are shown to be
      locally regulated. Moreover, using in situ hybridization, we show that the
      perinuclear accumulation of AChE transcripts also depends on signals that each
      nucleus receives locally. Thus AChE can be up- and downregulated in adjacent
      regions of the same myotubes. These results indicate that individual nuclei are
      responding to locally generated signals for cues regulating gene expression.

PMID- 10648697
TI  - Somatostatin modulates voltage-gated K(+) and Ca(2+) currents in rod and cone
      photoreceptors of the salamander retina.
AB  - We investigated the cellular localization in the salamander retina of one of the
      somatostatin [or somatotropin release-inhibiting factor (SRIF)] receptors,
      sst(2A), and studied the modulatory action of SRIF on voltage-gated K(+) and
      Ca(2+) currents in rod and cone photoreceptors. SRIF immunostaining was observed
      in widely spaced amacrine cells, whose perikarya are at the border of the inner
      nuclear layer and inner plexiform layer. sst(2A) immunostaining was seen in the
      inner segments and terminals of rod and cone photoreceptors. Additional sst(2A)
      immunoreactivity was expressed by presumed bipolar and amacrine cells. SRIF, at
      concentrations of 100-500 nM, enhanced a delayed outwardly rectifying K(+)
      current (I(K)) in both rod and cone photoreceptors. SRIF action was blocked in
      cells pretreated with pertussis toxin (PTX) and was substantially reduced by
      intracellular GDP(beta)S. Voltage-gated L-type Ca(2+) currents in rods and cones
      were differently modulated by SRIF. SRIF reduced Ca(2+) current in rods by 33%
      but increased it in cones by 40%, on average. Both effects were mediated via G
      protein activation and blocked by PTX. Ca(2+)-imaging experiments supported these
      results by showing that 500 nM SRIF reduced a K(+)-induced increase in
      intracellular Ca(2+) in rod photoreceptor terminals but increased it in those of
      cones. Our results suggest that SRIF may play a role in the regulation of
      glutamate transmitter release from photoreceptors via modulation of voltage-gated
      K(+) and Ca(2+) currents.

PMID- 10648698
TI  - Kinetic differences between synaptic and extrasynaptic GABA(A) receptors in CA1
      pyramidal cells.
AB  - GABA(A)-mediated IPSCs typically decay more rapidly than receptors in excised
      patches in response to brief pulses of applied GABA. We have investigated the
      source of this discrepancy in CA1 pyramidal neurons. IPSCs in these cells decayed
      rapidly, with a weighted time constant tau(Decay) of approximately 18 msec (24
      degrees C), whereas excised and nucleated patch responses to brief pulses of GABA
      (2 msec, 1 mM) decayed more than three times as slowly (tau(Decay), approximately
      63 msec). This discrepancy was not caused by differences between synaptic and
      exogenous transmitter transients because (1) there was no dependence of
      tau(Decay) on pulse duration for pulses of 0.6-4 msec, (2) responses to GABA at
      concentrations as low as 10 microM were still slower to decay (tau(Decay),
      approximately 41 msec) than IPSCs, and (3) responses of excised patches to
      synaptically released GABA had decay times similar to brief pulse responses.
      These data indicate that the receptors mediating synaptic versus brief pulse
      responses have different intrinsic properties. However, synaptic receptors were
      not altered by the patch excision process, because fast, spontaneous IPSCs could
      still be recorded in nucleated patches. Elevated calcium selectively modulated
      patch responses to GABA pulses, with no effect on IPSCs recorded in nucleated
      patches, demonstrating the presence of two receptor populations that are
      differentially regulated by intracellular second messengers. We conclude that two
      receptor populations with distinct kinetics coexist in CA1 pyramidal cells: slow
      extrasynaptic receptors that dominate the responses of excised patches to
      exogenous GABA applications and fast synaptic receptors that generate rapid
      IPSCs.

PMID- 10648699
TI  - Ca(2+) influx inhibits dynamin and arrests synaptic vesicle endocytosis at the
      active zone.
AB  - Ca(2+) entry into nerve terminals through clusters of voltage-dependent Ca(2+)
      channels (VDCCs) at active zones creates a microdomain of elevated intracellular
      free Ca(2+) concentration ([Ca(2+)](i)) that stimulates exocytosis. We show that
      this VDCC-mediated [Ca(2+)](i) elevation has no specific role in stimulating
      endocytosis but can inhibit endocytosis evoked by three different methods in
      isolated mammalian nerve terminals. The inhibition can be relieved by using
      either VDCC antagonists or fast, but not slow, binding intracellular Ca(2+)
      chelators. The Ca(2+)-dependent inhibition of endocytosis is mimicked in vitro by
      a low-affinity inhibition of dynamin I vesiculation of phospholipids. Increased
      [Ca(2+)](i) also inhibits dynamin II GTPase activity and receptor-mediated
      endocytosis in non-neuronal cells. VDCC-meditated Ca(2+) entry inhibits dynamin
      mediated endocytosis at the active zone and provides neurons with a mechanism to
      clear recycling vesicles to nonactive zone regions during periods of high
      activity.

PMID- 10648700
TI  - Altered entrainment and feedback loop function effected by a mutant period
      protein.
AB  - The period (per) and timeless (tim) genes encode interacting components of the
      circadian clock. Levels and phosphorylation states of both proteins cycle with a
      circadian rhythm, and the proteins drive cyclic expression of their RNAs through
      a feedback mechanism that is, at least in part, negative. We report here that a
      hypophosphorylated mutant PER protein, produced by creating a small internal
      deletion, displays increased stability and low-amplitude oscillations, consistent
      with previous reports that phosphorylation is required for protein turnover. In
      addition, this protein appears to be defective in feedback repression because it
      is associated with relatively high levels of RNA and high levels of TIM.
      Transgenic flies carrying the mutant PER protein display a temperature-dependent
      shortening of circadian period and are impaired in their response to light,
      particularly to pulses of light in the late night that normally advance the phase
      of the rhythm. Interestingly, per RNA is induced by light in these flies, most
      likely because of the removal of the light-sensitive TIM protein, thus
      implicating a more direct role for TIM in transcriptional inhibition. These data
      have relevance for mechanisms of feedback repression, and they also address
      existing models for the differential behavioral response to light at different
      times of the night.

PMID- 10648701
TI  - Metabotropic glutamate receptors trigger homosynaptic protein synthesis to
      prolong long-term potentiation.
AB  - We investigated the mechanisms by which previous "priming" activation of group I
      metabotropic glutamate receptors (mGluRs) facilitates the persistence of long
      term potentiation (LTP) in area CA1 of rat hippocampal slices. Priming of LTP was
      elicited by either pharmacological or synaptic activation of mGluRs before a weak
      tetanic stimulus that normally produced only a rapidly decaying phase of LTP that
      did not involve protein synthesis or mGluRs. Pharmacological priming of LTP
      persistence by a selective group I mGluR agonist was blocked by an inhibitor of
      group I mGluRs and by inhibitors of translation, but not by a transcriptional
      inhibitor. The same mGluR agonist increased (35)S-methionine incorporation into
      slice proteins. LTP could also be facilitated using a synaptic stimulation
      priming protocol, and this effect was similarly blocked by group I mGluR and
      protein synthesis inhibitors. Furthermore, using a two-pathway protocol, the
      synaptic priming of LTP was found to be input-specific. To test for the
      contribution of group I mGluRs and protein synthesis to LTP in nonprimed slices,
      a longer duration control tetanization protocol was used to elicit a more slowly
      decaying form of LTP than did the weak tetanus used in the previous experiments.
      The persistence of the LTP induced by this stronger tetanus was dependent on
      mGluR activation and protein synthesis but not on transcription. Together, these
      results suggest that mGluRs couple to nearby protein synthesis machinery to
      homosynaptically regulate an intermediate phase of LTP dependent on new proteins
      made from pre-existing mRNA.

PMID- 10648702
TI  - ERKI/II regulation by the muscarinic acetylcholine receptors in neurons.
AB  - Muscarinic acetylcholine receptors (mAChRs) are known to be involved in learning
      and memory, but the molecular basis of their involvement is not well understood.
      The availability of new and specific biochemical tools has revealed a crucial
      role for the mitogen-activated protein kinase (MAPK) family in learning and
      memory. Here, we examine the link between mAChRs and MAPK in neurons. Using the
      MAPK kinase (MEK)-specific inhibitor PD98059, we first demonstrate a necessary
      role for active ERKI/II in long-term potentiation in vivo. Using phospho-specific
      antibodies that recognize the activated form of ERKI/II, we find that the level
      of ERKI/II activation in brain is regulated by mAChRs. Carbachol, a muscarinic
      agonist, induces prolonged activation of ERKI/II, without effect on the related
      kinase SAPK/JNK (stress-activated protein kinase/c-Jun N-terminal protein kinase)
      in primary cortical cultures. ERKI/II activation is Src-dependent and partially
      phosphoinositide-3 kinase- and Ca(2+)-dependent but is PKC-independent. M1-M4
      mAChR subtypes expressed in COS-7 cells can all induce ERKI/II activation using a
      signal transduction pathway similar to that operating in neurons. The nature of
      the signal transduction suggests that ERKI/II can serve as a convergence site for
      mAChR activation and other neurotransmitter receptors.

PMID- 10648703
TI  - Role of circadian activation of mitogen-activated protein kinase in chick pineal
      clock oscillation.
AB  - A circadian pacemaker generates a rhythm with a period of approximately 24 hr
      even in the absence of environmental time cues. Several photosensitive neuronal
      tissues such as the retina and pineal gland contain the autonomous circadian
      pacemaker together with the photic-input pathway responsible for entrainment of
      the pacemaker to the daily light/dark cycle. We show here that, in constant
      darkness, chick pineal mitogen-activated protein kinase (MAPK) exhibited an in
      vivo circadian rhythm in tyrosine phosphorylation and in enzymatic activity with
      a peak during subjective night. Phosphorylated and hence activated MAPK was
      rapidly dephosphorylated after light illumination during the nighttime when light
      induces a phase-shift of the pacemaker. The circadian rhythmicity in MAPK
      phosphorylation was also observed in the cultured pineal gland, and importantly,
      MAPK kinase inhibitor treatment during subjective night not only shifted the time
      of-peak of MAPK phosphorylation but also induced a remarkable phase-delay of the
      circadian pacemaker. These results indicate an important role of MAPK for time
      keeping in circadian clock systems.

PMID- 10648704
TI  - Target-related and intrinsic neuronal death in Lurcher mutant mice are both
      mediated by caspase-3 activation.
AB  - The Lurcher (Lc) mutation in the delta2 glutamate receptor gene leads to the
      presence of a constitutive inward current in the cerebellar Purkinje cells of
      Lurcher heterozygous mice and to the postnatal degeneration of these neurons. In
      addition, cerebellar granule cells and olivary neurons of Lc/+ mice die as an
      indirect effect of the mutation after the loss of their target Purkinje cells.
      The apoptotic nature of Lc/+ Purkinje cell death remains controversial. To
      address this question, we studied the involvement of caspase-3, a key effector of
      apoptosis, in the neurodegenerative processes occurring in Lc/+ cerebellum.
      Several antibodies recognizing different regions of caspase-3 were used in
      immunoblotting and immunohistochemical experiments. We demonstrate that pro
      caspase-3 is specifically upregulated in the dying Lc/+ Purkinje cells, but not
      in granule cells and olivary neurons, suggesting that different death-inducing
      signals trigger variant apoptotic pathways in the CNS. The subcellular
      localization of pro-caspase-3 was shown to be cytoplasmic and mitochondrial.
      Active caspase-3 as well as DNA fragmentation was found in numerous granule cells
      and some Purkinje cells of the Lc/+ cerebellum. Thus, caspase-3 activation is
      involved in both the direct and indirect neuronal death induced by the Lurcher
      mutation, strongly supporting the idea that the Lc/+ Purkinje cell dies by
      apoptosis.

PMID- 10648705
TI  - The electrogenic sodium bicarbonate cotransporter: developmental expression in
      rat brain and possible role in acid vulnerability.
AB  - The electrogenic sodium bicarbonate cotransporter (NBC) is expressed in glial
      cells in the brain and plays an important role in the regulation of both
      intracellular and extracellular pH. Differential vulnerability to acidosis
      between neurons and glia has been noted and may contribute to infarction after
      cerebral ischemia. Ionic substitution studies and inhibition of injury by 4, 4'
      di-isothiocyanostilbene-2,2'-disulfonic acid suggest that NBC is involved in
      astrocyte vulnerability to acidic injury. Recently two NBC cDNAs differing in 5'
      untranslated and N-terminal coding sequence have been cloned from kidney and
      pancreas. We cloned one of these cDNAs from rat brain and demonstrate here that
      the clone is functional by expression in Xenopus oocytes. We determined the
      developmental and regional expression of NBC in the brain by in situ
      hybridization. Expression was observed in the spinal cord at embryonic day 17,
      whereas expression in brain was first seen at approximately postnatal day 0 (P0),
      increased at P15, and persisted in the adult brain. Expression was widespread
      throughout the cerebellum, cortex, olfactory bulb, and subcortical structures.
      Cellular resolution of the in situ hybridization signal and double labeling for
      glial fibrillary acidic protein were consistent with a glial localization for
      NBC. Expression of NBC in 3T3 cells that do not normally express this transporter
      rendered them vulnerable to acid injury. The expression profile suggests that
      this transporter is critical during the later stages of brain development and
      could be one of the factors contributing to the different patterns of injury seen
      in perinatal versus adult cerebral ischemia.

PMID- 10648706
TI  - The presynaptic calcium channel is part of a transmembrane complex linking a
      synaptic laminin (alpha4beta2gamma1) with non-erythroid spectrin.
AB  - Nerve regeneration studies at the neuromuscular junction (NMJ) suggest that
      synaptic basal lamina components tell the returning axon where to locate
      neurotransmitter release machinery, including synaptic vesicle clusters and
      active zones. Good candidates for these components are the synaptic laminins
      (LNs) containing alpha4, alpha5, or beta2 chains. Results from a beta2 laminin
      knockout mouse have suggested a linkage of this extracellular laminin to
      cytosolic synaptic vesicle clusters. Here we report such a transmembrane link at
      the electric organ synapse, which is homologous to the NMJ. We immunopurified
      electric organ synaptosomes and found on their surface two laminins of 740 and
      900 kDa. The 740 kDa laminin has a composition of alpha4beta2gamma1 (laminin-9).
      Immunostaining reveals that as in the NMJ, alpha4 and beta2 chains are
      concentrated at the electric organ synapse. Using detergent-solubilized
      synaptosomes, we immunoprecipitated a complex containing alpha4beta2gamma1
      laminin, the voltage-gated calcium channel, and the cytoskeletal protein
      spectrin. Other presynaptic proteins such as 900 kDa laminin are not found in
      this complex. We hypothesize that alpha4beta2gamma1 laminin in the synaptic basal
      lamina attaches to calcium channel, which in turn is attached to cytosolic
      spectrin. Spectrin could then organize synaptic vesicle clusters by binding
      vesicle-associated proteins.

PMID- 10648707
TI  - A role for voltage-gated potassium channels in the outgrowth of retinal axons in
      the developing visual system.
AB  - Neural activity is important for establishing proper connectivity in the
      developing visual system. Tetrodotoxin blockade of sodium (Na(+))-dependent
      action potentials impairs the refining of synaptic connections made by developing
      retinal ganglion cells (RGCs), but does not affect their ability to get out to
      their target. Although this may suggest neural activity is not required for the
      directed extension of RGC axons, in many species developing RGCs express
      additional, Na(+)-independent ionic mechanisms. To test whether the ability of
      RGC axons to extend in a directed fashion is influenced by membrane excitability,
      we blocked the principal modulators of the neural activity of a neuron, voltage
      dependent potassium (Kv) channels. First, we showed that RGCs and their growth
      cones express Kv channels when they are growing through the brain on the way to
      their main midbrain target, the optic tectum. Second, a Kv channel blocker, 4
      aminopyridine (4-AP), was applied to the developing Xenopus optic projection.
      Blocking Kv channels inhibited RGC axon extension and caused aberrant routing of
      many RGC fibers. With the higher doses, <25% of embryos had a normal optic
      projection. These data suggest that Kv channel activity regulates the guidance of
      growing axons in the vertebrate brain.

PMID- 10648708
TI  - Spatial distributions of guidance molecules regulate chemorepulsion and
      chemoattraction of growth cones.
AB  - It is generally assumed that gradients of chemotropic molecules are instrumental
      to the wiring of the nervous system. Recently, two members of the secreted class
      III semaphorin protein family have been implicated as repulsive (Sema3A) and
      attractive (Sema3C) guidance molecules for cortical axons (). Here, we show that
      stabilized gradients of increasing semaphorin concentrations elicit stereotyped
      responses from cortical growth cones, independent of the absolute concentration
      and the slope of these gradients. In contrast, neither repulsive effects of
      Sema3A nor attractive effects of Sema3C were observed when axons were growing
      toward decreasing semaphorin concentrations. Thus, growth cone guidance by
      gradients of chemotropic molecules is robust and reproducible, because it is
      primarily independent of the exact dimensions of the gradients.

PMID- 10648709
TI  - Nitric oxide influences injury-induced microglial migration and accumulation in
      the leech CNS.
AB  - Damage to the leech or mammalian CNS increases nitric oxide (NO) production and
      causes accumulation of phagocytic microglial cells at the injury site. The aim of
      this study was to determine whether NO plays a role in microglial migration and
      accumulation at lesions in which NO is generated by a rapidly appearing
      endothelial nitric oxide synthase (eNOS) in leeches. Immunohistochemistry and
      cytochemistry demonstrated active eNOS before and throughout the period of
      microglial accumulation at the lesion. Decreasing NO synthesis by application of
      the NOS inhibitor N(w)-nitro-L-arginine methyl ester (1 mM) significantly reduced
      microglial accumulation, whereas its inactive enantiomer N(w)-nitro-D-arginine
      methyl ester (1 mM) resulted in microglial accumulation similar to that in
      crushed controls. Increasing NO with the donor spermine NONOate (SPNO) (1 mM)
      also inhibited accumulation, but not in the presence of the NO scavenger 2-(4
      carboxyphenyl)-4,4,5, 5-teramethylimidazoline-oxyl-3-oxide (50 microM). The
      effect of SPNO was reversed by washout. SPNO application reduced average
      microglial migratory speeds and even reversibly arrested cell movement, as
      measured in living nerve cords. These results suggest that NO produced at a
      lesion may be a stop signal for microglia to accumulate there and that it can act
      on microglia early in their migration. Thus, NO may assume a larger role in nerve
      repair and recovery from injury by modulating accumulation of microglia, which
      appear to be important for axonal regeneration.

PMID- 10648710
TI  - Identification of an invariant response: stable contact with schwann cells
      induces veil extension in sensory growth cones.
AB  - Growth cones sense cues by filopodial contact, but how their motility is altered
      by contact remains unclear. Although contact could alter motile dynamics in
      complex ways, our analysis shows that stable contact with Schwann cells induces
      motility changes that are remarkably discrete and invariant. Filopodial contact
      invariably induces local veil extension. Even when contacts are brief, veils
      always extend before the filopodia retract. Contact at filopodial tips suffices
      for induction. Moreover, veils extend significantly sooner than on filopodia
      contacting laminin, which often detach without extending veils. The overall
      behavioral responses of the growth cone, such as increased area and turning,
      result from integrating multiple discrete responses. Cycles of veil induction
      enlarge the growth cone and often lead it onto the cell. Invariant veil induction
      is abolished by blocking N-cadherin signaling. We propose an axonal guidance
      model in which different guidance cues act by inducing different but discrete and
      invariant responses.

PMID- 10648711
TI  - The pattern of avian intramuscular nerve branching is determined by the
      innervating motoneuron and its level of polysialic acid.
AB  - Most skeletal muscles are composed of a heterogeneous population of fast and slow
      muscle fibers that are selectively innervated during development by fast and slow
      motoneurons, respectively. It is well recognized that, in both birds and mammals,
      fast and slow motoneurons have substantially different intramuscular branching
      patterns, a difference critical for proper motor function. However, the cellular
      mechanisms regulating these differences in motoneuron branching are unknown. In a
      previous study, we showed that the fast and slow pattern of intramuscular
      branching, in a chick muscle containing distinct fast and slow muscle regions,
      was remarkably similar to normal when formed by foreign motoneurons. Whether this
      was attributable to some property of the innervating "fast" or "slow" motoneurons
      or to some property of the developing fast-slow muscle fibers was not determined.
      To distinguish between these two possibilities, we performed chick-quail hindlimb
      chimeras to force slow chick plantaris motoneurons to innervate a fast quail
      plantaris muscle. The pattern of intramuscular nerve branching in the fast
      plantaris of these chimeras closely resembled the slow branching pattern normally
      observed in chick slow plantaris muscles. Enzymatic removal of polysialic acid
      (PSA) from nerve and muscle during normal quail plantaris development
      dramatically changed the normal fast pattern to more closely resemble a slow
      pattern. In contrast, removal of PSA from chick plantaris motoneurons and muscle
      fibers had little effect on the pattern of nerve branching. Together, these
      results indicate that the pattern of intramuscular nerve branching is determined
      by the level of PSA on the innervating motoneurons.

PMID- 10648712
TI  - Human arm movements described by a low-dimensional superposition of principal
      components.
AB  - A new method for analyzing kinematic patterns during smooth movements is
      proposed. Subjects are asked to move the end of a two-joint manipulandum to copy
      a smooth initial target path. On subsequent trials the target path is the
      subject's actual movement from the preceding trial. Using Principal Components
      Analysis, it is shown that the trajectories have very low dimension and that they
      converge toward a linear superposition of the first few principal components. We
      show similar results for handwriting on an electronic pen tablet. We hypothesize
      that the low dimensionality and convergence are attributable to combined
      properties of the internal controller and the musculoskeletal system. The low
      dimensionality may allow for efficient descriptions of a large class of arm
      movements.

PMID- 10648713
TI  - Septamer element-binding proteins in neuronal and glial differentiation.
AB  - Differentiation of progenitors into neurons and glia is regulated by interactions
      between regulatory DNA elements of neuron- and glia-specific genes and
      transcription factors that are differentially expressed by progenitors at
      progressive stages of neural development. We have identified a novel DNA
      regulatory element (TTTGCAT = septamer) present on the enkephalin (ENK), neuronal
      cell adhesion molecule, neurofilament of 68 kDa (NF68), growth-associated protein
      of 43 kDa, glial high-affinity glutamine transporter, tyrosine hydroxylase, etc.,
      genes. When septamer function was blocked by introducing septamer competitor DNA
      into primary differentiating neural cultures, mRNA levels of ENK, NF68, and glial
      fibrillary acidic protein decreased by 50-80%, whereas no effect was seen using a
      control DNA. Septamer elements serve as binding sites for lineage-specific
      multimeric complexes assembled from three distinct nuclear proteins. Progenitors
      express a 16 kDa protein (p-sept) which binds to DNA as a homodimer (detected as
      the 32 kDa P-band). Cells that entered the neuronal lineage express an additional
      29 kDa protein (n-sept) that binds to the homodimerized p-sept, and together they
      form a 62 kDa multimer (detected as N-band). Cells that entered the glial lineage
      express a distinct 23 kDa protein (g-sept), which along with the homodimerized p
      sept form a 56 kDa multimer (observed as G-band). The binding of the distinct
      protein complexes (P, G, and N) to the septamer site causes a lineage-specific
      DNA bending (P = 53 degrees; G = 72 degrees; and N = 90 degrees ), which may
      contribute to the regulatory effect of the septamer interaction. In summary,
      septamer and its binding proteins represent novel protein-DNA interactions that
      may contribute to the regulation of neuroglial differentiation in the developing
      mammalian CNS.

PMID- 10648714
TI  - Separate proliferation kinetics of fibroblast growth factor-responsive and
      epidermal growth factor-responsive neural stem cells within the embryonic
      forebrain germinal zone.
AB  - The embryonic forebrain germinal zone contains two separate and additive
      populations of epidermal growth factor (EGF)- and fibroblast growth factor (FGF)
      responsive stem cells that both exhibit self-renewal and multipotentiality.
      Although cumulative S phase labeling studies have investigated the proliferation
      kinetics of the overall population of precursor cells within the forebrain
      germinal zone through brain development, little is known about when and how
      (symmetrically or asymmetrically) the small subpopulations of stem cells are
      proliferating in vivo. This has been determined by injecting timed-pregnant mice
      with high doses of tritiated thymidine ((3)H-thy) to kill any stem cells
      proliferating within the striatal germinal zone in vivo and then by assaying for
      neurosphere formation in vitro. Injections of 0.8 mCi of (3)H-thy given every 2
      hr for 12 hr to timed-pregnant mice at E11, E14, and E17 resulted in significant
      depletions in the number of neurospheres generated by FGF-responsive stem cells
      at E11 and by EGF-responsive and FGF-responsive stem cells at E14 and E17. With
      increasing embryonic age, the depletions observed in the number of neurospheres
      generated in vitro in response to FGF2 after exposure to (3)H-thy in vivo
      decreased, suggesting there is an increase in the length of the cell cycle of FGF
      responsive neural stem cells through embryonic development. The results suggest
      that the FGF-responsive stem cell population expands between E11 and E14 by
      dividing symmetrically, but switches to primarily asymmetric division between E14
      and E17. The EGF-responsive stem cells arise after E11, and their population
      expands through symmetric divisions and through asymmetric divisions of FGF
      responsive stem cells.

PMID- 10648715
TI  - short stop is allelic to kakapo, and encodes rod-like cytoskeletal-associated
      proteins required for axon extension.
AB  - short stop (shot) is required for sensory and motor axons to reach their targets
      in the Drosophila embryo. Growth cones in shot mutants initiate at the normal
      times, and they appear normal with respect to overall morphology and their
      abilities to orient and fasciculate. However, sensory axons are unable to extend
      beyond a short distance from the cell body, and motor axons are unable to reach
      target muscles. The shot gene encodes novel actin binding proteins that are
      related to plakins and dystrophin and expressed in axons during development. The
      longer isoforms identified are predicted to contain an N-terminal actin binding
      domain, a long central triple helical coiled-coil domain, and a C-terminal domain
      that contains two EF-hand Ca(2+) binding motifs and a short stretch of homology
      to the growth arrest-specific 2 protein. Other isoforms lack all or part of the
      actin binding domains or are truncated and contain a different C-terminal domain.
      Only the isoforms containing full-length actin binding domains are detectably
      expressed in the nervous system. shot is allelic to kakapo, a gene that may
      function in integrin-mediated adhesion in the wing and embryo. We propose that
      Shot's interactions with the actin cytoskeleton allow sensory and motor axons to
      extend.

PMID- 10648716
TI  - The lack of Emx2 causes impairment of Reelin signaling and defects of neuronal
      migration in the developing cerebral cortex.
AB  - Neocorticogenesis in mice homozygous for an Emx2 null allele is the topic of this
      article. The development of both main components of neocortex, primordial
      plexiform layer derivatives and cortical plate, was analyzed, paying special
      attention to radial migration of neurons forming the cortical plate. The products
      of the Reelin gene, normally playing a key role in orchestrating radial migration
      of these neurons, display normal distribution at the beginning of the cortical
      neuronogenesis but are absent in the neocortical marginal zone of the mutant mice
      at the time when the cortical plate is laid down. As a consequence, the
      development of radial glia is impaired, and neurons making up the cortical plate
      display abnormal migration patterns. In addition, restricted defects along the
      rostrocaudal and the mediolateral axes are present in the subplate, suggesting an
      Emx2-specific role in priming the proper development of this layer.

PMID- 10648717
TI  - Structured long-range connections can provide a scaffold for orientation maps.
AB  - In the visual cortex of the cat and ferret, it is established that maturation of
      orientation selectivity is shaped by experience-dependent plasticity. However,
      recent experiments indicate that orientation maps are remarkably stable and
      experience-independent. We present a model to account for these seemingly
      paradoxical results. In this model, a scaffold consisting of non-isotropic
      lateral connections is laid down in horizontal circuitry before visual
      experience. These lateral connections provide an experience-independent framework
      for the developing orientation maps by inducing a broad orientation tuning bias
      in the model neurons. Experience-dependent plasticity of the thalamocortical
      connections sharpens the tuning while the preferred orientation of the neurons
      remains unchanged. This model is verified by computer simulations in which the
      scaffolds are generated both artificially and inferred from experimental optical
      imaging data. The plasticity is modeled by the BCM synaptic plasticity rule, and
      the input environment consists of natural images. We use this model to provide a
      possible explanation of the recent observation in which two eyes without common
      visual experience develop similar orientation maps. Finally, we propose an
      experiment involving the disruption of lateral connections to distinguish this
      model from models proposed by others.

PMID- 10648718
TI  - Decoding temporal information: A model based on short-term synaptic plasticity.
AB  - In the current paper it is proposed that short-term plasticity and dynamic
      changes in the balance of excitatory-inhibitory interactions may underlie the
      decoding of temporal information, that is, the generation of temporally selective
      neurons. Our initial approach was to simulate excitatory-inhibitory disynaptic
      circuits. Such circuits were composed of a single excitatory and inhibitory
      neuron and incorporated short-term plasticity of EPSPs and IPSPs and slow IPSPs.
      We first showed that it is possible to tune cells to respond selectively to
      different intervals by changing the synaptic weights of different synapses in
      parallel. In other words, temporal tuning can rely on long-term changes in
      synaptic strength and does not require changes in the time constants of the
      temporal properties. When the units studied in disynaptic circuits were
      incorporated into a larger single-layer network, the units exhibited a broad
      range of temporal selectivity ranging from no interval tuning to interval
      selective tuning. The variability in temporal tuning relied on the variability of
      synaptic strengths. The network as a whole contained a robust population code for
      a wide range of intervals. Importantly, the same network was able to discriminate
      simple temporal sequences. These results argue that neural circuits are
      intrinsically able to process temporal information on the time scale of tens to
      hundreds of milliseconds and that specialized mechanisms, such as delay lines or
      oscillators, may not be necessary.

PMID- 10648719
TI  - Do centrally administered neuropeptides access cognate receptors?: an analysis in
      the central corticotropin-releasing factor system.
AB  - To determine the extent to which centrally administered corticotropin-releasing
      factor (CRF) activates neurons that express CRF receptors (CRF-Rs), we followed
      the kinetics and distribution (relative to those of CRF-Rs) of Fos induction seen
      in response to intracerebroventricular (icv) injection of the peptide (1-10
      microg). CRF provoked widespread Fos expression: its strength was dose-related,
      it peaked at 2 hr after injection, and it was antagonized in a dose-dependent
      manner by coinjection of CRF-R antagonists. The activation pattern closely
      mimicked the distribution of CRF-R1 mRNA, in including widespread Fos induction
      throughout the cortical mantle, in cell groups involved in sensory information
      processing, and in the cerebellum and several of its major afferents and targets.
      Dual labeling revealed extensive correspondence of CRF-stimulated Fos
      immunoreactivity (Fos-ir) and CRF-R1 mRNA at these and other loci. Unique sites
      of CRF-R2 expression were relatively unresponsive to CRF but were more so after
      icv administration of urocortin (UCN), a new mammalian CRF-related peptide. Both
      CRF and UCN elicited activational responses in cell groups that are involved in
      central autonomic control but that express neither CRF-R, including the central
      amygdaloid and paraventricular hypothalamic nuclei, and brainstem
      catecholaminergic cell groups. The results support an ability of CRF-related
      peptides in the ventricular system to access receptor-expressing cells directly
      but leave open questions as to the basis for the recruitment of central autonomic
      structures, many of which have been identified as stress-related sites of CRF
      action.

PMID- 10648720
TI  - Specificity of projections from wide-field and local motion-processing regions
      within the middle temporal visual area of the owl monkey.
AB  - The middle temporal visual area (MT) of the owl monkey is anatomically organized
      with respect to both preferred direction of motion and different types of center
      surround interaction. The latter organization consists of clusters of neurons
      whose receptive fields have antagonistic surrounds that render them unresponsive
      to wide-field motion (local motion columns) interdigitated with groups of neurons
      whose receptive fields have additive surrounds and thus respond best to wide
      field motion (wide-field motion columns). To learn whether the information in
      these regions remained segregated further along the visual pathways, we made
      injections of retrograde tracers into two visual areas to which MT projects [the
      medial superior temporal area (MST) and fundus of the superior temporal sulcus
      (FST)] and then labeled the wide-field and local organization using 2
      deoxyglucose. In complementary experiments, we injected anterograde tracers into
      regions of MT that we had mapped using microelectrode recordings. Injections into
      both dorsal FST and ventral MST labeled clusters of cell bodies in MT that were
      concentrated within wide-field motion columns, whereas injections into dorsal MST
      labeled neurons predominantly within local motion columns. Results from the
      anterograde tracer experiments corroborated these findings. The high degree of
      specificity in the connections reinforces a model of functional organization for
      wide-field versus local motion processing within MT. Our data support the
      previously reported division of FST into separate dorsal and ventral areas, and
      they also suggest that MST of the owl monkey is, like MST of the macaque,
      functionally organized with respect to local versus wide-field motion processing.

PMID- 10648721
TI  - Fast network oscillations in the newborn rat hippocampus in vitro.
AB  - Spontaneous neural activity is crucial for the formation of the intricate
      patterns of cortical connectivity during development. In particular, temporal
      correlations in presynaptic and postsynaptic activity have been hypothesized to
      be a critical determinant in the selection of neurons that are to become wired
      together. To date, however, temporally correlated activity in the neonatal brain
      has been believed to take place with a precision of tens of milliseconds to
      seconds. Here we describe a novel type of a fast network oscillation associated
      with millisecond synchronization of pyramidal cell firing in newborn rat
      hippocampus in vitro. Individual pyramidal neurons fired mainly at lower gamma
      frequencies (20-40 Hz) but were synchronized into a high-frequency (100-400 Hz)
      population oscillation that was reflected in field potential spikes and
      intracellular AMPA-kainate receptor-mediated currents. The high-frequency
      population oscillation was patterned by a gamma-frequency modulatory oscillation.
      The gamma modulation was imposed by GABAergic currents, which exerted an
      inhibitory action on pyramidal neurons. Patterned activity based on GABAergic
      inhibition and glutamatergic excitation thus occurs already in newborn
      hippocampus. The network oscillations described here may be a mechanism for
      selective coincidence detection with a millisecond range temporal precision to
      shape the patterns of connectivity within the emerging hippocampal synaptic
      circuitry.

PMID- 10648722
TI  - Opioids suppress IPSCs in neurons of the rat medial septum/diagonal band of
      Broca: involvement of mu-opioid receptors and septohippocampal GABAergic neurons.
AB  - The medial septum/diagonal band region (MSDB), which provides a major cholinergic
      and GABAergic input to the hippocampus, expresses a high density of opioid
      receptors. Behaviorally, intraseptal injections of opioids produce deficits in
      spatial memory, however, little is known about the electrophysiological effects
      of opioids on MSDB neurons. Therefore, we investigated the electrophysiological
      effects of opioids on neurons of the MSDB using rat brain slices. In voltage
      clamp recordings with patch electrodes, bath-applied met-enkephalin, a
      nonselective opioid receptor agonist, decreased the number of tetrodotoxin and
      bicuculline-sensitive inhibitory synaptic currents in cholinergic- and GABA-type
      MSDB neurons. A similar effect occurred in brain slices containing only the MSDB,
      suggesting that opioids decrease GABA release primarily by inhibiting
      spontaneously firing GABAergic neurons located within the MSDB. Accordingly, in
      extracellular recordings, opioid-sensitive, spontaneously firing neurons could be
      found within the MSDB. Additionally, in intracellular recordings a subpopulation
      of GABA-type neurons were directly inhibited by opioids. All effects of met
      enkephalin were mimicked by a mu receptor agonist, but not by delta or kappa
      agonists. In antidromic activation studies, mu-opioids inhibited a subpopulation
      of septohippocampal neurons with high conduction velocity fibers, suggestive of
      thickly myelinated GABAergic fibers. Consistent with the electrophysiological
      findings, in double-immunolabeling studies, 20% of parvalbumin-containing
      septohippocampal GABA neurons colocalized the mu receptor, which at the
      ultrastructural level, was found to be associated with the neuronal cell
      membrane. Thus, opioids, via mu receptors, inhibit a subpopulation of MSDB
      GABAergic neurons that not only make local connections with both cholinergic and
      noncholinergic-type MSDB neurons, but also project to the hippocampus.

PMID- 10648723
TI  - Mechanisms of ionotropic glutamate receptor-mediated excitotoxicity in isolated
      spinal cord white matter.
AB  - Spinal cord injury involves a component of glutamate-mediated white matter
      damage, but the cellular targets, receptors, and ions involved are poorly
      understood. Mechanisms of excitotoxicity were examined in an in vitro model of
      isolated spinal dorsal columns. Compound action potentials (CAPs) were
      irreversibly reduced to 43% of control after 3 hr of 1 mM glutamate exposure at
      37 degrees C. AMPA (100 microM) and kainate (500 microM) had similar effects.
      Antagonists (1 mM kynurenic acid, 10 microM NBQX, 30 microM GYKI52466) were each
      equally protective against a glutamate challenge, improving mean CAP amplitude to
      approximately 80% versus approximately 40% without antagonist. Joro spider toxin
      (0.75 microM), a selective blocker of Ca(2+)-permeable AMPA receptors, was also
      protective to a similar degree. Ca(2+)-free perfusate virtually abolished
      glutamate-induced injury ( approximately 90% vs approximately 40%). MK-801 (10
      microM) had no effect. Glutamate caused damage (assayed immunohistochemically by
      spectrin breakdown products) to astrocytes and oligodendrocytes consistent with
      the presence of GluR2/3 and GluR4 in these cells. Myelin was also damaged by
      glutamate likely mediated by GluR4 receptors detected in this region; however,
      axon cylinders were unaffected by glutamate, showing no increase in the level of
      spectrin breakdown. These data may guide the development of more effective
      treatment for acute spinal cord injury by addressing the additional excitotoxic
      component of spinal white matter damage.

PMID- 10648724
TI  - Four-dimensional neuronal signaling by nitric oxide: a computational analysis.
AB  - Nitric oxide (NO) is now recognized as a transmitter of neurons that express the
      neuronal isoform of the enzyme nitric oxide synthase. NO, however, violates some
      of the key tenets of chemical transmission, which is classically regarded as
      occurring at points of close apposition between neurons. It is the ability of NO
      to diffuse isotropically in aqueous and lipid environments that has suggested a
      radically different form of signaling in which the transmitter acts four
      dimensionally in space and time, affecting volumes of the brain containing many
      neurons and synapses. Although "volume signaling" clearly challenges simple
      connectionist models of neural processing, crucial to its understanding are the
      spatial and temporal dynamics of the spread of NO within the brain. Existing
      models of NO diffusion, however, have serious shortcomings because they represent
      solutions for "point-sources," which have no physical dimensions. Methods for
      overcoming these difficulties are presented here, and results are described that
      show how NO spreads from realistic neural architectures with both simple
      symmetrical and irregular shapes. By highlighting the important influence of the
      geometry of NO sources, our results provide insights into the four-dimensional
      spread of a diffusing messenger. We show for example that reservoirs of NO that
      accumulate in volumes of the nervous system where NO is not synthesized
      contribute significantly to the temporal and spatial dynamics of NO spread.

PMID- 10648725
TI  - Enhanced and impaired attentional performance after infusion of D1 dopaminergic
      receptor agents into rat prefrontal cortex.
AB  - The role in spatial divided and sustained attention of D1 and D2-like dopamine
      (DA) receptors in the rat prelimbic medial prefrontal cortex (mPFC) was
      investigated in a five-choice serial reaction time task. Rats were trained to
      detect brief flashes of light (0.5-0.25 sec) presented randomly in a spatial
      array of five apertures. When performance stabilized, animals received bilateral
      microinfusions of either the D1 DA receptor antagonist SCH 23390, the D1 DA
      receptor agonist SKF 38393, or the D2 DA antagonist sulpiride into the mPFC. Rats
      were divided into two groups, with low (<75% correct) and high (>75%) baseline
      levels of accuracy. Infusions of the D2 receptor antagonist sulpiride had no
      significant effect on any task variable. SCH 23390 (0.3 microg) selectively
      impaired the accuracy of attentional performance in rats in the high baseline
      condition. By contrast, SKF 38393 (0.06 microg) enhanced the accuracy of
      attentional performance in the low baseline condition, a lower dose (0.03 microg)
      also increasing the speed of making correct responses. Finally, the beneficial
      effects of SKF-383893 on choice accuracy were antagonized by SCH 23390 (1.0
      microg). The results provide apparently the first demonstration of enhanced
      cognitive function after local administration of a D1 receptor agonist to the
      mPFC and suggest dissociable roles of D1 and D2 DA receptors of the mPFC in
      modulating attentional function.

PMID- 10648726
TI  - Coding of sound-source location by ensembles of cortical neurons.
AB  - We examined the coding of sound-source location by ensembles of neurons in the
      auditory cortex. Broadband noise bursts were presented from loudspeakers
      throughout 360 degrees in the horizontal plane. Sound levels varied from 20 to 40
      dB above neural thresholds. We recorded temporal spike patterns simultaneously at
      16 recording sites in area A2 of alpha-chloralose-anesthetized cats. Spike
      patterns of individual units varied in spike counts and in spike timing as a
      function of sound-source location. Ensembles of up to 19 units recorded
      simultaneously demonstrated additional location sensitivity in the form of
      relative spike counts and relative spike timing among neurons. We used an
      artificial neural network (ANN) algorithm to recognize ensemble spike patterns
      and, thereby, to infer the locations of sound sources. The ANN could estimate
      stimulus locations based on ensemble responses to single-stimulus presentations.
      Median errors (MEs) averaged 49.2 +/- 11.9 degrees (mean +/- SD; n = 34; chance
      level, 90 degrees ). The ANN maintained better-than-chance performance even when
      input spike patterns were expressed as relative spike counts across units (i.e.,
      no information available from absolute spike counts of individual units; ME, 63.0
      +/- 11.8 degrees ) or when spike latencies were represented as time relative to
      the first spike for each trial (i.e., no external time reference available; ME,
      54.3 +/- 12.4 degrees ). The ANN performance improved monotonically as the sizes
      of ensemble patterns were increased by combining patterns across the entire unit
      sample. The performance by ensembles of 128 units approached the level of
      localization performance of behaving cats.

PMID- 10648727
TI  - Behavioral evidence of depolarization block of dopamine neurons after chronic
      treatment with haloperidol and clozapine.
AB  - Electrophysiological studies have shown that chronic treatment with haloperidol
      causes depolarization block (DB) of dopamine cells in anesthetized and paralyzed
      rats. It has been proposed that the emergence of DB underlies the therapeutic and
      side effects of this drug. However, the relevance of DB to the clinical actions
      of haloperidol has been questioned on the grounds that chronic drug-induced DB
      has not yet been demonstrated in freely moving animals. In this study, responding
      for rewarding electrical brain stimulation was used to assess the occurrence of
      DB in rats chronically treated with haloperidol or clozapine. The time course of
      the effects of acute haloperidol (7.8-500 microg/kg) and clozapine (5-40 mg/kg)
      and of withdrawal from chronic drug treatment on reward and performance measures
      were also characterized. Haloperidol and clozapine dose-dependently attenuated
      reward and performance, haloperidol producing a predominant suppression of
      performance, and clozapine preferentially attenuating reward. Chronic (21 d)
      treatment with haloperidol (500 microg/kg) caused responding to cease in the six
      rats tested, and repeated injection with apomorphine restored the behavior in all
      of them; such an effect of apomorphine was observed in only two of six rats
      treated acutely with the same dose of haloperidol. Chronic treatment with
      clozapine (20 mg/kg) increased reward thresholds, an effect that was reversed by
      apomorphine in chronically, but not acutely, treated rats. The times at which
      chronic haloperidol-treated rats resumed responding was positively correlated
      with indices of behavioral supersensitivity after withdrawal, suggesting that the
      effect of apomorphine was not caused by direct stimulation of upregulated
      postsynaptic receptors. These findings constitute the first behavioral evidence
      of DB in unanesthetized, freely moving animals treated chronically with
      antipsychotics. They also demonstrate that the neural substrates mediating reward
      and performance are functionally independent and differentially sensitive to
      haloperidol and clozapine.

PMID- 10648728
TI  - Chronic administration of the triazolobenzodiazepine alprazolam produces opposite
      effects on corticotropin-releasing factor and urocortin neuronal systems.
AB  - In view of the substantial preclinical evidence that supports a seminal role of
      central corticotropin-releasing factor (CRF) neuronal systems in the physiology
      and pathophysiology of stress and anxiety, it is reasonable to suggest that the
      anxiolytic properties of benzodiazepines are mediated, at least in part, via
      regulation of CRFergic function. To begin to test this complex hypothesis, we
      examined the effects of acute and chronic administration of the
      triazolobenzodiazepine agonist alprazolam on CRF peptide concentrations, receptor
      binding density, and mRNA expression in the CNS. Additionally, we measured mRNA
      expression for urocortin, a recently discovered neuropeptide that is generally
      considered to be a second endogenous ligand for CRF receptors. Both acute and
      chronic alprazolam administration was found to decrease CRF concentrations within
      the locus coeruleus. Furthermore, chronic alprazolam decreased basal activity of
      the hypothalamic-pituitary-adrenal axis, CRF mRNA expression in the central
      nucleus of the amygdala, and CRF(1) mRNA expression and receptor binding in the
      basolateral amygdala. In marked contrast, urocortin mRNA expression in the
      Edinger-Westphal nucleus and CRF(2A) receptor binding in the lateral septum and
      ventromedial hypothalamus were increased. Similar findings of an inverse
      relationship between the CRF(1) and CRF(2A) receptor systems have been reported
      in an anxiety model based on adverse early-life experience, suggesting the
      intriguing possibility that CRF neuronal systems may be comprised of two
      separate, but interrelated, subdivisions that can be coordinately and inversely
      regulated by stress, anxiety, or anxiolytic drugs.

PMID- 10648729
TI  - The analgesic effects of supraspinal mu and delta opioid receptor agonists are
      potentiated during persistent inflammation.
AB  - This study examined the antihyperalgesic and antinociceptive effects of opioid
      receptor agonists microinjected in the rostral ventromedial medulla (RVM) of rats
      4 hr, 4 d, and 2 weeks after the induction of an inflammatory injury by injection
      of complete Freund's adjuvant (CFA) in one hindpaw. Nociceptive sensitivity of
      the ipsilateral, inflamed and the contralateral, uninflamed hindpaws was
      determined by the radiant-heat paw withdrawal test. The antihyperalgesic potency
      of the mu opioid receptor agonist [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]enkephalin
      (DAMGO), determined for the inflamed hindpaw, was enhanced 4 d and 2 weeks after
      injury. The antinociceptive potency of DAMGO, determined for the contralateral,
      uninflamed hindpaw, was also progressively enhanced 4 hr, 4 d, and 2 weeks after
      injury. The magnitude of enhancement paralleled the chronicity of the injury. The
      greatest potentiation occurred 2 weeks after injury when the ED(50) value of
      DAMGO in CFA-treated rats was one-tenth that in saline-treated rats. The
      antihyperalgesic and antinociceptive effects of the delta opioid receptor agonist
      [D-Ala(2),Glu(4)]deltorphin were also increased 2 weeks after injury. These
      results indicate that peripheral inflammatory injury alters the pharmacology of
      excitatory and inhibitory inputs that modulate the activity of RVM neurons in
      such a manner as to enhance the effects of opioid agonists in this region. These
      changes have ramifications not only for the alleviation of hyperalgesia at the
      site of injury but also for opioid-induced antinociception at sites remote to the
      injury as revealed by increases in the potency of opioid agonists to suppress
      nociceptive responses of the contralateral, uninflamed hindpaw.

PMID- 10648730
TI  - A developmental change in NMDA receptor-associated proteins at hippocampal
      synapses.
AB  - The membrane-associated guanylate kinases [Chapsyn-110/postsynaptic density-93
      (PSD-93), synapse-associated protein-90 (SAP-90)/PSD-95, and SAP-102] are
      believed to cluster and anchor NMDA receptors at the synapse and to play a role
      in signal transduction. We have investigated the developmental changes in
      expression of these proteins in rat hippocampus using biochemical analyses and
      quantitative immunogold electron microscopy. At postnatal day 2 (P2), SAP-102 was
      highly expressed, whereas PSD-93 and PSD-95 were low. SAP-102 expression
      increased during the first week, stayed stable through P35, and showed a reduced
      expression at 6 months. From P2 through 6 months, PSD-93 and PSD-95 increased.
      For PSD-95, the percent of labeled synapses increased almost threefold with age,
      whereas the number of gold particles per labeled synapse did not change
      significantly, suggesting that the increase in PSD-95 is attributable primarily
      to an increase in the number of synapses containing PSD-95. In contrast, for SAP
      102, both percent labeled synapses and the number of gold particles per labeled
      synapse decreased during this time. From Western blots of hippocampus and
      immunogold analysis of CA1 synapses, the high expression of NR2B at P2 coincides
      with the high level of SAP-102 at synapses, whereas the later expression of NR2A
      coincides with that of PSD-93 and PSD-95. To determine whether the changes in PSD
      93/95 and SAP-102 reflect preferred associations with NR2A and NR2B,
      respectively, we measured co-immunoprecipitation in the adult hippocampus. These
      studies suggest that there is a preference for complexes of NR2A/PSD-93/95 and
      NR2B/SAP-102. These results indicate that individual receptor-associated proteins
      may have specific functions that are critical to synapse development.

PMID- 10648731
TI  - Local morphine withdrawal increases c-fos gene, Fos protein, and oxytocin gene
      expression in hypothalamic magnocellular neurosecretory cells.
AB  - We measured stimulation of c-fos and oxytocin gene expression during excitation
      of oxytocin cells induced by systemic or local morphine withdrawal. Female rats
      were made morphine-dependent by intracerebroventricular morphine infusion over 5
      d. Morphine withdrawal, induced by systemic injection of the opioid antagonist
      naloxone (5 mg/kg) in conscious or anesthetized rats, increased the density of c
      fos messenger RNA and of oxytocin heterogeneous nuclear RNA in supraoptic nucleus
      cells compared with those of nonwithdrawn rats; c-fos messenger RNA was also
      increased in the magnocellular and parvocellular paraventricular nuclei of
      withdrawn rats. Morphine withdrawal increased the number of Fos-immunoreactive
      cells in the supraoptic and magnocellular paraventricular nuclei of conscious or
      pentobarbitone-anesthetized rats. Morphine withdrawal also increased Fos
      immunoreactive cell numbers in the parvocellular paraventricular nucleus of
      conscious but not anesthetized rats. Central administration of the alpha(1)
      adrenoreceptor antagonist benoxathian (5 microg/min) did not prevent morphine
      withdrawal-induced increases in the numbers of Fos-immunoreactive neurons in the
      supraoptic or magnocellular paraventricular nucleus. Unilateral microdialysis
      administration of naloxone (10(-5) M) into the supraoptic nucleus of anesthetized
      morphine-dependent rats increased Fos-immunoreactive cell numbers compared with
      the contralateral nucleus. Finally, we investigated whether dependence could be
      induced by chronic unilateral infusion of morphine into a supraoptic nucleus;
      systemic naloxone (5 mg/kg) increased Fos-immunoreactive cell numbers in the
      morphine-infused nucleus compared with the contralateral nucleus. Thus, morphine
      withdrawal excitation increases c-fos and oxytocin gene expression in supraoptic
      nucleus neurons. This occurs independently from excitation of their ascending
      noradrenergic inputs, and both dependence and withdrawal can be induced within
      the supraoptic nucleus.

PMID- 10648732
TI  - Brain-derived neurotrophic factor expands ocular dominance columns in visual
      cortex in monocularly deprived and nondeprived kittens but does not in adult
      cats.
AB  - Segregation and stabilization of thalamocortical afferents to eye-specific
      patches, so-called "ocular dominance (OD) columns," in visual cortex are
      hypothesized to be based on activity-dependent competition for trophic factors
      such as brain-derived neurotrophic factor (BDNF) between afferents representing
      the two eyes during the critical period of postnatal development. To test this
      hypothesis we observed effects of an intracortical infusion of BDNF on OD columns
      in monocularly deprived kittens and also compared effects between normal kittens
      and adult cats. BDNF had a hypertrophic action on afferents irrespective of
      visual inputs so that it desegregated OD columns in the visual cortex of deprived
      and normal kittens, but this action was not seen in the adults, substantiating
      its hypothesized trophic role in plasticity of OD columns in the developing
      visual cortex.

PMID- 10648733
TI  - Synaptic regulation of L-type Ca(2+) channel activity and long-term depression
      during refinement of the retinocollicular pathway in developing rodent superior
      colliculus.
AB  - The retinocollicular pathway undergoes activity-dependent refinement during
      postnatal development, which results in the precise retinotopic order seen in
      adults. This process is NMDA- and nitric oxide-dependent. Recent studies have
      shown that L-type Ca2+ channels may also play a role in synaptic plasticity, but
      such channel activity has not previously been reported in the developing superior
      colliculus (SC). Here we report the presence of a postsynaptic plateau potential
      mediated by L-type Ca2+ channels using whole-cell current clamp of the SC in an
      isolated brainstem preparation of rats. Seventy percent of SC neurons showed
      these potentials as early as postnatal day 0 (P0)-P2. The potential was blocked
      by nitrendipine and/or APV and facilitated by bicuculline, showing that the
      channel is activated by NMDA receptor-mediated EPSPs and deactivated by GABAA
      receptor-mediated IPSPs. Blockade of L-type Ca2+ channels also diminished long
      term depression, which we could induce in the retinocollicular pathway in
      neonatal animals. The incidence of plateau potentials decreased to 39% of neurons
      by P10-P14, suggesting that L-type calcium channels may contribute to
      retinocollicular pathway refinement in the developing SC.

PMID- 10648734
TI  - Copurification of brain G-protein beta5 with RGS6 and RGS7.
AB  - A structurally divergent G-protein beta subunit expressed in brain and retina,
      Gbeta5, exhibits functional specialization in its protein-protein interactions in
      vitro. In retina, Gbeta5 has been isolated in a soluble complex with regulator of
      G-protein signaling RGS7. The function and molecular associations of Gbeta5 in
      brain are unknown. To identify tightly bound proteins associated with Gbeta5 in
      the brain, it was immunoaffinity-purified from a nonionic detergent extract of
      washed mouse brain membranes using an antibody directed against its N terminus.
      Elution with cognate peptide revealed a broad band of 55 kDa that coeluted with
      Gbeta5 on SDS-PAGE. The copurifying 55 kDa band was identified as an
      approximately 1:1 mixture of RGS6 and RGS7 by matrix-assisted laser desorption
      ionization mass spectroscopic analysis of tryptic peptides. Gbeta5 and RGS7 could
      be reciprocally coimmunoprecipitated from unfractionated brain membrane extracts
      confirming the tight association of native proteins. In contrast, immunoblotting
      of the peptide eluate revealed no copurifying Galphaq/11, Galphai1/2, Ggamma2,
      Ggamma3, or Ggamma7. These findings implicate RGS6 and RGS7 in the function of
      Gbeta5 in the brain and suggest that a large fraction of membrane-targeted Gbeta5
      has no associated G subunit and therefore functions outside the canonical
      framework of G(beta)(gamma) interactions.

PMID- 10648735
TI  - The effects of natural cell loss on the regularity of the retinal cholinergic
      arrays.
AB  - The retina provides a paradigmatic example of the modularity of neuronal
      circuitry. Different cells are stacked in layers, and neurons of the same type
      are commonly regularly spaced within their layer. Although the orderly arrays
      formed by homotypic neurons provide the basis for parallel processing, the
      mechanisms responsible for regular cell spacing are just beginning to be
      elucidated. All the developing retinal arrays for which early markers have been
      identified are regular before being complete. This indicates that the positional
      constraints controlling mosaic formation are active at times when cell genesis,
      migration, and death also occur in the retina. To begin investigating how these
      different processes are coordinated, we have focused here on the effects of cell
      death on the spatial organization of the two rat cholinergic mosaics, the only
      arrays for which the development of spatial ordering has been described
      quantitatively to date. We have chosen an age interval when new cell genesis is
      over and death predominantly or nearly exclusively controls cell number in one of
      these array. We found that the regularity of this array is not improved by the
      loss of cells occurring in this age period. Rather, death appears to be largely
      independent of cell position.

PMID- 10648736
TI  - The AAGL classification system for laparoscopic hysterectomy.

PMID- 10648737
TI  - Plasma catecholamine responses during laparoscopic gynecologic surgery with CO(2)
      insufflation.
AB  - STUDY OBJECTIVE: To compare adrenergic-sympathetic responses during pelvic
      laparoscopic surgery with CO(2) insufflation with those during laparotomy.
      DESIGN. Prospective study (Canadian Task Force classification II-1). SETTING:
      Tertiary care university hospital. PATIENTS: Twenty-one infertile women with a
      clinical diagnosis of endometriosis. INTERVENTION: Plasma norepinephrine (NE) and
      epinephrine (E) levels were measured in patients undergoing laparoscopic or open
      pelvic surgery. MEASUREMENTS AND MAIN RESULTS: During laparoscopic surgery,
      increases in NE and E levels were correlated with arterial tension of CO(2)
      (PaCO(2)) and were greater in patients with a larger increase in PaCO(2) than in
      those undergoing laparotomy. Hemodynamic changes were also more evident during
      laparoscopic surgery, with larger PaCO(2) increases. CONCLUSION: The PaCO(2)
      increases due to CO(2) insufflation are associated with adrenergic-sympathetic
      activation and hemodynamic changes during laparoscopic pelvic surgery.

PMID- 10648738
TI  - Office transvaginal hydrolaparoscopy for early diagnosis of pelvic endometriosis
      and adhesions.
AB  - STUDY OBJECTIVE. To evaluate the feasibility of a new endoscopic technique,
      transvaginal hydrolaparoscopy, for early office screening of subfertile women.
      DESIGN. Retrospective, descriptive feasibility study (Canadian Task Force
      classification II-2). SETTING: Office in an infertility center. PATIENTS: One
      hundred fifty-seven continuous women with primary or secondary subfertility.
      INTERVENTION: Under local anesthesia, a Veress needle-cannula system was inserted
      into the posterior fornix with peritoneal distention by saline. MEASUREMENTS AND
      MAIN RESULTS: Access was achieved in 95% of patients. In 58.5% the findings were
      normal and in 28% an explorative or operative laparoscopy was indicated. No major
      complication occurred. Patients' pain scores were similar to those for office
      hysteroscopy. CONCLUSION: Transvaginal hydrolaparoscopy was successfully
      performed in the office. The technique allows early and complete endoscopic
      screening of subfertile women.

PMID- 10648739
TI  - Learning curves for transperitoneal laparoscopic and extraperitoneal endoscopic
      paraaortic lymphadenectomy.
AB  - STUDY OBJECTIVE: To compare learning curves for paraaortic lymphadenectomy by
      extraperitoneal endoscopic approach with those for transperitoneal laparoscopy.
      DESIGN: Randomized, long-term study (Canadian Task Force classification I).
      SETTING: Animal laboratory. SUBJECTS: Sixty-six pigs. INTERVENTION: Laparoscopic
      and endoscopic paraaortic lymphadenectomy, 33 pigs in each group, performed by
      two surgeons competent in laparoscopic surgery but without experience in
      endoscopic paraaortic lymphadenectomy. MEASUREMENTS AND MAIN RESULTS: The
      duration of the procedure, number of lymph nodes removed, and number of residual
      nodes revealed learning curves that stabilized after the tenth procedure for each
      surgeon and for each approach. Vascular trauma depended on experience, occurring
      during the first 10 procedures for each surgeon. Efficacy and operative morbidity
      were comparable for the two procedures. CONCLUSION: Endoscopic extraperitoneal
      lymphadenectomy has a steep learning curve similar to that for transperitoneal
      laparoscopy.

PMID- 10648740
TI  - Intended and stray radiofrequency electrical currents during resectoscopic
      surgery.
AB  - STUDY OBJECTIVE: To test the hypothesis that electrical burns of the genital
      tract and urethral strictures after hysteroscopic endometrial ablation and
      transurethral prostatectomy, respectively, are related to capacitive coupling
      and/or stray currents induced by intact and defective electrodes and/or
      resectoscopes. DESIGN: Basic in vitro measurements. SETTING: Laboratory.
      MATERIALS: Porcine muscle and liver, resectoscope, electrosurgical unit (ESU),
      and ESU analyzer. INTERVENTION: We measured electrical coagulation and cutting
      currents of rollerball and loop electrodes and the external sheath of the
      resectoscope from 80 to 200 W through a resistance load of 200 and 250 ohms,
      using intact electrodes and conditions simulating potential insulation defects
      along the shaft of the electrodes. MEASUREMENTS AND MAIN RESULTS: Approximately
      20% to 25% of current was induced by capacitive coupling to the resectoscope
      sheath. Touching porcine muscle or liver with small areas of the sheath while the
      generator was activated resulted in superficial tissue burn. Surrounding large
      segments of the sheath with tissue did not result in visible burns, indicating
      that under normal conditions the sheath acts as a dispersive electrode. Defective
      insulation of distal segments of the electrodes resulted in 100% transfer of
      current to the sheath and caused extensive electrical burns of tissue in contact
      with the sheath. CONCLUSIONS: Capacitive coupled currents induced by intact
      resectoscopes and electrodes may cause thermal injury to surrounding tissue
      during prolonged resectoscopic surgery. Stray currents from defective insulation
      of the electrodes result in direct coupling of current to the telescope and
      sheath and cause extensive burns of surrounding tissues in contact with the
      sheath.

PMID- 10648741
TI  - Operative hysteroscopy in the office setting.
AB  - STUDY OBJECTIVE: To describe the feasibility of operative hysteroscopy in the
      office setting. DESIGN. Descriptive study (Canadian Task Force classification II
      2). SETTING: University-based private practice. PATIENTS: Women undergoing
      assisted reproduction in whom diagnostic evaluation revealed uterine cavity
      pathology. INTERVENTION: Patients were offered office hysteroscopy and allowed to
      choose between paracervical block anesthesia supplemented with mild intravenous
      sedation or full conscious sedation, administered by an anesthesiologist. A
      MicroSpan Hysteroscopy system or HysteroSys Flexible Hysteroscope system was used
      for diagnostic purposes. When pathology was identified, resection was performed
      with 2-mm operative instruments or a VersaPoint hysteroscopic electrosurgical
      electrode using bipolar coagulation through an expandable operating channel.
      MEASUREMENTS AND MAIN RESULTS: Of 69 women with abnormal sonohysterographic and
      hysterosalpingogram studies, 44 agreed to office hysteroscopy. Thirty-three (48%)
      underwent VersaPoint resection and/or scissors resection, which was successfully
      accomplished in 32 (97%). Significant cervical stenosis in one woman precluded
      resection because of concern of creating a false passage. Concomitant diagnostic
      laparoscopy and operative hysteroscopy was performed in one patient. Average
      operating and anesthesia times were 45.2 +/- 20.3 minutes and 67.2 +/- 28.4
      minutes, respectively. One uterine perforation occurred (3.3%) during resection
      of intrauterine adhesions. CONCLUSION: Office hysteroscopy is a time-efficient
      and cost-effective procedure, made possible by the development of small
      instruments. Proper patient selection and training of office personnel are
      mandatory to minimize complications and maximize efficacy.

PMID- 10648742
TI  - Acceptability and pain of outpatient hysteroscopy.
AB  - STUDY OBJECTIVE: To investigate the pain and acceptability of diagnostic
      hysteroscopy performed without local anesthesia. DESIGN: Prospective,
      observational study (Canadian Task Force classification II-2). SETTING:
      University-associated department of obstetrics and gynecology. PATIENTS: The 1144
      consecutive women who underwent diagnostic hysteroscopy. INTERVENTIONS:
      Diagnostic hysteroscopy and endometrial biopsy as indicated. MEASUREMENTS AND
      MAIN RESULTS: Patients were asked to rate the pain experienced on a 10-cm visual
      analog scale and to state if they were willing to repeat the procedure. The mean
      pain score was 4.7 +/- 2.5; 398 patients (34.8%) experienced severe pain. No risk
      factors for painful hysteroscopy were found, although abnormality of the cervical
      canal was associated with high pain scores. Acceptance of the procedure was high,
      83.0% (950 women). CONCLUSION: Diagnostic hysteroscopy is a painful procedure
      even when performed with atraumatic technique by experienced surgeons. Most
      women, however, stated they were willing to have a second procedure under the
      same conditions.

PMID- 10648744
TI  - Laparoscopic surgery in obese women with endometrial cancer.
AB  - STUDY OBJECTIVE: To analyze perioperative and postoperative outcomes of
      laparoscopic treatment of endometrial cancer in two groups of women of different
      weight. DESIGN: Prospective, multicenter clinical study (Canadian Task Force
      classification II-1). SETTING: Three laparoscopic oncology centers. PATIENTS:
      Sixty-five consecutive women with endometrial cancer, of whom 32 were not obese
      (weight <81. 7 kg) and 33 were obese (weight (3)81.7 kg, body mass index 30-40).
      INTERVENTION: Laparoscopic surgery. MEASUREMENTS AND MAIN RESULTS: Three patients
      (1 nonobese, 2 obese) in whom laparoscopy was converted to laparotomy were
      removed from data analysis. Laparoscopy in the remaining 62 (94.38%) was
      completed successfully. Hysterectomy and pelvic and paraaortic lymphadenectomies
      were performed based on tumor grade and depth of myometrial invasion. In both
      groups, 28 women underwent pelvic lymphadenectomy and 21 paraaortic lymph node
      dissection or sampling. Eight patients had metastases in pelvic or paraaortic
      nodes. Deep myometrial invasion over 50% was present in five obese and two
      nonobese women. Mean operating time was 166 and 172 minutes, respectively. The
      rate of major complications and conversions was higher in the obese group (8 vs
      5). CONCLUSION: Laparoscopic surgery is feasible in obese women and may also be
      considered for endometrial cancer, which typically occurs in obese women.

PMID- 10648743
TI  - Sonographic, hysteroscopic, and histologic evaluation of the endometrium in
      postmenopausal women with breast cancer receiving tamoxifen.
AB  - STUDY OBJECTIVE: To evaluate the estrogenic effects of tamoxifen on the
      endometrium in postmenopausal women with breast cancer. DESIGN: Consecutive study
      (Canadian Task Force classification II-2). SETTING: University-affiliated
      hospital. PATIENTS: Thirty-three women. Interventions. All patients underwent
      transvaginal sonography (TVS) and color flow Doppler of endometrial vessels,
      hysteroscopy, and, if necessary, endometrial biopsy or other operative
      hysteroscopic procedures. MEASUREMENTS AND MAIN RESULTS: In four women the
      endometrium was thin on TVS and atrophic at hysteroscopic assessment. In 29 women
      with thick endometrium on TVS, hysteroscopy and endometrial biopsy showed atrophy
      (11 patients), hyperplasia (5), polyps (11), and well-differentiated
      adenocarcinoma (2). The two endometrial cancers were present in women with
      uterine bleeding. In women with positive histologic findings, the endometrium was
      significantly thicker (p = 0.04) and duration of tamoxifen therapy longer than in
      those with negative findings, although this was not statistically significant (p
      = 0.067). CONCLUSION: We believe regular assessment of the endometrium by TVS
      should be performed in postmenopausal patients at the start of the tamoxifen
      therapy, and hysteroscopy in women with a thick endometrium or postmenopausal
      bleeding. We believe that patients with thin endometrium on TVS at the beginning
      of tamoxifen therapy, who have no abnormal uterine bleeding should be screened
      with these examinations for 2 years.

PMID- 10648745
TI  - Endometrial cryoablation with ultrasound visualization in women undergoing
      hysterectomy.
AB  - STUDY OBJECTIVES: To evaluate tissue effects of cryosurgical endometrial ablation
      in women just before hysterectomy, characterize ultrasound monitoring of
      freezing, determine the feasibility of a new probe-angling procedure, and assess
      the safety profile by monitoring serosal surface temperatures. DESIGN: Single arm
      safety study enrolling ten women at two centers (Canadian Task Force
      classification II-2). SETTING: Two clinical sites. Patients. Ten women scheduled
      for hysterectomy. INTERVENTION: Hysterectomy with a new cryosurgical device
      (First Option, CryoGen, Inc., San Diego, CA) that achieves surface temperatures
      below -90 inverted exclamation mark C to freeze endometrium. MEASUREMENTS AND
      MAIN RESULTS: The freeze protocol involved angling the probe toward each cornu.
      Maximum ice front diameter at the end of the first angled freeze ranged from 24
      to 34 mm, and maximum ice ball diameter at the end of the second freeze ranged
      from 28 to 37 mm. The margin between the advancing ice front and serosal surface
      was monitored by ultrasound. In all cases the margin was safe and no reduction in
      serosal surface temperatures occurred. Depth of necrosis ranged from 9 to 12 mm
      as determined by tetrazolium staining and electron microscopy, and there was no
      full-thickness myometrial destruction. Total endometrial destruction was
      achieved. CONCLUSION: Cryosurgical ablation of the endometrium with the First
      Option system with angled freezes and ultrasound monitoring appears to be
      feasible and safe given our preliminary data.

PMID- 10648746
TI  - Extirpated uterine endometrial cryoablation with ultrasound visualization.
AB  - STUDY OBJECTIVE: To determine the efficacy of cryoablation of the uterus
      monitored by ultrasound. DESIGN: Observational research (Canadian Task Force
      classification II-2). SETTING: Clinic laboratory. SUBJECTS: Eight uteri obtained
      after hysterectomy. INTERVENTION: The uteri were subjected to freeze and thaw
      cycles in a 37 inverted exclamation markC water bath. Ultrasound was used to
      monitor the advancing ice front and ice ball diameter. MEASUREMENTS AND MAIN
      RESULTS: Specimens were sectioned and stained with tetrazolium red to determine
      the region of nonviable tissue. The maximum average ice ball diameter as measured
      by ultrasound was 33.2 mm (range 29.1-35.4 mm). The average maximum diameter of
      nonviable tissue region was 24 mm (range 21.4-28.4 mm), with depth of tissue
      destruction ranging from 6 to 12 mm. CONCLUSION: Cryosurgery at temperatures
      below -90 inverted exclamation mark C achieves excellent destruction of uterine
      tissue and complete destruction of endometrium. Ultrasound can be used to monitor
      freezing.

PMID- 10648747
TI  - Laparoscopic hysterectomy.
AB  - STUDY OBJECTIVE: To determine the soundness of laparoscopic hysterectomy compared
      with vaginal and abdominal hysterectomy Design. Nonrandomized, uncontrolled,
      retrospective study (Canadian Task Force classification III). SETTING: Medium
      size community hospitals. PATIENTS: One thousand six hundred forty-eight women
      undergoing laparoscopic hysterectomy, including those with uterine size 17 weeks'
      gestation or less. INTERVENTION: Laparoscopic hysterectomy staged as level 4,
      which includes laparoscopic dissection of the uterine artery. MEASUREMENTS AND
      MAIN RESULTS: The median duration of surgery was 36 minutes (range 24-104 min),
      compared with the usual 115 minutes for laparoscopic-assisted vaginal
      hysterectomy. Complication rate was 0.66%. No complications occurred in the last
      3 years when the procedures included transillumination of the ureters. Although
      the costs associated with disposable equipment are high, the technique is cost
      effective. CONCLUSION: With proper training and ureteral transillumination,
      laparoscopic hysterectomy is safe and effective, and with stents, ureteral injury
      is avoided.

PMID- 10648748
TI  - Laparoscopic management of suspected acute pelvic inflammatory disease.
AB  - STUDY OBJECTIVE: To evaluate the efficacy of acute-phase operative laparoscopy in
      women with suspected pelvic inflammatory disease (PID). DESIGN: Open series
      (Canadian Task Force classification II-3). SETTING: University hospital.
      PATIENTS: Thirty-three patients with clinically suspected PID. INTERVENTION:
      Acute-phase operative laparoscopy. MEASUREMENTS AND MAIN RESULTS: Laparoscopy
      confirmed the diagnosis of PID in 20 (61%) patients; 11 (33%) women had other
      disease and 2 (6%) had no evidence of disease. Laparoscopic procedures in women
      with PID were pelvic irrigation (all patients), lysis of adhesions (most cases),
      drainage and irrigation of unilateral or bilateral pyosalpinx (7), drainage and
      irrigation of tubo-ovarian abscess (3), and extirpation of disease (2).
      Laparoscopic intervention was also performed in 11 (85%) of 13 women without PID.
      No major complications occurred. CONCLUSION: Acute-phase operative laparoscopy
      provided a final diagnosis in all but three patients (91%).

PMID- 10648750
TI  - The effect of increasing age on the outcome of hysteroscopic endometrial
      resection for management of dysfunctional uterine bleeding.
AB  - STUDY OBJECTIVE: To determine the outcome of hysteroscopic endometrial resection
      for dysfunctional uterine bleeding according to women's age. DESIGN: Long-term
      follow-up by telephone interview (Canadian Task Force classification II-2).
      SETTING: University-affiliated medical center. Patients. One hundred sixty-nine
      women with abnormal uterine bleeding unresponsive to conservative medical
      management. INTERVENTION: Hysteroscopic endometrial resection. MEASUREMENTS AND
      MAIN RESULTS: Questionnaires were completed for 162 (95.9%) patients with mean +/
      SD follow-up of 32 +/- 17 months. The frequency of postoperative complications
      was not related to age. After ablation, the rate of amenorrhea was significantly
      higher in 31 women age 50 years or older than in younger women (p <0.001), and
      also in 72 women age 45 to 49 than in 59 age 44 or less (p <0.05). Complete
      relief of dysmenorrhea was achieved significantly more often in women age 45 to
      49 (p <0.005) and 50 or older (p <0.05) than in those age 44 or younger.
      Dissatisfaction with the outcome of endometrial resection was uncommon, but most
      frequent among women age 44 or younger (p <0.10). There was no difference in the
      proportion of women requiring second ablation or hysterectomy in any age group.
      CONCLUSION: Significantly higher rates of amenorrhea and complete relief of
      dysmenorrhea after endometrial resection are achieved in older than in younger
      women.

PMID- 10648749
TI  - Is local anesthesia an affordable alternative to general anesthesia for
      minilaparoscopy?
AB  - STUDY OBJECTIVE: To determine if minilaparoscopy under local anesthesia is at
      least as reliable and affordable as that performed under general anesthesia.
      DESIGN: Prospective, randomized study (Canadian Task Force classification I).
      SETTING: University-affiliated hospital. PATIENTS: One hundred sixty-four
      consecutive women evaluated for infertility. INTERVENTION: Diagnostic
      minilaparoscopy performed after women were randomized to receive general or local
      anesthesia with conscious sedation. MEASUREMENTS AND MAIN RESULTS: Levels of
      postoperative pain measured by visual analog scale; volume of CO(2) used; length
      of procedure, complete pelvic evaluation, and hospitalization; complications; and
      pathologic diagnosis were evaluated. The groups were comparable in age, years of
      infertility, and symptoms. For women receiving local anesthesia, 5.5% required
      general anesthesia to complete the procedure. Women in both groups required
      postoperative analgesics. The groups had no statistically significant differences
      in pain level 1 hour after the procedure, number of complications, and pelvic
      pathology. Patients who had local anesthesia required a smaller volume of CO(2)
      (p <0.01) and their hospitalization was significantly shorter (p <0.01). However,
      in 15% of these women pelvic visualization was incomplete, compared with 7.2% in
      the general anesthesia group. CONCLUSION: Minilaparoscopy performed under local
      anesthesia was as reliable and affordable as when performed under general
      anesthesia.

PMID- 10648751
TI  - Conservative management of adnexal torsion in premenarchal girls.
AB  - STUDY OBJECTIVE: To evaluate treatment of premenarchal girls with torsion of the
      adnexa. DESIGN: Retrospective review of medical records (Canadian Task Force
      classification II-2). SETTING: Tertiary care, university-affiliated hospital.
      PATIENTS: Eight premenarchal girls (age range 3-12 yrs) with twisted adnexa.
      INTERVENTION: Laparoscopic detorsion and follow-up with B scan and Doppler
      ultrasound imaging. MEASUREMENTS AND MAIN RESULTS: Duration of complaints ranged
      from 8 to 72 hours (mean 34.6 hrs) and the interval from admission to surgery
      ranged from 6 to 24 hours (mean 18.7 hrs). Four patients had torsion of normal
      appearing adnexa. The other four had ovarian neoplasms. Two had cystic mature
      teratomas (dermoid cysts) and one a serous cystadenoma that required additional
      operation. The fourth girl had a simple ovarian cyst that was aspirated
      laparoscopically. Seven girls (87%) had normal-appearing ovaries on follow-up
      ultrasound. In one patient, a small ovary was seen, with no intraovarian blood
      flow on color Doppler. CONCLUSION: Although the diagnosis of torsion of the
      adnexa in premenarchal girls is difficult and usually delayed, laparoscopic
      detorsion seems to be an effective adnexa-sparing approach. We suggest that
      laparoscopy should be the treatment of choice and that detorsion, rather than
      adnexectomy, be performed more often in these patients.

PMID- 10648752
TI  - Laparoscopic bipolar coagulation of uterine vessels to treat symptomatic
      leiomyomas.
AB  - Laparoscopic bipolar coagulation of uterine vessels was performed in three women
      with symptomatic myomas who required conventional surgical treatment. Uterine
      size and dominant myoma size were assessed by ultrasonography before and after
      surgery. Both uterine arteries, as well as anastomosis zone of uterine arteries
      with ovarian arteries, were occluded in all three women. Surgery was uneventful,
      and patients were hospitalized for only 2 days. All women experienced improvement
      in symptoms with no complications. Postoperative ultrasound showed progressive
      reduction in size of the dominant myoma. A larger series and longer follow-up are
      required to evaluate long-term effects and to identify appropriate candidates.

PMID- 10648753
TI  - Ureteral displacement associated with pelvic peritoneal defects and
      endometriosis.
AB  - Ten women had endometriosis and pelvic peritoneal defects of the posterior leaf
      of the broad ligament, with the consistent finding of medial displacement of the
      ureter toward the uterosacral ligament. Ureterolysis at the time of surgery
      revealed the underlying course of the ureter and its proximity to the uterosacral
      ligament, making it susceptible to surgical injury. It is important for surgeons
      to be aware of this anatomic alteration associated with these specific peritoneal
      defects.

PMID- 10648754
TI  - Laparoscopic excision of endocervicosis of the urinary bladder.
AB  - Endocervicosis is a benign lesion in which endocervical mucosa develops in
      anatomic locations distant from the endocervical canal. Two cases of infiltrating
      endocervicosis of the urinary bladder were managed by laparoscopic partial
      cystectomy. This avoided the morbidity of laparotomy and provided improved
      visualization of the extent of bladder resection required to remove the lesion
      completely.

PMID- 10648755
TI  - A modified tissue forceps for use during umbilical laparoscopic entry and
      closure.
AB  - A modification of the common tissue or thumb forceps facilitates initial
      transumbilical entry into the peritoneal cavity at the start of a laparoscopic
      procedure and at closure of that umbilical port. The modification consists of
      placement of teeth on the outside and inside of the forceps jaws. The instrument
      can be used to hold tissue and also as a spring retractor to hold open the
      umbilical crater. It is not now commercially available, but surgeons can obtain
      them from individual instrument makers.

PMID- 10648756
TI  - Genital tract electrical burns during hysteroscopic endometrial ablation: report
      of 13 cases in the United States and Canada.
AB  - We investigated 13 alleged thermal injuries to the genital tract of women
      undergoing hysteroscopic endometrial ablation. Possible mechanisms proposed to
      explain these injuries are hot-weighted speculum, povidone-iodine scrub solution,
      inadequate rinsing of Cidex sterilizing solution, and electrical burns. The
      history, nature, and distribution, as well as experimental evidence strongly
      support the hypothesis that these injuries are electrical due to capacitive
      coupled currents induced onto the sheath of the resectoscope, and/or stray
      currents generated by arcing or direct coupling from defective electrode
      insulation to the telescope, electrifying the entire resectoscope.

PMID- 10648757
TI  - Changes in hemostatic mechanisms associated with operative laparoscopy.
AB  - A 19-year-old woman underwent laparoscopic resection of extensive endometriosis
      of the cul-de-sac. At completion of surgery the abdomen was deflated for 3
      minutes with the patient still in Trendelenburg position, before she was
      reexamined for intraoperative bleeding. The patient was taken back to surgery 7
      hours postoperatively to arrest hemorrhage.

PMID- 10648758
TI  - Ascites and pleural and pericardial effusion after operative laparoscopy.
AB  - Rare cases of massive ascites associated with pelvic endometriosis have been
      reported. Our patient developed ascites several days after laparoscopy, probably
      as an infective complication.

PMID- 10648759
TI  - Incarcerated tubal herniation, an unusual complication of operative laparoscopy
      and an odd cause of pelvic pain.
AB  - Tubal herniation after laparoscopic surgery to relieve pelvic pain and adhesions
      was associated with long-term, chronic pelvic pain in the left lower quadrant.
      Laparoscopy was performed to diagnose and reduce the herniation. Review of the
      literature revealed no previous report of this complication.

PMID- 10648760
TI  - Bilateral tubal pregnancy after puerperal tubal ligation.
AB  - Ectopic pregnancy is one complication of tubal sterilization. A 39-year-old
      multiparous woman underwent puerperal transcutaneous tubal ligation in the
      infraumbilical region after delivery of her fourth child. Tubal pregnancy
      occurred in the right and left salpinx, respectively, at different times, with
      laparoscopic surgery performed after each one.

PMID- 10648761
TI  - Hysteroscopic training guidelines. The ad hoc committee on hysteroscopic training
      guidelines of the American Association of Gynecologic Laparoscopists.

PMID- 10648762
TI  - Hysteroscopic fluid monitoring guidelines. The ad hoc committee on hysteroscopic
      training guidelines of the American Association of Gynecologic Laparoscopists.

PMID- 10648763
TI  - The effect of influenza on hospitalizations, outpatient visits, and courses of
      antibiotics in children.
AB  - BACKGROUND: Despite high annual rates of influenza in children, influenza
      vaccines are given to children infrequently. We measured the disease burden of
      influenza in a large cohort of healthy children in the Tennessee Medicaid program
      who were younger than 15 years of age. METHODS: We determined the rates of
      hospitalization for acute cardiopulmonary conditions, outpatient visits, and
      courses of antibiotics over a period of 19 consecutive years. Using the
      differences in the rates of these events when influenzavirus was circulating and
      the rates from November through April when there was no influenza in the
      community, we calculated morbidity attributable to influenza. There was a total
      of 2,035,143 person-years of observation. RESULTS: During periods when
      influenzavirus was circulating, the average number of hospitalizations for
      cardiopulmonary conditions in excess of the expected number was 104 per 10,000
      children per year for children younger than 6 months of age, 50 per 10,000 per
      year for those 6 months to less than 12 months, 19 per 10,000 per year for those
      1 year to less than 3 years, 9 per 10,000 per year for those 3 years to less than
      5 years, and 4 per 10,000 per year for those 5 years to less than 15 years. For
      every 100 children, an annual average of 6 to 15 outpatient visits and 3 to 9
      courses of antibiotics were attributable to influenza. In winter, 10 to 30
      percent of the excess number of courses of antibiotics occurred during periods
      when influenzavirus was circulating. CONCLUSIONS: Healthy children younger than
      one year of age are hospitalized for illness attributable to influenza at rates
      similar to those for adults at high risk for influenza. The rate of
      hospitalization decreases markedly with age. Influenza accounts for a substantial
      number of outpatient visits and courses of antibiotics in children of all ages.

PMID- 10648764
TI  - Influenza and the rates of hospitalization for respiratory disease among infants
      and young children.
AB  - BACKGROUND: Young children may be at increased risk for serious complications
      from influenzavirus infection. However, in population-based studies it has been
      difficult to separate the effects of influenzavirus from those of respiratory
      syncytial virus. Respiratory syncytial virus often circulates with
      influenzaviruses and is the most frequent cause of hospitalization for lower
      respiratory tract infections in infants and young children. We studied the rates
      of hospitalization for acute respiratory-disease among infants and children
      during periods when the circulation of influenzaviruses predominated over the
      circulation of respiratory syncytial virus. METHODS: For each season from October
      to May during the period from 1992 to 1997, we used local viral surveillance data
      to define periods in Washington State and northern California when the
      circulation of influenzaviruses predominated over that of respiratory syncytial
      virus. We calculated the rates of hospitalization for acute respiratory disease,
      excess rates attributable to influenzavirus, and incidence-rate ratios for all
      infants and children younger than 18 years of age who were enrolled in either the
      Kaiser Permanente Medical Care Program of Northern California or the Group Health
      Cooperative of Puget Sound. RESULTS: The rates of hospitalization for acute
      respiratory disease among children who did not have conditions that put them at
      high risk for complications of influenza (e.g., asthma, cardiovascular diseases,
      or premature birth) and who were younger than two years of age were 231 per
      100,000 person-months at Northern California Kaiser sites (from 1993 to 1997) and
      193 per 100,000 person-months at Group Health Cooperative sites (from 1992 to
      1997). These rates were approximately 12 times as high as the rates among
      children without high-risk conditions who were 5 to 17 years of age (19 per
      100,000 person-months at Northern California Kaiser sites and 16 per 100,000
      person-months at Group Health Cooperative sites) and approached the rates among
      children with chronic health conditions who were 5 to 17 years of age (386 per
      100,000 person-months and 216 per 100,000 person-months, respectively).
      CONCLUSIONS: Infants and young children without chronic or serious medical
      conditions are at increased risk for hospitalization during influenza seasons.
      Routine influenza vaccination should be considered in these children.

PMID- 10648765
TI  - Apolipoprotein E genotype and the risk of recurrent lobar intracerebral
      hemorrhage.
AB  - BACKGROUND: Recurrent lobar intracerebral hemorrhage is the hallmark of cerebral
      amyloid angiopathy. The factors that predispose patients to early recurrence of
      lobar hemorrhage are unknown. One candidate is the apolipoprotein E gene, since
      both the epsilon2 and the epsilon4 alleles of apolipoprotein E appear to be
      associated with the severity of amyloid angiopathy. METHODS: We performed a
      prospective, longitudinal study of consecutive elderly patients who survived a
      lobar intracerebral hemorrhage. The patients were followed for recurrent
      hemorrhagic stroke by interviews at six-month intervals and reviews of medical
      records and computed tomographic scans. RESULTS: Nineteen of 71 enrolled patients
      had recurrent hemorrhages during a mean follow-up period of 23.9+/-14.8 months,
      yielding a 2-year cumulative rate of recurrence of 21 percent. The apolipoprotein
      E genotype was significantly associated with the risk of recurrence. Carriers of
      the epsilon2 or epsilon4 allele had a two-year rate of recurrence of 28 percent,
      as compared with only 10 percent for patients with the common apolipoprotein E
      epsilon3/epsilon3 genotype (risk ratio, 3.8; 95 percent confidence interval, 1.2
      to 11.6; P=0.01). Early recurrence occurred in eight patients, four of whom had
      the uncommon epsilon2/epsilon4 genotype. Also at increased risk for recurrence
      were patients with a history of hemorrhagic stroke before entry into the study
      (two-year recurrence, 61 percent; risk ratio, 6.4; 95 percent confidence
      interval, 2.2 to 18.5; P<0.001). CONCLUSIONS: The apolipoprotein E genotype can
      identify patients with lobar intracerebral hemorrhage who are at highest risk for
      early recurrence. This finding makes possible both the provision of prognostic
      information to patients with lobar hemorrhage and a method of targeting and
      assessing potential strategies for prevention.

PMID- 10648766
TI  - Transmission of Mycobacterium tuberculosis from a cadaver to an embalmer.

PMID- 10648767
TI  - Images in clinical medicine. Aortic coarctation and bicuspid aortic valve.

PMID- 10648768
TI  - Distribution of research awards from the National Institutes of Health among
      medical schools.
AB  - BACKGROUND: Previous studies have demonstrated that a small number of the 125
      medical schools in the United States receive a disproportionately large share of
      the research awards granted by the National Institutes of Health (NIH). We
      assessed whether the distribution of NIH research awards to medical schools
      changed between 1986 and 1997. METHODS: We used NIH data to rank medical schools
      in each year from 1986 to 1997 according to the number of awards each school
      received (as a measure of each school's activity in research, also referred to as
      research intensity). The proportion of awards received by schools ranked 1 to 10,
      11 to 30, 31 to 50, and 51 or lower in research activity was then calculated, and
      changes over time were examined. We also examined changes in the distribution of
      awards and changes in award amounts according to the type of department, the type
      of academic degree held by the principal investigator, and the awarding
      institute. RESULTS: Between 1986 and 1997, the proportion of research awards
      granted by the NIH to the 10 most research intensive medical schools increased
      slightly (from 24.6 percent of all awards to 27.1 percent), whereas the 75 least
      research intensive medical schools (those ranked 51 or lower) received
      proportionately fewer awards (declining from 24.3 percent to 21.8 percent). The
      increased proportion of awards to top-10 schools consisted primarily of increases
      in awards to clinical departments, awards to physicians, and awards from highly
      competitive NIH institutes. Basic-science departments received a smaller
      proportion of awards than clinical departments, both in 1986 and in 1997.
      CONCLUSIONS: Research funded by the NIH is becoming more concentrated in the
      medical schools that are most active in research.

PMID- 10648769
TI  - Congenital heart disease in adults. First of two parts.

PMID- 10648770
TI  - Case records of the Massachusetts General Hospital. Weekly clinicopathological
      exercises. Case 3-2000. A 66-year-old woman with diabetes, coronary disease,
      orthostatic hypotension, and the nephrotic syndrome.

PMID- 10648771
TI  - Is it time to give influenza vaccine to healthy infants?

PMID- 10648772
TI  - Lobar intracerebral hemorrhage.

PMID- 10648774
TI  - Correction: Vitamin A Supplementation for Extremely-Low-Birth-Weight Infants.

PMID- 10648773
TI  - The problems with punitive damages in lawsuits against managed-care
      organizations.

PMID- 10648775
TI  - ATP-hydrolysis-dependent conformational switch modulates the stability of MutS
      mismatch complexes.
AB  - The mismatch repair pathway in Escherichia coli has been extensively studied in
      vitro as well as in vivo. The molecular mechanisms by which nucleotide cofactors
      regulate the whole process constitute an area of active debate. Here we
      demonstrate that nucleotide (ADP or ATP) binding to MutS mediates a switch in
      protein conformation. However, in MutS that is DNA bound, this switch ensues only
      with ATP and not with ADP and is similar, irrespective of whether it is bound to
      a homo- or a heteroduplex. The results envisage a minimal model of three confor
      mational states of MutS as reflected in: (i) a specific and highly stable MutS
      mismatch complex in the absence of a nucleotide; (ii) a specific but less stable
      complex in the presence of ATP hydrolysis; and (iii) an irreversibly dissociated
      complex in the presence of ATP binding (ATPgammaS). Such transitions are of
      relevance to the protein's function in vivo where it has to first recognize a
      mismatch, followed by a search for hemimethylated sites.

PMID- 10648776
TI  - DNA sequence analysis of the photosynthesis region of Rhodobacter sphaeroides
      2.4.1.
AB  - This paper describes the DNA sequence of the photosynthesis region of Rhodobacter
      sphaeroides 2.4.1 (T). The photosynthesis gene cluster is located within a
      approximately 73 kb Ase I genomic DNA fragment containing the puf, puhA, cycA and
      puc operons. A total of 65 open reading frames (ORFs) have been identified, of
      which 61 showed significant similarity to genes/proteins of other organisms while
      only four did not reveal any significant sequence similarity to any gene/protein
      sequences in the database. The data were compared with the corresponding
      genes/ORFs from a different strain of R.sphaeroides and Rhodobacter capsulatus, a
      close relative of R. sphaeroides. A detailed analysis of the gene organization in
      the photosynthesis region revealed a similar gene order in both species with some
      notable differences located to the pucBAC = cycA region. In addition,
      photosynthesis gene regulatory protein (PpsR, FNR, IHF) binding motifs in
      upstream sequences of a number of photosynthesis genes have been identified and
      shown to differ between these two species. The difference in gene organization
      relative to pucBAC and cycA suggests that this region originated independently of
      the photosynthesis gene cluster of R.sphaeroides.

PMID- 10648777
TI  - Identification, purification and partial characterisation of an oligonucleotide
      receptor in membranes of HepG2 cells.
AB  - The low and unpredictable uptake and cytosolic transfer of oligonucleotides (ODN)
      is a major reason for their limited benefit. Improving the ODN potential for
      therapy and research requires a better understanding of their receptor-mediated
      endocytosis. We have undertaken to identify a membrane ODN receptor on HepG2
      cells by ligand blotting of cell extracts with [(125)I]ODN and by photolabelling
      of living cells with a [(125)I]ODN-benzophenone conjugate. A major band at 66 kDa
      was identified by the two methods. Its labelling was saturable and competed for
      by unlabelled ODN of various sequences and irrespective of the presence of a
      phosphodiester or phosphoro-thioate backbone. This protein remained sedimentable
      after carbonate extraction, indicating strong membrane association. About half of
      the total cell amount resisted extensive surface proteolysis, suggesting a dual
      localisation at the plasma membrane and cytoplasmic vesicles. The protein was
      purified using a biotinylated ODN-benzophenone conjugate by photocrosslinking
      followed by streptavidin affinity purification. A sequence obtained by Edman
      degradation showed no homology with known proteins. Using anti-peptide antisera,
      labelling by western blotting revealed at 66 kDa a band with comparable
      properties as found by ligand blotting. Thus, a new membrane protein acting as an
      ODN receptor has been demonstrated.

PMID- 10648778
TI  - Influence of correct secondary and tertiary RNA folding on the binding of
      cellular factors to the HCV IRES.
AB  - Structural integrity of the hepatitus C virus (HCV) 5' UTR region that includes
      the internal ribosome entry site (IRES) element is known to be essential for
      efficient protein synthesis. The functional explanation for this observation has
      been provided by the recent evidence that binding of several cellular factors to
      the HCV IRES is dependent on the conservation of its secondary structure. In
      order to better define the relationship between IRES activity, protein binding
      and RNA folding of the HCV IRES, we have focused our attention on its major stem
      loop region (domain III) and the binding of several cellular factors: two
      subunits of eukaryotic initiation factor eIF3 and ribosomal protein S9. Our
      results show that binding of eIF3 p170 and p116/p110 subunits is dependent on the
      ability of the domain III apical stem-loop region to fold in the correct
      secondary structure whilst secondary structure of hairpin IIId is important for
      the binding of S9 ribosomal protein. In addition, we show that binding of S9
      ribosomal protein also depends on the disposition of domain III on the HCV 5'
      UTR, indicating the presence of necessary inter-domain interactions required for
      the binding of this protein (thus providing the first direct evidence that
      tertiary folding of the HCV RNA does affect protein binding).

PMID- 10648779
TI  - RNA double cleavage by a hairpin-derived twin ribozyme.
AB  - The hairpin ribozyme is a small catalytic RNA that catalyses reversible sequence
      specific RNA hydrolysis in trans. It consists of two domains, which interact with
      each other by docking in an antiparallel fashion. There is a region between the
      two domains acting as a flexible hinge for interdomain interactions to occur.
      Hairpin ribozymes with reverse-joined domains have been constructed by dissecting
      the domains at the hinge and rejoining them in reverse order. We have used both
      the conventional and reverse-joined hairpin ribozymes for the design of a hairpin
      derived twin ribozyme. We show that this twin ribozyme cleaves a suitable RNA
      substrate at two specific sites while maintaining the target specificity of the
      individual monoribozymes. For characterisation of the studied ribozymes we have
      evaluated a quantitative assay of sequence-specific ribozyme activity using
      fluorescently labelled RNA substrates in conjunction with an automated DNA
      sequencer. This assay was found to be applicable with hairpin and hairpin-derived
      ribozymes. The results demonstrate the potential of hairpin ribozymes for multi
      target strategies of RNA cleavage and suggest the possibility for employing
      hairpin-derived twin ribozymes as powerful tools for RNA manipulation in vitro
      and in vivo.

PMID- 10648780
TI  - A long stringent sequence signal for programmed chromosome breakage in
      Tetrahymena thermophila.
AB  - Programmed chromosome breakage occurs at 50-200 specific sites in the genome of
      Tetrahymena thermo-phila during somatic nuclear (macronuclear) differentiation.
      Previous studies have identified a 15 bp sequence, the Cbs (for chromosome
      breakage sequence), that is necessary and sufficient to specify these sites. In
      this study we determined the effects of mutations in the Cbs on its ability to
      specify the chromosome breakage site and promote new telomere formation in
      conjugating cells. Twenty-one constructs with single nucleotide substitutions
      covering all 15 positions of the Cbs were made and tested. Fourteen of them
      (covering 11 positions) abolished breakage entirely, six (covering six positions,
      including the remaining four) caused partial loss of breakage function and one
      showed no detectable effect. This result indicates that the Cbs has an
      exceptionally long and stringent sequence requirement. It offers no evidence that
      the Cbs contains a separate domain for promoting new telomere formation. In
      addition, we found that a partially functional Cbs retained in the macronucleus
      does not induce chromosome breakage during vegetative growth and that excess
      copies of this germline-specific sequence in the somatic nucleus have little
      deleterious effect on cell growth.

PMID- 10648782
TI  - Hydration effects of Ni(2+) binding to synthetic polynucleotides with regularly
      alternating purine-pyrimidine sequences.
AB  - High precision ultrasonic and densimetric techniques have been used to study the
      interaction of Ni(2+)ions with right-handed poly[d(G-C)].poly[d(G-C)], poly-[d(A
      C)].poly[d(G-T)] and poly[d(A-T)].poly[d(A-T)] in 5 mM CsCl, 0.2 mM HEPES, pH 7.5
      at 20 degrees C. From these measurements the changes in the apparent molar volume
      and the apparent molar adiabatic compressibility due to the interaction have been
      obtained. The volume effects of the binding, calculated per mole of Ni(2+)ions,
      range from 11.7 to 23.9 cm(3)mol(-1)and the compressibility effects range from
      19.3 x 10(-4)to 43.1 x 10(-4)cm(3)mol(-1)bar(-1). These data are interpreted in
      terms of dehydration of the polynucleotides and Ni(2+)ions, i.e. the release of
      water molecules from the hydration shells of the molecules. An increase in G+C
      content gives an increase in volume and compressibility effects, indicating a
      rise in the extent of dehydration. The dehydration effects of Ni(2+)binding to
      poly[d(G-C)].poly[d(G-C)] are approximately twice those of poly[d(A-T)].poly[d(A
      T)]. The volume and compressibility effects of Ni(2+)-EDTA complex formation have
      also been measured and used as a model system for quantitative estimation. These
      values revealed that Ni(2+)ions can coordinate two atomic groups of poly[d(G-C)].
      poly[d(G-C)], while in the case of the Ni(2+)-poly[d(A-T)]. poly[d(A-T)] complex
      volume and compressibility effects correspond to one direct or two indirect
      (through water) contacts.

PMID- 10648781
TI  - Multiple copies of the Mason-Pfizer monkey virus constitutive RNA transport
      element lead to enhanced HIV-1 Gag expression in a context-dependent manner.
AB  - Retroviral gene expression requires nuclear export and translation of
      incompletely spliced RNA. In the case of human immunodeficiency virus (HIV), this
      is facilitated by the viral Rev protein binding to its cognate RNA response
      element (RRE), while other retroviruses contain constitutive transport elements
      (CTE) binding to cellular factors. These CTE can substitute for the HIV-1 Rev/RRE
      system, albeit with reduced efficiency. Here, we show that multimeric copies of
      the CTE restore HIV-1 protein expression to levels comparable to or higher than
      Rev/RRE in various cell lines from different species. We suggest that
      multimerization of export factors is important for CTE function, as reported for
      Rev. CTE function was not affected when the element was displaced from its
      natural position close to the poly(A) signal, while insertion of an intron into
      the 3'-untranslated region (3'-UTR) severely reduced CTE activity. In this case,
      cytoplasmic RNA degradation was observed, which may be mediated by nonsense
      mediated RNA decay. In contrast, Rev-dependent gene expression was insensitive to
      an intron in the 3'-UTR. Finally, we show that the putative CTE-binding protein
      RNA helicase A is not specifically translocated into the cytoplasm upon
      overexpression of CTE-containing RNA.

PMID- 10648784
TI  - Requirement for canonical base pairing in the short pseudoknot structure of
      genomic hepatitis delta virus ribozyme.
AB  - The tertiary structure of the 3'-cleaved product of the genomic hepatitis delta
      virus (HDV) ribozyme was solved by X-ray crystallographic analysis. In this
      structure, three single-stranded regions (SSrA, -B and -C) interact intricately
      with one another via hydrogen bonds between nucleotide bases, phosphate oxygens
      and 2'-OHs to form a nested double pseudoknot structure. Among these
      interactions, two Watson-Crick (W-C) base pairs, 726G-710C and 727G-709C, that
      form between SSrA and SSrC (P1.1) seem to be especially important for compact
      folding. To characterize the importance of these base pairs, ribozymes were
      subjected to in vitro selection from a pool of RNA molecules randomly substituted
      at positions 709, 710, 726 and 727. The results establish the importance of the
      two W-C base pairs for activity, although some mutants are active with one G-C
      base pair. In addition, the kinetic parameters were analyzed in all 16
      combinations with two canonical base pairs. Comparison of variant ribozymes with
      the wild-type ribozyme reveals that the difference in reaction rates for these
      variants (DeltaDelta G (double dagger)) is not simply accounted for by the
      differences in the stability of P1.1 (DeltaDelta G (0)(37)). The role played by
      Mg(2+)ions in formation of the P1.1 structure is also discussed.

PMID- 10648783
TI  - Characterization of the enzymatic activity of hChlR1, a novel human DNA helicase.
AB  - Recently, we cloned two highly related human genes, hChlR1 ( DDX11 ) and hChlR2 (
      DDX12 ), which appear to be homologs of the Saccharomyces cerevisiae CHL1 gene.
      Nucleotide sequence analysis suggests that these genes encode new members of the
      DEAH family of DNA helicases. While the enzymatic activity of CHL1 has not been
      characterized, the protein is required for the maintenance of high fidelity
      chromosome segregation in yeast. Here we report that the hChlR1 protein is a
      novel human DNA helicase. We have expressed and purified hChlR1 using a
      baculovirus system and analyzed its enzymatic activity. The recombinant hChlR1
      protein possesses both ATPase and DNA helicase activities that are strictly
      dependent on DNA, divalent cations and ATP. These activities are abolished by a
      single amino acid substitution in the ATP-binding domain. The hChlR1 protein can
      unwind both DNA/DNA and RNA/DNA substrates. It has a preference for movement in
      the 5'-->3' direction on short single-stranded DNA templates. However, unlike
      other DNA helicases, the hChlR1 DNA helicase can translocate along single
      stranded DNA in both directions when substrates have a very long single-stranded
      DNA region. The enzymatic activities of hChlR1 suggest that DNA helicases are
      required for maintaining the fidelity of chromosome segregation.

PMID- 10648785
TI  - Structure and expression of the human p68 RNA helicase gene.
AB  - Nuclear DEAD box protein p68 is immunologically related to SV40 large tumour
      antigen and both proteins possess RNA helicase activity. In this report, we
      describe the structural organisation of the human p68 gene and aspects of the
      regulation of its expression. Northern blot and primer extension analyses
      indicate that, although its level is variable, the p68 RNA helicase appears to be
      expressed from a single transcription start site in all tissues tested. Sequence
      analysis revealed that the p68 promoter harbours a 'TATA', a 'CAAT' and an
      initiator element and contains high affinity binding sites for Sp1, AP-2, CRE and
      Myc. This and functional promoter analyses in transient expression assays suggest
      that transcriptional regulation of the p68 gene is complex. Furthermore, there
      are indications that p68 expression is also regulated post-transcriptionally.
      Steady-state pools of poly(A)(+)RNA from human cells contain completely spliced
      p68 mRNA and alternatively spliced forms that contain introns 8-11 or 8-12 (from
      a total of 12 introns) and are not translated. Analysis of a conditionally p68
      overproducing HeLa cell line points to negative autoregulation at the level of
      splicing, which is confirmed by a recently reported association of p68 with
      spliceosomes in human cells.

PMID- 10648786
TI  - Discrete mobility of single-stranded DNA in non-denaturing gel electrophoresis.
AB  - Gel electrophoresis is the standard method to separate, identify and purify
      nucleic acids. SSCP detects single base changes by altered mobility of single
      stranded segments electrophoresed through non-denaturing polyacrylamide gels.
      Herein, changes in electrophoretic mobilities due to single base substitutions
      were measured for single-stranded segments of lengths ranging from 333 to 547 nt.
      A 484 nt segment in exon H of the human factor IX gene was studied most
      intensively. After SSCP, mobilities were determined by scanning autoradiograms at
      very high resolution (1200 d.p.i.), which allowed precise measurement of
      mobilities. When the mobilities of 46 single base substitutions were
      characterized, the distribution of mutant segments relative to a wild-type
      control was found to be discrete, i.e. the observed mobility values occurred in
      distinct ranges. Discrete mobility distributions were seen at different
      electrophoretic temperatures, buffer concentrations, segment lengths and segment
      sequences. In addition: (i) single base substitutions caused discontinuous
      distributions between highly dispersed and sharp bands; (ii) at least one single
      stranded segment produced two sharp bands of similar intensity. These
      observations suggest that: (i) the single base changes in DNA segments in the
      size range 333-547 nt result in discrete conformational changes; (ii) individual
      DNA molecules of the same DNA segment can occasionally adopt two or more discrete
      conformations.

PMID- 10648787
TI  - DNA binding mode of the Fab fragment of a monoclonal antibody specific for
      cyclobutane pyrimidine dimer.
AB  - Monoclonal antibodies specific for the cyclobutane pyrimidine dimer (CPD) are
      widely used for detection and quantification of DNA photolesions. However, the
      mechanisms of antigen binding by anti-CPD antibodies are little understood. Here
      we report NMR analyses of antigen recognition by TDM-2, which is a mouse
      monoclonal antibody specific for the cis - syn -cyclobutane thymine dimer (T[ c,
      s ]T). (31)P NMR and surface plasmon resonance data indicated that the epitope
      recognized by TDM-2 comprises hexadeoxynucleotides centered on the CPD. Chemical
      shift perturbations observed for TDM-2 Fab upon binding to d(T[ c, s ]T) and
      d(TAT[ c, s ]TAT) were examined in order to identify the binding sites for these
      antigen analogs. It was revealed that d(T[ c, s ]T) binds to the central part of
      the antibody-combining site, while the CPD-flanking nucleotides bind to the
      positively charged area of the V(H)domain via electrostatic interactions. By
      applying a novel NMR method utilizing a pair of spin-labeled DNA analogs, the
      orientation of DNA with respect to the antigen-binding site was determined: CPD
      containing oligonucleotides bind to TDM-2 in a crooked form, draping the 3'-side
      of the nucleotides onto the H1 and H3 segments, with the 5'-side on the H2 and L3
      segments. These data provide valuable information for antibody engineering of TDM
      2.

PMID- 10648788
TI  - Involvement of multiple subunit-subunit contacts in the assembly of RNA
      polymerase II.
AB  - RNA polymerase II from the fission yeast Schizo-saccharomyces pombe consists of
      12 species of subunits, Rpb1-Rpb12. We expressed these subunits, except Rpb4,
      simultaneously in cultured insect cells with baculovirus expression vectors. For
      the isolation of subunit complexes formed in the virus-infected cells, a
      glutathione S -transferase (GST) sequence was fused to the rpb3 cDNA to produce
      GST-Rpb3 fusion protein and a decahistidine-tag sequence was inserted into the
      rpb1 cDNA to produce Rpb1H protein. After successive affinity chromatography on
      glutathione and Ni(2+)columns, complexes consisting of the seven subunits, Rpb1H,
      Rpb2, GST-Rpb3, Rpb5, Rpb7, Rpb8 and Rpb11, were identified. Omission of the GST
      Rpb3 expression resulted in reduced assembly of the Rpb11 into the complex.
      Direct interaction between Rpb3 and the other six subunits was detected by
      pairwise coexpression experiments. Coexpression of various combinations of a few
      subunits revealed that Rpb11 enhances Rpb3-Rpb8 interaction and consequently Rpb8
      enhances Rpb1-Rpb3 interaction to some extent. We propose a mechanism in which
      the assembly of RNA poly-merase II is stabilized through multiple subunit-subunit
      contacts.

PMID- 10648789
TI  - Cloning and DNA-binding properties of a tobacco Ethylene-Insensitive3 (EIN3)
      homolog.
AB  - Ethylene-Insensitive3 (EIN3) is a transcription factor that works in the ethylene
      signaling pathway in Arabidopsis. We isolated a tobacco cDNA encoding an EIN3
      homolog as a sequence-specific DNA-binding protein. The encoded protein TEIL
      (tobaccoEIN3-like) shares 60% identity in amino acid sequence with EIN3. The DNA
      binding domain was localized in the N-terminal half, which shows 92% identity in
      amino acid sequence with the corresponding region of EIN3, suggesting a conserved
      function in DNA-binding specificity. TEIL was indeed functionally similar to EIN3
      because, like EIN3-overexpressing plants, transgenic Arabidopsis seedlings
      overexpressing TEIL cDNA exhibited constitutive triple response phenotypes.
      Random binding site selection analysis revealed that the consensus binding
      sequence for TEIL is AYGWAYCT, where Y and W represent A or C and A or T,
      respectively. A reporter plasmid containing the TEIL binding sites showed a 7- to
      10-fold higher activation relative to that containing a mutated TEIL-binding
      sequence in tobacco protoplasts. A further 2- to 3-fold increase in activation
      was observed when a plasmid for TEIL overproduction was co-transfected,
      indicating that TEIL is a transcriptional activator. Moreover, nuclear extracts
      from ethylene-treated leaves showed an increase in DNA-binding activity specific
      to the TEIL-binding sequence, despite the level of the transcripts being
      unchanged. These observations suggest that TEIL functions as a transcription
      activator with a relatively redundant DNA-binding specificity, and its function
      may be regulated at least in part by modulation of the DNA-binding activity
      through ethylene signaling.

PMID- 10648790
TI  - A catalytic antioxidant metalloporphyrin blocks hydrogen peroxide-induced
      mitochondrial DNA damage.
AB  - Reactive oxygen species (ROS) have been implicated as the cause of cumulative
      damage to DNA, proteins and lipids that can ultimately result in cell death. A
      common problem when measuring oxidative DNA damage has been the introduction of
      modifications in the native state of the molecule by many DNA isolation methods.
      We circumvented this problem by employing direct PCR (DPCR) of whole cell
      lysates. DPCR of mouse lung fibroblasts performed better than PCRs containing
      template acquired by phenol/chloroform extraction or a commercially available
      genomic DNA isolation kit. We investigated the direct use of whole cell
      preparations in the polymerase chain reaction (PCR) to detect hydrogen peroxide
      (H(2)O(2))-mediated DNA damage. We observed a concentration-dependent decrease in
      amplification efficiency of a 4.3 kb mitochondrial (mt)DNA target in H(2)O(2)
      treated mouse lung fibroblasts (MLFs). At low doses the efficiency of
      amplification returns to control levels over 24 h. We detected no change in
      amplification efficiency of a plasmid control containing our mtDNA target under
      any of the culture conditions employed in these studies. Treatment of MLFs with
      the catalytic antioxidant manganese(III) meso -tetrakis(4-benzoic acid)porphyrin
      (MnTBAP) attenuates the effects of H(2)O(2)exposure. When quantitated with an
      external standard the use of DPCR in tandem with a PCR amplification efficiency
      assay provides a powerful approach to assess oxidative mtDNA damage.

PMID- 10648791
TI  - Stp1p, Stp2p and Abf1p are involved in regulation of expression of the amino acid
      transporter gene BAP3 of Saccharomyces cerevisiae.
AB  - Expression of the BAP3 gene of Saccharomyces cerevisiae, encoding a branched
      chain amino acid permease, is induced in response to the availability of several
      naturally occurring amino acids in the medium. This induction is mediated via an
      upstream activating sequence (called UAS(aa)) in the BAP3 promoter, and dependent
      on Stp1p, a nuclear protein with zinc finger domains, suggesting that Stp1p is a
      transcription factor involved in BAP3 expression. In this paper, we show that
      Stp2p, a protein with considerable similarity to Stp1p, is also involved in the
      induction of BAP3 expression. To gain more insight into the roles of STP1 and
      STP2, we have overexpressed both Stp1p and Stp2p in yeast cells. Gel shift assays
      with the UAS(aa)as a probe show that the UAS(aa)can form two major complexes. One
      complex is dependent on Stp2p overexpression and the other is formed
      independently of STP1 or STP2, suggesting that the UAS(aa)is also bound by
      another factor. Here we show that the other factor is Abf1p, which binds
      specifically to the UAS(aa)of BAP3.

PMID- 10648792
TI  - Formaldehyde activation of mitoxantrone yields CpG and CpA specific DNA adducts.
AB  - Recently we have found that mitoxantrone, like Adria-mycin, can be activated by
      formaldehyde and subsequently form adducts which stabilise double-stranded DNA in
      vitro. This activation by formaldehyde may be biologically relevant since
      formaldehyde levels are elevated in those tumours in which mitoxan-trone is most
      cytotoxic. In vitro transcription analysis revealed that these adducts block the
      progression of RNA polymerase during transcription and cause truncated RNA
      transcripts. There was an absolute requirement for both mitoxantrone and
      formaldehyde in transcriptional blockage formation and the activated complex was
      found to exhibit site specificity, with blockage occurring prior to CpG and CpA
      sites in the DNA (non-template strand). The stability of the adduct at 37 degrees
      C was site dependent. The half-lives ranged from 45 min to approximately 5 h and
      this was dependent on both the central 2 bp blockage site as well as flanking
      sequences. The CpG specificity of mitoxantrone adduct sites was also confirmed
      independently by a lambda exonuclease digestion assay.

PMID- 10648793
TI  - Prediction of common secondary structures of RNAs: a genetic algorithm approach.
AB  - In this study we apply a genetic algorithm to a set of RNA sequences to find
      common RNA secondary structures. Our method is a three-step procedure. At the
      first stage of the procedure for each sequence, a genetic algorithm is used to
      optimize the structures in a population to a certain degree of stability. In this
      step, the free energy of a structure is the fitness criterion for the algorithm.
      Next, for each structure, we define a measure of structural conservation with
      respect to those in other sequences. We use this measure in a genetic algorithm
      to improve the structural similarity among sequences for the structures in the
      population of a sequence. Finally, we select those structures satisfying certain
      conditions of structural stability and similarity as predicted common structures
      for a set of RNA sequences. We have obtained satisfactory results from a set of
      tRNA, 5S rRNA, rev response elements (RRE) of HIV-1 and RRE of HIV-2/SIV,
      respectively.

PMID- 10648794
TI  - Statistical analysis of yeast genomic downstream sequences reveals putative
      polyadenylation signals.
AB  - The study of a few genes has permitted the identification of three elements that
      constitute a yeast polyadenyl-ation signal: the efficiency element (EE), the
      positioning element and the actual site for cleavage and poly-adenyl-ation. In
      this paper we perform an analysis of oligonucleotide composition on the sequences
      located downstream of the stop codon of all yeast genes. Several oligonucleotide
      families appear over-represented with a high significance (referred to herein as
      'words'). The family with the highest over-representation includes the
      oligonucleotides shown experimentally to play a role as EEs. The word with the
      highest score is TATATA, followed, among others, by a series of single-nucleotide
      variants (TATGTA, TACATA, TAAATA.) and one-letter shifts (ATATAT). A position
      analysis reveals that those words have a high preference to be in 3' flanks of
      yeast genes and there they have a very uneven distribution, with a marked peak
      around 35 bp after the stop codon. Of the predicted ORFs, 85% show one or more of
      those sequences. Similar results were obtained using a data set of EST sequences.
      Other clusters of over-represented words are also detected, namely T- and A-rich
      signals. Using these results and previously known data we propose a general model
      for the 3' trailers of yeast mRNAs.

PMID- 10648795
TI  - Recognition of 5'-terminal TAR structure in human immunodeficiency virus-1 mRNA
      by eukaryotic translation initiation factor 2.
AB  - TAR, a 59 nt 5'-terminal hairpin in human immuno-deficiency virus 1 (HIV-1) mRNA,
      binds viral Tat and several cellular proteins. We report that eukaryotic
      translation initiation factor 2 (eIF2) recognizes TAR. TAR and the AUG initiation
      codon domain, located well downstream from TAR, both contribute to the affinity
      of HIV-1 mRNA for eIF2. The affinity of TAR for eIF2 was insensitive to lower
      stem mutations that modify sequence and structure or to sequence changes
      throughout the remainder that leave the TAR secondary structure intact. Hence,
      eIF2 recognizes structure rather than sequence in TAR. The affinity for eIF2 was
      severely reduced by a 3 nt change that converts the single A bulge into a 7 nt
      internal loop. T1 footprinting showed that eIF2 protects nucleotides in the loop
      as well as in the strand opposite the A bulge. Thus, eIF2 recognizes the TAR loop
      and lower part of the sub-apical stem. Though not contiguous, these regions are
      brought into proximity in TAR by a bend in the helical structure induced by the
      UCU bulge; binding of eIF2 opens up the bulge context and apical stem. The
      ability to bind eIF2 suggests a function for TAR in HIV-1 mRNA translation.
      Indeed, the 3 nt change that reduces the affinity of TAR for eIF2 impairs the
      ability of reporter mRNA to compete in translation. Interaction of TAR with eIF2
      thus allows HIV-1 mRNA to compete more effectively during protein synthesis.

PMID- 10648796
TI  - Interstrand cross-linking by adriamycin in nuclear and mitochondrial DNA of MCF-7
      cells.
AB  - Activation of Adriamycin by formaldehyde leads to the formation of drug-DNA
      adducts in vitro and these adducts stabilise the DNA to such a degree that they
      function as virtual interstrand cross-links. The formation of these virtual
      interstrand cross-links by Adriamycin was investigated in MCF-7 cells using a
      gene-specific interstrand cross-linking assay. Cross-linking was measured in both
      the nuclear-encoded DHFR gene and in mitochondrial DNA (mtDNA). Cross-link
      formation increased linearly with Adriamycin concentration following a 4 h
      exposure to the drug. The rate of formation of Adriamycin cross-links in each of
      the genomes was similar, reaching maximal levels of 0.55 and 0.4 cross-links/10
      kb in the DHFR gene and mtDNA respectively, following exposure to 20 micro M
      Adriamycin for 8 h. The interstrand cross-link was short lived in both DNA
      compartments, with a half-life of 4.5 and 3.3 h in the DHFR gene and mtDNA
      respectively. The kinetics of total Adriamycin adduct formation, detected using
      [(14)C]Adriamycin, was similar to that of cross-link formation. Maximal adduct
      levels (30 lesions/10 kb) were observed following incubation at 20 micro M drug
      for 8 h. The formation of such high levels of adducts and cross-links could
      therefore be expected to contribute to the mechanism of action of Adriamycin.

PMID- 10648797
TI  - Fusions with histone H3 result in highly specific alteration of gene expression.
AB  - Hap1 is a yeast transcriptional activator which controls expression of genes such
      as CYC1 and CYC7. Our results show that Hap1 activity is dependent on a
      functional chromatin remodeling complex SWI/SNF. Using a modified two-hybrid
      screen with Hap1 as bait, we recovered expression vectors encoding the Gal4
      activation domain fused to histone H3 [Gal4(AD)-H3]. Hap1 activity at CYC1 or
      CYC7 was increased by Gal4(AD)-H3 and the effect was dependent on the presence of
      the activation domain of Hap1 and a functional SWI complex. Importantly,
      overexpression of H3 alone had no effect on Hap1 activity. Analysis of Gal4(AD)
      H3 revealed that the fusion is not incorporated into the nucleosome while a
      functional Gal4 activation domain is dispensable. Activity of many other
      transcriptional activators was unchanged or slightly affected in the presence of
      Gal4(AD)-H3. Thus, our results identify a new class of histone H3 variants that
      cause highly specific alteration of gene expression. Hap1 may interact directly
      with H3 favoring chromatin remodeling by the SWI/SNF complex.

PMID- 10648799
TI  - Production by quantitative photolithographic synthesis of individually quality
      checked DNA microarrays.
AB  - For DNA chip analyses, oligonucleotide quality has immense consequences for
      accuracy, sensitivity and dynamic range. The quality of chips produced by
      photolithographic in situ synthesis depends critically on the efficiency of photo
      deprotection. By means of base-assisted enhancement of this process using 5'-?2
      (2-nitrophenyl)-propyloxycarbonyl-2'-deoxynucleoside phosphoramidites, synthesis
      yields improved by at least 12% per condensation compared to current chemistries.
      Thus, the eventual total yield of full-length oligonucleotide is increased more
      than 10-fold in the case of 20mers. Furthermore, the quality of every individual
      array position was checked quantitatively after synthesis. Subsequently, the
      quality tested chips were used in successive hybridisation experiments.

PMID- 10648798
TI  - AP-2 family members regulate basal and cAMP-induced expression of human chorionic
      gonadotropin.
AB  - The AP-2 family of transcriptional regulator proteins has three members, alpha,
      beta and gamma. AP-2alpha and gamma are expressed in placenta and in the human
      trophoblast cell line JEG-3. AP-2 has been shown to regulate expression of the
      placental human chorionic gonado-tropin (hCG) alpha- and beta-subunit genes,
      however, previous work did not distinguish between the family members. Tryptic
      peptides of the AP-2 protein complexes purified from JEG-3 cells by oligo
      affinity chromatography using the hCGalpha AP-2 site match the amino acid
      sequence of AP-2gamma. The fact that AP-2gamma is present at significant levels
      and binds the hCGalpha trophoblast-specific element suggests that AP-2gamma is at
      least part of the binding complex in vivo and plays a role in regulating hCG
      expression. We show that mutation of each of four AP-2 binding sites within the
      hCGbeta promoter decreases expression in transfection assays, demonstrating that
      all four sites are required for maximal expression in JEG-3 cells. Furthermore,
      we find differences in regulation of the family members: AP-2alpha mRNA levels
      increase in response to cAMP while AP-2gamma mRNA levels do not. The demonstrated
      importance of the AP-2 sites in controlling hCGalpha and beta expression and the
      likely involvement of more than one family member suggest that a balance in AP-2
      proteins is involved in coordinate regulation of these genes. Moreover, many
      placenta-restricted genes are regulated by AP-2 proteins, thus members of this
      family may play an important overall role in placenta-specific expression.

PMID- 10648800
TI  - A simplified method of generating transgenic Xenopus.
AB  - Currently transgenic frog embryos are generated using restriction-enzyme-mediated
      integration (REMI) on decondensed sperm nuclei followed by nuclear
      transplantation into unfertilized eggs. We have developed a simplified version of
      this protocol that has the potential to increase the numbers of normally
      developing transgenic embryos.

PMID- 10648801
TI  - Progress in understanding structure-function relationships in respiratory chain
      complex II.
AB  - Complex II (succinate:quinone oxidoreductase) of aerobic respiratory chains
      oxidizes succinate to fumarate and passes the electrons directly into the quinone
      pool. It serves as the only direct link between activity in the citric acid cycle
      and electron transport in the membrane. Finer details of these reactions and
      interactions are but poorly understood. However, complex II has extremely similar
      structural and catalytic properties to quinol:fumarate oxidoreductases of
      anaerobic organisms, for which X-ray structures have recently become available.
      These offer new insights into structure-function relationships of this class of
      flavoenzymes, including evidence favoring protein movement during catalysis.

PMID- 10648802
TI  - Bcl-2 family: life-or-death switch.
AB  - The Bcl-2 family of proteins that consists of anti-apoptotic and pro-apoptotic
      members determines life-or-death of a cell by controlling the release of
      mitochondrial apoptogenic factors, cytochrome c and apoptosis-inducing factor
      (AIF), that activate downstream executional phases, including the activation of
      death proteases called caspases. Cytochrome c release is, thus, central to
      apoptotic signal transduction in mammals, making study of the mechanism for
      cytochrome c release a major issue. Several models for cytochrome c release have
      been proposed, including rupture of mitochondrial outer membrane and involvement
      of a specific channel. Here, we provide an overview of recent findings on the
      role of Bcl-2 family members in the life-or-death decision of a cell.

PMID- 10648803
TI  - The CREC family, a novel family of multiple EF-hand, low-affinity Ca(2+)-binding
      proteins localised to the secretory pathway of mammalian cells.
AB  - The CREC family consists of a number of recently discovered multiple (up to
      seven) EF-hand proteins that localise to the secretory pathway of mammalian
      cells. At present, the family includes reticulocalbin, ERC-55/TCBP-49/E6BP,
      Cab45, calumenin and crocalbin/CBP-50. Similar proteins are found in quite
      diverse invertebrate organisms such as DCB-45 and SCF in Drosophila melanogaster,
      SCF in Bombyx mori, CCB-39 in Caenorhabditis elegans and Pfs40/PfERC in
      Plasmodium falciparum. The Ca(2+) affinity is rather low with dissociation
      constants around 10(-4)-10(-3) M. The proteins may participate in Ca(2+)
      regulated activities. Recent evidence has been obtained that some CREC family
      members are involved in pathological activities such as malignant cell
      transformation, mediation of the toxic effects of snake venom toxins and putative
      participation in amyloid formation.

PMID- 10648804
TI  - Procollagen binds to both prolyl 4-hydroxylase/protein disulfide isomerase and
      HSP47 within the endoplasmic reticulum in the absence of ascorbate.
AB  - In cells, only properly folded procollagen trimers are secreted from the
      endoplasmic reticulum (ER), while improperly folded abnormal procollagens are
      retained within the ER. Ascorbic acid is a co-factor in procollagen
      hydroxylation, which in turn is required for trimer formation. We examined
      chaperone proteins which bound to procollagen in the absence of ascorbic acid, a
      model which mimics the human disease scurvy at the cellular level. We found that
      both prolyl 4-hydroxylase (P4-H)/protein disulfide isomerase (PDI) and HSP47
      bound to procollagen in the absence of ascorbic acid. However, the binding of PDI
      to procollagen decreased when HSP47 was co-transfected, suggesting that HSP47 and
      PDI compete for binding to procollagen. These data indicate that P4-H/PDI and
      HSP47 have cooperative but distinct chaperone functions during procollagen
      biosynthesis.

PMID- 10648805
TI  - Expression, purification, and initial structural characterization of YadQ, a
      bacterial homolog of mammalian ClC chloride channel proteins.
AB  - YadQ of Escherichia coli is a homolog of the mammalian chloride channels of the
      ClC family. The yadQ gene was cloned as a fusion protein with a hexahistidine tag
      and tobacco etch virus protease site for the removal of the tag. The protein was
      expressed in the membrane of E. coli and extracted with decylmaltoside.
      Purification was achieved by metal affinity chromatography followed by cation
      exchange. Circular dichroism revealed a high alpha-helical content. Size
      exclusion chromatography suggests that YadQ forms dimers. The similarity in
      primary, secondary, and quaternary structure and the ability to recombinantly
      express YadQ in the cell membrane make the protein a good candidate for the
      structural study of ClC chloride channels.

PMID- 10648806
TI  - Inositol 1,4,5-trisphosphate receptor associated with focal contact cytoskeletal
      proteins.
AB  - The linkage between inositol 1,4,5-trisphosphate (IP(3)) receptors (IP(3)Rs) and
      cytoskeletal proteins is considered to be important in cell function. In the
      present study, the association of IP(3)R subtypes with cytoskeletal proteins was
      examined using monoclonal antibodies specific to each IP(3)R subtype. We found
      that IP(3)R type 2 colocalized with talin, a focal contact cytoskeletal protein.
      IP(3)R type 2 exhibited a patchy distribution in the peripheral cytoplasm
      differently from type 1 and type 3 IP(3)R. Furthermore, IP(3)R subtypes co
      immunoprecipitated with talin, vinculin and alpha-actin, but not alpha-actinin or
      paxillin.

PMID- 10648807
TI  - The two dimeric forms of RNase A.
AB  - In 1965 Fruchter and Crestfield (J. Biol. Chem. 240, 2868-3874) observed that
      dimeric RNase A prepared by lyophilization from acetic acid could be separated
      into two forms. Surprisingly, no other structural or functional differences could
      be detected between the two forms. In 1998 a structure for dimeric RNase A was
      determined by X-ray crystallography by Liu et al. (Proc. Natl. Acad. Sci. USA 95,
      3437-3442). We found that the two forms of dimeric RNase A have indeed different
      structural and functional properties, and suggest that the dimer whose structure
      was investigated by Liu and coworkers may be identified with the lesser form of
      dimeric RNase A.

PMID- 10648808
TI  - The E358S mutant of Agrobacterium sp. beta-glucosidase is a greatly improved
      glycosynthase.
AB  - Glycosynthases are nucleophile mutants of retaining glycosidases that catalyze
      the glycosylation of sugar acceptors using glycosyl fluoride donors, thereby
      synthesizing oligosaccharides. The 'original' glycosynthase, derived from
      Agrobacterium sp. beta-glucosidase (Abg) by mutating the nucleophile glutamate to
      alanine (E358A), synthesizes oligosaccharides in yields exceeding 90% [Mackenzie,
      L.F., Wang, Q., Warren, R.A.J. and Withers, S.G. (1998) J. Am. Chem. Soc. 120,
      5583-5584]. This mutant has now been re-cloned with a His(6)-tag into a pET
      29b(+) vector, allowing gram scale production and single step chromatographic
      purification. A dramatic, 24-fold, improvement in synthetic rates has also been
      achieved by substituting the nucleophile with serine, resulting in improved
      product yields, reduced reaction times and an enhanced synthetic repertoire. Thus
      poor acceptors for Abg E358A, such as PNP-GlcNAc, are successfully glycosylated
      by E358S, allowing the synthesis of PNP-beta-LacNAc. The increased glycosylation
      activity of Abg E358S likely originates from a stabilizing interaction between
      the Ser hydroxyl group and the departing anomeric fluorine of the alpha-glycosyl
      fluoride.

PMID- 10648809
TI  - Modification of Cys-418 of pyruvate formate-lyase by methacrylic acid, based on
      its radical mechanism.
AB  - The recently determined crystal structure of pyruvate formate-lyase (PFL)
      suggested a new view of the mechanism of this glycyl radical enzyme, namely that
      intermediary thiyl radicals of Cys-418 and Cys-419 participate in different ways
      [Becker, A. et al. (1999) Nat. Struct. Biol. 6, 969-975]. We report here a
      suicide reaction of PFL that occurs with the substrate-analog methacrylate with
      retention of the protein radical (K(I)=0.42 mM, k(i)=0.14 min(-1)). Using [1
      (14)C]methacrylate (synthesized via acetone cyanhydrin), the reaction end-product
      was identified by peptide mapping and cocrystallization experiments as S-(2
      carboxy-(2S)-propyl) substituted Cys-418. The stereoselectivity of the observed
      Michael addition reaction is compatible with a radical mechanism that involves
      Cys-418 thiyl as nucleophile and Cys-419 as H-atom donor, thus supporting the
      functional assignments of these catalytic amino acid residues derived from the
      protein structure.

PMID- 10648810
TI  - A single d(GpG) cisplatin adduct on the estrogen response element decreases the
      binding of the estrogen receptor.
AB  - Both cisplatin and the estrogen receptor (ER) are known to bend DNA. The
      influence of the bending of sequences by the d(GpG)cisPt adduct binding of ER to
      estrogen response element (ERE)-like sequences was examined. Three ERE-like
      oligonucleotides with different affinities for ER and which include a GG in the
      linker sequence were designed in order to form a single central d(GpG)cisPt
      adduct. Using electrophoretic mobility shift assay and Scatchard analysis, it was
      shown that the presence of a single d(GpG)cisPt adduct in the linker sequence
      decreases the ER affinity for DNA. These results do not support a critical role
      of a DNA bend in the initial recognition of ERE by ER. Then, the platination of
      DNA outside of the ERE half-sites decreases the interaction of ER with ERE.

PMID- 10648811
TI  - Molecular cloning and functional expression of Ca(v)3.1c, a T-type calcium
      channel from human brain.
AB  - Low voltage-activated T-type calcium channels are encoded by a family of at least
      three genes, with additional diversity created by alternative splicing. This
      study describes the cloning of the human brain alpha1G, which is a novel isoform,
      Ca(v)3.1c. Comparison of this sequence to genomic sequences deposited in the
      GenBank allowed us to identify the intron/exon boundaries of the human CACNA1G
      gene. A full-length cDNA was constructed, then used to generate a stably
      transfected mammalian cell line. The resulting currents were analyzed for their
      voltage- and time-dependent properties. These properties identify this gene as
      encoding a T-type Ca(2+) channel.

PMID- 10648812
TI  - Effect of temperature on kinesin-driven microtubule gliding and kinesin ATPase
      activity.
AB  - DeCuevas et al. [J. Cell Biol. 116 (1992) 957-965] demonstrated by circular
      dichroism spectroscopy for the kinesin stalk fragment that shifting temperature
      from 25 to 30 degrees C caused a conformational transition. To gain insight into
      functional consequences of such a transition, we studied the temperature
      dependence of a full-length kinesin by measuring both the velocity of microtubule
      gliding across kinesin-coated surfaces and microtubule-promoted kinesin ATPase
      activity in solution. The corresponding Arrhenius plots revealed distinct breaks
      at 27 degrees C, corroborating the temperature-dependent conformational
      transition for a motility-competent full-length kinesin. Microtubules were found
      to glide up to 45 degrees C; at higher temperatures, kinesin was irreversibly
      damaged.

PMID- 10648813
TI  - Formation of cyclopentenones from all-(E) hydroperoxides of linoleic acid via
      allene oxides. New insight into the mechanism of cyclization.
AB  - Conversions of (Z,E)- and (E,E)-isomers of linoleic acid 13- and 9-hydroperoxides
      with flax and maize allene oxide synthase were studied. All-(E) but not (Z,E)
      hydroperoxides readily undergo cyclization via allene oxides into trans
      cyclopentenones. These results suggest that double bond geometry dramatically
      affects the formation of pericyclic pentadienyl cation intermediate and thus the
      capability of 18:2-allene oxides to undergo electrocyclization into
      cyclopentenones.

PMID- 10648814
TI  - Functional expression of His-tagged sensory rhodopsin I in Escherichia coli.
AB  - Sensory rhodopsin I (SRI) from Halobacterium salinarum was functionally expressed
      in Escherichia coli and subsequently purified to homogeneity using a C-terminal
      His-tag anchor. Yields of 3-4 mg SRI/l cell culture can be obtained. The
      absorption and photocycle properties of SRI were similar if not indistinguishable
      from those of the homologously expressed SRI. A global fit analysis of the
      photocycle data and the calculation of the spectra of states provided strong
      evidence for the existence of an N-like intermediate.

PMID- 10648815
TI  - Mildly oxidised low density lipoprotein induces platelet shape change via Rho
      kinase-dependent phosphorylation of myosin light chain and moesin.
AB  - Oxidised low density lipoprotein (LDL) plays an important role in the
      pathogenesis of atherosclerosis. Here we demonstrate that mildly oxidised (mox)
      LDL engages the GTPase Rho and its effector molecule p160 Rho-kinase to induce
      phosphorylation of myosin light chain and of moesin leading to platelet shape
      change. Pretreatment of platelets with the selective Rho inhibitor C3-transferase
      from Clostridium botulinum or with the Rho-kinase inhibitor Y-27632 blocked mox
      LDL-induced myosin light chain phosphorylation, moesin phosphorylation and shape
      change. Mox-LDL did not induce an increase in cytosolic Ca(2+) during shape
      change. We propose that Rho/Rho-kinase inhibition could be a strategy for
      prevention of the pathologic platelet activation during atherogenesis.

PMID- 10648816
TI  - The affinity of the GroEL/GroES complex for peptides under conditions of protein
      folding.
AB  - The affinity of four short peptides for the Escherichia coli molecular chaperone
      GroEL was studied in the presence of the co-chaperone GroES and nucleotides. Our
      data show that binding of GroES to one ring enhances the interaction of the
      peptides with the opposite GroEL ring, a finding that was related to the
      structural readjustments in GroEL following GroES binding. We further report that
      the GroEL/GroES complex has a high affinity for peptides during ATP hydrolysis
      when protein substrates would undergo repeated cycles of assisted folding.
      Although we could not determine at which step(s) during the cycle our peptides
      interacted with GroEL, we propose that successive state changes in GroEL during
      ATP hydrolysis may create high affinity complexes and ensure maximum efficiency
      of the chaperone machinery under conditions of protein folding.

PMID- 10648817
TI  - Different transcriptional properties of mSim-1 and mSim-2.
AB  - The mSim-1 and mSim-2 gene products are mammalian homologues of the Drosophila
      Sim gene. The dSim gene product transactivates through a DNA binding site known
      as the CNS midline enhancer (CME) element. We have investigated the
      transcriptional properties of mSIM-1 and mSIM-2 mediated through the CME element
      in concert with their dimerization partners, ARNT and ARNT-2. The mSIM-1/ARNT
      heterodimer transactivates reporter constructs via the ARNT carboxy-terminus.
      However, mSIM-2 quenches ARNT transactivation. We find that mSIM-2 competes with
      mSIM-1 for binding to ARNT, suggesting a possible antagonism between these
      transcription factors.

PMID- 10648818
TI  - Single amino acid substitutions affecting the specificity of the fungal ribotoxin
      mitogillin.
AB  - Mitogillin and related fungal ribotoxins are small basic ribonucleolytic proteins
      that inhibit protein synthesis by specifically hydrolyzing a single
      phosphodiester bond in the universally conserved alpha-sarcin/ricin loop (SRL) of
      large subunit ribosomal RNAs. It was previously shown that mitogillin is a
      natural derivative of a T1/U2-like ribonuclease with inserted domains that are
      involved in target selection and specificity. Site-directed mutagenesis was used
      to substitute single amino acids in the previously identified functional domains
      Ala1-Tyr24 (B1-L1-B2 domain) and Lys106-Lys113 (L4 region). Examination of the
      activities of the mutants in the digestion of polyinosinic acid (a ribonuclease
      substrate) and specific cleavage of the SRL shows that Asn7Ala and Lys111Gln
      substitutions lead to altered ribonuclease activity and diminished substrate
      specificity consistent with the proposed functions of these domains.

PMID- 10648819
TI  - Substrate specificity determinants of the checkpoint protein kinase Chk1.
AB  - The Chk1 protein kinase plays a critical role in a DNA damage checkpoint pathway
      conserved between fission yeast and animals. We have developed a quantitative
      assay for Chk1 activity, using a peptide derived from a region of Xenopus Cdc25C
      containing Ser-287, a known target of Chk1. Variants of this peptide were used to
      determine the residues involved in substrate recognition by Chk1, revealing the
      phosphorylation motif Phi-X-beta-X-X-(S/T)*, where * indicates the phosphorylated
      residue, Phi is a hydrophobic residue (M>I>L>V), beta is a basic residue (R>K)
      and X is any amino acid. This motif suggests that Chk1 is a member of a group of
      stress-response protein kinases which phosphorylate target proteins with related
      specificities.

PMID- 10648820
TI  - Association of Cbl with Fms and p85 in response to macrophage colony-stimulating
      factor.
AB  - Tyrosine phosphorylation of Cbl and its association with signal-transducing
      molecules in response to macrophage colony-stimulating factor (M-CSF) were
      analyzed by using cell lines which express the wild-type and a mutant M-CSF
      receptor, Fms. We found that in a clone, F723 TF-1 cells expressing mutant Fms in
      which tyrosine 723 had been substituted with phenylalanine, the M-CSF stimulation
      dependent association between Cbl and Fms was markedly impaired. However,
      phosphorylation of Cbl and its association with the p85 subunit of
      phosphatidylinositol 3-kinase were induced in these mutant cells as seen in the
      wild-type fms transfectant. These results suggest that phosphorylation of
      tyrosine 723 is particularly important for the recruitment of Cbl to the M-CSF
      receptor, but is not required for the phosphorylation and binding of Cbl to
      signal-transducing molecules such as p85.

PMID- 10648821
TI  - The role of conserved extracellular cysteine residues in vasopressin V2 receptor
      function and properties of two naturally occurring mutant receptors with
      additional extracellular cysteine residues.
AB  - The G protein-coupled vasopressin V2 receptor (V2 receptor) contains a pair of
      conserved cysteine residues (C112 and C192) which are thought to form a disulfide
      bond between the first and second extracellular loops. The conserved cysteine
      residues were found to be important for the correct formation of the ligand
      binding domain of some G protein-coupled receptors. Here we have assessed the
      properties of the V2 receptor after site-directed mutagenesis of its conserved
      cysteine residues in transiently transfected human embryonic kidney (HEK 293)
      cells. Mutant receptors (C112S, C112A and C192S, C192A) were non-functional and
      located mostly in the cell's interior. The conserved cysteine residues of the V2
      receptor are thus not only important for the structure of the ligand binding
      domain but also for efficient intracellular receptor transport. In addition to
      the functional significance of the conserved cysteine residues, we have also
      analyzed the defects of two mutant V2 receptors which cause X-linked nephrogenic
      diabetes insipidus (NDI) by the introduction of additional cysteine residues into
      the second extracellular loop (mutants G185C, R202C). These mutations are assumed
      to impair normal disulfide bond formation. Mutant receptor G185C and R202C were
      efficiently transported to the plasma membrane but were defective in ligand
      binding. Only in the case of the mutant receptor R202C, the more sensitive
      adenylyl cyclase activity assay revealed vasopressin-stimulated cAMP formation
      with a 35-fold increased EC(50) value and with a reduced EC(max), indicating that
      ligand binding is not completely abolished. Taking the unaffected intracellular
      transport of both NDI-causing mutant receptors into account, our results indicate
      that the observed impairment of ligand binding by the additional cysteine
      residues is not due to the prevention of disulfide bond formation between the
      conserved cysteine residues.

PMID- 10648822
TI  - Molecular cloning and characterization of a rice dehydroascorbate reductase.
AB  - Plant dehydroascorbate reductase (DHAR), which re-reduces oxidized ascorbate to
      maintain an appropriate level of ascorbate, is very important, but no gene or
      cDNA for plant DHAR has been cloned yet. Here, we describe a cDNA for a rice
      glutathione-dependent DHAR (designated DHAR1). A recombinant Dhar1p produced in
      Escherichia coli was functional. The expression sequence tag database suggests
      that Dhar1p homologs exist in various plants. Furthermore, the rice Dhar1p has a
      low similarity to rat DHAR, although the rice enzyme has a considerably higher
      specific activity than the mammalian one. The mRNA level of DHAR1, the protein
      level of Dhar1p and the DHAR activity in rice seedlings were elevated by high
      temperature, suggesting the protection role of DHAR at high temperature.

PMID- 10648823
TI  - Strongly decreased gap junctional permeability to inositol 1,4, 5-trisphosphate
      in connexin32 deficient hepatocytes.
AB  - Livers from connexin32 (Cx32) deficient mice have been shown to be defective in
      hormonally induced glucose mobilization. In order to determine whether this
      effect is due to decreased diffusion of the second messenger inositol 1,4,5
      trisphosphate (IP(3)) between hepatocytes, we injected iontophoretically
      different amounts of IP(3) in Fura-2 loaded hepatocyte doublets (i.e. cell pairs)
      from wild type or Cx32 deficient mice. Whereas 84% of wild type hepatocytes
      showed an intercellular Ca(2+) wave spreading from the injected cell to the
      neighboring cell, only 25% of Cx32 deficient hepatocyte doublets did so. The
      amount of IP(3) necessary to induce an intercellular Ca(2+) wave in Cx32
      deficient hepatocyte doublets was estimated to be about 25-fold higher than in
      wild type doublets. This confirms the notion that the low hormonally or
      electrically induced glucose mobilization found in Cx32 deficient livers relative
      to wild type livers is due to largely hindered diffusion of IP(3) between Cx32
      deficient hepatocytes.

PMID- 10648824
TI  - Stable cation coordination at a single outer pore residue defines permeation
      properties in Kir channels.
AB  - In epithelial Kir7.1 channels a non-conserved methionine in the outer pore region
      adjacent to the G-Y-G selectivity filter (position +2) was found to determine
      unique properties for permeant and blocking ions characteristic of a K(+) channel
      in a single-occupancy state. The monovalent cation permeability sequence of
      Kir7.1 channels expressed in Xenopus oocytes was
      Tl(+)>K(+)>Rb(+)NH(4)(+)>Cs(+)>Na(+)>Li(+), but the macroscopic conductance for
      Rb(+) was approximately 8-fold larger than for the smaller K(+) ions, and
      decreased approximately 40-fold with the conserved arginine at the +2 position
      (Kir7.1M125R). Moreover, in Kir7.1 Rb(+) restored the typical permeation
      properties of other multi-ion channels indicating that a stable coordination of
      permeant ions at the +2 position defines the initial step in the conduction
      pathway of Kir channels.

PMID- 10648825
TI  - Phosphorylation of the skeletal muscle glycogen-targetting subunit of protein
      phosphatase 1 in response to adrenaline in vivo.
AB  - The protein G(M), which targets protein phosphatase 1 (PP1) to the glycogen
      particles and sarcoplasmic reticulum (SR) of striated muscles, is known to be
      phosphorylated at Ser48 and Ser67 in vitro by adenosine 3',5' cyclic
      monophosphate-dependent protein kinase (PKA) and at Ser48 by MAP kinase-activated
      protein kinase-1 (MAPKAP-K1, also called p90 RSK). The phosphorylation of Ser48
      increases the rate at which the glycogen-associated PP1.G(M) complex
      dephosphorylates (activates) glycogen synthase, but the phosphorylation of Ser67
      has the opposite effect, suppressing the activity of PP1 toward glycogen-bound
      substrates. The phosphorylation of Ser67 overrides the activating effect of Ser48
      phosphorylation because it dissociates PP1 from G(M). Here, we use two phospho
      specific antibodies to demonstrate that the SR-associated form of G(M), as well
      as the glycogen-associated form of G(M), becomes phosphorylated at Ser48 and
      Ser67 in response to adrenaline, supporting the view that the PKA-mediated
      regulation of the PP1.G(M) complex plays a role in the adrenergic control of
      glycogen metabolism and SR function. In contrast, Ser48 is not phosphorylated
      significantly in response to insulin, and neither is Ser67. Thus the
      phosphorylation of G(M) at Ser48 by MAPKAP-K1 or other insulin-stimulated protein
      kinases is not involved in the activation of glycogen synthase by insulin.

PMID- 10648826
TI  - Combinatorial synthesis of omega-conotoxin MVIIC analogues and their binding with
      N- and P/Q-type calcium channels.
AB  - Omega-conotoxin MVIIC (MVIIC) blocks P/Q-type calcium channels with high affinity
      and N-type calcium channels with low affinity, while the highly homologous omega
      conotoxin MVIIA blocks only N-type calcium channels. We wished to obtain MVIIC
      analogues more selective for P/Q-type calcium channels than MVIIC to elucidate
      structural differences among the channels, which discriminate the omega
      conotoxins. To prepare a number of MVIIC analogues efficiently, we developed a
      combinatorial method which includes a random air oxidation step. Forty-seven
      analogues were prepared in six runs and some of them exhibited higher selectivity
      for P/Q-type calcium channels than MVIIC in binding assays.

PMID- 10648827
TI  - The allosteric ATP-inhibition of cytochrome c oxidase activity is reversibly
      switched on by cAMP-dependent phosphorylation.
AB  - In previous studies the allosteric inhibition of cytochrome c oxidase at high
      intramitochondrial ATP/ADP-ratios via binding of the nucleotides to the matrix
      domain of subunit IV was demonstrated. Here we show that the allosteric ATP
      inhibition of the isolated bovine heart enzyme is switched on by cAMP-dependent
      phosphorylation with protein kinase A of subunits II (and/or III) and Vb, and
      switched off by subsequent incubation with protein phosphatase 1. It is suggested
      that after cAMP-dependent phosphorylation of cytochrome c oxidase mitochondrial
      respiration is controlled by the ATP/ADP-ratio keeping the proton motive force
      Deltap low, and the efficiency of energy transduction high. After Ca(2+)-induced
      dephosphorylation this control is lost, accompanied by increase of Deltap, slip
      of proton pumping (decreased H(+)/e(-) stoichiometry), and increase of the rate
      of respiration and ATP-synthesis at a decreased efficiency of energy
      transduction.

PMID- 10648828
TI  - Inhibition of endosome fusion in primary hepatocytes prevents asialoglycoprotein
      degradation but not uptake of transferrin iron demonstrating that intracellular
      iron release occurs from early endosomes.
AB  - A comparison of the effects of inhibitors of membrane fusion on the uptake of
      asialoglycoprotein and transferrin by primary rat hepatocytes was made. This
      showed that while high potassium medium inhibited the degradation but not the
      uptake of asialoorosomucoid, both transferrin endocytosis and iron delivery to
      the cells were unaffected. This difference between the two pathways was also
      observed with an inhibitor of phospholipase A2, bromophenacyl bromide. With the
      latter, it was found that the asialoglycoproteins failed to traverse from a low
      density to a high-density intracellular compartment, implying a role for
      phospholipase A2 in the trafficking of asialoglycoprotein receptor but not that
      for transferrin or iron. This demonstrates that, after its release from
      transferrin, iron is transported to the cytoplasm directly from the early
      endosome without the need for fusion of the iron-containing vesicle with a
      lysosome.

PMID- 10648829
TI  - Identification of glucose 6-phosphate dehydrogenase deficiency in a population
      with a high frequency of thalassemia.
AB  - High frequencies of both thalassemia trait (5.2%) and glucose 6-phosphate
      dehydrogenase (G6PD) deficiency for only males (1.3%) have been observed in the
      Calabrian population. The G6PD activity measurement was carried out on 1239
      samples of whole blood from Calabrian subjects of both sexes (age range 10-55) by
      a differential pH-metry technique which was quite suitable to determine the G6PD
      deficiency in mass screenings. The analyzed subjects showed: only the thalassemia
      trait; or only the G6PD deficiency; or only the total iron serum deficiency; or
      G6PD deficiency associated with the thalassemia trait or with the total iron
      serum deficiency. The G6PD heterozygous subjects have an enzymatic activity which
      is masked by both the thalassemia trait and the total iron serum deficiency. In a
      population showing high frequencies of both thalassemia trait and G6PD
      deficiency, the comparison of G6PD activity of heterozygous subjects also
      affected with the thalassemia trait is more reliable if referred to the enzymatic
      activity of the carriers of the latter inherited anomaly rather than to G6PD
      activity of normal subjects.

PMID- 10648830
TI  - The endothelial monocyte-activating polypeptide II (EMAP II) is a substrate for
      caspase-7.
AB  - Endothelial monocyte-activating polypeptide II (EMAP II) is a proinflammatory
      cytokine and a chemoattractant for leukocytes. The mature cytokine is formed in
      apoptotic cells by cleavage of the precursor proEMAP II. Here we show that
      caspase-7 is capable of cleaving proEMAP II in vitro. A proEMAP II mutant, in
      which the ASTD cleavage site was changed to the sequence ASTA, was not processed
      by caspase-7. The caspase-7-mediated generation and release of mature EMAP II may
      provide a mechanism for leukocyte recruitment to sites of programmed cell death,
      and thus may link apoptosis to inflammation.

PMID- 10648831
TI  - Isolation and characterisation of the human rab18 gene after stimulation of
      endothelial cells with histamine.
AB  - Here we report the isolation of a cDNA encoding the complete human rab18 protein
      from histamine-stimulated endothelial cells using differential display. The amino
      acid sequence showed 98% homology with the previously isolated mouse rab18
      protein, which is implicated in apical/basolateral endocytosis. Northern blot
      analysis revealed two transcripts (2.5 kb and 1 kb) ubiquitously expressed in all
      examined organs, as well as in human umbilical vein endothelial and aortic cells.
      In blood cells rab18 transcripts were hardly detectable. The histamine-induced
      time-dependent increase of rab18 mRNA expression in human umbilical vein
      endothelial cells and peripheral blood mononuclear cells indicates for the first
      time a link between receptor-mediated signal transduction and the regulation of
      rab gene expression. This finding might also imply a role for rab proteins in
      inflammation.

PMID- 10648832
TI  - Amino-terminal truncation of procalcitonin, a marker for systemic bacterial
      infections, by dipeptidyl peptidase IV (DP IV).
AB  - Increased concentrations of procalcitonin (PCT) are found in the plasma of
      patients with thermal injury and in patients with sepsis and severe infection,
      making this molecule important as a diagnostic and prognostic marker in these
      diseases. Interestingly, only the truncated form of PCT, PCT(3-116), is present
      in the plasma of these patients. The enzyme responsible for this truncation is
      unknown as yet. Here, using capillary zone electrophoresis, mass spectrometry and
      Edman sequence analysis, we demonstrate that dipeptidyl peptidase IV (DP IV, EC
      3.4.14.5) is capable of catalyzing the hydrolysis of PCT(1-116), releasing the N
      terminal dipeptide Ala-Pro. We hypothesize that PCT(3-116) is the result of the
      hydrolysis of PCT(1-116) by soluble DP IV of the blood plasma or by DP IV
      expressed on the surface of cells.

PMID- 10648833
TI  - Role of TGF-beta in EGF-induced transformation of NRK cells is sustaining high
      level EGF-signaling.
AB  - We have been isolating and analyzing NRK cell mutants, which fail to transform by
      epidermal growth factor (EGF) and transforming growth factor (TGF)-beta. One such
      mutant, R14, can respond to the growth inhibitory signal of TGF-beta to the same
      extent as parental NRK but fail to respond to the growth stimulatory signal of
      EGF. This mutant has a defect in EGF receptor (EGFR) expression. When R14 mutant
      expressed a high level of EGFR, however, EGF not only induced proliferation in
      this mutant but also induced transformation without the aid of TGF-beta. These
      findings suggest that the major role of TGF-beta in this transformation system
      should be to counteract the ligand-dependent down-regulation of EGFR, thereby
      sustaining high-level EGF-signaling.

PMID- 10648834
TI  - Ozone potentiates vitamin E depletion by ultraviolet radiation in the murine
      stratum corneum.
AB  - As the outermost layer of the skin, the stratum corneum is exposed to
      environmental oxidants. To investigate putative synergisms of environmental
      oxidative stressors in stratum corneum, hairless mice were exposed to ultraviolet
      radiation (UV) and ozone (O(3)) alone and in combination. Whereas a significant
      depletion of alpha-tocopherol was observed after individual exposure to either a
      0.5 minimal erythemal dose of UV or 1 ppm O(3) for 2 h, the combination did not
      increase the effect of UV alone. However, a dose of 0.5 ppm O(3) x 2 h, which had
      no effect when used alone, significantly enhanced the UV-induced depletion of
      vitamin E. We conclude that concomitant exposure to low doses of UV and O(3) at
      levels near those that humans can be exposed to causes additive oxidative stress
      in the stratum corneum.

PMID- 10648835
TI  - Ephrin-B2 is a candidate ligand for the Eph receptor, EphB6.
AB  - No ligand has hitherto been designated for the Eph receptor tyrosine kinase
      family member, EphB6. Here, expression of an EphB6 ligand in the pro-B leukemic
      cell line, Reh, is demonstrated by binding of soluble EphB6-Fc fusion protein to
      the Reh cells. The ligand belongs to the subgroup of membrane spanning ligands,
      as suggested by the fact that phosphatidylinositol-specific phospholipase C
      treatment did not abrogate binding of EphB6-Fc. Two transmembrane Eph receptor
      ligands, ephrin-B1 and ephrin-B2, were identified in Reh cells. Analysis of EphB6
      Fc fusion protein binding to ephrin-B1 or ephrin-B2 transfected COS cells
      revealed a high-affinity saturable binding between EphB6-Fc and ephrin-B2, but
      not with ephrin-B1. In mice, EphB6 has previously been shown to be expressed in
      thymus. Here, we show expression of EphB6 in human thymus, as well as the
      expression of ephrin-B2 in both human and mouse thymus. We conclude that ephrin
      B2 may be a physiological ligand for the EphB6 receptor.

PMID- 10648836
TI  - Identification of a conserved residue responsible for the autoinhibition of cGMP
      dependent protein kinase Ialpha and beta.
AB  - We isolated a constitutively active form of cGMP-dependent protein kinase Ialpha
      (cGK Ialpha) by PCR-driven random mutagenesis. The replacement of Ile-63 by Thr
      in the autoinhibitory domain results in the enhancement of autophosphorylation
      and the basal kinase activity in the absence of cGMP. The hydrophobicity at
      position 63 is essential for the inactive state of cGK Ialpha, and Ile-78 of cGK
      Ibeta is also required for the autoinhibitory property. Furthermore, cGK Ialpha
      (Ile-63-Thr) is constitutively active in vivo. These findings suggest that a
      conserved residue in the autoinhibitory domain was involved in the autoinhibition
      of both cGK Is.

PMID- 10648837
TI  - Expression of canine interferon-beta by a recombinant vaccinia virus.
AB  - A recombinant vaccinia virus expressing canine interferon (IFN)-beta was
      constructed (vv/cIFN-beta). In rabbit kidney (RK13) and canine A72 cells infected
      with vv/cIFN-beta, the recombinant canine IFN-beta was detected in both cell
      extracts and supernatants, and the IFN activities of the culture supernatants
      were also detected. Inhibition of N-linked glycosylation by tunicamycin treatment
      indicated that the recombinant canine IFN-beta was modified by N-linked
      glycosylation in a different way between RK13 and A72 cells, and that N-linked
      glycosylation is essential for its secretion. The growth of vv/cIFN-beta at a low
      multiplicity of infection was inhibited by antiviral activity of canine IFN-beta,
      indicating that this recombinant virus could be used as a suicide viral vector.

PMID- 10648838
TI  - Identification of the two histidine residues responsible for the inhibition by
      malonyl-CoA in peroxisomal carnitine octanoyltransferase from rat liver.
AB  - Carnitine octanoyltransferase (COT), an enzyme that facilitates the transport of
      medium chain fatty acids through peroxisomal membranes, is inhibited by malonyl
      CoA. cDNAs encoding full-length wild-type COT and one double mutant variant from
      rat peroxisomal COT were expressed in Saccharomyces cerevisiae. Both expressed
      forms were expressed similarly in quantitative terms and exhibited full enzyme
      activity. The wild-type-expressed COT was inhibited by malonyl-CoA like the liver
      enzyme. The activity of the enzyme encoded by the double mutant H131A/H340A was
      completely insensitive to malonyl-CoA in the range assayed (2-200 microM). These
      results indicate that the two histidine residues, H131 and H340, are the sites
      responsible for inhibition by malonyl-CoA. Another mutant variant, H327A,
      abolishes the enzyme activity, from which it is concluded that it plays an
      important role in catalysis.

PMID- 10648839
TI  - Peroxynitrite generated from constitutive nitric oxide synthase mediates the
      early biochemical injury in short-term cultured hepatocytes.
AB  - Early loss of P450 in rat hepatocyte cultures appears directly related to nitric
      oxide (NO) overproduction. This study provides experimental evidence for the
      induction - shortly after isolation through the classical procedure - of strong
      oxidative stress that involves both oxygen-derived and NO-derived species. NO
      formation at this stage is due to the early activation of liver constitutive NO
      synthase (cNOS). Immunodetection of nitrated proteins provides direct evidence of
      endogenous peroxynitrite (PN) formation upon hepatocyte isolation. On the basis
      of the combined use of dihydrorhodamine 123 and NOS inhibitors, the analysis of
      the amount, time course and nature of the species involved supports the view that
      PN generated from cNOS-derived NO, while not affecting cell viability and
      hepatocyte monolayer development, is the main species likely responsible for the
      early biochemical injury commonly observed in hepatocyte cultures.

PMID- 10648840
TI  - Cloning, expression and characterization of a novel four EF-hand Ca(2+)-binding
      protein from olive pollen with allergenic activity.
AB  - A novel allergenic member of the family of Ca(2+)-binding proteins has been
      cloned from olive tree pollen. The isolated DNA codes for a protein of 171 amino
      acid residues, which displays four EF-hand sequence motifs. The encoded protein
      was overproduced in Escherichia coli and purified. The protein (18? omitted?795
      Da), which binds Ca(2+) and IgE antibodies from patients allergic to olive
      pollen, undergoes Ca(2+)-dependent conformational changes. It is retained on a
      phenyl-Sepharose column, which indicates the existence of regulatory EF-hand
      domains. This fact suggests its involvement in Ca(2+)-dependent signal
      transduction events of the pollen grain. This allergen could be considered as a
      member of a new subfamily of EF-hand Ca(2+)-binding proteins since it displays a
      low amino acid sequence similarity with the so far known proteins.

PMID- 10648841
TI  - Release of a product of growth arrest-specific gene 6 from rat platelets.
AB  - A product of growth arrest-specific gene 6 (Gas6) is known to be synthesized by
      growth-arrested cells. In this study, we found that several rat tissues including
      platelets contain Gas6 and activation of the platelets with thrombin provoked the
      release of Gas6. ADP and collagen, which as well as thrombin stimulated release
      of ATP from platelets, also enhanced the release of Gas6, suggesting that the
      mechanism of its release was similar to that of ATP release. This study provides
      the first evidence of growth arrest-independent secretion of Gas6 and suggests
      the involvement of Gas6 in vascular diseases as well as hemostasis.

PMID- 10648842
TI  - Hepatic epidermal growth factor-regulated mitogen-activated protein kinase kinase
      kinase activity in the rat: lack of identity with known forms of raf and MEKK.
AB  - Mitogenic signaling involves protein kinases that phosphorylate the mitogen
      activated protein kinase (MAPK) activator, MEK. In rats, basal hepatic MEK kinase
      activity is low in vivo in both adult rats and late gestation fetal rats, and is
      markedly stimulated by intraperitoneal administration of epidermal growth factor
      (EGF). The level of stimulated MEK phosphorylating activity is approximately 15
      times higher in fetal liver than in adult liver. To identify regulated forms of
      the two categories of MEK kinase, Raf and MEKK, Western immunoblotting,
      immunoprecipitation kinase assays and immunodepletion studies were performed.
      Western immunoblotting confirmed that Raf-1, A-Raf, B-Raf, MEKK1 and MEKK2 were
      present at similar levels in E19 and adult liver. However, specific
      immunoprecipitation kinase assays did not detect any kinases that could account
      for marked EGF sensitivity or the higher level of activity in E19 fetuses.
      Immunodepletion studies produced a marked reduction in immunoreactive Raf/MEKK
      content and activity, but a minimal decrease in the ability of chromatography
      fractions to phosphorylate and activate recombinant MEK-1. Our results indicate
      that hepatic, EGF-sensitive MEK kinase activity may reside with a previously
      unidentified and physiologically relevant form of Raf and/or MEKK.

PMID- 10648844
TI  - Reply by the authors(1)

PMID- 10648845
TI  - From the handling editor

PMID- 10648843
TI  - Comment on: Neurotoxicity of prion peptide 106-126 not confirmed, by Beat Kunz,
      Erika Sandmeier, Philipp Christen. FEBS Letters 485 (1999) 65-68.

PMID- 10648846
TI  - A genetic algorithm approach to multi-disorder diagnosis.
AB  - One of the common limitations of expert systems for medical diagnosis is that
      they make an implicit assumption that multiple disorders do not co-occur in a
      single patient. The need for this simplifying assumption stems from the fact that
      finding minimal sets of disorders that cover all symptoms for a given patient is
      generally computationally intractable (NP-hard). In this paper, we explain the
      need for performing multi-disorder diagnosis, review previous approaches,
      formulate the problem using set theory notation, and propose the use of a search
      method based on a genetic algorithm. We test the algorithm and compare it to
      another approach using a simple example. The genetic algorithm performs well
      independently of the order of symptoms, and has the potential to perform multi
      disorder diagnosis using existing or newly developed knowledge bases.

PMID- 10648847
TI  - Predicting the effectiveness of hydroxyurea in individual sickle cell anemia
      patients.
AB  - The study described in this paper was undertaken to develop the ability to
      predict the response of sickle-cell patients to hydroxyurea (HU) therapy. We
      analyzed the effect of HU on the values of 23 parameters of 83 patients. A
      Student's t-test was used to confirm (Rodgers GP, Dover GJ, Noguchi CT, Schechter
      AN, Nienhuis AW. Hematologic responses of patients with sickle cell disease to
      treatment with hydroxyurea, N Engl J Med 1990;322;1037-44) at the 0. 001 level
      that treatment with HU increases the proportion of fetal hemoglobin (HbF), and
      the average corpuscular volume (MCV) of the red blood cells. Correlation analysis
      failed to establish a statistically significant relationship between any of the
      23 parameters and the HbF response. Linear regression analysis also failed to
      predict a patient's response to HU. On the other hand, artificial neural network
      (ANN) pattern-recognition analysis of the 23 parameters predicts, with 86.6%
      accuracy, those patients that respond positively to HU and those that do not.
      Furthermore, we have found that the values of only 10 of the 23 parameters
      (listed in the body of this paper) are sufficient to train ANNs to predict which
      patients will respond to HU.

PMID- 10648848
TI  - Understanding of medico-technical reports.
AB  - Medical practice produces much in the form of written text. The under-usage of
      this medical text for research is largely due to difficulties in processing the
      information. The objective of the Aristotle project is to build an automatic data
      system that is capable of producing a semantic representation of the text in a
      canonical form. Understanding the text requires identifying objects mentioned in
      the text, their properties, and the links between them. The nature of the
      syntactic process allows the connection, step-by-step, of two lexical units. This
      connection is immediately controlled by the Interpreter, which assumes the
      semantic process and queries a knowledge base. The syntactic-semantic Interpreter
      processes one sentence at a time. The Assembler module links the meaning of the
      different sentences and structures into the output's shape.

PMID- 10648849
TI  - Automatic recognition of biological shapes with and without representations of
      shape.
AB  - In this work it is described how to use the curvature function, the Fourier
      descriptors, and the coordinate functions of a contour to achieve automatic
      recognition of biological shapes. Those representations of shape and the
      coordinate functions were applied to recognize human corneal endothelial cells
      embedded in a sample of tissue. We assume that when the coordinates of the points
      of contours are analyzed directly, no representation of shape is being used. We
      applied scale-space filtering to the coordinate functions, to compensate the
      effects of scaling and to minimize the error due to quantization. A technique for
      compensating the effects of rotation, with or without the use of a representation
      of shape, is proposed. Our results show that, for a wide range of biological
      shapes, no representation of shape is required to solve or avoid the problems
      caused by translation, scaling, and rotation. We conclude that for certain
      applications the use of a representation of shape can provide some advantages.
      However, the coordinate functions of contours, evolved in scale-space, can be
      efficiently used, yielding even better results in applications of robotics and
      computer vision related to the recognition of biological shapes.

PMID- 10648850
TI  - A CTL assay requiring only 150 microliter of mouse blood.
AB  - In this paper, we present a method for measuring antigen specific cytotoxic T
      lymphocyte (CTL) activity from individual mouse peripheral blood samples without
      animal sacrifice. Peripheral blood cells are stimulated in vitro with a cocktail
      of antigen, cytokines, costimulatory molecules and irradiated feeder cells
      resulting, 7 days later, in a readily detectable antigen specific signal from a
      well plated under limiting dilution conditions. This highly sensitive and antigen
      specific assay is more efficient than conventional CTL assays and thus increases
      the number of mice that can be tested in a single assay. Since blood samples can
      be assayed from an individual mouse at multiple times during the course of an in
      vivo study, the assay can facilitate and strengthen correlative studies on CTL
      responses and in vivo results.

PMID- 10648851
TI  - Simplified purification of human basophils.
AB  - Studies of human basophils have been limited by the low number present in
      peripheral blood and the difficulties of purification to homogeneity with
      reasonable yield and functional status. Reproducible purification of human
      basophils to 96.5+/-0.5% with a yield of 40.8+/-5.3% was obtained by negative
      selection using immunomagnetic beads following initial separation by density
      gradient centrifugation. Isolated cells demonstrated complete viability by vital
      dye exclusion and spontaneous histamine release following incubation of <5%.
      Stimulation with anti-IgE or calcium ionophore A23187 caused histamine release
      and leukotriene C(4) production. Basophils demonstrated dose-dependent chemotaxis
      to monocyte chemotactic protein-3. This simplified methodology results in fully
      functional basophils in very high purity and good yield.

PMID- 10648852
TI  - JLP5B9: new monoclonal antibody against polysialylated neural cell adhesion
      molecule is of value in phenotyping lung cancer.
AB  - Non-small-cell lung cancer (NSCLC) is currently one of the most prevalent
      malignant tumors. It displays a wide variety of phenotypes which includes
      neuroendocrine markers commonly found on small-cell lung cancers (SCLC) such as
      the neural cell adhesion molecule (NCAM) and in particular its highly
      polysialylated isoform, embryonic NCAM (eNCAM). NSCLC with neuroendocrine
      differentiation may represent a subset of tumors whose cells have a more
      aggressive biological behavior. A tumor marker that distinguishes this latter sub
      type could be of clinical relevance. Accordingly, we have raised a monoclonal
      antibody of the IgM type (JLP5B9) directed against capsular polysaccharides of N.
      meningitidis B which bears polysialic acid groups. We have demonstrated that
      JLP5B9 recognizes eNCAM with high affinity and that it is specifically directed
      against the polysialic acid moieties of NCAM. JLP5B9 was also found to react with
      human SCLC, NSCLC and neuroblastoma cell lines. We then used JLP5B9 as a specific
      probe for the detection of tissue eNCAM and found that it was expressed on up to
      20% of tumor cells obtained from 5 out of 13 patients with NSCLC. This mAb
      deserves further investigation to evaluate its potential as a tool for
      serodiagnosis of lung cancer.

PMID- 10648853
TI  - Effective induction and acquisition of human monoclonal IgE antibodies reactive
      with house-dust mite extracts.
AB  - IgE plays a critical role in acute hypersensitivity such as anaphylaxis, asthma,
      and atopic dermatitis. IgE antibody is, therefore, an essential reagent for
      studying the mechanisms of these diseases. However, it is difficult to obtain IgE
      antibody in amounts sufficient for research use because IgE-producing lymphocytes
      are very rare. To overcome this problem, we investigated the requirements for
      generating IgE-secreting human hybridomas using in vitro immunization of
      peripheral blood lymphocytes. First, culture conditions were optimized for IgE
      production by a combination of the immunomodulatory mediators interleukin-2,
      interleukin-4, interleukin-6, and muramyl dipeptide. Second, the addition of mite
      antigen to the cultures resulted in an increased production of antigen-specific
      IgE as well as antigen-specific IgG and IgM. When activated lymphocytes in these
      cultures were fused with Burkitt lymphoma cells, ICLU-B, antigen-specific IgE
      secreting hybridomas were obtained with high efficiency. These results
      demonstrate that our culture and in vitro immunization system for human
      peripheral blood lymphocytes is useful for obtaining antigen-specific IgE.

PMID- 10648854
TI  - Detection by ELISA of low transferrin levels in bronchoalveolar secretions of
      preterm infants.
AB  - Transferrin levels in bronchoalveolar secretions (BAS) are very low compared to
      serum levels in humans. For the exact measurement of transferrin concentrations
      in BAS a very sensitive assay was developed as a double sandwich enzyme
      immunoassay using the combination of a polyclonal and a monoclonal antibody
      against human transferrin. The measurable range of the assay was 1.5 to 100 ng/ml
      of human transferrin. The lowest measurable value was 0.84 ng/ml and the
      sensitivity of the assay was 0.88 ng/ml. The coefficient of variation was 14.1%
      for 25 ng/ml (intra-assay) and 11-20% (inter-assay). The levels measured in 123
      samples of BAS of preterm infants ranged between 0.03 and 8.93
      (microgram/microgram secretory component (SC)). The determination of transferrin
      in BAS of preterm infants is helpful in determining oxidative damage, e.g. the
      availability of free iron, in the neonatal lung. The transferrin concentration in
      BAS of neonates who recovered from respiratory distress syndrome (RDS) in the
      first six days of life was 0.48 compared to 0.52 ((microgram/microgram SC),
      median range) for infants who developed chronic lung disease.

PMID- 10648855
TI  - A stable and highly sensitive 3,3',5,5'-tetramethylbenzidine-based substrate
      reagent for enzyme-linked immunosorbent assays.
AB  - 3,3',5,5'-Tetramethylbenzidine (TMB) is a widely used chromogen for horseradish
      peroxidase-based detection systems because it yields reaction products with high
      absorption coefficients and lacks carcinogenicity. Unfortunately, TMB is labile
      and poorly soluble in aqueous buffers and such solutions must be freshly prepared
      before each experiment. Moreover, substrate depletion can occur under assay
      conditions. To overcome these problems we have developed a two-component TMB
      substrate system which has a lower detection limit and is more sensitive than
      many commercially available TMB reagents when compared in microtiter plate enzyme
      linked immunosorbent assays. Both components of the substrate system are stable
      for at least 1 year at 4 degrees C and the usual discoloration of TMB stock
      solutions is prevented by the addition of a stabilizer that decomposes upon
      mixing of the two components.

PMID- 10648856
TI  - Growth of human tumor xenografts in SCID mice quantified using an immunoassay for
      tumor marker protein in serum.
AB  - The accurate measurement of the response of a tumor to a given treatment is
      critical to evaluating novel therapeutic modalities. An experimental design is
      reported here that can be generally applied to monitoring human tumor xenografts
      growing in immunodeficient mice. A human non-small cell lung tumor cell line was
      transfected with a mammalian expression vector containing the gene encoding human
      prostate specific antigen (PSA) and has been shown to grow progressively
      following the subcutaneous, intraperitoneal and intravenous inoculation of the
      tumor into severe combined immunodeficient (SCID) mice. The transfected human
      tumor cells produce PSA that accumulates in the sera of all tumor inoculated SCID
      mice. An enzyme-linked immunoassay using a rabbit polyclonal and a mouse
      monoclonal antibody specific for PSA was designed and tested for the detection
      and quantification of serum PSA in tumor-bearing mice. Over a 5-week period, the
      serum levels of PSA of mice inoculated subcutaneously with the tumor increased
      progressively, and the estimated tumor volumes correlated with the amount of PSA
      detected in the serum. Serum PSA levels correlated even better with total tumor
      mass following the intraperitoneal inoculation of tumor cells into SCID mice.
      Serum PSA levels fell rapidly following the surgical debulking of tumor
      xenograft, reaching background levels of PSA in the serum 1 week after tumor
      removal. Serum PSA levels were also observed in SCID mice inoculated
      intravenously with a PSA transfected human lung tumor cell line adapted to grow
      orthotopically in the lung. The transfection of human tumors with a tumor marker
      and the use of an immunoassay to detect this marker establish an experimental
      design that provides a reliable, non-invasive, accurate and simple approach to
      monitor and quantify the growth of human tumor xenografts in SCID mice.

PMID- 10648857
TI  - Interferon-gamma-primed monocytoid cell lines: optimizing their use for in vitro
      detection of bacterial pyrogens.
AB  - In order to reduce animal testing for quality control of pharmaceutical agents
      intended for parenteral use, the Limulus amebocyte lysate (LAL) assay is now
      being accepted in many cases as an alternative to measuring pyrogenic activity of
      samples in rabbits. However, since the LAL test is specific for cell wall
      components from Gram-negative bacteria and is sometimes difficult to perform in
      samples containing large amounts of protein, this alternative still leaves a
      considerable diagnostic gap. Here, we have optimized a previously established
      test based on assessing the formation of neopterin or nitrite in interferon-gamma
      treated human (THP-1) or murine (J774A.1, RAW264.7) monocytoid cell lines,
      respectively, in response to bacterial pyrogens. Optimal results were obtained
      either with THP-1 cells in serum-containing media and using a high concentration
      of interferon-gamma (IFN-gamma) or with RAW264.7 cells in serum-free media and
      independent of the IFN-gamma dose. Results were significantly correlated with
      those obtained by another cell-culture-based assay in which formation of tumor
      necrosis factor-alpha by THP-1 1G3 cells was assessed. Also in RAW264.7 murine
      monocytoid cells, formation of nitrite and of tumor necrosis factor-alpha in
      response to a variety of samples was correlated. Samples shown to be pyrogenic in
      rabbits in a previous study were unambiguously detected with the test presented
      here. As expected, the LAL test was negative with cell-free supernatants from
      Staphylococcus aureus66 kDa). Taken together, these results indicate that the use
      of monocytoid cell lines and the detection of metabolites which are triggered in
      the course of immunostimulation could fill the gap left by the LAL test and help
      to further reduce animal testing for pyrogens.

PMID- 10648858
TI  - Development of a rapid, single-step procedure using protein G affinity
      chromatography to deplete fetal calf serum of its IgG and to isolate murine IgG1
      monoclonal antibodies from supernatants of hybridoma cells.
AB  - Fetal calf serum (FCS) was depleted of its immunoglobulin G (IgG) in a rapid
      procedure using protein G affinity chromatography. 20 ml of FCS was depleted of
      its IgG in less than 80 min by applying 5 ml of FCS to a 1 ml HiTrap protein G
      Sepharose column followed by appropriate elution. Various concentrations of IgG
      depleted FCS (G-FCS) were used in RPMI-1640 medium to grow the mouse hybridoma
      cell lines CAy-G (anti-HBs IgG1 mAb producing hybridoma cell) and CAy-M (anti-HBs
      IgM mAb producing hybridoma cell), which secreted hepatitis B virus surface
      antigen (HBsAg)-reactive IgG1 and IgM monoclonal antibodies (mAbs), respectively.
      Antibody production and cell growth were used as indices to compare the efficacy
      of RPMI/G-FCS with that of RPMI/FCS and serum/protein-free Hybri Max (Sigma, MO,
      USA) hybridoma medium. MAb production and cell growth of CAy-G and CAy-M
      hybridoma cell lines in RPMI/G-FCS were similar to culture in RPMI/FCS and
      significantly better than culture in Hybri Max. We found that G-FCS was superior
      to whole FCS as a culture supplement for the purification of IgG1 mAbs. IgG1 mAbs
      were isolated in a single-step procedure using protein G affinity chromatography,
      from the supernatant of CAy-G hybridoma cells cultured in RPMI/10% G-FCS (RPMI
      1640 medium supplemented with 10% G-FCS). SDS-PAGE analysis revealed that the
      purity of IgG isolated from the supernatant of CAy-G cells cultured in RPMI/10% G
      FCS was more than 99%.

PMID- 10648859
TI  - Quantitation of porcine cytokine and beta 2-microglobulin mRNA expression by
      reverse transcription polymerase chain reaction.
AB  - A quantitative reverse transcription polymerase chain reaction (Q-RT-PCR) method
      was developed to measure pig cytokine mRNA expression. The method utilized an
      internal control with primer sequences for interleukin (IL)-1alpha, 2, 4, 6, 8,
      10, tumor necrosis factor (TNF)-alpha, TNF-beta, interferon (IFN)-gamma and beta
      2 microglobulin (beta(2)-m). The control was modified by insertion of sequences
      for IL-12 (p35 and p40). Pig blood mononuclear cells (BMCs) were stimulated in
      vitro with phytohemagglutinin-P (PHA-P) or bacterial lipopolysaccharide and
      cytokine or beta(2)-m mRNA quantified. To evaluate method performance and the use
      of beta(2)-m as a housekeeping gene (HKG), beta(2)-m mRNA expression was
      examined. Quantitative analysis was achieved at up to threefold differences
      between control and target for beta(2)-m. Results were reproducible with
      coefficients of variations (CVs) ranging between 12.5% and 22.4%. There were no
      significant differences in beta(2)-m mRNA between treated and untreated cells or
      between untreated cells of three pigs (p>/=0.05) suggesting that beta(2)-m can be
      used as a HKG. The method allows quantitation of multiple cytokine mRNAs using a
      single internal control subjecting target and control to the same conditions
      throughout the Q-RT-PCR. The system is versatile since the control plasmid can be
      modified by insertion or deletion of sequences.

PMID- 10648860
TI  - In situ stimulation of a T helper cell hybridoma with a cellulose-bound peptide
      antigen.
AB  - Many enzyme-linked immunosorbent assays take advantage of immobilized antigens
      for the identification of antibody binding sites. Generally, the analysis of
      cellulose membrane-bound B-cell epitopes is currently considered of high utility.
      We adapted this methodology for the stimulation of a T helper cell hybridoma with
      known specificity. Forty overlapping peptides corresponding to the entire rabies
      virus nucleoprotein were synthesized in duplicates on a single sheet of 90x130 mm
      size amino-modified paper. The efficacy of the peptide assembly was monitored by
      color staining of the unreacted amino groups. After completion of the synthesis,
      the side-chain protecting groups were removed, and the membrane was thoroughly
      cleaned of all organic and inorganic contaminants. The membrane was cut into
      pieces, and a standard lymphokine release assay was performed directly from the
      paper-bound antigens. From all the 40 peptide spots only peptide 31D stimulated
      the proliferation of the 9C5.D8-H T-cell hybridoma, known to react to this
      peptide. By using this protocol, as little as 0.4 microgram (approximately 200
      pmole) of peptide could be detected. According to mass spectrometry the T-cell
      stimulation proceeded as a true solid-phase assay. The peptide neither leached
      from the membrane nor was cleaved by the medium-splenocyte mixture. Additionally,
      tryptic digestion of the cellulose membrane released the expected peptide
      fragments.

PMID- 10648861
TI  - Competitive PCR for quantification of minimal residual disease in acute
      lymphoblastic leukaemia.
AB  - A very precise and reproducible polymerase chain reaction (PCR) method was
      developed in order to quantify minimal residual disease (MRD) in children with
      acute lymphoblastic leukaemia (ALL). A clone-specific competitor was constructed
      by introducing a restriction site in a PCR product identical to parts of the
      highly specific rearranged T-cell receptor delta (TCR-delta), T-cell receptor
      gamma (TCR-gamma), or immunoglobulin heavy chain (IgH) genes of the malignant
      clone. Using primers located externally to the restriction site the competitor
      and the DNA from the malignant clone will be amplified under identical
      conditions. After restriction enzyme cleavage, the PCR products originating from
      the competitor and the malignant clone can be distinguished by size in a gel
      electrophoresis step and the amount of residual disease can be determined. The
      method is very sensitive with a detection limit of at least one malignant cell in
      10(5) normal cells. This method may be used for treatment stratification based on
      the early response to antileukaemic therapy.

PMID- 10648862
TI  - Rapid cloning of HLA class I cDNAs by locus specific PCR.
AB  - The human major histocompatibility complex (MHC) class I loci, human leukocyte
      antigen (HLA)-A, -B, -C, encode highly polymorphic molecules that mediate immune
      recognition of infectious pathogens and can initiate the rapid rejection of
      transplanted tissue. Cloning of HLA class I alleles is complicated by
      polymorphism as well as interlocus homology. Here, HLA class I cDNAs are
      amplified by PCR using one common primer with one of three locus specific primers
      whose 3' ends map to conserved, locus specific nucleotides. Using these primers,
      HLA-A, -B, and -C alleles were cloned from a number of cell lines and two
      different HLA-B alleles were cloned from a single, heterozygous cell line. The
      amplified products encode the entire extracellular portion of the class I
      molecules. An amplified HLA-A allele was cloned into an expression vector and the
      protein product was detected on the surface of a transfected cell. A premature
      termination codon was engineered into the HLA-A allele by site directed
      mutagenesis and the soluble protein product was detected in the culture medium of
      transfected cells. Therefore, these primers can be used to rapidly clone, alter,
      and express HLA class I molecules. This method may expedite the generation of
      reagents for testing the antigen specificity of antibodies, natural killer cells,
      or T cells.

PMID- 10648863
TI  - Analysis of immune system gene expression in small rheumatoid arthritis biopsies
      using a combination of subtractive hybridization and high-density cDNA arrays.
AB  - Subtractive hybridization of cDNAs generated from synovial RNA which had been
      isolated from patients with rheumatoid arthritis (RA) or normal controls was used
      in conjunction with high-density array hybridization to identify genes of
      immunological interest. The method was designed to detect gene expression in
      small needle biopsy specimens by means of a prior amplification of nanogram
      amounts of total RNA to full-length cDNA using PCR. The latter was cut with Rsa
      I, ligated with adapters, hybridized with unmodified driver cDNA, and subjected
      to suppression subtraction PCR. Differentially expressed products were cloned
      into E. coli and picked into 384 well plates. Inserts were obtained by PCR across
      the multiple cloning site, and the products arrayed at high density on nylon
      filters. The subtracted cDNAs were also labelled by random priming for use as
      probes for library screening. The libraries chosen were the subtracted one
      described above and a set of 45,000 ESTs from the I.M. A.G.E consortium. Clones
      showing positive hybridization were identified by sequence analysis and homology
      searching. The results showed that the subtracted hybridization approach could
      identify many gene fragments expressed at different levels, the most abundant
      being immunoglobulins and HLA-DR. The expression profile was characteristic of
      macrophage, B cell and plasma cell infiltration with evidence of interferon
      induction. In addition, a significant number of sequences without matches in the
      nucleotide databases were obtained, this demonstrates the utility of the method
      in finding novel gene fragments for further characterisation as potential members
      of the immune system. Although RA was studied here, the technology is applicable
      to any disease process even in cases where amounts of tissue may be limited.

PMID- 10648864
TI  - Quantifiable analysis of human immunoglobulin heavy chain class-switch
      recombination to all isotypes.
AB  - Somatic recombinational events, including the immunoglobulin heavy chain class
      switch, are a normal feature of B-cell maturation. To enable comprehensive and
      sensitive class-switch analysis in ex vivo human B cells, we have developed
      multiple digestion-circularization PCR (DC-PCR) techniques for quantifiable
      detection of switching to all immunoglobulin isotypes. This technology was
      validated by extensive sequencing of PCR products, tests with control non
      lymphoid cells and B-cell lines of known isotypic specificities, and by
      demonstrating DC-PCR selectivity in a model system. With tonsillar B-cell DNA,
      switching to gamma 3, gamma 1, alpha1, gamma 2, gamma 4 and alpha2 isotypes was
      reproducibly detectable among different individuals. Levels of epsilon switching
      were relatively low and usually required higher total amounts of template DNAs
      for detection. Quantitation of alpha1 class switching in a panel of human
      tonsillar whole B cells was performed by the internal-competitor approach, and
      showed a pattern consistent with previous studies on IgA+ tonsillar cells. We
      demonstrate that these assays can rapidly show germline status or specific switch
      rearrangements in B lymphoid cell lines.

PMID- 10648865
TI  - Characterization of a human pancreatic secretory trypsin inhibitor mutant binding
      to Legionella pneumophila as determined by a quartz crystal microbalance.
AB  - We describe the isolation from a large phagemid library of a human pancreatic
      secretory trypsin inhibitor (hPSTI) mutant that binds to Legionella pneumophila.
      To gain further insight into the binding kinetics of the isolated hPSTI mutant,
      an immunosensing system based on a quartz crystal microbalance (QCM) was used. In
      contrast to ELISA procedures, k(on) and k(off) rates could be derived from the
      QCM sensograms. Thus, it is possible to characterize specific intermolecular
      interactions between proteins and phages isolated from large phage display
      libraries by QCM.

PMID- 10648866
TI  - Universal PCR amplification of mouse immunoglobulin gene variable regions: the
      design of degenerate primers and an assessment of the effect of DNA polymerase 3'
      to 5' exonuclease activity.
AB  - Degenerate primers were designed for PCR amplification of unknown mouse
      immunoglobulin (Ig) light (L) and heavy (H) chain variable (V) genes. Each
      subgroup of mouse Ig gene sequences [Kabat, E.A., Wu, T. T., Perry, H.H.,
      Gottesman, K.S., Foeller, C., 1991. Sequences of Proteins of Immunological
      Interest, 5th edn. US Department of Health and Human Services, Public Health
      Service, NIH.] was analyzed, and highly degenerate primers in the framework one
      (FR1) region were designed. A single highly degenerate FR1 primer sufficed for
      the amplification of light chains; for heavy chains, a series of FR1 primers was
      used. At the same time, we assessed the effect of 3' to 5' exonuclease activity
      of DNA polymerase on the utilization of these degenerate primers. Using Taq
      polymerase, which lacks 3' to 5' exonuclease activity, we successfully amplified
      the Ig VL and VH genes expressed in more than a hundred monoclonal hybridoma cell
      lines reactive against a phosphonamidate hapten. Sequence analysis of the cloned
      VL and VH genes, 52 of each, showed that they are derived from multiple germline
      families (10 of the 17 VL families and 9 of the 14 VH families) as recently
      defined [Martinez, C., Lefranc, M., 1998. The mouse (Mus musculus) immunoglobulin
      kappa variable (IGKV) genes and joining (IGKJ) segments. Exp. Clin. Immunogenet.
      15, 184.]. The universality of our primers was also demonstrated by successful
      amplification of other mouse hybridoma cell lines that are specific to different
      antigens.

PMID- 10648868
TI  - Differential uptake and catabolism of prostaglandin (PG)E(2) versus PGF(2alpha)
      in the sheep choroid plexus during development.
AB  - The early postnatal decrease in prostaglandin (PG)E(2) levels in cerebrospinal
      fluid (CSF) likely contributes to the establishment of continuous breathing. To
      elucidate mechanisms underlying this event, choroid plexuses from lateral (L-CP)
      and third/fourth (III/IV-CP) ventricles were incubated with [3H]-PGE(2) and label
      uptake (tissue-to-medium ratio for radioactivity, T/M) and catabolism
      (%radioactivity associated with metabolites, PGM) were measured. [3H]-PGF(2alpha)
      was a reference. Uptake of [3H]-PGE(2) was lower than [3H]-PGF(2alpha) in the
      term fetus (L-CP: 5.9+/-0.5 vs. 9.6+/-0. 9, n=11; III/IV-CP: 2.7+/-0.4 vs. 7.7+/
      1.0, n=5) and 17 d lamb (L-CP: 5.3+/-0.8 vs. 11.0+/-1.2, n=7; III/IV-CP: 3.1+/
      0.2 vs. 11. 6+/-2.8, n=3 and 4, respectively). This difference was not
      significant in the pregnant adult. Release of the two compounds was similar and
      did not change with age. [3H]-PGE(2) uptake was reduced by probenecid (1 mM) and
      excess PG (60 microM PGE(2) or PGF(2alpha)). Excess PG also reduced catabolism in
      the fetus, which was extensive for [3H]-PGE(2) and [3H]-PGF(2alpha)60%). In the
      lamb, catabolism remained high for [3H]-PGE(2) (L-CP: 64+/-4%, n=7; III/IV-CP:
      41+/-4%, n=3), but not [3H]-PGF(2alpha) (L-CP: 26+/-4%, n=7; III/IV-CP: 4+/-1%,
      n=4). In the pregnant adult, catabolism was above background only for [3H]-PGE(2)
      in the L-CP (26+/-5%, n=11). Unlike the perinatal animal, this catabolism was
      reduced by probenecid. In conclusion, PGE(2) uptake and catabolism operate
      independently in the choroid plexus from perinatal sheep. Differences between
      PGE(2) and PGF(2alpha) are developmentally-regulated for both mechanisms. While
      neither process explains the postnatal decrease in CSF PGE(2), both may help keep
      CSF levels low during early postnatal development.

PMID- 10648867
TI  - MEK inhibitors block BDNF-dependent and -independent expression of GABA(A)
      receptor subunit mRNAs in cultured mouse cerebellar granule neurons.
AB  - Brain-derived neurotrophic factor (BDNF) can regulate the maturation of
      developing cerebellar granule neurons. Within 1-2 days of culture, BDNF induces
      the expression of granule neuron terminal differentiation markers, particularly
      GABA(A) receptor alpha6 subunit (GABA(A)alpha6) mRNA. Other trophic factors
      including insulin-like growth factor, the neurotrophin NT-3, pituitary adenylate
      cyclase-activating polypeptide (PACAP), and fetal bovine serum failed to induce
      this early expression. The expression of other GABA(A) receptor subunits,
      including alpha1 and gamma2, was also enhanced by exposure of developing granule
      neurons to BDNF. This BDNF-dependent expression of GABA(A) receptor subunit mRNAs
      could be effectively blocked by treatment with the mitogen-activated protein
      kinase kinase (MEK) inhibitors, PD98059 or U0126. In the absence of BDNF,
      GABA(A)alpha6 expression occurs but not until 3-4 days of culture. This BDNF
      independent expression of GABA(A)alpha6 was also inhibited by PD98059. Further
      studies showed that the BDNF-dependent expression GABA(A)alpha6 could also be
      reduced by LY294002, an inhibitor of the phosphatidylinositol 3-kinase, or
      depolarizing concentrations of KCl. These results thus suggest that both BDNF
      dependent and -independent expressions of GABA(A) receptor subunits require the
      activation of MEK and the mitogen-activated protein kinase (MAPK) pathway.
      However, it is also likely that other signaling pathways modulate this maturation
      process.

PMID- 10648869
TI  - Synchronous postnatal increase in alpha1 and gamma2L GABA(A) receptor mRNAs and
      high affinity zolpidem binding across three regions of rat brain.
AB  - The objective of this study was to correlate postnatal changes in levels of mRNAs
      encoding predominant GABA(A) receptor subunits with a functional index of
      receptor development. This study is the first to quantify the temporal
      relationship between postnatal changes in predominant GABA(A) receptor mRNAs and
      zolpidem-sensitive GABA(A) receptor subtypes. In Experiment 1, we measured
      zolpidem displacement of 3H-flunitrazepam from rat cerebral cortex, hippocampus,
      and cerebellum at 0, 6, 14, 21, 29, and 90 postnatal days. Three independent 3H
      flunitrazepam sites with high (K(i)=2. 7+/-0.6 nM), low (K(i)=67+/-4.8 nM), and
      very low (K(i)=4.1+/-0.9 mM) affinities for zolpidem varied in regional and
      developmental expression. In Experiment 2, we used RNAse protection assays to
      quantify levels of alpha1, alpha2, beta1, beta2, gamma2S and gamma2L mRNAs in the
      above regions at the same postnatal ages. Although there was a high degree of
      regional variation in the developmental expression of zolpidem-sensitive GABA(A)
      receptors and subunit mRNAs, a dramatic increase in high affinity zolpidem
      binding sites and alpha1 mRNA levels occurred within all three regions during the
      second postnatal week. Furthermore, a temporal overlap was observed between the
      rise in alpha1 mRNA and high affinity zolpidem binding and a more prolonged
      increase in gamma2L in each region. These results point to the inclusion of the
      alpha1 and gamma2L subunits in a GABA(A) receptor subtype with a high zolpidem
      affinity and suggest that a global signal may influence the emergence of this
      subtype in early postnatal life.

PMID- 10648870
TI  - Expression of serotonin transporter protein in developing rat brain.
AB  - Serotonin transporter (5-HTT), a transmembrane protein, has been shown in adult
      brain to be distributed not only on synaptic terminals but to a great extent on
      axons as well. Here we report the ontogeny of 5-HTT and its relationship with
      serotonin (5-HT) neurons using established 5-HTT and 5-HT antibodies. Both 5-HTT-
      and 5-HT-immunostaining (-im) appear in 5-HT neurons at embryonic day 12 (E12) in
      rostral raphe nuclei (RRN). Soon after appearing, 5-HTT-im is highly expressed on
      axons, similar to adult expression. However, in contrast to adult, 5-HTT-im also
      outlines the soma-dendrites. Rich 5-HTT-im appears along the entire length of
      projecting axons, extending to the growth tip. In the next 2 days, intensive 5
      HTT-im axons from RRN travel a course preferentially in the floor plate and
      later, the medial forebrain bundle trajectory. A group of new 5-HT-im neurons and
      5-HTT-im axons appear at E13 in caudal raphe nuclei. At E16-18, taking the exact
      trajectory course of 5-HT axons, 5-HTT-im axons reach ganglionic eminence,
      olfactory bulb, and cortex and disperse into many brain regions in E18-20. No 5
      HTT-im cell bodies were seen in nigral, locus ceruleus, or hypothalamus. However,
      the transient expression of 5-HTT on non-serotonergic system was seen in cortical
      and striatal neuroepithelia at E12 and sensory thalamic pathways at P0-P10.
      Prominent 5-HTT-im fibers in thalamocortical bundles project from sensory
      thalamic nuclei through reticular nucleus, internal capsule bundle and form
      barrels in somatosensory cortices. No 5-HTT-im was seen in glia-like cells using
      currently available antibody. These observations indicate that 5-HTT is: (a)
      associated preferentially with 5-HT neurons in brainstem, (b) temporally co
      expressed with 5-HT in 5-HT neurons, (c) expressed on axons prior to synaptical
      sites at target neurons, which strongly indicates a volumic (extrasynaptic)
      transmission, (d) expressed in non-5-HT neurons within a specific window, which
      may affect the development of the systems "borrowing" the 5-HT. The early
      appearance of 5-HTT may also endow functionality as well as vulnerabilities of 5
      HT, sensory thalamic, and cortical neurons to 5-HTT targeting drugs during
      pregnancy and after birth.

PMID- 10648871
TI  - Stimulation of axon growth from the spinal cord by a regenerating limb blastema
      in newts.
AB  - The effects of limb blastemas of Pleurodeles waltl on axon growth from fragments
      of spinal cord were studied in vitro. Cultured in a defined medium, spinal cord
      fragments regenerated sparse, short axons. The culture of spinal fragments in the
      presence of blastemas greatly enhanced the length, number and survival of axons.
      Testing separately each of the two components of the blastema showed that only
      the mesenchyme exerts a neurotropic effect on the spinal fragments. Other tissues
      such as muscle or skin had a limited neurotrophic effect. Additionally, the
      neurotrophic activity of blastemas seems to be dependent of its proliferation
      status. Compared with blastemas of regenerating limbs from young animals,
      irradiated blastemas (devoid of mitotic activity) and blastemas of regenerating
      limbs from old animals or differentiated blastemas (both characterized by a low
      mitotic activity), exhibited a weaker neurotrophic influence. The blastema
      neurotrophic factor is not an attachment molecule but a soluble one and cannot be
      nerve growth factor (NGF) or fibroblast growth factor (FGF). It has a relatively
      low molecular weight (less than 15 kDa) and its protein nature was ascertained by
      its sensitivity to heating and proteases. As the production of this mesenchyme
      derived neurotrophic factor depends upon mesenchymal cell proliferation of the
      blastema, we suggest that there is loop of positive regulation between spinal
      nerves and blastema. Blastema tissues may stimulate nerve regeneration allowing
      the stimulation of proliferation of blastema cells by regenerating nerve fibers.
      Alternatively, blastema cells may produce a neurotrophic factor whose secretion
      might be dependent on cell proliferation.

PMID- 10648872
TI  - Ionotropic glutamate receptor expression in human spinal cord during first
      trimester development.
AB  - Quantitative receptor autoradiography and immunoblotting were used to study the
      expression and distribution of AMPA, kainate and NMDA receptors in first
      trimester human spinal cord obtained from elective abortions ranging from 4 to
      11.5 weeks of gestational age. Spinal cord tissue sections were processed for
      receptor autoradiography with the ligands [3H]AMPA, [3H]kainate and [3H]MK-801
      and the optical density was measured separately in a dorsal region (alar plate)
      and ventral region (basal plate) of the autoradiographs. Binding sites for all
      three ligands were demonstrated already at 4-5.5 weeks of gestation and increased
      continuously during the first trimester both in the dorsal and ventral regions.
      [3H]AMPA binding to both high- and low-affinity sites increased from undetectable
      levels to about 35 and 400 fmol/mg tissue, respectively, during this period. A
      temporal difference in the distribution of [3H]AMPA binding sites was observed.
      The early homogeneous pattern of [3H]AMPA binding in both alar and basal plates
      had changed to a heterogeneous pattern at 11 weeks of gestation with the highest
      density of [3H]AMPA binding sites in the superficial layers of the immature
      dorsal horn. [3H]kainate and [3H]MK-801 binding sites were densely and
      homogeneously distributed already at 4 weeks, and steadily increased six- and two
      fold, respectively, to about 100 fmol/mg tissue at 11.5 weeks of gestation.
      Immunoreactive bands corresponding to the NMDA receptor subunits NR1, NR2A, NR2B,
      NR2C and NR2D were demonstrated by immunoblotting at the earliest between 4.5 and
      7 weeks and increasing concentrations were seen up to 11 weeks of gestation.
      These results suggest that AMPA, kainate and NMDA receptors are expressed in the
      human spinal cord early in embryogenesis.

PMID- 10648873
TI  - Maze learning and motor activity deficits in adult mice induced by iron exposure
      during a critical postnatal period.
AB  - Newborn mice were administered Fe(2+) (iron succinate: 7.5 mg/kg, b. wt) on
      either Days 3-5, 10-12 or 19-21, or vehicle (saline) at the same times,
      postnatally. Spontaneous motor behaviour and radial arm maze learning were tested
      at the age of 3 months. It was found that mice treated with Fe(2+) during
      postnatal Days 10-12 were markedly hypokinetic during the 1st 20-min test period
      and hyperkinetic during the 3rd and final 20-min test period. These mice showed
      an almost complete lack of habituation of spontaneous motor activity parameters
      to the test chambers. In the radial arm maze, the Days 10-12 treatment group
      evidenced significantly both more errors in arm choices and longer latencies to
      acquire all eight pellets; these mice showed also a severe trial-to-trial
      retention deficit as indexed by retention quotients. These behavioural deficits
      were observed also in animals treated with Fe(2+) during postnatal Days 3-5, but
      the effects were less pronounced, indicating the higher susceptibility of the
      brain for Fe(2+)-induced damage during Days 10-12 postpartum. Treatment with
      Fe(2+) on Days 19-21 did not induce behavioural alterations in comparison with
      its respective control (vehicle) group. Analysis of total brain iron content
      indicated significantly more iron (microg/g) accumulation in the basal ganglia,
      but not frontal cortex, of mice from the Days 3-5 and 10-12 Fe(2+) (7.5 mg/kg)
      treatment groups. The contribution of iron overload during the immediate
      postnatal to later functional deficits seems to implicate symptoms of
      Parkinsonism but the kinetics of iron uptake to the brain and its regional
      distribution at this critical period of development awaits elucidation.

PMID- 10648874
TI  - Apoptosis in the developing rat cochlea and its related structures.
AB  - Mammalian development involves proliferation and programmed cell death
      (apoptosis). This study was undertaken to analyse the spatial and temporal
      organisation of apoptosis in developing rat cochlear and associated tissues using
      in situ terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end
      labelling of DNA fragments (TUNEL), and light and electron microscopy. Embryonic
      (E12-E19 days) and postnatal rats (P0-P21 days) were studied. Fixed tissues were
      stained for apoptosis using TUNEL technique and the cytomorphology of apoptosis
      was confirmed by light and electron microscopy. Apoptotic cells were detected
      predominantly during the embryonic and early postnatal development of the
      cochlea. Apoptosis occurred in embryonic precursors of the cochlear duct
      epithelium, mainly in the region of its outgrowth between E12 and E16. In the
      periotic mesenchyme, apoptosis occurred in areas committed to develop into the
      middle ear cavity (peaking at E16) and perilymphatic compartments (peaking around
      E18-E19). Apoptosis in the VIIIth nerve (statoacoustic) ganglion was detected
      throughout the embryonic and early postnatal periods, peaking at E18-E19, around
      the time when the cochlear neural connections are being established. At later
      postnatal days, apoptosis was seen only occasionally in cochlear tissues,
      predominantly in tissues lining the middle ear cavity and sporadically in cells
      of the otic capsule. Therefore, apoptosis appears to occur in areas of
      remodeling, in areas of cavitation and in areas of differentiation. These
      findings provide a template for studying the molecular mechanisms involved in the
      development of the rat inner ear.

PMID- 10648875
TI  - Developmental profiles of SMI-32 immunoreactivity in monkey striate cortex.
AB  - A monoclonal antibody that recognizes a nonphosphorylated epitope on the medium
      and high molecular weight subunits of neurofilament (NF) proteins was used to
      investigate laminar and cell morphology changes in monkey striate cortex during
      post-natal development. Six cortices were obtained from monkeys of a variety of
      ages: five from developing animals with ages spanning the critical period and one
      adult. At post-natal day (PD) 0, immunohistochemistry with the SMI-32 antibody
      revealed immunoreactive (IR) cells in layer IVB and in infragranular layer VI.
      Early in the critical period (PD 7), these layers become more defined with an
      increase in the density of immunopositive cells. At the height of the critical
      period (PD 30 and 42), a drastic increase in the density of SMI-32 labelled
      pyramidal neurons in layers V and VI was observed. Similarly, layer IVC showed an
      abundance of dendritic fragments and dendrites that appeared to originate from
      the infragranular layers. At the end of the critical period (PD 103), a trend
      toward morphological maturation for individual neurons found within each layer
      was observed. During any developmental time point, neurons at first appearance
      tended to show an immature morphology with staining largely restricted to the
      cell bodies. As such, the characteristic arborizations common to mature pyramidal
      and multipolar cells was not evident. We propose that the staining pattern seen
      in this study is consistent with the idea that layers anatomically associated
      with the magnocellular (M) pathway develop earlier than their parvocellular (P)
      counterparts.

PMID- 10648876
TI  - kappa-Opioid receptors in the substantia nigra pars reticulata mediate the U
      50,488-induced locomotor activity of preweanling rats.
AB  - The purpose of the present study was to determine the neuroanatomical location
      where kappa-opioid receptor stimulation induces locomotor activity in the
      preweanling rat. To confirm that the U-50,488-induced locomotor activity of
      preweanling rats is mediated by kappa-opioid receptors, 18-day-old rats were
      initially injected with vehicle or the kappa-opioid receptor agonist U-50,488 (5
      mg/kg, s.c.) followed, 15 min later, by an injection of the kappa-opioid receptor
      antagonist nor-binaltorphimine (nor-BNI; 0, 2, 4, 8, or 12 mg/kg, s.c.). In
      subsequent experiments, 18-day-old rats were injected with vehicle or U-50,488 (5
      mg/kg, s.c.) 15 min prior to bilateral administration (0.25 or 0.5 microl per
      side) of nor-BNI (0, 5, 10, or 20 microg) into the substantia nigra pars
      reticulata (SNR) or medial dorsal striatum (MDS). In the final experiment, 18-day
      old rats received bilateral administration (0.25 microl per side) of vehicle or U
      50,488 (0.0, 0.8, 1.6, or 3.2 microg) into the SNR. Results showed that
      systemically administered nor-BNI (0-12 mg/kg, s.c.) produced a dose-dependent
      reduction in the U-50, 488-induced locomotor activity of preweanling rats. The
      site of action for U-50,488's locomotor-activating effects appeared to be the
      SNR, because (a) bilateral administration of nor-BNI (5, 10, or 20 microg) into
      the SNR caused a complete attenuation of U-50, 488-induced locomotion, and (b)
      bilateral administration of U-50,488 into the SNR caused a dose-dependent
      increase in the locomotor activity of preweanling rats. Striatal injections of
      nor-BNI did not affect U-50,488-induced locomotor activity. When these findings
      are considered together it is apparent that stimulation of kappa-opioid receptors
      in the SNR is both necessary and sufficient for the occurrence of U-50,488
      induced locomotor activity in the preweanling rat.

PMID- 10648877
TI  - Effect of altered thyroid hormone status on rat brain ferritin H and ferritin L
      mRNA during postnatal development.
AB  - The iron binding protein ferritin is a heterogeneous mix of 24 heavy (H) and
      light (L) subunits. The H subunit is associated with iron utilization, while the
      L subunit is responsible for iron storage. Examination of the developmental
      pattern of mRNA abundance in rat brain revealed that ferritin L mRNA is highest
      at birth and declines during the first postnatal week. A similar decline was seen
      in ferritin H mRNA, but was followed by an increase in ferritin H mRNA in the
      second postnatal week which continued through postnatal day 21. The pattern of H
      mRNA regulation is similar to that in previous reports of total ferritin protein
      in the developing rat brain and is consistent with the fact that brain ferritin
      is predominately ferritin H. The effect of thyroid hormone on the developmental
      regulation of ferritin mRNAs was examined by the subcutaneous injection of a
      single dose of exogenous thyroxine (T(4); 2 microg/g) on postnatal day 1.
      Hypothyroidism was induced in pregnant dams with propylthiouracil (PTU; 0.05% in
      drinking water) from gestational day 7. Northern analysis from postnatal days 2
      21 showed that T(4) increased ferritin H mRNA throughout development, while
      ferritin L mRNA was decreased compared to age-matched controls. PTU treatment
      decreased ferritin H and increased L mRNA in the later stages (days 14-21) of
      development. Given the distinct functions of ferritin H and L this suggests a
      role for thyroid hormone in the ability of the brain to regulate stored vs.
      utilizable iron during critical periods of development.

PMID- 10648878
TI  - Time-related changes in connexin mRNA abundance in the rat neocortex during
      postnatal development.
AB  - Gap junction coupling between neurons is important for the temporal and spatial
      co-ordination of neocortical development and can be visualised by dye-coupling.
      Neuronal dye-coupling in the rat neocortex is extensive during the first 2
      postnatal weeks and diminishes rapidly thereafter. We used RT (reverse
      transcriptase)-PCR to investigate the time-related changes in mRNA expression for
      the connexins (Cx) Cx 26, Cx 30, Cx 32, Cx 36, Cx 37, Cx 40, Cx 43, Cx 45 and Cx
      46 as well as for beta-actin and GAPDH in rat neocortex during the first 6
      postnatal weeks. The time courses for mRNA expression for GAPDH, Cx 30, Cx 36 and
      Cx 43 were also investigated by northern blotting. Cx 30 and Cx 45 mRNA abundance
      showed no time-dependent changes during the early postnatal period. The relative
      abundance of Cx 32, Cx 43 and Cx 46 mRNA increased significantly during the first
      2-3 weeks and then remained relatively constant during weeks 3-6. The relative
      abundance of Cx 26, Cx 36, Cx 37 and Cx 40 mRNA also increased significantly
      during the first 10-15 postnatal days but then declined significantly from their
      peak values during weeks 3-6. beta-actin mRNA expression showed no time-related
      changes but GAPDH mRNA expression increased significantly during the first
      postnatal week, then remained constant. The time-dependent changes in mRNA
      relative abundance for GAPDH, Cx 36 and Cx 43 determined by northern blotting
      corroborate the results from the RT-PCR study. None of the Cx exhibited time
      dependent changes in mRNA expression in homogenates of rat neocortex which
      parallel the changes in neuronal dye-coupling during postnatal development.

PMID- 10648879
TI  - Developmental switch in the expression of GABA(A) receptor subunits alpha(1) and
      alpha(2) in the hypothalamus and limbic system of the rat.
AB  - The GABA(A) receptor is a pentameric ligand gated ion channel complex assembled
      from a family of at least 17 different subunits encoded by distinct genes. Two
      subunits, alpha(1) and alpha(2), exhibit age dependent expression throughout
      several areas of the brain. In general, the density of immunoreactive product for
      alpha(1) is greatest in the adult brain, while alpha(2) is highest in younger
      tissue. Since the developmental switch in alpha(1) and alpha(2) coincides with
      the end of the sensitive period for steroid-mediated sexual differentiation of
      the brain, we hypothesized that GABA(A) receptor subunit expression may be
      involved in this process. We have examined the age-dependent expression of
      alpha(1) and alpha(2) in discrete regions of the hypothalamus and limbic system
      of males and females. While we did not detect any dramatic sex differences in
      alpha(1) or alpha(2) immunoreactive density, each region exhibited a unique
      developmental profile. In the ventromedial nucleus of neonatal animals
      immunoreactivity is highest for alpha(1), while in the adult the signal for
      alpha(2) is greater; the opposite of that observed in the ventrolateral thalamus.
      There is no age dependent change for alpha(1) in the preoptic area, while
      alpha(2) shows a small, but significant increase. Immunoreactive densities for
      both subunits increase in the arcuate nucleus and the hippocampus, but decrease
      in the lateral amygdala. We conclude that these regional differences in subunit
      expression across development determine individual characteristics of brain areas
      and may play a role in establishing unique physiological responses to GABA.

PMID- 10648880
TI  - Neuronal VEGF expression correlates with angiogenesis in postnatal developing rat
      brain.
AB  - When exposed to chronic sublethal hypoxia the developing brain responds with
      increases in permeability and angiogenesis. Vascular endothelial growth factor
      (VEGF) may mediate this response. Here, we present data on the localization of
      VEGF in the rat brain cortex during postnatal development and its correlation to
      vascularization. We reared newborn rats under normoxic conditions and in hypoxic
      chambers (FiO(2) 9.5%), removed them at postnatal days (P) 3, 8, 13, 24, and 33
      and prepared the cortical brain tissue for immunohistochemistry, in situ
      hybridization (ISH), Western blot analyses and vessel density counting. When
      compared to age-matched controls, hypoxic-reared animals displayed a significant
      increase in platelet endothelial cell adhesion molecule 1 (PECAM-1) protein
      levels, cerebral microvascular lumen diameter and number and density of vessels
      (number of capillaries per area). In control animals, ISH and
      immunohistochemistry revealed that localization of VEGF is restricted almost
      exclusively to cortical neurons at early stages of development. As the vascular
      bed begins to stabilize, predominant VEGF expression switches to maturing glial
      cells which invest vessels while neuronal expression is reduced to a basal level.
      In hypoxic animals, early localization of VEGF is also restricted to cortical
      neurons, however, during later developmental stages, glial cells express elevated
      levels of VEGF protein and high neuronal expression also persists. Thus chronic
      sublethal hypoxia disrupts the temporal-spatial expression of VEGF, which
      correlates with continuing hypoxia-driven angiogenesis.

PMID- 10648881
TI  - Differential regulation of NPY mRNA expression in embryonic sympathetic and
      chromaffin cultures by NGF.
AB  - RT-PCR analysis of NPY mRNA expression in chick embryonic sympathoadrenal cells
      in culture showed that NGF increases sympathetic but not adrenal NPY mRNA
      content. These results show that the previously reported differential effect at
      the protein level can also be detected at the mRNA level, suggesting a pre
      translational point of regulation. The differential NGF effect in such closely
      related phenotypes is particularly relevant to studies of plasticity and
      differentiation.

PMID- 10648882
TI  - Effects of acute restraint stress on tyrosine hydroxylase mRNA expression in
      locus coeruleus of Wistar and Wistar-Kyoto rats.
AB  - Norepinephrine (NE) is thought to play a role in the stress response, and may be
      involved in stress-related psychopathological conditions such as depression or
      anxiety. Heterogeneity in individual responses to the same stressor suggest that
      a genetic susceptibility to the effects of stress may contribute to such
      pathology. To address possible mechanisms underlying this genetic aspect of the
      stress response, we examined acute stress-induced changes in mRNA expression for
      several components of the NE system in the locus coeruleus (LC) and adrenal
      medullae of stress-susceptible Wistar-Kyoto (WKY) rats and their parent Wistar
      (W) strain. Expression of tyrosine hydroxylase (TH), NE transporter (NET) and
      alpha(2A) receptor mRNA were measured in the LC by in situ hybridization 30 min
      and 2 h after the onset of 30 min restraint stress. Adrenal TH mRNA was measured
      by slot blots. No basal differences were observed for any measure, but in the LC,
      expression of TH mRNA increased by 40% in W rats at 30 min (n=8, p<0.05) and
      returned toward baseline by 2 h, while WKY rats showed only a non-significant 29%
      increase at 2 h. In contrast, adrenal TH mRNA expression increased in WKY rats at
      2 h (n=3, p<0.05), with no significant change in W rats. NET and alpha(2A) mRNA
      were unaltered by restraint stress in both strains. Differences in the stress
      reactivity of TH gene expression in the central and peripheral noradrenergic
      systems may be related to differences in behavioral coping strategies and
      autonomic responsivity to stress in these strains, and suggest that differences
      in noradrenergic reactivity may contribute to genetic susceptibility to stress
      related pathology.

PMID- 10648883
TI  - Isolation and characterization of the human secretogranin II gene promoter.
AB  - The goal of this study was to isolate and functionally characterize the human
      secretogranin II (SgII) gene promoter. SgII is a member of the granin family of
      proteins which are selectively expressed in neurosecretory cells. The human SgII
      promoter contains a consensus TATA box and cyclic AMP response element (CRE) 35
      and 74 bp upstream of the transcription start site, respectively, elements also
      found in the mouse and rat SgII gene promoters. Transfection studies showed that
      869 bp of the human SgII promoter were sufficient to confer cell type-specific
      expression of an SgII promoter-luciferase reporter gene in neurosecretory PC-12,
      GH and BE(2)-M17 cells. The activity of the human SgII promoter was also compared
      in three N-type, human neuroblastoma cell lines [BE(2)-M17, SMS-KAN and SH-SY5Y],
      which differ markedly in the level of SgII expression. SgII promoter activities
      in the neuroblastoma cell lines correlated not only with the levels of SgII but
      also the levels of the cyclic AMP response element-binding protein CREB which
      were highest in BE(2)-M17 cells and lowest in SH-SY5Y cells. To establish that
      the activity of the human SgII promoter in these neuroblastoma cell lines is
      dependent on the level of CREB, rat CREB was overexpressed in SH-SY5Y cells. SgII
      promoter activity was up to 8-fold higher in SH-SY5Y cells overexpressing CREB.
      These results suggest that SgII expression is a marker for neuronal
      differentiation in human neuroblastoma cell lines and is dependent on the level
      of CREB expression.

PMID- 10648884
TI  - Calmodulin-dependent activation of p38 and p42/44 mitogen-activated protein
      kinases contributes to c-fos expression by calcium in PC12 cells: modulation by
      nitric oxide.
AB  - Calcium and nitric oxide (NO) are important messengers for the activity-dependent
      immediate-early gene (IEG) expressions in neuronal cells. In the present study,
      we have investigated the roles of two mitogen-activated protein (MAP) kinases,
      extracellular signal-regulated protein kinase (ERK) and p38 MAP kinase (p38
      kinase) in calcium- and NO-induced c-fos expression in PC12 cells. Membrane
      depolarization-induced calcium increases activated both ERK and p38 kinase within
      5 min. The activation of both ERK and p38 kinase by calcium was a calmodulin
      dependent process since the pretreatment of W13 or calmidazolium, specific
      calmodulin antagonists, blocked calcium-induced activation of both MAP kinases.
      Calcium-induced c-fos expression was significantly reduced by the pretreatment of
      either MEK inhibitor (PD98059) or p38 kinase inhibitor (SB203580). This finding
      indicates that the calmodulin-dependent activation of ERK and p38 kinase is
      involved in calcium-induced c-fos expression. However, sodium nitroprusside and
      SIN-1, known to release NO, dose-dependently activated only ERK. NO-induced c-fos
      expression was partially inhibited by the PD98059. We also observed that NO dose
      dependently potentiates not only calcium-induced c-fos expression but also
      calcium-induced ERK activation. In the presence of PD98059, the amplification of
      calcium-induced c-fos expression by NO was not observed. This result suggests
      that calcium- and NO-signals converge into the MEK/ERK pathway, thereby enhance
      IEG expressions in neuronal cells.

PMID- 10648885
TI  - Differential effects of intrastriatally infused fully and endcap phosphorothioate
      antisense oligonucleotides on morphology, histochemistry and prodynorphin
      expression in rat brain.
AB  - In the present study, we investigated the selectivity and specificity associated
      with continuous intrastriatal treatment with antisense oligonucleotides. Rats
      were given intrastriatal infusions for 72 h with phosphodiester, and fully and
      endcap phosphorothioated oligonucleotide probes complementary to prodynorphin
      mRNA. Dynorphin (Dyn) peptide levels were measured by radioimmunoassay. The
      integrity of three other striatal transmitter systems, the neuropeptide Y (NPY)
      ergic interneurons, the cholinergic interneurons and the dopaminergic afferent
      innervation, was assessed histochemically. The gross morphology of the striatum
      and the distribution of fluorescently labelled antisense probes were also
      investigated. Brains infused with phosphodiester probes had tissue Dyn levels not
      different from control. They also showed little or no change in staining for NPY,
      acetylcholinesterase (AChE) and tyrosine hydroxylase (TH) and essentially normal
      striatal gross morphology. In contrast, brains treated with fully
      phosphorothioated oligonucleotides showed significant decreases in striatal Dyn
      levels but also severe tissue damage accompanied by massive cell infiltration and
      decreases in immunoreactivities for the striatal neurochemical markers.
      Fluorescently labelled phosphorothioate probes were observed widely in the
      striatum and adjacent structures and, presumably retrogradely transported, in the
      dopamine cell bodies in the substantia nigra, also revealing the presence of
      abnormal cellular structures within the striatum. By comparison, endcap probes
      significantly reduced striatal Dyn levels and showed good tissue penetration
      without inducing major changes in tissue morphology or histochemistry of non
      dynorphinergic systems, except for cell infiltration. The deleterious tissue
      effects of fully phosphorothioated oligonucleotides and the ineffectiveness of
      phosphodiester oligonucleotides in inhibiting protein synthesis suggest that, of
      the probes examined in this study, endcap oligonucleotides are the most useful
      for in vivo studies in the central nervous system.

PMID- 10648886
TI  - The effects of mutated skeletal ryanodine receptors on calreticulin and
      calsequestrin expression in the brain and pituitary gland of boars.
AB  - Mutations in skeletal ryanodine receptors (sRyR) result in malignant hyperthermia
      in humans and Porcine Stress Syndrome (PSS) in pigs. Whether the sRyR is
      expressed in neuronal tissue and what impact it has on neuronal function is
      relatively unexplored. We have hypothesized that the presence of mutated sRyR may
      be accompanied by compensatory changes in Ca(2+)-binding protein expression. We
      were interested in whether pigs heterozygous for mutated sRyR would show changes
      in the expression of Ca(2+)-binding proteins, in specific regions of the brain,
      and whether changes in this expression would be accompanied by the presence of
      sRyR within that region. The objectives of the current experiments were to
      determine (1) whether calreticulin (CR) and calsequestrin (CS) are expressed in
      the pituitary gland and brain of the pig, (2) if boars heterozygous for mutated
      sRyR differed from wild-type boars in the expression of CR or CS, and (3) if
      altered Ca(2+)-binding protein expression would be accompanied by the presence of
      sRyR mRNA. Boars either heterozygous or wild-type (n=6) for the mutation in sRyR
      known to cause PSS, were euthanized and the pituitary gland and brains were
      collected for western blotting for CR and CS. An additional four wild-type boars
      were sacrificed and brains were collected for in situ hybridization for sRyR
      mRNA. Immunoreactive CR was expressed in porcine tissues with highest (p<0.0001)
      expression in the pituitary gland and lower but equivalent expression in the
      hypothalamus, frontal cortex, and hippocampus. Immunoreactive CS was not
      detectable in the pituitary gland while low levels were observed in the
      hypothalamus and frontal cortex. Dramatically higher (p<0.0001) levels of CS were
      found in the hippocampus. Genotype did not affect CR expression in the pituitary
      gland or any brain region examined. Immunoreactive CS levels were lower (p<0.002)
      in the hippocampus of heterozygous compared to wild-type boars. In situ
      hybridization experiments revealed the presence of sRyR mRNA in the hippocampus
      equally distributed across all cell subfields. In conclusion, both CR and CS were
      expressed in the porcine brain with specific patterns of expression across the
      brain regions examined. Boars heterozygous for mutated sRyR had lower CS in the
      hippocampus, which was accompanied by the expression of mRNA for sRyR.

PMID- 10648887
TI  - cAMP cascade leads to Ras activation in cortical neurons.
AB  - Monoaminergic G protein-coupled receptors (GPCRs) are highly expressed in the CNS
      at the cerebrocortical level, where they support a variety of behavioural
      responses. To elucidate possible intracellular signalling pathways coupled to
      these receptors, we have studied their ability to activate extracellular signal
      regulated kinases (ERKs) in cultured cortical neurons. An increase in ERK
      activity was observed after stimulation of neurons with dopamine or serotonin,
      and with agonists selective for various GPCRs. In addition, ERK activation was
      also observed following treatment with phorbol dibutyrate (PdBu) and forskolin,
      activators of protein kinase C (PKC) and protein kinase A (PKA), respectively.
      Concomitant with ERK activation, all the monoaminergic agonists tested also
      increased the level of active Ras (Ras-GTP). Surprisingly, Ras activation was
      also observed after activation of cAMP pathway, and this effect was at least in
      part mediated by PKA. Ras activation by cAMP was unique for neurons, since in
      PC12 cells forskolin caused activation of ERK but did not increase Ras-GTP level.
      These results highlight the relevance of Ras as a target for multiple signalling
      cascades leading to activation of the ERK pathway in neurons.

PMID- 10648888
TI  - Cell death in regenerating populations of neurons in BDNF mutant mice.
AB  - There are two populations of neurons which are continually renewed in the adult,
      the dentate gyrus granule neurons and the olfactory bulb granule and
      periglomerular neurons. In the dentate gyrus, a secondary proliferative zone
      termed the subgranular zone is established along the interface between the
      dentate gyrus and the hilus where granule cells are born throughout life.
      Olfactory bulb neurons are generated in the anterior subventricular zone of the
      lateral ventricle and migrate via the rostral migratory stream to the olfactory
      bulb. We examined animals lacking brain-derived neurotrophic factor (BDNF) in
      order to establish whether this neurotrophin could be involved in the generation
      and/or survival of these neurons in vivo. We find that cells in nestin-positive
      regions of both the subgranular layer of the dentate gyrus and the subventricular
      zone of the olfactory bulb undergo apoptosis starting 2 weeks after birth in the
      absence of BDNF. However, increased apoptosis was not limited to precursors, as
      apoptotic cells were also found in the granule cell layer of the dentate gyrus
      and in the granule and periglomerular layers of the olfactory bulb. The excessive
      cell death was limited to these populations of neurons as no excessive cell death
      was detected in other forebrain areas. We conclude that BDNF is essential for the
      survival of neurons specifically in populations which are continuously being
      regenerated in the brain.

PMID- 10648889
TI  - Differential onset of expression of mRNAs encoding proopiomelanocortin,
      prohormone convertases 1 and 2, and granin family members during Xenopus laevis
      development.
AB  - The production of peptide hormones through proteolytic cleavage of prohormones,
      e.g., proopiomelanocortin (POMC), involves a number of regulated secretory
      proteins, such as prohormone convertase PC1, PC2 and granin family members, that
      are co-expressed with the prohormone. Although the expression of these proteins
      has been well-studied in adult animals, data on their expression during
      development are limited. We used whole-mount in situ hybridization to visualize
      POMC mRNA expression in the intermediate and anterior pituitary of Xenopus
      tadpoles. A more sensitive analysis, namely semi-quantitative reverse
      transcription polymerase chain reaction (RT-PCR) on total RNA isolated from
      Xenopus developmental stages, revealed that the expression of POMC, PC1 and PC2
      mRNA commenced at stages 13 (neural plate stage), 15 (neural fold stage) and 19
      (neural tube stage), respectively, with a gradual increase in their expression
      levels during further development. Surprisingly, and in contrast to what holds
      for POMC and the convertases, mRNAs for secretogranin II and III (SgII, SgIII)
      and 7B2 were not only expressed during neural development, but could already be
      detected in unfertilized mature oocytes, the first cleavage stages and in
      blastula-stage embryos. These granins are thus maternally present in Xenopus
      embryos suggesting that they may have a role during oogenesis and/or early
      embryonic development.

PMID- 10648890
TI  - Pterin-4alpha-carbinolamine dehydratase in rat brain. I. Patterns of co
      localization with tyrosine hydroxylase.
AB  - The bifunctional protein, PCD/DCoH, is both a pterin-4alpha-carbinolamine
      dehydratase (PCD) and a dimerization cofactor of the hepatic nuclear factor
      1alpha (DCoH). In association with brain tyrosine hydroxylase (TH), which is
      required for dopamine synthesis, PCD catalyses dehydration and thus recycling of
      the cofactor tetrahydrobiopterin (BH(4)). PCD immunoreactivity in the
      catecholaminergic system of the rat brain was studied using a rabbit polyclonal
      antibody. Double immunofluorescence was performed to establish intracellular co
      localization with TH. PCD immunoreactivity was found to be high and consistently
      present in all the neuron groups expressing TH. More than 90% of the TH+ cells
      were also expressing PCD. The highest co-expression (99-100% of TH+ cells) was
      observed in pontine catecholaminergic cell groups including locus coeruleus.
      Lower co-expression was observed in substantia nigra (17% of TH+ cells without
      PCD) and particularly in arcuate nucleus (41% of TH+ cells without PCD). Our
      results argue in favor of a generalized recycling of BH(4) in catecholaminergic
      neurons except when the neuron terminal field is located outside the blood-brain
      barrier. The respective roles of synthesis and recycling of BH(4) in the control
      of TH activity are discussed.

PMID- 10648891
TI  - Concentration- and cell type-specific effects of calbindin D28k on vulnerability
      of hippocampal neurons to seizure-induced injury.
AB  - The calcium-binding protein calbindin D28k (CB) is expressed in limited
      subpopulations of neurons in the brain. In the hippocampus, CB is expressed in
      all dentate granule cells and a subpopulation of CA1 pyramidal neurons, but is
      absent from CA3 neurons. This pattern of CB expression is inversely correlated
      with neuronal vulnerability to seizure-induced damage suggesting the possibility
      that expression of CB confers resistance to excitotoxicity. While data from cell
      culture studies support an excitoprotective role for calbindin, it is not known
      whether CB is a key determinant of neuronal vulnerability in vivo. We therefore
      examined the pattern of damage to hippocampal neurons following intrahippocampal
      injection of the seizure-inducing excitotoxin kainate in CB homozygous (CB-/-)
      and CB heterozygous (CB+/-) knockout mice in comparison with wild-type mice
      (CB+/+). Whereas the extent of damage to CA1 neurons was similar in CB-/- and
      CB+/+ mice, damage to CA1 neurons was significantly reduced in CB+/- mice.
      Dentate granule neurons were not damaged following kainate-induced seizures in
      CB+/+, CB+/- or CB-/- mice. These findings suggest that CB can modify
      vulnerability of hippocampal CA1 neurons to seizure-induced injury, and that
      either CB is not a critical determinant of resistance of dentate granule neurons,
      or compensatory changes occur and lack of CB is not the only difference between
      CB-/- and CB+/+ mice.

PMID- 10648892
TI  - Glial glutamate transporter mRNAs in the genetically absence epilepsy rat from
      Strasbourg.
AB  - Recent studies support a critical role for the glutamatergic system and glutamate
      transporters in the pathogenesis of epilepsy. The glial glutamate transporters
      GLT-1 (L-glutamate transporter) and GLAST (L-glutamate/L-aspartate transporter)
      are known to be responsible for the majority of glutamate reuptake from the
      synaptic cleft and constitute one mechanism by which extracellular glutamate
      levels may be controlled. The present study therefore compared GLT-1 and GLAST
      mRNA levels in the genetically absence epilepsy rat from Strasbourg (GAERS) with
      those of age-matched non-epileptic controls. The GAERS rat has been proposed as
      an animal model of inherited human absence epilepsy, displaying recurrent,
      generalised, non-convulsive seizures that originate from thalamic and cortical
      structures. In situ hybridisation with 35S-labelled oligonucleotide probes
      demonstrated substantial and significant increases in GLT-1 mRNA levels in the
      ventromedial nucleus of the thalamus (VM) and the subthalamic nucleus (STN) of
      GAERS rats. Increases in GLAST mRNA were found in the primary somatosensory
      cortex (SS1) and temporal cortex (Te) of GAERS. These data, along with previous
      studies, suggest that regional imbalances in GABAergic and glutamatergic systems
      may be associated with the pathogenesis of absence seizures in GAERS.

PMID- 10648893
TI  - Sequential changes in glutamate transporter mRNA levels during Fe(3+)-induced
      epileptogenesis.
AB  - Severe head injury in humans can cause recurrent seizures; this form of epilepsy
      appears to correlate with the occurrence of parenchymal hemorrhage. The injection
      of ferric cations, one component of hemoglobin, into rat amygdala, causes lipid
      peroxidation, and recurrent spontaneous seizures. We wondered whether the
      regulation of glutamate might be perturbed as a result of severe head injury,
      which might then act as a mechanism of chronic epileptogenesis. Levels of
      glutamate transporter glutamate-aspartate transporter (GLAST), glutamate
      transporter-1 (GLT-1), and excitatory amino-acid carrier (EAAC-1) mRNA were
      measured in ipsilateral and contralateral hippocampi and cerebral cortex removed
      from rats at 60 min, 24 h, and 5, 15 and 30 days after FeCl(3) injection into the
      amygdaloid body. While the neuronal transporter EAAC-1 mRNA was elevated
      bilaterally for up to 30 days following the microinjection that initiated
      seizures, GLT-1 mRNA, derived from glial cells, returned to basal levels. At 15
      and 30 days after injection, however, when the experimental animals were
      experiencing spontaneous limbic behavioral seizures, GLAST mRNA was down
      regulated. Epileptogenesis may correlate with the impairment of glial glutamate
      transport, leading to an excitation and imbalance of transmitter influences
      within the hippocampi and cerebral cortex.

PMID- 10648894
TI  - Odor regulates the expression of the mitogen-activated protein kinase phosphatase
      gene hVH-5 in bilateral entorhinal cortex-lesioned rats.
AB  - Since it is known that several immediate early genes are induced by olfactory
      stimuli, we determined whether an olfactory stimulus also induces the expression
      of the mitogen-activated protein kinase (MAPK) phosphatase gene hVH-5 (homologue
      of vaccinia virus H1 phosphatase gene, clone 5), a member of a novel class of
      immediate early genes encoding dual-specificity protein phosphatases. The
      expression was studied by in situ hybridization in different brain structures
      involved in odor processing, in control and bilateral entorhinal cortex (EC)
      lesioned rats. EC-lesion did not significantly affect hVH-5 gene expression in
      the glomerular cell layer of the olfactory bulb (OB), while odor stimulation
      induced it in both control and EC-lesioned groups. In contrast, odor-induced
      expression of hVH-5 gene in mitral/granular cell layers was only evident after
      lesion of the EC. Similar results were obtained in the piriform cortex (PCx), a
      structure intimately connected to the mitral cell layer. In the CA1 hippocampal
      subfield, odor stimulation induced hVH-5 gene expression in both control and EC
      lesioned animals, the increase being potentiated in lesioned rats. CA3 and
      dentate gyrus exhibited a similar pattern of gene expression, the odor
      stimulating gene expression in both control and lesioned groups. The amygdala
      (Am) displayed no significant change. It appears that through the induction of a
      MAPK phosphatase, the EC controls MAPK activities differently after odor
      stimulation in OB, PCx and hippocampus (Hip). The results illustrate the notion
      that odor representation in the brain requires plastic modifications at both
      anatomical and functional levels.

PMID- 10648895
TI  - The disabled 1 gene is disrupted by a replacement with L1 fragment in yotari
      mice.
AB  - The yotari autosomal recessive mutant mouse has a phenotype that is almost
      identical to that of the reeler mouse. We reported in our previous study that the
      yotari mouse expresses a mutated form of disabled 1 (Dab1) mRNA resulting in no
      Dab1 protein. In this study, we demonstrate that the yotari mutation is caused by
      a replacement of gene sequence with a long interspersed nuclear element (L1)
      fragment. The nucleotides of two complete exons and part of an additional exon of
      Dab1 were eliminated as well as three introns by this substitution. The
      substituted L1 fragment contains 962 nucleotides and is highly homologous to the
      members of the T(F) subfamily of L1. It is truncated at both the 5' and 3' ends
      and contains two blocks in a head-to-head arrangement. Based on the DNA sequences
      around the replacement we developed a screening method that enables us to
      distinguish wild type, yotari, and heterozygous mice. This method should greatly
      contribute to analyses of the early anatomical and physiological consequences of
      the yotari mutation.

PMID- 10648896
TI  - Selective expression of JNK isoforms and stress-specific JNK activity in
      different neural cell lines.
AB  - The function of c-Jun N-terminal kinases (JNKs) in the nervous system is poorly
      understood and the majority of the data has been gained in neuronal and non
      neuronal cell lines. Thus, it is not clear to which extent the expression pattern
      and the degree of activation of the three JNK isoforms in different cell lines
      are representative for their activation in the adult brain. In the present study,
      the expression of JNK isoforms and the activity of JNK1 were determined following
      UV irradiation and exposure to H(2)O(2) and TNFalpha in three neural cell lines,
      rat PC12, murine Neuro2A and human SHSY5Y. These cell lines differ in their
      expression of JNK isoforms: PC12 cells express JNK1 and JNK2, whereas Neuro2A and
      SHSY5Y cells displays the expression of JNK1, JNK2 and JNK3. JNK3 was not
      inducible following stress and differentiation in PC12 cells. The stimulation
      paradigms evoked different degree of cell death: UV irradiation resulted in death
      of around 50% in all three cell lines; exposure to 200 microM H(2)O(2) for 6 h
      resulted in the death of 43% Neuro2A cells and 31% PC12 cells, SHSY5Y cells are
      less sensitive to H(2)O(2) since only 5 mM H(2)O(2) killed 59% of SHSY5Y cells
      after 6 h. Exposure to 50 ng/ml TNFalpha did not induce cell death in SHSY5Y,
      Neuro2A and naive PC12 cells. Although differentiated PC12 cells exhibit a
      similar activation of JNK1 compared to naive PC12 cells after exposure to
      TNFalpha, 42% of differentiated PC12 cells died after 24 h. H(2)O(2) that evoked
      only a moderate JNK1 activity in Neuro2A and PC12 cells induced only a moderate
      cell death. In contrast, SHSY5Y cells exhibit a much stronger JNK1 activation
      accompanied with a higher degree in cell death after exposure to H(2)O(2). JNK1
      activity induced by UV irradiation, however, could not be correlated with the
      extend of cell death. These data clearly demonstrate that expression and
      activation of JNK depends on the neuronal cell type and the applied stress
      paradigms, and that JNK activity is not simply linked to cell death.

PMID- 10648897
TI  - 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase expression in rat brain
      during development.
AB  - This study reports the expression of the ubiquitous 6-phosphofructo-2
      kinase/fructose-2,6-bisphosphatase gene (PFKFB3) (PFK-2/FBPase-2) in different
      stages of rat brain development. Northern blot and RT-PCR analysis demonstrated
      that ubiquitous PFK-2/FBPase-2 is expressed in rat brain from embryonic to adult
      life and shows a transient increase 1 day before birth, coincident with the
      maximum concentration of Fru-2,6-P(2) and PFK-2 activity. The levels of brain PFK
      2/FBPase-2 gene expression as well as the enzymatic activity and the
      concentration of Fru-2,6-P(2) appear to be remarkably constant during adult life,
      without significant differences in the brain hippocampus, cortex, cerebellum or
      striatum areas.

PMID- 10648898
TI  - The use of quantitative RT-PCR to measure mRNA expression in a rat model of focal
      ischemia--caspase-3 as a case study.
AB  - Quantitative reverse transcription and polymerisation chain reaction (RT-PCR)
      using Taqman?trade mark omitted? fluorogenic probes has been used to measure
      changes in gene expression in the cerebral cortex of rats in the permanent middle
      cerebral artery occlusion (pMCAO) model of focal ischemia. The mRNA levels of
      three housekeeping genes have been analysed in this model to determine which gene
      showed least change following experimental insult. In the lesioned cortex, beta
      actin mRNA increased at 24 h, while the levels of cyclophilin and glyceraldehyde
      3-phosphate dehydrogenase (GAPDH) did not change. We have also used this
      methodology to examine modulations in the level of caspase-3 mRNA during focal
      ischemia in the rat. Caspase-3 mRNA showed a 41% increase at 6 h post-MCAO, which
      was specific to the lesioned cortex. This change became more pronounced with
      time, showing an increase of 220% at 24 h. This methodology enables changes in
      mRNA expression to be analysed more sensitively and quantitatively than other
      available techniques and highlights the need for careful choice of control or
      housekeeping genes used for RNA comparisons.

PMID- 10648899
TI  - Cellular distribution of the splice variants of the receptor for pituitary
      adenylate cyclase-activating polypeptide (PAC(1)-R) in the rat brain by in situ
      RT-PCR.
AB  - Pituitary adenylate cyclase-activating polypeptide (PACAP) is a pleiotropic
      neuropeptide and its specific receptor (the PAC(1) receptor) is widely
      distributed in the rat brain. It has been reported that alternative splicing of
      the region encoding the third intracellular loop of the PAC(1) receptor generates
      six isoforms which are differentially coupled to signal transduction pathways,
      but the precise distribution and localization of these splice isoforms in the
      brain remain to be determined. Using the initial specific primer pairs which
      correspond to the 'hip' or 'hop' types of receptors for the solution-phase
      reverse transcription-polymerase chain reaction (RT-PCR), we demonstrated that
      the major splice variants of the PAC(1) receptor in various regions of the rat
      brain are the short splice isoform 'PAC(1)-R-s' which does not contain either the
      'hip' or 'hop' cassette and the another splice isoform, 'PAC(1)-R-hop', which
      contains the 'hop' cassette. With an innovative molecular histochemical
      technique, in situ RT-PCR, we determined that these two splice isoforms are both
      intensely expressed in the mitral cells of the olfactory bulb, the Purkinje cells
      of the cerebellum, the pyramidal cells of the hippocampus and neocortex, and many
      neurons in the nuclei of hypothalamus and thalamus as well as other regions. The
      initial mapping of the cell type-specific expression of these two splice variants
      of the PAC(1) receptor provides the basis for a better understanding of the
      functional significance of the PAC(1)-R and its ligand PACAP in various brain
      regions.

PMID- 10648900
TI  - Low-voltage-activated calcium channel subunit expression in a genetic model of
      absence epilepsy in the rat.
AB  - The Genetic Absence Epilepsy Rats from Strasbourg (GAERS) are an inbred strain of
      rats that display many of the characteristics of human absence epilepsy. In these
      rats, reciprocal thalamocortical projections play a critical role in the
      generation of spike-and-wave discharges that characterize absence seizures. When
      compared to those of the non-epileptic control strain, juvenile animals of the
      GAERS strain reportedly possess higher-amplitude T-type calcium currents in
      neurons of the thalamic reticular nucleus (nRt). We hypothesized that differences
      in calcium currents seen between GAERS and controls result from differences in
      expression of genes for low-voltage-activated calcium channels. Quantitative in
      situ hybridization was used to compare expression of alpha1G, alpha1H, alpha1I,
      and alpha1E calcium channel subunit mRNAs from adult and juvenile animals of the
      two strains. We found higher levels of alpha1H mRNA expression in nRt neurons of
      juvenile animals (34.9+/-2. 3 vs. 28.4+/-1.8 grains/10(3) pixels, p<0.05),
      perhaps accounting in part for earlier reports of elevated T-type current
      amplitude in those cells. In adult GAERS animals, we found elevated levels of
      alpha1G mRNA in neurons of the ventral posterior thalamic relay nuclei (64.8+/
      3.5 vs. 53.5+/-1.7 grains/10(3) pixels, p<0.05), as well as higher levels of
      alpha1H mRNA in nRt neurons (32.6+/-0.8 vs. 28.2+/-1.6 grains/10(3) pixels,
      p<0.05). These results suggest that the epileptic phenotype apparent in adult
      GAERS may result in part from these significant, albeit small ( approximately 15
      25%), elevations in T-type calcium channel mRNA levels.

PMID- 10648901
TI  - Concomitant changes in CRH mRNA levels in rat hippocampus and hypothalamus
      following immobilization stress.
AB  - By using in situ hybridization, we have demonstrated an increased expression of
      corticotropin-releasing hormone (CRH) mRNA in the hippocampus following
      immobilization stress (3 h) in rats. It paralleled that measured in the
      hypothalamic paraventricular nucleus (PVN). Pretreatment of control and stressed
      rats with MK-801 (a NMDA receptor antagonist) further increased CRH mRNA
      expression, in the two structures. The concomitant up-regulation of CRH mRNA
      expression in these structures suggests a common regulatory finality for a single
      molecule at two different loci.

PMID- 10648902
TI  - Localization of mRNA for SHIP2, SH2 domain-containing inositol polyphosphate 5
      phosphatase, in the brain of developing and mature rats.
AB  - The localization of mRNA for SHIP2, SH2 domain containing inositol 5-phosphatase
      SHIP isozyme, was examined by in situ hybridization histochemistry in the brain
      of developing and mature rats. SHIP2 mRNA was first detected in the ventricular
      germinal zone at embryonic stages. As the postnatal development proceeded, the
      expression signal was evident in cell of the white matters, presumptive
      oligodendrocytes, and no significant expression was seen in neurons throughout
      the development.

PMID- 10648903
TI  - The 2-phenylbenzotriazole-type water pollutant PBTA-2 has cytochalasin B-mimetic
      activity.
AB  - The 2-phenylbenzotriazole (PBTA)-type water pollutant, 2-[2-(acetylamino)-4-[N-(2
      cyanoethyl)ethylamino]-5-methoxyphenyl]-5- amino-7-bromo-4-chloro-2H
      benzotriazole (PBTA-2), has been recently identified in samples from the
      Nishitakase River in Kyoto, Japan, and shows potent mutagenic activities in
      Salmonella typhimurium in the presence of a microsomal metabolizing system (S9
      mix). In the present study, we conducted the in vitro micronucleus (MN) test on
      PBTA-2 in the absence and presence of S9 mix in two Chinese hamster cell lines,
      CHL and V79-MZ. In the MN test, PBTA-2 was weakly positive in CHL cells and
      strongly positive in V79-MZ cells. Because the positive results were accompanied
      by a statistically significant increase in the number of polynuclear (PN) and/or
      mitotic (M) cells, we examined treated cells in metaphase to see if numerical
      chromosome aberrations were being induced. We found that PBTA-2 induces
      polyploidy in both CHL and V79-MZ cells. A detailed analysis of MN preparations
      showed that in CHL cells, PBTA-2 predominantly induces equal-sized binucleated
      cells. Rhodamine phalloidin staining revealed that PBTA-2 causes actin filament
      abnormalities in both cell lines similar to those caused by cytochalasin B.
      Cytochalasin B induced PN cells predominantly and dose dependently, and almost
      all the cells were equal-sized and binucleate. The results suggest that PBTA-2
      has cytochalasin B-mimetic activity, although agents affecting actin filaments,
      such as cytochalasins, phallotoxins and chloropeptide, have been derived only
      from molds so far. This study also suggests that our MN test protocol may be used
      to identify chemicals that have cytochalasin B-mimetic activity as well as those
      that induce numerical aberrations.

PMID- 10648904
TI  - Comparison of the mutations at Hprt exon 3 of T-lymphocytes from B6C3F1 mice and
      F344 rats exposed by inhalation to 1,3-butadiene or the racemic mixture of
      1,2:3,4-diepoxybutane.
AB  - Experiments were conducted to define the spectra of mutations occurring in Hprt
      exon 3 of T-cells isolated from spleens of female B6C3F1 mice and F344 rats
      exposed by inhalation to 1,3-butadiene (BD) or its reactive metabolite, (+/-)
      diepoxybutane (DEB). Hprt mutant frequencies (Mfs) in BD-exposed (1250 ppm for 2
      weeks or 625 ppm for 4 weeks; 6 h/day, 5 days/week) and DEB-exposed (2 or 4 ppm
      for 4 weeks or 5 ppm for 6 weeks; 6 h/day, 5 days/week) mice and rats were
      significantly increased over concurrent control values. Mutant T-cell colonies
      from control and treated animals were screened for mutations in Hprt exon 3 using
      PCR amplification of genomic DNA and denaturing gradient gel electrophoresis,
      followed by sequence analysis. Exon 3 mutations were found at the following
      frequencies: 20/394 (5%) in control mice, 56/712 (8%) in BD-exposed mice, 59/1178
      (5%) in BD-exposed rats, 66/642 (10%) in DEB-exposed mice, and 51/732 (7%) in DEB
      exposed rats. Mutations in exposed animals included base substitutions, small
      deletions (1 to 74 bp), and small insertions (1 to 8 bp), with base substitutions
      predominating. Among the types of base substitutions observed in mice, the
      proportions of G.C-->A.T transitions (p=0.035, Fisher's Exact Test) and G.C-->C.G
      transversions (p=0.05) were significantly different in control vs. BD-exposed
      animals. Given the small number of exon 3 mutants analyzed, there was a high
      degree of overlap in the mutational spectra between BD-exposed mice and rats,
      between BD- and DEB-exposed mice, and between BD- and DEB-exposed rats in terms
      of the sites with base substitutions, the mutations found at those mutated sites,
      the relative occurrence of the most frequently observed base substitutions, and
      the occurrence of a consistent strand bias for the most frequently observed base
      substitutions. The spectra data suggest that adduction of both G.C and A.T bps is
      important in the induction of in vivo mutations by BD metabolites in exposed mice
      and rats.

PMID- 10648905
TI  - Cleistanthin A causes DNA strand breaks and induces apoptosis in cultured cells.
AB  - Cleistanthin A is a novel anticancer agent isolated from Cleistanthus collinus
      (Rox B). It caused chromatid aberrations in a dose dependent manner. However, the
      concentrations that induced the aberrations, neither affected viability nor
      induced DNA strand breaks. Only at higher concentrations and after long exposure,
      DNA strand breaks were observed. Cleistanthin A induced apoptosis in Chinese
      hamster ovary (CHO) cells, in cervical carcinoma (Si Ha) cells and in a p53
      deficient cell line K562. Cleistanthin A-induced cell death was low in bcl-2
      transfected cells. Cleistanthin A inhibited the incorporation of [3H]thymidine
      into DNA; however, it did not affect the transport of [3H]thymidine into these
      cells. These studies indicate that the cytotoxic effects of cleistanthin A are
      mediated by the inhibition of DNA synthesis, induction of DNA damage and
      apoptosis.

PMID- 10648906
TI  - Malaria-infected erythrocytes serve as biological standards to ensure reliable
      and consistent scoring of micronucleated erythrocytes by flow cytometry.
AB  - A procedure for optimizing the configuration of flow cytometers for enumerating
      micronucleated erythrocytes is described. The method is based on the use of a
      biological model for micronucleated erythrocytes, the malaria parasite Plasmodium
      berghei. P. berghei endows target cells of interest (erythrocytes) with a
      micronucleus-like DNA content. Unlike micronuclei, parasitized red blood cells
      have a homogenous DNA content, and can be very prevalent in circulation. These
      characteristics make malaria-infected erythrocytes extremely well suited for
      optimizing instrument setup on a daily basis. The experiment described herein was
      designed to test the hypothesis that malaria-infected erythrocytes can greatly
      enhance the consistency with which flow cytometers are configured for
      micronucleus analyses, and thereby minimize intra- and interexperimental
      variation. Data collected over the course of several months, on two different
      flow cytometers, supports the premise that malaria-infected blood represents a
      useful biological standard which helps ensure reliable and consistent flow
      cytometric enumeration of rare micronucleated erythrocytes.

PMID- 10648907
TI  - Effect of the topoisomerase-II inhibitor etoposide on meiotic recombination in
      male mice.
AB  - Unlike other chemicals that have been tested in mammalian germ cells, the type-II
      topoisomerase inhibitor etoposide exhibits significant mutagenicity in primary
      spermatocytes. Because this is the cell stage during which meiotic recombination
      normally occurs, and because topoisomerases play a role in recombination, we
      studied the effect of etoposide on crossing-over in male mice. Exposure to those
      meiotic prophase stages (probably early to mid-pachytene) during which specific
      locus deletion mutations can be induced resulted in decreased crossing-over in
      the p-Tyr(c) interval of mouse chromosome 7. Accompanying cytological studies
      with fluorescent antibodies indicated that while there was no detectable effect
      on the number of recombination nodules (MLH1 foci), there were marked changes in
      the stage of appearance and localization of RAD51 and RPA proteins. These
      temporal and spatial protein patterns suggest the formation of multiple lesions
      in the DNA after MLH1 has already disappeared from spermatocytes. Since etoposide
      blocks religation of the cut made by type II topoisomerases, repair of DNA damage
      may result in rejoining of the original DNA strands, undoing the reciprocal
      exchange that had already occurred and resulting in reduced crossing-over despite
      a normal frequency of MLH1 foci. Crossing-over could conceivably be affected
      differentially in different chromosomal regions. If, however, the predominant
      action of etoposide is to decrease homologous meiotic recombination, the chemical
      could be expected to increase nondisjunction, an event associated with human
      genetic risk. Three periods in spermatogenesis respond to etoposide in different
      ways. Exposure of (a) late differentiating spermatogonia (and, possibly,
      preleptotene spermatocytes) results in cell death; (b) early- to mid-pachytene
      induces specific-locus deletions and crossover reduction; and, (c) late pachytene
      through-diakinesis leads to genetically unbalanced conceptuses as a result of
      clastogenic damage.

PMID- 10648908
TI  - Detection of genotoxins in the marine environment: adoption and evaluation of an
      integrated approach using the embryo-larval stages of the marine mussel, Mytilus
      edulis.
AB  - In genetic ecotoxicology or eco-genotoxicology, there is lack of well-validated
      systems which could demonstrate the utility of multiple endpoints in
      environmental quality assessment. For an evaluation of genotoxic potential of
      heterogeneous marine sediment samples collected from a small fishing harbour in
      the UK, an in vivo test system using embryo-larval stages of the common mussel,
      Mytilus edulis was validated against direct and indirect acting reference
      mutagens. The system appeared to be sensitive and reproducible for cytogenetic
      endpoints analysed (sister chromatid exchanges (SCEs) and chromosomal aberrations
      (CAbs)). Following validation and chemical characterisation of the environmental
      samples, multiple endpoints were measured. Determination of the maximum tolerated
      dose (MTD) was carried out as a measure to determine cytotoxic effects as a
      confounding factor for genotoxicity, based on developmental and cytotoxic (in
      terms of proliferative rate index or PRI) effects. Evaluation of the genotoxic
      potential of the samples gave a positive response for all the endpoints tested,
      linking different levels of biological organisation (i.e., chromosomal, cellular
      and organismal) for the observed effects. The study also emphasises the need for
      the assessment of the short and long-term impacts of dredge disposal on marine
      biota by including laboratory-based bioassays and incorporating an integrated
      approach which could yield as much useful information as possible in overall
      hazard and risk assessment for aquatic genotoxicity.

PMID- 10648909
TI  - Analysis of DNA oxidative damage related to cell proliferation.
AB  - In vivo and in vitro cell populations exhibit a different sensitivity and a
      heterogeneous response to many genotoxic agents. Several studies have been
      carried out to evaluate the possibility that the different sensitivity of the
      cells is related to their proliferative status. In this study, the sensitivity of
      proliferating (P) and quiescent (Q) C3H10T1/2 cells to oxidative damage and their
      repair capability has been investigated by single cell gel electrophoresis (SCGE)
      and micronucleus test. Furthermore the possibility to simultaneously detect DNA
      damage and cell cycle position has been evaluated. Our results showed a dose
      related increase of DNA damage in exponential and plateau phase cells treated
      with hydrogen peroxide (doses ranging between 2.5 and 100 microM). DNA damage was
      almost completely repaired within 2 h after treatment in both culture conditions.
      The percentage of cells in the various phases of the cell cycle has been
      determined by comet assay and by flow cytometry, and a good agreement between the
      results of the two techniques was found. Untreated exponentially growing cells in
      G1 phase showed a lower tail moment than S and G2/M cells. The same cell cycle
      dependence was evidenced in cells treated with low doses of H(2)O(2), while, at
      the higher doses, all cells showed a similar level of damage. These results
      confirm the sensitivity of the Comet Assay in assessing DNA damage, and support
      its usefulness in evaluating cell cycle-related differential sensitivity to
      genotoxic agents.

PMID- 10648910
TI  - Genotoxicity of paraquat: micronuclei induced in bone marrow and peripheral blood
      are inhibited by melatonin.
AB  - The ability of melatonin to influence paraquat-induced genotoxicity was tested
      using micronucleated polychromatic erythrocytes as an index of damage in both
      bone marrow and peripheral blood cells of mice. Melatonin (10 mg/kg) or an equal
      volume of saline were administered intraperitoneally (ip) to mice 30 min prior to
      an ip injection of paraquat (20 mg/kgx2), and thereafter at 6-h intervals until
      the conclusion of the study (72 h). The number of the micronucleated
      polychromatic erythrocytes increased after paraquat administration both in
      peripheral blood and bone marrow cells. Melatonin administration to paraquat
      treated mice significantly reduced micronuclei formation in both peripheral blood
      and bone marrow cells; these differences were apparent at 24, 48 and 72 h after
      paraquat administration. The induction of micronuclei was time-dependent with
      peak values occurring at 24 and 48 h. The reduction in paraquat-related
      genotoxicity by melatonin is likely due in part to the antioxidant activity of
      the indole. We did not observe effects of melatonin over paraquat in
      paraquat+melatonin groups incubated at 0, 60 and 120 min. Mitomycin C, which was
      used as a positive control, also caused the expected large rises in micronuclei
      in both bone marrow and peripheral blood cells at 24, 48 and 72 h after its
      administration.

PMID- 10648911
TI  - Structure-activity relationship in potentially anti-tumor promoting benzalacetone
      derivatives, as assayed by the epstein-barr virus early antigen activation.
AB  - The in vitro anti-tumor promoting activities of antimutagenic benzalacetone (4
      phenyl-3-buten-2-one), its monosubstituted derivatives and related compounds,
      cinnamaldehydes and cinnamic acids, were evaluated by determining the inhibitory
      effect on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O
      tetradecanoylphorbol-13-acetate (TPA) in Raji cells. In this short-term assay,
      benzalacetone, which is the basic structure of dehydrozingerone (one-half analog
      of curcumin) inhibited the EBV-EA activation; the IC(50) value, the molar ratio
      of benzalacetone to TPA needed for inhibiting 50% of positive cells activated
      with 32 pmol TPA, was 129. IC(50) values of 2- and 4-methoxybenzalacetones were
      about one-half of that of benzalacetone and the methoxy compounds were more
      effective than hydroxybenzalacetones. IC(50) values of chloro- and
      trifluoromethyl-benzalacetones were higher than that of benzalacetone, indicating
      that these compounds are weaker inhibitors. In addition, the position of a
      substituent on the benzene ring affected the inhibitory effect. In benzalacetone
      derivatives substituted by a hydroxy-, methoxy-, chloro- or trifluoromethyl
      group, the 2-substituted derivatives exhibited the strongest inhibitory effect,
      followed by the 3- and the 4-substituents. Cinnamic acid derivatives also
      decreased the inhibitory effects in the same order. In the side chain of
      benzalacetone, the terminal group adjacent to the carbon-carbon double bond also
      affected the inhibitory effect. The conversions of the methylketone to aldehyde
      and carboxyl groups, i.e., cinnamaldehyde and cinnamic acid, increased the
      inhibitory effect: the IC(50) values were about one-third of that of
      benzalacetone. beta-Methyl styrene, which in the side chain has no carbonyl group
      adjacent to the double bond, inhibited the EBV-EA activation at the concentration
      of about one-third of that of benzalacetone, indicating that the carbonyl group
      negatively affects the inhibitory effect. This agreed with the previous
      observation between isoeugenol and dehydrozingerone, 4-hydroxy-3-methoxy
      derivatives of beta-methyl styrene and benzalacetone, respectively. The mechanism
      of the EBV-EA activation inhibition was discussed by being compared with the
      inhibition of mutagenesis for which the unsaturated bonded-carbonyl system is
      necessary.

PMID- 10648912
TI  - Cytogenetic biomonitoring of Spanish greenhouse workers exposed to pesticides:
      micronuclei analysis in peripheral blood lymphocytes and buccal epithelial cells.
AB  - In the present study, we evaluate whether or not occupational exposure to a
      complex mixture of pesticides results in a significant increase of micronuclei
      (MN) in both peripheral blood lymphocytes and buccal cells. Sixty four greenhouse
      workers from Almeria (Southeastern Spain), together with 50 men from the same
      area, without indication of exposure to pesticides, that served as controls were
      used in this investigation. The results obtained indicate that there are no
      statistically significant differences in the MN frequencies between the two
      groups. Each donor was assessed for the presence or absence of glutathione S
      transferase M1 (GSTM1) and glutathione S-transferase T1 (GSTT1), to look for
      relationships between the genotypes and the cytogenetic reponses. According to
      the GSTT1 genotype, there is a difference between both groups only for the
      cytokinesis-block proliferation index (CBPI). Neither GSTM1 nor smoking habit and
      age showed any effect in the overall analysis.

PMID- 10648913
TI  - An in vivo mouse micronucleus assay on musk ketone.
AB  - Musk ketone (3,5-dinitro-2,6-dimethyl-4-tert-butyl-acetophenone) was evaluated in
      an in vivo mouse micronucleus assay. Male and female mice were dosed with 250,
      500 or 1000 mg musk ketone/kg body weight by a single intraperitoneal injection
      in corn oil. Results of the assay showed that under the conditions of this test
      evaluated at 24, 48 and 72 h after dosing, musk ketone did not induce a
      significant increase in micronucleated polychromatic erythrocytes in either male
      or female mice at any dose or any time period. Musk ketone was considered to be
      negative in the mouse in vivo micronucleus test as well as in a battery of
      previously published in vitro genotoxicity tests. Based on the total weight of
      evidence available, it was concluded that musk ketone does not have significant
      potential to act as a genotoxic carcinogen.

PMID- 10648914
TI  - Effect of three diaryl tellurides, and an organoselenium compound in trout
      erythrocytes exposed to oxidative stress in vitro.
AB  - Previous literature reports have demonstrated that nucleated trout erythrocytes
      in conditions of oxidative stress are subjected to DNA and membrane damage, and
      inactivation of glutathione peroxidase. The present study was undertaken to
      evaluate the ability of three diaryl tellurides and the organoselenium compound
      ebselen to protect trout (Salmo irideus) erythrocytes against oxidative stress,
      induced thermally and by a variation of pH. The antioxidant ability of these
      molecules was evaluated through chemiluminescence. Impairment of DNA was assessed
      using the comet assay, a rapid and sensitive single cell gel electrophoresis
      technique, used to detect primary DNA damage in individual cells. At low
      concentrations (<10 microM), all the compounds used presented a protective effect
      on DNA damage without altering the hemolysis rate. In higher concentrations, they
      accelerated the hemolysis rate and two of the diaryl tellurides were strongly
      genotoxic.

PMID- 10648915
TI  - Evidence of p53 mutation in an early stage of liver cancer in European flounder,
      Platichthys flesus (L.).
AB  - A number of flounders dwelling in highly contaminated coastal areas of Northern
      Europe develop liver tumours. In order to increase our understanding of the
      molecular pathogenesis of these sporadic tumours, we examined p53 mutations in
      eleven hyperplasia and six adenoma. p53 introns 4 to 8 were first sequenced to
      allow individual amplification of exons 5 to 8. DNA extracted from formalin-fixed
      livers was amplified and PCR products were directly sequenced. Two major results
      were obtained. (i) Flounders from different geographical areas displayed a high
      rate of sequence variation. Base substitutions were identified in both tumour and
      normal tissues and thus may be considered as polymorphic variations in
      individuals. (ii) One mutation was detected in two hyperplastic foci from the
      same flounder. This mutation was a T:A to A:T transversion at codon 147,
      resulting in the replacement of valine for glutamic acid. This residue took place
      in the L2 loop of the DNA binding surface. Its substitution by an hydrophilic and
      charged residue could thus impair p53 (protein) biological activity.

PMID- 10648916
TI  - Cytogenetic study of workers exposed to chromium compounds.
AB  - The frequency of sister chromatid exchanges (SCEs), high SCE frequency cells
      (HFCs), and genetic polymorphism of genotypes glutathione S-transferase (GST) M1
      and T1 were analyzed in peripheral lymphocytes of 35 workers occupationally
      exposed to chromium (Cr) and 35 matched control group. Results showed that
      workers exposed to Cr showed 6.07 SCE/cell, as compared to 4.76 SCE/cell for the
      control group (p<0.01). Smokers showed a statistically significant higher
      frequency of SCE than non-smokers in both groups. The work duration of Cr workers
      was an important factor. Workers exposed for more than 5 years showed a
      significantly higher level of SCEs (p<0.05). Workers exposed to Cr for 5 or more
      years had higher HFC rates (51.4%) than those exposed for less than 5 years
      (22.9%), with an odds ratio of 4.5 times than those exposed for less than 5
      years. In HFC analysis, Cr workers who smoked showed a higher level of HFC (60%)
      than the control group (5.7%) and also had a higher odds ratio (60.4) compared
      with the control group. Among non-smokers, the odds ratio was 9.0. Another
      objective of this study is to investigate the relationship between SCE and
      genetic polymorphisms of GST M1 and T1 in Cr workers. The results showed that the
      incidence of GSTM1 null genotype was 60% in the control group and 77.1% in Cr
      workers, and percentages of GSTT1 deletion were 42.9% and 62.9% in control and
      exposed individuals, respectively. There was a slightly increased frequency of
      SCE among Cr workers with GSTM1 null genotype as opposed to non-null genotype
      individuals. A similar result was seen among the control group; however, there
      were no statistically significant differences. In conclusion, the current study
      found the positive induction of SCE in workers who smoked or/and were exposed to
      Cr. However, different GST genotypes did not influence the level of cytogenetic
      damage between groups. Despite slight variation in numbers, they all appear to be
      not different.

PMID- 10648917
TI  - Application of yeast cells transformed with GFP expression constructs containing
      the RAD54 or RNR2 promoter as a test for the genotoxic potential of chemical
      substances.
AB  - Yeast strains transformed with high copy number plasmids carrying the gene
      encoding a green fluorescent protein optimised for yeast (yEGFP3) under the
      control of the RAD54 or RNR2 promoter were used to investigate the activity of
      potentially DNA-damaging substances. The assays were performed on 96-well
      microtitre plates in the presence of different concentrations of the test
      substances. The synthesis of GFP protein was measured through the fluorescence
      signal and cell growth was monitored by absorption. Here, we demonstrate that
      this system can be used as a biosensor to assess the genotoxic potential of drugs
      and other chemical substances. The use of microtitre plates will enable full
      automation of the system and allows the inclusion of internal reference standards
      in each assay.

PMID- 10648920
TI  - Lysenko and Stalin: commemorating the 50th anniversary of the August 1948 LAAAS
      Conference and the 100th anniversary of T.D. Lysenko's birth, September 29, 1898.

PMID- 10648921
TI  - Genotoxic hazards of azo pigments and other colorants related to 1-phenylazo-2
      hydroxynaphthalene.
AB  - Azo pigments are used extensively as coloring agents in inks, paints and
      cosmetics. We have surveyed the literature for genotoxic and cancer data on nine
      colorants, which are structurally related to 1-phenylazo-2-hydroxynaphthalene
      (C.I. Solvent yellow 14). C.I. Solvent yellow 14 is metabolized by oxidative and
      peroxidative enzymes. Metabolically activated C.I. Solvent yellow 14 forms both
      RNA and DNA adducts. It induces liver nodules in rats upon oral administration.
      Although there is a mixture of negative and positive findings in short-term tests
      and in animal cancer studies, C.I. Solvent yellow 14 should be considered
      genotoxic. C.I. Pigment red 3 should be considered carcinogenic but is only
      weakly genotoxic. C.I. Solvent yellow 7, C.I. Pigment orange 5, C.I. Pigment red
      4, and C.I. Pigment red 23 should be considered genotoxic. C.I. Pigment red 53:1
      is not genotoxic, and observations of spleen tumors in male rats but not in
      female rats or mice seem to be related to toxic effects of high doses of C.I.
      Pigment red 53:1 in this organ. The data in the literature indicate that Pigment
      red 57:1 is not genotoxic or carcinogenic. We did not find sufficient data for a
      relevant evaluation of C.I. Pigment red 2 and C.I. Pigment red 64:1. Some of the
      colorants have in common the 2-amino-1-naphthol structure. This compound is not
      genotoxic. On the other hand, reductive cleavage of the azo bonds or hydrolysis
      of anilido bonds would produce aromatic amines, most of which have been under
      suspicion for genotoxicity or carcinogenicity. For C.I. Pigment red 53:1 and
      57:1, sulphonated aromatic amines would be formed that are not genotoxic.

PMID- 10648922
TI  - Telomeres, telomerase, and myc. An update.
AB  - Normal human somatic cells have a finite life span in vivo as well as in vitro
      and retire into senescence after a predictable time. Cellular senescence is
      triggered by the activation of two interdependent mechanisms. One induces
      irreversible cell cycle exit involving activation of two tumorsuppressor genes,
      p53 and pRb, and the proper time point is indicated by a critical shortening of
      chromosomal ends due to the end-replication problem of DNA synthesis. The
      development of a malignant cancer cell is only possible when both mechanisms are
      circumvented. The majority of human cancers and tumor cell lines produce
      telomerase, a ribonucleoprotein with two components required for core enzyme
      activity: telomerase RNA (TR) and a telomerase reverse transcriptase protein
      (TERT). Telomerase adds hexameric DNA repeats (TTAGGG) to telomeric ends and thus
      compensates the progressive loss of telomeric sequences inherent to DNA
      replication. While TR of telomerase is present in almost all human cells, human
      TERT (hTERT) was found rate limiting for telomerase activity. Ectopic expression
      of hTERT in otherwise mortal human cells induced efficient elongation of
      telomeres and permanent cell growth. While hTERT-mediated immortalization seems
      to have no effect on growth potential and cell cycle check points, it bestows an
      increased susceptibility to experimental transformation. One oncogene that might
      activate TERT in the natural context is c-myc. Myc genes are frequently
      deregulated in human tumors and myc overexpression may cause telomerase
      reactivation and telomere stabilization which, in turn, would allow permanent
      proliferation. Is this a general strategy of incipient cancer cells to escape
      senescence? Several recent observations indicate that other scenarios may be
      conceived as well.

PMID- 10648923
TI  - Generation of a large complex antibody library from multiple donors.
AB  - We have generated a large complex library of single chain antibodies based on
      four individual libraries from each of 50 donors. DNA coding for the heavy and
      light chain variable domains of the IgM and IgG repertoires was amplified by PCR
      using two different sets of primers. Each individual library was composed of
      approximately 1-5x10(7) independent clones giving a final combined library of
      4x10(9) members. Screening this library by phage display of single chain
      antibodies with small haptens, peptides and proteins yielded specific antibodies
      for each class of antigen.

PMID- 10648924
TI  - Antibody engineering via genetic engineering of the mouse: XenoMouse strains are
      a vehicle for the facile generation of therapeutic human monoclonal antibodies.
AB  - The major impediment to the development of murine monoclonal antibodies (mAbs)
      for therapy in humans has been the difficulty in reducing their potential
      immunogenicity. XenoMouse?trade mark omitted? mice obviate this problem while
      retaining the relative ease of generating mAbs from a mouse. XenoMouse strains
      include germline-configured, megabase-sized YACs carrying portions of the human
      IgH and Igkappa loci, including the majority of the variable region repertoire,
      the genes for Cmicro, Cdelta and either Cgamma1, Cgamma2, or Cgamma4, as well as
      the cis elements required for their function. The IgH and Igkappa transgenes were
      bred onto a genetic background deficient in production of murine immunoglobulin.
      The large and complex human variable region repertoire encoded on the Ig
      transgenes in XenoMouse strains support the development of large peripheral B
      cell compartments and the generation of a diverse primary immune repertoire
      similar to that from adult humans. Immunization of XenoMouse mice with human
      antigens routinely results in a robust secondary immune response, which can
      ultimately be captured as a large panel of antigen-specific fully human IgGkappa
      mAbs of sub-nanomolar affinities. Monoclonal antibodies from XenoMouse animals
      have been shown to have therapeutic potential both in vitro and in vivo, and
      appear to have the pharmacokinetics of normal human antibodies based on human
      clinical trials. The utility of XenoMouse strains for the generation of large
      panels of high-affinity, fully human mAbs can be made available to researchers in
      the academic and private sectors, and should accelerate the development and
      application of mAbs as therapeutics for human disease.

PMID- 10648925
TI  - Single domain antibodies: comparison of camel VH and camelised human VH domains.
AB  - The antigen binding sites of conventional antibodies are formed primarily by the
      hypervariable loops from both the heavy and the light chain variable domains.
      Functional antigen binding sites can however also be formed by heavy chain
      variable domains (VH) alone. In vivo, such binding sites have evolved in camels
      and camelids as part of antibodies, which consist only of two heavy chains and
      lack light chains. Analysis of the differences in amino acid sequence between the
      VHs of these camel heavy chain-only antibodies and VH domains from conventional
      human antibodies helped to design an altered human VH domain. This camelised VH
      proved, like the camel VH, to be a small, robust and efficient recognition unit
      formed by a single immunoglobulin (Ig) domain. Biochemical, structural and
      antigen binding characterisation properties of both camel VH domains and
      camelised human VH domains suggest that these can compete successfully with
      single chain variable domain (Fv) fragments from conventional antibodies in many
      applications. Of special importance in this respect is the use of such VH domains
      as enzyme inhibitors, for which they seem to be better suited than Fv fragments.
      This function appears to be closely related to their often very long third
      hypervariable loop, which is central for antigen recognition in their binding
      sites.

PMID- 10648927
TI  - Phage antibodies against human dendritic cell subpopulations obtained by flow
      cytometry-based selection on freshly isolated cells.
AB  - In one application of phage display technology, large libraries of antibody
      fragments displayed on phage particles are used to select antibodies that bind to
      molecules expressed on the surface of eukaryotic cells. The advantage of this
      method is that antibodies can be selected against antigens in their native
      configuration, without the need to purify or express the antigen as a recombinant
      protein. Moreover, this approach may be used to search for novel membrane
      molecules expressed by subpopulations of cells that are difficult to address by
      conventional methods, e.g., small numbers of cells present in heterogeneous
      mixtures. It has been shown that the isolation of cell-bound phages is compatible
      with immunofluorescence staining and flow cytometric identification and sorting
      of cells based on multiparameter analysis. Here, we have employed a semi
      synthetic phage display library of human single-chain Fv (scFv) antibody
      fragments in combination with flow cytometry to isolate antibodies against rare
      populations of precursor and mature dendritic cells (DCs) present in human
      peripheral blood. DCs are a phenotypically heterogeneous population of
      professional antigen presenting cells of bone marrow origin with complex and only
      partly understood developmental relationships and functions. We have isolated
      phage antibodies against subpopulations of blood DCs and analyzed the
      distribution of the target antigens. The results show that these phage antibodies
      are useful tools to further dissect relationships and function of DCs in healthy
      and diseased tissues.

PMID- 10648926
TI  - Phage display of cDNA repertoires: the pVI display system and its applications
      for the selection of immunogenic ligands.
AB  - The selection of phage displayed cDNA repertoires on an immobilised target has
      been reported to be an efficient way to rapidly identify interacting partners. To
      date, however, only a few successful applications have been reported. Here, we
      present a review of the current status of the display and selection of cDNA
      libraries using phage. As an example, we report the construction of a set of
      phage display vectors suitable for cDNA display based on fusion to the minor
      bacteriophage coat protein 6 (pVI) of filamentous phage. We have evaluated these
      vectors through the display of the C(H)3 domain of human IgG and of the
      Escherichia coli alkaline phosphatase (PhoA) gene. Both the C(H)3 domain of IgG
      and PhoA are shown to be displayed on pVI, and PhoA is also shown to be
      enzymatically active. We have constructed primary colorectal tumor cDNA
      repertoires in these vectors and performed selections on both a monoclonal
      antibody to beta2 microglobulin (beta2M) and polyclonal antibody sera to human
      IgG. In both cases, relevant ligands were recovered from the phage displayed cDNA
      repertoire. These vectors may be used for selection of phage displayed cDNA
      libraries with polyclonal sera from patients. This will allow the identifying
      antigenic cDNA products in such diseases as cancer, viral/bacterial infections or
      autoimmune disease. Furthermore, by selections with other specific biomolecules,
      this display system may aid the identification of interacting partners in
      functional genomics.

PMID- 10648928
TI  - Model systems to study the parameters determining the success of phage antibody
      selections on complex antigens.
AB  - Phage antibody display technology offers a powerful tool for the isolation of
      specific antibodies to defined target antigens. Most selection strategies
      described to date have relied on the availability of purified and often
      recombinant antigen, providing the possibility to perform selections on a well
      defined antigen source. However, when the target antigen cannot be purified
      (e.g., an integral membrane protein), or if the antigen is unknown (e.g., when
      searching for novel markers on cells or tissues), panning of phage antibody
      libraries has to be performed on complex antigen sources such as cell surfaces or
      tissue sections, or even by in vivo selection methods. This provides a series of
      technical and experimental challenges. One focus of our research is to select
      antibodies directed to novel cancer-induced antigens expressed by tumours and by
      the tumour vasculature. To understand the parameters governing selection on
      complex antigen sources and to assess the efficiency of these phage library
      selections, we have set up two model selection systems in which both tumour cells
      and vascular endothelial cells serve as target "antigen". We describe a model
      based on phage antibodies directed to the tumour antigen epithelial glycoprotein
      2, to compare phage antibody selections on a range of different antigen sources
      including purified and recombinant antigen, whole live cells, tissue cryosections
      and in vivo grown solid tumours. Secondly, we describe a model based on a phage
      antibody directed against the endothelial cell inducible adhesion molecule E
      selectin. We compare selections on cultured cell monolayers with selections on
      cell suspensions immobilised on columns, to determine which selection approach is
      most suitable for the identification of novel tumour endothelial cell markers.
      Our data provide insight into the efficiency and thus potency of different
      selection strategies and show that there are very large differences in the
      recovery and enrichment of binding phage between the different methods tested.
      Our results further demonstrate the feasibility of phage antibody selections on
      whole, intact cells and show that these may sometimes compare favourably to
      selections on purified antigen. Selections on endothelial cells immobilised on
      columns compare favourably with selections on cell-monolayers; the most
      favourable conditions for both selection procedures are described. The
      implications of our data for phage antibody selections on these different complex
      antigen sources using either non-immune or immune phage antibody repertoires are
      discussed. The use of model systems such as the ones described here will help to
      determine optimal experimental conditions for phage library selections on complex
      antigens and aid in developing more powerful selection procedures for target
      discovery.

PMID- 10648929
TI  - Analysis of cloned Fvs from a phage display library indicates that DNA
      immunization can mimic antibody response generated by cell immunizations.
AB  - BACKGROUND: Generation and cloning of antibodies against cell surface antigens
      can be simplified by combining DNA immunization which enables generation of
      antibodies against a protein in its natural configuration without the need for
      any protein purification step and antibody phage display which due to its immense
      screening power and physical coupling between the phenotype and genotype of
      antibodies simplifies the cloning of antibody genes. OBJECTIVES: Since DNA
      immunization is expected to elicit antibodies against a protein in its natural
      configuration, we wanted to see if it can mimic the antibody response generated
      by cell immunization. STUDY DESIGN: A phage display library made from splenic
      mRNA of a mouse immunized with mesothelin cDNA was panned on mesothelin-positive
      cells. The single-chain Fvs (scFvs) selected were then analyzed. RESULTS: We
      obtained several anti-mesothelin scFvs. One of these Fvs is almost identical to
      the Fv of a monoclonal antibody that was previously obtained from a hybridoma in
      which the mice were immunized with a mesothelin-positive ovarian cancer cell
      line. Another Fv was found to be specific for mesothelin present on human cells.
      CONCLUSION: Our results indicate that an antibody phage display library made from
      spleens of DNA-immunized mice is a rapid and efficient alternative to cell
      immunization for obtaining antibodies against different epitopes of a membrane
      antigen that is very difficult to purify in a native form.

PMID- 10648930
TI  - Selectively infective phage (SIP) technology: scope and limitations.
AB  - We review here the selectively infective phage (SIP) technology, a powerful tool
      for the rapid selection of protein-ligand and peptide-ligand pairs with very high
      affinities. SIP is highly suitable for discriminating between molecules with
      subtle stability and folding differences. We discuss the preferred types of
      applications for this technology and some pitfalls inherent in the in vivo SIP
      method that have become apparent in its application with highly randomized
      libraries, as well as some precautions that should be taken in successfully
      applying this technology.

PMID- 10648931
TI  - Selection of a human anti-progesterone antibody fragment from a transgenic mouse
      library by ARM ribosome display.
AB  - In antibody-ribosome-mRNA complex (ARM) ribosome display, stable complexes of
      nascent protein, mRNA and ribosomes are produced in a eukaryotic in vitro
      expression system, through coupled transcription and translation of DNA lacking a
      3' stop codon. Selection of the protein simultaneously captures the relevant
      mRNA, which is recovered as DNA by coupled reverse transcription-polymerase chain
      reaction (RT-PCR) performed on the intact complexes. Here, we describe the use of
      ARM display to select a specific human antibody fragment from a transgenic mouse
      library. The mice carry unrearranged gene segments of the human heavy (H) and
      kappa light (L) chain loci, while the endogenous murine H and kappa loci are
      functionally silenced; they respond to immunisation by production of fully human
      IgM antibodies. A library encoding human single-chain (sc) antibody (V(H)/K)
      fragments, in which V(H) domains and kappa light chains were combined at random
      by PCR, was prepared from spleen cells of transgenic mice immunised with
      progesterone-bovine serum albumin (BSA). Library diversity was demonstrated by
      sequencing. Progesterone-binding fragments were selected over five cycles of ARM
      display and the selected DNA cloned and expressed in Escherichia coli. Soluble
      V(H)/K fragments obtained in periplasmic extracts had the same specificity as
      ribosome-bound V(H)/K, supporting the view that folding and specificity of the
      displayed and soluble proteins are equivalent. The affinity of the expressed
      V(H)/K was approximately 10(-8) M. Sequencing showed that ARM display selected a
      single V(H)/V(L) combination (V(H)1-2, Vkappa4-1) and rearrangement, with a few
      mutational differences between clones. Monoclonal antibodies against progesterone
      BSA obtained from hybridomas were encoded by the same V(H) and V(L) segments and
      had similar properties to the fragments obtained in vitro. The combination of
      ribosome display and transgenic mouse technologies is a rapid means of generating
      fully human antibody fragments in vitro for expression and further manipulation.

PMID- 10648932
TI  - Ribosome display: an in vitro method for selection and evolution of antibodies
      from libraries.
AB  - Combinatorial approaches in biology require appropriate screening methods for
      very large libraries. The library size, however, is almost always limited by the
      initial transformation steps following its assembly and ligation, as other all
      screening methods use cells or phages and viruses derived from them. Ribosome
      display is the first method for screening and selection of functional proteins
      performed completely in vitro and thus circumventing many drawbacks of in vivo
      systems. We review here the principle and applications of ribosome display for
      generating high-affinity antibodies from complex libraries. In ribosome display,
      the physical link between genotype and phenotype is accomplished by a mRNA
      ribosome-protein complex that is used for selection. As this complex is stable
      for several days under appropriate conditions, very stringent selections can be
      performed. Ribosome display allows protein evolution through a built-in
      diversification of the initial library during selection cycles. Thus, the initial
      library size no longer limits the sequence space sampled. By this method, scFv
      fragments of antibodies with affinities in the low picomolar range have been
      obtained. As all steps of ribosome display are carried out entirely in vitro,
      reaction conditions of individual steps can be tailored to the requirements of
      the protein species investigated and the objectives of the selection or evolution
      experiment.

PMID- 10648933
TI  - Rapid production of single-chain Fv fragments in plants using a potato virus X
      episomal vector.
AB  - We have used a plant virus episomal vector, based on potato virus X (PVX) to
      transiently express a single-chain Fv (scFv) and its diabody derivative in
      plants. The scFv was directed against a continuous epitope (cryptotope) on the
      coat protein of potato virus V. A cloned, full-length PVX vector sequence,
      containing the scFv gene, was used to direct in vitro transcription and the
      resulting RNA was used to inoculate Nicotiana clevelandii plants. Within a few
      days, plants developed characteristic symptoms and immunoblot analysis showed
      that accumulation of scFv protein coincided with accumulation of PVX. Targeting
      of the scFv to the apoplast greatly increased protein accumulation compared with
      cytosolic scFv and produced more severe symptoms on infected plants. ELISA
      demonstrated that the scFv and diabody extracted from infected plants showed the
      same antigen-binding specificity as that of the parental monoclonal antibody. The
      PVX vector is a convenient, rapid, low-cost in planta expression system that can
      also be used for assessment of scFv production and function prior to stable plant
      transformation.

PMID- 10648934
TI  - Transgenic milk as a method for the production of recombinant antibodies.
AB  - Recombinant antibodies and their derivatives are increasingly being used as
      therapeutic agents. Clinical applications of antibodies often require large
      amounts of highly purified molecules, sometimes for multiple treatments. The
      development of very efficient expression systems is essential to the full
      exploitation of the antibody technology. Production of recombinant protein in the
      milk of transgenic dairy animals is currently being tested as an alternative to
      plasma fractionation for the manufacture of a number of blood factors (human
      antithrombin, human alpha-1-antitrypsin, human serum albumin, factor IX). The
      ability to routinely yield mg/ml levels of antibodies and the scale-up
      flexibility make transgenic production an attractive alternative to mammalian
      cell culture as a source of large quantities of biotherapeutics. The following
      review examines the potential of transgenic expression for the production of
      recombinant therapeutic antibodies.

PMID- 10648935
TI  - Antitransferrin receptor antibody-RNase fusion protein expressed in the mammary
      gland of transgenic mice.
AB  - Antibodies fused to human enzymes offer an alternative to specifically targeting
      tumors with antibodies linked to plant or bacterial toxins. Since large amounts
      of these reagents can be administered without eliciting non-specific toxicities,
      efficient methods of production are needed. The goal of this work was to express
      a complex immunoenzyme fusion protein (immunotoxin) in the mammary gland of
      transgenic mice. A chimeric mouse/human antibody directed against the human
      transferrin receptor (E6) was fused at its CH2 domain to the gene for a human
      angiogenic ribonuclease, angiogenin (Ang). It was expressed in the mammary gland
      of mice and secreted into mouse milk. Expression levels in milk were
      approximately 0.8 g/l. The chimeric protein retained antibody binding activity
      and protein synthesis inhibitory activity equivalent to that of free Ang. It was
      specifically cytotoxic to human tumor cells in vitro.

PMID- 10648936
TI  - Preparation of fcgamma for addition to sulfhydryl-expressing ligands with minimal
      disturbance of the hinge.
AB  - We described previously a scheme for linking functionally intact human normal
      Fcgamma1, via a thioether linkage emerging from its hinge, to any molecule
      expressing a free sulfhydryl group (SH). The scheme entails reducing the Fc to
      release four SH from the two inter-gamma disulfide bonds (SS) in the hinge,
      blocking one SH by a stochastic alkylation, restoring by SS-interchange the inter
      gamma SS whose two SH are still available, and attaching a bismaleimide linker to
      the one remaining SH. One thereby obtains Fc with a single maleimide group (Fc
      maleimide) for attachment to the SH-displaying partner. Restoration of the inter
      gamma SS is necessary if the final chimeric construct is to be able to activate
      the classical complement pathway. However, during this preparation of Fc
      maleimide, there is apparently some SS-formation between non-homologous SH, so
      that not all hinges emerge with a reconstituted inter-gamma SS. To reduce this
      error we have modified the preparative procedure after investigating an initial
      partial reduction of the hinge, and reviewing the conditions for stochastic
      alkylation. During partial reduction by dithiothreitol, the two hinge SS were
      cleaved apparently randomly: there was no evidence for one bond being more
      susceptible to reduction than the other, and little indication that the reduction
      of one bond enhanced the susceptibility of the other. By limiting reduction to an
      average of one SS per molecule, and alkylation to 0.8 SH per molecule, a final Fc
      maleimide product is obtained in which most of the molecules have passed through
      the entire preparation with one of their hinge SS, and by inference much of the
      hinge conformation, remaining intact.

PMID- 10648937
TI  - High avidity scFv multimers; diabodies and triabodies.
AB  - Multivalent recombinant antibody fragments provide high binding avidity and
      unique specificity to a wide range of target antigens and haptens. This review
      describes how careful choice of linker length between V-domains creates new types
      of Fv modules with size, flexibility and valency suited to in vivo imaging and
      therapy. Further, we review the design of multi-specific Fv modules suited to
      cross-linking target antigens for cell-recruitment, viral delivery and
      immunodiagnostics. Single chain Fv antibody fragments (scFvs) are predominantly
      monomeric when the V(H) and V(L) domains are joined by polypeptide linkers of at
      least 12 residues. An scFv molecule with a linker of 3 to 12 residues cannot fold
      into a functional Fv domain and instead associates with a second scFv molecule to
      form a bivalent dimer (diabody, approximately 60 kDa). Reducing the linker length
      below three residues can force scFv association into trimers (triabodies,
      approximately 90 kDa) or tetramers ( approximately 120 KDa) depending on linker
      length, composition and V-domain orientation. The increased binding valency in
      these scFv multimers results in high avidity (long off-rates). A particular
      advantage for tumor targeting is that molecules of approximately 60-100 kDa have
      increased tumor penetration and fast clearance rates compared to the parent Ig. A
      number of cancer-targeting scFv multimers have recently undergone pre-clinical
      evaluation for in vivo stability and efficacy. Bi- and tri-specific multimers can
      be formed by association of different scFv molecules and, in the first examples,
      have been designed as cross-linking reagents for T-cell recruitment into tumors
      (immunotherapy) and as red blood cell agglutination reagents (immunodiagnostics).

PMID- 10648938
TI  - Inhibition of expression of the Galalpha1-3Gal epitope on porcine cells using an
      intracellular single-chain antibody directed against
      alpha1,3galactosyltransferase.
AB  - The carbohydrate epitope Galalpha1-3Gal has been shown to be the major target of
      natural antibodies responsible for hyperacute rejection of porcine tissues
      transplanted into primates. We have sought to produce a phenotypic knockout of
      the alpha1, 3Galactosyltransferase enzyme that is responsible for generating this
      epitope, using an intracellular antibody approach. We have isolated high affinity
      anti-alpha1,3Galactosyltransferase single-chain antibodies from a semi-synthetic
      phage display library. Expression of a KDEL-tagged anti
      alpha1,3Galactosyltransferase single-chain antibody in a porcine endothelial cell
      line resulted in the decreased expression of the Galalpha1-3Gal epitope and
      increased resistance to lysis by human serum.

PMID- 10648939
TI  - Extended half-life and elevated steady-state level of a single-chain Fv intrabody
      are critical for specific intracellular retargeting of its antigen, caspase-7.
AB  - 8 h) and high steady-state levels of protein accumulation, while the H2
      intrabodies had a half-life of 2 h and less protein at steady state. These
      results suggest that the choice of sFv as an intrabody depends critically on the
      intracellular sFv protein having an extended half-life and elevated steady-state
      level. Thus, extended half-life must be considered together with sFv antibody
      specificity and affinity when choosing an optimal sFv intrabody for functional
      studies of cellular proteins.

PMID- 10648940
TI  - Human anti-HIV-1 tat sFv intrabodies for gene therapy of advanced HIV-1-infection
      and AIDS.
AB  - The early successes of highly active anti-retroviral therapies (HAART) for the
      treatment of HIV-1-infection and AIDS have raised the question as to whether
      there is a legitimate role for gene therapy in the treatment of this chronic
      infectious disease. However, in many patients the profound suppression of viral
      replication is short lived, particularly if patients have been treated with
      sequential monotherapies in the past, have been infected with a highly drug
      resistant isolate of HIV-1, or have temporarily discontinued therapy as a
      "holiday" or because of drug intolerance. In addition, life-long adherence to
      maintenance HAART will probably be required even in responding patients with
      undetectable viremia because of the reservoirs of latently infected cells that
      can persist for years. Gene therapy through the introduction of anti-retroviral
      "resistance" genes into CD4(+) T cells is one approach that could give long term
      protection to these HIV-1 susceptible cells in vivo. We have explored this
      approach by developing intrabodies to the critical HIV-1 transactivator protein,
      Tat that is absolutely required for HIV-1 replication. This provocative treatment
      approach, that will be tested in a clinical gene therapy trial, sets the
      groundwork for determining if anti-Tat intrabody gene therapy together with HAART
      can provide a treatment strategy for the immune reconstitution of HIV-1-infected
      patients with advanced disease.

PMID- 10648941
TI  - Infrared photodetection for the in vivo localisation of phage-derived antibodies
      directed against angiogenic markers.
AB  - Angiogenesis, the formation of new blood vessels from pre-existing ones, is a
      characteristic process which underlies many diseases, including cancer,
      rheumatoid arthritis and blinding ocular disorders. Antibodies capable of
      selective targeting and occlusion of neovasculature would open diagnostic and
      therapeutic opportunities. We have recently demonstrated that phage-derived human
      antibody fragments with high affinity for the extra-domain B (ED-B) of
      fibronectin, a marker of angiogenesis, selectively localise in new-forming blood
      vessels upon intravenous injection. Here, we show that infrared fluorescence
      methodologies nicely complement radioactive techniques for the study of the
      antibody-mediated targeting of angiogenesis in a variety of animal models.
      Methods are presented for the construction and use of infrared fluorescence
      imagers, as well as for the production and characterisation of recombinant
      antibodies labeled with infrared fluorophores.

PMID- 10648942
TI  - Generating improved single-chain Fv molecules for tumor targeting.
AB  - Due to their ease of isolation from phage display libraries and their ability to
      recognize conserved antigens, single-chain Fv (scFv) molecules are rapidly
      becoming commonplace. However, the monovalent nature of the scFv molecule often
      dictates, at best, transient interactions with target antigens when molecules
      with moderate to low affinity are employed. This, along with their rapid
      elimination from circulation, has limited the utility of scFv molecules for
      applications in the fields of cancer imaging and therapy. Recently, a number of
      strategies, including affinity maturation and modification of size and valence,
      have been evaluated for improving the in vivo efficacy of scFv molecules. In this
      review, we describe a number of these methods and discuss some of the
      characteristics that may belong to an optimal antibody-based targeting vehicle.

PMID- 10648943
TI  - Taking engineered anti-CEA antibodies to the clinic.
AB  - There is a need to improve on existing targeting technologies in order to develop
      effective cancer therapy. We have investigated this for colorectal cancer using
      antibodies directed against carcinoembryonic antigen (CEA). Chemical and
      molecular protein engineering has been used to produce antibody molecules which
      differ in molecular weight, affinity, valency and specificity. These have been
      characterised and tested in animal tumour models and clinical trials to test the
      parameters important for optimising tumour penetration, increasing residence time
      in viable areas of the tumour, accelerating clearance from normal tissues and
      improving therapeutic efficacy.

PMID- 10648944
TI  - Ignition of combustible/air mixtures by small radiatively heated surfaces.
AB  - Optical radiation as an ignition source in potentially explosive atmospheres was
      investigated for a number of explosive mixtures with respect to the most
      important case occurring in practice, i.e., absorption of the radiation by a
      solid target. Iron oxide was used as the target material. The combustibles were
      selected in compliance with the well-known temperature classes and apparatus
      groups to allow a useful graduation of the power limits to be applied.

PMID- 10648945
TI  - Monitoring of the pesticide levels in some water supplies and agricultural land,
      in El-Haram, Giza (A.R.E.).
AB  - Monitoring of pesticide residues were conducted at different locations in the El
      Haram region Giza, Egypt. The water samples were collected from El-Haram Giza,
      canal water supplies (El-Zomor, Abd-el-aal land and seaside and El-Mansorya), in
      addition to El-Moheet drainage water. The soil samples were collected from the
      arable land that surrounds water canals. Water samples were obtained by solid
      phase extraction (SPE) and soil samples by gel permeation chromatography (GPC).
      The combination of gas chromatography and mass spectroscopy with different
      ionization techniques was used for determination and identification of the
      pesticides, which were quantitatively determined as 1 microgram 1(-1) levels in
      environmental samples. The residues of pesticides were varied between different
      locations. Also, organochlorine pesticide residues in El-Moheet drainage water
      were relatively higher than in the canal water. The concentrations of
      organophosphorous compounds (chlorpyrifos, dimethoate and parathion) seem to be
      low in water as compared to soil samples. Most findings were less than 1
      microgram g(-1), which is considered a low-level finding. Sixteen organochlorine
      pesticides were detected in most of the water samples and the percent of positive
      samples followed the order drins > total BHC > total DDT > endosulfan >
      heptachlor epoxid > heptachlor. Pentachlorophenol (PCP) was detected only in El
      Zomor and Abd-el-aal canal water. Results obtained confirm the presence of
      different pesticide residues representing different chemical classes in the canal
      waters. This means that the discharging of wastes in to the water supplies must
      be controlled. Drainage water was highly polluted and contains much more
      pesticide residues than different canal waters.

PMID- 10648946
TI  - Reaction behaviors of decomposition of monocrotophos in aqueous solution by UV
      and UV/O processes.
AB  - The decomposition of monocrotophos (cis-3-dimethoxyphosphinyloxy-N-methyl
      crotonamide) in aqueous solution by UV and UV/O(3) processes was studied. The
      experiments were carried out under various solution pH values to investigate the
      decomposition efficiencies of the reactant and organic intermediates in order to
      determine the completeness of decomposition. The photolytic decomposition rate of
      monocrotophos was increased with increasing solution pH because the solution pH
      affects the distribution and light absorbance of monocrotophos species. The
      combination of O(3) with UV light apparently promoted the decomposition and
      mineralization of monocrotophos in aqueous solution. For the UV/O(3) process, the
      breakage of the >C=C< bond of monocrotophos by ozone molecules was found to occur
      first, followed by mineralization by hydroxyl radicals to generate CO(3)(2-),
      PO4(3-), and NO(3)(-) anions in sequence. The quasi-global kinetics based on a
      simplified consecutive-parallel reaction scheme was developed to describe the
      temporal behavior of monocrotophos decomposition in aqueous solution by the
      UV/O(3) process.

PMID- 10648948
TI  - Soil mixing of stratified contaminated sands.
AB  - Validation of soil mixing for the treatment of contaminated ground is needed in a
      wide range of site conditions to widen the application of the technology and to
      understand the mechanisms involved. Since very limited work has been carried out
      in heterogeneous ground conditions, this paper investigates the effectiveness of
      soil mixing in stratified sands using laboratory-scale augers. This enabled a low
      cost investigation of factors such as grout type and form, auger design,
      installation procedure, mixing mode, curing period, thickness of soil layers and
      natural moisture content on the unconfined compressive strength, leachability and
      leachate pH of the soil-grout mixes. The results showed that the auger design
      plays a very important part in the mixing process in heterogeneous sands. The
      variability of the properties measured in the stratified soils and the measurable
      variations caused by the various factors considered, highlighted the importance
      of duplicating appropriate in situ conditions, the usefulness of laboratory-scale
      modelling of in situ conditions and the importance of modelling soil and
      contaminant heterogeneities at the treatability study stage.

PMID- 10648949
TI  - Comparison of organic and inorganic packing materials in the removal of ammonia
      gas in biofilters.
AB  - Two organic and two inorganic packing materials were compared with regard to the
      removal of ammonia gas in a biofilter inoculated with night-soil sludge. By
      gradually increasing the inlet load of ammonia, the complete removal capacity,
      which was defined as the inlet load of ammonia that was completely removed, and
      the maximum removal capacity of ammonia, which was the value when the removal
      capacity leveled off for each packing material, were estimated. Both values which
      were based on a unit volume of packing material, were higher for organic packing
      materials than inorganic ones. By using kinetic analysis, the maximum removal
      rate of ammonia, V(m), and the saturation constant, K(s), were determined for all
      packing materials and the values of V(m) for organic packing materials were found
      to be larger. By using the kinetic parameters, the removal rates for ammonia were
      compared among the four packing materials, and the organic packing materials
      showed superior performance for the removal of ammonia in the concentration range
      of 0-300 ppm as compared to inorganic packing materials.

PMID- 10648947
TI  - Correlation model to predict residual immiscible organic contaminants in sandy
      soils.
AB  - Researchers in both environmental and petroleum engineering have conducted
      studies in one-dimensional columns to quantify the amount of residual nonaqueous
      phase liquids (NAPL) trapped in the porous media as a function of capillary,
      viscous and buoyancy forces. From these previous studies, it is proven that
      significant amounts of the original NAPL spill remain as a trapped residual. The
      objective of this research was to extend this body of work and to develop a
      correlation model that could predict residual NAPL saturation as a function of
      common soil characteristics and fluid properties. These properties include
      parameters derived from sieve analysis, namely, the uniformity coefficient
      (C(u)), the coefficient of gradation (C(c)), as well as fluid properties
      (interfacial tension, viscosity and density). Over 100 column experiments were
      conducted across a range of nine different soil gradations. The data produced by
      these tests, along with measured soil and fluid properties, were used to generate
      correlation models to predict residual NAPL saturation (S(rn)). The first
      correlation model predicts S(rn) for the region where residual NAPL saturation is
      independent of the capillary number, and dependent on C(u), C(c) and the Bond
      number. The second correlation model predicts S(rn) for the region where residual
      NAPL saturation is dependent on capillary number, as well as C(u), C(c) and the
      Bond number. The third correlation model predicts S(rn) over the entire region as
      a function of C(u), C(c) and the total trapping number. The correlation models
      have a R(2) value of 0.972, 0.934 and 0.825, respectively. Hence, the models may
      potentially be integrated into site characterization approaches.

PMID- 10648951
TI  - Evolving learnable neutral networks under changing environments with various
      rates of inheritance of acquired characters: comparison between Darwinian and
      Lamarckian evolution.
AB  - The processes of adaptation in natural organisms consist of two complementary
      phases: learning, occurring within each individual's lifetime, and evolution,
      occurring over successive generations of the population. In this article, we
      study the relationship between learning and evolution in a simple abstract model,
      where neural networks capable of learning are evolved using genetic algorithms
      (GAs). Individuals try to maximize their life energy by learning certain rules
      that distinguish between two groups of materials: food and poison. The connective
      weights of individuals' neural networks undergo modification, that is, certain
      characters will be acquired, through their lifetime learning. By setting various
      rates for the heritability of acquired characters, which is a motive force of
      Lamarckian evolution, we observe adaptational processes of populations over
      successive generations. Paying particular attention to behaviors under changing
      environments, we show the following results. Populations with lower rates of
      heritability not only show more stable behavior against environmental changes,
      but also maintain greater adaptability with respect to such changing
      environments. Consequently, the population with zero heritability, that is, the
      Darwinian population, attains the highest level of adaptation to dynamic
      environments.

PMID- 10648952
TI  - Design, observation, surprise! A test of emergence.
AB  - The field of artificial life (Alife) is replete with documented instances of
      emergence, though debate still persists as to the meaning of this term. We
      contend that, in the absence of an acceptable definition, researchers in the
      field would be well served by adopting an emergence certification mark that would
      garner approval from the Alife community. Toward this end, we propose an
      emergence test, namely, criteria by which one can justify conferring the
      emergence label.

PMID- 10648953
TI  - On the Baldwin effect.
AB  - In this article the effects of altering the rate and amount of learning on the
      Baldwin effect are examined. Using a version of the abstract tunable NK model, it
      is shown that the adaptation process is sensitive to the rate of learning,
      particularly as the correlation of the underlying fitness landscape varies.
      Typically a high learning rate proves most beneficial as landscape correlation
      decreases. It is also shown that the amount of learning can have a significant
      effect on the adaptation process, where increased amounts of learning prove
      beneficial under higher learning rates on uncorrelated landscapes.

PMID- 10648954
TI  - Evolution and development of a central pattern generator for the swimming of a
      lamprey.
AB  - This article describes the design of neural control architectures for locomotion
      using an evolutionary approach. Inspired by the central pattern generators found
      in animals, we develop neural controllers that can produce the patterns of
      oscillations necessary for the swimming of a simulated lamprey. This work is
      inspired by Ekeberg's neuronal and mechanical model of a lamprey [11] and follows
      experiments in which swimming controllers were evolved using a simple encoding
      scheme [25, 26]. Here, controllers are developed using an evolutionary algorithm
      based on the SGOCE encoding [31, 32] in which a genetic programming approach is
      used to evolve developmental programs that encode the growing of a dynamical
      neural network. The developmental programs determine how neurons located on a two
      dimensional substrate produce new cells through cellular division and how they
      form efferent or afferent interconnections. Swimming controllers are generated
      when the growing networks eventually create connections to the muscles located on
      both sides of the rectangular substrate. These muscles are part of a two
      dimensional mechanical simulation of the body of the lamprey in interaction with
      water. The motivation of this article is to develop a method for the design of
      control mechanisms for animal-like locomotion. Such a locomotion is characterized
      by a large number of actuators, a rhythmic activity, and the fact that efficient
      motion is only obtained when the actuators are well coordinated. The task of the
      control mechanism is therefore to transform commands concerning the speed and
      direction of motion into the signals sent to the multiple actuators. We define a
      fitness function, based on several simulations of the controller with different
      commands settings, that rewards the capacity of modulating the speed and the
      direction of swimming in response to simple, varying input signals. Central
      pattern generators are thus evolved capable of producing the relatively complex
      patterns of oscillations necessary for swimming. The best solutions generate
      traveling waves of neural activity, and propagate, similarly to the swimming of a
      real lamprey, undulations of the body from head to tail propelling the lamprey
      forward through water. By simply varying the amplitude of two input signals, the
      speed and the direction of swimming can be modulated.

PMID- 10648955
TI  - 'Niche Selection' and the evolution of a complex behavior in a changing
      environment--a simulation.
AB  - One of the key problems in theoretical biology is the identification of the
      mechanisms underlying the evolution of complexity. This paper suggests that some
      difficulties in current models could be avoided by taking account of"niche
      selection"as proposed by Waddington [21] and subsequent authors [2]. Computer
      simulations, in which an evolving population of artificial organisms"selects"the
      niche(s) that maximize their fitness, are compared with a Control Model in
      which"Niche Selection"is absent. In the simulations the Niche Selection Model
      consistently produced a greater number of"fit"organisms than the Control Model;
      although the Niche Selection Model tended, in general, to produce organisms
      occupying simple niches, it was nonetheless more effective than the Control Model
      in producing well-adapted organisms inhabiting complex niches. It is shown that
      the production of these organisms is critically dependent on the rate of
      environmental change: Slow change leads to fit but undifferentiated populations,
      dominated by organisms occupying simple niches; differentiated populations,
      including well-adapted organisms living in complex niches, require rates of
      environmental change lying just beyond a mathematically well-defined critical
      value. In simulation"Niche Selection,"unlike conventional"Natural
      Selection,"provides a permanent selective bias in favor of simplicity. This
      tendency is counterbalanced by statistical forces favoring shifts from
      rare"simple niches"to commoner niches of greater complexity. Fit organisms
      inhabiting complex niches only emerge in conditions where the rate of
      environmental change is high enough to avoid the concentration of the population
      in very simple niches, but slow enough to permit step-by-step adaptation to
      niches of gradually increasing complexity. This result appears to be robust to
      changes in simulation parameters and assumptions, and leads to interesting
      conjectures about the real world behavior of biological organisms (and other
      complex adaptive systems). It is suggested that some of these conjectures might
      be relatively easy to test.

PMID- 10648956
TI  - Translation termination and yeast prions.
AB  - Protein biosynthesis is the final step in the transfer of genetic information in
      the cell. In turn, its last step is the release of a nascent polypeptide from the
      ribosome. Therefore, termination of translation may be considered (if we do not
      take into account protein post-translational modification and folding) as a final
      step of the transition from genotype to phenotype through the classic DNA--RNA-
      protein pathway. In a narrow sense, termination of translation is the hydrolytic
      cleavage of peptidyl-tRNA into free tRNA and completed polypeptide chain carrying
      all the information encoded in the corresponding mRNA and DNA. Then the completed
      protein molecule is released from the ribosome and the ribosome dissociates into
      its components (subunits, factors, mRNA, tRNA, etc. ). After the synthesis is
      completed, the polypeptide chain is folded either cotranslationally or by an
      additional specialized mechanism, depending on the nature of the protein,
      organism, and other factors. This issue of Biochemistry (Moscow) highlights from
      various points of view the problem of translation termination, excluding protein
      folding. Yeast termination factors with prion-like properties are also
      considered.

PMID- 10648957
TI  - UGA: a dual signal for 'stop' and for recoding in protein synthesis.
AB  - UGA remains an enigma as a signal in protein synthesis. Long recognized as a stop
      signal that is prone to failure when under competition from near cognate events,
      there was growing belief that there might be functional significance in the
      production of small amounts of extended proteins. This view has been reinforced
      with the discovery that UGA is found at some recoding sites where frameshifting
      occurs as a regulatory mechanism for controlling the gene expression of specific
      proteins, and it also serves as the code for selenocysteine (Sec), the 21st amino
      acid. Why does UGA among the stop signals play this role specifically, and how
      does it escape being used to stop protein synthesis efficiently at recoding sites
      involving Sec incorporation or shifts to a new translational frame? These issues
      concerning the UGA stop signals are discussed in this review.

PMID- 10648958
TI  - Ribosomal RNAs in translation termination: facts and hypotheses.
AB  - It is now well established that ribosomal RNAs (rRNAs) play an active role in
      every aspect of translation. This review focuses on recent evidence for the
      involvement of rRNAs from both subunits of the ribosome in translation
      termination. This evidence comprises data obtained with rRNA mutants both in vivo
      and in vitro. In particular, mutations in specific regions of rRNAs caused
      readthrough of nonsense codons in vivo. Consistent with their in vivo
      characteristics, the mutations decreased the productive association of the
      ribosome with release factor 2 (RF2) and the efficiency of catalysis of peptidyl
      tRNA hydrolysis in the presence of RF2 in realistic in vitro termination systems.
      It is now evident that genetic selections for termination-defective mutants in
      vivo and their characterization in realistic in vitro termination assays will
      rapidly advance our understanding of the mechanism of termination.

PMID- 10648959
TI  - Translation termination and its regulation in eukaryotes: recent insights
      provided by studies in yeast.
AB  - In protein synthesis, the arrival of one or other of the three stop codons in the
      ribosomal A-site triggers the binding of a release factor (RF) to the ribosome
      and subsequent polypeptide chain release. In eukaryotes, the RF is composed of
      two proteins, eRF1 and eRF3. eRF1 is responsible for the hydrolysis of the
      peptidyl-tRNA, while eRF3 provides a GTP-dependent function, although its precise
      role remains to be defined. Recent findings on translation termination and its
      regulation from studies in the yeast Saccharomyces cerevisiae are reviewed and
      the potential role of eRF3 is discussed.

PMID- 10648960
TI  - Novel function of the eukaryotic polypeptide-chain releasing factor 3 (eRF3/GSPT)
      in the mRNA degradation pathway.
AB  - The mammalian GTP-binding protein GSPT, whose carboxy-terminal sequence is
      homologous to the eukaryotic elongation factor EF1alpha, binds to the polypeptide
      chain releasing factor eRF1 to function as eRF3 in translation termination.
      However, the amino-terminal domain of GSPT, which contains a prion-like sequence,
      is not required for the binding. Instead, the amino-terminal domain is capable of
      binding to the carboxy-terminal domain of polyadenylate-binding protein (PABP),
      whose amino terminus is associating with the poly(A) tail of mRNAs, presumably
      for their stabilization. Interestingly, multimerization of PABP with poly(A),
      which is ascribed to the action of its carboxy-terminal domain, was completely
      inhibited by the interaction with the amino-terminal domain of GSPT. This may
      facilitate shortening of the poly(A) tail of mRNAs by an RNase. Thus, GSPT/eRF3
      appears to function not only as a stimulator of eRF1 in the translation
      termination but also as an initiator of the mRNA degradation machinery. Further
      physiological and cell biological approaches will be necessary to show whether
      our current in vitro findings on GSPT/eRF3 indeed reflect its bifunctional
      properties in living cells.

PMID- 10648961
TI  - Eukaryotic translation termination factor 1 associates with protein phosphatase
      2A and targets it to ribosomes.
AB  - Purification of type 2A protein phosphatase (PP2A) from rabbit skeletal muscle
      resulted in the isolation of a trimeric phosphatase which is composed of a
      catalytic (PP2Ac), a structural (PR65alpha/Aalpha), and a regulatory
      (PR55alpha/Balpha) subunit, together with translation termination factor 1 (eRF1)
      and another protein of 55 kD (EMBO J., 15, 101-112). Yeast two-hybrid system
      analysis demonstrated that the eRF1 interacted with PP2Acalpha but not with
      PR65alpha/Aalpha or PR55alpha/Balpha. The N-terminal region of PP2Acalpha,
      comprising 50 amino acid residues, and the C-terminal part of eRF1, corresponding
      to an internal region between amino acids 338-381, were found to be necessary for
      eRF1--PP2Acalpha interaction in yeast. Immunoprecipitations using 12CA5
      antibodies and extracts from COS1 cells transiently transfected with eRF1 tagged
      with 9-amino acid epitope from influenza hemagglutinin (HA) demonstrated the
      presence of eRF1--PP2Acalpha--PR65alpha/Aalpha complex in these cells. In
      addition, polysomes obtained from COS1 cells overexpressing HA--eRF1 displayed
      several-fold higher PP2A activity than control polysomes. No effect of either
      PP2Ac or dimeric and trimeric PP2A holoenzymes on the rate of translation
      termination was detected using an in vitro reconstituted translation termination
      assay. In summary, eRF1 appears to represent a novel PP2A-targeting subunit that
      brings this phosphatase in contact with putative ribosomal substrate(s). It
      remains to be established whether termination of translation requires
      dephosphorylation of participating protein factor(s).

PMID- 10648962
TI  - Prions: infectious proteins with genetic properties.
AB  - The data on prions--proteinaceous infectious agents--are briefly summarized.
      Prions cause several incurable neurodegenerative diseases in mammals, while in
      lower eukaryotes the prion properties of proteins may be responsible for the
      inheritance of some phenotypic traits. The novel experimental models for finding
      and studying proteins with prion properties based on the yeast Saccharomyces
      cerevisiae and the fungus Podospora anserina are described. The significance of
      the prion phenomenon for biology and medicine is discussed.

PMID- 10648963
TI  - Overexpression and purification of recombinant eRF1 proteins of rabbit and
      Tetrahymena thermophila.
AB  - The polypeptide release factor (eRF1) gene was cloned from rabbit and its
      overexpression and purification system was established in parallel with that of
      the eRF1 gene of Tetrahymena thermophila that has been cloned recently in this
      laboratory. The rabbit eRF1 (Ra-eRF1) is composed of 437 amino acids and is
      completely identical to human eRF1 though 3% distinct in the nucleotide sequence.
      This is in sharp contrast to Tetrahymena eRF1 (Tt-eRF1) that is only 57%
      identical to human eRF1. The recombinant Ra-eRF1 was marked with a histidine tag,
      overexpressed, and purified to homogeneity by two-step chromatography using Ni
      NTA-agarose and Mono Q columns. In contrast to Ra-eRF1, Tt-eRF1 formed aggregates
      upon overexpression in Escherichia coli, hence it was purified under denaturing
      conditions, and used to raise rabbit antibody. The resulting anti-Tt-eRF1
      antibody proved useful for examining conditions for soluble Tt-eRF1 in test
      cells. Finally, a soluble Tt-eRF1 fraction was purified from Saccharomyces
      cerevisiae transformed with the Tt-eRF1 expression plasmid by three steps of
      affinity and anion exchange chromatography. The cloned Ra-eRF1 gene complemented
      a temperature-sensitive allele in the eRF1 gene, sup45 (ts), of S. cerevisiae,
      though the complementation activity was significantly impaired by the histidine
      tag, whereas Tt-eRF1 failed to complement the sup45 (ts) allele.

PMID- 10648964
TI  - The [URE3] yeast prion: from genetics to biochemistry.
AB  - [URE3] is a non-Mendelian genetic element of the yeast Saccharomyces cerevisiae,
      an altered prion form of Ure2 protein. We show that recombinant Ure2p is a
      soluble protein that can assemble in vitro into dimers, tetramers, and octamers
      or form insoluble fibrils observed for PrP in its filamentous form or for Sup35p
      upon self-assembling, suggesting a similar mechanism for all prions.
      Computational, genetic, biochemical, and structural data allow us to specify a
      new boundary between the so-called prion-forming and nitrogen regulator
      (catalytic) domains of the protein and to map this boundary to Met-94. We bring
      strong evidence that the COOH-terminal (94-354) part of the protein forms a
      tightly folded domain, while the NH2-terminal (1-94) part is unstructured. These
      domains (or various parts of these domains) were shown (by means of the two
      hybrid system approach and affinity binding experiments) to interact with each
      other (both in vivo and in vitro). We bring also evidence that the COOH-terminal
      (94-354) catalytically active part of the protein can be synthesized (both in
      vitro and in vivo) via an internal ribosome-binding mechanism, independently of
      the production of the full-length protein. We finally show that Ure2p aggregation
      in vivo (monitored by fluorescence of Ure2p--GFP fusion) does not necessarily
      give rise to [URE3] phenotype. The significance of these findings for the
      appearance and propagation of the yeast prion [URE3] is discussed.

PMID- 10648965
TI  - A sensitive assay of translational fidelity (readthrough and termination) in
      eukaryotic cells.
AB  - The process of translation termination in eukaryotes has been monitored by
      different types of assays, each with its own merits. We have developed an in vivo
      system where the reporter protein is secreted from the cells in culture thus
      enabling continuous monitoring of translation termination activity by simple
      sampling of the cell culture media. Using this system, cell cultures can be
      challenged with various stimuli during growth and the cellular responses on the
      translational level can be investigated in vivo as well as in vitro. Sampling is
      rapid, easy, and non-destructive to the cells, which enables measurement of
      translational fidelity in real time during time-course experiments. In particular
      with this system it is possible to assess very low levels of stop codon
      suppression. The reporter enzyme, secreted alkaline phosphatase (SEAP), becomes
      tagged with the S-peptide when there is readthrough of a stop codon placed
      between the C-terminus of the SEAP and the S-peptide. The tagged SEAP is bound to
      a matrix and the bound SEAP activity is measured versus total SEAP activity in
      the medium as a reference. With this assay we have confirmed that eRF1 acts as an
      antisuppressor in cells transfected with a cognate suppressor tRNA as well as in
      control cells, where a small but significant level of readthrough (suppression)
      could be detected. We have also characterized suppression of the three stop
      codons individually, and especially UGA is prone for wobbling.

PMID- 10648967
TI  - Notes on a "printomere" mechanism of cellular memory and ion regulation of
      chromatin configurations.
AB  - According to the proposed hypothesis, the memory of a cell about the achieved
      state of cytodifferentiation is based on the existence of a postulated genetic
      structure termed here as a "printomere". A printomere is a relatively small
      linear DNA fragment which is laterally located on the chromosomal body and armed
      at its termini with peculiar analogs of chromosomal telomeres, which in this case
      are designated as "acromeres". The printomere locates along its chromosomal
      original--protoprintomere--and is bound to this chromosomal segment via proteins.
      The printomere codes for so-called fountain RNAs (fRNAs). Molecules of fRNAs as a
      part of ribonucleoproteins, or fRNPs, specifically bind to the complementary for
      them DNA sites, or "fions", that are dispersed nearby many structural genes. fRNP
      -fion complexes help to open, for a very short time, closed ion channels in the
      inner nuclear membrane, and this occurs strictly nearby corresponding genes.
      Dosed and local entry of the specific ions from the perinuclear cistern of the
      nucleus modifies the local pattern of the chromatin decompaction and modulates
      the expression level of the corresponding genes. The implied role of the fRNAs
      was considered in the so-called "fountain theory" (A. M. Olovnikov (1997) Int. J.
      Dev. Biol., 41: 923-931; A. M. Olovnikov (1999) J. Anti-Aging Medicine, 2: 57-71;
      A. M. Olovnikov (1999) Advances in Gerontology (St. Petersburg), 3: 54-64).
      Transcripts (fRNAs) coded by printomeres participate in the creation and
      maintenance of the specific patterns of decompaction and compaction of chromatin,
      which are characteristic for corresponding cytodifferentiations. Printomeres of
      various differentiations differ in their nucleotide sequences. The printomere and
      its chromosomal original, the protoprintomere, located co-linearly, side by side
      with it, have their own ori. Their length may vary from several thousands of base
      pairs to tens of thousands of b.p. Printomere bound by its arms to the
      chromosomal DNA with chromatin proteins is able to pass over the replicative
      forks during printomere replication and replication of the chromosome. That is
      why any printomere can be stably retained on the chromosomal body in the course
      of numerous cell divisions. Owing to printomeres, cellular memory about the
      proper structure of chromatin decompactions is created, kept, and can be carried
      through the succession of doublings of differentiated cells.

PMID- 10648966
TI  - Phenoptosis: programmed death of an organism.
AB  - Programmed cell death (apoptosis) is well-established in many multicellular
      organisms. Apoptosis purifies a tissue from cells that became useless or even
      harmful for the organism. Similar phenomena are already described also at
      subcellular level (suicide of mitochondria, i.e., mitoptosis) as well as at
      supracellular level (degradation of some organs temporarily appearing in the
      course of ontogenesis and then disappearing by means of apoptosis of the organ
      composing cells). Following the same logic, one may put a question about
      programmed death of an organism as a mechanism of purification of a kin,
      community of organisms, or population from individuals who became unwanted for
      this kin, etc. A putative mechanism of such kind is proposed to be coined
      "phenoptosis" by analogy with apoptosis and mitoptosis. In a unicellular organism
      (the bacterium Escherichia coli), three different biochemical mechanisms of
      programmed death are identified. All of them are actuated by the appearance of
      phages inside the bacterial cell. This may be regarded as a precedent of
      phenoptosis which prevents expansion of the phage infection among E. coli cells.
      Purification of a population from infected individuals looks like an evolutionary
      invention useful for a species. Such an invention has high chances to be also
      employed by multicellular organisms. Most probably, septic shock in animals and
      humans serves as an analog of the phage-induced bacterial phenoptosis. It is
      hypothesized that the stress-induced ischemic diseases of brain and heart as well
      as carcinogenesis if they are induced by repeated stresses also represent
      phenoptoses that, in contrast to sepsis, are age-dependent. There are
      interrelations of programmed death phenomena at various levels of complexity of
      the living systems. Thus, extensive mitoptosis in a cell leads to apoptotic death
      of this cell and extensive apoptosis in an organ of vital importance results in
      phenoptotic death of an individual. In line with this logic, some cases are
      already described when inhibition of apoptosis strongly improves the postischemic
      state of the organism.

PMID- 10648968
TI  - [Neonatal period: full of hope, full of fear].

PMID- 10648969
TI  - [Neonatal skin].

PMID- 10648970
TI  - [Prescription writing: impact of neonatal pharmacological data].

PMID- 10648971
TI  - [Mucosa and skin anomalies of the newborn].

PMID- 10648972
TI  - [Dermatoses of the premature child].

PMID- 10648973
TI  - [Neonatal dermatological emergencies].

PMID- 10648974
TI  - [Neonatal pustular diseases].

PMID- 10648975
TI  - [Bullae of the newborn infants].

PMID- 10648976
TI  - [Cutaneous nodules in neonates].

PMID- 10648977
TI  - [Neonatal alopecia and hypotrichosis].

PMID- 10648978
TI  - [Prenatal diagnosis in dermatology].

PMID- 10648980
TI  - [In Process Citation]

PMID- 10648979
TI  - [Skin care for the newborn].

PMID- 10648981
TI  - [ [In Process Citation]

PMID- 10648982
TI  - [Angiogenesis: from research to pathology].

PMID- 10648983
TI  - [Hepatobiliary cystadenoma with mesenchymal stroma: a hormone dependent tumor.
      Report of five cases with immunohistochemical study of hormone receptors].
AB  - Hepatobiliary cystadenomas with mesenchymal stroma are rare neoplasms, which
      occur only in females; they have a strong tendency to recur and a potential for
      malignant transformation. Microscopic features are characteristic but clinical
      findings are highly variable and laboratory data non specific. We report 5 cases
      with immunohistochemical study, showing the characteristics of mesenchymal
      stromal cells: myofibroblastic phenotype and expression of progesterone receptors
      in all cases and estrogen receptors in 3 out of 5 cases. These results point out
      the possible hormonal dependance of this tumor.

PMID- 10648984
TI  - [Hodgkin disease with nodular lymphocytic predominance or type I (paragranuloma
      of Poppema-Lennert): a clinico-pathological entity. Study of 21 cases and review
      of the literature].
AB  - We have studied clinical and pathological features of a series of 21 patients
      followed at the hospital Saint-Louis for a nodal nodular lymphocytic predominant
      Hodgkin's disease or paragranuloma of Poppema-Lennert. Histopathologically, all
      these lymph nodes were involved by a nodular proliferation of atypical cells,
      called pop corn cells with a B cell phenotype, admixed with small lymphocytes.
      Clinically, most patients were young males. The disease was localized except in
      one case and the prognosis good (only one death). However, one patient relapsed
      and another developped an aggressive lymphoma. These results were in keeping with
      different studies in the literature and confirmed that the paragranuloma is a
      clinicopathological entity, distinct from the classical Hodgkin's disease.
      Nowadays, it's strongly suggested that the pop corn cell is of centroblastic
      origin. Treatment remains controversial, however, according to most of the
      authors, patients with localized disease could be followed without treatment
      after surgical excision.

PMID- 10648985
TI  - [Tumor angiogenesis].

PMID- 10648986
TI  - [Recent entities in soft tissue tumor pathology--part 1].

PMID- 10648987
TI  - [Paraneoplastic vanishing bile duct syndrome in a case of Hodgkin's disease].
AB  - We report the case of a man whose Hodgkin's disease was diagnosed at the same
      time as ductopenia. Cholestasis partially regressed after lymphoma was treated.
      When Hodgkin's disease relapsed two years later, cholestasis reappeared and liver
      biopsy again showed ductopenia. Treatment of relapse resulted in remission and
      cholestasis resolved. Liver biopsies never showed infiltration by lymphoma during
      the course of the disease. The usual causes of ductopenia were ruled out. This
      case report emphasizes that paraneoplastic ductopenia may complicate Hodgkin's
      disease. Such ductopenia may evolve towards biliary cirrhosis and require liver
      transplantation.

PMID- 10648988
TI  - [Primary muscular antro-pyloric hypertrophy in the adult: case report].
AB  - Primary hypertrophic antro-pyloric stenosis in adults is a misleading anatomic
      and radioclinical entity. It consists of hypertrophy of the internal muscular
      layer. Distal gastrectomy is the only effective treatment of the symptomatic form
      and allows a pathologic study of the gastrectomy, thus ruling out most causes of
      obstruction, including neoplastic ones. Its congenital origin has not been
      established. We report the case of a 59 year-old man who had primary hypertrophic
      pyloric stenosis.

PMID- 10648989
TI  - [Cystic mesothelioma of the peritoneum in a male].
AB  - We report a case of cystic mesothelioma of the peritoneum in a young male with
      local recurrences and whose diagnosis was confirmed by standard histological
      studies and immunohistochemistry. This rare tumor appears generally in young
      females through abdominal pain and mass. Local recurrences without distant
      metastases are a feature of this pathology. The adequate treatment requires
      complete resection.

PMID- 10648990
TI  - [Malignant peripheral nerve sheath tumor with rhabdomyoblastic differentiation
      and glandular component].
AB  - An exceptional case of malignant peripheral nerve sheath tumor with striated
      muscle differentiation and glandular component is reported, in a 52-year old man.
      This tumor measured 8 cm in diameter, and was localized in the chest wall,
      infiltrating the skeletal muscle. The mesenchymal portion of the tumor was
      composed mostly of spindle cells arranged in interlacing fascicles. Between these
      fascicles, there were large cells with abundant eosinophilic cytoplasm and clear
      elongated nucleus. Immunohistochemical study demonstrated cytokeratin, EMA and
      CEA expression in the glandular component and S100 protein expression in the
      major portion of the mesenchymal component. The large cells identified as
      rhabdomyoblasts, expressed desmin, myoglobin, alpha-SR actin and alpha-SM actin.
      The tumor recurred 5 years after its resection. Histological and
      immunohistochemical features were identical. We think that positivity of
      neoplastic striated muscle cells with alpha-SM actin reflects an early
      differentiation phase of these cells.

PMID- 10648991
TI  - [Primary pulmonary rhabdomyosarcoma: a case report].
AB  - We report a case of primary pulmonary rhabdomyosarcoma in a 52-year-old woman.
      The diagnosis was established after radical right pneumonectomy, mainly based on
      immunohistochemistry and electron microscopy findings. This type of tumor is rare
      in adults. Its primary origin is suggested when a pulmonary meta-stasis of
      rhabdomyosarcoma from another site or a component of a mixed tumor are ruled out.
      The best treatment is surgery. The prognosis is poor.

PMID- 10648992
TI  - [An unusual primary vascular tumor: intimal sarcoma of the pulmonary artery].
AB  - Primary sarcomas of great vessels are rare and involve the aorta, pulmonary
      artery and inferior vena cava. The pathologic classification of these tumors can
      be made on the location of the sarcoma in relation to the vessel wall, luminal or
      mural. Luminal sarcomas are usually intimal sarcoma and mural sarcoma are most
      frequently leiomyosarcoma. The myofibroblastic or endothelial differentiation of
      these tumors is still debated. We report a case of intimal sarcoma of the
      pulmonary artery.

PMID- 10648993
TI  - [Hydatid cyst of the kidney].

PMID- 10648994
TI  - [An unusual tumor of the spermatic cord].

PMID- 10648995
TI  - [A painful nodule of the vulva].

PMID- 10648996
TI  - [A rare mesenchymal tumor].

PMID- 10648997
TI  - [Protocol for the pathologic examination of cystectomy and cystoprostatectomy
      specimens. Proposal for a standardized form].
AB  - We present practice guidelines for the examination of bladder specimens removed
      for bladder cancer and propose an example of standardized form for their
      reporting. This approach takes place in looking for better quality and
      facilitates use of the morphologic data.

PMID- 10648998
TI  - [C-kit and gastrointestinal "stromal" tumors: more than a new marker].

PMID- 10648999
TI  - [Localized hypertrophic neuropathy: differential diagnosis of intraneural
      perineurioma].

PMID- 10649000
TI  - Simple chemiluminescence assays for free radicals in venous blood and serum
      samples: results in atopic, psoriasis, MCS and cancer patients.
AB  - OBJECTIVE: To investigate the generation of reactive oxygen species (ROS) in
      serum and venous blood as well as the serum antioxidative activity (AOA) in
      patients and healthy controls by means of a simplified chemiluminescence (CL)
      methodology. STUDY PARTICIPANTS: 48 Atopic eczema, 23 psoriasis, 15 multiple
      chemical sensitivity (MCS) and 35 cancer patients together with 22 healthy
      volunteers. METHODS: ROS generation/photon emission in blood and serum samples
      under basal conditions and after light exposure as well as the AOA of the serum
      samples was investigated at room temperature (22 degrees C) in all 143 fasted
      subjects. The 3-step methodology resumes in adding a constant amount of blood or
      serum to a constant amount of CL substrate (or to an ROS-generating mixture for
      the AOA test), followed by a short preincubation and registration of the photon
      counts over a 600-second time interval. RESULTS: In the basal and light exposure
      tests significantly higher photon counts (> 14, 000 counts/600 s) were registered
      in venous blood in all patient groups when compared to healthy controls (p <
      0.001), suggesting increased amounts of activated leukocytes and light
      sensitizing compounds, respectively. By contrast, most patient sera showed in all
      three CL tests a strongly inhibited light emission (p < 0.005), suggesting an
      adaptive antioxidative response to oxidant stress factors. CONCLUSIONS: Atopic,
      psoriasis, MCS and cancer patients are exhibiting significantly changed blood and
      serum CL patterns when compared to healthy controls. The described assays are
      simple, well reproducible and enable a fast assessment of ROS generation and AOA
      in biological samples at low operational costs.

PMID- 10649001
TI  - [Evaluation and critical review published in the European literature on
      osteopathic studies in the clinical field and in the area of fundamental
      research].
AB  - OBJECTIVE: Identification of studies of osteopathic treatment in defined
      countries. Evaluation of methods and results of the studies and assessment of the
      available evidence concerning the effectiveness of osteopathy. STUDY DESIGN:
      Systematic review. Assessment of the quality of the studies, with respect to the
      osteopathic concept and current methodological criteria according to predefined
      keys. DATA SOURCES: Clinical trials and fundamental studies originating from
      Germany, England, Austria, The Netherlands, Scandinavia +/- published or
      unpublished. RESULTS: Out of a total of 30 studies retrieved, 9 reached the
      predetermined minimum number of points to be rated into quality categories. In 2
      of these studies the osteopathic treatment was more effective than the control
      intervention (p < 0.05). CONCLUSIONS: No definitive conclusions about the
      effectiveness of osteopathy can be drawn so far because of the low number of
      evaluated studies. It seems necessary to scrutinize the relevance of osteopathy
      through further methodologically adequate studies. Additionally, criteria for
      evaluation are proposed which correspond to the highest international standards
      in order to ensure a valid (and commonly accepted) evaluation of the osteopathic
      literature.

PMID- 10649023
TI  - Editorial.

PMID- 10649002
TI  - Independent replication of pre-clinical research in homeopathy: a systematic
      review.
AB  - OBJECTIVE: To determine whether any pre-clinical research in homoeopathy has been
      independently replicated. SEARCH STRATEGY: CISCOM was searched using the key
      words 'homeopathy' and 'basic research'. Further references were obtained from
      reviews, bibliographies, citation tracking and contact with experts. SELECTION
      CRITERIA: Studies comparing the effects of one or more homoeopathic medicines to
      no homoeopathic treatment on any live biological material apart from humans or
      animals under veterinary care. Research on intoxication and basophil
      degranulation was excluded. DATA COLLECTION AND ANALYSIS: Publications were
      grouped in experimental models. Studies were considered to comprise the same
      model if the outcome variable, biological material and homoeopathic treatment
      were the same. Publications relating to each experimental model were then
      arranged in chronological order. A model was considered to have been
      independently replicated if the first author was different and fewer than half of
      all authors had previously published research using that model. RESULTS: 120
      papers reported 61 different experimental models. Only three models were
      investigated by different research teams: growth of yeast, growth of wheat
      coleoptiles and ultra-violet-induced erythema in albino guinea pigs. In the case
      of yeast, attempts to replicate findings showing increased growth after treatment
      with Pulsatilla were unsuccessful. For wheat, two experiments by different
      research teams were conducted, but no single hypothesis was tested in both papers
      with the same result. Different research teams conducted very similar experiments
      on erythema treatment by Apis, but the methodological quality of the publications
      was low. CONCLUSIONS: There is a lack of independent replication of any pre
      clinical research in homoeopathy. In the few instances where a research team has
      set out to replicate the work of another, either the results were negative or the
      methodology was questionable.

PMID- 10649135
TI  - Back to the future

PMID- 10649136
TI  - Regional Presidents' communications

PMID- 10649137
TI  - A primer for JWOCN authors. III: The research report and the review article.

PMID- 10649138
TI  - Down the rabbit hole or in search of evidence?

PMID- 10649139
TI  - Treatment of urinary incontinence in men with electrical stimulation: is practice
      evidence-based?
AB  - Electrical stimulation is frequently recommended for the treatment of urinary
      incontinence in men. However, few randomized, controlled trials allow
      practitioners to evaluate the evidence base for this practice. The purpose of
      this article is to determine, based on a review of the literature, whether
      adequate evidence exists to support the use of electrical stimulation as a
      treatment of male urinary incontinence. Urge, stress, and overflow incontinence
      are evaluated separately. This review led to 3 conclusions: (1) theoretical and
      urodynamic evidence exists to support the use of electrical stimulation for urge
      incontinence, (2) conflicting evidence exists in the use of electrical
      stimulation for stress urinary incontinence, and (3) treatment of overflow
      incontinence in men has not been evaluated in a systematic way. For both stress
      urinary or overflow incontinence, practitioners should consider the existing
      research before recommending electrical stimulation as a first line of treatment.
      For urge incontinence, electrical stimulation may be an effective first-line
      treatment strategy.

PMID- 10649140
TI  - The use of glutamine and its implications for the WOC nurse.
AB  - Glutamine is the most abundant free amino acid in the body. It is synthesized and
      stored in skeletal muscle and released in significant amounts during times of
      stress. Glutamine is primarily used by rapidly replicating cells such as
      enterocytes, lymphocytes, macrophages, and fibroblasts. The role of glutamine
      supplementation in certain disease states has been extensively studied during the
      past decade, with use of both animals and human subjects. This article will
      review glutamine supplementation and its implications for WOC nursing practice.

PMID- 10649141
TI  - Sensitivity and specificity of the Braden Scale in the cardiac surgical
      population.
AB  - PURPOSE: A descriptive study was conducted to investigate the sensitivity and
      specificity of the Braden Scale for Predicting Pressure Ulcer Risk in a cardiac
      surgical population. PATIENTS AND SETTING: A convenience sample of 337 pressure
      ulcer-free patients undergoing cardiothoracic surgery at a large midwestern
      national referral center were enrolled in the study. METHODS: Systematic skin and
      Braden Scale assessments were completed independently on the day of surgery and
      on postoperative days 1, 3, and 5. The presence of a pressure ulcer was
      determined and classified using the 4-stage scale developed by the WOCN Society.
      RESULTS: Sixteen patients (4.7%) developed a total of 22 pressure ulcers.
      Sensitivity and specificity of Braden scores were calculated for the day of
      surgery and for postoperative days 1, 3, and 5. The established Braden "cutoff"
      score of < or = 16 to identify those "at risk" had poor specificity and
      sensitivity in this patient population. The appropriate cutoff score varied by
      hospital day. A preoperative Braden score of 22 correctly classified 50% of the
      pressure ulcer-positive patients. The appropriate cutoff scores on postoperative
      day 1, 3, and 5 were 13, 14, and 20, respectively. Those scores correctly
      classified 67% of the pressure ulcer-positive patients on postoperative day 1,
      57% on postoperative day 3, and 50% on postoperative day 5. CONCLUSION: These
      results illustrate that optimum prediction of pressure ulcer risk can only be
      accomplished with reassessments and determination of the Braden cutoff score or
      scores that are reflective of the patient's changing clinical condition
      throughout the hospitalization.

PMID- 10649142
TI  - Treatment options for healing of a full-thickness wound after failed
      abdominoplasty.

PMID- 10649143
TI  - WOC nursing and the evolution to advanced nursing practice.

PMID- 10649144
TI  - A brief history of advanced practice nursing and its implications for WOC
      advanced nursing practice.
AB  - Although the evolution of clinical nurse specialists and nurse practitioners
      during the previous several decades has led to a sense of novelty regarding
      advanced practice, it is important to remember that nurses have engaged in such
      roles for nearly 100 years. This article will review the history of advanced
      nursing practice, summarize current definitions of specialty and advanced
      practice, discuss the evolution of advanced practice and its impact on
      contemporary nursing, and provide a background for advanced practice
      considerations for the WOC nurse, which are discussed in detail in subsequent
      articles by Janice Beitz (pp 55-64) and Dorothy Doughty (pp 65-8) in this issue.

PMID- 10649145
TI  - Specialty practice, advanced practice, and WOC nursing: current professional
      issues and future opportunities.
AB  - Interest in clarification of the role of the WOC nurse as a specialized or
      advanced practice practitioner is increasing. Although much has occurred to
      delineate practice parameters, lack of expectations for specialty versus advanced
      nursing practice still exists. This article will differentiate advanced,
      specialty, and WOC nursing practice by examining their legal definitions,
      educational requirements, licensure, certifications, and practice milieus.
      Implications for the future of WOC nursing are posed within the context of the
      evolving American health care system.

PMID- 10649146
TI  - Integrating advanced practice and WOC nursing education.
AB  - The increased use of advanced practice nurses (APNs) in all health care settings
      provides new practice options for WOC nurses and new challenges for WOC nursing
      education. A number of WOC nurses are moving into APN roles, and APNs who are not
      WOC specialists are providing much of the primary care for patients with wounds,
      ostomies, and incontinence. New educational approaches are needed to prepare APNs
      for specialty practice in wound, ostomy, and/or continence care. In addition, the
      need exists to incorporate key WOC nursing content into the core curriculum for
      APNs who provide primary care for patients with or at risk for wounds or
      disordered elimination. This article explores potential strategies for meeting
      these new demands.

PMID- 10649147
TI  - Evaluation of office-based intervention to improve prevention counseling for
      patients at risk for sexually acquired hepatitis B virus infection. Hepatitis B
      WARE Study Group.
AB  - The aim of this study was to determine the effectiveness of tools to identify and
      counsel patients at risk for sexually transmitted hepatitis B virus infection.
      Physicians were randomly assigned to either an intervention group or a control
      group. The intervention group was provided with materials intended to encourage
      patients to return for counseling and to guide counseling concerning prevention
      of hepatitis B virus infection. Baseline data on 457 patients at risk for
      hepatitis B virus infection showed that 7% had received prevention counseling and
      2% had begun hepatitis B vaccination. Counseling was least likely to occur in
      obstetric-gynecologic practices, among uninsured patients, and among patients
      whose only risk factor was a diagnosis of a sexually transmitted disease. After a
      6-month intervention period 26% of the intervention group patients and 7% of the
      control group patients had been counseled (P <.01). Vaccination was more likely
      among intervention group patients (8% vs <1%; P <.001). The use of tools to
      identify and counsel patients at risk for sexually transmitted hepatitis B virus
      infection resulted in increased office-based prevention activities.

PMID- 10649148
TI  - Proceedings of the American Urogynecologic Society Multidisciplinary Symposium on
      Defecatory Disorders.
AB  - The Multidisciplinary Symposium on Defecatory Disorders was created to delineate
      the breadth of defecatory disorders and propose investigations to address
      identified knowledge deficits. Seven experts in defecatory disorders and 24
      members of the American Urogynecologic Society were invited. The experts provided
      brief summaries of the scope of defecatory disorders from the perspectives of
      their specialties. The group then divided into 3 subgroups that focused on
      pathophysiology, imaging, and evaluation and treatment. Defecatory disorders,
      including anal incontinence and constipation, are common among women of all ages.
      Determination of their prevalence is complicated by a lack of standardized
      definitions. Defecatory disorders carry lengthy differential diagnoses. Imaging
      studies and anorectal testing, although not standardized, can aid in
      distinguishing different causes of dysfunction. The lack of uniformity in
      diagnosis and evaluation compromises comparisons of different treatments.
      Standardization of diagnoses and diagnostic modalities is essential to the design
      of meaningful evaluations of treatments for defecatory disorders.

PMID- 10649149
TI  - Efficacy of continuous sequential transdermal estradiol and norethindrone acetate
      in relieving vasomotor symptoms associated with menopause.
AB  - OBJECTIVE: This study was undertaken to evaluate the efficacy and tolerability of
      a combination estradiol plus norethindrone acetate transdermal delivery system
      given in a continuous sequential regimen with transdermal estradiol versus
      placebo in the treatment of vasomotor symptoms of menopause. STUDY DESIGN: This
      was a 12-week double-blind trial of 220 healthy postmenopausal women with > or =
      8 moderate to severe hot flushes and sweating episodes per day. Women were
      randomly assigned to wear transdermal placebo patches or a transdermal patch
      releasing 50 microg/d 17beta-estradiol alone (Vivelle) for days 1 to 14 of each
      cycle and a combination patch releasing 50 microg/d 17beta-estradiol plus 1 of 3
      dosage levels (140, 250, or 400 microg/d) of norethindrone acetate (CombiPatch)
      for days 15 through 28. RESULTS: There was a significant (P <.001) reduction by
      the second week in the mean number of daily hot flushes from baseline to end
      point with all 3 doses of estradiol plus norethindrone acetate compared with
      placebo. Significant (P <.001) reductions in the mean intensity of hot flushes
      and sweating were also noted with estradiol plus norethindrone acetate compared
      with placebo. The incidences of adverse events with all 3 doses of estradiol plus
      norethindrone acetate and with placebo were comparable. CONCLUSION: An estradiol
      plus norethindrone acetate transdermal delivery system administered in a
      continuous sequential regimen with transdermal estradiol was well tolerated and
      effective for the treatment of moderate to severe vasomotor symptoms in
      postmenopausal women.

PMID- 10649150
TI  - Granisetron, droperidol, and metoclopramide for the treatment of established
      postoperative nausea and vomiting in women undergoing gynecologic surgery.
AB  - OBJECTIVE: The aim of this study was to evaluate granisetron, droperidol, and
      metoclopramide for efficacy and safety in the treatment of established
      postoperative nausea and vomiting after major gynecologic surgery. STUDY DESIGN:
      One hundred twenty postoperative female patients were monitored for the first 3
      hours after anesthesia in the postanesthesia care unit and for the next 24 hours
      after anesthesia in the ward. Patients who had postoperative nausea and vomiting
      within the first 3 hours after anesthesia received intravenously, in a randomized
      double-blind manner, 40 microg/kg granisetron, 20 microg/kg droperidol, or 0.2
      mg/kg metoclopramide. Patients were then observed for 24 hours after drug
      administration. RESULTS: Complete control of established postoperative nausea and
      vomiting, defined as no emesis and no need for another rescue antiemetic
      medication, was more frequent among the patients who had received granisetron
      (88%) than among those who had received droperidol (55%) or metoclopramide (50%)
      (P <.05). The severity of nausea was less in patients who had received
      granisetron than in those who had received droperidol or metoclopramide (P <.05).
      No clinically adverse events were observed in any of the groups. CONCLUSION:
      Granisetron is more effective than droperidol or metoclopramide for the treatment
      of established postoperative nausea and vomiting during the first 3 hours after
      anesthesia in patients undergoing major gynecologic operations.

PMID- 10649151
TI  - Cardiovascular responses of perimenopausal women to hormonal replacement therapy.
AB  - OBJECTIVE: This study was undertake to test the hypothesis that hormone
      replacement therapy alters cardiovascular function during the first several
      months of therapy. STUDY DESIGN: Serial estimates of blood pressure, heart rate,
      stroke volume, and venous capacitance were obtained before and at 1, 5, 9, and 21
      weeks after the beginning of hormone replacement therapy with daily estradiol and
      intermittent norethindrone. Measurements were performed by means of
      electrocardiography, automated blood pressure measurement (Dynamap; Critikon
      Company LLC, Tampa, Fla), echocardiography, and plethysmography. RESULTS: Hormone
      replacement therapy did not alter heart rate, blood pressure, or venous
      capacitance. End-diastolic volume and stroke volume were unchanged after 1 week
      of hormone replacement therapy but rose thereafter. After 5 weeks of hormone
      replacement end-diastolic volume and stroke volume were increased by 13 +/- 5 mL
      and 9 +/- 2 mL, respectively, and after 9 weeks the increases totaled 23 +/- 5 mL
      and 17 +/- 3 mL, respectively. As a result cardiac output rose progressively to a
      level 1.1 +/- 0.3 L/min (18%) greater than pretreatment values and systemic
      vascular resistance fell 15%. These changes were associated with a 3-fold
      increase in serum estradiol levels. CONCLUSION: The studied regimen of hormone
      replacement therapy produces progressive cardiac remodeling and peripheral
      vasodilatation during the first 2 months of therapy.

PMID- 10649152
TI  - Risk factors among young women with endometrial cancer: a Danish case-control
      study.
AB  - OBJECTIVE: This study was undertaken to identify and quantify risk factors for
      endometrial cancer among young women. STUDY DESIGN: This case-control study
      included all Danish women <50 years old who had endometrial cancer diagnosed
      during the period 1987 to 1994. A total of 237 case patients and 538 population
      control subjects matched with the case patients for age and residence were
      included in the analysis. RESULTS: Women with a family history of endometrial
      cancer had an odds ratio for endometrial cancer of 2.1 (95% confidence interval,
      1.1-3.8)). Completion of 1 term pregnancy implied an odds ratio of 0.6 (95%
      confidence interval, 0.3-1.1). The risk of endometrial cancer decreased
      significantly with increasing age at first birth and with the number of induced
      abortions. Use of oral contraceptives for 1 to 5 years decreased the risk of
      endometrial cancer (odds ratio, 0.2; 95% confidence interval, 0.1-0.3). The odds
      ratio for endometrial cancer among women who received hormone replacement therapy
      for 1 to 5 years was 3.1 (95% confidence interval, 1.4-7.0). Body mass index was
      not demonstrated to be an independent risk factor in this study. The protective
      impacts of the different exposures (risk factors) can be expressed as etiologic
      fractions, which indicate how much each exposure reduces the occurrence of
      endometrial cancer compared with a situation without the existence of that
      particular exposure. These fractions were as follows: oral contraceptive use for
      > or =1 year, -45%; 2 term pregnancies, -88%; age > or =30 y when giving birth
      for the first time, -38%; and a history of incomplete pregnancy, -16%.
      CONCLUSION: A number of risk factors for endometrial cancer are common to
      premenopausal and postmenopausal women: family history, reproductive history,
      hormone replacement therapy, and the use of oral contraceptives. Among young
      women reproductive variables imply the greatest prophylactic potential.

PMID- 10649153
TI  - A prospective randomized study comparing modified Burch retropubic urethropexy
      and suburethral sling for treatment of genuine stress incontinence with low
      pressure urethra.
AB  - OBJECTIVE: The aim of this study was to compare a modified Burch procedure with a
      suburethral sling for the treatment of stress incontinence complicated by a low
      pressure urethra. STUDY DESIGN: Thirty-six women with stress incontinence, low
      pressure urethra, and urethral hypermobility (straining cotton swab angle >/=30
      degrees ) were randomly assigned to undergo either a modified Burch procedure (n
      = 19) or a suburethral sling (n = 17). Objective and subjective cure rates at 3
      months after the operation were the primary outcome measures. Comparisons of
      group means were performed with the Student t test for independent groups, and
      proportions were compared with the Fisher exact test. RESULTS: After the
      operation the 2 groups had statistically similar cure rates and voiding function.
      Urethral closure pressure, pressure transmission ratios, and maximum detrusor
      pressure during voiding were significantly higher in the sling group. CONCLUSION:
      At 3 months there were no clinically significant differences between the groups
      treated with suburethral sling and modified Burch procedures.

PMID- 10649154
TI  - Hypertrophy of labia minora: experience with 163 reductions.
AB  - OBJECTIVE: Our purpose was to describe the surgical procedure, its results, and
      its complications and to determine whether patients are satisfied with surgical
      reduction of labia minora in cases of hypertrophy. STUDY DESIGN: The records of
      163 patients who underwent reduction of the labia minora during a 9-year period
      were reviewed. The ages of the patients ranged from 12 to 67 years (median, 26).
      Motives for requesting surgery were aesthetic concerns in 87% of the cases,
      discomfort in clothing in 64%, discomfort with exercise in 26%, and entry
      dyspareunia in 43%. Anatomic results were assessed 1 month postoperatively.
      Patient satisfaction was assessed by means of a mailed questionnaire. RESULTS: No
      surgery-related significant complications were noticed. Anatomic results were
      satisfactory for 151 patients (93%). Ninety-eight completed questionnaires were
      returned. Eighty-one patients (83%) found that the results after surgery were
      satisfactory. Eighty-seven (89%) were satisfied with the aesthetic result, and 91
      (93%) approved the functional outcome. Four patients (4%) would not undergo the
      same procedure again. CONCLUSION: Labia minora reduction is a simple surgical
      procedure associated with a high degree of patient satisfaction.

PMID- 10649155
TI  - A novel intermittent regimen of norgestimate to preserve the beneficial effects
      of 17beta-estradiol on lipid and lipoprotein profiles.
AB  - OBJECTIVE: This study was undertaken to evaluate the effects of 3 dosage levels
      of intermittent norgestimate plus a constant dose of 17beta-estradiol on blood
      lipid and lipoprotein concentrations in 236 postmenopausal women. STUDY DESIGN:
      In this multicenter, double-blind, parallel-group trial the subjects were
      randomly assigned to receive 1 mg estradiol daily or 1 mg estradiol daily plus
      intermittent (3 days off and 3 days on) doses of 30 microg, 90 microg, or 180
      microg norgestimate for 360 days. RESULTS: The regimens of 1 mg estradiol plus 30
      microg norgestimate and 1 mg estradiol plus 90 microg norgestimate increased
      concentrations of high-density lipoprotein cholesterol, HDL(2) high-density
      lipoprotein cholesterol, HDL(3) high-density lipoprotein cholesterol (except the
      regimen of 1 mg estradiol plus 30 microg norgestimate at 7 months), and
      apolipoprotein apo A-I. They decreased total cholesterol concentration, low
      density lipoprotein cholesterol concentration, low-density lipoprotein/high
      density lipoprotein ratio, apolipoprotein apo B concentration, and Lp(a)
      lipoprotein concentration, and they attenuated estradiol-induced increases in
      triglyceride concentrations. In contrast, the regimen of 1 mg estradiol plus 180
      microg norgestimate reduced concentrations of high-density lipoprotein
      cholesterol, high-density lipoprotein HDL(3) cholesterol, and apolipoprotein apo
      A-I at 7 months and increased the low-density lipoprotein/high-density
      lipoprotein ratio at 7 months. CONCLUSIONS: An intermittent regimen of
      norgestimate at 30 or 90 microg daily administered for 3 days off followed by 3
      days on preserved the beneficial lipid and lipoprotein changes induced by
      continuous therapy with 1 mg 17beta-estradiol daily; however, 180 microg
      norgestimate did not do so.

PMID- 10649156
TI  - Fetal membrane distention: I. Differentially expressed genes regulated by acute
      distention in amniotic epithelial (WISH) cells.
AB  - OBJECTIVE: This study was undertaken to determine which genes were up-regulated
      by acute distention in an amniotic epithelial cell line and in human fetal
      membranes. STUDY DESIGN: WISH cells, a human amniotic epithelial cell line, were
      grown on silicone elastomer sheets coated with extracellular matrix and
      reproducibly distended by 40% in a novel device for 4 hours. Differential gene
      expression was analyzed by means of suppression subtractive hybridization.
      Expression of the identified genes was then quantitated by Northern blot analysis
      in fetal membrane explants after distention in the same device for 4 hours. The
      effect of distention on apoptosis of the cells and tissue samples was
      concomitantly studied by means of the terminal deoxynucleotidyl transferase
      mediated deoxyuridine triphosphate nick end labeling method. RESULTS: The genes
      for interleukin 8 and pre-B-cell colony-enhancing factor were found to be up
      regulated in both the WISH cells and the distended fetal membranes. The apoptotic
      index values in both the cells and the tissue samples were unaffected by
      distention. CONCLUSIONS: Acute distention induces the up-regulation of
      interleukin 8 and pre-B-cell colony-enhancing factor in both WISH cells and human
      fetal membranes and does not cause apoptosis.

PMID- 10649157
TI  - Fetal membrane distention: II. Differentially expressed genes regulated by acute
      distention in vitro.
AB  - OBJECTIVE: This study was undertaken to identify genes with expression up
      regulated by acute distention in the human fetal membranes. STUDY DESIGN: Fetal
      membrane explants were distended reproducibly in a novel device in vitro for 4
      hours, and suppression subtractive hybridization was used to identify the
      candidate genes for up-regulation of expression in response to this stimulus. The
      up-regulation in response to distention was confirmed by quantitative Northern
      blot analysis both after a 4-hour in vitro distention and after labor in vivo.
      RESULTS: Suppression subtractive hybridization identified 3 genes with expression
      up-regulated by acute distention: an interferon-stimulated gene encoding a 54-kd
      protein, the gene for huntingtin-interacting protein 2 (a ubiquitin-conjugating
      enzyme), and a novel transcript. Expression of each of the distention-responsive
      genes found to be up-regulated in vitro was also up-regulated in fetal membranes
      in association with labor. CONCLUSIONS: Suppression subtractive hybridization was
      successfully applied to a complex tissue, the human fetal membranes, and 3 novel
      distention-responsive genes were identified. Both acute in vitro distention and
      labor in vivo up-regulate expression of at least 3 genes in the human fetal
      membranes.

PMID- 10649158
TI  - Effectiveness of Agency for Health Care Policy and Research clinical practice
      guideline and patient education methods for pregnant smokers in medicaid
      maternity care.
AB  - OBJECTIVE: The purposes of this study were (1) to determine the extent to which
      tobacco exposure assessment and new patient education methods, derived from a
      meta-analysis and the Agency for Health Care Policy and Research guideline
      recommendations, could be provided routinely by trained Medicaid maternity care
      staff members and (2) to document the behavioral impact of these interventions
      among pregnant smokers. STUDY DESIGN: After 265 pregnant smokers were assigned at
      their first visit to an experimental group (n = 139) or a control group (n =
      126), they received standardized risk information and were advised to quit
      smoking. The experimental group also received evidence-based patient education
      methods, including the videocassette Commit to Quit During and After Pregnancy,
      the publication A Pregnant Woman's Guide to Quit Smoking, and a brief counseling
      session. Self-report and saliva cotinine assessments of tobacco exposure were
      performed at baseline and at the end of pregnancy. RESULTS: A significantly
      higher percentage of patients quit smoking in the experimental group (17.3%) than
      in the control group (8.8%). CONCLUSIONS: The application of principles of
      organizational development and quality improvement at the management and clinical
      practice levels and the delivery of evidence-based health education methods by
      trained prenatal care providers significantly increased smoking cessation rates
      among pregnant Medicaid recipients.

PMID- 10649159
TI  - Randomized trial of perineal massage during pregnancy: perineal symptoms three
      months after delivery.
AB  - OBJECTIVE: The aim of this study was to evaluate the effect of perineal massage
      performed during pregnancy on perineal symptoms 3 months after delivery. STUDY
      DESIGN: Pregnant women from 5 hospitals in the province of Quebec, Canada,
      participated in this single-blind, randomized, controlled trial. All participants
      received oral and written information on the prevention of perineal trauma. Women
      in the experimental group were taught the perineal massage technique and were
      asked to perform a 10-minute perineal massage daily from the 34th through 35th
      weeks of pregnancy until delivery. Participants completed a self-administered
      questionnaire on perineal pain, dyspareunia, sexual satisfaction, and
      incontinence of urine, flatus, and stool at the time of enrollment and 3 months
      after delivery. RESULTS: Among participants without a previous vaginal birth
      there were no differences between the massage (n = 283) and the control (n = 289)
      groups with respect to perineal pain, dyspareunia, sexual satisfaction, and
      incontinence of urine, gas, or stool 3 months post partum. Among women with a
      previous vaginal birth more women in the massage group (n = 187) than in the
      control group (n = 190) were free of perineal pain (93.6% vs 85.8%; P =.01) but
      the frequencies of dyspareunia and incontinence of urine, gas, or stool were
      similar in the 2 groups. CONCLUSIONS: Perineal massage during pregnancy neither
      impairs nor substantially protects perineal function at 3 months post partum.

PMID- 10649160
TI  - A pilot randomized controlled trial of two regimens of fetal surveillance for
      small-for-gestational-age fetuses with normal results of umbilical artery doppler
      velocimetry.
AB  - OBJECTIVE: This study was undertaken to determine whether the frequency of fetal
      surveillance could be safely reduced from twice weekly to fortnightly in the case
      of small-for-gestational-age fetuses with normal results of umbilical artery
      Doppler velocimetry studies. STUDY DESIGN: Pregnant women between 24 and 36
      weeks' gestation (n = 167) with small-for-gestational-age fetuses and normal
      results of umbilical artery Doppler velocimetry studies were randomly allocated
      to undergo twice-weekly or fortnightly fetal surveillance. Statistical analysis
      was carried out according to intention to treat. RESULTS: Eighty-five women were
      randomly assigned to undergo twice-weekly fetal surveillance and 82 were randomly
      assigned to undergo fortnightly fetal surveillance. Those randomly assigned to
      twice-weekly surveillance were delivered 4 days earlier (264 vs 268 days; P =.04)
      and were more likely to have labor induced (n = 70, 82%, vs n = 54, 66%; P =.02)
      than those randomly assigned to fortnightly surveillance. Fifty-four babies (23%)
      were admitted to the neonatal nursery, but there were no differences in neonatal
      morbidity between the groups. CONCLUSIONS: Maternal intervention (induction) was
      more common in the twice-weekly group. No differences in neonatal outcomes were
      detected. A much larger trial is required to determine the safety and potential
      benefits of less frequent surveillance of small-for gestational-age fetuses with
      normal results of umbilical artery Doppler velocimetry studies.

PMID- 10649161
TI  - Modulation of vascular tone by nitric oxide and endothelin 1 in myometrial
      resistance arteries from pregnant women at term.
AB  - OBJECTIVE: We evaluated the role of endothelium-derived nitric oxide and
      endothelin 1 in the modulation of myogenic tone, norepinephrine-induced tone, and
      flow-mediated responses in resistance arteries from pregnant women at term. STUDY
      DESIGN: Arteries (approximately 200 microm at 50 mm Hg; n = 27) were dissected
      from myometrial biopsies obtained from women undergoing elective cesarean
      delivery at term and mounted in a pressure arteriograph. Responses to
      intraluminal flow, pressure, and norepinephrine were studied in the absence and
      presence of the nitric oxide synthase inhibitor Nomega-nitro-L-arginine and the
      endothelin-converting enzyme inhibitor phosphoramidon. RESULTS: Pressure-induced
      (80 mm Hg) myogenic tone was significantly enhanced after incubation with Nomega
      nitro-L-arginine (33% +/- 8% vs 24% +/- 4%; P <.05), whereas phosphoramidon
      significantly reduced myogenic tone (24% +/- 5% vs 33% +/- 5%; P <.05). A
      combination of Nomega-nitro-L -arginine and phosphoramidon did not affect
      myogenic tone. Norepinephrine-induced tone was significantly enhanced after
      nitric oxide synthase inhibition (49% +/- 6% vs 41% +/- 5%; P <.05) but was not
      affected by phosphoramidon. Flow-mediated dilatation was increased in the
      presence of phosphoramidon compared with flow-induced dilatation in physiologic
      salt solution (maximum dilatation, 57% +/- 12% vs 30% +/- 5%; analysis of
      variance, P <.05), and all flow-induced dilatation was abolished by Nomega-nitro
      L -arginine. CONCLUSIONS: Nitric oxide and endothelin 1 may play a significant
      role in modulation of myogenic tone and flow-mediated responses in the resistance
      vasculature of the uterine circulation in normal pregnancy.

PMID- 10649162
TI  - Cerebral edema complicating eclampsia.
AB  - OBJECTIVE: This study was undertaken to describe and correlate clinical findings
      with computed tomographic and magnetic resonance imaging scan results in 10 women
      with eclampsia and widespread cerebral edema. STUDY DESIGN: This was a clinical
      descriptive study of 10 women with eclampsia and symptomatic cerebral edema who
      were encountered at Parkland Hospital from 1986 through 1998. During this 13-year
      period nearly 175 women had eclampsia from a total of >160, 000 women delivered.
      The clinical courses of these 10 women with eclampsia and symptomatic cerebral
      edema are described, along with findings from computed tomographic and magnetic
      resonance imaging scans. RESULTS: In 3 cases symptoms followed an acute and
      severe elevation of blood pressure while the patient was being treated for
      eclampsia. All 3 of these women had severe generalized edema with radiographic
      findings of impending transtentorial herniation. Herniation did occur in 1 of
      these women, and she died. The other 7 women had central nervous system symptoms
      that persisted after an initial eclamptic convulsion. Symptoms ranged from
      lethargy, confusion, and blurred vision to obtundation and blindness. Five of
      these women had multiple areas of edema mostly apparent at the gray matter-white
      matter junction. Two women demonstrated extensive unilateral brain involvement;
      however, their symptoms were similar to those of the women with multifocal areas
      of cerebral edema. CONCLUSION: Symptomatic cerebral edema developed in almost 6%
      of women with eclampsia. Its genesis probably represents a continuum of central
      nervous system lesions that result from eclampsia. We postulate that women with
      symptoms of extensive cerebral edema have a cytotoxic edema caused by ischemia
      that is intensified by a vasogenic edema associated with sudden or severe
      hypertension.

PMID- 10649163
TI  - Latent hemodynamic abnormalities in symptom-free women with a history of
      preeclampsia.
AB  - OBJECTIVE: Most women with a pregnancy complicated by preeclampsia have either
      hypertension or a disorder with a thrombophilic phenotype or both of these. In
      this study we evaluated whether hemodynamic variables and volume homeostasis in a
      subgroup of normotensive women with a history of preeclampsia with normal
      clotting function (defined as the symptom-free subgroup) were comparable with
      those in a healthy parous control group. STUDY DESIGN: In a group of 58 subjects
      with a history of preeclampsia and a group of 11 healthy parous control subjects
      we measured the following variables > or = 5 months post partum at day 5 +/- 2 of
      the menstrual cycle: body weight and length, mean arterial pressure, heart rate,
      cardiac output, plasma volume, glomerular filtration rate, effective renal plasma
      flow, and plasma concentrations of volume regulatory hormones, clotting factors,
      antiphospholipid antibodies, and homocysteine before and after a methionine load.
      From the measured data we calculated body mass index, body surface area, cardiac
      index, left ventricular work, total peripheral and renal vascular resistances,
      effective renal blood flow, and renal filtration fraction. RESULTS: Among women
      with a history of preeclampsia 26 were normotensive with thrombophilia (45%), 14
      had hypertension (24%), and 18 were normotensive without thrombophilia (31%).
      These last symptom-free subjects with a history of preeclampsia were more obese
      than were control subjects. They also had higher cardiac output and left
      ventricular work and a lower plasma volume than the healthy parous control
      subjects. Thus they resemble the second subgroup of subjects (subjects with
      hypertension and a history of preeclampsia) rather than the control subjects. The
      hemodynamic and renal functions in the subgroup of subjects with a history of
      preeclampsia with normotension and thrombophilia were similar to those in healthy
      parous control subjects. CONCLUSION: On the basis of this study we conclude that
      hemodynamic parameters and volume homeostasis in the symptom-free subgroup of
      women with a history of preeclampsia are different from those in healthy parous
      control subjects. Hemodynamic parameters and volume homeostasis in this subgroup
      resemble those of women with hypertension and a history of preeclampsia. We
      therefore propose the classification of these symptom-free subjects with a
      history of preeclampsia as having "latent" hypertension.

PMID- 10649164
TI  - Comparison of the Bishop score, ultrasonographically measured cervical length,
      and fetal fibronectin assay in predicting time until delivery and type of
      delivery at term.
AB  - OBJECTIVE: Our aim was to compare the Bishop score, fetal fibronectin assays, and
      ultrasonographic measurement of cervical length to determine the best markers for
      time until spontaneous labor at term and risk of cesarean delivery, especially
      for the indication of lack of progress of dilatation. STUDY DESIGN: This
      prospective study included 128 singleton vertex pregnancies with no clinical
      evidence of membrane rupture or regular contractions and a prenatal consultation
      between 39 weeks 4 days' gestation and 40 weeks 3 days' gestation. We
      successively assayed for fetal fibronectin, determined the Bishop score, and
      measured cervical length by transvaginal ultrasonography. The end points were the
      percentage of patients with a spontaneous onset of labor in the week after these
      tests and the type of delivery. RESULTS: The spontaneous onset of labor within a
      7-day period was closely associated with a Bishop score > or = 6 and with a
      cervical length < or = 26 mm but not with a positive result of the fetal
      fibronectin assay. On the other hand, vaginal delivery was significantly
      associated with the fibronectin assay result but not with either the Bishop score
      or cervical length. CONCLUSIONS: The Bishop score and ultrasonographic
      measurement of cervical length are valuable for predicting the onset of
      spontaneous labor within 7 days (when these assessments are performed close to
      term), whereas the fetal fibronectin assay is useful for evaluating the risk of
      cesarean delivery. These tests thus provide different physiologic data that are
      useful for different purposes.

PMID- 10649165
TI  - New simple endoscopic operations for interstitial pregnancies.
AB  - OBJECTIVES: Our aim was to report a new approach of endoscopic management
      (endoloop and encircling suture methods) for interstitial or cornual pregnancy
      and to determine the safety and effectiveness of these procedures and their
      effects on subsequent pregnancies. STUDY DESIGN: This is an uncontrolled
      retrospective review of 24 patients treated for interstitial pregnancies through
      endoscopic operations with 14 to 72 months of follow-up at a large urban medical
      center. Blood loss, operation time, changes of serum human chorionic gonadotropin
      levels, the resumption of menstruation, and subsequent pregnancy after operation
      were analyzed. RESULTS: Among 24 interstitial pregnancies, 3 had ruptured at the
      time of operation and 21 had not ruptured. Treatment consisted of either the
      vasopressin and electric cauterization method, the endoloop before evacuation of
      the conceptus method, or the encircling suture before evacuation of the conceptus
      method. The blood loss and operation time (mean +/- SD) for unruptured cases were
      133 +/- 134 mL and 51.6 +/- 7.6 minutes in the vasopressin and electric
      cauterization group (n = 3), 32 +/- 22 mL and 28.5 +/- 6.4 minutes in the
      endoloop group (n = 15), and 40 +/- 17 mL and 35.0 +/- 5.0 minutes in the
      encircling suture group (n = 3). In 3 patients with ruptured pregnancy treated
      with the endoloop method, the blood loss and operation time (mean +/- SD) were
      1100 +/- 854 mL and 82.5 +/- 51.6 minutes. Any of these operative methods
      resulted in rapid decline of serum human chorionic gonadotropin levels within 1
      week with the exception of 1 case, in which the endoloop method was used; this
      patient needed additional treatment with methotrexate. Seventeen patients desired
      pregnancy in the future, and 15 eventually became pregnant. One of these 15
      pregnancies ended in an ectopic pregnancy on the opposite side 6 months after the
      interstitial pregnancy. Three ended in a spontaneous abortion, and 11 were
      delivered by elective cesarean section at term before labor started. Operative
      records of cesarean section in 8 patients delivered at our institution showed
      little or no adhesions or defect in the cornual area of the previous operation.
      CONCLUSION: The endoloop method and the encircling suture method are simple,
      safe, effective, and nearly bloodless. There were no uterine ruptures in the
      pregnancies subsequent to these methods of endoscopic management.

PMID- 10649166
TI  - A multicenter, placebo-controlled pilot study of intravenous immune globulin
      treatment of antiphospholipid syndrome during pregnancy. The Pregnancy Loss Study
      Group.
AB  - OBJECTIVE: Treatment with heparin and low-dose aspirin improves fetal survival
      among women with antiphospholipid syndrome. Despite treatment, however, these
      pregnancies are frequently complicated by preeclampsia, fetal growth restriction,
      and placental insufficiency, often with the result of preterm birth. Small case
      series suggest that intravenous immune globulin may reduce the rates of these
      obstetric complications, but the efficacy of this treatment remains unproven.
      This pilot study was undertaken to determine the feasibility of a multicenter
      trial of intravenous immune globulin and to assess the impact on obstetric and
      neonatal outcomes among women with antiphospholipid syndrome of the addition of
      intravenous immune globulin to a heparin and low-dose aspirin regimen. STUDY
      DESIGN: This multicenter, randomized, double-blind pilot study compared treatment
      with heparin and low-dose aspirin plus intravenous immune globulin with heparin
      and low-dose aspirin plus placebo in a group of women who met strict criteria for
      antiphospholipid syndrome. All patients had lupus anticoagulant, medium to high
      levels of immunoglobulin G anticardiolipin antibodies, or both. Patients with a
      single live intrauterine fetus at </=12 weeks' gestation were randomly assigned
      to receive either intravenous immune globulin (1 g/kg body weight) or an
      identical-appearing placebo for 2 consecutive days each month until 36 weeks'
      gestation in addition to a heparin and low-dose aspirin regimen. Maternal
      characteristics, obstetric complications, and neonatal outcomes were compared
      with the Student t test and the Fisher exact test as appropriate. RESULTS:
      Sixteen women were enrolled during a 2-year period; 7 received intravenous immune
      globulin and 9 were given placebo. The groups were similar with respect to age,
      gravidity, number of previous pregnancy losses, and gestational age at the
      initiation of treatment. Obstetric outcomes were excellent in both groups, with
      all women being delivered of live-born infants after 32 weeks' gestation. The
      rates of antepartum complications such as preeclampsia, fetal growth restriction,
      and placental insufficiency (as manifested by fetal growth restriction or fetal
      distress) were similar between the 2 groups. Gestational age at delivery
      (intravenous immune globulin group, 34.6 +/- 1.1 weeks; placebo group, 36.7 +/-
      2.1 weeks) and birth weights (intravenous immune globulin group, 2249.7 +/- 186.1
      g; placebo group; 2604.4 +/- 868.9 g) were similar between the 2 groups. There
      were fewer cases of fetal growth restriction (intravenous immune globulin group,
      0%; placebo group, 33%) and neonatal intensive care unit admission (intravenous
      immune globulin group, 20%; placebo group, 44%) among the infants in the
      intravenous immune globulin group than those in the placebo group, but these
      differences were not significant. CONCLUSION: A multicenter treatment trial of
      intravenous immune globulin is feasible. In this pilot study intravenous immune
      globulin did not improve obstetric or neonatal outcomes beyond those achieved
      with a heparin and low-dose aspirin regimen. Although not statistically
      significant, the findings of fewer cases of fetal growth restriction and neonatal
      intensive care unit admissions among the intravenous immune globulin-treated
      pregnancies may warrant expansion of the study.

PMID- 10649167
TI  - Fetal membrane distention: determination of the intrauterine surface area and
      distention of the fetal membranes preterm and at term.
AB  - OBJECTIVE: This study was undertaken to obtain an accurate measurement of the
      intrauterine surface area and the degree of distention of the apposed fetal
      membranes preterm and at term. STUDY DESIGN: Serial longitudinal images of the
      uterus in 23 women between 25 and 41 weeks' gestation were obtained by
      ultrasonography. A Mathematica (Wolfram Research, Inc, Champaign, Ill) program
      assembled a 3-dimensional image and calculated the intrauterine surface area for
      each patient. The surface areas of the placental amnion and membranes were
      measured in vitro after delivery. From these measurements the degree of
      distention of each fetal membrane in vivo was calculated. RESULTS: The mean
      calculated intrauterine surface areas were as follows: 1037 +/- 70 cm(2) (25-29
      weeks' gestation, n = 4), 1376 +/- 121 cm(2) (30-34 weeks' gestation, n = 4), and
      1876 +/- 307 cm(2) (37-41 weeks' gestation, n = 15, P =.0021 by Wilcoxon rank sum
      test). The surface areas of the expelled membranes at 25 to 29, 30 to 34, and 37
      to 41 weeks' gestation were 737 +/- 61 cm(2), 855 +/- 77 cm(2), and 1115 +/- 149
      cm(2), respectively. The ratios of intrauterine surface area to the area of the
      expelled membrane and hence a measure of the degree of distention in vivo were
      1.4 +/- 0.05 at 25 to 29 weeks' gestation (n = 4), 1.6 +/- 0.2 at 30 to 34 weeks'
      gestation (n = 4), and 1.7 +/- 0.3 at term (n = 15). CONCLUSION: The intrauterine
      surface area in vivo increases during gestation. The surface area of the fetal
      membranes as measured in vitro increases to a lesser extent. The fetal membranes
      are therefore distended in vivo.

PMID- 10649168
TI  - Interleukin 16 in pregnancy, parturition, rupture of fetal membranes, and
      microbial invasion of the amniotic cavity.
AB  - OBJECTIVE: Interleukin 16 is a proinflammatory cytokine that promotes the
      recruitment of nonclonotypic T cells and eosinophils to sites of inflammation and
      induces resistance to activation-induced apoptosis. This peptide has no homology
      with members of the chemokine family and is produced by epithelial cells. No
      information is available about the expression of this cytokine during human
      pregnancy. This study was conducted to determine whether interleukin 16 is
      present in amniotic fluid and to examine the effects of labor and intrauterine
      infection on the concentrations of this cytokine. STUDY DESIGN: A cross-sectional
      study was constructed with 230 women in the following groups: (1) mid- trimester
      (n = 25); (2) term not in labor (n = 25), term in labor (n = 25), and term
      premature rupture of membranes not in labor (n = 40); (3) preterm labor and
      intact membranes with (n = 21) and without (n = 42) intra-ammiotic infection; and
      (4) preterm premature rupture of membranes in the presence (n = 29) and absence
      (n = 23) of microbial invasion of the amniotic cavity. Interleukin 16
      concentration was measured with sensitive and specific immunoassays validated for
      amniotic fluid. Data were analyzed with nonparametric statistics. RESULTS: (1)
      Interleukin 16 was detected in 87.8% (202/230) of amniotic fluid samples. (2)
      Amniotic fluid interleukin 16 concentrations were significantly higher in women
      in the midtrimester than in those at term not in labor (median, 321.5 pg/mL;
      range, 146.9-1185.8 pg/mL; vs median, 85.9 pg/mL; range, <25-409.8 pg/mL; P
      <.001). (3) Labor at term was not associated with a significant increase in the
      median amniotic fluid interleukin 16 concentration. (4) Patients with preterm
      labor who delivered preterm had a significantly higher median amniotic fluid
      interleukin 16 concentration than those with preterm labor who delivered at term
      (median, 328.1 pg/mL; range, 38. 9-4660 pg/mL; vs median, 119.8 pg/mL; range, <25
      558.5 pg/mL;P <.05). (5) Microbial invasion of the amniotic cavity was associated
      with a significant increase in median amniotic fluid interleukin 16 concentration
      in patients with preterm labor and intact membranes (microbial invasion of the
      amniotic cavity: median, 839 pg/mL; range, <25-8620 pg/mL; vs no microbial
      invasion of the amniotic cavity: median, 119.8 pg/mL; range, <25-558.5 pg/mL; P
      <.001) and in patients with preterm premature rupture of the membranes (microbial
      invasion of the amniotic cavity: median, 1005.8 pg/mL; range, <25-4590 pg/mL; vs
      no microbial invasion of the amniotic cavity: median, 204.9 pg/mL; range, 42.6
      2347 pg/mL; P <.05). (6) Spontaneous rupture of the membranes at term but not
      preterm was associated with a significant decrease in amniotic fluid
      concentrations of interleukin 16 (term premature rupture of the membranes:
      median, <25 pg/mL; range, <25-231.2 pg/mL; vs term intact membranes: median, 85.9
      pg/mL; range, <25-409.8 pg/mL; P <.05). CONCLUSIONS: Amniotic fluid interleukin
      16 concentrations decreased with advancing gestational age. Women with preterm
      labor that led to preterm delivery and women with microbial invasion of the
      amniotic cavity had higher interleukin 16 amniotic fluid concentrations than
      those with preterm labor who delivered at term or those with sterile amniotic
      fluid. Microbial invasion of the amniotic cavity but not spontaneous labor at
      term or rupture of membranes was associated with increased concentrations of
      interleukin 16 in amniotic fluid.

PMID- 10649169
TI  - Successful sealing of fetoscopic access sites with collagen plugs in the rabbit
      model.
AB  - OBJECTIVE: The aim of this study was to evaluate the efficacies of various
      plugging techniques in sealing the membrane defect created by fetoscopy in the
      rabbit at midgestation. STUDY DESIGN: Fetoscopy was performed in pregnant rabbits
      at 23 days' gestation (term, 32 days' gestation). In group 1 fetal sacs were left
      unclosed (positive control group, n = 24). In group 2 injection with commercially
      available extracellular matrix (Matrigel; BD Labware, Bedford, Mass) was
      performed and a myometrial suture was inserted (n = 23). In group 3 the entry
      site was plugged with collagen (Colgen; Inter-Phar, Paris, France) combined with
      a myometrial suture (n = 22). At 30 days' gestation the membrane integrity,
      amniotic fluid presence, and fetal lung/body weight ratios were assessed. The
      plugging site was examined histologically. RESULTS: The use of suture and
      collagen plugs (group 3) resulted in functional restoration of membrane integrity
      with preservation of amniotic fluid and normal fetal lung/body weight ratio at
      term in 82% of cases, compared with 42% in the positive control group (group 1; P
      <.05). Histologic examination revealed entrapment of membranes between the plug
      and the myometrium but no anatomic repair of the membranes. The use of suture and
      extracellular matrix (group 2) did not achieve better results than those seen in
      group 1 (positive control group). CONCLUSION: Collagen plugs achieved functional
      sealing of fetoscopic access sites in a rabbit model and prevented
      oligohydramnios and pulmonary hypoplasia.

PMID- 10649170
TI  - Blood flow and the degree of shunting through the ductus venosus in the human
      fetus.
AB  - OBJECTIVES: Our goal was to determine the degree of shunting through the ductus
      venosus in the human fetus and its possible association with fetal growth. STUDY
      DESIGN: Blood flow in the umbilical vein and the fetal ductus venosus was
      measured in 197 low-risk pregnancies in a cross-sectional ultrasonographic study
      at a gestational age of 18 to 41 weeks. The degree of shunting was compared to
      birth weight and ponderal index. RESULTS: The average fraction shunted through
      the ductus venosus was 28% to 32% at 18 to 20 weeks, decreased to 22% at 25
      weeks, and reached 18% at 31 weeks (with wide ranges expressed in the 10th and
      90th percentiles). Fetuses <10th percentile for birth weight had significantly
      more shunting (1.4%) than those >90th percentile (95% confidence interval, 0.1%
      2.7%; P =.04). CONCLUSIONS: In the human fetus a higher proportion of umbilical
      blood is directed to the liver and less is shunted through the ductus venosus, in
      comparison with what has previously been shown in animal experiments.

PMID- 10649171
TI  - Umbilical artery doppler screening for detection of the small fetus in need of
      antepartum surveillance.
AB  - OBJECTIVE: Our goal was to test the hypothesis that umbilical artery Doppler
      velocimetry identifies fetuses who are small for gestational age and in need of
      antenatal surveillance. STUDY DESIGN: Three hundred eight fetuses with either an
      ultrasonographic weight estimate <10th percentile for gestational age or an
      abdominal circumference <2.5th percentile for gestational age or both of these
      had an umbilical artery Doppler measurement of the systolic/diastolic ratio. A
      systolic/diastolic ratio >90th percentile for gestation was considered abnormal.
      The incidences of a birth weight <10th percentile, fetal distress, and metabolic
      acidemia were recorded for both groups (normal vs abnormal umbilical artery
      Doppler). RESULTS: Only the umbilical artery systolic/diastolic ratio predicted
      perinatal outcome in the group of fetuses who were presumed to be small for
      gestational age. Those 138 fetuses with elevated umbilical artery
      systolic/diastolic ratios had lower umbilical artery and vein pH values at birth
      (artery, 7.23 +/- 0.08 vs 7.25 +/- 0.1; P <.02; vein, 7.31 +/- 0.01 vs 7.34 +/-
      0.09; P =.01), an increased likelihood of fetal distress consistent with chronic
      hypoxemia (26.3% vs 8.6%; P <.0001), more admissions to the neonatal intensive
      care unit (40.7% vs 30.7%; P <.005), and a higher incidence of respiratory
      distress (66% vs 27.3%; P <.03). However, it is important that no fetus with a
      normal Doppler flow measurement was delivered with a metabolic acidemia
      associated with chronic hypoxemia. Further, the likelihood of a false-positive
      diagnosis of intrauterine growth restriction was increased in the group with a
      normal umbilical artery Doppler resistance. CONCLUSION: Antenatal surveillance
      may be unnecessary in fetuses with suspected intrauterine growth restriction if
      the umbilical artery systolic/diastolic ratio and amniotic fluid volume are
      normal, because the complications that occur are intrapartum. If these findings
      are confirmed in prospective trials, the cost implication of reducing the number
      of antenatal surveillance tests administered in this group of patients is great.

PMID- 10649173
TI  - Fetal fibronectin and bacterial vaginosis in smokers and nonsmokers. The National
      Institute of Child Health and Human Development Maternal- Fetal Medicine Units
      Network.
AB  - To determine whether maternal smoking influences the relationship between
      bacterial vaginosis and fetal fibronectin, the presence of cervical or vaginal
      fetal fibronectin, the presence of bacterial vaginosis, and smoking status were
      determined for 2899 women at 24 weeks' gestation. Fetal fibronectin was more
      common among women with bacterial vaginosis, but maternal smoking did not
      increase the likelihood that women with bacterial vaginosis would have fetal
      fibronectin detected. A previously reported impact of maternal smoking status on
      the relationship between bacterial vaginosis and fetal fibronectin thus was not
      confirmed.

PMID- 10649172
TI  - Monitoring pregnancy outcomes after prenatal drug exposure through prospective
      pregnancy registries: a pharmaceutical company commitment.
AB  - OBJECTIVE: Glaxo Wellcome becomes aware of prenatal exposures to its medications
      as early as the clinical trial phase of development. An international process for
      monitoring prenatal exposure to all Glaxo Wellcome medicines has been developed.
      For specific products there are prospective pregnancy registries. STUDY DESIGN:
      The registries are observational, case-registration, and follow-up studies
      designed to detect evidence of teratogenicity associated with specific
      medications. After prenatal exposure to the registry medication, pregnancies are
      registered prospectively, through voluntary reports by health care providers. An
      advisory committee of independent scientists for each registry reviews data and
      advises in dissemination of information. Risk of birth defects, as defined by the
      Centers for Disease Control and Prevention, is compared with published risks both
      in women in the general population and in women with the underlying condition
      being treated, if available. RESULTS: The following data show results from the
      prospective first-trimester exposures registered since establishment of each
      registry. The published risk of birth defects in the general population range is
      3% to 5%, and the risk in women with epilepsy is 6% to 9%. The proportions of
      outcomes with birth defects are as follows: in the Acyclovir (antiviral
      medication) Pregnancy Registry (1984-1998) (19/581), 3.3% (95% confidence
      interval, 2.0%-5.2%); in the Lamotrigine (monotherapy and polytherapy
      antiepileptic medication) Pregnancy Registry (1992-September 1998) (8/123), 6.5%
      (95% confidence interval, 3.1%-12.8%); in the Sumatriptan (migraine medication)
      Pregnancy Registry (1996-October 1998) (7/183), 3.8% (95% confidence interval,
      1.7%-8.0%). The Valacyclovir, Bupropion, and Naratriptan registries have
      insufficient data for analysis. CONCLUSION: None of the registries has provided a
      risk estimate exceeding that expected in the disorder treated, and no pattern of
      defects has been observed. Whereas information from the larger registries is
      reassuring regarding risk, these studies cannot rule out possible small excess
      risks from use of these drugs in pregnancy. Data obtained through these
      registries are shared with the medical community as a supplement to animal
      toxicology studies to assist in weighing potential risks and benefits of
      treatment for individual patients. The success of the registries depends on the
      continued willingness of the obstetrics and gynecology community to notify the
      registries of prenatal exposures.

PMID- 10649174
TI  - Ex vivo human placental transfer and the vasoactive properties of hydralazine.
AB  - OBJECTIVE: The purpose of this study was to determine the placental transfer and
      fetal vascular effects of hydralazine in an ex vivo human placental system. STUDY
      DESIGN: Nine placentas from uncomplicated term vaginal or cesarean deliveries
      were studied by means of the ex vivo single-cotyledon perfusion system.
      Antipyrine was used for the reference compound in the determination of the
      clearance index of hydralazine. Fetal vascular effects of hydralazine were
      determined by the effects on the perfusion pressure of the fetal artery in a
      constant-flow open system. Variations in fetal pressure were analyzed with the 1
      sample Student t test. RESULTS: The clearance index of hydralazine ranged from
      0.61 +/- 0. 18 to 0.73 +/- 0.14. The accumulation of hydralazine in the
      recirculated fetal compartment was linear in relationship to the maternal
      concentration. Fetal pressure changes were noted in 6 of the 9 placentas, or
      66.6%. The mean change in pressure was -4.1 +/- 4.4 mm Hg (P =.0231).
      CONCLUSIONS: Hydralazine readily crosses the ex vivo human placental perfusion
      system.

PMID- 10649175
TI  - Cost of neonatal care according to gestational age at birth and survival status.
AB  - OBJECTIVE: This study was undertaken to determine the cost of initial hospital
      care for newborn infants according to gestational age at birth and survival
      status. STUDY DESIGN: This was a retrospective review of prospectively collected
      data on hospital and physician costs for all infants born in the study
      institutions at < or = 32 weeks' gestation for 1989 through 1992. A cohort of
      term and near-term infants was selected at random. Variables were examined by
      multiple logistic regression for their independent effects on cost. RESULTS:
      Length of stay and gestational age were related to cost among survivors born at <
      or = 32 weeks' gestation but not among nonsurvivors. Total cost of initial care
      for the US population of neonates is estimated at $10.2 billion annually, with
      11.9% spent on infants born between 24 and 26 weeks' gestation and 42.7% spent on
      those born at > or = 37 weeks' gestation. CONCLUSIONS: Although costs for an
      individual surviving extremely premature baby may be high, the costs for
      extremely low gestational age infants is a small component of total neonatal care
      costs because so few infants are born at these gestational ages. The mathematic
      model developed from these data allows cost savings to be predicted for
      management strategies designed to alter gestational age at birth or survival.

PMID- 10649176
TI  - The effects of vascular endothelial growth factor on endothelial cells: a
      potential role in preeclampsia.
AB  - OBJECTIVES: Preeclampsia is primarily a disorder of the maternal endothelium. An
      as yet unidentified circulating factor causes widespread alteration in
      endothelial function, and levels of vascular endothelial growth factor are
      elevated in preeclampsia. We hypothesized that vascular endothelial growth factor
      is involved in the alteration of endothelial function and set out to find further
      evidence for this contention. STUDY DESIGN: Bovine microvascular endothelial
      cells (B-88) were cultured in vitro. These cultured cells were then stimulated
      with vascular endothelial growth factor and with plasma from women with
      preeclampsia in the presence and absence of anti-vascular endothelial growth
      factor antibody. Prostacyclin, nitric oxide, and lactate dehydrogenase levels
      were measured. RESULTS: Vascular endothelial growth factor induced a significant
      concentration-dependent increase in prostacyclin production but not nitric oxide
      production. Cells stimulated with plasma from women with preeclampsia showed
      increases in production of both prostacyclin and nitric oxide. Vascular
      endothelial growth factor concentration in plasma was correlated with
      prostacyclin production by stimulated cells. The increase in prostacyclin
      production that usually followed the addition of plasma did not occur when anti
      vascular endothelial growth factor antibody was present. CONCLUSIONS: Vascular
      endothelial growth factor has the ability to alter endothelial cell function in a
      manner analogous to that of plasma from women with preeclampsia.

PMID- 10649177
TI  - Congenital heart disease: the impact of delivery in a tertiary care center on
      SNAP scores (scores for neonatal acute physiology).
AB  - OBJECTIVE: It has been hypothesized that delivery in a tertiary care center might
      improve the clinical condition and outcome of infants born with congenital heart
      disease. The purpose of this study was to determine the effect of delivery in a
      tertiary care center on SNAP scores (scores for neonatal acute physiology) of
      infants admitted to the neonatal intensive care unit with major structural
      cardiac defects. STUDY DESIGN: This retrospective cohort study included 195
      infants with major congenital heart disease admitted to the neonatal intensive
      care unit at the New England Medical Center between July 1, 1992, and June 30,
      1998. SNAP scores were abstracted from the medical record. The values of 97
      neonates with major cardiac defects born at the New England Medical Center were
      compared with those of 98 neonates transferred to our center after delivery in a
      community setting. A 2-tailed Student t test for independent samples was used to
      compare the mean SNAP scores between the 2 cohorts. RESULTS: The SNAP scores for
      infants with major cardiac defects who were born at the New England Medical
      Center ranged from 0 to 41, with a mean of 10.6 +/- 8.8. The values for infants
      with congenital heart disease who were transferred to our center after birth in
      community-based hospitals ranged from 0 to 34, with a mean of 11.1 +/- 7.0. There
      was no significant difference between the 2 populations (P =.646). A comparison
      of the mean SNAP scores of infants with prenatally diagnosed disease who were
      delivered at our center versus infants with postnatally diagnosed disease who
      were delivered in community hospitals was also statistically not significant (P
      =.824). CONCLUSION: Delivery in a tertiary care center does not improve SNAP
      scores of infants with major structural cardiac defects.

PMID- 10649178
TI  - Critical appraisal of the use of nuchal fold thickness measurements for the
      prediction of Down syndrome.
AB  - OBJECTIVE: Nuchal fold thickness is the best ultrasonographic predictor of fetal
      trisomy 21. However, the risk assigned on the basis of the commonly used
      threshold of nuchal fold thickness >/=6 mm does not take into consideration the
      significant associations between nuchal fold thickness and gestational age and
      between maternal age and Down syndrome. We propose a new method of calculating
      Down syndrome probability that takes into account both gestational age at
      examination and previously assessed probability of Down syndrome. STUDY DESIGN:
      Nuchal fold thickness was measured at ultrasonographic examination at 14 to 22
      weeks' gestation without previous knowledge of the fetal karyotype. Nuchal cystic
      hygromas were excluded from analysis. Statistical analyses included correlation,
      logistic regression to control for other ultrasonographic predictors of trisomy
      21 and for maternal age, receiver operating characteristic curve, and likelihood
      ratios (defined as the ratio of the sensitivity to the false-positive rate). P
      <.05 was considered significant. RESULTS: Mean gestational age at ultrasonography
      was 16.9 weeks' gestation (range, 14-22 weeks' gestation). Mean (+/-SD) nuchal
      fold thickness in fetuses with trisomy 21 (4.7 +/- 1.6 mm; n = 29) was greater
      than in euploid fetuses (3.2 +/- 0.9; n = 780; P <.001). Logistic regression
      analysis established that nuchal fold thickness was a significant predictor of
      trisomy 21 independent both of the other ultrasonographic markers and of maternal
      age (P <.001). Regression analysis showed that nuchal fold thickness was
      significantly correlated with gestational age among both fetuses with trisomy 21
      and euploid fetuses and that the regression line of fetuses with trisomy 21 had a
      slope similar to that of euploid fetuses. The difference between observed and
      expected nuchal fold thicknesses on the basis of the biparietal diameter (as a
      function of gestational age) was used to obviate the confounding effect of
      gestational age. Differences between observed and expected nuchal fold
      thicknesses were then used to calculate likelihood ratios. These likelihood
      ratios could then be multiplied by the individual prior probability to obtain a
      patient-specific Down syndrome probability. CONCLUSION: Nuchal fold thickness is
      correlated with gestational age in both euploid fetuses and fetuses with Down
      syndrome. Use of the difference between observed and expected nuchal fold
      thicknesses to determine likelihood ratios allows the calculation of individual
      posterior probabilities of Down syndrome that take into consideration both
      gestational age and maternal age.

PMID- 10649179
TI  - Morbidity and mortality among very-low-birth-weight neonates with intrauterine
      growth restriction. The Vermont Oxford Network.
AB  - OBJECTIVE: We sought to determine the associations between intrauterine growth
      restriction and neonatal morbidity and mortality, as well as the impact of
      prenatal glucocorticoid administration on the frequency of specific complications
      of prematurity among neonates with intrauterine growth restriction. STUDY DESIGN:
      We examined the association between intrauterine growth restriction and adverse
      neonatal outcomes in a population of 19,759 singleton very-low-birth-weight
      neonates without major birth defects. We included neonates from 25 to 30 weeks'
      gestation entered in the Vermont Oxford Network database between 1991 and 1996 by
      196 institutions. Intrauterine growth restriction was defined as the 10th
      percentile for birth weight according to the 1993 US national statistics. Odds
      ratios were estimated according to stepwise logistic regression for each neonatal
      outcome. Potential explanatory variables included gestational age, intrauterine
      growth restriction, race, prenatal care, prenatal glucocorticoid administration,
      route of delivery, fetal sex, and birth within versus postnatal transfer to a
      network institution. RESULTS: There was a statistically significant association
      of intrauterine growth restriction with neonatal death (odds ratio, 2.77; 95%
      confidence interval, 2.31-3. 33), necrotizing enterocolitis (odds ratio, 1.27;
      95% confidence interval, 1.05-1.53), and respiratory distress syndrome (odds
      ratio, 1.19; 95% confidence interval, 1.03-1.36). There was a trend (P <. 10)
      toward association of intrauterine growth restriction with increased risks of
      intraventricular hemorrhage (odds ratio, 1.13; 95% confidence interval, 0.99
      1.29) and severe intraventricular hemorrhage (grades III and IV; odds ratio,
      1.25; 95% confidence interval, 0.98-1.59). Maternal prenatal glucocorticoid
      administration was associated with significantly lower risks of respiratory
      distress syndrome (odds ratio, 0.51; 95% confidence interval, 0.44-0.58),
      intraventricular hemorrhage (odds ratio, 0.67; 95% confidence interval, 0.61
      0.73), severe intraventricular hemorrhage (odds ratio, 0.50; 95% confidence
      interval, 0.43-0.57), and death (odds ratio, 0.54; 95% confidence interval, 0.48
      0.62). The benefits of prenatal glucocorticoid therapy for growth-restricted
      newborns were similar to those among normally grown infants. CONCLUSIONS:
      Intrauterine growth restriction within the range of 501 to 1500 g birth weight is
      associated with increased risks of neonatal death, necrotizing enterocolitis, and
      respiratory distress syndrome. Prenatal corticosteroid use was associated with
      decreased risks of all outcomes studied except necrotizing enterocolitis. We
      found no evidence that this benefit was dependent on fetal size.

PMID- 10649181
TI  - Electronic fetal heart rate monitoring: early neonatal outcomes associated with
      normal rate, fetal stress, and fetal distress.
AB  - OBJECTIVE: The purpose of this study was to test the ability of a clearly defined
      classification system for electronic fetal heart rate monitoring to predict early
      neonatal outcome. STUDY DESIGN: All labors of women with singleton pregnancies >
      or = 32 weeks' gestation electronically monitored at 2 institutions were
      examined. Tracings in the final hour before delivery were defined as normal,
      fetal stress, or fetal distress. After delivery, Apgar scores, cord blood gas
      values, and admission to the neonatal intensive care unit were examined as
      measures of early neonatal outcome. RESULTS: Among the 898 patients who qualified
      for study, 627 (70%) had tracings classified as normal, 263 (29%) had tracings
      classified as fetal stress, and 8 (1%) had tracings classified as fetal distress.
      There was a significant worsening of neonatal outcome across these 3 groups with
      regard to depressed Apgar scores 1 minute (5.1%, 18.3%, and 75.0%; P <.05),
      depressed Apgar scores at 5 minutes (1.0%, 3.8%, and 37.5%; P <.05), and
      admission to the neonatal intensive care unit (5.6%, 10.6%, and 37.5%; P <.05).
      There was also a progressive worsening of cord blood pH (7.27 +/- 0.06, 7.21 +/-
      0.08, and 7.06 +/- 0.14; P <.05), a progressive increase in PCO (2) (53.39 +/-
      8.34 mm Hg, 58.51 +/- 10.55 mm Hg, and 78.31 +/- 20.35 mm Hg; P <.05), and a
      progressive decline in base excess (-3.18 +/- 2.02 mEq/L, -5. 11 +/- 3.11 mEq/L,
      and -9.07 +/- 4.59 mEq/L; P <.05). CONCLUSION: This simple classification system
      for interpreting fetal heart rate tracings accurately predicts normal outcomes
      for fetuses as well discriminating fetuses in true distress. Further, it
      identifies an intermediate group of fetuses with a condition labeled fetal stress
      who might benefit from additional evaluation and possibly from expeditious
      delivery.

PMID- 10649180
TI  - Human immunodeficiency virus infection: in situ polymerase chain reaction
      localization in human placentas after in utero and in vitro infection.
AB  - OBJECTIVE: We compared localization of human immunodeficiency virus type 1 within
      human placentas infected in utero with localization within human placental
      explants infected in vitro. STUDY DESIGN: Placental tissues from 3 cases of
      vertical transmission of human immunodeficiency virus type 1 were studied. Human
      placental explants from 6 term pregnancies not complicated by human
      immunodeficiency virus type 1 infection were infected in vitro with human
      immunodeficiency virus type 1(Ba-L). Sections from each placental explant and
      each placenta infected in utero were analyzed for human immunodeficiency virus
      type 1 localization by means of in situ polymerase chain reaction. RESULTS: Human
      immunodeficiency virus type 1 was primarily localized within syncytiotrophoblast,
      Hofbauer cells, and extravillous mononuclear cells in placental tissue sections
      from cases of in utero infection. Within placental explants human
      immunodeficiency virus type 1 deoxyribonucleic acid was found in
      syncytiotrophoblast and Hofbauer cells. The distributions of viral localization
      were similar in placentas infected in utero and placental explants infected in
      vitro. CONCLUSION: Human immunodeficiency virus type 1 can be localized to
      specific human placental cells (eg, syncytiotrophoblast) after either in utero or
      in vitro infection, which demonstrates the specificity and selectivity of human
      immunodeficiency virus infection in the human placenta.

PMID- 10649182
TI  - Activity and expression of 15-hydroxyprostaglandin dehydrogenase in cultured
      chorionic trophoblast and villous trophoblast cells and in chorionic explants at
      term with and without spontaneous labor.
AB  - OBJECTIVE: The aim of this study was to investigate whether any changes occurred
      at term before and with labor in the 15-hydroxyprostaglandin dehydrogenase
      messenger ribonucleic acid level and in the 15-hydroxyprostaglandin dehydrogenase
      activity in cultured chorionic and villous trophoblast cells and in chorionic
      explants. STUDY DESIGN: Twelve placentas (labor group [vaginal delivery], n = 6;
      nonlabor group [elective cesarean delivery], n = 6) were collected. Chorionic
      trophoblast and villous trophoblast cells and chorionic disks were obtained,
      cultured, and incubated with 282-nmol/L prostaglandin F(2)(alpha). Medium was
      collected to measure the 13,14-dihydro-15-keto metabolite of prostaglandin
      F(2)(alpha), and the cells and disks were snap-frozen to quantify 15
      hydroxyprostaglandin dehydrogenase messenger ribonucleic acid expression by
      Northern blot analysis. RESULTS: The formation of the 13,14-dihydro-15-keto
      metabolite of prostaglandin F(2)(alpha) was significantly lower in the labor
      group than in the nonlabor group for both sets of cultured cells and for
      chorionic explants. 15-Hydroxyprostaglandin dehydrogenase messenger ribonucleic
      acid expression was lower in the chorionic trophoblast cells and chorionic disks
      of the labor group than those of the nonlabor group. However, the 15
      hydroxyprostaglandin dehydrogenase messenger ribonucleic acid level in the
      villous trophoblast cells did not differ between the labor and nonlabor groups.
      CONCLUSION: Prostaglandin metabolic activity in the chorion is reduced
      significantly at the time of labor.

PMID- 10649183
TI  - Postpartum umbilical cord blood collection for transplantation: a comparison of
      three methods.
AB  - OBJECTIVE: This study was undertaken to compare 3 methods of collection of human
      umbilical cord blood. STUDY DESIGN: Seventy-five women with uncomplicated vaginal
      deliveries were divided equally into 3 groups. One of 3 cord blood collection
      methods was applied to each woman. Method 1 was collection of cord blood into a
      standard donation blood bag. Methods 2 and 3 used a syringe to perform a sodium
      chloride solution flush and drain, which included withdrawal of cord blood by a
      syringe until the delivery of the placenta, followed by flushing through a
      catheter one of the umbilical arteries with sodium chloride solution and
      collection of the cord blood either into an open sterile container (method 2) or
      into a standard donation blood bag (method 3). Analyses included comparisons
      among the 3 groups of volume collected, total number of white blood cells, and
      bacterial contamination rates (positive culture results). In addition a
      correlation was made between the different variables and the collected cord blood
      nucleated cells. RESULTS: Cord blood collection by the blood bag method (method
      1), which is presently the standard clinical practice, resulted in a mean blood
      volume of 76.4 +/- 32.1 mL and a mean total white blood cell count of 835 +/- 507
      x 10(6) cells. With collection methods 2 and 3, in which as much blood as
      possible was withdrawn by syringe while the placenta was still in utero followed
      by a second collection after infusion of the umbilical artery with sodium
      chloride solution, the mean volume collected was significantly higher (P <.05) at
      174.4 +/- 42.8 mL and 173.7 +/- 41.3 mL, respectively, with significantly higher
      (P <.001) mean total white blood cell counts of 1624 +/- 887 x 10(6) cells and
      1693 +/- 972 x 10(6) cells, respectively. A direct correlation was observed
      between the cord blood volume collected and placental weight, whereas no
      correlations were observed with maternal age, pregnancy duration, or the
      neonate's weight. Bacterial contamination was significantly higher (P =.04) in
      cord blood collections obtained by method 2 (48%) than by methods 1 (16%) and 3
      (19%). CONCLUSIONS: The syringe-assisted sodium chloride solution flush
      collection method with a blood bag (method 3) was found to be the most effective
      method for human umbilical cord blood collection. This method doubles the total
      white blood cells collected with respect to current yields, which may make cord
      blood transplantation applicable for adults.

PMID- 10649184
TI  - Elimination of public funding of prenatal care for undocumented immigrants in
      California: a cost/benefit analysis.
AB  - OBJECTIVE: We compared the perinatal outcomes and costs of undocumented women
      with and without prenatal care and inferred the impact of denial of prenatal
      benefits to undocumented immigrants in California. STUDY DESIGN: We
      retrospectively reviewed the delivery records of a cohort of 970 undocumented
      immigrants. The effects of prenatal care on low birth weight and prematurity were
      evaluated by means of logistic regression. The difference in the costs of
      postnatal care between neonates with and without prenatal care was compared with
      the cost of prenatal care. This ratio was extrapolated to calculate the net cost
      to the state. Long-term morbidity costs were also considered. RESULTS: Nearly 10%
      of undocumented women had no prenatal care. These women were nearly 4 times as
      likely to be delivered of low birth weight infants (relative risk, 3.8; 95%
      confidence interval, 2.03-7.05) and >7 times as likely to be delivered of
      premature infants (relative risk, 7.4; 95% confidence interval, 4.35-12.59) as
      were undocumented women who had prenatal care. The cost of postnatal care for a
      neonate without prenatal care was $2341 more initially and $3247 more when
      incremental long-term morbidity cost was added than that for a neonate with
      prenatal care. For every dollar cut from prenatal care we expect an increase of
      $3. 33 in the cost of postnatal care and $4.63 in incremental long-term cost.
      Elimination of publicly funded prenatal care for undocumented women could save
      the state $58 million in direct prenatal care costs but could cost taxpayers as
      much as $194 million more in postnatal care, resulting in a net cost of $136
      million initially and $211 million in long-term costs. CONCLUSIONS: Elimination
      of public funding of prenatal care for undocumented immigrants in California
      could substantially increase low birth weight, prematurity, and postnatal costs.

PMID- 10649185
TI  - Angiogenesis of the ovary.
AB  - We present current data pertaining to angiogenesis of the ovary throughout the
      follicular and luteal phases of the ovarian cycle, in various ovarian pathologic
      conditions and in benign and neoplastic diseases. MEDLINE, Current Contents, and
      Index Medicus were searched for studies published between January 1966 and
      October 1998. All studies that incorporated human and animal models of
      angiogenesis of the normal ovarian physiologic state and pathologic conditions
      including both benign and neoplastic ovarian diseases were reviewed. Current
      literature supports that angiogenesis is an important component of both
      follicular and luteal phases of the ovarian cycle that correlates well with
      maturation of secretory endometrium. Angiogenesis also participates in various
      pathologic processes of the ovary, including follicular cyst formation,
      polycystic ovary, ovarian hyperstimulation syndrome, and both benign and
      malignant ovarian neoplasms. In the future a knowledge of specific angiogenic
      patterns of various pathologic processes may assist in the application of
      antiangiogenic medications in targeted therapy of benign and neoplastic diseases
      of the ovary.

PMID- 10649186
TI  - American Journal of Obstetrics and Gynecology, Volume 124, 1976: The remote
      prognosis of eclamptic women. Sixth periodic report.

PMID- 10649187
TI  - Recognition of the long-term sequelae of eclampsia.

PMID- 10649188
TI  - Jehovah's witnesses and bloodless surgery.

PMID- 10649190
TI  - Surgical training in selective pelvic arterial ligation or use of embolization
      only.

PMID- 10649192
TI  - Liver length in the small-for-gestational-age fetus and ductus venosus flow.

PMID- 10649194
TI  - Twenty-five years of excellence: the legacy and the challenge.

PMID- 10649195
TI  - Dilation of the pulmonary autograft after the Ross procedure.
AB  - OBJECTIVE: Dilation of pulmonary autograft after the Ross procedure is being
      recognized with increasing frequency. This study was undertaken to examine the
      extent of this problem and factors that may be associated with it. METHODS: The
      clinical, operative, and echocardiographic data of 118 patients who underwent the
      Ross procedure were reviewed. The mean age of 79 men and 39 women was 34 +/- 9
      years, range 17 to 57 years. Bicuspid or other congenital aortic valve disease
      was present in 81% of patients. The pulmonary autograft was sutured as a valve in
      the subcoronary position in 2 patients, as a root inside of the aortic root in
      45, and was used for complete aortic root replacement in 71. Teflon felt was not
      used to buttress the proximal or the distal anastomosis of the pulmonary
      autograft. The diameters of the sinuses of Valsalva, aortic anulus, and
      sinotubular junction were measured early and late after the operation with
      echocardiography. The mean follow-up was 44 months. RESULTS: The diameter of the
      sinuses of Valsalva increased from 31.4 +/- 0.4 mm to 33.7 +/- 0.5 mm (P =.01).
      Analysis of covariance revealed a significant change over time in this diameter,
      as well as a difference between operative techniques, with replacement of the
      aortic root being associated with a higher risk of dilation (P =. 0006). In 13
      patients the diameter ranged from 40 to 51 mm. The diameter of the aortic anulus
      decreased in most patients and increased in 15, but there was no interaction
      between these changes and the operative technique. The diameter of the
      sinotubular junction increased in patients who had aortic root replacement and
      decreased in patients who had aortic root inclusion (P =.007). Moderate aortic
      insufficiency developed in 7 patients, and 3 required replacement of the
      pulmonary autograft. All patients with moderate aortic insufficiency had dilation
      of the aortic anulus and/or sinotubular junction. CONCLUSIONS: Dilation of the
      pulmonary autograft after the Ross procedure may occur because of an intrinsic
      abnormality of the pulmonary root in patients with congenital aortic valve
      disease. The technique of aortic root replacement is associated with a higher
      risk of dilation of the sinuses of Valsalva and sinotubular junction than the
      technique of aortic root inclusion.

PMID- 10649196
TI  - Systematic off-pump coronary artery revascularization in multivessel disease:
      experience of three hundred cases.
AB  - OBJECTIVE: We sought to report our recent experience with off-pump coronary
      artery revascularization in multivessel disease. METHODS: Between October 1996
      and December 1998, 300 off-pump beating heart operations were performed at the
      Montreal Heart Institute by a single surgeon, representing 94% of all procedures
      undertaken during this same time frame (97% for 1998). This cohort of patients
      was compared with 1870 patients operated on with cardiopulmonary bypass from 1995
      to 1996. RESULTS: Mean age, sex distribution, and preoperative risk factors were
      comparable for the two groups. On average, 2.92 +/- 0.8 and 2.84 +/- 0.6 grafts
      per patient were completed in the beating heart and cardiopulmonary bypass
      groups, respectively. A majority of patients (70%) had either a triple or
      quadruple bypass. Coronary anastomoses were achieved with myocardial mechanical
      stabilization and heart "verticalization." Ischemic time was shorter in the
      beating heart group (29.8 +/- 0.9 vs 45 +/- 0.4 minutes, P <.05). Similarly, the
      need for transfusion was significantly less in the beating heart group (beating
      heart operations, 34%; cardiopulmonary bypass, 66%; P <.005). Reduced use of
      postoperative intra-aortic counterpulsation, as well as a lower rise in creatine
      kinase MB isoenzyme, was observed in the beating heart group. Operative mortality
      rates (beating heart operations, 1. 3%; cardiopulmonary bypass, 2%) and
      perioperative myocardial infarction (beating heart operations, 3.6%;
      cardiopulmonary bypass, 4.2%) were comparable for the two groups. CONCLUSION: In
      a majority of patients, off-pump complete coronary artery revascularization is an
      acceptable alternative to conventional operations, yielding good results given
      progressive experience, rigorous technique, and adequate coronary artery
      stabilization.

PMID- 10649197
TI  - Is there a relationship between systemic perfusion temperature during coronary
      artery bypass grafting and extent of intraoperative ischemic central nervous
      system injury?
AB  - OBJECTIVE: This study was designed to compare the volume of cerebral infarction
      in patients operated on under either hypothermic or tepid/normothermic perfusion
      for coronary revascularization. METHODS: A randomized trial with preoperative,
      postoperative, and late neurologic evaluation was conducted in patients
      undergoing coronary revascularization having either hypothermic or
      tepid/normothermic perfusion for coronary revascularization. The goal was to
      determine whether perfusion temperature correlated with neurologic dysfunction
      associated with coronary artery bypass. RESULTS: Twelve intraoperative ischemic
      strokes occurred during coronary revascularization in a series of 291 patients.
      Six of these were in the group receiving hypothermic perfusion and 6 in groups
      receiving the tepid/normothermic perfusion. Measuring the infarct volume
      documented that 3 of the strokes in each group resulted in minor or small
      infarcts and 3 in each group were significant, major strokes. The volume of
      infarction, whether including all 6 patients in each group or only those with
      major strokes, was no different between the hypothermic and the
      tepid/normothermic groups. CONCLUSIONS: In this series of 291 patients randomized
      to perfusion temperature, we observed no relationship between the size of a
      cerebral ischemic infarct and the perfusate temperature during coronary
      revascularization.

PMID- 10649198
TI  - Particulate emboli capture by an intra-aortic filter device during cardiac
      surgery.
AB  - OBJECTIVE: Particulate embolization is associated with neurologic morbidity after
      cardiac surgery. Crossclamp manipulation has been identified as the single most
      significant cause of particulate emboli release during cardiac surgery. A new
      intra-aortic filtration method has been assessed with regard to its safety and
      its ability to capture particulate emboli before they enter the central
      circulation. METHODS: Patients undergoing cardiac surgery with cardiopulmonary
      bypass through standard median sternotomy were selected for emboli management by
      means of intra-aortic filtration. A novel intra-aortic filter device was inserted
      through a modified 24F arterial cannula immediately before releasing the
      crossclamp in 77 patients. Filters remained in the aorta until cardiopulmonary
      bypass was discontinued and the heart was fully ejecting. The procedure was
      assessed for facility, safety, and effect on routine cardiopulmonary bypass
      operation and function. RESULTS: The insertion and removal of the intra-aortic
      filter were safe, easy, and uneventful in most patients. Patient hemodynamics and
      bypass flow rates remained normal throughout the filter dwell period. No strokes
      or gross neurologic defects were noted. Electron microscopic analysis of 12
      filters revealed an insignificant degree of platelet adhesion on filter surfaces.
      Histology samples (n = 44) were examined, and 66% (n = 29) showed evidence of
      atheromatous material, 36% (n = 16) with platelet-fibrin, 25% (n = 11) with true
      thrombus and/or blood clot, 7% (n = 3) with normal vessel wall, and 2% (n = 1)
      with aggregates of cholesterol or grumous portion of atheromatous plaque.
      CONCLUSION: The intra-aortic filter can be safely deployed and captures
      particulate emboli, the predominant origin of which is atheromatous. The
      beneficial effects of this device on neurologic outcomes have yet to be
      determined.

PMID- 10649199
TI  - Aprotinin preserves myocardial biochemical function during cold storage through
      suppression of tumor necrosis factor.
AB  - OBJECTIVE: Inflammatory cytokines, particularly tumor necrosis factor, contribute
      to myocardial dysfunction after ischemia-reperfusion injury. Aprotinin may
      improve outcomes in cardiac surgery through suppression of inflammatory
      mediators. We hypothesized that aprotinin may exert its beneficial effects
      through suppression of tumor necrosis factor alpha. METHODS: Adult rat hearts
      were precision cut into slices with a thickness of 200 microm and stored in
      crystalloid cardioplegic solution alone or with one of the following additions:
      aprotinin or tumor necrosis factor alpha, aprotinin plus tumor necrosis factor
      alpha, a monoclonal antibody to tumor necrosis factor alpha, or a polyclonal
      antibody to the tumor necrosis factor alpha receptor. Myocardial biochemical
      function was assessed by adenosine triphosphate content and capacity for protein
      synthesis immediately after slicing (0 hours) and after 2, 4, and 6 hours of
      storage at 4 degrees C. The content of tumor necrosis factor alpha was measured
      by an enzyme-linked immunosorbent assay. Six slices were assayed at each time
      point for each solution. The data were analyzed by analysis of variance and are
      expressed as the mean +/- standard deviation. RESULTS: When stored in
      cardioplegic solution containing aprotinin, the heart slices demonstrated (1) an
      increase in adenosine triphosphate content and protein synthesis (P <.0001), (2)
      a decrease in intramyocardial generation of tumor necrosis factor alpha (P
      </=.0311), and (3) a decrease in uptake of tumor necrosis factor alpha into the
      myocardium (P </=.002) compared with storage in cardioplegic solution alone. The
      presence of an antibody to tumor necrosis factor alpha or an antibody to the
      tumor necrosis factor alpha receptor in cardioplegic solution increased
      intramyocardial adenosine triphosphate content and protein synthesis (P <.0001).
      CONCLUSIONS: Aprotinin preserves myocardial biochemical function during cold
      storage. This preservation of biochemical function is mediated through
      suppression of the release, uptake, and activity of tumor necrosis factor alpha.

PMID- 10649200
TI  - Six-year experience of caring for forty-four patients with a left ventricular
      assist device at home: safe, economical, necessary.
AB  - OBJECTIVE: With increasing numbers of implantations, left ventricular assist
      device programs can put a financial strain on a hospital unless an efficient and
      safe outpatient program is developed. However, the left ventricular assist device
      is not widely recognized in the medical community as being reliable enough to
      support a patient at home. We reviewed our experience with these patients at home
      to assess the safety and the benefits of such a program. METHODS: Our
      institutional 6-year experience with 90 consecutive recipients of a wearable left
      ventricular assist device was analyzed. RESULTS: Forty-four (49%) of the 90
      patients who received TCI vented-electric left ventricular assist devices (Thermo
      Cardiosystems, Inc, Woburn, Mass) were discharged, spending a total of 4546 days
      (12.5 years) at home with an average of 103 +/- 16 days of outpatient support
      (range 9-436 days). Of these 44 patients, all were successfully bridged to
      transplantation (42 patients, 96%) or planned explantation (2 patients, 4%). None
      of the outpatients died. The cumulative events per outpatient month were 0.020
      for bleeding, 0.053 for device infection, 0.0068 for thromboembolus, and 0.020
      for major malfunctions. Our estimated average cost to bridge a patient to
      transplantation or explantation once discharged is $13,200 and as an inpatient
      over the same length of time, including only room and board, is $165,200. Thirty
      percent of outpatients were able to return to work or school, 33% to sexual
      activity, and 44% to driving. All outpatients performed activities of daily
      living. CONCLUSION: Current left ventricular assist device technology provides
      effective and economical outpatient support and is associated with limited
      morbidity and a satisfactory quality of life.

PMID- 10649201
TI  - Descending necrotizing mediastinitis: An analysis of the effects of serial
      surgical debridement on patient mortality.
AB  - OBJECTIVES: Descending necrotizing mediastinitis is a polymicrobial infection
      originating in the oropharynx with previously reported mortality rates of 25% to
      40%. This investigation reviews the effects of serial surgical drainage and
      debridement on the survival of patients with descending necrotizing
      mediastinitis. METHODS: A retrospective review of patients from 1980 through 1998
      with a diagnosis of descending necrotizing mediastinitis was performed. Their
      records were abstracted for personal demographics, hospital course, morbidity,
      and mortality. Also abstracted were all reports of patients with descending
      necrotizing mediastinitis published in English between 1970 and 1999. RESULTS: We
      treated 10 patients in whom descending necrotizing mediastinitis was identified.
      The mean age of the patients was 38 years. They underwent a mean of 6 +/- 4
      computed tomographic imaging studies, 4 +/- 1 transcervical drainage procedures,
      and 2 +/- 1 transthoracic drainage procedures. Three patients required abdominal
      exploration and 4 underwent tracheostomy. No deaths occurred. In contrast, 96
      patients with descending necrotizing mediastinitis were identified from the
      literature with a mean age of 38 years. They underwent a mean of 2 +/- 1 computed
      tomographic imaging studies, 2 +/- 1 transcervical drainage procedures, and 0.7 +
      0.3 transthoracic drainage procedures. Sixteen (17%) patients required abdominal
      exploration and 34 (35%) underwent tracheostomy. Twenty-eight (29%) patients from
      the literature cohort died during their treatment. CONCLUSION: Descending
      necrotizing mediastinitis remains a life-threatening infection. On the basis of
      experience accrued in treating these patients, an algorithm incorporating
      computed tomographic imaging for diagnosis and surveillance and serial
      transcervical and transthoracic operative drainage is outlined in the hope of
      reducing the excessive mortality of descending necrotizing mediastinitis.

PMID- 10649202
TI  - Evaluation and outcome of different surgical techniques for postintubation
      tracheoesophageal fistulas.
AB  - OBJECTIVE: We evaluated the outcome of different surgical techniques for
      postintubation tracheoesophageal fistula. METHODS: Thirty-two consecutive
      patients aged 51 +/- 23 years had tracheoesophageal fistulas resulting from a
      median of 30 days of mechanical ventilation via endotracheal (n = 12) or
      tracheostomy (n = 20) tubes. Tracheoesophageal fistulas were 2.5 +/- 1.2 cm long
      and were associated with a tracheal (n = 10) or subglottic (n = 3) stenosis in 13
      patients. RESULTS: All but 3 patients were weaned from respirators before repair.
      All operations were done through cervical incisions and included direct division
      and closure (n = 9), esophageal diversion (n = 3), muscle interposition (n = 6),
      or, more recently, tracheal or laryngotracheal resection and anastomosis with
      primary esophageal closure (n = 14). Nine thyrohyoid and two supralaryngeal
      releases reduced anastomotic tension. Twenty-three patients (74%) were extubated
      after the operation (n = 16) or within 24 hours (n = 7), and 7 required a
      temporary tracheotomy tube. One postoperative death (3%) was associated with
      recurrent tracheoesophageal fistula. Seven complications (22%) included recurrent
      tracheoesophageal fistula (n = 1), delayed tracheal stenosis (n = 2), dysphagia
      (n = 2), and recurrent nerve palsy (n = 2). Complications necessitated
      reoperation (n = 1), dilation (n = 2), definitive tracheostomy (n = 1),
      Montgomery T tubes (n = 1), and Teflon injection of the vocal cords (n = 1).
      Twenty-nine patients (93%) had excellent (n = 24) or good (n = 5) anatomic and
      functional long-term results. Complications have been less common (7% vs 38%) and
      long-term results better (93% vs 65%) recently with tracheal or laryngotracheal
      resection and anastomosis with primary esophageal closure as compared with
      previous procedures. CONCLUSIONS: Postintubation tracheoesophageal fistula is
      usually best treated with tracheal or laryngotracheal resection and anastomosis
      with primary esophageal closure even in the absence of tracheal damage.

PMID- 10649203
TI  - Eliminating the cervical esophagogastric anastomotic leak with a side-to-side
      stapled anastomosis.
AB  - BACKGROUND: Although the acute postoperative complications of a cervical
      esophagogastric anastomosis are less than those with an intrathoracic esophageal
      anastomosis, the long-term sequelae of a cervical anastomotic leak are not as
      minor as initially reported. Nearly 50% of cervical anastomotic leaks result in
      an anastomotic stricture, and the subsequent need for chronic dilatations negates
      the merits of an operation intended to restore comfortable swallowing. OBJECTIVE:
      This study was undertaken to determine whether construction of a side-to-side
      stapled cervical esophagogastric anastomosis after transhiatal esophagectomy
      could reliably eliminate the majority of anastomotic leaks. METHODS: In 114
      consecutive patients undergoing transhiatal esophagectomy, a functional side-to
      side cervical esophagogastric anastomosis was constructed with the Auto Suture
      Endo-GIA II stapler (United States Surgical Corporation, Auto Suture Company
      Division, Norwalk, Conn) applied directly through the cervical wound. This side
      to-side stapled anastomosis has 3 rows of staples. Early postoperative
      anastomotic morbidity, subsequent need for anastomotic dilatations, and patient
      satisfaction with swallowing were evaluated. RESULTS: Before the side-to-side
      stapled anastomosis, the incidence of cervical esophagogastric anastomosis leak
      in over 1000 patients undergoing transhiatal esophagectomy having a manually sewn
      anastomosis varied from 10% to 15%. Among the 111 survivors of transhiatal
      esophagectomy and a side-to-side stapled anastomosis, there were 3 (2.7%)
      clinically significant anastomotic leaks. This lowered incidence of leaks has
      contributed to reduction in the average length of stay after an uncomplicated
      transhiatal esophagectomy to 7 days and has provided more comfortable swallowing,
      ease of subsequent esophageal dilatations, and greater patient satisfaction.
      CONCLUSIONS: Construction of the cervical esophagogastric anastomosis with a side
      to-side stapled anastomosis greatly reduces the frequency of anastomotic leaks
      and later strictures. The side-to-side stapled anastomosis is a major technical
      advance in the progression of refinements of transhiatal esophagectomy and a
      cervical esophagogastric anastomosis.

PMID- 10649204
TI  - Bronchoscopic management of central airway obstruction.
AB  - OBJECTIVES: Patients with central airway obstruction are critically ill, with
      impending suffocation. They are seen with diverse anatomic and functional
      deficits caused by both benign and malignant obstructions. Such cases were
      reviewed to examine the indications, techniques, and outcomes of an algorithm
      approach to bronchoscopic management. METHODS: Between July 1992 and April 1996,
      97 patients underwent bronchoscopic procedures for the management of central
      airway obstruction, and their cases were used for a retrospective review of the
      airway management. RESULTS: There were 48 male and 49 female patients, aged 13 to
      85 years. There were 48 benign and 49 malignant pathologic conditions that gave
      rise to 108 stenoses. These were treated with 199 endoscopic procedures with an
      average of 1.7 interventions per endoscopy, including mechanical core-out (62),
      dilation (135), laser ablation (44), placement of brachytherapy catheters (9),
      and stent placement (88). Diagnoses included lung cancer, primary
      tracheobronchial tumors, tumors metastatic to the airway or mediastinum, and a
      variety of benign obstructions. In the group of 97 patients there were 2 (2%)
      perioperative deaths and 34 (34%) late deaths, 29 in the malignant group and 5 in
      the benign group. Median survival was 7.6 months (range 1 week-31 months). There
      were 7 (7%) complications among the group of 97, 4 in the malignant group, and 3
      in the benign group. CONCLUSIONS: Endobronchial surgical techniques can be used
      safely and systematically for the relief of benign and malignant central airway
      obstructions; a diversity of approaches and interventions are required to produce
      and maintain palliation of airway symptoms.

PMID- 10649205
TI  - In vivo adenovirus-mediated endothelial nitric oxide synthase gene transfer
      ameliorates lung allograft ischemia-reperfusion injury.
AB  - OBJECTIVE: Nitric oxide regulates vascular tone, inhibits platelet aggregation,
      and inhibits leukocyte adhesion, all of which are important modulators of
      ischemia-reperfusion injury. This study aimed to determine the effects of
      endothelial constitutive nitric oxide synthase gene transfer on ischemia
      reperfusion injury in a rat lung transplant model. METHODS: In group I, donor
      animals were injected intravenously with 5 x 10(9) pfu of adenovirus-encoding
      endothelial constitutive nitric oxide synthase. Groups II and III served as
      controls, whereby donor animals were injected with either 5 x 10(9) pfu of
      adenovirus encoding beta-galactosidase or saline solution, respectively. Twenty
      four hours after injection, left lungs were harvested and preserved for 18 hours
      at 4 degrees C, then implanted into isogeneic recipients, which were put to death
      24 hours later. Recombinant endothelial constitutive nitric oxide synthase gene
      expression was evaluated by Western blotting and immunohistochemistry. Lung
      grafts were assessed by measuring arterial oxygenation, myeloperoxidase activity,
      and wet/dry weight ratios. RESULTS: Western blotting confirmed the overexpression
      of endothelial constitutive nitric oxide synthase in lungs so transfected
      compared with controls. Twenty-four hours after reperfusion, mean arterial
      oxygenation was significantly improved in group I compared with group II and III
      controls (189.4 +/- 47.1 mm Hg vs 71.7 +/- 8.9 mm Hg and 67.8 +/- 12.2 mm Hg, P
      =.02, P =.01, respectively). Myeloperoxidase activity, a reflection of tissue
      neutrophil sequestration, was also significantly reduced in group I compared with
      groups II and III (0.136 +/- 0.038 DeltaOD/mg/min vs 0. 587 +/- 0.077 and 0.489
      +/- 0.126 DeltaOD/mg/min, P =.001, P =.01, respectively). CONCLUSION: Adenovirus
      mediated gene transfer with endothelial constitutive nitric oxide synthase
      ameliorates ischemia-reperfusion injury as manifested by significantly improved
      oxygenation and decreased neutrophil sequestration in transplanted lung
      isografts. Endothelial constitutive nitric oxide synthase gene transfer may
      reduce acute lung dysfunction after lung transplantation.

PMID- 10649206
TI  - The free radical spin trap alpha-phenyl-tert-butyl nitrone attenuates the
      cerebral response to deep hypothermic ischemia.
AB  - OBJECTIVE: The aim of this study was to assess the role of reactive oxygen
      species in the impairment of cerebral recovery that follows deep hypothermic
      circulatory arrest. METHODS: Twelve 1-week-old piglets were randomized to placebo
      (control group; n = 6) or 100 mg x kg(-1) intravenous alpha-phenyl-tert -butyl
      nitrone, a free radical spin trap (PBN group; n = 6). All piglets underwent
      cardiopulmonary bypass, cooling to 18 degrees C, 60 minutes of circulatory arrest
      followed by 60 minutes of reperfusion, and rewarming. Cerebral blood flow and
      metabolism were determined at baseline before deep hypothermic circulatory arrest
      and after 60 minutes of reperfusion. RESULTS: In control animals, mean global
      cerebral blood flow (+/- 1 standard error) before circulatory arrest was 48.4 +/-
      3.6 mL x 100 g(-1) x min(-1) and fell to 25.1 +/- 3.6 mL x 100 g(-1) x min(-1)
      after circulatory arrest (P =.001). Global cerebral metabolism fell from 3.5 +/-
      0.2 mL x 100 g(-1) x min(-1) before arrest to 2.2 +/- 0.2 mL x 100 g(-1) x min(
      1) after circulatory arrest (P =.0002). In the PBN group after circulatory
      arrest, the mean global cerebral blood flow and metabolism of 37.2 +/- 4.9 and
      3.6 +/- 0.5 mL. 100 g(-1). min(-1), respectively, were significantly higher than
      in the control group (P <.05). Recovery of cerebral blood flow in the PBN group
      was 78% of pre-arrest level compared with 52% in the control group (P =.002).
      Global cerebral metabolism after circulatory arrest was 100% of the pre-arrest
      value compared with 61% in the control group (P =.01). Regional recovery of
      cerebral metabolism in the cerebellum, brain stem, and basal ganglia was 131%,
      130%, and 115%, respectively, of pre-arrest values in the PBN group compared with
      85%, 78%, and 70% in the control group (P <.04). CONCLUSIONS: Reactive oxygen
      species contribute to the impairment of cerebral recovery that follows deep
      hypothermic circulatory arrest. The use of alpha-phenyl-tert -butyl nitrone
      before the arrest period attenuates the normal response to ischemia and improves
      recovery by affording protection from free radical-mediated damage.

PMID- 10649207
TI  - Primary repair minimizing the use of conduits in neonates and infants with
      tetralogy or double-outlet right ventricle and anomalous coronary arteries.
AB  - OBJECTIVE: The purpose of this study was to review our results with an approach
      of early primary repair for tetralogy of Fallot or double-outlet right ventricle
      with anomalous coronary arteries, using several techniques to minimize the use of
      a conduit. METHODS: Twenty consecutive neonates and infants with anomalous
      coronary arteries crossing an obstructed right ventricular outflow tract
      underwent primary repair. Median age was 5.5 months and mean weight 6.22 kg. The
      anomalous coronary arteries included the left anterior descending from the right
      coronary artery (n = 10), the right coronary artery from the left anterior
      descending (n = 1), the left anterior descending from the right sinus (n = 1),
      and a significant conal branch from the right coronary artery (n = 7) or left
      anterior descending (n = 1). Two neonates had pulmonary atresia. The right
      ventricular outflow tract was reconstructed without a conduit in 18 patients,
      including those with pulmonary atresia. Surgical techniques included main
      pulmonary artery translocation in 4 patients, transannular repair under a
      mobilized left anterior descending coronary artery in 2 patients, and displaced
      ventriculotomy with subcoronary suture lines in 8 patients. In 4 patients the
      right ventricular outflow tract was repaired via the ventriculotomy and/or
      pulmonary arteriotomy. A homograft was used as the sole right ventricle-pulmonary
      artery connection in 1 patient and in another a homograft was added to a
      hypoplastic native pathway. RESULTS: There have been no early or late deaths. The
      right ventricular/left ventricular pressure ratio within 48 hours of the
      operation was 0.47 +/- 0.10. There were 2 reoperations at 8 and 11 years after
      the operation, during a mean follow-up of 5.2 years (1-11.3 years). CONCLUSIONS:
      Primary repair of tetralogy of Fallot or double-outlet right ventricle with
      anomalous coronary arteries can be done in neonates and infants with excellent
      results. Alternative surgical techniques for right ventricular outflow tract
      reconstruction, such as main pulmonary artery translocation, can avoid the use of
      a conduit in most patients.

PMID- 10649209
TI  - Regional low-flow perfusion provides cerebral circulatory support during neonatal
      aortic arch reconstruction.
AB  - OBJECTIVE: Because of concerns regarding the effects of deep hypothermia and
      circulatory arrest on the neonatal brain, we have developed a technique of
      regional low-flow perfusion that provides cerebral circulatory support during
      neonatal aortic arch reconstruction. METHODS: We studied the effects of regional
      low-flow perfusion on cerebral oxygen saturation and blood volume as measured by
      near-infrared spectroscopy in 6 neonates who underwent aortic arch reconstruction
      and compared these effects with 6 children who underwent cardiac repair with deep
      hypothermia and circulatory arrest. RESULTS: All the children survived with no
      observed neurologic sequelae. Near-infrared spectroscopy documented significant
      decreases in both cerebral blood volume and oxygen saturations in children who
      underwent repair with deep hypothermia and circulatory arrest as compared with
      children with regional low-flow perfusion. Reacquisition of baseline cerebral
      blood volume and cerebral oxygen saturations were accomplished with a regional
      low-flow perfusion rate of 20 mL x kg(-1) x min(-1). CONCLUSIONS: Regional low
      flow perfusion is a safe and simple bypass management technique that provides
      cerebral circulatory support during neonatal aortic arch reconstruction. The
      reduction of deep hypothermia and circulatory arrest time required may reduce the
      risk of cognitive and psychomotor deficits.

PMID- 10649208
TI  - Class I and class II anti-HLA antibodies after implantation of cryopreserved
      allograft material in pediatric patients.
AB  - OBJECTIVES: Very little is known regarding the immune response to cryopreserved
      allograft valves and patch material used in the surgical repair of congenital
      heart defects. METHODS: We prospectively measured the frequency of panel reactive
      antibodies directed against HLA class I (HLA-A, B, and C) and class II (HLA
      DR/DQ) alloantigens in 24 children receiving cryopreserved allografts. We
      compared them with results in 11 previously reported control patients. Sixteen of
      the study patients underwent placement of a valved conduit (11 pulmonic, 5
      aortic) between the right ventricle and pulmonary arteries, 6 underwent patch
      angioplasty of stenotic vessels with cryopreserved pulmonary artery, and 2
      underwent placement of a pulmonary monocusp patch. Study patients had panel
      reactive antibodies measured before, 1 month, 3 months, and 1 year after the
      operation. RESULTS: With allograft implantation, panel reactive antibodies
      increased from 1.9% +/- 5% before the operation to 62% +/- 33% at 31 +/- 8 days
      after the operation, 92% +/- 15% at 3.3 +/- 0.6 months after the operation, and
      85% +/- 18% at 1.1 +/- 0.2 years after the operation. The control group showed no
      change in panel reactive antibodies, with a level of 1.6% +/- 1% before the
      operation, 3.2% +/- 1% 28 +/- 5 days after the operation, and 1.7% +/- 1% 2.7 +/-
      0.3 months after the operation. Class II antibodies (anti-HLA-DR/DQ) rose to 49%
      +/- 35% at 30 +/- 8 days and 70% +/- 26% at 3.3 +/- 0.6 months after the
      operation. CONCLUSIONS: Cryopreserved allograft material induces a marked
      response that involves both class I and class II anti-HLA antibodies within 3
      months after operation in children. This alloantibody response may represent a
      form of "rejection," may have implications for those who require subsequent
      cardiac transplantation, and may play a role in early allograft failure.

PMID- 10649210
TI  - Revision of previous Fontan connections to total extracardiac cavopulmonary
      anastomosis: A multicenter experience.
AB  - BACKGROUND: Conversion to total extracardiac cavopulmonary anastomosis is an
      option for managing patients with dysfunction of a prior Fontan connection.
      METHODS: Thirty-one patients (19.9 +/- 8.8 years) underwent revision of a
      previous Fontan connection to total extracardiac cavopulmonary anastomosis at
      four institutions. Complications of the previous Fontan connection included
      atrial tachyarrhythmias (n = 20), progressive heart failure (n = 17), Fontan
      pathway obstruction (n = 10), effusions (n = 10), pulmonary venous obstruction by
      an enlarged right atrium (n = 6), protein-losing enteropathy (n = 3), right
      atrial thrombus (n = 2), subaortic stenosis (n = 1), atrioventricular valve
      regurgitation (n = 3), and Fontan baffle leak (n = 5). Conversion to an
      extracardiac cavopulmonary connection was performed with a nonvalved conduit from
      the inferior vena cava to the right pulmonary artery, with additional procedures
      as necessary. RESULTS: There have been 3 deaths. Two patients died in the
      perioperative period of heart failure and massive effusions. The third patient
      died suddenly 8 months after the operation. All surviving patients were in New
      York Heart Association class I (n = 20) or II (n = 7), except for 1 patient who
      underwent heart transplantation. Early postoperative arrhythmias occurred in 10
      patients: 4 required pacemakers, and medical therapy was sufficient in 6. In 15
      patients, pre-revision arrhythmias were improved. Effusions resolved in all but 1
      of the patients in whom they were present before revision. The condition of 2
      patients with protein-losing enteropathy improved within 30 days. CONCLUSIONS:
      Conversion of a failing Fontan connection to extracardiac cavopulmonary
      connection can be achieved with low morbidity and mortality. Optimally, revision
      should be undertaken early in symptomatic patients before irreversible
      ventricular failure ensues.

PMID- 10649211
TI  - Preoperative risk-of-death prediction model in heart surgery with deep
      hypothermic circulatory arrest in the neonate.
AB  - OBJECTIVE: Our goal was to generate a preoperative risk-of-death prediction model
      in selected neonates with congenital heart disease undergoing surgery with deep
      hypothermic circulatory arrest. METHODS: We completed a single-center,
      prospective, randomized, double-blind, placebo- controlled neuroprotection trial
      in selected neonates with congenital heart disease requiring operations for which
      deep hypothermic circulatory arrest was used. An extensive database was generated
      that included preoperative, intraoperative, and postoperative variables.
      Variables (delivery, maternal, and infant related) were evaluated to produce a
      preoperative risk-of-death prediction model by means of logistic regression. An
      operative risk-of-death prediction model including duration of deep hypothermic
      circulatory arrest was also generated. RESULTS: Between July 1992 and September
      1997, 350 (74%) of 473 eligible infants were enrolled with 318 undergoing deep
      hypothermic circulatory arrest. The mortality was 52 of 318 (16.4%), unaffected
      by investigational drug. The resulting preoperative risk model contained 4
      variables: (1) cardiac anatomy (two-ventricle vs single ventricle surgery,
      with/without arch obstruction), (2) 1-minute Apgar score (</=5 vs >5), (3)
      presence of genetic syndrome, and (4) age at hospital admission for surgery (</=5
      or >5 days). Mortality for two-ventricle repair was 3.2% (4/130). Mortality for
      single ventricle palliation was 25.5% (48/188) and was significantly influenced
      by Apgar score, genetic diagnosis, and admission age. The preoperative model had
      a prediction accuracy of 80%. The operative risk model included duration of deep
      hypothermic circulatory arrest, which significantly (P =.03) increased risk of
      death, with a prediction accuracy of 82%. CONCLUSIONS: In this selected
      population, postoperative mortality risk is significantly affected by
      preoperative conditions. Identification of infants with varying mortality risks
      may affect family counseling, therapeutic intervention, and risk stratification
      for future study designs.

PMID- 10649212
TI  - Results of Norwood stage I operation: comparison of hypoplastic left heart
      syndrome with other malformations.
AB  - OBJECTIVE: We compared the Norwood stage I operation for hypoplastic left heart
      syndrome and other complex malformations with ductus-dependent systemic
      circulation. METHODS: A retrospective study of 194 patients who underwent a
      Norwood stage I palliation between 1990 and 1998 was conducted. Malformations in
      131 patients were classified as hypoplastic left heart syndrome, defined as
      aortic and mitral atresia or severe stenosis, normal segmental anatomy, intact
      ventricular septum, and hypoplasia of the left ventricle. Sixty three patients
      had other lesions: hypoplastic left ventricle with ventricular septal defect (n =
      18), unbalanced complete atrioventricular canal (n = 9), complex double-outlet
      right ventricle (n = 14), double-inlet left ventricle (n = 11), tricuspid atresia
      with transposition of the great arteries (n = 6), and others (n = 5), including
      heterotaxia. RESULTS: Operative (>30 days) and 1-year survivals were lower for
      patients with hypoplastic left heart syndrome than for those with other lesions
      (63.4% vs 81%, P =.008, and 51.2% vs 71.4%, P =.02, respectively). The presence
      of a nonhypoplastic left ventricle (n = 27) was associated with higher operative
      and 1-year survivals (96.3% vs 64.7%, P =.002; 88.9% vs 52. 7%, P <.001). A
      restrictive atrial septal defect and prematurity tended to increase mortality
      across both groups. Cox proportional hazards regression indicated that a single
      right ventricle was the most important independent predictor of death (P <.001).
      Operative mortality for all patients undergoing the stage I procedure decreased
      from 38.5% (1990-1994) to 21.4% after 1994 (P =.02). CONCLUSIONS: The survival of
      patients with malformations other than hypoplastic left heart syndrome after the
      Norwood procedure is greater than for those with hypoplastic left heart syndrome.
      Staged palliation is valid surgical therapy in these patients, with good results
      in intermediate follow-up.

PMID- 10649214
TI  - The anterior spinal artery: the main arterial supply of the human spinal cord--a
      preliminary anatomic study.

PMID- 10649213
TI  - Construction of a bioengineered cardiac graft.
AB  - OBJECTIVES: Currently available graft materials for repair of congenital heart
      defects cause significant morbidity and mortality because of their lack of growth
      potential. An autologous cell-seeded graft may improve patient outcomes. We
      report our initial experience with the construction of a biodegradable graft
      seeded with cultured rat or human cells and identify their 3-dimensional growth
      characteristics. METHODS: Fetal rat ventricular cardiomyocytes, stomach smooth
      muscle cells, skin fibroblasts, and adult human atrial and ventricular
      cardiomyocytes were isolated and cultured in vitro. These cells were injected
      into or laid onto biodegradable gelatin meshes, and their rate of proliferation
      and spatial location within the mesh was evaluated by using a cell counter and
      histologic analysis. RESULTS: Rat cardiomyocytes, smooth muscle cells, and
      fibroblasts demonstrated steady proliferation over 3 to 4 weeks. The gelatin mesh
      was slowly degraded, but this process was most rapid after seeding with
      fibroblasts. Human atrial cardiomyocytes proliferated within the gelatin meshes
      but at a slower rate than that of fetal rat cardiomyocytes. Human ventricular
      cardiomyocytes survived within the gelatin mesh matrix but did not increase in
      number during the 2-week duration of evaluation. Grafts seeded with rat
      ventricular cells exhibited spontaneous rhythmic contractility. All cell types
      preferentially migrated to the uppermost surface of each graft and formed a 300-
      to 500-microm thick layer. CONCLUSIONS: Fetal rat ventricular cardiomyocytes,
      gastric smooth muscle cells, skin fibroblasts, and adult human atrial
      cardiomyocytes can grow in a 3-dimensional pattern within a biodegradable gelatin
      mesh. Similar autologous cell-seeded constructs may eventually be applied to
      repair congenital heart defects.

PMID- 10649216
TI  - Surgical management of active infective endocarditis in a premature neonate
      weighing 950 grams.

PMID- 10649217
TI  - Bronchiolitis obliterans-organizing pneumonia after coronary artery bypass graft
      surgery.

PMID- 10649215
TI  - Prolonged cardiopulmonary bypass for severe drug intoxication.

PMID- 10649218
TI  - Reversible visceral ischemia detected by transesophageal echocardiography and
      near-infrared spectroscopy.

PMID- 10649219
TI  - Method of determination of aortic valve parameters for its reconstruction with
      autopericardium: An experimental study.

PMID- 10649220
TI  - Myocyte contractile dysfunction with hypertrophy and failure: relevance to
      cardiac surgery.

PMID- 10649221
TI  - Abciximab (ReoPro) removal during cardiopulmonary bypass with a hemoconcentrator.

PMID- 10649222
TI  - Abciximab (ReoPro) removal during cardiopulmonary bypass with a hemoconcentrator

PMID- 10649223
TI  - Transcutaneous extracorporeal cannulation for bilateral lung transplantation
      without splitting the sternum.

PMID- 10649224
TI  - Cardiac aspergillosis.

PMID- 10649225
TI  - Enhanced protein renaturation by temperature-responsive polymers.
AB  - The application of temperature-sensitive polymer (PNIPAAm) for the renaturation
      of beta-lactamase from inclusion bodies was investigated. It was observed that
      PNIPAAm was more effective than PEG in enhancing protein renaturation. At a
      concentration of 0.1%, PNIPAAm improved the yield of beta-lactamase activity by
      41% from 46. 5 to 65.4 IU/mL, compared to 26% with PEG from 46.5 to 58.7 IU/mL.
      Kinetic study indicated that PNIPAAm did not significantly affect the initial
      rate of protein renaturation but did increase final activity yield. In the
      presence of PEG and PNIPAAm, the activity yields increased with temperature,
      indicating that hydrophobic interactions between denatured protein and polymer
      molecules contributed to the enhanced protein renaturation with polymers. The
      sequential addition approach, aiming at enhancing protein renaturation by
      reducing local protein concentration during renaturation, was also shown
      effective in enhancing protein renaturation, especially in the presence of
      polymers. With the sequential addition approach, the activity yield was increased
      by 60. 5% from 46.5 to 74.6 IU/mL with PNIPAAm. Similar behavior was also
      observed with PEG. PNIPAAm exhibited similar behavior as PEG on the renaturation
      of beta-lactamase in terms of temperature effect and concentration effect,
      indicating that the mechanism for enhanced protein renaturation for the two
      polymers might be similar. PNIPAAm exhibits a lower critical solution temperature
      (LCST) of 32 degrees C and can be effectively separated from aqueous solution and
      recycled. A protein renaturation process employing PNIPAAm, which offers the
      advantages of enhanced renaturation efficiency, minimum loss of protein
      aggregates, and ease of polymers recycling, was proposed.

PMID- 10649226
TI  - Transesterification reaction between medium- and long-chain fatty acid
      triglycerides using surfactant-modified lipase.
AB  - Transesterification between medium-chain fatty acid triglycerides (MCT) and long
      chain fatty acid triglycerides (LCT) in a nonsolvent system was investigated
      using surfactant modified lipase which is a complex of lipase, Rhizopus japonicus
      and surfactant, sorbitan monostearate. 74% conversion of was obtained after a 48
      h reaction period, and the triglyceride composition was well described by the 1,
      3-random 2-random stochastic model. The transesterification reaction between MCT
      and LCT closely followed the simple kinetic model, and the change in MCT and LCT
      contents could be simulated using one parameter. The effects of the water
      activity (A(w)) of modified lipase, the water content of the reaction system and
      the reaction temperature on the reaction rate were studied. A modified lipase
      A(w) of 0.35 and a water content of the reaction system at 0.09 wt % showed the
      highest activity. Inactivation did not occur below 60 degrees C, however, the
      activity decreased at temperatures over 70 degrees C.

PMID- 10649227
TI  - Volume changes of isolated human K562 leukemia cells induced by electric field
      pulses.
AB  - Electropermeabilization of immobilized human leukemia K562 cells was studied by
      measuring changes in cell volume. Such changes reflect mass transfer between the
      cell and external medium. Electropermeabilization was carried out in an isosmotic
      water-sorbitol medium with a range of electric field strengths from 500 to 800 V.
      cm(-1), corresponding to low-energy levels. Electroporation of the K562 cell
      membrane was found to provoke an inflow of sorbitol and a corresponding osmotic
      inflow of water and/or an outflow of intracellular solutes due to Fick diffusion.
      Such flows were found to involve the shrinkage, swelling, or rupture of K562
      cells, depending on the characteristics of the electric field and of the
      physiological state of cells. The behavior of immobilized cells was observed
      during their exposure to the electric field. The response in immobilized cell
      volume corresponded with the theoretical pore size and pore opening time,
      permitting an explanation of the behavior of cell suspensions subject to
      electrical fields.

PMID- 10649228
TI  - Kinetics of syntrophic cultures: a theoretical treatise on butyrate fermentation.
AB  - Numerous microbial conversions in methanogenic environments proceed at (Gibbs)
      free energy changes close to thermodynamic equilibrium. In this paper we attempt
      to describe the consequences of this thermodynamic boundary condition on the
      kinetics of anaerobic conversions in methanogenic environments. The anaerobic
      fermentation of butyrate is used as an example. Based on a simple metabolic
      network stoichiometry, the free energy change based balances in the cell, and the
      flux of substrates and products in the catabolic and anabolic reactions are
      coupled. In butyrate oxidation, a mechanism of ATP-dependent reversed electron
      transfer has been proposed to drive the unfavorable oxidation of butyryl-CoA to
      crotonyl-CoA. A major assumption in our model is that ATP-consumption and
      electron translocation across the cytoplasmic membrane do not proceed according
      to a fixed stoichiometry, but depend on the cellular concentration ratio of ATP
      and ADP. The energetic and kinetic impact of product inhibition by acetate and
      hydrogen are described. A major consequence of the derived model is that Monod
      based kinetic description of this type of conversions is not feasible, because
      substrate conversion and biomass growth are proposed to be uncoupled. It
      furthermore suggests that the specific substrate conversion rate cannot be
      described as a single function of the driving force of the catabolic reaction but
      depends on the actual substrate and product concentrations. By using nonfixed
      stoichiometries for the membrane associated processes, the required flexibility
      of anaerobic bacteria to adapt to varying environmental conditions can be
      described.

PMID- 10649229
TI  - Part I. Bcl-2 and Bcl-x(L) limit apoptosis upon infection with alphavirus
      vectors.
AB  - Viral expression systems offer the ability to generate high levels of a
      particular protein within a relatively short period of time. In particular,
      alphavirus constructs based on Sindbis virus (SV) and Semliki Forest virus (SFV)
      are promising vehicles as they are cytoplasmic vectors with the potential for
      high expression levels. Two such alphavirus vectors were utilized during the
      current study to infect two commercially relevant cell lines, baby hamster kidney
      (BHK) and Chinese hamster ovary (CHO); the first was a fully competent SV
      derivative carrying the gene for chloramphenicol acetyltransferase (dsSV-CAT),
      while the second was a replication deficient SFV construct containing the human
      interleukin-12 (IL-12) p35 and p40 genes (SFV-IL-12). Since infection with these
      vectors induced apoptosis in both cell lines, the present effort was dedicated to
      determining the ability of anti-apoptosis genes to limit the cell death
      associated with these virus constructs. Infection with the dsSV-CAT vector
      resulted in the rapid death of BHK and CHO cells within 4 days, a phenomenon
      which was considerably delayed by stably overexpressing bcl-2 or bcl-x(L). In
      fact, cellular lifespans were doubled in both BHK-bcl2 and CHO-bclx(L) cells
      relative to the parental cell lines. Furthermore, the presence of these gene
      products provided increases of up to 2-fold in recombinant CAT production.
      Overexpression of bcl-2 and bcl-x(L) also altered the response of these cells
      upon infection with SFV-IL-12. While the parental cell lines were completely
      nonviable within 1 week, the BHK-bcl2, BHK-bclx(L), and CHO-bclx(L) cells each
      recovered from the infection, resuming exponential growth and regaining
      viabilities of over 90% by 9 days post-infection. Total IL-12 productivities were
      nearly doubled by Bcl-2 and Bcl-x(L) in the CHO cells, although this effect was
      apparently cell-line specific, as the native BHK cells were able to secrete more
      IL-12 than either of its transfected derivatives. Regardless, the presence of the
      anti-apoptosis genes allowed the production of IL-12 to be maintained, albeit at
      low levels, from each of the cell lines for the duration of the culture process.
      Therefore, overexpression of bcl-2 family members can have a significant impact
      on culture viabilities and recombinant protein production during alphavirus
      infections of mammalian cells.

PMID- 10649230
TI  - Part II. Overexpression of bcl-2 family members enhances survival of mammalian
      cells in response to various culture insults.
AB  - A number of bioreactor configurations have been developed for the manufacture of
      products from mammalian cell hosts. Even in the most efficient of these, however,
      problems such as nutrient exhaustion, growth factor deprivation, and toxin
      accumulations may arise. Consequently, the current effort focused on the
      feasibility of overexpressing anti-apoptosis genes in baby hamster kidney (BHK)
      and Chinese hamster ovary (CHO) cells as a means of limiting cell death upon
      exposure to three such insults. Extended periods of glucose deprivation, serum
      withdrawal, and treatment with ammonium chloride each caused significant damage,
      often apoptotic in nature, to BHK and CHO cells, typically rendering cultures
      completely nonviable. The overexpression of bcl-2 and bcl-x(L), however, was able
      to abrogate the cell death in BHK cultures, though to varying degrees. For
      instance, the presence of Bcl-2, which did little to suppress apoptosis upon
      glucose deprivation, significantly improved the viabilities of these cells during
      serum withdrawal. In contrast, bcl-x(L) overexpression provided BHK cells with
      enhanced protection in the absence of glucose, allowing cultures to remain viable
      throughout the entire three week study. CHO cultures, on the other hand,
      displayed similar trends in survival in response to both glucose and serum
      deprivation. During these studies, Bcl-x(L) was consistently able to afford cells
      the highest degree of protection, though Bcl-2 also enhanced culture viabilities
      and viable numbers. Death suppression following exposure to 50 mM ammonium
      chloride was observed to a limited extent in both BHK and CHO cells
      overexpressing bcl-2 and bcl-x(L). However, even during such harsh treatment, Bcl
      x(L) was able to enhance the survival of both cultures, providing CHO cells with
      viable numbers that were nearly 20-fold that of the controls after five days of
      exposure. Furthermore, the extensions in cell survival provided by the anti
      apoptosis gene products enabled the recovery of many of the cultures during
      rescue attempts in which the death-inducing stimulus was removed. Clearly,
      engineering cells to better withstand and recover from the insults common during
      the large scale cultivation of mammalian cells has a number of potential
      applications in the biopharmaceutical industries where cell death can limit
      culture productivities.

PMID- 10649231
TI  - Observations of green fluorescent protein as a fusion partner in genetically
      engineered Escherichia coli: monitoring protein expression and solubility.
AB  - We have constructed three plasmid vectors for the expression of green fluorescent
      protein (GFP) fusion proteins using the following motif: (His)(6)-GFP-EK-X, where
      X represents chloramphenicol acetyl-transferase (CAT), human interleukin-2 (hIL
      2), and organophosphorous hydrolase (OPH), respectively, (His)(6) represents a
      histidine affinity ligand for purification, and EK represents an enterokinase
      cleavage site for recovering the protein-of-interest from the fusion. The CAT and
      OPH fusion products ( approximately 63 kDa GFP/CAT and approximately 70 kDa
      GFP/OPH) were expressed at 4.85 microg/mL (19.9 microg/mg-total protein) and 1.42
      microg/mL (4.2 microg/mg-total protein) in the cell lysis supernatant, and, in
      both cases, enzymatic activity was retained while coupled to GFP. In the case of
      hIL-2 fusion ( approximately 52 kDa), however, the GFP fluorescence was
      significantly reduced and most of the fusion was retained in the cell pellet.
      Linear relationships between GFP fluorescence and CAT or OPH concentration, and
      with enzymatic activity of CAT or OPH, indicated, for the first time, that in
      vivo noninvasive quantification of proteins-of-interest, was made possible by
      simple measurement of GFP fluorescence intensity. The utility of GFP as a
      reporter was not realized without disadvantages however, in particular, an
      incremental metabolic cost of GFP was found. This could be offset by many
      benefits foreseen in expression and purification efficiencies.

PMID- 10649232
TI  - Metabolic fate of glutamate and evaluation of flux through the 4-aminobutyrate
      (GABA) shunt in Aspergillus niger.
AB  - Accumulation of GABA and a concurrent block in the Krebs cycle suggest a
      functional GABA bypass in the acidogenic Aspergillus niger. Apart from the
      demonstration of enzyme machinery required, a direct measurement of flux through
      this glutamate decarboxylation loop was attempted. The distribution of carbon
      from glucose and glutamate was studied using A. niger mycelia grown on different
      media. The uptake and incorporation of (14)C label into organic acids and amino
      acids was followed by paper chromatography. Flow of label from glucose into
      citrate, glutamate and GABA increased in cells harvested at later stages of
      acidogenic growth. Very little citrate was derived from glutamate while ten times
      more label reached GABA from labeled glutamate. Radioactivity from L-[U
      (14)C]glutamate and not from L-[1-(14)C]glutamate was recovered in GABA. This
      demonstrated that alpha-decarboxylation of L-glutamate was the source of GABA.
      Unless grown on GABA, A. niger mycelia did not take up externally supplied GABA.
      A direct measure of GABA shunt flux was thus not feasible. Therefore a
      combination of metabolite balance technique and the kinetic approach was applied
      to evaluate flux from glutamate to succinate in normal and acidogenic A. niger.
      The flux relative to TCA cycle was estimated by using uptake rate for
      radiolabeled glutamate, rate of accumulation of certain metabolites and the
      reactions of GABA metabolism. The analysis indicated that GABA shunt is operative
      in A. niger and its operation is enhanced during acidogenic growth of the fungus.
      This is the first report of an estimation of the flux through GABA shunt in a
      fungus.

PMID- 10649233
TI  - A high-yielding, generic fed-batch cell culture process for production of
      recombinant antibodies.
AB  - A fed-batch cell culture process was developed that has general applicability to
      all evaluated Sp2/0 (n = 8) and NS0 (n = 1) antibody-producing cell lines. The
      two key elements of this generic process were a protein-free concentrated feed
      medium, and a robust, metabolically responsive feeding strategy based on the off
      line measurement of glucose. The fed-batch process was shown to perform
      equivalently at the 15 L development scale and 750 L manufacturing scale.
      Compared to batch cultures, the fed-batch process yielded a 4. 3 fold increase in
      the average integral of viable cell concentration and a 1.7 fold increase in
      average specific antibody production rate, equivalent to a 7.6 fold increase in
      average final antibody concentration. The highest producing cell line reached a
      peak viable cell concentration of 1.0 x 10(7) cell mL(-1) and a final antibody
      concentration of 750 mg L(-1) in a 10 day process. For all lines evaluated,
      reducing bioreactor pH set point from 7.2 to 7.0 resulted in an additional 2.4
      fold increase in average final antibody concentration. The optimized fed-batch
      process consistently yielded a volumetric productivity exceeding 50 mg L(-1) day(
      1). This generic, high-yielding fed-batch process significantly decreased
      development time, and increased manufacturing efficiency, thereby facilitating
      the clinical evaluation of numerous recombinant antibodies.

PMID- 10649234
TI  - Vector unpacking as a potential barrier for receptor-mediated polyplex gene
      delivery.
AB  - Ligand-conjugated polymer (polyplex) gene delivery vectors have strong potential
      as targeted, in vivo gene transfer vehicles; however, they are currently limited
      by low delivery efficiency. A number of barriers to polyplex-mediated delivery
      have been previously identified, including receptor binding, internalization,
      endosomal escape, and nuclear localization. However, based on understanding of
      viral gene delivery systems, yet another potential barrier may exist; a limited
      ability to unpackage the plasmid DNA cargo following localization to the nucleus.
      We have developed a model system that employs a cationic polymer linked to
      epidermal growth factor (EGF) as a ligand to target delivery of plasmid DNA
      encoding the green fluorescent protein to mouse fibroblasts bearing the EGF
      receptor. Using fluorescence microscopy to simultaneously trace both the plasmid
      and polymer during gene delivery in combination with an in vitro transcription
      assay, we provide evidence that plasmid unpackaging can indeed be a limiting step
      for gene expression for sufficiently large polymer constructs. Short-term
      expression is significantly enhanced by using short polycations that dissociate
      from DNA more rapidly both in vitro and in vivo. Finally, we describe a
      thermodynamic model that supports these data by showing that shorter polycations
      can have a higher probability of dissociating from DNA. This work demonstrates
      that vector unpackaging should be added to the list of barriers to receptor
      mediated polyplex gene delivery, thus providing an additional design principle
      for targeted synthetic delivery vehicles.

PMID- 10649235
TI  - Hyperaccumulation of cadmium by hairy roots of Thlaspi caerulescens.
AB  - Hairy roots were used to investigate cadmium uptake by Thlaspi caerulescens, a
      metal hyperaccumulator plant with potential applications in phytoremediation and
      phytomining. Experiments were carried out in nutrient media under conditions
      supporting root growth. Accumulation of Cd in short-term (9-h) experiments varied
      with initial medium pH and increased after treating the roots with H(+)-ATPase
      inhibitor. The highest equilibrium Cd content measured in T. caerulescens roots
      was 62,800 microg g(-1) dry weight, or 6.3% dry weight, at a liquid Cd
      concentration of 3710 ppm. Cd levels in live T. caerulescens roots were 1.5- to
      1.7-fold those in hairy roots of nonhyperaccumulator species exposed to the same
      Cd concentration, but similar to the Cd content of autoclaved T. caerulescens
      roots. The ability to grow at Cd concentrations of up to 100 ppm clearly
      distinguished T. caerulescens hairy roots from the nonhyperaccumulators. The
      specific growth rate of T. caerulescens roots was essentially unaffected by 20 to
      50 ppm Cd in the culture medium; in contrast, N. tabacum roots turned dark brown
      at 20 ppm and growth was negligible. Up to 10,600 microg g(-1) dry weight Cd was
      accumulated by growing T. caerulescens hairy roots. Measurement of Cd levels in
      whole roots and in the cell wall fraction revealed significant differences in the
      responses of T. caerulescens and N. tabacum roots to 20 ppm Cd. Most metal was
      transported directly into the symplasm of N. tabacum roots within 3 days of
      exposure; in contrast, T. caerulescens roots stored virtually all of their Cd in
      the wall fraction for the first 7 to 10 days. This delay in transmembrane uptake
      may represent an important defensive strategy against Cd poisoning in T.
      caerulescens, allowing time for activation of intracellular mechanisms for heavy
      metal detoxification.

PMID- 10649236
TI  - Alginate hydrogel microspheres and microcapsules prepared by spinning disk
      atomization.
AB  - Our spinning disk atomization (SDA) can, relative to other existing techniques,
      produce micron-sized particles with very narrow size distribution. The aim of
      this work is to present this technology for the production of alginate
      microspheres and microcapsules. We atomized and gelled aqueous alginate solutions
      into very narrowly dispersed microspheres with sizes ranging from 300 to 600
      microm. Here, the interest is to produce, at high rate, particles of a given size
      with a narrow size distribution and also to show a new method of encapsulation
      using SDA. The viscosity and flow rate contributions in the drop formation is
      qualitatively analyzed to show how they affect droplet size. In addition, a
      technique for high degree of encapsulation is presented in which yeast is used as
      a model system. The production of yeast-loaded microspheres by SDA shows the
      potential of the technique for biotechnology applications.

PMID- 10649237
TI  - Altered regulation of pyruvate kinase or co-overexpression of phosphofructokinase
      increases glycolytic fluxes in resting Escherichia coli.
AB  - Glycolytic fluxes in resting Escherichia coli were enhanced by overexpression of
      heterologous pyruvate kinases (Pyk) from Bacillus stearothermophilus and
      Zymomonas mobilis, but not homologous Pyk. Compared to the control, an increase
      of 10% in specific glucose consumption and of 15% in specific ethanol production
      rates was found in anaerobic resting cells, expressing the heterologous Pyks,
      that were harvested from exponentially growing aerobic cultures. A further
      increase in glycolytic flux was achieved by simultaneous overexpression of E.
      coli phosphofructokinase (Pfk) and Pyk with specific glucose consumption and
      ethanol production rates of 25% and 35% greater, respectively, than the control.
      Fluxes to lactate were not significantly affected, contrary to previous
      observations with resting cells harvested from anaerobically growing cultures. To
      correlate the physiology of resting cells with the physiology of cells prior to
      harvest, we determined the relevant growth parameters from aerobic and anaerobic
      precultures. We conclude that glycolytic fluxes in E. coli with submaximal
      (aerobic) metabolic activity can be increased by overexpression of pyruvate
      kinases which do not require allosteric activation or co-overexpression with Pfk.
      However, such improvements require more extensive engineering in E. coli with
      near maximal (anaerobic) metabolic activity.

PMID- 10649238
TI  - Mythology and numerology in the sphere of melanoma.

PMID- 10649239
TI  - Secondary leukemia: twice is a coincidence?

PMID- 10649240
TI  - Classic kaposi sarcoma: epidemiology and risk factors.
AB  - BACKGROUND: Although Kaposi sarcoma (KS) initially was described over a century
      ago, its biology remains enigmatic and conflicting. Whereas the classic type
      occurs mainly in older men of Mediterranean or Eastern European backgrounds and
      is not linked to impairment of the host immune response, iatrogenic and human
      immunodeficiency virus (HIV)-associated KS are linked to such conditions. A
      recently discovered pathogen, KS-associated herpesvirus (KSHV) (also known as
      human herpesvirus 8 [HHV8]), is found in tissues from all four forms of KS
      (classic, iatrogenic, endemic [African], and HIV-associated). This universal
      detection of KSHV/HHV8 suggests a central role for the virus in the development
      of KS and a common etiology for all KS types. The epidemiology and risk factors
      of classic KS, along with the biology of KSHV/HHV8 and the prevalence of the
      virus among different populations, is presented. METHODS: The current review is
      based on multiple information sources, electronic health data in all languages
      from 1966 onward, and previously published scientific reports from the Americas,
      Europe, and Africa. RESULTS: Nearly 5000 cases of morphologically characterized
      classic KS have been reported in Europe, Mediterranean countries, and the
      Americas up to 1998. Geographic location, ethnicity, time interval, age, and
      gender heavily influence the incidence rate of classic KS. The rate of incidence
      of nonacquired immunodeficiency syndrome-associated KS correlates with the
      KSHV/HHV8 seroprevalence in the general population. CONCLUSIONS: Many
      contributory factors undoubtedly have etiologic and pathogenic significance in
      the development of classic KS; however, the interplay between these factors has
      complicated the understanding of the induction and development of the disease as
      well as the significance of each factor. As with other cell-transforming human
      DNA viruses, infection with KSHV/HHV8 alone is not sufficient for the development
      of KS and additional cofactors are required.

PMID- 10649241
TI  - H-ras gene mutations in salivary gland mucoepidermoid carcinomas.
AB  - BACKGROUND: The authors' recent investigation of salivary gland tumors in ras
      gene alteration has suggested that K-ras activation may not play a role in their
      oncogenesis but H-ras may, especially in mucoepidermoid carcinomas. A study was
      undertaken to assess the overall incidence of mutated H-ras genes in
      mucoepidermoid carcinomas and to discover its potential correlation with
      clinicopathologic parameters. METHODS: Fifty samples from patients with salivary
      gland mucoepidermoid carcinoma were analyzed for point mutations at codons 12,
      13, and 61 of the H-ras gene using the polymerase chain reaction followed by
      automated direct sequencing methodology. RESULTS: Mutated H-ras genes were
      detected in 9 patients, for an overall incidence of 18% (9 of 50 patients). All
      but 1 of the mutations occurred at codon 12: a GGC-to-GTC transversion in 8
      patients and a GGC-to-GAC transition in 1 patient, resulting in the amino acid
      substitution of valine and aspartic acid, respectively, for glycine. One of the
      samples showed concurrent mutations at codons 12 (GGC-to-GTC) and 13 (GGT-to
      GGA). None of the samples demonstrated mutations involving codon 61. The H-ras
      mutations were observed in 5% (1of 21), 17% (2 of 12), and 35% (6 of 17) of low,
      intermediate, and high grade lesions, respectively. CONCLUSIONS: These data
      suggest involvement of H-ras activation in conjunction with other yet-unknown
      events in the development and/or progression of mucoepidermoid carcinomas. It is
      noteworthy that a stepwise increase in the frequency of H-ras mutations strongly
      correlates with tumor grade (P = 0.017). Molecular analysis of this gene
      alteration may provide assistance in the determination of tumor grade and
      differentiation.

PMID- 10649243
TI  - Predictive factors for intrahepatic recurrence after percutaneous ethanol
      injection therapy for small hepatocellular carcinoma.
AB  - BACKGROUND: Percutaneous ethanol injection therapy has been used widely for small
      hepatocellular carcinoma. This study was undertaken to determine factors
      predictive of local recurrence or new nodular recurrence in patients with small
      hepatocellular carcinoma treated with percutaneous ethanol injection. METHODS:
      The authors studied 73 nodules treated with percutaneous ethanol injection in 49
      patients with small hepatocellular carcinoma. The usefulness of predictive
      factors for recurrence was assessed with the Kaplan-Meier method. The
      clinicopathologic variables examined included age, gender, Child-Pugh
      classification, number of tumors (single vs. multiple), tumor size, degree of
      tumor differentiation, ultrasonographic findings such as peripheral hypoechoic
      band (so-called 'halo'), intratumoral echo pattern, tumor staining on enhanced
      computed tomography, combination therapy with transcatheter arterial
      embolization, and serum alpha-fetoprotein level. RESULTS: The local recurrence
      rates were 19%, 27%, 33%, 33%, and 33%, respectively, and the new nodular
      recurrence rates were 19%, 51%, 74%, 83%, and 83%, respectively, at 1, 2, 3, 4,
      and 5 years after percutaneous ethanol injection therapy. The frequency of local
      recurrence was associated with the histologic differentiation of more than
      moderately differentiated (P < 0.001), presence of a sonographic halo (P < 0.
      005), an intratumoral heterogeneous echo pattern (P < 0.001), and positive tumor
      staining on enhanced computed tomography (P < 0.01). Multivariate analysis showed
      that the presence of a halo and an intratumoral heterogeneous echo pattern were
      the most important variables for predicting local recurrence. The frequency of
      new nodular recurrences was related to the presence of multiple tumors (P < 0.01)
      and a high serum alpha-fetoprotein level (P < 0.001). Multivariate analysis
      showed that a high serum alpha-fetoprotein level was a reliable predictor of new
      nodular recurrence. CONCLUSIONS: This study showed that the presence of a halo
      and an intratumoral echo pattern on ultrasonography were useful predictors for
      local recurrence after percutaneous ethanol injection therapy for small
      hepatocellular carcinoma, and that a high serum alpha-fetoprotein level was
      associated with a higher frequency of new nodular recurrences.

PMID- 10649242
TI  - Fas ligand expression in esophageal carcinomas and their lymph node metastases.
AB  - BACKGROUND: Although esophageal adenocarcinomas (EADCA) have been shown to have
      substantially reduced or absent Fas expression, the status of Fas ligand (FasL)
      in these tumors, especially adenocarcinomas, is largely unknown. METHODS: Using
      immunohistochemistry, the authors investigated FasL expression in sections of
      formalin fixed, paraffin embedded tissue from 13 EADCA. They also studied
      sections of 15 esophageal squamous cell carcinomas (ESCCA) and of lymph node
      metastases from 7 EADCA and 4 ESCCA. The percentage of FasL positive cells in
      each tumor was recorded. FasL expression in EADCA was compared with that in ESCCA
      and with lymph node status. Statistical analysis was performed using the Fisher
      exact test. RESULTS: No specific staining pattern was seen in adenocarcinomas. In
      ESCCA, FasL was often located in the cells at the periphery of tumor nests. All
      (100%) of EADCA showed FasL expression in greater than 25% of the cancer cells,
      and all were associated with lymph node metastasis. Fifty-three percent of ESCCA
      showed FasL expression in greater than 25% of the cancer cells and 33% had lymph
      node metastasis. Expression of FasL in greater than 25% of tumor cells was
      associated with a significantly higher incidence of lymph node metastasis
      (P=0.0001). All lymph node metastases from esophageal carcinomas showed FasL
      immunoreactivity in greater than 50% of the metastatic tumor cells. CONCLUSIONS:
      FasL expression in greater than 25% of cancer cells correlates with a high
      incidence of lymph node metastasis in esophageal carcinomas. All cancer
      metastases in lymph nodes express FasL in >50% of the cells. These findings
      indicate that FasL plays an important role in the immune evasion and metastasis
      of esophageal carcinomas.

PMID- 10649244
TI  - Is the pathologic TNM staging system for patients with hepatoma predictive of
      outcome?
AB  - BACKGROUND: The pathologic TNM (pTNM) staging system was designed to aid in
      determining the prognosis of cancer patients and in planning and evaluating their
      treatment. The current pTNM classification system was not found to be predictive
      for patients undergoing orthotopic liver transplantation (OLTx) in the presence
      of hepatocellular carcinoma (HCC). Therefore, the authors examined the current
      system to determine whether improvements would allow the development of a more
      predictive system. METHODS: Three hundred seven patients with HCC underwent OLTx
      between 1981 and 1997. Risk factors for recurrence were identified using the
      Kaplan-Meier method with the log rank test. The Cox proportional hazards model
      was used to identify factors independently predictive of recurrence which were
      then used to create a new staging system. RESULTS: There was neither a direct
      correlation between the current pTNM system and tumor free survival nor
      homogeneity in outcomes for patients within certain current pTNM categories.
      Depth of vascular invasion, lobar distribution, lymph node status, and largest
      tumor size were found to be independent predictors of tumor free survival; tumor
      number was not found to be significant in multivariate analysis. A new staging
      system is proposed, which takes into account the results of the multivariate
      analysis in which tumor free survival correlates directly with stage.
      CONCLUSIONS: The proposed staging system is superior to the current pTNM staging
      system in predicting tumor free survival following OLTx with HCC. Further studies
      will determine the appropriateness of this system for staging HCC after subtotal
      hepatic resection.

PMID- 10649245
TI  - Serum levels of des-gamma-carboxy prothrombin measured using the revised enzyme
      immunoassay kit with increased sensitivity in relation to clinicopathologic
      features of solitary hepatocellular carcinoma.
AB  - BACKGROUND: Des-gamma-carboxy prothrombin (DCP) is an established marker for
      hepatocellular carcinoma (HCC), but the conventional enzyme immunoassay (EIA) kit
      lacks adequate sensitivity. Thus, a revised EIA kit with increased sensitivity
      has been developed. In this kit, the sensitivity has increased while high
      specificity to HCC has been maintained. The authors have already reported the
      clinical usefulness of this revised EIA kit. In this study, they examined the
      serum levels of DCP measured by this revised EIA kit in relation to the
      clinicopathologic features of solitary HCC. METHODS: Fifty-six patients with
      solitary HCC who underwent hepatectomy were studied. The relation between the
      greatest dimension and the histologic differentiation of HCC was investigated in
      these 56 patients, as were the serum levels of DCP measured by the revised EIA
      kit (Sensitive DCP), alpha-fetoprotein (AFP), and DCP measured by the
      conventional EIA kit (DCP). The cutoff value for Sensitive DCP was set at 40
      mAU/mL, and the values for AFP and DCP were 20 ng/mL and 100 mAU/mL (0.1 AU/mL),
      respectively. RESULTS: The positivity rates for Sensitive DCP, AFP, and DCP (n =
      56) were 53.6%, 53.6%, and 35.7%, respectively, and the rate was 73.2% when
      Sensitive DCP was used in combination with AFP (Sensitive DCP + AFP). The
      positivity rates for these markers were as follows: 1) When the greatest
      dimension of HCC was more than 3 cm (n = 16) and less than 2 cm (n = 23), the
      rates were 81.3% and 30.4% for Sensitive DCP, 68. 8% and 39.1% for AFP, 56.3% and
      13.0% for DCP, and 93.8% and 56.5% for Sensitive DCP + AFP. 2) When HCC was
      moderately to poorly differentiated (n = 41) and well differentiated (n = 15),
      the rates were 68.3% and 13.3% for Sensitive DCP, 61.0% and 33.3% for AFP, 48. 8%
      and 0% for DCP, and 85.4% and 40% for Sensitive DCP + AFP. 3) When HCC was either
      more than 3 cm or moderately to poorly differentiated (n = 42) and either less
      than 2 cm or well differentiated (n = 27), the rates were 69.0% and 29.6% for
      Sensitive DCP, 61.9% and 37.0% for AFP, 47.6% and 11.1% for DCP, and 85.7% and
      51.9% for Sensitive DCP + AFP. CONCLUSIONS: DCP measured by the revised EIA kit
      with increased sensitivity has a stronger correlation than AFP with size and
      histologic differentiation of HCC. This Sensitive DCP is a very useful marker for
      HCC and should be used in combination with AFP.

PMID- 10649246
TI  - Differential retinoblastoma and p16(INK4A) protein expression in neuroendocrine
      tumors of the lung.
AB  - BACKGROUND: Neuroendocrine neoplasms of the lung represent a wide spectrum of
      phenotypically and biologically distinct entities. Their histopathologic
      diagnosis, which carries therapeutic and prognostic significance, may sometimes
      be difficult because of their overlapping features. We previously demonstrated
      that large cell neuroendocrine carcinomas (LCNECs) and small cell lung carcinomas
      (SCLCs) failed to show positive nuclear staining of RB protein (RB-), whereas
      typical and atypical carcinoids (TCs and ACs) showed nuclear RB immunostaining
      (RB+). METHODS: In the current study, a series of 58 surgically resected lung
      tumors, of which 33 tumors were initially diagnosed as SCLCs and 25 as TCs or
      ACs, were studied for RB and p16 protein expression by immunohistochemistry. They
      were also reviewed for their pathologic diagnosis; the reviewers were blinded to
      the RB and p16 protein status. RESULTS: Nineteen tumors were diagnosed as TCs, 5
      as ACs, 7 as LCNECs, and 27 as SCLCs. Three of seven LCNECs were RB+, whereas the
      other four were RB-. In contrast, all 19 TCs were RB+ and all 27 SCLCs were RB-.
      In addition, two of five ACs were RB+, whereas the other three were RB-.
      Interestingly, all 3 RB+ LCNECs and the 1 RB+ AC tested failed to show nuclear
      staining of p16 protein in any tumor cells (p16-), although some normal stromal
      cells showed nuclear staining of p16 protein (p16+) as positive internal
      controls, indicating loss of p16 function in these tumors. It is also noteworthy
      that the three RB+ LCNECs were initially diagnosed as SCLCs and one of the RB-
      ACs was initially considered a TC. With the exception of TCs, tumors were
      significantly more prevalent among heavy smokers with >20 pack-years compared
      with nonsmokers and light smokers with < or = 20 pack-years (P < 0.01).
      CONCLUSIONS: These findings suggest that all SCLCs and LCNECs have abnormalities
      in the p16:RB pathway, as do at least certain ACs, whereas the p16:RB pathway is
      normal in TCs.

PMID- 10649247
TI  - Gemcitabine and vinorelbine in advanced nonsmall cell lung carcinoma: a phase II
      study.
AB  - BACKGROUND: The authors conducted a Phase II study to evaluate the activity of
      the combination of gemcitabine and vinorelbine in patients with advanced nonsmall
      cell lung carcinoma (NSCLC). METHODS: Patients were eligible if they had Stage
      IIIB (malignant pleural effusion) or Stage IV NSCLC, no prior chemotherapy, and
      Cancer and Leukemia Group B performance status (PS) 0-2. Patients with brain
      metastases were eligible if they were neurologically stable after brain
      irradiation. Thirty-three patients from participating institutions were enrolled.
      One patient was ineligible due to untreated brain metastases. Patients were
      treated with gemcitabine 1250 mg/m(2) over 30 minutes (1000 mg/m(2) for the first
      6 patients) and vinorelbine 25 mg/m(2) over 6 minutes, both administered
      intravenously on Days 1 and 8 every 21 days. Treatment was planned for a total of
      six cycles or more if the patient had persistent benefit. Growth factors were not
      allowed. RESULTS: Among all 32 eligible patients, there were 8 partial responses,
      for an overall response rate of 25% (95% confidence interval [CI], 11.5-43. 4%).
      The median survival time was 8.3 months and the 1-year survival rate was 38% (95%
      CI, 24-59%). Patients with PS 0-1 had a median survival of 11.7 months and a 1
      year survival rate of 48%. Grade 3 and 4 neutropenia was observed in 13% and 25%
      of the 148 treatment cycles, respectively. One patient died of neutropenic
      sepsis. Only 2 episodes of Grade 3 and 4 thrombocytopenia were observed.
      Nonhematologic toxicity was minimal. CONCLUSIONS: Gemcitabine and vinorelbine is
      an active and well-tolerated regimen in patients with advanced NSCLC, with
      response and survival rates at least comparable to those achieved with standard
      platinum-based regimens. This combination may be particularly suitable for the
      elderly or for patients who cannot tolerate more toxic platinum-based regimens.

PMID- 10649248
TI  - Lung carcinoma in 36 patients with human immunodeficiency virus infection. The
      Italian Cooperative Group on AIDS and Tumors.
AB  - BACKGROUND: The current study describes the clinicopathologic characteristics of
      36 patients with lung carcinoma and human immunodeficiency virus (HIV) infection
      observed within the Italian Cooperative Group on AIDS and Tumors (GICAT).
      METHODS: Patients with lung carcinoma and HIV infection collected by the GICAT
      between 1986-1998 were evaluated retrospectively. As a control group, the authors
      analyzed 102 patients age < 60 years with lung carcinoma but without HIV
      infection who were seen at the CRO, National Cancer Institute, Aviano, Italy
      between 1995-1996. RESULTS: Patients with lung carcinoma and HIV infection were
      younger (38 years vs. 53 years) and previously smoked more cigarettes per day (40
      vs. 20) than the control group. The main histologic subtype was adenocarcinoma.
      TNM Stage III-IV disease was observed in 53% of the patients. The median CD4 cell
      count was 150/mm(3). The median overall survival was significantly shorter in the
      patients with HIV compared with the control group (5 months vs. 10 months; P =
      0.0001). CONCLUSIONS: The results of the current study demonstrate that lung
      carcinoma in the HIV setting affects mainly young individuals with a history of
      heavy tobacco smoking and a moderately advanced immunodeficiency status. Lung
      carcinoma is associated with a more adverse outcome in HIV patients and
      represents the cause of death in the majority of these patients.

PMID- 10649249
TI  - Expression of thrombopoietin and its receptor (c-mpl) in chronic myelogenous
      leukemia: correlation with disease progression and response to therapy.
AB  - BACKGROUND: Chronic myelogenous leukemia (CML) represents a paradigm of the
      stepwise increment in disease aggressiveness, resistance to therapy, and
      transformation. Thrombopoietin (TPO) and its receptor, c-mpl, support the
      proliferation of multiple types of immature hematopoietic progenitor cells, and
      induce clonal growth of leukemic cells. The authors investigated whether TPO or c
      mpl overexpression might correlate with progression of CML, disease
      aggressiveness, or response to therapy. METHODS: Expression of c-mpl and TPO was
      measured in bone marrow samples from 208 patients with CML by Western blot
      analysis and solid-phase plate radioimmunoassay (used for quantification).
      Samples obtained from individuals without evidence of hematologic abnormalities
      were used as controls. RESULTS: There were no significant differences in TPO or c
      mpl expression among patients in different phases of CML or between patients with
      Philadelphia chromosome positive and negative CML. When TPO and c-mpl levels were
      analyzed in relation to prognostically important host and disease characteristics
      in early chronic phase CML, platelet and white blood cell counts demonstrated
      significant differences in both TPO and c-mpl expression, but age and spleen size
      demonstrated significant differences in TPO expression only. Responses to
      interferon (INF)-alpha-based therapy and survival were not influenced by TPO or c
      mpl levels. CONCLUSIONS: TPO or c-mpl overexpression did not correlate with
      different CML phases, suggesting that they were not involved in CML progression
      from early to advanced phase. Neither TPO nor c-mpl overexpression was
      particularly evident in any risk group, suggesting lack of correlation between
      their expression and disease aggressiveness. This was supported by the finding of
      similar response to IFN-alpha-based therapy and survival regardless of the level
      of TPO or c-mpl expression.

PMID- 10649250
TI  - Prognostic value of intratumoral natural killer cells in gastric carcinoma.
AB  - BACKGROUND: Natural killer (NK) cells are a group of effector cells that act
      nonspecifically against tumor cells. The correlation between intratumoral NK cell
      infiltration and clinicopathologic features remains unclear. METHODS: The authors
      selected 146 patients with gastric carcinoma who underwent gastrectomy at
      Kagoshima University Hospital between 1985-1995. Immunohistochemical staining
      with the CD57 antibody was performed for the evaluation of NK cell infiltration.
      A total of 25 areas containing CD57 positive cells were selected and the number
      of NK cells were counted (magnification, x200). The patients were divided into 2
      groups: patients with a high level of NK infiltration (n = 39) (>25 NK cells/25
      high-power fields [HPF]) and patients with a low level of NK infiltration (n =
      107) (<25 NK cells/25 HPF). Intratumoral lymphocytic infiltration also was
      counted in 25 areas at a magnification of x200. Patients were classified into a
      high infiltrating lymphocyte (IL) group (n = 69) (>150 cells/HPF) and a low IL
      group (n = 77) (<150 cells/HPF). The Kaplan-Meier curve was used to analyze
      surgical outcome. Multivariate analyses were performed to evaluate prognostic
      factors. RESULTS: Patients with a high level of NK infiltration had a higher rate
      of early gastric carcinoma, fewer metastases to the lymph nodes (P < 0.01), and
      less lymphatic invasion (P < 0.05) than patients with a low level of NK
      infiltration. NK cell infiltration also was found to correlate with depth of
      invasion, clinical stage, and venous invasion. There was no correlation between
      NK cells and lymphocytic infiltration (P = 0.07; correlation coefficient = 0.15).
      The 5-year survival rate of patients with a high rate of NK infiltration was 78%,
      which was significantly better than that of patients with a low level of NK
      infiltration (P < 0.01). Multivariate analysis did not show NK cell infiltration
      to be a significant prognostic factor. Combination analysis of the number of NK
      cells and lymphocytic infiltration was shown to be an independent prognostic
      factor (P = 0.02; hazard ratio = 1.32). CONCLUSIONS: Patients with a high level
      of NK infiltration were found to have a better prognosis than those with a low
      level of NK infiltration. Combination analysis with lymphocytic infiltration may
      provide useful information regarding the immunologic condition of patients with
      gastric carcinoma.

PMID- 10649251
TI  - A clinical trial of intravenous vinorelbine tartrate plus tamoxifen in the
      treatment of patients with advanced malignant melanoma.
AB  - BACKGROUND: The aim of the current trial was to assess the efficacy and toxicity
      of weekly intravenous vinorelbine tartrate with daily oral tamoxifen in the
      treatment of patients with advanced or metastatic malignant melanoma. METHODS:
      Thirty-one patients were treated with vinorelbine tartrate, 30 mg/m(2)
      intravenously, weekly every 13 weeks and then every 2 weeks thereafter until
      progression of disease or severity of toxicity warranted discontinuation.
      Tamoxifen, 10 mg orally, twice a day was administered daily starting on Day 1 of
      chemotherapy with vinorelbine tartrate. Thirty patients had cutaneous melanoma
      with metastases and 1 patient had ocular melanoma with metastases. Eight patients
      had received prior chemotherapy. RESULTS: Of the 30 evaluable patients with
      cutaneous melanoma, 6 achieved a partial response, for an overall response rate
      of 20% (95% confidence interval, 7-38%). There was no response in the patient
      with ocular melanoma. Major sites of response include the adrenal gland, lung,
      tonsil, and cutaneous/subcutaneous tissues. Three patients had a prolonged
      duration of response lasting > or = 12 months. Side effects generally were mild
      and tolerable. Grade 3 or 4 hematologic toxicity occurred in 26% and 13% of
      patients, respectively. Nonhematologic toxicity included mild fatigue,
      paresthesia, and local arm discomfort from infusion. CONCLUSIONS: Weekly
      intravenous vinorelbine tartrate plus daily oral tamoxifen appears to be active
      in the treatment of patients with malignant melanoma. Further clinical trials in
      malignant melanoma patients treated with vinorelbine tartrate and tamoxifen
      appear warranted.

PMID- 10649252
TI  - Breslow thickness and clark level in melanoma: support for including level in
      pathology reports and in American Joint Committee on Cancer Staging.
AB  - BACKGROUND: Thickness is known to be an important survival prognosticator for
      cutaneous melanoma, but controversy exists as to whether Clark level of invasion
      retains prognostic significance once thickness has been accounted for. A recent
      proposal to eliminate Clark level from the staging system for melanoma of the
      American Joint Committee on Cancer (AJCC) prompted the authors to investigate
      whether level adds useful prognostic information to Breslow thickness. They used
      the data base of the New York University Melanoma Cooperative Group (NYU-MCG)
      Registry. METHODS: The analysis was based on 919 patients with AJCC Stage I or II
      melanomas diagnosed between 1972 and 1982 and followed for an average of 10.9
      years. Melanoma thicknesses were divided into 4 categories (< or = 0.75, 0.76
      1.50, 1.51-4.00, and >4.00 mm). Patients were cross-classified according to tumor
      thickness and Clark level (II-V). For each combination of thickness and level,
      the Kaplan-Meier survival curve and 10-year survival proportion were computed,
      using death from melanoma as the outcome. The impact of Clark level on survival
      was evaluated for each of the thickness categories. The Cox proportional hazards
      model was used to assess the simultaneous effect of thickness and level on
      survival while controlling for other important prognostic factors, i.e., age,
      tumor location, and presence or absence of ulceration. RESULTS: Level of invasion
      was a significant predictor of death from melanoma in each of the four thickness
      categories. Likewise, in the Cox analyses, level was a significant prognostic
      variable, even after thickness was included in the model and regardless of
      whether thickness was treated as a categoric or a continuous variable.
      CONCLUSIONS: These results confirm that both tumor thickness and level of
      invasion are important independent prognostic factors in AJCC Stage I and II
      melanomas. The authors recommend that Clark levels be kept as criteria in the
      AJCC staging system and be included in pathology reports. [See editorial on pages
      491-6, this issue.]

PMID- 10649253
TI  - Factors associated with local recurrence of mammographically detected ductal
      carcinoma in situ in patients given breast-conserving therapy.
AB  - BACKGROUND: The authors reviewed their institution's experience treating patients
      with mammographically detected ductal carcinoma in situ (DCIS) of the breast with
      breast-conserving therapy (BCT) to determine 10-year rates of local control and
      survival and to identify factors associated with local recurrence. METHODS: From
      January 1980 to December 1993, 132 breasts in 130 patients were treated with BCT
      for mammographically detected DCIS at William Beaumont Hospital, Royal Oak,
      Michigan. All patients underwent an excisional biopsy, and 64% were reexcised.
      All patients received postoperative whole-breast irradiation to a median dose of
      45.0 Gray (Gy) (range: 43.1-56.0 Gy). One hundred twenty-four cases (94%)
      received a boost to the tumor bed for a median total dose of 60.4 Gy (range: 45.0
      71.8 Gy). All cases underwent complete pathologic review by one pathologist. The
      median follow-up was 7.0 years. RESULTS: Of the entire study group, 13 patients
      developed recurrence within the ipsilateral breast, for 5- and 10-year actuarial
      rates of 8.9% and 10.3%, respectively. Nine of the 13 recurrences (69%) occurred
      within or immediately adjacent to the lumpectomy cavity and were designated as
      true recurrences or marginal misses (TR/MM). Four patients (31%) had recurrence
      elsewhere in the breast. Ten of the 13 recurrences (77%) were invasive, whereas 3
      (23%) were pure DCIS. Only 1 patient died of disease, corresponding to 5- and 10
      year actuarial cause specific survival rates of 100% and 99.0%, respectively.
      Multiple clinical, pathologic, and treatment-related factors were analyzed for
      association with ipsilateral breast failure or TR/MM. In multivariate analysis,
      only the absence of pathologic calcifications was significantly associated with
      ipsilateral breast failure. When specifically analyzed for TR/MM, younger age at
      diagnosis, number of slides with DCIS, number of DCIS and cancerization of
      lobules (COL) foci within 5 mm of the margin, and the absence of pathologic
      calcifications demonstrated a statistically significant association. Close or
      positive margin status did not significantly predict for either TR/MM (P = 0.14)
      or ipsilateral breast failure (P = 0.19). CONCLUSIONS: In patients with
      mammographically detected DCIS treated with BCT, adequate excision of all DCIS
      prior to RT can result in improved rates of local control. However, margin status
      may not adequately predict complete tumor extirpation. The volume of DCIS within
      5 mm of the margin appears to be a more reliable surrogate for the adequacy of
      excision. In addition, young patient age and the absence of pathologic
      calcifications are independent risk factors for the development of local
      recurrence.

PMID- 10649254
TI  - Morbidity following sentinel lymph node biopsy versus axillary lymph node
      dissection for patients with breast carcinoma.
AB  - BACKGROUND: Axillary lymph node dissection for staging the axilla in breast
      carcinoma patients is associated with considerable morbidity, such as edema of
      the arm, pain, sensory disturbances, impairment of arm mobility, and shoulder
      stiffness. Sentinel lymph node biopsy electively removes the first lymph node,
      which gets the drainage from the tumor and should therefore be associated with
      nearly zero morbidity. METHODS: Postoperative morbidity (increase in arm
      circumference, subjective lymphedema, pain, numbness, effect on arm strength and
      mobility, and stiffness) of the operated arm was prospectively compared in 35
      breast carcinoma patients after axillary lymph node dissection (ALND) of Level I
      and II and 35 patients following sentinel lymph node (SN) biopsy. RESULTS:
      Patient characteristics were comparable between the two groups. Postoperative
      follow-up was 15.4 months (range, 4-28 months) in the SN group and 17.0 months
      (range, 4-28 months) in the ALND group. Following axillary dissection, patients
      showed a significant increase in upper and forearm circumference of the operated
      arm compared with the SN patients, as well as a significantly higher rate of
      subjective lymphedema, pain, numbness, and motion restriction. No difference
      between the two groups was found regarding arm stiffness or arm strength, nor did
      the type of surgery affect daily living. CONCLUSIONS: SN biopsy is associated
      with negligible morbidity compared with complete axillary lymph node dissection.

PMID- 10649255
TI  - Use of complementary health practices by prostate carcinoma patients undergoing
      radiation therapy.
AB  - BACKGROUND: There has been increasing interest in complementary health practices
      among patients, popular media, and even institutional health care providers.
      However, there is still surprisingly little information on the use of alternative
      medicine by patients undergoing treatment for prostate carcinoma. METHODS: A
      prospective study of 50 consecutive patients undergoing radiation treatment for
      prostate carcinoma at a tertiary care referral center was conducted. Patients
      were surveyed after the initiation of radiation therapy whether they had used
      complementary health practices at any time. RESULTS: The authors found that a
      surprisingly high proportion of patients (37%) relied on complementary health
      practices not prescribed by physicians. In contrast, according to a separate
      survey of the treating physicians, the physicians believed that on average only
      4% of their patients resorted to such practices. The use of complementary health
      practices usually continued even after the initiation of definitive treatment for
      prostate carcinoma. Patients who used complementary health practices tended to
      have higher levels of education and income, whereas there were no differences in
      age, religion, perception of health status, stage of prostate carcinoma, or
      prostate specific antigen level. Herbal remedies were the most frequently
      utilized, by 60% of those using complementary health practices, followed by old
      time remedies (47%), high dose vitamins (41%), chiropractic/massage therapy and
      relaxation techniques (18% each), and special diets (12%). CONCLUSIONS: Patients
      undergoing radiation therapy for prostate carcinoma frequently rely on
      complementary health practices not prescribed by their treating physicians.
      Patients who do so tend to have higher education and income levels and continue
      their complementary practices during the conventional treatment. As the health
      implications of these practices are unclear, further research is clearly needed.

PMID- 10649256
TI  - Acute myelogenous leukemia after exposure to strontium-89 for the treatment of
      adenocarcinoma of the prostate.
AB  - BACKGROUND: Strontium-89 is a pure Beta-emitting radioactive analogue of calcium
      that has been shown to be beneficial in the palliation of pain due to osseous
      metastases from adenocarcinoma of the prostate. The most significant reported
      toxicity is dose-related, reversible, myelosuppression characterized primarily by
      thrombocytopenia. METHODS: A report of two patients in whom acute myelogenous
      leukemia (AML) developed after treatment with strontium-89 and a review of the
      literature are presented. RESULTS: The two patients described in the current
      study developed AML 17 months and 26 months, respectively, after exposure to
      strontium-89 for the treatment of prostate carcinoma. To the authors' knowledge
      these patients represent the first two reported cases of AML after strontium-89
      therapy for prostate carcinoma. CONCLUSIONS: The results of the current study
      suggest the leukemogenic potential of strontium-89 treatment in humans. To the
      authors' knowledge, the current study represents the first report of AML after
      therapeutic exposure to strontium-89. As this agent is used more frequently (and
      earlier in the disease course) in patients with prostate carcinoma, an increased
      incidence of secondary AML complicating the clinical management of patients with
      prostate carcinoma may be observed. [See editorial on pages 497-9, this issue.]

PMID- 10649257
TI  - Flat intraepithelial lesions of the urinary bladder.
AB  - BACKGROUND: In the 1998 World Health Organization and International Society of
      Urologic Pathology (WHO/ISUP) classification system for bladder neoplasms, flat
      intraepithelial lesions of the urinary bladder were categorized as reactive
      atypia, atypia of unknown significance, dysplasia, and carcinoma in situ. The
      clinical outcomes of patients diagnosed with these atypical urothelial
      proliferations are uncertain. METHODS: The authors studied a series of patients
      who were diagnosed with reactive atypia of the urinary bladder (25 patients),
      urothelial atypia of unknown significance (35), or urothelial dysplasia (26)
      between 1985 and 1993. All histologic slides were reviewed and classified
      according to the 1998 World Health Organization and International Society of
      Urologic Pathology classification system. Patients with a concomitant or prior
      history of carcinoma in situ or urothelial carcinoma were excluded. RESULTS:
      Patient age at diagnosis ranged from 24 to 88 years (mean, 65 years). The male-to
      female ratio was 3:1. The mean follow-up was 3.9 years (range, 0.1-13.4 years;
      median, 3.5 years). None of the patients with reactive atypia or atypia of
      unknown significance developed dysplasia, carcinoma in situ, or urothelial
      carcinoma. Four patients (15%) with urothelial dysplasia developed biopsy-proven
      cancer, including 3 patients with muscle-invasive cancer. The mean interval from
      the diagnosis of urothelial dysplasia to the development of cancer was 4.5 years.
      CONCLUSIONS: Patients with a diagnosis of urothelial atypia of unknown
      significance or reactive atypia do not have adverse clinical outcomes, whereas
      patients with urothelial dysplasia of the bladder have an increased risk for the
      development of carcinoma in situ and urothelial carcinoma.

PMID- 10649258
TI  - Inverted urothelial papilloma: is ploidy, MIB-1 proliferative activity, or p53
      protein accumulation predictive of urothelial carcinoma?
AB  - BACKGROUND: Inverted urothelial papilloma is an unusual neoplasm of the urinary
      tract. Although the association between inverted urothelial papilloma and
      urothelial carcinoma is not entirely clear, many studies indicate that patients
      with inverted papilloma are at increased risk for the development of urothelial
      carcinoma. In addition, aneuploid inverted papillomas have been associated with
      the subsequent development of urothelial carcinoma. The objective of this study
      was to determine whether ploidy, MIB-1 proliferative activity, or p53 protein
      staining in inverted papilloma were predictive of urothelial carcinoma. METHODS:
      Fifty-one cases of inverted papilloma were retrieved from the Tissue Registry of
      the Mayo Clinic. Clinical records were reviewed for patient age, length of follow
      up, and history of urothelial carcinoma (defined as carcinoma prior to,
      concurrent with, or subsequent to the diagnosis of inverted papilloma). DNA
      ploidy analysis was determined using Feulgen stained sections from paraffin
      embedded tissues using an image analysis system. Quantitation of MIB-1
      proliferative activity and p53 immunostaining was determined similarly using
      immunoperoxidase stained sections from paraffin embedded tissues. RESULTS: The
      mean age at diagnosis of inverted papilloma was 63.9 years (range, 37-87 years),
      and there were 39 men and 12 women. Patients were followed for a mean of 56.5
      months (range, 1-252 months). Tumors ranged in size from 0.2 to 4.3 cm (mean, 0.9
      cm). Eight patients (15.7%) had a prior, concurrent, or subsequent noninvasive
      World Health Organization and International Society of Urologic Pathology
      (WHO/ISUP) papillary neoplasm of low malignant potential or papillary carcinoma
      of low grade (formerly WHO Grade 1 or 2 papillary urothelial carcinoma). Inverted
      papillomas in patients with a history of urothelial carcinoma were all diploid
      and had a mean MIB-1 activity of 6.3% (range, 0.04-24.8%) and mean p53 protein
      staining of 12.6% (range, 0.5-24.9%). These inverted papillomas ranged in size
      from 0.3 to 1.0 cm (mean, 0.5 cm). Inverted papillomas in patients without a
      history of urothelial carcinoma were aneuploid in 6 cases (14.3%) and diploid in
      the remaining cases. These inverted papillomas had a mean MIB-1 activity of 1.6%
      (range, 0.06-9.0%) and mean p53 protein staining of 9.7% (range, 0.05-38.0%).
      Tumor size ranged from 0.2 to 4.3 cm (mean, 1.0 cm). There were no statistically
      significant differences in MIB-1 activity, p53 protein staining, ploidy, and
      morphologic features between inverted papillomas in patients with and without a
      history of urothelial carcinoma. CONCLUSIONS: Ploidy, MIB-1 proliferative
      activity, and p53 immunostaining in inverted urothelial papilloma were not useful
      in identifying patients who had a history of urothelial carcinoma.

PMID- 10649259
TI  - Safety and efficacy of a multicenter study using intraarterial chemotherapy in
      conjunction with osmotic opening of the blood-brain barrier for the treatment of
      patients with malignant brain tumors.
AB  - BACKGROUND: The aim of this study was to determine the safety and efficacy of
      intraarterial chemotherapy with osmotic opening of the blood-brain barrier (BBB)
      for the treatment of malignant brain tumors when administered across multiple
      centers. METHODS: Patients with primary central nervous system lymphoma (PCNSL),
      primitive neuroectodermal tumor (PNET), germ cell tumor, cancer metastasis to the
      brain, or low or high grade glioma were eligible. Prior to entry, magnetic
      resonance imaging or computed tomography brain scan, medical history, neurologic
      status, and Karnofsky performance status were reviewed at the coordinating
      center. Standardized anesthesia and intraarterial catheterization guidelines were
      followed by a multidisciplinary team at each center. Between March 1994 and
      November 1997, 5 universities treated 221 adult patients with intraarterial
      chemotherapy with or without osmotic opening of the BBB (2464 procedures).
      RESULTS: Of evaluable patients with PCNSL, 40 of 53 (75%) achieved complete
      response (CR). All evaluable patients with PNET (n = 17), metastatic disease (n =
      12), or germ cell tumor (n = 4) achieved stable disease (SD) or better. Of 57
      evaluable patients with glioblastoma multiforme, 45 (79%) achieved SD or better.
      Asymptomatic subintimal tear occurred in 11 of 221 patients (5%), pulmonary
      embolism in 6 of 221 (2.7%), and renal toxicity in 4 of 221 (1.8%). One patient
      with extensive glioma expired within 48 hours after treatment. CONCLUSIONS: Using
      standard guidelines and protocols, intraarterial chemotherapy with or without
      osmotic opening of the BBB is feasible across multiple centers with a low
      incidence of catheter-related complications. In patients with chemotherapy
      sensitive tumors, such as PCNSL, PNET, germ cell tumor, and cancer metastasis to
      the central nervous system, enhanced delivery results in a high degree of tumor
      response, with an efficacy profile that is reproducible across multiple centers.

PMID- 10649260
TI  - Feasibility and early results of accelerated radiotherapy for head and neck
      carcinoma in the elderly.
AB  - BACKGROUND: Accelerated radiotherapy (RT) represents a promising method with
      which to improve the treatment outcome in patients with head and neck carcinoma.
      However, its applicability to elderly patients has not been well established.
      This study assessed treatment toxicities, patient compliance, and oncologic
      results in patients age >/= 70 years who were treated with an accelerated
      concomitant boost RT schedule. METHODS: Between 1991 and 1997, 39 patients aged
      >/= 70 years (mean, 75 +/- 6 years) presenting with carcinomas of the oral
      cavity, pharynx, or larynx were treated radically with a modified concomitant
      boost RT schedule (planned dose of 69.9 grays [Gy] over 38 days). Based on
      American Joint Committee on Cancer staging, there were 14 patients with Stage I
      II disease and 25 patients with Stage III-IV disease. Eighty-one patients age <
      70 years who were treated with the same RT schedule served as a comparative
      group. The median follow-up for the surviving patients was 19 months (range, 3-65
      months) and 23 months (range, 2-76 months), respectively, for the elderly and
      younger patient groups. RESULTS: The planned RT schedule was completed in all
      cases. Three patients (8%) in the elderly group and none in the younger group had
      an unplanned treatment interruption because of acute toxicity or lack of
      compliance (P = 0.03). The median tumor dose (69.9 Gy; range, 67-73 Gy) and the
      median overall treatment time (41 days; range, 36-60 days) were identical in both
      groups. According to the Radiation Therapy Oncology Group grading system, Grade 3
      4 acute reactions were observed in 66% of elderly patients and in 71% of younger
      patients. Ten elderly patients (26%) and 19 younger patients (23%) required a
      nasogastric tube or a percutaneous gastrostomy for feeding, with a median weight
      loss of 4.1 kg and 4.4 kg, respectively, in the 2 groups. Grade 3-4 late
      complications were observed in 3% of the elderly patients and 10% of the younger
      patients (P = 0.43). Both elderly and younger patients had similar results with
      regard to 3-year actuarial overall survival (68% vs. 62%; P = 0.48) and
      locoregional control (73% vs. 68%; P = 0.31). CONCLUSIONS: The current study
      suggests that an accelerated concomitant boost RT schedule is feasible in elderly
      patients who are physically healthy enough to undergo curative treatment. The
      acute and late toxicities appear to be similar to those observed in younger
      patients, and treatment outcomes appear to be comparable.

PMID- 10649261
TI  - Cancer and comorbidity: redefining chronic diseases.
AB  - BACKGROUND: A narrow subspecialty model of cancer care has led to cancer
      treatment often being given outside the full medical context of the patient. The
      full range of comorbid illness must be considered in all aspects of diagnosis and
      treatment. This study was conducted to describe the prevalence of comorbidity in
      cancer patients and examine its relation with multiple demographic and clinical
      variables. METHODS: A case comparison study of 15,626 population-based incident
      cases of cancer was conducted between 1984-1992 in 3 metropolitan Detroit
      counties (a National Cancer Institute Surveillance, Epidemiology, and End Results
      program). Chronic disease status and demographics were collected by self-report;
      cancer diagnoses and staging were obtained by medical record review. Univariate
      and multiple logistic regression analyses were performed. RESULTS: Comorbidity
      was present in 68.7% of cancer patients, and 32.6% of these individuals had > or
      = 2 comorbid conditions. Frequency was increased in the elderly, African-American
      patients (particularly African-American women), smokers, and those with lower
      socioeconomic status. Rates also appeared to vary by specific tumor site.
      CONCLUSIONS: Comorbid chronic diseases are common in persons with cancer. The
      prevalence of comorbidities has important clinical, health service, and research
      implications. The disease specific model of oncology may limit appropriate care
      for these patients, and enhanced integration of primary care into the ongoing
      management of cancer may offer better outcomes.

PMID- 10649262
TI  - Early findings from a community-based, cluster-randomized, controlled oral cancer
      screening trial in Kerala, India. The Trivandrum Oral Cancer Screening Study
      Group.
AB  - BACKGROUND: Oral cancer satisfies the criteria for a suitable disease for
      screening, and oral visual inspection is a suitable test for oral cancer
      screening. The efficacy of screening in reducing mortality from oral cancer has
      not yet been evaluated. The authors describe a cluster-randomized, controlled
      oral cancer screening trial in southern India and its early results. METHODS:
      Apparently healthy subjects age 35 years or older in 13 clusters called
      panchayaths were randomized to either an intervention group (n = 7) or a control
      group (n = 6). Subjects in the intervention group will receive 3 rounds of
      screening consisting of oral visual inspection by trained health workers at 3
      year intervals. The first round of screening was carried out between October 1995
      and May 1998. Participants were visited in their homes and interviewed for
      sociodemographic details, tobacco-smoking and alcohol-drinking habits, and
      personal medical history. Those with tobacco or alcohol habits were advised to
      stop those habits. Subjects in the intervention group were offered screening, and
      those with lesions suggestive of oral leukoplakia, submucous fibrosis, or oral
      cancer were referred for examination by physicians. Confirmed leukoplakias were
      excised whenever possible, others were kept on follow-up, and those with
      confirmed oral cancers were referred for treatment. Data on oral cancer
      incidence, stage distribution, survival, and mortality in the study groups are
      obtained by record linkage with the Trivandrum population-based cancer registry
      and municipal death registration systems. RESULTS: There were 59,894 eligible
      subjects in the intervention group and 54,707 in the control group; 31.4% of the
      former group reported no tobacco or alcohol habits, compared with 44.1% of the
      latter. The distribution of age, education, occupation, income, and socioeconomic
      status were similar in the two groups. Of 3585 subjects in the intervention group
      referred, 52.4% were examined by physicians; 36 subjects with oral cancers and
      1310 with oral precancers were diagnosed. Of the 63 oral cancers recorded in the
      cancer registry, 47 were in the intervention group and 16 were in the control
      group, yielding incidence rates of 56.1 and 20.3 per 100,000 person-years in the
      intervention and control groups, respectively. The program sensitivity for
      detection of oral cancer was 76.6% and the specificity 76.2%; the positive
      predictive value was 1.0% for oral cancer. In the intervention group, 72.3% of
      the cases were in Stages I-II, as opposed to 12.5% in the control group. The 3
      year case fatality rates were 14.9% (7 of 47 patients) in the intervention group
      and 56.3% (9 of 16 patients) in the control group. CONCLUSIONS: Though compliance
      with referral for confirmatory examination in the first round was lower than the
      70% anticipated, intermediate end points, such as stage at diagnosis and case
      fatality, indicate that the trial is making fairly satisfactory progress.

PMID- 10649263
TI  - Current health behaviors and readiness to pursue life-style changes among men and
      women diagnosed with early stage prostate and breast carcinomas.
AB  - BACKGROUND: Cancer survivors are at increased risk for developing secondary
      tumors, diabetes, osteoporosis, and cardiovascular disease, thus making them an
      important target population for health-related interventions. However, little is
      known regarding cancer survivors' behaviors and their interest in pursuing
      healthier diets, exercise, and smoking cessation. METHODS: A 65-item survey was
      mailed to 1667 patients diagnosed with early stage carcinoma of the breast or
      prostate that requested data regarding demographics, health behaviors, stage of
      readiness for smoking cessation, exercise, increased fruit and vegetable (F&V)
      consumption, and decreased fat intake, as well as interest in specific health
      programs and when, relative to diagnosis, these programs should be offered.
      RESULTS: Responses from 978 cancer survivors suggested that the overwhelming
      majority (85%) reported their health as good to excellent. The majority of
      respondents (55%) ate fewer than 5 daily servings of F&Vs, with prostate
      carcinoma patients reporting eating significantly fewer servings than patients
      with breast carcinoma (P < 0.001). In contrast, 69% of respondents reported
      adherence to a low fat diet, again with lower practice rates among prostate
      carcinoma patients than patients with breast carcinoma (P = 0.006). The majority
      of respondents (58%) reported routine exercise and 8% were current smokers.
      Significantly more breast carcinoma patients than prostate carcinoma patients
      were current smokers (P = 0.03). There was strong interest in health promotion
      programs across behaviors, and a fair amount of concordance between low fat
      dietary behaviors and exercise, as well as consumption of five daily servings of
      F&Vs. The majority of patients expressed a preference for programs that could be
      delivered via mailed brochure, with 57% of respondents indicating that programs
      should be initiated at the time of diagnosis or soon after (within 6 months).
      CONCLUSIONS: The results of the current study suggest that although many cancer
      survivors already practice healthy life-style behaviors, there is a substantial
      proportion who do not. Interventions especially are needed to increase daily F&V
      intake; however, given the fair degree of clustering between dietary and exercise
      behaviors, multiple risk factor interventions also may be warranted. Among cancer
      survivors, receptivity is high for health promotion programs, especially those
      that can be delivered by mail and soon after diagnosis.

PMID- 10649264
TI  - Radiotherapy followed by high dose busulfan and thiotepa: a prospective
      assessment of high dose chemotherapy in children with diffuse pontine gliomas.
AB  - BACKGROUND: The role of high dose chemotherapy (HDC) in patients with pediatric
      brain tumors currently is ill-defined. The purpose of this pilot study was to
      assess the feasibility and the benefit of HDC after radiotherapy in a group of
      children with newly diagnosed diffuse pontine gliomas. METHODS: Patients eligible
      for study were ages 3-18 years with diffuse intrinsic tumors arising in the pons,
      who were not treated previously with radiotherapy or chemotherapy. Histologic
      confirmation was not mandatory, provided clinical findings and magnetic resonance
      imaging were typical. Patients were given focal radiotherapy followed 2-3 months
      later by HDC. Busulfan (150 mg/m(2) on Days 8, 7, 6, and 5) and thiotepa (300
      mg/m(2) on Days 4, 3, and 2) were administered prior to autologous bone marrow
      transplantation. Survival was the endpoint, and the statistical procedure was
      based on sequential subgroup analysis. RESULTS: Thirty-six patients were entered
      on to the study, 12 of whom underwent stereotactic biopsy or open surgery at the
      time of diagnosis. One patient eventually was excluded due to inappropriate
      eligibility criteria. All 35 eligible patients received irradiation. Early
      progression (9 patients) and parental refusal (2 patients) precluded the use of
      HDC in 11 patients. Three patients died of HDC-related complications. All 21
      patients who survived HDC eventually died of disease progression. The median
      survival time was 10 months for the study group. The median survival time in the
      subgroup of patients who received HDC was 10 months (range, 3-26 months).
      Statistical analysis did not suggest any evidence of survival benefit.
      CONCLUSIONS: For patients with diffuse pontine gliomas, survival using this
      aggressive treatment modality does not appear to be any better than that reported
      for conventional radiotherapy.

PMID- 10649265
TI  - Cerebral glucose metabolism in survivors of childhood acute lymphoblastic
      leukemia.
AB  - BACKGROUND: Cranial radiation therapy (CRT) has been suggested to be a principal
      factor responsible for long term neurocognitive deficits in survivors of acute
      lymphoblastic leukemia (ALL). However, neither reduction of the irradiation dose
      nor the elimination of irradiation entirely appear to have abolished
      neurocognitive impairment in long term ALL survivors. Positron emission
      tomography (PET) and [(18)F]-fluorodeoxyglucose (FDG) can be used to quantitate
      cerebral glucose metabolism, a potential indicator of treatment-induced adverse
      central nervous system (CNS) effects. The purpose of this study was to assess
      whether CRT is associated with defects in cerebral glucose metabolism in long
      term ALL survivors. The authors also studied whether chemotherapy and/or the
      severity of disease have deleterious effects on glucose metabolism. METHODS:
      Forty long-term survivors of childhood ALL were studied using FDG PET. All
      subjects went through an elaborate neurocognitive assessment. In 20 of these
      children, the prophylactic treatment of the CNS had been CRT combined with
      methotrexate (MTX), and it was MTX only in the remaining 20 children. RESULTS: No
      major differences were found in the regional cerebral glucose utilization or in
      neurocognitive performance between the irradiated and nonirradiated groups. A
      high leukocyte count at the time of diagnosis was found to be associated
      inversely with cerebral glucose utilization. CONCLUSIONS: CRT does not appear to
      affect cerebral glucose metabolism in long term survivors of ALL. By contrast,
      the association between the leukocyte count and glucose utilization implies that
      disease severity may be partly responsible for adverse CNS effects in long term
      survivors of childhood ALL.

PMID- 10649266
TI  - Evaluating the quality of cancer care: development of cancer quality indicators
      for a global quality assessment tool.
AB  - BACKGROUND: The rise of managed care has increased interest in measuring,
      reporting, and improving quality of care. To date, quality assessment has relied
      on a leading indicator approach, which may miss important variations in care. The
      authors developed cancer specific indicators using a novel case-based approach
      for a quality measurement tool designed to compare different managed care
      organizations. METHODS: Based on a review of the literature, quality indicators
      were developed for 6 types of cancer and the human immunodeficiency virus (HIV)
      as well as 39 general adult conditions (GAC). The validity and feasibility of
      these candidate indicators were evaluated using three modified Delphi expert
      panels. The strength of evidence, type of care (preventive, acute, or chronic),
      function (screening, diagnosis, treatment, and follow-up), and modality (history,
      physical examination, laboratory, medication, or other intervention) of the
      cancer/HIV quality indicators were compared with indicators developed for GAC.
      RESULTS: The final system included 117 of the 145 proposed cancer/HIV quality
      indicators (81%) and 569 of the 705 proposed GAC indicators (81%). A greater
      percentage of the cancer/HIV indicators were based on evidence from clinical
      trials compared with the GAC indicators (59% vs. 31%; P = 0.001). Cancer/HIV had
      significantly more indicators pertaining to chronic care than did GAC (74% vs.
      56%; P = 0.001) as well as more indicators for treatment (53% vs. 39%; P =
      0.004). CONCLUSIONS: Using the case-based approach, it is feasible to develop
      quality indicators for cancer that cover the continuum of care. Future studies
      will evaluate the reliability and validity of measurements made using these
      indicators in three managed care plans.

PMID- 10649267
TI  - Human immunodeficiency virus negative Kaposi sarcoma and lymphoproliferative
      disorders.

PMID- 10649268
TI  - Author reply

PMID- 10649270
TI  - Commentary

PMID- 10649269
TI  - Anorectal lymphoma and AIDS: an outcome analysis.
AB  - BACKGROUND AND OBJECTIVE: Primary lymphoma of the anus is an extremely rare
      problem. In patients with the Acquired Immune Deficiency Syndrome (AIDS), there
      is a marked increase in gastrointestinal non-Hodgkin's lymphomas (NHL). The aim
      of this study was to evaluate the outcome of patients with anorectal NHL and
      AIDS. METHODS: Over an 18-year period, we identified 6 patients with AIDS and
      primary anorectal NHL. Five were male. All were high-grade B-cell lymphomas and
      half showed systemic "B" symptoms. Patient's mean CD4 count was 93 (range 8 to
      201). RESULTS: The average life span for those with "B" symptoms was 6.7 months
      and 16 months for those without symptoms. No benefit was shown from radiation or
      chemotherapy in those with "B" symptoms. Younger patients and those without
      systemic constitutional symptoms of lymphoma do better. One patient without "B"
      symptoms was able to tolerate his radiation and chemotherapy and is disease free
      at 10 months. CONCLUSION: Despite traditional non-Hodgkin's lymphoma treatment
      regimens, our AIDS patients (and those examined in a review of the pertinent
      literature) with anorectal NHL and "B" symptoms have a poor prognosis. For those
      without "B" symptoms and who can tolerate the therapy, NHL remission may be
      obtained.

PMID- 10649271
TI  - In vitro augmentation of antitumor effect in combination with CPT-11 and CDDP for
      human colorectal cancer.
AB  - BACKGROUND AND OBJECTIVES: Irinotecan hydrochloride (CPT-11) is one of the
      camptothecin analogues that has shown a broad spectrum of strong antitumor
      effectiveness against various cancers, including colorectal cancer. In order to
      promote the clinical response of chemotherapy for colorectal cancer using CPT-11,
      one of the most effective strategies is to use it in combination with other
      anticancer agents. In the present study, anticancer effects after combining CPT
      11 and other antitumor agents were determined by a 3-(4,5-di-methylthiazol-2-yl)
      2,5-diphenyl tetrazolium bromide (MTT) assay of colorectal cancer cells,
      especially freshly isolated cancer cells. METHODS: Freshly isolated cancer cells
      from 20 patients with colorectal cancer and the established colon cancer cell
      lines were used in this study. The augmentation of the antitumor effectiveness of
      7-ethyl-10-hydroxy-CPT (SN-38) was analyzed in combination with other anticancer
      agents. Furthermore, the antitumor effectiveness using lower concentrations of
      anticancer agents was measured to understand the mechanism of the augmentation.
      RESULTS: The percent inhibition of SN-38 in combination with cisplatin (CDDP) and
      mitomycin revealed a high anticancer effect compared with each anticancer agent
      alone for freshly isolated rectal cancer. CDDP also had a synergistic effect in
      combination with SN-38 according to the fractional product concept. At lower than
      plasma peak concentrations of SN-38, the anticancer effects were augmented in
      combination with lower concentrations of CDDP for freshly isolated colorectal
      cancer. This augmentation showed a strong synergistic effect. CONCLUSIONS: These
      results may be supportive to ongoing clinical studies of chemotherapy by using
      CPT-11 and CDDP for advanced colorectal cancer.

PMID- 10649272
TI  - Treatment of advanced soft tissue sarcomas with ifosfamide and doxorubicin
      combination chemotherapy.
AB  - Our objective was to assess the efficacy of a standard dose ifosfamide and
      doxorubicin containing regimen in the treatment of advanced soft tissue sarcomas.
      Forty consecutive patients with a median age of 35.5 years were treated.
      Ifosfamide was administered at a dose of 2.5 g/m(2)/day as 72-hour continuous
      infusion with mesna at the same dosage and schedule. Doxorubicin was given at the
      dose of 60 mg/m(2)/day as 2-hour infusion on day 1. Six patients had a complete
      response (15%), and 9 (22.5%) had a partial response, fourteen patients (35%)
      stable disease, and 11 (27.5%) did not respond to chemotherapy. The median
      duration of response was 13 and 5 months for the complete and partial responders,
      respectively. The median survival was 37 months. Febrile neutropenia was
      encountered in 9 cases (22.5%). The present ifosfamide and doxorubicin
      combination is a moderately effective and well-tolerable regimen in the treatment
      of advanced soft tissue sarcomas.

PMID- 10649273
TI  - c-erbB-2 protein overexpression and p53 immunoreaction in primary and recurrent
      breast cancer tissues.
AB  - BACKGROUND AND OBJECTIVES: We investigated whether expression levels of c-erbB-2
      and p53 proteins in breast cancer tissues differ in primary and metastatic
      lesions. METHODS: Immunohistochemical staining or sandwich enzyme immunoassay was
      used to determine expression levels of c-erbB-2 and p53 proteins in 42 breast
      cancer samples from 21 patients. Estrogen (ER) and progesterone receptors (PgR)
      were also measured by enzyme immunoassay in each case. All patients had undergone
      radical surgery for primary tumors and surgical resection of asynchronous
      metastatic lesions. Thirteen patients (62%) were premenopausal and 14 (67%)
      received postoperative adjuvant therapies. Median disease-free survival time was
      26 months (range, 5-104). The resected metastatic lesions included 1 in the
      liver, 3 in the lung, and 3 in the supraclavicular lymph nodes. The remaining 14
      were local skin lesions. RESULTS: There was no difference in the positivity rate
      of c-erbB-2 (38%: 8/21) and p53 (39%: 7/18) expression between the primary tumors
      and the recurrent lesions. In addition, no discordant c-erbB-2 or p53 expression
      was observed between the primary tumors and their respective metastatic lesions.
      Positivity rates for ER and PgR were 50% (10/20) and 60% (12/20) for the primary
      tumors, but only 25% (5/20) and 30% (6/20) for the recurrent lesions,
      respectively (P = 0. 19 for ER and P = 0.11 for PgR). CONCLUSIONS: c-erbB-2 and
      p53 expression levels in breast cancer cells were almost unchanged as the disease
      progressed and/or in response to adjuvant therapies, regardless of the hormone
      receptor status.

PMID- 10649274
TI  - Treatment of extra-abdominal desmoid tumors with interferon-alpha with or without
      tretinoin.
AB  - BACKGROUND AND OBJECTIVES: Surgery is the main treatment for extra-abdominal
      desmoid tumors, but the results of further management remain uncertain.
      Therefore, a retrospective analysis was undertaken to evaluate the toxicity and
      efficacy of treatment with interferon-alpha (IFN-alpha) +/- tretinoin in this
      setting. METHODS: Thirteen patients with extra-abdominal desmoid tumors and a
      median age of 32 years (range, 15-73) received IFN-alpha. Seven of these patients
      received a combination of IFN-alpha and tretinoin in order to test further
      enhancement. RESULTS: After a mean observation period of 27 +/- 15 months (mean
      +/- standard deviation) under treatment with IFN-alpha +/- tretinoin, local
      control was seen in 11 of 13 patients (85%). Seven patients had no evidence of
      disease at a mean disease-free interval of 22 +/- 18 months; in two patients
      progressive disease occurred after only 7 and 9 months, respectively, of
      observation. In another four patients, progression of the desmoid tumor was
      stabilized. CONCLUSIONS: The data of this retrospective, nonrandomized study on
      therapy with IFN-alpha +/- tretinoin suggest that such treatment may be effective
      in prolonging the disease-free interval of patients after intralesional or
      marginal surgery. Because of the encouraging response rate, this regimen appears
      to be another nonsurgical treatment alternative.

PMID- 10649275
TI  - Ruptured retroperitoneal mucinous cystadenocarcinoma with synchronous gastric
      carcinoma and a long postoperative survival: case report.
AB  - We describe an 86-year-old woman with a long survival following surgey for a
      massive retroperitoneal mucinous cystadenocarcinoma and a synchronous gastric
      carcinoma. Computed tomography showed a huge tumor with septation and
      calcification. Upper gastrointestinal radiography showed the additional gastric
      lesion. At operation, the 23 x 20 x 12-cm retroperitoneal tumor had ruptured.
      Tumor resection and distal gastrectomy including regional lymph nodes were
      performed. Mucinous peritoneal implants were removed as completely as possible.
      Histologically, the mucinous tumor showed limited invasion, whereas the poorly
      differentiated gastric adenocarcinoma showed no serosal invasion. Among 18
      retroperitoneal mucinous cystadenocarcinomas reported in the English literature
      since 1965, only ours was associated with gastric carcinoma. Despite peritoneal
      implants, our patient has survived for 6 years without clinical recurrence. As at
      other sites, retroperitoneal mucinous cystadenocarcinoma often grows slowly.
      Total removal, even after peritoneal dissemination, can result in long survival.

PMID- 10649276
TI  - Full-thickness skin grafting.

PMID- 10649277
TI  - Abdominoperineal resection by ultrasonic shears without blood loss and ligatures.

PMID- 10649278
TI  - Approach to urinary diversion in the surgical patient.
AB  - Major surgical procedures may remove part or all of the bladder and make an
      incontinent or continent urinary diversion appropriate. Preoperative
      consideration must be given to 1) the stoma and its position, 2) the
      catheterizable channel, 3) the urinary continence mechanism, and 4) the
      substitute bladder reservoir. Complete bowel preparation and broad-spectrum
      antibiotics are desirable. The patient's motivation for taking care of a
      continent urinary diversion is important, since lifelong catheterization and
      mucous irrigation may be necessary. The status of the native bladder outlet and
      urinary sphincter is important in cases in which an orthotopic continent urinary
      diversion is considered. Preoperative evaluation by a stoma therapist is
      invaluable. Adequate urinary drainage is important in the immediate postoperative
      period. Patients with urinary diversions must be followed lifelong to rule out
      asymptomatic deterioration of their upper urinary tracts and to check for
      potential metabolic and nutritional problems.

PMID- 10649279
TI  - Sarcoma and metastatic carcinoma.
AB  - Primary tumors of the bone and soft tissue of the pelvis are rare. Proper
      surgical treatment requires a fundamental knowledge of the biology of malignant
      musculoskeletal neoplasms. This understanding allows stratification of sarcomas
      into a staging system. In addition to prognostic value, the careful staging of
      the neoplasms dictates the type of surgical margins necessary and guides in the
      use of adjuvant therapy. Limb salvage techniques developed for the reconstruction
      of major extremity structural deficits can be used for reconstruction of the
      pelvis. This review first addresses the biologic behavior and staging of
      malignant musculoskeletal neoplasms. The surgical techniques employed for the
      resection and the reconstruction of the pelvis are then discussed.

PMID- 10649280
TI  - Locally recurrent rectal cancer: role of composite resection of extensive pelvic
      tumors with strategies for minimizing risk of recurrence.
AB  - Locally recurrent cancer of the rectum has been under-recognized as a
      complication, although it affects up to 40% of patients treated with surgery
      alone. Even in the best centers, rates average 25%. While radiotherapy may reduce
      recurrence, it is now apparent that total mesorectal excision is the most
      effective modality, with rates as low as 5%. The dramatic decrease in local
      recurrence can also be linked to increased survival in prospective studies, an
      effect more significant than any adjuvant therapy. The options, however, for
      patients with locally recurrent cancer are limited. Fifteen percent of patients
      with this complication die without systemic spread. Salvage by surgery offers
      potential cure. Other than anastomotic recurrences that can be locally resected,
      the best approach for long-term survival is an extensive surgical procedure
      requiring en bloc removal of adjacent organs and pelvic structures-so-called
      composite resection. With careful selection, 30% 5-year survival can be achieved
      and palliation is considerable, with 50% long-term local control. Intraoperative
      radiotherapy and brachytherapy, and/or preoperative chemoradiation may provide
      better results in future. Newer techniques of coloanal anastomosis, improved
      urinary diversion, and myocutaneous flaps for perineal reconstruction radically
      reduce the morbidity of these procedures. The approach to recurrent rectal cancer
      requires a sophisticated multidisciplinary team to obtain optimum results.

PMID- 10649282
TI  - Biological timing mechanisms: a thematic special issue for the new millennium

PMID- 10649281
TI  - Voluminous pleomorphic adenoma of submandibular gland.

PMID- 10649283
TI  - An autonomous cell-cycle oscillator involved in the coordination of G1 events.
AB  - In early embryonic development, the cell cycle is paced by a biochemical
      oscillator involving cyclins and cyclin-dependent kinases (cdks). Essentially the
      same machinery operates in all eukaryotic cells, although after the first few
      divisions various braking mechanisms (the so-called checkpoints) become
      significant. Haase and Reed have recently shown that yeast cells have a second,
      independent oscillator which coordinates some of the events of the G1 phase of
      the cell cycle.(1) Although the biochemical nature of this oscillator is not
      known,it seems unlikely to be a redundant cyclin/cdk system. BioEssays 22:3-5,
      2000.

PMID- 10649284
TI  - Unraveling the mechanism for respiratory rhythm generation.
AB  - Breathing is generated by a neuronal network located within the caudal brainstem.
      One area of particular significance for respiratory rhythm generation is the pre
      Botzinger (preBotC) complex in the ventrolateral medulla. An important step
      towards understanding the cellular and network basis by which neurons within this
      region generate the respiratory rhythm was made in a recent study by Koshiya and
      Smith.(1) Using simultaneous image analysis and electrophysiological techniques
      these authors identified a discrete population of synaptically-coupled pacemaker
      neurons within the preBotC. They postulated that these neurons constitute the
      minimal essential network component (kernel) for generating the respiratory
      rhythm. BioEssays 22:6-9, 2000.

PMID- 10649285
TI  - The circadian clock of cyanobacteria.
AB  - A circadian clock, with physiological characteristics similar to those of
      eukaryotes, functions in the photosynthetic prokaryote, cyanobacteria. The
      molecular mechanism of this clock has been efficiently dissected using a
      luciferase reporter gene that reports the status of the clock. A circadian clock
      gene cluster, kaiABC, has been cloned via rhythm mutants of cyanobacterium,
      Synechococcus, and many clock mutations mapped to the three kai genes. Although
      kai genes do not share any homology with clock genes so far identified in
      eukaryotes, analysis of their expression suggests that a negative feedback
      control of kaiC expression by KaiC generates the circadian oscillation and that
      KaiA functions as a positive factor to sustain this oscillation. BioEssays 22:10
      15, 2000.

PMID- 10649286
TI  - Ultradian clocks in eukaryotic microbes: from behavioural observation to
      functional genomics.
AB  - Period homeostasis is the defining characteristic of a biological clock. Strict
      period homeostasis is found for the ultradian clocks of eukaryotic microbes. In
      addition to being temperature-compensated, the period of these rhythms is
      unaffected by differences in nutrient composition or changes in other
      environmental variables. The best-studied examples of ultradian clocks are those
      of the ciliates Paramecium tetraurelia and Tetrahymena sp. and of the fission
      yeast, Schizosaccharomyces pombe. In these single cell eukaryotes, up to seven
      different parameters display ultradian rhythmicity with the same, species- and
      strain-specific period. In fission yeast, the molecular genetic analysis of
      ultradian clock mechanisms has begun with the systematic analysis of mutants in
      identified candidate genes. More than 40 "clock mutants" have already been
      identified, most of them affected in components of major regulatory and
      signalling pathways. These results indicate a high degree of complexity for a
      eukaryotic clock mechanism. BioEssays 22:16-22, 2000.

PMID- 10649287
TI  - Circadian clocks in the mammalian brain.
AB  - Daily cycles in physiology and behaviour are probably a universal feature of
      multicellular organisms. These rhythms are predominantly driven by endogenous
      clocks with a periodicity approximating to one day, i.e. circadian. In mammals,
      the circadian clock governing activity/ rest, neuroendocrine and autonomic
      rhythms lies in the hypothalamus, in the suprachiasmatic nuclei (SCN). Intrinsic
      circadian oscillators are also present in the retina. The SCN "clockwork" is
      based on a cell autonomous, genetically determined mechanism. Mammalian
      homologues of a number of Drosophila genes which encode elements of the fly
      circadian mechanism have recently been identified. In Drosophila, the protein
      products of these genes interact in a negative feedback loop, establishing a
      circadian cycle in gene expression. Characterisation of the roles played by
      putative mammalian clock genes in the SCN, and how the emergent cellular signal
      imposes order over the entire neuraxis, will provide a fundamental contribution
      to our understanding of the molecular basis of behaviour. BioEssays 22:23-31,
      2000.

PMID- 10649288
TI  - The clocks controlling the tide-associated rhythms of intertidal animals.
AB  - The living clock that governs tide-associated organismic rhythms has previously
      been assumed to have a fundamental period of approximately 12.4 h, an interval
      that reflects the average period of the ebb and flow of the tide. But, in 1986,
      marine chronobiologists began to accumulate laboratory results that could not be
      explained by the action of such a clock. Prime among these findings was the
      discovery that, occasionally, one of the two daily peaks in an organism's rhythm
      assumed a different period from its partner. Similar results have since been
      observed in a host of different organisms. These data led to the circalunidian
      clock hypothesis that envisions two basic 24.8 h clocks, coupled together in
      antiphase, as the driving force for these rhythms. There is, however, only a
      slight difference (50 minutes) in running times between a solar-day clock with a
      period of approximately 24 h and a lunar-day clock with a period of approximately
      24.8 h, both of which display "circa" periods that overlap. Here, I postulate
      that the two clocks are fundamentally one and the same. BioEssays 22:32-37, 2000.

PMID- 10649289
TI  - Time measurement and the control of flowering in plants.
AB  - Many plants are adapted to flower at particular times of year, to ensure optimal
      pollination and seed maturation. In these plants flowering is controlled by
      environmental signals that reflect the changing seasons, particularly daylength
      and temperature. The response to daylength varies, so that plants isolated at
      higher latitudes tend to flower in response to long daylengths of spring and
      summer, while plants from lower latitudes avoid the extreme heat of summer by
      responding to short days. Such responses require a mechanism for measuring time,
      and the circadian clock that regulates daily rhythms in behaviour also acts as
      the timer in the measurement of daylength. Plants from high latitudes often also
      show an extreme response to temperature called vernalisation in which flowering
      is repressed until the plant is exposed to winter temperatures for an extended
      time. Genetic approaches in Arabidopsis have identified a number of genes that
      control vernalisation and daylength responses. These genes are described and
      models presented for how daylength might regulate flowering by controlling their
      expression by the circadian clock. BioEssays 22:38-47, 2000.

PMID- 10649290
TI  - clk-1, mitochondria, and physiological rates.
AB  - Mutations in the C. elegans maternal-effect gene clk-1 are highly pleiotropic,
      affecting the duration of diverse developmental and behavioral processes. They
      result in an average slowing of embryonic and post-embryonic development, adult
      rhythmic behaviors, reproduction, and aging.(1) CLK-1 is a highly conserved
      mitochondrial protein,(2,3) but even severe clk-1 mutations affect mitochondrial
      respiration only slightly.(3) Here, we review the evidence supporting the
      regulatory role of clk-1 in physiological timing. We also discuss possible models
      for the action of CLK-1, in particular, one proposing that CLK-1 is involved in
      the coordination of mitochondrial and nuclear function. BioEssays 22:48-56, 2000.

PMID- 10649291
TI  - Egg timers: how is developmental time measured in the early vertebrate embryo?
AB  - Eggs and early embryos appear to be programmed to undertake particular
      developmental decisions at characteristic times, although precisely how these
      decisions are timed is unknown. We discuss the possible roles and interactions
      during early vertebrate development of two broad categories of timers: 1) those
      that involve cyclic or sequential mechanisms, referred to as clocks; and 2) those
      that require an increase or decrease in some factor to a threshold level for
      progression of time, referred to as hourglass timers. It is concluded that both
      clock-like timers linked to various features of the cell cycle and hourglass
      timers are involved in early developmental timing. The possible involvement of
      elements of circadian clock timers is also considered. BioEssays 22:57-63, 2000.

PMID- 10649292
TI  - A cell-intrinsic timer that operates during oligodendrocyte development.
AB  - Multicellular organisms develop on a predictable schedule that depends on both
      cell-intrinsic timers and sequential cell-cell interactions mediated by
      extracellular signals. The interplay between intracellular timers and
      extracellular signals is well illustrated by the development of oligodendrocytes,
      the cells that make the myelin in the vertebrate central nervous system. An
      intrinsic timing mechanism operates in each oligodendrocyte precursor cell to
      limit the length of time the cell divides before terminally differentiating. This
      mechanism consists of two components, a timing component, which depends on the
      mitogen platelet-derived growth factor (PDGF) and measures elapsed time, and an
      effector component, which depends on thyroid hormone and stops cell division and
      initiates differentiation at the appropriate time. The cell-cycle inhibitor
      p27/Kip1 accumulates in the precursor cells as they proliferate and is part of
      both components of the timer. It seems likely that similar timing mechanisms
      operate in other cell lineages. BioEssays 22:64-71, 2000.

PMID- 10649293
TI  - A clock-work somite.
AB  - Somites are transient structures which represent the most overt segmental feature
      of the vertebrate embryo. The strict temporal regulation of somitogenesis is of
      critical developmental importance since many segmental structures adopt a
      periodicity based on that of the somites. Until recently, the mechanisms
      underlying the periodicity of somitogenesis were largely unknown. Based on the
      oscillations of c-hairy1 and lunatic fringe RNA, we now have evidence for an
      intrinsic segmentation clock in presomitic cells. Translation of this temporal
      periodicity into a spatial periodicity, through somite formation, requires Notch
      signaling. While the Hox genes are certainly involved, it remains unknown how the
      metameric vertebrate axis becomes regionalized along the antero-posterior (AP)
      dimension into the occipital, cervical, thoracic, lumbar, and sacral domains. We
      discuss the implications of cell division as a clock mechanism underlying the
      regionalization of somites and their derivatives along the AP axis. Possible
      links between the segmentation clock and axial regionalization are also
      discussed. BioEssays 22:72-83, 2000.

PMID- 10649294
TI  - Modeling the molecular regulatory mechanism of circadian rhythms in Drosophila.
AB  - Thanks to genetic and biochemical advances on the molecular mechanism of
      circadian rhythms in Drosophila, theoretical models closely related to
      experimental observations can be considered for the regulatory mechanism of the
      circadian clock in this organism. Modeling is based on the autoregulatory
      negative feedback exerted by a complex between PER and TIM proteins on the
      expression of per and tim genes. The model predicts the occurrence of sustained
      circadian oscillations in continuous darkness. When incorporating light-induced
      TIM degradation, the model accounts for damping of oscillations in constant
      light, entrainment of the rhythm by light-dark cycles of varying period or
      photoperiod, and phase shifting by light pulses. The model further provides a
      molecular dynamical explanation for the permanent or transient suppression of
      circadian rhythmicity triggered in a variety of organisms by a critical pulse of
      light. Finally, the model shows that to produce a robust rhythm the various clock
      genes must be expressed at the appropriate levels since sustained oscillations
      only occur in a precise range of parameter values. BioEssays 22:84-93, 2000.

PMID- 10649295
TI  - Neuropsychological mechanisms of interval timing behavior.
AB  - Interval timing in the seconds-to-minutes range is believed to underlie a variety
      of complex behaviors in humans and other animals. One of the more interesting
      problems in interval timing is trying to understand how the brain times events
      lasting for minutes with millisecond-based neural processes. Timing models
      proposing the use of coincidence-detection mechanisms (e.g., the detection of
      simultaneous activity across multiple neural inputs) appear to be the most
      compatible with known neural mechanisms. From an evolutionary perspective,
      coincidence detection of neuronal activity may be a fundamental mechanism of
      timing that is expressed across a wide variety of species. BioEssays 22:94-103,
      2000.

PMID- 10649296
TI  - Back-calculating the age-specific incidence of recurrent subclinical Haemophilus
      influenzae type b infection.
AB  - We consider the estimation of an age-specific incidence rate of a subclinical
      Haemophilus influenzae type b (Hib) infection from data recording the ages of
      children with a clinical Hib infection (Hib disease). The model is based on the
      assumption that the probability of being immune to clinical infection is
      determined by the time of the previous immunization caused by a subclinical
      infection, and by the distribution of the duration of immunity. We use a non
      parametric Bayesian intensity model to arrive at smooth estimates of incidence
      rates. The estimated age-specific incidence rate of subclinical Hib infection is
      almost constant which indicates that the observed age-specific pattern of
      clinical Hib infection incidence is mainly due to immunity by either maternally
      derived antibodies or by immunizing subclinical infections. The estimated rate is
      relatively high, corresponding to one immunizing subclinical infection in less
      than two years.

PMID- 10649297
TI  - Joint analysis of HIV and AIDS surveillance data in back-calculation.
AB  - AIDS surveillance data are the main source of information to perform back
      calculation of HIV incidence. We propose a method to incorporate additional
      information gained by linkage with an HIV surveillance system, containing data on
      the time of first positive HIV test. In this paper we generalize an earlier
      method that was developed to use HIV testing data available only for AIDS cases.
      The new method also makes use of cases with an HIV positive test who have not yet
      developed AIDS, typically a substantial proportion of the HIV-infected
      population. Furthermore, we use a more realistic model for the HIV testing rate,
      incorporating dependence on both time since infection and calendar time. The
      method makes use of an EM algorithm with generalized additive model smoothing,
      and is applied to data from Veneto, a region of northern Italy. Our results show
      that HIV incidence in Veneto peaked in the late 1980s, and decreased thereafter.
      Importantly, the HIV incidence estimates based on joint analysis of HIV and AIDS
      surveillance data are more efficient than estimates based on AIDS surveillance
      data alone. Our estimates also show a decreasing trend in the HIV testing rate
      over time, which leads to the conclusion that the interval between HIV infection
      and first positive test has lengthened over time. Furthermore, it is found that
      for infected individuals, the probability of seeking on HIV test is highest soon
      after infection.

PMID- 10649298
TI  - Bootstrap confidence intervals for the sensitivity of a quantitative diagnostic
      test.
AB  - We examine bootstrap approaches to the analysis of the sensitivity of
      quantitative diagnostic test data. Methods exist for inference concerning the
      sensitivity of one or more tests for fixed levels of specificity, taking into
      account the variability in the sensitivity due to variability in the test values
      for normal subjects. However, parametric methods do not adequately account for
      error, particularly when the data are non-normally distributed, and non
      parametric methods have low power. We implement bootstrap methods for confidence
      limits for the sensitivity of a test for a fixed specificity and demonstrate that
      under certain circumstances the bootstrap method gives more accurate confidence
      intervals than do other methods, while it performs at least as well as other
      methods in many standard situations.

PMID- 10649299
TI  - Saddlepoint approximations for small sample logistic regression problems.
AB  - Double saddlepoint approximations provide quick and accurate approximations to
      exact conditional tail probabilities in a variety of situations. This paper
      describes the use of these approximations in two logistic regression problems. An
      investigation of regression analysis of the log-odds ratio in a sequence or set
      of 2x2 tables via simulation studies shows that in practical settings the
      saddlepoint methods closely approximate exact conditional inference. The double
      saddlepoint approximation in the test for trend in a sequence of binomial random
      variates is also shown, via simulation studies, to be an effective approximation
      to exact conditional inference.

PMID- 10649300
TI  - Permutation tests for joinpoint regression with applications to cancer rates.
AB  - The identification of changes in the recent trend is an important issue in the
      analysis of cancer mortality and incidence data. We apply a joinpoint regression
      model to describe such continuous changes and use the grid-search method to fit
      the regression function with unknown joinpoints assuming constant variance and
      uncorrelated errors. We find the number of significant joinpoints by performing
      several permutation tests, each of which has a correct significance level
      asymptotically. Each p-value is found using Monte Carlo methods, and the overall
      asymptotic significance level is maintained through a Bonferroni correction.
      These tests are extended to the situation with non-constant variance to handle
      rates with Poisson variation and possibly autocorrelated errors. The performance
      of these tests are studied via simulations and the tests are applied to U.S.
      prostate cancer incidence and mortality rates.

PMID- 10649301
TI  - Multiple comparisons in carcinogenesis study with right-censored survival data.
AB  - This paper considers the practical problem in animal carcinogenesis experiments
      where several treatment groups are compared with a control group in a one-way
      layout and the observed survival data are subject to random right-censorship.
      Proposed herein are multiple testing procedures based on two-sample weighted
      logrank statistics, each comparing an individual treatment with the control, for
      determining which treatments are more effective than the control. The associated
      p-value of claiming a certain treatment is more effective than the control is
      also discussed. A test-based confidence set for the scale changes between each
      treatment and the control is then obtained. The comparative results of a Monte
      Carlo error rate and power study for small sample sizes are presented. Finally, a
      numerical example involving renal carcinoma in mice demonstrates the feasibility
      of the proposed multiple testing procedures and test-based confidence set.

PMID- 10649302
TI  - On the relative sample size required for multiple comparisons.
AB  - Multiple comparisons are commonly made in epidemiologic and genetic research. How
      to appropriately adjust for multiple comparisons remains a controversial issue.
      This note demonstrates, however, that large increases in the number of
      comparisons has a limited effect on the sample size required to maintain an
      experimentwise alpha-level. In particular, the relative sample size required
      increases only linearly with the logarithm of the number of comparisons made.

PMID- 10649303
TI  - Testing the equality of two dependent kappa statistics.
AB  - Procedures are developed and compared for testing the equality of two dependent
      kappa statistics in the case of two raters and a dichotomous outcome variable.
      Such problems may arise when each of a sample of subjects are rated under two
      distinct settings, and it is of interest to compare the observed levels of inter
      observer and intra-observer agreement. The procedures compared are extensions of
      previously developed procedures for comparing kappa statistics computed from
      independent samples. The results of a Monte Carlo simulation show that adjusting
      for the dependency between samples tends to be worthwhile only if the between
      setting correlation is comparable in magnitude to the within-setting
      correlations. In this case, a goodness-of-fit procedure that takes into account
      the dependency between samples is recommended.

PMID- 10649304
TI  - A semiparametric approach to analysing dose-response data.
AB  - In the analysis of a quantal dose-response experiment with grouped data, the most
      commonly used parametric procedure is logistic regression, commonly referred to
      as 'logit analysis'. The adequacy of the fit by the logistic regression curve is
      tested using the chi-square lack-of-fit test. If the lack-of-fit test is not
      significant, then the logistic model is assumed to be adequate and estimation of
      effective doses and confidence intervals on the effective doses can be made. When
      the tolerance distribution of the dose-response data is not known and cannot be
      assumed by the user, one can use non-parametric methods, such as kernel
      regression or local linear regression, to estimate the dose-response curve,
      effective doses and confidence intervals. This research proposes another
      alternative based on semi-parametric regression to analysing quantal dose
      response data called model-robust quantal regression (MRQR). MRQR linearly
      combines the parametric and non-parametric predictions with the use of a mixing
      parameter. MRQR uses logistic regression as the parametric portion of the model
      and local linear regression as the non-parametric portion of the model. Our
      research has shown that the MRQR procedure can improve the fit of the dose
      response curve by producing narrower confidence intervals for predictions while
      providing improved precision of estimates of the effective doses with respect to
      either logistic or local linear regression results.

PMID- 10649305
TI  - Multiple imputation for simple estimation of the hazard function based on
      interval censored data.
AB  - A data augmentation algorithm is presented for estimating the hazard function and
      pointwise variability intervals based on interval censored data. The algorithm
      extends that proposed by Tanner and Wong for grouped right censored data to
      interval censored data. It applies multiple imputation and local likelihood
      methods to obtain smooth non-parametric estimates for the hazard function. This
      approach considerably simplifies the problem of estimation for interval censored
      data as it transforms it into the more tractable problem of estimation for right
      censored data. The method is illustrated for two real data sets: times to breast
      cosmesis deterioration and times to HIV-1 infection for individuals with
      haemophilia. Simulations are presented to assess the effects of various
      parameters on the estimates and their variances.

PMID- 10649306
TI  - Design, Synthesis, and In Situ Characterization of New Solid Catalysts.
AB  - The precise atomic architecture of the catalytically active center is the central
      topic of the approach presented herein to the design of solid-state catalysts. A
      wide range of new catalysts may be designed that effect regioselective, shape
      selective, and enantioselective conversions, as well as producing high
      performance catalysts for the isomerization and hydrogenation of alkenes and the
      terminal oxidation of alkanes. All the new catalysts described are either
      microporous or mesoporous solids that have the dual advantages of possessing
      large specific surfaces and being amenable to delicate structural and
      compositional variation.

PMID- 10649307
TI  - How Do Charges Travel through DNA?-An Update on a Current Debate.
AB  - The effects of oligonucleotide sequence, base pairing, stacking, and duplex
      microstructure as well as donor-acceptor distance, labeling site, and driving
      force on charge-transfer reactions in DNA are of interest, yet relatively few
      experiments have been performed to address many of these issues. This article
      summarizes recent results on DNA-mediated charge transfer and highlights
      experimental and theoretical issues that are still unanswered or unresolved.

PMID- 10649308
TI  - Tyrosyl-tRNA Synthetase: A Housekeeping Protein and an Attractive Harbinger of
      Cellular Death.
AB  - Cytokine-type activities are observed for the human tyrosyl-tRNA synthetase,
      largely considered as an essential enzyme for protein synthesis, only after
      cleavage into two fragments. These peptide fragments are novel elements in the
      orchestration of the tissue response to a cellular suicide program and should be
      viewed as highly differentiated adaptions of peptide modules with biological
      activity in more than one kind of environment.

PMID- 10649309
TI  - Dynamics of Ligands and Water Molecules in Trinuclear Carboxylate Complexes.
AB  - Inelastic incoherent neutron scattering experiments can be used successfully to
      study the dynamics of ligands and hydrate water molecules. For assignment of the
      observed signals, however, the investigation of samples with different degrees of
      deuteration is necessary. The possible intramolecular coupling of the various
      water bands (OH stretching, H(2)O bending, and H(2)O rocking modes) must be
      reexamined, as shown with the example of a trinuclear chromium acetate complex.

PMID- 10649310
TI  - K
AB  - Tetrahedral framework structures with topologies that show close relationships to
      the feldspar group or to gismondine are formed by the zincoborophosphates
      A[ZnBP(2)O(8)] (see picture). The compounds are readily accessible under mild
      hydrothermal conditions (T(max)=170 degrees C) and are thermally remarkably
      stable (for example, 940 degrees C for A=Cs). Metalloborophosphates are a new
      class of compounds, which are expected to provide access to zeolite-like
      microporous systems.

PMID- 10649311
TI  - The Transmission of the Electronic Character of Guanin-9-yl Drives the Sugar
      Phosphate Backbone Torsions in Guanosine 3',5'-Bisphosphate.
AB  - The intrinsic flexibility of the pentoses in RNA allows dynamic transmission of
      information on the electronic character of the nucleobase to modulate the sugar
      conformation by an interplay of gauche and anomeric effects. This modulation in
      turn steers the phosphate backbone conformation by tuning the 3'-O-P-O(ester)
      anomeric effect, as shown by conformational analysis of EtpGpMe as a function of
      pD. This tunable transmission is stereoelectronic in nature, and operates by
      appropriate overlap between donor and acceptor orbitals (see scheme), which
      causes single-stranded RNA to behave as a molecular wire.

PMID- 10649312
TI  - "Figure Eight" Cyclooctapyrroles: Enantiomeric Separation and Determination of
      the Absolute Configuration of a Binuclear Metal Complex.
AB  - The hypothesized racemate separation of cyclooctapyrroles with chiral figure
      eight conformations-and of metal complexes derived from these ligands-has been
      realized. The cyclooctapyrrole 1 (as hexadecaethyl derivative), which according
      to NMR analysis exhibits restricted mobility, and its binuclear palladium and
      copper complexes could be separated into stable enantiomers by preparative
      chromatography on a chiral phase. In the case of the palladium complex and the
      free ligand 1 it was also possible to determine the absolute configuration of the
      enantiomers.

PMID- 10649313
TI  - Tightening the Belt on Polymerases: Evaluating the Physical Constraints on Enzyme
      Substrate Size.
AB  - To test the limits of polymerase enzyme activity on geometrically constrained
      DNAs, four very small synthetic circular DNAs were constructed by using newly
      developed methods. Surprisingly, even a 13-nucleotide circular DNA (1) can be
      copied successfully by both DNA and RNA polymerases, despite the very small
      diameter and large degree of distortion in this synthetic DNA. The picture shows
      models to indicate the relative sizes of 1 and the Klenow fragment of the DNA
      polymerase I from E. coli.

PMID- 10649314
TI  - Tetrametallic Reduction of Dinitrogen: Formation of a Tetranuclear Samarium
      Dinitrogen Complex.
AB  - The cooperative attack of four (dipyrromethanyl)Sm(II) units on dinitrogen
      resulted in a novel tetranuclear samarium dinitrogen complex (shown
      schematically). The presence of halogen atoms inhibited reactivity with
      dinitrogen through the assembly of divalent samarium clusters.
      dipyrr=diphenylmethyldipyrrolide dianion.

PMID- 10649315
TI  - A Paramagnetic Diniobium Complex with a Very Short Nb-Nb Distance: Evidence for a
      Pseudo Nb-Nb Triple Bond?
AB  - In spite of the short Nb-Nb distance (2.268 A) and the presumable existence of an
      Nb identical withNb bond, the paddle-wheel-shaped diniobium(II) complex 1 is
      paramagnetic. Theoretical calculations indicate that the presence of LiCl
      moieties on the intermetallic axis lowers the Nb-Nb bond order and is responsible
      for the observed paramagnetism.

PMID- 10649316
TI  - Towards the Total Synthesis of Saponaceolides: Synthesis of cis-2,4-Disubstituted
      3,3-Dimethylmethylenecyclohexanes.
AB  - Controlling diastereoselectivity by metal coordination: In the case of 3,3
      dimethylmethylenecyclohexanes 2-a structural unit present in many interesting
      natural products-the thermodynamically less stable cis-2,4-disubstituted
      compounds become available through a cyclization event wherein the configuration
      is determined by a carbopalladation step. Both the cycloisomerization of 1,7
      enynes 1 and the intramolecular Heck-type reaction of compounds of type 3 provide
      the cis product as the major product.

PMID- 10649317
TI  - Total Synthesis of (+)-Saponaceolide B.
AB  - Coupling of three fragments results in the first total synthesis of a
      saponaceolide (see scheme). The first fragment, the spiroketal portion, is formed
      from two moieties, one derived from geraniol and the other from allyl malonate. A
      sulfone alkylation-desulfonylation sequence joins the spiroketal portion to the
      methylene-3,3-dimethylcyclohexane unit. The subsequent stereoselective Wittig
      reaction attaches the final piece to complete the synthesis of saponaceolide B
      (1), one of the most biologically active members of this family.

PMID- 10649318
TI  - Teaching Old Indicators New Tricks: A Colorimetric Chemosensing Ensemble for
      Tartrate/Malate in Beverages.
AB  - The competition between tartrate and a common indicator (1) for a synthetic host
      (2) has been used to quantitate tartrate in beverages derived from grapes. The
      approach demonstrates a general method for the development of colorimetric assays
      in highly competitive media.

PMID- 10649319
TI  - New Efficient Multicomponent Reactions with C-C Coupling for Combinatorial
      Application in Liquid and on Solid Phase.
AB  - Up to nine C-C bonds are formed selectively from up to seven components starting
      from an alkene, a haloarene, and a dienophile [Eq. (1)]. A comparison of liquid-
      and solid-phase reactions reveals a surprising superiority of the solid-phase
      reaction.

PMID- 10649320
TI  - Incorporation of Magnetic Nanoparticles in New Hybrid Networks Based on
      Heteropolyanions and Polyacrylamide.
AB  - The copolymerization of acrylamide with the tetrafunctionalized polyanion [gamma
      SiW(10)O(36)(RSiO)(4)](4-) (R=C(3)H(6)OC(O)C(Me)=CH(2)), which acts as a cross
      linker, is performed in an aqueous dispersion of maghemite (gamma-Fe(2)O(3))
      nanoparticles. It results in a magnetic hybrid hydrogel with superabsorption
      properties (see scheme). The magnetic properties of the nanoparticles enables
      their mobility inside the network to be estimated and their release during the
      swelling of the hydrogel to be observed.

PMID- 10649321
TI  - Friedel-Crafts Alkylation of Alkenes: Ethylaluminum Sesquichloride Induced
      Alkylations with Alkyl Chloroformates.
AB  - The formal addition of propane to nonactivated double bonds can be achieved with
      isopropyl chloroformate (2) in the presence of Et(3)Al(2)Cl(3). Thus, a 1:1
      mixture of 10-isopropyloctadecanoic acid (3) and the 9-regioisomer is formed from
      oleic acid (1). The reaction may also be carried out with 1-alkenes by the
      addition of triethylsilane as a hydride donor.

PMID- 10649322
TI  - van't Hoff-Le Bel Stranger: Formation of a Phosphonium Cation with a Planar
      Tetracoordinate Phosphorus Atom.
AB  - A novel intriguing type of coordination mode in phosphorus chemistry has been
      established that is of fundamental interest in the understanding of chemical
      bonding. Besides the synthesis of the first planar phosphonium cation PR(4)(+) 1
      by a surprisingly simple metathesis reaction, a potentially general experimental
      method that reaches the seemingly impossible high-energy region of basic
      molecular and isoelectronic ER(4) systems (E=B(-), C, N(+), Al(-), Si, P(+)) is
      provided.

PMID- 10649323
TI  - Lectin-Mediated Drug Targeting: Discrimination of Carbohydrate-Mediated Cellular
      Uptake between Tumor and Liver Cells with Neoglycoconjugates Carrying Fucose
      Epitopes Regioselectively Modified in the 3-Position.
AB  - The circumvention of efficient "carbohydrate traps" in the liver is required for
      targeting glycoconjugates on tumor cells. As shown in the model system of bovine
      serum albumin (BSA) conjugates, the nature of R(1)-R(3) of the fucose epitope
      plays an important role in the discrimination of cellular uptake between tumor
      and liver cells as well as in the cytotoxic activity.

PMID- 10649324
TI  - Rolling Loop Scan: An Approach Featuring Ring-Closing Metathesis for Generating
      Libraries of Peptides with Molecular Shapes Mimicking Bioactive Conformations or
      Local Folding of Peptides and Proteins.
AB  - Libraries of loop-containing peptides (such as the one shown schematically) can
      be prepared from bis-N-alkylated peptides by ring-closing metathesis. In a
      general solid-phase procedure the peptides are accessible by site-specific N
      alkylation. Since the amino acid side chains are not involved in cyclization,
      they remain available for interaction with, for example, a receptor.

PMID- 10649325
TI  - P(2)O, the Phosphorus Analogue of N(2)O, as a Ligand in a Tetranuclear Cluster.
AB  - The first complex to contain the N(2)O analogue P(2)O as a ligand is the
      tetranuclear cluster [{Cp*Fe}{Cp"Co}(3)(P(2)O)(PO)(P(2))] (1), which is formed by
      the oxidation in air of [{Cp*Fe}{Cp"Co}(2)(P(4))(P)] (Cp*=C(5)Me(5); Cp"=1,3
      tBu(2)C(5)H(3)). The bent P(2)O ligand is doubly side-on as well as terminally
      coordinated (sigma,sigma,pi,pi) to the four metal atoms (see picture). In
      addition, 1 contains a PO and a P(2) ligand.

PMID- 10649326
TI  - Rhodium-Induced Selective B(3)/B(6)-Disubstitution of ortho-Carborane-1,2
      dithiolate.
AB  - The various reactive sites in the 16 e complex 1 invite addition reactions with
      alkynes. After addition of 2 to one of the Rh-S bonds, B-H activation takes place
      which finally leads to the complex 3, in which a B(3)/B(6)-disubstituted o
      carborane cage is present for the first time.

PMID- 10649327
TI  - Synthesis and Characterization of InAs/InP and InAs/CdSe Core/Shell Nanocrystals.
AB  - The effect of the outer surface of core/shell nanocrystals on the fluorescence
      quantum yield was observed for InAs/InP and InAs/CdSe core/shells (see picture).
      For InAs/CdSe we observed substantial enhancement of the fluorescence quantum
      yield compared to the InAs core, and up to two times larger than the laser dye IR
      140. Such core/shell nanocrystals have potential use as biological fluorescent
      markers in the near IR spectral range.

PMID- 10649328
TI  - Activation of
AB  - Reversible C(6)F(5) transfer takes place between the boron centers in the anion
      formed by methide abstraction from [MeZr{N(SiMe(3))(2)}(3)] or [Cp(2)ZrMe(2)]
      (L(n)M-CH(3) in the reaction scheme) by the perfluorinated diborane 1. The
      solution chemistry of the metallocenium ion pairs formed from 1 and
      [Cp(2)ZrMe(2)] is correlated with the observed ethylene polymerization behavior
      of 1 in comparison to the monoborane B(C(6)F(5))(3), the related diborane 1,2
      C(6)H(4)[B(C(6)F(5))(2)](2), and the 9,10-diboraanthracene compound 9,10
      (C(6)F(5))(2)C(12)B(2)F(8).

PMID- 10649329
TI  - Titanium-Thiolate-Aluminum-Carbide Complexes by Multiple C-H Bond Activation.
AB  - All three C-H bonds of a methyl group are activated in the reaction of
      [Cp(iPr(3)PN)Ti(SR)(2)] with AlMe(3) [Eq. (1)]. The Ti-Al-carbide clusters formed
      contain a severely distorted tetrahedral carbide carbon atom with a relatively
      short bond to Ti, which is attributed to a relative increase in the Lewis acidity
      of the Ti center as a result of the interaction of the S and N donors with Al.

PMID- 10649330
TI  - Enantioselective Addition of Allylic Trimethoxysilanes to Aldehydes Catalyzed by
      p-Tol-BINAP small middle dotAgF.
AB  - Catalytic asymmetric allylation of aldehydes with allylic trimethoxysilanes was
      achieved with the p-Tol-BINAP small middle dotAgF complex as catalyst [Eq. (a); p
      Tol-BINAP=2,2'-bis(di-p-tolylphosphanyl)-1,1'-binaphthyl)]. High anti and
      enantioselectivities were obtained in the reaction with crotyltrimethoxysilane,
      irrespective of the configuration at the double bond.

PMID- 10649331
TI  - Membrane Anchoring and Intervesicle Transfer of a Derivative of the Antibiotic
      Moenomycin A.
AB  - The anchoring of moenomycin A (1) to the bacterial cell cytoplasmic membrane is
      essential for its biological activity. The first details of the strength of this
      interaction and the kinetics of the diffusion-mediated intervesicle transfer have
      been obtained by means of fluorescence spectroscopic methods using a coumarin
      labeled moenomycin A derivative.

PMID- 10649332
TI  - Novel Polymeric Carbonylhaloruthenium(I) Polyanions: Rational Design and Self
      Reorganization in the Presence of CO(2) and H(2)O.
AB  - We just need to mix [Ru(CO)(3)Cl(2)(thf)] with methanolic NEt(4)OH-nature will do
      the rest: The unsaturated fragments thus generated spontaneously polymerize with
      production of CO(2) and H(2)O, which combine to give the carbonate ligands of the
      ruthena-crown species obtained (shown schematically). The carbonate groups,
      rarely seen in ruthenium carbonyl complexes, are responsible for the observed
      annulation, and hold consecutive Ru dimers together by acting as bridging and
      doubly chelating ligands.

PMID- 10649333
TI  - Asymmetric Synthesis of the Nakijiquinones-Selective Inhibitors of the Her-2/Neu
      Protooncogene.
AB  - A Wieland-Miescher type ketone and a tetramethoxyaryl derivative are the key
      building blocks for the enantioselective total synthesis of nakijiquinone C (1).
      The nakijiquinones are the only natural products known that selectively inhibit
      the Her-2/Neu tyrosine kinase, a protooncogene product that is vastly
      overexpressed in about 30 % of primary breast, ovary, and gastric carcinomas.

PMID- 10649334
TI  - Stepwise Replication of a Troger's Base Analogue.
AB  - Redox-controlled covalent templating and macrocyclization underlie a novel scheme
      for stepwise exponential self-replication. This process has been demonstrated by
      using Troger's base analogue 1 as the template.

PMID- 10649335
TI  - Selective Homogeneous Palladium(0)-Catalyzed Hydrogenation of Alkynes to (Z)
      Alkenes.
AB  - Zero-valent palladium precatalysts containing rigid bidentate
      bis(arylimino)acenaphthene ligands (shown schematically) facilitate the highly
      stereoselective homogeneous catalytic hydrogenation of alkynes to (Z)-alkenes.
      Internal, terminal, aryl-substituted, and cyclic alkynes are suitable substrates,
      as are some enynes, which are chemoselectively hydrogenated to dienes. E=CO(2)Me;
      R(1), R(2)=4-OCH(3), 4-CH(3), 2,6-(CH(3))(2).

PMID- 10649336
TI  - Self- and Directed Assembly of Hexaruthenium Macrocycles.
AB  - Rigid terpyridine-based building blocks allow easy access to large
      polymetallomacrocycles (see picture) through a self-assembly process. Such routes
      are envisioned to provide one-step methods to higher order motifs and facilitate
      the creation of precisely organized, metal-based networks for new energy storage
      devices.

PMID- 10649337
TI  - Synthesis of the First
AB  - A "true" allenophane with several rings and allenic bridges was synthesized. The
      key step in the preparation of 1 was the cyclization to a 28-membered macrocycle
      (52 % yield) starting from a linear molecule, which already contains three of the
      four allene units.

PMID- 10649338
TI  - [Pt]
AB  - The intermediacy of CO/NO substitution in the condensation of [Pt(19)(CO)(22)](4
      ) into [Pt(38)(CO)(44)](2-) (structure shown) has been demonstrated. Two high
      nuclearity carbonyl metal clusters, including one with an unprecedented nitrosyl
      ligand, have been synthesized and structurally characterized.

PMID- 10649339
TI  - The Electrophilic Behavior of Stable Phosphanylcarbenes Towards Phosphorus Lone
      Pairs.
AB  - As expected for a singlet carbene, the stable phosphanylsilylcarbene 1 possesses
      an accessible vacant orbital, as shown by reactions with Lewis bases such as
      phosphanes and a bimetallic complex containing a side-on-coordinated full
      blockC:full blockP identical withPfull blockC:full block moiety (see the reaction
      scheme). R=cHex(2)N.

PMID- 10649340
TI  - A Copper(I) Bis-phenanthroline Complex Buried in Fullerene-Functionalized
      Dendritic Black Boxes.
AB  - Virtual inaccessibility to external contact was revealed by electrochemical
      investigations for a bis(1,10-phenanthroline)copper(I) core embedded in
      dendrimers with up to 16 peripheral fullerene units (shown schematically). With
      increasing numbers of fullerene units, less and less light is available to the
      core, and the small quantity of light energy that reaches the central Cu(I)
      complex is returned to the external fullerenes by energy transfer-the central
      core is buried in a dendritic black box.

PMID- 10649341
TI  - 2-Phenylquinoline-Carbohydrate Hybrids: Molecular Design, Chemical Synthesis, and
      Evaluation of a New Family of Light-Activatable DNA-Cleaving Agents.
AB  - Artificial intercalator-carbohydrate hybrids such as that shown in the scheme
      cleave DNA at the site of guanine on irradiation with UV light with a long
      wavelength. The hybrids also exhibit strong cytotoxicity when irradiated. The
      hybrid system is very important for DNA cleavage, and the cytotoxic activity
      correlates with the DNA-cleaving capacity

PMID- 10649342
TI  - Novel, Spongelike Ruthenium Particles of Controllable Size Stabilized Only by
      Organic Solvents.
AB  - Soluble ruthenium nanoparticles of uniform size (see picture) with a porous
      spongelike structure were obtained by the reaction of [Ru(C(8)H(10))(C(8)H(12))]
      with H(2) in methanol or THF/methanol. The particle size can be controlled in the
      range 15-100 nm by varying the MeOH/THF ratio. The particles catalyze benzene
      hydrogenation without modification of their size or structure. Their formation is
      proposed to occur in the droplets of a nanosized emulsion, which act as
      nanoreactors.

PMID- 10649343
TI  - Broadening the Aldolase Catalytic Antibody Repertoire by Combining Reactive
      Immunization and Transition State Theory: New Enantio- and
      Diastereoselectivities.
AB  - Nine efficient aldolase antibodies were generated by using hapten 1. This hapten
      unites reactive immunization and the transition state analogue approach in a
      single molecule. Characterization of two of these antibodies reveals that they
      are highly proficient (up to 1000-fold better than any other antibody catalyst)
      and enantioselective catalysts for aldol and retro-aldol reactions and exhibit
      enantio- and diastereoselectivities opposite to that of antibody 38C2.

PMID- 10649344
TI  - Enantioselective
AB  - Even with only a catalytic amount of chiral bis(dihydrooxazole) 1 as external
      ligand, the rearrangement of benzyl ethers to alcohols [Eq. (1)] proceeds with
      high enantioselectivity (over 60 % ee). This reaction represents the first
      example of an enantioselective [1,2] Wittig rearrangement.

PMID- 10649345
TI  - The Design of Leadlike Combinatorial Libraries.
AB  - The optimization of low-potency leads into drugs is often accompanied by an
      increase in molecular weight (M(r)) and lipophilicity, as a consequence of
      affinity enhancement. Hits with affinity at uM levels discovered by screening
      leadlike libraries allow scope for this optimization process, as shown
      schematically by the distributions of M(r) for a leadlike library (1), oral drugs
      (2), and a typical combinatorial chemistry library (3). y=percentage with a
      particular molecular weight.

PMID- 10649346
TI  - Template-Mediated Synthesis of Polycyclic Aromatic Hydrocarbons:
      Cyclodehydrogenation and Planarization of a Hexaphenylbenzene Derivative at a
      Copper Surface.
AB  - The deposition of polycyclic aromatic hydrocarbons on substrate surfaces is a key
      step for using such disklike molecules in nanoelectronic devices. An alternative
      to the (frequently problematic) preparation by evaporation or deposition from
      solution is to use the substrate surface as a template for the planarization that
      accompanies the cyclodehydrogenation (see picture).

PMID- 10649347
TI  - Fluorescence Detection from Single Dendrimers with Multiple Chromophores.
AB  - The differences in the fluorescence behavior of a polyphenylene dendrimer with
      eight peryleneimides chromophores (1) and a single hexaphenylperyleneimide
      chromophore have been investigated at a single-molecule level through the
      combination of ultrasensitive fluorescence detection and microscopy.

PMID- 10649348
TI  - Life at the End of the Chromosome: Telomeres and Telomerase.
AB  - Telomerase, the enzyme that replicates the ends of linear chromosomes, is
      implicated in cellular aging and in cancer. The molecular components that form
      the catalytic core of this ribonucleoprotein enzyme (a section of the active site
      with bound substrates is depicted) have recently been identified in multiple
      organisms, including humans. The stage is now set for chemists to develop
      telomerase inhibitors, which hold promise as cancer chemotherapeutic agents.

PMID- 10649349
TI  - The Art and Science of Total Synthesis at the Dawn of the Twenty-First Century.
AB  - A new millenium has begun-grounds enough to question the present state of the
      total synthesis of natural products. In this review we answer this question by
      tracing the evolution of this fine art and science from its birth to the present
      time. This retrospective on total synthesis should serve to demonstrate how far
      we have come, yet show that the science of total synthesis is still in its
      infancy.

PMID- 10649350
TI  - Ferrocene: Ironclad History or Rashomon Tale?
AB  - What really happened? To recount a pivotal 20th century chemical discovery, the
      assignment of its structure to ferrocene, ain't easy! One might have thought that
      telling the story would be straightforward, from published papers and
      correspondence with some of their authors. Not so. One emerges with a good bit of
      sympathy for historians of science-who did just what and why is pretty hard to
      determine, even when less than fifty years have elapsed.

PMID- 10649351
TI  - Thermochemical Data of Organic Ions Obtained from Investigations in the More or
      Less "Diluted" Gas Phase.
AB  - How is a proton bound to an arene, how mobile is it in such a complex, and how
      much energy is required to remove it-these questions have been of fundamental
      interest in physical organic chemistry for half a century. The experimental
      determination of quantitative thermochemical data of organic elementary processes
      in the gas phase is discussed for recent examples, such as the alpha
      acidification of tertiary amines by complexation with boranes (see reaction) and
      the "local" C(alpha)-H acidities of alpha,alpha,alpha-trifluoromethylbenzene and
      higher analogues.

PMID- 10649352
TI  - "Simple" Carbonyls of Ruthenium: New Avenues from the Hieber Base Reaction.
AB  - A witches brew is an apt description of the mixture of carbonyl chlorides of
      ruthenium(II), which arise from the carbonylation of alcoholic solutions of
      commercially available hydrated ruthenium chloride "RuCl(3) small middle
      dotH(2)O". Recent studies by Lavigne et al. on [RuCl(2)COOH(CO)(2)](-), one of
      the key compounds in these catalytic "broths", have established that its
      formation is highly dependent on the conditions and the hydroxide source, and
      that the role of the chloride coligand is far from innocent. Related halide-free
      chemistry by Fachinetti et al., however, has revealed that there are intriguing
      and recurrent parallels between the two systems.

PMID- 10649353
TI  - Resorcarene-Based Nanoarchitectures: Metal-Directed Assembly of a Molecular Loop
      and Tetrahedron.
AB  - Large cavities and portals are present in the nanoscale molecular architectures
      formed from dithiocarbamate-functionalized resorcarene ligands and zinc(II) or
      copper(III) ions. With Zn(II) a molecular loop based on a triangle of resorcarene
      cups is prepared-the cavity is circular (shown on the left). A molecular cage
      based on a distorted tetrahedron of four resorcarene ligands assembled by eight
      Cu(III) ions contains triangular-shaped portals suitable for guest passage (shown
      on the right).

PMID- 10649354
TI  - Carbohydrates Exhibit a Distinct Preferential Solvation Pattern in Binary Aqueous
      Solvent Mixtures.
AB  - Molecular dynamics simulations reveal the entire solvation shell around a model
      disaccharide dissolved in the binary 1:3 molar mixture of dimethyl sulfoxide and
      water becomes distinctly structured (see drawing). Such preferential solvation is
      due to the large number of hydroxyl groups and the rich network of hydrogen bonds
      of a disaccharide formed with the solvent.

PMID- 10649355
TI  - Thermoregulated Optical Properties of Peptidic Pseudorotaxanes.
AB  - Natural peptide spine and artificial crown ether are blended together to form a
      hybrid structure. A dicationic benzylammonium guest threads through the crown
      ether pendants and the resulting noncovalent, self-assembled pseudorotaxane
      complex, shown schematically in the picture, is both stable and has optical
      properties dependant on temperature.

PMID- 10649356
TI  - Application of Combinatorial Procedures in the Search for Serine-Protease-Like
      Activity with Focus on the Acyl Transfer Step.
AB  - Recursive deconvolution of a 729-membered peptide library has identified three
      active sequences, in which both Ser and His are present in one of the two
      tripeptidic chains generated on a steroidal scaffold (see structural formula),
      for the cleavage of an activated p-nitrophenyl ester. This combinatorial approach
      aims at searching for serine-protease-like activity.

PMID- 10649357
TI  - A Self-Complexing
AB  - A supramolecular homodimer is formed in solution and in the solid state by a self
      complementary [2]catenane incorporating a 1,5-dioxynaphthalene-based macrocyclic
      polyether interlocked with a bipyridinium-based tetracationic cyclophane (shown
      schematically). This unique example of self-recognition is the result of a
      combination of cooperative pi small middle dot small middle dot small middle
      dotpi and C-H small middle dot small middle dot small middle dotpi interactions.

PMID- 10649358
TI  - X-Ray, Molecular Diffusion, and NOESY NMR Studies of Chiral, Tetranuclear Cu(I)
      Catalysts Based on Monodentate Thiol Analogues of TADDOL.
AB  - The new, stable, chiral thiol-TADDOL Cu(I) catalysts 1 (X=OH, OMe, NMe(2)) reveal
      an unexpected monodentate complexation mode, both in solution and in the solid
      state. For the first time, the aggregation state of organocopper complexes has
      been determined by NMR diffusion measurements. NOESY NMR data on model isocyanide
      Cu complexes reveal a different conformation of the TADDOL moiety as a function
      of the second potential donor group. TADDOL=alpha,alpha,alpha',alpha'-tetraaryl
      2,2-dimethyl-1,3-dioxolane-4,5-dimethanol.

PMID- 10649359
TI  - Acetyl Substitution of the O-Specific Caryan from the Lipopolysaccharide of
      Pseudomonas (Burkholderia) caryophylli Leads to a Block Pattern.
AB  - An exceptionally large repeating unit has been proposed for one of the two O
      specific polysaccharides of the lipopolysaccharide from Pseudomonas
      (Burkholderia) caryophylli, which is a homopolymer of the sugar caryose. This
      proposal is based on the unusual acetylation pattern of the carbohydrate (shown
      in the picture), as determined from the presence of eight independent spin
      systems observed by NMR spectroscopy. A=acetylated, D=non-acetylated caryose
      monomer.

PMID- 10649361
TI  - Immobilization of TADDOL with a High Degree of Loading on Porous Silica Gel and
      First Applications in Enantioselective Catalysis.
AB  - The versatile TADDOL moiety has been immobilized for the first time on an
      inorganic support (highly porous silica gel). This gives access to Ti - Lewis
      acids (see picture), which turn out to be very efficient in two standard
      enantioselective reactions. X=OiPr, OTos.

PMID- 10649360
TI  - Anchoring of Functional Dye Molecules in MCM-41 by Microwave-Assisted
      Hydrothermal Cocondensation.
AB  - Covalent anchoring of functional dyes in the pores of a mesoporous silicate host
      Si-MCM-41 (shown in the picture) is achieved with the microwave-assisted
      cocondensation presented here. The short reaction time (20 min) ensures that no
      dye degrades during the hydrothermal synthesis.

PMID- 10649362
TI  - Phosphane-Free Palladium-Catalyzed Coupling Reactions: The Decisive Role of Pd
      Nanoparticles.
AB  - Nanosized palladium colloids, generated in situ by reduction of Pd(II) to Pd(0)
      [Eq. (a)], are involved in the catalysis of phosphane-free Heck and Suzuki
      reactions with simple palladium salts such as PdCl(2) or Pd(OAc)(2), as
      demonstrated by transmission electron microscopic investigations.

PMID- 10649363
TI  - The Tetrakis(carbonyl)dioxoosmium(VI) Cation: trans-
AB  - The first carbonyl compound of a transition metal in the oxidation state +6 was
      obtained by reductive carbonylation of OsO(4) in SbF(5). Through the use of
      extensive IR, NMR, and UV/Vis spectroscopic studies as well as density functional
      calculations it was determined that the trans-[OsO(2)(CO)(4)](2+) cation adopts
      the octahedral structure shown in the picture with trans oxygen atoms.

PMID- 10649364
TI  - A Facile Route to Group 13 Difluorodiorganometalates:
AB  - A facile synthesis utilizing tetra-n-butylammonium hydrogen difluoride and Group
      13 alkyl compounds leads to the soluble salts 1 - 4. Compound 1 is the smallest
      difluoro-diorganoaluminate so far characterized. The corresponding gallium and
      indium derivatives 3 and 4 are not sensitive to moisture.

PMID- 10649365
TI  - Palladium-Catalyzed Intermolecular Controlled Insertion of Benzyne-Benzyne-Alkene
      and Benzyne-Alkyne-Alkene-Synthesis of Phenanthrene and Naphthalene Derivatives.
AB  - Aryne reagents, unlike alkynes, undergo insertion by allyl palladium complexes.
      The verification of the conversion described here is shown using Equation (1) as
      an example. The reaction proceeds in a few hours in refluxing acetonitrile to
      give the phenanthrene derivative in up to 71 % yield.

PMID- 10649366
TI  - The "Dendritic Effect" in Homogeneous Catalysis with Carbosilane-Supported
      Arylnickel(II) Catalysts: Observation of Active-Site Proximity Effects in Atom
      Transfer Radical Addition.
AB  - Advantages of homo- and heterogeneous catalysts are united in metallodendritic
      molecules where nickel-based catalysts are bound to carbosilane dendrimers. The
      first direct indication of a "dendritic effect" in the redox catalysis behavior
      is described: variation of the dendrimer support controls the proximity of the
      Ni(II) centers, which in turn controls catalytic activity. Catalyst deactivation,
      by means of Ni(III) formation, can be avoided by a larger separation of the
      Ni(II) centers (see picture).

PMID- 10649367
TI  - Aluminum Bis(trifluoromethylsulfonyl)amides: New Highly Efficient and Remarkably
      Versatile Catalysts for C - C Bond Formation Reactions.
AB  - Superacid-derived aluminum catalysts R(2)AlNTf(2) (2 - 5 mol%) are highly
      efficient and versatile and are suitable promoters for the allylation and
      pentadienylation of aldehydes, aldol reactions, aldol cross-coupling of ketones,
      and Michael additions (several products are shown). Furthermore, they can be
      converted into chemoselective Lewis acids. Tf=trifluoromethanesulfonyl.

PMID- 10649368
TI  - Ordered Two-Dimensional Monolayers of Au(55) Clusters.
AB  - Simply dipping polyethyleneimine-modified surfaces into aqueous solutions of acid
      functionalized Au(55) clusters generates two-dimensional hexagonal and cubic
      arrangements of the clusters. The picture shows the transmission electron
      micrograph of the cubic arrangement; the bar length corrsponds to 10 nm.

PMID- 10649369
TI  - Controlling Electronic Communication in Ethynylated-Polypyridine Metal Complexes.
AB  - By introduction of a naphthalene subunit in the middle of a butadiynylene spacer
      the triplet lifetime of the ruthenium chromophore in RR is prolongated to 475 ns.
      By increasing laser intensities the two Ru-terpy terminals are simultaneously
      promoted to the triplet state, and triplet - triplet annihilation occurs. In
      contrast, in the mixed Ru/Os complex (RO) the long inherent triplet lifetime of
      the Os-terpy fragment facilitates reverse triplet energy transfer.
      terpy=bis(2,2':6',2"-terpyridine).

PMID- 10649370
TI  - [Ti]
AB  - Tridentate binding of BH(4)(-) to a zero-valent metal center was found for the
      first time in [Ti(CO)(4)(eta(3)-BH(4))](-) (shown in the picture), which was
      obtained from the reaction of the carbonyl metalate anion [Ti(CO)(6)](2-) with
      BH(3) small middle dotTHF. Displacement of the unusually labile BH(4)(-) anion by
      a pyrrolyl anion provided the first metal(0) pyrrolyl complex [Ti(CO)(4)(eta(5)
      C(4)H(4)N)](-).

PMID- 10649371
TI  - A Metamagnetic Two-Dimensional Molecular Material with Nickel(II) and Azide.
AB  - Bridging azido ligands transmit both ferro- and antiferromagnetic interactions.
      The sheetlike structured complex [Ni(u-N(3))(2)(N,N-Et(2)-N'-Me-en)](n) (see
      picture) exhibits a range of magnetic behaviors at low temperature. Short-range
      ferromagnetic and three-dimensional antiferromagnetic ordering compete, giving
      metamagnetic behaviors. N,N-Et(2)-N'-Me-en=N,N-diethyl-N'-methylethylenediamine.

PMID- 10649372
TI  - Bis-Capsules: Cooperative Reversible Encapsulation of Two Molecules in Adjacent
      Separate Chambers.
AB  - Unprecedented communication takes place between guests G that are reversibly
      encapsulated in adjacent, but physically separate, chambers of a side-to-side bis
      capsule (shown schematically). This was shown by neighbor-dependent NMR chemical
      shifts of the identical or nonidentical guest molecules. Furthermore, no 1:1 host
      - guest species is formed.

PMID- 10649373
TI  - A Two-Step Spin Crossover in
AB  - Measurement of magnetic susceptibility with temperature of a powdered iron(III)
      catecholate complex clearly indicated a two-step spin-crossover process S=(1/2)<-
      >S=5/2. The picture shows the plot of chi(M)T against temperature.

PMID- 10649374
TI  - O-H small middle dot small middle dot small middle dotPt(II): Hydrogen Bond with
      a Strong Dispersion Component.
AB  - An MP2 ab initio study of the interaction between a H(2)O molecule and trans
      [Pt(OH)(2)(NH(3))(2)] revealed a HO-H small middle dot small middle dot small
      middle dotPt(II) hydrogen bond (see picture) with a strong dispersion component
      (ca. 4 kcal mol(-1)). This dispersion interaction is independent of the charge on
      the complex and is likely to be ubiquitous in aqueous solutions of Pt(II)
      complexes.

PMID- 10649375
TI  - Investigations of Thin Films with Amphiphilic Dendrimers Bearing Peripheral
      Fullerene Subunits.
AB  - In spite of a molecular mass of 7704.6 g mol(-1), third-generation compound G3
      (shown schematically; Z=C(8)H(17)) is able to form stable Langmuir films. In a
      systematic study, the amphiphilic properties of the corresponding dendrimers of
      first (G1) and second generation (G2), with one and two peripheral fullerene
      units, respectively, were investigated and a model could be proposed for the
      multilayer films obtained from G1.

PMID- 10649376
TI  - Acetamidoglycosylation with Glycal Donors: A One-Pot Glycosidic Coupling with
      Direct Installation of the Natural C(2)-N-Acetylamino Functionality.
AB  - Nitrogen transfer to glycals: A new method for direct C2-aza-glycosylation with
      glycal donors has been developed (see scheme), employing the new reagent
      combination of thianthrene-S-oxide and trifluoroacetic anhydride for glycal
      activation, in an overall one-pot procedure.

PMID- 10649377
TI  - [{Pt]
AB  - Prolonged evacuation of [{Pt(CO)(3)}(2)](2+) (1), the first homoleptic,
      dinuclear, cationic platinum(I) carbonyl complex, results in reversible
      disproportionation. Complex 1 was formed by dissolution of PtO(2) in concentrated
      H(2)SO(4) under an atmosphere of CO [Eq. (a)], and completely characterized by
      NMR ((13)C, (195)Pt), IR, and Raman spectroscopy.

PMID- 10649378
TI  - Enantioselective Total Synthesis of Epothilone A Using Multifunctional Asymmetric
      Catalyses.
AB  - A catalytic version has now been developed for the enantioselective total
      synthesis of epothilone A (1). The key is the use of multifunctional asymmetric
      catalyses for a direct aldol reaction and cyanosilylation. This successful
      approach demonstrated the usefulness of these reactions for the catalytic
      asymmetric synthesis of complex molecules.

PMID- 10649379
TI  - Enantioselective Construction of Vicinal Stereogenic Quaternary Centers by
      Dialkylation: Practical Total Syntheses of (+)- and meso-Chimonanthine.
AB  - All three stereoisomers of the hexacyclic 3a,3a'-bispyrrolidino[2,3-b]indoline
      moiety found in complex indole alkaloids can be prepared, as illustrated by total
      syntheses of meso-chimonanthine (1) and (+)-chimonanthine (2). A rare example of
      high diastereoselectivity arising from the combination of a prostereogenic
      enolate with a chiral electrophile containing a sp(3) carbon atom is the key
      feature of the asymmetric synthesis of the C(2) stereoisomer.

PMID- 10649380
TI  - How Strong Is the Coordination Bond between a Histidine Tag and Ni -
      Nitrilotriacetate? An Experiment of Mechanochemistry on Single Molecules.
AB  - Isolation of a His-tagged protein by means of a Ni - nitrilotriacetate
      functionalized chromatographic matrix or biosensor was simulated in a single
      molecule experiment, and the mechanochemistry-that is, the interplay between
      mechanical and chemical forces (shown schematically)-was studied with a scanning
      force microscope.

PMID- 10649381
TI  - Denticity Changes of Hydrotris(pyrazolyl)borate Ligands in Rh(I) and Rh(III)
      Compounds: From kappa(3)- to Ionic "kappa(0)"-Tp'
AB  - Isolated hydrotris(pyrazolyl)borate anions Tp' were obtained as salts of metal
      complex cations (see picture) by the displacement of Rh-coordinated kappa(3)
      N,N',N"-Tp' by PMe(3) (Tp'=Tp and Tp(Me2)). With [(kappa(3)
      Tp(Me2))Rh(C(2)H(4))(2)], stepwise diplacement of the Tp(Me2) ligand allowed the
      isolation of complexes exhibiting the kappa(2)- Tp(Me2) and kappa(1)-Tp(Me2)
      coordination modes.

PMID- 10649382
TI  - Synthesis and Structures of 1,3,5,7-Tetraazaheptatrienylsodium and -thallium(I).
AB  - Highly stable multinuclear metal complexes with planar [{Me(3)SiNC(H)N}(2)CH](-)
      ligands are obtained from MN(SiMe(3))(2) (M=Na, Tl) and 1,3,5-triazine (structure
      for Tl shown in the picture). These complexes display unusual structural features
      such as a pseudo-C(3) symmetry (Na complex).

PMID- 10649383
TI  - Genetic Engineering of Streptomyces coelicolor A3(2) for the Enantioselective
      Reduction of Unnatural beta-Keto-Ester Substrates.
AB  - Potential "reagents" for the enantioselective reduction, and other
      biotransformations, of beta-keto-esters result from the genetic engineering of
      Streptomyces coelicolor A3(2). For example, incubation of the N-acetylcysteamine
      thioester 1 with the recombinant strain CH999/pIJ5675 followed by treatment with
      MeOH/HCl gave the lactone 2 as essentially a single enantiomer.

PMID- 10649384
TI  - Twist Sense Bias Induced by Chiral Side Chains in Helically Folded Oligomers.
AB  - Cooperative interactions among the side chains of the helically folded phenylene
      ethynylene oligomer shown (n=2, 4, 6, 8, 10, 12, 14, 16, 18) can induce a twist
      sense bias. Therefore, the side chains can play more than just an ancillary role
      in these conformationally ordered oligomers. The onset of the twist sense bias
      lags significantly behind the appearance of helical conformations, possibly
      because a large ensemble of "collapsed" conformations is initially formed.

PMID- 10649385
TI  - Mixed-Valent Heptairon Complex with a Ground-State Spin Value of S=12/2
      Constructed from a Triiron Cluster Ligand.
AB  - The anionic triiron(III) cluster ligand [Fe(III)(3)(u(3)
      O)(bpca)(2)Cl(4)(EtO)(2)](-) (1; Hbpca=bis(2-pyridylcarbonyl)amine) was prepared
      as a building block for constructing larger metal assemblies. This "metal cluster
      complex ligand" was used in the synthesis of the mixed-valent heptairon complex
      [Fe(II)(1)(2)(EtOH)(2)], which has a ground-state spin value of S=12/2.

PMID- 10649386
TI  - Encoded Helical Self-Organization and Self-Assembly into Helical Fibers of an
      Oligoheterocyclic Pyridine - Pyridazine Molecular Strand.
AB  - The conformational information of an oligoheterocyclic strand containing a
      repeating pyridine - pyridazine codon self-organizes into a helical molecular
      unit, which subsequently self-assembles into helical fibers and macrofibers in
      dichloromethane and pyridine. The spontaneous formation of helical structures is
      based on a general self-organization process enforced by the conformational
      information encoded within the molecular strand itself.

PMID- 10649387
TI  - A New Enantioselective Approach to Total Synthesis of the Securinega Alkaloids:
      Application to (-)-Norsecurinine and Phyllanthine.
AB  - An inexpensive proline derivative and chiral control feature in the total
      synthesis of securinega alkaloids (-)-norsecurinine (1) and phyllanthine (2). Key
      steps in the synthesis of 1 include an intramolecular ketonitrile coupling and
      application of a radical-based generation of N-acylimines. The total synthesis of
      2 utilizes a stereoselective imino Diels - Alder construction of the
      methoxypiperidine ring.

PMID- 10649388
TI  - Formal Three-Electron Reduction by an f-Element Complex: Formation of
AB  - Steric crowding can be coupled with a U(III) reduction to make the complex
      [(C(5)Me(5))(3)U] a formal three-electron reductant in its reaction with
      C(8)H(8), which generates a product, 1, containing a bridging nonplanar
      C(8)H(8)(2-) ligand [Eq. (1)].

PMID- 10649389
TI  - Application of Reductive Samariation to the Synthesis of Small Unnatural
      Peptides.
AB  - Considering that the amide NH groups are neither protected nor deprotonated,
      reductive samariation in the presence of a carbonyl substrate is a remarkably
      efficient method for the formation of a C-C bond. This was shown for a series of
      dipeptides and a tripeptide [Eq. (a)]. For the latter the product was obtained in
      a good yield of 50 %, despite the presence of three amide protons.

PMID- 10649390
TI  - Antiferromagnetic Coupling in a Gadolinium(III) Semiquinonato Complex.
AB  - The strongest antiferromagnetic coupling to Gd(III) so far reported was found for
      the complex [Gd(Hbpz(3))(2)(dtbsq)] small middle dot2 CHCl(3) (1;
      Hbpz(3)=hydrotris(pyrazolyl)borate; dtbsq=3,5-di-tert-butylsemiquinonato; see
      structure). At 245 K the magnetic susceptibility of 1 is lower than expected for
      two uncorrelated spins of 7/2 and 1/2, and the lowering of chiT with increasing
      temperature suggests that this is due to antiferromagnetic interaction between
      Gd(III) and the radical.

PMID- 10649391
TI  - Improved Electrochemistry in Low-Polarity Media Using
      Tetrakis(pentafluorophenyl)borate Salts as Supporting Electrolytes.
AB  - The noncoordinating anion [B(C(6)F(5))(4)](-) solubilizes cations and
      polycations, allowing the generation and study of such systems in low-dielectric
      media. Thus, when [NBu(4)][B(C(6)F(5))(4)] is used as a supporting electrolyte,
      cyclic voltammetry is possible in aliphatic ethers and other solvents of very low
      polarity.

PMID- 10649392
TI  - Combinatorial Synthesis of Four-Helix Bundle Hemoproteins for Tuning of Cofactor
      Properties.
AB  - De novo proteins were assembled from two sets of helical peptides on cyclic
      peptide templates bound to cellulose membranes (see picture). The variation of
      the amino acids of the hydrophobic binding pocket in the antiparallel four-helix
      bundle tuned the redox potential of the reversibly bound Fe(III) - protoporphyrin
      IX group, as directly detected spectroscopically on the solid support.

PMID- 10649393
TI  - Complete Carbonylation of fac-
AB  - The rate constant of ligand exchange on the complex fac
      [(99)Tc(H(2)O)(3)(CO)(3)](+) was determined by means of (13)C, (17)O, and (99)Tc
      NMR spectroscopy under pressurized conditions in aqueous media. After keeping the
      sample under CO pressure for an extended period, the formation of
      [(99)Tc(CO)(6)](+) could unambiguously be detected in the (13)C and (99)Tc NMR
      spectra.

PMID- 10649394
TI  - Femtosecond Dynamics of Dioxygen - Picket-Fence Cobalt Porphyrins: Ultrafast
      Release of O(2) and the Nature of Dative Bonding.
AB  - The ultrafast release of O(2) from the O(2) adduct of picket-fence cobalt
      porphyrin (see picture) has been probed in real time, and has a total reaction
      time of 2 ps, without subsequent recombination over several nanoseconds. The
      dynamics of this ultrafast release of O(2) shows that relaxation within the
      porphyrin system (200 fs) precedes porphyrin-to-metal electron transfer, but the
      latter occurs at an enhanced rate (500 fs as opposed to the more usual 1 - 2 ps)
      because of the dative bonding of cobalt and O(2), which gives the adduct ground
      state significant Co(III)-O(2)(-) character.

PMID- 10649395
TI  - Femtosecond Dynamics of Norrish Type-II Reactions: Nonconcerted Hydrogen-Transfer
      and Diradical Intermediacy.
AB  - Norrish type-II and McLafferty rearrangements, which both involve an
      intramolecular transfer of a gamma H atom, can be differentiated on the
      femtosecond time scale. The McLafferty rearrangement results in ion fragmentation
      of the parent ketone, whereas the Norrish type-II reaction leads to a diradical
      species, which then either cyclizes or fragments (see scheme). For Norrish type
      II reactions, the reaction time for the transfer of the hydrogen atom is within
      70 - 90 fs, and the lifetime of the diradical intermediate is in the range of 400
      - 700 ps at the total energy studied.

PMID- 10649396
TI  - An EPR Investigation of the Kinetics of Inclusion of a Persistent Radical in
      Water-Soluble Calix
AB  - Distinct EPR signals are observed for the free and included species for the
      inclusion of the neutral benzyl tert-butyl nitroxide probe into a calix[4]arene
      host in water (shown schematically). Computer simulation of the EPR spectra
      recorded at various temperature enabled direct determination of the activation
      and kinetic parameters for this inclusion process.

PMID- 10649397
TI  - NMR Studies of Ligand Binding to Dihydrofolate Reductase.
AB  - Unique capabilities are offered by NMR spectroscopy for probing specific
      interactions of enzymes with substrates and substrate analogues, for
      characterizing the multiple conformations of the complexes, and for measuring
      rates of a wide range of dynamic processes. The most extensive studies of this
      type have been directed at complexes formed by dihydrofolate reductase with
      antifolate drugs and are described in this review.

PMID- 10649398
TI  - Zirconium - Phosphorus Chemistry: Strategies in Syntheses, Reactivity, Catalysis,
      and Utility.
AB  - Dramatic developments have taken place over the last few years in the chemistry
      of complexes containing Zr-P bonds and their utilization in organophosphorus
      chemistry. This review discusses the synthesis and reactivity of compounds
      containing Zr-P single and double bonds, phosphazirconacycles, and Zr complexes
      of substituent-free phosphorus. Applications in both stoichiometric and catalytic
      syntheses provide access to a variety of novel organophosphorus compounds and
      illustrate the potential of the organometallic approach to the synthesis of main
      group compounds.

PMID- 10649399
TI  - New Pathways in Plastics Recycling.
AB  - The catalytic degradation of polyethylene to short-chain hydrocarbons is possible
      with zirconium hydride compounds (see picture), and represents the first step in
      the reversal of Ziegler - Natta polymerization. Thus, even in the case of
      polyolefins the important target of plastics recycling, the recovery of reusable
      monomers from polymer waste, may be achieved.

PMID- 10649400
TI  - Oxygen and Osmium-A New Alliance for Dihydroxylations?
AB  - The activation of oxygen in new synthetic procedures dramatically expands the
      scope of osmium-catalyzed dihydroxylations [Eq. (1)]. Even air can now be used as
      the cooxidant in the asymmetric version of this reaction with little loss of
      selectivity.

PMID- 10649401
TI  - An Unprecedented (1infinity)
AB  - A chain of vertex-linked "bare" nido-Ge(9)(2-) clusters (shown in the picture) is
      featured by the novel polymeric Zintl anion formed from the binary alloy
      "KGe(4)", ethylenediamine, and [18]crown-6. The polymerization of nido-Ge(9)(4-)
      clusters is counterintuitive to known two-electron oxidation behavior of nido
      clusters and the existence of the isolated closo-Ge(9)(2-) ion. The novel
      semiconducting cluster "wire" establishes direct structural and mechanistic links
      between molecular Zintl cluster ions with the extended structures of Zintl phases
      and elemental nanophase materials.

PMID- 10649402
TI  - Block Copolymer Nanotubes.
AB  - Rigid cylindrical micelles are made from polyisoprene-block-poly(2-cinnamoylethyl
      methacrylate)-block-poly(tert-butyl acrylate). The PI-PCEMA-PtBA polymer
      assembles to micelles with PI as the core, PCEMA as the shell, and PtBA as the
      corona. The cylindrical structure is fixed by photocrosslinking the PCEMA shell,
      and PCEMA-PtBA nanotubes are obtained by degrading the PI core with ozone (see
      scheme).

PMID- 10649403
TI  - A Dicubane-Like Tetrameric Nickel(II) Azido Complex.
AB  - A combination of azido and dipyridylketone (dpk) ligands led to the isolation of
      the tetranuclear Ni(II) complex 1 (dpkOH and dpkOCH(3) result from solvolysis of
      dpk). The complex exhibits ferromagnetic behavior, and its structure can be
      described as a dicubane unit with two missing vertices (see picture).

PMID- 10649404
TI  - 5-(beta-Cyclodextrinylamino)-5-Deoxy-alpha-D-Riboses as Models for Nuclease,
      Ligase, Phosphatase, and Phosphorylase.
AB  - beta-Cyclodextrin derivatives crowned with ribose rings (such as 1) catalyzed the
      hydrolysis, esterification, and phosphorylation of catechol-derived phosphate
      esters. The vicinal cis-diols on the ribose groups appear to play a major role in
      the catalytic activity of these enzyme models by the formation of hydrogen bonds
      which activate the phosphorus atom to nucleophilic attack.

PMID- 10649405
TI  - Reducing Molecular Shuttling to a Single Dimension.
AB  - An analogy with a cart on a roller coaster partially explains the shuttling
      motion of macrocycles in peptide rotaxanes. Just above the barrier to shuttling,
      the macrocycle statistically populates the "track" rather than the low-energy
      "stations" (see the potential energy curve). The dynamics of the movement is
      described in terms of a simplified one-dimensional model based on the solution of
      the relevant quantum-mechanical equation. x=position.

PMID- 10649406
TI  - Enantioselective Reactions of Configurationally Unstable alpha-Thiobenzyllithium
      Compounds.
AB  - Too unstable for asymmetric deprotonation, alpha-sulfenyl carbanions can undergo
      asymmetric substitution reactions with high stereoselectivity [Eq. (1)]. The key
      to the asymmetric induction is the dynamic kinetic resolution of the complex
      formed between the organolithium compound and a chiral ligand, the most effective
      of which were bisoxazoline derivatives.

PMID- 10649407
TI  - Hydroxy-Directed, SmI(2)-Induced Conversion of Carbohydrates into Carbocycles.
AB  - Polyoxygenated six-membered carbocycles were derived from carbohydrates with
      complete stereocontrol through hydroxy-directed coupling cyclization induced by
      SmI(2). For example, the cis-1,3-cyclohexanediol 3 is obtained from the D
      glucopyranoside derivative 1 in excellent yield. The coupling cyclization is
      initiated by single-electron transfer from SmI(2) to the formyl group of the
      delta-hydroxy aldehyde 2 generated in an equilibrium process.

PMID- 10649408
TI  - Luminescence of Novel Neodymium Sulfonylaminate Complexes in Organic Media.
AB  - Luminescence of Nd(III) in an organic solvent having C-H bonds was achieved for
      the first time by complexing Nd(III) with long-chain perfluoroalkylated ligands
      such as bis(perfluorooctylsulfonyl)aminate (pos). The complex [Nd(pos)(3)] gave
      an emission quantum yield of 3.0+/-0.5 % in undeuterated acetone. The bulky pos
      ligands suppress the excitation of C-H vibrations, energy migration at
      diffusional collision, and the coordination of acetone molecules (see picture) to
      the Nd(III) center, which otherwise quench the luminescence.

PMID- 10649409
TI  - A Mechanistic Dichotomy Leading to a Ruthenium-Catalyzed cis-Addition for
      Stereoselective Formation of (Z)-Vinyl Bromides.
AB  - Either trans- or cis-haloalkylation is possible through a three-component
      coupling [Eq. (1)]. The cis-bromoruthenation of an alkyne by lithium bromide and
      [CpRu(CH(3)CN)(3)]PF(6), catalyzed by SnBr(4), gives (Z)-vinyl bromides with high
      chemoselectivity. The degree of control over the sterochemistry raises intriguing
      mechanistic questions as well as offering practical synthetic utility.

PMID- 10649410
TI  - Carbocyclic Ring Closure of Unsaturated S-, Se-, and C-Aryl Glycosides.
AB  - Triisobutylaluminum-promoted rearrangement of unsaturated glycosides containing
      electron-donating aglycons-such as C-aryl glycoside 1, or O-, S-, and Se
      glycosides-provides direct access to highly functionalized cyclohexane
      derivatives such as 2.

PMID- 10649411
TI  - Boron - Carbon Order in CeB(2)C(2).
AB  - Powder neutron diffraction studies show that boron and carbon atoms alternate in
      the planar pi-conjugated layers in CeB(2)C(2) and its lanthanide analogues,
      rather than being paired as was previously reported. Long and short B-C bonds
      correspond to the idealized arrangement of single and double bonds shown in the
      picture.

PMID- 10649412
TI  - Direct Experimental Evidence for the H(2)O(+)O(2)(-) Charge Transfer Complex:
      Crucial Support to Atmospheric Photonucleation Theory.
AB  - Where does rain come from? The first experimental evidence for the existence of
      the (H(2)O(+)O(2)(-)) charge transfer complex, predicted to play a key role as a
      nucleation center for atmospheric vapor photonucleation (see picture), is
      provided by the powerful neutralization - reionization mass spectrometric
      technique.

PMID- 10649413
TI  - Efficient Hydrolysis of RNA by a PNA - Diethylenetriamine Adduct.
AB  - The introduction of a urea bond linking a protected diethylenetriamine (DETA)
      unit and the terminal amino group of a resin-bound peptide nucleic acid (PNA)
      decamer gave access to a PNA - DETA adduct (shown here), which hydrolyzed the
      target 25-mer RNA rapidly and sequence specifically.

PMID- 10649414
TI  - Synthesis of Polycyclic Ethers by Two-Directional Double Ring-Closing Metathesis.
AB  - trans-Fused tricyclic ethers containing combinations of six-, seven-, eight-, and
      nine-membered rings are constructed using two-directional double ring-closing
      metathesis reactions (see scheme). Such double cyclizations of precursors bearing
      alkenes, allylic ethers, enol ethers, or alkynyl ethers offer a new strategy for
      the synthesis of brevetoxins and ciguatoxins. PMB=(p-MeOC(6)H(4)CH(2)).

PMID- 10649415
TI  - Solid-Phase Synthesis of a Monofunctional trans-a(2)Pt(II) Complex Tethered to a
      Single-Stranded Oligonucleotide.
AB  - Cross-linking ability is possible with the oligonucleotide-tethered,
      monofunctional trans-Pt(II) complex shown. It was synthesized by a novel solid
      phase approach comprising conjugation of immobilized tetrathymidylic acid with a
      trans-a(2)Pt(II) building unit, ammonolysis, and transformation of the resulting
      complex (R=1-N-cyclohexylmethylthyminate) into the chloro derivative (R=Cl).
      a=NH(2)CH(3), T=thymine.

PMID- 10649416
TI  - Total Synthesis of the Antimicrotubule Agent (+)-Discodermolide Using Boron
      Mediated Aldol Reactions of Chiral Ketones.
AB  - With a similar mechanism of action to taxol, the title compound 1 is a
      particularly promising candidate for development in cancer chemotherapy. This
      efficient synthesis, based on stereocontrolled aldol reactions, should help to
      overcome the scarce natural supply of 1 from the rare sponge source.

PMID- 10649417
TI  - Cofactor-Bound Cross-Linked Enzyme Crystals (CLEC) of Alcohol Dehydrogenase.
AB  - Horse liver alcohol dehydrogenase was crystallized in the presence of its
      cofactor. The cross-linked enzyme crystals (CLECs) produced showed good catalytic
      activity without the addition of extra cofactor (see scheme). The
      enantioselectivity and stereochemical preference of the CLEC were the same as
      with the soluble enzyme, and both cofactor and enzyme were considerably more
      stable in CLEC form. Cofactor regeneration studies on the reduction of
      cinnemaldehyde indicate the potential for a high level of catalyst productivity.

PMID- 10649418
TI  - In(8)(C(6)H(3)-2,6-Mes(2))(4) (Mes=C(6)H(2)-2,4,6-Me(3)): A Metal-Rich Main-Group
      Cluster with a Distorted Cubane Structure.
AB  - A distorted In(8) cubane core (see picture) is present in the novel indium
      cluster In(8)(C(6)H(3)-2,6-Mes(2))(4) (Mes=C(6)H(2)-2,4,6-Me(3)), which was
      synthesized by the reaction of LiC(6)H(3)-2,6-Mes(2) with InCl. It has an average
      In-In bond length of 2.92 A and represents a new addition to the range of heavier
      Group 13 element clusters.

PMID- 10649419
TI  - The Synthesis of a Novel Strained Diyneparacyclophane and Its Dimer by Metal
      Mediated Coupling.
AB  - Relieve strain with a twist! Synthesis of the paracyclophane 1 and its dimer 2
      employed a sequence of metal-mediated couplings. The X-ray analysis of 2 revealed
      a helical twist inherent in this structure, which created extended arms, that
      trapped a molecule of solvent. A carboxylic acid derivative of 1 was also
      prepared, and its structure indicated the diyne rod moiety of 1 is distorted more
      than in analogous compounds.

PMID- 10649420
TI  - Molecular Dispersion of Chains in the Mixed-Valence Complexes
AB  - A way to prepare molecular electronic wires in organic media is the
      solubilization of one-dimensional mixed-valence complexes with varied metal
      species through the formation of amphiphilic supramolecular assemblies (see
      picture). Dissociation and reassembly of the complex was detected as
      thermochromism in the intervalence (M(II)-->M(IV)) absorption bands.

PMID- 10649421
TI  - The First Organoxenon(IV) Compound: Pentafluorophenyldifluoroxenonium(IV)
      Tetrafluoroborate.
AB  - Xenon(IV) - carbon bonding has been realized for the first time in the product
      formed from the reaction of XeF(4) with C(6)F(5)BF(2) in CH(2)Cl(2) at -55
      degrees C [Eq. (1)]. [C(6)F(5)XeF(2)][BF(4)] is a strong oxidative fluorinating
      agent. This xenon(IV) compound fluorinates (C(6)F(5))(3)P to (C(6)F(5))(3)PF(2),
      C(6)F(5)I to C(6)F(5)IF(2), and I(2) to IF(5). In all cases, [C(6)F(5)Xe][BF(4)]
      was obtained as a by-product.

PMID- 10649422
TI  - Methylcorrinoids Methylate Radicals-Their Second Biological Mode of Action?
AB  - An unprecedented methylation of alkyl radicals is possible with the diamagnetic
      vitamin B(12) derivative methylcobalamin (see schematic representation).
      Methylcorrinoids can thus also be considered as methylating cofactors in radical
      C-methylations.

PMID- 10649423
TI  - Enzymatic Synthesis of Neoglycopeptide Building Blocks.
AB  - A transglutaminase-catalyzed transacylation is the major step in a practical,
      regioselective synthesis of N-linked spacer-modified glycopeptide analogues. The
      process requires minimal modification of the saccharide during the N
      glycosylation, photoinduced coupling of cysteamine, and final enzymatic reaction
      (see scheme).

PMID- 10649425
TI  - Hepta- and Octanitrocubanes.
AB  - Four of the eight nitro groups of octanitrocubane 1 are introduced by functional
      group modification, three more by the astonishingly rapid, low-temperature
      N(2)O(4) nitration of sequentially formed polynitrocubyl anions, and the eighth
      and last by nitrosation of the heptanitrocubyl anion followed by ozonation.

PMID- 10649424
TI  - Aliphatic Hydroxylation by a Bis(u-oxo)dicopper(III) Complex.
AB  - By using molecular oxygen bis(u-oxo)dicopper(III) complexes can be produced from
      Cu(I) complexes with ligand L(X) (L(X)=p-substituted N-ethyl-N-[2-(2
      pyridyl)ethyl]-2-phenylethylamine; X=OMe, Me, H, Cl, NO(2)) in which the benzylic
      position of the ligand is activated and hydroxylated by the Cu(2)O(2) core (see
      reaction scheme). Detailed characterization of this new C-H bond activation
      reaction by the bis(u-oxo)dicopper(III) core reveals important information on the
      fundamental chemistry underlying copper monooxygenase reactivity.

PMID- 10649426
TI  - Intermolecular Activation of n-Alkanes by a Trinuclear Ruthenium Pentahydride
      Complex-Formation of closo-Ruthenacyclopentadiene Complexes.
AB  - The successive activation of alkane C-H bonds on a trinuclear ruthenium cluster
      enables cleavage of six C-H bonds and the formation of a closo
      ruthenacyclopentadiene complex (the structure of the complex obtained with hexane
      is shown).

PMID- 10649428
TI  - Tandem Intermolecular - Intramolecular Carbolithiation: A Versatile Method for
      Synthesis of Cyclopentanes.
AB  - Polysubstituted cyclopentanes from readily available starting materials? A
      versatile anionic [3+2] approach is offered by the reaction of difunctional
      organolithium reagents 1 with alkenes 2 in a tandem intermolecular -
      intramolecular carbolithiation (see scheme). This convergent sequence is
      especially attractive as, not only are the precursors readily available, but the
      products provide valuable synthetic building blocks.

PMID- 10649427
TI  - Two New Carbaalanes: Compounds with an Al(7)C(5) and a
AB  - The hydroalumination of aluminum ethynides leads to the formation of carbaalanes
      as a new class of compounds, which have clusters exclusively formed by carbon and
      aluminum atoms. Two novel carbaalanes with Al(7)C(5) and Al(7)C(4) clusters are
      described-the latter is a remarkable analogue of closo-[B(11)H(11)](2-) with
      respect to its structure and the number of cluster electrons.

PMID- 10649429
TI  - Ca(11)N(6)(CN(2))(2) and Ca(4)N(2)(CN(2)): The True Nature of an "Unusual Binary
      Nitride" Is Finally Revealed.
AB  - One calcium nitride less! Several different binary nitrides of calcium have been
      reported: Ca(3)N(2), Ca(2)N, Ca(3)N(4), and Ca(11)N(8). X-ray structural analysis
      and spectroscopy revealed the latter is actually calcium nitride cyanamide and
      one of, so far, two examples of a new class of ternary phases (see boxes in the
      phase diagram).

PMID- 10649430
TI  - "Amphiphilic" Cleavage of gamma-Stannyl Ketones with ATPH/RLi: Application to
      Enone Fragmentation by the Conjugate Addition - Cleavage Sequence.
AB  - The use of a combined Lewis acid/base system consisting of aluminum tris(2,6
      diphenylphenoxide) (ATPH) and MeLi has allowed the electrophilically activated
      nucleophilic ("amphiphilic") cleavage of C(alpha)-C(beta) bonds in gamma-stannyl
      ketones. Through combination with the conjugate addition of alpha-stannyl
      carbanion to enone, this approach constitutes a novel two-step conjugate addition
      - cleavage sequence that leads to functionalized ketones (see reaction).

PMID- 10649432
TI  - Extracellular-signal regulated kinase signaling pathway mediates downregulation
      of type I procollagen gene expression by FGF-2, PDGF-BB, and okadaic acid in
      osteoblastic cells.
AB  - Although basic fibroblast growth factor (FGF-2) had been shown to inhibit type I
      collagen gene expression in osteoblast, its inhibitory mechanism is unknown. In
      the present study, we investigated the underlying mechanisms by which growth
      factors downregulate type I collagen gene expression. Treatment of mouse
      osteoblastic MC3T3-E1 cells with okadaic acid (40 ng/ml), an inhibitor of
      phosphoserine/threonine-specific protein phosphatase and activator of ERK1/2, for
      24 h and 48 h completely inhibited steady-state mRNA levels of type I collagen.
      FGF-2 (30 ng/ml), platelet-derived growth factor-BB (PDGF-BB), 30 ng/ml, and
      serum, which activate ERK mitogen-activated protein kinase (MAPK) pathway also
      inhibited collagen type I gene expression, suggesting that the activation of ERK
      pathway mediates inhibition of type I collagen mRNA. This observation was further
      confirmed by experiments using inhibitors of the ERK pathway (i.e., PD and
      U0126), which increased type I collagen mRNA in MC3T3-E1 cells, indicating that
      the inhibition of ERK pathway upregulates type I collagen gene expression. Low
      serum (0.3%) markedly increased type I collagen mRNA. MEK inhibitor PD inhibited
      c-fos induction by FGF-2 and PDGF-BB, suggesting that c-fos is the downstream
      target of ERK pathway. Our data have clearly demonstrated for the first time that
      the ERK MAPK pathway play an important role in the regulation of type I collagen
      gene expression in osteoblastic cells. Results also showed that one of the
      mechanisms by which FGF-2 and PDGF-BB downregulate type I collagen gene
      expression in the osteoblast is through the activation of ERK signaling pathway.

PMID- 10649433
TI  - Differential role for Sp1/Sp3 transcription factors in the regulation of the
      promoter activity of multiple cyclin-dependent kinase inhibitor genes.
AB  - Cyclin-dependent kinase inhibitors play a significant role in cell cycle
      progression and in cellular differentiation and their expression is regulated in
      different cellular settings. GC-rich regions in the promoter sequences of the
      cyclin-dependent kinase inhibitor genes p15INK4B and p21CIP1/WAF1 mediate the
      transcriptional response of these genes to extracellular stimuli. Similar GC-rich
      sequences in the promoter of the p15INK4A and p16INK4B gene can be targeted for
      transcriptional inactivation by methylation of cytosine residues. GC-rich regions
      represent putative target sites for binding of the ubiquitously expressed Sp1 and
      Sp3 transcription factors. Using a combination of functional and biochemical
      studies, we analyzed the potential role of the Sp1 and Sp3 factors in the
      regulation of CDKI p15, p16, and p21 promoter activities. Using transient
      reporter gene assays, we determined that Sp1 is a strong activator of these
      promoters, whereas Sp3 functions as a weak transactivator. We have identified
      multiple protein-binding sites in the proximal promoter sequences of these genes
      by footprinting analysis. Some of these sites are bound by Sp1 and Sp3, as
      demonstrated by gel-shift experiments using Sp1/Sp3-specific antibodies,
      permitting the demonstration that a differential role exists for Sp1 and Sp3 in
      the regulation of the activity of these promoters.

PMID- 10649434
TI  - Mutagenesis in the switch IV of the helical domain of the human Gsalpha reduces
      its GDP/GTP exchange rate.
AB  - The Galpha subunits of heterotrimeric G proteins are constituted by a conserved
      GTPase "Ras-like" domain (RasD) and by a unique alpha-helical domain (HD). Upon
      GTP binding, four regions, called switch I, II, III, and IV, have been identified
      as undergoing structural changes. Switch I, II, and III are located in RasD and
      switch IV in HD. All Galpha known functions, such as GTPase activity and
      receptor, effector, and Gbetagamma interaction sites have been found to be
      localized in RasD, but little is known about the role of HD and its switch IV
      region. Through the construction of chimeras between human and Xenopus Gsalpha we
      have previously identified a HD region, encompassing helices alphaA, alphaB, and
      alphaC, that was responsible for the observed functional differences in their
      capacity to activate adenylyl cyclase (Antonelli et al. [1994]: FEBS Lett 340:249
      254). Since switch IV is located within this region and contains most of the
      nonconservative amino acid differences between both Gsalpha proteins, in the
      present work we constructed two human Gsalpha mutant proteins in which we have
      changed four and five switch IV residues for the ones present in the Xenopus
      protein. Mutants M15 (hGsalphaalphaS133N, M135P, P138K, P143S) and M17
      (hGsalphaalphaS133N, M135P, V137Y, P138K, P143S) were expressed in Escherichia
      coli, purified, and characterized by their ability to bind GTPgammaS, dissociate
      GDP, hydrolyze GTP, and activate adenylyl cyclase. A decreased rate of GDP
      release, GTPgammaS binding, and GTP hydrolysis was observed for both mutants, M17
      having considerably slower kinetics than M15 for all functions tested.
      Reconstituted adenylyl cyclase activity with both mutants showed normal
      activation in the presence of AlF(4)(-), but a decreased activation with
      GTPgammaS, which is consistent with the lower GDP dissociating rate they
      displayed. These data provide new evidence on the role that HD is playing in
      modulating the GDP/GTP exchange of the Gsalpha subunit.

PMID- 10649435
TI  - Both locus control region and proximal regulatory elements direct the
      developmental regulation of beta-globin gene cluster.
AB  - Using ligation-mediated PCR and in vivo footprinting methods to study the status
      of DNA-protein interaction at hypersensitive site 2 of locus control region and
      beta(maj) promoter of erythroid cells of fetal liver and adult bone marrow, we
      found that during different developmental periods, the status of DNA-protein
      interaction at both hypersensitive site 2 and beta(maj) promoter changed
      significantly, and indicated that locus control region might function through a
      looping mechanism to regulate the expression of downstream genes, and that distal
      regulatory elements (locus control region, hypersensitive sites) as well as
      proximal regulatory elements (promoter, enhancer) of beta-globin gene cluster
      participate in the regulation of developmental specificity.

PMID- 10649436
TI  - Characterization of epidermal growth factor receptor function in lysophosphatidic
      acid signaling in PC12 cells.
AB  - Lysophosphatidic acid (LPA) is a lipid metabolite that induces the activation of
      mitogen-activated protein kinase (MAPK) through binding to the G protein-coupled
      receptor in a number of cell lines and cultures. Recent studies have revealed
      that LPA is able to rapidly induce the phosphorylation of MAPK through an
      epidermal growth factor (EGF) receptor-dependent pathway. We investigated the
      role of the EGF receptor in the signaling pathway initiated by LPA stimulation in
      nerve growth factor (NGF)-responsive PC12 cells well known to transiently retract
      their own neurites upon LPA stimulation. LPA-stimulated MAPK signaling was
      suppressed by the selective EGF receptor inhibitor and in the dominant negative
      mutant EGF receptor cell line. As in the EGF signaling pathway, the complex of
      EGF receptor with adapter proteins Shc and Sos was formed in response to LPA
      stimulation, suggesting there is an intracellular mechanism for transactivation.
      A neurite retraction assay was also performed to examine the role of the EGF
      receptor in PC12 cell differentiation, which related to the involvement of LPA
      induced neurite retraction. These results suggest that the receptor tyrosine
      kinase can be activated in a ligand-independent manner through intracellular
      crosstalk between the signaling pathways.

PMID- 10649437
TI  - Lactogenic hormones and tenascin-C regulate C/EBPalpha and beta in mammary
      epithelial cells.
AB  - Mammary epithelial cell differentiation depends on lactogenic hormones, growth
      factors, and cell-cell and cell-substrate interactions, all of which modulate
      transcription factors essential for milk protein gene expression. The
      CCAAT/enhancer binding protein (C/EBP) family and the signal transducer and
      activator of transcription 5 (Stat5) have been implicated in mammary epithelial
      cell growth and differentiation. We have investigated the effects of
      extracellular matrix components and lactogenic hormones on C/EBP and Stat5
      activity. In the mammary gland, tenascin is expressed mainly during embryogenesis
      and carcinogenesis and in cell culture tenascin downregulates beta-casein gene
      expression. In HC11 mammary cells, we found that tenascin, but not laminin or
      fibronectin, specifically downregulated C/EBPalpha levels but had no effect on
      Stat5 amount or DNA binding activity. Furthermore, we found that the lactogenic
      hormones, glucocorticoids, prolactin, and insulin, had no effect on C/EBPalpha
      and C/EBPbeta protein levels but downregulated the DNA binding activity of the
      transcriptional repressor C/EBPbetaLIP. Thus, C/EBPalpha and beta are regulated
      by tenascin and lactogenic hormones in mammary epithelial cells.

PMID- 10649438
TI  - Bacterial lipopolysaccharide activates protein kinase C, but not intracellular
      calcium elevation, in human peripheral T cells.
AB  - The increase of intracellular free calcium concentration ([Ca(2+)](i)) and
      protein kinase C (PKC) activity are two major early mitogenic signals to initiate
      proliferation of human peripheral T cells. Bacterial lipopolysaccharide (LPS) is
      nonmitogenic in human T cells. However, in the presence of monocytes, LPS becomes
      mitogenic to proliferate T cells. The aim of this study was to define the
      incompetency of LPS on two mitogenic signals in human peripheral T cells. T cells
      were isolated from human peripheral blood. [Ca(2+)](i) and pH(i) were determined
      by loading the cells with the fluorescent dyes, Fura-2 acetoxymethyl ester (Fura
      2/AM) and 2',7'-bis(2-carboxyethyl)-5-(and 6)carboxyfluorescein acetoxymethyl
      ester (BCECF/AM). PKC activity was determined by protein kinase assay and cell
      proliferation was estimated from the incorporation of [(3)H]-thymidine. The
      results indicated that (1) LPS (10 microg/ml) stimulated PKC activity
      significantly within 5 min, reached a plateau at 30 min, and maintained that
      level for at least 2 h; and (2) LPS stimulated cytoplasmic alkalinization but did
      not affect the levels of [Ca(2+)](i) and [(3)H]-thymidine incorporation into T
      cells. Moreover, the combination of calcium ionophore A23187 with LPS
      significantly stimulated [(3)H]-thymidine incorporation into T cells. Thus, the
      results demonstrate that LPS failed to proliferate T cells, probably because of a
      lack of the machinery necessary to stimulate the mitogenic signal on [Ca(2+)](i)
      elevation.

PMID- 10649439
TI  - Specific decrease in the level of Hic-5, a focal adhesion protein, during
      immortalization of mouse embryonic fibroblasts, and its association with focal
      adhesion kinase.
AB  - Hic-5 is a paxillin homologue with four LIM domains in its C-terminal region,
      localized mainly in focal adhesions in normal fibroblasts. Hic-5 is also known to
      associate with focal adhesion kinase (FAK) or the related CAKbeta, and with
      vinculin. In the present study, we examined changes in Hic-5 and paxillin protein
      levels in primary mouse embryo fibroblasts (MEF) during mortal and immortal
      stages. The Hic-5 level was markedly decreased when cells became immortalized,
      whereas that of paxillin was increased. The vinculin level was not changed
      significantly. Hic-5 was mainly localized in focal adhesion plaques of mortal MEF
      but was localized in the nuclear periphery in the immortalized MEF; the number of
      focal adhesion plaques was decreased in these cells. Mouse Hic-5 contains three
      LD domains in its N-terminal half, and the first LD domain (LD1) appears to be
      involved in interaction with FAK. However, this interaction was not essential for
      recruitment of Hic-5 to focal adhesions, since its subcellular localization was
      similar in FAK(-/-) cells. Forced expression of Hic-5 decreased colony forming
      ability of MEF from FAK(+/+) mice, but not of FAK(-/-) cells. These observations
      suggested the involvement of Hic-5 in determination of cellular proliferative
      capacity in collaboration with other cytoskeletal components.

PMID- 10649440
TI  - Ecto-alkaline phosphatase activity identified at physiological pH range on intact
      P19 and HL-60 cells is induced by retinoic acid.
AB  - The activity of membrane-bound alkaline phosphatase (ALP) expressed on the
      external surface of cultured murine P19 teratocarcinoma and human HL-60
      myeloblastic leukemia cells was studied at physiological pH using p
      nitrophenylphosphate (pNPP) as substrate. The rate of substrate hydrolysis
      catalyzed by intact viable cells remained constant for eight successive
      incubations of 30 min and was optimal at micromolar substrate concentrations over
      the pH range 7.4-8.5. The value of apparent K(m) for pNPP in P19 and HL-60 cells
      was 120 microM. Hydrolytic activity of the ecto-enzyme at physiological pH
      decreased by the addition of levamisole, a specific and noncompetitive inhibitor
      of ALP (K(i) P19 = 57 microM; K(i) HL-60 = 50 microM). Inhibition of hydrolysis
      was reversed by removal of levamisole within 30 min. Retinoic acid (RA), which
      promotes the differentiation of P19 and HL-60 cells, induced levamisole-sensitive
      ecto-phosphohydrolase activity at pH 7.4. After its autophosphorylation by ecto
      kinase activity, a 98-kDa membrane protein in P19 cells was found to be sensitive
      to ecto-ALP, and protein dephosphorylation increased after incubation of cells
      with RA for 24 h and 48 h. Orthovanadate, an inhibitor of all phosphatase
      activities, blocked the levamisole-sensitive dephosphorylation of the membrane
      phosphoproteins, while (R)-(-)-epinephrine reversed the effect by complexation of
      the inhibitor. The results demonstrate that the levamisole-sensitive
      phosphohydrolase activity on the cell surface is consistent with ecto-ALP
      activity degrading both physiological concentrations of exogenously added
      substrate and endogenous surface phosphoproteins under physiological pH
      conditions. The dephosphorylating properties of ecto-ALP are induced by RA,
      suggesting a specific function in differentiating P19 teratocarcinoma and HL-60
      myeloblastic leukemia cells.

PMID- 10649441
TI  - Transcriptional regulation of fibronectin gene by phorbol myristate acetate in
      hepatoma cells: a negative role for NF-kappaB.
AB  - The transcriptional regulation of the fibronectin (FN) gene in hepatoma cells by
      phorbol myristate acetate (PMA) was investigated. PMA increased the synthesis and
      mRNA levels of FN and its promoter activity in Hep3B hepatoma cells. The PMA
      induced activation of FN expression was blocked by a protein kinase C (PKC)
      inhibitor and did not require a new protein synthesis. Deletion analysis revealed
      that the sequence between positions -69 and +136 of the FN gene was responsible
      for the PMA induction. Two PMA-inducible nuclear protein complexes were found to
      bind to a putative NF-kappaB site at -41 and were identified as a p65/p50
      heterodimer and a p50/50 homodimer of NF-kappaB family. Mutations in the -41 NF
      kappaB site, however, did not block the PMA induction of the FN promoter but
      rather enhanced it. Overexpression of p65 increased the FN promoter activity.
      While overexpression of p50 alone did not affect the promoter activity, it
      decreased the p65-induced activation of the FN promoter. Mutations in the -41 NF
      kappaB site attenuated the p50-mediated suppression of the p65 transactivation of
      the FN promoter. Deletion of the sequence between +1 and +136 decreased the basal
      and PMA-induced activities of the FN promoter. This study shows that PMA induces
      the transcription of the FN gene in hepatoma cells via the PKC pathway. The DNA
      sequence between +1 and +136 is responsible, at least in part, for the PMA
      induced activation of the FN gene, while the -41 NF-kappaB binding site plays as
      a negative regulatory element for it. In addition, this study is the first to
      show a role for NF-kappaB p65 in the transcriptional activation of the FN gene.

PMID- 10649442
TI  - Human angiogenin is rapidly translocated to the nucleus of human umbilical vein
      endothelial cells and binds to DNA.
AB  - Human angiogenin is translocated to the nucleus of human umbilical vein
      endothelial cells in a time-dependent manner. Exogenous angiogenin appears in the
      nucleus in 2 min, reaches saturation in 15 min when 85% of the internalized
      angiogenin is in the nuclei, and remains associated with the nucleus for at least
      4 h. Endothelial cells cultured at low density have a much higher capacity to
      translocate angiogenin to the nucleus than do those cultured at high density.
      This observation is consistent with previous findings that both the ability of
      endothelial cells to proliferate in response to angiogenin and the expression of
      an angiogenin receptor on the cell surface depend on cell density. Nuclear (125)I
      angiogenin is not degraded and is neither spontaneously dissociated nor replaced
      by unlabeled angiogenin. It is, however, released by deoxyribonuclease I, but not
      by ribonuclease A, suggesting that angiogenin binds to DNA in the nucleus. These
      results suggest that in addition to acting as a ribonuclease, angiogenin may play
      a role in regulating gene expression by direct binding to DNA.

PMID- 10649443
TI  - Androgen and taxol cause cell type-specific alterations of centrosome and DNA
      organization in androgen-responsive LNCaP and androgen-independent DU145 prostate
      cancer cells.
AB  - We investigated the effects of androgen and taxol on the androgen-responsive
      LNCaP and androgen-independent DU145 prostate cancer cell lines. Cells were
      treated for 48 and 72 h with 0.05-1 nM of the synthetic androgen R1881 and with
      100 nM taxol. Treatment of LNCaP cells with 0.05 nM R1881 led to increased cell
      proliferation, whereas treatment with 1 nM R1881 resulted in inhibited cell
      division, DNA cycle arrest, and altered centrosome organization. After treatment
      with 1 nM R1881, chromatin became clustered, nuclear envelopes convoluted, and
      mitochondria accumulated around the nucleus. Immunofluorescence microscopy with
      antibodies to centrosomes showed altered centrosome structure. Although
      centrosomes were closely associated with the nucleus in untreated cells, they
      dispersed into the cytoplasm after treatment with 1 nM R1881. Microtubules were
      only faintly detected in 1 nM R1881-treated LNCaP cells. The effects of taxol
      included microtubule bundling and altered mitochondria morphology, but not DNA
      organization. As expected, the androgen-independent prostate cancer cell line
      DU145 was not affected by R1881. Treatment with taxol resulted in bundling of
      microtubules in both cell lines. Additional taxol effects were seen in DU145
      cells with micronucleation of DNA, an indication of apoptosis. Simultaneous
      treatment with R1881 and taxol had no additional effects on LNCaP or DU145 cells.
      These results suggest that LNCaP and DU145 prostate cancer cells show differences
      not only in androgen responsiveness but in sensitivity to taxol as well.

PMID- 10649444
TI  - Characterization of thiol-, aspartyl-, and thiol-metallo-peptidase activities in
      Madin-Darby canine kidney cells.
AB  - We combined fluorogenic substrates or internally quenched fluorescent peptides
      with specific inhibitors in the pH profile of proteolytic activity experiments in
      order to detect proteolytic activities in lysates of MDCK cells. Hydrolytic
      activities related to cathepsin B, L, and D were observed. Serine-proteinase was
      not detected; however, we clearly demonstrated the presence of a thiol-metallo
      endo-oligopeptidase, also called thimet-oligopeptidase (TOP). This peptidase from
      MDCK cells has substrate and inhibitor specificities as well as an activation
      profile with mercaptoethanol that are indistinguishable from the recombinant rat
      testis TOP (EC 3. 4.24.15). In addition, polyclonal purified antibodies to this
      enzyme depleted the TOP activity of MDCK cells in whole homogenate. Although we
      present only preliminary data, TOP is secreted by MDCK cells. The presence of TOP
      in a phenotype polarized MDCK cells can have special significance in the
      cytoplasmic selection, transport, or clearance of short peptides due to
      restriction of the enzyme to sequences from 6 to 17 amino acids. Therefore, the
      MDCK cell could be a very useful cellular model with which to study some of the
      suggested TOP biological functions as processing of biological active peptides
      and antigen presentation.

PMID- 10649445
TI  - Immunochemical characterization of myosin-specific phosphatase 1 regulatory
      subunits in bovine endothelium.
AB  - We have previously shown that myosin-specific phosphatase 1 (PPase 1) activity is
      critical for maintaining endothelial cell barrier function (Verin et al. [1995]
      Am. J. Physiol. 269:L99-L108). To further characterize myosin-specific PPase 1 in
      endothelium, we generated antibodies specific to published sequences of the
      myosin-associated PPase 1 regulatory subunit (M110) from smooth muscle. Peptide
      antigens were designed based upon consensus sequences for a single ankyrin repeat
      (ANK 110) and a leucine zipper motif region (LZ 110), which represents putative
      sites for binding the PPase 1 catalytic subunit (CS1) and myosin, respectively.
      Our initial study demonstrated that each antibody immunoprecipitated 2 proteins
      with an apparent Mr of 110 and 70 kD on SDS-PAGE. The CS1delta isoform, which
      appeared to be characteristic for the myosin-specific phosphatase, was co
      immunoprecipitated under non-denaturing conditions with ANK110 and LZ110 as was
      actin, myosin, and myosin light chain kinase (MLCK). Similarly,
      immunoprecipitation with specific anti-myosin or anti-MLCK antibodies under the
      same conditions, followed by immunostaining with either LZ110 or ANK110 revealed
      the same 110 and 70 kD protein bands. The 70 kD protein (p70) was immunoreactive
      with ANK 110 and LZ 110, was complexed with myosin and MLCK, and was detected in
      non-denaturing M110 immunoprecipitates. Consistent with these results,
      endothelial cell fractionation demonstrates the presence of p70 in both
      cytoskeletal and myosin-enriched fractions, but not in the myosin-depleted
      (cytosolic) fractions. These data suggest that endothelial cells may exhibit two
      distinct myosin-specific PPase 1 regulatory subunits which share certain
      structural features with the M110 regulatory subunit from smooth muscle and which
      are tightly associated with myosin and MLCK in a functional complex.

PMID- 10649446
TI  - Protein-protein interaction of FHL2, a LIM domain protein preferentially
      expressed in human heart, with hCDC47.
AB  - In the yeast two-hybrid library screening, the heart-specific FHL2 protein was
      found to interact with hCDC47. In vitro interaction study between FHL2 protein
      and hCDC47 was demonstrated. From the results of domain studies by the yeast two
      hybrid assay, the second and third LIM domains in conjunction with the first half
      LIM domain of FHL2 were identified to be important in binding with hCDC47.
      Besides, in Northern blot hybridization of human cancer cell lines, the highest
      FHL2 mRNA expression was detected in colorectal adenocarcinoma SW480 and HeLa
      cell S3. Our results imply that FHL2 protein may associate with cancer
      development and may act as a molecular adapter to form a multicomplex with hCDC47
      in the nucleus, thus it plays an important role in the specification or
      maintenance of the terminal differentiated phenotype of heart muscle cells.

PMID- 10649447
TI  - Effect of raloxifene-analog (LY 117018-Hcl) on the bone marrow of ovariectomized
      mice.
AB  - The effects of LY117018-Hcl (Ralox-A) on body metabolism and differentiation of
      bone marrow cells were studied in ovariectomized (OVX) mice. We used a mouse
      model in which estrogen depletion was established for a period of three months
      before treatment. After that period the animals were divided into three
      experimental groups consisting of sham-operated, OVX, and OVX-Ralox-A-treated
      mice. The OVX animals received daily treatment of Ralox-A during two time periods
      (35 and 65 days). After the treatment we measured the serum levels of protein,
      ion(s), lipid content, liver, and kidney functions. Our findings indicated that a
      change in hormonal state did not affect basic body metabolism except for causing
      an increase in triglycerides (TG) in the OVX mice, which was lowered by the Ralox
      A. A higher alkaline phosphatase (ALK-P) level was observed in serum of the OVX
      Ralox-A-treated mice than in serum of the OVX mice. We investigated the effects
      of estrogen depletion on the differentiation of hematopoietic and stromal cells
      that directly affect bone resorption and formation. OVX and OVX-treated mice were
      compared with the sham group and assessed for the alteration of these cells'
      differentiation. The proliferation of stromal stem cells was measured by CFU-F
      assay in vitro. A decrease in CFU-F colonies derived from OVX mice was observed
      and after the Ralox-A treatment the number of CFU-F reached sham levels. On the
      contrary, an upregulation of myeloid cells was observed when analyzed by FACS and
      by granulocyte/macrophage-colony forming unit (G/M-CFU) assay in selective
      culture conditions. The G/M-CFUs were increased in the OVX mice and were reduced
      to sham levels after Ralox-A treatment. In this study, we demonstrated cellular
      changes of stromal and hemopoietic cells in OVX mice and a beneficial Ralox-A
      effect that protected such cellular changes.

PMID- 10649448
TI  - Tandem repeat of C/EBP binding sites mediates PPARgamma2 gene transcription in
      glucocorticoid-induced adipocyte differentiation.
AB  - Bone marrow stromal stem cells differentiate into many different types of cells
      including osteoblasts and adipocytes. Long-term glucocorticoid treatment
      decreases osteoblastic activity but increases adipocytes. We investigated the
      mechanism of glucocorticoid-induced PPARgamma2 transcription. Treatment of human
      bone marrow stromal cells with dexamethasone induced the differentiation of these
      cells into adipocytes as measured by oil-red O staining, and Northern blot
      analysis showed that dexamethasone strongly induced PPARgamma2 mRNA expression in
      cells cultured in adipocyte induction medium. Moreover, the mRNA of C/EBPdelta,
      an adipocyte-promoting transcription factor, was also induced by dexamethasone in
      the presence of induction medium. Gel mobility shift assays using purified GST
      C/EBPdelta fusion protein showed that C/EBPdelta specifically binds to a 40-base
      pair DNA element from PPARgamma2 promoter, which was found to contain a tandem
      repeat of C/EBP binding sites. Transfection studies in mouse mesenchymal
      C3H10T1/2 cells showed that it is the tandem repeat of the C/EBP binding site in
      PPARgamma2 promoter region that regulates dexamethasone-mediated PPARgamma2 gene
      activation. We conclude that glucocorticoid-induced adipogenesis from bone marrow
      stromal cells is mediated through a reaction cascade in which dexamethasone
      transcriptionally activates C/EBPdelta; C/EBPdelta then binds to PPARgamma2
      promoter and transactivates PPARgamma2 gene expression. This activated master
      regulator, in turn, initiates the adipocyte differentiation.

PMID- 10649449
TI  - Cloning and characterization of the Yarrowia lipolytica squalene synthase (SQS1)
      gene and functional complementation of the Saccharomyces cerevisiae erg9
      mutation.
AB  - The squalene synthase (SQS) gene encodes a key regulatory enzyme, farnesyl
      diphosphate farnesyltransferase (EC 2.5.1.21), in sterol biosynthesis. The SQS1
      gene was isolated from a subgenomic library of the industrially important yeast
      Yarrowia lipolytica, using PCR-generated probes. Probes were based on conserved
      regions of homologues from different organisms. The complete nucleotide sequence
      of the coding region and the corresponding amino acid sequence were determined.
      The sequences showed extensive homologies with squalene synthase genes and
      enzymes from a number of other organisms and extreme amino acid conservation
      within the binding and catalytic domains. Direct cloning of a 4.3 kb genomic Y.
      lipolytica fragment, also comprising its own promoter and terminator sequences,
      into autonomously replicating plasmid YEp352 and subsequent transformation of a
      Saccharomyces cerevisiae mutant strain with relevant erg9: ura3-1 markers,
      resulted in functional complementation of these deficiencies, although Northern
      blot analyses did not reveal a unique full-length messenger. The availability of
      the Y. lipolytica SQS1 gene (GenBank Accession No. AF092497) offers prospects for
      metabolic engineering of the isoprenoid and sterol biosynthetic pathways.

PMID- 10649451
TI  - Aminopeptidase yscCo-II: a new cobalt-dependent aminopeptidase from yeast
      purification and biochemical characterization.
AB  - Saccharomyces cerevisiae aminopeptidase yscCo-II (APCo-II) was purified to
      apparent homogeneity by gel filtration, affinity chromatography and anion
      exchange chromatography. APCo-II is an hexameric cobalt-dependent metallo-enzyme
      with an estimated native molecular mass of 290 kDa. Enzyme activity is only
      detected in the presence of cobalt ions at pH 7.0. Substrate specificity studies
      indicate that aminopeptidase yscCo-II cleaves only basic N-terminal residues.
      PMSF, Cu(2+), 1,10-phenanthroline and bestatin were found to be very strong
      inhibitors of aminopeptidase yscCo-II activity. Kinetic studies indicated that
      the enzyme has a similar K(m) and Ka(Co )(activation constant of cobalt) and,
      following extraction of cobalt from the enzyme, activity was recovered only after
      cobalt addition.

PMID- 10649450
TI  - Asparagine as a nitrogen source for improving the secretion of mouse alpha
      amylase in Saccharomyces cerevisiae protease A-deficient strains.
AB  - A modified chemically defined medium was achieved by using asparagine as a
      nitrogen source to increase the production of secreted mouse alpha-amylase in
      several Saccharomyces cerevisiae protease A-deficient (pep4) strains. The
      specific productivity (quantity) and the 53 kDa non-glycosylated active form
      (quality) of mouse salivary alpha-amylase in liquid medium containing asparagine
      was remarkably improved compared to media containing other nitrogen sources,
      including ammonium sulphate, glutamic acid, arginine, casamino acids, yeast
      extract and peptone. Similar improvement was also observed on starch solid agar
      regarding the clarity and size of the halo zone formed by alpha-amylase activity.
      Compared with ammonium sulphate, advantages of using asparagine as the nitrogen
      source in liquid or solid medium included increasing the cell mass of test
      strains, recovering the viability of protease-deficient strains to levels similar
      to the wild-type strain, and increasing the copy number of the mouse alpha
      amylase expression vector in test strains. In turn, these advantages apparently
      contributed to the increase of secretion of mouse alpha-amylase in several test
      strains and especially in the protease A-deficient strains. In addition to
      demonstrating the use of modified chemically defined medium to improve the
      quality and quantity of secreted mouse alpha-amylase, this study also provides a
      new strategy to improve the secretion of heterologous proteins in protease A
      deficient strains.

PMID- 10649452
TI  - Flocculation of Saccharomyces cerevisiae is induced by transformation with the
      GAP1 gene from Kluyveromyces marxianus.
AB  - A non-flocculent strain of Saccharomyces cerevisiae was transformed with the GAP1
      gene which encodes p37, a GAPDH-like protein present in the cell wall of
      Kluyveromyces marxianus flocculent cells. The transformed cells were
      characterized with respect to flocculation behaviour, morphology, growth, cell
      wall integrity and GAPDH activity. A flocculent phenotype was acquired by the
      transformed cells, showing a behaviour in respect to flocculation/deflocculation
      very similar to that of K. marxianus. The presence of p37 in the cell wall was
      assessed by immunoprecipitation of biotinylated cell wall proteins and an
      accumulation of p37 was evident in the cell wall of transformed cells. This
      result was confirmed by studies using a chimeric protein resulting from fusing
      the p37 with a yeast-enhanced green fluorescent protein, yEGFP. The recombinant
      protein was localized mainly in the cell wall of the transformed strain, although
      the presence of p37 in the cytosol was indicated by an increase in GAPDH
      activity. Calcofluor white sensitivity tests indicated that the cell wall
      structure is affected by the accumulation of p37. These results provided further
      evidence of p37 function regarding flocculation and that although lacking a N
      terminal signal peptide p37 is targeted to the cell wall.

PMID- 10649453
TI  - Analysis of deletion phenotypes and GFP fusions of 21 novel Saccharomyces
      cerevisiae open reading frames.
AB  - As part of EUROFAN (European Functional Analysis Network), we investigated 21
      novel yeast open reading frames (ORFs) by growth and sporulation tests of
      deletion mutants. Two genes (YNL026w and YNL075w) are essential for mitotic
      growth and three deletion strains (ynl080c, ynl081c and ynl225c) grew with
      reduced rates. Two genes (YNL223w and YNL225c) were identified to be required for
      sporulation. In addition we also performed green fluorescent protein (GFP)
      tagging for localization studies. GFP labelling indicated the spindle pole body
      (Ynl225c-GFP) and the nucleus (Ynl075w-GFP) as the sites of action of two
      proteins. Ynl080c-GFP and Ynl081c-GFP fluorescence was visible in dot-shaped and
      elongated structures, whereas the Ynl022c-GFP signal was always found as one spot
      per cell, usually in the vicinity of nuclear DNA. The remaining C-terminal GFP
      fusions did not produce a clearly identifiable fluorescence signal. For 10 ORFs
      we constructed 5'-GFP fusions that were expressed from the regulatable GAL1
      promoter. In all cases we observed GFP fluorescence upon induction but the
      localization of the fusion proteins remained difficult to determine. GFP-Ynl020c
      and GFP-Ynl034w strains grew only poorly on galactose, indicating a toxic effect
      of the overexpressed fusion proteins. In summary, we obtained a discernible GFP
      localization pattern in five of 20 strains investigated (25%). A deletion
      phenotype was observed in seven of 21 (33%) and an overexpression phenotype in
      two of 10 (20%) cases.

PMID- 10649454
TI  - Inactivation of six genes from chromosomes VII and XIV of Saccharomyces
      cerevisiae and basic phenotypic analysis of the mutant strains.
AB  - Within the frame of the EUROFAN project, aimed at the functional analysis of the
      novel ORFs revealed by the systematic sequencing of the Saccharomyces cerevisiae
      genome, we have inactivated six ORFs encoding putative proteins with unknown
      function in the two S. cerevisiae strains FY1679 and W303-1B. Five ORFs are
      located on chromosome VII (YGR250c, YGR251w, YGR260w, YGR262c, YGR263c) and one
      on chromosome XIV (YNL234w). The genes have been inactivated in the FY1679 strain
      by a strategy that makes use of deletion cassettes containing the kanMX4 module,
      which confers resistance to geneticin to yeast cells, and short flanking regions
      homologous to the target locus (SFH). Tetrad dissection of heterozygous mutants
      and basic phenotypic analysis of the spores revealed that ORF YGR251w is an
      essential gene, while the disruption of YGR262c causes a severe slow-growth
      phenotype. Deletion of the remaining ORFs did not give rise to a detectable
      phenotype in the mutant strains. For each ORF we have cloned, in the pUG7
      plasmid, a replacement cassette that possesses long flanking regions homologous
      to the target locus (LFH) and, in the pRS416 plasmid, the cognate wild-type gene.
      The LFH replacement cassettes were used to inactivate the respective genes in the
      W303-1B strain. This work has been performed in the framework of the B0
      Consortium of the EUROFAN I project.

PMID- 10649455
TI  - Disruption and functional analysis of six ORFs on chromosome IV: YDR013w,
      YDR014w, YDR015c, YDR018c, YDR020c, YDR021w (FAL1).
AB  - The disruption of six novel yeast genes has been realized in two genetic
      backgrounds. Six open reading frames (ORFs) from chromosome IV, YDR013w, YDR014w,
      YDR015c, YDR018c, YDR020c and YDR021w, were disrupted using the KanMX4 marker and
      PCR-targeting with long flanking regions homologous (LFH) to the target locus.
      The deletants were verified at the molecular level, using PCR and Southern
      analysis. Sporulation and tetrad analysis revealed that ORFs YDR013w and YDR021w
      (also known as FAL1) are essential genes. Microscopical observations showed that
      ydr013wDelta haploid cells were blocked after one or two cell cycles and
      presented heterogeneous bud sizes. The ydr021wDelta haploid cells gave rise to
      microcolonies of about 20 cells. The other four ORFs are non-essential. Basic
      phenotypic analysis of the non-lethal deletant strains did not reveal any
      significant differences in cell morphology, growth on different media and
      temperatures, sporulation and mating efficiency between parental and mutant
      strains in the FY1679 background.

PMID- 10649456
TI  - Functional analysis of six novel ORFs on the left arm of chromosome XII in
      Saccharomyces cerevisiae reveals two essential genes, one of which is under cell
      cycle control.
AB  - Six novel Open Reading Frames (ORFs) located on the left arm of chromosome XII
      (YLL044w, YLL042c, YLL040c, YLL038c, YLL035w and YLL034c) have been analysed
      using short-flanking homology (SFH) gene replacement. Sporulation and tetrad
      analysis showed that YLL035w and YLL034c are essential for cell growth; yll035w
      spores arrested after two or three cell divisions, while the majority of yll034c
      spores stopped growth within two cell cycles after germination. Complementation
      of the yll035w deletion with its cognate clone, and a promoter-substitution
      experiment, indicated that the promoter of YLL035w may lie within the adjacent
      ORF, YLL036c. Transcriptional analysis demonstrated that YLL035w is under cell
      cycle regulation. Bioinformatic analyses produced significant matches between
      YLL034c and mammalian valosin and many other ATPases. The standard EUROFAN growth
      tests failed to reveal obvious phenotypes resulting from deletion of any of the
      four non-essential ORFs. Replacement cassettes, comprising the kanMX marker
      flanked by each ORF's promoter and terminator regions, were cloned into pUG7. All
      the cognate clones, except for YLL040c, were generated using direct PCR products
      amplified from genomic DNA or using gap-repair. All clones and strains produced
      have been deposited in the EUROFAN genetic stock centre (EUROSCARF, Frankfurt).

PMID- 10649489
TI  - Isolated complex I deficiency in children: clinical, biochemical and genetic
      aspects.
AB  - We retrospectively examined clinical and biochemical characteristics of 27
      patients with isolated enzymatic complex I deficiency (established in cultured
      skin fibroblasts) in whom common pathogenic mtDNA point mutations and major
      rearrangements were absent. Clinical phenotypes present in this group are Leigh
      syndrome (n = 7), Leigh-like syndrome (n = 6), fatal infantile lactic acidosis (n
      = 3), neonatal cardiomyopathy with lactic acidosis (n = 3), macrocephaly with
      progressive leukodystrophy (n = 2), and a residual group of unspecified
      encephalomyopathy (n = 6) subdivided into progressive (n = 4) and stable (n = 2)
      variants. Isolated complex I deficiency is one of the most frequently observed
      disturbance of the OXPHOS system. Respiratory chain enzyme assays performed in
      cultured fibroblasts and skeletal muscle tissue in general reveal similar
      results, but for complete diagnostics we recommend enzyme measurements performed
      in at least two different tissues to minimize the possibility of overlooking the
      enzymatic diagnosis. Lactate levels in blood and CSF and cerebral CT/MRI studies
      are highly informative, although normal findings do not exclude complex I
      deficiency. With the discovery of mutations in nuclear encoded complex I
      subunits, adequate pre- and postnatal counseling becomes available. Finally,
      considering information currently available, isolated complex I deficiency in
      children seems to be caused in the majority by mutations in nuclear DNA.

PMID- 10649490
TI  - Screening practices for mutations in the CFTR gene ABCC7.
AB  - Cystic fibrosis transmembrane conductance regulator (CFTR) gene studies are now
      one of the most frequent activities in clinical molecular genetics laboratories.
      The number of requests is growing, owing to the increasingly wide range of
      recognized CFTR gene diseases (cystic fibrosis, congenital bilateral absence of
      the vas deferens, disseminated bronchiectasis, allergic bronchopulmonary
      aspergillosis and chronic pancreatitis), and the availability of efficient
      molecular tools for detecting mutations. A growing number of tests capable of
      simultaneously detecting several frequent CF mutations are being developed, and
      commercial kits are now available. The most recent kits detect nearly 90% of
      defective alleles in Caucasians, a rate high enough for carrier screening and for
      the majority of diagnostic requests. However, because of the wide variety of
      molecular defects documented in the CFTR gene, only a limited number of
      laboratories have mastered the entire panoply of necessary techniques, while
      other laboratories have to refer certain cases to specialized centers with
      complementary and/or scanning tools at their disposal. A good knowledge of CFTR
      diseases and their molecular mechanisms, together with expertise in the various
      techniques, is crucial for interpreting the results. Diagnostic strategies must
      take into account the indication, the patient's ethnic origin, and the time
      available in the framework of genetic counseling. This review presents the
      methods most frequently used for detecting CFTR gene mutations, and discusses the
      strategies most suited to the different clinical settings.

PMID- 10649491
TI  - Mutations in the human TWIST gene.
AB  - Saethre-Chotzen syndrome is a relatively common craniosynostosis disorder with
      autosomal dominant inheritance. Mutations in the TWIST gene have been identified
      in patients with Saethre-Chotzen syndrome. The TWIST gene product is a
      transcription factor with DNA binding and helix-loop-helix domains. Numerous
      missense and nonsense mutations cluster in the functional domains, without any
      apparent mutational hot spot. Two novel point mutations and one novel
      polymorphism are included in this review. Large deletions including the TWIST
      gene have been identified in some patients with learning disabilities or mental
      retardation, which are not typically part of the Saethre-Chotzen syndrome.
      Comprehensive studies in patients with the clinical diagnosis of Saethre-Chotzen
      syndrome have demonstrated a TWIST gene abnormality in about 80%, up to 37% of
      which may be large deletions [Johnson et al., 1998]. The gene deletions and
      numerous nonsense mutations are suggestive of haploinsufficiency as the disease
      causing mechanism. No genotype phenotype correlation was apparent.

PMID- 10649492
TI  - Sequence variants of DLC1 in colorectal and ovarian tumours.
AB  - Loss of heterozygosity occurs frequently on the short arm of chromosome 8 in many
      neoplasms, including colorectal and ovarian cancer. Monochromosome transfer
      experiments into colorectal tumour cell lines have provided functional evidence
      for a tumour suppressor gene located at 8p22-23. One of the genes from this
      region that is expressed by our suppressed hybrids is a candidate tumour
      suppressor gene, DLC1 (deleted in liver cancer), which has homology to rat
      RhoGAP. We have delineated the structure of the DLC1 gene and used single
      stranded conformation polymorphism analysis (SSCP) to look for sequence variants
      in 126 colorectal and 33 ovarian primary tumours and cell lines. One exonic
      missense mutation and three intronic insertions/deletions were identified in
      primary colorectal tumours, as well as many polymorphisms present in germline
      DNAs. The rarity of exonic missense mutations, and the absence of protein
      truncating mutations, indicates that DLC1 is not the target of 8p LOH in
      colorectal or ovarian tumours. The delineation of the gene structure allows
      mutation analysis of DLC1 in other tumour types for which it remains a candidate
      tumour suppressor gene based on its location and homology to rhoGAP.

PMID- 10649493
TI  - Identification of P gene mutations in individuals with oculocutaneous albinism in
      sub-Saharan Africa.
AB  - Oculocutaneous albinism (OCA) is an inherited disorder resulting in
      hypopigmentation of the skin, hair, and eyes. OCA type 2 (tyrosinase-positive) is
      the most common recessively inherited disorder among southern African Blacks.
      OCA2 is also seen in southern African Caucasoids, but is less frequent. The gene
      responsible for this type of albinism, P, is the human homolog of the mouse pink
      eyed dilution gene. Mutations at this locus are also responsible for the milder
      hypopigmentation phenotype seen in individuals with brown oculocutaneous albinism
      (BOCA). A common African P mutation was identified in Black OCA2 individuals, and
      has since been shown to occur in Black individuals with brown OCA as well. This
      mutation is a 2.7 kb interstitial deletion. In this study, we undertook to screen
      the coding region of the P gene for mutations in the non-2.7 kb deletion alleles
      of OCA2 patients who did not carry the deletion allele in either one or both of
      their P genes. We identified four mutations (A334V, 614delA, 683insG [corrected],
      727insG) in a group of 39 unrelated Black OCA2 patients with a total of 52 non
      2.7 kb deletion OCA2 genes. When taking all OCA2 cases into consideration,
      including those homozygous for the 2.7 kb deletion mutation, these account for a
      further 1.7% of OCA2 mutations in southern African Blacks, increasing the overall
      mutation detection rate to 78.7%. Three mutations (E678K, L688F, I370T) were
      identified in a group of 15 Black patients with an initially unclassified type of
      OCA and another three mutations (IVS 14-2 (a-->g), V350M, P743L) were identified
      in nine Caucasoid OCA patients. Relatively few mutations, all with low frequency,
      were identified in the non-2.7 kb deletion OCA genes. We propose that other
      mutations may lie either within intronic sequence or within the promoter region
      of the gene.

PMID- 10649494
TI  - Identification of seven novel nucleotide variants in the hepatocyte nuclear
      factor-1alpha (TCF1) promoter region in MODY patients.
AB  - Maturity onset diabetes of the young (MODY) is a heterogeneous subtype of type II
      diabetes mellitus. To date, five MODY genes have been identified. Mutations in
      the hepatocyte nuclear factor-1alpha (HNF-1alpha) gene are associated with MODY3.
      In the present work, we implemented the HNF-1alpha promoter region in the
      screening of MODY-suspect patients and identified seven variants not detected in
      control subjects. The family was available for the -119delG variant, and
      segregration between MODY and the variant is observed. Most of these variants are
      located in highly conserved regions and may alter HNF-1alpha expression through
      binding alteration of nuclear factors or other mechanisms. We demonstrate by
      functional studies that the transcriptional activity of the -283A>C and -218T>C
      variant promoters were 30% and 70% of the wild type activity, respectively. These
      data suggest that HNF-1alpha promoter variants could be diabetogenic mutations,
      and emphasize that the accurate HNF-1alpha expression is important for the
      maintenance of normal pancreatic beta cell function.

PMID- 10649495
TI  - Glucocerebrosidase gene mutations in patients with type 2 Gaucher disease.
AB  - Gaucher disease, the most common lysosomal storage disorder, results from the
      inherited deficiency of the enzyme glucocerebrosidase. Three clinical types are
      recognized: type 1, non-neuronopathic; type 2, acute neuronopathic; and type 3,
      subacute neuronopathic. Type 2 Gaucher disease, the rarest type, is progressive
      and fatal. We have performed molecular analyses of a cohort of 31 patients with
      type 2 Gaucher disease. The cases studied included fetuses presenting prenatally
      with hydrops fetalis, infants with the collodion baby phenotype, and infants
      diagnosed after several months of life. All 62 mutant glucocerebrosidase (GBA)
      alleles were identified. Thirty-three different mutant alleles were found,
      including point mutations, splice junction mutations, deletions, fusion alleles
      and recombinant alleles. Eleven novel mutations were identified in these
      patients: R131L, H255Q, R285H, S196P, H311R, c.330delA, V398F, F259L, c.533delC,
      Y304C and A190E. Mutation L444P was found on 25 patient alleles. Southern blots
      and direct sequencing demonstrated that mutation L444P occurred alone on 9
      alleles, with E326K on one allele and as part of a recombinant allele on 15
      alleles. There were no homozygotes for point mutation L444P. The recombinant
      alleles that included L444P resulted from either reciprocal recombination or gene
      conversion with the nearby glucocerebrosidase pseudogene, and seven different
      sites of recombination were identified. Homozygosity for a recombinant allele was
      associated with early lethality. We have also summarized the literature
      describing mutations associated with type 2 disease, and list 50 different
      mutations. This report constitutes the most comprehensive molecular study to date
      of type 2 Gaucher disease, and it demonstrates that there is significant
      phenotypic and genotypic heterogeneity among patients with type 2 Gaucher
      disease. Hum Mutat 15:181-188, 2000. Published 2000 Wiley-Liss, Inc.

PMID- 10649496
TI  - Mutation detection by TaqMan-allele specific amplification: application to
      molecular diagnosis of glycogen storage disease type Ia and medium-chain acyl-CoA
      dehydrogenase deficiency.
AB  - We have devised an allele-specific amplification method with a TaqMan fluorogenic
      probe (TaqMan-ASA) for the detection of point mutations. Pairwise PCR
      amplification using two sets of allele-specific primers in the presence of a
      TaqMan probe was monitored in real time with a fluorescence detector. Difference
      in amplification efficiency between the two PCR reactions was determined by
      "threshold" cycles to differentiate mutant and normal alleles without post-PCR
      processing. The method measured the efficiency of amplification rather than the
      presence or absence of end-point PCR products, therefore allowing greater
      flexibility in designing allele-specific primers and an ample technical margin
      for allelic discrimination. We applied the TaqMan-ASA method to detect a
      prevalent 727G>T mutation in Japanese patients with glycogen storage disease type
      Ia and a common 985A>G mutation in Caucasian patients with medium-chain acyl-CoA
      dehydrogenase deficiency. The method can be automated and may be applicable to
      the DNA diagnosis of various genetic diseases.

PMID- 10649497
TI  - Nomenclature of trypsinogen mutations in hereditary pancreatitis.

PMID- 10649498
TI  - The International Federation of Human Genetics Societies: A nexus of
      communication among geneticists worldwide.

PMID- 10649499
TI  - Big Dye terminator cycle sequencing chemistry: accuracy of the dilution process
      and application for screening mutations in the TCF1 and GCK genes.

PMID- 10649500
TI  - A variation in the HINDIII restriction pattern of the dystrophin gene DMD with
      cDMD probe 11-14.

PMID- 10649501
TI  - Mutation analysis of the GALT gene in Czech and Slovak galactosemia populations:
      identification of six novel mutations, including a stop codon mutation (X380R).
AB  - A study of the galactose-1-phosphate uridyltransferase (GALT) gene from 37
      unrelated galactosemia families is reported here. A total of 16 sequence
      variations in eleven mutated alleles was found. The two most common molecular
      defects were the mutations Q188R (46.0%) and K285N (25.7%). Six novel mutations
      in the GALT gene, X380R, Y209S, E340K, L74fsdelCT, Q169K and L256/P257delGCC,
      were detected. Three mutations, V151A, L195P and R204X that were previously
      described in other populations, were also found. The mutation X380R, which breaks
      the stop codon of the GALT gene, causes elongation of the GALT enzyme's protein
      chain. A deletion of four nucleotides in the 5' promoter region, in a position
      116 - 119 nucleotides upstream from the initiate codon (5'UTR-119delGTCA), was
      revealed in Duarte (D2) alleles, in addition to N314D, IVS4nt-27g-->c, IVS5nt+62g
      ->a, and IVS5nt-24g-->a. An unusual molecular genotype was observed on 2 types of
      classical galactosemia alleles, with six variations from the normal nucleotide
      sequence presented in cis (mutation V151A or E340K plus five Duarte (D2)
      characteristic variations). In summary, galactosemia is a heterogeneous disorder
      at the molecular level, and mutation N314D, appears to be an ancient genetic
      variant of the GALT gene. Hum Mutat 15:206, 2000.

PMID- 10649502
TI  - Identification of three novel mutations of the palmitoyl-protein thioesterase-1
      (PPT1) gene in children with neuronal ceroid-lipofuscinosis.
AB  - Eight unrelated children with progressive neurological deterioration and granular
      osmiophilic deposits (GROD) due to an underlying palmitoyl-protein thioesterase
      deficiency were analyzed for mutations in the PPT1 gene. Three novel mutations
      (G118D, Q291X and F84del) were identified. The novel Q291X mutation was observed
      in an African-American child. The G118D and Q291X mutations occurred in infantile
      onset subjects. These two mutations would be predicted to have severe effects on
      enzyme activity. The novel F84del mutation involves an invariant phenylalanine
      residue. A missense mutation, Q177E, occurred in three subjects from two families
      with late-infantile NCL, confirming an association of the Q177E mutation with a
      late-infantile phenotype. Other previously described mutations were R151X (5/16
      alleles), T75P (3/16 alleles), R164X (1/16 alleles), and V181M (1/16 alleles).
      The current study expands the spectrum of mutations in PPT1 deficiency and
      further confirms the broad range of age of onset of symptoms resulting from an
      enzyme deficiency previously associated only with infantile NCL.

PMID- 10649503
TI  - Evidence of a single origin for the most frequent mutation (R402W) causing
      glutaryl-CoA dehydrogenase deficiency: identification of 3 novel polymorphisms
      and haplotype definition.
AB  - Glutaryl-CoA dehydrogenase (GCDH) deficiency causes glutaric aciduria type I (GA
      I), an inborn error of metabolism that is characterized clinically by dystonia
      and dyskinesia, biochemically by excretion of glutaric and 3-hydroxyglutaric
      acids in urine, and pathologically by neural degeneration of the caudate and
      putamen. To date, over 70 mutations in GCDH gene have been identified, single
      prevalent mutations have been found in communities in which GA I is particularly
      common, but generally GA I is heterogeneous. The most frequent mutation in
      Caucasians, R402W, has been identified in 12-16% of alleles. Here we report the
      frequency of mutation R402W in GA I Spanish patients, the characterization of
      three novel GCDH polymorphisms (IVS2+48T>C, IVS2-82T>G and 3'UTR 1518A>G) which,
      in combination with the two polymorphisms previously described (IVS2+64G>C,
      1209G>T) gave rise to the first definition of GCDH haplotypes and their
      frequencies in control population. Linkage disequilibrium has been found between
      mutation R402W and a specific haplotype, suggesting a single origin for this
      mutation. Hum Mutat 15:207, 2000.

PMID- 10649504
TI  - Five novel mutations in fourteen patients with Fabry Disease.
AB  - Fabry disease is an X-linked disorder caused by a deficiency of the lysosomal
      enzyme alpha-galactosidase A. The mutations responsible for Fabry disease are
      diverse and include large rearrangements as well as single base substitutions,
      and they are dispersed throughout the seven exons of the gene. In this study, we
      found five novel mutations in four different exons. We have detected the
      mutations by the PCR-SSCP method and then analysed them by direct sequencing.
      Three of the novel mutations were deletions: 1205delA, 1238del26 and 5236del18.
      We also found one novel nonsense mutation: W162X. The final novel mutation was an
      insertion combined with a deletion: 10995ins24del4.

PMID- 10649505
TI  - Novel Cystic Fibrosis mutation L1093P: functional analysis and possible Native
      American origin.
AB  - A novel mutation was detected using single-strand conformation polymorphism and
      heteroduplex analysis in a cystic fibrosis subject of mixed ancestry. Mutation
      3410T-->C in exon 17b caused the novel missense mutation L1093P; the other
      chromosome has mutation N1303K. The 31-year-old subject is pancreatic
      insufficient, had an FEV(1) score that was 33% of normal prior to a heart/lung
      transplant, and sweat chloride values of 116 and 95 mM when tested at ages 1 and
      11. Functional analysis using forskolin-stimulated efflux of (125)I in HEK cells
      transfected with an ABCC7 construct harboring the L1093P mutation confirmed that
      cAMP-mediated anion efflux was abnormal, but some function was preserved.
      Analysis of parental DNA established that N1303K was of English origin, while
      L1093P was of Greek, Irish or Native American (Cherokee) origin. Given the
      intensive screening for CF mutations in European populations, we hypothesize that
      L1093P is of Native American origin. Hum Mutat 15:208, 2000.

PMID- 10649506
TI  - Degeneration and regeneration of ganglion cell axons.
AB  - The retino-tectal system has been used to study developmental aspects of axon
      growth, synapse formation and the establishment of a precise topographic order as
      well as degeneration and regeneration of adult retinal ganglion cell (RGC) axons
      after axonal lesion. This paper reviews some novel findings that provide new
      insights into the mechanisms of developmental RGC axon growth, pathfinding, and
      target formation. It also focuses on the cellular and molecular cascades that
      underlie RGC degeneration following an axonal lesion and on some therapeutic
      strategies to enhance survival of axotomized RGCs in vivo. In addition, this
      review deals with problems related to the induction of regeneration after axonal
      lesion in the adult CNS using the retino-tectal system as model. Different
      therapeutic approaches to promote RGC regeneration and requirements for specific
      target formation of regenerating RGCs in vitro and in vivo are discussed.

PMID- 10649507
TI  - MAP1B expression and microtubule stability in growing and regenerating axons.
AB  - MAP1B is a microtubule-associated phosphoprotein that is particularly highly
      expressed in developing neurons. There is experimental evidence that it plays an
      important role in neuronal differentiation, especially the extension of axons and
      dendrites, but exactly what role is unclear. Recent experiments have shed light
      on the gene structure of MAP1B and identified some of the kinases that
      phosphorylate the protein. Implicit in these findings is the idea that MAP1B
      regulates the organisation of microtubules in neurites and is itself regulated in
      a complex way and at a number of levels.

PMID- 10649508
TI  - Strategies for studying microtubule transport in the neuron.
AB  - Microtubules are prominent cytoskeletal elements within the neuron. They are
      essential for the differentiation, growth, and maintenance of axons and
      dendrites. The microtubules within each type of process have a distinct pattern
      of organization, and these distinct patterns result in many of the morphological
      and structural features that distinguish axons and dendrites from one another.
      There are a number of challenges that must be met in order for the neuron to
      establish the microtubule arrays of axons and dendrites. One attractive model
      invokes the active transport of microtubules from the cell body of the neuron
      into and down these processes. In support of this model, specific motor proteins
      have now been identified within neurons that have the necessary properties to
      transport microtubules into developing axons and dendrites with the appropriate
      orientation for each type of process. An important goal is to develop microscopic
      methods that permit the visualization of microtubule transport within different
      regions of the neuron. To date, achieving this goal has met with mixed success,
      probably as a result of the geometry of the neuron and the inherent complexity of
      the neuronal microtubule arrays. While some approaches have failed to reveal
      microtubule transport, other more recent approaches have proven successful. These
      approaches provide strong visual support for a model based on microtubule
      transport, and provide hope that future approaches can provide even clearer
      demonstrations of this transport.

PMID- 10649509
TI  - Herpes simplex virus-mediated expression of the axonal protein tau in human model
      neurons (NT2-N cells).
AB  - The establishment of axonal-somatodendritic polarity is an important event during
      neuronal development. The analysis of the underlying molecular events requires
      experimental models that display characteristic steps in the development of
      polarity and that are accessible for experimental manipulations. Here we show
      that human model neurons (NT2-N cells) can be efficiently infected with an
      amplicon-based herpes simplex virus (HSV) system that expresses the axonal
      microtubule-associated protein tau. We demonstrate that the neurons express a
      high level of exogenous tau, which persists for several days, thus allowing us to
      analyze the morphological effects of the expressed protein. The intracellular
      interactions of tau and the effects on the microtubule structure of infected
      neurons, which were processed for immunocytochemistry, were determined using
      laser scanning microscopy (LSM). Exogenous tau expression does not result in an
      increased axon growth of the neurons but promotes neuronal microtubule assembly
      as indicated by an increased amount of total microtubule polymer as well as a
      labile, detyrosinated microtubule subpopulation. In contrast, tau expression does
      not induce a significant microtubule stabilization as judged from the
      quantitation of acetylated microtubule staining 24 hours after infection. The
      data demonstrate that HSV-mediated expression of proteins in human model neurons
      provides a useful system for analysis of the effect of neuronal proteins on the
      morphology and cytoskeletal organization of terminally differentiated polar
      neurons. In addition, it suggests a role for tau as a factor which locally
      promotes tubulin polymerization while the dynamics of axonal microtubules are
      preserved.

PMID- 10649510
TI  - Micro-scale chromophore-assisted laser inactivation of nerve growth cone
      proteins.
AB  - Directed growth cone movement is crucial for the correct wiring of the nervous
      system. This movement is governed by the concerted actions of cell surface
      receptors, signaling proteins, cytoskeleton-associated molecules, and molecular
      motors. In order to investigate the molecular basis of growth cone motility, we
      applied a new technique to functionally inactivate proteins: micro-scale
      Chromophore-Assisted Laser Inactivation [Diamond et al. (1993) Neuron 11:409
      421]. Micro-CALI uses laser light of 620 nm, focused through microscope optics
      into a 10-microm spot. The laser energy is targeted via specific Malachite green
      labeled, non-function-blocking antibodies, that generate short-lived protein
      damaging hydroxyl radicals [Liao et al. (1994) Proc Natl Acad Sci USA 91:2659
      2663]. Micro-CALI mediates specific loss of protein function with unachieved
      spatial and temporal resolution. Combined with time-lapse video microscopy, it
      offers the possibility to induce and observe changes in growth cone dynamics on a
      real time base. We present here the effects of the acute and localized
      inactivation of selected growth cone molecules on growth cone behavior and
      morphology. Based on our observations, we propose specific roles for these
      proteins in growth cone motility and neurite outgrowth.

PMID- 10649511
TI  - Characterization of several invertebrate muscle cell types: a comparison with
      vertebrate muscles.
AB  - Ultrastructural classification of invertebrate muscles is complex and not always
      clear. The aim of the present paper was to establish some criteria that might be
      useful for classification of invertebrate muscles and for a better understanding
      of the differences between them. The procedures used were: (1) immunochemical
      evaluation of those proteins that differentiated striated from smooth muscle
      (troponin, caldesmon, and calponin), and (2) calculations of several myofilament
      parameters to establish differences among muscles. The muscles studied were:
      striated muscles from the rat, Drosophila, the crab Callinectes, and the snail
      Helix (heart); obliquely striated muscles from the earthworm Eisenia foetida and
      Helix (mouth); and smooth muscles from the rat, and Helix (retractor, body wall,
      and intestinal wall). Immunochemical studies revealed that troponin was only
      present in the striated muscles and the obliquely striated muscle from Eisenia,
      whereas caldesmon and calponin were only present in the smooth muscles and the
      obliquely striated muscle from Helix. The highest thick filament/thin filament
      volume ratio was found in the striated muscles, followed by the obliquely
      striated muscles, and the smooth muscles. This suggests the order in which the
      contraction strength decreases. The myofilament length is inversely related to
      the contraction speed, which was higher in the striated muscles than in the
      obliquely striated muscles. In vertebrates, the smooth muscle seems to be less
      rapid than the striated muscle because their myofilaments are longer. This
      assertion cannot be generalized for invertebrate smooth muscle, because
      myofilament lengths vary widely in both striated and smooth muscles. In smooth
      muscles, the presence of apparently unordered electron-dense bodies instead of
      ordered Z lines and the absence of true sarcomeres permit a certain overlapping
      of thin filaments increasing the range of shortening.

PMID- 10649512
TI  - Autoradiographic distribution of radioactivity from (14)C-GABA in the mouse.
AB  - We investigated the distribution of radioactivity from (14)C-labeled gamma
      aminobutyric acid (GABA) in the mouse by in vivo autoradiography to clarify the
      tissues that show GABA uptake and/or GABA binding. Male mice were injected
      intravenously with (14)C-GABA in both the absence and presence of an excess of
      unlabeled GABA, baclofen and isoguvacine. Whole-body autoradiography of (3)H
      baclofen, a GABA(B) receptor agonist was also performed. At short intervals after
      (14)C-GABA injection ( 3 and 6 minutes), very high radioactivity was detected in
      the kidney cortex, liver, pineal gland, hypophysis, median eminence of the
      hypothalamus, and cervical ganglion. The hyaline cartilage and glandular part of
      the stomach showed moderate radioactivity. In the presence of an excess amount of
      unlabeled GABA, radioactivity in most of tissues decreased significantly, but no
      significant difference in radioactivity was observed in the presence of baclofen
      and isoguvacine, agonists of GABA(A) and GABA(B) receptors, respectively.
      Autoradiography of (3)H-baclofen showed that the kidney had high level of
      radioactivity, whereas the activity in other tissues and organs was similar or
      lower than in the blood except for the content of the urinary bladder and the
      pancreas at 15 minutes after injection. These data indicate that radioactivity
      from incorporated (14)C-GABA into a variety of cells is much higher than that
      from bound (14)C-GABA to the receptor sites. Our results suggest that GABA can be
      quickly localized in many organs of the mouse body after 3 minutes following
      injection, and GABA may serve multiple functions in those organs.

PMID- 10649513
TI  - Incredibly low false-negative proportion: watch out!

PMID- 10649515
TI  - Value of ultrasound-guided fine-needle aspiration in the management of ovarian
      and paraovarian cysts.
AB  - This study was designed to assess if cytology was accurate for an appropriate
      diagnosis of ovarian and paraovarian cysts, and if the ultrasound-cytology
      estradiol (UCE) triad was sufficient to discriminate functional vs. nonfunctional
      cysts, the latter requiring surgical resection. One hundred twenty-two ultrasound
      diagnosed adnexal cysts were punctured and surgically removed, and then subjected
      to cytologic and histologic examinations; 90 of these fluids were assayed for
      estradiol. Histologically, 30 cysts were functional and 92 were nonfunctional. A
      correct discrimination between functional and nonfunctional origin was obtained
      in 54.9% of cases with cytology, in 94.4% with estradiol assay, in 50.8% with
      ultrasonography, and in 97.8% with these three examinations combined (UCE triad).
      Among the 34 patients with no criteria of neoplastic origin (age >40,
      ultrasonographic findings), the UCE triad diagnosed six functional cysts.
      Therefore, 17.6% (6/34) of these young women could have avoided unnecessary
      surgery. Diagn. Cytopathol. 2000;22:70-80.

PMID- 10649514
TI  - Comparative analysis of DNA flow cytometry and cytology of bladder washings:
      review of discordant cases.
AB  - DNA analysis is becoming an important diagnostic and prognostic adjunct test in
      urinary cytology. The aim of this study was to compare the results of DNA flow
      cytometry (FCM) with the cytologic diagnosis of bladder washings (BW). DNA ploidy
      was evaluated in 251 BW. In 65 cases, follow-up surgical biopsies were available.
      Cytology results were classified as positive and negative, and FCM results were
      categorized as diploid and aneuploid. Both tests were evaluated independently.
      Cases were defined as discordant if the cytology was negative and FCM was
      aneuploid, or if the cytology was positive and FCM was diploid. All discordant
      cases were reviewed, and positive predictive values (PPV) for FCM and cytology
      were calculated for cases with follow-up biopsy results. Cytologic evaluation
      classified 181 cases as negative, with 175 of them diploid and 6 aneuploid; and
      70 as positive, with 53 of them diploid and 17 aneuploid. Overall, there were 59
      discordant cases (23.5%, with a confidence limit of 18.2-28.8%). Of 6
      aneuploid/cytology-negative cases, biopsies were available in 4 cases and showed
      one grade 1, two grade 2, and one grade 3 urothelial carcinoma (UC). Reanalysis
      of these 6 cytology specimens showed 1 case that should have been interpreted as
      positive (false negative), 4 true negatives, and 1 polyoma virus infection. Out
      of 53 diploid/cytology-positive cases, biopsies were available in 45 cases and
      showed nine grade 1, 14 grade 2, three grade 3 UCs, 11 UCs in situ, and eight
      negative biopsies. The PPV for cytology was 85%, and the PPV for FCM was 95%. We
      concluded that FCM, which requires a large number of cells, often cannot detect
      small aneuploid populations, which are present particularly in cases of UC in
      situ.

PMID- 10649516
TI  - Role of DNA flow cytometry and image cytometry on effusion fluid.
AB  - The objective of the study was to assess the value of DNA flow cytometry (FCM)
      and image cytometry (ICM) as an adjunct to routine diagnostic cytology. In this
      prospective study, 100 consecutive effusion fluids were studied for routine
      cytology, DNA FCM, and in selected cases, ICM. One half of the centrifuged fluid
      sample was used for routine cytology and the remaining portion was used for DNA
      FCM. Nuclear area, nuclear diameter, nuclear perimeter, nuclear convex perimeter,
      nuclear roundess, and nuclear convex area were measured on at least 100 cells by
      ICM in cytologically malignant or DNA aneuploid cases along with control cases.
      Clinical follow-up was done in all cases. There were 22 cytologically malignant
      cases and 78 cytologically benign cases. Among the 22 cytologically malignant
      cases, there were 11 aneuploid and diploid cases each by DNA FCM. Out of 78
      cytologically benign cases, six (7.7%) were aneuploid by DNA FCM. Smears of these
      cases showed predominantly reactive mesothelial cells, but the DNA histograms
      showed hypodiploid (one), hyperdiploid (three), tetraploid (one), and
      hypertetraploid (one) aneuploidy. Follow-up of these cases showed clinical or
      histologic features of malignancy except in one case of tetraploid aneuploidy,
      which did not show any features of malignancy and responded well to
      antitubercular therapy. Therefore, out of 27 malignant effusions, DNA FCM picked
      up 16 cases and routine cytology detected 22 cases. Sensitivity and specificity
      of DNA FCM were thus 59.25% and 98.63%, respectively. There was a statistically
      significant difference (Student's unpaired t-test, P < 0.05) between
      cytologically malignant cases and control benign cases in all the nuclear
      morphometric parameters except for nuclear roundness. There was, however, no
      statistically significant difference of nuclear morphometric parameters between
      cytologically benign vs. DNA aneuploid cases and control benign cases. DNA FCM is
      a useful adjunct for routine diagnostic cytology. Visual diagnostic cytology and
      morphometric digital microscopy miss some cases of malignancy which can be
      detected by DNA flow cytometry. Diagn. Cytopathol. 2000;22:81-85.

PMID- 10649517
TI  - Liquid-based cervical-cell collection with brushes and wooden spatulas: a
      comparison of 100 conventional smears from high-risk women to liquid-fixed
      cytocentrifuge slides, demonstrating a cost-effective, alternative monolayer
      slide preparation method.
AB  - Our purpose was to demonstrate that 17.5-mm liquid-based cytocentrifuge circle
      slides made using a Hettich (Andreas Hettich Co., Tuttlingen, Germany)
      cytocentrifuge are at least as efficacious as conventional smears for detecting
      cervical abnormalities. One hundred conventional smears were collected with
      cytobrushes and wooden spatulas from high-risk women. Both devices were then
      placed into CytoRich Red (AutoCyte, Inc., Burlington, NC). Cells were
      concentrated from CytoRich Red by centrifugation and suspended in CytoRich
      Yellow. Two 17.5-mm circle-slides were produced, compared to each other in order
      to test reproducibility of diagnoses between slides, and compared to conventional
      slides. Sixty-five normals, three ASCUS, three LSIL, and two HSIL matched.
      Overall, cytocentrifugation yielded 27 additional findings among 25 cases. Also,
      it downgraded one conventional ASCUS to normal (immature metaplasia and chronic
      inflammation) and one conventional HSIL to normal (transitional cell metaplasia).
      Cytocentrifugation of 14 conventional normals afforded four ASCUS and 10 LSIL.
      Cytocentrifugation of 11 conventional ASCUS afforded nine LSIL and two HSIL (one
      with AIS). One HSIL + AIS was found with a conventional HSIL. Cytobrushes and
      wooden spatulas can be used to collect material for liquid-based cervico-vaginal
      cytology if they are placed into CytoRich Red. Hettich cytocentrifuge slides were
      more reliable than conventional smears in presenting well-dispersed, sharply
      imaged cells, affording greater diagnostic sensitivity and certainty. Compared to
      previous split-sample studies, three different outcomes were noted: 1) the
      endocervical component was consistently well-represented; 2) AIS was seen more
      often in liquid-based slides; and 3) the liquid-based slide did not underdiagnose
      its conventional companion. The liquid-based preparations downgraded one ASCUS to
      normal and one conventional HSIL to transitional-cell metaplasia. Histology
      correlation of these two cases agreed with the liquid-based cytology diagnoses,
      which validates their specificity. These improvements are ascribed to differences
      in fixation and processing. The low cost, ease of operation, and reusable
      chambers of the Hettich cytocentrifuge make it a cost-effective liquid-based
      cytology instrument, especially for small to intermediate-size laboratories. The
      claims that this paper makes must be proven by additional studies, and test
      implementation needs to be scrutinized by appropriate regulatory agencies whose
      standards may vary from country to country. Diagn. Cytopathol. 2000;22:86-91.

PMID- 10649518
TI  - Initial evaluation of pulmonary abnormalities: CT-guided fine-needle aspiration
      biopsy and fluoride-18 fluorodeoxyglucose positron emission tomography
      correlation.
AB  - Fluoride-18 fluorodeoxyglucose positron emission tomography (FDG-PET) can
      evaluate patients with new pulmonary lesions. CT-guided fine-needle aspiration
      (FNA) biopsy is a well-described method in the diagnosis of pulmonary lesions. In
      order to correlate results from these testing modalities, retrospective findings
      from FNA biopsies of pulmonary lesions are compared to concurrent FDG-PET scans.
      Files of the Saint Louis University Hospital were retrospectively searched for
      patients with CT-guided FNA biopsies of the lung during a consecutive 3-yr
      period. Patients were collected, and corresponding FDG-PET scans were identified.
      Only new pulmonary lesions presenting for initial evaluation were included.
      Findings were correlated. Forty patients with a total number of 41 CT-guided FNA
      biopsies of the lung and thoracic cavity had corresponding FDG-PET scans. The
      combined positivity of the two testing modalities, i.e., cases where both FNA and
      FDG-PET scan were positive, yielded a sensitivity of 100% (37/37). Four patients
      had infectious/inflammatory processes by CT-guided FNA biopsy that were FDG-PET
      positive for malignancy. CT-guided FNA biopsies with FDG-PET scans of pulmonary
      lesions are important, complementary diagnostic tools which can contribute
      significantly to the management and treatment of pulmonary disease. Diagn.
      Cytopathol. 2000;22:92-96.

PMID- 10649519
TI  - Fine-needle aspiration cytology of desmoplastic malignant melanoma metastatic to
      the parotid gland: case report and review of the literature.
AB  - We report a case of desmoplastic malignant melanoma metastatic to the parotid
      gland initially evaluated by fine-needle aspiration. The cytologic findings
      consisted of scattered spindle cells in a background of heterogeneous lymphoid
      cells. The spindle cells were scant and displayed mild cytologic atypia. In
      addition, rare stromal fragments were also present. Cytoplasmic pigment and
      intranuclear cytoplasmic inclusions were not seen. The initial impression was
      that of a reactive lymph node with fibrosis. In retrospect, rare spindle cells
      displayed moderate atypia. In addition, the stromal fragments were cellular and
      contained spindle cells with mild atypia. These cytologic findings along with a
      known history of malignant melanoma should provide clues to the correct diagnosis
      of desmoplastic malignant melanoma. Diagn. Cytopathol. 2000;22:97-100.

PMID- 10649520
TI  - Fine-needle aspiration of cytomegalovirus sialadenitis in a patient with acquired
      immunodeficiency syndrome: pitfalls of diff-quik staining.
AB  - A case of cytomegalovirus (CMV) sialadenitis in a patient with acquired
      immunodeficiency syndrome (AIDS) diagnosed by fine-needle aspiration biopsy
      (FNAB) is reported. Although a diagnosis of CMV sialadenitis can be established
      on Diff-Quik-stained slides, the characteristic viral changes are the best
      appreciated on slides stained by the Papanicolaou (Pap) technique. Differential
      pitfalls are discussed. It needs to be stressed that clinically unsuspected
      diagnosis of CMV infection may uncover congenital or acquired defects of cellular
      immunity, and particularly AIDS. Diagn. Cytopathol. 2000;22:101-103.

PMID- 10649521
TI  - Fine-needle aspiration biopsy of metastatic chordoma: case report and review of
      the literature.
AB  - Chordoma is a distinct malignant neoplasm arising from the remnants of the
      notochord and occurring mostly in the fifth or sixth decade of life, and
      occupying most frequently the sacral area (Bibbo, Comprehensive Cytopathology
      1997; p 534). Metastases of the neoplasm may occur in 10-40% of cases (Jenkins et
      al., Clin. Radiol. 1995;50:416-417). Because of its rarity, the diagnosis of
      chordoma may be difficult to render, especially on fine-needle aspiration biopsy
      (FNAB). However, a clear-cut distinction of chordoma from other neoplasms is of
      utmost importance, since the prognosis and treatment of the patient will depend
      on the final diagnosis. This distinction in the case of metastases can be made
      easily, where correlation of previous histology has been done and/or ancillary
      studies have been performed. Diagn. Cytopathol. 2000;22:104-106.

PMID- 10649522
TI  - Fine-needle aspiration cytology of primary granulosa cell tumor of the adrenal
      gland: a case report.
AB  - Extraovarian granulosa cell tumors are extremely rare. We report on a primary
      granulosa cell tumor of the adrenal gland. A 69-yr-old African-American female
      presented with a 1-yr history of irregular uterine bleeding and a palpable right
      abdominal mass. CT scan showed a 9.0-cm suprarenal mass as well as an enlarged
      uterus. CT-guided fine-needle aspiration (FNA) cytology of the adrenal mass was
      interpreted as a malignant neoplasm. She underwent exploratory laparotomy, right
      nephrectomy, and hysterectomy with bilateral salpingo-oophorectomy. The gross,
      histologic, and immunohistochemical findings of the adrenal mass were
      characteristic of a granulosa cell tumor. The uterus contained multiple
      leiomyomas. The endometrium showed simple hyperplasia. Both fallopian tubes and
      ovaries showed no pathologic abnormality. There was no evidence of tumor
      elsewhere. Although rare, extraovarian granulosa cell tumor should be considered
      in the differential diagnosis of adrenal tumors in women showing the FNA features
      described herein, especially when there is evidence of excessive estrogen
      production. Diagn. Cytopathol. 2000;22:107-109.

PMID- 10649523
TI  - Vascular adrenal pseudocyst: cytologic and immunohistochemical study.
AB  - Adrenal vascular cysts are rare lesions that might be considered in the
      differential diagnosis of adrenal tumors. Their origin is not clear. We report
      the clinicopathological findings of a large adrenal hemorrhagic pseudocyst (AHP)
      in a 73-yr-old man who complained of abdominal pain. An abdominal CT showed a 9
      cm tumor in the left adrenal. A fine-needle aspiration biopsy (FNAB) was
      hemorrhagic and inconclusive. The tumor was excised and touch imprints were taken
      showing groups of spindled and fusiform cells with elongated nuclei, without
      atypia. Histologically, the tumor was well delimited by a fibrous capsule and
      contained numerous cystic spaces lined by endothelial cells and filled with
      erythrocytes, fibrin thrombus, and necrotic debris. Immunohistochemical study
      showed strong positivity for factor VIII-RA, CD31, and CD34. Also, the remaining
      adrenal showed a prominent frame of thin and medium caliber vessels, supporting a
      vascular origin for this entity. This case illustrates the difficulty in making a
      diagnosis by FNA and to keep in mind AHP when hematic aspirates are obtained from
      an adrenal tumor mass.

PMID- 10649524
TI  - Mesothelial hyperplasia with reactive atypia: diagnostic pitfalls and role of
      immunohistochemical studies-a case report.
AB  - The cytomorphologic features of highly reactive mesothelial cells can be
      difficult to distinguish from malignant cells. We report on an unusual case of
      mesothelial hyperplasia in a pericardial effusion. The specimen contained bizarre
      shaped cells and large tissue fragments in a patient with a history of lung
      carcinoma. The atypical cells were negative for CEA and LeuM-1 and positive for
      cytokeratins (AE1/3) and HBME-1. Strong HBME-1 positivity supported a mesothelial
      origin of the atypical cells and led to the diagnosis of reactive mesothelium.
      While HBME-1 cannot be used as the sole marker to establish an mesothelial
      origin; its use in a immunohistochemistry panel may be useful in individual cases
      to distinguish reactive mesothelial cells from carcinoma in effusion cytology.
      Diagn. Cytopathol. 2000;22:113-116.

PMID- 10649525
TI  - Application of the cell block method, utilizing mount quick mounting medium.
AB  - Our objective was to determine the applicability of cell transfer and cell block
      methods using Mount Quick (Daido Sangyo, Saitama, Japan) mounting medium (MQ) for
      hematoxylin-eosin (H&E) and immunohistochemical staining of several limited
      amounts of biological materials in slide preparations. The materials investigated
      were histopathologically confirmed malignant mesotheliomas (pleural effusions)
      and malignant lymphomas, a malignant melanoma, and an amelanotic melanoma in
      sealed slides. Monoclonal antibodies against carcinoembryonic antigen (CEA),
      epithelial membrane antigen (EMA), cancer antigen 125 (CA-125), vimentin,
      thrombomodulin (TM), cytokeratin, UCHL-1, L-26, melanoma-specific antigen
      (HMB45), and S-100 protein (S-100) were applied in the investigation. The
      malignant mesotheliomas were found to be positive for EMA, cytokeratin, vimentin,
      TM, and CA-125, and negative for CEA, with no differences being observed in
      findings from direct contact preparations. Using T-cell-type malignant lymphomas
      for immunohistochemistry, UCHL-1 positivity and L-26 negativity were clearly
      demonstrated. The malignant melanoma and amelanotic melanoma materials stained
      strongly for HMB45 and S-100. Cell transfer employing MQ is a suitable approach
      for immunohistochemical investigations of limited materials. In addition, cell
      blocks derived from MQ-embedded smears can be used for both H&E and
      immunohistochemical staining. Diagn. Cytopathol. 2000;22:117-119.

PMID- 10649526
TI  - Fine-needle aspiration cytopathology in diagnosis and classification of malignant
      lymphoma: accurate and reliable?
AB  - Diagnosis of malignant lymphoma by fine-needle aspiration biopsy (FNAB) remains a
      topic of skepticism and controversy. Because of the limitations of pure
      morphology, subclassfication of non-Hodgkin malignant lymphoma (NHML) by FNAB
      often requires ancillary studies which impose a challenge not typically required
      of other FNAB diagnoses. Despite the dubiousness expressed by many, the evidence
      shows that a large percentage of NHML cases can be recognized and correctly
      classified using FNAB. Diagnostic accuracy is dependent on several factors
      including the type of NHML. The emergent WHO classification of lymphomas is one
      that appears to more readily accommodate the cytologic methods for NHML
      diagnosis.

PMID- 10649527
TI  - Changing trends in breast fine-needle aspiration: results of the Papanicolaou
      Society of Cytopathology Survey.
AB  - Following the NCI-sponsored consensus conference on fine-needle aspiration of the
      breast, the Criteria and Nomenclature Task Force of the Papanicolaou Society of
      Cytopathology undertook a survey to assess the status of these issues and
      recommendations among practicing cytopathologists. The survey was designed to
      assess the impact of the changing trends in the diagnosis of breast lesions on
      cytopathology laboratories. It also intended to assess the impact of the
      recommendations of the consensus conference concerning the inclusion of a
      statement in breast FNA reports recommending the use of the triple test, the use
      of the proposed diagnostic terminology, and to evaluate criteria for specimen
      adequacy in breast FNAs used in different institutions. The results of this
      survey indicate the impact of an increasing use of core biopsies on the number of
      breast FNAs performed over the last several years. The recently recommended
      diagnostic terminology for breast FNA has quickly gained wide acceptance, as has
      the fundamental concept of the triple test. The issue of specimen adequacy,
      however, remains controversial, with some laboratories utilizing quantitative
      criteria, while the majority do not. Diagn. Cytopathol. 2000;22:126-130.

PMID- 10649528
TI  - Cytology of salivary duct carcinoma.

PMID- 10649529
TI  - Reply: cytology of salivary duct carcinoma

PMID- 10649530
TI  - Anaplastic spindle-cell squamous carcinoma arising in association with tall-cell
      papillary cancer of the thyroid: A potential pitfall
AB  - The following is a correction to the original article that appeared in Diagnostic
      Cytopathology 1999;21:413-418. Owing to a publisher's error, Figure 4C on p. 415
      was incorrectly reproduced. The correct illustrations and captions for this page
      are given here.

PMID- 10649531
TI  - Neurocognitive complaints in HIV-infection and their relationship to depressive
      symptoms and neuropsychological functioning.
AB  - We examined the degree to which depressive symptoms, clinical staging of HIV
      disease, and neuropsychological (NP) functioning were related to neurocognitive
      complaints in HIV-infection. One hundred adults with HIV-infection (12
      asymptomatic, 41 mildly symptomatic, and 47 with AIDS) were administered NP tests
      of attention and working memory, language, psychomotor speed, verbal memory, and
      conceptual problem-solving, the Beck Depression Inventory, and the Patient's
      Assessment of Own Functioning Inventory (Chelune, Heaton & Lehman, 1986), a
      subjective neurocognitive complaint questionnaire where patients rated their
      problems with memory, language and communication, sensory-motor skills, and
      higher-level cognitive and intellectual functions. Neurocognitive complaints
      (regardless of specific type) were correlated significantly with depressive
      symptoms and with NP measures of attention and working memory, psychomotor
      skills, and learning efficiency. However, multiple regression analyses revealed
      that depressive symptoms accounted for the majority of variance explained in
      neurocognitive complaints with psychomotor efficiency generally predicting the
      remaining variance. Neurocognitive complaints did not differ according to HIV
      clinical staging.

PMID- 10649532
TI  - Neuropsychiatric correlates of memory-metamemory dissociations in HIV-infection.
AB  - Ninety-one adults with HIV-infection who varied in the concordance between their
      subjective memory complaints (or metamemory) on the Patient's Assessment of Own
      Functioning (Chelune, Heaton, & Lehman, 1986) and their memory performance on the
      California Verbal Learning Test (CVLT), were compared on the Beck Depression
      Inventory (BDI), and on neuropsychological (NP) tests of attention, language,
      psychomotor speed, and conceptual problem-solving. Subjects with low memory
      complaints and normal CVLT performance (n = 29) had low BDI scores and were
      normal in all other NP abilities. Subjects with high memory complaints and
      impaired CVLT performance (n = 20) had elevations on the BDI as well as NP
      impairments in psychomotor speed and category fluency. Subjects with low memory
      complaints but impaired CVLT performance (n = 16) had low BDI scores and were
      selectively impaired in conceptual problem-solving. Subjects with high memory
      complaints but normal CVLT performance (n = 26) had high BDI scores and normal NP
      functioning in all other abilities. These results suggest that there are at least
      two key determinants to metamemory inaccuracy in HIV-infection, namely, frontal
      executive impairments and mood disturbance.

PMID- 10649533
TI  - Effects of depressed mood versus clinical depression on neuropsychological test
      performance among African American men impacted by HIV/AIDS.
AB  - The utility of self-report measures in identifying those at risk for depressive
      disorder and the adverse impact of depression versus depressed mood and HIV
      serostatus on neuropsychological (NP) test performance were examined in a large
      sample (N = 243) of gay and bisexual African American men. Results indicate high
      rates of depression relative to recent population estimates, regardless of
      methodology, but that the use of standard cut-scores for self-report inventories
      may significantly overestimate psychiatric morbidity. Limited independent effects
      of serostatus or depression on NP test performance were observed. More
      importantly, a complex set of adverse effects of depression and its interaction
      with serostatus which varied according to the methodology used to assess
      depression were observed. These findings are discussed in light of ongoing
      controversy regarding the relative influence of depression on neuropsychological
      functioning among people living with HIV/AIDS.

PMID- 10649534
TI  - Short-term memory deficit after focal parietal damage.
AB  - The neuropsychological symptomatology is reported for a 44-year-old patient of
      normal intelligence, EE, after removal of a circumscribed left hemispheric tumor
      the major part of which was located in the angular gyrus and in the subcortical
      white matter. EE had a distinct and persistent short-term memory impairment
      together with an equally severe impairment in transcoding numbers. On the other
      hand, his performance was flawless in calculation tasks and in all other tests
      involving number processing. Impairments in language tests could be attributed to
      his short-term memory deficit, which furthermore was characterized by a strong
      primacy effect in the absence of a recency effect. His graphomotoric output was
      temporarily inhibited. The patient, with a strong left-sided dominance,
      manifested a bi-hemispherical activation of the Broca and Wernicke regions in a
      positron-emission-tomographic investigation when required to produce verbs which
      he was to derive from nouns. The findings in EE suggest that unilateral and
      restricted lateral parietal damage can result in a profound short-term memory
      deficit together with a transcoding deficit for stimuli extending over only a few
      digits or syllables in the absence of any symptoms of the Gerstmann syndrome.

PMID- 10649535
TI  - Retrieval of long-term memory in patients with brain injuries.
AB  - Retrieval from long-term memory in patients with brain injuries was investigated
      with a memory scanning paradigm (Conway & Engle, 1994), that allows dissociation
      of scanning processes within short-term memory and memory retrieval processes
      from long-term memory. The study focused on the influence of brain injury on
      memory retrieval processes that are assumed to be automatic. Thirteen patients
      with memory impairment and 13 healthy matched control subjects were tested. In
      general, patients showed increased reaction times, but they showed set size
      independent retrieval from long-term memory indicating preserved automatic
      retrieval processes. In a subgroup of patients with more severe memory deficits,
      however, automatic retrieval processes appeared not to be intact. Learning
      profiles of the patients were characterized by smaller item chunks, indicating
      differences in the process of information acquisition.

PMID- 10649536
TI  - Cognitive support at episodic encoding and retrieval: similar patterns of
      utilization in community-based samples of Alzheimer's disease and vascular
      dementia patients.
AB  - The hypothesis that Alzheimer's disease (AD) and vascular dementia (VaD) differ
      in the pattern of episodic memory was examined in this study. Demented patients
      with AD and VaD and normal old adults were assessed on episodic memory tasks,
      including free recall and recognition of slowly and rapidly presented unrelated
      words and free and cued recall of organizable words. Results showed a general
      deficit in both demented groups across all memory variables, although the AD and
      VaD patients were indistinguishable across all measures. The normal old showed
      proficient utilization of more study time, organizability, and category cues. By
      contrast, the AD and VaD patients were able to benefit from cognitive support
      only when guidance was provided at both encoding and retrieval. In addition, in
      the normal old, recall of unrelated words was characterized by a relatively equal
      contribution from primary and secondary memory, whereas the demented patients
      relied predominantly on primary memory. The results suggests a similarity between
      AD and VaD patients with regard to the nature of the episodic memory impairment,
      despite etiologic differences between the diseases.

PMID- 10649537
TI  - Memory and learning are not impaired in presymptomatic individuals with an
      increased risk of Huntington's disease.
AB  - Retrieval from long-term memory in patients with brain injuries was investigated
      with a memory scanning paradigm (Conway & Engle, 1994), that allows dissociation
      of scanning processes within short-term memory and memory retrieval processes
      from long-term memory. The study focused on the influence of brain injury on
      memory retrieval processes that are assumed to be automatic. Thirteen patients
      with memory impairment and 13 healthy matched control subjects were tested. In
      general, patients showed increased reaction times, but they showed set size
      independent retrieval from long-term memory indicating preserved automatic
      retrieval processes. In a subgroup of patients with more severe memory deficits,
      however, automatic retrieval processes appeared not to be intact. Learning
      profiles of the patients were characterized by smaller item chunks, indicating
      differences in the process of information acquisition.

PMID- 10649538
TI  - Interhemispheric transfer of visual, auditory, tactile, and visuomotor
      information in children with hydrocephalus and partial agenesis of the corpus
      callosum.
AB  - Interhemispheric transfer was examined in 13 normal controls and in 13 children
      with hydrocephalus and partial agenesis of the corpus callosum involving a
      missing splenium associated with spina bifida meningomyelocele and aqueductal
      stenosis. Children with hydrocephalus demonstrated greater left visual-field
      superiority for forms indicative of difficulty in interhemispheric transfer of
      visual information. Interhemispheric transfer time (ITT) was somewhat longer in
      the children with hydrocephalus, but neither the ITT task nor the dichotic
      listening and tactile naming tasks provided clear evidence of difficulties in
      callosal transfer. Sensory and perceptual control tasks revealed similar visual
      acuity and monotic word perception but larger 2-point discrimination thresholds
      and poorer tactile matching.

PMID- 10649539
TI  - Long-term neuropsychological outcomes in very low birth weight children free of
      sensorineural impairments.
AB  - This study investigated the neuropsychological outcomes at school age of children
      with very low birth weight (VLBW) free of sensorineural impairments. Subjects
      included 19 children with VLBW identified at age 3 as 'suspect' for developmental
      problems, 19 children with VLBW identified at age 3 as developing normally, and
      30 children of normal birth weight (NBW). Results indicated that children in the
      VLBW 'suspect' group performed significantly more poorly on all of the
      neuropsychological measures compared to children of NBW. These findings suggest
      that VLBW children identified as 'suspect' for developmental problems because of
      impairments in cognitive skills at age 3 continued to show deficits at school age
      on intellectual and neuropsychological measures.

PMID- 10649540
TI  - Identifying simulators of cognitive deficit through combined use of
      neuropsychological test performance and event-related potentials.
AB  - Event-related potential (ERP) methods for identifying malingering of cognitive
      deficit assume that elements of brain/cognitive functioning are not under a
      person's direct control, whereas neuropsychological methods assume that
      malingered cognitive deficit will present differently than true impairment in
      terms of level or pattern of errors on tests of cognitive function. Two studies
      were conducted to examine the combined use of neuropsychological and ERP methods
      for identifying malingering because of the potential independence of these
      approaches. All normal control participants performing at their best level (n =
      25) were correctly classified by both ERP and neuropsychological methods. All
      participants simulating cognitive deficit (n = 35) were correctly classified on
      the basis of a positive outcome on either the neuropsychological or the ERP
      method. Results suggest that the neuropsychological and psychophysiological
      measures of malingering that were studied contribute non-redundant information in
      the classification of simulators.

PMID- 10649541
TI  - Dissociation of frequency and recency processing from list recall after severe
      closed head injury in children and adolescents.
AB  - To investigate judgment of the frequency and recency of events relative to word
      list recall in children following closed head injury (CHI), 124 children and
      adolescents, including 79 severe CHI patients (mean age at test = 13.2 years), 27
      mild CHI cases (mean age at test = 12.1 years), and 18 uninjured comparison
      subjects (mean age = 12.8 years) were studied. The mean postinjury interval was
      63.6 months for the severe and 46.7 months for the mild CHI groups. The
      experimental tasks included estimation of the frequency of presentation of words
      and designs and recency judgment to select the most recently presented of two
      stimuli on verbal (words) and nonverbal (faces) tasks. To compare frequency and
      recency judgments to performance on a task which has been shown to be sensitive
      to CHI severity and age at test, verbal recall was tested using the California
      Verbal Learning Test-Children's Version. Severity of CHI (group) affected verbal
      recall across trials and after delays, but had no effect on estimating frequency
      and isolated effects on judgment of recency. Age was also primarily related to
      verbal recall. A subgroup of severe CHI patients with frontal lesions was
      impaired on delayed recall. The results are discussed in relation to previous
      research on the effects of CHI on processing the frequency and recency of events.

PMID- 10649542
TI  - Dual task performance in HIV-1 infection.
AB  - Fifty HIV-infected individuals and 20 uninfected controls participated in an
      investigation of dual task performance in HIV-1 infection. Participants first
      engaged in a simple auditory reaction time (RT) task followed by a visual choice
      RT task (single task condition), and then they simultaneously engaged in both
      tasks (dual task condition). Under single task conditions, the HIV+ participants
      did not significantly differ from controls on either simple or choice RT (though
      a trend was evident on single task choice RT). In contrast, under dual task
      conditions the HIV+ group's performance decrement, relative to controls, was
      significantly greater on both simple and choice RT. This dual task decrement was
      also significantly associated with slower performance on the interference
      condition of the Stroop. Patients with AIDS tended to have greater dual task
      decrements than did the pre-AIDS group, though this fell short of statistical
      significance. These results suggest that HIV-1 infection leads to deficits in
      divided attention and the simultaneous processing of competing stimuli, deficits
      which have been linked to disruption of the anterior attentional system.

PMID- 10649543
TI  - Effects of severe traumatic brain injury on visual memory.
AB  - The study aimed to clarify the effects of severe traumatic brain injury (TBI) on
      visual memory. Three groups of participants (14 late-recovery and 14 early
      recovery TBI individuals and 18 controls) were administered the following: The
      Shum Visual Learning Test (SVLT), a test that measures the ability to remember
      visual patterns, an electronic maze test, a test that measures the ability to
      remember spatial positions, and the Rey Auditory Verbal Learning Test (RAVLT), a
      test of verbal memory and learning. The individuals with TBI (late- and early
      recovery) were found to be impaired on the SVLT and the RAVLT but not on the
      electronic maze. Specifically, on the SVLT, they were found to learn at a slower
      rate and make more false-positive errors than the controls. The advantages of the
      SVLT over visual memory tests used in previous studies and the significance of
      findings of the present study were discussed.

PMID- 10649544
TI  - Measurement of executive function: considerations for detecting adult age
      differences.
AB  - This review considers the validity and suitability of neuropsychological and
      other tests of executive function for the detection of adult age differences in
      executive function. Executive function is typically assessed using tests which
      have been found to be sensitive to frontal lobe dysfunction because theory links
      executive function with the frontal lobes. However, any age-related decline in
      executive function is expected to be mild, or sub-clinical, compared to the
      deficits shown among those with frontal lesions. Therefore, in order to detect
      the type of mild executive dysfunction expected among older adults we need to
      employ tests sensitive enough to detect any age-related deficit, yet which are
      not too stressful or tiring for older adults to perform. This review discusses
      some commonly used neuropsychological tests of executive function as well as
      tests devised to assess theoretical aspects of executive function. Indications
      are given throughout as to which tests appear to be most suitable for detecting
      age differences in executive function.

PMID- 10649545
TI  - Adaptive decision making, ecological validity, and the frontal lobes.
AB  - Existing neuropsychological procedures assess veridical, but not adaptive,
      decision making, which are based on different mechanisms. This severely curtails
      the tests' ecological validity, because most real-life decision making situations
      are adaptive, rather than veridical. Veridical decision making entails finding
      the correct response intrinsic to external situations and is actor-independent.
      Adaptive decision making is actor-centered and priority-based. Prefrontal cortex
      is critical for adaptive decision making. Innovative actor-centered decision
      making tasks are required to better understand frontal lobe functions. We have
      designed a prototype for such procedures, the Cognitive Bias Task (CBT). CBT
      elicited strong gender and hemispheric differences in the effects of focal
      frontal lesions, which are more robust than those elicited with veridical tasks,
      such as the Wisconsin Card Sorting Test.

PMID- 10649546
TI  - Performance on the Wisconsin Card Sorting Test among adolescents in Taiwan:
      norms, factorial structure, and relation to schizotypy.
AB  - The aims of this study were to assess developmental trends in performance on the
      Wisconsin Card Sorting Test (WCST) among 817 randomly selected adolescents aged
      13-15 years, and to explore WCST performance factor structure and relationship to
      schizotypy. The results showed that of the nine WCST indexes, only the Categories
      Achieved and Failure to Maintain Set scores were associated with age, and only
      the Learning to Learn scores reached adult levels. Factor analysis of WCST
      performance scores yielded a three-factor structure. Psychometrically defined
      schizotypic subjects did not perform significantly worse than control subjects on
      any WCST indexes. These findings suggest that performance on various WCST indexes
      might indicate developmental changes at different ages, and deficits in WCST
      performance might not be sensitive indicators of vulnerability to schizophrenia
      in adolescence.

PMID- 10649547
TI  - Demographically corrected norms for the California Verbal Learning Test.
AB  - The California Verbal Learning Test (CVLT) is designed to quantify components of
      verbal learning, retention and retrieval. The present study used multiple
      regression analyses to correct for demographic characteristics on CVLT
      performance measures. There were 906 subjects, of whom 549 were Caucasians (61%)
      and 357 were African Americans (39%). Age, education, ethnicity, and gender were
      found to be significant predictors of performance on several CVLT indices,
      including Total Words Recalled, Trial 1, Trial 5, List B, Short Delay Free Recall
      (SDFR), and Long Delay Free Recall (LDFR). Demographically corrected T-scores
      were calculated for a base sample of 672 subjects and cross-validated on 234
      separate subjects. Tables and regression equations are offered to convert raw
      scores into T-scores corrected for age, gender, education, and ethnicity.
      Demographically corrected Recognition Discriminability cutoff scores were
      calculated for age and education levels. In order to provide some indices of
      important memory processes, we also computed indices of retrieval, Short-Delay
      forgetting and Long-Delay forgetting and present normative information for them.

PMID- 10649548
TI  - Neuropsychological functioning among heart transplant candidates: a case control
      study.
AB  - Neuropsychological performance was examined among a group of patients with end
      stage heart disease undergoing routine evaluation for transplantation using a
      matched case-control design. Heart transplant candidates and controls were
      matched case by case for gender, race, education and age range. In order to match
      all 44 controls, a clinical series of 303 heart transplant candidates evaluated
      between October 1995 through March 1998 were considered. Although not
      specifically matched on variables of estimated IQ and socioeconomic status,
      statistical analysis showed no group differences on these variables. A separate
      analysis of variance on each neuropsychological test indicated that the heart
      transplant candidates performed significantly worse than controls on tasks of
      fine motor speed and dexterity (i.e., Grooved Peg Board), psychomotor speed and
      mental flexibility (i.e., Trail Making Test, Part B), and abstract reasoning and
      problem solving ability (i.e., Shipley Institute of Living Scale-Abstraction
      subtest). Implications of the results and future directions are discussed.

PMID- 10649549
TI  - Effects of immunosuppression and disease severity upon neuropsychological
      function in HIV infection.
AB  - Effects of immunosuppression and illness severity upon neuropsychological
      function were assessed in a group of homosexual men with AIDS across 6 months.
      Participants included 62 who were seronegative (HIV-), 74 asymptomatic
      seropositives (HIV+A), 31 symptomatic seropositives (HIV+S), 23 with AIDS
      defining illnesses (AIDS-DI), and 10 who were diagnosed with AIDS solely on the
      basis of CD4+ levels falling below 200 /mm3 (AIDS-CD4). Groups were equivalent in
      age, education, and IQ. None were drug users, and none experienced a change in
      disease status across the 6-month inter-test interval. There was little evidence
      of cognitive decline across time. Nonetheless, after collapsing across time
      intervals, the AIDS-DI group had worse new-learning than all other groups.
      Additionally, the AIDS-DI demonstrated a greater number of impaired performances
      than the other participant groups. The data suggest that cognitive impairment in
      AIDS is unlikely due to independent contributions of immunosuppression and
      illness. Rather neurobehavioral deficits are more likely attributable to a
      combination of the two.

PMID- 10649550
TI  - Neuropsychological functioning of adults with attention deficit hyperactivity
      disorder.
AB  - The neuropsychological functioning of adults with Attention Deficit Hyperactivity
      Disorder (ADHD) was compared to that of healthy controls and individuals with
      mild psychiatric disorders including attentional complaints. Thirty adults in
      each group were examined on the Conners' Continuous Performance Test (CPT) and
      measures of attention, executive function, psychomotor speed, and arithmetic
      skills. The ADHD group performed lower than healthy controls on most measures.
      However when compared to the psychiatric group, the performances of the ADHD
      group were not significantly lower on any of the measures. The predictive power
      of the tests was poor in discriminating ADHD from psychiatric disorder.
      Implications for the clinical diagnosis of ADHD are discussed.

PMID- 10649551
TI  - Autobiographical memory, depression and quality of life in multiple sclerosis.
AB  - The relationship between autobiographical memory, depression and quality of life
      (QoL) was investigated in a study of 30 persons with severe neurodisability
      resulting from multiple sclerosis. Sixty percent (n = 18) of patients were found
      to have deficits in autobiographical memory (AMI) for incidents in their earlier
      life; these deficits were associated with significant impairments in personal
      semantic memory of facts from their past life. Patients with impaired
      autobiographical memory who had been diagnosed for longer than 21 years reported
      significantly better QoL (SF-36: Role Physical) than those diagnosed more
      recently, or those with normal autobiographical memory; patients who had been
      diagnosed for longer were also significantly less depressed than patients
      diagnosed more recently. Patients with normal autobiographical memory reported
      the highest levels of depression (HADS) and the lowest levels of QoL (Role
      Physical). It is concluded that impairment of autobiographical memory affects
      perception of QoL; patients with deficits in autobiographical memory had impaired
      knowledge about their past QoL and may therefore be unable to make valid
      comparative judgements about the quality of their present life.

PMID- 10649553
TI  - Mild hearing impairment can reduce verbal memory performance in a healthy adult
      population.
AB  - We studied to what extent immediate and delayed recall in an auditory verbal
      learning paradigm was affected by basic information processing speed (digit
      copying) and hearing acuity (average hearing acuity at 1, 2 and 4 KHz at the
      better ear). A group of 453 individuals in the age between 23 and 82 years with
      no overt hearing pathology was recruited from a larger study of cognitive aging
      (Maastricht Aging Study, MAAS). After controlling for age, sex, educational
      level, and processing speed it was found that a mild to moderate hearing loss
      predicted lower verbal memory performance. Auditory administered verbal memory
      tests can underestimate true memory performance, particularly in older
      individuals with unknown hearing status.

PMID- 10649552
TI  - Intervening with everyday memory problems in dementia of Alzheimer type: an
      errorless learning approach.
AB  - Dementia of Alzheimer Type (DAT) is increasingly detected at an earlier stage of
      the disorder, when interventions to assist with everyday memory difficulties
      might be most valuable. Some learning is possible in DAT and a number of factors
      have been identified which may facilitate performance, although applications to
      everyday memory problems have been limited. The concept of errorless learning has
      not previously been directly examined in relation to DAT, but might provide a
      useful additional strategy. In the present study, 6 participants with early stage
      DAT (MMSE scores 21 - 26) received individually tailored interventions, based on
      errorless learning principles and targeted at a specific everyday memory problem.
      Five of the participants showed significant improvement on the target measures,
      and maintained this improvement up to 6 months later. The results suggest that it
      is feasible to intervene with everyday memory problems in the early stages

PMID- 10649559
TI  - How experts communicate.

PMID- 10649560
TI  - A taste for umami.

PMID- 10649561
TI  - Presynaptic facilitation by hyperpolarization-activated pacemaker channels.

PMID- 10649562
TI  - Neurodegeneration in the polyglutamine diseases: Act 1, Scene 1.

PMID- 10649563
TI  - Non-invasive visualization of cortical columns by fMRI.

PMID- 10649564
TI  - Rapid, synaptically driven increases in the intrinsic excitability of cerebellar
      deep nuclear neurons.

PMID- 10649565
TI  - A metabotropic glutamate receptor variant functions as a taste receptor.
AB  - Sensory transduction for many taste stimuli such as sugars, some bitter compounds
      and amino acids is thought to be mediated via G protein-coupled receptors
      (GPCRs), although no such receptors that respond to taste stimuli are yet
      identified. Monosodium L-glutamate (L-MSG), a natural component of many foods, is
      an important gustatory stimulus believed to signal dietary protein. We describe a
      GPCR cloned from rat taste buds and functionally expressed in CHO cells. The
      receptor couples negatively to a cAMP cascade and shows an unusual concentration
      response relationship. The similarity of its properties to MSG taste suggests
      that this receptor is a taste receptor for glutamate.

PMID- 10649566
TI  - Identification and characterization of the high-affinity choline transporter.
AB  - In cholinergic neurons, high-affinity choline uptake in presynaptic terminals is
      the rate-limiting step in acetylcholine synthesis. Using information provided by
      the Caenorhabditis elegans Genome Project, we cloned a cDNA encoding the high
      affinity choline transporter from C. elegans (cho-1). We subsequently used this
      clone to isolate the corresponding cDNA from rat (CHT1). CHT1 is not homologous
      to neurotransmitter transporters, but is homologous to members of the Na+
      dependent glucose transporter family. Expression of CHT1 mRNA is restricted to
      cholinergic neurons. The characteristics of CHT1-mediated choline uptake
      essentially match those of high-affinity choline uptake in rat brain
      synaptosomes.

PMID- 10649567
TI  - Receptors with opposing functions are in postsynaptic microdomains under one
      presynaptic terminal.
AB  - Fast excitatory synaptic transmission through vertebrate autonomic ganglia is
      mediated by postsynaptic nicotinic acetylcholine receptors (nAChRs). We
      demonstrate a unique postsynaptic receptor microheterogeneity on chick
      parasympathetic ciliary ganglion neurons-under one presynaptic terminal, nAChRs
      and glycine receptors formed separate but proximal clusters. Terminals were
      loaded with [3H]glycine via the glycine transporter-1 (GlyT-1), which localized
      to the cholinergic presynaptic terminal membrane; depolarization evoked
      [3H]glycine release that was calcium independent and blocked by the GlyT-1
      inhibitor sarcosine. Ganglionic synaptic transmission mediated by nAChRs was
      attenuated by glycine. Coexistence of separate clusters of receptors with
      opposing functions under one terminal contradicts Dale's principle and provides a
      new mechanism for modulating synaptic activity in vivo.

PMID- 10649568
TI  - Enhancement of synaptic transmission by cyclic AMP modulation of presynaptic Ih
      channels.
AB  - Presynaptic activation of adenylyl cyclase and subsequent generation of cAMP
      represent an important mechanism in the modulation of synaptic transmission. In
      many cases, short- to medium-term modulation of synaptic strength by cAMP is due
      to activation of protein kinase A and subsequent covalent modification of
      presynaptic ion channels or synaptic proteins. Here we show that presynaptic cAMP
      generation via serotonin receptor activation directly modulated hyperpolarization
      activated cation channels (Ih channels) in axons. This modulation of Ih produced
      an increase in synaptic strength that could not be explained solely by
      depolarization of the presynaptic membrane. These studies identify a mechanism by
      which cAMP and Ih regulate synaptic plasticity.

PMID- 10649569
TI  - Synaptic activity modulates presynaptic excitability.
AB  - Synaptic activity modulates synaptic efficacy and is important in learning and
      development. Here we show that development of excitability in presynaptic motor
      neurons required synaptic activation of postsynaptic muscle cells. Synaptic
      blockade broadened action potentials and decreased repetitive firing of
      presynaptic neurons. Consistent with these findings, synaptic blockade also
      decreased potassium-current density in the presynaptic cell. Application of
      neurotrophin-3, but not related neurotrophins, prevented these changes.
      Recordings from patches of somatic membrane indicated that modifications of
      presynaptic potassium and sodium currents occurred in a remote, nonsynaptic
      compartment. Thus, activity-dependent postsynaptic signals modulated presynaptic
      excitability, potentially regulating transmission at all synapses of the
      presynaptic cell.

PMID- 10649570
TI  - A new form of long-term depression in the perirhinal cortex.
AB  - We demonstrate a form of long-term depression (LTD) in the perirhinal cortex that
      relies on interaction between different glutamate receptors. Group II
      metabotropic glutamate (mGlu) receptors facilitated group I mGlu receptor
      mediated increases in intracellular calcium. This facilitation plus NMDA receptor
      activation may be necessary for induction of LTD at resting membrane potentials.
      However, depolarization enhanced NMDA receptor function and removed the
      requirement of synergy between group I and group II mGlu receptors: under these
      conditions, activation of only NMDA and group I mGlu receptors was required for
      LTD. Such glutamate receptor interactions potentially provide new rules for
      synaptic plasticity. These forms of LTD occur in the perirhinal cortex, where
      long-term decreases in neuronal responsiveness may mediate recognition memory.

PMID- 10649571
TI  - Polyglutamine expansion down-regulates specific neuronal genes before pathologic
      changes in SCA1.
AB  - The expansion of an unstable CAG repeat causes spinocerebellar ataxia type 1
      (SCA1) and several other neurodegenerative diseases. How polyglutamine expansions
      render the resulting proteins toxic to neurons, however, remains elusive.
      Hypothesizing that long polyglutamine tracts alter gene expression, we found
      certain neuronal genes involved in signal transduction and calcium homeostasis
      sequentially downregulated in SCA1 mice. These genes were abundant in Purkinje
      cells, the primary site of SCA1 pathogenesis; moreover, their downregulation was
      mediated by expanded ataxin-1 and occurred before detectable pathology. Similar
      downregulation occurred in SCA1 human tissues. Altered gene expression may be the
      earliest mediator of polyglutamine toxicity.

PMID- 10649572
TI  - High-resolution mapping of iso-orientation columns by fMRI.
AB  - Blood-oxygenation level-dependent (BOLD) functional magnetic resonance imaging
      (fMRI) is an important tool for localizing brain functions in vivo. However, the
      ability of BOLD fMRI to map cortical columnar structures is highly controversial,
      as the ultimate functional specificity of BOLD remains unknown. Here we report a
      biphasic BOLD response to visual stimulation in the primary visual cortex of
      cats. In functional imaging, the initial BOLD signal decrease accurately labeled
      individual iso-orientation columns. In contrast, the delayed positive BOLD
      changes indicated the pattern of overall activation in the visual cortex, but
      were less suited to discriminate active from inactive columns.

PMID- 10649573
TI  - Dynamics of perceptual oscillations in form vision.
AB  - Certain periodic dot patterns (Marroquin patterns) generate a percept of
      dynamically oscillating circles, and analogous effects were explored by op
      artists in the 1960s. Here we show psychophysically that circles are perceived in
      these patterns only around specific points that are quantitatively predicted by a
      neural model of configural units hypothesized to reside in cortical area V4.
      Circles superimposed on the pattern mask perception of illusory circles. A neural
      model of lateral inhibitory interactions among V4 configural units showing spike
      frequency adaptation quantitatively accounts for the human data. The model is
      consistent with ideas on the neural basis of attention in V4, and it suggests
      that attention may be biased via neuromodulation of slow hyperpolarizing
      potentials in cortical neurons.

PMID- 10649574
TI  - Motion perception during saccadic eye movements.
AB  - During rapid eye movements, motion of the stationary world is generally not
      perceived despite displacement of the whole image on the retina. Here we report
      that during saccades, human observers sensed visual motion of patterns with low
      spatial frequency. The effect was greatest when the stimulus was spatiotemporally
      optimal for motion detection by the magnocellular pathway. Adaptation experiments
      demonstrated dependence of this intrasaccadic motion percept on activation of
      direction-selective mechanisms. Even two-dimensional complex motion percepts
      requiring spatial integration of early motion signals were observed during
      saccades. These results indicate that the magnocellular pathway functions during
      saccades, and that only spatiotemporal limitations of visual motion perception
      are important in suppressing awareness of intrasaccadic motion signals.

PMID- 10649575
TI  - Thermosensory activation of insular cortex.
AB  - Temperature sensation is regarded as a submodality of touch, but evidence
      suggests involvement of insular cortex rather than parietal somatosensory
      cortices. Using positron emission tomography (PET), we found contralateral
      activity correlated with graded cooling stimuli only in the dorsal margin of the
      middle/posterior insula in humans. This corresponds to the thermoreceptive- and
      nociceptive-specific lamina I spinothalamocortical pathway in monkeys, and can be
      considered an enteroceptive area within limbic sensory cortex. Because lesions at
      this site can produce the post-stroke central pain syndrome, this finding
      supports the proposal that central pain results from loss of the normal
      inhibition of pain by cold. Notably, perceived thermal intensity was well
      correlated with activation in the right (ipsilateral) anterior insular and
      orbitofrontal cortices.

PMID- 10649577
TI  - The future of the clinical scientist.

PMID- 10649576
TI  - Expertise for cars and birds recruits brain areas involved in face recognition.
AB  - Expertise with unfamiliar objects ('greebles') recruits face-selective areas in
      the fusiform gyrus (FFA) and occipital lobe (OFA). Here we extend this finding to
      other homogeneous categories. Bird and car experts were tested with functional
      magnetic resonance imaging during tasks with faces, familiar objects, cars and
      birds. Homogeneous categories activated the FFA more than familiar objects.
      Moreover, the right FFA and OFA showed significant expertise effects. An
      independent behavioral test of expertise predicted relative activation in the
      right FFA for birds versus cars within each group. The results suggest that level
      of categorization and expertise, rather than superficial properties of objects,
      determine the specialization of the FFA.

PMID- 10649578
TI  - Experimental gene therapy for an in vitro model of proliferative
      vitreoretinopathy.
AB  - BACKGROUND: Proliferative vitreoretinopathy (PVR) is the leading cause of failure
      of retinal reattachment surgery. Since a key component of PVR is cell
      proliferation, we performed a study to examine whether the ribonucleotide
      reductase-deficient herpes simplex virus type I (HSV-I) mutant hrR3 can be
      effective at destroying proliferating retinal pigment epithelial (RPE) cells and
      thus prevent epiretinal membrane formation and PVR, while sparing nondividing
      cells, such as neurons. METHODS: Primary cultures of rat RPE cells and rat
      cortical neurons were infected with 300 microL of hrR3 HSV-I to achieve a
      multiplicity of infection of 1.0. After 1 hour at 37 degrees C, 700 microL of
      growth medium was added to raise the total volume of medium to 1 mL. At 0, 12, 24
      and 36 hours the cultures were observed, and the ratio of dead cells to live
      cells was determined. HSV infection and protein expression were confirmed by a
      beta-galactosidase histochemical assay or an antihuman HSV-I immunoassay, or
      both. RESULTS: At 24 hours more than 95% of the RPE cells and neurons stained
      positively for HSV infection, although beta-galactosidase was expressed
      predominantly in RPE cells. At 36 hours 72% (standard deviation 2.1%) of the RPE
      cells were dead. There was no noticeable cell death in the neuronal or mock
      infected control cultures. INTERPRETATION: The results suggest that the hrR3
      mutant strain of HSV-I can be used to infect and selectively kill actively
      proliferating rat RPE cells while sparing normal, nonreplicating cells. This
      model may be used to explore potential therapies for PVR in humans.

PMID- 10649579
TI  - Management of submacular hemorrhage with intravitreal sulfur hexafluoride: a
      pilot study.
AB  - BACKGROUND: Some success has been reported with the intravitreal use of tissue
      plasminogen activator (tPA) and perfluoropropane gas in the management of large
      submacular hemorrhages. However, the dosage of tPA that has been used (100
      micrograms) has a narrow margin of safety, and it remains to be shown that
      intravitreal tPA can cross the retina and effect subretinal clot lysis. We
      carried out a pilot study to evaluate the efficacy of intravitreally administered
      sulfur hexafluoride (SF6) gas alone in the management of large submacular
      hemorrhages secondary to age-related macular degeneration (AMD). METHODS: Three
      patients with large submacular hemorrhages secondary to AMD seen at a university
      affiliated teaching hospital in Ottawa were treated with an intravitreal
      injection of 0.6 mL of SF6 gas. They were instructed to assume a prone position
      for 7 to 10 days. The patients were followed 3, 7, 14 and 28 days after the
      procedure and monthly thereafter for at least 6 months. Colour photography and
      fluorescein and indocyanine green angiography were performed immediately before
      and 2 weeks after the procedure and, thereafter, at the discretion of the
      treating ophthalmologist. RESULTS: In all three cases significant inferior
      displacement of the submacular blood was observed. Two patients showed an
      improvement of vision from counting fingers to 20/70 and to 20/200. In one case
      the submacular blood was displaced such that laser photocoagulation of a
      juxtafoveal choroidal neovascular membrane became possible. INTERPRETATION: The
      results suggest that intravitreally administered SF6 alone may have a role in the
      management of selected cases of neovascular AMD complicated by significant
      submacular hemorrhage. These results call into question the utility of adjunctive
      intravitreal tPA in such cases.

PMID- 10649580
TI  - Visual outcome following penetrating globe injuries with retained intraocular
      foreign bodies.
AB  - BACKGROUND: In our institution the occurrence of endophthalmitis related to
      intraocular foreign bodies has been rare. In this review we analyse the outcome
      of eyes with retained intraocular foreign bodies presenting to two vitreoretinal
      surgeons over nearly 7 years. METHODS: Review of the records of 26 patients who
      presented to two surgeons in a tertiary care vitreoretinal service in Toronto
      between January 1989 and November 1995. Information documented included mechanism
      of injury, time from injury to definitive surgery, entry site, presence of
      vitreous hemorrhage, type of surgery performed, initial and final visual acuity,
      and development of endophthalmitis. RESULTS: All the injuries occurred in male
      patients, with a mean age of 36.1 (range 15 to 55) years. Most of the injuries
      occurred in the workplace, and in most cases (17 [65.4%]) the mechanism of injury
      was "metal on metal." The entry site was via a perforating wound of the cornea in
      16 cases (61.5%). Almost all cases were repaired within 48 hours by means of pars
      plana vitrectomy. Concurrent lensectomy was required in 18 cases (69.2%) for lens
      damage at the time of the original injury. Vitreous hemorrhage was present in 22
      cases (84.6%). One patient (3.8%) manifested clinically apparent endophthalmitis,
      which responded to intravitreal antibiotic therapy. Nineteen eyes (73.1%) had a
      final visual acuity of 6/24 or better. Eyes with coexisting or subsequent retinal
      detachment had significantly worse vision than those without retinal detachment
      (p < 0.001). INTERPRETATION: The incidence of endophthalmitis in our series is
      lower than that in other published series. Prompt definitive treatment was
      associated with a good prognosis in most cases.

PMID- 10649581
TI  - Delayed, recurrent hypotonous maculopathy following aqueous suppressant therapy
      in pseudophakia.

PMID- 10649582
TI  - Bacterial endophthalmitis associated with an intruded suture 15 years after
      scleral buckling surgery.

PMID- 10649583
TI  - Direct carotid-cavernous fistula following carotid endarterectomy.

PMID- 10649584
TI  - A primer on outcomes in dentistry.
AB  - Expectations for evidence of "value" on the part of dental care purchasers and
      growth in the evidence-based dentistry movement are beginning to demonstrate the
      narrow and incomplete nature of dentistry's knowledge of the outcomes of dental
      conditions and treatment. In this paper a classification scheme for dental
      outcomes is described that illustrates the broad range of outcomes information
      important to patients, health care providers, purchasers, and society. The uses
      for outcomes information are discussed and suggestions are offered for improving
      dentistry's knowledge of outcomes through the cooperative involvement of dental
      research, dental education, and dental practice.

PMID- 10649585
TI  - Pediatric oral health performance measurement: current capabilities and future
      directions.
AB  - This paper offers an overview of performance measurement in health care, provides
      a synopsis of the findings and recommendations of an Oral Health Expert Panel
      organized by the National Committee for Quality Assurance (NCQA) under contract
      with the Health Care Financing Administration (HCFA), and discusses challenges
      and possible future directions for pediatric oral health care performance
      measures development. Existing performance measures for pediatric oral health
      care are extremely limited; however, several new measures have been proposed and
      are in various stages of development and testing. Measures capable of being
      implemented in the short-term focus on access and use of services, rely on
      administrative data sources, and represent refinements and enhancements of
      current measures. Measures proposed for future implementation focus more on the
      effectiveness of care, consumer assessments of care and plan performance, and the
      value of services provided to enrolled children. Recommendations are targeted
      toward high-risk children who, for the most part, are covered by public programs
      (e.g., Medicaid and the Children's Health Insurance Program). Nevertheless, the
      entire set of recommended measures is considered to be relevant to all pediatric
      populations and applicable to all forms of dental care coverage, including state
      administered programs and commercial third party arrangements.

PMID- 10649586
TI  - Development of effectiveness of care and use of services measures for dental care
      plans.
AB  - OBJECTIVES: Standardized measures to assess clinical aspects of the performance
      of managed dental care plans are not available. This project sought to develop
      and evaluate measures for effectiveness of care and use of services that could be
      calculated using a plan's administrative data. METHODS: Two panels of stake
      holders representing dental plans, purchasers, and dental providers participated
      in a modified Delphi process to refine initial sets of effectiveness of care and
      use of services measures modeled after HEDIS measures for medical care. The
      refined measures were then pilot tested in two dental health maintenance
      organizations. RESULTS: The development process resulted in specification of
      seven effectiveness of care measures assessing disease activity classification,
      and prevention and outcomes for caries, periodontal disease, and tooth loss. Six
      use of services measures focusing on prophylaxes, third molar surgery,
      preventive, restorative, prosthetic, surgical, and endodontic care also were
      specified. Pilot testing of the measures indicated reasonable reliability and
      sensitivity, but also demonstrated the need for supervision or auditing of the
      process. CONCLUSIONS: These standardized measures for dental care plan
      performance are available for immediate use. However, because the measures depend
      on diagnostic information (periodontal probing data and diagnoses associated with
      restorative treatments) in the administrative data set, their adoption will
      require changes in most plans' data systems and data collection policies.

PMID- 10649587
TI  - Evaluation of audit-based performance measures for dental care plans.
AB  - OBJECTIVES: Although a set of clinical performance measures, i.e., a report card
      for dental plans, has been designed for use with administrative data, most plans
      do not have administrative data systems containing the data needed to calculate
      the measures. Therefore, we evaluated the use of a set of proxy clinical
      performance measures calculated from data obtained through chart audits. METHODS:
      Chart audits were conducted in seven dental programs--three public health
      clinics, two dental health maintenance organizations (DHMO), and two preferred
      provider organizations (PPO). In all instances audits were completed by clinical
      staff who had been trained using telephone consultation and a self-instructional
      audit manual. The performance measures were calculated for the seven programs,
      audit reliability was assessed in four programs, and for one program the audit
      based proxy measures were compared to the measures calculated using
      administrative data. RESULTS: The audit-based measures were sensitive to known
      differences in program performance. The chart audit procedures yielded reasonably
      reliable data. However, missing data in patient charts rendered the calculation
      of some measures problematic--namely, caries and periodontal disease assessment
      and experience. Agreement between administrative and audit-based measures was
      good for most, but not all, measures in one program. CONCLUSIONS: The audit-based
      proxy measures represent a complex but feasible approach to the calculation of
      performance measures for those programs lacking robust administrative data
      systems. However, until charts contain more complete diagnostic information
      (i.e., periodontal charting and diagnostic codes or reason-for-treatment codes),
      accurate determination of these aspects of clinical performance will be
      difficult.

PMID- 10649588
TI  - Dentist reliability in classifying disease risk and reason for treatment.
AB  - OBJECTIVES: The reliability of practicing dentists' classifications of patients'
      caries risk and periodontal disease risk and reason for treatment for individual
      teeth were determined. The risk classification protocols had been in use in a
      group practice for more than a year, and the reason-for-treatment protocol had
      been introduced six months previously. METHODS: Eight dentists' classifications
      for caries (n = 66) and periodontal disease risk (n = 66), and six dentists'
      classifications for reason for treatment (n = 73) were compared to those of a
      nominal standard examiner. Reliability was expressed as percent agreement and
      kappa values. RESULTS: Percent agreement was 76 percent, 83 percent, and 74
      percent for caries, periodontal disease, and reason for treatment, respectively,
      with kappa values of 0.56, 0.70, and 0.69. CONCLUSIONS: Dentists can attain
      reasonable levels of reliability using simple classification protocols with
      little formal training, although misclassification may be problematic for
      specific administrative or research-related purposes.

PMID- 10649589
TI  - A system of diagnostic codes for dental health care.
AB  - OBJECTIVES: We set out to develop and implement a system of diagnostic codes for
      use in the computerized management information system of the Community Dental
      Services of the North York Public Health Department. METHODS: We received staff
      input on common diagnoses, reviewed other diagnostic systems and established
      criteria for an ideal coding system. The codes are consistent with the format of
      other classification systems used in dental management information in Canada.
      They were implemented in 1997-98. RESULTS: We developed a system of four-digit,
      numeric codes for dental diagnoses. The diagnostic codes are specific at the
      level of the patient, consistent with current evidence on the natural history and
      classification of diseases, consistent with conventional measures of oral
      conditions, and fit the paradigm of the Canadian system of treatment codes. In
      the first year, 91 percent of 6,740 patients had at least one diagnosis, with a
      mean of 2.5 per patient. The five most common diagnoses were smooth surface
      caries, pit and fissure caries, calculus, teeth with deep fissures, and
      gingivitis. CONCLUSIONS: We have developed a coding system for dental diagnoses
      that has achieved high use and provided more accessible information on the
      conditions seen by staff dentists.

PMID- 10649590
TI  - A systematic review of clinical diagnostic criteria of early childhood caries.
AB  - OBJECTIVE: This paper reviews case definitions and clinical diagnostic criteria
      of early childhood caries (ECC) and severe ECC (S-ECC) in children aged 1 to 5
      years old. The acronym S-ECC as used in this paper refers to nursing caries, baby
      bottle tooth decay, rampant caries, labial caries, maxillary anterior caries, and
      other terms used to refer to severe dental caries in preschool children. METHODS:
      A search was carried out for articles published in peer-reviewed journals and
      indexed in MEDLINE using the following terms: nursing caries, baby bottle tooth
      decay, early childhood caries, rampant caries in preschool children, labial
      caries, maxillary anterior caries, and nursing bottle caries. MEDLINE's MeSH
      terms "dental caries" and "deciduous teeth" were used to search for other
      relevant studies. Reports were selected if they included children 1 to 5 years of
      age and described diagnostic criteria or case definitions of S-ECC. Three
      previous reviews were searched for other relevant reports. One unpublished report
      was included in this review and data from NHANES III were analyzed to provide
      information on caries patterns in preschool children in the United States. The
      first author read all the abstracts from the MEDLINE search and tagged relevant
      reports for photocopying. He also abstracted all the information from the
      reports. The first author calibrated the second author, who independently read
      all included and excluded reports. Disagreements were resolved by consensus.
      RESULTS: Out of 126 studies, 32 were excluded and 94 (93 published and 1
      unpublished) were included in this review. Eighty-one of the 94 published studies
      were cross-sectional surveys or clinical studies, 7 were case-control clinical
      studies, 2 studies were controlled clinical trials, and 4 were cohort or field
      trials. About two-thirds of the included studies did not report on calibration of
      examiners. Information on reliability of examiners was reported by 19 of the 94
      studies. The included studies varied widely in the name used to identify S-ECC,
      case definitions, and diagnostic criteria. "Cavitation" was the most common
      criterion used to define dental caries. Several studies measured early or
      noncavitated carious lesions. Twenty-seven studies used the presence of 1 dmf
      maxillary incisor to classify a child with S-ECC. Another 23 and 9 studies
      defined S-ECC by the presence of 2+ or 3+ dmf maxillary incisors, respectively.
      Dental caries in preschool children clusters in pits and fissures and on smooth
      tooth surfaces of primary molars and maxillary incisors. CONCLUSIONS: This review
      found a wide variation in the case definitions and diagnostic criteria used to
      diagnose ECC or define S-ECC. Dental caries in the maxillary incisors is one of
      several patterns of dental caries that may occur in primary teeth of preschool
      children. A consensus is needed on case definitions and diagnostic criteria that
      can assist researchers to test preventive interventions and study the etiology
      and epidemiology of ECC.

PMID- 10649591
TI  - Diagnosing and reporting early childhood caries for research purposes. A report
      of a workshop sponsored by the National Institute of Dental and Craniofacial
      Research, the Health Resources and Services Administration, and the Health Care
      Financing Administration.

PMID- 10649592
TI  - An evaluation of NHANES III estimates of early childhood caries.
AB  - OBJECTIVES: The purposes of this study were to estimate and evaluate the
      prevalence for the United States of early childhood caries (ECC) among children
      12 to 23 months of age. METHODS: The 1988-94 National Health and Nutrition
      Examination Survey (NHANES III) public-use data set was analyzed using SUDAAN.
      Two ECC case definitions were used. Definition #1 was restricted to the caries
      score called by the examiner. Definition #2 liberally included children
      identified by definition #1 and those possibly having questionable caries scores.
      RESULTS: The NHANES III six-year prevalence estimates of caries in the maxillary
      anterior incisors of children 12 to 23 months of age were 1.0 percent for
      definition #1 and 1.7 percent for definition #2. Mexican-American and
      economically disadvantaged children were disproportionally represented with ECC.
      CONCLUSIONS: The prevalence of ECC among children 12 to 23 months of age is
      barely detectable at the national level. Alternative study designs and improved
      case definitions are needed for further advances in ECC.

PMID- 10649593
TI  - What is your diagnosis? Metastatic mammary carcinoma.

PMID- 10649594
TI  - In vitro percutaneous absorption of fusidic acid and betamethasone 17-valerate
      across canine skin.
AB  - The penetration of betamethasone 17-valerate and fusidic acid through dog skin
      was measured in vitro. In order to detect the small amounts of diffused
      compounds, a liquid chromatography-mass spectrometric method was developed with
      sensitivity limits for both compounds of 5 ng/ml. After application to the skin
      surface of a topical gel preparation containing these compounds at the
      anticipated therapeutic dose rate, about 10 per cent of the betamethasone 17
      valerate penetrated the skin over a 24-hour period, with no significant
      metabolism of the ester. About 1.3 per cent of the applied dose of fusidic acid
      was similarly recovered. The results demonstrated rapid penetration of both
      compounds through the epidermis.

PMID- 10649595
TI  - Supracondylar femoral fractures in 159 dogs and cats treated using a normograde
      intramedullary pinning technique.
AB  - Three separate studies that collectively represent 107 dogs and 52 cats with
      supracondylar femoral fractures are presented. The animals were treated using a
      normograde intramedullary pinning technique at the Norwegian School of Veterinary
      Science during the period 1964 to 1993. The surgical technique involves insertion
      of one or two intramedullary pins normograde from the stifle joint without
      passing their proximal end proximal to the level of the femoral neck. The results
      of treatment were obtained for 73 dogs and 39 cats. Of these cases, 58 dogs (79.5
      per cent) and 32 cats (82.1 per cent) were found to be free of lameness after the
      completion of treatment. Differences in the results of treatment, based on
      species or size, were not found. Of all cases in which the results of treatment
      were known (n = 112), complications were recorded in nine animals (8.0 per cent).
      Infection and instability were the most common complications, affecting four and
      three cases, respectively.

PMID- 10649596
TI  - Vertebral physitis with epiphyseal sequestration and a portosystemic shunt in a
      Pekingese dog.
AB  - Vertebral physitis with bone sequestration and a portosystemic shunt were
      diagnosed in an 18-month-old female Pekingese dog. The latter was determined by
      the presence of low blood urea nitrogen, elevated serum bile acids, microhepatica
      and an increased portosystemic shunt fraction. It was managed with a home-cooked
      low protein diet. Vertebral physitis and bone sequestration was diagnosed by the
      presence of thoracolumbar hyperaesthesia, radiographic and scintigraphic changes,
      isolation of Staphylococcus intermedius from blood and the third lumbar vertebra,
      and histopathological examination of a surgical biopsy. A partial sequestrectomy
      was performed and a six-month course of amoxycillin-clavulanate was prescribed.
      The dog was pain-free and showed partial resolution of the radiographic signs
      four months after the discontinuation of antibiotics.

PMID- 10649597
TI  - Adult-onset demodicosis in two dogs due to Demodex canis and a short-tailed
      demodectic mite.
AB  - Infestation with a short-tailed demodectic mite and Demodex canis was diagnosed
      in both a six-and-a-half-year-old and a four-year-old dog. The clinical picture
      was compatible with generalised demodicosis complicated by staphylococcal
      pyoderma (case 1), or localised demodicosis (case 2). In both cases, the short
      tailed demodectic mite outnumbered D canis in superficial skin scrapings. The
      laboratory findings (lymphopenia, eosinopenia, increased serum alkaline
      phosphatase and alanine aminotransferase activities, diluted urine and
      proteinuria) and the results of a low dose dexamethasone suppression test were
      suggestive of underlying hyperadrenocorticism in the first case. Hypothyroidism
      was considered a possibility in the second case, owing to the sustained
      bradycardia and the extremely low basal total thyroxine value. Systemic treatment
      with ivermectin and cephalexin (case 1), or topical application of an amitraz
      solution in mineral oil, along with sodium levothyroxine replacement therapy
      (case 2), resulted in a complete resolution of the skin lesions and the
      disappearance of both types of demodectic mite after two and one and a half
      months, respectively.

PMID- 10649599
TI  - Thrombosis of the portal vein in a miniature schnauzer.
AB  - A miniature schnauzer with a history of apathy, anorexia and jaundice was
      presented to the Utrecht University Clinic for Companion Animals. Abnormal
      laboratory findings included highly increased levels of total bile acids and
      alkaline phosphatase, and hyponatraemia. Abdominal ultrasonography revealed that
      the right side of the liver was enlarged and the left side was small, together
      with a thrombus in the portal vein. Biopsies from the right side of the liver
      demonstrated subacute to chronic active hepatitis, for which the dog was treated
      with prednisolone (1 mg/kg/day for four weeks). No improvement was observed and
      the owner requested euthanasia. At necropsy the left lobes of the liver were
      found to be small and firm, while the right lobes were large and soft. There were
      two thrombi in the portal vein. Microscopic examination revealed chronic active
      hepatitis and cirrhosis.

PMID- 10649598
TI  - Nutritional secondary hyperparathyroidism in six cats.
AB  - Nutritional secondary hyperparathyroidism (NSH) was diagnosed in six cats during
      a three-year period, based on clinical, radiographic and laboratory findings.
      Clinical signs were attributable to severe osteopenia (n = 5) and hypocalcaemia
      (n = 4), which had resulted in spontaneous fractures of long bones, scapulae,
      pelvis, nasal bones, or spine, and in excitation, muscle twitching or seizures,
      respectively. Serum parathormone levels were markedly elevated, and 1,25(OH)2
      vitamin D3 mildly elevated, whereas 25(OH)-vitamin D3 was mildly decreased
      compared to age-matched healthy cats. Treatment was limited to short-term
      parenteral calcium gluconate injections, as clinically indicated, a balanced diet
      and cage rest, which resulted in quick clinical recovery in four cases. The
      remaining two cats had to be euthanased because of progressive neurological
      deficits secondary to spinal fractures. At the time of writing, a multitude of
      commercial balanced diets is widely available and diseases secondary to dietary
      deficiencies have become rare. Nevertheless, NSH is still an important clinical
      entity, and should be considered in growing cats presenting with spontaneous
      fractures or seizures.

PMID- 10649600
TI  - Spinal arachnoid cyst in four dogs: diagnosis, surgical treatment and follow-up
      results.
AB  - Spinal arachnoid cysts were diagnosed in four dogs; two schipperkes and two
      rottweilers. Myelography showed the cysts to be localised either at the second to
      third caudal vertebrae or between the eighth and tenth thoracic vertebrae. The
      cysts were drop-shaped with a dorsal midline localisation, intradural in the
      arachnoid space, and with a cranial opening. Surgical treatment was performed by
      one of two techniques; durotomy with drainage or durectomy with resection. As the
      pathological examination in one case revealed a lining of hyperplastic pia
      arachnoid meningothelial cells in the cyst, it was assumed that the cyst
      originates from a developmental disturbance during formation of the arachnoid
      membrane. Follow-up studies were carried out from 10 months to four years
      postoperatively and revealed that there were no further problems in three out of
      four of the dogs during this period.

PMID- 10649602
TI  - Extracorporeal shock wave therapy in calcific tendinitis of the shoulder.

PMID- 10649601
TI  - Canine vitamin D toxicosis.

PMID- 10649603
TI  - Cervical spine involvement in psoriatic arthritis.
AB  - The clinical and radiographic manifestations of cervical spine involvement in
      psoriatic arthritis remain incompletely described. Only one case-control study
      has been reported. OBJECTIVE: To conduct a case-control study of the clinical and
      radiographic manifestations of cervical spine involvement in psoriatic arthritis.
      PATIENTS AND METHODS: 30 psoriatic arthritis patients (mean age, 53.3 years (21
      78); sex ratio, 1; mean disease duration, 80.4 months (12-204); and mean
      Ritchie's index, 9.3 (2-30)) were compared with 30 controls with common low back
      pain (mean age, 53.8 years (21-78)). Each patient underwent a physical
      examination, completed a questionnaire on function, underwent cervical spine
      radiography (anteroposterior and lateral views and views in flexion and
      extension). All radiographs were evaluated by an independent observer. RESULTS:
      Patients were more likely than controls to have neck pain (22/30 (73%) vs 8/30
      (26%) P < 0.001). Among subjects with neck pain, the time pattern was more likely
      to be inflammatory in the patients than in the controls (14/22 vs 1/8, P <
      0.001). Functional impairment and pain severity were significantly greater in the
      patients. On radiographs, facet joint abnormalities (osteophytes, joint space
      loss, sclerosis) were significantly more common (P < 0.01) in the patients,
      particularly at C3-C4 and C4-C5. Also more common in the patients were signs of
      spondylitis (7 vs 0) and of facet joint arthritis (7 vs 2). No subjects had
      syndesmophytes. Three (10%) patients had anterior C1-C2 subluxation with an atlas
      dens interval greater than 4 mm. Within the patient group, no correlations were
      found between clinical patterns and radiographic findings. CONCLUSION: Our data
      confirm that psoriatic arthritis frequently involves the cervical spine, with the
      facet joints being a preferred target, and can cause anterior C1-C2 subluxation.

PMID- 10649604
TI  - Cyclooxygenase activity in chondrocytes from osteoarthritic and healthy
      cartilage.
AB  - OBJECTIVES: To compare prostaglandin production and cyclooxygenase activity in
      high-density primary cultures of chondrocytes from patients with osteoarthritis
      and from healthy controls. METHODS: Chondrocytes harvested from operative
      specimens obtained during hip or knee arthroplasty were cultured at a very high
      density for 48 h. Cyclooxygenase activity was evaluated based on prostaglandin E2
      levels (radioimmunological assay) after addition of arachidonic acid. The
      chondrocytes were cultured with and without IL-1 beta and TNF alpha. RESULTS:
      Prostaglandin E2 production and cyclooxygenase activity were significantly higher
      in cultures of chondrocytes from osteoarthritic than from healthy joints. Adding
      IL-1 beta to the osteoarthritic chondrocyte cultures further increased the high
      cyclooxygenase activity, whereas adding TNF alpha alone had no effect.
      CONCLUSION: Cultured chondrocytes from osteoarthritic joints showed increased
      prostaglandin E2 production and cyclooxygenase activity.

PMID- 10649605
TI  - Bone mineral density at the femur and lumbar spine in a population of young women
      treated for scoliosis in adolescence.
AB  - OBJECTIVES: To evaluate associations between scoliosis and bone mineral density.
      Many of the factors involved in the etiopathogenesis of idiopathic scoliosis also
      affect peak bone mass acquisition, which occurs primarily during puberty, a
      period of progression for scoliosis. METHOD: We compared 33 patients treated for
      scoliosis with 33 controls and looked for correlations between bone mineral
      density and a number of retrospectively collected parameters (e.g., duration of
      bracing, outcome in adulthood). RESULTS: Bone mineral density values were lower
      in the patients than in the controls. Among the patients, those with osteopenia
      wore a brace significantly longer and had more severe scoliosis in adulthood than
      those without osteopenia. CONCLUSIONS: These findings suggest a need for
      osteopenia screening and prevention in children with scoliosis, for monitoring
      physical activity and calcium intake during bracing, for preferring braces that
      allow greater mobility, and for closely monitoring the scoliosis during adulthood
      if osteopenia is present.

PMID- 10649606
TI  - Evaluation of an educational low back pain prevention program for hospital
      employees.
AB  - OBJECTIVES: To evaluate the impact of an educational low back pain prevention
      program in a cohort of hospital employees. METHODS: A cohort of 136 nonclerical
      hospital employees attended classes on safe postures and patient handling, then
      received advice by educators who observed them while they performed their typical
      workday tasks. Each of the subjects in this intervention group was matched on
      age, sex, and job category with a control. Musculoskeletal complaints and changes
      in habits during work and recreational activities were evaluated before the
      intervention (or the corresponding date in the control group) and after two
      years. RESULTS: In the intervention group, 36% of subjects with low back pain at
      baseline were free of this symptom at follow-up, whereas only 26% were in the
      opposite situation. The proportion of subjects with low back pain episodes
      lasting longer than 30 days increased significantly from baseline to follow-up in
      the control group (from 30% to 49%) but not in the intervention group. The number
      of sick leaves longer than 30 days decreased significantly in the intervention
      group. Only 33% of the intervention group subjects felt the intervention had been
      helpful; this proportion varied across job categories. CONCLUSION: Our data
      suggest that differences in job categories should be taken into account when
      designing educational programs for preventing low back pain. They also indicate
      that back school programs may be more effective in subjects with a history of low
      back pain, whereas instruction on safe postures and patient handling may be the
      best approach in subjects who have not previously experienced low back pain.
      Observing and providing advice to employees while they are performing their usual
      duties may be an essential component of low back pain prevention.

PMID- 10649607
TI  - Continuing medical education for rheumatologists in France. Results of a national
      survey.
AB  - OBJECTIVE: To determine how continuing medical education is rated and used by
      French rheumatologists. MATERIAL AND METHODS: All French rheumatologists (n =
      2579) were sent a questionnaire in September 1998. Results were evaluated using
      the test for differences between two proportions, with the significance level set
      at 0.05. RESULTS: 46% of the questionnaires (n = 1197) were returned completed.
      Mean age of respondents was 45 +/- 8 years; 41.2% of respondents were in full
      time office practice, 14.8% were in full-time hospital practice, and 32.7%
      divided their time between the office and hospital. Nineteen percent worked in
      the Paris area. Nearly all the respondents (99.6 to 100%) attended continuing
      education meetings. Respondents working in Paris were significantly (P < 0.05)
      more likely than those working elsewhere to attend national conventions (99.6% vs
      88.4%), whereas a difference in the other direction was found for regional and
      local conventions. The mean score assigned by respondents to national, regional
      and local conventions was 60/100. Respondents in full-time hospital practice were
      more likely than other respondents to attend international conventions; they were
      the only subgroup that assigned a score greater than 50/100 to this resource.
      University classes were attended by 44.4% of respondents and obtained a mean
      score of 65/100. Rheumatology journals were used by 99.2% of respondents and
      obtained scores greater than 65/100 in all subgroups. Respondents in full-time
      hospital practice were more likely to read international rheumatology journals
      than the other subgroups; they were the only subgroup that assigned a score
      greater than 50/100 to this resource. CD ROMs, videocassettes, and the Internet
      were used by less than one-fourth of respondents and were assigned low scores.
      The proportion of respondents who participated in the provision of education
      ranged from 23.6% to 53.3%. Opinions on the usefulness of the various educational
      resources varied across type-of-practice subgroups. CONCLUSIONS: Most respondents
      attended meetings and used resources for independent learning. The findings from
      our study could be used to plan further investigations into the use of continuing
      medical education by French rheumatologists, particularly those who did not send
      back our questionnaire.

PMID- 10649608
TI  - Autologous chondrocyte implantation. A review of techniques and preliminary
      results.
AB  - The treatment of deep focal bone and cartilage defects in weight-bearing areas of
      the knee remains challenging. Autologous chondrocyte implantation is a recently
      introduced alternative to drilling and mosaicplasty and is gaining ground in
      France under the impetus of favorable results obtained in other countries in
      highly selected cases. The technique and preliminary results are discussed
      herein.

PMID- 10649609
TI  - Contribution of genetically modified mouse models to the elucidation of bone
      physiology.
AB  - The development over the last few years of genetically modified mouse models has
      provided a wealth of new information on the intimate cellular mechanisms involved
      in bone physiology. This article reviews some of the new insights gained into non
      collagenous bone proteins. The bone matrix is no longer viewed as a passive
      support for bone cells, but rather as a key factor in the regulation of cell
      recruitment, proliferation, and differentiation. Studies using genetically
      modified mouse models have demonstrated the central importance of transcription
      factors such as Cbfa1, c-Fos, and c-Src in the differentiation of osteoblasts or
      osteoclasts from bone marrow stem cells. They have also allowed to identify the
      main cytokines involved in the regulation of bone cell activities, particularly
      in estrogen-deprived individuals. A discussion is provided in this article of the
      studies that identified the main communication pathway between osteoblasts and
      osteoclasts, in which the mediators are osteoprotegerin and its ligand, and that
      demonstrated the central position of these two factors in the regulation of
      osteoclast differentiation and activity.

PMID- 10649610
TI  - Rheumatology in Lebanon: half a century to look back on.

PMID- 10649611
TI  - Craniocervical junction tuberculosis in children.
AB  - A case of tuberculosis of the craniocervical junction in an eight-year-old is
      reported. Presenting symptoms were painful torticollis, dysphagia, and
      tetraparesis. Computed tomography and magnetic resonance imaging findings
      strongly suggested the diagnosis, which was confirmed by peroral aspiration of a
      retropharyngeal collection. Management was by immobilization and antituberculous
      agents. Surgery was not performed. After one year, the outcome was highly
      satisfactory.

PMID- 10649612
TI  - Erosive polyarthritis in Crohn's disease. Report of a case.
AB  - Erosive polyarthritis in Crohn's disease is rare and raises diagnostic and
      pathophysiological problems. A case with destructive lesions of the shoulders and
      hips is reported in a 43-year-old woman with a 26-year history of Crohn's
      disease. Ankylosis of the spine and hips, motion range limitation of the
      shoulders and wrists, and boutonniere deformity of the third finger of the right
      hand were present. Tests were negative for rheumatoid factor and the HLA-B27
      antigen. Plain radiographs showed a triple rail pattern at the spine; synostosis
      of the hips; and destructive lesions of the shoulders, wrists, tarsal bones, and
      third proximal interphalangeal joint of the right hand. Glucocorticoid therapy
      was effective in suppressing the bowel symptom flares but only partially improved
      the joint symptoms, whose treatment relied mainly on nonsteroidal
      antiinflammatory agents and rehabilitation therapy. Erosive arthritis in Crohn's
      disease is frequently monoarticular, with the hip being the most common target.
      It can complicate a spondylarthropathy or reveal granulomatous synovitis.
      Polyarticular forms pose difficult diagnostic and therapeutic challenges and add
      to the disability caused by the bowel disease. The potential role of genetic
      factors remains to be studied.

PMID- 10649613
TI  - Mechanical low back pain and sciatica revealing an epidural abscess fully
      responsive to short-course antibiotic therapy.

PMID- 10649614
TI  - Effect of tiludronate in fibrous dysplasia of bone. A case-report.

PMID- 10649616
TI  - Increasing the number of hepatitis B vaccine injections augments anti-HBs
      response rate in HIV-infected patients. Effects on HIV-1 viral load.
AB  - Preventing hepatitis B by vaccination is essential in HIV-infected patients
      (higher progression rate of HBV infection to chronicity, lower rate of serum HBe
      Ag loss). However, it has been shown a decreased anti-HBs response in these
      individuals after a standard vaccination (3 doses of 20 micrograms). Thus, we
      tested the hypothesis that doubling the number of hepatitis B vaccine injections
      might increase anti-HBs response rate. HIV-infected patients with CD4 >
      200/microliter, who were on stable antiretroviral treatment, as well as
      seronegative for HBV markers, and who have never been vaccinated against HBV,
      were given 3 intramuscular injections of Genhevac B 20 micrograms at 1 month
      intervals. Initial non responders were given 3 additional monthly injections.
      Anti-HBs titer was followed. We also evaluated the effects on HIV-1 viral load.
      Twenty patients with a median CD4 cell count of 470/microliter were enrolled. The
      response rate after three 20 micrograms injections was 55% (11/20), lower in
      individuals with CD4 between 200 and 500/microliter (4/12 = 33.3%), compared to
      patients with CD4 above 500/microliter (7/8 = 87.5%, P = 0.02). Among 9 initial
      non-responders, only 2 did not respond to 3 additional doses; thus, the overall
      response rate was 90% (18/20). Geometric mean titers of anti-HBs were 133 IU/l
      and 77.5 IU/l, after 3 and 6 Genhevac doses, respectively (P = 0.38). One year
      later, only 10/17 (58.8%) patients had protective anti-HBs. Five patients
      experienced a significant viral load increase, transient in 3 cases. These
      preliminary results suggest that doubling the number of hepatitis B vaccinations
      in HIV-infected patients might significantly improve anti-HBs response rate;
      however, close monitoring of anti-HBs is necessary because of its short-lived
      persistence. The effects on HIV-1 viral load are limited.

PMID- 10649615
TI  - Rectal and vaginal immunization with a macromolecular multicomponent peptide
      vaccine candidate for HIV-1 infection induces HIV-specific protective immune
      responses.
AB  - An effective vaccine for human immunodeficiency virus (HIV) is needed to
      stimulate the immune response of the genital mucus to prevent mucosal
      transmission of the virus. We have developed a macromolecular multicomponent
      peptide vaccine candidate, VC1. Both rectal and vaginal immunization of VC1 mixed
      with cholera toxin (CT) induced HIV-1-specific IgA antibody in mouse fecal
      extract solution and vaginal wash. These antibody productions were enhanced by
      the combination with IL-4 or GM-CSF expressing plasmids. Either fecal extract or
      vaginal wash solution from immunized mice inhibited production of HIV-1IIIB p24
      protein. The mononuclear cells from spleen, intestinal lymph nodes, or Peyer's
      patches from VC1- and CT-immunized mice released IFN-gamma or IL-4, when these
      cells were co-cultured with VC1 antigen. In addition, the regional lymphoid cells
      from rectal and vaginal region of mice immunized with VC1 and CT also elicited a
      substantial level of HIV-1-specific cytotoxic T cell (CTL) response. This CTL
      response was enhanced by the addition of IL-12 expressing plasmid. Our results
      clearly demonstrated that both rectal and vaginal immunization could induce
      systemic and mucosal immunities specific for HIV-1.

PMID- 10649617
TI  - A phase I trial in HIV negative healthy volunteers evaluating the effect of
      potent adjuvants on immunogenicity of a recombinant gp120W61D derived from dual
      tropic R5X4 HIV-1ACH320.
AB  - Thirty healthy HIV negative volunteers were randomised to receive 200 micrograms
      of rgp120W61D in either: 3D-MPL and QS21, with an oil and water emulsion (SBAS-2)
      (13); or 3D-MPL and QS21 (SBAS-1) (11); or alum (six). Immunizations were given
      at 0, 4 and 28 weeks and 23 (77%) participants completed the schedule. Adverse
      events were more frequent (P < 0.001) and more severe (P < 0.001) in the SBAS-2
      group. Binding antibodies to the homologous rgp120W61D were detected after the
      first immunisation only in those receiving SBAS-1 and SBAS-2, were maximal after
      the third immunization in all three groups, and persisted to week 84 only in the
      novel adjuvant groups. These differences were significant (p = 0.02).
      Neutralising antibodies to TCLA-strains of HIV-1 were observed after the second
      immunization in all three groups, were maximal after the third immunization, but
      did not neutralise homologous or heterologous PBMC derived primary HIV-1
      isolates. Proliferative T-cell responses to rgp120W61D were maximal after the
      second immunization and reached very high values in the SBAS-2 group. HIV-1
      specific CD8+ MHC Class I restricted cytotoxic T-lymphocytes were not seen in a
      subset of participants tested at a single timepoint. SBAS-2 with rgp120W61D
      induced antibody titres as high as those seen in HIV infection, but the quality
      of the antibodies remained different in that there was no evidence of primary
      isolate neutralisation. Although cell-mediated immunity was enhanced by SBAS-2 in
      terms of lymphoproliferative responses, HIV-1 specific CD8+ cytotoxicity was not
      demonstrated.

PMID- 10649618
TI  - A new protocol for a challenge test to assess the efficacy of live anticoccidial
      vaccines for chickens.
AB  - The search for vaccines to control coccidioses caused by Eimeria species in
      chickens (Gallus gallus) is intensifying because of the increasing threat of drug
      resistance to anticoccidial agents. It is important, therefore, to develop a
      reliable standard method for the assessment of multivalent vaccine efficacy,
      because many criteria generally used to judge drug efficacy are not appropriate
      for vaccines. The lack of correlations between oocyst production, severity of
      lesions and bird weight gains is discussed. Furthermore, not all Eimeria species
      cause pathognomonic lesions. A new protocol for a vaccine efficacy test is
      described which uses growth rate of chickens after virulent challenge as the
      primary criterion and feed conversion ratio as the secondary criterion for
      protection against each of the separate coccidioses caused by the seven species
      of Eimeria that parasitize the chicken. The benefits to this protocol over
      previous ad hoc experimental designs are: (1) immunization is carried out with
      multivalent vaccines of Eimeria species up to the maximum of seven that may
      infect chickens; (2) assessments of immunity are carried out for each species
      separately so results can not be confounded; (3) the criteria of efficacy are
      those that are crucial to demonstrate commercial usefulness; (4) the possibility
      of drawing erroneous conclusions based upon inappropriate criteria such as oocyst
      production or lesion scores is avoided; (5) because the same criteria are used
      for each species, direct comparisons may be made amongst immunities to all of the
      species in the vaccine being tested. Results are presented from tests of three
      commercial batches of Paracox attenuated anticoccidial vaccine, showing that
      separate virulent challenges with all seven Eimeria species were controlled in
      vaccinated chicks.

PMID- 10649619
TI  - Immunogenicity and protective capacity of Mycobacterium bovis BCG after oral or
      intragastric administration in mice.
AB  - After oral or intragastric administration of BCG to mice, comparable numbers of
      IFN gamma and TNF gamma producing cells were detected in both local (Peyer's
      patches) and central (spleen) lymphoid organs. Similar levels of precursors of
      CD8+ cytotoxic T lymphocytes specific for mycobacterial antigens were also found
      in the spleen and the mesenteric lymph nodes. These immune responses remained
      high over the course of 3 months, the duration of observation. Oral
      administration of BCG led to an enlargement of the cervical lymph nodes, which
      contained high levels of viable bacteria. In contrast, no adverse effects were
      observed in mice given the BCG via the intragastric route. These two routes of
      immunization induced similar levels of protective immunity to those observed in
      mice immunized via the subcutaneous route against a challenge with a virulent
      Mycobacterium tuberculosis strain (H37Rv).

PMID- 10649620
TI  - Oral tolerance elicited in mice by beta-lactoglobulin entrapped in biodegradable
      microspheres.
AB  - Oral administration of antigen is known to be appropriate for some vaccine
      purposes as well as oral tolerance induction. In the present study, oral
      administration of beta-lactoglobulin (BLG) loaded poly(D,L-lactide-co-glycolide)
      (D,L-PLG) microspheres induced tolerance was evaluated. A single feeding of 5
      micrograms of encapsulated BLG tolerized BALB/c mice to subsequent BLG parenteral
      challenge, suppressing the specific humoral, intestinal and cellular responses.
      The tolerogenic efficient dose was then reduced 10,000 times, compared to oral
      administration of soluble BLG. This suggests that loading food proteins into D,L
      PLG microspheres might be a potential tool for inducing oral tolerance with
      allergens.

PMID- 10649621
TI  - Pertussis immunization in HIV-1-infected infants: a model to assess the effects
      of repeated T cell-dependent antigen administrations on HIV-1 progression.
      Italian Register for HIV infection in children.
AB  - Several data evidence that HIV-1 replication may increase in temporal association
      with immunizations, raising concerns on potential negative effects of
      vaccinations on HIV-1 progression. Among patients prospectively followed by the
      "Italian Register for HIV infection in children", we evaluated, using the Cox
      Mantel method, conditional probabilities of progressing to CDC clinical
      categories 'B' or 'C', and immunological categories '2' or '3' in 88 children
      immunized against pertussis and 244 non-immunized. No selection criteria were
      followed in vaccinating children. No significant differences were observed
      between the two groups. The lack of a significant impact on clinical and
      immunological deterioration by the repeated administrations of a T cell-dependent
      vaccine endorses the current recommendations for routine immunizations in HIV-1
      infected children.

PMID- 10649622
TI  - The IgG subclass profile of anti-HBs response in vaccinated children and children
      seroconverted after natural infection.
AB  - The IgG subclass profiles of anti-HBs antibodies were investigated in 30 children
      who had recovered from acute hepatitis B and 40 children vaccinated against
      hepatitis B virus (HBV) with Engerix B. After natural seroconversion the mean
      geometric value of anti-HBs titres was ca 41-fold lower than at the peak of
      response in vaccinees, and specific antibodies were highly restricted to IgG1
      subclass followed by IgG3 with only a minor contribution of IgG2 and IgG4.
      Conversely, in children immunized with recombinant HBsAg, IgG1 and IgG3 dominated
      after two doses of vaccine and 1 month after the third injection but the response
      was less selective and more variable. One year after vaccination IgG4 anti-HBs
      antibodies became the second dominating isotype. Significant statistical
      differences in the profiles of IgG anti-HBs were observed when the age and
      maturity of humoral response were considered. While children vaccinated below 5
      years of age responded mainly with IgG1 and IgG3 subclasses, older children (> 5
      years) showed a high individual variability in the specific profiles with a high
      contribution of IgG4. We concluded that vaccination at a younger age leads to the
      production of antibody subclasses which are more effective for virus
      neutralization.

PMID- 10649623
TI  - Salivary anti-capsular antibodies in infants and children immunised with
      Streptococcus pneumoniae capsular polysaccharides conjugated to diphtheria or
      tetanus toxoid.
AB  - Saliva samples of infants and children immunised with pneumococcal vaccines were
      analysed for anti-polysaccharide (PS) antibodies against the Streptococcus
      pneumoniae (Pnc) vaccine serotypes 6B, 14, 19F, and 23F. The children received
      Pnc conjugate vaccine (1, 3, or 10 micrograms of PSs conjugated to diphtheria or
      tetanus toxoid) or placebo at 2, 4, and 6 months. At 7 months of age salivary PS
      antibodies were detected rarely. All children received Pnc conjugate or PS
      vaccine at 14 months of age. At 15 months, both IgA and IgG anti-Pnc PS were
      found, anti-19F and anti-14 antibodies occurring most frequently and in the
      highest concentrations. IgA was in the secretory form and predominantly IgA1. A
      negative dose dependency was observed in IgA anti-19F response. In general, no
      clear differences in salivary antibody responses were found between the children
      primed with conjugate vaccine in infancy and those who received their first Pnc
      vaccine at 14 months of age, suggesting that priming with Pnc conjugate vaccines
      does not lead to remarkable mucosal memory responses.

PMID- 10649624
TI  - Enhanced type I immune response to a hepatitis B DNA vaccine by formulation with
      calcium- or aluminum phosphate.
AB  - DNA vaccines induce protective humoral and cell-mediated immune responses in
      several animal models. When compared with conventional vaccines, however, DNA
      vaccines often induce lower antibody titers. We have now found that formulation
      of a DNA vaccine encoding hepatitis B surface antigen with calcium- or aluminum
      phosphate adjuvants can increase antibody titers by 10-100-fold and decrease the
      immunogenic dose of DNA by 10-fold. Furthermore, boosting an HBs protein-primed
      response with the adjuvanted DNA vaccine resulted in a dramatic increase in the
      HBs-specific IgG2a response reflecting a shift towards a TH1 response. The
      mechanism by which aluminum phosphate exerts its adjuvant effect is not through
      increased expression of HBsAg in vivo; rather, the adjuvant appears to increase
      the number and affinity of HBs peptide antigen-specific IFN-gamma and IL-2
      secreting T cells.

PMID- 10649625
TI  - Comparative study of the effects of peptidoglycan monomer and structurally
      related adamantyltripeptides on humoral immune response to ovalbumin in the
      mouse.
AB  - Peptidoglycan monomer, GlcNAc-MurNAc-L-Ala-D-isoGln-mesoDAP(omega NH2)-D-Ala-D
      Ala (PGM) originating from Brevibacterium divaricatum and synthetic
      adamantyltripeptides, diastereoisomers of D,L-(adamant-2-yl)-Gly-L-Ala-D-isoGln
      (AdTP1 and AdTP2) exhibit immunomodulating activity. An experimental model in the
      mouse has been established with suboptimal amounts of ovalbumin (OVA) as the
      immunogen, and parallel testing of adjuvant activity of these three
      immunomodulators was carried out in Balb/c, C57B16 or CBA mice. Tested compounds
      (100 or 200 micrograms/mouse) mixed with OVA in saline (50 micrograms/mouse) were
      administered s.c. Anti-OVA was assayed by ELISA in the sera of mice taken 7 days
      after the boosters (given on days 14 and 28). The treatment with PGM and one of
      the diastereoisomers, AdTP2, resulted in significantly higher increase in anti
      OVA IgG levels (stimulation index up to 46) with respect to controls and groups
      treated with AdTP1. The effect of AdTP2 treatment was comparable to that of PGM
      in most experiments after the first booster, but after the second booster PGM
      exhibited markedly better effect. PGM and AdTP2 also induced markedly higher
      levels of IgG1 and IgG2 anti-OVA subclasses than detected in controls and AdTP1
      treated mice, indicating that these two immunomodulators might upregulate both
      Th1-like and Th2-like immune responses.

PMID- 10649626
TI  - Effect of vaccination on the potentiation of porcine reproductive and respiratory
      syndrome virus (PRRSV)-induced pneumonia by Mycoplasma hyopneumoniae.
AB  - Porcine reproductive and respiratory syndrome virus (PRRSV) and Mycoplasma
      hyopneumoniae are frequently isolated pathogens from pigs with respiratory
      disease. A previous study conducted in our laboratory found that infection with
      M. hyopneumoniae increased the duration and severity of respiratory disease
      induced by PRRSV. The purpose of this experiment was to determine whether
      vaccination against M. hyopneumoniae and/or PRRSV decreased the enhancement of
      PRRSV-induced pneumonia. Both M. hyopneumoniae bacterin and PRRSV vaccine
      decreased the severity of clinical respiratory disease. Infection or vaccination
      with PRRSV appeared to decrease the efficacy of the M. hyopneumoniae bacterin.
      Vaccination with M. hyopneumoniae bacterin decreased the potentiation of PRRSV
      induced pneumonia observed in the dual infected pigs. However, PRRSV vaccination
      in combination with M. hyopneumoniae bacterin eliminated this benefit and the
      amount of pneumonia induced by PRRSV increased. PRRSV vaccine alone did not
      decrease the potentiation of PRRSV pneumonia by M. hyopneumoniae.

PMID- 10649627
TI  - Selection of an immunogenic peptide mimic of the capsular polysaccharide of
      Neisseria meningitidis serogroup A using a peptide display library.
AB  - The presently available meningococcal vaccine is poorly immunogenic in infants
      and fails to induce long-lasting immunity in adults. Efforts to convert this TI-2
      type vaccine into a T dependent vaccine are being actively pursued and include
      conjugate vaccine development. Alternatively, the meningococcal polysaccharide
      can be rendered into a T dependent antigen through the use of peptides which
      mimic the capsular polysaccharide complexed or conjugated to potent protein
      carrier molecules. We have previously developed an anti-idiotypic monoclonal
      antibody (mAb) based peptide mimic of meningococcal group C polysaccharide
      (MCPS). A direct approach to identification of peptide mimics of antigen is
      through the use of peptide display libraries. We have utilized a phage library
      and a mAb with specificity for meningococcal group A polysaccharide (MAPS) to
      screen for a peptide mimic of MAPS. Six different peptide motifs were selected
      with the use of the mAb. Thirty-eight of the 60 sequenced phage clones were
      represented by motif 1 and 2 which differed only in three amino acids at the
      carboxy terminus. Immunological assays were performed. Phage clones with motif 1
      and 2 were capable of binding human hyperimmune sera and inhibiting the binding
      of human hyperimmune sera to nominal antigen. Immunization with motif 1 peptide
      complexed to proteosomes resulted in an anti-MAPS antibody response. Priming with
      the peptide proteosome complex induced an anamnestic response indicating the
      formation of immunological memory.

PMID- 10649628
TI  - Biological activities of antibodies elicited by lipooligosaccharide based
      conjugate vaccines of nontypeable Haemophilus influenzae in an otitis media
      model.
AB  - Vaccination of chinchillas with nontypeable Haemophilus influenzae (NTHi)
      lipooligosaccharide (LOS) conjugates protected against otitis media. Correlations
      between the levels of conjugate-induced LOS antibodies (Abs) in sera and middle
      ear fluids (MEFs) and Ab-mediated biological functions and protection were
      examined. Following parenteral vaccination and middle ear challenge, all
      vaccinated animals, but none of the controls, had high titers of anti-LOS in
      their sera and MEFs. There was a correlation between the levels of anti-LOS IgG +
      M, IgG or IgA in the sera and in the MEFs (P < 0.001). An inverse correlation was
      found between the level of serum IgG + M and bacterial counts and between the
      levels of MEF Abs and bacterial counts at the early postchallenge stage (P <
      0.05). Of the 39 vaccinated animals, 44% showed complete protection against
      otitis media, 46% (18/39) of their sera inhibited adherence of NTHi to human
      epithelial cells, 49% (19/39) demonstrated bactericidal activity and 49% (19/39)
      showed opsonophagocytic activity. In contrast, none of the controls (19) were
      protected, none of their sera inhibited bacterial adherence or had bactericidal
      activity and only 21% showed opsonophagocytosis. Our interpretation is that
      vaccine-induced LOS Abs transuded into the middle ear and conferred immunity to
      NTHi by binding to LOS of NTHi, inhibition of NTHi adherence to epithelial cells
      and complement-mediated bacteriolysis (or opsonophagocytosis).

PMID- 10649630
TI  - Crossreactive neutralizing antibodies induced by immunization with caprine
      arthritis-encephalitis virus surface glycoprotein.
AB  - Four Saanen goats were immunized with affinity purified gp135 surface
      glycoprotein (SU) of caprine arthritis-encephalitis virus isolate 79-63 (CAEV-63)
      and evaluated for homologous and crossreactive serum neutralizing antibodies.
      CAEV-63 neutralizing antibodies were detected in all goats after seven
      immunizations with SU in Quil A adjuvant. Sera from three goats neutralized an
      independent CAEV isolate (CAEV-Co). However, serum from one goat did not
      detectably neutralize heterologous CAEV-Co and inhibited CAEV-Co neutralization
      by another serum.

PMID- 10649629
TI  - Activation of soluble polysaccharides with 1-cyano-4-dimethylaminopyridinium
      tetrafluoroborate (CDAP) for use in protein-polysaccharide conjugate vaccines and
      immunological reagents. II. Selective crosslinking of proteins to CDAP-activated
      polysaccharides.
AB  - Covalently linking protein to polysaccharides converts the anti-polysaccharide
      immune response from a T-cell independent response to one which is T-cell
      dependent. The organic cyanylating reagent 1-cyano-4-dimethylaminopyridinium
      tetrafluoroborate (CDAP) (Vaccine 14:190, 1996) has been used to activate
      polysaccharides, which can then be reacted with spacer reagents or directly with
      protein. We wished to explore ways in which proteins could be linked to CDAP
      activated polysaccharides to conjugate in a more controlled and selective
      fashion. To this end, we examined the reaction of nucleophilic amino acids with
      CDAP-activated polysaccharides under basic and acidic conditions. We found that
      lysine, cysteine and histidine but not methionine, serine or tyrosine conjugated
      to CDAP-activated dextran. We also examined the reaction of various spacer
      reagents with CDAP-activated dextran as a function of pH. The addition of
      hexanediamine was highly pH dependent and maximal at pH 9.3. In contrast, the
      addition of adipic dihydrazide, which has a pKa of ca 2.5 was essentially
      independent of pH. By performing the conjugation reaction at pH 5, we were able
      to selectively couple hydrazides even in the presence of high concentrations of
      amines. Proteins derivatized with limited numbers of hydrazides could be
      conjugated to CDAP-activated polysaccharides at pH5, where the native protein was
      not reactive. Proteins could be derivatized with hydrazides on carboxyls using
      adipic dihydrazide and a water soluble carbodiimide or on amines using a mild two
      step reaction. Tetanus toxoid-pneumococcal type 14 conjugates produced by
      coupling hydrazide-derivatized tetanus toxoid under acidic conditions induced
      anti-polysaccharide antibodies at titers comparable to that stimulated by
      conjugates produced using a basic coupling pH. Our data suggest that crosslinking
      was occurring only with the limited number of hydrazides on the protein and that
      we achieved limited and selective crosslinking between the protein and CDAP
      activated polysaccharide. This work also demonstrates that CDAP-mediated
      conjugation to polysaccharides can be applied even to very pH sensitive proteins
      and polysaccharides.

PMID- 10649631
TI  - Visual mate choice in poison frogs.
AB  - We investigated female mate choice on the basis of visual cues in two populations
      of Dendrobates pumilio, the strawberry poison frog, from the Bocas del Toro
      Archipelago in Panama, Central America. Mate choice experiments were carried out
      by presenting subject females of each of two morphs of this species (orange and
      green) from two different island populations (Nancy Key and Pope Island) with
      object frogs (one of each morph) under glass at one end of a terrarium. Recorded
      calls were played simultaneously from behind both object frogs. The experiments
      were carried out under two light regimes: (i) white light, and (ii) relatively
      monochromatic filtered blue light. Subject females from each population displayed
      a significant preference for their own morph under white light, but not under
      blue light. These results indicate that female D. pumilio use visual cues in mate
      choice, and suggest that colour may be the visual cue they use.

PMID- 10649632
TI  - Zinc tolerance and hyperaccumulation are genetically independent characters.
AB  - The hyperaccumulation of metals by a rare class of plants is a fascinating and
      little understood phenomenon. No genetic analysis has been possible since no
      intraspecific variation is known for this character. Here, we report on crosses
      between the zinc-hyperaccumulating and -tolerant species Arabidopsis halleri and
      the non-hyperaccumulating, non-tolerant species Arabidopsis petraea. The F2
      segregates for both characters and it appears that the two characters are
      genetically independent. The data for tolerance are consistent with a single
      major gene for this character (although the number of genes for hyperaccumulation
      cannot be determined), and is probably not very large.

PMID- 10649633
TI  - Relationships of the extinct moa-nalos, flightless Hawaiian waterfowl, based on
      ancient DNA.
AB  - The extinct moa-nalos were very large, flightless waterfowl from the Hawaiian
      islands. We extracted, amplified and sequenced mitochondrial DNA from fossil moa
      nalo bones to determine their systematic relationships and lend insight into
      their biogeographical history. The closest living relatives of these massive,
      goose-like birds are the familiar dabbling ducks (tribe Anatini). Moa-nalos,
      however, are not closely related to any one extant species, but represent an
      ancient lineage that colonized the Hawaiian islands and evolved flightlessness
      long before the emergence of the youngest island, Hawaii, from which they are
      absent. Ancient DNA yields a novel hypothesis for the relationships of these
      bizarre birds, whereas the evidence of phylogeny in morphological characters was
      obscured by the evolutionary transformation of a small, volant duck into a giant,
      terrestrial herbivore.

PMID- 10649634
TI  - Does interspecific hybridization influence evolutionary rates? An experimental
      study of laboratory adaptation in hybrids between Drosophila serrata and
      Drosophila birchii.
AB  - The low initial fitness of progeny from interspecific crosses in animals and the
      rarity of interspecific hybridization in natural environments have led to a
      debate about the evolutionary importance of this phenomenon. Here we directly
      assess the effects of hybridization between Drosophila serrata and Drosophila
      birchii on evolutionary rates. We looked at the effects on laboratory adaptation
      over 30 generations in two laboratory environments, one of which involved
      nutrition and temperature stress. Laboratory adaptation occurred over time in
      both environments as reflected by a marked change in viability. However, whilst
      hybrid lines at no stage performed poorly relative to parental lines, their rate
      of adaptation never exceeded that of the parentals. Thus, there was no evidence
      that hybridization increased evolutionary rates. Instead, hybrid lines converged
      phenotypically with one of the parental species.

PMID- 10649635
TI  - Languages, geography and HLA haplotypes in native American and Asian populations.
AB  - A number of studies based on linguistic, dental and genetic data have proposed
      that the colonization of the New World took place in three separate waves of
      migration from North-East Asia. Recently, other studies have suggested that only
      one major migration occurred. It is the aim of this study to assess these
      opposing migration hypotheses using molecular-typed HLA class II alleles to
      compare the relationships between linguistic and genetic data in contemporary
      Native American populations. Our results suggest that gene flow and genetic drift
      have been important factors in shaping the genetic landscape of Native American
      populations. We report significant correlations between genetic and geographical
      distances in Native American and East Asian populations. In contrast, a less
      clear-cut relationship seems to exist between genetic distances and linguistic
      affiliation. In particular, the close genetic relationship of the neighbouring Na
      Dene Athabaskans and Amerindian Salishans suggests that geography is the more
      important factor. Overall, our results are most congruent with the single
      migration model.

PMID- 10649636
TI  - Analysis of cytokine dynamics in corneal allograft rejection.
AB  - Motivated by the discovery of oscillations in tumour necrosis factor-alpha (TNF
      alpha) concentration in the aqueous humour of rabbits undergoing corneal
      allograft rejection, a simple mathematical model is developed for the regulation
      of TNF-alpha, which incorporates both negative feedback and amplification
      pathways. Mathematical analysis reveals a surprisingly rich behavioural
      repertoire for this simple cytokine pathway, including excitability, threshold
      behaviour, hysteresis, oscillations and bistability. This suggests new
      possibilities for experimental demonstration, and reveals the potential
      contributions of nonlinear dynamics to understanding cytokine regulation.

PMID- 10649637
TI  - A paradoxical improvement of misreaching in optic ataxia: new evidence for two
      separate neural systems for visual localization.
AB  - We tested a patient (A. T.) with bilateral brain damage to the parietal lobes,
      whose resulting 'optic ataxia' causes her to make large pointing errors when
      asked to locate single light emitting diodes presented in her visual field. We
      report here that, unlike normal individuals, A. T.'s pointing accuracy improved
      when she was required to wait for 5 s before responding. This counter-intuitive
      result is interpreted as reflecting the very brief time-scale on which visuomotor
      control systems in the superior parietal lobe operate. When an immediate response
      was required, A. T.'s damaged visuomotor system caused her to make large errors;
      but when a delay was required, a different, more flexible, visuospatial coding
      system--presumably relatively intact in her brain--came into play, resulting in
      much more accurate responses. The data are consistent with a dual processing
      theory whereby motor responses made directly to visual stimuli are guided by a
      dedicated system in the superior parietal and premotor cortices, while responses
      to remembered stimuli depend on perceptual processing and may thus crucially
      involve processing within the temporal neocortex.

PMID- 10649639
TI  - [MDR (multidrug resistance) proteins and acute myeloblastic leukemias].

PMID- 10649638
TI  - Models of axon guidance and bundling during development.
AB  - Diffusible chemoattractants and chemorepellants, together with contact attraction
      and repulsion, have been implicated in the establishment of connections between
      neurons and their targets. Here we study how such diffusible and contact signals
      can be involved in the whole sequence of events from bundling of axons, guidance
      of axon bundles towards their targets, to debundling and the final innervation of
      individual targets. By means of computer simulations, we investigate the
      strengths and weaknesses of a number of particular mechanisms that have been
      proposed for these processes.

PMID- 10649640
TI  - [Sea horse, silkworm, ram, hippopotamus, dolphin: the hippocampus or Ammon's horn
      bestiary].

PMID- 10649641
TI  - [Atherosclerotic plaque formation].
AB  - Atherosclerotic plaque formation involves 5 steps: 1. low density lipoprotein
      (LDL) accumulation in the intima; 2. oxidation of LDL; 3. recruitment of
      monocytes-macrophages; 4. uptake of oxidized LDL by macrophage scavenger
      receptors, and transformation of macrophages into foam cells; 5. formation of a
      fibrous cap containing smooth muscle cells, which permits stabilization of the
      plaque. At each step of this process, inflammatory cytokines are implicated
      making the atherosclerotic process a chronic inflammatory disease.

PMID- 10649642
TI  - [Complications of atherosclerotic plaques].
AB  - Atherosclerosis progression, which may lead to significant stenosis, is usually
      the consequence of a growth response of the plaque (lipid core, fibrosis,
      thrombus incorporation). The impact of plaque growth on lumen size is, however,
      dependent upon arterial remodelling. The major risk associated with an
      atherosclerotic lesion is the occurrence of an acute thrombotic event which is
      related to plaque rupture or erosion. Determinants of plaque vulnerability
      include "quantitative" factors such as the ratio of lipid core to fibrous cap and
      "qualitative" factors such as the balance between metalloproteinases and their
      inhibitors.

PMID- 10649643
TI  - [Epidemiology of atherosclerosis: risks and paradoxes].
AB  - Atherosclerosis is characterised by a wide range of clinical manifestations.
      Hypercholesterolaemia is an independent risk factor for coronary heart disease,
      the correction of which with statins decreases the incidence of ischaemic events.
      Hypertension is a major risk for strokes. Prevention of coronary events by an
      action on the sole arterial blood pressure has been difficult to establish.
      Tobacco consumption is mainly involved in the risk of lower-limb arterial
      disease. Diabetes is a major and global enhancer of cardiovascular disease.
      Assessment of the other "emerging" risk factors (such as vitamin E deficiency,
      homocysteine, or the type of alcohol consumed) is still in progress. The level of
      classical risk factors only accounts for the variations between populations that
      are observed in the United States and in the Northern European countries.

PMID- 10649644
TI  - [Etiology of atherosclerosis].
AB  - The object of aetiology is to unveil causes, conditions that are necessary
      (although not sufficient) for the occurrence of a disease. No authentic cause of
      atherosclerosis has been identified yet. So far, aetiologic research has only
      established risk factors, modifiable conditions that are neither necessary nor
      sufficient, which provide efficient but incomplete means for prevention. Other
      aetiologic tracks must be explored, where the levers for truly mastering
      atherosclerosis are to be found. Infection is but one example which is presently
      the object of keen interest, but remains quite far from definitive proof.

PMID- 10649645
TI  - [Preclinical detection of atherosclerosis].
AB  - Several markers of preclinical atherosclerosis are currently available, such as:
      wall thickening and stiffening and endothelial dysfunction of large peripheral
      arteries detected by ultrasonography, or coronary calcification detected by
      ultrafast computed tomography. They reflect the integrated effects over time of
      multiple risk factors, traditional and emerging, and some of them (wall
      thickening and coronary calcification) have demonstrated a powerful predictive
      value as regards subsequent clinical events. Also these markers are invaluable
      targets for testing the effects of preventive treatments. Their detection should
      help selecting those asymptomatic subjects at risk for cardiovascular disease in
      whom prevention is justified.

PMID- 10649646
TI  - [Description and mechanisms of ischemia in atherosclerosis].
AB  - The most common clinical manifestations of atherosclerotic disease are ischaemic
      syndromes related to an imbalance between tissue oxygen demand and supply, as a
      consequence of reduced blood perfusion. Atherosclerosis may cause either direct
      luminal arterial narrowing (stable lesion) or acute thrombus formation (unstable
      lesion). Atherosclerosis in the coronary artery system may manifest in the form
      of stable or unstable angina, acute myocardial infarction, or other main clinical
      manifestations of atherosclerosis are: sudden cardiac death; transient ischaemic
      attack or cerebral infarction in the brain; and intermittent claudication or
      acute ischaemia of the extremities in the lower limbs.

PMID- 10649647
TI  - [Primary prevention of atherosclerosis].
AB  - Primary prevention consists of acts that decrease the level of risk factors in
      order to avoid the occurrence of atherosclerosis or to limit its consequences.
      Even incomplete control of risk factors leads to substantial decrease in the
      overall risk. Such results should encourage individuals and physicians to
      continue their efforts. First, the absolute risk for an individual should be
      evaluated on a risk scale. Then, the various factors to be targeted are smoking,
      hypertension, plasma lipid anomalies, lack of balanced diet, overweight,
      sedentary life style and diabetes. Compliance to recommended changes in life
      style varies greatly, which probably explains why the observed benefit is less
      than expected. Prevention should be an integral part of daily practice, and the
      motivation of both physicians and individuals must be constantly supported.

PMID- 10649649
TI  - [Professional lives and families of physicians].

PMID- 10649650
TI  - [Neuroleptics. Principles and rules of their utilization].

PMID- 10649648
TI  - [Secondary prevention of atherosclerosis].
AB  - Secondary prevention of ischaemic diseases due to atherosclerosis, whatever their
      initial territory, relies on 2 drug classes: antiplatelet agents (mainly aspirin)
      and statins. Despite the proven benefit of these medications on cardiovascular
      morbidity and life expectancy they are underprescribed. Other drugs (angiotensin
      converting enzyme inhibitors, antibiotics active against Chlamydia pneumoniae)
      may soon increase our present therapeutic resources.

PMID- 10649651
TI  - [Tetanus. Physiopathology, diagnosis, prevention].

PMID- 10649652
TI  - [Cutaneo-mucosal infections with Candida albicans. Epidemiology, diagnosis,
      treatment].

PMID- 10649653
TI  - [Acute diarrhea in infants. Diagnostic orientation].

PMID- 10649654
TI  - [Uterine fibromyoma. Diagnosis, evolution, treatment].

PMID- 10649655
TI  - [Spinal trauma. Diagnosis, evolution].

PMID- 10649656
TI  - Women's health issues. Introducing a new series with an underlying emphasis on
      comprehensive care.

PMID- 10649657
TI  - Inflated consumer expectations erode healthcare quality.

PMID- 10649658
TI  - Setting the record straight on PDR criticisms.

PMID- 10649659
TI  - Role of systemic beta 2 agonists in treatment of asthma.

PMID- 10649660
TI  - Getting your hands on decision-support tools. Where to find clinical practice
      guidelines and best-practice information.

PMID- 10649661
TI  - Why changes in administration of polio vaccine?

PMID- 10649663
TI  - Does Raynaud's phenomenon increase pregnancy risks?

PMID- 10649662
TI  - Antifungal drug interactions. Avoidance requires more than memorization.

PMID- 10649664
TI  - Sexually transmitted diseases in women. Chlamydia trachomatis and herpes simplex
      infections.
AB  - C trachomatis infection is the most commonly reported STD in the United States,
      and the majority of women infected are asymptomatic. Screening is recommended for
      those at high risk, including women who are between 15 and 21 years of age, live
      in urban areas, are single, or have new or multiple sexual partners. The "gold
      standard" for diagnosis is chlamydial culture; however, techniques that use DNA
      and RNA amplification are nearly 100% sensitive and specific and may prove cost
      effective. Doxycycline is a recommended first-line therapy, but certain other
      antibiotics may also be effective. Herpes simplex virus affects more than one
      third of the world's population. It is diagnosed by observation of shallow,
      tender ulcerations around the genitalia and by viral isolation using tissue
      culture. Initial treatment is with antiviral drugs, which may also be necessary
      episodically or as a suppressive regimen for recurrences. Patient education about
      prevention of these and other STDs, as well as the impact of such disease on
      sexual partners, is critical. Physicians should therefore become comfortable
      questioning and counseling patients about sexual issues and risks for STDs.

PMID- 10649665
TI  - Viral pneumonias. Multifaceted approach to an elusive diagnosis.
AB  - Despite enhanced laboratory techniques such as viral culture, rapid antigen
      detection, and gene amplification, a confident diagnosis of viral pneumonia
      continues to be a challenge. The nonspecific nature of clinical characteristics
      and the extreme sensitivity of laboratory techniques make the diagnosis
      difficult, even when a viral agent is detected. Understanding the limitations of
      these technological advances and the use of histopathologic techniques can
      greatly enhance a skilled clinician's ability to make an accurate diagnosis.

PMID- 10649666
TI  - Compiling the identifying features of bacterial endocarditis. Vague clues may
      point to this dangerous infection.
AB  - Bacterial endocarditis is a life-threatening disease. Before the advent of
      antibiotics, its mortality rate was nearly 100%, but with today's diagnostic and
      therapeutic advances, it can be successfully managed in most cases. In this
      article, Drs Harris and Steimle explain the changes that occur when someone, who
      usually has an underlying cardiac defect, contracts bacteremia with an organism
      likely to adhere to heart valve surfaces. They describe risk factors, clinical
      presentations, identification of causative organisms, and empirical and specific
      therapy. A case report illustrates the many possible manifestations of the
      disease.

PMID- 10649667
TI  - Taking aim at erythema multiforme. How to spot target lesions and less typical
      presentations.
AB  - Erythema multiforme is a distinct cutaneous condition characterized by target
      lesions. Most cases are associated with HSV infection, which may be subclinical.
      When the classic target lesions are absent, skin biopsy may be necessary to
      confirm the diagnosis. Treatment is directed at suppressing outbreaks of HSV
      infection and controlling symptoms during acute episodes.

PMID- 10649668
TI  - When a thyroid abnormality is palpable. What it means and what you should do.
AB  - Clinicians faced with a palpable thyroid abnormality should ascertain whether
      there is evidence of thyroid dysfunction, concern for malignancy, and symptoms of
      obstruction. In the vast majority of cases, laboratory assessment of the thyroid
      with an sTSH assay establishes the presence or absence of thyroid dysfunction. In
      a nodular thyroid gland, fine-needle aspiration biopsy is the method of choice
      for determining whether malignancy is present. In a large goiter, the presence of
      obstructive symptoms or findings may be a clear indication that surgery is
      needed. The absence of these findings may warrant simple observation.

PMID- 10649669
TI  - Thyroid nodules and cancer. When to wait and watch, when to refer.
AB  - Thyroid nodules, a common problem in clinical practice, are usually benign; only
      about 5% of these nodules harbor malignancy. The first step in evaluation is
      measurement of serum TSH levels. When the TSH value is suppressed, a
      hyperfunctioning nodule is likely, and scintigraphy may be helpful for confirming
      the diagnosis. Because thyroid cancer is extremely rare in "hot" nodules, such a
      finding is reassuring. Observation alone or treatment with radioiodine is a
      reasonable alternative to surgery in many of these patients. Fine-needle
      aspiration biopsy is the single most important procedure for differentiating
      benign from malignant thyroid nodules, and its role in evaluation and management
      of nodular thyroid disease cannot be overemphasized. Ultrasound, scintigraphy,
      and radioiodine scanning, together with measurement of various tumor markers, are
      useful adjuncts in the preoperative and postoperative management of patients with
      thyroid cancer. A carefully thought-out management plan can help reduce the risk
      of unnecessary surgery in these patients.

PMID- 10649670
TI  - Demystifying autoimmune thyroid disease. Which disorders require treatment?
AB  - The term "autoimmune thyroid disease" encompasses all of the autoimmune thyroid
      conditions, including Hashimoto's thyroiditis, Graves' disease, most cases of
      silent thyroiditis, and postpartum thyroiditis. Extrathyroidal manifestations
      (e.g., ophthalmopathy, dermopathy) can occur in Graves' disease and, less
      commonly, Hashimoto's thyroiditis. Spontaneous hypothyroidism is common in
      patients with Hashimoto's thyroiditis, and when it develops, life-long therapy
      with levothyroxine is needed. In the United States, most adult patients with
      Graves' disease are initially or eventually treated with radioiodine thyroid
      ablation. For transient thyroiditis involving hypothyroidism or hyperthyroidism,
      short-term or symptomatic therapy is adequate.

PMID- 10649671
TI  - Disclosing subclinical thyroid disease. An approach to mild laboratory
      abnormalities and vague or absent symptoms.
AB  - Patients with subclinical thyroid disease often have no apparent symptoms or only
      nonspecific complaints. However, increasing evidence that early disease is
      associated with behavioral, psychiatric, biochemical, and organ-specific
      abnormalities has led several specialty organizations to publish or modify
      position papers. Serum TSH testing is the most sensitive method of identifying
      early thyroid dysfunction. It should be considered in patients who have risk
      factors for mild thyroid failure, have symptoms that could be related to thyroid
      disease, or are taking exogenous thyroid hormone. T4 therapy should be strongly
      considered in patients with a TSH level of 10 mIU/L or more. If observation is
      elected in asymptomatic patients with lesser TSH elevation, periodic measurements
      are advised. In patients with TSH suppression who are taking thyroid hormone, the
      dose should be lowered. If the TSH level is decreased because of endogenous
      suppression and free-T4 and T3 levels are normal, options include observation and
      treatment with an antithyroid drug or thyroid ablation. Early therapy should be
      considered in older patients and those with heart disease or nodular thyroid
      disease. The goal of all treatment methods should be to keep the TSH level in the
      normal range.

PMID- 10649672
TI  - Common urologic problems in the elderly. Prostate cancer, outlet obstruction, and
      incontinence require special management.
AB  - Urologic problems in elderly patients often require special management that
      considers life expectancy, general health, and the clinical significance of the
      disorder. For men with prostate carcinoma or outlet obstruction, new therapies
      have proliferated in the last 10 years. For elderly women with incontinence, an
      orderly evaluation process usually results in directed and effective treatment.
      Finally, long-term use of Foley catheters requires careful attention to detail so
      that serious problems can be avoided.

PMID- 10649673
TI  - Alcohol-acetaminophen syndrome. Even moderate social drinkers are at risk.
AB  - In long-term alcohol users, the syndrome of hepatotoxicity from acetaminophen
      taken in therapeutic or modestly excessive doses is distinctive. It is
      characterized by striking elevation of transaminase levels and the potential for
      acute liver failure with high morbidity and mortality rates. A high index of
      suspicion should be maintained; in any patient with evidence of acute hepatic
      injury, a complete history of over-the-counter drug use should be obtained and
      acetaminophen levels checked. If there is doubt about the dose or time of
      ingestion, one should err on the side of treatment with acetylcysteine, because
      it is both effective and safe. Therapy should be initiated as early as possible,
      but even late administration may be of benefit. Timely contact with a medical
      center that has liver transplantation capabilities should be made before
      encephalopathy becomes advanced. Heightened awareness of this preventable and
      treatable condition is needed by healthcare providers and acetaminophen users
      alike. Because the minimum safe dose of acetaminophen is not known in the setting
      of chronic alcohol use, it seems prudent in such situations to avoid
      acetaminophen altogether, especially during brief periods of abstinence.

PMID- 10649675
TI  - Acute chest syndrome in sickle cell disease. Crucial considerations in
      adolescents and adults.
AB  - Rapid recognition of acute chest syndrome is essential in patients with sickle
      cell disease. The condition can be particularly severe in adolescents and adults
      and often leads to death. In this article, the authors review the challenges of
      evaluating the syndrome and outline current treatment and supportive care.

PMID- 10649674
TI  - Cervical spine complications in rheumatoid arthritis patients. Awareness is the
      key to averting serious consequences.
AB  - Rheumatoid arthritis is associated with several pathologic changes in the
      cervical spine, including loss of articular cartilage, ligamentous destruction,
      and bone erosion. These changes may lead to one or a combination of
      complications, including atlantoaxial subluxation, cranial settling, subaxial
      cervical subluxation, and periodontoid pannus formation. Surgical management of
      these problems should focus on relieving pain, stabilizing the spine, and
      decompressing neural elements.

PMID- 10649676
TI  - Current recommendations for 'steroid burst' therapy.

PMID- 10649677
TI  - Dental nerve blocks. Toothache remedies for the acute-care setting.
AB  - Ideally, tooth pain is managed by a competent dentist, who can provide definitive
      care. However, timely access to such care may not be available late at night, on
      weekends, or in rural practice settings. This article introduces primary care
      physicians to dental nerve blocks that can be learned without extensive training
      and use in the acute-care setting to provide temporary relief of oral, dental,
      and facial pain.

PMID- 10649678
TI  - Pruritic papules on the shins. Lichen amyloidosis.

PMID- 10649679
TI  - Help for canker sores?

PMID- 10649680
TI  - Hypothyroidism.

PMID- 10649681
TI  - Amphotericin B does not increase peritoneal fluid removal.
AB  - Intraperitoneal use of amphotericin B (AmB) has been reported to increase
      ultrafiltration during short peritoneal dwell in rabbits. In this study, we
      investigated the effect of AmB on peritoneal fluid kinetics in rats. A 4 hour
      dwell using 25 mL of 2.27% glucose dialysis solution without AmB (control, n =
      6), with 1 mg/kg (L-AmB, n = 6) or with 10 mg/kg AmB (H-AmB, n = 6), and with
      frequent dialysate and blood sampling was done in Sprague-Dawley rats. 131I
      albumin was added to the solution as an intraperitoneal (i.p.) volume marker.
      There was no difference in the drainage volumes measured at 4 hours of the dwell
      (26.2 +/- 1.1 mL, 26.0 +/- 1.5 mL, and 26.0 +/- 1.1 mL for the control, L-AmB,
      and H-AmB groups, respectively.) However, the i.p. volumes were higher at 60
      minutes, 90 minutes, and 120 minutes of the dwell in the H-AmB group as compared
      to the other two groups (1 to 1.5 mL higher, all P < 0.05). There were no
      differences in the peritoneal fluid absorption rate (KE) and the lymphatic flow
      rate (KEB) between the three groups. The D/D0 for glucose and dialysis-over
      plasma concentration ratio (D/P) values for urea, sodium, and total protein, as
      well as the diffusive mass transport coefficient (KBD) values for these solutes
      did not differ among the three groups. However, the D/P as well as the KBD values
      for potassium were significantly higher in the H-AmB and L-AmB groups as compared
      to the control group, resulting in significantly higher potassium clearances
      among the two AmB groups as compared to the control group. Our results suggest
      that i.p. use of AmB did not increase peritoneal fluid removal after 4 hours of
      dwell in rats. Although the basic membrane permeability may not be altered by
      AmB, the higher D/P and KBD values as well as the higher clearances for potassium
      in the AmB groups may suggest a local release of potassium due to the cytotoxic
      effect of AmB. The contribution of water release from local cells to the increase
      in i.p. volume in the H-AmB group cannot be ruled out.

PMID- 10649682
TI  - Recombinant human erythropoietin (rHuEPO) therapy has no effect on peritoneal
      transport in CAPD patients: a short-term study.
AB  - While theoretically the vasoconstriction associated with the rise in hemoglobin
      (Hb) level may potentially alter peritoneal transport characteristics, the effect
      of recombinant human erythropoietin (rHuEPO) therapy on peritoneal transport in
      continuous ambulatory peritoneal dialysis (CAPD) patients remains unclear. We
      have therefore performed a prospective study on the short-term effect of rHuEPO
      on the peritoneal transport characteristics in terms of the change in corrected
      dialysate/plasma creatinine (D/Pcr) in the fast peritoneal equilibration test
      (PET). Eight consecutive CAPD patients started on rHuEPO had fast PETs performed
      before and 4 to 6 months after the initiation of rHuEPO therapy. Another 8 CAPD
      patients with stable Hb levels not receiving rHuEPO served as a control group.
      All patients (study and control) had been on CAPD therapy for more than 3 months
      upon enrollment, and none had peritonitis during the study period. Patients
      receiving rHuEPO showed significant increase in Hb level, while the Hb levels of
      those in the control group remained unchanged. Neither the study nor the control
      group patients showed significant change in the corrected D/Pcr value over a mean
      observation period of 5.25 +/- 0.89 months. While rHuEPO appears to be effective
      in increasing the Hb level in CAPD patients, there is no significant impact on
      the corrected D/Pcr in the fast PET test observed in this short-term study.

PMID- 10649683
TI  - Effect of peritoneal dialysis fluid measured in vivo in a rat-model of continuous
      peritoneal dialysis.
AB  - To study the long-term effects of dialysis fluids on the peritoneal cavity, an in
      vivo model for continuous peritoneal dialysis in rats was developed. Mini
      vascular access ports were implanted subcutaneously in the neck of the rats and
      an attached catheter was instilled into the peritoneal cavity. Rats were injected
      daily with 10 mL of standard 3.86% Dianeal or saline for a period up to 12 weeks.
      In the peritoneal cavity an initial increase in total cells was observed after 4
      weeks of fluid instillation. This had declined after 12 weeks. A similar trend
      was also seen for macrophage and neutrophil numbers, whereas the percentage of
      lymphocytes kept increasing in time. An effect of fluid instillation was observed
      on the density and the morphology of the mesothelial monolayer of the rats. A
      higher density of cells was observed after 12 weeks, and foci of young
      mesothelial cells within activated mesothelium were found. The results show that
      the rat model presented can be compared with the situation in the peritoneal
      cavity of continuous ambulatory peritoneal dialysis (CAPD) patients, and
      therefore is suitable for intervention studies.

PMID- 10649684
TI  - Ex vivo proliferation of mesothelial cells directly obtained from peritoneal
      effluent: its relationship with peritoneal antecedents and functional parameters.
AB  - The peritoneal membrane requires anatomico-functional integrity to guarantee long
      term stability for peritoneal dialysis (PD). Since mesothelial cells (MC) are
      active cells and the first part of the membrane to contact the dialysate, they
      are important in maintaining this stability. Mesothelial cells released daily
      into peritoneal effluent are able to grow in culture. This growth capacity may be
      related to some of the anatomicofunctional characteristics of each peritoneum.
      Our aim was to culture mesothelial cells taken from peritoneal effluents drained
      by 32 PD-stable patients, and relate this growth capacity to individual
      peritoneal data. Cells were taken from a residual fluid after sedimentation,
      washed twice with phosphate-buffered saline (PBS), and seeded into 25-cm2 tissue
      culture flasks. These flasks were incubated in a humidified 5%-CO2 atmosphere.
      After MC confluence, cells were detached by trypsinization, passaged into 24-well
      plates, and finally counted. Cells were identified by morphology and immuno
      histochemical characteristics. Cells from 28 out of 32 patients showed an
      appropriate growth in culture. Mesothelial cell confluence was reached in a mean
      of 18.2 +/- 8 days. After 7 days of seeding in plate wells, the cell growth
      showed a significant and progressive increase until day 16. Mesothelial cell
      growth rate was inversely related to PD duration. Neither peritonitis incidence
      nor other demographic characteristic were related to MC growth. Creatinine and
      urea mass transfer coefficients (MTC), but not ultrafiltration (UF) capacity,
      were significantly related to MC growth rate. In conclusion, the growth in
      culture of MC taken directly from PD bags is certainly possible. This growth is
      influenced by some of the intrinsic peritoneal characteristics derived from the
      peritoneal dialysis process. This tool could be useful in evaluating individual
      peritoneal conditions and, probably, as a method for peritoneal viability follow
      up, although further research is required.

PMID- 10649685
TI  - Phenotypic mapping of human mesothelial cells.
AB  - In recent years it has become clear that the mesothelium plays a prominent
      homeostatic role in the peritoneum, and can be profoundly altered in disease and
      during peritoneal dialysis. The cell-surface phenotype of the mesothelial cell
      has not been thoroughly investigated. This study begins to identify cell surface
      molecules which may be important in mesothelial functions such as adhesion and
      interaction with cells of the immune system. The expression of adhesion
      structures on mesothelial cells such as CD44, the beta integrin chain CD29, the
      beta 3 integrin chain CD61 and alpha chains CD49 alpha (alpha 1), CD49b (alpha
      2), CD49c (alpha 3), CD49e (alpha 5), and CD51 (alpha v) is described. In
      addition, a wide range of novel molecules including CD90, CD105, CD140b, CD142,
      CD147, CD151, CD157, CD165, and CD166 are identified. The role and function of
      such molecules in mesothelial biology and their significance for peritoneal
      dialysis is discussed.

PMID- 10649686
TI  - The effect of N-acetylglucosamine as a substrate for in vitro synthesis of
      glycosaminoglycans by human peritoneal mesothelial cells and fibroblasts.
AB  - The effect of N-acetylglucosamine (NAG) on in vitro synthesis of
      glycosaminoglycans by human peritoneal mesothelial cells and fibroblasts was
      studied. In contrast to isosmotic concentrations of glucose, NAG increases the
      synthesis of hyaluronan by mesothelial cells and fibroblasts in a dose-dependent
      manner. This effect of NAG can be demonstrated in the presence of increased
      glucose levels in a medium, or in a medium mixed with effluent dialysate obtained
      from continuous ambulatory peritoneal dialysis (CAPD) patients. Glucose inhibits
      synthesis of sulphated glycosaminoglycans by peritoneal mesothelial cells and
      fibroblasts, whereas NAG stimulates their production. Our results demonstrate
      that NAG is an effective stimulator of the in vitro glycosaminoglycans synthesis
      by human peritoneal mesothelial cells and fibroblasts.

PMID- 10649687
TI  - The characteristics of peritoneal healing after catheter insertion in a rat model
      of peritoneal dialysis.
AB  - The aim of this study was to characterize the process of peritoneal healing after
      catheter insertion in a rat model of peritoneal dialysis using a 1.36% solution
      (Baxter Dianeal). After catheter insertion (day 1 of experiment), 12 rats were
      injected daily with 20 mL of 1.36% dialysis solution for 2 weeks. Every second
      day a sample of 4 hour dialysate was taken from every rat for biochemical
      analysis, cell count, cell differentiation, and nitrites measurement. The
      measured parameters decreased during the experiment and stabilized during the
      second week after catheter insertion. In cell differentiation, we observed an
      increase in the number of macrophages, with a parallel decrease in the number of
      neutrophils that was reflected in a significant decrease in the
      neutrophils/macrophages ratio. Our results suggest that the process of peritoneal
      healing after catheter implantation in rats lasts about 2 weeks, and therefore
      that any biocompatibility study of peritoneal dialysis solutions in rats should
      be performed at least 2 weeks after catheter insertion.

PMID- 10649690
TI  - A commercially available PD fluid with high pH and low GDP induces different
      morphological changes of rat peritoneum in intermittent PD.
AB  - The aim of this study was to characterize the morphological changes in the
      peritoneum following experimental peritoneal dialysis of rats, and to compare the
      new high-pH and low glucose-derived degradation products (GDP)-level PD fluid PD
      Bio with the conventional PD fluid Gambrosol at two different exposure
      frequencies. Rats were subjected to 10 mL intraperitoneal injections three times
      per day at 3-hour intervals daytime for 9 days (2 successive weeks, excluding
      weekends) or once daily for 4 weeks. Untreated animals and animals exposed to
      Gambrosol or PD-Bio were compared. Biopsy samples were taken from the diaphragm
      and prepared for light microscopy. Morphometric analysis was used to compare the
      thickness and the cell density of the sub-mesothelial connective tissue.
      Intraperitoneal leukocyte numbers were counted. Both fluids induced a significant
      thickening of the submesothelial connective tissue and an increase in
      intraperitoneal leukocyte numbers. After exposure three times per day, Gambrosol
      induced a significantly greater submesothelial thickening than PD-Bio. The
      submesothelial tissue was more cell-dense after exposure to PD-Bio than after
      exposure to Gambrosol. The present results indicate that the structural changes
      of the peritoneum that follow peritoneal dialysis may be dependent upon the
      chemical composition of the PD fluids.

PMID- 10649689
TI  - Can recovered protein from the CAPD patient's own dialysis effluent substitute
      for dextrose?
AB  - Albumin has been evaluated as an osmotic agent for peritoneal dialysis as being
      physiologically safe and having modest colloidal osmotic pressure. However its
      extremely high cost inhibits clinical applications, and hypoalbuminemia is often
      seen in continuous ambulatory peritoneal dialysis (CAPD) patients, especially
      those with high peritoneal equilibration test (PET) values and who lose a large
      quantity of albumin everyday. This study aims at recovering protein from CAPD
      effluent and reusing it safely at reasonable cost as a substitute for dextrose.
      The dialysis effluent was collected and concentrated with a semipermeable
      membrane. Uremic toxins and low-molecular-weight solutes were removed by repeated
      filtration and water dilution. The concentrate was acidified with hydrochloric
      acid down to pH 2, thence de-acidified with water dialysis up to pH 5. At this
      point, the isoelectric point of albumin, at which precipitate was deposited, the
      precipitate was separated from the supernatant and re-dissolved into electrolyte
      solution. The acidified concentrate exhaled an unpleasant odor, like that of
      decayed food. The precipitate solution, however, did not smell at all. The
      initial ultrafiltration rate of the recovered protein solution was measured and
      compared with that of dextrose and dextran by using a high-sensitivity
      differential manometer, one end of which was connected with the test solution
      cell, and the other with the serum cell. The ends were separated by a
      semipermeable membrane. The recovered protein solution at 20 g/dL concentration
      was almost equivalent in initial ultrafiltration rate to the 2.0 g/dL dextrose
      solution and to 20 g/dL dextran (MW: 75,000 dalton) solution.

PMID- 10649691
TI  - Rapid growth in the use of automated peritoneal dialysis (APD) in adult patients
      on peritoneal dialysis.
AB  - Inadequate dialysis dose is associated with poor patient-survival in peritoneal
      dialysis (PD). Most patients would require more than four exchanges a day after
      losing residual renal function. The use of automated peritoneal dialysis (APD)
      seems to be a practical way to provide extra dialysis for these patients. In our
      Dialysis Centre in Northern Alberta, we started to use APD for our adult patients
      only from 1993. When we evaluated our practice recently, we found that we are
      progressively increasing the use of APD (including cyclers and night exchange
      devices) from 3% to 21% for our total adult PD patients in the last 3 years. This
      increase in the use of APD is mostly to accommodate PD prescription changes and
      not changes in lifestyle. Increase in the use of APD was associated with decrease
      in the rate of our PD dropout to hemodialysis. We conclude that to maintain
      adequate dialysis, rapid growth of APD will become common in North American PD
      centers in the future and will reduce transfer to hemodialysis.

PMID- 10649688
TI  - Saccharides as osmotic agents in peritoneal dialysate: determination of molecular
      weight essential for more efficient fluid removal.
AB  - Glucose has widely been used as an osmotic agent in continuous ambulatory
      peritoneal dialysis (CAPD) but owing to its low molecular weight (MW),
      ultrafiltration (UF) in a 6-hour dialysate exchange does not appear sufficient.
      Thus, in the present study, a search was made to find saccharides that would
      ensure optimal UF, exceeding that obtained with glucose in a 6-hour dwell period.
      Rats were intraperitoneally infused with peritoneal dialysate (20 mL/body)
      containing the same molar concentrations (75.5 mM, 126 mM, or 204 mM) of various
      osmotic agents including glucose (monosaccharide, MW = 180.16) at concentrations
      of 1.36%, 2.27%, and 3.86%; maltose (disaccharide, MW = 342.30) at concentrations
      of 2.58% and 4.32%; maltotriose (trisaccharide, MW = 504.44), at concentrations
      of 3.81% and 6.36%; and maltopentaose (pentasaccharide, MW = 828.72) at
      concentrations of 6.26% and 10.4%. Intraperitoneal-fluid volume was measured at
      1, 2, 3, 4, and 6 hours. With glucose as the osmotic agent, maximal UF was noted
      at 2 to 4 hours. UF was more efficient at 6 hours with maltotriose or
      maltopentaose as the osmotic agent. Even with a trisaccharide or pentasaccharide
      (molecular weights of 500 to 830), UF at 6 hours was found more efficient, as
      evidenced by the delay in peritoneal absorption. Fluid removal in 6 hours should
      be greater when using a dialysate containing oligosaccharides such as maltotriose
      or maltopentaose in place of glucose.

PMID- 10649692
TI  - CAPD with a night-exchange device is the only true CAPD?
AB  - In the treatment of uremia with continuous ambulatory peritoneal dialysis (CAPD),
      the long-night dwell has always been a problem because of fluid retention. The
      purposes of the study were, firstly, to compare the solute clearance between five
      exchanges a day using standard CAPD, with a long-night dwell, to the clearance
      obtained with five exchanges a day using CAPD with the night-exchange device
      (NXD), in which case a more even distribution of the exchanges over 24 hours is
      obtained. A second aim of the study was to identify the best obtainable solute
      clearance: CAPD with the night-exchange device, or a cycler with a wet day. In
      the past year and a half, we have optimized solute clearance, using the PD
      Adequest program in 60 patients. The five-exchanges-a-day CAPD with the night
      exchange device always gives a better solute clearance than standard CAPD with
      five exchanges a day and the long-night dwell. Solute clearance was always better
      with CAPD with NXD, except for Kt/V in patients with high membrane transport,
      compared to cycler therapy with a wet day. High-dose cycler therapy with a wet
      day plus a midday exchange always gives a better solute clearance than CAPD with
      NXD.

PMID- 10649693
TI  - Continuous tidal peritoneal dialysis (CTPD) prescription and adequacy targets.
AB  - NKF-DOQI guidelines suggest a Kt/V value of 2.1 and a creatinine clearance (CRCL)
      value of 63 L/1.73 m2 of body surface area per week as minimum targets in
      continuous cycling peritoneal dialysis (CCPD). Those targets are obtained by
      adapting the CAPD guidelines. The aim of our study was to verify the possibility
      of reaching the suggested targets with continuous tidal peritoneal dialysis
      (CTPD) and to check target modification in this automated treatment. Eight anuric
      patients underwent four consecutive CTPD sessions with increasing total
      prescribed volumes (17 L, 22 L, 27 L, and 32 L; night 9 h; fill 2.2 L; tidal 75%,
      day 2 dwells). The Kt/V increase was significant (P = 0.012), unlike that of
      CRCL, with larger volumes. Two patients did not reach target Kt/V, and four did
      not reach target CRCL. The volume normalized for 1.73 m2 corresponding to DOQI
      targets was 19.6 +/- 2.6 L for Kt/V and 20.2 +/- 2.4 for CRCL. The overall Kt/V
      was 2.29 +/- 0.66 and CRCL was 57.3 +/- 16.5 L/1.73 m2. CRCL/Kt/V overall ratio
      was 25.6 +/- 4.7 and significantly different from the target ratio (63/2.1 = 30,
      P < 0.001). The CRCL/Kt/V ratio showed a significant decrease with larger volumes
      (P = 0.001, linear trend P < 0.001). Adequacy targets can be reached only in some
      patients on CTPD even with high dialysis volumes. The changes in the CRCL/Kt/V
      ratio in relation to dialysis volume can be considered for adaptation and
      evaluation of adequacy targets in automated treatments.

PMID- 10649694
TI  - Calculation of Kt/V and creatinine [correction of creatine] clearance in APD.
AB  - The calculation of Kt/V and creatinine clearance per 1.73 m2 of body surface area
      (CrCl/1.73 m2 of BSA) varies according to whether the post- or pre-nightly
      dialysis treatment (NDT) values of the serum urea (sUrea), serum creatinine
      (sCreat), and body weight (BW) parameters are used. The purpose of this paper is
      to determine the difference between Kt/V and CrCl/1.73 m2 of BSA, calculated
      using the pre- and post-NDT values, and any correlation of such differences with
      different automated peritoneal dialysis (APD) methods. We took into consideration
      patients on APD treated using the tidal method with four different techniques:
      NTPD (9 patients; no daytime dwell), NTPD-1 (12 patients; one daytime dwell of 4
      7 hours), CTPD (10 patients; one daytime dwell), and CTPD-2 (8 patients; two
      daytime dwells). Body water (V) and body surface area (BSA) were calculated using
      the Watson and Du Bois formulas. The percentage difference between pre- and post
      NDT using the various methods is not statistically significant, while all the
      post-NDT parameters are significantly lower than the pre-NDT parameters. Since
      this difference is greater for sUrea (8.8%) and V (1.1%) than for sCreat (4.1%)
      and BSA (0.8%), the nightly Kt/V variation (11.2%) is greater than the nightly
      CrCl/1.73 m2 of BSA variation (5.2%). These variations do not differ
      significantly among the various methods. For APD, therefore, increase is to be
      expected in the CAPD targets of 10% and 5% respectively for Kt/V and CrCl/1.73 m2
      of BSA calculated using the post-NDT values of sUrea and sCreat and the pre-NDT
      value of BW.

PMID- 10649695
TI  - Adequacy of CPD: comparing Kt/V and creatinine clearance.
AB  - Presently, adequate dialysis in continuous peritoneal dialysis (CPD) patients is
      assessed by monitoring urea kinetics (Kt/V) or by measuring the total creatinine
      clearance (CC). Target Dialysis Outcome Quality Initiative (DOQI) goals are a
      weekly Kt/V of at least 2.0, and a CC of at least 60 L/wk per 1.73 m2. One
      hundred and four CPD patients in the New Haven continuous ambulatory peritoneal
      dialysis (CAPD) unit had their most recent Kt/V and CC reviewed. Of these
      patients, 58.7% attained the DOQI goals for Kt/V and CC, 14.4% had an acceptable
      Kt/V but low CC, 11.5% had an acceptable CC but low Kt/V, and 15.4% had both low
      Kt/V and low CC. A CC > 60 L/week per 1.73 m2 was associated with a residual
      renal function of > 25 L/wk per 1.73 m2. For a Kt/V of > 2.0, good residual renal
      function was helpful but not essential. A question left unanswered is whether
      patients with a low Kt/V and an adequate CC or low CC and acceptable Kt/V need
      more dialysis.

PMID- 10649696
TI  - Bedside peritoneoscopic peritoneal catheter placement of Tenckhoff and newer
      peritoneal catheters.
AB  - The success of Tenckhoff chronic peritoneal dialysis catheters depends more upon
      the skill of the physician in placing catheters and on the technique of placement
      than it does on the exact design of the peritoneal catheter. In this summary
      article, the existing types of peritoneal catheters are reviewed, including two
      recent alternative designs: Tenckhoff catheters with larger internal diameters,
      and the T-fluted catheter with grooved limbs adjacent to the parietal peritoneum.
      The three types of placement procedures for catheters (peritoneoscopy, surgical
      or dissective, and blind techniques) are described, and the complications of
      Tenckhoff catheters are compared according to placement technique.

PMID- 10649697
TI  - Temporary stoppage of peritoneal dialysis when laparoscopic procedures are
      performed on patients undergoing CAPD/CCPD: a change in policy.
AB  - Laparoscopic surgery has been gaining in popularity. Prior to 1995, whenever our
      patients had a laparoscopic procedure it was carried out with the standard
      precautions, and the patient stayed on peritoneal dialysis (PD). We noticed a
      high incidence (71.4%) of peritonitis post laparoscopic surgery. Four of the
      peritonitis patients had cholecystectomies and 1 had a gastrostomy for placement
      of a feeding tube laparoscopically. The patients' ages ranged from 31 to 74
      years; 4 (80%) were females. They had been on PD for a mean of 24 months (range 6
      48 months). Peritonitis was diagnosed within a mean of 22.2 hours (r: 12-36 h)
      post procedure. The causative organisms were Klebsiella in two cases, Staph.
      aureus in one, Pseudomonas in one, with no growth observed in one. Following
      this, we instituted a deliberate policy of temporary cessation of PD for 2 weeks
      post laparoscopic procedure, maintaining the patient on hemodialysis during this
      period. Since the adoption of this policy, we have had no peritonitis in 7
      patients who have undergone laparoscopic procedures.

PMID- 10649698
TI  - Videolaparoscopic peritoneal dialysis catheter implant and rescue procedures
      under local anesthesia with nitrous oxide pneumoperitoneum.
AB  - Videolaparoscopic techniques are an increasingly used modality for peritoneal
      dialysis catheter implant and rescue procedures. The greatest impediment for
      acceptance of the laparoscopic approach has been the necessity of general
      anesthesia because peritoneal insufflation of CO2 gas produces pain. In addition,
      complications of CO2 pneumoperitoneum include hypercarbia, acidosis, and cardiac
      arrhythmias. Renal failure patients commonly have severe coexisting medical
      conditions that make them an unacceptable risk for both general anesthesia and
      CO2 peritoneal insufflation. From December 1996 through November 1997,
      laparoscopy was performed utilizing nitrous oxide (N2O) as the insufflation gas.
      Since N2O produces neither pain nor metabolic effects, the laparoscopic procedure
      was safely performed under local anesthesia. Thirty-one patients have had
      laparoscopic implantation of peritoneal dialysis catheters under local anesthesia
      with 22 procedures performed on an ambulatory basis. The remaining cases were
      already hospitalized for complications of their renal failure. Four laparoscopic
      rescue procedures for catheter dysfunction were performed under local anesthesia
      with 3 cases as outpatients. Surgical laparoscopy under local anesthesia with N2O
      insufflation is a safe approach for both implantation procedures and salvaging of
      malfunctioning catheters. The procedure can be performed on an outpatient basis,
      frequently without delay in initiation or interruption of peritoneal dialysis.

PMID- 10649699
TI  - Important cost differences of blood transfusions and erythropoietin between
      hemodialysis and peritoneal dialysis patients.
AB  - Based on our previous study [House AA, Pham B, Page DE. Perit Dial Int 1997;
      17(Suppl 1):S74.], we compared the costs of blood transfusions and erythropoietin
      for 90 peritoneal-dialysis (PD) patients with those of 90 hemodialysis (HD)
      patients over a 1-year period. The mean monthly transfusion rate was higher in
      the HD group (0.47 units per month versus 0.19 per month for the PD group: P <
      0.01). The maintenance erythropoietin dose was higher for HD (7370 units/week
      versus 5970 units/week: P < 0.01). There was an average of 507 transfusions per
      year in the HD group (Cdn $152,280) compared to 205 transfusions per year in the
      PD group (Cdn $61,500). Since HD patients required more erythropoietin than the
      PD patients, the cost for the 90 HD patients per year was (Cdn $460,463) compared
      to (Cdn $361,747) for the 90 PD patients. Combining the annual costs of both
      blood transfusions and erythropoietin, the 90 patients on HD cost Cdn $189,435
      more than the 90 PD patients, a difference of Cdn $2105 per patient.

PMID- 10649700
TI  - Analysis of the reasons for transfers between hemodialysis and peritoneal
      dialysis and their effect on survivals.
AB  - Data on the outcomes of patients who are transferred between hemodialysis (HD)
      and peritoneal dialysis (PD) are scant. This study analyzes data on patients
      transferred from their initial modality at the University Hospital Gent between
      1978 and 1996 for the reasons for, and outcomes from, the transfer. The reasons
      for the transfer from HD to PD (n = 35) were access problems (25%),
      cardiovascular (40%) and blood pressure problems (25%), and personal choice
      (10%). For the transfer from PD to HD (n = 32) peritonitis (50%), social problems
      (14%), adequacy or ultrafiltration problems (25%), and leakage (11%) were the
      reasons. There were no differences in survivals between patients who started on
      HD and who were transferred to PD, and those who remained on HD (P = 0.4). There
      were improved survivals for the patients who started on PD and who were
      transferred to HD compared to those remaining on PD (P = 0.01). It is concluded
      that transferring problematic HD patients to PD does not improve their survivals,
      whereas the survival of patients with PD-related complications is improved by
      transferring them to HD. This is due to the differences in the reasons for
      transfer, which are PD-related complications in the case of PD patients, and
      cardiovascular problems in the case of HD patients.

PMID- 10649701
TI  - Peritoneal dialysis in patients with abdominal vascular prostheses.
AB  - Patients with intra-abdominal vascular catastrophes may develop acute and/or
      chronic renal failure requiring dialysis. To patients with in-situ vascular
      prostheses the use of peritoneal dialysis (PD) may offer considerable advantages
      including better hemodynamic control and avoidance of anti-coagulation in a
      critically ill patient. Institution of PD in such patients, however, often gives
      rise to concerns relating to peritonitis and subsequent infection of the
      prosthesis, fluid leaks, and abdominal wound dehiscence. A review of available
      literature suggests that PD has been utilized in both acute and chronic renal
      failure following intra-abdominal vascular procedures. PD appears to be an
      efficient mode of dialysis with a surprisingly small number of complications in
      these patients.

PMID- 10649702
TI  - Gastroesophageal reflux disease in CAPD patients.
AB  - Upper gastrointestinal (GI) symptoms are frequently observed in continuous
      ambulatory peritoneal dialysis (CAPD) patients. We conducted esophageal manometry
      and 24-hour esophageal pH monitoring in 4 CAPD patients (Group I) who had upper
      GI symptoms such as nausea and vomiting and compared them with 9 patients (Group
      II) who did not. The mean age in Group I was 48.5 +/- 13.7 years, and the male-to
      female ratio was 1:3. One patient was diabetic. There were no significant
      differences in clinical and biochemical data between the two groups. Comparing
      the results of esophageal manometry, supine lower esophageal sphincter pressure
      (LESP) at 2000 mL of infused dialysate was significantly lower in Group I than in
      Group II (23.2 +/- 4.4 vs 31.2 7.1 mmHg, P < 0.05), but supine LESPs at empty
      state and sitting LESPs were not different. Group I had a significantly higher
      total number of reflux episodes (89.0 +/- 16.5 vs 26.5 +/- 19.4, P < 0.05),
      number of reflux episodes longer than 5 minutes (2.3 +/- 2.6 vs 0.3 +/- 0.5, P <
      0.05), total time of pH < 4.0 (75.5 +/- 55.5 vs 11.0 +/- 6.8, P < 0.05), and
      total reflux score (19.7 +/- 10.2 vs 4.2 +/- 2.3, P < 0.05) in 24-hour esophageal
      pH monitoring. Three of 4 Group I patients met the criteria for abnormal
      gastroesophageal reflux set by the DeMeester scoring system. CAPD patients with
      upper GI symptoms such as nausea, vomiting, and epigastric discomfort should be
      evaluated for gastroesophageal reflux disease with esophageal manometry and pH
      monitoring.

PMID- 10649703
TI  - Peritoneal dialysate fill-volumes and hernia development in a cohort of
      peritoneal dialysis patients.
AB  - A retrospective case control study was performed on a cohort of 244 peritoneal
      dialysis patients followed over 5 years to determine whether dialysate fill
      volume was associated with hernia development. The laboratory and clinical
      parameters of patients who developed hernias during this time period were
      compared with those of patients who did not develop hernias. Information on 27
      patients who developed hernias was compared with that on 217 patients who did not
      develop hernias. Dialysate fill-volume was similar between groups (2.2 +/- .3 L
      for patients with hernias vs. 2.2 +/- .3 L for controls). Three patients with
      fill-volumes of 1.5 L developed hernias, and no patients with fill-volumes of 3 L
      developed hernias. Age, duration of time on dialysis, and body surface area were
      also similar between groups. This investigation could not find a relationship
      between fill-volume and hernia formation. From this study it would appear that
      physicians should not hesitate to increase fill-volume based on concerns of
      hernia development.

PMID- 10649704
TI  - The risk of hernia with large exchange volumes.
AB  - Large exchange volumes of 2.5 and 3 L are frequently necessary to improve
      clearances to the level suggested by the DOQI guidelines. However, abdominal wall
      hernias are a well known complication of peritoneal dialysis (PD) related to
      increased abdominal pressure, and might increase with higher exchange volumes. We
      studied the effect of using higher exchange volumes in PD patients on the
      incidence of hernia formation. Seventy-nine (12%) of 656 PD patients over a 15
      year span developed abdominal wall hernias. Eleven percent of patients using 2 L
      or smaller volumes, 15% of patients using more than 2 L but less than 3 L, and
      13% of patients using 3 L developed hernias (not significantly different). Five
      percent of patients on cyclers for their entire PD experience (3 of 63 patients)
      developed one or more hernias, compared to 13% of patients on continuous
      ambulatory peritoneal dialysis for at least part of their experience (P = 0.06).
      The use of larger volumes increased dramatically over time; only 11% of patients
      used more than 2-L exchange volumes during the years 1982 through 1986, compared
      to 73% in the period from 1992 to 1997. We conclude that increased volumes in PD
      patients do not lead to an increased risk of hernia formation. Exchange volumes
      can be increased as needed to improve clearances.

PMID- 10649705
TI  - Elevated 24-hour blood pressure in peritoneal dialysis patients with
      ultrafiltration failure.
AB  - Many patients treated with peritoneal dialysis (PD) are overhydrated. We
      investigated whether hypertension in PD patients is related to ultrafiltration
      failure-induced fluid retention. Twenty-four-hour blood pressure measurements
      were performed in 10 normotensive and 9 hypertensive PD patients, aged 20 to 77
      years, and treated with PD for 2 to 125 months. Antihypertensive medication had
      been discontinued for 3 weeks. Twenty-four-hour blood pressure was monitored with
      a Spacelabs 90207. Mean 24-hour systolic, mean, and diastolic pressure were
      calculated, together with the nighttime (23:00-07:00)/daytime (07:00-23:00)
      ratio. Ultrafiltration was determined separately during a standardized 4-hour
      peritoneal permeability analysis (SPA) with 1.36% glucose. Based on the SPA,
      patients were divided into a group with negative net ultrafiltration (NUF) and a
      group with positive net ultrafiltration (PUF). In 8 patients with NUF, systolic,
      mean, and diastolic pressures were 142 +/- 16 mmHg, 110 +/- 14 mmHg, and 95 +/-
      13 mmHg, compared to 135 +/- 22 (ns), 99 +/- 14 (ns), and 81 +/- 11 (P < 0.05) in
      11 patients with PUF. Net ultrafiltration during the test dwell correlated
      negatively with diastolic blood pressure (r = -0.53, P < 0.05). Diurnal blood
      pressure variations were not related to ultrafiltration capacity. In conclusion,
      hypertension in PD patients may in part be explained by fluid retention caused by
      impaired ultrafiltration.

PMID- 10649706
TI  - The rationale for, and role of, heparin in peritoneal dialysis.
AB  - The administration of intraperitoneal (i.p.) heparin enjoys time-honored use and
      is felt to be side-effect free. It is administered whenever fibrin is detected in
      the dialysate effluent. It is believed that there is no absorption of heparin
      across the peritoneal cavity. The aim of this article was to review the rationale
      behind the administration of i.p. heparin, to show that absorption and side
      effects may occur, and to present recent evidence that questions the routine use
      of this drug as an additive to dialysate fluid.

PMID- 10649707
TI  - New developments in peritoneal dialysis solutions.
AB  - Existing peritoneal dialysis (PD) solutions were formulated mainly for the
      maintenance of fluid and electrolyte balance, correction of metabolic acidosis,
      and the removal of metabolic waste products. New solutions in development, and
      recently approved in some countries, are designed to improve ultrafiltration
      during long dwells (polyglucose or icodextrin solutions), to treat malnutrition
      (amino-acids solutions), and to improve peritoneal biocompatibility (bicarbonate
      buffered solutions). Other new solutions under investigation are designed to
      address unmet clinical needs, including cardiovascular disease and sodium
      balance, through the use of a low-sodium PD solution; long-term peritoneal
      viability, through improvements in sterilization processes and the use of
      nonglucose osmotic agents; and PD adequacy, through the use of solution additives
      (such as glycosaminoglycans) and tailored PD prescriptions using APD. Future
      concepts for PD include remodeling of the peritoneum, perhaps using mesothelial
      gene therapy to introduce metabolic and anabolic machinery to remove or
      perpetually recycle metabolic wastes.

PMID- 10649708
TI  - Maltose and isomaltose in uremic plasma following icodextrin administration.
AB  - The presence of mixed disaccharides (maltose and isomaltose) in plasma from
      uremic patients has been previously investigated using gel-permeation
      chromatography. However, this method is unable to separate maltose (linked alpha
      1-4) from isomaltose (linked alpha-1-6). We describe an alternative method using
      high-performance anion-exchange chromatography with pulsed amperometric detection
      (HPAE-PAD) for the direct determination of maltose and isomaltose in uremic
      plasma. We measured maltose and isomaltose using HPAE-PAD in 6 normal subjects
      and in 15 uremic patients before and after once-daily icodextrin administration
      for at least 4 weeks. Both maltose and isomaltose were below limits of detection
      (< 1.0 mg/L) in plasma from normal controls. Patients with end-stage renal
      disease treated by continuous ambulatory peritoneal dialysis had elevated levels
      of isomaltose (23.6 +/- 8.3 mg/L) but low levels of maltose (< 3.0 mg/L).
      Treatment with icodextrin resulted in elevated plasma levels of maltose (range:
      500-1600 mg/L), while levels of isomaltose declined to 9.8 +/- 5.2 mg/L (P <
      0.0001 vs. baseline levels). We conclude that isomaltose (not maltose) is the
      primary disaccharide isomer that is elevated in the plasma of uremic patients,
      whereas maltose is the primary disaccharide isomer that is elevated following
      icodextrin administration. Furthermore, icodextrin administration results in an
      apparent reduction of isomaltose. Additional investigation will be required to
      address the mechanism for the reduction of isomaltose in patients treated by
      icodextrin.

PMID- 10649709
TI  - Peritonitis in the extended-care facility.
AB  - Many patients with end-stage renal disease (ESRD) require admission to an
      extended-care facility (ECF). Few data are available concerning the development
      of peritonitis among continuous peritoneal dialysis (CPD) patients residing in an
      ECF. We retrospectively reviewed the charts of 77 CPD patients admitted to an ECF
      between November 1993 and 31 August 1997. A total of 25 episodes of peritonitis
      developed among CPD patients in the ECF during this period for an overall
      peritonitis rate of 1 episode in 19.8 patient-months. The CPD patients developing
      peritonitis in the ECF were similar in age and gender to the CPD patients
      residing in the ECF not developing peritonitis. There were more African-Americans
      among the group of CPD patients residing in the ECF who developed peritonitis
      than among the ECF residents who did not develop peritonitis (41% vs. 23%,
      respectively; P < 0.05). Patients developing peritonitis in the ECF resided in
      the ECF significantly longer than the remaining CPD patients not developing
      peritonitis in the ECF (106 vs. 77 days, respectively; P < 0.05). The overall
      rate of peritonitis in the ECF was lower than that seen in the community (1
      episode in 19.8 patient-months vs. 1 episode in 10.0 patient-months,
      respectively). The rate of gram-positive peritonitis was lower than the rate of
      gram-positive peritonitis seen in the community setting (1 episode in 54.9
      patient-months vs. 1 episode in 14.9 patient-months, respectively). The rate of
      culture-negative peritonitis was higher among the ECF patients than among
      patients developing community-acquired peritonitis (1 episode in 61.9 patient
      months vs. 1 episode in 106.2 patient-months, respectively). The spectrum of
      organisms in the ECF was different than the spectrum noted among patients
      developing hospital-acquired peritonitis. Eleven of the 25 episodes of
      peritonitis were treated successfully at the ECF while the remaining 14 episodes
      of peritonitis were treated at an acute-care hospital. Continuous PD therapy was
      continued following 19 of the 25 episodes (76%), 1 patient transferred to
      hemodialysis, and 5 patients expired. We conclude that patients develop
      peritonitis in the ECF less frequently than in the community setting, with the
      spectrum of organisms different than the spectrum seen in the community and
      hospital settings. Seventy-six percent of the patients continue CPD therapy
      following an episode of peritonitis.

PMID- 10649710
TI  - Management of peritonitis in automated peritoneal dialysis patients.
AB  - The management of peritonitis in patients undergoing automated peritoneal
      dialysis (APD) deserves special consideration due to the technical differences
      between APD modalities and continuous ambulatory peritoneal dialysis (CAPD). The
      use of very short exchanges may preclude the prompt diagnosis of peritonitis by
      diluting the peritoneal-cell population and causing spuriously low cell counts
      and clear effluent. Very long diurnal cycles can have the opposite result and
      give a falsely elevated cell count. The effluent from the multiple automated
      exchanges must be visually examined before being discarded in order to make a
      prompt diagnosis. Direct drainage of effluent into the sewage without inspection
      should be avoided. If direct drainage becomes a common practice, other
      alternatives such as on-line cell counters or chemical detectors of possible
      infection will be necessary. The recommendations for antimicrobial therapy
      developed for CAPD apply as well to APD. If single-day dosage is to be used, the
      longer exchanges of APD are ideal for intra-peritoneal delivery of antibiotics.

PMID- 10649711
TI  - Continuous cycler therapy, manual peritoneal dialysis therapy, and peritonitis.
AB  - An increasing number of patients are prescribed a continuous-cycling regimen
      because standard manual peritoneal-dialysis exchanges alone are not sufficient in
      achieving adequate dialysis as defined by the Dialysis Outcome Quality
      Initiative. Consequently, the number of patients on continuous-cycler therapy is
      increasing. There is controversy as to whether there are differences in the
      development of peritonitis between patients maintained on manual therapy and
      those on continuous cycling therapy. As a result, we retrospectively reviewed the
      charts of all cycler peritoneal dialysis (CPD) patients maintained on either
      manual peritoneal dialysis (Baxter UltraBag; Group I) or continuous cycler
      peritoneal dialysis (Baxter HomeChoice Cycler; Group II) between 1 June 1994 and
      31 December 1996. A total of 239 patients were in Group I and 106 in Group II.
      Both groups were similar in age, race, gender, and presence of diabetes mellitus,
      coronary artery disease, peripheral vascular disease, and gastrointestinal
      disease. There was no difference in the overall rate of peritonitis between the
      two groups of patients [1 episode in 10.4 patient-months (Group I) vs. 1 in 10.0
      patient-months (Group II); -0.01843 to 0.02619]. The rates of Staphylococcus
      aureus peritonitis [1 episode in 48.5 patient-months (Group I) vs. 1 in 141.8
      patient months (Group II); -0.06152 to -1.1689]; polymicrobial peritonitis [1
      episode in 278.8 patient-months (Group I) vs. 1 in 1134 patient months (Group
      II): -0.0079 to -0.0478], and fungal peritonitis (1 episode in 202.7 patient
      months (Group I) vs. no episodes (Group II); 0.00202 to 0.00785] were
      significantly lower among patients maintained on the Baxter HomeChoice Cycler.
      The rate of gram-negative peritonitis was higher among patients maintained on the
      Baxter HomeChoice Cycler, but this difference was not statistically significant
      [1 episode in 82.6 patient-months (Group I) vs. 1 episode in 45.4 patient months
      (Group II); 0.4723 to -0.0248]. We conclude that individual rates of peritonitis
      were different for patients maintained on either manual or continuous CPD
      therapy, while the overall rate of peritonitis was found to be similar for both
      groups of patients. The finding that there may be a difference with the gram
      negative peritonitis rate is important since gram-negative peritonitis has been
      shown to have a more severe outcome in terms of morbidity, mortality, and patient
      dropout from CPD therapy. A larger, randomized, multicenter study comparing the
      rates of gram-positive, gram-negative, fungal, and polymicrobial peritonitis is
      warranted.

PMID- 10649712
TI  - Use of Amuchina 50% solution versus povidone-iodine 10% solution for transfer-set
      change in peritoneal dialysis patients.
AB  - The goal of this study was to compare the safety and efficacy of Amuchina 50%
      solution versus that of povidone-iodine 10% solution for transfer-set change in
      peritoneal dialysis (PD) patients in a tertiary referral university hospital. The
      transfer sets were changed using povidone-iodine 10% solution as disinfectant
      prior to March 1995. Thereafter Amuchina 50% solution was used. Thus data were
      collected on all the transfer sets changed between January 1993 and August 1997.
      Amuchina is an electrolytic chloroxidizer. Chlorine is the active ingredient with
      a pH of 9.5-10.5. Amuchina 50% solution contains chlorine (0.55%). One hundred
      ninety-nine transfer sets were changed using povidone-iodine 10% solution in 60
      PD patients from January 1993 to March 1995. One hundred twenty-eight transfer
      sets were changed using Amuchina 50% solution in 65 patients from April 1995 to
      August 1997. The soaking times and nursing times were 2 and 5 minutes,
      respectively, with Amuchina, and 10 and 20 minutes, respectively, with povidone
      iodine 10%. No episode of peritonitis occurred related to transfer-set change in
      either group. The transfer-set change using Amuchina 50% solution is safe and
      cost-effective in PD patients.

PMID- 10649713
TI  - How to record peritoneal catheter infections.
AB  - Due to discrepant definitions of exit-site infections and/or tunnel infections
      (ESI/TI), as well as to the variety of infection rates, data on ESI/TI are
      extremely difficult to compare. Twardwski et al. have defined exit site, while
      Nolph et al. have proposed new monitoring and reporting of ESI/TI. The aim of our
      prospective study was to try combining both systems. From January 1992 to
      December 1995 we treated 127 patients, in whom 147 double-cuff peritoneal
      catheters (PCs) were inserted. Tunnel infection was defined as external-cuff
      infection (ECI), inter-cuff segment infection (ICSI), and/or internal-cuff
      infection (ICI). Sixty-four PCs (43.5%) were infected. Thirty-eight (25.8%) had
      acute PC infection (PCI) from 2.4% to 4.7% of the total patient-months of care
      per year, and 26 (17.7%) PCs were chronically infected from 2.1 to 11.1% of the
      time per year. Almost all cases of removed acutely and chronically infected PCs
      had ECI in combination with ESI. According to our experience, ECI should be
      classified as TI. The proposed approach to monitoring and reporting is very
      useful for ESI, but does not include TI. Comparison between different peritoneal
      dialysis units is only possible when they share a common PC classification
      system, and when their personnel are well experienced, highly trained, and very
      accurate.

PMID- 10649714
TI  - New connection method for isolating and disinfecting intraluminal path during
      peritoneal dialysis solution-exchange procedures.
AB  - Microbiological data have been collected on the performance of a new method of
      isolating and disinfecting the intraluminal path at the connect/disconnect site
      of a peritoneal dialysis (PD)-exchange pathway. High-temperature moist-heat
      (HTMH) disinfection is accomplished by a new device that uses microwave energy to
      heat the solution contained in the pressure-tight inner lumen of PD connector
      pairs between the transfer-set connector-clamp and the bag-connector break-away
      seal. An 85 degrees C (S.D. = 2.4 degrees C, n = 10) rise in solution temperature
      is seen in 12 seconds, thus yielding temperatures under pressure well over 100
      degrees C with starting temperatures of 25 degrees C. Connector pairs were
      prepared by inoculation of a solution suspension containing at least 10(6) colony
      forming units (CFU) of a test micro-organism. Approximately 0.4 mL of solution
      was contained within the mated connector pair. Using standard D-value
      determination methods, data were obtained for surviving organisms versus five
      exposure times and a positive control to obtain a population reduction curve.
      Four micro-organisms (S. epidermidis, P. aeruginosa, C. albicans, and A. niger)
      recognized to be among the most prevalent or problematic in causing peritonitis
      were tested. After microwave heating, the treated solution was aseptically
      withdrawn from the connector pair using a needle and syringe, plated in growth
      media, and incubated. Population counts of CFUs after incubation were used to
      establish survival curves. Results showed a tenfold population reduction in less
      than 3 seconds for all organisms tested. A 30-second cycle time safely achieves a
      > 10(8) population-reduction for bacteria and yeast organisms, and a > 10(7)
      population reduction for fungi. One potential benefit of using this new
      intraluminal disinfection method is that it may help reduce peritonitis resulting
      from the even more problematic pathogens such as the gram-negative bacteria and
      fungal organisms.

PMID- 10649715
TI  - Effect of cefodizime on peritoneal mononuclear- and polymorphonuclear-cell
      chemotaxis.
AB  - In this study, a third-generation cephalosporin with proposed immunomodulatory
      properties, cefodizime, was investigated to see if it has any effect on the
      chemotactic activity of human peritoneal monocyte and polymorphonuclear cell
      populations ex vivo. Ten continuous ambulatory peritoneal dialysis patients with
      peritonitis were entered in the study. Monocytes and polymorphonuclear cells were
      isolated from the patients' peritoneal effluent prior to initiation of any
      antibiotic therapy. Chemotaxis was measured by the Boyden chamber method before
      and after 2-hour incubation with cefodizime (200 mg/2L). Following 2-hour
      incubation with 200 mg/2L cefodizime, monocyte chemotaxis was increased from 36.8
      +/- 5.6 microns to 50.2 +/- 6.6 microns (P = 0.0005). A similar increase was
      observed in polymorphonuclear cells from 42.0 +/- 8.8 microns to 48.7 +/- 10.3
      microns (P = 0.02). We conclude that cefodizime acts as a priming agent on
      peritoneal polymorphonuclear cells, particularly on monocytes, and increases
      their chemotactic movements.

PMID- 10649716
TI  - Sphingosine and sphinganine levels in human mesothelial cells in vitro as a
      potential index of signal transduction pathways impacted by microbes and
      osmolality.
AB  - Sphingolipids are emerging as important regulators of mammalian cell biology. In
      this study, the contents of six separate preparations of human omental
      mesothelial cells in vitro were examined for free sphingosine and sphinganine,
      and for the total levels of these sphingoid bases in ceramide-containing
      sphingolipids. Two high-performance liquid chromatography (HPLC) methods for
      determination of sphingoid base levels in cultured cells were compared. The rapid
      HPLC method was found to yield the highest recovery of internal standard.
      Mesothelial cells initially isolated by collagenase digestion of the omentum were
      found to have higher free- and total-sphingoid base levels than cells isolated by
      trypsin-EDTA digestion. Use of sphingoid base levels to gain insights into the
      status of cellular nutrition, inflammation, programmed cell death, exposure to
      microbial toxins, cytokines, and growth factors within the peritoneum will
      require a systematic description of sphingolipids in normal, diseased, and
      dialyzed mesothelium.

PMID- 10649717
TI  - Granulocyte macrophage-colony stimulating factor stimulates secretion of
      chemoattractive cytokines by peritoneal macrophages of CAPD patients.
AB  - The recruitment of immunocompetent cells to the site of inflammation represents
      an essential part of the host defense during continuous ambulatory peritoneal
      dialysis (CAPD)-related peritonitis. Recently, it was shown that intraperitoneal
      application of granulocyte macrophage-colony stimulating factor (GM-CSF) leads to
      a marked transient recruitment of macrophages, paralleled by an increase in
      monocyte chemoattractant protein (MCP)-1. We, therefore, tested the in vitro
      effect of GM-CSF on the release of the chemotaxins interleukin (IL)-8 and MCP-1
      by human peritoneal macrophages. Cells were stimulated with recombinant GM-CSF
      for 4, 12, and 20 hours in concentrations ranging from 0.1 to 100 pg/mL. Cells
      stimulated with lipopolysaccharide (LPS) or unstimulated cells served as control.
      Recombinant GM-CSF at concentrations found during CAPD peritonitis in vivo
      significantly increased the release of IL-8 and MCP-1 in a time- and dose
      dependent manner. The maximum effect of IL-8 was observed directly after cell
      isolation, and decreased after a culture period of 10 days. Thus, our results
      indicate that peritoneal macrophages are the potential source of chemokines
      released upon GM-CSF stimulation.

PMID- 10649718
TI  - Consequences of peritonitis episodes appearing late during peritoneal dialysis
      (PD) in patients able to continue PD.
AB  - The lack of specific information on the peritoneal-function consequences of late
      peritonitis episodes, and the concern about long-term consequences of peritoneal
      dialysis (PD), have prompted us to study the peritoneal function of long-term PD
      patients after a late peritonitis episode. The question is: Is the peritoneum
      more vulnerable to infections, in terms of functional effects, after a long time
      on PD? Forty-nine patients observed from baseline to the first year of PD with no
      peritonitis constituted the "early" control group; 31 other patients had one
      episode of peritonitis in the same period. Twenty-seven patients with no
      peritonitis from the fourth to fifth years comprised the "late" control group; 15
      other patients had one episode during the same period. The results presented here
      suggest that peritoneal vulnerability to infectious episodes depends on the PD
      stage in which they appeared. Certainly, episodes with similar aggressive
      capacity in terms of inflammation duration (3-4 days) happening during the fifth
      year led to a loss of ultrafiltration (UF) capacity that does not appear in
      patients who suffer an episode during the first PD year. A remarkable feature is
      that this UF-capacity decrease is not accompanied by the usual creatinine mass
      transfer coefficient increase. This fact suggests that the dependence between
      peritoneal-glucose-gradient maintenance and water transport has been partially
      modified over time on PD. In conclusion, late mild peritonitis has distinct
      peritoneal-function consequences relative to early peritonitis. Patients who
      continue PD after one late episode showed an accentuation of the usual change
      which happens on long-term PD, the loss of peritoneal ultrafiltration capacity.

PMID- 10649719
TI  - Nitric oxide is a marker of peritonitis in patients on continuous ambulatory
      peritoneal dialysis.
AB  - The aim of this study was to determine whether nitric oxide (NO) production is
      altered during peritonitis in patients receiving continuous ambulatory peritoneal
      dialysis (CAPD), and if so, whether there is an association between this
      alteration and the severity and prognosis of CAPD-induced peritonitis. The study
      population comprised 30 patients with 30 episodes of peritonitis. Thirteen
      patients without peritonitis were used as CAPD-control, and eighteen patients
      with normal renal function were used as normal-control. Total NO metabolites
      (NOx; nitrite + nitrate) were measured by the Griess method to reflect nitric
      oxide production. Peritoneal dialysate effluent and plasma were collected from 30
      patients during episodes of peritonitis every day for the first 3 days, and then
      every 3 days for 2 weeks or until the patients were discharged. Plasma NOx levels
      in the control, CAPD-control, and CAPD-peritonitis groups were 87.0 +/- 11.5,
      163.0 +/- 30.7 and 146.3 +/- 18.1 microM, respectively. Dialysate NOx levels in
      the CAPD-control and CAPD-peritonitis groups were 91.8 +/- 13.1 and 103.8 +/-
      14.1 microM, respectively, and dialysate NOx levels did not differ between the
      two groups. The peak dialysate/plasma (D/P) ratios during the acute phase
      exceeded 1.0 in 46.7% of the patients of the CAPD-peritonitis group. The D/P
      ratios of NOx levels before and after treatment were 1.03 +/- 0.07 and 0.56 +/-
      0.05, respectively. On the contrary, NOx levels in dialysate after treatment were
      not decreased, but those in plasma were increased after effective treatment. The
      peak D/P ratio increased 2.1-fold in the bacterial peritonitis group and 2.3-fold
      in the fungal peritonitis group, compared with the CAPD-control group. The lowest
      D/P ratios after treatment were similar to those in the CAPD-control group in
      patients with effective treatment, but remained 1.5-fold higher in patients for
      whom treatment was ineffective. In the evolutional study, the D/P ratios of NOx
      levels gradually declined to CAPD-control group levels (6.6 +/- 2.5 days) after
      effective antibiotic treatment, but it took longer for leukocyte counts in the
      peritoneal dialysate effluents (3.8 +/- 1.2 days) to normalize. In 5 patients
      with refractory peritonitis (Candida infection in three, Staphylococcus aureus
      infection in two), the D/P ratios of NOx levels remained elevated by 1.5-fold
      despite treatment, and the catheters were removed. These results suggest that
      dialysate NOx may be influenced not only by local NO production, but also by
      plasma NO or NOx diffusion. Therefore, we can suppose that the D/P ratio of NOx
      levels provides more clinical significance than dialysate NOx levels only. In
      conclusion, the D/P ratios of NOx levels may serve as a marker to assess the
      severity of peritoneal inflammation, treatment efficacy, and progression of
      refractory peritonitis in CAPD patients with peritonitis.

PMID- 10649720
TI  - Bone marrow immunoscintigraphy (BMIS): a new and important tool for the
      assessment of marrow fibrosis in renal osteodystrophy?
AB  - One of the classic histologic forms of renal osteodystrophy is osteitis fibrosa,
      and its distinguishing characteristic is bone marrow (BM) fibrosis, caused by the
      activation of marrow parenchymal cells. A bone biopsy must be performed in order
      to establish the diagnosis of renal osteodystrophy. The clinical use of bone
      biopsy is restricted, however, due to the invasiveness of the procedure. In
      recent studies, bone scans have provided information useful for the differential
      diagnosis between osteomalacia and osteitis fibrosa. However, bone scans can not
      provide information on the bone marrow status. Bone marrow immunoscintigraphy
      (BMIS) using Tc-99m anti-granulocyte antibody (AGA), a highly sensitive test for
      the detection of bone marrow abnormalities which is also a noninvasive method,
      has rarely been reported in chronic renal failure (CRF). BMIS can provide
      information in patients with myelofibrosis. The purpose of this study was to
      evaluate the usefulness of BMIS in CRF patients with special regards to
      biochemical parameters. Nineteen CRF patients (13 men, 6 women; mean age: 48 +/-
      11 years) in whom bone scintigraphy using Tc-99m MDP (methylene diphosphonate)
      showed the so-called superscan pattern were included in the study. Their primary
      renal diseases were chronic glomerulonephritis (n = 14), diabetes (n = 4), and
      polycystic kidney disease (n = 1). Modes of therapies were continuous ambulatory
      peritoneal dialysis (CAPD) (n = 13; mean duration: 9.5 months), HD (n = 5; mean
      duration: 7.8 months), and conservative treatment (n = 1). BMIS using Tc-99m
      labeled anti-granulocyte monoclonal mouse antibody BW250/183 was performed, and
      the results were compared with the biochemical parameters of the patients.
      According to the presence of BM expansion, which may represent marrow fibrosis,
      the 19 patients were divided into two groups: Group I (n = 7) with BM expansion
      and Group II (n = 12) with normal marrow distribution. The biochemical parameters
      and bone markers of Group I were compared with those of Group II. There was no
      significant difference in biochemical parameters (blood hemoglobin, serum
      ferritin, erythropoietin, BUN, creatinine) between the two groups. There were no
      significants difference in serum calcium, phosphorus, tartate-resistant acid
      phosphatase (TRAP), and intact parathyroid hormone (iPTH) between the two groups.
      Serum alkaline phosphatase (ALP) and osteocalcin were significantly (P < 0.05)
      higher in Group I than in Group II. These results suggest that patients with bone
      marrow expansion in BMIS have increased levels of ALP and osteocalcin, indicating
      an increased osteoblastic activity. BMIS may be useful for the detection of bone
      marrow expansion due to marrow fibrosis in renal osteodystrophy, and for the
      evaluation of the extent of bone marrow fibrosis.

PMID- 10649721
TI  - Hyperparathyroidism: a seven-year follow-up.
AB  - Hyperparathyroidism (HPT) is a common finding in patients with end-stage renal
      disease (ESRD). Most chronic peritoneal dialysis (CPD) patients with HTP can be
      successfully managed with phosphate binders, calcium supplements, and calcitriol
      therapy. Noncompliance with diet, prescribed binder, or calcitriol therapy may
      also lead to HPT. We reviewed New Haven CAPD unit patients who failed medical
      therapy and required parathyroidectomy (PTX) for control of severe HPT [sustained
      immunoreactive parathyroid hormone (iPTH) level > 600 pg/mL]. From 1990 to 1997,
      18 out of 620 patients (3.0%) required PTX. Time on dialysis prior to PTX was
      44.8 +/- 17.5 (mean +/- SD) months with a range of 13 to 71 months. The mean age
      was 43.6 +/- 11.8 years with a range of 30 to 66 years. There were 10 females and
      8 males. Of the 18 patients, 14 had total parathyroidectomy with arm implants,
      and 4 had subtotal PTX. Seven of 18 patients had iPTH levels of < 100 pg/mL at 1
      year post-PTX (5 patients with arm implants, 2 with subtotal PTX). Three patients
      required partial arm implant PTX to correct recurrent HPT. Pulse oral calcitriol
      (POC) was prescribed in 10 patients post PTX to maintain iPTH at target levels.
      Parathyroidectomy was necessary to correct HPT in 18 of 620 CPD patients from
      1990 to 1997. The majority of these patients had excellent results after their
      PTX. Intact PTH levels of < 100 pg/mL for 1 year or more were noted in 5 of 14
      patients with arm implants, and 2 of 4 patients with subtotal PTX. The
      significance of a persistent iPTH of < 100 pg/mL has yet to be determined in CPD
      patients.

PMID- 10649722
TI  - Comparison of in vitro AGE formation between standard PD fluid and a novel
      bicarbonate/lactate formulation.
AB  - Peritoneal advanced glycation end-product (AGE) formation may be accelerated by
      glucose degradation products produced as a consequence of heat sterilization of
      peritoneal dialysis (PD) fluid. The formation of these degradation products is
      reduced if the glucose is separated from the buffers during heat sterilization.
      This pilot study compared in vitro AGE formation in PD fluid (1.36% and 3.86%
      glucose) heat sterilized in a two-compartment bag (bicarbonate/lactate buffer)
      with that in a standard, single-compartment bag (lactate buffer, Dianeal).
      Peritoneal dialysis fluids were incubated with human serum albumin (HSA, 1 g/L),
      as a model protein, at 37 degrees C for 0, 5, and 20 days. Formation of AGEs was
      assessed by measuring fluorescence at each time point. Advanced glycation end
      product formation was greater in lactate PD fluid compared with
      bicarbonate/lactate PD fluid of equivalent glucose strength. Advanced glycation
      end-product formation in the lactate PD fluid containing 1.36% glucose was
      comparable to that in the bicarbonate/lactate PD fluid containing 3.86% glucose.
      The rate of increase in fluorescence per day was greater in the first 5 days of
      incubation than in the subsequent 15 days. These results are compatible with the
      presence of greater amounts of glucose-degradation products in the standard
      single-compartment bag resulting in enhanced AGE formation.

PMID- 10649723
TI  - In vitro and in vivo generation and kinetics of glycosylation products in
      peritoneal dialysis effluents.
AB  - There are indications that advanced glycosylation end-products (AGEs) may affect
      in some manner the functions of the peritoneum. Only a few reports discuss the
      actual generation of glycosylated proteins and the intraperitoneal kinetics
      involved during continuous ambulatory peritoneal dialysis (CAPD). To demonstrate
      the formation of AGEs and their time-courses in peritoneal dialysis (PD)
      effluents, measurements were made of furosine, carboxymethyl lysine (CML), and
      pentosidine as glycosylation markers in vitro and in vivo using PD effluents
      obtained every 2 hours for up to 8 hours from 3 nondiabetic CAPD patients.
      Furosine and CML were found to be generated relatively early (within 6 hours),
      and their de novo formation was markedly enhanced subsequent to glucose addition.
      Furosine and CML production increased in proportion to glucose concentration.
      Pentosidine production did not change with time for up to 24 hours, and was not
      induced by glucose during this period. Carboxymethyl lysine production appeared
      to be suppressed in vitro with the addition of serum protein. Furosine in the
      intraperitoneal dialysate was initially the same as that in the plasma, but
      increased to twice as much in just 2 hours in vivo. Production of CML increased,
      but apparently was suppressed with leakage of plasma protein into the dialysate;
      this possibly may have been due to dilutional or antiglycation effects in the
      plasma. No stimulation of pentosidine production could be detected in the
      intraperitoneal dialysate even at 8 hours. The initiation of glycosylation of
      peritoneal proteins, with generation of furosine and CML but not pentosidine, is
      clearly shown by the present results to occur relatively early in the
      intraperitoneal dialysate, i.e., within a matter of hours.

PMID- 10649724
TI  - Optimizing diabetes management.
AB  - Diabetes mellitus is the fastest growing cause of end-stage renal disease and an
      important source of comorbidity among renal patients. A better understanding of
      diabetic pathophysiology has contributed to the development of effective
      prevention or treatment of many of its complications. The systematic application
      of several therapeutic recommendations based on clinical evidence can
      significantly reduce the rate of diabetic complications and improve the quality
      of life of the diabetic patient. Some of the most important recommendations are:
      (1) meticulous glycemic control to maintain HbA1c < or = 7.2%; (2) control of
      arterial blood pressure to normal levels (< 130/85 mmHg); (3) tobacco abstinence;
      (4) avoidance of excessive protein intake in the early stages of nephropathy; (5)
      aggressive nutritional monitoring and support; (6) early myocardial
      revascularization; (7) avoidance of unnecessary use of radiographic contrast
      media; and (8) appropriate initiation of dialysis with adequate delivered dose.
      Every effort should be made to provide effective education of the patient and
      health professionals. We must also develop regimens that interfere minimally with
      lifestyles in order to improve patient compliance with therapy.

PMID- 10649725
TI  - Impact of peritoneal dialysis modality and acidosis on nutritional status in
      peritoneal dialysis patients.
AB  - Continuous ambulatory (CAPD) and continuous cyclic peritoneal dialysis (CCPD)
      differ in solute transport, and variances in mass balance could impact
      nutritional parameters. Chronic acidosis may decrease albumin synthesis and
      increase catabolism. We prospectively studied 50 peritoneal dialysis patients
      (age: 55 +/- 16 yrs; CAPD = 33; CCPD = 17) over 24 months. Acidosis was defined
      by an anion gap > 18 mEq/L. Bioimpedance analysis was used to estimate body cell
      mass and fat-free mass. Patients on CAPD had a lower body mass index than CCPD
      patients (27 +/- 5 kg/m2 vs. 29 +/- 9 kg/m2 respectively; P = 0.039). However no
      differences were observed in body cell mass (25 +/- 8 kg vs. 26 +/- 9 kg
      respectively; P = 0.787) or fat-free mass (53 +/- 14 kg vs. 50 +/- 18 kg
      respectively; P = 0.404). Urea kinetic modeling showed no differences in Kpt/V or
      nPCR (0.26 +/- 0.06 vs. 0.24 +/- 0.07; P = 0.709 and 0.67 +/- 0.29 g/kg per day
      vs. 0.65 +/- 0.23 g/kg per day; P = 0.709 for CAPD and CCPD respectively). When
      categorized by the presence of acidosis no differences were observed in body cell
      mass (24 +/- 8 kg vs. 27 +/- 9 kg respectively; P = 0.131) or fat-free mass (54
      +/- 15 kg vs. 50 +/- 16 kg respectively; P = 0.348), while body mass index was
      greater in acidotic than nonacidotic individuals (30 +/- 8 kg/m2 vs. 26 +/- 6
      kg/m2 respectively; P = 0.005). Dietary protein intake assessed as nPCR was
      similar in both groups (0.64 +/- 0.26 vs. 0.71 +/- 0.28 g/kg per day; P = 0.319,
      for CAPD and CCPD respectively). We conclude that over a 24-month period neither
      peritoneal dialysis modality nor the presence of acidosis has a detrimental
      influence on nutritional parameters in well dialyzed patients.

PMID- 10649726
TI  - Metabolic index in peritoneal dialysis.
AB  - To define protein anabolism or catabolism in our patients we retrospectively
      studied the 24-hour balances (B24 h), dietary protein intake (DPI),
      anthropometric parameters [body mass index (BMI), tricipital skin fold thickness
      (TF), and muscular arm circumference (MAC), using the rating scheme:
      undernourished (U): percentile (pc) < 15; normal (N): pc > 15 to pc < 85; obese
      (O): pc > 85], and urea kinetics (protein equivalent of nitrogen appearance) [PNA
      = PCR according to the Gotch-Borah (G), Blumenkrantz (B), and Randerson (R)
      formulas]. Nitrogen-balance [N-B = DPI(N)-PNA(N)], metabolic ratio (MR =
      DPI/PNA), and metabolic index (MI = IDPI/nPNA) were calculated as metabolic
      indicators. There were 215 evaluations (B24 h) in 44 patients, of whom 29 were
      male and 15 female, 35 on continuous ambulatory peritoneal dialysis (PD), 9 on
      automated PD, age 58.2 +/- 15.6 years, followed-up for 15.3 +/- 10.2 months.
      Undernourished patients (BMI) showed higher N-B, MR, and MI irrespective of the
      formula used, but MR was only significant using the Blumenkrantz formula. For N
      balance and metabolic index, analysis of variance (ANOVA) was significant with
      all formulas. The mean metabolic index (Randerson) in subgroups was: U: 1.09 +/-
      0.27, n = 54; N: 0.90 +/- 0.25, n = 135; O: 0.87 +/- 0.27, n = 26 (ANOVA: P <
      0.0001). The U-N and U-O subgroup comparison was significant (Newman-Keuls P <
      0.01). We concluded that: (1) The metabolic index is more discriminating for
      protein metabolism than N-balance or metabolic ratio. (2) Most of the
      undernourished patients (BMI) are anabolic according to metabolic index and N
      balance, and this indicates recovery. (3) Undernourished (low BMI) patients with
      metabolic index < 1 deserve special attention due to the risk of remaining
      malnourished.

PMID- 10649727
TI  - The influence of total, dialysis, and residual renal urea clearances on serum
      albumin in peritoneal dialysis.
AB  - Though serum albumin (SA) and Kt/V predict mortality in peritoneal dialysis (PD),
      the relationship between them remains unclear. We report a cross-sectional study
      of factors associated with SA in PD, and a prospective study of the effect of
      increasing dialysis dose on SA in hypoalbuminemic patients with Kt/V < 2.1.
      Multiple linear regression was performed in 56 subjects with dependent variable
      SA at 4 months after starting PD (SA2), and independent variables: age, sex,
      diabetes, 4h-D/Pcr, predialysis SA (SA1), nPCR, PD-duration, modality, Kt/V, Ccr,
      and daily volume excreted normalized to body water (Vt/V). Forward stepwise
      selection (alpha = 0.05) produced a model (r2 = 0.492, P < 0.001) containing
      predictors of SA2: SA1 and nPCR (positive), and Vt/V (negative). With Vt/V
      excluded, Kt/V became significant (negative). Broken into components, dialysate
      Kt/V was significant, but residual Kt/V was not significant. In 14
      hypoalbuminemic patients with Kt/V < 2.1, PD prescription was changed, targeting
      a Kt/V > 2.1. After 3.3 months, Kt/V rose from 1.7 +/- 0.25 to 2.21 +/- 0.36 (P =
      0.0001), and nPCR rose slightly, 0.71 +/- 0.13 to 0.78 +/- 0.19 (P = NS), with no
      significant change in SA, 30.5 +/- 3.0 g/L to 31.4 +/- 3.8 g/L (P = 0.268).
      Dialysate and urine volumes are negative predictors of SA. Volume-dependent
      dialysate-protein loss could account for poor correlation between Kt/V and SA,
      and lack of improvement in SA with increased Kt/V.

PMID- 10649728
TI  - Bioimpedance analysis of fluid compartments in female CAPD patients.
AB  - Dry weight is difficult to determine in continuous ambulatory peritoneal dialysis
      (CAPD) patients. Bioimpedance spectroscopy using a multi-frequency analyzer was
      used to measure total body water, extracellular water, and intracellular water in
      7 female CAPD patients and, for comparison, in 6 normal female controls. One
      patient was measured a second time after a 10-kg fluid loss. Mean weight in
      controls and CAPD patients was similar, as was the percent of body weight that
      was water. However, the ratio of extracellular water to intracellular water was
      0.814 in controls but 1.11 in CAPD patients, suggesting either more extracellular
      water and/or less intracellular water in the CAPD patients compared to the
      controls. When analyzed, the percent of total body water that was extracellular
      was significantly greater in the CAPD group. There was also a significant
      reduction in the percent of intracellular water that contributed to body weight
      in the CAPD patients. Body cell mass was 38.1% in controls but only 30.2% in CAPD
      patients. Serum albumin concentration ranged from 2.1 to 4.2 g/dL in CAPD and a
      linear relationship was present between serum albumin concentration and cell
      membrane capacitance. We conclude that 60% of body weight as body water may be an
      overestimate of volume (V) when the formula Kt/V is used to measure adequacy, and
      that bioimpedance spectroscopy may be a useful technique for assessing both fluid
      balance and body cell mass or nutritional status in CAPD patients.

PMID- 10649729
TI  - Mechanism for elevated plasma lipoprotein(a) concentrations in patients on
      dialysis: turnover studies.
AB  - Plasma concentrations of lipoprotein (a) [Lp(a)] are increased in patients on
      renal replacement therapy. Lipoprotein (a) is increasingly being recognized as an
      independent cardiovascular risk factor. In an effort to explore the mechanism for
      elevation of Lp(a) in patients on dialysis we have performed turnover studies of
      Lp(a) with radioactive iodine. Lp(a) was isolated from 1 patient on hemodialysis
      (HD) and 1 patient on continuous ambulatory peritoneal dialysis (CAPD); the
      protein was labeled with 125I and returned to each patient. Lipoprotein (a) was
      subsequently isolated from the patients over a 15-day period and the decay of the
      specific radioactivity of Lp(a) was used to determine the fractional catabolic
      rate (FCR), which was 0.27 (pool/day) for the HD patient and 0.28 (pool/day) for
      the CAPD patient. These rates are indistinguishable from those measured in 4
      patients with hypercholesterolemia (0.29, SEM = 0.01) and in 4 other familial
      hypercholesterolemic patients (0.29, SEM = 0.02) studied previously using the
      same method by Knight et al. (7). We found no difference in the FCR of patients
      on dialysis when compared to patients with hyperlipidemia and normal renal
      function. Increased plasma concentration of Lp(a) in our patients on renal
      replacement therapy is not due to decreased catabolism, but is caused by
      increased synthesis.

PMID- 10649730
TI  - ITDI is the preferred treatment for iron supplementation in rHuEpo-treated anemic
      PD patients.
AB  - In recombinant human erythropoietin (rHuEpo)-treated anemic peritoneal dialysis
      (PD) patients, oral iron therapy, despite its limited efficacy, remains an
      accepted and convenient method of iron supplementation. In this study, we
      compared infusion of total dose iron (ITDI) to oral iron for the treatment of
      anemia in PD patients. Thirteen patients with serum transferrin saturation (TSAT)
      < 25% received ITDI and 11 patients with TSAT between 25% to 35% received oral
      iron. Doses of rHuEpo were adjusted monthly to maintain target hematocrit at 35%.
      Both groups had similar baseline mean hematocrits (31.0 +/- 0.9% vs. 33.0 +/-
      1.0%), and comparable mean baseline weekly rHuEpo dose (7886 +/- 1449 units/week
      vs. 6370 +/- 1553 units/week). At the end of the 6-month study, the ITDI group
      had a 16% improvement in mean hematocrit compared to baseline. The final mean
      dose of weekly rHuEpo was also reduced by 59% in the ITDI group. During the same
      period, compared to baseline, the oral group had a 4.8% fall in mean hematocrit
      despite 51% higher requirement of rHuEpo doses. There was no adverse reaction to
      intravenous iron. We conclude that ITDI is the preferred treatment for iron
      supplementation in rHuEpo-treated anemic PD patients.

PMID- 10649731
TI  - Androgens for the treatment of anemia in peritoneal dialysis patients.
AB  - Before the advent of recombinant human erythropoietin (EPO), androgens were used
      for treatment of anemia in dialysis patients. However, after the availability of
      recombinant EPO in the 1980s, the use of these substances was abondoned. We have
      previously reported that androgens have beneficial actions on anemia in selected
      hemodialysis patients. In the present study we have analyzed the effects of
      androgen administration on hematologic parameters in peritoneal dialysis
      patients. We evaluated 9 patients treated for 6 months with nandrolone decanoate
      (200 mg/week intramuscularly). Hemoglobin and hematocrit values experienced a
      significant increment with respect to basal values during the study (9.2 +/- 0.7
      g/dL and 27.7% +/- 2.3% at basal vs. 11.9 +/- 0.5 g/dL and 35.3% +/- 1.6% at
      month 6, respectively; P < 0.001). In addition to the effects on the hematologic
      parameters, androgen administration also had beneficial anabolic actions with a
      significant increment in the serum concentration of total proteins and albumin
      (basal, 6.1 +/- 0.3 g/dL and 3.1 +/- 0.4 g/dL vs. 6.7 +/- 0.4 g/dL and 3.8 +/-
      0.4 g/dL at month 6, respectively, P < 0.01). The only adverse effect was a rise
      in the serum concentration of triglycerides (176 +/- 54 mg/dL vs. 144 +/- 53
      mg/dL, P < 0.01). In conclusion, androgen administration has beneficial effects
      on erythropoiesis as well as positive anabolic actions in patients under
      peritoneal dialysis.

PMID- 10649732
TI  - Effect of intraperitoneal immunoglobulin infusion on neutrophil function in CAPD
      children with and without peritonitis.
AB  - The present study was designed to assess the effect of intraperitoneal infusion
      of immunoglobulin (Ig) on neutrophil functions in uninfected and infected
      patients treated by continuous ambulatory peritoneal dialysis (CAPD). Fourteen
      children were included in the study. Healthy laboratory and medical personnel (n
      = 10) served as controls. Blood and peritoneal dialysate effluent (PDE) samples
      were obtained before and after Ig infusion. In all patients, chemotactic response
      of peripheral blood neutrophils (PBN) was significantly lower than in healthy
      controls. Peripheral blood neutrophils obtained from patients during peritonitis
      episodes (n = 10) showed significantly higher values compared to the values
      obtained from patients without peritonitis (n = 12). After the intraperitoneal
      infusion of Ig (100 mg/kg), chemotaxis of PBNs increased significantly in both
      patient groups. Chemiluminescence measures of PBN of the uninfected (n = 12) and
      infected patients (n = 7) were similar. They increased significantly in both
      groups after the Ig infusion, although they remained within the lower limits of
      the controls. The peritoneal neutrophils (PNs) showed significantly lower
      chemotactic activity in uninfected patients (n = 11) than in the infected ones (n
      = 10). The response of PNs to the Ig infusion was also more prominent in infected
      patients. Immunoglobulin infusion did not increase the chemiluminescence of PNs
      in infected patients (n = 7); the chemoluminescence of PNs did increase after Ig
      infusion in uninfected patients (n = 12). These data suggest the of
      administration intraperitoneal Ig for prophylaxis and/or treatment of peritonitis
      in CAPD patients.

PMID- 10649733
TI  - Does immunologic status predict peritonitis in children treated with CAPD?
AB  - The purpose of this study was to evaluate whether immunologic status could
      predict the development of peritonitis in children on continuous ambulatory
      peritoneal dialysis (CAPD). Twenty-one patients (12 boys, 9 girls) aged 10.1 +/-
      4.32 years (range: 23 months to 14 years) were studied. The mean duration of CAPD
      treatment was 12.88 +/- 6.69 months (range: 2-22 months). Twelve healthy children
      (mean age 11.5 years) were selected as a control group. Lymphocyte subpopulations
      (CD3, CD4, CD8, CD19, NK, and IL-2R) were determined by double-color flow
      cytometry (Becton-Dickinson). Statistical evaluation was made by Student's t
      test. CD4 (38.4 +/- 7.1% vs. 28.0 +/- 5.4%), CD4/CD8 ratio (1.30 +/- 0.4 vs. 0.96
      +/- 0.3), and B lymphocyte (19.9 +/- 8.9% vs. 12.0 +/- 3.2%) levels were
      significantly higher in CAPD patients compared with controls. CAPD patients
      showed significantly lower natural killer (NK) cell values than controls (12.7 +/
      7.0% vs. 27.3 +/- 8.3%). Apart from CD19 values (21.9 +/- 10.4% vs. 12.0 +/-
      3.2%) there were no significant differences between CAPD patients without
      infection and the control group in the laboratory parameters studied. On the
      other hand, CD3 (66.3 +/- 7.9% vs. 55.9 +/- 9.7%), CD4 (38.4 +/- 7.1% vs. 28.0 +/
      5.4%), and CD19 (6.3 +/- 3.3% vs. 12.0 +/- 3.2%) levels were significantly
      higher in CAPD patients with infection compared with the controls. CAPD patients
      with infection showed significantly lower NK activity (12.7 +/- 7.1% vs. 27.3 +/-
      8.3%) than those in the control group. In conclusion, these results can explain
      the increased vulnerability to peritonitis in CAPD patients compared with healthy
      subjects. Additionally, immunologic status can predict the development of
      peritonitis in children treated with CAPD.

PMID- 10649734
TI  - Peritoneal penetration of amphotericin B lipid complex and fluconazole in a
      pediatric patient with fungal peritonitis.
AB  - Fungal peritonitis is a rare event in patients receiving peritoneal dialysis.
      This case report describes the blood and dialysate concentrations of fluconazole
      and amphotericin B following intravenous administration in a 5-month-old infant
      with Candida albicans peritonitis receiving continuous cyclic peritoneal
      dialysis. Fluconazole rapidly and efficiently penetrated the peritoneal fluid
      achieving concentrations that exceed the minimal inhibitory concentration (MIC)
      for most Candida species. In contrast, the amount of amphotericin B in the
      dialysate was below the limit of quantification despite measurable blood
      concentrations. This suggests that fluconazole represents a better choice for
      antifungal therapy because of its excellent peritoneal penetration.

PMID- 10649735
TI  - Fungal peritonitis in pediatric patients.
AB  - Fungal peritonitis (FP) is a rare complication of peritoneal dialysis (PD).
      Although treatment with fluconazole (FCZ) has improved catheter survival and
      preservation of the peritoneal membrane, FP still carries a high morbidity and
      mortality in pediatrics. High-risk factors for FP include previous usage of
      systemic antibiotics and recurrent bacterial peritonitis. A prospective
      experience in the treatment of FP was conducted at the University of
      Miami/Jackson Children's Hospital from 1992 to 1997. All patients received either
      oral or intravenous loading dose of FCZ (5-7 mg/kg) followed by intraperitoneal
      (i.p.) FCZ (75 mg/L). Amphotericin B (amp B) was added when clinical sepsis was
      present. A total of 6 patients had FP (all Candida sp.; mean age: 6 years). Two
      of these patients were neonates with Tenckhoff-catheter placement at less than 1
      week of age. Five patients achieved sterilization of the peritoneal fluid. One
      patient required catheter removal (C. tropicalis). The 2 neonates were infection
      free for 29 and 41 days, respectively, but both died of superimposed bacterial
      sepsis. The remaining 4 patients survived and completed 6 weeks of FCZ treatment.
      Two have had preservation of the peritoneal membrane for more than 1 year. The
      other 2 were switched to hemodialysis. We conclude that FCZ is an effective
      treatment for fungal peritonitis in pediatric patients. Adjunct therapy with amp
      B is usually necessary if sepsis is present. Although eradication of the fungus
      is possible in a majority of cases, neonates and immunocompromised hosts remain
      at high risk for morbidity and mortality.

PMID- 10649736
TI  - Echocardiographic evaluation in children treated with CAPD.
AB  - The aim of this study was to evaluate systolic and diastolic cardiac functions in
      children treated with continuous ambulatory peritoneal dialysis (CAPD). This
      study included a total of 21 patients (12 boys, 9 girls), aged 23 months to 14
      years (average age: 10.1 +/- 4.32 years). The mean duration on CAPD was 12.88 +/-
      6.69 months (range: 2-22 months). Twenty age- and sex-matched healthy subjects
      served as controls. Evaluation was made at the beginning of CAPD treatment in
      these 21 patients. Tests were repeated in 9 of 21 patients who had completed a 1
      year follow-up period. We measured systolic functions [ejection fraction (EF),
      and fractional shortening (FS)], and diastolic functions [early (E) and late (A)
      diastolic peak inflow velocities, and E/A ratio, as well as early diastolic flow
      deceleration velocity (EF slope) and time (dt) functions] using two-dimensional,
      M-mode, color Doppler echocardiography. Interventricular septum thickness was
      also recorded. Blood pressure (BP) levels were monitored serially in all
      patients. Statistical evaluation was made using Student's t-test. Compared with
      control subjects, systolic and diastolic parameters were significantly inversely
      affected in patients on CAPD (P < 0.05). The mean BP levels did not differ
      significantly between CAPD patients and controls. In 9 patients with a second
      measurement on CAPD, systolic and diastolic cardiac functions tended to have
      deteriorated. However, these changes were not statistically significant (P >
      0.05). In conclusion, CAPD is the preferable option in children with end-stage
      renal disease to maintain stable cardiac functions. However, systolic and
      diastolic dysfunctions tend to progress in children on CAPD.

PMID- 10649737
TI  - Impact of increased intraperitoneal fill volume on tolerance and dialysis
      effectiveness in children.
AB  - The known relationship between peritoneal fill volume (IVP) and dialysis
      efficiency favors the use of an optimal IVP to enhance peritoneal dialysis (PD).
      Therefore, we have studied the effects of an increased IVP in consecutive stages
      [800, 1400, and 2000 mL/m2 of body surface area (BSA), respectively] in 8
      children on chronic PD (mean age: 9 years 6 months; range: 2-16 years). Each
      prescribed IVP was maintained for 60 minutes of dwell time, allowing a short
      peritoneal equilibration test. Tolerance was assessed clinically and by
      intraperitoneal pressure (IPP) measurements at the end of each dwell test.
      Determination of dialysate-to-plasma ratios, and calculation of mass transfer
      area coefficients (K0A) using the Henderson method for urea, creatinine, and
      phosphate, were used to assess the impact of an increased IVP on dialytic
      efficiency. Increasing IVP from 800 to 1400 and thereafter to 2000 mL/m2 induced
      an IPP increment, respectively, from 8.4 +/- 1.4 cm (of water) to 12.1 +/- 1.4 cm
      and thereafter to 18.3 +/- 1.4 cm, with a positive strong linear correlation (r =
      0.92; P = 0.001; IPP = 1.46 +/- 8.17(-3) IVP). In the same manner increasing IVP
      induced K0A increments for urea of 10.6 +/- 1.2 mL/min per m2 to 15.3 +/- 1.6
      mL/min per m2 and 17.1 +/- 1.9 mL/min per m2; for creatinine of 7.9 +/- 0.09
      mL/min per m2 to 11.2 +/- 0.18 mL/min per m2, and 12.3 +/- 0.21 mL/min per m2;
      and for phosphate of 5.2 +/- 0.08 mL/min per m2 to 6.7 +/- 0.09 mL/min per m2 and
      6.6 +/- 0.07 mL/min per m2, respectively. When K0A values were normalized to the
      values achieved at the IVP of 1400 mL/m2, the K0A gain obtained increasing IVP
      from 1400 to 2000 mL/m2 was only significant for urea, peaked for creatinine, and
      even slowly decreased for phosphate. Moreover, a fill volume over 1400 mL/m2,
      which appears to be the optimal volume in terms of dialysis efficiency, was only
      barely tolerated with clinical signs of discomfort and an increased IPP.
      Therefore, in our opinion, the maximal IVP in children over the age of 2 years
      should be nearly 1400 mL/m2, both in terms of abdominal tolerance and in terms of
      urea, creatinine, and phosphate peritoneal membrane purification capacities.

PMID- 10649738
TI  - Improvement of glycemic control by CAPD with intraperitoneal insulin in a child
      with IDDM and ESRD.
AB  - Use of intraperitoneal insulin in diabetic end-stage renal disease (ESRD)
      patients receiving continuous ambulatory peritoneal dialysis (CAPD) is known to
      result in improved glycemic control. This route of insulin administration,
      although standard in adult diabetic CAPD patients, has not previously been
      reported in children. A 12-year old boy with ESRD from renal dysplasia who also
      had insulin-dependent diabetes mellitus (IDDM) was treated with CAPD and
      intraperitoneal insulin prior to renal transplantation. Diabetes and renal
      dysplasia were both diagnosed at 11 weeks of age. When he reached end-stage he
      was initially started on hemodialysis via a central line but was switched to CAPD
      because of recurrent line sepsis. His IDDM had been poorly controlled up to that
      time. CAPD was performed using 4 exchanges per day of 1.5% dialysate with a fixed
      dose of insulin added to each bag and with adjustments made based on blood
      glucose. His glycemic control markedly improved, with a fall in his glycosylated
      hemoglobin from 13.6% to 6%. CAPD was continued for 7 months until a living
      related renal transplant was performed. Two episodes of peritonitis occurred
      while the patient received CAPD (1 episode/3.5 patient-months). We conclude that
      the use of intraperitoneal insulin in children with IDDM and ESRD leads to
      improved glycemic control. The rate of peritonitis, however, may be increased in
      these children.

PMID- 10649739
TI  - Growth posttransplantation in children previously treated with chronic dialysis
      and gastrostomy feeding.
AB  - Nasogastric and gastrostomy feeding are beneficial in providing nutritional
      support to children on chronic dialysis, but concerns have been raised about
      transfer to exclusive oral nutrition postrenal transplantation (TX). The present
      study reports the growth data and feeding outcomes in 14 children (9 male) who
      received combined dialysis [continuous cycling peritoneal dialysis (CCPD): n =
      12; hemodialysis (HD): n = 2] and gastrostomy button (GB) feeding for a mean
      duration of 15.6 months, and who were transplanted at a mean age of 5.4 years. In
      12 patients GB feeding was discontinued shortly after TX, and in 2 it was
      maintained for 3 and 8 months, respectively. No infective episodes were
      attributable to the GB post-TX, and the buttons were usually removed within 3
      months with the dialysis catheter. The mean height and weight standard deviation
      scores (SDS) were -2.44 and -2.29, respectively, prior to dialysis and GB
      feeding; -2.19 and -1.22, respectively, prior to TX; and had improved to -1.6 and
      -0.79, respectively, 12 months post-TX. The mean percentage weight-for-height at
      the time of TX was 105% (range: 86%-128%), and was unchanged 1 year post-TX. We
      conclude that GB feeding in this group of children resulted in few complications
      or feeding problems post-TX. The use of GB feeding without growth hormone
      maintained growth parameters in most children while on dialysis, and a
      significant improvement in growth occurred after the renal transplantation.

PMID- 10649741
TI  - Nursing contacts and outcomes in a pediatric CCPD program.
AB  - A specialist pediatric renal nursing service provides a link between hospital and
      home. Such support aims to reduce hospitalization and disruption to schooling and
      family routine. A 3-year prospective study monitored the progress and documented
      the nursing support to and contacts with 13 children (5 of whom were under 5
      years of age) who commenced continuous cycling peritoneal dialysis (CCPD). Mean
      duration of CCPD was 14 months. Home and clinic contacts included telephone calls
      (65% of contacts), home, school, nursery, respite care, and community visits.
      Nine families received respite care from a home-care pediatric renal nurse, with
      children under 5 years receiving 68% of such visits. A total of 388 inpatient
      days were recorded. These included admission for catheter and dialysis training
      (125 days). hypertension (83 days), dialysis-related admissions (66 days),
      peritonitis (43 days), vomiting (31 days), and surgical procedures and infections
      (40 days). Nine peritonitis episodes occurred in 8 children (incidence 1 per 20
      patient-months), and one death (cardiovascular collapse) occurred on CCPD. Seven
      children received a transplant, with the median waiting time for transplant being
      7 months (range: 3-14 months). This study documents the spectrum of nursing
      support we have evolved to support children on CCPD and their families in the
      hope of reducing morbidity and hospitalization.

PMID- 10649740
TI  - Mineral content of infant formula after treatment with sodium polystyrene
      sulfonate or calcium polystyrene sulfonate.
AB  - Options for the management of infants with hyperkalemia secondary to renal
      insufficiency are limited for infants not maintained on dialysis. Precipitation
      of potassium (K+) from infant formula with sodium polystyrene sulfonate (KX)
      prior to feeding has been reported. However, its effect on calcium (Ca2+) and
      sodium (Na+) has not been quantitatively defined. The purpose of this study was
      to examine the effects of two K+ exchange resins: KX and calcium polystyrene
      sulfonate (RC) on Na+, K+, and Ca2+. Infant formula powder (Similac PM 60/40,
      Ross Laboratories, Columbus, OH, USA) was prepared with deionized water (DW) and
      KX or RC (1 g/mEq of K+) was added. The formula was decanted after 50 minutes and
      Na+, K+, and Ca2+ were assayed in the supernatant. Na+ and K+ were also assayed
      in ready-to-feed PM 60/40 (RTF). KX decreased the K+ concentration by 4.5 fold (P
      < 0.001) and increased the Na+ content by 3.8 fold (P < 0.001). In RC there was a
      1.6-fold increase in Ca2+ content (P < 0.001), and a 13% decrease in K+
      concentrations (P < 0.05). Preparation of the formula with DW reduced the K+
      concentration by 30% compared to ready-to-feed formula (P < 0.001). We conclude
      that, although KX significantly reduces the K+ content of formulas, DW may be a
      more practical and convenient method of preparing formula for the hyperkalemic
      infant.

PMID- 10649742
TI  - Skies could get friendlier for animals.

PMID- 10649743
TI  - More on ear cropping and neutering.

PMID- 10649744
TI  - More on ear cropping and neutering.

PMID- 10649745
TI  - More on ear cropping and neutering.

PMID- 10649746
TI  - Setting the standards for internship programs.

PMID- 10649747
TI  - Research collaborations on rinderpest.

PMID- 10649748
TI  - What is your diagnosis? Sequestered bone with crystalline deposits between bony
      trabeculae.

PMID- 10649749
TI  - Theriogenology question of the month. Agarose gel immunodiffusion (AGID)
      serologic testing for brucellosis.

PMID- 10649750
TI  - Employment of male and female graduates of US veterinary medical colleges, 1999.

PMID- 10649751
TI  - Decision-based evaluation of recommendations for preexposure rabies vaccination.

PMID- 10649752
TI  - Correlation between age at neutering and age at onset of hyperadrenocorticism in
      ferrets.
AB  - OBJECTIVE: To determine prevalence of hyperadrenocorticism in ferrets in The
      Netherlands and evaluate age, sex, and age at neutering in affected ferrets.
      DESIGN: Prevalence survey and retrospective study. ANIMALS: 50 ferrets with
      hyperadrenocorticism and 1,267 ferrets without hyperadrenocorticism. PROCEDURE: A
      questionnaire was sent to 1,400 members of a ferret-owners organization in The
      Netherlands; 492 (35%) owners returned the questionnaire, providing usable data
      on 1,274 ferrets. Seven of these ferrets developed hyperadrenocorticism during
      the survey period; medical records for these ferrets and 43 ferrets with
      confirmed hyperadrenocorticism were reviewed. Hyperadrenocorticism was confirmed
      by histologic examination of an excised adrenal gland (92% of ferrets) or
      clinical improvement after excision. RESULTS: Prevalence of hyperadrenocorticism
      in the survey population was 0.55%. Sex was not associated with prevalence of
      disease. Median time interval between neutering and diagnosis of
      hyperadrenocorticism was 3.5 years. A significant linear correlation between age
      at neutering and age at time of diagnosis was detected. CONCLUSIONS AND CLINICAL
      RELEVANCE: Age at neutering may be associated with age at development of
      hyperadrenocorticism in ferrets.

PMID- 10649753
TI  - Assessment of five portable blood glucose meters, a point-of-care analyzer, and
      color test strips for measuring blood glucose concentration in dogs.
AB  - OBJECTIVE: To compare blood glucose concentrations obtained using a point-of-care
      (POC) analyzer, 5 portable blood glucose meters (PBGM), and a color reagent test
      strip with concentrations obtained using a reference method, and to compare
      glucose concentrations obtained using fresh blood samples in the PBGM with
      concentrations obtained using blood anticoagulated with lithium heparin. DESIGN:
      Case series. SAMPLE POPULATION: 110 blood samples from 34 dogs; glucose
      concentration of the samples ranged from 41 to 596 mg/dl. PROCEDURE: Logistic
      regression was used to compare blood glucose concentrations obtained with the
      various devices with reference method concentrations. Ease of use was evaluated
      subjectively. Percentage of times a clinical decision would have been altered if
      results of each of these methods had been used, rather than results of the
      reference method, was calculated. RESULTS: For 3 of the PBGM, blood glucose
      concentrations obtained with fresh blood were not significantly different from
      concentrations obtained with blood samples anticoagulated with lithium heparin.
      None of the devices provided results statistically equivalent to results of the
      reference method, but the POC analyzer was more accurate than the others. For
      some samples, reliance on results of the PBGM or the color test strip would have
      resulted in erroneous clinical decisions. CONCLUSIONS AND CLINICAL RELEVANCE:
      Although commercially available PBGM and color test strips provided blood glucose
      concentrations reasonably close to those obtained with reference methods, some
      devices were more accurate than others. Use of results from these devices could
      lead to erroneous clinical decisions in some cases.

PMID- 10649754
TI  - Evaluation of five portable blood glucose meters for use in dogs.
AB  - OBJECTIVE: To evaluate clinical and analytical accuracy of 5 portable blood
      glucose meters (PBGM) used to measure blood glucose concentrations in dogs and to
      determine potential sources of error. DESIGN: Prospective study. ANIMALS: 221
      dogs. PROCEDURE: Venous blood samples were obtained, and results of the 5 PBGM
      were compared with results of a hexokinase reference method. Agreement among
      methods was determined by use of error grid analysis and statistical methods.
      RESULTS: Accuracy of the PBGM varied with glucose concentration of the sample.
      The largest differences between results of the PBGM and results of the reference
      method were obtained with samples with high glucose concentrations; 4 PBGM tended
      to underestimate and 1 PBGM tended to overestimate the true glucose
      concentration. Absolute differences between results of the PBGM and results of
      the reference method were small for samples with low glucose concentrations and
      samples with concentrations in the reference range. None of the PBGM yielded
      measurements that would result in clinically unacceptable errors. Within-run and
      between-day precision was good for all PBGM, and results were not affected by use
      of EDTA or heparin to anticoagulate blood. Readings of the PBGM were
      significantly higher for blood samples with low Hct than for samples with normal
      Hct. For 3 PBGM, samples < 3 microliters resulted in inaccurate measurements.
      CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that currently available PBGM
      are sufficiently accurate for use in clinical practice to determine blood glucose
      concentrations in dogs.

PMID- 10649755
TI  - Vertebral scale system to measure heart size in radiographs of cats.
AB  - OBJECTIVE: To determine absolute and relative heart size in clinically normal
      cats by correlating heart size and selected skeletal structures. DESIGN:
      Prospective radiographic study. ANIMALS: 100 cats that did not have thoracic
      radiographic abnormalities. PROCEDURE: Standardized measurements of the long and
      short axes of the heart, midthoracic vertebrae, and other structures were made.
      Measurements were recorded in millimeters and number of thoracic vertebral
      lengths spanned by each dimension, measured caudally from T4 in a lateral
      radiograph. The long- and short-axis measurements of the heart, expressed in
      vertebral lengths, were added to yield vertebral heart size. RESULTS: Mean +/- SD
      vertebral heart size in lateral radiographs was 7.5 +/- 0.3 vertebrae. The long
      axis dimension correlated with the length of 3 sternebrae, measured from S2 to
      S4. The cardiac short-axis dimension correlated moderately with the length of 3.2
      vertebrae, measured from T4 to T6. The cardiac short-axis dimension in
      ventrodorsal radiographs was 3.4 +/- 0.25 vertebrae. CONCLUSIONS AND CLINICAL
      RELEVANCE: The vertebral heart-size method is easy to use, allows objective
      assessment of heart size, and may be helpful in determining cardiomegaly and
      comparing heart size in sequential radiographs.

PMID- 10649756
TI  - Use of doramectin for treatment of notoedric mange in five cats.
AB  - Five of 16 cats belonging to the same owner were brought to the veterinary
      hospital because of a 30-day history of signs of intense pruritus and alopecic
      and erythematous areas with bloody crusts. Notoedric mange was diagnosed and
      confirmed by microscopic examination of skin scrapings of all 5 cats. The
      remaining cats did not have clinical signs of mange, and Notoedres cati were not
      observed after microscopic examination of skin scrapings. A decision was made to
      treat all 16 cats with doramectin subcutaneously. In each cat, 0.1 ml of a 1%
      solution of doramectin was administered s.c. Body weights ranged from 2.9 to 7.1
      kg (6.4 to 14.2 lb) in the 16 cats and the final doses varied from 143 to 345
      micrograms/kg (65 to 157 micrograms/lb) of body weight, with a mean (+/- SD) of
      270.4 +/- 64 micrograms/kg (122.9 +/- 29.1 micrograms/lb). The mean dose for the
      5 affected cats was 292.2 +/- 44.8 micrograms/kg (132.8 +/- 20.4 micrograms/lb),
      with a range of 208 to 333 micrograms/kg (94.6 to 151.4 micrograms/lb). Lesions
      began to recede 1 week after treatment. Fifteen days after treatment, all 5
      affected cats were clinically normal. Findings in our cats suggest that a single
      mean dose of doramectin of approximately 290 micrograms/kg is sufficient to
      control notoedric mange in cats.

PMID- 10649757
TI  - Effect of insulin dosage on glycemic response in dogs with diabetes mellitus: 221
      cases (1993-1998).
AB  - OBJECTIVE: To evaluate glycemic response to insulin treatment in dogs with
      diabetes mellitus. DESIGN: Retrospective study. ANIMALS: 221 dogs with diabetes
      mellitus. PROCEDURE: Type and dosage of insulin used, minimum and maximum blood
      glucose concentrations, time of blood glucose concentration nadir, and optimal
      duration of action of insulin were determined on the basis of data obtained prior
      to initial examination at the teaching hospital (127 dogs), at the time of
      initial examination (212 dogs), at the time a second follow-up blood glucose
      curve was performed (59 dogs), and at the time of clinical control of diabetes
      mellitus (83 dogs). RESULTS: Prior to examination, 69 of 127 dogs (54%) received
      1 s.c. insulin injection daily. Thirty-one dogs (24%) received a high dose of
      insulin (i.e., > 1.5 U/kg [0.7 U/lb] of body weight); 27 of these dogs (87%)
      received 1 injection/d. Eleven of 16 dogs (69%) that were hypoglycemic (blood
      glucose concentration < 80 mg/dl) also received 1 injection/d. However, optimal
      duration of action of insulin was > 12 hours in only 5 of 83 dogs (6%) evaluated
      at the time diabetes mellitus was clinically controlled. At that time, only 1 dog
      (1%) received a high dose of insulin, and the dog received 2 injections/d.
      Moreover, 8 of 10 dogs (80%) with hypoglycemia received 1 injection/d.
      CONCLUSIONS AND CLINICAL RELEVANCE: Most dogs with diabetes mellitus are
      clinically regulated with 2 daily insulin injections. Administration of a high
      dose of insulin or development of hypoglycemia may be more common in diabetic
      dogs that receive insulin once daily, compared with dogs that receive insulin
      twice daily.

PMID- 10649758
TI  - Visceral mast cell tumors in dogs: 10 cases (1982-1997).
AB  - OBJECTIVE: To characterize the clinical features of visceral mast cell tumors
      (MCT) without associated cutaneous involvement in dogs. DESIGN: Retrospective
      study. ANIMALS: 10 dogs with histologically confirmed MCT without associated
      cutaneous lesions. PROCEDURE: Information on signalment, clinical signs,
      laboratory examinations, and time from first admission to death was obtained from
      the medical record of each dog. RESULTS: Purebred male dogs of miniature breeds
      appeared to have a higher prevalence of visceral MCT. Clinical signs included
      anorexia, lethargy, vomiting, and diarrhea. Anemia (n = 7), hypoproteinemia (5),
      and mastocythemia (5) were detected. Treatments, including glucocorticoids, were
      not successful. Primary sites of tumors were the gastrointestinal tract (n = 6)
      and the spleen or liver (1); the primary site was not confirmed in the remaining
      3 dogs. In 7 dogs, tumors were categorized as grade II or III, on the basis of
      histologic findings. The prognoses were poor, and all dogs died within 2 months
      after first admission. CONCLUSIONS AND CLINICAL RELEVANCE: Visceral MCT is
      uncommon in dogs, and the prognosis is extremely poor. Biological behavior and
      drug susceptibility of visceral MCT may be different from cutaneous MCT. The lack
      of specific clinical signs may result in delay of a definitive diagnosis. The
      rapid progression of clinical signs and difficulty in diagnosis contributes to a
      short survival time.

PMID- 10649760
TI  - Idiopathic hemorrhagic vasculopathy syndrome in seven black rhinoceros.
AB  - Idiopathic hemorrhagic vasculopathy syndrome (IHVS) was diagnosed in 7 black
      rhinoceros; this newly described syndrome is characterized by severe body
      swelling in conjunction with a rapid and profound decrease in Hct. The disorder
      may be acute or chronic, may recur, and is potentially fatal. Five of the
      rhinoceros survived an initial episode of IHVS, and 2 of these 5 survived a
      recurrent episode of IHVS. Two rhinoceros died during treatment of IHVS.
      Treatment protocols varied, but all 7 rhinoceros received broad-spectrum
      antibiotics, because an infectious cause was suspected. All rhinoceros also
      received nonsteroidal antiinflammatory drugs and supportive care. Idiopathic
      hemorrhagic vasculopathy syndrome has many similarities to other vasculopathies
      of domestic animals, such as equine purpura hemorrhagica, but it also appears to
      have unique identifying features. It has been hypothesized that IHVS may be an
      immune response to an as yet unidentified infectious agent. Thorough and
      extensive testing has not identified the potential causative agent, nor the
      factors that predispose some black rhinoceros to developing IHVS. Further
      research into the rhinoceros immune system is ongoing and should help elucidate
      the mechanisms through which IHVS develops.

PMID- 10649759
TI  - Suspected tolazoline toxicosis in a llama.
AB  - Clinical signs of tolazoline toxicosis developed in a 4-year-old llama that
      received 2 doses of tolazoline hydrochloride to reverse xylazine-induced
      sedation. The full first dose (4.3 mg/kg [2.0 mg/lb] of body weight) was
      erroneously injected i.v., and the second dose was administered half i.v., half
      i.m. 45 minutes later, because the llama became weak and recumbent. Signs of
      anxiety, hyperesthesia, profuse salivation, and tachypnea were the first
      detectable clinical signs of tolazoline toxicosis. Convulsions, hypotension,
      gastrointestinal tract hypermotility, and diarrhea also developed. The llama was
      treated successfully with i.v. administration of diazepam, phenylephrine, and
      lactated Ringer's solution supplemented with potassium chloride and oxygen
      administered via nasal insufflation. We suggest that the maximum dose of
      tolazoline administered at any one time to llamas not exceed 2 mg/kg (0.91
      mg/lb). Furthermore, tolazoline should be administered slowly i.v. or i.m. to
      reduce the risk of adverse reactions.

PMID- 10649761
TI  - MS-IRS PCR: a simple method for the isolation of microsatellites.

PMID- 10649762
TI  - Denaturing gradient gel electrophoresis resolves virus sequences amplified with
      degenerate primers.

PMID- 10649763
TI  - Improved determination method for plasmid copy number using pulsed field gel
      electrophoresis.

PMID- 10649764
TI  - Elimination of dumbbell bands and enhancement of resolution in MADGE using
      delayed start electrophoresis.

PMID- 10649765
TI  - Electrophoresis of unlabeled proteins in a sequencing gel apparatus.

PMID- 10649766
TI  - Rapid histone extraction for electrophoretic analysis.

PMID- 10649767
TI  - Construction of a rotisserie hybridization apparatus.

PMID- 10649768
TI  - Comparison of DNA polymerases for quantification of single nucleotide differences
      by primer extension assays.

PMID- 10649769
TI  - Optimized RAPD analysis generates high-quality genomic DNA profiles at high
      annealing temperature.

PMID- 10649770
TI  - Improved analysis of promoter activity in biolistically transformed plant cells.

PMID- 10649771
TI  - UV absorbance measurements of DNA in microplates.

PMID- 10649772
TI  - Improved purification of the double-stranded RNA from killer strains of yeast.

PMID- 10649773
TI  - Biology job resources on the Internet.

PMID- 10649774
TI  - Detection of eukaryotic cDNA in differential display is enhanced by the addition
      of E. coli RNA.
AB  - We describe a method to enhance the sensitivity of eukaryotic cDNA detection in
      differential display (DD). Typically, DD protocols require between 200 and 500 ng
      RNA for each reverse transcription reaction. The addition of Escherichia coli RNA
      before reverse transcription of eukaryotic RNA increases the detection of DD
      patterns more than tenfold. The method broadens the applicability of DD and
      allows the identification of genes that are differentially expressed when the
      amount of eukaryotic RNA is limited.

PMID- 10649776
TI  - Novel kanamycin/neomycin phosphotransferase cassette increases transformation
      efficiency in E. coli.
AB  - Stable transformation depends on the efficient delivery of DNA into cells and the
      robust expression of genes that encode proteins which provide resistance to
      selective (cytotoxic) compounds. We have examined the possibility that altering
      the 5'untranslated region (UTR) of a selectable marker may increase
      transformation efficiency. A 15-nucleotide synthetic UTR (the so-called universal
      translational enhancer [UTE]) was placed upstream of a kanamycin/neomycin
      phosphotransferase (kanaR) gene to create a novel expression cassette, UTE-kanaR.
      In comparison to a wild-type version of kanaR, UTE-kanaR produced up to 30-fold
      more transformants in E. coli. The superior performance of UTE-kanaR was
      independent of the promoter strength, indicating that the gene may find general
      use in routine transformation experiments.

PMID- 10649775
TI  - Green fluorescent protein as a quantitative reporter of relative promoter
      activity in E. coli.
AB  - Green fluorescent protein (GFP) has become a valuable tool for the detection of
      gene expression in prokaryotes and eukaryotes. To evaluate its potential for
      quantitation of relative promoter activity in E. coli, we have compared GFP with
      the commonly used reporter gene lacZ, encoding beta-galactosidase. We cloned a
      series of previously characterized synthetic E. coli promoters into GFP and beta
      galactosidase reporter vectors. Qualitative and quantitative assessments of these
      constructs show that (a) both reporters display similar sensitivities in cells
      grown on solid or liquid media and (b) GFP is especially well suited for
      quantitation of promoter activity in cells grown on agar. Thus, GFP provides a
      simple, rapid and sensitive tool for measuring relative promoter activity in
      intact E. coli cells.

PMID- 10649777
TI  - Localized electroporation: a method for targeting expression of genes in avian
      embryos.
AB  - Avian embryos are a popular model for cell and developmental biologists. However,
      analysis of gene function in living embryos has been hampered by difficulties in
      targeting the expression of exogenous genes. We have developed a method for
      localized electroporation that overcomes some of the limitations of current
      techniques. We use a double-barreled suction electrode, backfilled with a
      solution containing a plasmid-encoding green fluorescent protein (GFP) and a
      neurophysiological stimulator to electroporate small populations of cells in
      living embryos. As many as 600 cells express GFP 24-48 h after electroporation.
      The number of cells that express GFP depends on the number of trains, the pulse
      frequency and the voltage. Surface epithelial cells and cells deep to the point
      of electroporation express GFP. No deformities result from electroporations, and
      neurons, neural crest, head mesenchyme, lens and otic placode cells have been
      transfected. This method overcomes some of the disadvantages of viral techniques,
      lipofection and in vivo electroporation. The method will be useful to biologists
      interested in tracing cell lineage or making genetic mosaic avian embryos.

PMID- 10649779
TI  - High-throughput method for isolating plasmid DNA with reduced lipopolysaccharide
      content.
AB  - Isolating plasmid DNA from bacteria is a fundamental step in molecular biology.
      It is often accomplished by an alkaline lysis of bacteria and the subsequent
      adsorption of nucleic acids to silica oxide in the presence of chaotropic
      substances. Here we show that the addition of such chaotropic reagents is not
      required for the efficient DNA isolation with silica oxide. This surprising
      finding allowed us to purify plasmid DNA with significantly less
      lipopolysaccharides (LPS), which is otherwise a common bacterial contaminant of
      silica oxide-isolated DNA and inhibits subsequent applications. In addition, we
      have implemented a precipitation step that altogether leads to a reduction of the
      LPS content by a factor of 900 relative to published methods. Our novel protocol
      facilitates an inexpensive high-throughput analysis of pure plasmids in a 96-well
      format without the addition of hazardous reagents.

PMID- 10649778
TI  - Fifty-one kilobase HSV-1 plasmid vector can be packaged using a helper virus-free
      system and supports expression in the rat brain.
AB  - Herpes simplex virus type 1 (HSV-1) plasmid vectors have a number of attractive
      features for gene transfer into neurons. In particular, the large size of the HSV
      1 genome suggests that HSV-1 vectors might be designed to accommodate large
      inserts. We now report the construction and characterization of a 51 kb HSV-1
      plasmid vector. This vector was efficiently packaged into HSV-1 particles using a
      helper virus-free packaging system. The structure of the packaged vector DNA was
      verified by both Southern blot and PCR analyses. A vector stock was microinjected
      into the rat striatum, the rats were sacrificed at 4 days after gene transfer,
      and numerous X-gal positive striatal cells were observed. This 51 kb vector was
      constructed using general principles that may support the routine construction of
      large vectors. Potential applications of such HSV-1 vectors include
      characterizing large promoter fragments or genomic clones and co-expressing
      multiple genes.

PMID- 10649780
TI  - Chloroplast DNA extraction from herbaceous and woody plants for direct
      restriction fragment length polymorphism analysis.
AB  - The technique described here is a fast and simple method of extracting
      chloroplast DNA (cpDNA). It overcomes the need for differential centrifugation
      using density gradients. The leaves do not have to be kept in the dark and
      lyophilized before extraction, but lyophilization is still possible. The
      chloroplasts are specifically lysed in a cell extract of leaves, using a non
      ionic detergent. After isolation by centrifugation, the cpDNA is purified by the
      combined action of proteolytic enzymes and detergents, followed by the
      elimination of proteins using a mixture of chloroform and isoamyl alcohol. This
      method provided good quality restriction profiles for all species analyzed.

PMID- 10649781
TI  - Use of haploid mixtures and heteroduplex analysis enhance polymorphisms revealed
      by denaturing gradient gel electrophoresis.
AB  - PCR-based codominant genetic markers were developed by using primer sequences
      designed from cDNA clones of loblolly pine (Pinus taeda L.). Such markers offer
      certain advantages relative to simple-sequence repeat (SSR), also known as short
      tandem repeat (STR) markers, and include the ability to quantify and map DNA
      polymorphisms in expressed genes. However, detecting these DNA polymorphisms is
      more problematic because many DNA polymorphisms in genes involve base
      substitutions rather than insertions or deletions. Denaturing gradient gel
      electrophoresis (DGGE) is a sensitive and efficient method for detecting sequence
      differences among PCR fragments. This paper demonstrates the application of DGGE
      to genetically map expressed genes in loblolly pine. Also, heteroduplex DNA
      fragments, formed during the amplification of DNA from heterozygotes and from
      mixes of haploid DNAs from megagametophytes, enhanced and strengthened genetic
      interpretations and genotypic classifications.

PMID- 10649783
TI  - Method to reduce the volatility of radioactive iodine waste.

PMID- 10649782
TI  - Cloning trap for signal peptide sequences.
AB  - Novel secreted and/or type I transmembrane proteins containing N-terminal signal
      sequences have been successfully cloned using the signal sequence trapping (SST)
      method. Often this involves random cloning of short 5' cDNA terminal ends into an
      epitope-tagged expression vector and the detection of expressed recombinant
      proteins on the cell surfaces of transfected cells with an antibody to the tagged
      epitope. Here, we report a novel cloning system for the detection of secreted
      proteins also using SST. In this method, we used the human immunodeficiency virus
      (HIV-1) p24 as the epitope for tagging. To test the system, two constructs were
      created. The 5' terminal end of a human beta-chemokine (which was regulated upon
      activation, expressed by normal T cells and presumably secreted [RANTES]) and the
      5' end of a human CD4 receptor were cloned upstream of and in-frame with the p24
      cDNA. Secreted p24 was detectable in the culture media two days after
      transfection of either DNA construct into the human cell lines, HeLa and 293T.
      When the chimeric p24 expression constructs were transfected at a ratio of 1:100
      to the vector pcDNA3.1(+), p24 could still be detected in cell supernatants. The
      use of a secreted viral antigen like HIV-1 p24 (or of any noncellular protein) as
      a marker in SST cloning approaches is likely to be advantageous because it
      reduces the background noise in detection and also renders this system suitable
      for high-throughput screening.

PMID- 10649784
TI  - Mutation screening using automated bidirectional dideoxy fingerprinting.
AB  - The need continues to grow for mutation identification in genetic disease in both
      research and clinical settings. We have developed a rapid nonradioactive
      bidirectional dideoxy fingerprint mutation screening procedure that is performed
      using an automated DNA analyzer. This technique features standardized primers and
      easily interpreted results from separate, but simultaneously collected, images
      for coding and noncoding strands. Another advantage is simplified mutation
      verification by sequencing using the same amplified DNA templates and also
      application to large multi-exon genes. We demonstrate the efficiency and
      reproducibility of the method in which we screen a DNA fragment encompassing exon
      5 of the PTCH gene (in which mutations cause Gorlin Syndrome) in a panel of 22
      patients.

PMID- 10649786
TI  - Use of flow cytometry to rapidly optimize the transfection of animal cells.
AB  - Plasmid transfection is the first step in the generation of stably transformed
      animal cells and is also a useful tool for analyzing transient gene expression.
      Maximizing the transfection efficiency and expression level from the introduced
      plasmid is critical to the success of these processes. By means of lipid-mediated
      transfection, a plasmid vector expressing the green fluorescence reporter protein
      has been coupled with flow cytometry to conveniently investigate those parameters
      that impact the efficacy of transfection of lepidopteran insect cells. The key
      feature of this technique is the rapid and simultaneous quantification of
      transfection efficiency and heterologous protein expression level per cell. Using
      this technique, we developed an optimized transfection protocol for insect cells
      by investigating the following parameters: lipid incubation time, lipid/DNA
      mixture incubation time, lipid and DNA concentration, incubation vessel and
      transfection duration. Following optimization, transfection efficiencies of 37%
      40% were obtained for Bombyx mori Bm5 and Spodoptera frugiperda Sf-21 cells.

PMID- 10649787
TI  - Identification of proteins in cell-free extracts using liquid chromatography
      electrospray ionization mass spectrometry.
AB  - A rapid method for the identification and characterization of proteins in
      bacterial cell-free extracts has been developed using directly combined liquid
      chromatography-electrospray mass spectrometry. The usefulness of this technique
      is demonstrated for monitoring the expression and chemical modification of
      phosphoenolpyruvate-sugar phosphotransferase system (PTS) proteins from E. coli
      with molecular masses ranging from 9-65 kDa. The technique is characterized by
      minimal sample preparation, remarkable mass accuracy and resolution,
      reproducibility and the ability, unlike gel electrophoresis, to directly identify
      posttranslational modifications. The advantages of this technique over analogous
      matrix-assisted laser desorption ionization mass spectrometry approaches and its
      potential as a standard tool in the biomolecular research laboratory are
      discussed.

PMID- 10649785
TI  - Analysis of the p53 tumor suppressor gene by pyrosequencing.
AB  - Tumor suppressor genes are implicated in cell cycle progression. Inactivation of
      these genes predominantly occurs through mutations and/or allelic loss that
      involves both alleles. With inactivation by multiple mutations in a single gene,
      cloning of the amplified gene is necessary to determine whether the mutations
      reside on one or both alleles. Using pyrosequencing, a recently developed
      approach based on sequencing-by-synthesis, we studied genetic variability in the
      p53 tumor suppressor gene and could quantify the ratio between the mutated and
      wild-type amplified fragments. Furthermore, this sequencing technique also allows
      allelic determination of adjacent mutations with no cloning of amplified
      fragments.

PMID- 10649788
TI  - Mab-ZAP: a tool for evaluating antibody efficacy for use in an immunotoxin.
AB  - Immunotoxins, consisting of antibodies coupled to toxins, are extremely useful
      tools in the elimination of specific cell populations in vitro and in vivo for
      research and therapeutic applications. The antibody is used to target the toxin
      to a specific cell population, which is distinguished by its cell-surface
      antigen. Not all antibodies are suitable for creating an immunotoxin, and large
      numbers of antibodies may need to be screened. This is a time-consuming and
      expensive process if each potential candidate must be conjugated to the toxin and
      purified. A faster and more economical way to identify potential targeting
      antibodies is to use a second immunotoxin, an anti-IgG antibody that is coupled
      to the toxin. The second immunotoxin eliminates the need to couple every
      candidate antibody to the toxin because it can simply be added to cells in
      culture with the antibody of interest. Using this method, many antibodies can be
      screened quickly and efficiently for their ability to internalize.

PMID- 10649789
TI  - Macrocephaly--cutis marmorata telangiectatica congenita: report of five patients
      and a review of the literature.
AB  - Cutis marmorata telangiectatica congenita (CMTC) is a cutaneous disorder often
      accompanied by additional anomalies, most commonly segmental overgrowth. Recently
      a clinically discrete condition has been described comprising CMTC and congenital
      macrocephaly together with pre- and post-natal macrosomia, segmental overgrowth,
      central nervous system malformations, connective tissue abnormalities and
      intellectual handicap. We describe the natural history of macrocephaly-CMTC (M
      CMTC) syndrome in a further five patients including the oldest reported patient,
      a 22 year old. The addition of our five patients brings the total number of
      reported patients to 28 and now makes it possible to more accurately delineate
      the phenotype and the frequency of clinical manifestations. We add some further
      clinical associations to those previously described, including anomalies of the
      growth of hair and teeth, neuronal migration defects, dislocated hips and
      stridor. We discuss potential genetic mechanisms that might account for the
      pleiotropic manifestations of this apparently rare segmental overgrowth disorder.

PMID- 10649791
TI  - New autosomal dominant syndrome reminiscent of Coffin-Siris syndrome and
      Brachymorphism-Onychodysplasia-Dysphalangism syndrome.
AB  - We report a man and his two daughters (one stillborn) with an apparently unique
      constellation of anomalies including fifth finger/toe terminal phalanx and nail
      hypoplasia. The craniofacial manifestations include large boxy head, round face,
      hypertelorism with downslanting palpebral fissures and wide mouth. Other
      manifestations include brachydactyly, fifth finger clinodactyly and ventricular
      septal defect. Intelligence is normal. The resemblance to Coffin-Siris,
      Brachymorphism-Onychodysplasia-Dysphalangism and DOOR syndromes is discussed and
      we concluded that this family probably represents a new autosomal dominant
      syndrome.

PMID- 10649790
TI  - Severe microcephaly, choreiform movements, cataracts and sensorineural deafness
      in two patients: a new syndrome?
AB  - Two unrelated male patients are described with severe microcephaly, early-onset
      choreiform movements, cataracts, sensorineural deafness and profound
      developmental delay. Our patients have much in common with the three male
      siblings described by Tomiwa et al., who also had cataracts, deafness and
      developmental delay, but much less severe microcephaly and a different type of
      movement disorder with later onset [Tomiwa K et al. (1987). Neuropediatrics
      18:231-234]. An extensive literature search did not reveal any other reports of
      patients with a similar condition. We discuss the differential diagnosis.

PMID- 10649792
TI  - Two brothers with Hennekam syndrome and cerebral abnormalities.
AB  - We report two brothers with mental retardation, lymphoedema of the limbs and
      facial anomalies. Hennekam et al. (Am J Med Genet 34:593-600; 1989) described
      four patients with identical signs and intestinal lymphangiectasia. To confirm
      the diagnosis of Hennekam syndrome we undertook a duodenal biopsy from the older
      brother which revealed intestinal lymphangiectasia. So far only one patient with
      Hennekam syndrome and cerebral abnormalities has been described. This patient
      presented with pachygyria in the parietal area. Cerebral MRI in our two cases
      revealed small subcortical hyperintensities in both patients and a large cystic
      lesion in the younger patient probably representing an old media infarction.

PMID- 10649793
TI  - Wolf-Hirschhorn syndrome (WHS): a history in pictures.
AB  - The Wolf-Hirschhorn syndrome (WHS) is a well known chromosomal disorder, due to a
      deletion of distal chromosome 4p. The classical gestalt is striking and poses few
      diagnostic problems. However, due to the difficulty of detecting very small
      deletions by standard cytogenetics, diagnosis can be sometimes very difficult,
      particularly in older patients. In this paper we show the changes, occurring over
      time, in facial appearance of affected individuals, to improve insight into the
      evolution of the phenotype, and to increase its diagnostic potential.

PMID- 10649795
TI  - Dandy-Walker anomaly in Meckel-Gruber syndrome.
AB  - We report a fetus affected by Meckel-Gruber syndrome whose phenotype was
      characterized by macrocephaly, frontal bossing, a saddle nose, marked
      micrognathia, a distended abdomen, omphalocele, post-axial polydactyly and
      talipes equinovarus. The main neuropathological finding at autopsy was in a very
      large cyst located in an abnormally wide posterior cranial fossa consistent with
      a Dandy-Walker anomaly. Intestinal malrotation, enlarged cystic dysplastic
      kidneys and hepatic portal fibrosis coexisted. The occurrence of a Dandy-Walker
      malformation in Meckel-Gruber syndrome confirms a disturbance in rhombencephalon
      development. Although uncommon, it should be included among the central nervous
      anomalies representative of the syndrome.

PMID- 10649794
TI  - MURCS association with encephalocele: report of a second case.
AB  - We report a female fetus with occipital encephalocele, dysraphism of the cervical
      spine, right renal agenesis and Mullerian agenesis. Additional findings included
      posterior cleft palate, absent left umbilical artery and Meckel's diverticulum.
      This fetus had the features of MURCS association with occipital encephalocele.
      This is the second report of encephalocele with MURCS association.

PMID- 10649796
TI  - New clinical findings in oculo-ectodermal syndrome.
AB  - We report a 2-year-old male with aplasia cutis congenita of the scalp, epibulbar
      dermoids, strabismus and macrocephaly. In our opinion, he is affected by the
      Oculo-Ectodermal syndrome first described by Toriello et al. (1993). Am J Med
      Genet 45:764-766]. This is the sixth report of patients with this rare entity.
      Our case further expands the clinical spectrum of the syndrome to include mental
      retardation, seizures and microscopic hair changes.

PMID- 10649797
TI  - High myopia, and mild mental retardation in three brothers.
AB  - We describe three of a sibship of four brothers with high myopia and mild mental
      retardation but clinically normal parents. On review of the literature, there
      appear to be no reports of high myopia and mild mental retardation. We discuss
      whether this is a distinct entity.

PMID- 10649798
TI  - Interstitial deletion of the long arm of chromosome 2: a clinically recognizable
      microdeletion syndrome?
AB  - We report on a boy with an interstitial deletion of the long arm of chromosome 2
      with breakpoints in chromosome bands q23 and q24.3. Main features were low-set
      and malformed ears, digital anomalies and congenital heart defects, which have
      also been reported in most of the previously described cases. A comparison of the
      features of the present patient with those in previously reported cases suggests
      the deletion 2q23q24 to be a clinically recognizable syndrome.

PMID- 10649799
TI  - Characterization of a de novo partial trisomy 22q13-qter in a patient by
      microFISH.
AB  - Chromosomal microdissection and subsequent application of the generated probe for
      FISH (microFISH) allowed the characterization of a small extra band found by
      routine cytogenetic analysis on the short arm of chromosome 19 in a mentally
      retarded boy with various dysmorphic features. There is no cytogenetically
      visible loss of chromosome 19 material as verified by hybridization results using
      a subtelomeric probe for this region and therefore all anomalies found in the
      patient are most likely due to the partial trisomy of 22q13-qter. The approach
      used in this study should be generally applicable in comparable cases and allows
      a fast and straightforward identification of the origin of extra chromosomal
      material, which otherwise is very laborious or difficult to characterize.
      Clinical features of this 9-year-old patient such as mental and motor
      retardation, microcephaly, microphthalmia and hypogenitalism are compared with
      other cases showing this rare chromosomal aberration.

PMID- 10649800
TI  - Frontonasal dysplasia, macroblepharon, eyelid colobomas, ear anomalies,
      macrostomia, mental retardation, and CNS structural anomalies: another
      observation.
AB  - We report a Japanese girl with brachycephaly, a wide forehead, hypertelorism,
      macroblepharon with eyelid colobomas, ectropion, a broad nasal root, a depressed
      nasal tip, macrostomia, a small and grooved chin, ear anomalies, a structural
      anomaly of the corpus callosum, dilatation of the fourth ventricle, a urogenital
      sinus, and mental retardation. Cause and inheritance are unknown.

PMID- 10649801
TI  - Craniofacial anomalies, ocular findings, pigmented nevi, camptodactyly, and
      skeletal changes: a possible new autosomal recessive disorder.
AB  - A 20-year-old male is described with craniofacial anomalies, ocular findings,
      pigmented nevi, camptodactyly and skeletal changes. On the basis of the clinical
      and radiological differences with syndromes previously described we classify the
      present case as a new faciothoracoskeletal syndrome. Parental consanguinity
      supports autosomal recessive inheritance.

PMID- 10649802
TI  - Obesity and WAGR syndrome.
AB  - We describe a 15-year-old boy with WAGR syndrome and obesity and suggest that
      obesity should be added to the WAGR spectrum. It is also suggested that a
      putative gene for obesity might be located within the 11p13 band.

PMID- 10649803
TI  - A 68-year-old white female with Prader-Willi syndrome.
AB  - A 68-year-old white female with Prader-Willi syndrome is described. The clinical
      features are described and the progression of her condition is discussed and
      illustrated.

PMID- 10649805
TI  - Association of amelia and anal atresia is separate from VACTERL association.
AB  - Amelia and anal atresia with kidney agenesis and/or heart defects is discussed
      together with the hypotheses that this may either be the severest manifestation
      of VACTERL association or a separate association.

PMID- 10649804
TI  - Kallmann syndrome (hypogonadotropism-anosmia) and Klippel-Feil anomaly in the
      same patient.
AB  - A 27-year-old female is described with Kallman syndrome and Klippel-Feil anomaly.
      This is thought to be the first report of the coexistence of these two conditions
      in the same patient.

PMID- 10649806
TI  - Axial mesodermal dysplasia complex: a new case with parental consanguinity.
AB  - A female is described with axial mesodermal dysplasia complex (AMDC) born to a
      consanguineous couple. This is thought to be the first description of a patient
      with AMDC born to consanguineous parents.

PMID- 10649807
TI  - Radioulnar synostosis and XYY syndrome.
AB  - Radioulnar synostosis in a boy with XYY syndrome is discussed. Only four other
      cases of radioulnar synostosis with XYY syndrome have been reported in the
      literature.

PMID- 10649808
TI  - Limitations of the medical evaluation for child sexual abuse.
AB  - The purpose of this review is to highlight the inherent difficulties that a
      clinician faces during the evaluation of child sexual abuse cases. Each component
      of the medical evaluation has its own unique problems. Some of them are caused by
      the nature of the abusive relationship, while others are the result of the
      children's limited verbal skills. Readers should be aware of these limitations as
      they formulate an opinion at the conclusion of the examination.

PMID- 10649809
TI  - Impact of nafarelin and leuprolide for endometriosis on quality of life and
      subjective clinical measures.
AB  - OBJECTIVE: To examine the impact of treating endometriosis with nafarelin or
      leuprolide acetate depot on patient quality of life (QOL) and subjective clinical
      measures. STUDY DESIGN: A randomized, multicenter study was conducted on 192
      women with endometriosis. Patients received nafarelin or leuprolide for six
      months and were followed for up to six months after treatment. QOL was defined by
      seven items, including symptom severity, daily activities, pain medication use
      and need for bed rest. RESULTS: No significant differences were found at baseline
      between treatments for patients with mild, moderate or no endometriosis symptoms.
      Those with severe symptoms of endometriosis at baseline and taking nafarelin had
      a significantly greater improvement in QOL at the last posttreatment visit than
      those receiving leuprolide (P < .01). Nafarelin was associated with significantly
      fewer days with moderate or severe hot flashes than leuprolide during treatment
      (P < .05) and with significantly fewer moderate or severe hypoestrogenic symptoms
      overall at three months of treatment (P < .05). Additionally, poorer QOL was
      significantly associated with hypoestrogenic and endometriosis symptoms.
      CONCLUSION: Treatment of endometriosis with nafarelin was associated with fewer
      days of moderate or severe hot flashes as compared to leuprolide and with greater
      improvement in QOL after treatment in patients with severe symptoms at baseline.

PMID- 10649810
TI  - Low backache during pregnancy. Acute hemodynamic effects of a lumbar support.
AB  - OBJECTIVE: To determine whether a commercially available elastic/Velcro lumbar
      and abdominal support (Mother-To-Be, CMO, Inc., Barberton, Ohio) affects the
      hemodynamics of the fetus and pregnant woman. STUDY DESIGN: Healthy volunteers
      with low backache at 24-36 weeks' gestation were sought from our obstetric clinic
      population. The fetal heart rate (FHR), maternal blood pressure and maternal
      cardiac output were monitored for 20-minute intervals before, during and after
      placement of the support while standing and sitting. A sufficient number of
      subjects was used to detect a difference of 10% in cardiac output. RESULTS:
      Twenty-five women were enrolled between 24 and 36 weeks' gestation. No
      significant changes were encountered in the FHR baseline or beat-to-beat
      variability during placement of the support. The few FHR decelerations were
      isolated and not attributable to the support. The maternal systolic, diastolic
      and mean arterial blood pressures were unaffected by the support. The right-sided
      and left-sided cardiac outputs were unchanged during the monitoring periods. Each
      woman, when questioned two weeks later, reported improvement in back discomfort
      while sitting and standing. CONCLUSION: This elastic/Velcro lumbar and abdominal
      support, available to relieve low backache, did not acutely affect the
      hemodynamics of the fetus and mother.

PMID- 10649812
TI  - Relationship of phencyclidine and pregnancy outcome.
AB  - OBJECTIVE: To analyze the relationship of phencyclidine (PCP) and pregnancy
      outcome, as judged by low birth weight (< 2,500 g). STUDY DESIGN: A
      retrospective, case-control study of PCP use was conducted among pregnant women
      who delivered at a large hospital in New Orleans. PCP use was ascertained by
      urine screening at the time of obstetric admission. Three control patients were
      selected for each case, matched for age, parity and month of delivery. The study
      intended to address the prevalence of low birth weight. RESULTS: Between January
      1990 and June 1996, 13,653 patients delivered. Of these, 23 were identified as
      PCP users. PCP users had smaller infants (2,698 vs. 3,011 g, P < .05); that may
      have been accounted for by a reduction in gestational age (37.3 vs. 38.3 weeks, P
      = NS). The users were more likely to give histories of using tobacco, alcohol or
      marijuana but not cocaine. Syphilis and diabetes mellitus were found more often
      in the study group. Multisubstance use was also common in the study group. The
      prevalence of low birth weight was not statistically different for the study and
      control groups. CONCLUSION: PCP use was not associated with an increase in low
      birth weight. When identified, patients using PCP require comprehensive
      evaluation.

PMID- 10649811
TI  - A two-year, double-blind comparison of estrogen-androgen and conjugated estrogens
      in surgically menopausal women. Effects on bone mineral density, symptoms and
      lipid profiles.
AB  - OBJECTIVE: To compare the effects of two doses of conjugated equine estrogen
      (CEE) and two of esterified estrogen plus methyltestosterone (E + A) in
      surgically menopausal women. STUDY DESIGN: A two-year, parallel-group, double
      blind study of 311 women who were randomly assigned to one of four regimens: (1)
      CEE, 0.625 mg/d; (2) CEE, 1.25 mg/d; (3) esterified estrogens, 0.625 mg, +
      methyltestosterone, 1.25 mg/d; or (4) esterified estrogens, 1.25, +
      methyltestosterone, 2.5 mg/d. Study parameters were symptoms, lipids, bone
      mineral density, side effects and safety. RESULTS: All treatments prevented loss
      of bone in the spine and hip. The higher E + A dose increased spine and hip BMD
      more than other treatments (P < .002). All treatments improved menopausal
      symptoms, with non-significantly greater improvements in well-being and sexual
      interest in the E + A groups. Similar and significant decreases in low-density
      lipoprotein were observed in all groups, but high-density lipoprotein and
      triglycerides were increased only in the unopposed estrogen groups (P < .05).
      Hirsutism was uncommon and similar in all groups at two years. Discontinuation
      rates and reasons for withdrawal from the study were similar in both groups. No
      clinically significant side effects or laboratory test abnormalities were seen.
      CONCLUSION: As compared to estrogen alone, E + A significantly improved BMD and
      was well tolerated in surgically menopausal women.

PMID- 10649813
TI  - Unicornuate uterus with a rudimentary horn and ovarian dysgerminoma. A case
      report.
AB  - BACKGROUND: Several documented cases of endometrial and cervical carcinoma
      arising in unicornuate uteri have been described; however, ovarian malignancy
      occurring in conjunction with this mullerian anomaly has not been reported. CASE:
      An 18-year-old woman had a unicornuate uterus, noncommunicating rudimentary horn
      and homogeneous, solid, right ovarian mass found to be a dysgerminoma at surgery.
      CONCLUSION: Mullerian anomalies are unlikely to predispose women to ovarian
      malignancies. However, it is essential to keep in mind that women with such
      anomalies, though presenting at a young age, could still have cervical, uterine
      or even ovarian malignancies.

PMID- 10649814
TI  - Guidelines for the diagnosis and treatment of hyperprolactinemia.
AB  - Hyperprolactinemia is the most common endocrine disorder of the hypothalamic
      pituitary axis. While it can occur in men, it occurs more commonly in women. The
      prevalence of hyperprolactinemia ranges from 0.4% in an unselected normal adult
      population to as high as 9-17% in women with reproductive disorders. There are
      many possible causes of hyperprolactinemia, falling into three general
      categories: physiologic, pharmacologic and pathologic. When specific treatable
      underlying causes have been eliminated and in cases of severe hyperprolactinemia,
      the most likely cause is a prolactin (PRL)-secreting pituitary adenoma.
      Microadenomas should be treated medically, with a dopamine agonist, if there is
      an indication for therapy (such as amenorrhea, infertility or bothersome
      galactorrhea). If there is no indication for therapy, microadenomas may be
      followed conservatively, as growth is uncommon. Macroadenomas may grow larger;
      medical therapy is recommended initially, with neurosurgical evaluation reserved
      for specific clinical situations, such as failure of medical therapy and evidence
      of mass effect despite medical therapy. In the United States, the dopamine
      agonists indicated for treatment of hyperprolactinemia are bromocriptine and
      cabergoline. Bromocriptine is usually given once or twice daily, while
      cabergoline has a long duration of action and is given once or twice weekly.
      Results of comparative studies indicate that cabergoline is clearly superior to
      bromocriptine in efficacy (PRL suppression, restoration of gonadal function) and
      tolerability.

PMID- 10649815
TI  - Clinical presentation of hyperprolactinemia.
AB  - Prolactin is a polypeptide hormone essential for lactation. Its production in the
      lactotroph cells of the anterior pituitary is regulated primarily by the
      inhibitory action of hypothalamic dopamine. Hyperprolactinemia is the most common
      endocrine disorder of the hypothalamic-pituitary axis, occurring mostly in women
      and presenting most commonly with amenorrhea and galactorrhea. Causes of
      hyperprolactinemia include physiologic, pharmacologic and pathologic factors;
      pituitary adenoma is a common pathologic cause. Women may present with decreased
      libido, infertility, oligomenorrhea/amenorrhea and galactorrhea. Men may present
      with decreased libido, infertility, gynecomastia or impotence. In the absence of
      an identifiable and treatable underlying cause, hyperprolactinemia is generally
      treated with dopamine agonist medications.

PMID- 10649816
TI  - Indications for hyperprolactinemia therapy.
AB  - Before initiating treatment for hyperprolactinemia, it is necessary to verify the
      diagnosis. It is also essential to remember that hyperprolactinemia is in itself
      simply an abnormal "lab value" that reflects the presence of an underlying
      pathophysiologic cause. All possible causes must be considered and either
      identified or ruled out before therapy is initiated. The vast majority of people
      with hyperprolactinemia can be treated medically with dopamine agonist
      medications. The indications for treatment include: (1) the presence of
      significant symptoms, such as infertility, ovulatory dysfunction or galactorrhea
      in women and infertility or gynecomastia in men; (2) the presence of significant
      signs, such as visual field defects or cranial nerve palsies; and (3) abnormal
      test results, including visualization of a pituitary mass or lesion or detection
      of osteopenia.

PMID- 10649817
TI  - Diagnostic evaluation of hyperprolactinemia.
AB  - A serum prolactin (PRL) level is obtained in response to a specific clinical
      presentation, including symptoms of hyperprolactinemia (such as amenorrhea and
      galactorrhea); serum PRL measurement may also be performed as part of an
      infertility evaluation. An initial level above the normal range should be
      followed by a repeat level from a blood sample drawn in the morning with the
      patient in a fasting state. The medical history and a few laboratory tests can
      eliminate the most common physiologic and pharmacologic causes of
      hyperprolactinemia, including pregnancy, primary hypothyroidism and treatment
      with drugs (such as neuroleptics) that reduce dopaminergic effects on the
      pituitary. In the absence of such causes, radiologic imaging of the sella turcica
      is necessary to establish whether a PRL-secreting pituitary adenoma or other
      lesion is present. The vast majority of patients are treated medically, with
      dopamine agonist drugs. Surgery is reserved for the patient with the uncommon
      tumor that does not respond to medical therapy or has a large cystic component or
      for the occasional patient who cannot tolerate dopamine agonists or who
      experiences pituitary apoplexy.

PMID- 10649818
TI  - Following patients under treatment for hyperprolactinemia.
AB  - Management of patients receiving treatment for hyperprolactinemia depends on a
      few specific parameters: whether the patient has no pituitary lesion, a pituitary
      microadenoma or a pituitary macroadenoma. In each of these categories, management
      will differ depending on whether the patient desires to become pregnant. Some
      patients with hyperprolactinemia who are asymptomatic may be managed expectantly,
      with periodic measurement of serum prolactin levels and careful monitoring for
      emergence of symptoms. In the vast majority of cases, treatment with a dopamine
      agonist is appropriate and effective. If pregnancy is desired, efforts should be
      made to time it carefully and to discontinue the drug as soon as a pregnancy test
      is positive. Only patients with macroadenomas who do not respond adequately to
      medical therapy and show signs of a cranial mass effect from the lesion should be
      referred for neurosurgical evaluation.

PMID- 10649819
TI  - Dopamine agonist therapy in hyperprolactinemia.
AB  - Introduction of the dopamine agonist bromocriptine heralded a major advance in
      the management of hyperprolactinemic disorders. Although its side effects of
      nausea, dizziness and headache and its short elimination half-life are limiting
      factors, its efficacy established it as a reference compound against the activity
      of which several dopamine agonists, like pergolide, lysuride, metergoline,
      terguride and dihydroergocristine, fell by the wayside. More recently, two new
      agents, cabergoline and quinagolide, have been introduced and appear to offer
      considerable advantages over bromocriptine. Cabergoline, an ergoline D2 agonist,
      has a long plasma half-life that enables once- or twice-weekly administration.
      Quinagolide, in contrast, is a nonergot D2 agonist with an elimination half-life
      intermediate between those of bromocriptine and cabergoline, allowing the drug to
      be administered once daily. Comparative studies indicate that cabergoline is
      clearly superior to bromocriptine in efficacy (prolactin suppression, restoration
      of gonadal function) and in tolerability. In similar studies, quinagolide
      appeared to have similar efficacy and superior tolerability to that of
      bromocriptine. Results of a small crossover study indicate that cabergoline is
      better tolerated, with a trend toward activity superior to that of quinagolide.
      In hyperprolactinemic men and in women not seeking to become pregnant,
      cabergoline may be regarded as the treatment of choice.

PMID- 10649820
TI  - Implications of not treating hyperprolactinemia.
AB  - When a patient with hyperprolactinemia is not treated, a number of ramifications
      can result, the most significant of which is osteoporosis. Evidence-based
      analysis shows that bone mineralization also can be affected by such problems as
      gonadal dysgenesis and possibly adrenal dysfunction. The hypoestrogenism
      associated with hyperprolactinemia is commonly assumed to be a potential cause of
      osteopenia in premenopausal women with this disorder, just as decreased estrogen
      is associated with bone loss following menopause. A number of studies also have
      shown that hyperprolactinemia decreases bone density independently of the
      hypoestrogenic state. In most, but not all, such women, bone density may be
      reestablished if one is successful in restoring normal menstrual function with
      dopamine agonists. With the availability of safe dopamine agonists like
      bromocriptine and now cabergoline, it seems prudent to attempt to normalize serum
      prolactin levels early on, before long-term pathologies set in.

PMID- 10649821
TI  - Management of hyperprolactinemia in infertility.
AB  - Hyperprolactinemia is a frequent cause of anovulatory sterility, although
      spontaneous pregnancy may occur occasionally. Dopaminergic treatment is highly
      effective for both idiopathic and tumoral hyperprolactinemia. If the only cause
      of infertility is chronic anovulation due to hyperprolactinemia, a 60-80%
      pregnancy rate can be achieved. These results mean that surgical treatment is
      still needed only rarely. Either spontaneous or drug-induced pregnancy is usually
      uneventful for the mother and is not associated with any increase in abortion,
      twins or malformations. Pregnancy-related tumor growth occurs rarely and can be
      treated successfully with dopaminergic drugs. Pregnancy frequently leads to some
      improvement in the biochemical and clinical disorders associated with
      hyperprolactinemia.

PMID- 10649822
TI  - Management of prolactinomas during pregnancy.
AB  - Infertility is a common problem for women presenting with hyperprolactinemia, and
      lowering of prolactin (PRL) levels to normal or near normal is often necessary to
      permit ovulation. Dopamine agonists are effective in a majority of women, with
      cabergoline somewhat more effective than bromocriptine. Bromocriptine use by the
      mother appears to be safe for the developing fetus when its use is discontinued
      four to six weeks after conception. For women with microadenomas, the subsequent
      risk of adenoma growth during pregnancy appears to be 1% after discontinuing the
      drug, and symptomatic follow-up each trimester appears to be reasonable in such
      patients. For women with macroadenomas, bromocriptine may be discontinued after
      diagnosis of pregnancy (23% risk of tumor enlargement) or continued throughout
      pregnancy with monthly visual field testing. Alternatively, prepregnancy
      debulking of the tumor may be undertaken with appropriate follow-up (2.8% risk of
      tumor enlargement). Although data are less extensive on cabergoline, preliminary
      evidence does not suggest any increase in adverse fetal outcomes. As such,
      therapeutic abortion is not warranted if pregnancy occurs during cabergoline
      treatment. The drug appears reasonably safe for continued use. Further accrual of
      safety data will clarify that issue.

PMID- 10649823
TI  - Indications for surgery in the treatment of hyperprolactinemia.
AB  - Indications for pituitary surgery have been described in the medical literature,
      but they do not necessarily apply to prolactin-secreting (PRL-secreting)
      pituitary microadenomas or macroadenomas. Reviews of pituitary surgery done for
      microprolactinomas and macroprolactinomas have not demonstrated any significant
      beneficial effect on the clinical course of the hyperprolactinemia. At the same
      time, such surgery has been associated with definite risks, including an overall
      mortality of 0.9%. There is even the possibility that surgery and radiation for
      benign pituitary adenomas can facilitate malignant transformation and metastasis.
      Therefore, medical treatment with a dopamine agonist is the primary choice for
      all PRL-secreting microadenomas and macroadenomas. Referral for surgical
      evaluation is reserved for patients in whom neurologic deficits, such as visual
      field impairment or cranial nerve deficits, do not improve with medical therapy
      and for certain other, rare situations.

PMID- 10649824
TI  - Allostasis and allostatic load: implications for neuropsychopharmacology.
AB  - The primary hormonal mediators of the stress response, glucocorticoids and
      catecholamines, have both protective and damaging effects on the body. In the
      short run, they are essential for adaptation, maintenance of homeostasis, and
      survival (allostasis). Yet, over longer time intervals, they exact a cost
      (allostatic load) that can accelerate disease processes. The concepts of
      allostasis and allostatic load center around the brain as interpreter and
      responder to environmental challenges and as a target of those challenges. In
      anxiety disorders, depressive illness, hostile and aggressive states, substance
      abuse, and post-traumatic stress disorder (PTSD), allostatic load takes the form
      of chemical imbalances as well as perturbations in the diurnal rhythm, and, in
      some cases, atrophy of brain structures. In addition, growing evidence indicates
      that depressive illness and hostility are both associated with cardiovascular
      disease (CVD) and other systemic disorders. A major risk factor for these
      conditions is early childhood experiences of abuse and neglect that increase
      allostatic load later in life and lead individuals into social isolation,
      hostility, depression, and conditions like extreme obesity and CVD. Animal models
      support the notion of lifelong influences of early experience on stress hormone
      reactivity. Whereas, depression and childhood abuse and neglect tend to be more
      prevalent in individuals at the lower end of the socioeconomic ladder,
      cardiovascular and other diseases follow a gradient across the full range of
      socioeconomic status (SES). An SES gradient is also evident for measures of
      allostatic load. Wide-ranging SES gradients have also been described for
      substance abuse and affective and anxiety disorders as a function of education.
      These aspects are discussed as important, emerging public health issues where the
      brain plays a key role.

PMID- 10649825
TI  - The relationship between dorsolateral prefrontal neuronal N-acetylaspartate and
      evoked release of striatal dopamine in schizophrenia.
AB  - Schizophrenia has been linked to abnormal dopamine function, recently to
      excessive amphetamine-induced release of striatal dopamine, and also to pathology
      of prefrontal cortical neurons. It has been hypothesized that prefrontal
      pathology is a primary condition that leads to dopamine dysregulation. We
      evaluated in vivo the relationship between neuronal integrity in dorsolateral
      prefrontal cortex, assessed as N-acetylaspartate (NAA) relative concentrations
      measured with proton magnetic resonance spectroscopic imaging, and amphetamine
      induced release of striatal dopamine, assessed with 11C-raclopride Positron
      Emission Tomography (PET) in patients with schizophrenia and in healthy subjects.
      In the patients, NAA measures in dorsolateral prefrontal cortex selectively
      predicted striatal displacement of 11C-raclopride after amphetamine infusions
      (rho = -0.76, p < .02). In contrast, NAA measures in other cortical regions and
      in healthy subjects did not show any correlation. These results support the
      hypothesis that in schizophrenia neuronal pathology of dorsolateral prefrontal
      cortex is directly related to abnormal subcortical dopamine function.

PMID- 10649826
TI  - Genotype influences in vivo dopamine transporter availability in human striatum.
AB  - In vivo availability of striatal dopamine transporter (DAT) protein has been
      reported to be reduced among alcoholics, and allelic variation of the DAT gene
      (SLC6A3) has been associated with severity of alcohol withdrawal. We examined the
      VNTR polymorphism of the 3' untranslated region of SLC6A3 and DAT protein
      availability in 14 abstinent alcoholics and 11 control subjects. Single photon
      emission computed tomography (SPECT) and plasma levels of the radioligand [I
      123]beta-CIT were used to quantify DAT protein availability. Individuals with the
      9-repeat/10-repeat genotype had a mean 22% reduction of DAT protein availability
      in putamen compared with 10-repeat homozygous individuals (t = 2.14, df = 23, p <
      .05). Consistent with earlier studies, alcoholism, per se, was not significantly
      associated with either DAT availability or DAT genotype. These findings suggest
      that the VNTR polymorphism of the DAT gene effects translation of the DAT
      protein. This effect may explain a variety of clinical associations that have
      been reported with this polymorphism.

PMID- 10649827
TI  - Increase of dialysate dopamine in the bed nucleus of stria terminalis by
      clozapine and related neuroleptics.
AB  - Neuroleptics are known to stimulate dopamine release in neostriatal terminal
      areas. In the present study, we have investigated by brain microdialysis in
      freely moving rats the effect of typical and atypical neuroleptics on dopamine
      transmission in the bed nucleus of stria terminalis, a dopamine terminal area
      belonging to the limbic system and recently assigned the so-called extended
      amygdala. Mean basal dialysate dopamine values were 14.3 f moles/20 microliters
      sample. Dopamine output in dialysates was increased dose-dependently by clozapine
      (max + 158%, 298%, and 461% of basal at 5, 10, and 20 mg/kg i.p., respectively),
      risperidone (max + 115% and 221% of basal at 1 and 3 mg/kg i.p., respectively),
      olanzapine (max + 138% and 235% of basal at 3 and 6 mg/kg i.p., respectively),
      BIMG 80 (max + 64% and 164% of basal at 3 and 5 mg/kg i.p., respectively),
      amperozide (max + 110% and 194% of basal at 3 and 6 mg/kg i.p., respectively).
      The selective dopamine D4 antagonist L-745,870 increased dialysate dopamine but
      at rather high doses and not as effectively as clozapine (max + 32%, 89%, and
      130% of basal at 2.7, 5.4, and 10.8 mg/kg i.p., respectively). The typical
      neuroleptic haloperidol (0.1 and 0.5 mg/kg s.c.) and the selective D2 antagonist
      raclopride (0.14, 0.56, and 2.1 mg/kg s.c.), the serotonergic 5-HT2 antagonist
      ritanserin (0.5 and 1.5 mg/kg i.p.), and the adrenergic alpha 1 antagonist
      prazosin (0.91 and 2.73 mg/kg i.p.) did not affect dialysate dopamine in the bed
      nucleus of stria terminalis. Saline (1 ml/kg s.c. or 3 ml/kg i.p.) did not modify
      dialysate dopamine. Therefore, atypical neuroleptics share the ability of
      stimulating dopamine transmission in the bed nucleus of stria terminalis, but
      this property is not mimicked by any of the drug tested that selectively act on
      individual receptors among those that are affected by atypical neuroleptics.
      These observations raise the possibility that the property of increasing dopamine
      transmission in the bed nucleus of stria terminalis is the result of combined
      blockade of dopamine, serotonin, and noradrenaline receptors and that might be
      predictive of an atypical neuroleptic profile.

PMID- 10649828
TI  - Effects of corticotropin-releasing factor on neuronal activity in the
      serotonergic dorsal raphe nucleus.
AB  - The present study examined the regional localization of corticotropin-releasing
      factor (CRF)- and 5-hydroxytryptamine (5-HT)-immunoreactive (IR) fibers within
      the rat dorsal raphe nucleus (DRN) using immunohistochemistry. Additionally, the
      effects of CRF, administered intracerebroventricularly (0.1-3.0 micrograms) or
      intraraphe (0.3-30 ng), on discharge rates of putative 5-HT DRN neurons were
      quantified using in vivo single unit recording in halothane-anesthetized rats.
      CRF-IR fibers were present at all rostrocaudal levels of the DRN and exhibited a
      topographical distribution. CRF produced predominantly inhibitory effects on DRN
      discharge at lower doses and these effects diminished or became excitatory at
      higher doses. Inhibition of DRN discharge by CRF was attenuated by the
      nonselective CRF antagonist, DPheCRF12-41 and the CRF-R1-selective antagonist,
      antalarmin, implicating the CRF-R1 receptor subtype in these electrophysiological
      effects. The present findings provide anatomical and physiological evidence for
      an impact of CRF on the DRN-5HT system.

PMID- 10649829
TI  - The relationship between repetitive behaviors and growth hormone response to
      sumatriptan challenge in adult autistic disorder.
AB  - Autism is heterogeneous with respect to clinical symptoms and etiology. To sort
      out this heterogeneity in autism, we investigated whether specific
      neurobiological markers vary in parallel to core symptomatology. Specifically, we
      assessed growth hormone response to the 5-HT 1d agonist, sumatriptan, and linked
      this measure of serotonergic function to the severity of repetitive behaviors in
      adult autistic patients. Eleven adult patients with autism or Asperger's disorder
      were randomized to single dose sumatriptan (6 mg SQ) and placebo challenges,
      separated by a one-week interval. In adult autistic disorders, severity of
      repetitive behaviors at baseline, as measured by YBOCS-compulsion score,
      significantly positively correlated with both peak delta growth hormone response
      and area under the curve growth hormone response to sumatriptan. Thus, the
      severity of a specific behavioral dimension in autism (repetitive behaviors)
      parallels the sensitivity of the 5-HT 1d receptor, as manifest by sumatriptan
      elicited GH response.

PMID- 10649831
TI  - Strain differences in the behavioral effects of antidepressant drugs in the rat
      forced swimming test.
AB  - Wistar-Kyoto (WKY) rats provide a model of stress-induced depressive behavior,
      because they show enhanced vulnerability to the effects of stressors. The present
      study examined differences in the behavioral response to different types of
      antidepressant drugs between WKY and Sprague-Dawley (SD) rats in the forced
      swimming test (FST). WKY rats displayed significantly greater immobility than SD
      rats during their exposure to the FST. The noradrenergic antidepressant,
      desipramine, produced a dose-dependent reduction of immobility and increase of
      climbing behavior in the SD rats. In WKY rats, desipramine reduced immobility at
      a lower dose and produced increases of both swimming and climbing behavior. The
      serotonergic compounds, fluoxetine and 8-OH-DPAT, produced dose-dependent
      reductions of immobility and increases of swimming behavior in the FST in SD
      rats, but the response to the serotonergic drugs were blunted in WKY rats. These
      results indicate that genetic or constitutive differences may determine the
      distinct behavioral profiles for antidepressant compounds with selective
      pharmacological effects in different rat strains, and these effects may be
      related to genetic heterogeneity of antidepressant responses in depressed
      patients.

PMID- 10649830
TI  - Multiple 5-HT receptors in passive avoidance: comparative studies of p
      chloroamphetamine and 8-OH-DPAT.
AB  - The aim of this study was to examine the involvement of multiple 5-HT receptors
      in passive avoidance (PA) with a focus on 5-HT1A, 5-HT2A, and 5-HT2C receptors.
      Because increases in 5-HT transmission result in concomitant multiple 5-HT
      receptor activation, the effects of the 5-HT releasing compound p
      chloroamphetamine (PCA) were compared with those of the selective 5-HT1A receptor
      agonist 8-OH-DPAT in the rat. In addition, some results with the nonselective 5
      HT2C/2B/1B receptor agonist mCPP are presented. When injected before PA training,
      8-OH-DPAT, mCPP, and PCA produced a dose-related impairment of the 24-hour
      retention. The crucial involvement of the postsynaptic 5-HT1A receptors in the
      action of 8-OH-DPAT was confirmed. Thus, the 5-HT1A receptor antagonists WAY
      100635 and (-)-pindolol blocked the PA deficit by 8-OH-DPAT. The impairment of PA
      caused by PCA was attenuated by WAY 100635 and (-)-pindolol, suggesting an
      involvement of the 5-HT1A receptor. In contrast, the 5-HT2A and 5-HT2C receptors
      were of negligible importance in the 24-hour retention deficit induced by PCA.
      However, the ability of the 5-HT2C receptor antagonist Ro 60-0491 to block the
      inhibitory effects of mCPP indicated an important regulatory role of the 5-HT2C
      receptor in PA. The nonselective 5-HT receptor antagonist methiothepin attenuated
      the PA deficit by PCA but lacked activity versus 8-OH-DPAT. These data provide
      evidence for the hypothesis that, in addition to the 5-HT1A receptor, other 5-HT
      receptor subtypes are involved in the inhibitory actions of PCA. Importantly,
      changes in dopamine transmission seemed not to contribute to the PA impairment by
      PCA. The behavioral alterations caused by the drug treatments at the time of PA
      training could not be related to the subsequent retention performance. In
      conclusion, multiple 5-HT receptors are involved in PA with roles that probably
      differ at various stages of information processing. These findings also suggest
      that there probably exists a functional distinction between 5-HT receptor
      subtypes in different types of aversive learning.

PMID- 10649832
TI  - Nicotine impairs spatial working memory while leaving spatial attention intact.
AB  - We investigated the effects of nicotine on spatial working memory and spatial
      selective attention in young, healthy smokers. Spatial working memory was
      assessed by a delayed response task. Delayed response performance is associated
      with the integrity of the dorsolateral prefrontal cortex. Spatial interference
      and negative priming tasks were used to assess spatial selective attention.
      Nicotine impaired spatial working memory in smokers but it did not affect spatial
      selective attention. This result suggests that nicotine may impair dorsolateral
      prefrontal function, as assessed by the spatial working memory task in young
      smokers and that this deficit does not stem from impairments in spatial selective
      attention. However, the effects of nicotine on working memory and selective
      attention in nonsmokers or in psychiatric population with suspected nicotinic
      receptor abnormalities (e.g., schizophrenia patients) cannot be deduced from the
      present study.

PMID- 10649833
TI  - CSF 5-HIAA and nighttime activity in free-ranging primates.
AB  - Men with low CNS serotonin turnover, as measured by cerebrospinal fluid 5
      hydroxyindoleacetic acid (CSF 5-HIAA) concentrations, exhibit aberrant circadian
      activity patterns characterized by disrupted sleep rhythms and daytime
      hyperactivity. To assess whether similar patterns are found in nonhuman primates
      we examined the relationships between CSF 5-HIAA and nighttime activity in free
      ranging monkeys. CSF samples were obtained from 16 adult male rhesus macaques
      living on a 475 acre, heavily forested sea island. Each subject was captured,
      fitted with a radio-telemetry motion-detector collar, and then released back into
      its group. A receiver placed near the sleeping trees of the study subjects
      recorded activity between 2100 hrs and 0600 hrs. Trained observers recorded
      behavioral data during the day. The animals followed a typical diurnal activity
      pattern, as they were active 74% of the sampled time during the day and 37% of
      the sampled time during the night. CSF 5-HIAA concentrations were inversely
      correlated with total duration of nighttime activity as well as mean duration of
      all active events. Nighttime activity was inversely correlated with daytime
      activity. CSF 3-methoxy-hydroxyphenylglycol (MHPG) concentrations were positively
      correlated with total nighttime activity, and inversely correlated with daytime
      sleep frequency. We conclude that male rhesus with low CSF 5-HIAA concentrations
      have higher total nighttime activity, longer mean periods of nighttime activity,
      and sleep more during the day than do males with high CSF 5-HIAA concentrations.
      This suggests that low serotonergic neurotransmission is associated with aberrant
      diurnal activity, as evidenced by a disruption of nighttime sleep patterns and a
      compensatory higher rate of inactivity during the day.

PMID- 10649834
TI  - Tick-borne diseases.
AB  - Tick-transmitted infectious agents have assumed increased importance as causes of
      human disease in the United States. During the past two decades, Lyme
      borreliosis, ehrlichiosis, and babesiosis have emerged as newly described tick
      borne infectious diseases of significance for pediatricians and pediatric
      neurologists. In fact, the highest rates of infection for Lyme disease and Rocky
      Mountain spotted fever (RMSF), by decade of age, are in childhood. As such, tick
      borne infectious disease are of considerable public health concern, particularly
      for children residing in endemic regions. RMSF and human ehrlichioses can be life
      threatening but are also eminently treatable when recognized early. Delays in
      diagnosis and treatment can lead to adverse outcomes. This article reviews the
      clinical and epidemiological features of Lyme borreliosis, RMSF, and
      ehrlichiosis, important causes of neurological illness among children, and
      summarizes current therapeutic and preventive strategies.

PMID- 10649835
TI  - Neurocysticercosis and acquired cerebral toxoplasmosis in children.
AB  - Neurocysticercosis, prevalent wherever pigs are raised in the presence of poor
      sanitation, is the most common identifiable cause of new-onset epilepsy
      throughout the developing world. As immigration patterns have changed, children
      with neurocysticercosis are seen throughout the United States. Acute
      cysticercosis, the most common manifestation in children, reflects the host
      response to the dying parasite. Children typically present with seizures and have
      an excellent prognosis. Neuroimaging demonstrates a single ring or nodular
      enhancing lesion surrounded by edema. Short-term anticonvulsant therapy is
      indicated, but treatment with antiparasitic agents is not required. Other forms,
      such as active cysts (intact organism), intraventricular or subarachnoid racemous
      cysticercosis, and cysticercal meningoencephalitis, are less common
      manifestations of parasitic infection. Toxoplasmosis, caused by the parasite
      Toxoplasma gondii, can be acquired by ingestion of infected undercooked meat or
      from oocytes shed in cat feces. Acquired cerebral toxoplasmosis, due to primary
      or reactivated infections, rarely occurs in immunocompetent children. In children
      who are immunodeficient as the result of AIDS, chemotherapy, tissue
      transplantation, or congenital immunodeficiency, toxoplasmosis may be difficult
      to distinguish from cerebral lymphoma. A variety of techniques, including
      neuroimaging, Thallium-201 SPECT, polymerase chain reaction analysis of CSF, and
      special histological methods, may be used to diagnose acquired toxoplasmosis.
      Antiparasitic therapy, using pyrimethamine and sulfadiazine, and serial
      neuroimaging often enable clinicians to differentiate toxoplasmosis from other
      central nervous system lesions. Toxoplasmosis may respond to other
      antimicrobials, including macrolide antibiotics, dapsone, clinidamycin, and
      atovaquone. Suppressive treatment is generally required for life in
      immunodeficient patients. Immunodeficient children with acquired toxoplasmosis
      have high rates of mortality and neurological sequelae.

PMID- 10649836
TI  - Human herpesviruses and neurological disorders of childhood.
AB  - The human herpesviruses, a group of DNA viruses that includes herpes simplex
      viruses types 1 and 2, varicella zoster virus, cytomegalovirus, Epstein-Barr
      virus, and human herpes viruses types 6, 7, and 8, cause substantial neurological
      morbidity among infants and children. This review describes the biology of these
      viruses and summarizes the clinical manifestations and therapy of the diseases
      that result from childhood infection with these important pathogens.

PMID- 10649837
TI  - Advances in antimicrobial therapy.
AB  - Despite several decades of improved therapy and prevention of infectious
      diseases, infectious pathogens remain major causes of morbidity and mortality in
      humans worldwide. Among the most complex and daunting problems facing medical
      science is the evolution of antibiotic resistance among many common and once
      easily-treated infectious agents. This review summarizes the status of newer
      antimicrobial agents that have utility against pathogens infecting the central
      nervous system.

PMID- 10649838
TI  - Neuroimaging of postnatal pediatric central nervous system infections.
AB  - Pediatric neuroimaging plays an important role in the timely diagnosis of
      postnatal central nervous system (CNS) infections, and in some patients the
      imaging findings are sufficiently specific to suggest a cause. The sequela of CNS
      infection, including hydrocephalus, subdural collections, ischemia/infarction,
      cerebral abscess, demyelination, and vascular thrombosis, can be accurately
      depicted and serially followed with current imaging techniques. The purpose of
      this review is to describe the spectrum of pediatric postnatal CNS infections,
      emphasizing key pathological and neuroimaging features, and to outline the
      strengths, weaknesses, and applications of current neuroimaging technology. The
      prenatal and perinatal infections falling under the designation of TORCH
      (toxoplasmosis, other [e.g., syphilis, HIV], rubella, cytomegalovirus, and herpes
      simplex II) are not covered.

PMID- 10649839
TI  - Tuberculosis of the central nervous system in children.
AB  - Tuberculosis remains one of the most common and important infectious diseases in
      the world. Between 1% and 2% of children with untreated tuberculosis infection
      will develop tuberculous meningitis. In 1997, 186 cases of tuberculous meningitis
      were reported in the United States. The initial clinical manifestations of
      tuberculous meningitis are protean, making early disease difficult to recognize.
      The clinical and radiographic manifestations of tuberculous meningitis result
      from the combination of basilar meningitis, infarction, and vasculitis. Early
      diagnosis can be problematic as Mycobacterium tuberculosis is difficult to detect
      by rapid tests. Although the response to antituberculosis chemotherapy is
      generally favorable, complications commonly occur, particularly if the diagnosis
      is delayed. With appropriate public health management of known tuberculosis
      cases, cases of CNS tuberculosis in children can be prevented.

PMID- 10649840
TI  - Quantitative structure-toxicity relationships for chlorophenols to bioluminescent
      lux-marked bacteria using atom-based semi-empirical molecular-orbital
      descriptors.
AB  - Literature data on the toxicity of chlorophenols for three luminescent bacteria
      (Vibrio fischeri, and the lux-marked Pseudomonas fluorescens 10586s pUCD607 and
      Burkholderia spp. RASC c2 (Tn4431)) have been analyzed in relation to a set of
      computed molecular physico-chemical properties. The quantitative structure
      toxicity relationships of the compounds in each species showed marked differences
      when based upon semi-empirical molecular-orbital molecular and atom based
      properties. For mono-, di- and tri-chlorophenols multiple linear regression
      analysis of V. fischeri toxicity showed a good correlation with the solvent
      accessible surface area and the charge on the oxygen atom. This correlation
      successfully predicted the toxicity of the heavily chlorinated phenols,
      suggesting in V. fischeri only one overall mechanism is present for all
      chlorophenols. Good correlations were also found for RASC c2 with molecular
      properties, such as the surface area and the nucleophilic super-delocalizability
      of the oxygen. In contrast the best QSTR for P. fluorescens contained the 2nd
      order connectivity index and ELUMO suggesting a different, more reactive
      mechanism. Cross-species correlations were examined, and between V. fischeri and
      RASC c2 the inclusion of the minimum value of the nucleophilic susceptibility on
      the ring carbons produced good results. Poorer correlations were found with P.
      fluorescens highlighting the relative similarity of V. fischeri and RASC c2, in
      contrast to that of P. fluorescens.

PMID- 10649841
TI  - Respiratory, gastrointestinal, and other health effects among workers in two
      refuse-derived fuel plants.
AB  - This study was conducted to investigate health effects in workers at two refuse
      derived fuel processing plants. Cross-shift pulmonary function testing and self
      reporting of symptoms from questionnaires formed the basis of a cross-sectional
      epidemiological study. Other topics addressed were exploration of the possibility
      of a hand to mouth component resulting in diarrhoea observed historically by the
      microbiological testing of skin. Symptoms of sinus trouble, headaches, nose
      irritation, and diarrhoea were reported by over 50% of the employees. Small, but
      statistically significant, cross-shift decrements of 1.50% and 2.01% were noted
      for forced vital capacity (FVC) and forced expiratory volume in one second
      (FEV1), respectively. Workers employed seven years or more had significantly
      larger cross-shift decrements in FVC and FEV1 than those employed for a shorter
      period. No active cases of diarrhoea were observed. Low lung function decrements
      characterise the observed workforce. Elevated reporting of some symptoms and a
      cross-shift decrement that increases with length of employment indicate that
      further study is warranted.

PMID- 10649842
TI  - Ochratoxin A in blood of healthy population in Zagreb.
AB  - Healthy blood donors from the city of Zagreb were checked for the presence of a
      nephrotoxic mycotoxin ochratoxin A (OTA) in the plasma. Samples of blood were
      collected in June, September, and December 1997, and March 1998, totalling 200 or
      50 in each round. The concentrations of OTA were measured using high pressure
      liquid chromatography (HPLC) method (detection limit 0.2 ng OTA/ml of plasma).
      The frequency of OTA-positive samples (> 0.2 ng/ml of plasma) showed significant
      seasonal variation (P < 0.001). The frequency of OTA-positive samples was the
      highest in March (65%) and it gradually decreased towards December (12%). The
      high frequency of positive samples coincided with seasons favouring growth of
      moulds and production of toxins. The daily intake of OTA by healthy persons in
      Zagreb was estimated from the mean concentration of OTA in samples collected
      during the whole year (0.19 ng OTA/ml plasma). The estimated daily intake was
      0.26 ng/kg b.w., that is, substantially below the tolerable daily intake proposed
      by World Health Organization (16.0 ng/kg b.w.).

PMID- 10649843
TI  - Hygienic conditions in elementary and secondary schools in the county of Split
      Dalmatia.
AB  - This paper gives an assessment of hygienic conditions found in 22 primary and 12
      secondary schools in the city of Split during the school year 1990/91. The data
      were compared with the results of a similar investigation carried out in eight
      primary schools in the neighbouring Sinj area. The assessment consisted of the
      examination of the facilities, questionnaires, and microbiological analysis of
      numerous samples. Most schools failed to meet the recommendations for hygienic
      and sanitary maintenance, particularly with regard to sanitary facilities for
      students and staff. Exposure to noise, inadequate lighting, and poor maintenance
      of gymnasiums were noticed. Of the total number of smears taken from the
      students' hands and various surfaces in schools in the Sinj area, group D
      streptococcus was isolated in 62% and E. coli in 43% of samples. Both bacteria
      indicate faecal contamination. The data suggest a low level of personal and
      general hygiene in schools. It is necessary to improve the hygienic conditions in
      the schools of the Split and Sinj area and to focus on health education. It would
      reduce the risk of intestinal and respiratory infectious diseases and potential
      sight and hearing impairments in students.

PMID- 10649844
TI  - Comparison of two methods using atomic absorption spectrometry for determination
      of selenium in food.
AB  - This study describes and compares two methods of atomic absorption spectrometry
      (AAS) for the selenium (Se) analysis in food: electrothermal AAS (ET AAS) and
      hydride generation method of AAS (HG AAS). The accuracy of the two methods was
      established by analysing two biological reference materials: Wheat Flour 1567a
      and Bovine Liver 1577b from the National Institute of Standards and Technology,
      USA. Good agreement with certified values was obtained for both methods. The
      accuracy of ET AAS method is 109% and 103% for Wheat Flour and Bovine Liver,
      respectively. The respective accuracies for HG AAS method were 88% and 87%. The
      detection limit obtained for ET AAS was 1 microgram Se/L and for HG AAS 0.02
      microgram Se/L. The repeatability of ET AAS method was 5-11% and that of HG AAS
      14-17%. Both methods are similar in accuracy and repeatability, but hydride
      generation (HG AAS) is more sensitive than graphite furnace technique (ET AAS)
      for determination of selenium in food.

PMID- 10649845
TI  - A case report of acute human molybdenum toxicity from a dietary molybdenum
      supplement--a new member of the "Lucor metallicum" family.
AB  - The paper gives a brief review of human molybdenum metabolism and toxicity and
      presents the first known case of acute clinical poisoning with molybdenum from
      the dietary molybdenum (Mo) supplement in a male patient in late thirties. In
      over 18 days, the patient had consumed a cumulative dose of 13.5 mg Mo (300-800
      micrograms Mo/day). Followed the development of acute psychosis with visual and
      auditory hallucinations, a series of petit mal seizures, and one life threatening
      grand mal attack. The symptoms remitted several hours after the start of
      chelation therapy with calcium ethylene diamine tetraacetic acid (CaEDTA). A
      battery of neuropsychological tests and Spectral Emission Computer Tomography
      demonstrated evident frontal cortical damage of the brain. One year after the Mo
      poisoning, the patient was diagnosed toxic encephalopathy with executive
      deficiencies, learning disability, major depression, and post-traumatic stress
      disorder. The paper strongly advocates issuance of and strict adherence to
      written warnings on the instruction labels not to mix potentially harmful
      neurotoxic substances, such as molybdenum, with other nutriceuticals and to
      instructions stating maximal single and cumulative doses. Molybdenum is a new and
      unwelcome member of the "metal madness" family.

PMID- 10649846
TI  - [In vitro and in vivo micronucleus tests in genotoxicity research].
AB  - Working and living environment today is an unpredictable mixture of different
      chemical substances. Some of these chemicals are mutagenic carcinogens and others
      are aneugenic carcinogens. An additional burden to the human genome is the
      exposure to several kinds of radiations. Among a dozen genotoxicological methods
      in use in vitro and in vivo, the micronucleus assay has found application in the
      basic research, clinical research, and pharmacological studies. The advantage of
      in vivo and in vitro micronuclues assays is in the fact that they provide data on
      both clastogenic and aneugenic action of agents. Although several years behind
      the in vitro technique, the in vivo micronucleus assay has swiftly developed into
      a significant source of data in acute and chronic genotoxic investigations, as it
      does not require cell culture.

PMID- 10649847
TI  - Health effects studies related to occupational and environmental exposure.
AB  - This paper describes adverse health effect studies conducted at the Institute for
      Medical Research and Occupational Health since its foundation fifty years ago to
      the present day. The presentation of the studied problems is based mainly on the
      type of exposure--occupational or environmental--and partly on disease entities.
      The review is organised around the following topics: metals, organic solvents,
      and other organic chemicals, pneumoconioses and occupational pneumopathies,
      bronchial asthma and nonallergic bronchoconstrictive impairments, chronic
      nonspecific lung disease, studies of respiratory effects of exposure to air
      pollutants in schoolchildren, other problems concerned with pathology of work and
      workers' health protection, epidemiology of chronic noncommunicable diseases in
      general population groups, criteria for the assessment of disability and ability
      to work. The review concludes with a short description of achievements at the
      national and international level, and gives an anticipation of future research
      needs. Literature references provide a selection of publications on research
      activities presented herein.

PMID- 10649848
TI  - [The title of master in the history of health care].
AB  - The review examples of usage of the Latin term magister (master) in various
      common titles throughout the past, particularly in Croatia. As early as the Roman
      Empire and until the Middle Ages, the title magister designated various functions
      and duties, generally denoting authority, higher rank, or a responsible position.
      The review highlights certain historical events and persons related to the usage
      of the title magister. Ever since the Middle Ages, the title has specifically
      denoted various health care professions. The term was used in Latin, as it was
      the official language in Croatia at the time, for example, m. chirurgiae (master
      of surgery), m. obstetritiae (master of obstetrics), m. artis occularis (master
      of the eye-related skills), m. hospitalis (master of the hospice), m. sanitatis
      (health care master). As an example, the review shows the difference between the
      titles doctor medicinae and m. obstetritiae according to John the Baptist
      Lalangue (1743-1799), the official physician of the Varazdin county in the
      Hapsburg Empire and one of the most prominent figures in the history of health
      care in Croatia. Lalangue was the author of the first professional medical book
      in the Croatian language published in 1776 and of several other books in
      Croatian. The books were meant to teach medical professionals and ordinary people
      how to improve their health. Beside the title of medical doctor, Lalangue held
      the title of m. obstetritiae which he earned through additional education. He
      thought it was essential for a complete health provider to be trained both in
      general practice and in obstetrics which, at the time, included infant care.
      Nowadays in Croatia, only persons who are graduate pharmacists use magister
      pharmaciae as a professional title. The title is otherwise strictly reserved to
      denote an academic degree between the bachelor's and the doctoral in a particular
      field. The title magister scientiarum (Master of Science) is achieved upon
      completion of a postgraduate study and defence of the master's thesis.

PMID- 10649849
TI  - Effect of nitric oxide metabolism upon peripheral blood chemiluminiscence and
      leukocyte and erythrocyte adherence in multiple sclerosis.
AB  - BACKGROUND: It has become increasingly apparent that nitric oxide (NO) and
      related metabolic and effector systems play an important role in immune
      regulations, in inflammatory response and in cellular and tissue damage in
      multiple sclerosis (MS) and in its experimental models. OBJECTIVES: Various
      adherence interactions and metabolism of reactive oxygen species belong to the
      cellular functions associated with NO metabolism. The aim of the present study
      was to evaluate the effect of chemical compounds affecting NO metabolism on
      adhesive properties of leukocytes and erythrocytes and on the blood
      chemiluminiscence in MS patients in comparison with controls. The effects of NG
      Methyl-L-Arginine (NGMLA), a specific competitive NO antagonist, L-arginin, NO
      precursor, and sodium nitroprusside, an NO-releasing agent were tested. METHODS:
      Luminol dependent chemiluminiscence was measured with and without respective drug
      administration, the results were expressed as chemiluminiscence index. Adherence
      of peripheral blood cells to nylon wool was used for the adherence studies, the
      results were expressed in a form of adhesivity index. Studies were performed in a
      group of patients with active multiple sclerosis, in a group of neurological
      controls and in a group of healthy controls. The differences between MS patients
      and control groups were statistically evaluated using Mann and Whitney U-test.
      MAIN RESULTS: Sodium nitroprusside stimulated the luminol-dependent
      chemiluminiscence in MS patients and inhibited it in both control groups. The
      difference between MS patients and the control patient subgroup was proved to be
      statistically significant. Statistically significant inhibition of leukocyte
      adherence by arginine was found in MS patients in comparison to healthy controls,
      in whom stimulation of adherence was observed. When differentiating the effect of
      the agents upon particular leukocyte subpopulations the only statistically
      significant difference was found with arginine and granulocytes, the trend being
      similar as in the total leukocyte adherence. Sodium nitroprusside further
      stimulated the adherence of erythrocytes in MS patients and inhibited it in
      controls. CONCLUSIONS: Results indicate nitric oxide-dependent alterations of
      oxidative metabolic burst and of cellular adherence properties in patients with
      active multiple sclerosis. Our findings also question possible participation of
      granulocytes and erythrocytes in multiple sclerosis pathogenetic cascade.

PMID- 10649850
TI  - [Nitrergic structures in the spinal ganglia in rabbits].
AB  - Nitrergic structures in normal rabbit dorsal root ganglia (DRG) were demonstrated
      in this study. Histochemical reaction for detection of NADPH-d activity was used
      indicating, the presence of nitric oxide synthase (NOS). Diaphorase activity was
      found mostly in small ganglion cells. The cells defined as intermediate in size
      were stained less frequently, and no big cell expressed diaphorase activity. The
      intensity of staining varied from light blue and violet to very dark. The highest
      number of reactive cells was detected in the sacral DRG. Neurons expressed very
      low concentration of diaphorase activity in cervical, thoracic and lumbar DRGs.
      These findings suggest, that NADPH-diaphorase activity demonstrate a distinctive
      distribution depending upon spinal level.

PMID- 10649851
TI  - [Mechanisms of the effect of oxidants on the respiratory system].
AB  - BACKGROUND: It is known that oxidants may evoke changes of respiratory tract
      functions. The precise mechanisms of these changes are yet unknown. MAIN PURPOSE:
      In this study possible participation of eicosanoids, cytochrome P-450 and
      reactive oxygen species in the changes of airways reactivity evoked by toluene
      exposure as the source of free radicals was followed up by an indirect method.
      METHODS: Used drugs--naproxen (50 mg/kg b.w.), cimetidine (50 mg/kg b.w.) and N
      acetylcysteine (300 mg/kg b.w.) were administered in two doses (first 30 minutes
      before exposure to toluene, second six hours after first dose). After exposure to
      toluene (2 hours in each of 3 consecutive days) was followed up reactivity of
      tracheal and lung smooth muscle to histamine in "in vitro" conditions. The
      studied substances were not administered in the control group of animals.
      RESULTS: In pretreated animals exposed to toluene the administration of naproxen,
      cimetidine and N-acetylcysteine does not provoke pronounced changes of tracheal
      smooth muscle reactivity compared to control group. More pronounced effect of
      these drugs with decrease contraction amplitude was detected on lung smooth
      muscle reactivity. CONCLUSION: According to our results it is not possible to
      determine the precise mechanisms which participate in changes of airways
      reactivity. There are probably multifactorial in nature.

PMID- 10649852
TI  - [Role of free radicals, oxidative stress and antioxidant systems in liver
      diseases].
AB  - Recent experimental findings suggest that free radicals and oxidative stress play
      an important role in the pathogenesis of alcoholic and toxic liver diseases and
      viral hepatitis. The presented review summarizes knowledge on the pathomechanism
      of free radical reactions in liver diseases and the results of experimental
      observations of antioxidant systems and adjuvant antioxidant pharmacotherapy.
      Some of the hepatoprotective drugs have antioxidant activity and can produce such
      beneficial effects as membrane stabilisation, neutralization of free radicals and
      immunomodulation. Some liver diseases can be successfully prevented or treated by
      supplementation with antioxidant active substances of even plant origin.

PMID- 10649853
TI  - [Use of membranes based on collagen as tissue substitutes].
AB  - Collagen, as biocompatible and bioactive non-specific polymer, occupies prominent
      position in the field of tissue engineering. The advanced biomaterials prefer
      collagen as a matrix for biodegradable implants as are biosynthetic skin
      substitutes, tendon and ligament substitutes, but also cartilage. Many studies
      notice the application of chemically modified collagen membranes for hernia and
      anastomoses reparations, vascular prosthetic materials, or for collagen tubes
      used in regeneration of peripheral nerves. Besides of defining main problems of
      tissue engineering, the paper analyses the developmental tendency of these
      biomaterials in the world, and compares it with the situation in Slovak Republic.

PMID- 10649854
TI  - [Collagen in the treatment of rheumatic diseases--oral tolerance].
AB  - The term "oral tolerance" means antigen specific suppression of immune response
      after oral application of antigen. Primary mechanisms by which oral tolerance is
      mediated include: deletion, anergy and active cellular suppression. The
      determining factor in this process is the dose of applied antigen. High doses of
      antigen develop deletion and anergy of cells while low doses of antigen result in
      bystander suppression. Recently bystander suppression has attracted attention in
      the treatment of autoimmune diseases. This process is connected with induction of
      regulatory T cells of Th2/Th3 phenotypes in gut with characteristic profile of
      anti-inflammatory cytokines as IL-4, IL-10 and TGF-beta. By means of circulation
      the lymphocytes enter the affected place and when meeting again with the antigen,
      they produce the same profile of cytokines which they originally made in the gut.
      These cytokines then suppress local autoimmune and inflammatory reaction
      independently of the antigen type. After successful trials of treatment with low
      doses of orally applied collagen type II in animal models of experimental
      arthritis, this treatment was also studied in clinical trials in humans with
      rheumatoid arthritis. Although the results obtained to this date are very
      promising they can not be considered final. Several questions still need to be
      solved: identification of responders, determination of character and amount of
      collagen applied as well as the route of application. Another promising
      therapeutic approach could be the simultaneous application of collagen and the
      compounds enhancing the cell response of Th2 or Th3 lymphocytes such as TGF-beta,
      IL-2, antibodies to IL-12 which can augment the oral tolerance. In clinical
      praxis the treatment of osteoarthrosis with collagen type I has also been
      successfully applied. Induction of oral tolerance is new approach in the
      treatment of rheumatoid arthritis and as each new therapy, it requires
      refinement. In the future it is expected that an improved study design and a
      better understanding of the underlying mechanisms of oral tolerance will lead to
      an increased efficacy of the therapy in humans similar to the effectiveness
      previously demonstrated in animal models.

PMID- 10649855
TI  - [Lateral inhibition and its role in the physiology of sensory organs].
AB  - Lateral inhibition represents the neural mechanism stabilizing the activity in
      neural networks. The present paper introduces the different types of lateral
      inhibition and presents the neurophysiological data demonstrating its existence
      in the nervous system. Lateral inhibition is mainly discussed in sensory organs.
      However, its manifestation in psychophysics are ambiguous. Some psychophysical
      phenomena do support the concept of lateral inhibition, other contradict. A
      possible explanation is a covering of the existent lateral inhibition network by
      excitatory synapses. Lateral inhibition therefore does not dominate the behavior
      of the whole system, even though it is important in stabilizing the excitatory
      activity in it.

PMID- 10649856
TI  - House dust induces IL-6 and IL-8 response in A549 epithelial cells.
AB  - The in vitro potency of house dust to induce cytokine response in A549 lung
      epithelial cells was studied. Dusts collected from carpet, bed, shelf and floor
      of a villa and an apartment by vacuuming were found to trigger the production of
      interleukin-8 (IL-8) and interleukin-6 (IL-6) in a dose-dependent manner, and the
      interleukin production was several-fold higher than of swine dust (used as a
      positive control). The IL-8 and IL-6 production of pure Escherichia coli
      lipopolysaccharide was significantly lower than of the dusts and a peptidoglycan
      polysaccharide complex did not show any stimulatory effect at all. The
      lipopolysaccharide and peptidoglycan contents of the samples were determined by
      gas chromatography-tandem mass spectrometry analysis of, respectively, 3-hydroxy
      fatty acids and muramic acid; in addition, ergosterol was monitored for fungal
      biomass. The inflammatory properties of house dust upon inhalation may be
      reflected in its high potency to induce cytokine response in lung epithelial
      cells.

PMID- 10649857
TI  - Association of ventilation rates and CO2 concentrations with health and other
      responses in commercial and institutional buildings.
AB  - This paper reviews current literature on the associations of ventilation rates
      and carbon dioxide concentrations in non-residential and non-industrial buildings
      (primarily offices) with health and other human outcomes. Twenty studies, with
      close to 30,000 subjects, investigated the association of ventilation rates with
      human responses, and 21 studies, with over 30,000 subjects, investigated the
      association of carbon dioxide concentration with these responses. Almost all
      studies found that ventilation rates below 10 Ls-1 per person in all building
      types were associated with statistically significant worsening in one or more
      health or perceived air quality outcomes. Some studies determined that increases
      in ventilation rates above 10 Ls-1 per person, up to approximately 20 Ls-1 per
      person, were associated with further significant decreases in the prevalence of
      sick building syndrome (SBS) symptoms or with further significant improvements in
      perceived air quality. The carbon dioxide studies support these findings. About
      half of the carbon dioxide studies suggest that the risk of sick building
      syndrome symptoms continued to decrease significantly with decreasing carbon
      dioxide concentrations below 800 ppm. The ventilation studies reported relative
      risks of 1.5-2 for respiratory illnesses and 1.1-6 for sick building syndrome
      symptoms for low compared to high low ventilation rates.

PMID- 10649858
TI  - Evaluation of low-VOC latex paints.
AB  - Four commercially available low-volatile organic compound (VOC) latex paints were
      evaluated as substitutes for conventional latex paints by assessing both their
      emission characteristics and their performance as coatings. Bulk analysis
      indicated that the VOC contents of all four paints tested were considerably lower
      than those of conventional latex paints. Low VOC emissions were confirmed by
      small chamber emission tests. However, significant emissions of several
      aldehydes, especially formaldehyde which is a hazardous air pollutant, were
      detected in emissions from two of the four paints. American Society for Testing
      and Materials (ASTM) methods were used to evaluate the hiding power, scrub
      resistance, washability, dry to touch and yellowness index. The results indicated
      that one of the four low-VOC paints tested showed performance equivalent or
      superior to that of a conventional latex paint used as control. It was concluded
      that low-VOC latex paint can be a viable option to replace conventional latex
      paints for prevention of indoor air pollution. However, paints marketed as "low
      VOC" may still have significant emissions of some individual VOCs, and some may
      not have performance characteristics matching those of conventional latex paints.

PMID- 10649859
TI  - Assessment of pollutant emissions from dry-process photocopiers.
AB  - Processes involved in pollutant emissions from a dry-process photocopier have
      been investigated in a controlled room dynamic environmental chamber. Volatile
      organic compound (VOC) emissions occurred at a constant rate dependent on copy
      speed. However, VOC emission rates per copy were increased by increases in
      chamber temperature (e.g., a 20% increase resulted from increasing temperature
      from 23 degrees C to 32 degrees C) or changing from single- to double-sided
      operation (40% increase). Respirable particle emissions occurred under copier
      idle mode (probably from residues in the machine) as well as with copying. No
      significant chamber sink effects were observed for VOCs or respirable particles.
      Small emissions of nitrogen dioxide, ozone and formaldehyde were observed but
      were difficult to interpret. A procedure for assessing pollutant emissions from
      photocopiers is recommended.

PMID- 10649860
TI  - Determination of formaldehyde emission with field and laboratory emission cell
      (FLEC)--recovery and correlation to the chamber method.
AB  - The formaldehyde emission from wood-based building materials is usually
      determined in large chambers at a defined temperature, humidity and ventilation
      rate. In this article, a simpler method, the Field and Laboratory Emission Cell
      (FLEC), is described for determination of the formaldehyde emission and it is
      compared with the traditional chamber method. The formaldehyde from FLEC is
      collected on a silicagel cartridge impregnated with 2,4-dinitrophenylhydrazine
      (DNPH) and analysed with HPLC. The FLEC is easier to operate, requires a smaller
      sample, fewer analyses and is also more flexible than the chamber method. The
      emissions from different parts of a sample can be measured. Another advantage is
      that the equipment can be used to determine the volatile organic compounds (VOCs)
      emission at the same time. The FLEC method gives a good correlation to the
      chamber method for different building products. It also gives a good recovery. An
      average recovery of 98% was achieved, when two different FLEC-cells were tested
      with known formaldehyde sources with emissions of 0.06-0.7 mg/m2h.

PMID- 10649861
TI  - Ventilation efficiencies of desk-mounted task/ambient conditioning systems.
AB  - In laboratory experiments, we investigated two task/ambient conditioning systems
      with air supplied from desk-mounted air outlets to efficiently ventilate the
      breathing zone of heated manikins seated at desks. In most experiments, the task
      conditioning systems provided outside air while a conventional ventilation system
      provided additional space cooling but no outside air. Air change effectiveness
      (i.e., exhaust air age divided by age of air at the manikin's face) was measured
      with a tracer gas step-up procedure. Other tracer gases simulated the release of
      pollutants from nearby occupants and from the floor covering, and the associated
      pollutant removal efficiencies (i.e., exhaust air concentrations divided by
      concentrations at manikin's face) were calculated. High values of air change
      effectiveness (approximately 1.3 to 1.9) and high values of pollutant removal
      efficiency (approximately 1.2 to 1.6) were measured when these task conditioning
      systems supplied 100% outdoor air at a flow rate of 7 to 9 L s-1 per occupant.
      Air change effectiveness was reasonably well correlated with the pollutant
      removal efficiency. Overall, the experimental data suggest that these
      task/ambient conditioning systems can be used to improve ventilation and air
      quality or to save energy while maintaining a typical level of IAQ at the
      breathing zone.

PMID- 10649862
TI  - Stability of mechanical exhaust systems.
AB  - The mechanical exhaust system, where outdoor air is supplied through infiltration
      and devices in the building shell, is a common ventilation technique in multi
      family buildings in Europe. The objective of this paper is to determine how well
      the system meets indoor air quality standards and regulations and how sensitive
      it is to disturbances, such as window opening, temperature differences and
      resident behavior, and how different building construction parameters affect the
      airflow. A simple model of a multi-family building has been simulated with a
      multi-zone infiltration program. It was found that the system almost never
      fulfills the regulations and that the actions of one resident can often affect
      the airflow in other apartments. The use of standards and regulations defining
      indoor air quality and energy efficiency will be ineffective for these systems
      because they are not stable, that is, sensitive to disturbances such as weather
      changes and resident behavior.

PMID- 10649863
TI  - Indoor air quality and the law in Singapore.
AB  - With the greater use of air-conditioned offices in Singapore, achieving good
      indoor air quality has become an important issue. The laws that impose duties
      upon designers and contractors with respect to the design and construction of air
      conditioning and mechanical ventilation (ACMV) systems are set out in the
      Building Control Regulations and the Singapore Standard Code of Practice for
      Mechanical Ventilation and Air-conditioning in Buildings (hereinafter "SS CP
      13:1980"). ACMV maintenance is governed by the Environmental Public Health Act,
      the Building and Common Property (Maintenance and Management) Act, and the Land
      Titles (Strata) Act, as well as by lease or tenancy agreements. Designers,
      contractors, developers, building owners and management corporations may also be
      liable to the workers, occupants and other premises users for indoor air quality
      (IAQ)-related injuries under the general principles of contract and tort.
      Recently, the Guidelines for Good Indoor Air Quality in Office Premises was
      issued by the Ministry of Environment to complement SS CP 13:1980 toward
      improving the indoor air quality of air-conditioned office premises. Although the
      Guidelines have no statutory effect, they may be adopted as contractual
      requirements in construction, lease and maintenance contracts. They may also be
      used to determine the relevant standard of duty of care required to discharge
      tortious liability. This paper looks at the existing laws and rules affecting the
      design, construction and maintenance of air-conditioned offices in light of Part
      III of the Ministry's Guidelines.

PMID- 10649864
TI  - Thinking outside the box.

PMID- 10649865
TI  - Managing space problems.

PMID- 10649866
TI  - Digital radiographs.

PMID- 10649867
TI  - Cosmetic dentistry.

PMID- 10649868
TI  - Enzyme deficiency linked to periodontitis.

PMID- 10649869
TI  - Patient data protection recommendations being developed.

PMID- 10649870
TI  - Advances in biorestorative materials. What does the future hold?. Interview by
      Lawrence H. Meskin.

PMID- 10649871
TI  - Clinical evaluation of amalgam bonding in Class I and II restorations.
AB  - BACKGROUND: Many dental practitioners are bonding amalgam to tooth structure.
      Although in vitro studies support this procedure, its efficacy has not been
      adequately confirmed in the clinical environment. METHODS: The authors placed
      traditional Class I and Class II bonded and unbonded amalgam restorations in 76
      patients. Panavia 21 (J. Morita USA Inc.) was the bonding agent selected, and
      Aristaloy CR (Englehard Dental) and Tytin (Kerr Corp.) were the amalgam alloys
      used. Postoperative sensitivity and marginal fracture were evaluated at yearly
      intervals, for up to three years of clinical service. RESULTS: At the patients'
      appointment for polishing one to two weeks after restoration placement, and at
      each yearly recall appointment, the authors found no significant difference in
      postoperative sensitivity between bonded and unbonded restorations for either
      amalgam alloy (chi 2 analysis, alpha = .05). In addition, there was no
      significant difference between bonded and unbonded restorations for either
      amalgam alloy with respect to marginal fracture (analysis of variance and Tukey's
      contrasts at alpha = .05). Moreover, no cusp fractures were observed for either
      bonded or unbonded restorations. CONCLUSIONS: After three years of clinical
      service, amalgam bonding for traditional Class I and Class II restorations had no
      effect on postoperative sensitivity or marginal integrity. CLINICAL IMPLICATIONS:
      The merit of using adhesive bonding agents for traditional Class I and Class II
      amalgam restorations was not demonstrated in this three-year clinical study.

PMID- 10649872
TI  - Pharmacokinetics of bisphenol A released from a dental sealant.
AB  - BACKGROUND: Limited information is available regarding potentially estrogenic
      bisphenol A, or BPA, released from dental sealants. This study determined the
      rate- and time-course of BPA released from a dental sealant (Delton Opaque Light
      cure Pit and Fissure Sealant, Preventive Care/Dentsply) when applied at a dosage
      of 8 milligrams (one tooth) or 32 mg (8 mg on each of four teeth) to 40 healthy
      adults. METHODS: The authors recruited 40 healthy subjects (18 men and 22 women,
      20-55 years of age) who did not have histories of pit and fissure sealant
      placement or composite resin restorations. The authors collected saliva (30
      milliliters) and blood (7 mL) specimens from all subjects immediately before
      sealant placement (baseline) and at one hour, three hours, one day, three days
      and five days after sealant placement. They used high-pressure liquid
      chromatography to determine BPA (detection sensitivity 5 parts per billion, or
      ppb) in all specimens. RESULTS: The authors detected BPA in some saliva specimens
      (5.8-105.6 ppb) collected at one hour and three hours. The BPA, however, was not
      detectable beyond three hours or in any of the serum specimens. For the one- and
      three-hour saliva samples, the BPA concentration in the high-dose (32 mg) group
      was significantly greater than in the low-dose (8 mg) group (P < .05, Wilcoxon
      signed rank test). In the high-dose group, there was a significant decrease in
      saliva BPA concentrations from one hour to three hours (P < .01, Wilcoxon signed
      rank test). CONCLUSION: This study showed that BPA released orally from a dental
      sealant may not be absorbed or may be present in nondetectable amounts in
      systemic circulation. The concern about potential estrogenicity of sealant may be
      unfounded.

PMID- 10649873
TI  - Automated personal health inventory for dentistry: a pilot study.
AB  - BACKGROUND: The authors conducted a study to investigate the feasibility of
      having patients enter their health histories, or HHs, directly into a computer so
      the HHs then can be transferred into computer-based patient records. The authors
      examined a patient-completed, pen-based computerized HH questionnaire to
      determine if it is acceptable to patients, if patients answer sensitive questions
      on the HH questionnaire more forthrightly using a computer than a pen and paper,
      and if the availability of explanations and examples provided for each question
      on the computer questionnaire results in more accurate responses than on the
      paper version. METHODS: Fifty subjects completed two almost identical versions of
      a 78-item HH questionnaire, completing either the pen-based, computerized version
      first or the paper version first. After the subjects finished the questionnaires,
      they completed an opinion survey about using the computer to provide their HHs.
      RESULTS: Subjects responded favorably to the use of a pen-based computer
      questionnaire to provide their HH; 73 percent indicated that they would prefer to
      use it in the future rather than complete a paper questionnaire. The authors
      found that the overall reliability of answers was 93 percent with an average of
      5.4 inconsistent answers between the two HH questionnaires. CONCLUSIONS: HHs can
      be collected efficiently and reliably from patients using a computer. It is
      important, however, that oral health care professionals review the data provided
      on HHs with their patients regardless of method used to collect them. CLINICAL
      IMPLICATIONS: Practices can expand the use of computers into more areas of
      patient care by having patients complete a computerized HH questionnaire.
      Computerized data capture is more legible, complete and efficient than a paper HH
      and can be imported directly into clinical data systems, thus avoiding data
      entry.

PMID- 10649874
TI  - Formation of a facial hematoma during endodontic therapy.
AB  - BACKGROUND: Sodium hypochlorite, or NaOCl, is one of the most commonly used
      irrigating solutions in endodontic practice. Its clinically proven antibacterial,
      solvent and lubricating properties make it a very appealing choice as an
      intracanal medicament. CASE DESCRIPTION: The authors present a case of facial
      hematoma formation after an inadvertent injection of NaOCl into the periapical
      tissues. The NaOCl solution caused extensive tissue destruction. Management of
      the condition required the hospitalization, intravenous antibiotic therapy and
      multiple intraoral surgical incisions to facilitate drainage. CLINICAL
      IMPLICATIONS: Use of NaOCl must be confined to the root canal system. This report
      reviews this intracanal medicament's potential toxicity and emphasizes the need
      for clinicians to remain cognizant of possible problems while using the solution.

PMID- 10649875
TI  - Restoring screw-retained implant prostheses.

PMID- 10649876
TI  - A simple test for profound anesthesia.

PMID- 10649877
TI  - Myths of dental surgery in patients receiving anticoagulant therapy.
AB  - BACKGROUND: Continuous anticoagulant therapy with warfarin is administered to
      prevent a variety of medical complications, including thromboembolisms and
      stroke. When patients receiving continuous anticoagulant therapy are scheduled
      for dental surgery, a decision must be made whether to continue or interrupt the
      anticoagulant therapy. METHODS: The author reviewed the literature, focusing on
      dental surgery in patients receiving continuous anticoagulant therapy and in
      patients whose anticoagulant therapy was withdrawn before they underwent dental
      procedures. RESULTS: Of more than 950 patients receiving continuous anticoagulant
      therapy (including many whose anticoagulation levels were well above currently
      recommended therapeutic levels) who underwent more than 2,400 surgical
      procedures, only 12 (< 1.3 percent) required more than local measures to control
      hemorrhage. Only three of these patients (< 0.31 percent) had anticoagulation
      levels within or below currently recommended therapeutic levels. Of 526 patients
      who experienced 575 interruptions of continuous anticoagulant therapy, five (0.95
      percent) suffered serious embolic complications; four of these patients died.
      CONCLUSIONS: Serious embolic complications, including death, were three times
      more likely to occur in patients whose anticoagulant therapy was interrupted than
      were bleeding complications in patients whose anticoagulant therapy was continued
      (and whose anticoagulation levels were within or below therapeutic levels).
      Interrupting therapeutic levels of continuous anticoagulation for dental surgery
      is not based on scientific fact, but seems to be based on its own mythology.
      CLINICAL IMPLICATIONS: Dentists should recommend that therapeutic levels of
      anticoagulation be continued for patients undergoing dental surgery.
      Practitioners should consult with the patient's physician if necessary to
      determine his or her level of anticoagulation before performing dental surgery.

PMID- 10649878
TI  - The diversity of dentistry.
AB  - In a relatively brief time, the dental profession has evolved into one of the
      most recognized and respected professions. There still is, however, a lack of
      public knowledge about dentistry and the procedures dentists can accomplish in
      addition to restoring teeth. Life-enhancing, dramatically significant oral
      procedures now are available to the public. The diverse nature of the
      professional activities in which dentists may involve themselves needs to be made
      public knowledge. This education of the public should come from the individual
      members of the profession and from organized dental groups.

PMID- 10649879
TI  - Health promotion made easy--give a gift!

PMID- 10649880
TI  - Trends in untreated caries in primary teeth of children 2 to 10 years old.
AB  - BACKGROUND: This article is the second in a series of three that focus on recent
      changes in the caries status of children and adolescents in the United States.
      METHODS: This study is based on analyses of data regarding untreated carious
      primary teeth among children 2 to 10 years of age from the first and third
      National Health and Nutrition Examination Surveys, or NHANES I and NHANES III.
      The NHANES is conducted periodically by the National Center for Health Statistics
      of the Centers for Disease Control and Prevention. RESULTS: Overall, the number
      of carious primary teeth among children 2 to 10 years old decreased from 1.42 as
      measured in NHANES I to 0.63 as measured in NHANES III. The number of carious
      primary teeth in children 2 to 10 years old also decreased across four
      demographic variables: age, sex, race and poverty level. CONCLUSIONS: The number
      of untreated carious primary teeth among children has declined. Since the 1970s,
      the absolute difference in untreated caries between disadvantaged children in the
      United States and the rest of the U.S. child population has narrowed, although
      not to the same extent as in permanent teeth. PRACTICE IMPLICATIONS: On average,
      children of preschool and elementary-school age have less untreated caries than
      in the past. More often, dentists do not need to treat on a first visit. This
      provides more opportunity to introduce these children to preventive dentistry at
      an early age.

PMID- 10649881
TI  - The efficacy of a counter-rotational powered toothbrush in the maintenance of
      endosseous dental implants.
AB  - BACKGROUND: Although most patients with implants have lost their natural teeth
      because of poor oral hygiene, limited data exist to guide practitioners in their
      recommendations of home-care regimens for their patients' endosseous dental
      implants and maintenance of peri-implant soft-tissue health. The authors
      conducted a study to compare the home-care effectiveness of a counter-rotational
      powered tooth-brush with that of conventional home-care regimens. METHODS: Before
      starting the six-year study, the authors trained 85 clinical investigators at 32
      dental research centers across the United States in gathering periodontal data.
      Data for 2,966 implants were entered into a centralized database. Outcomes were
      derived from 24-month observations of a subset of the implants studied. RESULTS:
      Repeated-measures analysis of the toothbrushing methods used on 2,966 implants
      showed that the counter-rotational powered toothbrush removed plaque
      significantly better than manual methods (P < .0001 Wald statistic) from all
      implant surfaces and at all recall intervals up to 24 months. Similar results
      were demonstrated for the gingival index. CONCLUSIONS: The counter-rotational
      powered brush appears to be well-suited for home-care regimens aimed at
      maintaining optimal peri-implant soft-tissue health in patients with dental
      implants. CLINICAL IMPLICATIONS: The importance of maintaining the health of the
      peri-implant tissues is well-recognized by the dental profession. The counter
      rotational powered toothbrush is an effective tool in meeting the oral hygiene
      challenges associated with implant prosthesis maintenance.

PMID- 10649882
TI  - Treating hearing-impaired people.

PMID- 10649883
TI  - Phytochromes, cryptochromes, phototropin: photoreceptor interactions in plants.
AB  - In higher plants, natural radiation simultaneously activates more than one
      photoreceptor. Five phytochromes (phyA through phyD), two cryptochromes (cry1,
      cry2) and phototropin have been identified in the model species Arabidopsis
      thaliana. There is light-dependent epistasis among certain photoreceptor genes
      because the action of one pigment can be affected by the activity of others.
      Under red light, phyA and phyB are antagonistic, but under far-red light,
      followed by brief red light, phyA and phyB are synergistic in the control of
      seedling morphology and the expression of some genes during de-etiolation. Under
      short photoperiods of red and blue light, cry1 and phyB are synergistic, but
      under continuous exposure to the same light field the actions of phyB and cry1
      become independent and additive. Phototropic bending of the shoot toward
      unilateral blue light is mediated by phototropin, but cry1, cry2, phyA and phyB
      positively regulate the response. Finally, cry2 and phyB are antagonistic in the
      induction of flowering. At least some of these interactions are likely to result
      from cross talk of the photoreceptor signaling pathways and uncover new avenues
      to approach signal transduction. Experiments under natural radiation are
      beginning to show that the interactions create a phototransduction network with
      emergent properties. This provides a more robust system for light perception in
      plants.

PMID- 10649884
TI  - Mechanistic and kinetic aspects of photosensitization in the presence of oxygen.
AB  - Determining whether the first step of photooxygenation is Type I or Type II is a
      necessary prerequisite in order to establish the mechanism of photodynamic
      action. But this distinction is not sufficient, because other processes, both
      consecutive and competitive, commonly participate in the overall mechanism. Thus,
      in both Type I and Type II reactions, the initial products are often peroxides
      that can break down and induce free radical reactions. These aspects of
      photosensitization are discussed and illustrated by sensitizer/substrate systems
      involving (1) only radical reactions (decatungstate/alkane) and (2) reactions of
      singlet oxygen occurring in competitive and consecutive processes and possibly
      followed by radical reactions (methylene blue/2'-deoxyguanosine). Two other
      previously investigated systems involving, respectively, a Type II interaction
      followed by radical processes (methylene blue/alkene) and Type II reactions, some
      of which being competitive or consecutive (rose bengal/alkene), are briefly
      reconsidered.

PMID- 10649885
TI  - Photobiological properties of positively charged methylene violet analogs.
AB  - O-Methyl methylene violet (OMeMV), O-methyl bromomethylene violet (OMeBrMV) and O
      methyl iodomethylene violet (OMeIMV) have been prepared in order to test their
      potential utility as anti-viral and anti-tumor phototoxic dyes. Rates of
      photosensitized toxicity of KB cells with 633 nm irradiation are (x 10(-19)
      photon-1): 2.4, 2.2, 1.9 and 0.17 for OMeIMV, OMeBrMV, methylene violet (MV) and
      OMeMV, respectively. Rates of photosensitized inactivation of Sindbis virus in
      phosphate-buffered saline with 633 nm irradiation are (x 10(-18) photon-1): 3.3,
      1.8, 0.99, 0.15 for MV, OMeIMV, OMeBrMV and OMeMV, respectively. Quantum
      efficiencies for singlet oxygen formation were determined as OMeIMV, 0.64;
      OMeBrMV, 0.40; OMeMV, 0.054. Titration of the dyes with double-stranded (ds)DNA
      resulted in bathochromic shifts and hypochromic effects in the visible absorption
      spectra. Association constants for interaction of the methylated dyes with dsDNA
      of approximately 1 x 10(5) M-1 were determined by Scatchard analysis of
      equilibrium dialysis and UV absorption titration data. Photolysis of the
      halogenated dyes with DNA under argon led to covalent bond formation with the
      nucleic acid; there was no evidence of covalent binding in the dark.

PMID- 10649886
TI  - The photochemical behavior of colchicone and thiocolchicone.
AB  - The irradiation of colchicone 5 led to the formation of lumicolchicone 7. The
      same reaction cannot be obtained by using thiocolchicone 6 as substrate.
      Transient absorption spectroscopy of colchicone and beta-lumicolchicone showed
      that probably the photoisomerization occurred on colchicone in its first excited
      singlet state. The spectroscopic data are in agreement with the hypothesis that
      lumicolchicone was generated in the ground state from the S1 state of colchicone
      without the presence of any intermediate. Semiempirical calculations on
      colchicone and thiocolchicone showed that the highest single occupied molecular
      orbital and the lowest unoccupied molecular orbital of the singlet excited
      colchicone can give a disrotatory ring closure to 7, while thiocolchicone cannot
      give the same type of process.

PMID- 10649887
TI  - Use of styrene radical cations as probes for the complexation dynamics of charged
      guests with alpha- and beta-cyclodextrins.
AB  - The complexation dynamics of radical cations with cyclodextrins (CD) was studied
      using photophysical techniques. Radical cations of 4-vinylanisole and trans
      anethole were formed within alpha- and beta-CD cavities by two-photon photolysis
      of the respective styrene precursors. Exit of the radical cations from alpha-CD
      complexes with 1: 1 and 1:2 (guest: CD) stoichiometries and beta-CD complexes
      with 1:1 stoichiometries occurred with lifetimes shorter than 100 ns. Most of the
      radical cations formed escape from the CD cavities, but a small portion do react
      with alpha-CD when this host is present in high concentrations.

PMID- 10649888
TI  - Studies on the radiolytically produced transients of neutral red: triplet and
      reduced radicals.
AB  - The spectral and kinetic properties of reduced radicals and the triplet state of
      neutral red (NR), a phenazine-based dye, have been investigated using pulse
      radiolysis technique. A mixed water-isopropanol-acetone solvent has been used to
      study the reduced radicals of NR for a wide pH range of about 1-13, due to
      limitation of solubility of the dye in aqueous solutions particularly above pH 8.
      From pH-dependent absorption studies it has been established that the reduced
      radicals of NR can exist in four different prototropic forms in solution. Three
      pKa values for the corresponding prototropic equilibria have been estimated. The
      formation and decay rate constants of reduced radicals have also been measured.
      The triplet state characteristics of the dye have been investigated in neat
      benzene solutions, both in the presence and in the absence of triplet
      sensitizers. The T1-->Tn absorption spectrum and decay kinetics of the triplet
      state have been measured. The triplet state energy (ET) of NR in benzene have
      been estimated to be within 36-42 kcal mol-1, using an energy transfer method.

PMID- 10649889
TI  - Photophysical properties of neutral and cationic tetrapyridinoporphyrazines.
AB  - We describe the synthesis and photophysical properties of a series of neutral and
      cationic 3,4-tetrapyridinoporphyrazines, potential lead photosensitizers for
      photodynamic inactivation of bacteria. Tetracationic TPyPzs exist essentially as
      monomers in aqueous systems, but the presence of trialkylated compounds due to
      incomplete quaternization of the outer nitrogen atoms induces severe aggregation.
      The absorption, fluorescence, triplet, and singlet oxygen quantum yields for both
      the neutral and cationic compounds are comparable to those of the related
      phthalocyanines.

PMID- 10649890
TI  - Correlations between reported and measured ultraviolet radiation exposure of
      mothers and young children.
AB  - Cumulative and intermittent sun exposure are risk factors for skin cancer,
      highlighting the need to monitor exposure during childhood. There is currently
      very little available information concerning the accuracy of self-reported levels
      of sun exposure, particularly for very young children. In this study, UV
      radiation (UVR) exposure measured by polysulfone dosimeters worn on the wrist was
      compared with a measure of estimated exposure using a diary based on recall at
      the end of the 4 day study period and ambient dosimetric measures. Results of the
      study indicate that the relative UVR exposures expressed as a fraction of daily
      total ambient received during the 4 day period by young children and mothers are
      similar. A high level of association was obtained for the estimated levels of
      exposure between young children and their mothers. Moderate correlations were
      evident for dosimeter readings of mother and child on weekends with no
      significant association on weekdays. The association between estimated exposure
      and dosimeter readings was poor and needs improvement. This may be achieved by
      greater consideration of structural and environmental factors that influence the
      levels of UVR exposure received by individuals and by increasing the level of
      specificity in the measurement instruments. Methodological issues such as recall
      of exposure after several days, quantity of sun exposure and more precise
      measurement of grades of exposure when outside may have more impact than
      previously expected, and further information is being sought with a larger sample
      for exposure during the summer months.

PMID- 10649891
TI  - Ultraviolet B irradiation modulates the immune system of fish (Rutilus rutilus,
      Cyprinidae). II: Blood.
AB  - The effects of a single dose of ultraviolet B (UVB) radiation (0.4 J/cm2) on
      immunological functions by blood leukocytes and on hematological parameters was
      studied in roach (Rutilus rutilus), a teleostean fish. The respiratory burst of
      phorbol 12-myristate 13-acetate stimulated whole blood phagocytes increased
      significantly after UVB irradiation but spontaneous cytotoxicity of blood
      leukocytes toward 51chromium-labeled K562 target cells was not markedly altered.
      Differential cell counting revealed that UVB exposure significantly increased the
      proportion of granulocytes and significantly decreased the proportion of
      lymphocytes in the peripheral blood, whereas hematocrit and the total number of
      white and red blood cells were unchanged. Plasma cortisol concentration increased
      in UVB-exposed fish. Severe handling stress caused similar, although not as
      potent, effects on the measured parameters of fish blood as UVB irradiation.
      These observations suggest that in fish UVB brings about a stress response, which
      may account for the observed alterations in the immune parameters and leukocyte
      composition of blood. Exposure of fish to strong visible light induced no
      alterations in immunological or hematological parameters, making it unlikely that
      ultraviolet radiation mediates its effects through visual perception.

PMID- 10649892
TI  - Chlorophyll a self-assembly in polar solvent-water mixtures.
AB  - The conversion of chlorophyll a (Chl a) monomers into large aggregates in six
      polar solvents upon addition of water has been studied by means of absorption,
      fluorescence spectroscopy and fluorescence lifetime measurements for the purpose
      of elucidating the various environmental factors promoting Chl a self-assembly
      and determining the type of its organization. Two empirical solvent parameter
      scales were used for quantitative characterization of the different solvation
      properties of the solvents and their mixtures with water. The mole fractions of
      water f1/2 giving rise to the midpoint values of the relative fluorescence
      quantum yield were determined for each solvent, and then various solvent-water
      mixture parameters for the f1/2 values were compared. On the basis of their
      comparison, it is concluded that the hydrogen-bonding ability and the dipole
      dipole interactions (function of the dielectric constant) of the solvent-water
      mixtures are those that promote Chl a self-assembly. The influence of the
      different nature of the non-aqueous solvents on the Chl aggregation is manifested
      by both the different water contents required to induce Chl monomer-->aggregate
      transition and the formation of two types of aggregates at the completion of the
      transition: species absorbing at 740-760 nm (in methanol, ethanol, acetonitrile,
      acetone) and at 667-670 nm (in pyridine and tetrahydrofuran). It is concluded
      that the type of Chl organization depends on the coordination ability and the
      polarizability (function of the index of refraction) of the organic solvent. The
      ordering of the solvents with respect to the f1/2 values--methanol < ethanol <
      acetonitrile < acetone < pyridine < tetrahydrofuran--yielded a typical lyotropic
      (Hofmeister) series. On the basis of this solvent ordering and the disparate
      effects of the two groups of solvents on the Chl a aggregate organization, it is
      pointed out that the mechanism of Chl a self-assembly in aqueous media can be
      considered a manifestation of the Hofmeister effect, as displayed in the lipid
      phase behavior (Koynova et al., Eur. J. Biophys. 25, 261-274, 1997). It relates
      to the solvent ability to modify the bulk structure and to distribute unevenly
      between the Chl-water interface and bulk liquid.

PMID- 10649893
TI  - Isolation and initial characterization of 13(2)-hydroxychlorophyll a induced by
      cyclohexanedione derivatives in tobacco cell suspension cultures.
AB  - This paper reports that a new photobleaching compound, 2-(2-chloro-5
      propoxycarbonylphenyl)aminomethylidene-5-5-dim ethyl- cyclohexane-1,3-dione (RWH
      21), stimulates accumulation of 13(2)-hydroxychlorophyll a in cultured tobacco
      cells. This was shown based on isolation of 13(2)-hydroxychlorophyll a from
      pigment extracts of cultured tobacco cells by diode-array HPLC and subsequent
      fast atom bombardment mass spectrometry analysis. 13(2)-Hydroxychlorophyll a
      rapidly accumulates in tobacco cells both in the light and dark in the presence
      of RWH-21 (50 microM). Analysis of 13(2)-hydroxychlorophyll a formation in
      tobacco cells indicates that 13(2)-hydroxychlorophyll a is rapidly accumulated
      within 20 h incubation time both in the dark and light. Although the amount of
      13(2)-hydroxychlorophyll a is continuously increased in the dark, the amount of
      13(2)-hydroxychlorophyll a decreased remarkably in the light after 20 h
      incubation. Analysis of 13(2)-hydroxychlorophyll a formation and lipid
      peroxidation by determination malondialdehyde in tobacco cells suggests that RWH
      21-induced 13(2)-hydroxychlorophyll a has the potential to cause a photodynamic
      action in cultured tobacco cells.

PMID- 10649894
TI  - Virus photoinactivation in stroma-free hemoglobin with methylene blue or 1,9
      dimethylmethylene blue.
AB  - Photoinactivation of vesicular stomatitis virus (VSV) in stroma-free hemoglobin
      (SFH) was carried out using methylene blue (MB) or 1,9-dimethylmethylene blue
      (DMMB). The VSV was more sensitive to inactivation by 660 nm light with 1 microM
      DMMB than with the same concentration of MB. Under conditions that inactivated 6
      log10 of VSV, the methemoglobin content (Met-Hb[%]) and P50 of hemoglobin were
      changed by 1 microM MB phototreatment but were not changed by 1 microM DMMB
      phototreatment. The migration of hemoglobin during electrophoresis and the
      activity of superoxide dismutase were not changed by MB or DMMB phototreatment.
      In contrast to the results obtained with DMMB at 660 nm, 580 nm irradiation of
      SFH with DMMB resulted in a significant increase of Met-Hb(%) under conditions
      that only inactivated 1.19 log10 VSV. The 580 nm irradiation primarily activates
      the dimer and higher-order aggregates of the dyes, while 660 nm irradiation
      primarily activates the monomer. These results indicate that the monomer form of
      DMMB can effectively inactivate viruses without damage to SFH.

PMID- 10649896
TI  - Subcellular alterations induced by UV-oxidized low-density lipoproteins in
      epithelial cells can be counteracted by alpha-tocopherol.
AB  - Oxidized LDL (ox-LDL) have been involved in the pathogenesis of several human
      diseases including dermatological pathologies. Oxidative modification of low
      density lipoproteins (LDL) is accompanied by both extensive degradation of its
      polyunsaturated fatty acids and production of lipoperoxides. These highly
      reactive products induce an intracellular oxidative stress with a variety of
      cytotoxic effects. In order to evaluate cellular damage induced by oxidative
      stress in epidermal cells, a human epidermoid carcinoma cell line in culture (A
      431) was used as experimental model. Cell treatment with UV-oxidized LDL resulted
      in cytostatic and cytotoxic effects characterized by morphological and functional
      alterations: inhibition of cell proliferation, modifications of cytoskeleton
      network, microtubular derangement, loss of cell-cell and cell-substrate contacts,
      cell detachment and cell death by apoptosis. The ox-LDL-induced alterations were
      almost completely prevented by pre-incubating cells with alpha-tocopherol. The
      results presented here could be of relevance for a better comprehension of the
      pathogenic mechanisms of several human diseases, including dermatological
      pathologies, and could indicate that antioxidants such as alpha-tocopherol could
      represent an important therapeutic challenge in the maintenance of cell and
      tissue homeostasis in the long run.

PMID- 10649895
TI  - Sites of photodamage induced by photodynamic therapy with a chlorin e6
      triacetoxymethyl ester (CAME).
AB  - The acetoxymethyl ester of chlorin e6 (CAME) was initially designed to be a
      hydrophobic photosensitizing agent that would be recognized by an endocytic
      pathway and initially accumulated in lysosomes. This was expected to lead to
      hydrolysis of the ester groups, followed by redistribution of the free chlorin to
      other subcellular sites. In this study, we examined the patterns of localization
      of CAME and of subsequent photodamage in murine leukemia L1210 cells. The drug
      was initially localized at intracellular sites, yielding a pattern similar to
      that obtained with a fluorescent probe for acidic intracellular vesicles and
      endosomes. A brief (30 min) incubation with 10 microM CAME followed by
      irradiation led to mitochondrial photodamage and apoptotic cell death. At a
      higher drug level, or with a longer incubation time, we observed additional
      photodamage to the plasma membrane and to lysosomes. The higher photodynamic
      therapy dose led to inhibition of apoptosis, with cell death likely occurring via
      a necrotic process. Distribution of CAME among the components of human plasma was
      to albumin > high-density lipoprotein > low-density lipoprotein. These results
      have implications concerning the likely mechanism of CAME accumulation and
      subcellular distribution.

PMID- 10649897
TI  - Cytochrome b6/f complex as an indigenous photodynamic generator of singlet oxygen
      in thylakoid membranes.
AB  - Possible association of photodynamic sensitization by cytochrome b6/f complex
      (cyt b6/f) via singlet oxygen (1O2) mechanism with photoinhibition damage to
      photosystem II (PS II) was studied using such subthylakoid preparations as
      photosystem I (PS I) particles, PS II core complex and cyt b6/f from spinach
      leaves. Upon exposure to bright light, PS II core complex lost photosynthetic
      electron transport activity to a certain extent, whose-spectral dependence
      implied that pheophytin a is likely involved in photoinactivation of PS II core
      complex in itself. The presence of PS I particles exerted virtually no effect on
      PS II core photoinactivation. However, the inclusion of cyt b6/f in samples
      resulted in a marked exacerbation of the photoinactivation, particularly in UV-A
      and blue light. Such effect of cyt b6/f was suppressed by azide and enhanced by
      the medium deuteration. Photogeneration of 1O2 from cyt b6/f was confirmed by ESR
      and spectrophotometry, chemically trapping 1O2. Action spectra for both 1O2
      photoproduction and PS II core photoinactivation by cyt b6/f bore a close
      resemblance to each other, seemingly carrying the absorption characteristics of
      the Rieske Fe-S protein. A complex deficient in the Rieske protein prepared from
      intact cyt b6/f showed virtually no generation of 1O2 in light, whereas an
      efficient photoformation of 1O2 was seen in the Rieske protein preparation. The
      results suggest that cyt b6/f, rather specifically the Rieske center, may play a
      prominent role in photoinhibition processes through type II photosensitization in
      thylakoids.

PMID- 10649898
TI  - [Clinical features of essential tremor].
AB  - Essential tremor is a dominant hereditary disorder with incomplete penetration
      manifested in action, postural tremor with no signs of parkinsonism, cerebellar
      lesions or other neurological signs [1]. The diagnosis of essential tremor is
      established on the basis of the clinical picture, and is greatly variable and
      insufficiently defined [5]. MATERIAL AND METHODS: The study concerned patients
      with the diagnosis of essential tremor established by the International
      Association for Tremor Studies in 1995 where tremor was classified into
      definite++, possible and probable [6]. All patients were subjected to a special
      questionnaire including demographic and clinical characteristics of tremor.
      Detailed neurological examinations focusing the presence of extrapyramidal signs
      were carried out. Fischer's Exact test was used for statistical analysis.
      RESULTS: The study comprised 107 patients (55 males, 41 females), aged 17-84
      years (57.3 +/- 15.6) and 7-77 (46.3 +/- 17.9) at onset of the disease. Postural
      tremor was present in 36% of patients, postural tremor with intentional
      deterioration in 16%, statopostural tremor in 21% and continuous tremor in 17% of
      subjects. Extrapyramidal signs were present in 31% of patients, and clumsiness in
      fine alternating movements was present in 17 patients. The patients with longer
      duration of illness were significantly more clumsy in fine alternating movements
      (Fischer's Exact test; p = 0.507 < 0.05), but not in the presence of
      extrapyramidal signs (Fischer's Exact test; p = 0.507 > 0.05). DISCUSSION:
      Essential tremor is described as a dominant inherited postural tremor. Koller et
      al. [9] describe dominantly kinetic tremor occurring with movements, while
      Martinelli et al. [10] describe continuous tremor manifested at rest, posture and
      with movements. Static tremor was considered as a result of the disease
      progression [8]. In our patients those with longer duration of the disease were
      frequently more clumsy in fine alternating movements, but not in manifestation of
      extrapyramidal signs. Continuous tremor is probably a subgroup of essential
      tremor; suggests a more pronounced role of cerebellum in its genesis.

PMID- 10649899
TI  - [The captopril test--an aid in the detection of scarring nephropathy as a cause
      of arterial hypertension in children].
AB  - Renal scarring with and without vesicoureteral reflux (VUR) has been now
      recognized as an important cause of paediatric hypertension for many years [1-5].
      However, its pathogenesis has still remained uncleared. The widespread concept
      implicated the activation of renin-angiotensin system finding a powerfull support
      in higher peripheral plasma renin activity (PRA) in children with reflux
      nephropathy than in controls [6, 7] and in beneficial antihypertensive effects of
      ACE inhibitors. The latter, in form of captopril, has also been used in captopril
      test and in renal scintigraphy and isotope renography following the
      administration of captopril to provide evidence for renin dependent hypertension
      [8, 9]. Published studies of captopril test have centred on the identification of
      renovascular as opposed to essential hypertension [10-18, 20-22]. The aim of our
      study was to assess the usefulness of captopril test in differentiation between
      hypertensive children with renal scarring from those with essential hypertension.
      We studied blood pressure (BP) and PRA responses to a single dose of captopril in
      two groups of hypertensive children. Group A consisted of 29 patients, 14 boys
      and 15 girls, who had renal scaring as demonstrated by renal 99mTc
      dimercaptosuccinid acid scan (99m Tc DMSA) and/or intravenous pyelography. Group
      B included 19 patients, 19 boys and 10 girls who had arterial hypertension, while
      clinical examination excluded renal and other definable causes of BP elevation,
      and they were therefore considered to have essential hypertension. At the time of
      the study all patients had normal glomerular filtration rate and were not salt
      depleted. They did not receive any antihypertensive medication for at least two
      weeks. The test was performed in the morning in fasting sitting patients. At the
      start of the test a small vein in the hand or forearm was cannulated to permit
      blood sampling. BP was measured 10, 20, and 30 minutes before captopril
      administration to get baseline BP (mean of these three measurements) and to allow
      the children to become accustomed to the test procedure. A single oral dose of
      captopril 0.64 +/- 0.04 mg/kg body weight was given to patients from group A and
      almost the same dose of captopril, 0.63 +/- 0.05 mg/kg body weight, to patients
      from group B. The patients remained sitting and BP was measured every 15 minutes
      during an hour. Blood for PRA was drown in the sitting position (17 patients from
      group A and 16 patients from group B) before and one hour after the dose of
      captopril. Samples of blood for basal PRA were collected from 16 patients from
      group A and in 14 patients from in B in lying position after waking up in the
      morning. PRA was measured by radioimmunoassay using a commercially available kit,
      SB-REN 2, from CIS Bio International. According to the criteria of Muller et al.
      [10] the captopril test was positive if the post-captopril PRA (ng/ml/h) was
      greater than or equal to 12 with an increase of greater than or equal to 10 and
      relative increase of greater than or equal to 15% (400% if initial PRA was < 3).
      The results of our study are presented in Tables 1 and 2 and in Graphs 1 and 2.
      The age of patients, doses of captopril, initial BP and PRA before the use of
      captopril did not much differ between studied groups. Fall of BP and PRA increase
      were highly significant (p < 0.001) both in group A and group B. However, the
      hypotensive reaction of diastolic BP and MAP were more pronounced in group A
      (14.45 +/- 1.67% and 15.81 +/- 1.62%) than in group B (6.95 +/- 2.21% and 8.96 +/
      1.75%; p < 0.01), but there were no significant differences in PRA and systolic
      BP changes and positive results of captopril test between the studied groups.
      Hypotensive responses of diastolic BP and MAP greater than 10% of initial values
      were found to be more frequent in group A (79.32% and 79.31%) than in group B
      (26.61% and 31.57 degrees %; p < 0.001 and p < 0.01). Diastolic BP and MAP were
      directly related to the dose of cap

PMID- 10649900
TI  - [Buspirone in the treatment of cerebellar ataxia].
AB  - Ataxia is defined as a disturbance which, quite independent of any motor
      weakness, alters direction and extent of voluntary movement and impairs the
      sustained voluntary of reflex muscle contraction necessary for maintaining
      postiue and equilibrium [1]. Since pathophysiological basis of cerebeller ataxia
      is still not completely clear, the current therapeutic attempts are mainly
      symptom-oriented [3]. One possible approach could be a modification of
      potentially involved neurotransmitter systems of the cerebellum, where
      particularly interesting is the serotonergic system. However, attempts with
      levorotatory form of tryptophan (5-HT precursors) proved to be ineffective [4,
      5]. Since receptors in the cerebellum are mainly of 5-HTIA subtype, the use of
      specific agonists might be a more reasonable therapy [6]. The study initially
      involved 11 patients, but only 9 completed the protocol due to unfavorable side
      effects. Our open label prospective study lasted for 15 weeks. The patients were
      tested before the beginning of the treatment (initial visit), at 7th (first
      visit) and 11th week (second visit) of continuous therapy, and eventually at 15th
      week (final visit). The daily dose was 40 mg at the first and 60 mg at the second
      visit. We used the evaluation scale gurposed for cerebellar functions testing
      (speech, gait, coordination and ocular movements). Significant improvement of
      cerebellar ataxia in patients under buspiron therapy has been noted. We analyzed
      the results obtained from our 9 patients (4 females and 5 males), of which 6
      patients suffered from cerebellar degeneration, one from multiple sclerosis, one
      from Ramsey-Hunt syndrome, and one from pontine myelinolysis. At the initial
      visit the patient score was 18.9 (SD = 7.3), subsequently, at the iirst visit the
      score was 15.4 (SD = 8), while the second visit yielded the score of 12.9 (SD =
      8.2), and finally, after a two-weeks lasting wash-out period, it was 17.7 (SD =
      7.1) (Table 1). It was found that patients exhibiting mild ataxia showed a better
      improvement in comparison to the patients who had marked cerebellar symptoms at
      the beginning of the treatment (Table 2). In conclusion, our prospective study
      shows that buspiron treatment improves cerebellar symptoms.

PMID- 10649901
TI  - [Effect of economic sanctions on incidence, therapy and mortality in acute
      myocardial infarct at Belgrade clinical centers].

PMID- 10649902
TI  - [The role of apoptosis in urothelial carcinoma. 2. Significance of apoptosis in
      treatment of urothelial carcinoma].

PMID- 10649903
TI  - [Hyperhomocysteinemia--a risk factor in atherosclerosis].

PMID- 10649904
TI  - [Aminoglutethimide in the treatment of metastatic breast carcinoma].

PMID- 10649905
TI  - [Histiocytoid (oncocytic) cardiomyopathy. Case report].

PMID- 10649906
TI  - [Sarcoidosis of the spleen which led to hypersplenism].

PMID- 10649907
TI  - [Invasive amebic colitis--a separate disease or a complication of Crohn's
      colitis. Case report].

PMID- 10649908
TI  - [Treatment of chyloderma as a complication of primary lymphedema].

PMID- 10649909
TI  - [Pancreatic metastasis of renal carcinoma].

PMID- 10649910
TI  - Artificial caries removal and inhibition of artificial secondary caries by pulsed
      CO2 laser irradiation.
AB  - PURPOSE: To investigate the inhibition of artifical secondary caries around
      restorations placed after removal of artificial caries by pulsed CO2 laser
      irradiation and by mechanical means. MATERIALS & METHODS: Beveled cavities were
      prepared mechanically on the facial surfaces of extracted human molars. Each
      cavity was subsequently exposed to an artificial caries (demineralizing) solution
      (pH 5.0) for 7 d to generate a demineralized zone approximately 100-200 microns
      thick on the cavity surface. The artificial carious/demineralized zones of the
      cavities were removed by a pulsed CO2 laser operating at a wavelength of 9.3
      microns with pulse duration of 100 microseconds and an irradiation intensity of 5
      J/cm2. Artificial control caries were removed mechanically with a carbide bur in
      a slow speed handpiece. The cavities were slightly undercut and restored with a
      resin-based composite without etching and bonding and the restored teeth were
      subjected to pH cycling solutions for 10 d as follows: Demineralization solution,
      pH 4.5 for 6 hrs, followed by remineralization solution, pH 7.0 for 18 hrs.
      Cycled teeth were sectioned through the restorations and the resulting lesions
      were analyzed in thin section using polarized light and Knoop microhardness.
      RESULTS: Mean microhardness delta Z values, indicating mineral loss were: 549 (SD
      191) for control, and 140 (SD 127) N = 11. This difference is significant with t
      = 5.543 and P = 0.000 (Paired t-test). Caries penetration: Control side--231
      microns (SD 71), Laser treated side: 123 microns (SD 79) N = 6. This difference
      is significant with t = 5.198 and P = 0.003 (Paired t-test). The results show
      that the laser treatment not only removed artificial caries, but also inhibited
      decalcification of the cavity wall in a subsequent artificial caries challenge by
      as much as 81% compared to control samples. No etching and bonding was used in
      this pilot study, which might have influenced the results. Future studies should
      address the inhibition effect of the laser treatment as compared to adhesive
      techniques, fluoride treatments and fluoride release restorative materials.
      CONCLUSION: Caries removal by a pulsed lambda = 9.3 microns CO2 laser produces a
      cavity surface morphology with marked resistance to artificial secondary caries
      as compared to mechanical removal.

PMID- 10649911
TI  - Light and scanning electron microscopy of the inner surfaces of resins used in
      direct pulp capping.
AB  - PURPOSE: To investigate with the scanning electron microscopy (SEM) the inner
      surface of the resin restorative used as a direct pulp capping. MATERIALS AND
      METHODS: Class V cavities were prepared on the facial surfaces of 90 intact
      monkey teeth, and the pulps were intentionally exposed with a carbide bur through
      the cavity floor. Each exposed pulp was capped with one of three commercially
      available adhesive resin systems (BondWell LC, GC; Imperva Bond, Shofu; Clearfil
      Liner Bond II, Kuraray). The cavities were restored with an adhesive resin and a
      hybrid resin-based composite. Histopathological changes of the mechanically
      exposed pulp were evaluated at 3, 30 and 60 days postoperatively. The interface
      between the resin and pulp tissues on the inner surface of the resin restorative
      was observed by SEM. RESULTS: Bacterial penetration along the cavity walls and
      pulp tissue could not be detected in any specimen. Slight inflammatory cell
      infiltration was the main initial reaction, while dentin bridge formation was the
      major long-term reaction in all groups. The resin surface adjacent to the etched
      cavity floor contained numerous resin tags corresponding to the dentin tubules.
      Remnants of pulpo-dentin complex, such as fragments of blood clots, pulpal cell,
      and dentin were also seen scattered along the inner resin surface.

PMID- 10649912
TI  - Amalgam shear bond strength to dentin using single-bottle primer/adhesive
      systems.
AB  - PURPOSE: To evaluate the in vitro shear bond strengths (SBS) of a spherical
      amalgam alloy (Tytin) to dentin using several single-bottle primer/adhesive
      systems both alone: Single Bond (SB), OptiBond Solo (Sol), Prime & Bond 2.1 (PB),
      One-Step (OS) and in combination with the manufacturer's supplemental amalgam
      bonding agent: Single Bond w/3M RelyX ARC (SBX) and Prime & Bond 2.1 w/Amalgam
      Bonding Accessory Kit (PBA). Two, three-component adhesive systems, Scotchbond
      Multi-Purpose (SBMP) and Scotchbond Multi-Purpose Plus w/light curing (S + V) and
      w/o light curing (S+) were used for comparison. MATERIALS AND METHODS: One
      hundred eight extracted human third molars were mounted lengthwise in phenolic
      rings with acrylic resin. The proximal surfaces were ground to expose a flat
      dentin surface, then polished to 600 grit silicon carbide paper. The teeth were
      randomly assigned to 9 groups (n = 12), and dentin surfaces in each group were
      treated with an adhesive system according to the manufacturer's instructions,
      except for S + V specimens, where the adhesive was light cured for 10 s before
      placing the amalgam. Specimens were then secured in a split Teflon mold, having a
      3 mm diameter opening and amalgam was triturated and condensed onto the treated
      dentin surfaces. Twenty minutes after condensation, the split mold was separated.
      Specimens were placed in distilled water for 24 hrs, then thermocycled (300
      cycles, between 5 degrees C and 55 degrees C, with 12 s dwell time). All
      specimens were stored in 37 degrees C distilled water for 7 days, prior to shear
      strength testing using a Zwick Universal Testing Machine at a cross-head speed of
      0.5 mm/min. RESULTS: The highest to the lowest mean dentin shear bond strength
      values (MPa) for the adhesive systems tested were: S + V (10.3 +/- 2.3), SBX
      (10.2 +/- 3.5), PBA, (6.4 +/- 3.6), SOL (5.8 +/- 2.5), SBMP (5.7 +/- 1.8), S+
      (4.8 +/- 2.3), PB (2.7 +/- 2.6), SB (2.7 +/- 1.1) and OS (2.5 +/- 1.8). One-way
      ANOVA and Duncan's Multiple Range Test indicated significant differences among
      groups. SBX and S + V produced significantly higher amalgam to dentin shear bond
      strengths than all other adhesive systems. Bond strengths of amalgam to dentin
      for the single-bottle adhesives, SOL and PBA were comparable to the three
      component systems, SBMP and S+ and were significantly greater than OS, SB and PB
      (P < 0.05).

PMID- 10649913
TI  - Effect of home bleaching products on mercury release from an admixed amalgam.
AB  - PURPOSE: To test the effect of three carbamide peroxide bleaching products,
      Opalescence (O), Nite White (N), and Platinum (P) on mercury release from amalgam
      (Valiant PhD). MATERIALS AND METHODS: Sixty uniform amalgam specimens were
      prepared in Acrylite clear acrylic blocks. After aging for 1 week at 37 degrees
      C, the specimens were placed in individual polystyrene jars containing 20 mL of
      sterile saline, and divided into three groups A, B, and C. Specimens were
      bleached in cycles by removing them from the jars, blotting to remove excess
      moisture, and covering with either O, N, P, or saline control (SC). After 8
      hours, the specimens were cleaned with a toothbrush, rinsed with deionized water,
      and returned to the saline. Group A was tested for mercury release after 8 hours
      of bleaching, Group B after 40 total hours of bleaching, and Group C after 80
      total hours of bleaching. Mercury testing was performed by first reducing the
      mercury in solution in each jar with 1 mL of SnCl2, and then testing the
      remaining headspace with a Gold Film Mercury Vapor Analyzer. RESULTS: ANOVA
      indicated there was no significant difference between the bleaches and controls
      at 8 and 40 hours, however at 80 hours, O caused significantly more mercury
      release (P < 0.05). Means at 80 hours in mg/m3 were: O = 0.98 +/- 0.36; N = 0.58
      +/- 0.20; P = 0.47 +/- 0.11; SC = 0.52 +/- 0.14.

PMID- 10649914
TI  - Effect of air, dentin and resin-based composite thickness on light intensity
      reduction.
AB  - PURPOSE: To evaluate the effect of air, dentin and resin-based composite
      thickness on light intensity reduction. MATERIALS AND METHODS: Two different
      light-units were used in the study. Light intensity was measured using a curing
      radiometer. RESULTS: There was an exponential decrease in light intensity with
      distance. The light-intensity value at a specific distance from the tip during
      passage through a specific dental material was calculated. Both composite and
      dentin caused a dramatic reduction in light intensity rate, e.g. 2.0 mm of
      composite are sufficient to reduce the light-intensity to 6% of its initial
      value.

PMID- 10649915
TI  - Bond strength of compomers to dentin using acidic primers.
AB  - PURPOSE: To determine the in vitro bond strengths of seven compomer/bonding agent
      restorative systems to human dentin. MATERIALS AND METHODS: Seven
      compomer/bonding agents were bonded to human dentin, stored in water at 37
      degrees C for 24 hours, and debonded in tension. Bonding conditions were with and
      without phosphoric acid etching, with and without the use of combined
      primer/bonding agents, and under moist and wet bond interfaces. RESULTS: Without
      phosphoric acid etching, F2000/F2000 Compomer Primer/Adhesive and F2000/Single
      Bond Dental Adhesive System were less sensitive to dentin wetness. With moist
      dentin, bond strengths of Dyract/Prime & Bond 2.1, Dyract AP/Prime & Bond 2.1,
      Hytac/OSB light-curing, one-component bonding agent, F2000/Single Bond, and
      Freedom/STAE single component light-cured dentin/enamel adhesive system, were
      improved with phosphoric acid etching. Also, with moist dentin, the bond strength
      of F2000/F2000 Compomer Primer/Adhesive in the 3M Clicker dispensing system was
      higher without phosphoric acid etching, whereas bonds of Compoglass/Syntac Single
      component were not affected by phosphoric acid etching. Bonding did not occur
      without primer/bonding agent, regardless of surface condition or use of
      phosphoric acid etching.

PMID- 10649916
TI  - Clinical evaluation of a one-bottle bonding system for desensitizing exposed
      roots.
AB  - PURPOSE: To evaluate the effectiveness of a one-bottle adhesive system as a
      desensitizing treatment, with or without a prior phosphoric acid-etch step.
      MATERIALS AND METHODS: Two different clinical procedures using a one-bottle
      adhesive bonding system were tested for its efficacy on desensitizing exposed
      roots. Thirty subjects with a history of dentin hypersensitivity were selected
      and 60 exposed sensitive teeth were divided into two groups (n = 30). In Group 1
      samples, Scotchbond 1 bonding system (Single Bond in USA) was applied without a
      prior acid-etching, while in those of Group 2, the exposed sensitive roots were
      acid-etched with 35% phosphoric acid for 15 seconds, prior to application of
      bonding agents. The sensitivity was evaluated at 0, 1, 2, 4 weeks and 3 months
      using cold air blast stimuli, and recorded using a visual-analogue scale. The
      scores were analyzed as non-parametric data by means of the Mann-Whitney and Sign
      tests. Five samples from each group were randomly selected in order to make
      scanning electron microscope observations of the sensitive dentin surfaces at
      baseline and at each recall using the replica technique. RESULTS: At baseline,
      after both desensitizing procedures all the patients reported distinct reductions
      in dentin sensitivity. At 1- and 2-week recalls, 20 teeth of Group 1 and 17 teeth
      in Group 2 exhibited a return of sensitivity, and in five teeth in each group,
      the sensitivity score was between 5-8. During the first recall (1-2 weeks), the
      sensitive teeth were retreated and showed an immediate reduction of sensitivity.
      At the 1-month recall, eight teeth in Group 1 and four teeth in Group 2 showed a
      return of some sensitivity, and in six teeth in Group 1 and in three teeth in
      Group 2, old amalgam restorations were replaced and this procedure almost
      completely resolved the sensitivity. At the 3-month recall, only five teeth from
      each group showed residual mild sensitivity (score 1-2). For both Groups 1 and 2
      there was a statistically significant (P < 0.0005) reduction in sensitivity
      levels between the baseline pain scores and immediately after treatment, and
      between the first recall pre-treatment pain scores and the last recall pain
      scores. Overall, the two methods of treatment demonstrated a general decrease in
      sensitivity in both groups over the 3-month study period, adequately solving the
      clinical and patients' perception of the discomfort of sensitivity. The SEM
      observations of the replicas showed a progressive loss of the adhesive resin from
      the treated surfaces. This fact was more evident in the non-etched samples (Group
      2) than in those in Group 1. The results of this study showed that exposed root
      dentin sealed with Scotchbond 1, with or without prior acid-etching, did not show
      spontaneous sensitivity after 3 months.

PMID- 10649917
TI  - An ultra-morphological characterization of collagen-depleted etched dentin.
AB  - PURPOSE: To evaluate the ultramorphology of superficial and deep dentin after
      etching with 35% phosphoric acid (H3PO4) and after etching with 35% H3PO4
      followed by deproteinization with 5% sodium hypochlorite (NaOCl). MATERIALS AND
      METHODS: Two dentin disks (superficial and deep dentin) were obtained from each
      of 10 extracted human third molars by slow-speed sectioning. Dentin was polished
      with wet 600-grit SiC abrasive paper for 1 min to provide smooth surfaces. The
      occlusal surface of each disk was etched with 35% H3PO4 for 15 s and thoroughly
      rinsed. The specimens were kept moist and analyzed using Atomic Force Microscopy
      (AFM). Half of the specimens were deproteinized by rubbing with 5% NaOCl for 2
      min, followed by a 30 s rinse with deionized water. After AFM analysis of the
      deproteinized specimens, all disks were fixed in a solution of glutaraldehyde and
      paraformaldehyde, dehydrated in ethanol and dried in hexamethyldisilazane. The
      dentin disks were then mounted on aluminum stubs for field-emission scanning
      electron microscope (FESEM) observation. RESULTS: The surface of etched dentin
      displayed a granular layer of silica, which did not reach the peritubular
      collagen area. The silica was more uniformly distributed in superficial dentin
      than in deep dentin. In spite of the silica deposition, the intertubular porosity
      remained unobstructed when observed at high magnification. Under a lateral view,
      intertubular dentin was demineralized to a depth of 2.0 to 2.5 microns for
      superficial dentin, and 2.5 to 3.0 microns for deep dentin. Deproteinization with
      5% NaOCl removed the exposed collagen both for superficial and deep dentin. The
      number of open tubules was greater for deep dentin. Deproteinization of
      superficial dentin revealed an extensive labyrinth of lateral secondary tubules
      and anastomoses, which opened on the intertubular region and on the peritubular
      area close to the surface. This phenomenon decreased the area of exposed
      intertubular dentin as compared to etched specimens. In deproteinized deep
      dentin, the lateral anastomotic tubules were not consistently observed on the
      intertubular area, but were easily depicted on the peritubular area.

PMID- 10649918
TI  - Effect of in-line bacteriological filters on numbers of heterotrophic bacteria in
      water emitted from non-autoclavable dental air-water syringes.
AB  - PURPOSE: To determine the effect of in-line bacteriological filters on the
      heterotrophic bacterial count of water from non-autoclavable dental air-water
      syringes. MATERIALS AND METHODS: In-line bacteriological filters were placed in
      the waterlines of non-autoclavable dental air-water syringes. Filters were placed
      either as close as possible to the air-water syringe or at a distance of
      approximately 6 feet (1.8 meters) from the air-water syringe. After routine
      flushing of water lines and air-water syringes, water samples were collected
      aseptically. Samples were diluted, plated on NWRI agar, and incubated, and
      numbers of heterotrophic bacteria per ml were determined. RESULTS: Filtration
      substantially reduced heterotrophic contamination of air-water syringe water when
      the filter was placed immediately adjacent to the air-water syringe. However,
      there was no beneficial effect when the filter was at a distance from the air
      water syringe. Furthermore, filtered water containing no detectable heterotrophic
      bacteria was re-contaminated upon passage through the non-autoclavable air-water
      syringe.

PMID- 10649919
TI  - A predictable and accurate technique with elastomeric impression materials.
AB  - A method for obtaining more predictable and accurate final impressions with
      polyvinylsiloxane impression materials in conjunction with stock trays is
      proposed and tested. Heavy impression material is used in advance for
      construction of a modified custom tray, while extra-light material is used for
      obtaining a more accurate final impression.

PMID- 10649920
TI  - Efficacy of two dentifrices on removal of natural extrinsic stain.
AB  - PURPOSE: To evaluate the 6-week effect on natural extrinsic dental stain from the
      use of a dentifrice containing 10% aluminum oxide, 1500 ppm sodium
      monofluorophosphate in a precipitated calcium carbonate (PCC) base or a second
      dentifrice containing 0.5% calcium peroxide (CP), 1500 ppm sodium
      monofluorophosphate in a PCC base compared to a fluoride placebo dentifrice
      without stain removal ingredients. MATERIALS AND METHODS: A total of 94 subjects
      were entered in the study, and stratified into three balanced groups according to
      their baseline mean Lobene Stain Index scores. The three groups were randomly
      assigned to use one of the two test dentifrices or the placebo dentifrice. The
      three groups were well balanced with regard to their mean baseline stain index
      scores, gender and tobacco habits. Subjects were instructed to brush their teeth
      twice daily (morning and evening) for 1 minute with their assigned dentifrice and
      a commercially available soft bristled toothbrush. Extrinsic dental stain
      examinations, which included mean stain area and mean stain intensity, were
      conducted at baseline and 6 weeks. Examinations were conducted by the same dental
      examiner (F.A.) on the subjects at each examination. RESULTS: After 6 weeks' use
      of their assigned products, those subjects in the aluminum oxide/PCC dentifrice
      group and those subjects in the CP/PCC dentifrice group demonstrated
      statistically significant improvements, as compared to the fluoride placebo
      dentifrice group without stain removal ingredients.

PMID- 10649921
TI  - In vivo effect of a self-etching primer on dentin.
AB  - PURPOSE: To determine the ultrastructural aspects of the dentin collagen area in
      the cavity preparation floor produced in vivo after phosphoric acid acid-etching
      or after using Clearfil Liner Bond 2 self-etching primer (LB2 Primer). MATERIALS
      AND METHODS: Twenty-four non-carious third molars scheduled for extraction from
      young adult patients (16-30 years old) were used. Conventional Class I cavities
      (+/- 2 mm deep) were prepared on the occlusal surfaces of all teeth using a
      cylindrical diamond bur on a high-speed handpiece with copious water spray. To
      avoid dehydration of the dentin, the smear layer-covered dentin was briefly air
      dried for 2 seconds. Cavities were assigned at random to the following groups:
      Group A: Dentin etched for 15 seconds with 34% phosphoric acid, rinsed for 20
      seconds and then briefly air-dried for 2 seconds with oil-free compressed air
      leaving the surfaces slightly moist. Group B: LB2 Primer was applied to the
      cavity surfaces for 30 seconds and then briefly air-dried to remove the solvent.
      Group C: The untreated dentin smear layer was used as a control. In all three
      groups, the cavities were filled incrementally with a resin-based composite
      (APX), light curing every increment for 40 seconds. After 30 minutes, the teeth
      were extracted atraumatically and the samples immediately prepared for evaluation
      with the transmission electron microscope. RESULTS: The use of a self-etching
      primer did not produce significant morphological changes in the moist dentin
      substrate. Adverse morphological conditions where observed when there was an
      excess water on the dentin surface. Phosphoric acid altered the collagen more
      severely than the self-etching primer.

PMID- 10649922
TI  - Saliva contamination and resin micromorphological adaptation to cavity walls
      using single-bottle adhesives.
AB  - PURPOSE: To examine and compare the effect of saliva contamination on the resin
      micromorphologic adaptation of four single-bottle adhesives. MATERIALS AND
      METHODS: Prime & Bond 2.1, One-Step, Tenure Quik with fluoride and Syntac Single
      Component adhesives were evaluated. Sixty sound molars were divided into three
      subgroups for each of the four adhesives; Class V cavities were prepared with
      gingival margins at cementum. Each adhesive was tested under: Normal conditions
      (Group 1), contamination of the cavity with fresh whole saliva for 20 seconds and
      removing the excess (Group 2), and contamination of the cavity with fresh whole
      saliva for 20 seconds and rinsing the saliva for 20 seconds before adhesive
      application (Group 3). After curing the adhesive, the cavities were filled with
      Z100 composite, fixed in 2.0% glutaraldehyde and sectioned into two halves. The
      sectioned halves were fixed again and rinsed with 0.2 M sodium cacodylate buffer.
      The cut surfaces were wet ground, polished and sonicated in distilled water. The
      specimens were immersed in decalcifying solution, deprotenized, serially
      dehydrated, mounted on aluminum stubs, sputter coated and examined under the SEM.
      RESULTS: The four adhesives formed hybrid layer with resin tags penetration into
      the dentin. P & B 2.1 showed usually funnel-shaped resin tags; One-Step,
      cylindrical shape; Tenure Quick and Syntac SC, variable shapes. Saliva
      contamination did not prevent hybrid layer formation or resin penetration into
      the dentin tubules. Only Syntac SC displayed a relatively thin hybrid layer with
      the unwashed saliva-contaminated group.

PMID- 10649923
TI  - Bond strengths to endodontically-treated teeth.
AB  - PURPOSE: To evaluate the bond strengths of three different types of resin bonding
      systems to teeth prepared for endodontic treatment. MATERIALS AND METHODS: Access
      cavity preparation and removal of pulpal tissue were performed in bovine
      incisors. The root canals were chemically irrigated with saline (control), 5%
      sodium hypochlorite, 3% hydrogen peroxide, or combinations of both for 60 s.
      After storage in water for 1 d, the dentin surface was ground to a flat surface
      with 600-grit SiC under water. The area for bonding was demarcated with a vinyl
      tape (4 mm-in-diameter hole), and bonded using either Clearfil Liner Bond II,
      Single Bond, or Superbond C&B. After storage in 37 degrees C water for 1 d,
      tensile bond strengths were measured using a universal testing machine at a
      crosshead speed of 2 mm/min. Ten teeth were tested for each group. RESULTS: One
      way ANOVA and Fisher's PLSD test revealed that Single Bond and Superbond C&B had
      a statistically lower (P < 0.05) bond strengths in the chemical irrigation groups
      compared with the control group.

PMID- 10649924
TI  - Shear bond strength of hydrophilic adhesive systems to enamel.
AB  - PURPOSE: To compare the enamel shear bond strength of four hydrophilic adhesive
      systems: one multiple-bottle (Scotchbond Multi-Purpose Plus), two one-bottle
      (Stae, Single Bond) and one self-etching (Etch & Prime). MATERIALS AND METHODS:
      120 bovine incisor teeth were obtained, embedded in polyester resin, polished to
      600 grit to form standardized enamel surfaces, and randomly assigned to four
      groups (n = 30). Each adhesive system was used on enamel according to the
      manufacturer's instructions, and resin-based composite (Z100) cylinders with 3 mm
      diameter and 5 mm height were bonded. Specimens were stored in humid environment
      for 1 week, and bond strength was determined using a universal testing machine,
      at a crosshead speed of 0.5 mm/minute. RESULTS: The mean shear bond strength
      values (MPa +/- SD) were: Single Bond: 24.28 +/- 5.27 (a); Scotchbond Multi
      Purpose Plus: 21.18 +/- 4.35 (ab); Stae: 19.56 +/- 4.71 (b); Etch & Prime 3.0:
      15.13 +/- 4.92 (c). ANOVA revealed significant difference in means (P < 0.01) and
      Tukey's test showed the statistical differences that are expressed by different
      letters for each group. It could be concluded that the self-etching adhesive
      system did not provide as good a bond to enamel surface, as did the one- and
      multiple-bottle systems.

PMID- 10649925
TI  - Microleakage of composites and compomers in Class V restorations.
AB  - PURPOSE: To evaluate whether differences in material composition between various
      classes of resin-based composite and polyacid-modified resin-based composites
      (compomers) affect microleakage in Class V preparations. MATERIALS AND METHODS:
      Class V cavity preparations were made in the buccal/lingual surfaces of non
      carious human molars with the occlusal margins in enamel and the gingival margins
      in dentin. Enamel margins were beveled, preparations etched, and a single bottle
      dentin bonding agent was applied. Preparations were restored with the following
      materials (n = 20): Heliomolar RO, Tetric Ceram, Tetric Flow, Flow-It, Flow-It
      LF, Compoglass F, and Compoglass Flow. Restorations were polished and teeth
      thermocycled, stained, and sectioned to evaluate both linear and penetrating
      microleakage. RESULTS: Within all groups there was significant increase (P <
      0.05) in both linear and penetrating dentin microleakage when compared to enamel
      microleakage. Linear gingival microleakage results indicated that Compoglass Flow
      and Tetric Ceram had significantly less microleakage than Flow-It and Flow-It LF
      and that Compoglass Flow also had significantly less microleakage than Heliomolar
      RO. Heliomolar RO, Flow-It and Flow-It LF had significantly more penetrating
      dentin microleakage than Tetric Ceram. The fact that microleakage scores between
      groups of materials were not significantly different indicates that the ability
      to predict microleakage in Class V preparations among various classes of resin
      based composite or compomer materials is a much more complex phenomenon than can
      be simply gathered from focusing on compositional differences alone.

PMID- 10649927
TI  - Microleakage of resin-based composite restorations using different solvent-based
      bonding agents and methods of drying acid-etched dentin.
AB  - PURPOSE: To evaluate the effect of a wet, conventionally dried, and dry bonding
      technique on microleakage of Class V resin-based composite (RBC) restorations
      bonded with three different solvent-based adhesive agents. MATERIALS AND METHODS:
      Forty five extracted human premolars and molars were randomly assigned to nine
      groups for bonding with Syntac original, Syntac Single Component, or Syntac
      Sprint (all by Ivoclar/Vivadent). Cavities were cut in both the buccal and
      lingual surfaces. Half of each preparation was in enamel and the other was in
      cementum/dentin. The cavities were restored with RBC after the applications of
      dentin bonding agents to acid-conditioned cavities using a wet, conventionally
      dried, and a dry technique for each material. The teeth were thermocycled and the
      restorations examined microscopically for leakage using Procion Brilliant Red as
      a marker. SEM microphotographs were prepared from dye-labeled and non dye-labeled
      areas. RESULTS: All groups showed microleakage at the gingival margins with no
      significant difference between the groups irrespective of the bonding material or
      the method of drying acid-etched dentin [Kruskal-Wallis: (ANOVA) P = 0.1858].
      Neither was there a significant difference between the groups irrespective of
      bonding material or drying method at the enamel margin [Kruskal-Wallis: (ANOVA) P
      = 0.3434). SEM showed that in dye-labeled areas debonding was predominantly
      cohesive in resin.

PMID- 10649926
TI  - Dentin permeability after toothbrushing with different toothpastes.
AB  - PURPOSE: To evaluate the interaction of smear layer produced during brushing and
      dentifrice particles. MATERIALS AND METHODS: Dentin disks were obtained from
      extracted human third molars. Dentin permeability was evaluated using a hydraulic
      pressure apparatus working at 1 psi of pressure. After preparation, each sample
      was connected to the hydraulic pressure apparatus to evaluate the permeability of
      dentin with the smear layer produced during specimen preparation. After 5 min of
      measurements dentin was etched with 37% phosphoric acid gel for 2 min, washed and
      gently dried with cotton to measure the permeability after smear layer removal.
      This was done to measure the maximum permeability of each specimen (expressed as
      100%). Then a second smear layer was produced using a #400 carbide paper under
      water for 1 min. Dentin permeability of the smear layer covered dentin was then
      measured, and expressed as a percent of the maximum permeability of that
      specimen, permitting each specimen to serve as its own control. The three
      toothpastes used (Merfluan powder, Merfluan paste and Fluorigard) were applied on
      dentin surfaces using a small sponge to completely cover the dentin surface.
      After 5 s, each sample was connected to a mechanical device and brushed under
      water for 3 min with constant pressure of 250 gr using a Colgate medium
      toothbrush. After this treatment, each sample was gently washed with tap water,
      gently air dried for 3-5 s and connected with the pressure apparatus to remeasure
      the permeability after brushing. For SEM examination of dentin before and after
      treatment with toothpaste and brushing, each dentin and enamel sample was fixed
      in 2% buffered glutaraldehyde. RESULTS: Dentin permeability proved unaffected by
      dentifrice treatments. SEM observations demonstrated the presence of dentifrice
      particles on dentin surface and inside dentin tubules. Smear plugs produced
      during dentin brushing were not removed by dentifrices.

PMID- 10649928
TI  - Partial coverage indirect tooth-colored restorations: steps to clinical success.
AB  - This article provides steps to clinical success with indirect partial coverage
      tooth-colored restorative options. The focus of this article is more on clinical
      technique rather than specific materials as there are an array of acceptable
      tooth-colored indirect materials on the market and each comes with specific and
      detailed manufacturer recommendations.

PMID- 10649930
TI  - Pulse activation: reducing resin-based composite contraction stresses at the
      enamel cavosurface margins.
AB  - PURPOSE: To evaluate the effect of pulse activation light-curing of resin-based
      composites on the stress reduction at the enamel surface. MATERIALS AND METHODS:
      The rate of polymerization of a resin-based composite known to be accompanied by
      high contraction stress was examined by its surface hardness. The effects of
      polymerization stresses were examined with the use of dye penetration along
      enamel margins in cavities with a C-factor of 5. The occlusal-most layer of resin
      based composite was polymerized at different power densities and time intervals;
      40 s@600 mW/cm2, 40 s@100 mW/cm2 and pulse activation; 2 s@300-350 mW/cm2,
      followed by additional exposure of 10 s@600 mW/cm2. Diametral tensile strengths
      were measured for each parameter. RESULTS: The surface hardnesses of both the 40
      s@600 mW/cm2 group and the 40 s@100 mW/cm2 group developed at nearly the same
      rate. The surface hardness of the pulse activated group developed appreciably
      slower. The diametral tensile strengths of all three groups were not
      significantly different. There was significantly less dye penetration with the
      use of the lower power density but there was very little leakage noted with the
      pulse-activated group. It is believed that this is the result of a prolonged gel
      state, which allowed flow to occur in the resin-based composite. There is
      significant clinical potential for the use of pulse activation of light-cured
      resin-based composite materials.

PMID- 10649929
TI  - Dentin desensitizing effects of Gluma Alternate, Health-Dent Desensitizer and
      Scotchbond Multi-Purpose.
AB  - PURPOSE: To evaluate the effects of topical applications of Gluma Alternate, a
      Gluma Desensitizer version with reduced glutaraldehyde content, Health-Dent
      Desensitizer and Scotchbond Multi-Purpose (SMP) on hypersensitive
      erosion/abrasion lesions. MATERIALS AND METHODS: 55 patients were included in the
      trial with at least three teeth each presenting severe sensitivity. From a total
      of 184 teeth, 69 were treated with Gluma Alternate, 58 with Health Dent and 51
      treated SMP, serving as a control. Sensitivity was recorded as response to cold
      air stimulus prior to treatment, immediately after the topical application of the
      agents, and after 1 week, 1 month and 6 months. RESULTS: Both Gluma Alternate and
      SMP showed significant reduction in sensitivity between pre- and postoperative
      pain scores (P < 0.05). The post-treatment sensitivity scores (0 and 1) were no
      different between 1 week and 6 months. In the Health-Dent group only 10 of the 58
      teeth showed sensitivity reduction. For this reason the remaining 48 teeth
      received a "rescue treatment" with Gluma Desensitizer. At the end of the 6-month
      observation time, all teeth treated with Gluma Alternate, Gluma Desensitizer, and
      SMP showed no or very little dentin sensitivity.

PMID- 10649931
TI  - Bond strength of a resin-based composite to leucite-reinforced ceramic and
      dentin.
AB  - PURPOSE: To compare the in vitro tensile bond strengths of resin-based composite
      bonded to dentin and to a leucite-reinforced ceramic in an as-received condition
      (pre-silanated) or re-etched, re-silanated condition. MATERIALS AND METHODS:
      Caries-free human molars were ground to expose occlusal, superficial dentin.
      Dentin surfaces were etched with 37% phosphoric acid and rinsed, leaving a moist
      dentin surface. Leucite-reinforced ceramic inserts (SONICsys) also were tested as
      received (pre-etched, pre-silanated) or retreated with hydrofluoric acid and
      silane. Bonding agent (Syntac Single-Component) was applied in two layers and
      light cured. An all-purpose resin-based composite (Tetric Ceram) was used to
      prepare tensile bond strength specimens for the dentin and two ceramic groups.
      Fourteen specimens were prepared for each group. After 24 hours in distilled
      water, tensile bond strength (MPa) was measured using a testing machine. Analysis
      of variance was used to evaluate data. RESULTS: Bond strengths obtained were 10.2
      MPa for composite bonded to dentin, 10.5 MPa for composite bonded to as-received
      ceramic inserts, and 9.6 MPa for composite bonded to retreated ceramic inserts,
      with no statistical difference between the three groups. Re-treatment of leucite
      reinforced inserts did not increase or decrease bond strength to resin-based
      composite. Also, the bond strength of resin-based composite to dentin was similar
      to that of the ceramic to composite.

PMID- 10649932
TI  - Effects of handpiece lubrication on resin-based composite bond strength to
      enamel.
AB  - PURPOSE: To evaluate the effects of handpiece lubrication on the bond strengths
      of resin-based composite (RBC) to enamel using two different bonding systems.
      MATERIALS AND METHODS: Sixty extracted noncarious human maxillary incisors were
      imbedded in acrylic resin tray material with the facial surfaces exposed. 320
      grit sandpaper was used to create a flat surface of enamel. The embedded teeth
      were randomly divided into two bonding systems groups: half used All-Bond 2 and
      half used OpiBond FL. Within these two groups the teeth were again randomly
      divided into three subgroups: Dry: 10 teeth prepared with a sterilized
      unlubricated handpiece; Lube & Run: 10 teeth prepared with a handpiece that was
      lubricated and run for 30 seconds prior to use; Lube: 10 teeth prepared with a
      handpiece that was lubricated and not run prior to its use. The enamel was
      prepared by lightly roughening with a medium grit diamond in the respective
      handpieces. The preparations were etched for 15 s with 32% phosphoric acid,
      rinsed with water for 5 s, and dried with compressed air for 5 s. Either bond
      system was applied and light-cured. A hybrid RBC was placed and light-cured for
      60 s. The teeth were stored in water at 37 degrees C 1 week. Shear bond strengths
      were measured and the collected data subjected to an ANOVA followed by a Tukey's
      and Bonferroni t-test were performed. RESULTS: The Dry group and the Lube & Run
      group had stronger mean shear strengths than did the Lube group. The difference
      between the mean shear strengths for the Dry group and the Lube & Run group was
      not statistically significant (P < 0.05). A significant difference was found
      between the Dry group and the Lube group and between the Lube & Run group and the
      Lube group (P < 0.05). The mean shear strength for All-Bond 2 was higher than for
      OptiBond FL (P = 0.0054).

PMID- 10649933
TI  - 1-year clinical evaluation of Compoglass and Fuji II LC in cervical
      erosion/abfraction lesions.
AB  - PURPOSE: This study was undertaken to compare the clinical performance of a
      polyacid-modified resin-based composite and a resin-modified glass-ionomer
      restorative material over 1 year. MATERIALS AND METHODS: Thirty-four pairs of
      restorations of Compoglass (C) and Fuji II LC (F) were placed in 31 patients,
      with no patient receiving more than two pairs, and with materials assigned at
      random within the pairs. Caries-free cervical erosion/abfraction lesions of the
      facial surface were restored without tooth preparation according to
      manufacturers' instructions, except that tooth structure to be restored was
      etched with 37% phosphoric acid prior to placement of Compoglass. Restorations
      were clinically evaluated by two blinded examiners at baseline, 6 months, and 1
      year, using modified Ryge/USPHS criteria. Restorations receiving a score of
      "Charlie" in either retention or secondary caries were classified as failed
      restorations. The incidence of failures was statistically analyzed as a pairwise
      comparison, using an exact binomial test. RESULTS: Thirty-one pairs of
      restorations were available for recall at 1 year. The percentage of Alfa scores
      for each material in each category were: Retention (C = 84%, F = 100%), Color
      match (C = 81%, F = 100%), Marginal discoloration (C = 78%, F = 97%), Secondary
      caries (C = 88%, F = 100%), Anatomic form (C = 92%, F = 100%), and Marginal
      adaptation (C = 26%, F = 46%). Except for the failed restorations, no other
      Charlie scores were assigned. A significant difference in the incidence of failed
      restorations was found between the materials (P = 0.01).

PMID- 10649934
TI  - Cavity preparation factors and microleakage of Class II composite restorations
      filled at intraoral temperatures.
AB  - PURPOSE: To determine if alteration of any of the following factors could reduce
      microleakage following placement of Class II resin-based composites (RBC) at
      intraoral temperature: cavity preparation (vertical wall bevels), finishing
      technique (delayed vs. immediate), or postoperative re-bonding (marginal
      sealing). An additional purpose was to determine if a decalcification/clearing
      protocol was a valid technique for assessing three-dimensional microleakage.
      MATERIALS AND METHODS: Twenty recently extracted human molars had standardized
      Class II slot cavities prepared on the mesial and distal surfaces with the
      gingival floor located on dentin. The teeth were imbedded in a stone template,
      warmed to 37 degrees C and restored immediately upon removal from the oven with
      visible light-cured (VLC) adhesive (All-Bond 2) and three horizontal increments
      of VLC RBC (Bisfil P) using a metal matrix. Teeth were placed into one of four
      groups: (1) Control; (2) The preparation was modified to include 0.5-1.0 mm
      enamel bevels on the vertical walls (facial and lingual); (3) Finishing of the
      RBC was delayed 24 hours; (4) Following immediate finishing, all margins of the
      RBC restorations were sealed by dentin bonding agent application. Teeth were
      stored at 37 degrees C for 2 weeks, thermocycled 1000x at 5/55 degrees C, stained
      with silver nitrate, underwent a decalcification and clearing protocol, and
      evaluated for three-dimensional dye penetration. RESULTS: Axial-occlusal enamel
      margins exhibited minimal leakage and no differences among the groups. Vertical
      walls without bevels exhibited pronounced microleakage. Beveled vertical proximal
      walls exhibited significantly less facial and lingual wall microleakage compared
      to all other groups, and less gingival marginal leakage compared to the control
      group.

PMID- 10649935
TI  - Effect of refrigeration on shear bond strength of three dentin bonding systems.
AB  - PURPOSE: To determine whether use of dentin bonding agents directly from
      refrigerated storage would have adverse effects on their shear bond strength to
      dentin. MATERIALS AND METHODS: Resin-based composite cylinders were bonded to
      dentin on the ground occlusal surfaces of 60 extracted human molars using three
      different dentin bonding systems at 3.0 degrees C and 23.5 degrees C. The
      cylinders were then debonded using an Instron testing machine in compression mode
      at 0.5 mm/sec. The results were interpreted with t-test and Student-Newman-Keuls
      post hoc analysis. RESULTS: Scotchbond Multi-Purpose demonstrated significantly
      lower shear bond strengths at 23.5 degrees C (P < 0.05) than all other groups at
      both 3.0 degrees C and 23.5 degrees C. All-Bond 2 and Prime & Bond had higher
      shear bond strengths at refrigerated temperature, but the differences were
      insignificant in magnitude.

PMID- 10649936
TI  - Influence of tissue characteristics at margins on leakage of Class II indirect
      porcelain restorations.
AB  - PURPOSE: To evaluate the sealing ability of Class II porcelain inlays with
      margins placed in cementum-dentin and enamel, luted by two new different
      cementing materials. MATERIALS AND METHODS: Thirty extracted molars, free from
      caries and restorations, were selected. The sample cavities were prepared in a
      standardized manner and then were divided in three groups (n = 10) at random.
      Group 1: The cervical margin was located 1 mm below the CEJ and the inlays were
      luted with EBS Multi (Espe) bonding system in combination with Compolute 1.0
      Aplicap (CLA 1.0, Espe) experimental resin cement. Group 2: The cervical margin
      was placed 1 mm below the CEJ and Syntac bonding system (Vivadent) and Variolink
      II resin cement (Vivadent) were used. Group 3: The cervical margin was placed 0.5
      mm above the CEJ and the same materials selected for Group 1 were used. IPS
      Empress (Ivoclar) inlays were made following manufacturer's instructions. After
      luting procedures and 2500 thermal cycles (5 degrees and 55 degrees C), the
      samples were processed and evaluated for marginal leakage at cervical and
      occlusal site. Samples of Group 3 were first sectioned in the center of the
      restorations as in Group 1 and 2 and scored (Group 3A) and then two other cuts
      were made along the buccal and lingual areas (Group 3B) and also scored. After
      scoring dye penetration of Group 1 and 2 samples, half of the sections were
      randomly selected to evaluate: (1) resin cement thickness, (2) Hybrid layer
      formation at the interface between adhesive material and dental substrate and (3)
      to observe the morphology of the Class II cavity margins. The leakage data were
      statistically evaluated with the Mann-Whitney U test (P < 0.5). RESULTS:
      Statistically significant differences were found between Groups 3A and 3B at the
      occlusal site, and not at the cervical site. Samples of Group 1 showed a cement
      thickness of 92 microns, and 68 microns in Group 2. Hybrid layer and resin tag
      formation was evident in Group 1. In Group 2 samples, the hybrid layer formation
      was less evident and thinner than in Group 1. At cervical margins, an outer
      layer, not identifiable as sound dentin, of 200-300 microns thick, was noted.
      This layer was present in all three groups between outer margin and sound dentin.
      The margins located both cervically and axially in enamel mainly showed prisms
      cut along their long axis and a low level of structured etch pattern.

PMID- 10649937
TI  - Comparative efficacy of a rotary and a sonic powered toothbrush on improving
      gingival health in treated adult periodontitis patients.
AB  - PURPOSE: To compare the efficacy of two powered brushing instruments (Rota-dent,
      rotary action instrument and Sonicare, a sonic instrument) for reductions of
      plaque and gingivitis in a treated adult periodontal patient population.
      MATERIALS AND METHODS: Forty patients, randomly selected from a pool of patients
      in periodontal maintenance after surgical periodontal treatment, completed this
      study. A split mouth, blind, crossover design was utilized in this 12-week trial
      with each patient acting as his/her own control. After subjects alternately
      brushed one-half of their mouths with each of the instruments; a crossover in the
      brushing pattern occurred at 6 weeks, with no wash out period. Single-blind
      clinical assessments were made by a calibrated investigator at six sites per
      tooth for contralateral incisors, premolars and molars at baseline, 6 and 12
      weeks. Gingival Index (GI), Plaque Index (PI) and Papillary Bleeding Index (PBI)
      were determined. A prophylaxis was done for all subjects after baseline
      recordings. RESULTS: Mean percent reductions from baseline for GI, PI and PBI at
      the end of 6 and 12 weeks were 75.0%, 68.9%, 73.4% and 76.4%, 69.9%, 74.0%,
      respectively for the rotary instrument, and 57.7%, 53.3%, 54.3% and 57.7%, 53.6%,
      54.7%, respectively for the sonic brush. One-way ANOVA indicated that the rotary
      instrument was significantly more effective (P < 0.005) than the sonic brush in
      removing plaque and reducing gingivitis in treated adult periodontitis patients.

PMID- 10649938
TI  - Residual antimicrobial activity associated with a chlorhexidine endodontic
      irrigant used with sodium hypochlorite.
AB  - PURPOSE: To evaluate the in vitro efficacy of 2.0% chlorhexidine gluconate (CH)
      as an endodontic irrigant combined with the traditional irrigant, sodium
      hypochlorite (SH). MATERIALS AND METHODS: Extracted single-rooted human teeth
      were instrumented using one of three regimens: CH alone; SH alone until
      instrumentation with the last file, at which time CH was used as the filing
      irrigant; or SH alone followed by a single rinse with CH. After instrumentation,
      each root canal was dried with endodontic paper points, filled with sterile
      water, and maintained in a water-saturated environment. At 6, 12, 24, 48 and 72
      hours after instrumentation, the root canal fluid was absorbed with an endodontic
      paper point, and the canal was irrigated and refilled with sterile water. The
      paper points containing root canal fluids were assayed for antimicrobial activity
      by placing them on agar plates inoculated with Streptococcus mutans, and
      measuring zones of inhibition after incubation. RESULTS: Comparisons of the
      results obtained from the three treatment regimens indicated there were no
      significant differences (P > 0.5) in the relative in vitro antimicrobial activity
      remaining in the three groups of teeth.

PMID- 10649939
TI  - Psychological and medical effects of mercury intake from dental amalgam. A status
      report for the American Journal of Dentistry.
AB  - Studies examining health consequences of the release of mercury from dental
      amalgams have concluded that there is insufficient mercury released from these
      restorations to cause a medical problem. Although the mercury vapor generated
      during removal of amalgams will cause a transient increase in the patient's
      mercury level in tissue fluids, biochemical assays have demonstrated that the
      increase is too small to have a negative influence on organ systems. This is true
      even when patients have all their amalgams removed in a single session.
      Nevertheless, over the past decade, the release of mercury from dental amalgam
      has been frequently blamed for a variety of health complaints. A number of
      sensationalized media reports regarding the mercury issue have no doubt
      contributed to the public concern that has been aroused. Consequently, patients
      may present at the dentist's office, either self-diagnosed or looking for a cause
      implicating mercury. In actuality, these patients may have symptoms of either
      medical problems or psychological disorders such as depression or anxiety.
      Unfortunately, the incorrect diagnosis may not only mislead, but actually place
      the patient in a dangerous situation. Two well-controlled studies have indicated
      that (1) 89% of the patients with self-reported "amalgam illness" had psychogenic
      disorders, whereas only 6% of the matched-pair manifested symptoms of these
      psychological disorders; and (2) these alleged "amalgam illness" patients had
      preneurotic reactive/defensive mechanisms that did not allow them to recognize
      aggressive and threatening situations which the control group would quickly and
      readily regard as potentially difficult to manage. Other studies involving
      psychological assessment seem to confirm that dental therapy (removal of
      amalgams) for people with alleged "amalgam illness" may, at best, provide a
      "placebo effect".

PMID- 10649941
TI  - Clinical effectiveness of a Class V flowable composite resin system.
AB  - This clinical study evaluated a Class V flowable composite resin restoration
      system and its ability to reduce dentin sensitivity. Twenty-one patients required
      Class V restorations because of erosion, abrasion, or decay at the cervical area.
      Each patient exhibited moderate or severe sensitivity and required replacement of
      tooth structure. The degree of sensitivity was determined by either tactile
      scraping of the tip of an explorer over the surface of the tooth or by an air
      blast from a syringe for 5 seconds. A total of 52 restorations were performed.
      According to phone conversations and questionnaires, 1 patient experienced
      continued sensitivity on 1 treated tooth for a duration of 1 week, but this
      sensitivity was gone at 1-month, 3-month, 6-month, and 1-year recalls. None of
      the other patients exhibited sensitivity at any phone checks or during recall
      visits.

PMID- 10649943
TI  - From composite resins to compomers: what have we gained?

PMID- 10649942
TI  - Understanding wear in dentistry.
AB  - Tooth wear is an increasing problem in dentistry. Traditionally, it has been
      divided into three categories: abrasion, attrition, and erosion. However, most
      clinical cases of tooth wear involve more than one of these processes. It is
      often easier to make a diagnosis by looking for the signs of the fundamental wear
      processes rather than trying to categorize the individual case. Wear can be
      caused by direct surface-to-surface wear, an intervening slurry, or a corrosive
      environment. Wear occurs during mastication, but also at other times, often at
      night. Although it may be possible to institute a preventive regimen, this will
      not always help the patient if his or her prime concern is esthetics. The same
      processes that cause tooth wear will cause wear to restorative materials. To
      diagnose and prevent wear, its processes must be understood.

PMID- 10649944
TI  - The efficacy of modular transitional implants placed simultaneously with implant
      fixtures.
AB  - After the placement of implants in areas in which several teeth have been lost,
      both the clinician and the patient face many difficulties, particularly during
      healing. If no prosthesis is provided, the patient's quality of life suffers. If
      a removable prosthesis is provided for optimum mastication and speech, many
      complicated adjustments of the denture may become necessary during healing, and
      the possibility of osseointegration failure increases. This case report describes
      simultaneous placement of implant fixtures and modular transitional implants,
      providing occlusal function immediately after placement. The use of modular
      transitional implants is very effective in maintaining good oral function for the
      patient.

PMID- 10649945
TI  - The principles of uncomplicated exodontia: simple steps for safe extractions.
AB  - This article reviews the basic principles of patient evaluation and surgical
      techniques to accomplish extraction of teeth in an uncomplicated manner. Also
      presented are techniques for extraction-site grafting with bioactive glass.

PMID- 10649946
TI  - Creating natural vitality with direct-bonded composite veneers.

PMID- 10649947
TI  - Prospective study of the Langer modification of the Branemark 5.0-mm implant: 3
      year results.

PMID- 10649948
TI  - Microscope-assisted precision dentistry.
AB  - To enhance their vision for both clinical and laboratory procedures, an
      increasing number of dental practitioners are introducing magnification into
      their practices. Most are using either simple or compound loupes mounted on
      glasses frames. And although magnification is not new to dentistry, it is a trend
      that is gaining a broader acceptance among both seasoned practitioners and recent
      graduates. Many dental schools are allowing their students to use loupes on a
      discretionary basis, so the notion that magnification is reserved only to
      compensate for deteriorating vision is rapidly disappearing. Dental professionals
      have also begun to recognize that the quantity and quality of light in the
      working field is just as important as magnification. Headlamps with focused,
      color-correct light sources in combination with loupes are becoming popular. It
      is highly unlikely that a practitioner using loupes would relinquish them and
      return to practicing without magnification. The newest addition to the vision
      enhancement arena in dentistry is the operating microscope. In some medical
      subspecialties--such as otolaryngology, ophthalmology, plastic surgery, and
      neurosurgery--extensive microsurgical training is required to perform procedures
      at acceptable standards of precision. In 1998, the American Association of
      Endodontists (AAE) elected to mandate that all endodontic postgraduate students
      demonstrate proficiency using an operating microscope before they receive their
      certificates. Microscope use has also been reported in periodontics. For several
      decades, many dental laboratory technicians have used stereomicroscopes for
      trimming dies, refining castings, and performing other procedures that require a
      high degree of precision. However, according to microscope manufacturers, most
      current instrument sales are to general practitioners, who are not limiting the
      use of their microscopes to endodontic therapy--they are using them for a wide
      variety of procedures. Microscopes have the potential to enhance a dental
      practitioner's vision to unprecedented levels, but there are some practical
      questions that need to be addressed. What kind of visual acuity do dentists
      really need to perform high-quality dentistry? If a dentist wants to improve his
      or her vision, do loupes provide an adequate level of magnification? Is using a
      microscope too complicated for restorative and prosthodontic procedures, and how
      long does it take to become proficient with a microscope? These are some of the
      questions I posed to two outstanding dentists who have had extensive clinical
      experience using surgical microscopes. I also share my own experience with a
      microscope.

PMID- 10649949
TI  - Choosing the right computer system.
AB  - We are living in a world where virtually any information you desire can be
      acquired in a matter of moments with the click of a mouse. The computer is a
      ubiquitous fixture in elementary schools, universities, small companies, large
      companies, and homes. Many dental offices have incorporated computers as an
      integral part of their management systems. However, the role of the computer is
      expanding in the dental office as new hardware and software advancements emerge.
      The growing popularity of digital radiography and photography is making the
      possibility of a completely digital patient record more desirable. The trend for
      expanding the role of dental office computer systems is reflected in the
      increased number of companies that offer computer packages. The purchase of one
      of these new systems represents a significant commitment on the part of the
      dentist and staff. Not only do the systems have a substantial price tag, but they
      require a great deal of time and effort to become fully integrated into the daily
      office routine. To help the reader gain some clarity on the blur of new hardware
      and software available, I have enlisted the help of three recognized authorities
      on the subject of office organization and computer systems. This article is not
      intended to provide a ranking of features and shortcomings of specific products
      that are available, but rather to present a process by which the reader might be
      able to make better choices when selecting or upgrading a computer system.

PMID- 10649950
TI  - Air abrasion: an old technology reborn.
AB  - Recently, air abrasion has experienced a rebirth in restorative dentistry.
      Originally developed in the late 1940s, the principle of air abrasion is the
      imparting of kinetic energy to tiny aluminum oxide particles that are projected
      by a stream of compressed air or gas and expelled from a small nozzle. The force
      generated by the relatively hard particles striking a relatively hard surface is
      sufficient to cut into that surface. In the last decade, more than a dozen models
      of air abrasion units have been introduced into the marketplace and more are on
      the way. Manufacturers have developed air abrasion instruments that offer a broad
      range of features, from small table-top units to self-contained systems with
      compressors, vacuums, and curing lights. The costs range dramatically--from
      $1,000 to $20,000 or more--depending on the complexity of the features and
      attachments. Manufacturers make a variety of claims to support the value of this
      technology to the practicing dentist. A term often used to describe one of the
      benefits of air abrasion is microdentistry. The claim is that smaller, less
      invasive tooth preparations may be accomplished using air abrasion than with a
      traditional bur and air turbine. This may be true in some instances, but it would
      certainly depend on the operator's experience and ability to visually discern
      fine detail. Other claims about air abrasion are that it can be used to cut into
      tooth structure without local anesthesia and that it should be used on all
      stained grooves or fissures to determine if incipient carious lesions are
      present. Despite the limited number of clinical studies, the popularity of air
      abrasion continues to grow. To gain additional insight about these claims and to
      see what might be on the horizon for this technology, I spoke with three highly
      respected educators who are recognized for their expertise in air abrasion. What
      they said should give the reader a better understanding of how air abrasion might
      augment restorative dentistry procedures and techniques.

PMID- 10649951
TI  - Photographic imaging for esthetic restorative dentistry.
AB  - Patient dental records are the most critical component of every dental practice.
      Whether these records are maintained in traditional cardboard folders or as
      digital bytes of information, the completeness of their contents is important to
      successful patient care. Two trends are expanding the contents of the dental
      record to include photographs. One of these trends is the widespread interest in
      esthetic restorative dentistry and the other is the increasing level of
      expectations by the public. More than ever, patients are seeking dental treatment
      to alter the appearance of their teeth. Unfortunately, esthetic restorative
      dentistry often is not part of a formal dental education. In addition, esthetics
      is a subjective topic, and patient demands and expectations can easily exceed a
      dentist's skill and expertise. This can ultimately lead to an "unhappy patient
      syndrome" and cause conflict between the patient and the dental team. Sometimes
      this conflict can result in litigation, which is another reason that photographs
      are a valuable addition to the patient record. The information that is contained
      in a good-quality set of "before" and "after" photographs cannot be duplicated
      with other components of the dental record. Taking the time to assemble adequate
      baseline records is always critical before any patient care is initiated. In
      restorative dentistry, this includes the standard of care elements: a health
      history, soft-tissue examination, periodontal examination, teeth and restoration
      examination, study casts, and an adequate radiographic survey. The use of
      photography in dentistry has historically been limited to the field of
      orthodontics. It is the standard of care for orthodontic baseline records, but
      has not been mandated for restorative dentistry. Memories are rarely accurate
      about subtle details of one's appearance and people can easily forget what their
      original smiles looked like even though treatment time may only be a matter of
      days. Baseline photographs provide an irrefutable record of pretreatment
      conditions in correct context. More importantly, you do not have to be a dentist
      to interpret the general information that is displayed on a photograph. To gain
      additional perspective on this issue, we consulted a panel of three dentists who
      are well recognized for their expertise in dental esthetics and imaging.

PMID- 10649952
TI  - The current status of vital tooth whitening techniques.
AB  - Tooth whitening of vital teeth continues to have a major impact on the practice
      of dentistry. The growing public interest in having whiter, brighter teeth is
      clearly evident in the advertisements from toothpaste manufacturers on
      "whitening" formulations of their products and by the number of individuals
      seeking whitening procedures from their dentists. In addition, new over-the
      counter whitening products continue to emerge in a marketplace that cannot seem
      to get teeth white enough, bright enough, fast enough. What new products and
      procedures have evolved over the past decade to whiten teeth? Are they better,
      safer, faster, and more effective now? Are dentists meeting public demand for
      whiter teeth and is this quest having a positive or negative impact on the
      practice of dentistry or the patient's dental health? I posed these questions to
      a group of experts on whitening procedures to get their opinions and
      recommendations.

PMID- 10649953
TI  - Maxillary canine restoration: a case report.
AB  - The replacement of a single tooth with osseointegrated dental implants presents a
      unique challenge to both the prosthodontist and the surgeon. When anterior teeth
      are replaced, it is difficult to design an occlusal scheme that will direct
      forces down the long axis of an implant. This is especially true when the canine
      is involved. Wide-diameter implants offer advantages, such as increased surface
      area of implant to bone, stronger prosthetics, stronger implants, and less screw
      loosening or breakage when compared to standard-diameter implants. The single
      stage technique is advantageous in terms of soft-tissue predictability, and it
      eliminates the need for second-stage surgery.

PMID- 10649954
TI  - Bleeding tendency: a practical approach in dentistry.
AB  - The dental profession faces the problems of exaggerated bleeding on a daily
      basis. The hemostatic, as well as the fibrinolytic processes are better
      understood today, and the dentist should be familiar with them. The activation of
      coagulation factors and their clinical expression in the circulation are both
      described. The most frequently used blood coagulation tests are explained.
      Antithrombotic medications are frequently used and their implications in
      dentistry are accentuated. Protocols of prevention and treatment of exaggerated
      bleeding following dental procedures are included. Among them, the transfusion of
      clotting factors and the administration of antifibrinolytic medications
      (tranexamic acid) are recommended for both congenital or acquired bleeding
      tendencies.

PMID- 10649955
TI  - Three-dimensional CT scan analysis for implant-supported fixed prostheses.
AB  - Rapid technological advances in dental implantology, computer imaging, and dental
      radiography in combination with traditional prosthetic concepts offer today's
      clinicians unprecedented possibilities in diagnosis and treatment planning. This
      article presents information on the use of three-dimensional computed tomography
      scan analysis to determine the quality (density), quantity, and location of bone
      to establish the most effective implant placement. In addition, this article
      analyzes the correlation of prosthodontic, periodontic, and technological
      concepts necessary for completion of a maxillary and mandibular fixed, full-mouth
      rehabilitation.

PMID- 10649956
TI  - Furcation involvement in posterior teeth.
AB  - This article presents two cases in which different treatments were used for
      mandibular molars with furcation lesions. In the first case, a conventional
      amputation treatment of the distal root was performed to save the mesial root as
      a terminal tooth, which was used as a partial denture abutment. The second case
      describes a relatively new technique in which a root perforation was filled with
      graft material (synthetic bioglass) and covered with a resorbable membrane to
      treat an iatrogenic furcation lesion adjacent to the mesial root. Twelve months
      after surgery, periapical radiographs of both treated cases showed increased bone
      density. Follow-up in both cases--30 months in the first case and 12 months in
      the second--showed no pathological recurrence or clinical dysfunction. Root
      amputation may provide an alternative to extraction in periodontally involved
      molars. Synthetic bone replacement materials combined with guided tissue
      regeneration may also help to correct osseous defects incurred by recent
      furcation perforations with associated bone loss.

PMID- 10649957
TI  - Occupational HIV infections in health care workers.

PMID- 10649958
TI  - Conservative elective porcelain veneers.

PMID- 10649959
TI  - CRT for the next thousand years

PMID- 10649960
TI  - Water-soluble organotellurium compounds: catalytic protection against
      peroxynitrite and release of zinc from metallothionein.
AB  - The antioxidant properties of a number of water-soluble diorganyl tellurides have
      been investigated. These organotellurium compounds efficiently protect against
      peroxynitrite-mediated oxidation of dihydrorhodamine 123, hydroxylation of
      benzoate, and nitration of 4-hydroxyphenyl acetate. The peroxidation of the zinc
      storage protein, metallothionein, by tert-butyl hydroperoxide is also catalyzed
      by the water-soluble organotellurium compounds. As compared to selenium
      containing compounds (e.g., ebselen and selenocystamine), some of the tellurides
      that were tested ?e.g., 3-[4-(N,N-dimethylamino)benzenetellurenyl]propanesulfonic
      acid, sodium salt? exhibit a significantly higher reactivity in these assays,
      making them some of the most effective compounds tested thus far. The catalysis
      of destruction of zinc-sulfur clusters by water-soluble organotellurium compounds
      could have implications for the bioavailability of zinc in vivo. These compounds
      might be lead compounds for the development of a new class of water-soluble,
      tellurium-based antioxidant and zinc-releasing drugs.

PMID- 10649961
TI  - Formation of stable DNA adducts and apurinic sites upon metabolic activation of
      bay and fjord region polycyclic aromatic hydrocarbons in human cell cultures.
AB  - Carcinogenic polycyclic aromatic hydrocarbons (PAH), such as benzo[a]pyrene
      (B[a]P), 7,12-dimethylbenz[a]anthracene (DMBA), and dibenzo[a,l]pyrene
      (DB[a,l]P), are metabolically activated to electrophilically reactive bay or
      fjord region diol epoxides that bind to the exocyclic amino groups of purine
      bases in DNA to form stable adducts. In addition, it has been reported that these
      PAH can be enzymatically oxidized to yield radical cations that form apurinic
      (AP) sites in DNA via depurinating adducts. The formation of stable adducts and
      AP sites in DNA of human cells exposed to PAH was examined in cytochrome P450
      (P450)-expressing mammary carcinoma MCF-7 cells and in leukemia HL-60 cells,
      which display a high peroxidase but no P450-mediated activity, after exposure to
      these PAH. Stable DNA adducts were assessed by (33)P-postlabeling/HPLC analysis,
      and the induction of AP sites in DNA was analyzed by an aldehyde reactive probe
      (ARP) and a slot blot method. After exposure for 4 h, the levels of stable DNA
      adducts were comparable in MCF-7 cells treated with B[a]P and DMBA, but
      significantly lower than those observed in MCF-7 cells treated with the stronger
      carcinogen DB[a,l]P. While the levels of stable adducts increased more than 10
      fold (B[a]P and DMBA) or 100-fold (DB[a,l]P) after exposure for 24 h, the levels
      of AP sites remained low after both treatment periods. Thus, the levels of stable
      adducts were approximately 5-fold higher than the levels of AP sites after
      treatment with B[a]P or DMBA and more than 100-fold higher in cells exposed to
      DB[a,l]P for 24 h. None of these carcinogenic PAH formed detectable levels of
      stable DNA adducts or AP sites in HL-60 cells. The results demonstrate that
      metabolic activation of B[a]P, DMBA, and DB[a,l]P is catalyzed by P450 enzymes
      leading to diol epoxides that form predominantly stable DNA adducts but only low
      levels of AP sites.

PMID- 10649963
TI  - Enzymatic reduction of arsenic compounds in mammalian systems: reduction of
      arsenate to arsenite by human liver arsenate reductase.
AB  - An arsenate (As(V)) reductase has been partially purified from human liver. Its
      apparent molecular mass is approximately 72 kDa. The enzyme required a thiol and
      a heat stable cofactor for activity. The cofactor is less than 3 kDa in size. The
      thiol requirement can be satisfied by dithiothreitol (DTT). However, the extent
      of stimulation of reductase activity by glutathione, thioredoxin, or reduced
      lipoic acid was negligible compared to that of DTT. The heat stable cofactor does
      not appear to be Cu(2+), Mn(2+), Zn(2+), Mg(2+), or Ca(2+). The enzyme does not
      reduce monomethylarsonic acid (MMA(V)). The isolation and characterization of
      this enzyme demonstrates that in humans, the reduction of arsenate to arsenite is
      enzymatically catalyzed and is not solely the result of chemical reduction by
      glutathione as has been proposed in the past.

PMID- 10649962
TI  - Mutagenic potential of guanine N2 adducts of butadiene mono- and diolepoxide.
AB  - To explore the role of guanine N(2) adducts of stereoisomeric butadiene
      metabolites in butadiene-induced mutagenesis, 11-mer deoxyoligonucleotides were
      prepared containing adducts of (R)- and (S)-monoepoxide and (R,R)- and (S,S)
      diolepoxide. These adducted oligonucleotides were utilized in both in vivo and in
      vitro experiments designed to examine the mutagenic potency of each and their
      replication by Escherichia coli polymerases. Each of the four adducted
      deoxyoligonucleotides was ligated into a single-stranded M13mp7L2 vector and
      transfected into E. coli. The resulting plaques were screened for
      misincorporation at position 2 of the N-ras 12 codon. Although the mutagenic
      frequencies were low, different relative mutagenicities of the various
      stereoisomers were discernible. In addition, the biological effects of each
      adduct on the three major E. coli polymerases were determined via primer
      extension assays. The adducted 11-mers were ligated into a 60-mer linear DNA
      molecule to provide a sufficiently long template for primer elongation. All four
      guanine adducts were determined to be blocking to each of the three polymerases
      via primer extension assays.

PMID- 10649964
TI  - Isolation and characterization of a monoamine oxidase inhibitor from tobacco
      leaves.
AB  - Recent positron emission tomography imaging studies have demonstrated a
      significant decrease in both monoamine oxidase A and B (MAO-A and MAO-B)
      activities in the brains of smokers. Normal levels of activity are observed in
      former smokers, suggesting the presence of one or more compounds in tobacco smoke
      that may inhibit these enzymes. In this paper, we report the results of efforts
      to identify compounds present in flue-cured tobacco leaves that inhibit MAO. The
      isolation procedure was guided by estimating the inhibitory properties of tobacco
      leaf extracts on the liver mitochondrial MAO-B-catalyzed oxidation of 1-methyl-4
      (1-methylpyrrol-2-yl)-1,2,3, 6-tetrahydropyridine to the corresponding
      dihydropyridinium metabolite. Fractionation of extracts from flue-cured tobacco
      leaves led to the isolation of a competitive inhibitor of human MAO-A (K(i) = 3
      microM) and MAO-B (K(i) = 6 microM), the structure of which could be assigned by
      classical spectroscopic analysis and confirmed by synthesis. This information may
      help to provide insights into some aspects of the pharmacology and toxicology of
      tobacco products.

PMID- 10649965
TI  - Biotransformation of styrene in mice. Stereochemical aspects.
AB  - Biotransformation of styrene and its toxic metabolite, phenyloxirane (1), in mice
      in vivo was studied. Mice were treated with single intraperitoneal doses of
      styrene (400 mg/kg of body weight), and with (R)-, (S)-, or racemic styrene oxide
      (150 mg/kg of body weight). Profiles of neutral and acidic metabolites were
      determined by GC/MS. Mandelic acid (3) and two mercapturic acids, N-acetyl-S-(2
      hydroxy-2-phenylethyl)cysteine (5) and N-acetyl-S-(2-hydroxy-1
      phenylethyl)cysteine (6), were found to be major urinary metabolites of both
      styrene and phenyloxirane. 1-Phenylethane-1,2-diol (2) was the main neutral
      metabolite. The rate of excretion of this metabolite, as determined by GC, was 5
      10 times lower than that of mandelic acid. Several minor acidic metabolites were
      also identified. Among them, novel phenolic metabolites, namely, 2-(4
      hydroxyphenyl)ethanol (7), (4-hydroxyphenyl)acetic acid (11), and two isomeric
      hydroxymandelic acids (12), are of toxicological significance. Main stereogenic
      metabolites were isolated as methyl esters from extracts of pooled acidified
      urine treated with diazomethane. The mandelic acid that was obtained was
      converted to diastereomeric Mosher's derivatives prior to analysis by NMR.
      Mercapturic acids were analyzed directly by (13)C NMR. Pure enantiomers of 1 were
      metabolized predominantly but not exclusively to corresponding enantiomers of 3.
      Styrene yielded predominantly (S)-mandelic acid. Fractions of mercapturic acids 5
      and 6 isolated from urine amounted to 12-15% of the dose for all compounds that
      were administered. Conversion to mercapturic acids was highly regio- and
      stereoselective, yielding predominantly regioisomer 5. Styrene, as compared to
      racemic phenyloxirane, yielded slightly more diastereomers arising from (S)-1
      than from (R)-1. These data can be explained by formation of a moderate excess of
      the less mutagenic (S)-1 in the metabolic activation of styrene in mice in vivo.

PMID- 10649966
TI  - 4-Hydroxylated metabolites of the antiestrogens tamoxifen and toremifene are
      metabolized to unusually stable quinone methides.
AB  - Tamoxifen is widely prescribed for the treatment of hormone-dependent breast
      cancer, and it has recently been approved by the Food and Drug Administration for
      the chemoprevention of this disease. However, long-term usage of tamoxifen has
      been linked to increased risk of developing endometrial cancer in women. One of
      the suggested pathways leading to the potential toxicity of tamoxifen involves
      its oxidative metabolism to 4-hydroxytamoxifen, which may be further oxidized to
      an electrophilic quinone methide. The resulting quinone methide has the potential
      to alkylate DNA and may initiate the carcinogenic process. To further probe the
      chemical reactivity and toxicity of such an electrophilic species, we have
      prepared the 4-hydroxytamoxifen quinone methide chemically and enzymatically,
      examined its reactivity under physiological conditions, and quantified its
      reactivity with GSH. Interestingly, this quinone methide is unusually stable; its
      half-life under physiological conditions is approximately 3 h, and its half-life
      in the presence of GSH is approximately 4 min. The reaction between 4
      hydroxytamoxifen quinone methide and GSH appears to be a reversible process
      because the quinone methide GSH conjugates slowly decompose over time,
      regenerating the quinone methide as indicated by LC/MS/MS data. The tamoxifen GSH
      conjugates were detected in microsomal incubations with 4-hydroxytamoxifen;
      however, none were observed in breast cancer cell lines (MCF-7) perhaps because
      very little quinone methides is formed. Toremifene, which is a chlorinated
      analogue of tamoxifen, undergoes similar oxidative metabolism to give 4
      hydroxytoremifene, which is further oxidized to the corresponding quinone
      methide. The toremifene quinone methide has a half-life of approximately 1 h
      under physiological conditions, and its rate of reaction in the presence of
      excess GSH is approximately 6 min. More detailed analyses have indicated that the
      4-hydroxytoremifene quinone methide reacts with two molecules of GSH and loses
      chlorine to give the corresponding di-GSH conjugates. The reaction mechanism
      likely involves an episulfonium ion intermediate which may contribute to the
      potential cytotoxic effects of toremifene. Similar to what was observed with 4
      hydroxytamoxifen, 4-hydroxytoremifene was metabolized to di-GSH conjugates in
      microsomal incubations at about 3 times the rate of 4-hydroxytamoxifen, although
      no conjugates were detected with MCF-7 cells. Finally, these data suggest that
      quinone methide formation may not make a significant contribution to the
      cytotoxic and genotoxic effects of tamoxifen and toremifene.

PMID- 10649967
TI  - Synthesis and reactivity of a potential carcinogenic metabolite of tamoxifen: 3,4
      dihydroxytamoxifen-o-quinone.
AB  - Although tamoxifen is approved for the treatment of hormone-dependent breast
      cancer as well as for the prevention of breast cancer in high-risk women, several
      studies in animal models have shown that tamoxifen is heptocarcinogenic, and in
      humans, tamoxifen has been associated with an increased risk of endometrial
      cancer. One potential mechanism of tamoxifen carcinogenesis could involve
      metabolism of tamoxifen to 3,4-dihydroxytamoxifen followed by oxidation to a
      highly reactive o-quinone which has the potential to alkylate and/or oxidize
      cellular macromolecules in vivo. In the study presented here, we synthesized the
      3,4-dihydroxytamoxifen, prepared its o-quinone chemically and enzymatically, and
      studied the reactivity of the o-quinone with GSH and deoxynucleosides. The E
      (trans) and Z (cis) isomers of 3,4-dihydroxytamoxifen were synthesized using a
      concise synthetic pathway (four steps). This approach is based on the McMurry
      reaction between the key 4-(2-chloroethoxy)-3,4-methylenedioxybenzophenone and
      propiophenone, followed by selective removal of the methylenedioxy ring of (E, Z)
      1-[4-[2-(N,N-dimethylamino)ethoxy]phenyl]-1-(3, 4-methylenedioxyphenyl)-2-phenyl
      1-butene with BCl(3). Oxidation of 3,4-dihydroxytamoxifen by activated silver
      oxide or tyrosinase gave 3,4-dihydroxytamoxifen-o-quinone as a mixture of E and Z
      isomers. The resulting o-quinone has a half-life of approximately 80 min under
      physiological conditions. Reaction of the o-quinone with GSH gave two di-GSH
      conjugates and three mono GSH conjugates. Incubation of 3,4-dihydroxytamoxifen
      with GSH in the presence of microsomal P450 gave the same GSH conjugates which
      were also detected in incubations with human breast cancer cells (MCF-7).
      Reaction of 3, 4-dihydroxytamoxifen-o-quinone with deoxynucleosides gave only
      thymidine and deoxyguanosine adducts; neither deoxyadenosine nor deoxycytosine
      adducts were detected. Preliminary studies conducted with human breast cancer
      cell lines showed that 3, 4-dihydroxytamoxifen exhibited cytotoxic potency
      similar to that of 4-hydroxytamoxifen and tamoxifen in an estrogen receptor
      negative (ER(-)) cell line (MDA-MB-231); however, in the ER(+) cell line (MCF-7),
      the catechol metabolite was about half as toxic as the other two compounds.
      Finally, in the presence of microsomes and GSH, 4-hydroxytamoxifen gave
      predominantly quinone methide GSH conjugates as reported in the previous paper in
      this issue [Fan, P. W., et al. (2000) Chem. Res. Toxicol. 13, XX-XX]. However, in
      the presence of tyrosinase and GSH, 4-hydroxytamoxifen was primarily converted to
      o-quinone GSH conjugates. These results suggest that the catechol metabolite of
      tamoxifen has the potential to cause cytotoxicity in vivo through formation of
      3,4-dihydroxytamoxifen-o-quinone.

PMID- 10649968
TI  - Structural determinants of efficacy for kappa opioid receptors in the orvinol
      series: 7,7-spiro analogues of buprenorphine.

PMID- 10649969
TI  - Synthesis and pharmacological characterization of [(125)I]iodomethyllycaconitine
      ([(125)I]iodo-MLA). A new ligand for the alpha(7) nicotinic acetylcholine
      receptor.

PMID- 10649970
TI  - Structure-based discovery of small molecule inhibitors targeted to protein
      tyrosine phosphatase 1B.
AB  - Protein tyrosine phosphatases (PTPases) are involved in the control of tyrosine
      phosphorylation levels in the cell and are believed to be crucial for the
      regulation of a multitude of cellular functions. A detailed understanding of the
      role played by PTPases in various signaling pathways has not yet been achieved,
      and potent and selective PTPase inhibitors are essential in the quest to
      determine the functionality of individual PTPases. Using the DOCK methodology, we
      have carried out a structure-based, computer-assisted search of an available
      chemical database in order to identify low molecular weight, nonpeptidic PTP1B
      inhibitors. We have identified several organic molecules that not only possess
      inhibitory activity against PTP1B but which also display significant selectivity
      for PTP1B. This indicates that although structural features important for pTyr
      recognition are conserved among different PTPases, it is possible to generate
      selective inhibitors targeted primarily to the catalytic site. Kinetic analysis
      and molecular modeling experiments suggest that the PTP1B active site possesses
      significant plasticity such that substituted and extended aromatic systems can be
      accommodated. The newly identified molecules provide a molecular framework upon
      which therapeutically useful compounds can ultimately be based, and systematic
      optimization of these lead compounds is likely to further enhance their potency
      and selectivity.

PMID- 10649971
TI  - Structure-activity relationships and pharmacokinetic analysis for a series of
      potent, systemically available biphenylsulfonamide matrix metalloproteinase
      inhibitors.
AB  - A series of biphenylsulfonamide derivatives of (S)-2-(biphenyl-4-sulfonylamino)-3
      methylbutyric acid (5) were prepared and evaluated for their ability to inhibit
      matrix metalloproteinases (MMPs). For this series of compounds, our objective was
      to systematically replace substituents appended to the biphenyl and alpha
      position of 5 with structurally diverse functionalities to assess the effects
      these changes have on biological and pharmacokinetic activity. The ensuing
      structure-activity relationship (SAR) studies showed that biphenylsulfonamides
      substituted with bromine in the 4'-position (11c) significantly improved in vitro
      activity and exhibited superior pharmacokinetics (C(max), t(1/2), AUCs), relative
      to compound 5. Varying the lipophilicity of the alpha-position by replacing the
      isopropyl group of 11c with a variety of substituents, in general, maintained
      potency versus MMP-2, -3, and -13 but decreased the oral systemic availability.
      Subsequent evaluation of its enantiomer, 11c', showed that both compounds were
      equally effective MMP inhibitors. In contrast, the corresponding hydroxamic acid
      enantiomeric pair, 16a (S-isomer) and 16a' (R-isomer), stereoselectivity
      inhibited MMPs. For the first time in this series, 16a' provided nanomolar
      potency against MMP-1, -7, and -9 (IC(50)'s = 110, 140, and 18 nM, respectively),
      whereas 16a was less potent against these MMPs (IC(50)'s = 24, 78, and 84 microM,
      respectively). However, unlike 11c, compound 16a' afforded very low plasma
      concentrations following a single 5 mg/kg oral dose in rat. Subsequent X-ray
      crystal structures of the catalytic domain of stromelysin (MMP-3CD) complexed
      with inhibitors from closely related series established the differences in the
      binding mode of carboxylic acid-based inhibitors (11c,c') relative to the
      corresponding hydroxamic acids (16a,a').

PMID- 10649972
TI  - Antitumor agents. 199. Three-dimensional quantitative structure-activity
      relationship study of the colchicine binding site ligands using comparative
      molecular field analysis.
AB  - Inhibitors of tubulin polymerization interacting at the colchicine binding site
      are potential anticancer agents. We have been involved in the synthesis of a
      number of colchicine site agents, such as thiocolchicinoids and
      allocolchicinoids, which are colchicine analogues, and 2-phenyl-quinolones and 2
      aryl-naphthyridinones, which are the amino analogues of cytotoxic antimitotic
      flavonoids. The most cytotoxic of the latter compounds strongly inhibit binding
      of radiolabeled colchicine to tubulin, and these agents therefore probably bind
      in the colchicine site of tubulin. We have applied conventional CoMFA and q(2)
      GRS CoMFA to identify the essential structural requirements for increasing the
      ability of these compounds to form tubulin complexes. The CoMFA model for the
      training set of 51 compounds yielded cross-validated R(2) (q(2)) values of 0.637
      for conventional CoMFA and 0.692 for q(2)-GRS CoMFA. The predictive power of this
      model was confirmed by successful activity prediction for a test set of 53
      compounds with known potencies as inhibitors of tubulin polymerization. The
      activities of 88% of the compounds were predicted with absolute value of
      residuals of less than 0.5. The predictive q(2) values were 0.546 for
      conventional CoMFA and 0.426 for q(2)-GRS CoMFA. The conventional CoMFA model
      with the highest predictive q(2) (0.546) was analyzed in detail in terms of
      underlying structure-activity relationships.

PMID- 10649973
TI  - 3,4-dihydro-2(1H)-quinolinone as a novel antidepressant drug: synthesis and
      pharmacology of 1-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-3,4- dihydro-5
      methoxy-2(1H)-quinolinone and its derivatives.
AB  - To develop a novel antidepressant drug with central nervous system-stimulating
      activity, we prepared a series of 1-[omega-(4-substituted phenyl-1
      piperazinyl)alkyl]-3, 4-dihydro-2(1H)-quinolinone derivatives and examined their
      activities by their effects at 30 and 100 mg/kg po on the sleeping time of mice
      anesthetized with halothane and on the time required for recovery from coma
      induced in mice by cerebral concussion. We examined their binding affinities for
      sigma receptors by evaluating their ability to inhibit [(3)H]-1,3-di(o
      tolyl)guanidine ([(3)H]DTG) binding to the rat whole brain membrane in comparison
      with three putative sigma receptor agonists: 1,3-di(o-tolyl)guanidine (DTG, 66),
      (+)-1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(2-propenyl)-2, 6-methano-3-benzazecin
      8-ol (SKF10,047, 67), and (+)-1,2,3,4,5, 6-hexahydro-6,11-dimethyl-3-(3-methyl-2
      butenyl)-2, 6-methano-3-benzazecin-8-ol (pentazocine, 68). Among the series of
      derivatives, 1-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-3, 4-dihydro-5
      methoxy-2(1H)-quinolinone hydrochloride (34b) and its mesylate (34c), at a dose
      of 30 mg/kg po, reduced the sleeping time and the time for recovery from coma and
      they inhibited [(3)H]DTG binding for sigma receptors. The putative sigma receptor
      agonists reduced the sleeping time and the time for recovery from coma whereas
      two sigma receptor antagonists, alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)
      1-piperazinebutanol hydrochloride (BMY14802, 69) and cis-9-[3-(3, 5-dimethyl-1
      piperazinyl)propyl]carbazole dihydrochloride (rimcazole, 70), were inactive in
      the two tests. Preadministration of the putative sigma receptor antagonists 69 (3
      mg/kg po) and 70 (30 mg/kg po) completely antagonized the actions of 34b and the
      sigma receptor agonists in the test for recovery from coma. These results
      suggested that 34b and 34c are sigma receptor agonists. Furthermore, a single
      administration of 1 and 10 mg/kg po 34b and 34c showed antidepressant-like
      activity by reducing the immobility time in the forced-swimming test with mice,
      while a tricyclic antidepressant, 10, 11-dihydro-N,N-dimethyl-5H
      dibenz[b,f]azepine-5-propanamine hydrochloride (imipramine, 1) (10 and 30 mg/kg
      po), did not reduce the time after a single administration. 1 reduced the time
      after repeated administration of 30 mg/kg po once a day for 4 days. The structure
      activity relationship of the series of compounds is also discussed.

PMID- 10649974
TI  - A potential melanoma tracer: synthesis, radiolabeling, and biodistribution in
      mice of a new nitridotechnetium bis(aminothiol) derivative pharmacomodulated by a
      N-(diethylaminoethyl)benzamide.
AB  - Radioiodobenzamides are the best-known agents under study for the diagnosis of
      cutaneous melanoma and its metastases. We report the synthesis of a new BAT
      derivative radiopharmaceutical in which radioiodine is replaced by 99m
      technetium. The cyclic intermediary methyl 4-[3-(4,4,7,7-tetramethyl-5,6-dithia
      2, 9-diazacyclodecyl)-2-oxapropyl]benzoate (5) occurred in two different
      conformations identified by spectroscopic analysis. The final BAT ligand was
      radiolabeled using the nitridotechnetium core by a ligand-exchange reaction. Two
      different complexes were purified. After macroscopic 99-technetium synthesis, syn
      and anti isomers were identified. The global radiochemical yield was over 80%.
      The biodistribution of these two complexes was evaluated in mice bearing murine
      B16 melanoma. Extensive liver and kidney uptake was observed, but the benzamide
      tropism for the tumor was partially preserved.

PMID- 10649975
TI  - Synthesis and in vitro anti-mycobacterium activity of N-alkyl-1, 2-dihydro-2
      thioxo-3-pyridinecarbothioamides. Preliminary toxicity and pharmacokinetic
      evaluation.
AB  - Disseminated infections with Mycobacterium tuberculosis (MT) and Mycobacterium
      avium complex (MAC) are increasingly opportunistic diseases in patients with
      advanced acquired human immunodeficiency syndrome (AIDS). A series of N-alkyl-1,
      2-dihydro-2-thioxo-3-pyridinecarbothioamides has been synthesized, and MICs for
      MT and MAC strains, either standard or isolated from infected patients, have been
      determined. Preliminary tests show a good activity and a very low toxicity for
      some derivatives. Pharmacokinetic studies in the rat show a very rapid
      elimination from the body after intravenous administration and a poor absorption
      after oral administration.

PMID- 10649976
TI  - Novel 3-aminomethyl- and 4-aminopiperidine analogues of 1-[2
      (diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazines: synthesis and evaluation
      as dopamine transporter ligands.
AB  - We have undertaken a program to develop cocaine antagonists based on the premise
      that such compounds should block cocaine binding but permit reuptake of dopamine
      at the dopamine transporter (DAT). To evaluate the structural features of
      potential cocaine antagonists, 3-aminomethylpiperidine and 4-aminopiperidine
      moieties were incorporated at the central bridge region (piperazine ring) of GBR
      12935. The compounds were assayed as inhibitors of [(125)I]RTI-55 binding at the
      DAT and monoamine transport. The results indicated that most of the new compounds
      preferentially inhibited norepinephrine reuptake by its transporter (NET) but in
      some cases retained binding selectivity for the DAT. In general, the binding
      selectivity and potency of [(3)H]NE reuptake inhibition were very sensitive to
      modifications of the central bridge diamine moiety (position of two basic
      nitrogen atoms). Compound 6 exhibited the highest ratio (14-fold) of DA reuptake
      inhibition to RTI-55 binding inhibition at the DAT; however, in an in vitro assay
      of cocaine antagonism, this compound failed to reduce inhibition of [(3)H]DA
      uptake by cocaine. These results demonstrated that separation of biological
      activities into the binding and reuptake inhibition can be achieved by
      alterations in the internal diamine component of GBR 12935, but additional
      modifications are necessary before these agents constitute lead compounds for
      development as cocaine antagonists.

PMID- 10649977
TI  - Synthesis and biological evaluation of 3,4-diaryloxazolones: A new class of
      orally active cyclooxygenase-2 inhibitors.
AB  - A series of 3,4-diaryloxazolones were prepared and evaluated for their ability to
      inhibit cyclooxygenase-2 (COX-2). Extensive structure-activity relationship work
      was carried out within this series, and a number of potent and selective COX-2
      inhibitors were identified. The replacement of the methyl sulfone group on the 4
      phenyl ring by a sulfonamide moiety resulted in compounds with superior in vivo
      antiinflammatory properties. In the sulfonamide series, the introduction of a
      methyl group at the 5-position of the oxazolone ring gave rise to very COX-2
      selective compounds but with decreased in vivo activity. Selected 3,4
      diaryloxazolones exhibited excellent activities in experimental models of
      arthritis and hyperalgesia. The in vivo activity of these compounds was confirmed
      with the evaluation of their antipyretic effectiveness and their ability to
      inhibit migration of proinflammatory cells. As expected from their COX-2
      selectivity, most of the active compounds lacked gastrointestinal toxicity in
      vivo in rats after a 4-day treatment of 100 mg/kg/day. Within this novel series,
      sulfonamides 9-11 have been selected for further preclinical evaluation.

PMID- 10649978
TI  - Synthesis and evaluation of hydroxylated polyamine analogues as
      antiproliferatives.
AB  - The synthesis of four hydroxylated polyamine analogues, (2R, 10R)-N(1),N(11)
      diethyl-2,10-dihydroxynorspermine, (2S,10S)-N(1), N(11)-diethyl-2,10
      dihydroxynorspermine, (3S,12S)-N(1), N(14)-diethyl-3,12-dihydroxyhomospermine,
      and (3R,12R)-N(1), N(14)-diethyl-3,12-dihydroxyhomospermine, is described along
      with their impact on the growth and polyamine metabolism of L1210 murine leukemia
      cells. Four different synthetic approaches are set forth, two each for the
      hydroxylated norspermines and for the hydroxylated homospermines. The key step in
      the assembly of the norspermines was the coupling of either N-[(2R)-2,3
      epoxypropyl]-N-ethyl p-toluenesulfonamide or N-[(2S)-2,3-epoxypropyl]-N-ethyl
      trifluoromethanesulfonamide to N,N'-dibenzyl-1,3-diaminopropane. The key step
      with homospermines employed alkylation of putrescine with (3S)-N
      (benzyloxycarbonyl)-N-ethyl-3,4-epoxybutylamine or of N, N'
      bis(mesitylenesulfonyl)-1,4-butanediamine with (2R)-2-benzyloxy-4-[N
      (mesitylenesulfonyl)ethylamino]-O-tosyl-1-++ +butan ol. All of the hydroxylated
      analogues were active against L1210 cells with 96-h IC(50) values of </=2 microM,
      and they also effectively reduced putrescine and spermidine, although the effect
      on spermine pools ranged from moderate to insignificant. Interestingly, the
      impact of the hydroxylated analogues on ornithine decarboxylase (ODC) was
      significantly less than that of unhydroxylated parent drug (e.g., N(1),N(11)
      diethylnorspermine [DENSPM]) at 1 microM; however, S-adenosylmethionine
      decarboxylase (AdoMetDC) depletion was nearly identical to what was observed in
      cells treated with parent drug. The most notable difference between the parent
      and hydroxylated analogues was seen with spermidine/spermine N(1)
      acetyltransferase (SSAT) upregulation in the DENSPM series. The hydroxylated
      analogues, especially (R, R)-(HO)(2)DENSPM, were much less effective at
      upregulation than the parent DENSPM. Finally, a comparison of the toxicity of (R,
      R)-(HO)(2)DENSPM with that of DENSPM at subchronic doses revealed that the
      neurological effects seen with DENSPM were now absent.

PMID- 10649979
TI  - Secondary amides of (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid as
      inhibitors of pyruvate dehydrogenase kinase.
AB  - N'-methyl-N-(4-tert-butyl-1,2,5,6-tetrahydropyridine)thiourea, SDZ048-619 (1), is
      a modest inhibitor (IC(50) = 180 microM) of pyruvate dehydrogenase kinase (PDHK).
      In an optimization of the N-methylcarbothioamide moiety of 1, it was discovered
      that amides with a small acyl group, in particular appropriately substituted
      amides of (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid, are inhibitors of
      PDHK. Utilizing this acyl moiety, herein is reported the rationale leading to the
      optimization of a series of acylated piperazine derivatives. Methyl substitution
      of the piperazine at the 2- and 5-positions (with S and R absolute
      stereochemistry) markedly increased the potency of the lead compound (>1,000
      fold). Oral bioavailability of the compounds in this series is good and is
      optimal (as measured by AUC) when the 4-position of the piperazine is substituted
      with an electron-poor benzoyl moiety. (+)-1-N-[2,5-(S, R)-Dimethyl-4-N-(4
      cyanobenzoyl)piperazine]-(R)-3,3, 3-trifluoro-2-hydroxy-2-methylpropanamide (14e)
      inhibits PDHK in the primary enzymatic assay with an IC(50) of 16 +/- 2 nM,
      enhances the oxidation of [(14)C]lactate into (14)CO(2) in human fibroblasts with
      an EC(50) of 57 +/- 13 nM, diminishes lactate significantly 2.5 h post-oral-dose
      at doses as low as 1 micromol/kg, and increases the ex vivo activity of PDH in
      muscle, liver, and fat tissues in normal Sprague-Dawley rats. These PDHK
      inhibitors, however, do not lower glucose in diabetic animal models.

PMID- 10649980
TI  - N-cycloalkyl derivatives of adenosine and 1-deazaadenosine as agonists and
      partial agonists of the A(1) adenosine receptor.
AB  - A number of cycloalkyl substituents (from C-3 to C-8) have been introduced on the
      6-amino group of adenosine, 1-deazaadenosine, and 2'-deoxyadenosine, bearing or
      not a chlorine atom at the 2-position, to evaluate the influence on the A(1) and
      A(2A) affinity of steric hindrance and lipophilicity. Furthermore, the guanosine
      5'-triphosphate (GTP) shift and the maximal induction of guanosine 5'-(gamma
      thio)triphosphate ([(35)S]GTPgammaS) binding to G proteins in rat brain membranes
      were used to determine the intrinsic activity of these nucleosides at the A(1)
      adenosine receptor. All compounds of the ribose-bearing series proved to be full
      agonists, the 1-deaza derivatives showing affinities for the A(1) receptor about
      10-fold lower than the corresponding adenosines. On the other hand, all the 2'
      deoxyribose derivatives bind to the A(1) receptor with affinities in the high
      nanomolar range, with the 2-chloro substituted compounds showing slightly higher
      affinities than the 2-unsubstituted counterparts. In terms of the potencies, the
      most potent compounds proved to be those bearing four- and five-membered rings.
      Both GTP shifts and [(35)S]-GTPgammaS experiments showed that most of the 2'
      deoxyadenosine derivatives are partial agonists. The 2'-deoxyadenosine
      derivatives which were identified as partial agonists consistently detected fewer
      A(1) receptors in the high-affinity state than full agonists. However, it is
      worthwhile noting that there was not a simple linear relationship between
      receptor occupancy and activation. These results indicate that a critical density
      of A(1) adenosine receptors in the high-affinity state is required for G protein
      activation.

PMID- 10649981
TI  - Esterase-sensitive nitric oxide donors of the diazeniumdiolate family: in vitro
      antileukemic activity.
AB  - We have designed a novel prodrug class that is stable in neutral aqueous media
      but releases bioactive nitric oxide (NO) on metabolism by esterase.
      Diazeniumdiolates of structure R(2)N-N(O)=N-OR', in which R' = Na, were reacted
      with BrCH(2)OAc to convert the spontaneously NO-releasing salts 1a (R(2)N =
      diethylamino) and 1b (R(2)N = pyrrolidino) to prodrugs 2a (AcOM-DEA/NO) and 2b
      (AcOM-PYRRO/NO), respectively, where R' = CH(2)OAc. In contrast to anions 1a and
      1b (half-lives in pH 7.4 phosphate at 37 degrees C of 2 min and 3 s,
      respectively), 2a and 2b showed only minimal decomposition after 16 h under these
      conditions. Very rapid hydrolysis occurred in the presence of porcine liver
      esterase, however, with free anion 1a being observed as an intermediate in the
      esterase-induced generation of NO from 2a. The potential utility of this prodrug
      class is illustrated with a comparison of 1 and 2 as antiproliferative agents in
      NO-sensitive human leukemia cell lines HL-60 and U937. While the 72-h IC(50)'s
      for 1a and 1b (which generate NO throughout the medium) in HL-60 cell cultures
      were >600 microM, those of 2a and 2b were 8.3 and 6.4 microM, respectively. This
      result is consistent with our hypothesis that 2 is selectively hydrolyzed to 1
      and thence to NO intracellularly. For U937 cells, the 72-h IC(50) for both 2a and
      2b was 53 microM. By contrast, relatively high antiproliferative IC(50)'s (>100
      microM in U937 cells) were observed for analogues in which R' =
      CH(2)CH(2)SC(O)Me, from which acetyl and 2-mercaptoethyl groups must be
      successively cleaved to free the NO-releasing diazeniumdiolate function. Within
      24 h at initial concentrations of 50 microM, 2a and 2b induced apoptosis in 50%
      and 57% of the HL-60 cells, respectively (35% and 40% of the U937 cells,
      respectively). The data reveal significant in vitro antileukemic activity on the
      part of these novel compounds. Moreover, their substantial ease-of-handling
      advantages over the anionic diazeniumdiolates from which they are derived suggest
      their use as convenient agents for probing the biological roles of NO.

PMID- 10649982
TI  - A structure-affinity relationship study on derivatives of N-[2-[4-(4
      Chlorophenyl)piperazin-1-yl]ethyl]-3-methoxybenzamide, a high-affinity and
      selective D(4) receptor ligand.
AB  - N-[2-[4-(4-Chlorophenyl)piperazin-1-yl]ethyl]-3-methoxybenzamide (1), a high
      affinity and selective dopamine D(4) receptor ligand, was chosen as a lead, and
      structural modifications were done on its amide bond and on its alkyl chain
      linking the benzamide moiety to the piperazine ring and by preparing some
      semirigid analogues. The binding profile at dopamine D(4) and dopamine D(2),
      serotonin 5-HT(1A), and adrenergic alpha(1) receptors of 16 new compounds was
      determined. From the results emerged that the modification of the amide bond and
      the elongation of the intermediate alkyl chain caused a decrease in dopamine D(4)
      receptor affinity. All prepared semirigid analogues displayed D(4) receptor
      affinity values in the same range of the opened counterparts.

PMID- 10649983
TI  - Synthesis and antiviral activity of novel anti-VZV 5-substituted uracil
      nucleosides with a cyclopropane sugar moiety.
AB  - A series of 5-substituted uracil nucleoside derivatives with a 1(1'S, 2'R)-[1',2'
      bis(hydroxymethyl)cyclopropyl]methyl group as an acyclosugar moiety were
      synthesized and evaluated for their anti-herpetic activities. Among the compounds
      synthesized, (E)-5-halovinyluracil derivatives showed superior anti-varicella
      zoster virus (VZV) activity over acyclovir (ACV) but were less potent than ACV
      against herpes symplex virus type-1 (HSV-1). IC(50) values for the VZV Kawaguchi
      strain were 0.027 for Br, 0.070 for Cl, and 0.054 microg/mL for I derivatives and
      3.4 microg/mL for ACV. The most potent compound, (1'S,2'R)-5-[(E)-2-bromoethenyl]
      1-[[1', 2'-bis(hydroxymethyl)cycloprop-1'-yl]methyl]-2,4-(1H, 3H)-pyrimidinedione
      (3a), was 40-60-fold more potent than ACV against clinical isolates of VZV. It
      showed good oral bioavailability in rats (68.5%) and, unlike (E)-5-(2-bromovinyl)
      1-beta-D-arabinofuranosyluracil (BVaraU), did not result in the release of (E)-5
      (2-bromovinyl)uracil (BVU), a potent dihydropyrimidine dehydrogenase inhibitor,
      in plasma after oral administration.

PMID- 10649984
TI  - Structure-function relationships in aminoquinolines: effect of amino and chloro
      groups on quinoline-hematin complex formation, inhibition of beta-hematin
      formation, and antiplasmodial activity.
AB  - Comparison of 19 aminoquinolines supports the hypothesis that chloroquine and
      related antimalarials act by complexing ferriprotoporphyrin IX (Fe(III)PPIX),
      inhibiting its conversion to beta-hematin (hemozoin) and hence its
      detoxification. The study suggests that a basic amino side chain is also
      essential for antiplasmodial activity. 2- And 4-aminoquinolines are unique in
      their strong affinity for Fe(III)PPIX, and attachment of side chains to the amino
      group has relatively little influence on the strength of complex formation.
      Association with Fe(III)PPIX is necessary, but not sufficient, for inhibiting
      beta-hematin formation. Presence of a 7-chloro group in the 4-aminoquinoline ring
      is a requirement for beta-hematin inhibitory activity, and this is also
      unaffected by side chains attached to the amino group. In turn, beta-hematin
      inhibitory activity is necessary, but not sufficient, for antiplasmodial activity
      as the presence of an aminoalkyl group attached to the 4-amino-7-chloroquinoline
      template is essential for strong activity. We thus propose that the 4
      aminoquinoline nucleus of chloroquine and related antimalarials is responsible
      for complexing Fe(III)PPIX, the 7-chloro group is required for inhibition of beta
      hematin formation, and the basic amino side chain is required for drug
      accumulation in the food vacuole of the parasite.

PMID- 10649985
TI  - Carbonic anhydrase inhibitors: synthesis of membrane-impermeant low molecular
      weight sulfonamides possessing in vivo selectivity for the membrane-bound versus
      cytosolic isozymes.
AB  - Aromatic/heterocyclic sulfonamides act as strong inhibitors of the zinc enzyme
      carbonic anhydrase (CA; EC 4.2.1.1), but the presently available compounds do not
      generally discriminate between the 14 isozymes isolated in higher vertebrates.
      Thus, clinically used drugs from this class of pharmacological agents show many
      undesired side effects due to unselective inhibition of all CA isozymes present
      in a tissue/organ. Here we propose a new approach for the selective in vivo
      inhibition of membrane-bound versus cytosolic CA isozymes with a new class of
      positively charged, membrane-impermeant sulfonamides. This approach is based on
      the attachment of trisubstituted-pyridinium-methylcarboxy moieties (obtained from
      2,4, 6-trisubstituted-pyrylium salts and glycine) to the molecules of classical
      aromatic/heterocyclic sulfonamides possessing free amino, imino, hydrazino, or
      hydroxyl groups in their molecules. Efficient in vitro inhibition (in the
      nanomolar range) was observed with some of the new derivatives against three
      investigated CA isozymes: i.e., hCA I, hCA II (cytosolic forms), and bCA IV
      (membrane-bound isozyme) (h = human isozyme; b = bovine isozyme). Due to their
      salt-like character, the new type of inhibitors reported here, unlike the
      classical, clinically used compounds (such as acetazolamide, methazolamide, and
      ethoxzolamide), are unable to penetrate through biological membranes, as shown by
      ex vivo and in vivo perfusion experiments in rats. The level of bicarbonate
      excreted into the urine of the experimental animals perfused with solutions of
      the new and classical inhibitors undoubtedly proved that: (i) when using the new
      type of positively charged sulfonamides, only the membrane-bound enzyme (CA IV)
      was inhibited, whereas the cytosolic isozymes (CA I and II) were not affected;
      (ii) in the experiments in which the classical compounds (acetazolamide,
      benzolamide, etc.) were used, unselective inhibition of all CA isozymes (I, II,
      and IV) has been evidenced.

PMID- 10649987
TI  - Tropical pacific forcing of decadal SST variability in the western indian ocean
      over the past two centuries
AB  - A 194-year annual record of skeletal delta(18)O from a coral growing at Malindi,
      Kenya, preserves a history of sea surface temperature (SST) change that is
      coherent with instrumental and proxy records of tropical Pacific climate
      variability over interannual to decadal periods. This variability is superimposed
      on a warming of as much as 1.3 degrees C since the early 1800s. These results
      suggest that the tropical Pacific imparts substantial decadal climate variability
      to the western Indian Ocean and, by implication, may force decadal variability in
      other regions with strong El Nino-Southern Oscillation teleconnections.

PMID- 10649986
TI  - AIDS as a zoonosis: scientific and public health implications.
AB  - Evidence of simian immunodeficiency virus (SIV) infection has been reported for
      26 different species of African nonhuman primates. Two of these viruses, SIVcpz
      from chimpanzees and SIVsm from sooty mangabeys, are the cause of acquired
      immunodeficiency syndrome (AIDS) in humans. Together, they have been transmitted
      to humans on at least seven occasions. The implications of human infection by a
      diverse set of SIVs and of exposure to a plethora of additional human
      immunodeficiency virus-related viruses are discussed.

PMID- 10649989
TI  - Nanotube molecular wires as chemical sensors
AB  - Chemical sensors based on individual single-walled carbon nanotubes (SWNTs) are
      demonstrated. Upon exposure to gaseous molecules such as NO(2) or NH(3), the
      electrical resistance of a semiconducting SWNT is found to dramatically increase
      or decrease. This serves as the basis for nanotube molecular sensors. The
      nanotube sensors exhibit a fast response and a substantially higher sensitivity
      than that of existing solid-state sensors at room temperature. Sensor
      reversibility is achieved by slow recovery under ambient conditions or by heating
      to high temperatures. The interactions between molecular species and SWNTs and
      the mechanisms of molecular sensing with nanotube molecular wires are
      investigated.

PMID- 10649988
TI  - The role of the southern ocean in uptake and storage of anthropogenic carbon
      dioxide
AB  - An ocean-climate model that shows high fluxes of anthropogenic carbon dioxide
      into the Southern Ocean, but very low storage of anthropogenic carbon there,
      agrees with observation-based estimates of ocean storage of anthropogenic carbon
      dioxide. This low simulated storage indicates a subordinate role for deep
      convection in the present-day Southern Ocean. The primary mechanism transporting
      anthropogenic carbon out of the Southern Ocean is isopycnal transport. These
      results imply that if global climate change reduces the density of surface waters
      in the Southern Ocean, isopycnal surfaces that now outcrop may become isolated
      from the atmosphere, tending to diminish Southern Ocean carbon uptake.

PMID- 10649990
TI  - Single-file diffusion of colloids in one-dimensional channels
AB  - Single-file diffusion, prevalent in many processes, refers to the restricted
      motion of interacting particles in narrow micropores with the mutual passage
      excluded. A single-filing system was developed by confining colloidal spheres in
      one-dimensional circular channels of micrometer scale. Optical video microscopy
      study shows evidence that the particle self-diffusion is non-Fickian for long
      periods of time. In particular, the distribution of particle displacement is a
      Gaussian function.

PMID- 10649991
TI  - Three-dimensional direct imaging of structural relaxation near the colloidal
      glass transition
AB  - Confocal microscopy was used to directly observe three-dimensional dynamics of
      particles in colloidal supercooled fluids and colloidal glasses. The fastest
      particles moved cooperatively; connected clusters of these mobile particles could
      be identified; and the cluster size distribution, structure, and dynamics were
      investigated. The characteristic cluster size grew markedly in the supercooled
      fluid as the glass transition was approached, in agreement with computer
      simulations; at the glass transition, however, there was a sudden drop in their
      size. The clusters of fast-moving particles were largest near the alpha
      relaxation time scale for supercooled colloidal fluids, but were also present,
      albeit with a markedly different nature, at shorter beta-relaxation time scales,
      in both supercooled fluid and glass colloidal phases.

PMID- 10649992
TI  - Oxygen isotopes and emerald trade routes since antiquity
AB  - Oxygen isotopic compositions of historical emerald artifacts from the Gallo-Roman
      period to the 18th century indicate that during historical times, artisans worked
      emeralds originating from deposits supposedly discovered in the 20th century. In
      antiquity, Pakistani and Egyptian emeralds were traded by way of the Silk Route.
      Together with Austrian stones, they were the only source of gem-quality emeralds.
      Immediately after the discovery of the Colombian mines by Spaniards in the 16th
      century, a new trade route was established, first via Spain to Europe and India
      and then directly via the Philippines to India. Since then, Colombian emeralds
      have dominated the emerald trade, and most of the high-quality emeralds cut in
      the 18th century in India originated from Colombia.

PMID- 10649993
TI  - Quantum-critical conductivity scaling for a metal-insulator transition
AB  - Temperature (T)- and frequency (omega)-dependent conductivity measurements are
      reported here in amorphous niobium-silicon alloys with compositions (x) near the
      zero-temperature metal-insulator transition. There is a one-to-one correspondence
      between the frequency- and temperature-dependent conductivity on both sides of
      the critical concentration, thus establishing the quantum-critical nature of the
      transition. The analysis of the conductivity leads to a universal scaling
      function and establishes the critical exponents. This scaling can be described by
      an x-, T-, and omega-dependent characteristic length, the form of which is
      derived by experiment.

PMID- 10649994
TI  - Strength and breaking mechanism of multiwalled carbon nanotubes under tensile
      load
AB  - The tensile strengths of individual multiwalled carbon nanotubes (MWCNTs) were
      measured with a "nanostressing stage" located within a scanning electron
      microscope. The tensile-loading experiment was prepared and observed entirely
      within the microscope and was recorded on video. The MWCNTs broke in the
      outermost layer ("sword-in-sheath" failure), and the tensile strength of this
      layer ranged from 11 to 63 gigapascals for the set of 19 MWCNTs that were loaded.
      Analysis of the stress-strain curves for individual MWCNTs indicated that the
      Young's modulus E of the outermost layer varied from 270 to 950 gigapascals.
      Transmission electron microscopic examination of the broken nanotube fragments
      revealed a variety of structures, such as a nanotube ribbon, a wave pattern, and
      partial radial collapse.

PMID- 10649995
TI  - Cloning and heterologous expression of the epothilone gene cluster.
AB  - The polyketide epothilone is a potential anticancer agent that stabilizes
      microtubules in a similar manner to Taxol. The gene cluster responsible for
      epothilone biosynthesis in the myxobacterium Sorangium cellulosum was cloned and
      completely sequenced. It encodes six multifunctional proteins composed of a
      loading module, one nonribosomal peptide synthetase module, eight polyketide
      synthase modules, and a P450 epoxidase that converts desoxyepothilone into
      epothilone. Concomitant expression of these genes in the actinomycete
      Streptomyces coelicolor produced epothilones A and B. Streptomyces coelicolor is
      more amenable to strain improvement and grows about 10-fold as rapidly as the
      natural producer, so this heterologous expression system portends a plentiful
      supply of this important agent.

PMID- 10649996
TI  - Complementary neural mechanisms for tracking items in human working memory.
AB  - Recognition of a specific visual target among equally familiar distracters
      requires neural mechanisms for tracking items in working memory. Event-related
      functional magnetic resonance imaging revealed evidence for two such mechanisms:
      (i) Enhanced neural responses, primarily in the frontal cortex, were associated
      with the target and were maintained across repetitions of the target. (ii)
      Reduced responses, primarily in the extrastriate visual cortex, were associated
      with stimulus repetition, regardless of whether the stimulus was a target or a
      distracter. These complementary neural mechanisms track the status of familiar
      items in working memory, allowing for the efficient recognition of a currently
      relevant object and rejection of irrelevant distracters.

PMID- 10649997
TI  - Inhibitors of strand transfer that prevent integration and inhibit HIV-1
      replication in cells.
AB  - Integrase is essential for human immunodeficiency virus-type 1 (HIV-1)
      replication; however, potent inhibition of the isolated enzyme in biochemical
      assays has not readily translated into antiviral activity in a manner consistent
      with inhibition of integration. In this report, we describe diketo acid
      inhibitors of HIV-1 integrase that manifest antiviral activity as a consequence
      of their effect on integration. The antiviral activity of these compounds is due
      exclusively to inhibition of one of the two catalytic functions of integrase,
      strand transfer.

PMID- 10649998
TI  - A tale of two futures: HIV and antiretroviral therapy in San Francisco.
AB  - The effect of antiretroviral therapy (ART) in preventing human immunodeficiency
      virus (HIV) infections and averting acquired immunodeficiency syndrome (AIDS)
      deaths in the San Francisco gay community over the next 10 years was predicted. A
      transmission model was coupled with a statistical approach that enabled inclusion
      of a high degree of uncertainty in the potential treatment effects of ART (in
      terms of infectivity and survival), increase in risky behavior, and rate of
      emergence of drug resistance. Increasing the usage of ART in San Francisco would
      decrease the AIDS death rate and could substantially reduce the incidence rate.

PMID- 10649999
TI  - Redox signaling in chloroplasts: cleavage of disulfides by an iron-sulfur
      cluster.
AB  - Light generates reducing equivalents in chloroplasts that are used not only for
      carbon reduction, but also for the regulation of the activity of chloroplast
      enzymes by reduction of regulatory disulfides via the ferredoxin:thioredoxin
      reductase (FTR) system. FTR, the key electron/thiol transducer enzyme in this
      pathway, is unique in that it can reduce disulfides by an iron-sulfur cluster, a
      property that is explained by the tight contact of its active-site disulfide and
      the iron-sulfur center. The thin, flat FTR molecule makes the two-electron
      reduction possible by forming on one side a mixed disulfide with thioredoxin and
      by providing on the opposite side access to ferredoxin for delivering electrons.

PMID- 10650000
TI  - Voltage- and tension-dependent lipid mobility in the outer hair cell plasma
      membrane.
AB  - The mechanism responsible for electromotility of outer hair cells in the ear is
      unknown but is thought to reside within the plasma membrane. Lipid lateral
      diffusion in the outer hair cell plasma membrane is a sigmoidal function of
      transmembrane potential and bathing media osmolality. Cell depolarization or
      hyposmotic challenge shorten the cell and reduce membrane fluidity by half.
      Changing the membrane tension with amphipathic drugs results in similar
      reductions. These dynamic changes in membrane fluidity represent the modulation
      of membrane tension by lipid-protein interactions. The voltage dependence may be
      associated with the force-generating motors that contribute to the exquisite
      sensitivity of mammalian hearing.

PMID- 10650001
TI  - Creating a protein-based element of inheritance.
AB  - Proteins capable of self-perpetuating changes in conformation and function (known
      as prions) can serve as genetic elements. To test whether novel prions could be
      created by recombinant methods, a yeast prion determinant was fused to the rat
      glucocorticoid receptor. The fusion protein existed in different heritable
      functional states, switched between states at a low spontaneous rate, and could
      be induced to switch by experimental manipulations. The complete change in
      phenotype achieved by transferring a prion determinant from one protein to
      another confirms the protein-only nature of prion inheritance and establishes a
      mechanism for engineering heritable changes in phenotype that should be broadly
      applicable.

PMID- 10650002
TI  - Coupling of stress in the ER to activation of JNK protein kinases by
      transmembrane protein kinase IRE1.
AB  - Malfolded proteins in the endoplasmic reticulum (ER) induce cellular stress and
      activate c-Jun amino-terminal kinases (JNKs or SAPKs). Mammalian homologs of
      yeast IRE1, which activate chaperone genes in response to ER stress, also
      activated JNK, and IRE1alpha-/- fibroblasts were impaired in JNK activation by ER
      stress. The cytoplasmic part of IRE1 bound TRAF2, an adaptor protein that couples
      plasma membrane receptors to JNK activation. Dominant-negative TRAF2 inhibited
      activation of JNK by IRE1. Activation of JNK by endogenous signals initiated in
      the ER proceeds by a pathway similar to that initiated by cell surface receptors
      in response to extracellular signals.

PMID- 10650003
TI  - A simple model for complex dynamical transitions in epidemics.
AB  - Dramatic changes in patterns of epidemics have been observed throughout this
      century. For childhood infectious diseases such as measles, the major transitions
      are between regular cycles and irregular, possibly chaotic epidemics, and from
      regionally synchronized oscillations to complex, spatially incoherent epidemics.
      A simple model can explain both kinds of transitions as the consequences of
      changes in birth and vaccination rates. Measles is a natural ecological system
      that exhibits different dynamical transitions at different times and places, yet
      all of these transitions can be predicted as bifurcations of a single nonlinear
      model.

PMID- 10650004
TI  - Giving guidance on child discipline. Physical punishment works no better than
      other methods and has adverse effects.

PMID- 10650005
TI  - Keeping patients out of hospital. Patients like it.

PMID- 10650006
TI  - Psychosocial factors in selection for liver transplantation. Need to be
      explicitly assessed and managed.

PMID- 10650007
TI  - Information on community health services. More and better information is needed-
      not less.

PMID- 10650008
TI  - New formula for GP prescribing budgets. General practitioners in England need to
      understand its implications.

PMID- 10650009
TI  - Blair will have difficulty in matching European spending.

PMID- 10650011
TI  - Scientists discover how helicobacter survives gastric acid

PMID- 10650010
TI  - Government seems to soften pledge on NHS.

PMID- 10650012
TI  - University sues scientist for 400000 pounds for undeclared fees.

PMID- 10650013
TI  - In brief

PMID- 10650014
TI  - Global alliance launches plan to eliminate lymphatic filariasis.

PMID- 10650015
TI  - Trust accused of racism in awarding payments.

PMID- 10650016
TI  - First UK patents for cloning issued to creators of Dolly the sheep.

PMID- 10650017
TI  - Screening trial for lung cancer planned for UK.

PMID- 10650018
TI  - NHS owes pounds 2.8bn in negligence cases.

PMID- 10650019
TI  - College urges maximum of two embryos for in vitro fertilisation.

PMID- 10650020
TI  - South African minister accused of human rights abuse.

PMID- 10650021
TI  - Health at the Hustings.

PMID- 10650023
TI  - Patient satisfaction with outpatient hysteroscopy versus day case hysteroscopy:
      randomised controlled trial.
AB  - OBJECTIVE: To compare outpatient hysteroscopy with day case hysteroscopy in terms
      of patient satisfaction and acceptability. SETTING: Gynaecology clinic of a
      teaching hospital. PARTICIPANTS: 100 women. DESIGN AND INTERVENTIONS: Patients
      were randomly allocated to outpatient hysteroscopy or day case hysteroscopy
      provided they had no preference for either procedure. MAIN OUTCOME MEASURES:
      Satisfaction rate, requirements for postoperative analgesia, speed of recovery,
      time away from home, and time off work. RESULTS: The outpatient group recovered
      preoperative fitness more quickly than the day case group (2 days (range 1-2.7)
      versus 3 days (2-4), P<0.05). After the procedure, the outpatient group were also
      fully mobile more quickly than the day case group (0 minutes (0-5) versus 105
      minutes (80-120), P<0.001). Requirements for postoperative analgesia were similar
      in both groups. Overall, 78% of patients considered that the pain from outpatient
      hysteroscopy was less than that usually experienced during menstruation. Patient
      satisfaction was similar in both groups (83.6% in the outpatient group versus
      77.0% in the day case group). CONCLUSIONS: Outpatient hysteroscopy and day case
      hysteroscopy were equally acceptable to patients. Patients recovered
      significantly more quickly from outpatient hysteroscopy than from day case
      hysteroscopy.

PMID- 10650022
TI  - Risk of cardiovascular disease measured by carotid intima-media thickness at age
      49-51: lifecourse study.
AB  - OBJECTIVE: To quantify the direct and indirect effects of fetal life, childhood,
      and adult life on risk of cardiovascular disease at age 49-51 years. DESIGN:
      Follow up study of the "Newcastle thousand families" birth cohort established in
      1947. PARTICIPANTS: 154 men and 193 women who completed a health and lifestyle
      questionnaire and attended for clinical examination between October 1996 and
      December 1998. MAIN OUTCOME MEASURES: Correlations between mean intima-media
      thickness of the carotid artery (carotid intima-media thickness) and family
      history, birth weight, and socioeconomic position around birth; socioeconomic
      position, growth, illness, and adverse life events in childhood; and adult
      socioeconomic position, lifestyle, and biological risk markers. Proportions of
      variance in carotid intima-media thickness that were accounted for by each stage
      of the lifecourse. RESULTS: Socioeconomic position at birth and birth weight were
      negatively associated with carotid intima-media thickness, although only social
      class at birth in women was a statistically significant covariate independent of
      adult lifestyle. These early life variables accounted directly for 2.2% of total
      variance in men and 2.0% in women. More variation in carotid intima-media
      thickness was explained by adult socioeconomic position and lifestyle, which
      accounted directly and indirectly for 3.4% of variance in men (95% confidence
      interval 0.5% to 6.2%) and 7.6% in women (2.1% to 13.0%). Biological risk markers
      measured in adulthood independently accounted for a further 9.5% of variance in
      men (2.4% to 14.2%) and 4.9% in women (1.6% to 7.4%). CONCLUSIONS: Adult
      lifestyle and biological risk markers were the most important determinants of the
      cardiovascular health of the study members of the Newcastle thousand families
      cohort at age 49-51 years. The limited overall effect of early life factors may
      reflect the postwar birth year of this cohort.

PMID- 10650024
TI  - Prenatal ultrasound examinations and risk of childhood leukaemia: case-control
      study.

PMID- 10650025
TI  - Lichenoid drug eruption with proton pump inhibitors.

PMID- 10650026
TI  - Derivation of a needs based capitation formula for allocating prescribing budgets
      to health authorities and primary care groups in England: regression analysis.
AB  - OBJECTIVE: To develop a weighted capitation formula for setting target
      allocations for prescribing expenditures for health authorities and primary care
      groups in England. DESIGN: Regression analysis relating prescribing costs to the
      demographic, morbidity, and mortality composition of practice lists. SETTING:
      8500 general practices in England. SUBJECTS: Data from the 1991 census were
      attributed to practice lists on the basis of the place of residence of the
      practice population. MAIN OUTCOME MEASURES: Variation in age, sex, and temporary
      resident originated prescribing units (ASTRO(97)-PUs) adjusted net ingredient
      cost of general practices in England for 1997-8 modelled for the impact of health
      and social needs after controlling for differences in supply. RESULTS: A needs
      gradient based on the four variables: permanent sickness, percentage of
      dependants in no carer households, percentage of students, and percentage of
      births on practice lists. These, together with supply characteristics, explained
      41% of variation in prescribing costs per ASTRO(97)-PU adjusted capita across
      practices. The latter alone explained about 35% of variation in total costs per
      head across practices. CONCLUSIONS: The model has good statistical specification
      and contains intuitively plausible needs drivers of prescribing expenditure.
      Together with adjustments made for differences in ASTRO(97)-PUs the model is
      capable of explaining 62% (35%+0.65% (41%)) of variation in prescribing
      expenditure at practice level. The results of the study have formed the basis for
      setting target budgets for 1999-2000 allocations for prescribing expenditure for
      health authorities and primary care groups.

PMID- 10650027
TI  - Analysis of the ability of the new needs adjustment formula to improve the
      setting of weighted capitation prescribing budgets in English general practice.

PMID- 10650028
TI  - Is norethisterone a lifestyle drug? Results of database analysis.

PMID- 10650029
TI  - Chronic fatigue syndrome.

PMID- 10650030
TI  - ABC of heart failure.

PMID- 10650031
TI  - Exploring a fiscal food policy: the case of diet and ischaemic heart disease.

PMID- 10650033
TI  - How we improved our treatment of hypertension

PMID- 10650032
TI  - The home treatment enigma.

PMID- 10650034
TI  - Debate on cot death. These deaths must be prevented without victimising parents.

PMID- 10650035
TI  - Childhood vulval lichen sclerosus and sexual abuse are not mutually exclusive
      diagnoses.

PMID- 10650036
TI  - Antidepressant drugs have previously been shown to be ineffective in mild
      depression.

PMID- 10650037
TI  - Eradication of Helicobacter pylori infection in non-ulcer dyspepsia. Commentary
      did not inform or update general medical community.

PMID- 10650038
TI  - Stable chronic obstructive pulmonary disease. Incomplete evidence based reviews
      may condemn by omission.

PMID- 10650039
TI  - Young people should be included as partners.

PMID- 10650040
TI  - Moving the research agenda. Primary care research needs extending, not moving.

PMID- 10650041
TI  - Patient surveys identify needs.

PMID- 10650042
TI  - Patients need more than written prompts for communication to be successful.

PMID- 10650043
TI  - Risk assessment is open to public interpretation.

PMID- 10650044
TI  - Medical ethicists do not conform to stereotypes in ER.

PMID- 10650045
TI  - Quality at general practice consultations. Time may not lead to quality.

PMID- 10650047
TI  - Obituaries

PMID- 10650046
TI  - Is germ cell harvest and storage justified in minors treated for cancer?

PMID- 10650049
TI  - Flu

PMID- 10650048
TI  - Review body report 2000

PMID- 10650050
TI  - Surgical ethics

PMID- 10650052
TI  - Fundamentals of anaesthesia

PMID- 10650051
TI  - The unequal burden of cancer

PMID- 10650053
TI  - Have a heart

PMID- 10650054
TI  - Reducing multiple births

PMID- 10650055
TI  - So who's teaching whom?

PMID- 10650057
TI  - Craziness

PMID- 10650056
TI  - Looking for the man who fell off the roof

PMID- 10650058
TI  - Adult lifestyles count more than childhood factors in determining cardiovascular
      health

PMID- 10650059
TI  - Patients are equally satisfied with outpatient and day case hysteroscopy

PMID- 10650060
TI  - No association found between prenatal ultrasound and childhood leukaemia

PMID- 10650061
TI  - New allocation formula for primary care prescribing explains nearly two thirds of
      variation

PMID- 10650062
TI  - Norethisterone might be being used as a lifestyle drug

PMID- 10650063
TI  - British psychiatrists resist home treatment

PMID- 10650064
TI  - Apical hypertrophic cardiomyopathy.

PMID- 10650065
TI  - Synthesis, structure-activity relationships, and RARgamma-ligand interactions of
      nitrogen heteroarotinoids

PMID- 10650066
TI  - Urea-PETT compounds as a new class of HIV-1 reverse transcriptase inhibitors. 3.
      Synthesis and further structure-activity relationship studies of PETT analogues

PMID- 10650067
TI  - Entering the new millennium

PMID- 10650068
TI  - Norditerpenoid alkaloids from the roots of Delphinium stapeliosum.
AB  - From the roots of Delphinium stapeliosum three new norditerpenoid alkaloids, 14
      demethyltuguaconitine (1), 14-deacetyl-14-isobutyrylnudicauline (2), and 14
      deacetyl-14-isobutyrylajadine (3), and nine known norditerpenoid alkaloids,
      delbonine (4), methyllycaconitine (5), 14-deacetylnudicauline (6), ajacine (7),
      deltatsine (8), delcosine (9), 14-deacetylajadine (10), nudicauline (11), and
      ajadine (12), were isolated. Structure elucidation and identification were based
      on NMR and mass spectra.

PMID- 10650069
TI  - Novel oligorhamnosides from the stem bark of Cleistopholis glauca.
AB  - A reinvestigation of the stem bark of Cleistopholis glauca yielded 14 compounds,
      of which seven were either novel or had not been previously reported from this
      species. These were identified as the farnesane sesquiterpene methyl-(2E,6E)-10
      oxo-3,7, 11-trimethyl-dodeca-2,6-dienoate (1); the azaanthracene alkaloid
      cleistopholine (4); two partially acetylated oligorhamnoside derivatives, 1-O
      dodecanyl-2,3, 4-tri-O-acetyl-alpha-rhamnopyranosyl-(1-->3)-2, 4-di-O-acetyl
      alpha-rhamnopyranosyl-(1-->3)-4-O-acetyl-alpha-rhamnopy ranosyl-(1-->4)-alpha
      rhamnopyranoside (6) and 1-O-dodecanyl-2, 4-di-O-acetyl-alpha-rhamnopyranosyl-(1-
      >3)-2, 4-di-O-acetyl-alpha-rhamnopyranosyl-(1-->3)-4-O-acetyl-alpha-rhamnopy
      ranosyl-(1-->4)-alpha-rhamnopyranoside (8), for which the trivial names
      cleistetroside-7 and cleistetroside-6 were assigned, respectively; the
      dihydrobenzofuran neolignan rel-(2alpha, 3beta)-7-O-methylcedrusin (12); and the
      flavonoids dihydroquercetin (13) and quercetin (14). Structure assignments of all
      compounds were established by spectroscopic methods and comparison with published
      data. The chemosystematic significance of the occurrence of the isolated
      components is mentioned. Compounds 1, 6, and 8 are novel natural products.

PMID- 10650070
TI  - Longipinane derivatives from Stevia connata.
AB  - The hexane extracts of the roots of Stevia connata afforded three new longipinene
      derivatives, longipinane-7beta,8alpha, 9alpha-triol-1-one 7-angelate-8
      methylbutyrate (1), longipin-2-ene-7beta,8alpha,9alpha-triol-1-one 8,9-diangelate
      (6), and longipin-2-ene-7beta,8alpha,9alpha-triol-1-one 8-angelate-9
      methylbutyrate (8), together with the known longipinane-7beta,8alpha,9alpha-triol
      1-one 8,9-diangelate (2), longipinane-7beta,8alpha,9alpha-triol-1-one 7,9
      diangelate (3), longipinane-7beta,8alpha,9alpha-triol-1-one 7,8-diangelate (4),
      longipin-2-ene-7beta,8alpha,9alpha-triol-1-one 7,8-diangelate (5), longipin-2-ene
      7beta,8alpha,9alpha-triol-1-one 7-angelate-8-methylbutyrate (12), and
      stigmasterol. The structures of the new compounds were determined by chemical
      transformations and spectral methods including 2D NMR measurements. Spontaneous
      intramolecular transesterifications starting from the 8-angelate-9-methylbutyrate
      8 provided an equilibrated mixture of the 7-angelate-9-methylbutyrate 10, the 7
      angelate-8-methylbutyrate 12 and the starting material when stored in MeOH-H(2)O
      solution, while the 8,9-diangelate 6 only provided a binary mixture of the 7, 9
      diangelate 7 and the starting material under the same conditions. The structures
      of 6-8, 10, and 12 and those of the nonisolable reaction intermediates 9, 11, and
      14 were further evaluated by AM1 semiempirical calculations.

PMID- 10650071
TI  - New prenylated anthraquinones and xanthones from Vismia guineensis.
AB  - From the roots of Vismia guineensis 23 structurally related compounds were
      isolated and identified. Ten of them are new constituents, namely 3-O-(2-hydroxy
      3-methylbut-3-enyl)-emodin (1); 3-O-(2-methoxy-3-methylbut-3-enyl)-emodin (2); 1,
      8-dihydroxy-3-(2-methoxy-3-methylbut-3-enyloxy)-6-methylx anthone (3); 1,8
      dihydroxy-3-geranyloxy-6-methylxanthone (4); 1, 8-dihydroxy-3-isoprenyloxy-6
      methylxanthone (5); 1,8-dihydroxy-3-(3, 7-dimethyl-7-methoxyoct-2-enyloxy)-6
      methylxanthone (6); 3-O-(E-3-hydroxymethylbut-2-enyl)-emodin (7); 3-O-(3
      hydroxymethyl-4-hydroxybut-2-enyl)-emodin (8); 1, 8-dihydroxy-3-(E-3
      hydroxymethylbut-2-enyloxy)-6-methylxa nthone (9); and 1, 8-dihydroxy-3-(3
      hydroxymethyl-4-hydroxybut-2-enyloxy)-6- methylxantho ne (10). Their structures
      were established by means of EIMS and a combination of homonuclear and
      heteronuclear 2D NMR techniques. Furthermore, an in vitro preliminary screening
      of antimitotic activity of all the isolated compounds was also evaluated.

PMID- 10650072
TI  - Synthesis of the marine sponge cycloheptapeptide phakellistatin 5(1).
AB  - Phakellistatin 5 (1), a constituent of The Federated States of Micronesia (Chuuk)
      marine sponge Phakellia costada, was synthesized by solution-phase and solid
      phase techniques. Because the linear peptide bearing (R)-Asn resisted
      cyclization, the synthesis of this peptide was repeated using the PAL resin
      attachment proceeding from N-Fmoc-D-Asp-alpha-OCH(2)CH=CH(2). After addition of
      the final unit (Ala), the allyl ester was removed under neutral conditions with
      Pd(o) [P(C(6)H(5))(3)](4). Removal of the final Fmoc-protecting group and
      cyclization with PyAOP provided (R)-Asn-phakellistatin 5 (2) in 28% overall
      yield. The same synthetic route from (S)-Asp led to natural phakellistatin 5 (1)
      in 15% overall recovery. The solution-phase and solid-phase synthetic products
      derived from (S)-Asp were found to be chemically but not biologically identical
      with natural phakellistatin 5 (1). This important fact suggested that a trace,
      albeit highly cancer-cell growth inhibitory, constituent accompanied the natural
      product or that there is a subtle conformational difference between the synthetic
      and natural cyclic peptides.

PMID- 10650073
TI  - Dimerization of resveratrol by the grapevine pathogen Botrytis cinerea.
AB  - Resveratrol (trans-3,4',5-trihydroxystilbene) is produced by grapes (Vitis spp.)
      in response to microbial attack by the fungal grapevine pathogen Botrytis
      cinerea. Several reports indicate that pathogenic B.cinerea strains are capable
      of biotransforming resveratrol into an assortment of unidentified oxidized
      metabolites as a means of reducing the antifungal effects of resveratrol and
      facilitating Botrytis invasion into host-plant tissues. Studies utilizing growing
      incubations of Botrytis cinerea ATCC 11542 with resveratrol resulted in the
      production of three new (restrytisols A-C) (1-3) and three known (resveratrol
      trans-dehydrodimer, leachinol F, and pallidol) oxidized resveratrol dimers. All
      of the metabolites were evaluated for their anti-HIV-1, cytotoxic, and
      cyclooxygenase (COX) I and COX II inhibitory activities.

PMID- 10650074
TI  - Acylated flavonol glycosides from the flower of Inula britannica.
AB  - Three new acylated flavonol glycosides, patuletin 7-O-(6' '-isobutyryl)glucoside
      (1), patuletin 7-O-[6' '-(2-methylbutyryl)]glucoside (2), and patuletin 7-O-(6' '
      isovaleryl)glucoside (3), were isolated from the n-BuOH extract of Inula
      britannica flowers by bioassay-guided fractionation, together with other known
      flavonoids. The structures were elucidated by 1D and 2D NMR, FABMS, and other
      spectral analyses. The eight flavonoids, including new compounds (1-3),
      patulitrin (7), nepitrin (8), axillarin (10), patuletin (11), and luteolin (12),
      showed profound antioxidant activity in DPPH assay and cytochrome-c reduction
      assay using HL-60 cell culture system.

PMID- 10650075
TI  - Isoprene biosynthesis in Bacillus subtilis via the methylerythritol phosphate
      pathway.
AB  - Isoprene (2-methyl-1,3-butadiene), an abundant natural product of unknown
      function in plants, has recently been found to be one of the major volatiles
      formed by Bacillus subtilis. To understand the metabolic origins of isoprene in
      B. subtilis, we used (13)C- and (2)H-labeling methods with GC-MS analysis of
      released isoprene. The results indicate that, in this bacterium, isoprene is not
      formed by the mevalonate pathway or from catabolism of leucine, but, as in plant
      systems, it is a product of the methylerythritol phosphate pathway of isoprenoid
      synthesis. This work supports the idea that B. subtilis could be used as a
      microbial model for studying the biochemistry of isoprene formation.

PMID- 10650076
TI  - Biosynthetically diverse compounds from a saltwater culture of sponge-derived
      Aspergillus niger.
AB  - The new compound, asperic acid (1), and the known compounds hexylitaconic acid
      (2), malformin C (3), pyrophen (4), and asperazine (5) were isolated from the
      saltwater culture of Aspergillus niger derived from a Caribbean sponge, Hyrtios
      proteus. The structure elucidation of asperic acid is presented.

PMID- 10650077
TI  - Biotransformation of (4E,8R)-caryophyll-4(5)-en-8-ol by Botrytis cinerea.
AB  - Biotransformation of (4E,8R)-caryophyll-4(5)-en-8-ol (1) with Botrytis cinerea
      afforded 14 products (3-16). Thirteen of these (4-16) are described here for the
      first time. The main reaction paths involved the isomerization of the double bond
      at C-4/C-5 and hydroxylation of methyl groups.

PMID- 10650078
TI  - New terpenoids from Maytenus blepharodes.
AB  - Three new terpenoids, xuxuarine Ealpha (1), a triterpene dimer based on two
      pristimerin units, and two sesquiterpenoids with a dihydro-beta-agarofuran
      skeleton (2 and 3) were isolated from Maytenus blepharodes. Their structures were
      elucidated on the basis of spectral analysis, including homonuclear and
      heteronuclear correlation NMR experiments (COSY, ROESY, HMQC, and HMBC). The
      absolute configurations of 1 and 2 were determined by CD studies.

PMID- 10650079
TI  - New trichothecenes isolated from Holarrhena floribunda.
AB  - Bioassay-guided fractionation of an extract of Holarrhena floribunda stem, has
      led to the isolation of the new trichothecenes, 8-dihydrotrichothecinol A (1),
      loukacinol A (2), and loukacinol B (3), and the known compounds, trichothecolone
      (4), trichothecin (5), trichothecinol A (6), rosenonolactone (7), 6beta
      hydroxyrosenonolactone (8), and rosololactone (9). The structures were determined
      by spectral and chemical methods, and absolute configurations were established by
      a modified Horeau's method using HPLC. Compounds 1 and 6 exhibited significant
      cytotoxicity against several human tumor cell lines, whereas compound 8 showed
      moderate and weak antileishmanial activity toward extracellular and intracellular
      Leishmania donovani, respectively.

PMID- 10650080
TI  - Thirteen novel cycloartane-type triterpenes from Combretum quadrangulare.
AB  - Thirteen novel cycloartane-type triterpenes were isolated from Combretum
      quadrangulare, a Vietnamese medicinal plant. The structures of the novel
      triterpenes were determined by spectroscopic methods as well as by chemical
      transformations. Among those compounds, quadrangularic acids F (1), G (2), and H
      (4) and 24-epiquadrangularic acid G (3) are the first examples of cycloartane
      type triterpenes bearing carboxylic acid groups at both C-4 and C-20.
      Furthermore, norquadrangularic acid A (13) is the first example of a
      trinorcycloartane-type triterpene isolated from the genus Combretum.

PMID- 10650081
TI  - Triterpene glycosides from the Far-Eastern sea cucumber Pentamera calcigera. 1.
      Monosulfated glycosides and cytotoxicity of their unsulfated derivatives.
AB  - Three new monosulfated triterpene glycosides, calcigerosides B (2), C(1) (3), and
      C(2) (4), along with the known cucumarioside G(2) (1), have been isolated from
      the sea cucumber Pentamera calcigera. Their structures have been deduced from
      extensive spectral analysis (NMR and MS) and chemical evidence. Compounds 2-4
      present a novel pentasacharide chain never reported before in sea cucumber
      triterpene glycosides. The desulfated derivatives of calcigerosides B, C(1), and
      C(2) (5, 7, and 9, respectively) showed moderate cytotoxicity (IC(50) = 5
      microg/mL) against a selection of four human and mouse tumor cell lines.

PMID- 10650082
TI  - Isolation and structures of schleicherastatins 1-7 and schleicheols 1 and 2 from
      the teak forest medicinal tree Schleichera oleosa.
AB  - Bioassay (P-388 lymphocytic leukemia cell line)-guided separation of an extract
      prepared from the bark and stem of the Sri Lankan tree Schleichera oleosa led to
      the isolation of seven cancer cell growth inhibitory hydroxylated sterols
      designated schleicherastatins 1-7 (1-7) and two related sterols, schleicheols 1
      and 2 (8, 9). The structure of schleicherastatin 1 (1) was completely elucidated
      by X-ray crystal structure determination. Based upon that defined structure, the
      remaining new sterol structures were deduced by highfield (300 and 500 MHz) NMR
      and MS interpretations. In this new series of sterols, hydroxylation at C-22
      appears to be important for promoting cancer cell growth inhibition.

PMID- 10650083
TI  - Chemistry of sponges. 19. Novel bioactive metabolites from Hamigera tarangaensis.
AB  - Seven new compounds (1-6 and 10) with a unique carbon skeleton have been isolated
      from the sponge Hamigera tarangaensis, and the structure of a previously reported
      metabolite has been revised from 12 to 8. The structures have been assigned from
      extensive NMR examination. Compounds 3-6 showed moderate in-vitro cytotoxicity
      against P-388, while 3 showed 100% in-vitro virus inhibition against both the
      Herpes and Polio viruses, with only slight cytotoxicity.

PMID- 10650084
TI  - Five new stilbene dimers from the lianas of Gnetum hainanense.
AB  - Five new stilbene dimers, gnetuhainins A-E (1-5), were isolated together with
      resveratrol trans-dehydrodimer (6), resveratrol, oxyresveratrol, and (-)-epsilon
      viniferin from the lianas of Gnetum hainanense. Their structures and
      stereochemistry were determined on the basis of their chemical and spectral data.
      Compounds 1-5 are dimers formed by a resveratrol unit and an oxyresveratrol unit
      and belong to a new type of oligostilbenes polymerized from two different
      stilbene units.

PMID- 10650085
TI  - Hyalodendrosides A and B, antifungal triterpenoid glycosides from a lignicolous
      hyphomycete, Hyalodendron species.
AB  - Two antifungal triterpenoid glycosides, hyalodendrosides A and B (1 and 2), were
      isolated from a solid matrix fermentation of a lignicolous hyphomycete,
      Hyalodendron sp. Their structures were determined based upon extensive
      examination of spectral parameters, particularly NMR and MS data. Both compounds
      have beta-linked glucose moieties. Compounds 1 and 2 show weak to moderate
      antifungal activity against some clinically relevant fungi.

PMID- 10650086
TI  - Five phenolic glycosides from Alangium chinense.
AB  - From the dried leaves of Alangium chinense, five novel phenolic glycosides, 6'-O
      galloylsalicin (1); 4',6'-di-O-galloylsalicin (2); 4',6'-O-(S)
      hexahydroxydiphenoylsalicin (3); 4', 6'-O-(R)-hexahydroxydiphenoylsalicin (4);
      and pyrocatechol 1-O-beta-D-xylopyranosyl(1-->6)-beta-D-glucopyranoside (5) were
      isolated. The structures of these new compounds were determined by spectroscopic
      methods.

PMID- 10650087
TI  - Bioactive steroids from the whole herb of Euphorbia chamaesyce.
AB  - Three new ergostane-type steroids, 3beta-hydroxy-4alpha, 14alpha-dimethyl-5alpha
      ergosta-8,24(28)-dien-11 -one (1); 3beta, 11alpha-dihydroxy-4alpha,14alpha
      dimethyl-5alpha -ergosta-8, 24(28)-dien-7-one (2); and 3beta,7alpha-dihydroxy
      4alpha, 14alpha-dimethyl-5alpha-ergosta-8,24(28)-dien-11 -one (3), were isolated,
      together with two known triterpenoids, wrightial and lup-20(30)-ene-3beta,29-diol
      from the whole herb of Euphorbia chamaesyce. Compound 3 showed a potent
      inhibitory effect on Epstein-Barr virus early antigen activation induced by the
      tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA).

PMID- 10650088
TI  - New phloroglucinol derivatives from Hypericum papuanum.
AB  - Bioactivity-guided fractionation of the petroleum ether extract of the aerial
      parts of Hypericum papuanum led to the isolation of five new tricyclic
      phloroglucinol derivatives. On the basis of extensive 1D and 2D NMR experiments
      as well as MS studies, their structures were elucidated as the C-3 epimers of 8
      hydroxy-4,4, 7-trimethyl-9-(2-methylpropionyl)-3-(1-methylvinyl)-5beta -H
      tricyclo[ 5.3.1.0(1,5)]undec-8-ene-10,11-dione (1,2); the C-3 epimers of 8
      hydroxy-4,4, 7-trimethyl-9-(2-methylbutyryl)-3-(1-methylvinyl)-5beta-H-++
      +tricyclo[5. 3.1.0(1,5)]undec-8-ene-10,11-dione (3, 4), and 8-hydroxy-4,4, 7
      trimethyl-9-(2-methylpropionyl)-5beta-H-tricyclo[5.3 .1.0(1, 5)]undec-8-ene-10,11
      dione (5), and their corresponding tautomers (1a, 2a, 3a, 4a, 5a). Compounds 1/1a
      5/5a were named ialibinones A-E, respectively. Compounds 1/1a-4/4a showed
      antibacterial activity against Bacillus cereus, Staphylococcus epidermidis, and
      Micrococcus luteus.

PMID- 10650089
TI  - Two new diterpenoids, sarcophytins B and C, from the Indian Ocean soft coral
      Sarcophyton species.
AB  - Two new diterpenoids, sarcophytins B and C (1, 2), and the previously known
      sarcophytin (4) have been isolated from the Indian Ocean soft coral Sarcophyton
      sp. Structures of 1 and 2 were established by spectral data and supported by X
      ray analysis of 1.

PMID- 10650090
TI  - Novel epoxy steroids from the indian ocean soft coral Sarcophyton crassocaule.
AB  - A detailed further examination of the Indian Ocean soft coral Sarcophyton
      crassocaule resulted in the isolation of altogether 17 compounds of which two (1
      and 2) are novel 17beta,20beta-epoxy steroids and one is a new dihydroxygorgost-5
      en (3). The other compounds include the four hippurin steroids (4-7) reported
      earlier, and some known derivatives such as methyl arachidonate, batyl alcohol, a
      mixture of monohydroxy sterols, 3beta-hydroxypregn-5-en-20-one, two prostaglandin
      derivatives (PGB(2) acid and its methyl ester), and 9-oxo-9, 11-secogorgost-5-ene
      3beta,11-diol (8). The structure of new dihydroxygorgostene derivative was
      established as gorgost-5-ene-3beta,11alpha-diol (3), while the structures of the
      novel epoxy steroids were established as 17beta,20beta-epoxy-23, 24
      dimethylcholest-5-ene-3beta,22-diol (2) and its 3beta, 22-diacetate (1),
      respectively.

PMID- 10650091
TI  - New Moloka'iamine derivatives from an undescribed verongid sponge.
AB  - The polar extract of an undescribed Verongid sponge from the island of Molokai
      yielded three new bromotyramines. Two compounds terminate in a
      chlorocyclopentanedione enamine moiety. Their structures were elucidated by NMR
      spectra measured at -30 degrees C. The third compound is the N-methyl derivative
      of a known compound. This structure was determined by NMR spectra measured at
      room temperature.

PMID- 10650092
TI  - A new major triterpene saponin from the roots of Cucurbita foetidissima.
AB  - Foetidissimoside B (1), a novel triterpene saponin, was isolated from the roots
      of Cucurbita foetidissima. Based on spectroscopic data, especially direct and
      long-range heteronuclear 2D NMR analysis and on chemical transformations, the
      structure of 1 was elucidated as 3-O-beta-D-glucuronopyranosyl-echinocystic acid
      28-O-beta-D-glucopyranosyl-(1-->3)-beta-D-xylopyranosyl(1-->3)-[beta- D
      xylopyranosyl (1-->4)]-alpha-L-rhamnopyranosyl-(1-->2)-alpha-L-arabinopyranoside
      . Compound 1 did not show any ability to potentiate in vitro cisplatin
      cytotoxicity in a human colon cancer cell line.

PMID- 10650093
TI  - New carbazole alkaloids from Clausena anisata with antitumor promoting activity.
AB  - Four new carbazole alkaloids, named clausamine D (1), E (2), F (3), and G (4),
      were isolated from Clausena anisata as inhibitors of Epstein-Barr virus early
      antigen activation induced by 12-O-tetradecanoylphorbol-13-acetate in Raji cells.

PMID- 10650094
TI  - Euplectin and coneuplectin, new naphthopyrones from the lichen Flavoparmelia
      euplecta.
AB  - Two new naphthopyrones, euplectin (1) and coneuplectin (2), have been isolated
      from the lichen Flavoparmelia euplecta and their structures elucidated using
      multidimensional NMR spectroscopic methods, including highfield (600 MHz) gHMBC
      and gNOE experiments. Cytotoxicity of the more abundant naphthopyrone (1) against
      the murine P-815 mastocytoma cell line (IC(50) ca. 1.67 microg/mL) has also been
      evaluated. These compounds are the first lichen metabolites known to contain
      indenone or indanone moieties in their structure. F. euplecta was also found to
      contain the known metabolites usnic acid, protocetraric acid, and skyrin.

PMID- 10650095
TI  - Zygosporin D and two new cytochalasins produced by the fungus Metarrhizium
      anisopliae.
AB  - Zygosporin D (3) and two new cytochalasins (4 and 5) were isolated from the
      culture filtrate of the fungus Metarrhizium anisopliae and characterized on the
      basis of their spectral data and chemical conversions. The new cytochalasins, 4
      and 5, were determined to be deacetylcytochalasin C and (6R,16S,18R,21R)-18,21
      dihydroxy-16, 18-dimethyl-10-phenyl[11]cytochalasa-13(E),19(E)-diene-1,7,17-trio
      ne, respectively. Of these three cytochalasins, only zygosporin D is an effective
      inhibitor of shoot elongation of rice seedlings.

PMID- 10650096
TI  - Structural analysis of calcium spirulan (Ca-SP)-derived oligosaccharides using
      electrospray ionization mass spectrometry.
AB  - Detailed structural analyses of calcium spirulan (Ca-SP)-derived oligosaccharides
      were performed by ESI-MS and collision-induced dissociation tandem mass
      spectrometry. This study indicates that Ca-SP is composed of two types of
      disaccharide repeating units, O-rhamnosyl-acofriose and O-hexuronosyl-rhamnose
      (aldobiuronic acid).

PMID- 10650097
TI  - Constituents of the roots of Salvia prionitis.
AB  - From the roots of Salvia prionitis, a novel alkaloid named prioline (1) and a new
      diterpene, prineoparaquinone (2), were isolated together with taxodione;
      microstegiol; 8,11,13-dehydroabietane; and 2-isopropyl-8-methyl-3,4
      phenanthraquinone. The structures of the new compounds were established by
      spectroscopic means.

PMID- 10650098
TI  - Novel polyketide metabolites from a species of marine fungi.
AB  - Fermentation of a marine fungal species obtained from a tissue sample of a marine
      sponge collected in Indonesia in October 1996, yielded the novel hexaketide
      compounds iso-cladospolide B (1); seco-patulolide C (2); the 12-membered
      macrolides, pandangolide 1 (3) and pandangolide 2 (4); and the known terrestrial
      fungal metabolite, cladospolide B (5).

PMID- 10650099
TI  - Oligosaccharides from Hoya carnosa.
AB  - Oligosaccharides A, B, and C (1-3, respectively) were isolated from the stem of
      Hoya carnosa. Their structures were established by NMR and chemical methods.
      Compounds 1 and 2 were 6-deoxy-3-O-methyl-beta-allopyranosyl(1-->4)-beta
      cymaropyranosyl( 1-- >4)-beta-cymaropyranosyl(1-->4)-beta-cymaronic acid delta
      lactone and 6-deoxy-3-O-methyl-beta-allopyranosyl(1-->4)-beta-oleandropyranosyl++
      +(1 -->4)-beta-cymaropyranosyl(1-->4)-beta-cymaronic acid delta-lactone,
      respectively. Compound 3 was the sodium salt of 2.

PMID- 10650100
TI  - A cytotoxic 5alpha,8alpha-epidioxysterol from a soft coral Sinularia species.
AB  - A new sterol, (22R,23R,24R)-5alpha,8alpha-epidioxy-22, 23-methylene-24
      methylcholest-6-en-3beta-ol (1), as well as two known sterols, numersterol A (2)
      and pregnenolone (3), have been isolated from a soft coral Sinularia sp. The
      structure of metabolite 1 was determined by spectral analysis. Cytotoxicity of
      sterols 1-3 toward various cancer cell lines is also reported.

PMID- 10650101
TI  - A new depsipeptide from the sacoglossan mollusk Elysia ornata and the green alga
      Bryopsis species.
AB  - A new cyclic depsipeptide, kahalalide O (1), was isolated from the sacoglossan
      Elysia ornata and its algal diet Bryopsis sp. The structure was elucidated
      primarily by NMR and MS spectral methods, and the stereochemistry of the amino
      acid residues was determined by chiral HPLC and Marfey analyses. Unlike the
      related metabolite kahalalide F, which is in development as a potential
      anticancer agent, kahalalide O (1) was inactive in arresting the growth of P-388,
      A549, HT29, and MEL28 cancer cell lines in vitro.

PMID- 10650102
TI  - Herbacic acid, a simple prototype of 5,5,5-trichloroleucine metabolites from the
      sponge Dysidea herbacea.
AB  - Dysidea herbacea, collected at Harrier Reef on the Great Barrier Reef, contains
      the novel metabolite herbacic acid as the major trichloroleucine metabolite.
      Herbacic acid appears to be an early product of direct free-radical chlorination
      of leucine and is a prototype for further transformation of the free carboxylic
      acid group and generation of complex trichloromethyl metabolites, including
      natural products of the dysidenin family.

PMID- 10650103
TI  - Bleomycin: new perspectives on the mechanism of action.
AB  - The bleomycin group antitumor antibiotics have long been of interest as a
      consequence of their efficacy in the treatment of certain tumors, not to mention
      their unique structures and properties in mediating dioxygen activation and
      sequence selective degradation of DNA. At a chemical level, the structure
      originally assigned to bleomycin was subsequently reassigned and the new
      structure has been confirmed by total synthesis. Through the elaboration of
      structurally modified bleomycin congeners and fragments, synthetic efforts have
      also facilitated an understanding of the contribution of individual structural
      domains in bleomycin to sequence selective DNA binding and cleavage, and have
      also provided insights into the nature of the chemical processes by which DNA
      degradation takes place. Within the last several years, it has also become
      apparent that bleomycin can mediate the oxidative degradation of all major
      classes of cellular RNAs; it seems entirely plausible that RNA may also represent
      an important locus of action for this class of antitumor agent. In parallel with
      ongoing synthetic and mechanistic efforts using classical methods, the study of
      bleomycins attached to solid supports has been shown to provide important
      mechanistic insights, and the actual elaboration of modified bleomycins by solid
      phase synthesis constitutes a logical extension of such efforts.

PMID- 10650104
TI  - Renovascular disease.
AB  - The gold standard for the diagnosis of renal artery stenosis is angiography, with
      response to treatment the proof of its significance. Non-invasive methods of
      investigation are required and are now available including functional imaging,
      ultrasound, CT and MR angiography and the merits and limitations of these tests
      are discussed.

PMID- 10650105
TI  - The changes seen on high-resolution ultrasound in orchitis.
AB  - Orchitis and epididymitis are increasingly common lesions encountered in general
      practice. The clinical diagnosis of inflammation of the testis can be difficult
      as 10% of neoplasms present acutely with features of inflammation or torsion. The
      radiological diagnosis is also difficult as the changes seen on ultrasound,
      whether diffuse or focal, acute or chronic, have to be differentiated from the
      changes seen with tumours of the testis. The purpose of this review is to
      describe and illustrate the evolving changes seen in orchitis with reference to
      the anatomy and pathophysiology of testicular inflammation. We hope that
      recognition of this pattern may lead to a more confident diagnosis and
      appropriate management decisions.

PMID- 10650106
TI  - Infantile fibromatosis in childhood: findings on MR imaging and pathologic
      correlation.
AB  - AIM: The objective of this study was to analyse the MR imaging findings of
      infantile fibromatosis of childhood and to correlate them with histopathological
      features. MATERIALS AND METHODS: Seven patients with histologically proven
      infantile fibromatosis were included in this study. The findings on MR images
      were retrospectively evaluated and then correlated with the pathological
      features. Findings on MR imaging evaluated included signal intensity, extent of
      hyperintense area on T2-weighted images, margins of the lesion, the degree and
      pattern of enhancement and the presence of fatty tissue. Pathological features
      evaluated included cellularity, collagenization, and myxoid change. A five point
      scale was used for the evaluation of the extent of hyperintense area on MR
      imaging, and each of pathological features. RESULTS: On T1-weighted images, the
      lesions were iso-intense in two patients; iso- and hypointense in three; and iso
      , hypo- and hyperintense in two. On T2-weighted images, iso-, hypo- and
      hyperintense areas were mixed in all patients, the hyperintense area being the
      largest portion of the lesion. The margins of the lesions were infiltrative in
      four patients (57%), smooth in two (29%) and mixed in one (14%). Enhancement was
      marked in five patients (72%) and diffuse in five (71%). Regardless of the
      hyperintense signal intensity on T2-weighted images, the grades of each
      pathologic feature were variable. CONCLUSION: Infantile fibromatosis on MR
      imaging causes an enhancing mass, that is largely hyperintense on T2-weighted
      images. Areas of high signal intensity on T2-weighted images corresponded to
      variable grades of cellularity, collagenization, or myxoid change.

PMID- 10650107
TI  - Diagnostic accuracy of magnetic resonance cholangiopancreatography and ultrasound
      compared with direct cholangiography in the detection of choledocholithiasis.
AB  - AIM: To determine the diagnostic accuracy of magnetic resonance
      cholangiopancreatography (MRCP) and trans-abdominal ultrasound in the detection
      of choledocholithiasis, and to compare bile duct stone characteristics using
      endoscopic retrograde cholangiopancreatography (ERCP), MRCP and ultrasound.
      MATERIALS AND METHODS: Of 191 consecutive patients referred for diagnostic ERCP,
      choledocholithiasis was diagnosed in 34 patients using direct cholangiography.
      The latter took the form of ERCP (n = 29), intraoperative cholangiography (n = 3)
      or percutaneous transhepatic cholangiography (n = 2). All patients underwent MRCP
      and ultrasound examinations and their findings for choledocholitiasis were
      compared with those at direct cholangiography. Finally, in the 29 patients with
      choledocholithiasis diagnosed under ERCP, stone characteristics were compared
      across the three investigations of ERCP, MRCP and ultrasound. RESULTS: Compared
      with direct cholangiography, MRCP showed a sensitivity, specificity and
      diagnostic accuracy of 91%, 98% and 97%, respectively, in the diagnosis of
      choledocholithiasis. MRCP resulted in three false-negative and three false
      positive findings, four of which occurred due to confusion with lesions at the
      ampulla. Ultrasound showed a sensitivity, specificity and diagnostic accuracy of
      38%, 100% and 89%, respectively, in the diagnosis of choledocholithiasis. ERCP
      revealed a greater number of stones and these were more proximally distributed
      within the bile ducts when compared to MRCP. CONCLUSIONS: MRCP is highly accurate
      in the diagnosis of choloedocholithiasis and has the potential to replace
      diagnostic ERCP. MRCP underestimates the number of bile duct stones present.

PMID- 10650108
TI  - Computerized strain-gauge plethysmography - An alternative method for the
      detection of lower limb deep venous thrombosis?
AB  - AIM: To test the ability of computerized strain-gauge plethysmography to act as a
      screening test for lower limb deep venous thrombosis (DVT). MATERIALS AND
      METHODS: Over an 8-month period, all patients referred to our Medical Assessment
      Unit with suspected lower limb DVT were considered for inclusion in the study.
      Each patient underwent both plethysmography and ascending venography within 24 h,
      and the presence or absence of thrombus in the popliteal, superficial femoral or
      iliac veins was noted. The results of the two tests were then used to determine
      the accuracy of computerized strain-gauge plethysmography in detecting above knee
      DVT. RESULTS: The screening tests and venograms of 239 patients referred with
      clinically suspected lower limb DVT were compared. The false negative rate of
      plethysmography was 15.4%, which is significantly different from the 4.8% claimed
      by the manufacturers of this device (P = 0.00003). CONCLUSIONS: In a population
      of acute admissions with suspected lower limb DVT, computerized strain-gauge
      plethysmography is not suitable for use as a screening test due to an
      unacceptably high proportion of false negative screens.

PMID- 10650109
TI  - Correlation between ultrasound characteristics, mammographic findings and
      histological grade in patients with invasive ductal carcinoma of the breast.
AB  - AIM: To investigate the relationship between ultrasound characteristics,
      mammographic findings and histological grade in cases of invasive ductal
      carcinoma which produce a mass on ultrasound. MATERIAL AND METHODS: A
      retrospective review was performed of the imaging findings in 120 patients
      diagnosed with invasive ductal carcinoma of the breast between January 1996 and
      December 1997. Imaging findings were correlated with the histological grade of
      tumour. RESULTS: High-grade tumours were significantly larger both on ultrasound
      and mammography (P < 0.016). A spiculated margin on mammogram was documented in
      72% of low-grade tumours compared with only 24% of high-grade tumours (P =
      0.001). Twenty-two per cent of low-grade tumours had a poorly defined margin on
      mammography compared with 66% of high-grade tumours (P = 0.001). At ultrasound,
      16% of high-grade tumours (95% confidence limits 7-29%) had a well-defined
      margin. Acoustic enhancement was seen in 36% of high-grade tumours compared with
      only 9% of low and intermediate-grade tumours (P = 0.003): 22% of all tumours
      showed acoustic enhancement. Acoustic shadowing was seen in 71% of low-grade
      tumours compared with only 28% of high-grade tumours (P = 0.003). Malignant-type
      microcalcification was seen on mammogram in 6% of low-grade tumours compared with
      31% of high-grade tumours (P = 0.045). CONCLUSION: The classical appearance of a
      malignant breast mass as a spiculated mass on mammogram associated with acoustic
      shadowing on ultrasound is more typical of a low-grade tumour. In comparison,
      high-grade tumours are more likely to demonstrate posterior acoustic enhancement,
      and a proportion has a well-defined margin on ultrasound. Therefore, high-grade
      invasive ductal carcinoma may paradoxically display similar imaging features to a
      benign breast mass.

PMID- 10650110
TI  - Evaluation of patients undergoing lung volume reduction surgery: ancillary
      information available from computed tomography.
AB  - AIM: A number of imaging techniques have been used for the pre-operative
      assessment of patients for lung volume reduction surgery (LVRS). We evaluated
      whether data currently acquired from perfusion scintigrams and cine MR of the
      diaphragm are obtainable from high resolution CT (HRCT) of the thorax. MATERIALS
      AND METHODS: Thirty patients taking part in a randomized controlled trial of LVRS
      against maximal medical therapy were evaluated. HRCT examinations (n= 30) were
      scored for (i) the extent and distribution of emphysema; (ii) the extent of
      normal pulmonary vasculature; and (iii) diaphragmatic contour, apparent defects
      and herniation. On scintigraphy, (n= 28), perfusion of the lower thirds of both
      lungs, as a proportion of total lung perfusion (LZ/T(PERF)), was expressed as a
      percentage of predicted values (derived from 10 normal control subjects). On cine
      MR (n= 25) hemidiaphragmatic excursion and coordination were recorded. RESULTS:
      Extensive emphysema was present on HRCT (60% +/- 13.2%). There was strong
      correlation between the extent of normal pulmonary vasculature on HRCT and on
      perfusion scanning (r(s)= 0.85, P< 0.00005). Hemidiaphragmatic incoordination on
      MR was weakly associated with hemidiaphragmatic eventration on HRCT (P= 0.04).
      CONCLUSION: The strong correlation between lung perfusion assessed by HRCT and
      lung perfusion on scintigraphy suggests that perfusion scintigraphy is
      superfluous in the pre-operative evaluation of patients with emphysema for LVRS.

PMID- 10650111
TI  - Giant cisterna chyli: MRI depiction with gadolinium-DTPA enhancement.
AB  - AIM: To demonstrate the use of MRI with Gadolinium-DTPA enhancement in the
      diagnosis of giant cisterna chyli. MATERIALS AND METHODS: The study consisted of
      contrast enhanced MRI with ultrasound and CT correlation in three patients with a
      giant cisterna chyli. An analysis of the morphology, location and post-contrast
      MR signal characteristics in relation to time was performed. RESULTS: Cisterna
      chyli has a characteristic lobulated morphology and location but the unenhanced
      MRI appearances are not specific. The post-Gadolinium-DTPA MRI appearances are
      critically dependent on the time elapsed after injection of contrast medium.
      Within the first 5 min, there is no enhancement at all, but by 10 min there is
      early layering of contrast medium evident, which by 30 min produces a clear fluid
      fluid level. Delayed images at 4-5 h demonstrate a uniform enhancement of the
      cisternal contents producing a homogeneous intermediate signal. All of these
      features are best visualized on T1 fast saturation sequences. CONCLUSION: MRI
      with Gadolinium-DTPA enhancement is valuable in confirming the nature of the
      lymphatic ducts in the retroperitoneal space and helps to differentiate these
      normal structures from alternative lesions such as lymphadenopathy and tumour
      recurrence.

PMID- 10650112
TI  - The prevalence of asymptomatic carotid artery disease in patients with peripheral
      vascular disease.
AB  - AIM: To determine the prevalence and severity of asymptomatic carotid artery
      disease in patients with peripheral arterial disease using colour duplex
      ultrasound, and to determine any relationship to the severity of peripheral
      arterial disease or other associated atherosclerotic risk factors. METHOD: Two
      hundred patients with known peripheral arterial disease but no previous
      cerebrovascular history were prospectively screened for carotid artery disease,
      and any identified internal carotid artery (ICA) stenosis graded using
      established duplex ultrasound criteria. A detailed medical questionnaire
      established the presence or absence of associated risk factors, and the severity
      of peripheral arterial disease was graded and correlated with these. RESULTS: A
      total of 50 patients (25%) were found to have an ICA stenosis of > 50%, with 27
      (13.5%) of these having > 70% stenosis. Bilateral ICA stenosis (> 50%) was seen
      in 21 (10.5%) patients, of which 10 (5%) had bilateral stenoses of > 70%. No
      correlation was found between the severity of peripheral arterial disease and the
      presence of significant carotid artery disease, or between the latter and
      individual atherosclerotic risk factors. CONCLUSION: This study demonstrates a
      relatively high prevalence of significant carotid artery disease in patients with
      peripheral arterial disease compared to the general population. The significance
      of this with respect to the future screening of defined populations for
      asymptomatic carotid artery disease is discussed, with reference to recent
      studies comparing surgical and medical management of asymptomatic carotid artery
      disease.

PMID- 10650113
TI  - Using the departmental radiology information system to replace specialist
      registrars logbooks.
AB  - AIM: To produce and assess a robust and user friendly specialist registrar
      logbook using a Radiology departmental management system. MATERIALS AND METHODS:
      Our Radiology management system was modified to include logbook specific data
      fields. This allowed up to three registrars to be directly involved in any
      procedure, and two more to be observers to the reporting with only one screen
      entry, made on the terminals available throughout the department. Logbooks were
      produced by a PC based analysis program which also compared registrars'
      experience with updated averages. A comparison of computer generated logbooks
      with paper logbooks and a user satisfaction survey was undertaken after 1 year of
      running the system. RESULTS: Computer generated logbooks showed consistent
      numbers of complex procedures in comparison with other logbook types, with more
      comprehensive details of each procedure. A survey of the registrars showed an
      overwhelming preference for the computer generated logbook. CONCLUSION:
      Modification of a Radiology management system is a robust method of logbook
      provision, preferred by the registrars over paper or other electronic logbooks
      and providing the RCR tutor with consistent data on registrar training
      experience.

PMID- 10650114
TI  - Prostatic abscess following injection of internal haemorrhoids.

PMID- 10650115
TI  - Inguinal hernia - An unusual cause of bilateral renal obstruction.

PMID- 10650116
TI  - Bilateral acromial fractures in an infant with malignant osteopetrosis.

PMID- 10650117
TI  - MR findings in pulmonary hypertrophic osteoarthropathy.

PMID- 10650118
TI  - Intraluminal thrombus of the ascending aorta with systemic embolism detected by
      spiral CT.

PMID- 10650119
TI  - 1999 Undergraduate Prize: The Role of Imaging in the Diagnosis and Management of
      Brain Tumours.

PMID- 10650120
TI  - The radiological investigation of suspected lower limb deep vein thrombosis.

PMID- 10650121
TI  - Ultrasound, CT and MRI in patients with multiple symmetric lipomatosis.

PMID- 10650124
TI  - Pharmacological mechanisms mediating phencyclidine-induced apoptosis of
      striatopallidal neurons: the roles of glutamate, dopamine, acetylcholine and
      corticosteroids.
AB  - Phencyclidine (PCP) has recently been shown to induce apoptosis of a
      subpopulation of striatopallidal neurons which lie in the dorsomedial caudate
      putamen. The pharmacological mechanisms underlying this PCP-induced striatal
      death were investigated in a series of small experiments. Striatal silver
      methenamine-stained sections from rats injected acutely with dizocilpine (MK-801;
      1.5-5 mg/kg, i.p.) were analysed to determine whether other non-competitive N
      methyl-D-aspartate (NMDA) receptor antagonists could induce apoptotic-like
      changes in striatal cells. The effects of amphetamine (3-12 mg/kg, i.p.) were
      similarly investigated as PCP can elevate extracellular dopamine levels and
      dopamine has the potential to be neurotoxic. The potential involvement of
      dopamine transmission in PCP-induced striatal apoptosis was also tested by
      determining the effect of co-administering SCH23390 (D1 dopamine receptor
      antagonist) and quinpirole (D2 dopamine receptor agonist) on PCP (80 mg/kg, s.c.)
      induced striatal apoptotic-like cell death. Equivalent experiments were performed
      using scopolamine (cholinergic antagonist) as this drug blocks PCP-induced damage
      of the retrosplenial cortex and RU38486 (corticosteroid receptor antagonist) as a
      similar subpopulation of striatal neurons undergoes apoptosis following
      dexamethasone administration. Injection of neither MK-801 nor amphetamine induced
      elevations of apoptotic-like cells in the striatum nor did co-administration of
      SCH23390 or scopolamine affect the levels of PCP-induced striatal cell death. In
      contrast, quinpirole elevated the levels of PCP-induced apoptotic-like striatal
      cell death and RU38486 markedly reduced it. Within the retrosplenial cortex,
      scopolamine lowered PCP-induced apoptotic-like cell death whereas RU38486 was
      without effect. These results suggest that PCP-induced striatal apoptosis results
      from a corticosteroid-dependent mechanism. The results further demonstrate that
      different pathological mechanisms underlie PCP-induced neuronal damage in the
      striatum and the retrosplenial cortex.

PMID- 10650125
TI  - Immunohistochemical examination of the INK4 and Cip inhibitors in the rat
      neonatal cerebellum: cellular localization and the impact of protein calorie
      malnutrition.
AB  - Expression of the cyclin-dependent kinase inhibitors (CKIs) has been linked to
      the inhibition of cellular proliferation and the induction of differentiation.
      Based on structure function analysis, two distinct families of CDKIs, the INK4
      and the Cip/Kip family have been identified. The INK4 family member p16(Ink4),
      and the Cip/Kip protein p27(Kip1) have been implicated in normal development of
      the CNS and cerebellum. Recent studies have suggested a functional inter
      dependence between the CKI and the abundance of cyclin D1 in orchestrating growth
      factor-induced cellular proliferation. The neonatal rat cerebellum undergoes
      proliferative growth and differentiation, localized to distinct topographical
      regions and cell types. The cell type and the temporal profile of CKI expression
      during postnatal cerebellar development had not been described. The current
      studies determined the specific cerebellar cell types in which the CKIs were
      expressed during post natal development by co-staining for cell-type specific
      markers. p16(Ink4a) and p27(Kip1) immunostaining was identified in both neurons
      and glial cells, increasing progressively between postnatal days 6 to 13 into
      adulthood. By contrast, neuronal and glial cell p21(Cip1) staining was prominent
      at days 6-11 and decreased thereafter. Cyclin D1 was expressed in the
      proliferating external granular cells, with occassional staining in the
      molecular, and internal granular layers. Dual immunostaining demonstrated cyclin
      D1 within cells expressing CKI (p16(Ink4a), p21(Cip1),p27(Kip1)). Cerebellar
      cellular growth arrest, induced by protein-calorie malnutrition, inhibited cyclin
      D1 protein levels without affecting CKI immunostaining suggesting CKI do not
      mediate the developmental arrest. These results demonstrate that the CKIs are
      induced by differentiation cues in specific cell types with distinct kinetics in
      the developing cerebellum in vivo.

PMID- 10650126
TI  - The golgi apparatus is present in perisynaptic, subependymal and perivascular
      processes of astrocytes and in processes of retinal Muller glia.
AB  - The Golgi apparatus (GA) of innervated rat and chicken skeletal muscle is present
      in a typical perinuclear location, and in subsynaptic areas where it disperses
      after denervation. It was suggested that the subsynaptic segments of the GA are
      linked with functions involved in the maturation and targeting of synaptic
      proteins. Similarly, the GA of rat myocardium is found in a perinuclear location
      and between myofibrils, adjacent to the T system of tubules. These findings raise
      the question whether the GA of polarized cells is present in a typical
      perinuclear location, for the performance of general "housekeeping" functions,
      and in distal areas, for the mediation of specialized functions. Astrocytes may
      contain GA within their long cytoplasmic processes which are difficult to
      identify in thin sections. To ensure the astrocytic origin of GA in otherwise
      unidentifiable small processes, we used transgenic mice expressing the rat MG160
      medial Golgi sialoglycoprotein only in the GA of astrocytes, and visualized the
      GA with monoclonal antibody 10A8 (mAb10A8) which reacts only with rat MG160.
      Thus, we identified cisternae of the GA in distal perisynaptic and subependymal
      processes, in perivascular foot plates of cerebral astrocytes, and in processes
      of the Muller glia in the retina. A similar strategy may be adopted in future
      investigations aiming at the detection of elements of the GA in distal processes
      of neurons and oligodendrocytes. The functional implications of GA in
      perisynaptic astrocytic processes and other processes are unknown. However, the
      isolation and molecular characterization of the perisynaptic subset of astrocytic
      Golgi may be feasible, since others have purified the astrocytic glutamate
      transporter 1 (GLT1) from crude synaptosomal fractions in which astrocytic
      processes are probably unavoidable contaminants.

PMID- 10650127
TI  - Foreign metallothionein-I expression by transient transfection in MT-I and MT-II
      null astrocytes confers increased protection against acute methylmercury
      cytotoxicity.
AB  - The mechanisms associated with metallothionein (MT) gene regulation are complex
      and poorly understood. Only a modest increase in brain MT expression levels is
      attained by exposure to metals, MT gene transfection, and MT gene knock-in
      techniques. Accordingly, in the present study, MT null astrocytes isolated from
      transgenic mice deficient in MT-I and MT-II genes were introduced as a zero
      background model of MT expression. MT protein levels were determined by western
      blot analysis. MT proteins in MT-I and MT-II null astrocytes were undetectable.
      Transient MT-I gene transfection increased the levels of foreign MT expression in
      MT-I and MT-II null astrocytes by 2.3-fold above basal levels in wild-type
      astrocytes. Intracellular Na(2)51CrO(4) efflux and D-[2,3-3H]aspartate uptake
      were studied as indices of acute methylmercury (MeHg) (5 microM) cytotoxicity. In
      MT-I and MT-II knockout astrocytes MeHg led to significant (p<0.01) increase in
      Na(2)51CrO(4) efflux and a significant (p<0.05) decrease in the initial rate (1
      min) of D-[2, 3-3H]aspartate uptake compared to MT-I and MT-II knockout controls.
      Transfection of the MT-I gene in MT-I and MT-II null mice significantly (p<0.01)
      decreased the effect of MeHg on Na(2)51CrO(4) efflux in MT null, as well as wild
      type astrocytes. MT-I gene transfection in MT-I and MT-II null astrocytes
      reversed the inhibitory effect of MeHg on D-[2,3-3H]aspartate uptake, such that
      initial rates of uptake in MT-I transfected cells in the presence and absence of
      MeHg (5 microM) were indistinguishable. These results demonstrate that: (1)
      astrocytes lacking MTs are more sensitive to MeHg than those with basal MT
      protein levels, (2) the MT-I gene can be overexpressed in MT-I and MT-II null
      astrocytes by transient MT-I gene transfection, and (3) that foreign MT
      expression endows astrocytes with increased resistance to MeHg.

PMID- 10650128
TI  - Further evidence for a role of nitric oxide in experimental allergic
      encephalomyelitis: aminoguanidine treatment modifies its clinical evolution.
AB  - The role of nitric oxide (NO) in inflammatory/demyelinating diseases is
      undergoing extensive investigation as a potential target for therapeutic
      intervention. However, interference with NO production has resulted in
      contrasting effects on the development of experimental allergic encephalomyelitis
      (EAE), the most widely used experimental model for multiple sclerosis (MS).
      Purpose of this paper was both the analysis of the individual clinical evolution
      of EAE induced in Lewis female rats by active immunisation and the evaluation of
      the effect of treatment with aminoguanidine, a selective inhibitor for the
      inducible isoform of nitric oxide synthase (iNOS). In our experimental model,
      relapse occurred in 66% of animals. Aminoguanidine treatment, started 3 days
      before immunisation, guaranteed a complete recovery from the acute phase and a
      delayed, milder relapse. Moreover, 79 days after immunisation inflammatory
      cellular infiltrates in the spinal cord were reduced. These data further support
      the involvement of NO in EAE evolution.

PMID- 10650129
TI  - Fos induction in selective hypothalamic neuroendocrine and medullary nuclei by
      intravenous injection of urocortin and corticotropin-releasing factor in rats.
AB  - CRF and urocortin, administrated systemically, exert peripheral biological
      actions which may be mediated by brain pathways. We identified brain neuronal
      activation induced by intravenous (i.v.) injection of CRF and urocortin in
      conscious rats by monitoring Fos expression 60 min later. Both peptides (850
      pmol/kg, i.v.) increased the number of Fos immunoreactive cells in the
      paraventricular nucleus of the hypothalamus, supraoptic nucleus, central
      amygdala, nucleus tractus solitarius and area postrema compared with vehicle
      injection. Urocortin induced a 4-fold increase in the number of Fos-positive
      cells in the supraoptic nucleus and a 3.4-fold increase in the lateral
      magnocellular part of the paraventricular nucleus compared with CRF. Urocortin
      also elicited Fos expression in the accessory hypothalamic neurosecretory nuclei,
      ependyma lining the ventricles and choroid plexus which was not observed after
      CRF. The intensity and pattern of the Fos response were dose-related (85, 255 and
      850 pmol/kg, i.v.) and urocortin was more potent than CRF. Neither CRF nor
      urocortin induced Fos expression in the lateral septal nucleus, Edinger-Westphal
      nucleus, dorsal raphe nucleus, locus coeruleus, or hypoglossal nucleus. These
      results show that urocortin, and less potently CRF, injected into the circulation
      at picomolar doses activate selective brain nuclei involved in the modulation of
      autonomic/endocrine function; in addition, urocortin induces a distinct
      activation of hypothalamic neuroendocrine neurons.

PMID- 10650130
TI  - Long-term fluoxetine produces behavioral anxiolytic effects without inhibiting
      neuroendocrine responses to conditioned stress in rats.
AB  - The aim of the present study was to investigate the anxiolytic effects of long
      term treatment with fluoxetine in rats. Selective serotonin reuptake inhibitors
      (SSRIs), such as fluoxetine, are used to treat anxiety and panic disorders, in
      addition to treating depression. A major concern with SSRIs is a 2-3-week delay
      in their therapeutic effects. SSRIs share with anxiolytic 5-HT(1A) agonists the
      ability to produce desensitization of post-synaptic 5-HT(1A) receptors. To
      investigate the anxiolytic effects of fluoxetine, rats were treated for 14 days
      with fluoxetine (10 mg kg(-1) day(-1), i.p. ). The rats were stressed using a
      conditioned stress procedure and tested one day after the last fluoxetine
      injection. Fluoxetine decreased stress-induced defecation (by 60%), reversed the
      stress-induced suppression of exploring behavior (by 59%) and shortened the
      duration of stress-induced freezing behavior (by 11. 5%). However, the stress
      induced increase in plasma levels of ACTH, corticosterone, oxytocin, prolactin
      and renin were not inhibited by fluoxetine treatment. These findings suggest that
      neuroadaptive changes induced by sustained inhibition of serotonin (5-HT)
      reuptake, contribute to the mechanism of the anxiolytic effects of fluoxetine. In
      contrast, the neuroendocrine responses to conditioned stress are not affected by
      these neuroadaptive changes.

PMID- 10650131
TI  - 1-Methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (salsolinol) is toxic to
      dopaminergic neuroblastoma SH-SY5Y cells via impairment of cellular energy
      metabolism.
AB  - The endogenous neurotoxin 1-methyl-6,7-dihydroxy-1,2,3, 4-tetrahydroisoquinoline
      (salsolinol), which is structurally similar to 1-methyl-4-phenyl-1,2,3,6
      tetrahydropyridine (MPTP), has been reported to inhibit mitochondrial complex I
      (NADH-Q reductase) activity as does the MPTP metabolite 1-methyl-4
      phenylpyridinium ion (MPP(+)). However, the mechanism of salsolinol leading to
      neuronal cell death is still unknown. Thus, we correlated indices of cellular
      energy production and cell viability in human dopaminergic neuroblastoma SH-SY5Y
      cells after exposure to salsolinol and compared these results with data obtained
      with MPP(+). Both toxins induce time and dose-dependent decrease in cell survival
      with IC(50) values of 34 microM and 94 microM after 72 h for salsolinol and
      MPP(+), respectively. Furthermore, salsolinol and MPP(+) produce a decrease of
      intracellular net ATP content with IC(50) values of 62 microM and 66 microM after
      48 h, respectively. In contrast to MPP(+), salsolinol does not induce an increase
      of intracellular net NADH content. In addition, enhancing glycolysis by adding D
      glucose to the culture medium protects the cells against MPP(+) but not
      salsolinol induced cellular ATP depletion and cytotoxicity. These results suggest
      that cell death induced by salsolinol is due to impairment of cellular energy
      supply, caused in particular by inhibition of mitochondrial complex II (succinate
      Q reductase), but not complex I.

PMID- 10650132
TI  - Maternal deprivation regulates serotonin 1A and 2A receptors in the infant rat.
AB  - Several studies have demonstrated that 5-HT1A and 5-HT2A receptors are altered in
      rat brain following chronic stress. While this is true in the adult animal, this
      may be different in the developing animal, which has a limited corticosterone
      response to acute challenges between days 3 and 14 of life. METHODS: We
      investigated the effect of maternal deprivation on 5-HT2A and 5-HT1A receptor
      mRNA levels in the developing brain. In situ hybridization was used to quantify
      gene expression in rat pups at three ages: 6, 9, and 12 days old. In each age
      group, half were maternally deprived for 24 h and half were kept with their
      mothers. Maternally deprived animals showed elevated ACTH and corticosterone
      plasma levels when compared to NDEP animals, significantly elevated 5-HT1A mRNA
      levels in the CA1 hippocampal region and, significantly elevated 5-HT2A mRNA
      levels in the parietal cortex. No changes were observed in 5-HT1A or 5-HT
      transporter mRNA levels in the dorsal raphe. Our results indicate that post
      synaptic 5-HT receptors in the developing hippocampus and cortex are sensitive to
      maternal deprivation. Because hippocampal 5-HT1A gene expressions are known to
      decrease in the adult animal after chronic glucocorticoid elevation, this data
      also suggests that other mechanisms, perhaps central, predominate during
      development.

PMID- 10650133
TI  - Upregulation and interaction of TNFalpha and gelatinases A and B in painful
      peripheral nerve injury.
AB  - Chronic constriction injury (CCI) to peripheral nerve causes a painful neuropathy
      in association with a process of axonal degeneration and endoneural remodeling
      that involves macrophage recruitment and local increase in extracellular
      proteases and tumor necrosis factor alpha (TNF-alpha). Cell surface activation of
      TNF-alpha from its transmembrane precursor, as well as sequestration of TNF-alpha
      receptors II and I, is performed by the zinc-dependent endopeptidase family of
      matrix metalloproteinases (MMPs). Among TNF-alpha-converting MMPs, basal lamina
      degrading gelatinases are thought to play a role in sciatic nerve injury. In the
      present study, we determined the forms of TNF-alpha involved in the development
      of CCI neuropathy in rats, using Western blot analysis, and the temporal
      correlation of TNF-alpha and TNFRI protein profiles with gelatinases activity at
      the site of peripheral nerve injury. We observed two peaks in TNF-alpha protein
      during the first week of CCI that correspond to previously reported peaks in
      painful behavior. We propose that the first peak at 6 h post-CCI is due to the
      local expression of the cytotoxic transmembrane 26 kDa TNF-alpha protein released
      by resident Schwann cells, mast cells and macrophages. This peak in TNF-alpha
      protein expression corresponds to an increase in gelatinase B (MMP-9) activity,
      which is greatly upregulated as early as 3 h following CCI to rat sciatic nerve.
      The second peak occurs at 5 days post-CCI, and may represent TNF-alpha protein
      released by hematogenously recruited macrophages. This peak is marked by the
      increase in active soluble 17 kDa TNF-alpha and by gelatinase A (MMP-2)
      upregulation. These observations suggest that there is a pathogenic role for the
      TNF-alpha-converting function of MMP-2 in painful CCI neuropathy. We conclude
      that severe nerve injury induces MMPs, TNF-alpha and TNFRI, which interactively
      control the privileged endoneurial environment and the pathogenesis of the
      painful neuropathies associated with the macrophage-dependent processes of
      Wallerian degeneration.

PMID- 10650134
TI  - Dopaminergic modulation at the olfactory nerve synapse.
AB  - Dopamine can change the membrane potential, regulate cyclic nucleotides, and
      modulate transmitter release in central neurons. In the olfactory bulb (OB), the
      dopamine synthetic enzyme, tyrosine hydroxylase, is largely confined to neurons
      in the glomerular layer. After demonstrating dopamine D2 receptors in the
      glomerular and olfactory nerve (ON) layers, Nickell et al. [W.T. Nickell, A.B.
      Norman, L.M. Wyatt, M.T. Shipley, Olfactory bulb DA receptors may be located on
      terminals of the olfactory nerve, NeuroReport, 2 (1991) 9-12.] proposed that
      these receptors may reduce transmitter release due to their localization to ON
      presynaptic boutons. We have previously demonstrated that olfactory receptor
      neurons use glutamate to excite OB neurons through activation of glutamate
      receptors subtypes, NMDA and AMPA/kainate [D.A. Berkowicz, P.Q. Trombley, G.M.
      Shepherd, Evidence for glutamate as the olfactory receptor cell neurotransmitter.
      J. Neurophysiol., 71 (1994) 2557-2561]. Here, we used a hemisected turtle OB
      preparation and patch-clamp recording techniques to assess dopamine modulation of
      the ON/OB neuron synapse. We found that dopamine (10-300 microM) reversibly
      decreased the excitatory postsynaptic response to ON stimulation. This effect
      could be overcome by recruiting additional nerve fibers by increasing the
      intensity of ON stimulation. Quinpirole (10 microM), a D2 agonist, mimicked the
      effects of dopamine. Conversely, sulpiride (300 microM), a D2 antagonist,
      prevented the inhibitory effects of dopamine on synaptic transmission. Whereas
      dopamine appeared to equally affect the NMDA and AMPA/kainate receptor-mediated
      components of the synaptically evoked response, it had no direct effect on
      membrane currents evoked by exogenous glutamate, kainate or NMDA applied to
      cultured OB neurons. Our data, therefore, support the notion that dopamine
      modulates synaptic transmission between olfactory receptor neurons and OB neurons
      via a presynaptic mechanism involving D2 receptor activation. Our abstract
      (Berkowicz et al. (1994) Neuroscience Abs. 20:328) is the first report of these
      results.

PMID- 10650135
TI  - N-Acetylcysteine delays age-associated memory impairment in mice: role in
      synaptic mitochondria.
AB  - Mitochondrial oxidative damage is implicated in brain aging and in age-related
      neurodegenerative diseases. Since N-acetylcysteine (NAC) has recently been shown
      to prevent apoptotic death in neuronal cells and protect synaptic mitochondria
      proteins from oxidative damage in aged mice, we have investigated whether dietary
      administration of this thiolic antioxidant retards age-related memory loss. At 48
      weeks of age, a control female OF-1 mice group was fed standard food pellets and
      another group received pellets containing 0.3% (w/w) of NAC. After 23 weeks of
      this diet, the NAC had partially restored the memory deficit associated with
      aging in mice. Moreover, the lipid peroxide and protein carbonyl contents of the
      synaptic mitochondria were significantly decreased in the NAC-supplemented
      animals in comparison with their age-matched controls. The antioxidant properties
      and probable action on mitochondrial bioenergetic ability in the synaptic
      terminals may explain, at least partially, the beneficial action of NAC
      administration.

PMID- 10650136
TI  - Nitric oxide synthase and glutamate receptor immunoreactivity in the rat spinal
      trigeminal neurons expressing Fos protein after formalin injection.
AB  - Although recent studies implicated glutamate receptors and nitric oxide in
      nociception, much still needs to be known about their localisation in neurons
      involved in nociceptive transmission from the orofacial region. In this study, c
      fos expression indicated by Fos immunohistochemistry in the caudal spinal
      trigeminal nucleus induced by subcutaneous injection of formalin into the lateral
      face of the rat was used as a marker for nociceptive neurons. The study sought to
      determine whether Fos-positive neurons express nitric oxide synthase, glutamate N
      methyl-D-aspartate type receptor subunit 1, and glutamate alpha-amino-3-hydroxy-5
      methyl-4-isoxazolepropionic acid type receptor subunit 2/3; and whether they
      project to the thalamus. After formalin injection, many Fos-positive nuclei
      appeared in the superficial laminae of the ipsilateral trigeminal nucleus.
      Confocal laser scanning microscope revealed that almost all neurons with Fos
      immunofluorescent nuclei were colocalised with N-methyl-D-aspartate receptor 1,
      94% with glutamate receptor 2/3 and 14% with nitric oxide synthase. Some of them
      were closely related to neurons labelled by nitric oxide synthase. Lastly, some
      of the Fos-positive neurons were labelled by tetramethylrhodamine-dextran
      injected into the trigeminothalamic tract or the thalamic region. The results
      suggested that activation of N-methyl-D-aspartate receptor 1 and glutamate
      receptor 2/3 upon glutamate release in response to noxious stimulation to the
      orofacial region might mediate c-fos expression in neurons involved in
      nociception. The expression of Fos in the neurons could also be mediated by
      nitric oxide produced from the same, as well as neighbouring neurons, when
      nociceptive stimulation persisted. Fos-positive neurons in the spinal trigeminal
      nucleus may project to the thalamus, relaying orofacial nociception to the higher
      sensory centre.

PMID- 10650137
TI  - Decreased base excision repair and increased helicase activity in Alzheimer's
      disease brain.
AB  - Recent studies show an increase in DNA oxidation in brain and cerebrospinal fluid
      (CSF), and decreased levels of the free repair product in CSF in Alzheimer's
      disease (AD). This is a study of the activity of the base excision repair enzyme,
      8-oxoguanine glycosylase (responsible for the excision of 8-oxoguanine), and DNA
      helicase activity in nuclear protein samples from four brain regions of 10 AD and
      eight age-matched control subjects. Statistically significant (p<0.05) decreases
      in 8-oxoguanine glycosylase activity were observed in the nuclear fraction of AD
      hippocampal and parahippocampal gyri (HPG), superior and middle temporal gyri
      (SMTG), and inferior parietal lobule (IPL). DNA helicase activity was elevated in
      all nuclear samples except the IPL with statistically significant elevations in
      the HPG and CER. Statistically significant depletion of helicase activity was
      observed in the nuclear fraction in AD IPL. Our results demonstrate that the
      repair capabilities for 8-oxoguanine are decreased in AD. The modest increase in
      DNA helicase activity in some brain regions in AD may interfere with base
      excision repair mechanisms. Overall, the decreased repair of DNA damage could be
      involved in the pathogenesis of neurodegeneration in AD.

PMID- 10650138
TI  - Responses of nitric oxide synthase expression in the gracile nucleus to sciatic
      nerve injury in young and aged rats.
AB  - Neuronal nitric oxide synthase (nNOS) is induced in dorsal root ganglion neurons
      following axotomy in young rats, and is also increased in the gracile nucleus
      neurons of intact aged rats. The present study examined the influence of sciatic
      nerve axotomy on nNOS expression in the gracile nucleus in young compared to aged
      rats. The unilateral transection of the sciatic nerve was performed in young (4
      months) and old (24 months) Fischer rats. Sections of rat medulla obtained 14
      days after axotomy were immunolabelled using a polyclonal antibody directed
      against nNOS and stained by nicotinamide adenine dinucleotide phosphate
      diaphorase (NADPHd) histochemistry, a marker of nNOS activity. In young rats,
      unilateral axotomy produced increased NADPHd containing neurons in the rostral
      region and the caudal region of the ipsilateral gracile nucleus compared to the
      side with intact sciatic nerve. In old rats, the NADPHd containing neurons in the
      ipsilateral gracile nucleus were moderately increased by axotomy over the age
      changes seen in the contralateral side. Similar results were obtained with nNOS
      immunoreactivity in young rats, but more cells were seen with NADPHd staining
      compared to nNOS immunostaining in old rats. The results suggest that unilateral
      sciatic axotomy causes an increase in nNOS expression in the ipsilateral gracile
      nucleus of young rats, which is still seen in old rats as an increase over normal
      aging changes.

PMID- 10650139
TI  - Blockade of U50488H on sodium currents in acutely isolated mice hippocampal CA3
      pyramidal neurons.
AB  - The effect of opioid agonist U50488H on Na(+) currents was examined in freshly
      dissociated hippocampal neurons of mice using the whole-cell patch clamp
      technique. U50488H (1-100 microM) caused a concentration dependent reversible
      inhibition of the voltage-activated sodium currents. IC50 of 15.5 microM and Hill
      constant of 1.4 were calculated respectively. The inhibitory actions of U50488H
      on I(Na) were still observed in the presence of 30 microM naloxone. Moreover,
      under the action of U50488H, repetitive stimulation induced further inhibition
      which was frequency-dependent. The activation curve did not change before and
      after application of 10 microM U50488H. However, after exposure to 10 microM
      U50488H and repetitive depolarizing at 10 Hz, frequency-dependent inhibition
      occurred, and a mean shift of half-activation membrane potential by +20 mV could
      be induced. The inactivation curve was significantly changed toward negative
      membrane potential with 10 microM U50488H, and further negative shift was
      observed after repetitive depolarizing at 10 Hz. Our results indicate that
      U50488H could directly inhibit neuronal Na(+) currents without involvement in the
      activation of kappa-opioid receptors.

PMID- 10650140
TI  - Influence of visual experience deprivation on the postnatal development of the
      microvascular bed in layer IV of the rat visual cortex.
AB  - Cerebral vascular density is correlated with metabolic demands, which increase in
      highly active brain areas. External inputs are an essential requirement in the
      modeling of the visual cortex. Experience-mediated development is very active
      during the first postnatal month, when congruous blood supply is needed. We
      studied the development of visual cortex vascularization in relation to
      experience, comparing rats raised in darkness with rats reared in normal
      conditions. Vascular density, vascular area and their ratio vs. neuronal density
      were calculated. Conventionally stained semi-thin sections were used to measure
      the vascular area by computer assisted morphometry. Animals from both groups were
      sampled at 14, 21, and 60 days postnatal (dpn). We found a significantly lower
      density of vessels and neurons as well as a smaller vascular area in dark-reared
      adult rats while no differences were founded at the other ages. Our results also
      show no differences between the ratio of vessels/neuron, and vascular
      area/neuron, between both groups. The absence of visual experience causes
      decrease of cortical activity which correlates with lower vessels density and
      vascular area, without their ratio/neuron being affected.

PMID- 10650141
TI  - Inhibition of nitric oxide synthase does not alter basal permeability of the
      blood-brain barrier.
AB  - The goal of the present study was to determine the role of basal
      synthesis/release of nitric oxide on the basal permeability characteristics of
      the blood-brain barrier to various sized molecules in vivo. We examined the pial
      microcirculation in rats using intravital fluorescence microscopy. Permeability
      of the blood-brain barrier was quantitated by calculating the clearance of
      fluorescent-labeled albumin (mol.wt.=69,000 Da; FITC-albumin), fluorescent
      labeled dextran (mol.wt.=10,000 Da; FITC-dextran-10K) or sodium fluorescein
      (mol.wt.=376; NaFl) in the absence and presence of an inhibitor of nitric oxide
      synthase (N(G)-monomethyl-L-arginine; L-NMMA; 10 and 100 microM). During
      superfusion with vehicle, clearance of FITC-albumin, FITC-dextran-10K and NaFl
      from pial vessels and diameter of pial arterioles remained constant. To determine
      whether basal synthesis/release of nitric oxide affected basal permeability of
      the blood-brain barrier, we examined the effects of L-NMMA (10 and 100 microM).
      In addition, we examined the adherence of leukocytes to cerebral venular
      endothelium using rhodamine 6G. Although topical application of L-NMMA produced
      constriction of pial arterioles, L-NMMA did not alter the permeability
      characteristics of the blood-brain barrier to FITC-albumin, FITC-dextran-10K or
      NaFl. Further, the adherence of leukocytes to the endothelium appeared to be
      similar while suffusing with vehicle and L-NMMA (100 microM). Thus, the findings
      of the present study suggest that while basal synthesis/release of nitric oxide
      may play an important role in regulation of basal tone of cerebral blood vessels,
      it does not appear that basal synthesis/release of nitric oxide plays an
      important role in maintaining the integrity of the blood-brain barrier to large
      or small molecules.

PMID- 10650142
TI  - GABA-immunoreactive internuclear neurons in the ocular motor system of lampreys.
AB  - The presence of internuclear neurons in the abducens and oculomotor nuclei of
      lampreys [Gonzalez, M.J., Pombal, M.A., Rodicio, M.C. and Anadon, R.,
      Internuclear neurons of the ocular motor system of the larval sea lamprey, J.
      Comp. Neurol. 401 (1998) 1-15] indicates that coordination of eye movements by
      internuclear neurons appeared early during the evolution of vertebrates. In order
      to investigate the possible involvement of inhibitory neurotransmitters in
      internuclear circuits, the distribution of gamma-aminobutyric acid (GABA) in the
      extraocular motor nuclei of the lamprey was studied using immunocytochemical
      techniques. Small GABA-immunoreactive (GABAir) neurons were observed in the three
      ocular motor nuclei. Numerous GABAir neurons were observed in the group of
      internuclear neurons of the dorsal rectus oculomotor subnucleus. A second group
      of GABAir neurons was observed among and below the trochlear motoneurons. Two
      further groups of GABAir interneurons, periventricular and lateral, were located
      in the abducens nucleus among the cells of the caudal rectus and the ventral
      rectus motor subnuclei, respectively. In addition to the presence of GABAir
      neurons, in all the ocular motor nuclei the motoneurons were contacted by
      numerous GABAir boutons. Taken together, these results suggest that GABA is
      involved as a neurotransmitter in internuclear pathways of the ocular motor
      system of lampreys.

PMID- 10650143
TI  - Chronic treatment of human astrocytoma cells with lithium, carbamazepine or
      valproic acid decreases inositol uptake at high inositol concentrations but
      increases it at low inositol concentrations.
AB  - Inositol uptake was measured at concentrations of 25, 40 and 50 microM in human
      astrocytoma cell cultures treated for 1-3 weeks with pharmacologically relevant
      concentrations of LiCl, valproic acid or carbamazepine as well as in control
      cultures that had not been treated with any drug. After at least 2 weeks of
      treatment, each of these 3 conventional anti-bipolar drugs increased the uptake
      significantly at 25 microM inositol, had no effect at 40 microM, and decreased it
      at 50 microM inositol. Reduction of the drug concentrations by 50% abolished the
      stimulation of uptake at 25 microM inositol by lithium and valproic acid and
      reduced that by carbamazepine. These findings may contribute to an understanding
      of the mechanisms of action for anti-bipolar medication, and explain the
      controversy in the literature whether or not brain inositol is reduced after
      chronic administration of lithium.

PMID- 10650144
TI  - Relative sparing of calretinin containing neurons in the substantia nigra of 6
      OHDA treated rat parkinsonian model.
AB  - A certain calcium binding protein (CaBP) has been known to exert a
      neuroprotective effect in various neurodegenerative diseases. Using the 6-OHDA
      induced rat Parkinsonian model, we examined if calretinin (CR), one of CaBP
      family, could play the similar role in the Parkinson's disease because CR is
      profusely localized in dopaminergic neurons of the substantia nigra pars compacta
      (SNPC) of the rat. Employing immunohistochemical analyses, we found that the
      survival rate of CR neurons was significantly higher than that of tyrosine
      hydroxylase (TH) neurons in the SNPC of the Parkinsonian rat. Furthermore double
      labeled fluorescent microscopy revealed that almost all surviving TH neurons were
      also positive to CR. Our data suggest that CR-positive neurons are less
      vulnerable to 6-OHDA and CR in the dopaminergic neurons may have a protective
      function for survival of these neurons in the experimentally induced Parkinsonian
      rat.

PMID- 10650145
TI  - The neurosteroid, 3alpha-androstanediol, prevents inhibitory avoidance deficits
      and pyknotic cells in the granule layer of the dentate gyrus induced by
      adrenalectomy in rats.
AB  - Testosterone (T), dihydrotestosterone (DHT), 3alpha-diol (5alpha-androstane
      3alpha,17beta-diol), or vehicle was administered daily to gonadectomized,
      adrenalectomized male Long-Evans rats. Four days after adrenalectomy (ADX),
      animals were tested for inhibitory avoidance. Vehicle-treated rats had shorter
      latencies than 3alpha-diol-treated rats and non-corticosterone-depleted rats. All
      three androgens significantly reduced the number of pyknotic cells in
      corticosterone-depleted rats. Neurosteroids may mediate androgens' functional and
      morphological neuroprotective effects.

PMID- 10650146
TI  - Fos expression in feeding-related brain areas following intracerebroventricular
      administration of orphanin FQ in rats.
AB  - While the influence of orphanin FQ (OFQ) on the regulation of food intake has
      been substantiated, little is known about feeding-related brain regions that
      mediate OFQ-induced feeding. To further investigate this, we injected OFQ
      intracerebroventricularly and evaluated c-Fos immunoreactivity in brain areas
      thought to be involved in the regulation of food intake. Altered c-Fos expression
      as a consequence of OFQ injection was observed in the nucleus of the solitary
      tract, paraventricular nucleus of the hypothalamus, supraoptic nucleus, central
      nucleus of amygdala, lateral septal nucleus and lateral habenular nucleus.
      Presumably, OFQ modulates food ingestion through its action on these brain
      regions, most probably by activating feeding signals as well as suppressing
      satiety mechanisms.

PMID- 10650147
TI  - Experience-dependent phase-reversal of hippocampal neuron firing during REM
      sleep.
AB  - The idea that sleep could serve a cognitive function has remained popular since
      Freud stated that dreams were "not nonsense" but a time to sort out experiences
      [S. Freud, Letter to Wilhelm Fliess, May 1897, in The Origins of Psychoanalysis -
      Personal Letters of Sigmund Freud, M. Bonaparte, A. Freud, E. Kris (Eds.),
      Translated by E. Mosbacher, J. Strachey, Basic Books and Imago Publishing, 1954].
      Rapid eye movement (REM) sleep, which is associated with dream reports, is now
      known to be is important for acquisition of some tasks [A. Karni, D. Tanne, B.S.
      Rubenstein, J.J.M. Askenasy, D. Sagi, Dependence on REM sleep of overnight
      improvement of a perceptual skill, Science 265 (1994) 679-682; C. Smith, Sleep
      states and learning: a review of the animal literature, Biobehav. Rev. 9 (1985)
      157-168]; although why this is so remains obscure. It has been proposed that
      memories may be consolidated during REM sleep or that forgetting of unnecessary
      material occurs in this state [F. Crick, G. Mitchison, The function of dream
      sleep, Nature 304 (1983) 111-114; D. Marr, Simple memory: a theory for
      archicortex, Philos. Trans. R. Soc. B. 262 (1971) 23-81]. We studied the firing
      of multiple single neurons in the hippocampus, a structure that is important for
      episodic memory, during familiar and novel experiences and in subsequent REM
      sleep. Cells active in familiar places during waking exhibited a reversal of
      firing phase relative to local theta oscillations in REM sleep. Because firing
      phase can influence whether synapses are strengthened or weakened [C. Holscher,
      R. Anwyl, M.J. Rowan, Stimulation on the positive phase of hippocampal theta
      rhythm induces long-term potentiation that can be depotentiated by stimulation on
      the negative phase in area CA1 in vivo, J. Neurosci. 15 (1977) 6470-6477; P.T.
      Huerta, J.E. Lisman, Bidirectional synaptic plasticity induced by a single burst
      during cholinergic theta oscillation in CA1 in vitro, Neuron 15 (1995) 1053-1063;
      C. Pavlides, Y.J. Greenstein, M. Grudman, J. Winson, Long-term potentiation in
      the dentate gyrus is induced preferentially on the positive phase of theta
      rhythm, Brain Res. 439 (1988) 383-387] this experience-dependent phase shift,
      which developed progressively over multiple sessions in the environment, is
      consistent with the hypothesis that circuits may be restructured during REM sleep
      by selectively strengthening recently acquired memories and weakening older ones.

PMID- 10650148
TI  - Simultaneous detection of tyrosine hydroxylase-immunoreactivity and vasopressin
      mRNA in neurons of the human paraventricular and supraoptic nucleus.
AB  - Our purpose was to investigate the proportion of tyrosine hydroxylase (TH)
      immunoreactive (IR) neurons expressing vasopressin (VP) mRNA in the human
      paraventricular and supraoptic nuclei by combining in situ hybridization with
      immunohistochemistry on the same tissue section. A variability in the proportion
      of TH-IR neurons synthesizing VP mRNA was observed in adults which was usually
      more than 50%. In neonates almost all the TH-IR neurons appeared to contain VP
      mRNA.

PMID- 10650149
TI  - Selenium, an antioxidant, attenuates methamphetamine-induced dopaminergic
      toxicity and peroxynitrite generation.
AB  - Methamphetamine (METH) has been known to produce neurotoxicity via generation of
      reactive oxygen and nitrogen species. Selenium, an antioxidant, was reported to
      protect against METH-induced dopaminergic neurotoxicity in mouse caudate nucleus.
      In the present study, the in vitro and in vivo efficacy of the supplementation of
      selenium was studied in METH-induced generation of peroxynitrite. PC12 cell
      cultures were exposed to 200 microM METH either with or without 10 microM and 20
      microM selenium (30 min prior to METH exposure). After 24 h, METH exposure
      resulted in the significant depletion of dopamine, and its metabolites DOPAC and
      HVA, as well as the significant formation of 3-nitrotyrosine (3-NT), a marker of
      peroxynitrite generation, in PC12 cell cultures. Selenium supplementation
      attenuated the depletion of dopamine and its metabolites, DOPAC and HVA and the
      formation of 3-NT in PC12 cells. For in vivo studies, adult male mice were
      supplemented with selenium in drinking water, 1 week before and 1 week after the
      multiple injections of METH (4x10 mg/kg, i.p. at 2-h interval) or an equivalent
      volume of saline. The supplementation of Se attenuated the formation of 3-NT in
      the striatum resulting from METH treatment. These data suggest that METH-induced
      neurotoxicity is mediated by the production of peroxynitrite, and selenium plays
      a protective role in METH-induced neurotoxicity.

PMID- 10650150
TI  - Central leptin suppresses splenic lymphocyte functions through activation of the
      corticotropin-releasing hormone-sympathetic nervous system.
AB  - Leptin is one of the key afferent signals that regulate food intake and energy
      expenditure by acting on specific receptors in the hypothalamus. Recently, leptin
      was reported to activate the peripheral immune system by acting directly on
      lymphocytes. To elucidate the brain-mediated participation of leptin in the
      modulation of peripheral immune functions, we examined the effects of
      intracerebroventricular (icv) injection of murine recombinant leptin on the
      proliferative response to Concanavalin A (ConA response) of splenic lymphocytes
      in rats. The ConA response of splenic lymphocytes was markedly reduced 30 min
      after icv injection of leptin. The suppressive effect of leptin was abolished
      completely either by surgical severing of the splenic nerves or by icv injection
      of an antibody against corticotropin-releasing hormone (CRH), but only partially
      by an anti-urocortin antibody. Icv injection of CRH and urocortin also suppressed
      the ConA response of splenic lymphocytes, and the effect of urocortin was
      prevented by the anti-CRH antibody, while that of CRH was not prevented by the
      anti-urocortin antibody. These results suggest that leptin suppresses peripheral
      lymphocyte functions, in contrast to the direct activating effects, indirectly
      through the activation of the CRH (urocortin)-sympathetic nervous system.

PMID- 10650151
TI  - Mechanism of damnacanthal-induced [Ca(2+)](i) elevation in human dermal
      fibroblasts.
AB  - Damnacanthal is a potent and selective inhibitor of p56(lck) tyrosine kinase in a
      variety of tissues. We have found, however, using the Ca(2+) microfluorimetry
      technique, that damnacanthal releases intracellular Ca(2+) stores and promotes
      Ca(2+) entry in human dermal fibroblasts. The effect of damnacanthal on the peak
      [Ca(2+)](i) values and the latent time to the peak was concentration-dependent.
      Damnacanthal releases Ca(2+) from thapsigargin-sensitive Ca(2+) stores, and the
      Ca(2+) stores responding to damnacanthal were overlapped with those of
      bradykinin. Damnacanthal-induced Ca(2+) entry was mediated by voltage-dependent
      and voltage-independent Ca(2+) channels. This effect of damnacanthal on
      intracellular Ca(2+) mobilization was also observed in cultured bovine coronary
      endothelial cells but not demonstrated in freshly isolated rat basilar smooth
      muscle cells. Our study suggests that damnacanthal increases intracellular Ca(2+)
      by releasing Ca(2+) from internal stores and promoting Ca(2+) entry. The
      relationship between the actions of damnacanthal on tyrosine kinase and
      intracellular Ca(2+) requires further investigation.

PMID- 10650152
TI  - Mechanism of inhibition of platelet aggregation by HCL-31D.
AB  - The antiplatelet effect of the pyridazinone analogue, 4, 5-dihydro-6-[4-[2
      hydroxy-3-(3,4 dimethoxybenzylamino)propoxy]naphth-1-yl]-3(2H)-pyridazinone (HCL
      31D), was investigated in vitro with rabbit platelets. HCL-31D dose-dependently
      inhibited the platelet aggregation and ATP release induced by collagen (10
      microg/ml), arachidonic acid (100 microM) or thrombin (0.1 U/ml) with an IC(50)
      of about 0.95-5.41 microM. HCL-31D (0.5-5 microM) increased the platelet cyclic
      AMP level in a dose-dependent manner. Furthermore, HCL-31D potentiated cyclic AMP
      formation caused by prostaglandin E(1) but not that caused by 3-isobutyl-1
      methylxanthine (IBMX). HCL-31D also attenuated phosphoinositide breakdown and
      intracellular Ca(2+) elevation induced by collagen, arachidonic acid or thrombin.
      HCL-31D inhibited the formation of thromboxane B(2) induced by collagen or
      thrombin but not by arachidonic acid. In addition, HCL-31D did not affect
      platelet cylooxygenase and thromboxane synthase activity. These data indicate
      that HCL-31D is an inhibitor of phosphodiesterase and that its antiplatelet
      effect is mainly mediated by elevation of cyclic AMP levels.

PMID- 10650153
TI  - Characterization of the antinociceptive effects of TRK-820 in the rat.
AB  - We have already reported that TRK-820, (-)-17-cyclopropylmethyl-3, 14b-dihydroxy
      4, 5a-epoxy-6b-[N-methyl-trans-3-(3-furyl)acrylamido]morphinan hydrochloride, a
      new selective kappa-opioid receptor agonist, has affinity for kappa-subtype
      opioid receptors other than the kappa(1)-opioid receptor. It would be of interest
      to examine whether the different kappa-opioid receptor subtype properties of TRK
      820 participate in its antinociceptive action in the inflamed paw test and the
      formalin test. TRK-820 produced a potent antinociceptive effect, which was
      inhibited by the selective kappa-opioid receptor antagonist nor-binaltorphimine,
      but not by the mu-opioid receptor antagonist naloxone in the mechanical paw
      pressure test. TRK-820 also produced a potent antinociceptive effect in rats with
      adjuvant-induced arthritis. TRK-820 and morphine, a prototype mu-opioid receptor
      agonist, were equally effective in inhibiting the nociceptive responses in the
      arthritic rats and in the normal rats, while ICI-199441, 2-(3, 4-dichlorophenyl)
      N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]- acetamide, a kappa-opioid
      receptor agonist, was about 5-fold less potent in the arthritic rats than in the
      normal rats. In the formalin test TRK-820 had a very similar antinociceptive
      potency to that of ICI-199441, unlike in the arthritic rats in which TRK-820 was
      2.5 times more potent than ICI-199441. It is concluded that TRK-820 produced a
      potent antinociceptive action via the stimulation of kappa-opioid receptors in
      rats. TRK-820 has a unique antinociceptive profile different from that of the
      other kappa-opioid receptor agonists such as ICI-199441 in arthritic rats.

PMID- 10650154
TI  - The effects of a specific alpha(2)-adrenoceptor antagonist, atipamezole, on
      cognitive performance and brain neurochemistry in aged Fisher 344 rats.
AB  - The present experiments investigated the effects of a specific and potent
      alpha(2)-adrenoceptor antagonist, atipamezole, on cognitive performance and
      neurochemistry in aged rats. Aged control Fisher 344 rats, which had lower
      activities of choline acetyltransferase in the frontal cortex, were impaired in
      the acquisition of the linear arm maze task both in terms of repetition errors
      and their behavioural activity (the speed of arm visits), and they needed longer
      time to complete this task as compared to adult control rats. Atipamezole
      treatment (0.3 mg/kg) facilitated the acquisition of this task in the aged rats
      as they committed fewer errors and completed the task more quickly than saline
      treated aged control rats. A separate experiment indicated that atipamezole
      enhanced the turnover of noradrenaline both in the adult and aged rats, but this
      effect was more pronounced in the aged rats. Furthermore, atipamezole enhanced
      significantly the turnover of serotonin and dopamine only in the aged rats when
      analysed in the whole brain samples. As alpha(2)-adrenoceptor antagonists are
      known to alleviate akinesia in the experimental models of Parkinson's disease,
      the present results could be especially relevant for the development of
      palliative treatment for demented Parkinsonian patients.

PMID- 10650155
TI  - Sustained effect of metrifonate on cerebral glucose metabolism after immunolesion
      of basal forebrain cholinergic neurons in rats.
AB  - To evaluate the influence of cholinergic projections from the basal forebrain on
      brain metabolism, we measured the cerebral metabolic rate of glucose (CMR(glu))
      after unilateral lesioning of cholinergic basal forebrain neurons with the
      immunotoxin 192 IgG-saporin. CMR(glu) was determined in 24 cortical and 13 sub
      cortical regions using the [14C]2-deoxy-D-glucose technique of Sokoloff. Average
      hemispheric CMR(glu) decreased by 7% (P<0.02) and 5% (P<0.05), 7 and 21 days
      after lesion, respectively. Regional effects were restricted to parietal and
      retrosplenial cortices, lateral habenula and the basal forebrain. We have
      previously shown that metrifonate increased CMR(glu) in intact rats. In lesioned
      rats, metrifonate (80 mg/kg, i. p.) was still active but the metabolic activation
      was reduced in terms of both the average hemispheric CMR(glu) and the number of
      regions significantly affected. Although it is reduced, the sustained effect of
      metrifonate in lesioned rats makes an argument for the use of this compound as
      treatment of cholinergic deficit in Alzheimer's disease.

PMID- 10650156
TI  - Enhanced delta-opioid receptor-mediated antinociception in mu-opioid receptor
      deficient mice.
AB  - Inflammatory hyperalgesia was induced in wild-type, heterozygous and mu-opioid
      receptor knockout mice after an intraplantar injection of complete Freund's
      adjuvant. micro-Opioid receptor knockout mice exhibited faster recovery from
      hyperalgesia as compared to heterozygous (P<0.05) and wild-type (P<0.01) mice.
      Naloxone restored hyperalgesia in all genotypes. Naltrindole (delta-opioid
      receptor-selective antagonist) partially restored the hyperalgesia only in mu
      opioid receptor knockout mice (P<0.001). Nor-binaltorphimine (kappa-opioid
      receptor-selective antagonist) had no effect. The mu-opioid receptor-selective
      agonist, [D-Ala(2), MePhe(4),Gly-ol(5)]enkephalin (DAMGO), reduced the
      hyperalgesia in heterozygous and wild-type but not in mu-opioid receptor knockout
      mice while U69,593 ?(+)-(5alpha,7alpha, 8beta)-N-methyl-N-[7-(1-pyrrolidinyl)-1
      oxaspiro[4. 5]dec-8-yl]-benzeneacetamide, kappa-opioid receptor-selective?
      produced similar effects in all mice. The delta-opioid receptor-selective
      agonists, [D-Pen(2), D-Pen(5)]enkephalin (DPDPE) and deltorphin ([D
      Ala(2)]deltrophin-II), produced significantly greater antihyperalgesia in
      knockout mice (P<0.05). The findings suggest that mu-opioid receptors may be
      involved in the persistence of inflammatory hyperalgesia and that a delta-opioid
      receptor-mediated compensatory mechanism in the absence of the mu-opioid receptor
      is activated by persistent hyperalgesia.

PMID- 10650157
TI  - Differential effects of nicotine against stress-induced changes in dopaminergic
      system in rat striatum and hippocampus.
AB  - A number of studies have shown an increase in nicotine self-administration among
      smokers when exposed to stress. Since it is well known that nicotine or stress
      alter the dopaminergic system, we examined the effect of chronic nicotine
      administration on the dopamine level and its metabolism in the striatum and the
      hippocampus during stressful conditions in rats. Nicotine (0.4 mg/kg, i.p. for 14
      days) increased the dopamine level in the striatum (P<0. 05) and decreased it in
      the hippocampus (P<0.05) in comparison with the effect of saline. Three hours of
      water-immersion restraint stress sharply elevated the dopamine level (P<0.05) and
      reduced the 3-methoxytyramine level (P ranged from 0.05 to 0.001 depending on the
      area and time point) in both brain regions studied, while dihydroxyphenylacetic
      acid and homovanilic acid levels were not altered. Nicotine pretreatment
      attenuated some of these changes in a region- and time-dependent manner. However,
      stress induced a decrease in dopamine turnover in the hippocampus (P<0.05) but
      not in the striatum, and nicotine failed to prevent this effect. Stress-induced
      alterations gradually returned toward normal during the 48-h observation period,
      and in some cases this was facilitated by nicotine. Thus, we demonstrated
      differential, region- and time-dependent protective effects of chronic nicotine
      administration against stress-induced changes in dopamine levels and release in
      brain regions critically affected by stress.

PMID- 10650158
TI  - Imaging extrastriatal dopamine D(2) receptor occupancy by endogenous dopamine in
      healthy humans.
AB  - The effect of endogenous dopamine on in vivo measurement of dopamine D(2)
      receptors in extrastriatal regions (thalamus and temporal cortex) was evaluated
      with single photon emission computed tomography and the high affinity ligand
      [123I]epidepride by comparing the binding potential before and after acute
      dopamine depletion. Dopamine depletion was achieved by per-oral administration of
      5.5 g/70 kg body weight alpha-methyl-para-tyrosine given in 37 h. The alpha
      methyl-para-tyrosine treatment increased the binding potential significantly in
      the temporal cortex (13+/-15%, P=0.036) but not in the thalamus (2+/-9%). The
      increase of the binding potential in the temporal cortex correlated strongly with
      the increase of dysphoric mood evaluated by the Positive and Negative Symptom
      Scale (PANSS) (rho=0.88, P=0.004). These results imply that [123I]epidepride,
      coupled with acute dopamine depletion might provide estimates of synaptic
      dopamine concentration.

PMID- 10650159
TI  - Opposite modulation of apomorphine- or amphetamine-induced stereotypy by
      antagonists of CCK receptors.
AB  - Stereotyped behavior is elicited by activation of dopaminergic systems with drugs
      such as apomorphine and amphetamine. In previous studies, we have reported that
      the sulfated cholecystokinin octapeptide (CCK-8) decreased apomorphine-induced
      stereotypy in animals with normal and supersensitive dopamine receptors. The aim
      of the present study was to evaluate the effects of CCK(1) and CCK(2) receptor
      antagonists on stereotyped behavior induced by apomorphine or amphetamine. Rats
      were pretreated with the CCK(1) (SR 27897B; 1-[[2-(4-(2-chlorophenyl) thiazol-2
      yl) aminocarbonyl]indolyl]acetic acid; 500 microg/kg; i.p.) or CCK(2) (L-365,260;
      3R-(+)-N-(2,3-dihydro-1-methyl-2-oxo-5 phenyl-1H-1, 4-benzodiazepine-3-yl)-N'-(3
      methyl phenyl)-urea; 500 microg/kg; i.p. ) receptor antagonists or saline 15 min
      before apomorphine (0.6 mg/kg; s.c.) or amphetamine (9.0 mg/kg; i.p.) injection.
      Both CCK(1) and CCK(2) receptor antagonists significantly increased apomorphine
      induced stereotypy. In contrast, only the blockade of CCK(2) receptors
      significantly decreased amphetamine-induced stereotypy. The results suggest a
      dual opposite mechanism for CCK-dopamine interactions. These data also suggest
      that both apomorphine- and amphetamine-induced stereotypy should be used whenever
      effects of drugs acting on dopaminergic systems are being assessed.

PMID- 10650160
TI  - Effects of RO 60 0175, a 5-HT(2C) receptor agonist, in three animal models of
      anxiety.
AB  - There is some controversy as to whether 5-HT(2C) receptor agonists are anxiogenic
      or anxiolytic. The effects of the novel 5-HT(2C) receptor agonist, (S)-2-chloro-5
      fluoro-indol-1-yl)-1-methyl ethylamine fumarate (RO 60 0175), in three models of
      anxiety were therefore tested. RO 60 0175 was found to induce hypolocomotion in
      rats at doses greater than 0.5 mg/kg s.c., an effect reversed by the selective 5
      HT(2C) receptor antagonist, SB-242084. RO 60 0175 did not elicit anxiolytic-like
      responses in the social interaction test under high light unfamiliar conditions,
      but suppressed both time spent in social interaction and locomotion at doses of 1
      and 3 mg/kg s.c., suggesting a sedative response. In the Vogel conflict test, RO
      60 0175 had no significant action on the number of shocks taken. In the Geller
      Seifter test, RO 60 0175 (0.3 and 1 mg/kg s.c.) simultaneously reduced both
      unpunished and punished lever pressing, a profile consistent with sedation.
      Finally, RO 60 0175 was tested in a rat social interaction test under low light
      familiar conditions optimal for the detection of anxiogenic-like responses. At 1
      and 3 mg/kg s.c., RO 60 0175 reduced both time spent in social interaction and
      concurrent locomotion, a profile more consistent with sedation than anxiogenesis.
      In conclusion, RO 60 0175 induced sedative-like responses via 5-HT(2C) receptor
      activation, but was neither anxiolytic, nor clearly anxiogenic at the doses
      tested.

PMID- 10650161
TI  - The effects of valproate on the arachidonic acid metabolism of rat brain
      microvessels and of platelets.
AB  - Long-term administration of the antiepileptic drug valproate can induce
      hematologic, hepatic and endocrine abnormalities and morphologic alterations in
      the brain capillaries and glial cells. Valproate elicits bone marrow suppression,
      reducing the number of red blood cells and platelets, and causes platelet
      functional abnormalities. Various data suggest that more than one mechanism of
      valproate-associated toxicity may exist, but the pathomechanism of cell function
      alterations elicited by valproate has not yet been elucidated. The reported ex
      vivo experiments were designed to investigate the effects of valproate on the
      arachidonic acid cascade of rat brain capillaries and platelets. Valproate was
      administered (300 mg/kg body weight/day) in the drinking water to male Wistar
      rats for 2 weeks. Isolated platelets and brain microvessels were labelled with
      [14C]arachidonic acid and the released [14C]eicosanoids were separated by
      overpressure thin-layer chromatography and determined quantitatively by liquid
      scintillation counting. Valproate treatment reduced the synthesis of
      cyclooxygenase and lipoxygenase products in rat platelets. In brain microvessels
      valproate stimulated the synthesis of lipoxygenase metabolites and attenuated the
      cyclooxygenase pathway. Modifications of the arachidonate cascade in platelets
      and brain microvessels may contribute to the cell function alterations caused by
      valproate.

PMID- 10650162
TI  - Effects of inhibitors for tyrosine kinase and non-selective cation channel on
      capacitative Ca(2+) entry in rat ileal smooth muscle.
AB  - The effects of tyrosine kinase inhibitors and non-selective cation channel
      blockers on capacitative Ca(2+) entry were examined in the presence of
      methoxyverapamil in rat ileal smooth muscles. In Ca(2+)-free solution, carbachol
      or caffeine produced a rapid contraction mediated by Ca(2+) release from the
      stores (Ca(2+)-release response), and then led to Ca(2+) depletion of the stores.
      Subsequently, reintroduction of Ca(2+) caused a transient contraction due to
      capacitative Ca(2+) entry. Tyrosine kinase inhibitors, genistein and tyrphostin
      47 but not herbimycin A, suppressed the responses to Ca(2+)-reintroduction much
      greater than Ca(2+)-release responses to carbachol or caffeine. Similar
      inhibitory effects on the responses to Ca(2+)-reintroduction were obtained with
      daidzein and tyrphostin A1, respective inactive analogue of genistein and
      tyrphostins. After continuous depletion of the stores with thapsigargin, Ca(2+)
      reintroduction produced a sustained contraction, which was inhibited by these
      agents to different extents, but not by herbimycin A. In beta-escin-treated
      skinned muscles, genistein slightly reduced Ca(2+)-induced contraction. In fura-2
      loaded tissues, SK&F 96365 inhibited contractile and [Ca(2+)](i) responses to
      Ca(2+)-reintroduction but minimally affected Ca(2+)-release responses.
      Tetrandrine suppressed both responses to Ca(2+)-reintroduction and to Ca(2+)
      release. These results suggest that genistein and tyrphostin 47 inhibit
      capacitative Ca(2+) entry through an inhibition of Ca(2+) entry channels rather
      than tyrosine kinase. SK&F 96365, but not tetrandrine, seems to selectively
      inhibit the contractile responses to capacitative Ca(2+) entry in rat ileal
      smooth muscles.

PMID- 10650163
TI  - Choleretic activity of phloracetophenone in rats: structure-function studies
      using acetophenone analogues.
AB  - The relationship between the chemical structure and choleretic activity of
      phloracetophenone (2,4,6-trihydroxyacetophenone) was investigated in adult male
      rats. Fourteen acetophenone analogues, with different substituents on the benzene
      nucleus, were intraduodenally administered and bile samples were collected via a
      bile fistula. All of the compounds tested immediately induced choleresis. For the
      same number of substituents on the benzene ring, hydroxy analogues induced a
      greater choleresis. The number and position of hydroxy substituents on the
      benzene nucleus play an important role in determining choleretic activity and
      biliary secretion of bile acid, but had no relation to biliary excretion of
      cholesterol. The choleretic activity of the hydroxylated compounds was inversely
      related to hydrophobicity, as inferred by thin-layer chromatography (TLC). Among
      the hydroxylated acetophenone analogues, 2,4,6-trihydroxyacetophenone was
      identified as the most potent, with a choleretic activity of 231.8+/-6.1
      microl/mmol/min. It induced both a high bile flow rate and a high bile salt
      output and led to lower plasma cholesterol levels. This bile had a low lithogenic
      potential. The results suggest that a structural requirement for high choleretic
      activity of 2,4,6-trihydroxyacetophenone is a substituent hydroxy group at 4
      position. Additional hydroxy groups at 2- and 6-positions are essential for the
      induction of higher an output of bile acid, and possibly, other solid materials.

PMID- 10650164
TI  - The protective effect of glycyrrhizin on anti-Fas antibody-induced hepatitis in
      mice.
AB  - Fas ligand, which is a type II membrane protein, is a major inducer of apoptosis.
      The effect of glycyrrhizin on anti-Fas antibody-induced hepatitis in mice was
      studied. Pretreatment of mice with glycyrrhizin (100, 200 and 400 mg/kg, i.p.)
      inhibited the anti-Fas antibody (150 microg/kg, i.v.)-induced elevation of plasma
      aminotransferase activity in a dose-dependent manner. CPP32 is a cystein protease
      and CPP32-like activity induced by anti-Fas antibody injection was inhibited by
      glycyrrhizin (200 mg/kg). However, the addition of glycyrrhizin (up to 10(-4) M)
      to a liver cytosol fraction isolated from mice treated with anti-Fas antibodies
      (150 microg/kg, i.v.) did not inhibit the CPP32-like activity in vitro. The
      present results clearly show that glycyrrhizin inhibited anti-Fas antibody
      induced hepatitis by acting upstream of CPP32-like protease activation.

PMID- 10650165
TI  - The mechanism of action of amtolmetin guacyl, a new gastroprotective nonsteroidal
      anti-inflammatory drug.
AB  - Amtolmetin guacyl (2-methoxyphenyl-1-methyl-5-p-methylbenzoyl-pyrrol-2-acetamido
      acetate) (MED15) is a new nonsteroidal anti-inflammatory drug (NSAID) with anti
      inflammatory, analgesic and antipyretic properties similar to the traditional
      drugs, but with unexpected gastroprotective effects. In an in vivo rat model,
      amtolmetin guacyl administered orally demonstrates inhibition of gastric acid
      secretion following stimulation by various agonists, and up-regulation of gastric
      bicarbonate production. Pretreatment with MED15 also shows a significant
      reduction of indomethacin-induced gastric damage in the rat. The reason behind
      this behaviour appears to be bound to the presence in the MED15 molecule of a
      vanillic moiety known to stimulate capsaicin receptors. In fact, the
      antisecretive effect of MED15 is blocked by capsazepine (a specific capsaicin
      receptor antagonist). This effect is confirmed by the interference found with
      anti-histamine H(1) drugs. Owing to the connection between capsaicin and
      calcitonin gene-related peptide (CGRP), a possible effect of MED15 on CGRP
      receptors was hypothesized, considering the leading role played on gastric mucosa
      by the predominant sensory neuropeptide of the stomach wall, CGRP. In fact, the
      anti-secretive and gastroprotective effect of MED15 is abolished by CGRP-(8-37)
      (the specific CGRP receptor antagonist). The unmodified MED15 molecule is found
      throughout the gastroenteric tract for long periods of time following oral
      administration, as further confirmation of the mechanism of action being based on
      the presence of the vanillic moiety at receptor level.

PMID- 10650166
TI  - Neuropeptide-Y exerts antidepressant-like effects in the forced swim test in
      rats.
AB  - The effects of neuropeptide-Y were examined in the forced swim model of
      depression in rats. Following a 15-min preswim, four groups of rats were given
      three intracerebroventricular (i.c.v.) injections of neuropeptide-Y (0.5, 5, or
      10 microg) or saline over a 24-h period. Several behaviors were subsequently
      measured during a 5-min forced swim. Neuropeptide-Y treatment dose dependently
      increased swimming and decreased immobility. The pattern of results is consistent
      with that produced by serotonergic antidepressant drugs in this model.

PMID- 10650167
TI  - Differential down-regulation of the human delta-opioid receptor by SNC80 and [D
      Pen(2),D-Pen(5)]enkephalin.
AB  - We examined the contribution of the human delta-opioid receptor carboxyl terminal
      tail to (+)-4-[(alphaR)-alpha-((2S,5R)-4-allyl-2, 5-dimethyl-1-piperazinyl)-3
      methoxybenzyl]-N,N-diethylbenzamide (SNC80)- and cyclic[D-Pen(2),D
      Pen(5)]enkephalin (DPDPE)-mediated receptor down-regulation. Both SNC80 and DPDPE
      mediated down-regulation of an epitope tagged human delta-opioid receptor.
      Truncation of the human delta-opioid receptor after Gly(338) blocked DPDPE
      mediated down-regulation. However, SNC80 mediated significant down-regulation of
      the truncated receptor. These findings suggest that SNC80-mediated down
      regulation involves receptor domains in addition to the carboxyl terminal tail.

PMID- 10650168
TI  - Lethal seizures predicted after aminophylline therapy in cocaine abusers.
AB  - Mice with a history of chronic (10 days), but not acute, treatment with a non
      convulsant dose of cocaine showed increased sensitivity (P<0.001) to the toxic
      effects of aminophylline (seizures, lethality) relative to controls even days
      after the cessation of cocaine treatment. The present finding suggests that
      individuals with a history of cocaine use may be at increased risk for convulsive
      and lethal complications associated with the therapeutic use of aminophylline.

PMID- 10650169
TI  - Antagonism by the suramin analogue NF279 on human P2X(1) and P2X(7) receptors.
AB  - The effect of the suramin analogue 8,8'-(carbonylbis(imino-4, 1
      phenylenecarbonylimino-4,1-phenylenecarbonylimino))bis(1,3 , 5
      naphthalenetrisulfonic acid) (NF279) was analyzed on human P2X(1) and P2X(7)
      receptor subtypes (human P2X(1) and human P2X(7)) heterologously expressed in
      Xenopus oocytes using the two-microelectrode voltage-clamp technique. At
      activating ATP concentrations of 1 microM (human P2X(1)) and 10 microM ATP (human
      P2X(7)), IC(50) values of 0.05 microM and 2.8 microM were found for human P2X(1)
      and human P2X(7) receptors, respectively. An increase in the activating [ATP]
      shifted the NF279 concentration-inhibition curve rightwards for both receptors.
      NF279 slowed the activation of both human P2X(1) and human P2X(7) as well as the
      desensitization of human P2X(1). The data support a model in which
      desensitization of P2X(1) is dependent on preceding activation of these P2X
      receptors. It is concluded that NF279 acts as a competitive antagonist with much
      higher potency at human P2X(1) than at P2X(7) receptors. NF279 may hence be
      suited to discriminate between both receptors in native tissues.

PMID- 10650170
TI  - Gene expression, localization, and pharmacological characterization of endothelin
      receptors in diabetic rat bladder dome.
AB  - As there are significant amounts of functional endothelin receptors in the
      mammalian urinary tract, we examined the effect of experimental diabetes on the
      expression of endothelin receptors and their mRNAs in the rat bladder dome. The
      density of endothelin receptors in the rat bladder dome was higher (8 and 16
      weeks following the onset of diabetes) than in age-matched controls. Insulin
      treatment, started 8 weeks after the induction of diabetes, partially reversed
      the endothelin receptor alterations. The pharmacological profile of the
      endothelin receptors in the bladder dome was similar in all groups and was
      consistent with the predominance of the endothelin ET(A) receptor subtype
      (ET(A):ET(B)=approximately 4:1). Autoradiographic studies demonstrated that the
      endothelin receptors were located in all tissue components of the bladder,
      including epithelial and muscular layers. Semiquantitative reverse transcription
      polymerase chain reaction (RT-PCR) data indicated that diabetes increased the
      expression level of gene transcripts for both endothelin receptor subtypes and
      that insulin treatment reversed the mRNA upregulation.

PMID- 10650171
TI  - Characterisation of a 5-HT(7) binding site in mouse ileum.
AB  - The aim of the present study was to identify 5-hydroxytryptamine(7) (5-HT(7))
      binding sites in the mouse ileum, where the presence of mRNA for the receptor has
      been reported. Studies were performed using [3H]mesulergine, an antagonist with
      high affinity at 5-HT(7) receptors. In the presence of a combination of masking
      drugs to inhibit the binding of the radioligand to other receptors at which it
      has affinity, such as 5-HT(2A), 5-HT(2C) and dopamine D(2) receptors as well as
      alpha(1)/alpha(2)-adrenoceptors, [3H]mesulergine labelled two sites with pK(D)
      values of 9.7+/-0.7 and 7.4+/-0.4 and B(max) values of 37.2+/-21.4 and 247.8+/
      62.1 fmol mg protein(-1), respectively. Displacement studies also indicated the
      presence of non-homogenous binding sites, which showed a significant correlation
      (Pearson correlation factors of 0.91 and 0. 85) with the 5-HT(2C) and 5-HT(7)
      receptors, respectively. Total binding to the 5-HT(2C) receptor was minimal; <30%
      of the total specific receptor binding. The antagonist order of affinity at the
      greater proportion of receptors was: risperidone (pK(i)pindolol (5. 6). This
      receptor also showed a high affinity for 5-carboxamidotryptamine (5-CT; 10.6) and
      moderate affinity for (+/-)-2-dipropyl-amino-8-hydroxy-1,2,3,4,
      tetrahydronaphthalene (8-OH-DPAT; 7.2), which is typical of the 5-HT(7) receptor
      profile.

PMID- 10650172
TI  - Inhibition by antisense oligonucleotides of plasma membrane Ca(2+) ATPase in
      vascular endothelial cells.
AB  - Antisense oligodeoxynucleotides were used to knock down plasma membrane Ca(2+)
      ATPase, and the role of plasma membrane Ca(2+) ATPase was investigated in human
      aortic endothelial (HAE) cells. The peak of thapsigargin-evoked intracellular
      Ca(2+) concentration ([Ca(2+)](i)) was higher in antisense-treated than in
      untreated cells, but the declining time course was unaffected by the antisense
      treatment. The declining time was prolonged in both antisense-treated and
      untreated cells by reducing external Na(+), but the prolongation was more marked
      in the antisense-treated cells. These results provide the evidence of a
      functional role of plasma membrane Ca(2+) ATPase, although other mechanisms
      including Na(+)/Ca(2+) exchange may play the primary role in regulating
      [Ca(2+)](i).

PMID- 10650173
TI  - The role of afferents to the locus coeruleus in the handling stress-induced
      increase in the release of noradrenaline in the medial prefrontal cortex: a dual
      probe microdialysis study in the rat brain.
AB  - This study was aimed to identify the neuronal pathways that mediate the handling
      stress-induced increase in the release of noradrenaline in the medial prefrontal
      cortex of the rat brain. For that purpose a microdialysis probe was implanted in
      the vicinity of the locus coeruleus and a second probe was placed in the
      ipsilateral medial prefrontal cortex. Receptor specific antagonists acting on the
      alpha(2)-adrenoceptor (50 microM idazoxan), GABA(A) (50 microM bicuculline),
      GABA(B) (100 microM (3, 4-Dichlorophenyl)methyl]propyl](diethoxymethyl)
      phosphonic acid; CGP 52432), acetylcholine (10 microM atropine), corticotropin
      releasing factor (CRF) (100 microM butyl-ethyl-[2,5-dimethyl-7-(2,4, 6-trimethyl
      phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine; CP-154, 526), NMDA glutamate (300
      microM (+/-)-3(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid; CPP) and non
      NMDA glutamate receptors (500 microM 6,7-dinitroquinoxaline-2, 3-dione; DNQX)
      were infused into the locus coeruleus by retrograde dialysis, whereas
      extracellular noradrenaline was recorded in the ipsilateral medial prefrontal
      cortex. During infusion of the various compounds rats were gently handled for 10
      min. Infusion of idazoxan potentiates the handling-induced increase in the
      release of noradrenaline in the medial prefrontal cortex. The infusions of,
      atropine, bicuculline, CGP 52432 and DNQX were without effect on the handling
      response. Infusion of the NMDA receptor antagonist CPP or the non-peptide CRF
      receptor antagonist CP-154,526 suppressed the stimulation of noradrenaline during
      stress. It is concluded that alpha(2)-adrenoceptors, NMDA glutamate receptors and
      CRF receptors modify the handling stress response of locus coeruleus neurones.
      The data suggest no major role for glutamatergic, GABAergic, or cholinergic
      afferents to the locus coeruleus in mediating the stress response.

PMID- 10650174
TI  - Sympathoinhibition by adenosine A(1) receptors, but not P2 receptors, in the
      hamster mesenteric arterial bed.
AB  - The aim of the present study was to determine whether there are prejunctional
      inhibitory P2 purine receptors on sympathetic nerves in the hamster isolated
      perfused mesenteric arterial bed. Adenosine 5'-O-(3-thiotriphosphate (ATPgammaS;
      10 microM), adenosine 5'-O-(2-thiodiphosphate) (ADPbetaS; 100 microM) and AMP (10
      microM) had no significant effect on neurogenic contractions to electrical field
      stimulation. In contrast, P1 receptor agonists attenuated sympathetic
      vasoconstriction with a potency order of N(6)5'-(Nadenosine. The pEC(50) value
      for CPA was 7.5+/-0.1 (n=7). The concentration-inhibitory effect curve to CPA was
      shifted to the right by the adenosine A(1) receptor antagonist, 8-cyclopentyl-1,
      3-dipropyl-xanthine (DPCPX; 10 nM; apparent pK(B) 9.6; n=6-7). In methoxamine
      raised-tone mesenteries CPA (0.001-10 microM) did not elicit vasorelaxation, and
      NECA and adenosine were only weak vasorelaxants. These results indicate that
      adenosine A(1) receptors, but not P2 receptors, inhibit prejunctionally
      sympathetic neurotransmission in the hamster mesenteric arterial bed.

PMID- 10650175
TI  - Thromboxane A(2) modulates cyclic AMP relaxation and production in human internal
      mammary artery.
AB  - Two forms of thromboxane A(2) (TP) receptors, TPalpha and TPbeta receptors, have
      recently been cloned. These receptors regulate adenylate cyclase activity in two
      opposite ways: TPalpha receptors activate, whereas TPbeta receptors inhibit
      adenylate cyclase and cAMP generation. The aim of this study was to examine the
      effects of the thromboxane A(2) analogue, U46619 (9,11-dideoxy-9alpha,11 alpha
      methanoepoxy-prostaglandin F(2alpha)), on forskolin-induced relaxation and cAMP
      accumulation in human internal mammary artery (IMA) and saphenous vein (SV). In
      organ baths, IMA rings precontracted with U46619 (3.10(-9) and 3.10(-8) M) were
      less sensitive to forskolin than rings precontracted with methoxamine (3. 10(-6)
      M). In contrast, the sensitivity to forskolin was similar in SV rings contracted
      with the same concentrations of these agonists. U46619 reduced significantly the
      ten-fold increase in cAMP induced by forskolin in IMA but not in SV rings.
      Sensitivity and maximal relaxation in response to sodium nitroprusside were not
      altered in either IMA or SV. In summary, stimulation of TP receptors with the
      thromboxane A(2) analogue, U46619, inhibited the cAMP pathway of relaxation
      through the inhibition of cAMP synthesis in human IMA but not in SV. It is
      suggested that thromboxane A(2) may play a role in the control of muscle tone in
      IMA both by its potent contractile effect and by its inhibitory effect on the
      cAMP pathway of relaxation.

PMID- 10650176
TI  - Vascular reactivity to nifedipine and Ca(2+) in vitro: the role of preactivation,
      wall tension and geometry.
AB  - The purpose of the study was to investigate the influence of preactivation, wall
      tension and geometry on the reactivity of porcine coronary arteries to nifedipine
      and extracellular Ca(2+) in vitro. Porcine large coronary arteries were mounted
      as ring and cylindrical preparations and studied by wire- and balloon-based
      techniques. The sensitivity and maximal responses to nifedipine were more
      pronounced in 25 mM K(+) compared to 10 microM prostaglandin F(2alpha)-contracted
      preparations. Vascular sensitivity to nifedipine and Ca(2+) was enhanced under
      isometric compared to isobaric conditions. Under isometric conditions in the
      presence of 25 mM K(+), coronary rings were more sensitive to nifedipine, but
      less sensitive to Ca(2+) compared to cylindrical segments. In cylindrical
      segments, circumferential and axial tension increases augmented the extracellular
      Ca(2+)-dependent spontaneous resting tone and the sensitivity to extracellular
      Ca(2+). Coronary rings showed no resting tone at various resting tensions. These
      results suggest that preactivation, wall tension and vessel geometry are
      important determinants of Ca(2+)-influxes via nifedipine-sensitive voltage-gated
      Ca(2+) channels. Furthermore, axial wall tension appears to be a modulator of
      nifedipine-insensitive transmembrane Ca(2+)-influx that may play a role for the
      tone and reactivity in large coronary arteries.

PMID- 10650177
TI  - Increases of vascular endothelin-converting enzyme activity and endothelin-1
      level on atherosclerotic lesions in hyperlipidemic rabbits.
AB  - The aim of this study was to investigate vascular endothelin-converting enzyme
      activity and the tissue level of endothelin-1 in the aorta related to
      atherosclerotic lesions in high cholesterol diet-fed rabbits. Rabbits were fed
      two atherogenic diets, 0.5% and 1.5% cholesterol, and a normal diet for 16 weeks.
      Vascular endothelin-converting enzyme activity in the aortic arch and thoracic
      aorta was significantly increased (2.0-4.4 times) by the atherogenic diet as
      compared with the normal diet group as well as the levels of lipids and lipid
      peroxide in plasma were significantly increased. Tissue endothelin-1 levels in
      both aortas were also elevated (2.3-6.8 times), corresponding well to the
      increased tissue enzyme activity. In contrast, plasma endothelin-1 levels
      increased only in the 1.5% cholesterol diet group (2.7 times). These results
      indicate that the endothelin-converting enzyme activity and the corresponding
      endothelin-1 level in the vascular walls increase in association with the
      development of atherosclerotic lesions.

PMID- 10650178
TI  - The effect of experimental diabetes on cholinergic neurotransmission in rat
      trachea: role of nitric oxide.
AB  - We investigated the effect of nitric oxide (NO) on the responses of isolated
      tracheas to acetylcholine and to electrical field stimulation in streptozotocin
      diabetic and controls rats. The contractile responses to acetylcholine were
      neither different nor affected by the NO synthase blocker, N(omega)-nitro-L
      arginine methyl ester (L-NAME), in the two groups. Diabetic rat tracheas were
      supersensitive to field stimulation. L-NAME enhanced field stimulation-induced
      contractions at low frequencies in control rat tracheas, but had no effect in
      diabetic rat tracheas. After L-NAME treatment, there was no difference in
      sensitivity to field stimulation between the groups. The relaxation responses to
      sodium nitroprusside in acetylcholine-precontracted tracheas were not different
      between the groups. However, diabetic rat trachea was supersensitive to the
      relaxant effect of sodium nitroprusside on contractile responses to field
      stimulation. These results suggested that the increase in sensitivity to field
      stimulation in tracheas from diabetic rats might be due to impairment in the
      production and/or release of an endogenous NO-like factor.

PMID- 10650179
TI  - Relaxation of rabbit lower urinary tract smooth muscle by nitric oxide and carbon
      monoxide: modulation by hydrogen peroxide.
AB  - Recent studies suggest that the body produces two gaseous messengers, nitric
      oxide (NO) and carbon monoxide (CO), both of which activate soluble guanylyl
      cyclase and thus modulate the activity of smooth muscle cells. In the present
      study, the effects of NO and CO on the smooth muscle of the lower urinary tract
      were compared. In addition, the modulation of tissue NO- and CO-induced
      relaxation by hydrogen peroxide was examined. NO, produced endogenously by
      electrical field stimulation (EFS) or applied exogenously as a solution, induced
      a concentration-dependent relaxation of rabbit cavernosal and urethral smooth
      muscle strips, but not of bladder tissues. The cavernosal tissue was found to be
      three times more sensitive to the actions of NO than the urethra. CO also induced
      relaxation of both tissue types, but with no apparent difference in sensitivity
      between the tissues. However, CO was much less potent than NO with respect to
      smooth muscle relaxation. The mechanism of action of the two mediators was cyclic
      guanosine monophosphate (cGMP)-dependent, as evidenced by enhanced formation of
      cGMP and inhibition of relaxation by the guanylyl cyclase inhibitor,
      oxadiazoloquinoxaline-1-one (ODQ.) The data suggests that NO is the dominant
      messenger in these tissues, but does not exclude a role for CO. In the presence
      of hydrogen peroxide, the relaxation responses induced by both NO and CO were
      significantly increased, regardless of tissue type. The mechanism for this effect
      is unclear, but evidence points to a requirement for the activation of guanylyl
      cyclase and enhanced formation of cGMP, since potentiation by the peroxide was
      blocked by a specific guanylyl cyclase inhibitor. We suggest that H(2)O(2) may
      play a positive role in the amplification or NO and CO-mediated responses.

PMID- 10650180
TI  - Enhancement by escins Ib and IIb of Mg(2+) absorption from digestive tract in
      mice: role of nitric oxide.
AB  - The effects of escins Ib and IIb isolated from horse chestnuts on Mg(2+)
      absorption from the digestive tract and the role of endogenous nitric oxide (NO)
      were investigated in mice. Test samples were given orally to fasted mice 30, 120,
      180, 240 and 300 min before administration of 0.5 M MgSO(4) (10 ml/kg, p.o.). The
      serum Mg(2+) levels were determined 30, 60, 120 and 180 min after administration
      of MgSO(4). Escins Ib and IIb (12.5 and 25 mg/kg) significantly increased the
      serum Mg(2+) by 10.0-27.3%, 30, 120 and 180 min after administration of the
      samples, and 30, 60, 120 and 180 min after administration of MgSO(4). Escins Ib
      and IIb (12.5 mg/kg) significantly decreased the Mg(2+) content in the small
      intestinal fluid in MgSO(4)-loaded mice, but did not increase the serum Mg(2+)
      levels in normal mice. The effects of escins Ib and IIb (12.5 mg/kg) on serum
      Mg(2+) levels were attenuated in a dose-related manner by the pretreatment with
      N(G)-nitro-L-arginine methyl ester (L-NAME, 3-20 mg/kg, i.p., an inhibitor of
      constitutive and inducible NO synthase), but not with D-NAME (10 mg/kg, i.p., the
      inactive enantiomer of L-NAME) or dexamethasone (0.05 and 0.5 mg/kg, s.c., an
      inhibitor of inducible NO synthase). The effect of L-NAME was reversed by L
      arginine (600 mg/kg, i.p., a substrate of NO synthase), but not by D-arginine
      (900 mg/kg, i.p., the enantiomer of L-arginine). These results suggest that
      escins Ib and IIb enhance Mg(2+) absorption from the digestive tract in mice, in
      which the constitutive, but not the inducible, NO synthase plays an important
      role.

PMID- 10650182
TI  - Corrigendum to: cerebroprotective properties of SM-20220, a potent Na(+)/H(+)
      exchange inhibitor, in transient cerebral ischemia in rats

PMID- 10650181
TI  - Relative involvement of cannabinoid CB(1) and CB(2) receptors in the Delta(9)
      tetrahydrocannabinol-induced inhibition of natural killer activity.
AB  - We demonstrated that in vivo administration of Delta(9)-tetrahydrocannabinol in
      mice (15 mg/kg s.c.) significantly inhibited natural killer cell (NK) cytolytic
      activity without affecting Concanavalin A (ConA)-induced splenocyte
      proliferation. Moreover, we investigated the effect of in vivo pretreatment with
      cannabinoid receptor antagonists, namely, the selective cannabinoid CB(1)
      receptor antagonist SR 141716 [N-piperidin-5-(4-chlorophenyl)-1-(2, 4
      dichlorophenyl)-4-methyl-3-pyrazolecarboxamide] and the selective cannabinoid
      CB(2) receptor antagonist SR 144528 ?N-[(1S)-endo-1,3, 3-trimethyl bicyclo
      [2.2.1] heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazo le- 3
      carboxamide?, on Delta(9)-tetrahydrocannabinol-induced inhibition of NK cytolytic
      activity. Both antagonists partially reversed the Delta(9)-tetrahydrocannabinol
      inhibition of NK cytolytic activity, although the cannabinoid CB(1) receptor
      antagonist was more effective than the cannabinoid CB(2) receptor antagonist. The
      parallel measurement of interferon gamma and interleukin 2 levels revealed that
      Delta(9)-tetrahydrocannabinol significantly reduced (about 70%) the former
      cytokine without affecting the latter. Cannabinoid CB(1) and CB(2) receptor
      antagonists completely reversed the interferon gamma reduction induced by
      Delta(9)-tetrahydrocannabinol. Our results indicate that both types of
      cannabinoid receptors are involved in the complex network mediating NK cytolytic
      activity.

PMID- 10650183
TI  - A potent and highly selective nonpeptidyl nociceptin/orphanin FQ receptor (ORL1)
      antagonist: J-113397.
AB  - We discovered a potent nociceptin/orphanin FQ receptor (ORL1) receptor
      antagonist, J-113397 (1-[(3R, 4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]
      3-ethyl-1, 3-dihydro-2H-benzimidazol-2-one). J-113397 inhibited
      [125I][Tyr(14)]nociceptin binding to Chinese hamster ovary (CHO) cells expressing
      ORL1 receptor in a dose-dependent manner (IC(50); 2. 3 nM), but showed 600-fold
      or less affinity for mu-, delta- and kappa-opioid receptors. Nociceptin/orphanin
      FQ-induced suppression of cyclic AMP accumulation elicited by forskolin was
      completely inhibited by J-113397 with an IC(50) value of 26 nM. These results
      indicate that J-113397 is a potent and selective nonpeptidyl antagonist of the
      ORL1 receptor.

PMID- 10650184
TI  - The novel pyridoxal-5'-phosphate derivative PPNDS potently antagonizes activation
      of P2X(1) receptors.
AB  - Pyridoxal-5'-phosphate-6-(2'-naphthylazo-6'-nitro-4',8'-disulfonat e) (PPNDS)
      potently antagonized P2X(1) receptor-mediated responses in rat vas deferens
      (pK(B)=7.43) and Xenopus laevis oocytes (pIC(50)=7. 84). It showed lower (up to
      20,000-fold) inhibitory potency on ecto-nucleotidase in Xenopus oocytes and on
      P2Y(1) receptors in guinea-pig ileum (pA(2)=6.13). PPNDS did not interact with
      alpha(1A)-adrenoceptors, adenosine A(1) and A(2B), histamine H(1) and muscarinic
      M(3) receptors. Thus, PPNDS is a novel, specific P2 receptor antagonist and
      represents the pyridoxal-5'-phosphate derivative with the highest potency at
      P2X(1) receptors.

PMID- 10650185
TI  - Differential changes in accumbens shell and core dopamine in behavioral
      sensitization to nicotine.
AB  - Repeated treatment with nicotine has been shown to sensitize rats to its
      locomotor stimulant effects and to its properties to stimulate mesolimbic
      dopamine transmission. We investigated the relationship between sensitization of
      nicotine induced locomotor stimulation and activation of dopamine transmission in
      the nucleus accumbens shell and core. Rats were administered daily for 5 days
      with 0.4 mg/kg s.c. of nicotine or with saline and 24 h later, dopamine was
      monitored by microdialysis in the shell and in the core of nucleus accumbens and
      behavioral activity was scored after challenge with nicotine (0. 4 mg/kg s.c.).
      Behavioral sensitization to nicotine was associated with a reduced response of
      dopamine transmission in the shell and with an increased one in the core of
      nucleus accumbens.

PMID- 10650186
TI  - Performance of air sparging systems: a review of case studies.
AB  - Fluor Daniel GTI (now IT Corporation) has compiled a database of 49 completed in
      situ air sparging case studies. Air sparging is a commonly used remediation
      technology which volatilizes and enhances aerobic biodegradation of contamination
      in groundwater and saturated zone soil. The air sparging database was compiled to
      address questions regarding the effectiveness and permanence of air sparging, and
      to provide predictive indicators of air sparging success to aid in optimization
      of existing and future air sparging systems. In each case study, groundwater
      concentrations were compared before sparging was initiated, just before sparging
      was terminated, and in the months following shutdown of the sparging system. The
      case studies included both chlorinated solvents and petroleum hydrocarbon
      contamination, and covered a wide range of soil conditions and sparge system
      parameters. In many cases, air sparging achieved a substantial and permanent
      decrease in groundwater concentrations. Successful systems were achieved with
      both chlorinated and petroleum contamination, both sandy and silty soils, and
      both continuous and pulsed flow sparging. In other cases, however, a significant
      rebound of groundwater concentrations was observed after sparging was terminated.
      Rebound sometimes required 6 to 12 months to develop fully. Rebound was more
      frequently observed at sites contaminated with petroleum hydrocarbons than with
      chlorinated solvents. Petroleum-contaminated sites were more likely to rebound
      when initial groundwater contamination levels were high enough to suggest the
      presence of LNAPL or a smear zone of residual LNAPL. Rebound at petroleum sites
      appeared to be minimized by a high density of sparge wells addressing the entire
      source area and a high sparge air injection rate. In some cases, rebound appeared
      to be related to a rising water table.

PMID- 10650187
TI  - Site 5 air sparging pilot test, Naval Air Station Cecil Field, Jacksonville,
      Florida.
AB  - A 72-h air sparging pilot test was conducted at Site 5 (Operable Unit 2), Naval
      Air Station Cecil Field, Jacksonville, FL, to determine performance parameters
      necessary for full-scale design. The sparge well was completed to a depth of 29
      ft, several feet below the groundwater plume contaminated with volatile organic
      compounds (VOCs), primarily benzene, toluene, ethylbenzene, and xylenes (BTEX).
      Air flow rates supplied to the sparge well were 3 cubic feet/min (cfm) during the
      first day, 2 cfm during the second day, and 1 cfm during the third day. Water
      levels in monitoring wells initially rose approximately 2 ft during the first 4-5
      h of the test, then receded back to pre-test equilibrium levels over the next 15
      h, for a total duration of water mounding of about 20 h. A small (approximately
      0.5 ft) water table drop, with subsequent recovery to equilibrium level, occurred
      each time the air sparging rate was decreased. Although there is considerable
      variation depending on direction from the sparge well, the average radius of
      influence varied from approximately 30 ft at 1 cfm to 50 ft at 3 cfm. The air
      sparge system was capable of increasing the dissolved oxygen from 0 to 6 or 7
      mg/l within 12-15 h of air channels reaching a given location. A lag time of
      approximately 13 h was observed before air channels reached a radius of 30 ft and
      dissolved oxygen levels began to increase at that radius. CO(2) (stripped out of
      the groundwater by the sparging) decreased from a pre-test concentration of 150
      to 20 mg/l at r=5 ft, and from 150 to 50 mg/l at r=30 ft, within a period of
      about 24 h. The rate of VOC mass removal during the pilot test was 0.06 lb/day at
      a sparge rate of 3 cfm, and it appears that air sparging will effect a rapid
      cleanup of the VOCs in the Site 5 groundwater plume.

PMID- 10650188
TI  - Effect of groundwater flow on remediation of dissolved-phase VOC contamination
      using air sparging.
AB  - This paper presents two-dimensional laboratory experiments performed to study how
      groundwater flow may affect the injected air zone of influence and remedial
      performance, and how injected air may alter subsurface groundwater flow and
      contaminant migration during in situ air sparging. Tests were performed by
      subjecting uniform sand profiles contaminated with dissolved-phase benzene to a
      hydraulic gradient and two different air flow rates. The results of the tests
      were compared to a test subjected to a similar air flow rate but a static
      groundwater condition. The test results revealed that the size and shape of the
      zone of influence were negligibly affected by groundwater flow, and as a result,
      similar rates of contaminant removal were realized within the zone of influence
      with and without groundwater flow. The air flow, however, reduced the hydraulic
      conductivity within the zone of influence, reducing groundwater flow and
      subsequent downgradient contaminant migration. The use of a higher air flow rate
      further reduced the hydraulic conductivity and decreased groundwater flow and
      contaminant migration. Overall, this study demonstrated that air sparging may be
      effectively implemented to intercept and treat a migrating contaminant plume.

PMID- 10650189
TI  - A laboratory simulation of toluene cleanup by air sparging of water-saturated
      sands.
AB  - Laboratory air sparging experiments were performed in narrow acrylic tanks to
      evaluate the cleanup of toluene in water-saturated sands. Air flow channels in
      the sediment were identified by way of a colorimetric visualization technique,
      which allowed pore water samples to be collected at a known horizontal distance
      from an air channel. Pore water was sampled at periodic intervals during sparging
      experiments and analyzed by gas chromatography to yield toluene concentration vs.
      time data. Results indicate that channelized air flow is effective in reducing
      toluene concentrations in the range of 36-3 ppm, within 2 to 5 days, at least up
      to 185 mm from an active air channel. While relatively rapid, these toluene
      reduction times are longer than previously published data, from similar type
      experiments. The discrepancy is likely a function of air delivery flow rate and
      proximity of sampling sites to active air channels. Data from the current
      investigation were used to attempt an estimate of effective diffusion
      coefficients (D*) for toluene in clean, well-characterized sands in which the
      concentration gradient was imposed by sparge air. Calculated D* values range from
      2. 98x10(-8) m(2)/s to 5.74x10(-9) m(2)/s, and are significantly faster than
      previously published values of toluene diffusion in clay soils. However, the
      values are also slightly greater than diffusion coefficients for toluene in
      aqueous solutions, indicating that the calculations more likely estimate
      coefficients of hydrodynamic dispersion (D(L)).

PMID- 10650190
TI  - Centrifuge modeling of air sparging - a study of air flow through saturated
      porous media.
AB  - The success of air sparging as a remedial technology for treatment of
      contaminated aquifers is well documented. However, there is no consensus, to
      date, on the mechanisms that control the flow of injected air through the
      saturated ground. Currently, only qualitative results from laboratory experiments
      are available to predict the zone of influence of a sparging well. Given that the
      patterns of air flow through the soil will ultimately determine the efficiency of
      an air sparging treatment, it is important to quantify how sparged air travels
      through a saturated porous medium. The main objective of this research is to
      develop a model that describes air transport through saturated porous media. This
      paper presents results from an ongoing study that employs centrifuge modeling to
      reproduce in situ air sparging conditions. Centrifuge testing is an experimental
      technique that allows reduced-scale duplication, in the laboratory, of the
      stresses and pressure distributions encountered in the field. In situ conditions
      are critical in the development of actual air flow patterns. Experiments are
      being conducted in a transparent porous medium consisting of crushed borosilicate
      glass submerged in fluids of matching indices of refraction. Air is observed as
      it flows through the porous medium at varying gravitational accelerations.
      Recorded images of experiments allow the determination of flow patterns,
      breakthrough velocities, and plume shapes as a function of g-level and injection
      pressure. Results show that air flow patterns vary from fingering, at low g
      levels, to pulsing at higher accelerations. Grain and pore size distribution of
      the porous medium do not exclusively control air flow characteristics. Injector
      geometry has a definite effect on breakthrough velocities and air plume shapes.
      Experiments have been conducted to compare the velocity of air flow through the
      saturated porous medium to that of air in pure liquids. Results show that the
      velocity of air through the medium is lower than that in the pure fluid, as
      expected. At high g-levels however, plume breakthrough velocities are
      proportional to the velocity of the air in the pure fluid.

PMID- 10650191
TI  - Field and numerical analysis of in-situ air sparging: a case study.
AB  - An in-situ air sparging operation was used to remediate the sandy subsurface
      soils and shallow groundwater under a drum storage site near Chicago, IL, where
      either periodic or random spillage of a light non-aqueous phase liquid (LNAPL)
      occurred between 1980 and 1987. Both field measurements and model simulations
      using commercially available computer software suggested that microbial
      degradation was the most significant contributor to the removal of contaminant
      mass. Toluene, ethylbenzene and total xylenes (TEX), which were of major concern
      with regards to reaching clean-up criteria at the site, were observed to decline
      by 88% in concentration. Furthermore, up to 97% of the total mass removed through
      microbial degradation consisted of TEX. Of the total contaminant spill, up to 23%
      of initial organic chemical mass was removed through microbial degradation
      compared to less than 6% by physical stripping. Greater loss to microbial
      degradation is most likely attributed to the relatively low air injection rate
      used during the course of the air sparging remediation. Evaluation of air
      sparging at the site using model simulations supported this analysis by
      estimating 140 and 620 kg of total contaminant mass being removed through
      volatilization and biodegradation, respectively. An evaluation of several system
      design parameters using model simulations suggested that only the type of
      sparging operation (i.e. pulsed or continuous) was significant in terms of total
      contaminant removal time, while both the sparging operation and air injection
      rate were significant in terms of removal of a critical species, total xylenes.

PMID- 10650192
TI  - Mathematical modeling of air sparging for subsurface remediation: state of the
      art.
AB  - A review of published mathematical models used to simulate air sparging is
      provided. Applicability of the models, efforts to test the models using
      experimental data and contributions of modeling efforts to the practice of air
      sparging are also discussed. Compartmentalized lumped-parameter models and
      multiphase flow models have dominated air-sparging modeling efforts. In essence,
      each class of models requires the assumption of a continuum over some model
      domain. Each approach has significant benefits as well as some inherent
      disadvantages. Based on the literature, both lumped-parameter modeling and
      multiphase-flow modeling have been successful in improving our theoretical
      understanding of the air-sparging process and in facilitating practical
      development of sparging systems. Lumped-parameter models are simpler to use, and
      can lend considerable insight to sparging operations. Multiphase flow models have
      the potential to offer a more realistic simulation of the airflow process, but
      may require a considerable amount of data collection for model input. The
      literature suggests that for any air-sparging model to be useful for field
      applications, detailed model calibration is necessary. It is recommended that
      models incorporate, in some fashion, the diffusion and dispersion of contaminants
      to macro-scale air channels, and nonequilibrium interphase mass transfer of
      contaminants. These mass-transfer-limited processes are frequently listed as
      causes for the "tailing" of vapor-extraction effluent contaminant concentrations
      that are frequently observed during field applications. However, time-varying
      mixing of relatively clean and contaminated vapors in the extraction system may
      also explain this tailing. Geophysical imaging techniques and inverse modeling
      combined with air-sparging pilot tests and measurement of traditional
      hydrogeologic parameters may allow for successful modeling efforts.

PMID- 10650193
TI  - Air distribution during in situ air sparging: an overview of mathematical
      modeling.
AB  - The performance of in situ air sparging is controlled by the distribution of air
      pathways in the subsurface, which is in turn controlled by the structure of the
      medium to be sparged. The specific pathways that the air follows are determined,
      at the grain scale, by the distribution of air entry pressures of the pores. At
      the field scale, pore size distributions are usually correlated with
      heterogeneous structures (e.g. layers) within the medium, which control the
      macroscopic distribution of the air. The processes that produce an observed air
      distribution at a particular site are complicated, and are potentially well
      suited to modeling with multiphase flow models. Recent numerical modeling of
      heterogeneous media appears to successfully represent expected distributions of
      air; however, current models do not provide a tool to predict sparging
      performance. For this to be the case, the models need to represent the detailed
      structure of the medium at the site to be studied, as well as to capture the
      relevant aspects of the discrete air/water distribution (i.e., represent air
      channels at the centimeter or smaller scale). This will, in general, require a
      level of site data that is not available and numerical models that require many
      millions of computational elements. As a consequence, at least for the
      foreseeable future, numerical modeling of the air sparging process will continue
      to play a vital role as a conceptual tool with limited predictive capability at
      sites.

PMID- 10650194
TI  - Cellulase-free xylanases from Bacillus and other microorganisms.
AB  - Xylanases are used mainly in the pulp and paper industries for the pretreatment
      of Kraft pulp prior to bleaching to minimize use of chlorine, the conventional
      bleaching agent. This application has great potential as an environmentally safe
      method. Hydrolysis by xylanases of relocated and reprecipitated xylan on the
      surface of cellulose fibres formed during Kraft cooking facilitates the removal
      of lignin by increasing permeability to oxidising agents. Most of the xylanases
      reported in the literature contained significant cellulolytic activity, which
      make them less suitable for pulp and paper industries. The need for large
      quantities of xylanases which would be stable at higher temperatures and pH
      values and free of cellulase activity has necessitated a search for novel
      enzymes. We have isolated and characterised several xylanase-producing cultures,
      one of which (an alkalophilic Bacillus SSP-34) produced more than 100 IU ml(-1)
      of xylanase activity. The SSP-34 xylanases have optimum activity at 50 degrees C
      in a pH range 6-8, with only small amounts of cellulolytic activity (CMCase (0.4
      IU ml(-1), pH 7), FPase (0.2 IU ml(-1), pH 7) and no activity at pH 9).

PMID- 10650195
TI  - Characterization of the 5' subtilisin (aprE) regulatory region from Bacillus
      subtilis.
AB  - The aprE gene of Bacillus subtilis encodes the major serine alkaline protease
      known as subtilisin. It is expressed during the transition state and transcribed
      by the sigma(A) form of the RNA polymerase (RNAP). In this work, we characterized
      the regulatory region of the aprE gene (rraprE) from B. subtilis. By computer
      analysis and site-directed mutagenesis, we localized the aprE promoter sequence 7
      bp upstream from its transcription initiation site (TIS). We also characterized
      the static curvature properties of the rraprE DNA and found two different areas
      of DNA bending, within the first 400 bp upstream of its TIS. We postulate that
      these particular curved DNA regions could play a role in the interaction with
      some regulatory proteins and discuss possible implications related to aprE
      transcription regulation.

PMID- 10650196
TI  - Cloning, sequencing and variability analysis of the gap gene from Mycoplasma
      hominis.
AB  - The gap gene encodes the glycolytic enzyme glyceraldehyde 3-phosphate
      dehydrogenase (GAPDH). The gene was cloned and sequenced from the Mycoplasma
      hominis type strain PG21(T). The intraspecies variability was investigated by
      inspection of restriction fragment length polymorphism (RFLP) patterns after
      polymerase chain reaction (PCR) amplification of the gap gene from 15 strains and
      furthermore by sequencing of part of the gene in eight strains. The M. hominis
      gap gene was found to vary more than the Escherichia coli counterpart, but the
      variation at nucleotide level gave rise to only a few amino acid substitutions.
      To verify that the gene was expressed in M. hominis, a polyclonal antibody was
      produced and tested against whole cell protein from 15 strains. The enzyme was
      expressed in all strains investigated as a 36-kDa protein. All strains except
      type strain PG21(T) showed reaction to a 104-kDa band in addition to the expected
      36-kDa band. The protein reacting at 104 kDa is a M. hominis protein with either
      an epitope similar to one on GAPDH, or it is an immunoglobulin binding protein.

PMID- 10650197
TI  - Characterization of an Azospirillum brasilense Tn5 mutant with enhanced N(2)
      fixation: the effect of ORF280 on nifH expression.
AB  - Disruption of an open reading frame (ORF) of 840 bp (280 amino acids; ORF280) in
      an Azospirillum brasilense Tn5 mutant resulted in a pleiotrophic phenotype.
      Besides an enhanced N(2)-fixing capacity and altered expression pattern of a nifH
      gusA fusion, growth on the charged polar amino acids glutamate and arginine was
      severely affected. ORF280, similar to previously identified ORFs present in
      Bradyrhizobium japonicum (ORF277), Paracoccus denitrificans (ORF278) and
      Rhodobacter capsulatus (ORF277), exhibits in its C-terminus a significant
      similarity with the recently defined family of universal stress proteins.

PMID- 10650198
TI  - Ethyl carbamate precursor citrulline formation from arginine degradation by
      malolactic wine lactic acid bacteria.
AB  - Major commercially available strains for induction of malolactic fermentation in
      wine were examined for arginine metabolism in a resting cell system at wine pH
      with the aim of evaluating their ability to excrete and utilize citrulline, a
      precursor of carcinogenic ethyl carbamate (urethane). All strains tested excreted
      citrulline from arginine degradation. Citrulline was stored intracellularly
      during growth in arginine rich medium and was released upon lysis of the cells.
      All strains were found to degrade citrulline as a sole amino acid and some of
      them were able to reutilize previously excreted citrulline.

PMID- 10650199
TI  - Transcriptional analysis of a superoxide dismutase gene of Borrelia burgdorferi.
AB  - A single superoxide dismutase (Sod) gene was identified in Borrelia burgdorferi
      strains, Borrelia afzelii Ple and Borrelia garinii Pbi. Recombinant enzymatic
      activity was detected only when sod expression was controlled by the lacZ
      promoter in the cloning vector. Northern blot analysis with sod- or secA-specific
      probes identified a common 3.7-kb transcript. Reverse transcriptase-PCR analysis
      confirmed that secA and sod constitute a single transcriptional unit in B.
      burgdorferi. A transcriptional start site of this operon, containing -10 and -35
      regions of a sigma(70)-type promoter, was mapped to 100 bp upstream of the ATG
      start codon of secA.

PMID- 10650200
TI  - Rapid identification and quantification of Collinsella aerofaciens using PCR.
AB  - The number and incidence of Collinsella aerofaciens in the human intestine are
      the highest among Gram-positive non-spore-forming bacilli. Identification of this
      species is very difficult and requires considerable time. A PCR-based
      identification system using C. aerofaciens-specific primers is described. Using
      this PCR method, we identified 181 C. aerofaciens-like species isolated from
      human feces. These 181 strains were identified using the traditional method in
      past studies. Results of both methods matched. The direct detection method was
      performed using human feces samples from seven adults. Nested PCR was applied
      directly to the samples and all seven samples were positive. Quantification
      studies were performed using LightCycler?trade mark omitted?. The assay uses a
      double-stranded DNA dye to continuously monitor product formation and in a short
      time is able to quantify samples to 5 log units in concentration.

PMID- 10650201
TI  - Association of iron-regulated outer membrane proteins of Neisseria meningitidis
      with the RmpM (class 4) protein.
AB  - The RmpM (class 4) protein of Neisseria meningitidis has previously been shown to
      be associated with the outer membrane porins. In the present study, we
      demonstrate that this protein forms complexes with the lactoferrin receptor LbpA,
      the transferrin receptor TbpA and the siderophore receptor FrpB as well. This
      complexation apparently resulted in a stabilization of oligomeric forms of these
      iron-regulated proteins. In vitro experiments further revealed a reduced ability
      to acquire iron from human lactoferrin in the rmpM mutant. Furthermore, all TonB
      dependent receptors investigated here appeared to exist as oligomers (probably
      dimers), suggesting that this is a general feature of this class of proteins.

PMID- 10650202
TI  - Gene cloning, nucleotide sequence and biochemical properties of a cytoplasmic
      cyclomaltodextrinase (neopullulanase) from Alicyclobacillus acidocaldarius,
      reclassification of a group of enzymes.
AB  - A gene encoding a cyclomaltodextrinase (neopullulanase) was cloned from the
      thermoacidophilic bacterium Alicyclobacillus acidocaldarius ATCC27009 and its
      nucleotide sequence was determined. The encoded CdaA protein lacked an N-terminal
      signal sequence and aligned well with a family of bacterial proteins described as
      maltogenic alpha-amylases, neopullulanases or cyclomaltodextrinases. Escherichia
      coli cells harboring the cloned cdaA gene produced a 66-kDa protein that degraded
      pullulan in a sodium dodecyl sulfate-polyacrylamide gel. A. acidocaldarius cells
      grown on maltose, soluble starch or pullulan synthesized the same protein.
      Neopullulanase activity of the protein was cytoplasmic and its pH optimum of 5.5
      was close to the pH value of the cytoplasm. CdaA degraded cyclomaltodextrins
      rapidly and pullulan (to panose) more slowly. It is proposed that CdaA functions
      as a cytoplasmic cyclomaltodextrinase (EC 3.2.1.54).

PMID- 10650203
TI  - Identification and purification of the 69-kDa intracellular protease involved in
      the proteolytic processing of the crystal delta-endotoxin of Bacillus
      thuringiensis subsp. tenebrionis.
AB  - The dynamics of appearance of intracellular proteases in relation to the
      synthesis of crystal delta-endotoxin was studied to identify the native
      intracellular protease(s) involved in the proteolytic processing of the 73-kDa
      protoxin of Bacillus thuringiensis subsp. tenebrionis. In vitro proteolytic
      activation of the 73-kDa protoxin indicated the possible role of 69-kDa protease
      in the proteolytic processing of 73-kDa protoxin. The purified 69-kDa protease
      was able to cause the proteolytic activation of the 73-kDa protoxin to 68-kDa
      toxin and this conversion was inhibited by ethylenediamine tetraacetic acid and
      1,10-phenanthroline.

PMID- 10650204
TI  - Production and biochemical characterization of an alpha-amylase from the moderate
      halophile Halomonas meridiana.
AB  - Extracellular amylase production by the moderate halophile Halomonas meridiana
      was optimized and the enzyme was characterized biochemically. The highest amylase
      production was achieved by growing H. meridiana cultures in media with 5% salts
      and starch, in the absence of glucose until the end of the exponential phase. The
      amylase exhibited maximal activity at pH 7.0, being relatively stable in alkaline
      conditions. Optimal temperature and salinity for activity were 37 degrees C and
      10% NaCl, respectively. Moreover, activity at salinity as high as 30% salts was
      detected. Maltose and maltotriose were the main end products of starch
      hydrolysis, indicating an alpha-amylase activity.

PMID- 10650205
TI  - Identification of new transposable genetic elements in Burkholderia pseudomallei
      using subtractive hybridisation.
AB  - A subtraction library of Burkholderia pseudomallei was constructed by subtractive
      hybridisation of B. pseudomallei genomic DNA with Burkholderia thailandensis
      genomic DNA. Two clones were found to have significant sequence similarity to
      insertion sequences which have previously not been found in B. pseudomallei
      (designated ISA and ISB); and two clones showed sequence similarity to different
      regions of Burkholderia cepacia IS407 that has recently been detected in B.
      pseudomallei. The former, though possibly non-functional, represents new
      transposable genetic elements of B. pseudomallei. All three sequences were found
      to be present in multi-copy in the genomes of a number of B. pseudomallei strains
      and in B. thailandensis, which are the first transposable elements identified in
      this species.

PMID- 10650206
TI  - The microbial composition of three limnologically disparate hypersaline Antarctic
      lakes.
AB  - 16S rRNA clone library analysis was used to examine the biodiversity and
      community structure within the sediments of three hypersaline Antarctic lakes.
      Compared to sediment of low to moderate salinity Antarctic lakes the species
      richness of the hypersaline lake sediments was 2-20 times lower. The community of
      Deep Lake (32% salinity, average sediment temperature -15 degrees C) was made up
      almost entirely of halophilic Archaea. The sediment communities of two meromictic
      hypersaline lakes, Organic Lake (20% salinity, -7 degrees C) and Ekho Lake (15%
      salinity, 15 degrees C) were more complex, containing phylotypes clustering
      within the Proteobacteria and Cytophagales divisions and with algal chloroplasts.
      Many phylotypes of these lakes were related to taxa more adapted to marine-like
      salinity and perhaps derive from bacteria exported into the sediment from the
      lower salinity surface waters. The Ekho Lake clone library contained several
      major phylotypes related to the Haloanaerobiales, the growth of which appears to
      be promoted by the comparatively high in situ temperature of this lake.

PMID- 10650207
TI  - Influence of fluconazole at subinhibitory concentrations on cell surface
      hydrophobicity and phagocytosis of Candida albicans.
AB  - Cell surface hydrophobicity (CSH) status influences virulence of Candida albicans
      and decreases the susceptibility of yeast cells to phagocytic killing. We tested
      whether subinhibitory concentrations of fluconazole, which is widely used in the
      treatment and prophylaxis of candidiasis, affect CSH and the susceptibility of C.
      albicans to enzymatic digestion by glucanase and to phagocytic killing. Treatment
      of yeast cells with subinhibitory fluconazole concentrations resulted in greater
      phagocytosis. This effect was independent of CSH but may be related to increased
      cell wall porosity resulting from alterations in the cell envelope. The use of
      subinhibitory concentrations of fluconazole in patients with competent phagocytes
      may contribute to resistance to candidiasis regardless of yeast CSH status.

PMID- 10650208
TI  - Association of qacE and qacEDelta1 with multiple resistance to antibiotics and
      antiseptics in clinical isolates of Gram-negative bacteria.
AB  - Clinical isolates of Enterobacter cloacae, Citrobacter freundii, Pseudomonas
      aeruginosa, and Stenotrophomonas maltophilia were tested for resistance to
      antibiotics and to the antiseptics benzalkonium chloride and
      cetyltrimethylammonium bromide. Furthermore, they were examined for the presence
      of the resistance genes qacE and qacEDelta1. qacEDelta1 was detected by PCR in
      10% of all (n=103) and in 81% of multiply antibiotic-resistant strains (n=15).
      qacE was found in only one of 37 P. aeruginosa strains. The minimum inhibitory
      concentrations of benzalkonium chloride, cetyltrimethylammonium bromide, and
      ethidium bromide were not significantly different for qacEDelta1/qacE-positive or
      -negative strains. Our data indicate that multiply antibiotic-resistant Gram
      negative bacteria are not necessarily more resistant to quaternary ammonium
      compounds than antibiotic-sensitive strains even though qacE or qacEDelta1 is
      present.

PMID- 10650209
TI  - Identification of the cellulose-binding domain of Fibrobacter succinogenes
      endoglucanase F.
AB  - The cellulose-binding domain (CBD) of Fibrobacter succinogenes endoglucanase F
      (EGF) has been determined. The gene encoding EGF (celF) and its derivatives were
      expressed in Escherichia coli. We were able to obtain eight recombinant proteins
      and examine their cellulose-binding ability and endoglucanase activity. Because
      four recombinant proteins, which contain the first N-terminal reiterated region
      of EGF, bound to cellulose, the region has been identified as the CBD. Although
      the CBD did not show significant sequence similarity with any other CBDs, it did
      show significant similarity with a part of endoglucanase J (CelJ) of Clostridium
      thermocellum F1. Moreover, a large part of the C-terminal catalytic region of EGF
      showed sequence similarity with alpha-L-arabinofuranosidases of glycosyl
      hydrolase family 51.

PMID- 10650210
TI  - Pythium contiguanum nomen novum (syn. Pythium dreschleri Paul), its antagonism to
      Botrytis cinerea, ITS1 region of its nuclear ribosomal DNA, and its comparison
      with related species.
AB  - Pythium drechsleri Paul was described as a new species from soil samples taken in
      a salt-marsh of Arzew, Algeria [Paul, B. (1988) Une nouvelle espece de Pythium
      isolee d'une saline de l'ouest Algerien. Cryptogam. Mycol. 9, 325-333]. The name
      of the fungus, P. drechsleri, is a nomen invalidum, as it is a later homonym of
      P. drechsleri Rajgopalan and Ramakrishnan [Rajagopalan, S. and Ramakrishnan, K.
      (1971) Phycomycetes in agricultural soils with special reference to the
      Pythiaceae. Madras Univ. J. Sect. B 37,38, 100-117]. A new name, Pythium
      contiguanum is now being given to P. drechsleri Paul. This species is
      characterised by its contiguous inflated type of sporangia, smooth-walled oogonia
      and mostly monoclinous antheridia. Although the fungus is not known to be a
      pathogen, it has a very well developed appressorial system comprised of both
      sickle shaped and coiled appressoria. Morphological features, its antagonism
      towards the grape-vine pathogen Botrytis cinerea, together with the sequences of
      the ITS1 region of its nuclear ribosomal DNA and its comparison with related
      species are given here.

PMID- 10650211
TI  - Evidence of Dbps (decorin binding proteins) among European strains of Borrelia
      burgdorferi sensu lato and in the immune response of LB patient sera.
AB  - Decorin binding proteins DbpA and DbpB act as Borrelia burgdorferi (B.
      burgdorferi) adhesins to decorin, and are able to elicit a persistent antibody
      response in the mouse; accordingly DbpA protein would seem to be promising in
      immunoprofilaxis of Lyme borreliosis (LB). This study examines the distribution
      of Dbp epitopes in European strains of B. burgdorferi, of different genospecies
      and the presence of antibodies to Dbps in human sera from patients suffering from
      early and late LB, as revealed by immunoblotting. Different levels of expression
      of Dbp epitopes were found both among and within genospecies; data from human
      sera indicate that Dbps are expressed during infection though not as strongly as
      in the mouse infection.

PMID- 10650212
TI  - A colicin-tolerant Escherichia coli mutant that confers hfl phenotype carries two
      mutations in the region coding for the C-terminal domain of FtsH (HflB).
AB  - An Escherichia coli mutant, ER437, which was originally isolated for colicin
      tolerance, was found to carry two amino acid changes in the C-terminal portion of
      FtsH (HflB). These mutations were demonstrated to reduce the ability of FtsH to
      degrade the phage lambda CII protein in vivo and in vitro, providing a
      rationalization for the mutant Hfl phenotype.

PMID- 10650213
TI  - Characterization of a 29-kDa beta-1,3-glucanase from Trichoderma harzianum.
AB  - A beta-1,3-glucanase, from culture filtrates of Trichoderma harzianum, was
      purified in sequential steps by gel filtration, hydrophobic interaction and ion
      exchange chromatography. A typical procedure provided 69-fold purification with
      0.32% yield. The molecular mass of the protein was found to be approximately 29
      kDa, as estimated by SDS-PAGE on a 10% slab gel. The K(M) and V(max) values for
      beta-1,3-glucanase, using laminarin as substrate, were 1. 72 mg ml(-1) and 3.10 U
      ml(-1), respectively. The pH optimum for the enzyme was pH 4.4 and maximum
      activity was obtained at 50 degrees C. The enzyme was strongly inhibited by
      HgCl(2) and SDS. These results suggest that each beta-1,3-glucanase produced by
      T. harzianum is different and is probably encoded by different genes.

PMID- 10650214
TI  - Comparison of viable cell counts and fluorescence in situ hybridization using
      specific rRNA-based probes for the quantification of human fecal bacteria.
AB  - Conventional cultivation and fluorescence in situ hybridization (FISH) using 16S
      rRNA-based probes were compared for the enumeration of human colonic bacteria.
      Groups of common intestinal anaerobic bacteria were enumerated in slurries
      prepared from fecal samples of three healthy volunteers. To introduce variation
      between the samples, they were incubated for 48 h in batch culture (anaerobic)
      fermenters at 37 degrees C, and pure cultures of Bifidobacterium infantis,
      Clostridium perfringens, or Lactobacillus acidophilus were added. Samples were
      taken from the fermenters at different times. Total anaerobes, bifidobacteria,
      bacteroides, clostridia, and lactobacilli were enumerated by both plating and
      FISH. The results showed that plate counts of total anaerobes, bifidobacteria,
      lactobacilli and bacteroides were approximately ten-fold lower than the
      corresponding FISH counts. Numbers of clostridia were higher using the plating
      method, probably because the clostridia probe used in FISH analyses was designed
      to only detect part of the genus Clostridium. The introduced variation in the
      methods could be detected by both methods and was comparable.

PMID- 10650215
TI  - Purification and characterization of acidic endo-polygalacturonase encoded by the
      PGL1-1 gene from Saccharomyces cerevisiae.
AB  - The PGL1 gene of the yeast Saccharomyces cerevisiae has been shown to encode
      polygalacturonase. Cloning of the PGL1 open reading frame behind the ADH1
      promoter allowed overexpression of polygalacturonase activity in S. cerevisiae.
      This enzyme was purified to apparent homogeneity from cultures of recombinant S.
      cerevisiae on synthetic medium using one-step purification by anionic exchange
      chromatography. The enzyme, named Pgl1P, had an apparent M(r) of 42 kDa as shown
      by SDS-PAGE. Pgl1P was active from pH 3 to 5.5, with an optimum temperature at 25
      degrees C. This enzyme hydrolyzed polygalacturonic acid as an endo
      polygalacturonase as demonstrated by independent methods. The purified protein
      was N-glycosylated. However, the activity remained in the N-deglycosylated form.
      The N-terminal amino acid sequence was also determined as D-S-C-T-L-T-G-S-S-L.

PMID- 10650216
TI  - Alternative pathways of glucose transport in Prevotella bryantii B(1)4(1).
AB  - Prevotella bryantii B(1)4 grew faster on glucose than mannose (0.70 versus 0.45
      h(-1)), but these sugars were used simultaneously rather than diauxically. 2
      deoxy-glucose (2DG) decreased the growth rate of cells that were provided with
      either glucose or mannose, but 2DG did not completely prevent growth. Cells grown
      on glucose or mannose transported both (14)C-glucose and (14)C-mannose, but cells
      grown on glucose had over three-fold higher rates of (14)C-glucose transport than
      cells grown on mannose. The (14)C-mannose transport rates of glucose- and mannose
      grown cells were similar. Woolf-Augustinsson-Hofstee plots were not linear, and
      it appeared that the glucose/mannose/2DG carrier acted as a facilitated diffusion
      system at high substrate concentrations. When cultures were grown on nitrogen
      deficient (excess sugar) medium, isolates had three-fold lower (14)C-glucose
      transport, but the (14)C-mannose transport did not change significantly. (14)C
      glucose and (14)C-mannose transport rates could be inhibited by 2DG and either
      mannose or glucose, respectively. The (14)C-glucose transport of mannose-grown
      cells was inhibited more strongly by mannose and 2DG than those grown on glucose.
      Cells grown on glucose or mannose had similar ATP-dependent glucokinase activity,
      and 2DG was a competitive inhibitor (K(i)=0.75 mM). Thin layer chromatography
      indicated that cell extracts also had ATP-dependent mannose phosphorylation, but
      only a small amount of phosphorylated 2DG was detected. Glucose, mannose or 2DG
      were not phosphorylated in the presence of PEP. Based on these results, it
      appeared that P. bryantii B(1)4 had: (1) two mechanisms of glucose transport, a
      constitutive glucose/mannose/2DG carrier and an alternative glucose carrier that
      was regulated by glucose availability, (2) an ATP-dependent glucokinase that was
      competitively inhibited by 2DG but was unable to phosphorylate 2DG at a rapid
      rate, and (3) virtually no PEP-dependent glucose, mannose or 2DG phosphorylation
      activities.

PMID- 10650217
TI  - Effect of host bacteria genotype on spontaneous reversions of Bacillus subtilis
      bacteriophage phi29 sus17 nonsense codon.
AB  - Gene 17 of Bacillus subtilis bacteriophage Phi29 is an early gene playing a role
      in DNA replication. Its mutant sus17(112) carries the TAA nonsense triplet at the
      fifth codon of the gene. We isolated and sequenced 73 spontaneous revertants
      producing normal-size plaques on bacteria without an informational suppressor
      gene. In all revertants, the TAA triplet was changed by a one-base substitution
      and the sequences CAA, AAA, TTA, TAC and TAT were recovered at its place. The
      spectrum of these mutations was markedly influenced by the genotype of the
      bacteria in which the revertants arose. In agreement with the results described
      in Escherichia coli, the ratio of transversions to transitions (CAA being the
      only transition acceptable) was higher in strains harboring the functional allele
      recA(+) than in those with recA4. Our results support the idea that also in the
      Gram-positive B. subtilis, the spectra of spontaneous mutations are specifically
      modified by an SOS function. It is assumed that the single-stranded DNA chains
      generated in the course of phage DNA replication might act as an inducing factor.

PMID- 10650218
TI  - Kinetics and distribution of alcohol oxidising activity in Acholeplasma and
      Mycoplasma species.
AB  - Alcohol metabolism by Acholeplasma and Mycoplasma cell suspensions was determined
      using changes in dissolved oxygen tension to monitor oxygen uptake. All seven
      Acholeplasma test species oxidised ethanol and (where tested) propanol, butanol
      and pentanol. The rate of oxidation, at any particular substrate concentration,
      decreased with increasing alcohol molecular mass. Amongst 20 Mycoplasma species
      tested, M. agalactiae, M. bovis, M. dispar, M. gallisepticum, M. pneumoniae and
      M. ovipneumoniae oxidised ethanol. Propanol was also oxidised by M. dispar and
      isopropanol by M. agalactiae, M. bovis and M. ovipneumoniae. Isopropanol was
      oxidised at particularly high rates (V(max)100 nmol O(2) taken up min(-1) mg cell
      protein(-1)) and with a relatively high affinity (K(m) value<2 mM); oxygen uptake
      was consistent with oxidation to acetone. The significance of alcohol oxidation
      is unclear, as it would not be predicted to lead to ATP synthesis.

PMID- 10650219
TI  - Respiratory pathways and oxygen toxicity in Phanerochaete chrysosporium.
AB  - Phanerochaete chrysosporium maintained on glucose as the carbon source contained
      severely impaired mitochondria that were characterised by the loss of both
      succinate dehydrogenase and cytochrome oxidase activities. These cells maintained
      a constant value for energy charge using anaerobic metabolism. Cells with these
      properties express lignin peroxidase when supplied with a pure oxygen atmosphere,
      which may reflect a response to accumulating reactive oxygen species. Cells
      maintained on cellulose retained fully functional mitochondria, but expressed
      lignin peroxidase without being exposed to a pure oxygen atmosphere. In the cells
      maintained on cellulose, mitochondrial function may be limited by the supply of
      glucose, leading to the accumulation of reactive oxygen species.

PMID- 10650220
TI  - The periodontal pathogen Porphyromonas gingivalis harnesses the chemistry of the
      mu-oxo bishaem of iron protoporphyrin IX to protect against hydrogen peroxide.
AB  - The major haem component in the black pigment of Porphyromonas gingivalis is the
      mu-oxo bishaem of iron protoporphyrin IX and formation and cell-surface binding
      of this haem species is proposed as an extracellular buffer against reactive
      oxidants [Smalley, J.W. et al. (1998) Biochem. J. 331, 681-685]. P. gingivalis
      cells grown in the presence of the mu-oxo bishaem were protected against H(2)O(2)
      compared to control cells grown without it. When added to the growth medium,
      soluble mu-oxo bishaem inactivated H(2)O(2) and supported cell growth. Cells
      carrying a surface layer of mu-oxo bishaem were less susceptible to peroxidation
      by H(2)O(2). Cell-surface haems were slowly destroyed during reaction with
      H(2)O(2). Binding of mu-oxo bishaem by P. gingivalis may aid survival during
      neutrophil attack through inactivation of hydrogen peroxide.

PMID- 10650221
TI  - Streptococcus mutans strain N produces a novel low molecular mass non-lantibiotic
      bacteriocin.
AB  - Streptococcus mutans strain N was shown to have bacteriocin production and
      immunity characteristics consistent with those of Group I mutacin-producing
      strains of S. mutans. The bacteriocin mutacin N was purified from agar cultures
      of S. mutans strain N using XAD andp6 reversed phase chromatography. The
      molecular mass of mutacin N was 4806 Da and the entire 49 amino acid sequence was
      determined by N-terminal sequencing. Database searches indicate that mutacin N is
      a novel bacteriocin, but with some homology to the protein IIC domain of a
      hypothetical sugar-phosphotransferase enzyme from Acholeplasma florum.

PMID- 10650222
TI  - Nonactin biosynthesis: the potential nonactin biosynthesis gene cluster contains
      type II polyketide synthase-like genes.
AB  - Nonactin is the parent compound of a group of highly atypical polyketide
      metabolites produced by Streptomyces griseus subsp. griseus ETH A7796. In this
      paper we describe the isolation, sequencing, and analysis of 15? omitted?559 bp
      of chromosomal DNA, containing the potential nonactin biosynthesis gene cluster,
      from S. griseus subsp. griseus ETH A7796. Fourteen open reading frames were
      observed in the DNA sequence. Significantly, type II polyketide synthase (PKS)
      homologues were discovered in an apparent operon structure, which also contained
      the nonactate synthase gene (nonS), clustered with the tetranactin resistance
      gene. The deduced products of two of the genes (nonK and nonJ) are quite unusual
      ketoacyl synthase (KAS) alpha and KASbeta homologues. We speculate that nonactic
      acid, the polyketide precursor of nonactin, is synthesized by a type II PKS
      system.

PMID- 10650223
TI  - Identification and characterisation of a gene encoding aminoacylase activity from
      Lactococcus lactis MG1363.
AB  - Analysis of the sequence of a randomly cloned chromosomal DNA fragment (3.2 kb)
      from Lactococcus lactis revealed the presence of part of an open reading frame,
      designated amd1, which specifies a protein displaying significant similarity to
      aminoacylases from various bacteria. The presence of an immobilised copy of an
      IS982 element immediately upstream of the coding region of amd1 has probably
      resulted in the displacement of amd1's native promoter. This genetic organisation
      was shown to be retained in seven other dairy strains, one of which was only
      slightly different. The amd1 gene was overexpressed in L. lactis NZ9800 under the
      control of the inducible nisA promoter and the deacetylating capacity of its gene
      product was measured on a number of substrates.

PMID- 10650224
TI  - An efficient approach for cloning the dNDP-glucose synthase gene from
      actinomycetes and its application in Streptomyces spectabilis, a spectinomycin
      producer.
AB  - Specifically designed PCR primers were applied to amplify a segment of dTDP
      glucose synthase gene from six actinomycete strains. About 300-bp or 580-bp DNA
      fragments were obtained from all the organisms tested. By DNA sequence analysis,
      seven amplified fragments showed high homology with dTDP-glucose synthase genes
      that participate in the biosynthesis of secondary metabolites or in deoxy-sugar
      moieties in lipopolysaccharides. In addition, we have cloned a 45-kb region of
      DNA from Streptomyces spectabilis ATCC27741, a spectinomycin producer which
      contained the dTDP-glucose synthase and dTDP-glucose 4,6-dehydratase genes named
      spcD and spcE, respectively. The spcE gene was expressed in Escherichia coli and
      the activity was assayed in cell extracts. The enzyme showed substrate
      specificity only to dTDP-glucose.

PMID- 10650225
TI  - Synergistic effects of nisin and thymol on antimicrobial activities in Listeria
      monocytogenes and Bacillus subtilis.
AB  - Nisin Z and thymol were tested, alone and in combination, for antibacterial
      activity against Listeria monocytogenes ATCC 7644 and Bacillus subtilis ATCC
      33712. The antibacterial effect of nisin Z, produced by Lactococcus lactis KE3
      isolated from the traditional Moroccan fermented milk, was greatly potentiated by
      sub-inhibitory concentrations of thymol in both bacterial strains. Our data
      showed that the concentration of nisin required for effective control of food
      borne pathogenic bacteria could be considerably lowered by the use of thymol in
      combination. The use of low concentrations of nisin could lead to a less
      favourable condition for the occurrence of nisin-resistant bacterial sub
      populations.

PMID- 10650226
TI  - Occurrence of phages infecting Escherichia coli O157:H7 carrying the Stx 2 gene
      in sewage from different countries.
AB  - Shiga toxin-converting bacteriophages are involved in the pathogenicity of some
      enteric bacteria, such as Escherichia coli O157:H7. Recent studies have
      demonstrated a relatively high presence of Shiga toxin 2 phages in sewage from
      Spain, but no data on sewage from other areas were available. In order to
      evaluate the presence of such phages in sewage from diverse geographical origins,
      33 sewage samples, including samples from eight different European countries as
      well as from New Zealand and South Africa were analysed. Using an experimental
      approach based on the detection of Stx 2 gene by a phage enrichment culture
      followed by PCR, bacteriophages infecting E. coli O157:H7 carrying the Shiga
      toxin 2 gene were detected in 15 of the samples studied. Results presented here
      show that the presence of phages carrying the Stx 2 gene is common in sewage from
      developed countries.

PMID- 10650227
TI  - Diagnostic accuracy of myoglobin concentration for the early diagnosis of acute
      myocardial infarction.
AB  - STUDY OBJECTIVE: We evaluated the diagnostic accuracy of myoglobin determination
      for the early diagnosis of acute myocardial infarction (AMI). METHODS:
      Consecutive patients with chest pain were included in the study. Receiver
      operating characteristic (ROC) analysis was used to assess optimal timing of
      blood sampling and cutoff values. RESULTS: A total of 309 patients were included,
      of whom 162 patients had a diagnosis of AMI. ROC analysis revealed that the
      diagnostic accuracy of myoglobin concentration as indicated by the area under the
      ROC curve (AUC) increased significantly from 3 (0.89+/-0.026) and 4 hours (0.93+/
      0.019) to 5 hours after onset of symptoms (0. 96+/-0.014; P=.0040 and.035,
      respectively). At 5 hours (the earliest time point with maximal AUC), sensitivity
      was 87% and specificity was 97% using a myoglobin cutoff value of 90 microg/L.
      With a myoglobin cutoff value of 50 microg/L, sensitivity was 95% (95% confidence
      interval 90% to 98%), but specificity was 86% (95% confidence interval 80% to
      93%). CONCLUSION: Myoglobin has maximal diagnostic accuracy for the diagnosis of
      AMI at 5 hours after the onset of symptoms, using a cutoff value of 50 microg/L.
      In combination with the measurement of other biochemical markers, myoglobin
      determination could be particularly useful for triage of patients with AMI at an
      early stage.

PMID- 10650228
TI  - A negative SimpliRED D-dimer assay result does not exclude the diagnosis of deep
      vein thrombosis or pulmonary embolus in emergency department patients.
AB  - STUDY OBJECTIVE: To determine whether a negative SimpliRED D-dimer assay result
      excludes the diagnosis of deep vein thrombosis (DVT) or pulmonary embolus (PE) in
      emergency department patients. METHODS: This prospective, institutional review
      board-approved, clinical trial enrolled consecutive adult ED patients with the
      suspected diagnosis of venous thromboembolism (VTE) (DVT or PE). Initial ED
      evaluation included the SimpliRED D-dimer assay (American Diagnostica Inc,
      Greenwich, CT). Physicians were blinded to assay results. The diagnosis of DVT
      was made with positive findings on lower-extremity ultrasonography. PE was
      confirmed by a high-probability ventilation/perfusion (V/Q) scan, a positive
      pulmonary angiogram, or a positive finding on lower-extremity ultrasonography. A
      presumptive diagnosis of VTE was made in patients who had VTE at follow-up or
      unexplained death during the study period. RESULTS: One hundred ninety-eight
      patients were enrolled during the study period. Twenty-five patients were
      excluded from data analysis; 9 had no diagnostic testing and 16 were lost to
      follow-up. Of the 173 patients analyzed, 57 (33%) had VTE-16 of 48 evaluated for
      DVT and 41 of 125 for suspected PE. The SimpliRED assay had a sensitivity of 65%
      and a negative predictive value of 81% for detection of VTE. In patients
      evaluated for DVT alone, the sensitivity was 56% and the negative predictive
      value was 77%. For patients with suspected PE, the sensitivity and negative
      predictive value were 68% and 83%, respectively. CONCLUSION: In contrast to
      earlier reports on the SimpliRED D-dimer assay, a negative result failed to
      exclude the diagnosis of VTE in our ED population.

PMID- 10650229
TI  - Hypertension in patients presenting with epistaxis.
AB  - STUDY OBJECTIVE: We sought to evaluate whether patients with epistaxis in the
      emergency department have a higher arterial blood pressure compared with patients
      with other medical emergencies and to study the association of elevated blood
      pressure during epistaxis with sustained arterial hypertension. METHODS: In a
      prospective, cross-sectional, prevalence study we compared arterial blood
      pressure on admission in the ED in 213 consecutive patients treated for epistaxis
      with that of 213 sex- and age-matched control subjects. In 33 of those patients
      with elevated blood pressure during epistaxis, we evaluated the prevalence of
      sustained arterial hypertension. Main outcome measures were arterial blood
      pressure during epistaxis and evidence of sustained arterial hypertension, as
      determined by 24-hour ambulatory blood pressure measurement. RESULTS: Patients
      with epistaxis had significantly higher blood pressure values compared with those
      of control patients (systolic blood pressure 161+/-30 versus 144+/-22 mm Hg,
      P<.001; diastolic blood pressure 84+/-19 versus 75+/-15 mm Hg, P <.001). Of 33
      (30%) of 108 patients with elevated blood pressure during epistaxis who were
      further evaluated, 26 (79%) patients were classified as having sustained arterial
      hypertension. Nine (27%) patients with sustained arterial hypertension were
      unaware of a history of hypertension. Patients with sustained arterial
      hypertension had significantly more episodes of epistaxis compared with patients
      with elevated blood pressure during epistaxis and no sustained arterial
      hypertension (mean 5 versus 1; P=.004). CONCLUSION: Patients with epistaxis have
      a higher blood pressure compared with that of control patients. Twenty-six (79%)
      of 33 patients with elevated blood pressure during epistaxis had sustained
      arterial hypertension. Nine (27%) of these patients were unaware of a history of
      hypertension. Continued management of patients with epistaxis and high blood
      pressure should include confirmation or exclusion of sustained arterial
      hypertension by 24-hour ambulatory blood pressure recording.

PMID- 10650230
TI  - Safety and efficacy of diclofenac ophthalmic solution in the treatment of corneal
      abrasions.
AB  - STUDY OBJECTIVE: To determine whether the use of diclofenac ophthalmic solution
      is a safe and effective analgesic in the treatment of traumatic corneal abrasions
      in the emergency department. METHODS: We conducted a prospective, randomized,
      double-blinded, placebo-controlled clinical trial. Consenting consecutive
      patients with corneal abrasions who presented to a community-based ED from August
      through February 1998 were randomly assigned to receive either diclofenac or
      control vehicle drops. Pain relief was measured using a visual Numeric Pain
      Intensity Scale (NPIS) before and after treatment. Exclusion criteria were as
      follows: age younger than 18 years, pregnancy, history of glaucoma, ocular
      infection, recent eye surgery, other signs of ocular trauma, narcotics within 6
      hours, minimal pain (NPIS score <3), and any allergy to diclofenac or
      nonsteroidal anti-inflammatory drugs. Patients were discharged with study drug or
      control vehicle solution, a topical antibiotic, oxycodone-acetaminophen as a
      rescue analgesic, and a pain diary. The outcome measurements were improvement in
      NPIS score 2 hours after treatment, use of oxycodone-acetaminophen, and
      occurrence of any adverse effects. RESULTS: Forty-nine patients were enrolled in
      the study; 25 received diclofenac and 24 received control vehicle drops. Both
      groups were similar in gender, age, pretreatment pain duration, NPIS score, and
      analgesic use. There was significantly greater improvement in the 2-hour NPIS
      score in the diclofenac group (3.1; 95% confidence interval [CI] 2.3 to 4)
      compared with the control group (1.0; 95% CI 0.1 to 2.0). The difference between
      the 2 groups was 2.1+/-1.3 (95% CI 0.8 to 3.4). There was a trend toward fewer
      patients taking rescue oxycodone-acetaminophen in the diclofenac group (20%; 95%
      CI 4% to 36%) versus the control group (42%; 95% CI 22% to 62%). Other than
      transient mild stinging, there were no complications associated with diclofenac
      use. CONCLUSION: Diclofenac ophthalmic solution appears to be a safe and
      effective analgesic in the treatment of traumatic corneal abrasions in the ED.

PMID- 10650231
TI  - Cardiac arrest witnessed by emergency medical services personnel: descriptive
      epidemiology, prodromal symptoms, and predictors of survival. OPALS study group.
AB  - STUDY OBJECTIVE: The Utstein guidelines recommend that emergency medical services
      (EMS)-witnessed cardiac arrests be considered separately from other out-of
      hospital cardiac arrest cases. The objective of this study was to assess EMS
      witnessed cardiac arrest and to determine predictors of survival in this group.
      METHODS: This prospective cohort included all adults with an EMS-witnessed
      cardiac arrest in the 21 communities of the Ontario Prehospital Advanced Life
      Support (OPALS) study. Systems provided a basic life support with defibrillation
      (BLS-D) level of care. Case and survival definitions followed the Utstein style.
      Descriptive and univariate methods (chi(2) and t test) were used to characterize
      EMS-witnessed cardiac arrest. Multivariate logistic regression was undertaken to
      assess predictors of survival to hospital discharge. RESULTS: From January 1,
      1991, to December 31, 1996, there were 9,072 cardiac arrest cases in the study
      communities. Of these, 610 (6.7%) were EMS-witnessed. The majority had
      preexisting cardiac or respiratory disease (81.5%) and experienced prodromal
      symptoms before EMS personnel arrived (91.4%). An initial rhythm of pulseless
      electrical activity was present in 50.1% of the patients, ventricular
      fibrillation/ventricular tachycardia in 34.2%, and asystole in 15.7%. Survival to
      discharge was 12.6%. Multivariate analysis identified the following as
      independent predictors of survival (odds ratio with 95% confidence intervals
      [CIs]): nitroglycerin use before EMS arrival: 2.3 (95% CI 1.2 to 4.5), prodromal
      symptoms of chest pain: 2.5 (95% CI 1.4 to 4.5) or dyspnea: 0.5 (95% CI 0.3 to
      1.0), and unconsciousness on EMS arrival: 0.5 (95% CI 0.2 to 0.9). Patients with
      chest pain were more likely than dyspneic patients to experience ventricular
      fibrillation/ventricular tachycardia (62% versus 17%, P<.0001), and were 5 times
      more likely to survive (30.6% versus 6.3%, P<.0001). CONCLUSION: EMS-witnessed
      cases are clearly an important subset of out-of-hospital cardiac arrest and are
      characterized by 2 distinct symptom groups: chest pain and dyspnea. These
      symptoms are important predictors of survival and may also help determine
      underlying mechanisms before patient collapse. A later phase of the OPALS study
      will prospectively evaluate the impact of out-of-hospital advanced life support
      on the survival of victims of EMS-witnessed cardiac arrest.

PMID- 10650232
TI  - Ability of laypersons to estimate short time intervals in cardiac arrest.
AB  - STUDY OBJECTIVE: Estimates of time intervals by bystanders are considered
      critical in cardiac arrest, and are often used in other disorders such as stroke
      and myocardial infarction. Because they have never been previously studied, we
      sought to determine their accuracy. METHODS: This study was performed by
      prospective collection of bystander estimates (made at the time of the arrest) of
      the time from calling 911 to the arrival of urban fire department first
      responders, and comparison with actual measured response interval from
      computerized records, in all out-of-hospital cardiac arrests from January 1996
      through June 1998. RESULTS: The fire department responded to 1,015 patients in
      cardiac arrest during the study period. First responders arrived before advanced
      life support providers to 831 patients, who thus met study entry criteria.
      Bystander estimates were obtained in 497 of these 831 patients, who did not
      differ in key characteristics from those lacking estimates. The bystander's
      average estimated fire department response interval was 5.6 minutes (95%
      confidence interval [CI] 5.2 to 5.9 minutes) and the actual measured interval to
      the patient's side from computer records was 6.1 minutes (95% CI 5.9 to 6.4
      minutes). However, the median error of the bystander estimate (1.3 minutes) was
      32% of the median of the actual measured on-scene interval, and there was no
      correlation between the bystander estimates and the measured interval in
      individual cases (R </=0.14), regardless of which intervals were examined.
      Seventy-five percent of the bystander estimates erred by 20% or more. When
      bystanders estimated a response interval as excessively long, they were almost
      invariably wrong, but they also usually failed to identify intervals that
      actually were long. CONCLUSION: Although many diagnostic and research conclusions
      are based on interval estimates from laypersons, we found no correlation between
      estimates and actual measured intervals in cardiac arrest. Current methodology
      may not be developed well enough to provide reliable data for research or quality
      assurance, and other clinical time estimates by patients and bystanders may be
      equally unreliable.

PMID- 10650233
TI  - The role of emergency physicians in the care of the child in school.
AB  - Emergency physicians may contribute significantly to the health of children in
      the school setting. Because children spend the majority of their waking hours in
      school, they and their adult caretakers experience medical and surgical
      emergencies on a regular basis. These emergencies include a wide range of
      problems, such as asthma, seizures, firearms violence, and mass disasters.
      Additionally, many children in school have limited access to primary care, which
      increases their risk for medical emergencies. Recent reports from the National
      Academy of Sciences Institute of Medicine and the Maternal and Child Health
      Bureau's Emergency Medical Services for Children Program have described the
      challenges in improving the medical care of children in both the emergency and
      school settings. The prevalence of school health emergencies provides an
      opportunity for use of the expertise of emergency physicians. Emergency
      physicians have an important role in ensuring the proper treatment of emergency
      medical problems that occur in school. They need to be integrally involved in the
      development and organization of systems for prevention, initial stabilization,
      definitive management, and responsible follow-up of medical problems and
      injuries.

PMID- 10650234
TI  - Emergency medicine can play a leadership role in enterprise-wide clinical
      information systems.
AB  - At many institutions, the department of emergency medicine is uniquely suited to
      a leadership role in the deployment of new clinical decision support systems
      (computer systems that support clinical practice). Many factors favor such a
      leadership role, including institutional politics, organizational structure,
      extent of local control, clinician solidarity, openness to change, departmental
      size and scale, and willingness to take risks. Such a role should be undertaken
      in partnership with the institution's information services (IS) department, and a
      clear understanding of goals and responsibilities will facilitate such a
      partnership. A leadership position with respect to new information systems
      entails a certain risk, but the potential benefit to an emergency department in
      today's competitive environment is substantial. The authors' experience with one
      such collaborative development project is presented.

PMID- 10650235
TI  - New diagnostic tests for pulmonary embolism.
AB  - In 1990, the multicenter Prospective Investigation of Pulmonary Embolism
      Diagnosis (PIOPED), sponsored by the National Institutes of Health, compared the
      diagnostic value of the radioisotopic ventilation-perfusion lung scan (V/Q scan)
      with that of pulmonary angiography for the diagnosis of pulmonary embolism (PE).
      Despite the endurance of the radioisotopic V/Q scan as the most widely used test
      for evaluation of pulmonary embolism (PE), a better screening tool is clearly
      needed for use in the emergency department. During the past decade, several new
      modalities have emerged for evaluation of patients with suspected PE. We evaluate
      the diagnostic utility of the D-dimer test and the alveolar dead space
      determination as potential screening tests and of spiral computed tomography,
      magnetic resonance imaging, transthoracic echocardiography, and transesophageal
      echocardiography as potential confirmatory tests for PE. For comparison, recent
      data on the diagnostic utility of the alveolar-arterial oxygen gradient and the
      V/Q scan are included. The potential application of these new tests to a
      hypothetical ED population is described.

PMID- 10650236
TI  - Clots in the lung.

PMID- 10650237
TI  - Successful cricothyrotomy after thrombolytic therapy for acute myocardial
      infarction: a report of two cases.
AB  - Cricothyrotomy is an emergency airway procedure that is generally performed after
      failure of primary methods for securing the airway. Coagulopathy has
      traditionally been considered a relative contraindication to cricothyrotomy, but
      there is little evidence in the literature to support this. There have been no
      reports of successful cricothyrotomy in a patient who had received systemic
      thrombolytic therapy. This report, from the National Emergency Airway Registry,
      is the first to describe successful cricothyrotomy in this context. We describe 2
      patients who received thrombolytic therapy and then had cricothyrotomy performed
      after failure of other airway measures. The first patient was a 67-year-old man
      who developed severe pulmonary edema and respiratory failure less than 30 minutes
      after administration of tissue plasminogen activator using an accelerated
      regimen. Both intubation and attempts at ventilation using an esophageal/tracheal
      double-lumen airway (Combitube, Kendall-Sheridan, Argyle, NY) were unsuccessful,
      and the emergency physician then performed an uneventful cricothyrotomy using a
      vertical midline incision. There were no complications, and bleeding was minimal.
      The second patient was a 45-year-old man who developed severe angioedema with
      respiratory compromise after receiving streptokinase for acute myocardial
      infarction. Intubation was impossible, and a cricothyrotomy was performed.
      Significant bleeding was controlled initially with packing and was semielectively
      explored later in the ICU with ligation of several small bleeding vessels. Prior
      administration of thrombolytic therapy does not preclude successful
      cricothyrotomy.

PMID- 10650238
TI  - Alcohol-related fatal crash rates for youth reach historic low: strategies for
      combating juvenile DUI

PMID- 10650239
TI  - Commentary: juvenile DUI-more work

PMID- 10650240
TI  - The end of the line

PMID- 10650242
TI  - Assessment of clinical policy for the initial approach to patients presenting
      with acute toxic ingestion or dermal or inhalation exposure

PMID- 10650241
TI  - Assessment of clinical policy for the initial approach to patients presenting
      with acute toxic ingestion or dermal or inhalation exposure.

PMID- 10650243
TI  - Ipratropium bromide in emergency management of acute asthma exacerbation.

PMID- 10650244
TI  - Ipratropium bromide in emergency management of acute asthma exacerbation

PMID- 10650245
TI  - Accident or crash?

PMID- 10650246
TI  - Assuring that managed care organizations provide appropriate instructions
      regarding use of emergency departments.

PMID- 10650247
TI  - Emergency Physicians' patient care responsibilities outside of the emergency
      department

PMID- 10650248
TI  - Family leave of absence

PMID- 10650249
TI  - Hospital, medical staff, and payer respon-sibility for emergency department
      patients

PMID- 10650250
TI  - Injury Control/Trauma data banks

PMID- 10650251
TI  - How gastroenterologists screen for colonic cancer in ulcerative colitis: an
      analysis of performance.
AB  - BACKGROUND: The aim of this study was to assess the colorectal cancer
      surveillance practices of British gastroenterologists for patients with
      ulcerative colitis. METHODS: A questionnaire that investigated aspects of
      surveillance in patients with ulcerative colitis was mailed to all consultant
      gastroenterologists in the U.K. (n = 413). RESULTS: Three hundred forty-one
      questionnaires were returned (response rate 83%). Ninety-four percent of
      consultants practice cancer surveillance in ulcerative colitis, with 35%
      maintaining a registry of patients in surveillance programs. All
      gastroenterologists perform surveillance in patients with pancolitis, 24% in
      those with left-sided colitis and 2% in patients with proctitis. The mean
      duration of disease before surveillance is commenced is 9.2 years for pancolitis
      and 12.4 years for left-sided colitis (p < 0.0001). Only 4% of
      gastroenterologists routinely offer patients with disease of more than 10 years'
      duration a prophylactic colectomy. Colonoscopies are conducted by an accredited
      gastroenterologist in 65% of cases and biopsies are reviewed by specialists in
      gastrointestinal pathology in 45%. When histology reveals low-grade dysplasia
      only 4% advise colectomy and when high-grade dysplasia is found 53% recommend
      colectomy. Sixteen percent of gastroenterologists were unaware of the
      significance of a dysplasia associated lesion or mass. CONCLUSION: The majority
      of gastroenterologists practice surveillance on a disorganized basis. There is
      inconsistency in the management of patients with dysplasia and education of
      gastroenterologists is needed.

PMID- 10650252
TI  - Accuracy of endoscopic databases for assessing patient symptoms: comparison with
      self-reported questionnaires in patients infected with the human immunodeficiency
      virus.
AB  - BACKGROUND: Endoscopic databases are increasingly used for clinical research, but
      their validity as research instruments has not been assessed. We compared the
      accuracy of endoscopic indications recorded in an endoscopic database with
      patient symptom questionnaires. METHODS: All patients infected with the human
      immunodeficiency virus referred to the outpatient gastroenterology practice were
      prospectively evaluated using recognized symptom questionnaires. For patients
      undergoing esophagogastroduodenoscopy, the procedure indications recorded in the
      endoscopic database and the patient's self-reported symptom scores were compared.
      RESULTS: Ninety-three patients were evaluated. The symptoms of nausea/vomiting,
      diarrhea, and anorexia were highly predictive for the presence of these symptoms
      on the patient questionnaires. The symptoms of dyspepsia/abdominal pain did not
      predict well the presence of these symptoms on the questionnaire. Patients
      reported frequent and severe symptoms that were not recorded as indications for
      the procedures. The overall agreement (kappa statistic) was highly variable, from
      slight (kappa = 0.07 for anorexia) to moderate (kappa = 0.44 for diarrhea).
      CONCLUSIONS: Endoscopic indications are variably associated with self-reported
      symptom scores. These findings raise concerns about using some endoscopic
      database indications as accurate representations of patients' symptoms. Until
      performance characteristics of a given database are known, symptom-oriented
      research should use validated questionnaires whenever possible.

PMID- 10650253
TI  - Palliation of patients with esophagogastric neoplasms by insertion of a covered
      expandable modified Gianturco-Z endoprosthesis: experiences in 153 patients.
AB  - BACKGROUND: We aimed to evaluate the short- and long-term outcomes of treatment
      by insertion of a covered expandable modified Gianturco-Z endoprosthesis (Song
      stent) in patients with esophagogastric malignancies. METHODS: Consecutive
      patients with esophagogastric malignancies in whom a Song stent was inserted were
      included. Data were retrieved retrospectively. Dysphagia before and after stent
      placement was scored on a 5-point scale. Early (less than 30 days) and late
      complications (more than 30 days) were scored. RESULTS: Analysis included 164
      stents in 153 patients. Indications for stent placement were dysphagia and/or
      fistulas/perforations. The dysphagia score improved from a mean of 3.7 to 2.2
      after stent placement (p < 0.0001). Fistulas/perforations sealed in 87% of cases.
      Early complications after stent placement occurred in 29.9% of cases. These
      included stent migration (4.3%), stent obstruction (6. 1%), aspiration pneumonia
      (4.9%), bleeding (4.3%), perforation (1. 8%), and pain (15.9%). Late
      complications occurred in 27.8% of cases. These included stent migration (2.6%),
      stent obstruction (9.6%), aspiration pneumonia (2.6%), bleeding (7.0%),
      perforation (0.9%), and pain (12.2%). The 30-day mortality was 26%. Death related
      to stent placement occurred in 3.3%. CONCLUSION: Insertion of a Song expandable
      endoprosthesis in patients with esophagogastric malignancies significantly
      improves dysphagia, is successful in sealing fistulas/perforations, and is
      associated with acceptable morbidity and mortality rates.

PMID- 10650254
TI  - A new design metal stent (Flamingo stent) for palliation of malignant dysphagia:
      a prospective study. The Rotterdam Esophageal Tumor Study Group.
AB  - BACKGROUND: Metal stents are not superior to conventional endoprostheses with
      respect to the incidence of recurrent dysphagia because of tumor ingrowth with
      uncovered stents and migration with their covered counterparts. To overcome these
      limitations, a partially covered (inside-out covering) metal stent with a conical
      shape and a varying braiding angle of the mesh along its length, the Flamingo
      stent, has been developed. METHODS: From March 1997 to October 1997, 40
      consecutive patients with dysphagia due to malignant tumors had either a small
      diameter (proximal/distal diameter 24/16 mm; n = 21) or a large diameter Flamingo
      stent (proximal/distal diameter 30/20 mm; n = 19) placed. RESULTS: There was
      statistically significant improvement in dysphagia, but improvement was not
      greater with large diameter stents compared to small diameter stents (p = 0.21).
      Major complications (bleeding [4], perforation [1], fever [1] and fistula [1])
      occurred in 7 (18%) patients. Large diameter stents tended to be associated with
      more major complications than small diameter stents (5 vs. 2; p = 0.07). Pain
      following stent placement was observed in 9 (22%) patients and occurred more
      frequently in those who had prior radiation and/or chemotherapy (p = 0.02).
      Recurrent dysphagia (mainly due to tumor overgrowth) occurred in 10 (25%)
      patients. CONCLUSIONS: Flamingo stents are effective for palliation of malignant
      dysphagia, but the large diameter stent seems to be associated with more
      complications involving the esophagus than the small diameter stent. Because
      recurrent dysphagia is mainly due to tumor progression, further technical
      developments in stent design are needed.

PMID- 10650255
TI  - Recent nonsteroidal anti-inflammatory drug use increases the risk of early
      recurrence of bleeding in patients presenting with bleeding ulcer.
AB  - BACKGROUND: Nonsteroidal anti-inflammatory drug (NSAID) use is a well-known risk
      factor for ulcer formation and ulcer complications. The purpose of this study was
      to determine whether recent NSAID use increases the risk of early recurrence of
      bleeding in patients who present with bleeding ulcer. METHODS: Clinical and
      endoscopic data were collected prospectively. Dose, frequency, and duration of
      recent NSAID use were quantified. Recent NSAID use was defined as consumption of
      over-the-counter or prescription NSAIDs or aspirin for at least 5 days of the 2
      week period preceding the index episode of bleeding. Endoscopy was performed
      within 24 hours of admission to confirm the source of bleeding and endoscopic
      intervention was applied for stigmata of bleeding. Early recurrence of bleeding
      was defined as melena, hematochezia or blood per nasogastric tube with a 2 gm or
      greater decrease in hemoglobin during a period of 48 hours, occurring less than 2
      weeks from index episode of bleeding. RESULTS: One hundred twenty patients (52
      NSAID users and 68 nonusers) were enrolled in the study; mean age was 56 years.
      NSAID users were older than nonusers (p = 0.003); nonusers were more likely to
      have a history of ulcer disease (p < 0.0005) and higher prevalence of
      Helicobacter pylori infection (p = 0.05). Recent NSAID use was associated with a
      significantly higher frequency of early recurrence of bleeding and in-hospital
      recurrent bleeding compared with nonusers: 19% vs. 6%, p = 0.02, and 17% vs. 6%,
      p = 0.04, respectively. In multivariate logistic regression analysis, the
      significant association between recent NSAID use and early recurrence of bleeding
      persisted (p = 0.0048) while controlling for age and other covariates.
      CONCLUSIONS: Recent NSAID use predisposes bleeding ulcer patients to early and in
      hospital recurrent bleeding, probably via its effects on platelet function,
      mucosal prostaglandins, and ulcer healing.

PMID- 10650256
TI  - Cost analysis of antibiotic prophylaxis for PEG.
AB  - BACKGROUND: There are conflicting recommendations regarding the prophylactic use
      of antibiotics in patients undergoing placement of percutaneous endoscopic
      gastrostomy tubes. The purpose of this decision analysis was to assess the cost
      effectiveness of antibiotic prophylaxis in percutaneous endoscopic gastrostomy.
      METHODS: A decision tree was modeled using the data of 7 published prospective
      placebo-controlled trials. Infectious complications were classified as grade I
      (requiring local care), grade II (requiring intravenous antibiotics), or grade
      III (requiring surgery). Medication costs were estimated from the United States
      average wholesale prices of the 1998 Red Book. Physician and facility costs were
      estimated based on the 1998 Medicare costs. A one-way sensitivity analysis was
      performed by varying the probability rates of the complications associated with
      percutaneous endoscopic gastrostomy and the costs of their treatment. RESULTS:
      The average cost of prophylactic antibiotics was $13.10. Antibiotic prophylaxis
      led to expected cost savings of $76.72 per percutaneous endoscopic gastrostomy. A
      sensitivity analysis suggested that antibiotic prophylaxis for percutaneous
      endoscopic gastrostomy was the preferred strategy unless the average probability
      of grade III complications dropped below an improbably low threshold value of
      0.09%. CONCLUSION: Antibiotic prophylaxis in percutaneous endoscopic gastrostomy
      is a cost-effective strategy.

PMID- 10650257
TI  - Variceal band ligation and variceal band ligation plus sclerotherapy in the
      prevention of recurrent variceal bleeding in cirrhotic patients: a randomized,
      prospective and controlled trial.
AB  - BACKGROUND: The combination treatment of band ligation plus sclerotherapy has
      been proposed to hasten variceal eradication. The aim of this study was to assess
      the efficacy of band ligation alone versus band ligation plus sclerotherapy in
      the prevention of recurrent variceal bleeding. METHODS: Eighty cirrhotic patients
      were randomized to group I (band ligation) with 41 patients or to group II (band
      ligation plus sclerotherapy) with 39 patients in whom polidocanol (2%) was
      injected 1 to 2 cm proximal to each band. RESULTS: At baseline, both groups were
      similar with regard to clinical, demographic and laboratory data. Mean follow-up
      time (standard error) for group I was 336.5 +/- 43.4 days and for group II 386.1
      +/- 40.1 days (p = 0.4). No statistical differences were observed between group I
      and group II in relation to recurrence of bleeding (31.7% vs. 23%, p = 0.38),
      treatment failure (24.4% vs. 12. 8%, p = 0.18), death (39% vs. 30.8%, p = 0.44)
      and variceal eradication (65.8% vs. 74.4%, p = 0.40). Group II had a
      significantly higher number of complications than group I, 30.8% versus 7.3%,
      respectively (p = 0.05). The number of bleeding related deaths was higher in
      group I than in group II (22% vs. 10.3%, respectively; p = 0.15). CONCLUSIONS: No
      significant difference was observed between band ligation and band ligation plus
      sclerotherapy in prevention of recurrent variceal bleeding. Furthermore, there
      was a higher incidence of complications in the latter group.

PMID- 10650258
TI  - A prospective evaluation of new rapid urease tests before and after eradication
      treatment of Helicobacter pylori, in comparison with histology, culture and 13C
      urea breath test.
AB  - BACKGROUND: The rapid urease test is a simple and cost-effective method to detect
      Helicobacter pylori in biopsy specimens. The aim of this study was to evaluate
      the accuracy of two new rapid urease tests, Helicocheck and PyloriTek, before and
      after eradication. METHODS: A total of 278 patients, including 115 patients who
      had not undergone eradication of H pylori and 163 patients after eradication
      treatment, were enrolled. Eight biopsy specimens were taken from both the antrum
      and the body of the stomach for histology, culture, and two rapid urease tests.
      Assessment of H pylori infection was determined by the combination of histology,
      culture, and (13)C-urea breath test. RESULTS: Overall sensitivity, specificity,
      and positive and negative predictive values of the Helicocheck before eradication
      were 91.0%, 100%, 100%, and 62.5%; PyloriTek, 92.0%, 100%, 100%, and 65.2%. Those
      of Helicocheck after eradication were, respectively, 60. 5%, 99.2%, 95.8%, and
      89.2%; PyloriTek, 60.5%, 99.2%, 95.8%, and 89. 2%. For the Helicocheck,
      determination of the infection status of H pylori by biopsies from the gastric
      body had a significantly higher sensitivity than antral biopsies. After
      eradication, the combination of 1 antral biopsy and 1 biopsy from the body was
      not effective enough to improve the overall sensitivity. CONCLUSIONS: Helicocheck
      and PyloriTek have equally satisfactory overall sensitivity before eradication
      treatment. However, the sensitivity of these rapid urease tests was lower after
      eradication than before eradication.

PMID- 10650259
TI  - Endoscopic therapy of anastomotic bile duct strictures occurring after liver
      transplantation.
AB  - BACKGROUND: Optimal therapy for anastomotic biliary strictures occurring after
      orthotopic liver transplantation (OLT) remains to be defined. We reviewed our
      experience with endoscopic therapy for such strictures and contrasted it with
      reported data. METHODS: Endoscopic therapy was performed with balloon dilation
      alone; no patients received an endoprosthesis. Responses were characterized as
      good if the patient improved clinically and no subsequent procedures were
      required after one or more dilations within a 3-month period; partial if
      clinically significant obstruction resolved but cholestasis persisted or there
      was a need for further endoscopic management beyond the initial 3 months; poor if
      subsequent surgery or percutaneous procedures were required; and failed if
      endoscopic access or dilation could not be accomplished. RESULTS: Fifteen
      patients underwent 23 endoscopic retrograde cholangiopancreatographies for post
      OLT anastomotic strictures. Postprocedure follow-up averaged 25.2 months.
      Cholangiography was successful in all 23 procedures; free duct access was
      achieved in 22 of 23 procedures. The strictures were successfully accessed for
      dilation in 11 of 15 patients and in 19 of 23 procedures. Outcome was deemed good
      in 4 (27%), partial in 3 (20%), and poor in 5 (33%) patients. Endoscopic therapy
      failed in 3 (20%). Poor outcomes were due to the early recognition of severe
      lesions (2 treated surgically) or to short-term responses to dilation alone (3).
      The procedural complication rate of 17.4% included 3 episodes of transient
      cholangitis (i.e., elevation of liver enzymes associated with fever that lasted
      less than 3 days) and 1 self-limited episode of postsphincterotomy bleeding,
      which required the transfusion of 2 units packed red blood cells. In published
      series the combined success rate of balloon dilation alone for treatment of
      anastomotic strictures is 41%, whereas for dilation plus stent placement it is
      75%. CONCLUSION: Endoscopic balloon dilation alone is not a reliable method of
      therapy for anastomotic strictures occurring after OLT. Dilation followed by
      short- to intermediate-term stent placement appears to provide a more durable
      result.

PMID- 10650260
TI  - Choledocholithiasis: a prospective study of spontaneous common bile duct stone
      migration.
AB  - BACKGROUND: The rate of spontaneous migration of bile duct stones through the
      duodenal papilla is not well known. Endoscopic retrograde cholangiography (ERC)
      has been the standard method to diagnose bile duct stones, but accumulating data
      show there is a good agreement between ERC and endoscopic ultrasonography (EUS).
      The aim of the study was to evaluate the incidence and time course of stone
      migration in patients with bile duct stones by analyzing discrepancies between
      EUS and ERC as a function of the elapsed time between these two procedures. Stone
      migration was considered as the absence of stones at time of ERC regardless of
      the number of stones seen at EUS. METHODS: The main criterion for inclusion was
      the presence of bile duct stone as shown by EUS. Ninety-two consecutive patients
      were prospectively included in this study. RESULTS: Choledocholithiasis was
      absent at ERC in 12 patients. In univariate analysis, presence of gallbladder was
      significantly associated with an increased rate of stone migration (correction
      for multiple testing would remove this statistical significance). The size of the
      stone was the only independent factor to predict migration. CONCLUSION: Migration
      occurred in about 21% of cases within 1 month. Our study emphasizes the need to
      analyze carefully the results of comparative imaging studies of bile duct stones.

PMID- 10650261
TI  - Endoscopic management of sump syndrome after choledochoduodenostomy:
      retrospective analysis of 30 cases.
AB  - BACKGROUND: Side-to-side choledochoduodenostomy is a frequently performed
      operation. Postoperative biliary "sump syndrome" is infrequent, a complication
      for which endoscopic sphincterotomy is regarded as the treatment of choice.
      METHODS: We retrospectively analyzed 30 cases of sump syndrome and describe the
      symptoms, the delay before the appearance of symptoms, laboratory abnormalities,
      the nature of the biliary obstruction, and the outcome of endoscopic
      sphincterotomy including its efficiency and complications. RESULTS: The median
      clinical latency was 5 years (range 1 month to 28 years), the median delay
      between surgery and diagnosis was 6 years (range 1 month to 28 years). Fourteen
      patients had abdominal pain with fever, 5 had isolated abdominal pain, 4 had post
      prandial pain, 4 had hepatic abscesses, and 3 had acute pancreatitis. Liver
      function tests were abnormal in 79%. During endoscopic retrograde
      cholangiopancreatography, food debris was identified in 18 patients in the
      biliary sump, biliary calculi in 10 patients, and a mixture of food and calculi
      in 2 patients. All patients underwent endoscopic sphincterotomy without
      complication. Recurrence during a median follow-up of 36 months (range 3 months
      to 11 years) was not observed. CONCLUSIONS: Sump syndrome most often becomes
      symptomatic only after a long delay. Abdominal pain with fever was the most
      frequent symptom. Liver function tests were abnormal in the majority of patients.
      Food debris was the most frequent cause. Endoscopic sphincterotomy appeared to be
      a safe, reliable treatment.

PMID- 10650262
TI  - Factors predicting the number of EUS-guided fine-needle passes for diagnosis of
      pancreatic malignancies.
AB  - BACKGROUND: The factors that affect the number of needle passes needed to
      diagnose pancreatic malignancies using endoscopic ultrasound (EUS) -guided fine
      needle aspiration are unknown. METHODS: Patient and endosonographic data were
      prospectively recorded on 121 consecutive patients with pancreatic malignancy. Of
      these, 110 underwent EUS-guided fine-needle aspiration. A cytopathologist was in
      attendance for all aspiration procedures. RESULTS: Initial EUS detected a
      pancreatic mass in 96% of cases; 23% of these were not seen by computed
      tomography. EUS-guided fine-needle aspiration was performed in 109 of 110 (99%)
      patients, including 95 masses, 7 lymph nodes, and 7 hepatic metastases. EUS
      guided fine-needle aspiration provided a cytologic diagnosis of malignancy in 104
      of 110 (95%). Only tumor differentiation and the site of aspiration affected the
      number of passes. CONCLUSIONS: With the participation of a cytopathologist, EUS
      guided fine-needle aspiration can diagnose pancreatic malignancies with a high
      degree of accuracy. Only the aspiration site (mass versus node/liver metastasis)
      can be used to direct the number of passes if a cytopathologist is not present.
      Without a cytopathologist in attendance, 5 to 6 passes should be made for
      pancreatic masses and 2 to 3 for liver metastases or lymph nodes; however, this
      approach will be associated with a 10% to 15% reduction in definitive cytologic
      diagnoses, extra procedure time, increased risk and additional needles.

PMID- 10650263
TI  - Stigmata of recent hemorrhage in Dieulafoy's lesion.

PMID- 10650264
TI  - Endoscopic band ligation of Dieulafoy's lesion.

PMID- 10650265
TI  - Hyperplastic polyp causing ball-valve effect.

PMID- 10650266
TI  - Large gastric folds on plain x-ray.

PMID- 10650267
TI  - Endoscopic measurement of pancreatic tissue perfusion in patients with chronic
      pancreatitis and control patients.
AB  - BACKGROUND: Pancreatic blood flow is diminished in experimental models of acute
      and chronic pancreatitis. We attempted to develop a safe and reliable technique
      for its measurement in patients and to examine blood flow in patients with
      chronic pancreatitis and in control subjects. METHOD: Pancreatic blood flow was
      measured using the hydrogen gas clearance technique and an endoscopically placed
      platinum ductal electrode. Pancreatic blood flow was measured in 12 patients with
      chronic pancreatitis diagnosed clinically and radiographically, and in 11 control
      patients undergoing endoscopic retrograde cholangiopancreatography (ERCP) for non
      pancreatic pathology. RESULTS: Patients with chronic pancreatitis had a
      significantly lower pancreatic blood flow compared with control patients (51.5
      versus 91.7 mL/min/100 gm, p < 0.01). With secretin stimulation pancreatic blood
      flow increased in two control patients, whereas this notable rise was not seen in
      three patients with chronic pancreatitis. CONCLUSIONS: Measurement of pancreatic
      blood flow with an endoscopically placed electrode is relatively safe and simple
      to perform. The scarring and vascular fibrosis associated histologically with
      chronic pancreatitis is reflected in lower pancreatic blood flow.

PMID- 10650268
TI  - Prolonged ambulatory colonic manometric studies using endoclips.
AB  - BACKGROUND: It is difficult to study human colonic motility under physiologic
      conditions. An important limitation associated with prolonged colonic recording
      is the failure of the sensors to resist normal expulsive forces. METHOD: In this
      article we describe a method of endoscopically positioning a manometric catheter
      by using clips in conjunction with a solid-state catheter. With the use of a
      rotatable clip-fixing device loaded on to a colonoscope, the manometric catheter
      was clipped to the colonic mucosa. RESULTS: Recordings for up to 120 hours were
      obtained from 6 subjects without apparent migration of the catheter assembly. No
      complications were noted, the catheter does not interfere with defecation, and
      defecation does not result in its expulsion. CONCLUSION: The current technique
      will allow reliable ambulatory measurements over prolonged periods of time in
      relatively comfortable and unrestrained subjects. This technique should increase
      our understanding of normal and abnormal colonic motility.

PMID- 10650269
TI  - Prospective evaluation of an over-the-wire catheter US probe.
AB  - BACKGROUND: Pancreaticobiliary strictures identified at endoscopic retrograde
      cholangiopancreatography (ERCP) can be evaluated by intraductal ultrasonography
      (US). Two major difficulties are that sphincterotomy may be required and the
      stricture may not be traversable. We prospectively evaluated the ease and success
      of intraductal US using a new over-the-wire catheter US probe. METHODS: Biliary
      or pancreatic strictures discovered at ERCP were imaged with the new probe.
      Intraductal US performance times, image clarity, imaging depth and technical ease
      were measured. RESULTS: Twenty-one patients with a variety of inflammatory and
      malignant pancreaticobiliary lesions were studied. Thirteen of the 16 (81%)
      masses imaged by intraductal US were 10 mm or less in diameter. Sphincterotomy
      was not required. All strictures traversed by a guidewire were imaged. The
      sphincter of Oddi was successfully imaged in all patients with intact normal
      sphincters. Performance of intraductal US was rated as technically easy in all
      cases and image clarity was rated as good or very good in 15 of 21 (71%) cases.
      CONCLUSIONS: The new over-the-wire catheter US probe facilitates intraductal US.
      Sphincterotomy is avoided and strictures are successfully traversed. This probe
      makes it possible to image the sphincter of Oddi.

PMID- 10650270
TI  - Demonstration of Epstein-Barr virus localized in the colonic and ileal mucosa of
      a patient with ulcerative colitis.

PMID- 10650271
TI  - Successful endoscopic therapy of a gastric outlet obstruction due to a gallstone
      with intracorporeal laser lithotripsy: a case of Bouveret's syndrome.

PMID- 10650272
TI  - Pancreatic-pleural fistula: the role of ERCP in diagnosis and treatment.

PMID- 10650273
TI  - Acute pancreatitis complicating a huge ventral hernia: a case report.

PMID- 10650274
TI  - Acalculous cholecystitis presenting as hemobilia and jaundice.

PMID- 10650275
TI  - Effective hemostatic injection above the bleeding site for uncontrolled bleeding
      after endoscopic sphincterotomy.

PMID- 10650276
TI  - Diagnosis of recurrent rectal carcinoma by EUS-guided fine-needle aspiration.

PMID- 10650277
TI  - Multiple malignant gastric stromal tumors presenting with GI bleeding: a case
      report and a review of the literature.

PMID- 10650278
TI  - EUS appearance of esophageal pseudo-diverticulosis.

PMID- 10650279
TI  - Tracheoesophageal fistula from an indwelling endotracheal tube balloon: a report
      of two cases and review.

PMID- 10650280
TI  - Listeria sepsis as a complication of endoscopy.

PMID- 10650281
TI  - Colonoscopy in abdominal actinomycosis.

PMID- 10650282
TI  - Multifocal granular cell tumor of the biliary tree: case report and review.

PMID- 10650283
TI  - Surveying surveillance: are gastroenterologists consistently inconsistent,
      inconsistently consistent, or poorly educated?

PMID- 10650284
TI  - Endoscopy databases and endoscopic research.

PMID- 10650285
TI  - Basic techniques of ERCP

PMID- 10650286
TI  - Inflammatory bowel disease after India ink tattooing: too much of a good thing.

PMID- 10650287
TI  - Quality improvement of GI endoscopy--the "Endocard".

PMID- 10650288
TI  - Metaplastic ossification of a benign colonic polyp.

PMID- 10650289
TI  - Efficacy and safety of calcium channel blockers in heart failure: focus on recent
      trials with second-generation dihydropyridines.
AB  - BACKGROUND: Chronic heart failure (CHF) has high morbidity and mortality rates
      despite treatment with angiotensin-converting enzyme inhibitors, diuretics, and
      digoxin. Adjunctive vasodilation through calcium channel blockade has been
      suggested as potentially useful. However, the first-generation calcium channel
      blockers, including the dihydropyridine nifedipine, showed disappointing results
      in CHF. The second-generation dihydropyridines were expected to be of more value,
      and of all the calcium channel blockers, these drugs were the ones most studied
      in patients with CHF. METHODS AND RESULTS: The Medline databank was used to
      search studies in human beings (published in 1990 or later) that used
      dihydropyridines in patients with CHF. The references of the studies found were
      subsequently checked for additional data. In 17 studies and more than 2000
      patients with CHF, no consistent beneficial effect was observed with regard to
      exercise tolerance and functional capacity, whereas plasma neurohormones were not
      affected. On the other hand, in general, no worsening of CHF was seen with these
      second-generation dihydropyridines. Two larger studies (PRAISE and V-HeFT III)
      have given some estimates on the long-term effects of dihydropyridines, and no
      overall influence on mortality rate was found. Of note, subanalysis of the PRAISE
      study has suggested that in patients with a nonischemic cause of CHF, amlodipine
      might have a beneficial effect on survival. CONCLUSIONS: In this review we have
      focused on the efficacy and safety of dihydropyridines in patients with CHF, as
      reported in recent trials. The data do not support the use of dihydropyridines
      when primarily given as treatment for CHF. The results, however, suggest that
      these drugs can be safely given to patients with left ventricular dysfunction or
      CHF who need additional treatment for angina pectoris or hypertension.

PMID- 10650290
TI  - Percutaneous coronary artery intervention: the last five years and the next five
      years.

PMID- 10650291
TI  - Evolving trends in interventional device use and outcomes: results from the
      National Cardiovascular Network Database.
AB  - BACKGROUND: Although multiple new coronary interventional devices have been
      approved for marketing in the United States, use of these technologies in general
      clinical practice and their associated outcomes have not been reported. METHODS
      AND RESULTS: Using the National Cardiovascular Network's Coronary Interventional
      Database, we examined temporal trends in the use and outcomes of coronary stents,
      lasers, directional atherectomy, and rotational atherectomy devices at 12 US
      hospitals between January 1994 and December 1997 (n = 76,904). Over this period,
      the percentage of cases involving coronary stents rose more than 12-fold (from
      5.4% in 1994 to 69.0% in 1997). In contrast, use of atherectomy-type devices
      declined significantly. Device selection was strongly influenced by the patient's
      coronary anatomy and procedural indication, but less by age, sex, or race. Device
      use also varied significantly among individual centers (4-fold variation among
      sites in stent use and 6-fold variation in atherectomy use) even after adjusting
      for patient characteristics. Although overall mortality rates were unchanged
      during this 4-year period, procedural success rates have improved and
      complication rates have declined significantly. Lengths of postprocedure hospital
      stay also fell significantly for all patients undergoing coronary intervention in
      this time period. CONCLUSIONS: Percutaneous interventional strategies are rapidly
      changing with the explosive growth of coronary stent use and the decline in use
      of atherectomy devices. Patient outcomes, including complication rates and
      postprocedure lengths of stay, have also improved as the new interventional
      strategies have been refined in clinical practice.

PMID- 10650292
TI  - Primary intracoronary stenting in acute myocardial infarction: long-term clinical
      and angiographic follow-up and risk factor analysis.
AB  - BACKGROUND: Coronary stent placement may be an effective primary intervention in
      acute myocardial infarction. Recently published or reported data indicate that
      primary stenting may be superior to primary plain balloon angioplasty in this
      setting. The aim of this study was to analyze the long-term clinical and
      angiographic follow-up of patients treated with primary intracoronary stenting
      and to identify the predictive factors of an adverse outcome. METHODS: The study
      population was composed of 519 consecutive patients with acute myocardial
      infarction (43 in cardiogenic shock) and attempted primary stent implantation.
      Adverse clinical events such as death, recurrent infarction, and target vessel
      revascularization were recorded. Six-month follow-up angiography was performed in
      78.2% of the eligible patients, and coronary dimensions were assessed with an
      automated quantitative system. RESULTS: Procedural success was achieved in 500
      patients (96.3%). The incidence of reocclusion was 3.2%. Thirty-day mortality
      rate was 5. 4% (2.5% in patients without shock); adverse clinical events were
      encountered in 10.4% of the patients. Independent risk factors for an adverse
      outcome were longer time to treatment, Killip class, reduced left ventricular
      function, overlapping stents, and residual dissection. The incidence of
      angiographic restenosis was 30.6%. One-year survival rate was 89.0%; 86.5% of the
      patients did not have a myocardial infarction and 71.7% did not have any major
      adverse event. CONCLUSIONS: Primary intracoronary stenting in patients with acute
      myocardial infarction is associated with a favorable early and long-term outcome.
      This is the result of low reocclusion and restenosis rates achieved by stenting.

PMID- 10650293
TI  - Abnormal myocardial mechanics in Kawasaki disease: rapid response to gamma
      globulin.
AB  - BACKGROUND: The time course and rate of recovery of myocardial dysfunction in
      association with Kawasaki disease in response to intravenous gamma-globulin is
      unknown and may provide mechanistic clues. METHODS AND RESULTS: The acute changes
      in myocardial contractility in 25 patients with Kawasaki disease were evaluated
      by noninvasive stress-shortening and stress-velocity analysis. Echocardiograms
      were performed before and then daily for 4 days during which the patients
      received gamma-globulin 1.6 to 2 g/kg. Before treatment, contractility was
      abnormally low (<2 SD) in 14 patients (56%). Contractility increased
      significantly (2 SD increase) in 17 (68%), including 13 of 14 with depressed
      contractility and 4 whose initial contractility fell within normal limits. Of the
      14 patients with depressed contractility, 8 (57%) normalized within 24 hours and
      a further 5 (35.7%) normalized within 6 months. A clinical response to treatment
      (fall in C-reactive protein by 50% and/or resolution of fever within 4 days) was
      seen in 22 patients (88%). Contractility increased in 17 of the 22 clinical
      responders and was normal before therapy in the other 5. The 3 patients who did
      not respond clinically also had no change in contractility with gamma-globulin
      therapy. Long-term (more than 12 months) follow-up was available in 19 patients.
      All patients had normal contractility at late follow-up. CONCLUSIONS: More than
      half the patients with Kawasaki disease have abnormal contractility at
      presentation. Myocardial response to gamma-globulin therapy is associated with
      rapid improvement in myocardial mechanics, with a high concordance between the
      clinical and myocardial response to therapy. The speed of recovery suggests that
      depressed contractility in patients with Kawasaki disease is caused by a rapidly
      reversible process such as circulating toxins or activated cytokines. Long-term
      outcome is good even in those patients with slow recovery of myocardial function.

PMID- 10650294
TI  - Accuracy of dobutamine technetium 99m sestamibi SPECT imaging for the diagnosis
      of single-vessel coronary artery disease: comparison with echocardiography.
AB  - BACKGROUND: Recent experimental studies have shown that technetium 99m
      methoxyisobutyl isonitrile (MIBI) underestimates flow heterogeneity induced by
      dobutamine and that this might have an impact on the sensitivity of dobutamine
      MIBI in patients with single-vessel coronary artery disease (CAD). This study
      compares the accuracy of dobutamine MIBI single-photon emission computed
      tomography (SPECT) and simultaneous echocardiography in the diagnosis of single
      vessel CAD. METHODS AND RESULTS: Ninety-one patients (age 57 +/- 12 years) with
      single-vessel CAD or without significant CAD were studied with dobutamine (up to
      40 microg/kg per minute)-atropine (up to 1 mg) stress echocardiography (DSE) and
      simultaneous MIBI SPECT imaging. CAD was predicted on the basis of myocardial
      ischemia (transient wall motion abnormalities by DSE and reversible perfusion
      defects by MIBI). Ischemia was detected by MIBI in 30 of the 54 patients with and
      in 10 of the 37 patients without significant single-vessel CAD (sensitivity 56%,
      confidence interval [CI] 45 to 66; specificity 73%, CI 64 to 82; accuracy 63%, CI
      53 to 73). Ischemia was detected by DSE in 30 patients with and in 6 patients
      without significant CAD (sensitivity of DSE 56%, CI 45 to 66; specificity 84%, CI
      76 to 91; accuracy 67%, CI 57 to 77, P = not significant vs MIBI). For both
      imaging methods, sensitivity was significantly higher in patients with left
      anterior descending than in patients with left circumflex or right coronary
      artery stenosis (75% vs 40%, P <.05). The addition of echocardiography to MIBI
      did not improve the diagnostic accuracy (68% CI 59 to 78, P = not significant vs
      DSE or MIBI alone). CONCLUSIONS: DSE and MIBI SPECT imaging have similar moderate
      sensitivity for the diagnosis of single-vessel CAD. Sensitivity of each of these
      techniques is higher in patients with left anterior descending than in patients
      with left circumflex or right coronary artery stenosis. There is no improvement
      of diagnostic accuracy by use of the combination of both techniques.

PMID- 10650295
TI  - Assessment of resting perfusion with myocardial contrast echocardiography:
      theoretical and practical considerations.
AB  - BACKGROUND: The aim of this study was to perform a quantitative comparison
      between myocardial contrast echocardiography (MCE) and single-photon emission
      computed tomography (SPECT) in patients with prior myocardial infarction (MI). We
      also wanted to determine the optimal method for the intravenous administration of
      an ultrasound contrast agent in the clinical setting. METHODS AND RESULTS:
      Seventeen patients with resting perfusion defects in a single vascular territory
      on SPECT were studied. MCE was performed with intermittent harmonic imaging
      during continuous infusions of a second-generation ultrasound contrast agent
      (Sonovue, Bracco Diagnostics) in all 17 patients and after bolus injection in 8
      of them. During continuous infusions, the video intensity (VI) ratio between the
      abnormal and normal myocardium at a pulsing interval (PI) of 8 cardiac cycles
      correlated well with the activity ratio between these segments on SPECT (r =
      0.73, P <.01). When information regarding microbubble velocity (MV) denoted as
      change in VI with increasing PIs was added, the correlation with SPECT activity
      ratio improved (P <.05) significantly (r = 0.87, P <.0001). Higher microbubble
      doses resulted in higher VI during continuous infusions with good myocardial
      opacification and no far-field attenuation until the highest dose was reached.
      With bolus injections, the VI ratio between the abnormal and normal myocardium at
      PI of 1 and 5 cardiac cycles showed a modest correlation (r = 0.46 and r = 0.48,
      respectively, P <.05) with activity ratios between these regions on SPECT. When a
      dose of microbubbles administered as a bolus produced adequate myocardial
      opacification, it invariably resulted in far-field attenuation. CONCLUSIONS: In
      patients with prior MI, quantitative assessment of resting perfusion defects on
      MCE correlates well with regional activity on SPECT. Continuous infusions offer
      an advantage over bolus injections because they can provide an assessment of both
      relative VI and MV. Adjustment of the microbubble infusion rate produces adequate
      myocardial opacification without attenuation.

PMID- 10650296
TI  - Mobile thrombi in the abdominal aorta in cases of lower extremity embolic
      arterial occlusion: value of extended transthoracic echocardiography.
AB  - BACKGROUND: Lower extremity embolic arterial occlusion is often associated with
      proximal atherosclerotic and/or aneurysmal disease. Fixed atherosclerotic disease
      of the abdominal aorta has been demonstrated by ultrasonography, tomographic
      studies, and aortography, but mobile debris has not previously been described. We
      report detection of mobile thrombi in the abdominal aorta during transthoracic
      echocardiography screening in 6 patients with lower extremity embolic arterial
      occlusion. METHODS: Six patients were referred to the echocardiography laboratory
      for evaluation of a source of peripheral arterial embolism. The transthoracic
      echocardiogram was extended to include longitudinal and transverse images of the
      abdominal aorta. Additional investigations included abdominal ultrasound (6
      patients), computed tomography (2 patients), angiography (2 patients), and
      transesophageal echocardiography (4 patients). RESULTS: Six patients (4 men, 2
      women, aged 46 to 79 years) presented with a blue toe syndrome consistent with
      atheroembolism. During transthoracic echocardiography with examination of the
      abdominal aorta, all were found to have significant atherosclerotic disease of
      the abdominal aorta with one or more mobile components. This finding had a
      significant impact on treatment of each patient. Surgical resection of the
      involved portion of the abdominal aorta in one patient demonstrated an ulcerated
      atheroma with overlying thrombus. CONCLUSION: In patients with lower extremity
      embolic arterial occlusion, evaluation of the abdominal aorta during
      transthoracic echocardiography should be a routine extension of the
      echocardiographic examination. The finding of mobile thrombi in the abdominal
      aorta identifies a potential source of embolism for which effective treatment
      exists.

PMID- 10650297
TI  - Power doppler harmonic imaging: a feasibility study of a new technique for the
      assessment of myocardial perfusion.
AB  - BACKGROUND: The aim of the study was to assess the feasibility of a new
      technique, power Doppler harmonic imaging (PDHI), for assessing myocardial
      perfusion through a venous injection of microbubbles, with the use of a new
      ultrasound contrast agent. METHODS AND RESULTS: Fifteen patients with known
      coronary artery disease and a resting perfusion abnormality on Tc-99m sestamibi
      single-photon emission computed tomography (SPECT) underwent PDHI at rest during
      intravenous injections of 2 to 3 mL of Sonovue (Bracco SpA, Milan, Italy), a new
      second-generation ultrasound contrast agent. Myocardial perfusion was determined
      to be present or absent by use of a 5-segment model by 2 blinded observers for
      both PDHI and SPECT. Of a total of 75 possible myocardial segments, 7 (9%) were
      not analyzed because of obvious artifacts on PDHI. SPECT showed perfusion defects
      in 40 of the remaining 68 segments, whereas PDHI showed 39 defects. There was
      high concordance between the 2 imaging modalities for the presence (93%) as well
      as the location (96% for the anteroseptal region, 93% for the inferoposterior
      region, and 87% for the apical region) of the defects. CONCLUSIONS: These
      preliminary results suggest that PDHI is a feasible technique for the detection
      of resting myocardial perfusion defects in patients with coronary artery disease
      after a venous injection of a new second-generation ultrasound contrast agent.

PMID- 10650298
TI  - Exercise training and myocardial remodeling in patients with reduced ventricular
      function: one-year follow-up with magnetic resonance imaging.
AB  - BACKGROUND: Exercise training is now an accepted therapeutic intervention in
      patients with reduced ventricular function after a myocardial infarction.
      However, there are conflicting reports on the effects of training on the
      remodeling process of the heart, and previous studies have only assessed short
      term effects of training. METHODS AND RESULTS: Twenty-five patients with reduced
      ventricular function after myocardial infarction were randomly assigned to an
      intensive 2-month exercise training program or to a control group (control group:
      n = 13, aged 55 +/- 7 years, ejection fraction 33.3% +/- 6%; exercise group: n =
      12, aged 56 +/- 5 years, ejection fraction 31.5% +/- 7%) and followed up for 1
      year. Measures of left ventricular size, function, and wall thickness in the
      infarct and noninfarct areas were made by magnetic resonance imaging at baseline,
      after the 2-month training period, and 1 year later. Maximal oxygen uptake
      increased in the trained group, from 19.7 +/- 3 mL/kg per minute at baseline to
      25.1 +/- 5 and 24.2 +/- 5 mL/kg per minute after 2 months and 1 year,
      respectively (P <.05 vs baseline for both), whereas the control group did not
      change significantly. Ejection fraction, end-diastolic volumes, and end-systolic
      volumes did not change at any measurement point throughout the study period in
      either the trained or control groups. Myocardial wall thickness measurements at
      end-diastole and end-systole and their differences determined by magnetic
      resonance imaging yielded no significant interactions between groups. When
      myocardial wall thickness measurements were classified by infarct or noninfarct
      areas, no differences were observed between groups over the study period.
      CONCLUSIONS: Intensive exercise training in patients with reduced ventricular
      function resulted in a significant improvement in exercise capacity after 2
      months, and this improvement was sustained over 1 year. In contrast to some
      recent reports, training had no deleterious effects on left ventricular volume,
      function, or wall thickness regardless of infarct area.

PMID- 10650299
TI  - Predictors of medical events in patients enrolled in the cardiac insufficiency
      bisoprolol study (CIBIS): a study of the interactions between beta-blocker
      therapy and occurrence of critical events using analysis of competitive risks.
AB  - BACKGROUND: The risk of occurrence of medical events in a clinical trial is
      competitive in nature; that is, in a given patient the risk of having a critical
      event depends on the amount of time elapsed since random assignment and on the
      previous events that may have occurred in the patient. The purpose of this study
      was to examine the relations between baseline variables, the interactions between
      treatment, bisoprolol, or placebo, and the occurrence of critical events during
      the CIBIS trial, a mortality and morbidity trial of beta-blockade in patients
      with heart failure. METHODS AND RESULTS: A Cox model for censored data was used
      to analyze the relations between baseline variables, total deaths, permanent
      treatment withdrawals, nonlethal cardiovascular events, and their interactions
      with bisoprolol or placebo. We examined the influence of treatment on the
      occurrence of deaths, permanent treatment withdrawals, and nonlethal
      cardiovascular events by using the technique of event history analysis, which
      takes into account competitive risks between events. Compared with placebo,
      bisoprolol reduced mortality rates in patients with a left ventricular ejection
      fraction < or =20% (relative risk [RR] 0.49; 95% confidence interval [CI] 0.27 to
      0.88; P =.02). In patients whose baseline heart rate was in the upper tertile of
      distribution, permanent treatment withdrawals were less frequent in patients
      randomly assigned to bisoprolol than in patients randomly assigned to placebo (RR
      0.50; 95% CI 0.28 to 0.88; P =.02). Bisoprolol reduced the incidence of nonlethal
      cardiac events in patients in whom heart failure was present for at least 4 years
      (RR 0.44; 95% CI 0.27 to 0.71; P <.01). Event history analysis revealed that
      among patients who died under treatment after having at least 1 nonlethal
      cardiovascular event, 20 patients were treated with placebo but only 7 patients
      were treated with bisoprolol (RR 0.41; 95% CI 0.17 to 0.98; P <.05). CONCLUSIONS:
      Some patients with heart failure derive more benefit from beta-blocker therapy
      than others. In the CIBIS trial, they are those patients with the lower left
      ventricular ejection fractions and those who have nonlethal cardiovascular events
      but in whom beta-blocker therapy is not permanently discontinued.

PMID- 10650300
TI  - Primary and subsequent coronary risk appraisal: new results from the Framingham
      study.
AB  - BACKGROUND: Coronary heart disease continues to be one of the most common chronic
      illnesses in the United States and most of the developed world. Clinicians and
      health authorities have interest in identifying individuals at increased risk of
      CHD. The Framingham Heart Study has over the years produced mathematical "health
      risk appraisal models" that relate risk factors to the probability of developing
      CHD. METHODS AND RESULTS: New sex-specific models from The Framingham Heart Study
      for primary and secondary (subsequent) CHD have been produced. The primary CHD
      models are appropriate for assessing CHD risk in persons free of cardiovascular
      disease and contain risk factors such as triglyceride levels, alcohol use, and
      menopausal status, risk factors not included in previously published models. The
      subsequent CHD models are applicable for persons with a history of CHD or
      ischemic stroke who have survived the acute period after the event. Age, blood
      lipid levels (total cholesterol and HDL cholesterol), and diabetes status are
      significant for men and women. In addition, systolic blood pressure and cigarette
      smoking are significant predictors of subsequent CHD in women. CONCLUSIONS: These
      new models are useful tools for better understanding the relation between risk
      factors and the occurrences of CHD events in individuals who are free of
      cardiovascular disease as well as persons who have had a prior CHD event or
      stroke. With the development of these latter models, the importance of blood
      lipid levels, diabetes, and, in women, systolic blood pressure and cigarette
      smoking as independent predictors of risk is once again underscored.

PMID- 10650301
TI  - Sex and other predictors of intra-aortic balloon counterpulsation-related
      complications: prospective study of 1119 consecutive patients.
AB  - BACKGROUND AND OBJECTIVE: Intra-aortic balloon counterpulsation (IABC)
      complication rates remain significant despite technical advances that have
      simplified and expanded its use. Previous reports implicated patient height,
      diabetes, or peripheral vascular disease as risk factors. However, these studies
      were small and not prospective. Therefore a prospective study at one high-volume
      center was conducted examining the complications associated with IABC and the
      role of sex and other risk factors in the current era. METHODS: The study
      prospectively evaluated 1174 consecutive percutaneous IAB insertions in 1119
      patients between 1993 and 1997. Major complications were defined as embolism or
      limb ischemia requiring surgery; bleeding requiring transfusion or surgery;
      systemic infection; balloon rupture; or death from one of these causes. Minor
      complications were defined as limb ischemia or pulse loss resolving without
      surgery or after IAB removal or bleeding not requiring transfusion or surgical
      intervention. All variables were analyzed with univariate and stepwise
      multivariate analysis. RESULTS: Data were collected on 1119 patients (727 men and
      392 women) with a mean age of 65 +/- 11 years. The prevalence of diabetes,
      hypertension, and peripheral vascular disease was 27%, 52%, and 8%, respectively.
      Complications occurred in 166 patients (15%) and a major complication occurred in
      126 (11%) of the 1119 patients. Multivariate logistic regression analysis was
      done with demographic, clinical, and procedural variables in a cohort of 1106
      patients. The analysis identified peripheral vascular disease (relative risk [RR]
      4.1), female sex (RR 2.3), and body surface area (RR 0.26 per m(2)) as
      independent predictors of a major complication. In addition, cardiac index (RR
      0.7) was also identified as an independent predictor of any or major
      complications in a subset of 915 patients. In 754 high-risk patients (women or
      patients with peripheral vascular disease, diabetes, cardiac index <2.2
      L/min/m(2), or body surface area <1.8 m(2)), 114 major complications occurred
      (15%) compared with 8 (3%) among 278 non-high-risk patients (P <.0001).
      CONCLUSIONS: The current complication rate associated with IABC remains
      significant. Advances in IAB technology need to focus on the high-risk subset of
      patients that includes women, smaller patients, and those with peripheral
      vascular disease.

PMID- 10650302
TI  - Correlates of high HDL cholesterol among women with coronary heart disease.
AB  - BACKGROUND: The National Cholesterol Education Program (NCEP) has designated high
      density lipoprotein cholesterol (HDL-C) > or =60 mg/dL a "negative" coronary
      heart disease (CHD) risk factor, but a substantial proportion of coronary events
      occur among women despite high HDL-C levels. METHODS AND RESULTS: The objective
      of this study was to characterize postmenopausal women with prevalent CHD despite
      HDL-C > or =60 mg/dL and to identify factors that may attenuate the protective
      effect of high HDL-C. We analyzed baseline data from a randomized, double-blind
      study of estrogen/progestin replacement therapy in 2763 postmenopausal women <80
      years old with CHD. Demographics, CHD risk factors, medications, anthropometrics,
      and lipid levels were compared among women with low, normal, and high HDL-C by
      NCEP criteria with and without stratification by use of lipid-lowering
      medications. Independent correlates of high HDL-C were determined by logistic
      regression analysis. HDL-C > or =60 mg/dL was present in 20% of participants.
      Women with high HDL-C were older, better educated, had fewer CHD risk factors,
      lower triglyceride levels and total cholesterol/HDL-C ratio, and were more likely
      to report past estrogen and current calcium antagonist, niacin, and statin use.
      beta-Blocker, diuretic, and fibrate use was less common. Older age, alcohol
      consumption, niacin, and calcium antagonist use and prior estrogen use were
      independently associated with high HDL-C, whereas waist-to-hip ratio, smoking,
      triglyceride level, and beta-blocker and fibrate use were inversely associated
      (all P <.05). CONCLUSIONS: High HDL-C, as defined by the NCEP, occurred in 20% of
      women with CHD in this cohort without a concomitantly higher prevalence of other
      CHD risk factors. Redefinition of "high" HDL-C levels for women may be warranted.

PMID- 10650303
TI  - Role of hypertension, diabetes, obesity, and race in the development of
      symptomatic myocardial dysfunction in a predominantly minority population with
      normal coronary arteries.
AB  - BACKGROUND: Hypertension, diabetes, and obesity have been reported as risk
      factors for both vascular and myocardial disease. Myocardial disease may be
      manifest as systolic or diastolic dysfunction. The development of coronary artery
      disease frequently obscures or confounds the myocardial disease. Our purpose was
      to study the effect of these risk factors and race on the frequency and severity
      of myocardial disease in the absence of coronary artery disease. METHODS AND
      RESULTS: We studied patients referred to the cardiac catheterization laboratory.
      We selected 233 patients with normal coronary arteries and excluded patients with
      other structural cardiac disorders and other causes of myocardial disease.
      Systolic function and diastolic function were determined. We gathered
      demographic, risk factor, clinical, and hemodynamic data on each patient. A
      multivariate analysis was performed to determine factors important to the
      development of myocardial disease in the absence of coronary artery disease.
      Diastolic dysfunction (44%) and systolic dysfunction (25%) were common findings.
      The 3 risk factors were found most often in black and Hispanic patients, but
      hypertension and obesity were most severe (P <.001) in black patients.
      Multivariate analysis indicated that a prior diagnosis of hypertension, level of
      systolic blood pressure, and severe obesity were the 3 factors independently
      associated with myocardial disease. CONCLUSIONS: Systolic dysfunction and
      diastolic dysfunction are common in patients with normal coronary arteries who
      have hypertension, diabetes, and/or obesity. Because these risk factors are so
      frequent and severe in the black population, myocardial disease is significantly
      more common in this segment of the population.

PMID- 10650304
TI  - Association of remnant-like particle cholesterol with coronary artery disease in
      patients with normal total cholesterol levels.
AB  - BACKGROUND: Limited information is available as to whether there is a difference
      in the association of lipid and fibrinolytic variables with coronary artery
      disease according to the presence or absence of elevated serum total cholesterol.
      We examined the levels of various lipid and fibrinolytic variables including
      remnant-like particle cholesterol (RLP-C). RLP-C is a recently established simple
      assay method for the estimation of triglyceride-rich lipoprotein remnants.
      METHODS AND RESULTS: Levels of total cholesterol, low-density lipoprotein
      cholesterol, high-density lipoprotein cholesterol (HDL-C), triglyceride,
      lipoprotein(a), RLP-C, uric acid, blood glucose, tissue plasminogen activator,
      tissue plasminogen activator inhibitor type 1, antithrombin III, and protein C
      were measured in 208 patients who underwent diagnostic coronary angiograms. Of
      these 208 patients, 57 were hypercholesterolemic (> or =220 mg/dL) and 151 were
      normocholesterolemic. HDL-C showed significant differences between patients with
      and those without angiographically determined coronary artery stenosis in both
      hypercholesterolemic and normocholesterolemic patients (P =.0025 and P =.0003,
      respectively). Both RLP-C and uric acid showed significant differences only in
      the normocholesterolemic subgroup (P =.0006 and P =.0060, respectively). This
      difference in uric acid was not significant by multivariable analysis. The ratio
      of RLP-C/HDL-C was demonstrated to be highly significantly (P <.0001) associated
      with coronary artery stenosis in patients with normal total cholesterol, whereas
      there was no statistically significant association in the hypercholesterolemic
      patient subgroup. CONCLUSIONS: Our current study disclosed that RLP-C levels are
      strongly associated with coronary artery disease, especially in patients with
      normal total cholesterol levels. Moreover, RLP-C/HDL-C ratio may be even more
      significantly associated with the presence of coronary artery stenosis in
      normocholesterolemic patients.

PMID- 10650305
TI  - Characteristics and outcomes in patients with acute myocardial infarction with ST
      segment depression on initial electrocardiogram.
AB  - BACKGROUND: Acute myocardial infarction (AMI) with nonreciprocal ST-segment
      depression is said to have a poor prognosis, and early diagnosis and treatment
      are problematic. The aim of this study was to determine the proportion of
      unselected consecutive patients admitted to a university center with AMI with
      nonreciprocal ST-segment depression and to characterize these patients in terms
      of clinical features, treatment, and short- and long-term prognoses. METHODS AND
      RESULTS: Admission electrocardiographic data on 852 consecutive admissions with
      AMI were analyzed. Nonreciprocal ST-depression was an admitting feature in 95
      (11%) patients, the majority of whom had ST depression >3 mm. These were older
      (70.3 vs 66.8 years, P <.05), more likely to have had myocardial infarction (40%
      vs 25%, P <.01), and to have left ventricular failure (56% vs 42%, P <.5),
      cardiogenic shock (15% vs 9% P =.06), and atrial fibrillation (34% vs 19%, P
      <.01). Hospital mortality rate was significantly higher (31% vs 17%, P <.01).
      Patients were less likely to undergo thrombolysis (17% vs 31%, P <.01),
      angiography (22% vs 35%, P <.05), or percutaneous revascularization (5% vs 9%, P
      <.01). Patients with ST depression undergoing coronary angiography were more
      likely to have 3-vessel disease (71% vs 47%, P <.05). Mortality rate at follow-up
      (median 36 months) was significantly higher in patients with ST depression (56%
      vs 32%, P <.001). Analysis by individual electrocardiography demonstrated ST
      segment depression to be the third most frequent presentation after ST elevation
      (n = 327) and T-wave changes (n = 258), in whom hospital mortality rates were 24%
      and 9%, respectively. In multivariate analysis, previous myocardial infarction
      was an independent predictor of nonreciprocal ST depression at initial
      examination (odds ratio 2.04 [1.25 to 3.34], P <.005). No electrocardiographic
      presentation was an independent predictor of death in the hospital after AMI.
      CONCLUSIONS: In unselected cases of AMI, patients with ST-segment depression make
      up a significant minority (11%), who are likely to be older with a high
      prevalence of previous myocardial infarction and multivessel disease, and who
      have a poor prognosis.

PMID- 10650306
TI  - Role of soluble and platelet-bound P-selectin in discriminating cardiac from
      noncardiac chest pain at presentation in the emergency department.
AB  - BACKGROUND: It has been reported that selectins participate in the pathogenesis
      of acute coronary syndromes by modulating platelet-leukocyte-endothelium
      interactions. Elevated P-selectin level also has been observed in the clinical
      setting of myocardial ischemia and reperfusion; however, its utility in
      differentiating cardiac from noncardiac origins of chest pain is unknown. METHODS
      AND RESULTS: Soluble and platelet fractions of P-selectin were measured for 122
      patients with chest pain and 14 healthy persons acting as controls. Patients with
      a cardiac problem (unstable angina, congestive heart failure, acute myocardial
      infarction) had significantly elevated levels of soluble P-selectin (156.0 +/-
      58.8 ng/mL, P =.002) and platelet-bound P-selectin (11.7% +/- 6.4% positive
      cells, P =.013) compared with the P-selectin profile among controls (102.6 +/-
      29.0 ng/mL, 4.1% +/- 1.2% positivity) and among patients with noncardiac chest
      pain (114.7 +/- 36.6 ng/mL, 5.7% +/- 2.9% positivity). With a cutpoint of 10%
      positivity for membrane and 120 ng/mL for soluble P-selectin, the sensitivities
      were 0.442 and 0. 558, and the specificities were 0.915 and 0.553. CONCLUSIONS:
      When a patient arrives in the emergency department, measurement of membrane P
      selectin may serve as an additional diagnostic tool to detect heightened platelet
      activity, which is most prevalent among patients with a cardiac origin of chest
      pain. However, low sensitivity limits the utility of the P-selectin profile alone
      in suitably differentiating acute coronary syndromes within the overall
      population of patients with chest pain.

PMID- 10650307
TI  - Aortic atheroma morphology and the risk of ischemic stroke in a multiethnic
      population.
AB  - BACKGROUND: Protruding atheromas in the aortic arch are an independent risk
      factor for ischemic stroke in the elderly. However, the role of atheroma
      morphologic characteristics (ulceration and mobility) has been less well
      characterized. Moreover, data have been obtained in predominantly white
      populations, and little is known about the association between atheromas and
      stroke in minorities. METHODS AND RESULTS: We performed transesophageal
      echocardiography in 152 elderly patients with stroke (58 white, 45 black, 49
      Hispanic) and in 152 age- and race/ethnicity-matched control patients. Atheromas
      were classified as small (<4 mm in thickness), large noncomplex (> or =4 mm, no
      ulceration or mobility), and complex (ulcerated or mobile). Logistic regression
      analysis was performed to assess the risk of stroke associated with different
      definitions of atheroma in the overall group and in the race-ethnic strata after
      adjusting for the presence of other stroke risk factors. Complex atheromas were
      strongly associated with stroke in the overall group (22.4% in cases, 2.6% in
      control patients; adjusted odds ratio [OR] 17.1, 95% confidence intervals [CI]
      5.1 to 57.3), whereas large noncomplex atheromas conferred a mildly increased
      stroke risk (22.4% vs 16.5%; adjusted OR 2.4, 95% CI 1.1 to 5.1). Complex
      atheromas also were strongly associated with stroke in whites (adjusted OR 24. 3,
      95% CI 3.9 to 150.6) and Hispanics (adjusted OR 13.9, 95% CI 1.4 to 136). In
      blacks, complex atheromas were significantly more frequent in cases (15.6% vs 0%;
      P =.006), but their absence in control patients precluded the calculation of the
      OR. Complex atheromas were twice as frequent in white patients with stroke (32.
      3%) than in black or Hispanic patients (15.6% and 16.3%, respectively; P =.05).
      CONCLUSIONS: Aortic atheroma complexity rather than size is strongly associated
      with ischemic stroke in the elderly. Complex atheromas are significantly
      associated with stroke in all 3 race-ethnic subgroups.

PMID- 10650308
TI  - The iron (Fe) and atherosclerosis study (FeAST): a pilot study of reduction of
      body iron stores in atherosclerotic peripheral vascular disease.
AB  - BACKGROUND: Levels of body iron stores, represented by the serum ferritin
      concentration, rise with age after adolescence in men and menopause in women.
      This rise has been implicated mechanistically and epidemiologically in the
      pathogenesis of atherosclerosis through iron-induced oxygen free radical-mediated
      lipid oxidation. However, the precise contribution of iron stores to
      atherosclerosis and its complications are unknown because prospective randomized
      trials designed to test effects of reduction of iron stores on clinical outcomes
      in this disease have not been performed. METHODS AND RESULTS: In preparation for
      a prospective randomized trial, a randomized pilot study was conducted to
      evaluate the feasibility, safety, and methodologic accuracy of calibrated
      reduction in iron stores by phlebotomy in a cohort of patients with advanced
      peripheral vascular disease. Phlebotomy resulted in a significant reduction in
      serum ferritin concentration to near targeted levels. Thus the formula for
      calculating the volume of blood to be removed to achieve a predetermined
      decrement in serum ferritin concentration was accurate and phlebotomy was not
      associated with any adverse laboratory or clinical effects. CONCLUSIONS:
      Reduction of body iron stores to a predetermined level is feasible and can be
      achieved in a timely manner with excellent patient compliance. Prospective
      randomized trials of calibrated reduction of body iron stores may be undertaken
      to define their pathophysiologic significance in atherosclerosis and other
      diseases in which excessive iron-induced oxidative stress has been implicated.

PMID- 10650309
TI  - Hemodynamic characteristics of congenital aortic stenosis: a quantitative stress
      echocardiography study.
AB  - BACKGROUND: Several investigators have studied the effects of exercise on
      pressure gradients and valve area measurements in patients with senile calcific
      aortic stenosis. However, there are limited data on young patients with
      congenital aortic stenosis. The current study was conducted to assess the dynamic
      effect of exercise on aortic valve area and to determine whether pressure
      gradients or valve area determinations correlate with duration of exercise in
      these patients. METHODS AND RESULTS: Twenty-five young patients with congenital
      aortic stenosis and 10 normal control patients performed symptom-limited bicycle
      exercise stress tests with quantitative 2-dimensional and Doppler analysis.
      Compared with normal patients, there were no significant differences in the
      directional changes in blood pressure, left ventricular volumes, and ejection
      fraction. There was no correlation between either peak instantaneous or mean
      transaortic pressure gradient and exercise duration. A small but statistically
      significant correlation was detected between the continuity equation aortic valve
      area and duration of exercise (r = 0.49, P =.013). Aortic valve area did not
      change with exercise in the patient cohort (1.5 +/- 0.6 vs 1.5 +/- 0.6; P = not
      significant). CONCLUSIONS: Aortic valve area does not change significantly with
      exercise in asymptomatic patients with congenital aortic stenosis. Consistent
      with prior studies, there was no correlation between the duration of exercise and
      the mean resting aortic valve gradient. A modest but statistically significant
      correlation was detected between exercise duration and aortic valve area. Further
      studies are required to determine whether aortic valve area measurements would
      provide useful adjunctive data on which to base recommendations for participation
      in competitive sports.

PMID- 10650310
TI  - Spatial, individual, and temporal variation of the high-frequency QRS amplitudes
      in the 12 standard electrocardiographic leads.
AB  - BACKGROUND: Analysis of high-frequency QRS amplitudes (HF-QRS) may provide an
      additional diagnostic tool in patients with heart disease, but the basic
      properties of these waveforms have not been sufficiently investigated. This study
      describes the spatial, individual, and temporal variation at rest of HF-QRS
      recorded with the 12 standard electrocardiographic leads in patients with
      ischemic heart disease. METHODS AND RESULTS: Two consecutive electrocardiographic
      recordings from 67 patients were signal averaged and analyzed within a bandwidth
      of 150 to 250 Hz. The HF-QRS values were expressed as root mean square values.
      There was a spatial variation in HF-QRS among the 12 leads, with higher
      amplitudes in V(2) through V(4), II, aVF, and III. The individual variation among
      the patients was large for all leads. The sum of the HF-QRS for all 12 leads in
      each patient ranged from 20 to 75 microV (mean 36 +/- 11 microV). The mean of the
      temporal variation in HF-QRS for all 12 leads between the 2 recordings was only
      0.10 +/- 0. 09 microV. CONCLUSIONS: Because of the large individual variation,
      analysis of HF-QRS is probably most applicable in monitoring situations when it
      is possible to track changes in a patient over time. The temporal variation in HF
      QRS at rest is small, both in patients with and those without prior myocardial
      infarction.

PMID- 10650313
TI  - Efficacy of low-molecular-weight heparin in acute coronary syndromes.

PMID- 10650314
TI  - Combination therapy for acute myocardial infarction: fibrinolytic therapy and
      glycoprotein IIb/IIIa inhibition.
AB  - Reperfusion with a regimen of fibrinolytic therapy, aspirin, and unfractionated
      heparin is limited by a less than desirable reperfusion rate, an excessive
      reocclusion rate, a dose-limiting intracranial hemorrhage rate, and a competitive
      posture relative to direct coronary angioplasty. Only 50% to 60% of patients
      achieve early Thrombolysis in Myocardial Infarction grade 3 flow within 90
      minutes with the most effective thrombolytic regimens. Even after initial
      reperfusion is achieved, transient and permanent reocclusion occurs too often and
      is associated with a high mortality rate. As more older patients are being
      treated, intracranial hemorrhage is becoming more common. Finally, the risk of
      bleeding and procedural failure has been high in patients who received an acute
      percutaneous interventional procedure shortly after treatment with fibrinolytic
      therapy. Early studies combining full-dose fibrinolytic treatment and
      glycoprotein IIb/IIIa inhibitors have been promising with regard to overcoming
      these limitations, but concern about bleeding has hindered this strategy. Several
      recent trials have evaluated full-dose abciximab with reduced-dose fibrinolytic
      therapy and have yielded promising results. The complementary nature of the
      results from different trials is striking, with substantial evidence that
      approximately half the conventional dose of fibrinolytic therapy combined with
      full-dose glycoprotein IIb/IIIa inhibition with abciximab achieves high rates of
      grade 3 flow and excellent clinical outcomes. This approach will now be tested in
      a large-scale mortality trial.

PMID- 10650315
TI  - Clinical challenges of platelet glycoprotein IIb/IIIa receptor inhibitor therapy:
      bleeding, reversal, thrombocytopenia, and retreatment.
AB  - Randomized clinical trials of glycoprotein IIb/IIIa integrin inhibition during
      percutaneous coronary intervention and as adjunctive treatment of acute coronary
      syndromes have shown impressive clinical efficacy in reducing the morbidity and
      mortality rates of cardiovascular disease. Three agents are currently available
      in the United States: abciximab (ReoPro), eptifibatide (Integrilin), and
      tirofiban (Aggrastat). Pharmacodynamic studies show that abciximab is a high
      affinity agent with a low dissociation constant; eptifibatide and tirofiban are
      high-specificity agents with higher dissociation constants and concentration
      dependent antiplatelet effects. This article first reviews the relevant
      pharmacokinetic and pharmacodynamic properties of each of the agents. These
      principles are then applied to a discussion of the 4 primary clinical issues
      concerning their use: prevention of untoward bleeding, algorithms for acute
      reversal, recognition and treatment of thrombocytopenia, and the issue of
      readministration.

PMID- 10650316
TI  - Potent complementary clinical benefit of abciximab and stenting during
      percutaneous coronary revascularization in patients with diabetes mellitus:
      results of the EPISTENT trial.

PMID- 10650317
TI  - Platelet glycoprotein IIb/IIIa receptor blockers: An appropriate-use model for
      expediting care in acute coronary syndromes.

PMID- 10650319
TI  - Cardiomyopathy in childhood, mitochondrial dysfunction, and the role of L
      carnitine.
AB  - Cardiomyopathy in childhood is associated with high morbidity and mortality
      rates. Many metabolic causes have been identified, including genetic or acquired
      defects in mitochondrial energy production affecting beta-oxidation, carnitine
      transport, and the electron transport chain. Combining conventional inotropic and
      antiarrhythmic therapy with metabolic interventions has improved overall outcome.
      L-carnitine, a natural substance involved in mitochondrial transport of fatty
      acids, is one such therapy and plays a central role in the regulation of the
      inner mitochondrial supply of free coenzyme A. Carnitine deficiency can be caused
      by both genetic and environmental causes with resultant signs and symptoms of
      metabolic disease, including cardiomyopathy. Administration of L-carnitine can
      result in improvement or resolution of the cardiomyopathy.

PMID- 10650320
TI  - Mitochondrial defects in cardiomyopathy and neuromuscular disease.
AB  - Over the past 11 years, a considerable body of evidence has accumulated
      implicating defects in the mitochondrial energy-generating pathway, oxidative
      phosphorylation, in a wide variety of degenerative diseases including myopathy
      and cardiomyopathy. Most classes of pathogenic mitochondrial DNA mutations affect
      the heart, in association with a variety of other clinical manifestations that
      can include skeletal muscle, the central nervous system (including eye), the
      endocrine system, and the renal system. To better understand the pathophysiologic
      basis of mitochondrial diseases and their role in myopathy and cardiomyopathy,
      several mouse models of mitochondrial disease have been prepared. Mitochondrial
      DNA mutations from cultured cells have been introduced into mice; nuclear DNA
      genes involved in mitochondrial energy production and reactive oxygen species
      detoxification have been genetically inactivated, which resulted in mice with
      hypertrophic and dilated cardiomyopathy, respectively. Physiologic
      characterization of these mice has confirmed the importance of decreased
      mitochondrial energy production, increased mitochondrial reactive oxygen species
      production, and the mitochondrial initiation of apoptosis in mitochondrial
      disease. With these insights, new therapeutic approaches for neuromuscular and
      cardiac disease have been suggested.

PMID- 10650321
TI  - Design and implementation of the North American Pediatric Cardiomyopathy
      Registry.
AB  - The Pediatric Cardiomyopathy Registry (PCMR) was established to describe the
      epidemiologic features and clinical course of selected cardiomyopathies in
      patients aged 18 years or younger and to promote the development of etiology
      specific treatments. Sixty-one private and institutional pediatric cardiomyopathy
      practices in the United States and Canada were recruited to participate in the
      PCMR. The registry consists of a prospective, population-based cohort of patients
      in 2 regions (New England and the Central Southwestern United States) and a
      retrospective cohort of patients diagnosed between 1991 and 1996. Annual follow
      up data are collected on all patients. As of June 1999, the PCMR consisted of 337
      prospectively identified and 990 retrospectively identified patients. The PCMR
      has demonstrated the feasibility of establishing a large database of
      sociodemographic and clinical information on children with pediatric
      cardiomyopathy. Through this cooperative effort, the PCMR will obtain precise
      estimates of the incidence of pediatric cardiomyopathy and a better understanding
      of the natural history of this disease.

PMID- 10650322
TI  - Familial carnitine transporter defect: A treatable cause of cardiomyopathy in
      children.
AB  - Carnitine transporter defect is characterized by severely reduced transport of
      carnitine into skeletal muscle, fibroblasts, and renal tubules. All children with
      dilated cardiomyopathy or hypoglycemia and coma should be evaluated for this
      transporter defect because it is readily amenable to therapy that results in
      prolonged prevention of cardiac failure. This article details the cases of 3
      children who have carnitine transporter defect, 2 of whom had severe dilated
      cardiomyopathy. Plasma and skeletal muscle carnitine levels were extremely low
      and both children were treated with oral L-carnitine, resulting in resolution of
      severe cardiomyopathy and prevention of recurrence or cardiac enlargement for
      more than 5 years. The third child had hypoglycemia and coma as presenting
      findings of the transporter defect and had mild left ventricular hypertrophy but
      no cardiac failure. The prognosis for long-term survival in pediatric dilated
      cardiomyopathy is poor. Children with carnitine transporter defect can have a
      different outcome if their underlying condition is detected early and treated
      medically.

PMID- 10650323
TI  - Increased glycolytic substrate protection improves ischemic cardiac dysfunction
      and reduces injury.
AB  - Early clinical trials of glucose-insulin-potassium for acute myocardial
      infarction were inconclusive. However, several recent placebo-controlled,
      prospective, randomized clinical trials of glucose-insulin-potassium for acute
      myocardial infarction or metabolic support during and after cardiac surgery have
      demonstrated its efficacy. These clinical results are supported by experimental
      studies that have shown a strong protective effect of increased glycolytic
      substrate on ischemic myocardium in concert with an improved bioenergetic status.

PMID- 10650324
TI  - Regulation of carbohydrate metabolism in ischemia and reperfusion.
AB  - Administration of L-carnitine reduces ischemic myocardial injury in a number of
      experimental model systems and may improve the clinical outcomes of patients with
      acute myocardial infarction. The efficacy of carnitine in this setting is
      probably not attributable to an increase in fatty acid oxidation, which can be
      detrimental to myocardial recovery during reperfusion. Instead, recent research
      suggests that carnitine is also crucial in the regulation of carbohydrate
      metabolism in addition to its role in the oxidation of fatty acids. In isolated
      rat hearts, administration of carnitine increases the oxidation of glucose while
      decreasing the oxidation of palmitate. This increase in carbohydrate metabolism
      is accompanied by a significant improvement of contractile function during
      reperfusion of ischemic hearts. The beneficial effects of carnitine seen in
      patients after an acute MI may be attributable to an improvement in myocardial
      energy metabolism. Controlled clinical trials will be useful in confirming the
      results from these experimental studies.

PMID- 10650325
TI  - Three-year survival of patients with heart failure caused by dilated
      cardiomyopathy and L-carnitine administration.
AB  - We examined the efficacy of long-term L-carnitine administration for the
      treatment of heart failure caused by dilated cardiomyopathy in adult patients. To
      accomplish this, we studied 80 patients with moderate to severe heart failure
      (New York Heart Association classification III to IV) caused by dilated
      cardiomyopathy. This article reports on the nearly 3 years of follow-up data on
      patient mortality. Primary results will be published in the future. After a
      period of stable cardiac function up to 3 months, patients were randomly assigned
      to receive either L-carnitine (2 g/d orally) or placebo. There were no
      statistical differences between the 2 groups at baseline examination in clinical
      and hemodynamic parameters, such as ejection fraction, Weber classification,
      maximal time of cardiopulmonary exercise test, peak VO(2) consumption, arterial
      and pulmonary blood pressure, and cardiac output. After a mean of 33.7 +/- 11.8
      months of follow-up (range 10 to 54 months), 70 patients were in the study: 33 in
      the placebo group and 37 in the L-carnitine group. At the time of analysis, 63
      patients were alive. There were 6 deaths in the placebo group and 1 death in the
      L-carnitine group. Survival analysis with the Kaplan-Meier method showed that
      patients' survival was statistically significant (P <.04) in favor of the L
      carnitine group. L-carnitine appears to possess considerable potential for the
      long-term treatment of patients with heart failure attributable to dilated
      cardiomyopathy.

PMID- 10650326
TI  - Myocardial infarction and left ventricular remodeling: results of the CEDIM
      trial. Carnitine Ecocardiografia Digitalizzata Infarto Miocardico.
AB  - Left ventricular dilatation after acute myocardial infarction (MI) is a powerful
      predictor of progressive functional deterioration, culminating in heart failure
      and death. The most important determinants of post-MI left ventricular remodeling
      are the size of the infarct, the degree of residual stenosis in the infarct
      related artery, and the viability of the infarct zone. In addition to reperfusion
      therapy and angiotensin-converting enzyme inhibition, metabolic intervention with
      L-carnitine may represent a therapeutic approach for preventing left ventricular
      dilatation and preserving cardiac function. Ongoing studies with early metabolic
      intervention with carnitine in the acute phase of infarction may prove successful
      in protecting the microcirculation against ischemic damage and enhancing its
      ability to respond to blood flow resumption. The results of the multicenter,
      randomized, double-blind Carnitine Ecocardiografia Digitalizzata Infarto
      Miocardico (CEDIM) trial suggest that the early and long-term administration of L
      carnitine attenuates progressive left ventricular dilatation after acute anterior
      MI. Results show significant, consistent reductions in end-diastolic volume and
      end-systolic volume in patients who received L-carnitine compared with placebo.
      The ongoing CEDIM-2 trial (projected 4000 patients with acute MI) will assess the
      efficacy of L-carnitine in reducing the combined incidence of death and heart
      failure at 6 months. In addition to standard reperfusion therapy and angiotensin
      converting enzyme inhibition, metabolic intervention with L-carnitine may be a
      therapeutic approach for preventing left ventricular dilatation and preserving
      cardiac function by limiting infarct size, decreasing residual stenosis in the
      infarct-related artery, and increasing viability of the infarct zone.

PMID- 10650327
TI  - Establishment of a phagocytic cell line from Bombina orientalis.
AB  - Continuous serum-free culture of Bok-2 cells was generated from primary culture
      of the tail bud stage embryos of the toad, Bombina orientalis. Bok-2 cells can be
      maintained in modified L-15 serum-free medium prepared by mixing L-15 medium,
      lactalbumin enzymatic hydrolysate, sucrose and sodium bicarbonate. Bok-2 cells
      have an ameboid behavior and morphology. When Bok-2 and viable Candida albicans
      were co-cultured, Bok-2 cells showed an immune response characterized by
      chemotaxis, phagocytosis and partial clearing activity of Candida cells and
      colonies. And Bok-2 cells also showed phagocytosis of latex beads without serum
      treatment and displayed numerous pseudopodia, membrane evagination for
      phagocytosis and phagosome activity. On the basis of these results, Bok-2 cells
      were identified as professional phagocytes.

PMID- 10650328
TI  - Inhibition of prostaglandin synthesis reduces cyclic AMP levels and inhibits
      chondrogenesis in cultured chick limb mesenchyme.
AB  - The present study investigated effects of inhibiting the synthesis of
      prostaglandins (PGs) on cyclic AMP concentrations and chondrogenesis in cultured
      chick limb mesenchyme. Indomethacin produced concentration-dependent inhibition
      of both PGE(2) synthesis and chondrogenesis over a concentration range of 50--200
      microM. Half maximal inhibition of PGE(2) was achieved with 50 microM
      concentrations of the drug which also produced visibly reduced amounts of
      cartilage matrix in cell cultures as evaluated by Alcian green staining on day 6
      of culture. The inhibitory effects of indomethacin on chondrogenesis were largely
      reversed by addition of 1 mM dibutyryl cAMP, indicating that cells could still
      respond to cyclic AMP stimulation. Endogenous levels of cyclic AMP, which
      increased by 6 fold during the six days of culture in control cells, did not
      increase significantly from dissociated cells at the time of plating (day 0) in
      indomethacin- treated cultures. The results indicate that inhibition of the
      prechondrogenic rise in PGE(2) concentrations in limb mesenchyme prevents the
      increase in cyclic AMP levels which occur during this same period resulting in
      inhibition of chondrogenesis. The data provide further support for the hypothesis
      that PGE(2), through its effects on the adenylate cyclase-cAMP system, plays an
      important role in the differentiation of cartilage.

PMID- 10650330
TI  - List of contributors

PMID- 10650329
TI  - The human epithelial cell cytotoxicity assay for determining tissue specific
      toxicity.
AB  - The Human Epithelial Cell Cytotoxicity (HECC) Assay for determining organ
      specific cytotoxicity uses human epithelial cells from eight different human
      tissues, including: skin, mammary, prostate, renal, bronchial, oral, ecto-cervix,
      and liver. Although the initial studies using this assay were conducted using
      cancer chemopreventive agents, the HECC Assay can also be used to evaluate other
      types of drugs, personal care products, environmental chemicals, and potential
      toxicants. Human epithelial cells at an early passage are seeded into multi-well
      dishes. The cells are exposed to multiple concentrations of a test agent for a
      three day period. The concentration ranges for test agents in the assay are
      determined in a preliminary assay using an exposure of five days and log
      dilutions from the highest soluble concentration. At the end of the exposure
      period, the cultures are evaluated for inhibition of growth. In the HECC Assay,
      cultures are exposed for three days. At the end of the exposure period, the
      cultures are evaluated for inhibition of growth, mitochondrial function, and PCNA
      expression or albumin synthesis (hepatocytes). Data are analyzed to determine the
      concentration that inhibited and point by 50 percent (TC(50)). Values for each
      agent in each target epithelial cell line or culture and the target tissue
      specific sensitivity are compared to determine the relative sensitivity of each
      epithelial cell line to the test agent.

PMID- 10650331
TI  - Generation of useful cell culture data.
AB  - As the need for viable and interpretable cell culture systems increases, it is
      not sufficient to simply be successful at growing cells in vitro. Rather,
      vigilance is required to obtain repeatable data from these systems, especially if
      mechanistic or developmental experimental designs are attempted. We suggest that
      all aspects of basic cell culture are as important as growing cells. We offer the
      papers of this issue to help the cell scientist scrutinize and identify problems
      in many of these important areas, including obtaining tissue, eliminating
      microbial contamination, formulating a defined medium, isolating specific cell
      types from tissue and then using them for in vitro studies, cloning cells,
      selecting and developing methods for cell culture analyses, and recognizing
      abnormal cell culture activity.

PMID- 10650332
TI  - Thoughts on the source of tissue on subsequent cell culture success.
AB  - This paper describes attempts to initiate equine adipocyte cultures from necropsy
      cases with varying intervals from time of death to isolation and culture. Equine
      adipocytes were isolated from 21 necropsy cases, regardless of the interval from
      time after death to establishment in primary ceiling cultures. However, while all
      cultures produced adipocytes, only 2 attempts to produce long-term equine
      adipocyte cultures from the subcutaneous rump fat depots were successful and not
      contaminated. Findings from these experiments indicate that it is possible to
      collect and culture equine adipocytes from necropsy cases with varying intervals
      of time of death to culturing provided that the issue of contamination is
      addressed. Viable cells were produced from tissue with an interval of 38.5 hours
      as well as 45 minutes. This result encourages the continuation of research using
      equine necropsy cases as a source of adipose tissue.

PMID- 10650333
TI  - Ten commandments for preventing contamination of primary cell cultures.
AB  - Procedures for preventing contamination in primary cell cultures must be
      carefully defined and strictly followed in order to obtain healthy cells.
      Protocols have been developed and refined in our laboratory for establishing
      primary cultures of muscle and fat stem cells without contamination from a
      variety of animals. Contamination of cell cultures is not only frustrating, but
      is also very expensive both in time and loss of materials. Through the consistent
      use of proper aseptic techniques, most instances of contamination may be avoided.
      We suggest that the basic principles detailed here will find wide applicability
      in the culturing of primary cells without contamination from many different types
      of animals and tissues.

PMID- 10650334
TI  - Formulation of a defined medium to maintain cell health and viability in vitro.
AB  - The first step in formulating a defined medium is to conduct a thorough search of
      the scientific literature. If a defined medium formulation is located that might
      be compatible with the intended cell system, a pilot study should be carried out
      to evaluate the general performance of the medium. Depending on the initial data
      obtained from this study, individual components of the medium and their
      concentrations may need to be manipulated (added/subtracted, increased/decreased)
      to obtain the desired results. Also, sometimes the basal medium or proportions of
      basal media must be changed. Because the formulation of a defined medium is a
      circular process, alteration of the basal medium type or ratio of basal media
      will necessitate redoing all of the previous addition/subtraction and
      optimization steps. Revalidation must also be done if vendors of components are
      changed or whenever different cells or cells of other ages are used in the
      system. This paper presents a brief procedure for formulating a defined media and
      an overview of the application of two defined media in muscle cell culture.

PMID- 10650335
TI  - Methods for animal satellite cell culture under a variety of conditions.
AB  - Primary and clonal culture systems have been devised and refined for animal
      derived satellite cells. Satellite cell (SC) culture development includes
      efficient cell isolation techniques, establishment of effective plating and
      growth conditions, formulation of media requirements and thorough evaluation of
      experimental limitations. As the field of muscle cell culture has expanded, the
      number of animal species from which satellite cells have been isolated has
      increased. The focus of this paper is to compare and contrast SC culture
      conditions presently used by a variety of researchers and to introduce a new
      source of SC from wapiti (elk).

PMID- 10650336
TI  - Preparation of pure cell cultures by cloning.
AB  - Due to the heterogeneous nature of animal organs, primary cell cultures
      potentially contain more than one type of cell. Interpretation of data arising
      from studies using these mixed cultures can lead to difficulties, because it may
      not be possible to ascertain which of the cell types present may have responded
      to a given treatment. While a number of procedures have been used to enrich the
      cell population of interest, many scientists have resorted to cloning of cells in
      order to insure the purity of cell cultures. Three major strategies have been
      used to produce clones, namely, the dilution technique, cloning ring technique,
      and robotic cell transfer. Successful cloning is dependent on optimization of
      attachment substrata, basal media composition, serum source, and growth
      factor/hormone additions to support proliferation of the cell type at clonal
      (low) density.

PMID- 10650337
TI  - Traditional and emerging methods for analyzing cell activity in cell culture.
AB  - The selection of appropriate techniques to assay for markers of cell activity is
      important for obtaining optimal results in cell culture-based research. This
      paper is intended as a guide to many of the assays currently available and new
      techniques that have been recently introduced in the literature. This paper
      addresses both manual assay techniques, including the use of hemocytometers,
      phase contrast microscopy, cell staining, and the immunofluorescent antibody
      assay (IFA), and automated assays for cell activity, including stained optical
      density, proliferating cell nuclear antigen, creatine kinase assay, DNA
      quantification, electronic cell counting, flow cytometry, magnetic cell sorting,
      image analysis, chemiluminescence, radioisotope labeling, precursor
      incorporation, in-situ hybridization/ligand binding, and enzyme-linked immuno
      culture assay (ELICA). Advantages/disadvantages and applicability of these assays
      to different areas of cell culture research are discussed, and guidelines for
      selecting an appropriate assay are suggested.

PMID- 10650338
TI  - Interpretation of cell culture phenomena.
AB  - This paper discusses the dilemma of interpreting unusual or abnormal phenomena
      seen in cell cultures and is not intended to address the statistical design of
      experiments. Problems that can be encountered when growing cells in experimental
      situations include low or decreasing cell numbers, abnormal cell morphology,
      microbial contamination, and detachment of the cell monolayer. If any of these
      situations occur, it is not realistic to proceed with data analysis until the
      problem is corrected. The best policy is to attempt to standardize all types of
      cultures used for analysis and to avoid using any cultures that display atypical
      characteristics.

PMID- 10650339
TI  - Hexamethylenebisacetamide modulation of thyroglobulin and protein levels in
      thyroid cells is not mediated by phosphatidylinositol-3-kinase: a study with
      wortmannin.
AB  - Hexamethylenebisacetamide (HMBA) induces in murine erythroleukemia cells (MELC)
      the commitment to terminal differentiation leading to globin gene expression. In
      the thyroid, HMBA acts as a growth factor and also as a differentiating agent. In
      the present paper, we studied the effect of HMBA on the very specific thyroid
      marker thyroglobulin (Tg) in two different thyroid cell systems, i.e., porcine
      cells in primary culture and ovine cells in long term culture. Using wortmannin,
      a specific inhibitor of phosphatidylinositol-3-kinase, we investigated whether
      this enzyme is involved in HMBA mode of action. We found that HMBA is a positive
      modulator of Tg production in porcine cells, but a negative effector in the OVNIS
      cell line. As all HMBA effects studied in the present paper, i.e., Tg production
      and total protein levels, are not inhibited by wortmannin, we suggest the non
      involvement of phosphatidylinositol-3-kinase in HMBA mode of action.

PMID- 10650340
TI  - Uptake of [(3)H]glycine by synaptosomes of channel.
AB  - It is known that channel catfish erythrocytes can take up glycine by several
      distinct transport systems. Further, glycine is an inhibitory neurotransmitter in
      mammalian brain and spinal cord. Consequently, the uptake of [(3)H]glycine by
      catfish brain was investigated and found to be a saturable process, dependent on
      the presence of Na(++) and Cl(--) and sensitive to temperature. A kinetic
      analysis of transport was performed at 22C. This showed that a high-affinity
      system existed which exhibited a K(m) of 5.1 (+/- 2. 1) microM. Several
      structural analogues of glycine were capable of inhibiting uptake in a
      competitive manner. The most effective inhibitor was sarcosine (IC(50) 5 36
      microM). Uptake was also able to be inhibited by harmaline, a drug known to
      interfere with Na(+)-dependent transport processes. It is concluded that glycine
      transport by channel catfish brain has much in common with transport by mammalian
      nervous tissue which is carried out by the membrane carriers GLYT1 and GLYT2. On
      the other hand, synaptosomal transport differs somewhat from glycine transport by
      channel catfish erythrocytes.

PMID- 10650341
TI  - Effect of cadmium on the epidermic structure of Bufo arenarum tadpoles: influence
      of the chemical composition of the incubation media.
AB  - Epidermic alterations in premetamorphic Bufo arenarum tadpoles were analyzed by
      scanning electron microscopy after exposure to sublethal cadmium concentrations
      in distilled water, in 141 mOsm solutions of mannitol and NaCl and in artificial
      pond water of 5 mOsm. Animals kept in NaCl solutions and in artificial pond water
      containing Cd did not show epidermic alterations. Cadmium in distilled water and
      in mannitol solutions caused loosening of cellular binding, cellular deformation
      and detachment and perforations of the epithelial membrane. Observed alterations
      were rapid and independent of the incubation media osmolarity. The interpretation
      of results must be linked to the competition between Cd and Ca, which is
      recognized as a basic factor in cellular adhesiveness.

PMID- 10650342
TI  - Cardiorespiratory responses to interleukin-1beta in adult rats: role of nitric
      oxide, eicosanoids and glucocorticoids.
AB  - Interleukin-1beta (IL-1beta) receptors are abundantly expressed in brain stem
      regions involved in respiratory control. We hypothesized that systemic
      administration of IL-1beta would increase ventilation (V(E )), and that nitric
      oxide, eicosanoids, and glucocorticoid receptors would modulate IL-1beta-induced
      cardioventilatory responses. Intravenous injections of three doses (37.5 ng kg(
      1), 75 ng kg(-1 ) and 150 ng kg(-1)) of IL-1b induced monophasic increases in
      (V(E)), heart rate (HR), and blood pressure (BP) which had a distinctly different
      onset and duration of action compared to IL-1beta-induced body temperature
      elevations. Pre-treatment with the nitric oxide inhibitor L-NAME was associated
      with decreased peak V(E) responses, without affecting the latency and duration of
      IL-1beta. L-NAME also enhanced HR responses while pressor responses were
      attenuated. Eicosanoid inhibition with indomethacin resulted in markedly
      attenuated V responses. However, cardiovascular responses to IL-1beta were not
      modified by indomethacin. In contrast, pre-treatment with dexamethasone, was not
      associated with any changes in the IL-1beta-induced V(E), HR, or BP responses. We
      conclude that IL-1beta increases of V(E) are dose-dependent and are not time
      locked with the pyrexic response suggesting the possibility that distinct neural
      pathways may underlie these responses. In addition, nitric oxide and eicosanoid
      dependent mechanisms modulate IL-1beta ventilatory effects.

PMID- 10650343
TI  - Excitatory and inhibitory responses of the ongoing sympathetic discharge in
      single renal neurons to liminal stimulation of aortic C-fibres in the rabbit.
AB  - Excitatory and inhibitory responses of sympathetic discharge were recorded in
      single renal postganglionic neurons of rabbits anaesthetized with urethane and
      chloralose. The animals were vagotomized and had transected aortic nerves.
      Responses were elicited by single volleys in the aortic C-fibres. Excitatory
      responses consisted in short-lasting increase in the rate of ongoing sympathetic
      discharge and were followed by inhibitory responses. Excitatory effects together
      with inhibitory responses were seen in 68% of units (19/28). Only excitatory
      effects appeared in 2 neurons (7.1%) and only inhibitory effects in 7 neurons
      (25%). In renal neurons exhibiting both effects, the excitatory responses
      appeared after latency of 172 +/- 8 ms (x +/- S.D.) and had duration of 64 +/- 11
      ms. Inhibitory effects had latency o f 257 +/- 10 ms and their duration amounted
      to 265 +/- 22 ms. In more than half of recordings the excitatory responses were
      separated from the inhibitory effects by discharge lasting 33 +/- 4 ms.
      Significant correlations between latencies of excitatory and inhibitory responses
      and between duration of excitatory and latency of inhibitory responses suggest
      interaction between both effects. Increase in the number of afferent volleys (1
      through 5) evoked relatively small changes in duration of the excitatory effect
      indicating that temporal facilitation is of minor importance in generating this
      response. Temporal facilitation was found to play an important role in
      determining duration of the inhibitory response. Comparison of effects of
      unilateral and bilateral stimulation of the aortic C-fibres showed larger
      occlusion of durations of the excitatory than inhibitory responses.

PMID- 10650344
TI  - Medullo adrenal response to lesion of anterodorsal thalamic nuclei in rats.
AB  - Anterodorsal thalamic nuclei (ADTN) exert an inhibitory influence on hypophyso
      adrenal system (HAS) in rats. With the purpose of evaluating if ADTN are also
      involved in the control of medullo adrenal activity, experiments were conducted
      on female rats with bilateral lesion of these nuclei. Thirty days after lesion,
      plasma epinephrine (E) concentration in lesioned rats was higher than that in
      sham-lesioned control group (P < 0.02). Meanwhile, adrenal E content was
      significantly lower in lesioned animals than that found in the control group (P <
      0.005). Plasma norepinephrine (NE) values in lesioned rats were not significantly
      different from those in the control ones, however, there was a significant
      decrease in adrenal NE when compared to the control one (P < 0.02). Basal values
      of plasma ACTH and plasma and adrenal corticosterone (C) were signicantly higher
      than those in sham lesioned rats (P < 0.05; P < 0. 001; P < 0.001 respectively).
      These findings demonstrate that the ADTN in rats are involved in the regulation
      of both cortico and medullo adrenal activity.

PMID- 10650345
TI  - Pharmacokinetics of radioiodinated growth hormones in the turtle Chrysemys
      dorbigni.
AB  - Growth hormone binding proteins (GHBP) have been identified in the blood of many
      species. The aim of the present work is to study the physiological role of the
      GHBP in the turtle serum which we recently described. Binding studies were
      carried out using in vivo pharmacokinetic and chromatographic techniques as well
      as in vitro methods. When (125)I-GH was injected in physiological concentration
      into Chrysemys dorbigni turtles, the first step of pharmacokinetics was the
      binding of a significant fraction of the labeled GH by the GHBPs present in
      serum. The decay curve followed a three compartments model and gave the equation:
      Ae(-alphat) + Be(-betat) + Ce(-gammat). The fast compartment with t(1/2) of 14.4
      min or 25.2 min, for hGH and bGH represents 30.3% and 18.9% of total
      radioactivity, respectively, at hypothetical time zero (not experi mental).
      Chromatographic studies reveal that this rapid compartment represents free GH.
      The second and third compartments represent complex forms between GH and GHBPs
      present in the turtle serum, and represent 70% and 80% of total radioactivity for
      hGH and bGH, respectively. In vitro chromatographic studies showed direct
      evidence of the presence of GHBPs in the turtle serum. The presence of these
      GHBPs changed the pharmacokinetics of labeled GH in plasma and the subsequent
      liver uptake of GH. The labeled hGH or bGH binds to turtle serum in similar
      proportion, but maximal liver uptake of these hormones are completely different
      (L/B ratio of 9.2 +/- 0.6 (n = 5) for ( 125)I-hGH and 4.8 +/- 0.3 (n = 7) for
      (125)I-bGH). The reasons for these differences could be that human GH binds to
      lactogenic and somatotropic receptors and bovine GH binds only to somatotropic
      receptors.

PMID- 10650346
TI  - The weekend increases sleep-related traffic accidents.

PMID- 10650347
TI  - Endothelin-1 stimulates phosphoinositide hydrolysis in the rat pineal gland.
AB  - The presence of functional endothelin receptors and their signal transduction
      mechanism has not been determined so far in the pineal gland. We examined the
      effect of endothelin-1 (ET-1) on phosphoinositide turnover in whole pineal gland.
      Endothelin-1 increased monophosphate accumulation in a dose-dependent manner. The
      phosphoinositide (PI) response elicited by ET-1 was dependent on the presence of
      extracellular Ca (++) since its chelation resulted in a marked decrease in ET-1
      stimulated InsP(1) accumulation. On the contrary, phosphoinositide hydrolysis was
      not changed by the calcium blocker amlodipine. ET-1 induced PI breakdown was
      inhibited by neomycin, an inhibitor of phospholipase C. However, mastoparan 7, a
      G protein activator via Gi/Go s timulation, did not alter ET-1-induced InsP(1)
      accumulation. Our data indicate that stimulation of PI turnover constitutes one
      of the signaling pathways of ET in rat pineal gland through the stimulation of a
      receptor-coupled phospholipase C. And they demonstrate, for the first time, the
      presence of functional binding sites for endothelin in the pineal gland.

PMID- 10650348
TI  - A rat model of progressive isometric strength training.
AB  - This study presents an isometric model of strength resistance training in rats.
      Seven rats were trained for five weeks with increasing load, once a day for six
      days per week while seven rats served as control group. Mechanical strength of
      the hindlimb muscle group was measured on anaesthetised rats with a force
      transducer linked to the Achilles tendon after electrical stimulation of the
      sciatic nerve. Training resulted in a 74 +/- 2% strength gain in experimental (E)
      vs control (C) rats and in a reduction of fatigability with no change in
      gastrocnemius, soleus and extensor digitorum longus weights. The fibres
      composition of the gastrocnemius showed a 50% increase of IIA fibres and a 17%
      fall of IIB fibres. Consequently, this new model of isometric training is
      suitable for physiological studies.

PMID- 10650349
TI  - Sublethal maternal pre-exposure of fish to cadmium. Effect on the survival of the
      newly hatched alevins.
AB  - The aim of this study was to determine the effects of the exposure of pregnant
      females of a viviparous teleost Cnesterodon decemmaculatus to sublethal Cd
      solutions on the survival of their offspring. Ovigerous females were acclimated
      and accomodated in aquaria containing the following solutions: artificial
      freshwater medium (AFW) and AFW with 25, 50 and 100 microg Cd(2+) /L (as
      chloride). Part of the offspring born from control females was transferred to
      media contain-ing 25, 50 and 100 microg/L of cadmium; the rest of the fry stayed
      in AFW solutions without cadmium. The offspring born from the females maintained
      in solutions of cadmium were transferred to aquaria with AFW, and to solutions
      containing metal at the same concentration as their mother. In all cases
      mortality was recorded daily for 168 h. The results demonstrated that the
      survival of newborn offspring was always related to the concentration of Cd(2+)
      to which they were exposed at birth, regardless of the concentration of the metal
      to which the mother was exposed during its pregnancy. When exposed to Cd(2+),
      alevins from non-exposed females showed a constant linear death rate while in
      those from Cd-exposed it resulted exponential.

PMID- 10650350
TI  - Age-associated alteration of muscle oxygenation measured by near infrared
      spectroscopy during exercise.
AB  - The influence of ageing on the capacity to increase muscle oxygen delivery during
      exercise is unclear. This was investigated by comparing the evolution of Near
      InfraRed Spectroscopy (NIRS) in 10 old (67 +/- 5 years, Old group) and 13 young
      subjects (27 +/- 4 years, Young group), during a progressive maximal exercise.
      The NIRS probe was placed on the vastus lateralis; muscle oxygen saturation - IR
      SmO(2) - values were expressed on a scale using an arterial occlusion as the
      lower reference point and the subsequent reactive hyperaemia as the upper
      reference point. Resting IR-SmO( 2) was found to be significantly lower in the
      Old as co mpared to the Young group. During exercise, VO(2) increased similarly
      as a function of the workload whereas IR-SmO(2) decreased faster in old subjects
      than in young ones. Conversely, when expressed at the same percentage of VO(
      2max), IR-SmO(2) followed a similar evolution in both groups from rest to maximal
      exercise (27.3 +/- 16.7 vs 24.3 +/- 12.9% decrease, in Old and Young group,
      respectively, NS). Thus, the initial difference remained constant between the two
      groups. During recovery, the time to recover the signal variation was not
      different between the two groups. We concluded that Old subjects demonstrate a
      systematic lower muscle oxygen saturation than Young ones. This difference could
      be explained by an age related decrease in muscle blood flow limiting O(2)
      supply.

PMID- 10650351
TI  - The neuronal control of the lower urinary tract: A model of architecture and
      control mechanisms.
AB  - The human micturition cycle is controlled by central and peripheral nervous
      structures and connections. In literature, no complete or generally accepted
      model describes the principles of micturition control. In this paper, the
      integration of (neuro-)anatomy, (neuro-)physiology and control theory is used to
      describe and model the neuronal control of the lower urinary tract. Neuroanatomy
      supplies the most basic information necessary for the modellation of the
      peripheral pathways and central connections involved in the control of the
      uropoetic system. It is found that not all the nervous structures and connections
      have been identified as such yet. The linking up between several nervous
      structures (e.g., the presence of central and peripheral relay stations) is not
      completely clear. A s a consequence, each model to describe the micturition cycle
      from the perspective of control theory is yet of limited physiological value as
      it cannot exceed a rather general level of modellation. Adding functional
      considerations (neurophysiology and control theory) to the neuroanatomical
      skeleton completes the model. Some control mechanisms active during the
      micturition cycle can still not be revealed in detail. Crucial questions on the
      neuronal innervation of the human uropoetic system and the control mechanisms
      active during the micturition cycle remain, like how the supraspinal trigger
      mechanisms for micturition are organised, or how the voluntary cessation of
      voiding is realised. A simplified version of the model discussed in this paper
      can already be used for mathematical modelling, e.g., neural network simulations.

PMID- 10650352
TI  - A computer model for describing the effect of urethral afferents on simulated
      lower urinary tract function.
AB  - A computer model of mechanical properties of the bladder, the urethra and the
      rhabdosphincter, as well as their neural control is presented in this paper. The
      model has a rather simple design and processes sensory information from both the
      bladder wall tension and urethral stretch. It is assumed that afferent signals
      from the urethra are involved in a sacral excitatory reflex and a supraspinal
      inhibitory reflex. Pressure and flow signals that resemble experimentally
      measured normal human behaviour could be simulated with this model. From these
      simulations the relation between the neural control mechanisms used in the model
      and the neural control mechanism in vivo cannot be judged entirely because
      similar behaviour could be simulated with models that are bas ed on different
      neural control mechanisms. Also behaviour that resembles detrusor overactivity
      was simulated with our model after an externally induced rise in detrusor
      pressure was added. Detrusor overactivity, sometimes in combination with urethral
      relaxation, can occur during a urodynamic investigation. A possible explanation
      for this detrusor overactivity might be that the micturition reflex is triggered
      by unknown disturbances and is inhibited immediately after by the same mechanism
      that normally ceases voiding. The described model provides such a mechanism.
      Based on these simulations, therefore, it is concluded that urethral afferent
      signals might be important in lower urinary tract control.

PMID- 10650353
TI  - Three dimensional registration of mechanical bladder activity using polystyrene
      fluorescent spheres: A technical note.
AB  - Optical marker tracing methods have been applied successfully in recent years to
      quantify local material deformation of heart tissue, skin and striated muscles.
      In this study, polystyrene fluorescent spheres (d = 0.6 mm) are glued to the
      ventral serosal bladder wall in the rabbit. Three dimensional video registration
      of the polystyrene spheres is used to calculate two directions of principal
      strain (epsilon (1), epsilon (2) ) on the bladder surface in vivo. The aim is to
      investigate the feasibility of the technique for this new application in two
      experimental circumstances: during spontaneous bladder wall activity and after
      electrical stimulation of bladder innervating nerve fibers. During spontaneous
      activity, random contraction and relaxation occurred simultaneously and
      separately across the bladder wall for the two principal strains epsilon (1) and
      epsilon (2). After extradural electrical stimulation of sacral nerve root S2, the
      principal strains epsilon ( 1) and epsilon (2) synchronized in time in such a way
      that epsilon ( 1) and epsilon (2) both represented contraction or both
      represented relaxation. One and the same bladder wall area passed through phases
      of contraction followed by relaxation and vice versa. After multiple stimulation
      periods, the coordination between the two principal strains during stimulation
      was reduced. This technique allows to identify local areas of contraction and
      relaxation in the intact bladder wall in vivo. Three dimensional video
      registration of polystyrene fluorescent spheres to study bladder wall contraction
      and its relaxation proved to be a feasible technique, with which electrical
      stimulation effects and spontaneous activity could be measured.

PMID- 10650354
TI  - Sacral anterior root stimulation and cryotechnique: A new option for selective
      urethral sphincter block and reversible deafferentation in the future?
AB  - A possible application of cryotechnique might be a selective block of nerve fiber
      activity during sacral anterior root stimulation to achieve selective block of
      urethral sphincter and reversible deafferentation. In 13 foxhounds, electrical
      stimulation of sacral anterior roots S2 was performed while the accompanying
      spinal nerves were simultaneously cooled down from +25 degrees C in a stepwise
      fashion until a block of urethral sphincter activity was observed. The effects of
      cold block on the urethral sphincter and bladder were monitored by urodynamic
      investigation. In 2 additional dogs sacral posterior roots S2 were cooled down to
      +3 degrees C while accompanying anterior and posterior roots were stimulated
      distal to the cryothermode. Compound action potentials (APs) were registered
      proximal to the cryothermode before, during and after cooling and recovery time
      of cold blocked nerves was evaluated. Complete cold block of the urethral
      sphincter during spinal nerve cooling was achieved in all cases. Block
      temperature averaged +12 degrees C. Detrusor pressure was a mean 5,2 cm water.
      Recovery time was on average 5 min. The cold block was always reversible. In both
      dogs of the second series the compound action potentials disappeared nearly
      completely at +3 degrees C. Three min after the end of the cooling period the
      appearance of the compound action potentials was back to normal. In this study,
      cryotechnique proved to be effective for selective and reversible block of nerve
      fibers during sacral anterior root stimulation. In functional electrical
      stimulation this technique may lead to an improvement of quality of life in para-
      or tetraplegic patients resulting in optimization of voiding, standing, walking
      and grasping and does so without the necessity of surgical dorsal root rhizotomy.

PMID- 10650355
TI  - Sacral anterior root stimulation for bladder control: clinical results.
AB  - The Brindley bladder stimulator delivers intermittent stimulation to the anterior
      sacral roots. The stimulus parameters can be adjusted and set specifically for
      individuals. Its primary purpose is to improve bladder emptying, thereby to
      eliminate urinary infection and to preserve kidney function. It also assists in
      defecation and enables male patients to have a sustained full erection. In our
      unit so far 38 patients with a complete spinal cord lesion have received a
      Brindley bladder stimulator implant. One patient died 2 weeks after the surgery
      due to pulmonary embolism. Two other patients died due to unrelated causes during
      the follow up period. They used their implants for less than 1 year. Results
      relating to these 2 patients and the remaining 35 patients who regularly use
      their implant are presented. The follow-up period ranged from 3 months to 12
      years. Residual urine volumes are substantially reduced in all patients; in 24
      patients the residual urine volume is less than 30 ml. All patients have
      increased bladder capacity. Thirty-one patients are continent. Out of 33 males 29
      can achieve a sustained full erection using the stimulator. Twenty-seven patients
      use the implant for bowel function. The following complications were encountered:
      (1.) Cerebro-spinal fluid collection occurred around the implant in 3 patients
      during the post-operative period; (2.) Receiver failure occurred in 3 patients. A
      successful replacement with a new receiver block was carried out in these cases.
      It is concluded that the use of a bladder stimulator in selected patients gives
      long term favourable results.

PMID- 10650356
TI  - Intracellular recording of spontaneous electrical activity in human urinary
      bladder smooth muscle strips.
AB  - We studied the spontaneous electrical activity of human urinary bladder smooth
      muscle strips, with the eventual aim of uncovering the mechanism underlying the
      clinical syndrome of the unstable bladder. Intracellular microelectrodes were
      used to record the membrane potentials of detrusor cells in muscle bundles
      originating from biopsy samples. Spontaneous spike-shaped potential fluctuations
      were analysed automatically. The membrane potential at the start of the potential
      change (V(start)), amplitude, duration at 10% of the amplitude (d(10%)), and
      upstroke velocity (DeltaV/Deltat) were estimated and statistically analysed. The
      mean resting membrane potential of the detrusor strip cells was -42 mV (SD: 9
      mV). Different types of spontaneous activity could be recorded. On successive
      impalements within one preparation, the type of activity varied from one single
      spike-shaped potential to extensive bursts and was not correlated to the resting
      membrane potential. There was a large variation in size and shape of the spike
      shaped potentials between the biopsy samples and even within one cell. The
      results provide the first description of spontaneous electrical activity in human
      detrusor smooth muscle strips. This activity is asynchronous, which could aid to
      maintain a low pressure in the bladder. Most likely, this spontaneous detrusor
      activity is myogenic in origin.

PMID- 10650357
TI  - Conceptualization vs reality in the treatment of periodontal diseases.
AB  - This article addresses controversial issues associated with four different
      subjects: the usefulness of povidone iodine in the treatment of adult
      periodontitis, genetic susceptibility testing for severe periodontitis, local
      drug delivery in the treatment of periodontal diseases, and differentiating
      between statistical and clinical significance. Conclusions are drawn based on
      published evidence. Each subject is also assessed with regard to their practical
      application in the management of patients.

PMID- 10650358
TI  - Local delivery of chlorhexidine.
AB  - Clinicians are always looking for new ways to enhance patient care and expand
      their practices. When evaluating the value of new products on the market, it is
      important for clinicians to look at what is available, carefully evaluate what is
      necessary for their patient, and then determine what is best for the practice,
      the clinician, and the patient. This article discusses the use of chlorhexidine
      for gaining new attachment and reducing pocket depth. More specifically, the
      article describes the usefulness, efficacy, and safety of the PerioChip, a
      chlorhexidine chip that is placed in the periodontal pocket.

PMID- 10650359
TI  - Local delivery of doxycycline for the treatment of periodontitis.
AB  - The use of local drug delivery to treat periodontitis is effective in various
      clinical circumstances. This article describes clinical results after using
      locally delivered doxycycline to treat periodontitis and compares those results
      to scaling and root planing. Commonly asked questions concerning the use of local
      doxycycline treatment are also discussed.

PMID- 10650360
TI  - Evaluation of Periostat for patient management.
AB  - The cause of adult periodontitis involves complex bacteria-host interactions,
      with modifying influences exerted by genetic and environmental factors. Current
      thinking indicates that successful, long-term management of adult periodontitis
      requires a treatment approach that takes into account the various etiologic
      components of the disease. Recently, a formulation containing a subantimicrobial
      dose of doxycycline (Periostat) was approved for use as an adjunct to scaling and
      root planing (SRP) in the treatment of adult periodontitis. As an inhibitor of
      matrix metalloproteinases that have been implicated in the pathologic degradation
      of connective tissue collagen in periodontal support structures, Periostat in
      conjunction with SRP was shown to significantly improve clinical attachment and
      reduce probing depth compared with placebo in conjunction with SRP. This article
      reviews the clinical trial results leading to US Food and Drug Administration
      approved of Periostat and discusses the potential use of this host-modulatory
      agent as a complementary systemic pharmacotherapy in periodontal management
      programs.

PMID- 10650361
TI  - Periodontal pocket--predictable treatment.
AB  - Periodontal pocket depths and attachment loss are charted early in treatment to
      establish a benchmark against which the success of treatment regimens will be
      measured. They are considered both a measure of past inflammatory disease and a
      reservoir for periodontal pathogens capable of further destruction. The clinician
      must strive to identify predictable means of treating pockets. Three
      nonpharmaceutical approaches can be considered: maintain the present depth and
      hope for the best when treating a patient who has already demonstrated
      susceptibility; reduce the pocket by resective treatment, a frequently used and
      very predictable corrective methodology; reduce the probing depth by
      accomplishing periodontal regeneration. This last approach is the treatment of
      choice, but it is often impossible to achieve. This article describes a treatment
      regimen that recognizes the need for proper diagnosis and an initial nonsurgical
      debridement regimen before considering surgery. It then evaluates surgical
      treatment alternatives and concludes with a mandate for a well-constructed
      periodontal maintenance program. It also provides long-term detailed analysis of
      patient treatment.

PMID- 10650362
TI  - Solutions for postoperative sensitivity.

PMID- 10650363
TI  - Provisional restorative materials: a technology update.

PMID- 10650364
TI  - The maxillary central incisal edge: a key to esthetic and functional treatment
      planning.

PMID- 10650366
TI  - Crown lengthening revisited.
AB  - Over the last 37 years, crown-lengthening procedures have been used predictably
      to restore teeth broken down from caries, trauma, and extensive wear. With crown
      lengthening, the dentogingival junction is "re-created" at a more apical level on
      the root to accommodate the junctional epithelium and the connective tissue
      attachment. Forced eruption can be used in addition, or as an alternative, to
      tooth lengthening. The authors discuss the indications for tooth lengthening,
      forced eruption, and orthodontic extrusion, as well as the treatment planning for
      these procedures.

PMID- 10650365
TI  - COX-2 inhibitors: better than ibuprofen for dental pain?

PMID- 10650367
TI  - One-year clinical evaluation of SureFil packable composite.
AB  - The purpose of this trial was to clinically evaluate SureFil high-density
      posterior composite for Class II restorations of permanent first and second
      molars. All teeth were restored in occlusion with the natural dentition. After
      cavity preparation, the enamel was etched for 15 seconds with 34% phosphoric
      acid. No liner/base material was used for the dentin. Two applications of Prime
      and Bond 2.1 were placed for adhesion to the exposed dentin and etched enamel.
      One coat of adhesive was cured for 10 seconds with a curing light, and one thin
      coat was spread with a gentle jet of air. The cavity was restored in 3-mm to 5-mm
      increments. Evaluation was assessed immediately after placement (baseline), and
      at 3 months, 6 months, 9 months, and 1 year for retention, leakage, marginal
      integrity, color stability, abrasive resistance, surface staining, surface
      texture, postoperative sensitivity, and secondary caries. The restorations were
      evaluated indirectly for wear using a modified USPHS and indirect cast comparison
      method. At baseline, 25 restorations were graded Alfa in all categories. At 3-, 6
      , and 9-month recalls (N = 24), all restorations were graded Alfa in all
      categories. At the 1-year recall (N = 20), there were three Bravos for surface
      staining.

PMID- 10650368
TI  - A new approach to restorative dentistry: fabricating ceramic restorations using
      CEREC CAD/CAM.
AB  - Ceramic materials provide an alternative when choosing a tooth-colored
      restoration. Currently, posterior composite restorations can be used to achieve
      esthetic restorations; however, they have many disadvantages with regard to wear,
      polymerization shrinkage, discoloration, marginal leakage, and technique
      sensitivity. The use of CEREC CAD/CAM enables the dentist to place feldspathic
      porcelain (Vitablocs Mark II) and machinable glass ceramic (Dicor MGC)
      restorations in a single visit. When compared to composite materials, these
      materials closely approximate the physical properties of enamel in compressive
      and tensile strength and wear resistance. This study evaluated 50 CEREC CAD/CAM
      restorations after 4 years in service. Restorations ranged from Class I to 7/8s
      crown preparations.

PMID- 10650369
TI  - The paper-free dental practice: fact or fiction.

PMID- 10650370
TI  - Guided tissue healing for single-tooth implants.
AB  - The emergence profile of a single-tooth implant abutment has a significant effect
      on the esthetics of the final restoration. Most healing abutments are
      cylindrical, unlike the nonround contours of the natural teeth being replaced.
      The resulting peri-implant sulcus is round rather than having the correct
      anatomic cross-sectional shape. This disparity may compromise the ideal emergence
      profile of the final restoration. This article presents a technique in which a
      custom abutment and provisional crown or the definitive restoration can be placed
      at second-stage surgery to guide tissue healing to optimum form and esthetics.

PMID- 10650371
TI  - The functional esthetic interface.

PMID- 10650372
TI  - The esthetic management of dental midline problems with restorative dentistry.

PMID- 10650373
TI  - A general dentist's viewpoint of two new endodontic techniques.
AB  - Over 3 years ago, two new endodontic techniques were developed. The first was a
      straightforward, comprehensive approach for root canal instrumentation. The
      second was a simple and predictable obturation system. The combination of these
      systems lead to impressive results that were easily attained. The instrumentation
      method uses existing armamentarium, allowing nearly any canal to be shaped to
      ideal form to precisely match a tapered gutta percha point. The root canal sealer
      technique incorporates controlled placement of a modified epoxy-resin cement that
      allows for a thoroughly sealed, single-cone root canal fill. The results rival
      other available systems. This article presents a stepwise guide to achieve stress
      free, successful case results that general dentists and endodontists desire.

PMID- 10650374
TI  - Spontaneous gingival bleeding in an otherwise asymptomatic patient.
AB  - This case is presented to challenge the reader to formulate a differential
      diagnosis for a patient who visits the dentist with spontaneous, continuous
      gingival bleeding. When this situation occurs, it is serious and requires
      immediate attention and a specific treatment plan to arrive at the underlying
      diagnosis and control the bleeding. The signs and symptoms of a patient with
      gingival bleeding are presented for diagnosis; the history and management are
      detailed, and may be useful in diagnosing and treating similar patients.

PMID- 10650375
TI  - Using immunofluorescence in the diagnosis of chronic ulcerative lesions of the
      oral mucosa.
AB  - Chronic ulcerative diseases of the oral mucosa are commonly seen in clinical
      practice. On clinical and histological appearance, the lesions may be hard to
      differentiate from each other. The establishment of definite diagnosis is
      essential because the patient may require different management and have widely
      varying prognosis. Immunofluorescence studies aid greatly in the process of
      determining the diagnosis of a number of chronic ulcerative diseases. This
      article reviews these chronic ulcerative diseases, describing their clinical,
      microscopic, and immunofluorescence characteristics. Methods of diagnosis and
      management of the diseases also are discussed.

PMID- 10650376
TI  - Two in-office bleaching systems: a scanning electron microscope study.
AB  - The purpose of this investigation was to analyze by scanning electron microscopy
      the effects of heated and light-absorbing bleaching agents on enamel surface
      morphology. Twelve freshly extracted human anterior teeth were selected for this
      study. The teeth were randomly divided into four equal groups: Group I (control),
      Group II (teeth treated with Opalescence Quick, a heated bleaching agent), Group
      III (teeth treated with Opalescence Xtra, a light-absorbing bleaching agent),
      Group IV (teeth treated with Ultra-Etch 35% phosphoric acid etchant). After
      receiving a prophylaxis with a slurry of pumice, the bleaching materials were
      applied to the facial enamel surfaces following the manufacturer's
      specifications. The teeth in Group IV were etched for 15 to 20 seconds, washed,
      and air-dried. All specimens were prepared for scanning electron microscope
      evaluations. Scanning electron microscope micrographs indicated that only those
      specimens etched with phosphoric acid (Group IV) exhibited an etching pattern on
      the enamel surface. No differences in enamel surface morphology were observed
      between the untreated control specimens and the specimens treated with the
      bleaching materials.

PMID- 10650377
TI  - Modular transitional implants to support the interim maxillary overdenture.
AB  - It has been reported that for implants to become osseointegrated, they must heal
      in the absence of functional loads for 4 to 6 months. To address the need for
      undisturbed healing and patient demand for uninterrupted immediate function and
      esthetics, the Modular Transitional Implant and Prosthetic System has been
      developed. This case report describes the use of transitional implants to support
      a removable maxillary overdenture, including methodology and the advantages and
      disadvantages of the system. The histomorphometric analysis of one of these
      transitional implants and its surrounding osseous tissue showed a 45% bone-to
      implant interface after 6 months of functional loading. The transitional implant
      system is a sound and economical method of immediate patient restoration that
      allows for the protected healing of submerged implants.

PMID- 10650378
TI  - In-office bleaching system for quick esthetic change.

PMID- 10650379
TI  - Retrospective analysis of an implant system.
AB  - The reliability of dental implants results from a combination of design,
      placement, and reconstructive techniques. Retrospective analysis is one vehicle
      for evaluating implant success. This article presents the reliability of these
      techniques in Bicon dental implants. The survivability of this implant was
      evaluated retrospectively using life table survival analysis over a 10-year
      period in 13 practices. The parameters used for success included no implant loss,
      no mobility, no continuing bone loss that did not stabilize after 1 year, no
      discomfort, and no purulence.

PMID- 10650380
TI  - Evaluating the clinical performance of the Osseotite implant: defining prosthetic
      predictability.
AB  - A 5-year prospective, multicenter study is in progress at four private dental
      practices to determine the cumulative implant survival rate and prosthetic
      outcome when using the Osseotite dental implant in posterior maxillary and
      mandibular areas. An interim evaluation after 34.4 months of study progress is
      presented. A total of 219 Osseotite implants were placed in 74 patients (34 women
      and 40 men with a mean age of 57.8 +/- 15.2 years) using a conventional two-stage
      surgical protocol and 3- to 6-month healing time. Subsequently, patients were
      restored with fixed or removable restorations. Nineteen of the 74 patients
      reported smoking an average of 13.2 cigarettes per day. Restorative treatments
      included 40 single-unit restorations; 53 splinted 2-, 3-, 4-, and 5-unit implant
      supported maxillary and mandibular prostheses; 4 full-arch fixed maxillary
      prostheses; 1 mandibular fixed/detachable hybrid prosthesis; and 1 mandibular
      overdenture. The mean time from implant placement to second stage surgery was 6.2
      +/- 2.0 months; from restoration and implant loading to the most recent follow-up
      evaluation was 20.9 +/- 6.8 months. Of the 219 implants placed, three posterior
      maxillary implants developed infections and were removed prior to second stage
      surgery. No implant failures occurred at second stage surgery or after implant
      loading. Using the Kaplan-Meier method, the cumulative implant survival rate was
      100% for anterior implants and 98.4% for posterior implants at 28.5 +/- 5.7
      months. The cumulative postloading implant survival rate was 100% for both
      anterior and posterior implants. The results of this study indicate that the
      Osseotite dental implant achieved a high rate of integration that remained stable
      during nearly 2 years of implant function. In addition, because no postloading
      implant failures have occurred, the Osseotite implant has provided a high level
      of prosthetic predictability.

PMID- 10650381
TI  - Esthetic and functional reproduction of occlusal morphology with composite
      resins.
AB  - The increasing use of composite resin restorations in posterior sectors produces
      some difficulties in the exact reproduction of occlusal morphology. In this
      article we present a new operative method that allows a quick and precise
      reproduction of occlusal morphology with minimal carious destruction of the
      occlusal enamel of posterior dental elements in the case of initial carious
      lesions. This method is indicated for class I and II carious lesions and is based
      on a preoperative record of the occlusal morphology made with a transparent
      silicone mold. This mold is placed on the tooth after the application of the last
      layer of composite resin, which is then polymerized through the silicone.
      Illustrated as a clinical case, the method is particularly rapid, easy to
      perform, and contributes to the improved quality and subsequent success of
      composite restorations in posterior sectors.

PMID- 10650382
TI  - Materials for modern dental cementations.

PMID- 10650383
TI  - The versatility of calcium sulfate: resolving periodontal challenges.
AB  - The multifaceted properties of calcium sulfate demonstrate its usefulness in
      periodontal practice. Calcium sulfate can function as a resorbable space filler,
      a resorbable barrier (compatible with guided tissue regeneration principles) and
      as a vehicle for controlled-release chemotherapy. Various periodontal challenges
      are demonstrated through case reports using calcium sulfate.

PMID- 10650384
TI  - The role of Periostat in the management of adult periodontitis: a critical
      assessment.
AB  - This article addresses the role of Periostat in the treatment of adult
      periodontitis. Background information regarding the role of matrix
      metalloproteinases in the pathogenesis of periodontal diseases and the ability of
      tetracyclines to inhibit these enzymes are discussed. Data from large clinical
      trials concerning the benefits of using subantimicrobial doses of doxycycline are
      reviewed and critiqued with respect to their clinical significance. Overall, the
      mean data suggest that the use of Periostat provides a defined but limited
      improvement of periodontal status.

PMID- 10650385
TI  - Environmental surface disinfection: perspective and ongoing issues.

PMID- 10650386
TI  - Treatment options for postorthodontic esthetic enhancement.

PMID- 10650387
TI  - Adhesive bonding directions: where are things going?

PMID- 10650388
TI  - Florid osseous dysplasia of the mandible: report of a case.
AB  - In 1986, a 60-year-old African American woman visited the Marquette University
      School of Dentistry with a complaint of a vague, dull pain in her lower left
      quadrant. Tooth No. 19 was extracted 10 years earlier because of extensive decay,
      and tooth No. 18 had received root canal therapy. A panoramic radiograph revealed
      the presence of ill-defined, multilocular, mixed (radiopaque-radiolucent) lesions
      present throughout the lower jaw. She was treated with antibiotics and scheduled
      for follow-up visits. When the symptoms persisted, tooth No. 18 was re-treated
      with root canal therapy and a representative biopsy was taken from the left
      mandibular area. The biopsy showed the presence of chronic osteomyelitis. The
      patient was treated with antibiotics and was scheduled for periodic check-up
      visits. In February 1995, she returned with the same symptoms in the left
      mandible. A panoramic radiograph showed persistence of the mixed radiopaque
      radiolucent lesions throughout her mandible; however, the mass on the left side
      was more radiopaque and had assumed a "cotton wool" appearance. Tooth No. 18 was
      extracted and a biopsy was taken from the area. After correlating the clinical
      behavior, radiographic appearance, and histopathologic features, a diagnosis of
      florid osseous dysplasia with osteitis was made. This case represents a classic
      example of the difficulty in diagnosing fibro-osseous lesions using radiographic
      interpretation alone and the need to correlate the clinical, radiographic, and
      histopathologic features to reach a diagnosis. Additionally, the present case
      clearly shows treatment problems of an otherwise self-limiting condition when
      secondary involvement with osteomyelitis is also present. A brief description of
      the conditions that were included in the differential diagnosis and their
      management is presented.

PMID- 10650389
TI  - Incontinentia pigmenti: overcoming cosmetic challenges.
AB  - Incontinentia pigmenti is a rare syndrome of genetic origin that affects the
      melanin production of the melanocytes in the epidermis or superficial dermis. It
      is an X-linked dominate disease with lethality in males. The syndrome presents
      with skin and dental manifestations similar to ectodermal dysplasia and
      congenital syphilis. However, dental alternatives for achieving esthetic
      reconstruction differ. This article illustrates a case of cosmetic rehabilitation
      of an 18-year-old woman with incontinentia pigmenti.

PMID- 10650390
TI  - Periodontal esthetics and soft-tissue root coverage for treatment of cervical
      root caries.
AB  - As the pace of change accelerates in periodontics and esthetic dentistry, an
      increasing number of procedures are being developed that require knowledge and
      treatment from both fields. The synergy developed by combining these two fields
      of dentistry allows for better esthetic outcomes for our patients. Two of these
      procedures include esthetic crown lengthening and soft-tissue root coverage. As
      demonstrated in this article, soft-tissue root coverage can be performed on
      previously restored roots and as an option for treating root caries.

PMID- 10650391
TI  - Rationale for using single-use disposable air/water syringe tips.
AB  - The research discussed in this article was conducted to study the inaccessible
      lumen surfaces of used and unused metal tips of air/water syringes using a light
      and a scanning electron microscope. Factors affecting the selection of air/water
      syringe tips were enumerated and compared. Patient and dentist acceptance of
      reusable and single-use air/water syringe tips for use in the oral cavity was
      evaluated. Although heat sterilization may destroy microbial organisms, the
      internal surfaces of metal tips were found to be rough, making them the focus of
      mineral and bioburden deposits. With regard to cleaning and sterilization,
      disposable tips were found to be more acceptable in clinical use than metal tips.

PMID- 10650392
TI  - Managing bruxism and temporomandibular disorders using a centric relation
      occlusal device.
AB  - This article discusses the rationale, indications, and fabrication of the centric
      relation occlusal (CRO) device in the management of bruxism and temporomandibular
      disorders. Five methods of fabricating occlusal devices are briefly discussed.
      Two methods, preferred by the authors, are discussed in detail, including the
      laboratory phase. One method uses heat-cured acrylic resin, and the other method
      uses a heat-vacuum machine, thermoplastic splint resin material, and
      autopolymerizing clear acrylic resin. The use of the CRO device in the successful
      management of bruxism and temporomandibular disorders has been previously
      documented in the literature. Some patients may not successfully adjust to the
      wearing of occlusal devices (splints), which are not well-defined in terms of
      occlusal morphology, anterior guidance, and their relativity to centric relation.
      This problem usually is overcome when the dentist uses precise skill in the
      fabrication and delivery of a CRO device with mutually protected articulation.

PMID- 10650393
TI  - Report of a simplified endodontic technique.
AB  - Using a simplified step-back sequence, which consists of traditional .02 tapered
      stainless-steel hand reamers, the No. 2 peeso reamer, and four manual nickel
      titanium instruments, a dentist can easily, safely, and economically create a
      continuously tapered canal shape. This article discusses the complete coating of
      canal walls with EZ-Fill epoxy-resin sealer, which is delivered with a
      bidirectional spiral; and total obturation with a single gutta percha point,
      which is matched closely to the tapered shape. The results of this system are
      compared with other techniques.

PMID- 10650394
TI  - Infection control: perceptions and reality.

PMID- 10650395
TI  - Increased pain sensitivity of the upper extremities of TMD patients with myalgia
      to experimentally-evoked noxious stimulation: possibility of worsened endogenous
      opioid systems.
AB  - The purpose of this study was to examine whether or not temporomandibular
      disorder (TMD) patients with chronic masticatory myalgia have increased pain
      sensitivity at remote sites outside of the head and neck region, and to evaluate
      whether the endogenous pain inhibitory systems triggered ischemic pain functions
      favorably in those patients. Twenty female TMD patients with chronic myalgia and
      20 controls participated in this study. Ischemic pain was produced to activate
      endogenous opioids. The pain threshold time, pain tolerance time, pain intensity
      and pain unpleasantness were compared between the TMD patients and controls. The
      pressure pain thresholds in the hand were also compared before, between, and
      immediately after the ischemic pain. The TMD patients showed higher severe pain
      intensity and unpleasantness values and had lower pressure pain thresholds in the
      hand. Although both groups showed an increase in the pressure pain threshold,
      there was less of an increase in the pressure pain threshold in the TMD patients
      than in the controls. These findings indicate that TMD patients have increased
      pain sensitivity at remote sites, and also indicate additional evidence that the
      endogenous opioid systems may become impaired in TMD patients with chronic
      masticatory myalgia.

PMID- 10650396
TI  - The incidence and influence of abnormal styloid conditions on the etiology of
      craniomandibular functional disorders.
AB  - This study aimed to examine the incidence and influence of craniomandibular
      functional disorders caused by abnormal styloid-stylohyoid chains. Seven hundred
      sixty-five patients with temporomandibular joint (TMJ) disorders were divided
      into two groups (with and without radiographically visible abnormal styloid
      conditions). In the group with abnormal stylohyoid conditions, the etiology of
      TMJ disorders was further subdivided into poly-, oligo- and monoetiological
      factors, and, after this classification, evaluated regarding a clear, possible or
      unlikely involvement of abnormal stylohyoid conditions in TMJ disorders. One
      hundred thirty-six out of 765 patients presented abnormal styloid-stylohyoid
      chains. One hundred five of the patients (77.2%) demonstrated polyetiological
      causes of TMJ symptoms with an unlikely involvement of the abnormal styloid
      stylohyoid chain. Twenty-nine of the patients (21.3%) showed oligoetiological
      causes with possible involvement of the abnormal styloid-stylohyoid chain. In two
      patients (1.5%), the abnormal styloid conditions showed up as the only definite
      cause of TMJ symptoms (monoetiological). Detailed knowledge of variations and
      possible effects of suprahyoid structures is important for an accurate diagnosis
      of TMJ disorders. All in all, the incidence of a stylohyoid involvement in TMJ
      disorders is very low. However, after an initial subdivision into abnormal and
      normal stylohyoid conditions, the incidence of pathological stylohyoid chains
      gains significant importance in the etiology of TMJ disorders.

PMID- 10650397
TI  - Role of temporomandibular disorders (TMD) in facial pain: occlusion, muscle and
      TMJ pain.
AB  - Temporomandibular disorders (TMD) which comprise myogenic and arthralgic
      components have been reported to predispose subjects to headache and facial pain.
      The aim of this study was to evaluate the role of these components in patients
      with facial pain and to investigate the influence of treatment of TMD on pain of
      these patients. The subject group consisted of 25 patients suffering from facial
      pain. The clinical stomatognathic examination was performed before conservative
      treatment of TMD, and one-two weeks, three months and one year after treatment.
      The severity of TMD was assessed using the anamnestic (AI) and clinical
      dysfunction (DI) indices of Helkimo. The intensity of pain was evaluated on a
      numerical rating scale (NRS). According to clinical findings the patients were
      classified to following diagnostic subgroups: TMD myo (mainly myogenic), TMD
      arthro (mainly arthrogenous) and TMD comb (both myogenic and arthrogenous
      components involved). Fifteen patients were classified in the TMD myo group, nine
      in the TMD comb group and one in the TMD arthro group. The DI index decreased
      significantly one-two weeks after treatment and remained at this level at three
      month and one year follow-up examinations. At the first examination the TMD myo
      group had the highest level of NRS index, which decreased significantly during
      the time of follow-up, while no significant changes were found in other groups.
      Bruxism reported by the patient had a positive correlation with the amount of
      painful muscles on the right side at first examination. The results show that
      facial pain combined with TMD may be mostly of myogenic origin, and myogenic pain
      seems to have most favorable response to conservative treatment of TMD.

PMID- 10650398
TI  - Cinematic study of temporomandibular joint motion using ultra-fast magnetic
      resonance imaging.
AB  - Magnetic Resonance Images (MRI) of the temporomandibular joint (TMJ) are usually
      performed to study the opening/closing movements of the mandible and have up to
      now been pseudodynamic step-by-step images simulating condylar motion by post
      processing reconstruction. The aim of this study was: 1. to optimize a TMJ cine
      imaging method to give a better clinical result than the step-by-step methods; 2.
      to develop an ultra-fast MRI Gradient Echo (GE) sequence for this purpose; and 3.
      to analyze condylar movements in the sagittal, coronal and para-axial planes
      during border mandibular displacements and chewing. Both TM joints were studied
      in six asymptomatic volunteers. The method involved a compromise between in-plane
      resolution, slice thickness, signal-to-noise ratio and time resolution. Routine
      clinical use was found to be a GE pulse sequence providing three images per
      second with an isometric voxel resolution of approximately two millimeters in
      ridge. This did not allow visualization of the disk. Using this sequence enabled
      real and simultaneous condylar displacement observation in the three planes of
      space and therefore contributed to a better functional diagnosis of pathologic
      TMJ motions.

PMID- 10650399
TI  - A clinical study of specific signs and symptoms of CMD in bruxers classified by
      the degree of severity.
AB  - Two hundred and seventy-six CMD patients referred consecutively for diagnosis and
      treatment over a period of four years were assessed. Two hundred and eleven were
      classified as bruxers according to the use of a questionnaire and clinical
      examination. One hundred (47.39%) presented clinical characteristics of mild
      bruxers, 66 (31.27%) presented moderate bruxism and 45 (21.32%) demonstrated
      severe bruxism. Severe bruxers presented the lowest degree of jaw opening (39.21
      mm) and highest prevalence of capsulitis (97.77%), retrodiskal pain (84.44%) and
      disk-attachment pain (48.88%). As compared to the mild and moderate groups,
      severe bruxers also demonstrated significantly higher prevalence of protective
      splinting and transient locking or recent history of intermittent locking,
      masticatory pain, reciprocal clicking and signs and symptoms of Myofascial Pain
      Dysfunction Syndrome (MPDS). Because higher prevalence of specific muscle and
      joint disorders were observed in bruxers and such prevalence was progressive from
      the mild to the moderate and severe group, it may be concluded that bruxing
      behavior is a significant factor in the etiology and progression of muscle and
      joint disorders. Based on the review of the literature, the analysis of our data
      in comparison to other studies allowed us to conclude that severe bruxers are
      more impaired by muscular and joint disorders as compared to mild and moderate
      bruxers.

PMID- 10650401
TI  - Sliding plates on complete dentures as a treatment of temporomandibular disorder:
      a case report.
AB  - This work presents a case report of a woman, aged 62, who presented with signs
      and symptoms of temporomandibular disorder (TMD). The patient reported pain in
      the masticatory system and examination showed a reduction in the occlusal
      vertical dimension (OVD). She was treated with complete dentures incorporating a
      modification to the posterior regions developed by the authors and which were
      termed "sliding plates." Through analysis of photographs taken of the patient
      prior to the extraction of the patient's natural dentition, sliding plates were
      utilized to reestablish the OVD. The sliding plates also allowed for unrestricted
      eccentric mandibular movements, thereby accelerating the neuromuscular
      deprogramming and making it possible for the mandible to adopt a more physiologic
      position. The dentures reduced the pain and were well-accepted by the patient.
      Therefore, sliding plates may be of great benefit to completely edentulous
      patients with painful symptoms that result from alterations in the OVD and
      inappropriate condylar positioning.

PMID- 10650400
TI  - Proposed cephalometric diagnosis for osteogenic obstructive sleep apnea (OSA):
      the mandibular/pharyngeal ratio.
AB  - The purpose of this laboratory study is to devise a simple, diagnostic test to
      assess possible osteological deficiency as a probable cause of OSA. Modern day
      skulls of fifty males and forty eight females of Tuscan origin and an additional
      seventy-five skulls, from India, with their cephalograms were used for this
      study. Mandibular length and antero-posterior dimension of the nasopharynx-
      pharyngeal tubercle (PhT) to posterior nasal spine (PNS)--were measured on the
      Tuscan skulls. The nasopharynx was similarly measured on the Indian skulls and
      readings multiplied by 1.14, the magnification factor of the cephalometric
      apparatus used. The PhT-PNS distance was then plotted on the cephalogram of
      Indian skulls with point PhT at the basiocciput. The possible presence of an
      osteogenic etiology of OSA can be determined by comparison of the
      mandibular/pharyngeal ratio obtained from the skull cephalograms to that of the
      individual patient.

PMID- 10650402
TI  - Trigger point identification and treatment with microcurrent.

PMID- 10650403
TI  - A new survey instrument: a sample of a typical TMD practice.
AB  - The study evaluated 646 patients treated in a full time TMD practice with a new
      survey tool based on a patient self-report questionnaire. It would appear that
      this new approach to practice evaluation has not been previously reported in the
      literature. The results indicate that the average patient has a significant time
      delay of 24 to 120 months from onset of symptoms to the beginning therapy and
      that the majority of patients see three or more practitioners before reaching the
      TMD therapist. Most significantly, there are strong indications that early
      intervention and persistent compliance with prescribed therapy produces the
      highest level of success. Valuable practice statistics regarding patient
      treatments, patient outcomes and modalities of therapy have proven intensely
      useful in managing the patients, educating the public, communicating with the
      referral base, as well as in negotiating participation agreements with managed
      care institutions.

PMID- 10650404
TI  - Joint vibrations analysis in asymptomatic volunteers and symptomatic patients.
AB  - The joint sound is a common sign in TMD. The diagnosis is important to establish
      the treatment of pathological alterations which occur in the TMJ. In this study,
      two groups were selected: 1. Asymptomatic volunteers; and 2. Symptomatic patients
      who were diagnosed in a clinical examination. After the initial examination, they
      were submitted to evaluation using electrovibratography (SonoPAK II, BioResearch
      Assoc., Inc., Milwaukee, Wisconsin). The analysis of results indicated that the
      averages of the vibratory energy in the symptomatic group presented higher values
      in all stages of the mandibular movement when compared to the averages of
      vibratory energy registered in the asymptomatic group.

PMID- 10650405
TI  - The effects of a single intercuspal interference on electromyographic
      characteristics of human masticatory muscles during maximal voluntary teeth
      clenching.
AB  - In 13 healthy subjects (eight men and five women, mean age, 22 years), an
      aluminum intercuspal interference (height, 0.25 mm) was placed on the maxillary
      right first premolar to study its effect on the contractile symmetry of the right
      and left masseter and anterior temporalis muscles when measured through a
      Percentage Overlapping Coefficient (POC), derived from surface electromyographic
      recordings of maximum voluntary teeth clenching. Additionally, and to estimate
      the potential of the experimental intercuspal interference to induce lateral
      displacement of the mandible, a Torque Coefficient (TC) was derived from surface
      electromyographic recordings. The conclusion was that the experimental occlusal
      interference gave rise to asymmetric contractile activity in the studied
      mandibular elevator muscles as well as a potential to displace the mandible in a
      lateral direction.

PMID- 10650406
TI  - A study on the rotational torque movement of mandible in patients with TMJ closed
      lock.
AB  - The mandibular rotational angle and distance were measured during various
      movements of temporomandibular joint (TMJ) closed lock patients (17 women, 23.9
      +/- 6.6 years). The measurements were compared with those of the healthy controls
      (18 women, 24.0 +/- 1.4 years) using the BioPAK system (BioResearch Inc.
      Milwaukee, USA), which can analyze mandibular rotational torque movements. During
      maximum mouth opening movement, the parameters of the patient group were
      significantly larger than those of the control group in horizontal plane (p <
      0.05) but vice versa in frontal plane (p < 0.001). During protrusive movement,
      the parameters of patients were significantly larger than those of control group
      in frontal and horizontal plane (p < 0.01, p < 0.05). During lateral excursive
      movement to the affected side of patients, the parameters were significantly
      larger than those to the unaffected side in frontal plane (p < 0.05).

PMID- 10650408
TI  - Effects of two types of pillows on bilateral sternocleidomastoid EMG activity in
      healthy subjects and in patients with myogenic cranio-cervical-mandibular
      dysfunction.
AB  - This study was conducted in order to determine the effects of two types of
      pillows on bilateral electromyographic (EMG) activity of the sternocleidomastoid
      muscles. The study was performed on 15 patients with myogenic cranio-cervical
      mandibular dysfunction (CMD) and 15 healthy subjects. EMG recordings at rest and
      during swallowing of saliva and maximal voluntary clenching were performed by
      placing surface electrodes on the right and left sternocleidomastoid muscles. EMG
      activity was recorded in the supine position and in the lateral decubitus
      position (according to each individual's normal resting habit), with their eyes
      closed and with the head supported by means of: 1. a Sleep Easy Pillow (Interwood
      Marketing Groups, Concord, Ontario, Canada) and 2. a Standard Pillow (INDUVET).
      In the lateral decubitus position a significantly higher contralateral than
      ipsilateral EMG activity at rest in the sternocleidomastoid muscles was observed
      with both types of pillows in all the sample studied (ANOVA and Duncan's Multiple
      Range Test). Asymmetrical bilateral EMG activity in the lateral decubitus
      position with both types of pillows in healthy subjects and in patients with
      myogenic CMD, suggests that if this body posture is prolonged, it could be
      important in the genesis of sternocleidomastoid hyperactivity.

PMID- 10650407
TI  - Bruxism and cranial-cervical dystonia: is there a relationship?
AB  - To characterize the relationship between bruxism and dystonia, 79 patients (28
      men and 51 women) with cranial-cervical dystonia were studied. Sixty-two patients
      (78.5%), 22 men and 40 women, had bruxism. The mean age at onset of dystonia in
      patients with bruxism was 52.4 +/- 12.6 years (range 14-80), similar to patients
      with cranial-cervical dystonia without bruxism. Involuntary oromandibular
      movements (46 patients) and blepharospasm (34 patients) were the most common
      initial symptoms among patients with dystonia. About one-fourth of bruxism
      patients had associated dental problems including TMD (21%) and tooth wear (5%).
      A majority (58%) of the bruxism patients had diurnal bruxism and 12% had
      nocturnal bruxism. The bruxism patients were compared to 100 patients with
      Parkinson's disease (PD), cervical dystonia, cranial dystonia, and normal
      controls, respectively. The prevalence of bruxism was much higher in the cranial
      cervical dystonia patients when compared to normal controls (P < 0.001); however,
      this difference was not significant between other diseased groups and controls.
      Medications and botulinum toxin injections, used in the treatment of focal
      dystonia also provided effective relief of bruxism.

PMID- 10650409
TI  - Joint vibration analysis protocol modification: adding mandibular excursive
      movements.
AB  - This case study discusses the advantage of using both lateral and protrusive
      mandibular excursive movements to improve the accuracy of the joint vibration
      analysis rather than relying only on opening and closing movements of the
      mandible for analysis.

PMID- 10650410
TI  - Regeneration ad integrum of the condyle head in a patient with temporomandibular
      disorders.
AB  - A 14-year-old who had suffered from a beta-hemolytic streptococcus infection
      presented with serious temporomandibular disorders, including a reabsorption of
      the condyle head on the right side, and reabsorption in the cavern of the left
      side. Her masticatory muscles were electronically deprogramed, achieving a
      mandibular position supported by a relaxed musculature. The patient's signs and
      symptoms subsequently disappeared. Study of the magnetic resonance image a year
      later clearly showed a regeneration ad integrum of the condyle head and a
      spontaneous reinsertion of the articular disk. The results suggest the need for
      use of electronic elements in order to treat patients with temporomandibular
      disorders effectively.

PMID- 10650411
TI  - Community-based clinical education programs.

PMID- 10650412
TI  - The costs and financing of dental education.

PMID- 10650413
TI  - Public financing of dental care: impact and policy implications.

PMID- 10650414
TI  - Financial modeling of extramural programs: do they generate net savings?

PMID- 10650415
TI  - Advancing community-based education: curriculum issues.

PMID- 10650416
TI  - Financial issues in community-based clinical dental education programs.

PMID- 10650417
TI  - Managing community practice programs: a survey of critical issues.

PMID- 10650418
TI  - Dental education in community practices and clinics: a legal perspective.

PMID- 10650419
TI  - Community-based dental education at Boston University Goldman School of Dental
      Medicine.

PMID- 10650420
TI  - University of Colorado School of Dentistry's Advanced Clinical Training and
      Service Program.

PMID- 10650421
TI  - Columbia University's Community Dental Program as a framework for education.

PMID- 10650422
TI  - Community clinical programs at the School of Dental Medicine, University of
      Connecticut.

PMID- 10650423
TI  - Extramural programs at the University of Florida College of Dentistry.

PMID- 10650425
TI  - University of Michigan School of Dentistry's Community Practice 857.

PMID- 10650424
TI  - Community-based dental education: Marquette University School of Dentistry.

PMID- 10650426
TI  - Community-based dental programs: University of Medicine and Dentistry of New
      Jersey-New Jersey Dental School.
AB  - The dental school plans to incorporate CODE into the curriculum so that more
      students have community-based dental educational experiences. Future plans also
      include increasing standardization of reports, clinical and administrative
      procedures, resources, and processes across the sites in order to lower
      managerial overhead. This process will be aided by further enhancement of
      computerized information systems and electronic links. The major lesson learned
      is that new extramural programs can be created and sustained by pooling school
      resources with those from the private and public sectors. Funding sources and
      opportunities available to one party alone are insufficient. While one-time
      funding was used to build and furnish the NJDS extramural sites, the clinics were
      established only after business plans demonstrated the availability of funds to
      sustain their operations. The Statewide Network of Community Oral Health Care and
      CODE models are still evolving, but they are replicable not only in dental
      education but in other types of health services. The details of the partnerships
      and funding streams will vary from site to site, but through outreach and careful
      negotiation with potential partners and detailed contracts, the community service
      and educational missions of a health professions school can have a successful
      outcome.

PMID- 10650427
TI  - Community-based education: the University of Pennsylvania Dental Care Network.

PMID- 10650428
TI  - Community-based clinical education programs. Major findings and recommendations.

PMID- 10650429
TI  - Incentive compensation for nurses: is this professional practice?

PMID- 10650430
TI  - Implementing nursing practice standards in the post-Soviet nations of central and
      eastern Europe.
AB  - There is an increasing interest by the healthcare industry in the post-Soviet
      nations of Central and Eastern Europe in adopting and applying at least some
      aspects of Western healthcare management technology, such as TQM, to contain
      healthcare expenditures and improve healthcare outcomes. However, interest is not
      enough. There must be a firm, long-term commitment to fostering sustainable
      change by these governments and healthcare organization management to redesign
      academic curricula to include healthcare quality management concepts, to develop
      and implement professional clinical practice standards, and to continue to
      monitor the quality of healthcare services provided.

PMID- 10650431
TI  - Relationship of organizational culture and readiness for change to employee
      commitment to the organization.
AB  - OBJECTIVES: A study was undertaken to determine the relationships among
      organizational culture, organizational commitment, and organizational readiness
      in a sample of employees participating in a hospital-wide redesign process.
      METHODS: Employees of an organization undergoing patient-focused redesign were
      surveyed after a 6-month period of preparation and before the initiation of the
      new care delivery model. RESULTS: Organizational readiness, a variable rarely
      described in organizational change literature, was the strongest predictor of
      employee commitment to the organization. Constructive culture also was
      predictive, but less so than readiness for change. CONCLUSIONS: Additional
      research is needed to clarify how an organization's history and culture of change
      contribute to employee willingness to work for the goals of the organization.
      Findings suggest that when change is seen as a positive characteristic of the
      environment, employees are more likely to commit to the work of the institution.

PMID- 10650432
TI  - A guide to choosing technology to support the measurement of patient outcomes.
AB  - Personal computers, scanning systems, and hand-held computing devices are the
      latest tools being used to support the management of patient outcomes. Nurse
      executives can choose technologies needed to place nurses at the fore of
      multidisciplinary groups charged with improving the quality and cost
      effectiveness of patient care. The authors review three types of patient data
      management technologies and answer questions executives may have in selecting
      systems for their departments.

PMID- 10650434
TI  - An assessment and intervention strategy for managing staff needs during change.
AB  - Currently, change is rampant in healthcare. Amid the economic pressures of
      managed care, nursing leaders find themselves pouring over financial spread
      sheets and crunching numbers at the expense of staff interaction. While staff
      members feel overwhelmed by the whirlwind of change around them, nursing leaders
      struggle to balance staff needs with countless other responsibilities. The
      assessment and intervention strategy presented provides nursing leaders with a
      straightforward and efficient means of identifying and addressing issues that
      affect staff productivity, retention, and satisfaction.

PMID- 10650433
TI  - Unifying organizational approaches to measuring and managing patient outcomes.
AB  - Information about patient outcomes is increasingly available to guide consumers
      in their selection of healthcare. By unifying the traditionally separate programs
      of performance improvement, case management, and research, nurse executives can
      take control of care processes and outcomes. This article provides four case
      examples of patient care improvements achieved using performance improvement,
      case management, and research approaches. The use of the technologies outlined in
      the Johnson and Nolan article in this issue, "A Guide to Choosing Technology to
      Support the Measurement of Patient Outcomes", also is described.

PMID- 10650435
TI  - Using problem-based learning to redesign nursing administration masters programs.
AB  - Problem-based learning (PBL) is offered as an appropriate pedagogy to prepare
      nurse managers for the uncertainties of future administrative practice. It is a
      student-centered, experiential learning strategy aimed at developing clinical
      reasoning, structuring knowledge in real-life contexts, motivating learning, and
      developing self-learning skills. Health professions and business schools report
      positive feedback from their stakeholders after adopting this new learning
      paradigm.

PMID- 10650436
TI  - In memoriam: Robert W. Goy.

PMID- 10650437
TI  - Gender constancy judgments in children with gender identity disorder: evidence
      for a developmental lag.
AB  - Gender constancy judgments in children referred for problems in their gender
      identity development (N = 206) and controls (N = 95) were compared. On Slaby and
      Frey's (1975) gender constancy interview, the gender-referred children performed
      more poorly than the controls at three stage levels: gender identity, gender
      stability, and gender consistency. On the Boy-Girl Identity Task, a second
      measure of gender constancy (Emmerich et al., 1977), the gender-referred children
      also performed more poorly. Gender-referred children who had not attained gender
      consistency engaged in significantly less same-sex-typed play on a free-play task
      than the gender-referred children who had, but there were no gender consistency
      effects for the controls. Two other measures of sex-typed behavior were unrelated
      to gender consistency. In the gender-referred group alone, children who "failed"
      the gender identity or gender stability stages were more likely to draw an
      opposite-sex person first on the Draw-a-Person test and to evince more affective
      gender confusion on the Gender Identity Interview (Zucker et al., 1993) than
      children who had "passed." It is concluded that children referred for problems in
      their gender identity development have a developmental lag in gender constancy
      acquisition. Possible reasons for the lag are discussed.

PMID- 10650438
TI  - Gendered sex work in the San Francisco tenderloin.
AB  - The variable "gender" rarely appears in prostitution research. Its inclusion
      raises the same questions brought up with respect to other areas of work: Is
      there a gendered perspective with respect to the work and are gender inequalities
      reflected in it? This study examines gender differences in the work of 140 sex
      workers in the San Francisco Tenderloin. As well as women and men who are
      workers, we include transgender workers (genetic males who present themselves as
      women), further accentuating differences by gender. Looking at work-specific
      characteristics, we find that women do not suffer inequities of income. They are,
      however, more prone to occupational hazards. Transgenders, who suffer the most
      societal discrimination, are closer to women than men in their work situation.
      Examining the sexuality of sex workers, the women are the least likely to enjoy
      sex with clients. Men report more sexual enjoyment with clients and transgenders
      are closer to the men in this regard. Few differences are, however, found in
      sexual pleasure in the personal lives of the women, men, and transgenders. A
      gender difference that stands out is that the men have more noncommercial sex
      partners than the women. Again, transgenders are more like the men, although
      various aspects of their condition make for some unique differences.

PMID- 10650439
TI  - Sexual Coercion in India: an exploratory analysis using demographic variables.
AB  - A 14-item Sexual Coercion Inventory (SCI) was administered to an urban university
      sample in Western India. Twenty-six percent of the sample reported a total of 160
      incidents of sexual coercion ranging in severity from unwanted kissing to sexual
      intercourse. The most common outcome was intercourse and was followed by kissing
      and fondling. No gender differences were discovered regarding victim status or
      types of coercion tactics experienced. A MANOVA analysis found no overall gender
      effect, but marital status and protected class membership did have a significant
      effect with people who are married and protected class members reporting more
      sexual coercion. Reasons for the lack of an overall gender effect and limitations
      of this research are discussed.

PMID- 10650440
TI  - Allocation of attentional resources during habituation and dishabituation of male
      sexual arousal.
AB  - A secondary-task probe (tone) was presented intermittently while men viewed
      erotic film segments across a session involving 18 trials with the same film
      segment (habituation), then 2 trials with different film segments (novelty) and 2
      trials with reinstatement of the original segment (dishabituation). Reaction time
      to the tone (an index of the extent processing resources were being committed to
      the erotic stimulus) shifted during the session in parallel with changes that
      occurred in penile tumescence and subjective sexual arousal. The decrease in
      sexual arousal over the first 18 trials in the session was accompanied by a
      progressively faster reaction to the tone, novel stimulation led to recovery of
      sexual arousal and a slower reaction to the tone, and on trials 21 and 22 sexual
      arousal and reaction time levels were above the values that prevailed immediately
      prior to novel stimulation. Results are discussed with reference to the
      relationship between habituation and attention.

PMID- 10650442
TI  - Changes in sexual orientation in six male-to-female (MtF) transsexuals.

PMID- 10650441
TI  - Sexual desire discrepancies: effects on sexual and relationship satisfaction in
      heterosexual dating couples.
AB  - Sexual desire discrepancies and the associations between desire discrepancies and
      relationship adjustment (i.e., sexual and relationship satisfaction) in
      heterosexual dating couples (N = 72) were examined Desire discrepancies were
      assessed via two methods: (1) a couple-based index created using both
      individuals' reports of sexual desire and (2) an individual-based index using
      each person's own subjective perception of a desire discrepancy within the
      couple. Both indices were associated with women's adjustment, whereas only
      individual perceptions of discrepancies were associated with men's adjustment.
      The association between desire discrepancies and general relationship
      satisfaction was fully mediated by level of sexual satisfaction for both men and
      women. Women whose sexual desire level was lower than their partners' endorsed
      lower levels of relationship adjustment relative to women whose desire was either
      greater than or similar to their partners'. Implications for the assessment of
      sexual desire differences in couples are discussed.

PMID- 10650443
TI  - The NIMH perspective: next steps in schizophrenia research.

PMID- 10650444
TI  - Essential fatty acids, lipid membrane abnormalities, and the diagnosis and
      treatment of schizophrenia.
AB  - Recent research suggests that deficient uptake or excessive breakdown of membrane
      phospholipids may be associated with schizophrenia. We review available clinical
      research on abnormalities in membrane fatty acid composition and metabolism in
      schizophrenia, and therapeutic trials of fatty acid in this disorder. All
      potentially relevant English-language articles were identified from the medical
      and psychiatric literature with the aid of computer searches using key words such
      as lipids, phospholipids, prostaglandins and schizophrenia. All studies which
      include human subjects are reviewed. Empirical studies related to membrane
      hypotheses of schizophrenia focus on: 1) assessment of prostaglandins (PG) and
      their essential fatty acid (EFA) precursors in the tissues of patients with
      schizophrenia; 2) evaluation of the niacin flush test as a possible diagnostic
      marker; 3) evaluation of phospholipase enzyme activity; 4) NMR spectroscopy
      studies of brain phospholipid metabolism; and 5) therapeutic trials of PG
      precursors for the treatment of schizophrenia. The most consistent clinical
      findings include red blood cell fatty acid membrane abnormalities, NMR
      spectroscopy evidence of increased phospholipid turnover and a therapeutic effect
      of omega-3 fatty acid supplementation of neuroleptic treatment in some
      schizophrenia patients. Studies of EFA metabolism have proved fruitful for
      generating and testing novel etiologic hypotheses and new therapeutic agents for
      schizophrenia. Greater attention to factors that influence tissue EFA levels such
      as diet, tobacco and alcohol are required to reconcile inconsistent findings.
      Treatment studies, although promising, require independent replication.

PMID- 10650445
TI  - Metabotropic glutamate receptor mRNA expression in the schizophrenic thalamus.
AB  - BACKGROUND: The central role that the thalamus plays in information processing
      and sensory integration suggests that its dysfunction may be a factor in the
      pathophysiology of schizophrenia. Glutamate is a key neurotransmitter in thalamic
      function, and although all aspects of thalamic glutamate neurotransmission have
      not been elucidated, transcripts encoding members of each family of the glutamate
      receptors have been identified in the thalamus. Recently, activation of group II
      metabotropic glutamate receptors (mGluRs) was demonstrated in rats to ameliorate
      the behavioral effects associated with exposure to phencyclidine, an
      uncompetitive NMDA receptor antagonist that can induce psychotic symptoms,
      suggesting the possibility of mGluR abnormalities in schizophrenia. We
      investigated whether expression of thalamic mGluR mRNA is altered in this
      illness. METHODS: We examined the expression of the transcripts encoding the
      mGluR1, 2, 3, 4, 5, 7, and 8 receptors in postmortem thalamic tissue samples from
      elderly schizophrenic and control subjects, using in situ hybridization. We
      identified six thalamic nuclei in each section (anterior, dorsomedial, lateral
      dorsal, central medial, reticular, and nuclei of the ventral tier). RESULTS:
      There were no differences between elderly schizophrenic and control subjects in
      the expression of mGluR1, 2, 3, 4, 5, 7, or 8 transcript levels in any of these
      six thalamic nuclei. CONCLUSIONS: mGluR mRNA expression is not abnormal in the
      thalamus of patients with schizophrenia. The modulatory roles proposed for
      mGluRs, and the potentially important relationship between mGluRs and NMDA
      receptors, suggest that mGluRs may be involved in the pathophysiology of
      schizophrenia, but this is not detectable at this level of gene expression.

PMID- 10650446
TI  - Decreased levels of soluble intercellular adhesion molecule-1 (sICAM-1) in
      unmedicated and medicated schizophrenic patients.
AB  - BACKGROUND: The soluble intercellular adhesion molecule-1 (sICAM-1) is a marker
      for the activation of the cellular immune system. Since an activation of the
      immune system has been observed in a part of the schizophrenic patients, we
      measured the serum levels of soluble ICAM-1 (sICAM-1) in schizophrenic patients
      and correlated them to the patient's psychopathology. METHODS: To monitor a
      possible effect of antipsychotic therapy, 36 schizophrenic patients were examined
      twice: first without antipsychotic medication immediately after admission to the
      hospital and then, after clinical improvement before discharge. The results were
      compared with those of 36 age- and gender-related healthy individuals. RESULTS:
      The schizophrenic patients showed significantly decreased serum levels of sICAM-1
      at the first examination (248 +/- 95 ng/mL) and at re-examination (266 +/- 95
      ng/mL) compared with the comparison group (323 +/- 74 ng/mL). Patients with more
      pronounced negative symptoms showed higher levels of sICAM-1 at the first
      examination. CONCLUSIONS: We conclude that reduced sICAM-1 levels in
      schizophrenia indicate a reduced activity of the cellular immune system in at
      least a subgroup of schizophrenic patients.

PMID- 10650447
TI  - Working memory constrains abstraction in schizophrenia.
AB  - BACKGROUND: Abstraction has long been considered an area of differential
      cognitive deficit in schizophrenia, primarily because of patients' poor
      performance on the Wisconsin Card Sorting Test (WCST). Yet, the complexity and
      multidimensional nature of the WCST increases the likelihood that several
      different cognitive processes, perhaps mediated by different neural systems, are
      being tapped. METHODS: In the current study, the Abstraction and Working Memory
      (AIM) task was designed to disentangle abstraction and working memory so that the
      effects of each cognitive domain could be independently analyzed. The AIM task
      and a battery of neuropsychological tests were administered to 62 patients with
      schizophrenia and 62 matched healthy volunteers. RESULTS: Whereas patients with
      schizophrenia demonstrated deficits in simple abstraction, they were
      disproportionately impaired with the addition of a minimal memory requirement.
      CONCLUSIONS: Group differences on WCST performance appear to be attributable to
      patients' inability to maintain information over a short delay, before that
      information is used for more complex cognitive operations.

PMID- 10650448
TI  - Influence of stimulus control on the excitability of the electrically elicited
      blink reflex in patients with schizophrenia.
AB  - BACKGROUND: In humans, the excitability of the electrically evoked blink reflex
      is influenced by the subject's attention to the stimulus. The early reflex
      component R1 has been found to be facilitated in conditions of increased
      selective attention, whereas the late components R2 and R3 exhibited a marked
      suppression. Distraction from the stimulus leads to enhanced R2 and R3
      magnitudes. METHODS: We investigated the excitability of the distinct reflex
      components in 19 patients with schizophrenia and 19 healthy control subjects. In
      the control condition (EE), stimulation was elicited by the experimenter; in a
      second condition (SE), subjects released a key to evoke the reflex themselves.
      RESULTS: The SE patients with schizophrenia exhibited an abnormally increased R1
      facilitation and an impaired R2 inhibition in comparison with normal control
      subjects. An R3 component could be registered in EE in 13 of 19 patients but only
      in one control subject; SE resulted in a complete suppression of this component
      in all but two patients with schizophrenia. CONCLUSIONS: The abnormal R1
      facilitation and the impaired R2 inhibition may be regarded as neurophysiological
      markers of defective information processing in a condition of increased selective
      attention to a self-controlled stimulus in patients with schizophrenia. The
      enhanced excitability of the R3 component under standard conditions indicates
      defective attentional mechanisms in patients with schizophrenia in an
      uninstructed passive condition attending a stimulus triggered by the
      experimenter.

PMID- 10650449
TI  - Executive control is disturbed in schizophrenia: evidence from event-related
      potentials in a Go/NoGo task.
AB  - BACKGROUND: Schizophrenic patients suffer from cognitive and attentional
      deficits, particularly from failure of executive control functions. METHODS: This
      study investigated the cortical organization of executive control in
      schizophrenic patients and healthy control subjects using event-related
      potentials (ERPs). Event-related potentials were collected while subjects
      performed an auditory Go/NoGo task that required response inhibition. To exclude
      stimulus discriminability and early stimulus processing to confound results,
      stimuli were adjusted to the subject's individual discrimination ability and were
      presented in a simple and a difficult version. RESULTS: Schizophrenic patients
      performed similar to control subjects in the Go condition but worse than control
      subjects in the NoGo condition that required response inhibition. Event-related
      potentials revealed the neurophysiological substrate of this dysfunction. In the
      Go conditions, both healthy control subjects and schizophrenic patients showed
      the same voltage pattern. In the NoGo condition, control subjects and patients
      showed similar cortical activation only during early processing (N2 time window).
      However, in later stages of processing (P3 time window), healthy subjects showed
      left lateralization of ERPs over frontal areas while schizophrenic patients did
      not. CONCLUSIONS: We conclude that schizophrenic patients exhibit deficient
      processing in a neuronal network, including left frontal areas, that is involved
      in later stages of executive control function.

PMID- 10650450
TI  - Effective neuroleptic medication removes prepulse inhibition deficits in
      schizophrenia patients.
AB  - BACKGROUND: The magnitude of the startle eyeblink response is reduced if the
      startle eliciting stimulus is shortly preceded by another stimulus. There is
      evidence that schizophrenia patients exhibit impairments in this so-called
      prepulse inhibition. Our study investigated whether prepulse inhibition is
      affected by neuroleptic drug treatment as is suggested by animal research.
      METHODS: Prepulse inhibition was tested in five unmedicated and 20 medicated
      inpatients with schizophrenia, and 12 normal controls. RESULTS: The unmedicated
      schizophrenia patients showed a strong impairment of sensorimotor gating as
      indexed by the absence of prepulse inhibition. By contrast, the medicated
      patients showed a pronounced prepulse inhibition that did not differ from that of
      the normal controls. There was a substantial covariation between the rated
      severity of the positive syndrome and the amount of prepulse inhibition--i.e.,
      the patients whose positive symptoms were rated as more severe showed less
      prepulse inhibition. CONCLUSIONS: These data suggest that the impaired
      sensorimotor gating of schizophrenia patients is not a stable vulnerability
      indicator, but may rather be related to the positive syndrome and may be improved
      by treatments with neuroleptic medication.

PMID- 10650451
TI  - Neurologic soft signs and low birthweight: their association and neuropsychiatric
      implications.
AB  - BACKGROUND: We examine the relationship between neurologic soft signs and
      cognitive deficits, learning disorders, and psychiatric problems in low
      birthweight (LBW) and normal birthweight (NBW) children. METHODS: Representative
      samples of LBW and NBW children were selected from the 1983-1985 newborn
      discharges of two major hospitals in Michigan. Eight hundred-twenty three
      children (75% of the target sample) were evaluated at ages 6 and 11. A
      standardized neurologic evaluation was used by neurologists to measure neurologic
      soft signs at age 6 (children with frank neurologic impairment were excluded). IQ
      was measured by WISC-R and behavior problem lists were rated by mothers and
      teachers. Standard tests of academic achievement were used to identify learning
      disorders. All assessments were blind to LBW status. Using multiple regression
      analysis, applying generalized estimating equations (GEE), we estimated the
      effects of soft signs on 3 behavioral domains, based on information from multiple
      informants and times of assessment. RESULTS: LBW was associated with a two-fold
      increased risk for soft signs. Soft signs increased the risk for subnormal IQ and
      for learning disorders in children with normal IQ. Soft signs were associated
      with excess internalizing problems in LBW and NBW children, and with attention
      and externalizing problems in LBW children; the excess in externalizing problems
      in LBW children was observed only at age 6. CONCLUSIONS: Soft signs are a marker
      of high risk for cognitive and psychiatric problems. Of particular concern is
      their presence in LBW children, in whom they are associated with more severe
      cognitive deficits and more pervasive psychiatric problems.

PMID- 10650453
TI  - [Signal slitting as a basis of involvement of the natural cytotoxicity system
      into endogenous biological relay].

PMID- 10650452
TI  - Substance P (NK1) receptors in the cingulate cortex in unipolar and bipolar mood
      disorder and schizophrenia.
AB  - BACKGROUND: The substance P receptor (neurokinin-1 receptor) has been implicated
      in stress responses and anxiety traits in the rodent, and neurokinin-1 receptor
      antagonism may have antidepressant and anxiolytic effects. This suggests that the
      function and/or expression of neurokinin-1 receptor might be affected in subjects
      with mood disorders. METHODS: We measured neurokinin-1 receptor densities in the
      anterior cingulate cortex in subjects with unipolar (major) depression (n = 13),
      bipolar disorder (n = 13), schizophrenia (n = 14), and controls (n = 14) using
      quantitative autoradiography with [125I]BH-substance P. The anterior cingulate
      cortex was chosen for initial analysis since recent positron emission tomography,
      magnetic resonance imaging, and neuropathological data suggest its involvement in
      mood disorders. RESULTS: Neurokinin-1 receptor densities were higher in
      superficial than in deep laminae. Neurokinin-1 receptor densities increased with
      age and declined with prolonged autopsy interval. No differences were seen
      between the four groups. However, the ratio of superficial to deep laminar
      binding was lower in the subjects with unipolar depression compared with all
      other groups (p < .01) Neurokinin-1 receptor binding and the laminar ratio were
      unaffected by sex, medication history, pH, suicide, comorbid substance abuse, or
      a family psychiatric history. CONCLUSIONS: No overall change in neurokinin-1
      receptor densities occurs in the cingulate cortex in subjects with mood disorders
      or schizophrenia. However, the changed laminar ratio in unipolar depression may
      reflect alterations in specific neural circuits expressing neurokinin-1 receptor.

PMID- 10650454
TI  - [Effect of multiple microinjections of bicuculline into rostral caudal regions of
      neostriatum and globus pallidus on the escape behavior in rats].

PMID- 10650456
TI  - [Mechanisms of behavioral effects of potentiated forms of morphine].

PMID- 10650455
TI  - [Relationship between the density of beta-adrenoreceptors and the noradrenaline
      level in the cerebral cortex of the neonatal rats].

PMID- 10650457
TI  - [Functioning of staircase muscles during normal breathing and inspiratory
      resistive load].

PMID- 10650458
TI  - [Age characteristics of cardiac rhythm reaction of intact and desympathectomized
      rats to atropine administration].

PMID- 10650459
TI  - [Effect of cerebral cortex on the conduction of nociceptive signals of cardial
      genesis].

PMID- 10650460
TI  - [The value of cardiodynamics indices for prediction of cardiac insufficiency in
      massive pulmonary artery embolism].

PMID- 10650461
TI  - [Differences in the behavior and resistance to stomach ulcer during stress in
      August and Wistar rats adapted and not adapted to hypoxia].

PMID- 10650462
TI  - [Effect of adaptation to physical load on alpha-adrenergic reactions of isolated
      resistant artery during acute experimental myocardial infarction].

PMID- 10650463
TI  - [Changes in the erythropoiesis in normal mice after transplantation of peritoneal
      cells from syngeneic donors with prolonged sodium arsenite intoxication].

PMID- 10650464
TI  - [Effect of glucocorticoids and high density lipoproteins in the activity of
      hepatocyte nuclear apparatus].

PMID- 10650465
TI  - [Effect of L-lysine-A-oxidase on development of herpetic genital infection in
      guinea pigs].

PMID- 10650466
TI  - [Inhibitory effect of noradrenaline on thyrostimulating activity of oxytocin in
      rats].

PMID- 10650467
TI  - [Concentration and properties of albumin in blood and exudate during acute
      pancreatitis].

PMID- 10650468
TI  - [Effect of steroid sex hormones on lipid peroxidation and antiperoxide system of
      glutathione in rat skin tissues].

PMID- 10650469
TI  - [Superoxide dismutase activity in the brain of rats offspring during antenatal
      exposure to lead].

PMID- 10650470
TI  - [Collagenolytic proteases from invertebrates: major applications].

PMID- 10650471
TI  - [Biological activity of pharmacological properties of the anticoagulant complex
      (hirudin, plasma kallikrein inhibitor, prostaglandin) from the leech Hirudo
      medicinalis].

PMID- 10650472
TI  - [The role of interferon-gamma in the regulation of antiproliferative activity of
      nonadherent bone marrow cells].

PMID- 10650473
TI  - [The role of various subpopulations of B-lymphocytes in formation of nonspecific
      immunoglobulins induced by antigen administration].

PMID- 10650474
TI  - [Cytogenetic effects of acrylamide, acrylonitrile and their combination with
      verapamil in vivo].

PMID- 10650475
TI  - [Thyroliberin inhibits development of post-tetanic potentiation in synaptic
      systems of rat hippocampus].

PMID- 10650476
TI  - Physicians and cancer patients: communication and advance directives.

PMID- 10650477
TI  - Information is not enough: the place of statistics in the doctor-patient
      relationship.

PMID- 10650478
TI  - Cross-cultural issues in caring for patients with cancer.

PMID- 10650479
TI  - Religious/spiritual concerns in caring for the cancer patient.

PMID- 10650480
TI  - Are there limits to oncology care? (Futility).

PMID- 10650481
TI  - Role of palliative medicine in cancer patient care.

PMID- 10650482
TI  - Informed consent, the cancer patient, and phase I clinical trials.

PMID- 10650483
TI  - The ethical lessons of managed care applied to clinical trials.

PMID- 10650484
TI  - Kids and cancer: ethical issues in treating the pediatric oncology patient.

PMID- 10650485
TI  - Does reimbursement affect physician decision making?

PMID- 10650486
TI  - Protective effects of partially purified antigens of Actinobacillus
      pleuropneumoniae on experimentally infected mice.
AB  - Three different models of protection experiments in mice using partially purified
      Actinobacillus pleuropneumoniae antigens such as crude culture supernatant
      extract (CCSE) and partially purified cell extract (PPCE) were attempted.
      Biochemical analysis showed that these two immunogens had protein concentration
      of 0.17-0.2 mg/mL and pentose concentration of 0.012-0.014 mg/mL. In the first
      model intranasal (IN) vaccination with different doses (from 0.01-10 IN-LD50)
      against IN challenge with the dose of 20 IN-LD50 containing 1.2 x 10(9) colony
      forming unit (CFU)/50 microL showed that only those with the dose more than 1 IN
      LD50 had slight protection in terms of survival index (SI). In the second model
      of protection experiment, in which subcutaneous vaccination (s.c.) with the
      immunogens plus soybean oil against IN challenge with 10 IN-LD50 containing 6 x
      10(8) CFU/50 microL, showed that formalin-killed bacteria (bacterin) and CCSE
      plus PPCE had only a slight protection whereas vaccination with CCSE or PPCE
      immunogen alone had no protection. In the third model of protection experiment,
      in which the intramuscular (i.m.) vaccination with the immunogens plus aluminum
      hydroxide [Al(OH3)] gel against intraperitoneal (i.p.) challenge with the dose of
      either 2 or 6 i.p.-LD50 containing 1.2-3.6 x 10(8) CFU/0.5 mL of 0.3% mucin
      saline showed highly effective.

PMID- 10650487
TI  - Tumor necrosis factor-alpha and interleukin-6 profiles in children with
      pneumonia.
AB  - Pneumonia is a common cause of hospitalization and is associated with high
      morbidity in children. Tumor necrosis factor-alpha (TNF-alpha) and Interleukin-6
      (IL-6) are primary mediators of inflammation, and have been implicated in a large
      number of infectious and non-infectious inflammatory diseases. The serum
      concentrations of TNF-alpha and IL-6 were measured by enzyme-linked immunosorbent
      assay (ELISA) in 27 patients with bacterial pneumonia (n = 12) or respiratory
      syncytial virus (RSV) pneumonia (n = 15) and in 15 healthy control subjects. TNF
      alpha concentrations of patients with bacterial pneumonia in acute stage (16.94
      +/- 5.70 ng/L) were significantly higher than those in convalescent stage (5.80
      +/- 0.75 ng/L), in patients with RSV pneumonia (5.06 +/- 0.44 ng/L) and in
      healthy control subjects (5.39 +/- 0.68 ng/L) (p < 0.005). TNF-alpha
      concentrations of patients with RSV pneumonia were not significantly different
      from those of the control group. IL-6 concentrations of patients with bacterial
      pneumonia in acute stage (465.94 +/- 290.30 ng/L) were significantly higher than
      those in convalescent stage (22.04 +/- 15.08 ng/L), in patients with RSV
      pneumonia (7.65 +/- 2.58 ng/L), and in healthy control subjects (0.84 +/- 0.08
      ng/L) (p < 0.0005). There was significant difference between patients with RSV
      pneumonia and the healthy control group (p < 0.005). In summary, there were
      significant differences in TNF-alpha and IL-6 concentrations between acute stage
      and convalescent stage in patients with bacterial pneumonia, making them useful
      as markers for bacterial pneumonia. Further studies are needed to establish the
      potential diagnostic and prognostic value of TNF-alpha and IL-6.

PMID- 10650489
TI  - Clinical analysis of Mycobacterium tuberculosis infection in patients with
      acquired immunodeficiency syndrome.
AB  - From January 1990 to July 1998, twelve patients (10%) among 120 patients with
      human immunodeficiency virus infection who were hospitalized in the Veterans
      General Hospital-Taipei, were proved to have Mycobacterium tuberculosis
      infection. The mean age of these patients was 38 years, range: 25-62 years. All
      patients studied were in the advanced stage of acquired immunodeficiency syndrome
      (AIDS) with a mean circulatory CD4 lymphocyte count of 21/microL (range: 0
      64/microL) and a much higher HIV viral load at initial diagnosis of M.
      tuberculosis infection. Because of no significant difference in the HIV viral
      load between patients with active pulmonary tuberculosis and those with
      extrapulmonary tuberculosis in this study, dissemination of M. tuberculosis did
      not correlate directly with a high HIV viral load, but was possibly related to
      the virulence of the organism itself. Chest radiographic findings at initial
      diagnosis of pulmonary tuberculosis were variable and atypical. Most patients
      (62.5%) presented with a primary pattern (lower lobe or diffuse infiltrates),
      while hilar lymphadenopathy was noted in more than half of the patients and
      cavitation was less common (only one patient). Ten patients (83.3%) had
      extrapulmonary involvement; the most common site being the lymph nodes. Most
      patients with classic drug-sensitive tuberculosis responded well to conventional
      standard regimens of anti-tuberculosis therapy. Since tuberculosis is
      transmittable, treatable, and possibly preventable, moreover the clinical
      presentation of tuberculosis in the patients with AIDS may be atypical and
      unusual, clinical physicians must keep an alert dealing with these patients for
      early identification and early treatment.

PMID- 10650488
TI  - Surveillance of antibiotic resistance in Taiwan, 1998.
AB  - For the first national surveillance of antibiotic resistance in Taiwan, we
      collected in 1998 from 22 hospitals (6 medical centers, 15 regional hospitals,
      and 1 local hospital) 3,211 isolates in all parts of the country. Besides 50
      random successive isolates from inpatients, each hospital was requested to
      collect 25 isolates each from positive blood cultures, hospital-acquired
      infections, outpatients and the pediatric department. We re-speciated all the
      submitted specimens and determined their antibiotic susceptibility patterns. The
      most common isolates were Enterobacteriaceae (Escherichia coli, Klebsiella
      pneumoniae), Staphylococcus aureus, and Pseudomonas aeruginosa. Among hospital
      acquired infections, Acinetobacter spp. were among those which accounted for over
      10% of the isolates. The oxacillin resistance of S. aureus was 82% in isolates
      from hospital-acquired infections, and 40% from outpatients. Among Enterococcus
      spp., 85% were either E. faecalis or E. faecium. They were 14% resistant to
      vancomycin. Among gram-negative bacteria, K. pneumoniae and Acinetobacter
      baumanii were hospital-acquired isolates that were most clearly more resistant
      than community acquired isolates. This difference was less apparent in the case
      of Enterobacter cloacae, Serratia marcescens, and P. aeruginosa. These bacteria
      were generally more resistant from all sources. Fifty-one percent of Salmonella
      were resistant to ampicillin; however, these were all sensitive to ciprofloxacin.
      Isolates from the East were least resistant. Plotting the disc zone diameters of
      antibiotics within the susceptible range, we identified subpopulations with
      smaller diameters in the case of vancomycin against S. aureus, ciprofloxacin
      against E. coli, and ciprofloxacin against Salmonella spp. These findings
      represent one of the purposes of this surveillance as they may portend developing
      resistances which bear careful watching in the future.

PMID- 10650490
TI  - Prospective surveillance of children with invasive Haemophilus influenzae disease
      in Taiwan.
AB  - During the 16 months from January 1, 1996 through April 30, 1997, forty-three
      cases of invasive Haemophilus influenzae disease were identified in residents
      younger than 14 years of age in Taiwan. H. influenzae serotyping was performed on
      all isolated specimens. There were 33 (76.7%) cases of type b disease; three
      (7.0%), non-type b, and seven (16.3%), nontypeable cases. Among these H.
      influenzae type b cases, there were 18 (54.5%) male patients and 15 (45.5%)
      female patients. With regard to age-distribution, nine (27.3%) patients were aged
      2 to 5 years; nine (27.3%), between 1 to 2 years; fifteen (45.5%), younger than
      1; and none were younger than 3 months old. Demographical study indicated that 13
      patients (39.4%) located in northern Taiwan; 5 (15.2%), central Taiwan; 12
      (36.4%), southern Taiwan; 3 (9.0%) from eastern Taiwan. Among the 33 H.
      influenzae type b cases, twenty-five (75.8%) patients had meningitis and 8
      patients had other disease entities, i.e. pneumonia in 4 patients, bacteremia in
      3, and cellulitis in 1. In terms of prognosis, three (9.1%) patients died, all of
      whom having meningitis or sepsis; 7 (21.2%) developed hydrocephalus; 2 (6.1%) had
      seizure disorder without hydrocephalus and 21 (63.6%) patients recovered
      completely without sequelae.

PMID- 10650491
TI  - Pyogenic psoas abscess: analysis of 27 cases.
AB  - From 1993 to 1998, 29 pyogenic psoas abscesses occurring in 27 patients were seen
      in Taichung Veterans General Hospital. Their age range was 25 to 85 years.
      Diabetes mellitus was the leading underlying disease. Fever and pain in the flank
      area, back and hip were the usual manifestations. The duration of symptoms prior
      to the diagnosis ranged from 3 days to 6 months. Most abscesses were diagnosed by
      computed tomography (CT) images and proven by abscess cultures, which were
      divided into primary and secondary types. Eighteen of 29 abscesses were regarded
      as primary. Staphylococcus aureus was the most common pathogen in the primary
      abscesses, followed by Streptococcus agalactiae, Escherichia coli, viridans
      streptococci, S. epidermidis, and Salmonella spp.. In the secondary abscess
      category, E. coli was the leading organism in this series, followed by S. aureus,
      Klebsiella pneumoniae, viridans streptococci and Candida albicans. The associated
      conditions included epidural abscess, osteomyelitis, septic arthritis, perirenal
      abscess, pulmonary tuberculosis, empyema, hydronephrosis and trauma history. The
      initial empiric therapy comprised mostly of cefazolin or oxacillin with or
      without an aminoglycoside. Thirteen patients underwent percutaneous drainage,
      while six received surgical debridement, including two with a recurrent abscess.
      One patient had both drainage and debridement. Others received medical treatment
      only. Two of the patients with primary abscess died in spite of percutaneous
      drainage. Therefore, open drainage, besides appropriate antibiotic treatment, is
      still required to control complex abscesses with sepsis.

PMID- 10650492
TI  - [The effect of thermal power plant on microbial ecology and environmental
      quality].
AB  - To investigate the effect of thermal power plant on the microbial ecology and the
      environmental quality, the Hsieh-Ho Thermal Power Plant was chosen and the
      populations of microbes including bacteria, actinomycetes, fungi, and
      cellulolytic, phosphate-solubilizing and nitrogen-fixing microbes were selected
      as the parameters of microbial ecology. The pH values of the soil sample
      collected from inside and outside of the plant were 5.2-6.2 and 4.0-5.3,
      respectively. Moisture content in plant area was lower than that in the
      surrounding area. Microbial populations of the topsoils were higher than those of
      the subsoils. Each gram of soil contained 3.64 x 10(4)-5.16 x 10(7) colonies of
      bacteria, 1.75 x 10(3)-1.10 x 10(6) colonies of actinomycetes and 6.72 x 10(3)
      8.78 x 10(6) colonies of fungi in the plant area; while they were 5.52 x 10(4)
      2.14 x 10(7), 8.26 x 10(3)-7.25 x 10(5) and 3.49 x 10(3)-2.74 x 10(6) colonies of
      bacteria, actinomycetes and fungi, respectively, in the surrounding area. The
      effect of seasonal change on microbial populations was not significant. The ratio
      of cellulolytic, phosphate-solubilizing and nitrogen-fixing microbes to the total
      count in the plant area was also higher than that in the surrounding area, and
      some of them had significant differences. From the statistical analysis, the
      effect of thermal power generator on the population and distribution of microbes
      was significantly different.

PMID- 10650493
TI  - [Relatedness of Shigella sonnei isolates from six outbreaks in Tao-Yuan area,
      Taiwan].
AB  - Between November 1995 and January 1996, one larger-scale outbreak of Shigella
      sonnei infection occurred in the area of Tao-Yuan, Taiwan. Subsequently, five
      outbreaks of S. sonnei infection occurred in the same area during the period from
      October 1998 to February 1999. Fifty-five isolates obtained from these six
      outbreaks were differentiated by antimicrobial susceptibility testing, plasmid
      profile analysis (PPA) and pulsed-field gel electrophoresis (PFGE). They were
      classified into two and three types by antimicrobial susceptibility testing and
      PPA, respectively. However, only one pattern was observed by PFGE. The molecular
      epidemiology by PFGE in this study indicated that they were closely-related.
      These data suggest that the clinical isolates obtained during the period of
      January 1998 to January 1999 were probably derived from the outbreak strain of
      1995.

PMID- 10650494
TI  - [Different age of asthmatic patients affected by different aeroallergens].
AB  - A total of 1070 cases of bronchial asthma, aged from 3 to 70 years, were analyzed
      for their hypersensitivity to the four most common aeroallergens,
      Dermatophagoides pteronyssinus, German cockroaches, Penicillium notatum and
      Candida albicans. The severity of hypersensitivity was classified as mild,
      moderate and severe based on the concentration of allergen specific IgE in the
      sera. Results showed that there were 77.9% patients allergic to D. pteronyssinus,
      40.0% to G. cockroaches, 9.6% to P. notatum and 10.4% to C. albicans. The
      incidence and severity varied with age. For D. pteronyssinus, the highest
      incidence was 96.8% with the age between 11 and 20 years. Seventy percent of them
      were severe hypersensitivity. For P. notatum, the highest incidence was 18.9%
      with the age above 61 years. None of them were severe hypersensitivity and 11.9%
      of them were moderate hypersensitivity. For C. albicans, the highest incidence
      was 27.3% with the age between 51 and 60 years. All of them were mild
      hypersensitivity. For G. cockroaches, the highest incidence was 55.4% with the
      age between 21 and 30 years. 76.8% of them were mild hypersensitivity and 23.2%
      were moderate hypersensitivity. We concluded that different age of asthmatic
      patients affected by different aeroallergens. D. pteronyssinus was the most
      potent aeroallergen. Most asthmatic patients sensitized by mite were severe,
      particularly those patients with the age below 20 years of age.

PMID- 10650495
TI  - Non-typhoid Salmonella subdural empyema in children: report of two cases.
AB  - Subdural empyema caused by Salmonella in childhood is an uncommon condition. The
      predisposing factors for this condition are not clearly established, especially
      in young children. Here we present two cases of subdural empyema caused by non
      typhoidal Salmonella. Both of the patients suffered prolonged fever without local
      signs of infection on admission. Subdural empyema was subsequently detected by
      brain echo and brain computerized tomography (CT) scan in both cases.
      Cerebrospinal fluid (CSF) study was not done in case one due to prominent mass
      effect on brain CT; in case two the CSF analysis showed pleocytosis, but CSF
      bacterial culture was negative. Neither enteritis nor obvious meningeal sign was
      noted. Both cases responded well to surgical drainage and systemic antibiotics
      treatment.

PMID- 10650496
TI  - [Guidelines on antimicrobial therapy of pneumonia in Taiwan. The Infectious
      Diseases Society of the Republic of China].

PMID- 10650497
TI  - Bedside procedures. Solutions to the pitfalls of intrahospital transport.
AB  - The technology to perform diagnostic and therapeutic procedures at the bedside
      continues to advance. Because of documented hazards and the expense of
      intrahospital transport, the bedside is becoming an appealing site for procedures
      that are more commonly performed in radiologic, bronchoscopic, other procedural
      suites, and the operating room.

PMID- 10650498
TI  - Procedural anesthesia at the bedside.
AB  - Procedural anesthesia at the bedside offers patients relief from anxiety,
      discomfort, and pain and may expedite the procedure by increasing patient
      cooperation. Prospective planning requires knowledge of the condition of the
      patient and an assessment of the anesthetic requirements of the proposed
      procedure. The spectrum of anesthetic options includes sedation and analgesia,
      monitored anesthesia care, to total intravenous anesthesia (see Fig. 1).
      Identification of the at-risk patient and modifying the anesthetic should reduce
      complications (see Box 3). The choice of pharmaceuticals varies depending on the
      level of anticipated anesthesia. Personnel requirements also vary. Although an
      anesthesiologist is not required to administer medications and monitor the
      patient for sedation and analgesia or monitored anesthesia care, TIVA requires
      the services of an anesthesiologist. Costs are influenced by the personnel
      requirements and length of the procedure, which sets the drug requirements and
      drug costs. In the end, personal experience combined with knowledge should guide
      the provider to offer efficacious and cost-effective procedural anesthesia in the
      ICU.

PMID- 10650499
TI  - Renal replacement therapies.
AB  - Slow continuous renal replacement therapy is more hemodynamically stabilizing and
      is replacing conventional hemodialysis as the therapy of choice for acute renal
      failure in the intensive care unit. This article presents practical information,
      including basic terminology, basic physiology, technical aspects, and indications
      for and application of this technique.

PMID- 10650500
TI  - Bedside diagnostic ultrasound and therapeutic ultrasound-guided procedures in the
      intensive care setting.
AB  - The availability, portability, safety, and other features of ultrasound have
      ushered this relatively new imaging modality into the everyday clinical practice
      of multiple disciplines. Features unique to ultrasound lend this imaging modality
      the opportunity for extensive use in the ICU. A review of its uses in this
      capacity includes bedside diagnosis of common disorders seen in the ICU setting,
      such as DVT, cholecystitis, and abscess. Bedside sonography also can aid in the
      treatment of such disorders, including DGC of pseudoaneurysms, fluid aspirations,
      and abscess drainages. This article is a review and could not possibly cover all
      bedside uses of ultrasound or provide in-depth information of specific uses
      described in this article. Hopefully, this article will spark an interest and
      prove as a starting point on a rewarding learning adventure.

PMID- 10650501
TI  - Fiberoptic bronchoscopy for diagnosis and treatment.
AB  - Bedside fiberoptic bronchoscopy is a valuable tool in the diagnosis and treatment
      of various respiratory conditions in critically ill patients. The fiberoptic
      bronchoscope allows direct airway inspection, facilitating the diagnosis of
      benign and malignant airway lesions. In addition, pulmonary secretions or tissue
      samples can be collected using the bronchoscope and techniques that allow
      sampling of the lower airways with minimal or no upper airway contamination.
      Collection of lower airway samples is important in the diagnosis of pulmonary
      infiltrates in immunocompromised patients, in many patients with ventilator
      associated pneumonia, and in selected patients with CAP. The fiberoptic
      bronchoscope can be used for therapeutic interventions, such as insertion of an
      endotracheal tube, removal of an aspirated foreign body, clearance of tenacious
      secretions, promotion of hemostasis in patients with hemoptysis, instillation of
      drugs, and assistance in the placement of tracheobronchial prostheses (i.e.,
      airway stents). If proper preprocedural training and planning are done and the
      patient is monitored carefully during the procedure, fiberoptic bronchoscopy can
      be performed quickly and safely at the bedside in most critically ill patients.

PMID- 10650502
TI  - Bedside laparoscopy.
AB  - The improved technical sophistication of laparoscopy offers an attractive highly
      accurate diagnostic modality at the bedside for critically ill patients who are
      confined to the ICU and intensive monitoring unit and who are in need of timely
      abdominal evaluation. If the surgeon understands the physiologic effects of
      peritoneal insufflation and considers them during the procedure, the patient
      tolerates the procedure well. It is important to limit insufflation pressures and
      laparoscopy time. The author also recommends using the open Hasson technique. Its
      primary use is diagnostic in penetrating and blunt trauma and in the obscure
      abdomen. It has been successfully employed therapeutically for acalculous
      cholecystitis, abscess drainage, and correction of placement of gastrostomy tubes
      and peritoneal dialysis catheters. It helps avoid risky transport trips and
      negative or nontherapeutic laparotomy with its known associated risks.

PMID- 10650503
TI  - Minimally invasive surgery. Bedside tracheostomy and gastrostomy.
AB  - Minimally invasive surgical techniques have gathered tremendous momentum. Most
      patient benefit is realized in the ambulatory setting. Smaller incisions result
      in less pain and earlier return to activities. Critically ill patients typically
      do not benefit from minimally invasive techniques in this manner; however, they
      do benefit from other aspects of minimally invasive tracheostomy and gastrostomy.
      Small tracheostomy wounds are associated with reduced wound problems (infection
      and breakdown). The small stab wounds of minimally invasive gastrostomy are
      associated with less pain and with an absence of fascial dehiscence. Furthermore,
      because these procedures are performed easily and safely at the bedside,
      transport and operating room costs are avoided. Although these procedures are
      minimally invasive, they are major procedures. Devastating complications can
      become life-threatening. Attention to detail is required to avoid or respond
      promptly to complications. In this way, patients receive maximal benefit at
      minimal risk.

PMID- 10650504
TI  - Bedside orthopedic procedures.
AB  - Orthopedic bedside procedures commonly are performed and are appropriate. As the
      complexity of patient needs increases and resources are stretched, more patient
      care, including orthopedic procedures, will be performed in cost-effective but
      safe environments such as the monitored intensive care setting. Medical
      technology and expertise are expanding rapidly, and these improved resources can
      and will allow more procedures to be performed safely and effectively outside the
      operating room. The decision to perform a specific procedure on a specific
      patient in a specific environment requires careful consideration of the risk to
      benefit ratio. This consideration should involve the patient, the physicians, and
      the entire health care team.

PMID- 10650505
TI  - Bedside open abdominal surgery. Utility and wound management.
AB  - Abdominal pathology in the critically ill or injured patient frequently leads to
      the use of open abdominal techniques or the actual performance of abdominal
      surgery in the ICU. All individuals responsible for the care of patients in the
      ICU should be familiar with the concepts and techniques of open abdomen wound
      management. ICU bedside abdominal surgery may be indicated if the patient is too
      unstable for transport to the operating room and the surgeon believes a limited
      procedure, such as a decompression of IAH, will be life-saving. Smaller
      procedures are also feasible, such as intra-abdominal packing changes for which
      the operating room is unnecessary. Development of a successful Surgery Outside
      the Operating Room program depends on mature cooperation between the surgeons and
      other professional ICU staff. Logistic details of such a program should be
      discussed and a scheduling protocol should be prepared before an emergent need
      for bedside surgery.

PMID- 10650506
TI  - Prostate specific antigen and benign prostatic hyperplasia.
AB  - Benign prostatic hyperplasia is a common condition in males over 50 years, but
      prostate cancer can develop in the same population. Prostate specific antigen,
      the best marker for prostate cancer, is also produced by benign epithelial cells,
      and there is an overlapping phenomenon between both conditions. The better we
      understand the relationships between benign prostatic hyperplasia and prostate
      specific antigen, the higher will be the discrimination power of prostate
      specific antigen measurement as a marker for prostate cancer. Our scope includes
      a review of the latest published material to date on this subject.

PMID- 10650507
TI  - New technologies in transurethral resection of the prostate.
AB  - Different ablative treatments are in clinical use to lower perioperative
      morbidity and to maintain efficacy of transurethral resection of the prostate.
      Modifications to electrodes or high frequency units, or both, as well as
      improvements in laser technology have been tried. Transurethral resection is
      performed with a modified high frequency generator. The technique of 'coagulating
      intermittent cutting' allows reduction in morbidity and maintains the advantages
      of classical transurethral resection.

PMID- 10650508
TI  - New technologies for the surgical management of symptomatic benign prostatic
      enlargement: tolerability and morbidity of high energy transurethral microwave
      thermotherapy.
AB  - High-energy transurethral microwave thermotherapy is an attractive alternative
      outpatient single-session treatment for symptomatic benign prostatic enlargement,
      with good tolerability, low morbidity and few complications. This paper reviews
      recent published literature, with a focus on tolerability and morbidity.

PMID- 10650509
TI  - Endoprostatic stents for management of benign prostatic hyperplasia.
AB  - Endoprostatic stents have been developed for relieving bladder outlet obstruction
      secondary to benign hyperplasia of the prostate. The stents are designed either
      for permanent or for temporary placement. The short-term temporary stents of
      various biostable and biodegradable polymers are needed after minimally invasive
      therapy of prostate with heat. The temporary stents are a management option,
      whereas the permanent stents are a treatment option. Permanent stents offer
      immediate relief and their sustained results for 4-7 years make them ideally
      suited for medically compromised patients.

PMID- 10650510
TI  - Urinary tract infections: antimicrobial resistance.

PMID- 10650511
TI  - Management of recurrent urinary tract infection and vesicoureteral reflux in
      children.
AB  - The management of recurrent urinary tract infections and vesicoureteral reflux in
      neonates and children is still a challenging problem. This review critically
      summarizes the highlights and current innovations in diagnosis and therapy,
      focusing on the peer-reviewed literature of the past year. Future developments
      and research efforts are briefly discussed.

PMID- 10650512
TI  - Pathogenesis and management of recurrent urinary tract infection in women.
AB  - A number of pathogenic factors for the development of recurrent urinary tract
      infection, such as prolonged vaginal colonization with uropathogenic Escherichia
      coli, nonsecretion of ABH blood-group antigens, impaired local immune response,
      oestrogen deficiency in postmenopausal women and altered vaginal milieu caused by
      the use of contraceptives, are involved. Long-term use of antimicrobial agents is
      the cornerstone of prevention of recurrent urinary tract infection. Other
      approaches currently used involve self-start (on demand) therapy, oestrogen
      replacement in postmenopausal women, behavioural changes and alternative
      therapies, such as acupuncture.

PMID- 10650514
TI  - Influence of urogenital infection on sperm function.
AB  - Male accessory sex gland infections are considered to be hazards to male
      fertility. Various pathophysiologic concepts have evolved from experimental and
      clinical studies that begin to explain the effects of bacteria and immunologic
      events on spermatozoa. Recent studies have identified and evaluated mediators
      that are responsible for specific molecular processes in infections that
      particularly affect the function of spermatozoa.

PMID- 10650513
TI  - Role of bacteria in the development of kidney stones.
AB  - Currently, only struvite stones are regarded as deriving from bacteria. Recent
      work has suggested that calcium-based stones might also have an infectious
      origin. Nanobacteria, small intracellular bacteria found in human kidney stones,
      are capable of forming a calcium phosphate shell, and thus could serve as
      crystallization centres for renal calculi formation. Until now, however, all
      trials performed to confirm the presence of nanobacteria in human calculi, serum
      or urine have failed. In a hyperoxaluric rat model, tissue-residing macrophages
      were able to remove interstitial crystals and thus may not be primarily engaged
      in defending against micro-organisms, if present.

PMID- 10650515
TI  - Bibliography. Current world literature. Benign prostatic hyperplasia.

PMID- 10650516
TI  - Bibliography. Current world literature. Urinary tract infections and sexually
      transmitted diseases.

PMID- 10650517
TI  - [The chronopharmacology of the hippocampus].

PMID- 10650518
TI  - [An experimental validation of pharmacological agents to arrest the vestibulo
      autonomic syndrome (motion sickness)].
AB  - The results of development and experimental evaluation of the efficiency of
      pharmacological means of cupping the vestibulo-vegetative syndrome in man are
      presented. A model and procedure of evaluation of pharmacological cupping of the
      Vestibulo-vegetative syndrome are developed. The intramuscular injection of the
      mixture containing ephedrine, promethazine hydrochloride and strychnine (25, 50,
      and 1 mg, respectively) appeared most effective.

PMID- 10650519
TI  - [The anxiolytic effect of ondansetron and its capacity to eliminate the
      benzodiazepine abstinence syndrome in rats].
AB  - Ondansetron (GR38032F, zofran)--a specific blocker of 5-HT3-receptors in a dose
      range of 0.05 to 0. mg/kg causes an anxiolytic effect in experiments on mice and
      rats on a model of elevated plus maze. The drug does not produce a sedative and
      myorelaxant effect. A 0.05 mg/kg dose of ondansetron reduces the level of anxiety
      and convulsive manifestations which are induced by discontinuation of long-term
      diazepam administration. The results of the study bear evidence of selectivity of
      the anxiolytic effect of ondansetron in intact animals and its effectiveness in
      rats with diazepam abstinence.

PMID- 10650520
TI  - [The effect of clofelin, guanfacine and compound SHA-9 on the transmembrane ion
      potentials of snail neurons].
AB  - The effect of central adrenopositive drugs--clopheline, guanfacine, and 2,4,6
      trifluorine derivative of clopheline (SHA-9)--on Na, Ca, fast and slow K
      transmembrane ion currents in Lymnaea stagnalis neurons was studied using the
      intercell dialysis and voltage-clamp upon bath application of the drugs in doses
      1-1000 microM. A dose-dependent reversible suppression of the ion (Na > Ca > K)
      currents and nonspecific leakage currents is observed. The membrane stabilizing
      effect of the drugs comes out in descending order SHA-9 > clopheline >
      guanfacine.

PMID- 10650521
TI  - [The possibility of using Daphnia magna as an alternative test object for
      evaluating the receptor selectivity of cholinotropic substances].
AB  - The results of study of the selectivity of the effects of cholinonegative and
      cholinopositive agents obtained on Daphnia magna hydrobionts were compared with
      the results of investigations on rats. This allowed Daphnia to be recommended as
      an alternative test object for studying the selectivity of the effect of
      cholinotropic agents in relation to some subtypes of muscarine receptors in an
      intact organism.

PMID- 10650522
TI  - [The action of emoxipin, lithium oxybutyrate and pikamilon on the blood
      circulation of the ischemic brain].
AB  - Acute experiments were conducted on rats under nembutal anesthesia to compare the
      efficacy of emoxipin with that of lithium oxybutyrate and picamilon in the
      postischemic period after preventive and therapeutic injections in various doses.
      Emoxipin proved to be most effective in prevention of postischemic non
      restoration of the flow of blood in the brain and in preservation of the
      autoregulation responses of the cerebral vessels. The possible mechanisms of the
      effect of the drug are discussed.

PMID- 10650523
TI  - [Dopamine enhancement of the cerebral microcirculation in a local ischemic
      lesion].
AB  - The effect of dopamine on the local cerebral blood flow in parietal brain cortex
      region of rats was studied in conditions of local ischemia induced by middle
      cerebral artery occlusion. Registration of the local cerebral blood flow was
      performed on a ALF-21 laser doppler flowmeter ("Transonic System Inc.", USA).
      Dopamine produces a pronounced effect on cerebral circulation in conditions of
      local brain ischemia thus causing a significant increase in blood flow both in
      ischemic and intact hemispheres. The effect is observed both in the acute stage
      of ischemic brain injury and in the remote period of brain ischemia.

PMID- 10650524
TI  - [The effect of histochrome on the lipid peroxidation indices during the surgical
      treatment of patients with ischemic heart disease of different functional
      classes].
AB  - The cardioprotector effect of the antioxidant histochrom was studied during
      surgical creation of an aortocoronary shunt in patients suffering from ischemic
      heart disease with angina pectoris of different functional classes (FC). The
      initial content of lipid peroxidation (LPO) products in the blood of patients
      with angina pectoris of functional class II was much lower than that in patients
      with angina pectoris of FC IV. This difference disappeared practically after
      intravenous infusion of histochrom in the pre- and postoperative period. Besides
      with the use of histochrom the incidence of early postoperative complications
      reduced significantly.

PMID- 10650526
TI  - [The effect of the actoprotector preparation bromantane on the postnatal
      development of rat pups].
AB  - The purpose of this work was study of the late-term results of a course of the
      actoprotector bromantan on the formation and development of the rat progeny.
      Bromantan was given per os daily in doses of 30, 150, and 600 mg/kg once a day:
      females received the drug for 15 days (2.5 estrous cycles), males for 60 days
      (whole cycle of spermatogenesis). When the course of treatment with the drug
      ended, the females were put together with the males for two weeks. The
      experiments were subdivided into two series: in series I the progeny obtained
      from coupling of experimental males with intact females was studied, in series II
      the progeny of intact males and experimental females. According to the results of
      the investigation, bromantan produced a late-term effect on the formation and
      development of the offsprings. The number of females who gave birth in series I
      and II of the experiment, despite a low dose-dependent increase, did not differ
      significantly from the controls. In series I of the experiment the litter
      increased insignificantly depending on the dose (by 0.3, 14.9, and 23.4%,
      respectively). In distinction, in the case of experimental females given 30 and
      600 mg/kg bromantan before copulation (series II) the number of young rats in the
      litter insignificantly reduced (by 34.9 and 44.2%), in the case of rats given 150
      mg/kg bromantan the litter increased (by 45%, p < 0.05). Both in series I and
      series II the mean weight of the newborns in the first week was significantly
      higher than the weight of the controls. After that the growth in body weight was
      insignificantly slower. Evaluation of the functional condition of the nervous
      system and terms of physical development of the progeny in series I and II of
      copulation showed an insignificant increase in the rate of maturation of the
      sensorimotor reflexes and physical parameters of the young experimental rats. The
      "open-field" test conducted on the 40th day of life showed increase of motor (by
      8.0-21.6%) and exploration activity (by 94.5-109.9%, p < 0.05) in the young
      experimental rats of series I and, at the same time, decrease of the grooming
      parameters (by 26.9-63.5%, p < 0.05) and emotionality. In all experimental groups
      of series II horizontal and vertical motor and searching activity was reduced.
      The authors believe that the actoprotector bromantan, possessing a dopaminergic
      effect in the mechanism of its action, may cause a late-term influence on
      prolactin secretion in lactating rats. The deficiency in this hormone in the
      early period of postnatal development affects the neurochemical organization of
      the hypothalamo-hypophyseal region and the brain areas connected with it,
      involving in this case also the mechanisms of sexual differentiation of the brain
      and, as a consequence, the somatic and sexual development of the progeny.

PMID- 10650525
TI  - [The effect of n-3 polyunsaturated fatty acids on the lipid spectrum indices in
      the 2nd-3rd pregnancy trimesters].
AB  - The effect of picasol (a preparation of n-3 polyunsaturated fatty acids) on the
      serum lipid spectrum was studied upon administration of the drug to 60 pregnant
      women with a high-risk of developing placental insufficiency during II-III
      trimesters of pregnancy in accordance with a program of randomized placebo
      controlled double blind trial. In the absence of differences in the level of
      lipid spectrum parameters prior to picasol administration we found in the III
      trimester a reliably low content of triglycerides and cholesterol of extremely
      low density lipoproteids in patients who received picasol.

PMID- 10650527
TI  - [The correction of the increased blood viscosity syndrome in brain ischemia in
      rats with a combination of dikvertin and ascorbic acid].
AB  - In experiments in vitro on a model of the syndrome of increased blood viscosity
      dikvertin reduced blood viscosity, weakened aggregation of red cells and raised
      their property of becoming distorted. A mixture of dikvertin and ascorbic acid
      improved the hemorrheologic parameters better than do dikvertin and tanakan. On a
      model of chronic ischemia of the brain of rats attended with deterioration of
      blood rheologic parameters, it was demonstrated that a course of treatment with a
      dikvertin and ascorbic acid complex decreases the manifestations of the syndrome
      of increased blood viscosity.

PMID- 10650528
TI  - [The mechanism of the transport of organophosphorus compounds across the histo
      hematic barriers].
AB  - It was demonstrated in experiments on mice [correction of rats] that the
      transport of organophosphorus compounds (OPC) through membranes of the
      histohematic barriers (HHB) of the organism occurs by means of diffusion. The
      rate of this process depends on the interaction of OPC with the specific sites of
      binding with the tissues, among which the enzyme carboxylesterase plays an
      important part. It is suggested that both the rate and direction of OPC diffusion
      are determined by the relationship between the values of affinity of the ligands
      for the sites of their specific binding found on both sides of the HHB.

PMID- 10650529
TI  - [The immunomodulating activity of the heteropolysaccharides from German chamomile
      (Matricaria chamomilla) during air and immersion cooling].
AB  - Intragastric and parenteral administration of heteropolysaccharides of Matricaria
      chamomilla L. is found to normalize developing of the immune response upon air
      cooling and enhance (but do not normalize) this process upon immersion cooling.
      The immunomodulating effect of the heteropolysaccharides upon cooling is
      attributed to initiation of immunostimulating properties of heavy erythrocytes
      (macrocytes), activization of immunoregulation cells of peripheral blood, and
      increased sensitivity of effector cells to helper signals.

PMID- 10650530
TI  - [The allergenic and immunotropic properties of the preparation pantohematogen].
AB  - Experiments on CBA/Ca Lac mice showed that pantohematogen, a drug prepared from
      whole blood of Siberian deer, wapiti, and deer, when administered in a course in
      doses under study and in chosen conditions of the experiment does not possess
      allergenic and immunotoxic properties. The immunomodulating properties of the
      drug were characterized by marked stimulation of macrophage phagocytic activity
      and, under definite conditions, by activation of formation of antibody-producing
      cells in the spleen of mice immunized with sheep erythrocytes.

PMID- 10650531
TI  - [Cytisine pharmacokinetics when used in a transdermal therapeutic system in
      rabbits].
AB  - Experimental study of pharmacokinetics of transdermal system with cytisin in
      rabbits showed a possibility of controlled intake of the drug over a 4-day
      period. The two stages of attaining the stationary levels of cytisin
      concentrations are revealed. The first stage lasted during first 24h and the
      second stage during succeeding 3 days. Using the data on intravenous cytisin
      injection we found that the stationary concentrations and the rate of cytisin
      intake in the first stage is twice as large as in the second stage. Thus cytisin
      can be classed as a short-living drug.

PMID- 10650532
TI  - [The effect of x-ray contrast media on the concentration of intracellular calcium
      in mononuclear cells].
AB  - It was shown by the method of fluorescent probes that iodine-containing
      radiocontrast agents Triombrast > Omnipaque > Ultravist > Melitrast increase the
      content of intracellular Ca2+ in macrophages of the abdominal cavity of rats.
      Increase in the entry of Ca2+ from the external environment is the main factor of
      the change in the intracellular concentration of Ca2+ ions in the macrophages in
      interaction with radiocontrast agents.

PMID- 10650533
TI  - [The effect of immunomudulin on the structural-functional status of the organs of
      the immune and hematopoietic systems in chronic toxic hepatitis].
AB  - Long-term entry of the hepatotropic poison heliotropin induces the development of
      chronic active hepatitis attended with disturbance of the immune balance and
      hematologic disorders in it. Immunomodulin alleviates the destructive changes in
      the organs of the immune system, stimulates proliferation and differentiation of
      their cells, and promotes restoration of red blood parameters. It is suggested
      that immunoglobulin may be a promising measure in complex treatment of chronic
      liver diseases.

PMID- 10650534
TI  - [The drug treatment of the Lambert-Eaton myasthenic syndrome].

PMID- 10650536
TI  - Complaints of fatigue: related to too much as well as too little external
      stimulation?
AB  - Fatigue has been acknowledged as a widespread problem associated with a variety
      of factors. In the present paper, we attempt to explain fatigue complaints on the
      basis of Pennebaker's (1982) "competition of cues" notion. Competition of cues
      suggests that both extremely low and extremely high levels of external
      stimulation in daily life may be related to relatively higher frequencies of
      complaint. The dimensional structure of external stimulation is first explored
      and then the shape of the relation between external stimulation (i.e., stimuli
      perceived in daily life) and fatigue was studied in a sample of 777 general
      practice patients. Other risk factors for fatigue and moderating factors are also
      taken into consideration. Results show that quantity and quality of external
      stimulation can be distinguished. Both high quantity (high "experienced
      overload") and low quality (low "attractiveness of external stimulation") are
      related to higher fatigue frequencies. "Experienced overload" is a particularly
      strong predictor, in addition to "perceived health" of fatigue complaints. It is
      concluded that the "quality-quantity model for understanding fatigue" proposed
      here highlights psychological factors important for any theoretical framework of
      fatigue.

PMID- 10650537
TI  - Group cohesion in older adult exercisers: prediction and intervention effects.
AB  - Two studies were conducted to examine the relationship between class cohesion and
      exercise adherence in older adult exercisers. Study 1 examined the predictive
      ability of four dimensions of cohesion on exercise participation at 1, 6, and 12
      months following the initial assessment of cohesion. Study 2 examined the
      effectiveness of a team-building intervention, designed to enhance class cohesion
      (and based on Study 1 results), on improving exercise adherence and return rates.
      Participants were assigned to a team-building, placebo, or control condition.
      Study 1 showed that three measures of cohesion, Individual attractions to the
      group-social, Group integration-social, and Group integration-task, were all
      significantly related to exercise class attendance following a 1-month interval.
      Group integration-task was significantly related to class attendance following a
      6- and a 12-month interval. Study 2 showed that participants in the team-building
      condition (a) attended more classes than the control and placebo conditions and
      (b) had a higher return rate following a 10-week hiatus than the control
      condition. It was concluded that (a) class cohesion plays a significant role in
      exercise class participation, both short- and long-term, and (b) samples of older
      adult exercisers are appropriate groups for interventions based on developing
      class cohesion.

PMID- 10650535
TI  - Do cognitive processes predict mental health in individuals with rheumatoid
      arthritis?
AB  - The purpose of the present study was to assess the hypothesis that intellectual
      functioning affects the mental health of individuals with rheumatoid arthritis.
      Structural equation modeling techniques were used to assess the relative
      contributions of age, education, intellectual functioning, self-efficacy, and
      pain to mental health. It was hypothesized that individuals with rheumatoid
      arthritis who had higher intellectual functioning and higher self-efficacy would
      report better mental health than those with lower intellectual functioning and
      self-efficacy. One hundred twenty-one adults aged 34 to 84 with rheumatoid
      arthritis completed a battery of cognitive tasks, and multiple measures of self
      efficacy, pain, and mental health, twice in 1 month. The data provided a good fit
      to the hypothesized model. Intellectual functioning was directly related to
      mental health and, also, indirectly related to mental health through self
      efficacy and pain. Older individuals who performed poorly on cognitive tasks
      reported less self-efficacy, more pain, and poorer mental health than those
      individuals who performed well on cognitive tasks.

PMID- 10650539
TI  - Cardiac exposure history as a determinant of symptoms and emergency department
      utilization in noncardiac chest pain patients.
AB  - Although comparative studies differentiate noncardiac chest pain (NCCP), panic
      disorder, and coronary artery disease (CAD), little research has examined the
      defining features of NCCP, such as cardiac complaints, medical utilization, and
      learning history. We administered self-report measures to 80 Emergency Department
      (ED) patients with a primary complaint of chest pain who were subsequently found
      to not have CAD. Forty-eight percent of the ED utilization variance was accounted
      for by NCCP duration, age, cardiac distress symptoms, and prior exposure to both
      siblings' and friends' cardiac distress symptoms. In turn, 67% of the variance in
      cardiac distress symptoms was explained by education, age, NCCP duration, number
      of illnesses, noncardiac panic symptoms, prior exposure (friends), and prior
      observation of others' cardiac distress. No effects emerged for gender,
      ethnicity, avoidance, or depression. Results suggest that beyond the effects of
      age and distress intensity, prior exposure to other people's cardiac distress may
      influence NCCP.

PMID- 10650538
TI  - Cardiovascular and mood responses to quantified doses of cigarette smoke in oral
      contraceptive users and nonusers.
AB  - Previous research suggests that the female sex hormones may moderate
      cardiovascular and mood responses to cigarette smoking and abstinence. To test
      this possibility, acute effects of cigarette smoking on cardiovascular reactivity
      and mood were examined in 12 oral contraceptive users and 12 nonusers across two
      menstrual phases (early and late cycle). After overnight deprivation, each
      participant attended two sessions in which they first sham-smoked and then smoked
      two standard cigarettes, via a quantified smoke delivery system. Oral
      contraceptive users exhibited larger cigarette smoking-induced increases in heart
      rate compared with nonusers. In addition, cigarette smoking-induced
      cardiovascular changes varied with both the phase of the menstrual cycle and oral
      contraceptive use. No menstrual phase-dependent effects were observed for tobacco
      withdrawal symptoms, premenstrual symptoms, or moods prior to smoking.
      Cardiovascular hyperreactivity to cigarette smoke in oral contraceptive users may
      help explain the mechanisms by which smoking and oral contraceptive use
      contribute to an elevated risk for coronary heart disease.

PMID- 10650540
TI  - Associative modulation of the orienting response: distinct effects revealed by
      hippocampal lesions.
AB  - The ability of auditory stimuli to modulate rats' tendency to orient to visual
      targets was assessed. In Experiment 1, trials where an auditory stimulus (A)
      signaled one visual array (X) were intermixed with unsignaled presentations of a
      second array (Y). Comparison of the orienting responses (ORs) to X and Y revealed
      that A produced a transient (unconditioned) and an emerging (conditioned)
      disruptive influence on the OR to X. In Experiments 2 and 3, trials where A
      signaled X were intermixed with others where another auditory stimulus (B)
      signaled Y. Stimulus A's ability to modulate the OR to X was then assessed by
      presenting A prior to test arrays containing both X and Y. Control rats were more
      likely to orient to Y than X (Experiments 2 and 3) and rats with excitotoxic
      lesions of the hippocampus were more likely to orient to X than Y (Experiment 3).
      These results show that auditory stimuli exert distinct modulatory influences on
      the OR to visual stimuli with which they are associated.

PMID- 10650541
TI  - Motivational state regulates the content of learned flavor preferences.
AB  - Rats acquired a preference for an aqueous odor (almond) presented in simultaneous
      compound with sucrose. Separate presentations of saccharin reduced this
      preference in rats with ad-lib access to food during training or at test, but not
      in rats that were hungry during both training and test. In contrast, separate
      presentations of sucrose reduced the preference for the almond irrespective of
      deprivation state during training and test. We interpret the results to mean that
      a hungry rat forms odor-taste and odor-calorie associations, and its motivational
      state on test determines which of these associations controls the preference. In
      contrast, a rat that is not hungry during training only forms an odor-taste
      association, and its performance on test is independent of its level of hunger.

PMID- 10650542
TI  - Representation of the numerosities 1-9 by rhesus macaques (Macaca mulatta).
AB  - Three rhesus monkeys (Macaca mulatta) were trained to respond to exemplars of 1,
      2, 3, and 4 in an ascending, descending, or a nonmonotonic numerical order (1-->2
      ->3-->4, 4-->3-->2--1, 3-->1-->4-->2). The monkeys were then tested on their
      ability to order pairs of the novel numerosities 5-9. In Experiment 1, all 3
      monkeys ordered novel exemplars of the numerosities 1-4 in ascending or
      descending order. The attempt to train a nonmonotonic order (3-->1-->4-->2)
      failed. In Experiment 2A, the 2 monkeys who learned the ascending numerical rule
      ordered pairs of the novel numerosities 5-9 on unreinforced trials. The monkey
      who learned the descending numerical rule failed to extrapolate the descending
      rule to new numerosities. In Experiment 2B all 3 monkeys ordered novel exemplars
      of pairs of the numerosities 5-9. Accuracy and latency of responding revealed
      distance and magnitude effects analogous to previous findings with human
      participants (R. S. Moyer & T. K. Landaeur, 1967). Collectively these studies
      show that monkeys represent the numerosities 1-9 on at least an ordinal scale.

PMID- 10650543
TI  - Effects of priming, discriminability, and reinforcement on reaction-time
      components of pigeon visual search.
AB  - Pigeons searched computer screens for 1 of 4 letter targets among 55 alphanumeric
      distractors. In Experiment 1, valid-cue trials used distinctive patterns to
      signal the subsequent appearance of specific targets, whereas ambiguous-cue
      trials used a signal common to all targets. Search reaction times (RTs) after
      valid cues were shorter than after the ambiguous cue; increased target
      discriminability also reduced RT. In Experiment 2, when reinforcement for 2
      targets shifted from 10% to 20%, RTs to those targets dropped, whereas RTs to the
      other 2 targets rose. RT distributions suggested that precues and
      discriminability both affect the momentary probability of finding a target, as
      embodied in the decay constant of an underlying exponentially distributed RT
      component. Reinforcement changes appeared to affect different components of the
      response process, embodied in changes in the mean of an underlying lognormal
      distribution.

PMID- 10650544
TI  - Multiple points of entry into a circular enclosure prevent place learning despite
      normal vestibular orientation and cue arrays: evidence for map resetting.
AB  - This study identified sources of map orientation critical for successful spatial
      problem solving by rats of a plus maze embedded in water. Disorientation slowed,
      but it did not prevent acquisition of goal location. Use of a circular enclosure
      with multiple points of entry prevented reliable goal location. A single entry
      point enabled the rats to locate a fixed goal. A cue array within the enclosure
      was ineffective in providing orientation. These data suggest that stable map
      orientation can be derived from entry location when enclosure geometry is
      uniformative, but is not readily taken from cue arrays. They further suggest that
      map orientation is reset when rats enter an enclosure.

PMID- 10650545
TI  - Counterconditioning of an overshadowed cue attenuates overshadowing.
AB  - In 3 Pavlovian conditioned lick-suppression experiments, rats received
      overshadowing treatment with a footshock unconditioned stimulus such that
      Conditioned Stimulus (CS) A overshadowed CS X. Subjects that subsequently
      received CS X paired with an established signal for saccharin (CS B) exhibited
      less overshadowing of the X-footshock association than subjects that did not
      receive the X-B pairings (Experiment 1). Experiment 2 replicated this effect and
      controlled for some additional alternative accounts of the phenomenon. In
      Experiment 3, this recovery from overshadowing produced by counterconditioning CS
      X was attenuated if CS B was massively extinguished prior to counterconditioning.
      These results are more compatible with models of cue competition that emphasize
      differences in the expression of associations than those that emphasize
      differences in associative acquisition.

PMID- 10650546
TI  - Can squirrel monkeys (Saimiri sciureus) learn self-control? A study using food
      array selection tests and reverse-reward contingency.
AB  - Eight squirrel monkeys (Saimiri sciureus) were presented with 2 stimulus arrays,
      namely 1 and 4 pieces of food, but they received only the array other than the
      one they reached for. In this reverse-reward condition, all monkeys initially
      showed a strong preference for the larger array. One monkey learned to reach
      toward the smaller array when a large-or-none reward contingency was applied
      (i.e., no reward followed a reach toward the larger array, but this array was
      given for a reach toward the smaller array). When correction trials and time-out
      were added to the large-or-none procedure, all remaining monkeys except 1 learned
      this form of self-control. Performance was maintained when correction trials were
      discontinued, the original reverse-reward condition was rerun, and novel array
      size pairs were presented. This study demonstrates one form of self-control in a
      New World primate and shows the reverse-reward procedure to be a potentially
      valuable method for assessing species and individual differences in self-control
      and numerosity-related abilities.

PMID- 10650547
TI  - Reinforced variability and operant learning.
AB  - Reinforcement of variability may help to explain operant learning. Three groups
      of rats were reinforced, in different phases, whenever the following target
      sequences of left (L) and right (R) lever presses occurred: LR, RLL, LLR, RRLR,
      RLLRL, and in Experiment 2, LLRRL. One group (variability [VAR]) was concurrently
      reinforced once per minute for sequence variations, a second group also once per
      minute but independently of variations, that is, for any sequences (ANY), and a
      control group (CON) received no additional reinforcers. The 3 groups learned the
      easiest targets equally. For the most difficult targets, CON animals' responding
      extinguished whereas both VAR and ANY responded at high rates. Only the VAR
      animals learned, however. Thus, concurrent reinforcers--contingent on variability
      or not--helped to maintain responding when difficult sequences were reinforced,
      but learning those sequences depended on reinforcement of variations.

PMID- 10650548
TI  - Between the millennia: Freud, psychoanalysis--and JAPA.

PMID- 10650549
TI  - Freud at the crossing of the millennia.

PMID- 10650550
TI  - Freud and psychoanalysis: into the 21st century.

PMID- 10650551
TI  - The scientific status of unconscious processes: is Freud really dead?
AB  - At regular intervals for over half a century, critiques of Freud and
      psychoanalysis have emerged in the popular media and in intellectual circles,
      usually declaring that Freud has died some new and agonizing death, and that the
      enterprise he created should be buried along with him like the artifacts in the
      tomb of an Egyptian king. Although the critiques take many forms, a central claim
      has long been that unconscious processes, like other psychoanalytic constructs,
      lack any basis in scientific research. In recent years, however, a large body of
      experimental research has emerged in a number of independent literatures. This
      work documents the most fundamental tenet of psychoanalysis--that much of mental
      life is unconscious, including cognitive, affective, and motivational processes.
      This body of research suggests some important revisions in the psychoanalytic
      understanding of unconscious processes, but it also points to the conclusion
      that, based on controlled scientific investigations alone (that is, without even
      considering clinical data), the repeated broadside attacks on psychoanalysis are
      no longer tenable.

PMID- 10650552
TI  - On the scientific standing of psychoanalysis.
AB  - This paper speaks for the claim that psychoanalysis qualifies as a scientific
      enterprise. It will derive from the conceptual and evidential structure of
      psychoanalysis a causal empirical hypothesis that admits of scientific
      intraclinical testing. Relevant topics from the philosophy of science (especially
      the nature of causal explanation and the work of Grunbaum) and the psychoanalytic
      theories of pathogenesis and therapeutic action are discussed in a preliminary
      way to create a framework for the demonstration. The dynamic unconscious is
      examined as the core causal concept of psychoanalysis. Taken together with an
      account of the structure of the mental apparatus, a coherent picture of mental
      causation (the propagation of an unconscious impulse) comes into view. This leads
      to the formulation of a set of clinical propositions that unite to generate a
      causal empirical hypothesis based solely on data from the analytic setting-
      namely, that the transferences and symptoms that appear in free association in
      the analytic situation possess an interrelational structure that is theoretically
      implied and can be statistically confirmed.

PMID- 10650553
TI  - The reconstruction of reminiscence.
AB  - The lifting of repression and of infantile amnesia was an original aim and goal
      of clinical psychoanalysis. Memory may be more or less reliable and authentic.
      However, it tends to be subjective, self-serving, and selective, and there are
      different memory modalities and systems. The recovery of repressed childhood
      memory has been largely subsumed under the analysis of unconscious conflict and
      fantasy. "Hysterics suffer mainly from reminiscences," and these reminiscences
      interweave with and contribute to reconstruction, which is intrinsic to psycho
      analysis. Memory and reconstruction are subject to the influence of special
      interests, transference, and countertransference. Since open questions remain
      concerning preoedipal, and particularly preverbal, reconstruction, external
      confirmation may further both the analytic process and analytic research. The
      process of reconstruction integrates and transcends memory, facilitating
      personality reorganization.

PMID- 10650554
TI  - Passions in girls and women: toward a bridge between critical relational theory
      of gender and modern conflict theory.
AB  - This paper considers (1) some aspects of the lack of dialogue among
      psychoanalytic schools; (2) Brenner's (1982) conception of drives and drive
      derivatives as inextricably linked to relationships, and some of its less
      appreciated implications; (3) the debate over the importance of childhood
      sexuality in mental life; (4) the attempts by relational theorists to address and
      reintegrate the role of sexuality and gender, particularly in the study of
      feminine psychology; (5) the problematic role of aggression in psychoanalytic
      theories of women; (6) the avoidance by both men and women of women's passions
      and their anatomical loci, especially the clitoris, whose only function is the
      provision of pleasure; and (7) the suggestion that an integrated theory,
      including an understanding of the role of the body as well as of the passions and
      the defenses against them, results in the most effective clinical psychoanalytic
      approach. It then suggests that a bridge could be built between a relational
      point of view that takes into consideration the role of bodily experiences, and a
      classical point of view in which drive is seen as inextricably linked to
      relationships from birth on.

PMID- 10650555
TI  - Regression: essential clinical condition or iatrogenic phenomenon?

PMID- 10650556
TI  - How central is the analysis of aggression to clinical psychoanalysis?

PMID- 10650557
TI  - Freud's intrapsychic use of the Jewish culture and religion.

PMID- 10650558
TI  - Freud and feminism: a critical appraisal.
AB  - This paper traces the contributions made by women to Freud's ideas about women.
      Freud paid back the gifts he received from women with encouragement and support
      for their careers and with a theory that was instrumental in freeing women from
      both domestic bondage and fantasies of inferiority, but which was used by later
      "Freudians" as justification for returning women to an exclusively domestic life.
      Paying particular attention to Sabina Spielrein, Lou Andreas-Salome, and H.D.,
      the paper illustrates some of the contributions of women to early psychoanalysis,
      and speculates on ways in which Freud's thinking was guided by his belief that
      women are, and should be considered, equal to men.

PMID- 10650559
TI  - Freud and film: encounters in the Weltgeist.
AB  - Freud's antipathy toward film is striking, since film and dreams are formed by
      similar mechanisms. Nevertheless, Freud occasionally and unavoidably encountered
      film. This paper details some of these encounters. Ten years after viewing time
      lapse photography, a fore-runner of moving pictures, at the Salpetriere, he was
      conceptualizing a model of the mind and of the formation of dreams that in some
      ways parallels the film apparatus invented by the Lumiere brothers in December
      1895. On his visit to America in 1905, Freud saw movies in New York City. In
      1925, he refused a lucrative offer to consult on a film, and he discouraged Karl
      Abraham and Hanns Sachs from consulting on the first psychoanalytic film, Pabst's
      Secrets of a Soul (1926). He was, however, once sighted viewing an American
      double feature in Vienna. The paper closes with a critique of his acting in home
      movies.

PMID- 10650560
TI  - Reflections on Freud's letter from Florence, September 7, 1896.

PMID- 10650561
TI  - A letter from Freud to Martha Freud.

PMID- 10650562
TI  - Ferenczi's fatal illness in historical context.
AB  - In August 1932, Ferenczi was already manifesting symptoms of his fatal illness,
      pernicious anemia. This was diagnosed between September 20 and October 2 of that
      year, less than a month after the Twelfth International Psychoanalytic Congress
      in Wiesbaden. Despite seemingly successful treatment with injectable liver
      extract, he underwent an acute psychotic episode in March 1933, triggered by the
      neurological symptoms of his illness. These facts substantiate the subsequent
      claim of Freud and Jones that Ferenczi suffered from paranoia near the end of his
      life, but they do not support the commonly-held view that the writings and
      experiments in psychoanalytic technique of his last five years were symptomatic
      of a progressive mental illness.

PMID- 10650563
TI  - The Berlin Poliklinik: psychoanalytic innovation in Weimar Germany.
AB  - After Freud proposed in 1918 the creation of "institutions or out-patient clinics
      [where] treatment will be free," Max Eitingon, Ernst Simmel, and other
      progressive psychoanalysts founded the Berlin Poliklinik, a free outpatient
      clinic. Guided by Weimar Republic principles of "radical functionalism," the
      Poliklinik and its companion inpatient service, the Schloss Tegel Sanatorium,
      pioneered treatment and training methodologies still used--and still debated-
      today. Their funding strategies, statistics, and approaches to clinical problems
      like length of treatment tell the history of an innovative psychoanalytic
      institute where men and women were generally treated in equal numbers and
      patients (ranging in occupational status from unemployed to professional) of all
      ages were treated free. Franz Alexander, Karl Abraham, Theresa Benedek, Paul
      Federn, Otto Fenichel, Edith Jacobson, Karen Horney, Erich Fromm, Helene Deutsch,
      Hanns Sachs, Sandor Rado, Hermine von Hug-Hellmuth, Wilhelm Reich, Annie Reich,
      and Melanie Klein all worked at the Poliklinik, and from there initiated decades
      of original clinical theory, practice, and education.

PMID- 10650564
TI  - On the aesthetic illusion.
AB  - The aesthetic illusion--the experience of the content of a work of art as reality
      -occurs through the mobilization and intensification of typical infantile
      fantasies in the beholder. This necessarily evokes intrapsychic conflict in the
      mature adult. Two illusion-producing strategies ameliorate this conflict and
      effect the aesthetic illusion. The first illusion is that the artist's proffered
      fantasy is the beholder's own personal and private fantasy. This isolates the
      beholder from the shame- and guilt-evoking social surround. The second illusion
      is that the protagonist depicted in the work is an actual person. This defends
      the beholder from the painful emotions attendant upon his instinctually
      gratifying identification with the protagonist. The first illusion is necessary
      for the establishment of the second, but it is the second that establishes the
      aesthetic illusion. The aesthetic illusion exists in a highly unstable dynamic
      equilibrium with the beholder's usual reality orientation. If either orientation
      is too powerful, the dynamic equilibrium is disrupted and the aesthetic
      experience as such is abolished.

PMID- 10650565
TI  - Exploring the frontier from the inside out: John Sloan's nude studies.
AB  - The American realist artist John Sloan (1871-1951), a leading member of The Eight
      and the Ashcan School, is best known for his paintings and etchings of New York
      City life at the turn of the twentieth century--pictures that have endured as
      major documents in art history. Given the social nature of his early images,
      contemporaries were perplexed when Sloan became almost exclusively preoccupied
      with what was perhaps the most unpopular genre in American art--the female nude.
      Yet despite disapproval from his peers and lack of public interest, he continued
      to focus on nude studies for over twenty years, and created a series of unusual
      and disturbing images that so far have defied explanation. Formal analyses exist,
      but little has been written about the content of these pictures. My study
      bypasses the question of aesthetic quality that has troubled other art
      historians, and instead attempts to correlate these works with Sloan's personal
      life and his early career. When interpreted in the light of his history and his
      own words, these images reveal Sloan's intimate connection to his depicted female
      figures--a bond that emerges despite his attempt to maintain an objective
      distance from his subjects. My analysis is based on the work of D. W. Winnicott,
      who theorized that cultural production embodies our earliest, most profound
      relationship to our parents. As I will argue, the late nudes represent an intense
      period of mature, retrospective self-exploration. While this psychoanalytic
      investigation is certainly speculative, it is intended to open some possible new
      ways of understanding Sloan's representations of women.

PMID- 10650567
TI  - Personal history and the origins of psychoanalytic ideas

PMID- 10650566
TI  - Yesterday's silence: an irreverent invocation of Beckett's analysis with Bion.

PMID- 10650568
TI  - [Multicenter double-blind clinical trial comparing sucralfate vs placebo in the
      prevention of diarrhea secondary to pelvic irradiation].
AB  - BACKGROUND: Sucralfate has been used in the prophylaxis of acute enteric toxicity
      induced by radiation therapy of pelvic organs. The aim of the study was to
      demonstrate the efficacy of sucralfate in the prevention of the acute enteric
      toxicity induced by pelvic irradiation in cancer patients, compared with placebo,
      in a multicentric double-blind randomised clinical trial. PATIENTS AND METHOD:
      One hundred and twenty patients, with a localised pelvic cancer, 18 to 80 years
      old, with a Karnofsky index of 80% or more, and "normal" defecation habits (3-10
      defecations/week), undergoing whole pelvic irradiation, were included. The
      duration of the study was 7 weeks, with weekly controls. The first week all
      patients received placebo. In the second week the patients were randomised into
      two groups: sucralfate (61 patients, 2 g/tid p.o. before meals) and placebo (59
      patients). Radiotherapy started at the beginning of the third week and lasted
      until the end of the study. All patients received 45-50 Gy total dose (1.8-2
      Gy/day, 5 days/week) with the "box technique". The main variables were the number
      of stools per week and the number of loperamide pills per week. RESULTS: The
      number of stools per week showed no differences between groups. By the contrary
      in the group intention to treat (120 patients) and per protocol (100 cases) the
      percentage of diarrhoeal stools per week showed a statistical significance in
      favour of sucralfate: (p < 0.05) and (p < 0.03) respectively, concerning the
      evolution of this variable from the baseline (first week) to the end of the
      pelvic radiotherapy (seventh week). Furthermore, the consumption of loperamide
      was significantly lower in the sucralfate group (p < 0.001). CONCLUSION:
      Sucralfate is effective in the preparation of acute enteric toxicity induced by
      pelvic irradiation.

PMID- 10650569
TI  - [Tuberculous infection in nursing students: prevalence and conversion during a 3
      year follow-up].
AB  - BACKGROUND: The aim of this study was to ascertain the positive tuberculin
      prevalence among the nursing students at the beginning of their studies; to
      assess the annual tuberculin conversion rate during their studies; to obviate the
      possibility of false conversions, studying the booster effect. PATIENTS AND
      METHODS: Cohort study, prospective, 3 groups not parallels (n = 316), 32 months
      follow-up in all students. Mean age 21 years (SD = 4; range = 17-39). First
      phase: before beginning clinical practice, a tuberculin test was undertaken by
      Mantoux technique with PPD type RT-23 with Tween 80 of 2 TU; this was repeated
      after 7-10 days, to BCG vaccinated and PPD negative on the first one, to study
      the booster effect. Second phase: at 18 months we repeated the tuberculin test to
      PPD negatives including the vaccinates with booster effect but PPD negative. The
      end of the study was at 32 months, repeating the test to PPD negatives at the end
      of their nursing studies. RESULTS: Tuberculin prevalence of 12% (38/316); CI 95%:
      8.4%-15.6%. There were no significant differences of prevalence between
      vaccinated and unvaccinated nurse students. The prevalence in women was 8.9%
      (24/267) and 28.6% (14/49) in men. The only variables with statistical
      significance for being tuberculin positive were, age (p = 0.002) and sex (p =
      0.003). 3/42 vaccinated with BCG (7%) had initial PPD (+); 2/39 of the remaining
      (5%) showed to be tuberculin positive after the booster effect and 37 tuberculin
      negative and booster negative. In the conversion study there were 259 valid
      students at the end of 3 years; there were 14 (5.4%) converters in the second
      year and 9 (3.5%) in the third year. Tuberculin conversion annual rate was 3.8
      per 100 people/year. CONCLUSIONS: The tuberculous infection prevalence in nursing
      students was 12% (38/316). The annual frequency of tuberculin conversion (3.8 per
      100 people/year) was higher in our students than in the general population,
      reinforcing the suitability of making periodical tuberculin control tests in PPD
      negative student nurses with continuous hospital contact.

PMID- 10650570
TI  - [Costs of health care resources of ambulatory-care patients diagnosed with
      Alzheimer's disease in Spain].
AB  - BACKGROUND: The annual consumption and costs of the health care resources used by
      ambulatory Alzheimer's disease patients were estimated. Patients were classified
      according to the degree of severity of the disease using Folstein's Mini Mental
      State Examination scale. The sociodemographic characteristics of both patients
      and their careers were described. PATIENTS AND METHODS: Patients with an
      established diagnosis of Alzheimer's disease according to NINCDS/ADRDA criteria
      were included in the study. Information on the use of health and non-health care
      resources consumed during the last 12 months was recorded. The following scales
      were administered: MMSE, Global Deterioration Scale, Rapid Disability Rating
      Scale and Hachinski's scale modified by Rosen. Finally, the time dedicated by
      careers to look after the Alzheimer's disease patients was recorded. RESULTS: A
      total of 337 patients were considered to be valid for the analysis with an
      average of 72 (8.4) years and with an average duration of the disease of 48.3
      (35.7) months. The average annual cost per patient was 3,194,664 ptas. The
      average cost per patient in the group with MMSE > 18 was 2,119,889 ptas;
      2,723,159 ptas. in those with MMSE 12-18 and 3,676,707 ptas. in the MMSE < 12
      group. CONCLUSIONS: In patients with Alzheimer's disease an increase in cost
      directly related to functional cognition state was observed. The most important
      cost component was that imputed to value time dedicated by principal career.

PMID- 10650571
TI  - [Work and professional position of medical specialists trained at the Hospital
      Clinic of Barcelona].
AB  - BACKGROUND: To analyze the working and professional position of medical
      specialists trained at the Hospital Clinic of Barcelona (Spain) during the last
      years, and to inquiry about their opinion on both the quality of the training
      that they received and the ways to improve it. POPULATION AND METHODS: Self
      administered questionnaire of closed questions send to 402 specialists that
      finished their residency at our hospital from 1988 to 1996. RESULTS: 128
      completed questionnaires were received and analyzed. The median age in this
      sample was 34 years (range, 29,41, and 58% were males. 94% of those polled are
      engaged in medical practice as specialists, 76% have a full-time job. 55% of the
      specialists complement this main job with others, mainly in private practice. The
      40% have been sometimes unemployed, and, for half the specialists, more than one
      year elapsed from the end of residency to the first full-time job. 97% of those
      polled ranked the quality of the residency training as good, but most of them
      emphasized the need for more general knowledge and skills, in addition to the
      specialized training. CONCLUSION: Most medical specialists trained during the
      last several years have attained what seems to be an stable working and
      professional position. The scope of the specialists' training programs by must be
      broaden including more general knowledge and skills.

PMID- 10650572
TI  - [Nursing: profession with risk?].

PMID- 10650573
TI  - [Analysis of a case of severe congenital toxoplasmosis].
AB  - BACKGROUND: To describe a case of severe congenital toxoplasmosis because of
      inadequate surveillance of a seronegative pregnant woman and to evaluate the
      usefulness of different microbiological diagnostic methods after birth. METHODS:
      We applied serology, DNA amplification by one-tube semi-nested PCR, cell culture
      and mice inoculation analysis. RESULTS: Anti. T. gondii serology was useful for
      the diagnosis of congenital toxoplasmosis. PCR analysis of neonate cerebrospinal
      fluid and peripheral blood were positive, and yielded negative results after a
      few days of specific treatment. Cellular culture and mice inoculation yielded
      negative results. CONCLUSIONS: Our results suggest that serology and PCR are
      useful methods for the diagnosis of toxoplasmosis in newborns. Prenatal
      toxoplasmosis screening and suitable follow up of the seronegative pregnant women
      are necessary to prevent cases of severe infection in our area.

PMID- 10650574
TI  - [Disease management programs and their use in cardiovascular diseases].

PMID- 10650575
TI  - [Consensus document on tuberculosis prevention and control in Spain. Research
      Unit on Tuberculosis of Barcelona (UITB). Area of Tuberculosis and Respiratory
      Infections (TIR) of the Spanish Society of Pneumology and Thoracic Surgery
      (SEPAR) and Study Group on Aids (GESIDA) of the Spanish Society of Infectious
      Diseases and Clinical Microbiology (SEIMC)].

PMID- 10650576
TI  - [Orlistat and articles accepted for publication in Medicina Clinica].

PMID- 10650577
TI  - [Reversibility of severe hyperlipemia secondary to indinavir with micronized
      phenofibrate].

PMID- 10650578
TI  - [Efficacy and safety of thrombolytic treatment in pulmonary thromboembolism: meta
      analysis of controlled and randomized trials].

PMID- 10650579
TI  - [Etiology and admission criteria in febrile syndrome without focus].

PMID- 10650580
TI  - [In Process Citation]

PMID- 10650581
TI  - Context-dependent recognition memory: the ICE theory.
AB  - A solution to the problem of context-dependent recognition memory is presented in
      terms of the item, associated context, and ensemble (ICE) theory. It is argued
      that different types of context effects depend on how context information is
      encoded at both learning and retrieval. Matching associated context in memory and
      a retrieval cue produces increases in both hit and false alarm rates and may not
      be accompanied by a change in discrimination. Integrating item and context
      information in an ensemble and matching ensemble information in memory and a
      retrieval cue produces context-dependent discrimination. Empirical support for
      these predictions is presented.

PMID- 10650582
TI  - Age-related differences and similarities in dual-task interference.
AB  - Differences between younger adults (mean age, 20.7 years) and older adults (mean
      age, 72.7 years) in dual-task performance were examined in 7 experiments in which
      the overlap between 2 simple tasks was systematically varied. The results were
      better fit by a task-switching model in which age was assumed to produce
      generalized slowing than by a shared-capacity model in which age was assumed to
      reduce processing resources. The functional architecture of task processing
      appears the same in younger and older adults. There was no evidence for a
      specific impairment in the ability of older adults to manage simultaneous tasks.
      There was evidence for both input and output interference, which may be greater
      in older adults.

PMID- 10650583
TI  - Systematic analysis of deficits in visual attention.
AB  - A variety of impairments in visual attention can follow damage to the brain. The
      authors develop systematic methods for analyzing such impairments in terms of C.
      Bundesen's (1990) Theory of Visual Attention and apply these in a group of 9
      patients with parietal lobe lesions and variable spatial neglect. In whole
      report, patients report letters from brief, vertical arrays in left or right
      visual field. The results show substantial, largely bilateral impairments in
      processing capacity, implying a major nonlateralized aspect to neglect. In
      partial report, arrays contain 1 or 2 letters in red and/or green. The task is to
      report only those letters in a specified target color. In addition to the
      expected bias against left-sided letters, patients show striking, bilateral
      preservation of top-down control, or attentional priority for targets. The
      results show how differentiation of attentional impairments can be informed by a
      theory of normal function.

PMID- 10650584
TI  - Convergent behavioral and neuropsychological evidence for a distinction between
      identification and production forms of repetition priming.
AB  - Four experiments examined a distinction between kinds of repetition priming which
      involve either the identification of the form or meaning of a stimulus or the
      production of a response on the basis of a cue. Patients with Alzheimer's disease
      had intact priming on picture-naming and category-exemplar identification tasks
      and impaired priming on word-stem completion and category-exemplar production
      tasks. Division of study-phase attention in healthy participants reduced priming
      on word-stem completion and category-exemplar production tasks but not on picture
      naming and category-exemplar identification tasks. The parallel dissociations in
      normal and abnormal memory cannot be explained by implicit-explicit or perceptual
      conceptual distinctions but are explained by an identification-production
      distinction. There may be separable cognitive and neural bases for implicit
      modulation of identification and production forms of knowledge.

PMID- 10650585
TI  - Sentence processing in the face of semantic loss: a case study.
AB  - The modularity of the sentence processor, or lack thereof, remains a much-debated
      issue in psycholinguistics. The authors present evidence from a semantically
      impaired patient (DM) that bears on this issue. As demonstrated elsewhere (S. D.
      Breedin, E. M. Saffran, & H. B. Coslett, 1994), DM suffered a significant loss of
      semantic knowledge. Here, the authors show that this impairment did not
      compromise DM's ability to process syntactic information. DM performed well on
      grammaticality judgment tasks and on sentence comprehension tasks that required
      the use of syntactic information for the assignment of thematic roles. The
      resistance of syntactic operations to semantic loss would seem to pose a
      challenge for models in which "the syntactic and conceptual aspects of processing
      are ... inextricably intertwined" (J. L. McClelland, M. St. John, & R. Taraban,
      1989, p. 329).

PMID- 10650586
TI  - Memory retrieval and suppression: the inhibition of situation models.
AB  - When people retrieve newly learned facts on a recognition test, they are often
      increasingly slowed by the number of other newly learned facts that have a
      concept in common with the probed fact. This is called the fan effect. Assuming
      that people are using situation models of the learned information, the author
      considers whether the inhibition of competing representations is one of the
      processes involved in the fan effect. Evidence was found for negative priming of
      related but irrelevant situation models, thus supporting the idea that the
      inhibition of highly related memory traces is used in long-term memory retrieval.
      As such, this is a form of retrieval-based inhibition.

PMID- 10650587
TI  - Procedural skills in general practice. Are we going to lose this facet of general
      practice care?

PMID- 10650588
TI  - Men's health: we need outside help.

PMID- 10650589
TI  - The GP as gatekeeper?

PMID- 10650590
TI  - Prostate cancer screening.

PMID- 10650591
TI  - Prostate cancer screening.

PMID- 10650593
TI  - Removal of ear wax.

PMID- 10650592
TI  - Removal of ear wax.

PMID- 10650594
TI  - Skin signs of systemic disease.
AB  - BACKGROUND: Dermatological problems are a common presentation in general practice
      and skin disorders may be a manifestation of underlying systemic disease.
      OBJECTIVE: To describe cutaneous manifestations of some commonly occurring
      systemic diseases. DISCUSSION: This article alerts the general practitioner to
      those skin conditions that may warrant further assessment for underlying disease
      and those that may complicate known disorders such as diabetes.

PMID- 10650595
TI  - The value of clinical signs in rheumatology.
AB  - BACKGROUND: Eliciting and interpreting clinical signs is essential in diagnosing
      many rheumatic disorders but the sensitivity and specificity of many of these
      signs for any given disorder remains poorly categorised. OBJECTIVE: To discuss
      important clinical signs in rheumatological disease and to assess their clinical
      significance. DISCUSSION: Physical examination forms a vital part of the
      assessment of musculoskeletal and rheumatic disorders but there remains a need
      for studies to assess the clinical usefulness of a number of the clinical signs
      elicited. The patterns of presentation of groups of clinical signs are of more
      diagnostic significance than individual clinical signs.

PMID- 10650596
TI  - Issues in wound management.
AB  - BACKGROUND: Over the past 30 years there has been increased interest and research
      into wound management and the physiology of wound healing. OBJECTIVE: To address
      some of the myths associated with wound healing, and consider common questions or
      comments made by patients, nurses and doctors. DISCUSSION: The most effective
      approach to wound management involves a thorough history and examination to
      identify factors that are affecting healing and instituting a management plan to
      control or eliminate these factors. The type of wound dressing that is
      appropriate can be determined by the colour, depth and amount of exudate present.

PMID- 10650597
TI  - Clinical testing in general practice. What is the evidence?
AB  - BACKGROUND: Evidence based medicine (EBM) is a term being used widely in
      reference to diagnostic tests and treatments. In EBM a test or a treatment is
      only utilised when there is solid evidence that the likelihood of benefit to the
      patient outweighs the risk of harm. However, EBM is rarely considered in the
      clinical aspects of medicine: history taking and examination. In looking for
      clinical signs doctors need to consider the accuracy of those signs and the
      implications that false negative or false positive results will have for their
      patient. OBJECTIVE: The issues of sensitivity and specificity of clinical
      medicine are explored via the example of dementia testing in general practice.
      DISCUSSION: The article demonstrates that although two commonly used screening
      tests for dementia have a high sensitivity (75%) and specificity (70%), there is
      little benefit in the routine use of these assessments for screening in general
      practice. Clues from appropriate history taking may be of greater diagnostic use.

PMID- 10650598
TI  - Hormone replacement therapy. Current prescribing choices.

PMID- 10650600
TI  - Clinical audit activity. Prescribing for common conditions--hyperlipidaemia

PMID- 10650599
TI  - Myths about infant feeding. Facts or fiction?

PMID- 10650601
TI  - Hyperlipidaemia and heart disease.

PMID- 10650602
TI  - Danger signals and the combined oral contraceptive pill.
AB  - The COCP is a safe form of contraception for the majority of women. The challenge
      is to identify the women who have risk factors that make the use of COCP less
      safe. This approach is summarised by a recent consensus statement from an
      international conference on evidence based prescribing of COCPs. This states that
      'current evidence suggests only two prerequisites for the safe provision of
      COCPs: a careful personal and family medical history with particular attention to
      cardiovascular risk factors, and an accurate blood pressure measurement'.

PMID- 10650603
TI  - Radiology quiz. A case of chronic right upper quadrant pain.

PMID- 10650604
TI  - Management of hamstring pain.

PMID- 10650605
TI  - Motion sickness. Is it all in the mind?

PMID- 10650606
TI  - Connectedness. The social factor and health.

PMID- 10650607
TI  - Clockwork Young People's Health Service.

PMID- 10650608
TI  - Young and troubled. Childhood abuse, substance use and suicidal intent.

PMID- 10650609
TI  - Immunisation initiatives in general practice. Important lessons from division
      projects.
AB  - AIM: To examine immunisation projects undertaken by divisions of general practice
      through the Divisions and Project Grants Program in the period from 1993 to mid
      1997. METHOD: A simple descriptive frequency analysis was conducted of
      information from the National Information Service Divisions Project database and
      evaluation reports of the project characteristics and methodology such as: year
      commenced; duration; location; funding; target groups; intervention; needs
      assessment; aim(s); study design; measurement (assessment) and outcome(s).
      RESULTS: Forty-four funded immunisation projects were identified and of these, 12
      projects with completed evaluation reports were analysed. Most projects were of
      12-14 months duration, and were funded for a mean of $56,349 and median of
      $46,348 for the 44 funded projects and a mean $44,348 and median $40,318 for the
      12 with evaluation reports. Most projects included a needs assessment. The main
      target groups were general practitioners, the general community, and children. Of
      the wide spectrum of interventions used, education and/or promotion and register
      and/or reminder systems were the most common. Study designs, the quality of
      measurement and outcomes were variable. CONCLUSION: In the future with the move
      to outcome based block funding, it will be important for projects to adopt
      broader target groups, refine and develop interventions and develop greater
      sustainability through responding to local needs, improving design and evaluation
      and ongoing funding.

PMID- 10650610
TI  - Sexual abuse and suicidal issues in Australian young people. An interim report.
AB  - BACKGROUND: Youth suicide remains a significant issue in Australian society with
      suicide rates among young males being of particular concern. While there are many
      antecedents for suicidal behaviours one that is often overlooked is sexual abuse.
      In particular, sexual abuse in males has the potential to be an easily overlooked
      issue and yet may lead to significant emotional distress. OBJECTIVE: The
      objective of this study was to identify if sexual abuse played a significant role
      in depression and suicide risk, including suicidal intent. DISCUSSION: This study
      supports an apparent high prevalence of sexual abuse in young Australians and
      indicates that such abuse contributes to a number of health risk behaviours
      including self harm and suicidal intent. General practitioners need to be aware
      of this as a suicidal risk factor and need to raise it in discussion with any
      young person who presents with significant health risk behaviours such as drug
      taking, sexual risk taking and self harm.

PMID- 10650612
TI  - Outbreak of trichinellosis in south east England.

PMID- 10650611
TI  - Trends in selected gastrointestinal infections: 1999.

PMID- 10650614
TI  - [HIV infection can be treated].

PMID- 10650613
TI  - [Homocysteine as a risk factor for atherosclerosis].

PMID- 10650615
TI  - [Pulmonary function measures in infants].

PMID- 10650616
TI  - [Mortality of psychiatric patients discharged from mental hospitals].

PMID- 10650617
TI  - [A stroke in a young, pregnant woman].

PMID- 10650618
TI  - [A forgotten national parasite--a case report and a short review].

PMID- 10650619
TI  - [Treatment of functional constipation in children and patient instructions].

PMID- 10650620
TI  - [Spots on the skin].

PMID- 10650621
TI  - [Asymmetrical facial edema].

PMID- 10650622
TI  - [On diagnosing systemic lupus--a pediatrician's viewpoint].

PMID- 10650623
TI  - [Time for the cell to live--and die].

PMID- 10650624
TI  - [New immunological dimensions of apoptosis].

PMID- 10650625
TI  - [Apoptosis and cancer].

PMID- 10650626
TI  - [Apoptosis during development of the nervous system and in degenerative
      diseases].

PMID- 10650627
TI  - [Mechanisms of apoptotic cell death].

PMID- 10650628
TI  - [Ceramide and apoptosis].

PMID- 10650629
TI  - [Operating is fun but does the knife cure? ].

PMID- 10650630
TI  - [New variant of Creutzfeldt-Jakob disease].

PMID- 10650631
TI  - [Alopecia areata and its treatment].

PMID- 10650632
TI  - [Activins and inhibins--from laboratory to clinics].

PMID- 10650633
TI  - [Human umbilical cord blood as a source for stem cell transplantations].

PMID- 10650634
TI  - [Treating colonic diverticular bleeding with endoscopy].

PMID- 10650635
TI  - [Why is Minna thirsty?].

PMID- 10650636
TI  - [Treatment of laryngitis].

PMID- 10650637
TI  - [Problematic patient cases and specialist education in pediatrics].

PMID- 10650638
TI  - [Rib changes in a patient with breast cancer].

PMID- 10650639
TI  - [Children's physical examinations have not been proven unnecessary!].

PMID- 10650640
TI  - [Evolutionary medicine - a new viewpoint for current problems].

PMID- 10650641
TI  - [Meningococcus septicemia accompanied by perimyocarditis].

PMID- 10650642
TI  - [Who can be the author of an article?].

PMID- 10650643
TI  - [Osteomyelitis of the frontal bone (Pott's puffy tumor). A report of 5 patients].
AB  - BACKGROUND: Frontal bone osteomyelitis is considered to be rare but it may
      develop intracranial complications such as subperiosteal abscess that appears as
      a painful fluctuated forehead tumor (Pott's puffy tumor). METHODS: We reviewed
      retrospectively the clinical history of those patients showing frontal swelling
      tumour in our Neurosurgery and Infectious Diseases Departments between July 1994
      and December 1997 and whose definitive diagnosis was cranial osteomyelitis.
      RESULTS: We reported five cases of patients who had been submitted to a
      neurosurgical operation between 9 months and 27 years ago. The main clinical
      features were intermittent painful frontal swelling episodes (with or without
      fever). These episodes were self-limited or limited after short trend of
      antibiotics. Imaging techniques were necessary for the diagnosis and especially
      in order to exclude intracranial complications (such as epidural abscess found in
      two patients). The ascertain diagnosis is made by debriding, histological studies
      and cultures from the material. Staphylococcus aureus was isolated in three of
      the patients, Haemophilus influenzae in one patient and Pseudomonas aeruginosa in
      the other one. All patients were treated with surgery and specific antibiotic
      therapy during twelve weeks minimum, being definitively cured. CONCLUSIONS: It is
      not well know the etiopathogenic mechanism concerning this rare disease. We
      remark the importance of a prompt diagnosis because of the high frequency of
      intracranial complications as well as combined treatment: surgery and long term
      antibiotic therapy (not less than 8 weeks), is necessary to cure the disease.

PMID- 10650644
TI  - [Neonatal colonization by Ureaplasma urealyticum and the development of
      bronchopulmonary dysplasia].
AB  - OBJECTIVE: The study purpose was to investigate the association between neonatal
      Ureaplasma urealyticum isolation, and bronchopulmonary dysplasia (BDP), in
      infants who had birth weights < 1,500 g, admitted in the Pediatric Intensive Care
      Unit, La Fe Hospital, Valencia, Spain. METHODS: A cohort study was designed,
      since March 1996 until April 1998, with a cohort of exposed and no exposed,
      determined by isolation of U. urealyticum in tracheal aspirate or pharyngeal
      cultures. 137 infants were admitted to the intensive care unit in this period,
      and 101 of them were enrolled in this study. RESULTS: U. urealyticum was isolated
      in 27 (26.7%) patients. The infants with U. urealyticum positive culture had a
      significantly lower gestational age (mean 28.1, SD 2.4 vs 29.2, SD 2.4; p =
      0.048) than negative culture infants. BDP occurred in 30 infants (29.7%), and was
      significantly associated with decreasing gestational age (mean 26.9, SD 1.7 vs
      29.7, SD 2.2; p < 0.001) and lower birth weight (mean 965.8, SD 166.7 vs 1121.4,
      SD 232.1; p < 0.001). However, after correction for gestational age by logistic
      regression analysis, DBP was significantly related to decreasing gestational age,
      but not to the presence of a positive U. urealyticum culture. In the cohort of U.
      urealyticum positive infants, BPD occurred in 9 (33%) vs 21 (28%) in the not
      colonized cohort. The odds ratio associated with colonization was 1.3 (CI 95% 0.5
      3.2; p = 0.63). CONCLUSIONS: BPD was significantly associated with decreasing
      gestational age, independently of birth weight and U. urealyticum colonization.

PMID- 10650645
TI  - [The prevalence of methicillin-resistant Staphylococcus aureus phagotype 95 in
      the Hospitales Vall d'Hebron of Barcelona].
AB  - BACKGROUND: In our hospital endemic methicillin resistant Staphylococcus aureus
      (MRSA) has been documented since 1971, with epidemic and interepidemic periods.
      During these years phage groups I, I-III, and non-typable were found by the
      international set of phages Phage group 95 (F95) was unusual between 1986 (when
      phage typing was first available) and 1991, with prevalence of 5.2% (mean), and
      100% of sensibility to methicillin. In November 1991 appeared the first MRSA F95
      strain, and its prevalence has been increasing until 1997. MATERIAL AND METHODS:
      We have studied 133 strains of MRSA F95 isolated from 87 patients, 39 of them
      hospitalized in the General Hospital (HG), 38 in Traumatology Hospital (HT) and 8
      in the Children's Hospital (HI). Two of these patients had successive stancies in
      HG and HT. Antimicrobial susceptibility was determined by the disk diffusion
      method and microdilution to check oxacillin resistance. Moreover these method we
      have maked: detection of mecA, phage typing with the international set of phages
      and study of the PGFE patterns by digestion of chromosomic DNA with Smal.
      RESULTS: The percentage of methicillin resistance in F95 strains was increased
      since the appear of the first strain between 8.3% in 1991 to a maximum of 76.9%
      in 1995, we had a descens to 13.7% in 1996 but 1997 can back to augment it to
      72.5%. MICs for oxacillin of these strains were low (< or = 64 mg/l to 87.4% of
      strains), and all of them were mecA positive, 78.1% of them were resistant to
      macrolides, 96.5% to tobramycin and 84.9% to quinolones, but only 10.5% to
      gentamicin, 4.7% were resistant to cotrimoxazol, 1.2% to fosfomycin and 2.5% to
      rifampin. All of them were sensible to doxycycline, and vancomycin. The pulse
      field gel electrophoresis showed 7 restriction patterns in MRSA F95, 73.8% of
      strains correspond to one of them (B), spreading from the spinal cord injury unit
      and prevalent in HT; and 10.8% to another (C), the first that appear, spreading
      from the neurosurgical unit and with high prevalence in HG. 6.9% has pattern J a
      B subtype that appear in broth HG and HT. Pattern E is prevalent in HI it was
      spread from neonatology unit. CONCLUSIONS: The emergence in a Center with endemic
      resistance of new strains of MRSA, not all of them of the same clone, with
      characteristic resistance pattern to antibiotics and in convivence with other
      phage groups is one demonstration of genetic variability of SAMR in our entorn.

PMID- 10650646
TI  - [A biotype study of Gardnerella vaginalis isolated from patients with and without
      symptoms of bacterial vaginosis].
AB  - METHODS: A simple and reproducible proposed for Benito et al. scheme for
      identification biotypes of Gardnerella vaginalis has been developed, based on
      reactions for lipase, hippurate, hydrolysis, and beta-galactosidase. RESULTS: 11
      biotypes were found among 130 strains from women with and without bacterial
      vaginosis (non-specific vaginitis) 1A, 5B; 8B, 5C, 8C, 1E, 6G and 7G in women
      with vaginosis and the biotypes 1A, 5B, 8B, 1C, 8F and 6H in women without
      vaginosis. These biotypes 1A; 5B and 8B were found in two groups. CONCLUSIONS:
      These data suggest that some biotypes of G. vaginalis are associated with
      bacterial vaginosis.

PMID- 10650647
TI  - [The molecular epidemiology of the rotavirus in Spanish children. The Rotavirus
      Study Group (GER)].
AB  - BACKGROUND: Rotavirus are the most common etiologic agent of acute
      gastroenteritis in childhood. The knowledge of the circulating antigenic types is
      important in development of future vacunes. METHODS: Faeces from children (age <
      4 years) with acute gastroenteritis admitted in the two hospitals (Hospital
      Severo Ochoa-Madrid and Hospital General Vic-Barcelona) have been studied
      prospectively during one year (October-1996 to October-1997). The detection of
      rotavirus was performed by ELISA (IDEIA, Dako). All samples were G-serotyping by
      EIA-Mabs (Silenius Laboratories) and the indeterminate or non-serotypable samples
      were G-genotyping by RT-PCR. P genotypes were identified by RT-PCR. RESULTS: 322
      (45%) patients with acute diarrhoea causing for rotavirus were confirmed, 242
      coming from the Madrid metropolitan area and other 80 from the Barcelona area.
      The EIA-Mabs technique made it possible to identify the G serotypes in 287 cases
      (89%), corresponding 207 to G1 serotype, 70 to G4 serotype and 6 to G3 serotype.
      In 4 patients both G1 and G4 serotypes were detected. The EIA-Mabs could not
      determined the serotype in 35 (11%) patients, all of whom were confirmed by RT
      PCR (12 belonged to serotype G1 and 23 to serotype G4). Analysis of P genotypes
      was carried out in 25 patients obtained from Madrid and 17 from Barcelona; all
      cases were classified in the P[8] genotype. CONCLUSIONS: The most frequent
      serotype in both hospitals was G1. The EIA-Mabs technique were showed a high
      sensitivity, however, the RT-PCR technique used were even more efficient, making
      it possible for us to identify all the non-serotypable EIA-Mabs cases. The
      temporal study of circulating serotypes/genotypes of rotavirus is necessary to
      evaluate the efficiency of vaccines.

PMID- 10650648
TI  - [Visceral leishmaniasis: a comparative study of patients with and without human
      immunodeficiency virus infection].
AB  - BACKGROUND: The changes that HIV coinfection can induce in clinical symptoms,
      response to treatment and prognosis of visceral Leishmaniasis (VL) are not well
      known. METHOD: We retrospectively describe the characteristics of VL in patients
      with and without HIV infection, between 1988-1998. RESULTS: Fifty episodes of VL
      were diagnosed in 40 patients. Nineteen (47.5%) were HIV coinfected, 57.8% of
      them have had an aids defining illness, and the median of CD4+ lymphocytes was
      50/mm3. Clinical and laboratory data were similar to patients non HIV infected,
      except for lower levels of LDH (437 vs 578 U/ml; p = 0.02) and total lymphocytes
      (665 vs 1.500/mm3; p = 0.004) and higher levels of hemoglobin (9.8 vs 8.7 gr/dl;
      p = 0.01) and ESR (85 vs 44 mm; p = 0.01). The first episode of VL was diagnosed
      in 87.5% patients through bone marrow aspirate, and the other cases were
      diagnosed by biopsies of gum (2), lymph node (1) or liver (1). One patient was
      diagnosed clinically: he had a positive serology and a good response to
      antileishmanial therapy. Treatment failed in nine patients (22.5%), 7 HIV
      coinfected. Eight patients died (20%), 6 HIV-coinfected. Five deaths were
      directly attributed to VL. Six coinfected patients (31.5%) relapsed and only one
      (4.7%) in the other group. CONCLUSIONS: We did not find major differences in
      clinical manifestations or laboratory data between the two groups. Biopsies of
      several tissues can be particularly helpful for diagnosis in immunocompromised
      patients with negative bone marrow aspirates. Failures, mortality and relapses
      are more common in HIV infected patients. VL coinfection usually affects HIV
      infected patients when they develop severe immunodepression.

PMID- 10650649
TI  - [Urinary infection in the elderly].

PMID- 10650650
TI  - [Infantile otitis externa].

PMID- 10650651
TI  - [Prolonged diarrhea in an immunocompetent adult].

PMID- 10650652
TI  - [Multiple hemorrhagic cerebral toxoplasmosis and AIDS].

PMID- 10650653
TI  - [Bacteremic pneumonia due to Rhodococcus equi in a patient with human
      immunodeficiency virus infection and visceral leishmaniasis].

PMID- 10650654
TI  - [Acute hepatitis due to Coxiella burnetii with significant cytolysis].

PMID- 10650656
TI  - [Fusobacterium necrophorum in acute otitis media].

PMID- 10650655
TI  - [Gabapentin in the treatment of polyneuropathy associated with the human
      immunodeficiency virus].

PMID- 10650657
TI  - [Chronic meningococcemia due to Neisseria meningitidis serogroup B].

PMID- 10650658
TI  - [Necrotizing pneumonia due to Salmonella sp. complicated by pneumothorax in a
      patient infected with the human immunodeficiency virus].

PMID- 10650659
TI  - [Endocarditis due to Gemella haemolysans].

PMID- 10650660
TI  - [A necrotic ulcer due to Fusarium sp. in a neutropenic patient].

PMID- 10650661
TI  - [What is the risk of human immunodeficiency virus infection in health personnel?
      What are the criteria for postexposure prophylaxis?].

PMID- 10650662
TI  - [Diagnostic value of transjugular liver biopsy in liver transplant recipients].
AB  - Liver biopsy after hepatic transplantation essential for the correct diagnosis of
      grant dysfunction. However, seriously imparied coagulation or massive ascites
      contraindicate percutaneous liver biopsy. In these cases transjugular liver
      biopsy may be valid alternative. in this study the efficacy, feasibility and
      safety of 69 transjugular biopsies carried out in 56 liver transplant recipients
      are evaluated. The suprahepatic veins were catheterized in 100% of the patients
      and histological samples were obtained in 63 (91.3%). The number of portal tracts
      was greater than six in 20.6% of the samples, lower than three in 35% and
      oscillated between four and six in 44%. The specimens obtained were sufficient
      for diagnosis in 82.5% of the patients, the overall diagnostic efficacy being
      75.4%. The most common histological diagnosis (28.8%) was graft damage, while
      rejection represented 7.7%. Only one patient (1.18%) suffered a serious
      complication after transjugular biopsy. Transjugular biopsy is feasible and
      effective in liver transplant recipients with severely imparied coagulation.

PMID- 10650663
TI  - [Acute intermittent porphyria: a possible cause of abdominal pain].
AB  - Acute intermittent porphyria (AIP) is an inherited disorder of heme metabolism.
      It can produce a variety of symptoms including abdominal pain. In Spain it is an
      uncommon disease and consequently may not be included in the differential
      diagnosis of acute abdominal pain. Two cases of AIP are reported, both of which
      started with recurrent abdominal pain. A brief commentary of the main topics of
      the disease is made with special emphasis on the importance of an early
      diagnosis.

PMID- 10650664
TI  - [Hypertransaminasemia: indication for the diagnosis of celiac disease].
AB  - A high percentage of diagnosed cases of coeliac disease are oligosymptompatic.
      Various atypical manifestations such as hypertransaminasemia may guide diagnosis
      when the disease is suspected. We present two cases of coeliac disease, which
      were diagnosed on the basis of hypertransaminasemia of unknown origin. One of the
      patients lacked the gastrointestinal symptoms suggestive of disease. We also
      retrospectively review (January 1990-December 1998) all the cases of coeliac
      disease diagnosed in our center in order to establish the frequency of liver
      enzyme alterations in patients with coeliac disease and their evolution on a
      gluten-free diet. The importance of sprue suspicion in guiding diagnosis in
      patients with cryptogenic hypertransaminasemia is highlighted as is the need to
      rule out underlying liver disease in coeliac patients with persistent
      hypertransaminasemia after withdrawing gluten from the diet.

PMID- 10650665
TI  - [Atypical primary biliary cirrhosis or autoimmune cholangitis?].
AB  - The term autoimmune cholangitis is used for a disease with clinical and
      pathological features of primary biliary cirrhosis (PBC), lack of anti
      mitochondrial antibodies (AMA), presence of anti-nuclear antibodies (ANA), and
      good response to immunosuppresive therapy. The current knowledge of this
      condition is limited and it is not established whether or not it is a different
      syndrome from the CBP. We report a 51-year-old woman with chronic cholestasis,
      histological features of PBC, negative AMA and positive peripheral fluorescent
      ANA pattern, without response to prednisone.

PMID- 10650666
TI  - [Treatment of inoperable malignant gastric stenosis with self-expanding
      prosthesis].
AB  - We report two patients with inoperable malignant stenosis of gastric antrum who
      were treated with endoscopic placement of a 22 mm Wallstent metallic prosthesis.
      In one patient, the endoscope was introduced simultaneously with the prosthesis.
      Different types of pincers were introduced through the endoscope's canal, which
      aided the movement and placement of the prosthesis. In the other patient, to
      broaden the stenosis a pediatric endoscope was introduced with a guide inside the
      canal, which was held straight externally and which facilitated the positioning
      of the prosthesis. There were no complications and the patients were discharged
      after 48 hours able to follow a normal oral diet. Both patients are still living,
      six and four months respectively after the procedure.

PMID- 10650667
TI  - [Adhesion molecules: their role in physiopathology and treatment of inflammatory
      bowel disease].

PMID- 10650668
TI  - [Budesonide and inflammatory bowel disease].

PMID- 10650669
TI  - [Use of Helicobacter pylori (Hp) antigen test in stool samples to detect Hp
      infection].

PMID- 10650670
TI  - [Current controversy in the treatment of primary gastric lymphoma].

PMID- 10650671
TI  - [Pancreatic hydatidosis].

PMID- 10650673
TI  - Generational investment and social insurance for the elderly: balancing the
      accounts.

PMID- 10650672
TI  - [IgA nephropathy and intrahepatic percutaneous portosystemic shunt].

PMID- 10650674
TI  - The transfer of resources from middle-aged children to functionally limited
      elderly parents: providing time, giving money, sharing space.
AB  - The transfer of resources from middle-aged children to their functionally limited
      elderly parents is addressed from the perspective of the children who may
      allocate time to caregiving, share household space, and give money to parents. A
      simultaneous-equations model estimates the extent to which the three modes of
      transfer are interdependent, given the parents' needs for resources and the
      children's ability to provide them. Caregiving is the primary mode of resource
      transfer and is of overriding importance for individuals who depend daily on help
      from other persons. Coresidence and financial assistance complement direct human
      assistance and, at the margin, have a substantially large effect on caregiving
      time. It is, therefore, relevant to consider all modes of transfer in order to
      better understand how families accommodate the needs of their frail and disabled
      members.

PMID- 10650675
TI  - Caregiving as a life course transition among older husbands: a prospective study.
AB  - Guided primarily by transitions theory, this study examined changes over two
      points in time (approximately 5 years apart) in multiple life domains (i.e.,
      household tasks, social life, marital relationship, and well-being) between two
      groups of husbands aged 60 and older, who indicated that their wives were not in
      need of care or assistance due to an illness or disability at the initial
      interview. The two groups included husbands who identified themselves as a
      provider of care at Time 2 (T2; i.e., they had transitioned into the caregiver
      role; n = 26), and those married to healthy wives at T2 (i.e., noncaregivers; n =
      262). Data came from a national probability sample of U.S. adults who were
      primary respondents to the National Survey of Families and Households in 1987-88,
      and who were followed up longitudinally in 1992-93. Findings suggested that
      husbands who entered the caregiving role demonstrated significant changes in
      household responsibilities, social integration, marital relationship, and well
      being. Implications for practice and future research on the older husband
      caregiver are highlighted.

PMID- 10650676
TI  - The outcomes of an inpatient treatment program for geriatric patients with
      dementia and dysfunctional behaviors.
AB  - This study evaluated outcomes of an inpatient program designed to reduce severe
      agitated behavior in geriatric patients with dementia who could not be
      successfully treated on an outpatient basis. An individualized treatment plan was
      created for each patient (N = 250) that involved pharmacological and
      nonpharmacological interventions with behavioral, environmental, and
      psychological components. Assessment of behavioral, cognitive, and functional
      status was conducted for each patient on admission to the program and at
      discharge. Significant improvements on these assessments were observed. We
      conclude that the longitudinal, multidisciplinary approach used in this study was
      effective in significantly reducing intrusive and dangerous behaviors while
      preserving or enhancing patients' cognitive and functional abilities.

PMID- 10650677
TI  - A longitudinal study of predictors of nursing home placement for patients with
      dementia: the contribution of family characteristics.
AB  - The caregivers of elderly patients with dementia (N = 164) were followed for 2
      years to determine if characteristics of the multigeneration family predicted
      nursing home placement (NHP) over and above the effects of patient demographics,
      severity of patient disease, and characteristics of caregivers. Clinical
      assessment occurred at baseline, and caregivers were assessed by questionnaire
      and interview at baseline and every 6 months. No patient demographic, severity,
      or caregiver characteristic significantly predicted NHP. Families scoring high on
      emotional closeness, high on negative family feelings, and low on family
      efficiency institutionalized their ill elders at a significantly higher rate than
      other families, especially at low levels of patient severity. The findings argue
      that a careful examination of the multigeneration family should increase the
      prediction of NHP and the relevance of services offered to these families.

PMID- 10650678
TI  - HIV testing behaviors and attitudes regarding HIV/AIDS of adults aged 50-64.
AB  - This article explores knowledge, attitudes, and behaviors regarding HIV/AIDS for
      persons aged 50-64 by using data from the 1996 Behavioral Risk Factor
      Surveillance System. It examines what percentage have been tested for HIV, where
      and why they have been tested, knowledge about condom effectiveness, and self
      perceived risk. The purpose is twofold: First, it presents an epidemiologic
      analysis of HIV/AIDS-related attitudes and behaviors of adults aged 50-64;
      second, it explores whether theoretical models used on other groups fit well with
      this age group. The authors conclude that the conceptual model is less robust for
      this group and there is a substantial need for health promotion efforts directed
      at older adults.

PMID- 10650679
TI  - Caregiving networks of elderly persons: variation by marital status.
AB  - Using data from the 1982 National Long-Term Care Survey, this study examines the
      relationship between marital status and two dimensions of caregiving networks,
      size and composition. Results indicate that widowed and never married people have
      helping networks that are larger than those of married people. Diversity across
      marital statuses in sources of assistance is revealed in analyses of two measures
      of caregiving network composition: (a) having more kin than nonkin helpers and
      (b) presence of specific helpers (adult children, siblings, friends, and formal
      helpers). Moreover, gender interacts with marital status to influence the
      composition of caregiving networks.

PMID- 10650680
TI  - The effects of strength training on strength and health-related quality of life
      in older adult women.
AB  - The short-term effects of an accessible exercise intervention on the strength and
      health-related quality of life (HRQOL) among older adult women were evaluated. We
      conducted an 8-week resistance training intervention utilizing elastic bands in
      62 community-dwelling women with a mean age of 68 years. Participants were
      randomly assigned to either an exercise or a control group. Pre- and
      postintervention assessments included strength tests and HRQOL. Results revealed
      significant increases in three major muscles compared to the control group.
      However, there were no significant changes on either mental or physical health
      functioning. The elastic bands provide older adult women with an inexpensive,
      practical exercise program that effectively increases strength within 8 weeks but
      may have little effect on self-reported HRQOL.

PMID- 10650681
TI  - Predictors of use of traditional Korean healers among elderly Koreans in Los
      Angeles.
AB  - Many ethnic groups are known to use traditional healers often in conjunction with
      Western biomedical medicine, thus combining treatment regimens and medical advice
      as they see fit. Awareness of the use of traditional healers is an increasingly
      salient issue due to the growing diversity and aging of the U.S. population. To
      explore the determinants of use of traditional healers, we studied demographics,
      health status, and social support networks of a representative sample of elderly
      Koreans in Los Angeles County, California. The results revealed that chronic
      conditions such as arthritis, lung disease, and stomach pain, fewer depressive
      symptoms, availability of health insurance, and stronger social networks were
      significant predictors of use of traditional healers. Better understanding
      reasons for and patterns of health care use may enhance the delivery of care to
      the heterogeneous elderly population by preventing potential treatment
      complications and increasing health providers' cultural sensitivity.

PMID- 10650682
TI  - Functional improvement of elderly residents of institutions.
AB  - Studies have shown that some elderly persons who suffer decline in activities of
      daily living (ADL) functioning experience an improvement. This phenomenon has
      been examined mainly among elderly persons in the community using summary ADL
      indices. This article examines functional improvement among 2,527 residents of
      institutions for semi-independent and frail elders in Israel in four specific
      ADLs--bathing, eating, bladder continence, and mobility--at two points in time, 2
      to 4 years apart. Demographic, functional, and institutional variables were used
      to predict functional improvement through logistic regression. The variables were
      found to differentially affect each ADL, highlighting two opposite aspects of
      institutionalization--deterioration, on the one hand, and rehabilitation through
      intervention by highly trained staff, on the other.

PMID- 10650683
TI  - Elder rehab: a student-supervised exercise program for Alzheimer's patients.
AB  - The physical and mental benefits of exercise are universally recognized, but
      seldom available to persons with early to moderate stage dementia. Difficulty in
      initiating and maintaining purposeful behavior, coupled with the inability to
      travel independently, preclude most community-dwelling dementia sufferers from
      accessing organized fitness programs. Overburdened caregivers typically lack the
      inclination and know how to structure and supervise systematic exercise sessions.
      The University of Arizona Elder Rehab program offers independent study credit to
      students who serve as rehab partners and fitness supervisors to
      noninstitutionalized persons with dementia. In addition to regular aerobics and
      weight training workouts, participants engage in supervised volunteer work and
      memory- and language-stimulation activities with their student partners. Multiple
      benefits accrue to all participants. The program is cost effective, easily
      replicated, and may also be suitable for frail and depressed elderly persons
      without dementia.

PMID- 10650684
TI  - A multimedia intervention to support family caregivers.
AB  - The lack of choice and predominance of crisis-oriented care in relation to
      respite and long-term care for family carers and frail older people provided the
      authors with the rationale for the development, within the European-funded
      Assisting Carers using Telematic Interventions to meet Older person's Needs
      (ACTION) project, of two innovative multimedia programs. The key aim of the
      programs is to provide education, information, and support about respite care and
      planning for the future for family carers and frail older people in their homes.
      In this way, it is intended that family carers and frail older people will be
      able to make informed choices concerning their health and social care needs. The
      authors describe the conceptual basis of the multimedia programs, the research
      and development process, the content of the multimedia programs, and the
      evaluation of the developed product.

PMID- 10650685
TI  - Expanded managed care liability: what impact on employer coverage?
AB  - Policymakers are considering legislative changes that would increase managed care
      organizations' exposure to civil liability for withholding coverage or failing to
      deliver needed care. Using a combination of empirical information and theoretical
      analysis, we assess the likely responses of health plans and Employee Retirement
      Income Security Act (ERISA) plan sponsors to an expansion of liability, and we
      evaluate the policy impact of those moves. We conclude that the direct costs of
      liability are uncertain but that the prospect of litigation may have other
      important effects on coverage decision making, information exchange, risk
      contracting, and the extent of employers' involvement in health coverage.

PMID- 10650686
TI  - Individual versus job-based health insurance: weighing the pros and cons.
AB  - Although the majority of insured Americans receive their health insurance through
      their employers, some depend on the individual health insurance market. However,
      with increased criticism of the lack of choice in group coverage and various
      proposals including subsidies or tax credits to decrease the number of uninsured,
      the individual market may start to play a larger role. In this paper we conclude
      that although efficient large-group insurance will appropriately continue to
      exist, the individual market appears to be improving, in both administrative cost
      and protection against high premiums associated with high risk. For diverse
      workers now in small groups with little plan choice, the individual market might
      become a reasonable alternative.

PMID- 10650687
TI  - Expanding access and choice for health care consumers through tax reform.
AB  - A refundable tax credit for the uninsured would complement the existing job-based
      health insurance system while letting people keep their job-based coverage if
      they wish. Among the wide variety of design options for a tax credit, policy and
      political analysis does not reveal an obvious choice, but a tax credit based on a
      percentage of spending may have a slight advantage. Congress should give states
      maximum flexibility to use existing funding sources to supplement the value of a
      federal tax credit and encourage the use of techniques to create stable insurance
      pools.

PMID- 10650688
TI  - Who pays for employer-sponsored health insurance?

PMID- 10650689
TI  - Job-based health insurance, 1977-1998: the accidental system under scrutiny.
AB  - This paper highlights changes in employer-based health insurance from 1977 to
      1998, based on national household surveys conducted by the Agency for Health Care
      Policy and Research (AHCPR) in 1977, 1987, and 1996; and surveys of employers by
      the AHCPR in 1977, by the Health Insurance Association of America in 1988, and by
      KPMG Peat Marwick/Kaiser Family Foundation in 1998. During the study years, in
      1998 dollars, the cost of job-based insurance increased 2.6-fold, and employees'
      contributions for coverage increased 3.5-fold. The percentage of nonelderly
      Americans covered by job-based insurance plummeted from 71 percent to 64 percent.
      This decline occurred exclusively among non-college-educated Americans. An
      information-based global economy is likely to produce not only greater future
      wealth but also greater inequalities in income and health benefits.

PMID- 10650690
TI  - Trends in managed care and managed competition, 1993-1997.
AB  - According to the recent literature, we are experiencing a managed care
      "revolution," and managed competition is increasingly being embraced by private-
      and public-sector policymakers. Using two large employer health insurance
      surveys, this paper presents new estimates that both confirm and add to our
      understanding of changes taking place in employment-based health plans. The
      dramatic shifts in enrollment from indemnity to managed care largely reflect
      employers' choices about the types of plans to offer. Employees are limited in
      the number and types of plans from which they can choose. When choice is
      available, it is generally not governed by managed competition principles.

PMID- 10650691
TI  - At the helm of an insurance giant: Aetna's Richard L. Huber. Interview by James
      Robinson.

PMID- 10650692
TI  - Early experience with a new model of employer group purchasing in Minnesota.
AB  - The Buyers Health Care Action Group (BHCAG) in the Twin Cities has implemented a
      new purchasing initiative that offers employees a choice among care systems with
      nonoverlapping networks of primary care providers. These systems offer a
      standardized benefit package, submit annual bids, and are paid on a risk-adjusted
      basis. Employees are provided with information on quality and other differences
      among systems, and most have financial incentives to choose lower-cost systems.
      Generally, providers have responded favorably to direct contracting and to risk
      adjusted payments but have concerns about the risk-adjustment mechanism used and,
      more importantly, the strength of employers' commitment to the purchasing model.

PMID- 10650693
TI  - Why we should keep the employment-based health insurance system.

PMID- 10650694
TI  - Employer-based health insurance: a balance sheet.

PMID- 10650695
TI  - Stability and variation in employment-based health insurance coverage, 1993-1997.

PMID- 10650696
TI  - What drives Medicare managed care growth?
AB  - We conducted case studies of four markets--Los Angeles, New York City, Portland
      (OR), and Tampa-St. Petersburg--to learn more about why Medicare managed care
      develops differently across the country even when capitation rates are similar.
      Our analysis highlights the importance of prior managed care history, beneficiary
      characteristics, supplemental coverage patterns, the form of provider
      organization, practice patterns, care expectations, and other market
      characteristics to the development of Medicare managed care. Policymakers seeking
      to expand Medicare managed care need to go beyond national statistics to
      understand how local market forces affect its growth.

PMID- 10650697
TI  - Medicare HMO withdrawals: what happens to beneficiaries?
AB  - More than 400,000 Medicare beneficiaries had to seek other insurance arrangements
      when their health maintenance organization (HMO) withdrew from Medicare at the
      end of 1998. According to a new survey of 1,830 involuntarily disenrolled
      Medicare beneficiaries, two-thirds subsequently enrolled in another Medicare HMO;
      one-third experienced a decline in benefits, and 39 percent reported higher
      monthly premiums. One in seven lost prescription drug coverage; about one in five
      had to switch to a new primary care doctor or specialist. Those with traditional
      Medicare by itself or with Medigap, the disabled under age sixty-five, the oldest
      old, and the near-poor experienced the greatest hardship after their HMO
      withdrew.

PMID- 10650698
TI  - The pursuit of quality by business coalitions: a national survey.
AB  - The extent to which business coalitions and their employer members are catalysts
      for improving quality of care is of interest to policymakers, who need to know
      where and under what circumstances the marketplace succeeds on its own in
      assuring quality. Using data from the 1998 National Business Coalition on Health
      annual survey, this paper indicates that most coalitions have an infrastructure
      in place that could be tapped to advance quality goals. Although the survey data
      cannot tell us the extent to which coalitions are exercising their enhanced
      market influence specifically to improve quality, interviews with coalition
      leaders provide insights about how quality considerations can factor into
      coalition strategies.

PMID- 10650699
TI  - An employer's view of the U.S. health care market.

PMID- 10650700
TI  - Boundaries. What happens to the disabled poor when insurers draw a line between
      what's "medically necessary" and devices that can improve quality of life?

PMID- 10650701
TI  - Of wheelchairs and managed care.

PMID- 10650702
TI  - Comparing employee health benefits in the public and private sectors, 1997.
AB  - Data from the 1997 Robert Wood Johnson Foundation Employer Health Insurance
      Survey provide new information comparing public- and private-sector employee
      health benefits. The federal government is ahead of other employers in adopting
      managed competition principles using financial incentives and consumer
      information to promote choosing efficient plans. Federal employees experience a
      $200 annual compensation gap relative to those in the private sector, but it is
      partly explained by advantage in purchasing power. In contrast, state and local
      governments make higher payments toward health insurance than private-sector
      employers do. Their premiums are equivalent, but they pay a greater share of the
      total cost.

PMID- 10650703
TI  - Market incentives, plan choice, and price increases.
AB  - The Federal Employees Health Benefits Program (FEHBP) has attracted considerable
      interest for its ability to control health care costs. We examine the impact of
      the FEHBP's maximum dollar contribution on incentives to select low-cost plans
      and the growth in insurance premiums over time. Unless the maximum dollar
      contribution is pegged to a low-price plan, few enrollees select such plans.
      Moreover, premiums rise at least five percentage points per year faster among
      plans below this fixed subsidy level than they do in plans above it. Our results
      have important implications for the design of similar market-based approaches.

PMID- 10650704
TI  - The uninsured, the working uninsured, and the public.
AB  - Recent opinion surveys show a high level of public support for the current
      employer-based health insurance system. Many Americans are not aware that this
      system is endangered or that the number of uninsured persons is growing. The
      public appears to favor a two-track system for the working uninsured-
      strengthening the existing employer-based system and developing a parallel system
      for those without employer coverage.

PMID- 10650705
TI  - Beyond cost: 'responsible purchasing' of managed care by employers.
AB  - We explore the extent of "responsible purchasing" by employers--the degree to
      which employers collect and use nonfinancial information in selecting and
      managing employee health plans. Most firms believe that they have some
      responsibility for assessing the quality of the health plans they offer. Some pay
      attention to plan characteristics such as the ability to provide adequate access
      to providers and services and scores on enrollee satisfaction surveys. A more
      limited but still notable number of firms take specific actions based on
      responsible purchasing information. Because of countervailing pressures, however,
      it is not clear whether or not the firms most involved in responsible purchasing
      are signaling a developing trend.

PMID- 10650706
TI  - Wisconsin Blues conversion model.

PMID- 10650707
TI  - The National Quality Forum: a 'me-too' or a breakthrough in quality measurement
      and reporting?

PMID- 10650708
TI  - Legal challenges to managed care: another view.

PMID- 10650710
TI  - Spending growth rates: are the differences real?

PMID- 10650709
TI  - New Jersey's experiment: a 'dismal failure'.

PMID- 10650711
TI  - Purification and characterization of flavokinase from Neurospora crassa.
AB  - The ATP-dependent phosphorylation of riboflavin to FMN by flavokinase is the key
      step in flavin biosynthesis. Flavokinase has been purified from a fungal source
      for the first time. The enzyme purified from a cell wall lacking mutant of
      Neurospora crassa, slime, is a monomer of M(r) 35.5 kDa with maximal activity at
      alkaline pH and high temperature (55 degrees C). The K(m) for both substrates is
      the lowest reported for flavokinase from any source so far (120 nM for riboflavin
      and 210 nM for MgATP2-). The enzyme exhibits preference for Mg2+ over Zn2+ as the
      essential activator and is also significantly activated by several cations.
      Activation by orthophosphate may be physiologically relevant for the
      intracellular regulation of flavokinase.

PMID- 10650712
TI  - Kinetic mechanism of glucose dehydrogenase from Halobacterium salinarum.
AB  - The kinetic mechanism of glucose dehydrogenase (EC 1.1.1.47) from Halobacterium
      salinarum was studied by initial velocity and product inhibition methods. The
      results suggest that both, in the forward and reverse direction, the reaction
      mechanism is of Bi Bi sequential ordered type involving formation of ternary
      complexes. NADP+ adds first and NADPH formed dissociates from the enzyme last.
      For the reverse direction, NADPH adds first and NADP+ leaves last. Product
      inhibition experiments indicate that (a), the coenzymes compete for the same site
      and form of the enzyme and (b), ternary abortive complexes of enzyme-NADP(+)
      glucono-delta-lactone and enzyme-NADPH-glucose are formed. All the other
      inhibitions are noncompetitive.

PMID- 10650713
TI  - Characterization of a thermostable alpha-amylase from a thermophilic Streptomyces
      megasporus strain SD12.
AB  - An extracellular alpha-amylase (1,4-alpha D-glucan glucan hydrolase; EC 3.2.1.1)
      was isolated from the cell free broth of Streptomyces megasporus SD12 grown in
      glucose, soluble starch and raw starch. The enzyme was purified 55-fold with a
      specific activity of 847.33 U mg-1 of protein and with a yield of 36% activity.
      The apparent molecular mass of the enzyme was 97 kDa, as estimated by SDS-PAGE.
      The pI of the enzyme was 5.4 and it was stable at a pH range of 5.5 to 8.5 with
      an optimum pH 6. The enzyme was stable upto 85 degrees C with a half life of 60
      min. With soluble starch as substrate the enzyme exhibited a K(m) and kcat value
      of 4.4 mg ml-1 and 2335 U min-1 mg-1 of protein respectively. The major end
      products of starch hydrolysis were maltotriose and maltose depending on the
      incubation period. The production of the enzyme with agricultural wastes as
      substrates was 643 to 804 U min-1 mg-1 of protein in submerged fermentation
      whereas solid state fermentation could produce only 206 U min-1 mg-1 of protein.

PMID- 10650714
TI  - Biochemical and dynamic studies of collagen from human normal skin and keloid
      tissue.
AB  - Keloids are exuberant scars, in which collagen, fibronectin and
      glycosaminoglycans are overdeposited. Biochemical analysis of the collagen
      isolated from normal skin and keloid tissue by pepsin treatment, indicated an
      increase in the type III and GAG content. Viscosity measurements of collagen from
      normal skin and keloid tissue were used in the present study to establish the
      interaction between collagen and GAG. Physico-chemical properties such as
      intrinsic viscosity, reduced viscosity and hydrated volume were computed from
      viscosity measurements. These measurements were also used to determine the
      denaturation temperature of collagen which was further confirmed by DSC
      measurements. Chondroitinase has been used in this study to probe the influence
      of GAG on the physico-chemical characteristic of keloid collagen.

PMID- 10650715
TI  - Binding of cationic surfactants to DNA, protein and DNA-protein mixtures.
AB  - Extent of binding (gamma 2(1)) of cationic surfactants cetyltrimethyl ammonium
      bromide (CTAB), myristyltrimethyl ammonium bromide (MTAB) and dodecyl trimethyl
      ammonium bromide (DTAB) to calf-thymus DNA, bovine serum albumin (BSA) and to
      their binary mixture respectively have been measured as function of bulk
      concentration of the surfactant by using equilibrium dialysis technique. Binding
      of CTAB has been studied at different pH, ionic strength (mu), temperature and
      biopolymer composition and with native and denatured states of the biopolymers.
      The chain-length of different long chain amines plays a significant role in the
      extent of binding under identical solution condition. The binding ratios for CTAB
      to collagen, gelatin, DNA-collagen and DNA-gelatin mixtures respectively have
      also been determined. The conformational structures of different biopolymers are
      observed to play significant role in macromolecular interactions between protein
      and DNA in the presence of CTAB. From the experimental values of the maximum
      binding ratio (gamma 2m) at the saturation level for each individual biopolymer,
      ideal values (gamma 2m)id have been theoretically calculated for binary mixtures
      of biopolymers using additivity rule. The protein-DNA-CTAB interaction in mixture
      has been explained in terms of the deviation (delta) of (gamma 2m) from (gamma
      2m)id in the presence of a surfactant in bulk. The binding of surfactants to
      biopolymers and to their binary mixtures are compared more precisely in terms of
      the Gibbs' free energy decrease (-delta G degree) for the saturation of the
      binding sites in the biopolymers or biopolymer mixtures with the change of the
      bulk surfactant activity from zero to unity in the rational mole fraction scale.

PMID- 10650716
TI  - Effect of sulphur crosslinking on the stability and transition of triple helical
      DNA.
AB  - In continuation to our work on order-order and order-disorder transition in
      triple stranded DNA when it is bounded to netropsin, we report in this
      communication the stabilizing/destabilizing effect of disulphide linkage on the
      phase dynamics of the triplex using the amended Zimm-Bragg theory. It is observed
      that in contrast to the sequential triplex-->duplex -->single strand melting of
      the uncrosslinked triplex, crosslinking causes the triplex state to melt directly
      to the single stranded state, with no apparent intermediary of a duplex state.
      Since there is no overall difference in the enthalpy of crosslinked and
      uncrosslinked triplexes, the transition is entropy driven.

PMID- 10650717
TI  - Deconvolution of the fluorescence spectra into its component Gaussians: a method
      to analyze the binding of coumarin to bovine serum albumin.
AB  - 7-N,N-Diethylamino-4-methylcoumarin, (cou-1), a readily available laser dye
      binding to bovine serum albumin (BSA), at room temperature has been studied by
      steady state fluorescence spectroscopy. Existing methods of analysis of the
      binding to obtain the binding parameters are based on the change in fluorescence
      intensity at a particular wavelength. These methods are not convenient when there
      is a gradual shift in the emission maxima for increasing protein concentration.
      In this paper we present a method to obtain the binding constants of cou-1 to BSA
      using a Windows '95 based package to deconvolute the asymmetrical spectrum
      (fluorescence intensity versus wave number curve) into two Gaussians, each
      corresponding to the binding of the fluorophore to a particular site. This method
      is convenient to analyze the binding constant data and obtain the binding
      parameters of each binding site, and can also provide information about the
      microenvironment of each site, relating micropolarity and microviscosity.

PMID- 10650718
TI  - Designing of peptides with left handed helical structure by incorporating the
      unusual amino acids.
AB  - The conformational behaviour of delta Ala has been investigated by quantum
      mechanical method PCILO in the model dipeptide Ac-delta Ala-NHMe and in the model
      tripeptides Ac-X-delta Ala-NHMe with X = Gly, Ala, Val, Leu, Abu and Phe and is
      found to be quite different. The computational results suggest that in the model
      tripeptides the most stable conformation corresponds to phi 1 = -30 degrees, psi
      1 = 120 degrees and phi 2 = psi 2 = 30 degrees in which the > C = 0 of the acetyl
      group is involved in hydrogen bond formation with N-H of the amide group. Similar
      results were obtained for the conformational behaviour of D-Ala in Ac-D-Ala-NHMe
      and Ac-Ala-D-Ala-NHMe. The conformational behaviour of the amino acids delta Ala,
      D-Ala, Val and Aib in model tripeptides have been utilized in the designing of
      left handed helical peptides. It is shown that the peptide HCO-(Ala-D-Ala)3-NHMe
      can adopt both left and right handed helix whereas in the peptide Ac-(Ala-delta
      Ala)3-NHMe the lowest energy conformer is beta-bend ribbon structure. Left handed
      helical structure with phi = 30 degrees, psi = 60 degrees for D-Ala residues and
      phi = psi = 30 degrees for delta Ala is found to be more stable by 4 kcal mole-1
      than the corresponding right handed helical structure for the peptide Ac-(D-Ala
      delta Ala)3-NHMe. In both the peptides Ac-(Val-delta Ala)3-NHMe and Ac-(D-Val
      delta Ala)3-NHMe the most stable conformer is the left handed helix. Comparisons
      of results for Ac-(Ala-delta Ala)3-NHMe and Ac(Val-delta Ala)3-NHMe and Ac-(D-Ala
      delta Ala)3-NHMe and Ac-(D-Val-delta Ala)3-NHMe also reveal that the Val residues
      facilitate the population of 3(10) left handed helix over the other conformers.
      It is also shown that the conformational behaviour of Aib residue depends on the
      chirality of neighbouring amino acids, i.e. Ac-(Aib-Ala)3-NHMe adopts right
      handed helical structure whereas Ac-(Aib-D-Ala)3-NHMe is found to be in left
      handed helical structure.

PMID- 10650719
TI  - Changes in myosin ATPase activity in skeletal muscles of rat during cold stress.
AB  - Three skeletal muscles viz., gastrocnemius, pectoralis and diaphragm from rats
      acclimated to a low temperature (4 +/- 1 degrees C; 16 hr daily; maximum for 8
      weeks) exhibit an increased myosin ATPase activity. An analysis of native myosin
      from these muscles under non-dissociating conditions reveals two myosin isozymes
      instead of a single isozyme expressed in control muscles. Isoelectric focusing
      (IEF) coupled with two dimensional sodium dodecyl sulfate polyacrylamide gel
      electrophoresis (2-D SDS-PAGE) confirms an increased phosphorylation of myosin
      light chain 2 (MLC2) in muscles from cold acclimated rats.

PMID- 10650720
TI  - Effect of water stress on proline content and transcript levels in Lathyrus
      sativus.
AB  - Response of Lathyrus sativus plants to water stress showed that ABA responsive
      genes such as PLE 25, TAS 14 and RAB 17 are synthesized constitutively, the
      levels of which decline gradually with increase in water stress or ABA levels.
      Proline accumulation was highest in leaves (65-fold) followed by stem (56-fold),
      root (38-fold) and marginal increase in etiolated seedlings. Proline increase was
      also observed in plant parts not exposed to light.

PMID- 10650721
TI  - Nutritional properties of trans fatty acids.
AB  - The role of trans fatty acids (TFA) present in partially hydrogenated fats widely
      consumed in food and their link with coronary heart disease has been examined in
      this review. Most of the studies carried out have been on the effects of TFA on
      blood-lipid profile. The perceived effects of TFA intake depend on the fat or oil
      with which they are compared and appears to be in between that of dietary
      saturated fats and monounsaturated fatty acids. When compared to saturated fat,
      TFA intake shows lower levels of total and LDL-cholesterol in blood. But when
      both TFA and saturated fatty acids are compared with cis fatty acids or native
      unhydrogenated oil, increase in total and LDL-cholesterol are noted. The effects
      of TFA on HDL-cholesterol and Lp(a) are not clearly established. The undesirable
      effects of TFA can be overcome by inclusion of essential fatty acids at a minimum
      of 2 energy per cent level in the diet. The link between trans fatty acid intake
      and coronary heart disease (CHD) are not unequivocally established.

PMID- 10650722
TI  - Cloning and sequencing of an apparently recombinant promoter for napin gene from
      Brassica campestris genomic library and its evolutionary significance.
AB  - From a genomic library of Brassica campestris (brown sarson cv. B54), we have
      cloned and sequenced about 2 kb of upstream regulatory region from one of the 2S
      albumin-coding gene family. The sequence has several seed-specific promoter
      motifs. A sequence alignment of the 5' flanking regions of the available Brassica
      2S storage protein genes showed that our sequence is a double crossover
      recombinant product of the two members of the napin gene family. A possible
      explanation of this fact is that Brassica species evolved through gene
      duplication and recombination from a common ancestor with fewer number of
      chromosomes and genes.

PMID- 10650723
TI  - Synergistic effects in enzymic reactions.
AB  - It has been shown that when two enzymes showing similar actions act in close
      proximity of each other they influence each other synergistically. The phenomenon
      of synergism is, however, not observed if the two enzymes are of dissimilar
      action type. The condition of closest proximity has been simulated by conducting
      the enzymic reactions inside the reversed micelles. In the present study we have
      experimented with alpha-amylase and invertase both hydrolysing enzymes and also
      with peroxidase and invertase which do not show similar actions.

PMID- 10650724
TI  - Solubilization and binding of DNA-CTAB complex with SDS in aqueous media.
AB  - Extent of binding (gamma 2(1)) of sodium dodecyl sulphate (SDS) to the binary
      complex formed between calfthymus DNA and cetyltrimethylammonium bromide (CTAB)
      has been measured in mole per mole of nucleotide in the complex as function of
      concentration of SDS by using equilibrium dialysis technique at different
      temperatures and pH. Binding of SDS to thermally denatured DNA-CTAB complex has
      also been studied. The most interesting aspect to be noted in this experiment is
      that the water insoluble DNA-CTAB binary complex gets solubilized in the ternary
      mixture in presence of SDS but when DNA is thermally denatured, the ternary
      system DNA-CTAB-SDS remains insoluble. Significant change in the extent of
      binding has been noted with the variation of the relative composition of DNA and
      CTAB in their binary mixture. The data of binding of SDS to DNA-CTAB complex are
      compared more precisely in terms of the standard Gibbs' free energy decrease (
      delta G degree) for the saturation of the binding sites in the complex with the
      change of SDS activity from zero to unity in the rational mole fraction scale.

PMID- 10650725
TI  - Physicochemical characterization of hepatic glucocorticoid receptors from pre-
      and post-weaned mice.
AB  - The physicochemical parameters viz., molecular weight, stokes radius and ionic
      state of hepatic glucocorticoid receptors from pre-(10-day) and post-(60-day)
      weaned mice were studied. Gel permeation studies of the crude receptors showed a
      molecular mass of approximately 290 kDa for the unactivated receptors from both
      the age groups while the thermally activated receptors showed a molecular mass of
      approximately 90 kDa. The stokes radii were approximately 5.8 and 3.6 for the
      unactivated and activated receptors, respectively from both the age groups
      studied. Elution of the bound glucocorticoid receptors from anion-exchanger did
      not reveal any charge difference in the two age groups; the unactivated receptors
      eluted at approximately 250 mM KCl whereas the activated receptors eluted at
      approximately 100 mM KCl. Salt extraction of thermally activated nuclear bound
      receptors and immunological studies on the unactivated receptors revealed no age
      related variation in the two groups of mice. Our findings confirm that the
      physicochemical properties of hepatic glucocorticoid receptors remain unchanged
      at these developmental stages of mice.

PMID- 10650726
TI  - Targeting of piperine intercalated in mannose-coated liposomes in experimental
      leishmaniasis.
AB  - The leishmanicidal property of piperine intercalated in liposomes and in mannose
      coated liposomes was tested in experimental visceral leishmaniasis in hamsters.
      Mannose-coated liposomal piperine eliminated intracellular amastigotes of
      Leishmania donovani in splenic macrophages much more efficiently than did the
      liposomal piperine or free piperine. At a dose equivalent to 6 mg/kg body wt
      every 4th day for a total of 4 doses in 12 days, the mannose-coated liposomal
      piperine was found to reduce spleen parasite load to the extent of 90% in
      comparison to that achieved by liposomal piperine (77%) or free piperine (29%).
      Histological examination of spleen and liver function tests showed that the
      toxicity of piperine was reduced when mannosylated liposomal piperine was
      administered.

PMID- 10650727
TI  - IgG binding and expression of its receptor in rat intestine during postnatal
      development.
AB  - The binding of 125I labelled IgG to the microvillus membranes (MVM) has been
      studied during postnatal development of rat intestine. The levels of mRNA
      encoding IgG receptor were also analyzed by liquid hybridization under these
      conditions. The IgG binding to MVM reached maximum levels by day 12 and showed a
      gradual decline upon weaning. The FcRn mRNA was markedly low in adult rats and
      was maximum during second week of postnatal development. Administration of
      cortisone or thyroxine to suckling rats, induced precocious decline of both IgG
      binding and the receptor expression. However, insulin administration did not
      affect the receptor expression. Scatchard analysis of IgG binding to MVM in
      cortisone injected pups revealed that the observed inhibition in IgG binding was
      a consequence of a decrease, both in the affinity constant (-Ka) as well as in
      the number of receptor sites (n) while thyroxine administration caused a
      reduction in the number of receptor sites from 2.29 in control to 1.14 nmoles/mg
      protein in thyroxine injected pups. These observations indicate that expression
      of IgG receptor during postnatal development is a hormone regulated process.

PMID- 10650728
TI  - Purification and characterisation of gelonin from seeds of Gelonium multiflorum.
AB  - Gelonin, a ribosome-inactivating protein has been isolated from the seeds of
      Gelonium multifluorum of Euphorbiaceae family by two methods and the results are
      compared. In method-I conventional aqueous extraction, cation-exchange and gel
      filtration chromatography has been used. In method-II S-Sepharose fast flow gel
      has been used to purify the proteins from the seed extract, followed by ammonium
      sulfate fractionation, cation-exchange and gel-filtration chromatography.
      Extensive physico-chemical and immunological characterizations show that
      molecular weight of gelonin as determined by gel-filtration chromatography and
      SDS-PAGE is approximately 30 kDa. The non-proteinous material which binds to CMC
      gel in association with gelonin in method-I is substantially removed when gelonin
      is purified by method-II. Cation exchange, G-100 chromatography, RP-HPLC and SDS
      PAGE show that method-II yields 50% more purified gelonin when compared to the
      yield by method-I. The immunoreactivity of gelonin obtained by methods I and II
      vary from 22-26% and 50-66% respectively and the ribosome-inactivating property
      vary from 46-56% and 70-87% respectively.

PMID- 10650729
TI  - Enterocyte mitochondrial dysfunction due to oxidative stress.
AB  - The endogenous production of H2O2 in isolated rat intestinal mitochondria and
      oxidant induced damage to mitochondria were examined. There was an appreciable
      amount of H2O2 production in presence of succinate, glutamate and pyruvate, while
      the presence of rotenone with succinate further increased production. Superoxide
      generated by the X-XO system induced membrane permeability transition (MPT),
      calcium influx, lipid peroxidation and changes in membrane fluidity in
      mitochondria. A decreased mitochondrial ATPase activity and uncoupling of
      respiration was also observed. Spermine inhibited swelling induced by X-XO and
      also blocked the calcium influx and reversed the membrane fluidity changes.

PMID- 10650731
TI  - Incremental change: the pace of progress in health.

PMID- 10650730
TI  - High and low molecular weight proteolytic activities in prawn (Metapenaeus
      brevicornis) muscle.
AB  - Muscle extract of prawn (Metapenaeus brevicornis) expressed high azocoll lytic
      activity compared to extracts of many other prawn varieties; the activity was
      also inhibited to a small extent by dithiothreitol. Ammonium sulphate
      precipitation, subsequent extraction at pH 5.6 and chromatography revealed the
      occurrence of two types of azocoll lytic activities: one, high molecular weight
      (630 kDa) and the other low molecular weight (< 30 kDa) enzyme. The former was
      stimulated by dithiothreitol whereas the latter was inhibited. SDS PAGE of high
      molecular weight preparation did not show homogeneity but the profile was similar
      to that of the low molecular weight fraction. Gel filtration of high molecular
      weight enzyme following incubation at high pH revealed the formation of low
      molecular weight fractions having activity towards azocoll. Chymotrypsin-like
      activity associated with high molecular weight enzyme was also susceptible to
      dissociation by high pH. Azocoll lytic activity of both enzymes was strongly
      inhibited by 1,10-phenanthroline.

PMID- 10650732
TI  - The relationship of parental alcoholism and family dysfunction to stress among
      college students.
AB  - The relationship between collegiate adult children of alcoholics (ACOAs) and
      adult children from dysfunctional families (ACDFs) was examined to determine
      whether ACOAs and ACDFs were at greater risk of stress than non-ACOAs and non
      ACDFs. The participants were 549 students from a midwestern university. The data
      collection instruments were the Children of Alcoholics Screening Test, 6-Item
      Version (CAST-6); the Family Adaptability and Cohesion Evaluation Scales, Version
      II (FACES-II); and the Perceived Stress Scale (PSS). A substantial proportion of
      the sample was classified as ACOA, ACDF, or both, and there was considerable
      overlap between the two groups. Both ACOA and ACDF status were found to be
      significant predictors of stress, with ACDF status being a better predictor than
      ACOA status. Possible explanations for the results and implications for
      collegiate wellness programs are discussed.

PMID- 10650733
TI  - The longitudinal effects of a rape-prevention program on fraternity men's
      attitudes, behavioral intent, and behavior.
AB  - Rape myth acceptance, likelihood of raping, and sexually coercive behavior of 145
      fraternity men randomly assigned to a control group or a rape-prevention program
      were surveyed. One third of 23 fraternities on a mid-Atlantic public university
      campus volunteered to participate in the study. The rape-prevention intervention
      consisted of "the men's program," a victim empathy-based presentation titled "How
      to help a sexual assault survivor: What men can do." Although no evidence of
      change in sexually coercive behavior was found, significant 7-month declines in
      rape myth acceptance and the likelihood of committing rape were shown among
      program participants. In the case of rape myth acceptance, the 7-month decrement
      remained lower in the participant group than in the control group. Implications
      of using these initial findings from the men's program for rape-prevention
      programming are discussed.

PMID- 10650734
TI  - Conceptualization and measurement of the spiritual and psychological dimensions
      of wellness in a college population.
AB  - Wellness is commonly conceptualized as having many dimensions, but little effort
      has been made to evaluate how spiritual and psychological dimensions are related
      to overall wellness. To explore the relationship between measures of spiritual
      and psychological wellness and perceived wellness in a college student
      population, the authors administered a series of survey instruments to 112
      undergraduate students under quiet classroom conditions. They used the Life
      Attitude Profile to measure spiritual wellness, the Life Orientation Test and the
      Sense of Coherence Scale to measure psychological wellness, and the Perceived
      Wellness Survey to measure overall wellness. Path analysis performed with a
      proposed theoretical model revealed that the effect of life purpose on perceived
      wellness was mediated by optimism and sense of coherence, which had independent
      effects on perceived wellness beyond that of life purpose. The findings suggested
      that an optimistic outlook and sense of coherence must be present for life
      purpose to enhance a sense of overall well-being.

PMID- 10650735
TI  - Predictors of exercise relapse in a college population.
AB  - Exercise improves physical and mental health. Nevertheless, most 20-year-olds do
      not exercise, and approximately 50% of the participants in exercise programs drop
      out in the first 3 to 6 months. In view of the health benefits of exercise,
      college health educators and clinicians need to be able to identify factors that
      predict exercise relapse in a student population. The authors administered
      questionnaires measuring Prochaska's 10 processes of change for exercise, self
      efficacy, and decisional balance to 52 physically active undergraduate students.
      They assessed baseline exercise levels in October and reassessed them about 8
      weeks later. At baseline, relapsers had significantly lower self-efficacy scores
      than those who maintained their exercise levels. The relapsers also had higher
      perceived negative views of exercise. These findings provide support for applying
      the transtheoretical model of behavioral change to a college population.

PMID- 10650736
TI  - Development of a health service at a rural community college in Appalachia.
AB  - The successful implementation by a large public university health service of a
      satellite clinic involves a number of processes and funding issues. The authors
      discuss the development of such a program at a small community college in
      Appalachia. The first 4 years' experience in operating the satellite clinic
      created a number of valuable management lessons that they believe could assist
      others with similar goals for extending their services.

PMID- 10650737
TI  - Tuberculosis screening for international students.
AB  - Nonimmigrant, international students entering colleges in the United States are
      not required to undergo screening for tuberculosis (TB). Thirty-nine percent of
      active TB cases in the United States are in foreign-born individuals. In an
      effort to minimize the occurrence of active TB on a community campus with an
      increasing international student population, the college health service
      implemented a TB-screening policy for all newly enrolled international students.
      For the 1997/98 school year, 171 international students from 70 different
      countries enrolled in classes. Fifty-nine students (35%) screened for TB had a
      positive skin test (greater than 10 mm induration). Of those, 34 initiated
      isoniazid therapy, and 27 successfully completed the prescribed regimen under
      supervision of the campus health office.

PMID- 10650738
TI  - Asthma care--retaining students who breathe easier.

PMID- 10650739
TI  - Some remarks on failure-times, surrogate markers, degradation, wear, and the
      quality of life.
AB  - Suppose that data are available on failure-times and on a time-evolving process
      on each individual, called in some contexts wear or degradation. Four rather
      different types of relation between such a process and failure are described and
      brief comments on appropriate analysis sketched.

PMID- 10650740
TI  - Multi-state models in epidemiology.
AB  - I first discuss the main assumptions which can be made for multi-state models:
      the time-homogeneity and semi-Markov assumptions, the problem of choice of the
      time scale, the assumption of homogeneity of the population and also assumptions
      about the way the observations are incomplete, leading to truncation and
      censoring. The influence of covariates and different durations and time-dependent
      variables are synthesized using explanatory processes, and a general additive
      model for transition intensities presented. Different inference approaches,
      including penalized likelihood, are considered. Finally three examples of
      application in epidemiology are presented and some references to other works are
      given.

PMID- 10650741
TI  - Generalized proportional hazards model based on modified partial likelihood.
AB  - The proportional hazards (Cox) model is generalized by assuming that at any
      moment the ratio of hazard rates is depending not only on values of covariates
      but also on resources used until this moment. Relations with generalized
      multiplicative, frailty and linear transformation models are considered. A
      modified partial likelihood function is proposed, and properties of the
      estimators are investigated.

PMID- 10650742
TI  - Aalen's linear model for sampled risk set data: a large sample study.
AB  - Borgan and Langholz (1997) describe a method for estimating the parameter
      functions in Aalen's linear hazard regression model from sampled risk set data.
      Using a counting process formulation and the martingale central limit theorem, we
      provide a study of the asymptotic distributional properties of the estimator. The
      results are applied to study the efficiencies of the nested case-control and
      counter-matched designs relative to a full cohort analysis.

PMID- 10650743
TI  - Parametric analysis for matched pair survival data.
AB  - Hougaard's (1986) bivariate Weibull distribution with positive stable frailties
      is applied to matched pairs survival data when either or both components of the
      pair may be censored and covariate vectors may be of arbitrary fixed length. When
      there is no censoring, we quantify the corresponding gain in Fisher information
      over a fixed-effects analysis. With the appropriate parameterization, the results
      take a simple algebraic form. An alternative marginal ("independence working
      model") approach to estimation is also considered. This method ignores the
      correlation between the two survival times in the derivation of the estimator,
      but provides a valid estimate of standard error. It is shown that when both the
      correlation between the two survival times is high, and the ratio of the within
      pair variability to the between-pair variability of the covariates is high, the
      fixed-effects analysis captures most of the information about the regression
      coefficient but the independence working model does badly. When the correlation
      is low, and/or most of the variability of the covariates occurs between pairs,
      the reverse is true. The random effects model is applied to data on skin grafts,
      and on loss of visual acuity among diabetics. In conclusion some extensions of
      the methods are indicated and they are placed in a wider context of Generalized
      Estimation Equation methodology.

PMID- 10650744
TI  - [Spanish bibliographic index of health sciences. Cooperation with Latin America].

PMID- 10650745
TI  - [Control of tuberculosis in relation to the HIV/AIDS epidemic. Work Group at the
      Secretariat of the National Plan on AIDS].
AB  - On April 7, 1999, the Monographic Meeting on HIV Infection and Tuberculosis was
      held at the Secretariat of the National AIDS Plan for the purpose of setting out
      certain clinical and health care policy recommendations concerning the control of
      tuberculosis (TB) with regard to the HIV infection epidemic, those in attendance
      being listed in Appendix 1. This meeting was organized into a number of
      presentations of papers (Appendix 2) grouped into four subject areas, which were
      followed by the pertinent debates. These four areas were as follows: 1.
      Epidemiology of the Dual HIV-TB Infection. 2. Treatments to Combat TB. 3. TB
      Prevention. 4. Health Care/TB Control Programs. The papers presented regarding a
      review of current literature focused on the search for scientific evidence with
      regard to treating and preventing TB among HIV-positive patients. The rest of the
      papers presented were: 1) regarding epidemiological topics 2) regarding results
      of different TB control programs and 3) regarding the analysis of the
      international and national recommendations concerning TB treatments and prevent
      among HIV-positive patients. Following the meeting, this report has been prepared
      as a summary thereof and was revised by all those who were in attendance at the
      meeting, the goal of which is that of setting out some recommendations for health
      care control and clinical handling of the dual Mycobacterium tuberculosis and HIV
      infection. This report provides no systematic or sufficiently detailed review of
      the different topics analyzed, therefore opting with regard to the bibliography
      to recommend a number of brief articles and reference books as a general source
      for further consultation. In this report, the term of "dual" TB-HIV infection is
      used generally and, in others the more specific "dual TB-AIDS disease", depending
      upon the presence of infection or disease caused by M. Tuberculosis and also
      AIDS, therefore, in the latter case.

PMID- 10650746
TI  - [Survival of patients with HIV-related tuberculosis. Study of mortality during
      the first 9 months of treatment].
AB  - BACKGROUND: Among the individuals with tuberculosis who are infected with HIV a
      high degree of lethality has been found to exist during the first few weeks
      following the start of tuberculosis treatment. In this study, the survival of
      these individuals is studied within the framework of a retrospective cohort
      study. METHODS: This study included 1135 subjects infected by HIV over age
      fifteen and residents of Barcelona who were registered by the Barcelona
      Tuberculosis Prevention and Control Program and were diagnoses within the 1988
      1993 period. The variables analyzed were age, gender, former imprisonment,
      municipal district, risk group, percentage of T CD4+ lymphocytes, tuberculin
      test, AIDS diagnosis (as per CDC-1987), X-ray pattern, bacteriology and part of
      the body affected by the tuberculosis. The Cox semiparametric method, the Kaplan
      Meir curves and the log-rank test were employed. RESULTS: A 77% probability of
      survival during the first nine months was found to exist, with wide-ranging
      variations among the different subgroups. The only significant variables in the
      Cos multivariate model were AIDS, the percentage of T CD4+ lymphocytes and their
      interaction. The risk of death for an individual not having AIDS and a T CD4+
      lymphocyte percentage of 14% or lower was 7.69 times higher than the risk of
      dying for an individual not having AIDS who had a T CD4+ lymphocyte percentage of
      above 14%. CONCLUSIONS: The survival of those individuals having tuberculosis who
      are infected with HIV varies greatly. Those who died in the short term were
      diagnosed as having AIDS on starting the tuberculosis treatment and who also had
      a T CD4+ lymphocyte percentage of 14% or lower.

PMID- 10650747
TI  - [Opinion of the primary care veterinarians of Andalusia concerning the management
      of their professional practice].
AB  - BACKGROUND: This study describes the opinion of the veterinarians in Andalusia
      regarding the organization and management of their professional practice and
      pinpoints solutions to the problems found for the purpose of providing planning
      and management aspects in view of the reforms undertaken in the Andalusian Health
      Service Strategy Plan. METHOD: Descriptive opinion poll employing a questionnaire
      filled out by each individual among all of the Primary Care (PC) veterinarians in
      Andalusia (including those who have been currently employed who possess at least
      one year's experience, except substitutes). A description was provided of their
      personal traits, their opinion of the management-related factors involved in
      their professional practice. A description was also provided of the suggestions
      for improving the problems found to exist. RESULTS: Over 70% said they were aware
      of the objectives, although only the coordinators found them to be clearly
      motivating the practice. Their opinion was that the indicators of activity
      neither include any quality-related criteria nor afford the possibility of
      evaluating the activity they are carrying out. They believed that the
      contributions from other members of the multidisciplinary team improve their work
      and are in favor of continuing their involvement therein. They were satisfied
      with doing their work (the coordinators to a greater degree). They found the
      productivity pay to be too low and not useful as regards providing them with any
      incentive. They were not satisfied with the training with which they are provided
      and thought that what they are offered is far less than their other colleagues in
      the health care field. Most were of the opinion that they should remain under the
      authority of the Andalusian Health Service. CONCLUSIONS: This group prefers to
      continue working for the same organization, but improving the following
      management aspects: training offer, practice incentives and activity indicators.

PMID- 10650748
TI  - [Cardiovascular reactivity and cardiovascular risk factors in normotensive
      individuals of the Municipality of Rodas Cienfuegos].
AB  - BACKGROUND: A relationship exists between different cardiovascular risk factors
      and a significant rise in blood pressure in the presence of psychological or
      physical stress (cardiovascular reactivity). We studied this relationship in
      normotensive individuals who were subjected to stress caused by isometric
      exercise, which provided us with proof of the amount of weight withstood.
      METHODS: A descriptive study was conducted in which 267 normotensive individuals
      were divided into two groups. One of these groups was a study group comprised of
      cardiovascular hyperreactive (CVHR) with a greater blood pressure response (BP)(n
      = 58), with BP levels > or = 90/140 mm/Hg, and the other group as a control
      group, with BP < 90/140 mm/Hg, n = 209. The relationship was found between the
      age, gender, sedentary life, smoking habit (SH), alcoholic beverage intake (ABI)
      and clinical history of blood pressure disorders (CH of BPD with the condition of
      cardiovascular hyperreactivity. RESULTS: 21.7% of the subjects were CVHR. The
      risk factors SH, ABI and gender were not related to the CVHR P > 0.05. The risk
      factor of CVHR is twice as high on the part of sedentary individuals, age
      becoming a factor as of age 40, and those individuals with a CH of BPD had twice
      the risk of having a cardiovascular hyperreactivity 3.85 (2: 7, 19) as those who
      had no CH of BPD). CONCLUSIONS: A significant relationship exists between being
      over age 40, CH of BPD and lack of exercise with a CVHR condition. This was not
      found to be the case for other risk factors such as SH, gender and ABI.

PMID- 10650749
TI  - [Endeavors to eradicate measles in the Americas].

PMID- 10650750
TI  - [Strategies of measles eradication in the world].

PMID- 10650751
TI  - [Molecular epidemiology of measles virus].

PMID- 10650752
TI  - [Current situation of measles in Spain. A seroepidemiological study].

PMID- 10650753
TI  - [Eradication of measles. Vaccination coverage in Spain].

PMID- 10650754
TI  - [Eradication of measles. Strategies in the Autonomous Community of Catalonia].

PMID- 10650755
TI  - [Eradication of measles. Strategies of the Autonomous Community of Galicia].

PMID- 10650756
TI  - [Eradication of measles. Diagnostic strategies in Spain].

PMID- 10650758
TI  - [Medical losses of the Soviet troops during the war in Afghanistan (1)].
AB  - The first comprehensive review of the sanitary losses of the Soviet troops in
      Afghanistan given in detail with the analysis of its formation on the basis of
      the military situation development and on the nature of combat actions evolution.
      The article is based on the archives of the General Staff of the RF Armed Forces
      and its Medical Service together with the Department of Defense and the 40th Army
      documents.

PMID- 10650757
TI  - [Eradication of measles. Synthesis outline].

PMID- 10650759
TI  - [The automation of the management of the blood service].

PMID- 10650760
TI  - [Combat and special training in a consultative diagnostic center (polyclinic)].

PMID- 10650761
TI  - [The evaluation of the grounds for the hospitalization of surgical patients].
AB  - An analysis of in-patients' flow in the surgery sections of main military
      clinical hospitals shows that according to the experts' assessment, 89.3%
      patients were accommodated according to the profile of their illness. 5% patients
      needed accommodation in other sections (not surgical) and 5.7% should have been
      treated as out-patients in a military sanatorium (so called unreasonable
      hospitalization). Trauma sections were most often overloaded with patients that
      should be placed somewhere else (3.1%) but in the sections of purulent vascular
      and cavity surgery the number of misplaced patients was almost 10 times less-
      0.3%, 0.4%, 1.9% respectively. Elder people represent the majority of
      unreasonably hospitalized patients.

PMID- 10650762
TI  - [The mental health of children whose fathers suffer from alcoholism].

PMID- 10650763
TI  - [Anesthesiological and resuscitation care for the wounded in an armed conflict
      (2)].

PMID- 10650764
TI  - [Extremely high-frequency radiation and autologous hemotherapy in the treatment
      of odontogenic infections].

PMID- 10650765
TI  - [Skin lesions in lymphogranulomatosis].
AB  - 66 LGM patients' examination review with only one of them with specific skin
      lesion. Non-specific skin lesion number exceeded the total of patients since
      there were diverse changes in the same man. It is useful to distinguish the
      following LGM lesion cases of autotoxic origin--resulting after hematopoietic
      function disorders and those of hemostasis' chains' derivations, stipulated by
      medical treatment (corticosteroid hormones cytostatics and radiotherapy). Very
      often LGM reveals itself by autotoxic genesis skin lesion. The knowledge of these
      clinical signs helps to recognize and diagnose Hodgkin disease. There were no
      interaction between skin lesion and a specific histological type of LGM.

PMID- 10650766
TI  - [The use of xidifon in the combined therapy of neurogenic pain syndromes].

PMID- 10650767
TI  - [The new antipsychotic preparation Rispolept (risperidone)].

PMID- 10650768
TI  - [The use of air-plasma flow in the treatment of mine-blast injuries].

PMID- 10650769
TI  - [The assessment of the immune status of women exposed to the action of radiation
      and chemical factors].
AB  - Some results of a complex medical study of Chernobyl disaster liquidators and its
      contaminated catchment areas population. The immunity status of 279 women had
      been analyzed as compared to that of control groups of 92 women, living in
      similar conditions. It was found out, that long after the disaster factors'
      disappearance, in the women's immunity system a derangement has been noticed in
      the form of T-lymphocyte increased content and a suppressed functional activity
      of immune-competent cells, which should be born in mind at the regular medical
      check-ups. Long-time and low-intensive radiation usually resulted in cell and
      humoral immunity disorders. That in combination with chemical factors lead to a
      secondary immunodeficiency state development with a following pharmacological
      correction necessity (by cytokines).

PMID- 10650770
TI  - [The PU-1B device for sampling biological aerosols].

PMID- 10650771
TI  - [The order on performing military service. Interview by M. A. Velichko].

PMID- 10650772
TI  - [The development of organized forms of aviation medical evacuation].

PMID- 10650773
TI  - Provider tax must finally be removed.

PMID- 10650774
TI  - Fibula free flap reconstruction of composite oromandibular defects.
AB  - The surgical treatment of advanced oral cavity cancer presents a difficult
      reconstructive challenge since tumor resection can result in "through and
      through" bone and soft tissue defects. Reconstruction is essential for an
      acceptable aesthetic outcome, as well as functional oromandibular rehabilitation.
      The advent of microvascular free tissue transfer now allows immediate
      reconstruction of these large composite resections, and offers significant
      advantages over more traditional techniques. Success rates approach 90%-95% at
      most large centers. In this article, we describe the challenging decisions faced
      by clinicians treating these patients, and discuss our reconstructive method of
      choice, the fibula osteomyocutaneous free flap.

PMID- 10650775
TI  - Imperforate anus: an unusual presentation of a common disease.
AB  - Imperforate anus is a common problem facing the pediatric surgeon. Most cases of
      imperforate anus are discovered at birth during the initial physical examination
      and are corrected early. The pediatric population also accounts for 80% of all
      cases of ingested foreign bodies. Most of these pass through spontaneously and
      the treatment is observation. In this article, we present the case of a seven
      month-old child in whom failure to pass a swallowed coin led to the diagnosis of
      imperforate anus. This case illustrates an uncommon presentation of a common
      disorder and emphasizes the importance of vigilance and careful physical
      examination in the newborn.

PMID- 10650776
TI  - Diagnosis of pulmonary embolus by spiral CT: a case study.
AB  - A thirty-eight-year old immunosuppressed woman presented with respiratory
      distress and was diagnosed with Pneumocystis Carinii Pneumonia. Pulmonary
      embolism was also suspected on clinical grounds. A Ventilation-Perfusion Scan was
      indeterminate. Contrast-enhanced spiral computed tomography of the chest
      confirmed the presence of a central pulmonary embolus and helped to avoid
      pulmonary angiography in this critically ill patient.

PMID- 10650777
TI  - Clinicopathological and prognostic significance of thymidine phosphorylase
      expression in gastric carcinoma.
AB  - Tumor growth depends on angiogenesis. Thymidine phosphorylase (dThdPase) is
      identical to platelet-derived endothelial cell growth factor (PD-ECGF), and has
      angiogenic activity. We investigated the expression of dThdPase in 116 gastric
      carcinoma tissue samples by immunohistochemical staining, and assessed whether
      its expression was correlated with clinicopathological factors or with the
      prognosis. dThdPase expression was correlated with clinicopathological factors
      and may be a good prognostic indicator for gastric carcinoma. To determine
      whether dThdPase expression was a prognostic factor that was independent of the
      depth of invasion or lymph node metastasis, we conducted a survival analysis
      using Cox's proportional hazard model. This analysis revealed that dThdPase
      expression was the most significant prognostic indicator and was useful for
      predicting the outcome of gastric carcinoma.

PMID- 10650778
TI  - Alpha-fetoprotein producing Barrett's esophageal adenocarcinoma: a case report.
AB  - A 59-year-old man was admitted to our hospital with upper abdominal pain. His
      serum alpha-fetoprotein (AFP) level was very high, 1500 ng/ml. Upper
      gastrointestinal endoscopy revealed depressed lesion at 36 cm from the upper
      incisors, with columnar epithelium lining the esophagus circumferentially to the
      oral side of the lesion. Histological examination of biopsy specimens revealed a
      tubular adenocarcinoma as well as the presence of gastric columnar epithelium
      with intestinal metaplasia. Immunohistochemistry demonstrated AFP in the tumor
      cells. From these results, a diagnosis of AFP-producing esophageal adenocarcinoma
      occurring in Barrett's esophagus, a condition which is extremely rare in Japan,
      was established. Computed tomography (CT) showed multiple metastasis on the liver
      and wide-ranging lymph node metastasis. Chemotherapy was not effective and the
      patient died about 2 months after the start of treatment. The AFP-producing
      esophageal adenocarcinoma presented here had biological characteristics similar
      to those of AFP-producing gastric cancer.

PMID- 10650779
TI  - Stromal thrombospondin-1 expression is correlated with progression of esophageal
      squamous cell carcinomas.
AB  - Thrombospondin-1 (TSP1) is an extracellular matrix glycoproteins that affecting
      cell adhesion, motility and growth. Based on its effects on tumors, TSP1 is
      thought to be a potential regulator of tumor growth and metastasis. In this
      study, we clarified TSP1 immunoreactivity in human esophageal squamous cell
      carcinoma and its clinicopathological significance. TSP1 immunoreactivity was
      detected mainly in the cancer stroma and was observed infrequently in cancer
      cells. According to the TNM classification, 70.6% (12/17) of the T3 esophageal
      cancers were TSP1-positive, while only 26.9% (7/26) of the Tis and T1 cancers
      showed TSP1 expression. Lymph node metastasis and venous involvement was
      frequently found in the TSP1-positive cases (71.4% and 80.0%, respectively) of
      esophageal squamous cell carcinoma (p < 0.001). This observation suggested that
      TSP1 expression plays an important role in cancer cell growth and metastasis of
      human esophageal squamous cell carcinomas, and that stromal TSP1 immunoreactivity
      is a good predictor of venous involvement and lymph node metastasis.

PMID- 10650780
TI  - Phase II and III studies with new drugs for non-small cell lung cancer: a
      systematic review of the literature with a methodology quality assessment.
AB  - We carried out a systematic review of new drugs active in non-small cell lung
      carcinoma (NSCLC). Fifty five phase II and III trials were reviewed (vinorelbine
      (19 trials), paclitaxel (15), gemcitabine (11), docetaxel (6), topotecan (2) or
      irinotecan (2)). The first four ones could be considered as active drugs when
      given as single agent. More information is required for the camptothecin
      derivatives. Four phase III randomised studies were available, all concerning
      vinorelbine. They showed that in combination with cisplatin, vinorelbine improved
      the response rate and perhaps survival, in comparison to vinorelbine alone and
      that vinorelbine was better than 5 fluorouracil and vindesine. A quantitative
      overview was impracticable, because of too few randomised trials. A qualitative
      overview was carried out using the European Lung Cancer Working Party score. The
      overall median quality score was 65.3%. There was no statistically significant
      difference between the drugs, but there was a positive correlation between the
      score and the number of patients. There was also an improvement of the quality
      score in favour of the randomised trials. Some important methodological aspects
      were often missing in the articles. In conclusion, gemcitabine, vinorelbine,
      paclitaxel and docetaxel are active against NSCLC but more good-quality data are
      required to define their exact role in the routine.

PMID- 10650781
TI  - Immunohistochemical detection of matrix metalloproteinases (MMP) 1 and 2, and
      tissue inhibitor of metalloproteinase 2 (TIMP 2) in stage IB cervical cancer.
AB  - OBJECTIVE: Matrix metalloproteinases (MMPs) are a family of zinc-dependent
      metalloendopeptidases which participate in the degradation of collagen and other
      extracellular matrix macromolecules. Expression of gelatonic MMPs, such as MMP-2
      has been linked to enhanced tumor invasion and metastases in in vitro and in vivo
      model systems. It was the aim of this study to determine whether the expression
      of MMP-1, MMP-2, and TIMP-2 correlates with survival in patients with surgically
      treated cervical cancer stage IB. METHODS: A sample of 154 paraffin-embedded
      tumor specimens of surgical treated FIGO stage IB cervical cancer was
      immunohistochemically investigated. RESULTS: MMP-1, MMP-2, and TIMP-2 were
      detected by immunohistochemistry in 74% (113/154), 32% (49/154), and 80%
      (107/154) of the tumor samples, respectively. Correlation coefficients for MMP
      1/MMP-2, MMP-1/TIMP-2, MMP-2/TIMP-2 were 0.14 (p = 0.12), 0.37 (p = 0.0001), and
      0.17 (p: 0.005), respectively. A significant correlation was found between MMP-1
      and lymph node status (P < 0.01) and lymphvascular space invasion (P < 0.05). The
      expression of MMP-1 (log-rank test, p = 0.6), MMP-2 (log-rank test, p = 0.8), and
      TIMP-2 (log-rank test, p = 0.15) were not correlated with overall survival.
      CONCLUSION: MMP-1, detected by immunohistochemistry, seems to play a role in the
      development of lymphvascular space invasion and lymph node metastases, but is not
      helpful in predicting the prognosis of cervical cancer patients.

PMID- 10650782
TI  - Gelatinase A and B (MMP-2, MMP-9) in leukaemia MMP-2 may indicate a good
      prognosis in AML.
AB  - We studied the expression of gelatinase-A (MMP-2) and gelatinase-B (MMP-9) in
      bone marrow aspirates from 54 patients with leukaemia. Specific staining patterns
      for different leukaemia subtypes are described. Most intresting were findings in
      acute myeloid leukaemia (AML), where MMP-2 staining correlated strongly with
      prognosis. Three year event-free survival after conventional treatment for
      patients with MMP-2 positive blast cells was 82%, while all the conventionally
      treated patients with MMP-2 negative blasts relapsed within 13.5 months. After
      treatment with allogeneic bone marrow transplantation, 3-year event-free
      survivals were 100% and 80% for MMP-2 positive and negative patients
      respectively.

PMID- 10650783
TI  - Expression patterns of the novel catenin p120cas in gastrointestinal cancers.
AB  - p120cas is involved in signal transduction upon src or growth factor stimulation
      as well as in E-cadherin mediated cell adhesion and may play an important role in
      carcinogenesis. In this study, we evaluated immunohistochemically the expression
      and cellular localization of p120cas in 40 gastric, 43 colorectal and 20
      pancreatic carcinomas, and examined the relationship between p120cas expression
      and pathological features. Altered p120cas expression was observed in 70%, 65%
      and 60% of gastric, colorectal and pancreatic cancers, respectively. The most
      common abnormality was of cytoplasmic expression associated with loss of
      membranous distribution found in 37% of gastric, in 25% of colorectal and in 25%
      of pancreatic cancers. Heterogeneous staining was noted in 15%, 19% and 20%, and
      complete loss of expression in 18%, 21% and 15% of gastric, colorectal and
      pancreatic cancers, respectively. There was no correlation between p120cas
      staining pattern and tumour grade or stage. Aberrant expression of p120cas which
      may reflect changes in signal transduction pathways occurs frequently in human
      malignancies.

PMID- 10650785
TI  - Multidrug resistant malignant melanoma with intracranial metastasis responding to
      immunotherapy.
AB  - Metastatic malignant melanoma (MM) is well known for its poor response to
      chemotherapy, radiotherapy, and its remarkable susceptibility to interleukin-2
      (IL-2) based immunotherapies. MM with brain metastatis in particular, has 4-5
      months life expectancy from metastasis to death. Drug efflux pumps such as P
      glycoprotein (P-gp), or drug detoxifying mechanisms e.g. glutathion epsilon S
      transferase-pi (GST) are some of the possible multidrug resistance (MDR)
      mechanisms in MM. Here we report the first P-gp+ MDR MM with brain metastasis in
      the literature, demonstrating a remarkable response to IL-2, interferon-alpha
      (IFN), 5-fluorouracil (5FU) regimen. A 41-year old man was admitted with multiple
      inoperable brain lesions. Biopsies from intracranial and dermal lesions revealed
      MM. Cisplatin, carmustine, dacarbazine, tamoxifen (CCDT) together with external
      cranial radiotherapy were administered, and partial response in lesions and
      symptoms was achieved. However, after the third course of CCDT treatment, he was
      admitted to the emergency ward with dramatically increased intracranial lesions,
      and recurring dermal lesions. A biopsy from the recurred lesions revealed that MM
      cells were P-gp+, but GST. Administration of a IL-2, IFN and 5FU regimen achieved
      a remarkable decline in the brain lesions with almost total disappearance of
      symptoms. He was well and capable of doing work for 18 months. Dermal lesions had
      not recurred since the beginning of immunotherapy. In contrast, another 34-year
      old man who developed brain metastases after CCDT for MM, was negative for P-gp
      and GST. Cranial radiotherapy was started and the above mentioned IL-2 based
      regimen was administered. However, no response was observed. These two cases
      together with previous studies demonstrating the susceptibility of P-gp+ MDR
      cancer cell lines to IL-2 activated killer (LAK) cells in this report suggest
      that P-gp+ MDR MM is probably a good candidate for IL-2 based treatments.

PMID- 10650784
TI  - p27 expression correlates with prognosis in patients with hypopharyngeal cancer.
AB  - BACKGROUND: Hypopharyngeal cancer is closely associated with smoking, drinking,
      and malnutrition. Recent findings reveal that carcinogenesis depends on genetic
      aberrations. MATERIALS AND METHODS: Eighty-one patients with hypopharyngeal
      cancer were analyzed for p53, CCND1, and p27, and 72 patients were analyzed for
      p21, immunohistochemically. RESULTS: p53 overexpression was found in 70%, CCND1
      in 17%, p21 in 29%, and p27 in 32%. The low intensity of p27 expression
      correlated with poor prognosis, but the level of expression of p53, CCND1, and
      p21 did not. CONCLUSION: The immunohistochemical analysis of p27 provides a
      possible tool in determining the prognosis of patients with hypopharyngeal
      cancer.

PMID- 10650786
TI  - Clinicopathological significance of the expression of CD44v2 in colorectal
      cancer.
AB  - Expression of CD44 variant isoforms has been reported to be correlated with
      faster progression of neoplastic diseases, metastasis and reduced survival
      period. In this study, the correlation between the expression of CD44v2 (v2) or
      CD44v6 (v6) and clinicopathological features was examined in Dukes B and C
      colorectal cancer using immunohistochemistry. V6 expression was not correlated
      with any clinicopathological indices or prognosis in either Dukes B or C. On the
      other hand, v2 expression was correlated significantly with recurrence rate and
      poorer prognosis in Dukes B colorectal cancer although there was no correlation
      between v2 expression and prognosis in Dukes C patients. The results suggest that
      v2 is a candidate for a prognostic marker in Dukes B colorectal cancer. CD44v2
      expression may be an indication for adopting adjuvant chemotherapy in patients
      without lymph node metastasis.

PMID- 10650787
TI  - Acute hematologic feasibility of G-CSF supported dose-escalated FEC therapy as
      adjuvant treatment after breast cancer surgery.
AB  - A study of the feasibility of gradually increased epirubicin and cyclophosphamide
      dosage in an FEC regimen with G-CSF (granulocyte colony stimulating factor)
      support in 18 high-risk breast cancer patients as adjuvant treatment was carried
      out. The FEC regimen was initiated with 5-fluorouracil 600 mg/m2, epirubicin 75
      mg/m2 and cyclophosphamide 900 mg/m2 together with G-CSF 5 micrograms/kg
      subcutaneously on days 2-15 q 3 weeks for nine cycles, increasing individually
      through four dose levels to a maximum of 5-FU 600 mg/m2 (not escalated),
      epirubicin 120 mg/m2 and cyclophosphamide 1800 mg/m2. Transient cytopenias were
      regularly observed without major clinical complications. Rapid recovery and a
      biphasic overshoot of granulocytes required individualization of G-CSF support.
      During the 6-month treatment period, a general decline in granulocytes, platelets
      and haemoglobin was observed, resulting in maximal dose intensity in the middle
      of the treatment period. Compared to a conventional FEC regimen (5-Fluorouracil
      600 mg/m2, Epirubicin 60 mg/m2, Cyclophosphamide 600 mg/m2 q 3 w) without dose
      reductions, it was feasible to increase the dose of epirubicin by more than 50
      per cent with an increased dose intensity between 25 and 70 per cent. The dose of
      cyclophosphamide was increased by more than 100 per cent. All patients suffered
      from complete alopecia and moderate nausea, but there was no acute cardiac or
      severe mucosal toxicity. It was concluded that intensified, G-CSF supported FEC
      therapy can be safely administered in an outpatient setting, provided the
      patients are thoroughly informed and adequately monitored. High-risk patients are
      enrolled in a study comparing the described regimen and a myeloablative regimen
      including peripheral stem-cell support. Breast cancer seems to respond to
      chemotherapy in a dose dependent manner, suggesting the use of dose intensified
      regimens (1,8,9,11). This approach is currently under investigation in studies
      comparing standard regimens with myelo-ablative regimens in high-risk primary
      breast cancer (3,10). In a Scandinavian multicenter study (2), two high dose
      regimens, G-CSF supported dose-escalated FEC and myeloablative cyclophosphamide
      thiotepacarboplatin with peripheral stem cell support, are compared as adjuvant
      therapy in operable high-risk breast cancer. This phase I study was performed to
      assess the feasibility and achievable dose intensity of an individually dose
      escalated FEC regimen not in previous use.

PMID- 10650788
TI  - A new "anonymous" type of haemangioendothelioma.
AB  - BACKGROUND: Our report may contribute to a better understanding of the different
      possible presentations of endothelial tumors. METHODS AND RESULTS: We report a
      new type of haemangioendotheliomatous tumor of uncertain aggressiveness arisen in
      a benign haemangioma of the scalp and represented by a proliferation of small-
      and medium-sized arborescent vessels whose walls were totally replaced by
      endothelial-like, atypical cells. CONCLUSIONS: The features of our case do not
      fit those of the many types previously reported in the literature. As regards the
      name, we prefer to consider this new variety as an anonymous type in order to
      avoid further confusion on a topic deserving a drastic review.

PMID- 10650789
TI  - Fentanyl patches for the treatment of pain in dying cancer patients.
AB  - It has been claimed that fentanyl patches are less suitable for elderly patients
      and for patients who are terminally ill and dying. In a retrospective survey of
      205 cancer patients who died within the hospital-based home care in Norrkoping,
      Sweden between January 1997 and June 1998 we identified 34 patients who had used
      fentanyl patches. 30 patients were possible to evaluate for the analgesic
      efficacy of transdermal fentanyl. 18 out of 30 patients were treated with
      fentanyl until time of death. The estimated efficacy was good or moderate in 93%
      and 88%, respectively, of patients younger or older than 65 years of age.

PMID- 10650790
TI  - Detection of treated liver metastases using fluorine-18-fluordeoxyglucose (FDG)
      and positron emission tomography (PET).
AB  - The aim of the study was the evaluation of the detectability of treated liver
      metastases using one FDG-PET measurement. The study includes 42 patients (80
      lesions) from different primary tumours. Standardized Uptake Values (SUV) as well
      as the tumour to liver Ratio (T/L) were used for evaluation. A T/L > 1.0 was
      considered to be pathological. Clinical follow-up data for at least 6 months were
      used as a reference. The median value of the FDG-uptake was 2.9 SUV in all liver
      metastases. The sensitivity based on a T/L ratio exceeding 1.0 was 82.5% (66/80
      lesions). 25 of 80 (31%) lesions had a ratio T/L higher than 2.0 and were clearly
      visualized by PET. Negative results with a ratio T/L < 1.0 were raised in 14 of
      80 treated metastatic lesions (17.5%). Although these metastases were
      hypometabolic, they were correctly classified due to the image correlation with
      computed tomography (CT) or magnetic resonance (MR) images or due to a baseline
      FDG-study prior to the onset of therapy. False positive results were not noted in
      this study. FDG-PET is a reliable method for the evaluation of treated liver
      metastases. A baseline FDG study prior to therapy is preferable for the
      interpretation.

PMID- 10650791
TI  - Two cases of secondary angiosarcoma arising from fibrous dysplasia.
AB  - Angiosarcoma associated with fibrous dysplasia is very rare. We have recently
      experienced two cases of angiosarcoma that secondarily arose from fibrous
      dysplasia. The first patient, a 55 year-old man, had noticed a deformity in the
      right upper arm since he was five years old. At the age of 25 years, polyostotic
      fibrous dysplasia was diagnosed by X-ray examination. The patient complained of
      swelling and pain around the left shoulder. The diaphysis of the humerus was
      mostly non-observable due to severe bone destruction by tumor invasion and there
      was a large soft tissue tumor. Biopsy examination revealed grade II or III
      hemangioendothelioma with typical histologic findings of fibrous dysplasia. After
      interscapulothoracic amputation for wide tumor resection, he died of DIC. Autopsy
      revealed multiple liver metastatic lesions of angiosarcoma. The second patient
      was a 66-year-old woman. She presented with a pathological fracture in the right
      tibia, due to an osteolytic lesion with cortical bone swelling and thinning. The
      histologic diagnosis was fibrous dysplasia without any sarcomatous changes.
      However, after a 3-time recurrence, angiosarcoma arose from the same lesion. She
      is now still alive with disease-free period of 6.5 years after amputation.

PMID- 10650792
TI  - Oncological and functional results by horizontal glottectomy in laryngeal
      carcinomas.
AB  - BACKGROUND: The aim of this study is to describe the indications, surgical
      technique and results of horizontal glottectomy in laryngeal carcinomas.
      MATERIALS AND METHODS: Twenty patients suffering from differentiated glottal
      carcinoma (15 T1b and 5 T1a) were treated between 1985 and 1994. A classic
      horizontal glottectomy, with some modifications, not extended to the ventricular
      fold or to the arytenoid, was performed in every patient. All patients followed a
      postoperative rehabilitative program. Time of feeding tube removal, decannulation
      and voice production were considered. RESULTS: No local recurrence was recorded
      in any of the patients, however follow up on 4 cases was only three years. No
      postoperative radiotherapy was used. Two patients died from cardiovascular
      causes. Post-operative average times were: discharge from hospital after 10.5
      days; feeding tube removal after 7 days; decannulation after 9.5 days. No major
      pulmonary complications nor laryngeal stenosis following surgery was recorded. In
      all patients adequate voice production was achieved. CONCLUSIONS: Our results
      show that horizontal glottectomy is a safe procedure in the treatment of
      laryngeal cancer. Local control of disease, provided case selection is very
      accurate, can reach 100%. Rapid and excellent laryngeal function may thus be
      obtained and the voice production is adequate in every patient.

PMID- 10650793
TI  - Concurrent chemoradiotherapy for locally advanced esophageal cancer--a pilot
      study by using daily low-dose cisplatin and continuous infusion of 5
      fluorouracil.
AB  - BACKGROUND: Concurrent chemoradiotherapy (CCRT) has recently become a promising
      treatment for esophageal cancer. However, most investigators have adopted the
      conventional or modified Wayne-State PF (cisplatin plus 5-fluorouracil) regimen,
      which is inevitably associated with moderate to severe treatment-related
      toxicities. In this pilot study, we incorporated a daily low-dose regimen of
      cisplatin and 5-fluorouracil into CCRT in order to improve the compliance of the
      patients. PATIENTS AND METHODS: Between July 1993 and Dec. 1997, 25 patients with
      locally advanced esophageal cancer (T3, or N1 disease), received CCRT which
      consisted of daily low-dose cisplatin (6 mg/m2/day) and continuous infusion of 5
      FU (225 mg/m2/day) with radiotherapy (fraction size = 200-250 cGy/day). Except
      for the initial 9 patients, for whom post-CCRT esophagectomy was compulsory, all
      subsequent patients underwent esophagectomy only when inadequate response to CCRT
      was noted. The scheduled radiation dose was 50 Gy for the first 9 patients, and
      60 Gy for the rest of the patients. RESULTS: Eighteen patients (72%) completed
      the CCRT without interruption. Clinically, there were 8 CR and 9 PR, with a total
      response rate of 68% (47-87%, 95% C.I.). All patients were evaluable for
      toxicity. Grade 3/4 leukopenia and thrombo-cytopenia developed in 14 (56%) and 7
      (28%) patients, respectively. Grade 3/4 non-hematologic toxicity was seen in 4
      (16%) patients. The median survival of the whole group was 8 months (range: 2
      59+). The projected 3-year overall survival was 24%. CONCLUSION: We suggest that
      for locally advanced esophageal cancer CCRT with the aforementioned daily low
      dose regimen, is a treatment with good patient compliance.

PMID- 10650794
TI  - Epidermal growth factor receptor expression has no independent prognostic
      significance in advanced ovarian cancer.
AB  - BACKGROUND: This study was undertaken to evaluate whether overexpression of
      epidermal growth factor receptor (EGFR) was of possible prognostic and/or
      predictive significance in advanced ovarian cancer. STUDY DESIGN: Tumor specimens
      from 185 patients with stage III ovarian cancer, treated at the Department of
      Gynecologic Oncology of the Norwegian Radium Hospital, were examined
      immunohistochemically for overexpression of EGFR. Response was verified with
      second look laparotomy in 149 patients after 4 courses of platinum/anthracyclin
      chemotherapy. Correlations between EGFR status and classical clinicopathological
      parameters were examined, and uni- and multivariate survival analysis was
      performed. RESULTS: EGFR membrane immunostaining was observed in 22% of the
      cases. EGFR overexpression correlated positively with residual disease after
      first surgery (P = 0.048) and tended to correlate with increasing FIGO substage
      (P = 0.058). No correlation was found with response to chemotherapy. In
      univariate analysis age below the median, FIGO substage, residual disease,
      histology, differentiation grade and the presence of ascites correlated with
      disease-related survival. A tendency towards correlation was found for EGFR (P =
      0.0669). In muitivariate analysis only residual disease, histological type,
      differentiation grade and the presence of ascites retained independent prognostic
      significance. CONCLUSION: EGFR status was found to be of no independent
      prognostic or predictive significance in this large group of uniformly treated
      stage III ovarian cancer patients.

PMID- 10650795
TI  - Lung function and serum concentration of tumor necrosis factor-alpha, interleukin
      6 and fibronectin in patients treated with ABVD chemotherapy followed by
      radiotherapy for mediastinal Hodgkin's disease.
AB  - Mediastinal radiotherapy and polychemotherapy regimens can produce late toxicity
      leading to pulmonary fibrosis. There is evidence for the involvement of various
      cytokines in this process. We evaluated lung function in 20 patients with stage I
      IIA Hodgkin's disease and submitted to chemotherapy including bleomycin (ABVD)
      and radiotherapy. Lung function tests were performed before, at the end of
      treatment and after a median of 12 months from the end of therapy. Tumor necrosis
      factor-alpha (TNF-alpha), fibronectin and interleukin-6 (IL-6) were determined on
      serum samples collected at the same time intervals. A modification of tests
      indicative of a restrictive lung disease was observed at end of treatment,
      whereas a persistent decline of transfer lung factor for carbon monoxide (DLCO)
      was documented. TNF-alpha constantly decreased, fibronectin increased and IL-6
      showed a decline after treatment and a rise during the follow-up but the
      differences were not statistically significant. No significant correlations were
      observed between changes of lung function tests and serum cytokine concentration.
      CONCLUSIONS: This lack of correlation could be due to: a) incorrect selection of
      serum collection time, or b) to the fact that cytokine plasma concentration does
      not reflect events occurring in the alveolar phase.

PMID- 10650796
TI  - Preoperative high type I collagen degradation marker ICTP reflects advanced
      breast cancer.
AB  - Type I collagen synthesis (PINP, PICP) and degradation (ICTP) markers were
      analysed from preoperative serum samples of 138 women with breast cancer (BC), 94
      women with benign breast disease (BBD) and 100 healthy controls to evaluate the
      levels of these markers and the stage of BC at the time of diagnosis. We also
      compared the clinical utility of these markers in detecting BC with CA15-3 and
      CEA. The mean value of ICTP was statistically significantly elevated in the BC
      group (p < 0.001), as compared with the control group, but the elevated values in
      BC group were due to stage IV disease. The sensitivity of ICTP in detecting BC
      was 0.23, which was equal with CA15-3(0.24) or CEA(0.23). The sensitivity of both
      PICP and PINP for diagnosing BC was poor, but a tendency to higher serum levels
      of PINP and low PICP/PINP ratio was detected in patients with advanced stage IV
      disease. These results indicate that high preoperative serum levels of ICTP are
      associated with advanced BC, but like CA15-3 and CEA, its clinical value in
      diagnosing purpose is poor.

PMID- 10650797
TI  - Long-term follow-up study in breast cancer patients using serum tumor markers CEA
      and CA 15-3.
AB  - The aim of this study was to evaluate CEA and CA 15-3 changes in patients
      surgically treated for breast cancer. One hundred and three women (median age 59
      years, range 31-83 years) with pT1-2, pN0-1, M0 breast cancer were followed up
      for at least 5 years. CEA and CA 15-3 serum levels were measured before operation
      and every 6 months during follow-up. The diagnostic sensitivity of CEA and CA 15
      3 was 22.3% and 33.3% respectively. There was a significant difference (p < 0.01)
      between pre- and post-operative (6 months and 5 years after surgery) mean CEA
      serum levels independent of TNM staging. During follow-up, 21 (20.4%) patients
      showed recurrence of cancer and overall CEA and CA 15-3 sensitivity was 38.1% and
      61.1%, with 98.8% and 91.2% specificity, respectively. Tumor marker measurement
      may be useful in post-surgical follow-up, but at present they are neither
      sensitive nor specific enough for early diagnosis of malignancy.

PMID- 10650798
TI  - Malignant Leydig cell tumor of the testis associated with Klinefelter's syndrome.
AB  - We reported the case of a 35-year-old man with Klinefelter's syndrome and a
      malignant Leydig cell tumor of the testis. Bilateral gynecomastia and right
      testicular enlargement led the patient to seek medical assistance. Despite
      initial orchidectomy two years later the patient developed lung and iliac lymph
      node metastases. The tumor appeared to be refractory to chemotherapy and to
      hormonal treatments including op'DDD. Finally, the patient died within 20 months
      of developing metastases. Leydig cell tumor is an exceedingly rare tumor,
      especially when associated with Klinefelter's syndrome. This association as well
      as presentation, pathologic features, hormonal abnormalities, clinical course and
      response to therapy of malignant Leydig cell tumors are discussed.

PMID- 10650799
TI  - Reproductive and infectious risk factors for invasive cervical cancer in Taiwan.
AB  - A community-based case-control study was carried out to assess multiple risk
      factors for invasive cervical cancer in Taiwan. All of 183 cases of
      pathologically confirmed cervical cancer cases and 293 healthy neighborhood
      controls were recruited from Taipei metropolitus. Healthy controls were matched
      with cervical cancer cases for age and residence. Multiple risk factors for
      cervical cancer were obtained from study subjects through standardized interviews
      according to a structured questionnaire. Serotiters of antibodies to Chlamydia
      trachomatis (CLT), human cytomegalovirus (HCMV) and human herpes simplex virus
      type 2 (HSV-2) were determined by enzyme-linked immunosorbent assay. Multiple
      logistic regression analysis were used to derive maximum likelihood estimates of
      multivariate-adjusted odds ratios (AOR) and confidence intervals (CI). After
      adjustment for potential risk factors, parity and number of vaginal delivery were
      associated with an increased risk of invasive cervical cancer. The higher the
      number of vaginal delivery, the higher the risk of developing cervical cancer
      (AOR = 6.2, 95% CI = 1.7-22.6 for 7 or more deliveries compared with 0-2
      deliveries as the referent group). Increased cervical cancer risk was also
      significantly associated with the history of chronic cervicitis (AOR = 2.1, 95%
      CI = 1.1-3.8) and elevated serotiters of CLT (AOR = 7.0, 95% CI = 1.7-28.9), HCMV
      (AOR = 4.1, 95% CI = 1.5-11.3) and HSV-2 (AOR = 2.3, 95% CI = 1.1-4.6). The use
      of diaphragm for contraception was found to be associated with a decreased risk
      of cervical cancer (AOR = 0.4, 95% CI = 0.1-1.0).

PMID- 10650800
TI  - Carcinoma of the ampulla of Vater in Crete. A clinical and ERCP registry over
      eight years.
AB  - BACKGROUND: Carcinoma of the ampulla of Vater is an infrequent tumor that can be
      diagnosed, early. PATIENTS AND METHODS: Twenty-four patients with histologically
      proven carcinoma of the ampulla of Vater were retrospectively studied and their
      data were analyzed. RESULTS: Most common presenting symptoms were jaundice (67%),
      weight loss (58%), fever and pain (54%). Endoscopic biopsies which were taken in
      19 patients revealed carcinoma or dysplasia in 15 patients and were normal for in
      the rest. Twelve patients were treated with a Whipple's resection, 5 with local
      resection, 2 with palliative surgery and 2 received a stent endoscopically.
      During a mean follow-up period of 25 months, (range 1-82) 12 deaths were noted,
      and one patient was lost during follow-up. CONCLUSIONS: Presenting symptoms,
      endoscopic and histological findings were similar as in other series. The
      contribution of duodenoscopy, ERCP and endoscopic biopsy is essential for
      diagnosis but endoscopic biopsies may be misleading.

PMID- 10650801
TI  - Management of small cell lung cancer in elderly.
AB  - BACKGROUND: There is increasing interest in the treatment of elderly small cell
      lung cancer (SCLC) patients, however the patients enrolled in clinical studies
      are strictly selected elderlies. MATERIALS AND METHODS: We retrospectively
      reviewed the treatment of consecutive unselected patients more than 70 years of
      age in whom SCLC were diagnosed over the past 22 years. RESULTS: In patients who
      received cisplatin-containing chemotherapy, response rate(RR) and mean survival
      time(MST) were 53.8% and 9 months. Whereas, in patients who were treated with
      carboplatin-containing chemotherapy, RR and MST were 72.0% and 7 months. The
      latter group included the patients whose doses of carboplatinum was reduced 20 to
      50% in the first course of treatment. There was no difference found in RR,
      survival, and incidence of toxicity between these chemotherapy groups.
      CONCLUSION: Our results showed that in elderly SCLC patients, carboplatin could
      be substituted for cisplatin without apparent loss of therapeutic efficacy.

PMID- 10650802
TI  - Significance of vitamin D receptor gene polymorphism for prostate cancer risk in
      Japanese.
AB  - Vitamin D receptor gene (VDR) polymorphisms have been reported to be related to
      prostate cancer risk in the USA. We analyzed the distribution of TaqI RFLP and
      poly(A) of VDR in 100 prostate cancer patients and 202 urological controls. Among
      the control, 79.2% were homozygous (TT) for the absence of a TaqI RFLP, while
      17.8% were heterozygous (Tt) and 3.0% homozygous (tt) for its presence. The
      distribution was almost the same in the cancer group; 80% were homozygous TT, 18%
      heterozygous Tt, and 2.0% homozygous tt. Polymorphism of poly(A) sizes was
      categorized as a long allele (> or = 18 As) and a short allele (< 18 As). The
      distribution did not vary between the cancer and control groups; 80, 79.2% were
      LL, 18, 17.8% LS and 2.0, 3.0% SS, respectively. These results showed no
      significant association of two VDR polymorphisms with prostate cancer risk,
      however a different distribution of VDR polymorphisms between Japanese and non
      Japanese men.

PMID- 10650803
TI  - Serum tartrate resistant acid phosphatase as a potential marker of bone
      metastasis from breast cancer.
AB  - BACKGROUND: Tartrate resistant acid phosphatase (TRACP) is exclusively localized
      in osteoclasts and has been suggested to be a unique marker of bone metastasis.
      PATIENTS AND METHODS: TRACP activity using an improved spectrophotometric assay
      was measured in 56 healthy volunteers and 113 breast cancer patients, including
      35 with bone metastases (BM). RESULTS: TRACP activities (IU/l, mean +/- SD) of
      normal subjects in pre- and post-menopausal women were 5.7 +/- 1.3 and 6.6 +/-
      1.2, respectively (p < 0.02). The specificity, sensitivity, and accuracy of TRACP
      in patients, were 91.0%, 65.7%, and 83.2%, respectively. TRACP was significantly
      higher in patients with BM than in patients without BM (p < 0.01). In patients
      with BM, TRACP increased in proportion to the number of BM. Regarding clinical
      assessment of treatment of BM, TRACP was significantly higher in patients with
      progressive disease. CONCLUSION: TRACP is a useful marker of metastatic bone
      disease and response to treatment in breast cancer patients.

PMID- 10650804
TI  - Metastatic site and p53 primary tumor expression in previously untreated stage IV
      breast cancer patients.
AB  - p53 mutations have been reported to correlate with prognosis and response to
      therapy in patients with different tumor types. However, although p53 status is
      related to the primary tumor aggressiveness, an association between its
      expression and specific metastatic pattern has not yet been investigated. We
      immunohistochemically analyzed p53 (Pab1801) and ki67 (mib1) primary tumor
      expression in a series of advanced breast cancer patients presenting a selected
      pattern of distant metastases at the time of first diagnosis. Forty-eight percent
      of the overall series was classified as p53 positive while 22% as mib1 positive
      tumors. The overall agreement between p53 and mib1 expression was statistically
      significant (p = 0.03). While mib1 primary tumor expression did not show any
      association with the type of metastasis, p53 positivity was significantly higher
      in patients with soft tissue metastasis than in patients with bone or viscera
      metastasis (p = 0.002). No association with the probability of clinical response
      or different overall survival was found for patients with different p53 or mib1
      status either in the overall series of patients or in subgroups of cases with
      different sites of distant metastasis.

PMID- 10650805
TI  - Antiproliferative activity of interferon gamma in superficial bladder cancer.
AB  - BACKGROUND: Although the antiproliferative activity of interferon gamma has been
      reported in various tumours, this has not been studied in bladder cancer.
      Proliferative cell nuclear antigen and Ki67 growth fractions were estimated in
      this study in superficial bladder cancer, as a measure of the antiproliferative
      effect of interferon gamma. MATERIALS AND METHODS: Superficial bladder cancer
      samples before and after four weekly intravesical instillations of 0.7 mg IFN
      gamma were studied immunohistochemically for proliferative cell nuclear (PCNA)
      and Ki67 antigens in 25 evaluable patients. RESULTS: Ki67 growth fraction
      decreased from median 5% preoperatively to 1% postoperatively (p = 0.0015) and
      proliferating cell nuclear antigen from 20% to 5% respectively (p = 0.0001). Net
      reductions of both indices after the interferon instillations were significantly
      higher in T1 than in Ta tumours (p = 0.0431 for Ki67, and p = 0.0350 for PCNA).
      CONCLUSIONS: The intravesical instillations of the present dose of interferon
      gamma have a significant cytostatic effect on superficial bladder cancer cells as
      this is evidenced by the significant decrease of the growth fractions measured by
      means of the proliferating cell nuclear and the Ki67 antigens.

PMID- 10650806
TI  - Single-agent gemcitabine as second-line treatment in patients with advanced non
      small cell lung cancer (NSCLC): a phase II trial.
AB  - BACKGROUND: Although the use of salvage chemotherapy in advanced non-small cell
      lung cancer (NSCLC) is controversial, pretreated symptomatic patients often need
      some kind of treatment to achieve symptoms relief. Gemcitabine is one of the most
      active new drugs in advanced NSCLC and preliminary reports suggest that it is
      active also in patients previously treated with platinum compounds. AIM: to
      evaluate activity and toxicity and the effect on quality of life of gemcitabine
      in platinum-pretreated patients with advanced NSCLC. METHODS: single-stage phase
      2 trial with p0 = 5%, p1 = 20%, alfa = 5%, beta = 10%; 34 patients required and 4
      objective responses expected to warrant further studies. Gemcitabine was
      administered at dose of 1000 mg/m2, i.v., d 18-15, every 4 weeks, for a maximum
      of 6 cycles. Quality of life was measured by EORTC C-30 and LC-13 questionnaires.
      RESULTS: from September 1996 to July 1998, 30 patients have been enrolled. There
      were 6 (20% exact 95% CI 8-39%) partial responses (2 responses were in pts with
      brain metastases and 2 in patients progressed during first-line chemotherapy).
      All patients (but one died because myocardial infarction, progressed; median time
      to progression was 10 weeks (95% CI 7-12); 28 patients died; median survival was
      22 weeks (95% CI 17-29). Quality of life analysis showed no significant change
      but for the improvement of cough after 3 cycles of chemotherapy. There was no
      severe toxicity. CONCLUSION: gemcitabine is active as second line for patients
      with advanced NSCLC who received platinum-based first line treatment. In view of
      such results randomized trials comparing gemcitabine versus best supportive care
      are warranted.

PMID- 10650807
TI  - Radiotherapy in classic Kaposi's sarcoma (CKS): experience of the Institute of
      Radiology of University "La Sapienza" of Rome.
AB  - Between 1992 and 1995 24 histologically demon strated Kaposi's. Sarcoma in 14 HIV
      negative patients were treated at the Institute of Radiology of the University
      "La Sapienza" of Rome. All patients underwent irradiation with 60CO in three
      different fractionations: 800 cGy in 1 fraction in 2 (8%) cases, 2000 cGy in 5
      fractions in 18 (75%) and 300 cGy in 10 fractions in 4 (17%). Complete response
      was obtained in 13/24 (54%), partial response in 9/24 (38%), no change in 2/24
      (8%). In 2 cases there were out field relapses 2 and 3 months after the end of
      therapy, and one patient presented with a field recurrence at 4 months. The
      median duration of local control was 19.5 months (range 4-40 months). All
      patients had complete remission of symptoms. Our results seem to confirm the
      effectiveness of radiotherapy in the local control and palliation of symptoms of
      CKS.

PMID- 10650808
TI  - Cytokeratin fragment 19 (CYFRA 21-1) in healthy smokers.
AB  - Two hundred and ninety-three normal female non-smokers, 268 normal male non
      smokers, and 224 normal male smokers were included in our comparative study to
      determine possible effect of smoking on the serum levels of cytokeratin fragment
      19 (CYFRA 21-1). Immunoradiometric assay (IRMA) was used, and the results
      revealed that the mean +/- SD CYFRA 21-1 levels in the 293 normal female non
      smokers, 268 normal male non-smokers, and 224 normal male smokers were 1.28 +/-
      0.82, 1.38 +/- 0.74, and 1.47 +/- 0.62 ng/ml, respectively. There is no
      significantly statistical difference in the CYFRA 21-1 level among the three
      groups. In conclusion, we suggest that smoking has no effect on the serum levels
      of CYFRA 21-1.

PMID- 10650809
TI  - An immunohistochemical analysis of angiogenesis in invasive breast cancer with
      correlations to clinicopathologic predictors.
AB  - BACKGROUND: There is evidence that angiogenesis plays an important role in the
      biologic aggressiveness of breast carcinomas and might be used as a prognostic
      marker. MATERIALS AND METHODS: In a series of 140 invasive mammary carcinomas,
      microvessels were highlighted immunohistochemically using two endothelial
      markers, factor VIII-related antigen (FVIIIRA) and CD31. Cases were divided into
      high and low microvessel density groups according to the highest number of
      microvessels found in each tumour's most vessel-dense part. The data was
      statistically analysed with regard to classic clinicopathologic prognosticators
      (i.e., histologic type and grade, nuclear grade, tumour size, stage, lymph node
      status and steroid receptor immunoexpression) by univariate and multivariate
      analysis. RESULTS: Both markers' counts displayed just a weak skewness.
      Interestingly, CD31 angiogenesis grade was not influenced by any of the
      prognostic indicators assessed. FVIIIRA immunoreactivity was significantly
      affected only by nuclear grade (p = 0.041) in logistic regression analysis.
      Infiltrating lobular carcinomas frequently demonstrated higher FVIIIRA-positive
      microvessel densities than ductal invasive carcinomas, at least in the subgroup
      of patients with absence of nodal metastases and in those patients with highly
      oestrogen-dependent tumours. CONCLUSIONS: The lack of relation between
      angiogenesis and either disease stage or lymph node metastasis indicates that
      this process may be necessary, but not sufficient alone for breast cancer spread.

PMID- 10650810
TI  - Bcl2, p53 and clinical outcome in a series of 138 operable breast cancer
      patients.
AB  - Medical oncologists are increasingly interested in identifying reliable
      prognostic factors for breast cancer in order to distinguish subsets of breast
      cancer patients and to optimize therapeutic approaches. Among them, the p53 tumor
      suppressor gene and bcl2 protein continue to be extensively studied, but their
      role remains to be defined. Moreover the mechanism of action by which they affect
      cell kinetics has to be clarified, particularly with respect to the balance
      between cell proliferation and apoptosis. We studied 138 operable breast cancer
      patients in order to verify the relationships of p53 and bcl2 proteins with
      better known clinicopathological features and their impact on the clinical
      outcomes of relapse-free survival (RFS) and overall survival (OS). Our data
      indicated a significant relationship between bcl2 expression and steroid receptor
      positive status, wild-type p53 and low proliferative index. Mutant p53
      accumulation was found to be related to the absence of steroid receptors and high
      proliferation. Both were significant markers of better prognosis in univariate
      analysis. Multivariate analysis confirmed the favorable impact of bcl2 on both
      RFS and OS. On the contrary, we failed to observe any prognostic role for p53
      status. We describe herein an independent favorable prognostic impact for
      patients with positive bcl2 expression that appears to be worthy of larger
      confirmatory study. On the contrary, our series seems to confirm the decreasing
      prognostic relevance of p53 in clinical practice.

PMID- 10650811
TI  - Risk factors for hepatocellular carcinoma in Egypt: the role of hepatitis-B viral
      infection and schistosomiasis.
AB  - Hepatitis-B viral (HBV) infection and schistosomiasis are among the most common
      causes of liver cancer (hepatocellular carcinoma; HCC) in Egypt. The present
      study investigates the effects of both infectious diseases and other
      demographical and environmental factors on the risk of HCC among a representative
      group of Egyptian patients with HCC (n = 102) and controls with no signs of
      hepatopathology (n = 96). Factors associated with an increased risk of HCC in
      Egypt were age over 60 yrs-old, farming, cigarette smoking and occupational
      exposure to chemicals such as pesticides. However, schistosomiasis (relative
      risk, RR: 5.22; 95% confidence intervals, C.I.: 2.93-9.31) and HBV infection (RR:
      12.51; 95% C.I.: 6.11-25.59) were the major risk factors in the development of
      HCC. Schistosomiasis increased the severity of HBV infection and elevated the
      risk of HCC over that associated with the HBV infection alone. Understanding
      these relationships may enable us to determine the susceptibility to HCC among
      high risk groups and to provide these individuals with effective measures for
      early prevention or intervention.

PMID- 10650812
TI  - Analysis of 4-ABP-DNA adducts and p53 alterations in urinary bladder carcinoma.
AB  - BACKGROUND: Activated intermediates of 4-aminobiphenyl (4-ABP) are able to
      covalently interact with DNA to form adducts. There is a large body of evidence
      indicating that carcinogen-DNA adduct formation can be one of the cancer
      initiating mechanisms. MATERIALS AND METHODS: (4-ABP)-induced DNA damage in
      association with p53 overexpression and mutations were evaluated in specimens of
      urothelial bladder cancers from 106 patients. RESULTS: 4-ABP-DNA adduct levels
      resulted higher in smokers compared to non smokers, with a borderline statistical
      value. p53 nuclear overexpression was related to tumor grading, while no
      significant correlation with stage, 4-ABP-DNA adducts, smoking habit, and disease
      recurrence could be observed. Concerning molecular analysis, p53 point mutations
      were found in 17 of 106 cases (16%) and mutational pattern was significantly
      associated both with higher grade and stage, but no correlation was found with
      disease recurrence. CONCLUSIONS: These results suggest that other sources, in
      addition to tobacco smoke, may contribute to 4-ABP-DNA adducts formation in
      bladder tissue and that p53 expression/mutation cannot be considered a prognostic
      factor in bladder cancer.

PMID- 10650813
TI  - Intratumoral heterogeneity in colorectal carcinoma: trucut sampling for DNA
      ploidy analysis.
AB  - BACKGROUND: Solid tumors, such as colorectal carcinomas, consist of cell
      subpopulations that differ both genetically and in their clinical behavior. Many
      authors have examined cell kinetics and DNA content in colorectal tumors in
      correlation to clinical and pathological variables with different results. The
      interpretation of those results present some difficulties related to tumor
      heterogeneity that to date are unsolved. Our study is based on a new method of
      colon cancer sampling for DNA content determination. The aim of this work was to
      reduce the risk of incorrect DNA evaluation due to tumor heterogeneity. MATERIAL
      AND METHODS: Our study was based on eleven selected cases of T3 colorectal
      carcinoma. Fresh surgical specimens from the primary tumor site were taken during
      surgery. For each case at least four samples were taken using a 23 gauge trucut
      from the outside of the serosa through the tumor to the lumen of the colon. The
      specimens were stained according to a modified Feulgen method and DNA content was
      measured by image analysis. Three parameters were evaluated: DNA index, ploidy
      and proliferation level (considered as the sum of elements corresponding to the S
      and G2 phases). RESULTS: One of the eleven (9.1%) tumors showed a diploid
      pattern; four out of eleven (36.4%) cases showed a tetra/polyploid pattern and
      six out of eleven (54.5%) cases showed an aneuploid pattern. Three tumors were
      monoclonal (27.3%), one diploid and two aneuploid. Eight were polyclonal (72.7%).
      Considering the single specimen, seven out of sixty-eight specimens (10.3%) were
      inadequate because of scanty material. Twenty-five out of the sixty-one adequate
      specimens (41%) were monoclonal and thirty-six (59%) were polyclonal. Five tumors
      (three monoclonal and two polyclonal) showed the same cell clones on all the
      examined samples. The remaining six tumors showed interregional variability. The
      six of the eight polyclonal cases (75%) multiple stem lines were evident,
      analyzing only one sample taken close to colon serosa, while in one case (25%) it
      was necessary to examine two samples in order to see the polyclonality of the
      lesion. When samples taken close to mucosa where analyzed, however, one sample
      was not enough to show tumor polyclonality in five of the eight polyclonal
      examined cases. Proliferation level varied greatly in different parts of the same
      carcinoma and did not correlate to the site from which the sample was taken.
      CONCLUSION: In the present study, we demonstrated that DNA ploidy differences may
      exist between the superficial and the deep part of the same neoplasia and that
      tumor samples show a greater variability in the deeper layers. Using trucut
      samplings, it was possible to point out the majority of aneuploid cell
      populations close to the serosa. In conclusion, trucut biopsy permits full
      thickness sampling of the tumoral mass and allows, from few samples, to evaluate
      the multiple DNA stemlines present in different parts of a colorectal tumor.

PMID- 10650814
TI  - Chemosensitivity test is useful in evaluating the appropriate adjuvant cancer
      chemotherapy for stage III non-scirrhous and scirrhous gastric cancers.
AB  - A total of 183 cases with gastric cancer was retrospectively analyzed in terms of
      their chemosensitivity as determined by the 3-(4,5-dimethylthiazol-2yl)-2,5
      diphenyl-2H tetrazolium bromide (MTT) assay and their survival rates after
      surgery. After the patients were stratified into scirrhous or non-scirrhous
      carcinoma groups, they were tested for stage III or IV gastric cancer. In these
      four cohorts, the patients were categorized into sensitive and insensitive groups
      determined by the MTT assay. The sensitive group was treated with at least one
      drug that had been shown to be effective in the MTT assay, and the insensitive
      group was given a drug that had been shown to be ineffective in the MTT assay. In
      stage III gastric cancer, the sensitive group showed a favorable survival
      compared to the insensitive group in scirrhous and non-scirrhous carcinoma, while
      this difference was diminished in stage IV gastric cancer. There were no survival
      benefits in the sensitive group in stage III gastric cancer, when they were not
      treated with adjuvant cancer chemotherapy. These results suggested that MTT assay
      would be useful in evaluating the appropriate adjuvant cancer chemotherapy for
      stage III scirrhous and non-scirrhous gastric cancer.

PMID- 10650815
TI  - The prognostic significance of p53, p21 (Waf1/Cip1), and cyclin D1 protein
      expression in esophageal cancer patients.
AB  - Recently, various cell cycle regulators have been studied as biological markers
      of malignant potential. These regulators might influence survival rates and the
      effects of adjuvant therapies. In this study, we analyzed the expression of p53,
      p21(Waf1/Cip1), and cyclin D1 in 64 esophageal cancer patients and their relation
      to clinicopathologic parameters and patient survival. For p53, p21, and cyclin D1
      oncoprotein expression, we defined positive cases as those with over 10% of
      examined cells stained. Positive rates were 48.4%, 42.2%, and 43.8% for p53, p21,
      and cyclin D1, respectively. In a multivariate analysis, tumor depth,
      chemotherapy, and p21 expression were determined to be significant prognostic
      factors. Five-year survival rates of p53-negative/p21-positive and p53
      positive/p21-negative patients were 53.0% and 28.5%, respectively, and were not
      significantly different. These results suggest that, of various cell cycle
      regulators, p21 might be a good predictor of prognosis for esophageal cancer
      patients.

PMID- 10650816
TI  - Expression of vascular endothelial growth factor in primary superficial bladder
      cancer.
AB  - BACKGROUND: Angiogenesis is of vital importance during the development and
      progression of solid tumors. This study was performed to test the clinical
      significance of vascular endothelial growth factor (VEGF) expression in primary
      superficial bladder cancer. MATERIALS AND METHOD: A cohort of 185 cases of
      pTa/pT1 transitional cell bladder cancer and six cases of normal urothelium were
      studied by immunohistochemistry. Expression of VEGF was correlated with
      biological indicators of bladder cancer and examined for their prognostic value.
      RESULTS: Variable amounts of VEGF were detected in 35 cases (18.9%), with 17.9%
      and 20.3% in pTa and pT1 tumors respectively. There was a positive association of
      VEGF expression with histological grading (p = 0.03). Otherwise, no apparent
      correlation was observed with remaining biopathological indicators (p > 0.1,
      respectively). Risk factors in predicting tumor recurrence were multiple tumors
      at diagnosis and lamina propria invasion (p < 0.05, respectively). Patients with
      multiple tumors also had a lower survival rate than those with a solitary tumor
      (p = 0.0008). However, expression of VEGF was not correlated with risk of tumor
      recurrence or patient survival (p > 0.1). CONCLUSIONS: Expression of VEGF is one
      of the characteristics of tumor dedifferentiation and may play a role in the
      development of a subset of superficial bladder cancer. Evaluation of VEGF
      expression dose not provide independent prognostic information for patients with
      superficial bladder cancer.

PMID- 10650817
TI  - [The Bavarian Thromboembolic Risk Cohort Study (BATER). Study protocol, state of
      the investigation and first results].
AB  - OBJECTIVE: Familiar venous thromboembolic disease (VTE) is known to be related
      with factor V Leiden mutation (FVL), but also with other genetic markers. It is
      the objective to investigate of the BATER-study in a representative Bavarian
      cohort, and to assess whether they could predict VTE events. This paper shortly
      describes the study protocol, gives an overview of planned sub-studies, and
      provides first results of the historic cohort analysis. PATIENTS AND METHODS: The
      baseline survey of the cohort study of Bavarian women aged 18-49 years (random
      sample from the population) was performed in two samples in 1996 and 1997. It was
      planned to estimate a prevalence and predictive value of potential markers of VTE
      in a historic--prospective as well as concurrent approach with annual follow-up
      of the cohort. This representative cohort should build a basis for nested case
      control studies and serve as a reference group for other analytical
      epidemiological studies in young women. 1685 women were ascertained (response
      rate 61%), underwent an inquiry, and provided blood samples for a blood bank; for
      this paper, complete data are available from 1650 women. Laboratory parameters
      were measured to determine APC resistance, FVL-mutation, antithrombin-, protein C
      and S deficiency, and were correlated to the results of a detailed, life-time
      history of thrombembolic events. RESULTS: The prevalence of FVL mutation in the
      sample was 5.7% (95% confidence interval 4.6-6.6%). Other genetic VTE risk
      markers were observed to be less frequent than 1%. The positive predictive value
      (pPV) of FVL mutation for a VTE event is about 7%, but for a positive family
      history of VTE (first grade relatives) 3% only. CONCLUSIONS: VTE events are rare
      in the German population of young women, even in cases of FVL mutation. A
      positive family history is rarely associated with the occurrence of VTE in women
      under 50 years of age, and the predictive value of FVL mutation is low.
      Therefore, a screening for FVL mutation is not justified unless there is
      suspicion of a high VTE risk for other reasons.

PMID- 10650818
TI  - [Clinical presentation and therapy of Mycobacterium marinum infection as seen in
      12 cases].
AB  - BACKGROUND AND OBJECTIVE: Mycobacterium marinum (M.m.) is the causative pathogen
      of skin infections that have been called "swimming pool granulomas". An
      increasing number of reports that deep structures are involved in these
      infections was the reason for studying the clinical presentation and response of
      the infection to different therapeutic regimens. PATIENTS AND METHODS: All
      patients (eight men, four women, age range 18-73 years) were included in whom,
      between january 1991 and February 1995, M.m. infection had been proven by
      culture. The clinical data of these patients were retrospectively obtained by
      standardized questionnaire. RESULTS: The infection was limited to the skin in
      four of the twelve patients, deep structures only were involved in three, and
      five had both. Infections limited to the skin were successfully treated with
      sulphamethoxazole and trimethoprim or with tetracyclines, while rifampicin, alone
      or in combination with ethambutol, was efficacious when deep structures were
      involved. No surgical intervention was--or should be--performed. CONCLUSIONS:
      Infections with M.m. often involve deep structures, even in the absence of the
      skin being involved. The term "swimming pool granuloma" is, therefore, misleading
      when the infection is limited to he skin. A history of a chronic and indolent
      course, frequent changes of doctor and striking polypharmacy in its treatment are
      pointers to this infection.

PMID- 10650819
TI  - [Obstructive jaundice du to sludge in the common bile duct].
AB  - HISTORY AND FINDINGS: A 21-year-old woman developed increasing jaundice with
      severe pruritus and weight loss after a bout of dyspepsia. She had been taking
      contraceptives for 4 years (ciproteronacetate 2 mg, ethinylestradiol 0.035 mg).
      INVESTIGATIONS: Laboratory tests at first suggested cholestatic hepatitis (serum
      bilirubin > 5 mg/dl, predominantly indirect bilirubin, SGOT 77 U/l, SGPT 154 U/l,
      gamma-GT 138 U/l, alcaline phosphatase 630 U/l). Ultrasonography showed a gall
      bladder filled with biliary sludge and dilatation of the common bile duct and the
      smaller biliary passages. A tumour-like space-occupying lesion was noted near the
      papilla: it was not fixed and had no vascular supply. Endoscopic retrograde
      cholangiopancreatography (ERCP) also demonstrated a mobile space-occupying lesion
      in the common bile duct near the papilla and markedly dilated biliary passages.
      DIAGNOSIS, TREATMENT AND COURSE: The tumour-like obstruction was removed by
      balloon catheter after papillotomy. It consisted of several jelly-like viscous
      streaky bile without calculi. The procedure was complicated by subsequent
      pancreatitis which, however, soon subsided. Within a few days the jaundice
      disappeared and the pruritus ceased. At the same time the liver functions
      returned to normal. Ultrasonography no longer showed obstructed biliary passages
      and sludge. CONCLUSIONS: Obstructive jaundice may be due not only to strictures
      gall stones and benign or malignant tumours but also to thickened sludge in the
      biliary tract in women on oral contraceptives. The obstruction can be
      demonstrated by ERCP and removed by interventional procedures (i.e. endoscopic
      papillotomy).

PMID- 10650820
TI  - [Effect of inhibitors on the use of clotting factor concentrates].

PMID- 10650821
TI  - [Frequency of stroke in Germany: prevalence, incidence and sources of these
      data].

PMID- 10650822
TI  - [Connection of an external clearing house in the private liquidation of official
      clinical directors. Decision of the Administrative Court of Frankfurt am Main of
      07-19-1999].

PMID- 10650823
TI  - [Estrogen-progestagen substitution in pre-existing heart disease].

PMID- 10650824
TI  - [Therapy of symptomatic stenosis of the cerebral arteries: how does one
      proceed?].

PMID- 10650825
TI  - [Persistent antistreptolysin titer].

PMID- 10650826
TI  - [The self-portrait of physicians in 1900--illustrations in the DMW].

PMID- 10650827
TI  - [Loss of orientation and values in health services].

PMID- 10650828
TI  - [Guidelines in internal medicine. 7. Autumn Session of the Corporate Members of
      DGIM (German Society for Internal Medicine)].

PMID- 10650829
TI  - Value and perspectives of proton radiation therapy for limited stage prostate
      cancer.
AB  - BACKGROUND: This review article will focus on clinical results and limitations of
      proton beam irradiation. Possible technological, biological and medical
      perspectives will be addressed. PATIENTS AND METHODS: A total of 911 patients
      with limited stage prostate cancer were treated with proton beam irradiation at
      Loma Linda University between 1991 and 1996. Endpoints of this evaluation were
      biochemically no evidence of disease survival (bNED) as well as acute and late
      treatment-related toxicity. RESULTS: The bNED survival rate was 82% at 5 years.
      Among 870 patients evaluable for late toxicity the following late effects were
      observed: Grade 3/4: 0%, Grade 2 rectal: 3.5% and bladder: 5.4%. CONCLUSIONS:
      Despite relatively short follow-up times it seems justified to conclude that
      proton beam irradiation of prostate cancer can improve bNED rates by 10% and
      decrease Grade 2 late effects by more than 10%. There were no Grade 3 and 4 late
      effects.

PMID- 10650830
TI  - [Radiotherapy of lymphatic fistula and lymphocele].
AB  - BACKGROUND: The treatment of persistent postoperative lymphatic fistulas or
      lymphoceles is often a problem. Approximately 2% of patients will develop
      lymphatic fistula after vascular surgery. This can require a long lasting
      conservative therapy. If spontaneous cure fails, a second operation with wound
      revision becomes necessary. We studied low-dose percutaneous radiotherapy to be
      used as an alternative treatment in addition to conservative or surgical therapy.
      PATIENTS AND METHODS: Between 1989 and 1998 29 patients (25 with lymphatic
      fistulas, 4 with lymphoceles) received radiation therapy. Depending on the depth
      of the fistula 27 patients were treated with electrons (7 to 18 MeV). Two other
      patients suffering of retroperitoneal lymphoceles received a treatment with
      photons (15 MV). In all patients the fractionation was 4- to 5 x 1.0 Gy/week and
      the dose ranged from 3 to 12 Gy depending upon the onset of the radiation therapy
      effect. RESULTS: In 27 of 28 evaluable patients a complete disappearance of the
      fistula or lymphocele was achieved by radiation during therapy or shortly
      afterwards. In 1 case no benefit was observed after a dose of 11 Gy. This patient
      required further surgery with wound exploration. CONCLUSION: Low dose
      percutaneous radiotherapy (up to 10 to 12 Gy) is effective to heal lymphatic
      fistulas and lymphoceles without complications. Individual dosage is required
      because doses even lower than 10 Gy may be effective. Radiation can be effective
      even after a failed conservative therapy or instead of surgery.

PMID- 10650831
TI  - Carcinoma of the oropharynx: local failure as the decisive parameter for distant
      metastases and survival.
AB  - OBJECTIVE: How important and predictive are clinical parameters and locoregional
      failure after radical radiotherapy of oropharyngeal carcinomas for the
      probability of the occurrence of distant metastases? PATIENTS AND METHODS: From 1
      August 1990 to 1 October 1998, 139 patients with carcinomas of the oropharynx
      were treated in a prospective study by radical radiotherapy and evaluated in
      regard to the clinical parameters reflex-otalgia, predominant structure of tumor
      growth, T-category, presence of involved lymph nodes, and smoking and drinking
      habits. Twenty-nine patients received a concomitant chemotherapy. Twenty-five out
      of 139 patients had a planned neck dissection after completion of radiotherapy.
      Ten patients received a salvage operation. RESULTS: The median follow up time was
      24 months (range, 4 to 74). Two- and 5-year overall survival rates according to
      Kaplan Meier were 56.1 and 49.6%. The tumors were controlled in 77/139 patients
      (55%). The therapy failed in 62/139 patients (45%). Both groups, 62 patients with
      locoregional therapy failure and 77 patients with locoregionally control led
      tumors, were comparable in regard to performance status (Karnofsky index), age,
      gender, TNM-categories, histological differentiation, drinking habits,
      pretherapeutic diagnostics, total dose (Gy), and number of simultaneous
      chemotherapy cycles. Locoregional tumor control was significantly determined by
      the parameters reflex-otalgia (p < 0.0078), predominant growth pattern (p <
      0.012), T-category (p < 0.03), and smoking (p < 0.0285). The median survival time
      of patients with locoregional failure is 17 months. At this moment 81% of
      locoregionally controlled patients are still alive. In 14/62 patients (23%) with
      locoregional failure, distant metastases were detectable against 4/77 (5%) of
      locally controlled patients, p < 0.0026. Probability of local control and distant
      metastases, predominantly pulmonary, reached a plateau after 24 months.
      CONCLUSIONS: Locoregional tumor control, determined by several clinical
      parameters, is an important parameter for the probability of the development of
      distant metastases. Failure of local therapy is caused by the biologic
      aggressiveness of the tumor.

PMID- 10650832
TI  - Treatment of primary tracheal carcinoma. The role of external and endoluminal
      radiotherapy.
AB  - BACKGROUND AND PURPOSE: In a retrospective study the role of radiation therapy
      for the treatment of primary tracheal carcinoma was investigated. PATIENTS AND
      METHODS: Between 1984 and 1997, 25 patients with primary tracheal carcinoma were
      treated with external beam radiotherapy (17 squamous-cell carcinoma [SCC], 8
      adenoid cystic carcinoma [ACC], median dose SCC 60 Gy. ACC 55 Gy). An additional
      brachytherapy boost was carried out in 10/25 patients (median dose SCC 18 Gy, ACC
      15 Gy). Ten patients underwent operative treatment. RESULTS: The median survival
      (Kaplan-Meier) for patients with SCC was 33 months (ACC 94.2). The 1-, 2- and 5
      year survival rates (Kaplan-Meier) for patients with SCC were 64.7% (ACC 85.7%),
      64.7% (ACC 85.7%), and 26% (ACC 85.7%). Patients with ACC and patients with a
      complete remission after treatment had a significantly better survival
      probability (log rank test, p < 0.05). An excellent or good relief of clinical
      symptoms was achieved in 88% of the patients with SCC (ACC 88%). Eleven patients
      were locally controlled at last follow-up (SCC: 5/17; ACC: 6/8). Grade 1 to 2
      toxicity (RTOG/EORTC) occurred in 12% (SCC: 2/17, ACC: 1/8) and Grade 3 to 4
      toxicity in 8% (SCC: 0/17, ACC: 2/8) of the patients. Persistent or progressive
      local disease caused complications in 5 patients (fatal hemorrhage n = 2,
      esophagotracheal fistula n = 2, tracheal necrosis n = 1). CONCLUSION: Radiation
      therapy is an effective treatment for primary tracheal neoplasms. Surgery
      followed by adjuvant radiotherapy and primary radiotherapy in inoperable cases
      represent potentially curative treatment options. Prospective multicenter studies
      are needed to determine the optimal radiotherapeutic approach.

PMID- 10650834
TI  - [Effect if 3D compared with 2D radiotherapy planning within a conventional
      treatment schedule of advanced lung cancer].
AB  - BACKGROUND: The effect of 3D radiotherapy planning (3D RTP) in comparison to 2D
      radiotherapy planning (2D RTP) was evaluated in a usually practiced treatment
      schedule (starting by v./d. opposing portals, continued with computer-planned
      portals) for non-small-cell lung cancer. PATIENTS AND METHODS: In 20 patients
      with locally advanced non-small-cell lung cancer the computer-planned part of the
      treatment schedule was calculated 2- and 3-dimensionally. Target volume were the
      primary tumor, the involved and the electively irradiated mediastinal lymph
      nodes. The results of the 2D RTP were recalculated 3-dimensionally and the mean
      doses to target volume and organs at risk were defined. Further the normal tissue
      complications were calculated. RESULTS: Under the prerequisite of 44 Gy maximally
      allowed to the spinal cord and a dose to the reference point of 50 Gy a small,
      but significant advantage with 2.1 Gy to the target (p = 0.004) and a reduction
      of 3.6 Gy to the heart (p = 0.05) was achievable for 3D RTP. The dose to the
      lungs did not differ significantly (19.7 Gy for 2D RTP, 20.3 Gy for 3D RTP). The
      dose to the heart was not estimated critical by NTCP (normal tissue complication
      probability). The NTCP for the ipsilateral lung was 16.1 and 18.7% for 2D RTP and
      3D RTP, respectively. Regarding the simulator-planned ap/pa fields at the start
      of the radiotherapy the advantage of 3D RTP was further reduced but remained
      significant. Favorable with respect to the mean lung dose and the NTCP (18.7%
      NTCP ipsilateral lung for early onset of 3D planned radiotherapy vs 31.7% for
      late onset of 3D planned radiotherapy) but not significantly measurable is the
      early start of the treatment by computerized RTP. CONCLUSION: The main advantage
      of 3D RTP in treatment of advanced lung cancer is the better coverage of the
      target volume. A reduction of the mean lung dose cannot be expected. A dose
      escalation by 3D RTP to target volumes as described here seems not to be possible
      because of unchanged high lung exposure.

PMID- 10650833
TI  - An original accelerated radiotherapy schedule in stage III to IV head and neck
      cancers. Results in a multicenter setting.
AB  - BACKGROUND: Accelerated radiotherapy delivery has recently been shown to be
      effective in overcoming repopulation during fractionated radiotherapy. The
      therapeutic ratio may be particularly favorable for 5-week regimens. This study
      reports the feasibility and results of a particular accelerated schedule in Stage
      III to IV head and neck carcinomas used in a multicenter setting. PATIENTS AND
      METHODS: Seventy-four patients with Stage III (26 patients) or IV (48 patients)
      head and neck carcinomas were treated with a 5-week accelerated schedule (69.6 to
      69.8 Gy in 41 to 40 fractions over a period of 35 to 36 days). Treatment began
      with 20 Gy in 10 daily fractions to initial involved sites, followed by bi
      fractionated radiotherapy (2 x 1.6 Gy to 1.66 Gy/day) to a larger head and neck
      volume. Thirty-six (49%) patients received induction chemotherapy (median 3
      cycles, range 1 to 4 cycles). RESULTS: Grade 3 or 4 (RTOG) confluent mucositis
      was observed in 57 patients (77%) and Grade 3 dysphagia in 33 patients (44%).
      Grade 3 or 4 (RTOG-EORTC) late complications were scored in 10.5% of cases. The 5
      year actuarial locoregional control rate was 56% (95% CI: 42 to 71). The 5-year
      overall actuarial survival was 32% (95% CI: 18 to 46). Induction chemotherapy was
      not associated with a more favorable outcome. CONCLUSIONS: This study
      demonstrates the feasibility of this schedule in a multicenter setting. The
      oncologic results appear similar to those obtained by other accelerated regimens,
      while the rate of late complications seems acceptable. Five-week accelerated
      regimens warrant further evaluation, particularly in conjunction with concomitant
      chemotherapy, in the framework of prospective trials.

PMID- 10650835
TI  - Polymorphous low-grade adenocarcinoma of the nasopharynx. Case report and review
      of the literature.
AB  - BACKGROUND: The polymorphous low-grade adenocarcinoma of the nasopharynx is a
      rare disease. Polymorphous low-grade adenocarcinoma is a minor salivary gland
      neoplasm which occurs frequently in the mucosa of the soft and hard palates, in
      the buccal mucosa and in the upper lip. To date this entity has been identified
      within the oral cavity and only one case within the nasopharynx and some cases in
      the parotid gland. It has a slow infiltrating growing pattern with frequent
      perineural invasion and low metastatic potential. CASE REPORT: We report on a
      patient with non-papillary polymorphous low-grade adenocarcinoma in the
      nasopharynx which extended intracranially. The patient underwent primary
      radiotherapy. The CT showed partial response to radiotherapy and the patient is
      alive 51 months after the diagnosis his state being unchanged. CONCLUSION: The
      treatment for minor salivary gland tumor is primarily surgical. It is reported
      that the polymorphous low-grade adenocarcinoma has been known to have poor
      response to radiotherapy. However, we believe that in addition to its favorable
      biological behavior, the radiotherapy in this localization may result in longer
      survival.

PMID- 10650836
TI  - [Primary prevention of breast cancer in women with an increased risk for breast
      cancer--a prospective, randomized, double-blind study (NSABP-P1 study)].

PMID- 10650837
TI  - [Determination of oncogenes c-erbB-2 or Her-2/neu for prognosis in breast
      cancer].

PMID- 10650838
TI  - [Mechanisms of angiogenesis in the brain].

PMID- 10650839
TI  - Paleo-demography of the Drosophila melanogaster subgroup: application of the
      maximum likelihood method.
AB  - The species divergence times and demographic histories of Drosophila melanogaster
      and its three sibling species, D. mauritiana, D. simulans, and D. yakuba, were
      investigated using a maximum likelihood (ML) method. Thirty-nine orthologous loci
      for these four species were retrieved from DDBJ/EMBL/GenBank database. Both
      autosomal and X-linked loci were used in this study. A significant degree of rate
      heterogeneity across loci was observed for each pair of species. Most loci have
      the GC content greater than 50% at the third codon position. The codon usage bias
      in Drosophila loci is considered to result in the high GC content and the
      heterogenous rates across loci. The chi-square, G, and Fisher's exact tests
      indicated that data sets with 11, 23, and 9 pairs of DNA sequences for the
      comparison of D. melanogaster with D. mauritiana, D. simulans, and D. yakuba,
      respectively, retain homogeneous rates across loci. We applied the ML method to
      these data sets to estimate the DNA sequence divergences before and after
      speciation of each species pair along with their standard deviations. Using 1.6 x
      10(-8) as the rate of nucleotide substitutions per silent site per year, our
      results indicate that the D. melanogaster lineage split from D. yakuba
      approximately 5.1 +/- 0.8 million years ago (mya), D. mauritiana 2.7 +/- 0.4 mya,
      and D. simulans 2.3 +/- 0.3 mya. It implies that D. melanogaster became distinct
      from D. mauritiana and D. simulans at approximately the same time and from D.
      yakuba no earlier than 10 mya. The effective ancestral population size of D.
      melanogaster appears to be stable over evolutionary time. Assuming 10 generations
      per year for Drosophila, the effective population size in the ancestral lineage
      immediately prior to the time of species divergence is approximately 3 x 10(6),
      which is close to that estimated for the extant D. melanogaster population. The
      D. melanogaster did not encounter any obvious bottleneck during the past 10
      million years.

PMID- 10650840
TI  - Identification and phylogenetic analysis of novel human endogenous retroviral
      sequences belonging to the HERV-H family on human X and Y chromosomes.
AB  - HERV-H, a family of endogenous retroviral elements that has undergone successive
      expansions in the human genome, includes sequences that are expressed in placenta
      and T cells. With a PCR approach to the HERV-H using human monochromosomal
      somatic cell hybrid DNA, we identified 8 new HERV-H sequences on the X
      chromosome, and one novel HERV-H element, HY-1, the first reported such element
      on the Y chromosome, and compared these with sequences in the nucleotide sequence
      database. Phylogenetic analysis indicated that clone HX-1 and BAC clone 523A23 on
      the X chromosome were found to be in close relationship to the sequences of
      DJ088A21 on the human chromosome 7q31. This finding allows us to speculate that
      HERV-H elements may have evolved by intra-chromosomal spread. Our data may
      relevant to an understanding of human genomic plasticity.

PMID- 10650842
TI  - Characterization of the chalcone synthase genes expressed in flowers of the
      common and Japanese morning glories.
AB  - The CHS genes encoding chalcone synthase for flavonoid biosynthesis in the common
      and Japanese morning glories comprise a multigene family. Among these Ipomoea CHS
      genes, the CHS-D gene is the most abundantly expressed in the pigmented young
      flower buds and is primarily responsible for flower pigmentation. Majority of the
      remaining CHS transcripts in the flower buds are produced from the CHS-E gene. We
      characterized the genomic DNA segments of these CHS-D and CHS-E genes. Both genes
      have two exons with identical intron positions and carry several copies of two
      mobile element-like sequences with short terminal inverted repeats, MELS3 and
      MELS6 of around 200-300 bp. Small tandem repeats were also found in these CHS
      gene regions. The CHS-D and CHS-E genes are expressed predominantly in flower
      limbs and tubes, respectively. These structural and functional features and their
      evolutionary implications are discussed.

PMID- 10650841
TI  - Phylogenetic relationships of Australian skinks of the Mabuya group (Reptilia:
      Scincidae) inferred from mitochondrial DNA sequences.
AB  - Portions of two mitochondrial genes (12S and 16S ribosomal RNAs) were sequenced
      to analyze the phylogenetic relationships of the Mabuya group from the Australian
      region (Corucia, Egernia and Tiliqua). Results indicated the monophyly of these
      genera and their divergence from Asian and African members of this group. This
      suggests that the diversity of the Mabuya group in the Australian region has
      increased through an endemic radiation, not through multiple colonizations from
      outside. Among the genera from this region, Corucia and Tiliqua were closest to
      each other. This result contradicts with those of the previous hypotheses on the
      basis of morphological and immunological data that, respectively, suggested
      closest affinities between Corucia and Egernia, and Egernia and Tiliqua. We
      suppose that the morphological characters exclusively joining Corucia and Egernia
      are actually in plesiomorphic state.

PMID- 10650843
TI  - Meiotic contraction of CAG repeats in Saccharomyces cerevisiae.
AB  - Several human neurodegenerative disorders are caused by expansion of CAG repeats
      that occurs during meiosis or gametogenesis. We anticipated that the CAG repeats
      cloned in a plasmid of Saccharomyces cerevisiae might undergo a change in the
      number of repeats during meiosis and sporulation. To test this possibility, we
      devised a new method to change in vitro the number of CAG repeats and constructed
      plasmids carrying (CAG)39, (CAG)65 or (CAG)123 from a plasmid carrying (CAG)18.
      We monitored the number of colonies showing an altered length of the repeat
      tracts during mitosis and meiotic growth. Contraction of long CAG repeat was
      found to occur frequently, whereas a few cases of expansion were observed. The
      contraction was equally enhanced in both orientations when the host cells grew
      through meiosis. Thus, our results suggest that long CAG repeats are destabilized
      during meiosis or gametogenesis in S. cerevisiae.

PMID- 10650844
TI  - Promoter analysis of the class 2 flagellar operons of Salmonella.
AB  - The Salmonella flagellar operons are divided into three classes with reference to
      their relative positions in the transcriptional hierarchy. Expression of the
      class 2 operons requires the class 1 gene products, FlhD and FlhC, and is
      enhanced by an unknown mechanism in the presence of the class 3-specific sigma
      factor, FliA, and in the absence of its cognate anti-sigma factor, FlgM. In this
      study, the transcriptional start site mapping was performed by primer extension
      analysis for five class 2 operons, flgA, flgB, flhB, fliE and fliL. In all cases,
      one or a few major transcriptional start sites were identified. These start
      signals disappeared in the flhDC-mutant background, and their intensity decreased
      and increased in the fliA-mutant and flgM-mutant backgrounds, respectively.
      Therefore, we conclude that the FlhD/FlhC-dependent transcription is responsible
      for the FliA-dependent enhancement. Sequence comparison revealed that an
      imperfect inverted repetitious sequence is conserved upstream of the class 2
      operons. Truncation of this sequence from the flgB promoter reduced its
      transcriptional activity to the background level, indicating that this is an
      essential cis-acting element for transcription of the class 2 operons.

PMID- 10650846
TI  - Factor V G1691A and prothrombin G20210A in childhood spontaneous venous
      thrombosis--evidence of an age-dependent thrombotic onset in carriers of factor V
      G1691A and prothrombin G20210A mutation.
AB  - Risk factors for venous thrombosis in adults are the prothrombin (PT) G20210A,
      the factor (F) V G1691A mutations and hereditary deficiencies of protein C,
      protein S and antithrombin. However, data are limited on the relevance of these
      risk factors for thrombosis in children and adolescents. We therefore
      investigated 119 patients aged 0-18 with spontaneous venous thrombosis and
      controls (n = 100) for the presence of the factor V G1691A mutation and the
      prothrombin G20210A variant with respect to thrombotic onset and thrombosis
      location. The following frequencies (patients vs. controls), odds ratios (OR),
      95%-confidence intervals (CI) and p-values were found: FV G1691A, 19.3% vs. 5%,
      OR/CI 4.55/1.66-12.5, p = 0.0038 and prothrombin G20210A, 8.4% vs. 3%, OR/CI
      2.96/0.8-11, p = 0.17. A combination of the FV G1691A mutation with the PT
      G20210A variant was found in 3 children (2.5% of cases) but only once in the
      controls. With a median (range) age of 2 years (0-17), carriers of the FV
      mutation were significantly younger compared with patients carrying the PT
      variant (16 years: 0-18, p < 0.001). Vascular accidents in carriers of the FV
      mutation occurred in deep veins of the leg (n = 11), cerebral veins (n = 4),
      renal veins (n = 3) and portal veins (n = 2). Patients with the PT mutation
      showed spontaneous thrombosis in the majority of cases in the deep veins of the
      leg (n = 5) and in the central nervous system (n = 2). Combined defects were
      found in a neonate with renal venous thrombosis and in two adolescents with deep
      vein thrombosis. CONCLUSION: Data presented here suggest that the heterozygous FV
      mutation is the most commonly found prothrombotic risk factor responsible for
      spontaneous thrombosis during infancy and early childhood. In contrast, the PT
      G20210A variant is likely to be more important during puberty and adolescence.

PMID- 10650845
TI  - Multicentre evaluation of combined prothrombotic defects associated with
      thrombophilia in childhood. Childhood Thrombophilia Study Group.
AB  - To evaluate the role of multiple established and potential causes of childhood
      thrombophilia, 285 children with a history of thrombosis aged neonate to 18 years
      (first thrombotic onset) were investigated and compared with 185 healthy peers.
      APC-resistance (FV:Q506), protein C, protein S, antithrombin, heparin cofactor II
      (HCII), histidine-rich glycoprotein (HRGP), and prothrombin (F.II), factor XII
      (F.XII), plasminogen, homocysteine and lipoprotein (a) (Lp(a)) were investigated.
      In 59% of patients investigated one thrombotic defect was diagnosed, 19.6% showed
      two thrombotic risk factors, while in 21.4% of children investigated no risk
      factor could be identified. Single defects comprised established causes of
      inherited thrombophilia: FV:Q506 (homozygous n = 10, heterozygous n = 69),
      protein C (homozygous n = 1; heterozygous n = 31), heterozygous type I deficiency
      states of protein S (n = 7), antithrombin (n = 7) and homocystinuria (n = 6);
      potentially inherited clotting abnormalities which may be associated with
      thrombophilia: F.XII (n = 3), plasminogen (n = 2), HCII (n = 1), increased HRGP
      (n = 4); new candidate risk factors for thrombophilia: elevated plasma levels of
      Lp(a) (n = 26), F.II (n = 1). Heterozygous FV:Q506 was found in combination with
      heterozygous type I deficiency states of protein C (n = 2), protein S (n = 13),
      antithrombin (n = 8) and HCII (n = 1), increased Lp(a) (n = 13), and once each
      with elevated levels of F.II, moderate hyperhomocysteinemia, fibrinogen
      concentrations > 700 mg/dl and increased HRGP. In addition to the association
      with FV:Q506, heterozygous protein C type I deficiency was combined with
      deficiencies of protein S (n = 2), antithrombin (n = 1), and increased Lp(a) (n =
      3). One patient showed protein C deficiency along with familially increased von
      Willebrand factor > 250%. Besides coexistence with FV:Q506 and protein C
      deficiency, protein S deficiency was combined with decreased F.XII and increased
      Lp(a) in one subject each. Furthermore, we found combinations of antithrombin
      deficiency/elevated Lp(a), hyperhomocysteinemia/Lp(a), deficiency of
      HCII/plasminogen, and plasminogen deficiency along with increased Lp(a) each in
      one. Increased prothrombin levels were associated with fibrinogen concentrations
      > 700 mg/dl and with HCII deficiency in one child each. Carrier frequencies of
      single and combined defects were significantly higher in patients compared with
      the controls. CONCLUSION: In conclusion, data of this multicentre evaluation
      indicate that paediatric thromboembolism should be viewed as a multifactorial
      disorder.

PMID- 10650847
TI  - Role of genetic prothrombotic risk factors in childhood caval vein thrombosis.
AB  - Childhood caval vein thrombosis has a high incidence especially in the first year
      of life. Besides deficiencies of protein C, protein S, antithrombin and
      plasminogen, the factor (F) V G1691A mutation, the prothrombin (PT) G20210A
      variant, the methylenetetrahydro-folate reductase (MTHFR) TT677 genotype, or
      increased lipoprotein (Lp) (a) > 30 mg/dl have emerged as important prothrombotic
      risk factors in childhood vascular accidents. 27 consecutive childhood patients
      with inferior caval vein thrombosis and 100 healthy age-matched controls were
      investigated for the presence of these prothrombotic risk factors with respect to
      the first thrombotic onset. In 19 out of 27, patients thrombosis occurred during
      infancy; the remaining vascular accidents were diagnosed during puberty. In 13
      out of the 19 infants, vascular occlusion occurred spontaneously, five times
      associated with renal venous thrombosis. 68.4% of patients in the first year of
      life (n = 13) showed at least one prothrombotic risk factor. The FV mutation
      (heterozygous n = 4, homozygous n = 1). Lp (a) > 30 mg/dl and kringle 4 repeats <
      28 (n = 4), MTH FR TT677 with mild hyperhomocysteinaemia (> 95th age-dependent
      percentile, i.e. 8.5 micromol/l: n = 3) and antithrombin deficiency type II (n =
      1) were diagnosed with an overall odds ratio/95% confidence interval of 9.2/3.1
      27.4. In the adolescent group, genetic risk factors were found in 50% of patients
      investigated (FV mutation (n = 1), PT variant (n = 3); odds ratio/95% confidence
      interval: 4.2/0.97-18.6). CONCLUSION: Data presented here suggest that genetic
      prothrombotic risk factors play an important role in childhood caval vein
      thrombosis. Remarkably, during puberty and adolescence the predominant defect
      diagnosed was the PT G20210A variant, whereas the FV G1691A mutation had a higher
      incidence during infancy.

PMID- 10650848
TI  - The 677T genotype of the common MTHFR thermolabile variant and fasting
      homocysteine in childhood venous thrombosis.
AB  - Controlled data on the association of MTHFR genotypes, hyperhomocysteinaemia and
      their interaction with factor V G1691A with childhood thrombosis are not yet
      available. Therefore we conducted a case-control study comparing 141 childhood
      patients with venous thrombosis with 345 healthy controls. The MTHFR C677T
      genotypes, FV G1691A and prothrombin G20210A were evaluated; in addition, fasting
      homocysteine concentrations were measured in a subgroup of 60 children and 80
      healthy controls. 10.4% of the healthy control population showed the MTHFR TT
      genotype, 34.2% the CT genotype and 55.4% the CC variant. MTHFR genotypes account
      for fasting homocysteine concentrations in healthy controls (CC: 5.5 micromol/l
      (4-7.2); CT: 7 micromol/l (3.9-9.8); TT: 12.1 micromol/l (7.7-13.3)) with an
      upper age-specific 95th percentile of 8.3 micromol/l. The following frequencies
      (patients versus controls), odds ratios (OR) and 95% confidence intervals (CI)
      were found for single defects: MTHFR 677TT genotype (10.6% vs. 10.4%; OR/CI:
      1.02/0.54-1.93; P = 0.99) and CT genotype (43.8% vs. 34.2%; OR/CI: 2.12/1.42
      3.16; P = 0.0000). A combination of FV G1691A mutation and MTHFR 677CT genotype
      was found in 9.9% of patients and in 2.9% of the controls (OR/CI: 3.8/1.64-8.75;
      P = 0.027). Fasting homocysteine median (range) concentrations in the patient
      group were significantly higher than in the controls (7 micromol/l (3-23) vs. 5.5
      micromol/l (3-8.4): P = 0.0004), and homocysteine concentrations >8.3 micromol/l
      were found in 40% of patients vs. 2.5% of the controls (OR/CI: 22/2.64-183; P =
      0.0003). Conclusion Data of this childhood case-control study suggest that mildly
      elevated fasting homocysteine concentrations >8.3 micromol/l and the CT genotype
      of the MTHFR C677T variant are significant risk factors for venous vascular
      occlusion in children.

PMID- 10650849
TI  - Prothrombotic risk factors in childhood stroke and venous thrombosis.
AB  - Many studies have shown a high percentage of venous thromboses in children to be
      associated with haematological disorders. However, studies assessing the
      influence of haemostaseological disorders on paediatric stroke are rare. We
      compared 26 children with cerebral infarction (median age 2 months, range 0-16.2
      years) and 17 with venous thrombosis (median age 4.5 years, range 0-17 years)
      with regard to prothrombotic risk factors. Prothrombotic disorders were found in
      8 out of 26 patients with cerebral infarction (FV Leiden mutation: n = 4; protein
      C deficiency: n = 1; FV Leiden mutation + protein C deficiency: n = 2;
      prothrombin mutation G20210A: n = 1) and in 13 out of 17 with venous thrombosis
      (FV Leiden mutation n = 3; protein C deficiency n = 5; elevated HRGP + PAI: n =
      1, combined deficiency of AT, protein C and plasminogen: n = 1; F XII deficiency:
      n = 1; lupus anticoagulans n = 1; FV Leiden + F XII deficiency + lupus
      anticoagulans + PAI: n = 1). Comparison of these prevalences with those of 150
      healthy paediatric controls showed in children with FV Leiden mutation and/or
      protein C deficiency an increased risk of cerebral infarction (patients vs.
      controls: 26.9% vs. 6%; OR 5.77; 95%-CI 1.92-17.3; P = 0.0031) as well as of
      venous thrombosis (53% vs. 5.3% 19.9; 95%-CI 6-65.6; P < 0.0001). This result is
      in contrast with reports on thrombophilia in cerebral infarction in adult
      patients. CONCLUSION: Our results indicate that FV Leiden mutation and protein C
      deficiency may contribute to the multifactorial aetiology of stroke in early
      childhood.

PMID- 10650850
TI  - Genetic risk factors of thrombophilia in ischaemic childhood stroke of cardiac
      origin. A prospective ESPED survey.
AB  - Ischaemic stroke is a rare event in childhood. In approximately one-fourth of
      cases an underlying cardiac disease can be detected. We investigated the
      importance of genetic risk factors of venous thromboembolism in childhood or
      stroke in adulthood as risk factors for ischaemic stroke in children in a
      multicentre survey focusing on patients with a cardiac disease. 38 of 162 white
      infants and children (neonate-18 years) with ischaemic stroke were suffering from
      a cardiac disorder. An age-matched group of 100 children from the same geographic
      areas as the patients served as controls. Patients and controls were analysed for
      increased lipoprotein (a) levels > 30 mg/dl, for the presence of the factor V
      (FV) G1691A mutation, the prothrombin (PT) G20210 A variant, and deficiencies of
      protein C, protein S, and antithrombin. The following frequencies (patients vs.
      controls), odds ratios (OR) and confidence intervals (CI) of single risk factors
      were found: Lp(a) > 30 mg/dl (18.4% vs. 5%; OR/CI: 4.3/1.3-14.4; p = 0.03), FV
      G1691A (13.2% vs. 4%; OR/CI 3.63/0.92-14.3; p = 0.12) protein C type I deficiency
      (15.8% vs. 1%; OR/CI: 18.5/2.15-16.0; p = 0.0017), anticardiolipin antibodies
      (10.5% vs. 0%; p = 0.0051). No protein S or antithrombin deficiency was found.
      Combinations of haemostatic disorders were found in 10.5% of cases but in none of
      the controls (Fisher 0.005). CONCLUSION: While FV G1691A and prothrombin G20210 A
      mutations show no significant data in our study, lipoprotein (a) levels >30 mg/dl
      protein C deficiency, anticardiolipin antibodies and combined prothrombotic
      disorders seem to be important risk factors for manifestation of ischaemic
      strokes in children with underlying cardiac disorders.

PMID- 10650851
TI  - Coagulation-associated complications of indwelling arterial and central venous
      catheters during heparin prophylaxis--a prospective study.
AB  - A prospective observational study was carried out to investigate complications of
      arterial and venous indwelling catheters. All patients of a mixed NICU/PICU
      admitted during a 12-month period were enrolled in this study with a stringent
      protocol of catheter prophylaxis, using heparin via continuous infusion in a dose
      of 100 IU/kg/day body weight or at least 100 IU/kg/day for each arterial and/or
      central venous catheter. Patients were regularly monitored for edema, thrombus,
      ischemia and catheter obstruction, i.e. complications amenable to heparinization.
      A total of 292 catheters in 130 patients were recorded. Patients' weight ranged
      between approximately 600 g to 10,000 g. Depending on the insertion site or type
      of catheter the frequency of complications was as follows: edema 0-12%; catheter
      obstruction 7-24%; ischemia 28-40%. No case of persistent thrombosis was
      detected. CONCLUSION: A stringent protocol of heparinization leads to a low
      incidence of complications potentially amenable to anticoagulation.

PMID- 10650852
TI  - Heparin-induced thrombocytopenia in paediatric patients--a review of the
      literature and a new case treated with danaparoid sodium.
AB  - The immunological form of heparin-induced thrombocytopenia (HIT) is a potentially
      life-threatening adverse reaction of heparin medication. It is mediated by
      multimolecular complexes consisting of platelet factor 4 (PF4)-heparin-IgG which
      bind to platelets via platelet Fc gamma receptors. Cross-linking of multiple Fc
      gamma receptors results in platelet activation, platelet aggregation and enhanced
      thrombin generation with a increasing risk of developing new thrombosis. In
      children, data on HIT are sparse. This review of the literature reports on 8
      children aged 3 months to 15 years and 14 newborns suffering from HIT.
      Additionally, we report one new case treated with danaparoid sodium. Thrombotic
      complications were venous (n = 12) and arterial (n = 15). The children received
      heparin either for a spontaneous thrombotic event, for severe cardiac diseases or
      to maintain patency of intravascular catheters which are used for nutrition,
      blood sampling, and for application of medication. After diagnosis of HIT they
      were further anticoagulated with aspirin, warfarin, danaparoid sodium, lepirudin
      or low molecular weight heparin. CONCLUSION: Although HIT is less frequently
      reported in newborns and children, paediatricians should be aware of HIT in
      childhood as a potential complication of heparin application. The widespread
      practice of flushing catheters with heparin should also be debated in view of the
      risk of triggering the primary immune-response of HIT. In 1999, treatment options
      for further parenteral anticoagulation of HIT patients are danaparoid sodium (a
      low-molecular weight heparinoid) and lepirudin (a direct thrombin inhibitor).

PMID- 10650853
TI  - The low molecular weight heparin dalteparin for prophylaxis and therapy of
      thrombosis in childhood: a report on 48 cases.
AB  - We investigated the efficacy, safety and relation of dose to plasma anti-Xa
      activity of the low molecular weight heparin (LMWH) dalteparin in prophylaxis and
      therapy of arterial and venous thrombosis in pediatric patients. A total of 48
      children were enrolled: 10 received dalteparin for prophylaxis (group I), 8 for
      reocclusion prophylaxis following successful thrombolysis (group II), 5 following
      failed thrombolysis (group III) and 23 for primary antithrombotic therapy (group
      IV). Two children were treated with dalteparin for pulmonary veno-occlusive
      disease (PVOD) and for primary pulmonary hypertension (PPH), respectively.
      OUTCOME: In group I no thrombo-embolic event occurred. In group II recanalization
      was maintained or improved, in group III vascular occlusion persisted under
      dalteparin. In group IV we saw complete recanalization in 7/23 (30%), partial
      recanalization in 7/23 (30%) and no recanalization in 9/23 (40%) cases. The child
      with PVOD had recanalization proven by lung biopsy; the clinical condition of the
      child with PPH also improved. Minor bleeding occurred in 2/48 (4%) children. For
      prophylaxis 95 +/- 52 (mean and SD) anti-Xa IU/kg BW, for therapy 129 +/- 43
      (mean and SD) anti-Xa IU/kg BW proved effective. For both prophylaxis and therapy
      the required dose per kg BW was inversely related with age (r2 = 0.64, P = 0.017;
      r2 = 0.13, P = 0.013). CONCLUSION: Dalteparin proved to be an effective and well
      tolerated drug for prophylaxis and therapy of thrombosis in pediatric patients.
      Dose requirement for effective treatment was higher in younger children and
      decreased with age.

PMID- 10650854
TI  - Hemothorax under thrombolytic therapy with recombinant tissue: plasminogen
      activator (rt-PA) in a 16-year-old girl.
AB  - We present the case of a 16-year-old girl with an extended thrombosis of the
      femoral and iliac vein and the inferior vena cava during pleuropneumonia;
      predisposing risk factors for thrombophilia were: use of contraceptives, nicotine
      abuse and congenital deficiency of antithrombin III (not previously diagnosed).
      Thrombolytic therapy with recombinant tissue plasminogen activator (rt-PA;
      initial dose: 0.08 mg/kg/h) was started. 2 days later--after diagnosis of an
      extended hemothorax: 1500 ml blood were obtained after thoracocentesis,
      transfusion of packed red blood cells was necessary--rt-PA was stopped, with only
      heparin (400 U/kg/d) being administered. 36 h later--the thrombosis had not yet
      changed--the thrombolytic therapy with rt-PA was continued in a markedly reduced
      dose (0.015 mg/kg/d) with no further bleeding complications. 8 days later--after
      successful thrombolysis--t-PA was stopped, heparin was given for another 10 days,
      then cumarin was administered orally.

PMID- 10650855
TI  - Clinical relevance of genetic risk factors for thrombosis in paediatric oncology
      patients with central venous catheters.
AB  - We prospectively evaluated the clinical relevance of genetic risk factors of
      thrombosis in 137 paediatric patients with solid tumours or leukaemia/lymphoma.
      The factor V G1691A (FV-L), the prothrombin G20210A (FII-L) and the homozygous
      MTHFR variant were examined. In addition, protein C, protein S and antithrombin
      (AT) deficiency were evaluated in patients with ALL or thrombosis. The inter
      group incidence of risk factors and thrombotic events was compared. 73 of the 137
      patients had ALL and 64 another form of leukaemia, lymphoma or a solid tumour.
      They were treated according to the established paediatric tumour protocols ALL
      BFM, NHL-BFM, COSS, CWS and others. All patients had central venous lines. No
      patient received heparin or any other anticoagulant. Endpoints of the study were
      thrombosis, regular completion of chemotherapy or death. Incidence of mutations
      in the whole group: FV-L (7.3% heterozygous, 0.7% homozygous); FII-L (2.9%
      heterozygous, no homozygotes); MTHFR (51.8% heterozygous, 10.9% homozygous). Ten
      patients (7.3%), 6 with ALL and 4 with solid tumours, developed thrombosis. 4 of
      the 6 patients with ALL and thrombosis (67%) but only 21% of ALL patients without
      thrombosis had a genetic risk factor (P < 0.013, chi2). No genetic defect was
      found in the 4 patients with other malignancies and thrombosis. However, besides
      a tumour, these patients had additional exogenous risk factors including diabetes
      insipidus and hemiparesis. CONCLUSION: Genetic mutations appear to be additional
      risk factors for the development of thrombosis in patients with ALL. In contrast,
      these mutations do not appear to be relevant risk factors for thrombosis in the
      small number of children with other malignant diseases reported here. This
      difference may be due to asparaginase and corticosteroids being used in ALL but
      not in solid tumour protocols.

PMID- 10650856
TI  - Clinical importance of prothrombotic risk factors in pediatric patients with
      malignancy--impact of central venous lines.
AB  - To evaluate the role of inherited thrombophilia in the development of central
      venous line (CVL)-related thrombosis, the following parameters were determined in
      77 pediatric-oncologic patients with CVL: activated protein C (APC)-ratio, factor
      V (FV) G1691A and prothrombin G20210A mutation, protein C, protein S,
      antithrombin, coagulation factor XII, lipoprotein (a) and homocysteine. An
      inherited prothrombotic risk factor was found in 17 patients (23%). Four out of
      14 patients with a single detect (hyperlipoproteinemia, heterozygous FV G1691A
      and prothrombin G20210A mutation, protein C deficiency type I) and all three
      patients with combined defects (heterozygous FV G1691A mutation combined with
      heterozygous prothrombin G20210A variant, protein S deficiency or
      hyperlipoproteinemia) suffered from CVL-related thrombosis. In 11 out of 77
      patients (14%) a CVL-related thrombosis was detected. In 2 children thrombosis
      occurred a few days after asparaginase therapy and in another three thrombosis
      was associated with CVL-related septicemia caused by Staphylococcus epidermidis.
      After removal of CVL, thrombosis was detected in 5 children, in 2 without
      clinical symptoms but in the presence of inherited prothrombotic risk factors.
      CONCLUSION: The present study demonstrates the clinical importance of CVL in
      combination with inherited thrombophilia in the development of thrombosis in
      pediatric-oncologic patients. Before or shortly after insertion of CVL, patients
      should be tested for the presence of factor V G1691A mutation, prothrombin
      G20210A variant and increased lipoprotein (a) values.

PMID- 10650857
TI  - The course of fibrinolytic proteins in children with malignant bone tumours.
AB  - To evaluate the role of fibrinolytic and proteolytic proteins in children and
      adolescents suffering from Ewing sarcoma or osteosarcoma with respect to
      postoperative complications and late outcome, a prospective two-arm two-centre
      study was conducted. Plasminogen, plasminogen activator inhibitor (PAI)-1, tissue
      type plasminogen activator (t-PA) and urokinase plasminogen activator (u-PA) were
      investigated in the pre-surgical period and in the postoperative follow-up period
      in children suffering from Ewing sarcoma (ES; n = 36) or osteosarcoma (OS; n =
      39). In addition, the factor V mutation (FV) Q506, protein C, protein S,
      antithrombin and lipoprotein (a) were determined. All children received LMWH
      (EnoxaparinR) 1 mg/kg s.c. once daily over a period of 6 weeks to 3 months.
      Besides a short-lasting increase of PAI-1 in patients with OS on day 1 and in
      children with Es on day 14, a small and significant but clinically irrelevant
      difference was found on days 7-10 for plasminogen, t-PA and u-PA. No
      thromboembolic complications occurred in patients treated with LMWH and having a
      prothrombotic genetic risk factor. Within one year of surgery 7 out of 36
      patients with ES and 5 out of 39 children with OS showed a relapse of their
      disease. Prior to the first local tumour therapy, 5 out of 7 children with ES and
      relapse had elevated u-PA concentrations compared with 2 out of 5 children in the
      OS group. No such differences were found for PAI-1- or t-PA antigen. CONCLUSION:
      The role of u-PA as a possible follow-up marker for a poorer outcome in children
      with ES should be evaluated in a prospective multicentre study.

PMID- 10650859
TI  - Severe protein C deficiency and aseptic osteonecrosis of the hip joint: a case
      report.
AB  - Homozygous congenital protein C deficiency is accompanied by severe
      thrombophilia. Thrombotic events can be reduced in number and severity by
      lifelong oral anticoagulation therapy. A 4-year-old boy was first diagnosed as
      having severe congenital homozygous protein C deficiency during the neonatal
      period when purpura fulminans occurred as the first manifestation of thrombosis.
      From this time he had been treated with phenprocoumon (INR 3.5-4.5). During an
      infection of the upper respiratory tract he developed signs of a new episode of
      purpura fulminans (INR 2.6). Additional anticoagulation therapy with LMW heparin
      (Clexane) and protein C concentrate was given while the oral anticoagulation
      therapy was continued. On the third day of this episode the boy suffered from
      pain of unknown origin. MRI of the abdomen and of the pelvis revealed
      nontraumatic osteonecrosis of the hip joint. After a few weeks of immobilisation
      no special treatment was necessary. One year later he was able to walk with no
      problem. CONCLUSION: Aseptic osteonecrosis of the hip joint is associated with a
      variety of disorders including vascular thrombosis and haemorrhage. Especially
      young children and handicapped patients with thrombophilia and pain of unknown
      origin are suspected to have thrombosis in atypical regions.

PMID- 10650858
TI  - Antithrombin treatment of severe hepatic veno-occlusive disease in children with
      cancer.
AB  - Hepatic veno-occlusive disease (VOD) is a well-known complication of chemotherapy
      in Wilms tumor patients, particularly young children. Although this complication
      resolves uneventfully in most patients, fatal cases have been reported. Severe
      VOD after transplantation has a high mortality rate ranging from 45% to 98%. New
      hemostatic therapeutic strategies have significantly improved the prognosis of
      VOD. Chemotherapy-related VOD in Wilms tumor usually has a good prognosis. We
      describe two patients with Wilms tumor and one with acute lymphoblastic leukemia,
      who developed severe veno-occlusive disease of the liver according to the
      Baltimore criteria while undergoing chemotherapy; the symptoms were hepatomegaly,
      ascites, hyperbilirubinemia, weight gain and, in one patient, short-term
      lethargy. Elevated LDH levels of 872 to 12,000 U/l were observed in our patients.
      All patients had thrombocytopenia between 29,000 and 40,000/microl and decreased
      antithrombin (AT) and protein C levels; two patients had gastrointestinal
      bleeding. All patients developed a coagulopathy because of severe hepatic
      dysfunction. Two patients received low-dose heparin at the onset of VOD. The
      thrombolytic therapy was rapidly changed to AT supplementation (20-80 IU/kg bw 2x
      per day) without heparin when thrombocytes were very low or gastrointestinal
      bleeding occurred. Resolution of VOD was observed in all patients receiving AT
      alone. The chemotherapy was discontinued in a patient with accidental actinomycin
      D overdosage in view of the severity of symptoms. The remaining two patients
      received chemotherapy according to the therapy protocol after restitution. All
      patients survived without sequelae with a median follow-up of 28 months (range 8
      48 months). CONCLUSION: Hepatic veno-occlusive disease is a rare but increasingly
      recognized complication in pediatric cancer patients receiving conventional
      chemotherapy. AT supplementation constitutes a good alternative treatment of
      severe VOD in comparison with other thrombolytic therapies, particularly in
      patients at high risk of bleeding.

PMID- 10650860
TI  - Prevalence and outcome of intracranial haemorrhage in haemophiliacs--a survey of
      the paediatric group of the German Society of Thrombosis and Haemostasis (GTH).
AB  - A survey among centres of the paediatric group of the GTH was performed to
      evaluate the prevalence and outcome of haemophiliacs with intracerebral
      haemorrhage. A questionnaire sent to the centres covered the following points:
      number of patients with severe, moderate and mild haemophilia A and B; for each
      patient with ICH: birth date, age at bleeding, aetiology and neurological
      sequelae. Overall, 30 ICH in 744 haemophiliacs (4.0%) were reported by 17/40
      centres (42.5%). There was no significant difference between the prevalence of
      patients with haemophilia A and B (3.5% vs. 6.3%) and among the age groups.
      Bleeding was diagnosed within 1 week of birth in 11/27 patients (41%). For 3
      patients, no age-related information was given. The most important factor was
      trauma (17/30 = 57%), either during birth (9/30 = 30%) or later in life (8/30 =
      27%). Seizures were common, occurring in 19/30 patients (63%). As 1 patient died
      after posttraumatic ICH, the neurological outcome of 29 patients could be
      evaluated. Psychomotor and statomotor retardation and cerebral palsy were
      reported in 17/29 (59%), 15/29 (51%) and 13/29 (45%) patients respectively. Only
      7/29 (24%) showed no neurological sequelae. Severity of deficits was not
      correlated with birth date but to age at bleeding. Older children showed a better
      neurological outcome than neonates. CONCLUSION: The frequency and outcome of ICH
      in haemophiliacs have not changed in our cohort over the past 20 years. Trauma at
      birth is an important risk factor for ICH in patients with haemophilia A or B.
      Intracranial haemorrhages in older children are rare, and a better outcome may be
      expected.

PMID- 10650861
TI  - When are children diagnosed as having severe haemophilia and when do they start
      to bleed? A 10-year single-centre PUP study.
AB  - The aim of this single-centre study was to obtain data prospectively on when
      children are diagnosed as having severe haemophilia and when they start to bleed.
      Results of this 10-year PUP study suggest that severe haemophilia is nowadays
      diagnosed much earlier than in the Sixties. Patients with severe haemophilia (n =
      37: FV III <0.01 U/ml) start to bleed at very different ages. While 44% of
      patients have their first bleeding episode within the first year of life, others
      do not bleed before the age of four. The onset of joint bleedings generally
      occurs about half a year later than other types of bleeding. While half our
      patients developed their first bleeding by the age of 1.22 years, the mean age
      for the first joint bleeding was 1.91 years. CONCLUSION: Early-onset prophylactic
      therapy can prevent damage to the joints, but for rational therapy the age at
      onset of bleeding must also be taken into account. A non-bleeding child does not
      benefit from prophylactic treatment.

PMID- 10650862
TI  - A 2-year-old boy with recurrent severe bleeding: von Willebrand type 2B and ITP-
      or von Willebrand type 2B alone?

PMID- 10650863
TI  - DDAVP treatment in a child with von Willebrand disease type 2M.
AB  - von Willebrand disease (vWD) type 2M is characterized by the decreased platelet
      dependent function of the von Willebrand factor (vWF) that is not caused by the
      absence of HMW vWF multimers. We report here on a 4-year-old boy with vWD type
      2M, who underwent adenotomy and paracentesis after correction of his hemostatic
      defect by stimulation with DDAVP. The decreased basal levels of vWF Antigen (Ag),
      ristocetin cofactor activity (RiCoF) and collagen binding activity (CBA) (32%,
      14% and 9% respectively) could be stimulated to maximum levels of 69%, 70% and
      95% 2 h post DDAVP administration. DDAVP was administered in a dosage of 0.4
      microg/kg BW intravenously 30 min prior to surgery. No bleeding occurred intra-
      and perioperatively. vWF multimer analysis revealed supranormal multimers with an
      abnormal satellite banding pattern. The typical separation by gel electrophoresis
      into oligomers with a triplet structure was missing even after stimulation with
      DDAVP. Thus, the functional hemostatic defect was corrected in this patient after
      DDAVP administration, although the structural abnormalities of the vWF multimers
      were still persisting. CONCLUSION: In conclusion, type 2M vWD might be
      effectively treated with DDAVP administration in cases of elective surgery,
      dispensing with vWF replacement by pooled blood products.

PMID- 10650864
TI  - Analysis of von Willebrand factor in platelets of patients with various forms of
      von Willebrand disease: is there a clinical relevance?
AB  - Besides the investigation of coagulation factor VIII:c and von Willebrand factor
      in plasma. vWF antigen and vWF collagen-binding activity in platelets of 24
      patients with various forms of von Willebrand disease were analysed. No platelet
      vWF:Ag or vWF:CBA was detectable in type 3 patients (n = 4). In contrast 6 out of
      7 patients with type 2 vWD had normal or increased vWF levels. Two type I
      patients (out of n = 13) with low von Willebrand factor in platelets had no
      increased bleeding tendency. In two other individuals with normal amounts of von
      Willebrand factor in platelets and low plasmatic vWF and factor VIII:c, more
      frequent bleeding episodes reflecting the low plasmatic levels were observed in a
      long-term follow-up. CONCLUSION: In our patients, bleeding history corresponded
      to plasmatic levels of FVIII:c and vWF.

PMID- 10650865
TI  - Portal vein thrombosis in a patient with severe haemophilia A and F V G1691A
      mutation during continuous infusion of F VIII after intramural jejunal bleeding-
      successful thrombolysis under heparin therapy.
AB  - We report on a 14-year-old boy with severe haemophilia A who developed a portal
      vein thrombosis during continuous infusion of F VIII. For treatment of a
      posttraumatic intramural jejunal haematoma with extension into the mesenterium
      the patient received continuous infusion (CI) of a high purity F VIII
      concentrate, starting with an initial bolus injection of 100 IU F VIII/kg bw and
      followed by 4-5 IU F VIII/kg bw/h i.v. F VIII plasma activity ranged between 47
      and 88%. Resorption of the haematoma was proven by abdominal ultrasonic follow
      ups. After 3 weeks of CI a thrombus formation in the portal vein was detected by
      ultrasound and confirmed by duplex ultrasound. Subsequent to diagnosis the
      patient was heparinised with unfractionated heparin (UFH 300-450 IU/kg/d i.v.).
      In order to induce further resorption of the haematoma. F VIII concentrate was
      given concomitantly (50 IU/kg bw twice daily) during the initial phase of
      treatment. After 14 days of anticoagulant therapy with UFH, the regimen was
      changed to low molecular weight heparin (LMWH; Fraxiparin 0.3; 2850 IU anti-X
      activity/d s.c.; bw 60 kg). F VIII dosage was gradually reduced with advanced
      resorption of the haematoma and thereafter switched to prophylaxis (40 IU/kg bw 3
      times weekly). Complete lysis of the thrombus was observed after 6 months of
      treatment with UFH and LMWH respectively without any further complications.
      Thereafter LMWH was discontinued. Thrombophilic screening revealed no
      abnormalities except heterozygous F V G1691A. CONCLUSION: The coexistence of a
      common prothrombotic risk factor and haemophilia may cause severe complications,
      in particular if the bleeding disorder has to be corrected temporarily by
      administration of the concerning deficient agent.

PMID- 10650866
TI  - Can 3 oral 2 mg doses of vitamin K effectively prevent late vitamin K deficiency
      bleeding?
AB  - A 1 mg dose of vitamin K given intramuscularly at birth prevents almost all cases
      of late VKDB, whereas even two oral doses of 1 mg vitamin K given in the first
      week and a third given in week 5 to 6 are less effective. Is efficacy improved by
      increasing the dose to 3 x 2 mg? For active surveillance of VKDB, monthly
      postcards which include a nothing-to-report option, were sent to all heads of
      pediatric hospitals in Germany from January 1995 to December 1998. All reports
      were validated according to a standard case definition for late VKDB by means of
      a questionnaire. The incidence of VKDB with three oral doses of 2 mg vitamin K is
      compared to previously published rates for VKDB on 3 oral 1 mg oral doses, which
      had been ascertained with the same surveillance scheme. The number of cases of
      VKDB (excluding the failure-of-management cases) in children aged 8 days to 12
      completed weeks during the 4 year period was 23. 14 had intracranial hemorrhage,
      22 had been exclusively breastfed, and in 20 cholestasis was detected after the
      bleeding episode. 14/23 had been given all recommended 2 mg doses for vitamin K
      prophylaxis. Until 1996 all had been given the cremophor vitamin K preparation,
      whereas in 1997 to 1998 two children with late VKBD had received the new mixed
      micellar (MM) preparation, first licensed in July 1996. The incidence of VKBD per
      100,000 live births during the 1995 to 1998 period was 0.72, including children
      given no vitamin K prophylaxis, and 0.44 for children who had received all age
      related recommended vitamin K doses. These incidence rates are significantly
      lower than those previously published for the 3 x 1 mg dose regimen in Germany
      (1.8 cases of late VKDB per 100,000 live births in children who had received all
      recommended vitamin K doses). Not all cases of late VKDB, however, are prevented
      by the 3 x 2 mg dose regimen, even if the new mixed micellar preparation is given
      instead of the cremophor preparation.

PMID- 10650867
TI  - Treatment of consumption coagulopathy with antithrombin concentrate in children
      with acquired antithrombin deficiency--a feasibility pilot study.
AB  - Consumption coagulopathy is a serious problem in childhood. In addition to
      treatment of the underlying disease, consumption coagulopathy was previously
      treated with heparin. Nowadays it is treated by substitution of coagulation
      factors, especially antithrombin (AT) concentrate, alone or in combination with
      heparin. In this pilot study we administered AT concentrate (dosage 80 U/kgbw/d),
      without additional heparin treatment, to 29 children beyond infancy with acquired
      AT deficiency. Antithrombin, platelet count, fibrinogen, PT, and APTT were
      assayed before and during the course of AT substitution. These coagulation
      parameters returned to normal 48 hours after normalisation of the plasma AT
      level. AT levels normalised within 24 h of initial substitution in all children.
      Lethal outcome due to the underlying disease was observed in only two children.
      CONCLUSION: Data of this pilot study suggest that, concomitantly with the
      treatment of the underlying disease, consumption coagulopathy in childhood can be
      managed successfully with early substitution of AT concentrate.

PMID- 10650868
TI  - Systemic meningococcal infection: which children may benefit from adjuvant
      haemostatic therapy? Results from an observational study.
AB  - The potential benefits of haemostatic therapy (heparin, antithrombin (AT)
      concentrate, fresh frozen plasma (FFP)) in severe systemic meningococcal
      infections (SMI) are controversial. A reduction of the still high case fatality
      rate would be an important indicator for potential benefits of adjuvant
      haemostatic therapy in children with SMI. Observational data from nationwide,
      active surveillance for SMI in children under 16 years in all German paediatric
      hospitals over a one-year period were used to assess whether potentially
      beneficial effects of haemostatic therapy are related to the severity of disease.
      The Neisseria sepsis index (NESI), which grades the severity of SMI from 0 to 8
      and has proven to be a reliable tool for predicting the outcome of children with
      SMI, was used as an indicator of the severity of SMI. During the study period
      from July 1994 to June 1995, 305 children met the case definition; for 176 of
      these, complete data sets providing information on parameters underlying the NESI
      index and regarding the specific haemostatic therapy were available. As all
      recorded children with NESI 0-2 (n = 129; 73%) survived, a potential impact of
      haemostatic therapy (given to 45 of them) on survival would be undetectable in
      this group. A NESI between 3 and 8 was found in 47/176 patients (24%), 35 of whom
      received some kind of haemostatic therapy. The survival rates were 80% in
      children with haemostatic therapy (n = 35) and 50% in those without (n = 12)
      (odds ratio 0.25; 95% confidence interval 0.06-0.98). A subgroup analysis of
      patients with NESI 3-5 versus those with NESI scores above 5 showed that the
      beneficial effect of haemostatic therapy was almost confined to children in the
      NESI 3-5 subgroup. In this subgroup there were 28/31 (90%) survivors with, and
      6/11 (55%) survivors without adjuvant haemostatic therapy, whereas none of the
      patients (n = 5) with a NESI of 6-8 survived, although 4 had received adjuvant
      haemostatic therapy. CONCLUSION: Studies on the impact of adjuvant haemostatic
      therapy on survival in children with SMI should focus on those with NESI scores 3
      5. The data from this population-based, observational study suggests that
      haemostatic therapy might reduce the case fatality rate in these children. The
      optimal dosage and choice of preparations remains to be established. Alternative
      adjuvant therapeutic strategies may be required in children with SMI and NESI
      scores > 5.

PMID- 10650869
TI  - Post-trauma coagulation and fibrinolysis in children suffering from severe
      cerebro-cranial trauma.
AB  - The present study was designed to evaluate the post-trauma haemostatic changes in
      27 children with severe cranio-cerebral trauma defined by a modified Glasgow Coma
      Score (GCS) < 10. Blood samples for coagulation studies (fibrinogen, von
      Willebrand factor (vWf), factor VIII:C, antithrombin, protein C, plasminogen,
      tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor-1
      (PAI), D-dimer) were obtained within two hours of admission, 24 h later, and on
      days 3-5, 7-9, 21 and 35. Data of this study indicate that alterations of
      coagulation in paediatric patients are similar to those in adults: On
      hospitalisation, activated haemostasis was found with decreased fibrinogen,
      antithrombin and protein C along with enhanced t-PA and PAI. Twenty-four hours
      later, hypercoagulability with significantly increased vWF and fibrinogen
      started, with a peak level within the second week. Within 24 h of admission, 17
      children developed disseminated intravascular coagulation (DIC) with a clear-cut
      decrease of antithrombin and fibrinogen together with platelet consumption and
      enhanced D-dimer. The outcome of children with DIC was significantly poorer than
      in those without DIC. Complete recovery was seen in five patients; sequelae no
      handicap and moderate disability were each found in six patients. Severe
      disability was diagnosed in two children, and fulminant DIC with lethal outcome
      occurred in eight patients. The GCS (P < 0.01) and the occurrence of DIC (P <
      0.005) showed the strongest association with the patients' clinical outcome.
      CONCLUSION: Our data underline the significance of post-trauma disturbances of
      the haemostatic system for the clinical course and outcome in children with
      severe cranio-cerebral injuries.

PMID- 10650870
TI  - Anticoagulant response to Agkistrodon Contortrix venom (ACV) in infants and
      children with genetic defects in the protein C anticoagulant pathway.

PMID- 10650871
TI  - Plasma values for u-PA in children.
AB  - Urokinase-type plasminogen activator (u-PA) is one major activator of
      plasminogen. It is also involved in tissue remodelling, angiogenesis, cell
      migration, and tumour metastasis. In adults, increased u-PA levels have been
      identified in patients with chronic liver disease. No data exist for u-PA plasma
      levels in children. In the present study, u-PA plasma levels were measured by
      ELISA in 95 healthy children and adolescents aged 7 months to 17 years. We found
      a median value of 1.06 ng/ml u-PA (range 0.43-15.78 ng/ml), which is similar to
      that found in adults (2-20 ng/ml). No differences between males and females were
      recorded. In addition, we determined u-PA plasma levels of 16 patients with
      severe or mild type I plasminogen deficiency and found a median value of 1.06
      ng/ml (range 0.69-7.7 ng/ml). CONCLUSION: Normal plasma u-PA values in healthy
      children and adults are virtually no different from those reported in adults.

PMID- 10650872
TI  - Thrombocytopenic purpura: adverse reaction to a combined immunisation
      (recombinant hepatitis B and measles-mumps-rubella-vaccine) and after therapy
      with Co-trimoxazole.

PMID- 10650873
TI  - New insights on the biology of myelin basic protein gene: the neural-immune
      connection.
AB  - In the past 6 years, our conception of the major myelin protein genes has begun
      to change significantly because of recent findings documenting the existence of
      new exons encoding other products of these genes. A decade ago the myelin basic
      protein (MBP) and proteolipid protein (PLP) genes were thought to be expressed
      solely in myelin-forming cells, and their products were thought to be structural
      components of myelin. Since then, abundant evidence has been gathered identifying
      the presence of products of these genes in nonmyelinating cell types including
      both the immune and the nervous systems. Furthermore, within the nervous system,
      products of these genes have been identified in neurons and embryonic cells,
      clearly indicating that these myelin protein genes have additional functions in a
      number of cell types that are unrelated to myelination. In this brief
      communication, we review the recent literature that has resulted in this revision
      of our understanding of the MBP gene structure, products and expression.

PMID- 10650875
TI  - Biochemistry and neuropathology of mice doubly deficient in synthesis and
      degradation of galactosylceramide.
AB  - We have generated mice doubly deficient in both synthesis and degradation of
      galactosylceramide by cross-breeding twitcher mice and galactosylceramide
      synthase (UDP-galactose:ceramide galactosyltransferase, CGT) knockout mice. The
      prediction that the phenotype of the doubly deficient mice should be the same as
      the cgt -/- mice, since the degrading enzyme should not be necessary if the
      substrate is not synthesized, proved to be only partially correct. In early
      stages of the disease, the doubly deficient mice (galc -/-, cgt -/-) were
      essentially indistinguishable from the cgt -/- mice. However, the doubly
      deficient mice had a much shorter life span than cgt -/- mice. Both
      galactosylceramide and galactosylsphingosine (psychosine), were undetectable in
      the brain of the cgt -/- and the doubly deficient mice. The characteristic
      twitcher pathology was never seen in the galc -/-, cgt -/- mice. However, after
      43 days, neuronal pathology was observed in the brainstem and spinal cord. This
      late neuronal pathology has not been seen in the CGT knockout mice but has been
      described in some long surviving bone marrow-transplanted twitcher mice.
      Furthermore, the motor segment of the trigeminal nerve of the galc -/-, cgt -/-
      mice showed severe degeneration not seen in either twitcher or CGT knockout mice.
      Thus, the galc -/-, cgt -/- mice, while primarily showing the cgt -/- phenotype
      as predicted, develop late pathology that is seen only in twitcher mouse and also
      a unique pathology in the trigeminal nerve. These observations indicate that the
      functional relationship between galactosylceramidase and galactosylceramide
      synthase is complex.

PMID- 10650874
TI  - Major histocompatibility complex heavy chain accumulation in the endoplasmic
      reticulum of oligodendrocytes results in myelin abnormalities.
AB  - The immune cytokine interferon-gamma (IFN-gamma) is believed to be a key agent in
      the pathogenesis of immune-mediated demyelinating disorders. We have examined the
      possibility that one effect of this cytokine involves overloading the endoplasmic
      reticulum (ER) of oligodendrocytes through the induction of major
      histocompatibility complex (MHC) class I heavy chain (HC) gene expression. For
      these studies, we have utilized several genetic mouse models that yield different
      subcellular localizations of HC in oligodendrocytes. We show that transgenic mice
      that ectopically express HC in oligodendrocytes (MBP/MHC class I mice) fail to
      transport HC past the ER. These mice are hypomyelinated and have a tremoring
      phenotype. When oligodendrocytes deficient in beta-2 microglobulin (beta2m),
      which is required for MHC class I assembly and transport, were treated with IFN
      gamma in vitro, HC was transported past the ER to the trans-Golgi network but not
      onto the cell surface. When an asymptomatic line of mice that expresses MHC class
      I in the CNS due to transgene-derived IFN-gamma (MBP/IFN-gamma mice) was crossed
      onto the beta2m-/- background, the resulting mice were asymptomatic. In contrast,
      increasing the amount of MHC class I protein transported through the ER in
      MBP/MHC class I transgenic mice, by crossing them to the asymptomatic MBP/IFN
      gamma mice, exacerbated their phenotype. Taken together, these data indicate that
      the ER is a sensitive site in oligodendrocytes for accumulation of MHC class I HC
      and suggest a molecular mechanism for IFN-gamma's deleterious effects on these
      cells.

PMID- 10650876
TI  - Twitcher mice with only a single active galactosylceramide synthase gene exhibit
      clearly detectable but therapeutically minor phenotypic improvements.
AB  - Cross-breeding of mouse mutants, each defective in either synthesis (CGT
      knockout) or degradation (twitcher) of galactosylceramide, generates hybrids with
      a genotype of galc -/-, cgt +/-, in addition to doubly deficient mice. They are
      ideally suited to test the potential usefulness of limiting synthesis of the
      substrate as a treatment of genetic disorders due to degradative enzyme defects.
      The rate of accretion of galactosylceramide in the brain of CGT knockout carrier
      mice (cgt +/-) is approximately two-thirds of the normal, suggesting a gene-level
      compensation for the reduced gene dosage. Phenotype of twitcher mice with a
      single dose of normal cgt gene was indeed milder with statistical significance,
      albeit only slightly. Compared among 10 paired littermates, the difference in the
      life span was 7+/-3.9 days (S.D.) and the difference in the maximum attained body
      weight was 1.9+/-1.2 g (S.D.). Neuropathologists were able to distinguish blindly
      galc -/-, cgt +/- mice from galc -/-, cgt +/+ mice. The brain psychosine level in
      galc -/-, cgt +/- mice was also approximately two-thirds of the galc -/-, cgt +/+
      mice. These observations indicate that reduction of galactosylceramide synthesis
      to two-thirds of the normal level results in minor but clearly detectable
      phenotypic improvements. Because of the detrimental consequences of drastic
      reduction in galactosylceramide synthesis that may be required for pragmatically
      meaningful improvements, this approach by itself is unlikely to be useful as the
      sole treatment but may be helpful as a supplement to other therapies.

PMID- 10650877
TI  - Interaction of sulfoglucuronyl (HNK-1) carbohydrate and its binding protein, SBP
      1, in microexplant cultures of rat cerebellum.
AB  - Sulfoglucuronyl carbohydrate (SGC) is expressed on several neural cell-adhesion
      molecules and on glycolipids. SGC and its binding protein, SBP-1 are
      developmentally regulated in the nervous system and have been implicated in
      regulating neurite outgrowth and cell-cell recognition during neuronal cell
      migration. To elucidate the role of interaction between SGC and SBP-1,
      microexplant cultures of postnatal day 5 rat cerebellum were employed. In explant
      cultures, SGC was localized primarily in the neuronal cell processes,
      neurofilaments, and dendrites that emerge from the core of the explants up to 90
      microm, after 24 hr in culture. SGC was also present in the short astrocytic
      processes near the core of the explant. SBP-1 was localized mainly in the granule
      neuron cell bodies and faintly on cell plasma membranes and processes. Granule
      neurons, expressing SBP-1, migrated outward in close contact with the SGC bearing
      neuronal processes, suggesting interaction between SGC and SBP-1. The neurite
      outgrowth and cell migration were specifically and severely reduced, in dose
      dependent manners, by anti-SGC (HNK-1) and anti-SBP-1 antibodies and
      sulfoglucuronyl glycolipid (SGGL). Other irrelevant antibodies and glycolipids
      had little effect. The results showed that SBP-1 was required for neurite
      outgrowth and that SGC-SBP-1 interaction was important for cell-cell recognition
      and cell migration.

PMID- 10650878
TI  - Quantitative analysis of the dopamine D4 receptor in the mouse brain.
AB  - The D4 receptor (D4R), a member of the dopamine D2-like receptor family, has been
      implicated in the pathophysiology of several diseases and has been the target of
      various investigations regarding its distribution and quantification. The brain
      distribution of the D4R has been well described in various species, but the
      quantification is still an issue of controversy, because no specific ligand is
      commercially available. To circumvent this difficulty we have performed a
      biochemical and autoradiographical study in brain samples obtained from mice
      lacking D4Rs and their wild-type siblings; comparison of their binding parameters
      allows a more accurate quantification of the members of the D2-like receptor
      family (D2, D3, and D4 receptors). We found that the distribution of D2-like
      receptors in mouse brain is similar to that of rat brain, i.e., caudate putamen,
      nucleus accumbens, olfactory tubercle, and hippocampus. The contribution of the
      D4R to the overall population of D2-like receptors is 17% in nucleus accumbens,
      21% in caudate putamen and olfactory tubercle, and 40% in hippocampus. Based on
      our study we conclude that nemonapride probably binds to nondopaminergic sites
      that if not properly blocked may lead to overestimations of D4R levels. We
      observed that the experimental condition that better estimates the density of D4
      receptors is the displacement of D2 and D3 [3H]nemonapride binding sites with
      cold raclopride.

PMID- 10650879
TI  - Up-regulation of genes involved in cellular stress and apoptosis in a rat model
      of hippocampal degeneration.
AB  - Changes in gene expression within the hippocampus induced by denervation after
      electrolytic fimbria-fornix lesion in rat were compared to morphological and
      biochemical alterations. Fimbria-fornix lesion results in degeneration of
      hippocampal cholinergic terminals as evidenced by a sustained (2 days to 1 month)
      decrease in cholineacetyltransferase (ChAT) activity (50%). These changes were
      accompanied by a decrease in growth associated protein 43 (GAP-43)
      immunoreactivity in all hippocampal layers 4 days after lesion followed by a
      subsequent increase and return to normal levels by 20 days postinjury. This
      increase in GAP-43 expression in the hippocampus between 7 to 20 days after
      lesion may reflect heterotypic sprouting. TUNEL-positive cells were revealed by
      in situ assay within the hippocampus at 10 days, but not at 3 days, after lesion.
      Two subtracted cDNA libraries from the dorsal hippocampus of control and injured
      rats (at 3 and 10 days postlesion) were constructed in order to search for new
      genes potentially implicated in degeneration/regeneration phenomena. We analysed
      1,536 clones from each library by differential screening and found a total of 46
      up-regulated genes. Among the 15 known genes, 6 coded for proteins involved in
      signal transduction pathways. The upregulation of growth arrest DNA damage
      induced gene (GADD153), brain-specific RING finger protein, JNK interacting
      protein (JIP-1), protein kinase A (PKA), and Na+K+ ATPase was studied by
      quantitative polymerase chain reaction (PCR). Two of these genes, GADD153 and JIP
      1, have been previously shown to participate in cell modifications induced by
      stress and apoptosis.

PMID- 10650880
TI  - Abnormalities in 5-HT2A receptor mRNA expression in frontal cortex of chronic
      elderly schizophrenics with varying histories of neuroleptic treatment.
AB  - Alterations in the 5-HT2A receptor gene expression in the prefrontal cortex have
      been suggested to play a role in the pathophysiology and pharmacotherapy of
      schizophrenia. This study measured mRNA encoding 5-HT2A receptor in the left
      superior frontal gyrus from chronic elderly schizophrenics (n = 21) with varying
      neuroleptic-free intervals before death (72 hr to more than 5 years), and normal
      drug-free elderly controls (n = 14). Levels of 5-HT2A mRNA in schizophrenics
      correlated significantly and inversely with neuroleptic-free interval before
      death (r = -0.77; P < 0.0001). In schizophrenics who had been receiving
      neuroleptic until time of death, levels of 5-HT2A mRNA were similar to controls
      or greater. In schizophrenics who had been free of neuroleptic for more than six
      months levels of 5-HT2A mRNA were significantly lower than in controls. These
      results confirm previous findings of decreased expression of the 5-HT2A receptor
      gene in the frontal cortex of some schizophrenics and suggest that regulation of
      this gene may be involved in the therapeutic actions of typical neuroleptics.

PMID- 10650881
TI  - Wild-type and mutant forms of v-src differentially alter neuronal migration and
      differentiation in vivo.
AB  - The effects of three different forms of v-src on brain cell development were
      determined in vivo. Recombinant retroviral vectors encoding the marker lacZ
      (control) and either wild-type v-src or SH2 or SH3 domain-deleted forms of v-src
      (deltaSH2 or deltaSH3, respectively) were used to infect neuronal progenitor
      cells in the embryonic chicken midbrain (optic tectum; OT). Embryos were injected
      in the OT with retroviral concentrates on embryonic day (E) 3 and sacrificed at
      E6, E9, and later in development. Patterns of cell proliferation, migration, and
      differentiation of lacZ-marked clonal cell progeny were then analyzed. Relative
      to lacZ-only controls, cell clone size at E6 was significantly increased for v
      src-, unchanged for deltaSH2-, and smaller for deltaSH3-injected embryos. At E9,
      deltaSH2 cell clones were significantly larger than controls, suggesting
      increased survival from normal programmed cell death. Radial neuronal migration
      was impaired for v-src and deltaSH3 clones, whereas tangential neuronal migration
      was enhanced along fiber tracts in v-src and deltaSH2 clones. Moreover, radial
      glial cell development and differentiation was hindered in v-src and deltaSH3
      clones. These experiments demonstrate that ectopic v-src signaling alters
      proliferation, migration, survival, and differentiation of developing brain cells
      and suggest that src signaling pathways are involved in these developmental
      processes. Furthermore, certain effects of v-src on brain cells require specific
      src homology domains.

PMID- 10650882
TI  - Application of real-time polymerase chain reaction to quantitate induced
      expression of interleukin-1beta mRNA in ischemic brain tolerance.
AB  - A short duration of ischemia (i.e., ischemic preconditioning) was shown to result
      in significant tolerance to subsequent ischemic injury. Since previous reports
      suggest that interleukin-1beta (IL-1beta) may be involved in both ischemic damage
      and neuroprotection, the present work examined the expression of IL-1beta mRNA in
      cortical brain tissue after an established preconditioning (PC) stimulus known to
      produce significant brain tolerance to focal stroke after 1-7 days. Significant
      induction of IL-1beta mRNA was observed in the ipsilateral cortex at 6 hr (87+/-9
      copies of the mRNA per microgram of brain tissue compared to 16+/-5 copies in
      sham-operated samples, P < 0.001, n = 4) and 8 hr (46+/-4 copies, P < 0.01, n =
      4) after PC by means of real-time Taqman polymerase chain reaction (PCR). The
      peak expression of IL-1beta mRNA after PC was significantly (P < 0.01) lower than
      that after permanent occlusion of the middle cerebral artery (MCAO), i.e., 87+/-9
      and 546+/-92 copies of RNA per microgram tissue at peak levels for PC and focal
      stroke, respectively. Immunohistochemistry studies revealed a parallel induction
      of IL-1beta in the ipsilateral cortex after PC. The maximal expression of IL
      1beta was observed during the first week post-PC, showing marked parallelism with
      the duration of ischemic tolerance. These data suggest that the significant but
      low levels of IL-1beta induction after PC may contribute to ischemic brain
      tolerance.

PMID- 10650883
TI  - Three subpopulations of fast axonally transported retinal ganglion cell proteins
      are differentially trafficked in the rat optic pathway.
AB  - Post-Golgi trafficking of the major fast axonally transported (FT) proteins was
      investigated in the rat optic pathway. Following intra-ocular injection of 35S
      methionine, radiolabeled FT proteins in the optic tract (OT) and superior
      colliculus (SC) were analyzed by two-dimensional polyacrylamide gel
      electrophoresis (2D-PAGE) and fluorography. Twenty FT proteins, including a known
      plasma membrane protein (SNAP-25) and synaptic vesicle protein (synaptobrevin-2),
      displayed consistent 2D-PAGE migration behavior and were chosen for densitometric
      quantitative analysis. Results showed that at least three subpopulations of the
      20 FT proteins could be differentiated based on their trafficking behavior to
      axons (OT) vs. terminals (SC). To assess whether Golgi-independent processes
      (e.g., delayed somal release and/or retrograde transport) could account for the
      differential compartmentation behavior between the three FT classes, we assessed
      whether radiolabeled FT proteins became redistributed in the optic pathway
      following a nerve transection blockade. The results showed that radiolabelled FT
      proteins did not show a quantitative change in their axon vs. terminal
      compartmentation in response to disconnection from cell bodies or targets. Thus,
      the three classes of fast axonally transported proteins were likely trafficked to
      distinct destinations in the optic pathway by Golgi sorting mechanisms.

PMID- 10650884
TI  - Cynandione A from Cynanchum wilfordii protects cultured cortical neurons from
      toxicity induced by H2O2, L-glutamate, and kainate.
AB  - Oxidative stress has been implicated as a primary cause of neuronal death in
      certain neurodegenerative disorders and in aging brains. Natural products have
      been used in Asian societies for centuries for treating such neurodegenerative
      disorders as senile dementia. In an effort to identify active neuroprotective
      compounds from these products, we have employed cultures of rat cortical neurons
      as our screening system. A methanolic extract from dried roots of Cynanchum
      wilfordii Hemsley (Asclepiadaceae) significantly mitigated the neurotoxicity
      induced by H2O2 in this screening system. Activity-guided fractionation using
      several chromatographic techniques resulted in the isolation of the
      neuroprotective compound, cynandione A, a biacetophenone. At a concentration of
      50 microM, cynandione A significantly reduced neurotoxicity induced by H2O2.
      Cynandione A significantly attenuated decreases in levels of glutathione,
      superoxide dismutase, and other enzymes that participate in the cellular defense
      against oxidative stress. Furthermore, cynandione A alleviated neurotoxicity
      induced by the excitotoxic neurotransmitter, L-glutamate, the neurotoxicity
      induced by kainate, but not that mediated by N-methyl-D-aspartate. Cynandione A
      was demonstrated to be a natural antioxidant as it facilitated the breakdown of
      hydrogen peroxide in vitro; however, no mechanism was uncovered to explain its
      neuroprotectant effects against glutamate and kainate. Therefore, cynandione A
      may be efficacious in protecting neurons from oxidative stress mediated via
      activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate/kainate
      receptors since it exerted significant neuroprotective effects on cultured
      cortical neurons.

PMID- 10650885
TI  - Retroviral transfer of the beta-nerve growth factor gene into murine
      neuroectodermal tumor cells modulates cell proliferation rate, neurite formation,
      and NGF binding site expression.
AB  - The response of wild-type and genetically engineered neuroectodermal tumor (NET)
      cells to exogenous and endogenously synthesized nerve growth factor (NGF) was
      investigated. Differences in cell proliferation rate, neurite formation, and
      expression of NGF binding sites were quantitatively determined. Ecotropic
      retroviral vectors were used to transfer the genes for beta-galactosidase (beta
      GAL) and NGF into wild-type C-1300 and Neuro-2A murine neuroblastoma (MNB) and
      rat pheochromocytoma (PC-12) cells. Conditioned media obtained from NET cells
      infected with the NGF gene contained biologically active NGF, whereas media from
      beta-GAL infected cells did not. Infection with the NGF vector induced a short
      term decrease in cell proliferation rate and increased neurite formation in wild
      type, substrate-adherent PC-12 and Neuro-2A MNB cells (P > 0.05). Incubation of
      wild-type C-1300, Neuro-2A MNB, and PC-12 cells with NGF (0-200 ng/ml) for 5 days
      significantly reduced proliferation rates in a concentration-dependent manner and
      increased neurite extrusion. All NGF-NET cells had a significantly diminished
      response to the antiproliferative action of exogenous NGF. Ligand binding assays
      with 125I-NGF demonstrated a marked reduction in the number of NGF binding sites
      on NGF-NET cells compared to wild type. The attenuated response of NGF-NET cells
      to exogenous NGF correlated positively with the down-regulation of NGF binding
      sites. In conclusion, beta-NGF gene transfer into wild-type NET cells induces the
      synthesis and secretion of NGF, temporarily decreases cell proliferation rate,
      increases neurite extrusion, down-regulates NGF binding sites, and reduces NET
      cell responsiveness to NGF. A putative role for NGF may be the modulation of NET
      cell proliferation and differentiation.

PMID- 10650886
TI  - Diadenosine pentaphosphate increases levels of intracellular calcium in
      astrocytes by a mechanism involving release from caffeine/ryanodine- and IP3
      sensitive stores.
AB  - Diadenosine polyphosphates (ApnAs, n = 2 to 6 phosphate groups) activate P2-type
      cell-surface adenine nucleotide purinoreceptors, increase the influx of calcium
      into neural cells, and modulate the binding of ryanodine to ryanodine receptor
      regulated intracellular calcium release channels. In this study, we tested the
      hypothesis, using single cell fluorescence techniques and cultured human fetal
      astrocytes, that p1, P5-di(adenosine-5') pentaphosphate (Ap5A)-induced increases
      in levels of intracellular calcium ([Ca2+]i) resulted from release of calcium
      from intracellular pools. Basal [Ca2+]i were 141+/-12 nM and Ap5A increased
      [Ca2+]i to 980+/-150 nM. The effect of Ap5A on [Ca2+]i was mediated in part
      through activation of purinoceptors and influx of extracellular calcium because
      the purinoceptor antagonist pyridoxal-phosphate-6-azophenel-2', 4'-disuphonic
      acid blocked by 52%, and chelation of extracellular calcium with EGTA prevented,
      almost completely, Ap5A-induced increases in [Ca2+]i. Implicating calcium release
      from IP3- and ryanodine-regulated pools of intracellular calcium were findings
      that Ap5A-induced increases in [Ca2+]i were blocked, at least in part, by
      thapsigargin, ryanodine, caffeine, and xestospongin, and Ap5A increased by 2-fold
      the production of IP3. Release of calcium from IP3- and ryanodine-regulated
      intracellular pools may be an important signaling event in neural cells that are
      exposed to Ap5A.

PMID- 10650887
TI  - Passive transfer of experimental autoimmune encephalomyelitis in Wistar rats:
      dissociation of clinical symptoms and biochemical alterations.
AB  - We have used passive transfer of myelin-reactive lymphocytes in the Wistar rat
      model of experimental autoimmune encephalomyelitis (EAE) to investigate the
      nature of the central nervous system immunopathological alterations induced by
      these cells. Mononuclear cells from lymph nodes or spleen from sick
      myelin/complete Freund's adjuvant-immunized donors did not transfer clinical
      disease. However, depending on the previous treatment of the transferred cells,
      recipients develop central nervous system biochemical and histological
      alterations. Fresh cells from lymph nodes immediately transferred after
      procurement from the sick EAE donor rat were capable of inducing the most
      significant diminution in the content of myelin basic protein, sulfatides, and
      2',3'-cyclic nucleotide-3'-phosphohydrolase activity, with concomitant
      inflammatory infiltrations of white matter, principally in spinal cord and
      cerebellar lobules. Similar alterations were observed when animals were injected
      with spleen mononuclear cells activated in the presence of a nonspecific mitogen
      as concanavalin A. However, antigen-specific activated spleen cells generated by
      culturing in the presence of bovine myelin induced alterations to a lesser
      degree. Results point to a dissociation of the clinical disease from the central
      nervous system biochemical and histopathological lesions occurring in the EAE
      transferred Wistar rats and indicate that these alterations in EAE are induced
      principally by T cells activated in vivo rather than by cells activated in vitro
      by myelin antigens. Therefore, these findings suggest a possible participation of
      lymphocytes unlike the encephalitogenic T cells in the induction of the described
      alterations and provide a useful model to explore further the subclinical
      responses to this experimental disease.

PMID- 10650888
TI  - Distribution and circadian expression of dbp in SCN and extra-SCN areas in the
      mouse brain.
AB  - The expression of dbp, a putative clock-controlled transcription factor, was
      investigated in the mouse brain by in situ hybridization using antisense cRNA
      probe. Positive dbp mRNA signals were detected in various parts of the brain,
      with the highest expression in the suprachiasmatic nucleus (SCN). The circadian
      expression profile was investigated in SCN and extra-SCN areas. In the SCN, dbp
      mRNA signals showed a peak at early daytime (ZT/CT4) and a trough at early
      nighttime (ZT/CT16) in both light-dark and constant dark conditions. In the
      cerebral cortex and the caudate-putamen, dbp mRNA was also expressed in a
      circadian manner, but the phase of dbp mRNA expression in these structures showed
      a 4-8 hr delay compared to that in the SCN. These findings indicate that the
      circadian expression profile of dbp in the extra-SCN brain areas is different
      from that in the SCN.

PMID- 10650889
TI  - Complementary and alternative therapies in cancer?

PMID- 10650890
TI  - Palliative care in a small medical clinic in Zurich, Switzerland.
AB  - The first palliative unit in the region of Zurich was opened at the Bircher
      Klinik Susenberg in 1994. The 40-bed clinic specialises in internal medicine,
      geriatrics and rehabilitation and has given special importance to the holistic
      care of the patients since its foundation in 1939. In addition to symptom control
      and terminal care, rehabilitation was integrated into the concept of palliative
      care at an early stage. Most of the patients are referred from hospitals in or
      around Zurich, approximately 20% by the family physician. The mean age of
      palliative patients is around 69 years, and they stay an average of 27 days in
      the clinic. Close to 40% of them can return home, and the same percentage die
      during their stay in hospital; the rest are referred to homes for the elderly or
      nursing homes or to a central hospital.

PMID- 10650891
TI  - Unproven methods in cancer: a worldwide problem.
AB  - Questionable or unproven methods are used by cancer patients throughout the
      world. Treatments include drugs, vitamins, herbs, diets, healing, "psychological"
      treatments, folk medicines, and homeopathy. The exact frequency of questionable
      methods in cancer is difficult to evaluate because of the variety of methods,
      some being used as complementary treatments to conventional ones (and often not
      mentioned by patients) and others, as curative treatment (alternative treatment).
      In Europe, data are available for the Nordic countries, Switzerland, Germany,
      Austria, United Kingdom, The Netherlands, France and Italy. High frequencies of
      use are observed in German-speaking countries (52-65%). In North America, many
      publications give frequencies of between 7% and 54%. In Mexico, the frequency is
      50%, higher than in Argentina (17%). In Australia, 22% have used complementary
      medicines. In Asia, some data are available from India, Taiwan and Japan. In
      Tunisia (northern Africa), the results of 59 interviews also show the use of
      questionable methods among Arabic patients. There is a lack of data from
      countries in Africa and in Asia. While some products are used all over the world
      (e.g. mistletoe, vitamins), others are country specific (Moerman diet in The
      Netherlands). Some traditional medicines are also country specific (e.g., Chinese
      medicine, Ayurvedic medicine in India). Both alternative and complementary
      unproven methods are prescribed either according to classical concepts of cancer
      treatment or according to a new concept of the world and of life.

PMID- 10650892
TI  - Complementary therapies: the American experience.
AB  - This article explains the difference between complementary and alternative
      medicine and describes the current levels of use of such therapies in the United
      States of America, particularly among cancer patients. The complementary
      therapies that can help cancer patients during treatment for their disease and
      during rehabilitation are treated in greater depth.

PMID- 10650893
TI  - Americans' view of cancer.
AB  - This paper presents the concept of the town hall meeting and discusses how it can
      be used as a forum for those who have been touched by cancer. It can be a
      platform for people to express their views about cancer, not only in the
      community but also nationally. Empowerment is the hallmark of a town hall
      meeting. Those who are in leadership positions in health care and elected
      officials and community leaders are given the opportunity to hear the opinions of
      people who represent a broad-based constituency of individuals affected by
      cancer. The idea of holding a town hall meeting was first introduced in the
      cancer community by the National Coalition for Cancer Survivorship NCCS) as a
      means of identifying issues, exchanging information and considering creative
      solutions to problems. The first town hall meeting was held in 1994 in
      conjunction with the NCCS annual assembly. Since then, utilizing the guidelines
      set forth by the NCCS, 30 or more town hall meetings have been held across the
      United States. Cancer survivors have, by and large, been responsible for
      garnering the necessary support for conducting a town hall in their local area.
      Organizations such as the American Cancer Society, the Leukemia Society of
      America, hospitals, clinics, pharmaceutical and healthcare companies and also
      noncancer groups, such as the YMCA, churches, and radio/T.V. stations, join with
      the cancer survivors in organizing the meeting, planning related displays, and
      advertising the event. In 1998, seven town hall meetings were sponsored jointly
      by OnCare and NCCS in advance and support of the upcoming THE MARCH- Coming
      Together To Conquer Cancer, a national rally held in Washington, D.C. in
      September 1998. Attendees at the meetings included not only cancer survivors and
      their families, but also healthcare professionals, local and state legislators,
      community leaders and the media. Results of the 1998 town hall meetings are
      discussed and compared with the topics identified during the meetings held in
      1994-1996. Town hall participants were outspoken about what is needed in America
      if cancer is truly to become the nation's healthcare priority. They are asking
      for equal access to quality care, increases in financial backing for research,
      and more support for cancer advocacy efforts. Benefits of holding town hall
      meetings are identified.

PMID- 10650894
TI  - Current status of cancer patients' perception of alternative medicine in Japan. A
      preliminary cross-sectional survey.
AB  - Since there are no large-scale surveys of how cancer patients perceive unproven
      therapy in Japan, we wanted to clarify this issue by means of a cross-sectional
      questionnaire conducted among cancer patients. The survey revealed that 32% of
      cancer patients used unproven therapy without having sufficient information about
      it. There was a lack of communication between cancer patients and their
      physicians on topics relating to alternative medicine. Issues that we have to
      solve are concerned with the education of cancer patients, lay people and
      physicians on the meaning and role of alternative medicine and on the necessity
      for scientific evaluation of medical treatments in Japan.

PMID- 10650895
TI  - Patient reports of complications of bone marrow transplantation.
AB  - In recent years, significant improvements have been made in the management of
      neutropenia and thrombocytopenia and other potentially life-threatening
      complications of ablative chemotherapy. While these complications are of
      particular concern to physicians, patients receiving ablative therapy for bone
      marrow or blood stem cell transplants are often troubled by other side effects
      such as nausea, vomiting, diarrhea and mouth sores. The purpose of the study was
      to gain a better understanding of patients' experiences while undergoing a
      transplant. The same professional medical interviewer conducted in-depth
      interviews with 38 subjects (10 men, 28 women; mean age 46.9 years) who had
      received ablative therapy for bone marrow and/or peripheral blood stem cell
      transplants. Participants were consecutively identified through physician and
      patient referrals, cancer and BMT patient support groups, and newspaper
      advertisements. Twenty-eight patients (74%) received autologous stem cell
      transplants and 10 patients (26%) received allogeneic transplants. Participants
      reported mouth sores, nausea and vomiting, diarrhea, and fatigue as the most
      troubling side effects of their transplants. Mouth sores were selected as the
      single most debilitating side effect (42%), followed by nausea and vomiting
      (13%). Many patients mentioned that mouth sores made it difficult or impossible
      to eat (n = 23), swallow (n = 21), drink (n = 17), and/or talk (n = 8). Twenty
      patients reported pain in the mouth, throat, and/or esophagus. Two-thirds (66%)
      of patients reported receiving opioid analgesics, most frequently morphine, to
      relieve oral pain. For many, opioids caused incapacitating side effects,
      including hallucinations, a feeling of loss of control and a decrease in mental
      acuity. Patients receiving ablative chemotherapy identify oral mucositis as a
      significant cause of suffering and morbidity. Effective interventions to
      alleviate this complication are urgently needed.

PMID- 10650896
TI  - Physicians' attitudes to and problems with truth-telling to cancer patients.
AB  - Disclosure of a diagnosis of cancer to patients is a major problem among
      physicians in Italy. The aim of the study was to assess physicians' attitudes to
      and opinions about disclosure. A convenience sample of 675 physicians in Udine
      (North Italy) completed a ten-item questionnaire. About 45% indicated that, in
      principle, patients should always be informed of the diagnosis, but only 25%
      reported that they always disclosed the diagnosis in practice. Physicians with a
      surgical specialization employed in general hospitals endorsed disclosure of the
      diagnosis more frequently than GPs and older physicians. One third of the
      responding physicians persist in the belief that the patients never want to know
      the truth. Hospital doctors considered the hospital, rather than the patient's
      home, was the most appropriate place to inform the patients. The opposite result
      was found among GPs. Almost all the physicians endorsed the involvement of family
      members when disclosing the diagnosis, but, at the same time they also indicated
      that families usually prefer their ill relative not to be informed. Ninety-five
      per cent of physicians believed that the GP should always be involved in the
      processes of diagnosis and communication, and 48% indicated that the GP should
      communicate the diagnosis to the patient (as opposed to the physician who made
      the diagnosis). Having guidelines for breaking bad news to patients was indicated
      as an important need by 86% of the responding physicians. Despite changes in
      medical education, improvement of communication skills in dealing with cancer
      patients and their families represents an important need in healthcare settings.

PMID- 10650897
TI  - Control of high-dose-cisplatin-induced emesis with an all-oral three-drug
      antiemetic regimen.
AB  - In this pilot trial, the antiemetic efficacy and tolerability of an all-oral
      antiemetic combination in the prevention of both acute and delayed nausea and
      vomiting following high-dose cisplatin was evaluated. Fifty-two patients
      receiving cisplatin (median dose 100 mg/m2) were entered. Patients received (1)
      60 min prior to cisplatin: prochlorperazine spansule 15 mg, dexamethasone 20 mg,
      granisetron 2 mg; (2) 12 h after cisplatin: prochlorperazine spansule 15 mg,
      dexamethasone 10 mg; (3) on days 2 and 3: prochlorperazine spansule 15 mg b.i.d.,
      dexamethasone 8 mg b.i.d.; (4) on days 4 and 5: dexamethasone 4 mg b.i.d. All
      antiemetics were administered orally. The study period was the 120 h after
      cisplatin administration. The primary efficacy end-point was complete control (no
      vomiting, retching or antiemetic rescue) of delayed emesis (24-120 h after
      cisplatin). Complete control of delayed emesis was achieved in 26 patients (53%).
      Nineteen patients (39%) noted no delayed nausea. Complete control of acute emesis
      (24 h after cisplatin) was attained in 44 patients (86%). The no nausea rate
      during the first 24 h was 74%. Overall, 39 patients (80%) were satisfied or very
      satisfied with their outcome. Treatment was well tolerated with infrequent and
      minor adverse events. In conclusion, an all-oral combination of granisetron,
      dexamethasone and prochlorperazine is a highly effective and well-tolerated
      regimen for preventing acute cisplatin-induced emesis. Control of delayed emesis
      was not better than with current standard treatment, and more effective
      approaches are needed.

PMID- 10650899
TI  - Efficacy of treatment to relieve mucositis-induced discomfort.
AB  - To determine the efficacy of a mouthwash in relieving mucositis-induced
      discomfort in patients receiving chemotherapy, 31 (16 male, 15 female) with a
      mean age of 45 (range 16-80) were given an in-house three-drug (lidocaine,
      diphenhydramine and sodium bicarbonate in normal saline) mouthwash when they
      developed mucositis of any severity. The complications were assessed on the CALGB
      (Cancer and Leukemia Group B) scale. The response to the mouthwash was reported
      on a self-assessment scale. Patients' response data were analyzed with reference
      to: (1) relief throughout the duration of mucositis and (2) relief during the
      worst stage (for each episode) of mucositis. Five patients with fungal, viral or
      bacterial oral infection were excluded from study. Overall, 4 patients had grade
      I, 16 patients had grade II, 10 patients had grade III and 1 patient had grade IV
      mucositis. The average duration of mucositis was 7.9 days (range 3-23 days), and
      the mean duration of the worst stage of mucositis was 4.81 days (range 2-13
      days). The mean mucositis severity score was 1.9 (range 1-4), and the average
      self-assessment (response) score was 0.81 (range 0-2). The mean mucositis score
      during the worst stage of mucositis was 2.25 (range 1-4), and the average self
      assessment (response) score during the worst stage of mucositis was 0.91 (range 0
      2.7). These results suggests that this three-drug mouthwash provides effective
      symptomatic relief in patients with chemotherapy-induced mucositis.

PMID- 10650898
TI  - A double-blind, randomised, parallel study comparing intravenous dolasetron plus
      dexamethasone and intravenous dolasetron alone for the management of fractionated
      cisplatin-related nausea and vomiting.
AB  - Fractionated cisplatin-containing regimens are routinely used for chemotherapy in
      certain types of cancer. Dolasetron has been shown to be effective in preventing
      acute emesis related to high-dose cisplatin chemotherapy over 24 h; its
      effectiveness has not been evaluated in fractionated cisplatin-containing
      chemotherapy. This trial was designed to assess the efficacy of dolasetron alone
      or dolasetron plus dexamethasone in preventing nausea and vomiting related to
      fractionated cisplatin chemotherapy. The patients were 210 cancer in-patients,
      who were randomised to receive 100 mg dolasetron i.v. or 100 mg dolasetron i.v.
      plus 20 mg dexamethasone before chemotherapy primarily with cisplatin (15-50
      mg/m2) infused over < or =4 h for at least 2 but not more than 5 consecutive
      days. Dolasetron was administered to all patients 30 min before cisplatin.
      Dexamethasone was administered in double-blind fashion 5 min before cisplatin.
      Efficacy was measured at hour 24 of each study day using complete response (no
      vomiting and no rescue medication) and maximum severity of nausea, self-assessed
      by patients using a 100mm visual analogue scale. Most (198) of the patients
      completed the study and were evaluable. Overall complete response rates were
      significantly higher in the dolasetron plus dexamethasone group than in the
      dolasetron only group (72.9% vs. 40.8%, respectively; P<0.0001). Complete
      response rates on each study day were also significantly higher with dolasetron
      plus dexamethasone than with dolasetron alone (P<0.029), with an attenuated
      efficacy in the delayed phase in both groups. Chi-square test and logistic
      regression applied to daily response rates indicated a significant influence of
      treatment (day 1: P = 0.0002, day 2: P<0.0001, day 3: P = 0.0007, day 4: P =
      0.0007, day 5: P = 0.029). Treatment and duration of chemotherapy exerted the
      only statistically significant subgroup effects on complete response (P<0.0001).
      Both treatments were administered safely. As seen with other 5-HT3 receptor
      antagonist antiemetics, the addition of dexamethasone to dolasetron significantly
      increases effectiveness in preventing nausea and vomiting related to fractionated
      cisplatin chemotherapy. Both dolasetron and dolasetron plus dexamethasone were
      well tolerated.

PMID- 10650900
TI  - Factors determining the place of palliative care and death of cancer patients.
AB  - Factors determining the place of palliative care and death were studied by
      interviewing 40 patients using a semi-structured questionnaire. The 86 interviews
      assessed showed that both emotional and somatic factors played a part in the
      determination of whether patients were transferred and of their place of death.
      Emotional factors were mentioned in 41% as being of importance, and physical
      factors in 32%. Material and financial factors are probably underestimated owing
      to the methodology.

PMID- 10650901
TI  - High-dose loperamide in the treatment of 5-fluorouracil-induced diarrhea in
      colorectal cancer patients.
AB  - Thirty-seven colorectal cancer patients with grade 1-4 diarrhea (NCICTC) caused
      by chemotherapy with 5-FU-containing regimens, received oral loperamide at the
      initial dose of 4 mg followed by 4 mg every 8 h (total dose 16 mg/24 h). Twenty
      five patients (69%) were diarrhea-free and were considered to be treatment
      responders. Eight-four percent of the patients with grade 1 or 2 diarrhea
      achieved a response, but only 52% of those with grade 3-4 diarrhea. These data
      seem to suggest that high-dose loperamide is effective in patients with moderate
      diarrhea and can be regarded as the treatment of choice. The patients with more
      severe diarrhea did not respond so well, and should, perhaps, be given first-line
      treatment with more effective drugs, such as somatostatin analogues (e.g.,
      octreotide).

PMID- 10650902
TI  - Research controversies in management of oral mucositis.
AB  - The management of mucositis is the subject of many controversies, and the optimal
      treatment is still not known. Several evaluation scoring systems have been
      described, but no one of these is appropriate to all clinical situations: a
      simple scale such as that devised by the WHO can be used routinely, and more
      sophisticated ones can be implemented by trained experimenters working in
      research. We have considered the impact of each of the treatments currently
      available on each stage of mucositis. In attempts at prevention, self-care, in
      the sense of oral hygiene, must remain atraumatic. It is probably advisable to
      differentiate patients with good previous oral care, in whom tooth brushing is
      beneficial, from others, in whom the risk of hemorrhage and infection excludes
      any brushing. Before the dosage of chemotherapy is reduced, the curative or
      palliative intent of the strategy must be carefully evaluated. In the vascular
      phase protection of the proliferating cells is attempted by means of
      vasoconstriction (cryotherapy), cytoprotection (prostaglandin E2 and other
      antioxidants) or epithelial cell-inhibiting factors such as TGF-B3. Treatments
      applied in the epithelial phase are directed at increasing the cell proliferation
      to accelerate epithelial restoration by sucralfate and several growth factors:
      hematopoietic GF, which has demonstrated a direct effect on the mucosa (GM-CSF),
      or epithelial growth factors such as keratinocyte GF. In the ulcerative and
      bacteriological phase attempts are made to attenuate sepsis by means of
      antiseptics (chlorhexidine), amphotericin B and antiviral agents or antibiotic
      lozenges. In the healing phase application of the low-energy helium-neon laser
      has demonstrably been followed by a later time of onset, less pronounced peak
      severity and shorter duration of oral mucositis. After cancer treatment, oral
      hygiene, inhibition of oral flora, and pain relief are the main goals.
      Physiopathogen-specific treatment is the next step, with the emphasis on the
      inhibition of epithelial cell proliferation during drug exposure and facilitation
      of epithelial maturation and healing.

PMID- 10650903
TI  - Inverse covariation of spectral density and correlation dimension in cyclic EEG
      dynamics of the human brain.
AB  - The responsiveness or excitability of the central nervous system (CNS) to
      external or internal stimuli is systematically altered corresponding to transient
      changes of the EEG background activity, mainly in the alpha range. We hypothesise
      that a transient alpha power increase is due to an underlying increase in
      synchronisation or coupling strength between various neuronal elements or
      cortical networks. Consequently, the 'network' of the CNS may be more ordered
      and, hence, less complex in the case of high spectral density, and vice versa.
      The goals of the present paper are (1) to prove the inverse covariation between
      spectral density and correlation dimension for a set of human EEG data, (2) to
      falsify the null hypothesis that the observed relationship is a random one, and
      (3) to propose a neuronal approach which may explain the observed correlations. A
      sliding computation of the spectral density and correlation dimension
      [Grassberger P, Procaccia I (1983) Physica D 9:189-208] of mid-occipital EEG
      recordings derived from eight awake subjects with eyes closed was performed. The
      similarity between the two time courses was quantified by similarity measures and
      descriptive correlation coefficients. The temporal pattern of dimensional
      complexity showed an inverse relationship with simultaneously computed spectral
      power changes most pronounced in the alpha range. The group means of similarity
      measures and correlation coefficients were compared with the corresponding means
      of a sample set established by 20 Gaussian random signals. Statistically
      significant differences were obtained at the 0.1% level, rejecting the null
      hypothesis that the observed relationship is a random one. The results support
      the idea that the dynamics of the EEG signals investigated reflect a chaotic
      deterministic process with state transitions from 'high-dimensional' to 'low
      dimensional' non-linear dynamics, and vice versa. Adequate neuronal models and
      approaches to interpret the disclosed transients and the inverse covariation
      between spectral density and dimensional complexity are proposed, giving
      additional insight into the integrative functioning of the CNS with respect to
      the strategy of information processing.

PMID- 10650904
TI  - Parallel cascade identification as a means for automatically classifying protein
      sequences into structure/function groups.
AB  - Current methods for automatically classifying protein sequences into
      structure/function groups, based on their hydrophobicity profiles, have typically
      required large training sets. The most successful of these methods are based on
      hidden Markov models, but may require hundreds of exemplars for training in order
      to obtain consistent results. In this paper, we describe a new approach, based on
      nonlinear system identification, which appears to require little training data to
      achieve highly promising results.

PMID- 10650905
TI  - The discontinuous nature of motor execution. I. A model concept for single-muscle
      multiple-task coordination.
AB  - Human movement control requires adequate coordination of different movements,
      which is particularly important when different motor tasks are simultaneously
      executed by the same effector(s) (e.g. a muscle or a joint). The process of
      movement execution involves a series of highly nonlinear elements; for instance,
      a motor unit of a muscle produces force only in the direction of muscle
      shortening, thus representing a threshold operator that transforms the bipolar
      (i.e. excitatory or inhibitory) information at its spinal input into a purely
      unipolar signal (i.e. muscle force). This tripartite research report addresses
      the contribution of the nonlinearity of neuromuscular elements to the
      coordination of different motor tasks simultaneously executed by the same limb.
      In this first part of the series, a new hypothesis for such a single-muscle
      multiple-task coordination is presented which suggests an essentially threshold
      linear coordination mechanism. Control signals generated by the central nervous
      system for each individual movement independently and feedback information from
      peripheral receptors are linearly superimposed. This compound control/feedback
      signal is processed by a nonlinear limiter element reflecting the discontinuous
      properties of the muscle and its reflex circuitry. It is shown that threshold
      linear interaction of descending commands and afferent feedback information can
      lead to complex interdependent patterns of compound motor action. This includes
      the possibility of gating (i.e. the ability of one movement pattern to constrain
      or even impede the execution of another pattern) and of delayed response
      initiation when simultaneously performing more than one voluntary motor task. A
      theoretical analysis of the threshold-linear coordination mechanism and an
      extensive experimental validation of the model is provided in part II and part
      III of the report.

PMID- 10650906
TI  - Switching characteristics of a model for biochemical-reaction networks describing
      autophosphorylation versus dephosphorylation of Ca2+/calmodulin-dependent protein
      kinase II.
AB  - Ca2+/calmodulin-dependent protein kinase II (CaMKII) has been suggested to
      participate in various cellular phenomena triggered by Ca2+ signalling. In the
      present study, we addressed the functional role of CaMKII in molecular-signal
      transduction in cells by mathematical modelling of putative biochemical-reaction
      networks thought to represent an essential part of molecular events responsible
      for CaMKII-related cellular phenomena. These networks include Ca2+/calmodulin
      dependent threonine-286/287 (Thr286/287) autophosphorylation of CaMKII versus
      dephosphorylation of the enzyme. Computer simulation of the model was performed
      to examine the relation between the Ca2+-signalling pattern as an input and the
      resulting degree of Thr286/287 autophosphorylation (m) as an output. Under the
      simplified condition that the Ca2+ concentration during Ca2+ signalling was set
      to remain constant with time, the biochemical-reaction networks were shown to
      function as a switch. There is a threshold for gamma, a parameter representing
      the probability that the Thr286/287-dephosphorylated CaMKII subunit binds with
      the Ca2+/calmodulin complex; if gamma is above this threshold, m increases with
      time to a large degree (switch-on); otherwise, it remains near zero (switch-off).
      Mathematically, this sharp onset of m at the threshold can be accounted for by a
      change in the structure of the dynamic system describing the model, from
      bistability to monostability; this is analogous to the first-order phase
      transition in statistical physics. For the oscillatory time course of [Ca2+],
      switching characteristics were also shown with respect to the frequency and the
      maximum amplitude of the oscillation. These results suggest that graded
      information mediated by Ca2+ signalling is digitized into all-or-non information
      mediated by Thr286/287 autophosphorylation of CaMKII.

PMID- 10650907
TI  - Information processing in large-scale cerebral networks: the causal connectivity
      approach.
AB  - Today, cognitive functions are considered to be the offspring of the activity of
      large-scale networks of functionally interconnected cerebral regions. The
      interpretation of cerebral activation data provided by functional imaging has
      therefore recently moved to the search for the effective connectivity of
      activated regions, which aims at understanding the role of anatomical links in
      the activation propagation. Our assumption is that only causal connectivity can
      offer a real understanding of the links between brain and mind. Causal
      connectivity is based on the anatomical connection pattern, the information
      processing within cerebral regions and the causal influences that connected
      regions exert on each other. In our approach, the information processing within a
      region is implemented by a causal network of functional primitives, which are the
      interpretation of integrated biological properties. Our choice of a qualitative
      representation of information reflects the fact that cerebral activation data are
      only the approximate view, provided by imaging techniques, of the real cerebral
      activity. This explicit modeling approach allows the formulation and the
      simulation of functional and physiological assumptions about activation data. Two
      alternative models explaining results of the striate cortex activation described
      by Fox and Raichle (Fox PT, Raichle ME (1984) J. Neurophysiol 51:1109-1120; Fox
      PT, Raichle ME (1985) Ann Neurol 17:303-305) are provided as an example of our
      approach.

PMID- 10650908
TI  - An emergent mechanism of selective visual attention in Drosophila.
AB  - Due to the limited computational capacity of visual systems and the limited
      capacity to perform several mental operations at once, animals only select a
      small proportion of the stimuli available at any one time. It remains to be
      clarified how this process is related to the spatio-temporal dynamics of cell
      assemblies in the brain. By employing the flight simulator, selective visual
      attention behavior is studied in Drosophila. It has been found that for the
      visual objects presented, the tethered fruitflies display various attention
      patterns. Specifically, the learning memory mutants dunce and amnesiac possess
      attention patterns totally different from that of the wild-type fly. To explain
      these results from the viewpoint of dynamic cell assemblies, a neural network has
      been developed in which a possible link between the activity of cell assemblies,
      encoding of sensory information, and selective attention in Drosophila is
      proposed.

PMID- 10650909
TI  - Haptic interaction with virtual objects. Spatial perception and motor control.
AB  - This paper considers interaction of the human arm with "virtual" objects
      simulated mechanically by a planar robot. Haptic perception of spatial properties
      of objects is distorted. It is reasonable to expect that it may be distorted in a
      geometrically consistent way. Three experiments were performed to quantify
      perceptual distortion of length, angle and orientation. We found that spatial
      perception is geometrically inconsistent across these perceptual tasks. Given
      that spatial perception is distorted, it is plausible that motor behavior may be
      distorted in a way consistent with perceptual distortion. In a fourth experiment,
      subjects were asked to draw circles. The results were geometrically inconsistent
      with those of the length perception experiment. Interestingly, although the
      results were inconsistent (statistically different), this difference was not
      strong (the relative distortion between the observed distributions was small).
      Some computational implications of this research for haptic perception and motor
      planning are discussed.

PMID- 10650910
TI  - A central pattern generator to control a pyloric-based system.
AB  - A central pattern generator (CPG) is built to control a mechanical device (plant)
      inspired by the pyloric chamber of the lobster. Conductance-based models are used
      to construct the neurons of the CPG. The plant has an associated function that
      measures the amount of food flowing through it per unit of time. We search for
      the best set of solutions that give a high positive flow of food in the
      maximization function. The plant is symmetric and the model neurons are identical
      to avoid any bias in the space of solutions. We find that the solution is not
      unique and that three neurons are sufficient to produce positive flow. We propose
      an effective principle for CPGs (effective on-off connectivity) and a few
      predictions to be corroborated in the pyloric system of the lobster.

PMID- 10650911
TI  - Peroxisome proliferators: mechanisms of adverse effects in rodents and molecular
      basis for species differences.
AB  - Peroxisome proliferators (PPs), such as diethylhexylphthalate (DEHP), constitute
      a diverse class of chemicals with many therapeutic, industrial and environmental
      applications. In rodents, PPs are nongenotoxic hepatocarcinogens, raising
      concerns regarding the potential of PPs to harm human health. However, humans
      differ from rodents in their response to PPs and the weight of evidence supports
      the supposition that PPs do not pose a carcinogenic risk to humans. The effects
      of PPs in the rodent are mediated by peroxisome proliferator activated receptor
      alpha (PPARalpha). PPARalpha predominates in the liver whereas another isoform
      PPARgamma predominates in adipose tissue and in the immune system. This tissue
      specific pattern of PPARalpha expression is consistent with a role for PPARalpha
      but not PPARgamma or PPARbeta in PP-induced rodent hepatocarcinogenesis. Humans,
      marmosets and guinea-pigs appear refractory or less responsive to the adverse
      liver effects of PPs. However, humans give a therapeutic response to the fibrate
      PPs via an alteration in lipid metabolism mediated by PPARalpha. Such marked
      species differences may be explained by quantity of PPARalpha and/or the quality
      of the PPARalpha-mediated response. The lower expression of full-length
      functional PPARalpha in humans could be attributed to the presence of a
      truncated, inactive form of PPARalpha, which appears to be present in most
      individuals examined to date. In addition, there are species differences in
      sequence and responsiveness of the acyl CoA oxidase (ACO) gene promoter,
      suggesting that even in the presence of sufficient PPARalpha, the human
      equivalent of rodent genes associated with peroxisome proliferation may remain
      inactive.

PMID- 10650912
TI  - Modulation of tumor necrosis factor alpha expression in mouse brain after
      exposure to aluminum in drinking water.
AB  - Aluminum, a known neurotoxic substance and a ground-water pollutant, is a
      possible contributing factor in various nervous disorders including Alzheimer's
      disease. It has been hypothesized that cytokines are involved in aluminum
      neurotoxicity. We investigated the alterations in mRNA expression of tumor
      necrosis factor alpha (TNFalpha), interleukin-1beta (IL-1beta), and interferon
      gamma (IFNgamma), cytokines related to neuronal damage, in cerebrum and
      peripheral immune cells of mice after exposure to aluminum through drinking
      water. Groups of male BALB/c mice were administered aluminum ammonium sulfate in
      drinking water ad libitum at 0, 5, 25, and 125 ppm aluminum for 1 month. An
      additional group received 250 ppm ammonium as ammonium sulfate. After treatment,
      the cerebrum, splenic macrophages and lymphocytes were collected. The expression
      of TNFalpha mRNA in cerebrum was significantly increased among aluminum-treated
      groups compared with the control, in a dose-dependent manner. Other cytokines did
      not show any aluminum-related effects. In peripheral cells, there were no
      significant differences of cytokine mRNA expressions among treatment groups.
      Increased expression of TNFalpha mRNA by aluminum in cerebrum may reflect
      activation of microglia, a major source of TNFalpha in this brain region. Because
      the aluminum-induced alteration in cytokine message occurred at aluminum
      concentrations similar to those noted in contaminated water, these results may be
      relevant in considering the risk of aluminum neurotoxicity in drinking water.

PMID- 10650913
TI  - Real-time PCR-analysis of the cytochrome P450 1B1 codon 432-polymorphism.
AB  - The aim of the present study was to develop and validate a rapid assay for
      genotyping of CYP1B1 codon 432-polymorphism. The described method is a single
      tube assay and combines both rapid-cycle polymerase chain reaction (PCR) with
      real-time monitoring by amplification and generation of the melting profiles of
      an allele-specific fluorescent probe. With this method 300 samples were analysed
      from healthy, unrelated Germans. Genotype frequency determined for the mutated
      allele CYP1B1*2 was 0.40. The results show that genotyping of CYP1B1 codon 432
      polymorphism with a real-time fluorescence PCR method is a rapid and reliable
      assay for the analysis of large numbers of samples.

PMID- 10650914
TI  - The influence of cytochrome P450 1A1 and glutathione S-transferase M1 genotypes
      on biomarker levels in coke-oven workers.
AB  - The present study has the aim of evaluating gene-environment interaction on the
      levels of different biomarkers in coke-oven workers exposed to PAH. In order to
      assess whether the levels of some biomarkers (PAH-DNA adducts, nitro-PAH adducts
      to Hb and MN frequency) could be modulated by the genetic metabolic polymorphisms
      for CYP1A1 and GSTM1, we analysed in 76 coke-oven workers and 18 controls the
      CYP1A1 (MspI and Ile/Val sites) and the GSTM1 genotypes by a PCR assay. In
      individuals with shared setup of CYP1A1 or GSTM1 genotypes, we analysed how the
      specified biomarkers correlated with total PAH exposure (urinary levels of 1
      hydroxypyrene) both by a stratified analysis and logistic regression modelling.
      Statistically significant (P = 0.03 and P = 0.01) higher percentages of the more
      susceptible GSTM1- subjects compared to the GSTM1+ subjects and of the more
      susceptible CYP1A1 Ile/Val individuals compared to the CYP1A1 Ile/Ile individuals
      were detected for high levels of PAH-DNA adducts in the high exposure group
      (namely high levels of 1-OHP). A statistically significant association was
      observed between increased PAH-DNA adduct levels and the more susceptible GSTM1-
      genotype (P.O.R. = 4.18, P = 0.03) in a logistic regression modelling and a
      significant interaction between PAH exposure and GSTM1-genotype was found for PAH
      DNA adducts. No effect of these metabolic genotypes was observed for MN frequency
      and nitro-PAH adducts to Hb. In conclusion, a gene-environment interaction
      between PAH exposure and two metabolic genotypes involved in activation (CYP1A1)
      and detoxification (GSTM1) of PAHs, respectively, has been identified.

PMID- 10650915
TI  - Species differences in induction of hepatic enzymes by BM 17.0744, an activator
      of peroxisome proliferator-activated receptor alpha (PPARalpha).
AB  - BM 17.0744, a new anti-diabetic and lipid-lowering agent, leads also to strong
      hepatomegaly and carnitine acetyl transferase (CAT) increase in the liver of
      rats, a phenomenon known from fibrates. For information on the relevance of
      changes in liver of rats to other species, we investigated the effects of BM
      17.0744 on lipids and selected marker enzymes related to beta-oxidation in rats,
      dogs and guinea-pigs, so-called high and low responders to peroxisome
      proliferators. To examine selectivity other enzymes were also determined, e.g.
      esterase, urate oxidase (UOX) and cytochrome c oxidase (CYT.C.OX.). Lowering of
      triglycerides and cholesterol in blood serum and/or liver was observed in
      pharmacological dose range in the three species tested. In dogs and guinea-pigs,
      liver and kidney weights were unaffected even in dogs in medium and high dose
      groups with high systemic exposure and severe toxicity. In male Sprague-Dawley
      rats treatment with 1.5, 3, 6 and 12.5 mg/kg per day BM 17.0744 selectively
      elevated the activities of CAT and acyl-CoA oxidase (AOX) by < or =200 and 20
      fold, respectively. Administration of BM 17.0744 to Beagle dogs (1.5, 4, 12 mg/kg
      per day) and guinea-pigs (3 and 12 mg/kg per day) enhanced the activities of CAT
      and AOX dose-dependently by a factor of two to three only. Immunoblotting
      revealed a drug-specific enhancement of the amount of beta-oxidation enzymes in
      rats, which is in accord with the rapid and coordinated transcriptional
      activation shown in Northern dot blot analysis. Nuclear run-on assays
      demonstrated a real transcriptional activation. BM 17.0744 activates peroxisome
      proliferator-activated receptor alpha (PPARalpha), which could be shown by
      transactivation assays. The stimulation of PPARalpha by BM 17.0744 was stronger
      than that of the known ligands WY 14.643 and ETYA. Activation of PPARgamma can be
      excluded. Taken collectively, the data demonstrate an enhancement of the beta
      oxidation system by BM 17.0744 paralleled by lipid-lowering in all species
      investigated. The activation of the nuclear factor PPARalpha may explain the
      changes in liver and the metabolic effects on the molecular level. The lack of an
      increase in liver and kidney weights and the relatively moderate enhancement of
      activities of beta-oxidation-related enzymes in dogs and guinea-pigs indicate
      that the excessive response observed in rats is not applicable to other,
      predominantly non-rodent, species. On the basis of these data and the experience
      with fibrates a specific risk for humans is not expected.

PMID- 10650916
TI  - Suppression of apoptosis and induction of DNA synthesis in vitro by the phthalate
      plasticizers monoethylhexylphthalate (MEHP) and diisononylphthalate (DINP): a
      comparison of rat and human hepatocytes in vitro.
AB  - Diethylhexylphthalate (DEHP) and diisononylphthalate (DINP) are plasticizers with
      many important commercial, industrial and medical applications. However, both
      DEHP and DINP are rodent peroxisome proliferators (PPs), a class of compounds
      that cause rodent liver tumours associated with peroxisome proliferation,
      induction of hepatic DNA synthesis and the suppression of apoptosis. Despite
      these effects in the rodent, humans appear to be nonresponsive to the adverse
      effects of PPs. Previously, we have shown that the fibrate hypolipidaemic
      peroxisome proliferator, nafenopin, induced DNA synthesis and suppressed
      apoptosis in rat but not in human hepatocytes. In this work, we have examined
      species differences in the response of rat and human hepatocytes to DEHP and DINP
      in vitro. In rat hepatocytes in vitro, both DINP and MEHP (a principle metabolite
      of DEHP and the proximal peroxisome proliferator) caused a concentration
      dependent induction of DNA synthesis and suppression of both spontaneous and
      transforming growth factor beta1 (TGFbeta1)-induced apoptosis. Similarly, both
      MEHP and DINP caused a concentration-dependent induction of peroxisomal beta
      oxidation although the response to DINP was less robust. In contrast to the
      pleiotropic response noted in rat hepatocytes, neither DINP nor MEHP caused an
      induction of beta-oxidation, stimulation of DNA synthesis and suppression of
      apoptosis in human hepatocytes cultured from three separate donors. These data
      provide evidence for species differences in the hepatic response to the
      phthalates DEHP and DINP, confirming that human hepatocytes appear to be
      refractory to the hepatocarcinogenic effects of PPs first noted in rodents.

PMID- 10650917
TI  - Mechanism of enhanced lipid peroxidation in the liver of Long-Evans cinnamon
      (LEC) rats.
AB  - The Long-Evans Cinnamon (LEC) rat is a mutant strain of rats that accumulate
      copper (Cu) in the liver in much the same way as individuals who suffer from
      Wilson's disease (WD) and has been suggested as a model for this disease. Lipid
      peroxidation (LPO) is considered to be involved in the toxic action of Cu in the
      livers of LEC rats. We investigated the mechanism of LPO in the livers of LEC
      rats showing apparent signs of hepatitis. Several-fold higher LPO levels were
      observed in post-mitochondrial supernatant (S-9) fraction of livers from
      hepatitic LEC rats than in those from Wistar rats. To mimic living cells, we
      introduced NADPH-generating system (NADPH-gs) into the S-9 incubation system.
      Thus was ensured a constant supply of NADPH to vital enzymes that may be directly
      or indirectly involved in the generation and/or elimination of reactive oxygen
      species (ROSs), such as glutathione reductase (GSSG-R), which require NADPH for
      their reactions. The levels of LPO in liver S-9 from hepatitic LEC rats were
      further increased by incubating liver S-9 at 37 degrees C in the presence of
      NADPH-gs. This increase was inhibited by EDTA, butylated hydroxytoluene (BHT),
      and catalase (CAT), suggesting that some metal, most likely the accumulated Cu,
      and ROSs derived from hydrogen peroxide (H2O2) are involved in the increased
      levels of LPO in the livers of hepatitic LEC rats. The requirement of NADPH-gs
      for enhanced LPO in the livers of hepatitic LEC rats indicates the consumption of
      NADPH during reactions leading to LPO. It is known that H2O2, and consequently
      hydroxyl radical are generated during Cu-catalyzed glutathione (GSH) oxidation.
      The cyclic regeneration of GSH from GSSG by NADPH-dependent GSSG-R in the
      presence of NADPH-gs may cause sustained generation of hydroxyl radical in the
      presence of excess free Cu. The generation of H2O2 in S-9 fraction of livers from
      hepatitic LEC rats was observed to be significantly higher than that in S-9
      fraction of livers from non-hepatitic LEC rats and Wistar rats. Moreover, in
      addition to the reported decrease in glutathione peroxidase (GPX) activity, we
      found that CAT activity was markedly decreased in LEC rats with hepatitis. The
      increased generation of H2O2 with reduced activities of GPX and CAT may result in
      cellular accumulation of H2O2 in the liver of hepatitic LEC rats. Taken
      altogether, it is suggested that the accumulated H2O2 undergoes the Fenton-type
      reaction with also accumulated free Cu, thus generating hydroxyl radical in the
      livers of hepatitic LEC rats and increasing LPO levels in these animals.

PMID- 10650918
TI  - Evaluation of acute and chronic hepatotoxic effects exerted by anabolic
      androgenic steroid stanozolol in adult male rats.
AB  - Stanozolol (ST) is a 17alpha-alkyl anabolic-androgenic steroid (17alpha-AAS)
      often misused by athletes and bodybuilders. The use of anabolic-steroids by
      sportsmen and teenagers has increased dramatically, thus raising the question
      about their hepatotoxicity, specially those such as ST which are orally
      administered. Previously, we have reported diverse in vivo effects exerted by
      this steroid and published the existence of a highly specific ST-binding site in
      male rat liver microsomes. The existence of this binding site, the reported
      hepatic effects exerted in humans, and the very limited information about its
      potential hepatotoxicity led us to treat adult male rats acutely and chronically
      with ST and study different parameters that could indicate liver damage: serum
      levels of transaminases, concentration of monooxygenase enzymes in liver, liver
      membrane lipid peroxidation products, liver histopathology, and cell cycle/ploidy
      status of liver cells. In our study, no changes in serum transaminases or lipid
      peroxidation levels were obtained. However, acute stanozolol treatment
      significantly decreased the levels of cytochrome P450 (Cyt. P450) and cytochrome
      b5 (Cyt. b5) during the first 48 h of treatment, while subsequently, at 72 and 96
      h, these microsomal enzymes underwent a significant increase in their levels. In
      sharp contrast with this response to acute treatment, the content of these two
      enzymes during chronic treatment showed an important decrease. Interestingly,
      acutely and chronically ST-treated livers showed slight to moderate inflammatory
      or degenerative lesions in centrilobular hepatocytes. Flow cytometric analysis
      demonstrated that both acute and chronic ST treatment were capable of increasing
      the percentage of S-phase fraction (%SPF) of liver cells. These findings taken
      together clearly show that this steroid is capable of altering the liver capacity
      for metabolizing xenobiotics and indicate that high doses of ST could exert a
      proliferative effect on liver cells. Such data should be considered in risk
      evaluations for this compound.

PMID- 10650919
TI  - Comparative evaluation of benzodiazepines for control of soman-induced seizures.
AB  - This study evaluated the ability of six benzodiazepines to stop seizures produced
      by exposure to the nerve agent soman. Guinea pigs, previously prepared with
      electrodes to record electroencephalographic (EEG) activity, were pretreated with
      pyridostigmine (0.026 mg/kg, i.m.) 30 min before challenge with soman (56
      microg/kg, s.c.) and then treated 1 min after soman exposure with atropine (2.0
      mg/kg, i.m.) and pralidoxime chloride (2-PAM Cl; 25 mg/kg, i.m.). All animals
      developed seizures following this treatment. Benzodiazepines (avizafone,
      clonazepam, diazepam, loprazolam, lorazepam, and midazolam) were given i.m. 5 or
      40 min after seizure onset. All benzodiazepines were effective in stopping soman
      induced seizures, but there were marked differences between drugs in the rapidity
      of seizure control. The 50% effective dose (ED50) values and latencies for
      anticonvulsant effect for a given benzodiazepine were the same at the two times
      of treatment delay. Midazolam was the most potent and rapidly acting compound at
      both treatment times. Since rapid seizure control minimizes the chance of brain
      damage, use of midazolam as an anticonvulsant may lead to improved clinical
      outcome in the treatment of nerve agent seizures.

PMID- 10650920
TI  - Determination of urinary thymidine glycol using affinity chromatography, HPLC and
      post-column reaction detection: a biomarker of oxidative DNA damage upon kidney
      transplantation.
AB  - Reactive oxygen species are generated during ischaemia-reperfusion of tissue.
      Oxidation of thymidine by hydroxyl radicals (HO) leads to the formation of 5,6
      dihydroxy-5,6-dihydrothymidine (thymidine glycol). Thymidine glycol is excreted
      in urine and can be used as biomarker of oxidative DNA damage. Time dependent
      changes in urinary excretion rates of thymidine glycol were determined in six
      patients after kidney transplantation and in six healthy controls. A new
      analytical method was developed involving affinity chromatography and subsequent
      reverse-phase high-performance liquid chromatography (RP-HPLC) with a post-column
      chemical reaction detector and endpoint fluorescence detection. The detection
      limit of this fluorimetric assay was 1.6 ng thymidine glycol per ml urine, which
      corresponds to about half of the physiological excretion level in healthy control
      persons. After kidney transplantation the urinary excretion rate of thymidine
      glycol increased gradually reaching a maximum around 48 h. The excretion rate
      remained elevated until the end of the observation period of 10 days. Severe
      proteinuria with an excretion rate of up to 7.2 g of total protein per mmol
      creatinine was also observed immediately after transplantation and declined
      within the first 24 h of allograft function (0.35+/-0.26 g/mmol creatinine). The
      protein excretion pattern, based on separation of urinary proteins on sodium
      dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE), as well as
      excretion of individual biomarker proteins, indicated nonselective glomerular and
      tubular damage. The increased excretion of thymidine glycol after kidney
      transplantation may be explained by ischaemia-reperfusion induced oxidative DNA
      damage of the transplanted kidney.

PMID- 10650921
TI  - Protective effects of polyphenols against cadmium-induced glomerular mesangial
      cell myocontracture.
AB  - The main objective of this work was to determine the ability of polyphenols
      (procyanidoloic oligomers; PCO) to diminish the contracture of CdCl2-induced
      mesangial cells (smooth muscle cell type). Glomeruli were isolated by passing rat
      renal cortex pulp through calibrated sieves followed by a culture step for
      outgrowth of cells. PCO lethality was measured by microassay (Neutral Red
      uptake). This study has revealed an absence of PCO toxicity during exposure for
      24 h and for concentrations ranging from 0.031 to 1% (w/v) on rat renal mesangial
      cells. We observed a lack of cytotoxicity response for the PCO mixture dissolved
      in medium. Quantitative assessments of the planar cell surface area (PCSA) were
      performed with an accurate automatized image analyser. The use of isolated
      cultured mesangial cells permits us to evaluate by quantitative morphometric
      analysis the contracture elicited either with CdCl2 salts alone or by previous
      incubation with a non-lethal dose of PCO. When renal mesangial cells were exposed
      for 10 min to the PCO mixture, the Cd-mediated myocontracturant response of the
      mesangial cells was totally abolished. These results suggest that polyphenols
      could be effective against renal damages induced by cadmium.

PMID- 10650922
TI  - Differential substrate behaviours of ethylene oxide and propylene oxide towards
      human glutathione transferase theta hGSTT1-1.
AB  - The transformation of ethylene oxide (EO), propylene oxide (PO) and 1-butylene
      oxide (1-BuO) by human glutathione transferase theta (hGSTT1-1) was studied
      comparatively using 'conjugator' (GSTT1 + individuals) erythrocyte lysates. The
      relative sequence of velocity of enzymic transformation was PO > EO >> 1-BuO. The
      faster transformation of PO compared to EO was corroborated in studies with human
      and rat GSTT1-1 (hGSTT1-1 and rGSTT1-1, respectively) expressed by Salmonella
      typhimurium TA1535. This sequence of reactivities of homologous epoxides towards
      GSTT1-1 contrasts to the sequence observed in homologous alkyl halides (methyl
      bromide, MBr; ethyl bromide, EtBr; n-propyl bromide, PrBr) where the relative
      sequence MeBr >> EtBr > PrBr is observed. The higher reactivity towards GSTT1-1
      of propylene oxide compared to ethylene oxide is consistent with a higher
      chemical reactivity. This is corroborated by experimental data of acid-catalysed
      hydrolysis of a number of aliphatic epoxides, including ethylene oxide and
      propylene oxide and consistent with semi-empirical molecular orbital modelings.

PMID- 10650923
TI  - The acute pathology of fatty acid anilides and linoleic diester of 3-phenylamino
      1,2-propanediol in mice: possible implication as aetiologic agents for the toxic
      oil syndrome.
AB  - Two groups of compounds, the fatty acid anilides and the mono- and diester of 3
      phenylamino-1,2-propanediol (PAP) are suspected as aetiologic agents for the
      toxic oil syndrome (TOS). Intraperitoneal administration of oleoyl and linoleoyl
      anilides in mice caused severe weight loss followed by death in 50% of the
      animals and histopathological changes mainly to the lungs. Linoleic diester of
      PAP led to weight loss, haemorrhage, congestion and emphysema in the lungs and an
      increase in blood eosinophilia. Although not producing the full spectrum of
      symptoms the effects of the substances resemble the acute human disease.
      Possibly, the two groups of substances led together to the full spectrum of
      disease manifestations seen in TOS.

PMID- 10650924
TI  - Itai-itai disease is not associated with polymorphisms of the estrogen receptor
      alpha gene.
AB  - Itai-itai (or ouch-ouch) disease is a syndrome accompanied by bone mineral
      disorders, and which may be related to oral cadmium exposure. Itai-itai
      predominantly affects postmenopausal women with a history of multiple
      childbirths. Recently, it has been reported that polymorphisms of the estrogen
      receptor alpha (ERalpha) gene are associated with postmenopausal reduction of
      bone mineral density in Japanese women. However, estrogen receptors have never
      been studied in itai-itai disease. In this study, we examined the genotypic
      distributions of PvuII and XbaI restriction fragment length polymorphisms (RFLPs)
      of the ERalpha gene in patients with itai-itai disease and compared them with
      those of control subjects. The RFLPs are represented here as Pp (PvuII) and Xx
      (XbaI); the capital and small letters signify the absence and presence of
      restriction sites, respectively. The genotypic distributions of the patient group
      were: PP, 14.8%; Pp, 55.6%; pp, 29.6%; XX, 7.4%; Xx, 29.6%; and xx, 63.0%. These
      distributions were similar to those observed for the control groups, hence no
      pattern of genotypic distribution was observed that could be related to itai-itai
      disease. We conclude that RFLPs of the ERalpha gene may not be associated with
      itai-itai disease.

PMID- 10650925
TI  - Targeted gene disruption in endocrine research--the case of glucagon-like peptide
      1 and neuroendocrine function.

PMID- 10650926
TI  - Breeding stock-specific variation in peptidylglycine alpha-amidating
      monooxygenase messenger ribonucleic acid splicing in rat pituitary.
AB  - Peptidylglycine alpha-amidating monooxygenase (PAM) is a bifunctional enzyme that
      catalyzes the carboxyl-terminal amidation of glycine-extended peptides in a two
      step reaction involving a monooxygenase and a lyase. Several forms of PAM
      messenger RNA result from alternative splicing of the single copy PAM gene. The
      presence of alternately spliced exon A between the two enzymatic domains allows
      endoproteolytic cleavage to occur in selected tissues, generating soluble
      monooxygenase and membrane lyase from integral membrane PAM. While using an exon
      A antiserum, we made the unexpected observation that Charles River Sprague Dawley
      rats expressed forms of PAM containing exon A in their pituitaries, whereas
      Harlan Sprague Dawley rats did not. Forms of PAM containing exon A were expressed
      in the atrium and hypothalamus of both types of Sprague Dawley rat, although in
      different proportions. PAM transmembrane domain splicing also differed between
      rat breeders, and full-length PAM-1 was not prevalent in the anterior pituitary
      of either type of rat. Despite striking differences in PAM splicing, no
      differences in levels of monooxygenase or lyase activity were observed in tissue
      or serum samples. The splicing patterns of other alternatively spliced genes,
      pituitary adenylate cyclase-activating polypeptide receptor type 1 and cardiac
      troponin T, did not vary with rat breeder. Strain-specific variations in the
      splicing of transcripts such as PAM must be taken into account in analyzing the
      resultant proteins, and knowledge of these differences should identify variations
      with functional significance.

PMID- 10650927
TI  - Daily melatonin administration to middle-aged male rats suppresses body weight,
      intraabdominal adiposity, and plasma leptin and insulin independent of food
      intake and total body fat.
AB  - Pineal melatonin secretion declines with aging, whereas visceral fat, plasma
      insulin, and plasma leptin tend to increase. We have previously demonstrated that
      daily melatonin administration at middle age suppressed male rat intraabdominal
      visceral fat, plasma leptin, and plasma insulin to youthful levels; the current
      study was designed to begin investigating mechanisms that mediate these
      responses. Melatonin (0.4 microg/ml) or vehicle was administered in the drinking
      water of 10-month-old male Sprague Dawley rats (18/treatment) for 12 weeks. Half
      (9/treatment) were then killed, and the other half were submitted to cross-over
      treatment for an additional 12 weeks. Twelve weeks of melatonin treatment
      decreased (P<0.05) body weight (BW; by 7% relative to controls), relative
      intraabdominal adiposity (by 16%), plasma leptin (by 33%), and plasma insulin (by
      25%) while increasing (P<0.05) locomotor activity (by 19%), core body temperature
      (by 0.5 C), and morning plasma corticosterone (by 154%), restoring each of these
      parameters toward more youthful levels. Food intake and total body fat were not
      changed by melatonin treatment. Melatonin-treated rats that were then crossed
      over to control treatment for a further 12 weeks gained BW, whereas control rats
      that were crossed to melatonin treatment lost BW, but food intake did not change
      in either group. Feed efficiency (grams of BW change per g cumulative food
      intake), a measure of metabolic function, was negative in melatonin-treated rats
      and positive in control rats before cross-over (P<0.001); this relationship was
      reversed after cross-over (P<0.001). Thus, melatonin treatment in middle age
      decreased BW, intraabdominal adiposity, plasma insulin, and plasma leptin,
      without altering food intake or total adiposity. These results suggest that the
      decrease in endogenous melatonin with aging may alter metabolism and physical
      activity, resulting in increased BW, visceral adiposity, and associated
      detrimental metabolic consequences.

PMID- 10650928
TI  - Selective impairment of corticotropin-releasing factor1 (CRF1) receptor-mediated
      function using CRF coupled to saporin.
AB  - CRF is the main component in the brain neuropeptide effector system responsible
      for the behavioral, endocrine, and physiological activation that accompanies
      stress activation. Reduced CRF system activation plays a role in the etiology of
      a variety of psychiatric and metabolic disease states. We have developed a novel
      protein conjugate that joins native rat/human CRF to a ribosome-inactivating
      protein, saporin (CRF-SAP), for the purpose of targeted inactivation of CRF
      receptor-expressing cells. Cytotoxicity measurements revealed that CRF-SAP (1-100
      nM) produced concentration-dependent and progressive cell death over time in CRF1
      receptor-transfected L cells, but at similar concentrations had no effect on
      CRF2alpha receptor-transfected cells. The CRF-SAP-induced toxicity in CRF1
      transfected cells was prevented by coincubation with the competitive CRF1/CRF2
      receptor peptide antagonist, [D-Phe12]CRF-(12-41), or the selective nonpeptide
      CRF1 receptor antagonist, NBI 27914. Finally, in cultured rat pituitary cells
      that express native CRF1 receptors, CRF-SAP suppressed CRF-induced (1 nM) ACTH
      release. GnRH (1-10 nM) stimulated LH release was also assessed in the same
      pituitary cultures. Although there was a slight decrease in LH release from these
      cultures, this decrease was observed with CRF-SAP or SAP alone, suggesting that
      the response was nonspecific. Taken together, these results suggest the utility
      of CRF-SAP as a specific and subtype-selective tool for long term impairment of
      CRF1 receptor-expressing cells.

PMID- 10650929
TI  - Primary structure and function of three gonadotropin-releasing hormones,
      including a novel form, from an ancient teleost, herring.
AB  - The evolution of GnRH and the role of multiple forms within the brain are
      examined. Three forms of GnRH were purified from the brain of Pacific herring
      (Clupea harengus pallasi) and characterized using Edman degradation and mass
      spectrometry. Two forms correspond with the known structures of chicken GnRH-II
      and salmon GnRH that are found in many vertebrate species. The third form,
      designated herring GnRH (hrGnRH), has a primary structure of pGlu-His-Trp-Ser-His
      Gly-Leu-Ser-Pro-Gly-NH2. This novel peptide is a potent stimulator of
      gonadotropin II and GH release from dispersed fish pituitary cells. The content
      of hrGnRH in the pituitary was 8-fold that of salmon GnRH and 43-fold that of
      chicken GnRH-II, which provides supporting evidence that hrGnRH is involved in
      the release of gonadotropin. Herring is the most phylogenetically ancient animal
      in which three forms of GnRH have been isolated and sequenced. Our evidence
      suggests that the existence of three GnRHs in the brain of one species 1) is an
      ancestral condition for teleosts, 2) has the potential for separate regulation of
      the distinct GnRHs, and 3) may be an evolutionary advantage for refined control
      of reproduction in different environments.

PMID- 10650930
TI  - Activation of the sodium pump blocks the growth hormone-induced increase in
      cytosolic free calcium in rat adipocytes.
AB  - GH promptly increases cytosolic free calcium ([Ca2+]i) in freshly isolated rat
      adipocytes. Adipocytes deprived of GH for 3 h or longer are incapable of
      increasing [Ca2+]i in response to GH, but instead respond in an insulin-like
      manner. Insulin blocks the GH-induced increase in [Ca2+]i in GH-replete cells and
      stimulates the sodium pump (i.e. Na+/K+-ATPase), thereby hyperpolarizing the cell
      membrane. Blockade of the Na+/K+-ATPase with 100 microM ouabain reversed these
      effects of insulin and enabled GH to increase [Ca2+]i in GH-deprived adipocytes.
      Both insulin and GH activated the sodium pump in GH-deprived adipocytes, as
      indicated by increased uptake of 86Rb+. Decreasing availability of intracellular
      Na+ by blockade of Na+/K+/ 2Cl- symporters or Na+/H+ antiporters abolished the
      effects of both hormones on 86Rb+ uptake and enabled both GH and insulin to
      increase [Ca2+]i in GH-deprived adipocytes. The data suggest that hormonal
      stimulation of Na+/K+-ATPase activity interferes with activation of voltage
      sensitive calcium channels by either membrane hyperpolarization or some unknown
      interaction between the sodium pump and calcium channels.

PMID- 10650931
TI  - Central inhibition of gonadotropin-releasing hormone secretion in the growth
      restricted hypogonadotropic female sheep.
AB  - Growth retardation induced by dietary restriction results in hypogonadotropism,
      and thus, puberty is delayed. The present studies determined 1) whether reduced
      LH secretion in the growth-retarded condition is due to a reduction in the
      frequency and/or in the amplitude of GnRH secretion, and 2) whether the mechanism
      regulating LH secretion is being actively inhibited via central mechanisms. To
      determine whether GnRH pulse frequency and/or amplitude are reduced during growth
      restriction, blood samples were simultaneously collected from pituitary portal
      blood for GnRH and from jugular blood for LH determinations over a 4-h period in
      ovariectomized lambs (52 wk of age) that were either growth restricted (28 kg; n
      = 8) or growing normally (60 kg; n = 7). As expected, the growth-restricted
      females were hypogonadotropic and exhibited a long LH interpulse interval
      compared with the normally growing females. However, although the GnRH interpulse
      interval was longer in the growth-restricted lambs compared with that in the
      normally growing lambs, the pattern of GnRH secretion did not directly correspond
      with that of LH secretion in the growth-restricted group. In addition, high
      amplitude GnRH pulses that coincided with LH pulses and small, low amplitude GnRH
      pulses without a concomitant LH pulse occurred. The second study tested the
      hypothesis that diet-induced hypogonadotropism is the result of actively
      inhibited central mechanisms by investigating the effects of the nonspecific
      central nervous system inhibitor, sodium pentobarbital, on pulsatile LH secretion
      in the growth-restricted lamb. Serial blood samples were collected from 11
      ovariectomized lambs that were maintained at weaning weight (approximately 20 kg)
      by reduced diet. After a 4-h pretreatment period, six of the lambs were
      anesthetized with sodium pentobarbital for 4 h; the other five lambs were
      untreated and served as controls. Pentobarbital anesthesia reduced the LH
      interpulse interval (increased the frequency) and increased mean LH levels. These
      findings suggest that during growth restriction hypogonadotropism arises from a
      central inhibition of GnRH neurons and is manifest as a decrease in both
      frequency and amplitude of GnRH pulses.

PMID- 10650932
TI  - Delineation of the signaling pathways involved in glucocorticoid-induced and
      spontaneous apoptosis of rat thymocytes.
AB  - In primary rat thymocytes, both glucocorticoids and the withdrawal of in vivo
      survival factors elicit apoptosis. In this study we wanted to determine whether
      distinct pathways leading to apoptosis are engaged by these two stimuli. To
      address this question, we conducted a multiparametric analysis of cell viability,
      DNA fragmentation, activation of caspase-3-like activity, cell shrinkage, the
      loss of mitochondrial membrane potential, and externalization of
      phosphatidylserine in the absence and presence of protein and RNA synthesis. The
      role of caspase activity was also examined in both glucocorticoid-and survival
      factor withdrawal-induced cell death. We show that glucocorticoid-induced, but
      not spontaneous, loss of viability is dependent upon macromolecular synthesis and
      caspase activity. Furthermore, glucocorticoid-induced phosphatidylserine
      externalization and cell shrinkage are dependent upon gene regulation and caspase
      activity, whereas these features manifest independently of gene regulation and
      caspase activity in spontaneous death. In contrast, the loss of mitochondrial
      membrane potential was dependent upon macromolecular synthesis only in
      glucocorticoid-induced death and was independent of caspases in both spontaneous
      and dexamethasone-induced death. These results suggest that thymocytes can die by
      a caspase-independent mechanism and that a major difference between
      glucocorticoid- and survival factor deprivation-induced death is the dependence
      on gene expression.

PMID- 10650933
TI  - Impact of restriction of placental and fetal growth on expression of 11beta
      hydroxysteroid dehydrogenase type 1 and type 2 messenger ribonucleic acid in the
      liver, kidney, and adrenal of the sheep fetus.
AB  - We have investigated the effects of fetal growth restriction, induced by
      restriction of placental growth and function (PR), on 11beta-hydroxysteroid
      dehydrogenase type 1 (11betaHSD-1) and 11betaHSD-2 messenger RNA (mRNA)
      expression in fetal tissues in the sheep, using Northern blot analysis. Fetal
      liver, kidney, and adrenals were collected from normally grown fetuses at 90 days
      (n = 6), 125 days (n = 6), and 141-145 days (n = 7) and from PR fetuses at 141
      145 days (n = 6). Expression of 11betaHSD-1 mRNA in the fetal liver increased
      significantly between 125 days (7.4+/-0.8) and 141-145 days gestation (27+/-5.3).
      There was also an approximately 2-fold increase in the ratio of 11betaHSD-1
      mRNA/18S rRNA expression in the PR group (53.8+/-7.9) compared with that in
      control animals at 141-145 days gestation. There was a significant decrease in
      11betaHSD-2 mRNA in fetal adrenals between 125 days (41.6+/-2.4) and 141-145 days
      (26.7+/-1.1) gestation, but there was no effect of PR on the expression of
      adrenal 11betaHSD-2 mRNA. 11betaHSD-2 mRNA expression in the fetal kidney
      increased between 90 days (16.8+/-1.7) and 141-145 days gestation (31.7+/-4.3),
      but there was no effect of PR on the levels of 11betaHSD-2 mRNA in the fetal
      kidney. In summary, 11betaHSD-2 mRNA is differentially regulated in the fetal
      adrenal and kidney in the sheep fetus during late gestation. There is also a
      specific increase in the expression of 11betaHSD-1 mRNA in the liver of growth
      restricted fetuses in late gestation. This suggests that there is increased
      hepatic exposure to cortisol in the growth-restricted fetus, which may be
      important in the reprogramming of hepatic physiology that occurs after growth
      restriction in utero.

PMID- 10650934
TI  - Insulin-like growth factor I activates c-Jun N-terminal kinase in MCF-7 breast
      cancer cells.
AB  - Insulin-like growth factor I (IGF-I) is an important mediator of breast cancer
      cell growth, although the signaling pathways important for IGF-I-mediated effects
      in breast cancer cells are still being elucidated. We had demonstrated previously
      that increased intracellular cAMP in MCF-7 breast cancer cells inhibited cell
      growth and IGF-I-induced gene expression, as determined using a reporter gene
      assay. This effect of cAMP on IGF-I signaling was independent of IGF-I-induced
      activation of the mitogen-activated protein kinases extracellular signal
      regulated kinases 1 and 2 (ERK1 and -2). To determine whether this effect of cAMP
      may be mediated via another mitogen-activated protein kinase, the ability of IGF
      I to activate the c-Jun N-terminal kinases (JNKs) was investigated. Treatment of
      MCF-7 cells with 100 ng/ml IGF-I increased the level of phosphorylated JNK, as
      determined by Western blot analysis. JNK phosphorylation was not evident until 15
      min after treatment with IGF-I, and peak levels of phosphorylation were present
      at 30-60 min. This was in contrast to ERK phosphorylation, which was present
      within 7.5 min of IGF-I treatment. Determination of JNK activity using an immune
      complex assay demonstrated a 3.3- and 3.5-fold increase in JNK1 and -2 activity,
      respectively, 30 min after treatment with 100 ng/ml IGF-I. The use of PD98059,
      which inhibits activation of ERK1 and -2, and LY 294002, an inhibitor of
      phosphatidylinositol 3-kinase, demonstrated that IGF-I-induced activation of JNK1
      is independent of ERK and phosphatidylinositol 3-kinase activation. In contrast,
      increasing intracellular cAMP with forskolin resulted in abrogation of IGF-I
      induced JNK activity. In summary, these data demonstrate that IGF-I activates the
      JNKs in MCF-7 breast cancer cells and, taken together with the results of our
      previous study, suggest that JNK may contribute to IGF-I-mediated gene expression
      and, possibly, cell growth in MCF-7 breast cancer cells.

PMID- 10650935
TI  - B-type natriuretic peptide receptor expression and activity are hormonally
      regulated in rat ovarian cells.
AB  - Natriuretic peptides form a family of structurally related peptides known to
      regulate salt and water homeostasis and to cause vasodilation. Synthesis of
      atrial (ANP), brain (BNP), and C-type (CNP) natriuretic peptides occurs mainly in
      the heart and brain and has been identified recently in the female reproductive
      tract. The expression of ANP and CNP as well as their cognate guanylyl cyclase
      receptors (NPR-A and NPR-B, respectively) have been detected in the rat ovary. We
      have shown previously that the expression of the natriuretic peptides and their
      receptors in the rat ovary appears to be modulated by the estrous cycle. In the
      present study we have evaluated the expression of the natriuretic peptide system
      (peptide and receptor) in ovarian cells (granulosa and thecal-interstitial cells)
      obtained from immature female rats treated with either diethylstilbestrol (DES),
      an estrogen analog, or equine CG (eCG), a gonadotropin that possesses both LH and
      FSH activity. Using a whole cell RRA, we found that CNP binding was increased by
      2-fold in granulosa cells taken from animals treated with either DES or eCG.
      Semiquantitative RT-PCR revealed that granulosa cells from DES- or eCG-treated
      animals have increased levels of NPR-B messenger RNA (mRNA) transcripts, which
      was in good agreement with the increased binding. The activity of the receptors
      was assessed by ligand-dependent stimulation of cGMP release. CNP, but not ANP,
      stimulated the release of cGMP from granulosa cells obtained from DES-treated,
      but not from eCG-treated, animals. The relative levels of CNP mRNA in granulosa
      cells were unaltered by either DES or eCG treatment. In contrast, CNP mRNA levels
      were increased more than 2-fold, but only in theca-interstitial from the eCG
      treated animals. Our results indicate that CNP and NPR-B are expressed in the
      ovary, and their expression is responsive to hormonal treatments. Furthermore,
      expression of these components of the natriuretic peptide system appears to be
      compartmentalized, with CNP being derived from the extrafollicular compartment
      and acting, through NPR-B, on the granulosa cells.

PMID- 10650936
TI  - Understanding the role of glucocorticoids in obesity: tissue-specific alterations
      of corticosterone metabolism in obese Zucker rats.
AB  - The role of glucocorticoids in obesity is poorly understood. Observations in
      obese men suggest enhanced inactivation of cortisol by 5alpha-reductase and
      altered reactivation of cortisone to cortisol by 11betahydroxysteroid
      dehydrogenase type 1 (11betaHSD1). These changes in glucocorticoid metabolism may
      influence corticosteroid receptor activation and feedback regulation of the
      hypothalamic-pituitary-adrenal axis (HPA). We have compared corticosterone
      metabolism in vivo and in vitro in male obese and lean Zucker rats, aged 9 weeks
      (n = 8/group). Steroids were measured in 72-h urine and 0900 h trunk blood
      samples. 5alpha-Reductase type 1 and 11betaHSD activities were assessed in
      dissected tissues. Obese animals were hypercorticosteronemic and excreted more
      total corticosterone metabolites (2264+/-623 vs. 388+/-144 ng/72 h; P = 0.003),
      with a greater proportion being 5alpha-reduced or 11-oxidized. 11
      Dehydrocorticosterone was also elevated in plasma (73+/-9 vs. 18+/-2 nM; P =
      0.001) and urine (408+/-111 vs. <28 ng/72 h; P = 0.01). In liver of obese rats,
      5alpha-reductase type 1 activity was greater (20.6+/-2.7% vs. 14.1+/-1.5%;
      P<0.04), but 11betaHSD1 activity (maximum velocity, 3.43+/-0.56 vs. 6.57+/-1.13
      nmol/min/mg protein; P = 0.01) and messenger RNA levels (0.56+/-0.08 vs. 1.03+/
      0.15; P = 0.02) were lower. In contrast, in obese rats, 11betaHSD1 activity was
      not different in skeletal muscle and sc fat and was higher in omental fat(36.4+/
      6.2 vs. 19.2+/-6.6; P = 0.01), whereas 11betaHSD2 activity was higher in kidney
      (16.7+/-0.6% vs. 11.3+/-1.5%; p = 0.01). We conclude that greater inactivation of
      glucocorticoids by 5alpha-reductase in liver and 11betaHSD2 in kidney combined
      with impaired reactivation of glucocorticoids by 11betaHSD1 in liver may increase
      the MCR of glucocorticoids and decrease local glucocorticoid concentrations at
      these sites. By contrast, enhanced 11betaHSD1 in omental adipose tissue may
      increase local glucocorticoid receptor activation and promote obesity.

PMID- 10650937
TI  - The effect of phosphorylation by casein kinase 2 on the activity of insulin-like
      growth factor-binding protein-3.
AB  - Insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3) is known to be
      secreted as a phosphoprotein, constitutively phosphorylated at casein kinase 2
      (CK2) sites. To examine the effect of phosphorylation by CK2 on the properties of
      glycosylated human IGFBP-3, we phosphorylated plasma-derived IGFBP-3, containing
      less than 1 mol/mol phosphoserine, in vitro. As judged by incorporated 32P,
      enzymatic deglycosylation did not decrease the phosphate content of phospho-IGFBP
      3. Phosphorylation had no effect on IGF-I or IGF-II binding, but was inhibitory
      to acid-labile subunit binding in the presence of either IGF. Determined in
      simian virus 40-transformed human fibroblasts, cell association by phospho-IGFBP
      3 was inhibited approximately 50% compared with that of the nonphosphorylated
      preparation. Phospho-IGFBP-3 showed significant resistance to proteolysis by
      plasmin and a cysteine protease secreted by MCF-7 cells. However, no difference
      was seen between the two preparations in their inhibition of IGF-I-stimulated DNA
      synthesis when coincubated with IGF-I in neonatal skin fibroblasts or MCF-7
      breast cancer cells, and little difference was found in their ability to
      potentiate IGF-I-stimulated DNA synthesis when preincubated with fibroblasts.
      These results indicate that IGFBP-3 interaction with acid-labile subunit and with
      the cell surface, both of which involve basic carboxyl-terminal residues, may be
      modulated by phosphorylation. Relative resistance to proteolysis and poor binding
      to cells suggest that CK2-phospho-IGFBP-3 may be a significant inhibitor of IGF
      activity in the extracellular environment.

PMID- 10650938
TI  - Two estrogen receptor (ER) isoforms with different estrogen dependencies are
      generated from the trout ER gene.
AB  - A characteristic of all estrogen receptors (ER) cloned from fish to date is the
      lack of the first 37-42 N-terminal amino acids specific to the A domain. Here we
      report the isolation and characterization from trout ovary of a full-length
      complementary DNA (cDNA) clone encoding an N-terminal variant form of the rainbow
      trout ER (rtER). Sequence analysis of open reading frame of this cDNA predicts a
      622-amino acid protein. The C-terminal region of this protein, from amino acid
      position 45 to the end, was very similar to the previously reported rtER
      (referred to as the short form, or rtER(S)). In contrast, this novel rtER cDNA
      (referred to as the long form, or rtER(L)) contains an additional in-frame ATG
      initiator codon that adds 45 residues to the N-terminal region of the protein.
      This new N-terminal region may represent the A domain of ER found in tetrapod
      species. The first 227 bp of this new cDNA were similar to the 3'-end intronic
      sequence of the rtER gene intron 1. These data together with S1 nuclease, primer
      extension, and RT-PCR experiments demonstrate that the rtER(L) represents a
      second isoform of rtER that arises from an alternative promoter within the first
      intron of the gene. Transcripts encoding both rtER forms were expressed in the
      liver. In vitro translation of the rtER(L) cDNA produced 2 proteins with
      molecular masses of 71 and 65 kDa, whereas rtER(S) cDNA produced 1 65-kDa
      protein. Interestingly, Western blot analysis with a specific antibody against
      the C-terminal region of rtER revealed 2 receptor forms of 65 and 71 kDa in trout
      liver nuclear extracts, in agreement with the presence of the 2 distinct classes
      of rtER messenger RNA in this tissue. Functional analysis of both rtER isoforms
      revealed that although rtER(S) consistently exhibited a basal (estrogen
      independent) trans-activation activity that could be further increased in the
      presence of estrogens, the novel isoform rtER(L) is characterized by a strict
      estrogen-dependent transcriptional activity. These data suggest that the
      additional 45 residues at the N-terminal region of rtER(L) clearly modify the
      hormone-independent trans-activation function of the receptor.

PMID- 10650939
TI  - The human NAD+-dependent 15-hydroxyprostaglandin dehydrogenase gene promoter is
      controlled by Ets and activating protein-1 transcription factors and
      progesterone.
AB  - NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (PGDH) is a key catabolic
      enzyme in the inactivation of PGF2alpha and PGE2 and therefore serves as an
      important determinant in regulating their local concentrations. To gain insights
      into the transcriptional regulation of this enzyme, we have isolated 3.5 kb of
      the 5'-flanking sequence of the human PGDH promoter and characterized its control
      in hemopoietic cells and cells of myometrial and placental origin. Several
      potential binding sites for cAMP-responsive element-binding protein (CREB), Ets,
      and activating protein-1 (AP-1) transcription factors are present within 2368 bp
      of the 5'-flanking region. This region and deletions thereof were fused to the
      luciferase reporter gene and used for transient transfection experiments. In
      Jurkat leukemic T cells, which express PGDH endogenously, the transfected PGDH
      promoter was strongly induced by phorbol ester. Induction was reversed by
      coexpression of A-Fos, a dominant negative to AP-1. In primary cultures of
      myometrial smooth muscle cells (SMC), the Ets family members Ets-1, Ets-2, and
      PEA3 potently stimulated transcriptional activity of the PGDH promoter. PEA3
      mediated activation was partially repressed by A-Fos, suggesting an involvement
      of AP-1 proteins, which might be conferred by a distal and a proximal Ets/ AP-1
      composite element. The distal Ets/AP-1 element is flanked by two CRE-like
      sequences. Cotransfection of A-CREB, a dominant negative to CREB, inhibited
      stimulation of PGDH-2368/luc3 by PEA3 in myometrial SMC, whereas treatment with 8
      bromo-cAMP moderately enhanced promoter activity. Progesterone is believed to be
      an important stimulus for PGDH expression in the utero-placental unit, thus
      contributing to the maintenance of a quiescent uterus during pregnancy. In
      myometrial SMC, both isoforms of the progesterone receptor, PR-B and PR-A, caused
      a ligand-dependent activation of PGDH-2368/luc3. Transcriptional activity of PR
      B, but not PR-A, was further enhanced by the addition of 8-bromo-cAMP. We could
      not confirm a recently proposed transcriptional control of PGDH by
      mineralocorticoid receptor. No effect of mineralocorticoid receptor, in the
      absence or presence of aldosterone, with or without 8-bromo-cAMP, was observed on
      PGDH-2368/luc3. Taken together, these findings demonstrate control of the PGDH
      promoter by multiple pathways and provide evidence for cross-talk among Ets, AP
      1, cAMP, and PR-mediated signaling, suggesting complex regulatory mechanisms for
      the expression of PGDH.

PMID- 10650940
TI  - Iodide excess induces apoptosis in thyroid cells through a p53-independent
      mechanism involving oxidative stress.
AB  - Thyroid toxicity of iodide excess has been demonstrated in animals fed with an
      iodide-rich diet; in vitro iodide is cytotoxic, inhibits cell growth, and induces
      morphological changes in thyroid cells of some species. In this study, we
      investigated the effect of iodide excess in an immortalized thyroid cell line
      (TAD-2) in primary cultures of human thyroid cells and in cells of nonthyroid
      origin. Iodide displayed a dose-dependent cytotoxicity in both TAD-2 and primary
      thyroid cells, although at different concentrations, whereas it had no effect on
      cells of nonthyroid origin. Thyroid cells treated with iodide excess underwent
      apoptosis, as evidenced by morphological changes, plasma membrane
      phosphatidylserine exposure, and DNA fragmentation. Apoptosis was unaffected by
      protein synthesis inhibition, whereas inhibition of peroxidase enzymatic activity
      by propylthiouracil completely blocked iodide cytotoxicity. During KI treatment,
      reactive oxygen species were produced, and lipid peroxide levels increased
      markedly. Inhibition of endogenous p53 activity did not affect the sensitivity of
      TAD-2 cells to iodide, and Western blot analysis demonstrated that p53, Bcl-2,
      Bcl-XL, and Bax protein expression did not change when cells were treated with
      iodide. These data indicate that excess molecular iodide, generated by oxidation
      of ionic iodine by endogenous peroxidases, induces apoptosis in thyroid cells
      through a mechanism involving generation of free radicals. This type of apoptosis
      is p53 independent, does not require protein synthesis, and is not induced by
      modulation of Bcl-2, Bcl-XL, or Bax protein expression.

PMID- 10650941
TI  - Differential effects of acute and chronic exposure to interferon-gamma on cyclic
      adenosine 3',5'-monophosphate response element-regulated gene expression.
AB  - TSH stimulates proliferation and maintains differentiated function in thyroid
      follicular cells. The mitogenic activity and the stimulatory effects of TSH on
      thyroid-specific gene expression are impaired by interferon-gamma (IFNgamma);
      however, the mechanisms for these effects have not been elucidated in detail. We
      examined the effects of IFNgamma on acute responses to TSH in rat thyroid cells.
      IFNgamma did not impair TSH-stimulated p70/p85 ribosomal protein S6 kinase
      (p70/p85s6k) activity or cAMP response element (CRE)-regulated gene expression,
      although it inhibited DNA synthesis and thyroglobulin expression, effects
      measured over a more prolonged time course than those on kinase activity and
      reporter gene expression. Unexpectedly, when cells were chronically exposed to
      IFNgamma, CRE-lacZ promoter activity was decreased, whereas other cAMP-mediated
      signals, such as p70/p85s6k activity and CRE-binding protein phosphorylation,
      were unaffected. Activating protein-1-regulated promoters were also impaired by
      IFNgamma treatment, but with kinetics that differed from those of CRE-regulated
      promoters. Neither acute nor chronic treatment with interleukin-1beta impaired
      cAMP signaling, indicating that the effects of IFNgamma are specific. These
      studies identify CRE- and activating protein-1-regulated promoters as targets of
      IFNgamma in thyroid cells and fibroblasts. IFNgamma-mediated inhibition of these
      promoters, in addition to those containing thyroid-specific transcription factor
      1-binding sites, may contribute to the profound effects of IFNgamma on thyroid
      cells.

PMID- 10650942
TI  - Ontogenetic changes in the expression of estrogen receptor alpha and beta in rat
      pituitary gland detected by immunohistochemistry.
AB  - The physiological effects of estrogen on the pituitary, including cellular
      proliferation and regulation of hormone synthesis, are mediated by the nuclear
      estrogen receptor (ER). The purpose of this study was to determine ontogenetic
      expression of two types of ERs (ERalpha and ERbeta) in the pituitary using
      specific antibodies, monoclonal antibody (1D5) for ERalpha and polyclonal
      antibody generated against ERbeta. First, we confirmed the detection of 66- and
      55-kDa bands for ERalpha and ERbeta, respectively, in the rat pituitary extract
      by Western blotting. Then immunostaining with these antibodies was performed
      using fetal and adult Wistar rat tissues, combined with PRL or LHbeta
      immunohistochemistry. Intense ERbeta signal was detected throughout the pituitary
      from day 12 of gestation. However, staining for ERalpha only became detectable
      from day 17 of gestation. In contrast with the fetal period, nuclei stained for
      ERalpha were widely distributed in the anterior lobe in the adult rat, whereas
      ERbeta-positive cells were restricted in the anterior lobe. LHbeta, but not PRL,
      was colocalized in ERbeta-positive cells. Our results indicated that the major
      population of ER subtypes in the rat pituitary gland has changed around the day
      of birth and that the expression of ERbeta may be involved in the differentiation
      of pituitary cell function to synthesize a specific hormone.

PMID- 10650943
TI  - Potential involvement of FRS2 in insulin signaling.
AB  - Shp-2 is implicated in several tyrosine kinase receptor signaling pathways. This
      phosphotyrosine phosphatase is composed of a catalytic domain in its C-terminus
      and two SH2 domains in its N-terminus. Shp-2 becomes activated upon binding
      through one or both SH2 domains to tyrosine phosphorylated molecules such as Shc
      or insulin receptor substrates. We were interested in finding a new molecule(s),
      tyrosine phosphorylated by the insulin receptor (IR), that could interact with
      Shp-2. To do so, we screened a human placenta complementary DNA (cDNA) library
      with the SH2 domain-containing part of Shp-2 using a modified yeast two-hybrid
      system. In this system we induce or repress the expression of a constitutive
      active IR beta-subunit. When expressed, IR phosphorylates proteins produced from
      the library that can then associate with Shp-2. Using this approach, we isolated
      FRS2 as a potential target for tyrosine phosphorylation by the IR. After cloning
      the entire cDNA, we found that 1) in the yeast two-hybrid system, FRS2 interacts
      with Shp-2 in a fashion dependent on the presence of the IR; and 2) in the
      PC12/IR cell-line, insulin leads to an increase in FRS2 association with the
      phosphatase. We next wanted to determine whether FRS2 could be a direct substrate
      for IR. In an in vitro kinase assay we found that wheat-germ agglutinin-purified
      IR phosphorylates glutathione-S-transferase-FRS2 fusion protein. Finally, in
      intact cells we show that insulin stimulates tyrosine phosphorylation of
      endogenous FRS2. In summary, by screening a two-hybrid cDNA library, we have
      isolated FRS2 as a possible substrate for IR. We found that IR can directly
      phosphorylate FRS2. Moreover, in intact cells insulin stimulates tyrosine
      phosphorylation of FRS2 and its subsequent association with Shp-2. Taken together
      these results suggest that FRS2 could participate in insulin signaling by
      recruiting Shp-2 and, hence, could function as a docking molecule similar to
      insulin receptor substrate proteins.

PMID- 10650944
TI  - Epidermal growth factor and basic fibroblast growth factor increase the
      production of matrix metalloproteinases during in vitro decidualization of rat
      endometrial stromal cells.
AB  - Numerous growth factors are involved in mediating proliferation and
      differentiation of endometrial stromal cells during decidualization. During this
      period, the extracellular matrix of the endometrium undergoes extensive
      remodeling. We tested the hypothesis that epidermal growth factor (EGF), basic
      fibroblast growth factor (bFGF), and transforming growth factor-beta regulate
      expression of matrix metalloproteinases (MMPs) and their inhibitors, tissue
      inhibitors of metalloproteinases (TIMPs), during decidualization. Stromal cells
      were isolated from uteri hormonally sensitized to undergo decidualization and
      were cultured in the absence or presence of a growth factor. Using substrate-gel
      electrophoresis with gelatin as the substrate, we detected activity for
      gelatinase A and B, and collagenase-3, and using casein as a substrate, we
      detected activity for stromelysin-1. Increasing concentrations of EGF and bFGF
      resulted in increased activity of gelatinase B, collagenase-3, and stromelysin-1.
      Northern blot analyses revealed that EGF and bFGF also increased messenger RNA
      levels for these MMPs. There was no effect of these growth factors on gelatinase
      or TIMP-1, -2, and -3, nor was there an effect of transforming growth factor-beta
      on any MMP or TIMP examined. These data demonstrate that EGF and bFGF increase
      levels of proteolytic enzymes produced by endometrial stromal cells undergoing
      decidualization in vitro while having no effect on their inhibitors.

PMID- 10650946
TI  - Opposite effects of androgens and estrogens on adipogenesis in rat preadipocytes:
      evidence for sex and site-related specificities and possible involvement of
      insulin-like growth factor 1 receptor and peroxisome proliferator-activated
      receptor gamma2.
AB  - To investigate the role of sex steroid hormones in adipose tissue development and
      distribution, we have studied the effect of various sex steroids (testosterone,
      dihydrotestosterone (DHT), and 17beta-estradiol) in vitro, on the proliferation
      and differentiation processes in rat preadipocytes from deep (epididymal and
      parametrial) and superficial (femoral sc) fat deposits. All added steroids failed
      to affect the growth rate of preadipocytes from male rats when determined from
      day 1 to day 4 after plating, whether FCS was present or not in the culture
      medium. In contrast, in preadipocytes from female rats, we observed a positive
      effect (x2) of 17beta-estradiol (0.01 microM) on the proliferative capacities of
      sc but not parametrial preadipocytes. When preadipocytes were exposed to
      testosterone or DHT (0.1 microM) during the differentiation process, the glycerol
      3-phosphate dehydrogenase activity was significantly decreased in epididymal
      preadipocytes only. When preadipocytes from male rats were exposed to 17beta
      estradiol (0.01 microM), the differentiation capacities of preadipocytes were not
      modified. However, in parametrial preadipocytes from ovariectomized female rats,
      17beta-estradiol significantly increased (x1.34) the glycerol 3-phosphate
      dehydrogenase activity. In differentiated preadipocytes that had been exposed to
      sex steroids, expression of peroxisome proliferator-activated receptor gamma2 was
      up-regulated by 17beta-estradiol but not by androgens. As described in other cell
      types, sex steroids modulate insulin growth factor 1 receptor (IGF1R) expression
      in preadipocytes. Indeed, IGF1R levels were either enhanced by 17 beta-estradiol
      (0.01 microM) in sc preadipocytes from female ovariectomized rats or decreased by
      DHT (0.01 microM) in epididymal preadipocytes. These effects were reversed by
      simultaneous exposure to androgen or estrogen receptor antagonists. In
      conclusion, this study demonstrates that, in rat preadipocytes kept in primary
      culture and chronically exposed to sex hormones, androgens elicit an
      antiadipogenic effect, whereas estrogens behave as proadipogenic hormones.
      Moreover, our results suggest that these opposite effects could be related to
      changes in IGF1R (androgens and estrogens) and peroxisome proliferator-activated
      receptor gamma2 expression (estrogens).

PMID- 10650945
TI  - Transit of normal rat uterine stromal cells through G1 phase of the cell cycle
      requires progesterone-growth factor interactions.
AB  - Understanding of cell cycle regulation in hormonally responsive cells lags behind
      studies in other systems because few models have been available to identify the
      role of steroid hormones and their receptors in this process. This study
      investigates progesterone-dependent effects on the progression of normal uterine
      stromal cells through early G1 phase of the cell cycle. Quiescent rat uterine
      stromal cells were stimulated to reenter the cell cycle by adding serum-free
      medium containing medroxyprogesterone acetate (MPA) and basic fibroblast growth
      factor (FGF). [3H]thymidine incorporation increased significantly (P = 0.025) in
      cells stimulated with both FGF alone and MPA plus FGF compared with the control
      cells. Moreover, cells stimulated with MPA plus FGF incorporated significantly
      more (P = 0.01) [3H]thymidine than cells treated with FGF alone, suggesting
      requisite interactions between progesterone and FGF for stromal cell entry into S
      phase. Flow cytometric analysis of stimulated stromal cells showed FGF alone and
      MPA plus FGF increased significantly (P = 0.002) the percentage of cells in S
      phase at 12 h. Incorporation of bromodeoxyuridine into stromal cell nuclei
      indicated that FGF alone and MPA plus FGF increased the percentage of cells
      entering S phase at 18 and 24 h compared with the control cells. In addition, MPA
      plus FGF increased significantly (P = 0.001) the number of cells entering S phase
      at 24 h compared with FGF alone and sustained S phase entry compared with FGF
      alone, MPA alone, or the control cells. Stromal cells inhibited from G1 reentry
      by inhibition of mitosis showed accelerated entry into S phase in response to MPA
      plus FGF compared with FGF alone. Cyclin D1 messenger RNA increased in stromal
      cells treated with MPA plus FGF at 9, 12, and 15 h. Addition of RU 486 to cells
      stimulated with MPA plus FGF for 9 h reduced cyclin D1 messenger RNA accumulation
      by 40%. Western blot analysis of cyclin D1 immunoprecipitates indicated complex
      formation with both cyclin-dependent kinase 4 (Cdk4) and cyclin dependent kinase
      6 (Cdk6). Cyclin D1-Cdk complexes and kinase activity correlated temporally with
      increased cyclin D1 expression in cells cultured with MPA plus FGF. Taken
      together, these results show that progesterone-FGF interactions increase cyclin
      D1 expression, correlating with accelerated stromal cell entry into S phase
      compared with cells treated with FGF alone. Moreover, progesterone plus FGF
      sustains the timing of stimulation for transit of uterine stromal cells through
      G1 into S phase compared with FGF alone.

PMID- 10650947
TI  - Characterization and messenger ribonucleic acid distribution of a cloned
      pituitary adenylate cyclase-activating polypeptide type I receptor in the frog
      Xenopus laevis brain.
AB  - Pituitary adenylate cyclase-activating polypeptide (PACAP) has been found to
      modulate neuroendocrine functions in the frog brain and pituitary, but the
      nucleotide sequence and brain distribution of messenger RNA (mRNA) for the
      selective type I receptor for PACAP (PAC1) in the frog are still unknown. Here,
      we report the isolation and characterization of a PAC1 receptor complementary DNA
      (cDNA) clone from a frog (Xenopus laevis) tadpole brain cDNA library. This cDNA
      encoded a 466-amino acid protein that has 74% homology with human PAC1 receptor
      and 48% homology to the frog vasoactive intestinal peptide/PACAP receptor.
      Injection of in vitro synthesized mRNA of the cloned cDNA into Xenopus oocytes
      resulted in expression of selective high affinity PACAP receptors (Kd = 47 pM).
      IC50 values for PACAP-38, PACAP-27, and VIP were 27 pM, 110 pM and >1 microM,
      respectively. These results indicated that the cloned cDNA represents a Xenopus
      PACAP-preferring PAC1 receptor. Northern hybridization revealed that PAC1
      receptor mRNA was present at high levels in the brain. In situ hybridization
      showed that the PAC1 receptor gene was expressed highly in the pallium, preoptic
      nucleus, and nucleus of cerebellum, and moderately in the Purkinje cell layer of
      the cerebellum. Moderate PAC1 receptor mRNA signals were detected in the distal
      lobe of the pituitary. A knowledge of the molecular structure and expression
      pattern of the PAC1 receptor will facilitate further investigation of the
      physiological roles of PAC1 receptor in the frog brain.

PMID- 10650948
TI  - Human placental trophoblasts secrete a disintegrin metalloproteinase very similar
      to the insulin-like growth factor binding protein-3 protease in human pregnancy
      serum.
AB  - During the course of human pregnancy, there is a marked increase in insulin-like
      growth factor (IGF) binding protein (IGFBP)-3 protease activity in maternal serum
      that is first evident at 6 weeks of gestation, persists through term, and returns
      to nonpregnancy levels by day 5 postpartum. This protease activity cleaves IGFBP
      3 into smaller fragments that have markedly reduced affinity for the IGFs. To
      date, the precise identity and cellular origin of the pregnancy-associated serum
      IGFBP-3 protease have not been established. To investigate whether placental
      and/or decidual tissues, which uniquely develop during pregnancy, may be sources
      of the pregnancy-associated serum IGFBP protease, we examined the secretion of
      IGFBP-3 protease in vitro by isolated human cytotrophoblasts or fibroblasts from
      second trimester placentae and by in vitro decidualized human endometrial stromal
      cells. Cytotrophoblasts were either cultured alone, which favors aggregation and
      fusion, or cocultured with decidualized endometrial stromal cells, which favors
      differentiation to an invasive phenotype. IGFBP-3 protease activity was detected
      in trophoblast, but not in placental fibroblast or decidualized endometrial
      cultures, and was also present in trophoblast-endometrial cocultures. Western
      ligand blot and Western immunoblot analyses showed that most of the endogenous
      IGFBP-3 in trophoblast cultures was in the form of low molecular weight fragments
      with reduced IGF binding affinity. The substrate specificity of the trophoblast
      derived protease was identical to that in pregnancy serum, showing activity
      against IGFBP-2, -3, and -4, but being inactive against IGFBP-1. IGFBP-3
      proteolysis by both pregnancy serum and trophoblast conditioned medium showed a
      major peak of activity at neutral pH. The trophoblast-derived activity caused
      time-and temperature-dependent proteolysis of IGFBP-3 into fragments of identical
      size as those produced by pregnancy serum, and also shared its sensitivity to
      protease inhibitors: highly sensitive to EDTA and o-phenanthroline, partially
      sensitive to the serine protease inhibitors AEBSF and aprotinin, and insensitive
      to alpha2-antiplasmin, and to aspartic and cysteine protease inhibitors. IGFBP-3
      proteolysis by both pregnancy serum and trophoblast conditioned medium was also
      insensitive to tissue inhibitor of metalloproteinase-1, precluding the
      involvement of the matrix metalloproteinases. In contrast, both the pregnancy
      serum- and trophoblast-derived proteases were preferentially inhibited by a
      hydroxamic acid derivative with selective activity against the disintegrin
      metalloproteinase tumor necrosis factor-alpha converting enzyme. This study shows
      that placental trophoblasts produce an IGFBP-3 protease with characteristics very
      similar to the activity found in pregnancy serum and indicates these cells at the
      maternal-fetal interface are a potential source of the pregnancy-associated serum
      IGFBP-3 protease. The findings further suggest that the main IGFBP-3 protease
      activity in both pregnancy serum and trophoblast conditioned medium may
      correspond to a disintegrin-metalloproteinase type enzyme.

PMID- 10650949
TI  - Multiple cadherin superfamily members with unique expression profiles are
      produced in rat testis.
AB  - Adhesion between germ and Sertoli cells is thought to be crucial for
      spermatogenesis. Cadherin superfamily proteins, including classic cadherins and
      protocadherins, are important mediators of cell-cell adhesion. Using a degenerate
      PCR cloning strategy, we surveyed the expression of cadherin superfamily members
      in rat testis. Similar to brain, testis expressed a large number of cadherin
      superfamily members: 7 classic cadherins of both types I and II, 14
      protocadherins, 2 protocadherin-related cadherins, and 1 cadherin-related
      receptorlike protein. All three protocadherin families (alpha, beta, and gamma)
      were found in testis. Using a semiquantitative RT-PCR assay, messenger RNA
      expression was determined for each cadherin superfamily member during a postnatal
      developmental time-course and following ablation of specific testis cell types by
      ethanedimethanesulfonate, methoxyacetic acid, and 2,5-hexanedione. Diverse
      expression patterns were observed among the cadherins, suggesting that cadherin
      expression is cell type-specific in testis. The large number and variety of
      cadherin superfamily members found in testis supports a critical function for
      cadherin-mediated cell-cell adhesion in spermatogenesis.

PMID- 10650950
TI  - A Ras-dependent chloride current activated by adrenocorticotropin in rat adrenal
      zona glomerulosa cells.
AB  - In the present study, we report that ACTH induces a transient chloride current.
      The lack of correlation between ACTH-induced cAMP production and amplitude of the
      Cl- current, as well as the absence of stimulation by forskolin or 8Br-cAMP
      indicated that the ACTH-induced current was not cAMP-dependent. We explored the
      possibility that one or several elements of the Ras/Raf MAPK cascade were
      involved. Indeed, we found that ACTH at 10(-10) M induced activation of Ras.
      Inhibition of the current by QEHA peptide, a Gbetagamma sequestrant, demonstrated
      that Gbetagamma subunits transduced the message. Blockage of the Ras activation
      using an inhibitor of farnesyl transferase (BZA-5B) or the monoclonal antibody H
      Ras(259) abrogated the current. Moreover, the addition of Ras-GTPyS in the
      pipette medium gave rise to the Cl- current. Treatment of the cells with BZA
      decreased the aldosterone secretion induced by 10(-10) M ACTH but not that
      induced by 10(-8) M ACTH, confirming the involvement of Ras in steroid secretion.
      We conclude that ACTH triggers a Cl- current through the activation of the Ras
      protein by Gbetagamma subunits. This current, activated at physiological ACTH
      concentrations (1 to 100 pM) where cAMP production is very low, could play a
      significant role in aldosterone production.

PMID- 10650951
TI  - The release of lipoprotein lipase from 3T3-L1 adipocytes is regulated by
      microvessel endothelial cells in an insulin-dependent manner.
AB  - Lipoprotein lipase (LPL) is the rate-limiting enzyme in the hydrolysis of serum
      triglycerides associated with the lipoprotein particles very low density
      lipoprotein and chylomicrons. The cell biology of LPL is complex. It functions
      while tethered to the extracellular matrix of the capillary endothelium. LPL is
      synthesized, however, in the parenchymal cells (for example, adipocytes or muscle
      cells) subtending the endothelium. Thus, after synthesis in and release by the
      parenchymal cell, LPL must move to the endothelial cell and across this cell
      monolayer before expression at its physiologically relevant location. LPL
      expression on the endothelium is regulated by insulin. The intent of this study
      was to ascertain the role of microvessel endothelial cells in the release of LPL
      from 3T3-L1 adipocytes and to ascertain whether insulin regulates the function of
      the endothelial cells. Endothelial cells were treated with insulin, and the
      resultant culture medium conditioned by the endothelial cells was placed on 3T3
      L1 adipocytes. The release of LPL from the adipocytes induced by the endothelial
      cell-conditioned medium was then quantitated. Insulin concentrations as low as
      100 pM stimulated the release of a factor from the endothelial cells. This
      factor, when added to adipocytes, caused the quantitative release of LPL from the
      plasma membrane of the adipocytes. The effect of insulin on the endothelial cells
      was maximal within 15 min of insulin addition to the endothelial cells. Repeated
      challenges of the endothelial cells with insulin resulted in the repeated release
      of the LPL release factor from the endothelial cells if the challenges were
      separated by periods of 2-3 h. However, if the endothelial cells were chronically
      stimulated with insulin for 18 h, a subsequent acute stimulation with insulin did
      not generate any LPL release factor. Thus, microvessel endothelial cells regulate
      the mobilization of LPL from adipocytes in an insulin-dependent manner.

PMID- 10650952
TI  - Stage-specific expression of pituitary adenylate cyclase-activating polypeptide
      type I receptor messenger ribonucleic acid during ovarian follicle development in
      the rat.
AB  - Expression of pituitary adenylate cyclase-activating polypeptide (PACAP), a
      neuropeptide with considerable homology to vasoactive intestinal peptide, has
      been shown to be stimulated by gonadotropins in the ovary. The present studies
      further evaluated the cell-type specific expression and gonadotropin regulation
      of PACAP type I receptor (PACAPR) messenger RNA in immature rat ovaries and in
      cultured preovulatory follicles. Northern blot analysis of ovaries obtained from
      prepubertal rats revealed the increased expression of PACAPR during prepubertal
      development. The major cell types expressing PACAPR messenger RNA were granulosa
      cells of large preantral follicles. Treatment of immature rats with PMSG caused a
      decrease in ovarian PACAPR expression. In contrast, treatment with human (h) CG
      at 2 days after PMSG treatment stimulated ovarian PACAPR messenger RNA within 3-6
      h in granulosa cells of preovulatory follicles. Treatment of cultured
      preovulatory follicles in vitro with LH further confirmed the time- and dose
      dependent stimulation of PACAPR by gonadotropins in granulosa cells of
      preovulatory follicles. Moreover, RNase protection assay revealed that the short
      variant of ovarian PACAPR was the predominant form stimulated during prepubertal
      development and by gonadotropins. These results demonstrate the expression of
      PACAPR messenger RNA in granulosa cells of growing follicles and of preovulatory
      follicles stimulated by gonadotropins, and suggest that PACAP may play a role in
      the growth of developing follicles and in ovulation as an autocrine/paracrine
      factor.

PMID- 10650953
TI  - Sertoli cell prostaglandin D2 synthetase is a multifunctional molecule: its
      expression and regulation.
AB  - PGD2 synthetase (PGD-S; PGH2 D-isomerase; EC 5.3.99.2) is a bifunctional protein
      first identified in the mammalian brain. It acts as a PGD2-producing enzyme and a
      retinoid transporter. PGD-S is present in the testis, where its protein and
      messenger RNA levels are similar to those in the brain. In view of its
      diversified regulatory functions, we investigated its regulation using primary
      cultures of Sertoli cells in vitro to assess its role in the testis. When Sertoli
      cells were cultured in serum-free medium to allow the formation of specialized
      junctions, it was found that PGD-S expression increased steadily with time,
      coinciding with the formation of inter-Sertoli junctions in vitro. However,
      neither germ cells (using a Sertoli/germ cell ratio between 1:1 and 1:30 when
      Sertoli cells were cultured at a density of 5x10(4) cells/cm2) nor germ cell
      conditioned medium affected the expression of Sertoli cell PGD-S in vitro. These
      results thus unequivocally demonstrated that germ cells do not play a role in
      regulating testicular PGD-S expression. Although FSH, dihydrotestosterone, and
      testosterone had no apparent effect on Sertoli cell PGD-S expression, the
      addition of progesterone(1x10(-11) to 1x10(-9) M) and T3 (1x10(-11) to 1x10(-9)
      M) to Sertoli cell cultures elicited a significant increase in PGD-S expression
      by as much as 4.5- and 2.5 fold, respectively. As PGD-S is a known retinoid
      transporter, the effects of all-trans-retinoic acid and all-trans-retinal on
      Sertoli cell PGD-S expression were also assessed. Both compounds were found to
      induce Sertoli cell PGD-S expression. In summary, PGD-S is a putative Sertoli
      cell product whose expression is regulated by progesterone, metabolites of
      vitamin A, and T3. In view of its dual biological properties, a study of its
      regulation and physiology will yield new insights into understanding its role in
      the testis.

PMID- 10650954
TI  - The 3',5'-cyclic adenosine monophosphate response element binding protein (CREB)
      is functionally reduced in human toxic thyroid adenomas.
AB  - In human normal thyrocytes, the cAMP-responsive signaling pathway plays a central
      role in gene regulation, cell proliferation, and differentiation. Constitutive
      activation of the cAMP signal transduction system has been documented in thyroid
      autonomously hyperfunctioning adenomas in which activating mutations in either
      the TSH receptor gene or the Gsalpha protein gene (gsp oncogene) have been
      described. The molecular mechanism whereby cAMP induces thyrocyte proliferation
      is unknown, but recent evidence suggests that the transcription factor cAMP
      response element binding protein (CREB) may serve as an important biochemical
      intermediate in this proliferative response. Herein we have investigated the
      expression of CREB in normal and tumoral thyroid tissues from a series of ten
      unrelated patients with autonomously hyperfunctioning adenomas, previously
      screened for mutations in the TSH receptor and Gsalpha genes. In all tumors
      examined, the expression of the activated, phosphorylated form of CREB was
      markedly reduced compared with that of the corresponding paired normal thyroid
      tissue, and this reduction was independent of the presence of mutations in the
      TSH receptor gene and Gsalpha gene. Moreover, no correlation was observed in
      these tissues between CREB phosphorylation and either protein kinase A activity
      or protein phosphatase expression. Thus, these data suggest that in human
      hyperfunctioning thyroid adenomas, the PKA/CREB system does not play a role in
      cell proliferation.

PMID- 10650955
TI  - Gene structure of a new cardiac peptide hormone: a model for heart-specific gene
      expression.
AB  - Volume excess and mechanical load lead to the induction of the endocrine activity
      of the heart. The increased production and secretion of A- and B-type natriuretic
      peptides (ANP and BNP), in turn, unload the heart due to their physiological
      effects. To find out the mechanisms of cardiac-specific expression and
      sensitivity to mechanical stimuli of the natriuretic peptide genes, we have used
      salmon (Salmo salar) as our model organism, because osmoregulating fish have a
      particularly well developed defense mechanism against volume excess. We have
      previously cloned a complementary DNA from salmon heart encoding a novel
      vasorelaxant cardiac hormone, salmon cardiac peptide (sCP). Its production is
      restricted to the heart, and its release is very sensitive to mechanical load. We
      have now cloned the gene encoding sCP. The structure of the gene suggests that
      sCP may represent an ancestral form of the mammalian natriuretic peptides.
      Remarkably, despite the large phylogenetic distance, the sCP promoter is as
      effective as mammalian ANP promoters in cultured neonatal rat atrial
      cardiomyocytes. Therefore, structural and functional comparisons of the promoters
      of sCP and ANP provide an excellent means of identifying the elements and
      transcription factors required for atrial-specific gene expression and the
      regulation of the endocrine function of the heart. Isolation of the protein
      product of sCP gene from salmon atrium demonstrated that the storage form of sCP
      is the prohormone of 126 amino acids. The final processing of the prohormone
      appears to take place during exocytosis of the secretory granules, as the
      released and circulating form is the biologically active 29-amino acid sCP.

PMID- 10650956
TI  - Enhancement of insulin-like growth factor I activity by novel antisera: potential
      structure/function interactions.
AB  - Insulin-like growth factor I (IGF-I) is essential for normal growth and
      development, regulating cell proliferation, differentiation, and survival. Little
      IGF-I exists in the free form; rather, it is bound to one of a family of six
      specific IGF-binding proteins (IGFBPs). Usually, IGFBPs have a high affinity for
      IGF-I and inhibit its activity. Intriguingly, some IGFBPs also potentiate IGF-I
      action; the precise mechanism of this is unclear, but it is thought to include
      modification of the IGFBP to lower its affinity for IGF-I. We have previously
      generated a novel antihuman (h) IGF-I antiserum that, instead of inhibiting IGF-I
      activity, enhances it in vivo. As the enhancing anti-IGF-I antiserum and
      potentiating IGFBPs share several properties with regard to IGF action, the
      antibody may provide a model for examining the actions of enhancing IGFBPs. In
      this study we demonstrate that the antiserum can also enhance IGF-I activity in
      vitro, assessed as cell number of a bovine fibroblast cell line, suggesting that
      its actions might not merely be confined to changing the kinetics of IGF-I
      clearance or degradation. Epitope scanning using overlapping octamer and hexamer
      peptides spanning the entire sequence of IGF-I indicates that the enhancing
      antiserum recognizes a specific linear region spanning the C-terminal region of
      the C domain and the proximal A domain (residues Ser33 to Cys47), and that this
      recognition is not present in nonenhancing antisera. Further, this region is
      located on the opposite surface of IGF-I from putative type 1 receptor-binding
      residues, allowing the possibility that the antiserum might be able to modulate
      IGF-I receptor binding. Antibodies raised against a synthetic peptide
      corresponding to Ser33 to Cys47 of IGF-I also potentiated IGF-I activity in vivo.
      As IGF-I may be beneficial in various clinical conditions associated with
      catabolism or cell repair, we suggest that this potentiating anti-IGF-I antiserum
      has favorable properties that could form a basis for therapeutic strategy.

PMID- 10650957
TI  - Neuroendocrine function and response to stress in mice with complete disruption
      of glucagon-like peptide-1 receptor signaling.
AB  - Glucagon-like peptide-1 (GLP-1), a potent regulator of glucose homeostasis, is
      also produced in the central nervous system, where GLP-1 has been implicated in
      the neuroendocrine control of hypothalamic-pituitary function, food intake, and
      the response to stress. The finding that intracerebroventricular GLP-1 stimulates
      LH, TSH, corticosterone, and vasopressin secretion in rats prompted us to assess
      the neuroendocrine consequences of disrupting GLP-1 signaling in mice in vivo.
      Male GLP-1 receptor knockout (GLP-1R-/-) mice exhibit reduced gonadal weights,
      and females exhibit a slight delay in the onset of puberty; however, male and
      female GLP-1R-/- animals reproduce successfully and respond appropriately to
      fluid restriction. Although adrenal weights are reduced in GLP-1R-/- mice,
      hypothalamic CRH gene expression and circulating levels of corticosterone,
      thyroid hormone, testosterone, estradiol, and progesterone are normal in the
      absence of GLP-1R-/- signaling. Intriguingly, GLP-1R-/- mice exhibit
      paradoxically increased corticosterone responses to stress as well as abnormal
      responses to acoustic startle that are corrected by glucocorticoid treatment.
      These findings suggest that although GLP-1R signaling is not essential for
      development and basal function of the murine hypothalamic-pituitary-adrenal axis,
      abrogation of GLP-1 signaling is associated with impairment of the behavioral and
      neuroendocrine responses to stress.

PMID- 10650958
TI  - Characterization of the murine pituitary tumor transforming gene (PTTG) and its
      promoter.
AB  - We recently isolated rat pituitary tumor transforming gene (PTTG) complementary
      DNA and showed its potent in vitro and in vivo transforming activity. We now
      characterize the mouse PTTG gene and its promoter. The entire gene is composed of
      five exons and four introns and spans about 7 kb. Northern analysis showed that
      PTTG was expressed in several tumor cell lines examined, but not in all normal
      tissues, implying a correlation between PTTG and tumorigenesis. Using rapid
      amplification of 5'-cDNA ends, the transcription start site was localized at -303
      nucleotides upstream to the ATG codon in both F9 and AtT20 cells. An
      approximately 4.3-kb upstream region demonstrated promoter activity in AtT20
      cells as well as other cell lines tested, and in vivo, the cloned promoter
      driving an enhanced green fluorescent protein transgene exhibited transcriptional
      activation in testis and embryo. Serial deletions showed that -313 bp of the 5'
      flanking region was critical for promoter activity. Three elements contribute to
      promoter activity. Both element A (-313/-293) and element C (-180/-160), in an
      electrophoretic mobility shift assay using NIH-3T3 nuclear extract, formed three
      specific complexes, which were competed by a known Sp1 oligo; one complex was
      supershifted by Sp1 antibody, and the other two complexes were both supershifted
      by an Sp3 antibody. Two mutants disrupting element A resulted in up to 70% loss
      of promoter activity and abrogated formation of specific DNA-protein binding
      complexes, implying a more important role for element A. Element B (-249/-229)
      shows more than 80% homology to a consensus c-myb element, but formed two
      specific complexes that differed from that of c-myb in the electrophoretic
      mobility shift assay. Thus, the integrity and possible cooperation among these
      elements contribute to the basal promoter activity of the mouse PTTG oncogene
      homolog.

PMID- 10650959
TI  - Expression of mouse 17beta-hydroxysteroid dehydrogenase/17-ketosteroid reductase
      type 7 in the ovary, uterus, and placenta: localization from implantation to late
      pregnancy.
AB  - Rodent 17beta-hydroxysteroid dehydrogenase/17-ketosteroid reductase type 7
      (17HSD/KSR7) catalyzes the conversion of estrone (E1) to estradiol (E2) and is
      abundantly expressed in the ovaries of pregnant animals in particular. In the
      present work we demonstrate cell-specific expression of 17HSD/KSR7 in the
      ovaries, uteri, and placentas of pregnant and nonpregnant mice using in situ
      hybridization. The results show that mouse 17HSD/KSR7 (m17HSD/KSR7) messenger RNA
      is distinctly and exclusively expressed in a proportion of corpora lutea (CLs).
      During pregnancy, expression of m17HSD/KSR7 is most abundant around embryonic day
      14.5 (E14.5), when the ovaries are filled with CLs expressing 17HSD/KSR7. In the
      uterus, m17HSD/KSR7 is first detected on E5.5, when expression surrounds the
      implantation site on the antimesometrial side. As gestation progresses,
      m17HSD/KSR7 is expressed in the decidua capsularis on E8 and E9.5, disappearing
      thereafter from the antimesometrial decidua. On E9 onward, m17HSD/KSR7 messenger
      RNA expression takes place at the junctional zone of the developing placenta. On
      E12.5 and E14.5, m17HSD/KSR7 is abundantly expressed in the spongiotrophoblasts,
      where expression gradually declines toward parturition. In conclusion,
      m17HSD/KSR7 expression in the CL is related to the life span of the CL. Moreover,
      spatial and temporal expression of m17HSD/KSR7 in the uterus suggests that
      locally produced E2 plays a role in implantation and/or decidualization. Finally,
      the results indicate that mouse placenta is capable of converting E1 to E2 in
      situ, and that the synthesized E2 may be effective in a paracrine, autocrine,
      and/or intracrine manner and be involved in placentation.

PMID- 10650960
TI  - Kainate receptor subunit-positive gonadotropin-releasing hormone neurons express
      c-Fos during the steroid-induced luteinizing hormone surge in the female rat.
AB  - During the preovulatory and estradiol-progesterone-induced GnRH-LH surge, a
      subpopulation of GnRH neurons transiently expresses the transcription factor c
      fos, which is a useful marker of cell activation. To further characterize this
      subpopulation of GnRH neurons, multiple immunohistochemical procedures were
      applied to visualize GnRH, c-Fos, KA2, GluR5, GluR6, and GluR7 receptor subunits
      during different phases of the estrogen-progesterone-induced LH surge. The
      results show that the LH surge begins at 1400 h and peaks at 1600 h before
      returning to baseline late in the evening. At 1400 h, about 50% of the GnRH
      neurons contained c-Fos, and this percentage remained high at 65% at 1600 and
      2000 h. During the surge, 50% of the c-Fos-positive GnRH neurons contained KA2
      receptor subunit protein at 1400 h, 65% of the c-Fos-positive GnRH neurons
      expressed the KA2 subunit at 1600 h, and 50% of the c-Fos-positive GnRH neurons
      expressed the KA2 subunit at 2000 h. As KA2 subunits require other kainate
      preferring subunits to form functional receptor channels, we examined GnRH
      neurons for the presence of GluR5, GluR6, and GluR7 messenger RNA (mRNA) and
      protein. The results show that the KA2-containing GnRH neurons also contain GluR5
      receptor subunit mRNA and protein, and that these GnRH neurons are c-Fos positive
      during the steroid-induced LH surge. To determine whether administration of
      kainate is sufficient to induce c-Fos in GnRH neurons, steroid-primed animals
      received iv injections of subseizure-inducing amounts of kainic acid and were
      processed for immunohistochemistry and in situ hybridization. The results show
      that kainic acid causes a significant increase in circulating LH; however, it
      does not induce c-Fos in GnRH neurons, nor does it cause an increase in GnRH
      mRNA. Together, the results suggest that a large subset of GnRH neurons expresses
      KA2 as well as GluR5 receptor subunits, which would allow the formation of
      functional glutamate receptor channels, and that this subset of GnRH neurons is
      activated during the steroid-induced LH surge.

PMID- 10650961
TI  - Sensitivity of testicular germ cells to toxicant-induced apoptosis in gld mice
      that express a nonfunctional form of Fas ligand.
AB  - Germ cell apoptosis in testis is essential for functional spermatogenesis. Recent
      evidence suggests that the Fas signaling system is critical for the regulation of
      testicular germ cell apoptosis. To further evaluate the Fas signaling system in
      testis, we examined the incidence of germ cell apoptosis in gld mice that lack a
      functional Fas-signaling pathway. gld mice have a small, but significant,
      increase in testis weight and numbers of spermatid heads per testis compared with
      wild-type mice. In addition, gld mice have a small increase in the spontaneous
      incidence of germ cell apoptosis, as indicated by characteristic DNA
      fragmentation via the terminal deoxynucleotidyl-transferase-mediated deoxy-UTP
      nick end labeling assay. To test the role of the Fas system in toxicant-induced
      germ cell apoptosis, mice were exposed to either a Sertoli cell- or germ cell
      specific toxicant [mono-(2-ethylhexyl)phthalate (MEHP; 1 g/kg) or 5 Gy radiation,
      respectively]. These two exposure paradigms induced extensive increases in germ
      cell apoptosis in wild-type mice. However, exposure of gld mice to MEHP caused
      only a minimal increase in germ cell apoptosis, whereas they were as sensitive as
      wild-type mice to radiation exposure. These data indicate that the Fas signaling
      pathway is 1) involved in regulating the numbers of germ cells in the testis, 2)
      crucial for the initiation of germ cell apoptosis after MEHP-induced Sertoli cell
      injury, and 3) differentially active in the cell-specific regulation of germ cell
      apoptosis that occurs as a consequence of Sertoli cell vs. germ cell injury.

PMID- 10650962
TI  - Central administration of cocaine-amphetamine-regulated transcript activates
      hypothalamic neuroendocrine neurons in the rat.
AB  - We have recently shown that intracerebroventricular (i.c.v.) administration of
      the hypothalamic neuropeptide cocaine-amphetamine-regulated transcript (CART)
      inhibits food intake and induces the expression of c-fos in several nuclei
      involved in the regulation of food intake. A high number of CART-induced c-Fos
      positive nuclei in the paraventricular nucleus of the hypothalamus prompted us to
      examine the effect of i.c.v. recombinant CART-(42-89) on activation of CRH-,
      oxytocin-, and vasopressin-synthesizing neuroendocrine cells in the
      paraventricular nucleus (PVN). In addition, plasma levels of glucose were
      examined after central administration of CART-(42-89). Seventy-six male Wistar
      rats were fitted with i.c.v. cannulas and singly housed under 12-h light, 12-h
      dark conditions. One week postsurgery the animals were injected i.c.v. in the
      morning with 0.5 microg recombinant CART-(42-89) or saline. Trunk blood was
      collected by decapitation at 0 (baseline), 10, 20, 40, 60, 120, or 240 min. CART
      caused a strong increase in circulating corticosterone that was significantly
      different from saline at 20, 40, 60, and 120 min postinjection (P<0.05).
      Furthermore, CART caused a transient rise in plasma oxytocin levels (P<0.05 at 10
      and 20 min postinjection), whereas plasma vasopressin levels were unaffected by
      i.c.v. CART. Animals injected i.c.v. with CART showed a rise in blood glucose
      levels 10 min postinjection (P<0.05). To examine whether the stimulatory effect
      of i.c.v. CART on corticosterone and oxytocin secretion is caused by activation
      of paraventricular nucleus/supraoptic nucleus (PVN/SON) neuroendocrine neurons,
      we used c-Fos as a marker of neuronal activity. Animals injected with CART showed
      a strong increase in c-Fos-immunoreactive nuclei in the PVN. Double
      immunohistochemistry revealed that a high (89+/-0.4%) number of CRH
      immunoreactive neurons in the PVN contained c-Fos after CART i.c.v.. c-Fos
      expression was also observed in oxytocinergic cells (in both magnocellular and
      parvicellular PVN neurons as well as in the supraoptic nuclei) 120 min after CART
      administration, whereas none of the vasopressinergic neurons contained c-Fos.
      Triple immunofluorescence microscopy revealed that CART-immunoreactive fibers
      closely apposed c-Fos-positive CRH neurons, suggestive of a direct action of CART
      on PVN CRH neurons. In summary, i.c.v. CART activates central CRH neurons as well
      as both magnocellular (presumably neurohypophysial) and parvicellular (presumably
      descending) oxytocinergic neurons of the PVN. The effect of CART on CRH neurons
      most likely leads to corticosterone secretion from the adrenal gland, which may
      contribute to the inhibitory effects of CART on feeding behavior.

PMID- 10650963
TI  - Retinoic acid synthesis and expression of cellular retinol-binding protein and
      cellular retinoic acid-binding protein type II are concurrent with
      decidualization of rat uterine stromal cells.
AB  - Decidualization of stromal cells at the site of embryo implantation in the rat
      uterus is accompanied by expression of cellular retinol-binding protein and
      cellular retinoic acid-binding protein [CRABP(II)], whose presence has been shown
      to correlate with gain of ability to synthesize retinoic acid in other cells.
      Here we examined whether decidual cells also acquired the ability to synthesize
      retinoic acid, which would have important implications for understanding the
      implantation process. Decidual cells were isolated from the uterus on day 8 of
      pregnancy and cultured. When provided with retinol, they indeed synthesized and
      released retinoic acid to the medium. To follow acquisition of this ability more
      closely, artificial induction of decidualization was exploited. Ovariectomized
      rats were placed on a hormonal regimen that allows decidualization to occur in
      vivo, with oil stimulation, or in vitro, if cells are isolated on day 5 of the
      regimen and then cultured. Decidualization in vivo reproduced the expression of
      cellular retinol-binding protein and CRABP(II) seen during pregnancy. Stromal
      cells isolated on regimen day 2 synthesized little retinoic acid and expressed
      little alkaline phosphatase, a marker of decidualization. Stromal cells isolated
      on regimen day 5 had elevated levels of alkaline phosphatase, increasing during
      the 3 days of culture examined. The ability of the stromal cells to synthesize
      retinoic acid showed the same pattern: a substantially elevated production from
      that previously observed, on day 2, with production increasing significantly over
      the next 2 culture days. Thus, expression of CRABP(II) was correlated with gain
      of ability to synthesize retinoic acid. Retinoid signaling may be an important
      part of the process of embryo implantation.

PMID- 10650964
TI  - Selective estrogenic effects of a novel triphenylethylene compound, FC1271a, on
      bone, cholesterol level, and reproductive tissues in intact and ovariectomized
      rats.
AB  - FC1271a is a novel triphenylethylene compound with a tissue-selective profile of
      estrogen agonistic and weak antagonistic effects. It specifically binds to the
      estrogen receptor alpha and beta with affinity closely similar to that of
      toremifene and tamoxifen. To study the in vivo effects of the compound, 4-month
      old rats were sham operated (sham) or ovariectomized (OVX) and treated daily for
      4 weeks with various doses of FC1271a or vehicle (orally). FC1271a was able to
      oppose OVX-induced bone loss by maintaining the trabecular bone volume of the
      distal femur. Accordingly, the OVX-induced loss of bone strength was prevented at
      doses of 1 and 10 mg/kg. FC1271a also prevented the OVX-induced increase in serum
      cholesterol in a dose-dependent manner. No significant changes in uterine wet
      weight or morphology were observed in the OVX-rats treated with 0.1 or 1 mg/kg
      FC1271a, but at a dose of 10 mg/kg it had a slightly estrogenic effect. In
      immature rats the effect of FC1271a on uterine wet weight was less stimulatory
      than that of toremifene or tamoxifen, but more stimulatory than that of
      raloxifene or droloxifene. The appearance of the dimethylbenzanthracene (DMBA)
      induced mammary tumors was inhibited by treatment of DMBA-treated rats with
      FC1271a in a dose-dependent manner. In human MCF-7 breast cancer cell tumors
      raised in nude mice in the presence of estrogen, the growth and expression of pS2
      marker gene could not be maintained after estrogen withdrawal by treatment with
      FC1271a. No formation of DNA adducts was observed in the liver of the FC1271a
      treated rats. In conclusion, the bone-sparing, antitumor, and cholesterol
      lowering effects of FC1271a combined with a low uterotropic activity and lack of
      liver toxicity indicate that FC1271a could be an important alternative in
      planning antiosteoporosis therapy for estrogen deficiency.

PMID- 10650965
TI  - Castration-induced apoptotic cell death in the Brown Norway rat prostate
      decreases as a function of age.
AB  - Growth and differentiation of the prostate gland depends upon androgens, yet
      overgrowth of the human prostate occurs later in life when serum levels of
      testosterone are declining. We have reported a similar phenomenon in the Brown
      Norway rat, but the age-dependent overgrowth of the prostate is confined to the
      dorsal and lateral lobes and, hence, is lobe specific. Because tissue growth
      depends upon the balance between proliferation and death of cells, the present
      study was designed to investigate whether cell death differed in the various
      prostatic lobes of Brown Norway rats as a function of age. Apoptosis of cells in
      the ventral, dorsal, lateral, and anterior lobes of the prostate was examined in
      young (4-month-old) and old (24-month-old) Brown Norway rats after castration.
      Whereas castration caused tissue weights of all four prostatic lobes to decrease
      over the course of 10 days, this occurred more rapidly and to a greater magnitude
      in the ventral than in the dorsal, lateral, and anterior lobes. Tissue DNA
      content, a measure of cell number, decreased only in the ventral lobe after
      castration. DNA fragmentation, indicative of apoptotic cell death, was detected
      by in situ labeling using the terminal deoxynucleotidyltransferase-mediated dUTP
      nick end-labeling method and as intranucleosomal cleavage of genomic DNA analyzed
      by agarose gel electrophoresis. Both methods demonstrated the correlation between
      loss of DNA content and apoptotic cell death in the ventral lobe, whereas only
      the highly sensitive terminal deoxynucleotidyltransferase-mediated dUTP nick end
      labeling (TUNEL) method revealed relatively few dying cells in the dorsal,
      lateral, and anterior lobes after castration. Moreover, when examined as a
      function of age, less cell death occurred in all four lobes of old rats compared
      with young rats. In both young and old rat prostates, cell death was observed in
      epithelial and stromal cells within the ventral lobe where apoptotic cells were
      detected throughout the branched ductal network and were not restricted to a
      particular region. Taken together, these studies demonstrate the marked
      differences in cell death and survival between the different rat prostatic lobes
      in response to castration and further suggest that the androgen-sensitive
      apoptotic response is age dependent. Hence, the lower rates of cell death
      observed for the dorsal and lateral lobes, accompanied by the further decline
      that occurs with increasing age, are important components of the age-dependent
      and lobe-specific overgrowth observed for these lobes. Moreover, the age
      dependent decline in apoptotic cell death observed in the prostates of old rats
      suggests that prostatic cells develop androgen independence as a function of age,
      and survival of these cells does not require androgen.

PMID- 10650966
TI  - Conservation of a growth hormone-responsive promoter element in the human and
      mouse acid-labile subunit genes.
AB  - During extrauterine life, insulin-like growth factors (IGFs) circulate in a
      ternary serum complex with one IGF-binding protein-3 (IGFBP-3) or IGFBP-5 protein
      and with a single acid-labile subunit (ALS). GH increases levels of this ternary
      complex; in mice, this effect is achieved in part by the ability of GH to
      stimulate mouse ALS (mALS) transcription through an interferon-gamma-activated
      sequence-like element (GLE) in the mALS promoter. To begin studying how GH
      regulates human ALS (hALS) gene expression, we cloned the hALS gene and found
      that it spans approximately 3.3 kb of DNA at chromosomal region 16p13.3. The hALS
      gene has two exons separated by a 1235-bp intron, which is found at the identical
      site in rat and mouse ALS genes. Sequence analysis reveals that the hALS 5'
      flanking sequence is homologous to the mALS promoter, and that the GH-responsive
      GLE in the mALS promoter is conserved in both sequence and location in the hALS
      gene. The region spanning from -755 to -4 bp 5' to the hALS ATG translation start
      codon directs expression of a luciferase reporter gene in primary rat
      hepatocytes, and GH increases reporter expression in the presence of the native,
      but not a mutant, GLE in the hALS promoter. These data suggest that GH stimulates
      hALS and mALS gene expression by a similar mechanism, which involves at least in
      part a conserved GLE in the ALS promoter.

PMID- 10650967
TI  - Pendrin, the protein encoded by the Pendred syndrome gene (PDS), is an apical
      porter of iodide in the thyroid and is regulated by thyroglobulin in FRTL-5
      cells.
AB  - Pendred syndrome is an autosomal recessive disorder characterized by congenital
      deafness and thyroid goiter. The thyroid disease typically develops around
      puberty and is associated with a mild organification defect, characterized by an
      inappropriate discharge of iodide upon perchlorate stimulation (a positive
      perchlorate discharge test). The gene (PDS) mutated in Pendred syndrome is
      expressed in thyroid and encodes a 780-amino acid protein (pendrin) that has
      recently been shown to function as an iodide/chloride transporter. We sought to
      establish the location of pendrin in the thyroid and to examine the regulatory
      network controlling its synthesis. Using peptide-specific antibodies for
      immunolocalization studies, pendrin was detected in a limited subset of cells
      within the thyroid follicles, exclusively at the apical membrane of the
      follicular epithelium. Interestingly, significantly greater amounts of pendrin
      were encountered in thyroid tissue from patients with Graves' disease. Using a
      cultured rat thyroid cell line (FRTL-5), PDS expression was found to be
      significantly induced by low concentrations of thyroglobulin (TG), but not by
      TSH, sodium iodide, or insulin. This is different from the established effect of
      TG, more typically a potent suppressor of thyroid-specific gene expression.
      Together, these results suggest that pendrin is an apical porter of iodide in the
      thyroid and that the expression and function of both the apical and basal iodide
      porters are coordinately regulated by follicular TG.

PMID- 10650968
TI  - Involvement of insulin-like factor 3 (Insl3) in diethylstilbestrol-induced
      cryptorchidism.
AB  - Recently, it has been shown that targeted inactivation of the Insl3 gene in male
      mice results in cryptorchidism. The Insl3 gene encodes insulin-like factor 3
      (Insl3), which is expressed in fetal Leydig cells. The testicular factor Insl3
      appears to play an important role in the transabdominal phase of testis descent,
      which involves development of the gubernaculum. Other studies have demonstrated
      that in utero exposure to diethylstilbestrol (DES), a synthetic estrogen, can
      lead to cryptorchidism both in humans and in animal models. The present study was
      undertaken to investigate whether prenatal DES-exposure might interfere with
      testicular Insl3 mRNA expression. Furthermore, the effect of DES on steroidogenic
      factor 1 (SF-1) mRNA expression level was determined, since it has been shown
      that SF-1 plays an essential role in transcriptional activation of the Insl3 gene
      promoter. Timed pregnant mice were treated with DES (100 microg/kg body weight)
      or vehicle alone on days E9 (gestational day 9) through E17. Control and DES
      exposed mouse fetuses were collected at E16, E17 and E18, when transabdominal
      testis descent is taking place. Lack of gubernaculum development in DES-exposed
      animals was confirmed by histological analyses at E17. Expression of Insl3 and SF
      1 mRNAs was studied in testes of control and DES-exposed fetuses at E16 and E18
      by RNase protection assay. Prenatal DES-exposure resulted in a three-fold
      decrease in Insl3 mRNA expression level (P<0.005), at both E16 and E18. In
      contrast, DES treatment had no effect on the expression of SF-1 mRNA. These
      results support our hypothesis that DES may interfere with gubernaculum
      development by altering Insl3 mRNA expression, providing a possible mechanism by
      which DES may cause cryptorchidism.

PMID- 10650969
TI  - Amylin: a novel action in the brain to reduce body weight.
AB  - Amylin is a 37-amino acid peptide hormone that is co-secreted with insulin by
      pancreatic B cells in response to a nutrient stimulus (e.g., during meals). To
      test the hypothesis that amylin acts within the brain to reduce long-term food
      intake and body weight, we examined the effects of acute and chronic 3rd
      ventricular (i3vt) infusion of low doses of amylin on food intake and body weight
      in rats. In one experiment, separate groups of ad lib-fed male Long Evans rats
      were given one i3vt infusion (3 microl over 30 s) of synthetic cerebrospinal
      fluid vehicle or 1 to 100 pmol amylin, and food intake and body weight were
      monitored for 7 days. Amylin potently and dose-dependently reduced 1-h food
      intake, with all doses producing significant reductions. The largest dose (100
      pmol) significantly reduced 24-h intake by over 30%. The effect was persistent in
      that both 7-day cumulative food intake and body weight change were significantly
      decreased over the 7 days following a single injection of 100 pmol of amylin.
      Other groups of rats received continuous i3vt infusion (0.5 microl/h volume) of
      saline or 2.0 pmol/h amylin via osmotic minipumps over 10 days. Food intake over
      the 10-day infusion was significantly suppressed in amylin-treated rats as
      compared to that of controls. Consequently, by the 4th day of infusion, amylin
      rats weighed significantly less than baseline relative to saline controls, and
      this difference persisted throughout the remainder of the infusion period. At
      sacrifice (Day 10), the percent of body weight from retroperitoneal fat depots
      was significantly lower in the amylin-treated rats, indicative of a reduction of
      total body adiposity. In summary, the results support the hypothesis that amylin
      acts as a signal to the brain contributing to the maintenance of long-term energy
      balance.

PMID- 10650970
TI  - Cardiac loading conditions modify the ventricular repolarization in conscious
      dogs with heart failure.
AB  - Changes in myocardial loading conditions influence the ventricular action
      potential via mechanoelectric feedback, a mechanism impaired in pathology. In
      vivo the QT interval of the electrocardiogram which reflects the action potential
      duration allows appropriate determination of its modifications. The effects of
      changes in cardiac loading conditions (load reduction with trinitrin; volume
      loading with Plasmion) on regional function and ventricular local electrogram
      were investigated in conscious dogs before (control) and after 4 weeks of rapid
      pacing (dilated cardiomyopathy, DCM). In controls both interventions increased
      heart rate. Trinitrin increased end-diastolic wall thickness (EDWth, P<0.001) and
      reduced absolute QT interval duration (P<0.05). Plasmion decreased EDWth
      (P<0.001) and increased left ventricular end diastolic pressure (LVEDP, P<0.001)
      without QT interval alteration. However, the corrected QT interval was unchanged
      in both interventions. In DCM, trinitrin did not change the QT interval. Plasmion
      increased LVEDP (P<0.01) and prolonged QT and corrected QT intervals (P<0.01)
      despite the tachycardia. In controls the changes in cardiac loading conditions
      did not modify the QT interval, suggesting intact endogenous regulation of
      repolarization. The impaired adaptation observed in DCM contributed to an
      increase in QT interval following volume loading. In this model, a prolonged
      repolarization after abrupt volume loading may result from enhanced or disclosed
      mechanoelectric feedback.

PMID- 10650971
TI  - Electrophysiological evidence for an ATP-gated ion channel in the principal cells
      of the frog skin epithelium.
AB  - In the present study we investigated the effects of adenosine 5'-triphosphate
      (ATP) on Na+ transport in frog skin epithelium. An experimental set-up was
      constructed to allow simultaneous measurement of Na+ transport, measured as the
      amiloride-sensitive short circuit current (Isc), and free cytosolic Ca2+
      concentration ([Ca2+]i) measured with the Ca(2+)-sensitive dye fura-2. The cell
      potential (Vsc) was measured with microelectrodes. Addition of ATP (100 micrM) to
      the basolateral solution resulted in a fast transient decrease in Isc followed by
      a slower increase and a transient increase in [Ca2+]i. Microelectrode
      measurements showed that the primary response, i.e. the decline in Isc was
      accompanied by transient depolarisation, followed by a return to the control
      value. The decrease in current was Ca2+ independent; i.e. treatment with
      thapsigargin in Ca(2+)-free solutions abolished the Ca2+ transient but did not
      influence the current transient. The secondary response, i.e. the slow increase
      in current, was accompanied by slow depolarisation of the cell. Measurements of
      apical Na+ permeability showed that this was due to an opening or activation of
      apical Na+ channels. These data show that ATP causes a fast initial drop and a
      secondary, long-lasting increase in Na+ absorption. The ability of ATP to cause
      the initial decline in current is independent of Ca2+, i.e. it is not caused by
      secondary effects of the P2Y-type receptors present in the tissue. Measurements
      of intracellular potential indicate that the initial depolarisation is caused by
      opening of non-selective cation channels, suggesting that this decrease is due to
      a transient activation of P2X-type ATP receptors.

PMID- 10650972
TI  - Evidence for P2Y-type ATP receptors on the serosal membrane of frog skin
      epithelium.
AB  - The present study presents the first evidence for P2Y-type adenosine 5'
      triphosphate (ATP) receptors on the basolateral membranes of frog skin epithelial
      cells. Cytosolic calcium ([Ca2+]i) was measured with fura-2 and Calcium-Green-1
      using epifluorescence microscopy and confocal laser scanning microscopy
      respectively. In the presence of Ca2+ in the solutions ATP increased [Ca2+]i. The
      increase in [Ca2+]i was due to the agonist activity of ATP and not to the
      activity of the potential products of ATP metabolism, i.e. adenosine 5'
      diphosphate (ADP), adenosine 5'-monophosphate (AMP) or adenosine, as shown by a
      comparison of the magnitude of the increases in [Ca2+]i caused by the various
      compounds. The rise in [Ca2+]i was predominantly monophasic at low ATP
      concentrations (below 100 microM). At higher concentrations the initial spike was
      followed by a plateau phase. In the absence of Ca2+ in the extracellular solution
      ATP caused Ca2+ release from intracellular stores. This could be inhibited by pre
      treatment of the tissue with 1 microM thapsigargin, an inhibitor of the
      endoplasmic reticulum calcium ATPase. The nucleotide uridine 5'-triphosphate
      (UTP) had similar effects on [Ca2+]i although the plateau level of the [Ca2+]i
      response was higher with this P2Y agonist. Confocal laser scanning microscopy
      showed that all cell layers of the epithelium responded to ATP. Our data
      indicates that serosal ATP acts on serosal P2Y-type receptors in frog skin
      epithelium. This is the first evidence of a phospholipase C-coupled receptor in
      this tissue.

PMID- 10650973
TI  - Extracellular magnesium deficiency induces contraction of arterial muscle: role
      of PI3-kinases and MAPK signaling pathways.
AB  - The present study investigated the actions of extracellular Mg2+ ([Mg2+]o)
      deficiency on isolated rat aortae and rat aortic smooth muscle cells (RASMC).
      Exposure of isolated, intact rat aortic rings to Mg(2+)-free or Mg(2+)-deficient
      medium (0.15-0.6 mM) produced endothelium-independent, concentration-dependent
      contractions: the lower the [Mg2+]o, the stronger the contraction. Pre- or post
      incubation of the vessels with low concentrations of U0126, SB-203580, PD-98059,
      wortmannin, LY-294002, or a SH2 domain inhibitor peptide suppressed [Mg2+]o
      deficiency-induced contractions significantly. The concentrations of these
      antagonists required for half-maximal inhibition (IC50) were not very different
      from the inhibitory constants (Ki) for these drugs. A variety of specific
      pharmacological antagonists of several known endogenously-formed vasoconstrictors
      did not inhibit or attenuate the contractions induced by low [Mg2+]o. Mg(2+)-free
      medium induced a 6- to 7-fold increase in intracellular Ca2+ ([Ca2+]i) in RASMC.
      Pre- or post-treatment of the cells with U0126, SB-203580, PD-98059, wortmannin,
      LY-294002, or a SH2 domain inhibitor peptide markedly inhibited the increments in
      ([Ca2+]i) in RASMC induced by exposure to Mg(2+)-free medium. The present
      findings suggest that Mg(2+)-deficiency-induced contractions of rat aortae are
      associated with activation of several cellular signal pathways, such as mitogen
      activated protein kinase, phosphatidylinositol-3 (PI3) kinases, and SH2 domain
      containing proteins.

PMID- 10650974
TI  - Voltage gating of Cx43 gap junction channels involves fast and slow current
      transitions.
AB  - RIN cells transfected with mouse cDNA coding for connexin43 (Cx43) were used to
      further examine the electrical properties of single gap junction channels. The
      experiments involved measuring intercellular currents from cell pairs using dual
      whole-cell recording with the patch-clamp method. We found that the single
      channel currents exhibit two types of transitions and several conductance states.
      Besides fast transitions between the main open state and the residual state, the
      channels underwent slow transitions between an open state (i.e. main open state
      or residual state) and a closed state. The fast transitions lasted less than 2
      ms, the slow ones ranged from 3.5 to 145 ms. The incidence of slow transitions
      increased with increasing transjunctional voltage. These observations are
      consistent with the notion that Cx43 gap junction channels possess more than one
      mechanism of voltage gating.

PMID- 10650975
TI  - Nuclear pores collapse in response to CO2 imaged with atomic force microscopy.
AB  - Nuclear pore complexes (NPCs) are the rate-limiting barriers for the exchange of
      macromolecules (e.g. transcription factors or mRNA) between the nuclear and
      cytosolic compartments. NPC conformation determines movement of cargo in either
      direction and thus controls gene expression. ATP and calcium are known to induce
      an NPC shape change (increase in height and decrease in diameter) indicating pore
      contraction. Here we report a CO2-induced shape change which is different to the
      ATP/calcium response. Experiments were performed on the isolated nuclear envelope
      of Xenopus laevis oocytes. The nuclear envelope was spread on glass and the
      native cytoplasmic surface was imaged with atomic force microscopy (AFM). The
      preparation was scanned in a water-saturated 100% O2 atmosphere at room
      temperature. Exposure to 5% CO2 (95%O2) led over a time course of minutes to a
      dramatic NPC shape change (decrease in height and decrease in diameter)
      indicating pore closure. NPCs turned flat and central channel openings virtually
      disappeared. The CO2 response was only slowly reversible. We conclude that NPCs
      apparently collapse in response to CO2, a structural change that could lead to
      the functional isolation of the cell nucleus.

PMID- 10650976
TI  - Differential activation of ATP-sensitive potassium channels during energy
      depletion in CA1 pyramidal cells and interneurones of rat hippocampus.
AB  - In the hippocampus, pyramidal cells are more vulnerable than granule cells and
      interneurones to energy depletion during hypoxia and ischaemia. The aim of the
      present study was to explore whether this difference is related to the lower
      expression of adenosine 5'-triphosphate-sensitive potassium (K(ATP)) channels in
      pyramidal cells compared to other hippocampal neurones. Hippocampal slices were
      prepared from 10- to 13-day-old rats, and CAI pyramidal cells and interneurones
      of the stratum radiatum were visually and electrophysiologically identified.
      Energy depletion was produced by removing glucose from the bath or by inhibiting
      mitochondrial metabolism using rotenone. In the perforated-patch configuration,
      both protocols elicited outward currents in only a minority of the pyramidal
      cells but in most of the interneurones. The currents started to develop 9-57 min
      after glucose deprivation and 4-16 min after rotenone application and reversed
      near the K+ equilibrium potential. Bath-applied diazoxide (0.3 mM), an opener of
      K(ATP) channels, could activate additional currents. The sulphonylureas
      tolbutamide (0.5 mM) or glibenclamide (20 microM), two blockers of K(ATP)
      channels, totally inhibited the currents induced by energy depletion and
      activated by diazoxide. The results demonstrate the differential activation of
      K(ATP) channels during energy depletion in pyramidal cells and interneurones, and
      suggest that channel activation is neuroprotective against the deleterious
      effects of energy depletion.

PMID- 10650977
TI  - Delayed contractures induced by external cadmium ions in rat soleus muscle
      fibres.
AB  - Cd(2+)-induced contractures began with a delay of approximately =4 min after
      adding 3 mM Cd2+ to external solutions that contained Cl- as the major anion.
      Tension increased to approximately =20% of peak tetanic tension after 30 min and
      was maintained after Cd2+ washout. Tension developed more rapidly at higher
      [Cd2+] (up to 10 mM). There was a lack of correlation between the delay before
      the contracture and contracture tension: (1) tension was reduced by 2 mM CO2+ or
      50 microM nifedipine, although the delay remained at approximately =4 min, and
      (2) the delay fell to seconds when Cd2+ was added in SO42- solutions, although
      tension was the same as in Cl- solutions. Since (SO4)2- solutions swell T
      tubules, Cd2+ may enter the T-system before inducing contractures. Cd(2+)-induced
      contractures depended on external [Ca2+] since they were reduced when Ca2+ was
      omitted from solutions. The contractures did not depend on activation of
      excitation-contraction coupling, since tension was not altered when the voltage
      sensor was inactivated by depolarization in 40 mM K+. A small contracture
      developed with 3 mM Zn2+, but not 3 mM Co2+ or La3+. Both Cd2+ and Zn2+ activated
      the contractile proteins in skinned fibres. Cd(2+)-induced contractures may
      depend on external Cd2+ releasing Ca2+ from the sarcoplasmic reticulum (SR), or
      on Cd2+ entering the fibre, releasing Ca2+ from the SR and/or directly activating
      the contractile proteins.

PMID- 10650979
TI  - Nephritogenic ochratoxin A interferes with hormonal signalling in immortalized
      human kidney epithelial cells.
AB  - The ubiquitous nephritogenic and carcinogenic fungal metabolite ochratoxin A
      (OTA) affects function and growth of renal epithelial cells. We studied the
      possible contribution of changes in cellular Ca2+ homeostasis to the effects of
      nanomolar concentrations of OTA on immortalized human kidney epithelial (IHKE-1)
      cells. The effects of OTA on cellular calcium homeostasis ([Ca2+]i), cell
      proliferation and viability and its interaction with angiotensin II (Ang II) and
      epidermal growth factor (EGF) were investigated. OTA potentiated EGF- and Ang II
      induced cell proliferation Ca2+ dependently at OTA concentrations of 0.1 or 1
      nmol/l. A decrease in cell viability could be observed only after 24 h exposure,
      with threshold concentrations greater than 10 nmol/l. This reduction of cell
      viability was independent of Ca2+. Within seconds, OTA evoked reversible and
      concentration-dependent [Ca2+]i oscillations with a threshold concentration of <
      or =0.1 nmol/l. These oscillations were abolished by removal of extracellular
      Ca2+, by the Ca(2+)-channel blocker SKF 96365 and by inhibition of phospholipase
      C. OTA also stimulated thapsigargin-sensitive Ca(2+)-ATPase activity and
      increased the filling state of thapsigargin-sensitive Ca(2+)-stores. Exposure to
      OTA concentration dependently increased cellular adenosine 3',5'-cyclic
      monophosphate (cAMP) content. In addition, OTA-induced changes of [Ca2+]i were
      reduced significantly by the protein kinase A inhibitor H-89. Finally, 0.1 or 1
      nmol/l OTA potentiated the effects of Ang II and EGF on cellular Ca2+
      homeostasis. We conclude that OTA may impair cellular Ca2+ and cAMP homeostasis
      already at low nanomolar concentrations, resulting in concentration-dependent
      [Ca2+]i oscillations. OTA interferes also with hormonal Ca2+ signalling, thereby
      leading to altered cell proliferation. The reduction of cell viability at higher
      OTA concentrations seems not to depend on Ca2+.

PMID- 10650978
TI  - Release of taurine in apoptotic cerebellar granule neurons in culture.
AB  - Cell shrinkage is a distinctive feature of apoptotic death, but the mechanisms
      leading to cell volume loss are unclear at present. Activation of pathways
      extruding intracellular osmolytes such as K+, Cl- and organic molecules may be
      part of these mechanisms. This was examined in the present work measuring the
      release of taurine, gamma-amino-butyric acid (GABA) and glutamate in cerebellar
      granule neurons cultured in conditions resulting in apoptotic death after 4-7
      days in vitro (DIV). The basal release of [3H]taurine from cells started to
      increase (38%) after 3 DIV and reached a maximal enhancement (250%) at 5 DIV. The
      increase in taurine efflux closely followed the occurrence of apoptotic death
      markers such as caspase induction and chromatin condensation. The efflux of
      glutamate (traced as D-aspartate) and [3H]GABA also increased but notably less
      than that of taurine (90% and 75%, respectively) at 5 DIV. Taurine release
      associated with apoptosis was unaffected by 4,4'-diisothiocyanatostilbene 2,2'
      disulphonic acid (DIDS) and 5-nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB),
      blockers of the diffusive pathway activated during cell volume regulation in
      hyposmotic conditions. Taurine efflux was increased in Cl(-)-free (replaced by
      gluconate) and decreased in Na+-free media. Blockers of the energy-dependent
      glutamate and taurine carriers, dihydrokainate and guanidinoethane sulfonate,
      respectively, did not affect the release associated with apoptosis. These results
      implicate taurine in the mechanism of cell shrinkage during apoptosis.

PMID- 10650980
TI  - Thiazolidinedione-induced activation of the transcription factor peroxisome
      proliferator-activated receptor gamma in cells adjacent to the murine skeletal
      muscle: implications for fibroblast functions.
AB  - Nuclear peroxisome proliferator-activated receptor gamma (PPARgamma) is the
      target of antidiabetogenic thiazolidinediones (TZD). However, recent studies
      failed to show that TZD has an effect in vitro on insulin-regulated glucose
      uptake in skeletal muscles, the major site of glucose disposal. The potential
      effects of TZD on cells adjacent to skeletal muscles are not well characterized
      but may be involved in TZD's actions. Hence, we studied these cells from mice
      treated with the carrier and with the TZD ciglitazone (9 nmol/g body weight). The
      cells were typified by lipid enrichment (floating adipocytes and macrophages), by
      the ectopic expression of cellular fibronectin (fibroblasts), fibronectin and
      PPARgamma (preadipocytes), PPARgamma and CD11b/Mac-1 (active macrophages) as
      revealed by flow cytometry and immunoblotting. The glucose transporter 4 proteins
      (GLUT4) and the uptake of glucose and long-chain fatty acids (LCFA) were
      determined flow cytometrically using fluorescent derivatives of glucose (NBDG)
      and LCFA (C16-Bodipy). The expression of tumor necrosis factor alpha (TNFalpha)
      in CD11b/Mac-1-positive and CD11b/Mac-1-negative cells separated by magnetic
      immunobeads was analyzed. The results showed that TZD treatment upregulated GLUT4
      expression, and increased insulin-regulated NBDG uptake and C16-Bodipy binding
      and influx, at the same time as increasing the quantity of PPARgamma-expressing
      fibroblasts; this indicates the development of the preadipocyte phenotype. In
      contrast, TZD lowered the number of adipocytes (0.6-fold compared to the carrier
      treated control) perhaps through an action of TNFalpha from CD11b- and PPARgamma
      expressing macrophages. The data suggest that the regulatory effects of TZD on
      energy homeostasis involve two major targets: the PPARgamma-positive fibroblasts
      whose adipogenic program is promoted, and CD11b-PPARgamma-expressing macrophages
      which become cytotoxic and fibrogenic because of the effects of TNFalpha on
      neighboring adipocytes and fibroblasts, respectively.

PMID- 10650981
TI  - Volume dynamics in migrating epithelial cells measured with atomic force
      microscopy.
AB  - Migration of transformed renal epithelial cells (transformed Madin-Darby canine
      kidney cells, MDCK-F cells) relies on the activity of a Ca(2+)-sensitive K+
      channel (IK channel) that is more active at the rear end of these cells. We have
      postulated that intermittent IK channel activity induces local cell shrinkage at
      the rear end of migrating MDCK-F cells and thereby supports the cytoskeletal
      mechanisms of migration. However, due to the complex morphology of MDCK-F cells
      we have not yet been able to measure volume changes directly. The aim of the
      present study was to devise a new technique employing atomic force microscopy
      (AFM) to measure the volume of MDCK-F cells in their physiological environment
      and to demonstrate its dependence on IK channel activity. The spatial (x, y' and
      z) co-ordinates of each pixel of the three-dimensional image of MDCK-F cells
      allow calculation of the volume of the column "underneath" a given pixel. Thus,
      total cell volume is the sum of all pixel-defined columns. The mean volume of 17
      MDCK-F cells was 2500+/-300 fl. Blockade of the IK channel with the specific
      inhibitor charybdotoxin (CTX) increased cell volume by 17+/-4%; activation of IK
      by elevating the intracellular [Ca2+] with the Ca2+ ionophore ionomycin decreased
      cell volume by 19+/-3%. Subtraction images (experimental minus control) reveal
      that swelling and shrinkage occur predominantly at the rear end of MDCK-F cells.
      In summary, our experiments show that AFM allows the measurement not only of
      total cell volume of living cells in their physiological environment but also the
      tracing of local effects induced by the polarized distribution of K+ channel
      activity.

PMID- 10650982
TI  - Extracellular ATP regulates exocytosis in inhibiting multiple Ca(2+) channel
      types in bovine chromaffin cells.
AB  - Feedback modulation of voltage-dependent Ca2+ channels by ATP is a well
      documented phenomenon in bovine chromaffin cells. However, its influence in the
      control of hormone release is at present poorly understood. By using combined
      patch-clamp and fura-2 fluorescence measurements we provide evidence that the
      three Ca2+ channel types (L, N and P/Q) expressed in bovine chromaffin cells are
      inhibited by ATP (30 microM), and that their involvement in the secretory
      response, as assayed by capacitance measurements, is roughly proportional to
      their contribution to the whole-cell Ca2+ current (ICa) both in the absence and
      presence of ATP. ATP did not modify the capacitance increase observed in cells
      dialyzed with Ca(2+)-EGTA buffers (1.5 microM free Ca2+), thus excluding a direct
      effect of ATP on the secretory machinery. Voltage predepolarizations or long
      chemical (2 s, 70 mM KCl) depolarizations attenuate the effect of ATP on
      exocytosis by partially relieving the inhibition of ICa Likewise, a strong
      stimulation that depletes the readily releasable pool of vesicles prevents an
      inhibitory effect of ATP on the secretory response. While these results lend
      support to the hypothesis of autocrine modulation of exocytosis by endogenously
      released ATP acting on P2y-purinoceptors to inhibit ICa, feedback regulation of
      the rate of release will be a complex function of the occupancy of those
      receptors and of the electrical and secretory activity of the cell.

PMID- 10650983
TI  - Reduction of ionic strength activates single volume-regulated anion channels
      (VRAC) in endothelial cells.
AB  - We have previously shown that a reduction of intracellular ionic strength is
      involved in the activation of volume-regulated anion channels (VRAC). Here we
      show in a single-channel study that VRAC can be activated in a cell-attached
      patch when the cell interior is dialyzed with a solution of decreased ionic
      strength. For this purpose, bovine pulmonary endothelial (CPAE) cells) were
      permeabilized with alpha-staphylotoxin (alphaST) which has a molecular weight cut
      off size of 2 kDa. If the ionic strength in the bath solution is reduced from 160
      mM to 95 mM, single-channel activity is initiated in cell-attached patches sealed
      before permeabilization. Conductance is outwardly rectifying with approximately
      17 pS at negative and 57 pS at positive potentials. Single-channel currents
      reverse near the calculated equilibrium potential for Cl-. The averaged current
      shows inactivation at positive potentials. The current is blocked by 5-nitro-2-(3
      phenylpropylamino)-benzoic acid (NPPB). An increase in ionic strength reversibly
      inhibits current activation. It is concluded that a decrease in ionic strength
      activates single-channel currents through VRAC rather than shifting the set point
      of a hypothetical volume sensor.

PMID- 10650984
TI  - In colchicine-treated rats, cellular distribution of AQP-1 in convoluted and
      straight proximal tubule segments is differently affected.
AB  - In cells along the nephron, the recycling of various components between the
      plasma membrane and intracellular organelles by vesicle trafficking depends on
      intact microtubules (MT). Previous studies of rats treated with the MT-disrupting
      drug colchicine showed that some brush-border membrane (BBM) transporters in
      renal proximal convoluted tubule cells (PCTC) become internalized in numerous
      vesicles randomly scattered in the cytoplasm. In this study, we compare the
      intracellular distribution of MT and several BBM proteins [megalin, vacuolar (V)
      ATPase, water channel aquaporin-1 (AQP-1)] as well as endocytosis of the in-vivo
      injected fluorescent marker FITC-dextran in PCTC and proximal straight tubule
      cells (PSTC) in control and colchicine-treated rats. Immunoblotting and
      immunocytochemical data show that in the PCTC and PSTC colchicine treatment
      causes: (1) disappearance of MT, (2) strongly diminished endocytosis of FITC
      dextran, and (3) marked loss of megalin and V-ATPase from the BBM and their
      redistribution into intracellular vesicles. Similar pattern was observed for the
      distribution of AQP-1 in the PCTC. However, in the PSTC, the staining intensity
      of AQP-1 in the BBM, as well as its intracellular distribution remained
      unaffected by colchicine treatment. We conclude that in the PSTC, either MT play
      a minor role in the recycling of AQP-1 between the BBM and intracellular vesicles
      or BBM AQP-1 turns over much more slowly than in the PCTC.

PMID- 10650985
TI  - Effects of hydroxyl radicals on outwardly rectifying chloride channels in a
      cultured human bronchial cell line (16HBE14o-).
AB  - Respiratory pathologies can result from the exposure of airway epithelial cells
      to oxidative stress. We studied the effects of the hydroxyl radical *OH, for
      which there is no natural intra- or extracellular scavenger, on an outwardly
      rectifying chloride channel (ORCC). In the human bronchial cell line 16HBE14o-,
      the cytoplasmic side of ORCC in inside-out excised membrane patches was exposed
      to *OH created by simultaneously superfusing Fe2+ and H2O2 in front of the patch
      pipette. ORCC was activated by depolarizing voltage steps. Its open probability
      (Po) increased with bath [Ca2+] above 1 microM. Upon brief exposure to *OH, ORCC
      first closed and then alternated between periods of closure and normal activity.
      The duration of closure increased with the duration of *OH exposure but voltage
      steps could reopen the channel. After 10 min exposure to *OH, however, the
      channel closed irreversibly, regardless of the number of subsequent voltage steps
      or the duration of washing. Low [Ca2+] in the bath accelerated the irreversible
      closure of the channel in the presence of *OH. Intracellular application of *OH
      progressively inhibited ORCC activity by inducing long closure periods that
      increased with time. This might have important pathophysiological implications in
      the process of inflammation.

PMID- 10650986
TI  - Dynamic changes in sarcoplasmic reticulum function in cardiac hypertrophy and
      failure.
AB  - Previous studies have demonstrated that cardiac function changes with development
      of pressure overload-induced hypertrophy. The present study was undertaken to
      discover the basis for the changes in sarcoplasmic reticulum (SR) functions:
      uptake, (as related to the SR Ca2+ pump properties) and release in isolated,
      perfused hypertrophied rat hearts. Our results demonstrated significant
      prolongation of the time-to-90%-relaxation, both during the period of
      compensation (8 weeks after banding the ascending aorta, group HR1), when
      systolic function was preserved, and later with progressive hypertrophy (20 weeks
      after banding, group HR2) and contractile failure (20-22 weeks after banding,
      group F). The initial rates of the oxalate-supported SR Ca2+ uptake and the
      maximum transport rate (Vmax) of the SR Ca2+ pump, measured in the left
      ventricular homogenates, during blockade of the SR Ca2+ release channels with
      ruthenium red, were preserved in group HR1. To correlate early relaxation
      abnormalities with SR function, the [Ca2+] required for half-maximal pump
      activation (EC50) was examined and increased significantly in HRI vs. Sham1
      (0.95+/-0.06 vs. 0.81+/-0.04 microM, P<0.05) indicating that the affinity of the
      SR Ca2+ pump for Ca2+ was reduced. The same tendency was demonstrated in groups
      HR2 (0.94+/-0.06 vs. 0.79+/-0.05) and F (0.89+/-0.05 vs. 0.78+/-0.05). In
      addition, with progression of hypertrophy we observed a significant decline in
      the amount of SR Ca2+ pump, as assessed by the Vmax, from 31.22+/-1.20 (Sham2) to
      26.47+/-1.58 HR2) nmol/mg protein per min (P<0.05), and from 33.81+/-1.23 (Sham3)
      to 25.15+/-1.57 (F) nmol/mg protein per min, (P<0.01). This decrease was
      accompanied by a parallel reduction in the number of SR Ca2+ release channels by
      14% (HR2) and 23% (F), as determined by maximum [3H] ryanodine binding (Bmax).
      These results suggest that pressure overload-induced changes in SR Ca2+ uptake
      (as reflected by Vmax and EC50) and SR Ca2+ release (as reflected by Bmax), both
      leading to diminished Ca2+ sequestration, may contribute to impaired cardiac
      relaxation with compensatory hypertrophy and failure.

PMID- 10650987
TI  - Modification of alpha subunit of RIIA sodium channels by aconitine.
AB  - The effect of aconitine (AC), an alkaloid toxin, on the electrophysiological
      properties of the rat brain type IIA alpha subunit expressed heterologously in
      the Chinese Hamster Ovarian (CHO) cell line was studied under the whole-cell
      patch-clamp configuration. The activation threshold of modified channels shifted
      by about -40 mV. As the number of depolarizations increased, the transient
      current at 0 mV decreased and, in proportion, the AC-modified current at -50 mV
      increased. This suggests a transition of channels to an AC-modified state. The
      rate of modification was nearly four times faster when 50 microM AC was applied
      internally than when applied in the bath solution. This supports the idea that
      the AC-binding site is located close to the cytoplasmic mouth of the channel
      pore. The AC-modified sodium currents inactivated completely, although with
      slower kinetics. The steady-state inactivation followed a simple Boltzmann
      function. AC-modified currents activated without a sigmoidal delay. The
      permeability of the NH4+ ion was enhanced such that its permeability ratio
      increased from an initial value of 0. 18 to 0.95 and for Cs+ it was enhanced from
      0.03 to 0.07. These studies show that the AC-binding site resides at the pore
      region of the alpha subunit of the Na+ channel, and that the presence of beta
      subunit/s is not essential for AC binding.

PMID- 10650988
TI  - Modulation of the mdr-1b gene in the kidney of rats subjected to dehydration or a
      high-salt diet.
AB  - The localization of the multidrug resistance gene (mdr-1b) messenger ribonucleic
      acid (mRNA) along the rat nephron and its regulation was investigated under two
      different experimental situations: dehydration and high-Na+ diet. The mdr-1b mRNA
      was detected in glomeruli, proximal tubule segments, cortical and medullary thick
      ascending limbs, inner medullary collecting ducts and thin limbs of Henle's loop.
      Using the ribonuclease (RNase) protection assay (RPA), the abundance of mdr-1b
      mRNA was shown to be 35% less in renal cortex than in medulla. The mdr-1b mRNA
      expression in dehydrated rats in cortex or medulla did not differ from control.
      However, after 5 or 14 days on a high-Na+ diet, mdr-1b expression had decreased
      significantly in both cortex and medulla. There was no change in protein
      expression in dehydrated rats but a significant decrease occurred in rats fed the
      high-salt diet, confirming the results obtained with RPA. Our results suggest
      that the mdr-1b product is involved in extracellular volume regulation in rats.

PMID- 10650989
TI  - Maitotoxin induces insertion of different ion channels into the Xenopus oocyte
      plasma membrane via Ca(2+)-stimulated exocytosis.
AB  - The activation of cation channels in oocytes of Xenopus laevis by the marine
      poison maitotoxin (MTX) was monitored as membrane current (I(m)), conductance
      (Gm) and membrane surface area determined by continuous measurements of membrane
      capacitance (Cm). When MTX (25 pM) was added to the bathing solution there was an
      abrupt, large increase in inward membrane currents. Current/voltage relationships
      (I/V curves) were linear and suggested activation of voltage-independent non
      selective cation channels (NSCC). MTX-induced Ca(2+)-sensitive currents were
      mainly carried by Na+ and were suppressed by low (0 mM) or high (40 mM) external
      Ca2+ concentrations and removal of Na+. Gadolinium (Gd3+, 10-500 microM) also had
      inhibitory effects, demonstrating the possible involvement of stretch-activated
      cation channels (SACC). In a high concentration (500 microM), amiloride
      substantially reduced the MTX-activated current while lower amiloride
      concentrations (50-100 microM) stimulated the current further. Continuous
      measurements of Cm revealed that MTX induced exocytotic delivery and functional
      insertion of new channel proteins into the plasma membrane, indicated by a Ca(2+)
      dependent increase in membrane surface area by around 28%. From these data we
      conclude that MTX activates NSCC that require relatively high concentrations of
      amiloride to be blocked. Furthermore, MTX possibly stimulates activation of
      Gd(3+)- and Ca(2+)-sensitive mechanosensitive cation channels. Stimulation of
      these channels is achieved by exocytotic delivery and functional insertion of new
      channels into the plasma membrane in a pathway that depends on the presence of
      extracellular Ca2+.

PMID- 10650990
TI  - Ammonium triggers calcium elevation in cultured mouse microglial cells by
      initiating Ca(2+) release from thapsigargin-sensitive intracellular stores.
AB  - Microglial cells are thought to serve as sensors for pathologic events in the
      brain. In the present study we demonstrate that these cells respond with an
      increase in intracellular calcium concentration ([Ca2+]i) to intracellular
      alkaline shifts induced by either application of NH3/NH4+ or by an extracellular
      alkaline shift. The cytoplasmic pH (pHi) and [Ca2+]i in cultured mouse microglial
      cells were studied employing the fluorescent probes BCECF and fura-2,
      respectively. Application of NH3/NH4+ caused an initial rapid alkalinization
      followed by a slow recovery towards the resting level, while application of
      alkaline (pH 8.2) solution triggered a slower rise in pHi. The [Ca2+]i elevation
      triggered by NH3/NH4+ and extracellular alkaline shift were caused by different
      mechanisms: extracellular alkalinization induced a transmembrane Ca2+ entry,
      whereas NH3/NH4+ triggered Ca2+ release from thapsigargin- and ATP-sensitive
      intracellular pools. The mobilization of intracellular Ca2+ caused by NH3/NH4+
      was blocked by a specific inhibitor of phospholipase C, U-73122, but was not
      affected by an inhibitor of G-protein, pertussis toxin. This implies that NH3/NH4
      interacts with phospholipase C and leads to an increase in the intracellular
      level of inositol 1,4,5-trisphosphate (InsP3). In contrast to a previous study
      using a microglial cell line, application of NH3/NH4+ did not result in a release
      of tumor necrosis factor alpha (TNF-alpha), a marker of microglial activation, in
      the primary microglial cells. This implies that ammonium does not lead to
      activation of microglia in the culture model.

PMID- 10650991
TI  - Regulation of the Na+2Cl-K+ cotransporter in isolated rat colon crypts.
AB  - The Na(+2)Cl(-)K+ cotransporter accepts NH4+ at its K+-binding site. Therefore,
      the rate of cytosolic acidification after NH4+ addition to the bath (20 mmol/l)
      measured by BCECF fluorescence can be used to quantify the rate of this
      cotransporter. In isolated colon crypts of rat distal colon (RCC) addition of
      NH4+ led to an initial alkalinization, corresponding to NH3 uptake. This was
      followed by an acidification, corresponding to NH4+ uptake. The rate of this
      uptake was quantified by exponential curve fitting and is given in arbitrary
      units (delta fluorescence ratio units/1000 s). In pilot experiments it was shown
      that the pH signal caused by the Na(+)2Cl(-)K+ co-transporter could be amplified
      if the experiments were carried out in the presence of bath Ba2+ to inhibit NH4+
      uptake via K+ channels. Therefore all subsequent experiments were performed in
      the presence of 1 mmol/l Ba2+. In the absence of any secretagogue, preincubation
      of RCC in a low-Cl- solution (4 mmol/l) for 10 min enhanced the uptake rate
      significantly from 1.70+/-0.11 to 2.54+/-0.27 U/1000 s (n=20). The addition of
      100 mmol/l mannitol (hypertonic solution) enhanced the rate significantly from
      1.93+/-0.17 to 2.84+/-0.43 U/1000 s (n=5). Stimulation of NaCl secretion by a
      solution containing 100 micromol/l carbachol (CCH) led to a small but significant
      increase in NH4+ uptake rate from 2.06+/-0.34 to 2.40+/-0.30 U/1000 s (n= 11).
      The increase in uptake rate observed with stimulation of the cAMP pathway by
      isobutylmethylxanthine (IBMX) and forskolin (100 micromol/l and 5 micromol/l,
      respectively) was from 2.39+/-0.24 to 3.06+/-0.36 U/1000 s (n=24). Whatever the
      mechanism used to increase the NH4+ uptake rate, azosemide (500 micromol/l)
      always reduced this rate to control values. Hence three manoeuvres enhanced loop
      diuretic-inhibitable uptake rates of the Na(+)2Cl(-)K+ cotransporter: (1)
      lowering of cytosolic Cl- concentration; (2) cell shrinkage; (3) activation of
      NaCl secretion by carbachol and (4) activation of NaCl secretion by cAMP. The
      common denominator of all four activation pathways may be a transient fall in
      cell volume.

PMID- 10650992
TI  - Tools for flash-photolysis experiments on voltage-clamped muscle fibre segments.
AB  - An experimental set-up is described that allows the combination of rapid
      transmembrane voltage changes and photometric calcium recording with the fast
      photochemical turnover of substances applied externally or intracellularly to cut
      skeletal muscle fibres. It consists of a double-vaseline-gap system, designed for
      use with a xenon-flash-lamp device and a dual-wavelength microscope photometer.
      The pools of the vaseline gap chamber that contain the solutions surrounding the
      cut ends and the voltage-clamped segment of the muscle fibre are closed and have
      volumes of 20-50 microl. Thin tubes allow rapid solution change or continuous
      perfusion in the chamber compartments. Accessory tools were constructed to
      simplify focussing and measuring the flash-light intensity. A pilot light
      delivered from a red laser diode is used as a guide beam to target the
      ultraviolet (UV) flash to the preparation. The light distribution in the focal
      region and the relative changes in flash intensity with increasing numbers of
      flashes were quantified with an instrument that integrates the photo-current of a
      UV-sensitive silicon diode. The function of the set-up was demonstrated by
      measuring the efficiency of Ca2+ release from DM-nitrophen in quartz capillaries
      using the Ca(2+)-sensitive dye antipyrylazo III and by recording the flash
      induced recovery of L-type calcium currents in muscle fibres blocked by the light
      sensitive dihydropyridine drug nifedipine.

PMID- 10650993
TI  - Use of fluorescently labelled calmodulins as tools to measure subcellular
      calmodulin activation in living dorsal root ganglion cells.
AB  - We have used fluorescently labelled calmodulins to probe the activity of
      calmodulin in living dorsal root ganglion cells. Calmodulin labelled with the
      fluorophore 5-([4,6 dichlorotriazin-2yl]amino)-fluorescein (FL-CaM) does not
      change its fluorescence when it binds calcium, while calmodulin labelled at
      lysine 75 with 2-chloro-(6-(4-N,N-diethylamino-phenyl)-1,4,5-triazin-4-yl (TA
      CaM), an environment-sensitive probe, increases its fluorescence when it binds
      calcium. We micro-injected FL-CaM or TA-CaM into rat dorsal root ganglion cells
      and found that both probes localise to the cell nucleus. In contrast, endogenous
      cellular calmodulin, in dorsal root ganglion cells as in hippocampal neurones, is
      predominantly cytosolic unless the neurones are depolarised, then it moves to the
      nucleus. FL-CaM and TA-CaM, introduced into dorsal root ganglion cells via a
      patch pipette, also immediately move to the nucleus, indicating that the nuclear
      localisation is a property of the labelled calmodulins. Although the subcellular
      distribution of FL-CaM and TA-CaM does not necessarily match that of endogenous
      calmodulin, we show that FL-CaM can be used as a control for TA-CaM when studying
      calmodulin activation in different cellular compartments.

PMID- 10650994
TI  - Altered phosphorylation of sarcoplasmic reticulum contributes to the diminished
      contractile response to isoproterenol in hypertrophied rat hearts.
AB  - We tested the hypothesis that changes in phosphorylation of the sarcoplasmic
      reticulum (SR) protein, phospholamban (PIB) and myofibrillar proteins troponin I
      (TnI) and C protein are responsible for the decreased relaxant response to
      isoproterenol in cardiac hypertrophy and failure induced by ascending aortic
      banding in rats. In isolated perfused heart preparations under maximal
      isoproterenol stimulation, the capacity for in vitro cAMP-dependent
      phosphorylation of PIB was significantly increased at the compensatory stage of
      hypertrophy (126-130%, P<0.001), but decreased with failure (70-76%, P<0.001).
      Phosphorylation of TnI also decreased in the failing hearts, however to a lesser
      extent (80-83%, P<0.05). No significant hypertrophy-related difference was
      evident in isoproterenol-induced phosphorylation of C protein. The relative
      tissue level of PIB was increased (150-168%, P<0.001) in hypertrophied and
      decreased (71-83.8%, P<0.05) in failing hearts compared with the respective age
      matched sham-operated controls (100%). As a percentage above baseline, the
      maximal isoproterenol-induced increase in the EC50 of the SR Ca2+ pump in
      response to phosphorylation of PIB was 38.5+/-1.1% for sham-operated rats, and
      26.0+/-3.8% and 15.4+/-4.2% for hypertrophied and failing hearts respectively. As
      a consequence, linear correlation was observed between the maximal increase in
      EC50 and the maximal rate of relaxation [(-dP/dt)/DevP] upon isoproterenol
      stimulation, declining with progressive hypertrophy to failure. These data
      suggest that hypertrophy-induced alterations in PIB phosphorylation and protein
      level contribute to the diminished relaxant response of the hypertrophied and
      failing heart to adrenergic agonists.

PMID- 10650995
TI  - Plasma cortisol and beta-endorphin concentrations in trained and over-trained
      standardbred racehorses.
AB  - The effects of training and over-training on plasma cortisol and beta-endorphin
      (betaEP) concentrations at rest and after standardised exercise tests and the
      cortisol responses to adrenocorticotropin (ACTH) administration were investigated
      in standardbred horses. Twelve horses were divided randomly into control and over
      trained (OT) groups after 17 weeks slow- and moderate-intensity treadmill
      training. The standardised treadmill exercise test consisted of 2 min at
      velocities corresponding to 30, 50, 70 and 100% of maximum O2 consumption. Over
      training, defined as a significant decrease in body weight and treadmill run-time
      to-fatigue in an incremental velocity test, occurred in the OT group after 32
      weeks of training exercise. Peak cortisol concentrations after exercise decreased
      significantly in the OT group from 320+/-15.6 at week 8 to 245+/-17.0 nmol l(-1)
      at week 32, and mean cortisol concentrations over a 120-min period after exercise
      decreased from 258+/-11.7 to 192+/-16.6 nmol l(-1) (P<0.05). Mean and total
      cortisol and betaEP concentrations in resting horses were not significantly
      different after over-training. Peak cortisol concentrations after
      adrenocorticotropin (ACTH) administration were not significantly different in the
      over-trained group. Dysfunction of the hypothalamo-pituitary-adrenocortical axis
      occurs in over-trained horses, but this adaptation is not associated with a
      change in the adrenocortical responsiveness to ACTH.

PMID- 10650996
TI  - Modal behavior of the Kv1.1 channel conferred by the Kvbeta1.1 subunit and its
      regulation by dephosphorylation of Kv1.1.
AB  - Modulation of fast-inactivating voltage-gated K+ channels can produce plastic
      changes in neuronal signaling. Previously, we showed that the voltage-dependent
      K+ channel composed of brain Kv1.1 and Kvbeta1.1 subunits (alpha(beta) channel)
      gives rise to a current that has a fast-inactivating and a sustained component;
      the proportion of the fast-inactivating component could be decreased by
      dephosphorylation of a basally phosphorylated Ser-446 on the alpha subunit. To
      account for our results we suggested a model that assumes a bimodal gating of the
      alpha(beta) channel. In this study, using single-channel analysis, we confirm
      this model. Two modes of gating were identified: (1) an inactivating mode
      characterized by low open probability and single openings early in the voltage
      step, and (2) a non-inactivating gating mode with bursts of openings. These two
      modes were non-randomly distributed, with spontaneous shifts between them. Each
      mode is characterized by a different set of open time constants (tau) and mean
      open times (t(0)). The non-inactivating mode is similar to the gating mode of a
      homomultimeric alpha channel. The phosphorylation-deficient alphaS446Abeta
      channel has the same two gating modes. Furthermore, alkaline phosphatase promoted
      the transition to the non-inactivating mode. This is the first report of modal
      behavior of a fast-inactivating K+ channel; furthermore, it substantiates the
      notion that direct phosphorylation is one mechanism that regulates the
      equilibrium between the two modes and thereby regulates the extent of macroscopic
      fast inactivation of a brain K+ channel.

PMID- 10650997
TI  - Differential modulation of voltage-dependent Ca2+ currents by EGTA and BAPTA in
      bovine adrenal chromaffin cells.
AB  - Whole-cell patch-clamp recordings were made to examine the effects of the Ca2+
      chelators EGTA and BAPTA on the biophysical properties of voltage-operated Ca2+
      currents in bovine adrenal chromaffin cells. Ca2+ currents in the presence of
      either EGTA or BAPTA over a concentration range of 0.1-60 mM were recorded under
      otherwise identical conditions. Analysis of current-voltage relationships yielded
      unexpected differences in several important parameters such as the voltage
      dependence of activation, kinetics, slope, and reversal potential, which seemed
      to be unrelated to the Ca(2+)-binding properties of these chelators. Increasing
      concentrations of BAPTA augmented the peak Ca2+ current amplitude while current
      amplitudes in the presence of EGTA remained constant over the entire
      concentration range tested. Increasing concentrations of BAPTA shifted the
      voltage sensitivity of Ca2+ currents by about 15 mV towards positive voltages.
      EGTA, over the same concentration range, did not affect the voltage sensitivity.
      The shift in voltage sensitivity observed with BAPTA was unrelated to its faster
      Ca92+)-binding kinetics, as it was also observed when substituting Ca2+ with Ba2+
      as the charge carrier. The mechanism by which BAPTA affects Ca2+ channel voltage
      dependence also seems unrelated to kinase-mediated modulation of Ca2+ channels,
      since the protein-kinase-C- (PKC-) specific drugs bisindolylmaleimide and phorbol
      ester (PMA) neither mimicked nor prevented the action of BAPTA. The less specific
      kinase inhibitor staurosporine, however, augmented Ca2+ currents similarly to
      BAPTA, but without affecting the voltage sensitivity. The BAPTA-mediated shift in
      voltage sensitivity was partially suppressed by non-hydrolysable analogs of GTP
      (GDP[beta-S] and GTP[gamma-S]). Lowering [Mg2+]i mimicked the BAPTA-induced shift
      in voltage sensitivity and prevented further shifts in voltage sensitivity by
      BAPTA. The results demonstrate that BAPTA and EGTA, despite their similarities in
      terms of Ca2+ buffering, have disparate effects on the voltage dependence of Ca2+
      channels and careful selection of the chelator is required to quantitatively
      assess Ca2+ currents.

PMID- 10650998
TI  - Electrogenic Ca2+ entry in the rat colonic epithelium.
AB  - Capacitative Ca2+ entry in isolated rat colonic crypts was induced by dialysing
      the cells in the whole-cell patch-clamp mode with a pipette solution having a
      high Ca(2+)-buffering capacity. Under these conditions crypt cell resting
      potential was lower than normal. Flufe-namate, La3+ and Gd3+, blockers of non
      selective cation channels, hyperpolarized the crypt cells and decreased membrane
      current. This current exhibited a cation selectivity of Na+>Ca2+. In contrast to
      Na+, Ca(2+) inhibited the current at concentrations exceeding 1 mmol/l. Indirect
      evidence suggests that the non-selective cation conductance is activated after
      stimulation of muscarinic receptors. Carbachol, a cholinergic agonist, evoked a
      transient hyperpolarization and an increase in membrane outwards current. The
      half-time of the decay of the carbachol response was shortened strongly in the
      presence of La3+. Fura-2 experiments with isolated crypts confirmed that La3+
      inhibited the carbachol-induced increase in intracellular Ca2+. In parallel
      Ussing chamber experiments, La3+ suppressed the induction of Cl- secretion by
      carbachol. These results demonstrate that a non-selective cation conductance
      activated by store depletion may be involved in the regulation of electrolyte
      transport by agonists of the Ca2+ signalling pathway.

PMID- 10650999
TI  - Evidence for Na+/Ca2+ exchange in the rectal gland of Squalus acanthias.
AB  - Previously we have shown that stimulation of in vitro perfused rectal gland
      tubules (RGT) of the dog-fish Squalus acanthias by adenosine 3',5'-cyclic
      monophosphate (cAMP), (as a cocktail comprising 0.1 mmol/l dibutyryl-cAMP, 10
      micromol/l forskolin and 0.1 mmol/l adenosine, hereafter termed STIM) leads to an
      increase in cytosolic Ca2+ ([Ca2+]i) and that this assists Cl- secretion by
      enhancing basolateral K+ conductance. In the present study we examined the
      mechanism of the cAMP-induced increase in [Ca2+]i. [Ca2+]i was measured using the
      fura-2 technique in isolated in vitro perfused RGT. As before, STIM enhanced
      [Ca2+]i. This elevation of [Ca2+]i was prevented completely when STIM was added
      in the presence of the Na+2Cl-K+ cotransport inhibitor furosemide (0.5 mmol/l).
      This suggests that the increase in [Ca2+]i induced by STIM is caused by a
      concomitant increase in cytosolic Na+ ([Na+]i) and not by the activation of
      second messenger cascades. Furosemide prevents this increase in [Na+]i and hence
      the elevation of [Ca2+]i. Moreover, the plateau phase of the [Ca2+]i transient
      produced by carbachol (CCH, 0.1 mmol/l) was augmented strongly when bath Na+ was
      reduced to 5 mmol/l. These data suggest that the level of [Ca2+]i is determined
      by Na(+)-dependent Ca2+ export, most likely via a Na+/Ca2+ exchanger. The
      increase in [Na+]i accompanying stimulation of Cl- secretion reduces the rate of
      Ca2+ export leading to an elevation of [Ca2+]i, as does a reduction in bath Na+
      which augments the [Ca2+]i plateau produced by CCH.

PMID- 10651000
TI  - Passive stretch modulates denervation induced alterations in skeletal muscle
      myosin heavy chain mRNA levels.
AB  - The effect of denervation and denervation combined with immobilisation in either
      the shortened or lengthened position (passive stretch) upon myosin heavy chain
      (MyHC) mRNA levels was examined in three rat hind-limb muscles with differing
      phenotypes. Denervation alone caused a reduction in type I and type IIa MyHC
      transcripts in all three muscles. In contrast denervation caused a 72% increase
      in type IIb in the slow postural soleus muscle only which was prevented by
      immobilisation in the lengthened position. In the same muscle passive stretch
      also significantly retarded the effects of denervation upon the type I transcript
      (from 38% below control levels to 24% below) and type IIa transcript (from 59% to
      32% below control levels). The levels of both type I and IIa transcripts, in the
      fast phasic plantaris muscle, were both unaffected by stretch combined with
      denervation when compared to denervation alone. In the mixed gastrocnemius muscle
      stretch affected the level of the type I but not the type IIa transcript. These
      data suggest that passive stretch can modulate MyHC gene expression independently
      of innervation but that it does so in a muscle-specific manner.

PMID- 10651001
TI  - Evidence for the involvement of K+ channels and K(+)-Cl- cotransport in the
      regulatory volume decrease of newborn rat cardiomyocytes.
AB  - In order to delineate ion transport mechanisms involved in volume homeostasis of
      freshly isolated newborn rat ventricular myocytes, we investigated the effects of
      ion substitutions and pharmacological maneuvers upon (1) isotonic volume, (2)
      hypotonically induced initial swelling, and (3) the subsequent regulatory volume
      decrease (RVD), as determined by electronic cell sizing. Cardiomyocytes exposed
      to hypotonic medium (176 mosmol/l) swelled by 51+/-1% of isotonic volume, and
      they underwent a partial regulatory volume decrease (RVD), reaching a maximum
      regulation after 30 min (51+/-1% of initial swelling), with a half-time (t1/2) of
      6+/-1 min (n=60). RVD was associated with significant cardiomyocyte K+ loss (12+/
      4% at 5 min and 15+/-2% of isotonic control after 30 min: n=6, P<0.001), 71% of
      which was Cl- dependent (P<0.05). Within the 30-min experimental time frame,
      ouabain, a Na+/K+ pump inhibitor, had no significant effect on RVD (despite an
      inhibitory trend), cell swelling or on isotonic volume (n=6). Bumetanide (50
      microM), a Na+-K+-Cl- co-transport blocker, induced a significant reduction of
      isotonic cell volume (3+/-2%, n=6. P<0.05), potentiated initial swelling by 16+/
      1% (n=8, P<0.02), and it partially inhibited RVD (24+/-11% at 30 min, n=6),
      whereas Na+ omission had no significant effect on isotonic cell volume, cell
      swelling or RVD. The effects of bumetanide on initial swelling and RVD were
      prevented by gadolinium ion (10 microM), a stretch-activated cation channel
      blocker (n=5). Quinidine (500 microM), a non-selective Ca(2+)-activated potassium
      channel blocker with no side-effects on K(+)-Cl(-) cotransport, did not modify
      initial cell swelling, but inhibited RVD (50+/-3% at 5 min, n=9, P<0.01; 22+/-3%
      at 30 min), an effect which was cancelled by external Ca2+ chelation with EGTA
      (n=5), and reproduced by tetraethylammonium (TEA, 20 mM), another K+ channel
      blocker. 4,4'-Diisothiocyanatostilbene 2,2'-disulfonic acid (DIDS, 100 microM), a
      non-selective swelling-activated Cl- channel blocker with marginal side-effects
      on K(+)-Cl(-)cotransport, did not modify initial swelling, but inhibited RVD to
      the same extent as quinidine (42+/-3% at 5 min, and 23+/-3% at 30 min, n=15,
      P<0.05), whereas hypotonic Cl(-)-free solution had no effect on isotonic volume,
      but potentiated initial swelling by 16+/-2% (P<0.05) and fully inhibited RVD
      (n=5, P<0.001). R(+)-[(2-n-Butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H
      inde n-5yl)-oxy] acetic acid) (DIOA, 80 microM), a K(+)-Cl- cotransport blocker
      (with inhibitory potency toward Ca(2+)-activated K+ channels), inhibited 87+/-5%
      of the RVD process at 5 min (P<0.001) and 56+/-16% at 30 min (P<0.001), whereas
      it had a small effect on isotonic volume (+4%, P<0.01) and initial cell swelling
      (+2%, N.S.; n=9). In contrast to quinidine, DIOA was able to inhibit Ca(2+)
      omission-resistant RVD (full inhibition at 5 min, and 56+/-9% at 30 min; P<0.01,
      n=5). In conclusion, our results suggest that at least three distinct ion
      transport mechanisms are involved in the RVD in newborn rat cardiomyocytes: (1)
      K+ and Cl-channels, (2) K(+)-Cl- cotransport, and (3) Na(+)-K(+)-Cl- co
      transport.

PMID- 10651002
TI  - Investigation of a genetically engineered mutant of barnacle troponin C
      containing a central helix deletion.
AB  - To examine the importance of the central alpha-helix of troponin C (TnC) we have
      bacterially expressed one of the isoforms of barnacle TnC (BTnC2), BTnCWT, but
      without the aspartate residue at position 80 in the central helix (BTnC80-). This
      manipulation is expected to produce an approximately 100 degrees axial rotation
      of the C-domain with respect to the N-domain, and a net charge change of -1.
      BTnC80- mutant was able to restore force to TnC-depleted skinned barnacle
      myofibrillar bundles to a greater extent than wild-type protein (approximately =
      170%). Competition experiments between BTnC80- and BTnC2-4-, a mutant lacking
      both of the calcium-specific sites (sites II and IV), shows that deletion of a
      single amino acid in the central helix results in a protein with increased
      affinity for the thin filament and one that is bound preferentially compared to
      BTnC2-4- when at equimolar concentrations.

PMID- 10651003
TI  - Physiological significance of hyperpolarization-activated inward currents (Ih) in
      smooth muscle cells from the circular layers of pregnant rat myometrium.
AB  - The properties of hyperpolarization-activated current in pregnant rat uterus (17
      19 days gestation) were investigated using microelectrode and patch-clamp
      techniques, and isometric tension recording. The resting membrane potentials were
      -58.4 mV and -48.5 mV in longitudinal and circular muscle cells, respectively.
      Application of hyperpolarizing current pulses produced a time-dependent anomalous
      inward rectification of membrane potential only in circular muscle cells. Under
      voltage-clamp conditions, inward currents (Ih) were activated by long
      hyperpolarizing pulses below -60 mV in circular but not in longitudinal muscle
      cells. Application of extracellular but not intracellular Cs+ reduced the
      amplitude of I(h) in a concentration-dependent manner (an IC50( of 0.15 mM). The
      reversal potential for Ih was -26.2 mV and the slope conductance was 5 nS/pF.
      Changes in [K+]o and [Na+]o shifted the reversal potential, and Ih amplitude
      increased with excess [K+]o and decreased with low [Na+]o. The steady-state
      activation of Ih was well fitted by a Boltzmann equation with a half-activation
      potential of -84.3 mV and a slope factor of 9.6 mV. Time courses of activation
      and deactivation of the current strongly depended on membrane potential, and were
      well fitted by a single exponential function. The activation time constant of Ih
      was dependent on temperature. In isometric tension recording, application of
      extracellular Cs+ to the circular muscles reduced the frequency, but not the
      amplitude, of spontaneous contractions in a concentration-dependent manner. It is
      concluded that in pregnant rat uterus Ih channels are predominantly distributed
      in smooth muscle cells from the circular layer. Since Ih is activated at the
      resting membrane potential, it is likely that this current contributes to the
      maintenance of resting membrane potential and spontaneous activity in circular
      smooth muscle cells of late pregnant rats.

PMID- 10651004
TI  - Gating of alpha3beta4 neuronal nicotinic receptor can be controlled by the loop
      M2-M3 of both alpha3 and beta4 subunits.
AB  - Previous studies have shown that the gating mechanism of alpha3beta4 neuronal
      nicotinic receptors is affected by a residue in the middle of the M2-M3 loop of
      the beta4 subunit. We have extended the study of the same location to the alpha3
      subunit. Bovine alpha3beta4 receptors were mutated in position 268, substituting
      the residue present in wild-type receptors, i.e. leucine in alpha3 and asparagine
      in beta4, for an aspartate. Wild-type and mutated alpha3 and beta4 subunits were
      combined to form four different receptors. We have measured macroscopic currents
      in Xenopus oocytes elicited by nicotine, and related them to surface receptor
      expression measured with an epibatidine-binding essay. We also obtained single
      channel recordings of the receptors to study their kinetic behaviour. The results
      were analysed in terms of an allosteric model with three states. We found that
      the effect of the mutation in the alpha3 subunit on the gating of the receptor
      was similar to the corresponding mutation in the beta4 subunit. The effect when
      both subunits were mutated was additive, suggesting that the contribution of each
      subunit to the gating mechanism is independent.

PMID- 10651005
TI  - Human cytokines modulate arterial vascular tone via endothelial receptors.
AB  - Only a few cytokines have been tested for their possible role in modulating
      vascular function. Moreover, no direct effect of cytokines on vascular tone has
      yet been thoroughly studied. We therefore examined whether a wide range of well
      defined cytokines could directly affect vascular tone in isolated human arterial
      and venous segments from various organs. We found that the cytokines stem cell
      factor (maximal response with 1 mM), granulocyte colony-stimulating factor (0, 1
      mM) and erythropoietin (1 mM) relaxed, while tumor necrosis factor alpha (0.1
      mM), interleukin (IL) 6 (10 mM) and IL-10 (0.1 mM) induced contraction of
      arterial but not of venous segments. The cytokines (maximal concentration tested
      was 1 mM) IL-3, IL-5, IL-13, macrophage colony-stimulating factor and granulocyte
      macrophage colony-stimulating factor had no apparent effects on either arterial
      or venous tone. These vascular effects were endothelium-dependent as denuded
      arteries did not respond to any cytokine, and inhibition of nitric oxide synthase
      or endothelin receptor A abrogated the cytokine-induced changes in vascular tone.
      With immunohistochemistry we found receptors for the active cytokines on the
      arterial endothelium. In conclusion, several cytokines may modulate arterial
      vascular tone via endothelium-dependent mechanisms. Therefore cytokines might
      significantly modify blood supply to inflamed or ischemic tissues with elevated
      local concentrations of cytokines.

PMID- 10651007
TI  - Transient expression of an inwardly rectifying potassium conductance in
      developing inner and outer hair cells along the mouse cochlea.
AB  - Inwardly rectifying K+ currents in inner and outer hair cells (IHCs, OHCs) were
      studied during post-natal development of the mouse cochlea. Hyperpolarizing steps
      from a holding potential of -64 mV induced a rapidly activating current in both
      cell types. This current showed strong inward rectification around the K+
      equilibrium potential and, at potentials negative to -130 mV, partial
      inactivation. The activation range varied with extracellular K+ concentration.
      External application of Ba2+ and Cs+ reversibly blocked the elicited current. The
      results are consistent with the presence of an IK1-type inwardly rectifying
      potassium conductance in these cells. The maximum current was 60% larger in IHCs
      than in OHCs. In OHCs, but not IHCs, the amplitude of IK1 varied significantly
      with the cells' position along the cochlea. IK1 was maximal in cells located in
      the most basal region of the cochlea and its amplitude decreased in the apical
      coil. IK1 disappeared upon functional maturation: in OHCs at the end of the first
      postnatal week, and in IHCs at the onset of auditory function 12 days after
      birth. The current is active at the resting potential of the cells and plays a
      role in regulating the spiking behaviour characteristic of developing hair cells.

PMID- 10651006
TI  - Membrane potential and conductance of frog skin gland acinar cells in resting
      conditions and during stimulation with agonists of macroscopic secretion.
AB  - Frog skin glands were stripped of connective tissue and investigated using the
      nystatin-permeabilized whole-cell patch-clamp configuration. The membrane
      potential in unstimulated acinar cells was -69.5+/-0.7 mV, and the conductance
      was dominated by K+, based on ion substitution experiments. The cells were
      electrically coupled through heptanol- and halothane-sensitive gap junctions.
      During application of gap junction blockers, the whole-cell current/voltage
      relationship displayed strong outward rectification. Outward currents were
      blocked by barium. Stimulation by agonists known to cause increases in either
      cytosolic cAMP ([cAMP]c) (isoproterenol, prostaglandin E2, both at 2 microM) or
      free cellular Ca2+ concentration ([Ca2+]c) (noradrenaline, 10 microM, added with
      propranolol, 5 microM; carbachol, 100 microM) in the frog skin glands caused
      reversible depolarization: by 34+/-3 mV, 36+/-3 mV, 25+/-3 mV (plateau-phase),
      and 20+/-3 mV, respectively. Ion substitution experiments showed that stimulation
      through either pathway (cAMP or Ca2+) resulted in the activation of a Cl-
      conductance. Application of noradrenaline or adrenaline resulted in a faster
      depolarization (rates 22 mV/s, 26 mV/s) than stimulation by isoproterenol or
      prostaglandin E2 (5.6-5.7 mV/s). Cells that were depolarized by exposure to
      isoproterenol or prostaglandin E2 partially repolarized when stimulated by
      noradrenaline. The repolarization was blocked by Ba2+ (5 mM) or prazosine (1
      microM), consistent with the activation of Ca(2+)-dependent K+ channels via
      alpha1-adrenergic receptors. We conclude that in the frog skin gland both Ca(2+)
      dependent and cAMP-dependent Cl- channels are present in the apical membrane.
      Increases in free [Ca2+]c in the cAMP-stimulated gland results in the activation
      of K+ channels, thereby increasing the driving force for Cl- exit.

PMID- 10651008
TI  - Barium decreases endothelium-dependent smooth muscle responses to transient but
      not to more prolonged acetylcholine applications.
AB  - The influence of inhibiting the inward rectifier and Na/K pump on endothelium
      dependent hyperpolarizations in smooth muscle cells of the mesenteric artery was
      investigated. Membrane potential was measured with microelectrodes, and the
      influence of low concentrations of Ba2+ (30 microM) and of high concentrations of
      ouabain (0.5 mM) on smooth muscle hyperpolarization elicited by prolonged or by
      transient exposure to acetylcholine (ACh, 3x10(-7) M) was assessed in the
      continuous presence of NG-nitro-L-arginine (100 microM) and indomethacin (50
      microM). Pre-exposure to Ba2+ did not inhibit the magnitude of smooth muscle cell
      hyperpolarization induced by ACh superfusion, but significantly slowed its onset
      and time course. The membrane potential response to transient ACh applications,
      however, was impaired. After combined Ba2+ and ouabain pre-exposure, peak
      hyperpolarizations to ACh superfusion were somewhat decreased but not abolished.
      In addition, 4-5 mM increases of the extracellular K+ concentration consistently
      depolarized smooth muscle cells. These findings argue against the idea that
      smooth muscle inward rectifier K+ channels and Na/K pumping play a role in the
      ACh-induced endothelium-dependent hyperpolarization of this preparation.
      Moreover, the slowing of smooth muscle membrane hyperpolarization by Ba2+ is
      discussed in terms of the influence of this ion on the release of hyperpolarizing
      factor.

PMID- 10651009
TI  - Effect of the nicotine metabolite 5'-hydroxycotinine on glucose transport and
      glycogen synthase activity in rat skeletal muscle.
AB  - Cigarette smoke contains many potentially harmful substances, including nicotine
      and nicotine metabolites, which are likely to contribute to altered glucose
      homeostasis. We determined the effects of nicotine and nicotine derivatives on
      glucose transport in skeletal muscle. Split rat soleus muscles were pre-incubated
      in the presence of nicotine (range 0.01-100 microg/ml) or nicotine metabolites
      including nicotine 1'-N-oxide, cotinine, trans-3'-hydroxycotinine, 5'
      hydroxycotinine, gamma-3-pyridyly-oxo-butyric acid and nicotine iminium ion
      before measurement of 3-O-methylglucose transport rate and glycogen synthase
      activity. Nicotine (100 microg/ml) did not alter basal 3-O-methylglucose
      transport. Insulin-stimulated (0.6 nmol/l) glucose transport was unaltered
      following acute (50 min) exposure to nicotine (0.01-100 microg/ml). The nicotine
      metabolite 5'-hydroxycotinine increased basal glucose transport and glycogen
      synthase activity (up to 50%; P<0.05), with no effect on insulin-stimulated
      glucose transport and glycogen synthase activity. None of the other nicotine
      metabolites had any effect on basal or insulin-stimulated glucose transport.
      Acute exposure of skeletal muscle to the nicotine derivative 5'-hydroxycotinine
      appears to directly increase basal glucose transport and metabolism. Whether this
      leads to changes in whole-body glucose homeostasis in cigarette smokers requires
      further investigation.

PMID- 10651010
TI  - Decrease of subcutaneous adipose tissue lipolysis after exposure to hypoxia
      during a simulated ascent of Mt Everest.
AB  - The purpose of this study was to examine the effects of prolonged hypoxia on
      adipose tissue lipolysis, in relation to the weight loss usually observed at high
      altitude. Eight male subjects were exposed for 31 days to gradually increasing
      hypobaric hypoxia up to the equivalent altitude of 8848 m (Mt Everest) in a
      decompression chamber, after 7 days at 4350 m for altitude pre-acclimatization. A
      biopsy of subcutaneous adipose tissue was performed before and after hypoxic
      exposure, to study in vitro changes in adipose tissue sensitivity. Fat mass,
      adipocyte volume and spontaneous lipolysis were not impaired by the exposure to
      hypoxia. The in vitro lipolytic response to epinephrine, isoproterenol, growth
      hormone (GH) and parathormone (PTH) decreased significantly (P<0.01, P<0.05,
      P<0.01 and P<0.01 respectively), as did the plasma concentration of free fatty
      acid (P<0.01). The anti-lipolytic effect promoted by alpha2-adrenergic receptor
      stimulation (epinephrine with propranolol) was greater after hypoxia (P<0.05),
      while the anti-lipolytic activity of insulin was decreased (P<0.01). In
      conclusion, prolonged exposure to hypobaric hypoxia led to a potent reduction in
      lipid mobilization, through a decrease in the efficiency of beta-adrenergic, GH
      and PTH lipolytic pathways, as well as an increment in the alpha2-adrenergic
      receptor-mediated anti-lipolytic effects.

PMID- 10651012
TI  - Effects of naloxone on the haemodynamic and renal functional responses to plasma
      volume expansion in conscious rabbits.
AB  - We tested whether the opioid antagonist naloxone affects responses to plasma
      volume expansion (PVE) in conscious rabbits. Under basal conditions, naloxone (6
      mg x kg-(1) plus 0.3 mg x kg(-1) x min(-1) i.v.) had no observable effect, except
      to slightly reduce heart rate. During vehicle treatment, PVE (Haemaccel; 1 ml x
      kg(-1) min(-1) for 30 min plus 0.2 ml x kg(-1) x min(-1) for 60 min i.v.) reduced
      haematocrit by 7.1+/-0.8% (from 34.8+/-1.1%), and increased central venous
      pressure by 3.0+/-0.9 mmHg (from -2.8+/-1.5 mmHg), cardiac output by 42+/-9 ml
      min(-1) x kg(-1) (from 152+/-17 ml x min(-1) x kg(-1)), systemic vascular
      conductance by 0.49+/-0.11 ml x min(-1) x mmHg(-1) kg(-1) (from 1.58+/-0.23 ml x
      min(-1) x mmHg(-1) x kg(-1)), urine flow by 0.13+/-0.04 ml x kg(-)x min(-1) (from
      0.12+/-0.02 ml kg(-1) x min(-1)) and sodium excretion by 21+/-5 micromol x kg(-1)
      min(-1) (from 5+/-2 micromol x kg(-1) x min(-1)). During naloxone treatment, the
      PVE-induced changes in haematocrit and central venous pressure were similar to
      those during vehicle treatment, but the increases in cardiac output (24+/-7 ml
      kg(-1) min(-1)), systemic vascular conductance (0.25+/-0.05 ml min(-1) x kg(-1) x
      mmHg(-1)), urine flow (0.09+/-0.03 ml x kg(-1) min(-1)) and sodium excretion
      (11+/-4 micromol x kg(-1) x min(-1)) were 31-49% less. These observations
      indicate that endogenous opioids mediate some of the circulatory and renal
      excretory responses to PVE in conscious rabbits.

PMID- 10651011
TI  - Allosteric effects of mutations in the extracellular S5-P loop on the gating and
      ion permeation properties of the hERG potassium channel.
AB  - The hERG channel has an unusually long (39 amino acids) extracellular loop
      between the transmembrane S5 segment and the pore region that may play a role in
      channel function. We explored this possibility by mutating two histidine residues
      in this region (H578 and H587, referred to as H1 and H2) to various residues and
      examined the resulting changes in channel function. Both positions could tolerate
      drastic changes in side-chain properties (proline, cysteine, glutamate and
      lysine), indicating that they are solvent exposed. None of the H1 mutations
      affected hERG channel function. On the other hand, although replacing H2 with
      glutamate had little or no effect on hERG properties, putting a proline or lysine
      at this position disrupted the C-type inactivation process and the pore's K
      selectivity. There was also a hyperpolarizing shift in the voltage dependence of
      activation. The phenotype of the H2C mutant was similar to that of H2P or H2K.
      However, dithiothreitol (DTT, a thiol-reducing agent) treatment converted the H2C
      phenotype to that of the wild-type channel. These observations suggest that the
      peptide backbone conformation around position 587 in the extracellular S5-P loop
      of hERG channel can affect the channel's gating and ion selectivity functions.

PMID- 10651013
TI  - 1-EBIO stimulates Cl- secretion by activating a basolateral K+ channel in the
      mouse jejunum.
AB  - We investigated the effects of 1-ethyl-2-benzimidazolinone (1-EBIO) on ion
      transport in the mouse jejunum through the use of the short-circuit (Isc) current
      technique and the application of the patch-clamp technique to isolated jejunal
      crypts. In HCO3- Ringer's, 1-EBIO stimulated a dose-dependent (EC50 964
      micromol/l), bumetanide-sensitive increase in Isc consistent with stimulation of
      Cl- secretion. In contrast, in Cl(-)-free HCO3-Ringer's containing glucose, 1
      EBIO (500 micromol/l) did not increase the phloridzin (100 micromol/l) sensitive
      Isc, suggesting that electrogenic Na+ absorption was unaltered. Measurement of
      the membrane potential (Vm) with the perforated-patch technique indicated that in
      isolated crypts, 1-EBIO caused a reversible hyperpolarization of Vm and an
      increase in the change in Vm associated with step changes in bath K+, consistent
      with an increase in K+ conductance. In on-cell patch experiments with KCI
      Ringer's in the patch pipette and crypts bathed with NaCl Ringer's, 1-EBIO (500
      micromol/l) increased the open probability (NPo; 0.01+/-0.01 to 0.45+/-0.11, n=7)
      of an inwardly rectified intermediate conductance (g) channel. In inside-out
      patches with KCl Ringer's in the patch pipette and KCI Ringer's containing 100
      nmol/l Ca2+ in the bath, the current-voltage relationship of the channel was
      inwardly rectified (g of 10 and 52 pS at -Vp of 100 and -100 mV, respectively)
      and reversed at 0 mV (n=5). Replacement of bath K+ with Na+ shifted the reversal
      potential toward the equilibrium potential for K+. In the presence of 1-EBIO,
      reducing the bath Ca2+ from 200 nmol/l to nominally Ca(2+)-free conditions
      decreased NPo from 0.90+/-0.27 to 0.07+/-0.03 (n=3). We conclude that in the
      mouse jejunum, I-EBIO does not stimulate electrogenic Na+ absorption. It does,
      however, stimulate secretion primarily through the activation of a basolateral,
      intermediate conductance Ca(2+)-sensitive K+ channel.

PMID- 10651014
TI  - Parathyroid hormone-related protein is rapidly up-regulated in blood vessels of
      rat skeletal muscle by low-frequency stimulation.
AB  - To identify early changes in gene expression of fast-twitch rat muscle exposed to
      chronic low-frequency stimulation, differential display was applied comparing
      mRNA patterns between control and 12-h stimulated tibialis anterior (TA) muscles.
      Among the signals of differentially expressed mRNAs, a cDNA of approximately 300
      bp was identified as specific to the parathyroid-hormone-related protein (PTHrP).
      As verified by semi-quantitative reverse transcriptase polymerase chain reaction,
      this mRNA was present at low levels in normal slow-twitch soleus and fast-twitch
      TA muscles, but was approximately 80-fold elevated in TA muscles after 12 h of
      low-frequency stimulation. With ongoing stimulation for 2 or 4 days PTHrP mRNA
      returned to basal levels. PTHrP was located exclusively in blood vessels of both
      control and stimulated muscles. PTHrP immunohistochemistry revealed enhanced
      capillarization in 8-day stimulated muscles. In view of its vasodilative effect
      the up-regulation of PTHrP could be an important initial step related to enhanced
      capillarization in response to increased contractile activity.

PMID- 10651015
TI  - A bumetanide-sensitive, apically localized Na+2Cl-K+ cotransport in the rat inner
      medullary collecting duct.
AB  - To better characterize loop diuretic-sensitive ion fluxes in the inner medullary
      collecting duct (IMCD) we examined them in IMCD cells grown as a primary culture
      on permeable supports. A polarization of the cells with their basolateral side to
      the support was confirmed morphologically by electron microscopy and functionally
      by flux studies with ouabain. Within 7 days cells developed a transepithelial
      resistance of 974+/-52 omega per cm2 and a low transepithelial potential
      difference (-0.7+/-0.8 mV). Measurements of intracellular ion content by electron
      probe microanalysis in IMCD depleted of intracellular ions by preincubation in a
      Na(+)-K(+)-Cl(-)-free medium revealed, compared to the control receiving solvent,
      significant reductions in intracellular Na+ content (-17.6% within 10 min) and
      intracellular Cl- content (-43.8% within 30 min) by the addition of bumetanide
      (10(-4) mol/l) to the apical but not basolateral incubation medium. In 22Na+ and
      86Rb+ isotope uptake studies, fluxes from the apical side were significantly
      inhibited at bumetanide concentrations of 100 micromol/l by 0.27+/-0.10 and
      0.21+/-0.04 nmol/cm2 in 10 min, respectively, whereas basolateral fluxes of 86Rb+
      but not 22Na+ were significantly reduced by this substance. Removal of Cl- had a
      similar but not additional effect. mRNA encoding the apical isoform of the
      Na+2Cl(-)K+ cotransporter could be specifically amplified by reverse
      transcriptase polymerase chain reaction from the inner medulla and highly
      purified IMCD cells. Northern blot of mRNA isolated from the inner medulla with a
      riboprobe of the apical isoform revealed a transcript of approximately 4.9 kb.
      This probe localized under "low-stringency" conditions to the IMCD in in situ
      hybridization studies. These results suggest the presence of an apically
      localized isoform of bumetanide-sensitive Na+2Cl(-)K+ cotransport in at least a
      subfraction of IMCD cells. This transport may be involved in the ultimate
      adjustment of urinary electrolyte concentration by this final segment of the
      tubular system.

PMID- 10651016
TI  - Human chorionic gonadotropin dilates uterine and mesenteric resistance arteries
      in pregnant and nonpregnant rats.
AB  - Membrane receptors for human chorionic gonadotropin (hCG) are expressed in a
      variety of steroidogenic cells, and also in extragonadal tissues such as vessels
      of the female genital tract. We examined the possible contribution of hCG to the
      endocrine control of prearteriolar mesenteric and uterine vessels before and
      during pregnancy. Lumen diameters of isolated pressurized resistance arteries
      from Sprague-Dawley rats were measured using a video-electronic system. hCG
      produced marked and dose-dependent vasodilation. Uterine radial arteries were
      found to be highly sensitive to hCG (EC50 approximately =60 mU/ml) before and
      throughout gestation. Second-order mesenteric arteries from nonpregnant animals
      were even more sensitive (EC50=38 mU/ml), but, in these vessels, responsiveness
      to hCG was significantly attenuated by the pregnant state. Mechanical removal of
      the vascular endothelium did not reduce the degree of vasodilation mediated by
      hCG. The expression of hCG receptor mRNA in intact vessels could be demonstrated
      using reverse transcriptase polymerase chain reaction (RT-PCR). hCG appears to be
      an important embryonic signal, which could trigger adaptive cardiovascular
      changes in early pregnancy, simultaneously preserving a sufficient utero
      placental perfusion during the entire gestation period by an endothelium
      independent mechanism.

PMID- 10651017
TI  - Influence of NaCl, urea, potassium and pH on HSP72 expression in MDCK cells.
AB  - The renal inner medulla is characterised by elevated extracellular concentrations
      of NaCl, urea, potassium and hydrogen ions, an environment that may affect cell
      viability negatively. High amounts of HSP72, a stress protein allowing cells to
      resist harmful situations, are also observed in this region. The present study
      examined HSP72 induction by various medullary stress factors, individually or in
      combination, in MDCK cells, a renal epithelial cell line expressing
      characteristics of the medullary collecting duct. MDCK cells were incubated for 3
      days in media containing elevated concentrations of NaCl, urea, potassium and
      hydrogen ions individually or in combination. HSP72 mRNA and protein expression
      were determined by Northern and Western blot analyses, respectively. HSP72
      expression was enhanced moderately by addition of 50 mM NaCl to normal medium at
      pH 7.4 but enhanced strongly when added at pH 6.5. The latter degree of HSP72
      induction was comparable to that observed when 150 mM NaCl was added at pH 7.4.
      In normal medium (pH 7.4) containing 300 mM urea, MDCK HSP72 expression was not
      different from controls. In contrast, urea-induced HSP72 expression was clearly
      evident when medium pH was lowered to 6.5. Potassium at 20 or 40 mM induced HSP72
      only slightly. These results indicate that expression of HSP72 in renal
      epithelial cells is regulated synergistically by NaCl, urea and pH. Since HSP72
      is only slightly induced by increased potassium, this probably reflects the
      changes in medium osmolality rather than a specific effect of potassium. The high
      medullary HSP72 content observed even in diuresis may be due to co-operative
      effects of medullary solutes on HSP72 expression.

PMID- 10651018
TI  - Two-photon Na+ imaging in spines and fine dendrites of central neurons.
AB  - Dendritic spines are assumed to be the smallest units of neuronal integration.
      Because of their miniature size, however, many of their functional properties are
      still unclear. New insights in spine physiology have been provided by two-photon
      laser-scanning microscopy which allows fluorescence imaging with high spatial
      resolution and minimal photodamage. For example, two-photon imaging has been
      employed successfully for the measurement of activity-induced calcium transients
      in individual spines. Here, we describe the first application of two-photon
      imaging to measure Na+ transients in spines and dendrites of CA1 pyramidal
      neurons in hippocampal slices. Whole-cell patch-clamped neurons were loaded with
      the Na(+)-indicator dye SBFI (sodium-binding benzofuran-isophthalate). In situ
      calibration of SBFI fluorescence with ionophores enabled the determination of the
      actual magnitude of the [Na+]i changes. We found that back-propagating action
      potentials (APs) evoked Na+ transients throughout the proximal part of the
      dendritic tree and adjacent spines. The action-potential-induced [Na+]i
      transients reached values of 4 mM for a train of 20 APs and monotonically decayed
      with a time constant of several seconds. These results represent the first
      demonstration of activity-induced Na+ accumulation in spines. Our results
      demonstrate that two-photon Na+ imaging represents a powerful tool for extending
      our knowledge on Na+ signaling in fine cellular subcompartments.

PMID- 10651019
TI  - A stop-flow microperfusion technique for rapid determination of HCO3-
      absorption/H+ secretion by isolated renal tubules.
AB  - In the present experiments on microdissected tubules of rabbit kidney we present
      a refined stop-flow method for determining the rate of HCO3- absorption (J(HCO3))
      or H+ secretion (JH) that can be applied to isolated microperfused tubules. Using
      the pH-sensitive indicator dye BCECF (2',7'-bis [2-carboxyethyl]-5[6]
      carboxyfluorescein) the luminal perfusate pH is continuously measured with a
      microspectrofluorometric set-up, and the pH change following a sudden stop of
      perfusion is analysed. Because the tubules partially collapse after stop-flow the
      calculation of fluxes requires a correction for volume loss. This is achieved by
      referring all fluxes to the remaining luminal volume, which can be estimated from
      the decay of the 440 nm reference fluorescence. During perfusion of the lumen
      with pure HCO3- Ringer solution, and of the bath with the same solution but
      containing 5.5 mmol/l D-glucose as metabolic substrate, J(HCO3) averaged 4.4+/
      0.2 pmol cm(-1) x s(-1) (n=40) and 13.4+/-0.8 pmol x cm(-1) x s(-1) (n=5) in
      proximal straight tubules (PST) and in proximal convoluted tubules respectively.
      These values agree very well with data obtained in other laboratories with the
      picapnotherm technique. The present method has the advantage of requiring fewer
      micromanipulations and a shorter measuring time, thus allowing regulatory changes
      in J(HCO3) to be analysed. Moreover it does not involve measurements of
      radioactivity, and it also allows J(H) to be measured in HCO3(-) free solutions
      which in PST averaged 0.9 pmol x cm(-1) x s(-1) (n=8) in the present experiments.

PMID- 10651020
TI  - APO2L/TRAIL expression in human brain tumors.
AB  - APO2 ligand (APO2L)/TRAIL is a novel member of the tumor necrosis factor cytokine
      family and a potent inducer of apoptosis in tumor cell lines. We recently
      reported that APO2L is consistently expressed in low-grade astrocytomas,
      anaplastic astrocytomas, glioblastomas, and cell lines derived thereof, and that
      malignant glioma cell lines are susceptible to APO2L-induced apoptosis. In this
      study, we investigated whether APO2L is expressed in medulloblastoma or
      neuroblastoma cell lines and whether these cells are sensitive to APO2L-induced
      apoptosis. Immunoblot analyses revealed full-length APO2L protein expression in
      one (DAOY) of three medulloblastoma cell lines but not in two neuroblastoma cell
      lines (SKN-BE and SKN-LE). Viability assay performed after exposure to soluble
      APO2L for 16 h showed that DAOY medulloblastoma cells were the most sensitive and
      that apoptosis induced by APO2L was greatly enhanced when protein synthesis was
      inhibited by cycloheximide. Neuroblastoma cell lines were almost completely
      resistant to APO2L-induced apoptosis. We also carried out APO2L
      immunohistochemistry in a total of 115 tumors of the nervous system with
      different histogenesis and biological behavior. In all 9 pilocytic astrocytomas,
      the areas of dense fibrillary network showed diffuse and strong APO2L expression.
      In oligodendrogliomas, APO2L expression was observed in areas with a significant
      admixture of astrocytic cells, but was absent in neoplastic oligodendrocytes. In
      13 of 14 ependymomas, APO2L was expressed in perivascular pseudorosettes. In all
      12 medulloblastomas, strong APO2L expression was observed in intra-tumoral
      reactive astrocytes, but neoplastic cells did not show APO2L immunoreactivity.
      Thus, the pattern of APO2L expression was largely similar to that of glial
      fibrillary acidic protein (GFAP), except for choroid plexus tumors and 3 of 8
      anaplastic meningiomas, in which APO2L was focally expressed without concomitant
      GFAP expression. APO2L expression was absent in meningiomas, neurocytomas, and
      schwannomas. Thus, there is considerable heterogeneity of APO2L expression and
      susceptibility to APO2L-induced apoptosis among human brain tumors.

PMID- 10651021
TI  - Two autopsy cases with Pelizaeus-Merzbacher disease phenotype of adult onset,
      without mutation of proteolipid protein gene.
AB  - We report the autopsy cases of two brothers which are pathologically compatible
      with Pelizaeus-Merzbacher disease (PMD). Both patients had a late onset (at the
      ages of 29 and 42 years) and chronic neurological symptoms including tremor,
      ataxia and dementia. The T2-weighted magnetic resonance imaging of the younger
      brother demonstrated increased signal areas with sparing of small areas in the
      cerebral white matter. The postmortem examinations, obtained at the ages of 45
      and 61 years, showed similar neuropathological findings. Histologically, a
      cardinal finding was a lack of myelin in large parts of white matter with the
      preservation of islands of intact myelin, resulting in a "tigroid" appearance.
      Only small amounts of sudanophilic material were present. The axons were
      relatively well preserved, but oligodendrocytes were numerically reduced.
      Ultrastructurally, myelin sheaths in the white matter were markedly thin.
      Immunohistochemistry showed that proteolipid protein (PLP) was reduced in the
      affected white matter. However, genetic studies did not reveal exonic mutations
      or duplications of the PLP gene. We conclude that the two cases are a rare type
      of dysmyelinating disorder with PMD phenotype of adult onset and could be caused
      by previously unrecognized abnormalities of the PLP gene or other genes.

PMID- 10651022
TI  - NACP/alpha-synuclein-positive filamentous inclusions in astrocytes and
      oligodendrocytes of Parkinson's disease brains.
AB  - The precursor of the non-Abeta component of Alzheimer's disease amyloid (NACP),
      also called alpha-synuclein, is a major component of Lewy bodies in Parkinson's
      disease (PD) as well as of neuronal and oligodendroglial cytoplasmic inclusions
      in multiple system atrophy. We previously reported argyrophilic, tau-negative
      glial inclusions in the midbrains of patients with PD and have now conducted
      immunocytochemical and ultrastructural examinations. The PD glial inclusions also
      are immunoreactive for NACP/alpha-synuclein, but not for beta-synuclein, and
      ultrastructurally are composed of filamentous structures about 25-40 nm in
      diameter. Double immunolabeling showed that the inclusions were present in both
      astrocytic and oligodendroglial cells. They were located within the substantia
      nigra in 13 of 30 patients with PD and outside the nigra in 24. The number of
      inclusions was correlated with the severity of nigral neuronal loss. These
      findings indicate that abnormal accumulation of NACP/alpha-synuclein in glial
      cells is a pathological feature of PD related to its progression.

PMID- 10651023
TI  - Molecular analysis for p53 and mdm2 in intracranial germ cell tumors.
AB  - Intracranial germ cell tumors (ICGTs) are uncommon neoplasms. The histological
      appearance of ICGTs is indistinguishable from that of the usual testicular germ
      cell tumors (TGTs). Recently, several reports have associated molecular
      abnormalities of p53 and mdm2 in TGTs with their malignancies. However, whether
      ICGTs are associated with molecular abnormalities is still unknown. We analyzed a
      series of 16 ICGTs for mutations in the TP53 gene by single-strand conformation
      polymorphisms, and for amplification of the MDM2 gene using differential PCR. In
      addition, the same 16 tumors were examined for p53 and mdm2 protein
      overexpression using antibodies directed against p53 [monoclonal antibodies (mAb)
      1801 and DO7] and mdm2 (IF2), respectively. Twelve (75%) and 2 (13%) of the 16
      ICGTs reacted with DO7 and PAb1801, respectively, and 1 (6%) carried a TP53 gene
      mutation. Thirteen (81%) of the 16 ICGTs reacted with IF2, and 3 (19%) carried
      MDM2 gene amplification. The less frequent TP53 gene mutation compared with MDM2
      gene amplification, and the frequently expressed p53 and mdm2 protein, are
      similar to the case for TGTs. It is tempting to speculate that ICGTs might have
      the same cellular origins as TGTs with abnormalities in p53 and mdm2, which could
      play an important role of tumorigenesis.

PMID- 10651025
TI  - MELAS with the mitochondrial DNA 3243 point mutation: a neuropathological study.
AB  - We performed a neuropathological examination of the central nervous system from
      seven autopsied patients with mitochondrial myopathy, encephalopathy, lactic
      acidosis and stroke-like episodes (MELAS). Five of the seven cases were confirmed
      to have the mitochondrial DNA (mtDNA) 3243 point mutation. In addition to the
      changes reported previously, diffuse atrophy of the cerebral and cerebellar
      cortices, diffuse gliosis of cerebral and cerebellar white matter, and cactus
      formation of Purkinje cells were observed. Electron microscopy revealed
      accumulation of mitochondria in the cactus formations. These lesions are common
      in MELAS with the mtDNA 3243 point mutation, but cannot be explained solely by
      mitochondrial angiopathy, and suggest that intrinsic mitochondrial malfunction
      contributes to neuronal damage in MELAS pathology. Moreover, the pathological
      changes observed in the cerebellum suggest that cerebellar function should be
      evaluated more carefully at the clinical level.

PMID- 10651024
TI  - Cyclooxygenase-2 is induced in microglia during chronic cerebral ischemia in
      humans.
AB  - Cyclooxygenase-2 (COX-2) is known to be up-regulated in ischemic rodent brains,
      but only little information is available for the human brain. Using
      immunohistochemistry for COX-2, we investigated brains from control subjects and
      from patients with cerebrovascular diseases. COX-2 was markedly up-regulated in
      the neurons and endothelial cells in acute cerebral infarction, but was detected
      sparsely at chronic stages in these cellular compartments. In contrast, COX-2
      immunoreactivity in glial cells was localized to the perinuclear region even in
      control brains. This immunolabeling was more intense and occurred also in the
      glial cytoplasm in the brains with chronic cerebral ischemia such as Binswanger's
      disease. Double-labeling immunohistochemistry confirmed that COX-2-immunoreactive
      glia were mostly microglia. These results indicate that prostanoid synthesis is
      up-regulated in microglia during chronic cerebral ischemia, and that these cells
      may be involved in tissue repair or inflammation-mediated cell responses.

PMID- 10651026
TI  - Comparative morphometric evaluation of peripheral nerves and muscle fibers in
      myotonic dystrophy.
AB  - We compared peripheral nerve fibers and muscle fibers in myotonic dystrophy (MD)
      using a computer-assisted device for morphometry. In the 17 cases with MD
      studied, the sural nerves of 14 cases (82%) showed various degrees of reduction
      of the myelin sheath area (MSA) per endoneurial area. Of these, 8 cases (47%)
      presented with a mild reduction of the MSA, 5 cases (29.4%) with moderate
      reduction, and one case (6%) with severe reduction. The number of myelinated
      nerve fibers was not significantly reduced in MD when compared with control
      nerves, due to clusters of small regenerated nerve fibers. The mean diameter of
      the muscle fibers in 6 of the 17 cases was less than 40 microm. Of these 6
      severely affected cases, 5 revealed a considerable reduction of the MSA. Other
      cases, which appeared to be normal in respect to the diameter of muscle fibers,
      showed various degrees of reduction of the MSA. Thus, there is usually, but not
      always a morphometric correlation of the severity of changes between peripheral
      nerves and muscle. The severity of the peripheral neuropathy appears to depend
      largely on the patient's age, the stage of the disorder, and the time of
      progression. Electron microscopic examination of sural nerves showed significant,
      though non-specific pathological changes.

PMID- 10651027
TI  - Cerebellar degeneration in hereditary dentatorubral-pallidoluysian atrophy and
      Machado-Joseph disease.
AB  - We examined the mechanism of cerebellar degeneration in brains obtained at
      autopsy from six cases of hereditary dentatorubral-pallidoluysian atrophy (DRPLA)
      and six cases of Machado-Joseph disease (MJD), using terminal
      deoxynucleotidyltransferase-mediated in situ nick end labeling (TUNEL) and
      immunohistochemistry for apoptosis-related proteins, neurotrophin receptors and
      glutamate transporters. In three subjects with DRPLA, who developed dementia and
      cerebellar ataxia at over 50 years of age, the number of Purkinje cells was
      mildly reduced, TUNEL-positive cells were observed in the molecular layer of the
      cerebellar cortex, and immunoreactivities for calbindin D28K and excitatory amino
      acid transporter-1 (EAAT1) were altered in the molecular layer. In addition, all
      cases of DRPLA showed a reduction of immunoreactivity for EAAT1 in the dentate
      nucleus. In MJD, augmentation of Bcl-x expression by the Purkinje cells, and
      increases in Trk B- and GFAP-immunopositive glial cells in the granular layer
      were observed in half of the cases, whereas immunoreactivity for EAAT-1 was
      preserved both in the cerebellar cortex and dentate nucleus. One case of MJD
      showed TUNEL-positive granular cells in the cerebellar cortex. Age-matched
      control subjects did not show TUNEL-positive cells or immunohistochemical changes
      in the cerebellum. There were neither TUNEL-positive cells nor alteration of the
      in situ expression of apoptosis-related proteins in the dentate nucleus in either
      variant of hereditary spinocerebellar degeneration, although both exhibited
      grumose degeneration in the dentate nucleus. These findings indicate that latent
      degeneration in the cerebellar cortex may occur in DRPLA and MJD, in addition to
      the dentate change, which is the cardinal feature in the neuropathology of these
      two diseases. The lesion of Purkinje cells and their processes in the molecular
      layer associated with altered glutamate transport may be important in DRPLA,
      while the significance of the abnormalities observed in some MJD cases, which
      might be related to apoptotic mechanism, remains unclear.

PMID- 10651028
TI  - Local activation of the complement system in endoneurial microvessels of diabetic
      neuropathy.
AB  - Quantitative immunocytochemical analysis of complement proteins (CP) was
      performed on sural nerve biopsies from 15 patients with diabetic neuropathy (DN)
      and 18 nondiabetic patients with other forms of chronic neuropathy (ON). The mean
      age of the patients and the pathological severity of the neuropathy were similar
      in both groups. The percentage of patients that expressed strongly immunoreactive
      CP in the walls of endoneurial microvessels was significantly greater in DN than
      in ON for all proteins tested. C3d neoantigen was expressed in 100% of DN cases
      compared with 17% of ON; and membrane attack complex (MAC), C5b-9 neoantigen, in
      93% of DN and 17% of ON. In the cases with DN, 81% of endoneurial microvessels,
      as identified by the endothelial marker, Ulex europaeus, contained C5b-9
      neoantigen deposits, compared with 22% in those of ON, and the staining in DN was
      significantly more intense. Expression of the neoantigens of C3d and C5b-9 in
      nerve implies local activation of the complement system. In DN, activation of the
      complement pathway and formation of the MAC could injure blood vessels and
      adversely affect the circulation in the endoneurium.

PMID- 10651029
TI  - Detection of an Amadori product, 1-hexitol-lysine, in the anterior horn of the
      amyotrophic lateral sclerosis and spinobulbar muscular atrophy spinal cord:
      evidence for early involvement of glycation in motoneuron diseases.
AB  - Glycation is a series of non-enzymatic reactions initiated by addition of
      reducing sugars to epsilon-amino group of lysine residues and alpha-amino group
      of the N terminus of proteins, leading to the formation of advanced glycation end
      products (AGE). It is thought to be involved in aging and various
      neurodegenerative conditions. In the present study using anti-1-hexitol-lysine (1
      HL) antibody, Amadori product, an early glycation product, was detected in axonal
      spheroids in the anterior horn of amyotrophic lateral sclerosis and in atrophic
      neurons of spinobulbar muscular atrophy (SBMA, Kennedy disease with abnormally
      expanded triplet repeats in androgen receptor gene) but not in other regions of
      the central nervous system. Furthermore, Amadori product was undetectable in the
      tissues from age-matched controls. Thus, 1-HL formation could not reflect
      physiological aging.

PMID- 10651030
TI  - Schwann cell-onion bulb tumor of the trigeminal nerve: hyperplasia, dysplasia or
      neoplasia?
AB  - Onion bulbs are concentric lamellar structures formed by Schwann or perineurial
      cells, which may be seen in several generalized or localized diseases of the
      peripheral nerve. There is debate regarding the pathogenesis of localized
      tumefactions displaying these microscopic structures. We report the fifth case,
      to our knowledge, of a Schwann cell-onion bulb tumor, which arose in the
      trigeminal nerve of a child with an unclassifiable, probably distinct,
      neurocutaneous syndrome; we also provide evidence for a neoplastic or
      hamartomatous origin. Molecular studies failed to establish an abnormality in the
      NF1, NF2, PMP22, or Connexin 32 genes. Similar and previously reported cases are
      discussed, as well as other onion bulb-forming entities.

PMID- 10651031
TI  - Parkinsonism, dementia and vertical gaze palsy in a Guamanian with atypical
      neuroglial degeneration.
AB  - A 58-year-old Chamorro female patient, who died in 1993, was examined
      clinicopathologically. At the age of 51, she suffered from hemiparkinsonism, then
      bradykinesia, rigidity without tremor, and dementia. Extrapyramidal symptoms
      developed, and at the age of 57, vertical gaze palsy was noted. The clinical
      diagnosis was parkinsonism-dementia complex (PDC) with vertical gaze palsy. The
      brain showed atrophy in the frontal and temporal lobes, and the atrophy was
      accentuated in the dentate gyrus, Ammon's horn and parahippocampal gyrus. The
      basal ganglia, thalamus and midbrain were moderately atrophic. The substantia
      nigra and locus ceruleus were completely depigmented. Numerous neurofibrillary
      tangles (NFTs) were seen in the subiculum and amygdaloid nucleus. Many NFTs were
      evident in the parahippocampal gyrus, lateral occipitotemporal gyrus, insula,
      Sommer sector, basal nucleus of Meynert, lateral nucleus of the thalamus,
      subthalamic nucleus and brain stem, and several were observed in the globus
      pallidus and hypothalamus. The Sommer sector, substantia nigra, locus ceruleus
      and basal nucleus of Meynert showed severe loss of neurons, and a moderate loss
      of neurons was exhibited by the globus pallidus. These findings were apparently
      consistent with those associated with PDC. However, in this patient, severe
      neuronal loss was seen in the subthalamic nucleus and lateral nucleus of the
      thalamus, and grumose degeneration, which has not previously been reported in
      PDC, was seen in the dentate nucleus. In addition, many tufted astrocytes, which
      have been reported to occur in progressive supranuclear palsy (PSP) and
      postencephalitic parkinsonism, but scarcely observed in PDC, were present.
      Furthermore, astrocytic plaques, which have been considered as a specific finding
      of corticobasal degeneration (CBD), were observed in the cerebral cortex. On the
      other hand, granular hazy astrocytic inclusions, previously reported to occur in
      PDC, were not seen. Chromatolytic neurons were not observed. The question thus
      arises as to whether it is appropriate to consider this patient as having
      suffered from a combination of PDC, PSP and CBD. From the view points of absence
      of granular hazy astrocytic inclusions and chromatolytic neurons, and of tufted
      astrocytes in the neostriatum, it is conceivable that this patient is a case of a
      new disease entity.

PMID- 10651032
TI  - Rapidly progressive aphasia and motor neuron disease: a clinical, radiological,
      and pathological study of an autopsy case with circumscribed lobar atrophy.
AB  - This report concerns an autopsy case of rapidly progressive aphasia and motor
      neuron disease. The patient was a Japanese woman who was 75 years old at the time
      of death. The family history did not reveal hereditary burden. She developed
      language disturbances and difficulty in swallowing at age 74. Neurological
      examination 1 month after the disease onset revealed motor aphasia without
      dementia and bulbar sign, followed by muscle weakness of the four extremities.
      Neuroradiological examination revealed progressive atrophy of the anterior part
      of the left temporal lobe. She died of respiratory difficulty 10 months after the
      disease onset. Macroscopically, neuropathological examination showed
      circumscribed atrophy of the left perisylvian region and, histologically,
      neuronal loss in the cerebral cortex, including the primary motor area,
      substantia nigra, brain stem motor nuclei, and anterior horns of the spinal cord,
      in addition to obvious degeneration of the pyramidal tracts and presence of
      Bunina bodies. Ubiquitin-immunoreactive neuronal inclusions were present in the
      hippocampal dentate granular cells and frontotemporal cortical layer II neurons.
      Based on these clinicopathological findings and a review of the literature, we
      concluded that our case is the first reported case of amyotrophic lateral
      sclerosis with dementia that clinically showed rapidly progressive aphasia.

PMID- 10651033
TI  - A fourth generation synchrotron at SLAC?

PMID- 10651034
TI  - Derivation of protein-specific pair potentials based on weak sequence fragment
      similarity.
AB  - A method is presented for the derivation of knowledge-based pair potentials that
      corrects for the various compositions of different proteins. The resulting
      statistical pair potential is more specific than that derived from previous
      approaches as assessed by gapless threading results. Additionally, a methodology
      is presented that interpolates between statistical potentials when no homologous
      examples to the protein of interest are in the structural database used to derive
      the potential, to a Go-like potential (in which native interactions are favorable
      and all nonnative interactions are not) when homologous proteins are present. For
      cases in which no protein exceeds 30% sequence identity, pairs of weakly
      homologous interacting fragments are employed to enhance the specificity of the
      potential. In gapless threading, the mean z score increases from -10.4 for the
      best statistical pair potential to -12.8 when the local sequence similarity,
      fragment-based pair potentials are used. Examination of the ab initio structure
      prediction of four representative globular proteins consistently reveals a
      qualitative improvement in the yield of structures in the 4 to 6 A rmsd from
      native range when the fragment-based pair potential is used relative to that when
      the quasichemical pair potential is employed. This suggests that such protein
      specific potentials provide a significant advantage relative to generic
      quasichemical potentials.

PMID- 10651035
TI  - Computer simulations of the properties of the alpha2, alpha2C, and alpha2D de
      novo designed helical proteins.
AB  - Reduced lattice models of the three de novo designed helical proteins alpha2,
      alpha2C, and alpha2D were studied. Low temperature stable folds were obtained for
      all three proteins. In all cases, the lowest energy folds were four-helix
      bundles. The folding pathway is qualitatively the same for all proteins studied.
      The energies of various topologies are similar, especially for the alpha2
      polypeptide. The simulated crossover from molten globule to native-like behavior
      is very similar to that seen in experimental studies. Simulations on a reduced
      protein model reproduce most of the experimental properties of the alpha2,
      alpha2C, and alpha2D proteins. Stable four-helix bundle structures were obtained,
      with increasing native-like behavior on-going from alpha2 to alpha2D that mimics
      experiment.

PMID- 10651036
TI  - Structural studies of FIV and HIV-1 proteases complexed with an efficient
      inhibitor of FIV protease.
AB  - Three forms of feline immunodeficiency virus protease (FIV PR), the wild type
      (wt) and two single point mutants, V59I and Q99V, as well as human
      immunodeficiency virus type 1 protease (HIV-1 PR), were cocrystallized with the
      C2-symmetric inhibitor, TL-3. The mutants of FIV PR were designed to replace
      residues involved in enzyme-ligand interactions by the corresponding HIV-1 PR
      residues at the structurally equivalent position. TL-3 shows decreased (improved)
      inhibition constants with these FIV PR mutants relative to wt FIV PR. Despite
      similar modes of binding of the inhibitor to all PRs (from P3 to P3'), small
      differences are evident in the conformation of the Phe side chains of TL-3 at the
      P1 and P1' positions in the complexes with the mutated FIV PRs. The differences
      mimick the observed binding of TL-3 in HIV-1 PR and correlate with a significant
      improvement in the inhibition constants of TL-3 with the two mutant FIV PRs.
      Large differences between the HIV-1 and FIV PR complexes are evident in the
      binding modes of the carboxybenzyl groups of TL-3 at P4 and P4'. In HIV-1 PR:TL
      3, these groups bind over the flap region, whereas in the FIV PR complexes, the
      rings are located along the major axis of the active site. A significant
      difference in the location of the flaps in this region of the HIV-1 and FIV PRs
      correlates with the observed conformational changes in the binding mode of the
      peptidomimetic inhibitor at the P4 and P4' positions. These findings provide a
      structural explanation of the observed Ki values for TL-3 with the different PRs
      and will further assist in the development of improved inhibitors.

PMID- 10651037
TI  - Crystal structure of CHO reductase, a member of the aldo-keto reductase
      superfamily.
AB  - Chinese hamster ovary (CHO) reductase is an enzyme belonging to the aldo-keto
      reductase (AKR) superfamily that is induced by the aldehyde-containing protease
      inhibitor ALLN (Inoue, Sharma, Schimke, et al., J Biol Chem 1993;268: 5894). It
      shows 70% sequence identity to human aldose reductase (Hyndman, Takenoshita,
      Vera, et al., J Biol Chem 1997;272:13286), which is a target for drug design
      because of its implication in diabetic complications. We have determined the
      crystal structure of CHO reductase complexed with nicotinamide adenine
      dinucleotide phosphate (NADP)+ to 2.4 A resolution. Similar to aldose reductase
      and other AKRs, CHO reductase is an alpha/beta TIM barrel enzyme with cofactor
      bound in an extended conformation. All key residues involved in cofactor binding
      are conserved with respect to other AKR members. CHO reductase shows a high
      degree of sequence identity (91%) with another AKR member, FR-1 (mouse fibroblast
      growth factor-regulated protein), especially around the variable C-terminal end
      of the protein and has a similar substrate binding pocket that is larger than
      that of aldose reductase. However, there are distinct differences that can
      account for differences in substrate specificity. Trp111, which lies horizontal
      to the substrate pocket in all other AKR members is perpendicular in CHO
      reductase and is accompanied by movement of Leu300. This coupled with movement of
      loops A, B, and C away from the active site region accounts for the ability of
      CHO reductase to bind larger substrates. The position of Trp219 is significantly
      altered with respect to aldose reductase and appears to release Cys298 from
      steric constraints. These studies show that AKRs such as CHO reductase are
      excellent models for examining the effects of subtle changes in amino acid
      sequence and alignment on binding and catalysis.

PMID- 10651038
TI  - Crystal structure of tropomyosin at 7 Angstroms resolution.
AB  - Tropomyosin is a 400A-long coiled coil that polymerizes to form a continuous
      filament that associates with actin in muscle and numerous non-muscle cells.
      Tropomyosin and troponin together form a calcium-sensitive switch that is
      responsible for thin-filament regulation of striated muscle. Subtle structural
      features of the molecule, including non-canonical aspects of its coiled-coil
      motif, undoubtedly influence its association with f-actin and its role in thin
      filament regulation. Previously, careful inspection of native diffraction
      intensities was sufficient to construct a model of tropomyosin at 9A resolution
      in a spermine-induced crystal form that diffracts anisotropically to 4A
      resolution. Single isomorphous replacement (SIR) phasing has now provided an
      empirical determination of the structure at 7A resolution. A novel method of
      heavy-atom analysis was used to overcome difficulties in interpretation of
      extremely anisotropic diffraction. The packing arrangement of the molecules in
      the crystal, and important aspects of the tropomyosin geometry such as non
      uniformities of the pitch and variable bending and radius of the coiled coil are
      evident.

PMID- 10651039
TI  - Structural basis of the catalytic role of Glu301 in Anabaena PCC 7119 ferredoxin
      NADP+ reductase revealed by x-ray crystallography.
AB  - The three-dimensional crystal structure of the Glu301Ala site-directed mutant of
      ferredoxin-NADP+ reductase from Anabaena PCC 7119 has been determined at 1.8A
      resolution by x-ray diffraction. The overall folding of the Glu301Ala FNR mutant
      shows no significant differences with respect to that of the wild-type enzyme.
      However, interesting conformational changes are detected in the side chain of
      another glutamate residue, Glu139, which now points towards the FAD cofactor in
      the active center cavity. The new conformation of the Glu139 side chain is
      stabilized by a network of five hydrogen bonds to several water molecules, which
      seem to hold the carboxylate side chain in a rather fixed position. This
      interacting network connects the Glu139 side chain to the Ser80 side chain
      through a series of three water molecules. These observations are discussed in
      terms of the reactivity of Glu301Ala ferredoxin-NADP+ reductase towards its
      substrates, and the role of Glu301 in the catalysis is re-examined. Moreover, a
      structural explanation of the different reoxidation properties of this mutant is
      given on the basis of the reported structure by modeling the hypothetical flavin
      C(4a)-hydroperoxide intermediate. The model shows that the distal oxygen of the
      peroxide anion could be in an appropriate situation to act as the proton donor in
      the reoxidation process.

PMID- 10651040
TI  - Solution structure of BmKTX, a K+ blocker toxin from the Chinese scorpion Buthus
      Martensi.
AB  - BmKTX is a toxin recently purified from the venom of Buthus Martensi, which
      belongs to the kaliotoxin family. We have determined its solution structure by
      use of conventional two-dimensional NMR techniques followed by distance-geometry
      and energy minimization. The calculated structure is composed of a short alpha
      helix (residues 14 to 20) connected by a tight turn to a two-stranded
      antiparallel beta-sheet (sequences 25-27 and 32-34). The beta-turn connecting
      these strands belongs to type I. The N-terminal segment (sequence 1 to 8) runs
      parallel to the beta-sheet although it cannot be considered as a third strand.
      Comparison of the conformation of BmKTX and toxins of the kaliotoxin family
      clearly demonstrates that they are highly related. Therefore, analysis of the
      residues belonging to the interacting surface of those toxins allows us to
      propose a functional map of BmKTX slightly different from the one of KTX and
      AgTX2, which may explain the variations in affinities of these toxins towards the
      Kv1.3 channels.

PMID- 10651041
TI  - QSD quadratic shape descriptors. 2. Molecular docking using quadratic shape
      descriptors (QSDock).
AB  - We present a new shape-based polynomial time algorithm for the rapid docking of
      rigid ligands into their macromolecular receptors. The method exploits molecular
      surface complementarity existing between a putative ligand and its receptor
      protein. Molecular shapes are represented by using a new shape descriptor that is
      based on local quadratic approximations to the molecular surface. The quadratic
      shape descriptor is capable of representing a plethora of molecular shapes and is
      not limited to describing convex or concave regions of molecular surface. A
      single pair of complementary descriptors is sufficient for computing the
      transformation matrix that positions a ligand into the receptor site. We
      demonstrate the capabilities of our algorithm by successfully reproducing the
      crystallographically determined orientation for a test set of 20 ligand-protein
      complexes.

PMID- 10651042
TI  - New sequence motifs in flavoproteins: evidence for common ancestry and tools to
      predict structure.
AB  - We describe two new sequence motifs, present in several families of
      flavoproteins. The "GG motif" (RxGGRxxS/T) is found shortly after the
      betaalphabetadinucleotide-binding motif (DBM) in L-amino acid oxidases, achacin
      and aplysianin-A, monoamine oxidases, corticosteroid-binding proteins, and
      tryptophan 2-monooxygenases. Other disperse sequence similarities between these
      families suggest a common origin. A GG motif is also found in protoporphyrinogen
      oxidase and carotenoid desaturases and, reduced to the central GG doublet, in the
      THI4 protein, dTDP-4-dehydrorhamnose reductase, soluble fumarate reductase,
      steroid dehydrogenases, Rab GDP-dissociation inhibitor, and in most flavoproteins
      with two dinucleotide-binding domains (glutathione reductase, glutamate synthase,
      flavin-containing monooxygenase, trimethylamine dehydrogenase...). In the latter
      families, an "ATG motif" (oxhhhATG) is found in both the FAD- and NAD(P)H-binding
      domains, forming the fourth beta-strand of the Rossman fold and the connecting
      loop. On the basis of these and previously described motifs, we present a
      classification of dinucleotide-binding proteins that could also serve as an
      evolutionary scheme. Like the DBM, the ATG motif appears to predate the
      divergence of NAD(P)H- and FAD-binding proteins. We propose that flavoproteins
      have evolved from a well-differentiated NAD(P)H-binding protein. The bulk of the
      substrate-binding domain was formed by an insertion after the fourth beta-strand,
      either of a closely related NAD(P)H-binding domain or of a domain of completely
      different origin.

PMID- 10651043
TI  - Modeling implicit reorganization in continuum descriptions of protein-protein
      interactions.
AB  - The determination of free energies that govern protein-protein recognition is
      essential for a detailed molecular understanding of biological specificity.
      Continuum models of macromolecular interactions, in which the solvent is treated
      by an implicit representation and the proteins are treated semi-microscopically,
      are computationally tractable for estimating free energies, yet many questions
      remain concerning their accuracy. This article reports a continuum analysis of
      the free-energy changes underlying the binding of 31 interfacial alanine
      substitutions of two complexes of the antihen egg white lysozyme (HEL) antibody
      D1.3 bound with HEL or the antibody E5.2. Two implicit schemes for modeling the
      effects of protein and solvent relaxation were examined, in which the protein
      environment was treated as either homogeneous with a "protein dielectric
      constant" of epsilon(p) = 4 or inhomogeneous, with epsilon(p) = 4 for neutral
      residues and epsilon(p) = 25 for ionized residues. The results showed that the
      nonuniform dielectric model reproduced the experimental differences better, with
      an average absolute error of +/-1.1 kcal/mol, compared with +/-1.4 kcal/mol for
      the uniform model. More importantly, the error for charged residues in the
      nonuniform model is +/-0.8 kcal/mol and is nearly half of that corresponding to
      the uniform model. Several substitutions were clearly problematic in determining
      qualitative trends and probably required explicit structural reorganization at
      the protein-protein interface.

PMID- 10651044
TI  - Biological activities of lipopolysaccharides extracted from porcine vaccine
      strains.
AB  - Lipopolysaccharides (LPSs) were purified from Actinobacillus pleuropneumoniae
      serotype 2, Bordetella bronchiseptica and Haemophilus parasuis serotype 5, which
      were used for vaccine production in Japan, by the phenol-water procedure. In SDS
      PAGE analysis, A. pleuropneumoniae LPS, as well as Escherichia coli LPS,
      demonstrated a typical ladder profile of a smooth-type LPS. On the other hand, B.
      bronchiseptica and H. parasuis LPSs lacked the ladder profiles. It was found that
      the biological activity of these LPSs was comparable to those of E. coli LPS in
      terms of activation of the clotting enzyme of Limulus amoebocyte lysate,
      mitogenic activity of mouse spleen cells, stimulation of TNF-alpha and nitric
      oxide production, but IL-6 production could hardly be observed in any LPS.

PMID- 10651045
TI  - Experimental hypocalcemia induced by hemodialysis in goats.
AB  - To evaluate whether hemodialysis with a dialysate containing no calcium (Ca-free
      HD) can induce hypocalcemia and restore the clinical signs and blood biochemical
      changes in naturally occurred hypocalcemic disorder in ruminants, the clinical
      signs and the changes in plasma electrolytes and minerals concentrations were
      observed in goats during 6-hr hemodialysis. The four goats received hemodialysis
      with the dialysate containing calcium (Ca HD), and 10 days later they had Ca-free
      HD. The plasma ionized Ca (Ca++) and total Ca (TCa) concentrations were not
      affected by Ca HD, whereas the levels significantly decreased during whole period
      of Ca-free HD. The Ca++ and TCa concentrations were 0.69+/-0.06 mmol/l and 5.9+/
      0.3 mg/dl at 6 hr of Ca-free HD, respectively. The clinical signs observed during
      Ca-free HD seemed to resemble to those in naturally occurred hypocalcemic cases
      that were reported previously. Therefore, Ca-free HD was suggested to be one of
      the possible methods to induce experimental hypocalcemia in ruminants.

PMID- 10651046
TI  - Role of the nitric oxide-cGMP system in the regulation of ductus arteriosus
      patency in fetal rats.
AB  - The purpose of this study was to examine the role of the nitric oxide (NO) and
      cyclic guanosine monophosphate (cGMP) system in the regulation of the ductus
      arteriosus (DA) patency in fetal rats. Pregnant rats were administered N(G)-nitro
      L-arginine methyl ester (L-NAME, 50 mg/kg, ip), an NO synthase (NOS) inhibitor;
      methylene blue (30, 50 and 100 mg/kg, ip), a soluble guanylate cyclase inhibitor;
      or indomethacin (3 mg/kg, po), a cyclooxygenase inhibitor, at various times
      before cesarean section. Dams were decapitated to obtain the fetuses by cesarean
      section, and fetuses were rapidly frozen in an acetone-dry ice mixture. Using
      rapid freezing and shaving methods, the calibers of the DA, pulmonary artery (PA)
      and descending aorta (Ao) were measured to evaluate the effects of treatment. L
      NAME reduced the DA calibers to 86% of the initial values, but recovery to the
      control levels occurred 6 hr after the injection. Indomethacin decreased the DA
      calibers to 34% of the control values and sustained the DA constriction until 24
      hr after the treatment. Methylene blue caused DA constriction to almost the same
      degree as indomethacin, but the levels normalized within 24 hr after the
      treatment. We conclude that L-NAME caused a slight constriction of the DA,
      whereas methylene blue and indomethacin caused marked constriction of the
      vessels, suggesting that the NO-cGMP system as well as prostaglandins contribute
      to the DA patency.

PMID- 10651047
TI  - Allelic variation of the D4 dopamine receptor polymorphic region in two dog
      breeds, Golden retriever and Shiba.
AB  - The D4 dopamine receptor (D4DR) polymorphic region, which is possibly related to
      the personality trait known as novelty seeking in humans, was examined in 34 dogs
      from two breeds (Golden retriever and the Japanese indigenous breed, Shiba) by
      the polymerase chain reaction (PCR), and the DNA sequences of each allele were
      determined. The polymorphic region of the dog D4DR gene was composed of 39- and
      12- base pair (bp) units, and four alleles (A-D) were identified based on the
      number and/or order of these units. Intra- and inter-breed allele variations were
      observed. The frequency of the short A allele was dominant (78.9%) in the Golden
      retriever, while the long D allele was most common (46.7%) in the Shiba. These
      findings suggested that the allele frequency varied significantly between
      different breeds, and that analysis of the polymorphism in D4DR might be of use
      for understanding the behavioral traits of dogs.

PMID- 10651049
TI  - The comparison between the cerebral blood flow directly measures and cerebral
      blood flow velocity in the middle and basilar cerebral arteries measured by
      transcranial Doppler ultrasonography.
AB  - Transcranial Doppler ultrasonography (TCD) may be useful for determining
      alterations in cerebral blood flow (CBF) during excessive hemodynamic changes by
      non-invasive measurement of the CBF velocity. The purpose of this study was to
      measure the correlation between CBF and the middle cerebral artery (MCA) and
      basilar artery (BA) flow velocities, as measured by TCD during excessive
      hemodynamic changes produced by hypertension and hypotension in adult dogs. The
      peak, diastolic, and mean flow velocities were measured by TCD. Arterial
      hypertension was induced by administration of dopamine at 5 and 15 microg/kg/min,
      and hypotension was induced by hemorrhage. During the hemodynamic changes, the BA
      velocity correlated more closely with the alteration in the CBF than the MCA
      velocity. In terms of percentages of the values during anesthesia, there was good
      correlation between CBF and the MCA and BA velocities. In conclusion, our
      findings indicate that MCA and BA velocity measurements, as a percentage of the
      values during anesthesia, both give an equally accurate indication of alterations
      in CBF during excessive hemodynamic changes.

PMID- 10651048
TI  - Development of a PCR test for rapid diagnosis of contagious equine metritis.
AB  - In order to establish a rapid diagnostic method for contagious equine metritis
      (CEM), we developed and evaluated a polymerase chain reaction (PCR) test. Species
      specific PCR primer sets were derived from the DNA sequence of a cloned DNA
      fragment of Taylorella equigenitalis that did not hybridize with the genome of a
      taxomonically related species, Oligella urethralis. Single step PCR with primer
      set P1-N2 and two-step semi-nested PCR with primer sets P1-N2 and P2-N2 detected
      as low as 100 and 10 CFU of the bacteria, respectively. Single-step PCR detected
      T. equigenitalis from genital swabs of experimentally infected mares with
      sensitivity comparable to that of bacterial isolation. Furthermore, two-step PCR
      was more sensitive than the culture method. Upon examination of field samples, 12
      out of 3,123 samples were positive by single-step PCR while only 2 were positive
      by bacterial culture. The 12 PCR-positive samples originated from 5 mares, of
      which 3 animals were considered to be carriers based on previous bacteriologic
      and serologic diagnoses for CEM. The PCR test described in this study would
      provide a specific and highly sensitive tool for the rapid diagnosis of CEM.

PMID- 10651050
TI  - Pathogenicity of Sendai viruses adapted into polarized MDCK cells.
AB  - Apically and basally released Sendai viruses (SeV) were obtained after infection
      of polarized Madin-Darby canine kidney (MDCK) cells grown on permeable membrane
      culture inserts. After 20 passages of adaptation in MDCK cells, we compared their
      in vivo and in vitro pathogenicity with the parental Mol-strain of SeV. These
      viruses had comparable in vitro pathogenicity, but the in vivo pathogenicities
      were varied. The apically released MDCK-adapted virus showed comparable
      pathogenicity with the parental virus, in contrast with the basally released MDCK
      adapted virus, which showed in vivo attenuation.

PMID- 10651051
TI  - Pathogenicity of Mycobacterium avium complex serovar 9 isolated from painted
      quail (Excalfactoria chinensis).
AB  - Avian tuberculosis accompanied with many tubercular lesions in the liver and
      spleen was found in a painted quail at a zoological garden in Japan.
      Mycobacterium avium complex (MAC) serovar 9 without insertion sequence of IS901
      was isolated from the liver (1.3 x 10(8) CFU/g), oviduct (9.4 x 10(7) CFU/g), and
      intestine (1.5 x 10(5) CFU/g). The isolates were inoculated intravenously to
      chickens. The inoculated chickens showed clinical symptoms of avian tuberculosis.
      Birds are susceptible to MAC serovar 9 without IS901.

PMID- 10651052
TI  - Comparison of prevalence of feline herpesvirus type 1, calicivirus and parvovirus
      infections in domestic and leopard cats in Vietnam.
AB  - A serosurvey of feline herpesvirus type 1 (FHV-1), feline calicivirus (FCV), and
      feline parvovirus (FPV) in cats from Ho Chi Minh City area in southern Vietnam
      was conducted in December 1998, and we compared the results with our previous
      results in northern Vietnam (Hanoi area). The positive rate of FHV and FCV in
      domestic cats were 44% and 74%, respectively. They were rather higher than those
      in Hanoi area, while the seropositivity of FPV (44%) was similar to that in Hanoi
      area. In leopard cats, the positive rate of FPV was high (3/4) and it indicated
      that FPV was prevailing in leopard cats in Vietnam.

PMID- 10651053
TI  - Cloning and sequencing of a bottle-nosed dolphin (Tursiops truncatus) interleukin
      1alpha and -1beta complementary DNAs.
AB  - The bottle-nosed dolphin (Tursiops truncatus) IL-1alpha and IL-1beta cDNA were
      cloned from mitogen stimulated peripheral blood mononuclear cells (PBMC) RNA
      utilizing the reverse transcription-polymerase chain reaction (RT-PCR). The
      sequences of these cDNAs showed that dolphin IL-1alpha and IL-1beta clones
      contained open reading frames encoding 265 and 266 amino acids, respectively.
      Comparison of the deduced amino acid showed that dolphin IL-1alpha sequence
      shared 77, 77, 77, 74, 71, 65 and 57% similarity with the bovine, ovine, porcine,
      equine, feline, human and mouse IL-1alpha sequences, respectively. Similarly, the
      amino acid sequence showed that dolphin IL-1beta shared 77, 77, 74, 69, 65, 64
      and 63% similarity with the bovine, ovine, porcine, equine, feline, human and
      mouse IL-1beta sequences, respectively. The relatedness of dolphin IL-1alpha and
      IL-1beta were relatively distant with 21% amino acid homology.

PMID- 10651054
TI  - Spinal oligodendroglioma with diffuse arachnoidal dissemination in a Japanese
      Black heifer.
AB  - A gelatinous focus with cystic spaces, was found in the posterior funiculus of
      the 2nd to 3rd lumbar levels of the spinal cord of a Japanese Black heifer, 2
      years old, with clinical signs of severe dysstasia. Histopathological examination
      revealed that the spinal lesion consisted of multifocal and diffuse proliferation
      of round cells with abundant vacuolar cytoplasm and hyperchromatic nuclei. In the
      lesions there was a number of cystic spaces containing aggregates of small round
      cells. The neoplastic foci showed a honeycomb structure divided by thin blood
      vessels, representing typical lesions of oligodendroglioma. Diffuse and
      multifocal proliferation of these round cells were also recognized in the
      subarachnoidal space in the sacral spinal cord. Immunohistochemically, the
      proliferating round cells were negative for glial fibrillary acidic protein.
      Based on these morphological features, the case was diagnosed as lumbar spinal
      oligodendroglioma with diffuse arachnoidal dissemination.

PMID- 10651055
TI  - Spontaneous lymphoma in a Japanese White rabbit.
AB  - Lymphoma was observed in a 4-month-old female Japanese White rabbit. Grossly, the
      markedly enlarged mesenteric lymph nodes, prominent Peyer's patches of jejunum,
      splenomegaly, and enlargement of tracheobronchial lymph nodes, adrenal glands and
      ovaries were observed. Histologically, neoplastic lymphoid cells proliferated
      diffusely showing frequent mitotic figures and a characteristic 'starry sky'
      appearance. Their basophilic cytoplasm contained a few lipid droplets. The
      mesenteric lymph nodes, Peyer's patches of jejunum, and tracheobronchial lymph
      nodes were largely replaced by the tumor tissues. The stomach, small intestines,
      especially the jejunum, liver, spleen, ovaries, and adrenal glands were heavily
      infiltrated with neoplastic cells. These results suggest that the present
      lymphoma may have originated from the gastrointestinal lymphoid tissue.

PMID- 10651056
TI  - DNA polymorphism of srRNA gene among Eimeria tenella strains isolated in Japan.
AB  - DNA polymorphism in twelve starains of Eimeria tenella isolated from various
      places in Japan was examined using 1.l kb small subunits ribosomal RNA amplified
      by PCR. Genetic variation was evaluated by random amplification of polymorphic
      DNA (RAPD) analysis. DNA fingerprint patterns were grouped into two, indicating
      that at least two DNA polymorphisms exist in Japanese E. tenella strains.

PMID- 10651057
TI  - A canine peripheral nerve sheath tumor including peripheral nerve fibers.
AB  - Peripheral nerve sheath tumor was found in a 7-year-old male mongrel dog. The
      tumors were located in the right cheek subcutis and oral submucosa.
      Histologically, neoplastic cells were arranged in streaming bundles, occasionally
      interlacing bundles or whorls of elongated and spindle cells. Cellular atypia was
      poor and mitotic figures were rarely observed. Ultrastructurally, neoplastic
      cells had basement membrane, typical of Schwann cells. One bundle of normal
      peripheral nerve fibers and some myelinated axons were seen within the tumor
      tissues. Immunohistochemically, neoplastic cells reacted to vimentin, glial
      fibrillary acidic protein, S-100 protein and neuron specific enolase. In addition
      to the above immunoreactions, the included nerve fibers were positive for myelin
      basic protein and neurofilament protein. This paper also discusses
      immunohistochemical findings on differential diagnosis in comparison with those
      of canine hemangiopericytomas reported hitherto.

PMID- 10651058
TI  - Helminth fauna of carnivores distributed in north-western Tohoku, Japan, with
      special reference to Mesocestoides paucitesticulus and Brachylaima tokudai.
AB  - In the winter of 1998-1999, we collected parasitological data from 54 wild
      carnivores in the north-western part of Tohoku region, Japan. These consisted of
      38 martens (Martes melampus melampus), 14 raccoon dogs (Nyctereutes procyonoides
      viverrinus) and 2 foxes (Vulpes vulpes japonica). Collected helminth parasites
      were 11 nematode, 10 trematode, 3 cestode, and a single acanthocephalan species,
      including 5 hitherto unknown species for this research area or the mainland of
      Japan (Honshu). Mesocestoides paucitesticulus was for the first time recorded
      from martens as well as from carnivores distributed in Honshu. Brachylaima
      tokudai originally recorded from Urotrichus talpoides in the central part of
      Honshu was for the first time found from a raccoon dog.

PMID- 10651059
TI  - Equipotent in vitro actions of alpha- and beta-CGRP on guinea pig basilar artery
      are likely to be mediated via CRLR derived CGRP receptors.
AB  - The aim of the present study was to investigate and compare specific in vitro
      pharmacological actions of human alpha- and beta-CGRP applied as single
      concentrations to prostaglandin F2alpha precontracted segments of guinea pig
      basilar artery. To support the suggestion of a possible link between the
      pharmacological actions of alpha- and beta-CGRP and a specific receptor, we
      wished to determine whether mRNAs required for the expression of calcitonin
      receptor-like receptor (CRLR) derived CGRP receptors were present in the guinea
      pig basilar artery. In the pharmacological experiments we demonstrated an
      increase in the cAMP content by 2.5-fold and a concomitant significant
      vasorelaxation of the precontracted basilar artery segments following 1 min of
      stimulation by 10(-7) M alpha- or beta-CGRP. In another set of experiments, the
      time course of alpha- and beta-CGRP induced vasodilatation was investigated and
      concentration dependent responses of the two peptides were demonstrated. No
      significant differences between the actions of alpha- and beta-CGRP regarding
      induction of cAMP formation, amount of vasodilatation, time course of
      vasodilatation and mode of inhibition by the CGRP receptor antagonist, human
      alpha-CGRP(8-37), could be detected. The presence of mRNA encoding the guinea pig
      CRLR and the guinea pig CGRP receptor component protein (RCP) in the guinea pig
      basilar artery was demonstrated by RT-PCR methods. Furthermore, a partial
      sequence of mRNA encoding the guinea pig CRLR was determined. The expression in
      this tissue of a CRLR derived CGRP receptor and a functional RCP is therefore
      likely, and the equipotent pharmacological actions of alpha- and beta-CGRP might
      be mediated via CRLR derived CGRP receptors.

PMID- 10651060
TI  - Small intestinal and pancreatic microstructures are modified by an intraduodenal
      CCK-A receptor antagonist administration in neonatal calves.
AB  - The aim of the present study was to investigate the role of CCK on the upper gut
      and pancreas microstructure and on pancreatic juice secretion in neonatal calves
      assessed by a repetitive intraduodenal administration of FK480, a CCK-A receptor
      antagonist, during the first 6 days of life. The experiment was performed on 10
      neonatal calves surgically fitted with a pancreatic accessory duct catheter and
      duodenal cannulas. Calves were sacrificed on day 7 for tissue sampling. Treatment
      with FK480 resulted in: reduction of preprandial pancreatic juice secretion at
      days 1-3, smaller size of pancreatic acini and number of cells per acinus,
      reduction in intestinal crypt depth (except in the duodenal bulb), numerous
      modifications of intestinal villi length and width, lower mitotic index of crypt
      cells, and increased number and size of enterocytes with 'empty vacuoles'. In
      conclusion, the blockade of CCK-A receptors during early life both reduced
      pancreatic exocrine secretion and induced complex changes in pancreatic
      microstructure. The influence of CCK on the upper gut microstructure in neonatal
      calves could be either direct via activation of CCK-A receptors located in the
      mucosa of the upper gut or indirect by modulation of the secretion of pancreatic
      juice.

PMID- 10651061
TI  - Pharmacological evidence for both neuronal and smooth muscular PAC1 receptors and
      a VIP-specific receptor in rat colon.
AB  - The receptors for vasoactive intestinal peptide (VIP) and pituitary adenylate
      cyclase activating peptide (PACAP) were characterised in vitro on rat colon
      longitudinal smooth muscle with adherent myenteric ganglia. VIP, PACAP-38 and
      PACAP-27 all caused concentration-dependent relaxations. PACAP-27 and PACAP-38
      were equipotent, while VIP was less potent. Tetrodotoxin (10(-6) M), L-NAME (10(
      4) M), 7-NINA (10(-5) M) and ODQ (3 x 10(-6) M) reduced the amplitude of the
      relaxatory responses to PACAP-38 but did not affect relaxations induced by VIP or
      PACAP-27. Apamin (10(-6) M) almost totally abolished the PACAP-27- and PACAP-38
      induced relaxations, while VIP-induced relaxations were only slightly reduced.
      Tetraethylammonium (TEA) reduced VIP- but not PACAP-27-induced relaxations, while
      charybdotoxin was ineffective. Cross-desensitisation between PACAP-27, PACAP-38
      and VIP could be revealed to some extent. IN CONCLUSION: VIP, PACAP-27 and PACAP
      38 are effective relaxants in rat colon longitudinal muscle. The receptors
      involved are classified as: (1) a neuronal PAC1 receptor localised on NO
      synthesising neurones, the preferred ligand being PACAP-38. Activation of this
      receptor leads to an increased NO production. (2) A smooth muscle PAC1 receptor,
      the preferred ligand being PACAP-27. However, also PACAP-38 and, to a less
      extent, VIP activate this receptor. The relaxatory responses elicited by both
      PACAP-27 and PACAP-38 are abolished by apamin and thus mediated through small
      conductance Ca2+-activated K+ channels. (3) A VIP-specific receptor localised on
      smooth muscle cells. The mechanisms whereby this receptor elicits a relaxatory
      response involve, at least to some extent, TEA-sensitive K+ channels.

PMID- 10651062
TI  - Epitope mapping of secreted mouse leptin utilizing peripherally administered
      synthetic peptides.
AB  - We have recently reported that intraperitoneal (i.p.) administration of synthetic
      peptide amides corresponding to amino acids 106-140 of mouse leptin significantly
      reduced food intake and body weight gain in female C57BL/6J ob/ob mice. These
      results suggested that leptin activity was localized in domains toward its C
      terminus between residues 106-140. In the present study, 14 overlapping peptides
      encompassing the complete sequence of secreted mouse leptin were synthesized, and
      their effects on body weight and food intake in female C57BL/6 J ob/ob mice were
      assessed. When given as seven daily 1-mg i.p. injections, only peptides
      corresponding to amino acids 106-120, 116-130 and 126-140 caused significant
      reductions in body weight and food intake. These results confirmed our earlier
      study and suggest that in contrast to the domain encompassed by amino acids 106
      140, the N-terminal of mouse leptin between amino acids 21-105 may not contain
      functional epitopes that can be utilized as lead compounds in the development of
      peripherally administered bioactive peptide analogs or nonpeptide mimetics of
      leptin, which may have potential usefulness in treatment of the energy imbalance
      associated with obesity.

PMID- 10651063
TI  - Atrial natriuretic factor inhibits norepinephrine biosynthesis and turnover in
      the rat hypothalamus.
AB  - We have previously reported that atrial natriuretic factor (ANF) increased
      neuronal norepinephrine (NE) uptake and reduced basal and evoked neuronal NE
      release. Changes in NE uptake and release are generally associated to
      modifications in the synthesis and/or turnover of the amine. On this basis, the
      aim of the present work was to study ANF effects in the rat hypothalamus on the
      following processes: endogenous content, utilization and turn-over of NE;
      tyrosine hydroxylase (TH) activity; cAMP and cGMP accumulation and
      phosphatidylinositol hydrolysis. Results showed that centrally applied ANF (100
      ng/microl/min) increased the endogenous content of NE (45%) and diminished NE
      utilization. Ten nM ANF reduced the turnover of NE (53%). In addition, ANF (10
      nM) inhibited basal and evoked (with 25 mM KCl) TH activity (30 and 64%,
      respectively). Cyclic GMP levels were increased by 10 nM ANF (100%). However,
      neither cAMP accumulation nor phosphatidylinositol breakdown were affected in the
      presence of 10 nM ANF. The results further support the role of ANF in the
      regulation of NE metabolism in the rat hypothalamus. ANF is likely to act as a
      negative putative neuromodulator inhibiting noradrenergic neurotransmission by
      signaling through the activation of guanylate cyclase. Thus, ANF may be involved
      in the regulation of several central as well as peripheral physiological
      processes such as cardiovascular function, electrolyte and fluid homeostasis,
      endocrine and neuroendocrine synthesis and secretion, behavior, thirst, appetite
      and anxiety that are mediated by central noradrenergic activity.

PMID- 10651064
TI  - Cholecystokinin-8S levels in discrete hypothalamic nuclei of weanling rats
      exposed to maternal protein malnutrition.
AB  - Perinatal malnutrition and growth retardation at birth are suggested to be
      important risk factors for the development of overweight and syndrome X in later
      life. Underlying mechanisms are unknown. Body weight and food intake are
      regulated, e.g. by hypothalamic neuropeptidergic systems which are thought to be
      highly vulnerable to persisting malorganization due to perinatal malnutrition. To
      investigate possible consequences for hypothalamic cholecystokinin-8S (CCK-8S) in
      the offspring, pregnant Wistar rats were fed an 8% protein diet during pregnancy
      and lactation (low-protein group; LP) while control mothers (CO) received a 17%
      protein isocaloric standard diet. LP offspring displayed underweight at birth (P
      < 0.05) and during suckling (P < 0.001), while leptin levels were not altered. At
      weaning, under basal conditions CCK-8S was decreased in LP offspring in the
      paraventricular hypothalamic nucleus and arcuate hypothalamic nucleus (P < 0.05),
      as well as in the dorsomedial hypothalamic nucleus, lateral hypothalamic area and
      ventromedial hypothalamic nucleus (P < 0.01). In summary, these data indicate (1)
      an inhibition of the satiety peptide CCK-8S in main regulators of body weight and
      food intake in low-protein malnourished newborn rats; (2) no direct relationship
      of hypothalamic CCK-8S to circulating leptin at this age; and (3) no
      neurochemical signs of hypothalamic CCKergic dysregulation in this animal model
      at the age of weaning.

PMID- 10651066
TI  - Herpes zoster: focus on treatment in older adults.

PMID- 10651065
TI  - Altered influence of CCK-B/gastrin receptors on HDC expression in ECL cells after
      neoplastic transformation.
AB  - Gastrin is one of the main factors controlling enterochromaffin-like (ECL) cell
      endocrine function and growth. Long-standing hypergastrinemia may give rise to
      ECL cell carcinoids in the gastric corpus in man and in experimental models. We
      have analysed the expression and function of CCK-B/gastrin receptors in normal
      ECL cells and in ECL cell tumours (gastric carcinoids) of the African rodent
      Mastomys natalensis. Hypergastrinemia induced by short-term (5 days) histamine2
      receptor blockade (loxtidine) resulted in increased histidine decarboxylase (HDC)
      mRNA expression in the gastric oxyntic mucosa. This increase was significantly
      and dose-dependently reversed by selective CCK-B/gastrin receptor blockade
      (YM022). Long-term (12 months) hypergastrinemia, induced by histamine2-receptor
      blockade, gave rise to ECL cell carcinoids in the gastric oxyntic mucosa. CCK
      B/gastrin receptor mRNA was only slightly elevated while HDC mRNA expression was
      eight-fold elevated in ECL cell carcinoids and was not influenced by CCK
      B/gastrin receptor blockade. Thus CCK-B/gastrin receptor blockade of
      hypergastrinemic animals reduces the HDC mRNA expression in normal mucosa but not
      in ECL cell carcinoids. These results demonstrate that HDC mRNA expression in
      neoplastic ECL cells is not controlled by CCK-B/gastrin receptors.

PMID- 10651067
TI  - Acute murine cytomegalovirus infection: a model for determining antiviral
      activity against CMV induced hepatitis.
AB  - Acute intraperitoneal infection of weanling BALB/c mice with murine
      cytomegalovirus (MCMV) resulted in an inoculum titer-dependent weight loss,
      mortality and elevation of plasma transaminases (ALT: alanine transaminase and
      AST: aspartate transaminase). Three days post infection (p.i.) with 10(4.85)
      plaque forming units (pfu) there was 90% mortality with a mean death day p.i. of
      4.1 +/- 0.2. Plasma levels of ALT and AST were elevated 24- and 15-fold,
      respectively. Organ titers of virus (log10 pfu/g tissue) were 6.16 in the liver,
      6.05 in the spleen, 4.0-4.7 in the lung, heart, kidney and intestine and
      undetectable in the muscle and brain. Organ concentrations (units/g wet-weight)
      of ALT were highest in the liver, whilst for AST the highest levels were found in
      the heart. The concentrations of ALT but not AST were reduced (35-55%) in the
      infected liver; the concentrations of ALT and AST were not changed in other
      infected organs. There were excellent correlations (r > 0.95) between viral
      titers in the liver, increases of plasma ALT and depletion of liver ALT. HPMPC
      and ganciclovir administered either p.o. or s.c. reduced mortality, increases in
      plasma transaminases and viral burdens in the liver and prevented depletion of
      liver ALT. HPMPC was approximately 10-fold more potent than ganciclovir. These
      results strongly suggest that intraperitoneal infection of the BALB/c mouse with
      MCMV represents an animal model of CMV hepatitis that can be monitored by
      measuring plasma ALT.

PMID- 10651068
TI  - Inhibition of beta-globin gene expression by 3'-azido-3'-deoxythymidine in human
      erythroid progenitor cells.
AB  - 3'-Azido-3'-deoxythymidine (AZT) treatment in HIV-infected patients is limited by
      bone marrow suppression including neutropenia and anemia. Previous studies had
      shown a direct effect of high concentrations of this drug on globin gene
      expression in K-562 erythroleukemia cells. To better define the mechanism(s) of
      AZT-induced bone marrow toxicity, the present study evaluates these effects in
      more relevant human erythroid progenitor liquid cultures, because AZT is 100
      times more toxic to human bone marrow cells than K-562 cells. At a clinically
      relevant concentration of 1 microM, AZT inhibited specifically erythroid cell
      growth by approximately 58% as compared with untreated cells. The percentage of
      cells synthesizing hemoglobin was decreased also by 47% in AZT-treated cells with
      beta-globin mRNA levels accounting for 0.27 pmol in treated cells as compared
      with 1.44 under control conditions while beta-actin levels remained unchanged.
      Under the same conditions, AZT inhibited the beta-globin chain synthesis by
      approximately 60% as compared with the control. Consistent with the data
      described above was the finding that a concentration as low as 0.1 microM of AZT
      decreased by almost 40% the binding level of the erythroid-specific transcription
      factor GATA-1. These findings demonstrate that AZT, at clinical relevant
      concentrations, specifically inhibits beta-globin gene expression in human
      erythroid progenitor liquid cell culture.

PMID- 10651069
TI  - Analysis of immune responses to varicella zoster viral proteins induced by DNA
      vaccination.
AB  - In this study we sought to examine the mechanism by which immune responses were
      induced following intramuscular injection of mice with DNA expression vectors
      encoding genes of varicella zoster virus (VZV). Both VZV-specific antibody and T
      cell proliferative responses were induced by immunization with DNA sequences for
      the immediate early 62 (IE62) and glycoprotein E (gE). The viral proteins were
      shown to be expressed in non-regenerating, rather than regenerating muscle cells.
      After primary immunization, muscle cells did not express major histocompatibility
      complex (MHC) class II transcripts and little inflammatory response was detected
      at the site of inoculation. Histochemical staining and non-isotopic in situ
      hybridization demonstrated that a second injection of IE62 plasmid DNA was again
      associated with protein synthesis in non-regenerating muscle cells but that a
      marked inflammatory infiltrate was induced in muscle tissue. These cells, but not
      muscle cells, expressed MHC class II transcripts. Significantly, PCR analyses
      demonstrated that IE62 DNA localized specifically to local draining lymph nodes
      following primary DNA immunization by intramuscular inoculation. These
      experiments indicate that transport of plasmid DNA to sites of antigen
      presentation in regional lymphoid tissue may play an important role in the
      initial generation of immune responses and that enhancement by secondary
      inoculation is mediated by immune cells that traffic to the site of viral protein
      synthesis in muscle cells.

PMID- 10651070
TI  - Inhibitory effect of Ephedrae herba, an oriental traditional medicine, on the
      growth of influenza A/PR/8 virus in MDCK cells.
AB  - Using several herbal extracts, we investigated whether certain Kampo medicines
      exert an inhibitory effect on the acidification of intracellular compartments
      such as endosomes and lysosomes (referred to as ELS), and thereby inhibit the
      growth of influenza A virus in Madin-Darby canine kidney cells. The vital
      fluorescence microscopic study showed that the extract of Ephedrae herba (EHext)
      among five herbal extracts inhibited acidification of endosomes and lysosomes in
      a concentration-dependent manner (100-400 microg/ml). Moreover the growth of
      influenza A/PR/8/34 (H1N1) (PR8) virus was inhibited when the cells were treated
      with EHext for 1 h immediately after infection, or treated as early as 5-10 min
      after infection. Conversely, virus growth resumed concomitantly with the
      reappearance of acidified ELS after removal of EHext. The fact that the
      inhibitory effect of EHext was completely or partially reversed by FeCl3, a
      tannin-reactive agent, strongly suggests that tannin is one of the active
      components in the extract.

PMID- 10651071
TI  - Inhibition of herpes simplex virus type 1 and adenovirus type 5 by heterocyclic
      Schiff bases of aminohydroxyguanidine tosylate.
AB  - Eleven heterocyclic Schiff bases of aminohydroxyguanidine tosylate (SB-AHGs),
      compounds I-XI, were tested for antiviral activity against herpes simplex virus
      type 1 (HSV-1) and adenovirus type 5 (Ad 5) via plaque reduction and virus yield
      reduction assays. This work was undertaken to test the hypothesis that low
      molecular weight SB-AHGs (MW < 235 for the free SB) make better antiviral agents
      than high MW SB-AHGs (MW > 300). The plaque reduction assay method demonstrated
      that three compounds, I, VII and IX, had moderate activity against HSV-1, with
      50% inhibitory concentration (IC50) values of 38.0, 23.5 and 52.1 microM,
      respectively. Against Ad 5, compounds I, VIII and XI exhibited moderate activity,
      with IC50 values of 52.7, 19.3 and 5.1 microM, respectively. Among the compounds
      screened, compound I (1-[(3'-hydroxy-6'-methyl-2'-pyridyl)methylene]amino-3
      hydroxyguanidi ne tosylate) was the most promising antiviral candidate, with
      selectivity indices (SI) of 10.2 (HSV-1) and 7.6 (Ad 5), respectively. Virus
      yield reduction assays indicated that compound I had less antiviral potency
      against HSV-1 than against Ad 5. The antiviral effects of compound I at a high
      input virus multiplicity of infection (MOI > 5) indicated that compound I had
      effective anti-adenoviral activity at 24 h post infection. This work demonstrated
      that some of SB-AHGs only have moderate antiviral activities against Ad 5 and HSV
      1 viruses. In general, low MW SB-AHGs have low cytotoxicities to the host cells.

PMID- 10651072
TI  - Infective arthritis in adults--experience at a teaching hospital in Kuwait.
AB  - Infective arthritis (InfectA) has a variable geographical pattern. A 'Medline'
      search did not yield any earlier series on epidemiological pattern of InfectA
      from Kuwait or the Gulf region. Therefore, an observational prospective study of
      sequential cases seen over a period of 4 years was carried out. Of a total of
      2021 patients seen during this period, 36 (1.8%) were diagnosed to have InfectA.
      There were 6 (16.7%) cases of neisserial and 30 (83.3%) of non-neisserial
      InfectA. Predisposing factors were seen in 17 (47.2%), all with non-neisserial
      InfectA. Microbiological diagnosis was proven in 15 (41.7%) cases, and included
      Neisseria gonorrhoeae in 5, Brucella spp. in 4, Staphylococcus aureus in 3, and
      Neisseria meningitidis, Salmonella spp. and Mycobacterium tuberculosis in 1 each.
      In the remaining 21 (58.3%) cases the diagnosis was made on clinical grounds and
      confirmed on therapeutic response. The most common presentation of neisserial
      InfectA was acute polyarthritis while that of non-neisserial InfectA was acute
      monoarthritis. All patients recovered with little disability and no mortality.

PMID- 10651073
TI  - Assessment of keratoconjunctivitis sicca in patients with fibromyalgia: results
      of a prospective study.
AB  - Patients with fibromyalgia (FM) often describe the presence of dry eyes and other
      ocular symptoms. It has been claimed that a subgroup of patients with FM might
      have features suggestive of primary Sjogren syndrome. In others, such a
      relationship could not be found. The purpose of the present study was to
      investigate the association and prevalence of keratoconjunctivitis sicca (KCS) in
      patients with FM. Among 285 patients with FM, 40 patients reporting sicca
      symptoms were screened with Schirmer's I test, break-up time and Rose-Bengal
      score. KCS was diagnosed when two of the selected three tests gave pathological
      results. A detailed ophthalmological examination was also performed. In 15
      patients the diagnosis of KCS could be confirmed. Eighteen of 40 patients had
      been taking low-dose antidepressants and 7 of them had objective signs of KCS.
      Eight of 40 patients had signs of chronic blepharitis and 4 of them had KCS.
      Fourteen patients showed unremarkable test results. Chronic blepharitis and the
      use of tricyclic antidepressants may play a role in developing KCS. It seems that
      the rate of KCS does not increase in patients with FM and they probably have
      objective ocular findings comparable with the normal population.

PMID- 10651074
TI  - Effects of interferon-alpha2a treatment on serum levels of tumor necrosis factor
      alpha, tumor necrosis factor-alpha2 receptor, interleukin-2, interleukin-2
      receptor, and E-selectin in Behcet's disease.
AB  - This study was performed to investigate serum levels of various cytokines and E
      selectin in patients with Behcet's disease (BD) before and after treatment with
      interferon-alpha2a (IFN-alpha). The study population consisted of 22 patients
      with active BD; 15 age- and sex-matched healthy adults served as the control
      group. IFN-alpha (3 million units subcutaneously) was given to all patients twice
      a week for 3 months. Twenty of twenty-two patients experienced clinical
      improvement with this therapy. Pre- and post-treatment serum levels of tumor
      necrosis factor-alpha (TNF-alpha), TNF-alpha2-receptor (TNFalpha2R), interleukin
      2 (IL-2), IL-2 receptor (IL-2R), and E-selectin were measured by sandwich-type
      enzyme immunoassay. Baseline E-selectin, TNF-alpha, and TNF-alpha2R levels of the
      patients were increased in comparison with the control group and post-treatment
      values. However, IL-2 and IL-2R levels did not change either with treatment or
      compared with the control group levels. In conclusion, these results confirm the
      previously described efficacy of IFN-alpha in the treatment of BD. Serum levels
      of TNF-alpha, TNF-alpha2R, and E-selectin are prominently increased during active
      stage of the disease, indicating presence of immune system activation and
      endothelial injury/activation. Improvement of the pathological cytokinemia and
      endothelial disturbance accompany interferon-alpha-induced disease remission.

PMID- 10651075
TI  - Thrombomodulin in systemic lupus erythematosus: association with clinical and
      laboratory parameters.
AB  - Thrombomodulin is an endothelial cell membrane glycoprotein and is detected in
      plasma and serum after endothelial injury. In our study comprising 311 patients
      with systemic lupus erythematosus (SLE) clinical and laboratory associations of
      elevated thrombomodulin serum concentrations were examined. Elevated
      thrombomodulin concentrations were detected in 7.1% of the SLE patients and were
      associated with nephritis including the laboratory parameters proteinuria and
      erythrocyte casts, vasculitis and neurological involvement of the central nervous
      system. These correlations remained significant after consideration of the
      influence of renal function. In SLE, the serum thrombomodulin concentration may
      become a marker to monitor damage of endothelial cells and involvement of the
      central nervous system.

PMID- 10651076
TI  - High resolution computed tomography of the lungs in patients with rheumatoid
      arthritis.
AB  - Pulmonary involvement is one of the most common extra-articular manifestations of
      rheumatoid arthritis (RA). The aim of this prospective study was to assess
      pulmonary involvement with high resolution computerized tomography (HRCT) in
      lifelong non-smoking patients with RA. Twenty-six female and eight male patients
      with a mean age of 45.26 +/- 11.6 years and without any evidence or symptoms of a
      respiratory disease were included in the study. Data were obtained regarding
      duration of disease, clinical symptoms and disease activity parameters. Standard
      chest roentgenographs, pulmonary function tests (PFT) and HRCT were performed.
      PFT was abnormal in eight (23.5%) and HRCT was abnormal in 23 patients (68%). The
      most frequent abnormalities obtained on HRCT were interstitial involvement
      including septal and peribronchial thickening and fibronodular infiltration,
      which were found in 23 patients, and bronchiectasis was found in nine patients.
      Using a highly sensitive technique such as HRCT the incidence of pulmonary
      abnormalities in asymptomatic rheumatoid patients may be much higher than
      previously reported.

PMID- 10651077
TI  - Increased CD4+CD16+ and CD4+CD56+ T cell subsets in Behcet's disease.
AB  - Behcet's disease is a systemic vasculitis of unknown etiology. Various immune
      abnormalities have previously been shown in Behcet's disease. We investigated T
      lymphocyte subsets associated with cytotoxic activity and natural killer (NK)
      cells by flow cytometry in 37 patients with Behcet's disease, 38 healthy
      controls, and 17 diseased control patients. Compared to the healthy controls,
      CD4+CD16+ and CD4+CD56+ subsets were found to be higher in the Behcet's disease
      group as well as in the disease control group (CD4+CD16+: BD = 5 +/- 3, DC = 14
      +/- 14, HC = 3 +/- 2, P = 0.001; CD4+CD56+: BD = 11 +/- 5, DC = 18 +/- 17, HC = 8
      +/- 6, P = 0.01). CD8+CD16+ and CD8+CD56+ T cell subsets were at normal levels in
      Behcet's disease but found to be elevated in disease controls. Similarly, NK
      cells (CD16+CD56+) were high only in the disease control group. Significant
      increases in CD4+CD16+ and CD4+CD56+ cell subsets in Behcet's patients and
      disease controls suggest that T cell activation patterns of these subsets in
      Behcet's disease are similar to those in other inflammatory disorders.

PMID- 10651078
TI  - Muscle performance in fibromyalgia syndrome.
AB  - The objective of the study was to examine the muscle performance, isokinetic
      muscle strength, muscle endurance ratio, and submaximal aerobic performance in
      fibromyalgia syndrome (FMS) patients, to evaluate the relation between muscle
      performance, pain severity, clinical findings, and physical activity level, and
      to compare the results with healthy control subjects. Twenty-four FMS patients
      and 15 control subjects participated in this study. Data were obtained about the
      symptoms, location and onset of pain, treatment, and associated symptoms.
      Patients and controls underwent an examination of isokinetic muscle strength of
      right quadriceps on a Cybex dynamometer, and submaximal aerobic performance tests
      (PWC-170) were done for all subjects. Maximal voluntary muscle strength of the
      quadriceps was significantly lower in patients compared with the control group.
      Endurance ratios showing the work capacity were not statistically different
      between two groups. Submaximal aerobic performance scores were higher in the
      control group. There was not a relation between the decreased muscle performance
      and clinical findings, including pain severity, number of tender points, and
      duration of the symptoms of FMS patients. We found a reduced quadriceps muscle
      strength and submaximal aerobic performance in patients with FMS, indicating that
      patients have impaired muscle function.

PMID- 10651079
TI  - Clinical utility of the flow cytometric technique for shared rheumatoid epitope.
AB  - The shared rheumatoid epitope (SRE) on the MHC class II antigen-presenting
      molecule constitutes a probable genetic risk factor for the occurrence of
      rheumatoid arthritis (RA) and may also determine disease severity. We have used a
      novel flow cytometric technique to determine the SRE in over 500 predominantly
      Caucasian patients attending a general rheumatology clinic. This technique has
      been validated against a polymerase chain reaction (PCR)/SSO molecular method.
      The SRE was observed in 90% of patients with Felty's syndrome (n = 10) and 75% of
      patients with RA (n = 178) as compared with 39% of patients with osteoarthritis
      or non-inflammatory rheumatic disorders (n = 73). Thus, the SRE determined by
      this method has a sensitivity for RA of 0.75, a specificity of 0.62 and an
      estimated positive predictive value of 0.02. In our RA cohort, there was no
      correlation between the functional outcome (health assessment questionnaire
      score) and SRE status. In conclusion, the determination of the SRE status by a
      flow cytometric method was found to have only modest sensitivity and specificity
      for RA; furthermore, the SRE did not correlate with functional outcomes. The
      clinical utility of the SRE assay is yet to be defined.

PMID- 10651080
TI  - Oxidant/antioxidant status of plasma samples from patients with rheumatoid
      arthritis.
AB  - This study aims to elucidate plasma oxidant/antioxidant status in patients with
      rheumatoid arthritis (RA). Fasting blood samples were obtained from 24 patients
      with RA and 20 control subjects. Antioxidant potential (AOP) value, nonenzymatic
      superoxide radical scavenger activity (NSSA), and malondialdehyde (MDA) levels
      were measured to establish plasma oxidant/antioxidant status in the patient and
      control groups. Patients with RA had lower AOP and NSSA but higher MDA levels
      than those of the control subjects, which was an indication of reduced
      antioxidant capacity and oxidant stress in these patients. Results suggest that
      the antioxidant system is impaired and peroxidation reactions are accelerated in
      patients with RA. We suppose that therapeutic use of some antioxidants may be
      beneficial in this regard.

PMID- 10651081
TI  - Expression of RANTES in biopsies of skin and upper gastrointestinal tract from
      patients with systemic sclerosis.
AB  - Inflammatory infiltrates and upregulated collagen production are hallmarks of
      systemic sclerosis (SSc). There are indications that chemokines are involved in
      accumulation of inflammatory and matrix-synthesizing cells in SSc skin lesions.
      Therefore, we searched for the expression and localization of the chemokine
      RANTES ("regulated upon activation and normal T cells expressed and secreted") in
      skin and esophageal biopsies from patients with SSc. Using immunohistochemistry
      and in situ hybridization, skin biopsies derived from clinically involved and
      noninvolved skin of 18 patients with early and long-term SSc were examined for
      RANTES expression and compared with nondiseased skin sections of seven patients
      without SSc. In addition, esophageal snap biopsies were taken in a subgroup of
      six SSc patients. Strong expression of RANTES could be detected in the epidermis
      in keratinocytes of patients with short-term and long-term disease, both on the
      mRNA and protein level. The percentage of RANTES-expressing cells were
      significantly higher in clinically noninvolved skin sections than in involved
      skin areas. In contrast, no RANTES expression was found in esophageal biopsies or
      in the control group. The results indicate that RANTES is present in human
      sclerodermatous skin. RANTES may be involved in early pathogenesis of SSc as well
      as in fibrosis pathways, either by chemoattraction of immunocompetent cells
      and/or by modulation of collagen production.

PMID- 10651082
TI  - Clinical relevance of IgA rheumatoid factor (RF) in children with juvenile
      rheumatoid arthritis.
AB  - This study proposed to investigate the prevalence and clinical relevance of serum
      immunoglobulin A (IgA) rheumatoid factor (RF) in juvenile rheumatoid arthritis
      (JRA) as published reports vary in their conclusion. Sera of 82 children with JRA
      and 25-age and sex-matched healthy children were measured for IgA RF by an enzyme
      linked immunoassay using human IgG as the antigen. Forty-three percent of the
      disease population were positive and the prevalence in pauciarticular,
      polyarticular and systemic onset was 9/18 (50%), 21/47 (44.7%) and 5/17 (27.7%)
      respectively when mean + 2SD of normal was taken as the cut-off value. By
      defining the upper limit of normal as mean + 6SD, 16/47 (34%) were positive in
      the polyarticular as compared to 2/18 (11.1%) in pauciarticular and 1/17 (5.8%)
      of systemic onset disease groups. The prevalence in the polyarticular subset with
      the upper cut-off limit was significantly higher than the pauciarticular and the
      systemic onset group (P < 0.05). Furthermore, the mean level of IgA RF was
      significantly higher in the polyarticular group compared to the mean level in the
      systemic onset group (P < 0.05). The mean level of IgA RF was also significantly
      higher (P < 0.05) in 61 children with active diseases.

PMID- 10651083
TI  - Musculoskeletal manifestations with panniculitis--a hospital based study on 62
      patients in Kuwait.
AB  - The study describes 62 patients seen over a period of 4 years mainly presenting
      with an acute inflammatory ankle arthritis/periarthritis associated with
      panniculitis. Based upon the clinical characteristics of panniculitis two
      distinct categories could be defined. These included patients with characteristic
      lesions of erythema nodosum, seen in 51 (82%), the idiopathic form in 29 (57%),
      and secondary EN in 22 (43%). Associated conditions included Behcet's disease,
      oral contraceptive pills, pregnancy and penicillin treatment. Patients clinically
      not having typical EN was seen in 11 (18%). In this group the histopathology
      showed erythema induratum in 4, cutaneous-polyarteritis nodosa with minimal
      panniculitis in 3, Weber-Christian disease, cytophagic histiocytic panniculitis,
      and 'mixed' lobular and septal variety of panniculitis in 1 each. (In 1 patient
      the disease was not panniculitis but cutaneous variant of granuloma annulare). It
      is concluded that in a hospital setting EN associated with acute musculoskeletal
      symptoms, mainly ankle arthritis/periarthritis or an acute peripheral
      polyarthritis, was a common rheumatological problem in Kuwait. However, other
      forms of panniculitides also presented with musculoskeletal manifestations
      requiring accurate histopathological diagnosis for appropriate treatment.

PMID- 10651084
TI  - ABO and Rh blood group distribution in seropositive rheumatoid arthritis.

PMID- 10651085
TI  - Systemic sclerosis and antineutrophil cytoplasmic autoantibody-associated renal
      failure.
AB  - We report three patients who developed antineutrophil cytoplasmic autoantibody
      (ANCA)-associated crescentic glomerulonephritis, two of whom showed clinical
      features of limited scleroderma and one whose results of serological tests were
      suggestive of limited scleroderma without cutaneous features. All had
      anticentromere antibodies and antimyeloperoxidase antibodies. No patient showed
      the features of typical scleroderma renal crisis such as accelerated hypertension
      or microangiopathy. Our patients were normotensive at the time of onset of renal
      failure, and the clinical picture was characterised by only modest features of
      limited scleroderma. All three patients had crescentic glomerulonephritis at
      various stages of chronicity. One patient responded to immunosuppressive therapy
      with improvement in renal function; the other two patients rapidly developed end
      stage renal failure. These patients and others recently described may represent a
      newly described form of scleroderma renal disease.

PMID- 10651087
TI  - Reflex sympathetic dystrophy arising in a patient with familial Mediterranean
      fever.
AB  - A 14-year-old girl with familial Mediterranean fever (FMF) had had acute attacks
      of fever, abdominal pain, and arthritis for 4 years. Her last arthritis attack
      was protracted, leading to reflex sympathetic dystrophy (RSD) in her right lower
      extremity. Physical therapy along with sympathetic ganglion block and
      corticosteroid therapy was used for the treatment. To our knowledge, this is the
      first reported case of RSD arising in a patient with FMF. Early recognition of
      RSD in FMF patients is important, and physical therapy should be applied along
      with medical treatment.

PMID- 10651086
TI  - Polymyositis occurring during alpha-interferon treatment for malignant melanoma:
      a case report and review of the literature.
AB  - Polymyositis is a systemic autoimmune disorder characterised by proximal muscle
      weakness which most frequently involves the limbs, neck and trunk. Alpha
      interferon is an antiviral molecule with well-known immunomodulatory and
      antiproliferative effects, but its use is often associated with a variety of side
      effects, in particular autoimmune phenomena. We report the occurrence of
      polymyositis during treatment with alpha-interferon in a patient affected by
      malignant melanoma. Indirect evidence suggests that in this case the patient's
      myositis was not linked to her neoplasia, since the melanoma was confirmed to be
      in remission both at the time of the diagnosis of the muscle disease and again
      after more than one year of follow-up.

PMID- 10651088
TI  - Protracted familial Mediterranean fever arthritis.
AB  - Familial Mediterranean fever (FMF) is an inherited disorder characterized by
      recurrent attacks of fever and abdominal, chest, and articular pain. The
      articular attack of FMF is typically an acute, self-limited, large joint
      monoarthritis most often affecting the knee or hip. Rarely, a more protracted
      arthritis may occur. We describe two unusual cases of long-standing FMF arthritis
      with excellent response to synovectomy.

PMID- 10651089
TI  - A case of acquired partial lipodystrophy associated with localized scleroderma
      and undifferentiated connective tissue disease.
AB  - The authors describe a case of a 43-year-old woman affected by acquired partial
      lipodystrophy associated with localized scleroderma and undifferentiated
      connective tissue disease. Moreover, they review the literature on pathogenetic
      mechanisms suspected to be involved in partial lipodystrophy and their
      association with autoimmune diseases.

PMID- 10651090
TI  - Histochemistry and cell biology: what's in a name?
AB  - Histochemistry represents an integrative discipline aiming at the in situ
      detection, localization and functional characterization of cellular and
      extracellular components in single cells and complex organs. Therefore, the
      development of new methods and improvement of existing ones continues to be
      important. This, however, is with the declared intent for their application in
      the various fields of developmental and cell biology as well as pathology in
      order to contribute to the solution of open problems. This review summarizes
      recent advancements in these fields.

PMID- 10651091
TI  - Localization of laminin-5, HD1/plectin, and BP230 in the submandibular glands of
      developing and adult mice.
AB  - We studied the distributions of laminin-5 and hemidesmosome components,
      HD1/plectin and BP230, in the submandibular glands of adult and developing mice.
      In adult mice, laminin-5 was expressed in the basement membranes of both the
      myoepithelial cells and excretory ducts. The former expression was predictable
      because laminin-5 is a ligand for hemidesmosomes, which appear in myoepithelial
      cells and stratified epithelium. However, the latter expression pattern suggested
      that the non-stratified epithelium of the excretory duct might also be associated
      with hemidesmosomes. During fetal development, laminin-5 was found in the
      basement membrane of developing ducts but not epithelial end buds in which future
      lobules are formed by epithelial branching. The expression of HD1/plectin but not
      BP230 was noted in the developing duct at early embryonic stages, indicating the
      presence of type II hemidesmosomes. Expression of BP230 appeared in the excretory
      duct epithelium at around the day of birth. At this stage, the typical
      hemidesmosome was observed in the duct epithelium. Our results suggest that
      laminin-5 is involved in duct development rather than epithelial branching. The
      results also suggest that the developing duct epithelium interacts with laminin-5
      through the type II hemidesmosome, which later matures into a typical
      hemidesmosome upon the onset of expression of BP230.

PMID- 10651092
TI  - Localisation and quantification of dehydrogenase activities in single muscle
      fibers of mdx gastrocnemius.
AB  - The kinetics of succinate (SDH) and lactate (LDH) dehydrogenases were determined
      in single muscle fibres in unfixed sections of the gastrocnemius of dystrophic
      mdx mice (with an X-linked genetic disorder lacking a cytoskeletal protein,
      dystrophin) and age-matched C57BL/10 control mice. Quantitative gel substrate
      film techniques and a real-time image analysis system were used. Three main fibre
      types were observed in regenerated mdx gastrocnemius and in corresponding
      controls: small fibres (S) with high SDH and LDH initial reaction velocities and
      activities, large fibres (L) with low activities of these dehydrogenases and
      intermediate-sized fibres (I) with intermediate enzyme activities. The small and
      intermediate fibres in both mdx and control muscles exhibited respectively high
      and moderate sub-sarcolemmal SDH and LDH activities attributable to accumulated
      mitochondria. The ratios of the initial velocities of the intrinsic enzyme
      reactions in the sarcoplasm, excluding the subsarcolemmal regions, of mdx muscle
      fibres compared to those in control fibres were 0.958 (S), 1.09 (I) and 0.959 (L)
      for SDH, and 1.03 (S), 1.06 (I) and 1.07 (L) for LDH. A parameter a, a measure of
      the diffusion of LDH out of muscle sections during incubation on gel substrate
      films, was found to be 0.981 and 1.00 in mdx and control muscles, respectively.
      Thus there are no significant differences in the activities and microenvironments
      of the enzymes between regenerated mdx muscle fibres and normal control muscle
      fibres. These data suggest that dystrophin deficiency in mdx muscles has no
      effects on the interactions of LDH with cytoskeletal proteins or on SDH
      activities in mitochondria whose number and morphology differ in mdx muscle
      fibres compared to those in normal controls. SDH and LDH activities were also
      found in the mitochondria clustered on two longitudinally directed poles of each
      central nucleus in regenerated mdx muscle fibres. They were proportional to the
      activities in the sarcoplasm excluding the subsarcolemmal regions.

PMID- 10651093
TI  - Immunohistochemical localization of thrombomodulin in the stratified epithelium
      of the rat is restricted to the keratinizing epidermis.
AB  - The expression and function of thrombomodulin (TM), an endothelial cofactor
      protein for thrombin-mediated protein C activation, in the epithelium are not
      fully characterized. This report describes the distribution and localization of
      TM in the various types of epithelia in the rat by light and electron microscopic
      immunocytochemistry. TM showed a limited distribution and was expressed by the
      keratinizing stratified epithelia of the skin, tongue, and esophagus, but was not
      present on the non-keratinizing epithelia of the vagina, ureter, trachea,
      stomach, or gut. An identical pattern of TM expression was seen in mucocutaneous
      junctions, transitional zones from a non-keratinizing stratified epithelium to a
      keratinizing epithelium at the edge of the eyelid and in the anal canal. As the
      keratinization of the stratified epithelia proceeded, the staining intensity
      increased in the transitional zones. Within the keratinizing stratified
      epithelia, TM staining was limited to the keratinocytes of the spinous layer, the
      spinous cells. The subcellular localization of TM on the spinous cells was
      restricted to the plasma membrane facing the intercellular spaces. TM was not
      detectable on the desmosomes or the two membranes making up the junction,
      presumably the nexus. The functional significance of TM in keratinizing epithelia
      is discussed.

PMID- 10651094
TI  - "In vivo cryotechnique" in combination with replica immunoelectron microscopy for
      caveolin in smooth muscle cells.
AB  - A novel "in vivo cryotechnique" with replica immunoelectron microscopy was
      developed for detecting caveolin localization on replica membranes prepared
      directly from living smooth muscle cells. After quick-freezing mouse duodenal
      walls by our "in vivo cryotechnique", the specimens were prepared for freeze
      fracture and deep-etch replica membranes. Then they were treated with 5% SDS and
      0.5% collagenase to keep some antigens on the replica membranes. The immunogold
      method could be used to clarify the localization of the caveolin antigen in
      relation to three-dimensional ultrastructures of living smooth muscle cells. Our
      new cryotechnique can provide native organization of functional molecules in
      living cells.

PMID- 10651095
TI  - Localization of factor VIII-related antigen in the endothelium of the chick
      embryo chorioallantoic membrane.
AB  - In this study, by using a polyclonal antibody against factor VIII-related antigen
      (FVIII-RA), we have examined the expression of FVIII-RA in the blood and
      lymphatic vessels of the chick embryo chorioallantoic membrane (CAM). The
      antibody marked the endothelium of blood and lymphatic vessels starting from day
      8 of incubation and the cytoplasm of the allantoic epithelial cells. The
      application of this antibody may be useful for quantifying neovascularization in
      response to various angiogenic stimuli applied to the CAM.

PMID- 10651096
TI  - Identification of prostaglandin F-producing cells in the liver.
AB  - Prostaglandin (PG) F synthase forms PGF(2alpha) and 9alpha, 11beta-PGF2 from PGH2
      and PGD2, respectively. PGH2 is synthesized from arachidonic acid by
      cyclooxygenase (COX) and then metabolized to various PGs and thromboxane by
      specific enzymes. PGD2 is synthesized from PGH2 by PGD synthase. To identify PGF2
      producing cells in the rat liver, the occurrence and localization of PGF synthase
      and COX were studied with immunochemical and immunohistochemical techniques using
      anti-liver-type PGF synthase and anti-COX antibodies. In Western blot analyses,
      positive bands of liver-type PGF synthase and constitutive COX-1 were observed at
      positions approximately 37 kDa and 70-72 kDa, respectively. However, inducible
      COX-2 was not detected. In the immunohistochemical study, PGF synthase was
      present in the cytoplasm of the sinusoidal endothelial cells. COX-1 was present
      on the membranes of the nucleus and endoplasmic reticulum of the endothelial
      cells and Kupffer cells. Double immunostaining for PGF synthase and COX-1 showed
      that both enzymes were present in the same endothelial cells. These results
      suggest that the main site of PGF2 synthesis in the liver is the sinusoidal
      endothelial cell.

PMID- 10651097
TI  - Characterisation of Kir2.0 proteins in the rat cerebellum and hippocampus by
      polyclonal antibodies.
AB  - Rabbit polyclonal antibodies were raised to rat Kir2.0 (Kir2.1, Kir2.2 and
      Kir2.3) inwardly rectifying potassium ion channel proteins. The antibody
      specificities were confirmed by immunoprecipitation of [35S]-methionine-labelled
      in vitro translated channel proteins and western blotting. Immunohistochemistry
      revealed a different patterns of expression of Kir2.0 subfamily proteins in the
      rat hind-brain (cerebellum and medulla) and fore-brain (hippocampus). Notably,
      only Kir2.2 protein was detected in the cerebellum and medulla, Kir2.1, Kir2.2
      and Kir2.3 proteins were expressed in the hippocampus and immunostaining was not
      limited to neuronal cell types. Anti-Kir2.1 (fore-brain only) and anti-Kir2.2
      (fore- and hind-brain) antibodies showed positive staining in macroglia,
      endothelia, ependyma and vascular smooth muscle cells. In contrast, anti-Kir2.3
      (fore-brain only) immunostaining was limited to neurons, macroglia and vascular
      smooth muscle. These results indicate that specific regions within the rat fore-
      and hind-brain have differential distributions of inwardly rectifying potassium
      ion channel proteins.

PMID- 10651098
TI  - Zymographic analysis of equine laminitis.
AB  - To investigate the role of matrix metalloproteinase (MMP) activity in the
      pathophysiology of equine laminitis, the techniques of in situ zymography and
      quantitative SDS-PAGE zymography were used to analyse the lamellae and plasma and
      serum of horses with carbohydrate overload-induced laminitis. The gelatinase
      activity localised within the epidermal lamellae of laminitic hooves did not
      differ significantly from normal hooves. In laminitis sections there was an
      increase in vascular gelatinase activity, possibly associated with the
      perivascular cuffing of polymorphonucleocytes. Both plasma and serum samples from
      horses developing laminitis showed a rapid increase in the concentration of
      circulating latent MMP-9, while MMP-2 remained relatively constant. These results
      support the hypothesis that laminitis histopathology results from an inadequate
      regulation of gelatinase activity, resulting in selective degradation of basement
      membrane components, leading to laminitis due to failure of the basement membrane
      epidermis attachment.

PMID- 10651099
TI  - Terminal differentiation of erythroblasts leads to RNP segregation and formation
      of heterogeneous ectopic RNP-derived structures.
AB  - We show an as yet unnoticed feature of mammalian erythrocyte maturation, i.e.,
      the formation of heterogeneous ectopic RNP-derived structures in the nucleus of
      erythroblasts, occurring in parallel with chromatin condensation. Inside these
      structures, RNPs are always recognized by specific antibodies, which demonstrates
      that the protein moieties of RNPs still preserve (at least partially) their
      native organization. This phenomenon shares extensive similarity with the
      segregation and clustering of nuclear RNPs occurring during spontaneous apoptosis
      of rat thymocytes and in several other cell models in which transcription is
      physiologically arrested.

PMID- 10651100
TI  - Distribution of connexin37, connexin40 and connexin43 in the aorta and coronary
      artery of several mammals.
AB  - Intercellular communication between cells of the vessel wall is established by a
      combination of diffusion and convection of humoral and endothelial factors in the
      extracellular fluid or by direct intercellular contacts present in the form of
      gap junctions composed of proteins called connexins. At least connexin (Cx)37,
      Cx40 and Cx43 are expressed in the vessel wall, but disparate findings with
      regard to the cell specific localisation of connexins in the vasculature indicate
      that the distribution of connexins may be species and vessel specific. Moreover,
      differences in expression exist between cells in culture and tissue sections. We
      performed an inventory immunohistochemical study on the localisation of Cx37,
      Cx40 and Cx43 on tissue sections of the bovine, micropig and rat aorta and
      coronary system, which represent morphologically and functionally different types
      of vessels in the arterial system. We could observe Cx40 labelling most commonly,
      although with various intensities, between endothelial and smooth muscle cells of
      the species studied, with the exception of rat aortic smooth muscle cells. The
      distribution of Cx43 is more differentiated and mostly confined to smooth muscle
      cells, although it can be detected scarcely between endothelial cells. Cx37, when
      detectable, is predominantly expressed between endothelial cells in a
      heterogeneous pattern. We conclude that Cx40 is the constitutive vascular gap
      junction protein in situ and guarantees cell coupling between cells in the vessel
      wall. The differentiated distribution of both Cx37 and Cx43 suggests they are
      involved in more dynamic processes.

PMID- 10651101
TI  - Catecholaminergic activity in the medial preoptic area and nucleus infundibularis
      median eminence of anestrous ewes in normal physiological state and under stress
      condition.
AB  - The stressful events induce in organism both excitatory and inhibitory mechanisms
      for rapid physiological adjustment to environmental stressors. Pull-push
      technique was used to determine extracellular concentrations of NE, DA, and their
      metabolites MHPG and DOPAC in the medial preoptic area (MPOA) and nucleus
      infundibularis-median eminence (NI/ ME) of anestrous ewes in normal physiological
      state and under stress condition. In non-stressed ewes the level of NE in the
      MPOA was substantially lower than in the NI/ME, whereas DA was found only in the
      NI/ME. No regional differences in the concentrations of MHPG, DOPAC in these
      structures were found. On the first day, footshock stimulation activated
      noradrenergic system in the MPOA and both noradrenergic and dopaminergic system
      in the NI/ME during the first 1.5 h followed by gradual desensitisation of these
      systems. On the third day during whole period of stimulation the concentration of
      all these neurochemical compounds were significantly lower than in controls. It
      indicates that prolonged intermittent stress elicits a neurochemical processes in
      the MPOA and NI/ME whose effects lead to the suppression of catecholamines
      release and their metabolism. The basal concentration and stress induced changes
      of NE, DA, MHPG, DOPAC in the fluid of the III-rd brain ventricle (V-III) reflect
      a dynamic relationship between extracellular levels of catecholamines and their
      metabolites in the hypothalamus and cerebral fluid. The consequences of these
      long-term response of catecholaminergic system in the MPOA and NI/ME may be
      essential for changes in LHRH release from the hypothalamus which we observed in
      ewes subjected to prolonged stressful experience (Tomaszewska et al., 1999).

PMID- 10651102
TI  - The role of D2 and D3 dopamine receptors in the mediation of emesis in Cryptotis
      parva (the least shrew).
AB  - This study introduces Cryptotis parva (the least shrew) as a new dopaminergic
      animal model of emesis. The potential emetogenic effects of a nonselective
      dopamine agonist [apomorphine], two D1 agonists [SKF-38393 and SKF-82958], a D2
      preferring agonist [quinpirole], and two D3-preferring agonists [7-(OH) DPAT and
      PD 128, 907] were investigated. Intraperitoneal administration of D1 agonists
      failed to induce emesis. However, other agonists caused a dose-dependent increase
      in the percentage of animals vomiting as well as potentiating the mean frequency
      of emesis with the following ED50, potency order: 7-(OH) DPAT < apomorphine <
      quinpirole < PD 128, 907. For antagonist studies a 2 mg/kg dose of these agonists
      were used to induce emesis. Thus, the inhibitory dose-response effects of a D2
      preferring [sulpride], a D3-preferring [U 99194A] and combination of varying
      doses of these antagonists [sulpride + U 99194A] were evaluated on the ability of
      the cited agonists to produce vomiting. Sulpride decreased the number of shrews
      vomiting and the mean vomiting frequency produced by the cited agonists in a dose
      dependent fashion with the following ID50 order [apomorphine < PD 128, 907 < 7
      (OH) DPAT < quinpirole]. By itself, U 99194A failed to significantly alter the
      emesis produced by any of the cited agonists, however, it potentiated (3-8 times)
      the antiemetic effects of sulpride both in reducing the number of shrews vomiting
      as well as decreasing the mean vomiting frequency with the following ID50 order:
      PD 128, 907 < 7-(OH) DPAT < quinpirole. However, U 99194A attenuated the potent
      antiemetic effect of sulpride on the apomorphine-induced emesis. The results
      suggest that the tested agonists primarily activate dopamine D2 receptors to
      induce emesis in the least shrew whereas activation of D3 sites potentiate the
      vomiting action of D2 dopamine receptors.

PMID- 10651103
TI  - The anticataleptic effect of 7-OH-DPAT: are dopamine D3 receptors involved?
AB  - The paper examined the effect of 7-OH-DPAT (7-hydroxy-N,N-di-n-propyl-2
      aminotetralin), a dopamine D3 receptors-prefering agonist, on the catalepsy
      evoked by reserpine, haloperidol and fluphenazine in rats (male Wistar), as well
      as the influence of nafadotride, a dopamine D3 receptors-prefering antagonist, on
      that effect. The obtained results show that 7-OH-DPAT, as well as L-DOPA, a drug
      of choice in the therapy of Parkinson's disease, used for comparison, antagonize
      the catalepsy induced by reserpine, haloperidol and fluphenazine. Nafadotride,
      used in a dose (0.2 mg/kg) which inhibits the 7-OH-DPAT-evoked locomotor
      hyperactivity but does not affect the hypermotility induced by amphetamine and
      quinpirole, antagonizes the anticataleptic effect of 7-OH-DPAT or L-DOPA. It is
      therefore assumed that dopamine D3 receptors are involved in the anticataleptic
      effect of both 7-OH-DPAT and L-DOPA.

PMID- 10651105
TI  - Selective changes in the contents of noradrenaline, dopamine and serotonin in rat
      brain areas during aging.
AB  - This study examines the age-associated changes in noradrenaline (NA), dopamine
      (DA), 3,4-dihydroxyphenyl-acetic acid (DOPAC), serotonin (5-HT) and 5-hydroxy-3
      indoleacetic acid (5-HIAA) in different brain areas of rats. DA and DOPAC
      concentrations in striatum increased at third month of age, remaining without
      significant variations until 12th month of age, and decreasing in 24-month-old
      rats. DA concentration dropped in hippocampus, amygdala and brainstem of 24-month
      old-rats, whereas DOPAC levels decreased only in hippocampus. These changes
      suggest an age-dependent deficit of the dopaminergic system, presumably related
      to a reduced number/activity of DA nigrostriatal and mesolimbic neurons. An age
      induced decline in NA content was found in the pons-medulla, the area containing
      NA neuronal bodies. Concentrations of 5-HT were reduced with aging in frontal
      cortex, showing a tendency to decrease in all brain areas examined. The increased
      5-HIAA/5-HT ratio found in frontal cortex, amygdala and striatum suggests an age
      related decreased synthesis and an accelerated 5-HT metabolism. The 5-HIAA
      content decreased in brainstem of the oldest rats. These findings point to a
      selective impairment of nigrostriatal and mesolimbic DA in aging rats, whereas
      reductions in NA were restricted to cell bodies region and 5-HT showed changes of
      different extent in areas of terminals and neuronal cell bodies.

PMID- 10651104
TI  - Dynamic changes in glucose metabolism of living rat brain slices induced by
      hypoxia and neurotoxic chemical-loading revealed by positron autoradiography.
AB  - Fresh rat brain slices were incubated with 2-deoxy-2-[18F]-fluoro-D-glucose
      ([18F]FDG) in oxygenated Krebs-Ringer solution at 36 degrees C, and serial two
      dimensional time-resolved images of [18F]FDG uptake were obtained from these
      specimens on imaging plates. The fractional rate constant (= k3*) of [18F]FDG
      proportional to the cerebral glucose metabolic rate (CMRglc) was evaluated by
      applying the Gjedde-Patlak graphical method to the image data. With hypoxia
      loading (oxygen deprivation) or glucose metabolism inhibitors acting on oxidative
      phosphorylation, the k3* value increased dramatically suggesting enhanced
      glycolysis. After relieving hypoxia < or = 10-min, the k3* value returned to the
      pre-loading level. In contrast, with > or = 20-min hypoxia only partial or no
      recovery was observed, indicating that irreversible neuronal damage had been
      induced. However, after loading with tetrodotoxin (TTX), the k3* value also
      decreased but returned to the pre-loading level even after 70-min TTX-loading,
      reflecting a transient inhibition of neuronal activity. This technique provides a
      new means of quantifying dynamic changes in the regional CMRglc in living brain
      slices in response to various interventions such as hypoxia and neurotoxic
      chemical-loading as well as determining the viability and prognosis of brain
      tissues.

PMID- 10651106
TI  - Discrepancies in apparent dopamine D2 receptor occupancy between 3H-raclopride
      and 3H-N-methylspiperone.
AB  - Competitive inhibition of 3H-raclopride (RAC) and 3H-N-methylspiperone (NMSP)
      binding against haloperidol, raclopride and NMSP was measured in the mouse
      striatum. 3H-RAC binding was more sensitive to competitive inhibition by all
      three compounds compared with 3H-NMSP. For example, 0.3 mg/kg of haloperidol
      resulted in 95% inhibition of 3H-RAC binding, however only 60% of inhibition of
      3H-NMSP binding was found at the same dose of haloperidol. The cross-inhibition
      experiments using non-radioactive RAC or NMSP as competitors indicated different
      binding sites for 3H-RAC and 3H-NMSP in mouse striatum. Specifically, about 40%
      of 3H-NMSP binding was not displaced by treatment with a very high dose of
      raclopride (3 mg/kg). The time course of inhibition of the specific binding of 3H
      RAC and 3H-NMSP were measured following i.p. injection of 0.5 mg/kg of
      haloperidol. No significant differences in the kinetics of haloperidol inhibition
      were observed between two radioligands.

PMID- 10651107
TI  - The effect of glia-conditioned medium on dopamine neurons in culture. Modulation
      of apoptosis, tyrosine hydroxylase expression and 1-methyl-4-phenylpyridinium
      toxicity.
AB  - Recent experiments have shown that glia-conditioned medium (GCM) protects against
      L-3,4-Dihydroxyphenylalanine (L-DOPA) toxicity for dopamine neurons in culture.
      In this study we have investigated the effect of GCM on the number of tyrosine
      hydroxylase (TH) immunoreactive neurons, levels of dopamine, number of high
      affinity dopamine uptake sites, and percentage of apoptotic cells in midbrain
      neuronal cultures, before and after exposure to 1-methyl-4-phenylpyridinium
      (MPP+). Fetal midbrain neuronal cultures were treated with vehicle, MPP+, 10(-5)
      M, mesencephalic GCM, or MPP+ plus GCM. GCM was administered a) simultaneously,
      b) 24 hours before MPP+, and c) 24 and d) 72 hours after MPP+, respectively. In
      the absence of GCM, MPP+ reduced the number of TH immunoreactive neurons and
      increased apoptosis. GCM increased the number of TH+ neurons and the levels of
      dopamine and decreased apoptosis. In the cultures treated with GCM and MPP+, GCM
      counteracted the effects of MPP+ and increased the length and arborization of TH+
      neurites. The protective effect of GCM was maximal in cultures co-treated with
      GCM and MPP+ simultaneously, but it also restored dopamine parameters in cultures
      receiving GCM 1 or 3 days after MPP+. The protective effect of GCM was negligible
      in cultures pretreated with GCM and receiving MPP+ 24 hours later. In neuronal
      cultures, grown for 8 days in vitro untreated with MPP+, short term exposure to
      GCM reversed the effect of aging and restored the number of TH+ neurons to levels
      higher than those observed at the time of seeding. Therefore, GCM does not only
      protect against MPP+ but does also induce de novo expression of dopamine
      phenotype in midbrain cultures.

PMID- 10651108
TI  - Nocturnal sleep structure and temperature slope in MPTP treated monkeys.
AB  - The nocturnal sleep of three 1-Methyl, 4-phenyl, 1,2,3,6-tetrahydropyridine
      (MPTP) treated monkeys (one non-motor disabled and two severely motor disabled),
      while held in a primate chair was registered using a reversible system for head
      fixation and chronic recordings. Two electroencephalogram (EEG) channels, one
      electrooculogram (EOG) and one electromyogram (EMG) channel were monitored
      constantly and tape recorded during eight nights for posterior analyses.
      Subcutaneous temperature was registered each minute using a radio telemetry
      system. An analysis of sleep patterns and temperature parameters revealed lighter
      sleep, decreased amounts of slow wave and rapid eye movement (REM) sleep and
      lower temperature values in the two motor disabled MPTP-treated monkeys than in
      the non-motor disabled monkey. The temperature linear slope was negative in the
      case of one disabled monkey for just one night. Although the motor disability of
      the two monkeys was similar, their sleep organization patterns and temperatures
      slopes differed. The present study confirmed the differential vulnerability of
      the nigrostriatal system of monkeys to MPTP, suggesting that if a high cumulative
      dose was needed to reach stable motor alterations, the cumulative dose-effect of
      the toxin independent of the nigrostriatal system might be responsible for non
      motor symptoms that also appear in Parkinson's disease besides the classic
      tetrad.

PMID- 10651109
TI  - Inhibition of catechol-O-methyltransferase (COMT) in the brain does not affect
      the action of dopamine and levodopa: an in vitro electrophysiological evidence
      from rat mesencephalic dopamine neurons.
AB  - In order to study whether the membrane hyperpolarization and firing inhibition
      caused by dopamine and levodopa on rat midbrain dopamine cells are affected by
      the inhibition of brain catechol-O-methyl-transferase (COMT), intracellular
      electrophysiological recordings were made from these neurons maintained in vitro.
      Here we report that a treatment of the cerebral tissue with tolcapone, a central
      and peripheral inhibitor of COMT, does not change the membrane responses of
      midbrain dopamine neurons to dopamine and levodopa. The lack of modification of
      the dopaminergic effects by tolcapone suggests that the pharmacological
      inhibition of intracerebral COMT does not have detectable action on dopamine
      neurotransmission. Therefore, the therapeutic action of tolcapone in Parkinson's
      disease, might be dependent on the reduction of COMT activity in the
      extracerebral tissue.

PMID- 10651110
TI  - GABA transporters (GAT-1) in Alzheimer's disease.
AB  - The presynaptically located gamma-aminobutyric acid (GABA) transporter (GAT-1)
      was studied in a group of patients with Alzheimer's disease (AD) and in a control
      group using the GAT-1 selective radioligand [3H]tiagabine. Post mortem brain
      tissue from frontal cortex, temporal cortex, and caudate nucleus from 18 AD
      patients and 23 age-matched controls were studied. The binding was saturable (Kd
      26 nM) and region specific. There were no significant differences between the
      groups with respect to the binding capacity (Bmax) and binding affinity (Kd). The
      unaltered [3H]tiagabine binding to GAT-1 protein indicates that intrinsic GABA
      neurons are spared in Alzheimer's disease.

PMID- 10651111
TI  - Amyloid precursor proteins in the cerebellar cortex of Alzheimer's disease
      patients devoid of cerebellar beta-amyloid deposits: immunocytochemical study of
      five cases.
AB  - Five human brains affected by Alzheimer's disease (AD), but without cerebellar
      amyloid (A beta) deposits, were investigated for the presence and location of
      amyloid precursor proteins (APP). This was parallel to 6 AD brains with A beta
      deposits, 6 young controls and 6 age-matched controls. Antibodies against A beta
      and two epitopes of APP (amino and carboxy terminals, APP(60-100) and APP(643
      695), respectively) were employed. Accumulations of APP in neurons (mainly
      Purkinje cells) and glial cells in the upper part of the molecular layer were far
      greater than those in age-matched control brains and similar to those in AD
      brains with A beta deposits. This suggests that changes in APP production and/or
      metabolism occur before A beta deposition, or that these changes can occur
      without amyloidogenic processing. More than 60% of positive Purkinje neurons were
      of normal appearance; most of them showed both APP(60-100) and APP(643-695)
      immunoreactivity, but a small number (<21%) reacted with only a single antiserum.
      A small number of Golgi, Lugaro and granule cells were APP immunopositive. In all
      cases, stellate and basket cells were negative, as were most glial cells other
      than those of the molecular layer. Folia showed two different appearances, which
      were particularly well displayed in three cases: "strongly" immunopositive folia
      with high reactivity in Purkinje cells and other neurons, and "weakly"
      immunopositive folia with low neuronal reactivity, but with a large number of
      positive glial cells in the molecular layer. The results are discussed in
      relation to the possible existence of types or stages of the AD process and local
      factors, including specific and non-specific cell factors, in the induction of
      APP accumulation. All these 5 cases were female, but the Apo-E 4 genotype was
      displayed only in two cases.

PMID- 10651112
TI  - Damaged neuronal energy metabolism and behavior are improved by Ginkgo biloba
      extract (EGb 761).
AB  - The standardized extract EGb 761 from the dried green leaves of Ginkgo biloba is
      a complex mixture of ingredients with an uniquely broad spectrum of
      pharmacological activities on the central nervous system e.g. in memory enhancing
      properties and in the regulation of cerebral glucose/energy metabolism. To test
      these effects on both behavioral and metabolic brain parameters, the animal model
      of intracerebroventricular (i.c.v.) streptozotocin (STZ) treatment was used. To
      quantify the experimental data more precisely, animals that were good performers
      were separated from poor performers by means of the holeboard test before i.c.v.
      administration of STZ. Good performers only were considered for the study. After
      a 1-week training period on the holeboard improvement was seen in all animals in
      learning, memory and cognition, and the improvement was maintained over the
      investigation period of 12 weeks in the control group. In this group, the energy
      pool in the cerebral parietotemporal cortex was found to be large and the energy
      turnover high. After triplicate i.c.v. STZ injection, working memory (WM),
      reference memory (RM), and passive avoidance (PA) behavior fell off and continued
      to deteriorate throughout the investigation period. Otherwise there were no
      significant differences in locomotor activity, excluding the possibility that
      activity per se might have contributed to the behavioral abnormalities. These
      were accompanied by a permanent deficit in cerebral energy metabolism. The
      ongoing deterioration in behavior and the maintained deficit in cerebral energy
      metabolism occurring after a triplicate i.c.v. STZ injection were significantly
      slowed down by EGb761. The deficits in learning, memory and cognition were
      partially compensated, and the disturbances in cerebral energy metabolism
      returned to almost completely normal values. These findings underscore the
      beneficial effect of EGb761 that had been reported in dementia disorders.

PMID- 10651114
TI  - Effects of chronic haloperidol and clozapine on vacuous chewing and dopamine
      mediated jaw movements in rats: evaluation of a revised animal model of tardive
      dyskinesia.
AB  - Rats received haloperidol (1.0 mg/kg i.p.) or clozapine (10 mg/kg i.p.), twice
      daily for 4 weeks: vacuous chewing--recorded 26 h after the final injection-
      similarly increased in both groups. Three h later, the rats were challenged with
      dopaminomimetics, and automatically recorded jaw movements were analysed. Both
      apomorphine and a mixture of D1 and D2 receptor agonists (SKF 38393 resp.
      quinpirole) increased jaw movements in haloperidol-treated, but not clozapine
      treated rats; SKF 38393 or quinpirole remained ineffective, when given alone. A
      fixed dose of quinpirole together with increasing doses of SKF 38393, but not a
      fixed dose of SKF 38393 together with increasing doses of quinpirole, produced a
      dose-dependent increase in jaw movements in otherwise non-treated rats,
      suggesting that the noted haloperidol-induced increase was due to a shift in the
      D1-D2 receptor balance towards a predominance of D1 receptors. This study
      presents a new animal model of tardive dyskinesia with predictive validity, good
      reliability and, especially, great efficiency.

PMID- 10651113
TI  - NMDA receptor antagonists acting at the glycineB site in rat models for
      antipsychotic-like activity.
AB  - Several partial agonist and full antagonists acting at the glycine site of the
      NMDA receptors were tested for potential antipsychotic-like properties in rats.
      As models, amphetamine- and phencyclidine (PCP)-induced locomotor activation in
      the open field and PCP-induced impairment of prepulse inhibition of the acoustic
      startle response were employed. In the open field test, partial agonists, D
      cycloserine failed to show any effect, aminocyclopropane carboxylic acid (ACPC)
      enhanced the action of PCP (but not that of amphetamine) and R(+)HA-966
      attenuated the locomotor activation produced by both amphetamine and PCP. Both
      full glycineB antagonists, L-701,324 and MRZ 2/576 attenuated the action of
      amphetamine and PCP but at the doses that also produce transient behavioural
      inhibition in naive animals. A competitive NMDA receptor antagonist CGP 39551 was
      ineffective. In the prepulse inhibition test neither L-701,324 nor MRZ 2/576
      changed sensorimotor gating in naive animals nor attenuated the disrupting
      effects of PCP. The present data do not support antipsychotic profile of glycineB
      full antagonists. However, psychotomimetic potential of glycineB antagonists
      seems to be low.

PMID- 10651115
TI  - Glycogen synthase kinase-3beta, beta-catenin, and tau in postmortem bipolar
      brain.
AB  - Therapeutic concentrations of the anti-bipolar drug lithium inhibit the activity
      of glycogen synthase kinase-3beta, which raises the possibility that this enzyme
      and its substrates may be altered in the brain of subjects with bipolar disorder.
      Therefore, in prefrontal cortical samples from subjects with bipolar disorder and
      age-matched control subjects, we examined the levels of glycogen synthase kinase
      3beta and of two proteins modified by it, beta-catenin and the microtubule
      associated protein tau. There were no significant differences between subject
      groups among these measurements, but there was a tendency for the tau isoform
      profile to be modified in bipolar tissue. Thus, while there are no differences
      between bipolars and controls in prefrontal cortical levels of glycogen synthase
      kinase-3beta, beta-catenin, or tau, tau isoform levels or phosphorylation states
      may be modified in bipolar disorder.

PMID- 10651116
TI  - Mosaicism for a serotonin transporter gene promoter-associated deletion:
      decreased recombination in depression.
AB  - Transcriptional activity of the human serotonin transporter gene (5HTT) is
      modulated by complex interaction of multiple genomic and cellular factors.
      Variability of a polymorphic repetitive element (5HTTLPR) is associated with
      anxiety, depression, and aggression-related traits and may influence the risk to
      develop affective spectrum disorders. 5HTTLPR variants display a unique DNA
      secondary structure that has the potential to regulate the transcriptional
      activity of the associated 5HTT promoter. The structure of the 5HTTLPR is also
      likely to precipitate a 381-bp somatic deletion in the 5HTT's promoter region
      [del(17)(q11.2)] that is observed in 20-60% of genomic DNA isolated from
      mononuclear blood cells and postmortem brain. The localization of the deletion
      breakpoints adjacent to identical putative signal sequences (CAGCC) suggests a
      V(D)J recombinase-like rearrangement event. In comparison with healthy controls,
      del(17)(q11.2)/wildtype sequence ratios showed a decrease of the deleted variant
      in recurrent unipolar depression. Our results also suggest that mosaicism of
      del(17)(q11.2) is likely to be regulated by tissue-specific as well as 5HTTLPR
      dependent mechanisms. The findings confirm that the pericentric region of human
      chromosome 17 is highly unstable and furnishs additional evidence for intricate
      complexity of 5HTT regulation under physiological condition and in disease.

PMID- 10651117
TI  - Descriptive epidemiology of non-Hodgkin lymphomas in a southwestern French
      hematology center: absence of significant relationship with hepatitis C virus
      infection.
AB  - From January 1995 to June 1998, 136 new cases of non-Hodgkin lymphomas (NHLs)
      were seen in our center which serves all the French Basque Country (300000
      inhabitants). The crude and standardized incidence rates were respectively 13.2
      and 7.6 cases/100000/year. The distribution of histologic subtypes according to
      the REAL classification showed a good correlation with the previous published
      data. Eleven patients (8%) were HIV-positive and two (1.4%) were HCV carriers.
      Hence, in our region, contrary to Italy, there is no evidence of relationship
      between HCV and NHLs.

PMID- 10651118
TI  - Therapy related acute myeloid leukemia after exposure to 5-fluorouracil: a case
      report.
AB  - Therapy related acute myeloid leukemia occurs after exposure to various cytotoxic
      agents. Among typical chemotherapeutic agents are the alkylating agents and
      topoisomerase II inhibitors. This type of leukemia has been reported after the
      use of antimetabolites. We report here a patient who developed therapy related
      acute myeloid leukemia secondary to the use of 5-fluorouracil.

PMID- 10651119
TI  - Unfractionated peripheral blood stem cell autografts and CD(34+)-enriched
      autografts have similar long-term culture initiating capacity in multiple
      myeloma.
AB  - CD(34+)-enriched peripheral blood stem cells (PBSC) are increasingly being used
      as an autograft in patients with multiple myeloma (MM). The rationale for the use
      of the CD34+-enriched fraction in MM is the ability to obtain a graft with a
      significant reduction of contamination by plasma cells. However, the effect of
      such a manipulation on the proliferating potential of the engrafted cells is not
      known. We wished to study, as part of a randomized trial comparing the outcome in
      MM patients transplanted with either CD(34+)-enriched cells or unfractionated
      PBSC, the primitive hematopoietic cell content of the autografts using long-term
      culture initiating cell (LTC-IC) assays in 7 MM patients. In 3 patients
      CD(34+)cell-enriched fraction was compared to unfractionated PBSC whereas in the
      remaining 4 patients the LTC-IC assay was performed on total PBSC. The mean
      percentage of CD34+ cells of the CD34+ selected fraction in three patients was
      82% (range 71%-96%) whereas the same percentage in PBSC varied from 0.6% to 10%
      in 4 patients (mean: 4.2%). Out of three patients transplanted with CD34+ cell
      fraction, two patients were found to have a very similar LTC-IC generating
      potential in their CD34+ versus PBSC fractions as this was assessed by the
      clonogenic cell output at week+5 per 10(4) CD34+ cells initiating the culture
      (PBSC: 92 and 168 and CD34+ fraction: 102 and 16, respectively) whereas one
      patient had a slightly different values (PBSC: 51 and CD34+ fraction: 103). When
      the PBSC fraction was compared in all 7 patients, the LTC-IC generation potential
      was very heterogenous, varying from 1.4 to 168. To determine if the selection
      procedure influences the numbers of LTC-IC's in both fractions, we have performed
      limiting dilution assays to determine both the frequency of distribution of
      hematopoietic colonies and the frequency of LTC-IC's in two patients. The
      frequency of distribution of hematopoietic colonies was linear in both CD34+ and
      PBSC fractions as was the frequency of LTC-IC when the corrections were made with
      regard to the CD34+ cell-content of the cultures (1/20). Our results indicate
      that the CD34+ selection procedure used in all three patients (Ceprate) is not
      deleterious for the generation of LTC-IC's and these findings support the
      rationale for the use of this procedure in multiple for the purposes of tumor
      depletion.

PMID- 10651120
TI  - Changes in AgNOR configurations during the evolution and treatment of chronic
      lymphocytic leukemia.
AB  - The evolution of the pattern of nucleolar organiser regions (AgNORs) in
      circulating lymphocytes during the stable phase and after chemotherapy in CLL was
      analysed. Peripheral blood smears were stained by the AgNOR technique at
      diagnosis, during observation follow-up in stable phase, or at the beginning and
      at the end of chemotherapy in patients with progressive disease. The changes in
      the AgNOR pattern were compared with those of TTM used as a tumour burden
      parameter. Among 52 cases that entered the study, 29 were in stable phase and 23
      had progressive disease and received chemotherapy. During stable phase, the
      AgNORs as well as TTM remained constant. In treated patients, the relative
      reduction of tumour mass was correlated with a decrease in the percentage of
      lymphocytes containing one AgNOR cluster. The percentage of cells with one
      compact nucleolus before chemotherapy was inversely correlated with the relative
      amount of tumor reduction after treatment. We conclude that the AgNOR pattern in
      CLL describes the cell kinetic changes during the evolution of the disease and is
      a prognostic factor for tumor reduction after treatment.

PMID- 10651121
TI  - Comparison of the classical manual pushed wedge films, with an improved automated
      method for making blood smears.
AB  - Comparison of apparatus for automatically spreading peripheral blood films
      (GENES) to manual wedge-pull technique has been performed, showing that the
      average size of optimal area for counting is twice larger in automated smears
      compared to manual ones. The variability of WBC repartition has been studied in
      doing differential count on manual and automated smears and both are compared to
      results obtain with an independent technique (Coulter STKS) for differential. The
      correlation coefficients for each WBC population show a closer relationship
      between automated smear preparations and reference instrument (STKS) than with
      manual spreading smears. Monocyte differential is particularly influenced by the
      variability of manual spreading procedures.

PMID- 10651122
TI  - New results in clinical severity of homozygous sickle cell anemia, in Dakar,
      Senegal.
AB  - Despite the unicity of its genetic mutation, Sickle cell homozygosity presents
      different clinical features. Our objectives were to evaluate disease severity in
      Senegalese patients. Sixty (60) homozygous sickle cell patients were followed up
      monthly during one year and disease severity was assessed using the "severity
      index" (SI) which is resulting from epidemiologic, clinic and biological data.
      Mean age was 20.13, sex ratio was 0.87 and mean age of diagnosis was 9.8 years.
      90% of patients presented vaso-occlusive crisis (2.53 per patient), 73.3% had
      infectious episodes (1.9 per patient), 69.3% had never been transfused and 25% of
      patients had presented chronic complications linked to anemia or ischemia. Mean
      hemoglobin value was 8.1 g/dl and mean Hb F was 8.2%. Low seric ferritin was
      found in 1.7% of patients. Benign form of homozygous sickle cell anemia (SI< or
      =6) was found in 48.3% of patients. Our data confirm the relative good tolerance
      of homozygous sickle cell disease in Senegal. The haplotype Senegal may play an
      important role but others host and environmental factors operate certainly
      because some severe cases were identified in our patients. The identification of
      all these factors might contribute to a better follow up of sickle cell disease.

PMID- 10651123
TI  - Conception and organisation of a cell therapy unit of Nantes, France.
AB  - Manufacturing of cell therapy products has to follow several requirements to
      obtain sanitary security and quality of the product. Thus, at its conception, the
      cell therapy unit (CTU) of Nantes choose to integrate a quality assurance system:
      - The good manufacturing practices (GMP's) are a technical reference for the
      Unit. They are a quality criteria necessary to guarantee the security of products
      in term of staff, premises, material, matter and method; - The ISO 9001 standards
      are a model for quality assurance in design, development, production,
      installation and servicing. They established a quality system; - The creation,
      the running and the maintenance of premises are an essential aspect of the
      quality system and they are described in this paper. Thus, from October 1994 to
      June 1998, 450 cell processing (with or without cryopreservation and storage of
      cells) have been realised at the CTU of Nantes, leading to 160 injections without
      major undesirable effect and without microbiological contamination.

PMID- 10651124
TI  - Primary MALT lymphoma of the kidney.
AB  - A primary mucosa associated lymphoid tissue tumor (MALT) of the kidney in a 50
      year-old man who suffered from on therapy resistant high blood pressure over 15
      years period is presented. A mass in the right kidney (6x5x3 cm) during routine
      check up was discovered on ultrasonography and confirmed on CT scan and NMR. The
      patient was submitted to nephrectomy. A mass involving kidney, pyelon and upper
      part of the ureter was found. Histology showed low grade non-Hodgkin B-cell
      lymphoma of MALT type. The neoplastic cells were positive for monoclonal
      antibodies CD20, CD79alpha, surface and cytoplasmic and IgM immunoglobulins and
      showed light chain restriction (kappa+). After histology was available, a careful
      staging was performed. The disease was not found anywhere else. It was concluded
      that the patient belonged to the stage IE of primary kidney MALT lymphoma.
      Gastroscopy showed signs of chronic superficial gastritis. Urease test was
      positive and IgG antibodies against Helicobacter pylori in titer 421 were found
      as well. Except for Helicobacter pylori no additional therapy was given.

PMID- 10651125
TI  - Splenic lymphoma with villous lymphocytes: dissociated response with fludarabin.

PMID- 10651126
TI  - Crystallization in the nephron.

PMID- 10651127
TI  - Anatomy and physiology of the male urethral sphincter and its preservation in
      prostatic surgery.

PMID- 10651128
TI  - The effect of pH changes on the crystallization of calcium salts in solutions
      with an ion composition corresponding to that in the distal tubule.
AB  - The effect of pH changes on the crystallization in solutions with an ion
      composition assumed to correspond to that of urine in the distal part of the
      distal tubule was examined by recording the number and volume of crystals with a
      Coulter Multisizer and by studying the crystal morphology with scanning electron
      microscopy at different degrees of volume reduction. The experiments were carried
      out with 100 ml samples at different starting pH values without and with 20% of
      dialysed urine (dU). The number of crystals increased in response to the volume
      reduction. In solutions without dU, 100 or more crystals with a diameter in the
      range 2.4-45 microm were observed already at a volume reduction of 40% when the
      initial pH was 7.28. For solutions with a pH of 5.80 and 6.45 the corresponding
      values were 60% and 80%, respectively. In the presence of dU, an appearance of
      crystals was recorded at volume reductions of less than 20%. In solutions with an
      initial pH of 5.80 and 6.45, the crystal number was greater with dU than without;
      such a difference was not recorded at pH 7.28. In samples containing dU, the mean
      crystal volume (MCV) varied very little when the sample volume was reduced. The
      same was found in solutions without dU when the initial pH was 5.80 and 7.28,
      whereas the MCV was greater in the samples with pH 6.45. Scanning electron
      microscopy of solutions reduced to 30-40% of the original volume showed that
      calcium phosphate had formed in solutions with a starting pH of 7.28 and 6.45. In
      solutions with pH 5.80 calcium oxalate crystals were observed with calcium
      phosphate.

PMID- 10651130
TI  - Study of inhibition mechanisms of glycosaminoglycans on calcium oxalate
      monohydrate crystals by atomic force microscopy.
AB  - Atomic force microscopy (AFM) was applied to the (-101) faces of calcium oxalate
      monohydrate (COM) crystals grown from calcium oxalate (CaOx) solutions.
      Microstructures of many spiral hillocks with step height of 1 nm were observed on
      the faces. Then using AFM in situ, we analysed the re-growth process of the
      spiral steps on the face of COM seed-crystals in CaOx growth solutions that
      contained growth inhibitors of glycosaminoglycans and studied their inhibition
      mechanisms on COM crystals. The total morphology of the faces of COM seed
      crystals re-grown in the CaOx growth solutions was assessed by scanning electron
      microscopy (SEM). In the growth solution without glycosaminoglycans (control
      experiment) or with chondroitin sulphate (ChS), AFM images and SEM micrographs of
      the faces of the re-grown seed crystals showed two-dimensional (2D) nucleation
      although 2D nucleation was delayed in the presence of ChS. However, the addition
      of dermatan sulphate (DS) to the growth solution resulted in isotropic growth by
      a step flow mode and spiral mechanism. With regard to the main inhibition
      mechanisms of two glycosaminoglycans (ChS and DS) on COM crystals, it can be
      concluded from these results that ChS delays 2D nucleation and DS inhibits 2D
      nucleation.

PMID- 10651129
TI  - Crystallization during volume reduction of solutions with a composition
      corresponding to that in the collecting duct: the influence of hydroxyapatite
      seed crystals and urinary macromolecules.
AB  - To examine the effect of hydroxyapatite (HAP) seed crystals and urinary
      macromolecules on the crystallization under conditions similar to those in the
      collecting duct, we evaporated 100 ml samples of salt solutions with an ion
      composition assumed to correspond to that in the collecting duct without and with
      HAP seed crystals. The crystallization in seeded solutions was assessed both with
      and without dialysed urine (dU). After evaporation the number and volume of
      crystals were recorded in a Coulter Multisizer and the crystal morphology
      examined with scanning electron microscopy (SEM) and X-ray crystallography.
      Addition of HAP crystals was apparently followed by an approximately 15-20%
      increase in heterogeneous nucleation of calcium oxalate (CaOx). In these
      experiments SEM and X-ray crystallography showed a high percentage of CaOx in the
      precipitate. In samples reduced to 40-69 ml, addition of dU to the collecting
      duct solution containing HAP seed resulted in a greater mean (SD) number of
      crystals; 3895 (1841) in samples with dU and 1785 (583) in samples without. This
      was mainly explained by an increased mean (SD) number of small crystals. The mean
      crystal volume was 17.8 (1.1) and 34.3 (9.1) in samples reduced to 40 69 ml with
      and without dU, respectively. This might reflect the inhibitory effect of dU on
      the growth and/or aggregation of the CaOx-CaP precipitate or a promoted
      nucleation resulting in a large number of small crystals. It is concluded that
      calcium phosphate formed above the collecting duct might induce heterogeneous
      nucleation of CaOx at lower levels of the renal collecting system, and that
      urinary macromolecules are powerful modifiers of these processes.

PMID- 10651131
TI  - Feline penile erection induced by transurethral administration of sodium
      nitroprusside.
AB  - Nitric oxide (NO) is an important mediator in the relaxation of cavernosal smooth
      muscle. The aim of this study was to investigate the in vivo feline erectile
      response after transurethral administration of sodium nitroprusside (SNP), a NO
      donor drug. Erectile responses after administration of transurethral SNP were
      compared with those elicited by an intracavernosal control triple-drug
      combination (1.65 mg papaverine, 25 microg phentolamine, and 0.5 microg
      prostaglandin E1). SNP was administered via a 20-gauge Jelco intravenous catheter
      in a volume of 200 microl and changes in intracavernosal pressure, penile length,
      and systemic blood pressure were monitored. The control triple-drug combination
      was administered via a 30-gauge needle at the end of each experiment to serve as
      a control reference. Transurethral administration of SNP (1-4 mg) induced penile
      erection in a dose-dependent manner with minimal changes in systemic blood
      pressure. The maximum increase in intracavernosal pressure and penile length
      after transurethral administration of SNP (4 mg) was significantly less than
      after the intracavernosal injection of the control triple-drug combination
      (P<0.01). These data suggest that transurethral administration of SNP can induce
      an erectile response in cats with minimal side effects.

PMID- 10651132
TI  - Comparison of the synergistic effects of tamsulosin versus phentolamine on penile
      erection: in vitro and in vivo studies.
AB  - In vitro and in vivo studies were performed to determine the potential use of
      tamsulosin (TAM) versus phentolamine (PHE) for intracavernosal injection (ICI)
      therapy when mixed with papaverine (PAP) and/or prostagladin E1 (PGE1) or with
      vasoactive intestinal polypeptide (VIP) for the treatment of erectile
      dysfunction. We performed isometric tension studies on rabbit (n = 15), dog (n =
      5), and human (n = 10) cavernous smooth muscle strips with TAM, PAP, PHE, VIP,
      PGE1, and the combinations of PAP and PHE; PAP and TAM; VIP and PHE; VIP and TAM;
      PAP, PGE1 and PHE; and PAP, PGE1 and TAM. TAM-containing trimix (PAP 18.75 mg,
      PGE1 6.25 micromg, and TAM 0.875 mg per ml) or PHE-containing trimix (PAP, PGE1,
      and PHE 0.625 mg per ml) were also injected into the cavernous bodies of ten
      mongrel dogs. Among the single agents, TAM and PGE1 (only in human) had the
      strongest effect on the relaxation of cavernous muscles in rabbit, dog, and human
      strips (P<0.05). Relaxation responses to 2- or 3-drug mixtures containing
      tamsulosin were also significantly better (P<0.05) than PHE-containing ones in
      rabbit, dog, and human strips. The increase in intracavernosal pressure with a
      TAM-containing trimix was higher than with a PHE-containing one (0.03 ml; 81.2
      vs. 75.8 mm Hg, 0.04 ml; 103.2 vs. 94.3 mm Hg), although not statistically
      different. The drop in systemic blood pressure was lower after injection of a TAM
      containing trimix than a PHE-containing one, although not statistically
      different. In conclusion, tamsulosin might be a more efficacious and safer agent
      to use for ICI therapy than phentolamine.

PMID- 10651133
TI  - Up-regulation of endothelin (ET(A) and ET(B)) receptors and down-regulation of
      nitric oxide synthase in the detrusor of a rabbit model of partial bladder outlet
      obstruction.
AB  - Bladder outlet obstruction (BOO) is associated with altered bladder structure and
      function. Endothelin-1 (ET-1) has mitogenic and potent contractile properties.
      There are two ET receptors: ET(A) and ET(B). Nitric oxide synthase (NOS) is the
      enzyme responsible for the synthesis of nitric oxide (NO) which is involved in
      smooth muscle relaxation. We investigated whether there are any changes in the
      density of ET-receptors and NOS in the detrusor and bladder neck in a rabbit
      model of BOO. Partial BOO was induced in adult male New Zealand White rabbits.
      Sham operated age-matched rabbits acted as controls. After six weeks the urinary
      bladders were excised and detrusor and bladder neck sections incubated with
      radioligands for ET-1, ET(A) and ET(B) receptors and with [3H]-1-NOARG (a ligand
      for NOS). NADPH histochemistry was also performed. BOO bladder weights were
      significantly increased (P = 0.002). ET-1 binding and ETA receptor binding sites
      were significantly increased in the BOO detrusor smooth muscle (P = 0.04, P =
      0.03 respectively) and urothelium (P = 0.002, P = 0.02 respectively). ET(B)
      receptor binding sites were also significantly increased in the BOO detrusor
      smooth muscle (P = 0.04). However, there was no change in the BOO bladder neck.
      NOS was significantly decreased in the detrusor smooth muscle (P = 0.003) and
      urothelium (P = 0.0002). In the bladder neck NOS was also significantly reduced
      in the urothelium (P = 0.003). NADPH staining was decreased in the detrusor and
      bladder neck. The up-regulation of ET receptors along with the down-regulation of
      NOS in the detrusor may contribute to the symptoms associated with BOO. Since ET
      1 has a mitogenic role, especially via its ETA receptors, the increase in ETA
      receptors may also be involved in detrusor hyperplasia and hypertrophy in BOO. ET
      antagonists may therefore have a role in the treatment of patients with BOO.

PMID- 10651134
TI  - The effects of cold-restraint stress on urinary bladder wall compared with
      interstitial cystitis morphology.
AB  - Stress is associated with many diseases of unknown aetiology. This study
      demonstrates the effects of cold-restraint stress on the morphology of the
      urinary bladder. Additionally, it compares the results obtained with the
      morphology of the interstitial cystitis. The animals were subjected to three
      hours of cold-restraint stress and then starved for 48 h. The morphology and
      histochemistry of the urinary bladder was investigated with light and electron
      microscopy. The proliferative activity was analysed via flow cytometry. Increased
      and degranulated mast cells in the mucosa, leucocyte infiltration in the lamina
      propria, vacuole formation in the urothelial cells, loose tight junction, dilated
      intercellular spaces and altered proliferative activity were observed in the
      stress group when compared with the control. The increase in the number of mast
      cells and especially degranulated mast cells and vacuole formation and the loose
      tight junction of the urothelium correlated with the histopathological findings
      of interstitial cystitis.

PMID- 10651135
TI  - Obstructive uropathy versus nephropathy: compartmental analysis in radioisotopic
      renography as a new methodology.
AB  - A study was carried out to determine the spatial-temporal distribution of the
      radiopharmaceutical, 99mTc-DTPA in the kidney and its compartments during
      renography and the use of compartmental analysis to improve the diagnostic
      capability of renography. A total of 60 individuals formed three groups: group A
      consisted of 30 normals taken as controls, group B consisted of 15 patients with
      unilateral nephropathy, and group C consisted of 15 patients with unilateral
      obstructive uropathy. This retrospective study was performed by processing of the
      frames acquired in the various stages of renography and determination of the time
      distribution of radioactivity in the aorta, the renal parenchyma and the renal
      pelvis. The data acquired were used to produce three curves instead of one for
      each kidney and to study renal function as a system of six compartments (aorta,
      left and right renal parenchyma, left and right renal pelvis, and bladder). In
      all the above compartments the differences among the three groups were
      significant and were quantified using the flow coefficients of the aortorenal
      compartments. The differences between the aortic flow coefficients (k1) were
      statistically significant not only between normal controls and patients, but also
      between individuals with parenchymatic dysfunction and patients with
      pelvocalyceal obstruction. The same differences were seen comparing the
      pelvocalyceal coefficients (k3) of all three groups. The parenchymatic
      coefficient (k2) presented statistically significant differences between normals
      and patients which were not observed between the two groups of patients (B and
      C). Compartmental analysis thus increases the sensitivity of renography, is
      objective by utilizing quantitative parameters, enables the separate analysis of
      the functional behavior of the various renal compartments, and improves the
      differential diagnosis between parenchymatic dysfunction and pelvocalyceal
      obstruction.

PMID- 10651136
TI  - Alterations in the formation of cyclic nucleotides and prostaglandins in the
      lower urinary tract of the diabetic rabbit.
AB  - Dysfunction of the urinary bladder is a recognised complication of diabetes
      mellitus (DM) which has been attributed, in part, to a direct effect on bladder
      smooth muscle tissue. The objective of this study was to investigate the effect
      of alloxan-induced DM on endogenous modulators of smooth muscle tone such as
      cyclic AMP (cAMP), cyclic GMP (cGMP) and prostaglandins. Male New Zealand white
      rabbits were rendered diabetic (hyperosmolar, non-ketotic) with an i.v. injection
      of alloxan. After 6 months, the urinary bladders and urethrae were excised, cut
      into segments, incubated with stimulators and the formation of prostaglandins
      (PG), cAMP and cGMP measured using radioimmunoassays. PGE2 and PGI2 formation was
      impaired in response to arachidonic acid stimulation, whereas it was increased in
      response to acetylcholine in DM detrusor, bladder neck and urethra compared to
      controls. Cyclic AMP and cGMP formation in response to forskolin and sodium
      nitroprusside, respectively, was significantly reduced in the DM tissues of the
      lower urinary tract compared to the control. Alterations in the formation of
      prostaglandins, cAMP and cGMP by the smooth muscle of DM lower urinary tract
      suggests that these biochemical mediators may have a pathophysiological role in
      the urinary bladder dysfunction associated with DM.

PMID- 10651137
TI  - Sprouting of bladder nerves into cystoplastic cecal segment in the rat.
AB  - Incorporation of bowel into the bladder (enterocystoplasty) has been widely used
      to increase bladder capacity. It has been reported by others that the response of
      smooth muscle from the cystoplastic segment of the intestine shifts from that of
      the intestine (relaxation to alpha-agonists and ATP) to that of the bladder
      (contraction to alpha-agonists and ATP). This suggests a functional integration
      of the intestinal muscle into the bladder; the mechanisms are unknown. The aims
      of the present study were (1) to elucidate if there are signs of bladder nerves
      sprouting across the anastomosis into the intestinal segment, and (2) to study
      what happens with the intrinsic innervation of the intestinal segment. As a
      model, we used cecocystoplasty in rats. The bladder was opened and a patch of
      cecum with intact vascular supply was anastomosed to the bladder. After two to 11
      months the rats were sacrificed and the bladders mounted as wholemounts and
      stained for acetylcholinesterase-containing nerves, or embedded in paraffin for
      histology. A pronounced degeneration of the myenteric plexus was found in the
      cecal segments. In some areas, this had proceeded to the extent that the ganglia
      were isolated ovoid lumps of cells with no apparent connection to other ganglia.
      Areas lacking ganglia and nerve trunks but still with muscle could be found in
      all specimens. Abundant axon bundles were demonstrated sprouting from the cut
      bladder nerves close to the anastomosis. The bundles spread out in a fan-like
      pattern or were organized as fewer thicker nerves. There were many nerve bundles
      entering the cecal segment where they branched and the diameter decreased till
      they no longer became visible. Some nerves reached surviving lumps of myenteric
      ganglion cells. The results show that the bladder nerves sprout into the
      anastomosed cecal segment. It is reasonable to assume that these nerves are
      responsible for the changes in receptor pharmacological properties of the cecal
      smooth muscle towards that of bladder muscle.

PMID- 10651138
TI  - Clinical application of an in vitro chemosensitivity test, the Histoculture Drug
      Response Assay, to urological cancers: wide distribution of inhibition rates in
      bladder cancer and renal cell cancer.
AB  - To investigate the variations in chemosensitivity of individual cancers, we
      performed an in vitro chemosensitivity test, the Histoculture Drug Response Assay
      (HDRA), on fresh biopsied or surgical specimens. They were 26 bladder cancers and
      19 renal cell cancers. Ten anticancer drugs were tested. By prolonging the drug
      exposure time to 7 days, we obtained reliable results. The mean inhibition rates
      (IRs) were higher for bladder cancer than for renal cell cancer, and the
      difference was significant for cisplatin, carboplatin, vinblastine, mitomycin C,
      and adriamycin. There was no significant correlation between the histological
      grade of the tumor and HDRA sensitivity. IR values showed a wide distribution and
      cancers could be classified into two groups of sensitive and resistant. This was
      especially true for 4-hydroxy-ifosfamide. Three bladder cancer patients with
      evaluable lesions were treated with drugs selected on the basis of the results of
      the HDRA. One patient achieved a complete response and the other patients showed
      a partial response. Our results suggest that chemosensitivity is independent of
      the clinicopathological classification of cancer, and that the HDRA may be useful
      for selecting the effective anticancer drug for patients with urological cancer.

PMID- 10651139
TI  - Influence of interferon-alpha2b (IFN-alpha2b) on the prevention of locally
      advanced bladder carcinoma in mice.
AB  - In the model of chemically induced bladder carcinoma in mice following
      application of betahydroxylbutylnitrosamine (BBN) we could not detect a
      therapeutic influence of systemic treatment with intraperitoneal injection of
      interferon-alpha2b (10x3x10(5) IU IFN-alpha2b) on the rate of locally advanced
      bladder carcinoma (IFN-alpha2b 37% versus control 41%) nor on the development of
      tumor precursors (severe dysplasia 100% in both groups).

PMID- 10651140
TI  - Sphingolipid receptor signaling and function in human bladder carcinoma cells:
      inhibition of LPA- but enhancement of thrombin-stimulated cell motility.
AB  - Sphingosine-1-phosphate (SPP) induces a variety of cellular responses, including
      Ca2+ signaling, proliferation, and inhibition of motility, apparently by acting
      at specific G protein coupled receptors. Here, the expression, signaling, and
      motile responses of sphingolipid receptors were examined in human bladder
      carcinoma (J82) cells, for which lysophosphatidic acid (LPA) and thrombin act as
      potent agonists. SPP potently and rapidly mobilized Ca2+, stimulated
      phospholipases C and D, and inhibited cAMP accumulation, without affecting growth
      of J82 cells, which express the recently identified SPP receptors, Edg-1 and Edg
      3. The effects of SPP were mimicked by sphingosylphosphorylcholine (SPPC) and
      strongly attenuated by pertussis toxin (PTX). SPP and SPPC by themselves induced
      a small, PTX-sensitive motile response. However, stimulation of cell motility by
      LPA, which by itself was also PTX-sensitive, was blocked by SPP and SPPC. In
      contrast, motility stimulation by thrombin, which by itself was PTX-insensitive,
      was strongly augmented by the sphingolipids in a PTX-sensitive manner. The
      bidirectional regulation of LPA- and thrombin-stimulated motility was not due to
      selective alterations in the activation of Rho GTPases which control cell
      motility. In fact, RhoA activation and Rho-dependent actin stress fiber formation
      induced by LPA and thrombin were mimicked, but not altered by SPP and SPPC. We
      conclude that J82 cells express sphingolipid receptors, coupled via G proteins to
      several signaling pathways. Most importantly, these sphingolipid receptors
      potently regulate thrombin- and LPA-stimulated motility, but in opposite
      directions, suggesting that migration of these human bladder carcinoma cells is
      controlled by a complex network of interacting extracellular ligands.

PMID- 10651141
TI  - 5-HT1B receptors modulate release of [3H]dopamine from rat striatal synaptosomes:
      further evidence using 5-HT moduline, polyclonal 5-HT1B receptor antibodies and 5
      HT1B receptor knock-out mice.
AB  - In previous paper based on classical pharmacological tools, we identified a Gi
      protein-coupled presynaptic 5-hydroxytryptamine (5-HT) 1B receptor causing
      inhibition of dopamine (DA) release in rat striatal synaptosomes. It was the aim
      of the present study to further explore this receptor, using 5-HT moduline, a
      polyclonal antibody directed against 5-HT1B receptors and 5-HT1B receptor knock
      out mice. Preincubation of rat striatal synaptosomes with 5-HT moduline (0.1, 1,
      or 10 microM) significantly reduced the inhibitory effect of CP93,129, a
      selective rat 5-HT1B receptor agonist, on K+-evoked overflow of [3H]DA in a non
      competitive manner: 5-HT moduline did not modify the IC50 of CP93,129, but
      concentration-dependently reduced the maximal inhibitory effect. Preincubation of
      rat striatal synaptosomes with a specific polyclonal 5-HT1B receptor antibody
      also resulted in a significant attenuation of the inhibitory effect of CP93,129
      on K+-evoked overflow of [3H]DA. In female 129/Sv wild-type mice, CP93,129 and 5
      carboxyamidotryptamine maleate (5-CT), a non-selective 5-HT1B receptor agonist,
      inhibited the K+-evoked [3H]DA overflow in a concentration-dependent manner.
      Sumatriptan, a selective rat 5-HT1D receptor agonist, did not modify the overflow
      of [3H]DA. SB224289, a selective 5-HT1B receptor antagonist, abolished the
      inhibitory effects of CP93,129 and 5-CT. The inhibitory effects of CP93,129 and 5
      CT were absent in synaptosomes from 5-HT1B receptor knockout mice. No
      compensatory inhibition effect in mutant mice was observed using sumatriptan. In
      conclusion, the results show that a non-competitive antagonist of the 5-HT1B
      receptor concentration-dependently decreases the maximal inhibitory effect of a 5
      HT1B receptor agonist on the synaptosomal K+-evoked release of [3H]DA in
      striatum. Moreover, a specific antibody raised against the receptor and
      particularly directed against a region of the receptor protein involved in signal
      transduction, namely the coupling with the G-protein, also antagonizes the
      inhibitory effect of the stimulation of 5-HT1B receptor on the release of [3H]DA.
      Ultimately the disruption of 5-HT1B receptor gene in 5-HT1B knock-out mice leads
      to a total suppression of the effect of 5-HT1B receptor agonists on [3H]DA
      release. These observations further support our previous observations using
      selective agonists/antagonists, indicating that 5-HT1B receptors control the
      release of neuronal DA as presynaptic heteroreceptors.

PMID- 10651142
TI  - Inhibition of serotonin release in the mouse brain via presynaptic cannabinoid
      CB1 receptors.
AB  - We studied whether serotonin release in the CNS is inhibited via cannabinoid
      receptors. In mouse brain cortex slices preincubated with [3H]serotonin and
      superfused with medium containing indalpine and metitepine, tritium overflow was
      evoked either electrically (3 Hz) or by introduction of Ca2+ (1.3 mM) into Ca2+
      free K+-rich (25 mM) medium containing tetrodotoxin. The effects of cannabinoid
      receptor ligands on the electrically evoked tritium overflow from mouse brain
      cortex slices preincubated with [3H]choline and on the binding of [3H]WIN 55,212
      2 and [35S]GTPgammaS to mouse brain cortex membranes were examined as well. In
      superfused mouse cortex membranes preincubated with [3H]serotonin, the
      electrically evoked tritium overflow was inhibited by the cannabinoid receptor
      agonist WIN 55,212-2 (maximum effect of 20%, obtained at 1 microM; pEC50=7.11)
      and this effect was counteracted by the CB1 receptor antagonist SR 141716
      (apparent pA2=8.02), which did not affect the evoked tritium overflow by itself.
      The effect of WIN 55,212-2 was not shared by its enantiomer WIN 55,212-3 but was
      mimicked by another cannabinoid receptor agonist, CP-55,940. WIN 55,212-2 also
      inhibited the Ca2+-evoked tritium overflow and this effect was antagonized by SR
      141716. Concentrations of histamine, prostaglandin E2 and neuropeptide Y, causing
      the maximum effect at their respective receptors, inhibited the electrically
      evoked tritium overflow by 33, 69 and 73%, respectively. WIN 55,212-2 (1 microM)
      inhibited the electrically evoked tritium overflow from mouse brain cortex slices
      preincubated with [3H]choline by 49%. [3H]WIN 55,212-2 binding to mouse cortex
      membranes was inhibited by CP-55,940, SR 141716 and WIN 55,212-2 (pKi=9.30, 8.70
      and 8.19, respectively) but not by the auxiliary drugs indalpine, metitepine and
      tetrodotoxin (pKi<4.5). [35S]GTPgammaS binding was increased by WIN 55,212-2
      (maximum effect of 80%, pEC50=6.94) but not affected by WIN 55,212-3. In
      conclusion, serotonin release in the mouse brain cortex is inhibited via CB1
      receptors, which may be located presynaptically and are not activated by
      endogenous cannabinoids. The extent of inhibition is smaller than that obtained
      (1) via another three presynaptic receptors on serotoninergic neurones and (2)
      via CB1 receptors on cholinergic neurones in the same tissue.

PMID- 10651143
TI  - Sodium bromide: effects on different patterns of epileptiform activity,
      extracellular pH changes and GABAergic inhibition.
AB  - Results regarding the anticonvulsant potency of bromide have been questioned, and
      the mechanisms of its action are unclear. Using combined rat hippocampus
      entorhinal cortex slices we analyzed the effects of NaBr on four types of
      epileptiform discharges in two different models of epilepsy, the low-Ca2+ and the
      low-Mg2+ model. NaBr concentration-dependently reduced the frequency and finally
      blocked the low Ca2+-induced discharges. Low Mg2+-induced short recurrent
      discharges were also reduced in a concentration-dependent manner. In the
      entorhinal cortex the frequency of seizure-like events was reduced by 3 and 5 mM
      and the discharges were blocked by 7 mM NaBr. Also, the late recurrent discharges
      in the entorhinal cortex which do not respond to most clinically employed
      anticonvulsants were reduced by concentrations of 10 and 15 mM and completely
      blocked by 30 mM NaBr. Using pH-sensitive microelectrodes different effects of
      NaBr were seen than those of acetazolamide on extracellular pH under control
      conditions and after stimulation. Acetazolamide at 1 mM caused a reversible
      acidification of delta pH: 0.2+/-0.14 at rest whereas no change on extracellular
      pH was seen with 5 mM NaBr. Acetazolamide increased the transient alkalosis
      induced by repetitive stimulation of the stratum radiatum in area CA1 and reduced
      the subsequent acidosis. NaBr also increased the alkalosis but had no effect on
      the subsequent acidosis. A significant increase in paired-pulse inhibition was
      seen in a paired-pulse stimulation protocol used to monitor the efficacy of
      GABAergic inhibition at concentrations of 5 mM NaBr. This finding was confirmed
      in whole-cell patch clamp recordings from cultured hippocampal neurons showing an
      increase in inhibitory postsynaptic current amplitude. In summary, our results
      suggest a broad-spectrum anticonvulsant activity which is likely to be caused by
      its effects on membrane excitability, by an increase in GABAergic inhibition and
      is less likely caused by its effects on extracellular pH.

PMID- 10651144
TI  - Cholecystokinin (CCK) increases GABA release in the rat anterior nucleus
      accumbens via CCK(B) receptors located on glutamatergic interneurons.
AB  - The effects of cholecystokinin sulfate octapeptide (CCK-8S) on [3H]gamma
      aminobutyric acid (GABA) release have been studied in the anterior side of the
      rat nucleus accumbens on tissue punches exposed in superfusion to 30 mM KCl. CCK
      8S in a concentration dependent manner (10-3000 nM) increased K+-evoked [3H]GABA
      release (EC50=192 nM). The increase caused by 1 microM CCK-8S ranged from 37% to
      42%. CR 2945, (beta-[2-[[2-(8-azaspiro[4.5]dec-8-ylcarbonyl)-4,6-dimethylp henyl]
      amino]-2-oxoethyl]-(R)-1-naphthalenepropanoic acid), a potent and selective
      nonpeptidergic CCK(B) antagonist, concentration-dependently blocked CCK-8S effect
      (IC50=2.16 nM). CCK-8S-induced increase in [3H]GABA overflow was completely
      blocked by 1 microM tetrodotoxin. Both the alpha-amino-3-hydroxy-5
      methylisoxazole-4-propionate (AMPA)/kainate receptor antagonist 6,7
      dinitroquinoxaline-2,3-dione (DNQX) and the N-methyl-D-aspartic acid (NMDA)
      receptor antagonist dizocilpine (MK-801) antagonized the CCK-8S effect. By
      contrast, (+)-bicuculline, a GABA(A) receptor antagonist, was completely
      ineffective. Phaclofen, a selective GABA(B) antagonist, increased K+-evoked
      [3H]GABA release but did not affect the facilitative effect of CCK-8S. Moreover,
      tetrodotoxin failed to block AMPA-evoked [3H]GABA release but completely
      prevented the effect of NMDA (Mg2+ free conditions). The data presented suggest
      that CCK(B) receptors modulating [3H]GABA release from anterior accumbal punches
      may not be present on GABAergic terminals but could be located on glutamatergic
      interneurons.

PMID- 10651145
TI  - Tolerance to the motor impairment, but not to the reversal of PCP-induced motor
      activities by oral administration of the mGlu2/3 receptor agonist, LY379268.
AB  - The potent metabotropic glutamate (mGlu) receptor agonist, LY379268, selectively
      activates mGlu2/3 receptors with EC50 values in the low nanomolar range. We have
      previously shown in rats that LY379268 reverses phencyclidine (PCP)-induced motor
      activations (increases in ambulations and fine movements, and decreases in the
      animals time at rest). Here, we have investigated: (1) the dose-response and time
      course for this action of LY379268 following oral (p.o.) administration and (2)
      the therapeutic index in this model following acute versus subchronic (4 days)
      p.o. dosing. LY379268 (3 mg/kg p.o.) evoked a maximal effect on PCP (5 mg/kg
      s.c.)-elicited behaviors 4 h post-dosing. At this time point, p.o. LY379268
      inhibited the effects on PCP-elicited activities with a similar potency (ED50
      values ca 1 mg/kg) to that previously obtained following s.c. administration.
      Doses up to 3 mg/kg p.o. LY379268 were without effect on the rotorod performance
      of rats when measured at 1, 2, 4, 8, and 24 h post-administration. In agreement
      with the peak time-effect on PCP-evoked motor behaviors, 10 mg/kg p.o. LY379268
      only significantly impaired rotorod performance at the 4-h time point.
      Interestingly, acute motor impairment produced by higher doses of LY379268 (10,
      30, or 100 mg/kg p.o.) was absent following 4-day repeated administration of
      LY379268. In contrast, the potency of LY379268 for the inhibition of PCP-evoked
      motor activities was not affected following multiple dosing over a similar
      period. These results demonstrate that although the reduction of PCP motor
      activities by LY379268 is maintained after subchronic dosing, tolerance to the
      motor impairment evoked by the compound occurs, thus greatly widening the
      therapeutic index of LY379268.

PMID- 10651146
TI  - Effects of chronic administration of S-adenosyl-L-methionine on brain oxidative
      stress in rats.
AB  - S-adenosyl-L-methionine (SAM), used to treat liver diseases and as a coadjuvant
      in antidepressive medication, has neuroprotective effects in animal models. The
      aim of this study was to discover whether SAM has antioxidant effects in rat
      brain tissue. Ten male Wistar rats were killed by decapitation and the forebrains
      incubated with SAM for in vitro experiments. To study the effects of long-term
      administration, animals in four groups of ten rats each were given 10 mg SAM/kg
      per day s.c., and 40 other rats were given an equivalent volume of L-lysine (the
      commercial solvent for SAM). Treatment was started at the end of lactation, and
      animals were killed by decapitation after 15 days or 1, 6 or 22 months of
      treatment. The forebrain of each animal was used to test membrane lipid
      peroxidation by determining thiobarbituric acid-reactive substances (TBARS),
      glutathione level and enzyme activities related to glutathione (reduced form GSH,
      oxidized form GSSG) metabolism: GSH-peroxidase (GSHpx), GSSD-reductase (GSSGrd)
      and GSH-transferase (GSHtf). Chronic treatment with SAM decreased maximum
      forebrain production of TBARS by 46% compared with animals given L-lysine and
      increased glutathione levels by 50%, GSHpx activity by 115% and GSHtf activity by
      81.4%. The results of in vitro experiments were qualitatively similar: lipid
      peroxidation was inhibited (13.1+/-1.3 nmol/mg protein in controls vs. 5.9+/-0.8
      nmol/mg protein in samples incubated with 1000 micromol/l SAM) and glutathione
      levels were stimulated (0.97+/-0.06 micromol/g tissue in control samples vs.
      1.55+/-0.08 micromol/g tissue in samples incubated with 1000 micromol/l SAM), as
      were GSHpx and GSHtf. No significant effect was seen in any of the experiments
      with L-lysine. We conclude that SAM has antioxidant effects in rat brain tissue
      both in vitro and ex vivo. The effect is seen both as inhibition of lipid
      peroxide production and as an enhancement of the endogenous glutathione
      antioxidant system.

PMID- 10651147
TI  - Differential gene transcriptional regulation of Gi isoforms and Gs protein
      expression in diabetic rat hearts.
AB  - Many cardiac diseases can be associated with alterations in the function and
      quantity of G proteins. We examined the gene expressions and protein levels of Gi
      1alpha, Gi-2alpha, Gi-3alpha and G(s alpha) in ventricular myocardial
      preparations from rats 4-6 weeks after induction of diabetes with streptozotocin
      in comparison with those from age-matched control rats. Diabetic rat myocardium
      exhibited reductions in the protein levels of Gi-2alpha and Gi-3alpha by 22+/-2%
      and 57+/-2%, respectively. In diabetes, 22% and 53% reductions in myocardial mRNA
      levels of Gi-2alpha and Gi-3alpha were observed. Although a faint protein signal
      of Gi-1alpha was detectable, no apparent expression of mRNA for Gi-1alpha was
      found in either control or diabetic myocardium. The reduced protein and mRNA
      levels of Gi-2alpha and Gi-3alpha were prevented by insulin therapy. No change
      was found in the protein and mRNA levels of G(s alpha) in diabetic myocardium. In
      conclusion, diabetes leads to a differential regulation of protein expressions of
      G(i alpha) isoforms and G(s alpha) in ventricular myocardium. The reduced
      expression of Gi-2alpha and Gi-3alpha proteins can be explained, at least in
      part, by the decreases in the transcriptional levels.

PMID- 10651148
TI  - Catecholaminergic activity and 3',5'-cyclic adenosine monophosphate levels in
      heart right ventricle after naloxone induced withdrawal.
AB  - This study evaluated the adaptive changes in noradrenergic neurons and the
      concomitant production of cAMP during morphine dependence and withdrawal in the
      right ventricle of the rat. Rats were made dependent on morphine by morphine
      pellet implantation for 7 days. On the day of sacrifice animals received an acute
      injection of saline or naloxone (1 mg/kg s.c.) and were decapitated 30 min later.
      Pretreatment with propranolol 15 min prior to naloxone was conducted to evaluate
      the possible implication of beta-adrenoceptors. The contents of noradrenaline and
      dopamine and their metabolites were examined. After naloxone administration to
      morphine-dependent rats (withdrawal) there was a pronounced increase in the
      content of normetanephrine and 3,4-dihydroxyphenylacetic acid and increased
      noradrenaline and dopamine turnover. In addition cAMP levels were increased after
      naloxone administration to morphine-treated rats. Propranolol did not block the
      hyperactivity of catecholaminergic neurons or the enhancement of cAMP observed in
      the heart during withdrawal. The present results indicate that heart
      catecholaminergic neurons play a significant role in the alterations in heart
      functions during morphine abstinence syndrome and suggest that those alterations
      are mediated through cAMP.

PMID- 10651149
TI  - Electrophysiological effects of fluoxetine in mammalian cardiac tissues.
AB  - Fluoxetine is a widely used antidepressant compound having selective serotonin
      reuptake inhibitor properties. In this study, the actions of fluoxetine were
      analyzed in guinea pig, rat, rabbit and canine ventricular myocardiac
      preparations using conventional microelectrode and whole cell voltage clamp
      techniques. Low concentrations of fluoxetine (1-10 micromol/l) caused significant
      shortening of action potential duration (APD) and depression of the plateau
      potential in guinea pig and rabbit papillary muscles and single canine
      ventricular myocytes. In rat papillary muscle, APD was not affected by fluoxetine
      (up to 100 micromol/l), however, the drug decreased the force of contraction with
      EC50 of 10 micromol/l. Fluoxetine (10 micromol/l) also decreased the maximum
      velocity of depolarization and action potential overshoot in each species
      studied. At this concentration no effect was observed on the resting membrane
      potential; high concentration (100 micromol/l), however, caused depolarization.
      In voltage clamped canine ventricular myocytes, fluoxetine caused concentration
      dependent block of the peak Ca2+ current at 0 mV with EC50 of 5.4+/-0.94
      micromol/l and Hill coefficient of 1.1+/-0.14 (n=6). In addition, 10 micromol/l
      fluoxetine shifted the midpoint of the steady-state inactivation curve of the
      Ca2+ current from -20.7+/-0.65 to -26.7+/-1 mV (P<0.001, n=8) without changing
      its slope factor. These effects of fluoxetine developed rapidly and were fully
      reversible. Fluoxetine did not alter voltage-dependence of activation or time
      constant for inactivation of I(Ca). Fluoxetine had no effect on the amplitude of
      K+ currents (I(K1) and I(to)). The inhibition of cardiac Ca2+ and Na+ channels by
      fluoxetine may explain most cardiac side effects observed occasionally with the
      drug. Our results suggest that fluoxetine may have antiarrhythmic (class I + IV
      type), as well as proarrhythmic properties (due to impairment of atrioventricular
      or intraventricular conduction and shortening of repolarization). Therefore, in
      depressed patients with cardiac disorders, ECG control may be suggested during
      fluoxetine therapy.

PMID- 10651150
TI  - Inhibitory effect of mibefradil on contractions induced by sympathetic
      neurotransmitter release in the rat tail artery.
AB  - This study tested whether mibefradil exerts a stronger inhibitory effect than
      verapamil on sympathetic neurotransmitter release provoked by electrical field
      stimulation. Tail arteries (diameter 620+/-9 microm) were obtained from male
      Wistar rats. Ring segments of 2 mm length were mounted in an isometric wire
      myograph. After an appropriate period of equilibration and a priming procedure
      the vessels were either subjected to electrical field stimulation (EFS; frequency
      0.25-4 Hz for 30 s) or a concentration-response curve was generated with either
      noradrenaline (concentration range 0.03-3 microM) or ATP (concentration 0.3 mM)
      which served as baseline parameters. EFS-induced contractions were stable and
      reproducible and were blocked by tetrodotoxin (1 microM), guanethidine (3
      microM), and the combination of suramin (0.5 mM) and prazosin (3 microM). EFS
      induced contractions (1 Hz) were almost completely inhibited by 10 microM
      mibefradil (97%) but only partly by 10 microM verapamil (73%). Log IC50 values
      were -5.6 for mibefradil and -6.6 for verapamil. Calcium antagonists were
      equipotent in inhibiting noradrenaline (maximum inhibition by mibefradil and
      verapamil by 70% and 75%, respectively; log IC50: -6.5 and -6.7, respectively)
      and ATP-mediated contractions (maximum inhibition by mibefradil and verapamil by
      92% and 97%, respectively; log IC50: -6.5 and -7.0, respectively). Consequently
      mibefradil displays an additional effect on contractions provoked by EFS-induced
      sympathetic noradrenaline release which cannot be explained by L-type calcium
      channel blockade. Probably this effect of mibefradil is mediated by the blockade
      of prejunctional N-type calcium channels, thereby inhibiting sympathetic
      noradrenaline release. Since activation of the sympathetic nervous system in
      hypertension is both common and undesirable, a calcium antagonist displaying both
      L- and N-type calcium channel blocking activities, would have major advantages
      over calcium antagonists lacking N-type calcium channel blocking activities.

PMID- 10651151
TI  - Nociceptin inhibits the neurogenic vasopressor response in the pithed rat via
      prejunctional ORL1 receptors.
AB  - Nociceptin (or orphanin FQ), the endogenous ligand for the opioid receptor-like 1
      (ORL1) receptor, decreases blood pressure in the conscious and anesthetized rat.
      This study examined whether prejunctional inhibitory ORL1 receptors located on
      the postganglionic sympathetic neurons innervating the resistance vessels are
      detectable in pithed rats. In pithed and vagotomized rats electrical stimulation
      of the preganglionic sympathetic nerve fibers, injection of nicotine (2
      micromol/kg) or noradrenaline (1 nmol/kg) increased blood pressure by about 30
      mmHg. The electrically induced vasopressor response was decreased dose
      dependently by nociceptin (0.001-1 micromol/kg; decrease by about 60% at 1
      micromol/kg). Nociceptin 0.1 micromol/kg reduced the nicotine-induced vasopressor
      response by about 40% but at doses up to 1 micromol/kg failed to affect the
      increase in blood pressure evoked by noradrenaline. The inhibitory action of
      nociceptin on the electrically and nicotine-induced increase in blood pressure
      was attenuated by the ORL1 receptor antagonists naloxone benzoylhydrazone (5
      micromol/kg) and/or [Phe1psi(CH2-NH)Gly2]-nociceptin(1-13)NH2 (1 micromol/kg) but
      was not affected by naloxone 10 micromol/kg. In conclusion, the present data
      suggest that the postganglionic sympathetic nerve fibers innervating the
      resistance vessels of the rat are endowed with prejunctional ORL1 receptors,
      activation of which causes inhibition of noradrenaline release.

PMID- 10651152
TI  - Effects of metformin on intestinal 5-hydroxytryptamine (5-HT) release and on 5
      HT3 receptors.
AB  - Nearly 30% of patients treated with metformin experience gastrointestinal side
      effects. Since release of 5-hydroxytryptamine (5-HT) from the intestine is
      associated with nausea, vomiting, and diarrhea, we examined whether metformin
      induces 5-HT release from the intestinal mucosa. In 40% of tissue biopsy
      specimens of human duodenal mucosa, metformin (1, 10, and 30 microM) caused an
      increase in 5-HT outflow by 35, 70, and 98%, respectively. Peak increases in 5-HT
      outflow were observed after 10-15 min exposure to metformin, returning to
      baseline levels after 25 min. Tetrodotoxin (1 microM) reduced by about 50% the
      metformin-evoked increase in 5-HT outflow (P<0.05). Metformin-evoked release was
      not affected by scopolamine + hexamethonium, propranolol, the 5-HT3 receptor
      antagonist dolasetron, naloxone, or the NK1 receptor antagonist L703606. In the
      presence of tetrodotoxin (1 microM), somatostatin (1 microM) further reduced
      metformin-induced 5-HT release by 15-20%. In view of the 5-HT releasing effects
      of selective 5-HT3 receptor agonists to which metformin (N-N-dimethylbiguanide)
      is structurally related, we investigated whether metformin directly interacts
      with 5-HT3 receptors. Receptor binding (inhibition of [3H]-GR65630 binding) and
      agonist effects (stimulation of [14C]-guanidinium influx) at 5-HT3 receptors were
      studied in murine neuroblastoma N1E-115 cells, which express functional 5-HT3
      receptors. Metformin up to 0.3 mM failed to inhibit [3H]-GR65630 binding and to
      modify displacement of [3H]-GR65630 binding induced by 5-HT. 5-HT (3 microM)
      stimulated the influx of [14C]-guanidinium in intact N1E-115 cells. Metformin up
      to 1 mM failed to modify basal influx, 5-HT-induced influx, and 5-HT+ substance P
      induced influx of [14C]-guanidinium. Our results indicate that metformin induces
      5-HT3 receptor-independent release of 5-HT from human duodenal mucosa via
      neuronal and non-neuronal mechanisms. Part of the gastrointestinal side effects
      observed during treatment with metformin could, thus, be produced by the release
      of 5-HT and other neurotransmitter substances within the duodenal mucosa.

PMID- 10651153
TI  - The effect of urapidil and ramipril on hyperglycemia in streptozotocin diabetic
      rats.
AB  - Angiotensin-converting enzyme inhibitors and alpha1-adrenoceptor antagonists
      improve glucose disposal in diabetes mellitus. We compared the effect of the
      antihypertensive hybrid drug urapidil [alpha1-adrenoceptor antagonist serotonin
      1A (5-hydroxytryptamine 1A, 5-HT1A) receptor agonist] on hyperglycemia in
      streptozotocin diabetic rats with the angiotensin-converting enzyme inhibitor
      ramipril. 5-HT1A receptor agonists induce hyperglycemia. This could be an
      important disadvantage during treatment of diabetes mellitus with urapidil.
      Diabetes was induced by streptozotocin (70 mg/kg i.p.). Treatment for 7 days
      (ramipril 10 mg/kg p.o.; urapidil 20 mg/kg p.o.) significantly decreased mean
      blood glucose values (urapidil: 15.7+/-0.9 mmol/l, P=0.007; ramipril: 15.0+/-0.8
      mmol/l, P=0.038 vs. diabetic control group: 18.7+/-1.0 mmol/l). Both drugs
      reduced significantly blood pressure, urinary glucose, water consumption, and
      food requirement. Serotonin concentration in the brain (medulla oblongata,
      pituitary) was not affected. A normalization comparable with healthy control rats
      was observed only in a diabetic control group with insulin therapy. In
      conclusion, our results demonstrate that the antihypertensive drug urapidil has
      no detrimental effect on hyperglycemia compared with the angiotensin-converting
      enzyme inhibitor ramipril in experimental diabetes mellitus despite its 5-HT1A
      receptor agonistic properties.

PMID- 10651154
TI  - Co-regulation between cyclo-oxygenase-2 and inducible nitric oxide synthase
      expression in the time-course of murine inflammation.
AB  - Many in vitro studies have used cell cultures to focus on the relationships
      between cyclo-oxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS)
      isoforms. We have investigated the time-course of regulation and the role of COX
      2 and iNOS in a model of experimental inflammation in mice, the air pouch
      injected with zymosan. This study demonstrates that there is an early acute phase
      (4 h) mediated mainly by eicosanoids, with high levels of prostaglandin E2 (PGE2)
      produced by cyclo-oxygenase-1. In addition, in the later phase (from 12 h) there
      is a participation of nitric oxide (NO) and PGE2 accompanied by co-induction of
      both iNOS and COX-2. These enzymes were detected in migrating leukocytes as well
      as in macrophages lining the air pouch. Administration of NS398 or indomethacin
      inhibited PGE2 levels and COX activity, but also nitrite levels and iNOS
      activity, which was accompanied by a reduction in iNOS expression. Aminoguanidine
      inhibited nitrite levels and iNOS activity in addition to exerting inhibitory
      effects on the COX pathway. Treatment of animals with dexamethasone reduced
      nitrite and PGE2 concentrations in air pouch exudates, as well as iNOS and COX-2
      expression in migrating cells. Our results indicate that PGE2 and NO may play in
      vivo mutual modulatory roles in the inflammatory response caused by zymosan
      injection into the mouse air pouch, a suitable model to study drugs acting on
      those pathways.

PMID- 10651155
TI  - Potential and pitfalls of electron-beam computed tomography in detecting coronary
      atherosclerosis.

PMID- 10651157
TI  - Visualization and comparison of drug effects after local paclitaxel delivery with
      different catheter types.
AB  - BACKGROUND: The microtubule stabilizing compound paclitaxel has proved to have
      potent antiproliferative effects on smooth muscle cells both in vitro and in
      vivo. It induces cellular modifications that result in reduced proliferation,
      migration and signal transduction by shifting the cellular microtubule
      equilibrium towards assembly. We therefore reasoned that a visualization of the
      altered cytoskeleton could enable an evaluation of the drug effects following
      local drug delivery. METHODS AND RESULTS: 3 catheters - the porous balloon, the
      microporous balloon and the double balloon catheter - were chosen for this study
      representing the spectrum from passive to active, pressure-driven delivery. After
      the induction of a defined plaque in the right carotid arteries of 40 New Zealand
      rabbits by electrical stimulation, 32 animals underwent balloon dilatation and 8
      animals served as pre-interventional control group with electrostimulation only.
      In 24 animals (n = 8 in each group) subsequent local paclitaxel delivery (10
      micromol/L) was performed. 8 animals served as control with angioplasty only.
      Vessels were excised 1 week following intervention. Immunohistochemistry with
      antibodies against bromodeoxyuridine, alpha-actin, macrophages, von Willebrand
      factor and alpha-tubulin was performed. Cytoskeletal changes were analyzed by
      electron microscopy. Tubulin staining and electron microscopy revealed changes
      with distinct staining patterns for the different catheters. Specific catheter
      induced injuries could be identified for the porous and double balloon catheter.
      Intimal proliferation, percentage of macrophages and extent of injury favor the
      double balloon catheter for local paclitaxel delivery. CONCLUSIONS: The
      alterations of the cytoskeleton induced by paclitaxel allowed for the detection
      of drug action by staining of tubulin and electron microscopy. This enables an
      evaluation of transfer, distribution and drug effects directly in the vasculature
      without marker substances. The double balloon catheter appears to be best suited
      for local paclitaxel therapy.

PMID- 10651156
TI  - The upregulation of endothelin and its receptors in porcine coronary arteries in
      a double balloon injury model of restenosis.
AB  - Endothelin, a potent vasoconstrictor, mitogen, and stimulant of collagen
      synthesis, is reported to be increased after vascular injury. We tested the
      hypothesis that tissue endothelin levels and its receptor expression are
      increased following double balloon injury in a porcine coronary artery model of
      restenosis. Male miniature swine maintained on a hyperlipidemic diet underwent
      oversized balloon injury to both the proximal right coronary artery and left
      circumflex coronary artery. Two weeks following the initial injury, the arteries
      were repeat injured at the same site and subsequently harvested four weeks later.
      Proximal balloon injured (BI) and distal non-balloon-injured (NBI) segments from
      the same artery were collected. Tissue endothelin-1 (ET-1) levels were measured
      by ELISA. Endothelin receptors were assayed by radioligand binding using 125I-ET
      1 and also immunolabeling. Tissue endothelin levels were 4-5 fold greater in BI
      arteries as compared to NBI. There was a significant increase in tissue ET-1
      levels and endothelin receptor binding following double balloon injury relative
      to NBI control arteries. Western blots showed an increased expression of ET(A)
      receptor protein in injured vessels compared to non-injured arteries.
      Immunohistochemistry using an ET(A) receptor specific antibody confirmed
      increased receptor density following balloon injury. Thus, in an in vivo double
      balloon injury model for coronary artery restenosis, the response to vascular
      injury is increased tissue ET-1 content and upregulation of ET(A) receptor
      density associated with increased receptor protein.

PMID- 10651158
TI  - Density dependent expression of PDGF-A modulates the angiotensin II dependent
      proliferation of rat cardiac fibroblasts.
AB  - The proliferative effect of angiotensin II (Ang-II) on primary cardiac
      fibroblasts is not well understood and controversially discussed. Results
      described here show that fibroblasts from adult rat hearts exhibit a cell density
      dependent Ang-II induced cell proliferation. Whereas we could not detect a
      proliferative effect of Ang-II on confluent cells, which are still able to divide
      as shown by stimulation with platelet derived growth factor (PDGF), we observed
      an Ang-II induced cell division of approximately 20 % in non-confluent cells. At
      both densities, signal transduction molecules such as the mitogen activated
      protein kinases (MAPK) are activated. There has been substantial evidence that
      Ang-II may induce the expression and secretion of several growth factors. We
      demonstrated an approximately fivefold increase in platelet derived growth factor
      A (PDGF-A) chain and transforming growth factor beta1 (TGF-beta1) mRNA-expression
      within non-confluent cardiac fibroblasts by semiquantitative reverse polymerase
      chain reaction, RT-PCR. In contrast, the mRNA-expression of basic fibroblast
      growth factor (bFGF), insulin-like growth factor 1 (IGF-1), PDGF-A/-B chains, and
      TGF-beta1 remained unchanged within confluent cardiac fibroblasts. Experiments
      with neutralizing antibodies showed that PDGF-AA is an important growth factor
      regulating cell proliferation, whereas TGF-beta1 interferes with cell size
      regulation. In summary, we could show that the Ang-II induced cell proliferation
      in adult cardiac fibroblasts is mainly due to cell density dependent expression
      of growth factors like PDGF-AA.

PMID- 10651159
TI  - Blockade of A1 adenosine receptors prevents the ischaemia-induced sensitisation
      of adenylyl cyclase: evidence for a protein kinase C-mediated pathway.
AB  - OBJECTIVE: Acute myocardial ischaemia leads to a transient sensitisation of
      adenylyl cyclase which may contribute to the occurrence of malignant arrhythmias
      and the propagation of myocardial necrosis. It is prevented by blockade of
      protein kinase C (PKC) which is activated in early ischaemia as shown by its
      translocation from the cytosol to the plasma membranes. Translocation of PKC may
      also occur in ischaemic preconditioning, a process thought to be induced by
      activation of adenosine A1 receptors. In this study it was investigated whether
      A1 adenosine receptors may be involved in the sensitisation of adenylyl cyclase
      and the activation of PKC induced by ischaemia. METHODS: Isolated rat hearts were
      perfused with the specific A1 adenosine antagonist 8-cyclopentyl-1,3
      dipropylxanthine (DPCPX, 1 microM) or adenosine (1 microM) prior to ischaemia
      induced by stop of perfusion for 5 and 10 min. Adenylyl cyclase activity was
      determined in plasma membranes stimulated by forskolin or stimulated via beta
      receptors by isoproterenol. Total PKC activity was measured in purified plasma
      membranes and in the cytosolic fraction using histone III-S as a substrate.
      RESULTS: Myocardial ischaemia induced a beta-receptor-independent sensitisation
      of adenylyl cyclase (forskolin-stimulated activity 515+/-55 vs. 384+/-30
      pmol/min/mg protein) which was completely blocked by pre-perfusion with DPCPX
      (385+/-23 vs. 386+/-24 pmol/min/mg protein). DPCPX alone did not alter the
      responsiveness of adenylyl cyclase to stimulation. The stimulated adenylyl
      cyclase activity was increased by 20 % after pre-perfusion with adenosine,
      mimicking the ischaemia-induced sensitisation. The effect of adenosine was not
      augmented by additional ischaemia. PKC activity was translocated from the cytosol
      to the plasma membranes by acute ischaemia, indicating an activation of the
      enzyme. This effect was completely abolished by DPCPX. CONCLUSION: These data
      demonstrate that in the rat heart the sensitisation of adenylyl cyclase in acute
      myocardial ischaemia is dependent on activation of A1 adenosine receptors. It is
      suggested that the sensitisation of adenylyl cyclase by adenosine or ischaemia
      might be mediated by an activation of PKC.

PMID- 10651160
TI  - Heavy long-term ethanol consumption induces an alpha- to beta-myosin heavy chain
      isoform transition in rat.
AB  - Alcoholic heart muscle disease is characterized by structural changes which
      include chamber dilation, ventricular hypertrophy, and myocyte damage. These
      effects often lead to contractile dysfunction and ultimately to heart failure if
      alcohol consumption is not terminated. In rat models for heart failure in which
      heart failure is induced by pressure or volume overload, there is a shift in the
      myosin heavy chain (MHC) isoforms, from alpha to beta. As a result of this MHC
      transition, there is typically a decrease in myosin ATPase activity. We utilized
      a rat model of chronic alcohol consumption in order to determine if alcohol
      causes a similar shift in MHC isoforms and changes in myosin ATPase activity. A
      liquid diet containing 9% ethanol (46% of daily calories; 11.8 g/kg/day) was
      administered to adult rats for a period of 60 or 90 days. This heavy consumption
      of ethanol resulted in an average blood ethanol content of 150 mg %. The relative
      abundance of beta-MHC isoform protein increased from a control level of 9.7% to
      35.1% in hearts of ethanol-fed rats, following 90 days of ethanol consumption. In
      a separate set of experiments, the levels of alpha-MHC and beta-MHC mRNA were
      demonstrated to increase by 150% and 230%, respectively. Following a 60 day
      treatment, there was a significant reduction in the actomyosin Mg2+ -ATPase
      activity in the myofibrillar preparations from hearts of ethanol-fed rats
      compared to hearts from control-fed rats. In addition, the myosin Ca2+ -ATPase
      activity was decreased 17% and 30% after 60 and 90 days of ethanol consumption,
      respectively. The present study demonstrates that chronic ethanol consumption
      induces an increase in the proportion of the total MHC content composed of the
      beta-isoform. This isoform transition is accompanied by an accumulation of beta
      MHC mRNA, suggesting that the switch is organized pretranslationally. A
      functional consequence of this transition in MHC phenotype is demonstrated by
      significant decreases in the myofibrillar and myosin ATPase activities.

PMID- 10651161
TI  - Reperfusion arrhythmias in the murine heart: their characteristics and alteration
      after ischemic preconditioning.
AB  - In this study, we examined the features of reperfusion arrhythmias and the effect
      of preconditioning (PC) in the mouse for future application of genetically
      engineered mice to study mechanisms of this type of arrhythmia. Under
      pentobarbital anesthesia, reperfusion arrhythmias were induced by temporary
      occlusion of the left anterior descending coronary artery and reperfusion in
      BALB/c AJc1 mice. In the first protocol, the coronary artery was occluded for
      periods ranging from 2 to 15 min and then reperfused. In the second protocol,
      hearts were preconditioned with 2- or 3-min ischemia and 5-min reperfusion prior
      to the 5 min of coronary occlusion. An electrocardiogram was recorded throughout
      the experiment, and arrhythmias were diagnosed according to the Lambeth
      Convention criteria. The incidences of reperfusion-induced ventricular
      tachycardia (VT) in hearts that received 2, 3, 5, 10 and 15-min ischemia (n = 10
      approximately 14) were 0, 9, 73, 55 and 30 %, respectively. Ventricular
      fibrillation (VF) was not observed upon reperfusion regardless of the ischemia
      duration. PC with 2-min ischemia and with 3-min ischemia (n = 10 for each PC)
      reduced the incidences of reperfusion VT after 5-min ischemia to 40% and 10%,
      respectively. However, in mice that developed reperfusion VT, the VT duration was
      similar to that in non-preconditioned controls, ranging from 1 to 16 s. These
      results suggest that the relationship between ischemia duration and incidence of
      VT upon subsequent reperfusion is "bell shaped" and that PC has anti-arrhythmic
      effects in the mouse, as it does in anesthetized rat hearts. However, there
      appear to be differences in the incidence of reperfusion-induced VF and the
      duration of reperfusion VT between these species. Thus, the present murine
      preparation appears to be a useful model for studying the mechanism of
      reperfusion VT and PC, though it does not share all of the features of
      reperfusion arrhythmias with the anesthetized rat preparation.

PMID- 10651162
TI  - Inducible lethal ventricular arrhythmias in swine with pacing-induced heart
      failure.
AB  - INTRODUCTION: Rapid pacing-induced heart failure provides an excellent animal
      model for the study of heart failure. We studied the development of ventricular
      tachyarrhythmias using programmed stimulation in a pacing-induced heart failure
      model. We also studied action potential characteristics and the relationship
      between action potential and heart rate. METHODS AND RESULTS: Ten pigs were
      instrumented and were studied before the onset and every week after rapid pacing
      was instituted. Weekly echocardiograms and programmed stimulation were done in a
      sedated state. In vitro electrophysiologic studies were done on left ventricular
      myocardium in 4 heart-failure animals and 4 controls. All animals developed
      progressive heart failure with left ventricular dilatation and reduced percentage
      fractional shortening. No arrhythmias were induced at baseline or the first and
      second weeks. Ventricular fibrillation was induced in one animal on the third
      week and 4 animals on week 4, while there was no appreciable worsening in
      echocardiographic indices of ventricular dysfunction between weeks 3 and 4.
      Ventricular effective refractory period was unchanged during the 4 weeks. In
      vitro studies showed action potential prolongation in heart failure myocardium.
      However, action potential duration at pacing rates >100 bpm were similar to
      controls. No early or delayed afterdepolarizations were observed. CONCLUSION:
      This study demonstrated an increased susceptibility to ventricular fibrillation
      with the development of heart failure which was not related to the degree of
      ventricular dysfunction. Also, the normalization of action potential duration at
      higher heart rates suggests that the increased incidence of inducible ventricular
      fibrillation in this model may not be solely due to prolonged action potential
      duration.

PMID- 10651163
TI  - Interleukin-10 in cutaneous disorders: implications for its pathophysiological
      importance and therapeutic use.
AB  - With its antiinflammatory and immunosuppressive properties interleukin-10 (IL-10)
      plays a dominant role in several immune reactions including regulatory mechanisms
      in the skin. The overexpression of this mediator has been reported in some
      inflammatory dermatoses as well as in various skin tumors. These observations are
      of importance since they may explain the limitation of hyperinflammatory
      conditions as in eczemas and erythemas on the one hand and the suppression of an
      adequate antitumor response and thereby the progression of malignant tumors on
      the other hand. Moreover, elevated IL-10 expression might contribute to an
      enhanced risk of development of microbacterial superinfections, a frequent
      finding in several dermatoses, and might also be involved in the pathogenesis of
      connective tissue diseases. In contrast, recent studies indicate a relative IL-10
      deficiency in psoriasis. Early clinical data from psoriatic patients treated with
      recombinant human IL-10 suggest the therapeutic potential of this cytokine and
      underline its impact on the regulation of the skin immune system.

PMID- 10651164
TI  - Autosomal dominant aplasia cutis congenita: report of a large Italian family and
      no hint for candidate chromosomal regions.
AB  - We studied a three-generation pedigree in which seven individuals were affected
      by aplasia cutis congenita, a rare disorder characterized by the congenital
      absence of the epidermis, dermis and subcutaneous tissue of the vertex or
      occipital region. Accurate clinical and formal genetic analysis suggested that
      this family was affected by the autosomal dominant form of the disease, a
      hereditary condition due to mutations of an unknown gene. To define the map
      position of this locus, we performed linkage analysis on candidate chromosomes
      (long arm of chromosomes 1 and 12). Negative lod scores were obtained for all
      markers analysed and linkage with genes located in these chromosomal regions was
      excluded.

PMID- 10651165
TI  - Maintenance of human skin in organ culture: role for insulin-like growth factor-1
      receptor and epidermal growth factor receptor.
AB  - Recent studies have shown that adult skin incubated in low-Ca2+ (0.15 mM) medium
      rapidly degenerates but that normal architecture is maintained when the tissue is
      incubated in high-Ca2+ medium (1.4 mM Ca2+). To investigate whether the skin cell
      produced growth factors insulin-like growth factor-1 (IGF-1) and epidermal growth
      factor (EGF) play a role in these events, 2-mm skin punch biopsies were obtained
      and maintained for 8 to 10 days in a basal medium containing 0.15 mM Ca2+ with
      and without growth factors, or containing 1.4 mM Ca2+ with and without antibodies
      to the same growth factors. In parallel experiments, cultured human keratinocytes
      were incubated for 2 days in the same basal medium in the presence or absence of
      the same growth factors and antibodies. Consistent with previous reports, organ
      cultures incubated in the low-Ca2+ (0.15 mM) medium rapidly degenerated. Neither
      IGF-1 nor EGF prevented the complete degeneration of epidermis and dermis in
      these organ cultures. Interestingly, the addition of an anti-IGF-1 receptor (IGF
      1R) antibody to the organ cultures maintained in high-Ca2+ medium induced changes
      reminiscent of those seen when the organ cultures were maintained in low-Ca2+
      medium, i.e. tissue degeneration. In contrast, antibodies to EGF receptor, used
      for comparison, only produced focal areas of epidermal necrosis. In vitro, IGF-1
      is a known mitogen for keratinocytes. In cultured human keratinocytes, anti-IGF
      1R antibody partially inhibited the IGF-1-mediated stimulation of human
      keratinocyte proliferation without affecting normal spontaneous growth.
      Additionally, IGF-1R immunolocalized to basal keratinocytes in vivo, exhibited
      specific binding to IGF-1 in vitro. This indicated a critical role for IGF-1R in
      both organ cultures ex vivo and cultured cells in vitro. Messenger RNA encoding
      both IGF-1 and IGF-1R were readily detected by RT-PCR in organ cultures incubated
      in both low- and high-Ca2+ medium. There were no detectable differences in IGF-1
      mRNA in organ cultures growing in the low- or high-Ca2+ medium, but lower levels
      of IGF-1R mRNA were observed in the organ cultures maintained in low-Ca2+ medium
      than in those in high Ca2+ medium. These findings are consistent with homeostatic
      changes in the tissue grown under different calcium concentrations. IGF-1 mRNA
      was detected in several skin cell populations in vitro, even though it was
      undetectable in cultured keratinocytes. Taken together these findings indicate
      that (1) the IGF-1/ IGF-1R loop is critically involved in maintenance of human
      skin organ cultures ex vivo, and (2) IGF-1, locally produced by skin cells other
      than keratinocytes, interacts with its receptor, predominantly expressed in basal
      keratinocytes, to maintain tissue homeostasis.

PMID- 10651166
TI  - Regulation of the contact sensitivity response to urushiol with anti-urushiol
      monoclonal antibody ALG 991.
AB  - The objective of the studies was to demonstrate that the contact sensitivity (CS)
      response to poison ivy/oak could be downregulated following treatment with a
      monoclonal antibody (mAb) reacting with the allergen urushiol. Conjugation of
      urushiol and its synthetic analogue 3-n-pentadecylcatechol (PDC) to N
      acetylcysteine yielded hydrosoluble derivatives which induced humoral immune
      responses in BALB/c mice. Hybridomas secreting monoclonal antibodies (mAbs)
      reacting with urushiol and PDC were generated by fusion of B lymphocytes from
      immunized mice with mouse myeloma P3NS0 cells. The specificity of mAb ALG 991
      (IgM isotype) was defined by inhibition of antibody binding by PDC analogues.
      This demonstrated that mAb ALG 991 reacted with the catechol moiety of urushiol,
      the region of the allergen being critically important in the induction of contact
      dermatitis. The CS response to urushiol in BALB/c mice was suppressed by
      stimulation with mAb ALG 991 and the role of sensitized T cells, including
      suppressor T cells, has been considered. Suppression of CS was most effective
      with low doses (1 microg) of mAb incorporated into a vaccine with Freund's
      adjuvant. This treatment suppressed CS responses in BALB/c mice already
      sensitized to urushiol.

PMID- 10651167
TI  - The housekeeping gene glyceraldehyde-3-phosphate dehydrogenase is inappropriate
      as internal control in comparative studies between skin tissue and cultured skin
      fibroblasts using Northern blot analysis.

PMID- 10651168
TI  - Effects of N-acetylcysteine on nitroglycerin-induced relaxation and protein
      phosphorylation of porcine coronary arteries.
AB  - We investigated the effects of the sulfhydryl-donor, N-acetylcysteine (NAC), on
      nitroglycerin (NTG)-induced relaxation of the vascular smooth muscle. Addition of
      histamine to isolated porcine coronary arteries induced an initial rapid
      contraction followed by a gradual decrease in tonic contraction. NTG applied to
      the coronary artery strips before histamine caused relaxation of the histamine
      induced rapid (3 min) and tonic (48 min) contraction. The inhibition of the tonic
      contraction by NTG was less at 48 min than at 3 min. Application of NAC (NTG-NAC)
      enhanced the relaxing effects of NTG on the histamine-induced tonic contraction
      rather than the acute contraction. In phosphorylation studies, changes in the
      phosphorylation of an intermediate filament, desmin, were parallel with changes
      in contraction in NTG-treated and NTG-NAC samples at 48 min. These
      phosphorylation changes of desmin at 48 min, which might be responsible for tonic
      phase contraction, were more extensive than those of myosin light chain (MLC)
      phosphorylation at 3 min, which might be responsible for acute contraction. These
      results suggest that treatment with the sulfhydryl donor, NAC, inhibited the
      phosphorylation of desmin associated with the enhancement of NTG-induced
      relaxation, which might be related to the mechanisms of recovery from NTG
      tolerance by sulfhydryl groups.

PMID- 10651169
TI  - Diastolic ventricular interaction in chronic heart failure: relation to heart
      rate variability and neurohumoral status.
AB  - It is likely that abnormal baroreflex control mechanisms are at least partially
      responsible for autonomic dysfunction in chronic heart failure. We recently
      demonstrated that diastolic ventricular interaction is associated with impaired
      baroreflex control of vascular resistance in heart failure. We reasoned that by
      constraining left ventricular filling, such interaction would decrease baroreflex
      activity and, thereby, increase sympathetic and decrease parasympathetic outflow.
      We hypothesized, therefore, that diastolic ventricular interaction in chronic
      heart failure patients would be associated with autonomic dysfunction. We used
      radionuclide ventriculography to measure changes in left and right ventricular
      end-diastolic volumes during acute volume unloading achieved by -30 mm Hg lower
      body negative pressure in 30 patients with chronic heart failure. An increase in
      left ventricular volume in association with a reduction in right ventricular
      volume indicates diastolic ventricular interaction (a larger increase indicating
      a greater degree of interaction). We also measured heart rate variability (n =
      23) and resting venous plasma norepinephrine (n = 24), epinephrine (n = 24), and
      atrial natriuretic peptide (ANP) (n = 14). During lower-body negative pressure,
      while right ventricular volume decreased in all patients (P < 0.001), left
      ventricular end-diastolic volume increased (from 152 +/- 25 to 157 +/- 36 ml/m2,
      P = 0.01). The change in left ventricular volume was positively correlated with
      resting plasma norepinephrine (P < 0.01) and ANP (P < 0.005), and negatively
      correlated with the standard deviation of normal to normal R-R intervals (P <
      0.005), the root-mean-square of differences between successive normal to normal R
      R intervals (P < 0.05), total power (P < 0.01), low-frequency power (P < 0.01),
      and high-frequency power (P < 0.05). Diastolic ventricular interaction in
      patients with chronic heart failure is associated with sympathetic nervous system
      activation evidenced by increased plasma norepinephrine and reduced heart rate
      variability.

PMID- 10651171
TI  - Some factors that influence mechanical behavior of the left ventricle of the
      human heart in late systole: a feasibility study using finite element analysis.
AB  - In systole the left ventricle of the heart behaves mechanically in two modes
      simultaneously, passive and active. When in the former mode, the ventricle has to
      carry and react to the pressure increase within the cavity, while in the latter,
      force is generated within the myocardium itself through the contraction, i.e.,
      active self-shortening, of the muscle fibers. When the deformations of these two
      opposing modes balance, isovolumic contraction occurs. After this phase, when the
      aortic valve has opened, the active mode dominates. Many models of the left
      ventricle under passive internal pressure have been reported, usually for
      analyzing the situation in diastole. Only a few attempts have been made to
      incorporate the self-activation effect present in systole. In this paper, a model
      for systole is described in which the active component has been treated by
      analogy to thermal stress analysis methods common in dealing with conventional
      engineering structures. The model was applied to the pressure and volume data for
      the ventricles of four patients with cardiac disease. A parametric study was then
      undertaken to investigate the influence of some of the mechanical factors on
      ventricular behavior. It was found that fiber angle has a very significant effect
      on the deformation of the ventricle and also that for ventricles with stiff
      myocardia, the passive component to the reaction of the ventricle was negligible.

PMID- 10651170
TI  - Forearm vasoconstriction during dynamic leg exercise in patients with chronic
      heart failure.
AB  - Previous studies assessing vascular responses in nonexercising beds during
      exercise in patients with chronic heart failure (CHF) have yielded varying
      results. We proposed that the clinical and hemodynamic severity of heart failure
      may explain some of the variation. We reasoned that diastolic ventricular
      interaction (DVI), by limiting the ability of such patients to increase left
      ventricular (LV) volume and stroke volume during exercise, would attenuate
      baroreflex activation, resulting in increased sympathetic activation and hence
      exaggerated vasoconstriction. We hypothesized therefore that vasoconstriction in
      nonexercising beds would be exaggerated in patients with symptomatic and
      hemodynamically severe heart failure, particularly if associated with DVI. We
      measured forearm vascular resistance (FVR) during semierect cycle exercise in 22
      CHF patients and 23 control subjects. DVI was assessed by measuring changes in
      ventricular volumes (radionuclide ventriculography) during volume unloading (-30
      mm Hg lower-body negative pressure) in the heart failure patients and was
      inferred when LV end-diastolic volume paradoxically increased. Patients with
      symptoms of heart failure developed larger increases in FVR during exercise than
      did asymptomatic patients. There were significant correlations between the change
      in FVR during peak exercise and the resting mean pulmonary arterial pressure and
      pulmonary vascular resistance. CHF patients with DVI developed exaggerated
      increases in FVR (median [25th to 75th percentile]) compared with the remaining
      patients during low-workload exercise (138 [66 to 171] vs 6.4 [-4.3 to 28] units,
      P = 0.002) and during peak exercise (160 [90 to 384] vs 61 [-7.4 to 75] units, P
      < 0.02). Vasoconstriction in nonexercising beds is exaggerated in CHF patients
      with clinically and hemodynamically severe heart failure, particularly if
      associated with DVI. This may explain some of the reported variation in the
      degree of sympathetic activation that occurs during exercise in CHF patients.

PMID- 10651172
TI  - An infant with hypereosinophilic syndrome and heart failure markedly responded to
      prednisolone: serial changes of left ventricular wall thickening and left
      ventricular diastolic dysfunction observed by echocardiography.
AB  - We encountered an infant with congestive heart failure due to idiopathic
      hypereosinophilic syndrome. The patient showed marked thickening of the left
      ventricular wall and left ventricular diastolic dysfunction, both of which,
      shortly after prednisolone therapy, markedly improved together with improvement
      of the congestive heart failure and hypereosinophilia. Observation of pulmonary
      venous flow patterns detected by pulsed Doppler echocardiography may be useful
      for evaluation of left ventricular diastolic function.

PMID- 10651173
TI  - A new method for right ventricular endomyocardial biopsy via the femoral veins: a
      novel approach employing a right ventriculography catheter (Nishiya type).
AB  - We have devised a new method for right ventricular endomyocardial biopsy, in
      which the use of a right ventriculography catheter (Nishiya Type) allows us to
      ensure the introduction of a guiding sheath (Cordis, right-angled long sheath) to
      the apical portion of the right ventricle by way of the femoral vein. With this
      method, we have biopsied the endomyocardium in 52 patients during the last 4
      years. In each case, it only took us several minutes to complete the biopsy
      procedure. Neither failed applications nor significant complications were seen.
      We believe that this technique provides a clinically beneficial means as it
      enables us to readily and safely achieve right ventricular endomyocardial biopsy.

PMID- 10651174
TI  - Psychiatric morbidity in people born in Ireland.
AB  - BACKGROUND: Irish immigrants are reported to be over-represented in psychiatric
      admission statistics for England when compared to native whites. This study
      examines whether this finding is sustained for users of psychiatric services as a
      whole and explicates the reasons for any differential uptake of mental health
      care by comparison with community morbidity rates in the same population.
      METHODS: Demographic and clinical data were collected from staff concerning all
      adults living in a multiethnic inner-city health district and using mental health
      services during a 6-month period. A separate interview-based survey of private
      household residents in the same area was undertaken to ascertain the prevalence
      of psychiatric disorder in the community. RESULTS: Psychiatric service use was
      found to be greater for Irish-born people compared to the remainder of the white
      population. However, this finding only persisted for alcohol use disorders, the
      rates for schizophrenic and affective disorders being comparable in the two
      groups. Access to psychiatric care was also similar both with respect to overall
      morbidity as well as for affective and alcohol use disorders, levels of service
      use being attributable to patterns of morbidity in the population rather than
      nosocomial factors. CONCLUSIONS: The excess morbidity for alcohol use disorders
      reported in people born in Ireland is affirmed and the need for longitudinal and
      ethnographic research into this important public health issue emphasised.

PMID- 10651175
TI  - Prevalence, incidence and age at onset of psychiatric disorders in Norway.
AB  - BACKGROUND: Increased demands for psychiatric services and increased rates of
      sickness absence for depression have raised the question of the occurrence of
      psychiatric disorders in Norway, and whether there is in fact a rising incidence
      rate. METHODS: Between 1989-1991, 2015 and 617 persons participated in a two
      phase population study. Phase I comprised screening by the Hopkins Symptom Check
      List 25 items (HSCL-25), and phase II a diagnostic interview by the Composite
      International Diagnostic Interview (CIDI), including report of date (year) of the
      first occurrence of any symptoms, and any consequent diagnosis: RESULTS: A
      symptom score of 1.75 or more was found in 19.8% of the women and 9.3% of the men
      by the HSCL-25. Depression, anxiety or somatoform disorder by CIDI was found in
      21.5% of the women and 11.5% of the men. The incidence rate increased
      significantly from 3.3 to 12.8 per 1000 person years from 1930 to 1991. The
      incidence rate in the year before the interview was 42.6 per 1000 person years.
      Age of onset became lower. More women became ill, but the illness seemed to last
      longer in men. A major problem in comparing results between studies is the
      different concepts and operationalisations of psychiatric illness, and the
      varying time periods given for estimates. CONCLUSION: The findings provide
      evidence of psychiatric illness being a rising and major health problem, but the
      role of recall bias must be further investigated.

PMID- 10651176
TI  - The prevalence of psychiatric disorders and use of care by homeless people in
      Paris.
AB  - BACKGROUND: Homelessness is a growing problem in the cities of the western world,
      and homeless people have a plethora of mental health and social difficulties.
      These are, nevertheless, difficult to evaluate epidemiologically. METHOD: In this
      paper we present a population survey using the Composite International Diagnostic
      Interview (CIDI) conducted in the city of Paris in winter 1996 on a
      representative sample of 838 homeless people. Night shelters as well as food
      kitchens were randomly sampled, and the mean response rate was around 65%.
      RESULTS: The sample was relatively young and predominantly male (85%). Forty
      percent were born outside France, 96% had worked at some time, and one-third
      reported no resources at all. The lifetime prevalence of psychiatric disorders
      was 57.9%, while the 1-year prevalence was 29.1%. For definite psychotic
      disorders, prevalence was 16% (lifetime) and 6% (1 year). Generally, this
      Parisian homeless population had some access to care: in the preceding 6 months
      57.7% of them had been medically attended and 14.2% of these had been
      hospitalised. The survey was cross-sectional, and did not evaluate regular access
      to care or the quality of care. CONCLUSIONS: The implications for health and
      social systems are discussed in the light of comparisons with European and North
      American data.

PMID- 10651177
TI  - Mental health and use of care in people receiving a French social benefit.
AB  - BACKGROUND: This paper presents and epidemiological survey of 300 adults randomly
      sampled among the Parisian population and 207 randomly sampled recipients of a
      social benefit. The RMI (Revenu Minimal d'Insertion) provides a regular minimal
      income to any person with resources below a certain level. It is not targeted at
      people with mental health problems. METHODS: The subjects were evaluated by
      trained interviewers using collateral information provided by an informant,
      together with CIDIS, a simplified version of the CIDI, covering: somatisation,
      panic attack, phobias, generalised anxiety, major depression and alcohol and
      illegal drug abuse (DSM-III-R and ICD-10 classifications). RESULTS: The response
      rate was 79% for the Parisian sample and 75% for the RMI recipients. As expected,
      the sociodemographic composition of the two groups adjusted for age differed
      considerably: RMI recipients were likely to be unemployed and single or divorced.
      The collateral information showed that psychoses of all types were more frequent
      among RMI recipients (4.2% vs 1.2%, P < 0.02). There were large differences in
      rates for substance abuse and dependence, antisocial personality and lifetime
      depressive disorders, but no difference for mental deficiency. This corresponded
      partly with the direct CIDIS measure: male RMI recipients suffered significantly
      more from severe depression than male Parisian controls: 16.7% compared to 3.4%
      (P < 0.01 lifetime) and from drug and alcohol abuse or dependency disorders.
      Depressed RMI recipients made less use of available medical care for their
      depression than Parisians controls, mainly because RMI recipients did not consult
      psychiatrists, whereas controls did (21%, P < 0.0001). On average, the duration
      of depressive episodes is longer in RMI recipients, especially in women.
      CONCLUSION: The high rate of psychiatric disorders and poor access to resources
      in RMI recipients have implications for the health system. Care would be improved
      if social workers administering the benefit were better trained to recognise
      psychiatric problems, and able to link their clients with (particularly) primary
      care services.

PMID- 10651178
TI  - Early manifestations, personality traits and pathways into care for Asian and
      white first-onset cases of schizophrenia.
AB  - BACKGROUND: Previous studies have shown that manifestations of symptoms and
      premorbid personality of patients with schizophrenia differ across cultures.
      However, these have only been demonstrated in cultural settings apart from each
      other. METHOD: We set out to compare these across different ethnic groups from a
      catchment area in west London. The Asian and the white group had similar
      inception rates of schizophrenia and we therefore decided to compare these two
      groups to ascertain similarities in social, demographic and personality factors
      and pathways into care. First-onset cases of schizophrenia were studied on a
      number of parameters using previously validated instruments. RESULTS: There were
      more similarities than differences between the two groups. When compared with the
      findings of a previous multicentre study in India, London Asians, like their
      counterparts in India, were more likely than the London white sample to present
      with loss of appetite, become more religious and behave as if hearing voices.
      However, compared to their Indian counterparts, the onset of symptoms was more
      likely to be insidious and alternative sources of healing were less likely to be
      approached. CONCLUSIONS: These findings are discussed in relation to the findings
      for white patients and recommendations made for future research.

PMID- 10651179
TI  - Life events, ethnicity and perceptions of discrimination in patients with severe
      mental illness.
AB  - BACKGROUND: Whilst it is commonly believed that black and ethnic minority (B&EM)
      people living in the UK experience social disadvantage compared with the white
      British (WB) population, no study has specifically addressed this issue in
      patients with severe mental illness. We sought to test the hypothesis that B&EM
      patients experience more negative life events than their WB counterparts, and to
      examine the extent to which they attribute these events to discrimination.
      METHOD: Thirty-four WB, 78 African Caribbean (AC) and 35 other ethnic minority
      patients with psychotic illnesses, defined using Research Diagnostic Criteria,
      were asked to complete a Racial Life Event Questionnaire examining life events
      and perceptions of discrimination at baseline and 12 and 24 months later.
      RESULTS: African Caribbean patients experienced more 'Financial' life events
      across the study period, otherwise there were no significant differences between
      patient groups in number of life events experienced. The B&EM group collectively
      (n = 113), however, were significantly more likely than the WB group (n = 34) to
      attribute 'Assault', and 'Legal' life events to discrimination. The AC patient
      group were significantly more likely than the other two ethnic groups to
      attribute the 'Financial' and 'Health' life events they experienced to
      discrimination. The B&EM group was also significantly more likely, and
      particularly the AC patient group, to report that members of their own ethnic
      group are adversely affected by discrimination. Further analyses showed skin
      colour rather than ethnicity or nationality to be the major contributing factor
      to perception of discrimination; thus, the Irish (n = 11) had similar scores to
      the WB while Africans (n = 16) scored like the ACs. CONCLUSION: Our study shows
      that B&EM patients do not experience significantly more life events than WB
      patients; however, their perception of these events is clearly different, and
      significantly more often attributed to racism. It is reasonable to suppose that
      patients may be disinclined to utilise services they believe to be prejudiced
      against them on the basis of their skin colour, and service providers need to be
      aware of this in order to create health care services that B&EM patients feel
      confident to use.

PMID- 10651180
TI  - Suicides by drug poisoning among the elderly in Sweden 1969-1996.
AB  - BACKGROUND: Previous studies have shown an association between the rates of
      suicide employing certain types of medications and the availability of those
      drugs. During recent years, prescription patterns of psychoactive drugs commonly
      used in suicides have undergone some major changes. This study examines whether
      altered prescription patterns are associated with changes in the rates of drug
      related suicides in the elderly. METHODS: An ecological study was performed, in
      which rates of suicide by drug poisoning were related to prescription sales of
      different psychotropic drugs, derived from the National Prescription Survey (1987
      1996). RESULTS: Benzodiazepines were the dominant drug type used by elderly
      persons who committed suicide by drug poisoning. Rates of suicide using
      benzodiazepines increased despite decreasing prescription sales. Decreasing
      tricyclic antidepressant sales and increasing SSRI (selective serotonin reuptake
      inhibitors) sales were paralleled by decreasing rates of suicides employing
      antidepressants. The fatality ratio (FR) decreased for the antidepressant group,
      increased for benzodiazepines and remained more or less unchanged for analgesics
      among the elderly during the study period. CONCLUSIONS: Rates of suicide using
      benzodiazepines increased in the elderly despite decreasing prescription sales.
      Benzodiazepines should be prescribed restrictively to this age group.

PMID- 10651181
TI  - Acidosis-induced coronary constriction in the rat heart: evidence for the
      activation of L-type calcium channels.
AB  - Perfused rat hearts were used to study the effects of acidosis on coronary tone.
      When pH was decreased, over the range pH 7.4 to pH 6.2, by reducing perfusate
      bicarbonate levels, under constant flow conditions, there was a transient
      decrease in coronary perfusion pressure (CPP), followed by a sustained acidosis
      dependent increase in CPP, which reversed when pH was returned to pH 7.4. This
      increase in CPP was seen at perfusion rates of 5, 10, and 20 ml/min(-1). When
      using constant pressure perfusion acidosis reduced coronary flow. In a HEPES
      buffered bicarbonate-free solution, acidosis did not cause a transient fall in
      CPP but it did produce a sustained increase in CPP. Addition of ammonium chloride
      (10 mM) reduced CPP, while washout of ammonium chloride increased CPP. The
      acidosis-induced increase in CPP was not affected by indomethacin, nitro-L
      arginine, the nonselective adenosine receptor antagonist, 8-phenyl theophylline,
      or the thromboxane receptor antagonist, ZD 1542. The acidosis-induced increase in
      CPP was independent of the myocardial depressant effects of acidosis, but was
      attenuated by three different L-type calcium channel blockers. These results
      demonstrate that the coronary circulation of the rat constricts in response to
      acidosis. Experiments performed with L-type calcium channel blockers, and the
      calcium channel activator BAY K8644, suggest that constriction occurs via
      activation of L-type calcium channels. This would not be expected on the basis of
      electrophysiological studies, which have shown an inhibition of L-type calcium
      channels by acidosis.

PMID- 10651182
TI  - Mechanism of pulmonary venous pressure and flow waves.
AB  - The pulmonary venous systolic flow wave has been attributed both to left heart
      phenomena, such as left atrial relaxation and descent of the mitral annulus, and
      to propagation of the pulmonary artery pressure pulse through the pulmonary bed
      from the right ventricle. In this study we hypothesized that all waves in the
      pulmonary veins originate in the left heart, and that the gross wave features
      observed in measurements can be explained simply by wave propagation and
      reflection. A mathematical model of the pulmonary vein was developed; the
      pulmonary vein was modeled as a lossless transmission line and the pulmonary bed
      by a three-element lumped parameter model accounting for viscous losses,
      compliance, and inertia. We assumed that all pulsations originate in the left
      atrium (LA), the pressure in the pulmonary bed being constant. The model was
      validated using pulmonary vein pressure and flow recorded 1 cm proximal to the
      junction of the vein with the left atrium during aortocoronary bypass surgery.
      For a pressure drop of 6 mmHg across the pulmonary bed, we found a transit time
      from the left atrium to the pulmonary bed of tau approximately 150ms, a
      compliance of the pulmonary bed of C approximately 0.4 ml/mmHg, and an inertance
      of the pulmonary bed of 1.1 mmHgs2/ml. The pulse wave velocity of the pulmonary
      vein was estimated to be c approximately 1m/s. Waves, however, travel both
      towards the left atrium and towards the pulmonary bed. Waves traveling towards
      the left atrium are attributed to the reflections caused by the mismatch of
      impedance of line (pulmonary vein) and load (pulmonary bed). Wave intensity
      analysis was used to identify a period in systole of net wave propagation towards
      the left atrium for both measurements and model. The linear separation technique
      was used to split the pressure into one component traveling from the left atrium
      to the pulmonary bed and a reflected component propagating from the pulmonary bed
      to the left atrium. The peak of the reflected pressure wave corresponded well
      with the positive peak in wave intensity in systole. We conclude that the gross
      features of the pressure and flow waves in the pulmonary vein can be explained in
      the following manner: the waves originate in the LA and travel towards the
      pulmonary bed, where reflections give rise to waves traveling back to the LA.
      Although the gross features of the measured pressure were captured well by the
      model predicted pressure, there was still some discrepancy between the two. Thus,
      other factors initiating or influencing waves traveling towards the LA cannot be
      excluded.

PMID- 10651183
TI  - An equation to predict the changes in peak left ventricular pressure in
      hypertrophic obstructive cardiomyopathy after treatment: application to the
      administration of disopyramide.
AB  - A theoretical equation was derived based on the time-varying elastance model to
      predict theoretically the relationship between the delay in the onset of left
      ventricular outflow obstruction and the reduction in peak left ventricular
      pressure (LVP) caused by treatment in hypertrophic obstructive cardiomyopathy
      (HOCM). ECG, LVP, and other hemodynamic parameters were measured during
      catheterization at a constant heart rate with atrial pacing in 16 patients with
      HOCM before and after intravenous administration of disopyramide (1 mg/kg). After
      disopyramide administration, the duration between the R wave of the ECG and the
      onset of obstruction (T1) was prolonged significantly (from 117 +/- 30 to 155 +/-
      32 ms, P < 0.0001), and peak LVP was reduced significantly (from 222 +/- 42 to
      177 +/- 39 mmHg, P < 0.0001). The relation between the prolongation of T1 and the
      percent reduction in peak LVP was predicted well by the theoretical equation
      (coefficient of determination R2 = 0.926). Our model simplifies the therapeutic
      strategy for reducing the left ventricular outflow pressure gradient in patients
      with HOCM, which is to delay the time of onset of obstruction by some methods.

PMID- 10651184
TI  - Myocardial mechanical restitution and potentiation partly underlie alternans
      decay of postextrasystolic potentiation: simulation.
AB  - We have reported that the postextrasystolic potentiation (PESP) decays in
      alternans or monotonically, respectively, depending on whether the first
      postextrasystolic beat interval has a compensatory pause or not, in the canine
      left ventricle. To get better mechanistic insight into the alternans PESP decay,
      we hypothesized that the myocardial mechanical restitution and potentiation could
      partly account for both types of PESP decay. To test this hypothesis, we
      simulated PESP decay on a computer using a documented equation combining
      myocardial mechanical restitution and potentiation. We changed the first
      postextrasystolic beat interval after a fixed extrasystolic beat interval without
      changing regular and other postextrasystolic beat intervals. The simulated PESP
      decayed in alternans or monotonically as a function only of the first
      postextrasystolic beat interval. Thus, the myocardial mechanical restitution and
      potentiation could partly account for both alternans and monotonic decay of PESP.
      We conclude that myocardial mechanical restitution and potentiation may partly
      underlie the initial two alternating beats, the first beat being the most
      potentiated and the second beat being the most depressed, of alternans PESP decay
      in the canine heart.

PMID- 10651185
TI  - Perioperative correlates of malignant ventricular tachyarrhythmias complicating
      coronary surgery.
AB  - Sustained ventricular tachyarrhythmias (VT), such as monomorphic or polymorphic
      ventricular tachycardia, and ventricular fibrillation, represent the most serious
      arrhythmic events that can complicate the postoperative course of coronary artery
      bypass grafting (CABG). The perioperative factors potentially associated with
      post-CABG sustained VT onset have not been thoroughly investigated. As a
      consequence, the aim of our study was to identify which perioperative variables
      might predict post-CABG VT occurrence. One hundred and fifty-two consecutive
      patients who underwent CABG surgery at our Institute were included in the study.
      Post-CABG VT occurred in 13 out of 152 patients (8.5%, six cases of monomorphic
      ventricular tachycardia and seven cases of ventricular fibrillation). Univariate
      analysis revealed that VT patients were significantly younger (54.8 +/- 6.6 vs
      60.1 +/- 8.8, P = 0.038), exhibited more severe coronary artery disease (CAD)
      (no. of diseased vessels, 2.92 +/- 0.3 vs 2.45 +/- 0.7, P = 0.023; and percentage
      of patients with three-vessel CAD, 91.7 vs 57.3%, P = 0.043), and received a
      greater number of CABGs than those remaining in sinus rhythm (SR) (percentage of
      patients receiving three or more CABGs, 76.9 vs 38.8%, P = 0.018) Moreover, VT
      patients more frequently developed intra- or postoperative myocardial infarction
      (total CK > 1,000, 76.9 vs 38%, P = 0.016; and MB-CK > normal range, 72.7 vs
      30.7%, P = 0.014), electrolyte derangement (84.6 vs 45.6%, P = 0.017), and a
      severe hemodynamic impairment (need for intra-aortic balloon pump (IABP), 23 vs
      2.9%, P = 0.009). On multivariate analysis, total CK > 1,000, postoperative
      electrolyte imbalance, the need for three or more CABGs, and for IABP all were
      independent correlates for VT. In conclusion, post-CABG VT seem to be related to
      the preexistence of a severe underlying coronary artery disease along with
      perioperative triggering factors, such as acute ischemia, electrolytic disorders,
      and sudden hemodynamic impairment.

PMID- 10651186
TI  - Negative chronotropic and inotropic effects of class I antiarrhythmic drugs
      assessed in isolated canine blood-perfused sinoatrial node and papillary muscle
      preparations.
AB  - The present study was designed to assess the negative chronotropic and inotropic
      effects of 10 class I antiarrhythmic drugs, using isolated canine blood-perfused
      sinoatrial node and papillary muscle preparations. Each drug showed negative
      chronotropic and inotropic effects in a dose-related manner. The potency of the
      suppressive effect on the sinoatrial automaticity was in the order of aprindine,
      quinidine, flecainide, lidocaine, mexiletine, cibenzoline, disopyramide,
      procainamide, tocainide, and phenytoin, while the effect on the ventricular
      contraction was in the order of aprindine, flecainide, cibenzoline, lidocaine,
      mexiletine, disopyramide, tocainide, phenytoin, quinidine, and procainamide. The
      differences in the suppressive effects could not necessarily be explained by
      their subclassification, based either on action potential duration or kinetic
      properties of dissociation or association with sodium channels. On the other
      hand, we found a good correlation between the negative inotropic effects of class
      I drugs in this study and the canine antiarrhythmic plasma concentrations for the
      digitalis- and coronary ligation-induced ventricular arrhythmia models in our
      previous studies. However, the negative chronotropic effects of the drugs showed
      a poor correlation with the antiarrhythmic plasma drug concentrations. The data
      shown in this paper may provide a convenient guideline for predicting acute
      cardiosuppressive effects of antiarrhythmic drugs, especially in patients with
      reduced cardiac function.

PMID- 10651187
TI  - Improvement of eosinophilic heart disease after steroid therapy: successful
      demonstration by endomyocardial biopsied specimens.
AB  - A 62-year-old man with acute eosinophilic endomyocarditis developed congestive
      heart failure. The biopsy specimens revealed degranulated eosinophils and
      eosinophil cationic protein (ECP) in the endocardium, and in activated
      eosinophils and the myocardial interstitium. On electronmicroscopy, a
      characteristic cardiac myocytolytic change showing disruption at the
      intercellular junctional site was observed. After steroid treatment, clinical
      symptoms, systolic dysfunction and laboratory data dramatically improved. In the
      subsequent biopsy specimens, eosinophilic infiltration and ECP disappeared.
      Steroid therapy provided a beneficial effect in preventing the progression of
      cardiac damage. This effect was clearly documented by histochemical studies of
      the serial endomyocardial biopsy samples.

PMID- 10651188
TI  - Molecular genetics of age-related macular degeneration: current status.
AB  - Age-related macular degeneration (AMD), a multifactorial human disorder, is the
      most common cause of acquired visual impairment in people over the age 60. It is
      estimated to affect millions of individuals worldwide. Prevalence increases with
      age; among persons 75 years and older, mild, or early forms occur in nearly 30%
      and advanced forms in about 7% of the population. AMD has been associated both
      with environmental and genetic factors. However, the clinical heterogeneity, late
      age at onset, and complex etiology have confounded genetic studies of the
      disorder. Methods applicable to the study of single-gene and some complex
      disorders (i.e., linkage analysis, sib-pair analysis, transmission disequilibrium
      test, etc.) have had limited utility in elucidating the genetic components of the
      complex AMD trait. Recently, substantial progress has been made in determining
      the genetic basis of monogenic eye disorders. On a monthly basis mutations are
      identified in new genes responsible for some form of retinal degeneration. Most,
      if not all, of these genes become candidates for potential involvement in
      multifactorial disorders especially if the phenotypes of the early-onset
      Mendelian diseases they cause resemble later onset complex traits. Unfortunately,
      to date mutational analyses of the candidate genes in AMD patients to date have
      not yielded the highly anticipated information: statistically significant
      association of sequence variants with AMD. Whether this is due to the
      unsuccessful selection of the right candidate genes for the analysis, or the
      methods employed, or both, has to be elucidated. This review summarizes current
      knowledge of genetic research aimed at delineating the molecular genetic basis of
      age-related macular degeneration. Moreover, it attempts to offer some approaches
      for the future studies directed towards understanding the genetic components of
      this complex disorder.

PMID- 10651189
TI  - Dacryoliths in chronic dacryocystitis and their composition (spectrophotometric
      analysis).
AB  - PURPOSE: To present the findings from histological and chemical analysis of large
      dacryoliths and correlate them with previous reports. MATERIALS AND METHODS:
      Dacryoliths were found in 8% of 216 dacryocystorhinostomy operations. In two
      cases with mild chronic dacryocystitis, large dacryoliths were extracted. The
      first case was a 42-year-old male with three dacryoliths in a lacrimal sac,
      presenting diverticulum-like formations, the second was a 22-year-old woman with
      one dacryolith at the entrance of the nasolacrimal duct. Chemical analysis was
      based on atomic absorption spectrophotometry (F.AAS) and on atomic emission
      spectrometry (AES). Light histological examination was also done.
      RESULTS/CONCLUSIONS: The findings were the same in both cases. Histological
      examination revealed amorphous organic material, and limited areas with the
      characteristics of calcium salt depositions. Chemical analysis showed mainly
      organic material with only minimal inorganic material. Explanations are offered
      about the formation of these dacryoliths.

PMID- 10651190
TI  - Treatment of acute bacterial conjunctivitis with topical lomefloxacin 0.3%
      compared to topical ofloxacin 0.3%.
AB  - PURPOSE: The main purpose of this prospective study was to compare the efficacy,
      local tolerance, and safety of topical lomefloxacin 0.3% and topical ofloxacin
      0.3% in the treatment of acute bacterial conjunctivitis. PATIENTS AND METHODS:
      Forty patients with acute bacterial conjunctivitis were included in a randomized,
      prospective, parallel-group study. Twenty patients were assigned to the
      lomefloxacin group (Okacin, CIBA Vision Ophthalmics) and 20 patients to ofloxacin
      (Oflox, Allergan). Lomefloxacin 0.3% was given 1 drop every 2 hours during waking
      hours on the first day then twice daily for one week. Ofloxacin 0.3% eyedrops
      were given four times daily. All patients underwent eye examination and clinical
      findings were graded and recorded according to severity of lid hyperemia, lid
      edema, lid crusting, conjunctival edema and discharge, bulbar conjunctival
      hyperemia, palpebral conjunctival hyperemia, corneal edema, and ocular
      discomfort. The score for each clinical sign was recorded before and after
      treatment. The mean cumulative sum score (CSS) was obtained by adding the scores
      for signs and symptoms. All conjunctival swabs were cultured and tested for
      sensitivity. Patients with confirmed bacterial conjunctivitis were included.
      RESULTS: There were 10 male and 10 female patients in each group. The age range
      was from 1 to 78 years, and the mean age was 35 years in the lomefloxacin group.
      In the ofloxacin group the age range was from 1 to 70 years, and the mean age was
      26 years. There was no significant difference between the two groups in relation
      to age or sex. The causative organisms were Staphylococcus epidermidis in 16
      cases (36%), alpha-hemolytic Streptococci in 9 (20%), Haemophilus spp. 6 (13%),
      Staphylococcus aureus 5 (11%), Streptococcus pneumoniae 4 (9%), Pseudomonas
      aeruginosa 3 (7%), and other 2 (4%). The mean CSS for conjunctivitis was 12.1
      before therapy in the lomefloxacin group and 12.7 in the ofloxacin group. On the
      7th day of therapy, the mean CSS was 0.7 in the lomefloxacin group, and 1.6 for
      ofloxacin. All patients showed improvement, but a total of 18 out of 20 (88%) in
      the lomefloxacin group showed complete resolution compared to 15 (75%) in the
      ofloxacin group. The difference was not statistically significant (p = 0.08).
      Tolerance was excellent in both groups, and no side effects were reported. A
      burning sensation was noted by two patients, one in each group. CONCLUSIONS:
      Lomefloxacin and ofloxacin were equally effective and safe in the treatment of
      acute bacterial conjunctivitis.

PMID- 10651191
TI  - Posterior chamber silicone intraocular lens for the correction of myopia: an
      experimental study in rabbits.
AB  - PURPOSE: To establish whether ocular lesions arise after implantation of
      posterior chamber silicone intraocular lenses (IOL) for the correction of high
      myopia. METHODS: Twenty-three posterior chamber silicone IOL were implanted in 23
      eyes of the same number of pigmented rabbits. After different follow-up time
      (from one week to one year) the eyes were enucleated and processed for
      histopathological study after determining the protein concentration in the
      aqueous humor. The IOL were removed for staining and examination, and adhered
      cells were counted. Ten eyes analogous to those operated upon were used as
      controls. RESULTS: Intense inflammation was observed in the early postoperative
      period in all cases. Protein concentration in the aqueous humor was initially
      high and decreased over time, though without reaching normal values at one year.
      Mono- and multinucleated cells were seen adhering to the IOL, though they
      decreased in number over time and were practically absent after one year.
      Friction between the posterior surface of the iris and the IOL had no clinical
      repercussions. The only pigment accumulations were in the iris and in the
      peritrabecular zone. There were no significant differences in the accumulation of
      granules in relation to IOL diameter or power. Excluding three cataracts
      morphologically similar to traumatic cataracts, five lens opacifications were
      observed: two were anterior subcapsular cataracts, and the other three were only
      precapsular deposits. The IOL had no synechiae to the ocular tissues.
      CONCLUSIONS: Opacification of the lens is the main concern with implanted
      posterior chamber silicone IOL. Larger series of eyes must be analysed to
      establish the true incidence and reversibility of these opacities.

PMID- 10651192
TI  - Iris fluorescein angiography and iris indocyanine green videoangiography in
      pseudoexfoliation syndrome.
AB  - BACKGROUND: Precise evaluation of the iris vascular pattern in pseudoexfoliation
      syndrome (PXS) may be difficult with iris fluorescein angiography (IFA) because
      of the frequent presence of a heavily pigmented iris and conspicuous late
      leakage. However, iris indocyanine green videoangiography (IICGV) can precisely
      visualize details of the iris vascular pattern. This study analyzed the utility
      of IICGV in detecting microvascular changes in PXS and compared these findings
      with those of IFA. METHODS: Twenty-eight patients with PXS in both eyes underwent
      an ophthalmic examination including IFA and IICGV. IICGV was done with the
      IMAGEnet system H1024. RESULTS: IICGV gave better visualization of iris
      hypoperfusion and anastomotic vessels whereas iris microneovascularisation was
      far more clearly visible on IFA. IICGV also detected iris pigment epithelium
      defects. CONCLUSIONS: IICGV can be considered a useful tool for evaluation of the
      iris vascular pattern in PXS. Iris hypoperfusion did not appear to contribute to
      the development of iris microvascular changes.

PMID- 10651193
TI  - Fibrinolytic activity of subretinal fluid after cryopexy.
AB  - PURPOSE: To measure the tissue plasminogen activator antigen (t-PA Ag) content
      and plasminogen activator inhibitor type 1 (PAI-1) activity of SRF and blood.
      METHODS: 22 patients aged from 20 to 77 years (median: 57.3 years), were studied,
      undergoing retinal detachment surgery. Excluded were patients with vein or
      arterial disease and any other factors that could change the parameters
      evaluated. Subretinal samples were obtained at the time of routine drainage
      during retinal detachment surgery, after cryopexy. Venous blood samples were
      taken from the cubital vein into sodium citrate solution (9:1) immediately after
      induction of anesthesia but before surgery. T-PA Ag concentration and PAI-1
      activity in subretinal fluid and citrated plasma and their relation to patients'
      age and sex, the duration and extent of retinal detachment, and degenerative
      changes of the retina were assessed. RESULTS: The median t-PA Ag concentration in
      22 samples of SRF was 6.7 ng/ml (interquartile range 3.6 ng/ml) and PAI-1
      activity 14.0 IU/ml (interquartile range 7.5 IU/ml). The median levels of t-PA Ag
      and PAI in plasma were respectively 10.7 ng/ml (interquartile range 8.6 ng/ml)
      and 15.7 IU/ml (interquartile range 12.2 IU/ml). There were no differences
      between the t-PA Ag concentration and PAI-1 activity in SRF and blood. We found
      no correlation between the levels of t-PA Ag and PAI-1 activity in SRF and age,
      sex, the degree of myopia, the duration and extent of retinal detachment, or
      retinal degenerative changes. CONCLUSIONS: The parameters of the fibrinolytic
      cascade studied here indicated the presence of high levels of t-PA Ag and PAI-1
      activity in SRF.

PMID- 10651194
TI  - Bilateral medial rectus recession in convergence excess esotropia, with and
      without distance orthophoria.
AB  - PURPOSE: To evaluate the effectivity and safety of bilateral medial rectus
      recession for the correction of acquired convergence excess esotropia, with and
      without distance orthophoria. METHODS: Thirty-five pediatric patients with
      acquired convergence excess esotropia were operated with bilateral medial rectus
      recessions based on the near angle measured through the distance correction.
      Preoperatively, in 26 patients, full hypermetropic correction did not fully
      correct the distance angle; these patients were operated for the residual angle
      for distance and near. In nine patients full hypermetropic correction produced
      distance orthophoria and these cases also had near orthophoria through a near
      add; these patients could have used bifocals, but surgery was chosen instead.
      RESULTS: Postoperatively, 19 of the 26 patients with distance esotropia (73%) and
      6 of the 9 with distance orthophoria (66.6%) were successfully aligned.
      Consecutive exotropia developed in two patients (7.6%) in the distance esotropia
      group and one (11.1%) in the distance orthophoria group. CONCLUSIONS: These
      results suggest that bilateral recession of the medial recti based on the near
      deviation is effective in eliminating the near angle in convergence excess
      esotropia. In patients with distance orthophoria this operation can be used as an
      initial treatment instead of bifocals. Although the risk of consecutive exotropia
      was low in this series, a larger number of patients would determine its actual
      rate more accurately.

PMID- 10651195
TI  - Coralline hydroxyapatite sphere in orbit restoration.
AB  - PURPOSE: To restore the anophthalmic socket, primarily or secondarily, using a
      hydroxy-apatite sphere (HA). METHODS: We used HA in 33 patients (25 male, 8
      female), aged from 4 to 68 years (mean 38.1 years) for 19 primary and 14
      secondary implantations. HA spheres measured 16 mm in one patient, 18 mm in 21
      and 20 mm in 11. The spheres were wrapped in donor sclera preserved in absolute
      alcohol. All six extraocular muscles were isolated, in the cases where this was
      possible. Buccal membrane was grafted in three patients to restore the fornices.
      Drilling was done on four patients using a 3.8 serrated plastic sheath. RESULTS:
      During follow-up of 7-69 months we observed no complications except for slight
      edema in the immediate postoperative period. All patients gained very good to
      excellent motility of the implant, acceptable symmetric appearance in the case of
      primary implantation, and a dramatic improvement of facial appearance in the case
      of secondary implantation. CONCLUSIONS: HA spheres are an excellent orbital
      implant for primary and secondary restoration of the anophthalmic socket causing
      no serious complications.

PMID- 10651196
TI  - Orbital emphysema and diplopia following thoracotomy.
AB  - PURPOSE: To describe the clinical and radiological findings in a patient with
      diplopia and orbital emphysema following thoracotomy. METHODS: Reported is a 71
      year-old woman who presented with diplopia several days following thoracotomy.
      RESULTS: Physical examination revealed diffuse subcutaneous emphysema and a right
      hypertropia. Head computed tomography revealed facial and palpebral subcutaneous
      emphysema extending into the infratemporal fossa and orbits bilaterally. A chest
      tube was replaced and her diplopia resolved. CONCLUSIONS: Subcutaneous emphysema
      can lead to diplopia and orbital emphysema in the absence of orbital trauma.
      Contrary to previously suggested mechanisms of orbital emphysema associated with
      subcutaneous emphysema, computed tomography imaging suggested that air entry into
      the orbit in this case was through the inferior orbital fissure.

PMID- 10651197
TI  - Twelve years' continuous wear of the same therapeutic soft contact lens: a case
      report.
AB  - PURPOSE: To describe a case of a patient who had worn the same therapeutic soft
      contact lens (TSCL) continuously for twelve years, since he had failed to attend
      normal follow-up visits. METHODS: Microbiological histological and scanning
      electron microscopic (SEM) studies of conjunctiva, cornea and TSCL were done.
      RESULTS: Cultures were negative. Corneal histology revealed mild stromal edema
      and mild epithelial parakeratosis. Corneal SEM was remarkable for the
      preservation to some extent of normal corneal epithelial specialization with
      microtricae and microvillae. SEM of the TSCL showed a ruffed multi-layer surface
      with several cracks including different types of cells. CONCLUSIONS: The patient
      showed surprising tolerance to the continuous wear of the same contact lens for
      12 years.

PMID- 10651198
TI  - Nanophthalmic uveal effusion syndrome after prophylactic laser treatment.
AB  - PURPOSE: We report a case of nanophthalmic uveal effusion syndrome (NUES) with
      total exudative retinal detachment (RD) after prophylactic argon laser (AL)
      treatment. The RD subsided and eventually resolved with i.v. steroid therapy.
      METHODS: A 45-year-old woman was referred to us with NUES and total exudative RD
      after prophylactic AL treatment for retinoschisis performed elsewhere. The
      patient had been scheduled for surgical intervention and was given i.v.
      prednisolone. RESULTS: Two days after starting i.v. prednisolone, the subretinal
      fluid partially resolved. Intervention had therefore been postponed. After 15
      days the RD almost disappeared and vision improved to 20/400. Ten days later the
      macula was flat and vision was 20/200. At the six-month follow-up visit vision
      was 20/40. CONCLUSIONS: To our knowledge this is the first report of NUES and
      total exudative RD following AL treatment that resolved with i.v. steroid therapy
      alone. Since the AL treatment clearly seemed to play a role in the pathogenesis
      of the NUES and associated RD we strongly advise careful assessment of the
      risk/benefit ratio of prophylactic laser treatment in nanophthalmic patients.
      Although sclerectomy and vortex vein decompression are well-established
      techniques, we believe steroid therapy might be tried before proceeding to
      surgery.

PMID- 10651199
TI  - Cellular and molecular mechanisms of coronary artery spasm: lessons from animal
      models.
AB  - Coronary artery spasm plays an important role in the pathogenesis of a wide
      variety of ischemic heart diseases, especially in the Japanese population.
      Because coronary artery spasm can be induced by a variety of stimuli with
      different mechanisms of action, the occurrence of the spasm appears to be due to
      the local hyperreactivity of the coronary artery rather than to an enhanced
      stimulation with a single mechanism of action. Several lines of evidence indicate
      that coronary artery spasm is caused primarily by smooth muscle hypercontraction
      whereas the contribution of endothelial dysfunction may be minimal. In order to
      elucidate the cellular and molecular mechanisms of the spasm, porcine models of
      the spasm were developed. In the first model with balloon injury and high
      cholesterol feeding, a close topological correlation between the early
      atherosclerotic lesions and the spastic sites was noted, whereas in the second
      model with an inflammatory cytokine the potential importance of coronary
      inflammatory changes, especially at the adventitia, was noted. Subsequent studies
      in vivo and in vitro demonstrated that protein kinase C (PKC) and Rho-kinase are
      substantially involved in the intracellular mechanism of the spasm, resulting in
      increases in the mono- and diphosphorylations of myosin light chain (MLC).
      Furthermore, molecular biological analyses demonstrated that Rho-kinase is
      upregulated at the spastic site (at all levels, including mRNA, protein, and
      activity), resulting in the inhibition of MLC phosphatase through the
      phosphorylation of its myosin binding subunit and thereby causing the increase in
      MLC phosphorylations. Preliminary results also suggest that the long-term
      inhibition of Rho-kinase is effective in inhibiting the development of
      arteriosclerotic vascular lesions in several porcine models. Thus, Rho-kinase
      could be regarded as a novel therapeutic target for coronary arteriosclerosis in
      general and coronary artery spasm in particular.

PMID- 10651200
TI  - Role of off-pump coronary artery bypass grafting in patients with malignant
      neoplastic disease.
AB  - Although the long-term benefits of conventional coronary artery bypass grafting
      (CABG) are obvious, postoperative morbidity and mortality and the length of
      recovery associated with cardiopulmonary bypass are the main concerns of cardiac
      surgeons and cardiologists. The aim of this study was to demonstrate the
      effectiveness and advantage of the off-pump CABG for patients with concomitant
      malignant disorders requiring myocardial revascularization. From March 1997 to
      February 1999, 51 patients underwent off-pump CABG. Of these, there were 9
      patients who had concomitant malignant disease requiring noncardiac surgery:
      gastric cancer (4), urinary bladder cancer (2), cholangioma (1), lung cancer (1)
      and colon cancer (1). Off-pump CABG was performed through a sternotomy, left
      thoracotomy or subxiphoid incision. Five patients received single grafting and 4
      received double. The mean operative time for the off-pump CABG was 167 min. The
      total amount of bleeding during the off-pump CABG was 450-890 ml. Simultaneous
      noncardiac operations were carried out in 5 patients. The other 4 patients
      underwent subsequent operations for the malignancy uneventfully. In contrast, of
      the 4 patients with concomitant malignant disorders who underwent standard CABG
      during the period before the use of off-pump CABG, 2 died without undergoing the
      subsequent noncardiac operation. Off-pump CABG is quite efficient and is of great
      advantage in patients with malignancy who require myocardial revascularization in
      addition to noncardiac surgery for the cancer.

PMID- 10651201
TI  - Plasma and urinary levels of heart fatty acid-binding protein in patients
      undergoing cardiac surgery.
AB  - To evaluate the clinical significance of the plasma and urinary levels of heart
      fatty acid-binding protein (H-FABP) in patients undergoing cardiac surgery, a
      prospective study was conducted. Ten patients undergoing coronary artery bypass
      grafting were enrolled. Blood samples for determination of plasma H-FABP (pH
      FABP), the MB isoenzyme of creatine kinase (CK-MB) and troponin-T (TnT), and
      urine samples for determination of urinary H-FABP (uH-FABP) were collected
      serially. None of the patients had perioperative myocardial infarction. The time
      to reach the peak level after aortic declamping was significantly (p<0.05)
      shorter for pH-FABP (1.4+/-0.5 h) than for CK-MB (2.5+/-0.5 h), TnT (6.6+/-1.3 h)
      or uH-FABP (3.0+/-0.6 h). Peak levels of pH-FABP correlated with those of CK-MB
      (r = 0.51, p = 0.04), TnT (r = 0.60, p = 0.03) and uH-FABP (r = 0.61, p = 0.03),
      and peak levels of uH-FABP correlated with CK-MB (r = 0.57, p = 0.04).
      Postoperative uH-FABP levels correlated inversely with the left ventricular
      stroke work index (r = -0.63, p = 0.04). This study demonstrated that H-FABP
      appears rapidly in plasma after reperfusion and reaches its peak earlier than
      other available biochemical markers; it appears also in urine and the levels
      correlated with cardiac function. Plasma and urinary H-FABP may be an early and
      sensitive biochemical marker for the diagnosis of myocardial injury in patients
      undergoing cardiac surgery.

PMID- 10651202
TI  - Pulmonary ventricular outflow reconstruction with a size-reduced cryopreserved
      pulmonary valve allograft: mid-term follow-up.
AB  - Surgical reduction of pulmonary allografts is being performed because of the
      shortage of allografts of suitable size for pediatric use. However, the outcome
      of size-reduced pulmonary allografts for pulmonary conduits is unknown. In the
      present study, cryopreserved pulmonary allografts harvested from adults at the
      time of kidney donation were size-reduced and used in 4 children, 2 with
      pulmonary atresia and ventricular septal defect and 2 with atrioventricular
      discordance, pulmonary atresia and ventricular septal defect. They all had
      undergone right and/or left modified Blalock-Taussig shunt operations with a 5-mm
      synthetic graft prior to the reparative operations. They underwent definitive
      repair with a size-reduced cryopreserved pulmonary allograft valved conduit and
      were followed up for 2-5 years. Postoperative echocardiographic and
      cineangiographic assessments revealed excellent function of the pulmonary
      bicuspidalized valves with a minimal pressure gradient and no, or only trivial,
      regurgitation. Although the long-term result of a cryopreserved bicuspid
      pulmonary valved conduit remains unknown, the remodeled bicuspid pulmonary
      allograft conduits showed excellent hemodynamic characteristics in mid-term
      follow-up and appear to be a reasonable alternative to other types of conduits
      when an appropriate-sized allograft is not available.

PMID- 10651203
TI  - Physiological role of endothelin-1 in nonworking muscles during exercise in
      healthy subjects.
AB  - Endothelin-1 (ET-1) is a potent vasoconstrictor peptide produced by vascular
      endothelial cells. However, the role of ET-1 in exercise-induced physiological
      responses is still to be investigated. The purpose of the present study was to
      investigate in healthy volunteers whether the ET-1 plasma concentration in
      nonworking muscles is changed by exercise and to investigate the physiological
      role of ET-1 during exercise. Bicycle ergometer cardiopulmonary exercise tests
      were performed in 36 healthy men (mean age, 22.5 years). Blood samples for
      measuring ET-1 were drawn from the cubital vein during rest and immediately after
      the exercise test. The ET-1 change ratio was calculated as ET-1 immediately
      following exercise/ET-1 during the resting state. Cardiac output (CO) was
      measured during the exercise test by the impedance method. Arterial venous oxygen
      difference (AVO2D) when CO reached 10L/min or 15L/min was calculated as AVO2D =
      VO2/CO. Results were as follows: (1) the ET-1 change ratio correlated inversely
      with exercise time at the anaerobic threshold (r = -0.37, p = 0.03) and peak
      exercise time (r = -0.35, p = 0.04); (2) the ET-1 change ratio tended toward an
      inverse correlation with deltaVO2/deltawork rate (r = -0.29, p = 0.09); (3) the
      ET-1 change ratio correlated positively with AVO2D when CO reached 10L/min (r =
      0.42, p = 0.02) and tended toward a positive correlation with AVO2D when CO
      reached 15 L/min (r = 0.32, p = 0.08). These results indicate that an increase in
      ET-1 in nonworking muscles may participate in the exercise-induced redistribution
      of blood flow and in increasing the blood flow to working muscles.

PMID- 10651204
TI  - Age-adjusted heart rate variability as an index of the severity and prognosis of
      heart failure.
AB  - The age-adjusted, heart rate variability (HRV) was evaluated as a parameter for
      the severity of heart failure and its prognosis. HRV was obtained by 24-h Holter
      monitoring in patients with left ventricular dysfunction (LVD). New York Heart
      Association (NYHA) functional classification, echocardiography, radioisotope
      ventriculography, and blood examination were performed, and compared between
      patients and normal subjects. The evaluation was repeated during the follow-up
      period. Finally, using the lower limit of HRV, patients were divided into either
      normal or abnormal group for each low-frequency power (LF) and high-frequency
      power (HF) (age-adjusted HRV). Other parameters of heart failure and prognosis
      were compared between these 2 groups. HRV tended to be lower in patients with
      LVD. HF decreased at the early stage of heart failure, but did not decrease
      progressively. LF decreased progressively. HRV change paralleled the change of
      NYHA. The abnormal HRV group showed a poor prognosis for cardiac death, but not
      for sudden cardiac death. In patients with LVD, HRV was decreased compared with
      the normal subjects. Change in HRV correlated with the change in NYHA
      classification. Age-adjusted HRV correlated with cardiac-death prognosis, but not
      for sudden cardiac death.

PMID- 10651205
TI  - Decreased RR interval complexity and loss of circadian rhythm in patients with
      congestive heart failure.
AB  - The present study investigated how the RR interval complexity and variability and
      their circadian rhythms alter for patients with congestive heart failure (CHF).
      Sixteen patients aged between 41 and 72 years with CHF and 20 control subjects
      were included. 24-h ambulatory electrocardiographic recordings were analyzed, and
      digitized data was partitioned into sections of 30-min duration. For each
      section, time- and frequency-domain indices, and complexity indices of heart rate
      variability were calculated. For CHF patients, 24-h average values of all indices
      were significantly decreased. The circadian rhythms of mean RR intervals were
      preserved and resembled the abnormal circadian rhythms of the low-frequency
      power. The circadian rhythms of high-frequency power and all complexity indices
      shown in the normal control were lost. Conclusively, the patients with CHF showed
      decreased RR interval complexity and loss of its circadian rhythm, in addition to
      decreased frequency-domain RR interval variability and its abnormal circadian
      rhythm.

PMID- 10651206
TI  - Retrospective analysis of cerebral complications after coronary artery bypass
      grafting in elderly patients.
AB  - The present study retrospectively investigated cerebral complications of coronary
      artery bypass grafting in 205 consecutive patients aged 70 years or older, who
      underwent elective cardiopulmonary bypass from 1990 to 1997. Computed tomography
      of the brain and chest was done before surgery. Ten patients had so-called
      'aortic no-touch surgery' and suffered no cerebral complications; the other 195
      patients had conventional surgery. Adverse cerebral events occurred in 8.7%,
      including cerebral infarction (4.1%), diffuse encephalopathy (1.0%), convulsions
      (1.0%), transient disturbance of consciousness (1.0%), and severe loss of
      volition (1.5%). Multivariate analysis showed that only the detection of
      calcification of the ascending aorta was significantly associated with cerebral
      complications (p = 0.029). Total clamping tended to be superior to partial
      clamping for prevention of cerebrovascular accidents. The mortality rate was
      7.3%. In-hospital death was related to age (p = 0.0062), cerebral complications
      (p = 0.0032), and a low left-ventricular function (p = 0.018). Therefore, chest
      computed tomography to assess the ascending aorta should be performed
      preoperatively. Modified techniques like aortic no-touch surgery or other
      therapies combined with coronary intervention may be needed in elderly patients
      with severe calcification of the ascending aorta.

PMID- 10651207
TI  - Lipoprotein(a) is a potential coronary risk factor.
AB  - Lipoprotein(a) (Lp(a)) is recognized as a new coronary risk factor, but few
      studies have quantitatively assessed the relationship of serum Lp(a) levels with
      other coronary risk factors in many patients undergoing coronary cineangiography.
      Seventeen coronary risk factors were quantified (i.e., age, gender, hypertension,
      impaired glucose tolerance, cerebrovascular accident, hyperuricemia, smoking,
      family history of ischemic heart disease (IHD), history of hyperlipidemia, Lp(a),
      total cholesterol, high density lipoprotein (HDL)-cholesterol, triglyceride, low
      density lipoprotein-cholesterol, apolipoproteins(apo)A-I,B, E) to determine their
      relationship with the numbers of involved coronary vessels using multiple
      regression test in 1,006 patients who underwent coronary cineangiogram (280 non
      IHD patients: 144 men, 136 women; 726 IHD patients: 460 men, 266 women; age 16-84
      years, mean 60.5+/-0.3). Multiple regression test indicated R = 0.506 and items
      that showed high beta weight and significant p level were age, Lp(a), impaired
      glucose tolerance, total cholesterol, cerebrovascular accidents, HDL-cholesterol,
      smoking, gender, family history of IHD, and apo-A-I (0.221, p<0.001; 0.174,
      p<0.001; 0.616, p<0.001; 0.138, p<0.001; 0.122, p<0.001; -0.12, p<0.001; 0.092,
      p<0.01; 0.091, p<0.01; 0.067, p<0.05; -0.065, p<0.05; respectively). It was
      concluded that Lp(a) is an independent, potential, and modifiable coronary risk
      factor, and that reduction of serum Lp(a) is important in the clinical management
      of patients with IHD.

PMID- 10651209
TI  - Adriamycin causes dual inotropic effects through complex modulation of myocardial
      Ca2+ handling.
AB  - Effects of adriamycin (ADR) on the twitch contraction of isolated guinea pig
      cardiac muscles were examined to elucidate its actions on intracellular Ca2+
      mobilization. In right ventricular papillary muscles, ADR (100-300 micromol/L)
      caused positive inotropy when the muscles were constantly stimulated at low
      frequencies (0.1-0.5 Hz), whereas it caused negative inotropy when the muscles
      were stimulated at higher frequencies (2.0-3.0 Hz). Action potential duration was
      prolonged significantly by ADR, especially at the lower frequencies. The
      potentiation of twitch contraction of the first beat (B 1) following a short rest
      period (2-10 s) in ventricular muscles was inhibited by ADR. In untreated
      papillary muscles, B1 contraction showed time-dependent decay in response to a
      prolongation of the preceding rest period up to 120 s. ADR (300 micromol/L)
      caused ryanodin-like acceleration for the early B1 decay with rest period less
      than 20 s, but a substantial deceleration for the later B1 decay (> or =30 s). In
      left atrial muscles stimulated constantly, ADR had significant negative inotropy
      throughout the entire range of stimulation frequencies tested (0.1-4.0 Hz). The
      post-rest potentiation of B 1 contraction of atrial muscle in the presence of
      nifedipine was also inhibited by ADR. These findings suggest that ADR has dual
      inotropic effects through a complex modulation of myocardial Ca2+ handling, which
      may involve (1) an increase of Ca2+ influx through a prolongation of action
      potential duration, (2) ryanodine-like inhibition of Ca2+ release from the
      sarcoplasmic reticulum, and (3) inhibition of sarcolemmal Ca2+ extrusion probably
      through the Na+/Ca2+ exchange.

PMID- 10651208
TI  - Cardiac dendritic cells and acute myocarditis in the human heart.
AB  - Cardiac dendritic cells are considered to play an important role in the
      immunoresponse of the heart. However, it is unclear whether these cells occur in
      human myocarditis and whether they function in similar ways to those in rats.
      Cardiac samples were obtained from 22 autopsied patients with myocarditis, and
      compared with 20 age-and sex-matched controls. Formalin-fixed hearts were
      immunostained by the LSAB method. Cardiac dendritic cells were detectable even in
      the control hearts (1.5 cells/high power field (HPF)). In the acute phase of
      myocarditis, the number of cardiac dendritic cells increased up to 12.6 cells/HPF
      (p<0.001). In the subacute phase of myocarditis, T cells (36.6 cells/HPF) and HLA
      DR+ cells (10.2 cells/HPF) continued to infiltrate the periphery of the
      inflammatory lesions, but they had no expression without inflammation. In this
      study, cardiac dendritic cells were reactive for HLA-DR, but negative for CD68,
      and were characteristically large monocytes with long, slender, dendritic
      processes. Accordingly, they were clearly distinguishable from macrophages. In
      the human heart, cardiac dendritic cells may be recruited in the acute phase of
      myocarditis, and seem to play an important role in the succeeding immunoresponse.

PMID- 10651210
TI  - Long-term low-dose cibenzoline in patients with chronic renal failure undergoing
      hemodialysis.
AB  - Because most anti-arrhythmic drugs are eliminated from the kidney, anti
      arrhythmic drug therapy is largely restricted in patients undergoing hemodialysis
      (HD). Cibenzoline is a widely used antiarrhythmic drug excreted mainly from the
      kidney. The present study evaluated the safety and efficacy of reduced doses of
      cibenzoline (25 and 50 mg/day chronically) in 8 patients with maintenance HD.
      Cibenzoline was administered for more than 3 months without any problems in 7 of
      the 8 patients, although the medication was discontinued in 1 patient due to
      nausea and anorexia. With cibenzoline administration, the incidence and duration
      of atrial fibrillation decreased or disappeared in 6 of 7 patients and the
      frequency of complex ventricular arrhythmias was also reduced in 3 of 4 patients.
      No adverse side effects were noted. Plasma concentration of cibenzoline ranged
      from 169 to 220 ng/ml with the 25-mg/day dosage, and from 408 to 500 ng/ml with
      the 50-mg/day dosage. The concentrations remained stable during the study. In
      conclusion, low doses of cibenzoline are safe and effective in patients
      undergoing maintenance HD. However, intermittent monitoring is essential to
      ensure therapeutic drug concentrations.

PMID- 10651211
TI  - Pulmonary edema after cardioversion for paroxysmal atrial flutter: left
      ventricular diastolic dysfunction induced by direct current shock.
AB  - This report describes a patient with the pulmonary edema after cardioversion for
      paroxysmal atrial flutter without organic heart disease. A 68-year-old man was
      admitted to hospital for paroxysmal atrial flutter. Antiarrhythmic agents were
      not effective, and direct current cardioversion was performed on the 4th hospital
      day. Three hours after cardioversion, the patient complained of dyspnea, and a
      chest X-ray showed pulmonary edema. He responded to oxygen, intravenous
      furosemide and drip infusion of nitroglycerine. During tapering of the
      medication, his condition remained stable. The patient was discharged on the 7th
      day after admission. Echocardiographic findings indicated that transient left
      ventricular diastolic dysfunction due to direct current shock was the most likely
      cause of the lung edema.

PMID- 10651212
TI  - Transesophageal echocardiographic observation of multiple myeloma involving the
      pericardium: a case report.
AB  - This report presents a case of multiple myeloma with a mass lesion on the
      pericardium and pericardial effusion. The response to intrapericardial
      combination chemotherapy (cisplatin and betamethasone) was evaluated by repeated
      transesophageal echocardiograms. Following the treatment, complete resolution of
      the tumor and effusion were observed for 6 months after which the patient died of
      bacterial pneumonia. Intrapericardial combination chemotherapy can be an
      effective treatment for myelomatous involvement of the pericardium.

PMID- 10651213
TI  - Purulent pericarditis due to group B streptococcus and mycotic aneurysm of the
      ascending aorta: case report.
AB  - A 61-year-old female, with a history of uterine and cervical cancer treated with
      radical hysterectomy and 2 years of postoperative chemotherapy, presented to the
      emergency department with dyspnea on exertion. Computed tomography of the chest
      revealed a large pericardial effusion and a sacciform aneurysm of the ascending
      aorta. The patient subsequently underwent emergency pericardiocentesis with
      drainage of approximately 330 ml of a bloody and turbid effusion. Cultures from
      the effusion yielded group B streptococcus. Multiple organ failure and
      disseminated intravascular coagulation syndrome occurred in the acute phase, but
      gradually improved with continuous antibiotic therapy. On the 194th hospital day,
      in situ reconstruction of the ascending aorta was successfully performed using a
      synthetic graft. Although rarely reported, both purulent bacterial pericarditis
      and mycotic aneurysm can be life-threatening.

PMID- 10651214
TI  - Acute renal failure in the new millennium: time to consider combination therapy.
AB  - Acute renal failure (ARF) occurs frequently and results in an unacceptably high
      morbidity and mortality. There is no currently accepted specific therapy that
      alters the course of ischemic ARF. Recent experimental advances and continued
      funding of ARF studies should allow rapid progress in the new millennium. This
      will require novel approaches to both basic and clinical evaluations. New
      experimental models and studies evaluating multiple therapies are needed. In
      addition, methods to identify ARF early in its course are likely to improve
      outcomes. Clinical studies should employ very specific definitions of ARF,
      outcomes evaluated, indications for renal replacement therapy, and severity of
      illness evaluation methods. Such studies and aggressive preventative measures
      will significantly improve the incidence and outcome of ARF in the 21st century.

PMID- 10651215
TI  - Future molecular approaches to the diagnosis and treatment of glomerular disease.
AB  - Current diagnoses and treatment decisions for renal disease are made based upon a
      combination of clinical and pathological determinations. With the advances in
      both biochemical and molecular biological techniques, identifying the underlying
      biochemical and genetic changes that may have initiated and/or contributed to the
      disease is possible. We describe here technologies that may lead to significant
      changes in renal disease diagnosis, characterization, treatment, and potentially
      prevention. For example, differential display techniques and DNA gene chip arrays
      show the changes in mRNA expression patterns and can potentially identify
      previously unknown genes and reveal new roles for previously known genes in renal
      disease. The generation of the single nucleotide polymorphisms (SNP) genomic map
      will facilitate genetic screening that may identify a gene or combination of
      genes that produce enhanced disease susceptibility. Combining genomic analysis
      with epidemiological studies may identify environmental factors that contribute
      to renal disease onset in genetically susceptible individuals. A number of novel
      therapies are already on the horizon. These include reagents that abrogate the
      function of specific cytokines, chemokines, and effector cells. With the list of
      renal disease genes in hand, their role in renal physiology and pathophysiology
      can be determined, which should lead to the discovery of pharmacological
      intervention directed at those genes and their products that play a role in the
      pathogenesis of renal disease.

PMID- 10651216
TI  - New prospects for treatment of lupus nephritis.
AB  - Systemic lupus erythematosus (SLE) is envisioned to arise from hyperactivate
      helper T-cells that cause polyclonal B-cell secretion of pathogenic
      autoantibodies and formation of immune complexes which deposit in sites such as
      the kidney. The most widely used immunosuppressive drugs, notably corticosteroids
      and cyclophosphamide, are often criticized as being nonspecific. In fact, these
      agents may be effective in SLE and lupus nephritis because broad, rather than
      highly selective, effects are required to control the aberrant immune system.
      Nonetheless, these agents are not uniformly effective and are associated with
      substantial toxicities. The lack of universal efficacy raises the specter that
      lupus is a heterogeneous disorder with different etiopathogenesis in different
      subsets of patients (as in lupus-prone mice). Therapeutic prospects for the
      upcoming millennium include new forms and combinations of chemotherapeutic agents
      (mycophenolate and adenosine analogues), attempts to achieve immunological
      reconstitution using near-ablative chemotherapy (with or without bone marrow or
      stem cell rescue), monoclonal antibodies, and other inhibitors of T-cell
      costimulatory pathways (e.g., anti-CD154 and/or CTLA4-Ig). The prospect for gene
      therapy has already been realized in some animal models of SLE. In human SLE, the
      feasibility of gene therapy will depend on further definition of lupus-promoting
      genes and availability of methods to establish stable expression of potentially
      corrective genes.

PMID- 10651217
TI  - Low renin hypertension in the next millennium.
AB  - With the expression cloning of the subunits of the epithelial sodium channel, a
      new era has evolved in our basic understanding of the low-renin forms of human
      hypertension. The monogenic hypertensive syndromes manifest dysregulation of the
      epithelial sodium channel in the cortical collecting tubule. These rare syndromes
      provide a schema for organizing our thinking about the more common form(s) of low
      renin hypertension, and raise the possibility that dysregulation of sodium
      channel activity and consequent salt retention and volume expansion provide a
      basic pathophysiological mechanism for low-renin hypertension. What are needed
      are more specific agents to interrupt the mineralocorticoid response pathways,
      and clinically relevant approaches to measuring sodium channel activity at the
      level of the collecting tubule in the individual patient. The combined use of
      aldosterone antagonists and angiotensin-converting enzyme inhibitors or
      angiotensin receptor antagonists could have a beneficial effect on "progression"
      of renal disease associated with glomerular and interstitial fibrosis, especially
      if the effects of hyperkalemia on the heart and aldosterone secretion can be
      minimized.

PMID- 10651218
TI  - How will gene therapy apply to the kidney in the 21st century?
AB  - Nephrology is entering the age of genomics-based drug discovery and development.
      Once only a theoretical objective, gene therapy is now being tested in various
      diseases. New and substantially improved vector systems and related technologies
      are undergoing development, many have shown promise in animal studies, and some
      are now being used in clinical trials. Recent advances in the molecular basis for
      renal diseases, organ transplant rejection, and hypertension have led to
      preclinical tests of gene therapeutic approaches. The most impressive of these
      strategies will likely soon be studied in the clinic. This review details recent
      advances in gene therapy technology and highlights potential novel applications
      of gene therapy in the treatment of renal diseases and hypertension. While the
      manufacture and widespread use of gene therapy products as conventional
      pharmaceuticals for renal diseases and hypertension may seem to be a goal for the
      remote future, much of the needed genetic information, technology, and
      intellectual resources are rapidly becoming available.

PMID- 10651219
TI  - Challenges for chronic dialysis in the new millennium.
AB  - Although significant technical advances have occurred in the dialysis industry in
      the last 20 to 30 years, their collective impact on clinical outcomes has been
      less well-documented than their commercial successes. This article delineates the
      technical, administrative, and socioeconomic challenges which must be overcome in
      the next millennium in order to incorporate predicted technological advances into
      substantive improvements in quality of life, patient satisfaction, and adequacy
      of renal replacement therapy in the end-stage renal disease population.
      Technological advances envisioned include new athrombogenic materials for
      dialyzers and blood lines; membranes with absorptive properties; more efficient
      dialyzers; biofeedback sensor systems for physiological control of dialysis, on
      line screening, and trend analysis; increased utilization of frequent dialysis;
      new vascular access techniques; increasing use of practice guidelines; global
      capitation; and attention to patients' views on standards of care, quality of
      life, and operation of dialysis facilities. Whereas many new technologies will be
      available, their application will largely depend on both fundamental research and
      socioeconomic factors.

PMID- 10651220
TI  - Bioartificial kidney for full renal replacement therapy.
AB  - The rapid understanding of the cellular and molecular basis of organ function and
      disease processes will be translated in the next millennium into new therapeutic
      approaches to a wide range of clinical disorders, including acute and chronic
      renal failure. Central to these new therapies are the developing fields of gene
      therapy, cell therapy, and tissue engineering. These new technologies are based
      on the ability to expand stem or progenitor cells in tissue culture to perform
      differentiated tasks and to introduce these cells into the patient either in
      extracorporeal circuits or as implantable constructs. Cell therapy devices are
      currently being developed to replace the filtrative, metabolic, and
      endocrinologic functions of the kidney lost in both acute and chronic renal
      failure. This article summarizes the current state of device development for a
      renal tubule assist device, a bioartificial hemofilter, and a regulatable
      erythropoietin cell therapy device. These individual devices have the promise to
      be combined to produce a wearable or implantable bioartificial kidney for full
      renal replacement therapy. These new approaches may result in therapeutic
      modalities that significantly diminish the morbidity and mortality in patients
      with acute renal failure or end-stage renal disease.

PMID- 10651221
TI  - Transplantation for the millennium: attaining tolerance in our time--the Holy
      Grail.
AB  - Despite tremendous advances in organ transplantation over the past 40 years, life
      long immunosuppression is still required to maintain the transplanted organ. The
      induction of human tolerance to defined foreign antigens while maintaining
      completely intact all the rest of the immune repertoire, in the absence of
      maintenance immunosuppression, continues to be the dream of the transplant
      scientist and clinician, the "Holy Grail," the quest which energizes much recent
      research. This article presents an overview on recent developments on
      transplantation tolerance.

PMID- 10651223
TI  - CD19 is a central response regulator of B lymphocyte signaling thresholds
      governing autoimmunity.
AB  - The CD19/CD21 complex is categorized among the 'response regulator' class of
      receptors which determine the magnitude and outcomes of B cell receptor signals.
      Small changes in CD19 expression have dramatic effects on signaling thresholds
      within B cells, which in turn has considerable impact on the balance between
      humoral immune responses and tolerance induction. B cell signaling thresholds
      lowered by increased CD19 expression may significantly augment host
      susceptibility to the development of autoimmunity. Signals generated by C3d
      antigen complex binding to CD21 may also be involved in the development of
      autoimmunity by regulating CD19 function. Since CD19 serves as a central
      regulator of signaling thresholds in B cells, the CD19/CD21 complex may be an
      appropriate target for suppressing the development of autoimmunity.

PMID- 10651222
TI  - Training the academic nephrologist for the new millennium.
AB  - Physician-scientists play a key role in bringing basic science advances
      anticipated in the new millennium to the bedside. However, the existence of such
      individuals is in jeopardy, the reasons for which are summarized in first part of
      this article. Solutions to this problem are suggested and specific
      recommendations are directed at government and private agencies, industry,
      trainees, mentors, and academic institutions. Time is short and decisive action
      needs to be taken if we are to reap the full rewards of medical knowledge in the
      21st century.

PMID- 10651225
TI  - The effects of substance P and vasoactive intestinal peptide on interleukin-6
      synthesis in cultured human keratinocytes.
AB  - Interleukin-6 (IL-6) is a cytokine implicated as a key mediator of immune and
      inflammatory responses in psoriasis. Recent studies have shown that
      neuropeptides, substance P (SP) and vasoactive intestinal peptide (VIP), can
      modulate a production of IL-6 from cells, such as monocytes and astrocytes,
      participating in an immune reaction. The aim of this study was to assess the role
      of the neuropeptides on cytokine production of keratinocytes in physiologic or
      pathologic conditions. Cultured human keratinocytes derived from normal foreskin
      and psoriatic lesions were treated with various concentrations of SP or VIP, in
      the presence or absence of fetal bovine serum. The secretion of IL-6 by the
      treated keratinocytes was analyzed by enzyme-linked immunosorbent assay. Although
      neither SP nor VIP, by itself, was able to induce IL-6 synthesis in cultured
      human keratinocytes, we have found that SP, not VIP, significantly reduced 5%
      fetal bovine serum-induced IL-6 production in time- and dose-dependent fashion.
      This down-regulatory effect of SP was reversed by spantide, a SP antagonist.
      Lesional psoriatic keratinocytes showed a similar, but weaker, response when
      compared with normal keratinocytes. These data suggested that SP might modulate
      IL-6 synthesis of keratinocytes in either physiologic or pathologic conditions
      such as psoriasis.

PMID- 10651224
TI  - The changes of serum soluble intercellular adhesion molecule-1 after systemic
      steroid treatment in vitiligo.
AB  - Cell surface adhesion molecules are thought to play an important role in
      establishing intercellular contacts that are necessary for immunological
      reactions. Intercellular adhesion molecule-1 (ICAM-1, CD54) is a crucial adhesion
      molecule in mediating cell to cell adhesion during inflammatory responses,
      including non-MHC-restricted cytotoxicity. In this study, the sICAM-1 levels of
      ten healthy control subjects and seven generalized active vitiligo patients were
      measured by ELISA. The sICAM-1 levels were also correlated with the clinical
      courses in 33 patients with active vitiligo, who received systemic steroid
      treatment for 3 months. The average serum level of sICAM-1 was significantly
      higher in patients with active vitiligo than in the healthy control subjects. The
      sICAM-1 levels significantly decreased after systemic steroid treatment in the
      clinically improved group. These results suggest that immune activation is
      involved in active vitiligo and that changes of sICAM-1 levels can be a marker in
      the course of vitiliginous lesions.

PMID- 10651227
TI  - Expression of Bcl-2, p53, c-jun and c-fos protooncogenes in keloids and
      hypertrophic scars.
AB  - Keloids and hypertrophic scars represent a model of altered wound healing
      characterized by overproduction of extracellular matrix and dermal fibroblasts
      with high mitotic rate. Alteration of apoptosis and cell proliferation has been
      implicated in the etiology of keloids. The bcl-2 protooncogene encodes a protein
      that protects cells from programmed cell death while p53 protein functions as
      negative regulator of cell proliferation. Both protooncogenes have been shown to
      play a role in tissue homeostasis as apoptotic regulatory genes. The c-jun and c
      fos protooncogenes are transactivating factors also involved in fibroblast
      proliferation. In our study we investigated, by immunohistochemistry, skin
      specimens from three clinically active hypertrophic scars and keloids, two
      resting keloids and two early phase morphea to detect both bcl-2 and p53 protein
      expression, in order to evaluate these apoptotic regulatory genes in different
      fibrotic conditions. The c-jun and c-fos, at protein and mRNA level, and Ki67
      nuclear antigen expression were also investigated. In hypertrophic scars and
      active keloids we could detect intense Bcl-2 staining in basal keratinocytes and
      in scattered fibroblast-like and perivascular spindle-shaped cells, while no p53
      expression could be demonstrated. The c-jun and c-fos mRNA and protein expression
      was mainly found in dermal fibroblast-like cells and elongated perivascular cells
      in all skin biopsies, and similar immunostaining pattern was observed for Ki67
      antigen. No protooncogene expression in morphea patients and normal skin, unless
      Bcl-2 staining in the basal layer of normal epidermis, was documented. Our
      results suggest that Bcl-2, c-jun and c-fos protein expression and lack of p53
      detection in fibroblast-like and perivascular spindle cells are related to
      increased fibroblast proliferation, confirmed by Ki67 positivity, probably due to
      alteration of these regulatory apoptotic genes resulting in pathological
      scarring.

PMID- 10651226
TI  - Telomerase activity is spontaneously increased in lymphocytes from patients with
      atopic dermatitis and correlates with cellular proliferation.
AB  - Telomerase is a ribonucleoprotein enzyme involved with cellular proliferation and
      cellular senescence. The aim of the present study was to investigate telomerase
      activity in lymphocytes from patients with atopic dermatitis (AD) and to observe
      its regulation of cellular proliferation. Peripheral blood mononuclear cells
      (PBMC) were isolated from 15 patients with AD and 13 healthy donors. Cells were
      stimulated with purified protein derivative (PPD) of tuberculin (10 microg/ml),
      interleukin 2 (IL-2) (100 U/ml), anti-CD3 monoclonal antibody (anti-CD3) (1
      microg/ml), anti-CD3 plus IL-2, and staphylococcal enterotoxin A (SEA) (0.1
      microg/ml). Telomerase activity was measured by the telomeric repeat
      amplification protocol-based telomerase polymerase chain reaction enzyme-linked
      immunosorbent assay at 0 and 72 h of incubation. In addition, DNA synthesis of
      the cells was assayed using 3H-thymidine incorporation. We found that telomerase
      activity in non-stimulated PBMC from patients with AD was significantly up
      regulated without any stimulation during the 72 h of in vitro incubation. The
      most potent stimulator of telomerase activity was SEA, followed by anti-CD3 plus
      IL-2, anti-CD3 alone, and PPD. IL-2 did stimulate telomerase activity and DNA
      proliferation with increasing dosage of IL-2. The DNA proliferation was
      paralleled by increase in telomerase activity. There was no significant
      difference between telomerase activity in stimulated lymphocytes from AD patients
      and normal donors, but the relative increase in telomerase activity tended to be
      less in AD patients. A spontaneously higher telomerase activity in lymphocytes
      from AD patients could indicate that T lymphocytes are already stimulated in vivo
      or that a population of T cells in peripheral blood exhibits an increased
      telomerase activity compatible with cellular immaturity.

PMID- 10651228
TI  - Growth-stimulating effects of tumor necrosis factor-alpha on simian virus 40
      transformed human keratinocytes is linked to phosphorylation of retinoblastoma
      protein.
AB  - In this report, we show that tumor necrosis factor-alpha (TNF-alpha) has a strong
      growth-stimulating effect on simian virus 40 (SV40)-transformed keratinocytes,
      while it exerts a potent growth-inhibitory effect on normal human keratinocytes.
      Addition of TNF-alpha to SV40-transformed keratinocytes stimulated cell growth by
      216, 246, or 248% at 25, 50, or 250 ng/ml after 4 days culture compared with
      untreated cells, while addition to normal human keratinocytes reduced growth to
      65, 38, and 32% at the same concentrations, respectively. Cell cycle analysis by
      flow cytometry showed that treatment of SV40-transformed keratinocytes with 250
      ng/ml TNF-alpha for 48 h increased the S-phase cells from 19.8 +/- 0.3 to 49.7 +/
      2.4%. The percentage of G1/G0 phase cells decreased from 62.6 +/- 1.6 to 32.4 +/
      3.3%. We also demonstrated by immunofluorescent staining that SV40 large T
      antigen was enhanced by TNF-alpha incubation. Additionally, we examined the hyper
      and hypo-phosphorylated state of retinoblastoma protein (pRB), the cell cycle
      regulatory protein. TNF-alpha induced hyperphosphorylated pRB in SV40-transformed
      keratinocytes. On the other hand, TNF-alpha suppressed it in normal
      keratinocytes. We hypothesize that the enhancement of SV40 large T antigen and
      hyperphosphorylated pRB is involved in the mechanism of growth stimulation of
      SV40-transformed keratinocytes by TNF-alpha.

PMID- 10651229
TI  - Tocoretinate inhibited the contraction of collagen gel matrices by human dermal
      fibroblasts with tenascin-C expression.
AB  - Retinoids are strong tissue modifiers and have been used to treat severe acne,
      keloids and photo-aged skin. Tocoretinate (TR), ester bound retinoic acid and
      tocopherol, has been topically applied for skin ulcers and, more recently, for
      sclerotic skin diseases. To clarify the mechanism of tissue softening by
      retinoids and TR, we investigated their effects on the contraction of hydrated
      type-1 collagen gel matrices by human dermal fibroblasts and on tenascin-C
      expression. TR, 13-cis-retinoic acid/isotretinoin and all trans-retinoic acid
      significantly inhibited collagen gel matrices contraction at concentrations from
      10(-4) to 10(-8) M without significant changes of the fibroblast growth. TR and
      the other two retinoids dose-dependently induced tenascin-C expression in the
      fibroblasts. Since tenascin-C is involved in cellular detachment and tissue
      remodeling, these results suggest that TR and other retinoids down-regulated the
      tensile tension of fibroblasts in collagen gel matrices by the induction of
      tenascin-C.

PMID- 10651230
TI  - Objective scratch monitor evaluation of the effect of an antihistamine on
      nocturnal scratching in atopic dermatitis.
AB  - We previously reported a simple and easy-to-use device, Scratch Monitor for
      evaluation of nocturnal scratching. In the present study, the effect of an
      antihistamine (azelastine hydrochloride) on atopic dermatitis was investigated
      using this device. In 40 patients with atopic dermatitis, nocturnal scratching
      was measured by the monitor, when taking the drug and while off medication.
      Neither the 'sleeping time' nor the 'pre-asleep time' differed significantly, but
      there was a significant difference in 'scratch rate', 'minute scratch records',
      'hourly awake number' and 'awake rate', which indicated that this drug alleviated
      nocturnal scratching and sleep disturbance. The difference was most prominent
      especially in patients with a serum IgE > or = 1000 IU/ml as well as in patients
      with mild symptoms and normal serum lactate dehydrogenase levels. The drug was
      more effective for nocturnal scratching in the early period, when the 'sleeping
      time' was divided into three equal parts (early, mid and late periods) and each
      period was compared.

PMID- 10651231
TI  - Calcium oxide and magnesium oxide inhibit plasma coagulation by Staphylococcus
      aureus cells at the lower concentration than zinc oxide.
AB  - We examined the effect of ceramic powder slurries on the coagulation of plasma by
      Staphylococcus aureus cells. Plasma coagulation by S. aureus strains or their
      cultured supernatant was inhibited in the plasma with 0.12% calcium oxide or
      0.25% magnesium oxide after incubation for 24 h at 37 degrees C. Inhibition of
      plasma coagulation by calcium oxide and magnesium oxide was observed at the lower
      concentration than zinc oxide.

PMID- 10651232
TI  - Demonstration of the high affinity IgE receptor on Langerhans cells.

PMID- 10651233
TI  - 25 years of contributions to characterizing gene expression and replication
      within the three-dimensional context of nuclear architecture.

PMID- 10651234
TI  - Evolution of transcriptional control from prokaryotic beginnings to eukaryotic
      complexities.
AB  - Mechanisms for regulating gene transcription became increasingly complex as
      organisms evolved. In prokaryotes the relatively simple mechanism of repression
      is based on a few proteins that bind to specific DNA sequences in a ligand
      dependent fashion. In eukaryotes large complexes that include ligand binding
      proteins regulate transcription. Lower eukaryotes developed an additional level
      of control based on protein complexes that include modifying enzymes. The
      DNA/histone complex, in combination with gene-specific transcriptional factors,
      is the basis of gene regulation in eukaryotes. Higher eukaryotes took regulation
      a level further by methylating CpGs in promoter sequences of DNA, thereby
      allowing binding of histone deacetylases and inhibiting transcription. Finally,
      long-lasting "superrepression" provides another mechanism for coordinate
      transcriptional regulation of large blocks of genes.

PMID- 10651235
TI  - Interrelationships of transcriptional machinery with nuclear architecture.
AB  - There is increasing evidence for functional linkages between nuclear architecture
      and the regulation of gene expression. The nuclear matrix provides a paradigm for
      involvement of nuclear morphology in assembly of the biochemical machinery for
      physiological control of transcription. Mechanisms are being experimentally
      defined that direct regulatory factors to subnuclear sites that support gene
      expression. Consequently, we are gaining insight into the rules that govern
      transcriptional control within the three-dimensional context of nuclear
      organization.

PMID- 10651236
TI  - Synthesis, processing, and transport of RNA within the three-dimensional context
      of the cell nucleus.
AB  - Fluorescence in situ hybridization and immunocytochemical techniques have
      contributed significantly to our current understanding of how transcription, RNA
      processing, and RNA transport are spatially and temporally organized in the cell
      nucleus. New technologies enabling the visualization of nuclear components in
      living cells specifically advanced our knowledge of the dynamic aspects of these
      nuclear processes. The picture that emerges from the work reviewed here shows
      that the positioning of genes within the three-dimensional nuclear space is of
      crucial importance, not only for its expression, but also for the efficient
      processing of its transcripts. Splicing factors are recruited from speckles to
      sites of active transcription, which can be present within, at the periphery, or
      at a relatively large distance from speckles. Furthermore, results are discussed
      showing that transcripts are exported by means of random diffusion.

PMID- 10651237
TI  - Nuclear structure, gene expression and development.
AB  - This article considers the extent to which features of nuclear structure are
      involved in the regulation of genome function. The recent renaissance in imaging
      technology has inspired a new determination to assign specific functions to
      nuclear domains or structures, many of which have been described as "factories"
      to express the idea that they coordinate nuclear processes in an efficient way.
      Visual data have been combined with genetic and biochemical information to
      support the idea that nuclear organization has functional significance.
      Particular DNA sequences or chromatin structures may nucleate domains that are
      permissive or restrictive of transcription, to which active or inactive loci
      could be recruited. Associations within the nucleus, as well as many nuclear
      structures, are transient and change dynamically during cell cycle progression
      and development. Despite this complexity, elucidation of the possible structural
      basis of epigenetic phenomena, such as the inheritance of a "cellular memory" of
      gene expression status, is an important goal for cell biology. Topics for
      discussion include the regulatory effect of chromatin structure on gene
      expression, putative "nuclear addresses" for genes and proteins, the functional
      significance of nuclear bodies, and the role of the nuclear matrix in nuclear
      compartmentalization.

PMID- 10651238
TI  - Intranuclear trafficking of messenger RNA.
AB  - Within the nucleus, protein-encoding genes are transcribed into messenger RNA by
      RNA polymerase II. Messenger RNAs migrate to the cytoplasm, but before reaching
      their final destination the primary transcripts must undergo a series of
      modifications that include 5'-capping, splicing, and 3'-cleavage/polyadenylation.
      Errors in these processing events can originate aberrant products that, if
      translated, would produce abnormal proteins. Therefore, it is not surprising that
      eukaryotes have evolved a surveillance mechanism that recognizes and rapidly
      degrades aberrant mRNAs. Recent experiments provide exciting insights into how
      proper mRNAs are distinguished and selected for export. Transcription by RNA
      polymerase II is directly coupled to pre-mRNA processing, and the mechanism that
      targets the processing machinery to the polymerase complex suggests a model for
      co-transcriptional proofreading. Furthermore, there is evidence that at least
      some mRNAs move randomly throughout the nucleus, presumably by free diffusion. In
      this light, retention of aberrant mRNAs by the transcription/processing machinery
      is crucial to prevent their diffusion to the nuclear pores and eventual
      translocation to the cytoplasm.

PMID- 10651239
TI  - Interplay between chromatin modifying and remodeling complexes in transcriptional
      regulation.
AB  - The question of a possible functional relationship between different chromatin
      altering enzymatic activities is of great interest. Several remarkable parallels
      have been revealed regarding the action of the remodeling complex SWI/SNF and the
      histone acetylation complex SAGA during transcriptional activation in S.
      cerevisiae. Many promoters, but not all, that require one complex require the
      other as well. Mutations that disrupt both complexes cause much more severe
      phenotypes than single mutations. Both types of complexes are recruited to
      specific promoters by interaction with DNA-bound acidic activators, resulting in
      targeted acetylation and transcriptional activation. Taken together the data
      argue for independent mechanisms, but similar recruitment and functional
      interplay between these two types of chromatin-altering activities.

PMID- 10651240
TI  - Histone acetyltransferase complexes and their link to transcription.
AB  - Early studies revealing the relationship between the state of histone acetylation
      and gene transcription were largely indirect. Increasing information regarding
      the enzymes that catalyze transcription linked acetylation is beginning to
      clarify this issue. This review attempts to relate previous data regarding the
      distribution of histone acetylation within different chromatin regions with
      recent data regarding the substrate specificity, subunit composition, and
      recruitment of the known histone acetyltransferase complexes.

PMID- 10651241
TI  - Chromatin structure revisited.
AB  - Independently of the enormous progress in our understanding of the structure of
      the core particle, there remain a multitude of structural questions still to be
      answered. The main points discussed here can be summarized as follows: (1) The
      meaning of the term 'core particle' should be widened to reflect the fact that
      the actual length of DNA wrapped around the histone octamer in the context of the
      chromatin fiber may vary between approximately 100 and approximately 170 bp. (2)
      In the chromatosome, the linker histone forms a bridge between one terminus of
      the chromatosomal DNA and a point close to the dyad axis. (3) The particle that
      contains one molecule of HMG1 may be classified as a bona fide chromatosome. (4)
      In the extended fiber, the partition of the nucleosomal DNA into core and linker
      is a dynamic feature, responding to environmental influences; fiber structure
      related constraints demand that linker length be beyond a certain minimal value.
      (5) The compact fiber structure seems to be rather irregular; the precise nature
      of this structure is still to be determined. Finally, the term 30-nm fiber should
      be dropped as a designator of the compact or condensed chromatin fiber structure.

PMID- 10651242
TI  - Lamins and lamin-binding proteins in functional chromatin organization.
AB  - Lamins are the major components of the nuclear lamina, a two-dimensional
      filamentous network at the periphery of the nucleus in higher eukaryotes,
      directly underlying the inner nuclear membrane. Several integral proteins of the
      inner nuclear membrane bind to lamins and may link the nuclear membrane to the
      core lamina network. The lamins and the lamin-binding proteins lamina-associated
      polypeptide (LAP)2beta and lamin B receptor (LBR) have been described to bind to
      DNA or to interact with chromatin via histones, BAF-1, and HP1 chromodomain
      proteins, respectively, and may provide anchorage sites for chromatin fibers at
      the nuclear periphery. In addition, lamin A structures on intranuclear filaments,
      or lamin B in replication foci have been described in the nuclear interior, but
      their specific roles remain unclear. An isoform of the LAP2 protein family,
      LAP2alpha, has been found to colocalize with A-type lamins in the nucleoplasm and
      might be involved in intranuclear structure organization. In the course of cell
      cycle-dependent dynamics of the nucleus in higher eukaryotes, lamins as well as
      lamin-binding proteins seem to possess important functions during various steps
      of post-mitotic nuclear reassembly, including cross-linking of chromatides,
      nuclear membrane targeting, nuclear lamina assembly, and the formation of a
      replication-competent nucleus.

PMID- 10651243
TI  - Chromatin structure and nuclear remodeling.
AB  - Nuclear architecture is remodeled during interphase in response to changes in
      gene activity as well as to changing structural and functional requirements
      during cell division. Using the monoclonal antibody mAb2A, we have identified two
      proteins that appear to play important roles in these processes: JIL-1 is a
      tandem serine-threonine kinase implicated in the regulation of chromatin
      structure, whereas Skeletor is a novel protein participating in structural
      nuclear remodeling during the cell cycle. Antibody staining and live imaging of
      JIL-1-GFP transgenic flies show that JIL-1 localizes to the gene-rich interband
      regions of larval polytene chromosomes and is upregulated almost twofold on the
      hypertranscribed male X chromosome compared with autosomes. We propose that JIL-1
      may play a role in transcriptional control potentially by regulating chromatin
      structure. The other mAb2A antigen, Skeletor, is distributed in a nuclear
      meshwork pattern that can be observed in stereo pair images to reorganize during
      the cell cycle to form a spindle-like structure at prometaphase that is distinct
      from the microtubule spindle apparatus. Taking advantage of the powerful
      molecular and genetic approaches offered in Drosophila, the study of these two
      proteins promises to yield new insight into what defines nuclear architecture at
      the molecular level and how its remodeling is regulated.

PMID- 10651244
TI  - Chromosomal DNA loops may constitute basic units of the eukaryotic genome
      organization and evolution.
AB  - In eukaryotic cell nuclei the genome is organized into large loops attached to
      the nuclear matrix. Rearrangements of the genome frequently occur via an
      illegitimate recombination between loop anchorage sites resulting in deletion or
      repositioning of DNA loops. The illegitimate recombination between loop anchorage
      sites is possibly mediated by topoisomerase II. Treatments stabilizing
      intermediate covalent complexes of topoisomerase II with DNA seem to increase the
      possibility of illegitimate recombination between loop anchorage regions. On the
      basis of these and some other observations we suggest that chromosomal DNA loops
      constitute basic units of the genome evolution, or, in other words, structural
      blocks of the eukaryotic genome.

PMID- 10651245
TI  - The nuclear lamina: molecular organization and interaction with chromatin.
AB  - The nuclear lamina is located between the inner nuclear membrane and the
      peripheral chromatin. It is composed mainly of nuclear lamins and lamina
      associated proteins. The nuclear lamina is involved in nuclear organization, cell
      cycle regulation, and differentiation. As such, impairment in its architecture
      and/or function leads to genetic diseases and apoptosis. This article describes
      the molecular organization of the nuclear lamins, their assembly into filaments,
      their distribution within the nucleus, and the complex network of interactions
      between them and other proteins of the inner nuclear membrane. Recent findings
      unraveled evidence for specific interactions between proteins of the nuclear
      lamina and the chromatin. These include interactions between nuclear lamins and
      core histones, Lamina Associated Polypeptide 2 (LAP2), and the Barrier to
      Autointegration Factor (BAF) and interactions between lamin B receptor (LBR) and
      the chromodomain protein HP1. Taken together, these studies attribute a role for
      both the nuclear lamins and the lamina-associated proteins, LAP2 and LBR, in
      nuclear organization and nuclear assembly.

PMID- 10651246
TI  - MARs of antigen receptor and co-receptor genes.
AB  - MARs are cis-acting DNA sequences that function both negatively and positively in
      conjunction with transcriptional enhancers to regulate antigen receptor and co
      receptor genes. Evidence exists that certain tissue-specific nuclear proteins are
      involved in this regulation, including SATB1, Bright, and Cux/CDP, possibly by
      modulating intranuclear gene location, histone acetylation, DNA methylation,
      and/or nucleosome positioning.

PMID- 10651247
TI  - Origin and roles of nuclear matrix proteins. Specific functions of the MAR
      binding protein MeCP2/ARBP.
AB  - HnRNP proteins are the major protein components of the nuclear matrix, and sites
      of nascent transcripts and RNA maturation are its main sources. The evidence for
      and the roles of functional and structural loops in interphase chromatin and
      metaphase chromosomes is discussed. Recent data suggest a specific role for the
      matrix attachment region (MAR)- and methyl-CpG-binding protein MeCP2/ARBP. This
      repressor protein binds to MARs and, through interaction with mSin3A, recruits a
      corepressor complex containing histone deacetylases. This in turn is thought to
      generate a localized silenced chromatin structure. Transfection experiments are
      presented in support of this model.

PMID- 10651248
TI  - Does NuMA have a scaffold function in the interphase nucleus?
AB  - We review the properties of NuMA, concentrating on a possible role for NuMA as a
      scaffold protein in the interphase nucleus. NuMA is a component of the nuclear
      matrix in interphase cells and translocates to the spindle poles in mitosis. NuMA
      has a secondary structure in which a long central rod domain that forms a double
      stranded coiled coil is flanked by globular terminal domains. In vitro assembly
      experiments with bacterially expressed recombinant protein showed that NuMA seems
      not to form filaments, but instead builds multiarm oligomers by interaction of
      the C-terminal globular domains. Transient overexpression of NuMA in HeLa cells
      induced the formation of a three-dimensional lattice with a quasihexagonal
      organization that fills the nucleus. Use of mutant constructs showed that the
      lattice spacing depended on the length of the rod domain. Using a 12-arm oligomer
      as the structural unit, computer modeling can explain the observed nuclear
      lattices. The flexibility of the NuMA molecule as well as its dynamic capacity to
      form lattices is a hint that NuMA may play a structural role in the architecture
      of the normal interphase nucleus.

PMID- 10651249
TI  - Nuclear matrix and protein kinase CK2 signaling.
AB  - The dynamic functional nature of the nuclear matrix dictates that it provide a
      locus for molecules involved in nuclear transduction of signals, such as those
      participating in cell growth control. Protein kinases are key elements in a
      variety of signaling mechanisms and certain of these enzymes have been shown to
      associate with the NM. Among these, the protein ser/thr kinase CK2 has attracted
      considerable attention because of its involvement in cell growth. NM appears to
      be a preferential locus for CK2, as evidenced from its rapid modulation in the NM
      in response to hormonal and growth factor signals. Differential regulation of CK2
      is also noted in the transcriptionally active and inactive nucleosomes. A number
      of potential substrates for CK2 are localized to the NM. Likewise, distinct
      substrates for CK2 are noted in the transcriptionally active compared with
      inactive nucleosomes. The dynamics of phosphorylation of these substrates and
      that of the association of CK2 activity to these fractions suggests that CK2 may
      play a role in the functional activities of NM and provide a link between the NM
      and nucleosomes by serving as a factor in promoting the transition of inactive to
      active nucleosome.

PMID- 10651250
TI  - The role of the nuclear matrix in cancer chemotherapy.
AB  - The nuclear matrix is the site of many nuclear functions including transcription,
      replication, formation of chromatin loops, and control of DNA supercoiling. It
      contains various structural and functional components that represent targets for
      antineoplastic agents. Antimetabolites and topoisomerase II inhibitors interact
      specifically with matrix-associated enzymes, DNA primase, and DNA topoisomerase
      II, respectively. Alkylating agents and ionizing radiation interact with nuclear
      matrix proteins and matrix-associated DNA. Many nuclear functions, including
      multidrug resistance, and others which lead to cell death, have been shown to be
      compromised when these anticancer agents interact with the nuclear matrix.

PMID- 10651251
TI  - Functional links between nuclear structure, gene expression, DNA replication, and
      methylation.
AB  - Over the last decades it became clear that mammalian nuclei are highly organized.
      Nuclear processes like DNA replication and RNA metabolism take place in distinct
      subnuclear foci, which are enriched for enzymes involved in the corresponding
      biochemical reactions. This colocalization of functions with their respective
      factors is often referred to as functional organization of the nucleus. This
      organization is achieved by assembly of different enzymes and regulatory factors
      into high-molecular-weight complexes that are tethered to insoluble nuclear
      structures. Recently, several links between nuclear structure, gene expression,
      DNA replication, and methylation have been described that illustrate the
      interrelation of higher-order structures and nuclear functions. New insights into
      the functional organization of the nucleus and how it could explain the high
      precision and overall coordination of nuclear processes are discussed.

PMID- 10651252
TI  - DNA replication and nuclear organization: prospects for a soluble in vitro
      system.
AB  - The role of nuclear structure in the replication of eukaryotic DNA has been the
      subject of debate for many decades. The recent demonstration that once-per-cell
      cycle replication can take place in vitro without a nucleus, providing
      sufficiently high concentrations of replication factors are supplied, suggests
      that one role of the nucleus is to concentrate essential factors. This important
      finding has paved the way for the establishment of a purified biochemical system
      for replication of eukaryotic DNA. However, this soluble system, derived from
      Xenopus egg extracts, initiates replication within any DNA sequence and does not
      recapitulate the spatial and temporal regulation of DNA replication that is
      observed in most cells. In both Xenopus and Drosophila embryos, site-specific
      initiation of replication is not observed until after nuclei become
      transcriptionally active at the blastula stage of development. Furthermore,
      programmed changes in both the locations of origins and the time during S-phase
      at which sequences are replicated accompany key stages of metazoan development.
      Recent findings indicate that these changes correlate with changes in nuclear
      organization and that the spatial and temporal program for replication is
      established early in G1-phase when nuclei are structurally and functionally
      reorganized after mitosis.

PMID- 10651253
TI  - The effects of heat-shock on nuclear matrix-associated DNA-replication complexes.
AB  - To better understand the role of the nuclear matrix in heat-induced cell killing,
      we have investigated the effects of heat shock on DNA replication complexes.
      Changes in protein extractability are observed following heat shock, including
      stabilization of which stabilize DNA replication complexes in association with
      the nuclear matrix. This situation is accompanied by differential delays in the
      progress and completion of DNA synthesis and the transition from type I to type
      II DNA replication patterns. Interestingly, prolonged delays in restarting DNA
      synthesis produced significant protection from heat-induced cell killing. These
      results show that nuclear matrix-associated DNA replication complexes may be
      important targets for heat-induced cell killing.

PMID- 10651254
TI  - Rules to remodel by: what drives nuclear envelope disassembly and reassembly
      during mitosis?
AB  - In higher eukaryotic cells the nuclear envelope is reversibly disassembled during
      mitosis. Under in vivo conditions this process occurs in a sequential, stepwise
      fashion and involves a variety of structural intermediates. Here we discuss the
      topological features of these intermediates and their transient interactions with
      chromatin and the cytoskeleton. As it becomes apparent, nuclear envelope
      disassembly and reassembly are regulated at multiple levels by modulating the
      affinity of protein-protein interactions, limiting the availability of structural
      subunits in different areas of the mitotic cytoplasm, and redirecting mechanical
      forces exerted by the microtubules.

PMID- 10651255
TI  - Endothelin: emerging role in diabetic vascular complications.
AB  - Since the discovery of endothelin-1 as the most potent endothelial-derived
      vasoconstrictor/mitogenic peptide a decade ago, considerable evidence has
      implicated this peptide in various cardiovascular disease states, including
      diabetes mellitus. Plasma and tissue concentrations of endothelin-1 as well as
      responses to the peptide are changed in various forms of the disease in humans
      and animals. Endothelin activity is also altered in atherosclerotic and ischaemic
      disease, nephropathy, retinopathy, erectile dysfunction, and neuropathy, many of
      the well-known complications of diabetes. Striking new evidence shows that
      antagonists of the endothelin system might beneficially affect and potentially
      overcome some of these complications. Despite this, lack of direct proof of
      causation makes this peptide's role in the disease uncertain. This review
      examines the current state of thought on the role of endothelin in diabetes and
      in the complications of the disease as well as the likely roles of altered
      metabolic variables in modulating endothelin-1 concentrations and its activity.
      It is concluded that although alterations in endothelin-1 release and action are
      clearly associated with the diabetic state, further studies using inhibitors of
      the endothelin system are warranted to determine its precise role in the
      complications of the disease.

PMID- 10651256
TI  - Worldwide increase in incidence of Type I diabetes--the analysis of the data on
      published incidence trends.
AB  - AIMS/HYPOTHESIS: Several reports on the incidence of Type I (insulin-dependent)
      diabetes mellitus have suggested that the incidence is increasing. The aim of
      this study was to find out whether the incidence is increasing globally or
      restricted to a selected populations only and to estimate the magnitude of the
      change in incidence. METHODS: During 1960 to 1996 37 studies in 27 countries were
      carried out. To fulfil the inclusion criteria the study periods ranged from 8-32
      years. The temporal trend was fitted by linear regression, with the logarithm of
      the age-standardized incidence as the dependent variable and the calendar year as
      the independent variable. Then, the regression coefficient (x 100%) is
      approximately the average relative increase in incidence per year (as
      percentage). RESULTS: Results from the pooled data from all 37 populations showed
      that the overall increase in incidence was 3.0% per year (95% CI 2.6; 3.3, p =
      0.0001). The statistically significant increase was found in 24 of 37 populations
      including all high incidence (> 14.6 per 100000 a year) populations. The relative
      increase was, however, steeper in the populations with a lower incidence. The
      correlation between logarithm of the incidence and the increase in incidence was
      r = -0.56, p = 0.0004. CONCLUSION/INTERPRETATION: The incidence of Type I
      diabetes is increasing worldwide both in low and high incidence populations. By
      the year 2010 the incidence will be 50 per 100000 a year in Finland and also in
      many other populations it will exceed 30 per 100000 a year.

PMID- 10651257
TI  - An aldose redutase inhibitor prevents the intimal thickening in coronary arteries
      of galactose-fed beagle dogs.
AB  - AIMS/HYPOTHESIS: Although increased polyol pathway activity has been implicated
      in the pathogenesis of diabetic microangiopathy, the relation with diabetic
      macroangiopathy remains unclear. Galactose feeding is known to stimulate the
      polyol pathway and to develop abnormalities similar to those in diabetic
      microangiopathy. Our study was conducted to investigate whether an activation of
      polyol pathway by long-term treatment with galactose produced morphological
      changes in coronary arteries of dogs and the effect of an aldose reductase
      inhibitor, epalrestat, was also studied. METHODS: Dogs received either normal
      chow or chow containing 30% galactose with or without epalrestat given orally (20
      or 50 mg x kg(-1)). After 44 months, morphometric analyses of coronary arteries
      were carried out and the galactitol contents in aortas were measured. RESULTS:
      The ratio of areas of the intimal layer to those of the medial layer, an
      indicator of intimal thickening, was statistically significantly increased in
      galactose-fed dogs compared with control dogs. Galactose-fed dogs had a
      remarkable accumulation of galactitol in their aortas. These morphological and
      biochemical deficits were reduced by treatment with epalrestat.
      CONCLUSION/INTERPRETATION: This report morphologically shows diabetes-like
      macrovascular abnormalities in galactosaemic animals, suggesting that polyol
      pathway hyperactivity is closely related to the development of diabetic
      macroangiopathy, which could be prevented by aldose reductase inhibition.

PMID- 10651258
TI  - Gastric emptying in Type II (non-insulin-dependent) diabetes mellitus before and
      after therapy readjustment: no influence of actual blood glucose concentration.
AB  - AIMS/HYPOTHESIS: Hyperglycaemia that is induced short-term slows gastric emptying
      in healthy subjects and patients with diabetes mellitus. Little information is
      available on the impact of longer-lasting, naturally occurring blood glucose
      increases and their reduction to euglycaemic values. We studied the relation
      between gastric emptying and pre-prandial and postprandial blood glucose
      concentrations in patients with Type II (non-insulin-dependent) diabetes mellitus
      and secondary failure to respond to oral hypoglycaemic treatment (a) before
      readjusting hypoglycaemic therapy and (b) 1 week thereafter. METHODS: We studied
      9 female and 1 male patient (age 60-78 years, BMI 21.9-32.5 kg/m2, diabetes
      duration 3-33 years, HbA1c 8.8-13.2%). Gastric emptying of a radiolabelled
      semisolid 1168 kJ meal was recorded scintigraphically. RESULTS: Blood glucose
      concentration pre-prandial and postprandial was considerably lower subsequent to
      than before therapy readjustment in all patients (fasting, 7.9 mmol/l+/-1.5 SD vs
      11.7+/-1.7 mmol/l; 60 min postprandial, 11.7+/-2.0 vs 15.4+/-2.2 mmol/l). By
      contrast, gastric emptying was unchanged (residual radioactivity in stomach 50
      min postprandial 65.7+/-14.1% vs 66.5+/-12.9%). There was no relation between
      emptying and either fasting blood glucose concentration or its postprandial
      increase. CONCLUSION/INTERPRETATION: The data do not support a major impact of
      actual, longer-lasting, naturally occurring blood glucose concentrations upon the
      rate of gastric emptying in patients with Type II diabetes.

PMID- 10651259
TI  - An untranslated insertion variant in the uncoupling protein 2 gene is not related
      to body mass index and changes in body weight during a 26-year follow-up in
      Danish Caucasian men.
AB  - AIMS: Associations between a 45 bp 3'untranslated insertion polymorphism in the
      uncoupling protein 2 (UCP2) gene and both body mass index (BMI) and sleeping
      metabolic rate have previously been reported. We investigated the impact of this
      polymorphism on BMI and long-term body weight changes. METHODS: The allelic
      frequency of the UCP2 insertion variant was determined in a cohort of 744 obese
      Danish Caucasian men who had a BMI of at least 31 kg/m2 at the draft-board
      examinations and a randomly selected control cohort consisting of 872 draftees.
      Follow-up measurements of BMI were done on average 26 years after the draft-board
      examinations. RESULTS: The prevalence of the insertion allele was 30.4% (95%
      confidence interval: 28.0-32.8%) among the obese and 29.6% (27.4-31.8%) in the
      control group (p = 0.6). In a lean group selected as the 354 subjects with a BMI
      less than 25 kg/m2 at 46 years of age from the control group, the frequency of
      insertion allele was 29.0% (27.2-30.8%) (p = 0.5 compared with the obese cohort).
      The BMI at the ages of 20 and 46 years did not differ between genotypes either in
      the obese or the control group. Similarly, the changes in BMI/year between
      examinations at 20 and 46 years of age did not differ between genotypes in either
      group. CONCLUSION/INTERPRETATION: In a large group of Danish Caucasian men we
      found no association between a 3'untranslated insertion polymorphism in the UCP2
      gene and obesity. Neither did we identify a relation between this variant and BMI
      changes during adult age.

PMID- 10651260
TI  - Induction of glycation suppresses glucokinase gene expression in HIT-T15 cells.
AB  - AIMS/HYPOTHESIS: Chronic hyperglycaemia in patients with Type II (non-insulin
      dependent) diabetes mellitus often leads to a decline in glucose-responsive
      insulin secretion from pancreatic beta cells, a phenomenon called glucose
      toxicity. Upon hyperglycaemia, glycation reaction occurs in the beta cells and
      induces oxidative stress. To understand the molecular basis of the beta-cell
      glucose toxicity, we investigated the possible effects of glycation on the
      expression and enzymatic activity of glucokinase, which plays a crucial part in
      glucose-responsive insulin secretion. METHODS: Glycation and reactive oxygen
      species were induced in HIT-T15 cells by treatment with D-ribose and effects on
      glucokinase gene transcription, glucokinase protein amount, glucose
      phosphorylation activity, and DNA-binding activities of putative glucokinase gene
      transcription factors were evaluated. RESULTS: When glycation was induced in HIT
      T15 cells, the activity of the human glucokinase gene beta-cell-type promoter was
      suppressed substantially (83% reduction at 60 mmol/l D-ribose). Also, similar
      reductions in mRNA and protein amounts of glucokinase and in the Vmax of its
      enzymatic activity were observed. In agreement with the reduction in the promoter
      activity, the two major transcription factors of the glucokinase gene, the Pal
      binding factor and PDX-1, reduced their binding to their target sequences in the
      glucokinase gene promoter in glycation-induced HIT cells. Because these effects
      of D-ribose were counteracted by aminoguanidine or N-acetylcysteine, reactive
      oxygen species, generated by the glycation reaction, appears to be involved in
      the phenomena. CONCLUSION/INTERPRETATION: The induction of the glycation
      reaction, which is known to occur in pancreatic beta cells in chronic
      hyperglycaemia, suppresses the glucokinase gene transcription and its enzymatic
      activity. Thus, hyperglycaemia-dependent inhibition of glucokinase activity could
      in part explain beta-cell glucose toxicity.

PMID- 10651261
TI  - Angiotensin converting-enzyme inhibitor treatment reduces glomerular p16INK4 and
      p27Kip1 expression in diabetic BBdp rats.
AB  - AIMS/HYPOTHESIS: Renal hypertrophy occurs early in diabetes mellitus and precedes
      the development of glomerulosclerosis and tubulointerstitial fibrosis. We have
      previously shown that cultured mesangial cells exposed to high glucose are
      arrested in the G1-phase of the cell cycle and undergo cellular hypertrophy. High
      glucose-mediated induction of p27Kip1, an inhibitor of cyclin-dependent kinases,
      is essential in this process. Further investigations have also shown that p27Kip1
      and p21Cip1, other cyclin-dependent kinase inhibitors, are up regulated in the
      kidneys of mice with Type I (insulin-dependent) as well as Type II (non-insulin
      dependent) diabetes mellitus. Our study was undertaken to test a potential effect
      of short-term treatment with the angiotensin-converting enzyme inhibitor
      enalapril on the glomerular expression of the cyclin-dependent kinase inhibitors
      p16INK4, p21Cip1, and p27Kip1 in BBdp rats, an autoimmune model of Type I
      diabetes. METHODS: We evaluated p16INK4, p21Cip1, and p27Kip1 protein expression
      in isolated glomeruli by western blots. We also assessed p27Kip1 positive
      glomerular cells by immunohistochemistry. RESULTS: Glomerular expression of all
      three cyclin-dependent kinase inhibitors were stimulated in BBdp rats compared
      with non-diabetic BBdr animals. Enalapril treatment for 3 weeks, started after
      the onset of diabetes, reduced the glomerular expression of p16INK4 and p27Kip1
      but not of p21Cip1. Enalapril also prevented the increase in kidney weights
      observed in BBdp rats but had no effect on systolic blood pressure or glucose
      concentrations. CONCLUSION/INTERPRETATION: Our data show that enalapril
      attenuates the glomerular expression of cyclin-dependent kinase inhibitors in
      diabetes and suggest a molecular mechanism of how angiotensin-converting enzyme
      inhibitors prevent renal hypertrophy in diabetes.

PMID- 10651263
TI  - Clinical relevance of heteroplasmic concentration of mitochondrial A3243G
      mutation in leucocytes.

PMID- 10651262
TI  - Troglitazone reduces hyperglycaemia and selectively acute-phase serum proteins in
      patients with Type II diabetes.
AB  - AIMS/HYPOTHESIS: Inflammation could play a part in insulin resistance.
      Thiazolidinediones, new antidiabetic drugs, possess anti-inflammatory effects in
      vitro. We investigated if acute-phase serum proteins are increased in patients
      with Type II (non-insulin-dependent) diabetes mellitus who had been treated with
      insulin and whether troglitazone has anti-inflammatory effects in vivo. METHODS:
      A total of 27 patients (age 63.0+/-1.7 years, HbA1c 8.8+/-0.3%, BMI 32.7+/-0.8
      kg/m2, duration 15.2+/-1.4 years, insulin dose 73.3+/-7.0 U/day) participated in
      the study. The patients received daily either 400 mg troglitazone or placebo for
      16 weeks. Blood samples were taken at baseline, at the end of therapy and after a
      follow-up time of 23+/-4 days. RESULTS: The concentrations of serum amyloid A
      (6.2+/-1.1 mg/l) and C-reactive protein (6.1+/-1.1 mg/l) were increased (p <
      0.001) and complement protein C3 (1.69+/-0.05 g/l) was also above the reference
      range for healthy subjects. Placebo treatment had no effect on glucose or
      inflammation, whereas troglitazone reduced fasting glucose (from 10.4+/-0.6
      mmol/l to 8.1+/-0.5 mmol/l, p < 0.01), HbA1c (from 8.7+/-0.3% to 7.5+/-0.3%, p <
      0.01), insulin requirements (from 75+/-10 U/day to 63+/-10 U/day, p < 0.05),
      serum amyloid A (from 6.3+/-1.5 mg/l to 4.0+/-1.3 mg/l, p = 0.001), alpha-1-acid
      glycoprotein (from 906+/-51 mg/l to 729+/-52 mg/l, p = 0.001) and C3 (from 1.72+/
      0.07 g/l to 1.66+/-0.06 g/l, p < 0.05) but not alpha-1-antitrypsin,
      ceruloplasmin, C-reactive protein or haptoglobin significantly. Concentrations of
      glucose and acute-phase reactants had returned to those before treatment at the
      follow-up visit. CONCLUSION/INTERPRETATION: In Type II diabetic patients serum
      amyloid A and complement protein C3 are raised. Troglitazone exerts a selective
      reversible action on some acute-phase proteins and C3 but not on others in
      conjunction with the improvement in glucose metabolism.

PMID- 10651264
TI  - Autoantibodies to human tissue transgutaminase identify silent coeliac disease in
      Type I diabetes.

PMID- 10651265
TI  - Expression of kinase-inactive mutant insulin receptors does not rescue insulin
      receptor-deficient mice from perinatal death.

PMID- 10651266
TI  - Is islet autoimmunity really detectable at birth?

PMID- 10651267
TI  - Conformational variation of calcium-bound troponin C.

PMID- 10651268
TI  - MCSS functionality maps for a flexible protein.
AB  - The Multiple Copy Simultaneous Search (MCSS) methodology for finding
      energetically favorable positions and orientations of small functional groups in
      a binding site is extended to include flexibility of the target. This makes
      possible the finding of novel minima not present in a fixed structure and so
      extends the diversity of inhibitors that can be constructed starting with the
      MCSS procedure. Quenched molecular dynamics is used to generate energetically
      favorable positions and orientations of the functional groups in the field of a
      flexible protein. The method is applied to the viral protein HIV-1 protease with
      methanol and methyl ammonium as a test case. If the protein is quenched with many
      copies of functional groups randomly distributed in the binding site, the
      resulting minima have ligand-protein interaction energies that are, on average,
      less favorable than those obtained with standard MCSS. This is a consequence of
      the renormalized potential function employed in the Locally Enhanced Sampling
      (LES) approximation. However, local optimizations of existing MCSS minima with a
      flexible protein results in lower energy minima in regions of the protein that
      are of particular interest. Their use in constructing a consensus protein model
      for ligand design is discussed.

PMID- 10651269
TI  - Improved modeling of side-chains in proteins with rotamer-based methods: a
      flexible rotamer model.
AB  - Side-chain modeling has a widespread application in many current methods for
      protein tertiary structure determination, prediction, and design. Of the existing
      side-chain modeling methods, rotamer-based methods are the fastest and most
      efficient. Classically, a rotamer is conceived as a single, rigid conformation of
      an amino acid sidechain. Here, we present a flexible rotamer model in which a
      rotamer is a continuous ensemble of conformations that cluster around the classic
      rigid rotamer. We have developed a thermodynamically based method for calculating
      effective energies for the flexible rotamer. These energies have a one-to-one
      correspondence with the potential energies of the rigid rotamer. Therefore, the
      flexible rotamer model is completely general and may be used with any rotamer
      based method in substitution of the rigid rotamer model. We have compared the
      performance of the flexible and rigid rotamer models with one side-chain modeling
      method in particular (the self-consistent mean field theory method) on a set of
      20 high quality crystallographic protein structures. For the flexible rotamer
      model, we obtained average predictions of 85.8% for chi1, 76.5% for chi1+2 and
      1.34 A for root-mean-square deviation (RMSD); the corresponding values for core
      residues were 93.0%, 87.7% and 0.70 A, respectively. These values represent
      improvements of 7.3% for chi1, 8.1% for chi1+2 and 0.23 A for RMSD over the
      predictions obtained with the rigid rotamer model under otherwise identical
      conditions; the corresponding improvements for core residues were 6.9%, 10.5% and
      0.43 A, respectively. We found that the predictions obtained with the flexible
      rotamer model were also significantly better than those obtained for the same set
      of proteins with another state-of-the-art side-chain placement method in the
      literature, especially for core residues. The flexible rotamer model represents a
      considerable improvement over the classic rigid rotamer model. It can, therefore,
      be used with considerable advantage in all rotamer-based methods commonly applied
      to protein tertiary structure determination, prediction, and design and also in
      predictions of free energies in mutational studies.

PMID- 10651270
TI  - Folding Lennard-Jones proteins by a contact potential.
AB  - We studied the possibility to approximate a Lennard-Jones interaction by a
      pairwise contact potential. First we used a Lennard-Jones potential to design off
      lattice, protein-like heteropolymer sequences, whose lowest energy (native)
      conformations were then identified by molecular dynamics. Then we turned to
      investigate whether one can find a pairwise contact potential, whose ground
      states are the contact maps associated with these native conformations. We show
      that such a requirement cannot be satisfied exactly, i.e., no such contact
      parameters exist. Nevertheless, we found that one can find contact energy
      parameters for which an energy minimization procedure, acting in the space of
      contact maps, yields maps whose corresponding structures are close to the native
      ones. Finally, we show that when these structures are used as the initial point
      of a molecular dynamics energy minimization process, the correct native folds are
      recovered with high probability.

PMID- 10651271
TI  - Unit-vector RMS (URMS) as a tool to analyze molecular dynamics trajectories.
AB  - The Unit-vector RMS (URMS) is a new technique to compare protein chains and to
      detect similarities of chain segments. It is limited to comparison of C(alpha)
      chains. However, it has a number of unique features that include exceptionally
      weak dependence on the length of the chain and efficient detection of
      substructure similarities. Two molecular dynamics simulations of proteins in the
      neighborhood of their native states are used to test the performance of the URMS.
      The first simulation is of a solvated myoglobin and the second is of the protein
      MHC. In accord with previous studies the secondary structure elements (helices or
      sheets) are found to be moving relatively rigidly among flexible loops. In
      addition to these tests, folding trajectories of C peptides are analyzed,
      revealing a folding nucleus of seven amino acids.

PMID- 10651272
TI  - Hydrophobicity at the surface of proteins.
AB  - A new method is presented to quantitatively estimate and graphically display the
      propensity of nonpolar groups to bind at the surface of proteins. It is based on
      the calculation of the binding energy, i.e., van der Waals interaction plus
      protein electrostatic desolvation, of a nonpolar probe sphere rolled over the
      protein surface, and on the color coding of this quantity on a smooth molecular
      surface (hydrophobicity map). The method is validated on ten protein-ligand
      complexes and is shown to distinguish precisely where polar and nonpolar groups
      preferentially bind. Comparisons with existing approaches, like the display of
      the electrostatic potential or the curvature, illustrate the advantages and the
      better predictive power of the present method. Hydrophobicity maps will play an
      important role in the characterization of binding sites for the large number of
      proteins emerging from the genome projects and structure modeling approaches.

PMID- 10651273
TI  - Graphical method for force analysis: macromolecular mechanics with atomic force
      microscopy.
AB  - We present a graphical method for a unifying, quantitative analysis of molecular
      bonding-force measurements by atomic force microscopy (AFM). The method is
      applied to interpreting a range of phenomena commonly observed in the
      experimental AFM measurements of noncovalent, weak bonds between biological
      macromolecules. The analysis suggests an energy landscape underlying the
      intermolecular force and demonstrates that many observations, such as "snaps-on,"
      "jumps-off," and hysteresis loops, are different manifestations of a double-well
      energy landscape. The analysis gives concrete definitions for the operationally
      defined "attractive" and "adhesive" forces in terms of molecular parameters. It
      is shown that these operationally defined quantities are usually functions of the
      experimental setup, such as the stiffness of the force probe and the rate of its
      movement. The analysis reveals a mechanical instability due to the multistate
      nature of molecular interactions and provides new insight into macromolecular
      viscosity. The graphical method can equally be applied to a quantitative analysis
      of multiple unfolding of subunits of the giant muscle protein titin under AFM.

PMID- 10651274
TI  - Redesigning the hydrophobic core of a model beta-sheet protein: destabilizing
      traps through a threading approach.
AB  - An off-lattice 46-bead model of a small all-beta protein has been recently
      criticized for possessing too many traps and long-lived intermediates compared
      with the folding energy landscape predicted for real proteins and models using
      the principle of minimal frustration. Using a novel sequence design approach
      based on threading for finding beneficial mutations for destabilizing traps, we
      proposed three new sequences for folding in the beta-sheet model. Simulated
      annealing on these sequences found the global minimum more reliably, indicative
      of a smoother energy landscape, and simulated thermodynamic variables found
      evidence for a more cooperative collapse transition, lowering of the collapse
      temperature, and higher folding temperatures. Folding and unfolding kinetics were
      acquired by calculating first-passage times, and the new sequences were found to
      fold significantly faster than the original sequence, with a concomitant lowering
      of the glass temperature, although none of the sequences have highly stable
      native structures. The new sequences found here are more representative of real
      proteins and are good folders in the T(f) > T(g) sense, and they should prove
      useful in future studies of the details of transition states and the nature of
      folding intermediates in the context of simplified folding models. These results
      show that our sequence design approach using threading can improve models
      possessing glasslike folding dynamics.

PMID- 10651275
TI  - A method for the improvement of threading-based protein models.
AB  - A new method for the homology-based modeling of protein three-dimensional
      structures is proposed and evaluated. The alignment of a query sequence to a
      structural template produced by threading algorithms usually produces low
      resolution molecular models. The proposed method attempts to improve these
      models. In the first stage, a high-coordination lattice approximation of the
      query protein fold is built by suitable tracking of the incomplete alignment of
      the structural template and connection of the alignment gaps. These initial
      lattice folds are very similar to the structures resulting from standard
      molecular modeling protocols. Then, a Monte Carlo simulated annealing procedure
      is used to refine the initial structure. The process is controlled by the model's
      internal force field and a set of loosely defined restraints that keep the
      lattice chain in the vicinity of the template conformation. The internal force
      field consists of several knowledge-based statistical potentials that are
      enhanced by a proper analysis of multiple sequence alignments. The template
      restraints are implemented such that the model chain can slide along the template
      structure or even ignore a substantial fraction of the initial alignment. The
      resulting lattice models are, in most cases, closer (sometimes much closer) to
      the target structure than the initial threading-based models. All atom models
      could easily be built from the lattice chains. The method is illustrated on 12
      examples of target/template pairs whose initial threading alignments are of
      varying quality. Possible applications of the proposed method for use in protein
      function annotation are briefly discussed.

PMID- 10651276
TI  - Serine proteases: an ab initio molecular dynamics study.
AB  - In serine proteases (SPs), the H-bond between His57 and Asp102 and that between
      Gly193 and the transition state intermediate play a crucial role in enzymatic
      function. To shed light on the nature of these interactions, we have carried out
      ab initio molecular dynamics simulations on complexes representing adducts
      between the reaction intermediate and elastase (one protein belonging to the SP
      family). Our calculations indicate the presence of a low-barrier H-bond between
      His57 and Asp102, in complete agreement with NMR experiments on enzyme-transition
      state analogue complexes. Comparison with an ab initio molecular dynamics
      simulation on a model of the substrate-enzyme adduct indicates that the Gly193
      induced strong stabilization of the intermediate is accomplished by charge/dipole
      interactions and not by H-bonding as previously suggested. Inclusion of the
      protein electric field in the calculations does not affect significantly the
      charge distribution.

PMID- 10651277
TI  - Crystal structure of a thermophilic alcohol dehydrogenase substrate complex
      suggests determinants of substrate specificity and thermostability.
AB  - The crystal structure of a thermophilic alcohol dehydrogenase (TBAD) from
      Thermoanaerobacter brockii has been determined in a binary complex with sec
      butanol as substrate to a resolution of 3.0 A. Van der Waals interactions of the
      carbon C1 atom of sec-butanol with atoms in His59, Ala85, Trp110, Asp150, and
      Leu294 account for the substrate preference of this enzyme for secondary over
      primary alcohols. A crevice from the surface to the active site provides access
      for substrates and products. This opening is lined with the hydrophobic residues
      Ile49, Leu107, Trp110, Tyr267, Leu294 as well as Cys283 and Met285 from another
      molecule within the tetrameric assembly. This might explain the tolerance of this
      enzyme toward organic solvents. The zinc ion occupies a position in the active
      site, which is too remote for direct interaction with the alcohol group. A
      mechanism is suggested whereby the introduction of NADP would trigger a
      displacement of the zinc ion to its catalytic site. Features important for the
      unusually high melting temperature of 98 degrees C are suggested by comparison to
      the crystal structure of a highly homologous mesophilic alcohol dehydrogenase
      from Clostridium beijerinckii (CBAD). The thermophilic enzyme has a more
      hydrophilic exterior, a more hydrophobic interior, a smaller surface area, more
      prolines, alanines, and fewer serines than CBAD. Furthermore, in the thermophilic
      enzyme the number of all types of intersubunit interactions in these tetrameric
      enzymes is increased: more salt bridges, hydrogen bonds, and hydrophobic
      interactions. All these effects combined can account for the higher melting
      temperature of the thermophilic enzyme.

PMID- 10651278
TI  - Locating interaction sites on proteins: the crystal structure of thermolysin
      soaked in 2% to 100% isopropanol.
AB  - Multiple-solvent crystal structure determination (MSCS) allows the position and
      orientation of bound solvent fragments to be identified by determining the
      structure of protein crystals soaked in organic solvents. We have extended this
      technique by the determination of high-resolution crystal structures of
      thermolysin (TLN), generated from crystals soaked in 2% to 100% isopropanol. The
      procedure causes only minor changes to the conformation of the protein, and an
      increasing number of isopropanol interaction sites could be identified as the
      solvent concentration is increased. Isopropanol occupies all four of the main
      subsites in the active site, although this was only observed at very high
      concentrations of isopropanol for three of the four subsites. Analysis of the
      isopropanol positions shows little correlation with interaction energy computed
      using a molecular mechanics force field, but the experimentally determined
      positions of isopropanol are consistent with the structures of known protein
      ligand complexes of TLN.

PMID- 10651279
TI  - Non-Boltzmann thermodynamic integration (NBTI) for macromolecular systems:
      relative free energy of binding of trypsin to benzamidine and benzylamine.
AB  - The relative free energies of binding of trypsin to two amine inhibitors,
      benzamidine (BZD) and benzylamine (BZA), were calculated using non-Boltzmann
      thermodynamic integration (NBTI). Comparison of the simulations with the crystal
      structures of both complexes, trypsin-BZD and trypsin-BZA, shows that NBTI
      simulations better sample conformational space relative to thermodynamic
      integration (TI) simulations. The relative binding free energy calculated using
      NBTI was much closer to the experimentally determined value than that obtained
      using TI. The error in the TI simulation was found to be primarily due to
      incorrect sampling of BZA's conformation in the binding pocket. In contrast, NBTI
      produces a smooth mutation from BZD to BZA using a surrogate potential, resulting
      in a much closer agreement between the inhibitors' conformations and the omit
      electron density maps. This superior agreement between experiment and simulation,
      of both relative binding free energy differences and conformational sampling,
      demonstrates NBTI's usefulness for free energy calculations in macromolecular
      simulations.

PMID- 10651280
TI  - Structure-based analysis of protein dynamics: comparison of theoretical results
      for hen lysozyme with X-ray diffraction and NMR relaxation data.
AB  - An analytical approach based on Gaussian network model (GNM) is proposed for
      predicting the rotational dynamics of proteins. The method, previously shown to
      successfully reproduce X-ray crystallographic temperature factors for a series of
      proteins is extended here to predict bond torsional mobilities and reorientation
      of main chain amide groups probed by 15N-H nuclear magnetic resonance (NMR)
      relaxation. The dynamics of hen egg-white lysozyme (HEWL) in the folded state is
      investigated using the proposed approach. Excellent agreement is observed between
      theoretical results and experimental (X-ray diffraction and NMR relaxation) data.
      The analysis reveals the important role of coupled rotations, or cross
      correlations between dihedral angle librations, in defining the relaxation
      mechanism on a local scale. The crystal and solution structures exhibit some
      differences in their local motions, but their global motions are identical. Hinge
      residues mediating the cooperative movements of the alpha- and beta-domains are
      identified, which comprise residues in helix C, Glu35 and Ser36 on the loop
      succeeding helix B, Ile55 and Leu56 at the turn between strands II and III. The
      central part of the beta-domain long loop and the turn between strands I and II
      display an enhanced mobility. Finally, kinetically hot residues and key
      interactions are identified, which point at helix B and beta-strand III as the
      structural elements underlying the stability of the tertiary structure.

PMID- 10651281
TI  - Computer simulations of the dynamics of human choriogonadotropin and its alpha
      subunit.
AB  - Human choriogonadotropin (hCG) belongs to a family of heterodimeric glycoprotein
      hormones involved in reproduction. Over 75 ns of molecular dynamics simulations
      of this heterodimer and the free alpha subunit were performed and validated by
      experimental information to arrive at a qualitative dynamical description of
      these molecules. A number of 5-ns simulations at 400 degrees K describe a
      sufficiently stable heterodimer structure, whereas the free alpha subunit shows
      the experimentally observed partial unfolding. From the main collective
      fluctuations of the free alpha subunit, it can be derived that residues alpha35
      55 form a domain that is highly flexible with respect to the other domain, which
      contains all five disulfide bonds. The apparent loss of secondary structure in
      the region alpha33-58 may very well be induced by this. Dynamic domains can also
      be determined from the hCG heterodimer simulations. The most important collective
      mode of motion shows that the flexibility of the alpha subunit is reduced by
      concerted rotation with both the long loop and the determinant loop of the beta
      subunit. The motion of the free alpha subunit does not differ significantly from
      the motion it has in the hCG heterodimer, but the amplitudes along the most
      important eigenvectors are larger.

PMID- 10651282
TI  - Enhanced conformational diversity search of CDR-H3 in antibodies: role of the
      first CDR-H3 residue.
AB  - Through a conformation search by a simulation calculation, the relationships
      between the amino acid sequences and the conformations of the third
      complementarity-determining region of the antibody heavy chain (CDR-H3) were
      investigated to characterize the large conformational varieties of antibodies.
      Here, we focused on the structural role of the first CDR-H3 residue, and we
      selected two antibodies, 28B4 and PLG, whose CDR-H3 conformations are
      significantly different, having Trp and Gly at the first position, respectively.
      Multicanonical molecular dynamics simulations, with the advantage of enhanced
      sampling efficiency, were performed for the CDR-H3 fragments of 28B4 and PLG, and
      a modified CDR-H3 model of 28B4, where the first Trp residue was substituted with
      Gly. When the first CDR-H3 residue is Trp, almost all of the observed CDR-H3
      loops were bent at the first residue. In contrast, when the first residue is Gly,
      large varieties of loop conformations were observed. The structural role of this
      Gly residue is discussed from the perspective of the other antibody structures in
      the database. When the surrounding residues were included in the calculations,
      CDR-H3 loop structures similar to those in the crystal structures were reproduced
      as the major conformations for both the 28B4 and PLG antibodies.

PMID- 10651283
TI  - A structural model for the rolA protein and its interaction with DNA.
AB  - The study of the plant oncogene rolA has been hampered by a lack of structural
      information. Here we show that, despite a lack of significant sequence similarity
      to proteins of known structure, the rolA sequence adopts a known fold; that of
      the papillomavirus E2 DNA-binding domain. This fold is reliably identified by
      modern threading programs, which consider predicted secondary structure, but not
      by others. Although the rolA sequence is only around 16% identical to those of
      the available template structures, a structural model could be built that
      performed well against protein structure verification programs. The adopted
      strategy involved alignment corrections, justified by multiple model building and
      evaluation, with particular attention paid to the hydrophobic core residues. We
      find that rolA protein is predicted to resemble the template proteins in two key
      aspects; existence as a dimer and ability to bind DNA. rolA protein has recently
      been shown experimentally to possess DNA binding ability. This model predicts Lys
      24 and Arg 27 to be involved in sequence-specific interactions and eight other
      residues to hydrogen-bond phosphate groups of the DNA.

PMID- 10651284
TI  - Probing local environments of tryptophan residues in proteins: comparison of 19F
      nuclear magnetic resonance results with the intrinsic fluorescence of soluble
      human tissue factor.
AB  - 19F nuclear magnetic resonance (19F NMR) of 5-fluorotryptophan (5F-Trp) and
      tryptophan (Trp) fluorescence both provide information about local environment
      and solvent exposure of Trp residues. To compare the information provided by
      these spectroscopies, the four Trp residues in recombinant soluble human tissue
      factor (sTF) were replaced with 5F-Trp. 19F NMR assignments for the 5F-Trp
      residues (14, 25, 45, and 158) were based on comparison of the wild-type protein
      spectrum with the spectra of three single Trp-to-Phe replacement mutants.
      Previously we showed from fluorescence and absorption difference spectra of
      mutant versus wild-type sTF that the side chains of Trpl4 and Trp25 are buried,
      whereas those of Trp45 and Trp158 are partially exposed to bulk solvent
      (Hasselbacher et al., Biophys J 1995;69:20-29). 19F NMR paramagnetic broadening
      and solvent-induced isotope-shift experiments show that position 5 of the indole
      ring of 5F-Trp158 is exposed, whereas that of 5F-Trp45 is essentially
      inaccessible. Although 5F-Trp incorporation had no discernable effect on the
      procoagulant cofactor activity of either the wild-type or mutant proteins, 19F
      NMR chemical shifts showed that the single-Trp mutations are accompanied by
      subtle changes in the local environments of 5F-Trp residues residing in the same
      structural domain.

PMID- 10651285
TI  - Structural characterization of two tandemly arranged DNA methyltransferase genes
      from Neisseria gonorrhoeae MS11: N4-cytosine specific M.NgoMXV and nonfunctional
      5-cytosine-type M.NgoMorf2P.
AB  - Two adjacent genes encoding DNA methyltransferases (MTases) of Neisseria
      gonorrhoeae MS11, an active N4-cytosine specific M. NgoMXV and an inactive 5
      cytosine type M. NgoMorf2P, were cloned into Escherichia coli and sequenced. We
      analyzed the deduced amino acid sequence of both gene products and localized
      conserved regions characteristic for DNA MTases. Structure prediction, threading
      derived alignments, and comparison with the common fold for DNA MTases allowed
      for construction of super-secondary and tertiary models for M.NgoMorf2P and
      M.NgoMXV, respectively. These models helped in identification of amino acids and
      structural elements essential for function of both enzymes. The implications of
      this putative structural model on the catalytic mechanism of M.NgoMXV and its
      possible relation to the common ancestor of modern DNA amino-MTases are also
      discussed.

PMID- 10651286
TI  - Insights into the mechanisms of catalysis and heterotropic regulation of
      Escherichia coli aspartate transcarbamoylase based upon a structure of the enzyme
      complexed with the bisubstrate analogue N-phosphonacetyl-L-aspartate at 2.1 A.
AB  - A high-resolution structure of Escherichia coli aspartate transcarbamoylase has
      been determined to 2.1 A; resolution in the presence of the bisubstrate analog N
      phosphonacetyl-L-aspartate (PALA). The structure was refined to a free R-factor
      of 23.4% and a working R-factor of 20.3%. The PALA molecule is completely
      saturated with interactions to side chain and backbone groups in the active site,
      including two interactions that are contributed from the 80s loop of the adjacent
      catalytic chain. The charge neutralization of the bound PALA molecule (and
      presumably the substrates as well) induced by the electrostatic field of the
      highly positively charged active site is an important factor in the high binding
      affinity of PALA and must be important for catalysis. The higher-resolution
      structure reported here departs in a number of ways from the previously
      determined structure at lower resolution. These modifications include alterations
      in the backbone conformation of the C-terminal of the catalytic chains, the N-
      and C-termini of the regulatory chains, and two loops of the regulatory chain.
      The high-resolution of this structure has allowed a more detailed description of
      the binding of PALA to the active site of the enzyme and has allowed a detailed
      model of the tetrahedral intermediate to be constructed. This model becomes the
      basis of a description of the catalytic mechanism of the transcarbamoylase
      reaction. The R-structural state of the enzyme-PALA complex is an excellent
      representation of the form of the enzyme that occurs at the moment in the
      catalytic cycle when the tetrahedral intermediate is formed. Finally, improved
      electron density in the N-terminal region of the regulatory chain (residues 1 to
      7) has allowed tracing of the entire regulatory chain. The N-terminal segments of
      the R1 and R6 chains are located in close proximity to each other and to the
      regulatory site. This portion of the molecule may be involved in the observed
      asymmetry between the regulatory binding sites as well as in the heterotropic
      response of the enzyme.

PMID- 10651288
TI  - Fatty acid composition of four microsporidian species compared to that of their
      host fishes.
AB  - The fatty acid composition of four microsporidian species (Glugea atherinae,
      Spraguea lophii, Glugea americanus, and Pleistophora mirandellae) and their host
      fishes has been determined using gas chromatography. Twenty-four fatty acids were
      identified with differences in relative abundance of fatty acids among the four
      parasites. Certain even-saturated fatty acids were found in a very high
      proportion: palmitic acid (16:0) represented one-third of total fatty acids in
      Pleistophora mirandellae. The level of docosahexaenoic acid (22:6omega3) attained
      26-28% in Glugea atherinae, Spraguea lophii, and Glugea americanus, but only 8-9%
      in P. mirandellae. With respect to fatty acid compositions of host organs, some
      significant differences were evident between marine and freshwater fishes.
      Palmitic acid was prevalent in the marine fishes, Atherinae boyeri and Lophius
      piscatorius, and oleic acid (18:1omega9) in the freshwater fish Leuciscus
      cephalus. The proportion of docosahexaenoic acid in marine fishes was two or
      three times as great as in freshwater fish Leuciscus. The high polyunsaturated
      fatty acid content in both parasites and host fishes may be related to the
      scavenging of these fatty acids by the parasites rather than a microsporidia
      specific fatty acid biosynthesis pathway.

PMID- 10651287
TI  - An indexed genomic library for Paramecium complementation cloning.
AB  - Recent pioneering work opened the way for cloning genes in Paramecium by
      functional complementation of mutants. We present here the construction and pilot
      utilization of a new indexed library of Paramecium macronuclear DNA. The library
      is made of 61,440 clones containing inserts mostly between 6 and 12 kilobases. It
      has already allowed the complementation cloning of four new genes, and this
      library has proven to be very useful for rapid hybridization cloning.

PMID- 10651289
TI  - Recent advances in the molecular genetics of Paramecium.
AB  - Paramecium continues to be used to study motility, behavior, exocytosis, and the
      relationship between the germ and the somatic nuclei. Recent progress in
      molecular genetics is described. Toward cloning genes that correspond to mutant
      phenotypes, a method combining complementation with microinjected DNA and library
      sorting has been used successfully in cloning several novel genes crucial in
      membrane excitation and in trichocyst discharge. Paramecium transformation en
      masse has now been shown by using electroporation or bioballistics. Gene
      silencing has also been discovered in Paramecium, recently. Some 200 Paramecium
      genes, full length or partial, have already been cloned largely by homology.
      Generalizing the use of gene silencing and related reverse-genetic techniques
      would allow us to correlate these genes with their function in vivo.

PMID- 10651290
TI  - Protists as opportunistic pathogens: public health impact in the 1990s and
      beyond.
AB  - Protist organisms (protozoa and fungi) have become increasingly prominent as
      opportunistic pathogens among persons infected with human immunodeficiency virus
      (HIV) and among organ transplant recipients--two immunocompromised populations
      that have increased dramatically in the past two decades. Pneumocystis carinii
      pneumonia continues to be the most common serious opportunistic infection (OI)
      among HIV-infected persons in the United States, occurring frequently among
      persons not previously receiving medical care. Toxoplasmosis, cryptococcosis,
      cryptosporidiosis, and isosporiasis occur frequently in HIV-infected persons in
      the developing world. Candidiasis and aspergillosis are common OIs in organ
      transplant recipients. As these populations of immunosuppressed patients continue
      to expand worldwide new OIs caused by protist pathogens are likely to emerge.

PMID- 10651291
TI  - Clinical presentation and significance of emerging opportunistic infections.
AB  - In recent years the clinical face of the Acquired Immune Deficiency Syndrome has
      changed significantly as a consequence of use of prophylaxis against Pneumocystis
      carinii pneumonia and combination antiretroviral therapy. In this context several
      opportunistic pathogens have emerged as causes of clinically important disease.
      Many of these infective agents have previously been defined by specific
      geographical locations. Their clinical presentation frequently mimics other (non)
      opportunistic infections with which they may co-exist. The diagnosis is
      frequently delayed as the diagnostic possibility may not be in the clinician's
      differential diagnosis. Invasive procedures are frequently required in order to
      secure a diagnosis. Despite treatment, prognosis is often poor. Clinicians should
      be aware of these opportunistic pathogens in order that a timely diagnosis may be
      made and appropriate therapy given.

PMID- 10651292
TI  - Penicillium marneffei: an insurgent species among the penicillia.
AB  - Most species of Penicillium are considered relatively benign with respect to
      causing human disease. However, one species, P. marneffei, has emerged as a
      significant pathogen particularly among individuals who live in Southeast Asia
      and are concurrently infected with the human immunodeficiency virus. While
      environmental and epidemiological studies have yet to resolve the reason for the
      heightened virulence of P. marneffi, one characteristic does distinguish this
      fungus from other Penicillium species. Whereas the latter grow as monomorphic
      moulds bearing typical asexual propagules (conidia), P. marneffei is thermally
      dimorphic. At room temperature, P. marneffei exhibits the morphology
      characteristic of the genus. In contrast to other Penicillia, though, P.
      marneffei grows as a yeast-like entity (arthroconidium) when found in diseased
      tissue or cultivated at 37 degrees C. Studies in our laboratory have focused on
      the differential gene expression between the mould and arthroconidial phases.
      Many of the genes whose expression differs during mould-to-arthrocondium
      transition are related to energy metabolism. A better understanding of gene
      expression during morphogenesis in P. marneffei may help detect unique target
      sites or cellular processes that can be exploited in the development of
      antifungal agents or immunomodulation therapies.

PMID- 10651294
TI  - Leishmania, Trypanosoma and monoxenous trypanosomatids as emerging opportunistic
      agents.
AB  - Immunosuppression is associated with the occurrence of a large variety of
      infections, several of them due to opportunistic protozoa. The parasitic protozoa
      of the family Trypanosomatidae vary greatly in their importance as potential
      opportunistic pathogens. African trypanosomiasis is no more common nor severe
      during AIDS. The situation with Chagas' disease, however, is much different.
      Although the process is not clearly understood, there appears to be a
      reactivation of Trypanosoma cruzi infection, which can lead to severe
      meningoencephalitis. In persons with AIDS, leishmaniasis is often exacerbated,
      particularly Leishmania infantum, which causes visceral leishmaniasis in southern
      Europe. Since 1990, 1,616 cases of visceral leishmaniasis/HIV co-infection have
      been reported, mainly from southern Europe, and particularly from Spain, southern
      France, and Italy. The co-infected patients are primarily young adults and belong
      to the risk group of intravenous drug users. Isoenzymatic identification of 272
      isolates showed 18 different L. infantum zymodemes, of which 10 represent new
      zymodemes hitherto found only during HIV co-infection. New foci of co-infection
      are emerging in various parts of the world, including Brazil and East Africa.
      Moreover, since 1995, non-human monoxenous trypanosomatids have been found in
      AIDS patients, causing both diffuse cutaneous lesions and visceral infections. In
      countries where visceral leishmaniasis is endemic, particularly in southern
      Europe, immunosuppressive treatments for organ transplants or malignant diseases
      often result either in reactivation of asymptomatic visceral leishmaniasis or in
      facilitation of new infections.

PMID- 10651293
TI  - The increasing importance of Acanthamoeba infections.
AB  - Free-living amebae belonging to the genus Acanthamoeba are the causative agents
      of granulomatous amebic encephalitis, a chronic progressive disease of the
      central nervous system, and of amebic keratitis, a chronic eye infection.
      Granulomatous amebic encephalitis occurs more frequently in immunocompromised
      patients while keratitis occurs in healthy individuals. The recent increased
      incidence in Acanthamoeba infections is due in part to infection in patients with
      acquired immune deficiency syndrome, while that for keratitis is due to the
      increased use of contact lenses. Understanding the mechanism of host resistance
      to Acanthamoeba is essential since the amebae are resistant to many therapeutic
      agents. Studies in our laboratory as well as from others have demonstrated that
      macrophages from immunocompetent animals are important effector cells against
      Acanthamoeba. We have demonstrated also that microglial cells, resident
      macrophages of the brain, elicit cytokines in response to A. castellanii.
      Neonatal rat cortical microglia from Sprague-Dawley rats co-cultured with A.
      castellanii produced mRNA for the inflammatory cytokines, interleukin 1alpha,
      interleukin 1beta, and tumor necrosis factor alpha. In addition, scanning and
      transmission electron microscopy revealed that microglia ingested and destroyed
      A. castellanii in vitro. These results implicate macrophages as playing an
      effector role against Acanthamoeba and suggest immune modulation as a potential
      alternative therapeutic mode of treatment for these infections.

PMID- 10651295
TI  - Protein kinase activation and protein phosphorylation in Naegleria fowleri amebae
      in response to normal human serum.
AB  - Activation of signal transduction pathways in response to serum complement in
      Naegleria fowleri amebae was investigated. We examined the activation of protein
      kinases and changes in the phosphorylation state of proteins in N. fowleri
      stimulated by normal human serum (NHS). To determine differences in
      phosphorylation of proteins when amebae were exposed to NHS or heat inactivated
      serum (HIS) lacking complement, amebae were labeled with [32P] orthophosphate. An
      increase in phosphorylation of relatively low molecular weight proteins was noted
      in N. fowleri incubated in NHS with a concomitant decrease in phosphorylation of
      high molecular mass polypeptides. To investigate whether serine/threonine or
      tyrosine kinases were stimulated by NHS, amebae were treated with protein kinase
      inhibitors H7, staurosporine or genistein, prior to serum exposure and examined
      for susceptibility to complement. Treatment with each of these inhibitors
      resulted in increased complement lysis. Incubation of N. fowleri with genistein
      specifically inhibited tyrosine phosphorylation of proteins stimulated by NHS. A
      tyrosine kinase activity assay using exogenous polyGlu-Tyr substrate demonstrated
      differential activation of tyrosine kinases in amebae treated with NHS when
      compared to treatment with HIS. The results suggest that activation of protein
      kinases and subsequent protein phosphorylation are important in mediating
      complement resistance in N. fowleri.

PMID- 10651296
TI  - Identification of proteins in Encephalitozoon intestinalis, a microsporidian
      pathogen of immunocompromised humans: an immunoblotting and immunocytochemical
      study.
AB  - Microsporidia are unicellular and obligate intracellular spore-forming parasites.
      The spore inoculates the host cell with its non-motile infectious content, the
      sporoplasm, by way of the polar tube--the typical invasive apparatus of the
      microsporidian spore. Molecules involved in host cell invasion were investigated
      in Encephalitozoon intestinalis. Mouse polyclonal and monoclonal antibodies were
      raised against spore proteins and their reactivity was tested by Western-blotting
      and immunolocalization techniques, including electron and confocal microscopy.
      The antibodies thus generated could be divided into two major groups. One group
      reacted to the surface of the parasite at different developmental stages, mostly
      presporous stages and mature spores, whereas the other group recognized the polar
      tube. Of the antibodies reacting to the spore wall, one identified an exospore
      protein at 125 kDa while all others recognized a major doublet at 55-60 kDa, and
      minor proteins present at the surface of sporogonic stages and in the endospore.
      All antibodies recognizing spore wall proteins reacted also to the material
      forming septa in the parasitophorous vacuole. A major polar tube protein at 60
      kDa was identified by another group of antibodies.

PMID- 10651297
TI  - First record of Lagenophrys dennisi (Ciliophora: Peritrichia) on the exoskeleton
      of crayfish Cambarellus patzcuarensis.
AB  - Lagenophrys dennisi, a peritrich ciliate, was observed attached to the
      exoskeleton of the crayfish Cambarellus patzcuarensis in Lake Patzcuaro,
      Michoacan, Mexico. Lagenophrys dennisi presents a hemispheroidal, suboval or oval
      lorica in dorsal view, the distinctive lorica aperture consists of a pair of lips
      highly arched, unthickened, and smooth. Comparison of morphometric characters of
      the ciliate with previous records is made. Structures such as a "V"-shaped lorica
      suture, collar ridges, and myoneme are proposed for species identification. An
      anterior crescentic thickening on the dorsal surface of the lorica was observed
      under the scanning electron microscope. Lagenophryids were associated with 11 of
      13 body parts with antennules and rostrum showing the highest prevalence.
      Lagenophrys dennisi was also found attached to submerged glass slides. This study
      represents the first record of L. dennisi on C. patzcuarensis and the first
      record of its presence in Mexico.

PMID- 10651298
TI  - Comparison of growth efficiencies of protozoa growing on bacteria deposited on
      surfaces and in suspension.
AB  - Bacteria were deposited in tubes as compact pellets by centrifuging suspensions
      of cultured Vibrio at stationary phase. Numbers and protein biomass of
      flagellates added to these tubes and of the Vibrio, were followed and compared
      with the growth of the same and other protists on identical, uncentrifuged
      Vibrio. The flagellates Bodo saliens and Caecitellus parvulus, which could not be
      seen to multiply in tubes of suspended bacteria, grazed deposited bacteria
      actively as did the more versatile flagellate Cafeteria roenbergensis. The growth
      of these flagellates and their consumption of deposited bacteria were very
      similar to those of the flagellate Pteridomonas danica or the ciliate Uronema
      marinum fed with suspended bacteria, although deposit-feeders grew more slowly.
      Gross growth efficiencies (30-60%) of deposit-feeding flagellates were similar to
      those of the suspension-feeding protists. Caecitellus consumed 55 Vibrio to
      produce one flagellate, while 4,500 Vibrio were consumed to produce one Uronema.
      Surface-feeding flagellates are shown to be efficient bacterivores, capable of
      restricting the numbers of bacteria deposited on surfaces just as other protozoa
      control numbers of suspended bacteria.

PMID- 10651299
TI  - Molecular phylogeny of parabasalids based on small subunit rRNA sequences, with
      emphasis on the Trichomonadinae subfamily.
AB  - We determined small subunit ribosomal DNA sequences from three parabasalid
      species, Trichomitus batrachorum strain R105, Tetratrichomonas gallinarum, and
      Pentatrichomonas hominis belonging to the Trichomonadinae subfamily. Unrooted
      molecular phylogenetic trees inferred by distance, parsimony, and likelihood
      methods reveal four discrete clades among the parabasalids. The Trichomonadinae
      form a robust monophyletic group. Within this subfamily T. gallinarum is closely
      related to Trichomonas species as supported by morphological data, with P.
      hominis and Pseudotrypanosoma giganteum occupying basal positions. Our analysis
      does not place T. batrachorum within the Trichomonadinae. Trichomitus batrachorum
      (strains R105 and BUB) and Hypotrichomonas acosta form a well-separated cluster,
      suggesting the genus Trichomitus is polyphyletic. The emergence of T. batrachorum
      precedes the Trichomonadinae-Tritrichomonadinae dichotomy, emphasizing its
      pivotal evolutionary position among the Trichomonadidae. A third cluster unites
      the Devescovinidae and the Calonymphidae. The fourth clade contains the three
      hypermastigid sequences from the genus Trichonympha, which exhibit the earliest
      emergence among the parabasalids. The addition of these three new parabasalid
      species did not however resolve ambiguities regarding the relative branching
      order of the parabasalid clades. The phylogenetic positions of Tritrichomonas
      faetus, Monocercomonas sp., Dientamoeba fragilis, and the unidentified
      Reticulitermes flavipes gut symbiont 1 remain unclear.

PMID- 10651300
TI  - Oligonucleotide probes for the identification of three algal groups by dot blot
      and fluorescent whole-cell hybridization.
AB  - Photosynthetic pico- and nanoplankton dominate phytoplankton biomass and primary
      production in the oligotrophic open ocean. Species composition, community
      structure, and dynamics of the eukaryotic components of these size classes are
      poorly known primarily because of the difficulties associated with their
      preservation and identification. Molecular techniques utilizing 18S rRNA
      sequences offer a number of new and rapid means of identifying the picoplankton.
      From the available 18S rRNA sequence data for the algae, we designed new group
      specific oligonucleotide probes for the division Chlorophyta, the division
      Haptophyta, and the class Pelagophyceae (division Heterokonta). Dot blot
      hybridization with polymerase chain reaction amplified target rDNA and whole-cell
      hybridization assays with fluorescence microscopy and flow cytometry were used to
      demonstrate probe specificity. Hybridization results with representatives from
      seven algal classes supported the phylogenetic affinities of the cells. Such
      group- or taxon-specific probes will be useful in examining community structure,
      for identifying new algal isolates, and for in situ detection of these three
      groups, which are thought to be the dominant algal taxa in the oligotrophic
      regions of the ocean.

PMID- 10651301
TI  - Molecular characterization of myxozoan parasites from Lake Sasajewun, Algonquin
      Park, Ontario, by riboprinting.
AB  - The small subunit-rRNA genes of 18 myxozoans from Lake Sasajewun, Algonquin Park
      were amplified and digested with restriction endonucleases for riboprinting
      analysis. Identical riboprints were not found between the myxosporeans and the
      actinosporeans. The distinct riboprinting patterns observed among these myxozoans
      indicate considerable genetic diversity within this group. Identical riboprints
      were found between Myxobolus pendula and Myxobolus pellicides, and between
      triactinomyxon 'C' and Triactinomyxon ignotum. Parsimony analysis of the
      riboprints demonstrated that neither the myxosporeans nor the actinosporeans
      formed a monophyletic group. Some species of Myxobolus are more closely related
      to forms of triactinomyxon, echinactinomyxon or raabeia than to other Myxobolus
      species. These results are consistent with the two-host life cycle hypothesis of
      myxozoans that myxosporeans and actinosporeans are alternating stages of the same
      organisms.

PMID- 10651302
TI  - Cryptosporidium andersoni n. sp. (Apicomplexa: Cryptosporiidae) from cattle, Bos
      taurus.
AB  - A new species of Cryptosporidium is described from the feces of domestic cattle,
      Bos taurus. Oocysts are structurally similar to those of Cryptosporidium muris
      described from mice but are larger than those of Cryptosporidium parvum. Oocysts
      of the new species are ellipsoidal, lack sporocysts, and measure 7.4 x 5.5 microm
      (range, 6.0-8.1 by 5.0-6.5 microm). The length to width ratio is 1.35 (range,
      1.07-1.50). The colorless oocyst wall is < 1 microm thick, lacks a micropyle, and
      possesses a longitudinal suture at one pole. A polar granule is absent, whereas
      an oocyst residuum is present. Oocysts were passed fully sporulated and are not
      infectious to outbred, inbred immunocompetent or immunodeficient mice, chickens
      or goats. Recent molecular analyses of the rDNA 18S and ITS1 regions and heat
      shock protein 70 (HSP-70) genes demonstrate this species to be distinct from C.
      muris infecting rodents. Based on transmission studies and molecular data, we
      consider the large form of Cryptosporidium infecting the abomasum of cattle to be
      a new species and have proposed the name Cryptosporidium andersoni n. sp. for
      this parasite.

PMID- 10651303
TI  - Quantitative detection of lac-Z-transfected CC531 colon carcinoma cells in an
      orthotopic rat liver metastasis model.
AB  - Disseminated colon carcinoma metastases in the liver are associated with low cure
      rates and constitute a serious therapeutic problem. Appropriate experimental
      models which mimic metastases development and outgrowth can provide insight into
      the mechanism of this lethal process and facilitate the finding of new approaches
      for its control. We established an orthotopic liver metastases model based on
      CC531 rat colon adenocarcinoma cells which were transfected with a beta
      galactosidase gene as marker to facilitate their detection. Intraportal injection
      of CC531-lac-Z cells resulted in a rapid and locally aggressive growth within the
      liver and was characterised by a tumour volume doubling time of 20 h and abundant
      angiogenesis. A commercially available chemi-luminescence assay allowed rapid,
      quantitative and sensitive detection of the diffusely growing tumour cells.
      Immunogenicity of CC531-lac-Z cells induced by the marker gene was significantly
      reduced by co-administering the tumour cells with matrigel. Within an observation
      period of three weeks following tumour cell injection only 6% of the animals
      showed lung involvement, thus indicating a specific homing of CC531-lac-Z cells
      to the liver. This period appears long enough to allow therapeutic manipulations
      at various stages of tumour growth in the liver. It is envisaged that the model
      will have applications for various therapeutic strategies.

PMID- 10651304
TI  - Beta1-integrin-mediated dynamic adhesion of colon carcinoma cells to
      extracellular matrix under laminar flow.
AB  - To resist substantial wall shear stress exerted by blood flow metastasizing colon
      carcinoma cells have to form adhesive contacts with endothelial cells and
      subendothelial extracellular matrix (ECM). At secondary sites tumor cells have to
      stabilize these initial adhesive interactions to prevent detachment and
      recirculation. Previously we found that adhesion of colon carcinoma cells to ECM
      components under static conditions is mediated, in part, by various beta1
      integrins. Since other malignant cells possess adhesive properties that are
      different under static and dynamic conditions, we analyzed human colon carcinoma
      cell adhesion under flow by decreasing the flow (wall shear stress, WSS) of cell
      suspensions and allowing cells to interact with collagen-coated surfaces in a
      laminar flow chamber. HT-29 colon carcinoma cells were used to study wall shear
      adhesion threshold (WSAT), dynamic adhesion rate (DAR) and adhesion stabilization
      rate (ASR). DAR was determined after a low flow period using a WSS set at 50% of
      WSAT. ASR was calculated 60 sec after reestablishment of high WSS. Glass slides
      were coated with collagen I (C I) or bovine serum albumin (BSA, negative
      control). In some experiments cells were pretreated with function-blocking anti
      beta1 or nonspecific IgG. Rolling of cells occurred on C I- and BSA-coated
      surfaces at high WSS. By decreasing WSS cell sticking without definite adhesion
      was found, and cells stuck to BSA at WSS lower than that found for C I. Further
      decreasing WSS below WSAT enabled stable cell adhesion to C I, but only a few
      cells adhered to BSA. ASR was found to be 73% of primarily adherent cells (to C
      I). Pretreatment with anti-beta1 did not affect cell rolling but did inhibit cell
      sticking and adhesion completely, whereas nonspecific IgG was without effect.
      Activation of PKC using phorbol ester resulted in an increase of adhesive
      interactions under dynamic and static conditions, whereas its inhibition reduced
      adhesion. Adhesive interactions of HT-29 colon carcinoma cells with ECM-coated
      surfaces under laminar flow conditions occurred in various steps: (1) rolling,
      (2) sticking or initial adhesion, and (3) stabilization of adhesion. Under shear
      flow rolling of tumor cells on ECM-coated surfaces appeared to be mediated mainly
      by physical/mechanical and nonspecific surface-cell membrane interactions,
      whereas stabilized adhesion to ECM was specifically mediated by beta1-integrin
      binding to ECM components. PKC seems to be involved in the regulation of adhesion
      stabilization under static and flow conditions.

PMID- 10651305
TI  - Chemokines induce the cellular migration of MCF-7 human breast carcinoma cells:
      subpopulations of tumour cells display positive and negative chemotaxis and
      differential in vivo growth potentials.
AB  - We previously reported that chemotactic cytokines (chemokines) induce the
      directional migration of cells derived from the breast carcinoma cell line MCF-7
      in vitro, however it was apparent that only a small percentage of cells displayed
      the ability to migrate upon stimulation. In the present study three sub-lines
      derived from the parental MCF-7 cell line were selected for their ability to
      migrate in response to MIP-1alpha, MIP-1beta or RANTES across Transwell filters
      of 8 microm pore size. The first round selection of migratory cells resulted in
      sub-populations which demonstrated an increased chemotactic response compared
      with parental cells. Cells migrating to MIP-1beta were subjected to four further
      rounds of positive or negative selection, resulting in two sub-lines, MCF-7L4 and
      MCF-7U4 which displayed an increased and decreased chemotactic response
      respectively to MIP-1alpha MIP-1beta and RANTES. No difference in chemokine
      receptor RNA message expression between these sub-lines and the parental MCF-7
      line were detected, although increased levels of alpha3, alpha6 and alphav
      integrin sub-units were shown for MCF-7L4 (positively selected sub-line) compared
      with MCF-7U4 cells. Moreover, the in vivo growth of cells derived from the two
      MCF-7 sub-lines was inversely correlated with their chemotactic response. The
      results of this study depict further the inherent heterogeneity in cancer,
      suggesting that the chemotactic response may influence the migratory traits of
      sub-populations within the tumour and potentially contribute to their in vivo
      behavior, growth and survival.

PMID- 10651306
TI  - Alterations in proteolytic activity at low pH and its association with invasion:
      a theoretical model.
AB  - The extracellular pH (pHe) of solid tumours is often lower than in normal
      tissues, with median pH values of about 7.0 in tumours and 7.5 in normal tissue.
      Despite this more acidic tumour microenvironment, non-invasive measurements of
      intracellular pH (pHi) have shown that the pHi of solid tumours is neutral or
      slightly alkaline compared to normal tissue (pHi 7.0-7.4). This gives rise to a
      reversed cellular pH gradient between tumours and normal tissue, which has been
      implicated in many aspects of tumour progression. One such area is tumour
      invasion: the incubation of tumour cells at low pH has been shown to induce more
      aggressive invasive behaviour in vitro. In this paper the authors use
      mathematical models to investigate whether altered proteolytic activity at low pH
      is responsible for the stimulation of a more metastatic phenotype. The authors
      examined the effect of culture pH on the secretion and activity of two different
      classes of proteinases: the metalloproteinases (MMPs), and the cysteine
      proteinases (such as cathepsin B). The modelling suggests that changes in MMP
      activity at low pH do not have significant effects on invasive behaviour.
      However, the model predicts that the levels of active-cathepsin B are
      significantly altered by acidic pH. This result suggests a critical role for the
      cysteine proteinases in tumour progression.

PMID- 10651307
TI  - Resistance to apoptosis induced by microenvironmental stresses is correlated with
      metastatic potential in Lewis lung carcinoma.
AB  - The apoptosis-resistant phenotype of cloned high-metastatic A11 and low
      metastatic P29 cells isolated from Lewis lung carcinoma was compared. The results
      showed that A11 cells were more resistant to apoptosis induced by
      microenvironmental stresses such as serum starvation, glucose deprivation and
      hypoxia than P29 cells as judged by viability, DNA laddering, and chromatin
      condensation and fragmentation. Both cell lines were insensitive to tumor
      necrosis factor-alpha-mediated apoptosis. P29 cells expressed a much higher level
      of Fas antigen on the cell surface than A11 cells. However, both cell lines were
      also insensitive to Fas-mediated apoptosis. The apoptosis resistant phenotype of
      A11 cells was associated with the expression level of caspase-3, but not with
      those of Bcl-2, Bcl-X(L) Bax, p27Kip1 and DAP kinase. There was no difference
      between A11 and P29 cells in the expression of E-cadherin, the adhesiveness to
      the extracellular matrix components or the expression levels of metastasis
      associated genes such as c-Ha-ras, c-jun, p53 and nm23. Furthermore, A11 cells
      exhibited lower motile and invasive abilities than P29 cells. These results
      suggest that the apoptosis-resistant phenotype is an important factor for
      determining the metastatic ability of A11 cells. Supporting this, P29 cells
      became more apoptosis-resistant after treatment of the cells with
      dimethylsulfoxide which is reported to enhance the experimental metastatic
      potential of the cells.

PMID- 10651308
TI  - Multi-organ metastatic capability of Chinese hamster ovary cells revealed by
      green fluorescent protein (GFP) expression.
AB  - Stable high-level green fluorescent protein (GFP)-expressing Chinese hamster
      ovary cells (CHO) were used to visualize the degree of metastatic behavior of
      this cell line in nude and SCID mice. A stable GFP high-expression CHO clone,
      selected in 1.5 microM methotrexate, was injected subcutaneously in nude and
      severe combined immunodeficient (SCID) mice and implanted orthotopically in the
      ovary of nude mice. CHO proved to be highly metastatic from both the subcutaneous
      and orthotopic sites as brightly visualized by GFP fluorescence. High-level GFP
      expression allowed the visualization of metastatic tumor in fresh live host
      tissue in great detail. Metastases were visualized by GFP expression in the lung,
      pleural membrane, spleen, kidney, ovary, adrenal gland, and peritoneum after
      orthotopic implantation in nude mice. Metastases were visualized by GFP
      expression mainly in the lung, pleural membrane after subcutaneous implantation
      in nude mice. Metastases were visualized in the lung and pleural membrane, liver,
      kidney, and ovary after subcutaneous implantation in SCID mice. The construction
      of highly fluorescent stable GFP transfectants of CHO has revealed the multi
      organ metastatic capability of CHO cells. CHO has such a high degree of
      malignancy that it is metastatic from both the orthotopic and subcutaneous
      transplant sites. This highly malignant GFP-expressing cell-line with multi-organ
      metastatic affinity should serve as a powerful tool to study tumor-host
      interaction.

PMID- 10651309
TI  - A modified Boyden chamber assay for tumor cell transendothelial migration in
      vitro.
AB  - We have developed a modified Boyden chamber system for assessing tumor cell
      transmigration across endothelial monolayer in vitro. This radiometric-based
      method allows us to take into account the cells which have traversed but detached
      from the filter, a significant fraction not included in the existing method of
      visual counting. The method was applied to examine six malignant and one non
      malignant cell lines. The variable invasive potentials of these cells were found
      to correlate with their ability to disrupt the endothelial cell monolayers.

PMID- 10651310
TI  - Matrix metalloproteinase 9 is induced by the Epstein-Barr virus BZLF1
      transactivator.
AB  - Type IV collagenases, matrix metalloproteinase (MMP) 2 and MMP9 are implicated in
      tumor invasion and metastasis. In patients with nasopharyngeal carcinoma (NPC),
      poor prognosis due to development of local and distant metastasis has been
      reported to be predicted by antibody titers against the Z protein which is an AP
      1 family transcription factor encoded by the EBV BZLF1 immediate-early gene. Here
      we report that in patients with NPC, expression of Z in tumor cells correlates
      with advanced cervical lymph node metastasis which may suggest that Z affects
      tumor invasion and metastasis. We therefore tested if Z would induce expression
      of type IV collagenases. Transfection of Z expression plasmid into the C33A
      epithelial cell line increased expression of MMP9, but MMP2 expression was
      unaltered. Mutational analysis of the Z protein revealed that, in addition to all
      three functional domains of Z (dimerization domain, DNA binding domain, and
      activation domain), the carboxyl terminal 17 amino acids which stabilize the Z
      protein were necessary for induction of MMP9 expression. Analysis of the MMP9
      promoter demonstrated that only AP-1 site close to the transcriptional start-site
      was essential for transactivation by Z. Previously we reported that Epstein-Barr
      virus latent membrane protein 1 (LMP1) stimulates MMP9 expression (Yoshizaki et
      al. Proc. Natl. Acad. Sci. 1998; 95: 3621-6). Thus, Z together with LMP1 may
      contribute to invasion and metastasis of NPC by inducing expression of MMP9.

PMID- 10651311
TI  - N-linked oligosaccharides and metastatic propensity in in vivo selected mouse
      mammary adenocarcinoma cells.
AB  - Studies using metastatic variant selected in vivo from a cloned parental cell
      line demonstrate that the expression of beta1-6 branched, N-linked carbohydrates
      and sialic acid were positively associated with in vitro invasiveness and
      inversely associated with metastatic potential, adherence, and in vivo growth
      rate. These results suggest that at least within one tumor model, a negative
      association occurs between metastatic potential and 1-6 branched oligosaccharide
      expression. In these studies two metastatic variants, Cl-66M1 and Cl-66M2, were
      selected following serial in vivo passage of Cl-66, a clonal cell line obtained
      from a mouse mammary adenocarcinoma cell line. The parent cell line and the two
      metastatic variants were approximately equal in their adherence to fibronectin,
      laminin, and collagen type IV coated plastic. In contrast, both Cl-66M1 and Cl
      66M2 had a significantly increased ability to invade through matrigel invasion
      chambers and expressed significantly increased levels of beta1-6 branched, N
      linked carbohydrates, and sialic acid compared to the clonal parental cell line,
      Cl-66. Furthermore, the in vivo tumor growth rates of these selected variants
      were decreased compared to Cl-66 with the longest tumor volume doubling time
      observed with Cl-66M2.

PMID- 10651312
TI  - Thymidine phosphorylase expression in endometrial carcinomas.
AB  - Thymidine phosphorylase (TP) is a potent angiogenic molecule shown to induce
      endothelial cell migration and proliferation. We investigated the expression of
      TP in a series of 156 endometrial carcinomas, using immunohistochemical methods.
      Histopathological parameters of known prognostic significance and the molecular
      factors of p53, bcl-2 and angiogenesis were also assessed. Thymidine
      phosphorylase was expressed in cancer cells, stromal fibroblasts and myometrial
      cells. The pattern of TP staining was nuclear or mixed nuclear/cytoplasmic, and
      only exceptionally was purely cytoplasmic. An exclusively cytoplasmic staining
      was documented for the tumour-associated foamy macrophages. Cancer cell
      reactivity was rather limited; only 3.2% of endometrial carcinomas expressed TP
      in more than 50% of the neoplastic cell population and only 12% expressed the
      enzyme in more than 10% of the cancer cells. By contrast, TP reactivity was
      frequent in the fibroblasts of the tumour supporting stroma and the
      fibroblasts/myometrial cells at the invading tumour front, where approximately
      1/3 of the cases expressed TP in more than 50% of the respective constituent
      cells. A high TP reactivity in the stromal fibroblasts was significantly
      associated with the presence of foamy macrophages and an intense lymphocytic
      response. A high TP reactivity at the invading tumour front was significantly
      associated with an intense lymphocytic response and the adverse prognostic
      parameters of high tumour grade, deep myometrial invasion, advanced stage of
      disease and the non-endometrioid carcinomas. There was no significant association
      of cancer cell TP reactivity with any of the parameters studied, including
      nuclear p53 accumulation, cytoplasmic/perinuclear bcl-2 expression, microvessel
      density (MVD) and prognosis. Similarly, no relationship was established between
      fibroblastic or fibroblastic/myometrial TP reactivity and MVD. It is concluded
      that TP is not a major angiogenic factor in endometrial carcinomas. However, a
      prominent TP activity at the invading tumour front, which is probably induced by
      cytokines of histiocytic and lymphocytic origin, may promote tumour invasion and
      progression.

PMID- 10651313
TI  - In vivo treatment of rats with unfractionated heparin (UFH) or low molecular
      weight heparin (LMWH) does not affect experimentally induced colon carcinoma
      metastasis.
AB  - Recent randomized trials have suggested that treatment with low molecular weight
      heparin (LMWH) improves survival of cancer patients with venous thromboembolism,
      as compared to treatment with unfractionated heparin (UFH). Experimental studies
      have shown that UFH has activities besides its anticoagulant function which may
      affect progression of malignancy, including stimulation of new blood vessel
      formation. In contrast, LMWH has been suggested to inhibit angiogenesis. In the
      present study, we compared quantitatively the effects of treatment with UFH, LMWH
      or placebo on the development of experimentally induced colon carcinoma
      metastases in rat liver and on tumor-associated angiogenesis. It is shown that
      UFH and LMWH in therapeutic dosages neither affect development of metastases nor
      tumor blood vessel formation in this animal model. These results indicate that
      heparins do not affect colon cancer metastasis in liver. Further studies in other
      animal models are required to establish the mechanisms by which heparins
      potentially affect cancer.

PMID- 10651314
TI  - Induction of c-met proto-oncogene expression at the metastatic site.
AB  - In metastatic processes, gene expression may variously alter through interactions
      between tumor and host stromal cells at the metastatic site. Using a tail vein
      injection-lung metastatic model and differential display, we analyzed alteration
      of gene expression in experimentally metastasized lesions. We found that
      expression of the c-met proto-oncogene was elevated in the lungs metastasized by
      MC-1 cells. The up-regulation of c-met was also observed in the lungs
      metastasized by B16 melanoma cells. In situ hybridization analysis revealed that
      the elevation of c-met expression apparently occurred in tumor cells but did not
      in lung stromal cells at the metastatic site. The c-Met protein was also highly
      expressed and phosphorylated. The upregulation of c-met appeared to be caused by
      induction of gene expression but not to be due to preferential selection of tumor
      cells highly expressing c-met. These findings suggest that the c-met proto
      oncogene is up-regulated at the transcription level through some interactions
      between tumor and host stromal cells.

PMID- 10651316
TI  - The structural bases of the regulation of neuron sensitivity.

PMID- 10651315
TI  - The involvement of intracerebral monoamines in the development of intracellular
      process in neocortex neurons.

PMID- 10651318
TI  - Responses of granulation tissue to acetylcholine and noradrenaline during
      denervation.

PMID- 10651317
TI  - Changes in the cholecystokinin-synthesizing system of the hypothalamus in
      experimental diabetes mellitus in rats.

PMID- 10651319
TI  - A model of adaptive visual processes of primary image processing.
AB  - A computer model of adaptive segmentation of two-dimensional visual objects was
      developed, based on neurophysiological and psychophysiological principles. The
      model imitates several stages of visual information processing. At the first
      stage, a preliminary assessment of the image is performed using a brightness
      pattern analyzer. At the second stage, control parameters are formed on the bases
      of the initial assessment. A defined control vector is synthesized for each type
      of starting image, which allows adaptive processing; this initiates two parallel
      mechanisms of primary image description: one contains the outlines of images and
      the sharp boundaries between their fragments, and the second contains areas of
      uniform intensity. The control parameter vector is applied to these two
      descriptions to analyze their brightnesses and spatial characteristics, and this
      is used as the basis for forming the regime for subsequent processing, which
      includes a set of processing operators whose parameters are tuned for each
      fragment of the image. The primary phasic and tonic descriptions are then used to
      extract individual fragments of the image (i.e., discrimination of figures from
      the background) and to form the final presentation. The resulting descriptions
      complement each other, creating a basis for quantitative measurements of image
      characteristics and allowing various signs needed for image classification to be
      formed. The computer program for adaptive image segmentation was tested using a
      large number of different two-dimensional half-tone objects, the purposes of
      these exercises including segmentation and measurement of objects in morphometric
      and cytometric studies.

PMID- 10651320
TI  - Electromyographic activity of the respiratory muscles in hyperbaric conditions.
AB  - Divers are known to have difficulty breathing in conditions of increased
      respiratory gas density. This report presents results obtained from
      electromyographic studies of the inspiratory muscles in conditions imitating a
      pressure chamber using neon and helium. Electromyographic investigations of the
      respiratory muscles allows the roles of these muscles in the respiratory act to
      be assessed and the present study is an attempt to demonstrate the possible
      neurophysiological mechanisms of respiratory difficulty in high-pressure
      conditions.

PMID- 10651321
TI  - Studies of the functional characteristics of central neurons of the brain in a
      behavioral experiment.
AB  - The activity of central integrative brain neurons is associated with the overall
      assessment of functionally diverse signals of different sensory modalities which
      converge on these neurons via parallel inputs. Processing this information, these
      neurons take part in organizing the animal's various actions and in the
      mechanisms involved in switching from one action to another. Therefore,
      understanding of the functional characteristics of central brain neurons requires
      studies in which the dynamics of neuron activity are recorded continuously
      throughout a sequence of actions performed by an animal. Traditional methods of
      analyzing neuron activity, such as the construction of post- and peristimulus
      histograms and cross-correlation analysis, are inadequate for this purpose. These
      methods allow analysis to be applied to neuron spike activity only around each
      synchronization point Their use for studies of a developed program of animal
      actions unavoidably leads to a set of separate histograms providing no
      information on the dynamics of neuron activity corresponding to continuous
      behavior. A complex approach to studying the neuronal correlates of behavior is
      suggested, designed to overcome these difficulties. The method is based on the
      use of a developed behavioral program with recording of several neurons in
      parallel, with analysis of neuron activity using a relative time scale based on
      the duration of each sequentially performed action. Non-traditional methods of
      processing neuron spike activity were developed for analysis of the resulting
      data, including construction of relative histograms and multidimensional
      statistics methods. These approaches allowed us to study the dynamics of neuron
      activity continuously through all the stages of performance of a behavioral
      program and obtain data on the involvement of each group of those neurons which
      were studied in functionally different actions. This methodology was tested using
      studies of the functional characteristics of striatum neurons in monkeys.
      Comparable data were obtained on the individual responses of neurons and on the
      dynamics of their activity at different stages of the animals' performance of a
      multicomponent behavioral program. This revealed the lack of functional
      specialization in striatum neurons and different patterns of their involvement in
      motor and cognitive functions.

PMID- 10651322
TI  - Compensatory restorative processes and operant reflexes in rats after neurotoxin
      lesioning of the inferior olive.
AB  - Studies on rats showed that complete neurotoxin lesioning of the inferior olive
      obviated the possibility of developing and restoring previously learned operant
      balance reflexes. Motor deficit and compensatory-restorative processes in rats
      treated with 3-acetylpyridine and high section of the dorsolateral funiculus of
      the spinal cord depended directly on the level of disruption of the inferior
      olive. Prolonged observation of rats with incomplete lesions to the inferior
      olive revealed improvements in the compensation of motor lesions and
      stabilization of operant reflexes.

PMID- 10651324
TI  - Cyclic GTP imitates the potentiating effect of the nootrope vinpocetine on the
      high-threshold A-current in mollusk neurons.
AB  - Isolated common snail neurons were studied using two-microelectrode potential
      clamping to record high-threshold (threshold = 10 mV) rapidly-inactivating
      potassium current (I(Aht)); the effects of the nootrope vinpocetine on this
      current were studied and were compared with the effects of cyclic nucleotides.
      Intracellular application of dibutyryl derivatives of cyclic adenosine
      monophosphate (dcAMP) and guanosine monophosphate (dcGMP) was used. The results
      showed that vinpocetine potentiates or fails to alter I(Aht) in different cells,
      while dcGMP imitates the effect of vinpocetine. Simultaneous application of
      vinpocetine and dcGMP did not result in additive effects. Unlike dcGMP, dcAMP did
      not imitate the effects of vinpocetine, and decreased I(Aht) in most cells. These
      data suggest that cGMP mediates the potentiating effect of vinpocetine on I(Aht).

PMID- 10651323
TI  - Striatal mechanism of action of corticoliberin on behavior in dogs in conditions
      of dopamine deficiency.
AB  - This report describes studies of the interaction of the integrative dopaminergic
      and corticoliberin systems in the neostriatum during performance of situational
      food-related conditioned reflexes. Studies were performed in dogs with
      chemotrodes implanted in the substantia nigra and the head of the caudate
      nucleus. 6-Hydroxydopamine was injected into the substantia nigra at a dose of 50
      microg, and 10 microg of corticoliberin was injected into the caudate nucleus.
      Blood cortisol and catecholamine levels were determined. Analysis of the result
      showed that an interaction takes place in the neostriatum between the
      corticoliberin and dopaminergic systems, and that in conditions in which
      dopaminergic structures are excluded, the efficacy of corticoliberin in the
      performance of behavioral acts decreases by 30-40%, i.e., complete expression of
      its regulatory role of motor situational conditioned reflexes is lost.

PMID- 10651325
TI  - A micromanipulator for two-channel recording of neuron activity with high
      impedance electrodes in freely moving animals.

PMID- 10651326
TI  - The effects of development of a food-related operant reflex on the receptor
      binding of glutamate in the rat brain.
AB  - Receptor binding of glutamate was studied in the striatum, hippocampus, and
      cerebral cortex of rats with different abilities to acquire an operant food
      related reflex in a Skinner box. The striatum of rapidly-learning rats and rats
      unable to learn showed significantly higher levels of glutamate binding than
      controls were not trained in the Skinner box (p < 0.05). Striatal receptor
      binding of glutamate in slow-learning rats was lower than that in rapidly
      learning rats and rats which were unable to learn (p < 0.05). In the hippocampus,
      all groups of rats (rapidly-learning, slow-learning, and those unable to learn)
      showed increased receptor binding of glutamate as compared with controls (p <
      0.05), in the cerebral cortex, there was a significant decrease in glutamate
      binding as compared with controls in all groups of animals subjected to training
      (p < 0.05).

PMID- 10651327
TI  - Visual evoked potentials in humans during recognition of emotional facial
      expressions.
AB  - Visual evoked potentials were recorded from the occipital, parietal, central,
      frontal, and posterior temporal areas of the cortex during recognition of
      emotionally positive, negative and neutral facial expressions and during passive
      observation in 22 right-handed healthy subjects. These studies showed that in the
      posterior temporal areas, the latencies of the N90, P150, and N180 waves of
      potentials evoked by faces with emotionally negative expressions were
      significantly shorter than those evoked by other types of facial stimuli.
      Differences were seen both on recognition and during passive observation. Correct
      recognition involved both hemispheres and was characterized by high levels of
      interhemisphere temporal correlation of the processes occurring during the
      development of the P150 wave in the posterior temporal and the N180 wave in the
      frontal parts of the cortex. The possible relationship of these data to primary
      subthreshold recognition of facial expressions in the posterior temporal fields
      of the cortex is discussed, as is the role of the frontal cortex in completing
      this process and in taking the correct decision about the nature of the image.

PMID- 10651328
TI  - Visual evoked potentials induced by illusory outlines (Kanizsa's square).
AB  - This report describes studies of visual evoked potentials (VEP) in ten subjects
      produced in response to Kanizsa's square and a control stimulus which did not
      involve a visual illusion but which had a similar spatial organization. The
      results showed that the amplitude-time characteristics of VEP depended on the
      illusory outlines. Differences in the parameters of VEP produced using the two
      stimuli were seen in the occipital, parietal, and temporal areas. VEP amplitude
      differences between the peaks of the N180 and P230 waves increased and the latent
      period of the N300 wave decreased on presentation of the illusory outlines as
      compared with the control stimulus. Interstimulus differences in amplitude were
      seen in the left and right occipital and left temporal areas, while differences
      in latency were seen in the left occipital lead. The data supported the
      suggestion that the visual perception system includes two areas encoding illusory
      outlines, which are associated with different aspects of visual analysis-
      encoding of individual signs and their complexes (O1 and O2) and comparing
      sensory codes with codes stored in memory (T5).

PMID- 10651329
TI  - Retrieval of attention-dependent long-term memory traces.
AB  - The stage of retrieving long-term memory traces is discussed; studies of this
      stage can be performed using the phenomenon of dissociated brain states. These
      states arise in response to various external influences and are accompanied by
      selective, reversible derangements of retrieval processes without alteration of
      the mechanisms involved in perceiving and fixing information. Analysis of the
      appearance of dissociated states induced by pharmacological treatments leads to
      several conclusion: a) reversible derangements affecting the retrieval function
      are typical of types of memory which depend on attention; b) the hippocampus
      plays a key role in selecting engrams for extraction from long-term memory; c)
      the brain's cholinergic and GABAergic mediator systems are involved in regulating
      the retrieval of long-term memory traces; d) stable derangements of the retrieval
      of long-term memory traces are accompanied by deep molecular-cellular changes in
      the hippocampus, including alterations in genetic elements and phosphorylation of
      synaptic proteins.

PMID- 10651330
TI  - Cytochemical parameters of synaptic neurons in rats with different abilities to
      learn a food-procuring habit.
AB  - The characteristics of protein metabolism associated with cognitive activity were
      studied in neurons of layers III and IV of the sensorimotor cortex of rats, using
      two groups of Wistar rats. Regardless of the success of learning, information
      loading was most clearly reflected in the associative neurons of layer III. In
      rats with poor learning ability, these neurons showed increases in nuclear and
      cytoplasmic size, along with increases in protein concentration and content. The
      clearest changes in efferent neurons (layer V) were increases in the area and
      protein content, occurring only in the cytoplasm. In rats with good learning
      outcomes, all cytochemical parameters responded to information loading with
      decreases in layer III and increases in layer V protein contents and
      concentrations, affecting both the cytoplasm and nucleus. The question of whether
      the vector of changes in neuronal protein metabolism in response to information
      loading can be regarded as a measure of the individual features of higher nervous
      activity is discussed, as is the question of whether the magnitude of these
      changes is a measure of the complexity of a cognitive task.

PMID- 10651331
TI  - Reciprocal inhibition of the AMPA and NMDA components of excitatory postsynaptic
      potentials in field CA1 of the rat hippocampus in vitro.
AB  - The mutual effects of components of excitatory postsynaptic potentials (EPSP)
      induced by activation of glutamate receptors sensitive to alpha-amino-3-hydroxy-5
      methyl-4-isoxazole-propionic acid (AMPA) and N-methyl-D-aspartate (NMDA) were
      studied on living slices of rat hippocampus. Evoked responses were recorded in
      the radial layer (stratum radialis) in field CA1 after stimulation of collateral
      commissural fibers. The contribution of the NMDA component to the total EPSP was
      altered by extracellular application of solutions containing different
      concentrations of magnesium. At low magnesium concentrations, when both
      components made significant contributions to EPSP, inhibition of one of the
      components by application of antagonists of the appropriate receptors led to
      increases in the area of the other component. Thus, the total magnitude of
      pharmacologically isolated components were significantly greater than the control
      response (for example, at 0.1 mM magnesium, the sum of the components was 340 +/-
      120% of the control two-component EPSP (p < 0.01; N = 6). These results suggest
      that in controls, the AMPA and NMDA components of EPSP inhibit each other. The
      mutual inhibition of components may be an important factor affecting the
      conductivity and plastic properties of central glutamatergic synaptic pathways.

PMID- 10651332
TI  - The effects of atropine on associative-type ultrastructural postsynaptic
      plasticity in the rat neocortex.

PMID- 10651333
TI  - Neocognitron's parameter tuning by genetic algorithms.
AB  - The further study on the sensitivity analysis of Neocognitron is discussed in
      this paper. Fukushima's Neocognitron is capable of recognizing distorted patterns
      as well as tolerating positional shift. Supervised learning of the Neocognitron
      is fulfilled by training patterns layer by layer. However, many parameters, such
      as selectivity and receptive fields are set manually. Furthermore, in Fukushima's
      original Neocognitron, all the training patterns are designed empirically. In
      this paper, we use Genetic Algorithms (GAs) to tune the parameters of
      Neocognitron and search its reasonable training pattern sets. Four contributions
      are claimed: first, by analyzing the learning mechanism of Fukushima's original
      Neocognitron, the correlations amongst the training patterns are claimed to
      affect the performance of Neocognitron, tuning the Neocognitron's number of
      planes is equivalent to searching reasonable training patterns for its supervised
      learning; second, a GA-based supervised learning of the Neocognitron is carried
      out in this way, searching the parameters and training patterns by GAs but
      specifying the connection weights by training the Neocognitron; third, other than
      traditional GAs which are unsuitable for the large searching space of training
      patterns set, the cooperative coevolution is incorporated to play this role;
      fourth, an effective fitness function is given out when applying the above
      methodology into numeral recognition. The evolutionary computation in our initial
      experiments is implemented based on the original training pattern set, e.g. the
      individuals of the population are generated from Fukushima's original training
      patterns during initialization of GAs. The results prove that our correlation
      analysis is reasonable, and show that the performance of a Neocognitron is
      sensitive to its training patterns, selectivity and receptive fields, especially,
      the performance is not monotonically increasing with respect to the number of
      training patterns, and this GA-based supervised learning is able to improve
      Neocognitron's performance.

PMID- 10651334
TI  - A new measurement of noise immunity and generalization ability for MLPs.
AB  - This paper shows a quantitative relation between the regularization techniques,
      the generalization ability, and the sensitivity of the Multilayer Perceptron
      (MLP) to input noise. Although many studies about these topics have been
      presented, in most cases only one of the problems is addressed, and only
      experimentally obtained evidence is provided to illustrate some kind of
      correlation between generalization, noise immunity and the use of regularization
      techniques to obtain a set of weights after training that provides the
      corresponding MLP with generalization ability and noise immunity. Here, a new
      measurement of noise immunity for a MLP is presented. This measurement, which is
      termed Mean Squared Sensitivity (MSS), explicitly evaluates the Mean Squared
      Error (MSE) degradation of a MLP when it is perturbed by input noise, and can be
      computed from the statistical sensitivities (previously proposed) of the output
      neurons. The MSS provides an accurate evaluation of the MLP performance loss when
      its inputs are perturbed by noise and can also be considered a measurement of the
      smoothness of the error surface with respect to the inputs. Thus, as the MSS can
      be used to evaluate the noise immunity or the generalization ability, it gives a
      criterion to select among different weight configurations that present a similar
      MSE after training.

PMID- 10651335
TI  - DNA fragment assembly using neural prediction techniques.
AB  - The paper describes an alternative approach to the fragment assembly problem. The
      key idea is to train a recurrent neural network to tracking the sequence of bases
      constituting a given fragment and to assign to a same cluster all the sequences
      which are well tracked by this network. We make use of a 3-layer Recurrent
      Perceptron and examine both edited sequences from a ftp site and artificial
      fragments from a common simulation software: the clusters we obtain exhibit
      interesting properties in terms of error filtering, stability and self
      consistency; we define as well, with a certain degree of approximation, a metric
      on the fragment set. The proposed assembly algorithm is susceptible to becoming
      an alternative method with the following properties: (i) high quality of the
      rebuilt genomic sequences, (ii) high parallelizability of the computing process
      with consequent drastic reduction of the running time.

PMID- 10651336
TI  - Recognition of handwritten similar Chinese characters by self-growing
      probabilistic decision-based neural network.
AB  - Recognition of similar (confusion) characters is a difficult problem in optical
      character recognition (OCR). In this paper, we introduce a neural network
      solution that is capable of modeling minor differences among similar characters,
      and is robust to various personal handwriting styles. The Self-growing
      Probabilistic Decision-based Neural Network (SPDNN) is a probabilistic type
      neural network, which adopts a hierarchical network structure with nonlinear
      basis functions and a competitive credit-assignment scheme. Based on the SPDNN
      model, we have constructed a three-stage recognition system. First, a coarse
      classifier determines a character to be input to one of the pre-defined
      subclasses partitioned from a large character set, such as Chinese mixed with
      alphanumerics. Then a character recognizer determines the input image which best
      matches the reference character in the subclass. Lastly, the third module is a
      similar character recognizer, which can further enhance the recognition accuracy
      among similar or confusing characters. The prototype system has demonstrated a
      successful application of SPDNN to similar handwritten Chinese recognition for
      the public database CCL/HCCR1 (5401 characters x200 samples). Regarding
      performance, experiments on the CCL/HCCR1 database produced 90.12% recognition
      accuracy with no rejection, and 94.11% accuracy with 6.7% rejection,
      respectively. This recognition accuracy represents about 4% improvement on the
      previously announced performance. As to processing speed, processing before
      recognition (including image preprocessing, segmentation, and feature extraction)
      requires about one second for an A4 size character image, and recognition
      consumes approximately 0.27 second per character on a Pentium-100 based personal
      computer, without use of any hardware accelerator or co-processor.

PMID- 10651337
TI  - A modular neural network architecture for pattern classification based on
      different feature sets.
AB  - We propose a novel connectionist method for the use of different feature sets in
      pattern classification. Unlike traditional methods, e.g., combination of multiple
      classifiers and use of a composite feature set, our method copes with the problem
      based on an idea of soft competition on different feature sets developed in our
      earlier work. An alternative modular neural network architecture is proposed to
      provide a more effective implementation of soft competition on different feature
      sets. The proposed architecture is interpreted as a generalized finite mixture
      model and, therefore, parameter estimation is treated as a maximum likelihood
      problem. An EM algorithm is derived for parameter estimation and, moreover, a
      model selection method is proposed to fit the proposed architecture to a specific
      problem. Comparative results are presented for the real world problem of speaker
      identification.

PMID- 10651338
TI  - A festschrift to John Elias Skandalakis, M.D., Ph.D., F.A.C.S.

PMID- 10651339
TI  - Benign diagnosis by image-guided core-needle breast biopsy.
AB  - Image-guided core-needle breast biopsy (IGCNBB) is widely used to evaluate
      patients with abnormal mammograms; however, information is limited regarding the
      reliability of a benign diagnosis. The goal of this study was to demonstrate that
      a benign diagnosis obtained by IGCNBB is accurate and amenable to mammographic
      surveillance. Records of all patients evaluated by IGCNBB from July 1993 through
      July 1996 were reviewed. Biopsies were classified as malignant, atypical, or
      benign. All benign cases were followed by surveillance mammography beginning 6
      months after IGCNBB. Of the 1110 patients evaluated by IGCNBB during the study
      period, 855 revealed benign pathology. A total of 728 of the 855 patients (85%)
      complied with the recommendation for surveillance mammography. A total of 196
      IGCNBBs were classified as malignant; 59 cases were classified as atypical. The
      atypical cases were excluded from the statistical analysis. Only two patients
      have demonstrated carcinoma after a benign IGCNBB during the 2-year minimum
      follow-up period. The sensitivity and specificity of a benign result were 100.0
      and 98.9 per cent, respectively. A benign diagnosis obtained by IGCNBB is
      accurate and therefore amenable to mammographic surveillance. The results of this
      study support IGCNBB as the preferred method of evaluating women with abnormal
      mammograms.

PMID- 10651340
TI  - Bronchiolitis obliterans organizing pneumonia mimicking multiple pulmonary
      metastases.
AB  - A 45-year-old woman with no history of cancer presented with a radiological and
      clinical diagnosis of metastatic tumor in the lungs. On the basis of the
      findings, the patient underwent an extensive investigation attempting to locate a
      primary tumor. After an unsuccessful workup, the patient was referred for biopsy,
      which showed findings of bronchiolitis obliterans organizing pneumonia (BOOP).
      This case illustrates that the clinical, roentgenographic, and CT findings of
      BOOP are nonspecific and in some cases can be confused with those of metastatic
      tumor in the lungs.

PMID- 10651341
TI  - Accidental injuries by HIV-contaminated instruments in health provider or
      research environments: can seroconversion be prevented?
AB  - The rate of seroconversion from percutaneous needlestick exposure to HIV
      infection is approximately 0.3 per cent. To investigate the possibility of local
      confinement of HIV, 100 to 200 nm Tc-99m sulfur colloid particles were injected
      in the canine model subcutaneously at the knee level and collected proximally at
      the groin from the cannulated femoral vein and lymphatic channel. Tourniquet
      compression (250 mm Hg) was used as an intervention to possibly restrict particle
      spread. It was found that particles arrived in the blood at 2.81 +/- 0.54
      minutes, with later arrival in the lymph at 6.0 +/- 1.47 minutes. Tourniquet
      application delayed the appearance of the particulate matter in the blood up to
      7.11 +/- 1.5 minutes and in lymph up to 40.0 +/- 5.10 minutes. The concentration
      of radioactivity in the lymph was higher than in the venous blood. The
      distribution of the particles reflected by flux was comparable in both pathways.
      The accumulation curves did not reach plateaus during 45 minutes in lymph and 15
      minutes in blood. Radioactive scanning revealed that about 90 per cent of the
      injected particles remained locally with gradual release for at least 45 minutes.
      Our results suggest that HIV, introduced by needlestick injury, can be contained
      for possible viricidal treatment if the response includes rapid immobilization
      and tourniquet of the area.

PMID- 10651342
TI  - A review of septic shock.
AB  - The mortality of septic shock, both in percentage of septic shock cases and total
      number of septic shock cases, has been increasing over the past several decades.
      This is despite major advances in diagnosis and treatment. The basic cause of
      traumatic and septic shock has only partially been elucidated. This review
      presents information about the basic cause and mechanism of septic shock as well
      as a new treatment based on this information. Data sources include research
      papers on the subject of septic shock from 1875 until the present. These papers
      numbered more than 10,000, most of which are not included in the reference list
      because many are duplicative. The main result of the review of literature is that
      all of a wide variety of treatments of septic shock have not resulted in a
      lowering of mortality, but in fact have increased it. Another toxin (in addition
      to endotoxin and its secondarily induced host mediators) is proposed. This toxin
      causes disseminated intravascular coagulation, which may obstruct the
      microcirculation of any and all organs, producing multiple organ failure by
      microclots. These microclots may be lysed by plasminogen activator and
      circulation to the organs restored.

PMID- 10651343
TI  - Laparoscopic cholecystectomy for an abnormal hepato-iminodiacetic acid scan: a
      worthwhile procedure.
AB  - Patients with symptoms similar to symptomatic cholelithiasis but with no
      sonographic evidence of gallstones can be difficult to manage. Cholecystokinin
      (CCK)-stimulated hepatobiliary scans can be helpful in determining whether the
      biliary tract is the potential source of the symptoms. We retrospectively
      reviewed the medical records of 69 patients at our institution who underwent CCK
      stimulated hepatobiliary scans over a 2-year period. Twenty-nine of 69 patients
      had an abnormal gallbladder ejection fraction (defined as 35% or less). All 29
      patients had no sonographic evidence of cholelithiasis. Seventeen of the 29
      underwent cholecystectomy. There were no complications or deaths within the
      operative group. Fifteen of the pathologic specimens had evidence of chronic
      cholecystitis, one was cytomegalovirus cholecystitis, and one showed only
      cholesterolosis. There was no other intraperitoneal pathology to explain the
      abdominal symptoms. At an average follow-up of 11 months, eight patients (47%) in
      the operative group had complete resolution of their symptoms, six (35%) had
      significant improvement, two (12%) were unchanged, and one (6%) was worse. Twelve
      of 29 patients did not have a cholecystectomy. At an average follow-up of 11
      months, four (33%) of these patients had improvement and eight (66%) reported no
      change or worsening of their symptoms. In the operative group, 53 per cent had
      reproduction of their symptoms with CCK stimulation, and in the nonoperative
      group, 33 per cent reported symptoms. Average gallbladder ejection fraction was
      10 per cent (range, 0-32) in the operative group and 23 per cent (range, 0-35) in
      the nonoperative group. Liver function tests were similar in each group. CCK
      stimulated hepatobiliary scans were helpful in defining biliary tract disease in
      patients without gallstones. These patients may benefit from cholecystectomy with
      minimal risk of morbidity and mortality.

PMID- 10651344
TI  - Percutaneous cholecystostomy is an effective treatment for high-risk patients
      with acute cholecystitis.
AB  - We sought to determine the safety, efficacy, and outcome of percutaneous
      cholecystostomy (PC) in all patients undergoing the procedure at our
      institutions. We reviewed 53 consecutive cases of acute cholecystitis seen at our
      hospitals over 5.5 years in which PC was performed at the initial treatment.
      Follow-up was obtained by chart review and telephone questionnaire. Acute
      cholecystitis was the primary admitting diagnosis in 18 cases. In the remaining
      35, cholecystitis developed during hospitalization. All patients were considered
      high surgical risks on the basis of the presence of comorbid conditions. The
      gallbladder was successfully catheterized under radiologic guidance in all
      patients and with no immediate procedure-related morbidity. Acute cholecystitis
      resolved in 44 of 53 patients (83%), whereas nine patients (17%) did not improve
      clinically after PC and died during the same hospitalization. A total of 33 (62%)
      eventually survived hospitalization. Elective cholecystectomy was done in 25
      patients with no mortality. After cholecystectomy, three of these patients
      subsequently died of other causes, whereas 22 are alive. Eight patients did not
      undergo cholecystectomy because of underlying medical conditions or because they
      had acalculous cholecystitis. These patients remained free of biliary problems
      after removal of their cholecystostomy tube, but two have subsequently died of
      nonbiliary conditions. Percutaneous cholecystostomy is a safe, effective
      treatment for high-risk patients with acute cholecystitis. Cholecystostomy can be
      followed by elective cholecystectomy at a later time if the patient's condition
      permits or by expectant conservative management in patients who have had
      acalculous cholecystitis or have a very high mortality risk with surgery.

PMID- 10651345
TI  - Comparison of tamoxifen with danazol in the management of idiopathic
      gynecomastia.
AB  - Idiopathic gynecomastia, unilateral or bilateral, is a common physical finding in
      normal men. Successful treatment using tamoxifen (antiestrogen) and danazol
      (antiandrogen) has recently been reported. We compared the efficacy of tamoxifen
      and danazol in the treatment of idiopathic gynecomastia. We reviewed the clinical
      records of patients with idiopathic gynecomastia presenting to the Department of
      Surgery, University of Hong Kong, between August 1990 and September 1995. Medical
      treatment with either tamoxifen (20 mg/d) or danazol (400 mg/d) was offered and
      continued until a static response was achieved. The treatment response was
      compared. Sixty-eight patients with idiopathic gynecomastia were seen in the
      Breast Clinic. The median age was 39.5 years (range, 13-82), with a median
      duration of symptoms of 3 months (range, 1-90). The median size was 3 cm (range,
      1-7). Twenty-three patients were treated with tamoxifen and 20 with danazol.
      Complete resolution of the gynecomastia was recorded in 18 patients (78.2%)
      treated with tamoxifen, whereas only 8 patients (40%) in the danazol group had
      complete resolution. Five patients, all from the tamoxifen group, developed
      recurrence of breast mass. In conclusion, hormonal manipulation is effective in
      the treatment of patients with idiopathic gynecomastia. Although the effect is
      more marked for tamoxifen compared with danazol, the relapse rate is higher for
      tamoxifen. Further prospective randomized studies would be useful in defining the
      role of these drugs in the management of patients with idiopathic gynecomastia.

PMID- 10651346
TI  - Fibrin glue reduces intra-abdominal adhesions to synthetic mesh in a rat ventral
      hernia model.
AB  - Postoperative intra-abdominal adhesions are associated with significant morbidity
      and mortality. In this study, the effect of topical fibrin glue (FG) on adhesion
      formation in a rat model was investigated. Forty Sprague-Dawley male rats
      underwent midline laparotomy. Bilateral peritoneal-muscular abdominal wall
      defects were created and then replaced with premeasured soft tissue Goretex
      patches. Rats were randomized to FG sprayed over the patches or to a control
      group. Two observers blinded to the randomization assessed the severity of
      adhesions to the patch by scoring the density of adhesions (grades 0-3) and the
      percentage of the patch area covered by adhesions (0-100%). The mean percentage
      of the patch covered by adhesions was 32.8 +/- 6.1 per cent for the FG group
      versus 57.9 +/- 6.7 per cent for the control group (P < 0.01). The mean density
      of adhesions for the FG group was 0.95 (+/-0.17) versus 2.0 (+/-0.21) for the
      control group (P = 0.001). Topical FG reduces the severity and density of intra
      abdominal adhesions in a rat model.

PMID- 10651347
TI  - Malignant tumors of the small intestine: a review of 144 cases.
AB  - Cancer of the small intestine represents less than two per cent of all the
      malignant tumors of the gastrointestinal tract. Because they are infrequent
      tumors, a review of a tumor registry was performed to analyze response to
      treatment of the disease and prognostic factors. A retrospective review of
      patients with primary cancer of the small intestine was performed using the
      Department of Defense Tumor Registry. The registry was accessed to determine
      stage, types of cancer, intervention, and patient outcomes. TNM staging and
      follow-up were available on 144 patients from 1970 to 1996. Median follow-up was
      38.9 months. There were 92 (64%) males and 52 (38%) females. The median age was
      55.7 years. The types of small intestinal cancer included 68 patients (47%) with
      adenocarcinoma, 41 patients (28%) with carcinoid, 18 patients (13%) with
      leiomyosarcoma, and 17 patients (12%) with lymphoma. The overall 5-year survival
      was 57 per cent and the median survival was 52 months. Survival of patients with
      adenocarcinoma was not dependent on location within the small bowel. Survival was
      best for early-stage tumors and when lesions could be completely resected.

PMID- 10651348
TI  - Schwannoma of the cervical sympathetic chain: it's not a carotid body tumor.
AB  - Schwannoma of the cervical sympathetic chain is a rare nerve tumor with fewer
      than 40 confirmed cases in the English literature. These lesions typically
      present as an asymptomatic neck mass and are easily mistaken for a carotid body
      tumor during the initial workup. We report a case of schwannoma of the cervical
      sympathetic chain in a 35-year-old man followed by a review of the current
      literature.

PMID- 10651349
TI  - Emergency room thoracotomy: a single surgeon's thirteen-year experience.
AB  - Our objectives were to elucidate the postoperative complications in patients who
      have had emergency room thoracotomy (ERT), to define anatomic and physiologic
      parameters that are compatible with survival and to document the evolution of
      management of these patients. A single surgeon's experience over a 13-year period
      was reviewed. All patients where he was the primary or supervising surgeon for
      the ERT were included. Data were analyzed for mechanism (penetrating/blunt),
      hospital where performed, survival to intensive care unit, survival to discharge,
      and postoperative complications. Among survivors, data were analyzed for the
      anatomic injuries and the patients' physiologic condition in the field and on
      arrival. There were a total of 102 patients; penetrating injury 94 (92 percent);
      blunt, 8 (8 percent). Ten patients (10 percent) reached the intensive care unit
      alive. Three of the ten (30 percent) died at 2 hours, 12 hours, and 7 days
      postoperatively. Seven patients survived to hospital discharge. All seven had
      penetrating chest injuries and were not in cardiac arrest when first examined by
      paramedics. Four of the seven survivors (57 percent) had major complications.
      Survival for the early period was 1.6 percent (1/62) and for the later period 15
      percent (6/40); P < 0.05. During the study period, changes in patient management
      included 1) for penetrating torso injury, withholding ERT when survival was
      extremely unlikely; 2) increased use of blood- and fluid-warming measures; 3)
      elimination of aortic cross-clamping, instead judiciously using manual
      compression; 4) making the main purpose of ERT the relief of cardiac tamponade;
      and 5) immediately controlling any cardiac injury with a simple running suture on
      a large needle. We conclude the following: 1) The postoperative course after ERT
      carried significant mortality and morbidity. 2) Compatibility with survival
      required both the absence of cardiac arrest when initially evaluated in the field
      and the presence of penetrating chest injury. 3) Significant changes occurred in
      patient management during this 13-year period. Survival was higher in the latter
      part of this period.

PMID- 10651350
TI  - Adult sacrococcygeal teratomas.
AB  - We report a rare case of a benign adult sacrococcygeal teratoma discovered during
      pregnancy. The cystic mass was confirmed on CT scan and magnetic resonance
      imaging. In the fifth postpartum month, three cysts (1, 2.5, and 6 cm) were
      excised. Pathologically, the specimens contained differentiated tissue from all
      three germ layers, including endocrine tissue within the ectopic exocrine
      pancreas.

PMID- 10651351
TI  - Axillary lymph node dissection in breast cancer: an evolving question?
AB  - Axillary lymph node dissection (ALND) is performed for staging purposes. Sentinel
      lymph node biopsy may decrease the cost and morbidity of ALND. Are there patients
      that the procedure is not indicated avoiding cost and morbidity? We
      retrospectively studied the incidence of lymph node metastasis in 423 patients
      with T1 breast cancer. Thirty-one T1a, 146 T1b, and 246 T1c tumors were seen. The
      mean age was 61 years. Ten per cent were premenopausal, and 84 per cent were
      postmenopausal. Tumor size averaged 1.29 cm. Eighty-one per cent of the tumors
      were node negative and 19 per cent were node positive. One T1a patient (3 per
      cent) had an axillary metastasis, 19 T1b patients (13%), and 61 T1c patients
      (25%) were node positive, respectively. Seventy-three per cent were ER positive.
      Thirty-three patients (8%) died from cancer. Eighty-seven per cent received
      surgery with axillary lymph node dissection (ALND), and three per cent had
      surgery without ALND. Younger age, increased tumor size, premenopausal status,
      and ER negativity affected node positivity rates (P < 0.05). Death from breast
      cancer was more common among node-positive patients (P < 0.05). No difference was
      found regarding the performance of ALND and survival (P > 0.05). We feel that
      ALND can be safely omitted in T1a to reduce the morbidity and the expense of
      breast cancer treatment. In T1b and T1c tumors, the use of ALND is necessary, but
      morbidity and cost can be reduced by the use of sentinel lymph node biopsy.

PMID- 10651352
TI  - Clinical features and prognostic factors associated with adrenocortical
      carcinoma: Lahey Clinic Medical Center experience.
AB  - Adrenocortical carcinoma is a rare tumor associated with a commonly poor
      prognosis. However, data on the natural history and response to therapy of
      patients with this malignancy have often been conflicting. Our objective of this
      retrospective study was to evaluate the clinical course and survival of patients
      with adrenocortical carcinoma and to identify relevant prognostic factors.
      Between 1966 and 1996, 31 patients with histologically documented adrenocortical
      carcinoma were observed at the Lahey Clinic Medical Center. Patient information
      was obtained from chart review. At the time of diagnosis, 48 per cent of patients
      had endocrine symptoms with compatible hormonal studies, 19 per cent had
      involvement of the inferior vena cava by tumor thrombus, and 32 per cent had
      metastatic disease. The median survival time was 17 months (range, 1-205 months)
      for the entire group, and the 5-year survival rate was 26 per cent. Age <54
      years, absence of metastatic disease at the time of diagnosis, and completeness
      of surgical resection were associated with better prognosis. Evaluation of
      survival with the Cox proportional hazards model suggested that age <54 years,
      absence of metastatic disease, and nonfunctioning tumor status were independently
      associated with improved survival. The prognosis of patients with adrenocortical
      carcinoma is poor but appears more favorable in patients <54 years, with
      localized disease, or nonfunctioning tumor status. Complete tumor resection may
      be associated with improved survival.

PMID- 10651353
TI  - Retroperitoneal compartment syndrome after renal transplantation.
AB  - We report the case of a 21-year-old man with end-stage renal disease secondary to
      systemic lupus erythematosus who underwent living related renal transplantation
      and developed an extraperitoneal compartment syndrome postoperatively.

PMID- 10651354
TI  - Intussusception after Roux-en-Y gastric bypass.
AB  - Intussusception is a common pediatric surgical problem. Its occurrence in adults
      is rare and usually involves a specific lead point such as a small bowel tumor or
      other mass. We describe two adults who developed intussusception after Roux-en-Y
      gastric bypass. Signs and symptoms of small bowel obstruction were seen in both
      of these patients, but the responsible pathology was unusual. Because of the
      increasing frequency with which these gastric bypass procedures are being
      performed, a high index of suspicion must be employed when dealing with these
      postoperative patients who present with abdominal complaints.

PMID- 10651355
TI  - Pelvic actinomycosis presenting as malignant large bowel obstruction: a case
      report and a review of the literature.
AB  - Actinomycosis is an infrequent chronic infectious disease. In most cases the
      diagnosis is made postoperatively because of its unusual clinical presentation.
      Moreover, abdominal actinomycosis may mimic cancer, inflammatory bowel disease,
      or diverticulitis. Delay in diagnosis leading to inadequate management and
      unnecessary procedures has been reported. We report the case of a 49-year-old
      woman with large bowel obstruction secondary to extensive pelvic actinomycosis
      involving the rectosigmoid and cecum. She required emergency surgery, which
      involved both resection and colostomy. A review of the literature on abdominal
      actinomycosis during the last 50 years is also reported. Rarely has emergency
      surgery been described in this condition. Although the incidence of actinomycosis
      has decreased, the abdominal-pelvic form has been increasing over the past 10
      years secondary to increased prolonged use of the intrauterine device. As the
      clinical spectrum of actinomycosis has dramatically changed, so have the
      therapeutic considerations. Aggressive surgical management in advanced cases with
      multiorganic involvement seems to have reemerged in recent years. Consideration
      of actinomycosis in a woman with prolonged use of an intrauterine device and
      symptoms of bowel obstruction could help to improve the preoperative diagnosis
      and management of this rare disease.

PMID- 10651356
TI  - Critical decisions in the management of endoscopic perforations of the colon.
AB  - The ideal management of suspected colon perforation following colonoscopy remains
      elusive because the incidence is only 0.1 to 2.0 per cent. The patient with
      obvious perforation deserves immediate exploration, but the patient with
      equivocal findings poses a diagnostic dilemma. We propose an algorithm based on
      the results of water-soluble contrast enema that allows for rapid, definitive
      surgical decision-making. If perforation is confirmed, early operation allows for
      primary repair without resection or colostomy, or if no perforation is
      identified, medical management can be undertaken with confidence. This algorithm
      should ensure that the surgical management of this potentially lethal
      complication is not unnecessarily delayed.

PMID- 10651357
TI  - The French Revolution and the rise of surgery.

PMID- 10651358
TI  - Endoscopic intracranial craniofacial and monobloc osteotomies with the aid of a
      malleable high-speed pneumatic drill: a cadaveric and clinical study.
AB  - Endoscopic techniques are now an accepted part of the surgical armamentarium and
      are used routinely in a number of aesthetic and reconstructive procedures.
      Endoscopic techniques are now being used commonly by plastic surgeons in forehead
      and face lifts. In both craniofacial surgery and in neurosurgery, the application
      of endoscopy potentially allows the surgical team to perform wide dissection of
      the dura mater in a minimally invasive fashion, thereby potentially reducing the
      risk of dural and brain injury. Also reduced by this surgical approach is
      potential injury to the major venous structures, such as the sagittal sinus,
      along with overall reduced bleeding. After an extensive laboratory study of 10
      cadaveric dissections, the authors have refined a new endoscopic technique for
      completing an endoscopic intracranial craniofacial osteotomy. This study was
      conducted in the Department of Pathology at the University of Brno (Czech
      Republic), and was performed as a cooperative multicenter project between the
      University of Palermo, the Albert Einstein College of Medicine/ Montefiore
      Medical Center, the Hospital Infantil de Mexico, "Federico Gomez," and the
      Medtronic Midas Rex Institute, (Fort Worth, TX). During this cadaveric anatomic
      study and using small trephinations and skin incisions the authors were able to
      develop several different craniofacial and endoscopic monobloc procedures. To
      accomplish intracranial and facial osteotomies, a new malleable high-speed drill
      was designed for use in the endoscopic craniofacial approach. Using these newly
      developed cadaveric techniques and instrumentation, the authors performed two
      intracranial craniofacial procedures on children with congenital craniofacial
      anomalies. There would appear to be several significant advantages for the
      craniofacial patient as result of these new techniques: reduced surgical trauma,
      operative bleeding, surgical time, and hospitalization, along with a reduced risk
      of infection. It became quickly apparent, as a result of these cadaveric studies,
      that the learning curve for this endoscopic procedure is quite steep. Tutino M,
      Chico F, Tutino M, Goodrich JT, Ortiz Monasterio F. Endoscopic intracranial
      craniofacial and monobloc osteotomies with the aid of a malleable high-speed
      pneumatic drill: a cadaveric and clinical study.

PMID- 10651359
TI  - Evaluation of velopharyngeal insufficiency with magnetic resonance imaging and
      nasoendoscopy.
AB  - Several radiological methods have been utilized to assess velopharyngeal
      function. The more recent imaging technique, magnetic resonance imaging (MRI),
      which has a number of advantages over radiographic and computed tomographic
      imaging, has been used rarely for evaluating velopharyngeal insufficiency. In
      this study, 5 normal volunteers and 10 patients with surgically repaired cleft
      palate were examined with MRI using midsagittal, coronal, and axial images.
      Nasoendoscopy was also performed to complete and confirm the diagnoses. Complete
      and tight closure of the velopharynx and full backward and upward movement of the
      soft palate was observed in volunteers. In coronal images, medial movement of
      lateral pharyngeal walls could also be seen. Despite this, patients with
      surgically repaired cleft palate had some degree of motion of the soft palate,
      ranging from no movement to maximal movement. In most of the patients, short soft
      palates with restricted motion was seen. MRI visualizes the velopharyngeal
      sphincter in all planes and provides high-resolution images of the soft tissues.
      Objective measurements can be made as well. In this study, MRI and nasoendoscopy
      were used together in the diagnosis of velopharyngeal insufficiency and gave
      satisfactory results.

PMID- 10651360
TI  - Use of tissue expanders with external ports.
AB  - The high number of reconstructive dilemmas brought about by more aggressive
      treatment of congenital malformations and burns has created the need for large
      quantities of donor skin for local coverage. Tissue expansion with external ports
      has become part of the authors' surgical armamentarium. From January 1996 to
      November 1998 the authors placed 34 expanders in 28 patients to correct
      congenital malformations or burn sequelae. The average patient age at the time of
      operation was 6.3 years, the average time of expansion was 49 days, and minimal
      and maximal expansion volume was 60 and 600 cc respectively. Serial injection was
      carried out every 2 days until total expansion was achieved, and the expanded
      area was two to three times as wide as the recipient defect. No major
      complications occurred. The most serious complications of infection and erosion
      of tissue overlying the device occurred in 17.6% of patients. There are several
      advantages to this technique: less tissue dissection, painless injections,
      shorter operating time, and early detection of leaks. Lozano ST, Drucker MZ. Use
      of tissue expanders with external ports.

PMID- 10651361
TI  - The hemideltoid muscle flap.
AB  - The deltoid muscle is a reliable source of well-vascularized tissue for bulk to
      obliterate wounds that particularly involve the adjacent glenohumeral joint. A
      homologue of the gluteus maximus muscle, the deltoid muscle also has two
      independent dominant vascular pedicles, making this a type IIl muscle flap.
      Consequently, the muscle can be split vertically into two halves to form
      hemideltoid flaps, with the undisturbed portion still remaining innervated to
      preserve its function as a major arm abductor-an important point because this
      muscle as a whole is not usually considered expendable. Because of its short
      vascular pedicle, the arc of rotation is limited so that larger defects of the
      shoulder are covered preferably with more traditional alternatives. Hallock GG.
      The hemideltoid muscle flap.

PMID- 10651362
TI  - Utilization of the depressor anguli oris musculocutaneous flap for lip
      reconstruction.
AB  - The authors describe the anatomic aspects and surgical technique of the depressor
      anguli oris musculocutaneous flap for reconstruction of the upper and lower lips.
      Twenty patients were submitted to surgical treatment, 19 for carcinoma and for
      upper lip scar deformity. In all patients the repair was performed with the
      depressor anguli oris musculocutaneous island flap. At the follow-up, lip
      function was satisfactory in 19 patients and unsatisfactory in 1 patient. The
      aesthetic results were considered satisfactory in all patients. The depressor
      anguli oris musculocutaneous island flap is safe for upper and lower lip
      reconstruction, with good functional and aesthetic results, and can be added as a
      new flap for lip reconstruction.

PMID- 10651363
TI  - Oromandibular reconstruction for oncological purposes.
AB  - The authors compared different vascularized bone grafts in 15 patients with
      different oncological diagnoses that were treated with hemimandibulectomy in 9
      patients, total mandibulectomy in 1 patient, resection of the mandible involving
      the anterior arch and the symphysis in 3 patients, 1 patient who underwent a
      segmental mandibular resection, and 1 patient in whom the entire hemimandible was
      reconstructed because of mandibular hypoplasia diagnosed during the resection of
      a parotid neoplasm. The flaps used included fibular free flaps in 11 patients,
      iliac crest in 3 patients, and a radial forearm osteocutaneous flap in 1 patient.
      Two patients had major complications and 1 patient experienced recurrence of the
      primary tumor. The fibular free flap was the preferred method in this series due
      to the size of the defect, which in most patients did not require extensive soft
      tissue reconstruction, and due to the nature of the bone defect involving the
      symphysis and condyle in 9 patients. The different vascularized bone grafts
      provided adequate osseous and soft tissue for oromandibular reconstruction.

PMID- 10651364
TI  - A pilot study of short- and long-term sequelae to rigid fixation across
      metacarpal physes in a baboon model.
AB  - The use of rigid fixation for fractures of the extremities has become
      commonplace. The short- and long-term effects of rigid fixation on the growing
      hand, however, have not been studied thoroughly. In this project, the use of
      rigid fixation across metacarpal growth plates (physes) in growing primate hands
      was examined. The hypothesis to be tested was that long-term placement of rigid
      fixation devices across physes during stabilization of mid-shaft osteotomies will
      cause the physes to close prematurely. Fixation devices with screws placed in the
      epiphysis and left in place for 4 months or 1 year resulted in open physes, in
      support of the null hypothesis. However, in physes plated for 1 year, biochemical
      changes associated with increased bone differentiation were apparent. Findings
      suggest that rigid fixation across physes for as long as 1 year can be used
      appropriately in growing individuals when necessary. However, until additional
      investigation establishes whether the open physes are still capable of producing
      bone-lengthening hypertrophic chondrocytes, caution should be used in long-term
      placement of rigid fixation devices.

PMID- 10651365
TI  - Delayed prefabricated arterial composite venous flaps: an experimental study in
      rabbits.
AB  - Prefabrication of composite arteriovenous flaps with implantation of an
      autologous graft (cartilage) or an alloplastic material (porous polyethylene) was
      studied in 40 rabbits. Abdominal flaps based on bilateral epigastric pedicles
      were elevated. An ear cartilage graft or a porous polyethylene implant was
      inserted under the flap. Two weeks after the operation, 10 flaps with cartilage
      graft and 10 flaps with porous polyethylene were raised, converted to
      arteriovenous flaps, and resutured in place in the experimental groups. In the
      other 20 rabbits of the control groups, the flaps (10 with cartilage graft and 10
      with porous polyethylene) were raised and resutured in place as conventional
      axial flaps. At the end of the second and fourth week postoperatively, samples
      were obtained from the flap tissues (including a part of the graft or
      implantation material) and were prepared for histologic examination in all
      rabbits. The viable areas of all flaps were assessed at the end of fourth week
      after the second operation. The mean survival rates were 99.4%, 99.7%, 99.5%, and
      99.8% in the arteriovenous and control flaps prefabricated with cartilage graft
      and the arteriovenous and control flaps prefabricated with porous polyethylene
      respectively. The features of wound healing in the experimental and control
      groups were similar. The study showed that arteriovenous perfusion can nourish a
      prefabricated flap containing an implanted material (autologous or alloplastic)
      and these 2-week delayed composite flaps have a similar survival rate to delayed
      prefabricated conventional axial flaps.

PMID- 10651366
TI  - A neurocutaneous island flap model: an experimental study in rats.
AB  - Neurocutaneous flaps have been popularized recently in clinical reconstructive
      surgery. However, controversies exist concerning their anatomy and physiology.
      The particular role of neural vasculature in the survival of these skin flaps is
      also quite undefined in the experimental setting, and additional studies on this
      subject are necessary. The goal of this study was to describe a neurocutaneous
      flap in a rat model and to investigate its blood supply. Thirty male Sprague
      Dawley rats weighing 300 to 350 g were used in this study, which was conducted in
      two stages. During the first stage, the lower extremities of 10 rats were
      dissected for the anatomic study of the neurocutaneous flap. A constant cutaneous
      nerve innervating the anterolateral thigh skin was exposed. It arose either from
      the saphenous nerve or the superficial epigastric nerve and was accompanied by a
      constant longitudinal arterial plexus. The tiny neural vessels were conveyed by
      the superficial fascia along their course. A 30 x 30-mm cutaneous island flap,
      which was based only on the cutaneous nerve with its accompanying vessels and a
      strip of superficial fascia, was raised on the anterolateral thigh skin using an
      operating microscope. The well-perfused skin territory was marked after sodium
      fluorescein injection. The stained skin territory was located centrally and
      medially on the whole island flap, and it was approximately 10 x 20 mm. This
      finding was confirmed by the qualitative assessment of the vascularity for this
      skin territory in microangiography. After studying the pedicle anatomy and
      determining the optimal viable skin island, the second stage of the study was
      performed. The remaining 20 rats were divided into two groups. In the
      experimental group (N = 10), a neurocutaneous island flap (10 x 20 mm) was
      outlined on the anterolateral aspect of the thigh at its middle third. It was
      designed in such a way that its short and long axes lay in the center of the
      distance between the anterior superior iliac spine and the anterior aspect of the
      knee joint. After identification and dissection of the neurovascular pedicle, the
      flap was raised in a lateral-to-medial direction without including the deep
      fascia. At this point the flap remained connected only by the pedicle and a strip
      of superficial fascia surrounding it. It was sutured in the same place. In the
      control group (N = 10), the pedicle of the flap was severed and the skin island
      was sutured back as a composite graft. All the experimental flaps survived well.
      In the control group, none of the flaps survived except one that was partially
      viable. The flaps in the experimental group were reelevated as neurocutaneous
      island flaps on day 7 for microangiographic study, and specimens were processed
      for histologic staining. Microangiography revealed the extent of neural
      vasculature and vascularization of the skin through cutaneous perforators.
      Histologic investigation demonstrated the neural vessels that were related
      closely to the superficial fascia. The authors propose a neurocutaneous island
      flap model in the lower extremity of the rat in which the survival of the flap
      depended mainly on the neural arterial supply. It was also demonstrated that the
      superficial fascia played a role as a connective tissue framework for conveying
      tiny neural blood vessels to reach the skin. This model may serve as a
      reproducible and reliable neurocutaneous island flap model for additional studies
      in this field.

PMID- 10651367
TI  - Increased axonal regeneration through a biodegradable amnionic tube nerve
      conduit: effect of local delivery and incorporation of nerve growth
      factor/hyaluronic acid media.
AB  - The authors emphasize the possible pharmacological enhancement of axonal
      regeneration using a specific growth factor/ extracellular media incorporated in
      a biodegradable nonneural nerve conduit material. They investigated the early
      effects on nerve regeneration of continuous local delivery of nerve growth factor
      (NGF) and the local incorporation of hyaluronic acid (HA) inside a newly
      manufactured nerve conduit material from fresh human amnionic membrane. Human
      amnionic membrane contains important biochemical factors that play a major
      neurotrophic role in the nerve regeneration process. The process of manufacturing
      a nerve conduit from fresh human amnionic membrane is described. This nerve
      conduit system was used in rabbits to bridge a 25-mm nerve gap over 3 months. NGF
      was released locally, over 28 days, at the distal end of the tube via a system of
      slow release, and HA was incorporated inside the lumen of the tube at the time of
      surgery. NGF/HA treatment promoted axonal regeneration across the amnionic tube
      nerve conduit (8,962 +/- 383 myelinated axons) 45% better than the nontreated
      amnionic tube group (6,180 +/- 353 myelinated axons). The authors demonstrate
      that NGF/HA media enhances additional axonal regeneration in the amnionic tube
      nerve conduit. This result is secondary to the effect of the amnion promoting
      biochemical factors, in combination with the NGF/HA effect on facilitating early
      events in the nerve regeneration process.

PMID- 10651368
TI  - Hsp72 induction: a potential molecular mediator of the delay phenomenon.
AB  - The molecular basis of enhanced ischemic tissue survival in flaps preconditioned
      by surgical delay is poorly understood. Because elevated expression of so-called
      heat shock or stress proteins has been shown to protect tissues/organs against
      ischemic injury, the authors examined whether the levels of the most highly
      induced stress protein-hsp72-were elevated in delayed muscle flaps using a rat
      muscle flap model. Bilateral latissimus dorsi muscle flaps based on the
      thoracodorsal vessels were elevated in 16 male Sprague-Dawley rats. For each
      animal, one side was selected randomly to undergo preconditioning by surgical
      delay for a 7-day period prior to elevation. Delay was accomplished by preserving
      the thoracodorsal pedicle and a single large distal intercostal perforating
      vessel. After bilateral flap elevation, latissimus dorsi tissue was harvested
      from proximal, central, and distal flap segments 0, 1, 3, and 7 days
      postoperatively (N = 4 for each group), and was analyzed for the expression of
      hsp72 via Western blot analysis. At the time of harvest, flap viability was
      assessed by staining with nitroblue tetrazolium. Flap perfusion was measured
      prior to muscle elevation and harvest using laser Doppler flowmetry. The results
      demonstrate that delayed muscle flaps had significantly greater total perfusion
      (p < 0.05) and survival (p < 0.03) 1, 3, and 7 days after elevation compared with
      the acutely elevated control tissue. Western blot analysis revealed that tissues
      harvested from the delayed flaps expressed substantially higher levels of hsp72
      compared with the acutely elevated control samples. Segmental analysis also
      revealed a proximal > middle > distal expression of hsp72 in the delayed flaps (p
      < 0.05). Flap preconditioning by surgical delay increases the expression of
      hsp72. Moreover, regional differences in hsp72 gene expression are associated
      with differences in perfusion and survival of delayed muscle flaps. These results
      indicate that hsp72 may play a substantial role in mediating the delay
      phenomenon.

PMID- 10651369
TI  - Stewart-Treves syndrome: lymphangiosarcoma following mastectomy.
AB  - Lymphangiosarcoma (LAS) is an aggressive, malignant vascular tumor following long
      lasting chronic lymphedema. Patients with LAS demonstrate a history of breast
      cancer treated by radical mastectomy in the majority of patients. In the 1960s
      the incidence of LAS in patients with a 5-year survival after radical mastectomy
      varied from 0.07 to 0.45%. Today, due to changes in the operative techniques of
      breast cancer, less chronic lymphedema is seen with only a scant number of LAS
      patients. The etiology of this enigmatic tumor is not yet completely understood.
      Histologically, LAS arises from vascular endotheliocytes, and all vascular
      sarcomas originating in the setting of a chronic lymphedema are categorized as
      LAS. There is no standard treatment of LAS. The treatment options include radical
      ablative surgery, radiation therapy, and chemotherapy. The prognosis of LAS is
      poor; long-term survival is the exception. Only early recognition and radical
      surgery offer a chance of cure.

PMID- 10651370
TI  - Congenital midline sinus of the upper lip.
AB  - A rare case of congenital midline sinus of the upper lip is presented. The
      patient had recurrent cellulitis with swelling at the base of the medial crus of
      the right lower lateral cartilage. Excision was performed using the intraoral
      approach. Theories concerning the etiology of the midline sinus of the upper lip
      are discussed.

PMID- 10651371
TI  - Spontaneous exercise-induced thrombosis of the radial artery: a case report and
      literature review.
AB  - A 36-year-old man sustained a thrombosis of the radial artery at the wrist while
      performing bench presses. Surgical exploration six weeks later demonstrated a 7
      cm segmental thrombosis that was successfully bypassed with a reversed vein
      graft. The patient returned to full work duty without symptoms.

PMID- 10651372
TI  - Topical 5-fluorouracil as primary therapy for keratoacanthoma.
AB  - Keratoacanthoma is a common, benign cutaneous neoplasm that displays rapid growth
      on sun-exposed skin. Keratoacanthomas usually involute spontaneously after
      several months but rarely progress to squamous cell carcinoma. Because this is a
      benign, self-limited lesion of exposed skin, effective treatment should emphasize
      patient comfort and cosmetic results in addition to effectiveness. The authors
      present 2 patients with keratoacanthomas treated with topical 5-fluorouracil.
      Both patients had complete resolution of their lesions within 8 weeks. The
      cosmetic result was superb in both patients. Patient satisfaction with this
      therapy was excellent. Treatment can be instituted based on a clinical diagnosis;
      no diagnostic biopsy is necessary. Most keratoacanthomas respond to topical 5
      fluorouracil therapy within 3 weeks, whereas squamous cell carcinomas respond
      poorly. Any lesion that shows a poor response after 3 weeks of therapy or that
      does not resolve within 8 weeks should undergo prompt excisional biopsy for
      definitive diagnosis and treatment. Topical 5-fluorouracil is an effective,
      convenient, relatively inexpensive treatment for keratoacanthoma that produces
      excellent cosmetic results. It should be added to the therapeutic armamentarium
      of all physicians who treat keratoacanthoma.

PMID- 10651373
TI  - Metastatic spinal basal cell carcinoma: a case report and literature review.

PMID- 10651374
TI  - Psychological issues in cosmetic surgery: a functional overview.
AB  - The relevance of psychological issues in cosmetic surgery has been well
      established in the literature. Early articles considered psychopathology to be
      prevalent in the plastic surgery population, whereas more recent views consider
      the typical cosmetic surgery candidate to be more psychologically stable. Despite
      these changes, the potential for psychopathology continues to be recognized.
      Consequently, screening for psychopathology during the preoperative interview has
      remained essential. To facilitate a working knowledge of psychological issues
      that may be useful in preoperative screening, this article reviews the current
      literature on the psychology of plastic surgery. In addition to discussing the
      psychological impact of cosmetic surgery, patient's motivations and expectations
      for surgery are discussed in the context of self-image. After reviewing potential
      types of psychopathology, various preoperative screening techniques are
      discussed.

PMID- 10651375
TI  - Psychiatric patients who desire aesthetic surgery: identifying the problem
      patient.
AB  - Plastic surgeons are often confronted with psychiatric patients seeking aesthetic
      surgery. It is imperative for surgeons to recognize underlying psychiatric
      illnesses and to acknowledge their influence over patient motives and judgment.
      It is the goal of this paper to present the defining characteristics of the major
      psychiatric disorders as illustrated in the Diagnostic and Statistical Manual of
      Mental Disorders, fourth edition, in a manner that will allow plastic surgeons to
      incorporate and utilize this information in daily practice. It is the authors'
      hope that this paper will assist plastic surgeons in ultimately preventing
      patient dissatisfaction within the population of patients with psychiatric
      disorders.

PMID- 10651376
TI  - Damn the Yankees. Damn the truth.

PMID- 10651377
TI  - Re: Closure of chronic abdominal wall defects: a long-term evaluation of the
      components selection method.

PMID- 10651378
TI  - Eosinophilic granuloma of the orbit producing extensive bony destruction in a 32
      month-old male infant.

PMID- 10651379
TI  - A practical method of needle retrieval and grasping microsurgery.

PMID- 10651380
TI  - Effects of the Er:YAG laser on cartilaginous tissue.

PMID- 10651381
TI  - Necrotizing fasciitis after underlying illness and steroid intake.

PMID- 10651382
TI  - Anterior chest wall reconstruction with cervicohumeral flap.

PMID- 10651383
TI  - Patients' worries regarding laser resurfacing.

PMID- 10651384
TI  - New uses for old drugs in HIV infection: the role of hydroxyurea, cyclosporin and
      thalidomide.
AB  - The tenacious effort to develop new, specific agents to treat HIV infection is
      currently accompanied by a reconsideration of existing drugs on the basis of
      their known or putative effects on the retroviral life cycle and/or the tuning of
      immune mechanisms. Three specific 'older' compounds that interfere with HIV
      infection by both a direct antiviral activity, and a modulation of T-cell
      activation and proliferation have received the most attention. Hydroxurea, a
      classical chemotherapeutic agent, inhibits retroviral reverse transcription by
      targeting a cellular enzyme responsible for the synthesis of deoxynucleoside
      triphosphates. It may also have a role in reducing viral load while maintaining
      low numbers of potential target T cells. Beneficial effects of hydroxyurea in
      combination with didanosine and/or stavudine on viral load have been shown in a
      number of clinical trials. Cyclosporin, a known immunosuppressant, blocks the
      activation of T cells, hence reducing the permissivity to HIV, and also prevents
      proper HIV virion maturation. However, clinical studies have produced conflicting
      results in HIV-infected patients with regard to immunological and disease effects
      and toxicity. Thalidomide may have antiretroviral effects as a result of its
      primarily inhibitory effects on the production of tumour necrosis factor alpha
      (TNFalpha). TNFalpha induces expression of HIV from chronically infected cell
      lines by stimulating a cellular transcription factor, and blocking of TNFalpha
      stimulated HIV replication by thalidomide has been shown in vitro and ex vivo.
      However, the effects on TNFalpha production in vivo have been inconsistent.
      Thalidomide has shown potential in treating some AIDS-related conditions
      [cachexia (weight loss and muscle wasting), and aphtous oral, oesophageal or
      genital ulcers]. However, because of its numerous and major adverse effects,
      thalidomide should always be used cautiously. In summary, some older drugs have
      potential as anti-HIV agents and offer the advantage of extensive clinical
      experience in other therapeutic areas. They should be considered as potential
      partners for the products emerging from more recent research and development.

PMID- 10651385
TI  - Platelet glycoprotein IIb/IIIa receptor antagonists: current concepts and future
      directions.
AB  - Platelets play a key role in the development of thrombosis. Glycoprotein (GP)
      IIb/IIIa antagonists are a new class of potent drugs that profoundly inhibit
      platelet function by blocking the key receptor involved in platelet aggregation.
      Several antiplatelet agents with varying characteristics have emerged in the past
      few years and have been evaluated in a variety of potential clinical settings.
      Clinical trials have established the effectiveness of these drugs in conditions
      where thrombosis plays a major contributing role such as unstable angina
      pectoris, myocardial infarction, and high-risk coronary intervention. Despite
      their potent antiplatelet effects, GP IIb/IIIa antagonists appear to be
      remarkably well tolerated, provided that the concomitant use of other
      anticoagulants such as heparin is managed carefully. Ongoing and future studies
      will further refine the role of GP IIb/IIIa antagonists, explore new
      applications, and further test their safety and cost effectiveness in the short
      and long term.

PMID- 10651386
TI  - Chemotherapy for retinoblastoma: a current topic.
AB  - Retinoblastoma is the most common primary intraocular tumour in children, with an
      incidence of 1 in 15,000 live births. Treatment strategies for retinoblastoma
      have gradually evolved over the past few decades. There has been a trend away
      from enucleation (removal of the eye) and external beam radiation therapy toward
      focal 'conservative' treatments. Every effort has been made to save the child's
      life with preservation of eye and sight, if possible. Primary enucleation
      continues to be the commonly used method of treatment for retinoblastoma. It is
      employed in situations where eyes contain large tumours, long standing retinal
      detachments, neovascular glaucoma and suspicion of optic nerve invasion or
      extrascleral extension. Most of these eyes either have or are expected to have no
      useful vision. Radiation therapy continues to be an effective treatment option
      for retinoblastoma. However, external beam radiotherapy has unfortunately been
      associated with secondary non-ocular cancers in the field of radiation (primarily
      in children carrying the RB-1 germline mutation). Ophthalmic plaque brachytherapy
      has a more focal and shielded radiation field, and may carry less risk.
      Unfortunately, its applicability is limited to small to medium-sized
      retinoblastomas in accessible locations. Cryotherapy and transpupillary
      thermotherapy (TTT) have been used to provide control of selected small tumours.
      TTT is an advanced laser system adapted to the indirect ophthalmoscope which
      provides flexible nonsurgical treatment for small retinoblastomas. Recent
      research in the treatment of retinoblastoma has concentrated on methods of
      combining chemotherapy with other local treatment modalities (TTT, radiotherapy,
      cryotherapy). This approach combines the principle of chemotherapeutic debulking
      in paediatric oncology with conservative focal therapies in ophthalmology. Termed
      chemoreduction, intravenous or subconjunctival chemotherapy is used to debulk the
      initial tumour volume and allow for local treatment with TTT, cryotherapy and
      plaque radiotherapy. Cyclosporin has been added to the chemotherapy regimen in
      several centres. Other clinical settings where chemotherapy is considered are
      situations where the histopathology suggests a high risk for metastatic disease
      and where there is extraocular extension. There is no consensus that chemotherapy
      is needed when choroidal invasion is observed on histopathology. However, in
      patients where the retinoblastoma is noted beyond the cut end of the optic nerve
      or if there is disruption of the sclera with microscopic invasion of the orbital
      tissue, treatment has been helpful. Systemic and intrathecal chemotherapy with
      local and cranial radiotherapy has improved the survival of these patients. Most
      recently, the use of new chemotherapy modalities with haematopoietic stem cell
      rescue or local radiotherapy has increased the survival of patients with distant
      metastasis. Nevertheless, the prognosis of patients with central nervous system
      involvement is still poor.

PMID- 10651387
TI  - Guidelines for stroke prevention in patients with atrial fibrillation.
AB  - Atrial fibrillation (AF) is a major independent risk factor for stroke. AF is
      most commonly associated with nonvalvular cardiovascular disease and is
      especially frequent among the elderly. The annual risk for stroke in patients
      with AF is approximately 5% with a wide range depending on the presence of
      additional risk factors. For patients who cannot successfully be converted and
      maintained in normal sinus rhythm (NSR), antithrombotic therapy is an effective
      method for preventing stroke. The 2 drugs which are indicated for stroke
      prophylaxis in patients with AF are warfarin and aspirin. For primary prevention,
      warfarin reduces the risk of stroke approximately 68%. Aspirin therapy is less
      effective, resulting in a 20 to 30% risk reduction. Combination therapy with
      aspirin and low intensity warfarin adjusted to an International Normalised Ratio
      (INR) of 1.2 to 1.5 has not been shown to be superior to standard intensity
      warfarin with a target INR of 2.0 to 3.0. In patients with AF and a prior history
      of stroke or transient ischaemic attack (TIA), the absolute risk reduction with
      warfarin is even greater because of the high risk of stroke in this population.
      In contrast, aspirin has not been shown to significantly reduce the risk of
      stroke in patients with AF when used for secondary prevention. When appropriately
      managed, warfarin is associated with a low risk of major bleeding. In controlled
      trials of highly selected patients, the annual rate of intracranial haemorrhage
      (ICH) with warfarin was approximately 0.3%. Studies have shown that specialty
      anticoagulation clinics can achieve similar low rates of major bleeding. However,
      these results cannot be extrapolated to the general population. Factors which
      have been identified as predictors of bleeding include advanced age, number of
      medications and most importantly, the intensity of anticoagulation. INR values
      above 4.0 have been associated with an increased risk of major bleeding while
      values below 2.0 have been associated with thrombosis. Slow careful dosage
      titration, regular laboratory monitoring and patient education can substantially
      reduce the risk of complications. In patients with AF, antithrombotic therapy has
      been shown to be cost effective. For high risk patients, warfarin is the most
      cost-effective therapy, provided the risks for bleeding are minimised. In
      contrast, aspirin is the most cost-effective agent for low risk patients. Current
      practice guidelines for stroke prophylaxis recommend warfarin (target INR 2.5:
      range 2.0 to 3.0) for AF patients at high risk for stroke including those over 75
      years of age or younger patients with additional risk factors. Aspirin should be
      reserved for low risk patients or those unable to take warfarin. Although these
      recommendations are strongly supported by the clinical trial evidence, studies
      show that many patients are not receiving appropriate antithrombotic therapy. In
      particular, warfarin is underutilised in high risk elderly patients. Additional
      studies are needed to identify barriers that prevent implementation of the
      clinical trial findings into clinical practice.

PMID- 10651388
TI  - A practical guide to the management of hypertension in renal transplant
      recipients.
AB  - Hypertension as well as hypotension can be harmful to a newly transplanted renal
      allograft. Elevated blood pressure is also a major risk factor for cardiovascular
      death, which is a frequent occurrence despite successful renal transplantation.
      Renal artery stenosis, immunosuppressive drugs, chronic rejection, retained
      native kidneys, and excessive extracellular fluid volume may all contribute to
      post-transplant hypertension. Antihypertensive agents are widely used in the
      management of post-transplant hypertension. Careful clinical judgement and
      knowledge of the pharmacology, pharmacodynamics, pharmacokinetics, adverse drug
      reaction profiles, potential contraindications, and drug-drug interactions of
      antihypertensive agents are important when therapy with antihypertensive drugs is
      initiated in renal transplant recipients. Since blood pressure elevation in any
      individual is determined by a large number of hormonal and neuronal systems, the
      effect of antihypertensive agents on the allograft should be considered a
      critical factor in the management of hypertension in renal transplant recipients.
      Most renal transplant recipients have other risk factors for premature
      cardiovascular death such as diabetes mellitus, hypercholesterolemia, insulin
      resistance, obesity, left ventricular hypertrophy and ischaemic heart disease.
      Initial antihypertensive therapy should be tailored individually according to the
      patient's risk factors. A realistic therapeutic goal for blood pressure
      management in the initial post-operative state is a systolic blood pressure <160
      mm Hg and a diastolic blood pressure <90 mm Hg with lower pressure targets
      becoming applicable late post-transplantation.

PMID- 10651389
TI  - Daclizumab: a review of its use in the prevention of acute rejection in renal
      transplant recipients.
AB  - The humanised monoclonal antibody daclizumab is an immunosuppressive agent that
      reduces acute rejection in renal transplant recipients. It is specific for the
      alpha subunit (Tac/CD25) of the interleukin-2 (IL-2) receptor on activated T
      cells and achieves immunosuppression by competitive antagonism of IL-2-induced T
      cell proliferation. Daclizumab has advantages over murine antibodies to the IL-2
      receptor, including improved effector function, a low potential for
      immunogenicity and long elimination half-life. When added to standard cyclosporin
      based immunosuppressive therapy with or without azathioprine, daclizumab (1 mg/kg
      prior to surgery and once every 2 weeks thereafter for a total of 5 doses)
      significantly reduced the 6-month rate of acute rejection compared with placebo
      in 2 phase III studies. The mean number of rejection episodes was significantly
      reduced and the time to first acute rejection significantly increased in
      daclizumab versus placebo recipients. Patient survival at 1 year after
      transplantation was significantly higher with daclizumab than placebo in 1 study
      and showed a trend in favour of the drug in the other study. The 1-year graft
      survival rate tended to be greater in daclizumab than in placebo recipients in
      both studies, In a phase II study, acute rejection rates in patients treated with
      both daclizumab and mycophenolate mofetil (plus standard cyclosporin-based
      immunosuppression) were lower than those achieved with mycophenolate mofetil
      alone. Preliminary results indicate that daclizumab is also a useful agent in
      paediatric renal transplant recipients. Further investigation of the efficacy and
      tolerability of the drug in this patient group is clearly warranted. Daclizumab
      does not increase the incidence of adverse events when added to standard
      cyclosporin-based therapy. The incidence of opportunistic infections,
      lymphoproliferative disorders and malignancies was not increased above that seen
      with placebo. CONCLUSIONS: Although the effects of daclizumab on long term graft
      and patient survival require further investigation, available data indicate that
      daclizumab is an important advance in renal transplant immunosuppression,
      reducing acute graft rejection without affecting the tolerability of standard
      cyclosporin-based immunosuppression.

PMID- 10651390
TI  - Dofetilide: a review of its use in atrial fibrillation and atrial flutter.
AB  - Dofetilide is a 'pure' class III antiarrhythmic agent which has demonstrated
      efficacy in the conversion of atrial fibrillation or flutter to sinus rhythm and
      the maintenance of sinus rhythm. By blocking the rapid component of the cardiac
      delayed rectifier potassium current (I(Kr)), dofetilide prolongs the cardiac
      action potential duration and the effective refractory period. This is thought to
      increase the likelihood of a re-entrant wavefront encountering refractory tissue
      and terminating the arrhythmia. Preliminary findings from the EMERALD (European
      and Australian Multicenter Evaluative Research on Atrial Fibrillation Dofetilide)
      and SAFIRE-D (Symptomatic Atrial Fibrillation Investigation and Randomized
      Evaluation of Dofetilide) studies suggest that oral dofetilide is effective in
      the conversion of atrial fibrillation or flutter to sinus rhythm. Both studies
      have yet to be published in full. In SAFIRE-D, dofetilide 500microg twice daily
      for 3 days achieved a conversion rate of 32% compared with a 1% rate for placebo.
      A similar conversion rate was achieved after 3 days in EMERALD with dofetilide
      500microg twice daily (29%) which was significantly greater than that achieved
      with sotalol 80mg twice daily (6%; p < 0.05). Oral dofetilide also appears to be
      effective in the maintenance of sinus rhythm. An abstract report of EMERALD
      participants who had been converted to sinus rhythm showed that 71% of patients
      who received oral dofetilide remained in sinus rhythm after 6 months (compared
      with 26% of placebo and 59% of sotalol recipients: both p < 0.05). Restoration of
      sinus rhythm using intravenous dofetilide is more likely in patients with recent
      onset versus prolonged-duration arrhythmia, and in those with atrial flutter
      rather than atrial fibrillation. Limitations of comparative data for intravenous
      dofetilide are such that few conclusions can be drawn. Although generally well
      tolerated in clinical trials, dofetilide has proarrhythmic potential. Torsade de
      pointes ventricular tachycardia was reported in up to 3.3% of patients who
      received oral dofetilide in the DIAMOND (Diamond Investigations of Arrhythmia and
      Mortality on Dofetilide) studies, although only a small proportion of patients in
      these studies had atrial fibrillation; most episodes occurred within the first 3
      days. Whether the propensity of dofetilide for this life-threatening arrhythmia
      is similar to that of other class III antiarrhythmic agents has yet to be
      determined. Importantly, the long term use of oral dofetilide in patients at high
      risk for sudden cardiac death is not associated with an increased risk of
      mortality, although these DIAMOND findings cannot necessarily be extrapolated to
      patients with atrial fibrillation. CONCLUSIONS: Dofetilide offers an alternative
      to currently available antiarrhythmic agents for the pharmacological conversion
      of atrial fibrillation or atrial flutter to sinus rhythm and for the maintenance
      of sinus rhythm after cardioversion. However, further comparative data are
      necessary before its definitive place can be determined.

PMID- 10651392
TI  - Didanosine: an updated review of its use in HIV infection.
AB  - Didanosine, like zidovudine, stavudine and lamivudine, is a nucleoside analogue
      reverse transcriptase inhibitor (NRTI). In the target cell for HIV, didanosine is
      converted to its active moiety, dideoxyadenosine-5'-triphosphate (ddATP), which
      inhibits HIV reverse transcriptase and terminates viral DNA growth. It is now
      well established that didanosine therapy produces beneficial effects on
      virological and immunological markers of HIV disease and improves clinical
      outcome in adults or children with HIV infection. In numerous clinical trials,
      pronounced and sustained decreases in plasma HIV RNA levels and increases in CD4+
      cell counts occurred in previously untreated or antiretroviral therapy
      experienced patients treated with didanosine in combination with at least 1 other
      antiretroviral drug; zidovudine, stavudine, lamivudine, nevirapine, nelfinavir
      and hydroxyurea (hydroxycarbamide) are among the drugs that have been given in
      combination with didanosine. Of note, HIV RNA levels decreased to below the
      limits of detection in some patients receiving triple or dual therapy with
      didanosine-containing regimens. In double-blind, placebo-controlled trials,
      triple therapy with didanosine, zidovudine and nevirapine was significantly more
      effective than dual therapy with various combinations of these agents in
      improving surrogate disease markers in treatment-naive patients and in delaying
      disease progression or death in treatment-experienced patients with advanced
      disease. Improvements in virological and immunological markers were greater with
      didanosine-containing triple regimens than with dual therapy or monotherapy in
      comparative trials. Triple therapy with didanosine, stavudine and indinavir
      showed efficacy similar to that of various other triple therapy regimens in
      nonblind comparative trials. Comparator regimens included combinations of
      stavudine, lamivudine plus indinavir, zidovudine, lamivudine plus indinavir and
      didanosine, stavudine and nevirapine. Combination therapy with didanosine plus
      hydroxyurea as dual therapy or with a third agent produced marked and sustained
      decreases in HIV RNA levels in the plasma and in lymph nodes. Combination therapy
      with didanosine and zidovudine delays disease progression and prolongs survival
      in patients with intermediate or advanced HIV infection. In large, randomised,
      double-blind, clinical trials, dual therapy with didanosine plus zidovudine was
      significantly more effective than zidovudine monotherapy in preventing disease
      progression and prolonging survival in previously untreated or antiretroviral
      therapy-experienced patients with intermediate or advanced HIV infection.
      Pancreatitis and peripheral neuropathy are serious adverse effects of didanosine.
      These effects are dose-related and usually reversible after discontinuation of
      treatment. Nausea, vomiting, diarrhoea and/or abdominal pain have been reported
      in patients receiving treatment with the drug. CONCLUSIONS: Didanosine is an
      effective and generally well tolerated drug in previously untreated and
      antiretroviral therapy-experienced patients with HIV infection. Given once or
      twice daily, it has an important role as a component of triple combination
      regimens for the treatment of patients with symptomatic or asymptomatic HIV
      infection.

PMID- 10651393
TI  - Leflunomide: a review of its use in active rheumatoid arthritis.
AB  - A77 1726, the active metabolite of leflunomide, is an immunomodulator which
      inhibits cell proliferation in activated lymphocytes in patients with active
      rheumatoid arthritis. Because A77 1726 has a long half-life (approximately 2
      weeks), treatment with oral leflunomide is initiated with a loading dose of 100mg
      once daily for 3 days and continued with 20mg once daily. Results of large
      randomised, double-blind, multicentre trials of up to 24 months' duration have
      shown that leflunomide is significantly superior to placebo and at least as
      effective as sulfasalazine in improving primary outcome measures, such as tender
      joint counts, swollen joint counts and physicians' and patients' global
      assessment, in adult patients with active rheumatoid arthritis. Whereas
      improvement in all primary outcome measures with leflunomide was similar to or
      significantly less than that with methotrexate after 12 months, the efficacy of
      both agents was similar after 24 months. The therapeutic effect of leflunomide
      appears earlier (at 4 weeks) than that of sulfasalazine or methotrexate, and
      reduction from baseline values in functional disability was significantly greater
      with leflunomide than with sulfasalazine, methotrexate or placebo at end-point.
      Leflunomide was at least as effective as sulfasalazine or methotrexate in
      delaying the rate of radiological progression of disease. The most common adverse
      events reported in patients receiving leflunomide in randomised double-blind,
      placebo-controlled trials were diarrhoea (27%), respiratory infections (21%),
      nausea (13%), headache (13%), rash (12%), increased serum hepatic
      aminotransferases (10%), dyspepsia (10%) and alopecia (9%). Leflunomide was as
      well tolerated as sulfasalazine or methotrexate in clinical trials. Monitoring of
      serum hepatic enzyme levels is recommended in patients receiving leflunomide. The
      drug is not recommended in female patients who are or may become pregnant. Drug
      treatment should be discontinued, and hastened drug elimination procedure should
      be considered, in male patients wishing to father a child. 16 potential cases of
      pancytopenia and 9 cases of serious skin reactions have been associated with the
      use of leflunomide in 76,000 patients to date. CONCLUSIONS: Leflunomide is a
      disease-modifying antirheumatic drug which reduces the signs and symptoms of
      inflammatory arthritis and delays the radiological progression of disease in
      adult patients with active rheumatoid arthritis. The drug appears to be as
      effective and as well tolerated as sulfasalazine or methotrexate, and represents
      a suitable alternative to these agents in adult patients with active rheumatoid
      arthritis. Benefits with leflunomide are evident within 4 weeks and efficacy is
      maintained for durations of up to 24 months.

PMID- 10651391
TI  - Quinupristin/dalfopristin: a review of its use in the management of serious gram
      positive infections.
AB  - Quinupristin/dalfopristin is the first parenteral streptogramin antibacterial
      agent, and is a 30:70 (w/w) ratio of 2 semisynthetic pristinamycin derivatives.
      The combination has inhibitory activity against a broad range of gram-positive
      bacteria including methicillin-resistant staphylococci, vancomycin-resistant
      Enterococcus faecium (VREF), drug-resistant Streptococcus pneumoniae, other
      streptococci, Clostridium perfringens and Peptostreptococcus spp. The combination
      also has good activity against selected gram-negative respiratory tract pathogens
      including Moraxella catarrhalis, Legioniella pneumophila and Mycoplasma
      pneumoniae. Quinupristin/dalfopristin has poor activity against E. faecalis. The
      combination is bactericidal against staphylococci and streptococci, although
      constitutive erythromycin resistance can affect its activity. As for many other
      agents, quinupristin/dalfopristin is generally bacteriostatic against E. faecium.
      In patients with methicillin-resistant S. aureus (MRSA) or VREF infections
      participating in prospective emergency-use trials, quinupristin/dalfopristin 7.5
      mg/kg every 8 or 12 hours achieved clinical or bacteriological success in > or
      =64% of patients. Emergence of resistance to quinupristin/dalfopristin was
      uncommon (4% of patients) in those with VREF infections.
      Quinupristin/dalfopristin 7.5 mg/kg 8- or 12-hourly also achieved similar
      clinical success rates to comparator agents in patients with presumed gram
      positive complicated skin and skin structure infections or nosocomial pneumonia
      (administered in combination with aztreoman) in 3 large multicentre randomised
      trials. Systemic adverse events associated with quinupristin/dalfopristin include
      gastrointestinal events (nausea, vomiting and diarrhoea), rash and pruritus.
      Myalgias and arthralgias also occur at an overall incidence of 1.3%, although
      higher rates (2.5 to 31%) have been reported in patients with multiple
      comorbidities. Venous events are common if the drug is administered via a
      peripheral line; however, several management options (e.g. use of central venous
      access, increased infusion volume) may help to minimise their occurrence.
      Hyperbilirubinaemia has been documented in 3.1% of quinupristin/dalfopristin
      recipients versus 1.3% of recipients of comparator agents.
      Quinupristin/dalfopristin inhibits cytochrome P450 3A4 and therefore has the
      potential to increase the plasma concentrations of substrates of this enzyme.
      CONCLUSIONS: Quinupristin/dalfopristin, the first parenteral streptogramin,
      offers a unique spectrum of activity against multidrug-resistant gram-positive
      bacteria. In serious gram-positive infections for which there are other treatment
      options available, the spectrum of activity and efficacy of quinupristin/
      dalfopristin should be weighed against its tolerability and drug interaction
      profile. However, in VREF or unresponsive MRSA infections, where few proven
      treatment options exist, quinupristin/dalfopristin should be considered as a
      treatment of choice for these seriously ill patients.

PMID- 10651396
TI  - Computer-based radiation safety training for hospital radiation workers.
AB  - Conducting a hospital-based radiation safety training class may lead to temporary
      technologist staffing shortages resulting in a reduction of patient services or
      even the cessation of all routine patient services. Use of an interactive
      computer-based radiation safety training software program may provide a practical
      alternative for hospital diagnostic and therapeutic radiation departments, as
      well as other hospital departments utilizing radiation sources, in meeting annual
      radiation safety training requirements for radiation workers. Medical radiation
      workers' participation in computer-based radiation safety training can make a
      positive impact on radiation safety awareness in the hospital, assist license
      holders in satisfying regulatory training requirements, ensure maximum
      participation of staff technologists, and reduce the burden of technologist
      staffing shortages caused by traditional methods of training.

PMID- 10651395
TI  - Overdose risk with selective serotonin reuptake inhibitors.

PMID- 10651397
TI  - An alternative for cost-effective remediation of depleted uranium (DU) at certain
      environmental restoration sites.
AB  - Numerous sites in the United States and around the world are contaminated with
      depleted uranium (DU) in various forms. A prevalent form is fragmented DU
      originating from various scientific tests involving high explosives and DU during
      weapon development programs, at firing practice ranges, or war theaters where DU
      was used in armor-piercing projectiles. The contamination at these sites is
      typically very heterogeneous, with discreet, visually identifiable DU fragments
      mixed with native soil. That is, the bulk-averaged DU activity is quite low,
      while specific DU fragments, which are distinct from the soil matrix, have much
      higher specific activity. DU is best known as a dark, black metal that is nearly
      twice as dense as lead, but DU in the environment readily weathers (oxidizes) to
      a distinctive bright yellow color that is readily visible. While the specific
      activity (amount of radioactivity per mass of soil) of DU is relatively low and
      presents only a minor radiological hazard, the fact that it is radioactive and
      visually identifiable makes it desirable to remove the DU "contamination" from
      the environment. The typical approach to conducting this DU remediation is to use
      radiation detection instruments to identify the contaminant and separate it from
      the adjacent soil, packaging it for disposal as radioactive waste. This process
      can be performed manually or by specialized, automated equipment. Alternatively,
      in certain situations a more cost-effective approach might be simple mechanical
      or gravimetric separation of the DU fragments from the host soil matrix. At
      SNL/NM, both the automated and simple mechanical approaches have recently been
      employed. This paper discusses the pros/cons of the two approaches.

PMID- 10651398
TI  - A custom-built shielded storage cabinet for LLRW.
AB  - A shielded storage cabinet has been designed to eliminate the problems associated
      with the use of storage pits for the decay-in-storage of short-lived low-level
      radioactive waste (LLRW).

PMID- 10651394
TI  - Indinavir: a review of its use in the management of HIV infection.
AB  - Indinavir is a protease inhibitor used in the treatment of patients with HIV
      infection. Combination antiretroviral therapy with indinavir plus 2 nucleoside
      reverse transcriptase inhibitors (NRTIs) is associated with greater reductions in
      viral load, greater increases in CD4+ cell counts, and reduced morbidity and
      mortality when compared with 2 NRTIs alone. In the landmark clinical trial ACTG
      320, the rate of progression to AIDS or death (primary end-point) among
      zidovudine-experienced patients treated with indinavir, zidovudine and lamivudine
      was approximately half that of patients who received only zidovudine plus
      lamivudine (6 vs 11%; p < 0.001). The durability of an indinavir-containing
      regimen was demonstrated in Merck protocol 035, an ongoing trial in which a
      significant proportion of patients had sustained viral suppression for up to 3
      years. Merck protocol 039, also an ongoing trial, showed a greater effect on
      surrogate markers of HIV disease progression with indinavir-based triple therapy
      than with zidovudine plus lamivudine or indinavir monotherapy in patients with
      advanced disease (median baseline CD4+ count 15 cells/microL). Numerous
      additional clinical trials have established the beneficial antiviral and
      immunological effects of indinavir in both antiretroviral-naive and -experienced
      patients with HIV infection. Indinavir is associated with various drug class
      related adverse events, including gastrointestinal disturbances (e.g. nausea,
      diarrhoea), headache and asthenia/fatigue. A lipodystrophy syndrome has been
      commonly reported with indinavir and other protease inhibitors combined with
      NRTIs, but it has also been reported in many protease inhibitor-naive patients,
      and a definitive causal link has not been established between the syndrome and
      protease inhibitors. Nephrolithiasis may develop in about 9% of patients
      receiving indinavir but does not appear to be associated with other protease
      inhibitors; <0.5% of patients receiving indinavir discontinue the drug because of
      nephrolithiasis, which may be the extreme end of a continuum of crystal-related
      renal syndromes. Additional renal problems (e.g. nephropathy) have been reported
      in small numbers of patients receiving indinavir. In summary, indinavir is a
      protease inhibitor with well documented efficacy when used as part of combined
      therapy in patients with HIV infection. Both US and UK treatment guidelines
      continue to recommend protease inhibitor-based regimens including indinavir as a
      first-line option. Indinavir is being studied as a twice daily and once daily
      regimen with a low dosage of ritonavir as a way to alleviate tolerability, drug
      interaction and patient compliance/adherence issues. Indinavir-containing triple
      therapy has demonstrated positive effects not only on surrogate markers of
      disease progression, but also on clinical end-points of mortality and morbidity
      in patients with HIV disease. Protease inhibitors are a significant advance in
      the care of patients with HIV infection, and, in an era of evidence-based
      medicine, indinavir represents an important component of antiretroviral treatment
      strategies.

PMID- 10651399
TI  - A worst case scenario.

PMID- 10651400
TI  - Development of a rapidly deployed Department of Energy emergency response
      element.
AB  - The Federal Radiological Emergency Response Plan (FRERP) directs the Department
      of Energy (DOE) to maintain a viable, timely, and fully documented response
      option capable of supporting the responsible Lead Federal Agency in the event of
      a radiological emergency impacting any state or United States territory (e.g.,
      CONUS). In addition, the DOE maintains a response option to support radiological
      emergencies outside the continental United States (OCONUS). While the OCONUS
      mission is not governed by the FRERP, this response is operationally similar to
      that assigned to the DOE by the FRERP The DOE is prepared to alert, activate, and
      deploy radiological response teams to augment the Radiological Assistance Program
      and/or local responders. The Radiological Monitoring and Assessment Center (RMAC)
      is a phased response that integrates with the Federal Radiological Monitoring and
      Assessment Center (FRMAC) in CONUS environments and represents a stand-alone DOE
      response for OCONUS environments. The FRMAC/RMAC Phase I was formally "stood up"
      as an operational element in April 1999. The FRMAC/RMAC Phase II proposed "stand
      up" date is midyear 2000.

PMID- 10651402
TI  - The application of ALARA for occupational exposures, NCRP Statement No. 8, issued
      June 8, 1999. National Council on Radiation Protection.

PMID- 10651401
TI  - The dissolution vessel for plutonium pits at the U.S. DOE Pantex Plant.
AB  - The U.S. DOE Pantex Plant has been given the mission to recertify and requalify
      plutonium pits for reuse in existing War Reserve nuclear weapons. The first
      process common to both recertification and requalification is cleaning the
      plutonium pit. The pit will be cleaned in a dissolution vessel using N-methyl
      pyrrolidone (NMP) solvent. The recertification and requalification programs are
      both in the design concept phase at Pantex Plant The U.S. DOE Pantex Plant
      secures the national security of the United States by using safe vessels for
      cleaning plutonium pits in a manner that protects the health and safety of
      employees, the public and the environment.

PMID- 10651403
TI  - Oversight in the November 1999 Operational Radiation Safety.

PMID- 10651404
TI  - John J. Conley, MD, 1912-1999--in celebration of a life.

PMID- 10651405
TI  - Harvesting human hair cells.
AB  - The sensory hair cells of the inner ear are responsible for converting balance
      and hearing stimuli into electrical signals. Until recently, all previous studies
      of hair cell physiology had been performed on tissue obtained from non-mammals
      and rodents. In primates, hair cells are difficult to access, because they rest
      within the densest structure of the body, the otic capsule of the temporal bone.
      In this report, we describe a technique that we have used in physiological
      studies to harvest living human hair cells. We collected vestibular and cochlear
      tissue specimens from adult humans undergoing translabyrinthine and transotic
      surgical approaches for resection of lateral skull base tumors. Viable hair cells
      were identified and visualized with light microscopy. The ability to study normal
      hair cells from humans may further the study of normal and pathological human
      sensation, hair cell regeneration, and genetic causes of balance and hearing
      disorders.

PMID- 10651406
TI  - Results of tympanoplasty in children after 15 to 27 years.
AB  - Results of tympanoplasty in children with noncholesteatomatous chronic otitis
      media are presented in a 16- to 27-year follow-up. During the 13-year period from
      1968 to 1980, 116 children (124 ears) were operated on, and they were submitted
      to several follow-ups with audiometry and otomicroscopy. The attendance at the
      last follow-up was 70%, and the minimum time since surgery for these patients was
      15 years. All dry ears were operated on transcanally with a fixed ear speculum,
      without any lateral incision of the ear canal skin. Cumulatively, in total, 14
      ears (11%) had reperforation: 7 ears early and 7 ears late. At 6 months, there
      were 6% early reperforations; some were surgically closed and some reappeared
      later, even after several years, as late perforations. At 2 to 15 years of follow
      up, there were 4% reperforations, and at 16 to 27 years, 6%. Hearing was good and
      stable. The results were the same in ears operated on at the ages of 2.5 to 7
      years and 8 to 14 years, as well as with preoperatively positive and negative
      Valsalva maneuvers. In total, 14% of ears were revised during the entire
      observation period. It is concluded that transcanal tympanoplasty, even in young
      children, has good long-term stability and can definitively and permanently solve
      the problem of noncholesteatomatous chronic otitis in children.

PMID- 10651407
TI  - Resistant bacteria in middle ear fluid at the time of tympanotomy tube surgery.
AB  - This study was performed to determine the prevalence of resistant Streptococcus
      pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis isolated from
      middle ear fluid of children undergoing placement of ventilation tubes. The
      extent of resistance to commonly prescribed antibiotics and the risk factors
      associated with this resistance were also examined. Children who had fluid
      present in their middle ears at the time of ventilation tube placement from May
      1996 to May 1997 were included in the study. Middle ear fluid was plated onto
      culture media in the operating room, and antimicrobial resistance of cultured
      organisms was ascertained. Risk factors for this resistance were determined from
      the medical history and analyzed. Cultures of 244 patients (355 ears) were
      positive for organisms in 29.6%. Penicillin resistance was found in 38.2% of S
      pneumoniae cultures. Beta-lactamase production was found in 65.1% and 100% of H
      influenzae and M catarrhalis specimens, respectively. Risk factor analysis
      revealed young age, day care attendance, and number of antibiotic courses to most
      reliably predict the presence of resistant microorganisms.

PMID- 10651408
TI  - Extraneous round window membranes and plugs: possible effect on intratympanic
      therapy.
AB  - Recently there has been increasing interest in the possibility of treating inner
      ear disorders by application of medication into the middle ear on the premise
      that it will diffuse through the round window membrane into the inner ear. We
      examined 202 temporal bones from 117 patients to determine the frequency of round
      window niche obstruction. Patients ranged in age at the time of death from 31 to
      97 years. Eleven percent of the ears were found to have fibrous tissue or a fat
      plug, and 21% had an extraneous (false) round window membrane. Of the 85 patients
      from whom both temporal bones were examined, 56% had no obstruction in either
      ear, while 22% had obstruction in both ears. We conclude that anatomic variations
      of the round window niche may explain the wide variations found in dosage of
      medication required to produce a clinical result.

PMID- 10651409
TI  - Estimation of volume referent bone turnover in the otic capsule after sequential
      point labeling.
AB  - Using fluorochrome labeling and a newly validated method for bone turnover
      estimation, we determined absolute values for canine perilabyrinthine bone
      remodeling. The overall capsular bone turnover was found to be 2.1% per year,
      compared to 13.9% per year for the neighboring cranial bones and 7.4% per year
      for the humerus compacta. This gross 2.1% per year conceals a vast range, from
      0.13% per year for the innermost perilymphatic zone, through a centrifugal
      increment toward 8% to 10% per year in the periphery. The underlying individual
      bone remodeling units exhibit a similar centrifugal pattern in numerical density
      and size. These findings indicate an inhibition of remodeling, seemingly
      emanating from the perilymphatic spaces, and affecting both the activation of
      osteoclasts and the extent of resorption by the osteoclasts. These values
      satisfactorily explain the preservation of such fetal remnants as the globuli
      ossei, the interglobular spaces, and the skein bone. In humans, local ineffective
      inhibition of bone resorption may play a role in the initiation of otosclerosis.

PMID- 10651410
TI  - Isolated large vestibular aqueduct syndrome in a family.
AB  - This paper presents the second case in the literature of large vestibular
      aqueduct syndrome without associated cochlear anomalies in 2 members of the same
      family. The syndrome is frequently associated with sensorineural hearing loss
      presenting in childhood. The onset is commonly sudden, following an event causing
      increased intracranial pressure. On the basis of an emerging pattern of
      inheritance, we recommend screening siblings of an affected child. We also
      discuss the importance of characterizing the extent of disease of the inner ear.

PMID- 10651411
TI  - Reversible sensorineural hearing loss following administration of muromonab-CD3
      (OKT3) for cadaveric renal transplant immunosuppression.
AB  - This prospective study is a follow-up to a case report noting reversible
      sensorineural hearing loss after administration of OKT3 for immunosuppression in
      a steroid-resistant renal cadaveric transplant patient who was rejecting his
      transplant. The objective is to determine the interval estimate for incidence of
      sensorineural hearing loss following treatment with OKT3. Seven patients were
      admitted to the Renal Transplant Service at Montefiore Medical Center from July
      1996 to July 1997 with steroid-resistant rejection of renal cadaveric transplants
      and received OKT3 as an immunosuppressant. All 7 patients received 3 audiograms:
      the first, prior to the administration of the first dose of OKT3, the second, 48
      to 72 hours after administration of OKT3, and the third, approximately 2 weeks
      after administration of OKT3. Five of the 7 patients (71%) demonstrated a
      sensorineural hearing loss of 15 dB or greater at frequencies of 8 to 12 kHz.
      Four of the 5 patients with audiographic changes had near-complete to complete
      recovery of their high-frequency thresholds after discontinuation of the drug
      regimen. In conclusion, OKT3 can cause sensorineural hearing loss. This side
      effect is mainly reversible after 2 weeks following discontinuation of the drug.
      Patients receiving OKT3 should be forewarned of this possible side effect prior
      to the administration of OKT3.

PMID- 10651413
TI  - Nuchal fibroma: a clinicopathological review.
AB  - Nuchal fibroma, or collagenosis nuchae, is a benign soft tissue tumor that arises
      from the posterior cervical subcutaneous tissue, with a predilection for the
      interscapular and paraspinal regions. Because of its benign clinical course and
      its close histopathologic similarity to other benign head and neck lesions, this
      lesion may be misdiagnosed and underreported. The purpose of this paper is to
      review the histopathologic and radiologic findings unique to nuchal fibroma, and
      compare and contrast it to the other soft tissue neoplasms within the clinical
      differential diagnosis. These include several benign (elastofibroma, lipoma,
      fibrolipoma, nodular fasciitis) and rare malignant entities (fibrosarcoma,
      liposarcoma, fibromatosis).

PMID- 10651412
TI  - Schwannoma of the cervical sympathetic chain. The Virginia experience.
AB  - We present 4 cases of schwannomas arising from the cervical sympathetic chain.
      These lesions are uncommon and most often present as an asymptomatic solitary
      neck mass. Preoperative diagnosis can be difficult, even with the aid of computed
      tomography, magnetic resonance imaging, ultrasound, and angiography. While a
      paraganglioma can often be ruled out, exact determination of the nerve of origin
      is frequently elusive until the time of surgery. Operative excision remains the
      treatment of choice, often requiring sacrifice of a portion of the sympathetic
      chain. Postoperative Horner's syndrome is common, but does not appear to have an
      adverse effect on the patient.

PMID- 10651415
TI  - Giant cell tumor of the larynx.
AB  - Giant cell tumors are benign tumors generally found in the long bones. Very
      rarely, they can occur in the larynx and may present with dysphonia, dysphagia,
      or dyspnea. A case of giant cell tumor of the larynx was recently identified and
      successfully treated by a partial laryngectomy. A literature review has revealed
      18 case reports of giant cell tumor of the larynx. All cases occurred in men.
      These 19 cases are reviewed, and follow-up data presented where available. There
      have been no reports of recurrence regardless of treatment, and an excellent
      prognosis can be expected when one encounters this unusual laryngeal neoplasm.

PMID- 10651414
TI  - Dendritic cells in selected head and neck tumors.
AB  - Specimens from 17 head and neck tumor patients were immunohistochemically stained
      with monoclonal antibodies against HLA-DR, CD1a, RFD1, LAG, CD3, CD4, CD8,
      CD45RO, CD68, and cytokeratin to identify the nature and distribution of
      dendritic cells (DCs), T cells, and macrophages. Small numbers of DCs were
      present in all but 2 specimens. They were located between the tumor cells and in
      the stroma, especially in areas of inflammatory cell infiltration. Variable
      numbers of T lymphocytes (cytotoxic and memory type) occurred in the same
      locations. Numerous macrophages were found in the epithelium, in the stroma, and
      in the vicinity of tumor cells. The presence of DCs in head and neck tumors
      indicates that the organism has activated the immune surveillance system and is
      trying to present tumor antigens. Considering the sparsity of DCs in the
      malignant tissues, the T cell response can be only limited.

PMID- 10651416
TI  - Morphometric and histochemical study of the human vocal muscle.
AB  - The present study was conducted on vocal muscles removed at autopsy from adult
      individuals (10 men and 8 women, ages ranging from 48 to 78 years) with no
      laryngeal disease. Histologic analysis was performed with hematoxylin and eosin
      staining, and histochemical analysis was performed by nicotinamide-adenine
      dinucleotide tetrazolium reductase, succinate dehydrogenase, and acid and
      alkaline myofibrillar adenosine triphosphatase reactions. The histochemical
      reactions showed that the muscle consists of slow-twitch oxidative (SO), fast
      twitch glycolytic (FG), and fast-twitch glycolytic oxidative (FOG) fibers
      distributed in mosaic form. The frequencies of SO, FOG, and FG fibers were
      40.50%, 54.75%, and 4.75%, respectively. The higher frequency of SO and FOG
      oxidative fibers characterizes the muscle as having aerobic metabolism,
      resistance to fatigue, and fast contraction. The mean minimum diameters were
      31.37 microm for SO fibers and 36.46 microm for FOG and FG fibers.

PMID- 10651417
TI  - Spontaneous respiration anesthesia for respiratory papillomatosis.
AB  - Several anesthetic techniques for microlaryngeal laser surgery in children have
      been advocated. The objective of this study was to evaluate the operative
      conditions and safety of the spontaneous respiration anesthesia technique for
      carbon dioxide laser surgery in children with recurrent respiratory
      papillomatosis (RRP). The anesthetic and operative records of 60 pediatric
      patients with RRP who underwent microlaryngeal laser surgeries between 1991 and
      1997 were reviewed. Papilloma location, severity of involvement, oxygen
      saturation, airway stability, need for intubation, duration of procedure, and
      complications were recorded. The patients underwent 744 surgical procedures. Two
      hundred two procedures were randomly studied (statistical power > or = 80%). The
      supraglottis and glottis were most commonly involved. Most of the papillomas were
      graded as moderate or severe disease. Complications occurred in 11 procedures.
      The surgical procedure was completed in all cases. No variable had predictive
      value regarding the outcome. Spontaneous respiration anesthesia is an efficient
      and relatively safe technique for microlaryngeal laser surgery in children with
      RRP.

PMID- 10651418
TI  - Biomechanical and histologic observations of vocal fold fibrous proteins.
AB  - This article discusses the molecular composition of the vocal fold and the
      relationship of fibrous molecules to the biomechanical and physiological
      performance of the tissue. The components of the extracellular matrix may be
      divided into fibrous proteins and interstitial proteins. The fibrous proteins,
      consisting of collagens and elastins, are the focus of this report. Elastin
      concentration varies by tissue depth in the vocal folds. Variation of elastin by
      age is reported, but some controversy exists. The biomechanical terms of stress
      and strain (and stress-strain curves of human vocal folds) are related to the
      fibrous proteins of the vocal folds. The fibrous proteins, their role in stress,
      and their effect on the dynamic range of vocal pitch are presented.

PMID- 10651419
TI  - Encounters with challenging bronchial foreign bodies: impromptu adaptation of
      technique.
AB  - We present a retrospective review of 2 cases of unusual foreign bodies and
      discuss methods needed for successful removal of the objects. The review stresses
      the need for preparation in managing difficult and unexpected situations.
      Specific instrumentation as well as surgical resourcefulness provided for
      successful removal of a carrot fragment in one instance and a plastic bead in the
      other. The need to individualize tracheobronchial foreign body extraction is
      stressed, as is the importance of keeping some of the "old-time" instruments in
      one's instrument cabinet.

PMID- 10651421
TI  - Changes in epidermal growth factor receptors in olfactory epithelium associated
      with aging.
AB  - To clarify the mechanisms of age-related changes in the olfactory epithelium, we
      investigated age-related changes in epidermal growth factor receptors (EGFRs) in
      the epithelium. We examined 3 mice at each of the following stages: embryonal
      (embryonic days 14 and 16), neonatal (postnatal days 1 and 7), adult (postnatal
      weeks 5 and 12), and aged (postnatal years 1.5 to 2). The olfactory epithelium of
      each mouse was stained with sheep anti-human EGFR polyclonal IgG by an
      immunohistochemical method. The EGFRs were observed in all layers of the
      olfactory epithelium at the embryonal and neonatal stages. They were identified
      only in the basal layer of the olfactory epithelium at adult and aged stages, and
      the number of regions in which EGFRs were identified in the basal layer of the
      olfactory epithelium decreased in aged mice compared to adult mice. We believe
      that a decrease in EGFRs in the olfactory epithelium induces the inhibition of
      cell proliferation, with resultant atrophy of the olfactory epithelium.

PMID- 10651420
TI  - Mucosal leishmaniasis: quantitative nasal cytology as a marker of disease
      activity and indicator of healing.
AB  - Mucosal leishmaniasis (ML) follow-up is based on subjective parameters. Using
      simplified quantitative cytology of nasal lavages (QNCs), we studied 20 ML
      patients, 10 patients with cutaneous leishmaniasis (CL), and 10 healthy subjects.
      Patients with ML were treated with antimony and followed up with
      otolaryngological examination plus QNCs for 6 months. At the first evaluation,
      the median total number of cells in ML patients (1,540,000) was greater than that
      in CL patients (215,000) or that in healthy subjects (250,000). Neutrophils were
      predominant in ML patients, in contrast to both sets of controls, in whom
      epithelial cells were more frequent. During treatment, we found a significant
      reduction in total nasal cell counts in ML patients who were cured, and
      encountered a switch in predominant cell type. The cytology of 2 patients who did
      not respond to antimony remained the same. It is therefore possible to detect
      nasal inflammation in ML patients through QNCs, which may indicate extension of
      mucosal involvement, providing an objective parameter to monitor therapy.

PMID- 10651422
TI  - Nasopharyngeal tonsil's provision of the surface secretions with immunocytes, a
      property additional to antigen processing.
AB  - As we recently found that IgA, IgM, and IgG are produced and secreted by
      immunocytes present in nasopharyngeal secretions, we tested the hypothesis that B
      and T-lymphocytes in the surface secretions are derived from the nasopharyngeal
      tonsil in an active process. By immunohistochemistry, we found that numerous B-
      and T-lymphocytes were often accumulated in restricted areas in the epithelium,
      and some of these cells were demonstrated just beneath the epithelial surface or
      could be observed protruding into the lumen. A portion of these cells were Ki
      67+, indicating clonal expansion and/or immunoglobulin class switching. Analyses
      of the surface secretions by immunocytochemistry also demonstrated B- and T
      lymphocytes, as well as Ki-67+ cells--a finding that indicates that
      immunologically active cells are transported into the surface secretions. The
      results imply that there is a substantial migration from the nasopharyngeal
      tonsil of immunologically active cells into the surface secretions.

PMID- 10651423
TI  - Pediatric mandibular aneurysmal bone cyst.

PMID- 10651424
TI  - Paraneoplastic syndromes in patients with laryngeal and hypopharyngeal cancers.

PMID- 10651425
TI  - The decline of ear surgery in the 21st century.

PMID- 10651426
TI  - Please don't close the patent office yet.

PMID- 10651427
TI  - Earmarks of art history: cerumen and medieval art.

PMID- 10651428
TI  - Superior canal dehiscence syndrome.
AB  - OBJECTIVE: To present the symptoms, signs, and findings on diagnostic tests of
      patients with the superior canal dehiscence syndrome and to describe the surgical
      procedures used to treat the dehiscence in five patients. DESIGN AND SETTING:
      Prospective study of a series of patients identified as having this syndrome at a
      tertiary care referral center. PATIENTS AND RESULTS: Seventeen patients with
      vertigo, oscillopsia, or both evoked by intense sounds or stimuli that caused
      changes in middle ear and/or intracranial pressure were identified over a 4-year
      period. The evoked eye movements had vertical and torsional components, with the
      direction corresponding to the effect of the stimuli in causing excitation
      (Valsalva against pinched nostrils, tragal compression, sounds) or inhibition
      (Valsalva against a closed glottis or jugular venous compression) of the affected
      superior semicircular canal. Thirteen (76%) of these patients also experienced
      chronic dysequilibrium that was often the most debilitating symptom. Dehiscence
      of bone overlying the superior semicircular canal on the affected side was
      confirmed with computed tomographic scans in each case. Surgical procedures
      through the middle fossa approach to plug or resurface the superior canal were
      performed in five patients (canal plugging in three cases and resurfacing of the
      dehiscence without plugging in two). The debilitating symptoms resolved or
      improved after the procedures. Signs of vestibular hypofunction, without loss of
      hearing, were noted in one patient after plugging of the superior canal and in
      one other patient after resurfacing of the canal. CONCLUSIONS: The superior canal
      dehiscence syndrome is identified based on characteristic symptoms, signs, and
      computed tomographic findings. The clinical presentation and findings can be
      understood in terms of the effect of the dehiscence on the physiology of the
      labyrinth. The syndrome is a treatable cause of vestibular disturbance.

PMID- 10651429
TI  - The buffering effect of middle ear negative pressure by retraction of the pars
      tensa.
AB  - OBJECTIVE: To measure the middle ear (ME) volume displaced when the pars tensa
      (PT) retracts during conditions of atelectasis (AT). STUDY DESIGN: Measurements
      were carried out on AT tympanic membrane (TM). SETTING: Measurements were carried
      out on ambulatory patients in a private clinic. PATIENTS: Thirty-nine patients
      treated for otologic disorders who came for a routine follow-up. INTERVENTIONS:
      Quantitative assessment of ME volume displaced by retraction of the PT was
      achieved by measuring the amount of fluid needed to fill up the retracted part of
      a TM. The fluid-3% aqueous boric acid solution was colored with gentian violet.
      MAIN OUTCOME MEASURES: Retraction of the PT may prevent formation of high ME
      negative pressure by reducing the ME volume. Retraction of the PT acts as a
      pressure buffer according to Boyls law, in which volume x pressure = constant.
      RESULTS: Direct correlation was found between the degree of AT and the ME volume
      displaced by the AT. Measurements of 12 AT ears grade I showed them to have a
      volume of 5 microL to 31 microL (average, 19.5 microL) and ten AT ears grade II
      had a volume of 15 microL to 87 microL (average, 39.5 microL). Eight AT ears
      grade III had a volume of 26 microL to 67 microL (average, 54.3 microL), and nine
      AT ears grade IV had 80 microL to 200 microL (average, 130.6 microL).
      CONCLUSIONS: Retraction of the PT may counteract an important potential negative
      ME pressure (up to several hundred millimeters of water) depending on the degree
      of retraction and the extent of mastoid pneumatization.

PMID- 10651431
TI  - Soft-wall reconstruction for cholesteatoma surgery: reappraisal.
AB  - OBJECTIVE: To reevaluate the validity of the soft-wall reconstruction method of
      the posterior meatal wall in surgeries for cholesteatomas. STUDY DESIGN:
      Retrospective case review. PATIENTS: Subjects consisted of 52 patients (54 ears)
      with fresh cholesteatoma (excluding residual or recurrent cholesteatomas) who
      were operated by the soft-wall reconstruction method in our clinic and observed
      for more than 2 years after surgery, and 29 patients (29 ears) who were operated
      by canal-wall-down and open method. MAIN OUTCOME MEASURES: Postoperative period
      required for complete epithelization (dry ear), hearing, and incidence of the
      residual and recurrent cholesteatomas were compared with those operated by canal
      wall-down and open method. The postoperative conditions of the soft posterior
      meatal wall was also investigated. RESULTS: Postoperative period to be a dry ear
      was significantly shorter in the soft-wall reconstruction group than in the canal
      wall-down and open group (Student's t-test, t = 2.99, p < 0.01). There was no
      significant difference in the postoperative hearing or incidence of residual and
      recurrent cholesteatomas between the two groups. CONCLUSIONS: These results
      indicate that the soft-wall reconstruction method seems more versatile than the
      canal-wall-down and open method for cholesteatoma surgery.

PMID- 10651430
TI  - Efficacy of ondansetron for prevention of postoperative nausea and vomiting after
      outpatient ear surgery under local anesthesia.
AB  - OBJECTIVE: To assess the efficacy and safety of intravenous ondansetron (4 mg)
      for the prevention of nausea and vomiting after middle ear surgery under local
      anesthesia. SETTING: The study was conducted by Division of Otorhinolaryngology
      in Prince of Wales Hospital, which is a tertiary referral center and teaching
      hospital for The Chinese University of Hong Kong. STUDY DESIGN: A double-blind
      randomized controlled trial. PATIENTS: Fifty-eight Chinese patients undergoing
      tympanoplasty under local anesthesia from July 1995 to June 1997 were recruited.
      The mean age of patients was 42.8 years (range 18-71 years). INTERVENTION:
      Patients were randomly allocated to receive a single dose of intravenous
      ondansetron (4 mg) (n = 29) or placebo (n = 29) immediately before surgery. MAIN
      OUTCOME MEASURES: Patients were assessed for severity and frequency of
      postoperative nausea and vomiting at the 1st, 2nd, 4th, 8th, and 24th hours after
      middle ear surgery. RESULTS: Female patients showed a higher prevalence of
      postoperative nausea and vomiting. Twenty-eight percent of the patients
      experienced postoperative nausea, of whom 14% also experienced vomiting. Although
      the ondansetron group demonstrated a lower prevalence of postoperative nausea and
      vomiting (PONV) (24% nausea and 10% vomiting) than the placebo group (31% nausea
      and 17% vomiting), significant reduction in postoperative vomiting only occurred
      in the first postoperative hour (p = 0.038). No complications or adverse side
      effects were found to be associated with the use of ondansetron. CONCLUSIONS:
      Single-dose ondansetron (4 mg) given intravenously preoperatively significantly
      reduces postoperative vomiting in patients after tympanoplasty under local
      anesthesia and causes no adverse effects.

PMID- 10651432
TI  - Labyrinthine fistula after cholesteatomatous chronic otitis media.
AB  - OBJECTIVES: To report on cases of labyrinthine fistula diagnosed in an ear, nose,
      and throat department and to study the incidence, location, pre- and
      postoperative symptoms (hearing loss, tinnitus, vertigo, facial palsy),
      preoperative diagnostic imaging, and surgical treatment of two types of
      cholesteatomatous labyrinthine fistulae-the extensive fistula that erodes both
      the bony and membranous labyrinths and the bone fistula that affects only the
      bony labyrinth. STUDY DESIGN: Retrospective case review. PATIENTS: Fifty-four
      patients with cholesteatomatous chronic otitis media with labyrinthine fistulae.
      SETTING: Tertiary referral center. INTERVENTIONS: Diagnosis and treatment. MAIN
      OUTCOME MEASURES: Clinical, imaging, and surgical correlation of extensive
      fistulae and bone fistulae. RESULTS: The incidence of labyrinthine fistulae was
      7% in all patients who underwent surgery for chronic otitis media. The bone type
      (66%) is more common than the extensive type (33%). Compared with bone fistulae,
      the outcome for extensive fistulae is more severe in terms of hearing loss,
      vertigo, and facial palsy. In terms of preoperative diagnosis, computed
      tomography imaging ensured early diagnosis in 89% of extensive cases and in 28%
      of bone cases. For extensive fistulae, the surgical technique was more radical,
      requiring an open technique in 66% of cases versus 22% of the bone fistulae
      cases. The most common location is the lateral semicircular canal (61%).
      CONCLUSIONS: The breach in the membranous labyrinth is consistent with a more
      aggressive pathology, causing more severe pre- and postoperative symptoms.
      Preoperative computed tomography is more sensitive for diagnosing extensive
      fistulae, which also require a more radical treatment.

PMID- 10651434
TI  - The effect of the "floating mass transducer" in the middle ear on hearing
      sensitivity.
AB  - OBJECTIVE: The Vibrant soundbridge is a semi-implantable hearing device; the
      transducer is implanted, coupled directly to the incus. The influence of the
      implant surgery and the presence of the transducer on hearing sensitivity was
      studied in six implanted subjects. STUDY DESIGN: Longitudinal case reports.
      SETTING: Tertiary referral center. Subjects. The subjects had bilateral
      sensorineural hearing loss with an average hearing loss of 40 to 70 dB HL.
      RESULTS: In five of the six subjects, no long-term effect of the surgery or the
      presence of the transducer on hearing thresholds was found. In the remaining
      subject, a deterioration in hearing thresholds was found of 20 dB, with a high
      and low frequency component. In the 2-kHz region, hearing sensitivity was not
      deteriorated. In addition, chronic negative middle ear pressure occurred after
      surgery. CONCLUSION: Hearing thresholds did not change significantly in five of
      the six patients after placement of the "floating mass transducer." It was
      speculated that the high frequency component of the hearing deterioration in the
      remaining patient was caused by cochlear damage caused by the surgery and that
      the low frequency component was caused by the chronic aeration problems
      indirectly related to the surgery.

PMID- 10651433
TI  - Labeling of the glucocorticoid receptor and Na,K-ATPase in a rat otitis media
      model.
AB  - HYPOTHESIS: Glucocorticoid hormones exert an influence on the inflammatory
      response of the middle ear during acute otitis media. Rats with experimentally
      induced purulent otitis media were given either glucocorticoid hormones in excess
      or a glucocorticoid hormone blocker that deprived the animals of the hormone.
      BACKGROUND: Acute otitis media is a common inflammatory disease among children.
      Streptococcus pneumoniae is the most usual causative agent. The standard
      treatment today is phenoxymethylpenicillin. The role of glucocorticoid hormones
      in inflammatory reactions in the middle ear has been widely debated. METHODS: In
      an otitis media model, a suspension of pneumococci was inoculated into the bulla
      of the rat, after the animals were pretreated with either a dose of
      corticosteroid hormones or the glucocorticoid receptor blocking agent RU 486.
      Rats with induction of otitis media only, but no pretreatment, were used as
      control subjects, as were the left control-operated ears of all rats. The
      inflammatory response in the inner ear and in the middle ear was evaluated. The
      presence of glucocorticoid receptors and the enzyme Na,K-ATPase was investigated
      with immunohistochemistry. RESULTS: The inflammatory response in the animals with
      untreated otitis media and in the group with otitis media in rats pretreated with
      the receptor blocker was much more extensive than in the group of animals
      pretreated with corticosteroids. In the corticosteroid-treated group, the
      tympanic membrane and the mucous membrane of the middle ear were less edematous,
      but the middle ear cavity contained more pus. Only a few lymphocytes were found
      in the inner ears of these rats. When the inner ear was labeled with antibodies
      against glucocorticoid receptors, there seemed to be no difference between the
      labeling patterns in the three groups. This was also the case for antibody
      labeling against Na,K-ATPase. CONCLUSION: The present results indicate that the
      reaction in the middle ear mucous membrane is more pronounced in rats that had
      been pretreated with the hormone receptor blocking drug. An increase of
      corticosteroid hormone levels during the inflammatory process seem to diminish
      the reaction in the tympanic membrane and the middle ear mucosa. Neither the
      hormone receptor blocking drug nor the steroid hormones change the content of
      glucocorticoid receptors and Na,K-ATPase in the inner ear in the otitis media rat
      model.

PMID- 10651435
TI  - Cochlear view: postoperative radiography for cochlear implantation.
AB  - OBJECTIVE: This study aimed to define a spatial position of the cochlea in the
      skull based on anatomical studies and to design an appropriate method of skull
      radiography for demonstration of the multichannel intracochlear electrode array
      and the structures of the inner ear, for use in evaluating the electrode position
      and its related pitch perception. BACKGROUND: The conventional skull radiograph
      (plain radiograph) can offer a complete and direct image of an intracochlear
      electrode array, if the x-ray is directed to the cochlea and parallel to the axis
      of the cochlea. METHODS: Measurement from computed tomography imaging and three
      dimensional reconstruction were performed to define the spatial position of the
      cochlea in the skull. RESULTS: A radiographic projection, the cochlear view, was
      designed. A detailed radiographic method and radiologic interpretation of the
      cochlear view is described. An improved clinical method for measuring the
      longitudinal and angular position of the electrodes from the cochlear view is
      recommended. CONCLUSIONS: The application of the cochlear view has proved that it
      is beneficial postoperatively in documenting the results of cochlear
      implantation, and in evaluating the depth of insertion and position of individual
      electrodes. It serves as a valuable reference for managing frequency mapping,
      optimizing speech processing strategies, and further research purposes. The
      method can be widely used in cochlear implant clinics because of its simplicity,
      low radiation, speed, and minimal cost.

PMID- 10651436
TI  - The development of speech perception in children using cochlear implants: effects
      of etiologic factors and delayed milestones.
AB  - HYPOTHESIS: Speech perception outcomes for cochlear implantation of children vary
      over a wide range, and it is hypothesized that central pathologic states
      associated with certain causes of hearing impairment account for a substantial
      part of the variance. STUDY DESIGN: A retrospective analysis was carried out to
      ascertain the relationships between speech perception, etiologic factors, and
      central pathologic states as indicated by preoperative delayed motor milestones
      and/or cognitive delays. SETTING: Data were obtained from the pre- and
      postoperative records of patients attending a hospital cochlear implant clinic.
      PATIENTS: Results for 75 consecutive patients up to age 5 years who underwent
      implantation were included in the study. INTERVENTION: Patients received a 22
      electrode cochlear prosthesis and were seen by the clinic for regular tune-up and
      assessments. Home- and school-based habilitation was recommended by the clinic.
      MAIN OUTCOME MEASURES: Speech perception measures were classified on a five-point
      scale to allow for different evaluation procedures at different ages and
      developmental stages. RESULTS: The incidence of motor and cognitive delays were
      fairly evenly spread across etiologic factors, except for cytomegalovirus, which
      had a much higher than average incidence. Children with motor and/or cognitive
      delays were significantly slower than other children in the development of speech
      perception skills after implantation. Etiologic factors did not have a
      statistically significant effect on speech perception outcome. CONCLUSIONS: It is
      likely that central pathologic states account for a substantial part of the
      variance among children using cochlear implants. Specific indicators of central
      pathologic states should be used to assess a child's prognosis in preference to
      less specific information based on etiologic factors alone.

PMID- 10651437
TI  - Effect of amniotic fluid cellular content on attic aeration pathways: histologic
      observations of infants aged 2 to 4 months.
AB  - HYPOTHESIS: The tissue-fixed amniotic fluid cellular content (AFCC) in the middle
      ear and mastoid antrum causes foreign body type reactions that may later severely
      restrict the aeration pathways to the main attic and to Prussak's space.
      BACKGROUND: It was shown by Aschoff 100 years ago that AFCC remained in the
      neonate ears and caused sterile otitis media. Recent data show that children born
      through thick meconium are at risk for large quantities of AFCC entering the
      middle ear cleft, the ensuing inflammatory reaction being related to the amount
      of AFCC. Spread of AFCC in the neonate occurred along the aeration pathways with
      corresponding tissue fixation but further systematic data in young infants are
      lacking. METHODS: Five temporal bones of three infants aged 2 to 4 months were
      embedded in celloidin, serially sectioned at 20 microns, and every 10th section
      stained with Hematoxylin and eosin and mounted on slides. All slides were studied
      and relevant details of aeration pathways and all compartments photographed.
      RESULTS: The histologic changes were characterized by the development of masses
      of pseudocystic granulation tissue, with some remnants of the original AFCC,
      mainly in the form of fragments of hair. The tympanic isthmus was involved to
      varying extent, maximally to half of its size. Posterior tympanum and the stapes
      region had masses of fresh granulation tissue, the maturing of which might cause
      marked indrawing of the posterior pars tensa and further reduction of the
      tympanic isthmus. Aeration of Prussak's space was severely involved in two bones,
      favored by the narrow pathway through the posterior pouch. Features of recent
      acute or secretory otitis media were associated with the early changes caused by
      AFCC. CONCLUSIONS: The granulation tissue in this age group is immature and its
      final fate is decided by the nature of the future ear disease. If the AFCC
      contamination is slight, the granulation tissue after maturing may appear only in
      the form of thin cords and sheets, a frequent chance finding in ear surgery.
      Large amount of AFCC may lead to chronic inflammation, which may predispose the
      child to recurring middle ear infections during infancy. Further histologic and
      clinical studies in older infants and young children are needed to find out the
      final outcome after a massive AFCC contamination of the new-born middle ear.

PMID- 10651438
TI  - Isolated congenital stapes ankylosis: an embryologic survey and literature
      review.
AB  - OBJECTIVE: Isolated congenital stapes ankylosis is rare but is a definite entity.
      Both small series and case reports have been published in various languages. The
      aim of this study was to review the world literature regarding isolated
      congenital stapes ankylosis and to critically evaluate the embryonic development
      of the stapes to explain the possible pathologic development of this ankylosis.
      DATA SOURCES: All the publications in the English, German, and French literature
      regarding congenital stapes anomalies were reviewed, and original research
      articles on the embryonic development of the stapes and related structures were
      extensively and critically reviewed. STUDY SELECTION: Of the many varieties of
      congenital stapes anomalies described in the literature, only the isolated
      congenital stapes fixation due to footplate or suprastructure fixations were
      selected in this study. DATA SYNTHESIS: After extensive and critical review of
      the embryonic development of the stapes, the complex and confusing embryonic
      development is explained in a simplified way with schematic illustrations for
      easy understanding. The possible theories of congenital stapes ankylosis are
      explained on an embryologic basis and supplemented with schematic illustrations.
      CONCLUSION: Based on the development of the stapes an attempt has been made to
      explain the possible theories for the basis of suprastructure fixation. Theories
      of congenital fixation of footplate also discussed.

PMID- 10651439
TI  - Extratympanic electrocochleography: diagnostic and predictive value.
AB  - OBJECTIVE: To define the clinical value of extratympanic electrocochleography
      (ECoG) in the diagnosis of Meniere's disease. STUDY DESIGN: Retrospective case
      review. SETTING: An otology/neurotology referral center. PATIENTS: A group of 252
      patients with symptoms consistent with Meniere's disease and 20 normal-hearing
      control subjects. INTERVENTION: All patients underwent audiologic testing and
      extratympanic ECoG at the time of initial evaluation and, when possible,
      following treatment. MAIN OUTCOME MEASURES: Audiologic thresholds and summating
      and action potential ratios (SP:AP). RESULTS: Patients were classified into
      definite, probable, possible, and bilateral Meniere's disease groups according to
      American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) guidelines.
      The definite Meniere's group demonstrated an elevated SP:AP ratio in 74% of
      cases, the possible Meniere's group in 64%, and the bilateral group demonstrated
      elevated ratios in both ears in 66%. Contralateral ears produced elevated ratios
      in 42% for unilateral cases, whereas 40% of these ears reported at least one
      contralateral symptom. All 40 control ears were normal (SP:AP > or = 0.50).
      Results statistically correlated (p = 0.004) with the Meniere's staging system
      set forth in the 1995 AAO-HNS guidelines. No correlation was found between ECoG
      results and disease duration. Although 72% of the 86 follow-up patients reported
      complete or substantial vertigo control, changes from initial ECoG results did
      not specifically correlate to vertigo, tinnitus, or aural fullness improvement.
      CONCLUSIONS: Extratympanic ECoG can be useful in the diagnosis of Meniere's
      disease, lending promise to possible cases where objective audiologic data are
      lacking. Each testing center should study its own results to establish meaningful
      parameters and confidence levels.

PMID- 10651440
TI  - Comparison of pure tone and transient otoacoustic emissions screening in a grade
      school population.
AB  - HYPOTHESIS: Otoacoustic emissions provide an alternative to traditional pure tone
      hearing screening in a diverse grade school population. BACKGROUND: Mandated pure
      tone hearing screening programs for grade school children have several
      significant limitations. Otoacoustic emissions have been shown to be a reliable
      screening test in newborns, but there are no data on screening a diverse grade
      school population. METHODS: Five hundred eighty-three grade school children in
      four separate school populations were screened for hearing loss using the
      standard pure tone four-frequency protocol and transient evoked otoacoustic
      emissions. Students failing either test received a comprehensive audiogram by an
      audiologist that served as the "gold standard." Sensitivity and specificity of
      both tests were compared. RESULTS: The sensitivity and specificity of pure tone
      screening was 87% and 80%, respectively, compared with 65% and 91% for transient
      evoked otoacoustic emissions. CONCLUSION: Pure tone screening was a statistically
      significant better screening test for detecting hearing loss in this population
      of grade school children.

PMID- 10651441
TI  - Experience from a multidisciplinary "dizzy" clinic.
AB  - OBJECTIVE: To describe the experience of a combined otolaryngology and neurology
      multidisciplinary clinic in the evaluation, investigation, and management of
      patients with dizziness. STUDY DESIGN: Prospective clinical study. SETTING:
      Patients were seen in a tertiary referral, multidisciplinary clinic at The
      Toronto Hospital, University of Toronto, Ontario, Canada. INTERVENTION: A
      thorough history, formal otoneurologic examination, and appropriate laboratory
      investigations were performed. After their assessment, the patient's diagnoses
      were classified as peripheral, central, psychogenic, or undiagnosed and were then
      subdivided into specific clinical diagnoses. RESULTS: The first 812 consecutive
      patients seen in the multidisciplinary clinic from January 1, 1993 to December
      31, 1998 are reported. Five hundred twenty-five (64.7%) patients were found to
      have a peripheral vestibular cause for their dizziness, 66 (8.1%) had a central
      cause, 108 (13.3%) had a diagnosis unknown, and 73 (9.0%) were thought to be
      psychogenic. In 40 (4.9%) patients, a peripheral and central cause were found.
      More than one type of peripheral disorder was noted in 17.9% of patients with a
      peripheral vestibular cause for their dizziness, and 12.3% of patients with a
      central cause for their dizziness had more than one specific type of central
      nervous system disorder. CONCLUSIONS: Most patients that were seen in a
      multidisciplinary clinic had a peripheral vestibular disorder. Central causes of
      dizziness were relatively uncommon. Serious diseases such as tumor, multiple
      sclerosis, and encephalitis were rare and unlikely to present with dizziness
      only. It is important to realize that a patient may have more than one type of
      disorder accounting for the symptoms, which may represent a spectrum of disease
      affecting the inner ear.

PMID- 10651442
TI  - A modified retrosigmoid approach for direct exposure of the fundus of the
      internal auditory canal for hearing preservation in acoustic neuroma surgery.
AB  - OBJECTIVE: This is a clinical report on a modified retrosigmoid approach with
      direct exposure of the fundus of the internal auditory canal for hearing
      preservation in acoustic neuroma surgery. STUDY DESIGN: Retrospective case
      review. SETTING: Tertiary referral center of an ear, nose, and throat department
      in a public hospital. PATIENTS: One hundred fifty consecutive procedures were
      reviewed, including 61 males and 89 females with an age range of 13 to 69 years
      and a mean age of 47 years. There were 15 patients with tumor occupying solely
      the internal auditory canal and 135 patients with extension into the
      cerebellopontine angle with an extrameatal diameter of up to 52 mm and a mean of
      11.5 mm. INTERVENTION: The retrosigmoid approach included a wide craniotomy, a
      perimeatal petrous bone removal up to the blue line of the labyrinth, and a
      direct exposure of the fundus at the orifices of the facial and cochlear nerves.
      The quadrant of the superior vestibular nerve remained unexposed. MAIN OUTCOME
      MEASURES: Hearing was measured according to the American Academy of
      Otolaryngology-Head and Neck Surgery criteria for reporting results of hearing
      preservation and by comparison with the preoperative level. Facial nerve function
      was measured using the House-Brackmann grading. The radicality of tumor removal
      was investigated with mid- to long-term magnetic resonance imaging (MRI).
      RESULTS: Measurable hearing was preserved in 45.3%, and in 32.4% of these cases,
      it was within 15 dB/15% discrimination. Grade 1 or 2 facial function was
      preserved in 85.3%. MRI follow-up revealed a 3.3% tumor residual or regrowth in
      the complete series. No residual tumor was found at the 3-year MRI in the last
      series of patients operated on with direct control of the fundus. CONCLUSIONS:
      This modified retrosigmoid approach permits the direct exposure of the facial and
      cochlear quadrants of the fundus. This allows tumor dissection under direct
      visual control. Removing the tumor from the vestibular quadrant of the fundus is
      done blindly in a minority of cases and carries a minimal risk of residual tumor.
      This technique requires only conventional equipment and skills of neurotology.

PMID- 10651443
TI  - Cavernous hemangioma of the internal auditory canal arising from the inferior
      vestibular nerve: case report and review of the literature.
AB  - OBJECTIVE: To describe a case of cavernous hemangioma arising from the inferior
      vestibular nerve, limited to the internal auditory canal. STUDY DESIGN:
      Retrospective case review and review of literature. SETTING: A tertiary referral
      clinic. INTERVENTIONS: Extended middle cranial fossa surgery. RESULTS: The
      hemangioma was completely resected through the extended middle cranial fossa
      approach. No serious complications occurred, and the hearing and the facial nerve
      function were preserved. CONCLUSIONS: Originating from the capillary plexus
      surrounding Scarpa's ganglion, this hemangioma has to be differentiated from
      intratemporal hemangioma at the geniculate ganglion. Because of extrinsic growth
      pattern, the potential for preservation of the facial nerve function is high if
      surgery is performed early. Complete resection through the extended middle fossa
      approach is the treatment of choice for cavernous hemangioma with limited
      extension into the cerebellopontine angle. It remains difficult to distinguish
      preoperatively from the more common tumors, and surgery is usually planned on
      assumption of vestibular schwannoma.

PMID- 10651444
TI  - Study on facial motoneuronal death after proximal or distal facial nerve
      transection.
AB  - BACKGROUND: Among the cranial nerves, the facial nerve is most liable to be
      damaged. Pathologic changes in the facial motor nucleus (FMN) after nerve injury
      are not well recognized, and the optimal time for facial nerve reconstruction
      after axotomy is controversial. In this study, to clarify the pathologic change
      in the FMN after axotomy and to determine the best time for surgery, facial
      motoneuronal death was investigated after facial nerve injury. METHODS: Sixty
      Wistar rats were divided into proximal and distal groups. In the proximal group,
      the right facial nerve was transected at the porus of internal acoustic meatus.
      In the distal group, the nerve was cut at the stylomastoid foramen. The animals
      were sacrificed from day 3 to day 60 after surgery, and the brainstem was fixed
      with 4% paraformaldehyde. The FMN were then examined in serial sections stained
      with Cresyl Violet, and facial motoneurons were counted under a light microscope.
      RESULTS: The death rate of facial motoneurons in the animals that underwent
      proximal axotomy was found to be higher and cell death occurred earlier than in
      the distal axotomy animals at every time point. Moreover, neuron death increased
      with time and peaked at 15 days after surgery. CONCLUSIONS: The results indicate
      that the injury site was correlated with facial motoneuronal death, and suggest
      that reconstructive surgery should be performed as early as possible.

PMID- 10651445
TI  - Intraoperative videomonitoring of the facial nerve.
AB  - OBJECTIVE: To propose the application of an intraoperative videomonitoring system
      in otologic and otoneurologic surgery. The authors also compare results obtained
      by using this system with findings deriving from electromyography and
      pneumosensorial monitoring methods. STUDY DESIGN: The single-subject design
      study, involving six patients with middle ear or otoneurosurgery, compares
      reliability of different monitoring procedures, especially in terms of advantages
      and drawbacks. SETTING: Video system versus electrophysiologic and
      pneumosensorial systems. PATIENTS: Two patients affected with chronic otitis
      media, two from Meniere's disease, and two from Acoustic Neuroma. INTERVENTIONS:
      Intraoperative diagnostic and prognostic. RESULTS: Electrophysiologic method
      shows more sensibility, but is affected by a moderate grade of false positive
      because of electric artifacts; videomonitoring system showed less sensibility,
      but appears reliable; pneumosensorial system gives in-between results.
      CONCLUSIONS: In intraoperative monitoring techniques, reliability and feasibility
      are the most important factors and are achieved, in this study, by the
      videomonitorig system. Video recording of images have permitted further off-line
      analysis.

PMID- 10651446
TI  - Facial-motion analysis with a video and computer system: a preliminary report.
AB  - HYPOTHESIS: To investigate the feasibility of a video and computer-assisted
      system for evaluating the temporal and spatial aspects of facial motion during
      selected facial expressions in a pilot group of six normal adults. Evaluation of
      the diverse medical and surgical treatments for facial paralysis and paresis
      cannot occur until objective, reliable, and sensitive measures of the spatial and
      temporal aspects of facial function at specific facial landmarks are developed.
      METHODS: Facial motion at predetermined facial locations was assessed using a
      commercially available computer-interactive motion analysis system, which is
      based on videography principles. The displacement, velocity, and acceleration
      data were averaged across all trials and subjects. Time plots also were obtained
      for the left versus right side. RESULTS: The greatest mean maximum displacement
      (resultant vector) occurred during the eyebrow lift expression, reaching 1.2 cm
      in magnitude. The mean maximum velocity (resultant vector), which ranged from 4.5
      to 8.5 cm/s for the dynamic facial expressions, was greatest for the eyes closed
      tight expression. The mean maximum acceleration (resultant vector), which ranged
      from 193 to 465 cm/s/s, was greatest for the eyebrow lift expression. Symmetrical
      time plots were obtained. The system documented synkinesis by revealing
      substantial left upper eyelid motion during the nose-wrinkle expression in an
      illustrative case with slight left facial dysfunction. CONCLUSION: This approach
      to facial motion analysis is feasible for the simultaneous, multiregional,
      spatial-temporal assessment of facial expressions. Because motion at relatively
      remote regions could be quantified, this approach is potentially useful for the
      evaluation of synkinesis.

PMID- 10651447
TI  - Identification of differentiating cochlear hair cells in vitro.
AB  - HYPOTHESIS: The expression of hair cell-specific genes involved in
      differentiation was studied in the cell line UB/OC-1 (University Bristol/Organ of
      Corti). BACKGROUND: Studies of gene expression in cochlear hair cells are
      restricted by the small number of cells available and by their experimental
      inaccessibility. The cell line was derived from the H2K(b)tsA58 transgenic mouse,
      which harbors a conditionally expressed immortalizing gene. Two genes that are
      characteristic of hair cells were upregulated during differentiation of UB/OC-1
      cells in vitro. They are the transcription factor Brn3.1, which is essential for
      hair cell differentiation, and the alpha9 subunit of the nicotinic acetylcholine
      receptor that is involved in olivocochlear efferent innervation. METHODS: The
      expression of Brn3.1 and alpha9, at different time points under differentiating
      conditions, was analyzed by semiquantitative reverse-transcription polymerase
      chain reaction (RT-PCR). Western blot analysis and immunofluorescence analysis
      were performed on the cell line with anti-Brn3.1 antibody. RESULTS: Reaction
      products for alpha9 were detected after 3 to 6 days under differentiating
      conditions. Low levels of Brn3.1 were detectable under proliferating conditions
      and increased under differentiating conditions. All cells expressed Brn3.1 under
      differentiating conditions. This temporal pattern of gene expression is very
      closely similar to that found in vivo. CONCLUSION: The cochlear hair cell line
      UB/OC-1 provides a valuable experimental system because it conditionally
      expresses genes essential for normal differentiation and electrophysiology. It
      should prove valuable in the identification and characterization of genes
      involved in development and may provide material for screening new therapeutic
      methods of stimulating recovery and regeneration of hair cells.

PMID- 10651448
TI  - Imaging case of the month. Magnetic resonance imaging demonstrating the origin of
      a vestibular schwannoma to be the superior division of the vestibular nerve.

PMID- 10651449
TI  - Temporal bone pathology case of the month. Congenital fixation of the incus.

PMID- 10651451
TI  - The detection of small acoustic tumors: the stacked derived-band ABR procedure.

PMID- 10651450
TI  - The surgical management of Bell's palsy: a review.
AB  - Facial nerve paralysis is a devastating problem for those affected. Few areas in
      otolaryngology have been as controversial as the management of Bell's palsy. The
      past several decades have witnessed many theories about the etiology and
      pathogenesis of Bell's palsy. In concert with each of these theories has been an
      appropriate management scheme. Because of the nature of the literature, it has
      been difficult for clinicians to unequivocally outline management algorithms. In
      the forefront of this debate is the issue of surgical therapy for a subset of
      these patients. Recent technology has provided some concrete insights into the
      mechanisms underlying Bell's palsy. Further, new clinical studies, albeit
      retrospective, support the need to re-evaluate surgery in the treatment of
      selected patients. The literature regarding the pathophysiology of Bell's palsy
      and the history of facial nerve surgery for this disease are reviewed.

PMID- 10651452
TI  - Diagnosis of acoustic tumors.

PMID- 10651453
TI  - Lower extremity bypass using only duplex ultrasonography: is the time now?
AB  - Imaging for lower extremity arterial bypasses continues to evolve as distal
      target vessels are more frequently small infragenicular arteries. For these
      procedures to be properly planned and executed, accurate anatomic knowledge of
      the lower extremity arterial system and potential venous conduits is essential.
      The utility of current imaging methods for planning lower extremity
      revascularization is examined, including the relatively recent use of duplex
      arterial mapping. Arteriography is a poor "gold standard" in many cases of iliac
      and infrainguinal arterial occlusive disease. Duplex arterial scanning can be
      performed successfully in patients being considered for lower extremity
      revascularization. Patients with isolated stenoses or short occlusions,
      particularly those above the inguinal ligament, may be identified in whom
      percutaneous endovascular therapy is appropriate, depending on their clinical
      presentation. Patients with more severe disease may be taken to the operating
      room, where the quality of the inflow is evaluated with arterial pressure
      measurement. If the inflow pressure is not equal to systemic pressure,
      arteriography with pullback pressure measurements can be performed, and the
      responsible lesion can be identified and appropriately treated. Once inflow
      obstruction has been corrected, intraoperative outflow arteriography is
      performed. If duplex arterial mapping does not demonstrate a distal site for
      bypass, arteriography should be performed, as a preoperative or intraoperative
      study, before considering amputation. This approach should decrease the cost and
      complications of lower extremity revascularization while allowing treatment
      planning for lower extremity vascular occlusive disease to be based on accurate
      anatomic and physiological data.

PMID- 10651454
TI  - Can duplex ultrasound replace arteriography in screening for mesenteric ischemia?
AB  - Duplex examination of the mesenteric vasculature is not a widely performed
      examination, but the published literature documents the ability of this test to
      accurately identify chronic atherosclerotic occlusive disease. The test is a
      recent addition to the armamentarium of noninvasive duplex technology, with
      studies of adequate size for statistical analysis appearing only since 1991. Two
      primary sets of diagnostic threshold values for significant stenoses of the
      superior mesenteric artery (SMA) and the celiac artery have been published and
      subsequently tested for accuracy. One of these recommends use of peak systolic
      velocity (PSV), whereas end diastolic velocity (EDV) was found to be most
      accurate in the other. Both sets of criteria identify overall accuracy of greater
      than 90% for identification of SMA stenosis, and greater than 80% for diagnosis
      of celiac stenosis. Identification of celiac disease may be aided by analysis of
      blood flow direction in the common hepatic artery. The finding of retrograde
      hepatic flow is virtually diagnostic of severe celiac stenosis or complete
      occlusion. Duplex also has been shown capable of identifying anatomic anomalies
      of the mesenteric vessel origins, a situation that occurs in approximately 20% of
      the population. Finally, mesenteric duplex has utility in a variety of less
      common abdominal visceral disorders, but statistical analysis of accuracy and
      adequate identification of quantitative velocity thresholds have not been
      performed. Skilled technologists who have access to appropriate training and
      equipment can master this test. There is little doubt that it can replace
      angiography as a screening tool in the setting of suspected chronic mesenteric
      ischemia.

PMID- 10651455
TI  - Screening and preoperative imaging of candidates for carotid endarterectomy.
AB  - Randomized clinical trials have provided us with clinical guidelines regarding
      the indications for performing carotid endarterectomy in patients who have
      symptomatic and asymptomatic disease. Logically, any patient with a history of
      transient ischemic attacks, amaurosis fugax, or stroke should be evaluated for
      extracranial carotid artery occlusive disease. In asymptomatic patients, however,
      carotid artery surveillance may be helpful in identifying those at risk before
      neurological events. Patients at particularly high risk include those identified
      with (1) manifestations of systemic atherosclerotic disease (peripheral vascular
      disease, coronary artery disease, renovascular disease); (2) presence of a
      carotid bruit; (3) advanced age (> 65 years); and (4) ABI less than 0.7. Duplex
      ultrasonography remains the best and most widely used noninvasive screening
      method, but its accuracy is highly technologist dependent. A high-quality duplex
      study may, in itself, be adequate to determine whether the severity of
      extracranial carotid occlusive disease warrants surgical intervention. Catheter
      based arteriography may be used as an adjunct to validate duplex results, but its
      invasive nature and risk of complications has popularized alternative imaging
      methods. Of these, magnetic resonance angiography (MRA) and spiral computed
      tomographic angiography (CTA) show excellent promise as noninvasive imaging
      techniques for the evaluation of extracranial carotid artery occlusive disease.

PMID- 10651456
TI  - Duplex imaging of lower extremity bypasses, angioplasties, and stents.
AB  - Duplex scan surveillance after lower extremity bypass and endovascular
      interventions can have a favorable impact on outcome. Its application during an
      arterial intervention to exclude technical or hemodynamic abnormalities and as
      part of a postoperative surveillance program to detect stenosis has been shown to
      improve patency. Results of duplex imaging can identify the arterial
      reconstruction at high risk of failure/thrombosis, which requires more intensive
      surveillance. Based on stenosis severity and anatomy, duplex scanning can suggest
      which repair technique (open surgery vs percutaneous balloon angioplasty [PTA])
      is more appropriate. The use of duplex imaging during PTA of graft or peripheral
      artery stenoses (duplex-monitored balloon angioplasty) is recommended to verify
      normalization of velocity spectra, because this end point is associated with
      improved stenosis-free patency. A duplex surveillance program combined with
      correction of progressively stenotic lesions is recommended after lower limb
      bypass and PTA.

PMID- 10651457
TI  - The impact of intravascular ultrasound (IVUS) on endovascular interventions.
AB  - Intravascular ultrasound (IVUS) has undergone rapid evolution with the recent
      expansion of endovascular techniques and devices. This device can aid the
      surgeon, cardiologist, and interventional radiologist by increasing the accuracy
      of imaging and by adding important information to peripheral vascular and
      coronary interventions. Modern intravascular ultrasound provides a detailed view
      of the lumen, wall, and surrounding structures of blood vessels. Compared with
      other modalities, the diagnostic advantages of IVUS for examining arterial wall
      architecture and lesion morphology are evident. IVUS can determine lesion shape,
      length, and configuration, as well as identifying and examining the origins of
      branches and tributaries. Using this information, IVUS can guide the choice of
      appropriate angioplasty techniques, aid in the placement of endovascular devices,
      and assess and follow the efficacy of such interventions. IVUS helps reduce the
      use of radiation and contrast agents. Even though intravascular ultrasound
      requires additional equipment, personnel, and interpretative skills, it can be
      invaluable as a sensitive real-time imaging tool for complex endovascular
      interventions, therapeutic challenges, and diagnostic dilemmas.

PMID- 10651458
TI  - Screening and preoperative imaging of candidates for conventional repair of
      abdominal aortic aneurysm.
AB  - This article summarizes considerations in screening for abdominal aortic aneurysm
      (AAA) and preoperative imaging before conventional surgical repair. Because death
      of this relatively common disease can be prevented by an effective treatment,
      there is great interest in early detection and elective repair. The prevalence of
      AAA in older adults (65 to 80 years of age) varies from 4% to 7%. Factors
      associated with AAA include smoking, age, coronary artery disease, high serum
      cholesterol level, family history, and hypertension. A higher prevalence of AAA
      has been found among first-degree relatives of AAA patients, particularly in men,
      and smoking is an important factor in the development and progression of AAA.
      Screening for AAA may be appropriate in male patients older than 65 years with a
      smoking history, particularly current smokers, who have carotid occlusive
      disease, coronary artery disease, or lower extremity occlusive disease.
      Ultrasound is the screening method of choice and has the benefit of being
      inexpensive and noninvasive. Preoperative imaging serves mainly to establish the
      indication for operation. The vascular surgeon comfortable with discovering
      potentially confusing anatomic configurations or adverse extensions of pathology
      at the time of operation may not require any imaging beyond ultrasound. Specific
      indications for arteriography include suggestion of juxtarenal aneurysm by
      ultrasound or physical examination, clinical evidence of lower extremity arterial
      occlusive disease, uncontrolled hypertension or unexplained creatinine elevation,
      or prior arterial reconstruction. Spiral computed tomography (CT) scan with 3
      dimensional reconstruction and gadolinium magnetic resonance (MR) angiography are
      increasingly useful alternatives to contrast arteriography.

PMID- 10651459
TI  - Preoperative imaging of the aortoiliac anatomy in endovascular aneurysm surgery.
AB  - Endovascular aneurysm repair (EAR) requires precise measurement of aortoiliac
      lengths and diameters to select the most suitable endograft. A combination of
      computed tomography (CT) scanning and contrast arteriography is usually applied
      for this purpose. We have investigated whether spiral CT angiography with
      specialized data processing (CTA) may replace these imaging methods as a sole
      technique for sizing of endografts for EAR and present these data as a background
      for discussion of preoperative imaging before EAR. Typical measurements for EAR
      were performed using CTA, conventional CT scanning, and arteriography. The
      resulting measurements were compared, and their consequences on graft selection
      were studied. Graft diameters based on arteriography were too small in 62% of the
      patients, as compared with CTA. The difference in length sizing between CTA and
      arteriography never exceeded 1 cm. A similar graft diameter was selected by
      conventional CT scan and CTA in 81% of the patients, whereas minor graft
      oversizing by conventional CT scan was found in 14% of the patients. Length
      sizing by conventional CT scanning resulted in underestimation of graft length in
      91% of the patients. Neither conventional CT scanning nor arteriography is
      adequate as a sole preoperative radiological investigation for endograft sizing
      in EAR. Spiral CTA with special processing combines the specific advantages of
      both imaging techniques and should be regarded as the method of first choice for
      this purpose.

PMID- 10651460
TI  - Imaging equipment and techniques for optimal intraoperative imaging during
      endovascular interventions.
AB  - Because endovascular procedures represent an ever-increasing portion of many
      vascular surgery practices, many surgeons are faced with difficult choices.
      Endovascular procedures often require open surgery, and open surgical techniques
      increasingly require fluoroscopic imaging. Without good intraoperative imaging,
      endovascular procedures are difficult and endovascular aneurysm repair is
      impossible. How does one balance the need for optimal imaging without sacrificing
      the ability to safely perform open surgical procedures, especially in the early
      stages of a developing endovascular program? Strategies include the use of a
      portable c-arm and carbon fiber table in the operating room (OR), adding a fixed
      imaging platform to an OR, gaining access to an angiography suite that does not
      meet OR requirements, and modifying it into an interventional suite that does
      meet operating room standards. Once the optimal equipment and facilities have
      been chosen, other choices must be considered. Should a radiology technician be
      hired? Should an interventional radiologist be available to assist or be
      incorporated as a routine member of the team? How will typical operating room
      procedures and technique need to be altered in an effort to optimize
      intraoperative imaging for endovascular procedures? This article gives an
      overview of the many issues that arise as a vascular surgery practice evolves to
      incorporate complex endovascular procedures.

PMID- 10651461
TI  - Postoperative imaging after endovascular AAA repair.
AB  - Unlike open aortic aneurysm repair, follow-up is vital for endovascular aneurysm
      repair. If there is no perigraft flow or endoleak after endograft placement, the
      natural history is a decrease in aneurysm size. However, a significant number of
      aneurysms after endograft repair enlarge without apparent endoleak, and ruptures
      have occurred in this situation. Aneurysms so treated also can develop a late,
      secondary endoleak that leads to rupture. Late stent deformation has been noted
      in abdominal and thoracic applications, and deformation can ultimately lead to
      graft thrombosis, endoleak, and aneurysm rupture. For these reasons, regular
      postoperative imaging will likely be needed for the life of the patient after
      endovascular aortic aneurysm repair, and it must be capable of accurately
      detecting endoleak, aneurysm expansion, graft migration, and graft deformation.
      As with the entire field of endovascular surgery, imaging techniques and
      recommendations regarding their use are changing rapidly. However, a combination
      of examinations appears superior to any single test. Only long-term follow-up
      data can determine which methods will become standard, but physical examination,
      abdominal radiographs, and spiral computed tomography (CT) with specialized 3D
      reconstruction protocols are the current gold standard. In centers of excellence,
      color or power Doppler ultrasound is a useful adjunctive study and ultimately may
      decrease the required frequency of more expensive studies such as CT with
      specialized protocols.

PMID- 10651462
TI  - The role of imaging techniques in evaluating possible graft infections.
AB  - Imaging plays a central role in the management of graft infections. Most graft
      infections are clinically apparent, and imaging techniques are used primarily for
      diagnostic confirmation and operative planning. The accurate diagnosis of less
      overt graft infections requires a thorough understanding of the available imaging
      options. Late aortic graft infections (more than 3 months postoperative) are best
      evaluated initially by computed tomography (CT) or magnetic resonance (MR)
      scanning. CT findings consistent with a graft infection include ectopic gas,
      perigraft fluid, perigraft inflammatory changes, anastomotic pseudoaneurysm, and
      thickening of adjacent bowel. MRI offers the additional advantage of T2-weighted
      images to identify perigraft inflammation and minute quantities of perigraft
      fluid. Radionuclide scanning techniques such as 111indium-labeled WBC scans are
      highly sensitive but suffer from a relative lack of specificity. Duplex
      ultrasonography is best applied to the diagnosis of late infections of
      superficial grafts. Sonographic findings of a graft infection include perigraft
      fluid and pseudoaneurysms. The imaging of early postoperative grafts (less than 3
      months) for infection is problematic because perigraft fluid and inflammatory
      changes persist for up to 3 months postoperatively. Suspected early graft
      infections often require operative exploration for diagnosis. A thorough
      understanding of the utility and limitations of imaging techniques will enable
      the clinician to develop a reasonable diagnostic algorithm that is appropriate
      for each case.

PMID- 10651463
TI  - Enantiospecific pharmacokinetics and pharmacodynamics of ketoprofen in sheep.
AB  - Pharmacokinetic and pharmacodynamic parameters were established for the
      enantiomers of the 2-arylpropionic acid (APA) nonsteroidal anti-inflammatory drug
      (NSAID), ketoprofen (KTP). Each enantiomer was administered separately (1.5
      mg/kg) and in a racemic mixture (3 mg/kg) intravenously (i.v.) to a group of
      eight sheep in a four-way, four-period cross-over study using a tissue cage model
      of inflammation. Plasma disposition of each KTP enantiomer was similar following
      separate administration of the pure compounds compared to administration of the
      racemic mixture. S(+)KTP volume of distribution (Vd(area)) was higher and
      clearance (ClB) faster than those of R(-)KTP. S(+) and R(-)KTP achieved
      relatively low concentrations in exudate and transudate. Unidirectional limited
      chiral inversion of R(-) to S(+)KTP was demonstrated. After R(-)KTP
      administration S(+)KTP was detected in plasma, but not in either exudate or
      transudate. Pharmacokinetic/pharmacodynamic (PK/PD) modelling of the data could
      not be undertaken following R(-)KTP administration because of chiral inversion to
      S(+)KTP, but the pharmacodynamic parameters, calculated maximum effect (Emax),
      concentration producing 50% effect (EC50), Hill's coefficient (N), rate constant
      of elimination of drug effect from the compartment (KeO) and mean equilibration
      half-life (t1/2KeO) were determined for S(+)KTP after administration of the
      racemic mixture as well as the pure compound.

PMID- 10651464
TI  - Plasma angiotensin converting enzyme activity and pharmacokinetics of benazepril
      and benazeprilat in cats after single and repeated oral administration of
      benazepril.HCl.
AB  - The plasma pharmacokinetics of benazepril and its active metabolite,
      benazeprilat, were determined in cats after oral administration of benazepril.HCl
      at dosages of 0.25, 0.5 and 1.0 mg/kg as a single dose (n = 5 per group) and
      after once daily application for 8 days (n = 6 per group). Pharmacodynamics were
      assessed by measurement of plasma angiotensin converting enzyme (ACE) activity.
      After single administration of benazepril.HCl, maximum benazepril concentrations
      were recorded at the first sample (2 h) and declined relatively rapidly with an
      elimination half life (t1/2) of 1.4 h. Highest benazeprilat concentrations were
      recorded at the first sample (2 h) in most cats and declined biphasically with
      half lives of each phase of 2.4 and 27.7 h. With repeated administration, plasma
      benazeprilat concentrations accumulated slightly with accumulation ratios (R) of
      1.46, 1.36 and 1.24 for the 0.25, 0.5 and 1.0 mg/kg dosages of benazepril.HCl,
      respectively (median value of 1.36 for all dosages). All three dosages of
      benazepril.HCl caused marked inhibition of plasma ACE activity in all cats. The
      maximum effect (Emax, % inhibition of ACE as compared to baseline) was > or = 98%
      after single and 100% with repeated administration. The duration of action of
      benazepril.HCl was long, with > 87% (single) and > 90% (repeat) inhibition of
      plasma ACE persisting 24 h after dosing. Benazepril.HCl was well tolerated in all
      animals. Dosages of 0.25-1.0 mg/kg benazepril.HCl once daily are recommended for
      clinical testing in cats.

PMID- 10651465
TI  - A pharmacokinetic study including some relevant clinical effect of medetomidine
      and atipamezole in lactating dairy cows.
AB  - Medetomidine is the most potent and selective alpha2-agonist used in veterinary
      medicine and its effects can be antagonized by the alpha2-antagonist atipamezole.
      The pharmacokinetics of medetomidine and atipamezole were studied in a cross-over
      trial in eight lactating dairy cows. The animals were injected intravenously
      (i.v.) with medetomidine (40 microg/kg) followed by atipamezole i.v. (200
      microg/kg) or saline i.v. after 60 min. Drug concentrations in plasma were
      measured by HPLC. After the injection of atipamezole, the concentration of
      medetomidine in plasma increased slightly, the mean increment being 2.7 ng/mL and
      the mean duration 12.1 min. However, atipamezole did not alter the
      pharmacokinetics of medetomidine. It is likely that the increase in medetomidine
      concentration is caused by displacement of medetomidine by atipamezole in highly
      perfused tissues. The volume of distribution at steady state (Vss) for
      medetomidine followed by saline and medetomidine followed by atipamezole was 1.21
      and 1.32 L/kg, respectively, whereas the total clearance (Cl) values were 24.2
      and 25.8 mL/min x kg. Vss and Cl values for atipamezole were 1.77 mL/kg and 48.1
      mL/min x kg, respectively. Clinically, medetomidine significantly reduced heart
      rate and increased rectal temperature for 45 min. Atipamezole reversed the
      sedative effects of medetomidine. However, all the animals, except one, relapsed
      into sedation at an average of 80 min after injection of the antagonist.

PMID- 10651467
TI  - Molecular and pharmacological characterization of the canine brainstem alpha-2A
      adrenergic receptor.
AB  - This study characterizes the alpha2-adrenergic receptors present in canine
      brainstem. Radioligand binding and reverse transcriptase-polymerase chain
      reaction (RT-PCR) experiments were performed in canine brainstem to identify the
      receptors present and determine the pharmacological properties of these
      receptors. The pKi values derived from radioligand competition curves for a
      number of adrenergic receptor agents at the four alpha2-adrenergic receptor
      subtypes were compared to the canine brainstem. The pKi values at the canine
      brainstem alpha2-adrenergic receptor were consistent with the presence of the
      alpha2A-adrenergic receptor. To determine whether the canine brainstem expressed
      the message for the alpha2A-adrenergic receptor, RT-PCR was performed with
      specific primers for the four subtypes of alpha2-adrenergic receptors. In the
      canine brainstem, only the primers corresponding to a region in the human alpha2A
      adrenergic receptor produced a PCR product. No bands were detected in the canine
      brainstem lanes with the alpha2B-, alpha2C-, or alpha2D-receptor primers. These
      data suggest that the canine brainstem contains the alpha2A-adrenergic receptor.

PMID- 10651466
TI  - Diclazuril in the horse: its identification and detection and preliminary
      pharmacokinetics.
AB  - Diclazuril (4-chlorophenyl [2,6-dichloro-4-(4,5-dihydro-3H-3,5-dioxo-1,2,4
      triazin-2-yl)pheny l] acetonitrile), is a benzeneacetonitrile antiprotozoal agent
      (Janssen Research Compound R 64433) marketed as Clinacox . Diclazuril may have
      clinical application in the treatment of Equine Protozoal Myeloencephalitis
      (EPM). To evaluate its bioavailability and preliminary pharmacokinetics in the
      horse we developed a sensitive quantitative high-pressure liquid chromatography
      (HPLC) method for diclazuril in equine biological fluids. MS/MS analysis of
      diclazuril in our HPLC solvent yielded mass spectral data consistent with the
      presence of diclazuril. After a single oral dose of diclazuril at 2.5 g/450 kg
      (as 500 g Clinacox), plasma samples from four horses showed good plasma
      concentrations of diclazuril which peaked at 1.077 +/- 0.174 microg/mL (mean +/-
      SEM) with an apparent plasma half-life of about 43 h. When this dose of Clinacox
      was administered daily for 21 days to two horses, mean steady state plasma
      concentrations of 7-9 microg/mL were attained. Steady-state levels in the CSF
      ranged between 100 and 250 ng/mL. There was no detectable parent diclazuril in
      the urine samples of dosed horses by HPLC or by routine postrace thin layer
      chromatography (TLC). These results show that diclazuril is absorbed after oral
      administration and attains steady-state concentrations in plasma and CSF. The
      steady state concentrations attained in CSF are more than sufficient to interfere
      with Sarcocystis neurona, whose proliferation is reportedly 95% inhibited by
      concentrations of diclazuril as low as 1 ng/mL. These results are therefore
      entirely consistent with and support the reported clinical efficacy of diclazuril
      in the treatment of clinical cases of EPM.

PMID- 10651468
TI  - Development of a cough induction test in pigs: effects of SR 48968 and enalapril.

PMID- 10651469
TI  - [EEG findings in hemolytic-uremia syndrome cases without consciousness disorder
      or convulsions].

PMID- 10651470
TI  - Effect of gamma-linolenic acid on plasma and membrane lipids and renal
      prostaglandins in old subjects.

PMID- 10651471
TI  - 5th California Microscopy Colloquium. The California State University and
      Northern California Society for Microscopy. October 2, 1999. Abstracts.

PMID- 10651472
TI  - Commentary: has hypericum found its place in antidepressant treatment?

PMID- 10651473
TI  - Cancer survival in Britain. Diagnosis in primary care is important.

PMID- 10651474
TI  - Cancer survival in Britain. Reliable data on stage distribution are essential.

PMID- 10651475
TI  - Cancer survival in Britain. Perhaps Britain should adopt French model.

PMID- 10651476
TI  - Cancer survival in Britain. Survival for over five years after diagnosis does not
      mean cure.

PMID- 10651477
TI  - Evidence based palliative care. Specialist palliative care teams are going to
      have to take on end stage non-cancer disease.

PMID- 10651478
TI  - Relation of C pneumoniae antibodies to ischaemic heart disease. Finnish study
      finds significant association between raised IgG, but not IgA, titres and
      mortality.

PMID- 10651479
TI  - Breast feeding and obesity. Prolonging breast feeding to reduce obesity may be a
      burden.

PMID- 10651480
TI  - Effectiveness of glucocorticoids in treating croup. General practitioners must be
      ready to treat children.

PMID- 10651481
TI  - Effectiveness of glucocorticoids in treating croup. Suitable formulations of oral
      glucocorticoids are available in primary care.

PMID- 10651482
TI  - Effectiveness of glucocorticoids in treating croup. Children with croup should
      receive corticosteroids in primary care: results of audit.

PMID- 10651483
TI  - Appearances can be deceptive: an APC 1893del4 mutation with unusual properities.
      Mutations in brief no. 171. Online.
AB  - During a systematic search for germ-line APC mutations causative of familial
      adenomatous polyposis, we discovered what appeared to be an insertion mutation
      while simply checking exon 14PCR products by agarose gel electrophoresis (AGE).
      On AGE, exon 14PCR product from the known affected member of this family gave two
      bands: one of normal length, the other retarded on the gel equivalent to an
      increase in length of some 20-25 bp. Direct sequencing of DNA purified from the
      two bands gave identical results, and was consistent with amplification from the
      same two alleles: one wild-type, and the other having an 1893del4 mutation. This
      suggested that the normal length band on AGE consisted of DNA homoduplexes
      (normal:normal and mutant:mutant) and the retarded band consisted of DNA
      heteroduplexes (normal:mutant and mutant:normal). This hypothesis was tested by
      subjecting purified material from each of the two bands alone to a single cycle
      of heat denaturation and annealing, which showed that either band was equally
      capable of regenerating both bands. Because the anomalous migration of the
      heteroduplexes is observed in the presence of ethidium bromide, it implies that
      they have a cruciform of cruciform-like structure. This case illustrates the
      necessity to be aware of anomalous DNA migration and always sequence all putative
      mutations.

PMID- 10651484
TI  - Five novel somatic CDKN2/p16 mutations identified in melanoma, glioma and
      carcinoma of the pancreas. Mutations in brief no. 170. Online.
AB  - Germ-line mutations in the p16/CDKN2 gene are known to predispose to melanoma.
      This gene belongs to a family of cyclin-dependent kinase inhibitors and blocks G1
      S progression. The occurrence of p16/CDKN2 germline mutations in 12 Icelandic
      melanoma kindreds (kindreds with two or more cases of melanoma or melanoma,
      pancreas and/or glioma cases) was examined. No germ-line mutation was found,
      however five mutations not previously discribed in solid tumours were identified,
      Pro48Leu, Ala57Val, Gly89Asp, Leu117Met, Tyr129Stop.

PMID- 10651485
TI  - Two novel mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene in X
      linked retinitis pigmentosa (RP3). Mutations in brief no. 172. Online.
AB  - Recently a new gene called RPGR (retinitis pigmentosa GTPase regulator) was
      isolated in Xp21.1 and found to be mutated in patients with RP3 type X-linked
      retinitis pigmentosa. Two new mutations, the first a single base pair deletion
      and the other a two base pairs deletion, have been found in one Spanish and one
      Italian family.

PMID- 10651486
TI  - First mutation (S340X) in choroideremia gene in a Spanish family. Mutations in
      brief no. 173. Online.
AB  - A study of choroideremia gene was performed in Spanish families affected with
      this disorder. One abnormal pattern was detected in exon eight corresponding to a
      new mutation not described before. The mutation was identified as a nonsense
      mutation S340X.

PMID- 10651487
TI  - Identification and molecular characterization of the new alpha-1-antitrypsin
      deficient allele PI Y barcelona (Asp256-->Val and Pro391-->His). Mutations in
      brief no. 174. Online.
AB  - To characterize the molecular basis of the "new" alpha1-antitrypsin (alpha1AT)
      deficient variant, PI Y barcelona, DNA sequence analysis of the coding exons of
      the alpha1AT gene was carried out using an amplification DNA technique and direct
      sequencing. The PI Y barcelona allele differs from the normal M1(Val213) allele
      sequence by two point substitutions: a transversion of GAT TO GTT in exon III in
      the codon for residue 256, resulting in the amino acid change of Asp256 to
      Val256, and a transversion of CCC to CAC in exon V in the codon for residue 391,
      resulting in the amino acid substitution of Pro391 to His391. On isoelectric
      focusing analysis these substitutions result in a cathodal migration of the "new"
      variant close to the PI Z. The index case, diagnosed with severe obstructive
      pulmonary disease, initially phenotyped a PI ZZ, was homozygous for PI Y
      barcelona. The patient's serum alpha1AT level was 16 mg/dL (normal values 115-220
      mg/dL). Inheritance of the PI Y barcelona was confirmed by family study. Amino
      acid substitution in postion 391 occurs in the C-terminal peptide region, which
      shows a high degree of homology with the family of serpins. Pro391 is considered
      to have special relevance in the secretion of alpha1AT.

PMID- 10651488
TI  - A novel missense mutation D513G in exon 10 of the cystic fibrosis transmembrane
      conductance regulator (CFTR) gene identified in a French CBAVD patient. Mutations
      in brief no. 175. Online.
AB  - Congenital bilateal absence of the vas deferens (CBAVD) with obstructive
      azoospermia is a congenital reproductive disorder that affects one in 10000 male
      individuals. The observation that many men presenting with CBAVD have mutations
      in their CFTR genes had led to the proposal that CBAVD may be a primary genital
      form of cystic fibrosis. We report here one novel mutation located in exon 10 of
      the CFTR gene. This mutation, named D513G (A-->G at position 1670), has been
      found in one of 83 patients with CBAVD from France, the analysis of exon 10 using
      a chemical clamp DGGE assay allowed us to identify three CF mutations AEF508
      (37/166; 22%), AE1507 (1/166; 0/6%) and D513G (1/166; 0.6%), and two variants
      M470V and E528E (1716 G>A). The novel D513G mutation has not been found in more
      than 200 non-CF chromosomes and in a sample of 300 CF chromosomes from French
      classical CF patients.

PMID- 10651490
TI  - Emergency care. Cycle saviors.

PMID- 10651489
TI  - Barley aleurone cell death is not apoptotic: characterization of nuclease
      activities and DNA degradation.
AB  - Barley aleurone cells undergo programmed cell death (PCD) when exposed to
      gibberellic acid (GA), but incubation in abscisic acid (ABA) prevent PCD. We
      tested the hypothesis that PCD in aleurone cells occurs by apoptosis, and show
      that the hallmark of apoptosis, namely DNA cleavage into 180 bp fragments, plasma
      membrane blebbing, and the formation of apoptotic bodies do not occur when
      aleurone cells die. We show that endogenous barley aleurone nucleases and
      nucleases present in enzymes used for protoplast preparation degrade aleurone DNA
      and that DNA degradation by these nucleases is rapid and can result in the
      formation of 180 bp DNA ladders. Methods are described that prevent DNA
      degradation during isolation from aleurone layers or protoplasts. Barley aleurone
      cells contain three nucleases whose activities are regulated by GA and ABA. CA
      induction and ABA repression of nuclease activities correlate with PCD in
      aleurone cells. Cells incubated in ABA remain alive and do not degrade their DNA,
      but living aleurone cells treated with GA accumulate nucleases and hydrolyze
      their nuclear DNA. We propose that barley nucleases play a role in DNA cleavage
      during aleurone PCD.

PMID- 10651491
TI  - Youths & violence. Intervention policy.

PMID- 10651492
TI  - Nursing home squeeze. Therapist exodus.

PMID- 10651494
TI  - Women's health. Progress--for some.

PMID- 10651493
TI  - Insurance ratings. Point of no return?

PMID- 10651495
TI  - Should biomedical research be published on the Web?

PMID- 10651496
TI  - Managed care. Avoidance tactics.

PMID- 10651497
TI  - Tailored health info. Surfing's up.

PMID- 10651498
TI  - A pregnant job candidate.

PMID- 10651499
TI  - Office visits. Losing the wait.

PMID- 10651500
TI  - Policing the Web. For kids' sake.

PMID- 10651501
TI  - In tempo. Interview by Chris Serb.

PMID- 10651502
TI  - Four e-mails.

PMID- 10651503
TI  - Challenges spark creativity.

PMID- 10651504
TI  - Y2K plans. Party central.

PMID- 10651505
TI  - Asthma management. Learning to breathe.

PMID- 10651507
TI  - Professional education. Back to school.

PMID- 10651506
TI  - Pain management. No-pain gain.

PMID- 10651508
TI  - Raise income levels for Medicare disabled?

PMID- 10651510
TI  - Case management. Consumer consultant.

PMID- 10651509
TI  - Brand identity. The dreaded H-word.

PMID- 10651511
TI  - The cost of doctors' perks.

PMID- 10651513
TI  - Odd contrasts.

PMID- 10651512
TI  - On the front line. Interview by Chris Serb.

PMID- 10651514
TI  - Time for accountability.

PMID- 10651515
TI  - Recent insights into pathogenesis and control of asthma and atopic diseases.

PMID- 10651516
TI  - Proceedings of the World Conference on Pediatric Neurosurgery, 2000 A.D.
      Martinique, 27 November - 4 December 1999.

PMID- 10651517
TI  - Directive 98/44/EC of the European Parliament and of the Council of 6 July 1998
      on the legal protection of biotechnological inventions.

PMID- 10651518
TI  - Biotechnologies and acute hepatic failure.
AB  - Orthotopic liver transplantation survival for patients with acute liver failure
      is poor (50%). Mortality on the waiting list is high due to the lack of donors.
      For these reasons, the possibility of sustaining hepatic function by extra
      corporeal liver perfusion must be considered. In this experimental research, two
      groups of pigs have been submitted to total de-vascularisation of the liver
      causing acute hepatic failure. In the first group (4 pigs) no extra-corporeal
      assistance has been used after total de-vascularisation. All pigs died between 16
      and 33 hours after the acute hepatic failure was induced. In the second group (8
      pigs) after complete hepatic de-vascularisation an extra-corporeal hepatic
      support by continuous allo-perfusion of isolated liver was performed using the
      Abouna-Costa extra-corporeal circuit. All pigs were observed during the acute
      hepatic failure which lasted from 6.30 to 7.30 hours. The data that were more
      positively influenced by the extra-corporeal assistance were ammonia and lactates
      that improved after the application of hepatic assistance.

PMID- 10651520
TI  - Web alert. Biopolymers model systems.

PMID- 10651519
TI  - Guess what? Inflammatory disseminated morphea profunda.

PMID- 10651521
TI  - Anion recognition: synthetic receptors for anions and their application in
      sensors.
AB  - Important contributions to the field of anion sensing include electrochemical
      lipophilic uranyl salophene receptors incorporated into membranes that act as
      fluoride-selective potentiometric microsensors. A promising optical-based sensor,
      selective for cyclic AMP, involves a preorganized, molecularly imprinted polymer
      employing an intrinsic fluorophore. Competition methods using ensembles of
      recognition units and external indicators have been used to sense citrate in
      highly competitive media and micromolar concentrations of inositol(tris)phosphate
      in water. In addition, DNA dendrimers immobilized on a quartz-crystal
      microbalance acted as an elegant biosensor for Cryptosporidium DNA. These designs
      display the varied methods of anion detection currently being pursued.

PMID- 10651522
TI  - [Twenty-seven years with the nomenclature of Achromobacter xylosoxidans].

PMID- 10651523
TI  - [Diagnosis of enterohaemorrhagic Escherichia coli by the detection of vero toxin
      (or Shiga toxin)].

PMID- 10651524
TI  - Management of renal angiomyolipoma: a report of 53 cases.

PMID- 10651525
TI  - Frequency and causes of fluid absorption: a comparison of three techniques for
      resection of the prostate under continuous pressure monitoring.

PMID- 10651526
TI  - Contemporary results of radical radiotherapy for bladder transitional cell
      carcinoma in a district general hospital.

PMID- 10651527
TI  - The tunnelled nephrostomy tube.

PMID- 10651528
TI  - A simple method of treating priapism in children.

PMID- 10651529
TI  - Bloodless circumcision.

PMID- 10651530
TI  - The biomechanics of prevention and treatment for low back pain: 2nd international
      workshop.

PMID- 10651532
TI  - [Clinical course of symptomatic duodeno-jejunal Crohn's disease].
AB  - AIMS: To describe retrospectively the characteristics of inaugural, symptomatic
      Crohn's disease of the upper gastrointestinal tract. METHODS: Eighteen patients
      (12 male and 6 female) with symptomatic Crohn's disease of the upper intestinal
      tract and without previous distal localisation were studied. RESULTS: Mean age of
      patients at diagnosis (21.3 years) was less than that usually reported in Crohn's
      disease. The time elapsed from first symptoms to diagnosis (mean = 29.8 months)
      was remarkably long for some patients, mainly as a result of an unusual clinical
      presentation. Abdominal pain and weight loss were the most common presenting
      features; diarrhea was rarely the main symptom. Persistent anorexia and weight
      loss without digestive symptoms had led to a diagnosis of anorexia nervosa in 4
      patients. Zollinger-Ellison syndrome was the initial diagnosis in 3 other
      patients. Sixteen patients were followed during at least 2 years. All were
      treated with steroids for their first attack and 75 % required immunosuppressive
      therapy for steroid dependence. At the end of follow-up, 6 patients only were in
      remission without treatment or under mesalamine. CONCLUSION: Crohn's disease with
      initial symptomatic lesions of the upper gastrointestinal tract occurs mainly in
      young male patients. The clinical presentation may be very unusual, leading to
      misdiagnosis. The clinical course is close to that of diffuse jejunoileitis.

PMID- 10651531
TI  - [Percutaneous radiofrequency ablation of hepatic metastases. Preliminary
      experience].
AB  - AIM: To evaluate the efficiency of percutaneous radiofrequency ablation in the
      treatment of liver metastases. METHODS: Eighteen patients with 31 liver
      metastases, mainly from colorectal cancer, 10 - 35 mm in diameter (m = 23),
      underwent 26 courses of percutaneous radiofrequency ablation. Fifteen patients
      had previously undergone hepatectomy, and 3 patients had contra-indications to
      surgery. Imaging guidance was ultrasound in 21 patients, CT in 4 (tumors not seen
      with ultrasound), and both in 1. A generator working at 450 KHz with a maximum
      output power of 150 W was used to treat each lesion for 18 - 20 min. Treatment
      was monitored with real time ultrasound. RESULTS: Among the 12 patients followed
      more than 3 months, only one of the 24 treated lesions recurred after a mean
      follow up of 259 ? 109 days. Liver disease was controlled in 8 of the 12 patients
      after 90 - 509 days (m = 306). Among these 8 patients, 3 were tumor free after
      559, 378 and 90 days, respectively; 2 died tumor free of non-tumoral disease
      (pulmonary embolism, digestive bleeding); 3 developed lung metastases treated
      with chemotherapy (n = 2) or surgery (n = 1). Three of the 12 patients had
      widespread hepatic tumor occurrence, and one patient died of these metastases.
      Six patients experienced mild skin burns, but no major complication was observed.
      CONCLUSION: Radiofrequency ablation of hepatic metastases appears safe and
      promising in this preliminary experience. Further investigation is needed.

PMID- 10651533
TI  - [Epidemiology of gastro-esophageal-reflux in general practice. . Predictive
      factors for health care utilization in the course of a year].
AB  - AIM: To assess the epidemiology and course of GORD, treatment demand, and factors
      predictive of GORD course in a 1-year study in patients with heartburn consulting
      general practitioners. METHODS: A total of 984 patients with pyrosis were
      included by general practitioners. After the initial visit, they had follow up at
      3, 6 and 12 months by phone contact. RESULTS: Most patients (87%) had been
      suffering from heartburn for 4+/-1.5 years; upper GI endoscopy had been performed
      in 63% of patients. Patients evaluated the symptoms of the current episode as
      mild (6%), moderate (60%), or severe/incapacitating (34%). During the year of
      follow up, 12% of the patients were free of heartburn; the mean number of
      consultations with general practitioners and gastroenterologists was 5.1 and 0.5
      respectively. At day 90, discomfort due to heartburn was absent in 4% of
      patients, slight in 51%, moderate in 32%, and severe in 6%. At day 360,
      predictive factors for discomfort were: discomfort related to heartburn on D90,
      the length of time the patients had been suffering from GORD, and the main reason
      for consultation on D1; patients for whom heartburn was not the main reason for
      consultation on D1 experienced a higher level of discomfort. The predictive
      factors for the extent of treatment demand over 12 months were: age, discomfort
      related to heartburn on D90, severity on D1, the frequency of episodes prior to
      the episode on D1 and the levels of stress and anxiety measured on D1.
      CONCLUSIONS: Epidemiologic characteristics of patients with heartburn consulting
      a general practitioner were different from these of the general population.
      Treatment demand depends both on severity of heartburn and level of stress and
      anxiety.

PMID- 10651535
TI  - [Acute pancreatitis and interferon].

PMID- 10651536
TI  - [Endoscopic biliary sphincterotomy can be insufficient for the treatment of
      benign sphincter of Oddi stenosis].

PMID- 10651534
TI  - [New drugs in gastrointestinal oncology. Current status and future directions].

PMID- 10651537
TI  - [Symptomatic gastric diverticulum].

PMID- 10651538
TI  - [Risk of transmission of hepatitis C virus by biopsy clamps during
      gastrointestinal biopsy].

PMID- 10651539
TI  - [Hepatitis C virus genotypes among chronic hemodialysis patients in Dakar].

PMID- 10651541
TI  - Analysis of genetic and environmental factors in common diseases. Proceedings of
      the Genetic Analysis Workshop 11. Arcachon, France, September 8-10, 1998.

PMID- 10651540
TI  - [Cystic duct morphology and stones of the main bile duct].

PMID- 10651542
TI  - [Current trends in the studies of myasthenia gravis].

PMID- 10651543
TI  - [Drug-resistant Neisseria gonorrhoeae--with special reference to new quinolone
      resistant Neisseria gonorrhoeae].

PMID- 10651544
TI  - High frequency of bacteremia with endoscopic treatment of esophageal varices in
      advanced cirrhosis.
AB  - OBJECTIVES: The fregency of bacteremia after endoscopic variceal band ligation
      (EVL) is reported to be lower when compared to that after endoscopic variceal
      sclerotherapy (EVS). However, there are conflicting reports on the infectious
      sequelae after EVL. AIM: To compare the frequency on bacteremia and infectious
      sequelae after EVL and EVS in patients with cirrhosis of liver. METHODS:
      Bacteremia and infectious sequelae were studied in 32 sessions of EVL in 18
      cirrhotic patients (Child-Pugh class A-6, B-5, C-7), 30 sessions of EVS in 22
      cirrhotic patients (Child-Pugh class A-2, B-5, C-15) and 14 diagnostic upper
      gastrointestinal endoscopies. Blood cultures were collected before, during and 30
      minutes after the procedure. Patients were observed for infectious sequelae
      during subsequent hospitalization. RESULTS: Before the procedure, bacteremia was
      present in 7/62 (11%) sessions. Significant bacteremia during and 30 min post
      procedure developed in 8/32 (25%) and 12/30 (40%) of EVL and EVS sessions,
      respectively (p = ns), and in 1/14 (7%) upper gastrointestinal endoscopy
      sessions. There was more frequent bacteremia with severe liver disease (Child
      Pugh class A-0/6, B-1/5. C-7/21; p = 0.09) in the EVL but not in the EVS group
      (Child-Pugh class A-1/3, B-2/5, C-9/22; p = ns). The incidence was higher with
      emergency sclerotherapy compared to elective sclerotherapy (6/8 [75%] vs 6/22
      [27%]; p <0.01). One patient in the EVS group developed spontaneous bacterial
      peritonitis. CONCLUSIONS: Bacteremia occurs frequently following EVL and EVS in
      patients with advanced liver diseases. In the EVS group it is more common after
      emergency sclerotherapy. This bacteremia is rarely associated with significant
      infectious sequelae.

PMID- 10651545
TI  - Response to 'The multiple self: working with dissociation and trauma'.

PMID- 10651546
TI  - Comment on 'The multiple self'.

PMID- 10651547
TI  - Art within analysis: scapegoat, transference and transformation.
AB  - Through clinical example and pictorial illustration, the author examines ways in
      which art offers a particular means of psychological transformation in states
      which may otherwise be in expressable. A transference to the art work itself is
      proposed. It is submitted that, mediated within the transference/
      countertransference dynamic, this 'scapegoat transference' facilitates a
      particular process of psychological differentiation. The aesthetic qualities of
      art presented within analysis will resonate with other countertransference
      affects. Clinical material demonstrates how observation of this--aesthetic
      countertransference--leads to a distinction between the 'diagrammatic' and the
      'embodied image. The process of integration of shadow material is furthered by
      the temporary safe-keeping of the art work by the analyst.

PMID- 10651548
TI  - The relevance of attachment theory to a contemporary Jungian view of the internal
      world: internal working models, implicit memory and internal objects.
AB  - In this paper I examine the various meanings of the term 'internal object' and
      the differences between various theoretical models for the formation of internal
      objects. I suggest that the idea in attachment theory of 'internal working
      models' emphasizes the internal world as one consisting of unconscious
      internalized patterns of emotional relationships. The term 'internal object'
      lacks this clarity and the different meanings it carries within differing
      theoretical frameworks are a source of confusion. I describe the role implicit
      memory plays in the formation of 'internal working model's and suggest that these
      offer us an alternative explanation for unconscious fantasy and for object
      relationships to that of instinctual drives. This model is then brought to bear
      on contemporary Jungian concepts of the internal world, with a suggestion that,
      seen in this light, Jung's formulation of the concept of the complex has many
      features in common with the 'internal working model' of attachment theory.

PMID- 10651549
TI  - Is analytical psychology a religion? Jung's search for a substitute for lost
      faith.
AB  - Analytical psychology does not aim at curing neurotic symptoms, but at bringing
      about a change in the patient's attitude to him or her self, and therefore to
      life in general. This new attitude can be described as religious, but it has
      nothing to do with creeds or conventional forms of worship. Analytical psychology
      is not a religon, but can be described as a prolegomenon to religion or religion
      in statu nascendi.

PMID- 10651550
TI  - Is analytical psychology a religion? In statu nascendi.
AB  - This paper elucidates and discusses Jung's conceptions of the relation between
      psychology, psychotherapy and religion.

PMID- 10651551
TI  - Is analytical psychology a religion? Rationalist and romantic approaches to
      religion and modernity.
AB  - The relationship between analytical psychology and religion is part of the larger
      issue of the relationship between modernity and religion. There are three main
      views on the issue. The fundamentalist position sets religion against modernity
      and opts for religion over modernity. What I call the 'rationalist' position
      likewise sets religion against modernity but opts for modernity over religion. By
      contrast to both views, what I call the 'romantic' position reconciles religion
      with modernity. Rationalists maintain that religion can exist only in so far as
      it serves as an explanation of the physical world, which the rise of science now
      precludes. Romantics maintain that religion, while serving as an explanation of
      the physical world till dislodge by science, is at heart anything but an
      explanation. The toppling of the religions explanation by the scientific one, far
      from dooming religion, prods religion into making explicit what it has in fact
      been all along. By this categorization, Jung is overwhelmingly a romantic. For
      him, the function of religion has always been more psychological than
      explanatory, and the rise of science does not preclude the continuing existence
      of religious myths as a psychological rather than an explanatory phenomenon. For
      those for whom science does spell the demise of religion, secular myths can
      replace religious ones, and those secular myths are more secular versions of
      religions myths than secular alternatives to religions myths. Yet even if for
      Jung religion can still exist today because religion is in fact psychology, it
      does not follow that psychology is therefore a religion.

PMID- 10651552
TI  - Comments on Storr's and Shamdasani's articles.

PMID- 10651553
TI  - Metaphor, mysticism and madness. A response to the three papers on 'Is analytical
      psychology a religion?'.

PMID- 10651554
TI  - An appreciation of Jane Bunster. 17 April 1930-16 June 1999.

PMID- 10651555
TI  - Recreational physical activity and the risk of cholecystectomy in women.

PMID- 10651556
TI  - Recreational physical activity and the risk of cholecystectomy in women.

PMID- 10651557
TI  - The risk of recurrent deep venous thrombosis.

PMID- 10651558
TI  - Reboxetine and hyponatremia.

PMID- 10651560
TI  - Fever in immunocompromised patients.

PMID- 10651559
TI  - Amiodarone in out-of-hospital cardiac arrest.

PMID- 10651561
TI  - Hot-tub therapy for type 2 diabetes mellitus.

PMID- 10651562
TI  - Hot-tub therapy for type 2 diabetes mellitus.

PMID- 10651564
TI  - US tightens on 'speculative' claims.

PMID- 10651563
TI  - Rapid serogroup switching in Neisseria meningitidis.

PMID- 10651565
TI  - Taking the squeeze off sperm.

PMID- 10651566
TI  - Genomics companies boom on New York stock exchange.

PMID- 10651567
TI  - 'The role of science is to illuminate political choices, not enforce them'.

PMID- 10651568
TI  - Parry-Romberg syndrome with ipsilateral cerebral atrophy of neonatal onset.

PMID- 10651569
TI  - Symmetrical reinfection lupus vulgaris.

PMID- 10651570
TI  - An additional case of epidermolysis bullosa simplex herpetiformis of Dowling
      Meara with mottled pigmentation.

PMID- 10651571
TI  - HLA-B27-positive familial case of a daughter with juvenile pustular psoriasis and
      her father with ankylosing spondylitis.

PMID- 10651573
TI  - [Psychiatric state in epilepsy: the current concept].

PMID- 10651572
TI  - Oral cimetidine treatment of molluscum contagiosum.

PMID- 10651574
TI  - [Image analysis and physiopathology of the mechanism of sleep- wakefulness].

PMID- 10651575
TI  - [Japanese Society of Family Study and Family Therapy: recent development in
      family therapy].

PMID- 10651576
TI  - [Concerning the question: Abdominal tumors in children].

PMID- 10651577
TI  - [Standing up for scientific dentistry].

PMID- 10651578
TI  - [Dental care in Switzerland--a model case for the organization of public health
      services?].

PMID- 10651579
TI  - [Of the tooth of time].

PMID- 10651580
TI  - [Basel--a pivotal support of dentistry in Switzerland].

PMID- 10651581
TI  - [Oral surgeons found a society].

PMID- 10651582
TI  - [The trump card for us dentists: quality guidelines].

PMID- 10651583
TI  - [Emerging issues and future directions in remineralization. A report on the
      Remineralization Symposium of 22-24 June 1999 in the Forsyth Dental Center,
      Boston, USA].

PMID- 10651584
TI  - [Anonymous (South German/Austrian): "Saint Apollonia", The BonaDent Collection].

PMID- 10651585
TI  - [2nd. comments on the reader's letter "The fluoride content in children's
      toothpastes"].

PMID- 10651586
TI  - Enamel fluorosis.

PMID- 10651587
TI  - [A crime of murder in Zurich. Who was the treating dentist?].

PMID- 10651588
TI  - [Health resources in units of the Health Secretariat, 1998].

PMID- 10651589
TI  - [The Cornelia de Lange syndrome].

PMID- 10651590
TI  - [Major General of the Guards in the medical service (on the centenary of the
      birth of A. N. Grigor'ev)].

PMID- 10651591
TI  - [An outstanding military field ophthalmologist (on the centenary of the birth of
      B. L. Poliak)].

PMID- 10651593
TI  - [Dissertations defended in 1999].

PMID- 10651592
TI  - [Directives from the Main Military Medical Administration of the Ministry of
      Defense of the Russian Federation].

PMID- 10651594
TI  - [The diagnosis and treatment of prostatic cancer].

PMID- 10651595
TI  - [Physical methods in the combined treatment of tuberculosis patients].

PMID- 10651596
TI  - Infectious aortitis: an uncommon manifestation of infection with Streptococcus
      pneumoniae.

PMID- 10651597
TI  - Effectiveness of manual physical therapy and exercise in osteoarthritis of the
      knee. A randomized, controlled trial.
AB  - BACKGROUND: Few investigations include both subjective and objective measurements
      of the effectiveness of treatments for osteoarthritis of the knee. Beneficial
      interventions may decrease the disability associated with osteoarthritis and the
      need for more invasive treatments. OBJECTIVE: To evaluate the effectiveness of
      physical therapy for osteoarthritis of the knee, applied by experienced physical
      therapists with formal training in manual therapy. DESIGN: Randomized, controlled
      clinical trial. SETTING: Outpatient physical therapy department of a large
      military medical center. PATIENTS: 83 patients with osteoarthritis of the knee
      who were randomly assigned to receive treatment (n = 42; 15 men and 27 women
      [mean age, 60 +/- 11 years]) or placebo (n = 41; 19 men and 22 women [mean age,
      62 +/- 10 years]). INTERVENTION: The treatment group received manual therapy,
      applied to the knee as well as to the lumbar spine, hip, and ankle as required,
      and performed a standardized knee exercise program in the clinic and at home. The
      placebo group had subtherapeutic ultrasound to the knee at an intensity of 0.1
      W/cm2 with a 10% pulsed mode. Both groups were treated at the clinic twice weekly
      for 4 weeks. MEASUREMENTS: Distance walked in 6 minutes and sum of the function,
      pain, and stiffness subscores of the Western Ontario and McMaster Universities
      Osteoarthritis Index (WOMAC). A tester who was blinded to group assignment made
      group comparisons at the initial visit (before initiation of treatment), 4 weeks,
      8 weeks, and 1 year. RESULTS: Clinically and statistically significant
      improvements in 6-minute walk distance and WOMAC score at 4 weeks and 8 weeks
      were seen in the treatment group but not the placebo group. By 8 weeks, average 6
      minute walk distances had improved by 13.1% and WOMAC scores had improved by
      55.8% over baseline values in the treatment group (P < 0.05). After controlling
      for potential confounding variables, the average distance walked in 6 minutes at
      8 weeks among patients in the treatment group was 170 m (95% CI, 71 to 270 m)
      more than that in the placebo group and the average WOMAC scores were 599 mm
      higher (95% CI, 197 to 1002 mm). At 1 year, patients in the treatment group had
      clinically and statistically significant gains over baseline WOMAC scores and
      walking distance; 20% of patients in the placebo group and 5% of patients in the
      treatment group had undergone knee arthroplasty. CONCLUSIONS: A combination of
      manual physical therapy and supervised exercise yields functional benefits for
      patients with osteoarthritis of the knee and may delay or prevent the need for
      surgical intervention.

PMID- 10651598
TI  - Epidemiologic relation between HIV and invasive pneumococcal disease in San
      Francisco County, California.
AB  - BACKGROUND: Patients with AIDS have a high incidence of invasive pneumococcal
      disease, but no population-based data are available on secular trends or rates of
      this disease in specific demographic groups. OBJECTIVE: To compare clinical
      characteristics, rates, and trends of pneumococcal disease in HIV-infected and
      non-HIV-infected persons. DESIGN: Population-based laboratory surveillance and
      chart review. SETTING: All of the 13 microbiology laboratories in San Francisco
      County, California. PATIENTS: Persons who had a sterile site culture that was
      positive for Streptococcus pneumoniae between October 1994 and June 1997.
      MEASUREMENTS: Stratified incidence rates and adjusted rate ratios, serotyping of
      isolates, and comparison of secular trends and rates according to census tract by
      Poisson regression. RESULTS: Persons infected with HIV accounted for 54.2% of 399
      patients 18 to 64 years of age who had pneumococcal disease. The incidence of
      pneumococcal disease per 100 000 person-years was 35.0 cases overall and 802.9
      cases in patients with AIDS. Compared with persons who were not known to be HIV
      infected, the rate ratio for patients with AIDS was 46:0 (95% CI, 36.0 to 58.9);
      55.2% of cases were attributable to HIV. In HIV-infected patients, 82.5% of
      isolates were serotypes that are included in the pneumococcal polysaccharide
      vaccine. The incidence of pneumococcal disease in black patients with AIDS
      (2384.6 cases per 100 000 person-years) was 5.4 times that in nonblack patients
      with AIDS. Rates by census tract were inversely associated with income (P <
      0.001), During the study period, the incidence of pneumococcal disease decreased
      from 10.6 cases per 1000 person-years to 4.2 cases per 1000 person-years in
      patients with AIDS (P = 0.004, Poisson regression). CONCLUSIONS: In a community
      with a high prevalence of HIV infection, much of the burden of pneumococcal
      disease was attributable to AIDS. High incidence rates were seen in young adults
      and especially in black persons. Efforts to increase pneumococcal vaccination
      rates should target HIV-infected adults, particularly those living in poor urban
      areas.

PMID- 10651600
TI  - Discontinuation of chemoprophylaxis against Pneumocystis carinii pneumonia in
      patients with HIV infection. HIV Outpatient Study (HOPS) Investigators.
AB  - BACKGROUND: HIV-infected patients with sustained immunologic improvement from
      antiretroviral therapy may be able to discontinue chemoprophylaxis against
      Pneumocystis carinii pneumonia (PCP). OBJECTIVE: To compare PCP incidence in HIV
      infected patients who had sustained CD4+ lymphocyte counts greater than 200
      cells/mm3 and who either discontinued or continued PCP prophylaxis. DESIGN:
      Nonrandomized prospective cohort study. SETTING: 10 HIV clinics in eight U.S.
      cities. PATIENTS: 146 patients had follow-up visits for a mean of 18.2 months
      after discontinuation of PCP prophylaxis, and 345 patients who continued PCP
      prophylaxis had follow-up visits for a mean of 14.0 months. MEASUREMENTS:
      Incidence of PCP. RESULTS: Patients who discontinued PCP prophylaxis had higher
      maximum and minimum CD4+ cell counts and lower vira loads than patients who
      continued PCP prophylaxis. Pneumocystis carinii pneumonia did not develop in
      either group (upper 95% exact binomial confidence limit of incidence for those
      who discontinued PCP prophylaxis, 2.3/100 person-years). CONCLUSIONS:
      Discontinuation of PCP chemoprophylaxis may be appropriate for some HIV-infected
      ambulatory patients.

PMID- 10651599
TI  - Resource use and survival of patients hospitalized with congestive heart failure:
      differences in care by specialty of the attending physician. SUPPORT
      Investigators. Study to Understand Prognoses and Preferences for Outcomes and
      Risks of Treatments.
AB  - BACKGROUND: Previous studies suggest that specialty care is more costly but may
      produce improved outcomes for patients with acute cardiac illnesses. OBJECTIVE:
      To determine whether patients with congestive heart failure who are cared for by
      cardiologists experienced differences in costs, care patterns, and survival
      compared with patients of generalists. DESIGN: Prospective cohort study. SETTING:
      5 U.S. teaching hospitals between 1989 and 1994. PATIENTS: 1298 patients
      hospitalized with an exacerbation of congestive heart failure. MEASUREMENTS:
      Hospital costs; average daily Therapeutic Intervention Scoring System (TISS)
      score; and survival censored at 30, 180, and 365 days and 31 December 1994.
      RESULTS: Compared with patients of generalists, patients of cardiologists were
      younger (mean age, 63.3 and 71.4 years; P < 0.001) and had lower Acute Physiology
      Scores at the time of admission (35.1 and 36.7; P < 0.001) but were more likely
      to have a history of ventricular arrhythmias (21.0% and 10.2%; P < 0.001). At 6
      months, 201 (27%) patients of cardiologists and 149 (27%) patients of generalists
      had died. After adjustment for sociodemographic characteristics and severity of
      illness, patients of cardiologists incurred costs that were 42.9% (95% CI, 27.8%
      to 59.8%) higher and average daily TISS scores that were 2.83 points (CI, 1.96 to
      3.68 points) higher than those of patients of generalists. Patients of
      cardiologists were more likely to undergo right-heart catheterization (adjusted
      odds ratio, 2.9 [CI, 1.7 to 4.9]) or cardiac catheterization (adjusted odds
      ratio, 3.9 [CI, 2.4 to 6.2]) and had higher odds for transfer to an intensive
      care unit and electrocardiographic monitoring. Adjusted survival did not differ
      significantly between groups at 30 days; however, there was a trend toward
      improved survival among patients of cardiologists at 1 year (adjusted relative
      hazard, 0.82 [CI, 0.65 to 1.04]) and at maximum follow-up (adjusted relative
      hazard, 0.80 [CI, 0.66 to 0.96]). CONCLUSIONS: In this observational study of
      patients hospitalized with congestive heart failure, cardiologist care was
      associated with greater costs and resource use and no difference in survival at
      30 days of follow-up. Whether the trend toward better survival at longer follow
      up represents differences in care or unadjusted illness severity is uncertain.

PMID- 10651602
TI  - Assessing and managing depression in the terminally ill patient. ACP-ASIM End-of
      Life Care Consensus Panel. American College of Physicians - American Society of
      Internal Medicine.
AB  - Psychological distress often causes suffering in terminally ill patients and
      their families and poses challenges in diagnosis and treatment. Increased
      attention to diagnosis and treatment of depression can improve the coping
      mechanisms of patients and families. This paper reviews the clinical
      characteristics of normal grief and clinical depression and explains strategies
      for differential diagnosis. Although some literature discusses the psychological
      issues facing elderly patients and terminally ill patients with cancer, less is
      known about patients with end-stage pulmonary, cardiac, renal, and neurologic
      disease. Data on the effectiveness of interventions in terminally ill patients
      are lacking. Treatment recommendations in this paper represent extrapolations
      from existing literature and expert opinion. Diagnosing and treating depression
      in terminally ill patients involve unique challenges. Evidence of hopelessness,
      helplessness, worthlessness, guilt, and suicidal ideation are better indicators
      of depression in this context than neurovegetative symptoms. Although terminally
      ill patients often have suicidal thoughts, they are usually fleeting. Sustained
      suicidal ideation should prompt a comprehensive evaluation. Clinicians should
      have a low threshold for treating depression in terminally ill patients.
      Psychostimulants, because of their rapid onset of action, are useful agents and
      are generally well tolerated. Selective serotonin reuptake inhibitors and
      tricyclic antidepressants may also be used. Psychological interventions-including
      eliciting concerns and conveying the potential for connection, meaning,
      reconciliation, and closure in the dying process-can also facilitate coping.

PMID- 10651601
TI  - Evidence of zoonotic transmission of Cryptococcus neoformans from a pet cockatoo
      to an immunocompromised patient.
AB  - BACKGROUND: Although cryptococcosis has been associated with birds for almost 50
      years, point sources for infection have not been identified. OBJECTIVE: To
      document zoonotic transmission of Cryptococcus neoformans. DESIGN: Case report.
      SETTING: A home in Boston, Massachusetts. PATIENT: A 72-year-old woman who
      received a diagnosis of cryptococcal meningitis in November 1998. The patient,
      who had been taking immunosuppressant drugs since undergoing renal
      transplantation in 1989, owned a pet cockatoo. MEASUREMENTS: Cryptococcus
      neoformans was isolated from the feces of the cockatoo. Isolates from excreta and
      from the patient were compared by using biochemical profiles, monoclonal antibody
      binding patterns, restriction fragment length polymorphism analysis, and
      karyotyping. RESULTS: The isolates from the patient and the cockatoo had
      identical biochemical profiles, the same monoclonal antibody immunofluorescence
      patterns, and indistinguishable patterns on restriction fragment length
      polymorphism analysis and karyotyping. CONCLUSIONS: The indistinguishable patient
      and cockatoo isolates strongly suggest that the patient's infection resulted from
      exposure to aerosolized cockatoo excreta. Although the incidence of cryptococcal
      infection due to such exposure is unknown, it may be prudent to advise
      immunocompromised patients to avoid pet birds and avian excreta.

PMID- 10651603
TI  - Update in allergy and immunology.

PMID- 10651604
TI  - Sensitivity and specificity of helical computed tomography in the diagnosis of
      pulmonary embolism: a systematic review.
AB  - PURPOSE: To determine the sensitivity and specificity of helical computed
      tomography (CT) for the diagnosis of pulmonary embolism and to determine the
      safety of withholding anticoagulant therapy in patients who have clinically
      suspected pulmonary embolism and negative results on helical CT. DATA SOURCES:
      The MEDLINE database was searched for all reports published from 1986 to October
      1999 that evaluated the use of helical CT for the diagnosis of pulmonary
      embolism. Bibliographies of the retrieved articles were cross-checked to identify
      additional studies. STUDY SELECTION: All prospective English-language studies
      were selected. Retrospective studies, review articles, and case reports were
      excluded, and 5 of the 20 identified articles were excluded. The scientific
      validity of the remaining 15 articles was assessed. DATA EXTRACTION: Two of the
      authors used a priori, pre-defined criteria to independently assess each study. A
      third author resolved disagreements by adjudication. The pre-defined criteria
      were inclusion of a consecutive series of all patients with suspected pulmonary
      embolism, inclusion of patients with and those without pulmonary embolism, a
      broad spectrum of patient characteristics, performance of helical CT and
      pulmonary angiography (or an appropriate reference test) in all patients, and
      independent interpretation of the CT scan and pulmonary angiogram (or reference
      test). Specific data on sensitivity and specificity and the associated 95% CIs
      were recorded when available. DATA SYNTHESIS: No study met all of the predefined
      criteria for adequately evaluating sensitivity and specificity. The reported
      sensitivity of helical CT ranged from 53% to 100%, and specificity ranged from
      81% to 100%. In no prospective study was anticoagulant therapy withheld without
      further testing for venous thromboembolism in consecutive patients with suspected
      pulmonary embolism. One prospective study reported the outcome of selected
      patients with negative results on helical CT who did not receive anticoagulant
      therapy. CONCLUSIONS: Use of helical CT in the diagnosis of pulmonary embolism
      has not been adequately evaluated. The safety of withholding anticoagulant
      treatment in patients with negative results on helical CT is uncertain.
      Definitive large, prospective studies should be done to evaluate the sensitivity,
      specificity, and safety of helical CT for diagnosis of suspected pulmonary
      embolism.

PMID- 10651605
TI  - The diastolic blood pressure in systolic hypertension.
AB  - Because antihypertensive therapy is effective in elderly patients with isolated
      systolic hypertension, attention has been focused on the systolic blood pressure
      as a predictor of cardiovascular risk. However, it is a normal diastolic pressure
      that separates patients with isolated systolic hypertension from those with
      essential hypertension. The normal diastolic and elevated systolic pressures are
      largely due to age-related stiffening of the aorta. An indistensible aorta causes
      the pressure pulse to travel faster than normal, where it is quickly reflected
      off the peripheral resistance. The reflected wave then returns to the central
      aorta in systole rather than diastole. This augments the systolic pressure
      further, increasing cardiac work while reducing the diastolic pressure, on which
      coronary flow is dependent. The potential harm of further reducing the diastolic
      pressure with antihypertensive therapy, especially in patients with coronary
      heart disease, underlies the controversial "J curve." By decreasing the blood
      pressure, all antihypertensive agents improve aortic distensibility, but no
      agents do so directly; the nitrates come the closest. Such an agent would be
      useful because any therapeutic increase in aortic distensibility would decrease
      systolic pressure without greatly reducing diastolic pressure. The problem is
      complicated by the suspected inaccuracy of the cuff technique in predicting the
      aortic diastolic pressure. New noninvasive methods to predict the aortic
      diastolic pressure may help in the future. At present, the combination of a high
      systolic and normal diastolic pressure-a widened pulse pressure-seems to be the
      best predictor of cardiovascular risk in patients with hypertension or heart
      disease. Patients with isolated systolic hypertension should be treated, but
      marked diastolic hypotension should be avoided.

PMID- 10651606
TI  - Congestive heart failure: who should provide care?

PMID- 10651607
TI  - Helical computed tomography and the diagnosis of pulmonary embolism.

PMID- 10651608
TI  - Effect of low-dose continuous estrogen and progesterone therapy with calcium and
      vitamin D on bone in elderly women.

PMID- 10651609
TI  - Effect of low-dose continuous estrogen and progesterone therapy with calcium and
      vitamin D on bone in elderly women.

PMID- 10651610
TI  - Effect of low-dose continuous estrogen and progesterone therapy with calcium and
      vitamin D on bone in elderly women.

PMID- 10651611
TI  - HFE genotype in patients with hemochromatosis and other liver diseases.

PMID- 10651612
TI  - HFE genotype in patients with hemochromatosis and other liver diseases.

PMID- 10651613
TI  - Medical uncertainty and practice variation.

PMID- 10651614
TI  - Regression of rectal mucosa-associated lymphoid tissue lymphoma unrelated to
      Helicobacter pylori.

PMID- 10651615
TI  - The ambulist, a counterpart of the hospitalist.

PMID- 10651616
TI  - Cardiology textbooks on disk.

PMID- 10651617
TI  - [White piedra].

PMID- 10651618
TI  - [South American furunculoid myiasis].

PMID- 10651619
TI  - [Question of the month: how do you treat minimally extensive plaques of fungoid
      mycosis?].

PMID- 10651620
TI  - [The monthly bibliographic selection: prophylactic adenectomy of a melanoma
      sentinel node].

PMID- 10651621
TI  - Silver-containing polymers.

PMID- 10651622
TI  - Silver-containing polymers.

PMID- 10651623
TI  - Increase in resistance of methicillin-resistant Staphylococcus aureus to beta
      lactams caused by mutations conferring resistance to benzalkonium chloride, a
      disinfectant widely used in hospitals.

PMID- 10651624
TI  - Influence of a pulmonary surfactant on the in vitro activity of tobramycin
      against Pseudomonas aeruginosa.

PMID- 10651625
TI  - Effect of garlic on vancomycin-resistant enterococci.

PMID- 10651626
TI  - Conformational effects in biological catalysis: an antibody-catalyzed oxy-cope
      rearrangement.
AB  - Antibody AZ-28 was generated against the chairlike transition-state analogue
      (TSA) 1 and catalyzes the oxy-Cope rearrangement of substrate 2 to product 3. The
      germline precursor to AZ-28 catalyzes the reaction with a 35-fold higher rate
      (k(cat)/k(uncat) = 163 000), despite a 40-fold lower binding affinity for TSA.1
      (K(D) = 670 nM). To determine the structural basis for the differences in the
      binding and catalytic properties of the germline and affinity-matured antibodies,
      the X-ray crystal structures of the unliganded and TSA.1 complex of antibody AZ
      28 have been determined at 2.8 and 2.6 A resolution, respectively; the structures
      of the unliganded and TSA.1 complex of the germline precursor to AZ-28 were both
      determined at 2. 0 A resolution. In the affinity-matured antibody.hapten complex
      the TSA is fixed in a catalytically unfavorable conformation by a combination of
      van der Waals and hydrogen-bonding interactions. The 2- and 5-phenyl substituents
      of TSA.1 are almost perpendicular to the cyclohexyl ring, leading to decreased
      orbital overlap and decreased stabilization of the putative transition state. The
      active site of the germline antibody appears to have an increased degree of
      flexibility-CDRH3 moves 4.9 A outward from the active site upon binding of TSA.1.
      We suggest that this conformational flexibility in the germline antibody, which
      results in a lower binding affinity for TSA.1, allows dynamic changes in the
      dihedral angle of the 2-phenyl substituent along the reaction coordinate. These
      conformational changes in turn lead to enhanced orbital overlap and increased
      catalytic rate. These studies suggest that protein and substrate dynamics play a
      key role in this antibody-catalyzed reaction.

PMID- 10651627
TI  - A unique zinc-binding site revealed by a high-resolution X-ray structure of
      homotrimeric Apo2L/TRAIL.
AB  - Apoptosis-inducing ligand 2 (Apo2L, also called TRAIL), a member of the tumor
      necrosis factor (TNF) family, induces apoptosis in a variety of human tumor cell
      lines but not in normal cells [Wiley, S. R., Schooley, K., Smolak, P. J., Din, W.
      S., Huang, C.-P., Nicholl, J. K., Sutherland, G. R., Smith, T. D., Rauch, C.,
      Smith, C. A., and Goodwin, R. G. (1995) Immunity 3, 673-682; Pitti, R. M.,
      Marsters, S. A., Ruppert, S., Donahue, C. J., Moore, A., and Ashkenazi, A. (1996)
      J. Biol. Chem. 271, 12687-12690]. Here we describe the structure of Apo2L at 1.3
      A resolution and use alanine-scanning mutagenesis to map the receptor contact
      regions. The structure reveals a homotrimeric protein that resembles TNF with
      receptor-binding epitopes at the interface between monomers. A zinc ion is buried
      at the trimer interface, coordinated by the single cysteine residue of each
      monomer. The zinc ion is required for maintaining the native structure and
      stability and, hence, the biological activity of Apo2L. This is the first example
      of metal-dependent oligomerization and function of a cytokine.

PMID- 10651628
TI  - Modulating the midpoint potential of the [4Fe-4S] cluster of the nitrogenase Fe
      protein.
AB  - Protein-bound [FeS] clusters function widely in biological electron-transfer
      reactions, where their midpoint potentials control both the kinetics and
      thermodynamics of these reactions. The polarity of the protein environment around
      [FeS] clusters appears to contribute largely to modulating their midpoint
      potentials, with local protein dipoles and water dipoles largely defining the
      polarity. The function of the [4Fe-4S] cluster containing Fe protein in
      nitrogenase catalysis is, at least in part, to serve as the nucleotide-dependent
      electron donor to the MoFe protein which contains the sites for substrate binding
      and reduction. The ability of the Fe protein to function in this manner is
      dependent on its ability to adopt the appropriate conformation for productive
      interaction with the MoFe protein and on its ability to change redox potentials
      to provide the driving force required for electron transfer. Phenylalanine at
      position 135 is located near the [4Fe-4S] cluster of nitrogenase Fe protein and
      has been suggested by amino acid substitution studies to participate in defining
      both the midpoint potential and the nucleotide-induced changes in the [4Fe-4S]
      cluster. In the present study, the crystal structure of the Azotobacter
      vinelandii nitrogenase Fe protein variant having phenylalanine at position 135
      substituted by tryptophan has been determined by X-ray diffraction methods and
      refined to 2.4 A resolution. A comparison of available Fe protein structures not
      only provides a structural basis for the more positive midpoint potential
      observed in the tryptophan substituted variant but also suggests a possible
      general mechanism by which the midpoint potential could be controlled by
      nucleotide interactions and nitrogenase complex formation.

PMID- 10651629
TI  - Tumor suppressor INK4: quantitative structure-function analyses of p18INK4C as an
      inhibitor of cyclin-dependent kinase 4.
AB  - We report the first detailed structure-function analyses of p18INK4C (p18), which
      is a homologue of the important tumor suppressor p16INK4A (p16). Twenty-four
      mutants were designed rationally. The global conformations of the mutants were
      characterized by NMR, while the function was assayed by inhibition of cyclin
      dependent kinase 4 (CDK4). Most of these mutants have unperturbed global
      structures, thus the changes in their inhibitory abilities can be attributed to
      the mutated residues. The important results are summarized as follows: (a) some
      residues at loops 1 and 2, but not 3, are important for the inhibitory function
      of p18, similar to the results for p16; (b) two residues at the first helix-turn
      helix motif and two at the third are important for inhibition; (c) while the
      results generally agree with the prediction based on the crystal structures of
      p16-CDK6 and p19-CDK6 binary complexes, there are significant differences in a
      few residues, suggesting that the interactions in the binary complexes may not
      accurately represent the interactions in the ternary complexes (in the presence
      of cyclin D2); (d) most importantly, the extra loop of p18 appears to contribute
      to the function of p18, even though the crystal structure of the p19INK4D-CDK6
      complex indicates no interactions involving this loop; (e) detailed analyses of
      the crystal structures and the functional results suggest that there are notable
      differences in the interactions between different members of the INK4 family and
      CDKs.

PMID- 10651630
TI  - Structure-function relationships in sorcin, a member of the penta EF-hand family.
      Interaction of sorcin fragments with the ryanodine receptor and an Escherichia
      coli model system.
AB  - Sorcin, a 21.6 kDa cytosolic EF-hand protein which undergoes a Ca(2+)-induced
      translocation from cytoplasm to membranes, has been assigned to the newly defined
      penta EF-hand family. A molecular model of the C-terminal Ca(2+)-binding domain
      has been generated using as a template the X-ray coordinates of the corresponding
      domain in the calpain light subunit, the family prototype [Lin, G., et al. (1997)
      Nat. Struct. Biol. 4, 539-546]. The model indicates that in sorcin the three
      dimensional structure is conserved and in particular that of EF1, the novel EF
      hand motif characteristic of the family. On this basis, two stable fragments have
      been obtained and characterized. Just like the native protein, the sorcin Ca(2+)
      binding domain (residues 33-198) is largely dimeric, interacts with the ryanodine
      receptor at physiological calcium concentrations, and undergoes a reversible,
      Ca(2+)-dependent translocation from cytosol to target proteins on Escherichia
      coli membranes. In contrast, the 90-198 fragment (residues 90-198), which lacks
      EF1 and EF2, does not bind Ca(2+) with high affinity and is unable to
      translocate. Binding of calcium to the EF1-EF2 pair is therefore required for the
      activation of sorcin which uses the C-terminal calcium-binding domain for
      interaction with the ryanodine receptor, a physiological target in muscle cells.

PMID- 10651631
TI  - Disulfide bridge engineering in the tachykinin NK1 receptor.
AB  - As in most other seven-transmembrane receptors, the central disulfide bridge from
      the extracellular end of TM-III to the middle of the second extracellular loop
      was essential for ligand binding in the NK1 receptor. However, introduction of
      "extra", single Cys residues in the second extracellular loop, at positions where
      disease-associated Cys substitutions impair receptor function in the vasopressin
      V2 receptor and in rhodopsin, did not cause mispairing with the Cys residues
      involved in this central disulfide bridge. Cys residues were introduced in the N
      terminal extension and in the third extracellular loop, respectively, in such a
      way that disulfide bridge formation could be monitored by loss of substance P
      binding and breakage of the bridge could be monitored by gain of ligand binding.
      This disulfide bridge formed spontaneously in the whole population of receptors
      and could be titrated with low concentrations of reducing agent, dithiothreitol.
      Another putative disulfide bridge "switch" was constructed at the extracellular
      ends of TM-V and -VI, i.e., at positions where a high-affinity zinc site
      previously had been constructed with His substitutions. Disulfide bridge
      formation at this position, monitored by loss of binding of the nonpeptide
      antagonist [3H]LY303.870, occurred spontaneously only in a small fraction of the
      receptors. It is concluded that disulfide bridges form readily between Cys
      residues introduced appropriately in the N-terminal extension and the third
      extracellular loop, whereas they form with more difficulty between Cys residues
      placed at the extracellular ends of the transmembrane segments even at positions
      where high-affinity metal ion sites can be constructed with His residues.

PMID- 10651632
TI  - Buried polar interactions and conformational stability in the simian
      immunodeficiency virus (SIV) gp41 core.
AB  - For human (HIV) and simian (SIV) immunodeficiency viruses, the gp41 envelope
      protein undergoes a receptor-activated conformational change from a labile native
      structure to an energetically more stable fusogenic conformation, which then
      mediates viral-cell membrane fusion. The core structure of fusion-active gp41 is
      a six-helix bundle in which three antiparallel carboxyl-terminal helices are
      packed against an amino-terminal trimeric coiled coil. Here we show that a
      recombinant model of the SIV gp41 core, designated N36(L6)C34, forms an alpha
      helical trimer that exhibits a cooperative two-state folding-unfolding
      transition. We investigate the importance of buried polar interactions in
      determining the overall fold of the gp41 core. We have replaced each of four
      polar amino acids at the heptad a and d positions of the coiled coil in
      N36(L6)C34 with a representative hydrophobic amino acid, isoleucine. The Q565I,
      T582I, and T586I variants form six-helix bundle structures that are significantly
      more stable than that of the wild-type peptide, whereas the Q575I variant
      misfolds into an insoluble aggregate under physiological conditions. Thus, the
      buried polar residues within the amino-terminal heptad repeat are important
      determinants of the structural specificity and stability of the gp41 core. We
      suggest that these conserved buried polar interactions play a role in governing
      the conformational state of the gp41 molecule.

PMID- 10651633
TI  - W276 mutation in the endothelin receptor subtype B impairs Gq coupling but not Gi
      or Go coupling.
AB  - The mutation of W276 to cysteine within the human endothelin receptor subtype B
      (ET(B)R) is associated with Hirschsprung's disease, a congenital intestinal
      disease. The sequence surrounding W276 is highly conserved between the endothelin
      receptor subtypes A and B. We have introduced sets of mutations into W275 and
      W276 of the ET(B)R gene, and the corresponding W257 and W258 of the ET(A)R gene,
      and studied their coupling properties with G(i), G(o), and G(q) in reconstituted
      phospholipid vesicles. The prepared mutants all showed a similar affinity for
      endothelin-1. The W276C/ET(B)R and W276A/ET(B)R mutants had reduced activities in
      G(q) coupling but not in G(i)/G(o) coupling, while the W275A/ET(B)R displayed
      reduced activities in G(i)/G(q) coupling, with normal G(o) coupling. On the other
      hand, W257A/ET(A)R and W258A/ET(A)R exhibited wild-type activities in all
      examined G protein couplings. These results suggest that the defects in the G(q)
      signaling pathway by the ET(B)R are connected with Hirschsprung's disease and
      that the two conserved tryptophans play distinct roles in signal transduction by
      the two receptor subtypes. In addition, W275 and W276, which are thought to be
      located near the extracellular side of the transmembrane helix 5, play important
      roles in forming the active structure of ET(B)R.

PMID- 10651634
TI  - Mechanisms regulating the cell surface residence time of the alpha 2A-adrenergic
      receptor.
AB  - Despite considerable insights concerning the mechanisms regulating short-term
      agonist-mediated G protein-coupled receptor (GPCR) internalization, little is
      known about the mechanisms regulating GPCR surface residence over long periods of
      time. Herein, we experimentally evaluated mechanisms regulating the surface
      t(1/2) of various alpha(2A)-adrenergic receptor (alpha(2A)AR) structures. The
      Delta 3i alpha(2A)AR (lacking the third intracellular loop), D79N alpha(2A)AR
      (impaired G protein coupling), and CAM alpha(2A)AR (enhanced G protein coupling)
      all exhibited a cell surface alpha(2A)AR turnover in Chinese hamster ovary cells
      that was faster than that of the wild type (WT). Cell surface receptor turnover
      could be slowed with ligand occupancy of D79N alpha(2A)AR (agonist or antagonist)
      and CAM alpha(2A)AR (antagonist only) but not the Delta 3i- or WT alpha(2A)AR.
      This selective ligand-induced surface stabilization was paralleled by a dramatic
      ligand-dependent receptor density upregulation for D79N- and CAM alpha(2A)AR
      structures. Receptors which exhibited surface turnover and density that could be
      modulated by ligand (D79N and CAM) also demonstrated structural instability,
      measured by a loss of radioligand binding capacity in detergent solution over
      time without parallel changes in receptor protein content. In contrast, the
      shorter surface t(1/2) of the Delta 3i alpha(2A)AR, whose cell surface t(1/2) and
      steady state density were not altered by ligand occupancy, occurred in the
      context of a structurally stable receptor in detergent solution. These results
      demonstrate that changes in receptor structure which alter receptor-G protein
      coupling (either an increase or decrease) are paralleled by structural
      instability and ligand-induced surface stabilization. These studies also provide
      criteria for assessing the structural instability of the alpha(2A)AR that can
      likely be generalized to all GPCRs.

PMID- 10651635
TI  - Role of highly conserved residues in the reaction catalyzed by recombinant Delta7
      sterol-C5(6)-desaturase studied by site-directed mutagenesis.
AB  - The role of 15 residues in the reaction catalyzed by Arabidopsis thaliana Delta7
      sterol-C5(6)-desaturase (5-DES) was investigated using site-directed mutagenesis
      and expression of the mutated enzymes in an erg3 yeast strain defective in 5-DES.
      The mutated desaturases were assayed in vivo by sterol analysis and
      quantification of Delta5,7-sterols. In addition, the activities of the
      recombinant 5-DESs were examined directly in vitro in the corresponding yeast
      microsomal preparations. One group of mutants was affected in the eight
      evolutionarily conserved histidine residues from three histidine-rich motifs.
      Replacement of these residues by leucine or glutamic acid completely eliminated
      the desaturase activity both in vivo and in vitro, in contrast to mutations at
      seven other conserved residues. Thus, mutants H203L, H222L, H222E, P201A, G234A,
      and G234D had a 5-DES activity reduced to 2-20% of the wild-type enzyme, while
      mutants K115L, P175V, and P175A had a 5-DES activity and catalytical efficiency
      (V/K) that was similar to that of the wild-type. Therefore, these residues are
      not essential for the catalysis but contribute to the activity through
      conformational or other effects. One possible function for the histidine-rich
      motifs would be to provide the ligands for a presumed catalytic Fe center, as
      previously proposed for a number of integral membrane enzymes catalyzing
      desaturations and hydroxylations [Shanklin et al. (1994) Biochemistry 33, 12787
      12794]. Another group of mutants was affected in residue 114 based on previous in
      vivo observations in A. thaliana indicating that mutant T114I was deficient in 5
      DES activity. We show that the enzyme T114I has an 8-fold higher Km and 10-fold
      reduced catalytic efficiency. Conversely, the functionally conservative
      substituted mutant enzyme T114S displays a 28-fold higher Vmax value and an 8
      fold higher Km value than the wild-type enzyme. Consequently, V/K for T114S was
      38-fold higher than that for T114I. The data suggest that Thr 114 is involved in
      stabilization of the enzyme-substrate complex with a marked discrimination
      between the ground-state and the transition state of a rate-controlling step in
      the catalysis by the 5-DES.

PMID- 10651636
TI  - The first 28 N-terminal amino acid residues of human heart muscle carnitine
      palmitoyltransferase I are essential for malonyl CoA sensitivity and high
      affinity binding.
AB  - Heart/skeletal muscle carnitine palmitoyltransferase I (M-CPTI) is 30-100-fold
      more sensitive to malonyl CoA inhibition than the liver isoform (L-CPTI). To
      determine the role of the N-terminal region of human heart M-CPTI on malonyl CoA
      sensitivity and binding, a series of deletion mutations were constructed ranging
      in size from 18 to 83 N-terminal residues. All of the deletions except Delta83
      were active. Mitochondria from the yeast strains expressing Delta28 and Delta39
      exhibited a 2.5-fold higher activity compared to the wild type, but were
      insensitive to malonyl CoA inhibition and had complete loss of high-affinity
      malonyl CoA binding. The high-affinity site (K(D1), B(max1)) for binding of
      malonyl CoA to M-CPTI was completely abolished in the Delta28, Delta39, Delta51,
      and Delta72 mutants, suggesting that the decrease in malonyl CoA sensitivity
      observed in these mutants was due to the loss of the high-affinity binding entity
      of the enzyme. Delta18 showed only a 4-fold loss in malonyl CoA sensitivity but
      had activity and high-affinity malonyl CoA binding similar to the wild type.
      Replacement of the N-terminal domain of L-CPTI with the N-terminal domain of M
      CPTI does not change the malonyl CoA sensitivity of the chimeric L-CPTI,
      suggesting that the amino acid residues responsible for the differing sensitivity
      to malonyl CoA are not located in this N-terminal region. These results
      demonstrate that the N-terminal residues critical for activity and malonyl CoA
      sensitivity in M-CPTI are different from those of L-CPTI.

PMID- 10651637
TI  - Expression and stereochemical and isotope effect studies of active 4
      oxalocrotonate decarboxylase.
AB  - 4-Oxalocrotonate decarboxylase (4-OD) and vinylpyruvate hydratase (VPH) from
      Pseudomonas putida mt-2 form a complex that converts 2-oxo-3-hexenedioate to 2
      oxo-4-hydroxypentanoate in the catechol meta fission pathway. To facilitate
      mechanistic and structural studies of the complex, the two enzymes have been
      coexpressed and the complex has been purified to homogeneity. In addition, Glu
      106, a potential catalytic residue in VPH, has been changed to glutamine, and the
      resulting E106QVPH mutant has been coexpressed with 4-OD and purified to
      homogeneity. The 4-OD/E106QVPH complex retains full decarboxylase activity, with
      comparable kinetic parameters to those observed for 4-OD in the wild-type
      complex, but is devoid of any detectable hydratase activity. Decarboxylation of
      (5S)-2-oxo-3-[5-D]hexenedioate by either the 4-OD/VPH complex or the mutant
      complex generates 2-hydroxy-2,4E-[5-D]pentadienoate in D(2)O. Ketonization of 2
      hydroxy-2,4-pentadienoate by the wild-type complex is highly stereoselective and
      results in the formation of 2-oxo-(3S)-[3-D]-4-pentenoate, while the mutant
      complex generates a racemic mixture. These results indicate that 2-hydroxy-2, 4
      pentadienoate is the product of 4-OD and that 2-oxo-4-pentenoate results from a
      VPH-catalyzed process. On this basis, the previously proposed hypothesis for the
      conversion of 2-oxo-3-hexenedioate to 2-oxo-4-hydroxypentanoate has been revised
      [Lian, H., and Whitman, C. P. (1994) J. Am. Chem. Soc. 116, 10403-10411].
      Finally, the observed (13)C kinetic isotope effect on the decarboxylation of 2
      oxo-3-hexenedioate by the 4-OD/VPH complex suggests that the decarboxylation step
      is nearly rate-limiting. Because the value is not sensitive to either magnesium
      or manganese, it is likely that the transition state for carbon-carbon bond
      cleavage is late and that the metal positions the substrate and polarizes the
      carbonyl group, analogous to its role in oxalacetate decarboxylase.

PMID- 10651638
TI  - Glutamate synthase: identification of the NADPH-binding site by site-directed
      mutagenesis.
AB  - To contribute to the understanding of glutamate synthase and of beta subunit-like
      proteins, which have been detected by sequence analyses, we identified the NADPH
      binding site out of the two potential ADP-binding regions found in the beta
      subunit. The substitution of an alanyl residue for G298 of the beta subunit of
      Azospirillum brasilense glutamate synthase (the second glycine in the GXGXXA
      fingerprint of the postulated NADPH-binding site) yielded a protein species in
      which the flavin environment and properties are unaltered. On the contrary, the
      binding of the pyridine nucleotide substrate is significantly perturbed
      demonstrating that the C-terminal potential ADP-binding fold of the beta subunit
      is indeed the NADPH-binding site of the enzyme. The major effect of the G298A
      substitution in the GltS beta subunit consists of an approximately 10-fold
      decrease of the affinity of the enzyme for pyridine nucleotides with little or no
      effect on the rate of the enzyme reduction by NADPH. By combining kinetic
      measurements and absorbance-monitored equilibrium titrations of the G298A-beta
      subunit mutant, we conclude that also the positioning of its nicotinamide portion
      into the active site is altered thus preventing the formation of a stable charge
      transfer complex between reduced FAD and NADP(+). During the course of this work,
      the Azospirillum DNA regions flanking the gltD and gltB genes, the genes encoding
      the GltS beta and alpha subunits, respectively, were sequenced and analyzed.
      Although the Azospirillum GltS is similar to the enzyme of other bacteria, it
      appears that the corresponding genes differ with respect to their arrangement in
      the chromosome and to the composition of the glt operon: no genes corresponding
      to E. coli and Klebsiella aerogenes gltF or to Bacillus subtilis gltC, encoding
      regulatory proteins, are found in the DNA regions adjacent to that containing
      gltD and gltB genes in Azospirillum. Further studies are needed to determine if
      these findings also imply differences in the regulation of the glt genes
      expression in Azospirillum (a nitrogen-fixing bacterium) with respect to enteric
      bacteria.

PMID- 10651639
TI  - DnaB helicase stimulates primer synthesis activity on short oligonucleotide
      templates.
AB  - DnaB helicase stimulated the second-order RNA primer synthesis activity of
      primase by over 5000-fold on DNA templates that were 23 nucleotides long. This
      template length is the same as the DnaB helicase thermodynamic binding site size
      [Jezewska, M. J., and Bujalowski, W. (1996) Biochemistry 35, 2117-2128]. This
      phenomenal stimulation was achieved by increasing the template affinity of
      primase by over 300-fold and increasing the catalytic rate by over 15-fold. It
      was necessary to determine the optimal amount of DnaB helicase to achieve this
      stimulation because helicase stimulation was cooperative at low concentration and
      inhibitory at high helicase concentration. The cooperative stimulation at low
      concentration indicated the presence of a time-dependent assembly step that
      preceded the active state. Besides stimulating primase activity, DnaB helicase
      also prevented primase from synthesizing RNA primers that were longer than the
      template sequence. In the absence of DnaB helicase, the majority of primers
      synthesized by primase were longer than the template and were named "overlong
      primers" [Swart, J. R., and Griep, M. A. (1995) Biochemistry 34, 16097-16106]. In
      contrast, the helicase-stimulated RNA primers were from 10 to 14 nucleotides in
      length with the 12-mer representing the majority of the total RNA primers
      produced. It was shown that DnaB helicase stabilized the open or single-stranded
      conformation of the template, which favored the synthesis of the template-length
      dependent primers. In contrast, when primase acted alone, it stabilized the 3'
      end hairpin conformation of the template so that the template's 3'-hydroxyl
      served as a "DNA primer" from which primase elongated to create the overlong
      primers.

PMID- 10651640
TI  - DnaB helicase affects the initiation specificity of Escherichia coli primase on
      single-stranded DNA templates.
AB  - The effect of DnaB helicase on the initiation specificity of primase was studied
      biochemically using a series of single-stranded DNA templates in which each
      nucleotide of the trinucleotide d(CTG) initiation sequence was systematically
      varied. DnaB helicase accelerated the rate of primer syntheisis, prevented
      "overlong" primers from forming and decreased the initiation specificity of
      primase. In the presence of DnaB helicase, all trinucleotides could serve as the
      primer initiation site although there was a distinct preference for d(CAG). These
      data may explain the high chromosomal prevalence of octanucleotides containing
      CTG on the leading strand and its complement CAG on the lagging strand. The
      specificity of DnaB helicase places it on the lagging strand template where it
      stimulates the initiation of Okazaki fragment synthesis. In the absence of DnaB
      helicase, primase preferentially primed the d(CTG) template. In the presence of
      DnaB helicase, the initiation preference was not only altered but also the
      preferred initiating nucleotide was found to be GTP rather than ATP, for both the
      d(CTG) and the d(CAG) templates. This suggested that the specificity of primase
      for the d(CTG) initiation trinucleotide was predominantly unaffected in the
      absence of DnaB helicase on short ssDNA templates, whereas in conjunction with
      DnaB helicase, the specificity was altered and this alteration has significant
      implications in the replication of Escherichia coli chromosome in vivo.

PMID- 10651642
TI  - DNA base excision repair in human malaria parasites is predominantly by a long
      patch pathway.
AB  - Mammalian cells repair apurinic/apyrimidinic (AP) sites in DNA by two distinct
      pathways: a polymerase beta (pol beta)-dependent, short- (one nucleotide) patch
      base excision repair (BER) pathway, which is the major route, and a PCNA
      dependent, long- (several nucleotide) patch BER pathway. The ability of a cell
      free lysate prepared from asexual Plasmodium falciparum malaria parasites to
      remove uracil and repair AP sites in a variety of DNA substrates was
      investigated. We found that the lysate contained uracil DNA glycosylase, AP
      endonuclease, DNA polymerase, flap endonuclease, and DNA ligase activities. This
      cell-free lysate effectively repaired a regular or synthetic AP site on a
      covalently closed circular (ccc) duplex plasmid molecule or a long (382 bp),
      linear duplex DNA fragment, or a regular or reduced AP site in short (28 bp),
      duplex oligonucleotides. Repair of the AP sites in the various DNA substrates
      involved a long-patch BER pathway. This biology is different from mammalian
      cells, yeast, Xenopus, and Escherichia coli, which predominantly repair AP sites
      by a one-nucleotide patch BER pathway. The apparent absence of a short-patch BER
      pathway in P. falciparum may provide opportunities to develop antimalarial
      chemotherapeutic strategies for selectively damaging the parasites in vivo and
      will allow the characterization of the long-patch BER pathway without having to
      knock-out or inactivate a short-patch BER pathway, which is necessary in
      mammalian cells.

PMID- 10651641
TI  - Interactions of the nuclear matrix-associated steroid receptor binding factor
      with its DNA binding element in the c-myc gene promoter.
AB  - Steroid receptor binding factor (RBF) was originally isolated from avian oviduct
      nuclear matrix. When bound to avian genomic DNA, RBF generates saturable high
      affinity binding sites for the avian progesterone receptor (PR). Recent studies
      have shown that RBF binds to a 54 bp element in the 5'-flanking region of the
      progesterone-regulated avian c-myc gene, and nuclear matrix-like attachment sites
      flank the RBF element [Lauber et al. (1997) J. Biol. Chem. 272, 24657-24665]. In
      this paper, electrophoretic mobility shift assays (EMSAs) and S1 nuclease
      treatment are used to demonstrate that the RBF-maltose binding protei (MBP)
      fusion protein binds to single-stranded DNA of its element. Only the N-terminal
      domain of RBF binds the RBF DNA element as demonstrated by southwestern blot
      analyses, and by competition EMSAs between RBF-MBP and the N-terminal domain.
      Mass spectrometric analysis of the C-terminal domain of RBF demonstrates its
      potential to form noncovalent protein-protein interactions via a potential
      leucine-isoleucine zipperlike structure, suggesting a homo- and/or possible
      heterodimer structure in solution. These data support that the nuclear matrix
      binding site (acceptor site) for PR in the c-myc gene promoter is composed of RBF
      dimers bound to a specific single-stranded DNA element. The dimers of RBF are
      generated by C-terminal leucine zipper and the DNA binding occurs at the N
      terminal parallel beta-sheet DNA binding motif. This complex is flanked by
      nuclear matrix attachment sites.

PMID- 10651643
TI  - Effects of phosphorylation on binding of catecholamines to tyrosine hydroxylase:
      specificity and thermodynamics.
AB  - As the catalyst for the rate-limiting step in the biosynthesis of the
      catecholamine neurotransmitters, the activity of tyrosine hydroxylase is tightly
      regulated. A principle means of posttranslational regulation is reversible
      phosphorylation of serine residues in an N-terminal regulatory domain.
      Phosphorylation of serine 40 has been shown to have a large effect on the rate
      constant for dissociation of dopamine and a much smaller effect on that for DOPA
      [Ramsey, A. J., and Fitzpatrick, P. F. (1998) Biochemistry 37, 8980-8986]. To
      determine the structural basis for the differences in affinity and to further
      test the validity of the previously proposed model for regulation, the effects of
      phosphorylation of serine 40 on the affinities for a series of catechols have
      been determined. The affinities of the unphosphorylated enzyme vary by 3 orders
      of magnitude due to differences in the rates of dissociation. The highest
      affinities are found with catecholamines which lack a carboxylate. The affinities
      of the phosphorylated enzyme show a much smaller range. In the case of binding of
      dihydroxyphenylalanine, the decrease in affinity upon phosphorylation is due
      primarily to a decrease in the enthalpy of the interaction. Based upon these
      results, a structural model for the effect of phosphorylation is proposed.

PMID- 10651644
TI  - Characterization of cobalt(II)-substituted peptide deformylase: function of the
      metal ion and the catalytic residue Glu-133.
AB  - Peptide deformylase (PDF) catalyzes the hydrolytic removal of the N-terminal
      formyl group from nascent ribosome-synthesized polypeptides in eubacteria. PDF
      represents a novel class of mononuclear iron protein, which utilizes an Fe(2+)
      ion to catalyze the hydrolysis of an amide bond. This Fe(2+) enzyme is, however,
      extremely labile, undergoing rapid inactivation upon exposure to molecular
      oxygen, and is spectroscopically silent. In this work, we have replaced the
      native Fe(2+) ion with the spectroscopically active Co(2+) ion through
      overexpression in the presence of Co(2+). Co(2+)-substituted PDF (Co-PDF) has an
      activity 3-10-fold lower than that of the Fe(2+)-PDF but is highly stable. Steady
      state kinetic assays using a series of substrates of varying deformylation rates
      indicate that Co-PDF has the same substrate specificity as the native enzyme. Co
      PDF and Fe-PDF also share the same three-dimensional structure, pH sensitivity,
      and inhibition pattern by various effector molecules. These results demonstrate
      that Co-PDF can be used as a stable surrogate of Fe-PDF for biochemical
      characterization and inhibitor screening. The electronic absorption properties of
      the Co(2+) ion were utilized as a probe to monitor changes in the enzyme active
      site as a result of site-directed mutations, inhibitor binding, and changes in
      pH. Mutation of Glu-133 to an alanine completely abolishes the catalytic
      activity, whereas mutation to an aspartate results in only approximately 10-fold
      reduction in activity. Analysis of their absorption spectra under various pH
      conditions reveals pK(a) values of 6.5 and 5.6 for the metal-bound water in E133A
      and E133D Co-PDF, respectively, suggesting that the metal ion alone is capable of
      ionizing the water molecule to generate the catalytic nucleophile, a metal-bound
      hydroxide. On the other hand, substrate binding to the E133A mutant induces
      little spectral change, indicating that in the E.S complex the formyl carbonyl
      oxygen is not coordinated with the metal ion. These results demonstrate that the
      function of the active-site metal is to activate the water molecule, whereas Glu
      133 acts primarily as a general acid, donating a proton to the leaving amide ion
      during the decomposition of the tetrahedral intermediate.

PMID- 10651645
TI  - Threonine 201 in the diiron enzyme toluene 4-monooxygenase is not required for
      catalysis.
AB  - The diiron enzyme toluene 4-monooxygenase from Pseudomonas mendocina KR1
      catalyzes the NADH- and O(2)-dependent hydroxylation of toluene. A combination of
      sequence alignments and spectroscopic studies indicate that T4MO has an active
      site structure closely related to the crystallographically characterized methane
      monooxygenase hydroxylase. In the methane monooxygenase hydroxylase, active site
      residue T213 has been proposed to participate in O(2) activation by analogy to
      certain proposals made for cytochrome P450. In this work, mutagenesis of the
      comparable residue in the toluene 4-monooxygenase hydroxylase, T201, has been
      used to investigate the role of an active site hydroxyl group in catalysis. Five
      isoforms (T201S, T201A, T201G, T201F, and T201K) that retain catalytic activity
      based on an in vivo indigo formation assay were identified, and detailed
      characterizations of the purified T201S, T201A, and T201G variants are reported.
      These isoforms have k(cat) values of 1.2, 1.0, and 0.6 s(-)(1), respectively, and
      k(cat)/K(M) values that vary by only approximately 4-fold relative to that of the
      native isoform. Moreover, these isoforms exhibit 80-90% coupling efficiency,
      which also compares favorably to the >94% coupling efficiency determined for the
      native isoform. For the T201S, T201A, and T201G isoforms, the regiospecificity of
      toluene hydroxylation was nearly identical to that of the natural isoform, with p
      cresol representing 90-95% of the total product distribution. In contrast, the
      T201F isoform caused a substantial shift in the product distribution, and gave o-
      and p-cresol in a 1:1 ratio. In addition, the amount of benzyl alcohol was
      increased approximately 10-fold with the T201F isoform. For reaction with p
      xylene, previous studies have shown that the native isoform reacted to give 4
      methybenzyl alcohol and 2, 5-dimethylphenol in a 4:1 ratio [Pikus, J. D., Studts,
      J. M., McClay, K., Steffan, R. J., and Fox, B. G. (1997) Biochemistry 36, 9283
      9289]. For comparison, the T201S, T201A, and T201F isoforms gave a slightly
      relaxed 3:1 ratio of these products, while the T201G isoform gave a dramatically
      relaxed 1:1 ratio. On the basis of these studies, we conclude that the hydroxyl
      group of T201 is not essential to maintaining the turnover rate or the coupling
      of the toluene 4-monooxygenase complex. However, changing the volume occupied by
      the side chain at the position of T201 can lead to alterations in the
      regiospecificity of the hydroxylation, presumably by producing different
      orientations for substrate binding during catalysis.

PMID- 10651646
TI  - Novel heme-containing lyase, phenylacetaldoxime dehydratase from Bacillus sp.
      strain OxB-1: purification, characterization, and molecular cloning of the gene.
AB  - A novel dehydratase that catalyzes the stoichiometric dehydration of Z
      phenylacetaldoxime to phenylacetonitrile has been purified 483-fold to
      homogeneity from a cell-free extract of Bacillus sp. strain OxB-1 isolated from
      soil. It has a M(r) of about 40 000 and is composed of a single polypeptide chain
      with a loosely bound protoheme IX. The enzyme is inactive unless FMN is added to
      the assay, but low activity is also observed when sulfite replaces FMN. The
      activity in the presence of FMN is enhanced 5-fold under anaerobic conditions
      compared to the activity measured in air. The enzyme has maximum activity at pH
      7.0 and 30 degrees C, and it is stable at up to 45 degrees C at around neutral
      pH. The aerobically measured activity in the presence of FMN is also enhanced by
      Fe(2+), Sn(2+), SO(3)(2)(-), and NaN(3). Metal-chelating reagents, carbonyl
      reagents, electron donors, and ferri- and ferrocyanides strongly inhibit the
      enzyme with K(i) values in the micromolar range. The enzyme is active with
      arylalkylaldoximes and to a lesser extent with alkylaldoximes. The enzyme prefers
      the Z-form of phenylacetaldoxime over its E-isomer. On the basis of its substrate
      specificity, the enzyme has been tentatively named phenylacetaldoxime
      dehydratase. The gene coding for the enzyme was cloned into plasmid pUC18, and a
      1053 base-pair open reading frame that codes for 351 amino acid residues was
      identified as the oxd gene. A nitrilase, which participates in aldoxime
      metabolism in the organism, was found to be coded by the region just upstream
      from the oxd gene. In addition an open reading frame (orf2), whose gene product
      is similar to bacterial regulatory (DNA-binding) proteins, was found just
      upstream from the coding region of the nitrilase. These findings provide genetic
      evidence for a novel gene cluster that is responsible for aldoxime metabolism in
      this microorganism.

PMID- 10651647
TI  - A distinct ER/IC gamma-secretase competes with the proteasome for cleavage of
      APP.
AB  - The deposition of amyloid-beta peptides (Abeta) in senile plaques (SPs) is a
      central pathological feature of Alzheimer's disease (AD). Since SPs are composed
      predominantly of Abeta1-42, which is more amyloidogenic in vitro, the enzymes
      involved in generating Abeta1-42 may be particularly important to the
      pathogenesis of AD. In contrast to Abeta1-40, which is generated in the trans
      Golgi network and other cytoplasmic organelles, intracellular Abeta1-42 is
      produced in the endoplasmic reticulum/intermediate compartment (ER/IC), where it
      accumulates in a stable insoluble pool. Since this pool of insoluble Abeta1-42
      may play a critical role in AD amyloidogenesis, we sought to determine how the
      production of intracellular Abeta is regulated. Surprisingly, the production of
      insoluble intracellular Abeta1-42 was increased by a putative gamma-secretase
      inhibitor as well as by an inhibitor of the proteasome. We further demonstrate
      that this increased generation of Abeta1-42 in the ER/IC is due to a reduction in
      the turnover of Abeta-containing APP C-terminal fragments. We conclude that the
      proteasome is a novel site for degradation of ER/IC-generated APP fragments.
      Proteasome inhibitors may augment the availability of APP C-terminal fragments
      for gamma-secretase cleavage and thereby increase production of Abeta1-42 in the
      ER/IC. Based on the organelle-specific differences in the generation of Abeta by
      gamma-secretase, we conclude that intracellular ER/IC-generated Abeta1-42 and
      secreted Abeta1-40 are produced by different gamma-secretases. Further, the fact
      that a putative gamma-secretase inhibitor had opposite effects on the production
      of secreted and intracellular Abeta may have important implications for AD drug
      design.

PMID- 10651648
TI  - Kinetic analysis of Sp1-mediated transcriptional activation of a TATA-containing
      promoter.
AB  - Using a HeLa cell nuclear extract (NE)-based in vitro runoff transcription
      system, we have examined the effect of Sp1 on the activation of a TATA-containing
      chimeric DNA polymerase beta (pAS8) promoter. The results demonstrated that the
      TATA element-dependent basal activity of the pAS8 promoter was stimulated 4-fold
      by supplementation of a Sp1-depleted HeLa cell nuclear extract (NEd) with
      purified human Sp1, indicating that pAS8 promoter activity is dependent upon Sp1.
      A detailed kinetic analysis based on a three-step kinetic model of transcription
      initiation showed that Sp1 stimulates the activity of the pAS8 promoter by
      increasing the amount of closed preinitiation complex (RP(c)) assembly as well as
      by enhancing the rate of promoter clearance (k(3)). There was no significant
      effect of Sp1 on the apparent rate of open complex (RP(o)) formation (k(2)) of
      the pAS8 promoter. These studies define more precisely the kinetic mechanisms by
      which Sp1 may regulate the rate of transcript formation of a TATA-containing
      promoter.

PMID- 10651649
TI  - Transmembrane biogenesis of Kv1.3.
AB  - Using a combination of protease protection, glycosylation, and carbonate
      extraction assays, we have characterized the topogenic determinants encoded by
      Kv1.3 segments that mediate translocation events during endoplasmic reticulum
      (ER) biogenesis. Transmembrane segments S1, S2, S3, S5, and S6 initiate
      translocation, only S1 and S2 strongly (>60%) anchor themselves in the membrane,
      S5 exhibits signal anchor activity and contains a cryptic cleavage site, and S3
      and S6 fail to integrate into the membrane. Elongation of each single
      transmembrane construct to include multiple transmembrane segments alters
      integration and translocation efficiencies, indicating that multiple topogenic
      determinants cooperate during Kv1. 3 topogenesis and assembly. Several surprising
      findings emerged from these studies. First, in the presence of T1, the N-terminal
      recognition domain, S1 was unable to initiate either translocation or membrane
      integration. As a result, S2 likely functions as the initial signal sequence to
      establish Kv1.3 N-terminus topology. Second, S4 independently integrates into the
      membrane. Third, S6 plus the C-terminus of Kv1.3 is a secretory protein but can
      be converted to a membrane-integrated protein with a correctly oriented,
      cytosolic C-terminus by linking S6 to S5 and the pore loop. These results have
      implications for the role of the N-terminus in Kv biogenesis and on the
      mechanisms of dominant negative suppression of Kv1.3 by truncated Kv1.3 fragments
      [Tu et al. (1996) J. Biol. Chem. 271, 18904-18911].

PMID- 10651650
TI  - Origin of the anomalous Fe-CO stretching mode in the CO complex of Ascaris
      hemoglobin.
AB  - We report an unusually high frequency (543 cm(-)(1)) for an Fe-CO stretching mode
      in the CO complex of Ascaris suum hemoglobin as compared to vertebrate
      hemoglobins in which the frequency of the Fe-CO mode is much lower. A second Fe
      CO stretching mode in Ascaris hemoglobin is observed at 515 cm(-1). We propose
      that these two Fe-CO stretching modes arise from two protein conformers
      corresponding to interactions of the heme-bound CO with the B10-tyrosine or the
      E7-glutamine residues. This postulate is supported by spectra from the B10-Tyr -
      > Phe mutant in which the 543 cm(-1) line is absent. Thus, a strong polar
      interaction, such as hydrogen bonding, of the CO with the distal B10 tyrosine
      residue is the dominant factor that causes this anomalously high frequency.
      Strong hydrogen bonding between O(2) and distal residues in the oxy complex of
      Ascaris hemoglobin has been shown to result in a rigid structure, rendering an
      extremely low oxygen off rate [Gibson, Q. H., and Smith, M. H. (1965) Proc. R.
      Soc. London B 163, 206-214]. In contrast, the CO off rate in Ascaris hemoglobin
      is very similar to that in sperm whale myoglobin. The high CO off rate relative
      to that of O(2) in Ascaris hemoglobin is attributed to a rapid equilibrium
      between the two conformations of the protein in the CO adduct, with the off rate
      being determined by the conformer with the higher rate.

PMID- 10651651
TI  - The brave new world--what can we realistically expect to achieve through cancer
      control early in the new millennium?
AB  - Cancer control requires strategic planning, and thus knowledge about the trends
      of incidence and mortality associated with cancer as well as future projections,
      in order that appropriate decisions on priorities can be made. Cancer prevention
      requires tobacco control and dietary modification. Screening should utilize only
      effective strategies. The trends in Canada are expected to be mainly favourable
      by the year 2020, apart from rising trends in non-Hodgkin's lymphoma. Tobacco
      control policies in Canada are having an impact, while dietary modification is
      probably having an impact on colorectal cancer incidence. Screening for cancer of
      the cervix has achieved maximum impact with present levels of compliance, but as
      yet there is no evidence of an impact of breast screening. Priority for the
      future will have to be placed on prevention, especially on encouraging young
      adults to quit smoking and on dietary modification starting at young ages, and
      care should be taken with cost-effective application of screening.

PMID- 10651652
TI  - A simple method for estimating incidence from prevalence.
AB  - A two-state deterministic model is used to estimate the incidence of an
      irreversible disease from prevalence and mortality data. The method is simpler
      than those described previously. Diabetes and dementia are used as examples.

PMID- 10651653
TI  - Marital status, dementia and institutional residence among elderly Canadians: the
      Canadian Study of Health and Aging.
AB  - The association between marital status and mortality is well known; marital
      status has also been related to morbidity. In this paper, we examine the
      importance of marital status in relation to the presence or absence of dementia
      and to institutional residence, using data from the Canadian Study of Health and
      Aging. Three groups are compared: married, single and previously married. We show
      that the age-standardized prevalence of dementia and the proportions of elderly
      Canadians living in institutions with and without dementia are highest among
      single people and are also high for those who were previously married. These
      associations hold true for both women and men, but the relation between marital
      status and institutionalization is much stronger for men. Possible explanations
      and implications for the future care of the elderly are discussed.

PMID- 10651654
TI  - Colorectal cancer prevention in ulcerative colitis: a case-control study.
AB  - BACKGROUND: The risk of colorectal cancer (CRC) in ulcerative colitis (UC)
      increases with extent and duration of disease. Identifying other risk factors
      would allow targeting of sub-groups at greatest risk, enabling more cost
      effective surveillance. METHODS: We conducted a case-control study comparing 102
      cases of CRC in UC with matched controls. Odds ratios (OR) for cancer risk were
      estimated by conditional logistic regression. A multivariate model assessed the
      contribution of individual variables. RESULTS: Regular 5-aminosalicylic acid (5
      ASA) therapy reduces cancer risk by 75% (OR 0.25, 95% CI: 0.13-0.48, P <
      0.00001). Adjusting for other variables, taking mesalazine regularly reduces risk
      by 81% (OR 0.19, 95% CI: 0.06-0.61, P=0.006) and visiting a hospital doctor more
      than twice a year also reduces risk (OR 0.16, 95% CI: 0.04-0.60, P=0.007).
      Considering variables independently, having a family history of sporadic CRC in
      any relative increases risk fivefold (OR 5.0, 95% CI: 1.10-22.82, P < 0.04).
      CONCLUSIONS: CRC risk among UC patients can be reduced by regular therapy with 5
      ASA medication. Colonoscopic surveillance may be best targeted on those unable to
      take 5-ASAs (e.g. due to allergy) and those with a positive family history of
      CRC.

PMID- 10651655
TI  - Limited exposure of the healthy distal colon to orally-dosed formulation is
      further exaggerated in active left-sided ulcerative colitis.
AB  - BACKGROUND: Active distal ulcerative colitis is often resistant to topically
      acting oral formulations. We speculated that the left side of the colon is
      underexposed to orally-dosed topical agents in patients with active distal
      colitis. METHODS: Twenty-two healthy volunteers (12 males, aged 22-47 years), and
      10 patients (6 males, aged 33-73 years) with active left-sided ulcerative colitis
      ingested a Eudragit-coated gelatine capsule containing 111In-labelled amberlite
      resin on four successive days. Regional colonic distribution, transit times and
      percentage of daily dose resident were calculated from the average of four serial
      gamma camera images on the 4th day. RESULTS: (mean [95% CI]). When compared to
      controls, patients with colitis had significantly faster total colon transit
      (24.3 h [9.5-39.1] vs. 51.7 h [41.1-62.3]) as well as faster proximal colon
      transit (18.7 h [9.1-28.3] vs. 36.7 [28.5-44.9]), and distal colon transit (3.1 h
      [-0.5 to 6.8] vs. 15.0 h [10.5-19.5]), respectively (all P < 0.01). Material was
      asymmetrically distributed in health (proximal colon 69% [63-76] vs. distal colon
      31% [24-37]). This asymmetry was more extreme in colitis, with corresponding
      values of 91% [85-96] vs. 9% [4-15]. As a result colitics had less material in
      the left-sided colon (9% [4-15] vs. 31% [24-37]), P < 0. 001. Colitics had a
      significantly lower percentage of the daily dose resident within the left side of
      the colon compared to controls (13% [-2 to 28] vs. 63% [44-81]), P < 0.01.
      CONCLUSIONS: Delayed release oral formulation is asymmetrically distributed
      within the colon in health. This asymmetry is exaggerated in active left-sided
      ulcerative colitis and, together with faster colonic transit, results in reduced
      exposure of the distal colon to orally-dosed topical agents.

PMID- 10651656
TI  - Gastrointestinal spread of oral prolonged-release mesalazine microgranules
      (Pentasa) dosed as either tablets or sachet.
AB  - BACKGROUND: There is increasing interest in using higher dosages of mesalazine
      for the treatment of inflammatory bowel disease; however, with current mesalazine
      products this involves the use of 8-16 tablets per day. AIM: To evaluate the
      disposition, dispersion and movements of Pentasa prolonged-release microgranules
      following single dosing of either tablets (2 x 500 mg) or a new 1 g sachet (unit
      dose, microgranules in a foil bag). METHODS: A randomized crossover study in
      eight healthy volunteers was undertaken. Both formulations were radiolabelled by
      neutron activation and dosed in the fasted state. Location of the preparations in
      the bowel was assessed over 24 h by scintigraphy. RESULTS: Dissolution testing at
      pH 7.5 showed comparable in vitro mesalazine release properties for the tablet
      and sachet preparations. In vivo disposition of the microgranules administered as
      either tablets or sachet was comparable in terms of gastric emptying, small
      intestinal transit and colon arrival. CONCLUSIONS: Pentasa sachets 1 g unit dose
      offers the same release of mesalazine as Pentasa 500 mg tablets. Drug release
      occurs throughout the gastrointestinal tract from stomach to colon, with the
      advantage of fewer oral doses and ease of swallowing.

PMID- 10651657
TI  - Mycophenolate mofetil: lack of efficacy in chronic active inflammatory bowel
      disease.
AB  - BACKGROUND: Mycophenolate mofetil (MMF) is a new immunosuppressant with
      pharmacodynamic properties comparable to azathioprine. Recent reports found MMF
      to be effective in inflammatory bowel disease (IBD). METHODS: An open-label
      prospective and uncontrolled multicentre 6 month trial of MMF in combination with
      steroids was conducted in 24 chronic active IBD patients. A daily steroid demand
      of >/= 10 mg prednisone in the preceding 2 months and a Crohn's disease activity
      index (CDAI) > 150, or moderate to severe activity according to Truelove, served
      as criteria for chronic activity. The treatment consisted of a steroid pulse and
      tapering protocol in combination with MMF 2 g/day. A prednisone dose of 5 mg/day
      was maintained during months 4-6. The primary end-point was induction and
      maintenance of remission. RESULTS: Only 10 of 24 patients had achieved remission
      after 3 months. All but one Crohn's disease patient had relapsed by the end of
      the study at 6 months. Depression and migraine necessitated drug withdrawal in
      two patients. CONCLUSION: In conclusion, MMF 2 g/day was unable to induce and
      maintain remission for a period of 6 months in 23 of 24 chronic active IBD
      patients. Further controlled investigations are required in view of recent
      conflicting reports.

PMID- 10651658
TI  - Pharmacoepidemiology of non-steroidal anti-inflammatory drug use in Nottingham
      general practices.
AB  - AIM: To investigate the pharmacoepidemiology of NSAID usage in Nottingham general
      practices. DESIGN: Questionnaire sent to 1137 consecutive recipients of an NSAID
      prescription from 21 doctors in six general practices with computerized records.
      Patient responses were subsequently linked to data held on the practice records.
      SETTING: General practices in and around Nottingham, selected to reflect local
      variations in number of partners, list size, geographical location, deprivation,
      prescribing burden and prescribing rate. SUBJECTS: Unselected patients receiving
      NSAIDs prescribed for all indications. MAIN OUTCOME MEASURES: Indication for
      treatment, differences in prescribing to different age groups, compliance and
      overall scheme drug exposure, drug effectiveness and tolerability, possible drug
      related adverse events, patients' overall satisfaction with treatment and
      estimated costs of care. RESULTS: NSAIDs were used for a wide range of conditions
      and only a small number of patients had rheumatoid arthritis. The main drugs used
      were ibuprofen, diclofenac and naproxen. Patients making short-term use of NSAIDs
      had low compliance if they experienced adverse drug effects, whilst conversely in
      long-term users, those with high compliance reported more adverse drug effects.
      Calculated compliance did not vary with age although older patients (over 65
      years) claimed in their questionnaires to be more compliant than younger
      patients. Half the patients reported good or complete symptom relief. Half of
      those questions (and two thirds of those with good or complete symptom relief)
      rated their NSAID as the best treatment they had received for their current
      condition. The frequency of gastrointestinal adverse events was higher in the
      young and the old, which correlated with the use of anti-ulcer drugs, and
      increased with the total number of medications used. CONCLUSIONS: NSAIDs are used
      for a wide-range of conditions. They give symptom relief to, and are perceived as
      effective by, most patients taking them.

PMID- 10651659
TI  - Ibuprofen versus other non-steroidal anti-inflammatory drugs: use in general
      practice and patient perception.
AB  - OBJECTIVE: To investigate whether ibuprofen was as well-regarded by patients as
      other non-steroidal anti-inflammatory drugs (NSAIDs). DESIGN: Questionnaire sent
      to 1137 consecutive recipients of an NSAID prescription from 21 doctors in six
      general practices with computerized records. Patient responses were subsequently
      linked to data held on the practice records. SETTING: General practices in and
      around Nottingham, selected to reflect local variations in number of partners,
      list size, geographical location, deprivation, prescribing burden and prescribing
      rate. SUBJECTS: Unselected patients receiving NSAIDs prescribed for all
      indications for use. MAIN OUTCOME MEASURES: Effectiveness of ibuprofen and other
      NSAIDs, possible drug related adverse events, patients' overall satisfaction with
      ibuprofen and other NSAIDs, factors associated with choice of ibuprofen, drug
      costs of ibuprofen and other NSAIDs. RESULTS: The main NSAIDs used were
      ibuprofen, diclofenac and naproxen. Ibuprofen use ranged from 1.0% of
      prescriptions in one practice to 69.1% in another. Although ibuprofen was
      generally prescribed in low doses, it was perceived by patients as being as
      effective as the other NSAIDs used, even after allowing for severity of the pre
      treatment condition. Overall, 50.5% of patients rated their NSAID the best
      treatment they had received for their condition with no differences between
      individual drugs. CONCLUSIONS: Ibuprofen is as highly regarded as other NSAIDs
      when used in similar circumstances. Switching patients to ibuprofen may be a
      realistic way of reducing financial and medical costs associated with NSAIDs.

PMID- 10651660
TI  - Do mucosal defensive agents improve the cure rate when used with dual or triple
      therapy regimens for eradicating Helicobacter pylori infection?
AB  - BACKGROUND: Some of mucosal defensive agents have anti-Helicobacter pylori
      activities. However, their effectiveness in eradicating H. pylori infection has
      not been evaluated. AIM: To assess the additive effect of mucosal defensive
      agents in eradication regimens using statistical analysis. METHODS: Pertinent
      studies were retrieved using the Medline and the Igaku-chuo-zasshi databases in
      Japan, reference and congress abstract lists. Studies in which regimens consisted
      of dual or triple therapy with mucosal defensive agents and without them, were
      selected from the retrieved studies. Eradication rates were extracted from
      studies according to intention-to-treat analysis. We evaluated the efficacies of
      mucosal defensive agents by pooled relative risk of eradication rates and its 95%
      confidence intervals (95% CI), which were calculated by Mantel-Haenszel method.
      Heterogeneity among the studies in treatment effect was evaluated by a chi2-test.
      RESULTS: In dual therapy regimens, mucosal defensive agents demonstrated
      significant additive effects (pooled relative risk 1.41; 95% CI: 1.24-1.61). In
      triple therapy regimens, these agents did not provide significant additive
      effect. The clinical usefulness of specific agents could not be established, when
      each agent was analysed independently. CONCLUSIONS: Mucosal defensive agents
      improve the cure rate when used with existing dual therapy regimens for
      eradicating H. pylori infection.

PMID- 10651661
TI  - Non-steroidal anti-inflammatory drugs, Helicobacter pylori and bleeding gastric
      ulcer.
AB  - BACKGROUND: Helicobacter pylori infection and NSAID usage are considered to be
      independent risk factors for gastric ulcer (GU). Whether they interact to
      influence the risk of bleeding in GU is unclear. AIM: To determine the prevalence
      of H. pylori infection and NSAID ingestion in a group of patients with GU and
      determine their roles in bleeding and non-bleeding GU. METHODS AND RESULTS: From
      January 1993 to June 1996, a total of 217 GU patients (150 male, 67 female,
      median age 61 years, range 26-94) were eligible for the study. Eighty-five per
      cent were H. pylori-positive and 15% were H. pylori-negative. NSAID usage within
      4 weeks prior to endoscopy was present in 30%, more in the H. pylori-negative
      than H. pylori-positive patients (59% vs. 25% P = 0.0002). Aspirin was most
      commonly used (43%). One hundred patients bled from GU (69 male, 31 female, mean
      age 67 years, range 26-94) and 117 did not (81 male, 36 female, mean age 57
      years, range 28-86). Univariate logistic regression showed that advanced age (>/=
      65 years) and NSAID usage carried an increased risk of bleeding GU (odds ratio
      3.4 and 6.8, respectively) while H. pylori infection alone was not associated
      with additional risk (OR = 0.8). However, when three variables were considered
      jointly in a multiple logistic regression, the OR associated with H. pylori
      infection increased to 2.4, suggesting that in the presence of NSAIDs and
      advanced age, H. pylori also increases the risk of bleeding GU, indicating an
      interaction between the variables. CONCLUSION: NSAID usage and advanced age are
      risk factors for bleeding GU, whereas H. pylori infection by itself is not. In
      the presence of NSAIDs and advanced age, an increased risk of bleeding GU with H.
      pylori is observed, indicating the possibility of an interaction between these
      factors.

PMID- 10651662
TI  - Furazolidone combination therapies for Helicobacter pylori infection in the
      United States.
AB  - BACKGROUND: Antibiotic resistance has begun to impair the ability to cure
      Helicobacter pylori infection. AIM: To evaluate furazolidone as a component of
      combination therapies for treatment of H. pylori infection in the United States.
      METHODS: Patients with active H. pylori infection received furazolidone
      combination therapy for 14 days (furazolidone 100 mg and tetracycline 500 mg
      t.d.s.; omeprazole 20 mg o.d. in the morning and, depending on the pre-treatment
      antimicrobial susceptibility pattern, 500 mg of metronidazole or clarithromycin
      t.d.s.). RESULTS: A total of 27 patients received the metronidazole containing
      combination (cure rate 100%) and seven received the clarithromycin combination
      (cure rate 86%). Overall the cure rates for intention-to-treat was 97% (95% CI:
      85% to 100%). The single failure took the clarithromycin containing combination
      for only 2 days (per protocol cure rate = 100%). Side-effects were common and led
      to discontinuation of therapy in 26% of patients. An attempt to eliminate
      metronidazole and clarithromycin and use furazolidone, tetracycline, and
      lansoprazole b.d. produced an unsatisfactory cure rate of 72%. CONCLUSION:
      Furazolidone combination therapy appears to be effective. Additional studies with
      different antimicrobial combinations and duration of therapy are warranted.

PMID- 10651663
TI  - Comparison of lansoprazole-based triple and dual therapy for treatment of
      Helicobacter pylori-related duodenal ulcer: an Asian multicentre double-blind
      randomized placebo controlled study.
AB  - BACKGROUND: [corrected] In Asian countries with limited resources, clarithromycin
      based triple therapy may not be readily available. There are also few direct
      comparisons of different regimens in Asia. AIM: To compare two lansoprazole-based
      non-clarithromycin triple therapies and one dual therapy in a prospective double
      blind placebo-controlled study of Helicobacter pylori eradication and duodenal
      ulcer healing. METHODS: Fourteen centres in Asia participated in this study.
      Patients with acute duodenal ulcer who were H. pylori-positive were recruited.
      They were randomized to receive: (a) lansoprazole 30 mg b.d., amoxycillin 1 g
      b.d. and metronidazole 500 mg b.d. for 2 weeks (LAM-2 W), or (b) LAM for 1 week
      and placebo (LAM-1 W), or (c) lansoprazole 30 mg b.d., amoxycillin 1 g b.d. and
      placebo for 2 weeks (LA-2 W). Upper endoscopy was repeated at week 6 to check for
      duodenal ulcer healing. Symptoms and side-effects were recorded. RESULTS: A total
      of 228 patients were recruited, and two patients took less than 50% of the drugs.
      H. pylori eradication rates (intention-to-treat) were 68 out of 82 (83%) with LAM
      2 W, 55 out of 71 (78%) with LAM-1 W and 43 out of 75 (57%) with LA-2 W. There
      were significant differences (P=0. 001) in eradication rates when comparing
      either LAM-2 W or LAM-1 W with LA-2 W. The eradication rate in patients with
      metronidazole resistant H. pylori strains were significantly lower than those
      with metronidazole sensitive strains (P=0.0001). The duodenal ulcer healing rates
      at week 6 were 85%, 85% and 72% in LAM-2 W, LAM-1 W and LA-2 W, respectively
      (P=0.065). Side-effects occurred in 13%, 11% and 9% in LAM-2 W, LAM-1 W and LA-2
      W, respectively. H. pylori eradication and initial ulcer size were factors
      affecting duodenal ulcer healing. CONCLUSIONS: This Asian multicentre study
      showed that 1-week lansoprazole-based triple therapy without clarithromycin has
      similar efficacy in H. pylori eradication and ulcer healing compared with a 2
      week regimen. Both triple therapies were significantly better than dual therapy
      in H. pylori eradication. Therefore, 1-week lansoprazole-based triple therapy is
      as safe and effective as 2-week therapy in eradication of H. pylori infection and
      healing of duodenal ulcer in these Asian centres.

PMID- 10651665
TI  - Low-dose intravenous erythromycin: effects on postprandial and fasting motility
      of the small bowel.
AB  - BACKGROUND: Erythromycin is a motilin agonist and its effects on gastrointestinal
      motility are dependent on both dose and whether it is administered during the
      postprandial or fasting state. AIM: To study the motility response of the small
      bowel to a low dose of intravenous erythromycin after meal intake and during
      fasting. METHODS: Eighteen healthy subjects with mean age of 25 years were
      studied by small bowel manometry. Erythromycin was administered intravenously
      (0.75 mg per kg body weight) during 20 min in the postprandial (n=9) and the
      fasting state (n=9), and the motility response was recorded. RESULTS:
      Erythromycin significantly reduced the frequency of propagated contractions (P <
      0.001) and the amplitude of contractions (P < 0.02) in the small bowel during
      established postprandial motility. During the fasting state, erythromycin
      invariably initiated a phase III-like activity, which was similar to the
      spontaneous nocturnal phase III and migrated significantly more slowly than the
      diurnal phase III (P < 0.01). CONCLUSIONS: A low dose of erythromycin
      administered intravenously during the postprandial state significantly inhibits
      small bowel motility, whereas administration during the fasting state initiates a
      phase III resembling the nocturnal rather than the diurnal phase III. These
      effects of erythromycin may indicate interference with vagal pathways. Due to its
      inhibitory effects, the clinical use of erythromycin in patients with
      hypomotility should be reconsidered, and the potential usefulness of these
      effects in patients with exaggerated intestinal motility deserves further
      attention.

PMID- 10651666
TI  - Similarities between ileal Crohn's disease and indomethacin experimental jejunal
      ulcers in the rat.
AB  - BACKGROUND: Both Crohn's disease ileal ulcers and indomethacin-induced jejunal
      ulcers in the rat have a predilection for the mesenteric margin of the bowel
      wall. Unlike the anti-mesenteric margin, the mesenteric margin is supplied by
      small end-arteries that might render it more sensitive to ischaemic injury. AIM:
      To examine, in both situations, the histological relationship between the precise
      localization of small bowel ulcers and the mesenteric margin. METHODS: Ileal
      Crohn's disease ulcers identified in surgical resection specimens (n=5) and
      indomethacin-induced lesions in the rat jejunum (n=6) were examined
      macroscopically and histologically. RESULTS: In both the human ileum and the rat
      jejunum, ulcers occurred consistently along the mesenteric margin, with the most
      extensive mucosal injury occurring at two adjacent sites on either side of the
      midline of this margin. At these two sites, feeding arteries entered the
      muscularis propria. CONCLUSIONS: For anatomical reasons apparently related to the
      vasculature of the human and rodent small bowel, specific sites along the
      mesenteric margin are susceptible to Crohn's disease ulceration and NSAID damage,
      respectively.

PMID- 10651664
TI  - Triple therapy in the eradication of Helicobacter pylori in patients with
      duodenal ulcer disease: results of a multicentre study in South-East Asia. South
      East Asia Multicenter Study Group.
AB  - BACKGROUND: The efficacy of proton pump inhibitor based triple therapy in
      patients from South-East Asia, where metronidazole resistance is reportedly high,
      has not been formally assessed in randomized, multicentre trials. AIM: To compare
      the eradication rates of Helicobacter pylori, ulcer healing rates and side
      effects of three regimens of omeprazole triple therapy in patients with duodenal
      ulcer from South-East Asia and to study the impact of metronidazole resistance.
      METHODS: A single blind, randomized parallel group, comparative multicentre
      study. A total of 246 patients from 15 centres in four South-East Asian countries
      were randomized to receive OAC (omeprazole 20 mg b.d., amoxycillin 1 g b. d.,
      clarithromycin 500 mg b.d.), OAM (omeprazole 20 mg b.d., amoxycillin 1 g b.d.,
      metronidazole 400 mg b.d.) or OMC (omeprazole 20 mg b.d., metronidazole 400 mg
      b.d., clarithromycin 500 mg b.d.) for 7 days. After triple therapy, the patients
      were further randomized to receive either omeprazole or placebo for 7 days. Upper
      gastrointestinal endoscopy was performed before treatment and 4 weeks after
      treatment. Biopsies for culture and for histopathological examination for H.
      pylori were taken from corpus and antrum before treatment and 4 weeks after
      treatment. RESULTS: The eradication rates were intention-to-treat/per protocol
      (95% CI): OAC 87% (79-94%)/94% (89-100%); OAM 80% (70-89%)/91% (83-98%); OMC 85%
      (77-93%)/94% (88-100%). The difference in eradication rates between the three
      groups was not statistically significant (P=0.419). Pre-treatment metronidazole
      resistance, was found in 34% of isolates and was a significant prognostic factor
      in patients receiving OAM (odds ratio 5.26) but not in patients receiving OAC or
      OMC. CONCLUSIONS: All three treatment regimens were safe, well tolerated and
      highly effective for eradication of H. pylori and ulcer healing. Pre-treatment
      metronidazole resistance reduced the efficacy of OAM but did not affect the
      efficacy of OMC.

PMID- 10651667
TI  - Characterization of M cell development during indomethacin-induced ileitis in
      rats.
AB  - BACKGROUND: M cells play an important role in the intestinal immune system as
      they have a high capacity for transcytosis of a wide range of microorganisms and
      macromolecules. However, little is known about the role of M cells during
      intestinal inflammation. AIM: We studied M cell development during indomethacin
      induced intestinal inflammation in rats. METHODS: Ileitis in rats was induced by
      two subcutaneous injections with indomethacin (7.5 mg/kg) given 24 h apart. Rats
      were sacrificed after 14 days and tissue was analysed by fluorescence microscopy
      and electron microscopy. M cells could be visualized by using the FITC-labelled
      mAb anti-cytokeratin (CK)-8 (clone 4.1.18), which was recently identified as
      specific M cell marker in rats. The number of cytokeratin-8 positive M cells was
      related to the surface of the follicle associated epithelium. For morphological
      studies, we used both transmission electron microscopy (T.E.M.) and scanning
      electron microscopy (S.E.M.). RESULTS: In non-inflamed ileum M cells were scarce.
      Only 4% of the follicle associated epithelium were M cells, whereas an increase
      of M cells up to 11% was found in inflamed follicle associated epithelium (P <
      0.001). The rate of M cell induction depended on the macroscopic degree of
      inflammation. T.E.M./S.E.M. studies showed that in inflamed tissue most M cells
      underwent apoptosis with typical morphological signs. In contrast to apoptotic M
      cells, the neighbouring enterocytes usually appeared intact. The number of
      mononuclear cells below the follicle associated epithelium was significantly
      increased. S.E.M. studies revealed that during induced ileitis mononuclear cells
      migrated from the lamina propria into the gut lumen by passing through apoptotic
      M cells. CONCLUSIONS: During indomethacin-induced ileitis in rats the increase in
      M cell number in association with apoptosis of M cells may alter the intestinal
      barrier function. These observations may play a pivotal role in the pathogenesis
      of chronic intestinal inflammation, e.g. in inflammatory bowel disease.

PMID- 10651668
TI  - Anaesthesia for organ donation in the brainstem dead--why bother?

PMID- 10651669
TI  - Validation of outcome prediction in elderly patients.
AB  - We recently described an equation for predicting the 1-year survival of
      critically ill patients aged over 70 years. The aim of this study was to check
      the performance of this equation in a validation group of 555 patients. The
      required demographic details (age, diagnosis, acute physiology score) of all
      elderly patients admitted between 1/4/95 and 31/9/96 were recorded and patients
      were followed for 1 year. One hundred and six patients died on the intensive care
      unit (19% mortality) and a further 134 died within 1 year (43% total 1-year
      mortality). The performance of the predictive equation was modest; the goodness
      of-fit p-value was 0.04 and the area under the receiver operating characteristic
      curve was 0.75. For both groups, the combined 1-year survival of all critically
      ill elderly patients was 55% but the outcome of patients aged over 85 years
      remains poor (37%).

PMID- 10651670
TI  - A new method of predicting pulmonary capillary wedge pressure: the arterial
      pressure ratio.
AB  - The response of arterial blood pressure to an increase in intrathoracic pressure
      has been shown to be predictive of pulmonary capillary wedge pressure. We devised
      a new method, which we termed the arterial pressure ratio. We defined arterial
      pressure ratio as the ratio of systolic blood pressure of the final beat during
      the strain phase of the Valsalva manoeuvre to that during apnoea before the
      manoeuvre, and tested the accuracy of arterial pressure ratio in predicting
      pulmonary capillary wedge pressure. In 30 patients scheduled for elective
      abdominal aortic reconstruction, following induction of general anaesthesia and
      tracheal intubation, a 20-G catheter and pulmonary artery catheter were inserted
      through the radial artery and right internal jugular vein, respectively.
      Pulmonary capillary wedge pressure was then measured during a brief period of
      apnoea and the Valsalva manoeuvre was performed by application of pressure to the
      reservoir bag. Airway pressure was maintained at 30 cmH2O for 10 s and then
      released. Radial arterial pressure and airway pressure were recorded
      simultaneously, and arterial pressure ratio was calculated. There was a close
      linear correlation between arterial pressure ratio and pulmonary capillary wedge
      pressure (r = 0.88, p < 0.0001).

PMID- 10651671
TI  - Analgesic effect of low-dose intrathecal morphine and bupivacaine in laparoscopic
      cholecystectomy.
AB  - We assessed the peri-operative analgesic efficiency of low-dose intrathecal
      morphine combined with a low dose of bupivacaine after elective laparoscopic
      cholecystectomy since postoperative pain in such procedures, although less than
      after a conventional open technique, may be significant, particularly during the
      first 12-24 h. After informed consent, 34 ASA I or II patients were randomly
      allocated to one of two groups to receive either a lumbar intrathecal injection
      of morphine (75 or 100 microg) combined with 5 mg of isobaric bupivacaine (spinal
      group) or a subcutaneous injection of a saline solution (control group). Intra
      operatively, opioid requirements, blood pressure response and heart rate changes
      after insufflation were recorded. Postoperatively, morphine requirements, pain
      scores and opioid-related side-effects were assessed by a physician blinded to
      the randomisation. Intra-operative opioid requirements did not differ
      significantly between groups. Mean (SD) postoperative morphine requirements were
      significantly lower in the spinal group [13 (10) vs. 23 (10) mg; p = 0.04] as
      were postoperative pain scores (p < 0.001). Side-effects were of comparable
      incidence and severity between groups. Low-dose intrathecal morphine combined
      with low-dose bupivacaine provided effective postoperative analgesia for elective
      laparoscopic cholecystectomy.

PMID- 10651672
TI  - Percutaneous tracheostomy by forceps dilation: report of 162 cases.
AB  - A prospective, observational clinical study evaluated the safety of percutaneous
      single-step dilatational tracheostomy over a 43-month period. One hundred and
      sixty-two patients were deemed suitable for the procedure. The mean duration of
      tracheal intubation prior to tracheostomy was 6 days. The mean duration of the
      procedure was 9.3 min. Intra-operative complications occurred in 27 patients
      (16.6%), most of which were minor technical difficulties without morbidity.
      Postoperative complications, some of which were associated with morbidity,
      occurred in 16 patients. There were two deaths secondary to premature
      decannulation, one case of severe bleeding and five pneumothoraces. Long-term
      complications were assessed in 81 patients; there were four tracheal stenoses
      requiring surgery or laser therapy and seven patients with granulation tissue at
      the stoma site which did not require treatment. Forceps dilatational percutaneous
      tracheostomy appeared to be a convenient bedside procedure. However,
      complications do occur and further studies should address late sequellae, such as
      tracheal stenosis.

PMID- 10651673
TI  - Acute phase response to nitroprusside-induced controlled hypotension in patients
      undergoing radical prostatectomy.
AB  - This study evaluated the effects of sodium nitroprusside-induced controlled
      hypotension on the acute phase response in patients undergoing radical
      prostatectomy. Thirty patients were randomly allocated to two groups, a
      hypotension group (mean arterial blood pressure was adjusted to 50 mmHg) and a
      control group (mean arterial blood pressure > 70 mmHg). C-reactive protein
      increased significantly in the hypotension group from 0.13 (0.23) to 9.85 (2.84)
      microg x ml-1 and in the control group from 0.15 (0.27) to 7.38 (3.02) microg x
      ml-1. In both groups, serum amyloid A increased significantly, but levels were
      higher in the hypotension group [585 (125) microg x l-1] than in the control
      group [460 (187) microg x l-1]. Interleukin-6 increased significantly in both
      groups, but was higher in the hypotension group [139 (124) pg x ml-1] than the
      control group [56 (27) pg x ml-1]. Elastase showed no significant changes in the
      control group but in the hypotension group there was a significant increase from
      65 (51) to 122 (75) ng x ml-1. Sodium nitroprusside-induced hypotension was
      associated with a more pronounced acute phase reaction.

PMID- 10651674
TI  - An assessment of the staffing level required for a high-dependency unit.
AB  - High-dependency units are increasing in number and becoming an ever more
      important part of a hospital's facilities. The optimum staffing ratio is unknown,
      but the Department of Health and the Intensive Care Society recommend a level of
      one nurse to two patients. We recorded Therapeutic Intervention Scoring System-28
      scores and Nurse Dependency Scores for all admissions to our adult, general high
      dependency unit over 7 months. We found a weak correlation between the nurse
      dependency score and the Therapeutic Intervention Scoring System-28 score. The
      median Therapeutic Intervention Scoring System-28 score was 23 points
      (interquartile range 19-26), and the median Nurse Dependency Score was 1.0. These
      results are approximately two-thirds of those for European intensive care units.
      We conclude that a nurse-to-patient ratio of 1:2 may be insufficient for an adult
      general high-dependency unit, and would recommend a nurse-to-patient ratio of
      2:3.

PMID- 10651675
TI  - Succinylcholine-associated postoperative myalgia.
AB  - The subject of postoperative myalgia associated with the use of succinylcholine
      is reviewed. We discuss the mechanisms of succinylcholine-induced myalgia and the
      techniques available to prevent and treat the myalgia. In situations where
      patients are at risk of developing myalgia and succinylcholine is the
      neuromuscular blocker of choice, the use of a combination of techniques may prove
      to be a useful strategy.

PMID- 10651676
TI  - Anti-infective measures and Entonox equipment: a survey.
AB  - We surveyed 102 maternity suites to investigate whether the guidelines of the
      Association of Anaesthetists of Great Britain and Ireland, for the use of anti
      infective filters or fully disposable anaesthetic breathing systems for each
      patient, were being followed with regard to Entonox equipment on labour wards. Of
      100 units giving information (98%), only seven used filters and only two replaced
      tubing between cases. Our survey shows that the recommended policy is not being
      applied to Entonox apparatus in delivery suites.

PMID- 10651677
TI  - Glycinothorax: a new complication of transurethral surgery.
AB  - A 76-year-old woman sustained inadvertent perforation of her posterior bladder
      wall during transurethral resection of a bladder tumour. In the immediate
      postoperative period, she developed life-threatening respiratory failure
      following the formation of a large, unilateral pleural effusion. After
      therapeutic drainage, biochemical analysis of the effusion revealed that it had a
      high concentration of glycine. The fluid used for intra- and postoperative
      bladder irrigation had leaked from the perforated bladder and collected in the
      pleural cavity. This type of hydrothorax complicating endoscopic urological
      surgery has not been described previously.

PMID- 10651678
TI  - Gorham syndrome: anaesthetic management.
AB  - Gorham syndrome is a rare chronic disease of children and young adults, featuring
      massive osteolysis with pathological fractures and complicated by respiratory and
      neurological deficits. To date, 175 cases have been reported in the literature
      but information on anaesthetic management is sparse. We present a child with
      Gorham syndrome who underwent urgent surgical medullary decompression and who
      subsequently developed bilateral pleural effusions.

PMID- 10651679
TI  - Anaesthetic management of a patient with pemphigus vulgaris for emergency
      laparotomy.
AB  - A 45-year-old man with a long-standing history of duodenal ulcer presented with
      symptoms and signs of perforation peritonitis. He also had lesions of pemphigus
      vulgaris throughout the body, involving both skin and mucous membranes. Care was
      taken to avoid pressure and friction during placement of monitoring devices,
      intravenous and arterial lines. Since the patient had to undergo exploratory
      laparotomy, intubation was performed in an atraumatic manner after rapid sequence
      induction. However, there was minor bleeding from the mucous lesions of the oral
      cavity, which was controlled by a saline adrenaline throat pack. The patient was
      extubated at the end of the surgery and steroids were continued in the peri
      operative period.

PMID- 10651680
TI  - Effect of cricoid pressure on the incidence of nausea and vomiting in the
      immediate postoperative period.
AB  - This study aimed to evaluate whether the application of cricoid pressure at the
      time of induction of anaesthesia was associated with a lesser incidence of
      postoperative nausea or vomiting in the immediate postoperative period compared
      with a group in which no cricoid pressure was applied, in patients undergoing day
      care gynaecological laparoscopy. One hundred ASA I and II females were randomly
      allocated to receive cricoid pressure at the time of induction. The peri
      operative anaesthetic technique was standardised. The incidence of postoperative
      nausea and vomiting in the group who received cricoid pressure was 16% in the
      recovery room compared with 26% in the no cricoid group. When the period was
      extended to the first 6 h post anaesthesia the incidence was 30% in the cricoid
      and 44% in the no cricoid group. This difference did not achieve statistical
      significance in either period (p > 0.05). The results suggest that application of
      cricoid pressure at the time of induction does not significantly alter the
      incidence of postoperative nausea and vomiting in the first 6 h of recovery from
      anaesthesia.

PMID- 10651681
TI  - A comparison of the effects of desflurane and isoflurane on arterial oxygenation
      during one-lung ventilation.
AB  - In a randomised prospective cross-over study, we compared the effects of
      desflurane and isoflurane on arterial oxygenation, heart rate and mean arterial
      pressure during one-lung anaesthesia. Thirty patients scheduled for
      oesophagogastrectomy were randomly assigned to one of two groups. One group of 15
      patients received desflurane to an end-tidal concentration of 6% in oxygen from
      induction until the end of 30 min of open chest one-lung ventilation in the
      lateral position. This was followed by isoflurane to an end-tidal concentration
      of 1.1% in oxygen for the next 30 min of one-lung ventilation. The other group of
      15 patients received the two anaesthetic agents in the reverse order. We found no
      significant difference in arterial oxygenation, heart rate or mean arterial
      pressure between the two inhalational agents. In the subgroup of 10 patients with
      pulmonary artery catheters, we found no significant differences in mixed venous
      saturation, derived shunt or cardiac output. We conclude that during one-lung
      ventilation, the choice between desflurane and isoflurane does not significantly
      influence arterial oxygenation.

PMID- 10651682
TI  - The effect of facial hair and sex on the dispersal of bacteria below a masked
      subject.
AB  - Surgical face masks prevent the dispersal of bacteria from the upper airway to
      surfaces immediately in front of and below the face during talking. However, mask
      wiggling has been reported to increase dermabrasion and bacterial contamination
      of surfaces immediately below the face. Facial hair and recent shaving may alter
      the quantity of particles shed by dermabrasion when the mask is wiggled. We
      investigated the effect of mask wiggling in 10 bearded and 10 clean-shaven male
      subjects, and 10 female subjects. Wiggling the mask significantly increased the
      degree of bacterial shedding onto agar plates 15 cm below the lips in bearded
      males (p = 0.03) and females (p = 0.03), but not in clean-shaven males. At rest
      without mask wiggling the bearded subjects shed significantly more bacteria than
      clean-shaven males (p = 0.01) or females (p = 0.001). To reduce the risks of
      contamination of the sterile field when face masks are worn females and bearded
      males should avoid wiggling the face mask. Bearded males may also consider
      removing their beards.

PMID- 10651683
TI  - Entonox equipment as a potential source of cross-infection.
AB  - A survey of the hospitals with obstetric units within the Anglia and Oxford
      Region was performed to assess current practices regarding the cleaning of, and
      use of filters with, Entonox apparatus. The survey revealed that there was no
      consensus regarding the cleaning of the equipment and, in contrast to anaesthetic
      machines in which microbiological filters are recommended and in widespread use,
      only 10% of the hospitals surveyed were using such filters with the Entonox
      apparatus in their units. Cleaning procedures were changed in 75% of hospitals
      when dealing with known 'high-risk' patients, the remaining hospitals treating
      all patients as 'high-risk' or denied caring for such patients. All patients
      should be protected from potential cross-infection, and the recommendation that a
      microbiological filter should be placed between patients and the breathing system
      should be extended to Entonox equipment.

PMID- 10651684
TI  - Training in obstetric general anaesthesia: a vanishing art?
AB  - General anaesthesia in obstetric practice has largely been replaced by the use of
      regional techniques. We have studied this phenomenon and the subsequent impact on
      training in this technique both retrospectively and with a prospective audit.
      There has been a decline in the use of general anaesthesia for Caesarean section
      such that trainee anaesthetists are getting less practical exposure to this
      important procedure. Audit revealed a deficit with consultant involvement in
      training and heightened awareness has resulted in improved supervision. Possible
      implications for future consultant working practices are discussed.

PMID- 10651685
TI  - Can you COPE with CONSORT?

PMID- 10651686
TI  - Solar urticaria.

PMID- 10651687
TI  - Gluten and psoriasis.

PMID- 10651688
TI  - Detoxifying enzyme genotypes and susceptibility to cutaneous malignancy.
AB  - While ultraviolet (UV) exposure is thought to be a major risk factor for basal
      cell carcinoma (BCC) and squamous cell carcinoma, more recent research has
      focused on genetic factors predisposing to these cancers. UV constitutes an
      oxidative stress with generation of free radicals, leading to lipid and DNA
      damage and gene mutation. It could therefore be hypothesized that individual
      ability to deal with these products may be important in cutaneous carcinogenesis.
      It is clear from recent studies that polymorphisms in detoxifying enzyme genes
      are important in determining susceptibility to skin cancer. The magnitude of
      effect in BCC is similar to that seen with many other previously described risk
      factors. However, uncertainties exist regarding the phenotypic consequences of
      some of these polymorphisms and relevant substrates. This review describes the
      influence of polymorphisms in detoxifying enzymes in determining susceptibility
      to skin cancer (in particular to BCC) and give a brief overview of the
      biochemistry of the detoxification process.

PMID- 10651689
TI  - Extracorporeal photopheresis in cutaneous T-cell lymphoma. Inconsistent data
      underline the need for randomized studies.
AB  - Edelson et al.7 first reported the use of extracorporeal photopheresis (ECP) to
      treat cutaneous T-cell lymphoma (CTCL) in 1987, and since then several studies
      reporting response rates and survival data have appeared in the literature.
      Several modes of action have been proposed for ECP. In CTCL there is an
      accumulating body of evidence to show that 8-methoxypsoralen-treated cells
      display increased quantities of antigenic peptides at their cell surfaces, and
      this in turn leads to an enhanced cytotoxic response against the neoplastic T
      cell population. This mechanism requires the presence of malignant cells in the
      peripheral circulation, and may account for the observation that ECP produces
      higher response rates in erythrodermic CTCL than at other stages of disease.
      However, patients with inflammatory skin diseases such as reactive erythroderma
      may also respond to ECP, and it is therefore crucial that a diagnosis of Sezary
      syndrome is confirmed by demonstrating a clonal population of T cells in the
      peripheral blood. Unfortunately, most studies have not employed T-cell receptor
      gene analysis routinely, and this may account for the different response rates
      and survival data reported with ECP in the literature. To date, ECP has not been
      tested in a randomized study against conventional forms of therapy.

PMID- 10651690
TI  - Guidelines for topical PUVA: a report of a workshop of the British
      photodermatology group.
AB  - Psoralen photochemotherapy [psoralen ultraviolet A (PUVA)] plays an important
      part in dermatological therapeutics, being an effective and generally safe
      treatment for psoriasis and other dermatoses. In order to maintain optimal
      efficacy and safety, guidelines concerning best practice should be available to
      operators and supervisors. The British Photodermatology Group (BPG) have
      previously published recommendations on PUVA, including UVA dosimetry and
      calibration, patient pretreatment assessment, indications and contraindications,
      and the management of adverse reactions.1 While most current knowledge relates to
      oral PUVA, the use of topical PUVA regimens is also popular and presents a number
      of questions peculiar to this modality, including the choice of psoralen,
      formulation, method of application, optimal timing of treatment, UVA regimens and
      relative benefits or risks as compared with oral PUVA. Bath PUVA, i.e.
      generalized immersion, is the most frequently used modality of topical treatment,
      practised by about 100 centres in the U.K., while other topical preparations tend
      to be used for localized diseases such as those affecting the hands and feet.
      This paper is the product of a recent workshop of the BPG and includes guidelines
      for bath, local immersion and other topical PUVA. These recommendations are
      based, where possible, on the results of controlled studies, or otherwise on the
      consensus view on current practice.

PMID- 10651691
TI  - The clinical and photobiological characteristics of solar urticaria in 40
      patients.
AB  - Forty patients with solar urticaria, 16 male and 24 female, were examined
      personally during the past 25 years. The median age at onset of symptoms was 32
      years, ranging from 13 to 76 years. Most commonly (45%) solar urticaria first
      appeared during the third decade. The mean duration of the disease was 3.6 years
      at presentation. The action spectrum was found in the visible light range in 24
      patients (60%), in the ultraviolet (UV) A range in four, in the UVB in four, from
      the UVA to UVB in three, from the UVA to visible light in one and in a broad
      range from UVB to visible light in four patients. An inhibition spectrum was
      detected in 13 of 19 patients (68%), occurring at longer wavelengths than the
      action spectrum in 12 of these cases. The augmentation spectrum was found in only
      four of 14 patients (29%) examined. Twenty-four of 31 patients (77%) developed an
      urticarial reaction to autologous serum, which had been previously irradiated in
      vitro at the action spectrum for that patient. In a single patient, solar
      urticaria was caused by a drug, namely chlorpromazine. In two patients,
      polymorphic light eruption occurred in association with solar urticaria. No
      single modality of treatment was satisfactory, but combined use of
      antihistamines, sunbathing, psoralen UVA photochemotherapy and/or sunscreening
      agents partially suppressed the symptoms.

PMID- 10651692
TI  - Half-side comparison study on the efficacy of 8-methoxypsoralen bath-PUVA versus
      narrow-band ultraviolet B phototherapy in patients with severe chronic atopic
      dermatitis.
AB  - In patients with severe chronic atopic dermatitis (AD), both photochemotherapy
      [psoralen ultraviolet A (PUVA)] and narrow-band (TL-01) UV B phototherapy have
      been reported to be very effective. As no data exist on the relative therapeutic
      efficacy of these two regimens, we performed a randomized investigator-blinded
      half-side comparison study on 12 patients with severe chronic AD. Half-side
      irradiation with threshold erythemogenic doses of 8-methoxypsoralen bath-PUVA and
      narrow-band UVB was performed three times weekly over a period of 6 weeks. The
      severity of the disease was assessed separately for the paired halves of the
      patients' bodies by a modified SCORAD score at baseline and after 2, 4 and 6
      weeks of treatment. Ten of the 12 patients completed the trial. All but one
      showed marked improvement or complete remission with both treatments. The mean
      baseline SCORAD score decreased by 65.7% by the bath-PUVA treatment and by 64.1%
      by the narrow-band UVB treatment (P = 0.48). No serious adverse reactions to
      either of the two regimens were observed. Our data confirm the high efficacy of
      bath-PUVA and narrow-band UVB phototherapy in the treatment of patients with
      chronic severe AD. Both regimens appear to be equally effective when administered
      in equi-erythemogenic doses.

PMID- 10651693
TI  - Psoriasis patients with antibodies to gliadin can be improved by a gluten-free
      diet.
AB  - In a previous screening study, 16% of patients with psoriasis had IgA and/or IgG
      antibodies to gliadin (AGA). The aim of the present study was to evaluate the
      effect of a gluten-free diet (GFD) in 33 AGA-positive and six AGA-negative
      psoriasis patients. Of the 33 AGA-positive patients, two had IgA antibodies to
      endomysium (EmA) and 15 an increased number of lymphocytes in the duodenal
      epithelium, but in some this increase was slight. Two patients had villous
      atrophy. A 3-month period on a GFD was followed by 3 months on the patient's
      ordinary diet. The severity of psoriasis was evaluated with the psoriasis area
      and severity index (PASI). The examining dermatologists were unaware of the EmA
      and duodenal biopsy results throughout the study. Thirty of the 33 patients with
      AGA completed the GFD period, after which they showed a highly significant
      decrease in mean PASI. This included a significant decrease in the 16 AGA
      positive patients with normal routine histology in duodenal biopsy specimens. The
      AGA-negative patients were not improved. After GFD, the AGA values were lower in
      82% of those who improved. There was a highly significant decrease in serum
      eosinophil cationic protein in patients with elevated AGA. When the ordinary diet
      was resumed, the psoriasis deteriorated in 18 of the 30 patients with AGA who had
      completed the GFD period. In conclusion, psoriasis patients with raised AGA might
      improve on a GFD even if they have no EmA or if the increase in duodenal
      intraepithelial lymphocytes is slight or seemingly absent.

PMID- 10651695
TI  - The Roswell Park Cancer Institute experience with extramammary Paget's disease.
AB  - Extramammary Paget's disease (EMPD) is a rare intraepithelial neoplasm. Common
      sites of occurrence include the vulva, perianal region, perineum and scrotum.
      Despite frequent recurrences, surgery is the standard treatment. This study
      examines the recurrence rate for EMPD treated by conventional surgical
      management. Alternative and multimodal therapeutic approaches are reviewed. This
      retrospective analysis included all 30 patients treated for EMPD at Roswell Park
      Cancer Institute (RPCI) between 1970 and 1998. Following conventional surgical
      treatment, 44% of our patients developed recurrence. Vulvectomy provided the
      lowest recurrence rate, but involved extensive tissue loss and functional
      debility. Multimodal treatment using Mohs' micrographic surgery and photodynamic
      therapy has been used at RPCI to manage EMPD with minimal tissue loss and no
      functional impairment. Surgical treatment offers a moderate chance of EMPD cure.
      Long-term multimodal approaches require close follow-up, but may conserve both
      tissue and function.

PMID- 10651694
TI  - Cyclosporin for severe childhood atopic dermatitis: short course versus
      continuous therapy.
AB  - Cyclosporin (CyA) has been shown to be highly effective and well tolerated in the
      short-term treatment of severe childhood atopic dermatitis; however, there is
      limited experience in its longer-term use. The aim of this study was to compare
      multiple short courses of CyA with continuous therapy for 1 year, with respect to
      efficacy, safety, tolerability and quality of life. Children aged 2-16 years,
      with a diagnosis of severe atopic dermatitis refractory to topical steroid
      therapy, were randomly assigned to receive short course therapy (multiple courses
      of 12 weeks) or continuous therapy. The starting dose and maximum dose for all
      patients was 5 mg/kg per day. Disease activity was monitored using the Six Area
      Six Sign Atopic Dermatitis score and the 'Rule of Nines' area score. Pruritus,
      sleep disturbance and irritability were measured using visual analogue scales,
      and topical therapy was monitored. Safety measurements included monitoring of
      serum creatinine, blood pressure and adverse events. Forty patients were included
      in the efficacy analysis, 21 of whom were randomized to the short course group
      (of whom six were withdrawn) and 19 to the continuous group (of whom five were
      withdrawn). Significant improvements were seen in all efficacy parameters at
      every time-point. There were no significant differences between groups, although
      the improvement was more consistent in the continuous arm. In the short course
      arm, 7 out of 21 patients could be managed by at least two short courses. The
      remaining 14 patients includes 12 who could not be controlled by at least two
      short courses, one patient who failed to return after week 12 and another patient
      who was withdrawn at week 4 due to an adverse event. Quality of life improved for
      both the children and their families. Tolerability was considered good or very
      good in at least 80% of the patients at week 12 and at the end of the study. No
      clinically significant change was seen in mean serum creatinine and no change was
      seen in mean blood pressure in either group. CyA is effective in controlling
      severe atopic dermatitis in children over a 1-year period and is well tolerated.
      More consistent control is achieved with continuous treatment; however, short
      course therapy was adequate for some patients, indicating that treatment should
      be tailored to the individual patient's needs. Short course treatment may produce
      prolonged remission in some cases and reduce the cumulative exposure to the drug.

PMID- 10651696
TI  - Educating patients about malignant melanoma: computer-assisted learning in a
      pigmented lesion clinic.
AB  - This prospective controlled study aimed to evaluate the effectiveness and
      acceptability of a computer program (CAL) designed to educate patients about skin
      protection including signs of melanoma. Two hundred and twenty-seven patients
      were recruited either from the Pigmented Lesion Clinic (PLC) or the Orthopaedic
      Fracture Clinic (OFC). A baseline measure of anxiety was obtained and subjects
      were allocated to either non-interactive, interactive or control conditions.
      Measures of anxiety and knowledge about malignant melanoma and skin protection
      were obtained prior to discharge from the clinic and knowledge was assessed again
      at 1-week follow-up. Results indicate that, although anxiety in the PLC subjects
      decreased significantly more than in the OFC patients, there was no significant
      effect of intervention. There was a significant effect of intervention on
      knowledge (F = 81.06, d.f. 2, 218, P < 0.0001) with participants having better
      knowledge on leaving the clinic in the interactive CAL condition than in both the
      Non-interactive condition and control. Non-interactive CAL was associated with
      higher knowledge than control. Knowledge gains were maintained at 1-week follow
      up.

PMID- 10651697
TI  - Development of a polymerase chain reaction dot-blotting system for detecting
      cutaneous tuberculosis.
AB  - For a definitive diagnosis of cutaneous tuberculosis the demonstration of
      mycobacteria is essential, but this is generally not possible in skin lesions.
      Routinely available techniques have poor sensitivity and are time consuming,
      therefore, delaying the institution of timely therapy. The high sensitivity and
      speed of polymerase chain reaction (PCR) for the detection of infectious agents
      has prompted investigators to use this technique for the detection of
      Mycobacterium tuberculosis in body fluids such as cerebrospinal fluid or pleural
      fluid. In the present study, PCR was used to examine punch biopsy specimens from
      the affected skin of 10 patients with clinical diagnoses of tuberculosis
      verrucosa cutis, lupus vulgaris, scrofuloderma, papulonecrotic tuberculide and
      erythema induratum. A control group of 20 patients included individuals having
      skin manifestations with definite clinical diagnoses other than cutaneous
      tuberculosis, such as leprosy, fungal mycetoma, chronic bullous disease of
      childhood and pemphigus vulgaris. The PCR amplified products were dot hybridized
      with a probe which was random prime labelled with 32P. The results were compared
      with routine microbiological and histological findings. Among the test group, six
      of 10 (60%) were positive for M. tuberculosis by PCR, although their
      histopathology showed non-specific chronic inflammation with no definite
      diagnosis. Microbiological investigations, including acid-fast bacillus smear and
      culture, were positive in a single case of scrofuloderma. All patients in the
      control group were negative by PCR for M. tuberculosis. The data indicate that
      the combination of dot hybridization with PCR markedly increased the sensitivity
      and specificity of PCR. This may be a useful tool in the diagnosis of
      tuberculosis when conventional methods fail.

PMID- 10651699
TI  - Allergic contact dermatitis to plant extracts in patients with cosmetic
      dermatitis.
AB  - Cosmetic contact allergy is commonly seen in patients undergoing patch testing,
      with fragrance one of the most frequently implicated ingredients. Many cosmetics
      contain plant extracts either as a fragrance or for medicinal properties. With a
      vogue for natural products there is an increase in their use. We have performed a
      prospective study over a 2-year period looking at the prevalence of contact
      allergy to plants in patients diagnosed with cosmetic dermatitis. In addition, we
      have performed a review of the products of two popular cosmetic companies,
      examining product labelling and the prevalence of use of plant extracts. We
      suggest that patients allergic to fragrance be advised to avoid plant extracts,
      which are separately labelled, in their personal care products.

PMID- 10651698
TI  - Response of naevus of Ota to Q-switched ruby laser treatment according to lesion
      colour.
AB  - Lesions of naevus of Ota range in colour from light brown to blue, and even
      greenish-black. To develop guidelines for optimal treatment, we evaluated the
      number of Q-switched ruby laser treatments required to eliminate the pigmentation
      of such lesions classified by colour. Over a period of 6 years, we evaluated 151
      Japanese patients with naevus of Ota who had been treated with the Q-switched
      ruby laser at a low energy level (wavelength 694.3 nm; pulse duration 28 x 10-9
      s; energy fluence 5 J/cm2; spot size 6.5 mm) every 2 months. Each lesion was
      classified by colour as brown (n = 22), brown-violet (n = 42), violet-blue (n =
      81) and blue-green (n = 6). The 22 predominantly brown lesions attained an
      excellent (100-95%) or good (95-75%) cosmetic result following three laser
      treatments in all patients who received this number of treatments. In the 42
      brown-violet lesions, 25 of the 29 good or excellent results were achieved after
      four treatments; the 13 less successful results were in patients who had one to
      three treatments. In the 81 violet-blue lesions, 54 of the 65 good or excellent
      results were achieved after four treatments and 64 of 65 after five treatments,
      whereas all 16 less good results were in patients who had only one to three
      treatments. However, in the six blue-green lesions, six or more treatments were
      required to achieve a similarly favourable result. At the end of treatment, the
      area was virtually free of scarring, and its texture resembled that of the
      surrounding normal skin. We have confirmed that the use of the Q-switched ruby
      laser at a low energy level can eliminate the pigmentation of naevus of Ota.
      While the desired improvement can be obtained within 1 year, the number of
      treatments appears to depend on the predominant colour of the lesion.

PMID- 10651700
TI  - Keratin expression in the normal nail unit: markers of regional differentiation.
AB  - Differentiation within the nail unit was examined using a range of antikeratin
      monoclonal antibodies including the recently described antibody LHTric-1,
      specific to the acidic hair-type keratin Ha1. Keratinocytes of the nail matrix,
      nail bed and the digit pulp were characterized by different patterns of keratin
      expression. Nail matrix was the sole site of expression of Ha1, which colocalized
      in suprabasal matrix epidermis with epidermal keratins K1 and K10. Small amounts
      of K17 were found at the apex of the matrix in some cases. K6 and K16 were found
      where the epidermal surface folds forwards to become the ventral aspect of the
      proximal nail fold. The nail bed was distinguished by the absence of hair-type
      keratin Ha1 and the absence of markers of cornified epidermis and mucosal
      differentiation K1/K10 and K4/K13, respectively, while K6, K16 and K17 were
      detected. The basal keratin conformation marker, LH6, was expressed suprabasally
      throughout the nail bed. This complement of keratins exists in the nail bed in
      the absence of notable proliferative activity, and suggests a state of minimally
      developed differentiation which may be afforded by the physical or biological
      properties of the overlying nail. Keratins, K6, K16 and K17 were all found in the
      digit pulp in limited amounts, possibly in association with the epidermal
      component of the eccrine duct. The simple epithelial keratins, K7, K8 and K18,
      were found in small amounts in the specimens from younger individuals, mainly in
      epibasal cells of the apex of the matrix and in putative Merkel cells.

PMID- 10651701
TI  - A double-blind, randomized study to compare the efficacy and safety of
      terbinafine (Lamisil) with fluconazole (Diflucan) in the treatment of
      onychomycosis.
AB  - In a randomized, double-blind, double-placebo, multicentre study, terbinafine 250
      mg daily for 12 weeks was compared with fluconazole 150 mg once weekly for 12 or
      24 weeks in the treatment of onychomycosis. A total of 137 patients with culture
      confirmed onychomycosis was divided into three groups: group A received
      terbinafine for 12 weeks, group B received fluconazole for 12 weeks, while group
      C received fluconazole for 24 weeks. At completion of the study (week 60), the
      mycological cure rate was higher in the terbinafine group than in the fluconazole
      groups: 89% vs. 51% and 49%, respectively (P < 0.001). The length of unaffected
      nail increased until week 24 in group B and until week 36 in group C, but was
      still increasing in group A at the final visit (week 60). Complete clinical cure
      of the target nail at week 60 was 67% in the terbinafine group, compared with 21%
      and 32% in the fluconazole groups, respectively. The incidence of adverse events
      was low for both study agents. We conclude that terbinafine 250 mg daily for 12
      weeks is significantly more effective in the treatment of onychomycosis than
      fluconazole 150 mg once weekly for either 12 or 24 weeks.

PMID- 10651702
TI  - The presence of antibodies against virus-like particles of epidermodysplasia
      verruciformis-associated humanpapillomavirus type 8 in patients with actinic
      keratoses.
AB  - Epidermodysplasia verruciformis-associated human papillomaviruses (EV-HPVs) are
      possibly involved in the development of actinic keratoses and may play a part in
      the pathogenesis of squamous cell carcinoma (SCC) of the skin, as the DNA of
      these viruses is frequently detected in biopsies of such lesions. Properly
      designed epidemiological studies, using serological tests to investigate the role
      of infection with EV-HPVs in cutaneous oncogenesis, are still rare. An IgG
      specific enzyme-linked immunosorbent assay using virus-like particles composed of
      the major capsid protein L1 of the EV-specific HPV 8 (HPV 8 VLPs) was developed
      and used to test the seroprevalence of HPV 8 in 114 inhabitants of a tropical
      island, of whom 13 had developed SCC, and 19 had developed basal cell carcinoma.
      Gender, age, eye and hair colour, sun exposure and number of actinic keratoses
      were recorded for all individuals. The presence of antibodies against HPV 8 VLPs
      was associated with the development of large numbers of actinic keratoses. After
      adjusting for gender, age, eye and hair colour, and sun exposure, the odds ratio
      to develop 37 (the median in this dataset) or more actinic keratoses in the
      presence of antibodies against HPV 8 VLPs was 2.3 (95% confidence interval: 1.0;
      5.3). Similarly, after adjustment for the same factors, the presence of these
      antibodies was associated with SCC with an odds ratio of 3.1 (0.74; 13.3), but
      the small number of individuals with SCC does not permit any definite
      conclusions. The presence of these antibodies did not appear to be associated
      with basal cell carcinoma as, after adjustment for the same factors, the odds
      ratio was 0.73 (0.23; 2.4). This study provides serological evidence that
      infection with EV-HPVs may play a part in the pathogenesis of actinic keratoses.
      The role of EV-HPVs in the development of SCC, however, remains to be elucidated.

PMID- 10651703
TI  - Sebum excretion rates in mothers and neonates.
AB  - As neonates have a high sebum production compared with 6-month-old babies, we
      wished to investigate the relationship of sebum production in mother and neonate.
      The sebum excretion rate (SER) was therefore measured in 10 mothers prenatally,
      and in each mother and baby as soon after birth as possible, and again 5-12 weeks
      postnatally. There was a significant correlation between the maternal and
      neonatal SER perinatally. The perinatal SER in the babies was markedly higher
      than the postnatal sample. These observations suggest an important role for the
      maternal hormonal environment on the infant sebaceous glands. There is animal
      evidence which suggests that the endocrine environment of the neonate influences
      the sebaceous gland development in puberty, but it is not known whether babies
      with a high SER are more prone to seborrhoea and acne in later life.

PMID- 10651704
TI  - Assessment of minimal phototoxic dose following 8-methoxypsoralen bath: maximal
      reaction on average after 5 days.
AB  - An essential procedure before starting bath psoralen ultraviolet (UV) A (PUVA)
      photochemotherapy is the evaluation of the minimal phototoxic dose (MPD), which
      is traditionally assessed 3 days after irradiation. However, there are no
      controlled studies supporting the 72 h peak of bath-PUVA erythema. The aim of
      this study was therefore to determine the exact time course of the erythematous
      reaction in human skin following bath-PUVA. For this purpose, the skin of 10
      volunteers was exposed to 0.5-3.0 J/cm2 UVA directly after a 20-min 8
      methoxypsoralen bath (0.5 mg/L, 37 degrees C). At 24, 48, 72, 96, 120 and 144 h
      (1-6 days) after irradiation, the MPD and the erythema sum score (ESS) were
      determined in each subject. The results showed a maximal erythematous reaction on
      average 5 days after irradiation. The mean MPD gradually decreased from day 2 (>
      3.0 J/cm2) to day 5 (mean +/- SD 1.15 +/- 0.63 J/cm2) and started to increase at
      day 6 (mean +/- SD 1.6 +/- 0.52 J/cm2). The mean +/- SD ESS correspondingly
      increased from day 2 (0 +/- 0) to day 5 (10.5 +/- 3. 7) with a decrease at day 6
      (7.5 +/- 3.1) (difference between day 3 and beyond statistically significant at P
      < 0.05). As our study indicates a maximal erythematous reaction to the bath-PUVA
      up to 5 days after irradiation, the traditional MPD assessment at 3 days
      generates a risk of phototoxic side-effects within the phototherapy course by
      underestimating the phototoxic effect in some patients. These findings contribute
      towards a more defined understanding of the kinetics of the phototoxic reaction
      in bath-PUVA therapy.

PMID- 10651705
TI  - A case of erythema elevatum diutinum associated with B-cell lymphoma: a rare
      distribution involving palms, soles and nails.
AB  - We report a case of erythema elevatum diutinum (EED) in association with
      malignant B-cell lymphoma. A 62-year-old man developed EED with an unusual
      distribution involving the palms, soles and nails. Treatment with dapsone was
      effective for his skin and nails until he developed generalized lymphadenopathy
      which turned out to be malignant lymphoma. Many haematological diseases, e.g. IgA
      paraproteinaemia and myeloma, have been reported in association with EED, but not
      malignant lymphoma. Even though it may just be a coincidence, we would like to
      add malignant lymphoma as one of the diseases associated with EED because the
      activity of EED and malignant lymphoma fluctuated in parallel.

PMID- 10651706
TI  - Two cases of primary hyperparathyroidism associated with primary cutaneous
      lymphoma.
AB  - Primary hyperparathyroidism has been described previously in association with
      malignancy, but to our knowledge has not been reported in association with
      primary cutaneous lymphoma. We report two cases of parathyroid adenoma with
      primary cutaneous lymphoma, the first in a 42-year-old woman with CD30-negative
      cutaneous large cell lymphoma, and the second in a 67-year-old man with mycosis
      fungoides and CD30-positive anaplastic large cell lymphoma.

PMID- 10651707
TI  - Mycosis fungoides bullosa simulating pyoderma gangrenosum.
AB  - A patient with mycosis fungoides (MF) bullosa had a rapidly growing, painful
      necrotic mass on the left ankle which extended by peripheral bulla formation,
      clinically resembling pyoderma gangrenosum. Histopathology confirmed MF bullosa
      with both intraepidermal and subepidermal bulla formation.

PMID- 10651708
TI  - Polypoid Spitz naevus: the benign counterpart of polypoid malignant melanoma.
AB  - Polypoid malignant melanoma is a peculiar morphological variant of melanoma with
      a distinct exophytic pattern of growth. This form of melanoma is usually very
      thick and the prognosis is accordingly poor. We present here a previously
      undescribed form of Spitz naevus which had a similar polypoid exophytic
      silhouette and marked cytological atypia. Despite these close morphological
      similarities, polypoid Spitz naevus evolves in a completely benign manner.
      Morphologically, polypoid Spitz naevus can be distinguished from polypoid
      melanoma by the absence of mitoses and by the prominent stromal reaction
      throughout the lesion.

PMID- 10651709
TI  - A sporadic case of progressive mucinous histiocytosis.
AB  - Hereditary progressive mucinous histiocytosis is a rare autosomal dominant non
      Langerhans cell histiocytosis. We describe a sporadic case of this syndrome in a
      64-year-old woman who had multiple dark-red dome-shaped papulonodules located
      mainly on the back of her hands, forearms and thighs. Light microscopy revealed a
      circumscribed upper dermal aggregate of ovoid or spindle-shaped histiocytes with
      abundant mucin deposition. Iron deposits and numerous mast cells were scattered
      throughout the tumour but giant cells were rare. Electron microscopy revealed a
      high number of zebra bodies and myeloid bodies in the cytoplasm of the
      histiocytes. Immunohistochemistry showed positive labelling with alpha-1
      antitrypsin, Factor XIIIa and CD68, while CD1a, CD34 and S100 protein were
      negative. The differential diagnosis of histiocytic syndromes is discussed.

PMID- 10651710
TI  - Linear congenital smooth muscle hamartoma with follicular spotted appearance.
AB  - Congenital smooth muscle hamartoma (CSMH) with follicular spotted appearance is a
      rare clinical variant of CMSH in which patients have marked perifollicular
      papules in the patches. A linear distribution of CSMH is also extremely rare. We
      report a 16-year-old Korean girl with this uncommon form of CSMH who had linearly
      arranged, hyperpigmented lesions with follicular papules extending from the right
      flank to the right lower leg from birth. Pathological findings, including
      immunohistochemical stains, were consistent with smooth muscle hamartoma. To
      date, there are only four reports on this rare, follicular form and one report on
      the linear form of CSMH in the literature. This paper describes the first
      combined occurrence of follicular spotted lesions and linear arrangement in CSMH.

PMID- 10651711
TI  - Pemphigoid nodularis with IgA autoantibodies against the intracellular domain of
      desmoglein 1.
AB  - Pemphigoid nodularis is a rare variant of bullous pemphigoid. We report a 49-year
      old Japanese male with clinical and histopathological features of pemphigoid
      nodularis including circulating and in vivo-bound IgG antibasement membrane zone
      antibodies and IgA anti-intercellular antibodies. Although the precise molecular
      target of the IgG autoantibodies could not be determined, intriguingly,
      immunoblotting showed that the IgA in the patient's serum reacted with the
      intracellular domain of desmoglein 1, the target antigen in cases of pemphigus
      foliaceus. However, the IgA did not react with the extracellular domain of
      desmoglein 1 in sensitive enzyme-linked immunosorbent assay studies using a
      baculovirus system. These results suggest therefore that these IgA antibodies may
      possibly not be pathogenic. The mechanism for the production of different
      autoantibodies is unknown, but this case provides further illustration of the
      atypical skin immunoreactants often seen in this unusual subtype of bullous
      pemphigoid.

PMID- 10651712
TI  - Distichiasis-lymphoedema: clinical features, venous function and
      lymphoscintigraphy.
AB  - Distichiasis-lymphoedema is a rare variant of the genetically determined
      lymphoedemas; distichiasis is the abnormal development of the meibomian glands
      causing aberrant growth of eyelashes. However, a better understanding of this
      clinically distinct subgroup may provide useful information on the genetic
      inheritance of all types of lymphoedema. This report provides phenotype data on a
      very large family with distichiasis-lymphoedema. Lymphoscintigraphy and light
      reflection rheography (venous function) were undertaken to identify the phenotype
      more clearly. As a result of lymphoscintigraphy several subjects were
      reclassified phenotypically (unaffected or affected) with implications for
      genetic linkage studies. Associated congenital abnormalities were found and
      venous abnormalities were almost always present in affected limbs. A dominant
      inheritance with incomplete penetrance was confirmed.

PMID- 10651713
TI  - Penile Kaposi's sarcoma preceded by chronic penile lymphoedema.
AB  - Kaposi's sarcoma localized to the penis with striking lymphoedema is
      extraordinary. We report a middle-aged Haitian man who was human herpesvirus-8
      seropositive, without evidence of immunosuppression or human immunodeficiency
      virus infection. He was first seen with Kaposi's sarcoma of 6 months duration
      localized to his penis, preceded by a 3-year history of chronic penile
      lymphoedema. His tumour regressed completely after radiotherapy. We propose that
      chronic lymphoedema in this patient predisposed to the development of Kaposi's
      sarcoma.

PMID- 10651714
TI  - Ichthyosis follicularis with alopecia and photophobia in a mother and daughter.
AB  - A mother and daughter having ichthyosis follicularis with alopecia and
      photophobia (IFAP) are reported, with histopathological and electron microscopic
      findings. We have followed the clinical course of the mother for 26 years since
      she was 5 years old, and the daughter since birth. They have had almost all the
      classical and some of the minor symptoms of IFAP, including severe photophobia,
      extensive non-inflammatory follicular hyperkeratosis, generalized non-scarring
      alopecia, hyperkeratosis of the extensor aspect of the four extremities, nail
      deformity and recurrent cheilitis. In addition, their facial appearance greatly
      resembles that of previously reported patients. A consistent feature in the
      mother was florid keratotic inflammatory eruptions on the genital region during
      each of her pregnancies, which rapidly improved after the delivery. Skin biopsy
      of the genital lesion showed marked acanthosis with dyskeratosis and spongiotic
      changes. The electron microscopic examination of diseased skin showed damaged
      desmosomes with spongiosis. No obvious changes were found in normal appearing
      skin.

PMID- 10651715
TI  - Face dermatitis from contaminants on a mask for anaesthesia.
AB  - Allergic and irritant contact reactions to face masks for anaesthesia have rarely
      been reported. We present a 55-year-old female patient who developed facial
      allergic contact dermatitis after an operation requiring general anaesthesia.
      Patch tests showed positive reactions to cocospropylenediamin-guanidinium
      diacetate (trivial name Dodigen 3558), a preservative used in disinfectants for
      medical instruments. It could be proven that residues of the causative allergen
      in the disinfectant adhered to the mask. This is the first report of a clinically
      relevant sensitization to this increasingly widely used agent.

PMID- 10651716
TI  - Dexamethasone-induced healing of chronic leg ulcers in a patient with defective
      organization of the extracellular matrix of fibronectin.
AB  - Previous investigations have shown that skin fibroblasts derived from patients
      affected by Ehlers-Danlos syndrome (EDS) lack an organized extracellular matrix
      (ECM) of fibronectin (FN). As retarded wound healing is a sign of EDS, we
      hypothesized that a young healthy man suffering from chronic recalcitrant leg
      ulcers might be affected by a defect of FN-ECM organization similar to that
      observed in EDS. Immunofluorescence of cultured skin fibroblasts obtained from
      skin biopsies from the patient and a control demonstrated that the patient's
      fibroblasts lacked FN-ECM organization, in contrast with those of the control;
      this was restored by 10-7 mol/L dexamethasone (DEX) in vitro. DEX treatment of
      the patient was associated with healing of his leg ulcers. In conclusion, DEX may
      be effective in reversing impaired wound healing associated with a lack of FN-ECM
      organization

PMID- 10651717
TI  - Successful treatment of aphthous ulcerations in AIDS patients using topical
      granulocyte-macrophage colony-stimulating factor.
AB  - Oral recurrent aphthous ulceration (RAU) is a well-recognized complication in
      patients infected with human immunodeficiency virus. RAU can be progressive and
      destructive, causing dysphagia and secondary malnutrition. The aetiology of RAU
      remains unknown, and its response to available treatments is often
      unsatisfactory. We describe three patients with advanced AIDS who suffered from
      extensive RAU which failed to respond to several treatments, including topical
      viscous lidocaine and topical and systemic glucocorticoids. Owing to difficulties
      in using thalidomide (two patients had neurological conditions which precluded
      thalidomide use), all three patients were treated with an oral solution
      containing recombinant human granulocyte-macrophage colony-stimulating factor (GM
      CSF, 400 microg in 5% glucose 200 mL). From the first application, all three
      patients showed significant improvement of their lesions and amelioration of
      pain, and they were completely cured in a few days. No adverse effects were
      recorded. The patients did not show relapses of RAU over a prolonged follow-up.
      Controlled trials are warranted in order to establish the role of GM-CSF as a
      valid, alternative option for aphthous ulcerations of the mouth in AIDS patients
      in whom corticosteroids or thalidomide are not suitable.

PMID- 10651718
TI  - Haematology in the new millennium.

PMID- 10651719
TI  - The introduction of citrate as an anticoagulant for transfusion and of glucose as
      a red cell preservative.

PMID- 10651720
TI  - The management of patients with leukaemia: the role of cytogenetics in this
      molecular era.

PMID- 10651721
TI  - Diagnosis and management of haemochromatosis since the discovery of the HFE gene:
      a European experience.

PMID- 10651722
TI  - Clinical and laboratory evaluation of all-trans retinoic acid modulation of
      chemotherapy in patients with acute myelogenous leukaemia.
AB  - All-trans retinoic acid (ATRA) is synergistic with chemotherapy in leukaemia cell
      lines. We treated 53 patients with newly diagnosed acute myelogenous leukaemia
      (AML) with high-dose cytarabine-based chemotherapy followed by ATRA. Peripheral
      blood and bone marrow samples were obtained to study the effect of in vitro
      exposure to ATRA and to measure apoptosis and bcl-2. The response rate was 72%
      for patients under age 60 years and 46% for patients aged 60 years or above.
      There was no difference in the percentage of responding patients, time to
      recurrence or overall survival for patients receiving chemotherapy with ATRA vs.
      historical controls receiving chemotherapy without ATRA. After in vitro exposure
      of day 3 bone marrow samples to ATRA, there was an increase in apoptotic cells in
      25% of patient samples compared with samples not exposed to ATRA. Later date of
      peak apoptosis in peripheral blood and higher percentage of apoptotic cells in
      bone marrow on day 3 of treatment were associated with lack of clinical response
      to treatment. Increased bcl-2 in patient samples was associated with shorter time
      to recurrence and poor cytogenetic risk. The addition of ATRA to chemotherapy did
      not improve patient outcome. However, evidence of in vitro response to ATRA in
      25% of patients suggests that retinoid pathways should be studied further in
      patients with AML.

PMID- 10651723
TI  - P-glycoprotein and multidrug resistance-associated protein, but not lung
      resistance protein, lower the intracellular daunorubicin accumulation in acute
      myeloid leukaemic cells.
AB  - The in vitro intracellular daunorubicin accumulation (IDA) of blast cells from 69
      patients with newly diagnosed acute myeloid leukaemia (AML) was correlated with
      the expression and functional activity of the multidrug resistance (MDR)
      proteins, P-glycoprotein (Pgp), multidrug resistance-associated protein (MRP) and
      lung-resistance protein (LRP). An inverse and significant association was found
      between IDA and Pgp-related efflux activity (r = -0.31, P = 0.01) and also MRP (r
      = -0.25, P = 0.04) but not with LRP (r = -0.13, P = 0.28). Coexpression of the
      MDR proteins had an additive effect in further lowering of IDA levels, suggesting
      that the clinical MDR phenotype is dependent on the sum of multiple MDR factors
      available to the leukaemic cell. Thus, the median IDA of leukaemic cells without
      any MDR proteins was significantly higher than that of blasts carrying two MDR
      proteins (0.466 vs. 0.296, P = 0.046). Seven patients with no expression of Pgp,
      MRP and LRP still had low IDA levels, suggesting the presence of efflux MDR
      mechanisms other than those studied. The relation of IDA to clinical parameters
      known to be associated with poor prognosis, such as age, secondary AML,
      karyotype, peripheral blood blast and CD34 counts, was also studied, but no
      significance was found on multifactorial analysis. There was a non-significant
      trend for earlier relapse in patients with low IDA levels (leukaemia-free
      survival of 16.3 months compared with 21.1 months in patients with high IDA
      levels). Our data suggest that, while the IDA assay is a quick and relatively
      easy test for the combined efflux MDR phenotype, it is unable to detect other MDR
      mechanisms, such as LRP, which may be important to the clinical outcome of
      patients with AML.

PMID- 10651724
TI  - Quantitative expression of erythropoietin receptor (EPO-R) on acute leukaemia
      cells: relationships between the amount of EPO-R and CD phenotypes, in vitro
      proliferative response, the amount of other cytokine receptors and clinical
      prognosis. Japan Adult Leukaemia Study Group.
AB  - Expression of erythropoietin (EPO) receptor (EPO-R) was analysed in leukaemia
      cells from 150 patients with acute myeloid leukaemia (AML) or acute lymphoblastic
      leukaemia (ALL). EPO-R was expressed in 81 (60%) out of 136 AML, and in vitro
      treatment with EPO led to proliferation of leukaemia cells in 13 (16%) out of 81
      AML examined. EPO-R expression and in vitro response to EPO were observed in all
      subtypes of AML according to the French-American-British (FAB) classification.
      All eight patients with FAB-M6 expressed EPO-R, and one out of four showed an in
      vitro response to EPO. Although there was no significant correlation (r = 0.2522)
      between the amount of EPO-R and the in vitro response to EPO, all of the AML
      patients who showed in vitro response expressed EPO-R. Stem cell factor
      significantly enhanced both EPO-R expression and in vitro response to EPO.
      Interleukin-3 tended to increase in vitro response to EPO. CD phenotypes, the
      amount of granulocyte colony-stimulating factor (G-CSF) receptors and the amount
      of TPO receptors had no significant relationship with the amount of EPO-R.
      Patients with both EPO-R expression and in vitro response to EPO had shorter
      duration of complete remission than those without EPO-R (P = 0.0053). EPO-R was
      expressed in four (29%) out of 14 ALL, and none out of five ALL showed in vitro
      response to EPO.

PMID- 10651725
TI  - Effects of interferon and hydroxyurea on bone marrow fibrosis in chronic
      myelogenous leukaemia: a comparative retrospective multicentre histological and
      clinical study.
AB  - A retrospective multicentre clinicopathological study was performed on sequential
      bone marrow trephine biopsies in 100 patients with Ph1+-chronic myelogenous
      leukaemia (CML) to elucidate the effect of interferon (IFN) alpha 2b and
      hydroxyurea (HU) treatment on myelofibrosis and megakaryopoiesis. According to
      strictly defined therapeutic regimens, 38 patients received IFN as monotherapy,
      23 patients a combination of IFN and HU and 39 patients HU only. Using
      standardized intervals of biopsies and histochemical and morphometric methods, a
      significant increase in reticulin fibre density and in the number of CD61+
      megakaryocytes was detectable in the majority of IFN-treated patients. To a
      lesser degree, these changes were also expressed in the cohort with a combined
      IFN and HU regimen. In contrast to these findings, in the group of patients with
      HU as single-agent treatment, a stable state or reversal of myelofibrosis was
      detectable together with corresponding changes in megakaryopoiesis. Further
      evaluations revealed that these effects had occurred within the first year,
      mostly after 6 months of treatment, and were prominently expressed in those
      patients with a slight to relevant grade of myelofibrosis at presentation. In
      conclusion, this study provides persuasive evidence that monotherapy by IFN
      exerts a fibrogenic effect, while HU treatment seems to prevent and even resolves
      bone marrow fibrosis in CML. Probably, in relation to the complex pathomechanisms
      responsible for the generation of myelofibrosis, the changing content of
      reticulin fibres was usually accompanied by corresponding alterations in the
      number of CD61+ megakaryocytes, including atypical microforms and precursor
      cells.

PMID- 10651726
TI  - Age of onset evidence for anticipation in familial non-Hodgkin's lymphoma.
AB  - Anticipation, a phenomenon in which an inherited disease is diagnosed at an
      earlier age in each successive generation of a family, has been demonstrated in
      certain neurological and haematological disorders. This study was conducted to
      determine whether anticipation occurs in familial non-Hodgkin's lymphoma (NHL).
      Eleven published reports of multigenerational familial NHL were analysed for
      evidence of anticipation, together with 18 previously unreported families with
      familial NHL. Differences in disease-free survival between generations were
      determined. The difference between age at onset for each affected parent-child
      pair was tested against the null hypothesis that there was no difference in age
      at onset. These analyses were also performed separately using only parent-child
      pairs with age of onset > 25 years to avoid ascertainment bias. In addition, the
      age at onset distribution of the studied cases was compared with that of the
      Surveillance Epidemiology and End Results (SEER) Program using data for 1973-98.
      The median ages at onset in the child and parent generations of all families
      (48.5 and 71.3 years respectively) and in the selected pairs (52.5 and 71.5 years
      respectively) were significantly different (P < 0.000002 and P < 0.000001
      respectively). The null hypothesis was rejected for all (P < 0.000001) as well as
      selected pairs (P < 0.000003). A significant difference was observed between the
      ages of onset of the child generation and the SEER population (P < 0.009), but
      not between the parent generation and the SEER population. Anticipation occurs in
      familial NHL, which suggests a genetic basis for it.

PMID- 10651727
TI  - Marked heterogeneity in protein levels and functional integrity of the
      thrombopoietin receptor c-mpl in polycythaemia vera.
AB  - Polycythaemia vera (PV) is a myeloproliferative disorder (MPD) characterized by
      an increased production of mature blood cells. The underlying pathogenic
      mechanisms behind PV are largely unknown. Thrombopoietin (TPO) is the most
      important cytokine for stimulation of megakaryocyte growth and formation of
      functional platelets. Recently, it has been shown that the receptor for TPO, c
      mpl, is expressed on haematopoietic stem cells, and that TPO promotes the growth
      of these stem cells via binding to c-mpl. Quantitative or qualitative
      abnormalities of c-mpl function could thus theoretically play a role in the
      pathogenesis of different MPDs. Previous studies of the integrity of the c-mpl
      system in PV have produced conflicting results. We therefore studied c-mpl
      protein expression using immunoblot analysis in 15 PV patients and 10 healthy
      controls. Seven out of 15 PV patients (47%) exhibited similar c-mpl protein
      levels to the controls, whereas eight out of 15 patients (53%) showed either
      markedly reduced or absent levels of c-mpl. Five of the seven c-mpl-positive
      patients had only been treated by phlebotomy, whereas six out of eight c-mpl
      negative patients were receiving treatment with hydroxyurea, anagrelide or alpha
      interferon. Disease duration tended to be slightly longer in c-mpl-negative
      patients compared with c-mpl-positive patients (mean = 55 vs. 43 months).
      Tyrosine phosphorylation of JAK-2 in immunoprecipitates of platelets obtained
      after stimulation with TPO (100 and 1000 ng/ml) was normal in c-mpl-positive
      patients, whereas it could not be detected in c-mpl-negative patients. We
      therefore conclude that there exists a marked heterogeneity in c-mpl protein
      levels and functional integrity in PV. However, it seems less likely that c-mpl
      abnormalities per se are directly involved in the pathogenesis leading to the
      occurrence of PV, as c-mpl levels were similar to those seen in healthy
      individuals in about half of the patients under study.

PMID- 10651728
TI  - Features of essential thrombocythaemia in childhood: a study of five children.
AB  - Essential thrombocythaemia (ET) is usually considered a disease of the middle
      aged but, with the advent of automated platelet counting, ET is diagnosed with
      increasing frequency in young adults and, even more rarely, in children. We
      report five paediatric patients (four girls and one boy, mean age 89 months)
      diagnosed with ET in agreement with Polycythaemia Vera Study Group criteria. The
      patients had a persistent thrombocytosis over 900 x 10(9)/l and, at the time of
      diagnosis, their platelet count ranged between 1,112 and 3,178 x 10(9)/l. A 9
      month-old girl had thrombosis of the inferior cava vein, two children had
      headaches and two others remained asymptomatic throughout the follow-up period.
      Megakaryocytes in the bone marrow were increased in number. The chromosomal
      analysis was normal, and bcr rearrangement was always negative. None of the
      patients had spontaneous BFU-E or altered levels of serum erythropoietin and
      thrombopoietin. Two patients showed alteration of platelet aggregation, and all
      had decreased levels of intraplatelet serotonin. In spite of the diagnosis of ET
      in our patients, we are not sure that the cases reported here are really
      myeloproliferative disorders. The features could suggest that the cases observed
      may be affected by an 'idiopathic thrombocytosis' without myeloproliferation.
      Possible variants of ET are described in young adults, and the heterogeneous
      nature of ET is also suggested by our paediatric patients. Only careful long-term
      follow-up of patients such as these will clarify the natural history of these
      disorders and suggest therapeutic management.

PMID- 10651729
TI  - Role of P-glycoprotein in all-trans retinoic acid (ATRA) resistance in acute
      promyelocytic leukaemia cells: analysis of intracellular concentration of ATRA.
AB  - We analysed the relationship between all-trans retinoic acid (ATRA) resistance
      and P-glycoprotein (P-gp)-associated multidrug resistance (MDR) in acute
      promyelocytic leukaemia (APL). There was no difference in the intracellular ATRA
      accumulation between NB4 cells and an MDR1 cDNA-transduced NB4 subline and
      between ATRA-resistant NB4 cells (NB4/RA) and an MDR1 cDNA-transduced NB4/RA
      subline. PSC833, a MDR modifier, did not increase the intracellular accumulation
      of ATRA or affect the expression of CD11b, the nitroblue tetrazolium (NBT)
      reduction activity, the proportion of apoptotic cells or the morphology of these
      four ATRA-treated cell lines. Similar results were obtained in the analysis of
      APL cells from five patients relapsed after ATRA-induced complete remission.

PMID- 10651731
TI  - Danish patients with untreated multiple myeloma do not harbour human herpesvirus
      8.
AB  - The role of human herpesvirus 8 (HHV-8) in multiple myeloma (MM) remains
      controversial. We examined 15 Danish MM patients before cytoreductive therapy.
      Mononuclear cells isolated from peripheral blood and bone marrow aspirates, as
      well as long-term cultured bone marrow stromal cells, were assayed for the
      presence of HHV-8 DNA. All material was tested by three simple unnested
      polymerase chain reaction (PCR) assays (amplifying regions of ORF26, ORFK1 and
      ORF75) and two nested PCR assays (amplifying regions of ORF26). HHV-8 was not
      demonstrated in any of the samples. Our findings do not suggest an association
      between HHV-8 and MM in the Danish population.

PMID- 10651730
TI  - Low-dose melphalan induces favourable responses in elderly patients with high
      risk myelodysplastic syndromes or secondary acute myeloid leukaemia.
AB  - We treated 21 elderly patients with high-risk myelodysplasia (n = 14) or
      secondary acute myeloid leukaemia (n = 7) with 2 mg of melphalan orally once a
      day until a complete peripheral response was obtained or until there was evidence
      of treatment failure. We observed seven (30%) complete and two (10%) partial
      peripheral responses occurring within 4-16 weeks and lasting for 12 + to 55
      weeks. In relapse, retreatment was successful in most of the patients. Responses
      were associated with the absence of complex cytogenetic abnormalities and with a
      normal or reduced bone marrow cellularity.

PMID- 10651732
TI  - The combined effect of total body irradiation (TBI) and cyclosporin A (CyA) on
      the risk of relapse in patients with acute myeloid leukaemia undergoing
      allogeneic bone marrow transplantation.
AB  - One hundred and fifty acute myeloid leukaemia (AML) patients in first remission
      received an allogeneic bone marrow transplant (BMT), after conditioning with
      cyclophosphamide 120 mg/kg and total body irradiation (TBI) 3.3 Gy x 3 (total
      nominal dose 9.9). The received dose, as recorded by thermoluminescent
      dosimeters, ranged between 7. 83 and 12.25 Gy. Patients who received TBI < 9.9 Gy
      (n = 34) had a significantly higher relapse rate when compared with patients
      receiving >/= 9.9 Gy (n = 116) (43% vs. 19%; P = 0.002). Graft versus host
      disease (GvHD) prophylaxis consisted of cyclosporin A (CyA) with or without
      methotrexate (MTX). The dose of CyA was either 1 or 5 mg/kg/day i.v. from day -1
      to + 20, then 10 mg/kg/day orally until day + 365. Patients receiving 5 mg/kg CyA
      (n = 40) had a higher risk of relapse (49% vs. 15%; P = 0.0001). Thus, low-dose
      TBI (< 9.9 Gy) and high-dose CyA (5 mg/kg) were significant predictors of
      leukaemia relapse. Patients were then divided into three groups: those who had
      both negative predictors (< 9.9 Gy TBI and 5 mg/kg CyA; n = 26); those who had
      only one (either < 9.9 Gy TBI or 5 mg/kg CyA; n = 22); and those who had neither
      (>/= 9.9 Gy TBI and 1 mg/kg CyA; n = 102). The three groups were comparable for
      FAB subtype, interval diagnosis transplant and age. The 5-year actuarial relapse
      rate for these three groups of patients was 49%, 41% and 15%, with no difference
      between the first two and a significant difference when compared with the latter
      (P < 0.01). These data indicate that acute myeloid leukaemia can be cured with
      allogeneic bone marrow transplantation given an intensive conditioning regimen
      and low-dose immunosuppression post-graft. Either alone is insufficient to
      produce long-term disease-free survival. These results may be relevant for
      programmes of reduced intensity conditioning designed for patients with acute
      leukaemia.

PMID- 10651733
TI  - Immune reconstitution after transplantation of autologous peripheral CD34+ cells:
      analysis of predictive factors and comparison with unselected progenitor
      transplants.
AB  - The recovery of lymphocyte count, CD4+ and CD8+ T-cell subsets, natural killer
      (NK) cells and CD19+ B-cells was evaluated in a cohort of 15 patients receiving
      autologous CD34+ peripheral blood progenitor cells (PBPCs; group A) for
      haematological malignancies and in 20 patients transplanted with autologous
      unselected PBPCs (group B). Lymphocyte count recovered in both patient cohorts,
      being significantly lower in group A than in group B 1 (P = 0.008) and 2 months
      (P = 0.0035) after progenitor cell infusion. The repopulation of CD3+ T-cells
      occurred more rapidly in group B than in group A (P = 0.034 on week 4); CD19+ B
      lymphocytes did not return to reference ranges in either group of patients. The
      count of CD4+ T-lymphocytes remained < 200/microl during the study period in
      patients transplanted with CD34+ PBPCs, significantly lower than group B levels
      (P = 0.034 and P = 0.021 on weeks 4 and 8 respectively). CD8+ T-cells increased
      rapidly in both groups; thus, the CD4 to CD8 ratio was severely reduced. CD4+ and
      CD8+ T-cells displayed an activated phenotype in both groups of patients, co
      expressing the HLA-DR antigen throughout the study period. NK cells followed a
      similar repopulation kinetics in both study groups, although their expansion was
      greater in group B than in group A (P = 0.014 on week 4). In the CD34+ group,
      post-transplant administration of granulocyte colony-stimulating factor predicted
      a faster lymphocyte recovery in multivariate analysis (P = 0.025); interestingly,
      the amount of passively transferred lymphocytes correlated inversely with time to
      achieve a lymphocyte count > 0.5 x 10(9)/l (r = -0.63, P = 0.01). Further
      investigations are necessary to characterize T-cell competence after
      transplantation of CD34+ PBPCs.

PMID- 10651734
TI  - Red blood cell phenotyping is a sensitive technique for monitoring chronic
      myeloid leukaemia patients after T-cell-depleted bone marrow transplantation and
      after donor leucocyte infusion.
AB  - Fifteen consecutive patients with Philadelphia chromosome (Ph)-positive chronic
      myeloid leukaemia (CML) who relapsed from T-cell-depleted bone marrow
      transplantation (BMT) were successfully treated with donor leucocyte infusions
      (DLIs). Chimaerism was analysed using red blood cell phenotyping (RCP), and the
      results were compared with cytogenetic analysis and outcome of qualitative and
      quantitative polymerase chain reaction (PCR) for breakpoint molecules. In all
      patients, an increase in autologous erythrocytes and/or a decrease in donor red
      cells indicated relapse. Donor erythrocytes started to increase from 4 to 20
      (median 12) weeks after DLI. At 6 and 12 months after DLI, complete donor
      chimaerism was found in 11 and 15 patients, respectively, and all patients were
      in cytogenic remission. A high percentage of autologous red cells at the time of
      DLI predicted pancytopenia. During relapse and after DLI, the percentage of
      autologous red cells was strongly correlated with the reappearance and
      disappearance of Ph-positive metaphases (r = 0.90; P < 0.001 and r = 0.96; P <
      0.001 respectively). The same was true for the correlation between the percentage
      of autologous red cells and positivity/negativity in PCR for Bcr-Abl breakpoint
      molecules (r = 0.94; P < 0.001). A normalized Bcr-Abl dose of greater than 10-3
      in real-time quantitative PCR correlated well with relapse and the presence of
      autologous red blood cells (r = 0.77; P < 0.001). We conclude that RCP is a
      sensitive, easy to perform and fast technique for the prediction of pending
      relapse after BMT for CML. RCP also predicts the response to DLI and the
      occurrence of bone marrow aplasia after DLI.

PMID- 10651735
TI  - High levels of antiphospholipid antibodies are associated with cytomegalovirus
      infection in unrelated bone marrow and cord blood allogeneic stem cell
      transplantation.
AB  - Antiphospholipid antibodies (APA) are a family of autoimmune and alloimmune
      immunoglobulins recognizing protein-phospholipid complexes in in vitro laboratory
      test systems. These antibodies have been associated with several conditions
      (malignancies, autoimmune diseases, infections, use of drugs); moreover, a
      syndrome capable of inducing thromboembolic disease has recently been associated
      with the presence of these antibodies. The aim of this prospective study was to
      investigate the levels of APA in subjects affected by haematological malignancies
      undergoing allogeneic haematopoietic stem cell transplantation (ASCT). Between
      March 1996 and December 1997, 32 patients undergoing ASCT were studied
      prospectively until day +180 from transplant. The mean values of IgG and IgM
      anticardiolipin antibodies (ACA) increased in recipients of stem cells from
      anunrelated donor, and a statistically significant difference inACA IgG mean
      value between unrelated and related transplanted patients was demonstrated
      between days +95 and +180. All of the subjects who received stem cells from an
      unrelated donor had APA levels higher than the mean normal value +3 SD vs. 35% of
      those receiving stem cells from a related donor (P < 0.01). The reason for such a
      difference may be a result of the different incidence in documented
      cytomegalovirus (CMV) infection in the two groups (83% vs. 23%; P < 0.01), as
      indicated by the significant correlation between APA positivity and CMV infection
      (P < 0.05). No relationship was found between APA, conditioning regimen and acute
      or chronic graft vs. host disease (GVHD). Moreover, we did not observe any
      thromboembolic disorder or veno occlusive disease (VOD).

PMID- 10651736
TI  - Diagnosis of invasive aspergillosis in bone marrow transplant recipients by
      polymerase chain reaction.
AB  - A nested polymerase chain reaction (PCR) test targeting Aspergillus spp. large
      ribosomal subunit genes was evaluated retrospectively on 175 serum samples from
      37 bone marrow transplant recipients, 70% of whom received grafts from unrelated
      donors. Six patients had proven infection, seven had probable infection, and
      three had possible infection, using the revised EORTC case definitions. These 16
      patients were all PCR positive (57 out of 93 samples tested). Two additional
      patients who did not fulfil current diagnostic criteria, but in whom invasive
      aspergillosis (IA) was thought clinically probable, were also PCR positive (five
      out of nine samples). Invasive aspergillosis was unlikely in the remaining 19
      patients, four of whom were PCR positive on a single occasion (four out of 70
      samples). Three samples were inhibitory to PCR. Sensitivity of PCR in diagnosing
      patients with IA was 100%, specificity was 79% and positive predictive value was
      80%, using the criterion of a single positive result. If two positive results
      were required, these values were 81%, 100% and 100% respectively. The median
      duration of infection documented by PCR was 36 days (range 3-248 days) in 17 out
      of 18 patients (94%) who did not survive. Positive PCR results predated the
      institution of antifungal therapy in two-thirds of patients. Four patients became
      PCR positive during pretransplant conditioning therapy.

PMID- 10651737
TI  - Neuropeptide control of bone marrow neutrophil production is mediated by both
      direct and indirect effects on CFU-GM.
AB  - Noradrenaline- and peptide-containing nerve fibres project into the bone marrow
      and terminate in association with stromal cells and within the parenchyma.
      Peptidergic nerve terminals are also associated with antigen-processing and 
      presenting cells throughout the body and have been shown to be important in
      leucocyte trafficking and wound healing, as well as haemopoiesis. Here, we tested
      the in vivo effects of deleting the peripheral neuropeptide network on
      haemopoiesis and also investigated whether the target cell population for these
      substances was myeloid progenitor cells (colony-forming unit
      granulocyte/macrophage, CFU-GM). Deletion of the neuropeptides, substance P (SP)
      and calcitonin gene-related peptide (CGRP) by capsaicin abrogates normal blood
      cell production. These neuropeptides produced significant stimulation of colony
      formation from unfractionated bone marrow and elicited production of soluble
      factors capable of stimulating highly enriched CFU-GM. CGRP also had a direct
      stimulatory effect on highly enriched CFU-GM. Noradrenaline elicited factors that
      inhibited colony formation and had no direct effect on CFU-GM. We conclude that
      the neuropeptides form the positive arm of a neural control system and that
      noradrenaline acts as a negative regulator.

PMID- 10651738
TI  - Demonstration of mRNA for five species of cytochrome P450 in human bone marrow,
      bone marrow-derived macrophages and human haemopoietic cell lines.
AB  - The expression of mRNA for five cytochrome P450s (CYP1A1, 2A6/7, 2D6, 2E1 and
      3A4) was studied in human bone marrow, bone-marrow-derived macrophages and blood
      monocyte-derived macrophages. Reverse transcriptase polymerase chain reaction (RT
      PCR) detected expression of all five CYPs in each of these cell populations. All
      five CYPs were also expressed in the haemopoietic cell lines HL-60 and HEL and in
      Epstein-Barr virus (EBV)-transformed B-lymphoblastoid cell lines. The data
      suggest that bone marrow macrophages and probably other bone marrow cell types
      are capable of metabolizing xenobiotics. This metabolic potential may play a role
      in the bone marrow damage induced by some drugs and chemicals.

PMID- 10651739
TI  - Antibody engagement of intercellular adhesion molecule 3 triggers apoptosis of
      normal and leukaemic myeloid marrow cells.
AB  - Intercellular adhesion molecule 3 (ICAM-3, CD50) is an immunoglobulin (Ig) domain
      containing cell-cell adhesion receptor that binds to the lymphocyte function
      antigen 1 (LFA-1; CD11a/CD18) integrin. It is constitutively expressed on
      haematopoietic precursors and differentiated leucocytes, as well as on most
      leukaemic cells. ICAM-3/LFA-1 binding during a lymphocyte-mediated cellular
      immune response has been well established; however, its role in the marrow
      compartment is unclear. In this study, marrow cells from normal and acute
      leukaemic donors, as well as leukaemic cell lines, were cultured in the presence
      of various monoclonal antibodies (mAbs) to ICAM-3, and apoptosis was subsequently
      measured by annexin V binding. Anti-ICAM-3 mAb ICR 1.1 engagement triggered
      increased percentages of apoptosis among normal and leukaemic marrow myeloid
      cells. Fab fragments of ICR 1.1 mimicked the intact mAb, suggesting that the
      apoptotic signal was independent of Fc receptor interactions and did not require
      bivalent epitope engagement. In addition, the apoptotic signal was found to be
      independent of ICAM-1/LFA-1 binding interactions, as well as Fas/FasL and tumour
      necrosis factor alpha (TNF-alpha)/TNF receptor-activated pathways, as
      neutralizing antibodies to CD11a/CD18, Fas and TNF-alpha failed to abrogate the
      response.

PMID- 10651740
TI  - Clinical and laboratory evidence for a trilineage haematopoietic defect in
      patients with refractory Diamond-Blackfan anaemia.
AB  - Diamond-Blackfan anaemia (DBA) is a constitutional pure red cell aplasia
      presenting in early childhood. In some patients, neutropenia and/or
      thrombocytopenia have also been observed during the course of the disease. We
      have followed 28 patients with steroid-refractory DBA for up to 13 years with
      serial peripheral blood counts and bone marrow (BM) aspirates and biopsies. In
      21/28 (75%) patients, moderate to severe generalized BM hypoplasia developed,
      with overall cellularities ranging from 0% to 30%. Marrow hypoplasia correlated
      with the development of neutropenia (9/21; 43%) and/or thrombocytopenia (6/21;
      29%) in many patients. No patient had either cytogenetic abnormalities or
      progressed to acute leukaemia, although one 13-year-old developed marked marrow
      fibrosis and trilineage dysplasia. We used the in vitro long-term culture
      initiating cell (LTC-IC) assay to quantify multilineage, primitive haematopoietic
      progenitors in a representative subset of these patients. LTC-IC assays showed
      equivalent frequencies of cobblestone area-forming cells (CAFCs) with a mean of
      5.42/10(5) cells +/- 1.9 SD and 6.13/10(5) cells +/- 2.6 SD in nine patients and
      six normal controls respectively. The average clonogenic cell output per LTC-IC,
      however, was significantly lower in DBA patients (mean 2.16 +/- 1.2 SD vs. 7. 36
      +/- 2.7 SD in normal controls, P = 0.0008). Our results suggest that the
      underlying defect in patients with severe refractory DBA may not be limited to
      the erythroid lineage, as was evidenced by the development of pancytopenia, bone
      marrow hypoplasia and reduced clonogenic cell output in LTC-IC assays.

PMID- 10651741
TI  - Dominant beta-thalassaemia: a highly unstable haemoglobin is caused by a novel 6
      bp deletion of the beta-globin gene.
AB  - Beta-thalassaemia is inherited as an autosomal recessive trait in most families.
      Particular interest has recently been focused on the molecular pathology of the
      rare forms with a dominant mode of inheritance. The index patient and her mother,
      who are described in this report, displayed typical clinical and haematological
      features of beta-thalassaemia intermedia with significant ineffective
      erythropoiesis and additional peripheral haemolysis. Molecular analysis
      demonstrated a heterozygous genotype for a novel 6 bp (TGGTCT) deletion of the
      beta-globin gene involving codons 33-35. This deletion results in the removal of
      two valine residues from the beta-globin chain at position 33/34 (B15/B16) and
      the substitution of the tyrosine residue at position 35 (C1) by an aspartic acid
      (beta 33-35 [B15-C1] Val-Val-Tyr-->0-0-Asp). According to the index patient's
      place of birth, this abnormal haemoglobin has been termed Hb Dresden. The
      stability of the variant and the normal beta-globin chains were similar during
      the incubation period of in vitro globin chain synthesis analysis. However, Hb
      Dresden is exquisitely unstable and cannot be detected in the peripheral blood by
      haemoglobin electrophoresis, high-performance liquid chromatography (HPLC) or
      isoelectric focusing. This instability can be explained by the vital structural
      role of the three affected amino acids that, in normal haemoglobin, establish a
      total of nine intermolecular bonds (five hydrophobic and four polar) at both the
      alpha1beta1 (alpha2beta2) and the alpha1beta2 (alpha2beta1) interface.

PMID- 10651742
TI  - The prothrombin Denver patient has two different prothrombin point mutations
      resulting in Glu-300-->Lys and Glu-309-->Lys substitutions.
AB  - Dysprothrombinaemia is a rare, congenital cause of bleeding. Fewer than 25
      families who express a functional prothrombin (factor II) defect have been
      reported. The original patient with prothrombin Denver had a severe haemophilia
      like bleeding disorder treated with weekly prophylactic factor replacement.
      Analysis of factor II activity and antigen in the patient showed a factor II
      activity of 5 units/dl and factor II antigen of 21 units/dl. Genomic DNA from the
      patient, mother and brother was obtained from peripheral blood white cells.
      Oligonucleotides were constructed, and prothrombin exons were amplified via
      polymerase chain reaction (PCR). The entire sequence of the thrombin portion of
      the molecule (exons VIII-XIV) and that of exons I-II and IV-VII was determined.
      This moderately severe dysprothrombinaemia was found to be associated with
      compound heterozygosity for two different Glu-->Lys point mutations, at amino
      acid positions 300 and 309. Assays of plasma from the prothrombin Denver proband
      suggested that the functional defect was in the activation of zymogen to enzyme.

PMID- 10651743
TI  - Heightened proteolysis of the von Willebrand factor subunit in patients with von
      Willebrand disease hemizygous or homozygous for the C2362F mutation.
AB  - We studied the proteolytic pattern of the mutant von Willebrand factor (VWF) in
      four patients with von Willebrand disease (VWD) who were either homozygous or
      hemizygous for the mutation C2362F. A significant decrease in the native fragment
      of 225 kDa was evident in all the patients, together with a marked increase in
      the 176 and 140 kDa fragments, a pattern usually observed in type 2A VWD. The
      proteolytic pattern measured in four heterozygotes for C2362F was within the
      normal range, suggesting that the mutant VWF C2362F present in the plasma of
      these patients may be protected from proteolysis by normal VWF.

PMID- 10651744
TI  - Increased soluble P-selectin levels following deep venous thrombosis: cause or
      effect?
AB  - Deep vein thrombosis (DVT) is associated with coagulation abnormalities, but
      evidence of excess platelet activity is scant. Soluble P-selectin is a marker of
      platelet activity, with high levels being found in patients with thrombotic
      disease. We measured soluble P-selectin by enzyme-linked immunosorbent assay
      (ELISA) in plasma from 89 patients with objectively confirmed DVT and in 126
      healthy age- and sex-matched control subjects, and found higher levels in the
      patients (P = 0.011). Taking the risk of DVT with a level of soluble P-selectin <
      238 ng/ml to be 1, the relative risk of DVT with a soluble P-selectin level >238
      ng/ml was 2.1 (95% CI 1. 2-3.6). These high levels may be a reflection of a
      generalized hypercoagulable state that, with factors such as the presence of
      persistent thrombin generation, could be responsible for excess platelet
      activation.

PMID- 10651745
TI  - Transmission of symptomatic parvovirus B19 infection by fibrin sealant used
      during surgery.
AB  - Human parvovirus B19 infection has been shown to be transmissible by blood and
      blood products and to result in transient aplastic crisis in patients with rapid
      red cell turnover. We report three cases of iatrogenic parvovirus B19 infection
      resulting from the use of the same batch of fibrin sealant under operation.
      Fibrin sealant, which is a typical haemostatic agent produced from blood, has
      been used during surgery. Human parvovirus is resistant to existing virus
      inactivating techniques, suggesting that infection may occur from blood products
      contaminated with it. Use of recombinant products for these proteins may thus be
      necessary.

PMID- 10651746
TI  - Circulating IGF-I and its protective role in the pathogenesis of diabetic
      angiopathy.
AB  - Poor glycaemic control in type 1 diabetes is associated with elevated serum IGFBP
      1 levels and reduced rather than elevated serum IGF-I levels. Increasing age is
      accompanied by a further decrease in serum IGF-I levels as well as an increase in
      IGFBP-l levels in adult diabetic type 1 and type 2 subjects. This is especially
      observed in diabetic type 1 subjects with manifest microvascular complications.
      IGFBP-I has been proposed as one of the IGF-I inhibitors in the serum of
      diabetics. Lowered IGF-I and increased IGFBP-1 levels in the blood may thus
      result in decreased IGF-I bioavailability at the tissue level. We hypothesize
      that the premature and progressive decline in serum IGF-I bioactivity during
      ageing in diabetics ultimately results in insufficient protective effects by IGF
      I in the kidneys, eyes and neurones, and thus the progression of diabetic
      microvascular complications. If this hypothesis is proven to be right, treatment
      of diabetic patients with IGF-I (eventually complexed to IGFBPs) as an adjunct to
      insulin might prevent and not worsen the development of diabetic microvascular
      complications.

PMID- 10651747
TI  - Growth hormone, IGF-I and diabetic angiopathy revisited.

PMID- 10651748
TI  - Deflazacort: towards selective glucocorticoid receptor modulation?

PMID- 10651749
TI  - The effects of growth hormone replacement therapy on overnight metabolic fuels in
      hypopituitary patients.
AB  - OBJECTIVE: Hypopituitary adults on conventional replacement have low
      concentrations of metabolic fuels throughout the night, possibly related to GH
      deficiency or to decreased cortisol levels overnight. We investigated whether GH
      replacement corrects the overnight fuel deficiency. DESIGN: We measured
      circulating levels of metabolic fuels: glucose, non-esterified fatty acids
      (NEFA), glycerol and 3-hydroxybutyrate (3-OHB) and insulin concentrations over 24
      h (from 0730 h to 0700 h) in hypopituitary adults before and after GH treatment
      in a randomized double-blind placebo-controlled trial of 3 months' duration.
      PATIENTS: Thirteen hypopituitary patients, 8 women and 5 men, were studied.
      RESULTS: Six patients (4 women and 2 men) received GH and 7 patients (4 women and
      3 men) were allocated to receive placebo. There was no difference in fasting
      (0730 h), area under the curve (AUC) between 2400 h and 0700 h (overnight) and
      AUC over 24 h for plasma glucose, 3-OHB, glycerol and insulin concentrations as a
      result of GH treatment. Fasting and overnight AUC for NEFA were significantly
      higher on GH treatment ((mean +/- SEM) 243 +/- 29 vs. 446 +/- 90 micromol/l, P =
      0.03, 1522 +/- 208 vs. 2167 +/- 123 micromol/l H, P = 0.046, respectively), but
      AUC over 24 h was not affected significantly. No significant changes in any fuel
      were seen in the placebo group. The changes in fasting, overnight and 24 h AUC
      for glucose, 3-OHB, glycerol and insulin levels with GH and with placebo for 3
      months were similar. The changes in fasting and overnight AUC for NEFA before and
      after 3 months were significantly different in the group treated with GH vs. the
      group treated with placebo (median (lower-upper quartile) 104 (90-276) vs. -89 (
      98 to 26) micromol/l, P = 0.002; 633 (263-967) vs. -895 (-1379 to -494)
      micromol/l h, P = 0.002, respectively), but the changes in 24-h AUC for NEFA were
      not significant between the two groups. CONCLUSIONS: GH replacement in
      hypopituitary adults increases fasting and overnight (between 2400 h and 0700 h)
      non-esterified fatty acid concentrations, consistent with the known lipolytic
      effect of GH. GH did not influence the concentrations of other metabolic fuels or
      insulin.

PMID- 10651750
TI  - Circadian variation in serum free and total insulin-like growth factor (IGF)-I
      and IGF-II in untreated and treated acromegaly and growth hormone deficiency.
AB  - OBJECTIVE: It is generally accepted that there is no clinically significant
      circadian variation in total insulin-like growth factor (IGF)-I or total IGF-II
      in healthy subjects. In contrast there is a significant nocturnal decrease in
      free IGF-I in healthy subjects, corresponding to the nocturnal increase in IGF
      binding protein-1. In this study we have investigated the circadian variation in
      circulating free IGF-I and IGF-II in patients with acromegaly and patients with
      adult onset growth hormone deficiency. PATIENTS: Seven acromegalic patients were
      studied with and without treatment with a slow-release formulation of octreotide.
      Seven GH-deficient patients were studied without GH replacement. In addition 5 of
      the GH-deficient patients were studied during GH replacement. DESIGN: Serum
      samples were obtained every hour for 24 h. Free IGF-I and IGF-II were measured
      every 2nd hour. Total IGF-I and IGF-II were measured every 2nd hour (acromegalic
      patients) or every 4th hour (GH deficient patients). IGF binding protein (IGFBP)
      1 was measured every 2nd hour (acromegalic patients) or every hour (GH deficient
      patients). RESULTS: In the untreated acromegalic patients there was a significant
      nocturnal decrease in free IGF-I, but not free IGF-II, before treatment. During
      treatment there was a significant nocturnal decrease in both free IGF-I and free
      IGF-II. Peak values of free IGF-I were 112% and 75% above trough (treatment and
      withdrawal, respectively). In the GH-deficient patients there were no significant
      circadian variations in free IGF-I or free IGF-II in either of the two occasions.
      In contrast, there was a significant circadian variation of total IGF-I after
      adjustment for changes in plasma volume in both treated and untreated acromegaly
      and GH deficiency in all cases with a peak between 0300 h and 0400 h. The
      nocturnal increase in total IGF-I ranged from 20% to 35%. CONCLUSIONS: A
      significant circadian variation in free IGF-I and IGF-II was demonstrated in
      acromegalic patients. In contrast no significant circadian variation in free IGF
      I and IGF-II was found in GH-deficient patients. Part of the variations may be
      due to poorly understood variations in IGF-I release. It is not clear whether and
      to what extent the observed circadian changes in free and total IGF-I are
      involved in circadian changes in IGF-I bioactivity.

PMID- 10651751
TI  - Absence of somatostatin receptor type 2 A mutations and gip oncogene in pituitary
      somatotroph adenomas.
AB  - OBJECTIVE: Somatostatin, acting via specific receptors in the anterior pituitary,
      tonically inhibits pituitary growth hormone secretion and somatotroph
      proliferation. Reduction of growth hormone secretion and tumour regression in GH
      secreting pituitary adenomas treated with long-acting somatostatin analogues
      varies widely. In 30-40% of these tumours dominant somatic mutations of the
      Gsalpha gene (gsp) have been demonstrated leading to constitutive adenylyl
      cyclase induction. A relationship between somatostatin sensitivity and tumour
      pathogenesis in some tumours has been suggested. Changes in the function of the
      somatostatin receptor or intracellular signal elements may be of relevance.
      Somatostatin receptor type 2 A (sst2A) and Gi2 are proposed to mediate
      selectively the inhibition of GH release in the somatotroph. We therefore
      investigated the presence of sst2A mutations and gip oncogene in somatotrophic
      pituitary adenomas. DESIGN: Tumour samples from 15 patients with pituitary
      somatotroph adenomas were obtained. RNA was isolated and used for reverse
      transcription and subsequent polymerase chain reaction. All samples were screened
      for the presence of sst2A mutations and of the gip oncogene by SSCP analysis and
      sequencing. For comparison, the gsp oncogene was examined. The relationship
      between clinical data and molecular analysis results was investigated. RESULTS:
      Seven of the tumours harboured a gsp mutation. No mutations affecting the sst2A
      protein were found in any of the tumours analysed. Furthermore, gip oncogene was
      absent in all tumours. CONCLUSION: Mutations of the somatostatin receptor type 2
      A and the gip oncogene are unlikely to be involved in the pathogenesis of
      acromegaly.

PMID- 10651752
TI  - CSF rhinorrhoea following treatment with dopamine agonists for massive invasive
      prolactinomas.
AB  - OBJECTIVE: The management of CSF rhinorrhoea following dopamine agonist (DA)
      treatment for invasive prolactinomas is difficult and there is no clear consensus
      for its treatment. Our objective was therefore to investigate the different
      treatments for this condition. DESIGN AND PATIENTS: We examined the case notes of
      five patients with invasive prolactinomas and CSF rhinorrhoea following DA
      treatment. The different ways in which this complication had been managed is
      detailed along with a review of the literature. RESULTS: Five patients aged 24-67
      years (3 male) with massive invasive prolactinomas (serum prolactin 95000-500000
      mU/l) eroding the skull base were treated with dopamine agonists (3
      bromocriptine, 1 cabergoline and 1 both). CSF rhinorrhoea developed in all
      patients between 1 week and 4 months after commencing dopamine agonist treatment.
      In two patients (cases 1 and 4), CSF rhinorrhoea ceased within a few days of
      stopping bromocriptine but restarted when treatment was resumed. One of these
      (case 4), a 67-year-old woman had no further treatment and CSF leakage stopped
      completely. She died of unrelated medical problems 3 years later. In one patient
      staphylococcus aureus meningitis and pneumocephalus developed as a complication
      of CSF rhinorrhoea. Three patients had endoscopic nasal surgery to repair the
      fistula using muscle grafts, and to decompress the pituitary tumour, with success
      in two. One patient had intracranial surgery and dural repair, which was
      successful in sealing the leak. CONCLUSIONS: We suggest that surgery as soon as
      is feasible is the treatment of choice for the repair of a CSF leak following
      dopamine agonist treatment. An additional strategy is the withdrawal of dopamine
      agonist to allow tumour re-growth to stop the leak.

PMID- 10651753
TI  - Disrupted cortisol-ACTH relationships in elderly women given corticotrophin
      releasing hormone two weeks after proximal femur fracture.
AB  - OBJECTIVE: In elderly women with hip fractures plasma cortisol is persistently
      higher than in healthy elderly women, possibly causing undesirable catabolic
      effects. A lack of corresponding changes in plasma ACTH or in the cortisol
      response to exogenous ACTH has prompted us to study cortisol-ACTH relationships
      after giving corticotrophin-releasing hormone (CRH) to such subjects. SUBJECTS:
      Seventeen women aged 70-90 years who had sustained a hip fracture about two weeks
      previously were compared with 19 healthy women aged 68-85 years. MEASUREMENTS:
      100 microg CRH was injected into each subject and ACTH and cortisol
      concentrations were measured at intervals for 90 minutes beforehand and 180
      minutes afterwards. The concentrations of vasopressin and various cytokines and
      related peptides were also measured during the baseline period. RESULTS: Under
      baseline conditions plasma cortisol was higher and plasma ACTH lower in the
      injured patients than in the healthy subjects. The patients showed smaller
      incremental ACTH and cortisol responses to CRF but because of the higher baseline
      value the peak cortisol concentration was enhanced. A strong correlation between
      the cortisol and ACTH responses in the healthy subjects was completely lost in
      the patients and the slope of the ACTH-cortisol dose-response relationship varied
      greatly between individuals, with no overall increase. The concentrations of
      vasopressin, interleukin-1 receptor antagonist and soluble tumour necrosis factor
      receptors were higher in the patients but did not correlate with the responses to
      CRH. CONCLUSIONS: The results are not consistent with increased sensitivity to
      ACTH and suggest an independent stimulus to the adrenals of hip-fracture
      patients. Its identity is unknown as the non-ACTH stimuli proposed hitherto are
      reported to enhance sensitivity to ACTH.

PMID- 10651755
TI  - Mutations in the type II 3beta-hydroxysteroid dehydrogenase (HSD3B2) gene can
      cause premature pubarche in girls.
AB  - OBJECTIVE: Most previous studies have failed to demonstrate any mutations in the
      type II 3beta hydroxysteroid dehydrogenase (HSD3B2) gene in patients satisfying
      the hormonal criteria of nonclassic 3beta-hydroxysteroid dehydrogenase
      deficiency, suggesting that a mutant 3beta-hydroxysteroid dehydrogenase protein
      is not the cause of this disorder. We screened the HSD3B2 gene for mutations in
      girls with premature pubarche and a hormonal diagnosis of 3beta-hydroxysteroid
      dehydrogenase deficiency. DESIGN: From 30 girls with premature pubarche, we
      selected 9 whose ACTH-stimulated 17-hydroxypregnenolone levels were elevated (>
      or =6 SD) and screened the HSD3B2 gene for mutations. MEASUREMENTS: All patients
      were submitted to a standard ACTH stimulation test. Serum steroids were measured
      and compared to the mean level of pubertal stage matched control subjects. The
      four exons and exon-intron boundaries of the HSD3B2 gene were amplified by
      polymerase chain reaction and screened for mutations by denaturing gradient gel
      electrophoresis. The fragments with abnormal migration on denaturing gradient gel
      electrophoresis were directly sequenced. RESULTS: A homozygous T259M mutation was
      identified in one girl and a new compound heterozygous G129R/P222H mutation was
      identified in two sisters. The highest ACTH-stimulated 17-hydroxypregnenolone
      levels, 147, 339 and 351 nmol/l, were found in those patients with mutations in
      the HSD3B2 gene. In the patients without mutations, ACTH-stimulated 17
      hydroxypregnenolone ranged from 48 to 111 nmol/l. ACTH-stimulated
      dehydroepiandrosterone levels had an overlap among the girls with and without
      mutations and the normal controls. CONCLUSIONS: Premature pubarche can be caused
      by mutations in the type II 3beta hydroxysteroid dehydrogenase gene.

PMID- 10651754
TI  - Sexual dimorphism of cortisol metabolism is maintained in elderly subjects and is
      not oestrogen dependent.
AB  - OBJECTIVE: The net interconversion of inactive cortisone to active cortisol by
      11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) may determine hepatic and
      adipose tissue exposure to glucocorticoid action. Cortisol metabolism exhibits a
      sexual dimorphism with an apparently lower activity of 11betaHSD1 in females
      that, in an animal model, has been attributed to the effects of oestrogen. The
      aim of this study is to determine whether the sexual dimorphism of cortisol
      metabolism persists between post-menopausal, oestrogen-deficient women and
      elderly men. PATIENTS: Fifteen healthy men, aged 60.8-82.0 years, and 7 healthy
      women, aged 62.4-87.5 years, were studied. None of the subjects was receiving
      steroid medication at the time of the study. All the women were post-menopausal
      and none was receiving sex steroid replacement therapy. MEASUREMENTS: 24-h urine
      collections were taken from each patient and assayed for steroid metabolites by
      gas chromatography. Body composition was determined by dual energy X-ray
      absorptiometry. Blood was drawn, after an overnight fast, for the determination
      of serum IGF-I and IGFBP1 levels. RESULTS: The ratio of 11-hydroxy cortisol
      metabolites to 11-oxo cortisol metabolites (Fm/Em) was significantly higher in
      men than in women, 0.80 (0.55-1.86) vs. 0.67 (0.46-0.98) (P < 0.02), as was the
      ratio of allo-tetrahydrocortisol (5alpha-THF) + tetrahydrocortisol
      (THF)/tetrahydrocortisone (THE), 0.74 (0.37-2.08) vs. 0.40 (0.22-1.10) (P <
      0.047). In the group as a whole there was a negative correlation between Fm/Em
      and percent body fat, r = - 0. 43 (P < 0.05), and the negative relationship
      between cortisol and cortisone metabolite (Fm/Em) and total fat mass approached
      significance, r = - 0.39 (P = 0.07). These relationships were not apparent in the
      women when considered alone. Among the men there were negative relationships
      between Fm/Em and total fat mass, r = - 0.48, and Fm/Em and trunk fat mass, r = -
      0.48 which approached significance (both P = 0.07). Serum IGFBP-1 levels were not
      significantly different between the two sexes. There was a significant
      correlation between IGFBP-1 and Fm/Em in the men, r = 0. 84 (P < 0.0001) which
      persisted when total body fat mass, r = 0.85 (P < 0.0001) and trunk fat mass, r =
      0.83 (P < 0.0001), were controlled for. This relationship was not evident among
      the women. CONCLUSION: This study demonstrates that the previously described
      sexual dimorphism in cortisol metabolism is not dependent on oestrogen, although
      the possibility that oestrogen exerts a permanent modifying effect on 11beta-HSD1
      gene expression during the pre-menopausal period cannot be excluded. The findings
      confirm the primary importance of body fat as a determinant of cortisol-cortisone
      conversion.

PMID- 10651756
TI  - Endogenous inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 do not
      explain abnormal cortisol metabolism in polycystic ovary syndrome.
AB  - OBJECTIVE: The aetiology of enhanced adrenal androgen secretion in polycystic
      ovary syndrome is poorly understood. Previous reports suggest that enhanced
      peripheral metabolism of cortisol results in decreased negative feedback
      suppression of ACTH secretion, either by enhanced inactivation of cortisol by
      5alpha-reductase or impaired reactivation of cortisol by 11beta-hydroxysteroid
      dehydrogenase type 1 (11beta-HSD1). Endogenous inhibitors of hepatic 11beta-HSD1
      can be extracted from urine. We have tested the hypothesis that these are
      increased in patients with polycystic ovary syndrome. DESIGN: A case-control
      study. PATIENTS: 57 patients with polycystic ovary syndrome and 27 healthy
      control women. MEASUREMENTS: Aliquots from 24 h urine samples were extracted with
      Sep-Paks and incubated with rat liver microsomes in which 11beta-HSD1 activity
      was quantified by conversion of 3H-corticosterone to 3H-11-dehydrocorticosterone.
      RESULTS: Inhibition of 11beta-HSD1 activity was not different in extracts from
      patients compared with controls (40.8 +/- 18.9 arbitrary units in patients vs.
      42.7 +/- 16.6 in controls, mean (+/- SEM, P > 0.60) and did not correlate with
      ratios of cortisol metabolites in urine or with body mass index. CONCLUSIONS: The
      altered cortisol metabolism in polycystic ovarian syndrome, which is consistent
      with impaired 11beta-HSD1 activity, cannot be accounted for by increased
      production of measurable endogenous inhibitors of this enzyme.

PMID- 10651757
TI  - The prevalence of polycystic ovaries in women with type 2 diabetes mellitus.
AB  - OBJECTIVE: Polycystic ovary syndrome (PCOS) and type 2 diabetes mellitus are both
      common conditions associated with insulin resistance and compensatory
      hyperinsulinaemia. Previous reports have noted that impaired glucose tolerance
      and diabetes are common in women with PCOS. In this report we present the results
      of the converse study: the prevalence of polycystic ovaries in premenopausal
      women presenting with type 2 diabetes mellitus. SUBJECTS: Subjects were recruited
      from a hospital Diabetes Clinic. A search of computerized records identified 49
      premenopausal women with type 2 diabetes mellitus being treated with diet alone
      or oral hypoglycaemic agents of whom 38 (76%) patients agreed to be studied.
      DESIGN: A cross-sectional study recording clinical, demographic and
      anthropometric data. Measurements of fasting metabolic parameters, reproductive
      endocrine profiles and ovarian dimensions were taken. RESULTS: Eighty-two percent
      of women with type 2 diabetes mellitus had polycystic ovaries on ultrasound. Of
      these women, 52% had clinical evidence of cutaneous hyperandrogenism and/or
      menstrual disturbance. Correlations between metabolic and reproductive parameters
      were consistent with a stimulatory action of insulin on the ovary. There was no
      significant difference between the PCO and non-PCO groups with respect to
      metabolic profiles. CONCLUSIONS: Women with type 2 diabetes mellitus have a
      higher prevalence of polycystic ovaries than that reported in the general
      population. Not all women with hyperinsulinaemia due to type 2 diabetes mellitus,
      however, develop PCO suggesting that hyperinsulinaemia alone is not sufficient
      for the expression of this ovarian morphology.

PMID- 10651758
TI  - Suppression of endogenous insulin secretion by exogenous insulin in patients with
      insulinoma.
AB  - OBJECTIVE: Previous studies have demonstrated that endogenous insulin secretion
      is not suppressed by exogenous insulin in patients with insulinoma. In this study
      we examined whether insulin secretion in insulinoma patients is suppressed by
      exogenous insulin during hypoglycaemia. SUBJECTS AND METHODS: Sixteen insulinoma
      patients (5 men and 11 women) and 10 normal subjects were studied.
      Hyperinsulinaemic glucose clamp studies were performed at both euglycaemia (4.5
      mmol/l glucose) and hypoglycaemia (2.5 mmol/l glucose). RESULTS: In normal
      subjects, plasma C-peptide levels were suppressed by 66% during the euglycaemic
      hyperinsulinaemic clamps (P < 0.01). In contrast, in insulinoma patients, plasma
      C-peptide levels increased by 25% during the clamps (P < 0.05). In the
      hypoglycaemic hyperinsulinaemic clamps, plasma C-peptide levels were nearly
      completely (91%) suppressed in normal subjects and partially (39%) suppressed in
      patients with insulinoma (P < 0.01). The decrease in C-peptide levels during the
      hypoglycaemic clamps was > 30% in 12 (75%) of 16 insulinoma patients and > 50% in
      8 (50%) patients. CONCLUSIONS: This study demonstrated that in patients with
      insulinoma, insulin secretion was not suppressed by exogenous insulin during
      euglycaemia but was suppressed during hypoglycaemia, although the degree of
      suppression was less than that in normal subjects. Our results suggest that the
      feedback regulation of insulin secretion by exogenous insulin is partially
      retained in patients with insulinoma.

PMID- 10651759
TI  - The insulin resistance syndrome and the binding capacity of cortisol binding
      globulin (CBG) in men and women.
AB  - BACKGROUND: Both insulin resistance and cortisol binding globulin (CBG) capacity
      have been found to correlate with plasma free fatty acid (FFA) concentration.
      OBJECTIVE: To examine the changes in CBG binding with varying degrees of insulin
      resistance and plasma FFA levels. SUBJECTS AND METHODS: Anthropometric
      parameters, serum cortisol levels, plasma CBG, CBG binding and insulin
      sensitivity (using the frequently sampled intravenous glucose tolerance test with
      minimal model analysis) were measured in a group of 38 healthy subjects (19 men,
      mean age 36.2 +/- 1.9; body mass index (BMI) 28.8 +/- 1.2, range 22.2-35.7), and
      19 women, age 34.9 +/- 1.4; BMI 28.1 +/- 0.8, range 19-37.9)]. RESULTS: Plasma
      CBG levels did not differ between men and women. In men, CBG binding was
      associated with several parameters of the insulin resistance syndrome, including
      area under the curve for glucose during an oral glucose tolerance test (MBG, r =
      0.45, P = 0.04), fasting insulin (r = 0.66, P = 0. 002), plasma triglycerides (r
      = 0.75, P < 0.0001), VLDL-triglycerides (r = 0.59, P = 0.007), fasting FFA (r =
      0.72, P = 0.002), uric acid (r = 0.57 (P = 0.01) and insulin sensitivity (SI, r =
      - 0.58, P = 0.008). Free cortisol (estimated as the ratio of cortisol to CBG) was
      not associated with waist-to-hip ratio (WHR) or parameters of insulin
      sensitivity. In contrast to men, CBG binding was not associated with MBG, fasting
      insulin, plasma triglycerides, VLDL-triglycerides, FFA, uric acid or SI (all P =
      NS) in women. Serum free cortisol, however, correlated positively with WHR (r =
      0. 62, P = 0.02) and negatively with SI (r = - 0.68, P = 0.01) in obese women. A
      multiple linear regression to predict CBG binding was constructed, with plasma
      CBG concentration and insulin sensitivity as independent variables. In this
      model, only SI entered the equation at a statistically significant level (P =
      0.0012) contributing to 52% of the variance in CBG binding in men. When plasma
      FFA levels were added to the model, both SI (P = 0.04) and FFA levels (P = 0.039)
      contributed to 66% of the variance of CBG binding in men. In women, both plasma
      CBG concentration (P = 0.0005) and insulin sensitivity (P = 0.047) entered the
      equation at a statistically significant level, contributing to 60% of the
      variance in CBG binding. When plasma FFA levels were added to the model, only
      plasma CBG concentration (P = 0.043) was found to significantly contribute to 38%
      of the variance in CBG binding. The latter finding suggests that FFA levels
      constituted a confounding variable in the association between SI and CBG binding
      in women. CONCLUSIONS: Both plasma free fatty acid and insulin sensitivity
      influence cortisol binding globulin binding capacity in men. Whether cortisol
      binding globulin binding is a factor implicated in the pathophysiology of insulin
      resistance or represents an adaptative tool in this situation awaits further
      studies.

PMID- 10651760
TI  - Leptin concentrations in Prader-Willi syndrome before and after growth hormone
      replacement.
AB  - OBJECTIVE: This study explored leptin concentrations in Prader-Willi syndrome
      (PWS), a genetic disorder characterized by significant obesity and presumed
      hypothalamic dysfunction. The potential interaction of leptin metabolism with the
      growth hormone (GH) axis was also studied. STUDY DESIGN: Plasma leptin
      concentrations and percent body fat were determined by radioimmunoassay and dual
      energy x-ray absorptionmetry, respectively, in 23 children with Prader-Willi
      syndrome and 23 children with exogenous obesity. RESULTS: Log plasma leptin
      concentrations were positively correlated with percentage body fat in PWS (r =
      0.844) and exogenous obesity (r = 0.869). When the regression lines for the two
      groups were compared, there were no differences in their slopes (P = 0.737) or
      intercepts (P = 0.701). Administration of recombinant human growth hormone to PWS
      children for 12 months significantly reduced both percentage body fat and plasma
      leptin concentrations, but the relationship of log plasma leptin to percentage
      body fat was unchanged. CONCLUSION: Prader-Willi syndrome is not accompanied by
      deranged leptin concentrations and there was no evidence of an interaction of the
      GH axis with leptin metabolism in these GH-deficient children.

PMID- 10651761
TI  - The innate immune response and type 2 diabetes: evidence that leptin is
      associated with a stress-related (acute-phase) reaction.
AB  - OBJECTIVE: Leptin is produced by adipose tissue and controls food intake and body
      weight. Although blood levels of leptin reflect energy stores, cytokines also
      stimulate leptin production from fat. Because we have proposed that type 2
      diabetes mellitus is associated with a cytokine-mediated acute-phase or stress
      response, part of the innate immune system, we sought evidence that leptin is
      increased in type 2 diabetes partly as a stress response, independently of
      obesity and sex. DESIGN: We selected two groups of type 2 diabetic patients with
      either a low acute-phase response (< 2.30 mmol/l serum concentration of the acute
      phase marker sialic acid) or high response (> 2.30 mmol/l sialic acid), but pair
      matched for body mass index (BMI) and sex. PATIENTS: Twenty type 2 diabetic
      subjects (11 male, 9 female) in each group, whose body mass index (BMI) and age
      were comparable (mean +/- SD: 28.8 +/- 3.8 vs. 28.9 +/- 3.8 kg/m2, and 60.7 +/-
      8.9 vs. 61.9 +/- 12.3 years, low vs. high acute-phase responders, respectively).
      The glycaemic control was also similar in each group (glycated haemoglobin: 9.1
      +/- 2.2 vs. 8.9 +/- 1.9%). MEASUREMENTS: Serum concentrations of sialic acid,
      leptin, interleukin-6 (IL-6) (the major cytokine mediator of the acute-phase
      response) and cortisol were assayed in fasting venous blood samples from patients
      and the results compared. RESULTS: Serum leptin concentration was increased in
      the high compared to the low acute-phase group (median 13.2 (range 3.6-55) vs.
      8.1 (2.0-22.5) microg/l, P = 0.004). IL-6 and cortisol concentrations were also
      higher in the high-stress group (1.9 (1.0-6.4) vs. 1.4 (0.4-7.5) ng/l, P = 0.02;
      and 409 (180-875) vs. 290 (157-705) nmol/l, P = 0.02, respectively). Leptin was
      strongly correlated with BMI (r = 0.61, P < 0.001), but also with sialic acid (r
      = 0.40, P = 0.01) and IL-6 (r = 0.38, P = 0.04). CONCLUSIONS: Serum leptin
      concentrations in type 2 diabetes are partly related to an acute-phase or stress
      response, independent of BMI and sex. The association of hyperleptinaemia with
      elevated serum cortisol provides a mechanism for leptin resistance in type 2
      diabetes (glucocorticoids inhibit the central action of leptin). This study
      provides further support for the theory that type 2 diabetes is asociated with
      chronic innate immune activation.

PMID- 10651762
TI  - Weight gain reverses bone turnover and restores circadian variation of bone
      resorption in anorexic patients.
AB  - OBJECTIVE: The present study was conducted in order to describe the variations
      and circadian rhythm of biochemical markers of bone remodelling at baseline and
      after weight gain in patients with anorexia nervosa (AN). SUBJECTS: We studied 9
      women (mean age 21 years, range: 16-30) with established AN who remained
      amenorrhoeic during the study and with a low body mass index (BMI) after
      refeeding and 6 female controls (mean age 20 years, range, 18-24 and BMI: 20.6 +/
      1.1 kg/m2). Refeeding was not associated with any other intervention or
      treatment, especially oestrogen replacement or hormonal contraception. Serum
      levels of oestradiol remained below 70 pmol/l before and after refeeding.
      MEASUREMENTS: During the study, PTH and 25-hydroxyvitamin D measurements were
      performed. Markers of bone formation: serum intact osteocalcin (iBGP) and serum
      intact BGP + fragments (iBGP+F) and markers of bone resorption: urine C-teloptide
      of type I collagen (uCTX) and serum C-telopeptide ofvtype 1 collagen (s-CTX) were
      measured. RESULTS: At baseline, PTH and 25 OH-vitamin D concentrations were
      within the normal range in AN patients and no significant variation was observed
      after refeeding. Bone formation markers were found to be significantly different
      at baseline between AN patients and controls. After refeeding, iBGP and iBGP+F
      levels increased by 172% and 154%, respectively, to values no different from
      controls. Intact BGP and iBGP+F exhibited a significant circadian variation in
      controls (P < 0.05 and P < 0.002, respectively), whereas we did not find any such
      circadian rhythm in AN patients. After refeeding no significant circadian
      variation was observed; however, iGBP+F tended to peak in early morning and
      exhibited a nadir in the afternoon. At baseline, sCTX was 2-fold higher in AN
      patients than in controls. After weight gain sCTX decreased significantly and
      reached control values. Refeeding induced a non-significant 40% decrease in uCTX.
      We found positive correlations between uCTX and the 24-h mean value of sCTX
      levels (r2 = 0.93, P < 0.0001) and between uCTX and the mean value of sCTX peak
      levels at 0800 h (r2 = 0.65, P < 0.0003). Serum CTX exhibited a significant
      circadian variation in controls (P < 0.001) with a peak at 0800 h and a nadir at
      1600 h with a 60% decrease between peak and nadir values. We found that anorexia
      nervosa suppressed the sCTX circadian variation which was restored by refeeding.
      We found a significant non-linear relationship between BMI and sCTX/iBGP ratio in
      AN (r2 = 0.6, P < 0.0001), thus illustrating the influence of nutritional status
      on bone remodelling. CONCLUSIONS: In this study we found that weight gain,
      related to refeeding only, reversed the anorexia nervosa-induced uncoupling of
      bone remodelling and restored circadian variation of a bone resorption marker.

PMID- 10651763
TI  - Adrenal insufficiency as the first clinical manifestation of the primary
      antiphospholipid antibody syndrome.
AB  - We describe a 60-year-old man who developed clinical symptoms and signs of
      Addison's disease, which was subsequently confirmed biochemically; no cause was
      apparent. Several months later the patient represented with a fit, followed by a
      large and extensive venous thrombosis in the right iliac vein and in the veins of
      the right leg. He had strongly positive antibodies to cardiolipin, strongly
      suggesting a diagnosis of primary antiphospholipid syndrome. While Addison's
      disease is a well-recognized, albeit rare, manifestation of the antiphospholipid
      syndrome, the Addison's disease preceded other clinical evidence of the syndrome
      by several months, in our patient, at variance with previous cases described in
      the literature. The antiphospholipid syndrome should be considered as a possible
      pathogenetic process in patients presenting with Addison's disease where the
      aetiology is not obvious.

PMID- 10651764
TI  - Animals and allergy.

PMID- 10651765
TI  - Colophony hypersensitivity revisited.

PMID- 10651766
TI  - Dendritic cells and lung antigen responses.

PMID- 10651767
TI  - Cromolyn sodium or nedocromil in childhood asthma: does it matter?

PMID- 10651768
TI  - Endothelin in nasal mucosa: role in nasal function and inflammation.

PMID- 10651769
TI  - The role of neurotrophins in allergic bronchial asthma.

PMID- 10651770
TI  - Reduced risk of hay fever and asthma among children of farmers.
AB  - BACKGROUND: The prevalence of atopic diseases is on the rise. Traditional
      lifestyles may be associated with a reduced risk of atopy. OBJECTIVES: To test
      the hypothesis that children living on a farm have lower prevalences of atopic
      diseases. To identify differences in living conditions between farmers and other
      families which are associated with the development of atopic conditions. DESIGN:
      Cross-sectional survey among children entering school (aged 5-7 years). A written
      questionnaire including the ISAAC core questions and asking for exposures on a
      farm and elsewhere was administered to the parents. SETTING: School health entry
      examination in two Bavarian districts with extensive farming activity. SUBJECTS:
      10 163 children. MAIN OUTCOME MEASURES: The prevalence of doctor's diagnoses and
      symptoms of hay fever, asthma and eczema as assessed by parental report. RESULTS:
      Farmers' children had lower prevalences of hay fever (adjusted odds ratio = 0.
      52, 95% CI 0.28-0.99), asthma (0.65, 0.39-1.09), and wheeze (0.55, 0. 36-0.86)
      than their peers not living in an agricultural environment. The reduction in risk
      was stronger for children whose families were running the farm on a full-time
      basis as compared with families with part-time farming activity. Among farmers'
      children increasing exposure to livestock was related to a decreasing prevalence
      of atopic diseases (aOR = 0.41, 95% CI 0.23-0.74). CONCLUSIONS: Factors related
      to environmental influences on a farm such as increased exposure to bacterial
      compounds in stables where livestock is kept prevent the development of allergic
      disorders in children.

PMID- 10651771
TI  - Austrian children living on a farm have less hay fever, asthma and allergic
      sensitization.
AB  - BACKGROUND AND OBJECTIVES: In some studies, the prevalence of hay fever and
      asthma has been found to be lower in children from rural areas than in children
      from an urban environment. We hypothesized that living on a farm might be
      protective against development of allergic sensitization and allergic diseases.
      METHODS: In a cross-sectional survey, parents of 2283 children aged 8-10 years
      from a mostly rural area in Austria answered a standardized questionnaire on
      allergic diseases and environmental factors. 1137 children performed a skin prick
      test to seven local allergens. RESULTS: The prevalence of hay fever (3.1 vs
      10.3%, P = 0.0002), asthma (1.1 vs 3.9%, P = 0.017) and a positive skin prick
      reactivity to at least one of the common local allergens (18.8 vs 32.7%, P = 0.
      001) was significantly lower in children living on a farm than in children from a
      non-farming environment. In a multivariate logistic regression model, adjusting
      for genetic background, parent education, living and housing conditions and
      dietary factors did not change the odds ratio for the association of farming and
      allergic sensitization. Only after including 'regular contact with livestock and
      poultry' into the model did the odds ratio change significantly (cOR 0.48 95% CI
      0.30-0.75 to aOR 0.75 95% CI 0.37-1.52) indicating an association between regular
      contact with farm animals and reduced risk of atopic sensitization. CONCLUSION:
      Possible explanations for the lower prevalence of hay fever, asthma and allergic
      sensitization in children living on a farm might be the development of
      immunotolerance or the stimulation of TH1 cells and suppression of TH2 cells by
      increased exposure of farm children to microbial antigens in the stables or
      farmhouses.

PMID- 10651772
TI  - Farm environment in childhood prevents the development of allergies.
AB  - BACKGROUND: A protective effect of infections in early life might explain the
      firmly reported finding of an inverse association between atopic disorders and
      large sibships. OBJECTIVE: To study the effect of childhood farm, rural non-farm
      and urban environment, as well as family size and other factors on the occurrence
      of asthma, wheezing and atopic disorders up to young adulthood. METHODS: Data on
      lifetime prevalence of physician-diagnosed asthma, allergic rhinitis and/or
      allergic conjunctivitis, atopic dermatitis, as well as self-reported episodic
      wheezing from 10 667 Finnish first-year university students aged 18-24 years were
      collected by a postal questionnaire. Associations of lifetime prevalence of the
      diseases with living on a farm, in a rural non-farm and urban environment during
      childhood were estimated by logistic regression analysis. Adjustment was made for
      potential confounding by gender, parental atopy, parental education, number of
      older siblings, day care outside the home and passive smoking. RESULTS: The
      childhood farm environment independently reduced the risk for physician-diagnosed
      allergic rhinitis and/or allergic conjunctivitis (adjusted odds ratio 0.63, 95%
      CI 0.50-0.79, P < 0.001), and for diagnosed asthma and episodic wheezing analysed
      together (OR 0.71, 95% CI 0.54-0.93, P < 0.05), but not for atopic dermatitis
      during lifetime. Urban childhood environment did not show independent increased
      risk when compared with rural non-farm residence. The inverse association of
      sibship size with the occurrence of allergic rhinitis and/or allergic
      conjunctivitis was found among subjects with one (OR 0.86, 95% CI 0.77-0.96, P <
      0.01) or at least four older siblings (OR 0.47, 95% CI 0.26-0.84, P < 0.05).
      CONCLUSION: Childhood farm environment seems to have a protective effect against
      allergic rhinitis and/or conjunctivitis, and more weakly against asthma and
      wheezing irrespective of family size. Environmental exposure to immune modulating
      agents, such as environmental mycobacteria and actinomycetes, favouring
      manifestation of a nonatopic phenotype could explain the finding.

PMID- 10651773
TI  - Colophony: an in vitro model for the induction of sensitization.
AB  - BACKGROUND: The potential of colophony fumes from soldering flux to induce asthma
      has been known since the 1970s, however, no direct in vitro or in vivo evidence
      has been reported. The present study investigated the potential of colophony to
      stimulate human phagocytic cells to produce reactive oxygen species. METHODS: The
      human cell line HL-60 was differentiated to produce cells with a monocyte-like
      and a neutrophil-like phenotypes. A number of procedures were used to confirm the
      phenotype of these differentiated cells including morphology, esterase activity,
      flow cytometry and phagocytosis. The potential of colophony to stimulate human
      phagocytic cells to produce reactive oxygen species was monitored using flow
      cytoenzymology. RESULTS: We were able to show that intracellular peroxide levels
      were increased in both monocyte-like and neutrophil-like cells, but not in
      undifferentiated HL-60 cells following the addition of colophony. CONCLUSIONS:
      The resin acid epoxides and hydroperoxides which have been suggested to be
      sensitizers in contact allergy, are degraded during the soldering process.
      However, conditions for the oxidation of colophony may occur in vivo as a result
      of the colophony-induced oxidative burst from neutrophils and monocytes. These
      oxidation products may then interact with body proteins to further initiate
      immune responses. Therefore for the preparation of low molecular weight chemical
      (LMWC)-protein conjugates, consideration must be taken to determine whether the
      LMWC is undergoing a reaction in vivo before it is interacting with body
      proteins.

PMID- 10651774
TI  - Sensitization to inhaled antigen by intratracheal instillation of dendritic
      cells.
AB  - BACKGROUND: Airway dendritic cells (DCs) capture and present inhaled antigen. It
      is not known whether antigen presentation by DCs in the airways is sufficient to
      induce sensitization to inhaled antigen in vivo. METHODS: Rats were immunized by
      intratracheal instillation of ovalbumin (OVA) -pulsed bone marrow-derived DCs or
      macrophages and exposed 10 days later to a 30-min aerosol of OVA on 3 consecutive
      days. Total and differential cell counts and flow cytometry on bronchoalveolar
      lavage (BAL) fluid, airway histology and serum OVA-immunoglobulin (Ig) E levels
      were analysed 24 h after the last exposure. RESULTS: As few as 2 x 104 OVA-DC
      induced sensitization to inhaled OVA. The secondary response to OVA-aerosol
      consisted of an antigen-specific increase in the number of bronchoalveolar
      mononuclear cells, activated CD4-positive alphabeta-TCR T lymphocytes,
      neutrophils and few eosinophils. Peribronchial and perivascular mononuclear cell
      infiltrates were seen on histological analysis. There was no production of
      systemic OVA-IgE. Bone marrow-derived macrophages did not induce sensitization.
      CONCLUSION: Delivering antigen to the respiratory tract via professional antigen
      presenting DCs sensitizes for a secondary response to inhaled antigen leading to
      airway inflammation. This model will prove very useful for studying the early
      events of sensitization to inhaled antigen using the respiratory route.

PMID- 10651775
TI  - Sensory neuropeptides induce histamine release from bronchoalveolar lavage cells
      in both nonasthmatic coughers and cough variant asthmatics.
AB  - BACKGROUND: Sensory neuropeptides have been suggested to play a role in the
      pathogenesis of a number of respiratory diseases including asthma and chronic non
      productive cough. OBJECTIVES: To investigate the action of sensory neuropeptides
      on airway mast cells obtained by bronchoalveolar lavage (BAL). METHODS: BAL was
      performed on 23 nonasthmatic patients with cough (NAC), 11 patients with cough
      variant asthma (CVA) and 10 nonatopic controls. Washed lavage cells were
      stimulated (20 min, 37 degrees C) with calcitonin gene-related peptide (CGRP),
      neurokinin A (NKA) and substance P (25 and 50 micromol/L). RESULTS: The
      neuropeptides tested induced histamine release in all groups studied. Only CGRP
      (50 micromol/L) induced significantly more histamine release from both NAC and
      CVA patients compared with control subjects (P = 0.038 and 0.045, respectively).
      CONCLUSION: Regardless of aetiology, mast cells from patients with chronic cough
      appear to have an increased responsiveness to CGRP compared with controls. The
      results of the present study suggest that the role of CGRP in chronic cough
      should be further investigated.

PMID- 10651776
TI  - Serum immunoglobulin E levels predict human airway reactivity in vitro.
AB  - BACKGROUND: Airway hyperresponsiveness to non-specific stimuli is one
      characteristic feature of airway diseases such as bronchial asthma and chronic
      bronchitis. Until now, studies aiming to demonstrate a relationship between in
      vivo conditions associated with airway hyperreactivity and in vitro airway
      responsiveness have been inconclusive. OBJECTIVE: Since serum immunoglobulin (Ig)
      E is believed to be one determinant of airway reactivity in vivo, we studied
      whether in vitro airway reactivity in lung resection material from patients with
      elevated levels of serum IgE was increased as compared with patients with
      undetectable IgE. By this approach, we aimed to elucidate the role of circulating
      IgE for bronchial smooth muscle reactivity in vitro. METHODS: Bronchial rings
      from nine patients with total serum IgE levels above 200 U/mL and 10 patients
      with total serum IgE levels below 10 U/mL were passively sensitized, i.e.
      incubated overnight with buffer or sensitizing serum containing high levels of
      total IgE (> 250 U/mL). Afterwards, contractile responses to histamine were
      assessed in the organ bath. RESULTS: Histamine responsiveness was significantly
      increased in airways obtained from patients with IgE levels above 200 U/mL as
      compared with airways from patients with IgE levels below 10 U/mL (P < 0.05).
      Passive sensitization of bronchi from patients with low IgE significantly
      increased histamine responsiveness, as compared with non-sensitized controls from
      the same patients (P < 0.05). In contrast, passive sensitization of airways from
      patients with elevated IgE did not further increase responsiveness. There was no
      difference in histamine reactivity between non-passively sensitized and passively
      sensitized tissue preparations from patients with IgE above 200 U/mL and
      passively sensitized tissues from patients with IgE below 10 U/mL. CONCLUSION:
      Our findings reveal that elevated levels of serum IgE predict airway
      hyperresponsiveness to histamine in vitro. At the same time, they indicate that
      the in vitro model of passive sensitization, in addition to its ability to induce
      allergen responses, also mimics conditions of non-specific airway
      hyperreactivity, which are relevant under in vivo conditions.

PMID- 10651777
TI  - Phleum pratense-specific T cells of allergic rhinitis patients display a broader
      recognition pattern than phleum pratense-specific serum immunoglobulin E.
AB  - BACKGROUND: The role of allergen-specific CD4+ T lymphocytes in the
      pathophysiology of atopic disease is well established. Previous studies on
      allergen-specific T-cell responses have focused on the recognition of single
      major allergens to identify T-cell epitopes. OBJECTIVE: However, it is not clear
      whether immune responses to allergen extracts are exclusively targeted at major
      allergens or whether additional proteins are recognized. METHODS: Here we
      describe the Phleum pratense-specific immunoglobulin E (IgE) and T-cell responses
      of six allergic rhinitis patients. Reactivity was measured to size-separated
      fractions of a P. pratense extract as well as to the purified major allergens Phl
      p 1, Phl p 2/3 and Phl p 5. RESULTS: The specificity of the patients' serum IgE,
      measured in a fluid phase assay, was restricted to one or two of the major
      allergens. Even though the majority of the patients had IgE antibodies reactive
      with a single major allergen, one patient reacted with both Phl p 5 and with Phl
      p 2/3. Analysis of the T-cell repertoire with P. pratense-specific T-cell lines
      (TCLs) and CD4+ T-cell clones (TCCs) revealed that at least six different
      proteins were recognized, including the three major allergens, most notably Phl p
      5. Simultaneous production of IL-5 and interferon (IFN) -gamma was detected in
      supernatants of the TCLs stimulated with P. pratense extract and the major
      allergens. CONCLUSION: These results indicate that allergic rhinitis patients
      have a large pool of circulating allergen-specific CD4+ T cells that recognize
      many different proteins in an allergenic extract, whereas only a small number of
      these proteins are recognized by serum IgE.

PMID- 10651778
TI  - Interleukin-5 enhances eosinophil adhesion to bronchial epithelial cells.
AB  - BACKGROUND: Eosinophil-bronchial epithelial cell interactions are thought to be
      central to the pathogenesis of asthma, both in terms of the epithelium as a
      source of pro-inflammatory mediators and as a target for eosinophil-mediated
      damage. We have therefore investigated adhesion interactions between these two
      cell types. OBJECTIVES: To determine the role of eosinophil and epithelial
      activation on eosinophil adhesion to bronchial epithelium and to characterize the
      adhesion receptors mediating eosinophil adhesion. METHODS: Eosinophils were
      purified from human peripheral blood by immunomagnetic selection and adhesion to
      confluent cultures of the airway epithelial cell lines A549 and BEAS-2B was
      studied. RESULTS: Stimulation of A549 cells with TNFalpha, IFNgamma or a
      combination of 50 ng/mL of TNFalpha, IFNgamma and IL-1 (cytomix) did not effect
      eosinophil binding despite an increase in ICAM-1 expression. Similarly
      stimulation of eosinophils with PAF or IL-5 had no effect on eosinophil binding
      to medium- or cytokine-treated A549 cells. In contrast stimulation of BEAS-2B
      cells with cytomix caused a significant increase in eosinophil adhesion. This was
      associated with an increase in expression of ICAM-1 and induced expression of
      VCAM-1. Treatment of eosinophils with Mn2+ and IL-5 but not eotaxin, RANTES or
      PAF also significantly enhanced eosinophil adhesion to medium-treated BEAS-2B
      cells. Using blocking mAbs we were able to demonstrate that the increased
      adhesion resulting from stimulation of eosinophils or BEAS-2B cells was in both
      cases mediated by a combination of CD18 and alpha4 integrins. CONCLUSIONS: This
      study demonstrates a selective role for IL-5 in mediating integrin-dependent
      eosinophil adhesion to airway epithelium and once again emphasizes the importance
      of this cytokine in controlling eosinophil activation in diseases such as asthma.

PMID- 10651779
TI  - The search of latex sensitization in spina bifida: diagnostic approach.
AB  - BACKGROUND: Sensitization to latex has become a major problem in children with
      spina bifida. Life-threatening reactions may occur in these patients, therefore
      the search of latex sensitization must be an active task in all of these
      children. OBJECTIVE: To design an approach for the diagnosis of latex
      sensitization in children with spina bifida. METHODS: We studied 100 consecutive
      unselected patients. Skin prick tests with a commercial latex extract were
      performed, latex-specific serum immunoglobulin (Ig) E was determined by CAP test,
      and risk factors were studied. Originally, patients with an area of latex skin
      test > 50% of the area of histamine and/or CAP class > or = 3 were considered
      sensitized to latex. Diagnostic tests were also performed in a control group of
      51 atopic and nonatopic children. RESULTS: After performing a receiver-operating
      characteristics curve for both tests we recommend skin tests > 25% of the area of
      histamine (sensitivity - SEN = 79%, specificity - SPE = 100%, positive predictive
      value - PPV = 100%, negative predictive value - NPV = 90%), or CAP class > or = 2
      (SEN = 88%, SPE = 100%, PPV = 100%, NPV = 94%) as diagnostic cut-off points. The
      anamnesis had a SEN of 44% for diagnosis, and a SPE of 100%. Latex sensitization
      was associated with more than 5 operations (OR = 8, 95% CI = 3-21.3), a personal
      history of atopy (OR = 11.5, 95% CI = 2.3-57.1), and serum total IgE > or = 2 z
      units (OR = 4, 95% CI = 1. 6-10). CONCLUSION: For the routine evaluation of
      children with spina bifida, we propose a diagnostic algorithm with skin prick
      tests as a first step and CAP second.

PMID- 10651780
TI  - Are anaphylactic reactions to snake bites immunoglobulin E-mediated?
AB  - BACKGROUND: Bites by poisonous European snakes of the genus Vipera lead to local
      tissue damage and systemic symptoms such as generalized oedema, hypotension,
      gastrointestinal symptoms, haemolysis and renal dysfunction. Not rarely
      anaphylactic symptoms like urticaria, localized angioedema and asthma are
      observed. OBJECTIVE: To look for snake venom-specific immunoglobulin (Ig) E
      antibodies in patients with a history of bites by European vipers and for cross
      reactions with Hymenoptera venoms, that have a similar composition. METHOD: Ten
      patients with a history of bites by Vipera aspis or Vipera berus were
      investigated. Three patients had been bitten only once, and two of these had
      developed only local reactions. Four reported previous allergic reactions to
      Hymenoptera stings. All patients, 10 Hymenoptera venom-allergic and five
      nonallergic individuals who served as controls underwent i.c. skin test endpoint
      titration with snake (V. aspis, V. berus) and Hymenoptera venoms (honey bee,
      Vespula spp.) and were investigated for specific serum IgE antibodies to the same
      venoms. RESULTS: Seven of the eight patients with systemic snake bite reactions
      had both positive skin tests and serum IgE antibodies to snake venoms, while
      these tests were negative in the two patients with only local reactions to snake
      bites and all controls. Seven of the eight patients with systemic snake bite
      reaction also had positive skin tests and specific IgE with one or both
      Hymenoptera venoms. By RAST-inhibition with sera of four patients with high IgE
      to both Vipera and Hymenoptera venoms, partial cross-reactivity could be
      demonstrated in one. CONCLUSIONS: Anaphylactic reactions following snake bites
      may be IgE-mediated, especially in patients with repeated bites.

PMID- 10651781
TI  - Allergic sensitization and clinical reactions to latex, food and pollen in adult
      patients.
AB  - BACKGROUND: Many latex-allergic patients are sensitized to one or more foods.
      Patients allergic to tree and/or grass pollens are also often sensitized to plant
      derived foods. Atopy, defined in most studies as sensitivity to an aeroallergen,
      is a risk factor for latex allergy. The relative importance of pollen
      sensitivity, a sign of atopy, as a risk factor for food allergy in latex-allergic
      patients has not, however, been examined. OBJECTIVE: To investigate the
      relationship between pollen sensitivity and sensitivity to food in latex-allergic
      patients. METHODS: Forty-four latex-allergic patients (Groups 1 and 2), 24 of
      whom were also allergic to tree and/or grass pollen (Group 1) and 25 pollinosis
      patients who were not allergic to latex (Group 3) were studied. We obtained a
      history of reactions to food and skin tested them with 12 fresh-frozen fruits.
      RESULTS: All 12 foods induced a skin test reaction in at least one patient in
      each of the three Groups. There were, however, twice as many positive skin test
      reactions to food in patients with pollinosis, whether or not they were allergic
      to latex, as there were in patients allergic to latex but not to pollen. Latex
      allergic patients were most likely to have a positive skin test and a history of
      a reaction to avocado or banana whereas patients with pollinosis only were most
      likely to have a positive skin test and a history of a reaction to apple, peach
      or celery. CONCLUSIONS: These results suggest that concomitant allergy to pollen
      is an important risk factor in determining which plant-derived foods sensitize
      latex-allergic patients.

PMID- 10651782
TI  - Investigation of the anti-allergic activity of azelastine on the immediate and
      late-phase reactions to allergens and histamine using telethermography.
AB  - BACKGROUND: Due to the interest in azelastine's diverse modes of action, this
      study investigated its effects on immediate and late-phase cutaneous allergic
      reactions using visual methods and telethermography. OBJECTIVE: The aim of the
      study was to investigate the effect of azelastine on the immediate and late-phase
      skin reactions using both planimetric evaluation of weal and erythema and a
      telethermographic technique. METHODS: The study was a double-blind crossover
      study; medication consisted of one tablet per day for 7 days of either placebo or
      azelastine 4 mg. Eight allergic patients were assessed on five occasions: prior
      to treatment, at the end of the first 7-day treatment, after a 21-day washout
      period, following the second 7-day treatment period and finally following a 2-6
      week washout period. Skin prick tests with timothy grass and intradermal tests
      with Alternaria allergens were performed on the patients' back. In addition,
      patients were tested with intradermal histamine as a positive control. Surfaces
      of weal, erythema and infiltration were calculated using computerized planimetry
      at 0, 20, 40 and 60 min, and 3, 6 and 8 h. Thermographic images were recorded and
      the thermographic area and the increase in average temperature (DeltaT) were
      calculated. RESULTS: The coefficient of variation within baseline reactions
      ranged from 3 to 32% for weal and erythema and from 5 to 25% for
      thermographically recorded reactions. The stronger the reaction, the more
      constant the baseline was. Treatment with azelastine (4 mg/os once daily)
      inhibited immediate reactions to allergens by 65% (range 55-74) and to histamine
      by 68% (range 47-82). The late-phase reactions to allergens were less well
      defined and showed larger individual differences in the degree of inhibition
      caused by azelastine, they were inhibited by 49% (range 32-67). Late-phase
      reactions to histamine were less intense and could only be detected with
      thermography; only thermographic units showed a decrease (26%) in response to
      azelastine. CONCLUSION: This study has confirmed azelastine's histamine-blocking
      activity. In addition, the late-phase results suggest that azelastine has anti
      inflammatory activity. The reproducibility and sensitivity of the thermographic
      results confirm the usefulness of this technique in immunopharmacology.

PMID- 10651783
TI  - Guidelines for measles vaccination in egg-allergic children.

PMID- 10651784
TI  - Into the 20th volume and the 21st century

PMID- 10651785
TI  - The effect of interferential therapy upon cutaneous blood flow in humans.
AB  - The aim of the current controlled and blinded study was to investigate the effect
      of various interferential current frequencies upon cutaneous blood flow in humans
      using laser Doppler flowmetry, in an attempt to define the physiological
      mechanisms involved. Following approval from the university's ethical committee,
      50 healthy volunteers (25 male, 25 female; age 18-34 years) were randomly
      allocated into one of five experimental groups: (i) control; neither suction nor
      interferential current was applied, (ii) placebo; suction only was applied, (iii)
      IFT 1; 10-100 Hz beat frequency applied, (iv) IFT 2; 80-100 Hz beat frequency
      applied, and (v) IFT 3; 10-20 Hz beat frequency applied. In the IFT groups,
      interferential currents were applied through four suction electrodes positioned
      to target the quadriceps femoris muscle. The following parameters were used in
      all IFT groups: 125 micros pulse duration, 4 kHz carrier frequency and a 6/6
      sweep. In IFT groups 1 and 2 only, the rotating vector system was made active.
      Ambient and skin temperatures were measured concomitantly. Repeated-measures
      ANOVA showed a significant difference between groups (P=0.0361) and over time
      (P=0.0001) for blood flow data; one-factor ANOVA showed a significant increase in
      blood flow in the IFT 3 group (10-20 Hz) when compared to all experimental groups
      at 12 min (P=0.0156). In addition, at 21 min, there were significant differences
      between the IFT 3 group and all other groups except control (P=0.0213).
      Statistical analysis of skin temperature data demonstrated significant
      differences over time (P=0.0001) and a significant interactive effect (P=0.0022),
      with no significant differences observed between groups. These findings provide
      some evidence of a putative vasodilatory effect caused by interferential current
      therapy when applied through suction electrodes at a modulated frequency of 10-20
      Hz.

PMID- 10651786
TI  - Forearm metabolism during infusion of adrenaline: comparison of the dominant and
      non-dominant arm.
AB  - Human skeletal muscle metabolism is often investigated by measurements of
      substrate fluxes across the forearm. To evaluate whether the two forearms give
      the same metabolic information, nine healthy subjects were studied in the fasted
      state and during infusion of adrenaline. Both arms were catheterized in a cubital
      vein in the retrograde direction. A femoral artery was catheterized for blood
      sampling, and a femoral vein for infusion of adrenaline. Forearm blood flow was
      measured by venous occlusion strain-gauge plethysmography. Forearm subcutaneous
      adipose tissue blood flow was measured by the local 133Xe washout method.
      Metabolic fluxes were calculated as the product of forearm blood flow and a-v
      differences of metabolite concentrations. After baseline measurements, adrenaline
      was infused at a rate of 0.3 nmol kg-1 min-1. No difference in the metabolic
      information obtained in the fasting state could be demonstrated. During infusion
      of adrenaline, blood flow and lactate output increased significantly more in the
      non-dominant arm (8.12 +/- 1.24 versus 6.45 +/- 1.19 ml 100 g-1 min-1) and (2.99
      +/- 0.60 versus 1.83 +/- 0.43 micromol 100 g-1 min-1). Adrenaline induced a
      significant increase in oxygen uptake in the non-dominant forearm (baseline
      period: 4.98 +/- 0.72 micromol 100 g-1 min-1; adrenaline period: 6.63 +/- 0.62
      micromol 100 g-1 min-1) while there was no increase in the dominant forearm
      (baseline period: 5.69 +/- 1.03 micromol 100 g-1 min-1; adrenaline period: 4. 94
      +/- 0.84 micromol 100 g-1 min-1). It is concluded that the two forearms do not
      respond equally to adrenaline stimulation. Thus, when comparing results from
      different studies, it is necessary to know which arm was examined.

PMID- 10651787
TI  - Changes in transfer factor of the lung in response to bronchodilatation.
AB  - Measurement of the transfer factor for carbon monoxide (TLCO) is a widely used
      clinical lung function test. Although it is frequently applied in patients with
      bronchial obstruction, there is little information on the effects of
      bronchodilatation on the test. We therefore measured TLCO in 40 patients before
      and after inhalation of terbutaline. TLCO was measured with the single-breath
      technique in 20 patients and with the intra-breath technique in 20 patients. TLCO
      was also measured in 20 healthy subjects with the single-breath technique. Forced
      expiratory volume (FEV1) increased from 2.9 +/- 1. 1 to 3.2 +/- 1.2 l in patients
      with bronchial obstruction in response to terbutaline inhalation. TLCO increased
      from 8.2 +/- 2.6 to 8.6 +/- 2.7 mmol min-1 kPa-1 (P< 0.001) and alveolar volume
      (VA) from 5.74 +/- 1.21 to 5.90 +/- 1.21 l (P<0.001). There was no difference
      between the single-breath and the intra-breath techniques. There was little
      change in FEV1 in the healthy subjects in response to terbutaline. TLCO increased
      from 10.2 +/- 2.1 to 10.5 +/- 2.2 mmol min-1 kPa-1 (P< 0.01), but there was no
      change in VA. The increase in TLCO in patients may partly be explained by
      improved distribution of the inhaled gas. In healthy subjects, terbutaline may
      increase pulmonary capillary volume. We conclude that bronchodilatation results
      in a small increase in TLCO in patients with light to moderate
      bronchoconstriction as well as in healthy subjects. The effect is small and
      should in most cases be simple to account for in the interpretation of pulmonary
      function tests, provided the patient's treatment is known.

PMID- 10651788
TI  - Systolic and diastolic changes in human coronary blood flow during Valsalva
      manoeuvre.
AB  - Valsalva manoeuvre is reported to be sometimes successful for the relief of
      angina pectoris. The present study investigated how haemodynamic changes produced
      by Valsalva manoeuvre can interact to improve the relationship between cardiac
      work and coronary blood flow. Ten male subjects aged 53 +/- 12 years (SD) were
      considered. Blood velocity in the internal mammary artery, previously anastomosed
      to the left descending coronary artery, was studied with Doppler technique. The
      subjects performed Valsalva manoeuvres by expiring into a tube connected to a
      mercury manometer, to develop a pressure of 40 mmHg. The arterial blood pressure
      curve was continuously monitored with a Finapres device from a finger of the left
      hand. During expiratory effort, an increase in heart rate and a decrease in
      arterial pulse pressure were followed by a more delayed and progressive increase
      in mean and diastolic pressures. Systolic blood velocity markedly decreased along
      with the reduction in pulse pressure and increase in heart rate. By contrast,
      diastolic and mean coronary blood velocities did not show any significant change.
      Since it is known that the Valsalva manoeuvre strongly reduces stroke volume and
      cardiac output, it is likely that a reduction in cardiac work also takes place.
      Since in diastole, i.e. when the myocardial wall is better perfused, coronary
      blood velocity did not show any significant reduction, it is likely that
      unchanged perfusion in the presence of reduced cardiac work is responsible for
      the relief from angina sometimes observed during Valsalva manoeuvre. It is also
      likely that the increase in heart rate prevents the diastolic and mean blood
      coronary velocity from decreasing during the expiratory strain, when an increased
      sympathetic discharge could cause vasoconstriction through the stimulation of the
      coronary alpha-receptors.

PMID- 10651789
TI  - Reliability of position sense testing assessed with a fully automated system.
AB  - Position sense testing has increased as a tool for augmenting evaluation of joint
      injury. In the present study, we investigated the inter-day reliability for four
      different types of position sense tests using a fully automated system. The tests
      included (1) passive presentation/active replication, (2) passive
      presentation/passive replication, (3) semi-passive presentation/semi-passive
      replication (where semi-passive denotes passive movement during antagonist muscle
      contraction), and (4) active presentation/active replication. The absolute
      difference between presented target and replicated position was used as a measure
      of position sense accuracy. Ten healthy subjects who were blindfolded and seated
      with the arm in a moveable rig performed the tests on two occasions, separated by
      3-4 days. For each type of position sense test, horizontal abduction from a
      starting position of 0 degrees (relative to the sagittal plane) to target
      positions of 32 degrees and 64 degrees, and horizontal adduction from a starting
      position of 80 degrees to 48 degrees and 16 degrees were conducted. A two-way
      ANOVA revealed no differences in absolute error between days or between testing
      procedures. However, intra-class correlations (ICC), which are most often used to
      express test-retest reliability, were moderate at best, ranging from 0.40 to 0.61
      for the four types of position sense tests. Hence, the present study indicates
      that the ability of repositioning tests to detect alterations in proprioceptive
      function is limited, suggesting that their use in clinical evaluation be
      approached with prudence.

PMID- 10651790
TI  - The relation between mitral annulus motion and ejection fraction changes with age
      and heart size.
AB  - Mitral annulus motion (MAM) has recently been introduced as an index of left
      ventricular function. Several echocardiographic studies have shown good agreement
      between ejection fraction (EF) and MAM x 5, where MAM is the total mitral annulus
      motion, measured in mm, and EF is expressed as a percentage. This means that if
      MAM is used for estimation of left ventricular function, the conversion factor 5
      is used, if the function is expressed as EF. In these studies, the mean age of
      the patients was over 60 years. The present study, including 102 patients, shows
      that in patients aged 20-40 years, the conversion factor is about 4.3, in
      patients aged 41-60 years it is about 4.6 and in patients aged 61-80 years it is
      about 5.0. It was also found that the ratio EF/MAM decreases with increasing
      height and left ventricular diameter, both variables closely connected to heart
      size. The results suggest that when MAM is used in assessment of left ventricular
      function, it is unwise to express the function in terms of EF. It is preferable
      to use MAM as a direct index of ventricular function, using reference values
      referred to aged and height. If the estimated function is expressed in terms of
      EF, different converting factors must be used depending on the age of the
      patients.

PMID- 10651791
TI  - The relation between mitral annulus motion and left ventricular ejection fraction
      in atrial fibrillation.
AB  - Mitral annulus motion (MAM) has recently been introduced as an index of left
      ventricular function. Previous studies have shown a good agreement between MAM
      (mm) x 5 and ejection fraction in middle-aged and elderly patients. These studies
      only included patients with sinus rhythm, while patients with atrial fibrillation
      were excluded. In the present study, MAM was reduced in patients with atrial
      fibrillation while ejection fraction (EF) did not differ from age-matched control
      patients with sinus rhythm. The 'conversion factor' (EF/MAM) was 7.2 in the group
      with atrial fibrillation and 5. 1 in controls with sinus rhythm. This difference
      must be taken into account when MAM is used to estimate left ventricular function
      in patients with atrial fibrillation. Patients with atrial fibrillation had lower
      stroke volume and higher heart rate than patients with sinus rhythm. A decreased
      systolic long-axis shortening was found (P<0.005) compared to patients with sinus
      rhythm, but no difference in short-axis diameter shortening.

PMID- 10651792
TI  - Upright body position and weight loss improve respiratory mechanics and daytime
      oxygenation in obese patients with obstructive sleep apnoea.
AB  - To determine whether upright body position and weight loss would improve daytime
      gas exchange in moderately obese patients with obstructive sleep apnoea (OSAS),
      13 patients with mild or moderate OSAS were studied before and after weight loss.
      Pulmonary function tests, arterial blood gases and respiratory gas analysis were
      measured prior to and after a very low calorie diet (VLCD) period of six weeks.
      Arterial blood gases were measured in supine and standing positions and closing
      volume in supine and sitting positions before and after weight loss. In the
      upright position, there was a significant increase in PaO2 (P<0.005) accompanied
      by a significant decrease in alveolar-arterial PO2 difference (P<0.005) and
      closing volume (P<0.05). The median weight loss was 11 kg (range 5-18). The
      number of desaturation episodes (four percentage units or more per hour during
      sleep) (ODI4) decreased (P<0.01) after weight loss. The change in PaO2 with
      weight loss correlated with the decrease in ODI4 (r=0.73, P<0.01). The increase
      in expiratory reserve volume (ERV) was closely related to the amount of weight
      lost (r=0.895, P<0.01). The results indicate that weight loss and upright body
      position improved daytime respiratory mechanics and gas exchange in obese
      patients with OSAS. The findings suggest that obesity plays an important role in
      the pathogenesis of daytime gas exchange disturbances in obese OSAS patients. The
      adoption of a more upright sleep posture might improve nocturnal oxygenation in
      obese patients with OSAS.

PMID- 10651793
TI  - Volumetric measurements of peripheral oedema in clinical conditions.
AB  - Water-displacement volumetry can be used for quantifying the volume of the leg.
      However, not much is known about its application in patients with peripheral
      oedema of cardiopulmonary origin. We measured the reproducibility of a water
      displacement apparatus with a solid object and in ten non-oedematous clinical
      patients (group A). The day-to-day variability of the leg volume was assessed in
      the same group. The diurnal variability was assessed in ten patients with
      persisting peripheral oedema (group B). The effect of treatment on the severity
      of peripheral oedema was evaluated in another nine patients with peripheral
      oedema, who were in need of diuretic treatment (group C). Volumetric results were
      compared to the ankle circumference method and the body weight method. The
      coefficient of variation was 0.16% in the fixed object and 0.47% in group A. The
      day-to-day variability was 1.52% after 1 day and 1.76% after a mean interval of
      4.8 days. In group B, leg volume and circumference increased during the day
      (5.9%, P<0.001, and 2.4%, P<0.01, respectively), while body weight remained
      unchanged. In group C, leg volume, circumference and body weight decreased
      significantly after treatment (13.1%, P<0.01, 7.1%, P<0.05, and 5.9%, P<0.05).
      The correlation between the changes in volume and body weight was poor (r=0.37,
      P=0.33). In conclusion, (1) water-displacement volumetry is highly reproducible,
      (2) a diurnal variability of peripheral oedema was found, and (3) volumetry is a
      suitable tool for monitoring peripheral oedema, while the body weight method
      appears to be less accurate.

PMID- 10651794
TI  - Evaluation of the interrupter technique in measuring post-exercise bronchodilator
      responses in children.
AB  - A significant response in a bronchodilation test is one of the main diagnostic
      criteria of asthma. However, it is not known what the significant bronchodilator
      response (BDR) is by the interrupter technique (IR), measuring respiratory
      resistance (Rint) during tidal breathing. Fifty children with symptoms suggestive
      for asthma underwent an 8 min free running test outdoors. Flow-volume spirometry
      (FVS) and IR measurements were performed before and 10 min after running.
      Thereafter, all children received a salbutamol inhalation, and pulmonary function
      measurements were repeated 15 min later. The study population was classified into
      three groups according to the post-exercise pulmonary function: FEV1 > 100% of
      predicted (group I, n=15), FEV1 86-99% of predicted (group II, n=20) and FEV1 <
      85% of predicted (group III, n=15). There were no differences in BDRs between
      groups I and II; the mean increases in FEV1 were 4-6% and in MMEF 20-23%, and the
      mean decreases in Rint were 23-26%. The mean changes in group III were
      significantly higher: 15% (P=0.004) in FEV1, 55% (P=0.021) in MMEF and 38% (P=0.
      014) in Rint. BDR was positive (FEV1 rise >10%) in 15 children; five were in
      group II and 10 in group III. For MMEF and Rint, the best combination of
      sensitivity and specificity was achieved by a limit of 35%. By this limit, MMEF
      identified 14 and Rint 17 positive cases. The IR technique agreed with both FEV1
      and MMEF in 73% of the cases. The IR technique provides an alternative to
      conventional ventilatory function measurements in bronchodilation tests in
      children. We suggest a decrease of 35% or more in Rint as diagnostic in post
      exercise bronchodilation tests.

PMID- 10651796
TI  - Beat-to-beat QRS amplitude variability in elite endurance athletes.
AB  - Results from variance electrocardiography, displaying the wide-band, phase-locked
      electrical micro-variability during the depolarization phase, was analysed versus
      clinical data, echocardiographic structural and functional variables and
      myocardial scintigraphic findings in 174 elite orienteers compared with 37 age
      matched elite endurance athletes and 50 age-matched, healthy medical students.
      PCA analysis identified a subgroup of five orienteers deviating from the rest of
      the study group and both control groups with regard to their QRS amplitude
      variability. No correlations were found between pathology by medical history or
      any of the echocardiographic and scintigraphic variables or by the variance
      electrocardiographic aberrations in any of the groups studied.

PMID- 10651795
TI  - Electrocardiographic ST-segment depression in children with fontan circulation.
AB  - Despite successful operation, many patients palliated with a Fontan-type
      procedure continue to show effort limitation. We previously observed that these
      children showed electrocardiographic ST depression during exercise tests. The
      purpose of the study was to investigate whether electrocardiographic ST
      depression is a common finding in children with Fontan circulation. Forty-two
      children in two groups were examined: group A consisted of 14 patients who had
      all undergone a modified Fontan procedure, and group B consisted of 28 children
      with a structurally normal heart, matched for length, weight and gender to group
      A. Complete echocardiographic examinations were performed in all patients and
      controls. All 14 patients and all 28 healthy children underwent standard 24 h
      ambulatory electrocardiographic monitoring. All the recordings were analysed by a
      PC-based Holter system where an analysis of ST changes was performed. Seven
      patients and 14 matched healthy children were exercised on bicycle ergometers.
      Four patients and eight matched healthy children underwent exercise testing by
      walking/running a treadmill. Ten of 13 patients analysed had significant ST
      depressions on ambulatory electrocardiogram (>0.20 mV). Three of the 10 patients
      with ST depression were on digoxin. Three patients showed depressions of the ST
      segment in the electrocardiogram during exercise, with a maximal depression of
      0.20-0.35 mV. None of the 28 matched healthy children showed electrocardiographic
      ST depression on the ambulatory 24 h ECG. These findings indicate that ST
      depression in daily activity is a common finding in children with Fontan
      circulation.

PMID- 10651797
TI  - Production of recombinant human beta2-microglobulin for scintigraphic diagnosis
      of amyloidosis in uremia and hemodialysis.
AB  - Amyloid of beta2-microglobulin (beta2m) origin can be diagnosed using 131I
      radiolabelled-beta2m scintigraphy in patients with uremia and hemodialysis
      treatment. As the tracer beta2m is isolated from another patient, it carries the
      common risks, including viral infections such as Hepatitis B, C and HIV, which
      are associated with human plasma products. In order to exclude these risks we
      have produced recombinant human beta2m (rhbeta2m) in Escherichia coli. The
      expression vector pASK40DeltaLbeta2m(His)5 contains a C-terminal (His)5-tag for
      purification via immobilized metal ion affinity chromatography (IMAC). Size
      exclusion chromatography on a Superose 12 column represents the second step of
      purification. The isolated rhbeta2mH5 reacted in an immunochemically identical
      manner to native human beta2m, and showed a single band of approximately 11.8 kDa
      in Western blot analysis and revealed a single spot in two-dimensional gel
      electrophoresis. Mass spectrometry analysis revealed a single peak at the
      expected molecular mass of 12 415.8 Da. Uniformity was further proven by
      crystallization and N-terminal amino-acid sequence analysis. The rhbeta2mH5
      protein was then produced under conditions that allow the intravenous use in
      humans. Intraveneously applied indium-111-labelled rhbeta2mH5 was monitored in
      hemodialysed patients with and without known beta2m-amyloidosis. The tracer was
      localized specifically to particular areas known to contain amyloid. Thus, this
      rhbeta2mH5 preparation is suitable for detecting amyloid-containing organs of the
      beta2m-class in vivo and fulfils the requirements of a tracer for common use.
      Finally, the use of indium-111 instead of iodine-131 has reduced the radioactive
      load and resulted in higher resolution.

PMID- 10651798
TI  - Mouse brain and muscle tissues constitutively express high levels of Homer
      proteins.
AB  - In order to characterize expression of Homers in mouse brain and peripheral
      tissues we have developed a coupled reverse transcription (RT)-PCR/restriction
      digestion approach. This has allowed us to determine the molecular composition
      and relative levels of the constitutive expression of the Homer-1, -2 and -3
      mRNAs across mouse tissues. We report here that mammalian brain constitutively
      expresses high levels of the Homer-1, -2 and -3 mRNAs. Expression of the Homer-1
      mRNAs reaches 66% of the brain total Homer mRNAs expression, followed by Homer-3
      mRNA (22%) and Homer-2 mRNAs (12%). Quantitative RT-PCR analysis and the Western
      blotting using pan-Homer antibody revealed that mouse heart, skeletal muscle and
      diaphragm constitutively express high levels of the Homer proteins and their
      mRNAs. We have shown that the molecular profile of expression of Homer-1, -2 and 
      3 mRNAs in muscle containing tissues resembles that obtained for mammalian brain.

PMID- 10651799
TI  - Formation of sarcoglycan complex with differentiation in cultured myocytes.
AB  - The sarcoglycan complex consists of four transmembrane protein subunits. Mutation
      of any one of the genes encoding these four subunits causes complete loss or
      marked decrease in expression of the whole complex, resulting in the phenotype of
      Duchenne-like autosomal recessive muscular dystrophy, termed sarcoglycanopathy.
      As the basis for understanding this process, we examined how the sarcoglycan
      complex is formed and associates with other proteins during myogenic
      differentiation, using a myogenic cell line. Accumulation of the sarcoglycan
      subunits and formation of the sarcoglycan complex were accomplished with myotube
      formation. In protein transport inhibition experiments with blefeldin A, we found
      that the sarcoglycan complex is formed in the endoplasmic reticulum and then
      associates with the dystroglycan complex and sarcospan en route from the Golgi
      apparatus to the cell surface. In early myotubes, limited kinds of incomplete
      sarcoglycan complexes were observed. Their analyses would provide information on
      the possible patterns of formation of the sarcoglycan complex.

PMID- 10651800
TI  - The relative importance of passive and P-glycoprotein mediated anthracycline
      efflux from multidrug-resistant cells.
AB  - For the four anthracyclines idarubicin, daunorubicin, epirubicin and doxorubicin
      the passive and active efflux rates in intact multidrug resistant cells were
      compared. Although highly similar structurally, these anti-tumor agents differ in
      lipophilicity and membrane permeability (k). The method we used was based on the
      continuous measurement of the cellular efflux and determination of the ratio
      (RVp) of transport rates just before and just after inhibition of the active
      transport with verapamil (Vp). Hence, RVp - 1 should reflect the active transport
      rate relative to the passive transport rate. If cells were single, well-stirred
      compartments, RVp - 1 should equal Vmax/(k.Km), where Vmax is the maximal pumping
      rate and Km is the Michaelis constant. However, using the plasma membrane
      permeabilizing agent digitonin, we found an effective intracellular anthracycline
      store. Particularly, when the efflux was fast, e.g. with idarubicin or in
      intensively pumping cells, the intracellular transport began to control the
      cellular efflux. Under these conditions, k underestimated the true plasma
      membrane permeability (k0) and RVp - 1 underestimated Vmax/(k.Km). Based on the
      effects of digitonin on the efflux rates in pumping and nonpumping cells, we
      developed an index (RVp,corrected - 1) which should equal Vmax/(k0. Km). The term
      Vmax/(k0.Km) varied substantially between the drugs. It appears that differences
      in lipophilicity between the drugs do not affect passive efflux and pumping
      equally. This demonstrates that passive permeation plays a substantial and
      independent role in determining the drug resistance for these anthracyclines. The
      methods developed here enable dissection of this role from that of drug pumping
      and intracellular subcompartmentation.

PMID- 10651801
TI  - The three transglycosylation reactions catalyzed by cyclodextrin
      glycosyltransferase from Bacillus circulans (strain 251) proceed via different
      kinetic mechanisms.
AB  - Cyclodextrin glycosyltransferase (CGTase) catalyzes three transglycosylation
      reactions via a double displacement mechanism involving a covalent enzyme
      intermediate complex (substituted-enzyme intermediate). Characterization of the
      three transglycosylation reactions, however, revealed that they differ in their
      kinetic mechanisms. Disproportionation (cleavage of an alpha-glycosidic bond of a
      linear malto-oligosaccharide and transfer of one part to an acceptor substrate)
      proceeds according to a ping-pong mechanism. Cyclization (cleavage of an alpha
      glycosidic bond in amylose or starch and subsequent formation of a cyclodextrin)
      is a single-substrate reaction with an affinity for the high molecular mass
      substrate used, which was too high to allow elucidation of the kinetic mechanism.
      Michaelis-Menten kinetics, however, have been observed using shorter amylose
      chains. Coupling (cleavage of an alpha-glycosidic bond in a cyclodextrin ring and
      transfer of the resulting linear malto-oligosaccharide to an acceptor substrate)
      proceeds according to a random ternary complex mechanism. In view of the
      different kinetic mechanisms observed for the various reactions, which can be
      related to differences in substrate binding, it should be possible to mutagenize
      CGTase in such a manner that a single reaction is affected most strongly.
      Construction of CGTase mutants that synthesize linear oligosaccharides instead of
      cyclodextrins thus appears feasible. Furthermore, the rate of interconversion of
      linear and circular conformations of oligosaccharides in the cyclization and
      coupling reactions was found to determine the reaction rate. In the cyclization
      reaction this conversion rate, together with initial binding of the high
      molecular mass substrate, may determine the product specificity of the enzyme.
      These new insights will allow rational design of CGTase mutant enzymes
      synthesizing cyclodextrins of specific sizes.

PMID- 10651802
TI  - The hybrid-cluster protein ('prismane protein') from Escherichia coli.
      Characterization of the hybrid-cluster protein, redox properties of the [2Fe-2S]
      and [4Fe-2S-2O] clusters and identification of an associated NADH oxidoreductase
      containing FAD and [2Fe-2S].
AB  - Hybrid-cluster proteins ('prismane proteins') have previously been isolated and
      characterized from strictly anaerobic sulfate-reducing bacteria. These proteins
      contain two types of Fe/S clusters unique in biological systems: a [4Fe-4S]
      cubane cluster with spin-admixed S = 3/2 ground-state paramagnetism and a novel
      type of hybrid [4Fe-2S-2O] cluster, which can attain four redox states. Genomic
      sequencing reveals that genes encoding putative hybrid-cluster proteins are
      present in a range of bacterial and archaeal species. In this paper we describe
      the isolation and spectroscopic characterization of the hybrid-cluster protein
      from Escherichia coli. EPR spectroscopy shows the presence of a hybrid cluster in
      the E. coli protein with characteristics similar to those in the proteins of
      anaerobic sulfate reducers. EPR spectra of the reduced E. coli hybrid-cluster
      protein, however, give evidence for the presence of a [2Fe-2S] cluster instead of
      a [4Fe-4S] cluster. The hcp gene encoding the hybrid-cluster protein in E. coli
      and other facultative anaerobes occurs, in contrast with hcp genes in obligate
      anaerobic bacteria and archaea, in a small operon with a gene encoding a putative
      NADH oxidoreductase. This NADH oxidoreductase was also isolated and shown to
      contain FAD and a [2Fe-2S] cluster as cofactors. It catalysed the reduction of
      the hybrid-cluster protein with NADH as an electron donor. Midpoint potentials
      (25 degrees C, pH 7.5) for the Fe/S clusters in both proteins indicate that
      electrons derived from the oxidation of NADH (Em NADH/NAD+ couple: -320 mV) are
      transferred along the [2Fe-2S] cluster of the NADH oxidoreductase (Em = -220 mV)
      and the [2Fe-2S] cluster of the hybrid-cluster protein (Em = -35 mV) to the
      hybrid cluster (Em = -50, +85 and +365 mV for the three redox transitions). The
      physiological function of the hybrid-cluster protein has not yet been elucidated.
      The protein is only detected in the facultative anaerobes E. coli and Morganella
      morganii after cultivation under anaerobic conditions in the presence of nitrate
      or nitrite, suggesting a role in nitrate-and/or nitrite respiration.

PMID- 10651803
TI  - Viresin. A novel antibacterial protein from immune hemolymph of Heliothis
      virescens pupae.
AB  - Immune hemolymph was collected from fifth instar larvae and 1-day-old pupae of
      Heliothis virescens after injection of prepupae with live Enterobacter cloacae.
      Induction of antibacterial activity against Escherichia coli K12 D31 was 7.5
      times greater in pupal than in larval immune hemolymph. Lysozyme activity of
      immune pupal hemolymph against Micrococcus lysodeikticus was 11 times greater
      when compared with lysozyme activity of immune larval hemolymph. Early pupal
      immune response with regard to antibacterial activity was much greater than
      larval immune response in H. virescens. Normal pupal hemolymph showed an increase
      in antibacterial activity and lysozyme that was induced during metamorphosis.
      Antibacterial protein was isolated together with lysozyme by gel filtration
      chromatography and then separated from lysozyme by sequential electrophoresis
      with a native acid gel and SDS gel. Molecular mass of antibacterial protein was
      estimated to be 12 kDa. The N-terminal amino acid sequence of 12-kDa protein was
      different from those of antibacterial molecules found in other insects and has
      not been identified before. A sample containing 12-kDa protein was negative for
      immunoblotting with anti-synthetic cecropin B antibody. We have named the novel
      12-kDa antibacterial protein viresin. Viresin showed antibacterial activity
      against several Gram-negative bacteria including E. cloacae but not against Gram
      positive bacteria.

PMID- 10651804
TI  - Energy metabolism and lipid peroxidation of human erythrocytes as a function of
      increased oxidative stress.
AB  - To study the influence of oxidative stress on energy metabolism and lipid
      peroxidation in erythrocytes, cells were incubated with increasing concentrations
      (0.5-10 mM) of hydrogen peroxide for 1 h at 37 degrees C and the main substances
      of energy metabolism (ATP, AMP, GTP and IMP) and one index of lipid peroxidation
      (malondialdehyde) were determined by HPLC on cell extracts. Using the same
      incubation conditions, the activity of AMP-deaminase was also determined. Under
      nonhaemolysing conditions (at up to 4 mM H2O2), oxidative stress produced,
      starting from 1 mM H2O2, progressive ATP depletion and a net decrease in the
      intracellular sum of adenine nucleotides (ATP + ADP + AMP), which were not
      paralleled by AMP formation. Concomitantly, the IMP level increased by up to 20
      fold with respect to the value determined in control erythrocytes, when cells
      were challenged with the highest nonhaemolysing H2O2 concentration (4 mM). Efflux
      of inosine, hypoxanthine, xanthine and uric acid towards the extracellular medium
      was observed. The metabolic imbalance of erythrocytes following oxidative stress
      was due to a dramatic and unexpected activation of AMP-deaminase (a twofold
      increase of activity with respect to controls) that was already evident at the
      lowest dose of H2O2 used; this enzymatic activity increased with increasing H2O2
      in the medium, and reached its maximum at 4 mM H2O2-treated erythrocytes (10-fold
      higher activity than controls). Generation of malondialdehyde was strictly
      related to the dose of H2O2, being detectable at the lowest H2O2 concentration
      and increasing without appreciable haemolysis up to 4 mM H2O2. Besides
      demonstrating a close relationship between lipid peroxidation and haemolysis,
      these data suggest that glycolytic enzymes are moderately affected by oxygen
      radical action and strongly indicate, in the change of AMP-deaminase activity, a
      highly sensitive enzymatic site responsible for a profound modification of
      erythrocyte energy metabolism during oxidative stress.

PMID- 10651805
TI  - Characterization of a human alternatively spliced truncated reduced folate
      carrier increasing folate accumulation in parental leukemia cells.
AB  - Human CEM-7A cells established by gradual deprivation of leucovorin from the
      growth medium, display 100-fold overexpression of methotrexate transport
      activity. We found that this was associated with 10-fold reduced folate carrier
      gene amplification and 50-fold overexpression of both the principal 3 kb reduced
      folate carrier transcript and, surprisingly, a novel truncated 2 kb reduced
      folate carrier mRNA poorly expressed in parental CEM cells. The molecular basis
      for the generation of this truncated reduced folate carrier transcript and its
      potential functional role in folate accumulation were studied. Reduced folate
      carrier genomic and cDNA sequencing revealed that the truncated transcript had an
      internal deletion of 987 nucleotides which was a result of an alternative
      splicing utilizing a cryptic acceptor splice site within exon 6. This deletion
      consisted of the 3'-most 480 nucleotides of the reduced folate carrier ORF and
      the following 507 nucleotides of the 3'-UTR. These resulted in a truncated
      reduced folate carrier protein, which lacks the C-terminal 160 amino acids, but
      instead contains 58 new C-terminal amino acids obtained from reading through the
      3'-UTR. Consequently, a truncated reduced folate carrier protein is generated
      that lacks the 12th transmembrane domain and contains a new and much shorter C
      terminus predicted to reside at the extracellular face. Western analysis with
      plasma-membrane fraction from CEM-7A cells revealed marked overexpression of both
      a broadly migrating approximately 65-90 kDa native reduced folate carrier and a
      approximately 40-45 kDa truncated reduced folate carrier, the core molecular
      masses of which were confirmed by in vitro translation. However, unlike the
      native reduced folate carrier, the truncated reduced folate carrier protein
      failed to bind the affinity labels NHS-[3H]MTX and NHS-[3H]folic acid. Stable
      transfection of the truncated reduced folate carrier cDNA into mouse L1210
      leukemia cells: increased folate accumulation, decreased their leucovorin and
      folic acid growth requirements, and increased their sensitivity to methotrexate.
      This constitutes the first documentation of an expressed alternatively spliced
      truncated reduced folate carrier that, when coexpressed along with the native
      carrier, augments folate accumulation and consequently decreases the cellular
      folate growth requirement. The possible mechanisms by which the truncated reduced
      folate carrier may increase folate accumulation and/or metabolism in cells
      coexpressing the truncated and native reduced folate carrier are discussed.

PMID- 10651806
TI  - An immunoreceptor tyrosine-based inhibitory motif, with serine at site Y-2, binds
      SH2-domain-containing phosphatases.
AB  - Clustering of the mast cell function-associated antigen by its specific
      monoclonal antibody (G63) inhibits the FcepsilonRI-mediated secretory response.
      The cytosolic tail of the mast cell function-associated antigen contains a SIYSTL
      stretch, a potential immunoreceptor tyrosine-based inhibition motif. To
      investigate the possible functional role of this sequence, as well as identify
      potential intracellular proteins that interact with it, peptides corresponding to
      residues 4-12 of the mast cell function-associated antigen's N-terminal
      cytoplasmic domain, containing the above motif, were synthesized and used in
      affinity chromatography of mast cell lysates. Both tyrosyl phosphorylated and
      thiophosphorylated mast cell function-associated antigen peptides bound the src
      homology domain 2 (SH2)-containing tyrosine phosphatases-1 (SHP-1), -2 (SHP-2)
      and inositol 5'-phosphatase (SHIP), though with different efficiencies. Neither
      the nonphosphorylated peptide nor its tyrosyl phosphorylated reversed sequence
      peptide bound any of these phosphatases. Point mutation analysis of mast cell
      function-associated antigen pITIM binding requirements demonstrated that for SHP
      2 association the amino acid residue at position Y-2 is not restricted to the
      hydrophobic isoleucine or valine. Glycine and other amino acids with hydrophilic
      residues, such as serine and threonine, at this position also maintain this
      binding capacity, whereas alanine and acidic residues abolish it. In contrast,
      SHP-1 binding was maintained only when serine was substituted by valine,
      suggesting that the Y-2 position provides selectivity for peptide binding to SH2
      domains of SHP-1 and SHP-2. These results were corroborated by surface plasmon
      resonance measurements of the interaction between tyrosyl phosphorylated mast
      cell function-associated antigen peptide and recombinant soluble SH2 domains of
      SHP-1, SHP-2 and SHIP, suggesting that the associations observed in the cell
      lysates may be direct. Taken together these results clearly indicate that the
      SIYSTL motif present in mast cell function-associated antigen's cytosolic tail
      exhibits characteristic features of an immunoreceptor tyrosine-based inhibition
      motif, suggesting it is a new member of the growing diverse family of
      immunoreceptor tyrosine-based inhibition motif-containing receptors.

PMID- 10651807
TI  - Purification and some properties of serine hydroxymethyltransferase from
      Trypanosoma cruzi.
AB  - A single form of serine hydroxymethyltransferase (SHMT) was detected in
      epimastigotes of Trypanosoma cruzi, in contrast to the three isoforms of the
      enzyme characterized from another trypanosomatid, Crithidia fasciculata
      [Capelluto D.G.S., Hellman U., Cazzulo J.J. & Cannata J.J.B. (1999) Mol. Biochem.
      Parasitol. 98, 187-201]. The T. cruzi SHMT was found to be highly unstable in
      crude extracts. In the presence of the cysteine proteinase inhibitors N-alpha-p
      tosyl-L-lysine chloromethyl ketone and Ltrans-3-carboxyoxiran-2-carbonyl-L
      leucylagmatine, however, the enzyme could be purified to homogeneity. Digitonin
      treatment of intact cells suggested that the enzyme is cytosolic. T. cruzi SHMT
      presents a monomeric structure shown by the apparent molecular masses of 69 kDa
      (native) and 55 kDa (subunit) determined by Sephadex G-200 gel filtration and
      SDS/PAGE, respectively. This is in contrast to the tetrameric SHMTs described in
      C. fasciculata and other eukaryotes. The enzyme was pyridoxal phosphate-dependent
      after L-cysteine and hydroxylamine treatments and it was strongly inhibited by
      the substrate analog folate, which was competitive towards tetrahydrofolate and
      noncompetitive towards L-serine. Partial sequencing of tryptic internal peptides
      of the enzyme indicate considerable similarity with other SHMTs, particularly
      from those of plant origin.

PMID- 10651808
TI  - Ethanol increases superoxide anion production stimulated with 4beta-phorbol 12
      myristate 13-acetate in human polymorphonuclear leukocytes. Involvement of
      protein kinase C.
AB  - Stimulation of human polymorphonuclear leukocytes (PMNs) with PMA initiates a
      cascade of events leading to the production and release of superoxide anion (O
      2), a major component in anti-bacterial defense. Generation of O-2 by PMA
      stimulated PMNs occurs through the translocation and activation of protein kinase
      C (PKC). In this study, using freshly isolated PMNs, we examined the effect of
      ethanol on this response to PMA. Our results show that the basal production of O
      2 was not affected by ethanol. In contrast, the response induced by PMA was
      potentiated by ethanol. This potentiation was observed even at high doses of PMA
      (200 nM) which alone had stimulated the O-2 response maximally. This enhanced
      response was not due to an increase of PMA uptake by PMNs. The maximal effect was
      obtained when the cells were preincubated with 80 mM of ethanol before PMA
      stimulation. Measurement of PKC activity in the cytosolic and membrane fractions
      showed that pretreatment of PMNs with ethanol increased twofold the PMA
      stimulated PKC activity in the membrane fraction. Furthermore, Western blot
      analysis verified that this increase in PKC activity in the membrane fraction was
      linked to an increase in the translocation of PKC-alpha and -beta isoforms to the
      membrane. These results suggest that ethanol potentiates PMA-induced O-2
      production through increasing PKC translocation and activity in PMNs.

PMID- 10651809
TI  - Spectroscopic characterization of the conformational adaptability of Bombyx mori
      apolipophorin III.
AB  - Apolipophorin III (apoLp-III) from the silkmoth, Bombyx mori, has been over
      expressed in Escherichia coli, purified and characterized. Far-UV CD
      spectroscopic analysis revealed 65% alpha-helix secondary structure. Near-UV CD
      spectra obtained in buffer or complexed with dimyristoylglycerophosphocholine
      (DMPC), provided evidence that apoLp-III alpha-helices reorient upon interaction
      with lipid, indicative of a protein conformational change. In guanidine
      hydrochloride (GdnHCl) denaturation studies, a transition midpoint of 0.33 M was
      observed, corresponding to a DeltaGDH2O = 2.46 kcal. mol-1. Fluorescence studies
      of the sole tryptophan residue (Trp40) in apoLp-III revealed an emission
      lambdamax = 327 nm. Compared to free tryptophan, Stern-Volmer constants (KSV) for
      acrylamide and KI quenching of Trp40 fluorescence were decreased by 20-fold and
      sevenfold, respectively. In studies of apoLp-III-DMPC disc complexes, far-UV CD
      spectroscopy revealed an increase in alpha-helix content to approximately 85% and
      a ninefold increase in the GdnHCl-induced denaturation transition midpoint to 3
      M. In studies of lipid interaction, apoLp-III was shown to disrupt both
      negatively charged and zwitterionic phospholipid bilayer vesicles, transforming
      them into discoidal complexes. Characterization of apoLp-III-DMPC discs, using 5
      doxyl or 12-doxyl stearic acid as lipid-based quenching agents, revealed that
      Trp40 localizes near the phospholipid polar head groups. KSV values for
      acrylamide and KI quenching of intrinsic fluorescence of apoLp-III-DMPC discs
      indicate that Trp40 is embedded in the lipid milieu, with little or no
      accessibility to the aqueous quenchers. Given the large amount of alpha-helix in
      apoLp-III, the data presented support a model in which amphipathic alpha-helical
      segments are stabilized by helix-helix interactions and lipid association induces
      a protein conformational change which results in substitution of helix-helix
      interactions for helix-lipid contacts.

PMID- 10651810
TI  - Molecular cloning and characterization of calreticulin, a calcium-binding protein
      involved in the regeneration of rice cultured suspension cells.
AB  - A full-length cDNA clone encoding a phosphoprotein (pp56) involved in the
      regeneration of rice (Oryza sativa L.)-cultured suspension cells was isolated by
      screening a rice cultured suspension cell cDNA library. The 1558-bp cDNA sequence
      contains an ORF encoding an acidic (pI 4.38) protein of 424 amino acids (47.9
      kDa), sharing 70-93% and 50-53% homology with other plant and mammalian
      calreticulins, respectively. Sequence analysis of the cDNA clone revealed several
      significant conserved motifs, including a calreticulin family repeat motif in the
      central domain and two calreticulin family motifs in the N-domain, indicating
      that this gene is a rice calreticulin (CRO1). The CRO1 gene in long-term rice
      cultured suspension cells shows constitutive expression in both suspension
      culture and regeneration media. In contrast, expression of the CRO1 gene in short
      term rice cultured suspension cells, which possess regeneration potential, is
      increased dramatically when these cells are transferred to the regeneration
      medium. After approximately 2 weeks in the regeneration medium, the expression of
      the CRO1 gene reverts to constitutive levels. These results demonstrate the
      presence of calreticulin in rice cultured suspension cells and its developmental
      regulation during the regeneration of rice cultured suspension cells.

PMID- 10651811
TI  - The membrane-bound DnaJ protein located at the cytosolic site of glyoxysomes
      specifically binds the cytosolic isoform 1 of Hsp70 but not other Hsp70 species.
AB  - DnaJ proteins are located in various compartments of the eukaryotic cell. As
      previously shown, peroxisomes and glyoxysomes possess a membrane-anchored form of
      DnaJ protein located on the cytosolic face. Hints as to how the membrane-bound co
      chaperone interacts with cytosolic soluble chaperones were obtained by examining
      the affinity between the DnaJ protein and various potential partners of the Hsp70
      family. Two genes encoding cytosolic Hsp70 isoforms were isolated and
      characterized from cucumber cotyledons. In addition, cDNAs encoding Hsp70 forms
      attributed to the cytosol, plastids and the lumen of the endoplasmic reticulum
      were prepared. His-tagged DnaJ proteins and glutathione S-transferase-Hsp70
      fusion proteins were constructed. Using these tools, it was demonstrated that the
      soluble His-tagged form of DnaJ protein exclusively binds the cytosolic isoform 1
      of Hsp70. This interaction was further analyzed by characterizing the interaction
      between the glyoxysome-bound form of the DnaJ protein and various isoforms of
      Hsp70. Specific binding to the glyoxysomal surface was only observed in the case
      of cytosolic isoform 1 of Hsp70. This interaction was strictly dependent on the
      presence of ADP. Glyoxysomes did not bind other cytosolic or plastidic isoforms
      or the BiP-related form of Hsp70. Analyzing the enzymatic properties of cytosolic
      Hsp70s, we showed that the ATPase-modulating activity of DnaJ was highest when
      isoform 1 was assayed. Collectively, the data indicate that the partner of the
      DnaJ protein anchored at the glyoxysomal membrane is the cytosolic isoform 1 of
      Hsp70. In addition to the chaperones located at the surface of glyoxysomes, two
      isoforms of Hsp70 and one soluble form of DnaJ protein were detected in the
      glyoxysomal matrix.

PMID- 10651812
TI  - Solution structure of oxidized microsomal rabbit cytochrome b5. Factors
      determining the heterogeneous binding of the heme.
AB  - Cytochrome b5 is heterogeneous in solution because of the presence of two isomers
      (A and B), differing in the rotation of the heme plane around the axis defined by
      the alpha and gamma meso protons. For rabbit cytochrome b5, the A/B ratio is 5 :
      1. The solution structure of the major form of the oxidized soluble fragment of
      rabbit microsomal cytochrome b5 (94 amino acids) is here solved through NMR
      spectroscopy. From 1908 NOEs, of which 1469 were meaningful, there were 246
      pseudocontact shifts and 18 3J couplings, a family of 40 energy-minimized
      conformers were obtained with average backbone rmsd (for residues 4-84) of 0.060
      +/- 0.016 nm and average target function of 0.0078 nm2, no distance violations
      being larger than 0.03 nm. The structure was compared with the solution
      structures of the A (major) and B (minor) isomers of the rat cytochrome in the
      oxidized form. The A/B ratio for the rat cytochrome is 1.5 : 1, despite the very
      high sequence similarity (93%) to the rabbit protein. This comparison has
      provided insights into the factors determining the distribution in solution of
      the two isomers differing with respect to heme orientation. It appears that
      residues 23 and 74 are both important in determining this distribution, through
      interaction of their side chains with the prosthetic group. Hydrophobic and
      steric interactions are the key factors in determining the relative stability of
      one isomer with respect to the other.

PMID- 10651813
TI  - A model of a gp120 V3 peptide in complex with an HIV-neutralizing antibody based
      on NMR and mutant cycle-derived constraints.
AB  - The 0.5beta monoclonal antibody is a very potent strain-specific HIV-neutralizing
      antibody raised against gp120, the envelope glycoprotein of HIV-1. This antibody
      recognizes the V3 loop of gp120, which is a major neutralizing determinant of the
      virus. The antibody-peptide interactions, involving aromatic and negatively
      charged residues of the antibody 0.5beta, were studied by NMR and double-mutant
      cycles. A deuterated V3 peptide and a Fab containing deuterated aromatic amino
      acids were used to assign these interactions to specific V3 residues and to the
      amino acid type and specific chain of the antibody by NOE difference
      spectroscopy. Electrostatic interactions between negatively charged residues of
      the antibody Fv and peptide residues were studied by mutagenesis of both antibody
      and peptide residues and double-mutant cycles. Several interactions could be
      assigned unambiguously: F96(L) of the antibody interacts with Pro13 of the
      peptide, H52(H) interacts with Ile7, Ile9 and Gln10 and D56(H) interacts with
      Arg11. The interactions of the light-chain tyrosines with Pro13 and Gly14 could
      be assigned to either Y30a(L) and Y32(L), respectively, or Y32(L) and Y49(L),
      respectively. Three heavy-chain tyrosines interact with Ile7, Ile20 and Phe17.
      Several combinations of assignments involving Y32(H), Y53(H), Y96(H) and Y100a(H)
      may satisfy the NMR and mutagenesis constraints, and therefore at this stage the
      interactions of the heavy-chain tyrosines were not taken into account. The
      unambiguous assignments [F96(L), H52(H) and D56(H)] and the two possible
      assignments of the light-chain tyrosines were used to dock the peptide into the
      antibody-combining site. The peptide converges to a unique position within the
      binding site, with the RGPG loop pointing into the center of the groove formed by
      the antibody complementary determining regions while retaining the beta-hairpin
      conformation and the type-VI RGPG turn [Tugarinov, V., Zvi, A., Levy, R. &
      Anglister, J. (1999) Nat. Struct. Biol. 6, 331-335].

PMID- 10651814
TI  - Characterization of a nif-regulated flavoprotein (FprA) from Rhodobacter
      capsulatus. Redox properties and molecular interaction with a [2Fe-2S]
      ferredoxin.
AB  - A flavoprotein from Rhodobacter capsulatus was purified as a recombinant (His)6
      tag fusion from an Escherichia coli clone over-expressing the fprA structural
      gene. The FprA protein is a homodimer containing one molecule of FMN per 48-kDa
      monomer. Reduction of the flavoprotein by dithionite showed biphasic kinetics,
      starting with a fast step of semiquinone (SQ) formation, and followed by a slow
      reduction of the SQ. This SQ was in the anionic form as shown by EPR and optical
      spectroscopies. Spectrophotometric titration gave a midpoint redox potential for
      the oxidized/SQ couple of Em1 = +20 mV (pH 8.0), whereas the SQ/hydroquinone
      couple could not be titrated due to the thermodynamic instability of SQ
      associated with its slow reduction process. The inability to detect the
      intermediate form, SQ, upon oxidative titration confirmed this instability and
      led to an estimate of Em2 - Em1 of > 80 mV. The reduction of SQ by dithionite was
      significantly accelerated when the [2Fe-2S] ferredoxin FdIV was used as redox
      mediator. The midpoint redox potential of this ferredoxin was determined to be 
      275 +/- 2 mV at pH 7.5, consistent with FdIV serving as electron donor to FprA in
      vivo. FdIV and FprA were found to cross-react when incubated together with the 1
      ethyl-3-(3-dimethylaminopropyl)carbodiimide, giving a covalent complex with an Mr
      of approximately 60 000. Formation of this complex was unaffected by the redox
      states of the two proteins. Other [2Fe-2S] ferredoxins, including FdV and FdVI
      from R. capsulatus, were ineffective as electron carriers to FprA, and cross
      reacted poorly with the flavoprotein. The possible function of FprA with regard
      to nitrogen fixation was investigated using an fprA-deleted mutant. Although
      nitrogenase activity was significantly reduced in the mutant compared with the
      wild-type strain, nitrogen fixation was apparently unaffected by the fprA
      deletion even under iron limitation or microaerobic conditions.

PMID- 10651815
TI  - Structure of a glycerol teichoic acid-like O-specific polysaccharide of Proteus
      vulgaris O12.
AB  - A phosphorylated O-specific polysaccharide (O-antigen) was obtained by mild acid
      degradation of Proteus vulgaris O12 lipopolysaccharide and studied by sugar and
      methylation analyses, 1H-, 13C- and 31P-NMR spectroscopy, including two
      dimensional COSY, TOCSY, NOESY, H-detected 1H, 13C and 1H, 31P heteronuclear
      multiple-quantum coherence experiments. It was found that the polysaccharide
      consists of pentasaccharide repeating units connected via a glycerol phosphate
      group, and has the following structure: where FucNAc is 2-acetamido-2,6
      dideoxygalactose and the degree of O-acetylation at position 4 of GalNAc is
      approximately 25%. Immunochemical studies with P. vulgaris O12 O-antiserum
      suggested that the lipopolysaccharide studied shares common epitopes with the
      lipopolysaccharide core of P. vulgaris O8 and with the O-antigens of P. penneri
      strains 8 and 63.

PMID- 10651816
TI  - Membrane fusion by proline-rich Rz1 lipoprotein, the bacteriophage lambda Rz1
      gene product.
AB  - The fusogenic properties of Rz1, the proline-rich lipoprotein that is the
      bacteriophage lambda Rz1 gene product, were studied. Light scattering was used to
      monitor Rz1-induced aggregation of artificial neutral
      (dipalmitoylphosphatidylcholine/cholesterol) and negatively charged
      (dipalmitoylphosphatidylcholine/cholesterol/dioleoylphosphatidylserin e)
      liposomes. Fluorescence assays [the resonance energy transfer between N-(7-nitro
      2,1,3-benzoxadiazol-4-yl)phosphatidylethanolamine and N-(lissamine rhodamine B
      sulfonyl)dihexadecanol-sn-glycero-3-phosphoethanolamine lipid fluorescent probes,
      as well as fluorescent complex formation between terbium ions and dipicolinic
      acid encapsulated in two liposome populations and calcein fluorescence] were used
      to monitor Rz1-induced lipid mixing, contents mixing and leakage of neutral and
      negatively charged liposomes. The results demonstrated that Rz1 caused adhesion
      of neutral and negatively charged liposomes with concomitant lipid mixing;
      membrane distortion, leading to the fusion of liposomes and hence their internal
      content mixing; and local destruction of the membrane accompanied by leakage of
      the liposome contents. The use of artificial membranes showed that Rz1 induced
      the fusion of membranes devoid of any proteins. This might mean that the proline
      stretch of Rz1 allowed interaction with membrane lipids. It is suggested that Rz1
      induced liposome fusion was mediated primarily by the generation of local
      perturbation in the bilayer lipid membrane and to a lesser extent by
      electrostatic forces.

PMID- 10651817
TI  - Overexpression of the crgA gene abolishes light requirement for carotenoid
      biosynthesis in Mucor circinelloides.
AB  - This work describes the isolation and characterization of crgA, a Mucor
      circinelloides gene, which has a dominant-positive effect on light-regulated
      carotenogenesis. The crgA gene was originally identified in a transformation
      experiment as a 3'-truncated open reading frame which caused carotenoid
      overaccumulation in the dark. The complete cloning and sequencing of crgA
      revealed that its putative product presented several recognizable structural
      domains: a RING-finger zinc binding domain near the N-terminus, a putative
      nuclear localization signal, two stretches of acidic amino acids, glutamine-rich
      regions and a putative isoprenylation motif. The expression of exogenous copies
      of the complete crgA gene or two different 3'-truncated versions, produced a
      similar dominant-positive effect on the light-inducible carotenogenesis of M.
      circinelloides. The presence of these exogenous sequences also caused a
      missregulation of the endogenous crgA gene, resulting in its overexpression.
      Collectively, these observations suggest that crgA is involved in the regulation
      of carotenoid biosynthesis by light.

PMID- 10651818
TI  - Structure of the O-specific polysaccharide of Proteus penneri 71 and
      classification of cross-reactive P. penneri strains to a new proposed serogroup
      O64.
AB  - A neutral O-specific polysaccharide (O-antigen) was isolated from the
      lipopolysaccharide (LPS) of the bacterium Proteus penneri 71. On the basis of
      sugar analysis and 1H- and 13C-NMR spectroscopic studies, including two
      dimensional COSY, 13C,1H heteronuclear COSY and ROESY, the following structure of
      the trisaccharide repeating unit of the polysaccharide was established: -->3)
      beta-D-GlcpNAc-(1-->4)-beta-D-GlcpNAc-(1-->3)-alpha-D-Galp-(1-- > The
      polysaccharide has the same carbohydrate backbone as the O-specific
      polysaccharide of P. penneri 19 and both are similar to that of P. penneri 62
      studied by us previously. A cross-reactivity of anti-P. penneri 71, 19 and 62 O
      antisera with 11 P. penneri strains was revealed and substantiated at the level
      of the O-antigen structures. These strains could be divided into three subgroups
      within a new proposed Proteus O64 serogroup containing P. penneri strains only.

PMID- 10651819
TI  - Structure of a 2-aminoethyl phosphate-containing O-specific polysaccharide of
      Proteus penneri 8 from a new serogroup O67.
AB  - An acidic O-specific polysaccharide was obtained by mild acid degradation of the
      Proteus penneri 8 lipopolysaccharide and found to contain D-glucose, D
      galacturonic acid, 2-acetamido-2-deoxy-D-glucose, 2-acetamido-2-deoxy-D
      galactose, 2-acetamido-2,6-dideoxy-L-galactose (L-FucNAc) and 2-aminoethyl
      phosphate (PEtn) in the ratios 2 : 1 : 1 : 1 : 1 : 1. 1H and 13C NMR spectroscopy
      was applied to the intact and dephosphorylated polysaccharides, and the following
      structure of the hexasaccharide repeating unit was established: The O-specific
      polysaccharide has a unique structure, and, accordingly, we propose for P.
      penneri 8 a new Proteus O67 serogroup, in which this strain is at present the
      single representative. The nature of epitopes on LPS of P. penneri 34, P.
      mirabilis O16, P. mirabilis O23 and P. vulgaris O22, which cross-react with O
      antiserum against P. penneri 8, is discussed.

PMID- 10651820
TI  - Trp scanning analysis of Tet repressor reveals conformational changes associated
      with operator and anhydrotetracycline binding.
AB  - We analysed the conformational states of free, tet operator-bound and
      anhydrotetracycline-bound Tet repressor employing a Trp-scanning approach. The
      two wild-type Trp residues in Tet repressor were replaced by Tyr or Phe and
      single Trp residues were introduced at each of the positions 162-173,
      representing part of an unstructured loop and the N-terminal six residues of
      alpha-helix 9. All mutants retained in vivo inducibility, but anhydrotetracycline
      binding constants were decreased up to 7.5-fold when Trp was in positions 169,
      170 and 173. Helical positions (168-173) differed from those in the loop (162
      167) in terms of their fluorescence emission maxima, quenching rate constants
      with acrylamide and anisotropies in the free and tet operator-complexed proteins.
      Trp fluorescence emission decreased drastically upon atc binding, mainly due to
      energy transfer. For all proteins, either free, tet operator bound or
      anhydrtetracycline-bound, mean fluorescence lifetimes were determined to derive
      quenching rate constants. Solvent-accessible surfaces of the respective Trp side
      chains were calculated and compared with the quenching rate constants in the
      anhydrotetracycline-bound complexes. The results support a model, in which
      residues in the loop become more exposed, whereas residues in alpha-helix 9
      become more buried upon the induction of TetR by anhydrotetracycline.

PMID- 10651821
TI  - Biosynthesis of beta1,4- and beta1,beta1-galactopyranosyl xylopyranosides in the
      mammary gland of lactating cow.
AB  - Lactose is a principal carbohydrate in nearly all species of mammalian milk. In
      order to examine the acceptor substrate specificity of lactose synthase in vivo,
      D-xylose as an acceptor substrate was injected into the jugular vein of a
      Holstein cow during lactation, then a milk sample obtained by milking. beta1,
      beta1-galactopyranosyl xylopyranoside, a nonreducing disaccharide, was separated
      from the bovine milk sample after elimination of reducing sugars, identified by
      fast-atom bombardment (FAB)-MS and 1H-NMR analysis. A mixture of beta1,beta1- and
      beta1, 4-galactopyranosyl xylopyranoside fractions was also obtained by thin
      layer chromatography from the milk sample and elucidated by electrospray
      ionization (ESI)-MS and 1H NMR analysis. Comparison of the integrated intensity
      of the products shows that the beta1,beta1 and beta1,4 isomers are present in a
      ratio of 1.0 : 1.4, suggesting that D-xylose, transported from capillary blood
      across the plasma membrane of the mammary gland, was recognized by lactose
      synthase in its normal and reverse orientation owing to high symmetry of its
      structure. While the beta1,4-isomer is known as a fragment of the linkage region
      between the protein and the polysaccharide chain of proteoglycans, the
      beta1,beta1-isomer has not been identified in vivo. Here, we demonstrate that
      galactosylation of D-xylose transported from the capillary blood can occur by
      lactose synthase catalysis in the mammary gland while the usual galactosylation
      of D-glucose proceeds. In addition, these results suggest that the possibility of
      endogenous occurrence of the beta,beta-trehalose type disaccharide in the mammary
      gland of lactating mammals may not be ruled out.

PMID- 10651822
TI  - Interpretation of biological activity data of bacterial endotoxins by simple
      molecular models of mechanism of action.
AB  - Lipid A moiety has been identified as the bioactive component of bacterial
      endotoxins (lipopolysaccharides). However, the molecular mechanism of biological
      activity of lipid A is still not fully understood. This paper contributes to
      understanding of the molecular mechanism of action of bacterial endotoxins by
      comparing molecular modelling results for two possible mechanisms with the
      underlying experimental data. Mechanisms of action involving specific binding of
      lipid A to a protein receptor as well as nonspecific intercalation into
      phospholipid membrane of a host cell were modelled and analysed. As the cellular
      receptor for endotoxin has not been identified, a model of a peptidic
      pseudoreceptor was proposed, based on molecular structure, symmetry of the lipid
      A moiety and the observed character of endotoxin-binding sites in proteins. We
      have studied the monomeric form of lipid A from Escherichia coli and its seven
      synthetic analogues with varying numbers of phosphate groups and correlated them
      with known biological activities determined by the Limulus assay. Gibbs free
      energies associated with the interaction of lipid A with the pseudoreceptor model
      and intercalation into phospholipid membrane calculated by molecular mechanics
      and molecular dynamics methods were used to compare the two possible mechanisms
      of action. The results suggest that specific binding of lipid A analogues to the
      peptidic pseudoreceptor carrying an amphipathic cationic binding pattern BHPHB
      (B, basic; H, hydrophobic; P, polar residue, respectively) is energetically more
      favourable than intercalation into the phospholipid membrane. In addition,
      binding affinities of lipid A analogues to the best minimum binding sequence
      KFSFK of the pseudoreceptor correlated with the experimental Limulus activity
      parameter. This correlation enabled us to rationalize the observed relationship
      between the number and position of the phosphate groups in the lipid A moiety and
      its biological activity in terms of specific ligand-receptor interactions. If
      lipid A-receptor interaction involves formation of phosphate-ammonium ion-pair(s)
      with cationic amino-acid residues, the specific mechanism of action was fully
      consistent with the underlying experimental data. As a consequence, recognition
      of lipid A variants by an amphipathic binding sequence BHPHB of a host-cell
      protein receptor might represent the initial and/or rate-determining molecular
      event of the mechanism of action of lipid A (or endotoxin). The insight into the
      molecular mechanism of action and the structure of the lipid A-binding pattern
      have potential implications for rational drug design strategies of endotoxin
      neutralizing agents or binding factors.

PMID- 10651823
TI  - Site-directed mutagenesis of the active site serine290 in flavanone 3beta
      hydroxylase from Petunia hybrida.
AB  - Flavanone 3beta-hydroxylase (FHT) catalyzes a pivotal reaction in the formation
      of flavonoids, catechins, proanthocyanidins and anthocyanidins. In the presence
      of oxygen and ferrous ions the enzyme couples the oxidative decarboxylation of 2
      oxoglutarate, releasing carbon dioxide and succinate, with the oxidation of
      flavanones to produce dihydroflavonols. The hydroxylase had been cloned from
      Petunia hybrida and expressed in Escherichia coli, and a rapid isolation method
      for the highly active, recombinant enzyme had been developed. Sequence alignments
      of the Petunia hydroxylase with various hydroxylating 2-oxoglutarate-dependent
      dioxygenases revealed few conserved amino acids, including a strictly conserved
      serine residue (Ser290). This serine was mutated to threonine, alanine or valine,
      which represent amino acids found at the corresponding sequence position in other
      2-oxoglutarate-dependent enzymes. The mutant enzymes were expressed in E. coli
      and purified to homogeneity. The catalytic activities of [Thr290]FHT and
      [Ala290]FHT were still significant, albeit greatly reduced to 20 and 8%,
      respectively, in comparison to the wild-type enzyme, whereas the activity of
      [Val290]FHT was negligible (about 1%). Kinetic analyses of purified wild-type and
      mutant enzymes revealed the functional significance of Ser290 for 2-oxoglutarate
      binding. The spatial configurations of the related Fe(II)-dependent isopenicillin
      N and deacetoxycephalosporin C synthases have been reported recently and provide
      the lead structures for the conformation of other dioxygenases. Circular
      dichroism spectroscopy was employed to compare the conformation of pure flavanone
      3beta-hydroxylase with that of isopenicillin N synthase. A double minimum in the
      far ultraviolet region at 222 nm and 208-210 nm and a maximum at 191-193 nm which
      are characteristic for alpha-helical regions were observed, and the spectra of
      the two dioxygenases fully matched revealing their close structural relationship.
      Furthermore, the spectrum remained unchanged after addition of either ferrous
      ions, 2-oxoglutarate or both of these cofactors, ruling out a significant
      conformational change of the enzyme on cofactor-binding.

PMID- 10651824
TI  - The structural basis of substrate activation in yeast pyruvate decarboxylase. A
      crystallographic and kinetic study.
AB  - The crystal structure of the complex of the thiamine diphosphate dependent
      tetrameric enzyme pyruvate decarboxylase (PDC) from brewer's yeast strain with
      the activator pyruvamide has been determined to 2.4 A resolution. The asymmetric
      unit of the crystal contains two subunits, and the tetrameric molecule is
      generated by crystallographic symmetry. Structure analysis revealed
      conformational nonequivalence of the active sites. One of the two active sites in
      the asymmetric unit was found in an open conformation, with two active site loop
      regions (residues 104-113 and 290-304) disordered. In the other subunit, these
      loop regions are well-ordered and shield the active site from the bulk solution.
      In the closed enzyme subunit, one molecule of pyruvamide is bound in the active
      site channel, and is located in the vicinity of the thiazolium ring of the
      cofactor. A second pyruvamide binding site was found at the interface between the
      Pyr and the R domains of the subunit in the closed conformation, about 10 A away
      from residue C221. This second pyruvamide molecule might function in stabilizing
      the unique orientation of the R domain in this subunit which in turn is important
      for dimer-dimer interactions in the activated tetramer. No difference electron
      density in the close vicinity of the side chain of residue C221 was found,
      indicating that this residue does not form a covalent adduct with an activator
      molecule. Kinetic experiments showed that substrate activation was not affected
      by oxidation of cysteine residues and therefore does not seem to be dependent on
      intact thiol groups in the enzyme. The results suggest that a disorder-order
      transition of two active-site loop regions is a key event in the activation
      process triggered by the activator pyruvamide and that covalent modification of
      C221 is not required for this transition to occur. Based on these findings, a
      possible mechanism for the activation of PDC by its substrate, pyruvate, is
      proposed.

PMID- 10651825
TI  - Identification of the site where the electron transfer chain of plant
      mitochondria is stimulated by electrostatic charge screening.
AB  - Modular kinetic analysis was used to determine the sites in plant mitochondria
      where charge-screening stimulates the rate of electron transfer from external
      NAD(P)H to oxygen. In mitochondria isolated from potato (Solanum tuberosum L.)
      tuber callus, stimulation of the rate of oxygen uptake was accompanied by a
      decrease in the steady-state reduction level of coenzyme Q, and by a small
      decrease in the steady-state reduction level of cytochrome c. Modular kinetic
      analysis around coenzyme Q revealed that stimulation of the rate was due to
      stimulation of quinol oxidation via the cytochrome pathway (cytochrome bc1,
      cytochrome c and cytochrome c oxidase). It was not a consequence of any effect on
      quinone reduction (by external NADH or NADPH dehydrogenase). This explains the
      salt-induced decrease in the steady-state reduction level of coenzyme Q. Analysis
      around cytochrome c revealed that stimulation by salts was due to a dual effect
      on the respiratory chain. The kinetic curves for the oxidation and reduction
      pathways of cytochrome c revealed that they were both activated by salt, the
      simultaneity explaining the small variation observed in the steady-state
      reduction level of cytochrome c. A simple kinetic core model is used to show that
      changes in the rate of dissociation of cytochrome c from the membrane can explain
      the observed kinetic changes in both cytochrome c reduction and cytochrome c
      oxidation. The stimulation is proposed to be the result of an increase in the
      rate constant of cytochrome c dissociation from the membrane induced by cation
      screening. We conclude that this type of modular kinetic analysis is a powerful
      tool to identify and quantitatively characterize multiple-site effects on the
      mitochondrial respiratory chain.

PMID- 10651826
TI  - The role of mitochondria in the regulation of calcium influx into Jurkat cells.
AB  - In electrically nonexcitable cells the activity of the plasma membrane calcium
      channels is controlled by events occurring in mitochondria, as well as in the
      lumen of the endoplasmic reticulum. Thapsigargin, a specific inhibitor of
      endoplasmic reticulum Ca2+-ATPase, produces the release of calcium from the
      endoplasmic reticulum and thus, activation of store-operated calcium channels in
      the plasma membrane. However, thapsigargin failed to produce significant
      activation of the channels in Jurkat cells that had been pretreated with
      mitochondria-directed agents: an uncoupler (carbonyl cyanide m
      chlorophenylhydrazone) and oligomycin. This is in spite of the fact that Jurkat
      cells pretreated with carbonyl cyanide m-chlorophenylhydrazone plus oligomycin
      are otherwise energetically competent, due to a high rate of glycolysis and the
      inhibition of mitochondrial F1Fo-ATPase by oligomycin. The pool of intracellular
      ATP was found not to be influenced by the pretreatments of cells with oligomycin
      or with oligomycin plus carbonyl cyanide m-chlorophenylhydrazone. In the control
      cells, we found that the ATP pool amounted to 23.2 +/- 1.9 nmoles per 107 cells
      (n = 4). In cells pretreated with oligomycin the level of ATP was 21.8 +/- 1.9
      nmoles per 107 cells (n = 4), and in cells pretreated with both oligomycin and an
      uncoupler the level of ATP was 22.1 +/- 0.2 nmoles per 107 cells (n = 3).
      Moreover, in cells pretreated with oligomycin plus carbonyl cyanide m
      chlorophenylhydrazone and suspended in a nominally calcium-free medium,
      thapsigargin produces transient increases in cytosolic calcium identical to those
      in the control cells. Thus, this pretreatment does not modify either the content
      of intracellular calcium stores and/or the activity of calcium ATPase in the
      plasma membrane. Similar results were obtained when Jurkat cells were challenged
      by myxothiazol, a potent inhibitor of mitochondrial cytochrome bc1
      oxidoreductase. Thapsigargin, although producing calcium release from
      intracellular stores, was ineffective in triggering the activation of calcium
      channels in the plasma membrane in the case of cells pretreated with myxothiazol
      and oligomycin. Our results suggest that coupled mitochondria participate
      directly in the control of calcium channel activity in the plasma membrane of
      Jurkat cells. When the mitochondrial protonmotive force is collapsed, either by
      carbonyl cyanide m-chlorophenylhydrazone or myxothiazol, the channel remains
      inactive even under conditions of empty intracellular calcium stores.

PMID- 10651827
TI  - In vitro folding, purification and characterization of Escherichia coli outer
      membrane protease ompT.
AB  - OmpT is a protease present in the outer membrane of Escherichia coli. The enzyme
      was overexpressed without its signal sequence in E. coli using a T7 system,
      resulting in the accumulation of OmpT as inclusion bodies. After solubilization
      of the inclusion bodies in urea, the protein could be folded in vitro by dilution
      in the presence of detergent n-dodecyl-N, N-dimethyl-1-ammonio-3
      propanesulphonate. The addition of lipopolysaccharide to the protein was
      essential to obtain active enzyme. The correctly folded protein was purified to
      homogeneity by ion exchange chromatography with a 57% overall yield.
      Autoproteolysis between Lys217-Arg218 was a major problem during purification,
      but degradation could be abolished by introducing the mutations G216K and K217G.
      A novel fluorimetric assay using the internally quenched substrate Abz-Ala-Arg
      Arg-Ala-Tyr(NO2)-NH2 (where Abz is o-aminobenzoyl and Tyr(NO2) is 3
      nitrotyrosine) enabled the determination of the kinetic parameters. The wild-type
      enzyme has an affinity Km of 0.4 microM for the substrate and a turnover number
      kcat of 40 s-1. The Km and kcat for the double variant were 1.1 microM and 1.6 s
      1, respectively. The pH profiles of the wild type and variant were identical,
      showing optimal activity at pH 6.5 and pKa values of 5.6 and 7.5, respectively.
      Circular dichroism spectra of both enzymes indicated a high content of beta
      strand conformation, and on that basis a beta-barrel topology model is proposed.

PMID- 10651828
TI  - Peptides with antimicrobial activity from four different families isolated from
      the skins of the North American frogs Rana luteiventris, Rana berlandieri and
      Rana pipiens.
AB  - The skins of frogs of the genus Rana synthesize a complex array of antimicrobial
      peptides that may be grouped into eight families on the basis of structural
      similarity. A total of 24 peptides with differential growth-inhibitory activity
      towards the Gram-positive bacterium Staphylococcus aureus, the Gram-negative
      bacterium Escherichia coli and the yeast Candida albicans were isolated from
      extracts of the skins of three closely related North American frogs, Rana
      luteiventris (spotted frog), Rana berlandieri (Rio Grande leopard frog) and Rana
      pipiens (Northern leopard frog). Structural characterization of the antimicrobial
      peptides demonstrated that they belonged to four of the known families: the
      brevinin-1 family, first identified in skin of the Asian frog Rana porosa
      brevipoda; the esculentin-2 family, first identified in the European frog Rana
      esculenta; the ranatuerin-2 family, first identified in the North American
      bullfrog Rana catesbeiana; and the temporin family, first identified in the
      European frog Rana temporaria. Peptides belonging to the brevinin-2, ranalexin,
      esculentin-1 and ranatuerin-1 families were not identified in the extracts.
      Despite the close phylogenetic relationship between the various species of Ranid
      frogs, the distribution and amino-acid sequences of the antimicrobial peptides
      produced by each species are highly variable and species-specific, suggesting
      that they may be valuable in taxonomic classification and molecular phylogenetic
      analysis.

PMID- 10651829
TI  - Engineering a disulfide bond and free thiols in the lantibiotic nisin Z.
AB  - The antimicrobial peptide nisin contains the uncommon amino acid residues
      lanthionine and methyl-lanthionine, which are post-translationally formed from
      Ser, Thr and Cys residues. To investigate the importance of these uncommon
      residues for nisin activity, a mutant was designed in which Thr13 was replaced by
      a Cys residue, which prevents the formation of the thioether bond of ring C.
      Instead, Cys13 couples with Cys19 via an intramolecular disulfide bridge, a bond
      that is very unusual in lantibiotics. NMR analysis of this mutant showed a
      structure very similar to that of wild-type nisin, except for the configuration
      of ring C. The modification was accompanied by a dramatic reduction in
      antimicrobial activity to less than 1% of wild-type activity, indicating that the
      lanthionine of ring C is very important for this activity. The nisin Z mutants
      S5C and M17C were also isolated and characterized; they are the first
      lantibiotics known that contain an additional Cys residue that is not involved in
      bridge formation but is present as a free thiol. Secretion of these peptides by
      the lactococcal producer cells, as well as their antimicrobial activity, was
      found to be strongly dependent on a reducing environment. Their ability to
      permeabilize lipid vesicles was not thiol-dependent. Labeling of M17C nisin Z
      with iodoacetamide abolished the thiol-dependence of the peptide. These results
      show that the presence of a reactive Cys residue in nisin has a strong effect on
      the antimicrobial properties of the peptide, which is probably the result of
      interaction of these residues with thiol groups on the outside of bacterial
      cells.

PMID- 10651830
TI  - Functional characteristics of two BKCa channel variants differentially expressed
      in rat brain tissues.
AB  - cDNAs encoding large-conductance Ca2+-activated K+ channel alpha-subunit (rSlo)
      were obtained from rat brain. From the DNA sequence of multiple rslo clones, we
      identified a specific sequence variation of 81 nucleotides, which is either
      absent from or present at the N-terminal region of a putative Ca2+-sensing domain
      of the channel. Transcripts containing such variations were detected in different
      ratios from several brain regions, and their functional significance was further
      examined. When heterologously expressed in Xenopus oocytes, both rSlo variants,
      named rSlo0 and rSlo27, generated Ca2+-activated and voltage-activated K+
      currents characteristic of neuronal large-conductance Ca2+-activated K+ (BKCa)
      channels. Single-channel recordings of the two channels showed almost identical
      permeation characteristics and steady-state gating behavior. Noticeable
      differences between rSlo0 and rSlo27 were revealed when the macroscopic currents
      were measured at various voltages and intracellular Ca2+ concentrations. rSlo27
      activated was more rapidly than rSlo0 in the presence of the same voltage
      stimulus, and the differences in these activation kinetics were dependent on the
      concentration of intracellular Ca2+. Despite their similar apparent affinities
      for Ca2+, rSlo0 and rSlo27 showed significant differences in their co-operative
      gating behavior. The Hill coefficient for intracellular Ca2+ was estimated to be
      about 3.7 for rSlo27 regardless of the membrane voltage, and that for rSlo0 was
      reduced from about 5 to 2 as the membrane voltage changed from 40 to 140 mV. As
      activation of BKCa channels is involved in rapid hyperpolarization of action
      potentials, the differential processing of rslo transcripts, and the generation
      of channels with different activation kinetics and Ca2+ cooperativity may be a
      mechanism for tuning the excitability of neurons in different brain regions.

PMID- 10651831
TI  - Molecular characterization of a human scavenger receptor, human MARCO.
AB  - Murine MARCO has been identified recently in subsets of macrophages located in
      the peritoneum, marginal zone of the spleen, and the medullary cord of lymph
      nodes, where it has been proposed that it serves as a bacteria-binding receptor.
      A scavenger receptor family member with an extended collagenous domain, murine
      MARCO has also been demonstrated in atherosclerotic lesions of susceptible mice.
      We report here the identification, tissue and chromosomal localization, and
      pharmacological characterization of human (h)MARCO. hMARCO was identified from a
      macrophage cDNA library by electronic screening with the murine MARCO sequence.
      Nucleotide sequence analysis confirmed that the full-length hMARCO clone encoded
      a 519-amino acid protein sharing 68.5% identity with murine MARCO. RNA blot
      analysis indicated that the hMARCO transcript is 2.0 kb in length and is
      predominantly expressed in human lung, liver, and lymph nodes. Radiation hybrid
      mapping localized hMARCO to chromosome 2q14. Ligand-binding studies of COS cells
      expressing hMARCO demonstrated significant specific binding of both Escherichia
      coli and Staphylococcus aureus. In contrast, the hMARCO receptor expressed in COS
      cells did not specifically bind the scavenger receptor ligand acetylated low
      density lipoprotein (LDL), despite its similarity to the elongated collagen-like
      binding domain of the macrophage scavenger receptor. In addition, acetylated
      (Ac)LDL and oxidized (Ox)LDL did not inhibit E. coli binding to hMARCO. These
      data suggest that hMARCO may play an important role in host defense, but it has
      no obvious role in the accumulation of modified lipoproteins during
      atherogenesis.

PMID- 10651832
TI  - T-cell activation: a cellular target for antiretroviral therapy.

PMID- 10651833
TI  - Association of serum sialic acid and MMP-9 with lipids and inflammatory markers.
AB  - BACKGROUND: Inflammation of the arterial wall has emerged to be an important
      contributor to the process of atherosclerosis, the major cause of coronary heart
      disease. Several factors are currently under investigation as inflammatory
      markers of atherosclerosis. Serum sialic acid and matrix metalloproteinase-9 may
      provide such markers. We studied their association with the lipid profile and
      with the inflammatory markers C-reactive protein and leukocyte count in a
      clinically healthy population of men. MATERIALS AND METHODS: Cardiovascular risk
      related laboratory tests were carried out in 65 consecutive male employees in
      connection with an occupational health survey in 1996. The subjects were divided
      into tertiles on the basis of serum sialic acid or matrix metalloproteinase-9
      concentration. RESULTS: In a stepwise polychotomous logistic regression model
      adjusting for coronary heart disease risk factors, serum sialic acid
      concentration was not associated with markers of inflammation but rather with the
      lipid risk factors of atherosclerosis: inversely with HDL cholesterol (OR =
      0.081, 95% CI 0.0068-0.97) and positively with total cholesterol (OR = 2.4, 95%
      CI 1-5.6). Matrix metalloproteinase-9 levels had a significant positive
      correlation with the leukocyte count (OR = 2.3, 95% CI 1.4-4). CONCLUSIONS: Serum
      sialic acid does not appear to be an indicator of inflammation but is somehow
      connected with the level of total and HDL cholesterol. Serum matrix
      metalloproteinase-9 may provide a useful marker of inflammation because it
      correlates with the leukocyte count and is not associated with the lipid profile.

PMID- 10651834
TI  - Effects of percutaneous transluminal coronary angioplasty on coronary adenosine
      concentrations in humans.
AB  - BACKGROUND: Even minimal amounts of adenosine is released during myocardial
      ischemia. Its role in coronary blood flow has been extensively studied, but
      little is known about its behaviour during percutaneous transluminal angioplasty
      (PTCA) in man. MATERIAL AND METHODS: Using in situ samples the aim of this study
      was to evaluate adenosine plasma concentration before and after PTCA. Ten
      patients (8 men and 2 women, mean age 65 +/- 9 years) with a single stenosis of
      the left anterior descending coronary artery (LAD) of at least 70% and 10 healthy
      volunteers (4 men and 6 women, mean age 55 +/- 9 years) were included in the
      study. RESULTS AND DISCUSSION: We found that there is a close relationship
      between the degree of the stenosis and the adenosine concentrations in the great
      cardiac vein and in the LAD, and that after PTCA there is a drop in adenosine
      concentration downstream from the stenosis. This study confirms the crucial role
      of adenosine in coronary blood flow control.

PMID- 10651835
TI  - Evaluation of factors controlling glucose tolerance in patients with HCV
      infection before and after 4 months therapy with interferon-alpha.
AB  - BACKGROUND: Epidemiological data suggest that chronic hepatitis C virus (HCV)
      infection may contribute to the development of diabetes mellitus. Therapy of HCV
      infection with recombinant interferon-alpha (r-IFN-alpha) can also impair of
      glucose metabolism. METHODS: To investigate the impact of HCV infection and the
      therapy with r-IFN-alpha on glucose metabolism we measured insulin sensitivity,
      glucose effectiveness, and first and second phase insulin secretion, using the
      minimal modelling analysis of frequently sampled intravenous glucose tolerance
      tests in 13 nondiabetic patients with HCV-induced liver disease before and after
      therapy with r-INF-alpha (6 x 106 U, subcutaneously, three times a week over 4
      months). Liver biopsy was performed to evaluate and score liver fibrosis as a
      marker of HCV-induced cell injury. RESULTS: Insulin sensitivity (r = - 0.59, P <
      0.05) and first phase insulin secretion (r = - 0.66, P < 0.03) were negatively
      related to the fibrosis score. Insulin sensitivity rose from 1.96 (SEM 0.37, n =
      8) to 5.69 (SEM 0.99, n = 8) 10-4 min-1 per microU mL-1 (P < 0.01) in responders
      and from 2.51 (SEM 0.61, n = 5) to 6.95 (SEM 1.99, n = 5) in nonresponders after
      4 months r-INF-alpha therapy. Fasting free fatty acids decreased significantly to
      about 50% (P < 0.01) in patients with and without therapy response after 4
      months, whereas first phase insulin secretion did not change. CONCLUSIONS: HCV
      induced liver injury is related to the deterioration of insulin sensitivity and
      first phase insulin response, thus impairing glucose homeostasis in these HCV
      infected patients. The administration of r-INF-alpha three times a week over 4
      months is not associated with an impairment of glucose homeostasis.

PMID- 10651836
TI  - Assessment of human muscle glycogen synthesis and total glucose content by in
      vivo 13C MRS.
AB  - BACKGROUND: Obesity is often accompanied by a decreased ability of insulin to
      stimulate glucose uptake and glycogenesis in skeletal muscle. The aim of this
      study was to investigate the rate of glycogen formation and of muscular glucose
      content in relation to insulin sensitivity under euglycemic conditions. MATERIALS
      AND METHODS: We applied a hyperinsulinemic (430 pmol m-2 min-1) euglycemic clamp
      with infusion of 20% glucose (30% enriched with 13C-1-glucose) to 8 subjects with
      a wide range of insulin sensitivities. Glycogen and glucose levels were monitored
      simultaneously by in vivo 13C MRS of the calf muscle on a clinical MR system at
      1.5T field strength. RESULTS AND CONCLUSIONS: Glycogen synthesis rate showed a
      strong correlation with whole body glucose uptake during the clamp (r = 0.93, P <
      0.01). With the use of 13C MRS, total muscular glucose content could be
      determined in vivo, and showed a positive, linear correlation with glycogen
      synthesis rate (r = 0.85, P < 0.01). 13C MRS provides important information
      regarding in vivo insulin action. Preliminary results indicate that the glycogen
      synthesis rate improves after treatment with troglitazone.

PMID- 10651837
TI  - The effect of coffee on gastric emptying and oro-caecal transit time.
AB  - BACKGROUND: The consumption of coffee allegedly induces or aggravates
      gastrointestinal symptoms. In order to investigate the effect of coffee on
      gastrointestinal motility we studied the effect of coffee on gastric emptying and
      oro-caecal transit time. METHODS: In a randomised, controlled, cross-over study
      gastric emptying and oro-caecal transit time were studied in 12 healthy
      volunteers, using applied potential tomography and lactulose hydrogen breath
      test, respectively. After 1 day of coffee abstinence and an overnight fast,
      coffee or the control drink (water) was drunk and 10 min thereafter a liquid
      nutrient meal was ingested together with lactulose. During 150 min, recordings
      were made with applied potential tomography and breath samples were taken every 5
      min. Lag-phase duration and gastric half-emptying time were determined by two
      blinded observers. RESULTS: The lag-phase duration after coffee (median 19.8 min,
      range 6-47 min) was not significantly different from that after water (median
      19.3 min, range 11-37.5), nor was the gastric half-emptying time (median 75.7
      min, range 56-157.6 vs. median 83.4 min, range 64. 6-148.4). Likewise, coffee had
      no significant effect on oro-caecal transit time (median 135 min, range 60-270
      vs. median 140 min, range 55-270). No significant correlation between any of
      these parameters and mean daily coffee intake was found. CONCLUSIONS: Coffee does
      not affect gastric emptying of a liquid meal or small bowel transit.

PMID- 10651838
TI  - Effect of cholestyramine on bile acid pattern and synthesis during administration
      of ursodeoxycholic acid in man.
AB  - BACKGROUND: Cholestyramine is the first-line treatment for cholestasis-induced
      pruritus and is prescribed along with ursodeoxycholic acid (UDCA) in patients
      with cholestatic liver diseases. Impairment of the intestinal absorption of
      endogenous hydrophobic bile acids by cholestyramine is well known. It is unclear,
      however, whether cholestyramine also impairs the absorption of the hydrophilic
      bile acid, UDCA, in man. AIMS: To study serum levels of UDCA and endogenous bile
      acids as well as endogenous bile acid synthesis during simultaneous or separate
      administration of UDCA and cholestyramine in vivo; and absorption of UDCA both in
      the presence and absence of its hydrophobic epimer, chenodeoxycholic acid (CDCA),
      by cholestyramine in vitro. PATIENTS AND METHODS: Five healthy subjects received
      UDCA (12.5 +/- 0.5 mg kg-1 daily) as a single dose for periods of 14 days with or
      without cholestyramine (4 g daily). Fasting serum levels of bile acids and of
      7alpha-hydroxy-4-cholesten-3-one (alpha-HC), a measure of endogenous bile acid
      synthesis, were determined by gas chromatography and high pressure liquid
      chromatography, respectively. In vitro, bile acid solutions were incubated for 24
      h in the presence or absence of cholestyramine, and bile acid concentrations were
      determined in the supernatant. RESULTS: Simultaneous administration of UDCA and
      cholestyramine in man led to a decrease of fasting serum levels of UDCA by 60%
      when compared to UDCA serum levels during administration of UDCA alone. In
      contrast, serum levels of endogenous bile acids were not affected and alpha-HC
      serum levels were found increased 2. 7-fold indicating stimulation of endogenous
      bile acid synthesis by cholestyramine. Administration of cholestyramine and UDCA
      at an interval of 5 h tended to diminish the effect of cholestyramine on UDCA
      serum levels. In vitro, conjugated and unconjugated UDCA were effectively bound
      by cholestyramine both in the presence and absence of hydrophobic bile acids.
      CONCLUSIONS: The results strongly support the recommendation to administer UDCA
      and cholestyramine at different times of day.

PMID- 10651839
TI  - Lactose (mal)digestion evaluated by the 13C-lactose digestion test.
AB  - BACKGROUND: The prevalence of genetically determined lactase nonpersistence is
      based on the results of the lactose H2 breath test. This test, however, is an
      indirect test, which might lead to misinterpretation. DESIGN: We determined
      lactase activity in healthy Chinese and Dutch students using a novel 13C-lactose
      digestion test. The cut-off value of this test was established in a Chinese
      population with a homogenous genetic background of lactase nonpersistence and was
      compared with the results obtained in a Caucasian population. Twenty-five grams
      of a 13C-lactose solution was consumed by 12 known H2-positive and 5 H2-negative
      Chinese students and 48 Dutch students and, subsequently, 13C-glucose
      concentration in plasma and H2 excretion in breath were measured. RESULTS: A
      similar 13C-glucose response curve was found in all Chinese students. The mean
      response curve in the Dutch students was more pronounced (P < 0.01). The 1 h
      (peak) plasma 13C-glucose concentration was the best discriminator between
      lactose digesting and maldigesting subjects. The cut-off level of 2 mmol L-1 13C
      glucose in plasma was defined in the H2-positive Chinese students group. Based on
      the 13C-glucose response the prevalence of lactose maldigestion in the Dutch
      subjects was 25%; based on the lactose H2 breath test 17%. CONCLUSIONS: Using the
      13C-lactose digestion test the results demonstrate a higher prevalence of lactose
      maldigestion in a Caucasian population than indicated by the results of the H2
      breath test. A moderate increase in the plasma 13C-glucose concentration after
      consumption of 13C-lactose in the young adult Chinese subjects indicates a
      residual lactase activity in that age group, even when a positive H2 breath test
      result is obtained. These results indicate that the 13C-glucose concentration in
      plasma more accurately reflects the small intestinal lactose digestion capacity
      than the lactose H2 breath test.

PMID- 10651840
TI  - Characteristics of thyroid carcinomas in aging patients.
AB  - BACKGROUND: To investigate the clinical features of thyroid cancer in aging
      patients and to present the results of treatment. From this we can provide bases
      for earlier diagnoses and better treatment of thyroid malignancies in older
      patients. MATERIALS AND METHODS: In this study a retrospective analysis was
      performed with 204 thyroid cancer patients aged 60 years or older (132 women,
      with a mean age of 68.3 +/- 6.6 years; 72 men, with a mean age of 67.0 +/- 5.3
      years). RESULTS: Of the 204 patients, 142 had well-differentiated thyroid
      carcinomas (96 papillary thyroid carcinomas, 43 follicular carcinomas, three
      Hurthle cell carcinomas) and three medullary carcinomas. Sixty-nine (33.8%) of
      the 204 patients died after treatment. Of these, three patients died of causes
      not related to thyroid cancer. For well-differentiated thyroid carcinomas, male
      gender, follicular carcinoma, and a larger tumour size indicated a poor
      prognosis. Of the 59 non-well-differentiated thyroid carcinomas, 39 were
      anaplastic thyroid carcinomas, nine metastatic cancers of the thyroid, seven
      lymphomas, and four squamous cell carcinomas. After treatment, 40 (67.8%) of the
      59 patients died. In multivariant analysis of the differences in clinical
      parameters between aging and younger thyroid cancer patients, the current status,
      tumour size, follow-up period, sex, and stage at diagnosis were independent
      factors. From this data the delayed diagnosis of aging patients with thyroid
      cancer was of note when compared with younger patients. CONCLUSION: Thyroid
      cancer in older patients is not a benign clinical disorder. Early diagnosis and
      urgent aggressive treatment are recommended courses of action for this type of
      cancer, especially for non-well-differentiated thyroid cancers.

PMID- 10651841
TI  - Effectiveness of recombinant erythropoietin and iron sucrose vs. iron therapy
      only, in patients with postpartum anaemia and blunted erythropoiesis.
AB  - BACKGROUND: To compare efficacy between recombinant human erythropoietin (rhEPO)
      plus parenteral iron vs. iron alone (parenteral vs. oral) in postpartum anaemia.
      METHODS: Sixty patients (haemoglobin 8.6 +/- 1.1 g dL-1) were randomized to rhEPO
      plus intravenous (i.v.) iron sucrose (group 1), rhEPO placebo plus i.v. iron
      sucrose (group 2), or oral iron alone (group 3), daily for 4 days beginning 48-72
      h postpartum. Erythropoiesis and iron status were assessed before, and on 4, 7
      and 14 days after, starting therapy. RESULTS: On day 7 the group 1 haematocrit
      increase was 7.7 +/- 3.1% vs. 5.3 +/- 1.9% (group 2, P < 0.01) and 4.4 +/- 3.2%
      (group 3, P < 0.01), and on day 14, 11.3 +/- 2.9% vs. 9.2 +/- 3.4% (group 2, P <
      0.05) and 8 +/- 2.8% (group 3, P < 0.01). The odds of achieving a target
      haematocrit > 32% on day 7 and > 35% on day 14 were higher on rhEPO (1.5-2.7)
      than on either iron regimen alone. Group 1 reticulocyte counts were also higher
      on days 4 (P < 0.05 vs. oral iron) and 7 (P < 0.01 vs. oral and parenteral iron).
      CONCLUSION: All three regimens were effective in postpartum anaemia, but the
      haematocrit and reticulocyte responses to rhEPO plus parenteral iron were
      significantly greater than to iron alone. Benefit was greatest in the blunted
      erythropoiesis subgroup with elevated post-Caesarean section C-reactive protein
      levels.

PMID- 10651842
TI  - Hydroxyurea interferes with antigen-dependent T-cell activation in vitro.
AB  - BACKGROUND: Hydroxyurea is believed to inhibit human immunodeficiency virus type
      1 (HIV-1) in HIV disease by decreasing the amount of intracellular
      deoxynucleotides needed for viral replication. A plasma concentration of 400
      micromol L-1 is tolerated in oncological diseases. The present study focused on
      the possible interference of hydroxyurea with antigen-dependent T-cell activation
      as an alternative explanation for inhibiting HIV replication in vivo. METHODS:
      The effect of hydroxyurea on common antigen-induced cell proliferation was
      studied in peripheral blood mononuclear cells (PBMC) in vitro. RESULTS:
      Hydroxyurea inhibited Candida albicans-induced cell proliferation at a low
      concentration (1 micromol L-1), while at least 10 micromol L-1 was required to
      block HIV-1 replication in phytohaemagglutinin (PHA)-stimulated PBMC. CONCLUSION:
      Hydroxyurea inhibits antigen-induced lymphoproliferation in vitro at a
      concentration at which it does not inhibit PHA-induced HIV replication.
      Hydroxyurea may inhibit HIV-1 in CD4+ T cells in vivo not only by decreasing the
      amount of intracellular deoxynucleotides, but more specifically by interfering
      with antigen-dependent T-cell activation, thereby causing a reduction in the
      number of HIV target cells.

PMID- 10651843
TI  - Evaluation of CD14 in host defence.
AB  - An extensive search for the cell membrane targets for lipopolysaccharide (LPS),
      the major causative agent of Gram-negative septic shock, resulted in the
      identification of CD14 as the major endotoxin 'receptor'. Besides recognition of
      LPS, several new aspects of its biological functions have been described
      recently. In this review the different CD14 forms, their most important
      biological and biochemical features, signalling properties, cellular and
      subcellular distribution and association with different diseases are discussed in
      detail, showing that these molecules posses several unique biological functions
      and further proving their central role in innate immunity.

PMID- 10651844
TI  - Identification and efficient genotyping of an (A)n/(T)m polymorphism within the
      5' untranslated region of the human IL6 gene.

PMID- 10651845
TI  - Polymorphism of LMP2, TAP1, LMP7 and TAP2 in Brazilian Amerindians and
      Caucasoids: implications for the evolution of allelic and haplotypic diversity.
AB  - In the class II region of the major histocompatibility complex (MHC), four genes
      implicated in processing of MHC class I-presented antigens have been described.
      Two of these (TAP1 and TAP2) code for endoplasmic reticulum membrane transporter
      proteins and the other two (LMP2 and LMP7) for proteasome subunits. These genes
      are polymorphic, although much less so than classical MHC class I and II genes.
      There is controversy concerning the possible functional implications of this
      variation. Population genetics is one of the means of investigating the
      evolutionary and functional significance of genetic polymorphisms; however, few
      populations have been analysed with respect to TAP and LMP diversity. We present
      here the polymorphism of TAP1, TAP2, LMP2 and LMP7 genes in the Kaingang and
      Guarani Amerindian tribes, and in the Caucasoid population of the Brazilian State
      of Parana. Allele frequencies found in the Caucasoids were close to those
      described for similar populations. Amerindians had a somewhat more restricted
      polymorphism, and allele and haplotype frequencies differed greatly between the
      two tribes. Overall linkage disequilibrium (LD) between the four genes was low in
      the Caucasoids, but high in the Amerindians, for which significant LD was seen
      for all informative pairs of loci. Comparing results of this and previous studies
      we observed that, whenever significant LD occurs in non-Amerindians, it tends to
      be similar in the different ethnic groups. While this might be interpreted as
      evidence of co-evolution of genes in the TAP-LMP region, the high haplotypic
      diversity in all populations and low LD in non-Amerindians indicate absence of co
      evolution of the different genes. Distributions of allele and genotype
      frequencies are consistent with the hypothesis of selective neutrality. We
      conclude that genetic polymorphism of the human TAP and LMP genes and haplotypes
      is of little, if any, functional significance.

PMID- 10651846
TI  - Analysis of the genetic variability of the 1st (CCC/ACC, P52T) and the 10th exons
      (bp 1012-1704) of the TSH receptor gene in Graves' disease.
AB  - We determined the genetic variability of the 1st (CCC/ACC, P52T polymorphic
      variant) and 10th exons (bp 1012-1704) of the TSH receptor (TSHR) gene in Graves'
      disease. A total of 101 Graves' patients and 163 control subjects were screened.
      The A253 mutant allele was carried by nine patients with Graves' disease (8.91%)
      and 13 control subjects (7.98%) in heterozygous genotype. No significant
      difference in the frequency of the mutant allele was found between Graves'
      patients and control subjects. These results provide evidence that the A253
      polymorphism has no genetic relevance in Graves' disease. Moreover, the DNA
      nucleotide sequence of 693 bp of the 10th exon (bp 1012-1704) of the TSHR gene
      was determined in 15 Graves' patients. Six patients were homozygous for the wild
      type allele and nine were heterozygous for the mutant allele at the 253rd
      nucleotide of the first exon. No polymorphism was found in the DNA sequences
      obtained from leukocytes of Graves' patients, similarly to the sequences obtained
      from the nine control subjects. None of the nine patients carrying the A253
      polymorphism in the 1st exon of the TSHR had polymorphism in the examined part of
      the 10th exon, including two additional patients whose thyroid tissue was
      directly analysed. In all likelihood, the polymorphisms of the examined regions
      of either the 1st or the 10th exon of the THSR gene do not contribute to the
      genetic susceptibility to Graves' disease.

PMID- 10651847
TI  - Identification of further DLA-DRB1 and DQA1 alleles in the dog.
AB  - Three novel DLA-DRB1 alleles and one novel DQA1 allele have been identified in a
      panel of 367 dogs. These were suggested by unusual reaction patterns found in
      sequence specific oligonucleotide probing (SSOP) data. Four new alleles were
      confirmed using DNA cloning and sequencing.

PMID- 10651848
TI  - Analysis of deletions in three McLeod patients: exclusion of the XS locus from
      the Xp21.1-Xp21.2 region.
AB  - The McLeod syndrome is a rare X-linked recessive disorder characterized by blood
      group, neuromuscular and haematopoietic abnormalities. It is caused by XK gene
      defects and may include large deletions in the Xp21 region. Analysis of three
      unrelated McLeod patients for the presence of the XK, DMD, CYBB, ETX1, RPGR and
      OTC loci, as well as for the DXS709 marker, revealed deletions from the 39th exon
      of DMD to the ETX1 locus (patient Be), from the XK to RPGR loci (patient Bi) and
      from the XK to CYBB loci (patient Lh). All three patients normally expressed the
      Lutheran (Lu) red cell antigens, thus excluding the interval between the RPGR and
      DMD genes as site of the XS locus, previously mapped to the Xp21.2-Xq21.1 region
      and thought to regulate the expression of the LU blood group gene on chromosome
      19.

PMID- 10651849
TI  - Rare polymorphisms in the promoter regions of the human interleukin-12 p35 and
      interleukin-12 p40 subunit genes.
AB  - We have described two rare, single-nucleotide polymorphisms within the promoter
      regions of the IL-12 p35 and p40 subunit genes. Transitions C to T at position 
      916 from the transcription start of the IL-12 p35 gene and G to T at position 
      1287 in the IL-12 p40 gene were observed.

PMID- 10651850
TI  - Human immunoglobulin VH4 sequences resolved by population-based analysis after
      enzymatic amplification and denaturing gradient gel electrophoresis.
AB  - Exhaustive gene identification followed by assignment of the genes identified to
      corresponding loci is a key step in elucidating the physical structure of a
      multigene family. However, problems occur in this process because genes in a
      multigene family usually share a high degree of sequence identity and are highly
      polymorphic. To address these problems, an efficient population-based approach
      was developed. Using this approach, sequences in the human immunoglobulin VH4
      family were amplified by PCR with family-specific primers. Denaturing gradient
      gel electrophoresis (DGGE) was used to separate the resulting sequences with
      either very similar or identical sizes and differing by as little as 1 base pair
      (bp). Eighteen distinct bands and 21 banding patterns were observed in the
      samples collected from 41 unrelated individuals. Of the 18 bands, 12 were
      polymorphic. No sample had all 18 bands. The estimated frequencies for the
      alleles represented by the 18 bands ranged from 1.2 to 100%. The 18 sequences
      differed from each other by 1-19 bases (0.7 to 13%) within the 145-146-bp
      amplified region. Sequences in eight bands (44%) were not reported previously.
      These results were used to assign the majority (14 out of 18) of the VH4
      sequences to 10 loci. This PCR-DGGE method, in conjunction with a population
      based assay, may also be used to study other multigene families including those
      involved in the development of the immune system.

PMID- 10651851
TI  - Polymorphism of HLA-A, -B, -DRB1, -DQA1 and -DQB1 haplotypes in a Croatian
      population.
AB  - We describe for the first time extended haplotypes in a Croatian population. The
      present study gives the HLA-A, -B, -DRB1, -DQA1 and -DQB1 allele and haplotype
      frequencies in 105 families with at least two offspring. All individuals were
      studied by conventional serology for HLA class I antigens (A and B), while class
      II alleles (DRB1, DQA1, DQB1) were typed using the PCR-SSOP method. HLA
      genotyping was performed by segregation in all 105 families. For extended
      haplotype analysis, 420 independent parental haplotypes were included. Fourteen
      HLA-A, 18 HLA-B, 28 DRB1, 9 DQA1 and 11 DQB1 alleles were found in the studied
      population. Most of the DRB1 alleles in our population had an exclusive
      association with one specific DQA1-DQB1 combination. This strong linkage
      disequilibrium within the HLA class II region is often extended to the HLA-B
      locus. A total of 10 HLA-A, -B, -DRB1, -DQA1, -DQB1 haplotypes were observed with
      a frequency </= 1.0%. The three most frequent haplotypes were HLA-A1, B8,
      DRB1*0301, DQA1*0501, DQB1*0201; HLA-A3, B7, DRB1*1501, DQA1*0102, DQB1*0602 and
      HLA-A24, B44, DRB1*0701, DQA1*0201, DQB1*02. These results should provide a
      useful reference for further anthropological studies, transplantation studies,
      and studies of associations between HLA and diseases.

PMID- 10651852
TI  - A novel polymorphism in the human interleukin-13 (IL-13) promoter.
AB  - Using PCR-SSCP and automated nucleotide sequencing we have identified a novel
      single nucleotide C --> T polymorphism in the human IL-13 promoter, at position 
      1055 relative to the transcription start site. Allele frequency analysis in a
      population of normal cord blood donors indicated frequencies of 0.833 (C) and 0.
      167 (T).

PMID- 10651853
TI  - Nomenclature for factors of the HLA system, update September 1999.

PMID- 10651854
TI  - Do neurons have a reserve of sodium channels for the generation of action
      potentials? A study on acutely isolated CA1 neurons from the guinea-pig
      hippocampus.
AB  - The density of voltage-gated sodium channels is high in several regions of the
      neuronal membrane. It is unclear if this density of channels represents a reserve
      for the neuron, or if it fulfils a special role in action potential firing. This
      problem was addressed by studying sodium currents and action potentials in
      acutely isolated hippocampal CA1 neurons whose number of active sodium channels
      was acutely changed by applying the sodium channel blocker tetrodotoxin (TTX) at
      different concentrations. The results show that more than a third of the sodium
      channels can fail without affecting the single action potential. Thus, the
      neurons have a remarkable surplus of sodium channels. The surplus, however, is
      necessary for repetitive action potential firing, as every decrease in the
      fraction of sodium channels reduces the maximal frequency of action potentials
      that can be generated by the neuron.

PMID- 10651855
TI  - Routes of zinc entry in mouse cortical neurons: role in zinc-induced
      neurotoxicity.
AB  - Exposure of central neurons to Zn2+ triggers neuronal death. The routes of Zn2+
      entry were investigated in living cortical neurons from the mouse using the
      specific Zn2+ fluorescent dye N-(6-methoxy-8-quinolyl)-p-toluene sulphonamide
      (TSQ), which preferentially detects membrane-bound Zn2+. Exposure of cortical
      neurons to increasing concentrations of Zn2+ (1-100 microM) induced a progressive
      increase in the fluorescence of TSQ. This fluorescence signal was not attenuated
      by the permeation of plasma membrane with digitonin. Accordingly, the major part
      of TSQ fluorescence (two-thirds) was associated to the particulate fraction of
      cortical neurons exposed to Zn2+. These results suggest that Zn2+ detected with
      TSQ in neurons is mainly bound to membranes. TSQ fluorescence measured in neurons
      exposed to 3 microM Zn2+ was enhanced by Na+-pyrithione, a Zn2+ ionophore, alpha
      amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), N-methyl-D-aspartate
      (NMDA) or KCl-induced depolarization. However, in the absence of any treatment,
      TSQ labelling of neurons exposed to 3 microM Zn2+ was only decreased by NMDA
      receptor antagonists, whereas it remained unaltered in the presence of
      antagonists of AMPA receptors or L-type voltage-gated Ca2+ channels. Zn2+ entry
      through NMDA receptors did not contribute to Zn2+-induced neuronal death, as it
      was prevented by antagonists of NMDA receptors only when they were added after
      the Zn2+ exposure. Finally, Zn2+ induced a delayed accumulation of extracellular
      glutamate which might be responsible for the delayed NMDA receptor activation
      that leads to neuronal death.

PMID- 10651856
TI  - Differential regulation of the dopamine D1, D2 and D3 receptor gene expression
      and changes in the phenotype of the striatal neurons in mice lacking the dopamine
      transporter.
AB  - Mice with a genetic disruption of the dopamine transporter (DAT-/-) exhibit
      locomotor hyperactivity and profound alterations in the homeostasis of the
      nigrostriatal system, e.g. a dramatic increase in the extracellular dopamine
      level. Here, we investigated the adaptive changes in dopamine D1, D2 and D3
      receptor gene expression in the caudate putamen and nucleus accumbens of DAT-/-
      mice. We used quantitative in situ hybridization and found that the constitutive
      hyperdopaminergia results in opposite regulations in the gene expression for the
      dopamine receptors. In DAT-/- mice, we observed increased mRNA levels encoding
      the D3 receptor (caudate putamen, +60-85%; nucleus accumbens, +40-107%), and
      decreased mRNA levels for both D1 (caudate putamen, -34%; nucleus accumbens, 
      45%) and D2 receptors (caudate putamen, -36%; nucleus accumbens, -33%).
      Furthermore, we assessed the phenotypical organization of the striatal efferent
      neurons by using double in situ hybridization. Our results show that in DAT+/+
      mice, D1 and D2 receptor mRNAs are segregated in two different main populations
      corresponding to substance P and preproenkephalin A mRNA-containing neurons,
      respectively. The phenotype of D1 or D2 mRNA-containing neurons was unchanged in
      both the caudate putamen and nucleus accumbens of DAT-/- mice. Interestingly, we
      found an increased density of preproenkephalin A-negative neurons that express
      the D3 receptor mRNA in the nucleus accumbens (core, +35%; shell, +46%) of DAT-/-
      mice. Our data further support the critical role for the D3 receptor in the
      regulation of D1-D2 interactions, an action being restricted to neurons
      coexpressing D1 and D3 receptors in the nucleus accumbens.

PMID- 10651857
TI  - Transient neuromotor phenotype in transgenic spastic mice expressing low levels
      of glycine receptor beta-subunit: an animal model of startle disease.
AB  - Startle disease or hereditary hyperekplexia has been shown to result from
      mutations in the alpha1-subunit gene of the inhibitory glycine receptor (GlyR).
      In hyperekplexia patients, neuromotor symptoms generally become apparent at
      birth, improve with age, and often disappear in adulthood. Loss-of-function
      mutations of GlyR alpha or beta-subunits in mice show rather severe neuromotor
      phenotypes. Here, we generated mutant mice with a transient neuromotor deficiency
      by introducing a GlyR beta transgene into the spastic mouse (spa/spa), a
      recessive mutant carrying a transposon insertion within the GlyR beta-subunit
      gene. In spa/spa TG456 mice, one of three strains generated with this construct,
      which expressed very low levels of GlyR beta transgene-dependent mRNA and
      protein, the spastic phenotype was found to depend upon the transgene copy
      number. Notably, mice carrying two copies of the transgene showed an age
      dependent sensitivity to tremor induction, which peaked at approximately 3-4
      weeks postnatally. This closely resembles the development of symptoms in human
      hyperekplexia patients, where motor coordination significantly improves after
      adolescence. The spa/spa TG456 line thus may serve as an animal model of human
      startle disease.

PMID- 10651858
TI  - Convergence of segregated pheromonal pathways from the accessory olfactory bulb
      to the cortex in the mouse.
AB  - The accessory olfactory system mediates intraspecies pheromonal communication.
      Two subsets of spatially segregated vomeronasal sensory neurons, presumably
      handling functionally and structurally different sets of ligand molecules, can be
      distinguished. The two subsets of sensory neurons project their axons to
      segregated zones of the accessory olfactory bulb (AOB) and connect with zonally
      separated mitral/tufted (M/T) cells, suggesting that the accessory olfactory
      system is divided into two distinct pathways up to the level of the AOB. To
      examine whether the segregation is maintained at the accessory olfactory cortical
      (AOC) regions, we selectively tracer-labelled mitral/tufted cells located in the
      rostral, caudal or in both zones of the adult mouse AOB. The results demonstrate
      that the axonal projection patterns of rostral zone and caudal zone M/T cells
      were indistinguishable in the AOC regions. Mitral/tufted cell axons from either
      zone of the AOB covered the entire area of all four AOC regions: the bed nucleus
      of the accessory olfactory tract, the medial amygdaloid nucleus, the
      posteromedial cortical amygdaloid nucleus and the bed nucleus of the stria
      terminalis. Therefore, over the entire area of each AOC region, ensembles of
      cortical neurons receive input from both zonal subsets of M/T cells of the AOB.
      However, the present results do not rule out the possibility that individual
      cortical neurons sample information from M/T cells of a single zone. These
      results are consistent with the idea that the segregation of zonal pathways
      collapses in the AOC regions. Clusters of cortical neurons in each AOC region may
      combine information from both families of pheromone receptors and thus handle
      signals from structurally and functionally different categories of pheromone
      molecules.

PMID- 10651859
TI  - Spatiotemporal profile of synaptic activation produced by the electrical and
      visual stimulation of retinal inputs to the optic tectum: a current source
      density analysis in the pigeon (Columba livia).
AB  - The optic tectum of the pigeon is a highly organized, multilayered structure that
      receives a massive polystratified afference of at least five different
      populations of retinal ganglion cells and gives rise to various anatomically
      segregated efferent systems. The synaptic organization of retino-tectal circuitry
      is, at present, mostly unknown. To investigate the spatiotemporal profile of
      synaptic activation produced by differential (electrical and visual) stimulation
      of the retinal inputs, we performed a high-spatial-resolution current source
      density analysis in the optic tectum of the anaesthetized pigeon. Electrical
      stimuli consisted of brief pulses of different durations applied to the optic
      nerve head, while visual stimuli consisted of light flashes of different
      intensities. Electrical stimulation generated sinks confined to retinorecipient
      layers. The temporal structure, spatial location and thresholds of these sinks
      indicated that they are all due to primary tectal synapses of retinal fibers with
      different conduction velocities. Sinks evoked by the fastest retinal axons were
      more superficially located than sinks produced by slower retinal fibers. Visual
      stimulation, on the other hand, resulted in a more complex pattern of current
      sinks, with various sinks located in the retinorecipient layers and also well
      below. Visual stimulation induced action potentials at superficial as well as
      deep tectal levels. We conclude that electrical stimulation activates most of the
      populations of ganglion cells as well as their primary tectal synapses, but is
      unable to elicit a significant activation of secondary tectal synapses. Visual
      stimulation, on the contrary, activates just some of the incoming retinal
      populations, but in a way that produces noticeable secondary activation of
      intratectal circuits. Laminar segregation of retinally evoked tectal activity, as
      reported here, has also been found in other vertebrates. Similarities and
      differences with previous studies are discussed.

PMID- 10651860
TI  - Impaired cerebral autoregulation 24 h after induction of transient unilateral
      focal ischaemia in the rat.
AB  - Cerebral blood flow (CBF) and cerebral autoregulation have been investigated 24 h
      after transient focal ischaemia in the rat. Cerebral blood flow was measured
      autoradiographically before and during a moderate hypotensive challenge, to test
      autoregulatory responses, using two CBF tracers, (99m)Tc-d,l
      hexamethylproyleneamine oxide and 14C-iodoantipyrine. Prior to induced
      hypotension, CBF was significantly reduced within areas of infarction; cortex (28
      +/- 20 compared with 109 +/- 23 mL/100 g/min contralateral to ischaemic focus, P
      = 0.001) and caudate (57 +/- 31 compared with 141 +/- 32 mL/100 g/min
      contralaterally, P = 0.005). The hypotensive challenge (mean arterial pressure
      reduced to 60 mmHg by increasing halothane concentration) did not compromise grey
      matter autoregulation in the contralateral hemisphere; CBF data were not
      significantly different at normotension and during hypotension. However, in the
      ipsilateral hemisphere, a significant volume of cortex adjacent to the infarct,
      which exhibited normal flow at normotension, became oligaemic during the
      hypotensive challenge (e.g. frontal parietal cortex 109 +/- 15% to 65 +/- 15% of
      cerebellar flow, P < 0.01). This resulted in a 2.5-fold increase in the volume of
      cortex which fell below 50% cerebellar flow (39 +/- 34 to 97 +/- 46 mm3, P =
      0.003). Moderate hypotension induced a significant reduction in CBF in both
      ipsilateral and contralateral subcortical white matter (P < 0.01). In peri
      infarct caudate tissue, CBF was not significantly affected by hypotension. In
      conclusion, a significant volume of histologically normal cortex within the
      middle cerebral artery territory was found to have essentially normal levels of
      CBF but impaired autoregulatory function at 24 h post-ischaemia.

PMID- 10651861
TI  - Combined lesions of cholinergic and serotonergic neurons in the rat brain using
      192 IgG-saporin and 5,7-dihydroxytryptamine: neurochemical and behavioural
      characterization.
AB  - This study assessed behavioural and neurochemical effects of i.c.v. injections of
      both the cholinergic toxin 192 IgG-saporin (2 microgram) and the serotonergic
      toxin 5,7-dihydroxytryptamine (5,7-DHT; 150 microgram) in Long-Evans female rats.
      Dependent behavioural variables were locomotor activity, forced T-maze
      alternation, beam walking, Morris water-maze (working and reference memory) and
      radial-maze performances. After killing by microwave irradiation, the
      concentrations of acetylcholine, monoamines and 5-hydroxyindoleacetic acid (5
      HIAA) were measured in the hippocampus, frontoparietal cortex and striatum. 192
      IgG-saporin reduced the concentration of acetylcholine by approximately 40% in
      the frontoparietal cortex and hippocampus, but had no effect in the striatum. 5,7
      DHT lesions reduced the concentration of serotonin by 60% in the frontoparietal
      cortex and 80% in the hippocampus and striatum. Noradrenaline was unchanged in
      all structures except the ventral hippocampus where it was slightly increased in
      rats given 192 IgG-saporin. Cholinergic lesions induced severe motor deficits but
      had no other effect. Serotonergic lesions produced diurnal and nocturnal
      hyperactivity but had no other effect. Rats with combined lesions were more
      active than those with only serotonergic lesions, showed motor dysfunctions
      similar to those found in rats with cholinergic lesions alone, and exhibited
      impaired performances in the T-maze alternation test, the water-maze working
      memory test and the radial-maze. Taken together and although cholinergic lesions
      were not maximal, these data show that 192 IgG-saporin and 5,7-DHT lesions can be
      combined to selectively damage cholinergic and serotonergic neurons, and confirm
      that cholinergic-serotonergic interactions play an important role in some aspects
      of memory, particularly in spatial working memory.

PMID- 10651862
TI  - Release of classical transmitters and nitric oxide in the rat olfactory bulb,
      evoked by vaginocervical stimulation and potassium, varies with the oestrus
      cycle.
AB  - In vivo microdialysis was used to investigate the effects of ovariectomy and the
      oestrus cycle on vaginocervical stimulation-evoked classical transmitter and
      nitric oxide release in the olfactory bulb of anaesthetized (urethane) and
      conscious rats. During pro-oestrus/oestrus, vaginocervical stimulation (1 or 10
      min) significantly increased concentrations of glutamate, aspartate, GABA,
      noradrenaline, dopamine and nitric oxide (citrulline) but failed to do so in met
      oestrus/di-oestrus or following ovariectomy. Potassium chloride-evoked GABA,
      noradrenaline and nitric oxide release in the olfactory bulb was also
      significantly enhanced during pro-oestrus/oestrus. The effects of vaginocervical
      stimulation on olfactory bulb transmitter release during pro-oestrus/oestrus were
      significantly reduced by pelvic or vagus nerve section. Basal concentrations of
      classical transmitters and nitric oxide in the olfactory bulb did not vary across
      the oestrus cycle although noradrenaline and dopamine levels were reduced
      following ovariectomy. These results confirm our previous electrophysiological
      data showing that the olfactory bulb mitral cells are only excited by
      vaginocervical stimulation during pro-oestrus/oestrus. They also suggest that sex
      hormones acting primarily at the level of the olfactory bulb dramatically enhance
      the ability of vaginocervical stimulation to evoke release of both classical
      transmitters and nitric oxide in this region. Such alterations in neurochemical
      release in the olfactory bulb may be important for mediating plasticity changes
      underlying olfactory recognition of mates or offspring.

PMID- 10651863
TI  - Distinct immunohistochemical localization of two isoforms of Ca2+/calmodulin
      dependent protein kinase kinases in the adult rat brain.
AB  - Ca2+/calmodulin-dependent protein kinase IV (CaM-KIV) is thought to be involved
      in regulating gene expression by phosphorylating various transcriptional factors.
      CaM-KIV as well as CaM-KI are activated upon phosphorylation by two distinct
      isoforms of Ca2+/calmodulin-dependent protein kinase kinases, CaM-KKs alpha and
      beta. In this study, we raised isoform-specific monoclonal antibodies against CaM
      KKs and examined the immunohistochemical localization of CaM-KKs in the rat
      brain, compared with that of CaM-KIV. CaM-KK alpha-immunoreactivity was rather
      widely distributed in neurons throughout the brain, except cerebellar cortex. The
      highest levels of CaM-KK alpha-immunoreactivity were observed in the cerebral
      cortex, facial nucleus and motor neurons of the spinal cord. Moderate CaM-KK
      alpha-immunoreactivity was observed in the hippocampal formation, pontine nuclei
      and various brain stem nuclei including trigeminal, vestibular, cochlear and
      hypoglossal nuclei. In contrast, CaM-KK beta-immunoreactivity was relatively
      restricted in some neuronal populations. The highest levels of CaM-KK beta
      immunoreactivity were observed in the cerebellar granule cell layer, and moderate
      immunoreactivity was observed in the cerebral cortex, hippocampal formation,
      caudate putamen, pontine nuclei, cochlear nucleus and molecular layer of the
      cerebellum. In contrast to the prominent nuclear localization of CaM-KIV, both
      isoforms of CaM-KKs were localized in the perikaryal cytoplasm, dendrites and
      nerve terminals, but not in the cell nuclei. The distinct localization of two
      isoforms of CaM-KKs suggests that the complicated mechanisms for activation of
      CaM-KIV by CaM-KKs may be exerted in region-specific manners as well as
      intracellularly.

PMID- 10651864
TI  - Neurotrophins from dorsal root ganglia trigger allodynia after spinal nerve
      injury in rats.
AB  - Injury to peripheral nerves often results in chronic pain which is difficult to
      relieve. The mechanism underlying the pain syndrome remains largely unknown. In
      previous studies we showed that neurotrophins are up-regulated in satellite cells
      around sensory neurons following sciatic nerve lesion. In the present study, we
      have examined whether the neurotrophins in the dorsal root ganglia play any role
      in allodynia after nerve injury. Antibodies to different neurotrophins, directly
      delivered to injured dorsal root ganglia, significantly reduced (with different
      time sequences) the percentage of foot withdrawal responses evoked by von Frey
      hairs. The antibodies to nerve growth factor acted during the early phase but
      antibodies to neurotrophin-3 and brain-derived neurotrophic factor were effective
      during the later phase. Exogenous nerve growth factor or brain-derived
      neurotrophic factor, but not neurotrophin-3, directly delivered to intact dorsal
      root ganglia, trigger a persistent mechanical allodynia. Our results showed that
      neurotrophins within the dorsal root ganglia after peripheral nerve lesion are
      involved in the generation of allodynia at different stages. These studies
      provide the first evidence that ganglia-derived neurotrophins are a source of
      nociceptive stimuli for neuropathic pain after peripheral nerve injury.

PMID- 10651865
TI  - Bone morphogenetic protein-7 enhances dendritic growth and receptivity to
      innervation in cultured hippocampal neurons.
AB  - Members of the bone morphogenetic protein (BMP) family of growth factors are
      present in the central nervous system during development and throughout life.
      They are known to play an important regulatory role in cell differentiation, but
      their function in postmitotic telencephalic neurons has not been investigated. To
      address this question, we examined cultured hippocampal neurons following
      treatment with bone morphogenetic protein-7 (BMP-7, also referred to as
      osteogenic protein-1). When added at the time of plating, BMP-7 markedly
      stimulated the rate of dendritic development. Within 1 day, the dendritic length
      of BMP-7-treated neurons was more than twice that of controls. By three days the
      dendritic arbors of BMP-7-treated neurons had attained a level of branching
      similar to that of 2-week-old neurons cultured under standard conditions. Several
      findings indicate that BMP-7 selectively enhances dendritic development. While
      dendritic length was significantly increased in BMP-7-treated neurons, the length
      of the axon was not. In addition, the mRNA encoding the dendritic protein MAP2
      was significantly increased by BMP-7 treatment, but the mRNA for tubulin was not.
      Finally, BMP-7 did not enhance cell survival. Because dendritic maturation is a
      rate-limiting step in synapse formation in hippocampal cultures, we examined
      whether BMP-7 accelerated the rate at which neurons became receptive to
      innervation. Using two separate experimental paradigms, we found that the rate of
      synapse formation (assessed by counting synapsin I-positive presynaptic vesicle
      clusters) was increased significantly in neurons that had been exposed previously
      to BMP-7. Because BMP-7 and related BMPs are expressed in the hippocampus in
      situ, these factors may play a role in regulating dendritic branching and synapse
      formation in both development and plasticity.

PMID- 10651866
TI  - Differential signalling of the chemokine receptor CXCR4 by stromal cell-derived
      factor 1 and the HIV glycoprotein in rat neurons and astrocytes.
AB  - CXCR4 is the Gi protein-linked seven-transmembrane receptor for the alpha
      chemokine stromal cell-derived factor 1 (SDF-1), a chemoattractant for
      lymphocytes. This receptor is highly conserved between human and rodent. CXCR4 is
      also a coreceptor for entry of human immunodeficiency virus (HIV) in T cells and
      is expressed in the CNS. To investigate how these CXCR4 ligands influence CNS
      development and/or function, we have examined the expression and signalling of
      this chemokine receptor in rat neurons and astrocytes in vitro. CXCR4 transcripts
      and protein are synthesized by both cell types and in E15 brain neuronal
      progenitors. In these progenitors, SDF-1, but not gp120 (the HIV glycoprotein),
      induced activation of extracellular signal regulated kinases (ERKs) 1/2 and a
      dose-dependent chemotactic response. This chemotaxis was inhibited by Pertussis
      toxin, which uncouples Gi proteins and the bicyclam AMD3100, a highly selective
      CXCR4 antagonist, as well as by an inhibitor of the MAP kinase pathway. In
      differentiated neurons, both SDF-1 and the glycoprotein of HIV, gp120, triggered
      activation of ERKs with similar kinetics. These effects were significantly
      inhibited by Pertussis toxin and the CXCR4 antagonist. Rat astrocytes also
      responded to SDF-1 signalling by phosphorylation of ERKs but, in contrast to
      cortical neurons, no kinase activation was induced by gp120. Thus neurons and
      astrocytes can respond differently to signalling by SDF-1 and/or gp120. As SDF-1
      triggers directed migration of neuronal progenitors, this alpha chemokine may
      play a role in cortex development. In differentiated neurons, both natural and
      viral ligands of CXCR4 activate ERKs and may therefore influence neuronal
      function.

PMID- 10651867
TI  - Cellular and synaptic effect of substance P on neonatal phrenic motoneurons.
AB  - Experiments were carried out on the in vitro brainstem-spinal cord preparation of
      the newborn rat to analyse the effects of substance P (SP) on phrenic motoneuron
      (PMN) activity. In current-clamp mode, SP significantly depolarized PMNs,
      increased their input resistance, decreased the rheobase current and shifted the
      firing frequency-intensity relationships leftwards, but did not affect spike
      frequency adaptation or single spike configuration. The neurokinin receptor
      agonist NK1 had SP-mimetic effects, whereas the NK3 and NK2 receptor agonists
      were less effective and ineffective, respectively. In a tetrodotoxin-containing
      aCSF, only SP or the NK1 receptor agonist were still active. No depolarization
      was observed when the NK1 receptor agonist was applied in the presence of
      muscarine. In voltage-clamp mode, SP or the NK1 receptor agonist produced an
      inward current (ISP) which was not significantly reduced by extracellular
      application of tetraethylammonium, Co2+, 4-aminopyridine or Cs+. In aCSF
      containing tetrodotoxin, Co2+ and Cs+, ISP was blocked by muscarine. No PMN
      displayed any M-type potassium current but only a current showing no voltage
      sensitivity over the range -100 to 0 mV, reversing near the expected EK +, hence
      consistent with a leak current. SP application to the spinal cord only (using a
      partitioned chamber) significantly increased the phrenic activity. Pretreatment
      with the NMDA receptor antagonist DL-2-amino-5-phosphonovaleric acid (AP5)
      decreased the C4 discharge duration and blocked the effect of SP, thus exhibiting
      an NMDA potentiation by SP. In conclusion, SP modulates postsynaptically the
      response of phrenic motoneurons to the inspiratory drive through the reduction of
      a leak conductance and the potentiation of the NMDA component of the synaptic
      input.

PMID- 10651868
TI  - Intrathecally injected neurotrophins and the release of substance P from the rat
      isolated spinal cord.
AB  - The aim of this study was to investigate the effects of intrathecally delivered
      trophic molecules nerve growth factor (NGF), neurotrophin-3 (NT-3) and glial cell
      line-derived neurotrophic factor (GDNF) on substance P (SP) release and content
      in the rat spinal cord and SP content in sciatic nerve. SP release was assayed
      with an in vitro dorsal roots-attached spinal cord preparation, in which the
      roots were stimulated at A- or C-fibre strength, and SP levels were measured by
      radioimmunoassay (RIA). NGF but not NT-3 and GDNF treatment caused a significant
      increase in basal SP outflow; NGF, NT-3 but not GDNF increased C-fibre
      stimulation-evoked SP release, and capsaicin superfusion-induced SP release. The
      increase in C-fibre stimulation-evoked SP release over basal outflow was greater
      in NGF- than NT-3-treated cords, and nociceptive threshold testing showed that
      intrathecal NGF, but not NT-3 or GDNF treatment was associated with thermal
      hyperalgesia. There was no detectable A-fibre stimulation-induced SP release from
      any group as well as no change in SP content in the sciatic nerve and spinal
      cord. Systemic treatment with the NGF-sequestering fusion protein trkA-IgG
      significantly inhibited electrically or capsaicin-evoked SP release without
      affecting basal outflow and SP content in spinal cord and sciatic nerve. These
      results suggest that: (i) NGF tonically regulates the central synaptic function
      of SP-containing primary afferents; (ii) increased SP-release from the spinal
      cord is not necessarily associated with behavioural hyperalgesia as in NT-3
      treated rats there was increased SP release but no detectable hyperalgesia; and
      (iii) because A-fibre stimulation failed to increase SP release in any group,
      these neurotrophins are unlikely to be responsible for the de novo upregulation
      of SP in large afferents seen after peripheral inflammation or nerve injury.

PMID- 10651869
TI  - Endogenous and exogenous nitric oxide enhance the DNA strand scission induced by
      tert-butylhydroperoxide in PC12 cells via peroxynitrite-dependent and independent
      mechanisms, respectively.
AB  - A short-term exposure to tert-butylhydroperoxide (tB-OOH) promoted a
      concentration-dependent formation of DNA single-strand breaks in PC12 cells.
      These events were paralleled by an increase in the cytosolic concentration of
      Ca2+ that was in part cleared by the mitochondria. Unlike the extent of Ca2+
      mobilization and/or mitochondrial Ca2+ clearance, the DNA strand scission evoked
      by the hydroperoxide was markedly reduced by the nitric oxide (NO) scavenger 2
      phenyl-4,4,5,5-tetramethylimidazolin-1-oxyl-3-oxide (PTIO) or by the NO synthase
      inhibitor N-nitro-L-arginine methylester (L-NAME). Inhibitors of electron
      transport (rotenone and myxothiazol), ruthenium red (RR, a polycation which
      inhibits the calcium uniporter of mitochondria), or peroxynitrite scavengers
      (Trolox and L-methionine) were as effective as PTIO or L-NAME in inhibiting the
      DNA-damaging response mediated by tB-OOH. Rotenone, RR or peroxynitrite
      scavengers did not further reduce the residual DNA cleavage observed following
      treatment with tB-OOH in L-NAME-supplemented cells. Exogenous NO also increased
      the DNA damage caused by tB-OOH in L-NAME-supplemented cells and this response
      was blunted by RR or by inhibitors of electron transport but was insensitive to
      peroxynitrite scavengers. We conclude that both endogenous and exogenous NO
      enhance the DNA cleavage generated by tB-OOH in PC12 cells. However, only
      endogenous NO set the bases for an involvement of peroxynitrite in this DNA
      damaging response.

PMID- 10651870
TI  - Spontaneous and locomotor-related GABAergic input onto primary afferents in the
      neonatal rat.
AB  - The in vitro brain stem-spinal cord preparation of neonatal rats (0-5 days old)
      was used to examine the contribution of GABAA (gamma-aminobutyric acid) receptors
      to the spontaneous and locomotor-related antidromic firing in the dorsal roots of
      neonatal rats. Spontaneous bursts of antidromic discharges were generated by the
      underlying afferent terminal depolarizations reaching spiking threshold. The
      number of antidromic action potentials increased significantly in saline solution
      with Cl- concentration reduced to 50% of control. Bath application of the GABAA
      receptor antagonist bicuculline, at low concentrations (1-2 microM), or
      picrotoxin blocked the antidromic discharges in the dorsal roots almost
      completely. The increase in Cl- conductance was therefore mediated by an
      activation of GABAA receptors. Increasing the concentration of bicuculline to 10
      20 microM never blocked these discharges further. On the contrary, in half of the
      preparations, the number of antidromic action potentials was higher in the
      presence of high concentrations of bicuculline (10-20 microM) than in the
      presence of picrotoxin or low concentrations of bicuculline. This suggests that
      bicuculline, at high concentrations, may have other effects, in addition to
      blocking GABAA receptors. Dorsal root firing was observed during fictive
      locomotion induced by bath application of excitatory amino acids and serotonin. A
      rhythmical pattern was often demonstrated. Bicuculline at low concentrations
      caused a decrease of the antidromic discharge whereas, at high concentrations,
      bursts of discharges appeared. A double-bath with a barrier built at the L3 level
      was then used to separate the mechanisms which generate locomotion from those
      mediating primary afferent depolarizations. Excitatory amino acids and serotonin
      were perfused in the rostral pool only. Decreasing the concentration of chloride
      in the caudal bath caused a sharp increase in the number of antidromic action
      potentials recorded from the L5 dorsal root. These discharges, which were
      modulated in phase with the locomotor rhythm, were blocked by bicuculline. These
      data demonstrate the existence of a locomotor-related GABAergic input onto
      primary afferent terminals in the neonatal rat.

PMID- 10651871
TI  - Different spatiotemporal expression of DOC2 genes in the developing rat brain
      argues for an additional, nonsynaptic role of DOC2B in early development.
AB  - DOC2A and DOC2B are two homologous genes implicated in synaptic vesicle
      exocytosis. Their complementary, nonoverlapping expression patterns in adult rat
      brain suggest that they exert similar functions in different neurons. We have
      analysed the expression pattern of the two genes in the developing rat brain by
      in situ hybridization. Unexpectedly, we found no parallel expression of the two
      genes during development. DOC2B mRNA was highly expressed as early as embryonic
      day 12 (E12) throughout the neuroepithelium, long before synaptic transmission is
      functional, and the expression remained abundant from E12 onwards. In contrast,
      faint expression of DOC2A transcripts was first detected at E17 in ventral brain
      areas, and it extended gradually to other brain structures in the sequence of
      their ontology, i.e. structures that had formed first also expressed DOC2A first.
      At postnatal day 3, both genes were highly expressed throughout the brain. This
      overlapping expression diverged to the complementary distribution of the adult
      brain. The temporal and spatial differences in expression point to a functional
      divergence between these homologous genes during brain development: the pattern
      of DOC2A is consistent with its proposed synaptic function, whereas that of DOC2B
      suggests an additional, nonsynaptic role in proliferating cells.

PMID- 10651872
TI  - The architecture of the colour centre in the human visual brain: new results and
      a review.
AB  - We have used the technique of functional magnetic resonance imaging (fMRI) and a
      variety of colour paradigms to activate the human brain regions selective for
      colour. We show here that the region defined previously [Lueck et al. (1989)
      Nature, 340, 386-389; Zeki et al. (1991) J. Neurosci., 11, 641-649; McKeefry &
      Zeki (1997) Brain, 120, 2229-2242] as the human colour centre consists of two
      subdivisions, a posterior one, which we call V4 and an anterior one, which we
      refer to as V4alpha, the two together being part of the V4-complex. The posterior
      area is retinotopically organized while the anterior is not. We discuss our new
      findings in the context of previous studies of the cortical colour processing
      system in humans and monkeys. Our new insight into the organization of the colour
      centre in the human brain may also account for the variability in both severity
      and degree of recovery from lesions producing cerebral colour blindness
      (achromatopsia).

PMID- 10651873
TI  - APPENDIX. A computer model of the Land Mondrian retinex experiment.

PMID- 10651874
TI  - L-type Ca2+ channels and purinergic P2X2 cation channels participate in calcium
      tyrosine kinase-mediated PC12 growth cone arrest.
AB  - During development and regeneration of the nervous system, growth cones of the
      various nerve cells navigate and direct neurite elongation by detecting and
      responding to cues in the environment. To investigate changes in growth cone
      behaviour due to calcium influx we used nerve growth factor (NGF)-induced growth
      cones of PC12 (rat pheochromocytoma cells) cells as a model. High external
      concentrations of potassium and ATP depress growth cone motility, induce club
      shaped growth cones and reduce filopodia length and the number and relative F
      actin contents of single growth cones (r.a.c.), respectively. The cellular
      responses are mediated by a sustained increase in the intracellular free Ca2+
      concentrations ([Ca2+]i) as monitored by calcium-sensitive fluorescent dyes and
      confocal microfluorimetry. The responses are not detectable in the presence of
      the protein tyrosine kinase inhibitor genistein. Immunocytochemistry revealed an
      increased level of tyrosine-phosphorylated proteins in cell bodies and growth
      cones but not in cell nuclei. Paxillin, a cytoskeleton-associated protein located
      in neurites and growth cones, was detected among the phosphotyrosine proteins.
      The sustained (> 30 s) Ca2+ influx through voltage-gated L-type but not N- or P
      type Ca2+ channels induced the F-actin loss and tyrosine phosphorylation. Ca2+
      entry through P2X2 ligand-gated channels caused the same effects. Our data
      suggest the following mechanism: increased [Ca2+]i levels activate tyrosine
      kinases located close to the ion channels which then leads to changes in
      morphology due to tyrosine phosphorylation of proteins, e. g. paxillin.

PMID- 10651875
TI  - Precise matching of olivo-cortical divergence and cortico-nuclear convergence
      between somatotopically corresponding areas in the medial C1 and medial C3 zones
      of the paravermal cerebellum.
AB  - The paravermal cerebellar cortex contains three spatially separate zones (the C1,
      C3 and Y zones) which form a functionally coupled system involved in the control
      of voluntary limb movements. A series of 'modules' has been postulated, each
      defined by a set of olivary neurons with similar receptive fields, the cortical
      microzones innervated by these neurons and the group of deep cerebellar nuclear
      neurons upon which the microzones converge. A key feature of this modular
      organization is a correspondence between cortical input and output, irrespective
      of the zonal identity of the microzone. This was tested directly using a combined
      electrophysiological and bi-directional tracer technique in barbiturate
      anaesthetized cats. During an initial operation, small injections of a mix of
      retrograde and anterograde tracer material (red beads combined with Fluoro-Ruby
      or green beads combined with biotinylated dextran amine or Fluoro-Emerald) were
      made into areas of the medial C1 and medial C3 zones in cerebellar lobule V
      characterized by olivo-cerebellar input from the ventral forelimb. The inferior
      olive and the deep cerebellar nuclei were then scrutinized for retrogradely
      labelled cells and anterogradely labelled axon terminals, respectively. For
      individual experiments, the degree of C1-C3 zone terminal field overlap in the
      nucleus interpositus anterior was plotted as a function of either the regional
      overlap of single-labelled cells or the proportion of double-labelled cells in
      the dorsal accessory olive. The results were highly positively correlated,
      indicating that cortico-nuclear convergence between parts of the two zones is in
      close proportion to the corresponding olivo-cerebellar divergence, entirely
      consistent with the modular hypothesis.

PMID- 10651876
TI  - Reversible protein kinase C activation in PC12 cells: effect of NGF treatment.
AB  - Although protein kinase C (PKC) is a key enzyme in the signal transduction
      process, there is little information on the mechanism leading to PKC activation
      in living cells. Using a new fluorescence imaging method, we studied this
      mechanism and correlated PKC conformational changes with intracellular Ca2+
      concentration. PC12 cells were simultaneously loaded with Fura-2-AM and Fim-1,
      two fluorescent probes, which recognize Ca2+ and PKC, respectively. KCl and
      carbachol (an agonist to muscarinic receptors) applications induced dose
      dependent increases of fluorescence for both probes. Both Ca2+ and PKC responses
      were observed within seconds following KCl or carbachol application, and were
      reversible upon stimulus withdrawal. PKC activation kinetics was slightly more
      rapid than the Ca2+ response after KCl application. After nerve growth factor
      (NGF) treatment of the cells, the amplitude of the KCl-induced PKC responses was
      larger indicating an increase in the activated PKC-pool in these cells. This
      difference between control and NGF-treated cells was not observed following
      carbachol application, suggesting the involvement of different PKC pools. While
      the Ca2+ response uniformly occurred in the cytosol, the PKC response displayed a
      patch pattern with higher intensities in the peripheral zone near the plasma
      membrane. This heterogeneous distribution of PKC activation sites was similar to
      the immunocytological localization of Ca2+-dependent and independent PKC
      isoforms, which suggested that at least several PKC isoforms interacted with
      intracellular elements. Upon repeated stimulation, the PKC response rapidly
      desensitized.

PMID- 10651877
TI  - A novel carboxypeptidase B that processes native beta-amyloid precursor protein
      is present in human hippocampus.
AB  - The processing of beta-amyloid precursor protein (APP) and generation of beta
      amyloid (Abeta) are associated with the pathophysiology of Alzheimer's disease
      (AD). As the proteases responsible for the process in the human brain have yet to
      be clarified, we have searched for activities capable of cleaving native brain
      APP in the human hippocampus. A 40-kDa protein with proteolytic activity that
      degrades native brain APP in vitro was purified and characterized; molecular
      analysis identified it as a novel protease belonging to the carboxypeptidase B
      (CPB) family. PC12 cells overexpressing the cDNA encoding this protease generate
      a major 12-kDa beta-amyloid-bearing peptide in cytosol, a peptide which has also
      been detected in a cell-free system using purified brain APP as substrate.
      Although the protease is homologous to plasma CPB synthesized in liver, it has
      specific domains such as C-terminal 14 amino acid residues. Western analysis,
      cDNA-cloning process and Northern analysis suggested a brain-specific expression
      of this protease. An immunohistochemical study showed that the protease is
      expressed in various neuronal perikarya, including those of pyramidal neurons of
      the hippocampus and ependymal-choroid plexus cells, and in a portion of the
      microglia of normal brains. In brains of patients with sporadic AD, there is
      decreased neuronal expression of the protease, and clusters of microglia with
      protease immunoreactivity associated with its extracellular deposition are
      detected. These findings suggest that brain CPB has a physiological function in
      APP processing and may have significance in AD pathophysiology.

PMID- 10651878
TI  - Metabotropic glutamate receptors and blockade of glial Krebs cycle depress
      glycinergic synaptic currents of mouse hypoglossal motoneurons.
AB  - Metabotropic glutamate receptors are known to depress synaptic transmission by
      inhibiting transmitter release from presynaptic nerve terminals. This study
      reports the effects of presynaptic metabotropic glutamate receptor activation on
      inhibitory synaptic transmission in hypoglossal motoneurons in brainstem slice
      preparations of neonatal mice. Whole-cell patch-clamp recordings were performed
      on hypoglossal motoneurons of 2-6-day-old mice. Monosynaptic glycinergic currents
      were elicited by electrical stimulation of the nucleus of Roller. Application of
      the specific metabotropic glutamate receptor agonists (+/-)-1-aminocyclopentane
      trans-1,3,dicarboxylic acid (t-ACPD), (2S, 2'R,3'R)-2-(2',3'
      dicarboxylcyclopropyl)-glycine (DCG-IV) or L-2-amino-4-phosphonobutyric acid (L
      AP4) depressed stimulus-evoked glycinergic inhibitory postsynaptic currents
      (IPSCs) by an average of 39.5, 59.4 and 39.2%, respectively. In the presence of t
      ACPD, glycinergic miniature IPSCs were reduced in frequency but not in amplitude,
      which is indicative of a presynaptic mechanism. A similar reduction of IPSC
      amplitude was observed in the presence of elevated extracellular glutamate or
      during application of D, L-threo-hydroxyaspartate (THA), a blocker of glutamate
      transport, respectively. The data suggest that uptake of glutamate, which is
      predominately carried out by glial cells, can prevent spill-over of glutamate and
      activation of metabotropic glutamate receptors. A reduction of IPSCs was also
      observed following application of monofluoroacetic acid, a substance acting
      specifically on glial cells. Our results suggest that glial regulation of
      extracellular glutamate uptake can prevent spill-over of glutamate, and
      glutamatergic depression of glycinergic inhibition in hypoglossal motoneurons.

PMID- 10651879
TI  - Substantia nigra pars reticulata units in 6-hydroxydopamine-lesioned rats:
      responses to striatal D2 dopamine receptor stimulation and subthalamic lesions.
AB  - In order to increase our understanding of Parkinson's disease pathophysiology, we
      studied the effects of intrastriatally administered selective dopamine receptor
      agonists on single units from the substantia nigra pars reticulata of 6
      hydroxydopamine (6-OHDA)-lesioned rats with or without an additional subthalamic
      nucleus lesion. Nigral pars reticulata units of 6-OHDA-lesioned rats were
      classified into two types, showing regular and bursting discharge patterns,
      respectively ('non-burst' and 'burst' units). Non-burst and burst units showed
      distinct responses to intrastriatal quinpirole (the former were excited and burst
      units inhibited). Furthermore, subthalamic nucleus lesions significantly
      decreased the number of nigral units showing a spontaneous bursting pattern, and
      reduced the proportion of units that responded to quinpirole. In contrast,
      subthalamic lesions did not alter the proportion of nigral units that responded
      to SKF38393, although the lesions changed some response features, e.g. response
      type and magnitude. Burst analysis showed that quinpirole did not modify the
      discharge pattern of burst units, whereas SKF38393 produced a shift to regular
      firing in 62% of the burst units tested. In conjunction, our results support
      that: (i) the subthalamic nucleus has an important influence on output nuclei
      firing pattern; (ii) striatal D2 receptors have a strong influence on nigral
      firing rate, and a less relevant role in controlling firing pattern; (iii) burst
      and non-burst units differ in their response to selective stimulation of striatal
      dopamine receptors; (iv) the effects of striatal D2 receptors on nigral units are
      mainly, though not exclusively, mediated by the subthalamic nucleus; and (v)
      nigral responses to SKF38393 involve the subthalamic nucleus.

PMID- 10651880
TI  - Comparison of the selectivity of postsynaptic potentials and spike responses in
      cat visual cortex.
AB  - Intracellular recordings were made from neurons in the cat visual cortex (area
      17) to compare the orientation and direction selectivities of the output of a
      cell with those of the input the cell receives. The input to a cell was estimated
      from the PSPs (postsynaptic potentials) evoked by visual stimulation, and the
      output estimated from the number of spikes generated during the same responses.
      For the whole sample, selectivity of the output of cells was significantly higher
      than selectivity of their input. Upon PSP to spike transformation, the
      selectivity index was, on average, doubled. However, the degree of the
      selectivity improvement in individual cells was very different, varying from
      cases in which highly selective output was created from a poorly selective input
      and thus selectivity was greatly improved, to little or no improvement in other
      neurons. The improvement of selectivity was not correlated with resting membrane
      potential, threshold for action potential generation, background discharge rate
      or amplitude of optimal PSP response. Further, no systematic difference was found
      between simple and complex cells in the input-output relations, indicating that
      the 'tip of the iceberg' effect on shaping the response selectivity was cell
      specific, but not cell type specific. This supports the notion that multiple
      mechanisms are responsible for generation of the response selectivity, and that
      the contribution of any particular mechanism may vary from one cell to the other.
      The heterogeneity of the input-output relations in visual cortical cells could
      indicate different functions of cells in the cortical network; some cells are
      creating selectivity de novo, the function of other neurons probably being
      repetition and amplification of the selected signal and arrangement of the output
      of a whole column.

PMID- 10651881
TI  - Selective suppression of horizontal propagation in rat visual cortex by
      norepinephrine.
AB  - The release of norepinephrine in the cerebral cortex from axon terminals of locus
      coeruleus neurons was suggested to be involved in the control of attention.
      Accumulating data indicate that the responses of cortical neurons are varied when
      norepinephrine is applied iontophoretically in the vicinity of the cells being
      recorded. However, it is not known how the pattern of excitatory propagation is
      modified when norepinephrine is applied over a wide area in the visual cortex. By
      applying optical imaging to rat visuocortical slices, we found a new mode of
      norepinephrine action; a prominent suppression of the horizontal propagation in
      layers II/III. This action of norepinephrine was confirmed by the simultaneous
      recording of field potentials from multiple sites by use of a multi-electrode
      dish. Furthermore, our electrophysiological recordings showed that this
      norepinephrine action is exerted through suppression of excitatory neural
      transmission and enhancement of inhibitory transmission to the pyramidal neurons
      in these layers. Because the release of norepinephrine in the visual cortex is
      regulated by the level of attention, the neural basis of visual attention may
      relate partially to the suppression of the integration of visual information by
      norepinephrine resulting in a state-dependent restructuring of the receptive
      field.

PMID- 10651882
TI  - Mechanisms of human motion perception: combining evidence from evoked potentials,
      behavioural performance and computational modelling.
AB  - Based on single cell recordings in monkey, it has been suggested that neural
      activity can be related directly to psychophysically measured threshold
      behaviour. Here, we investigated in humans whether evoked potentials correlate
      with behavioural measurements like discrimination thresholds and reaction time.
      Subjects were asked to report the perceived direction of object motion stimuli
      which contained variable amounts of coherent motion. Simultaneously, we recorded
      evoked potentials with a multielectrode array, or measured the reaction time. We
      show here that motion coherence had a strong influence on both amplitude and
      latency of the evoked potential. Stronger motion signals evoked stronger and
      faster cortical responses. The latency reduction of the motion onset response
      with increasing coherence correlated very well with the concurrent decrease in
      reaction time. Taken together, these results suggest that temporal integration is
      an important step in analysing motion signals to generate a reliable behavioural
      response. We stimulated a two-dimensional array of correlation-type motion
      detectors with the same motion sequences, and analysed the distribution of local
      motion signals according to signal detection theory. Performance resembled that
      of human subjects when the decision strategy was optimized so as to exclude small
      signals and, in particular, when the ideal observer had some knowledge about a
      region of interest in which the object was to be expected.

PMID- 10651883
TI  - Glucocorticoid receptor impairment alters CNS responses to a psychological
      stressor: an in vivo microdialysis study in transgenic mice.
AB  - To study the consequences of impaired functioning of the glucocorticoid receptor
      (GR) for behavioural, neuroendocrine and neurochemical responses to a
      psychological stressor, a transgenic mouse expressing antisense RNA against GR
      was used. Previous studies on these transgenic mice have shown that impairment of
      GR evolves in disturbed neuroendocrine regulation and certain behavioural
      responses to stress. Here we investigated putative disturbances on the level of
      brain neurotransmission in GR-impaired (GR-i) mice using an in vivo microdialysis
      method. Through a microdialysis probe in the hippocampus, serotonin (5-HT), 5
      hydroxyindoleacetic acid (5-HIAA) and free corticosterone [as an index of
      hypothalamic-pituitary-adrenocortical (HPA) axis activity] were monitored.
      Moreover, specific behaviours (e.g. grooming, eating/drinking, sniffing, nest
      building and locomotion) displayed by the mice during collection of the
      dialysates were scored. Measurement of dialysate concentrations of corticosterone
      on days 1 and 3 after insertion of the microdialysis probe showed that the free
      levels of this glucocorticoid were significantly lower in GR-i mice toward the
      evening. On day 2 after insertion of the microdialysis probe, baseline values of
      dialysate corticosterone, 5-HT and 5-HIAA were assessed, after which mice were
      exposed to a rat placed into their home cage. The rat and mouse were separated by
      a Plexiglas wall. A positive correlation between baseline hippocampal
      extracellular levels of 5-HT and 5-HIAA and the time spent performing active
      behaviours was observed in both genotypes. The main active behaviour performed at
      the baseline was grooming behaviour. During the rat exposure period, control mice
      remained mostly sitting and/or lying with their eyes fixed on the rat. Moreover,
      they showed a profound rise in free corticosterone levels. In contrast, GR-i mice
      displayed significantly more activities along the separation wall and a trend
      toward more grooming behaviour, but no increase of free corticosterone. In both
      mouse lines, exposure to a rat increased hippocampal extracellular levels of 5-HT
      and 5-HIAA. The rise in 5-HT was, however, more pronounced in the GR-i mice. From
      these data it may be concluded that life-long GR impairment has profound
      consequences for behavioural and neuroendocrine responses to a psychological
      stressor. Moreover, long-term impaired functioning of GR evolves in hyper
      responsiveness of the raphe-hippocampal serotonergic system.

PMID- 10651884
TI  - Clonidine blocks stress-induced reinstatement of heroin seeking in rats: an
      effect independent of locus coeruleus noradrenergic neurons.
AB  - Using a reinstatement procedure, it has been shown that intermittent footshock
      stress reliably reinstates extinguished drug-taking behaviour in rats. Here we
      studied the role of noradrenaline (NE), one of the main brain neurotransmitters
      involved in responses to stress, in reinstatement of heroin seeking. We first
      determined the effect of clonidine, an alpha-2 adrenergic receptor agonist that
      decreases NE cell firing and release, on stress-induced reinstatement of heroin
      seeking. Rats were trained to self-administer heroin (0.1 mg/kg per infusion, IV,
      three 3-h sessions per day) for 9-10 days. Extinction sessions were given for up
      to 11 days during which saline was substituted for the drug. Tests for
      reinstatement were then conducted after exposure to intermittent footshock (5, 15
      and 30 min, 0.5 mA). During testing, clonidine was injected systemically (10-40
      microgram/kg, i.p.) or directly into the lateral or fourth ventricles (1-3
      microram). Clonidine (1-2 microgram per site) or its charged analogue, 2-[2, 6
      diethylphenylamino]-2-imidazole (ST-91, 0.5-1 microgram per site), was also
      injected bilaterally into the locus coeruleus (LC), the main noradrenergic cell
      group in the brain. Clonidine blocked stress-induced reinstatement of drug
      seeking when injected systemically or into the cerebral ventricles. In contrast,
      neither clonidine nor ST-91 consistently altered stress-induced reinstatement
      when injected into the locus coeruleus. We therefore studied the effect of
      lesions of the lateral tegmental NE neurons on stress-induced reinstatement. 6
      Hydroxydopamine (6-OHDA) lesions performed after training for heroin self
      administration had no effect on extinction of heroin-taking behaviour, but
      significantly attenuated reinstatement induced by intermittent footshock. These
      data suggest that: (i) clonidine prevents stress-induced relapse to heroin
      seeking by its action on neurons other than those of the locus coeruleus; and
      (ii) activation of the lateral tegmental NE neurons contributes to stress-induced
      reinstatement of heroin seeking.

PMID- 10651885
TI  - Neurophysiological correlates of face gender processing in humans.
AB  - Event-related potentials (ERPs) were recorded while subjects were involved in
      three gender-processing tasks based on human faces and on human hands. In one
      condition all stimuli were only of one gender, preventing any gender
      discrimination. In a second condition, faces (or hands) of men and women were
      intermixed but the gender was irrelevant for the subject's task; hence gender
      discrimination was assumed to be incidental. In the third condition, the task
      required explicit gender discrimination; gender processing was therefore assumed
      to be intentional. Gender processing had no effect on the occipito-temporal
      negative potential at approximately 170 ms after stimulation (N170 component of
      the ERP), suggesting that the neural mechanisms involved in the structural
      encoding of faces are different from those involved in the extraction of gender
      related facial features. In contrast, incidental and intentional processing of
      face (but not hand) gender affected the ERPs between 145 and 185 ms from stimulus
      onset at more anterior scalp locations. This effect was interpreted as evidence
      for the direct visual processing of faces as described in Bruce and Young's model
      [Bruce, V. & Young, A. (1986) Br. J. Psychol., 77, 305-327]. Additional gender
      discrimination effects were observed for both faces and hands at mid-parietal
      sites around 45-85 ms latency, in the incidental task only. This difference was
      tentatively assumed to reflect an early mechanism of coarse visual
      categorization. Finally, intentional (but not incidental) gender processing
      affected the ERPs during a later epoch starting from approximately 200 ms and
      ending at approximately 250 ms for faces, and approximately 350 ms for hands.
      This later effect might be related to attention-based gender categorization or to
      a more general categorization activity.

PMID- 10651886
TI  - Neuroanatomical correlates of the near response: voluntary modulation of
      accommodation/vergence in the human visual system.
AB  - This study identifies brain regions participating in the execution of eye
      movements for voluntary positive accommodation (VPA) during open-loop vergence
      conditions. Neuronal activity was estimated by measurement of changes in regional
      cerebral blood flow (rCBF) with positron emission tomography and 15O-water.
      Thirteen naive volunteers viewed a checkerboard pattern with their dominant right
      eye, while a lens interrupted the line of gaze during alternate 1.5 s intervals.
      Three counterbalanced tasks required central fixation and viewing of a stationary
      checkerboard pattern: (i) through a 0.0 diopter (D) lens; (ii) through a -5.0-D
      lens while avoiding volitional accommodation and permitting blur; and (iii)
      through a -5. 0-D lens while maintaining maximal focus. The latter required large
      amplitude, high-frequency VPA. As an additional control, seven of the subjects
      viewed passively a digitally blurred checkerboard through a 0.0-D lens as above.
      Optometric measurements confirmed normal visual acuity and ability to perform the
      focusing task (VPA). Large-amplitude saccadic eye movements, verified absent by
      electro-oculography, were inhibited by central fixation. Image averaging across
      subjects demonstrated multifocal changes in rCBF during VPA: striate and
      extrastriate visual cortices; superior temporal cortices; and cerebellar cortex
      and vermis. Decreases in rCBF occurred in the lateral intraparietal area,
      prefrontal and frontal and/or supplementary eye fields. Analysis of regions of
      interest in the visual cortex showed systematic and appropriate task dependence
      of rCBF. Activations may reflect sensorimotor processing along the reflex arc of
      the accommodation system, while deactivations may indicate inhibition of systems
      participating in visual search.

PMID- 10651887
TI  - Evaluation of simple and complex sensorimotor behaviours in rats with a partial
      lesion of the dopaminergic nigrostriatal system.
AB  - We have examined the behavioural consequences of a partial unilateral
      dopaminergic denervation of the rat striatum. This partial lesion was obtained by
      an intrastriatal 6-hydroxy-dopamine injection (6-OHDA, 20 or 10 microgram divided
      between two injection sites) and was compared with a unilateral complete lesion
      resulting from an injection of 6-OHDA (2 x 6 microgram) into the medial forebrain
      bundle. Quantification of striatal dopamine (DA) and its metabolites, and the
      immunohistochemical evaluation of the nigrostriatal DA system confirmed the
      complete and partial lesions. Animals with complete striatal denervation
      displayed both apomorphine- and amphetamine-induced rotations whereas the partial
      denervation elicited amphetamine-induced rotations only. However, the rates of
      amphetamine-induced rotation were not correlated with the size of the lesion. In
      contrast, the paw-reaching impairments were significantly correlated with the
      striatal dopaminergic depletion. When evaluated in the staircase test, animals
      with partial denervation were impaired exclusively for the paw contralateral to
      the side of the lesion. This motor deficit (50-75%) included all components of
      the skilled paw use (i.e. attempt, motor coordination and success) and was
      observed at least 12 weeks after the lesion. However, these animals were able to
      perform normal stepping adjustments with the impaired paw, indicating that the
      partial lesion induced a coordination deficit of the paw rather than a deficit of
      movement initiation. After a complete lesion, stepping adjustments of the
      contralateral paw were dramatically impaired (by 80%), an akinesia which almost
      certainly accounted for the great deficit in skilled paw use. The paw-reaching
      impairments resulting from the partial striatal denervation are proposed as a
      model of the early symptoms of Parkinson's disease and may be useful for the
      development of restorative therapies.

PMID- 10651888
TI  - Evolution of changes in neuronal activity in the subthalamic nucleus of rats with
      unilateral lesion of the substantia nigra assessed by metabolic and
      electrophysiological measurements.
AB  - Cellular expression of cytochrome oxidase subunit I (COI) mRNA has recently been
      used as a metabolic marker for neuronal activity to study the functional changes
      in the subthalamic nucleus (STN) in parkinsonism. The previous experimental
      studies have been performed when the pathological state was stabilized at a
      maximal level. In order to determine the evolution of changes in neuronal
      activity in the STN after nigrostriatal denervation, we analysed by in situ
      hybridization the cellular expression of COI mRNA in the subthalamic neurons at
      different times, from 6 h to 14 days, after unilateral intranigral microinjection
      of 6-hydroxydopamine (6-OHDA) in rats. In parallel, the time-dependent changes of
      the unit neuronal activity of subthalamic neurons have been recorded. Levels of
      COI mRNA increased by 41% in subthalamic neurons from 24 h after 6-OHDA
      intoxication, to 14 days (+26%). Similarly, electrical activity started to
      increase slightly 24 h after lesion (+20%) and remained significantly higher at
      14 days after the lesion (+189%). Changes in neuronal mean discharge rate were
      associated with changes in the pattern of spiking activity, from a regular firing
      pattern to an irregular one with a high bursting activity. These results show
      that: (i) the hyperactivity of the STN represents a very early phenomenon in the
      physiopathology of parkinsonian syndromes; and (ii) that changes in COI mRNA
      expression slightly precede changes in electrical neuronal activity.

PMID- 10651889
TI  - Age-related impairment in LTP is accompanied by enhanced activity of stress
      activated protein kinases: analysis of underlying mechanisms.
AB  - The age-related impairment in long-term potentiation in the rat dentate gyrus is
      coupled with an increase in the proinflammatory cytokine, interleukin-1beta (IL
      1beta). It is possible that this increase in IL-1beta might be a consequence of
      the age-related increase in reactive oxygen species production in hippocampal
      tissue. In this study we set out to identify the underlying cause of the age
      related increase in reactive oxygen species production and to establish whether
      any consequences of such a change might impact on the ability of aged rats to
      sustain long-term potentiation (LTP). We report that there was an age-related
      increase in the activity of superoxide dismutase but no parallel increases in
      activities of glutathione peroxidase or catalase, while age-related decreases in
      the concentration of the scavengers, vitamins E and C and glutathione were also
      observed. We propose that these compromises in antioxidative strategies may
      result in an increase in reactive oxygen species production. The data described
      indicate that IL-1beta and H2O2 increase the activity of two stress-activated
      mitogen-activated protein kinases, c-Jun NH2-terminal kinase (JNK) and p38 in
      vitro, while age-related increases in both kinases were observed. We propose that
      the endogenous increase in these parameters which occurs with age induces the
      increase in activity of the stress-activated kinases, which in turn impacts on
      the ability of the aged rat to sustain LTP.

PMID- 10651890
TI  - Scale-invariant superiority of foveal vision in perceptual categorization.
AB  - The recognition of objects is exceedingly difficult in indirect view. This
      complication cannot be explained in terms of retino-cortical magnification, as
      size scaling fails to establish position invariance both for character
      recognition [Strasburger, H. & Rentschler, I. (1996) Eur. J. Neurosci., 8 1787
      1791] and pattern classification [Juttner, M. & Rentschler, I. (1996) Vision
      Res., 36, 1007-1021]. Thus we compared, for two tasks of discrimination learning
      and category learning with respect to a common set of grey-level patterns, how
      humans perform in foveal and extrafoveal vision. Observers learnt to discriminate
      (size-scaled) images equally well in foveal and extrafoveal view, whereas they
      displayed profound deficiencies in extrafoveal category learning for the same
      patterns. From the behavioural learning data, internal representations of the
      learning signals were reconstructed by means of computer simulations. For foveal
      view, these representations were found to be veridical to their physical
      counterparts for both learning tasks. For extrafoveal view, they were severely
      distorted for category learning but not for discrimination learning. A variance
      reduction of the pattern classes by a factor of 100 reduced the dissociation
      between extrafoveal categorization and discrimination but did not remove it.
      These observations suggest a scale-invariant superiority of foveal vision for
      learning object categories. This implies a high degree of space variance of
      visual cognition which is vastly underestimated by classical measures of visual
      performance, e.g. acuity, visual field and contrast sensitivity.

PMID- 10651891
TI  - Different forms of LTD in the CA1 region of the hippocampus: role of age and
      stimulus protocol.
AB  - In this study, we have investigated the developmental range over which different
      stimulus protocols induce long-term depression (LTD). Low-frequency stimulation
      (LFS; 900 stimuli, 1 Hz) produced LTD in hippocampal slices from rats younger
      than approximately 40 days old, but not in animals aged between approximately 40
      days and 16 weeks. We demonstrate, however, that different stimulus protocols can
      result in LTD in the adult hippocampus. Whilst one paired-pulse low-frequency
      stimulus protocol [PP-LFS; 50 ms paired-pulse interval (PPI), 900 pairs of
      stimuli] produced N-methyl-D-aspartate (NMDA) receptor-independent LTD, another
      PP-LFS protocol (200 ms PPI; 900 pairs) produced NMDA receptor-dependent LTD.
      Furthermore, the saturation of NMDA receptor-dependent LTD did not prevent the
      induction of further NMDA receptor-independent LTD. This lack of occlusion
      suggests that different mechanisms of expression may underlie each of the above
      forms of LTD in the adult hippocampus. In contrast to the adult hippocampus, NMDA
      receptor-dependent LTD was induced by both LFS and PP-LFS (50 ms PPI) in slices
      from young animals (12-20 days). Although they share a common induction
      mechanism, LTD induced by PP-LFS may be expressed through other mechanisms in
      addition to those underlying LFS-induced LTD in the young hippocampus. In
      conclusion, the results in this study demonstrate that mechanisms of long-term
      synaptic depression within the hippocampus can alter radically with development
      of the central nervous system and with the use of different induction protocols.

PMID- 10651893
TI  - Connective tissue growth factor: a novel player in tissue reorganization after
      brain injury?
AB  - Recent studies have suggested a role of connective tissue growth factor (CTGF) in
      repair processes of the skin as well as in various types of fibrotic disease.
      However, a function of this molecule in central nervous system (CNS) repair has
      not been demonstrated yet. In this study we analysed the temporal and spatial
      expression pattern of CTGF after unilateral kainic acid lesions of the
      hippocampal CA3 region in mice. We found a strong induction of CTGF mRNA and
      protein expression in neurons and glial cells of the lesioned hippocampus.
      Interestingly, increased expression of this mitogen was accompanied by elevated
      levels of the extracellular matrix molecule fibronectin, which is a known target
      of CTGF action. Therefore, our data indicate a novel function of CTGF in
      postlesional restructuring of the hippocampus, where it possibly participates in
      glial scar formation.

PMID- 10651892
TI  - Involvement of a basolateral amygdala complex-nucleus accumbens pathway in
      glucocorticoid-induced modulation of memory consolidation.
AB  - Systemic or intracerebral administration of glucocorticoids modulates memory
      consolidation in several tasks. Previously, we have shown that these memory
      modulatory effects depend on an intact basolateral complex of the amygdala (BLC)
      and efferents from the BLC that run through the stria terminalis. It is currently
      unknown, however, what BLC efferent structures mediate these effects. The present
      experiments were designed to determine whether the nucleus accumbens (NA), which
      receives BLC efferents through the stria terminalis and is involved in several
      BLC-dependent behaviours, is involved in glucocorticoid-induced modulation of
      memory consolidation. In experiment 1, rats with bilateral sham or N-methyl-D
      aspartate (NMDA)-induced lesions of the NA were trained on a one-trial, footshock
      motivated inhibitory avoidance task, and given immediate post-training injections
      of either the synthetic glucocorticoid dexamethasone (0.3 or 1.0 mg/kg, s.c.) or
      vehicle. Testing 48 h later revealed that dexamethasone significantly enhanced
      retention in sham-lesioned rats but that the enhancing effect was blocked in NA
      lesioned rats. An asymmetrical, or crossed-lesion design was employed in
      experiment 2. Rats with a unilateral NMDA-induced lesion of the BLC and a
      unilateral lesion of either the ipsilateral or contralateral NA were trained as
      in experiment 1. Testing 48 h later revealed that dexamethasone enhanced
      retention in ipsilaterally lesioned rats, but that this effect was blocked in
      contralaterally lesioned rats. These findings indicate that an intact BLC-NA
      pathway is critical for the enhancing effects of glucocorticoids on memory
      consolidation, and are consistent with the view that the BLC regulates memory
      consolidation in other brain regions.

PMID- 10651895
TI  - Dynamics of munc18-1 phosphorylation/dephosphorylation in rat brain nerve
      terminals.
AB  - Munc18-1 is a mammalian member of the SEC1 protein family implicated in neuronal
      secretion. Its sequence contains several consensus sites for phosphorylation by
      protein kinase C (PKC), a kinase known to enhance secretion. We have
      characterized the phosphorylation of the synaptic munc18-1 pool by endogenous,
      presynaptic PKC-isoforms. In isolated rat brain nerve terminals, munc18-1 was
      almost completely nonphosphorylated. Its phosphorylation state increased by 250%
      on inhibition of endogenous phosphatases and by 1500% on additional, direct PKC
      activation using phorbol esters. K+-evoked depolarization also increased munc18-1
      phosphorylation, by 50% within 5 s in a Ca2+-dependent manner. Munc18-1
      phosphorylation in nerve terminals was blocked by PKC inhibitors. Activation of
      endogenous PKC in nerve terminals inhibited the interaction of synaptic munc18-1
      with its binding partner syntaxin-1A by 50%. Munc18-1 antisera precipitated 80%
      of native, brain-derived munc18-1 from salt solutions, but only 12% from
      synaptosomal lysates, together with 6% synaptic syntaxin-1A/B; these amounts were
      not changed by PKC activation. In this 12%, the phosphate incorporation per mole
      of munc18 was four-fold lower than the total pool. We conclude that the synaptic
      munc18-1 pool can be readily and rapidly phosphorylated by endogenous presynaptic
      PKC isoforms. A high constitutive phosphatase activity keeps its basal
      phosphorylation state low so that PKC activation can increase the phosphorylation
      state dramatically. These phosphorylation dynamics and the effects on the
      interaction with syntaxin-1A make munc18-1 a prominent candidate to account for
      PKC-dependent enhancement of secretion.

PMID- 10651894
TI  - Localization of the fragile X mental retardation 2 (FMR2) protein in mammalian
      brain.
AB  - The transcriptional silencing of the FMR2 gene has been implicated in FRAXE
      mental retardation. FRAXE individuals have been shown to exhibit learning
      deficits, including speech delay, reading and writing problems. FMR2 encodes a
      large protein of 1311 amino acids and is a member of a gene family encoding
      proline-serine-rich proteins that have properties of nuclear transcription
      factors. To characterize the expression of the fragile X mental retardation 2
      (FMR2) protein, polyclonal antibodies were raised against two regions of the
      human FMR2 protein and used in immunofluorescence experiments on mouse brain
      cryosections. Our results demonstrate for the first time that the FMR2 protein is
      localized in neurons of the neocortex, Purkinje cells of the cerebellum and the
      granule cell layer of the hippocampus. FMR2 staining is shown to colocalize with
      the nuclear stain 4,6-diamidino-2-phenylindole (DAPI) confirming that FMR2 is a
      nuclear protein. The localization of FMR2 protein to the mammalian hippocampus
      and other brain structures involved with cognitive function is consistent with
      the learning deficits seen in FRAXE individuals.

PMID- 10651896
TI  - Serotonin may stimulate granule cell proliferation in the adult hippocampus, as
      observed in rats grafted with foetal raphe neurons.
AB  - The long-term effects of hippocampal serotonergic denervation and reinnervation
      by foetal raphe tissue were examined in the dentate gyrus where neurons are
      continously born in the adult. Complete lesion of serotonin neurons following
      injections of 5, 7-dihydroxytryptamine in the dorsal and medial raphe nuclei
      produced long-term decreases in the number of newly generated granule cells
      identified with 5-Bromo-2'-deoxyuridine (BrdU) and the polysialylated form of
      neural cell adhesion molecule (PSA-NCAM) immunostaining, as observed in 2-month
      survival rats. The raphe grafts, but not the control grafts of embryonic spinal
      tissue, reversed the postlesion-induced decreases in the density of BrdU- and PSA
      NCAM-labelled cells detected in the granule layer. Inhibition of serotonin
      synthesis in animals with raphe grafts reversed back to lesion-induced changes in
      granule cell proliferation. Furthermore, extensive serotonergic reinnervation of
      the dentate gyrus in the area proximal to the raphe graft could be associated
      with supranormal density of BrdU-labelled cells. These results indicate that
      serotonin may be considered a positive regulatory factor of adult granule cell
      proliferation. Finally, the lack of effect of embryonic nonserotonergic tissue
      grafted to serotonin-deprived rats suggests that neurotrophic factors may not be
      involved in the effects of serotonin on adult neurogenesis.

PMID- 10651897
TI  - Abnormal substance P release from the spinal cord following injury to primary
      sensory neurons.
AB  - The neuropeptide substance P (SP) modulates nociceptive transmission within the
      spinal cord. Normally, SP is uniquely contained in a subpopulation of small
      calibre axons (Adelta- and C-fibres) within primary afferent nerve. However, it
      has been shown that after nerve transection, besides being downregulated in small
      axons, SP is expressed de novo in large myelinated Abeta-fibres. In this study we
      investigated whether, following peripheral nerve injury, SP was released de novo
      from the spinal cord after selective activation of Abeta-fibres. Spinal cords
      with dorsal roots attached were isolated in vitro from rats 2 weeks following
      distal sciatic axotomy or proximal spinal nerve lesion (SNL). The ipsilateral
      dorsal roots were electrically stimulated for two consecutive periods at low- or
      high-threshold fibre strength, spinal cord superfusates were collected and SP
      content was determined by radioimmunoassay. SNL, but not axotomized or control
      rat cords, released significant amounts of SP after selective activation of Abeta
      fibres. Not only do these data support the idea that Abeta myelinated fibres
      contribute to neuropathic pain by releasing SP, they also illustrate the
      importance of the proximity of the lesion to the cell body.

PMID- 10651898
TI  - Altering the concentration of GABA in the synaptic cleft potentiates miniature
      IPSCs in rat occipital cortex.
AB  - We have tested the effect of dextran (40 kDa, 5%) on miniature IPSCs (mIPSCs)
      recorded in layer V cortical pyramidal cells. This compound increases the
      amplitude of mIPSCs at room and physiological temperatures by 15%, leaving their
      duration unaffected at room temperature and slightly increased at physiological
      temperature. The amplitude increase is attributable to an increase in the number
      of receptors bound by GABA during synaptic transmission, as shown by the
      occlusion between the effects of dextran and zolpidem on mIPSC amplitude at room
      temperature. As dextran presumably enhances the concentration and dwell time of
      GABA in the synaptic cleft, these results demonstrate that the postsynaptic GABAA
      receptors are not saturated at room and physiological temperatures.

PMID- 10651899
TI  - Dissociable roles of the central and basolateral amygdala in appetitive emotional
      learning.
AB  - The amygdala is considered to be a core component of the brain's fear system.
      Data from neuroimaging studies of normal volunteers and brain-damaged patients
      perceiving emotional facial expressions, and studies of conditioned freezing in
      rats, all suggest a specific role for the amygdala in aversive motivation.
      However, the amygdala may also be critical for emotional processing in positive
      or appetitive settings. Using an appetitive Pavlovian approach procedure we show
      a theoretically important dissociation in the effects of excitotoxic lesions of
      the central nucleus and basolateral area of the amygdala, in the rat. Whilst
      central nucleus lesions impair appetitive Pavlovian conditioning, basolateral
      lesions do not. Together with other data, these results not only support the
      hypothesis that the amygdala is critical for appetitive as well as aversive
      learning, but are also consistent with amygdala subsystems subserving distinct
      aspects of emotional learning. Lesions of the dorsal or ventral subiculum were
      without effect on autoshaping, indicating the lack of involvement of hippocampal
      processing in this form of emotional behaviour and emphasizing further the neural
      specificity of the effects seen following central amygdala lesions.

PMID- 10651900
TI  - Cell cycle mechanisms of sister chromatid separation; roles of Cut1/separin and
      Cut2/securin.
AB  - The correct transmission of chromosomes from mother to daughter cells is
      fundamental for genetic inheritance. Separation and segregation of sister
      chromatids in growing cells occurs in the cell cycle stage called 'anaphase'. The
      basic process of sister chromatid separation is similar in all eukaryotes: many
      gene products required are conserved. In this review, the roles of two proteins
      essential for the onset of anaphase in fission yeast, Cut2/securin and
      Cut1/separin, are discussed with regard to cell cycle regulation, and compared
      with the postulated roles of homologous proteins in other organisms. Securin,
      like mitotic cyclins, is the target of the anaphase promoting complex
      (APC)/cyclosome and is polyubiquitinated before destruction in a manner dependent
      upon the destruction sequence. The anaphase never occurs properly in the absence
      of securin destruction. In human cells, securin is an oncogene. Separin is a
      large protein (MW approximately 180 kDa), the C-terminus of which is conserved,
      and is thought to be inhibited by association with securin at the nonconserved N
      terminus. In the budding yeast, Esp1/separin is thought to be a component of
      proteolysis against Scc1, an essential subunit of cohesin which is thought to
      link duplicated sister chromatids up to the anaphase. Whether fission yeast
      Cut1/separin is also implicated in proteolysis of cohesin is discussed.

PMID- 10651901
TI  - The loose coupling mechanism in molecular machines of living cells.
AB  - Living cells have molecular machines for free energy conversion, for example,
      sliding machines in muscle and other cells, flagellar motors in bacteria, and
      various ion pumps in cell membranes. They are constructed from protein molecules
      and work in the nm (nanometer), pN (piconewton) and ms (millisecond) ranges,
      without inertia. In 1980s, a question was raised of whether the input-output or
      influx-efflux coupling in these molecular machines is tight or loose, and an idea
      of loose coupling was proposed. Recently, the long-distance multistep sliding of
      a single myosin head on an actin filament, coupled with the hydrolysis of one ATP
      molecule, was observed by Yanagida's group using highly developed techniques of
      optical microscopy and micromanipulation. This gave direct evidence for the loose
      coupling between the chemical reaction and the mechanical event in the sliding
      machine. In this review, I will briefly describe a historical overview of the
      input-output problem in the molecular machines of living cells.

PMID- 10651902
TI  - Rho-dependence of Schizosaccharomyces pombe Pck2.
AB  - BACKGROUND: In metazoans, the HR1 domain, a motif found in a number of proteins
      including the protein kinase C-related PRKs, is responsible for an interaction
      with Rho-GTPases. The structural similarity between the Schizosaccaromyces pombe
      Pck proteins and the mammalian Rho-dependent protein kinase C-related family, has
      led us to investigate the relationship between the function of Rho and that of
      Pck1/2. RESULTS: Rho1 is shown to interact with the conserved N-terminal HR1
      domain of Pck1/2 in vitro and in vivo. Lethal overproduction of Rho1 is
      neutralized by co-expression of the Pck2 HR1 domain, which by itself compromises
      growth when overproduced. The Pck2-Rho1 interaction has a profound effect on the
      steady state expression of Pck2 and this is shown to parallel the
      immunoprecipitated activity and phosphorylation of Pck2 at its activation loop
      site. It is further shown that Pck2 becomes localized at the septum, where Rho1
      is also located. CONCLUSIONS: The results demonstrate that the Pck proteins are
      Rho1 effectors in fission yeast and that the HR1 domain is a universal motif for
      the Rho-GTPase interaction. Furthermore, the evidence supports the contention
      that the yeast Pck1 and Pck2 proteins are primitive protein kinases, which in
      vertebrates have evolved into the two distinct PKC and PRK families.

PMID- 10651903
TI  - Regulation of interaction of the acetyltransferase region of p300 and the DNA
      binding domain of Sp1 on and through DNA binding.
AB  - BACKGROUND: The coactivator p300 acts as a transcriptional adaptor for many DNA
      binding activators. The finding that p300 possesses intrinsic acetyltransferase
      activity which, by chemically modifying histone tails affects the nucleosomal
      environment and transcription, has greatly advanced our understanding of its
      function. Subsequent recent studies have shown that non-histone proteins are also
      acetylated. However, one central question which has remained unanswered is how
      the coactivator/acetyltransferase interacts with DNA-binding activators to
      modulate their actions. RESULTS: Here we have demonstrated physical and
      functional interaction between the acetyltransferase region of p300 and the DNA
      binding domain (DBD) of the transcription factor Sp1. This interaction stimulates
      DNA binding by the DBD of Sp1, which is mediated primarily by physical
      interaction rather than acetylation, despite acetylation of the DBD of Sp1 by the
      acetyltransferase region of p300. Furthermore, DNA binding by the DBD of Sp1
      inhibits both its association and acetylation by the acetyltransferase region of
      p300. CONCLUSIONS: These findings suggest a new role for p300 in regulating
      promoter access by DNA-binding activators through multiple regulatory
      interactions.

PMID- 10651904
TI  - amiB, a novel gene required for the growth/differentiation transition in
      Dictyostelium.
AB  - BACKGROUND: The differentiation programme of Dictyostelium discoideum is
      initiated by starvation. Nutrient depletion triggers the differentiation of
      Dictyostelium cells through the transcriptional inactivation of some growth-phase
      genes, as well as through the transcriptional activation of essential genes
      required for the aggregation of the cells. The adenylyl cyclase (ACA) gene, acaA,
      is one of the earliest genes expressed following starvation. ACA produces
      intracellular and extracellular cAMP that drives further differentiation by
      inducing chemotaxis, developmental gene expression and morphogenesis of
      Dictyostelium cells. Although several genes have been identified as being
      essential for the initiation of differentiation process, such as the
      transcriptional activation of ACA expression, the molecular mechanisms of the
      growth/differentiation transition remain to be explored. RESULTS: Using
      insertional mutagenesis, we have isolated a mutant that does not aggregate upon
      starvation. The disrupted gene, amiB (aggregation minus B), is predicted to
      encode a novel protein of 298.9 kDa. When starved, amiB- cells produced an
      undetectable level of cAMP. Analyses of gene expression showed that amiB- cells
      fail to turn off the expression of one of the growth-phase genes, cprD, and to
      turn on the expression of ACA following starvation. The ectopic expression of ACA
      from a constitutive promoter rescued the differentiation and morphogenesis of
      amiB- mutants. Furthermore, the ectopic expression of a putative transcriptional
      factor DdMyb2 or a catalytic subunit of cAMP-dependent protein kinase (PKA-C),
      both of which are thought to be involved in ACA expression pathway(s), also
      rescued the starvation-induced ACA expression and further differentiation of the
      amiB- mutant. CONCLUSION: These results suggest that AmiB plays a role at the
      start of Dictyostelium differentiation through induction of the ACA expression
      which is essential for cAMP signalling.

PMID- 10651905
TI  - A hrs binding protein having a Src homology 3 domain is involved in intracellular
      degradation of growth factors and their receptors.
AB  - BACKGROUND: Hrs (hepatocyte growth factor (HGF)-regulated tyrosine kinase
      substrate) is an early endosomal protein that is rapidly tyrosine-phosphorylated
      in cells stimulated with growth factors. Hrs is thought to play a regulatory role
      in the endocytosis of growth factor/receptor complexes through early endosomes.
      In this study, we searched for Hrs-interacting molecules which may regulate the
      function of Hrs, using a yeast two-hybrid system. RESULTS: We isolated a cDNA
      clone encoding a novel Src homology 3 (SH3)-containing protein, and named it 'Hrs
      binding protein' (Hbp). Hbp was co-immunoprecipitated with Hrs, and its
      intracellular localization was similar to that of Hrs. The association between
      Hbp and Hrs was mediated through the coiled coil motifs in Hbp and Hrs. Deletion
      mutants of Hbp lacking either the SH3 domain or the Hrs binding domain showed
      dominantly negative effects on the intracellular degradation of a growth factor
      and its receptor, but not on the internalization of growth factor/receptor
      complexes. CONCLUSIONS: Hbp is thought to be closely associated with Hrs on early
      endosomes. Hbp, together with Hrs may play a regulatory role in the vesicular
      transport of growth factor/receptor complexes through early endosomes, for their
      degradation.

PMID- 10651906
TI  - Mouse Ror2 receptor tyrosine kinase is required for the heart development and
      limb formation.
AB  - BACKGROUND: A mouse receptor tyrosine kinase (RTK), mRor2, which belongs to the
      Ror-family of RTKs consisting of at least two structurally related members, is
      primarily expressed in the heart and nervous system during mouse development. To
      elucidate the function of mRor2, we generated mice with a mutated mRor2 locus.
      RESULTS: Mice with a homozygous mutation in mRor2 died just after birth,
      exhibiting dwarfism, severe cyanosis, and short limbs and tails. Whole-mount in
      situ hybridization analysis showed that mRor2 was expressed in the branchial
      arches, heart and limb/tailbuds, in addition to the developing nervous system.
      The mutants had cardiac septal defects, mainly a ventricular septal defect. In
      addition, an examination of the skeletal systems revealed that the mutants had
      shorter limbs, vertebrae and facial structure, with a particular defect in their
      distal portions, and that almost no calcification was observed in their distal
      limbs. Histological examination showed abnormalities in the chondrocytes.
      CONCLUSIONS: Our findings suggest that mRor2 plays essential roles in the
      development of the heart and in limb/tail formation, in particular cardiac septal
      formation and ossification of distal portions of limbs and tails.

PMID- 10651907
TI  - Desiccation and starvation resistance in Drosophila: patterns of variation at the
      species, population and intrapopulation levels.
AB  - A substantial number of Drosophila studies have investigated variation in
      desiccation and starvation resistance, providing an opportunity to test for
      consistent patterns of direct and correlated responses across studies and across
      the species and population levels. In general, responses to laboratory selection
      for these traits in D. melanogaster are rapid and indicate abundant genetic
      variation in populations. However, slower responses to selection for desiccation
      resistance occur in other species including D. simulans. Clines suggest adaptive
      divergence although specific selection pressures have not been documented
      empirically. Drosophila species differ markedly in desiccation and starvation
      resistance and there is also marked variation within species for desiccation
      resistance that may be linked to local climatic conditions. Laboratory selection
      experiments on starvation resistance in D. melanogaster suggest that changes in
      lipid content are largely responsible for resistance variation but this factor
      may be less important in explaining variation among species. For desiccation,
      lines with increased resistance show reduced rates of water loss but no changes
      in the minimum water content that flies can tolerate. Changes in life history
      traits are sometimes associated with altered levels of stress resistance.
      Increased starvation resistance is associated with longer development time and
      reduced early age reproduction in different studies. However, other associations
      are inconsistent between studies as in the case of stress resistance changing
      following selection for longevity. Multiple mechanisms may underlie genetic
      variation in stress resistance and future studies should address the evolutionary
      importance of the different mechanisms at the population and species levels.

PMID- 10651909
TI  - Host race or species? Allozyme characterization of the 'flowering dogwood fly', a
      member of the Rhagoletis pomonella complex.
AB  - The term 'flowering dogwood fly' has been used in the literature for a poorly
      understood member of the Rhagoletis pomonella sibling species complex infesting
      the fruits of flowering dogwood (Cornus florida). Electrophoretic analysis of 17
      allozyme loci in 21 populations reveals significant frequency differences between
      the flowering dogwood fly and its closest relative the apple maggot fly, R.
      pomonella, and between it and the somewhat more distant 'sparkleberry fly'.
      Frequency differences between the flowering dogwood fly and R. pomonella are as
      great as 0.817 in the north, but are less in the south, with a maximum difference
      at one site of only 0.328. No fixed allozyme differences distinguish the
      flowering dogwood fly anywhere; its only consistent, unique feature is the
      highest frequency of Aat-259 in the pomonella species group. Population structure
      of the flowering dogwood fly is moderate with FST=0.084 and fewer latitudinal
      clines than R. pomonella. The conclusion from the allozyme and life history data
      is that the flowering dogwood fly is a species, although some interspecific gene
      flow may be occurring. Additional issues discussed include how to estimate
      interspecific gene flow when genetic markers are under divergent selection, the
      appropriate species concept when there is gene flow, and the future of the
      flowering dogwood fly in the face of the dogwood anthracnose epidemic. The
      possible utility of a new species concept for phytophagous insects, using as a
      criterion the capacity of a host race to regenerate the ancestral population, is
      also discussed.

PMID- 10651908
TI  - Quantitative genetics of ultrasonic advertisement signalling in the lesser
      waxmoth Achroia grisella (Lepidoptera: pyralidae).
AB  - Males of the lesser waxmoth Achroia grisella (Lepidoptera: Pyralidae) produce
      ultrasonic advertisement signals attractive to females within several metres.
      Previous studies showed that females prefer male signals that are louder,
      delivered at a faster rate, and have a greater asynchrony between pulses produced
      by the right and left wings. These three signal characters vary considerably
      within populations but are repeatable within individuals. Breeding experiments
      employing half-sib designs were conducted on both collectively and individually
      reared moths to determine genetic variance within and covariance among these
      signal characters. Heritabilities of all signal characters were significant among
      collectively reared moths. Heritabilities for signal rate and right-left wing
      asynchrony interval were not significant, however, among individually reared
      moths, suggesting the presence of significant nonadditive genetic variance or
      common environmental variation. Development time was also significantly
      heritable, but only under individual rearing. The only significant genetic
      correlation was between signal rate and length of the right-left wing asynchrony
      and this was negative. Our findings on heritability of signal characters are
      consistent with a coevolutionary sexual selection mechanism, but the absence of
      signal x development genetic correlation fails to support specifically a good
      genes mechanism. The variation in heritability among conditions suggests that
      environmental variance may be high, and may render selection on signal characters
      by female choice ineffective. Thus, additive genetic variance for these
      characters may be maintained in the presence of directional female choice.

PMID- 10651910
TI  - Spontaneous changes in Drosophila melanogaster transposable elements and their
      effects on fitness.
AB  - Twenty-eight spontaneous alterations modifying the hybridization banding pattern
      of six families of transposable elements (297, Foldback, copia, jockey, P and
      hobo) have been fixed in a set of mutation-accumulation lines of Drosophila
      melanogaster. Their effect on fitness has been studied by competition with the
      original pattern. Most alterations affecting transposable elements were shown to
      be rearrangements with no detectable effect on fitness, showing that spontaneous
      transposable element mutations mainly generate minor fitness mutations.

PMID- 10651911
TI  - Phylogeographical autocorrelation of phenotypic evolution in honey bees (Apis
      mellifera L.).
AB  - The analysis of phenotypic divergence among local populations within a species
      has been traditionally performed in a spatial context, although advances in
      genetic analysis using mtDNA have permitted a simultaneous evaluation of
      geographical and historical patterns of variation, so-called phylogeographical
      analysis. In this paper, we combine these two dimensions of variation
      (geographical space and phylogenetic history) to evaluate patterns of phenotypic
      evolution in honey bees (Apis mellifera L.). Data on 39 phenotypic traits,
      derived from 417 colonies grouped into 14 subspecies, were analysed using
      autocorrelation methods. Mantel tests indicated that the relationship between
      phenotypic divergence, estimated by Euclidean distances among subspecies'
      morphological centroids, was significant both when compared to geographical
      distance (r=0.371; P < 0.01) and to genetic distance (estimated as sequence
      divergence (%) in a mtDNA region encompassing part of the NADH dehydrogenase
      subunit 2 and isoleucine transfer RNA (r=0.329; P < 0.01)). For the analysis of
      each trait, the effects of the geographical co-ordinates (latitude and longitude
      of subspecies geographical range) and of the phylogenetic patterns (defined by
      eigenvectors of the genetic distance matrix) on phenotypic variation were
      simultaneously analysed using an extension of a recently developed model, called
      Phylogenetic Eigenvector Regression (PVR). In general terms, the partial
      regression slopes indicated that the variation in the characters traditionally
      associated with adaptive processes, such as body and wing size, were better
      explained by geographical position. However, characters usually thought to be
      neutral, such as wing venation angle, were more associated with phylogeny. This
      is expected because PVR can be interpreted as a partition model, in which
      adaptive variation tends to be independent of phylogeny (and, in this case,
      associated with geography). In addition, the first principal component derived
      from the expected values of the model for each trait, which can be interpreted as
      the phenotypic variation predicted by phylogeny, is more structured in a north
      south cline than are the original data, supporting an adaptive interpretation.
      The phylogeographical autocorrelation analyses performed in this study show that
      different traits are more related to one of the two dimensions of variation
      (geography and phylogeny), and these patterns can furnish insights into the
      nature of phenotypic evolution in these organisms.

PMID- 10651912
TI  - Genetic characterization of the silkworm Bombyx mori by simple sequence repeat
      (SSR)-anchored PCR.
AB  - Thirteen diverse strains of the silkworm Bombyx mori were analysed using the
      simple sequence repeat anchored polymerase chain reaction (SSR-anchored PCR) or
      Inter-SSR-PCR (ISSR-PCR). A set of four 5'-anchored and two 3'-anchored repeat
      primers amplified a total of 239 bands out of which 184 (77%) were polymorphic.
      The 5'-anchored primers revealed more distinct polymorphic markers than the 3'
      anchored primers and the ISSR-PCR method showed greater variability than RAPDs.
      The strain-specific pattern was shown to be inherited and segregated in a
      Mendelian fashion. A dendrogram constructed using the UPGMA method revealed two
      distinct groups, one comprising nondiapausing and one comprising diapausing
      strains. These results suggest that the ISSR-PCR method is potentially useful for
      genetic fingerprinting of silkworm genotypes and as a mapping tool in the
      silkworm.

PMID- 10651913
TI  - Heritability, phenotypic and genetic correlations of size and shape of Drosophila
      mediopunctata wings.
AB  - We have studied the morphology of wings of Drosophila mediopunctata employing the
      ellipse method, a procedure that allows precise descriptions of wing size (SI),
      wing shape outline (SH), and placement of longitudinal wing veins. We have found
      that the SH and the points which determine the position of the apices of the
      third, fourth and fifth longitudinal wing veins show high heritability in nature
      (the lower bound for the natural heritability is above 0.25). The values found
      are similar to those obtained for the broad-sense heritabilities (H2) in the
      laboratory. However, SI and the point which determines the apex of the second
      longitudinal wing vein showed small lower bounds for heritability in nature, 0.05
      and 0.07, respectively, in spite of the high estimates of H2 in the laboratory.
      These results suggest that size and shape have different genetic properties. We
      observed a high positive phenotypic correlation between the SH, the fourth and
      the fifth longitudinal wing veins, which contrasts with a negative correlation
      between these traits and the second longitudinal vein. That is, as the SH gets
      longer, the apices of the second and fifth veins become closer to each other.
      Positive genetic correlations in the field were detected between SH, the fourth
      and the fifth longitudinal veins and also between the third and the fourth veins.

PMID- 10651914
TI  - Change in sexual size dimorphism as a correlated response to selection on
      fecundity.
AB  - Fecundity selection is often suggested as the main causal factor underlying the
      prevalence of female-biased sexual size dimorphism (SSD), but this assumption has
      not been empirically tested. We selected female Drosophila melanogaster for
      increased or decreased fecundity (eggs laid over a single 18-h period, between
      days 5 and 7 posteclosion) for 20 generations, to see what effect this would have
      on SSD in three morphological traits (thorax width, abdomen width and thorax
      length). A direct response to fecundity selection was found in the downward
      direction (16.6%), whereas the response to upward selection (5.7%) was not
      statistically significant. Significant sex by selection interaction terms in the
      ANOVAs for thorax width and abdomen width indicate that the two sexes responded
      differently. Females usually showed a greater correlated response than males. In
      lines selected for increased fecundity, the correlated response in females for
      thorax and abdomen width was greater than the direct response in standard
      deviation units. SSD generally increased with selection for increased fecundity,
      but showed no consistent trend with selection for decreased fecundity. These
      results support the general hypothesis that SSD can evolve rapidly in response to
      fecundity selection. Selection on fecundity also produced correlated responses in
      life history traits. Downward selection resulted in flies that had lower
      viability and longevity, and both directions of selection were associated with an
      increase in development time.

PMID- 10651915
TI  - Crosses between sexual and apomictic dandelions (Taraxacum). I. The inheritance
      of apomixis.
AB  - Some dandelions, Taraxacum, are diplosporous gametophytic apomicts. Crosses
      between closely related diploid sexuals and triploid apomicts were made to study
      the inheritance of apomixis. Seed-set was less than one-third of that in diploid
      x diploid crosses, probably because of the inviability of aneuploid pollen or
      zygotes. Almost 90% of the viable offspring were diploid and the result of
      selfing, as was shown by a discriminating allozyme marker. Aneuploid outcross
      pollen had a mentor effect on self-pollen, causing a breakdown of the sporophytic
      self-incompatibility system. A similar phenomenon has been reported before in
      wide crosses. Of the 26 allozyme-confirmed hybrids, four were diploids, 15 were
      triploids and seven were tetraploids. Diploid hybrids were significantly less
      frequent than triploid hybrids, suggesting either low fitness of haploid pollen
      or more numerous formation of diploid pollen. Emasculation and bagging of flowers
      indicated apomictic seed-set in none of the diploid, in one-third of the triploid
      and in all of the tetraploid hybrids. All apomictic hybrids showed partial seed
      set, but additional cross-pollination did not increase seed-set. Cytological
      analysis of the F2 progeny confirmed that partial apomixis was caused by
      semisterility and not by residual sexuality (facultative apomixis). The
      difference in segregation for apomixis between triploid and tetraploid hybrids
      may be because the triploids originated from partially reduced diploid pollen
      grains, whereas the tetraploids originated from unreduced triploid pollen grains.

PMID- 10651916
TI  - Crosses between sexual and apomictic dandelions (Taraxacum). II. The breakdown of
      apomixis.
AB  - Some dandelions are diplosporous gametophytic apomicts. In order to study the
      inheritance and breakdown of apomixis, crosses were made between diploid sexuals
      and triploid apomicts. To investigate their breeding system, four nonapomictic
      diploid and 10 nonapomictic triploid hybrids were pollinated with diploids and
      the progenies were analysed. Seed fertility was significantly reduced in two
      diploid hybrids. Nine triploid hybrids were fertile and could be classified into
      three types, with respect to the composition of their progenies. Type A produced
      n+n hybrids. Type B produced either a mixture of n + n and 2n + n hybrids, or a
      mixture of pseudogamous 2n + 0 apomicts and 2n + n hybrids. Type C produced
      exclusively 2n + n hybrids. Inheritance of a microsatellite marker strongly
      suggested that 2n egg cells in type C plants were produced by a first division
      restitution mechanism. As in apomicts, microsporogenesis in type C plants was
      reductional. This suggests that type C plants are diplosporous plants that lack
      parthenogenesis. Such plants are very rare in other apomictic plant species. It
      is concluded that 'elements of apomixis', diplospory and parthenogenesis, can be
      uncoupled. This is inconsistent with the single-locus model for apomixis in
      Taraxacum as suggested by Mogie (1992). Instead, our results suggest that several
      loci are involved in the genetic control of apomixis in Taraxacum.

PMID- 10651917
TI  - Genetic diversity in mesoamerican populations of mahogany (Swietenia
      macrophylla), assessed using RAPDs.
AB  - Swietenia macrophylla King, a timber species native to tropical America, is
      threatened by selective logging and deforestation. To quantify genetic diversity
      within the species and monitor the impact of selective logging, populations were
      sampled across Mesoamerica, from Mexico to Panama, and analysed for RAPD DNA
      variation. Ten decamer primers generated 102 polymorphic RAPD bands and pairwise
      distances were calculated between populations according to Nei, then used to
      construct a radial neighbour-joining dendrogram and examine intra- and
      interpopulation variance coefficients, by analysis of molecular variation
      (AMOVA). Populations from Mexico clustered closely together in the dendrogram and
      were distinct from the rest of the populations. Those from Belize also clustered
      closely together. Populations from Panama, Guatemala, Costa Rica, Nicaragua and
      Honduras, however, did not cluster closely by country but were more widely
      scattered throughout the dendrogram. This result was also reflected by an
      autocorrelation analysis of genetic and geographical distance. Genetic diversity
      estimates indicated that 80% of detected variation was maintained within
      populations and regression analysis demonstrated that logging significantly
      decreased population diversity (P = 0.034). This study represents one of the most
      wide-ranging surveys of molecular variation within a tropical tree species to
      date. It offers practical information for the future conservation of mahogany and
      highlights some factors that may have influenced the partitioning of genetic
      diversity in this species across Mesoamerica.

PMID- 10651918
TI  - Quantitative genetics of floral traits in a gynodioecious wild strawberry
      Fragaria virginiana: implications for the independent evolution of female and
      hermaphrodite floral phenotypes.
AB  - The independent evolution of floral phenotype is an important part of the process
      of gender specialization during the evolution of dioecy from hermaphroditism.
      However, we have little information on the genetic variation of floral traits in
      species with separate genders. Gynodioecious species (co-occurrence of females
      and hermaphrodites) have a breeding system intermediate between hermaphroditism
      and complete separation of the sexes (dioecy) and thus can provide insight into
      the genetic architecture underlying floral phenotype with respect to both primary
      (stamens and carpels) and secondary (petals) sexual traits. I used a nested
      breeding design to examine the potential for response to selection on floral
      traits and to examine whether this response would be similar in the two sex
      morphs of gynodioecious Fragaria virginiana. There was significant genetic
      variation underlying all floral traits, although narrow-sense heritabilities
      (ranging from -0.25 to 0.44) were, in most cases, much lower than broad-sense
      ones (ranging from 0.28 to 1. 53). Moreover, the sex morphs differed
      significantly in their heritabilities for shared traits, such as stamen length,
      and showed a tendency towards differing significantly in others, like carpel
      number and petal length. In addition, correlations between the sex morphs for
      these traits (ranging from 0.41 to 0.58) were significantly greater than 0, but
      less than 1. These results indicate that greater sexual dimorphism could evolve
      in this population of F. virginiana, even if selection on these traits is not
      divergent. However, strong developmental integration of floral traits (e.g.
      stamen length and petal length) and high levels of nonadditive genetic variance
      may represent barriers to the evolution of complete sexual dimorphism.

PMID- 10651919
TI  - A study of fluctuating asymmetry in hybrids of dwarf and normal lake whitefish
      ecotypes (Coregonus clupeaformis) from different glacial races.
AB  - Fish ecotypes found in north temperate lakes are increasingly used as model
      organisms to explore patterns and processes of population divergence that may
      ultimately cause speciation. Processes involved in their reproductive isolation
      are, however, still poorly understood. Recent experimental studies on whitefish
      ecotypes from different glacial races revealed that embryonic mortality of
      hybrids was 2.4-4.7 times higher than for parental forms. In this study, we
      compared fluctuating asymmetry (FA) in morphological traits of these same hybrid
      and pure crosses to test the hypothesis that genetic stress observed in hybrids
      at embryonic stages is also manifested at later developmental stages. Twelve
      morphological traits were used to measure asymmetry. Variable degrees of
      asymmetry were observed depending on traits and crosses, however there was no
      significant difference in FA among crosses. These results thus provided no
      evidence in support of the working hypothesis and indicated that genetic stress
      may differ among life stages. It is more likely that high hybrid embryonic
      mortality acts together with ecological factors at later stages to increase
      further the extent of reproductive isolation between sympatric whitefish
      ecotypes.

PMID- 10651920
TI  - Development and characterization of microsatellite markers for genetic analysis
      of a Brazilian endangered tree species Caryocar brasiliense.
AB  - In this work we report the development and characterization of 10 microsatellite
      loci for the endangered tree species Caryocar brasiliense. Using genomic library
      enrichment, the efficiency of SSR marker development was 14.4% from sequencing
      data to operationally useful loci. Primer sequences for this set of 10 loci are
      made available together with their estimates of expected heterozygosity,
      probability of paternity exclusion and probability of identity. Mendelian
      inheritance and segregation was confirmed for all 10 loci in open-pollinated half
      sib families as well as the absolute transferability of these 10 loci to five
      other species of the same genus. Number of alleles per locus ranged from 10 to 22
      with a mean value of 16 and expected heterozygosity varying from 0.84 to 0.94.
      The combined probability of genetic identity was on the order of 10-17 clearly
      demonstrating that SSR multilocus genotypes are likely to be unique and capable
      of readily discriminating individuals of C. brasiliense. The very high combined
      probability of paternity exclusion (0.99999995) also indicates that these markers
      will permit detailed parentage studies in natural populations even in situations
      where both maternity and paternity are unknown. The battery of microsatellite
      markers developed and characterized in this study opens a new perspective for the
      generation of fundamental population genetic data for devising sound collection
      and conservation procedures for C. brasiliense and related species of the genus.

PMID- 10651921
TI  - Quantitative genetics of intraspecies hybrids.
AB  - Quantitative genetics generally is based on the properties of the randomly
      fertilized (RF) population or inbred derivatives of it. Simple hybrids and hybrid
      swarms do not conform to this model; and only some properties of hybrid means
      appear to have been available. In this paper, several genetical properties are
      derived, including genotype and allele frequencies, genotypic variance, broad
      sense heritability, and outbreeding coefficient. The earlier mean is confirmed,
      and hybrid vigour is examined critically. These results make it possible to
      evaluate quantitatively both natural selection and forward selection (in plant
      breeding) from hybrids. An important finding is that hybrids with maximum hybrid
      vigour do not maximize genetic advance from forward selection, i.e. evolution is
      unlikely to enhance hybrid vigour. Another finding is that the concepts of
      additive genetic variance and narrow-sense heritability are inappropriate for
      hybrids, owing to the genetic disequilibrium inherent from their origin, and to
      the ephemeral nature of their population structure.

PMID- 10651922
TI  - KC production in the cornea in response to Pseudomonas aeruginosa challenge.
AB  - Pseudomonas aeruginosa can cause ulcerative bacterial keratitis. A feature of
      keratitis is the rapid infiltration of the avascular corneal stroma by
      neutrophils. KC is a potent neutrophil chemokine. The present study used a mouse
      model of ocular infection to assess the relationship between KC and inflammation
      in the cornea in response to challenge with a strain of P. aeruginosa causing
      keratitis. Low levels of KC mRNA and protein were detected by in situ
      hybridization and ELISA, respectively, in unchallenged corneas. Dramatically
      increased numbers of KC mRNA+ cells were present in P. aeruginosa strain 6294
      challenged corneas. Expression of KC mRNA was found to be up-regulated in the
      corneal epithelium in response to wounding alone. The KC mRNA+ cells were located
      in the epithelium and corresponding to infiltrating neutrophils cells in the
      stroma. Quantification of KC protein at different time points showed peak levels
      at 8 h of bacterial challenge. These results suggest that KC may be involved with
      the regulation of leucocyte infiltration early during bacterial keratitis.

PMID- 10651923
TI  - The peripheral lymphoid compartment is disrupted in flaky skin mice.
AB  - Flaky skin (fsn) is an autosomal recessive mutation on mouse chromosome 17 that
      causes severe anaemia, forestomach papillomatosis and a papulosquamous skin
      disease that resembles psoriasis in humans. In the present paper, it is reported
      that fsn causes peripheral lymphadenopathy, CD4/CD8 imbalance and
      hyperresponsiveness to T cell growth factors. Peripheral lymph nodes (PLN) of
      adult mutant (fsn/fsn) mice were found to contain almost 10-fold more leucocytes
      than PLN from phenotypically normal littermates (+/fsn or +/+, hereafter referred
      to as +/?). Analysis of PLN cells using mAbs and flow cytometry revealed that
      this predominantly lymphoid hyperplasia was characterized by approximately
      equivalent increases in the numbers of CD3+ T cells and CD19+ B cells. However,
      expansion within the T cell compartment was non-random, because fsn/fsn PLN had a
      considerably reduced ratio of CD4+ to CD8+ T cells (1.08 +/- 0.37) compared to
      +/? PLN (2.47 +/- 0.44, P < 0.0001). In vitro assays of cellular proliferation in
      response to T and B cell growth factors showed that fsn/fsn PLN cells were
      hyperresponsive to IL-2, IL-4 and IL-7 when compared with PLN cells from +/?
      mice. Studies using mesenteric lymph node and peripheral blood cells showed that
      hyperresponsive cells are widely distributed in fsn/fsn mice. Experiments in
      newborn mice showed that the lymphoid disturbances caused by fsn are established
      at least as early as 2 weeks of age, a time that precedes the onset of the
      earliest clinical skin lesions. These data implicate a role for the fsn gene
      product in regulating the size and content of the peripheral lymphoid
      compartment.

PMID- 10651924
TI  - Partial T cell activation with an altered superantigenic ligand.
AB  - T cells have the capacity to respond to ligands as full, weak, partial or null
      agonists, or indeed as antagonists. In the present paper, it is reported that
      staphylococcal enterotoxin B (SEB) mutated in a T cell receptor (TCR) contact
      site (SEBDelta61Y) behaves as an altered ligand for a T cell clone (AC20) that
      expresses the Vbeta17 TCR. The T cells were partially activated by SEBDelta61Y,
      as shown by TCR down-modulation and up-regulation of the IL-2 receptor. However,
      these cells did not secrete IL-2, IL-3, IL-4 or IFN-gamma, nor did they
      proliferate. Analysis of intracellular protein tyrosine phosphorylation after
      cellular activation provided further evidence that SEBDelta61Y could transduce a
      signal via the Vbeta17 TCR. The events following receptor ligation were clearly
      different when the T cells were stimulated with SEB or SEBDelta61Y, manifested as
      both quantitatively and qualitatively different patterns of phosphorylation of
      intracellular substrates. In contrast, only quantitative differences were
      apparent when a transfectant expressing the same alpha/beta TCR was stimulated
      with the different superantigens. Together, these results provide the first
      demonstration that altered TCR ligands are not restricted to peptides substituted
      at secondary TCR contact residues. Rather, an altered superantigenic ligand
      mutated in the TCR binding site can behave as a partial agonist.

PMID- 10651925
TI  - The anti-idiotypic antibody 1F7 selectively inhibits cytotoxic T cells activated
      in HIV-1 infection.
AB  - Circulating CD8+ T lymphocyte numbers rise substantially following infection with
      HIV-1. This expanded CD8+ T cell population includes HIV-specific CTL and CTL
      that kill activated uninfected CD4+ lymphocytes. Experimental, epidemiological
      and clinical evidence supports the possibility that expansion of CD8+ CTL
      contributes to CD4+ T cell depletion and disease progression in human HIV
      infection. Therefore, modulation of CD8+ T cell numbers or of certain CD8+ CTL
      activated in HIV-infected individuals may be beneficial. It was found that 1F7, a
      mAb against an idiotype common to anti-HIV and anti-simian immunodeficiency virus
      (SIV) antibodies, selectively inhibited both anti-HIV CTL and CTL against
      uninfected CD4+ T cells. Alloantigen-specific CTL and NK cells from either HIV
      infected individuals or controls were unaffected by 1F7. Prolonged incubation of
      CD8+ T cells from HIV-infected individuals with 1F7 induces apoptosis, which was
      shown to be reflected functionally in reduced total CTL activity and in
      especially reduced CTL activity against uninfected CD4+ lymphocytes. The
      selective reactivity of 1F7 with certain CD8+ CTL could be applied towards the
      modulation of CD8+ T cell responses involved in AIDS pathogenesis.

PMID- 10651926
TI  - Therapeutic immunization against Helicobacter pylori infection in the absence of
      antibodies.
AB  - Helicobacter pylori is an important human pathogen. Prophylactic immunization
      with bacterial antigen plus an adjuvant protects mice against challenge with live
      H. pylori. Surprisingly, it was found that immunizations of mice already infected
      with Helicobacter also influenced bacterial colonization. This concept of
      therapeutic immunization is a novel phenomenon. Because H. pylori lives in the
      lumen of the stomach, it was initially hypothesized that the protective mechanism
      would involve induction of secretory IgA. However, work with knockout mice has
      demonstrated that prophylactic immunization is equally effective in mice
      deficient in IgA and even in microMT mice lacking B lymphocytes. Currently
      nothing is known about therapeutic vaccination and the effect of immunizing a
      host with an ongoing ineffective immune response. To address this, we infected B
      cell deficient, microMT mice with H. pylori and therapeutically immunized them
      four times in 3 weeks with bacterial sonicate and cholera toxin adjuvant. These
      immunizations significantly reduced colonization by H. pylori. The antibody-
      negative status of the microMT mice was confirmed by ELISA. Thus, therapeutic
      immunization stimulates an immune response, which reduces H. pylori infection via
      a mechanism that is antibody independent. How this is achieved remains to be
      determined, but may well involve a novel immune mechanism.

PMID- 10651927
TI  - Modulatory effects of dietary lipids on immune system functions.
AB  - Dietary lipid manipulation may affect a great number of immune parameters, such
      as lymphocyte proliferation, cytokine synthesis, natural killer (NK) cell
      activity, phagocytosis and so on. The immunomodulation induced by dietary fatty
      acids may be applied in the amelioration of inflammatory disorders, such as
      autoimmune diseases. However, the mechanisms that participate in these processes
      are still poorly understood. It is probable that modulation of immune system by
      fatty acids of the diet may occur by alteration of membrane fluidity, lipid
      peroxide formation, eicosanoid production or regulation of gene expression.
      However, recent studies have reported the effects of several free fatty acids on
      apoptosis induction of in vitro cultures. In fact, a possible explanation of the
      effects that fatty acids promote on the immune system cells could be associated
      with an apoptotic process performed in an irreversible way. In vivo studies have
      demonstrated the ability of fatty acids to alter the survival of animals fed
      diets containing oils and infected with a pathogenic bacterium. Experimental
      infection in animals fed dietary lipids produces a modification of resistance to
      micro-organisms. The present review analyses all of these parameters that dietary
      fatty acids are capable of altering in order to modify the immune response.
      Further studies will be needed to establish the mechanisms involved in immune
      system regulation, reduction of symptoms derived from autoimmune pathologies and
      so on.

PMID- 10651928
TI  - Dietary fats affect macrophage-mediated cytotoxicity towards tumour cells.
AB  - In the present study, the effects of feeding mice diets of different fatty acid
      compositions on the production of TNF-alpha and nitric oxide by
      lipopolysaccharide-stimulated peritoneal macrophages and on macrophage-mediated
      cytotoxicity towards L929 and P815 cells were investigated. C57Bl6 mice were fed
      on a low-fat (LF) diet or on high-fat diets (21% fat by weight), which included
      coconut oil (CO), olive oil (OO), safflower oil (SO) or fish oil (FO) as the
      principal fat source. The fatty acid composition of the macrophages was markedly
      influenced by that of the diet fed. Lipopolysaccharide (LPS)-stimulated
      macrophages from FO-fed mice showed significantly lower production (up to 80%) of
      PGE2 than those from mice fed on each of the other diets. There was a significant
      positive linear correlation between the proportion of arachidonic acid in
      macrophage lipids and the ability of macrophages, to produce PGE2.
      Lipopolysaccharide-stimulated TNF-alpha production by macrophages decreased with
      increasing unsaturated fatty acid content of the diet (i.e. FO < SO < OO < CO <
      LF). Macrophages from FO-fed mice showed significantly lower production of TNF
      alpha than those from mice fed on each of the other diets. Nitrite production was
      highest for LPS-stimulated macrophages from mice fed on the LF diet. Macrophages
      from FO-fed mice showed significantly higher production of nitrite than those
      from mice fed on the OO and SO diets. Compared with feeding the LF diet, feeding
      the CO, OO or SO diets significantly decreased macrophage- mediated killing of
      P815 cells (killed by nitric oxide). Fish oil feeding did not alter killing of
      P815 cells by macrophages, compared with feeding the LF diet; killing of P815
      cells was greater after FO feeding than after feeding the other high fat diets.
      Compared with feeding the LF diet, feeding the OO or SO diets significantly
      decreased macrophage-mediated killing of L929 cells (killed by TNF). Coconut oil
      or FO feeding did not alter killing of L929 cells by macrophages, compared with
      feeding the LF diet. It is concluded that the type of fat in the diet affects
      macrophage composition and alters the ability of macrophages to produce cytotoxic
      and immunoregulatory mediators and to kill target tumour cells.

PMID- 10651929
TI  - Anti-oxidants as modulators of immune function.
AB  - In order to confirm the hypothesis of the immunomodulating action of anti
      oxidants (bringing back altered immune function to more optimum values), the
      possibility that anti-oxidants may be useful in two experimental models of
      altered immune function has been studied. The first is a pathological model, that
      is, lethal murine endotoxic shock caused by an LPS injection of 100 mg/kg, in
      which the lymphocytes show increased adherence and depressed chemotaxis. The
      injection of N-acetylcysteine (150 mg/kg), which increased both functions in
      control animals, decreased adherence and increased chemotaxis in mice with
      endotoxic shock. The second is a physiological model; aged human subjects (70 +/-
      5-year-old men) who, in their largest segment of population ('standard' group)
      showed an increased lymphocyte adherence and decreased lymphoproliferative
      response to mitogens compared with younger adults. The ingestion of vitamin E
      (200 mg daily for 3 months in this standard group) lowered adherence and
      stimulated lymphoproliferation. However, a smaller segment of the human
      population tested showed 'non-standard' values in these lymphocyte functions,
      that is, very low adherence and very high proliferation. In those subjects,
      vitamin E showed the opposite effects, namely adherence increase and depressed
      lymphoproliferation. In both age groups of men, these functions reached adult
      levels after vitamin E ingestion. These data suggest that anti-oxidants preserve
      adequate function of immune cells against homeostatic disturbances such as those
      caused by endotoxic shock and ageing.

PMID- 10651930
TI  - Immune response to orally consumed antigens and probiotic bacteria.
AB  - The gut mucosal system must fulfil conflicting roles in suppressing immune
      responses against orally fed antigens (tolerance) while still retaining the
      ability to respond to potential enteric pathogens. It must also, to a large
      degree, not mount an immune response against commensal enteric bacteria and the
      administration of large numbers of probiotic bacteria formulated as dietary
      supplements in food products. Contrary to this dogma, it has been found that
      feeding ovalbumin as a marker antigen, in association with selected probiotic
      bacteria, appears to prime for an intestinal immune response that is further
      augmented by skin vaccination. Skin immunization is known to stimulate a strong
      innate, humoral and cellular immune response. Such dominant immunogenic signals
      appear to override tolerogenic signals engendered by oral feeding of antigen.
      High-dose antigen feeding stimulated a strong Th2-dependent antibody response to
      skin vaccination but completely suppressed cytotoxic T cell responses. This was
      true even when ovalbumin was administered in conjunction with various selected
      probiotic bacteria. However, while yeast appeared to be better at priming for an
      enhanced humoral response, Lactobacillus fermentum and Staphylococcus carnosus
      were more effective in enhancing the postvaccinal lymphoproliferative response
      against ovalbumin.

PMID- 10651931
TI  - Modulating immune responses with probiotic bacteria.
AB  - For many years, probiotic bacteria have been known to confer health benefits to
      the consumer. One possible mechanism for this may be the ability of probiotic
      bacteria to modulate immune responses. Oral administration of Lactobacillus casei
      strain Shirota (LcS) has been found to enhance innate immunity by stimulating the
      activity of splenic NK cells. Oral feeding with killed LcS was able to stimulate
      the production of Th1 cytokines, resulting in repressed production of IgE
      antibodies against Ovalbumin in experimental mice. The ability to switch mucosal
      immune responses towards Th1 with probiotic bacteria provides a strategy for
      treatment of allergic disorders. Growth of Meth A tumour cells in the lungs was
      also inhibited by intrapleural injection of LcS. Oral administration of other
      probiotic bacteria, such as Streptococcus thermophilus (St), Lactobacillus
      fermentum (Lf) and yeast (Y), elicited different immune responses. Mice that were
      prefed yeast or Lf followed by feeding with ovalbumin (OVA) responded better to
      vaccination with OVA than mice not given either probiotic or OVA or mice that had
      been prefed only OVA. However, antibody responses were significantly suppressed
      in response to vaccination with OVA in mice that had been prefed yeast followed
      by yeast and OVA as well as mice prefed Lf followed by Lf and OVA. Prefeeding St
      followed by OVA feeding enhanced cellular immune responses against ovalbumin. In
      contrast, mice prefed St followed by St + OVA were hyporesponsive against OVA.
      While antigen feeding alone appears to prime for an immune response, cofeeding
      antigen with probiotic bacteria can suppress both antibody and cellular immune
      responses and may provide an efficacious protocol to attenuate autoimmune
      diseases, such as experimental allergic encephalomyelitis, by jointly dosing with
      myelin basic protein and probiotic bacteria.

PMID- 10651932
TI  - Bioactive molecules in milk and their role in health and disease: the role of
      transforming growth factor-beta.
AB  - Human breast milk is rich in nutrients, hormones, growth factors and immunoactive
      molecules, which influence the growth, development and immune status of the
      newborn infant. Although several of these factors are also present in bovine
      milk, the greater susceptibility of the formula-fed infant to infection and
      disease and the development of allergy is often attributed to the reduced level
      of protective factors in milk formulas. Nevertheless, modifying manufacturing
      processes may preserve the biological activity of some bioactive molecules in end
      products. Transforming growth factor (TGF)-beta is one such molecule. TGF-beta is
      a polypeptide, which has been described in both human and bovine milk. It is
      implicated in many processes, including epithelial cell growth and
      differentiation, development, carcinogenesis and immune regulation. The present
      article discusses the biological activity of TGF-beta2 that has been preserved
      and activated in a cow's milk-based product. More specifically, it addresses
      possible mechanisms of action in the intestinal lumen and speculates on how milk
      products containing naturally occurring TGF-beta2 could be exploited in
      functional foods for the infant or as therapies for specific intestinal diseases.

PMID- 10651933
TI  - Survival and therapeutic potential of probiotic organisms with reference to
      Lactobacillus acidophilus and Bifidobacterium spp.
AB  - The present paper provides an overview on the use of probiotic organisms as live
      supplements, with particular emphasis on Lactobacillus acidophilus and
      Bifidobacterium spp. The therapeutic potential of these bacteria in fermented
      dairy products is dependent on their survival during manufacture and storage.
      Probiotic bacteria are increasingly used in food and pharmaceutical applications
      to balance disturbed intestinal microflora and related dysfunction of the human
      gastrointestinal tract. Lactobacillus acidophilus and Bifidobacterium spp. have
      been reported to be beneficial probiotic organisms that provide excellent
      therapeutic benefits. The biological activity of probiotic bacteria is due in
      part to their ability to attach to enterocytes. This inhibits the binding of
      enteric pathogens by a process of competitive exclusion. Attachment of probiotic
      bacteria to cell surface receptors of enterocytes also initiates signalling
      events that result in the synthesis of cytokines. Probiotic bacteria also exert
      an influence on commensal micro-organisms by the production of lactic acid and
      bacteriocins. These substances inhibit growth of pathogens and also alter the
      ecological balance of enteric commensals. Production of butyric acid by some
      probiotic bacteria affects the turnover of enterocytes and neutralizes the
      activity of dietary carcinogens, such as nitrosamines, that are generated by the
      metabolic activity of commensal bacteria in subjects consuming a high-protein
      diet. Therefore, inclusion of probiotic bacteria in fermented dairy products
      enhances their value as better therapeutic functional foods. However,
      insufficient viability and survival of these bacteria remain a problem in
      commercial food products. By selecting better functional probiotic strains and
      adopting improved methods to enhance survival, including the use of appropriate
      prebiotics and the optimal combination of probiotics and prebiotics (synbiotics),
      an increased delivery of viable bacteria in fermented products to the consumers
      can be achieved.

PMID- 10651934
TI  - Immunostimulatory bacterial DNA sequences activate dendritic cells and promote
      priming and differentiation of CD8+ T cells.
AB  - CD8+ T lymphocytes producing high levels of interferon-gamma (IFN-gamma) and
      expressing antigen specific cytotoxic activity are effectively induced after
      plasmid DNA vaccination and mediate protection against several intracellular
      micro-organisms. Recent evidence suggests that the priming of CD8+ T-cell
      responses following DNA injection involves antigen presentation mediated by
      dendritic cells. Here, we show that bacterial DNA and synthetic oligonucleotides
      containing dinucleotide (CpG) motifs activate cytokine expression in dendritic
      cells and modulate in vivo CD8+ T-cell priming and differentiation.

PMID- 10651935
TI  - Cellular but not humoral immune responses generated by vaccination with dendritic
      cells protect mice against leukaemia.
AB  - Dendritic cells (DC) are extremely efficient at generating both prophylactic and
      therapeutic anti-tumour immunity. We aimed to analyse the respective roles of
      humoral and cellular immune responses generated in mice vaccinated with bone
      marrow (BM)-derived DC in terms of in vivo anti-leukaemia effect. We used the
      murine L1210 B lymphocytic leukaemia genetically modified to express on the cell
      surface of human CD4 (hCD4) (L1210/hCD4) as a model tumour-associated antigen
      (TAA). DC cultures were loaded with either purified soluble hCD4 (shCD4) protein
      or unfractionated L1210/hCD4 extracts and injected as vaccine into mice. The
      efficacy of these vaccinations was compared with that of vaccination with shCD4
      protein emulsified in Freund's adjuvant (FA). We evaluated the immune responses
      generated after these vaccinal protocols and the survival rate of vaccinated mice
      subsequently challenged with a lethal injection of L1210/hCD4 cells. Our results
      demonstrated that vaccination with shCD4 protein or tumour extract-loaded DC
      mainly generated an hCD4 antigen-specific cell-mediated cytotoxic immune response
      that was associated with a specific protection against leukaemia. In contrast,
      vaccination with the protein emulsified in FA only generated potent humoral
      immune responses that were not protective against leukaemia. Altogether, our
      results indicate that the unique property of loaded DC to trigger an anti
      leukaemia protective effect is mainly associated with cellular immune responses.

PMID- 10651936
TI  - Carcinogen-modified dendritic cells induce immunosuppression by incomplete T-cell
      activation resulting from impaired antigen uptake and reduced CD86 expression.
AB  - Exposure of the skin to environmental stimuli, such as chemical or physical
      carcinogens, modifies the local skin environment, including depletion of
      epidermal Langerhans' cells (LC). Any subsequent exposure of the LC-depleted skin
      to antigen results in the generation of antigen-specific tolerance. In this study
      we evaluated the antigen-bearing cells in the draining lymph nodes by
      capitalizing on the fluorescent nature of the contact sensitizer, fluorescein
      isothiocyanate (FITC). When FITC was applied to the skin of normal mice, two
      distinct populations of antigen-bearing cells were identified in the draining
      lymph nodes. They were classified as either FITChi or FITClo on the basis of
      their fluorescence intensity and thus the amount of antigen they internalized.
      Only FITClo cells were detected in the lymph nodes draining FITC-treated murine
      skin that had been depleted of epidermal LC by prior treatment with the complete
      carcinogen 9,10-dimethyl 1,2-benzanthracene (DMBA). Functional analysis of these
      cells revealed that the FITChi cells, but not the FITClo cells, induced antigen
      specific T-cell proliferation. Further analysis of the FITClo cells from the DMBA
      treated mice demonstrated that these cells had reduced levels of CD80 expression,
      had substantially reduced levels of CD86 expression and performed poorly as co
      stimulator cells in an anti-CD3-mediated proliferative assay. Nonetheless these
      cells still induced early signs of T-cell activation and interleukin-12
      production. Consequently the FITClo cells migrating from the LC-depleted skin,
      through a combination of reduced antigen presentation and reduced co-stimulatory
      activity, induced a state of unresponsiveness or anergy in the responder T cells
      in a similar manner to that observed when antigen presentation occurs in the
      absence of co-stimulation. We propose that these unresponsive, or anergic cells,
      account for the antigen-specific tolerance observed in these experiments.

PMID- 10651937
TI  - Cellular interactions in bovine tuberculosis: release of active mycobacteria from
      infected macrophages by antigen-stimulated T cells.
AB  - The outcome of Mycobacterium bovis infections depends on the interactions of
      infected macrophages with T lymphocytes. Several studies in humans and in mouse
      models have suggested an important role for cytotoxicity in the protective immune
      response to mycobacterial infections, and both CD4+ and CD8+ T cells have been
      shown to elicit appropriate cytolytic activity. The present study investigated in
      vitro interactions of T cells with M. bovis-infected macrophages in bovine
      tuberculosis. The results showed that following interaction with antigen
      stimulated peripheral blood mononuclear cells (PBMC) from infected cattle, there
      was an increased presence of M. bovis in the extracellular compartment of
      infected macrophage cultures, as measured by incorporation of [3H]uracil into
      mycobacterial RNA. Furthermore, out of a panel of T-cell clones from infected
      cattle, it was found that a higher proportion of CD8+ clones produced an increase
      in the number of metabolically active extracellular M. bovis organisms compared
      with CD4+ clones. Finally, a positive correlation between percentage of antigen
      dependent release of mycobacteria and total uracil uptake by M. bovis within
      culture systems was detected. This could be regarded as an indication of
      preferential intracellular control of mycobacteria by activated macrophages.

PMID- 10651938
TI  - Mucosal immunogenicity of plant lectins in mice.
AB  - The mucosal immunogenicity of a number of plant lectins with different sugar
      specificities was investigated in mice. Following intranasal (i.n.) or oral
      administration, the systemic and mucosal antibody responses elicited were
      compared with those induced by a potent mucosal immunogen (cholera toxin; CT) and
      a poorly immunogenic protein (ovalbumin; OVA). After three oral or i.n. doses of
      CT, high levels of specific serum antibodies were measured and specific IgA was
      detected in the serum, saliva, vaginal wash, nasal wash and gut wash of mice.
      Immunization with OVA elicited low titres of serum IgG but specific IgA was not
      detected in mucosal secretions. Both oral and i.n. delivery of all five plant
      lectins investigated ?Viscum album (mistletoe lectin 1; ML-1), Lycospersicum
      esculentum (tomato lectin; LEA), Phaseolus vulgaris (PHA), Triticum vulgaris
      (wheat germ agglutinin (WGA), Ulex europaeus I (UEA-1) stimulated the production
      of specific serum IgG and IgA antibody after three i. n. or oral doses.
      Immunization with ML-1 induced high titres of serum IgG and IgA in addition to
      specific IgA in mucosal secretions. The response to orally delivered ML-1 was
      comparable to that induced by CT, although a 10-fold higher dose was
      administered. Immunization with LEA also induced high titres of serum IgG,
      particularly after i. n. delivery. Low specific IgA titres were also detected to
      LEA in mucosal secretions. Responses to PHA, WGA and UEA-1 were measured at a
      relatively low level in the serum, and little or no specific mucosal IgA was
      detected.

PMID- 10651939
TI  - The C5a receptor is expressed in normal renal proximal tubular but not in normal
      pulmonary or hepatic epithelial cells.
AB  - C5a, a 74 amino acid peptide cleaved from the complement protein C5, is an
      extremely potent anaphylatoxin. Expression of the receptor for the anaphylatoxin
      C5a (C5aR) has been thought to be restricted to cells of myeloid origin. However,
      recent evidence suggests that the C5aR is also expressed in hepatocytes as well
      as in pulmonary epithelial, endothelial and smooth muscle cells. In the present
      study, we investigated the tissue distribution of C5aR by immunohistochemistry in
      normal human lung, liver, intestine and kidney using well-defined monoclonal
      antibodies (mAbs) directed against the extracellular N-terminus of the receptor.
      In all tissues examined, macrophages displayed an abundant expression of C5aR
      protein. However, in the normal human lung, C5aR expression was not detectable in
      bronchial and alveolar epithelial cells or in vascular smooth muscle or
      endothelial cells. In the normal human liver, no C5aR protein was detected in
      hepatocytes, whereas Kupffer cells strongly expressed the C5aR. In normal human
      kidney, the C5aR was detectable only in proximal tubular cells. C5aR gene
      transcription in Kupffer cells and proximal tubular cells was confirmed by in
      situ hybridization. Thus, our results point to an as yet unknown role of the C5aR
      in normal renal physiology. In the normal lung and liver, however, previous
      evidence for the ubiquitous expression of C5aR in epithelial, endothelial and
      smooth muscle cells in situ should be re-evaluated.

PMID- 10651940
TI  - Production and functional analysis of rat CD59 and chimeric CD59-Crry as active
      soluble proteins in Pichia pastoris.
AB  - Crry (CR1-related gene/protein) is a rodent complement regulator that inhibits C3
      convertases. CD59 is a conserved protein inhibitor active towards C8 and C9. We
      have previously produced rat Crry as a recombinant soluble (rs) protein in Pichia
      pastoris. In this study we produced functionally active rat rsCD59 and a chimeric
      rsCD59-Crry protein in P. pastoris. The GPI anchor addition site of rat CD59 (Asn
      79) was replaced either by a stop codon to produce rsCD59, or with the sequence
      of the first five short consensus repeats of Crry to produce rsCD59-Crry.
      Proteins were generated by fermentation and purified by affinity chromatography
      on an anti-CD59 column. In a standard classical pathway haemolysis assay, all
      three rs proteins had inhibitory activity, with 50% inhibition at 0.5 microM
      (rsCrry and rsCD59-Crry) and 4.4 microM (rsCD59). In an assay examining
      inhibition of C5b-9, in which C5b-7 was first formed, followed by purified C8 and
      C9, rsCD59 and rsCD59-Crry were active with 50% inhibition at 0.8 microM (rsCD59
      Crry) and 1.3 microM (rsCD59). The degree of inhibition was independent of
      whether the C8 and C9 were of rat or human origin. Therefore, we have produced
      rsCD59 and rsCD59-Crry in P. pastoris. The rsCD59 retains its inhibitory activity
      towards C5b-9, while rsCD59-Crry appears to have the combined activities of Crry
      and CD59. In a haemolytic assay, the inclusion of CD59 to Crry is of no
      additional benefit to Crry, which may illustrate the overall importance of the C3
      convertase step. Yet, inclusion of Crry to CD59 increases the potency of CD59
      towards C5b-9.

PMID- 10651941
TI  - A polymorphic CD40 ligand (CD154) molecule mediates CD40-dependent signalling but
      interferes with the ability of soluble CD40 to functionally block CD154:CD40
      interactions.
AB  - We report the characterization of a naturally occurring polymorphism in CD40
      ligand (CD40L, CD154) expressed by activated T cells from a young female patient.
      This polymorphism encodes a nonconservative Gly --> Arg substitution in amino
      acid 219 in the extracellular, CD40 binding domain of the molecule. Studies
      carried out with 293 epithelial cells ectopically expressing the polymorphic
      protein (CD154/G219R) revealed reduced levels of binding to different anti-CD154
      monoclonal antibodies (mAb) and CD40-immunoglobulin (CD40-Ig). However,
      recognition of the polymorphic and wild-type CD154 molecules by a polyclonal
      antiserum was comparable, suggesting that the polymorphism affects the ability of
      the protein to interact with CD40 but does not significantly alter its surface
      expression. To determine if reduced cross-linking of CD40 mediated decreased
      functional effects, three CD40-dependent properties were measured. We found that
      pathways leading to the induction of surface CD23, CD80, and Igamma transcription
      were activated in response to CD154/G219R signalling. However, the decrease in
      affinity for CD40 by the mutated CD154 affected the ability of CD40-Ig to
      efficiently interfere with the binding and effectively block induced CD80
      expression. In contrast, we found that the 5c8 mAb, which recognized the
      polymorphic molecule to a similar extent as wild-type CD154, effectively blocked
      the interaction between CD154/G219R and CD40 as measured by CD80 expression.
      These findings suggest that naturally occurring polymorphisms in the CD154
      molecule may affect the ability of CD40-mediated functions to be blocked by
      soluble CD40 or anti-CD154 mAb in the therapeutic treatment of disease and graft
      rejection.

PMID- 10651942
TI  - Convergence between CD98 and integrin-mediated T-lymphocyte co-stimulation.
AB  - CD98 is a widely expressed cell surface heterodimeric glycoprotein, which is
      rapidly up-regulated upon activation of T lymphocytes. Monoclonal antibody (mAb)
      80A10 recognizes an epitope on CD98 and in combination with CD3 antibody causes
      proliferation of peripheral blood T lymphocytes. CD98 co-stimulatory activity,
      mediated by either mAb 80A10 or 4F2, a well-characterized CD98-specific mAb, is
      blocked in the presence of the soluble beta1 integrin antibody 18D3. Previously
      we have reported that co-stimulatory activity of antibodies to integrins
      alpha4beta1, alpha5beta1, alphaLbeta2 and alpha4beta7 is inhibited by 18D3,
      whereas co-stimulation mediated by non-integrins was unaffected. Thus the non
      integrin CD98 is uniquely sensitive to the inhibitory effects of beta1 integrin
      blocking antibodies, which may reflect convergent signalling mechanisms between
      integrins and CD98. This is consistent with recent reports suggesting that CD98
      may regulate integrin-mediated adhesive events.

PMID- 10651943
TI  - CD95 ligand expression as a mechanism of immune escape in breast cancer.
AB  - Interaction of CD95 (Apo-1/Fas) and its ligand (CD95L) plays an important role in
      the regulation of the immune response, since CD95+ lymphocytes may be killed
      after engagement of the CD95 receptor. Studying the CD95/CD95L system in 40 cases
      of breast cancer, the malignant cells expressed CD95L, but lost CD95 expression,
      when compared with non-malignant mammary tissue. Jurkat T cells incubated on
      breast cancer sections underwent CD95L-specific apoptosis. The rate of apoptosis
      correlated with the CD95L mRNA levels of the tissue samples. In four breast
      cancer cell lines, CD95L expression was increased by interferon-gamma (IFN
      gamma), which resulted in higher levels of CD95L-specific apoptosis in co
      cultured Jurkat T cells. Since IFN-gamma is mainly secreted by activated T cells,
      up-regulation of CD95L in breast cancer cells in response to IFN-gamma may thus
      counterselect activated tumour-infiltrating T cells and favour the immune escape
      of breast cancer. As demonstrated by inhibition of matrix metalloproteinases,
      CD95L expressed on breast cancer cells can also be shed from the cell membrane
      into the culture supernatant. Supernatants derived from cultured breast cancer
      cells induced apoptosis in Jurkat T cells via CD95L. In breast cancer patients,
      depletion of CD4+ and CD8+ peripheral blood lymphocytes was significantly
      correlated with CD95L expression in the tumours. This might be suggestive for a
      relationship between CD95L expression by breast cancer and systemic
      immunosuppression.

PMID- 10651944
TI  - Molecular cloning, genomic organization and cell-binding characteristics of mouse
      Spalpha.
AB  - Several group B scavenger receptor cysteine-rich (SRCR) proteins have been shown
      to function as modulators in the immune response. Recently, we reported the
      cloning of a new member of this family, human Spalpha (hSpalpha). Herein we
      report the cloning and characterization of the mouse homologue of hSpalpha. Like
      its human counterpart, mouse Spalpha (mSpalpha), is a secreted protein containing
      three SRCR domains. Most lymphoid tissues express RNA transcripts encoding
      mSpalpha. Characterization of a genomic clone encoding the mature mSpalpha
      protein showed that each of the SRCR domains of mSpalpha is encoded by a single
      exon. Comparison of the sequence of mSPalpha with those of other published
      proteins indicates that it is the same as the recently reported protein named AIM
      (apoptosis inhibitor expressed by macrophages). Cell-binding studies with a
      mSpalpha immunoglobulin (mSpalpha-Rgamma) fusion protein indicated that mSpalpha
      is capable of binding to spleen-derived CD19+ B cells and minimally to peritoneal
      cavity-derived CD19+ B cells but not to peripheral blood-derived B cells. Spleen
      derived CD3+ T cells also bound mSpalpha-Rgamma; however, no binding was observed
      to either peripheral blood mononuclear cells or peritoneal cavity-derived CD3+ T
      cells. The mSpalpha-Rgamma fusion protein was also shown to bind to the mouse
      cell lines WEHI3 (monocytic) and EL-4 (thymoma, T cell). The cloning of cDNA and
      genomic clones encoding mSpalpha and the identification of cells expressing a
      putative mSpalpha receptor(s) should facilitate in vivo studies designed to
      investigate the function of Spalpha in the immune compartment.

PMID- 10651945
TI  - Disaccharides generated from heparan sulphate or heparin modulate chemokine
      induced T-cell adhesion to extracellular matrix.
AB  - We have found previously that disaccharides (DS) enzymatically generated from
      heparin or heparan sulphate can modulate tumour necrosis factor-alpha (TNF-alpha)
      secretion from immune cells in vitro and cell-mediated immune reactions in vivo.
      Here, we show that such DS can modulate the adhesion and migration of human T
      cells. We found that certain heparin- and heparan sulphate-derived DS induced, in
      a dose-dependent manner, the adhesion of human T cells to both extracellular
      matrix (ECM) and immobilized fibronectin (FN); maximal T-cell adhesion occurred
      with 1 ng/ml of DS. The levels of T-cell adhesion to ECM that were induced by the
      tested DS molecules resembled those induced by the prototypic chemokine,
      macrophage inflammatory protein 1beta (MIP-1beta). However, the kinetics of DS
      induced T-cell adhesion to FN resembled that induced by phorbol myristate acetate
      (PMA), but not that induced by MIP-1beta. This adhesion appeared to involve beta1
      integrin recognition and activation, and was associated with specific
      intracellular activation pathways. Although a first exposure of T cells to
      certain DS molecules appeared to result in cell adhesion, a subsequent exposure
      of T cells to pro-adhesive chemokines, such as MIP-1beta or RANTES, but not to
      other pro-adhesive stimuli, for example interleukin-2 or CD3 cross-linking,
      resulted in inhibition of T-cell adhesion to and chemotactic migration through
      FN. Hence, we propose that the breakdown products of tissues generated by
      inflammatory enzymes are part of an intrinsic functional programme, and not
      necessarily molecular waste. Moreover, because the DS molecules exert their
      modulatory functions within a limited time, it appears that the historical
      encounters of the tissue-invading cells with the constituents of inflamed loci
      may dictate the cells' behaviour upon subsequent exposure to proinflammatory
      mediators.

PMID- 10651946
TI  - Graft-versus-host-disease-associated donor cell engraftment in an F1 hybrid model
      is dependent upon the Fas pathway.
AB  - The graft-versus-host disease (GVHD) generated in BDF1 mice by the injection of
      spleen cells from the C57BL/6 parental strain induces a direct cell-mediated
      attack on host lymphohaematopoietic populations, resulting in the reconstitution
      of the host with donor cells. We examined Fas-Fas ligand (FasL) interactions in
      donor and host haematopoietic cells over a prolonged period of parental-induced
      GVHD. Fas expression on bone marrow cells of both donor and host origin increased
      at 2 weeks. Host cell incubation with anti-Fas antibody induced apoptosis, and
      the number of haematopoietic progenitor cells decreased. Fas-induced apoptosis by
      the repopulating donor cells, however, did not increase until 12 weeks, when more
      than 90% of the cells were donor cells. The expression of various cytokines, such
      as interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha), and
      FasL gene expression in the bone marrow increased concomitantly. To examine
      directly whether FasL has a major role in the development of donor cell
      engraftment, FasL-deficient (gld) mice were used as donors. Injection of B6/gld
      spleen cells induced significantly less host lymphohaematopoietic depletion,
      resulting in a failure of donor cell engraftment. Furthermore, injection of IFN
      gamma gene knockout (gko) B6 spleen cells failed to augment Fas and FasL
      expression in recipient mice, resulting in a failure of donor cell engraftment.
      This suggests that the induction of apoptosis by Fas-FasL interactions in host
      cells may contribute to a reconstitution of the host with donor cells and that
      donor-derived IFN-gamma plays a significant role for Fas-FasL interactions in
      host cells during parental-induced GVHD.

PMID- 10651947
TI  - DNase I footprinting of the human interleukin-5 gene promoter.
AB  - A characteristic feature of allergic asthma is the overexpression of the T helper
      type 2 (Th2) cytokines interleukin-4 (IL-4), IL-5 and IL-13 by T lymphocytes. Of
      these cytokines, IL-5 is critical for the growth, survival and recruitment of
      eosinophils which are thought to be responsible for the tissue damage observed in
      asthmatic airways. The expression of human IL-5 is primarily regulated at the
      transcriptional level; however, little is known about the mechanisms that control
      its transcription. Using nuclear extracts from allergen-specific human T-cell
      clones we have performed DNase I footprinting of the human IL-5 promoter in order
      to establish sites occupied by transcription factors. We show footprints covering
      the conserved lymphokine element 0 ?(CLE0) -60 to -44 base pairs (bp) and GATA (
      73 to -62 bp) elements, which have previously been identified to be important in
      the regulation of the murine IL-5 promoter. We also describe a footprint covering
      a considerably extended Octamer binding site (-249 to -217 bp), which encompasses
      two hitherto unidentified CCAAT/enhancer binding protein consensus binding sites.
      We have also identified a previously unknown Ets binding site (-274 to -264 bp).
      These novel data on the regions of the human IL-5 promoter that are bound by
      transcription factors should allow dissection of the regulatory mechanisms
      involved in the transcription of IL-5 in the T-helper lymphocytes of asthmatics.

PMID- 10651948
TI  - Role of beta1 and beta2 subunits of the interleukin-12 receptor in determining T
      helper 1/T helper 2 responses in vivo in the rat.
AB  - Interleukin-12 (IL-12) responsiveness, and hence capacity to mount a T helper
      type 1(Th1) immune response, may be regulated via differential expression of the
      IL-12 receptor beta2 subunit at least in vitro in human and murine cells. To test
      whether a similar phenomenon operates in vivo in the rat we cloned and sequenced
      partial cDNAs for rat IL-12Rbeta1 and IL-12Rbeta2 subunits and analysed
      expression of these genes in vivo in two rat strains with different Th1/Th2 bias.
      After treatment with mercuric chloride (HgCl2), Brown-Norway rats develop Th2
      biased autoimmunity whereas Lewis rats do not develop autoimmunity, instead
      becoming resistant to Th1-biased diseases to which they are normally susceptible.
      We report close sequence homology between the segments of the rat IL-12R genes
      sequenced and corresponding mouse genes (95.6% and 92% for IL-12Rbeta1 and IL
      12Rbeta2, respectively). Both Brown-Norway and Lewis rats express both beta1 and
      beta2 subunits of IL-12 receptor in vivo in spleen; Brown-Norway rats express the
      beta2 subunit at a lower level than Lewis rats. After HgCl2 treatment, IL
      12Rbeta1 expression was not altered but there was down-regulation of IL-12Rbeta2
      expression in both strains. We conclude that relative under-expression of IL
      12Rbeta2 by Brown-Norway rats contributes to their Th2 bias, and that down
      regulation of IL-12Rbeta2 after HgCl2 administration in Lewis rats underlies
      subsequent resistance to induction of Th1-biased diseases.

PMID- 10651949
TI  - Neutralizing antibodies to granulocyte-macrophage colony-stimulating factor,
      interleukin-1alpha and interferon-alpha but not other cytokines in human
      immunoglobulin preparations.
AB  - Human immunoglobulin preparations are used therapeutically for various disorders.
      Such therapy is generally safe but adverse effects occasionally occur in
      recipients. It has been suggested that antibodies to cytokines present in
      clinical immunoglobulin products may contribute to undesirable effects in
      recipients. Therefore, we investigated intravenous and intramuscular
      immunoglobulin products for the presence of cytokine-specific neutralizing
      antibodies. Using validated bioassays, we detected neutralizing activity against
      human granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon
      alpha2a (IFN-alpha2a) and interleukin-1alpha (IL-1alpha) in immunoglobulin
      products. We found no neutralization of granulocyte colony-stimulating factor,
      macrophage colony-stimulating factor, stem cell factor, IL-1beta, IL-2, IL-3, IL
      4, IL-6, IL-9, IL-10, IL-12, tumour necrosis factor-alpha, oncostatin M (OSM) and
      IFN-gamma. Most batches which neutralized IFN-alpha2a activity also neutralized
      other IFN-alpha subtypes, IFN-omega and IFN-beta. Most products (94%) neutralized
      the biological activity of GM-CSF. No correlation between batches and their
      ability to neutralize bioactivities of GM-CSF, IFN-alpha2a and IL-1alpha was
      found. This neutralizing activity could be traced to plasma pools used for
      manufacture of immunoglobulins. The neutralization was mediated by specific
      cytokine antibodies contained within immunoglobulin products as it was present in
      specific immunoglobulin G (IgG) fractions eluted from cytokine affinity
      chromatography columns. Specific binding of such IgG fractions to cytokines in
      immunoblots and in enzyme-linked immunosorbent assays (ELISAs) was observed. This
      contrasts with the broad non-specific recognition of cytokine proteins observed
      using unfractionated immunoglobulins in ELISAs. This is the first comprehensive
      study showing the presence of neutralizing antibodies against GM-CSF, IL-1alpha,
      or IFN-alpha2a in immunoglobulin products.

PMID- 10651950
TI  - The regulation of prostaglandin output from term intact fetal membranes by anti
      inflammatory cytokines.
AB  - Prostaglandins are some of the main mediators which control parturition, and
      their production by intrauterine tissues can be up-regulated by pro-inflammatory
      cytokines. Anti-inflammatory cytokines may oppose these effects, and in this
      study we have investigated how two such cytokines affected fetal membrane
      function. Interleukin-10 (IL-10) inhibited the output of prostaglandin E2 (PGE2)
      from intact fetal membranes under basal and lipopolysaccharide (LPS)-stimulated
      conditions, and there was a parallel decrease in the expression of mRNA for COX
      2. IL-10 also inhibited the production of interleukin-1beta (IL-1beta) and the
      expression of mRNA for IL-1beta, indicating that this cytokine has a broad anti
      inflammatory effect. Transforming growth factor-beta1 (TGF-beta1), which is
      generally considered to be anti-inflammatory had opposite effects on PGE2
      production, in that it increased the output of PGE2 for up to 8 hr. TGF-beta1
      increased levels of type-2 cyclo-oxygenase (COX-2) and cytosolic phospholipase A2
      (cPLA2) protein, and also activated the cPLA2 enzyme present; the profile of
      effects is similar to that of the pro-inflammatory cytokine IL-1beta, and was not
      expected. Combinations of TGF-beta1 with IL-1beta also increased PGE2 output and
      caused appropriate changes in prostaglandin pathway enzymes, whereas TGF-beta1
      and IL-1alpha had more limited effects. Further studies are needed to establish
      the physiological significance of these findings, but TGF-beta1 does not seem to
      act as an inhibitory cytokine in intact fetal membranes at term.

PMID- 10651951
TI  - Studies of delayed systemic effects of ultraviolet B radiation (UVR) on the
      induction of contact hypersensitivity, 2. Evidence that interleukin-10 from UVR
      treated epidermis is the critical mediator.
AB  - Acute, low-dose ultraviolet B radiation (UVR) alters cutaneous immunity at the
      local site as well as systemically. Within 2-3 days of UVR exposure, recipient
      mice lose their capacity to develop contact hypersensitivity (CH) when hapten is
      painted on unexposed skin. This loss correlates temporally with a functional
      deficit among dendritic antigen-presenting cells within non-draining lymph nodes
      and spleen. In the experiments described, the delayed systemic immune deficiency
      following acute, low-dose UVR exposure was found to be eliminated with
      neutralizing anti-interleukin-10 (IL-10) antibody. Intracutaneous injection of IL
      10 generated a deficiency of systemic immunity as well as a functional deficit
      among lymph node dendritic cells that was similar to that induced by UVR. The
      skin itself was found to be the source of the IL-10 responsible for these
      defects, and epidermis (presumably keratinocytes) rather than mast cells was
      found to be the source of IL-10 within UVR-exposed skin. The potential
      relationships are discussed between the delayed systemic immune deficit created
      by acute, low-dose UVR, and the systemic immune deficits caused by chronic, high
      dose UVR and by a single, high-dose UVR exposure.

PMID- 10651952
TI  - The role of endogenous steroid hormones in the generation of T helper 2-mediated
      autoimmunity in mercuric chloride-treated Brown-Norway rats.
AB  - Injection of Brown-Norway rats with mercuric chloride (HgCl2) activates a T
      helper type 2 (Th2) autoimmune response, with production of a number of
      autoantibodies and vasculitis primarily affecting the gut. Glucocorticoids have
      been shown to suppress Th1 and to promote the development of Th2-type responses.
      Conversely dehydroepiandrosterone (DHEA) promotes Th1 responses with suppression
      of Th2 responses. This study set out to define the role of these hormones in this
      animal model. Rats were adrenalectomized (Adx) with no steroid replacement (n =
      11), Adx with basal steroid replacement given by a 25 mg corticosterone pellet
      inserted subcutaneously (n = 13), or sham-Adx (n = 14) prior to administration of
      HgCl2. In both groups of Adx animals there was a delay in the production of
      immunoglobulin E (IgE) and serum concentrations on day 9 were marginally lower (P
      = 0.035, repeated measures ANOVA). All of the animals Adx with no steroid
      replacement and two Adx animals with steroid replacement died between 10 and 14
      days after HgCl2 challenge. There was no difference in the severity of caecal
      vasculitis between the groups. A significant increase in adrenal size was noted
      following administration of HgCl2. Administration of subcutaneous DHEA implants
      (100 mg and 200 mg) had no significant effect on IgE concentrations or severity
      of vasculitis. These observations do not support the hypothesis that
      corticosterone and DHEA play a central role in setting the Th1/Th2 balance in
      this experimental Th2-mediated autoimmune disease; in contrast with the Th1
      mediated autoimmune disease experimental allergic encephalomyelitis where
      corticosterone plays a key role in immunoregulation.

PMID- 10651953
TI  - DBA/2J (Mls-1a) B-cell differentiation in BALB.xid recipients.
AB  - Studies of superantigens (SAg) have focused primarily on their impact on CD4+ T
      cells, largely bypassing the impact of the sequelae of this interaction upon the
      antigen-presenting cell (APC). Sequelae of SAg-induced CD4+ T-cell activation
      include the 'bathing' of the SAg-presenting cell with cytokines that promote the
      differentiation of the APC. In this report, the SAg-induced differentiation of
      Mls+ DBA/2J B cells was studied in vivo by their transplantation into B-cell
      defective BALB.xid recipients. Rapid, high-level serum immunoglobulin M (IgM)
      production was noted shortly after transfer, disappearing by 3 weeks. Donor B
      cells, as evidenced after their chemical and genetic impairment and by the use of
      an IgM allotype-disparate donor-recipient combination, contributed to this
      transient IgM production. These results clarify a discrepancy in the literature
      regarding donor B-cell contribution to IgM production and illustrate a model
      system to utilize SAg to study B-lymphocyte diversity.

PMID- 10651954
TI  - The gills are an important site of iNOS expression in rainbow trout Oncorhynchus
      mykiss after challenge with the gram-positive pathogen Renibacterium
      salmoninarum.
AB  - Following injection challenge of rainbow trout with the Gram-positive pathogen
      Renibacterium salmoninarum, serum nitrate levels increased indicative of NO
      production. The timing and amount of nitrate produced varied with the virulence
      of the bacterial strain used, with the highest levels seen in fish challenged
      with the most virulent (autoaggregating) strain. Immunization with a killed R.
      salmoninarum preparation in Freund's incomplete adjuvant significantly increased
      nitrate levels after challenge. Inducible nitric oxide synthase (iNOS) transcript
      expression was detectable in rainbow trout tissues after injection challenge with
      R. salmoninarum, and its induction in the gills was both quick (between 3 and 6
      hr) and relatively prolonged (lasting several days). iNOS expression in the
      kidney was also seen at a later stage (24 hr) but appeared to switch off
      relatively rapidly. Bath challenge with R. salmoninarum also induced iNOS
      expression in gill, and a variable expression in the gut and kidney also
      occurred. These results highlight the importance of the gills, not only as a
      point of entry of pathogens but also as a tissue capable of mounting an immune
      response.

PMID- 10651955
TI  - Cigarette smoking, sexually transmitted diseases, and HIV/AIDS.

PMID- 10651957
TI  - Five conundrums* about Western world dermatology in the second millennium.

PMID- 10651956
TI  - Onychomycosis: treatment perspective.

PMID- 10651958
TI  - Epidemiology of vitiligo in the French West Indies (Isle of Martinique).
AB  - BACKGROUND: The frequency of vitiligo in white populations has been generally
      estimated to be about 0.5-1%. The same prevalence is expected in black
      populations, despite the few investigations reported. No studies have been
      performed in black populations living in the Caribbean Islands. Therefore, our
      purpose was to report an epidemiologic study of vitiligo in the French West
      Indies (Isle of Martinique). METHODS: We performed a prospective study between
      October 1995 and March 1996; 2077 outpatients of the Department of Dermatology at
      the Fort de France University Hospital were examined to detect vitiligo.
      Concurrently, 32 patients (23 women and nine men), presenting with vitiligo, were
      questioned about their family history, personal diseases, age, and circumstances
      of vitiligo occurrence. RESULTS: Vitiligo was found in seven patients (five women
      and two men) out of 2077. The prevalence in the studied population was 0.34%. Of
      the 32 patients with vitiligo who were investigated, 11 (34%) had a family
      history of vitiligo, two (6%) suffered from thyroid disease, two (6%) from
      psoriasis, and one (3%) from atopic dermatitis. The median age at vitiligo onset
      was 29 years. CONCLUSIONS: Despite the bias due to the recruitment of patients in
      the Dermatology Department, this study demonstrates a prevalence in a black
      population comparable, or slightly inferior, to the currently accepted data in
      white people. Our results concerning the age of onset and pathologic associations
      showed no difference with the literature data related to white populations.

PMID- 10651959
TI  - Survey on the epidemiology of Microsporum canis infections in Crete, Greece over
      a 5-year period.
AB  - BACKGROUND: Microsporum canis is a frequent cause of tinea capitis and tinea
      corporis in Europe and especially in the Mediterranean area. Objective This study
      was undertaken to examine the epidemiologic features of all cases of M. canis
      infections recorded in Crete, Greece, during a 5-year period (1994-1998).
      METHODS: The epidemiology of 111 cases of dermatophytoses due to M. canis was
      analyzed according to the sex, age, origin of the infection, place of residence,
      body site affected, and seasonal progression. RESULTS: M. canis constituted 24.5%
      of all dermatophytes isolated during the study period. Women were more frequently
      affected than men (54%), and infections were most prevalent in patients up to the
      age of 9 years (46.8%). Cats were identified as the commonest source of the
      infection (82%). As regarding the place of residence, most of the infected
      patients came from rural areas (64.9%). The commonest sites of M. canis infection
      (in decreasing order of frequency) were: the head, the lower extremities, the
      trunk, and the upper extremities. The greatest number of cases were seen in
      September and December. CONCLUSIONS: The findings of the present study indicate
      that M. canis infections have gradually decreased in recent years in this
      geographic area. Eradication requires elimination of the natural source of the
      infection, represented mainly by stray animals.

PMID- 10651960
TI  - Tinea pedis in Korean children.
AB  - BACKGROUND: Tinea pedis is an infrequent disease in children before the age of
      puberty. There are few epidemiologic and clinical data regarding cases of tinea
      pedis observed in children. Materials and methods We prospectively collected all
      cases of tinea pedis in children diagnosed during the years 1995-1997. Only those
      showing a positive result with potassium hydroxide preparation were included in
      the study. We performed fungal cultures in Sabouraud's agar in all cases to
      document the etiologic fungi. The clinical characteristics were investigated.
      RESULTS: A total of 21 children, aged 3 months to 14 years, were included.
      Fifteen patients were boys and six were girls. The mean age was 7.1 years. All
      the children were otherwise healthy. Prior to the establishment of the diagnosis
      of tinea pedis, 17 patients (80.9%) were treated for eczema without improvement.
      The intertriginous type was most common (53.3%). The first or second toe-webs
      were the sites of predilection (32.3%). Eighteen children (86%) had a family
      history of tinea pedis and more than half of cases (52.4%) showed occurrence in
      the summer. The results of fungal cultures were positive in 13 patients (57%).
      Trichophyton rubrum was the most commonly isolated pathogen (69.2%). The other
      associated dermatoses were onychomycosis (33.3%), atopic dermatitis (14%),
      plantar warts (10%), and chronic urticaria (5%). Tinea pedis and onychomycosis
      cleared after treatment with topical antifungals with or without systemic
      antifungals in all cases. CONCLUSIONS: Tinea pedis in children can occur more
      frequently than suspected. Our study shows the strong association with a family
      history and the seasonal relationship with occurrence in summer in more than half
      of cases. We suggest that tinea pedis should be considered in the differential
      diagnosis of foot dermatitis in children.

PMID- 10651961
TI  - Delayed cutaneous reaction to jellyfish.
AB  - A 57-year-old woman presented with a widespread papulonodular eruption. The
      dermatitis had appeared about 1 week after her return from a trip to the Red Sea,
      where she had come into contact with a shoal of unidentified jellyfish; however,
      that contact had not been followed by cutaneous lesions and/or symptoms. The
      patient also stated that she had had previous contacts with jellyfish during
      other trips to exotic seaside resorts. The dermatitis was characterized by
      papulonodular lesions, round or oval in shape, of a few millimeters in diameter,
      with a color ranging from pink to red to brown, and with a smooth and regular
      surface. The lesions were grouped in an apparently random fashion (Fig. 1) or
      arranged linearly (Fig. 2). The patient complained of pruritus and burning.
      Histopathologic examination showed the presence of some necrotic keratinocytes;
      in the upper and mid dermis, edema and a predominantly perivascular and
      periadnexal lymphohistiocytic infiltrate, with numerous neutrophils and
      eosinophils, were observed (Fig. 3). The patient was treated with hydroxyzine
      (37.5 mg/day) and hydrocortisone butyrate, which resulted in the rapid
      disappearance of the symptoms; however, the cutaneous lesions persisted for about
      3 weeks.

PMID- 10651962
TI  - Inflammatory linear verrucous epidermal nevus (ILVEN) and psoriasis in a child?

PMID- 10651963
TI  - Juvenile psoriatic arthritis with nail psoriasis in the absence of cutaneous
      lesions.

PMID- 10651964
TI  - Cutaneous histoplasmosis associated with acquired immunodeficiency syndrome
      (AIDS).

PMID- 10651965
TI  - Cutaneous tuberculosis and pyoderma gangrenosum.

PMID- 10651966
TI  - New topical treatments change the pattern of treatment of psoriasis:
      dermatologists remain the primary providers of this care.
AB  - BACKGROUND: Psoriasis is a common chronic skin disorder that can be debilitating
      both physically and psychologically. The treatment of psoriasis is complicated by
      the many manifestations of the disease, different patients' subjective impression
      of the disease, and the availability of numerous topical agents, systemic agents,
      and phototherapy options for the disease. Purpose The purpose of this study was
      to characterize how topical psoriasis treatment is changing in the USA. Methods
      Data from the National Ambulatory Medical Care Survey (1990-1996) were used to
      characterize the use of medication at physician office visits for psoriasis
      vulgaris. Corticosteroid agents in the years 1990-1994 were classified by
      relative potency. Results There were 1.0 million yearly visits for psoriasis.
      Dermatologists were responsible for 95% of these office visits. Topical
      corticosteroids were the only medication listed at 50% of psoriasis visits, and
      were used in combination with another medication in an additional 26% of visits.
      High and superpotent corticosteroid agents accounted for 55% of all topical
      corticosteroid agents listed. Topical calcipotriene was the most commonly used
      noncorticosteroid treatment, and its use in combination with corticosteroids
      increased from 17% to 84% between 1994 and 1996. CONCLUSION: s 80% or more of
      people with psoriasis do not see a physician for the disease in any given year. A
      combination of different topical medications is commonly used to treat psoriasis.
      Patients should be aware of the availability of new therapeutic options and the
      special expertise of dermatologists in managing complex treatment regimens for
      psoriasis.

PMID- 10651967
TI  - Azithromycin for the treatment of acne.
AB  - BACKGROUND: Acne affects a large number of young adults, including women, who
      often present with facial as well as truncal involvement. Systemic antimicrobial
      agents currently used for the reduction of inflammatory papules and cysts require
      frequent administration and are sometimes associated with uncomfortable side
      effects contributing to a decrease in compliance. METHODS: Ninety-nine episodes
      of inflammatory acne in 79 patients treated with oral antimicrobial agents were
      studied retrospectively over a period of 46 weeks. Patients were treated with
      tetracycline, erythromycin, minocycline, and doxycycline, the most commonly
      prescribed oral antimicrobials used to treat acne. Individuals that were unable
      to tolerate this therapy or had failed conventional therapy were treated with the
      azalide antibiotic azithromycin, given in a single oral 250-mg dose three times a
      week. The other agents were administered daily in divided doses as is current
      practice. Patients were also on topical care. RESULTS: The efficacy and reported
      side-effects were examined for all agents. Significant improvement was noted in 4
      weeks. All agents were effective in reducing inflammatory lesions and improving
      acne. Azithromycin produced a slightly higher percentage of patients with a
      greater than 80% reduction in their inflammatory acne lesions (85.7%) vs. an
      average of 77.1% for all other agents. All differences observed were not
      statistically significant. CONCLUSIONS: The results show that azithromycin is a
      safe and effective alternative in the treatment of inflammatory acne with few
      side-effects and good compliance, and suggest the need for further investigation
      with a clinical trial that will compare the long-term efficacy and tolerability.

PMID- 10651969
TI  - Climatotherapy of atopic dermatitis at the Dead Sea: demographic evaluation and
      cost-effectiveness.
AB  - BACKGROUND: About 21% of the patients coming yearly to the DMZ Clinic at the Dead
      Sea for climatotherapy suffer from atopic dermatitis. This is a common, chronic,
      and relapsing disease which necessitates drug treatment (topical corticosteroids,
      antimicrobials, antihistamines, or immunomodulators), phototherapy, or
      climatotherapy. Objective and methods As the improvement in the condition of
      patients after 4 weeks of climatotherapy at the Dead Sea is remarkable, we
      undertook to evaluate the demographic factors that have the strongest impact on
      this beneficial effect, in adults and children. The major factors studied were:
      gender, previous medical history, previous stays at the Dead Sea, skin type, skin
      involvement, age, and duration of treatment. Results A retrospective study of
      1718 patients revealed that previous treatments at the Dead Sea and stays longer
      than 4 weeks caused a clearance greater than 95%, the length of sun exposure was
      no longer than 5 h daily, and there was no impact of the percentage of skin
      involvement on the clearance of patients staying more than 4 weeks. CONCLUSION: s
      Climatotherapy of atopic dermatitis at the Dead Sea is a highly effective
      modality for treating this disease. It is also a highly cost-effective method, as
      the patients take no medications and experience no side-effects. Successful
      climatotherapy of atopic dermatitis requires strict medical supervision
      throughout the whole length of the patient's stay on shore.

PMID- 10651968
TI  - Improvement in psoriasis after intradermal administration of heat-killed
      Mycobacterium vaccae.
AB  - BACKGROUND: New treatments for psoriasis are being developed, but many are
      associated with limited efficacy, side-effects, or rapid recurrence after
      discontinuation. Thus, the aim of new agents is to induce longer term remissions
      with fewer side-effects. Preliminary studies have shown that Mycobacterium
      vaccae, a nonpathogenic organism prepared as a heat-killed suspension, may induce
      periods of remission in some psoriasis patients when administered intradermally.
      METHODS: To further assess the efficacy and tolerability of M. vaccae in patients
      with moderate to severe psoriasis (psoriasis area and severity index (PASI) of 12
      35), we conducted an open label study whereby 24 patients received two
      intradermal inoculations of M. vaccae in lesion-free deltoid skin, separated by a
      period of 3 weeks. RESULTS: Twelve weeks after starting treatment, 14 of 24
      patients (58%) showed marked improvement in the PASI score (greater than 50%
      reduction), two had moderate improvement (25-50% reduction), six were unchanged
      (< 25% reduction), and two had worsened (> 5% increase). By 24 weeks, 11 of 22
      patients continued to show greater than 50% improvement. Five patients had
      complete clearance of skin lesions that lasted for at least 6 months.
      CONCLUSIONS: Intradermal administration of heat-killed M. vaccae suspension was
      well tolerated and induced clinically significant improvement in a majority of
      psoriasis patients in this cohort. Placebo-controlled testing to further define
      the efficacy of this treatment is warranted.

PMID- 10651970
TI  - The rise and fall of the Turkish bath in Victorian England.

PMID- 10651971
TI  - Biases in medical literature.

PMID- 10651972
TI  - Fluvastatin in combination with cyclosporin in renal transplant recipients: a
      review of clinical and safety experience.
AB  - Cardiovascular disease remains a significant cause of morbidity and mortality in
      patients who have undergone renal transplantation, with one of the main risk
      factors being post-transplantation hyperlipidaemia. To date, however, optimal
      management of elevated lipid levels in such patients has been hindered by the
      lack of both effective and safe treatments, coupled with concerns over probable
      interactions with immunosuppressive therapy, particularly cyclosporin. Numerous
      studies confirm that the 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA)
      reductase inhibitors, such as fluvastatin, are effective lipid-lowering agents in
      renal transplant recipients, supporting findings in other patients' groups.
      Moreover, based on investigations of metabolic profile and clinical observation,
      fluvastatin (at dosages of up to 80 mg/day) is well tolerated in renal transplant
      recipients receiving cyclosporin. In clinical trials to date, no instances of
      rhabdomyolysis have been observed during co-administration of fluvastatin and
      cyclosporin. The potential of fluvastatin for improving survival in renal
      transplant recipients, in terms of both cardiovascular mortality and graft
      rejection, is currently being investigated in two ongoing studies: ALERT
      (Assessment of Lescol [fluvastatin] in Renal Transplantation) and SOLAR (Study of
      Lescol [fluvastatin] in Acute Rejection). The results of these landmark studies
      should confirm the safe utility of fluvastatin in the renal transplantation
      setting.

PMID- 10651973
TI  - Viral sexually transmitted infections: current management strategies.
AB  - Viral sexually transmitted infections are a major health problem associated with
      considerable morbidity. This article reviews the current strategies used in the
      management of infections such as genital warts, genital herpes and molluscum
      contagiosum. Pros and cons of different treatment regimens have been discussed
      with an emphasis on a selective approach to therapy. The importance of education,
      counselling and follow-up is highlighted and issues relating to the associated
      psychosexual morbidity have been addressed. Treatment of these infections in
      pregnancy and HIV has also been described.

PMID- 10651974
TI  - rhDNase therapy for the treatment of cystic fibrosis patients with mild to
      moderate lung disease.
AB  - OBJECTIVE: To assess the cost-effectiveness of rhDNase (Pulmozyme(R)) for
      patients with cystic fibrosis (CF) aged 5 years or more, with mild to moderate
      lung disease. The review addresses four questions: a) does rhDNase therapy work
      in the short term?, b) does rhDNase therapy work more effectively in certain
      groups of patients?, c) does rhDNase therapy work in the long term? and d) what
      is the cost-effectiveness of rhDNase therapy? METHODS: A structured rapid review
      with modelling and cost-effectiveness calculations. Electronic searches were
      carried out to identify randomised controlled trials (RCTs), systematic reviews,
      epidemiological and economic information. Databases searched included Cochrane
      Library, Medline, Healthstar, Embase, PreMedline and NHS Economic Evaluation
      Database (NHS EED). Exclusion criteria were trials of very short duration (14
      days or less) and those which looked at CF patients with severe lung disease.
      Open label extensions providing information on longer term outcomes were
      included. RESULTS: Nine published RCTs were identified, although only one met the
      inclusion criteria. This large RCT was of good methodological quality, and shows
      that treatment with rhDNase over a 6-month period improves lung function, and
      decreases the risk of respiratory exacerbations. Expert opinion suggests that
      there are identifiable subgroups of patients showing improvement, little or no
      change, and deterioration after treatment with rhDNase. However, the best
      supporting evidence for this comes from a retrospective case series, showing that
      response to rhDNase is highly variable, and that early improvement was a good
      predictive marker for long-term benefit. Evidence for the long-term impact of
      rhDNase is not yet available from any RCTs. A simplified model was therefore
      developed to estimate the decline in lung function for patients treated with
      rhDNase, compared with those who were not treated. From this model it appears
      that the continued use of rhDNase over the lifetime of a CF patient might extend
      their life expectancy by 2 years. If treatment is limited to a subgroup of
      patients with moderate lung disease who respond to treatment, the continued use
      of rhDNase might extend their life expectancy by 7 years. Using the model, the
      discounted cost per life year gained for all patients is estimated at
      approximately pound52 500, with a range of between approximately pound25 000-57
      000 from sensitivity analysis. For the subgroup of patients, the discounted cost
      per life year gained is estimated at approximately pound16 000, with a range of
      between approximately pound18 000-36 600 from sensitivity analysis. CONCLUSIONS:
      Although there is short-term evidence that the use of rhDNase improves lung
      function and decreases the risk of respiratory exacerbations, at present there is
      no evidence from RCTs to indicate whether this effect is sustained over a longer
      time period, or whether rhDNase is associated with a reduction in mortality. RCTs
      to date have been of insufficient duration to answer important questions about
      long term outcomes, particularly the effects of rhDNase on lung function,
      respiratory exacerbations and mortality. Further long-term research is needed,
      with economic analysis to evaluate the long term cost-effectiveness of rhDNase.
      Research is also needed to identify, in advance, which patients would benefit
      most from this expensive treatment.

PMID- 10651975
TI  - Explaining variations in prescribing costs: results from a comparison of nursing
      home patients with matched pairs living in the community.
AB  - OBJECTIVES: To examine and explain variations in prescribing costs associated
      with nursing home patients and patients matched by age and sex living in the
      community. DESIGN: A 12-month case control study. SUBJECTS: All nursing home
      residents over 65-years-old registered with nine general practices and patients
      matched with them for age and sex living in the community. METHOD: Multivariate
      regression analysis of variations in monthly GP prescribing costs. RESULTS:
      Multivariate regression models explaining cost variations in terms of the GP
      practice delivering care and patients' age and sex had little explanatory power
      (R(2)=0.07 for nursing home patients, R(2)=0.03 for matched pairs). A fuller
      model for nursing home patients only, incorporating the patient's Barthel score
      and initial diagnosis as additional explanatory variables, added little to the
      explanatory power of the model (R(2)=0.16). CONCLUSION: The ability of the
      multivariate models used here to explain variations in prescribing costs among a
      group of elderly patients is poor. Adjusting weighted capitation formulae with
      respect to older patients to take account of such information or referring to it
      in negotiations on prescribing budgets would not appear to be warranted.

PMID- 10651976
TI  - Measuring mania and critical appraisal of rating scales.
AB  - BACKGROUND: In clinical trials of acute mania, a number of measures have been
      used to assess the severity of illness and its response to treatment. Rating
      instruments need to be validated in order for a clinical study to provide
      reliable and meaningful estimates of treatment effects. OBJECTIVE: To critically
      assess rating scales used in measuring mania. METHOD: A systematic search of the
      literature, retrieval of reports of clinical trials of drugs used in mania and
      the rating scales and a critical and systematic appraisal of their quality.
      RESULTS: Eight symptom-rating scales were identified. The Mania Rating Scale
      (MRS) was the most commonly used for assessing treatment response. Two more
      recently developed scales are the Manchester Nurse Rating Scale for Mania (MNRS
      M) and the Clinician-Administered Rating Scale for Mania (CARS-M). The latter
      appears well validated but its in-use reliability needs to be explored further.
      The translation of observed changes in instrumental ratings into clinically
      meaningful change has to be established further. In particular, the relative
      weighting to be attached to the individual items needs further study. The
      advantage of the MRS is that there is a relatively extensive database of studies
      based on it and this will no doubt ensure that it remains a gold standard for the
      foreseeable future. CONCLUSION: Useful rating scales are available for measuring
      mania but further cross-validation and validation against clinically meaningful
      global changes are required.

PMID- 10651977
TI  - Microbiological and HPLC analysis of miconazole in skin, serum and phase
      solubility studies.
AB  - OBJECTIVE: To develop stability-indicating assays for miconazole. METHODS: A
      reversed phase high-performance liquid chromatographic assay and a bioassay were
      developed. RESULTS: The HPLC and the bioassay were linear in the range of 0.5-100
      and 0.64-1.56 microg/ml, respectively. The sensitivity of HPLC and bioassay were
      0.5 and 0. 64 microg/ml, respectively. The bioassay was less cumbersome and much
      faster than the HPLC assay by obviating the need for extraction from serum.
      Miconazole content in the phase-solubility studies and in the serum samples was
      comparatively evaluated by both assay methods. There was good correlation between
      the two methods (r2 > 0. 99). The drug extraction efficiency from the serum and
      the skin were 97.7 and 90.2%, respectively. Where necessary, the bioassay can be
      an alternative choice for the HPLC analysis. The within and between day
      variations of the HPLC assay were 3.6 and 4.9%, respectively.

PMID- 10651978
TI  - A survey of the advertising of nine new drugs in the general practice literature.
AB  - OBJECTIVE: To undertake a survey of the advertising of new drugs in the general
      practice literature as part of a larger study investigating the factors which
      influence the introduction of new drugs into clinical practice. METHOD: The
      advertisements for nine new drugs from a range of therapeutic groups were
      monitored for 30 months in 12 journals, which are received by most GPs. The
      amount of prescribing, in defined daily doses, of each new drug by 50 GPs,
      selected as regular users of a teaching hospital, was also recorded during this
      period. RESULTS: Of the journals, 798 issues were surveyed (93% of the total
      published). The total number of advertisements was almost 33 000, of which 2163
      (6.6%) were for the study drugs. The pattern of advertising of each study drug
      was very complex and varied from month to month and between journals. There was
      no consistent pattern in the way the drugs were advertised, with large variations
      in the amount and timing of advertisements. The prescribing data showed wide
      variations in the number of GPs prescribing each drug and in the amount
      prescribed. CONCLUSION: There was no clear relationship between the extent of the
      advertising of a drug and the amount of prescribing by the GPs. This suggests
      that advertising in journals is only one of many factors which are important in
      influencing GPs to prescribe new drugs. However, the study may have been
      insufficiently comprehensive to capture complex relationships between advertising
      and prescribing.

PMID- 10651980
TI  - In this issue

PMID- 10651979
TI  - Substance P antagonists: the next breakthrough in treating depression?
AB  - Several lines of evidence implicate the neuropeptide substance P in depression,
      either in the pathogenesis or as a novel target for amelioration of symptoms. NK1
      (substance P) receptor antagonists have been reported to have antidepressant-like
      actions in animal models. The first clinical trial of an NK1 antagonist showed
      promising results. A second trial, using a more potent compound, is underway. If
      the clinical trials show that NK1 (substance P) antagonism represents a well
      tolerated, distinct mechanism for antidepressant activity, novel antidepressant
      agents will emerge as mono- or adjunct-therapy.

PMID- 10651982
TI  - Topical mevalonic acid stimulates de novo cholesterol synthesis and epidermal
      permeability barrier homeostasis in aged mice.
AB  - Extracellular lipids of the stratum corneum, which are composed of cholesterol,
      fatty acid, and ceramides, are essential for the epidermal permeability barrier
      function. With damage to the barrier, a decreased capacity for epidermal lipid
      biosynthesis in aged epidermis results in an impaired repair response. Mevalonic
      acid is an intermediate after the rate-limiting step in cholesterol biosynthesis,
      which is catalyzed by 3-hydroxy-3-methylglutaryl coenzyme A reductase. In the
      present study, we investigated the effect of topical mevalonic acid on the murine
      epidermal permeability barrier function, comparing it with that of cholesterol.
      Topical treatment with acetone caused linear increases in transepidermal water
      loss, in proportion to the number of treatments more rapidly in aged mice than in
      young mice. Administration of mevalonic acid on aged murine epidermis enhanced
      its resistance against damage and the recovery rate of barrier function from
      acute barrier disruption. In contrast, although cholesterol also had the same
      effect, it required a much higher amount than mevalonic acid. In young mice,
      neither mevalonic acid nor cholesterol had any effect on resistance against
      acetone damage nor the recovery rate from acetone damage. In the skin of mice
      topically administered with mevalonic acid, stimulation of cholesterol synthesis
      and 3-hydroxy-3-methylglutaryl coenzyme A reductase activity were both observed,
      whereas none was seen with stimulation by equimolar cholesterol. These data
      indicate that a topical application of mevalonic acid enhances barrier recovery
      in aged mice, which is accompanied by not only acceleration of cholesterol
      synthesis from mevalonic acid but also stimulation of the whole cholesterol
      biosynthesis.

PMID- 10651981
TI  - Possible involvement of enhanced prostaglandin E2 production in the
      photosensitivity in xeroderma pigmentosum group A model mice.
AB  - Xeroderma pigmentosum group A (XPA) gene-deficient mice cannot repair UV-induced
      DNA damage and easily develop skin cancers by UV irradiation. Therefore, XPA
      deficient mice are a useful model of human XP and represent a promising tool for
      photobiologic studies of the disorder. Exposure to ultraviolet (UV) B (280-320
      nm) radiation greatly enhanced inflammation and immunosuppression in these mice.
      To investigate the molecular mechanisms of enhanced UV inflammation and
      immunosuppression, we determined the amount of prostaglandin (PG) E2, an
      inflammatory mediator and immunomodulator, and analysed the expression of
      cyclooxygenase (COX) mRNA in the ear skin of XPA-deficient mice after UV
      irradiation. In XPA-deficient mice, the amount of PGE2 significantly increased at
      48 and 72 h after UVB irradiation to the level that was 8- and 16-fold higher
      than those in wild-type mice, respectively. The expression level of COX-2 mRNA
      increased in a time-dependent manner, although COX-1 mRNA was constantly
      expressed. Treatment with indomethacin, a potent inhibitor of PG biosynthesis,
      inhibited UV-induced ear swelling, abrogated local immunosuppression, and
      decreased the amount of PGE2 in the ear skin of XPA-deficient mice. These results
      indicate that the excess DNA photoproducts remaining in XPA-deficient cells after
      UV radiation may induce COX-2 expression. The induced production of PGE2 may be
      involved in the enhanced inflammation and immunosuppression caused by UV
      radiation in XPA-deficient mice and XP patients.

PMID- 10651983
TI  - Thymidine dinucleotides inhibit contact hypersensitivity and activate the gene
      for tumor necrosis factor alpha1.
AB  - DNA is a target for ultraviolet-B-induced inhibition of contact hypersensitivity,
      and small DNA fragments such as thymidine dinucleotides (pTpT) can simulate
      several ultraviolet-induced effects. To determine whether pTpT mimics the
      suppressive influence of ultraviolet-B on contact hypersensitivity, we compared
      the effects of topical application of pTpT with those of ultraviolet-B
      irradiation on C57BL/6 mice sensitized to dinitrofluorobenzene. Mice pretreated
      with pTpT or ultraviolet-B irradiation showed markedly suppressed ear swelling
      responses to dinitrofluorobenzene challenge. Because tumor necrosis factor alpha
      mediates ultraviolet-B-induced suppression of contact hypersensitivity, and
      because pTpT exerts many ultraviolet-mimetic effects by augmenting mRNA and
      protein levels of effector molecules, we asked if pTpT mimics ultraviolet-B's
      upregulatory influence on tumor necrosis factor alpha expression. Using
      transgenic mice carrying a chloramphenicol acetyl transferase reporter linked to
      the tumor necrosis factor alpha promoter, we examined effects of ultraviolet-B
      irradiation versus intradermal injection of pTpT on tumor necrosis factor alpha
      gene transcription. Both treatments induced cutaneous chloramphenicol acetyl
      transferase activity. Ultra- violet-B or pTpT treatment of cultured dermal
      fibroblasts from these mice also stimulated chloramphenicol acetyl transferase
      activity. To determine whether human cells responded similarly, a well-
      differentiated ultraviolet-responsive human squamous cell carcinoma line was
      treated with pTpT. pTpT increased tumor necrosis factor alpha mRNA expression and
      protein secretion in a dose-dependent manner. Our findings expand the spectrum of
      ultraviolet effects mimicked by pTpT to include inhibition of contact
      hypersensitivity and activation of the tumor necrosis factor alpha gene. These
      results support the hypothesis that DNA photoproducts and/or their repair
      intermediates trigger many of the biologic consequences of ultraviolet
      irradiation.

PMID- 10651984
TI  - Inhibition of telomerase activity by a hammerhead ribozyme targeting the RNA
      component of telomerase in human melanoma cells.
AB  - Reactivation of telomerase, an RNA-dependent DNA polymerase that synthesizes new
      telomeric repeats at the end of chromosomes, is a very common feature in human
      cancers. Telomerase is thought to be essential in maintaining the proliferative
      capacity of tumor cells and, as a consequence, it could represent an attractive
      target for new anti-cancer therapies. In this study, we generated a hammerhead
      ribozyme composed of a catalytic domain with flanking sequences complementary to
      the RNA component of human telomerase and designed to cleave specifically a site
      located at the end of the telomerase template sequence. In vitro the ribozyme
      induced cleavage of a synthetic RNA substrate obtained by cloning a portion of
      the RNA component of human telomerase. The extent of cleavage was dependent on
      the ribozyme/substrate ratio as well as the Mg2+ concentration. Moreover, when
      added to cell extracts from two human melanoma cell lines (JR8 and M14), or three
      melanoma surgical specimens, the ribozyme inhibited telomerase activity in a
      concentration- and time-dependent manner. When the ribozyme was delivered to
      growing JR8 melanoma cells by (N-(1-(2,3 dioleoxyloxy)propil)-N,N,N
      trimethylammonium methylsulfate-mediated transfer, a marked inhibition of
      telomerase activity was observed. Next, the ribozyme sequence was cloned in an
      expression vector and JR8 cells were transfected with it. The cell clones
      obtained showed a reduced telomerase activity and telomerase RNA levels and
      expressed the ribozyme. Moreover, ribozyme transfectants had significantly longer
      doubling times than control cells and showed a dendritic appearance in monolayer
      culture. No telomere shortening, however, was observed in these clones. Overall,
      our results indicate that the hammerhead ribozyme is a potentially useful tool
      for the inactivation of telomerase in human tumors.

PMID- 10651985
TI  - Downregulation of tyrosinase activity in human melanocyte cell cultures by
      yohimbine.
AB  - Treatment of human melanocyte cell cultures with the alpha-2 adrenergic receptor
      antagonist yohimbine results in a marked down-regulation of tyrosinase activity.
      A 30% decrease occurs within 12 h of exposure of cells to yohimbine (100 microM),
      and by 48 h tyrosinase activity in treated melanocytes is less than a fifth that
      of control cultures. The inhibition is dose dependent and occurs in human
      melanocytes derived from either black or white skin types, and also in mouse
      melanoma cells. The yohimbine-induced decrease in tyrosinase activity is
      reversible, with enzyme levels returning to 90% of control values 48 h after
      removal of drug. Although tyrosinase activity is markedly suppressed by
      yohimbine, the compound has no effect on cell proliferation, cellular
      translation, or DNA synthesis. Treatment of melanocyte cultures with yohimbine
      blocks the increase in tyrosinase activity by either 3-isobutyl-1-methylxanthine,
      dibutyryl cAMP, or forskolin. Results of cAMP immunoassays, show that
      intracellular levels of the cyclic nucleotide are unaffected in cells treated
      with yohimbine. Tyrosinase inhibition by yohimbine does not involve a decrease in
      substrate availability since tyrosine uptake studies show that yohimbine has no
      effect on the amount of tyrosine entering the cell. Incubation of a melanosome
      enriched fraction with yohimbine does not cause a lowering of tyrosinase
      activity, suggesting that an intact cell is required for yohimbine action. In
      addition, tyrosinase extracts show no reduction in activity when incubated
      directly with yohimbine, indicating that the drug does not act as a direct
      inhibitor of the enzyme. Finally, results of western immunoblotting show that
      yohimbine does not significantly lower the amount of tyrosinase protein in human
      melanocytes. These findings suggest that yohimbine acts through an as yet
      unidentified signaling pathway to lower the catalytic activity of pre-existing
      tyrosinase molecules present in melanocytes.

PMID- 10651986
TI  - Mutation and allelic loss of the PTEN/MMAC1 gene in primary and metastatic
      melanoma biopsies.
AB  - The PTEN/MMAC1 gene on chromosome 10q23 encodes a lipid phosphatase with tumor
      suppressive properties. Germline PTEN/MMAC1 mutations have been implicated as the
      predisposing factor in Cowden disease and other hamartoma syndromes, and somatic
      mutations and deletions have been identified in a wide range of human cancers,
      including 30-40% of metastatic melanoma cell lines. To study further the possible
      role of PTEN/MMAC1 in the pathogenesis and progression of malignant melanoma, we
      examined uncultured specimens from 16 primary and 61 metastatic tumors from 67
      patients. Denaturing gradient gel electrophoresis was used to analyze
      systematically the coding region of PTEN/MMAC1 and revealed mutations in four of
      the metastatic samples (7%). Sequence analysis of the mutants identified a 1 bp
      frameshift insertion, a 2 bp frameshift deletion, an 11 bp frameshift deletion,
      and a single base substitution resulting in the generation of a premature stop
      codon. Analysis of two intragenic polymorphisms showed allelic loss in three of
      eight informative primary tumors (38%) and in 18 of 31 metastatic tumors (58%).
      One of the mutant cases showed allelic loss, suggesting that both PTEN/MMAC1
      alleles were inactivated in this tumor. Altogether, these results suggest that
      mutation and deletion of PTEN/MMAC1 may contribute to the development and
      progression of malignant melanoma.

PMID- 10651987
TI  - Impaired responses of peripheral blood mononuclear cells to staphylococcal
      superantigen in patients with severe atopic dermatitis: a role of T cell
      apoptosis.
AB  - Staphylococcus aureus colonization is an almost universal feature of atopic
      dermatitis. In order to investigate the role of staphylococcal enterotoxin B in
      the pathogenesis of atopic dermatitis, we assessed the correlation between
      clinical disease severity and proliferative response of peripheral blood
      mononuclear cells to staphylococcal enterotoxin B in patients with atopic
      dermatitis. Peripheral blood mononuclear cells from patients with mild atopic
      dermatitis showed significantly increased proliferative responses to
      staphylococcal enterotoxin B compared to controls. In contrast, peripheral blood
      mononuclear cells from patients with severe atopic dermatitis showed markedly
      suppressed proliferative responses. Additionally, longitudinal evaluation of
      peripheral blood mononuclear cell samples from the same patient demonstrated that
      proliferative responses were suppressed only at times of severe disease
      exacerbation. Mixing experiments, using autologous T cells and antigen presenting
      cells that were isolated at different time points from the same patient,
      demonstrated that T cells of severe atopic dermatitis patients were
      dysfunctional, but their antigen presenting cell function remained intact. We
      found no significant differences of interleukin-2 levels in the culture
      supernatants between healthy controls and atopic dermatitis groups. Fluorescence
      activated cell sorter analysis for APO2.7 antigen, an early apoptosis cell
      marker, demonstrated that approximately 60% of staphylococcal-enterotoxin-B
      stimulated T cells expressed APO2.7 antigen in severe atopic dermatitis cases. By
      contrast, 5%-20% of T cells expressed APO2.7 after staphylococcal enterotoxin B
      stimulation in cases of mild atopic dermatitis and in healthy controls. Nuclear
      staining with Hoechst 33258 also showed approximately 40% apoptotic cells in the
      CD19-CD16-PBMC of severe atopic dermatitis patients, compared with only 5%-10% in
      the mild atopic dermatitis group and in healthy controls. Blocking monoclonal
      antibody to Fas ligand partially prevented the staphylococcal-enterotoxin-B
      induced apoptosis detected by APO2.7 expression and Hoechst 33258 staining.
      Suppressed proliferation of peripheral blood mononuclear cells in severe atopic
      dermatitis patients may be secondary to T cell death by apoptosis. These results
      suggest that an infection of S. aureus producing staphylococcal enterotoxin B may
      play a role in aggravation of atopic dermatitis by inducing apoptosis in T cells.

PMID- 10651988
TI  - Induction of skin papillomas, carcinomas, and sarcomas in mice in which the
      connexin 43 gene is heterologously deleted.
AB  - It has been suggested that blocked gap junctional intercellular communication
      plays a crucial part in multistage carcinogenesis. The mouse skin tumor-promoting
      phorbol esters are potent inhibitors of gap junctional intercellular
      communication and this inhibition is considered to be a mechanism by which clonal
      expansion of "initiated" cells is promoted. We examined whether mice in which the
      gene for a gap junction protein, connexin 43, is heterozygously deleted are more
      susceptible to chemical carcinogenesis; connexin 43 is expressed in the basal
      cell layer and the dermis of the skin. When the back skin was painted with 7,12
      dimethylbenz[a]anthracene and 12-O-tetradecanoylphorbol 13-acetate, the incidence
      and yields of both papillomas and carcinomas were similar in connexin 43+/- and
      connexin 43+/+ mice; for this experiment, the original mice with C57BL/6 genetic
      background was crossed with CD1 strain for three generations. Subcutaneous
      injection of 7, 12-dimethylbenz[a]anthracene resulted in induction of
      fibrosarcomas in connexin 43+/- and connexin 43+/+ mice to a similar extent. All
      papillomas and carcinomas induced with 7, 12-dimethylbenz[a]anthracene and 12-O
      tetradecanoylphorbol 13-acetate contained the 7,12-dimethylbenz[a] anthracene
      specific mutation in the ras gene (A to T transversion at the 61st codon). About
      50% of fibrosarcomas also contained this mutation, but in the Ki-ras gene; there
      was no difference in the prevalence of this mutation in tumors from connexin 43+/
      and connexin 43+/+ mice. None of the tumors examined, however, showed any
      mutation in the connexin 43 gene. These results suggest that the deletion of one
      allele of the connexin 43 gene does not significantly contribute to, nor alter,
      the molecular events involved in skin carcinogenesis. These results are
      compatible with previous observations that nongenetic disruption of function
      rather than mutations of connexins, commonly occurs in cancer cells.

PMID- 10651989
TI  - Human CD4+ T lymphocytes with remarkable regulatory functions on dendritic cells
      and nickel-specific Th1 immune responses.
AB  - The contribution of T helper (Th) and T cytotoxic (Tc) type 1 lymphocytes in the
      expression of allergic contact dermatitis to haptens has been amply documented.
      Conversely, the existence of T cell-based regulatory mechanisms has been poorly
      investigated. Here, we examined the properties of a subset of nickel-specific
      CD4+ T cells displaying the cytokine profile (IL-10 , IL-5 , IFN-gamma+/-, IL-4+/
      ) of T regulatory cells 1 (Tr1) and with the potential to down-modulate immune
      responses to nickel. Tr1 clones were isolated from skin challenged with NiSO4 and
      peripheral blood of nickel-allergic patients, and from the blood of healthy
      individuals. Tr1 clones expressed CD25, CD28, CD30, CD26, and the IL-12 receptor
      beta2 chain upon activation, whereas the lymphocyte activation antigen-3 was
      present on 50% of the clones. Monocytes precultured with Tr1 cells in the
      presence of nickel, or treated with Tr1-derived supernatant, exhibited a markedly
      diminished capacity to stimulate nickel-specific Th1 responses. Tr1 supernatants
      also blocked the differentiation of dendritic cells (DC) from monocytes, as well
      as DC maturation and IL-12 production induced by lipopolysaccharide. As a
      consequence, the ability of DC to stimulate nickel-specific Th1 and Tc1 responses
      was greatly impaired. These inhibitory effects were completely prevented by IL
      10, but not IL-5, neutralization. In aggregate, the results indicate that Tr1
      cells can potently regulate the expression of Th1-mediated allergic diseases via
      release of IL-10.

PMID- 10651990
TI  - Wavelength and fluence effect on vascular damage with photodynamic therapy on
      skin.
AB  - Normal skin phototoxicity is clinically predictable during photodynamic therapy
      with light at 690 and 458 nm wavelengths, in the first 5 h after intravenous
      bolus infusion of benzoporphyrin derivative mono-acid ring A. This study goal was
      to determine histologic milestones that lead to tissue necrosis with exposure to
      red (690 nm) and blue (458 nm) light. The threshold doses for skin necrosis on
      rabbits were equal at both wavelengths. Lower, equal to, and higher than
      threshold fluences were delivered in duplicates at hourly intervals, with 40%
      increments, at constant irradiance. Pathology specimens from irradiated and
      control sites, were collected at 0, 2, 7, 24, 48 h, and 2 wk after treatment and
      were paired to equivalent treated sites for clinical evaluation. Immediately
      after irradiation, at 690 and 458 nm thresholds, light microscopy showed stasis
      and inflammatory infiltrate in the papillary dermis, respectively; electron
      microscopy demonstrated pericyte and endothelial cell damage - greater at 690
      than 458 nm. At day 1, vascular stasis in the dermis showed a steeper dose
      response with red than blue light, and led to necrosis of skin appendages (day 1)
      and epidermis (days 1-2) at both wavelengths. Sub-threshold fluences induced
      similar, but significantly milder (p < 0.05) changes and epidermis recovered.
      Skin necrosis, at threshold fluences in photodynamic therapy with benzoporphyrin
      derivative mono-acid ring A, was primarily due to vascular compromise to a depth
      potentially reaching the subcutaneous muscle at 690 nm, whereas at 458 nm
      vascular damage was confined to upper dermis. This system facilitates selective
      destruction of skin vasculature, sparing normal epidermis.

PMID- 10651991
TI  - The association of psoriasis with human leukocyte antigens in Korean population
      and the influence of age of onset and sex.
AB  - To identify HLA markers that may contribute to the genetic susceptibility of
      Koreans to psoriasis, we studied 84 psoriasis patients, with serologic HLA types
      of A, B, and genotypes of HLA-Cw, DRB1, DQA1, DQB1, DPB1 alleles. The
      distribution of HLA markers and the associated haplotypes were analyzed according
      to age and sex. HLA-Cw*0602 showed the strongest association with psoriasis
      (relative risk = 36.0, p < 10-8, Pc < 8 x 10-7). The frequencies of A1 (relative
      risk = 17.0, p < 9 x 10-7, Pc < 7 x 10-5), A30 (relative risk = 5.5, p < 2 x 10
      5, Pc < 0.001), B13 (relative risk = 5.6, p < 4 x 10-6, Pc < 3 x 10-4), B37
      (relative risk = 30.3, p < 7 x 10-7, Pc < 6 x 10-5), DRB1*07 (relative risk =
      5.9, p < 2 x 10-6, Pc < 8 x 10-5), DRB1*10 (relative risk = 26.4, p < 4 x 10-6,
      Pc < 3 x 10-4), DQA1*02 (relative risk = 6.2, p < 5 x 10-7, Pc < 4 x 10-4),
      DQB1*02 (relative risk = 2.5, p < 0.005, Pc = ns) and DPB1*1701 (relative risk =
      24.6, p < 9 x 10-6, Pc < 7 x 10-4) were also significantly increased in Korean
      psoriasis patients. Type I and type II psoriasis were subdivided into groups of
      below and above 30 y of age, because of the significant difference found in HLA
      Cw*0602 phenotype frequency between the two groups (83.9% vs. 54.5%, p < 0. 009).
      In addition to HLA-Cw*0602, the frequencies of B37 and DPB1*1701 were
      significantly higher in type I as opposed to type II psoriasis. HLA-A30-B13
      Cw*0602-DRB1*07-DQA1* 02-DQB1*02 was identified as a high risk haplotype. This
      was particularly true at an early age in the female. HLA-A33-B44-Cw*1401-DRB1*13
      DQA1* 01-DQB1*06-DPB1*0401 was defined as a protective haplotype for psoriasis.
      The extended haplotype HLA-A1-B37-Cw*0602-DRB1*10-DQA1*01-DQB1*05 was discovered
      to be a high-risk factor in Koreans. To summarize, this study demonstrates the
      differential association of HLA according to sex, and identifies a newly found
      high-risk haplotype and a protective haplotype in Korean psoriasis patients.

PMID- 10651992
TI  - Distinct roles for nerve growth factor and brain-derived neurotrophic factor in
      controlling the rate of hair follicle morphogenesis.
AB  - Increasing evidence suggests that neurotrophins play an important part in the
      control of the development of ectodermal derivatives, such as the hair follicle.
      Here, we show that, during hair follicle morphogenesis in C57BL/6 mice, nerve
      growth factor, brain-derived neurotrophic factor and their corresponding high
      affinity tyrosine kinase receptors, TrkA and TrkB, show stringently controlled
      spatiotemporal expression patterns in the follicular epithelium and mesenchyme.
      Constitutive overexpression of nerve growth factor in mice is associated with a
      discrete, but significant acceleration of hair follicle morphogenesis, whereas
      this is not seen in brain-derived neurotrophic factor transgenic mice. In
      neonatal skin organ culture, nerve growth factor and brain-derived neurotrophic
      factor differentially influence hair follicle development: nerve growth factor
      accelerates late stages of hair follicle morphogenesis, whereas brain-derived
      neurotrophic factor does not show significant effects. This suggests that the
      morphogenetic properties of locally generated neurotrophins in the skin, similar
      to their classical neurotrophic functions, are quite distinct and depend on the
      response patterns of the corresponding neurotrophin target receptor-expressing
      cells in the developing hair follicle. These data further strengthen the concept
      that neurotrophin signaling is an important element in controlling the rate of
      hair follicle morphogenesis, yet also highlight the complexity of this signaling
      system.

PMID- 10651993
TI  - Changing patterns of localization of putative stem cells in developing human hair
      follicles.
AB  - In rodents, the hair follicle stem cells lie in a well-defined bulge in the outer
      root sheath; however, the bulge as a stem cell site of human hair follicle
      epithelium is still controversial. Epidermal stem cells are thought to express
      high levels of beta1 integrin and low levels of E-cadherin and beta- and gamma
      catenin. In order to clarify the ontogenic distribution of possible stem cells
      during hair follicle development, the expression patterns of beta1 integrin
      subunits, E-cadherin, and beta- and gamma-catenins in the skin samples from human
      fetuses of a series of estimated gestational ages (EGA) were examined. beta1
      integrin-rich, E-cadherin-, and beta- and gamma-catenin-poor cells, possible stem
      cells, were localized to the entire hair germ (65-84 d EGA) and later to the
      outermost cells of hair peg (85-104 d EGA). In the bulbous hair peg (105-135 d
      EGA) and in the differentiated lanugo hair follicle (>135 d EGA), they were
      settled in the bulge and the outermost layer of the outer root sheath. This
      sequential localization was similar to that of cells rich in epidermal growth
      factor receptor expression and positive with keratin 19, a putative marker of
      epidermal stem cells. In addition, these beta1 integrin-rich, E-cadherin-, and
      beta- and gamma-catenin-poor cells showed similar, undifferentiated morphologic
      features by electron microscopy. This information of ontogenic localization of
      possible hair follicle stem cells contributes to the further understanding of
      mechanisms of human hair follicle morphogenesis and supports the idea that the
      human fetal hair follicle bulge is a site of stem cells for follicular
      epithelium.

PMID- 10651994
TI  - Ultraviolet-B exposure of human skin induces cytochromes P450 1A1 and 1B1.
AB  - The cytochromes P450 belong to a multigene superfamily and are responsible for
      the metabolic activation of both xenobiotics and endobiotics. The expression of
      cytochrome P450 genes in target cells is an important determinant of human
      susceptibility to cancers and other chemically initiated diseases. In this study
      using immunohistochemistry, reverse transcription polymerase chain reaction, and
      western blot analysis, we investigated the cellular distribution and localization
      of cytochrome P450 1A1 and cytochrome P450 1B1 in human skin, and their induction
      by ultraviolet-B. Through the use of immunohistochemistry, cytochrome P450 1A1
      was found to be primarily localized in the basal cell layer of the epidermis in
      non-ultraviolet-B exposed skin, whereas cytochrome P450 1B1 was localized in the
      epidermal cells other than the basal cell layer. Thus, localizations of
      cytochrome P450 1A1 and cytochrome P450 1B1 in human skin are different and may
      be related to keratinocyte differentiation. Ultraviolet-B exposure to solar
      ultraviolet-protected skin (buttock site) resulted in an ultraviolet-B dose
      dependent (0-4 minimal erythema doses) and time-dependent (0-48 h) induction of
      both cytochrome P450 1A1 and cytochrome P450 1B1 in the epidermis. Reverse
      transcription polymerase chain reaction and western blot analyses revealed that
      exposure of human skin to ultraviolet-B (4 minimal erythema doses) resulted in
      enhanced expression of mRNA and protein of both cytochrome P450 1A1 and
      cytochrome P450 1B1 in the epidermis. Ultraviolet-B induction of both cytochrome
      P450 1A1 and cytochrome P450 1B1 in human skin will probably result in enhanced
      bioactivation of polycyclic aromatic hydrocarbons and other environmental
      pollutants to which humans are exposed, which in turn could make the human skin
      more susceptible to ultraviolet-B-induced skin cancers or allergic and irritant
      contact dermatitis.

PMID- 10651995
TI  - Histamine induces melanogenesis and morphologic changes by protein kinase A
      activation via H2 receptors in human normal melanocytes.
AB  - Hyperpigmentation frequently accompanies chronic or acute inflammation. A number
      of inflammatory mediators have been shown to stimulate melanin synthesis in human
      melanocytes. Although histamine is ubiquitous as an inflammatory factor, its
      involvement in pigmentation remains obscure. In this work, we examined the
      effects of histamine on cultured human melanocytes. Treatment of human
      melanocytes with 0.1-10 microM histamine evoked morphologic changes and increases
      in tyrosinase activity. The concomitant increases in melanin content of the
      histamine-treated melanocytes indicated an elevation of melanin synthesis by
      tyrosinase activation. These stimulatory effects of histamine were completely
      inhibited by an H2 antagonist, famotidine, whereas H1 and H3 antagonists had no
      inhibitory effect whatsoever. In addition, an H2 agonist, dimaprit, induced the
      same degree of melanogenesis as histamine at concentrations of 0.1-10 microM. We
      observed an increase in the intracellular cAMP contents of human melanocytes
      induced by histamine via the H2 receptors. We know that this cAMP accumulation
      and subsequent protein kinase A activation plays a critical role in histamine
      induced melanogenesis, because a specific protein kinase A inhibitor, H-89,
      completely suppressed these stimulatory effects of histamine, and because
      dibutylic cAMP, a specific protein kinase A activator, stimulated human
      melanocytes as potently as histamine. Taken together, we show here that histamine
      induces melanogenesis of human cultured melanocytes by protein kinase A
      activation via H2 receptors.

PMID- 10651996
TI  - Cutaneous metallothionein induction by ultraviolet B irradiation in interleukin-6
      null mice.
AB  - The mediators of cutaneous metallothionein induction by ultraviolet radiation
      have not been defined. In this study we sought to identify cytokines that might
      be involved. We examined the role of interleukin-6, using the IL-6 null (IL-6-/-)
      mouse, which has been observed to be highly sensitive to ultraviolet radiation
      damage. Whereas cutaneous metallothionein concentration, measured by
      radioimmunoassay, began to rise in wild-type (IL-6+/+) mice by 12 h after
      ultraviolet irradiation, there was a significant delay in the IL-6-/- mice until
      48 h after UV irradiation. Immunohistologically, metallothionein appeared in IL
      6+/+ mice at 24 h in dermal fibroblasts, and then by 48 h in epidermal basal
      keratinocytes, with intensity increasing until 72 h, and was coincident with
      proliferating cell nuclear antigen-positive staining. Corresponding
      metallothionein expression in IL-6-/- mouse skin was significantly delayed. Serum
      interleukin-6 was elevated in IL-6+/+ mice following ultraviolet irradiation,
      with peak concentration at 4 h, but no increase in serum interleukin-1beta was
      found in either IL-6+/+ or IL-6-/- mice. Interestingly, tumor necrosis factor
      alpha concentration in serum was elevated at 12 h postirradiation in IL-6+/+
      mice, but there was an earlier (at 4 and 8 h) time-dependent increase in tumor
      necrosis factor alpha in serum of the IL-6-/- mice. Skin zinc and copper
      concentrations were not altered by ultraviolet irradiation in either IL-6+/+ or
      IL-6-/- mice. The results suggest that interleukin-6 may be a very early mediator
      of cutaneous metallothionein induction by ultraviolet radiation, but that this
      role is possibly assumed by alternative cytokines like tumor necrosis factor
      alpha when interleukin-6 is deficient.

PMID- 10651997
TI  - The role of specific retinoid receptors in sebocyte growth and differentiation in
      culture.
AB  - Retinoic acid derivatives (retinoids) exert their pleiotropic effects on cell
      development through specific nuclear receptors, the retinoic acid receptors and
      retinoid X receptors. Despite recent progress in understanding the cellular and
      molecular mechanisms of retinoid activity, it is unknown which of the retinoid
      receptor pathways are involved in the specific processes of sebocyte growth and
      development. In this study, we investigated the roles of specific retinoid
      receptors in sebocyte growth and differentiation, by testing the effects of
      selective retinoic acid receptor and retinoid X receptor ligands at
      concentrations between 10-10 M and 10-6 M in a primary rat preputial cell
      monolayer culture system. Cell growth was determined by number of cells and
      colonies, and cell differentiation by analysis of lipid-forming colonies. All
      trans retinoic acid and selective retinoic acid receptor agonists (CD271 =
      adapalene, an RAR-beta,gamma agonist; CD2043 = retinoic acid receptor pan
      agonist; and CD336 = Am580, an RAR-alpha agonist) caused significant decreases in
      numbers of cells, colonies, and lipid-forming colonies, but with an exception at
      high doses of all-trans retinoic acid (10-6 M), with which only a small number of
      colonies grew but they became twice as differentiated as controls (42.2 +/- 4.0%
      vs 22.6 +/- 2.7%, mean +/- SEM, lipid-forming colonies, p < 0.01). Furthermore,
      the RAR-beta,gamma antagonist CD2665 antagonized the suppressive effects of all
      trans retinoic acid, adapalene, and CD2043 on both cell growth and
      differentiation. In contrast, the retinoid X receptor agonist CD2809 increased
      cell growth slightly and lipid-forming colonies dramatically in a clear dose
      related manner to a maximum of 73.7% +/- 6.7% at 10-6 M (p < 0. 001). Our data
      suggest that retinoic acid receptors and retinoid X receptors differ in their
      roles in sebocyte growth and differentiation: (i) retinoic acid receptors,
      especially the beta and/or gamma subtypes, mediate both the antiproliferative and
      antidifferentiative effects of retinoids; (ii) retinoid X receptors mediate
      prominent differentiative and weak proliferative effects; (iii) the
      antiproliferative and antidifferentiative effects of all-trans retinoic acid are
      probably mediated by retinoic acid receptors, whereas its differentiative effect
      at high dose may be mediated by retinoid X receptors via all-trans retinoic acid
      metabolism to 9-cis retinoic acid, the natural ligand of retinoid X receptors.

PMID- 10651999
TI  - Keratinocytes influence the maturation and organization of the elastin network in
      a skin equivalent.
AB  - Elastic fibers form a complex network that contributes to the elasticity of
      connective tissues. Alterations in the elastic fiber network are involved in
      several disease affecting organs in which compliance of the connective tissue is
      essential: skin, main vasculature, lung, joints, muscle, and ligament. The aim of
      our work was to study the deposition, maturation, and organization of elastic
      fiber components in a dermal equivalent model consisting of collagen-GAG-chitosan
      seeded with fibroblasts. The influence of keratinocytes was studied in parallel,
      thus constituting a skin equivalent model. These models were examined by
      transmission electron microscopy (TEM) and by immunohistochemistry to determine
      the staining patterns of fibrillin-1 and elastin proteins representative of the
      microfibrillar framework and of the elastic fibers, respectively. After 2 mo of
      fibroblast culture in the dermal equivalent, elastin was undetectable, whereas
      fibrillin-1 staining was weak and microfibrils were infrequently observed by TEM.
      In the skin equivalent, fibrillin-1 and elastin were detected by immunostaining
      15 d after epidermization and TEM revealed the typical structure and organization
      of the elastic network in the dermis, with elastin deposition on the
      microfibrillar scaffold. This in vitro skin equivalent model is to our knowledge
      the first in which elastic fibers have been detected, thus demonstrating the
      influence of keratinocytes on the maturation and organization of the elastic
      network.

PMID- 10651998
TI  - Redox cycling of phenol induces oxidative stress in human epidermal
      keratinocytes.
AB  - A variety of phenolic compounds are utilized for industrial production of phenol
      formaldehyde resins, paints, lacquers, cosmetics, and pharmaceuticals. Skin
      exposure to industrial phenolics is known to cause skin rash, dermal
      inflammation, contact dermatitis, leucoderma, and cancer promotion. The
      biochemical mechanisms of cytotoxicity of phenolic compounds are not well
      understood. We hypothesized that enzymatic one-electron oxidation of phenolic
      compounds resulting in the generation of phenoxyl radicals may be an important
      contributor to the cytotoxic effects. Phenoxyl radicals are readily reduced by
      thiols, ascorbate, and other intracellular reductants (e.g., NADH, NADPH)
      regenerating the parent phenolic compound. Hence, phenolic compounds may undergo
      enzymatically driven redox-cycling thus causing oxidative stress. To test the
      hypothesis, we analyzed endogenous thiols, lipid peroxidation, and total
      antioxidant reserves in normal human keratinocytes exposed to phenol. Using a
      newly developed cis-parinaric acid-based procedure to assay site-specific
      oxidative stress in membrane phospholipids, we found that phenol at subtoxic
      concentrations (50 microM) caused oxidation of phosphatidylcholine and
      phosphatidylethanolamine (but not of phosphatidylserine) in keratinocytes. Phenol
      did not induce peroxidation of phospholipids in liposomes prepared from
      keratinocyte lipids labeled by cis-parinaric acid. Measurements with ThioGlo-1
      showed that phenol depleted glutathione but did not produce thiyl radicals as
      evidenced by our high-performance liquid chromatography measurements of GS.-5, 5
      dimethyl1pyrroline N-oxide nitrone. Additionally, phenol caused a significant
      decrease of protein SH groups. Luminol-enhanced chemiluminescence assay
      demonstrated a significant decrease in total antioxidant reserves of
      keratinocytes exposed to phenol. Incubation of ascorbate-preloaded keratinocytes
      with phenol produced an electron paramagnetic resonance-detectable signal of
      ascorbate radicals, suggesting that redox-cycling of one-electron oxidation
      products of phenol, its phenoxyl radicals, is involved in the oxidative effects.
      As no cytotoxicity was observed in keratinocytes exposed to 50 microM or 500
      microM phenol, we conclude that phenol at subtoxic concentrations causes
      significant oxidative stress.

PMID- 10652000
TI  - Basement membrane zone remodeling during appendageal development in human fetal
      skin. The absence of type VII collagen is associated with gelatinase-A (MMP2)
      activity.
AB  - Epithelial cell adhesion, migration, and differentiation are controlled by
      interactions at the basement membrane zone (BMZ). Type VII collagen is the major
      collagenous component of anchoring fibrils that are essential for the attachment
      of the epidermis to the dermis. Gelatinase A (MMP-2) is believed to be necessary
      for the degradation of type VII collagen. In this study we have examined the in
      vivo distribution of type VII collagen and gelatinase A (Gel A) in the developing
      human epidermis and its appendages. At 13-15 wk of gestation a marked decrease in
      type VII collagen immunoreactivity was seen in the BMZ surrounding invading
      appendageal buds; however, type VII collagen mRNA was strongly expressed in the
      budding epidermal keratinocytes adjacent to the BMZ. At these stages, Gel A
      positive mesenchymal-like cells were found scattered throughout the stroma with
      numerous Gel A-containing cells in direct contact with the developing appendageal
      buds. In situ zymography was used to show Gel A-activity in vivo. Gel A-mediated
      lysis was present at the interface between the appendageal buds and the
      underlying BMZ. By 20-25 wk of gestational age, immunostaining for type VII
      collagen protein was absent from the BMZ surrounding the distal portion of
      invading appendageal epithelial cords of both hair follicles and sweat glands. In
      contrast, type VII collagen mRNA was present in the basal keratinocytes adjacent
      to the BMZ surrounding the distal portion of these invading appendageal
      epithelial cords. At these stages Gel A-positive cells were present in the stroma
      directly adjacent to the distal portion of developing appendageal cords that
      lacked type VII collagen. In situ zymography showed zones of Gel A-mediated
      stromal lysis at the distal portion of developing appendageal cords.
      Interestingly, no differences were seen in the distribution of type IV collagen
      in the BMZ of both budding and resting fetal epidermis. These observations
      suggest that the absence of type VII collagen protein correlates directly with
      the presence of Gel A-activity at the BMZ. Gel A appears to play a major role in
      appendageal development and contributes to remodeling of the BMZ during fetal
      skin morphogenesis.

PMID- 10652001
TI  - Mutation reports: epidermolysis bullosa simplex associated with severe mucous
      membrane involvement and novel mutations in the plectin gene.
AB  - We report a novel case of epidermolysis bullosa simplex with severe mucous
      membrane involvement and mutations in the plectin gene (PLEC1). The patient
      suffered from extensive blistering of the skin and oral and laryngeal mucous
      membranes. Electron microscopy of a lesional skin biopsy showed cleft formation
      within the basal cell layer of the epidermis. Antigen mapping displayed entirely
      negative staining for plectin, a large (>500 kDa) multifunctional adhesion
      protein present in hemidesmosomes of the basal keratinocytes. Mutation analysis
      revealed compound heterozygous, previously undisclosed nonsense mutations, Q1713X
      and R2351X, of paternal and maternal origin, respectively, within exon 32 of
      PLEC1. Based on earlier reports, plectin deficiency is associated with late onset
      muscular dystrophy in patients with epidermolysis bullosa. No signs of muscle
      weakness have been observed during the 4 y follow-up of our patient. This case
      illustrates the fact that molecular pathological analyses have prognostic
      implications in identification and evaluation of patients who appear to be at
      risk for development of muscular dystrophy later in life.

PMID- 10652002
TI  - Epidermolysis bullosa: novel and de novo premature termination codon and deletion
      mutations in the plectin gene predict late-onset muscular dystrophy.
AB  - Epidermolysis bullosa (EB) with late-onset muscular dystrophy (EB-MD) is a
      hemidesmosomal variant of EB due to mutations in the plectin gene (PLEC1). The
      age of onset of muscle involvement has been noted to vary from infancy to the
      fourth decade of life. Immunofluorescence of the patients' skin and muscle
      biopsies is usually negative for staining with antibodies recognizing plectin, a
      large cytoskeleton-associated anchorage protein. In this study we report novel
      plectin mutations in two families with EB. In both families, the proband was a
      newborn with neonatal blistering with no evidence for muscle weakness as yet.
      Peripheral blood DNA was isolated and examined by heteroduplex scanning strategy,
      protein truncation test (PTT), and/or direct sequencing of the plectin gene. One
      of the probands was compound heterozygote for nonsense mutations E2005X/K4460X,
      and the proband in the second family was compound heterozygote for deletion
      mutations 5083delG/2745-9del21, the latter mutation extending from -9 to +12 at
      the intron 22/exon 23 border. The mutations K4460X and 5083delG were not present
      in either one of the parents, thus being de novo events. In both cases,
      nonpaternity was excluded by microsatellite marker analysis. The stop codon
      mutations are predicted to result in the synthesis of a truncated protein lacking
      the carboxy-terminal globular domain of the protein and possibly causing nonsense
      mediated decay of the corresponding mRNA. The 2745-9del21 deletion mutation
      abolishes the splice site at the intron 22/exon 23 junction, predicting abnormal
      splicing events. Because plectin deficiency is associated with muscular
      dystrophy, molecular diagnostics of the plectin gene provides prognostic value in
      evaluation of these patients who appear to be at risk to develop muscular
      dystrophy.

PMID- 10652003
TI  - A glutamine insertion in the 1A alpha helical domain of the keratin 4 gene in a
      familial case of white sponge nevus.
AB  - White Sponge Nevus (WSN) is a rare, autosomal dominant disorder that
      predominantly affects noncornified stratified squamous epithelia. Clinically, it
      is characterized by the presence of soft, white, and "spongy" plaques in the oral
      mucosa. The characteristic histopathologic features are epithelial thickening,
      parakeratosis, and vacuolization of the suprabasal layer of oral epithelial
      keratinocytes. Mutations in keratin 4 (K4) and keratin 13 (K13) genes have
      already been demonstrated to be responsible for WSN; the identification of new
      keratin mutations in a stratified squamous epithelia closely related to epidermis
      is of relevance for the understanding of the biochemistry of intermediate
      filaments, and for genotype phenotype correlations. In this study we investigated
      a 27-y-old, female Italian patient, affected by white asymptomatic oral plaques.
      Sequence analysis revealed a 3 bp (ACA) heterozygous insertion localized in the
      helix initiation motif of the 1A alpha helical domain of K4. We report this new
      K4 gene mutation and describe an amino acid insertion, in the 1A domain,
      responsible for a keratin disease.

PMID- 10652004
TI  - Indolinone derivatives inhibit constitutively activated KIT mutants and kill
      neoplastic mast cells.
AB  - Mastocytosis is a neoplastic disease caused at least in part by somatic mutations
      of the c-KIT proto-oncogene resulting in constitutive activation of its protein
      product, KIT, the receptor tyrosine kinase for stem cell factor. KIT stimulates
      mast cell proliferation and prevents apoptosis of neoplastic mast cells. To
      develop potential therapies for mastocytosis we used indolinones, small molecules
      that inhibit tyrosine kinases. Four indolinone derivatives (SU4984, SU6663,
      SU6577, and SU5614) inhibited wild-type KIT, but variably inhibited
      constitutively activated KIT mutants. SU4984, SU6577, and SU5614 were effective
      against KIT with juxtamembrane activating mutations, whereas only SU6577 could
      suppress KIT containing either juxtamembrane or kinase domain activating
      mutations. Furthermore, SU4984, SU6577, and SU5614 killed neoplastic mast cells
      expressing a juxtamembrane-mutated KIT, whereas SU4984 and SU6577 killed
      neoplastic mast cells expressing KIT bearing a kinase domain mutation. These data
      show a direct correlation between inhibition of constitutively activated KIT and
      the death of neoplastic mast cells, and point to specific tyrosine kinase
      inhibitors as a potential therapy aimed directly at a cause of mastocytosis.

PMID- 10652005
TI  - Studies of a magnetically focused electrostatic mirror. I. Experimental test of
      the first order properties
AB  - When a uniform magnetic field is superimposed on a uniform electrostatic field,
      the combination can act as a magnetically focused mirror. This mirror is
      predicted to have aberrations of opposite sign to those of a magnetic lens and
      may therefore be useful as a corrector. We have built an electron optical system
      to test these ideas. The results are presented in two papers. This first paper
      describes the general design and the results of the measurements of the first
      order properties. The second paper (Tsai, F., J. Microsc. 197 (2000) 118-135)
      will describe the measurements of the aberration properties.

PMID- 10652006
TI  - Studies of a magnetically focused electrostatic mirror. II. Aberration
      corrections
AB  - A magnetically focused electrostatic mirror is shown to be able to correct the
      spherical and chromatic aberrations of a probe forming system simultaneously. The
      probe forming system comprises a uniform magnetic lens and a uniform
      electrostatic mirror. Previous theoretical investigations showed that the
      spherical and chromatic aberration coefficients of these two components are the
      same values but with opposite sign, whose combination will therefore be free from
      aberrations. The experimental arrangement used a solenoid to produce a uniform
      magnetic field, and a series of plate electrodes to produce a uniform
      electrostatic field. These fields are shown to satisfy the experimental
      requirements. By deliberately changing the extraction voltage to defocus the
      electron beam, the author is able to observe correction of chromatic aberration
      by one order of magnitude. By deliberately changing the lens field and the mirror
      field, the author is able to observe the reduction of the asymmetry caused by the
      spherical aberration, which the author believes also indicates correction by one
      order of magnitude.

PMID- 10652007
TI  - Multiple frequency fluorescence lifetime imaging microscopy.
AB  - The experimental configuration and the computational algorithms for performing
      multiple frequency fluorescence lifetime imaging microscopy (mfFLIM) are
      described. The mfFLIM experimental set-up enables the simultaneous homodyne
      detection of fluorescence emission modulated at a set of harmonic frequencies.
      This was achieved in practice by using monochromatic laser light as an excitation
      source modulated at a harmonic set of frequencies. A minimum of four frequencies
      were obtained by the use of two standing wave acousto-optic modulators placed in
      series. Homodyne detection at each of these frequencies was performed
      simultaneously by mixing with matching harmonics present in the gain
      characteristics of a microchannel plate (MCP) image intensifier. These harmonics
      arise as a natural consequence of applying a high frequency sinusoidal voltage to
      the photocathode of the device, which switches the flow of photoelectrons 'on'
      and 'off' as the sinus voltage swings from negative to positive. By changing the
      bias of the sinus it was possible to control the duration of the 'on' state of
      the intensifier relative to its 'off' state, enabling the amplitude of the higher
      harmonic content in the gain to be controlled. Relative modulation depths of 400%
      are theoretically possible from this form of square-pulse modulation. A phase
      dependent integrated image is formed by the sum of the mixed frequencies on the
      phosphor of the MCP. Sampling this signal over a full period of the fundamental
      harmonic enables each harmonic to be resolved, provided that the Nyquist sampling
      criterion is satisfied for the highest harmonic component in the signal. At each
      frequency both the phase and modulation parameters can be estimated from a
      Fourier analysis of the data. These parameters enable the fractional populations
      and fluorescence lifetimes of individual components of a complex fluorescence
      decay to be resolved on a pixel-by-pixel basis using a non-linear fit to the
      dispersion relationships. The fitting algorithms were tested on a simulated data
      set and were successful in disentangling two populations having 1 ns and 4 ns
      fluorescence lifetimes. Spatial invariance of the lifetimes was exploited to
      improve the accuracy significantly. Multiple frequency fluorescence lifetime
      imaging microscopy was then successfully applied to resolve the fluorescence
      lifetimes and fluorescence intensity contributions in a rhodamine dye mixture in
      solution, and green fluorescent protein variants co-expressed in live cells.

PMID- 10652008
TI  - CARS microscopy with folded BoxCARS phasematching
AB  - Three-dimensional microscopy based on coherent anti-Stokes Raman scattering
      (CARS) is a powerful new imaging technique, in which the contrast arises from
      molecular vibrations. Based on a simple numerical model, it is shown how the CARS
      interaction volume depends on the focusing parameters and the type of
      phasematching used. Collinear phasematching yields an ellipsoidal interaction
      volume, with lateral dimensions that readily cause vignetting of the CARS signal
      emission at the collection microscope objective. A folded BoxCARS phasematching
      geometry, on the other hand, results in an almost cylindrical interaction volume 
      at the cost of a reduced resolution, for which the possible vignetting of the
      CARS emission is much reduced. In addition, this type of phasematching provides
      spatial separation of the signal from the input laser beams, permitting simple
      signal detection of low frequency vibrational modes. Calculations show that when
      CARS is performed in a microscopic volume, the phasematching restraint on tuning
      over the vibrational band is strongly relaxed. A first example of CARS imaging
      using a folded BoxCARS imaging geometry is shown.

PMID- 10652009
TI  - Freeze-substitution of rabbit tibial articular cartilage reveals that radial zone
      collagen fibres are tubules.
AB  - Investigations of the micromorphology of rabbit tibial articular cartilage using
      scanning and transmission electron microscopy revealed that the collagenous
      elements in the tissue form fluid-containing tubular structures. The commonly
      described radial or deep zone longitudinal fibres were found to be tubular
      structures with internal diameters of 1-2 microm. The walls of the tubules were
      composed of tightly packed fibrils of collagen. The tangential zone, close to the
      tibial plateau, was composed mainly of a spongy arrangement of collagen fibrils,
      containing bunches of tangentially lying small (< 1 microm) diameter tubules. The
      application of conventional chemical fixation techniques resulted in the fine
      detail of this tissue being obscured. When the tissue was frozen, followed by
      cryo-scanning electron microscopy or freeze-drying, prior to observation in the
      scanning electron microscope the tubule structures were not obviously present. It
      was only by applying freeze-substitution techniques, followed by critical point
      drying or resin embedding, that the structure was revealed clearly. Segregation
      of water into ice crystals did occur during the freezing process, but the
      formation of those crystals played no part in creating the tubular morphology
      observed. A similar structure was still revealed following pre-treatment with
      glycerol, methanol or Triton X-100, provided that concentration of these
      additives was not too high. The walls of the tubules in the radial region were
      composed of straight, longitudinally arranged as well as helically arranged, 30
      nm diameter fibrils. The lumen of the tubules appears to be lined by a
      circumferentially arranged array of approximately 10 nm diameter fibres, spaced
      at regular intervals of 50-70 nm.

PMID- 10652011
TI  - Automatic image acquisition, calibration and montage assembly for biological X
      ray microscopy.
AB  - We describe a system for the automatic acquisition and processing of digital
      images in a high-resolution X-ray microscope, including the formation of large
      field high-resolution image montages. A computer-controlled sample positioning
      stage provides approximate coordinates for each high-resolution subimage.
      Individual subimages are corrected to compensate for time-varying, non-uniform
      illumination and CCD-related artefacts. They are then automatically assembled
      into a montage. The montage assembly algorithm is designed to use the overlap
      between each subimage and multiple neighbours to improve the performance of the
      registration step and the fidelity of the result. This is accomplished by
      explicit use of recorded stage positions, optimized ordering of subimage
      insertion, and registration of subimages to the developing montage. Using this
      procedure registration errors are below the resolution limit of the microscope
      (43 nm). The image produced is a seamless, large-field montage at full
      resolution, assembled automatically without human intervention. Beyond this, it
      is also an accurate X-ray transmission map that allows the quantitative
      measurement of anatomical and chemical features of the sample. Applying these
      tools to a biological problem, we have conducted the largest X-ray microscopical
      study to date.

PMID- 10652012
TI  - Identification of weak interfaces in composites using transmission electron
      microscopy
AB  - A new experimental technique was developed to identify crack paths with a
      resolution of nanometres in fibre-reinforced composites. Cracks were introduced
      through Vickers indentations on one side of the sample prior to starting the
      thinning process. Indentations were placed close to the fibres in order to get
      enough cracks at the fibre/matrix interface in the electron-transparent region of
      the thinned sample. The technique was used in a Nicalon-fibre Al2O3 matrix
      composite prior to and after a heat treatment at 1200 degrees C for 1 h. The
      analysis of the crack paths allowed the identification of the weakest interface
      in each condition.

PMID- 10652013
TI  - Atomic force microscopy imaging of polycrystalline CuInSe2 thin films
AB  - In this study, atomic force microscopy (AFM) imaging has been used to study the
      structural properties of polycrystalline CuInSe2 films, which are widely used as
      absorber materials in thin film solar cell devices. This technique demonstrated
      an excellent capability for the reproducible imaging of these rough
      polycrystalline materials. AFM imaging in combination with statistical analysis
      revealed distinct differences in the structural properties (i.e. grain width and
      height distributions, root-mean-square (RMS) and peak to valley (R(p-v))
      roughness values) as a function of the specific growth technique used and the
      bulk composition of the films. In the case of Cu-rich films, prepared by the
      H2Se/Ar treatment of Cu/In/Cu alloys, rough surface structures were in general
      observed. Statistical analysis revealed two distinct distribution of grains in
      these samples (1.0-2.5 &mgr;m and 3-5.5 &mgr;m) with large RMS and R(p-v)
      roughness values of 380 nm and 2.6 &mgr;m, respectively. In-rich films were
      characterized by the presence of much smaller, roughly circular clusters with a
      significant reduction in both the width and height distributions as well as RMS
      and R(p-v) roughness values. The most successful growth techniques, in terms of
      producing homogeneous and dense films, were in the cases of H2Se/Ar treated
      metallic InSe/Cu/InSe alloys and the coevaporation of all materials to form
      CuInSe2. Both these techniques produced absorber films with very narrow grain
      width and height distributions as well as small roughness values. It was possible
      to establish that high efficiency devices are associated with the use of absorber
      films with narrow width distributions between 0.5 and 2 &mgr;m and small RMS (>
      300 nm) roughness values. These values are used as a figure of merit in our
      laboratories to evaluate the structural properties of our CuInSe2 thin films.

PMID- 10652014
TI  - Physiologic and molecular aspects of the Na+:HCO3- cotransporter in health and
      disease processes.
AB  - Approximately 80% of the filtered load of HCO3- is reabsorbed in the proximal
      tubule via a process of active acid secretion by the luminal membrane. The major
      mechanism for the transport of HCO3- across the basolateral membrane is via the
      electrogenic Na+:3HCO3- cotransporter (NBC). Recent molecular cloning experiments
      have identified the existence of three NBC isoforms (NBC-1, NBC-2, and NBC-3).1
      Functional and molecular studies indicate the presence of all three NBC isoforms
      in the kidney. All are presumed to mediate the cotransport of Na+ and HCO3- under
      normal conditions and may be functionally altered in certain pathophysiologic
      states. Specifically, NBC-1 may be up-regulated in metabolic acidosis and
      potassium depletion and in response to glucocorticoid excess and may be down
      regulated in response to HCO3- loading or alkalosis. Recent studies provide
      molecular evidence indicating the expression of NBC-1 in pancreatic duct cells.
      NBC is activated by cystic fibrosis transmembrane conductance regulator (CFTR)
      and plays an important role in HCO3- secretion in the agonist-stimulated state in
      pancreatic duct cells. The purpose of this review is to summarize recent
      functional and molecular studies on the regulation of NBCs in physiologic and
      pathophysiologic states. Possible signals responsible for the regulation of NBCs
      in these conditions are examined. Furthermore, the possible role of this
      transporter in acid-base disorders (such as proximal renal tubular acidosis) is
      discussed.

PMID- 10652015
TI  - Glomerular heparan sulfate alterations: mechanisms and relevance for proteinuria.
AB  - Heparan sulfate (HS) is the anionic polysaccharide side chain of HS proteoglycans
      (HSPGs) present in basement membranes, in extracellular matrix, and on cell
      surfaces. Recently, agrin was identified as a major HSPG present in the
      glomerular basement membrane (GBM). An increased permeability of the GBM for
      proteins after digestion of HS by heparitinase or after antibody binding to HS
      demonstrated the importance of HS for the permselective properties of the GBM.
      With recently developed antibodies directed against the GBM HSPG (agrin) core
      protein and the HS side chain, we demonstrated a decrease in HS staining in the
      GBM in different human proteinuric glomerulopathies, such as systemic lupus
      erythematosus (SLE), minimal change disease, membranous glomerulonephritis, and
      diabetic nephropathy, whereas the staining of the agrin core protein remained
      unaltered. This suggested changes in the HS side chains of HSPG in proteinuric
      glomerular diseases. To gain more insight into the mechanisms responsible for
      this observation, we studied GBM HS(PG) expression in experimental models of
      proteinuria. Similar HS changes were found in murine lupus nephritis, adriamycin
      nephropathy, and active Heymann nephritis. In these models, an inverse
      correlation was found between HS staining in the GBM and proteinuria. From these
      investigations, four new and different mechanisms have emerged. First, in lupus
      nephritis, HS was found to be masked by nucleosomes complexed to antinuclear
      autoantibodies. This masking was due to the binding of cationic moieties on the N
      terminal parts of the core histones to anionic determinants in HS. Second, in
      adriamycin nephropathy, glomerular HS was depolymerized by reactive oxygen
      species (ROS), mainly hydroxyl radicals, which could be prevented by scavengers
      both in vitro (exposure of HS to ROS) and in vivo. Third, in vivo renal perfusion
      of purified elastase led to a decrease of HS in the GBM caused by proteolytic
      cleavage of the agrin core protein near the attachment sites of HS by the HS
      bound enzyme. Fourth, in streptozotocin-induced diabetic nephropathy and during
      culture of glomerular cells under high glucose conditions, evidence was obtained
      that hyperglycemia led to a down-regulation of HS synthesis, accompanied by a
      reduction in the degree of HS sulfation.

PMID- 10652016
TI  - Novel mutation in the nephrin gene of a Japanese patient with congenital
      nephrotic syndrome of the Finnish type.
AB  - BACKGROUND: Congenital nephrotic syndrome (CNS) of the Finnish type is a rare
      autosomal-recessive disorder. Kestila et al reported that a positionally cloned
      gene for a novel glomerular protein nephrin is mutated in CNS. Most Finnish
      patients have one of two mutations. In this study, we described a Japanese CNS
      family associated with a novel missense point mutation in the nephrin gene.
      METHODS: Reverse transcription-polymerase chain reaction, polymerase chain
      reaction, and sequence analysis were used. RESULTS: The patient had the three
      missense mutations homozygously. One mutation was already reported as sequence
      variant. The two other novel mutations were the GAG to AAG transition, leading to
      a Glu447Lys and the GAC to GTC transition, predicting an Asp819Val substitution
      in the nephrin protein. CONCLUSION: Our findings indicate that an abnormality of
      nephrin may cause CNS of the Finnish type in Japanese subjects.

PMID- 10652017
TI  - Risk of advanced diabetic nephropathy in type 1 diabetes is associated with
      endothelial nitric oxide synthase gene polymorphism.
AB  - Risk of advanced diabetic nephropathy in type 1 diabetes is associated with
      endothelial nitric oxide synthase gene polymorphism. BACKGROUND: Polymorphisms in
      the endothelial nitric oxide synthase gene (eNOS) may be implicated in the
      development of nephropathy in patients with type 1 or insulin-dependent diabetes
      mellitus (IDDM). METHODS: Three groups of IDDM patients were selected to study
      this hypothesis: cases with advanced diabetic nephropathy (N = 78), cases with
      overt proteinuria but normal serum creatinine (N = 74), and controls with
      normoalbuminuria despite 15 years of diabetes (N = 195). Parents of 132 cases and
      53 controls were also examined and were used for the transmission disequilibrium
      test, a family-based study design to test association. RESULTS: We examined four
      eNOS polymorphisms, and two were associated with diabetic nephropathy in the case
      control comparisons: a T to C substitution in the promoter at position -786 and
      the a-deletion/b-insertion in intron 4. For the former, the risk of developing
      advanced nephropathy was higher for C allele homozygotes than for the other two
      genotypes (odds ratio 2.8, 95% CI, 1.4 to 5.6). For the latter polymorphism, it
      was the a-deletion carriers that had the higher risk (odds ratio 2.3, 95% CI, 1.3
      to 4.0) in comparison with noncarriers. Both polymorphisms were analyzed together
      as haplotypes in a family-based study using the transmission disequilibrium test.
      The C/a-deletion haplotype was transmitted from heterozygous parents to cases
      with advanced diabetic nephropathy with a significantly higher frequency than
      expected (P = 0.004). CONCLUSION: The findings of the case-control and family
      based studies demonstrate clearly that DNA sequence differences in eNOS influence
      the risk of advanced nephropathy in type 1 diabetes.

PMID- 10652018
TI  - Cyclooxygenase-2-selective inhibitors impair glomerulogenesis and renal cortical
      development.
AB  - BACKGROUND: Antenatal exposure to nonsteroidal anti-inflammatory drugs (NSAIDs)
      has been associated with renal dysgenesis in humans. METHODS: These studies
      characterized cyclooxygenase-2 (COX-2) versus COX-1-selective inhibition on
      nephrogenesis in the rodent using histomorphometry, immunohistology, and in situ
      hybridization. RESULTS: Administration of a COX-2-selective inhibitor (SC58236),
      started during pregnancy until weaning, significantly impaired development of the
      renal cortex and reduced glomerular diameter in both mice and rats. An identical
      phenotype was demonstrated in COX-2 -/- mice. In contrast to its effects on the
      developing kidney, a COX-2 inhibitor had no effect on glomerular volume in adult
      mice. This effect was specific for COX-2 because maternal administration of a COX
      1-selective inhibitor (SC58560) did not affect renal development despite
      significantly inhibiting gastric mucosal prostaglandin E2 (PGE2) synthesis in
      pups. The expression of COX-2 immunoreactivity peaked in the first postnatal week
      and was localized to S-shaped bodies and the macula densa in the cortex.
      Treatment with a COX-2 inhibitor during this period (from postnatal day 0 to day
      21) severely reduced glomerular diameter, whereas treatment limited to pregnancy
      did not affect glomerular size. CONCLUSION: These data demonstrate an important
      role for COX-2 activity in nephrogenesis in the rodent, and define a specific
      time period of susceptibility to these effects.

PMID- 10652019
TI  - Insulin-like growth factor system components in hyperparathyroidism and renal
      osteodystrophy.
AB  - BACKGROUND: The insulin-like growth factor (IGF) system plays a key role in
      regulation of bone formation. In patients with renal osteodystrophy, an elevation
      of some IGF binding proteins (IGFBPs) has been described, but there is no study
      measuring serum levels of both IGF-I and IGF-II as well as IGFBP-1 to -6 in
      different forms of renal osteodystrophy and hyperparathyroidism. METHODS: In a
      cross-sectional study, we investigated 319 patients with mild (N = 29), moderate
      (N = 48), preuremic (N = 37), and end-stage renal failure (ESRF; N = 205). The
      ESRF group was treated by hemodialysis (HD; N = 148), peritoneal dialysis (PD; N
      = 27), or renal transplantation (RTX; N = 30). As controls without renal failure,
      we recruited age-matched healthy subjects (N = 87) and patients with primary
      hyperparathyroidism (pHPT; N = 25). Serum levels of total and free IGF-I, IGF-II,
      IGFBP-1 to -6, and biochemical bone markers including intact parathyroid hormone
      (PTH), bone alkaline phosphatase (B-ALP), and osteocalcin (OSC) were measured by
      specific immunometric assays. IGF system components and bone markers were
      correlated with clinical and bone histologic findings. Mean values +/- SEM are
      given. RESULTS: With declining renal function a significant increase was measured
      for IGFBP-1 (range 7- to 14-fold), IGFBP-2 (3- to 8-fold), IGFBP-3 (1.5- to 3
      fold), IGFBP-4 (3- to 19-fold), and IGFBP-6 (8- to 25-fold), whereas IGFBP-5
      levels tended to decrease (1.3- to 1. 6-fold). In contrast, serum levels of IGF
      I, free IGF-I, and IGF-II remained constant in most patients. Compared with renal
      failure patients, pHPT patients showed a similar decline in IGFBP-5 levels and
      less elevated levels of IGFBP-1 (3.5-fold), IGFBP-2 (2-fold), IGFBP-3 (1.2-fold),
      and IGFBP-6 (4-fold) but no elevation of IGFBP-4 levels. In all subjects, free
      and total IGF-I levels showed significant negative correlations with IGFBP-1,
      IGFBP-2, and IGFBP-4 (that is, inhibitory IGF system components) and significant
      positive correlations with IGFBP-3 and IGFBP-5 (that is, stimulatory IGF system
      components). A positive correlation was observed between IGF-II and IGFBP-6. ESRF
      patients with mixed uremic bone disease and histologic evidence for osteopenia
      revealed significantly (P < 0.05) higher levels of IGFBP-2 and IGFBP-4 but lower
      IGFBP-5 levels. Histologic parameters of bone formation showed significant
      positive correlations with serum levels of IGF-I, IGF-II, and IGFBP-5. In
      contrast, IGFBP-2 and IGFBP-4 correlated positively with indices of bone loss.
      Moreover, dialysis patients with low bone turnover (N = 24) showed significantly
      (P < 0.05) lower levels of IGFBP-5, PTH, B-ALP, and OSC than patients with high
      bone turnover. CONCLUSION: Patients with primary and secondary
      hyperparathyroidism showed lower levels of the putative stimulatory IGFBP-5 but
      higher levels of IGFBP-1, -2, -3, and -6, whereas total IGF-I and IGF-II levels
      were not or only moderately increased. The marked increase in serum levels of
      IGFBP-4 appeared to be characteristic for chronic renal failure. IGFBP-5
      correlated with biochemical markers and histologic indices of bone formation in
      renal osteodystrophy patients and was not influenced by renal function.
      Therefore, IGFBP-5 may gain significance as a serological marker for osteopenia
      and low bone turnover in long-term dialysis patients.

PMID- 10652020
TI  - Apoptosis in parathyroid hyperplasia of patients with primary or secondary uremic
      hyperparathyroidism.
AB  - BACKGROUND: Chronic oversecretion of parathyroid hormone (PTH) is associated with
      parathyroid hyperplasia, reflecting a disturbed balance between cell
      proliferation and apoptosis. This study addressed the unsolved issue of apoptosis
      in hyperparathyroidism. METHODS: Parathyroid glands from 19 patients with primary
      (1 degrees ) and 11 patients with secondary (2 degrees ) uremic
      hyperparathyroidism, as well as 13 normal parathyroid glands, were examined.
      Apoptosis was evaluated by terminal deoxynucleotidyl transferase (Tdt)-mediated
      dUTP nick end-labeling assay (TUNEL). Because the apoptotic process is regulated
      by several oncoproteins, the expression of Bcl-2 and Bax was analyzed by
      immunohistochemistry. RESULTS: The numbers of apoptotic cells in 1 degrees
      parathyroid adenoma (0.99 +/- 0.03 per 1000 cells, mean +/- SE, P < 0.009) and 2
      degrees parathyroid hyperplasia (1.20 +/- 0.54 per 1000 cells, P < 0.005) were
      significantly higher than in normal parathyroid tissue (0.13 +/- 0. 06 per 1000
      cells). Light microscopy examination of hyperplastic parathyroid tissue from a
      uremic patient showed the presence of nuclei with dense chromatin characteristic
      of apoptosis. Bcl-2 staining was strong in normal tissues but weak or negative in
      several sections of 1 degrees and 2 degrees hyperparathyroid tissues, mostly in
      nodular areas. Bax staining was homogeneous in normal tissue but patchy in
      several hyperplastic tissues. CONCLUSION: These results suggest that
      hyperparathyroidism is associated with a compensatory increase in apoptosis,
      possibly favored by a diminished Bcl-2/Bax ratio. This renders highly improbable
      the hypothesis that parathyroid hyperplasia is due to a decreased rate of
      apoptosis.

PMID- 10652021
TI  - Glycosphingolipid depletion in fabry disease lymphoblasts with potent inhibitors
      of glucosylceramide synthase.
AB  - BACKGROUND: Fabry disease is an inherited X-linked disorder resulting in the loss
      of activity of the lysosomal hydrolase alpha-galactosidase A and causing the
      clinical manifestations of renal failure, cerebral vascular disease, and
      myocardial infarction. The phenotypic expression of this disorder is manifest by
      the accumulation of glycosphingolipids containing alpha-galactosyl linkages, most
      prominently globotriaosylceramide. METHODS: Based on quantitative structure
      activity studies, we recently reported two newly designed glucosylceramide
      synthase inhibitors based on 1-phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol
      (P4). These inhibitors, 4'-hydroxy-P4 and ethylenedioxy-P4, were evaluated for
      their ability to deplete globotriaosylceramide and other glucosylceramide-based
      lipids in Fabry lymphocytes and were compared with N-butyldeoxynojirimycin,
      another reported glucosylceramide synthase inhibitor. RESULTS: Concentrations as
      low as 10 nmol/L of 4'-hydroxy-P4 and ethylenedioxy-P4 resulted in 70 and 80%
      depletion, respectively, of globotriaosylceramide, with maximal depletion
      occurring at three days of treatment. There was no impairment of cell growth. In
      contrast, N-butyldeoxynojirimycin only minimally lowered globotriaosylceramide
      levels, even at concentrations as high as 10 micromol/L. Globotriaosylceramide
      depletion was confirmed by the loss of binding of FITC-conjugated verotoxin B
      subunit to the lymphoblasts. CONCLUSIONS: These findings suggest that selective
      glucosylceramide synthase inhibitors are highly effective in the depletion of
      globotriaosylceramide from Fabry cell lines. We suggest that these compounds have
      potential therapeutic utility in the treatment of Fabry disease.

PMID- 10652022
TI  - Down-regulation of interferon-gamma signaling by gene transfer of Stat1 mutant in
      mesangial cells.
AB  - BACKGROUND: Interferon-gamma (IFN-gamma) is secreted by T lymphocytes and natural
      killer (NK) cells in the cellular immunity-mediated inflammatory lesion,
      including endocapillary or extracapillary proliferative glomerulonephritis. It
      induces and/or enhances multiple histocompatibility complex (MHC) class I and II,
      intercellular adhesion molecule-1 (ICAM-1), inducible nitric oxide synthase
      (iNOS), and Fc receptor expression in renal resident cells, resulting in the
      initiation and promotion of inflammation. Recently, the signaling mechanism of
      IFN-gamma has been investigated, and it appears that Stat1alpha is essential for
      signaling. We investigated Stat1alpha activation by IFN-gamma in mesangial cells
      and attempted to regulate the signal transduction by gene transfer. METHODS:
      Western blot with anti-Stat1 and antiphosphotyrosine after immunoprecipitation of
      Stat1 and Northern blot for detection of Stat1 mRNA were performed. The dominant
      negative form of Flag-tagged Stat1 was expressed in cultured rat mesangial cells.
      Flag was immunostained in transfectants, and luciferase reporter assay was
      carried out to measure the transcriptional activity of Stat1alpha. The expression
      of IFN-gamma-inducible genes such as MHC class II (Ia-Aalpha) and MHC class II
      transactivator (CIITA) was detected by reverse transcriptase-polymerase chain
      reaction (RT-PCR). RESULTS: Stat1alpha was tyrosine phosphorylated and activated
      by IFN-gamma in mesangial cells, and the mRNA and protein level of Stat1alpha
      increased upon stimulation by IFN-gamma. Overexpression of Stat1-mutant lacking
      35 C-terminal amino acids strongly suppressed the IFN-gamma-induced signal
      transduction and inhibited the expression of MHC class II and CIITA genes in
      mesangial cells. CONCLUSIONS: Stat1alpha is a critical molecule in the signal
      transduction of IFN-gamma in mesangial cells. The inhibition of an endogenous
      function of Stat1alpha by gene transfer of the Stat1 mutant may be a new method
      to reduce the inflammatory effects of IFN-gamma in localized inflammation of the
      kidney.

PMID- 10652023
TI  - Small heat shock protein alteration provides a mechanism to reduce mesangial cell
      contractility in diabetes and oxidative stress.
AB  - BACKGROUND: Small heat shock proteins are expressed in many tissues and are
      proposed to regulate actin filament dynamics when dissociated into small
      aggregates and phosphorylated in a p38 mitogen-activated protein kinase (p38MAPK)
      dependent manner. METHODS: p38MAPK activity and small heat shock protein-25
      (Hsp25) were determined in glomeruli from rats with experimental diabetes induced
      by streptozotocin administration and in isolated glomeruli exposed to a free
      radical stress. Contractile responsiveness of mesangial cells was determined by
      the serum-induced contraction of cell-embedded type I collagen gels. RESULTS: In
      experimental diabetes, there is an activation of p38MAPK, a decrease in the size
      of Hsp25 molecular aggregates, from large to small homo-oligomers, and an
      increase in the phosphorylation of Hsp25. In control glomeruli, a free radical
      stress, H2O2, activated p38MAPK and increased Hsp25 in a concentration-dependent
      manner. Additionally, H2O2 decreased the contractility of cultured mesangial
      cells concomitant with an increase in Hsp25 phosphorylation and a reduction in
      Hsp25 aggregate size. These effects were significantly reduced by SB202190, an
      imidazole-derivative cell-permeable inhibitor of p38MAPK. CONCLUSIONS: It has
      been proposed that the generation of oxygen-derived free radicals in diabetes may
      be linked causally to a loss of glomerular contractile reactivity and thus
      hyperfiltration in the early stages of diabetes mellitus. This study provides a
      mechanism for alteration of mesangial cell contractile responsiveness through
      phosphorylation of Hsp25 and may be a mechanism underlying abnormalities in
      glomerular hemodynamics in diabetes and in the presence of free radical stress.

PMID- 10652024
TI  - Accessory role of human peritoneal mesothelial cells in antigen presentation and
      T-cell growth.
AB  - BACKGROUND: To assess the role of human peritoneal mesothelial cells (HPMCs) in
      the generation of an immune response during peritonitis, we tested their ability
      to activate T-cells by antigen presentation (AP) and by the secretion of
      interleukin-15 (IL-15). IL-15 is a potent leukocyte activator that stimulates the
      proliferation of CD4+, CD8+, and B and natural killer (NK) cells. METHODS: HPMCs
      and mononuclear cells were derived from six volunteer patients who underwent
      elective abdominal surgery. Flow cytometry was used to analyze human lymphocyte
      antigen-DR (HLA-DR), intercellular adhesion molecule-1 (ICAM-1), and B7 molecules
      on HPMCs. Affinity-purified CD4 cells were used for AP assays. We used a specific
      enzyme-linked immunosorbent assay to detect interferon-gamma (IFN-gamma), IL-2,
      and IL-15 protein and reverse transcription-polymerase chain reaction for mRNA
      analysis. RESULTS: HPMCs expressed HLA-DR molecules following IFN-gamma
      treatment. ICAM-1 molecules were expressed at high levels, and B7-1 and B7-2
      molecules could not be detected. The accessory function of HPMCs was assayed by T
      cell stimulation using anti-CD3 antibodies (OKT3). HPMCs were essential for a
      significant OKT3-induced T-cell proliferation. Anti-ICAM-1 antibodies blocked
      OKT3-induced proliferation. HPMCs served as effective antigen-presenting cells
      when Tetanus toxoid (TT) or Staphylococcus aureus-alpha-toxin were used as
      antigens. IFN-gamma, IL-2, and IL-15 accumulated during AP reactions. We found
      that IL-15 is produced by HPMCs, and IFN-gamma up-regulated its mRNA levels and
      protein secretion in a dose-dependent manner. We also detected IL-15 in the
      peritoneal effluent of patients undergoing continuous peritoneal dialysis
      treatment. In patients suffering from peritonitis, IL-15 levels were elevated
      (35.0 +/- 6.0 pg/mL, N = 10) as compared with noninfected patients (16.2 +/- 4.0
      pg/mL, N = 7). CONCLUSIONS: HPMCs participate in the peritoneal immune response
      against invading pathogens by AP. For this process, ICAM-1 is the major accessory
      molecule. In addition, HPMCs may contribute to T-cell activation by secretion of
      IL-15.

PMID- 10652025
TI  - Expression of decorin, biglycan, and collagen type I in human renal fibrosing
      disease.
AB  - BACKGROUND: The extracellular matrix proteoglycans decorin and biglycan may have
      a pathogenic role in renal fibrosing disease via regulation of the activity of
      growth factors, such as transforming growth factor-beta, and effects on collagen
      type I fibrillogenesis. The expression of decorin and biglycan in human
      glomerular diseases characterized by mesangial sclerosis is unknown. METHODS:
      Decorin, biglycan, and collagen type I were localized immunohistochemically in
      human renal biopsy cases of amyloidosis (N = 18), diabetic nephropathy (N = 11),
      fibrillary glomerulonephritis (N = 5), immunotactoid glomerulopathy (N = 5),
      light-chain deposition disease (N = 4), idiopathic mesangial sclerosis (N = 4),
      and nephrosclerosis (N = 6), and in morphologically normal tissues obtained from
      tumor nephrectomies (N = 8). Decorin and biglycan mRNA synthesis was evaluated by
      in situ hybridization. RESULTS: Decorin and biglycan protein were not identified
      in normal glomeruli. Decorin accumulated in amyloid deposits, but not in deposits
      of fibrillary glomerulonephritis or immunotactoid glomerulopathy. Biglycan weakly
      accumulated in amyloid deposits, and both decorin and biglycan weakly stained
      mesangial nodules in cases of morphologically advanced light-chain deposition
      disease and diabetic nephropathy. In all analyzed cases, irrespective of the
      underlying disease, decorin and biglycan accumulated in glomeruli in areas of
      fibrous organization of the urinary space and in areas of tubulointerstitial
      fibrosis. Biglycan, but not decorin, accumulated in the neointima of
      arteriosclerotic blood vessels. Decorin and biglycan mRNA synthesis was detected
      at sites of proteoglycan accumulation in glomeruli, interstitium, and neointima.
      Collagen type I colocalized with decorin and biglycan deposits. CONCLUSIONS:
      Differences in extracellular matrix proteoglycan composition may be
      diagnostically useful in distinguishing morphologically similar diseases.
      Distinct patterns of proteoglycan expression may be related to modulation of
      specific growth factor activity in different glomerular diseases.

PMID- 10652026
TI  - Expression of macrophage migration inhibitory factor in human glomerulonephritis.
AB  - BACKGROUND: We have recently demonstrated that macrophage migration inhibitory
      factor (MIF) plays a pathogenic role in experimental glomerulonephritis (GN). The
      aim of the current study was to investigate MIF expression in human GN. METHODS:
      MIF expression was examined by in situ hybridization and immunohistochemistry
      staining in 65 biopsies from a variety of glomerulonephridities. RESULTS: There
      is constitutive expression of MIF mRNA and protein in normal human kidney that is
      largely restricted to tubular epithelial cells and to some glomerular epithelial
      cells. There was little change in the pattern of MIF expression in
      nonproliferative forms of GN such as minimal change disease and membranous GN.
      However, there was a marked increase in both glomerular and tubular MIF
      expression in proliferative forms of GN, including focal segmental
      glomerulosclerosis (FGS), lupus nephritis, crescentic GN, and mesangiocapillary
      proliferative GN. The prominent macrophage and T-cell infiltrate in these
      diseases were largely restricted to areas with marked up-regulation of MIF
      expression, contributing to glomerular hypercellularity, glomerular focal
      segmental lesions, crescent formation, tubulitis, and granulomatous lesions. De
      novo MIF expression was evident in glomerular endothelial cells and mesangial
      cells in proliferative forms of GN. In addition, many infiltrating macrophages
      and T cells showed MIF mRNA and protein expression. Quantitative analysis found
      that increased glomerular and tubular MIF expression gave a highly significant
      correlation with macrophage and T-cell accumulation, the severity of histologic
      lesions, and the loss of creatinine clearance. CONCLUSIONS: Renal MIF expression
      is markedly up-regulated in proliferative forms of human GN, and this correlates
      with leukocyte infiltration, histologic damage, and renal function impairment.
      These results suggest that MIF may be an important mediator of renal injury in
      progressive forms of human GN. Based on these findings, together with the known
      pathogenic role of MIF in experimental GN, we propose that MIF is an attractive
      therapeutic target in the treatment of progressive forms of GN.

PMID- 10652027
TI  - Dominant T cells in idiopathic nephrotic syndrome of childhood.
AB  - BACKGROUND: Because of several studies, idiopathic nephrotic syndrome (INS) of
      childhood is suspected to have an immunologic pathogenesis with T cells playing a
      major role. To investigate this hypothesis further, we studied the diversity of
      the CDR3 region of the T-cell receptor (TCR) beta-chain from peripheral T cells
      isolated from patients with INS. METHODS: The study was performed over a three
      year period to obtain longitudinal data on the repertoire of peripheral T cells.
      mRNA from peripheral mononuclear cells (PBMCs) of seven INS patients and two
      healthy controls (NHD) was prepared and analyzed for CDR3 length polymorphism of
      TCR beta-chain by spectratyping. RESULTS: All INS patients presented individually
      skewed spectratype histograms in at least one Vbeta-family. Patients suffering
      from a frequent relapsing course of INS or a focal global sclerosis showed some
      alterations to persist in all samples isolated in the observation period (up to 3
      years). In addition, sequence analyses of the beta-chain of the TCR CDR3 region
      confirmed clonal expansion of peripheral T cells in those patients who had
      displayed spectratype alterations. CONCLUSIONS: The data give strong evidence for
      an direct involvement of CD8+ T cells in the complicated course of INS.

PMID- 10652028
TI  - Endogenous interleukin-10 regulates Th1 responses that induce crescentic
      glomerulonephritis.
AB  - BACKGROUND: Interleukin (IL)-10 plays a pivotal role in regulating the Th1/Th2
      predominance of immune responses. Exogenously administered IL-10 suppresses
      nephritogenic Th1 responses, inhibits macrophage function, and attenuates
      crescentic glomerulonephritis (GN). To determine the role of endogenous IL-10,
      the development of the nephritogenic immune response and crescentic GN was
      compared in IL-10-deficient (IL-10-/-) and normal (IL-10+/+) C57BL/6 mice.
      METHODS: GN was initiated in sensitized mice by the intravenous administration of
      sheep antimouse glomerular basement membrane globulin. Renal injury was evaluated
      21 days later. RESULTS: Following the administration of anti-glomerular basement
      membrane globulin, normal (IL-10+/+) C57BL/6 mice developed proliferative GN with
      occasional crescents, glomerular CD4+ T-cell and macrophage accumulation, and
      fibrin deposition. Using an identical induction protocol, IL-10-/-mice developed
      more severe GN. Crescent formation (IL-10-/-, 23 +/- 2% of glomeruli; IL-10+/+, 5
      +/- 2%), glomerular CD4+ T cells [IL-10-/-, 1. 0 +/- 0.2 cells per glomerular
      cross-section (c/gcs); IL-10 +/+, 0.3 +/- 0.05 c/gcs], glomerular macrophages (IL
      10-/-, 4.8 +/- 0.3 c/gcs; IL-10 +/+, 1.7 +/- 0.2 c/gcs), fibrin deposition
      [fibrin score (range 0 to 3+); IL-10-/-, 1.10 +/- 0.04; IL-10+/+, 0.6 +/- 0. 07],
      and serum creatinine (IL-10-/-, 30 +/- 2 micromol/L; IL-10 +/+, 23 +/- 1
      micromol/L) were all significantly increased in IL-10-/- mice (P < 0.05).
      Circulating antibody (IL-10-/-, 1.05 +/- 0.16 OD units; IL-10+/+, 0.63 +/- 0.08
      OD units) and cutaneous delayed-type hypersensitivity (skin swelling; IL-10-/-,
      0.21 +/- 0.03 mm; IL-10+/+, 0.12 +/- 0.02 mm) to the nephritogenic antigen (sheep
      globulin) were also increased (both P < 0.05). Interferon-gamma production by
      cultured splenocytes was increased (IL-10-/- 7.9 +/- 2. 5 ng/4 x 106 cells, IL
      10+/+ 0.28 +/- 0.09 ng/4 x 106 cells, P < 0. 05), but IL-4 production was
      unchanged. CONCLUSIONS: Endogenous IL-10 counter-regulates nephritogenic Th1
      responses and attenuates crescentic GN.

PMID- 10652029
TI  - Contribution of gamma glutamyl transpeptidase to oxidative damage of ischemic rat
      kidney.
AB  - BACKGROUND: A variety of mechanisms have been considered in the pathogenesis of
      the cell damage occurring in the kidney that is undergoing transient ischemia.
      However, little information is available about the role of oxidative stress in
      building up the tissue injury in the hypoxic organ during short-term ischemia.
      METHODS: After a standard brief period (25 min) of unilateral kidney ischemia in
      rats, pretreated or not with acivicin (60 micromol/L/kg i.v.), tissue samples
      from both ischemic and not ischemic kidneys were obtained to measure
      malondialdehyde (MDA) and glutathione (GSH) content, gamma glutamyl
      transpeptidase (GGT) activity by spectrophotometry, localization and intensity of
      enzyme activity, and tissue damage by histochemistry. RESULTS: GGT activity was
      found to be increased in both cortical and medullar zones of the ischemic
      kidneys, where the GSH level was only slightly decreased and the MDA level, in
      contrast, was markedly increased; in parallel, the cytosolic volume of the
      proximal tubular (PT) cells showed a significant increment. The animal
      pretreatment with acivicin, a specific inhibitor of GGT, besides preventing the
      up-regulation of the enzyme during ischemia, afforded good protection against the
      observed changes of MDA and GSH tissue levels, as well as of tubular cell volume.
      CONCLUSIONS: Ex vivo data supporting a net pro-oxidant effect of up-regulated GGT
      during short-term ischemia of rat kidney have been obtained. The enzyme
      stimulation appears to contribute to the renal morphological damage exerted by a
      brief hypoxic condition at the level of PT cells. The actual impact on kidney
      function by GGT-dependent oxidative damage during transient ischemia and the
      potential protective action of GGT inhibitors require subsequent investigation.

PMID- 10652030
TI  - Dopamine inhibits renal Na+:HCO3- cotransporter in rabbits and normotensive rats
      but not in spontaneously hypertensive rats.
AB  - BACKGROUND: Dopamine (DA) is thought to regulate renal proximal transport through
      the inhibition of the Na+,K+-ATPase and/or Na+/H+ exchanger. Defects in this
      dopaminergic system are proposed to be a pathogenic factor of genetic
      hypertension. However, microperfusion studies have not consistently confirmed
      direct tubular effects of DA. METHODS: Isolated proximal straight tubules were
      perfused peritubularly with Dulbecco's modified Eagle's tissue culture medium
      (DMEM) containing norepinephrine (NE) to improve incubation conditions.
      Intracellular Na+ concentrations ([Na+]i) and cell pH (pHi) were measured with
      fluorescence probes. RESULTS: When incubated in DMEM plus NE, DA increased [Na+]i
      in rabbit tubules. Inhibition of Na+,K+-ATPase could not explain this response,
      as it was not suppressed by ouabain. An analysis of pHi responses to bath HCO3-
      reduction revealed that DA, SKF 38393 (a DA1 agonist), and adenosine 3',5'-cyclic
      monophosphate (cAMP) inhibited the basolateral Na+:HCO3- cotransporter in rabbit
      and Wistar-Kyoto rat (WKY), if its transport stoichiometry was converted to 3
      HCO3-:1 Na+ by DMEM plus NE incubation. The inhibitory effect of DA was abolished
      by SCH 23390, a DA1 antagonist, but not by (-)-sulpiride, a DA2 antagonist. In
      spontaneously hypertensive rats (SHRs), however, DA and SKF 38393 failed to
      inhibit the cotransporter, although the inhibitory effects of cAMP and
      parathyroid hormone were comparable to those in WKY. CONCLUSION: These results
      indicate that DA inhibits the Na+:HCO3- cotransporter in renal proximal tubules
      and also suggest that dysregulation of the cotransporter, possibly through the
      defect in DA1 receptor signaling, could play an important role in development of
      hypertension in SHRs.

PMID- 10652031
TI  - Distal tubule bicarbonate reabsorption in intact and remnant diabetic kidneys.
AB  - BACKGROUND: In the diabetic patient, hyperkalemia and hyperchloremic metabolic
      acidosis has been attributed to one or more of the following factors associated
      with diabetic nephropathy: hypoaldosteronism, altered potassium homeostasis, or a
      distal tubular (DT) defect in hydrogen ion secretion. To evaluate maximal in vivo
      DT acidification in streptozotocin (STZ) diabetes, unidirectional bicarbonate
      reabsorption (JHCO3) was measured in DTs after acid loading and in surviving DT
      after 2/3 nephrectomy (Nx). METHODS: Acid gavage induced hyperchloremic metabolic
      acidosis in four groups of rats: diabetic rats with hyperglycemia two (a) and (b)
      eight weeks after STZ injection, (c) diabetic rats with tight glucose control two
      weeks after STZ injection and insulin pump implantation; and (d) control
      nondiabetic rats. Another group of diabetic rats underwent (e) Nx one week after
      STZ injection; these rats were neither acid loaded nor pump implanted. RESULTS:
      In the acidotic rats, the plasma potassium concentration, the plasma and urine
      acid-base parameters in the three STZ diabetic groups was not different from
      control rats, whereas JHCO3 fluxes were brisk without important differences
      between groups. In Nx rats, although the plasma potassium concentration and acid
      base status were normal, surviving JHCO3 fluxes were still brisk and not
      different from the acid-loaded rats. CONCLUSIONS: These in vivo measurements
      indicate there is no impairment in DT unidirectional bicarbonate reabsorption in
      the intact or remnant STZ diabetic kidney.

PMID- 10652032
TI  - Calcium phosphate supersaturation regulates stone formation in genetic
      hypercalciuric stone-forming rats.
AB  - BACKGROUND: Hypercalciuria is the most common metabolic abnormality observed in
      patients with nephrolithiasis. Hypercalciuria raises urine supersaturation with
      respect to the solid phases of calcium oxalate and calcium phosphate, leading to
      an enhanced probability for nucleation and growth of crystals into clinically
      significant stones. However, there is little direct proof that supersaturation
      itself regulates stone formation. Through successive inbreeding of the most
      hypercalciuric progeny of hypercalciuric Sprague-Dawley rats, we have established
      a strain of rats, each of which excrete abnormally large amounts of urinary
      calcium and each of which forms calcium phosphate kidney stones. We used these
      hypercalciuric (GHS) rats to test the hypothesis that an isolated reduction in
      urine supersaturation, achieved by decreasing urine phosphorus excretion, would
      decrease stone formation in these rats. METHODS: Thirty 44th-generation female
      GHS rats were randomly divided into three groups. Ten rats received a high
      phosphorus diet (0.565% phosphorus), 10 a medium-phosphorus diet (0.395%
      phosphorus), and 10 a low-phosphorus diet (0.225% phosphorus) for a total of 18
      weeks. The lowered dietary phosphorus would be expected to result in a decrease
      in urine phosphorus excretion and a decrease in urinary supersaturation with
      respect to the calcium phosphate solid phase. Every two weeks, 24-hour urine
      collections were obtained. All relevant ions were measured, and supersaturation
      with respect to calcium oxalate and calcium hydrogen phosphate were determined.
      At the conclusion of the experiment, each rat was killed, and the kidneys,
      ureters, and bladder were dissected en block and x-rayed to determine whether any
      stones formed. A decrease in stone formation with a reduction in urinary
      supersaturation would support the hypothesis that supersaturation alone can
      regulate stone formation. RESULTS: Decreasing the dietary phosphorus intake led
      to a progressive decrease in urine phosphorus excretion and an increase in urine
      calcium excretion, the latter presumably caused by decreased intestinal calcium
      phosphate binding and increased calcium absorption. With decreasing dietary
      phosphorus intake, there was a progressive decrease in saturation with respect to
      the calcium phosphate solid phase. Fifteen of the 20 kidneys from the 10 rats fed
      the high-phosphorus diet had radiographic evidence of kidney stone formation,
      whereas no kidneys from the rats fed either the medium- or low-phosphorus diet
      developed kidney stones. CONCLUSIONS: A decrease in urine phosphorus excretion
      not only led to a decrease in urine supersaturation with respect to the calcium
      phosphate solid phase but to an elimination of renal stone formation. The results
      of this study support the hypothesis that variation in supersaturation alone can
      regulate renal stone formation. Whether a reduction of dietary phosphorus will
      alter stone formation in humans with calcium phosphate nephrolithiasis remains to
      be determined.

PMID- 10652033
TI  - Genetic polymorphism of the renin-angiotensin system and organ damage in
      essential hypertension.
AB  - BACKGROUND: The renin-angiotensin-aldosterone system (RAAS) plays a significant
      role in the development of hypertensive cardiac and vascular remodeling.
      Recently, several genetic variants of its key components, which may be clinically
      relevant and thus prove to be useful in the evaluation of cardiovascular risk,
      have been described. We therefore investigated the association between ACE I/D,
      AGT M235T, and AT1 A1266C gene polymorphisms and early signs of target organ
      damage in 215 untreated patients with essential hypertension (EH). METHODS:
      Genotyping was based on the polymerase chain reaction technique, with further
      restriction analysis when required. Albuminuria was measured as the albumin-to
      creatinine ratio (ACR). The left ventricular mass index (LVMI) was assessed by
      echocardiography (LVH = LVMI > or = 125 g/m2), carotid wall thickness (IMT) by an
      ultrasonographic (US) scan, and retinal vascular changes by direct ophthalmoscopy
      (Keith-Wagener classification). RESULTS: The prevalence of microalbuminuria (Mi),
      LVH, and retinal vascular changes was 14, 46, and 74%, respectively. ACE, AGT,
      and AT1 genotype distribution was in agreement with the Hardy-Weinberg
      equilibrium. There was no difference in age, duration of disease, body mass index
      (BMI), blood pressure, and lipid profile when data were analyzed on the basis of
      genotype. Serum levels of angiotensin-converting enzyme (ACE) were related to the
      ACE genotype (10.2 +/- 0.5, DD; 8.2 +/- 0.3, ID; 6.5 +/- 0.4 IU/mL, II; P < 0.
      0001 by analysis of variance). The ACE genotype independently influences serum
      ACE levels and accounts for approximately 14% of its variations (F = 26.7, r2 =
      0.1393, df 1 to 214, P < 0.0001). Patients with DD and ID genotypes showed higher
      levels of ACR (1.59 +/- 0.2, DD + ID; 0.8 +/- 0.2 mg/mmol, II; P < 0.006 by
      ANOVA) and bigger LVMI (124.1 +/- 2.3, DD + ID vs. 117.8 +/- 3.6 g/m2, II; P <
      0.01 by ANOVA). No differences in the prevalence and degree of target organ
      damage (TOD) were found when data were analyzed on the basis of the AGT and AT1
      genotypes, respectively. Potentially unfavorable combinations of genotypes were
      also investigated by K-means cluster analysis. Two subgroups of patients were
      identified (cluster 1, N = 70; cluster 2, N = 57), and each differed
      significantly with regards to the presence and degree of TOD and patterns of RAAS
      gene polymorphisms (F, 15.97 for ACR; F, 7.19 for IMT; F, 217.03 for LVMI; F,
      3.91 for ACE; F, 4.06 for AGT; and F, 5. 22 for AT1; df 1 to 214, P < 0.02, for
      each one of the variables examined). CONCLUSION: The D allele of the ACE gene may
      be an independent risk factor for the development of target organ damage, and
      evaluating it could be useful for assessing cardiovascular risk in EH.
      Unfavorable patterns of RAAS genotypes seem to predispose patients to subclinical
      cardiovascular disease in EH.

PMID- 10652035
TI  - Anemia management of adult hemodialysis patients in the US results: from the 1997
      ESRD Core Indicators Project.
AB  - BACKGROUND: The Health Care Financing Administration's End-Stage Renal Disease
      (ESRD) Core Indicators Project collects clinical information on prevalent adult
      patients receiving in-center hemodialysis (HD) care in the United States to
      assess the quality of care delivered. Although hematocrit values, transferrin
      saturations, and iron prescription practices have improved over the last five
      years, we sought to determine whether continued opportunities for improvement of
      this domain of care exist. METHODS: A random sample of 7292 adult in-center HD
      patients was selected. Dialysis facility staff provided clinical information for
      the period of October through December 1996 for 6858 (94%) patients; complete
      laboratory information was available from 4991 (73%) returned forms. Hematocrit
      values, transferrin saturations, serum ferritin concentrations, epoetin alfa
      dosing, and iron prescriptions were abstracted from patient medical records to
      assess anemia management practices. RESULTS: The mean hematocrit for this cohort
      was 32.6 +/- 3.5%. Seventy-two percent of patients had hematocrit values> 30%.
      Forty-two percent had hematocrit values of 33 to 36%, and 10% were severely
      anemic (hematocrit <28%). Ninety-four percent of the patients received epoetin
      alfa intravenously (i.v.) and 6% subcutaneously. The mean weekly dose was 202.4
      +/- 137.2 units/kg. The mean transferrin saturation was 27.4 +/- 12.6%; 73% of
      patients had a mean transferrin saturation > or = 20%. The mean serum ferritin
      concentration was 386 +/- 422 ng/mL; 79 and 12% of patients had a serum ferritin
      concentration of> 100 and> 800 ng/mL, respectively. Nine percent of the sample (N
      = 434) had a transferrin saturation <20% and serum ferritin concentration <100
      ng/mL. Regardless of the patient's transferrin saturation, approximately three
      fourths of the patients received either oral or i.v. iron, and only approximately
      one half of the patients received i.v. iron. Of the subset of patients with
      transferrin saturation <20% and serum ferritin concentration <800 ng/mL, only 53%
      were prescribed intravenous iron. Multivariate linear regression analysis
      revealed that serum albumin, urea reduction ratio, age, and transferrin
      saturation were significantly positively associated with hematocrit. Epoetin alfa
      dose and serum ferritin concentration were significantly and negatively
      associated with the hematocrit (P < 0.001). CONCLUSION: Although substantial
      improvements have been made in anemia management for adult in-center HD patients
      over the past five years, significant opportunities persist to improve iron
      prescription practices.

PMID- 10652034
TI  - The angiotensin type II receptor tonically inhibits angiotensin- converting
      enzyme in AT2 null mutant mice.
AB  - BACKGROUND: Pharmacologic inhibition of the angiotensin-converting enzyme (ACE)
      limits angiotensin II (Ang II)-induced vasoconstriction and cellular
      proliferation. There is emerging evidence that some of the beneficial effects of
      ACE inhibitors may be endogenously available through the angiotensin receptor
      type 2 (AT2). METHODS: To evaluate whether AT2 modulates ACE activity, we used an
      high-performance liquid chromatography (HPLC)-based enzymatic assay in tissues
      from AT2 knockout mice (Agtr2-/y) and cultured cells. These studies were
      complimented by physiologic studies of pharmacologic inhibition of AT2. RESULTS:
      Circulating (C) and tissue ACE activities in heart (H), lung (L), and kidney (K)
      were doubled in Agtr2-/y mice compared with wild-type mice [162.9 +/- 17.6 mU/mL
      (C), 97.7 +/- 20.7 (H), 6282.1 +/- 508.3 (L), and 2295.0 +/- 87.0 (K) mU/g tissue
      for Agtr2-/y vs. 65.3 +/- 35.4 mU/mL (C), 44.5 +/- 8.7 (H), 3392.4 +/- 495.2 (L),
      and 1146.1 +/- 217.3 (K) mU/g tissue for wild-type mice, P < or = 0.05, 0.025,
      0.002, and 0.0001, respectively]. Acute pharmacologic inhibition of AT2 [PD123319
      (PD), 50 microg/kg/min, i. v.] significantly increased ACE activity in kidneys of
      wild-type mice (1591.2 +/- 104.4 vs. 1233.6 +/- 88.0 mU/g tissue in saline
      infused mice, P < 0.05; P < 0.01 vs. uninfused, wild-type mice). Moreover, ACE
      activity increased in A10 cells exposed to PD (10-6 mol/L) together with Ang II
      (10-7 mol/L), but not with an AT1 antagonist (losartan, 10-6 mol/L). This
      heightened ACE activity appears functionally relevant because infusion of
      angiotensin I caused more prompt hypertension in Agtr2-/y mice than in wild-type
      littermates. Likewise, infusion of bradykinin, also a substrate for ACE, caused
      significantly less hypotension in Agtr2-/y mice than controls. CONCLUSIONS: These
      studies indicate that AT2 functions to decrease ACE activity tonically, which
      may, in part, underlie AT2's increasingly recognized attenuation of AT1-mediated
      actions.

PMID- 10652036
TI  - Long-term effects of angiotensin-converting enzyme inhibition and metabolic
      control in hypertensive type 2 diabetic patients.
AB  - Long-term effects of angiotensin-converting enzyme inhibition and metabolic
      control in hypertensive type 2 diabetic patients. BACKGROUND: In hypertensive
      type 2 diabetic patients, treatment with angiotensin-converting enzyme (ACE)
      inhibitors is associated with a lower incidence of cardiovascular events than
      those treated with calcium channel-blocking agents. However, the long-term renal
      effects of ACE inhibitors in these patients remain inconclusive. In 1989, we
      commenced a placebo-controlled, double-blind, randomized study to examine the
      anti-albuminuric effects of enalapril versus nifedipine (slow release) in 102
      hypertensive, type 2 diabetic patients. These patients have been followed up for
      a mean trial duration of 5.5 +/- 2.2 years. We examined the determinants,
      including the effect of ACE inhibition on clinical outcomes in these patients.
      METHODS: After a six-week placebo-controlled, run-in period, 52 patients were
      randomized double-blind to receive nifedipine (slow release) and 50 patients to
      receive enalapril. After the one-year analysis, which confirmed the superior anti
      albuminuric effects of enalapril (-54%) over nifedipine (+11%), all patients were
      continued on their previously assigned treatment with informed consent. They were
      subdivided into normoalbuminuric (N = 43), microalbuminuric (N = 34), and
      macroalbuminuric (N = 25) groups based on two of three 24-hour urinary albumin
      excretion (UAE) measurements during the run-in period. Renal function was shown
      by the 24-hour UAE, creatinine clearance (CCr), and the regression coefficient of
      the yearly plasma creatinine reciprocal (beta-1/Cr). Clinical endpoints were
      defined as death, cardiovascular events, and/or renal events (need for renal
      replacement therapy or doubling of baseline plasma creatinine). RESULTS: In the
      whole group, patients treated with enalapril were more likely to revert to being
      normoalbuminuric (23.8 vs. 15.4%), and fewer of them developed macroalbuminuria
      (19.1 vs. 30.8%) compared with the nifedipine-treated patients (P < 0.05). In the
      microalbuminuric group, treatment with enalapril (N = 21) was associated with a
      13.0% (P < 0.01) reduction in 24-hour UAE compared with a 17.3% increase in the
      nifedipine group (N = 13). In the macroalbuminuric patients, enalapril treatment
      (N = 11) was associated with stabilization compared with a decline in renal
      function in the nifedipine group, as shown by the beta-1/Cr (0.65 +/- 4.29 vs. 
      1.93 +/- 2.35 1/micromol x 10-3, P < 0.05) after adjustment for baseline values.
      Compared with the normoalbuminuric and microalbuminuric patients, those with
      macroalbuminuria had the lowest mean CCr (75.5 +/- 24.1 vs. 63.5 +/- 21.3 vs.
      41.9 +/- 18.5 mL/min, P < 0.001) and the highest frequency of clinical events
      (4.7 vs. 5.9 vs. 52%, P < 0. 001). On multivariate analysis, beta-1/Cr (R2 =
      0.195, P < 0.001) was independently associated with baseline HbA1c (beta = 
      0.285, P = 0.004), whereas clinical outcomes (R2 = 0.176, P < 0.001) were
      independently related to the mean low-density lipoprotein cholesterol (beta =
      2.426, P = 0.018), high-density lipoprotein cholesterol (beta = -8.797, P =
      0.03), baseline UAE (beta = 0.002, P = 0.04), and mean CCr during treatment (beta
      = -0.211, P = 0.006). CONCLUSION: In this prospective cohort analysis involving
      102 hypertensive, type 2 diabetic patients with varying degrees of albuminuria
      followed up for a mean duration of five years, we observed the importance of good
      metabolic and blood pressure control on the progression of albuminuria and renal
      function. Treatment with enalapril was associated with a greater reduction in
      albuminuria than with nifedipine in the entire patient group, and especially in
      those with microalbuminuria. In the macroalbuminuric patients, the rate of
      deterioration in renal function was also attenuated by treatment with enalapril.

PMID- 10652037
TI  - Renoprotective effects of angiotensin II receptor blockade in type 1 diabetic
      patients with diabetic nephropathy.
AB  - BACKGROUND: Angiotensin I-converting enzyme (ACE) inhibitors reduce angiotensin
      II formation and induce bradykinin accumulation. Animal studies suggest that
      bradykinin may play a role for the effects of ACE inhibition on blood pressure
      and kidney function. Therefore, we compared the renal and hemodynamic effects of
      specific intervention in the renin-angiotensin system by blockade of the
      angiotensin II subtype-1 receptor to the effect of ACE inhibition. METHODS: A
      randomized, double-blind, cross-over trial was performed in 16 type 1 diabetic
      patients (10 men), age 42 +/- 2 years (mean +/- SEM). The study consisted of five
      periods, each lasting two months. The patients received losartan 50 mg, losartan
      100 mg, enalapril 10 mg, enalapril 20 mg, and placebo in random order. At the end
      of each period, albuminuria, 24-hour blood pressure, and glomerular filtration
      rate (GFR) were determined. RESULTS: Both doses of losartan and enalapril reduced
      albuminuria (P < 0.05) and mean arterial blood pressure (MABP; P < 0.05), whereas
      GFR remained stable. Albuminuria was reduced by 33% (95% CI, 12 to 51) on
      losartan 50 mg, 44% (95% CI, 26 to 57) on losartan 100 mg, 45% (95% CI, 23 to 61)
      on enalapril 10 mg, and 59% (95% CI, 39 to 72) on enalapril 20 mg, and MABP fell
      by 9 +/- 2, 8 +/- 2, 6 +/- 3, and 11 +/- 3 mm Hg (mean +/- SEM), respectively. No
      significant differences were found between the effects of losartan 100 mg and
      enalapril 20 mg. HbA1C and sodium intake remained unchanged throughout the study,
      whereas a significant rise in serum potassium occurred during ACE inhibition.
      CONCLUSION: The angiotensin II subtype 1 receptor antagonist, losartan, reduces
      albuminuria and MABP similar to the effect of ACE inhibition. These results
      indicate that the reduction in albuminuria and blood pressure during ACE
      inhibition is primarily caused by interference in the renin-angiotensin system.
      Our study suggest that losartan represents a valuable new drug in the treatment
      of hypertension and proteinuria in type 1 diabetic patients with diabetic
      nephropathy.

PMID- 10652038
TI  - Potassium-magnesium citrate versus potassium chloride in thiazide-induced
      hypokalemia.
AB  - BACKGROUND: The purpose of this study was to compare the value of potassium
      magnesium citrate (KMgCit) with potassium chloride in overcoming thiazide-induced
      hypokalemia. METHODS: Sixty normal subjects first took hydrochlorothiazide (HCTZ;
      50 mg/day). After three weeks of treatment (or earlier if hypokalemia developed),
      they were randomized to take KMgCit (42 mEq K, 21 mEq Mg, and 63 mEq citrate/day)
      or potassium chloride (42 mEq/day) for three weeks while continuing on HCTZ.
      RESULTS: KMgCit significantly increased the serum potassium concentration from
      3.42 +/- 0.30 mEq/L on HCTZ alone to about 3.8 mEq/L (P < 0.001). Potassium
      chloride produced a similar increase in serum potassium concentration from 3.45
      +/- 0.44 mEq/L to about 3.8 mEq/L (P < 0. 001). KMgCit significantly increased
      the serum magnesium concentration by 0.11 to 0.12 mEq/L (P < 0.01), whereas
      potassium chloride produced a marginal decline or no significant change. KMgCit
      was less effective than potassium chloride in correcting HCTZ-induced
      hypochloridemia and hyperbicarbonatemia. KMgCit, but not potassium chloride,
      significantly increased urinary pH (by about 0.6 unit), citrate (by about 260
      mg/day), and urinary magnesium. CONCLUSIONS: KMgCit is equally effective as
      potassium chloride in correcting thiazide-induced hypokalemia. In addition,
      KMgCit, but not potassium chloride, produces a small but significant increase in
      serum magnesium concentration by delivering a magnesium load, and it confers
      alkalinizing and citraturic actions.

PMID- 10652039
TI  - Clonal spread of staphylococci among patients with peritonitis associated with
      continuous ambulatory peritoneal dialysis.
AB  - BACKGROUND: Peritonitis is the most important complication of continuous
      ambulatory peritoneal dialysis (CAPD). Coagulase-negative staphylococci (CNS) are
      the most common causes of peritonitis, only limited information is available
      regarding the distribution and epidemiology of different CNS species associated
      with CAPD peritonitis. METHODS: CNS isolated from dialysis effluent from CAPD
      patients with peritonitis was identified by species and further analyzed with
      pulsed-field gel electrophoresis (PFGE). RESULTS: A total of 216 microorganisms
      (206 bacteria and 10 Candida species) were isolated from 196 consecutive culture
      positive CAPD samples obtained from 75 patients. One hundred and twenty-one (56%)
      isolates represented staphylococci. The four most frequently isolated
      staphylococcal species were Staphylococcus epidermidis (70 isolates),
      Staphylococcus aureus (31 isolates), Staphylococcus hemolyticus (10 isolates),
      and Staphylococcus hominis (4 isolates). PFGE analysis revealed the clonal spread
      among patients of three different clones of S. epidermidis and one clone of S.
      aureus among the investigated patients. Indistinguishable isolates of either S.
      epidermidis, S. hominis, or S. aureus were also isolated in repeated samples from
      several patients. CONCLUSION: PFGE is a useful method for the epidemiological
      evaluation of staphylococci-associated CAPD infections and should replace older
      and less accurate methods, such as antibiotic sensitivity patterns. We recommend
      that CNS isolates from patients with CAPD-associated peritonitis should be saved
      for future investigations and typing, which would aid in the management of this
      patient category.

PMID- 10652041
TI  - Association of plasminogen activator inhibitor-1 4G/4G genotype and type 2
      diabetic nephropathy in Chinese patients.
AB  - BACKGROUND: Plasminogen activator inhibitor-1 (PAI-1) is a key regulator of
      fibrinolytic pathway and extracellular matrix (ECM) turnover. Because diabetic
      nephropathy is characterized by the presence of basement membrane thickening and
      mesangial expansion, we examined the role of PAI-1 gene polymorphisms in the
      development of type 2 diabetic nephropathy. Evidence also suggested that the
      PA/plasmin system and the renin-angiotensin system (RAS) interact together to
      affect the risk of fibrosis and thrombosis. Hence, we also studied the
      synergistic effect between PAI-1 and angiotensin-converting enzyme (ACE) gene
      polymorphisms. METHODS: The PAI-1 and ACE (D/I) gene polymorphisms were examined
      in a cohort of Chinese type 2 diabetic patients who had diabetes for an average
      of 14 years. These patients were sex and age matched. Group A (N = 46) consisted
      of patients without diabetic nephropathy (normoalbuminuric with creatinine <120
      micromol/L), and group B (N = 95) was with diabetic nephropathy (with albuminuria
      or renal impairment, including patients on dialysis). RESULTS: Patients with type
      2 diabetic nephropathy had a higher frequency of PAI-1 (4G/4G) genotypes than
      those without nephropathy [4G/4G:4G/5G:5G/5G = 41:38:21 (%) vs. 15:65:20(%), P =
      0.005]. Diabetic patients with coexistence of PAI-1 4G/4G genotype and ACE D
      alleles had a higher incidence of diabetic nephropathy (22 vs. 7%, P = 0.012)
      than those with other combinations of genotypes. Multivariate logistic regression
      analysis showed that PAI-1 4G/4G (P = 0.01) and the prevalence of hypertension (P
      < 0.0001) are independent risk factors of development of type 2 diabetic
      nephropathy. CONCLUSIONS: These results suggest that the PAI-1 4G/4G genotype is
      associated with an increased risk for type 2 diabetic nephropathy in Chinese
      patients, which is an independent risk factor for the development of nephropathy.
      The PAI-1 4G/4G genotype also exhibits a synergistic effect with the ACE D allele
      on development of diabetic nephropathy.

PMID- 10652040
TI  - Expression of heat shock proteins 47 and 70 in the peritoneum of patients on
      continuous ambulatory peritoneal dialysis.
AB  - BACKGROUND: Peritoneal sclerosis, characterized by collagen accumulation, is a
      serious complication in continuous ambulatory peritoneal dialysis (CAPD) therapy.
      Heat shock protein 47 (HSP47) is a collagen-specific molecular chaperon and is
      closely associated with collagen synthesis. METHODS: We determined the expression
      of HSP47 and HSP70 (nonspecific for collagen synthesis) by immunohistochemistry
      in peritoneal tissues of patients on CAPD. The tissue for collagen III, alpha
      smooth muscle actin (alpha-SMA), and CD68 (a marker for macrophages) were also
      stained. Thirty-two peritoneal samples were divided into three groups (group A1,
      11 patients who had no ultrafiltration loss; group A2, 9 patients who had
      ultrafiltration loss; and group B, 12 specimens who had end-stage renal disease
      prior to induction of CAPD. RESULTS: In group B, staining for HSP47, HSP70, and
      collagen III in peritoneal tissues was faint, and only a few cells were positive
      for alpha-SMA and CD68. In contrast, HSP47, HSP70, and collagen III were
      expressed in areas of thickened connective tissues in fibrotic peritoneal
      specimens of CAPD patients. The expression level of HSP47, HSP70, collagen III,
      and alpha-SMA and the number of CD68-positive cells in group A2 were
      significantly higher than those in groups A1 and B. HSP47/HSP70-positive cells
      were mesothelial cells, adipocytes, and alpha-SMA-positive myofibroblasts.
      Furthermore, the expression level of HSP47 was significantly higher in peritoneal
      specimens from patients with refractory peritonitis than without it and was
      significantly higher in patients with more than 60 months of CAPD therapy than
      that in patients with less than 60 months of CAPD. CONCLUSION: Our results
      indicate that CAPD therapy may induce HSPs in the peritoneal tissue, and that
      peritonitis in CAPD patients may be associated with the progression of peritoneal
      sclerosis at least through HSP47 expression and chronic macrophage infiltration.
      Our data also suggest that the progression of peritoneal sclerosis in such
      patients is associated with deterioration of peritoneal ultrafiltration function.

PMID- 10652042
TI  - Determinants of type and timing of initial permanent hemodialysis vascular
      access.
AB  - BACKGROUND: We undertook a population-based study of hemodialysis (HD) patients
      to determine which factors are important in predicting the type of permanent
      access initially placed and if a functional permanent access is in place at the
      start of HD. METHODS: Selected characteristics were abstracted from the United
      States Renal Data System (USRDS) Dialysis Morbidity and Mortality Study (DMMS)
      Wave 2. Logistic regression was used to estimate the independent contribution of
      specific characteristics in predicting whether the initial permanent access
      placed was an arteriovenous (AV) fistula compared with a polytetrafluoroethylene
      (PTFE) graft, and in predicting whether permanent access (fistula or graft) was
      in place at the initiation of dialysis. RESULTS: Sixty-seven percent of the
      patients had an AV graft placed as their first permanent access. Characteristics
      important in predicting if a fistula was initially placed included age (per
      decade; aOR = 0.84, P < 0.001), female gender (aOR = 0.52, P < 0.001), body mass
      index (per standard deviation; aOR = 0.70, P = 0.09), avoiding blood draws (aOR =
      1.96, P < 0.001), ability to ambulate (aOR = 2.24, P = 0.008), underlying renal
      disease (glomerular compared with diabetes, aOR = 2.19, P = 0.009), college
      education (aOR = 1.72, P = 0.002), and sharing in decision making (aOR = 1.50, P
      = 0.02). Thirty-four percent of patients (34.4%) had functional permanent access
      at the start of HD. Characteristics important in predicting which patients had
      functional permanent access included serum albumin (per 1 mg/dL increase, aOR
      =1.55, P = 0.003), erythropoietin prior to starting HD (aOR = 1.79, P = 0.002),
      fewer predialysis nephrologist visits (aOR = 0.21, P < 0.001), and when the
      patient was told they had renal disease (aOR = 0.33, P = 0.002). CONCLUSIONS:
      PTFE grafts were the most common initial permanent access. The majority of
      patients did not have permanent access at the start of dialysis. Factors that are
      thought to compromise identification of adequate veins were important predictors
      of PTFE graft placement. Permanent access at the start of HD was largely a
      function of early patient education and early referral to a nephrologist.

PMID- 10652044
TI  - alpha-galactosyl epitopes on glycoproteins of porcine renal extracellular matrix.
AB  - BACKGROUND: The pig is the donor animal of choice for human xenotransplantation.
      In the most relevant pig-to-baboon model, pig organs transplanted into baboons
      are hyperacutely rejected by natural xenoantibodies, which mainly bind to alpha
      galactosyl (alphaGal) epitopes expressed at the surface of endothelial cells.
      Recent advances in controlling hyperacute rejection have led to improved survival
      of these xenografts, and it is now important to identify alphaGal binding sites
      in other cells and tissues that may be subject to immunologic attack. To this
      end, we have studied whether alphaGal antibodies bind to glycated proteins of the
      extracellular matrix in the kidney and other organs most likely to be used for
      human xenotransplantation. METHODS: High-titer anti-alphaGal antibodies, similar
      to human natural xenoantibodies, were prepared in baboons, and their reactivity
      with components of pig extracellular matrix was tested by serology and
      immunohistology. RESULTS: The antibodies recognized epitopes of immobilized
      murine, bovine or porcine thyroglobulin, laminin, heparan sulfate proteoglycans,
      and fibronectin. In sections of pig tissue, the antibodies bound to endothelial
      and certain epithelial cells, as shown in previous studies, and also to
      mesenchymal cells, basement membranes, and extracellular matrices, in which they
      colocalized with matrix glycoproteins, especially laminin and heparan sulfate
      proteoglycans. CONCLUSIONS: These results suggest that when pig xenografts can be
      made to survive for prolonged periods, the reactivity of alphaGal antibody with
      matrix molecules can induce basement membrane and matrix lesions similar to those
      induced in laboratory animals by antilaminin and antiheparan sulfate
      proteoglycans antibodies.

PMID- 10652043
TI  - Recombinant human insulin-like growth factor-1 induces an anabolic response in
      malnourished CAPD patients.
AB  - BACKGROUND: Insulin-like growth factor-1 (IGF-1) is an anabolic hormone that
      mediates most of the growth effects of growth hormone. This study tested the
      hypothesis that recombinant human IGF-1 (rhIGF-1) will induce an anabolic
      response in malnourished patients undergoing continuous ambulatory peritoneal
      dialysis (CAPD). METHODS: Six CAPD patients with protein-energy malnutrition
      underwent nitrogen balance studies in a clinical research center for 35 days
      each. Throughout the study, patients were maintained on their same CAPD regimen
      prior to hospitalization, and were fed a constant protein and energy intake that
      was similar to their diet prior to hospitalization. The first 15 hospital days
      were a baseline period; during the subsequent 20-day period, patients were given
      subcutaneous injections of rhIGF-1 (100 microg/kg/12 h), except for one patient
      who received 50 microg/kg/12 h for the first five days, followed by 100
      microg/kg/12 h for the following 15 days. RESULTS: During the treatment with
      rhIGF-1, serum IGF-1 increased by about 100% (P = 0.03), and nitrogen balance
      became strongly positive (+2.0 g/day, P = 0.015 vs. baseline). This anabolic
      effect was observed within hours after commencing the rhIGF-1 treatment and was
      largely caused by a 20% decrease in peritoneal dialysate effluent nitrogen. There
      was a proportionate reduction in urine nitrogen and serum urea nitrogen. This
      decrease in nitrogen output was sustained during the entire 20 day of treatment
      with rhIGF-1. Serum phosphorus decreased significantly during the first several
      days of rhIGF-1 treatment, whereas serum calcium increased significantly during
      the rhIGF-1 treatment. Serum potassium and albumin did not change during the
      rhIGF-1 injections. There was no change in body weight and body composition, as
      assessed by anthropometry during the baseline or treatment phases of the study.
      Some patients exhibited minor possible adverse events that included a reduction
      in blood pressure and transient tachycardia. CONCLUSION: Injections of rhIGF-1
      induce a strong and sustained anabolic effect, as indicated by a positive
      nitrogen balance in CAPD patients with protein-energy malnutrition. rhIGF-1
      administration may be an effective method for treating malnutrition in
      maintenance dialysis patients.

PMID- 10652045
TI  - Increased plasma adrenomedullin levels in hemodialysis patients with sustained
      hypotension.
AB  - BACKGROUND: Sustained hypotension in end-stage renal disease patients is
      characterized, despite an overactivation of the sympathetic and renin-angiotensin
      systems, by decreased vascular resistance and a blunted vascular response to
      pressor stimuli. An increased production of one or more vasodilator substances
      might play a role in the reduced vascular resistance and response to pressor
      stimuli in these patients. We evaluated the possible role of an increased
      production of nitric oxide and/or adrenomedullin (ADM) in the pathophysiology of
      chronic hypotension in hemodialysis (HD) patients. METHODS: Three groups of
      hypotensive (N = 9), normotensive (N = 10), and hypertensive (N = 9) HD patients
      were included in the study. Plasma renin activity (PRA) and plasma levels of
      catecholamines, ADM, nitrite/nitrate (an estimator of nitric oxide production),
      tumor necrosis factor (TNF), and interleukin-1beta (IL-1beta) were measured.
      Plasma volume and left ventricular ejection fraction (LVEF) were also evaluated.
      RESULTS: Plasma levels of nitrite/nitrate and ADM were elevated in HD patients
      with respect to the reference values in normal subjects. Plasma ADM levels, but
      not nitrite/nitrate levels, were higher in hypotensive (368.1 +/- 25.4 pg/mL)
      than normotensive (225 +/- 9.9 pg/mL) and hypertensive HD patients (278.2 +/-
      15.5 pg/mL, P < 0.01). When considering hypotensive and normotensive patients
      together, the mean blood pressure inversely correlated with time on HD (r = -0.
      53, P < 0.05) and plasma ADM levels (r = -0.78, P < 0.01). CONCLUSIONS: Plasma
      ADM and nitrite/nitrate levels are increased in HD patients, but only ADM levels
      were higher in hypotensive than in normotensive and hypertensive HD patients. The
      higher plasma levels of this peptide in hypotensive patients and its inverse
      correlation with mean arterial pressure suggest that ADM may be involved in the
      pathophysiology of chronic hypotension in HD patients.

PMID- 10652046
TI  - Pretransplantation assessment of renal viability with NADH fluorimetry.
AB  - BACKGROUND: A pathophysiologic feature possibly involved in ischemic injury in
      transplant kidneys is mitochondrial dysfunction caused by disintegration of
      oxidative metabolic pathways. Because the ability to synthesize ATP by
      respiratory activity determines the organ's capacity to recover from ischemic
      injury, an assessment of respiratory activity may provide information related to
      graft viability. METHODS: NADH fluorimetry can be used to monitor kidney cortex
      metabolism noninvasively. During perfusion with (an)-aerobic perfusate, NADH
      fluorescence images were recorded. We evaluated the NADH oxidation kinetics of 20
      rat kidneys, which were divided over four experimental groups. For six minimally
      damaged kidneys and six kidneys that had been stored for one hour at 37 degrees
      C, perfusion was followed by transplantation. We related the kinetic parameters
      of these kidneys with their post-transplantation function and histology. The
      transplant function was monitored by serum creatinine and urea levels. RESULTS:
      Storage of transplant kidneys for one hour at 37 degrees C significantly reduced
      the post-transplantation function. Isolated perfusion of grafts, however, was not
      detrimental for renal function. The rate of NADH oxidation decreased with
      decreasing graft quality, and a good correlation between NADH oxidation kinetics
      and post-transplantation function was found. CONCLUSIONS: A reduction of NADH
      oxidation rates as a consequence of warm ischemia supports the view that
      mitochondrial respiratory activity is impaired by ischemic injury. The
      correlation between NADH oxidation kinetics in perfused grafts and their post
      transplantation function indicates that NADH fluorimetry may be useful in
      predicting the viability of preserved grafts prior to transplantation.

PMID- 10652047
TI  - Pamidronate therapy as prevention of bone loss following renal transplantation.
AB  - BACKGROUND: Very rapid bone loss, osteopenia and skeletal morbidity after renal
      transplantation have been well documented and found to occur in a sex dependent
      fashion. Glucocorticoids, cyclosporine and pre-existing uremic osteodystrophy
      have been implicated in the pathogenesis of the skeletal lesions. Glucocorticoid
      induced osteopenia is also a serious clinical problem in patients with various
      nonrenal diseases and can be prevented, or at least attenuated, by pamidronate
      and other bisphosphonates. METHOD: We prospectively studied 26 male patients
      undergoing renal transplantation, and randomized them to receive either placebo
      or intravenous pamidronate (0.5 mg/kg) at the time of transplantation and again
      one month later. All patients received immunosuppression comprising prednisolone,
      cyclosporine and azathioprine. The bone mineral density (BMD) of the second,
      third and fourth lumbar vertebrae and of the femoral neck was measured at the
      time of transplantation and at three months and 12 months after transplantation
      using dual energy X-ray absorptiometry (DXA). RESULTS: Twelve months after
      transplantation, the mean (+/- SEM) BMD of the lumbar vertebrae in patients who
      received placebo had decreased 6.4% (P < 0.05). In contrast, patients who
      received pamidronate experienced no significant reduction of BMD at the lumbar
      vertebrae. At the femoral neck, placebo-treated patients showed a reduction of
      BMD of 9% (P < 0.005), whereas there was no significant change in the pamidronate
      treated group. The two study groups had similar patient profiles, serum
      parathyroid hormone (PTH) and aluminium concentrations. After transplantation,
      comparable falls in the serum creatinine and PTH concentration were found in the
      two groups. Apart from transient hypocalcemia in two patients, no significant
      adverse effects of pamidronate were noted. CONCLUSION: This study has shown that
      the early rapid bone loss that occurs in men during the first 12 months after
      renal transplantation can be prevented by two intravenous doses of pamidronate
      given at transplantation and one month later. The regimen was simple to
      administer, well tolerated and potentially applicable to other clinical groups of
      glucocorticoid treatment patients.

PMID- 10652048
TI  - Preservation of glomerular filtration rate on dialysis when adjusted for patient
      dropout.
AB  - BACKGROUND: Residual renal function (RRF) plays an important role in dialysis
      patients. Studies in patients on maintenance dialysis suggest that RRF is better
      preserved in patients receiving peritoneal dialysis (PD) vis-a-vis those
      receiving hemodialysis (HD). We speculated that regardless of the patient's type
      of therapy, the estimate obtained for the rate of decline in glomerular
      filtration rate (GFR) may be biased because of informative censoring associated
      with patient dropout. Informative censoring occurs when patients who die or
      transfer to another modality very early have associated with them a lower
      starting GFR or a higher rate of decline of GFR than patients who either complete
      the study or who die or transfer much later. If patient dropout is indeed related
      to the rate of decline in GFR and if this relationship is ignored in the
      analysis, then the estimate obtained of the rate of decline in GFR may be biased.
      METHODS: In an attempt to determine if there is a relationship between patient
      dropout and the decline in GFR, we reanalyzed the CANUSA data by modeling GFR as
      a nonlinear function of time with the rate of decline being exponential. RESULTS:
      This article highlights the significance of "informative censoring" when studying
      the decline of RRF on dialysis. The results show that for the CANUSA cohort, the
      mean initial GFR was significantly lower, and the rate of decline was
      significantly higher for patients who died or transferred to HD than for patients
      who were randomly censored or received a transplant. It is important to emphasize
      that the impact of informative censoring on previous analyses of the decline of
      RRF between PD versus HD is presently unclear. If bias caused by informative
      censoring is the same regardless of what therapy a patient is on, then
      conclusions from previous studies comparing the decline in GFR between PD and HD
      would still be valid. However, if the magnitude of the bias differs according to
      therapy, then additional adjustments would be needed to fairly compare the
      decline in GFR between PD and HD. Because this analysis is restricted to patients
      on PD, it would be scientifically incorrect to interpret previous studies solely
      on the basis of the results from this analysis. CONCLUSION: In any longitudinal
      study designed to estimate trends in an outcome measured over time, it is
      important that the analysis of the data takes into account any effect patient
      dropout may have on the estimated trend. This analysis demonstrates that among PD
      patients, both the starting GFR and the rate of decline in GFR are associated
      with patient dropout. Consequently, future studies aimed at estimating the rate
      of decline in GFR among PD patients should also account for any dependencies
      between dropout and GFR. Similarly, data analyzing for apparent differences in
      the rate of decline of GFR between PD and HD should also adjust for possible
      informative censoring.

PMID- 10652049
TI  - Transforming growth factor-beta is involved in the pathogenesis of dialysis
      related amyloidosis.
AB  - BACKGROUND: Advanced glycation end product-modified beta2-microglobulin (AGE
      beta2m) is an important component of dialysis-related amyloidosis (DRA). Its
      presence induces monocyte chemotaxis and the release of the proinflammatory
      cytokines through macrophage activation. Transforming growth factor-beta (TGF
      beta) is a multifunctional cytokine that also has chemotactic activity for
      monocytes at very low (0.1 to 10 pg/mL) concentrations and inhibits
      proinflammatory cytokine production of macrophages. In this study, we
      investigated the role of TGF-beta in the pathogenesis of DRA. METHODS: We
      performed an immunohistochemical study of DRA tissues (8 cases) to confirm the
      existence of TGF-betas and their receptors; we also performed a chemotaxis assay
      of human monocytes as well as enzyme-linked immunosorbent assay (ELISA) of TGF
      beta1, tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and
      interleukin-1 receptor antagonist (IL-1Ra) in the supernatant of human monocyte
      derived macrophage cell culture under varying conditions of incubation with TGF
      beta1, AGE-beta2m, and TGF-beta1 antibody additions. RESULTS: There was positive
      staining for TGF-betas (types 1, 2, and 3) and their receptors (types I, II, and
      III) in infiltrated macrophages (CD68+), synovial lining cell, as well as
      vascular walls around amyloid deposition. AGE-beta2m also induced TGF-beta1
      production by macrophages in a dose-dependent manner (410 +/- 80 pg/mL at 12.5
      microg/mL, 621 +/- 62 pg/mL at 25 microg/mL, and 776 +/- 62 pg/mL at 50 microg/mL
      of AGE-beta2m). AGE-beta2m induced significant TNF-alpha and IL-1Ra production by
      macrophage. The addition of exogenous TGF-beta1 (0.1 to 10 ng/mL) decreased AGE
      beta2m-induced TNF-alpha production and increased IL-1Ra production in a dose
      dependent fashion. IL-1beta production was not effected by any experimental
      conditions. In chemotaxis assay, anti-TGF-beta1 antibody (0.1 to 10 microg/mL)
      attenuated AGE-beta2m-induced monocyte chemotaxis. CONCLUSIONS: These results
      provide the first evidence to our knowledge for the presence of TGF-beta in DRA
      tissue, as well as the stimulatory action of AGE-beta2m on tissue macrophages. In
      turn, TGF-beta suppresses the proinflammatory activation of macrophages,
      suggesting a dual role for TGF-beta in the inflammatory process of DRA. These
      observations may provide a pathophysiologic link between TGF-beta and DRA.

PMID- 10652050
TI  - Adoptive transfer of nuclear factor-kappaB-inactive macrophages to the
      glomerulus.
AB  - BACKGROUND: Macrophages have been regarded as "blackguards" in the generation of
      glomerular injury. However, it is still unclear what kind of cellular machinery
      is responsible for their pathogenic actions. To explore this issue, this
      investigation aims at developing a novel strategy using adoptive transfer of
      "loss-of-function" macrophages to the glomerulus. As a prototypal investigation,
      this study examines a role for nuclear factor-kappaB (NF-kappaB) in effector
      actions of macrophages within the glomerular microenvironment. METHODS: NF-kappaB
      inactive macrophages, NIKMACNR, were created by transduction of NR8383 rat
      macrophages with retrovirus encoding a super-repressor mutant of IkappaBalpha,
      IkappaBalphaM. The effector functions of NIKMACNR cells on resident cells were
      evaluated by coculture, cross-feeding, and in vivo macrophage transfer. RESULTS:
      Rat mesangial cells cocultured with control macrophages showed abundant
      expression of activation markers, including monocyte chemoattractant protein-1,
      stromelysin, and gelatinase B. In contrast, coculture with NIKMACNR macrophages
      induced only modest gene expression. Similarly, culture medium conditioned by
      activated, control macrophages triggered mesangial cells and isolated glomeruli
      to express the activation markers, whereas the stimulatory effect was not
      observed in medium conditioned by NIKMACNR macrophages. To evaluate effector
      actions of NIKMACNR macrophages in the glomerulus, control macrophages and
      NIKMACNR cells were transferred into normal rat glomeruli via renal artery
      injection. After the transfer of control macrophages, substantial induction of
      the activation marker stromelysin was observed in resident glomerular cells. This
      induction was dramatically diminished in the glomeruli transferred with NIKMACNR
      macrophages. CONCLUSIONS: Inactivation of NF-kappaB in macrophages effectively
      disrupted paracrine, stimulatory loops from macrophages to resident glomerular
      cells. A combination of "loss-of-function" strategies with the technique for
      adoptive cell transfer is thus useful to explore pathophysiologic roles for
      certain machinery of macrophages within the glomerulus.

PMID- 10652051
TI  - Quantitation of mRNA expression in glomeruli using laser-manipulated
      microdissection and laser pressure catapulting.
AB  - BACKGROUND: Laser-manipulated microdissection (LMM) is a method to cut out a
      single cell or limited tiny region from a specimen under microscopic observation
      by a laser beam. Laser pressure catapulting (LPC) is a method to push up and
      collect samples that were microdissected using a strong laser. METHODS: To induce
      experimental glomerulonephritis, anti-Thy1.1 monoclonal antibody (OX-7) was
      injected intravenously into rats. Control and disease model kidneys were
      obtained. Six-micrometer thick cryostat sections were mounted onto a 1.35 microm
      thin polyethylene membrane. Ten glomeruli were collected from 6 microm frozen
      sections of rat kidney by LMM and LPC. Isolated glomeruli were used to quantitate
      the expression of mRNA by real-time polymerase chain reaction (PCR). RESULTS:
      Transforming growth factor-beta1 (TGF-beta1) mRNA was not detected in glomeruli
      isolated by the LMM and the LPC methods on day 0, although G3PDH mRNA was
      measurable in the same samples. On day 7 after the treatment with OX-7, the ratio
      of TGF-beta1/G3PDH mRNA was 1.89 +/- 0.96 (N = 6). CONCLUSIONS: We established
      methods to isolate glomeruli from standard histochemical specimens by LMM and
      LPC, and to quantify mRNA expression in the targeted glomeruli using real-time
      PCR. We confirmed the up-regulation of TGF-beta1 mRNA expression in isolated
      glomeruli from frozen sections of the anti-Thy1.1 glomerulonephritis model.

PMID- 10652052
TI  - High blood pressure and the kidney: the forgotten contribution of William
      Senhouse Kirkes.
AB  - The realization of the key role for raised intra-arterial pressure as a
      pathogenetic agent in hypertension is usually credited to Ludwig Traube, but
      Traube in his writings gives credit for the idea to a little-known English
      doctor, William Senhouse Kirkes (1822-1864). Kirkes' main interest was in
      cardiology and vascular disease, and he gave the first account of embolism from
      vegetations in infective endocarditis in 1852. Three years later, he published a
      study of apoplexy in Bright's disease, in which he pointed clearly to the role of
      raised intra-arterial tension in the causation of arterial disease, a point that
      had eluded Bright, Johnson, and other contemporaries. Kirkes died at the age of
      only 42 while working on a book summarizing his work on cardiology and renal
      disease, and the neglect of his contribution probably resulted from his early
      death. We have traced his life history from the few available records; as a boy,
      Kirkes was apprenticed to become a surgeon and only later trained as a physician.
      We place his contributions within the setting of the development during the 19th
      century of understanding of the relationship between the kidney, vascular
      disease, and high blood pressure.

PMID- 10652053
TI  - Preventing bone loss after renal transplantation with bisphosphonates: we can...
      but should we?

PMID- 10652055
TI  - In this issue

PMID- 10652054
TI  - Recapitulation of phylogeny by ontogeny in nephrology.

PMID- 10652056
TI  - Medical education comes of age.

PMID- 10652057
TI  - Teaching the teachers.

PMID- 10652058
TI  - Medical students, drugs and alcohol: time for medical schools to take the issue
      seriously.

PMID- 10652059
TI  - Medical service increment for teaching (SIFT): not an anachronism but essential
      to promote quality in medical education.

PMID- 10652060
TI  - Evaluating the outcome of communication skill teaching for entry-level medical
      students: does knowledge of empathy increase?
AB  - BACKGROUND: While the literature shows the clinical value for medical
      practitioners of skill in communicating with patients in an empathetic manner,
      objective evaluations of methods to teach empathy are few. PURPOSES: This paper
      describes a method of teaching entry-level medical students the elements of
      effective communication with patients, in preparation for their first practical
      exercises. The paper focuses on how the outcomes of the teaching were evaluated
      with special attention to empathy. METHODS: Student evaluative ratings were
      collected after training, and students also completed a pencil-and-paper test of
      empathy, both before and after the training. While all data were anonymous,
      student pre- and post-training empathy scores could be compared to assess
      individual changes in knowledge of empathy after training. RESULTS: Most students
      (81%) felt better prepared to interview after the training. The pencil-and-paper
      measure of empathy has good reliability, both internal (alpha 0.83 and 0.91) and
      inter-rater (kappa 0.96). Overall, students made significant gains in their
      ability to make empathetic responses, although some (30%) showed no gains.
      CONCLUSIONS: Further research is required to identify students who fail to
      acquire skill in expressing empathy after undergoing training, and to validate
      the pencil-and- paper measure of empathy against real-life performance.

PMID- 10652061
TI  - Undergraduate projects - do they have to be within the conventional medical
      environment?
AB  - OBJECTIVES: Undergraduate medical curricula now include increasing amounts of
      project work aimed at developing skills related to lifelong learning. One course
      allows students to choose from a wide range of projects, including 'conventional'
      hospital specialties and also from topics outside the mainstream of medicine.
      DESIGN: 'Conventional' and 'external' projects were compared in terms of the
      prior academic abilities of the students undertaking them, the assessment results
      and student and supervisor feedback, in order to consider whether the
      unconventional projects were equally valid within the undergraduate medical
      curriculum. SETTING: School of Medicine, University of Leeds, UK. SUBJECTS:
      Medical students. RESULTS: No difference between the assessment results of the
      student groups was present, with over 85% of all students reaching a standard of
      'excellent' or 'good' in their overall final grade. There was no difference in
      prior academic abilities between the student groups. Enjoyment of modules was
      comparable between student groups ('conventional' 89%, 'external' 93%) with good
      levels of satisfaction with the quality of supervision. There were no differences
      in students' self-appraisal of generic skill acquisition. Students who had
      undertaken 'external' projects felt they had gained less experience in data
      handling and problem-solving skills. However, 'external' projects were rated
      higher by students in terms of having realistic and achievable objectives, and
      the supervisors of these projects were also more realistic about time commitments
      involved in project supervision. CONCLUSIONS: 'External' modules were very
      popular, with over 45% of students requesting places which were available for
      fewer than 20% of students per year. Concerns regarding the appropriateness of
      self-directed undergraduate medical student projects outside the mainstream of
      medical practice were unfounded.

PMID- 10652062
TI  - Student perceptions of a new integrated course in clinical methods for medical
      undergraduates.
AB  - CONTEXT: In line with recent General Medical Council recommendations a new, 8
      week integrated course in clinical methods has been introduced into the
      undergraduate curriculum at Leicester University. OBJECTIVES: To describe student
      perceptions of the course and to identify areas for improvement. DESIGN: A
      questionnaire survey. SETTINGS: These were 50 general practices, three teaching
      hospitals and the academic Department of General Practice and Primary Health
      Care. SUBJECTS: A total of 180 third- and fourth-year medical students. RESULTS:
      The questionnaires were completed by 93% of students. The latter expressed higher
      satisfaction with practice teaching compared with hospital teaching, on a 5-point
      scale, with regard to questions on 'teaching content' (4.0 vs. 2.7, P < 0.0001)
      and 'teaching process' (4.1 vs. 2.7 P < 0.0001), which was reinforced by free
      text comments. Of the respondents, 92% agreed that their teaching practice had
      satisfied the required teaching timetable and 87% of students found their
      departmental tutor enthusiastic and stimulating. CONCLUSION: It is possible to
      deliver an integrated course in clinical methods, teaching generic clinical
      skills, in a mix of hospital and practice settings. Nevertheless there were
      substantial differences in student perceptions of the relative quality and impact
      of teaching in the two settings. This may be related to the more detailed
      programme of preparation of practice teachers and the greater extent to which
      practice teachers were required, and able, to create protected time for the
      teaching task. These differences should be minimized if hospital teachers undergo
      similar preparation for the teaching task and have similar levels of protected
      teaching time.

PMID- 10652063
TI  - Review of ethics curricula in undergraduate medical education.
AB  - Medical ethics education, it has been said, has 'come of age' in recent years in
      terms of its formal inclusion in undergraduate medical curricula. This review
      article examines the background to its inclusion in undergraduate curricula and
      goes on to examine the consensus that has arisen on the design of ethics
      curricula, using Harden's curriculum and S.P.I.C.E.S models as templates. While
      there is consensus on content for undergraduate medical ethics education, there
      is still significant debate on learning and teaching methods. Despite the broad
      agreement on the need to apply adult education principles to ethics teaching,
      there would appear to be some tension between balancing the need for experiential
      learning and achieving the 'core curriculum'. There are also as yet unresolved
      difficulties with regards to resources for delivery, academic expertise,
      curriculum integration and consolidation of learning. Assessment methods also
      remain contentious. Although there is consensus that the ultimate goal of medical
      ethics, and indeed of medical education as a whole, is to create 'good doctors',
      the influence of the 'hidden curriculum' on students' development is only
      beginning to be recognized, and strategies to counteract its effects are in their
      infancy. The need for proper evaluation studies is recognized. It is suggested
      that the areas of debate appearing in the literature could be used as a starting
      point for evaluation studies, which would form the empirical basis of future
      curriculum development.

PMID- 10652064
TI  - A systematic review of the effectiveness of critical appraisal skills training
      for clinicians.
AB  - The aim of this paper is to undertake a descriptive systematic review of the
      effectiveness of critical appraisal skills training for clinicians. Of the 10
      controlled studies which examined this issue and were found to meet the
      eligibility criteria of this review, all used a study population of either
      medical students or doctors in training. The studies used a variety of different
      intervention 'dosages' and reported a range of outcomes. These included
      participants' knowledge of epidemiology/biostatistics, their attitudes towards
      medical literature, their ability to appraise medical literature, and medical
      literature reading behaviour. An overall improvement in assessed outcomes of 68%
      was reported after critical appraisal skills training, particularly in knowledge
      relating to epidemiology and biostatistics. This review appears to provide some
      evidence of the benefit of teaching critical appraisal skills to clinicians, in
      terms of both knowledge of methodological/statistical issues in clinical research
      and attitudes to medical literature. However, these findings should be considered
      with caution as the methodological quality of studies was generally poor, with
      only one study employing a randomized controlled design. There is a need for
      educators within the field of evidence-based health to consider the implications
      of this review.

PMID- 10652065
TI  - Promoting effective teaching and learning: hospital consultants identify their
      needs.
AB  - OBJECTIVES: The aim of this study was to help hospital consultants identify their
      needs in relation to teaching skills, leading to the development of a teacher
      training programme. DESIGN: The study was directed at all 869 consultants in the
      region and initially involved a postal questionnaire which had a 60.5% response
      rate. SETTING: Hospitals throughout Northern Ireland. SUBJECTS: Hospital
      consultants. RESULTS: Results from this questionnaire indicated that while the
      majority of respondents were interested teachers, only 34% had received any
      teacher training. The questionnaire was followed by a focus group study involving
      three groups of consultants drawn randomly from those who had responded to the
      questionnaire. Participants in these groups identified the following key areas of
      hospital education: qualities of hospital teachers; selection procedures;
      problems of teaching in hospitals; the need for teacher training and how it
      should be provided. CONCLUSION: The study highlighted that hospital teachers need
      to acquire and update their teaching skills through attending courses that should
      include basic teaching and assessment/appraisal skills. These courses should last
      1 or 2 days and be provided at a regional or subregional level. As a result of
      this study, teacher training courses have been developed in this region.

PMID- 10652066
TI  - Teaching the consultant teachers: identifying the core content.
AB  - OBJECTIVES: To determine the key themes for teaching hospital consultants how to
      teach. DESIGN: 1. In-depth interviews with a total of 19 experts, consultants and
      junior doctors to identify key topics. 2. Literature review from 1969 to obtain
      the main themes from the medical educational literature. 3. Analysis of the main
      themes in 11 'Teaching the teachers' courses. 4. Triangulation of interview data,
      literature themes and teaching courses content to generate 15 criteria for a
      questionnaire. 5. Questionnaire study to 593 senior and junior hospital doctors.
      SETTING: Hospitals in the West Midlands Region in England. SUBJECTS: Consultants
      and junior hospital doctors. RESULTS: Overall, 441 doctors replied (74% response
      rate). The top five themes were giving feedback constructively, keeping up to
      date as a teacher, building a good educational climate, assessing the trainee and
      assessing the trainee's learning needs. Results showed no statistically
      significant differences in the order of themes for all groups analysed, including
      seniority, gender, specialty, origin by medical school and consultants of
      different ages. CONCLUSIONS: Consultants need teaching in these topics. There are
      implications for funding and providing these courses for postgraduate deans,
      Royal Colleges and universities. Further research is needed to evaluate whether
      such an initiative does produce better teaching and learning, and a better
      educational climate in hospitals.

PMID- 10652067
TI  - Feasibility analysis of a personalized training plan for learning research
      methodology.
AB  - OBJECTIVES: To determine the performance in learning clinical research
      methodology (CRM) by means of the Keller Plan (KP), to assess its impact on
      attitudes towards research (AR) and to estimate its acceptability. DESIGN: An
      educational intervention trial was employed with control group (CG) and random
      assignment. SETTING: The Family and Community Medicine Teaching Unit in Valencia,
      Spain, 1997. SUBJECTS: Third-year family residents. RESULTS: In the KP both
      specific written self-teaching material and interactive computer programme were
      used, focusing on the tutored resident, with compulsory assessments to continue.
      In the CG a conventional course was followed. Knowledge of CRM and the AR test
      (previously validated in another study) were measured at the start. Four tests of
      successive knowledge, time spent studying, tutorials, final AR test and
      acceptability were conducted. Non-parametric tests were used. Forty (89%)
      residents participated, 22 were assigned to KP and 18 to CG. Similar basic
      characteristics, with exception of AR test (medians 55 Keller, 58 control). KP
      knowledge tests significantly higher (P = < 0.05) than the CG (medians 101, 88)
      along with time spent studying (medians 53, 23.4 h). There were no significant
      differences in AR test, although there was an improvement in both groups,
      significant in KP but not in CG (median increase of 4.5 and 2). Nine residents
      used and positively assessed the computer programme. Better acceptability was
      obtained by the KP in overall evaluation, recommendation of the method and
      learning dynamic. CONCLUSIONS: The KP obtained better knowledge, motivated
      studying and was positively accepted.

PMID- 10652068
TI  - Dealing with the issue 'care of the dying' in medical education - results of a
      survey of 592 European physicians.

PMID- 10652069
TI  - Alcohol and drug use in second-year medical students at the University of Leeds.
AB  - OBJECTIVE: In view of recent media attention concerning the high level of alcohol
      and drug use reported in a group of newly qualified junior doctors, the aim of
      the present study was to assess the alcohol and drug habits of a group of current
      medical students. METHODS: Information about alcohol and illicit drug use was
      obtained from 136 second-year medical students (46 men, 90 women) at the
      University of Leeds by means of a personally administered questionnaire. Levels
      of anxiety and depression were also assessed. RESULTS: 86% of the students drank
      alcohol and among those who drank, a high proportion (52.6% of the men and 50.6%
      of the women), exceeded the recommended weekly limit of alcohol consumption of 21
      units for men and 14 units women per week). Illicit drug use was reported by
      33.1% of students (28.3% of men, 35.6% of women). The drug most commonly used was
      cannabis. According to the Hospital Anxiety and Depression (HAD) scale, 41.2% of
      the students (37% of men, 43.3% of women) had anxiety ratings within the
      clinically significant range (HAD scale> 8); 9.5% of students demonstrated
      clinically significant levels of depression (HAD scale> 8). However, these high
      levels of anxiety and depression did not correlate with high levels of alcohol
      consumption or drug use.

PMID- 10652070
TI  - First step: report on a pilot course for personal and professional development.
AB  - OBJECTIVE: To describe a pilot course in personal and professional development,
      entitled 'Becoming a doctor: the first step' and our suggestions for what might
      be incorporated into future courses. SETTING AND CONTEXT: Leeds Medical School
      begins a new curriculum in September 1999 with a proportion of the first 3 years
      being devoted to a new module on personal and professional development. This
      module will include courses involving communication skills, ethics, working in
      groups and early patient contact through community visits. Some of these topics
      were piloted in a short course for first-year medical students in 1998. LEARNING
      METHODS: The course ran for 9 weeks and was largely experiential. The group
      facilitators came from diverse health and social care backgrounds. A variety of
      learning methods were used, concentrating on self-reflection, discussion,
      community visits and information gathering. EVIDENCE FOR EFFECTIVENESS: The views
      of both facilitators and students were analysed. Students particularly
      appreciated the community visits and group work. The facilitators were positive
      about the course overall while suggesting improvements, including their own
      involvement in future development of the course. CONCLUSIONS: The pilot course
      has helped us to focus on objectives for the new curriculum and to plan the new
      course. In particular there is a need for more attention to be given to the
      involvement of facilitators in course development.

PMID- 10652071
TI  - Amplified fragment length polymorphism (AFLP) markers reveal that population
      structure of triploid dandelions (Taraxacum officinale) exhibits both clonality
      and recombination.
AB  - Highly variable amplified fragment length polymorphism (AFLP) fingerprints of
      triploid apomictic dandelions obtained from three localities in an area where
      diploids are lacking were analysed to infer the predominant modes of
      reproduction. The distribution of markers was analysed using character
      compatibility to infer whether many genotypes agree with a tree-like structure in
      the data set. The presence of incompatible character state combinations (matrix
      incompatibility; MI) was used as a measure of genetic exchange. The detection of
      overrepresented genotypes, of which some were widespread, confirmed asexual
      reproduction. Not all genotypes were overrepresented; approximately half of the
      genotypes in the three localities were found only once. Because, in terms of
      genotype frequencies, only a part of the genetic variation is described, more
      important aspects of the molecular data such as relationships between markers or
      genotypes have been studied. The analysis of character compatibility indicated a
      disagreement of the data with a clonal structure. Nearly all genotypes
      contributed to MI and this contribution varied considerably among genotypes in
      each sampled locality. A gradual decrease of matrix incompatibility upon
      successive deletion of genotypes showing the highest contribution to MI indicated
      that marker distribution of virtually all genotypes disagreed with a tree-like
      structure in the data. This result suggested that many genotypes were separated
      by one or more sexual generations. Consistent with this conclusion was the fact
      that markers that show a low probability of contributing to MI are different in
      every sampled locality, which is most easily explained as the result of
      recombination. Apparently, asexual reproduction has resulted in overrepresented,
      widespread genotypes but sexual recombination has also substantially contributed
      to genetic variation in the sites studied.

PMID- 10652072
TI  - Morphological and molecular evidence for hybridization and introgression in a
      willow (Salix) hybrid zone.
AB  - Hybrid zones provide biologists with the opportunity to examine genetic and
      ecological interactions between differentiated populations. Accurate
      identification of hybrid genealogies is considered a necessary prerequisite to
      understanding observed patterns of hybridization-related phenomena. We analysed
      molecular and morphological data from individuals in a hybrid zone between two
      species of willows (Salix sericea Marshall and S. eriocephala Michaux) and report
      the use of randomly amplified polymorphic DNA (RAPD), chloroplast DNA (cpDNA),
      and ribosomal DNA (rDNA) markers, as well as vegetative morphology and foliar
      chemistry data to identify individuals in terms of hybrid genealogy and to infer
      the direction and extent of backcrossing and introgression within the hybrid
      zone. A novel version of a maximum likelihood estimate approach (developed for
      this study) was used to calculate hybrid index scores from RAPD marker data; this
      method produced results similar to those obtained using traditional arithmetic
      methods. Distribution of rDNA, cpDNA, and chemistry data were examined within the
      graphical context of RAPD-based hybrid index score histograms and principal
      component analyses (PCA) on RAPD and morphology data. Seven of the 21 plants
      classified as S. eriocephala in the field were possible introgressants. Another
      plant presented an unequivocal example of backcrossed S. sericea chemistry and
      RAPD markers. Inter- and intraspecific chloroplast diversity found within the
      hybrid zone suggests both historic introgression (perhaps in a glacial refugium),
      and contemporary hybridization. Patterns of inheritance and expression within the
      hybrid zone suggest that morphological characters are often not expressed in a
      simple additive fashion, and problems associated with both morphological and
      molecular data are considered.

PMID- 10652073
TI  - Assessment of natural and artificial propagation of the white-clawed crayfish
      (Austropotamobius pallipes species complex) in the Alpine region with nuclear and
      mitochondrial markers.
AB  - In a joint analysis of nuclear (allozyme) and mitochondrial markers (sequence and
      restriction fragment length polymorphism (RFLP) analysis of the 12S and 16S
      genes), five genetically distinct groups of the Austropotamobius pallipes
      Lereboullet species complex were detected in the Alpine region. The geographical
      distribution of these evolutionary lineages coincided largely with several taxa
      (A.p. pallipes, A. berndhauseri, A.(p.) italicus) formerly defined on the basis
      of morphological characters. A low level of genetic variability was found within
      these lineages. For some populations, the combination of the two markers gave
      additional information about the likelihood of their natural or artificial
      origin. A hybrid zone was detected between A.p. pallipes and A. berndhauseri in
      the Lake Geneva area. The mosaic distribution of the five evolutionary lineages
      indicated that conservation efforts should be aimed at the level of local
      populations.

PMID- 10652074
TI  - Species relationships and population structure of Littorina saxatilis Olivi and
      L. tenebrosa Montagu in Ireland using single-strand conformational polymorphisms
      (SSCPs) of cytochrome b fragments.
AB  - Littorina saxatilis is a ubiquitous snail of intertidal habitats in the North
      Atlantic. Shell type in littorinids is extremely polymorphic and defined by
      habitat. Taxonomy based upon shell type has been revised in the light of anatomic
      and genetic information, but uncertainties remain. In this study, the population
      structure of L. saxatilis and L. tenebrosa was studied at 11 sites in Ireland
      using single-strand conformational polymorphisms of a 375-bp portion of the
      cytochrome b gene, and the status of L. tenebrosa, the small, fragile-shelled,
      brackish water type, was considered. The genetic patterns among L. saxatilis and
      L. tenebrosa populations were examined over varying distances and L. tenebrosa
      was compared with adjacent L. saxatilis populations at four sites on the west
      coast of Ireland and one site on the east coast. Haplotype diversity was high
      with 32 haplotypes present among 995 individuals. Pairwise tests suggest gene
      flow over small scales among and between habitat types and may reflect the
      stochastic legacy of postglacial recolonization over larger scales. In AMOVA
      tests, geography explained nearly twice as much of the variance (30%) as habitat
      type (18%), indicating that gene flow is more restricted by distance than by
      habitat type, and supporting the status of L. tenebrosa as an ecotype of L.
      saxatilis rather than a separate species.

PMID- 10652075
TI  - Genetic relationships in the peregrine falcon (Falco peregrinus) analysed by
      microsatellite DNA markers.
AB  - Microsatellite DNA markers were developed from a peregrine falcon (Falco
      peregrinus) and genetic relationships among peregrine falcons in southern Norway
      were analysed using the markers. The genomic DNA library was screened for the
      presence of dinucleotide microsatellite repeats. Twelve loci revealed
      polymorphism through the initial analysis of 24 unrelated peregrine falcons, and
      Mendelian inheritance was confirmed in two peregrine falcon families bred in
      captivity. The estimated mean probability of identical genotypes in two unrelated
      individuals was 3 x 10-8, and the combined exclusion probability for parentage
      testing was 0.99 and 0.94 for one or both parents unknown, respectively. The
      markers were used to investigate the parentage of peregrine broods from the same
      nest site from different breeding seasons, and subsequently the nest-site
      fidelity of the breeding peregrines. High nest-site fidelity was found by
      studying pairwise comparisons of relatedness (rxy) estimates among chicks at six
      nest sites from three different breeding seasons. Cross-species amplifications
      showed that most loci also appeared to amplify polymorphic products in the
      gyrfalcon (F. rusticolus), merlin (F. columbarius), hobby (F. subbuteo) and
      kestrel (F. tinnunculus), demonstrating that the loci will provide powerful
      genetic markers in these falcons too.

PMID- 10652076
TI  - Random amplified polymorphic DNA (RAPD) and quantitative trait analyses across a
      major phylogeographical break in the Mediterranean ragwort Senecio gallicus Vill.
      (Asteraceae).
AB  - Random amplified polymorphic DNA (RAPD) and quantitative trait variation of the
      widespread and ephemeral Senecio gallicus were surveyed in 11 populations sampled
      from the Iberian Peninsula and southern France. The aim of the study was to
      compare population relationships and levels of geographical differentiation with
      chloroplast (cp) DNA and allozyme variation assessed previously in the same
      populations. Employing multivariate statistics, a moderate level of intraspecific
      differentiation was observed among populations from Iberian coastal and inland
      regions for both RAPDs and quantitative traits. However, RAPDs provided greater
      resolution in identifying additional population structure within the
      hypothesized, Pleistocene refugial source area of the species in coastal Iberia.
      A major part of the geographical subdivision in RAPD and quantitative traits was
      concordant with the coastal vs. inland divergence as previously inferred from
      cpDNA haplotype frequencies, but strongly contrasted with the geographical
      uniformity of the species for allozymes. This concordance across various nuclear
      and cytoplasmic markers (RAPDs/quantitative traits, cpDNA) suggests that
      geographical uniformity for allozymes is more attributable to low rates of
      evolution and/or small genome sampling rather than high rates of pollen
      dispersal, slow rates of nuclear lineage sorting, or indirect balancing
      selection. The present study underscores the value of using additional classes of
      nuclear markers for narrowing the numbers of competing causal hypotheses about
      intraspecific cpDNA-allozyme discrepancies and their underlying evolutionary
      processes.

PMID- 10652077
TI  - Molecular evidence for multiple infections of a new subgroup of Wolbachia in the
      European raspberry beetle Byturus tomentosus.
AB  - Wolbachia, a group of maternally inherited intracellular parasitic bacteria,
      alter host reproduction, including the induction of thelytokous parthenogenesis,
      feminization of genetic males, son killing and, most commonly, the induction of
      cytoplasmic incompatibility (CI), in a diverse array of arthropods. CI can result
      in infertility and has attracted attention because of its potential in biological
      control and as an agent in speciation. Although there has been some analysis of
      overall infection rates in arthropods and within individual insect orders, there
      has been little exploration of within-species variation. In this study, primers
      specific for the ftsZ gene of Wolbachia were used to amplify it from different
      geographical samples of the European raspberry beetle (Byturus tomentosus),
      confirming the presence of Wolbachia. More than 99% of UK individuals were found
      to be infected with Wolbachia and 97% of these B. tomentosus beetles harboured
      multiple infections. Preliminary analysis of B. tomentosus beetles from
      continental European populations revealed a lower level of infection (24%) than
      those from the UK. Phylogenetic analysis using the ftsZ DNA sequences places
      Wolbachia from B. tomentosus into a new clade (Abt) within the A division, with
      some revisions to the existing Wolbachia phylogeny.

PMID- 10652078
TI  - Glacial refugia of limber pine (Pinus flexilis James) inferred from the
      population structure of mitochondrial DNA.
AB  - To make inferences about the glacial refugia that harboured the limber pine,
      Pinus flexilis James, we examined the range-wide population structure of
      mitochondrial DNA (mtDNA) with eight size variants in the second intron of nad1.
      The data consisted of haplotypes from 704 trees collected from 40 localities. The
      value of FST for these populations was 0.80, which is a much larger value than
      has been reported for allozymes and chloroplast DNA (cpDNA) in limber pine, and
      it suggests that the number of seeds moving among localities per generation is
      approximately 0.12. Gene flow of this magnitude would allow mutation and
      subsequent genetic drift to have a substantial impact on the population structure
      of mtDNA. The majority of the mtDNA haplotypes are restricted to minor portions
      of the geographical range. The data are consistent with mtDNA differentiation in
      seven glacial refugia, followed by dispersal out of those refugia.

PMID- 10652079
TI  - Multiple paternity in side-neck turtles Podocnemis expansa: evidence from
      microsatellite DNA data.
AB  - Multiple paternity was found in two clutches of Podocnemis expansa using eight
      microsatellite loci. When loci were analysed separately a minimum of two males
      was estimated for nest N23, and three for nest C17. When all loci were combined,
      three patrilines were detected in N23, and six in C17. The distribution of full
      sib cluster sizes indicated a disproportionate contribution of one male to clutch
      C17, consistent with possible sperm competition, or the mixing of leftover and
      newly acquired sperm. High mutation rates were detected at several loci. Multiple
      paternity has positive implications for this endangered species as it may slow
      the loss of genetic variability caused by drift. This is the first report of
      multiple paternity in the suborder Pleurodira.

PMID- 10652080
TI  - Microsatellite primers for the wild brown capuchin monkey Cebus apella.

PMID- 10652081
TI  - Polymorphic microsatellite DNA markers for the marine gastropod Littorina
      subrotundata.

PMID- 10652082
TI  - New microsatellite markers for assessment of paternity in the squid Loligo
      forbesi (Mollusca: Cephalopoda).

PMID- 10652083
TI  - Isolation of microsatellite loci for paternity testing in Phillyrea angustifolia
      L. (Oleaceae).

PMID- 10652084
TI  - Variable microsatellite loci for the leafcutter ant Acromyrmex echinatior and
      their applicability to related species.

PMID- 10652085
TI  - Isolation and characterization of microsatellite loci in the Pacific giant
      salamander Dicamptodon tenebrosus.

PMID- 10652086
TI  - Molecular ecology in the year 2000

PMID- 10652087
TI  - Adaptation to the environment: Streptococcus pneumoniae, a paradigm for
      recombination-mediated genetic plasticity?
AB  - Genetic plasticity plays a central role in the biology of the human pathogen
      Streptococcus pneumoniae. This is illustrated by the existence of at least 90
      different capsular types (the polysaccharide capsule has an essential
      antiphagocytic function) as well as by the rapid emergence of penicillin
      resistant (PenR) pneumococcal isolates. Natural genetic transformation is
      believed to be essential for this genetic plasticity; capsular types can be
      switched by intraspecies transformation, whereas interspecies transformation is
      responsible for the appearance, in the PenR isolates, of mosaic pbp genes, which
      encode proteins with reduced affinity for penicillin. Data on the regulation of
      competence for transformation in S. pneumoniae, on the control of intra- and
      interspecies genetic exchange and on the shuffling and capture of exogenous
      sequences during transformation are reviewed. Possible links between
      transformation and changes in environmental conditions are discussed, and the
      adaptive 'strategy' deduced for S. pneumoniae is compared with that of
      Escherichia coli.

PMID- 10652088
TI  - The Tat protein export pathway.
AB  - The Tat (twin-arginine translocation) system is a bacterial protein export
      pathway with the remarkable ability to transport folded proteins across the
      cytoplasmic membrane. Preproteins are directed to the Tat pathway by signal
      peptides that bear a characteristic sequence motif, which includes consecutive
      arginine residues. Here, we review recent progress on the characterization of the
      Tat system and critically discuss the structure and operation of this major new
      bacterial protein export pathway.

PMID- 10652089
TI  - Identification of a novel genetic locus that is required for in vitro adhesion of
      a clinical isolate of enterohaemorrhagic Escherichia coli to epithelial cells.
AB  - Enterohaemorrhagic Escherichia coli (EHEC) are food-borne intestinal pathogens
      with a low infectious dose. Adhesion of some EHEC strains to epithelial cells is
      attributed, in part, to intimin, but other factors may be required for the
      intestinal colonizing ability of these bacteria. In order to identify additional
      adherence factors of EHEC, we generated transposon mutants of a clinical EHEC
      isolate of serotype O111:H-, which displayed high levels of adherence to cultured
      Chinese hamster ovary (CHO) cells. One mutant was markedly deficient in CHO cell
      adherence, human red blood cell agglutination and autoaggregation. Sequence
      analysis of the gene disrupted in this mutant revealed a 9669 bp novel
      chromosomal open reading frame (ORF), which was designated efa1, for EHEC factor
      for adherence. efa1 displayed 28% amino acid identity with the predicted product
      of a recently described ORF from the haemolysin-encoding plasmid of EHEC O157:H7.
      The amino termini of the putative products of these two genes exhibit up to 38%
      amino acid similarity to Clostridium difficile toxins A and B. efa1 occurred
      within a novel genetic locus, at least 15 kb in length, which featured a low G+C
      content, several insertion sequence homologues and a homologue of the Shigella
      flexneri enterotoxin ShET2. DNA probes prepared from different regions of efa1
      hybridized with all of 116 strains of attaching-effacing E. coli (AEEC) of a
      variety of serotypes, including enteropathogenic E. coli (EPEC) and EHEC, but
      with none of 91 non-AEEC strains. Nevertheless, efa1 was not required for the
      attachment-effacement phenotype, and the efa1 locus was not physically linked to
      the locus for enterocyte effacement (LEE) pathogenicity island, which is
      responsible for this phenotype in EPEC. These findings suggest that efa1 encodes
      a novel virulence-associated determinant of AEEC, which contributes to the
      adhesive capacity of these bacteria.

PMID- 10652090
TI  - pH-regulated activation and release of a bacteria-associated phospholipase C
      during intracellular infection by Listeria monocytogenes.
AB  - Listeria monocytogenes grows in the cytosol of mammalian cells and spreads from
      cell to cell without exiting the intracellular milieu. During cell-cell spread,
      bacteria become transiently entrapped in double-membrane vacuoles. Escape from
      these vacuoles is mediated in part by a bacterial phospholipase C (PC-PLC), whose
      activation requires cleavage of an N-terminal peptide. PC-PLC activation occurs
      in the acidified vacuolar environment. In this study, the pH-dependent mechanism
      of PC-PLC activation was investigated by manipulating the intracellular pH of the
      host. PC-PLC secreted into infected cells was immunoprecipitated, and both forms
      of the protein were identified by SDS-PAGE fluorography. PC-PLC activation
      occurred at pH 7.0 and lower, but not at pH 7.3. Total amounts of PC-PLC secreted
      into infected cells increased several-fold over controls within 5 min of a
      decrease in intracellular pH, and the active form of PC-PLC was the most abundant
      species detected. Bacterial release of active PC-PLC was dependent on Mpl, a
      bacterial metalloprotease that processes the proform (proPC-PLC), and did not
      require de novo protein synthesis. The amount of proPC-PLC released in response
      to a decrease in pH was the same in wild-type and Mpl-minus-infected cells.
      Immunofluorescence detection of PC-PLC in infected cells was performed. When
      fixed and permeabilized infected cells were treated with a bacterial cell wall
      hydrolase, over 97% of wild-type and Mpl-minus bacteria stained positively for PC
      PLC, in contrast to less than 5% in untreated cells. These results indicate that
      intracellular bacteria carry pools of proPC-PLC. Upon cell-cell spread, a
      decrease in vacuolar pH triggers Mpl activation of proPC-PLC, resulting in
      bacterial release of active PC-PLC.

PMID- 10652091
TI  - Role of penicillin-binding protein PBP 2B in assembly and functioning of the
      division machinery of Bacillus subtilis.
AB  - We have characterized the role of the penicillin-binding protein PBP 2B in cell
      division of Bacillus subtilis. We have shown that depletion of the protein
      results in an arrest in division, but that this arrest is slow, probably because
      the protein is relatively stable. PBP 2B-depleted filaments contained, at about
      their mid-points, structures resembling partially formed septa, into which most,
      if not all, of the division proteins had assembled. Although clearly deficient in
      wall material, membrane invagination seemed to continue, indicating that membrane
      and wall ingrowth can be uncoupled. At other potential division sites along the
      filaments, no visible ingrowths were observed, although FtsZ rings assembled at
      regular intervals. Thus, PBP 2B is apparently required for both the initiation of
      division and continued septal ingrowth. Immunofluorescence microscopy showed that
      the protein is recruited to the division site. The pattern of localization
      suggested that this recruitment occurs continually during septal ingrowth. During
      sporulation, PBP 2B was present transiently in the asymmetrical septum of
      sporulating cells, and its availability may play a role in the regulation of
      sporulation septation.

PMID- 10652092
TI  - Generalized transduction of serotype 1/2 and serotype 4b strains of Listeria
      monocytogenes.
AB  - This is the first report of generalized transduction in the gram-positive, food
      borne pathogen Listeria monocytogenes. Bacteriophages were isolated from the
      environment and from lysogens, or were obtained from other laboratories. Of the
      59 bacteriophages tested, 34 proved to be capable of transduction. We exploited
      the ability of L. monocytogenes to grow at room temperature and isolated
      bacteriophages that were incapable of growth at 37 degrees C. Transductions at
      this temperature therefore eliminated transductant killing and lysogeny, as did
      inclusion of citrate and the use of a low multiplicity of infection. Transducing
      bacteriophages were found for each of the well-characterized L. monocytogenes
      strains: EGD, 10403, Mack (serotype1/2a), L028 (serotype 1/2c), Scott A (serotype
      4b) and strains from the Jalisco and Halifax, Nova Scotia outbreaks (serotype
      4b). P35 (phiLMUP35) is a particularly useful generalized transducing
      bacteriophage with a wide host range (75% of all serotype 1/2 strains tested).
      Its disadvantages are that it is small and transduction is relatively infrequent.
      U153(phiCU-SI153/95) is larger than P35 and transduction frequency increased 100
      fold, but it has a very narrow host range. We demonstrated interstrain
      transduction and used transduction to test linkage between transposon insertions
      and mutant phenotypes in a variety of strains.

PMID- 10652093
TI  - Complete nucleotide sequence, molecular analysis and genome structure of
      bacteriophage A118 of Listeria monocytogenes: implications for phage evolution.
AB  - A118 is a temperate phage isolated from Listeria monocytogenes. In this study, we
      report the entire nucleotide sequence and structural analysis of its 40 834 bp
      DNA. Electron microscopic and enzymatic analyses revealed that the A118 genome is
      a linear, circularly permuted, terminally redundant collection of double-stranded
      DNA molecules. No evidence for cohesive ends or for a terminase recognition (pac)
      site could be obtained, suggesting that A118 viral DNA is packaged via a headful
      mechanism. Partial denaturation mapping of DNA cross-linked to the tail shaft
      indicated that DNA packaging proceeds from left to right with respect to the
      arbitrary genomic map and the direction of genes necessary for lytic development.
      Seventy-two open reading frames (ORFs) were identified on the A118 genome, which
      are apparently organized in a life cycle-specific manner into at least three
      major transcriptional units. N-terminal amino acid sequencing, bioinformatic
      analyses and functional characterizations enabled the assignment of possible
      functions to 26 ORFs, which included DNA packaging proteins, morphopoetic
      proteins, lysis components, lysogeny control-associated functions and proteins
      necessary for DNA recombination, modification and replication. Comparative
      analysis of the A118 genome structure with other bacteriophages revealed local,
      but sometimes extensive, similarities to a number of phages spanning a broader
      phylogenetic range of various low G+C host bacteria, which implies relatively
      recent exchange of genes or genetic modules. We have also identified the A118
      attachment site attP and the corresponding attB in Listeria monocytogenes, and
      show that site-specific integration of the A118 prophage by the A118 integrase
      occurs into a host gene homologous to comK of Bacillus subtilis, an
      autoregulatory gene specifying the major competence transcription factor.

PMID- 10652094
TI  - Negative constrained DNA supercoiling in archaeal nucleosomes.
AB  - Archaeal histones have significant sequence and structural similarity to their
      eukaryal counterparts. However, whereas DNA is wrapped in negatively constrained
      supercoils in eukaryal nucleosomes, it has been reported that DNA is positively
      supercoiled by archaeal nucleosomes. This was inferred from experiments performed
      at low temperature and low salt concentrations, conditions markedly different
      from those expected for many archaea in vivo. Here, we report that the archaeal
      histones HMf and HTz wrap DNA in negatively constrained supercoils in buffers
      containing potassium glutamate (K-Glu) above 300 mM, either at 37 degrees C or at
      70 degrees C. This suggests that high salt concentrations allow an alternate
      archaeal nucleosome topology: a left-handed tetramer rather than the right-handed
      tetramer seen in low salt conditions. In contrast, the archaeal histone MkaH
      produces DNA negative supercoiling at all salt concentrations, suggesting that
      this duality of structure is not possible for this atypical protein, which is
      formed by the association of two histone folds in a single polypeptide. These
      results extend the already remarkable similarity between archaeal and eukaryal
      nucleosomes, as it has been recently shown that DNA can be wrapped into either
      positive or negative supercoils around the H3/H4 tetramer. Negative supercoiling
      could correspond to the predominant physiological mode of DNA supercoiling in
      archaeal nucleosomes.

PMID- 10652095
TI  - Identification and characterization of mycobacteriophage L5 excisionase.
AB  - The well-characterized mycobacteriophage L5 forms stable lysogens in
      Mycobacterium smegmatis. Establishment of lysogeny involves integration of the
      phage genome into the chromosome of its mycobacterial hosts through an integrase
      mediated site-specific recombination event. As L5 lysogens spontaneously generate
      free phage particles, prophage excision must also occur, although an L5
      excisionase gene had not been identified. We show here that L5 gene 36 encodes
      the phage excisionase and is a small, heat-stable 56-amino-acid protein that
      strongly stimulates excisive recombination both in vivo and in vitro. The ability
      to manipulate the highly directional phage integration and excision reactions
      will provide powerful tools for the introduction, curing and recovery of foreign
      genes in recombinant mycobacterial strains.

PMID- 10652096
TI  - The linker peptide of the ArsA ATPase.
AB  - Plasmid R773 encodes an As(III)/Sb(III)-translocating ATPase that confers
      resistance to those metalloids in Escherichia coli. The catalytic subunit of the
      pump, the ArsA ATPase, consists of homologous N- and C-terminal nucleotide
      binding domains connected by a 25-residue linker. The role of this linker
      sequence was examined by deletion of five, 10, 15 or 23 residues or insertion of
      five glycine residues. Cells expressing arsA with the 5-residue insertion had
      wild-type arsenite resistance. Resistance of cells expressing modified arsA genes
      with deletions was dependent on the linker length. Cells with five or 10 deleted
      residues exhibited slightly reduced resistance. Deletion of 15 or 23 residues
      resulted in further decreases in resistance. Each altered ArsA was purified. The
      enzyme with the 5-residue insertion had the same affinity for ATP and Sb(III) as
      the wild-type enzyme. Enzymes with 5-, 10-, 15- or 23-residue deletions exhibited
      decreased affinity for both Sb(III) and ATP. The enzyme with a 23-residue
      deletion exhibited only basal ATPase activity and was unable to be allosterically
      activated by Sb(III). These results suggest that the linker has evolved to a
      length optimal for bringing the two halves of the protein into proper contact
      with each other, facilitating catalysis.

PMID- 10652097
TI  - Characterization of the 20S proteasome from the actinomycete Frankia.
AB  - Frankia is an actinomycete that fixes atmospheric nitrogen in symbiotic
      association with the root systems of a variety of non-leguminous plants,
      denominated actinorhizal plants. Information on the biology of proteolysis in
      Frankia is almost non-existent as it is extremely difficult to grow this
      organism. We have purified 20S proteasomes from Frankia strain ACN14a/ts-r. It is
      composed of one alpha-subunit and one beta-subunit, which assemble into the
      canonical structure of four rings of seven subunits each. The enzyme displayed a
      chymotrypsin-like activity against synthetic substrates and was sensitive to
      lactacystin, a specific proteasome inhibitor. Analysis of the structural genes
      and the flanking regions revealed a similar organization to Rhodococcus
      erythropolis, Mycobacterium tuberculosis and Streptomyces coelicolor and showed
      that the beta-subunit is encoded with a 52-amino-acid propeptide that is cleaved
      off in the course of the assembly. We report also for the first time the in vitro
      assembly of chimeric proteasomes composed of Frankia and Rhodococcus erythropolis
      subunits, which are correctly assembled and proteolytically active.

PMID- 10652098
TI  - Cross-talk between ammonium transporters in yeast and interference by the soybean
      SAT1 protein.
AB  - Ammonium uptake in the yeast Saccharomyces cerevisiae involves three membrane
      transporters (Mep1, -2 and -3) belonging to an evolutionarily conserved protein
      family that also includes the rhesus (Rh) blood group polypeptides of
      erythrocytes. We show here that, in the 26972c mutant defective in NH4+
      transport, the Mep1 protein carrying an amino acid substitution in its
      cytoplasmic C-terminus trans-inhibits the closely related Mep3 protein. The same
      mutation introduced into Mep3 leads to loss of transport activity and this
      inactive form also trans-inhibits native Mep3. Inhibition of Mep3 is post
      translational and can be overcome by overexpression. These results are consistent
      with a direct interaction between Mep proteins, as is the case for the Rh
      polypeptides. The soybean GmSAT1 gene, recently cloned for its ability to
      complement the NH4+ transport defect of strain 26972c, has been described as an
      NH4+ channel protein involved in the transfer of fixed nitrogen from the
      bacteroid to the host plant. We show here that GmSAT1 contains a sequence
      homologous to the DNA-binding domain of basic helix-loop-helix (bHLH)
      transcription factors. We also show that GmSAT1 restores NH4+ uptake in the yeast
      mutant by interfering with the inhibition of Mep3. Our results are not consistent
      with a direct role of GmSAT1 in ammonium transport.

PMID- 10652099
TI  - Protein kinase A encoded by TPK2 regulates dimorphism of Candida albicans.
AB  - External signals induce the switch from a yeast to a hyphal growth form in the
      fungal pathogen Candida albicans. We demonstrate here that the catalytic subunit
      of a protein kinase A (PKA) isoform encoded by TPK2 is required for internal
      signalling leading to hyphal differentiation. TPK2 complements the growth defect
      of a Saccharomyces cerevisiae tpk1-3 mutant and Tpk2p is able to phosphorylate an
      established PKA-acceptor peptide (kemptide). Deletion of TPK2 blocks
      morphogenesis and partially reduces virulence, whereas TPK2 overexpression
      induces hyphal formation and stimulates agar invasion. The defective tpk2
      phenotype is suppressed by overproduction of known signalling components,
      including Efg1p and Cek1p, whereas TPK2 overexpression reconstitutes the cek1 but
      not the efg1 phenotype. The results indicate that PKA activity of Tpk2p is an
      important contributing factor in regulating dimorphism of C. albicans.

PMID- 10652100
TI  - Induction of neutral trehalase Nth1 by heat and osmotic stress is controlled by
      STRE elements and Msn2/Msn4 transcription factors: variations of PKA effect
      during stress and growth.
AB  - Saccharomyces cerevisiae neutral trehalase, encoded by NTH1, controls trehalose
      hydrolysis in response to multiple stress conditions, including nutrient
      limitation. The presence of three stress responsive elements (STREs, CCCCT) in
      the NTH1 promoter suggested that the transcriptional activator proteins Msn2 and
      Msn4, as well as the cAMP-dependent protein kinase (PKA), control the stress
      induced expression of Nth1. Here, we give direct evidence that Msn2/Msn4 and the
      STREs control the heat-, osmotic stress- and diauxic shift-dependent induction of
      Nth1. Disruption of MSN2 and MSN4 abolishes or significantly reduces the heat-
      and NaCl-induced increases in Nth1 activity and transcription. Stress-induced
      increases in activity of a lacZ reporter gene put under control of the NTH1
      promoter is nearly absent in the double mutant. In all instances, basal
      expression is also reduced by about 50%. The trehalose concentration in the msn2
      msn4 double mutant increases less during heat stress and drops more slowly during
      recovery than in wild-type cells. This shows that Msn2/Msn4-controlled expression
      of enzymes of trehalose synthesis and hydrolysis help to maintain trehalose
      concentration during stress. However, the Msn2/Msn4-independent mechanism exists
      for heat control of trehalose metabolism. Site-directed mutagenesis of the three
      STREs (CCCCT changed to CATCT) in NTH1 promoter fused to a reporter gene
      indicates that the relative proximity of STREs to each other is important for the
      function of NTH1. Elimination of the three STREs abolishes the stress-induced
      responses and reduces basal expression by 30%. Contrary to most STRE-regulated
      genes, the PKA effect on the induction of NTH1 by heat and sodium chloride is
      variable. During diauxic growth, NTH1 promoter-controlled reporter activity
      strongly increases, as opposed to the previously observed decrease in Nth1
      activity, suggesting a tight but opposite control of the enzyme at the
      transcriptional and post-translational levels. Apparently, inactive trehalase is
      accumulated concomitant with the accumulation of trehalose. These results might
      help to elucidate the general connection between control by STREs, Msn2/Msn4 and
      PKA and, in particular, how these components play a role in control of trehalose
      metabolism.

PMID- 10652101
TI  - An Agrobacterium catalase is a virulence factor involved in tumorigenesis.
AB  - Most plant pathogenic bacteria adopt the type III secretion systems to secrete
      virulence factors and/or avirulence gene products, which trigger the plant
      hypersensitive response (HR) and the oxidative burst with hydrogen peroxide
      (H2O2) as the main component. However, the soil-borne plant pathogen
      Agrobacterium tumefaciens uses the type IV secretion pathway to deliver its
      oncogenic T-DNA that causes crown gall tumours on many plant species. A.
      tumefaciens does not elicit a typical HR on those plants. Here, we report that
      inactivation of one of A. tumefaciens catalases (which converts H2O2 to H2O and
      O2) by a transposon insertion highly attenuated the bacterial ability to cause
      tumours on plants and to tolerate H2O2 toxicity, but not the bacterial viability
      in the absence of exogenous H2O2. This provides the first genetic evidence that
      the Agrobacterium-plant interaction involves a plant defence response, such as
      H2O2 production, and that catalase is a virulence factor for a plant pathogen.

PMID- 10652102
TI  - Fus3 controls Ty1 transpositional dormancy through the invasive growth MAPK
      pathway.
AB  - Fus3, the mitogen-activated protein kinase (MAPK) of the mating pheromone
      response pathway, inhibits a post-translational step of Ty1 retrotransposition.
      Fus3 also inhibits haploid invasive growth by blocking cross-activation of
      invasive growth gene expression by the pheromone response signal cascade. Here,
      we show that Fus3 kinase activity and dosage co-ordinately regulate Ty1
      transposition and invasive growth. A chromosomal copy of the kinase-defective
      fus3-K42R allele fails to inhibit either Ty1 transposition or invasive growth.
      When overexpressed, kinase-defective Fus3 weakly inhibits both Ty1 transposition
      and invasive growth, but is much less inhibitory than wild-type Fus3 expressed at
      the same level. Moreover, increasing the dosage of wild-type Fus3 intensifies the
      inhibition of both Ty1 transposition and invasive growth. To demonstrate that
      Fus3 regulates Ty1 transposition via its negative regulation of the invasive
      growth pathway, we show by epistatic analysis that the invasive growth pathway
      transcription factors Ste12 and Tec1 are both required for Fus3-mediated
      inhibition of Ty1 transposition. When haploid invasive growth is stimulated by
      high-copy expression of TEC1, by expression of the dominant hypermorphic allele
      STE11-4 or by deletion of HOG1, Ty1 transposition is concomitantly activated. In
      summary, these results demonstrate that the haploid invasive growth pathway
      activates Ty1 transposition at both transcriptional and post-transcriptional
      levels and that Fus3 inhibits Ty1 transposition by inhibiting the invasive growth
      pathway.

PMID- 10652103
TI  - Na+ translocation by complex I (NADH:quinone oxidoreductase) of Escherichia coli.
AB  - Following on from our previous discovery of Na+ pumping by the NADH:ubiquinone
      oxidoreductase (complex I) of Klebsiella pneumoniae, we show here that complex I
      from Escherichia coli is a Na+ pump as well. Our study object was the Escherichia
      coli mutant EP432, which lacks the Na+/H+ antiporter genes nhaA and nhaB and is
      therefore unable to grow on LB medium at elevated Na+ concentrations. During
      growth on mineral medium, the Na+ tolerance of E. coli EP432 was influenced by
      the organic substrate. NaCl up to 450 mM did not affect growth on glycerol and
      fumarate, but growth on glucose was inhibited. Correlated to the Na+ tolerance
      was an increased synthesis of complex I in the glycerol/fumarate medium. Inverted
      membrane vesicles catalysed respiratory Na+ uptake with NADH as electron donor.
      The sodium ion transport activity of vesicles from glycerol/fumarate-grown cells
      was 40 nmol mg-1 min-1 and was resistant to the uncoupler carbonyl-cyanide m
      chlorophenylhydrazone (CCCP), but was inhibited by the complex I-specific
      inhibitor rotenone. With an E. coli mutant deficient in complex I, the Na+
      transport activity was low (1-3 nmol mg-1 min-1), and rotenone was without
      effect.

PMID- 10652104
TI  - Emergency derepression: stringency allows RNA polymerase to override negative
      control by an active repressor.
AB  - The uspA promoter, driving production of the universal stress protein A in
      response to diverse stresses, is demonstrated to be under dual control. One
      regulatory pathway involves activation of the promoter by the alarmone guanosine
      3',5'-bisphosphate, via the beta-subunit of RNA polymerase, whereas the other
      consists of negative control by the FadR repressor. In contrast to canonical dual
      control by activation and repression circuits, which depends on concomitant
      activation and derepression for induction to occur, the ppGpp-dependent
      activation of the uspA promoter overrides repression by an active FadR under
      conditions of severe cellular stress (starvation). The ability of RNA polymerase
      to overcome repression during stringency depends, in part, on the strength of the
      FadR operator. This emergency derepression is operative on other FadR-regulated
      genes induced by starvation and is argued to be an essential regulatory mechanism
      operating during severe stress.

PMID- 10652105
TI  - Expression cloning of the Candida albicans CSA1 gene encoding a mycelial surface
      antigen by sorting of Saccharomyces cerevisiae transformants with monoclonal
      antibody-coated magnetic beads.
AB  - The mycelial surface antigen recognized by monoclonal antibody (mAb) 4E1 has
      previously been shown to be present predominantly in the terminal third of the
      hyphal structures in Candida albicans. We report here the expression cloning of
      the corresponding gene (CSA1 ) by mAb 4E1-coated magnetic beads sorting of
      Saccharomyces cerevisiae transformants expressing a C. albicans genomic library.
      The strategy is both highly selective and highly sensitive and provides an
      additional genetic tool for the cloning and characterization of C. albicans genes
      encoding surface proteins. CSA1 is an intronless gene encoding a 1203-residue
      protein composed of repetitive motifs and domains. Northern analysis indicates
      that CSA1 is preferentially expressed during the mycelial growth phase, although
      a low level of CSA1 mRNA can be detected in the yeast form. As evidenced by
      indirect immunofluorescence microscopy with mAb 4E1, Csa1p is not randomly
      distributed over the surface of yeast cells, but localizes predominantly in the
      growing buds. This suggests that the distribution of Csa1p may be restricted to
      sites of cell surface elongation. Both heterozygous and homozygous C. albicans
      csa1Delta mutants are viable. Upon induction of mycelial growth, the number and
      size of hyphal structures derived from the mutants are similar to those observed
      in the parental wild-type strain. The physiological role of Csa1p has yet to be
      determined. However, the presence in Csa1p of repeated cysteine-rich hydrophobic
      domains with significant sequence similarity to motifs found in surface proteins
      (Ag2 and Pth11) from two distantly related fungal pathogens (Coccidioides immitis
      and Magnaporthe grisea respectively) suggests a common function in host
      interaction.

PMID- 10652106
TI  - Mutant DnaA proteins defective in duplex opening of oriC, the origin of
      chromosomal DNA replication in Escherichia coli.
AB  - We characterized three mutant DnaA proteins with an amino acid substitution of
      R334H, R342H and E361G that renders chromosomal replication cold (20 degrees C)
      sensitive. Each mutant DnaA protein was highly purified from overproducers, and
      replication activities were assayed in in vitro oriC replication systems. At 30
      degrees C, all three mutant proteins exhibited specific activity similar to that
      seen with the wild-type protein, whereas at 20 degrees C, there was much less
      activity in a replication system using a crude replicative extract. Regarding the
      affinity for ATP, the dissociation rate of bound ATP and binding to oriC DNA, the
      three mutant DnaA proteins showed a capacity indistinguishable from that of the
      wild-type DnaA protein. Activity for oriC DNA unwinding of the two mutant DnaA
      proteins, R334H and R342H, was more sensitive to low temperature than that of the
      wild-type DnaA protein. We propose that R334H and R342H have a defect in their
      potential to unwind oriC DNA at low temperatures, the result being the cold
      sensitive phenotype in oriC DNA replication. The two amino acid residues of DnaA
      protein, located in a motif homologous to that of NtrC protein, may play a role
      in the formation of the open complex. The E361 residue may be related to
      interaction with another protein present in a crude cell extract.

PMID- 10652107
TI  - Two opposing effects of mismatch repair on CTG repeat instability in Escherichia
      coli.
AB  - The expansion of normally polymorphic CTG microsatellites in certain human genes
      has been identified as the causative mutation of a number of hereditary
      neurological disorders, including Huntington's disease and myotonic dystrophy.
      Here, we have investigated the effect of methyl-directed mismatch repair (MMR) on
      the stability of a (CTG)43 repeat in Escherichia coli over 140 generations and
      find two opposing effects. In contrast to orientation-dependent repeat
      instability in wild-type E. coli and yeast, we observed no orientation dependence
      in MMR- E. coli cells and suggest that, for the repeat that we have studied,
      orientation dependence in wild-type cells is mainly caused by functional mismatch
      repair genes. Our results imply that slipped structures are generated during
      replication, causing single triplet expansions and contractions in MMR- cells,
      because they are left unrepaired. On the other hand, we find that the repair of
      such slipped structures by the MMR system can go awry, resulting in large
      contractions. We show that these mutS-dependent contractions arise preferentially
      when the CTG sequence is encoded by the lagging strand. The nature of this
      orientation dependence argues that the small slipped structures that are
      recognized by the MMR system are formed primarily on the lagging strand of the
      replication fork. It also suggests that, in the presence of functional MMR,
      removal of 3 bp slipped structures causes the formation of larger contractions
      that are probably the result of secondary structure formation by the CTG
      sequence. We rationalize the opposing effects of MMR on repeat tract stability
      with a model that accounts for CTG repeat instability and loss of orientation
      dependence in MMR- cells. Our work resolves a contradiction between opposing
      claims in the literature of both stabilizing and destabilizing effects of MMR on
      CTG repeat instability in E. coli.

PMID- 10652108
TI  - Novel bacteriocins with predicted tRNase and pore-forming activities in
      Pseudomonas aeruginosa PAO1.

PMID- 10652109
TI  - Lowering of the electric potential on the membrane as a possible signal
      modulating the expression of virulence factors in Vibrio cholerae.

PMID- 10652110
TI  - Neurogastroenterology and motility: at last, an equal partnership.

PMID- 10652111
TI  - The search for the origin of rhythmicity in intestinal contraction; from tissue
      to single cells.
AB  - More than a century ago, rhythmic propulsive contractile activity was observed in
      the intestine after blockade of nerve conduction, thus demonstrating a form of
      peristalsis that appeared to be under myogenic control. During this century,
      light and electron microscopic investigations provided the hypothesis that
      interstitial cells of Cajal (ICC) could be the cells of origin for this
      rhythmicity. In recent years, physiological studies demonstrated a link between
      the presence of electrical slow wave activity and the presence of ICC. The
      recognition that the ICC cell membrane harbours the Kit protein sparked rapid
      advancement in ICC research, and has been essential in the identification of ICC
      in tissue and in culture through Kit immunohistochemistry and kit mRNA reverse
      transcriptase polymerase chain reaction (RT-PCR). With these techniques,
      electrophysiology was carried out on positively identified single ICC in culture.
      These methods revealed that single ICC generate spontaneous rhythmic inward
      currents and slow waves in membrane potential, thus providing strong evidence
      that ICC generate the electrical pacemaker activity for the gut musculature.

PMID- 10652113
TI  - Preserved extrinsic neural connection between gallbladder and residual stomach is
      essential to prevent dysmotility of gallbladder after distal gastrectomy.
AB  - Many reports have been made on gallbladder dysfunction after gastric surgery. We
      reported that the gallbladder contractions were abolished after antrectomy. Our
      hypothesis is that preservation of the neural connection along gastric vessels
      maintains normal gallbladder function during fasting after antrectomy. Six dogs
      underwent antrectomy with preservation of the extrinsic nerves and six other dogs
      underwent conventional antrectomy with dissection of the extrinsic nerves and
      vessels. Laparotomy alone was performed on another six control dogs. Motor
      activities of the gallbladder and upper gastrointestinal tract were recorded by
      strain gauges in conscious dogs. Motilin and CCK-OP were used for pharmacological
      interventions. In conventional antrectomy, the amplitudes of the cyclic motor
      activity of the gallbladder and the stomach during fasting were significantly
      reduced, while this activity was maintained in dogs when extrinsic nerves were
      preserved. The coordination of the motor activity among the gallbladder, stomach
      and the duodenum was not impaired in the dogs when extrinsic nerves were
      preserved. The contractions of the gallbladder induced by exogenous motilin were
      reduced significantly in conventional antrectomy. Therefore, the preserved neural
      connection along the gastric vessels maintains normal gallbladder function in the
      fasting state even after distal gastrectomy.

PMID- 10652112
TI  - Initiation of phase III contractions in the jejunum by atropine, hexamethonium
      and xylocaine in conscious dogs.
AB  - Mechanisms of initiation of phase III contractions in the jejunum during the
      digestive state are not well understood. To test whether phase III can be induced
      by a local injection of various agents in a jejunal segment, a polyethylene tube
      was chronically placed in a branch of the jejunal artery, and force transducers
      were chronically placed in the upper jejunum. Local injection of atropine,
      hexamethonium and xylocaine induced caudal-migrating phase III in the injected
      segment only in the digestive state, and simultaneous intra-arterial infusions of
      L-arginine, an NK-1 antagonist, or 5-hydroxytryptamine (5-HT) 1P and 3
      antagonists inhibited the induced phase III. Intravenous atropine and
      hexamethonium also inhibited xylocaine-induced phase III contractions. Atropine
      and hexamethonium-induced phase III were brought about by inhibition of neural
      transmission at nicotinic receptors in the inhibitory pathway to NO neurones. NK
      1, 5-HT1P and 5-HT3 receptors are present in the excitatory but not the
      inhibitory pathway to NO neurones. Xylocaine appears to stop neuronal
      transmission from mechanoreceptors to NO neurones. Thus, the initiation of
      spontaneous occurrence of phase III in the digestive jejunum is likely to be
      brought about by transient cessation of postprandial contractions in a segment of
      the jejunum.

PMID- 10652114
TI  - Inhibitory effects of NPY on ganglionic transmission in myenteric neurones of the
      guinea-pig descending colon.
AB  - Intracellular recordings were made from myenteric neurones of the guinea-pig
      descending colon. Neuropeptide Y (NPY) and related pancreatic polypeptides were
      applied by superfusion and the effects upon the amplitude of fast excitatory
      synaptic potentials (ESPs) and the ratio of paired fast ESPs evoked by
      stimulation of internodal fibre tracts were noted. NPY produced a concentration
      dependent inhibition in fast ESP amplitude in the majority of neurones (17/21)
      with a calculated IC50 value of 7 nM; in some neurones this inhibition was
      mediated via the local release of noradrenaline. Peptide YY (PYY) (eight out of
      11 neurones; IC50 = 1 nM), NPY(3-36) (three out of three neurones) and [Leu31,
      Pro34]NPY (four out of five neurones) also decreased the amplitude of fast ESPs.
      The effects of two or more pancreatic polypeptides or analogues on fast synaptic
      transmission were compared directly in six neurones; the apparent relative
      potency of agonists suggested the involvement of Y2-receptors and at least one
      other Y-receptor type. In the absence of any direct postsynaptic effects of
      pancreatic polypeptides on the active or passive properties of myenteric
      neurones, or on their sensitivity to ionophoretically applied acetylcholine,
      inhibition of fast ganglionic transmission was presumed to be presynaptic in
      origin. It is concluded that, in addition to their previously described
      depressant actions on neuro-effector transmission to colonic smooth muscle,
      pancreatic polypeptides can exert powerful inhibitory effects on myenteric
      neurones of the descending colon.

PMID- 10652115
TI  - Nissen-type fundoplication and its effects on the emetic reflex and gastric
      motility in the ferret.
AB  - Recurrent vomiting with failure to thrive is a common problem in neurologically
      impaired children. Many undergo fundoplication to control the underlying gastro
      oesophageal reflux. The results of surgery are not always satisfactory and post
      operative retching may be a major problem - a symptom indicative of activation of
      the emetic reflex. An animal model of antireflux surgery has been developed and
      used to investigate the effects of such surgery upon the emetic reflex and vagal
      influences on gastric motility. Following surgery, animals responded to a
      previously subemetic dose of a centrally acting opiate receptor agonist
      (loperamide), suggesting that fundoplication may sensitize the emetic reflex. A
      gastric vago-vagal reflex (tonic inhibition of corpus tone) and responses to
      direct stimulation of vagal motor efferents (both cholinergic and nonadrenergic
      noncholinergic responses) were not significantly affected by antireflux surgery.
      Mechanisms by which neural damage may sensitize the emetic reflex are discussed,
      together with the possible clinical implications for the management of post
      operative symptoms in neurologically impaired children.

PMID- 10652116
TI  - Influence of a 5HT1 receptor agonist on gastric accommodation and initial
      transpyloric flow in healthy subjects.
AB  - Sumatriptan, a 5HT1 receptor agonist, inhibits antral motor activity, delays
      gastric emptying and relaxes the gastric fundus. The aim of this study was to
      characterize the effect of sumatriptan on transpyloric flow and gastric
      accommodation during and immediately after ingestion of a liquid meal using
      duplex sonography. Ten healthy subjects were investigated twice on separate days.
      In random order either sumatriptan 6 mg (Imigran 0.5 mL) or a placebo were given
      s.c. 15 min before ingesting 500 mL of a meat soup. The subjects were examined
      during the 3-min period before ingestion of the liquid meal, the 3-min spent
      drinking the meal and 10 min postprandially. Sumatriptan caused a significant
      widening of both the gastric antrum (P=0.02) and the proximal stomach (P=0.01) 10
      min postprandially as compared with placebo. It caused no significant differences
      in time to initial gastric emptying (P=0.2), but significantly delayed
      commencement of peristaltic-related transpyloric flow (P=0.04). Sumatriptan had
      no significant effect on mean abdominal symptom scores, but after sumatriptan
      there was a significant negative correlation between width of postprandial antral
      area and postprandial nausea and between width of postprandial antral area and
      postprandial bloating. We therefore conclude that sumatriptan causes a
      postprandial dilatation of both the distal and the proximal stomach with no
      change in dyspeptic symptoms nor in length of time to first gastric emptying.
      Time to commencement of peristaltic-related emptying is delayed.

PMID- 10652117
TI  - Leucine rich repeats are the main epitopes in Leishmania infantum PSA during
      canine and human visceral leishmaniasis.
AB  - The PSA protein is one of the major antigens of the surface of the Leishmania
      infantum parasite membrane. We describe the immune humoral response against the
      PSA in dogs and human patients with visceral leishmaniasis caused by L. infantum.
      The immunodominant region of the PSA was determined by subcloning, expression and
      purification of three fragments covering the complete protein. The analysis
      revealed that the antibodies are mostly directed against the central region,
      which is formed exclusively by leucine rich repeats. This region is recognized by
      100% of the sera from the infected dogs and 40% of the human sera. These
      percentages are significantly higher than those observed when the complete
      protein was used as antigen. The analysis of the isotype of the G immunoglobulins
      raised against the immunodominant determinants of the PSA indicates that both
      IgG1 and IgG2 classes are produced during natural infections but that the IgG2
      predominates over that of the IgG1.

PMID- 10652118
TI  - Relative protective properties of three membrane glycoprotein fractions from
      Haemonchus contortus.
AB  - Jacalin lectin was used as a ligand to isolate a fraction containing two distinct
      protective antigens from detergent extracts of membranes from Haemonchus
      contortus. The first antigen was identified as a complex which appeared very
      similar to Haemonchus galactose-containing glycoprotein (H-gal-GP), which is a
      previously described protective protease complex, except that it was
      substantially depleted of one of the main H-gal-GP components, a 230 kDa
      metallopeptidase-containing band. The new complex was termed Haemonchus
      sialylated galactose-containing glycoprotein (H-sialgal-GP), because it bound to
      jacalin but not to peanut lectin and only jacalin will bind the sialylated form
      of galactosyl (beta-1, 3) N-acetylgalactosamine. Two protection trials with sheep
      showed that H-sialgal-GP and H-gal-GP were equally efficacious, reducing numbers
      of Haemonchus eggs by between 86% and 93% and worms by between 52% and 75%,
      respectively. The second jacalin-binding protective antigen fraction was
      separated from H-sialgal-GP by ion exchange and gel filtration chromatography. It
      was greatly enriched for two proteins termed p46 and p52 according to their
      apparent molecular weights. Immunization of sheep with these proteins gave
      protection values of 78% for eggs and 33% for worms, which are significantly
      lower than those obtained with either H-gal-GP or H-sialgal-GP. N-terminal amino
      acid sequence data from p46 and p52 showed that both proteins were closely
      related to a previously described 45 kDa Haemonchus membrane protein, which had
      conferred protection against Haemonchus in guinea-pigs.

PMID- 10652119
TI  - Immunotherapy with live BCG plus heat killed Leishmania induces a T helper 1-like
      response in American cutaneous leishmaniasis patients.
AB  - Previous work has shown that American cutaneous leishmaniasis (ACL) patients
      treated with viable BCG plus heat killed promastigotes of Leishmania amazonensis
      show the same rate of cure as patients receiving conventional chemotherapy. The
      treatment is safe and economical, but the immunological correlates of cure have
      not been examined. In the present study, T cell responses have been analysed in
      43 ACL patients, including patient groups sampled before and after therapy, and
      in 10 endemic controls. Lymphocyte proliferation, interferon (IFN)-gamma and
      interleukin (IL)-5 responses to crude antigen (L. amazonensis, MEL; Mycobacterium
      tuberculosis PPD; M. bovis BCG) stimulation, and serum IL-5 levels, were
      analysed. In endemic volunteers, proliferative responses to BCG were high and IFN
      gamma responses low. In contrast, localized cutaneous (LCL) and mucocutaneous
      (MCL) patients showed low proliferative and high IFN-gamma responses to BCG.
      Treatment enhanced the IFN-gamma response and further decreased the proliferative
      response to BCG, especially in MCL patients. LCL and MCL patients showed an
      increase in proliferative and IFN-gamma responses to MEL with treatment, but the
      response was not exaggerated in MCL patients, either before or after treatment,
      compared to LCL patients. IL-5 production was low in T cell assays, and > 62% of
      untreated patients had very low serum IL-5 levels. There were no significant
      changes in serum IL-5 with treatment. Overall results show enhanced antigen
      specific IFN-gamma responses to the two components of the immunotherapy, live M.
      bovis BCG and heat killed L. amazonensis, which is consistent with a shift in
      balance of T cell response towards a T helper 1 response and clinical cure
      mediated by IFN-gamma.

PMID- 10652120
TI  - Helper T cell and antibody responses to infection of CBA mice with Babesia
      microti.
AB  - Helper T cell cytokine and antibody responses were investigated in mice after
      infection with Babesia microti (King strain). Infection of CBA mice with 106
      parasitized erythrocytes resulted in the development of a transitory high
      parasitaemia which peaked 14 days post infection (DPI), and was resolved at 24
      DPI. Th1 responses were activated predominately during the acute phase (6-18 DPI)
      whereas Th2 responses predominated during the recovery phase (14-28 DPI) as
      detected by the reverse transcriptase polymerase chain reaction. Increased
      expression of Th1 cytokines was first detected at 6 DPI (IL-2) and 8 DPI (IFN
      gamma) and their peak levels were reached at 12 DPI. After the peak levels were
      reached, they progressively declined and fell to baseline levels (22 DPI).
      Increased expression of Th2 cytokines (IL-4 and IL-10) first appeared at 14 DPI,
      peaked at 20 DPI and Th2 cytokine levels were elevated till the end of the study
      (28 DPI). Levels of serum IFN-gamma detected by a sandwich ELISA correlated well
      with IFN-gamma gene expression and were detectable at 8-18 DPI. IgM against B.
      microti was first detected in serum by ELISA at 4 DPI, and peaked at 10 DPI. The
      levels of IgM subsequently declined but remained positive at low titre till the
      end of study. IgG against B. microti was first detected at 8 DPI and peak levels
      were reached at 24 DPI and remained at that level until the end of study. The
      results of the present study show that Th1 cytokines predominated in the early
      inflammatory response and might be involved in control of levels of acute
      parasitaemia whereas the Th2-associated responses, including expression of IL-4
      and IL-10 and the production of parasite-specific IgG, might be the functional
      means for the reduction and clearance of the parasite from the body. It was
      concluded that an effective vaccine against Babesia spp. should be designed to
      induce Th1 responses to maintain the parasitaemia at unfulminating levels and
      also maintain Th2 responses to clear the parasite from the body.

PMID- 10652121
TI  - Human antibody responses to Wuchereria bancrofti infective larvae.
AB  - Human IgG antibody responses to Wuchereria bancrofti third stage infective larvae
      (L3) surface and somatic antigens were studied by indirect immunofluorescence
      (IFA) and immunoblot with endemic Egyptian sera (n = 115) with the aim of
      identifying targets of protective immunity. Human sera variably recognized 14
      major bands in L3 by immunoblot. The statistical significance of group
      differences in antibody prevalence was assessed by the chi-squared test. Children
      and young adults (aged 10-20 years) tended to have antibodies to more L3 somatic
      antigens than older adults, with significant differences for bands at 66, 60 and
      5 kDa. Infected subjects had more consistent antibody responses to antigens at
      55, 50 and 6 kDa than endemic normal subjects with negative serum filarial
      antigen tests, who are presumed to be uninfected. A 5 kDa antigen was
      preferentially recognized by the latter group. Antibodies to L3 surface antigens
      were equally prevalent in uninfected children (75%) and adults (90%) but less
      prevalent in people with microfilaremia (38%) than in amicrofilaremic subjects
      with or without filarial antigenemia (81%) (P < 0.001). IFA-positive sera showed
      significantly enhanced recognition of antigens at 66, 40 and 14 kDa in
      immunoblots relative to IFA-negative sera. Additional studies are needed to
      further characterize antigens identified in this study and to establish whether
      they are indeed targets of protective immunity in humans.

PMID- 10652122
TI  - The effect of nitric oxide on the growth of Plasmodium falciparum, P. chabaudi
      and P. berghei in vitro.
AB  - Protective immune mechanisms to the asexual erythrocytic stages of the malaria
      parasite Plasmodium chabaudi AS strain include antibody-independent mechanisms.
      Nitric oxide (NO) is produced during the infection and indirect evidence suggests
      that it can contribute to the antiparasitic mechanisms. We examined the effect of
      an NO producer, S-nitroso-acetyl-penicillamine (SNAP), on the growth and survival
      in vitro of P. chabaudi AS, P. berghei and P. falciparum. Growth of the parasites
      was monitored by the uptake of tritiated hypoxanthine and, in the case of P.
      falciparum, by morphological examination in stained blood smears. DL
      penicillamine and sodium nitrite, as controls, had no inhibitory activity at the
      concentrations used. The results showed that at SNAP concentrations of
      approximately 182 microM and above NO was cytotoxic to P. falciparum but, at
      lower concentrations, there was a cytostatic effect and some parasites resumed
      growth and division after NO production had ceased. Rings were less susceptible
      to NO effects than later stages in the asexual cycle. The antimalarial activity
      of NO from SNAP also extended to the rodent parasites but, under the experimental
      conditions used, they were less sensitive than the human species. In the cultures
      of P. chabaudi, increasing the numbers of noninfected erythrocytes present did
      not diminish the antimalarial activity of SNAP, suggesting that here at least
      haemoglobin was not scavenging NO significantly.

PMID- 10652123
TI  - Stachyose synthesis in seeds of adzuki bean (Vigna angularis): molecular cloning
      and functional expression of stachyose synthase.
AB  - Stachyose is the major soluble carbohydrate in seeds of a number of important
      crop species. It is synthesized from raffinose and galactinol by the action of
      stachyose synthase (EC 2.4.1.67). We report here on the identification of a cDNA
      encoding stachyose synthase from seeds of adzuki bean (Vigna angularis Ohwi et
      Ohashi). Based on internal amino acid sequences of the enzyme purified from
      adzuki bean, oligonucleotides were designed and used to amplify corresponding
      sequences from adzuki bean cDNA by RT-PCR, followed by rapid amplification of
      cDNA ends (RACE-PCR). The complete cDNA sequence comprised 3046 nucleotides and
      included an open reading frame which encoded a polypeptide of 857 amino acid
      residues. The entire coding region was amplified by PCR, engineered into the
      baculovirus expression vector pVL1393 and introduced into Spodoptera frugiperda
      (Sf21) insect cells for heterologous expression. The recombinant protein was
      immunologically reactive with polyclonal antibodies raised against stachyose
      synthase purified from adzuki bean and was shown to be a functional stachyose
      synthase with the same catalytic properties as its native counterpart. High
      levels of stachyose synthase mRNA were transiently accumulated midway through
      seed development, and the enzyme was also present in mature seeds and during
      germination.

PMID- 10652124
TI  - An Arabidopsis gene encoding a chloroplast-targeted beta-amylase.
AB  - beta-Amylase is one of the most abundant starch degrading activities found in
      leaves and other plant organs. Despite its abundance, most if not all of this
      activity has been reported to be extrachloroplastic and for this reason, it has
      been assumed that beta-amylases are not involved in the metabolism of chloroplast
      localized transitory leaf starch. However, we have identified a novel beta
      amylase gene, designated ct-Bmy, which is located on chromosome IV of Arabidopsis
      thaliana. Ct-Bmy encodes a precursor protein which contains a typical N-terminal
      chloroplast import signal and is highly similar at the amino acid level to
      extrachloroplastic beta-amylases of higher plants. Expression of the ct-Bmy cDNA
      in E. coli confirmed that the encoded protein possesses beta-amylase activity. CT
      BMY protein, synthesized in vitro, was efficiently imported by isolated pea
      chloroplasts and shown to be located in the stroma. In addition, fusions between
      the predicted CT-BMY transit peptide and jellyfish green fluorescent protein
      (GFP) or the entire CT-BMY protein and GFP showed accumulation in vivo in
      chloroplasts of Arabidopsis. Expression of the GUS gene fused to ct-Bmy promoter
      sequences was investigated in transgenic tobacco plants. GUS activity was most
      strongly expressed in the palisade cell layer in the leaf blade and in
      chlorenchyma cells associated with the vascular strands in petioles and stems.
      Histochemical staining of whole seedlings showed that GUS activity was largely
      confined to the cotyledons during the first 2 weeks of growth and appeared in the
      first true leaves at approximately 4 weeks.

PMID- 10652125
TI  - Arabidopsis thaliana AtHAL3: a flavoprotein related to salt and osmotic tolerance
      and plant growth.
AB  - We have isolated two Arabidopsis thaliana genes, AtHAL3a and AtHAL3b, showing
      homology with HAL3, a yeast protein which regulates the cell cycle and tolerance
      to salt stress through inhibition of the PPZ1 type-1 protein phosphatase.
      Expression of AtHAL3a in yeast hal3 mutants partially complements their LiCl
      sensitivity, suggesting possible conserved functions between both proteins.
      AtHAL3a and AtHAL3b are induced by salt stress and AtHAL3a is the most expressed
      in non-stressed plants, particularly in seeds. In situ hybridization demonstrates
      enrichment of AtHAL3a mRNA in seed embryos and in the vascular phloem of
      different plant tissues. AtHAL3 proteins show striking homology with a group of
      proteins found in fungi, plants and animals and some homology with a large family
      of prokaryotic flavoproteins. Recombinant AtHAL3a protein purified from
      Escherichia coli was yellow because it contained a non-covalently bound
      chromophore revealed as flavin mononucleotide. Trans- genic Arabidopsis plants,
      with gain of AtHAL3a function, show altered growth rates and improved tolerance
      to salt and osmotic stress.

PMID- 10652126
TI  - Transient expression of members of the germin-like gene family in epidermal cells
      of wheat confers disease resistance.
AB  - The wheat genome encodes a family of germin-like proteins that differ with
      respect to regulation and tissue specificity of expression of the corresponding
      genes. While germin exhibits oxalate oxidase (E.C. 1.2.3.4.) activity, the germin
      like proteins (GLPs) have no known enzymatic activity. A role of oxalate oxidase
      in plant defence has been proposed, based on the capacity of the enzyme to
      produce H2O2, a reactive oxygen species. The role in defence of germin and other
      members of the germin-like gene family was functionally assessed in a transient
      assay system based on particle bombardment of wheat leaves. Transient expression
      of the pathogen-induced germin gf-2.8 gene, but not of the constitutively
      expressed HvGLP1 gene, reduced the penetration efficiency of Blumeria (syn.
      Erysiphe) graminis f.sp. tritici, the causal agent of wheat powdery mildew, on
      transformed cells. Two engineered germin-gf-2.8 genes and the TaGLP2a gene, which
      all encoded proteins without oxalate oxidase activity, also reduced the
      penetration efficiency of the fungus, demonstrating that oxalate oxidase activity
      is not required for conferring enhanced resistance. Instead, activity tagging
      experiments showed that in cells transiently expressing the germin gf-2.8 gene,
      the transgene product became insolubilized at sites of attempted fungal
      penetration where localised production of H2O2 was observed. Thus, germin and
      GLPs may play a structural role in cell-wall re-enforcement during pathogen
      attack.

PMID- 10652127
TI  - Plant interstitial telomere motifs participate in the control of gene expression
      in root meristems.
AB  - The promoters of Arabidopsis eEF1A genes contain a telomere motif, the telo-box,
      associated with an activating sequence, the tef-box. Database searches indicated
      the presence of telo-boxes in the 5' region of numerous genes encoding components
      of the translational apparatus. By using several promoter constructs we
      demonstrate that the telo-box is required for the expression of a beta
      glucoronidase gene in root primordia of transgenic Arabidopsis. This effect was
      observed when a telo-box was inserted upstream or downstream from the
      transcription initiation site, and occurred in synergy with the tef-box. These
      results clearly indicate that interstitial telomere motifs in plants are involved
      in control of gene expression. South-western screening of a lambdaZAP library
      with a double-stranded Arabidopsis telomere motif resulted in characterization of
      a protein related to the conserved animal protein Puralpha. The possibility of a
      regulation process similar to that achieved by the Rap1p in Saccharomyces
      cerevisiae is discussed.

PMID- 10652128
TI  - Identification of a novel peptide motif that mediates cross-linking of proteins
      to cell walls.
AB  - A cDNA clone representing a member of a novel class of cell wall proteins was
      isolated from tobacco plants. We have designated this protein NtTLRP for tyrosine
      and lysine-rich protein. It is structurally related to the previously identified
      TLRP from tomato plants, sharing a high amino-acid sequence similarity at the C
      terminal region. This region contains what appears to be a novel peptide motif
      which we call CD for cysteine-rich domain, and which is common to several other
      cell-wall proteins. By using a functional test in transgenic plants, we
      demonstrate that the presence of the CD domain is per se sufficient to cross-link
      previously soluble proteins to the cell wall. We present evidence that NtTLRP is
      cross-linked and specifically localizes to the cell wall of lignified cells. The
      highly localized deposition of NtTLRP in these cells indicates that this class of
      cell-wall proteins may have a specialized function in the formation of xylem
      tissue.

PMID- 10652130
TI  - Sucrose availability on the aerial part of the plant promotes morphogenesis and
      flowering of Arabidopsis in the dark.
AB  - Conditions to promote dark morphogenesis and flower-ing in Arabidopsis have
      previously been limited to liquid cultures and to a few laboratory ecotypes. We
      have obtained development and flowering of Arabidopsis plants under complete
      darkness by growing them on vertical Petri dishes containing solid agar medium
      with sucrose. Under these conditions, all the ecotypes tested were able to
      develop, giving rise to etiolated plants that flowered after producing a certain
      number of leaves. Dark-grown plants showed similarities with phytochrome
      deficient mutants and were different from de-etiolated or constitutive
      photomorphogenesis mutants such as det and cop. Late- and early-flowering
      ecotypes, showing large differences in flowering time and leaf number under long
      days, flowered with a similar number of leaves when grown in the dark. Rapid dark
      flowering of late-flowering ecotypes was not an effect of darkness but the result
      of the interaction between dark and sucrose availability at the aerial part of
      the plant, since sucrose also had an effect when plants were grown in the light.
      Gibberellin-deficient and insensitive mutants were delayed in the initiation of
      flowers in the dark, indicating a role for these hormones in flowering promotion
      in the dark. The late-flowering phenotype of mutants at different loci of the
      autonomous and long-day-dependent flowering induction pathways was rescued in
      dark growth conditions. However, the late-flowering phenotype of ft and fwa
      mutants was not rescued by sucrose either in the dark or in the light, suggesting
      a different role for these genes in flowering induction.

PMID- 10652129
TI  - Elicitor-responsive, ethylene-independent activation of GCC box-mediated
      transcription that is regulated by both protein phosphorylation and
      dephosphorylation in cultured tobacco cells.
AB  - In cultured XD6S tobacco cells, xylanase from Trichoderma viride (TvX) induced
      the expression of a luciferase reporter gene that was under the control of a GCC
      box, which is an 11 bp sequence (TAAGAGCCGCC) that is found in the 5'-upstream
      region of pathogen-responsive defence genes that include genes for class I basic
      chitinase. TvX-induced biosynthesis of ethylene was not required for the TvX
      activated transcription. The TvX-induced, GCC box-mediated transcription of the
      reporter gene was completely blocked not only by staurosporine, an inhibitor of
      serine/threonine protein kinases, at 1 microM, but also by calyculin A, an
      inhibitor of protein phosphatases 1 and 2A, at 0.2 microM. It appeared also that
      protein synthesis de novo was required for the GCC box-mediated transcription of
      the reporter gene. Accumulation of mRNAs for various ERFs (ethylene-responsive
      transcription factors), which have been shown to bind specifically to the GCC
      box, was also induced by TvX prior to increases in the level of mRNA for a class
      I basic chitinase. In particular, the level of mRNA for EFR2 reached a maximum
      from 3 to 6 h, whereas levels of mRNAs for ERF3 and ERF4 were highest 0.5 h after
      the start of treatment of TvX and decreased thereafter. Moreover, induction of
      accumulation of the mRNA for ERF2 was inhibited by staurosporine and calyculin A.
      These results suggest that ERF2 might play a major role in TvX-induced, GCC box
      mediated transcription of genes and that both protein kinase(s) and protein
      phosphatase(s) might be involved, as positive regulators, in the signal
      transduction pathway that leads to expression of ERF2 and subsequent GCC box
      mediated transcription of genes.

PMID- 10652131
TI  - A tomato homeobox gene (HD-zip) is involved in limiting the spread of programmed
      cell death.
AB  - Antisense suppression in transgenic tomato plants of H52, a gene encoding a new
      homeodomain protein of the HD-Zip class, produces a conditional lethal phenotype.
      The transgenic lines that survive exhibit spontaneous misregulation of cell death
      control in leaves, which, once initiated, propagates and engulfs the entire leaf.
      Activation of defence genes, over-accumulation of ethylene and conjugated
      salicylic acid, and growth reduction of virulent pathogens also occurs in these
      plants. In wild-type plants, H52 is up-regulated upon infection, mirroring the
      generation of the oxidative burst which normally precedes the hypersensitive
      response (HR). Thus, H52 appears to be a transcription factor involved in
      cellular protection by limiting spread of programmed cell death in plants.

PMID- 10652132
TI  - Transcriptional activation of a heat shock gene promoter in sunflower embryos:
      synergism between ABI3 and heat shock factors.
AB  - Transient expression analyses in sunflower embryos demonstrated that ABI3, a seed
      specific transcription factor from Arabidopsis, activated chimaeric genes with
      the Ha hsp17.7 G4 promoter. Nucleotide substitutions at crucial positions of heat
      shock cis-elements established that they are required for the transcriptional
      activation involving ABI3. Trans-activation with Lp-HSFA1, a heat shock factor
      from tomato, reproduced the activation patterns of wild-type and mutant promoters
      observed with ABI3. In addition, ABI3 and Lp-HSFA1 synergistically activated the
      Ha hsp17. 7 G4 promoter, but only when it contained the intact proximal and
      distal heat shock cis-elements. The activation domain of Lp-HSFA1 was necessary
      for promoter activation. An amino terminal deletion of ABI3 had dominant negative
      effects on activation by Lp-HSFA1. We failed to detect a substantial
      transcriptional activation by ABI3 in the absence of either functional heat shock
      factors or heat shock elements (HSEs). Furthermore, the wild-type, but not the
      mutant HSEs (from - 136 to - 49 in Ha hsp17.7 G4) were sufficient, in the context
      of a - 46 CaMV 35S promoter, to support activation by Lp-HSFA1, or Lp-HSFA1 and
      ABI3. These results demonstrate, for the first time, transcriptional activation
      of a heat shock protein promoter by ABI3. We also suggest that ABI3 functions as
      a transcriptional co-activator through heat shock factors.

PMID- 10652133
TI  - Cloning and expression of flavone synthase II from Gerbera hybrids.
AB  - In Gerbera hybrids, flavone synthesis is controlled by the locus Fns. The
      responsible enzyme, flavone synthase II, belongs to the NADPH-dependent
      cytochrome P450 monooxygenases. From two different chemogenetic defined Gerbera
      lines with the dominant (fns +.) or recessive (fns fns) alleles at the locus Fns,
      a cytochrome P450 fragment (CypDDd7a) was isolated using a differential display
      technique with upstream primers based on the conserved heme-binding region of
      cytochrome P450 proteins. The full-length cDNA (CYP93B2) which contained the open
      reading frame and part of the CypDDd7a sequence was isolated via 5'-RACE and end
      to-end PCR with gene specific primers. Northern blot analysis of total RNA of
      Gerbera hybrids indicated that the CYP93B2 gene was only transcribed in lines
      with the dominant allele fns + and that the transcript levels during flower
      development are in agreement with the measured enzyme activity of FNS II and
      flavone accumulation. Microsomes from yeast cells expressing CYP93B2 catalysed
      the direct formation of [14C]-flavones from the respective [14C]-flavanones.
      Thus, CYP93B2 was shown to encode flavone synthase II. This is the first report
      of the isolation and expression of a functional FNS II cDNA clone from any
      species. The comparison of amino acid sequences revealed that CYP93B2 had 54%
      identity with the sequence of CYP93B1, which has recently been reported as a (2S)
      flavanone 2-hydroxylase of Glycyrrhiza echinata L.

PMID- 10652134
TI  - Side chains of pectic polysaccharides are regulated in relation to cell
      proliferation and cell differentiation
AB  - The occurrence and function of the side chains occurring in the
      rhamnogalacturonan I domain of pectic poly- saccharides have been investigated
      during carrot cell development using monoclonal antibodies to defined epitopes of
      (1-->4)-beta-D-galactan and (1-->5)-alpha-L-arabinan. Immunolocalization studies
      of carrot root apices indicated that cell walls in the central region of the
      meristem contained higher levels of (1-->5)-alpha-arabinan than the cell walls of
      surrounding cells. In contrast (1-->4)-beta-galactan was absent from the cell
      walls of the central meristematic cells but appeared abundantly at a certain
      point during root cap cell differentiation and also appeared in cell walls of
      differentiating stele and cortical cells. This developmental pattern of epitope
      occurrence was also reflected in a suspension-cultured carrot cell line that can
      be induced to switch from proliferation to elongation by altered culture
      conditions. (1-->4)-beta-galactan occurred at a low level in cell walls of
      proliferating cells but accumulated rapidly in cell walls following induction,
      before any visible cell elongation, while (1-->5)-alpha-arabinan was present in
      cell walls of proliferating cells but was absent from cell walls of elongated
      cells. Immunochemical assays of the cultured cells confirmed the early appearance
      of (1-->4)-beta-galactan during the switch from cell proliferation to cell
      elongation. Anion-exchange chromatography confirmed that (1-->4)-beta-galactan
      was attached to acidic pectic domains and also indicated that it was separate
      from a distinct homogalacturonan-rich component. These results indicate that the
      neutral components of pectic polysaccharides may have important roles in plant
      cell development.

PMID- 10652135
TI  - Molecular domains of the cellulose/xyloglucan network in the cell walls of higher
      plants.
AB  - Cellulose and xyloglucan (XG) assemble to form the cellulose/XG network, which is
      considered to be the dominant load-bearing structure in the growing cell walls of
      non-graminaceous land plants. We have extended the most commonly accepted model
      for the macromolecular organization of XG in this network, based on the
      structural and quantitative analysis of three distinct XG fractions that can be
      differentially extracted from the cell walls isolated from etiolated pea stems.
      Approximately 8% of the dry weight of these cell walls consists of XG that can be
      solubilized by treatment of the walls with a XG-specific endoglucanase (XEG).
      This material corresponds to an enzyme-susceptible XG domain, proposed to form
      the cross-links between cellulose microfibrils. Another 10% of the cell wall
      consists of XG that can be solubilized by concentrated KOH after XEG treatment.
      This material constitutes another XG domain, proposed to be closely associated
      with the surface of the cellulose microfibrils. An additional 3% of the cell wall
      consists of XG that can be solubilized only when the XEG- and KOH-treated cell
      walls are treated with cellulase. This material constitutes a third XG domain,
      proposed to be entrapped within or between cellulose microfibrils. Analysis of
      the three fractions indicates that metabolism is essentially limited to the
      enzyme-susceptible domain. These results support the hypothesis that enzyme
      catalyzed modification of XG cross-links in the cellulose/XG network is required
      for the growth and development of the primary plant cell wall, and demonstrate
      that the structural consequences of these metabolic events can be analyzed in
      detail.

PMID- 10652136
TI  - The tomato I-box binding factor LeMYBI is a member of a novel class of myb-like
      proteins.
AB  - The RBCS3A gene of tomato belongs to a small gene family consisting of five
      members. Although the RBCS1, RBCS2 and RBCS3A promoters contain closely related
      cis regulatory sequences, the expression patterns of the genes are different.
      Whereas the RBCS1 and RBCS2 genes are expressed in both leaves and young fruit,
      the RBCS3A promoter is highly active in leaves, but not in young fruit. This lack
      of transcription could be due to a mutation in the RBCS3A promoter creating the
      so-called F-box, a protein binding site located between the activating cis
      elements, the I-box and G-box. In order to identify proteins that bind to the
      RBCS3A I-box/F-box region, the yeast one-hybrid system was used. One clone,
      LeMYBI was isolated which contains strong similarity to plant myb transcription
      factors. The encoded LeMYBI protein is at least 188 amino acids in length and
      contains two myb-like domains located at the amino terminus and close to the
      carboxy terminus, separated by a negatively charged domain. The protein contains
      a SHAQKYF amino acid signature motif in the second myb-like repeat, which is
      highly conserved in a number of recently identified plant myb-related genes, thus
      defining a new class of plant DNA-binding proteins. LeMYBI binds specifically to
      the I-box sequence of the RBCS1, RBCS2 and RBCS3A promoters, therefore
      representing the first cloned I-box binding factor. LeMYBI acts as a
      transcriptional activator in yeast and plants, and binds to the I-box with a DNA
      binding domain located in the carboxyterminal domain.

PMID- 10652138
TI  - Metabolic engineering of p-hydroxybenzylglucosinolate in Arabidopsis by
      expression of the cyanogenic CYP79A1 from Sorghum bicolor.
AB  - Glucosinolates are natural products in cruciferous plants, including Arabidopsis
      thaliana. CYP79A1 is the cytochrome P450 catalysing the conversion of tyrosine to
      p-hydroxyphenylacetaldoxime in the biosynthesis of the cyanogenic glucoside
      dhurrin in sorghum. Both glucosinolates and cyanogenic glucosides have oximes as
      intermediates. Expression of CYP79A1 in A. thaliana results in the production of
      high levels of the tyrosine-derived glucosinolate p-hydroxybenzylglucosinolate,
      which is not a natural constituent of A. thaliana. This provides further evidence
      that the enzymes have low substrate specificity with respect to the side chain.
      The ability of the cyanogenic CYP79A1 to integrate itself into the glucosinolate
      pathway has important implications for an evolutionary relationship between
      cyanogenic glucosides and glucosinolates, and for the possibility of genetic
      engineering of novel glucosinolates.

PMID- 10652137
TI  - Chlorophyll breakdown by chlorophyllase: isolation and functional expression of
      the Chlase1 gene from ethylene-treated Citrus fruit and its regulation during
      development.
AB  - We report on the isolation, functional expression and characterization of a cDNA
      encoding chlorophyllase, the enzyme catalyzing the first step in the chlorophyll
      breakdown pathway. The Chlase1 cDNA from Valencia Orange (Citrus sinensis cv.
      Valencia) was obtained by RT-PCR using degenerate primers based on the amino acid
      sequence of the previously purified protein. Chlase1 encodes a protein of 329
      amino acids, including a sequence domain characterizing serine-lipases and a
      putative chloroplast-directing transit peptide. The Chlase1 gene encodes an
      active chlorophyllase enzyme which catalyzes the dephytylation of chlorophyll as
      shown by in vitro recombinant enzyme assays. Chlorophyllase expression at the
      transcript level in Valencia orange peel was found to be low and constitutive
      during natural fruit development without significant increase towards color-break
      and ripening. However, ethylene treatment induced an increase in chlorophyllase
      transcript at all stages of development. An enhanced response to ethylene
      treatment was observed during the months of October and November, corresponding
      to the time of natural color-break. The senescence-delaying regulator gibberellin
      A3 (GA3) inhibited the effect of ethylene on chlorophyllase transcript
      accumulation. The data presented suggest that chlorophyllase may not be the
      regulator of chlorophyll breakdown during natural fruit ripening but is
      consistent with the notion that chlorophyll is gradually degraded during ripening
      due to a negative balance between synthesis and breakdown. According to this
      model, exogenous application of ethylene accelerates chlorophyll breakdown due to
      increased de novo synthesis of chlorophyllase. Further experimentation on the
      regulation and role of chlorophyllase in planta will be facilitated by the gene
      tools established in this work.

PMID- 10652139
TI  - 14-3-3 proteins double the number of outward-rectifying K+ channels available for
      activation in tomato cells
AB  - Outward-rectifying K+ channels are modulated in response to environmental stimuli
      by a range of intracellular factors, such as cytoplasmic Ca2+, pH, kinases and
      phosphatases. Here we report that voltage-dependent outward-rectifying K+
      channels in tomato cells are also targets for modulation by 14-3-3 proteins. In
      whole-cell patch-clamp experiments, recombinant 14-3-3 protein (tomato isoform
      TFT7) was introduced into tomato cell protoplasts via the patch pipette. As a
      result the steady-state outward K+ current increased twofold and this increase
      was not dependent upon the presence of cytoplasmic ATP. A phosphorylated peptide
      that contained a phosphorylated 14-3-3 target-binding motif (RSTS*TP), derived
      from nitrate reductase, blocked the effect of 14-3-3, thus showing the specific
      nature of 14-3-3 action. Kinetic parameters of the conductance, like
      (de)activation kinetics, voltage dependence of gating and activation potential,
      were not significantly different between control and 14-3-3 infused cells.
      Analysis of single-channel activity and whole-cell noise indicated that the
      single-channel conductance was not affected by 14-3-3 infusion. We conclude that
      14-3-3 proteins recruit 'sleepy' channels into a voltage-activatable state. The
      molecular mechanism underlying the 1 : 1 ratio of constitutively active and 14-3
      3 recruited channels is discussed in the light of known functions of 14-3-3
      dimers.

PMID- 10652140
TI  - FALSIFLORA, the tomato orthologue of FLORICAULA and LEAFY, controls flowering
      time and floral meristem identity.
AB  - Characterization of the tomato falsiflora mutant shows that fa mutation mainly
      alters the development of the inflorescence resulting in the replacement of
      flowers by secondary shoots, but also produces a late-flowering phenotype with an
      increased number of leaves below first and successive inflorescences. This
      pattern suggests that the FALSIFLORA (FA) locus regulates both floral meristem
      identity and flowering time in tomato in a similar way to the floral identity
      genes FLORICAULA (FLO) of Antirrhinum and LEAFY (LFY) of Arabidopsis. To analyse
      whether the fa phenotype is the result of a mutation in the tomato FLO/LFY gene,
      we have cloned and analysed the tomato FLO/LFY homologue (TOFL) in both wild-type
      and fa plants following a candidate gene strategy. The wild-type gene is
      predicted to encode a protein sharing 90% identity with NFL1 and ALF, the FLO/LFY
      like proteins in Nicotiana and Petunia, and about 80 and 70% identity with either
      FLO or LFY. In the fa mutant, however, the gene showed a 16 bp deletion that
      results in a frameshift mutation and in a truncated protein. The co-segregation
      of this deletion with the fa phenotype in a total of 240 F2 plants analysed
      supports the idea that FA is the tomato orthologue to FLO and LFY. The gene is
      expressed in both vegetative and floral meristems, in leaf primordia and leaves,
      and in the four floral organs. The function of this gene in comparison with other
      FLO/LFY orthologues is analysed in tomato, a plant with a sympodial growth habit
      and a cymose inflorescence development.

PMID- 10652141
TI  - Nuclear export of proteins in plants: AtXPO1 is the export receptor for leucine
      rich nuclear export signals in Arabidopsis thaliana.
AB  - Transport across the nuclear envelope is mediated by transport receptors from the
      Importin beta family. We identified Exportin 1 from Arabidopsis (AtXPO1/AtCRM1)
      as the nuclear export receptor for proteins carrying leucine-rich nuclear export
      signals (NESs). AtXPO1 shares 42-50% identity with its functional homologues from
      humans and yeasts. We functionally characterised AtXPO1 by its interaction with
      NESs of animal and plant proteins, which is inhibited by the cytotoxin leptomycin
      B (LMB), and also by its interaction with the small GTPase Ran1 in the yeast two
      hybrid system. Furthermore, we demonstrated the existence of a nuclear export
      pathway for proteins in plants. For the characterisation of nuclear export
      activities, we established an in vivo assay based on the localisation equilibrium
      of a GFP reporter protein fused to both a nuclear localisation signal (NLS) and
      an NES motif. Using this in vivo assay we demonstrated that the NES of the
      heterologous protein Rev is also functional in plants and that its export is
      inhibited by LMB. In addition, we identified a leucine-rich NES in the
      Arabidopsis protein AtRanBP1a. The NES, which is located at the carboxy terminus
      of the protein, is disrupted by mutating three long chain hydrophobic amino acid
      residues to alanine (L176A, L179A, V181A). In BY-2 protoplasts the NES of
      AtRanBP1a is functionally indistinguishable from the Rev NES. Our results
      demonstrate that the machinery for the nuclear export of proteins is functionally
      conserved in plants.

PMID- 10652142
TI  - The different pH optima and substrate specificities of extracellular and vacuolar
      invertases from plants are determined by a single amino-acid substitution.
AB  - Different plant invertase isoenzymes are characterized by a single amino-acid
      difference in a conserved sequence, the WEC-P/V-D box. A proline residue is
      present in this sequence motif of extracellular invertase sequences, whereas a
      valine is found at the same position of vacuolar invertase sequences. The role of
      this distinct difference was studied by substituting the proline residue of
      extracellular invertase CIN1 from Chenopodium rubrum with a valine residue, by
      site-directed mutagenesis. The mutated gene was heterologously expressed in an
      invertase-deficient Saccharomyces cerevisiae strain. The single amino-acid
      difference was shown to be the molecular basis for two enzymatic properties of
      invertase isoenzymes, for both the pH optimum and the substrate specificity. A
      proline in the WEC-P/V-D box determines the more acidic pH optimum and the higher
      cleavage rate of raffinose of extracellular invertases, compared to vacuolar
      invertases that have a valine residue at this position.

PMID- 10652143
TI  - Short communication: the N-terminal fragment of Arabidopsis photomorphogenic
      repressor COP1 maintains partial function and acts in a concentration-dependent
      manner.
AB  - Arabidopsis seedlings exhibit distinct developmental patterns according to their
      light environment: photomorphogenesis in the light and etiolation or
      skotomorphogenesis in darkness. COP1 acts within the nucleus to repress
      photomorphogenesis in darkness, while light depletes COP1 from nucleus and
      abrogates this repression. COP1 contains three structural modules: a RING finger
      followed by a coiled-coil domain, and a WD40 repeat domain at the C-terminus. By
      introducing various domain deletion mutants of COP1 into cop1 null mutant
      backgrounds, we show that all three domains are essential for the function of
      COP1 in vivo. Interestingly, a fragment containing the N-terminal 282 amino acids
      of COP1 (N282) with both the RING finger and coiled-coil modules is sufficient to
      rescue the lethality of the cop1 null mutations at low expression level. However,
      high expression levels of the N282 fragment result in a phenocopy of the cop1
      null mutation. The sensitivity of the seedling to levels of N282 could reflect
      the importance of the abundance of COP1 for the appropriate regulation of
      photomorphogenic development.

PMID- 10652144
TI  - Technical advance: transcript profiling in rice (Oryza sativa L.) seedlings using
      serial analysis of gene expression (SAGE)
AB  - Serial analysis of gene expression (SAGE) was applied for profiling expressed
      genes in rice seedlings. In the SAGE method, a 9-11 bp fragment (tag) represents
      each transcript, and frequency of a tag in the sample directly reflects the
      abundance of the respective mRNA. We studied 10 122 tags derived from 5921
      expressed genes in rice (Oryza sativa L.) seedlings, among which only 1367 genes
      (23.1%) matched the rice cDNA or EST sequences in the DNA database. SAGE showed
      that most of the highly expressed genes in rice seedlings belong to the category
      of housekeeping genes (genes encoding ribosomal proteins or proteins responsible
      for metabolism and cell structure). Unexpectedly, the most highly expressed gene
      in rice seedlings was a metallothionein (MT) gene, and together with three other
      messages for MT, it accounts for 2.7% of total gene expression. To our knowledge,
      this is the first quantitative study of global gene expression in a higher plant.
      We further applied the SAGE technique to identify differentially expressed genes
      between anaerobically treated and untreated rice seedlings. Additionally, we show
      that a longer cDNA fragment can be easily recovered by PCR using the SAGE tag
      sequence as a primer, thereby facilitating the analysis of unknown genes
      identified by tag sequence in SAGE. In combination with micro-array analysis,
      SAGE should serve as a highly efficient tool for the identification and isolation
      of differentially expressed genes in plants.

PMID- 10652145
TI  - Graft transmission of post-transcriptional gene silencing: target specificity for
      RNA degradation is transmissible between silenced and non-silenced plants, but
      not between silenced plants.
AB  - Using the grafting procedure, we examined the transmission of post
      transcriptional gene silencing (PTGS) in Nicotiana benthamiana which had been
      transformed with the coat protein gene, including the 3' non-translated region of
      the sweet potato feathery mottle potyvirus. Transmission of PTGS from silenced
      lines to non-silenced ones was bidirectional, but occurred efficiently from root
      stocks to scions. The level of transgene methylation in non-silenced scions
      grafted onto silenced root stocks was not increased. When grafted scions which
      had become silenced were removed from silenced root stocks and regrafted onto non
      silenced or vector-transformed root stocks, PTGS was maintained. However, their
      progeny did not show PTGS. Previously we reported that our transgenic lines had
      different target specificities of PTGS for RNA degradation: one line recognized
      only the 3' part of the transgene mRNA while others involved the whole transgene
      mRNA (Sonoda et al. 1999, Phytopathology, 89, 385-391). Using these lines, we
      showed that target specificity of PTGS induced in non-silenced scions after
      grafting was determined by that in silenced root stocks. However, unexpectedly,
      target specificity of PTGS induced in silenced scions was not changed [corrected]
      by grafting onto silenced root stocks showing different target specificity,
      indicating that the second PTGS from silenced root stocks was not superimposed to
      silenced scions.

PMID- 10652146
TI  - Arabidopsis ecotypes and mutants that are recalcitrant to Agrobacterium root
      transformation are susceptible to germ-line transformation.
AB  - Germ-line transformation (vacuum infiltration) is frequently used to transform
      Arabidopsis thaliana using Agrobacterium tumefaciens. We have recently identified
      several Arabidopsis ecotypes and T-DNA-tagged mutants that are recalcitrant to
      Agrobacterium-mediated transformation of cut root segments. Some of these
      ecotypes and mutants are deficient in their ability to bind bacteria. Some are
      deficient in T-DNA integration. We report here that using a germ-line
      transformation protocol we transformed these ecotypes and mutants, including
      attachment- and integration-defective Arabidopsis plants, with a frequency
      similar to that of highly susceptible wild-type plants. However, we could not
      transform otherwise highly susceptible Arabidopsis plants by germ-line or root
      transformation using several vir and attachment-deficient Agrobacterium mutants.
      These results indicate that certain plant factors important for transformation
      may exist in germ-line tissue but may be lacking in some somatic cells.

PMID- 10652147
TI  - Immunological analysis of the phosphorylation state of maize C4-form
      phosphoenolpyruvate carboxylase with specific antibodies raised against a
      synthetic phosphorylated peptide.
AB  - The phosphoenolpyruvate carboxylase (PEPC) isozyme involved in C4 photosynthesis
      is known to undergo reversible regulatory phosphorylation under illuminated
      conditions, thereby decreasing the enzyme's sensitivity to its feedback
      inhibitor, L-malate. For the direct assay of this phosphorylation in intact maize
      leaves, phosphorylation state-specific antibodies to the C4-form PEPC were
      prepared. The antibodies were raised in rabbits against a synthetic
      phosphorylated 15-mer peptide with a sequence corresponding to that flanking the
      specific site of regulatory phosphorylation (Ser15) and subsequently purified by
      affinity-chromatography. Specificity of the resulting antibodies to the C4-form
      PEPC phosphorylated at Ser15 was established on the basis of several criteria.
      The antibodies did not react with the recombinant root-form of maize PEPC
      phosphorylated in vitro. By the use of these antibodies, the changes in PEPC
      phosphorylation state were semi-quantitatively monitored under several
      physiological conditions. When the changes in PEPC phosphorylation were monitored
      during the entire day with mature (13-week-old) maize plants grown in the field,
      phosphorylation started before dawn, reached a maximum by mid-morning, and then
      decreased before sunset. At midnight dephosphorylation was almost complete. The
      results suggest that the regulatory phosphorylation of C4-form PEPC in mature
      maize plants is controlled not only by a light signal but also by some other
      metabolic signal(s). Under nitrogen-limited conditions the phosphorylation was
      enhanced even though the level of PEPC protein was decreased. Thus there seems to
      be some compensatory regulatory mechanism for the phosphorylation.

PMID- 10652148
TI  - Distinct features of post-transcriptional gene silencing by antisense transgenes
      in single copy and inverted T-DNA repeat loci.
AB  - The application of antisense transgenes in plants is a powerful tool to inhibit
      gene expression. The underlying mechanism of this inhibition is still poorly
      understood. High levels of antisense RNA (as-RNA) are expected to result in
      strong silencing but often there is no clear correlation between as-RNA levels
      and the degree of silencing. To obtain insight into these puzzling observations,
      we have analyzed several petunia transformants of which the pigmentation gene
      chalcone synthase (Chs) is post-transcriptionally silenced in corollas by
      antisense (as) Chs transgenes. The transformants were examined with respect to
      the steady-state as-RNA level, transcription level of the as-transgenes, the
      repetitiveness and structure of the integrated T-DNAs, and the methylation status
      of the transgenes. This revealed that the transformants can be divided in two
      classes: the first class contains a single copy (S) T-DNA of which the as-Chs
      gene is transcribed, although several-fold lower than the endogenous Chs genes.
      As there are not sufficient as-RNAs to degrade every mRNA, we speculate that
      silencing is induced by double-stranded RNA. The second class contains two T-DNAs
      which are arranged as inverted repeats (IRs). These IR loci are severely
      methylated and the as-Chs transgenes transcriptionally barely active. The
      strongest silencing was observed with IR loci in which the as-Chs transgenes were
      proximal to the centre of the IR. Similar features have been described for co
      suppression by IRs composed of sense Chs transgenes, suggesting that silencing by
      antisense IRs also occurs by co-suppression, either via ectopic DNA pairing or
      via dsRNA.

PMID- 10652149
TI  - Glycosyl-phosphatidylinositol-anchor addition signals are processed in Nicotiana
      tabacum.
AB  - Recent studies have demonstrated the existence of glycosyl-phosphatidylinositol
      (GPI)-anchored proteins in higher plants. In this study we tested whether GPI
      addition signals from diverse evolutionary sources would function to link a GPI
      anchor to a reporter protein in plant cells. Tobacco protoplasts were transiently
      transfected with a truncated form of the Clostridium thermocellum endoglucanase E
      reporter gene (celE') fused with a tobacco secretion signal (PR-1a) at the N
      terminus and either a yeast (GAS1), mammalian (Thy-1) or putative plant (LeAGP-1)
      GPI-anchor addition signal at the C-terminus. The yeast and plant C-terminal
      signals were found to be capable of directing the addition of a GPI-anchor to the
      endoglucanase protein (EGE') as shown by the sensitivity of the lipid component
      of GPI to phosphatidylinositol-specific phospholipase C (PI-PLC) digestion. In
      contrast, the mammalian signal was poorly processed for anchor addition. When
      EGE' was fused to a truncated form of the LeAGP-1 signal (missing three amino
      acids predicted to be critical to signal cleavage and anchor addition), a GPI
      anchor was not linked to the EGE' protein indicating the necessity for the
      missing amino acids. Our results show the conservation of the properties of GPI
      signals in plant cells and that there may be some similar preferences in GPI
      addition signal sequences for yeast and plant cells.

PMID- 10652150
TI  - The soybean Eu3 gene encodes an Ni-binding protein necessary for urease activity.
AB  - Mutation in Eu3 eliminates activity of both soybean ureases, the embryo-specific
      (encoded by Eu1) and the tissue-ubiquitous (encoded by Eu4). eu3-e1 is a
      completely recessive null allele. Eu3-e3 is a semi-dominant specifying 0.1% wild
      type urease activity in the homozygous state and 5-10% as a heterozygote (Meyer
      Bothling et al. 1987). Antibodies to plant UreG, a homologue of the bacterial
      urease accessory protein, revealed a 32 kDa protein (p32) in embryos of the
      Eu3/Eu3 precursor genotype. p32 is identical to UreG by the criteria of size,
      antigenicity, and its ability to bind Ni2+, a trait expected from the deduced
      histidine-rich N-terminus of UreG. UreG was absent in eu3-e1/eu3-e1, and lack of
      UreG co-segregated with eu3-e1. Eu3-e3 specified a UreG transcript which coded
      valine in place of alanine at residue 142 (A142V) confirming thatEu3 encodes
      UreG, which is renamed Eu3. Eu3 (A142V) retained Ni-binding ability. Eu3 is
      directly involved in urease activation, since anti-Eu3 (UreG) antibodies
      inhibited the in vitro activation of urease. Eu1 (embryo urease) and Eu3
      accumulated in parallel in the developing embryo. The presence of Eu1 was not
      necessary for the high embryonic level of Eu3. However, the presence of Eu3
      appeared to be important for accumulation of Eu1, perhaps by stabilizing it by Ni
      insertion. At the level of sensitivity employed Eu3 was detected in crude
      extracts of embryos but not non-embryonic tissues which have 1/500th the embryo
      urease activity. Functional Eu3, however, is necessary for activation of the
      ubiquitous urease in non-embryonic tissues.

PMID- 10652151
TI  - Post-transcriptional defects in tobacco chloroplast mutants lacking the
      cytochrome b6/f complex.
AB  - A variety of post-transcriptional mechanisms govern the synthesis and assembly of
      photosynthetic protein complexes in chloroplasts. To test whether such mechanisms
      are conserved between photosynthetic algae and vascular plants, we have
      interrupted the chloroplast petA, petB and petD genes of tobacco, which encode
      three subunits of the cytochrome b6/f complex, and compared our results to those
      previously obtained with Chlamydomonas reinhardtii. As expected, the mutants
      exhibited high chlorophyll fluorescence, consistent with the loss of a functional
      cytochrome b6/f complex. Unlike the corresponding mutants of Chlamydomonas,
      however, cytochrome f was barely detectable in the DeltapetB or DeltapetD
      mutants. The amounts of petB- and petD-containing mRNAs were reduced in the
      mutants compared to wild-type plants, but the remaining mRNA was normally
      associated with polysomes. In contrast, there was a decrease in polysome
      association of the polycistronic petA mRNA in the DeltapetB and DeltapetD
      mutants, suggesting that the synthesis of cytochrome f may be decreased in the
      absence of cytochrome b6 or SUIV. These results are discussed in light of the
      translational autoregulation model that has been proposed for cytochrome b6/f
      complex assembly in Chlamydomonas.

PMID- 10652152
TI  - Agrobacterium transient expression system as a tool for the isolation of disease
      resistance genes: application to the Rx2 locus in potato.
AB  - Rx2 confers resistance against potato virus X (PVX). To clone Rx2, we developed a
      system based on Agrobacterium-mediated transient expression of candidate R genes
      in transgenic tobacco leaves expressing the PVX coat protein elicitor of Rx2
      mediated resistance. Using this system, a potato gene eliciting HR specifically
      in the presence of the elicitor was identified. Based on genetical and functional
      analysis, it is concluded that the cloned gene is Rx2. The transient expression
      system is potentially adaptable to cloning of any other resistance gene. The Rx2
      locus is on chromosome V of potato and the encoded protein is highly similar to
      the products of Rx1 and Rxh1 encoded on potato chromosome XII. Rxh1 has been
      shown elsewhere to encode a potato cyst nematode resistance gene Gpa2. All three
      proteins are in the leucine zipper-nucleotide binding site-leucine rich repeat
      class of resistance gene products. Rx1 and Rx2 are functionally identical and are
      almost identical in the C terminal region consistent with a role of the leucine
      rich repeats in recognition of the PVX coat protein. In the N terminal, half
      there are some regions where the Rx1 and Rx2 proteins are more similar to each
      other than to the Rxh1 protein. However, in other regions these proteins are more
      similar to Rxh1 than to each other. Based on this mosaic pattern of sequence
      similarity, we conclude that sequence exchange occurs repeatedly between
      genetically unlinked disease resistance genes through a process of gene
      conversion.

PMID- 10652153
TI  - An abundant TIP expressed in mature highly vacuolated cells.
AB  - Aquaporins are water channel proteins found in vacuolar membranes and plasma
      membranes, and belong to the major intrinsic protein (MIP) family of proteins. In
      the present study, we purified a 75 kDa MIP protein from a crude fraction of
      spinach leaf intracellular membranes. Upon urea/SDS-PAGE, the 75 kDa protein
      appeared as a 21 kDa polypeptide, and the 75 kDa species therefore probably
      represents a tetramer. The corresponding cDNA was obtained by PCR cloning and had
      an open reading frame encoding a 25.1 kDa protein. The protein, So-deltaTIP, was
      most homologous to the tonoplast intrinsic protein (TIP) subfamily of plant MIPs.
      Using affinity-purified So-deltaTIP-specific peptide antibodies, we investigated
      the subcellular and tissue distribution of So-deltaTIP. So-deltaTIP was
      specifically located in the vacuolar membrane. It was abundant in most vacuolated
      cells in all vegetative organs, but was excluded from the leaf epidermis as well
      as from the root phloem parenchyma and meristem. In spite of the high sequence
      homology between delta-TIPs of spinach, Arabidopsis, sunflower and radish, their
      expression patterns were totally different. However, a comparison of the
      expression pattern of So-deltaTIP with that of more distantly related TIPs showed
      similarities with Arabidopsis gamma-TIP, which is expressed in zones of cell
      elongation/differentiation but excluded from meristematic tissues. Meristematic
      cells are characterized by many small vacuoles as opposed to elongating and
      mature cells, which generally harbour a single, large vacuole. Our results
      indicate that the expression of So-deltaTIP may be induced when the large vacuole
      is formed.

PMID- 10652154
TI  - The ethylene-inducible PK12 kinase mediates the phosphorylation of SR splicing
      factors.
AB  - The tobacco PK12 is induced by the plant hormone ethylene and is a member of the
      LAMMER family of protein kinases. Members of this family contain in their C
      terminus a unique 'EHLAMMERI/VLGPLP' motif of unknown function, and are related
      to cyclin- and mitogen-activated protein (MAP)-dependent kinases. The animal
      members of this class play a role in differentiation. They phosphorylate and
      physically interact with serine/arginine-rich (SR) splicing factors in vivo to
      alter their activity and the splicing of target mRNAs. SR proteins have been
      recently described in plants. The capability of PK12 LAMMER kinase to bind and
      phosphorylate SR proteins was tested in vitro by kinase and binding assays. The
      tobacco PK12 phosphorylated both animal and plant SR proteins and specifically
      interacted with the plant splicing factor atSRp34/SR1. In addition, by site
      directed mutagenesis, the LAMMER motif was found to be required for PK12 kinase
      activity but was not necessary for substrate binding. Consistent with a role in
      phosphorylation of splicing factors, PK12 was found to localize to the nucleus
      when transiently over-expressed in suspension cells.

PMID- 10652155
TI  - An efficient screen for reproductive pathways using mature seeds of monocots and
      dicots.
AB  - Seed samples of 32 species (obligate and facultative sexuals and apomicts of
      monocots and dicots) were investigated by flow cytometry to reveal the pathway of
      reproduction. Ten different pathways of seed formation could be reconstructed
      considering whether the female and/or male gametes were reduced or unreduced, the
      embryos arose via the zygotic or parthenogenetic route and the endosperm via the
      pseudogamous or autonomous route. The screen is suited to select sporophytic or
      gametophytic mutants in sexual species, to identify pure sexual or obligate
      apomictic genotypes from facultative apomictic species, and to analyze the
      inheritance of the individual reproductive processes. Corresponding unique
      results are presented for Arabidopsis, Arabis, Hypericum and Poa. The screen of
      mature seeds by flow cytometry yielded more information about the reproductive
      behavior of individual plants than any other available test, and is very useful
      both in basic research and plant breeding.

PMID- 10652156
TI  - In vivo fluorescence correlation microscopy (FCM) reveals accumulation and
      immobilization of Nod factors in root hair cell walls.
AB  - Fluorescence correlation microscopy (FCM) is a new single-molecule detection
      technique based on the confocal principle to quantify molecular diffusion and
      concentration of fluorescent molecules (particles) with sub-micron resolution. In
      this study, FCM is applied to examine the diffusional behaviour of fluorescent
      Nod factor analogues on living Vicia sativa root hairs. Three recently described
      Nod factors with a fluorescent acyl chain (Goedhart et al. Biochemistry 1999, 38,
      10898-10907) were used. Plasmolysis of fluorescently labelled root hairs showed
      that the Nod factors are predominantly located in the cell wall, as hardly any
      fluorescence could be detected in the plasma membrane. After Nod factor-induced
      root hair deformation, the new outgrowth was not labelled, indicating a lack of
      migration of Nod factors to the newly synthesized cell wall. In agreement, FCM
      showed a > 1,000-fold reduction of molecular mobility of the fluorescence Nod
      factors upon binding to the cell wall. In addition, FCM demonstrated that Nod
      factors, when exogenously applied in aqueous solution at 10 nM, markedly
      concentrate in the cell wall of root hairs (up to 50-fold). The feasibility of
      applying FCM for the study of living plant cells as well as the implications of
      our results for the perception of Nod factors are discussed.

PMID- 10652157
TI  - Mannose binding lectin polymorphisms are associated with early age of disease
      onset and autoimmunity in common variable immunodeficiency.
AB  - Mannose binding lectin (MBL) is an important component of the innate immune
      response. Low producing MBL alleles are associated with an increased risk of
      infection, especially when adaptive immunity is already compromized. We
      investigated the role of MBL polymorphism in common variable immunodeficiency
      (CVID), a disease of unknown aetiology characterized by defective humoral
      immunity, recurrent infections and highly variable clinical phenotype. Six
      biallelic single nucleotide polymorphisms in the MBL promoter and coding region (
      550, - 221, + 4, codons 52, 54 and 57) were haplotyped using a novel PCR-SSP
      method in 163 CVID patients and 100 controls. Low producing coding alleles and
      promoter haplotypes were associated with early age of disease onset. The mean age
      of disease onset was 14.5 years in patients with low producing MBL coding
      alleles, compared with 25 years in patients with wild type coding regions (t-test
      P = 0.002). Mean age of onset in patients with the low producing LXPA haplotype
      was 6.8 years, compared with 29.3 years for the HYPA haplotype (P = 0.003). The
      MBL + 4 Q allele was associated with autoimmune disease (P = 0.003, OR 4.4).
      These results suggest that MBL deficiency compounds the antibody deficiency in
      CVID, and reinforces the ostensible role of MBL in innate immunity. MBL
      deficiency may also facilitate the development of autoimmune disease in CVID.

PMID- 10652158
TI  - Cytotoxic T-lymphocyte clones, established by stimulation with the HLA-A2 binding
      p5365-73 wild type peptide loaded on dendritic cells In vitro, specifically
      recognize and lyse HLA-A2 tumour cells overexpressing the p53 protein.
AB  - Mutations in the tumour suppressor gene p53 are among the most frequent genetic
      alterations in human malignancies, often associated with an accumulation of the
      p53 protein in the cytoplasm. We have generated a number of cytotoxic T
      lymphocyte (CTL) clones that specifically recognize the HLA-A*0201 p53 wild type
      peptide RMPEAAPPV [65-73], designated R9V, by the in vitro stimulation of CD8
      enriched peripheral blood lymphocytes from a healthy HLA-A*0201 donor using
      peptide loaded autologous dendritic cells. A total of 22 CTL clones were
      generated from the same bulk culture and demonstrated to carry identical T-cell
      receptors. The CTL clone, 2D9, was shown to specifically lyse the HLA-A*0201+
      squamous carcinoma cell line SCC9 and the breast cancer cell line MDA-MB-468. Our
      data demonstrate that human peripheral blood lymphocytes from normal healthy
      individuals comprise T cells capable of recognizing p53 derived wild type (self)
      peptides. Furthermore, the capacity of R9V specific T cell clones to exert HLA
      restricted cytotoxicity, argues that the R9V peptide is naturally presented on
      certain cancer cells. This supports the view that p53 derived wild type peptides
      might serve as candidate target antigens for the immunotherapeutic treatment of
      cancer.

PMID- 10652159
TI  - Recognition of auto- and exoantigens by V4-34 gene encoded antibodies.
AB  - The antigenic specificities of 24 V4-34-encoded monoclonal antibodies were
      compared with the amino acid sequence. The specificities were divided into three
      categories, red blood cells, B lymphocytes and auto/exoantigens. Six anti-I
      monoclonal antibodies, with multiple substitutions in their VH region, did not
      bind B lymphocytes or auto/exoantigens. Reactivity to these two antigens
      segregated with the 16 anti-i monoclonal antibodies, which were derived from the
      near germline V4-34 gene. All anti-i monoclonal antibodies bound B lymphocytes,
      albeit with varying intensities. B-cell binding correlated with basic amino acids
      in the VH-CDR3. Reactivity to auto/exoantigens was demonstrated only by a subset
      anti-i monoclonal antibodies and did not correlate with B-lymphocyte or i-antigen
      binding. These anti-ssDNA reactive monoclonal antibodies had basic amino acids in
      the VH-CDR3, strongly supporting the suggested role of arginine in DNA binding.
      However, an arginine-rich CDR3 was not enough to ensure DNA reactivity, since six
      other anti-i monoclonal antibodies that fulfilled this criteria did not bind
      ssDNA. Thus it is possible that the anti-DNA reactivity of V4-34-encoded
      monoclonal antibodies is mediated by the classic antigen-binding groove generated
      by the CDRs of the heavy/light chains. In contrast, anti-B-cell/i-antigen
      reactivity is mediated, unconventionally, by the V4-34 protein with a dominant
      influence of the VH-CDR3.

PMID- 10652160
TI  - Acute phase serum amyloid A protein increases high density lipoprotein binding to
      human peripheral blood mononuclear cells and an endothelial cell line.
AB  - Serum Amyloid A (SAA) is an acute-phase protein secreted mainly by hepatocytes
      and is largely associated with high-density lipoprotein (HDL) in plasma. It has
      been suggested that SAA alters HDL binding to the cell surface and that this in
      turn changes HDL-mediated cholesterol delivery to cells. Incorporation of SAA
      into HDL at concentrations equivalent to those found physiologically in moderate
      inflammation mediated a 1.5-fold increase in the binding of HDL to adherent
      peripheral blood mononuclear cells but had no effect on binding of the
      lipoprotein to the monocyte cell lines, U937 or THP-1. SAA incorporation also
      increased binding to an endothelial cell line, EA.hy.926. Hepatoma cells (HuH-7)
      showed no change in specific binding of the SAA-enriched HDL particle compared to
      normal HDL. These results suggest that a specific receptor for HDL-bound SAA is
      found on differentiated human macrophages and an endothelial cell line, which may
      have functional significance in lipid metabolism or other macrophage responses
      during inflammation.

PMID- 10652161
TI  - Diversity of lung and spleen immune responses in mice with slowly progressive
      primary tuberculosis.
AB  - The aim of the present study was to assess the compartmentalized immune response,
      in terms of cytokine secretion and cell activation, in lungs and spleens of mice
      with slowly progressive primary tuberculosis. Immunocyte populations from both
      organs were isolated and stimulated with concanavalin A, purified protein
      derivatives and MPT 59. Production of interferon-gamma (IFN-gamma) and
      interleukin-4 (IL-4) was measured using an enzyme-linked immunosorbent assay, and
      cell activation was measured using a tetrazolium colorimetric assay. The IFN
      gamma and IL-4 levels in the supernatants of Mycobacterium tuberculosis antigen
      (Ag)-stimulated lung immunocytes from infected mice were higher than the levels
      from uninfected mice. However, only IL-4 levels were raised in the supernatants
      of Ag-stimulated spleen immunocytes from infected mice. Spontaneous and Ag
      stimulated immunocyte activation was lower only in the lungs of infected mice
      compared with uninfected mice. The level of lung immunocyte activation was
      inversely associated with the extent of gross pulmonary pathology. In conclusion,
      cytokine secretion and cell activation were different between lungs and spleens
      in slowly progressive primary murine tuberculosis. Cytokine diversity may explain
      the confinement of tuberculous lesions in the lungs and the absence of lesions in
      the spleens of mice with slowly progressive tuberculosis.

PMID- 10652162
TI  - A novel activation induced lymphocyte surface antigen, 90.12, is also expressed
      on apoptotic cells.
AB  - We describe a monoclonal antibody, mAb 90.12, which recognizes a novel activation
      induced lymphocyte surface antigen. Flow cytometric analysis of normal tissues
      shows the antigen to be expressed on higher percentages of B lymphocytes in the
      bone marrow than in the spleen and the lymph node. Similarly, the 90.12 antigen
      is expressed on higher percentages of thymocytes than peripheral T cells. MAb 90.
      12 immunoprecipitates three proteins with a molecular weight of 12-18 kDa which
      are not linked to the membrane by phosphotidylinositol. Expression of the 90.12
      antigen is increased on activated B cells and the extent of upregulation varies
      with the stimulus. Lipopolysaccharide (LPS) stimulation results in expression on
      most B cells, while expression is upregulated on only a subset of B cells
      stimulated with anti-immunoglobulin M (IgM), interleukin(IL)4 and IL5. Finally,
      we show that 90.12 antigen expression is also increased on apoptotic cells.

PMID- 10652163
TI  - Recruitment of monocyte derived dendritic cells ex vivo from SIV infected and non
      infected cynomolgus monkeys.
AB  - This study shows that characteristic dendritic, antigen presenting cells, can be
      generated from adherent peripheral blood mononuclear cells (PBMC)/monocytes of
      uninfected and SIVsm-infected cynomolgus monkeys after stimulation in vitro with
      granulocyte macrophage colony stimulating factor (GM-CSF) and interleukin (IL)-4.
      The recruitment of monocyte derived dendritic cells (MDDC) was usually possible
      irrespective of the level of immunodeficiency (CD4-level) and viremia. The
      cynomolgus MDDC closely resembled their human counterpart (immature MDDC) with
      regard to capacity to upregulate CD1a, CD40, CD86 and human leukocyte antigen
      (HLA)-DR and develop dendrites and veiled processes. Such MDDC also increased
      their capacity for antigen uptake (dextran endocytoses/macropinocytosis) and for
      induction of T-cell proliferation in mixed leukocyte reaction (MLR) assays.
      However, although no clear difference with regard to phenotype and morphology was
      seen between MDDC from SIV-infected and uninfected monkeys, a reduction in MLR
      responsiveness in MDDC from SIV infected monkeys was consistently detected within
      each experiment.

PMID- 10652164
TI  - Early changes in peripheral blood T cell subsets induced by antiretroviral
      treatment of human immunodeficiency virus-1 positive individuals.
AB  - Human immunodeficiency virus (HIV)-1 infection causes a gradual decline in
      peripheral blood CD4+ T cells. Shortly after the primary infection, an expansion
      of the activated memory CD8+ T-cell pool is also observed paralleling increased
      levels of plasma viraemia. In the present study we investigated the immediate
      effects of zidovudine therapy on peripheral blood T-cell subsets during the first
      3 weeks of therapy in a group of HIV-1 positive individuals receiving influenza
      vaccine. HIV-1 positive individuals who received vaccine, but no treatment, were
      included as controls. Both the number of CD4+ and CD8+ T cells increased during
      the first week of therapy in parallel with a decline in plasma viraemia. The
      majority of CD4+ T cells contributing to this expansion expressed CD28, CD45RO
      and Fas, whereas the expanded CD8+ T cells were predominantly CD28-, CD45RO+,
      CD38+, Fas+ and Fas+ (CD95). We propose that the increase in the number of
      activated memory T cells observed in peripheral blood immediately after the onset
      of antiretroviral treatment is most likely caused by the redistribution of cells
      from various lymphoid organs in response to decreased levels of viral load in
      these compartments. The degree of T-cell redistribution is probably dependent on
      the magnitude of virus suppression.

PMID- 10652165
TI  - Allergen induced mRNA expression of interleukin-5, but not of interleukin-4 and
      interferon-gamma, in peripheral blood mononuclear cells obtained before the
      pollen season predicts the clinical efficacy of immunotherapy for seasonal
      allergic rhinitis.
AB  - The primary aim of this study was to investigate whether the allergen-induced
      synthesis of cytokines by peripheral blood mononuclear cells (PBMCs) obtained
      immediately before the pollen season could predict the clinical efficacy of
      immunotherapy during the following pollen season. PBMCs (1.0 x 106 cells/ml) were
      obtained from 17 nonatopic subjects and from 60 patients receiving immunotherapy
      for seasonal allergic rhinitis (caused by Japanese cedar pollens) immediately
      before the pollen season of 1998, and were cultured for 24 h in the presence of
      10 mg/ml of Cry j 1, a major allergen of Japanese cedar pollens, at 37 degrees C
      in a fully humidified 5% CO2 atmosphere. Total cellular RNA was extracted from
      the PBMCs, and the allergen-induced interleukin (IL)-4, IL-5 and interferon-gamma
      (IFN-gamma) mRNA expression was determined using a reverse transcription
      polymerase chain reaction. According to the nasal symptoms during the pollen
      season of 1998, the 60 patients on immunotherapy were divided into 36 good
      responders (who had no nasal symptoms and no requirement for rescue medications)
      and 24 poor responders who needed rescue medications to control nasal symptoms.
      Neither IL-4 mRNA nor IL-5 mRNA was expressed in any of the 17 nonatopic
      individuals. By contrast, IL-4 mRNA was expressed in 26 good responders and in 22
      poor responders, and IL-5 mRNA was expressed in eight good responders (22.2%) and
      in 23 poor responders (95.8%). IFN-gamma mRNA was expressed in four nonatopic
      subjects, in nine good responders and in seven poor responders. The expression of
      IFN-gamma did not differ significantly among the nonatopic subjects, the good
      responders and the poor responders. The mRNA expression of IL-5 (P < 0.0001), but
      not of IL-4 (P = 0.0999) and IFN-gamma (P = 0. 7713), differed significantly
      between the good and poor responders. Therefore, our study has highlighted that
      positive expression of IL-5 mRNA in PBMCs sampled immediately before the pollen
      season could be predictive of a poor clinical outcome of immunotherapy during the
      following pollen season and that the down-regulation of IL-5 mRNA expression in
      PBMCs could be an important mechanism of pollen immunotherapy related to the
      clinical efficacy.

PMID- 10652166
TI  - Dysregulated production of interferon-gamma, interleukin-4 and interleukin-6 in
      early tuberculosis patients in response to antigen 85B of Mycobacterium
      tuberculosis.
AB  - Both interferon-gamma (IFN-gamma) and interleukin (IL)-4 expression in T cells
      and IL-6 expression in cells of the monocyte/macrophage lineage were monitored
      using antigen 85B (Ag85B) protein and purified protein derivative (PPD) antigen
      in the early stages of tuberculosis (TB). We showed that the levels of cell
      associated IFN-gamma and IL-4 (mRNA and intracellular cytokine) in Ag85B
      stimulated T cells were significantly depressed in TB patients compared with
      those in healthy tuberculin reactors. On the other hand, the capacity of
      peripheral blood mononuclear cells (PBMC) to produce IL-6 spontaneously ex vivo
      was enhanced in patients (P < 0. 001), but their corresponding capacities to
      respond to Ag85B were not significantly different from those of normal donors.
      After 2 months of antituberculosis therapy, the mean blastogenic responses of
      Ag85B-stimulated PBMC from seven TB patients were increased 6. 1-fold (P =
      0.011). Furthermore, the proportions of both IFN-gamma- (P < 0.01) and IL-4- (P =
      0.05) producing T cells were significantly increased. However, those of IL-6
      producing cells were diminished in response to Ag85B (P = 0.05). Our results
      suggest that there may be an altered regulation of IFN-gamma, IL-4 and IL-6 to
      Ag85B in the early stages of TB.

PMID- 10652167
TI  - Photoscreening for amblyogenic factors by public health personnel: the Eyecor
      Camera System.
AB  - OBJECTIVES: This pilot study was designed to assess the ability of a
      photoscreening camera to detect amblyogenic factors such as high refractive
      error, anisometropia, media opacities and strabismus in children, compared to the
      standard vision screening techniques employed by the local state public health
      screening personnel. METHODS: Public health personnel in Illinois used the Eyecor
      prototype to the current commercially available MTI PS-100 photoscreening camera
      (manufactured by Medical Technology Inc.) to screen 127 non-dilated subjects,
      ages 7 months to 20 years (mean age, 6 years), for amblyogenic factors. All
      participants were concurrently subjected to the "standard" vision screening
      employed routinely by state public health personnel. The study participants
      included a group of normal inner-city children and one group of special-needs
      children. The normal children came from both a public school and a private
      school. The special-needs children included a group of children from a state-run
      school for the deaf and hard-of-hearing and a separate group of children
      attending a multi-disciplinary Easter Seals clinic. RESULTS: In the population of
      normal children, the mean sensitivity and specificity for the observers using the
      Eyecor Camera system was 81% and 83% with a mean positive predictive value of
      83%, and a mean negative predictive value of 55%. Standard vision screening
      techniques employed by public health service certified vision screeners had a
      sensitivity of 88%, a specificity of 91%, a positive predictive value of 67% and
      a negative predictive value of 97% in the same subjects. In the population of
      special-needs children with hearing impairment and developmental delay, the mean
      sensitivity and specificity for the observers using the Eyecor Camera system was
      74% and 82% with a mean positive predictive value of 69% and a mean negative
      predictive value of 85%. Standard vision screening techniques employed by public
      health service certified vision screeners had a sensitivity of 100%, a
      specificity of 55%, a positive predictive value of 62% and a negative predictive
      value of 100% in the same subjects. (See Table 1) CONCLUSIONS: This study shows
      that the Eyecor Photoscreening Camera is useful in screening normal children for
      amblyogenic factors. Photoscreening was at least as effective as standard
      screening methodologies performed by certified vision screeners as required by
      state public health policy. In addition, photoscreening is particularly useful in
      testing those children "unscreenable" by conventional vision screening
      procedures.

PMID- 10652168
TI  - Incidence of and risk factors for cataract among diabetes clinic attenders.
AB  - The incidence of and risk factors for cataract during a mean (standard deviation
      (SD)) follow-up period of 5.0 (3.0) (range 0.1-12.4) years were examined among
      3606 patients (2001 male and 1605 female) with diabetes mellitus from three
      outpatient clinics at the University Hospital, Nottingham. Among the 3606
      patients free of cataract at initial registration who attended the clinic at
      least twice in the period 1979-1992, the mean (SD) age was 49.2 (17.8) years with
      a mean (SD) duration of diabetes of 7.6 (9.8) years at initial registration. The
      incidence of cataract was 10.4 (95% confidence interval (CI), 9.0, 11.9) per 1000
      person-years based on 18089 person-years of follow-up. The incidence for females
      (13.6 (95% CI, 11.0, 16.1)) was greater than in males (8 (95% CI, 6.3, 9. 7))
      (P<0.001). The incidence of cataract in insulin-dependent diabetes mellitus
      (IDDM), non-insulin-treated and insulin-treated non-insulin-dependent diabetes
      mellitus (NIDDM) were 7.1 (95% CI, 5. 4, 8.9), 11.7 (95% CI, 9.1, 14.3) and 17.8
      (95% CI, 12.9, 22.7) per 1000 person-years, respectively. Age-adjustment
      substantially changed the ordering of risk associated with different types of
      diabetes. Using a Cox's Proportional Hazards Model for IDDM and NIDDM (insulin
      and non-insulin-treated) diabetes separately, age and any retinopathy were
      significant independent predictors of cataract for all groups. Poor metabolic
      control also was a significant independent predictor of cataract for the IDDM and
      insulin-treated NIDDM diabetes groups. Duration of diabetes was a significant
      independent predictor of cataract for the IDDM group. Age at diagnosis of
      diabetes, systolic and diastolic blood pressure, body mass index, proteinuria,
      cigarette smoking and creatinine had no significant independent association with
      cataract when other covariates were considered. These findings will help the
      identification of those diabetic patients at particular risk of cataract so that
      clinic time for screening of eyes can be appropriately focused and health care
      planning for people with diabetes considered.

PMID- 10652169
TI  - Ocular findings after ivermectin treatment of patients with high Loa loa
      microfilaremia.
AB  - Hemorrhages in the palpebral conjunctiva (HPCs) have been recorded in patients
      living in an area endemic for loiasis who developed serious reactions after
      ivermectin treatment. A study was designed to evaluate the frequency of these
      lesions, and to identify risk factors associated with their appearance. The
      conjunctivae of 1,682 patients who complained of reactions were systematically
      examined. HPCs were found in 41 patients. The initial mean Loa loa microfilaremia
      in the individuals with HPCs was 14,900 microfilariae (mf) per mL, as compared
      with 14.5 mf/mL in the other patients. Mansonella perstans microfilaremia and
      male gender were also associated with HPCs. Post-treatment fundus examinations
      were performed on 37 patients, and a close relationship was found between the
      occurrence of HPCs and the presence of retinal lesions. The vascular pathological
      processes leading to the ocular lesions may be similar to those which occur at
      the cerebral level in patients harboring high L. loa microfilaremia who develop
      neurologic troubles after ivermectin treatment. Retinal lesions may represent a
      special feature of the Loa-related encephalopathies useful for differential
      diagnosis, and the HPCs may be useful as an alarm sign to identify those
      individuals who might develop serious reactions after ivermectin treatment.

PMID- 10652170
TI  - Prevalence and pattern of retinal diseases at the Guinness Eye Hospital, Onitsha,
      Nigeria.
AB  - OBJECTIVES: To determine the prevalence and pattern of retinal diseases at the
      Guinness Eye Hospital, Onitsha, Nigeria. MATERIALS AND METHODS: This was a
      prospective study. All new patients seen by the author at the outpatients clinic
      of the Guinness Eye Hospital, Onitsha, Nigeria were examined for evidence of
      retinal diseases, using the Snellen chart, tonometry, indirect ophthalmoscopy
      after full mydriasis, slit-lamp examination with a 78D non-contact fundus lens,
      fundus contact lens examination, and slit-lamp examination of the anterior
      segment. Ancillary tests performed, as applicable, included Mantoux, skin-snip,
      hemoglobin genotype, urinalysis, fasting blood sugar, oral glucose tolerance
      test, full blood count, platelet count, ESR, VDRL, and HIV tests. RESULTS: 8.1%
      of the patients had retinal diseases. The leading retinal diseases were age
      related macular degeneration (ARMD), diabetic retinopathy, retinal vein
      occlusion, retinal tears/detachment, retinitis pigmentosa and retinochoroiditis
      with epiretinal membrane. ARMD, diabetic retinopathy, and retinitis pigmentosa
      often caused bilateral lesions. Bilateral blindness was present in 14% and
      bilateral visual impairment in 16%, with macular degeneration, retinitis
      pigmentosa and retinal vascular diseases as major causes. CONCLUSIONS: Retinal
      diseases may be a significant cause of blindness and visual impairment in this
      part of Nigeria. Since most of the diseases are treatable with laser and
      vitrectomy techniques, it is recommended that these facilities be provided in all
      major eye hospitals in the area.

PMID- 10652171
TI  - Decimalization of The Oxford Clinical Cataract Classification and Grading System.
AB  - BACKGROUND: A secure methodology for the classification of cataracts into
      subtypes and for their separate quantification forms a fundamental underpinning
      of cataract research. The Oxford Clinical Cataract Classification and Grading
      System provides for this need across a wide range of cataract subtypes.
      Consideration of the advantages of finer scale intervals in terms of both
      increased precision and increased sensitivity to change (responsiveness) has
      stimulated the development of a decimal version of the Oxford system. AIM: To
      describe rules for the decimalization of the Oxford system and to document the
      performance following decimalization. METHOD: Theoretical considerations followed
      by iterative piloting were used to define a set of rules for the decimalization
      of grading for 10 cataract features. The performance of the decimal version was
      then formally tested by means of inter- and intra-observer comparisons of
      repeated measurements. 217 paired observations were pooled to produce a statement
      relevant to the 'multi-user' environment typical of many clinical research
      programmes. RESULTS: Repeatability indices were good to excellent for most
      features. The use of finer scale intervals improved the system's ability to
      detect change (reduced 95% tolerance limits for change) by a factor of around 2
      for most features. CONCLUSION: The finer scale intervals provided by
      decimalization of the Oxford system have produced substantial improvements in
      reliability as evidenced by high levels of repeatability and scale sensitivity.
      These improvements provide practical advantages in clinical cataract research.

PMID- 10652172
TI  - Exposure to diagnostic x-rays and incident age-related eye disease.
AB  - OBJECTIVE: The purpose of this study was to evaluate whether a self-reported
      history of computed tomography or other x-rays of the head were associated with
      the incidence of age-related cataracts and maculopathy five years later. METHOD:
      A 5-year longitudinal follow-up of the Beaver Dam Eye Study cohort (n=3,684, 43
      86 years at baseline). RESULTS: There was no evidence of a relationship between
      the x-ray exposures and the incidence of nuclear or cortical cataracts, or early
      maculopathy. There was a significant relationship to the incidence of posterior
      subcapsular cataract after adjusting for age only. CONCLUSIONS: Adult patients in
      whom medical conditions warrant diagnostic x-rays of the head appear to be at
      little or no increased risk of age-related cataract or maculopathy. However,
      research efforts with more precise measures of x-ray exposure, longer follow-up,
      and further attempts to define uncontrolled confounders are warranted.

PMID- 10652173
TI  - Prevalence of amblyopia among defaulters of preschool vision screening.
AB  - The prevalence of amblyopia among screening defaulters is an important
      determinant of the efficacy of amblyopia detection by preschool vision screening.
      A retrospective cohort study was therefore performed to assess an orthoptist
      based preschool vision screening programme. The preschool vision screening status
      of children in the cohort was determined by reviewing their Community Child
      Health records. The prevalence of amblyopia among screening defaulters was
      determined by reviewing each child's school entry vision test (performed at 5.5
      years of age), with retesting if a Snellen line acuity of 6/6 in each eye had not
      been documented. For comparison, the prevalence of amblyopia among screening
      attenders was also determined. The preschool vision screening status was known
      for 86.0% (772/898) of the cohort. The attendance rate at preschool vision
      screening was 79.2%. The prevalence of amblyopia among screening defaulters was
      1.3% (95% CI 0.2% to 4.5%). The prevalence of amblyopia among screening attenders
      was 2.5% (95% CI 1.4% to 4.1%). There was no significant difference in the
      prevalence of amblyopia between screening defaulters and screening attenders
      (P=0.53). The efficacy of amblyopia detection by preschool vision screening is
      therefore highly dependent on its attendance rate. Preschool vision screening
      programmes with a low attendance rate will fail to detect a significant
      proportion of children with amblyopia.

PMID- 10652174
TI  - Prevalence of usual-corrected binocular distance visual acuity impairment in
      Hispanic and non-Hispanic adults.
AB  - OBJECTIVES: The purpose of this study was to perform comparative analyses of the
      population-based prevalence of usual-corrected binocular distance visual acuity
      impairment among Hispanics and non-Hispanics in the United States. METHODS: Data
      from the Hispanic Health and Nutrition Examination Survey (HHANES), 1982-1984,
      and the National Health and Nutrition Examination Augmentation Survey I (NHANES I
      A), 1974-1975, were analyzed to investigate the epidemiology of usual-corrected
      binocular distance acuity in adults 25 to 74 years of age among Cuban-Americans
      (N=396), Mexican-Americans (N=1,381), Puerto Ricans (N=513), African-Americans
      (N=250), and non-Hispanic white Americans (N=2, 660). Binocular distance acuity
      was assessed using Sloan Letters or Landolt Rings with the participants wearing
      their corrective lenses, if any. RESULTS: Prevalences of 20/50 or worse usual
      corrected binocular distance acuity were 3.5%, 4.6%, and 6.6% for Cuban
      Americans, Mexican-Americans, and Puerto Ricans, respectively, in the HHANES; and
      7.7% and 4.1% for African-Americans and non-Hispanic whites, respectively, in the
      NHANES I-A. Within the HHANES, after adjustment for gender and age, Puerto Rican
      adults were found to have a significantly higher prevalence of visual impairment
      (20/50 or worse) and were significantly less likely to become unimpaired with
      usual correction than Cuban-American adults. Within the NHANES I-A, African
      Americans were found to have a higher prevalence of visual impairment (20/50 or
      worse) and were significantly less likely to become unimpaired with usual
      correction than non-Hispanic whites. Higher prevalences of visual impairment
      (20/50 or worse) were associated with increasing age for all ethnic groups. After
      controlling for age, odds of usual-corrected visual impairment (20/50 or worse)
      were significantly higher in women than in men for Cuban-Americans and Mexican
      Americans (odds ratios: 4.5 and 2.6, respectively). CONCLUSIONS: The results from
      this study suggest that compared to other Hispanic groups and non-Hispanic
      whites, Puerto Rican and African-American adults may not be receiving similar eye
      care services and/or may have more severe eye diseases.

PMID- 10652175
TI  - Virus safety of avital bone tissue transplants: evaluation of sterilization steps
      of spongiosa cuboids using a peracetic acid-methanol mixture.
AB  - The aim of this study was to validate the virus-inactivating/eliminating capacity
      of the manufacturing process of spongiosa cuboids. Both the sterilization step
      with peracetic acid (PAA)/ethanol and the defatting step of bones with
      chloroform/methanol (2:1, v/v) were investigated. Relevant enveloped, non
      enveloped, and model viruses belonging to different virus families were included
      in the investigation: human immunodeficiency virus type 2 (HIV-2), hepatitis A
      virus (HAV), poliovirus (PV-1), pseudorabies virus (PRV), porcine parvovirus
      (PPV), and bovine virus diarrhoea virus (BVDV). Treatment of virus-spiked
      spongiosa cuboids for 4 hours at room temperature (RT) with 1% PAA/24% ethanol
      (PES) efficiently inactivated most viruses. Titres were reduced by more than 4
      log(10)with the exception of HAV. The defatting step with chloroform/methanol
      reduced HAV titres by a factor of >/=7.0 log(10). From these results it can be
      concluded that the treatment of spongiosa cuboids with (i) chloroform/methanol
      and (ii) 1% PAA/24% ethanol solution leads to a virus-safe medicinal product.

PMID- 10652176
TI  - Comparability testing of a humanized monoclonal antibody (Synagis) to support
      cell line stability, process validation, and scale-up for manufacturing.
AB  - Biochemical and functional testing of a humanized monoclonal antibody directed
      against Respiratory Syncytial Virus (Synagis) has been performed to evaluate cell
      line stability, support process validation, and to demonstrate "comparability"
      during the course of process development. Using a variety of analytical methods,
      product manufactured at different sites and in bioreactors from 20 litres to
      10,000 litres was shown to be biochemically and functionally equivalent. The
      biochemical testing for microheterogeneity found on Synagis included evaluation
      of changes in post-translational modifications such as deamidation, truncation,
      and carbohydrate structure. Studies were also performed to support cell line
      stability assessment and cell culture process validation. Cell culture conditions
      were deliberately varied in an attempt to determine if this would have an impact
      on the microheterogeneity of the product. In these studies Synagis was produced
      from cells cultured beyond the population doublings achieved at the maximum
      manufacturing scale, under conditions of low glucose, and using harvest times
      outside of the historical manufacturing operating range. Results showed that
      there was a different pattern of glycosylation during the early stages of
      bioreactor culture. No other changes in microheterogeneity were apparent for the
      other culture conditions studied. In summary, comparability assessment
      demonstrated that the Synagis manufacturing process is robust and consistent
      resulting in a predictable and reproducible monoclonal antibody product.

PMID- 10652178
TI  - Mutual interactions between DTaP-IPV and Haemophilus influenzae type b (Hib)
      conjugated vaccines in laboratory animal models.
AB  - Potency and/or immunogenicity of three different Haemophilus influenzae type b
      conjugated vaccines (Hib) and a DTaP-IPV vaccine alone, and their mutual
      interactions in DTaP-IPV-Hib combination was tested. In a mouse model, only
      combination of Act-Hib, in which tetanus toxoid (TT) was as active as non
      conjugated TT, significantly increased the immunogenicity and potency of TT
      component of DTaP-IPV vaccine. Also, only combination of Hib-TITER, in which
      CRM197 was used as the carrier with DTaP-IPV, increased the potency of diphtheria
      toxoid (DT) component of DTaP-IPV vaccine significantly. It shows that the
      additive effect of tested Hib vaccines on immunogenicity and/or potency of TT and
      DT was mostly due to the existence of TT and CRM197, respectively, as the carrier
      in the mentioned Hib vaccines. No difference was shown in inoculation of DTaP-IPV
      and Hib conjugated vaccines in the same syringe or at separate sites. DTaP-IPV
      had dual effects on anti-Hib capsular polysaccharide (HibCP) responses to Hib
      vaccines in the mouse model. This duality was probably related to the carrier B
      cell epitopes activity of Hib conjugated vaccines. The immunogenicity of TT
      component of Act-Hib and Amvax Hib-TT in the guinea pig model was shown and
      combination of mentioned Hib vaccines with DTaP-IPV, remarkably increased anti-TT
      antibody responses to the TT component of DTaP-IPV vaccine. These confirmed our
      results in the mouse model. Using two different protocols to evaluate the guinea
      pig model for induction of anti-HibCP immunity showed that a "long interval"
      protocol does not have any advantage over the "short interval" protocol. Also,
      combination of DTaP-IPV with Hib vaccines did not have any noticeable effect on
      anti-HibCP antibodies in the guinea pig model. Taken together, our observations
      in laboratory animal models may facilitate a better understanding of the mutual
      interactions between the different antigen components of a combined vaccine such
      as DTaP-IPV-Hib vaccine.

PMID- 10652177
TI  - Detection of mutants in polio vaccine viruses using pooled antipoliovirus
      monoclonal antibodies.
AB  - We prepared six monoclonal antibodies (mAbs) for type 1 polioviruses, and
      analysed their neutralizing specificities for use in safety tests in oral
      poliomyelitis vaccine (OPV) production. Pools of two or more individual mAbs
      showed high neutralizing activity against high-titre (approximately 10(7) CCID
      (50)/25 microl) of Sabin type 1 virus. It was demonstrated that the pooled mAbs
      can be utilized effectively in detection tests of adventitious viruses, which are
      among the safety tests in OPV production. Moreover, some pooled mAbs were shown
      to be capable of detecting very small amounts of type 1 virulent viruses and
      mutants in high-titre Sabin type 1 virus suspensions. Neutralizing antibody
      titres of these pooled mAbs decreased with increasing numbers of mutants
      containing neurovirulent activity in high-titre Sabin type 1 viruses which were
      repeatedly passaged in culture. It is expected that these pooled mAbs will
      contribute greatly to safety tests for OPV production.

PMID- 10652179
TI  - A real time quantitative PCR-based method for the detection and quantification of
      simian virus 40.
AB  - A real time quantitative PCR-based simian virus 40 (SV40) detection and
      quantification method has been developed. This method takes advantage of the 5'
      to 3'-exonuclease activity of Taq DNA polymerase and utilizes the PRISM 7700
      sequence detection system of PE Applied Biosystems for direct monitoring of PCR
      product accumulation through a dual-labelled fluorogenic probe. This method
      provides accurate, precise and reproducible quantification of SV40 DNA over a
      linear dynamic range of at least 100,000-fold with a minimum detection level of
      6.4 copy equivalents/microL of SV40 viral particle in test samples. The sample
      preparation procedure employed allows for efficient and consistent recovery of
      SV40 DNA from test samples. High concentrations of protein and cellular DNA
      presenting in test samples have been demonstrated to have no impact on SV40
      quantification. This method offers significant advantages over other PCR methods
      and cell-based infectivity assays currently available for SV40 detection and
      quantification. The availability of this method should greatly facilitate the
      pathogenic investigation of SV40, as well as viral clearance evaluations required
      for the development of new biological products.

PMID- 10652180
TI  - Real time quantitative PCR as a method to evaluate simian virus 40 removal during
      pharmaceutical protein purification.
AB  - Continuous cell lines used for pharmaceutical protein manufacturing have the
      potential to be contaminated by viruses. To ensure the safety of pharmaceutical
      proteins derived from continuous cell lines, validation of the ability of the
      manufacturing process to clear potential contaminating viruses is required for
      product registration. In this paper, a real time quantitative PCR method has been
      applied to the evaluation of simian virus 40 (SV40) removal during chromatography
      and filtration procedures. This method takes advantage of the 5'-3' exonuclease
      activity of Taq DNA polymerase and utilizes the PRISM 7700 sequence detection
      system of PE Applied Biosystems for automated SV40 DNA quantification through a
      dual-labeled fluorogenic probe. This method provides accurate and reproducible
      quantification of SV40 DNA. The SV40 clearance during chromatography and
      filtration procedures determined by this method is highly comparable with that
      determined by the cell-based infectivity assay. This method offers significant
      advantages over cell-based infectivity assays, such as higher sensitivity,
      greater reliability, higher sample throughput and lower cost. This method can be
      potentially used to evaluate the clearance of all model viruses during
      chromatography and filtration procedures. This method can be used to substitute
      cell-based infectivity assays for process validation of viral removal procedures
      and the availability of this method should greatly facilitate and reduce the cost
      of viral clearance evaluations required for new biologic product development.

PMID- 10652182
TI  - WHO Consultation on Diagnostic Procedures for Transmissible Spongiform
      Encephalopathies: Need for Reference Reagents and Reference Panels. Geneva,
      Switzerland, 22-23 March 1999.

PMID- 10652181
TI  - Use of vegetable-derived tween 80 for virus inactivation by solvent/detergent
      treatment.

PMID- 10652183
TI  - WHO Expert Committee on Biological Standardization. Highlights of the 49th
      Meeting, October 1998.

PMID- 10652184
TI  - Re: Laboratory tests for live attenuated poliovirus vaccine. Subhash C. Arya;
      Biologicals, Volume 26, pp. 245-246, 1998.

PMID- 10652185
TI  - Thyroid hormone regulation of the NADH shuttles in liver and cardiac
      mitochondria.
AB  - Thyroid hormone can potentially regulate the malate/aspartate and alpha
      glycerophosphate shuttle pathways in cardiac mitochondria either directly, by
      altering gene expression, or indirectly, by increasing myocardial workload. The
      goal of the current study was to determine the influence of thyroid hormone on
      the NADH shuttles in cardiac and liver mitochondria. Malate/aspartate and alpha
      glycerophosphate shuttle capacities were significantly increased in cardiac
      mitochondria from adult rats treated for 9 days with T3 compared to saline
      treated controls. Liver mitochondria demonstrated a significant increase in alpha
      glycerophosphate and no change in malate/aspartate shuttle capacity. T3 increased
      steady-state mRNA levels and activity of mitochondrial alpha-glycerophosphate
      dehydrogenase in both myocardium and liver. Quantitative immunoblot studies
      demonstrated a significant increase in aspartate-glutamate carrier levels in T3
      treated myocardium suggesting a regulatory role of the aspartate/glutamate
      carrier in T3-treated hearts. Thyroid hormone effects on the NADH shuttles are
      tissue-specific. Changes in the NADH shuttles in the presence of thyroid hormone
      excess occur both directly at the gene level and indirectly as an adaptive
      response.

PMID- 10652186
TI  - Effects of external acidosis on HERG current expressed in Xenopus oocytes.
AB  - We investigated effects of external acidosis on HERG current expressed in Xenopus
      oocytes. HERG current was rapidly and reversibly suppressed by external acidosis
      in a voltage-independent manner. The slope conductance was decreased from 143 +/-
      11 to 93.4 +/- 6.8 microS by changing external pH (pH(o)) from 7.6 to 6.0
      (P<0.05). Steady-state activation was shifted by about 20 mV in a depolarized
      direction with a change from pH(o) 7.6 to 6.0, while steady-state inactivation
      was not significantly changed. Activation time constants were increased,
      deactivation and recovery time constants were decreased, while those of
      inactivation showed no significant change. When external K(+) concentration
      ([K(+)](o)) was increased from 2 mM to 10 mM, a ratio of slope conductance at
      pH(o) 6.0 to pH(o) 7.6 was significantly smaller in 2 mM (pH(o) 6.0/pH(o) 7.6 =
      0.65 +/- 0.04) than in 10 mM[K(+)](o) (0.83 +/- 0.06, P<0.05). The changes in
      activation, deactivation and recovery from inactivation were not affected by
      change in [K(+)](o). The results indicated that external acidosis suppressed HERG
      current mainly by shifting the voltage-dependence of the activation and
      deactivation kinetics, and partly by decreasing slope conductance. Moreover, the
      reduction of HERG current could be partly antagonized with increasing [K(+)](o).

PMID- 10652188
TI  - Infarct size and nitric oxide synthase in murine myocardium.
AB  - Controversy surrounds the involvement of nitric oxide (NO) in myocardial
      ischaemia-reperfusion injury and the balance between deleterious and beneficial
      effects. NO synthase (NOS) is expressed constitutively as two isoforms:
      endothelial (eNOS) and neuronal (nNOS). Knockout mice lacking the gene for either
      eNOS (eNOS KO) or nNOS (nNOS KO), were compared with wild-types (WT) during a
      protocol of global ischaemia-reperfusion injury. Thirty-six mouse hearts (12 from
      each group) were isolated and the aorta cannulated for Langendorff perfusion with
      modified Krebs solution at constant pressure. An apical suture connected the left
      ventricle to a force transducer via a light weight coupling rod. Following
      stabilization hearts were subjected to 30 min of global ischaemia at 37 degrees
      C. During 30 min reperfusion, the recovery of baseline force-rate product (F%)
      was recorded. Hearts were then stained with tetrazolium, frozen, sliced, and
      fixed with formalin. Slices were compressed between plexiglas plates, and a
      magnified video image digitized to allow planimetry for infarct size (as
      percentage of ventricular volume I/R). Although recovery of contractile function
      did not differ between groups, eNOS KOs suffered significantly larger infarcts
      than WT or nNOS KOs (41 v 33 and 30% respectively, P<0.05 for both comparisons).
      A protective role for eNOS against global ischaemia-reperfusion injury has been
      demonstrated for the first time in murine myocardium. This may have important
      clinical implications for future pharmacotherapy to enhance myocardial
      protection.

PMID- 10652187
TI  - Angiotensin blockade inhibits SIF DNA binding activities via STAT3 after
      myocardial infarction.
AB  - The in vivo activation of transcription factors, which is important for cell
      regulation by gene expression, has not been well examined in myocardial infarcted
      heart. The purpose of this study was to determine whether myocardial signal
      transducer and activator of transcription (STAT) pathway is activated as sis
      inducing factor (SIF) in infarcted heart, and to assess the angiotensin blockade
      on SIF activity in ischemic and non-ischemic myocardium of rat. Myocardial
      infarction was made by ligation of the coronary artery in Wistar rats. In
      electrophoretic mobility shift assay, myocardial SIF DNA binding activities
      gradually increased and reached to peak at 1 week in infarcted and non-infarcted
      regions after myocardial infarction. Imidapril and candesartan cilexitil
      significantly prevented the increase in SIF DNA binding activity in infarcted and
      non-infarcted regions. This increased SIF DNA complex was supershifted by
      specific anti-STAT3 antibody, indicating that increased SIF complex at least
      contained activated STAT3 proteins in myocardial infarcted heart. Furthermore,
      immunoprecipitation-Western blot analysis revealed that STAT3 of infarcted and
      non-infarcted regions were tyrosine-phosphorylated at 1 week after myocardial
      infarction. Imidapril and candesartan cilexitil prevented the increase in
      phosphorylated STAT3. Thus, the transcriptional activation of STAT3 through AT1
      receptor may be partially involved in cardiac remodeling after myocardial
      infarction.

PMID- 10652189
TI  - Heat production of atherosclerotic plaques and inflammation assessed by the acute
      phase proteins in acute coronary syndromes.
AB  - Several studies have shown that inflammation plays an important role in the
      pathogenesis of coronary heart disease (CHD). Serum amyloid A (SAA) and C
      reactive protein (CRP) reactants of the acute phase of inflammation, have been
      shown to be increased in patients with CHD. Recently ex vivo studies demonstrated
      that some types of atherosclerotic plaques show substantially warmer regions. A
      catheter-based technique has been developed to measure the temperature of human
      arteries in vivo. Therefore, the aim of the present study was to measure the
      luminal surface temperature in patients with CHD and to correlate it with the
      acute phase proteins in order to discriminate the role of inflammation in heat
      production in acute coronary syndromes. Sixty patients were studied with CHD (20
      with stable angina, 20 with unstable angina and 20 with acute myocardial
      infarction) and 20 sex- and age-matched controls without coronary artery disease,
      by measuring plasma levels of SAA, CRP, plasma lipids and intracoronary arterial
      luminal wall temperature. Intracoronary temperature was measured with a
      thermography catheter developed in our Institution: a thermistor probe with a
      temperature accuracy of 0.05 degrees C, was attached at the distal end of a long
      3F polyurethane shaft. It was found that the median temperature differences at
      the site of the lesion from the core temperature was increased in patients with
      unstable angina (1.025 degrees C) and acute myocardial infarction (2.150 degrees
      C) compared with stable angina (0.300 degrees C), P<0.001 for each comparison.
      Furthermore, stable angina has increased temperature differences compared with
      controls (0.200 degrees C, P<0.001). There were very good correlations between
      CRP and SAA with the temperature (r=0.796, P=0.01 and r=0.848, P=0.01,
      respectively). Local heat at the site of lesion is increased in patients with
      acute coronary syndromes and may arise from an aggressive inflammatory response
      occurring in these situations. The sensitive measurement of plaque temperature as
      a prognostic marker may be useful in the management of coronary heart disease.

PMID- 10652190
TI  - Caspase activation and mitochondrial cytochrome C release during hypoxia-mediated
      apoptosis of adult ventricular myocytes.
AB  - Oxygen deprivation for prolonged periods leads to cardiac cell death and
      ventricular dysfunction. The ability to prevent myocardial cell death would be of
      significant therapeutic value in maintaining cardiac function after injury. While
      caspases have been suggested to play a critical role in apoptosis, their
      involvement during hypoxic injury has not been formally determined. In this
      report, we show that adult ventricular myocytes subjected to hypoxia for 1 h
      undergo a three-fold increase (P<0.05) in the incidence of apoptosis as
      determined by TUNEL analysis and Hoechst 33258 nuclear staining. Western blot
      analysis of hypoxic myocytes revealed a 10-fold increase in the proteolytic
      processing of caspase 3 to p17 with a concomitant cleavage of the caspase 3
      substrate PARP from 116 kd to p85 kd compared to normoxic controls. Defects in
      mitochondrial membrane integrity were also observed as evidenced by the
      translocation of cytochrome c from the mitochondrial to cytosolic compartment of
      hypoxic cells. Pretreatment of ventricular myocytes with the peptide-caspase
      inhibitor known to block caspases related to caspase 1 (Ac-YVAD-CHO) attenuated
      cytochrome c release, processing of caspase 3, and apoptosis. While the caspase
      inhibitor (Ac-DEVD-CHO) which blocks caspases related to caspase 3, suppressed
      the cleavage of PARP and apoptosis, it had no effect on cytochrome c release by
      mitochondria. The data provide direct evidence for the proteolytic activation of
      caspases during hypoxia-mediated apoptosis of adult ventricular myocytes.
      Furthermore, the data suggest a hierarchical scheme for caspase activation with
      mitochondrial cytochrome c release occurring proximally to DEVD-CHO-inhibitable
      caspases.

PMID- 10652191
TI  - Elevation of vascular endothelial growth factor-A serum levels following acute
      myocardial infarction. Evidence for its origin and functional significance.
AB  - Following the onset of acute myocardial infarction (AMI), a number of serum
      parameters show well-defined changes reflecting myocardial injury. During the
      consecutive repair phase, compensatory processes are initiated including the
      formation of a collateral circulation on the basis of angiogenesis and
      arteriogenesis. An important angiogenic factor is vascular endothelial growth
      factor-A (VEGF-A), shown to be upregulated in the ischemic myocardium. It is
      unclear, however, whether acute myocardial ischemia leads to a detectable
      elevation of VEGF-A serum concentrations. With the use of an immunoradiometric
      assay, we measured the levels of VEGF-A in the serum of patients after AMI at
      defined time intervals, of patients with unstable angina pectoris (UAP) and of
      healthy individuals. In addition, in a small group of patients with subacute
      myocardial infarction VEGF-A concentrations were measured in coronary sinus
      blood. The data are given as median followed by the 25th and 75th percentiles. In
      the group with AMI serum VEGF-A measured 105 [78; 176] pg/ml on day 1 and 114
      pg/ml [72; 163] pg/ml on day 3 after onset of AMI. Serum levels of VEGF-A
      significantly increased on day 7 after AMI to 189 [119; 373] pg/ml (P=0.0103) and
      on day 10 to 255 [162; 371] pg/ml (P=0.0007). The VEGF-A serum level in healthy
      controls and in patients with UAP measured 98 [75; 137] pg/ml and 116 [57; 140]
      pg/ml, respectively. Serum at day 10 after AMI contained VEGF-A at a biologically
      relevant concentration capable of stimulating proliferation of endothelial cells.
      Surprisingly, VEGF-A serum levels were similar in samples taken from the coronary
      sinus with 61 [43; 83] pg/ml. Therefore the main source for VEGF-A in the blood
      stream is not the infarcted myocardium. However, the number of platelets, a rich
      source of VEGF-A, is significantly increased after myocardial infarction, i.e.
      284 [252; 363] x 10(9)/litre v 220 [177; 250] x 10(9)/litre. In conclusion, the
      time course of VEGF-A elevation following AMI strongly suggests that VEGF-A plays
      a role as an endogenous activator of coronary collateral formation in the human
      heart. The most likely source of the elevated VEGF-A are platelets, rather than
      the infarcted myocardium.

PMID- 10652193
TI  - Calcium extrusion during aftercontractions in cardiac myocytes: the role of the
      sodium-calcium exchanger in the generation of the transient inward current.
AB  - Spontaneous release of calcium from the sarcoplasmic reticulum leads to delayed
      afterdepolarizations which may represent an arrhythmogenic mechanism in the
      intact heart. The current underlying delayed afterdepolarizations is the
      transient inward current, but how this is triggered by a spontaneous rise in
      cytoplasmic calcium concentration is a matter of debate. We have investigated
      this by rapid application of caffeine to isolated guinea-pig cardiac myocytes,
      before and after drive train-induced aftercontractions. Mean (+/- s.e.m.)
      sarcoplasmic reticulum content reduced from 85 +/- 11 micromol/l accessible cell
      volume to 53 +/- 9 micromol/l accessible cell volume (n=11) during the course of
      the aftercontraction. The charge movement expected to result from extrusion of
      this calcium via the sodium-calcium exchanger was 70.1 +/- 5.4 pC, compared with
      charge measured during the transient inward current of 70.1 +/- 10.8 pC in the
      same cells (P=0.9969). Rapid inhibition of the sodium-calcium exchanger, by
      replacement of the superfusate with a sodium and calcium free solution between
      the end of the drive train and the aftercontraction, completely abolished the
      transient inward current (from 90.4 +/- 10.2 pA inward current to 23.8 +/- 14.9
      pA outward current, P<0.001). We conclude that the transient inward current in
      this species is explained entirely by sodium-calcium exchange current without the
      need to invoke other calcium-activated conductances.

PMID- 10652192
TI  - Angiotensin-converting enzyme inhibitor prevents plasminogen activator inhibitor
      1 expression in a rat model with cardiovascular remodeling induced by chronic
      inhibition of nitric oxide synthesis.
AB  - Plasminogen activator inhibitor-1 (PAI-1) may participate in the development of
      cardiovascular remodeling by inhibiting extracellular matrix turnover and
      fibrinolysis. However, little is known about physiological regulators of PAI-1 in
      vivo. Angiotensin II has been shown to stimulate PAI-1 in vitro. We previously
      reported that long-term inhibition of nitric oxide (NO) synthesis with Nomega
      nitro-L-arginine methyl ester (L-NAME) causes cardiovascular remodeling (vascular
      medial thickening and fibrosis) associated with increased tissue angiotensin
      converting enzyme (ACE) activity. In the present study, we examined whether
      treatment with an ACE inhibitor modulates the cardiovascular PAI-1 expression in
      this model in vivo. Wistar-Kyoto rats were treated with either no drugs, L-NAME
      (100 mg/kg x day), or L-NAME plus the ACE inhibitor imidapril (20 mg/kg day).
      Marked increases in PAI-1 mRNA and protein levels in the aorta and left ventricle
      were observed after the first and fourth weeks of PAI-1 treatment. PAI-1
      immunoreactivity was increased in the endothelium and the media of the aorta and
      coronary arteries after treatment of L-NAME. This increase in PAI-1 levels was
      associated with an increase in ACE activity of the aorta and left ventricle. ACE
      inhibition with imidapril significantly prevented both the increases in PAI-1
      levels and the development of cardiovascular remodeling. These findings suggest
      that the local renin-angiotensin system regulates PAI-1 expression, and that the
      increased PAI-1 levels may contribute to the cardiovascular remodeling in this
      model.

PMID- 10652194
TI  - Identification of cis-acting DNA elements required for expression of the human
      cardiac troponin I gene promoter.
AB  - The human cardiac troponin I (TnIc) gene exhibits both cardiac-specific and
      developmentally regulated expression. The structure and expression of this gene
      as well as the identification of putative regulatory elements have been described
      previously. This study shows that a minimal promoter containing 98 bp of sequence
      is sufficient to drive transcription in neonatal rat cardiac myocytes. This
      region contains several putative cis -regulatory elements including an Initiator
      element surrounding the start site of transcription, an A/T-rich (TATA/MEF-2)
      element, two GATA elements and a cytosine-rich region containing overlapping CACC
      box and Sp1 elements. Using electrophoretic mobility shift assays (EMSAs) this
      study demonstrates the binding of MEF-2, Oct-1, and recombinant TBP to the A/T
      rich element and of GATA-4 to both GATA elements. The CACC/Sp element binds the
      zinc finger transcription factors Sp1 and Sp3 in addition to an unidentified
      complex present in neonatal rat cardiac myocytes. Mutation of each of these sites
      has a deleterious effect on promoter activity as assayed by transient
      transfection into cardiac myocytes. The data suggest that transcriptional
      activity of the human TnIc gene can be driven by a compact promoter region and
      that within this region GATA, MEF-2 Sp1 and CACC box-binding factors are required
      for optimal activity. Furthermore, a comparison with data obtained for identical
      elements in the promoters of rodent TnIc genes identifies differences between
      species which may be of consequence for species-specific promoter function.

PMID- 10652195
TI  - Effects of gene deletion of the tissue inhibitor of the matrix metalloproteinase
      type 1 (TIMP-1) on left ventricular geometry and function in mice.
AB  - Alterations in the expression and activity of the matrix metalloproteinases
      (MMPs) and the tissue inhibitors of the MMPs (TIMPs) have been implicated in
      tissue remodeling in a number of disease states. One of the better characterized
      TIMPs, TIMP-1, has been shown to bind to active MMPs and to regulate the MMP
      activational process. The goal of this study was to determine whether deletion of
      the TIMP-1 gene in mice, which in turn would remove TIMP-1 expression in LV
      myocardium, would produce time-dependent effects on LV geometry and function. Age
      matched sibling mice (129Sv) deficient in the TIMP-1 gene (TIMP-1 knock-out (TIMP
      1 KO), n=10) and wild-type mice (n=10) underwent comparative echocardiographic
      studies at 1 and 4 months of age. LV catheterization studies were performed at 4
      months and the LV harvested for histomorphometric studies. LV end-diastolic
      volume and mass increased (18+/-4 and 38+/-3%, respectively, P<0.05) at 4 months
      in the TIMP-1 KO group; a significant increase compared to wild-type controls
      (P<0.05). At 4 months, LV and end-diastolic wall stress was increased by over two
      fold in the TIMP-1 KO compared to wild type (P<0.05). However, LV systolic
      pressure and ejection performance were unchanged in the two groups of mice. LV
      myocyte cross-sectional area was unchanged in the TIMP-1 KO mice compared to
      controls, but myocardial fibrillar collagen content was reduced. Changes in LV
      geometry occurred in TIMP-1 deficient mice and these results suggest that
      constitutive TIMP-1 expression participates in the maintenance of normal LV
      myocardial structure.

PMID- 10652196
TI  - Antioxidative enzymes in human hearts with idiopathic dilated cardiomyopathy.
AB  - The present study investigates intracellular enzymatic pathways involved in the
      elimination of reactive oxygen species in the left ventricular myocardium of 10
      individuals without heart failure and 12 patients with end-stage heart failure
      due to idiopathic dilated cardiomyopathy. Left ventricular enzyme activities,
      mRNA and protein levels of the hydrogen peroxide scavenging enzymes catalase
      (CAT) and glutathione peroxidase (GPX), and the superoxide anion scavenging
      enzymes mitochondrial (Mn-SOD) and cytosolic (Cu/Zn-SOD) superoxide dismutases
      were measured. In failing myocardium, there was a significant decrease in CAT
      activity (4.83+/-0.32 U/mg v 6.59+/-0.52, P<0.01) despite unchanged mRNA
      expression and protein levels. GPX, Mn-SOD and Cu/Zn-SOD were similar concerning
      activity, mRNA and protein levels. As indirect free radical markers, similar
      levels of the products of lipid peroxidation, malondialdehyde and 4-hydroxy
      alkenals, and similar tissue nitrotyrosin content were measured. The decrease in
      CAT activity appears to be a post-transcriptional mechanism. A decreased
      myocardial capacity to scavenge hydrogen peroxide might lead to a shift in the
      intracellular redox balance which potentially results in activation of redox
      sensitive signalling pathways. Direct reactive oxygen species mediated damage was
      not detected by the methods applied.

PMID- 10652197
TI  - Early changes induced in the left ventricle by pressure overload. An experimental
      study on swine heart.
AB  - The purpose of this study was to evaluate the early changes in sarcoplasmic
      reticulum (SR) function and the parallel morphological and hemodynamic
      modifications occurring in the heart following pressure overload. As regards SR
      function, we also explored the levels of acylphosphatase, an enzyme which might
      have a regulatory effect on the SR Ca(2+) pump by hydrolyzing the phosphorylated
      intermediate of this transport system. Pigs subjected to pressure overload by
      aortic stenosis for 6, 12, 24, 48, 72, and 96 h were compared to sham-operated
      controls. At each of the considered times both SR Ca(2+)-ATPase activity and
      Ca(2+) uptake, as well as acylphosphatase activity, were significantly enhanced
      in the pressure overloaded compared to the control hearts, with a maximal
      increase at 6 h; moreover, a positive and significant correlation was found
      between these parameters. The modifications in the activities of Ca(2+)-ATPase
      and acylphosphatase reflected an increased expression of these proteins, while
      phospholamban did not show significant changes in its concentration nor in its
      phosphorylation status. As for hemodynamic parameters, rapid changes in the left
      ventricular function were observed and especially the early hours following the
      aortic stenosis appeared to be crucial for the adjustment of heart function. The
      most relevant morphological finding was a focal disarrangement of the
      myofibrillar pattern which was very evident at 6 h, and progressively attenuated
      at later times. Taken together our data suggest that an early adaptation to the
      increased hemodynamic working overload is a consistent activation of the
      contractile apparatus which reflects, at least in part, an enhanced SR function.
      Besides the changes in Ca(2+) pump protein expression, increased acylphosphatase
      levels might also contribute to this effect.

PMID- 10652198
TI  - Changes in function of cardiac receptors mediating the effects of the autonomic
      nervous system in the muscular dystrophy (MDX) mouse.
AB  - Adrenergic and muscarinic receptor mediated effects on the force of contraction
      and heart rate were studied in the isolated left atria and right atria from
      dystrophin-deficient mdx mice and age matched C57BL/10ScSn (C57) mice,
      respectively. The pD(2) and pA(2) values of (-)-isoprenaline and CGP 20712A,
      respectively, were not different in left atria and right atria from mdx and C57
      mice. (-)-Phenylephrine produced a small positive inotropic effect on mdx left
      atria that could be antagonized by prazosin, whereas in C57 left atria no
      positive inotropic response was seen. In contrast, the positive chronotropic
      effect of (-)-phenylephrine was reduced in right atria from mdx compared to C57
      right atria (P<0.05). The potency and efficacy to carbachol in the presence of (
      )-isoprenaline were higher in right atria from mdx compared to C57 mice (P<0.05),
      although in left atria only a greater efficacy was evident in mdx mice. In left
      atria, basal force of contraction and maximum Ca(2+)-induced increases in force
      of contraction were lower from mdx compared to C57 mice (P<0. 001 and P<0.05,
      respectively). In conclusion, marked changes were demonstrated in the function of
      alpha1-adrenoceptors and muscarinic receptors, but not in beta1-adrenoceptors in
      left and right atria from mdx mice.

PMID- 10652199
TI  - Bradykinin regulates captopril-induced upregulation of beta-adrenergic receptor
      in cultured neonatal rat cardiomyocytes.
AB  - The aim of this study was to elucidate the role of bradykinin in mediating
      captopril-induced upregulation of beta-adrenergic receptor (beta-AR). The density
      of beta-AR on the surface of cardiac myocytes was measured by binding assay using
      [(3)H]CGP-12177. Treatment of cultured neonatal rat cardiomyocytes with captopril
      resulted in a time-dependent elevation of bradykinin concentration in the culture
      medium. The increased bradykinin concentration was significant at 2, 3 and 6 h,
      but not at 12 h after exposure to captopril. This time-dependent effect of
      captopril on enhancement of bradykinin levels paralleled that of beta-AR
      upregulation. Exogenously applied bradykinin increased beta-AR density by 22, 30
      and 35% at 0.01, 0.1 and 1 microm concentrations, respectively. Myocytes treated
      with 1 microm bradykinin responded to isoproterenol (ISP) in a dose-dependent
      manner, as demonstrated by acceleration of spontaneous beating frequency. These
      beating acceleration effects of bradykinin were abolished by Hoe 140. Stimulation
      of bradykinin B2 receptor by exogenously added bradykinin for 6 h was sufficient
      to produce beta-AR up-regulation to a level similar to that seen after 24 h. Our
      results indicate that bradykinin potentiation by ACE inhibitors regulates, at
      least in part, captopril-induced beta-AR up-regulation.

PMID- 10652200
TI  - On the nature of cell death during remodeling of hypertrophied human myocardium.
AB  - Cardiocyte loss during myocardial hypertrophy leads to progressive dysfunction in
      human hearts with chronic hemodynamic overload. The mechanism for such cell
      elimination is unknown. We examined lysosomal participation in cardiocytic
      degradation present in human cardiac biopsies, utilizing electron microscopic
      cytochemistry (acid phosphatase). Lysosomes were significantly increased in
      number (t-test, P<0.001) in 50 hemodynamically overloaded hearts (375+/-69,
      mean+/-s.e.m., per 5,000 microm(2) cardiocytic area; eight controls, 38+/-11).
      Secondary lysosomes were prominent near degenerative intracellular organelles in
      both hypertrophic and atrophic cardiocytes. Increased lysosomal and phagocytic
      activity in the cytoplasm without typical nuclear apoptosis resembled cytoplasmic
      degradation in developmental programmed cell death described in different
      tissues. We also demonstrated cardiocytic DNA degradation (in situ nick-end
      labeling) in autopsy hearts, including 299 nuclei normalized per 10(6) observed
      nuclei from five concentrically hypertrophied hearts, 1961 nuclei from five
      eccentrically hypertrophied hearts, and no positive nuclei in five controls. We
      postulate a chronic self-controlled cytoplasmic proteolysis in cardiocytes, not
      initially associated with either nuclear degradation or intercellular dehiscence
      but later possibly accompanied by apoptotic nuclear elimination, and leading to
      apoptotic cell death.

PMID- 10652201
TI  - Alternative forms of beta-pol mRNA are not tumor-specific and are not the result
      of mutations in the DNA.

PMID- 10652202
TI  - Activin A is an essential cofactor for osteoclast induction.
AB  - Recently, receptor activator of NF-kappaB ligand (RANKL) was shown to be
      necessary for osteoclast formation. We now report that activin A, a cytokine
      enriched in bone matrix and secreted by osteoblasts and osteoclasts, powerfully
      synergized with RANKL for induction of osteoclast-like cells (OCL) from bone
      marrow precursors depleted of stromal cells. Moreover, OCL formation in RANKL was
      virtually abolished by soluble type II A activin receptors (ActR-II(A)),
      suggesting that activin A is essential for OCL formation. Activin A was most
      effective when precursors were exposed to RANKL and activin A simultaneously:
      resistance to OCL-induction that occurs when precursors are pre-incubated in M
      CSF was reduced. Incubation on bone matrix also enhanced the sensitivity of
      precursors to OCL-induction by RANKL; and this was prevented by soluble ActR
      II(A). Thus, activin A in bone matrix, or released from osteoblastic or other
      cells, enhances the osteoclast-forming potential of precursors and synergizes
      with RANKL in inducing osteoclastic differentiation.

PMID- 10652203
TI  - Comparative analysis of artificial antisense RNA regulation in fission yeast and
      human cells.
AB  - The fission yeast Schizosaccharomyces pombe has recently been established as an
      experimental model for the study of antisense RNA-mediated gene suppression. To
      validate the use of S. pombe as a host for identifying antisense genes for use in
      human cells, it was important to determine if sequences identified in yeast were
      as equally effective in a human cell line. This report describes the comparison
      of a range of lacZ antisense RNAs targeting a lacZ gene expressed in HeLa cells
      in a comparable manner to its expression in S. pombe cells in earlier studies. In
      both cell types, the same lacZ gene target was expressed using the same promoter.
      Antisense genes were expressed episomally in both experimental systems and the
      levels of suppression determined. In all cases, the relative level of suppression
      of the lacZ gene was similar in the mammalian and yeast cells. This result
      indicates that, at least for lacZ antisense RNA, results obtained in fission
      yeast are predictive of their behavior in the mammalian cellular environment.

PMID- 10652204
TI  - Acetylation at the N-terminus of actin strengthens weak interaction between actin
      and myosin.
AB  - The N-terminus of all actins so far studied is acetylated. Although the pathways
      of acetylation have been well studied, its functional importance has been
      unclear. A negative charge cluster in the actin N-terminal region is shown to be
      important for the function of actomyosin. Acetylation at the N-terminus removes a
      positive charge and increases the amount of net negative charges in the N
      terminal region. This may augment the role of the negative charge cluster. To
      examine this possibility, actin with a nonacetylated N-terminus (nonacetylated
      actin) was produced. The nonacetylated actin polymerized and depolymerized
      normally. In actin-activated heavy meromyosin ATPase assays, the nonacetylated
      actin showed higher K(app) without significantly changing V(max), compared with
      those of wild-type actin. This is in contrast to the effect of the N-terminal
      negative charge cluster, which increases V(max) without changing K(app). These
      results indicate that the acetylation at the N-terminus of actin strengthens weak
      actomyosin interaction.

PMID- 10652205
TI  - A REIC gene shows down-regulation in human immortalized cells and human tumor
      derived cell lines.
AB  - Normal human cells stop proliferation after a certain number of cell divisions.
      This phenomenon is called cellular aging. The fact that the senescence phenotype
      is dominant and the immortal one is recessive indicates that immortalization of
      human cells may be caused by loss of functions of certain genes in normal cells.
      Based on this evidence, several cDNA clones whose expression was down-regulated
      during the immortalization process of human cells were isolated by the
      representative difference analysis (RDA) system in our laboratory. One of them,
      which was named REIC, was expressed to a lower degree in three human immortalized
      cell lines as compared with their parental normal counterparts. In addition, the
      expression of REIC was markedly lower in eight human tumor-derived cell lines
      (Hep3B and HuH-7 hepatocellular carcinomas, HuH-6 Clone 5 hepatoblastoma, HuCCT-1
      cholangiocarcinoma, A549 lung cancer, HaCaT immortalized keratinocyte, HeLa
      cervical carcinoma, and Saos-2 osteosarcoma). In contrast, among the human
      tissues examined, the heart and brain, which contain a large number of post
      mitotic cells, showed the highest expression of REIC. The full-length REIC cDNA
      revealed that the predicted protein is 350 amino acids in length and possesses
      coiled-coil tertiary structures in each of the amino- and carboxyl-termini.
      Furthermore, a search of the protein database revealed a match of this gene
      product with Dkk-3, which is a novel inhibitor of Wnt oncogene. These results
      indicate that the REIC cloned by us may function as a tumor suppressor.

PMID- 10652206
TI  - Linkage between alpha(1) adrenergic receptor and the Jak/STAT signaling pathway
      in vascular smooth muscle cells.
AB  - The Jak/STAT pathway is activated following stimulation of the type I angiotensin
      II receptor. To examine whether this pathway is shared among other G-protein
      coupled receptors, we studied the linkage between the alpha(1) adrenergic
      receptor and this pathway. The alpha(1) agonist phenylephrine induced tyrosine
      phosphorylation of Jak2, Tyk2, and STAT1 in vascular smooth muscle cells. The
      phosphorylation of Jak2 was prevented by the alpha(1) receptor antagonists
      prazosin and chloroethylclonidine, but not by WB4101, and that of STAT1 was
      inhibited by prazosin and the Jak2 inhibitor AG490. After stimulation with
      phenylephrine, Jak2 and STAT1 were found to associate with alpha(1B) receptor.
      Phenylephrine stimulated the DNA binding activity of STAT1. Protein synthesis
      promoted by phenylephrine was inhibited by prazosin, AG490, and the introduction
      of a decoy oligonucleotide for STAT1. These results suggested that alpha(1)
      receptor is linked to the Jak/STAT pathway and that this pathway mediates
      alpha(1) agonist-induced smooth muscle hypertrophy.

PMID- 10652207
TI  - Molecular mechanism of detectable catalase-containing particles, peroxisomes, in
      fibroblasts from a PEX2-defective patient.
AB  - Patients with peroxisome biogenesis disorders (PBD) can be identified by
      detection of peroxisomes in their fibroblasts, by means of immunocytochemical
      staining using an anti-catalase antibody. We report here data on three PBD
      patients with newly identified mutations (del550C and del642G) in the PEX2 gene
      which encodes a 35-kDa peroxisomal membrane protein containing two membrane
      spanning and a C-terminal cysteine-rich region. Some of the fibroblasts from the
      patient with the del642G mutation contained numerous catalase-containing
      particles, whereas no fibroblasts containing such particles were found in the
      patient with the del550C mutation. We confirmed that the del642G mutation caused
      a partial defect in peroxisome synthesis and import by expression of the mutated
      PEX2 into PEX2-defective CHO mutant cells. We propose that the two putative
      membrane-spanning segments in Pex2p are important domains for peroxisome assembly
      and import and that a defect in one of these domains severely affects PBD
      patients. Furthermore, a defect in the C-terminal portion of Pex2p exposed to the
      cytosol containing a RING finger motif caused the mild phenotype, residual enzyme
      activities, and mosaic detectable peroxisomes in fibroblasts from the patient.

PMID- 10652208
TI  - Morphological assessment of the effect of growth hormone on preantral follicles
      from 11-day-old mice in an in vitro culture system.
AB  - The present study was carried out to verify that the cells attached to the
      outside of the basement membrane of mechanically isolated follicles are theca
      cells and to evaluate the effect of growth hormone (GH) on these cells. Preantral
      follicles, 100-140 micrometer in diameter, were mechanically isolated from 11-day
      old BDF1 hybrid immature mice, divided randomly into two groups, and cultured in
      vitro. One group was treated with 0.1% collagenase immediately after mechanical
      isolation in an attempt to remove theca cells attached to the outside of the
      basement membrane. The other group was untreated. Morphological examination
      revealed that 86.1% of mechanically isolated follicles before collagenase
      treatment had at least one theca cell around the basement membrane on the single
      section. However, after collagenase treatment no theca cells remained on the
      basement membrane of the follicles. Androstenedione secretion as a result of
      stimulation by 100 ng/ml hCG was significantly higher in the culture medium of
      the follicles with theca cells than in those of collagenase-pretreated follicles
      (p < 0.0001), indicating that the cells attached to the outside of the basement
      membrane were actually functional theca cells, not interstitial cells. To
      elucidate the effect of GH on theca cells, preantral follicles cultured in the
      presence of 1.0 mIU/ml GH were morphologically examined. Preantral follicles
      mechanically isolated from immature mice showed significant proliferation of not
      only granulosa cells but also theca cells in the presence of GH. In particular,
      theca cells, which remained dotted on the basement membrane in a small number
      just after isolation, proliferated and finally formed complete layers after the
      culture with GH. This is the first report that GH induced the proliferation of
      theca cells to form morphologically complete layers around the preantral follicle
      from 11-day-old mice.

PMID- 10652209
TI  - The rat asialoglycoprotein receptor binds the amino-terminal domain of
      thyroglobulin.
AB  - We have previously reported that the rat hepatic lectin-1 (RHL-1) subunit of rat
      asialoglycoprotein receptor (ASGPr), the endocytic receptor found on the
      basolateral surface of hepatocytes, was expressed in rat thyroid tissue and
      localized on the apical surface of polarized rat thyroid FRT cells. Here we show
      that PC Cl3 cells, a differentiated rat thyroid cell line, bound thyroglobulin
      (Tg) via ASGPr. In fact, both the bacterial recombinant carbohydrate recognition
      domain of RHL-1 (rCRD(RHL-1)) and the anti-rCRD(RHL-1) antibody markedly
      inhibited (125)I-Tg binding to the cell surface of PC Cl3 cells. Ligand blot
      assays with deglycosylated Tg show that the rCRD(RHL-1) was able to interact with
      Tg even after remotion of sugars. The region of Tg involved in the binding to RHL
      1 was investigated by ligand blot assays with biotinylated rCRD(RHL-1) on
      thermolysin-digested native and desialated rat thyroglobulin. It is shown that
      the rCRD(RHL-1) specifically recognized a thyroglobulin fragment with an apparent
      M(r) of 68,000, corresponding to the amino-terminal part of the molecule. To our
      knowledge, this is the first report that attributes to the amino-terminal portion
      of Tg molecule, containing its earliest and major hormonogenic site, the function
      of binding to a cell surface receptor of the thyroid. Moreover, we show that
      oligosaccharides are not the only molecular signals for binding to RHL-1, but
      amino acidic determinants could also play a role.

PMID- 10652210
TI  - Sphingosine 1-phosphate stimulates tyrosine phosphorylation of focal adhesion
      kinase and chemotactic motility of endothelial cells via the G(i) protein-linked
      phospholipase C pathway.
AB  - We have previously shown that sphingosine 1-phosphate (S1P) stimulates motility
      of human umbilical vein endothelial cells (HUVECs) (O.-H. Lee et al., Biochem.
      Biophys. Res. Commun. 264, 743-750, 1999). To investigate the molecular
      mechanisms by which S1P stimulates HUVEC motility, we examined tyrosine
      phosphorylation of p125 focal adhesion kinase (p125(FAK)) which is important for
      cell migration. S1P induces a rapid increase in tyrosine phosphorylation of
      p125(FAK). Compared with other structurally related lipid metabolites such as
      sphingosine, C2-ceramide, and lysophosphatidic acid, S1P uniquely stimulated
      p125(FAK) tyrosine phosphorylation and migration of HUVECs. The effect of S1P on
      p125(FAK) tyrosine phosphorylation was markedly reduced by treatment with
      pertussis toxin or U73122, a phospholipase C (PLC) inhibitor. As a downstream
      signal of PLC, p125(FAK) tyrosine phosphorylation in response to S1P was totally
      blocked by depletion of the intracellular calcium pool. However, protein kinase C
      (PKC) inhibitor had no effect on the response to S1P. Finally, chemotaxis assays
      revealed that inhibition of PLC but not PKC significantly abrogated S1P
      stimulated HUVEC migration. These results suggest that the G(i)-coupled receptor
      mediated PLC-Ca(2+) signaling pathway may be importantly involved in S1P
      stimulated focal adhesion formation and migration of endothelial cells.

PMID- 10652212
TI  - Effect of interleukin-1beta on aromatase activity and cell proliferation in human
      osteoblast-like cells (HOS).
AB  - Osteoblast cells have a capacity to produce estrogen from androgen. It is known
      that inflammatory cytokines in bone increase during estrogen deficiency. In the
      present study, the effect of interleukin-1beta (IL-1beta) on aromatase (Arom)
      activity in human osteoblast-like cells (HOS) was investigated. We also
      investigated the effect of IL-1beta and estradiol (E2) on cell proliferation in
      HOS. [(3)H] water method was employed to measure Arom activity. Expression of
      Arom mRNA was determined by the reverse-transcription polymerase chain reaction
      (RT-PCR) method. The PCR products were confirmed by Southern blot analysis. Cell
      proliferation was measured by an ELISA-bromo deoxyuridine (BrdU) kit. Addition of
      IL-1beta increased Arom activity in a dose-dependent manner and addition of IL
      1beta (10 ng/ml) resulted in 40% greater activity than control. Addition of 500
      ng/ml of human recombinant IL-1 receptor antagonist neutralized the increased
      Arom activity to control level. Stimulation of Arom mRNA expression by IL-1beta
      was also found. IL-1beta and E2 stimulate osteoblastic cell proliferation
      significantly. These findings suggest for the first time that IL-1beta stimulates
      Arom activity through the IL-1 receptor and also cell proliferation in osteoblast
      like cells. It is also demonstrated that this stimulatory effect may be through
      the IL-1 receptor. Cell proliferation stimulated by IL-1beta was reduced by the
      addition of the Arom inhibitor fadrozole-HCL (CGS-16949A). These results imply
      that IL-1beta has a stimulatory effect on estrogen formation and sequentially
      cell proliferation in bone, and this mechanism may play an important role in
      osteoblastic function especially in postmenopausal women.

PMID- 10652211
TI  - Possible involvement of Shc in IL-4-induced germline epsilon transcription in a
      human B cell line.
AB  - The IL-4Ralpha contains the I4R motif which binds to the phosphotyrosine binding
      domain of several adaptor proteins, including IRS-1/2 and Shc. Although the
      involvement of IRS-1/2 in IL-4-induced PI3-kinase activation is known, there is
      little information on the role of Shc in IL-4 signaling. In this study, we found
      the preferential utilization of Shc by the IL-4Ralpha in a human Burkitt's B
      lymphoma cell line, DND39. IL-4 induced the association of tyrosine
      phosphorylated Shc with the IL-4Ralpha, whereas no detectable tyrosine
      phosphorylation of IRS-1 or IRS-2 was induced. IL-4-induced germline epsilon
      promoter activation was enhanced by overexpression of Shc and was inhibited by
      truncated Shc lacking the collagen-homologous domain. We further found the
      association of Shc with PLCgamma1. Although direct tyrosine phosphorylation of
      PLCgamma1 was not detectable, the amount of PLCgamma1 coprecipitable with anti
      phosphotyrosine was increased after IL-4 stimulation. These results suggest that
      Shc can function as an adaptor protein of the IL-4Ralpha and mediate the germline
      epsilon transcription.

PMID- 10652213
TI  - A bacterial high-affinity GABA binding protein: isolation and characterization.
AB  - A gamma-aminobutyric acid (GABA) binding protein (GBP) was isolated from a
      bacterial mutant which has high-affinity GABA binding characteristics comparable
      with the GABA(A) brain receptor in mammals. The GBP was partially purified and
      characterized and was shown to be a periplasmic protein of approximately 42,000
      molecular weight. To determine the molecular weight, a bacterial GABA binding
      assay was used with SDS-PAGE. This procedure did not require large amounts or
      complete purification of protein and may be useful as a simple method in
      estimating the molecular weight of other bacterial binding proteins.

PMID- 10652214
TI  - Purification and characterization of a growth factor-like which increases
      capillary permeability from Vipera lebetina venom.
AB  - We have investigated the effect of Vipera lebetina venom on capillary
      permeability and isolated an increasing capillary permeability protein (ICPP)
      which is devoid of arginine ester hydrolase and phospholipase A2 activities. This
      protein was purified with a yield of about 0.2% by fast protein liquid
      chromatography (FPLC) using successively Superose 12, Mono Q, and Mono S columns
      and by high-pressure liquid chromatography (HPLC) on a C8 reverse-phase column.
      The purified protein migrated on SDS-PAGE as a band of about 27 kDa under
      nonreducing conditions and as a band of about 16 kDa under reducing conditions.
      Chromatography on a C8 column of reduced and alkylated protein yielded a single
      peak suggesting that this protein is homodimeric. This protein was refractory to
      Edman degradation chemistry. We used successfully a chemical unblocking involving
      the incubation of the protein with HCl in anhydrous methanol. The N-terminal
      amino acid sequence clearly shows considerable similarity to that of vascular
      endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF).

PMID- 10652215
TI  - Investigation of Fanconi anemia protein interactions by yeast two-hybrid
      analysis.
AB  - Fanconi anemia is a chromosomal breakage disorder with eight complementation
      groups (A-H), and three genes (FANCA, FANCC, and FANCG) have been identified.
      Initial investigations of the interaction between FANCA and FANCC, principally by
      co-immunoprecipitation, have proved controversial. We used the yeast two-hybrid
      assay to test for interactions of the FANCA, FANCC, and FANCG proteins. No
      activation of the reporter gene was observed in yeast co-expressing FANCA and
      FANCC as hybrid proteins, suggesting that FANCA does not directly interact with
      FANCC. However, a high level of activation was found when FANCA was co-expressed
      with FANCG, indicating strong, direct interaction between these proteins. Both
      FANCA and FANCG show weak but consistent interaction with themselves, suggesting
      that their function may involve dimerisation. The site of interaction of FANCG
      with FANCA was investigated by analysis of 12 mutant fragments of FANCG. Although
      both N- and C-terminal fragments did interact, binding to FANCA was drastically
      reduced, suggesting that more than one region of the FANCG protein is required
      for proper interaction with FANCA.

PMID- 10652216
TI  - Redox control of caspase-3 activity by thioredoxin and other reduced proteins.
AB  - Caspases are cysteine proteinases that play a critical role in the execution
      phase of apoptosis. The active site cysteine residue must be reduced for caspase
      activity. Thioredoxins are redox proteins that catalyze the reduction of cysteine
      residues. We have examined the ability of various recombinant human thioredoxins
      to activate caspase-3. The EC(50) for caspase-3 activation by reduced thioredoxin
      1 was 2.5 microM, by reduced glutathione 1.0 mM and by dithiothreitol 3.5 mM. A
      catalytic site redox-inactive mutant thioredoxin-1 was almost as active as
      thioredoxin-1 in activating caspase-3. Caspase activation was shown to correlate
      with the number of reduced cysteine residues in the thioredoxins. Reduced insulin
      and serum albumin were as effective on a molar basis as thioredoxin-1 in
      activating caspase-3. Thus, caspase-3 activation is not a specific effect of
      thioredoxins but is a property shared by other reduced proteins.

PMID- 10652217
TI  - Concentration of caveolin-1 in the cleavage furrow as revealed by time-lapse
      analysis.
AB  - Caveolin-1 is a major component of caveolae. Recent studies have suggested a
      possible role of caveolin-1 in cell transformation and normal cell proliferation.
      To observe the behavior of caveolin-1 in living mitotic cells, we prepared cDNA
      constructs encoding the chimeric protein of alpha- or beta-caveolin-1 and green
      fluorescent protein (GFP) and transfected culture cells with them. Correct
      targeting of the chimera to the caveolae was confirmed by colocalization with the
      caveolar inositol 1,4,5-trisphosphate receptor-like protein. By time-lapse
      observation of mitotic MDCKII cells, the GFP-caveolin-1 chimeras were seen
      throughout the plasma membrane before cell division, but became markedly
      concentrated at the cleavage furrow during cytokinesis. Accumulation around the
      spindle poles was also observed at late telophase. The result showed that
      caveolin-1 undergoes a drastic distributional change during cell division and
      suggested that the protein may be involved in the cytokinetic process.

PMID- 10652218
TI  - Differential regulation of melanin-concentrating hormone and orexin genes in the
      agouti-related protein/melanocortin-4 receptor system.
AB  - Agouti protein and agouti-related protein (AGRP) antagonize alpha-melanocyte
      stimulating hormone that binds to and activates the melanocortin-4 receptor (MC4
      R) in the hypothalamus, thereby stimulating food intake. Melanin-concentrating
      hormone (MCH) and orexin are orexigenic peptides that specifically are
      synthesized in the lateral hypothalamus. MCH gene expression was augmented in
      A(y)/a (agouti) mice which overexpress agouti protein, but orexin mRNA was not.
      AGRP administered intracerebroventricularly into wild-type rats augmented MCH but
      not orexin gene expression. Also, SHU9119, a peptidergic antagonist of MC4-R,
      increased only MCH mRNA. These findings indicate that interruption of signaling
      at MC4-R activates the MCH but not the orexin gene. The biosyntheses of MCH and
      orexin are regulated through different pathways.

PMID- 10652219
TI  - Real-time monitoring of the hybridization reaction: application to the
      quantification of oligonucleotides in biological samples.
AB  - We describe here a competitive hybridization assay using TRACE technology which
      can be used for real-time monitoring of oligonucleotide hybridization. This assay
      quantifies all kinds of oligonucleotides in biological fluids without extraction.
      The assay makes use of two different probes and involves a fluorescent transfer
      process. As fluorescence measurements are not destructive, they can be
      sequentially repeated, thereby allowing comparison of the hybridization kinetics
      and binding strength of chemically modified backbone oligonucleotides (>0.5 nM)
      in biological media. The assay was validated for pharmacokinetic analysis of
      phosphodiester and phosphorothioate oligonucleotides in plasma and in different
      organs (liver, kidneys, lungs, spleen) at low concentrations (0.4 mg/kg,
      corresponding to clinical doses). Respective sensitivities for phosphodiester and
      phosphorothioate were 0.2 and 0.8 pmol/ml in plasma and 2 and 8 pmol/g in
      tissues, which allow to recover intact phosphorothioate sequences in some organs
      even after 24 h.

PMID- 10652220
TI  - Differential expression of the transcription factor NF-kappaB during human
      mononuclear phagocyte differentiation to macrophages and dendritic cells.
AB  - An important role for the Rel/NF-kappaB family of transcription factors in the
      differentiation process of dendritic cells (DC) and macrophages (MAC) was
      recently suggested by a number of mouse knockout studies but only little
      information is available for defined populations of human cells. To investigate
      the role of individual NF-kappaB proteins [p50, p52, p65 (RelA), RelB] in the
      differentiation of monocyte-derived cell types we analyzed and compared the
      expression pattern and DNA binding activity of NF-kappaB members in human
      monocytes (MO), MO-derived MAC, and MO-derived DC. Constitutive expression of p65
      and RelB mRNA was found in MO and no significant regulation was observed during
      differentiation of MO into MAC or immature DC. Only during lipopolysaccharide
      induced terminal differentiation of DC was a marked increase in RelB mRNA
      detected. In DNA binding assays performed with nuclear extracts from blood MO,
      p50/p50 homodimers were mainly detected, whereas complexes containing p50/RelB
      and p50/p65 heterodimers were less abundant. DNA-bound protein complexes
      containing p50/RelB and p50/p65 increased and additional p65/p65 complexes
      appeared during differentiation of MO into either MAC or immature DC. A strong
      increase in complexes containing p50/RelB was observed during terminal
      differentiation of DC. Therefore, gradual differences in the DNA binding
      activities of different NF-kappaB homo- and heterodimers correlate with
      differentiation stages of MO, MAC, and DC and are probably important for the
      biological role of these cells.

PMID- 10652221
TI  - Peptide mimicking sialyl-Lewis(a) with anti-inflammatory activity.
AB  - Peptides mimicking carbohydrate structure sialyl-Lewis a (SA-Le(a)) have been
      selected from a diverse dodecapeptide library using monoclonal antibody (MAb)
      NS19-9. Families of peptides with a consensus sequence consisting of three to
      nine amino acids and peptides that do not show a conserved core amino acid region
      were identified. Peptide DLWDWVVGKPAG was selected based on the consensus
      sequence DXXDXXVG shared with other peptides and strong binding in Western blot.
      Peptide competes with antibody binding to its native carbohydrate antigen, SA
      Le(a), at 50% inhibitory concentration (IC(50)), 700 microM, implying that it
      represents a structural mimic of the carbohydrate epitope recognized by MAb.
      Statistically significant reduction of neutrophil recruitment into the
      intraperitoneal cavity was observed upon administration of this peptide in a
      murine acute inflammation model in vivo. Results suggest that the peptide mimic
      of SA-Le(a) carbohydrate might bind to E-selectin and block its interaction with
      another ligand, sialyl-Lewis X (SA-LeX), expressed on neutrophils.

PMID- 10652222
TI  - The yeast retrotransposons Ty1 and Ty3 require the RNA Lariat debranching enzyme,
      Dbr1p, for efficient accumulation of reverse transcripts.
AB  - A mutant screen has been initiated to identify host genes important for the
      replication of retrotransposons in Saccharomyces cerevisiae. Two mutants were
      identified that undergo Ty1 and Ty3 transposition at <10% of the wild-type
      frequency. Both these mutants have deficiencies in the accumulation of full
      length Ty1 and Ty3 cDNAs, although Ty proteins (including reverse transcriptase)
      accumulate at wild-type levels. The DBR1 gene, encoding the yeast debranching
      enzyme, complements both mutants. This suggests that Dbr1p is important for
      either reverse transcription or the stability of Ty cDNA, roles that have not
      been previously reported for this protein. The deficiency in accumulation of Ty
      cDNAs in dbr1 mutants is apparent when engineered Ty elements are expressed for
      short time periods (6-10 h) but is not apparent following long expression periods
      (>24 h).

PMID- 10652223
TI  - Effects of terminal deletions in C5 protein on promoting RNase P catalysis.
AB  - Deletion derivatives of C5 protein, the protein cofactor of Escherichia coli
      RNase P, were constructed as soluble MBP (maltose-binding protein) fusion
      proteins to assess the deletion effects on promoting RNase P catalysis and on
      binding to M1 RNA, the catalytic subunit of the enzyme. The C5 protein, with
      large terminal deletions, retained its promoting activity of RNase P catalysis
      under protein excess conditions in vitro. Some deletion derivatives complemented
      the temperature sensitive phenotype of E. coli A49 cells carrying the rnpA49
      mutation. This ability also suggests that part of the C5 protein is enough to
      produce the catalytic activity of RNase P in vivo. Both the central conserved
      region, called the RNR motif, and the C-terminal region are essential for the
      binding of C5 protein to M1 RNA. Meanwhile, the N-terminal region contributes to
      promoting RNase P catalysis in ways other than binding to M1 RNA.

PMID- 10652224
TI  - Ligation of the T cell receptor complex results in phosphorylation of Smad2 in T
      lymphocytes.
AB  - TGF-beta modulates immune responses by regulating T cell function. The Smad
      family of proteins has been recently shown to transduce signals for the TGF-beta
      superfamily and Smad2 mediates TGF-beta signaling. Here, we showed that TGF-beta
      phosphorylated Smad2 and induced interaction between Smad2 and Smad4 in primary T
      cells and the Jurkat T cell line. Interestingly, ligation of the T cell receptor
      (TCR)/CD3 complex with anti-CD3 mAb also phosphorylated Smad2, but failed to
      induce interaction between Smad2 and Smad4 in the Jurkat T cell line.
      Phosphorylation of Smad2 via the TCR/CD3 complex was not abrogated by treatment
      with neutralizing antibody against TGF-beta. Furthermore, PD98059, a MEK
      inhibitor, suppressed Smad2 phosphorylation by stimulation with anti-CD3 mAb in
      Jurkat T cell line. These findings indicated that not only TGF-beta but also
      stimulation via the TCR/CD3 complex phosphorylated Smad2 through mitogen
      activated protein (MAP) kinase cascades, suggesting that Smad2 may function in
      both TGF-beta- and TCR/CD3 complex-mediated signaling pathways in T cells.

PMID- 10652225
TI  - Activation of human progelatinase A/promatrix metalloproteinase 2 by Escherichia
      coli-derived serine proteinase.
AB  - Treatment of human uterine cervical fibroblasts with commercial
      lipopolysaccharide (LPS) preparations from different serotypes of Escherichia
      coli effectively augmented the processing of mammalian progelatinase A/promatrix
      metalloproteinase (proMMP)-2 to a 62-kDa form of MMP-2. When purified proMMP-2
      was incubated with LPS preparations, the proenzyme was similarly processed into
      the 62-kDa active MMP-2 in a time- and dose-dependent manner. By contrast,
      progelatinase B/proMMP-9 and prostromelysin 1/proMMP-3 were not activated. A
      serine proteinase inhibitor, phenylmethylsulfonyl fluoride, completely interfered
      with this LPS-mediated activation of proMMP-2. This is novel evidence that E.
      coli serine proteinase is a specific activator of proMMP-2. Thus, it is very
      likely that E. coli infection plays a crucial role in the degradation of
      connective tissues via the activation of proMMP-2, and the resultant active MMP-2
      participates in the dysfunction of connective tissues such as in the preterm
      rupture of fetal membranes.

PMID- 10652226
TI  - Inhibitors of beta-amyloid formation based on the beta-secretase cleavage site.
AB  - A series of inhibitors of beta-amyloid formation have been developed based on the
      beta-secretase cleavage site (VNL-DA) of the Swedish mutant Amyloid Precursor
      Protein. A simple tripeptide aldehyde was found to be the most potent (IC(50) =
      700 nM) in the series displaying an inhibitory profile which is different from
      reported inhibitors of beta-amyloid formation.

PMID- 10652227
TI  - Effects of C5 protein on Escherichia coli RNase P catalysis with a precursor
      tRNA(Phe) bearing a single mismatch in the acceptor stem.
AB  - Escherichia coli RNase P, an RNA-processing enzyme that cleaves precursor tRNAs
      to generate the mature 5'-end, is composed of a catalytic component (M1 RNA) and
      a protein cofactor (C5 protein). In this study, effects of C5 protein on the
      RNase P catalysis with a precursor E. coli tRNA(Phe) having a single mismatch in
      the acceptor stem were examined. This mutant precursor unexpectedly generated
      upstream cleavage products at the -8 position as well as normal cleavage products
      at the +1 position. The cleavage at the -8 position was essentially effective
      only in the presence of C5 protein. Possible secondary structures for cleavage at
      the -8 position deviate significantly from the structures of the known RNase P
      substrates, implying that C5 protein can allow the enzyme to broaden the
      substrate specificity more than previously appreciated.

PMID- 10652228
TI  - Activation of the guanine nucleotide exchange factor Dbl following ACK1-dependent
      tyrosine phosphorylation.
AB  - Signals triggered by diverse receptors modulate the activity of Rho family
      proteins, although the regulatory mechanism remains largely unknown. On the basis
      of their biochemical activity as guanine nucleotide exchange factors (GEFs), Dbl
      family proteins are believed to be implicated in the regulation of Rho family GTP
      binding proteins in response to a variety of extracellular stimuli. Here we show
      that GEF activity of full-length proto-Dbl is enhanced upon tyrosine
      phosphorylation. When transiently coexpressed with the activated form of the non
      receptor tyrosine kinase ACK1, a downstream target of Cdc42, Dbl became tyrosine
      phosphorylated. In vitro GEF activity of Dbl toward Rho and Cdc42 was augmented
      following tyrosine phosphorylation. Moreover, accumulation of the GTP-bound form
      of Rho and Rac within the cell paralleled ACK-1-dependent tyrosine
      phosphorylation of Dbl. Consistently, activation of c-Jun N-terminal kinase
      downstream of Rho family GTP-binding proteins was also enhanced when Dbl was
      tyrosine-phosphorylated. Collectively, these findings suggest that the tyrosine
      kinase ACK1 may act as a regulator of Dbl, which in turn activates Rho family
      proteins.

PMID- 10652229
TI  - Involvement of intracellular labile zinc in suppression of DEVD-caspase activity
      in human neuroblastoma cells.
AB  - Age-related tissue Zn deficiency may contribute to neuronal and glial cell death
      by apoptosis in Alzheimer's dementia. To investigate this, we studied the effects
      of increasing or decreasing the levels of intracellular labile Zn on apoptosis of
      human neuroblastoma BE(2)-C cells in vitro. BE(2)-C cells were primed for 18 h
      with butyrate (1 mM) before addition of staurosporine (1 microM), an effector
      enzyme of apoptosis, for a further 3 h to induce DEVD-caspase activity. An
      increase in intracellular Zn using Zn ionophore pyrithione suppressed DEVD
      caspase activity, while a decrease in intracellular Zn induced by Zn chelator
      TPEN mimicked staurosporine by activating DEVD-caspase in butyrate-primed cells.
      The distribution of intracellular Zn in the cells was demonstrated with the UV
      excitable Zn-specific fluorophore Zinquin. Confocal images showed distinct
      cytoplasmic and cytoskeletal fluorescence. We propose that Zn decreases the level
      of apoptosis in neuronal cells exposed to toxins, possibly by stabilizing their
      cytoskeleton.

PMID- 10652230
TI  - Fluorescein fluorescence hyperpolarization as an early kinetic measure of the
      apoptotic process.
AB  - The ability to identify apoptotic cells within a complex population is crucial in
      the research and diagnosis of normal physiology and disease states. The Cellscan
      mark S (CS-S) cytometer was used in this study to detect intracellular
      fluorescence intensity and polarization (FI and FP) in several well-established
      models of apoptosis: Following spontaneous apoptosis, as well as glucocorticoid
      or anti Fas-induced apoptosis, CS-S individual cell-based analysis revealed the
      appearance of a cell cluster characterized by low FI and high FP. Temporal
      analysis of annexine V binding and FP measurements following DXM treatment showed
      that hyperpolarization preceded phosphatidylserine appearance on the outer plasma
      membrane. The early increase in FP was found to be dose dependent and inversely
      related to cell diameter. Cell dehydration and alteration of plasma membrane
      transport properties, both occurring during early stages of apoptosis, may be
      involved in the phenomena of intracellular fluorescein hyper-polarization in
      apoptosis.

PMID- 10652231
TI  - Rhythmic expression of BMAL1 mRNA is altered in Clock mutant mice: differential
      regulation in the suprachiasmatic nucleus and peripheral tissues.
AB  - BMAL1 is a putative clock gene which encodes a basic helix-loop-helix (bHLH)-PAS
      transcription factor. To examine whether the CLOCK protein is required for the
      circadian expression of BMAL1 mRNA, in situ hybridization and Northern blot
      analysis were performed in the suprachiasmatic nucleus (SCN) and peripheral
      tissues of homozygous Clock mutant mice. In the SCN of Clock mutants, BMAL1 mRNA
      did not oscillate significantly but apparently expressed with low levels, while
      in wild-type mice the mRNA was robustly oscillated in a circadian manner. The
      peak-trough amplitudes of BMAL1 mRNA levels were 6.5-, 8.6-, and 6.7-fold in
      liver, heart, and kidney of wild-type mice, respectively. In Clock mutants, the
      amplitudes were extremely damped to 1.2-, 2.1-, and 1.4-fold, respectively.
      Furthermore, expressions of BMAL1 mRNA in the peripheral of Clock mutant mice
      were close to the peak level in wild-type mice, whereas mPer2 mRNA levels were
      severely blunted at trough values. Daily expression of albumin site D-binding
      protein (DBP), a clock controlled output gene (CCG), was also abolished at trough
      values by the Clock mutation in all tissues examined. These observations suggest
      that the circadian expression of BMAL1 mRNA is affected by the CLOCK-induced
      transcriptional feedback loop in the SCN and peripheral tissues in a different
      way and that the regulation mechanism appeared to be different from those in
      mPer2 and DBP expressions in vivo.

PMID- 10652232
TI  - Regulatory roles for CD14 and phosphatidylinositol in the signaling via toll-like
      receptor 4-MD-2.
AB  - The complex consisting of Toll-like receptor 4 (TLR4) and associated MD-2 signals
      the presence of lipopolysaccharide (LPS) when it is expressed in cell lines. We
      here show that normal human mononuclear cells express TLR4 and signal LPS via
      TLR4. CD14 is a molecule that binds to LPS and facilitates its signaling. Little
      is known, however, about the relationship of CD14 with TLR4-MD-2. We show that
      CD14 helps TLR4-MD-2 to sense and signal the presence of LPS. CD14 has also been
      implicated in recognition of apoptotic cells, which leads to phagocytosis without
      activation. Membrane phospholipids such as phosphatidylserine (PS) or
      phosphatidylinositol (PtdIns) are thought to serve as the ligands for CD14 in
      apoptotic cells. We find that PtdIns acts as an LPS antagonist in the signaling
      via TLR4-MD-2. TLR4-MD-2 seems to discriminate LPS from phospholipids. The
      signaling via TLR4-MD-2 is thus regulated by CD14 and phospholipid such as
      PtdIns.

PMID- 10652233
TI  - Inhibitory effect of a proline-to-alanine substitution at codon 12 of peroxisome
      proliferator-activated receptor-gamma 2 on thiazolidinedione-induced
      adipogenesis.
AB  - Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a member of the
      nuclear hormone receptor superfamily of transcription factors and appears to be a
      key regulator of adipogenesis. Members of the thiazolidinedione class of insulin
      sensitizing agents act as high-affinity ligands for PPARgamma, indicating that
      PPARgamma is also important in systemic insulin action. To determine whether
      Pro(12) --> Ala (P12A) mutation in PPARgamma gene contributes to the development
      of obesity or insulin sensitivity, we examined the effects of the P12A mutation
      on the function of PPARgamma by expression of the mutant protein in COS or 3T3-L1
      cells. The abilities of the P12A mutant of PPARgamma to mediate both
      transcriptional activation of a luciferase reporter gene construct containing the
      peroxisome proliferator response element and adipogenesis induced by a
      thiazolidinedione drug were reduced compared with those of the wild-type protein.
      These results suggest that the P12A substitution in PPARgamma gene may be
      associated with abnormalities of adipose tissue formation and insulin
      sensitivity.

PMID- 10652234
TI  - Endostatin inhibits microvessel formation in the ex vivo rat aortic ring
      angiogenesis assay.
AB  - Endostatin has demonstrated potent antiangiogenic and antitumor activity in mouse
      models. We have investigated the ex vivo rat aortic ring assay and a human vein
      model to assess the biological activity of murine and human endostatin. Rat
      aortic rings were exposed to recombinant murine endostatin (Spodoptera frugipera;
      Calbiochem, San Diego, CA) or recombinant human endostatin (Pichia pastoris;
      EntreMed, Rockville, MD). After 5 days, murine endostatin (500 microgram/ml)
      demonstrated inhibition of microvessel outgrowth with dose-dependent effects
      (down to 16 microgram/ml). No significant inhibition was observed with human
      endostatin in the rat assay. Human endostatin at 250 and 500 microgram/ml
      inhibited outgrowths from human saphenous vein rings after a 14-day incubation.
      Electron microscopy assessed the formation of basal lamina, confirming that the
      microvessels were progenitors of patent vessels. Immunostaining for Factor VIII
      or CD34 demonstrated that the microvessel cells were endothelial. BrdU
      incorporation assays supported the presence of proliferating endothelial cells,
      correlating with neovascularization from the aortic wall. We conclude that the
      rat aortic ring assay confirms the antiangiogenic activity of murine but not
      human endostatin, suggesting that the model may have species specificity.
      However, the human form shows biological activity against human vascular tissue.

PMID- 10652235
TI  - 17beta-estradiol prevents programmed cell death in cardiac myocytes.
AB  - The cardioprotective effects of estrogens are clearly established. However, the
      underlying mechanisms are poorly understood. Because programmed cell death
      (apoptosis) probably contributes to the loss of cardiac myocytes in heart failure
      and because estrogens prevent apoptosis in breast cancer cells, we investigated
      whether the loss of cardiac myocytes by programmed cell death could be prevented
      by physiological doses of 17beta-estradiol. Apoptosis of cultured cardiac
      myocytes was induced by staurosporine. 17beta-estradiol (10 nM) had an
      antiapoptotic effect as determined by morphological analysis, vital staining
      using the Hoechst dye 33342 and terminal transferase dUTP nick-end labeling
      (TUNEL). As a potential mechanism for the antiapoptotic effect of 17beta
      estradiol we found a reduced activity of the ICE-like protease caspase-3 in
      hormone-treated myocytes. Furthermore, inhibition of apoptosis by estradiol was
      associated with a reduced activity of NF-kappaB transcription factors,
      particularly p65/RelA and p50. To our knowledge, these data provide the first
      indication that 17beta-estradiol in physiological concentrations inhibits
      apoptosis in cardiac myocytes. The antiapoptotic effect of estrogens might
      contribute to the known cardioprotective effect of estrogens and provides a
      starting point for the development of future treatment options.

PMID- 10652236
TI  - Specific antagonists of NMDA receptors prevent osteoclast sealing zone formation
      required for bone resorption.
AB  - N-Methyl-d-aspartate (NMDA) glutamate receptors, widely distributed in the
      nervous system, have recently been identified in bone. They are expressed and are
      functional in osteoclasts. In the present work, we have studied the effects of
      specific antagonists of NMDA receptors on osteoclast activation and bone
      resorption. Using an in vitro assay of bone resorption, we showed that several
      antagonists of NMDA receptors binding to different sites of the receptor inhibit
      bone resorption. Osteoclast activation requires adhesion to the bone surface,
      cytoskeletal reorganization and survival. We demonstrated by autoradiography that
      the specific NMDA receptor channel blocker, MK 801, binds to osteoclasts. This
      antagonist had no effect on osteoclast attachment to bone and did not induce
      osteoclast apoptosis. In contrast, MK 801 rapidly decreased the percentage of
      osteoclasts with actin ring structures that are associated with actively
      resorbing osteoclasts. These results suggest that NMDA receptors expressed by
      osteoclasts may be involved in adhesion-induced formation of the sealing zone
      required for bone resorption.

PMID- 10652237
TI  - Identification and characterization of the rhp23(+) DNA repair gene in
      Schizosaccharomyces pombe.
AB  - We have identified rhp23(+), the ortholog of the Saccharomyces cerevisiae RAD23
      and human HHR23A and HHR23B genes, in Schizosaccharomyces pombe and examined its
      role in cell survival and DNA repair. In S. pombe two repair mechanisms are
      operative on UV-induced photoproducts, i.e., UV damage repair (UVDR) and
      nucleotide excision repair (NER). Here we show that Rhp23 is solely involved in
      NER and study its role in DNA repair in the absence of the UVDR pathway. S. pombe
      rhp23-deficient cells are sensitive toward UV irradiation, although not as
      sensitive as complete NER-deficient cells. Furthermore we demonstrate that the
      residual survival observed in rhp23-deficient cells is NER dependent. Despite
      this NER-dependent survival, uvde rhp23 double mutants are unable to repair
      cyclobutane pyrimidine dimers. The inability to remove these photolesions from
      both DNA strands clearly demonstrates that rhp23(+) is involved in transcription
      coupled repair as well as global genome repair.

PMID- 10652238
TI  - Anabolic response of mouse bone-marrow-derived stromal cell clone ST2 cells to
      low-intensity pulsed ultrasound.
AB  - The effects of 20-min exposure to low-intensity, pulsed ultrasound were
      investigated in ST2 cells of bone marrow stromal origin. They responded to
      ultrasound with elevated levels of IGF mRNAs, osteocalcin, and bone sialoprotein
      mRNAs. The upregulated expression of these messages appeared in a biphasic
      manner, with the first peak resistant to the protein synthesis inhibitor
      cycloheximide, and a second peak that was eliminated by NS398, an inhibitor of
      the inducive prostaglandin G/H synthase (cyclooxygenase-2). A cumulative effect
      of mechanical loading called the memory effect, which has been observed in vivo,
      can be explained from such a biphasic anabolic reaction mediated by
      prostaglandins. The upregulation of IGF or osteocalcin mRNAs can be observed even
      at 24 h after the initiation of the 20-min exposure to ultrasound. Our results
      suggest that this low-intensity, pulsed ultrasound, which has been clinically
      used to accelerate the healing processes of fractured bone, induces a direct
      anabolic reaction of osteogenic cells, leading to bone matrix formation.

PMID- 10652239
TI  - Regulation of genes for inducible nitric oxide synthase and urea cycle enzymes in
      rat liver in endotoxin shock.
AB  - Arginine is an intermediate of the urea cycle in the liver. It is synthesized by
      the first four enzymes of the cycle, carbamylphosphate synthetase I, ornithine
      transcarbamylase, argininosuccinate synthetase, and argininosuccinate lyase, and
      is hydrolyzed to urea and ornithine by arginase I, forming the cycle. In
      endotoxemia shock, inducible nitric oxide (NO) synthase (iNOS) is induced in
      hepatocytes and arginine is utilized for NO production. Regulation of the genes
      for iNOS and the urea cycle enzymes was studied using lipopolysaccharide (LPS)
      treated rat livers. When rats were injected intraperitoneally with LPS, iNOS mRNA
      was markedly induced. Cationic amino acid transporter-2 and C/EBPbeta mRNAs were
      also highly increased. In contrast, mRNAs for all the urea cycle enzymes except
      ornithine transcarbamylase were gradually decreased and reached 16-28% of
      controls at 12 h. However, all these enzymes remained unchanged at protein level
      up to 24 h. In light of these results, we suggest that synthesis of urea cycle
      enzymes is downregulated and that the protein synthetic capacity is directed to
      synthesis of proteins required for defense against endotoxemia.

PMID- 10652240
TI  - Molecular cloning, expression, and chromosomal localization of a human
      tubulointerstitial nephritis antigen.
AB  - Tubulointerstitial nephritis antigen (TIN-ag) is an extracellular matrix basement
      protein which was originally identified as a target antigen involved in anti
      tubular basement membrane (TBM) antibody-mediated interstitial nephritis (TIN).
      Further investigations elucidated that TIN-ag plays a role in renal tubulogenesis
      and that TIN-ag is defected in hereditary tubulointerstitial disorder such as
      juvenile nephronophthisis. We previously isolated and characterized 54 kDa
      glycoprotein as TIN-ag. cDNA encoding rabbit and mouse TIN-ag has recently been
      identified. In the present study, the cDNA of the human homologue of TIN-ag was
      cloned and its nucleotide sequence was determined (Accession No. AB022277; the
      DDBJ nucleotide sequence database). Deduced amino acid sequence (476 aa)
      exhibited the presence of a signal peptide (1-18 aa), cysteine residues termed
      follistatin module, six potential glycosylation sites, and an ATP/GTP-binding
      site. Homology search revealed approximately 85% homology with both rabbit and
      mouse TIN-ag, and also some ( approximately 40%) similarity with C. elegans.
      Human TIN-ag contained a sequence similar to several classes of extracellular
      matrix molecules in amino terminal region and to cathepsin family of cysteine
      proteinases in the carboxyl terminal region. Northern blot analysis revealed
      exclusive expression of this molecule in human adult and fetal kidney tissues.
      Using a monoclonal antibody recognizing human TIN-ag, protein expression (
      approximately 50 kDa) was identified in cultured COS-1 cells transfected with
      human TIN-ag cDNA. The human TIN-ag was mapped to chromosome 6p11.2-12 by
      fluorescence in situ hybridization. These results may provide further evidence
      for understanding TIN-ag molecule and clues for gene analysis of juvenile
      nephronophthisis.

PMID- 10652241
TI  - Role of cytosolic phospholipase A(2) as a downstream mediator of Rac in the
      signaling pathway to JNK stimulation.
AB  - Rac is an important regulatory molecule implicated in c-jun N-terminal kinase
      (JNK) activation in response to stress and cytokines. However, the signaling
      events that mediate the activation of JNK by Rac are not yet well characterized.
      To broaden our understanding of downstream mediators that link Rac signals to the
      JNK pathway, we investigated whether cytosolic phospholipase A(2) (cPLA(2)) is
      involved in Rac activation of JNK. In this report we demonstrate that either co
      transfection with antisense cPLA(2) oligonucleotide or pretreatment with
      arachidonyltrifluoromethyl ketone (AACOCF3), a potent and specific inhibitor of
      cPLA(2), inhibits Rac-mediated JNK activation, implying a potential role of
      cPLA(2) in Rac-signaling to JNK activation. In accordance with this observation,
      we demonstrate that the addition of exogenous arachidonic acid (AA), a principal
      product of Rac-activated cPLA(2), or leukotrienes, products of 5-lipoxygenase (5
      LO) of AA, caused a specific stimulation of JNK. Together, our findings suggest
      that cPLA(2) mediates, at least partly, the signaling cascade by which Rac
      stimulates JNK.

PMID- 10652242
TI  - The flavonoid apigenin suppresses vitamin D receptor expression and vitamin D
      responsiveness in normal human keratinocytes.
AB  - Apigenin, a flavonoid with chemopreventive properties, induces cellular growth
      arrest, with concomitant inhibition of intracellular signaling cascades and
      decreased proto-oncogene expression. We report that apigenin potently inhibited
      vitamin D receptor (VDR) mRNA and protein expression in human keratinocytes
      without changes in VDR mRNA half-life. Concurrently, downregulation of retinoid X
      receptor alpha, a dramatic loss of c-myc mRNA, and upregulation of p21(WAF1) took
      place. Furthermore, a nearly complete suppression of vitamin D responsiveness was
      observed as estimated by induction of 24-hydroxylase mRNA. The apigenin effect on
      VDR expression was shared by some other (quercetine and fisetine) but not all
      tested flavonoids. Interestingly, the apigenin-mediated VDR suppression was
      counteracted by the NFkappaB inhibitors sodium salicylate and caffeic acid
      phenethyl ester. The presented results propose suppression of nuclear receptor
      levels as a novel mechanism whereby flavonoids exert their pleiotropic effects.
      This study may also contribute to the understanding of the regulation of VDR
      expression in epidermal keratinocytes.

PMID- 10652243
TI  - Ingestion of fumonisin B1-containing culture material decreases cardiac
      contractility and mechanical efficiency in swine.
AB  - Fumonisins are mycotoxins produced primarily by Fusarium verticillioides, a
      fungus that commonly contaminates corn. Fumonisin ingestion increases plasma and
      tissue sphingosine and sphinganine concentrations and causes porcine pulmonary
      edema, which has been attributed to acute left-sided heart failure or increased
      vascular permeability. We investigated the effect of short-term ingestion of
      fumonisin B1-containing culture material on cardiac function in pigs. Treated
      male pigs (n = 7) received fumonisin-containing culture material which was mixed
      into the grower diet at 20 mg fumonisin B1/kg body weight each day, while control
      pigs (n = 7) were fed only the grower diet on the same schedule as the treated
      pigs. Pigs were anesthetized after 3 days of receiving either diet and
      instrumented to accurately characterize the cardiovascular effects of fumonisin
      ingestion. Fumonisin-treated pigs had lower cardiac outputs and heart rates than
      control pigs. Fumonisin-treated pigs also had a marked reduction in cardiac
      contractility, as indicated by decreased values for end-systolic elastance (the
      gold standard in vivo measure of cardiac contractility), V(0) (the intercept
      value for the end-systolic pressure-volume relationship), and mechanical
      efficiency. These data indicate that in pigs, short-term ingestion of fumonisin
      B1-containing culture material produces negative inotropic and chronotropic
      effects and decreases mechanical efficiency of the left ventricle. Theses
      cardiovascular effects are consistent with fumonisin-induced, sphingosine
      mediated l-type Ca(2+) channel blockade and suggest that pulmonary edema in pigs
      fed fumonisin is primarily due to acute left-sided heart failure instead of
      increased vascular permeability.

PMID- 10652244
TI  - High concentrations of bisphenol A induce cell growth and prolactin secretion in
      an estrogen-responsive pituitary tumor cell line.
AB  - PR1 cells are a prolactin (PRL)-secreting cell line derived from pituitary
      lactotroph tumors found in 17beta-estradiol (E(2))-treated female Fischer 344
      rats. Recently, we reported that as little as 0. 01 pM E(2) could induce half
      maximal cell proliferation, whereas the antiestrogen ICI 182,780 (ICI) inhibited
      proliferation. Interestingly, the cell proliferation response is 1000-fold more
      sensitive to E(2) than the PRL response (induction of prolactin protein
      synthesis), suggesting that there is a distinction between cell proliferation and
      the PRL response in PR1 cells. Bisphenol A (BPA) is a monomer of plastics and
      epoxy resins that is widely used in dentistry and the food packaging industry.
      Although it has low estrogenic activity in somatolactotrophs and breast cancer
      cell lines, its presence in the environment and its long biological half-life
      have raised concerns about potential effects in humans. We analyzed the effect of
      BPA and compared its activity with E(2) in the PR1 cell line. PR1 cells show half
      maximal proliferation upon treatment with 10 nM BPA, which is 10,000- to 100,000
      fold less active than E(2). BPA-induced PR1 cell proliferation is decreased by
      the pure antiestrogen ICI, suggesting that BPA-induced PR1 cell proliferation is
      mediated by the estrogen receptor (ER). The decreased affinity of BPA for the ER
      is illustrated by the fact that 1 nM of ICI inhibited 100 nM BPA-induced cell
      proliferation, whereas 100 nM ICI was required to block 1 nM E(2)-induced cell
      proliferation. The PRL response to BPA required 1000 nM BPA to match the PRL
      secretion induced by 0.01 nM E(2). A competitive binding assay showed that the
      K(i) of BPA for the ER in PR1 cells is approximately 30-60 nM, which is 1000- to
      2000-fold lower than that of E(2). Our study suggests the PR1 cell line can be
      used as an in vitro assay system for analyzing the effects of weak estrogens on
      ER-mediated responses and the activities of various estrogenic compounds present
      in small amounts in the environment.

PMID- 10652245
TI  - Exposure to 60-Hz magnetic fields and proliferation of human astrocytoma cells in
      vitro.
AB  - Epidemiological studies have suggested that exposure to electric and magnetic
      fields (EMF) may be associated with an increased incidence of brain tumors, most
      notably astrocytomas. However, potential cellular or molecular mechanisms
      involved in these effects of EMF are not known. In this study we investigated
      whether exposure to 60-Hz sinusoidal magnetic fields (0.3-1.2 G for 3-72 h) would
      cause proliferation of human astrocytoma cells. Sixty-Hertz magnetic fields (MF)
      caused a time- and dose-dependent increase in proliferation of astrocytoma cells,
      measured by (3)H-thymidine incorporation and by flow cytometry, and strongly
      potentiated the effect of two agonists (the muscarinic agonist carbachol and the
      phorbol ester PMA). However, MF had no effect on DNA synthesis of rat cortical
      astrocytes, i.e., of similar, nontransformed cells. To determine the amount of
      heating induced by MF, temperatures were also recorded in the medium. Both 1.2 G
      MF and a sham exposure caused a 0.7 degrees C temperature increase in the medium;
      however, (3)H-thymidine incorporation induced by sham exposure was significantly
      less than that caused by MF. GF 109203X, a rather specific protein kinase C (PKC)
      inhibitor, and down-regulation of PKC inhibited the effect of MF on basal and on
      agonist-stimulated (3)H-thymidine incorporation. These data indicate that MF can
      increase the proliferation of human astrocytoma cells and strongly potentiate the
      effects of two agonists. These findings may provide a biological basis for the
      observed epidemiological associations between MF exposure and brain tumors.

PMID- 10652246
TI  - Physiologically based pharmacokinetic modeling of glycyrrhizic acid, a compound
      subject to presystemic metabolism and enterohepatic cycling.
AB  - Glycyrrhizic acid is currently of clinical interest for treatment of chronic
      hepatitis. It is also applied as a sweetener in food products and chewing
      tobacco. In some highly exposed subgroups of the population, serious side effects
      such as hypertension and electrolyte disturbances have been reported. In order to
      analyze the health risks of exposure to this compound, the kinetics of
      glycyrrhizic acid and its active metabolites were evaluated quantitatively.
      Glycyrrhizic acid and its metabolites are subject to complex kinetic processes,
      including enterohepatic cycling and presystemic metabolism. In humans, detailed
      information on these processes is often difficult to obtain. Therefore, a model
      was developed that describes the systemic and gastrointestinal tract kinetics of
      glycyrrhizic acid and its active metabolite glycyrrhetic acid in rats. Due to the
      physiologically based structure of the model, data from earlier in vitro and in
      vivo studies on absorption, enterohepatic cycling, and presystemic metabolism
      could be incorporated directly. The model demonstrates that glycyrrhizic acid and
      metabolites are transported efficiently from plasma to the bile, possibly by the
      hepatic transfer protein 3-alpha-hydroxysteroid dehydrogenase. Bacterial
      hydrolysis of the biliary excreted metabolites following reuptake of glycyrrhetic
      acid causes the observed delay in the terminal plasma clearance of glycyrrhetic
      acid. These mechanistic findings, derived from analysis of experimental data
      through physiologically based pharmacokinetic modeling, can eventually be used
      for a quantitative health risk assessment of human exposure to glycyrrhizic acid
      containing products.

PMID- 10652247
TI  - Trimethyltin and triethyltin differentially induce spontaneous noradrenaline
      release from rat hippocampal slices.
AB  - The environmental contaminants trimethyltin (TMT) and triethyltin (TET)
      stimulated the spontaneous release of [(3)H]noradrenaline ([(3)H]NA) from
      hippocampal slices in a time- and concentration-dependent manner. TMT was the
      most potent compound, exhibiting an EC50 value 10-fold lower (3.8 microM) than
      that of TET (39.5 microM). Metal-evoked [(3)H]NA release did not increase in the
      absence of desipramine and was completely blocked by reserpine preincubation,
      indicating a vesicular origin of [(3)H]NA release but not a mechanism involving
      reversal of the transmitter transporter. The voltage-gated Na(+) channel blocker
      tetrodotoxin (TTX) did not affect metal-evoked [(3)H]NA release. [(3)H]NA release
      elicited by TMT was partially extracellular Ca(2+)-dependent, since it was
      significantly decreased in a Ca(2+)-free EGTA-containing medium, whereas TET
      induced an extracellular Ca(2+)-independent release of [(3)H]NA. Neither
      inhibitors of Ca(2+)-entry through Na(+)/Ca(2+)exchanger and voltage-gated
      calcium channels, nor agents that interfere with Ca(2+)-mobilization from
      intracellular stores affected [(3)H]NA release induced by TMT. TET-evoked
      [(3)H]NA release was reduced by ruthenium red, which depletes mitochondrial
      Ca(2+)stores, but was not modified by caffeine and thapsigargin, which interfere
      with Ca(2+)mobilization from endoplasmic reticulum. The fact that TET effect was
      also attenuated by DIDS, an inhibitor of anion exchange, indicates that the
      effect of TET on spontaneous [(3)H]NA release may be mediated by intracellular
      mobilization of Ca(2+) from mitochondrial stores through a Cl(-) dependent
      mechanism.

PMID- 10652248
TI  - Cytochrome c release from mitochondria of early postimplantation murine embryos
      exposed to 4-hydroperoxycyclophosphamide, heat shock, and staurosporine.
AB  - Cell death is an early and common event in the pathogenesis associated with the
      abnormal development induced by a variety of teratogens. Previously, we showed
      that the cell death induced in day 9 mouse embryos by three teratogens,
      hyperthermia (HS), 4-hydroperoxycyclophosphamide (4-CP), and sodium arsenite
      (As), is apoptotic in nature involving the activation of caspase-3, cleavage of
      poly(ADP-ribose) polymerase (PARP), and DNA fragmentation. We now show that HS, 4
      CP, and staurosporine (ST) induce the release of cytochrome c from mitochondria
      with kinetics suggesting a causal relationship with the activation of caspase-3
      and caspase-2. This causal relationship is supported by data showing that
      procaspase-3 and -2 can be activated in vitro by the addition of cytochrome c to
      a S-100 fraction prepared from control day 9 embryos. Together, these data
      support the notion that these three teratogens induce changes in embryonic
      mitochondria resulting in the release of cytochrome c and the subsequent
      activation of caspase-9, the upstream activator of caspase-3. Previously, we also
      showed that cells within the day 9 mouse embryo are differentially
      sensitive/resistant to the cell death-inducing potential of HS, 4-CP, and As. The
      most dramatic example of this differential sensitivity is the complete resistance
      of heart cells, characterized by the lack of caspase-3 activation, PARP cleavage,
      and DNA fragmentation. We now show that this block in the terminal phase of the
      apoptotic pathway in heart cells is associated with a lack of teratogen-induced
      release of cytochrome c. Together, our data indicate that mitochondria play a
      pivotal role in cell death during the early phases of teratogenesis.

PMID- 10652250
TI  - Chemical index for volume 162

PMID- 10652249
TI  - Down-regulation of the endoplasmic reticulum chaperone GRP78/BiP by vomitoxin
      (Deoxynivalenol).
AB  - The mechanisms by which trichothecene mycotoxins cause immunological effects in
      leukocytes such as cytokine up-regulation, aberrant IgA production, or apoptotic
      cell death are not fully understood. In the present study, mRNA differential
      display analysis was used to evaluate changes in gene expression induced by the
      trichothecene vomitoxin (VT or deoxynivalenol) in a T-cell model, the murine EL-4
      thymoma, that was stimulated with phorbol 12-myristate 13-acetate (PMA) and
      ionomycin (ION). Ten differentially expressed fragments of cDNA were isolated and
      sequenced and three of these were identified as the known genes GRP78/BiP,
      P58(IPK), and RAD17. Most notably, expression of GRP78/BiP (a 78-kDa glucose
      regulated protein), a stress-response gene induced by agents or conditions that
      adversely affect endoplasmic reticulum (ER) function, was found to decrease in VT
      exposed cells. Competitive RT-PCR analysis revealed that 250 ng/ml VT decreased
      GRP78/BiP mRNA expression in both unstimulated and PMA/ION-stimulated EL-4 cells
      at 6 and 24 h after VT treatment. Western blotting confirmed that VT (50 to 1000
      ng/ml) also significantly diminished GRP/BiP protein levels in a dose-response
      manner in PMA/ION-stimulated cells. GRP78/BiP has been shown to play a role in
      regulation of protein folding and secretion, and to protect cells from apoptosis.
      When PMA/ION-stimulated cells were incubated with 50 to 1000 ng/ml VT for 24 h,
      200-bp DNA laddering, a hallmark of apoptosis, increased in a dose-dependent
      manner. In addition to GRP78, mRNA expression of the cochaperone P58(IPK), which
      is the 58-kDa cellular inhibitor of the double-stranded RNA-regulated protein
      kinase (PKR), was also shown to be suppressed by VT-treatment. GRP78 and P58(IPK)
      are critical for maintenance of cell homeostasis and prevention of apoptosis. The
      down-regulation of these molecular chaperones by VT represent a novel observation
      and has the potential to impact immune function at multiple levels.

PMID- 10652251
TI  - Polarization of cell growth in yeast.
AB  - The actin cytoskeleton provides the structural basis for cell polarity in
      Saccharomyces cerevisiae as well as most other eukaryotes. In Part I of this two
      part commentary, presented in the previous issue of Journal of Cell Science, we
      discussed the basis by which yeast establishes and maintains different states of
      polarity through &Rgr; GTPases and cyclin-dependent protein kinase signaling.
      Here we discuss how, in response to those signals, the actin cytoskeleton guides
      growth of the yeast cell. A polarized array of actin cables at the cell cortex is
      the primary structural determinant of polarity. Motors such as class V myosins
      use this array to transport secretory vesicles, mRNA and organelles towards
      growth sites, where they are anchored by a cap of cytoskeletal and regulatory
      proteins. Cortical actin patches enhance and maintain this polarity, probably
      through endocytic recycling, which allows reuse of materials and prevents
      continued growth at old sites. The dynamic arrangement of targeting and recycling
      provides flexibility for the precise control of morphogenesis.

PMID- 10652252
TI  - ERGIC-53 and traffic in the secretory pathway.
AB  - The ER-Golgi intermediate compartment (ERGIC) marker ERGIC-53 is a mannose
      specific membrane lectin operating as a cargo receptor for the transport of
      glycoproteins from the ER to the ERGIC. Lack of functional ERGIC-53 leads to a
      selective defect in secretion of glycoproteins in cultured cells and to
      hemophilia in humans. Beyond its interest as a transport receptor, ERGIC-53 is an
      attractive probe for studying numerous aspects of protein trafficking in the
      secretory pathway, including traffic routes, mechanisms of anterograde and
      retrograde traffic, retention of proteins in the ER, and the function of the
      ERGIC. Understanding these fundamental processes of cell biology will be crucial
      for the elucidation and treatment of many inherited and acquired diseases, such
      as cystic fibrosis, Alzheimer's disease and viral infections.

PMID- 10652253
TI  - Evidence that actin and myosin are involved in the poleward flux of tubulin in
      metaphase kinetochore microtubules of crane-fly spermatocytes.
AB  - We studied the effects of various drugs on the poleward flux of tubulin in
      kinetochore microtubules in metaphase-I crane-fly spermatocytes. We used as a
      measure of tubulin flux a 'gap' in acetylation of kinetochore microtubules
      immediately poleward from the kinetochore; the 'gap' is caused by a time lag
      between incorporation of new tubulin subunits at the kinetochore and subsequent
      acetylation of those subunits as they flux to the pole. We confirmed that the
      'gap' is due to flux by showing that the 'gap' disappeared when cells were
      treated briefly with the anti-tubulin drug nocodazole, which decreases
      microtubule dynamics. The 'gap' disappeared when cells were treated for 10
      minutes with anti-actin drugs (cytochalasin D, latrunculin B, swinholide A), or
      with the anti-myosin drug 2,3-butanedione 2-monoxime. The 'gap' did not disappear
      when cells were treated with the actin stabilizing drug jasplakinolide. We
      studied whether these drugs altered spindle actin. We used fluorescent phalloidin
      to visualize spermatocyte F-actin, which was associated with kinetochore spindle
      fibers as well as the cell cortex, the contractile ring and finger-like
      protrusions at the poles. Spindle F-actin was no longer seen after cells were
      treated with cytochalasin D, swinholide A or a high concentration of latrunculin
      B, whereas a low concentration of latrunculin B, which did not completely remove
      the 'gap', caused reduced staining of spindle actin. Neither 2,3-butanedione 2
      monoxime nor jasplakinolide altered spindle actin. These data suggest that an
      actomyosin mechanism drives the metaphase poleward tubulin flux.

PMID- 10652254
TI  - Regulation of cell migration by amphoterin.
AB  - Amphoterin, a major form of HMG (high mobility group) 1 proteins, is highly
      expressed in immature and malignant cells. A role in cell motility is suggested
      by the ability of amphoterin to promote neurite extension through RAGE (receptor
      of advanced glycation end products), an immunoglobulin superfamily member that
      communicates with the GTPases Cdc42 and Rac. We show here that cell contact with
      the laminin matrix induces accumulation of both amphoterin mRNA and protein close
      to the plasma membrane, which is accompanied by extracellular export of
      amphoterin. A role for amphoterin in extracellular matrix-dependent cell
      regulation is further suggested by the finding that specific decrease of
      amphoterin mRNA and protein, using antisense oligonucleotides transfected into
      cells, inhibits cell migration to laminin in a transfilter assay whereas the
      oligonucleotides in the culture medium have no effect. Moreover, affinity
      purified anti-amphoterin antibodies inhibit cell migration to laminin, supporting
      an extracellular role for the endogenous amphoterin in cell motility. The finding
      that amphoterin expression is more pronounced in cells with a motile phenotype as
      compared to cells of dense cultures, is consistent with the results of the cell
      migration assays. Our results strongly suggest that amphoterin is a key player in
      the migration of immature and transformed cells.

PMID- 10652255
TI  - Dictyostelium myosin IK is involved in the maintenance of cortical tension and
      affects motility and phagocytosis.
AB  - Dictyostelium discoideum myosin Ik (MyoK) is a novel type of myosin distinguished
      by a remarkable architecture. MyoK is related to class I myosins but lacks a
      cargo-binding tail domain and carries an insertion in a surface loop suggested to
      modulate motor velocity. This insertion shows similarity to a secondary actin
      binding site present in the tail of some class I myosins, and indeed a GST-loop
      construct binds actin. Probably as a consequence, binding of MyoK to actin was
      not only ATP- but also salt-dependent. Moreover, as both binding sites reside
      within its motor domain and carry potential sites of regulation, MyoK might
      represent a new form of actin crosslinker. MyoK was distributed in the cytoplasm
      with a significant enrichment in dynamic regions of the cortex. Absence of MyoK
      resulted in a drop of cortical tension whereas overexpression led to
      significantly increased tension. Absence and overexpression of MyoK dramatically
      affected the cortical actin cytoskeleton and resulted in reduced initial rates of
      phagocytosis. Cells lacking MyoK showed excessive ruffling, mostly in the form of
      large lamellipodia, accompanied by a thicker basal actin cortex. At early stages
      of development, aggregation of myoK null cells was slowed due to reduced
      motility. Altogether, the data indicate a distinctive role for MyoK in the
      maintenance and dynamics of the cell cortex.

PMID- 10652256
TI  - 4-hydroxynonenal induces a cellular redox status-related activation of the
      caspase cascade for apoptotic cell death.
AB  - 4-Hydroxynonenal (HNE), a diffusible product of lipid peroxidation, has been
      suggested to be a key mediator of oxidative stress-induced cell death. In this
      study, we partially characterized the mechanism of HNE-mediated cytotoxicity.
      Incubation of human T lymphoma Jurkat cells with 20-50 microM HNE led to cell
      death accompanied by DNA fragmentation. Western blot analysis showed that HNE
      treatment induced time- and dose-dependent activation of caspase-8, caspase-9 and
      caspase-3. HNE-induced caspase-3 processing was confirmed by a flow cytometric
      demonstration of increased catalytic activity on the substrate peptide. HNE
      treatment also led to remarkable cleavage of poly(ADP-ribose) polymerase (PARP),
      which was prevented by pretreatment of cells with DEVD-FMK as a caspase-3
      inhibitor. The HNE-mediated activation of caspases, cleavage of PARP and DNA
      fragmentation were blocked by antioxidants cysteine, N-acety-L-cysteine and
      dithiothreitol, but not by two other HNE-reactive amino acids lysine and
      histidine, or by cystine, the oxidized form of cysteine. HNE rapidly decreased
      levels of intracellular reduced glutathione (GSH) and its oxidized form GSSG, and
      these were also attenuated by the reductants. Coincubation of Jurkat cells with a
      blocking anti-Fas antibody prevented Fas-induced but not HNE-induced activation
      of caspase-3. HNE also activated caspase-3 in K562 cells that do not express
      functional Fas. Our results thereby demonstrate that HNE triggers oxidative
      stress-linked apoptotic cell death through activation of the caspase cascade. The
      results also suggest a possible mechanism involving a direct scavenge of
      intracellular GSH by HNE.

PMID- 10652257
TI  - Tyrosine 766 in the fibroblast growth factor receptor-1 is required for FGF
      stimulation of phospholipase C, phospholipase D, phospholipase A(2),
      phosphoinositide 3-kinase and cytoskeletal reorganisation in porcine aortic
      endothelial cells.
AB  - Fibroblast growth factor-mediated signalling was studied in porcine aortic
      endothelial cells expressing either wild-type fibroblast growth factor receptor-1
      or a mutant receptor (Y766F) unable to bind phospholipase C-(&ggr;). Stimulation
      of cells expressing the wild-type receptor resulted in activation of
      phospholipases C, D and A(2) and increased phosphoinositide 3-kinase activity.
      Stimulation of the wild-type receptor also resulted in stress fibre formation and
      a cellular shape change. Cells expressing the Y766F mutant receptor failed to
      stimulate phospholipase C, D and A(2) as well as phosphoinositide 3-kinase.
      Furthermore, no stress fibre formation or shape change was observed. Both the
      wild-type and Y766F receptor mutant activated MAP kinase and elicited
      proliferative responses in the porcine aortic endothelial cells. Thus, fibroblast
      growth factor receptor-1 mediated activation of phospholipases C, D and A(2) and
      phosphoinositide 3-kinase was dependent on tyrosine 766. Furthermore, whilst
      tyrosine 766 was not required for a proliferative response, it was required for
      fibroblast growth factor receptor-1 mediated cytoskeletal reorganisation.

PMID- 10652258
TI  - Migration of human vascular smooth muscle cells involves serum-dependent repeated
      cytosolic calcium transients.
AB  - Migration of vascular smooth muscle cells (VSMC) is a key event in the formation
      of neointima during atherosclerosis. Fura-2 loaded VSMCs were used to investigate
      calcium homeostasis during cell migration. Multiple spontaneous transient
      increases in cytosolic free calcium [Ca(2+)](i)were observed in single human
      VSMCs migrating on type I collagen. Such [Ca(2+)](i)transients were dependent on
      the presence of serum or PDGF-BB. Removal of serum, or loading cells with BAPTA,
      abolished the transients and decreased cell migration speed. The transients were
      not affected by disruption of cell polarization by dihydrocytochalasin B.
      Adhesion was used to investigate the specific role of cell-substrate interactions
      in the generation of transients. Transients are seen in VSMCs adhering either on
      collagen or on poly-L-lysine, suggesting that generation of transients is not
      strictly dependent on integrins. Buffering [Ca(2+)](i) with BAPTA led to
      accumulation of (beta)1 integrins at the cellular tail, and to increased release
      of integrin on the extracellular matrix. These results demonstrate a role for
      [Ca(2+)](i) transients in the rapid, serum-dependent migration of VSMCs. These
      [Ca(2+)](i)transients are present in migrating VSMCs only when two simultaneous
      events occur: (1) substrate independent spreading and (2) stimulation of cells by
      serum components such as PDGF-BB.

PMID- 10652259
TI  - Expression and nuclear localization of BLM, a chromosome stability protein
      mutated in Bloom's syndrome, suggest a role in recombination during meiotic
      prophase.
AB  - Bloom's syndrome (BS) is a recessive human genetic disorder characterized by
      short stature, immunodeficiency and elevated risk of malignancy. BS cells have
      genomic instability and an increased frequency of sister chromatid exchange. The
      gene mutated in BS, BLM, encodes a 3'-5' helicase (BLM) with homology to
      bacterial recombination factor, RecQ. Human males homozygous for BLM mutations
      are infertile and heterozygous individuals display increased frequencies of
      structural chromosome abnormalities in their spermatozoa. Also, mutations in the
      Saccharomyces cerevisiae homolog of BLM, Sgs1, cause a delay in meiotic nuclear
      division and a reduction in spore viability. These observations suggest that BLM
      may play a role during meiosis. Our antibodies raised against the C terminus of
      the human protein specifically recognize both mouse and human BLM in western
      blots of cell lines and in successive developmental stages of spermatocytes, but
      fail to detect BLM protein in a cell line with a C-terminally truncated protein.
      BLM protein expression and location are detected by immunofluorescence and
      immunoelectron microscopy as discrete foci that are sparsely present on early
      meiotic prophase chromosome cores, later found abundantly on synapsed cores,
      frequently in combination with the recombinases RAD51 and DMC1, and eventually as
      pure BLM foci. The colocalization of RAD51/DMC1 with BLM and the statistically
      significant excess of BLM signals in the synapsed pseudoautosomal region of the X
      Y chromosomes, which is a recombinational hot spot, provide indications that BLM
      protein may function in the meiotic recombination process.

PMID- 10652260
TI  - Association of mammalian SMC1 and SMC3 proteins with meiotic chromosomes and
      synaptonemal complexes.
AB  - In somatic cells, the heterodimeric Structural Maintenance of Chromosomes (SMC)
      proteins are involved in chromosome condensation and gene dosage compensation
      (SMC2 and 4), and sister chromatid cohesion and DNA recombination (SMC1 and 3).
      We report here evidence for an involvement of mammalian SMC1 and SMC3 proteins in
      meiosis. Immunofluorescence analysis of testis sections showed intense chromatin
      association in meiotic prophase cells, weaker staining in round spermatids and
      absence of the SMC proteins in elongated spermatids. In spermatocyte nuclei
      spreads, the SMC1 and SMC3 proteins localize in a beaded structure along the
      axial elements of synaptonemal complexes of pachytene and diplotene chromosomes.
      Both SMC proteins are present in rat spermatocytes and enriched in preparations
      of synaptonemal complexes. Several independent experimental approaches revealed
      interactions of the SMC proteins with synaptonemal complex-specific proteins SCP2
      and SCP3. These results suggest a model for the arrangement of SMC proteins in
      mammalian meiotic chromatin.

PMID- 10652262
TI  - Induced detachment of acentric chromatin from mitotic chromosomes leads to their
      cytoplasmic localization at G(1) and the micronucleation by lamin reorganization
      at S phase.
AB  - Acentric and atelomeric double minute chromatin found in human cancer cells are
      eliminated from cells by selective incorporation into the micronuclei. We showed
      previously that most of the micronuclei were formed at S phase and mediated by
      the nuclear bud-shaped structures that selectively entrap double minutes. In this
      paper, we have examined the behavior of double minutes in relation to the nuclear
      lamin protein in cell cycle-synchronized human COLO 320DM tumor cells. At the
      G(1) phase, we observed that a portion of double minutes was localized at the
      cytoplasm and showed no association with lamin. The frequency of this
      localization was increased by hydroxyurea, an inducer of micronuclei, if treated
      at the preceding S phase. The acentric double minutes were normally segregated to
      daughter cells by attaching to the mitotic chromosomes, and the hydroxyurea
      treatment induced their detachment, possibly through the introduction of the
      double strand break. When the cells entered S phase, our data suggested that the
      lamin protein accumulated around the cytoplasmic double minutes at the proximity
      of the nucleus leading to the formation of the nuclear bud-shaped structure and
      the initiation of DNA replication. This association of cytoplasmic double minutes
      with lamin coincided with the large-scale rearrangement of the intranuclear lamin
      protein. The implication of these findings as well as their application to a
      broad spectrum of other acentric, atelomeric and autonomously replicating
      molecules are discussed.

PMID- 10652261
TI  - The replication capacity of intact mammalian nuclei in Xenopus egg extracts
      declines with quiescence, but the residual DNA synthesis is independent of
      Xenopus MCM proteins.
AB  - In eukaryotes, the initiation of DNA synthesis requires the assembly of a pre
      replicative complex (pre-RC) at origins of replication. This involves the
      sequential binding of ORC (origin-recognition-complex), Cdc6 and MCM proteins, a
      process referred to as licensing. After origin firing, the Cdc6 and MCM proteins
      dissociate from the chromatin, and do not rebind until after the completion of
      mitosis, thereby restricting replication to a single round in each cell cycle.
      Although nuclei normally become licensed for replication as they enter G(1), the
      extent to which the license is retained when cells enter the quiescent state
      (G(0)) is controversial. Here we show that the replication capacity of nuclei
      from Swiss 3T3 cells, in Xenopus egg extracts, is not lost abruptly with the
      onset of quiescence, but instead declines gradually. The decline in replication
      capacity, which affects both the number of nuclei induced to replicate and their
      subsequent rate of DNA synthesis, is accompanied by a fall in the level of
      chromatin-bound MCM2. When quiescent nuclei are incubated in egg extracts, they
      do not bind further MCMs unless the nuclei are first permeabilized. The residual
      replication capacity of intact nuclei must therefore be dependent on the
      remaining endogenous MCMs. Although high levels of Cdk activity are known to
      block MCM binding, we show that the failure of intact nuclei in egg extracts to
      increase their bound MCMs is not due to their uptake and accumulation of Cdk
      complexes. Instead, the failure of binding must be due to exclusion of some other
      binding factor from the nucleus, or to the presence within nuclei of an inhibitor
      of binding other than Cdk activity. In contrast to the situation in Xenopus egg
      extracts, following serum stimulation of intact quiescent cells, the level of
      bound MCMs does increase before the cells reach S phase, without any disruption
      of the nuclear envelope.

PMID- 10652263
TI  - The Dictyostelium RasS protein is required for macropinocytosis, phagocytosis and
      the control of cell movement.
AB  - Endocytosis and cell migration both require transient localised remodelling of
      the cell cortex. Several lines of evidence suggest a key regulatory role in these
      activities for members of the Ras family of small GTPases. We have generated
      Dictyostelium cells lacking one member of this family, RasS, and the mutant cells
      are perturbed in endocytosis and cell migration. Mutant amoebae are defective in
      phagocytosis and fluid-phase endocytosis and are impaired in growth. Conversely,
      the rasS(-)cells show an enhanced rate of cell migration, moving three times
      faster than wild-type controls. The mutant cells display an aberrant morphology,
      are highly polarised, carry many elongated actin protrusions and show a
      concomitant decrease in formation of pinocytic crowns on the cell surface. These
      morphological aberrations are paralleled by changes in the actin cytoskeleton,
      with a significant proportion of the cortical F-actin relocalised to prominent
      pseudopodia. Rapid migration and endocytosis appear to be mutually incompatible
      and it is likely that RasS protein is required to maintain the normal balance
      between these two actin-dependent processes.

PMID- 10652264
TI  - Comparison of the glycosyl-phosphatidylinositol cleavage/attachment site between
      mammalian cells and parasitic protozoa.
AB  - It was previously hypothesised that the requirements for glycosyl
      phosphatidylinositol (GPI) anchoring in mammalian cells and parasitic protozoa
      are similar but not identical. We have investigated this by converting the GPI
      cleavage/attachment site in porcine membrane dipeptidase to that found in the
      trypanosomal variant surface glycoprotein 117 and expressing the resulting
      mutants in COS-1 cells. Changing the entire (omega), (omega)+1 and (omega)+2
      triplet in membrane dipeptidase from Ser-Ala-Ala to Asp-Ser-Ser resulted in
      efficient GPI anchoring of the mutant proteins, as assessed by cell-surface
      activity assays and susceptibility to release by phosphatidylinositol-specific
      phospholipase C. Immunoelectrophoretic blot analysis with antibodies recognising
      epitopes either side of the native (omega) residue in porcine membrane
      dipeptidase, and expression of a mutant in which potential alternative
      cleavage/attachment sites were disrupted, indicated that alternative GPI
      cleavage/attachment sites had not been used. These results indicate that the
      requirements for GPI anchoring between mammalian and protozoal cells are not as
      different as previously suggested, and that rules for predicting the probability
      of a sequence acting as a GPI cleavage/attachment site need to be applied with
      caution.

PMID- 10652265
TI  - TrioGEF1 controls Rac- and Cdc42-dependent cell structures through the direct
      activation of rhoG.
AB  - Rho GTPases regulate the morphology of cells stimulated by extracellular ligands.
      Their activation is controlled by guanine exchange factors (GEF) that catalyze
      their binding to GTP. The multidomain Trio protein represents an emerging class
      of &Rgr; regulators that contain two GEF domains of distinct specificities. We
      report here the characterization of Rho signaling pathways activated by the N
      terminal GEF domain of Trio (TrioD1). In fibroblasts, TrioD1 triggers the
      formation of particular cell structures, similar to those elicited by RhoG, a
      GTPase known to activate both Rac1 and Cdc42Hs. In addition, the activity of
      TrioD1 requires the microtubule network and relocalizes RhoG at the active sites
      of the plasma membrane. Using a classical in vitro exchange assay, TrioD1
      displays a higher GEF activity on RhoG than on Rac1. In fibroblasts, expression
      of dominant negative RhoG mutants totally abolished TrioD1 signaling, whereas
      dominant negative Rac1 and Cdc42Hs only led to partial and complementary
      inhibitions. Finally, expression of a Rho Binding Domain that specifically binds
      RhoG(GTP) led to the complete abolition of TrioD1 signaling, which strongly
      supports Rac1 not being activated by TrioD1 in vivo. These data demonstrate that
      Trio controls a signaling cascade that activates RhoG, which in turn activates
      Rac1 and Cdc42Hs.

PMID- 10652266
TI  - Regulation of protein sorting at the TGN by plasma membrane receptor activation.
AB  - We show that in the rat basophilic leukemia cell line RBL, the physiological
      stimulation of the IgE receptor or direct activation of PKC leads to the
      missorting of proteins to the plasma membrane, diverting them from their normal
      intracellular destination. This is demonstrated for two classes of proteins that
      are normally targeted to the secretory lysosomes via completely different
      mechanisms, i.e. proteoglycans and the aspartic protease cathepsin D. In the
      latter case, normal processing of the enzyme is also affected, leading to
      secretion of the immature form of cathepsin. The present study shows how
      completely different sorting mechanisms, such as those for delivering
      proteoglycans and cathepsin D to secretory lysosomes, might share common
      regulatory signals and are similarly affected when the levels of these signals
      are perturbed. Finally, protein kinase C appears to be a major player in the
      signal transduction pathways, leading to proteoglycan and cathepsin D missorting.

PMID- 10652267
TI  - The coregulator exchange in transcriptional functions of nuclear receptors.

PMID- 10652268
TI  - Pan-neural Prospero terminates cell proliferation during Drosophila neurogenesis.
AB  - Organogenesis requires coordination between developmental specific regulators and
      genes governing cell proliferation. Here we show that Drosophila prospero encodes
      a critical regulator of the transition from mitotically active cells to terminal
      differentiated neurons. Loss of pros results in aberrant expression of multiple
      cell-cycle regulatory genes and ectopic mitotic activity. In contrast, ectopic
      pros expression causes transcriptional suppression of multiple cell-cycle
      regulatory genes and premature termination of cell division. pros activity,
      hence, provides a critical regulatory link between neuronal lineage development
      and transcriptional regulation of cell cycle regulatory genes.

PMID- 10652269
TI  - An essential role in liver development for transcription factor XBP-1.
AB  - XBP-1 is a CREB/ATF family transcription factor highly expressed in
      hepatocellular carcinomas. Here we report that XBP-1 is essential for liver
      growth. Mice lacking XBP-1 displayed hypoplastic fetal livers, whose reduced
      hematopoiesis resulted in death from anemia. Nevertheless, XBP-1-deficient
      hematopoietic progenitors had no cell-autonomous defect in differentiation.
      Rather, hepatocyte development itself was severely impaired by two measures:
      diminished growth rate and prominent apoptosis. Specific target genes of XBP-1 in
      the liver were identified as alphaFP, which may be a regulator of hepatocyte
      growth, and three acute phase protein family members. Therefore, XBP-1 is a
      transcription factor essential for hepatocyte growth.

PMID- 10652270
TI  - Direct regulation of nacre, a zebrafish MITF homolog required for pigment cell
      formation, by the Wnt pathway.
AB  - We have shown that Wnt signals are necessary and sufficient for neural crest
      cells to adopt pigment cell fates. nacre, a zebrafish homolog of MITF, is
      required for pigment cell differentiation. We isolated a promoter region of nacre
      that contains Tcf/Lef binding sites, which can mediate Wnt responsiveness. This
      promoter binds to zebrafish Lef1 protein in vitro, and a nacre reporter construct
      is strongly repressed by dominant-negative Tcf in melanoma cells. Mutation of
      Tcf/Lef sites abolishes Lef1 binding and reporter function in vivo. Wnt signaling
      therefore directly activates nacre, which in turn leads to pigment cell
      differentiation.

PMID- 10652271
TI  - Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF
      beta and promotes tumor invasion and angiogenesis.
AB  - We have uncovered a novel functional relationship between the hyaluronan receptor
      CD44, the matrix metalloproteinase-9 (MMP-9) and the multifunctional cytokine TGF
      beta in the control of tumor-associated tissue remodeling. CD44 provides a cell
      surface docking receptor for proteolytically active MMP-9 and we show here that
      localization of MMP-9 to cell surface is required for its ability to promote
      tumor invasion and angiogenesis. Our observations also indicate that MMP-9, as
      well as MMP-2, proteolytically cleaves latent TGF-beta, providing a novel and
      potentially important mechanism for TGF-beta activation. In addition, we show
      that MMP-9 localization to the surface of normal keratinocytes is CD44 dependent
      and can activate latent TGF-beta. These observations suggest that coordinated
      CD44, MMP-9, and TGF-beta function may provide a physiological mechanism of
      tissue remodeling that can be adopted by malignant cells to promote tumor growth
      and invasion.

PMID- 10652272
TI  - Rhomboid and Star facilitate presentation and processing of the Drosophila TGF
      alpha homolog Spitz.
AB  - Activation of the Drosophila epidermal growth factor receptor (DER) by the
      transmembrane ligand, Spitz (Spi), requires two additional transmembrane
      proteins, Rhomboid and Star. Genetic evidence suggests that Rhomboid and Star
      facilitate DER signaling by processing membrane-bound Spi (mSpi) to an active,
      soluble form. To test this model, we use an assay based on Xenopus animal cap
      explants in which Spi activation of DER is Rhomboid and Star dependent. We show
      that Spi is on the cell surface but is kept in an inactive state by its
      cytoplasmic and transmembrane domains; Rhomboid and Star relieve this inhibition,
      allowing Spi to signal. We show further that Spi is likely to be cleaved within
      its transmembrane domain. However, a mutant form of mSpi that is not cleaved
      still signals to DER in a Rhomboid and Star-dependent manner. These results
      suggest strongly that Rhomboid and Star act primarily to present an active form
      of Spi to DER, leading secondarily to the processing of Spi into a secreted form.

PMID- 10652273
TI  - A mechanism of suppression of TGF-beta/SMAD signaling by NF-kappa B/RelA.
AB  - A number of pathogenic and proinflammatory stimuli, and the transforming growth
      factor-beta (TGF-beta) exert opposing activities in cellular and immune
      responses. Here we show that the RelA subunit of nuclear factor kappaB (NF
      kappaB/RelA) is necessary for the inhibition of TGF-beta-induced phosphorylation,
      nuclear translocation, and DNA binding of SMAD signaling complexes by tumor
      necrosis factor-alpha (TNF-alpha). The antagonism is mediated through up
      regulation of Smad7 synthesis and induction of stable associations between ligand
      activated TGF-beta receptors and inhibitory Smad7. Down-regulation of endogenous
      Smad7 by expression of antisense mRNA releases TGF-beta/SMAD-induced
      transcriptional responses from suppression by cytokine-activated NF-kappaB/RelA.
      Following stimulation with bacterial lipopolysaccharide (LPS), or the
      proinflammatory cytokines TNF-alpha and interleukin-1beta (IL-1beta, NF
      kappaB/RelA induces Smad7 synthesis through activation of Smad7 gene
      transcription. These results suggest a mechanism of suppression of TGF-beta/SMAD
      signaling by opposing stimuli mediated through the activation of inhibitory Smad7
      by NF-kappaB/RelA.

PMID- 10652274
TI  - Mechanisms of Hox gene colinearity: transposition of the anterior Hoxb1 gene into
      the posterior HoxD complex.
AB  - Transposition of Hoxd genes to a more posterior (5') location within the HoxD
      complex suggested that colinearity in the expression of these genes was due, in
      part, to the existence of a silencing mechanism originating at the 5' end of the
      cluster and extending towards the 3' direction. To assess the strength and
      specificity of this repression, as well as to challenge available models on
      colinearity, we inserted a Hoxb1/lacZ transgene within the posterior HoxD
      complex, thereby reconstructing a cluster with a copy of the most anterior gene
      inserted at the most posterior position. Analysis of Hoxb1 expression after
      ectopic relocation revealed that Hoxb1-specific activity in the fourth rhombomere
      was totally abolished. Treatment with retinoic acid, or subsequent relocations
      toward more 3' positions in the HoxD complex, did not release this silencing in
      hindbrain cells. In contrast, however, early and anterior transgene expression in
      the mesoderm was unexpectedly not suppressed. Furthermore, the transgene induced
      a transient ectopic activation of the neighboring Hoxd13 gene, without affecting
      other genes of the complex. Such a local and transient break in colinearity was
      also observed after transposition of the Hoxd9/lacZ reporter gene, indicating
      that it may be a general property of these transgenes when transposed at an
      ectopic location. These results are discussed in the context of existing models,
      which account for colinear activation of vertebrate Hox genes.

PMID- 10652275
TI  - Dynamic organization of chromosomal DNA in Escherichia coli.
AB  - We have revealed the subcellular localization of different DNA segments that are
      located at approximately 230-kb intervals on the Escherichia coli chromosome
      using fluorescence in situ hybridization (FISH). The series of chromosome
      segments is localized within the cell in the same order as the chromosome map.
      The large chromosome region including oriC shows similar localization patterns,
      which we call the Ori domain. In addition, the localization pattern of the large
      segment including dif is characteristic of the replication terminus region. The
      segment also shows similar localization patterns, which we call the Ter domain.
      In newborn cells, Ori and Ter domains of the chromosome are differentially
      localized near opposite cell poles. Subsequently, in the B period, the Ori domain
      moves toward mid-cell before the initiation of replication, and the Ter domain
      tends to relocate at mid-cell. An inversion mutant, in which the Ter domain is
      located close to oriC, shows abnormal subcellular localization of ori and dif
      segments, resulting in frequent production of anucleate cells. These studies thus
      suggest that the E. coli chromosome is organized to form a compacted ring
      structure with the Ori and Ter domains; these domains participate in the cell
      cycle-dependent localization of the chromosome.

PMID- 10652276
TI  - Relief of gene repression by torso RTK signaling: role of capicua in Drosophila
      terminal and dorsoventral patterning.
AB  - Differentiation of the embryonic termini in Drosophila depends on signaling by
      the Tor RTK, which induces terminal gene expression by inactivating at the
      embryonic poles a uniformly distributed repressor activity that involves the Gro
      corepressor. Here, we identify a new gene, cic, that acts as a repressor of
      terminal genes regulated by the Tor pathway. cic also mediates repression along
      the dorsoventral axis, a process that requires the Dorsal morphogen and Gro, and
      which is also inhibited by Tor signaling at the termini. cic encodes an HMG-box
      transcription factor that interacts with Gro in vitro. We present evidence that
      Tor signaling regulates terminal patterning by inactivating Cic at the embryo
      poles. cic has been evolutionarily conserved, suggesting that Cic-like proteins
      may act as repressors regulated by RTK signaling in other organisms.

PMID- 10652278
TI  - A forkhead gene, FoxE3, is essential for lens epithelial proliferation and
      closure of the lens vesicle.
AB  - In the mouse mutant dysgenetic lens (dyl) the lens vesicle fails to separate from
      the ectoderm, causing a fusion between the lens and the cornea. Lack of a
      proliferating anterior lens epithelium leads to absence of secondary lens fibers
      and a dysplastic, cataractic lens. We report the cloning of a gene, FoxE3,
      encoding a forkhead/winged helix transcription factor, which is expressed in the
      developing lens from the start of lens placode induction and becomes restricted
      to the anterior proliferating cells when lens fiber differentiation begins. We
      show that FoxE3 is colocalized with dyl in the mouse genome, that dyl mice have
      mutations in the part of FoxE3 encoding the DNA-binding domain, and that these
      mutations cosegregate with the dyl phenotype. During embryonic development, the
      primordial lens epithelium is formed in an apparently normal way in dyl mutants.
      However, instead of the proliferation characteristic of a normal lens epithelium,
      the posterior of these cells fail to divide and show signs of premature
      differentiation, whereas the most anterior cells are eliminated by apoptosis.
      This implies that FoxE3 is essential for closure of the lens vesicle and is a
      factor that promotes survival and proliferation, while preventing
      differentiation, in the lens epithelium.

PMID- 10652279
TI  - The DnaX-binding subunits delta' and psi are bound to gamma and not tau in the
      DNA polymerase III holoenzyme.
AB  - The DnaX complex subassembly of the DNA polymerase III holoenzyme is comprised of
      the DnaX proteins tau and gamma and the auxiliary subunits delta, delta', chi,
      and psi, which together load the beta processivity factor onto primed DNA in an
      ATP-dependent reaction. delta' and psi bind directly to DnaX whereas delta and
      chi bind to delta' and psi, respectively (Onrust, R., Finkelstein, J., Naktinis,
      V., Turner, J., Fang, L., and O'Donnell, M. (1995) J. Biol. Chem. 270, 13348
      13357). Until now, it has been unclear which DnaX protein, tau or gamma, in
      holoenzyme binds the auxiliary subunits delta, delta', chi,and psi. Treatment of
      purified holoenzyme with the homobifunctional cross-linker
      bis(sulfosuccinimidyl)suberate produces covalently cross-linked gamma-delta' and
      gamma-psi complexes identified by Western blot analysis. Immunodetection of cross
      linked species with anti-delta' and anti-psi antibodies revealed that no tau
      delta' or tau-psi cross-links had formed, suggesting that the delta' and psi
      subunits reside only on gamma within holoenzyme.

PMID- 10652280
TI  - Early embryonic lethality of H ferritin gene deletion in mice.
AB  - Ferritin molecules play an important role in the control of intracellular iron
      distribution and in the constitution of long term iron stores. In vitro studies
      on recombinant ferritin subunits have shown that the ferroxidase activity
      associated with the H subunit is necessary for iron uptake by the ferritin
      molecule, whereas the L subunit facilitates iron core formation inside the
      protein shell. However, plant and bacterial ferritins have only a single type of
      subunit which probably fulfills both functions. To assess the biological
      significance of the ferroxidase activity associated with the H subunit, we
      disrupted the H ferritin gene (Fth) in mice by homologous recombination. Fth(+/-)
      mice are healthy, fertile, and do not differ significantly from their control
      littermates. However, Fth(-/-) embryos die between 3.5 and 9.5 days of
      development, suggesting that there is no functional redundancy between the two
      ferritin subunits and that, in the absence of H subunits, L ferritin homopolymers
      are not able to maintain iron in a bioavailable and nontoxic form. The pattern of
      expression of the wild type Fth gene in 9.5-day embryos is suggestive of an
      important function of the H ferritin gene in the heart.

PMID- 10652277
TI  - Antiapoptotic activity of Stat5 required during terminal stages of myeloid
      differentiation.
AB  - Stat5 is activated by multiple receptors of hematopoietic cytokines. To study its
      role during hematopoiesis, we have generated primary chicken myeloblasts
      expressing different dominant-negative (dn) alleles of Stat5. This caused a
      striking inability to generate mature cells, due to massive apoptosis during
      differentiation. Bcl-2 was able to rescue differentiating cells expressing
      dnStat5 from apoptosis, suggesting that during cytokine-dependent differentiation
      the main function of the protein is to ensure cell survival. Our findings with
      dnStat5-expressing chicken myeloblasts were confirmed with primary hematopoietic
      cells from Stat5a/Stat5b-deficient mice. Bone marrow cells from these animals
      displayed a strong increase in apoptotic cell death during GM-CSF-dependent
      functional maturation in vitro. The antiapoptotic protein Bcl-x was induced by GM
      CSF and IL-3 in a Stat5-dependent fashion. Ectopic expression of Bcl-x rescued
      Stat5-deficient bone marrow cells from apoptosis, indicating that Stat5 promotes
      the survival of myeloid progenitor cells through its ability to induce
      transcription of the bcl-x gene. Finally, the recruitment of myeloid cells to
      inflammatory sites was found strongly impeded in Stat5-deficient mice. Taken
      together, our findings suggest that Stat5 may promote cytokine-dependent survival
      and proliferation of differentiating myeloid progenitor cells in stress or
      pathological situations, such as inflammation.

PMID- 10652281
TI  - Enantioselective epoxidation and carbon-carbon bond cleavage catalyzed by
      Coprinus cinereus peroxidase and myeloperoxidase.
AB  - We demonstrate that myeloperoxidase (MPO) and Coprinus cinereus peroxidase (CiP)
      catalyze the enantioselective epoxidation of styrene and a number of substituted
      derivatives with a reasonable enantiomeric excess (up to 80%) and in a moderate
      yield. Three major differences with respect to the chloroperoxidase from
      Caldariomyces fumago (CPO) are observed in the reactivity of MPO and CiP toward
      styrene derivatives. First, in contrast to CPO, MPO and CiP produced the (S)
      isomers of the epoxides in enantiomeric excess. Second, for MPO and CiP the
      H(2)O(2) had to be added very slowly (10 eq in 16 h) to prevent accumulation of
      catalytically inactive enzyme intermediates. Under these conditions, CPO hardly
      showed any epoxidizing activity; only with a high influx of H(2)O(2) (300 eq in
      1.6 h) was epoxidation observed. Third, both MPO and CiP formed significant
      amounts of (substituted) benzaldehydes as side products as a consequence of C
      alpha-C-beta bond cleavage of the styrene derivatives, whereas for CPO and
      cytochrome c peroxidase this activity is not observed. C-alpha-C-beta cleavage
      was the most prominent reaction catalyzed by CiP, whereas with MPO the relative
      amount of epoxide formed was higher. This is the first report of peroxidases
      catalyzing both epoxidation reactions and carbon-carbon bond cleavage. The
      results are discussed in terms of mechanisms involving ferryl oxygen transfer and
      electron transfer, respectively.

PMID- 10652282
TI  - Tyrosine nitration by simultaneous generation of (.)NO and O-(2) under
      physiological conditions. How the radicals do the job.
AB  - Radiation chemical experiments demonstrate that the reaction of tyrosyl radical
      (TyrO(.)) with (.)NO(2) yields 45 +/- 3% 3-nitrotyrosine and that a major product
      of the reaction of TyrO(.) with (.)NO is 3,3'-dityrosine. Radiolysis was used to
      generate (.)NO and O-(2) in the presence of tyrosine and bicarbonate at pH 7.5 +/
      0.1. The nitration yield was found to be dose rate-dependent, and the yield per
      radical produced by pulse radiolysis was identical to that obtained with
      authentic peroxynitrite. The proposed mechanism that accounts for the data is as
      follows: (i) In the presence of CO(2) the reaction of (.)NO with O-(2) yields 33%
      (.)NO(2) and CO-(3), where the latter reacts rapidly with tyrosine to form
      TyrO(.); (ii) The formation of 3-nitrotyrosine takes place via the reaction of
      (.)NO(2) with TyrO(.), which is the main process at high dose rates; and (iii)
      Under continuous generation of (.)NO and O-(2), the formation of 3-nitrotyrosine
      is strongly suppressed because of efficient scavenging of (.)NO(2) by tyrosine.
      The proposed model shows that the highest nitration yield is obtained for similar
      fluxes of (.)NO and O-(2) and is completely inhibited upon excess production of O
      (2) because of efficient scavenging of TyrO(.) by O-(2). The biological
      implications of these findings are discussed.

PMID- 10652283
TI  - Enkephalins are transported by a novel eukaryotic peptide uptake system.
AB  - We have identified an oligopeptide transporter in the yeast Saccharomyces
      cerevisiae which mediates the uptake of tetra- and pentapeptides, including the
      endogenous opioids leucine enkephalin (Tyr-Gly-Gly-Phe-Leu) and methionine
      enkephalin (Tyr-Gly-Gly-Phe-Met). The transporter is encoded by the gene OPT1.
      Yeast expressing OPT1 can utilize enkephalins to satisfy amino acid auxotrophic
      requirements for growth. The transport of radiolabeled leucine enkephalin
      exhibits saturable kinetics, with a K(m) of 310 microM. Transport activity is
      optimum at acidic pH and sensitive to reagents which uncouple oxidative
      phosphorylation, suggesting an energy dependence on the proton gradient. Growth,
      transport, and chromatographic data indicate that leucine enkephalin is not
      hydrolyzed in the extracellular medium and as such is translocated intact across
      the cell membrane. The system is specific for tetra- and pentapeptides and can be
      inhibited by the opioid receptor antagonists naloxone and naltrexone. To date,
      this is the first example of a eukaryotic transport system which can use
      enkephalins as a substrate, opening the possibility that a homologue exists in
      higher eukaryotes.

PMID- 10652284
TI  - Conformational transitions of the three recombinant domains of human serum
      albumin depending on pH.
AB  - Human serum albumin (HSA) is a protein of 66.5 kDa that is composed of three
      homologous domains, each of which displays specific structural and functional
      characteristics. HSA is known to undergo different pH-dependent structural
      transitions, the N-F and F-E transitions in the acid pH region and the N-B
      transition at slightly alkaline pH. In order to elucidate the structural behavior
      of the recombinant HSA domains as stand-alone proteins and to investigate the
      molecular and structural origins of the pH-induced conformational changes of the
      intact molecule, we have employed fluorescence and circular dichroic methods.
      Here we provide evidence that the loosening of the HSA structure in the N-F
      transition takes place primarily in HSA-DOM III and that HSA-DOM I undergoes a
      structural rearrangement with only minor changes in secondary structure, whereas
      HSA-DOM II transforms to a molten globule-like state as the pH is reduced. In the
      pH region of the N-B transition of HSA, HSA-DOM I and HSA-DOM II experience a
      tertiary structural isomerization, whereas with HSA-DOM III no alterations in
      tertiary structure are observed, as judged from near-UV CD and fluorescence
      measurements.

PMID- 10652285
TI  - Molecular cloning and analysis of strictosidine beta-D-glucosidase, an enzyme in
      terpenoid indole alkaloid biosynthesis in Catharanthus roseus.
AB  - Strictosidine beta-D-glucosidase (SGD) is an enzyme involved in the biosynthesis
      of terpenoid indole alkaloids (TIAs) by converting strictosidine to cathenamine.
      The biosynthetic pathway toward strictosidine is thought to be similar in all TIA
      producing plants. Somewhere downstream of strictosidine formation, however, the
      biosynthesis diverges to give rise to the different TIAs found. SGD may play a
      role in creating this biosynthetic diversity. We have studied SGD at both the
      molecular and enzymatic levels. Based on the homology between different plant
      beta-glucosidases, degenerate polymerase chain reaction primers were designed and
      used to isolate a cDNA clone from a Catharanthus roseus cDNA library. A full
      length clone gave rise to SGD activity when expressed in Saccharomyces
      cerevisiae. SGD shows approximately 60% homology at the amino acid level to other
      beta-glucosidases from plants and is encoded by a single-copy gene. Sgd
      expression is induced by methyl jasmonate with kinetics similar to those of two
      other genes acting prior to Sgd in TIA biosynthesis. These results show that
      coordinate induction of the biosynthetic genes forms at least part of the
      mechanism for the methyl jasmonate-induced increase in TIA production. Using a
      novel in vivo staining method, subcellular localization studies of SGD were
      performed. This showed that SGD is most likely associated with the endoplasmic
      reticulum, which is in accordance with the presence of a putative signal
      sequence, but in contrast to previous localization studies. This new insight in
      SGD localization has significant implications for our understanding of the
      complex intracellular trafficking of metabolic intermediates during TIA
      biosynthesis.

PMID- 10652286
TI  - Syndecan-1 shedding is enhanced by LasA, a secreted virulence factor of
      Pseudomonas aeruginosa.
AB  - Microbial pathogens frequently take advantage of host systems for their
      pathogenesis. Shedding of cell surface molecules as soluble extracellular domains
      (ectodomains) is one of the host responses activated during tissue injury. In
      this study, we examined whether pathogenic bacteria can modulate shedding of
      syndecan-1, the predominant syndecan of host epithelia. Our studies found that
      overnight culture supernatants of Pseudomonas aeruginosa and Staphylococcus
      aureus enhanced the shedding of syndecan-1 ectodomains, whereas culture
      supernatants of several other Gram-negative and Gram-positive bacteria had only
      low levels of activity. Because supernatants from all tested strains of P.
      aeruginosa (n = 9) enhanced syndecan-1 shedding by more than 4-fold above control
      levels, we focused our attention on this Gram-negative bacterium. Culture
      supernatants of P. aeruginosa increased shedding of syndecan-1 in both a
      concentration- and time-dependent manner, and augmented shedding by various host
      cells. A 20-kDa shedding enhancer was partially purified from the supernatant
      through ammonium sulfate precipitation and gel chromatography, and identified by
      N-terminal sequencing as LasA, a known P. aeruginosa virulence factor. LasA was
      subsequently determined to be a syndecan-1 shedding enhancer from the findings
      that (i) immunodepletion of LasA from the partially purified sample resulted in
      abrogation of its activity to enhance shedding and (ii) purified LasA increased
      shedding in a concentration-dependent manner. Our results also indicated that
      LasA enhances syndecan-1 shedding by activation of the host cell's shedding
      mechanism and not by direct interaction with syndecan-1 ectodomains. Enhanced
      syndecan-1 shedding may be a means by which pathogenic bacteria take advantage of
      a host mechanism to promote their pathogenesis.

PMID- 10652287
TI  - Characterization of two polyketide methyltransferases involved in the
      biosynthesis of the antitumor drug mithramycin by Streptomyces argillaceus.
AB  - A DNA chromosomal region of Streptomyces argillaceus ATCC 12596, the producer
      organism of the antitumor polyketide drug mithramycin, was cloned. Sequence
      analysis of this DNA region, located between four mithramycin glycosyltransferase
      genes, showed the presence of two genes (mtmMI and mtmMII) whose deduced products
      resembled S-adenosylmethionine-dependent methyltransferases. By independent
      insertional inactivation of both genes nonproducing mutants were generated that
      accumulated different mithramycin biosynthetic intermediates. The M3DeltaMI
      mutant (mtmMI-minus mutant) accumulated 4-demethylpremithramycinone (4-DPMC)
      which lacks the methyl groups at carbons 4 and 9. The M3DeltaM2 (mtmMII-minus
      mutant) accumulated 9-demethylpremithramycin A3 (9-DPMA3), premithramycin A1
      (PMA1), and 7-demethylmithramycin, all of them containing the O-methyl group at C
      4 and C-1', respectively, but lacking the methyl group at the aromatic position.
      Both genes were expressed in Streptomyces lividans TK21 under the control of the
      erythromycin resistance promoter (ermEp) of Saccharopolyspora erythraea. Cell
      free extracts of these clones were precipitated with ammonium sulfate (90%
      saturation) and assayed for methylation activity using different mithramycin
      intermediates as substrates. Extracts of strains MJM1 (expressing the mtmMI gene)
      and MJM2 (expressing the mtmMII gene) catalyzed efficient transfer of tritium
      from [(3)H]S-adenosylmethionine into 4-DPMC and 9-DPMA3, respectively, being
      unable to methylate other intermediates at a detectable level. These results
      demonstrate that the mtmMI and mtmMII genes code for two S-adenosylmethionine
      dependent methyltransferases responsible for the 4-O-methylation and 9-C
      methylation steps of the biosynthetic precursors 4-DPMC and 9-DPMA3,
      respectively, of the antitumor drug mithramycin. A pathway is proposed for the
      last steps in the biosynthesis of mithramycin involving these methylation events.

PMID- 10652288
TI  - Transcriptional induction of endothelial nitric oxide gene by cyclosporine A. A
      role for activator protein-1.
AB  - We have previously shown that the immunosuppressant cyclosporine A (CsA)
      increases the activity, the protein level, and the steady-state levels of the
      mRNA of the endothelial nitric-oxide synthase (eNOS) gene in bovine aortic
      endothelial cells (BAEC). We have now investigated the mechanisms responsible for
      these effects. Preincubation with an inhibitor of RNA polymerase II abolished CsA
      induced eNOS up-regulation. Nuclear run-on experiments demonstrated a 1.6-fold
      increase in the induction of eNOS gene by CsA. In agreement with these results,
      transient transfections showed that CsA augmented the transactivation of the eNOS
      promoter. Electrophoretic mobility shift assays showed an increase in the
      activator protein-1 (AP-1) DNA binding activity in BAEC treated with CsA. An
      increase in the level of c-fos mRNA and in the nuclear content of c-Fos protein
      was detected in BAEC treated with CsA. Site-directed mutagenesis of the AP-1 cis
      regulatory element in the context of the human eNOS promoter resulted in the
      abrogation of the induction mediated by CsA. Hence, up-regulation of eNOS mRNA by
      CsA is a transcriptional phenomenon involving the proximal AP-1 site in the 5'
      regulatory region of the human eNOS gene. Furthermore, our data exemplify how
      immunosuppressive drugs may result in the regulation of specific genes involved
      in the homeostasis of endothelial function, such as eNOS.

PMID- 10652289
TI  - Tumor necrosis factor alpha up-regulates in an autocrine manner the synthesis of
      plasminogen activator inhibitor type-1 during induction of monocytic
      differentiation of human HL-60 leukemia cells.
AB  - Tumor necrosis factor-alpha (TNFalpha) critically regulates several cellular
      functions during monocyte/macrophage differentiation. We therefore investigated
      during the phorbol ester (phorbol 12-myristate 13-acetate (PMA))-induced
      monocyte/macrophage differentiation of the human HL-60 leukemia cells, if
      TNFalpha contributed to plasminogen activator inhibitor type-1 (PAI-1) synthesis
      that is initiated by a protein kinase Cbeta-extracellular signal-regulated kinase
      2-dependent pathway (Lopez, S., Peiretti, F., Morange, P., Laouar, A., Fossat,
      C., Bonardo, B., Huberman, E., Juhan-Vague, I., and Nalbone, G. (1999) Thromb.
      Haemostasis 81, 415-422). Following PMA treatment, the level of TNFalpha mRNA
      strongly increased and appeared earlier than PAI-1 mRNA. An anti-TNFalpha
      antibody significantly inhibited the PMA-induced PAI-1 mRNA and protein levels.
      The recombinant human TNFalpha, which is inactive on native HL-60 cells in terms
      of PAI-1 synthesis, optimally potentiates it once HL-60 cells are committed into
      the differentiation process. The use of 1) the HL-525 cell line, a clone issued
      from HL-60 cells rendered resistant to PMA-induced differentiation, and 2) the
      transforming growth factorbeta-1/vitamin D3 differentiative mixture confirmed the
      relationships between the induction of differentiation and the potency of
      TNFalpha to up-regulate PAI-1 synthesis. In conclusion, we showed that during the
      induction of monocyte/macrophage differentiation, TNFalpha and PAI-1 gene
      expressions are activated and that synthesized TNFalpha up-regulates and
      prolongs, in an autocrine manner, the synthesis of PAI-1.

PMID- 10652290
TI  - Fibroblast quiescence and the disruption of ERK signaling in mechanically
      unloaded collagen matrices.
AB  - Fibroblasts in mechanically unloaded collagen matrices had low levels of DNA
      synthesis compared with cells in mechanically loaded matrices. Under the former
      conditions, the cellular ERK signaling pathway appeared to be disrupted. Also,
      pharmacologic inhibition of ERK signaling blocked DNA synthesis by fibroblasts in
      mechanically loaded matrices. These results were consistent with the idea that
      mechanoregulation of fibroblast DNA synthesis in collagen matrices occurs at the
      level of the ERK signaling pathway.

PMID- 10652291
TI  - Collagen XVII is destabilized by a glycine substitution mutation in the cell
      adhesion domain Col15.
AB  - Collagen XVII is a hemidesmosomal transmembrane molecule important for epithelial
      adhesion in the skin. It exists in two forms, as a full-length protein and as a
      soluble ectodomain that is shed from the keratinocyte surface by furin-mediated
      proteolysis. To obtain information on the conformation and the functions of this
      unusual collagen, its largest collagenous domain, Col15, was expressed in a
      eukaryotic episomal expression system and purified by DEAE and fast protein
      liquid- Mono S chromatography. The protein was triple-helical (T(m) of 26.5
      degrees C) when produced in cultures containing ascorbic acid. When the vitamin
      supply was limited, the 4-hydroxyproline content was reduced from 74 to 9%,
      which, in turn, resulted in a drastic reduction of the stability of the triple
      helix. The glycine substitution mutation G627V associated with junctional
      epidermolysis bullosa, a human blistering skin disease, also had a striking
      effect on thermal stability of rCol15 causing partial unfolding already at 4
      degrees C. Col15 promoted cell adhesion of epithelial and fibroblastic cell lines
      with a beta1 integrin-mediated mechanism. In concert with this, in acquired
      autoimmune blistering skin diseases, circulating IgG and IgA autoantibodies were
      found to target rCol15r.

PMID- 10652293
TI  - Transcriptional regulation of the cyclooxygenase-2 gene in activated mast cells.
AB  - Activation of mast cells by aggregation of their IgE receptors induces rapid and
      transient synthesis of cyclooxygenase-2 (COX-2). In this study we investigated
      (i) the cis-acting response elements and transcription factors active at the COX
      2 promoter and (ii) the signal transduction pathways mediating COX-2 induction
      following aggregation of mast cell IgE receptors. Transient transfection assays
      with COX-2 promoter/luciferase constructs suggest that a consensus cyclic AMP
      response element is essential for induced COX-2 expression. Cotransfection
      studies with plasmids expressing c-Jun, dominant negative Ras, dominant negative
      c-Jun NH(2)-terminal kinase, and dominant negative MEKK1 demonstrate that
      activation of the Ras/MEKK1/c-Jun NH(2)-terminal kinase/c-Jun pathway is required
      for COX-2 promoter-mediated luciferase expression. Attenuation of COX-2 promoter
      activity by dominant negative constructs for Raf-1, ERK1, and ERK2 suggests that
      the Ras/Raf-1/extracellular signal-regulated kinase pathway is also necessary for
      COX-2 induction. Although mutating the two NF-IL6 sites individually did not
      affect COX-2 promoter activity, mutating both NF-IL6 sites substantially inhibits
      COX-2 promoter activity. Moreover, overexpression of wild type CCAAT/enhancer
      binding protein-beta (C/EBPbeta) augments COX-2 promoter activity in activated
      mast cells and cotransfection of a dominant negative C/EBPbeta construct
      completely blocks COX-2 promoter/luciferase expression. Our data suggest that in
      activated mast cells, a Ras/MEKK1/c-Jun NH(2)-terminal kinase signal transduction
      pathway activating c-Jun, a Ras/Raf-1/extracellular signal-regulated kinase
      pathway, and activated C/EBPbeta facilitate COX-2 induction via the cyclic AMP
      response element and NF-IL6 sites of the COX-2 promoter.

PMID- 10652292
TI  - The Pit-1 homeodomain and beta-domain interact with Ets-1 and modulate
      synergistic activation of the rat prolactin promoter.
AB  - Pit-1/GHF-1 is a pituitary-specific, POU homeodomain transcription factor
      required for development of somatotroph, lactotroph, and thyrotroph cell lineages
      and regulation of the temporal and spatial expression of the growth hormone,
      prolactin (PRL), and thyrotropin-beta genes. Synergistic interaction of Pit-1
      with a member of the Ets family of transcription factors, Ets-1, has been shown
      to be an important mechanism regulating basal and Ras-induced lactotroph-specific
      rat (r) PRL promoter activity. Pit-1beta/GHF-2, an alternatively spliced isoform
      containing a 26-amino acid insert (beta-domain) within its transcription
      activation domain, physically interacts with Ets-1 but fails to synergize. By
      using a series of Pit-1 internal-deletion constructs in a transient transfection
      protocol to reconstitute rPRL promoter activity in HeLa cells, we have determined
      that the functional and physical interaction of Pit-1 and Ets-1 is mediated via
      the POU homeodomain, which is common to both Pit-1 and Pit-1beta. Although the
      Pit-1 homeodomain is both necessary and sufficient for direct binding to Ets-1 in
      a DNA-independent manner, an additional interaction surface was mapped to the
      beta-domain, specific to the Pit-1beta isoform. Thus, the unique transcriptional
      properties of Pit-1 and Pit-1beta on the rPRL promoter may be due to the
      formation of functionally distinct complexes of these two Pit-1 isoforms with Ets
      1.

PMID- 10652294
TI  - Rac1 regulates interleukin 1-induced nuclear factor kappaB activation in an
      inhibitory protein kappaBalpha-independent manner by enhancing the ability of the
      p65 subunit to transactivate gene expression.
AB  - We have examined the involvement of Rac1 in nuclear factor kappaB (NFkappaB)
      activation by interleukin 1 (IL1). IL1 induced a rapid and sustained activation
      of Rac1 in the thymoma cell line EL4.NOB-1. Transient transfection with dominant
      negative RacN17 inhibited IL1-induced kappaB-dependent reporter gene expression
      but not IkappaBalpha degradation, whereas constitutively active RacV12
      potentiated kappaB-dependent reporter gene expression in response to IL1 but had
      no effects on its own. Using porcine aortic endothelial cells stably transfected
      with RacV12 or RacN17 under the control of an inducible promoter, we confirmed
      that RacV12 did not affect IkappaBalpha degradation, nor did RacN17 inhibit the
      IL1-induced response. RacV12 was also unable to induce nuclear translocation of
      NFkappaB. These effects suggested a role for Rac1 in p65-mediated transactivation
      of NFkappaB, independent of IkappaBalpha regulation. In support of this we found
      that IL1 activated a pathway leading to increased p65 transactivation activity
      and that RacV12 alone could drive this response in both cell systems.
      Additionally, RacN17 inhibited IL1-driven p65-mediated transactivation. From data
      using specific inhibitors of p38 and p42/p44 kinases we propose that both p38 and
      p42/p44 lie downstream of Rac1 on the IL1 pathway leading to enhanced
      transactivation by p65.

PMID- 10652295
TI  - The effect of pH on beta(2) adrenoceptor function. Evidence for protonation
      dependent activation.
AB  - The transition of rhodopsin from the inactive to the active state is associated
      with proton uptake at Glu(134) (1), and recent mutagenesis studies suggest that
      protonation of the homologous amino acid in the alpha(1B) adrenergic receptor
      (Asp(142)) may be involved in its mechanism of activation (2). To further explore
      the role of protonation in G protein-coupled receptor activation, we examined the
      effects of pH on the rate of ligand-induced conformational change and on receptor
      mediated G protein activation for the beta(2) adrenergic receptor (beta(2)AR).
      The rate of agonist-induced change in the fluorescence of NBD-labeled, purified
      beta(2)AR was 2-fold greater at pH 6.5 than at pH 8, even though agonist affinity
      was lower at pH 6.5. This biophysical analysis was corroborated by functional
      studies; basal (agonist-independent) activation of Galpha(s) by the beta(2)AR was
      greater at pH 6.5 compared with pH 8.0. Taken together, these results provide
      evidence that protonation increases basal activity by destabilizing the inactive
      state of the receptor. In addition, we found that the pH sensitivity of beta(2)AR
      activation is not abrogated by mutation of Asp(130), which is homologous to the
      highly conserved acidic amino acids that link protonation to activation of
      rhodopsin (Glu(134)) and the alpha(1B) adrenergic receptor (Asp(142)).

PMID- 10652296
TI  - Analysis of the yeast arginine methyltransferase Hmt1p/Rmt1p and its in vivo
      function. Cofactor binding and substrate interactions.
AB  - Many eukaryotic RNA-binding proteins are modified by methylation of arginine
      residues. The yeast Saccharomyces cerevisiae contains one major arginine
      methyltransferase, Hmt1p/Rmt1p, which is not essential for normal cell growth.
      However, cells missing HMT1 and also bearing mutations in the mRNA-binding
      proteins Npl3p or Cbp80p can no longer survive, providing genetic backgrounds in
      which to study Hmt1p function. We now demonstrate that the catalytically active
      form of Hmt1p is required for its activity in vivo. Amino acid changes in the
      putative Hmt1p S-adenosyl-L-methionine-binding site were generated and shown to
      be unable to catalyze methylation of Npl3p in vitro and in vivo or to restore
      growth to strains that require HMT1. In addition these mutations affect
      nucleocytoplasmic transport of Npl3p. A cold-sensitive mutant of Hmt1p was
      generated and showed reduced methylation of Npl3p, but not of other substrates,
      at 14 degrees C. These results define new aspects of Hmt1 and reveal the
      importance of its activity in vivo.

PMID- 10652297
TI  - Molecular and biochemical evidence for the involvement of calcium/calmodulin in
      auxin action.
AB  - The use of (35)S-labeled calmodulin (CaM) to screen a corn root cDNA expression
      library has led to the isolation of a CaM-binding protein, encoded by a cDNA with
      sequence similarity to small auxin up RNAs (SAURs), a class of early auxin
      responsive genes. The cDNA designated as ZmSAUR1 (Zea mays SAURs) was expressed
      in Escherichia coli, and the recombinant protein was purified by CaM affinity
      chromatography. The CaM binding assay revealed that the recombinant protein binds
      to CaM in a calcium-dependent manner. Deletion analysis revealed that the CaM
      binding site was located at the NH(2)-terminal domain. A synthetic peptide of
      amino acids 20-45, corresponding to the potential CaM binding region, was used
      for calcium-dependent mobility shift assays. The synthetic peptide formed a
      stable complex with CaM only in the presence of calcium. The CaM affinity assay
      indicated that ZmSAUR1 binds to CaM with high affinity (K(d) approximately 15 nM)
      in a calcium-dependent manner. Comparison of the NH(2)-terminal portions of all
      of the characterized SAURs revealed that they all contain a stretch of the basic
      alpha-amphiphilic helix similar to the CaM binding region of ZmSAUR1. CaM binds
      to the two synthetic peptides from the NH(2)-terminal regions of Arabidopsis SAUR
      AC1 and soybean 10A5, suggesting that this is a general phenomenon for all SAURs.
      Northern analysis was carried out using the total RNA isolated from auxin-treated
      corn coleoptile segments. ZmSAUR1 gene expression began within 10 min, increased
      rapidly between 10 and 60 min, and peaked around 60 min after 10 microM alpha
      naphthaleneacetic acid treatment. These results indicate that ZmSAUR1 is an early
      auxin-responsive gene. The CaM antagonist N-(6-aminohexyl)5-chloro-1
      naphthalenesulfonamide hydrochloride inhibited the auxin-induced cell elongation
      but not the auxin-induced expression of ZmSAUR1. This suggests that calcium/CaM
      do not regulate ZmSAUR1 at the transcriptional level. CaM binding to ZmSAUR1 in a
      calcium-dependent manner suggests that calcium/CaM regulate ZmSAUR1 at the post
      translational level. Our data provide the first direct evidence for the
      involvement of calcium/CaM-mediated signaling in auxin-mediated signal
      transduction.

PMID- 10652298
TI  - Structure-function analysis of CD14 as a soluble receptor for lipopolysaccharide.
AB  - CD14 is a glycophosphatidylinositol-linked protein expressed by myeloid cells and
      also circulates as a plasma protein lacking the glycophosphatidylinositol anchor.
      Both membrane and soluble CD14 function to enhance activation of cells by
      lipopolysaccharide (LPS), which we refer to as receptor function. We have
      previously reported the LPS binding and cell activation functions of a group of
      five deletion mutants of CD14 (Viriyakosol, S., and Kirkland, T.N. (1995) J.
      Biol. Chem. 270, 361-368). We have now studied the functional impact of these
      mutations on soluble CD14. We found that some deletions that abrogated LPS
      binding in membrane CD14 have no effect on LPS binding in soluble CD14. In fact,
      some of the soluble CD14 deletion mutants bound LPS with an apparent higher
      affinity than wild-type CD14. Furthermore, we found that all five deletions
      essentially ablated soluble CD14 LPS receptor function, whereas only two of the
      deletions completely destroyed membrane CD14 LPS receptor function. Some of the
      mutants were able to compete with wild-type CD14 in soluble CD14-dependent assays
      of cellular activation. We concluded that the soluble and membrane forms of CD14
      have different structural determinants for LPS receptor function.

PMID- 10652299
TI  - Biochemical analysis of the arginine methylation of high molecular weight
      fibroblast growth factor-2.
AB  - The post-translational methylation of the N-terminally extended or high molecular
      weight (HMW) forms of fibroblast growth factor-2 (FGF-2) has been shown to affect
      the nuclear accumulation of the growth factor. In this study, we determined the
      extent and position of methyl groups in HMW FGF-2. Using mass spectrometry and
      amino acid sequence analysis, we have shown that the 22- and 22.5-kDa forms of
      HMW FGF-2 contain five dimethylated arginines located at positions -22, -24, -26,
      -36, and -38 using the methionine residue normally used to initiate the 18-kDa
      form as position 0. The 24-kDa form of HMW FGF-2 contains seven to eight
      dimethylated arginines located at positions -48, -50, and -52, in addition to
      positions -22, -24, -26, -36, and -38. In vitro methylation reactions demonstrate
      that the N-terminal extension of HMW FGF-2 acts as a specific substrate for yeast
      Hmt1p and human HRMT1L2 arginine methyltransferases. These findings indicate that
      HMW FGF-2, with the presence of five or more dimethylated Gly-Arg-Gly repeats,
      contains an RGG box-like domain, which may be important for protein-protein
      and/or protein-RNA interactions.

PMID- 10652300
TI  - Degradation of cyclin A does not require its phosphorylation by CDC2 and cyclin
      dependent kinase 2.
AB  - Many cyclins are degraded by the ubiquitination/proteasome pathways involving the
      anaphase-promoting complex and SCF complexes. These degradations are frequently
      dependent on phosphorylation by cyclin-dependent kinases (CDKs), providing a self
      limiting mechanism for CDK activity. Here we present evidence from in vitro and
      in vivo assay systems that the degradation of human cyclin A can be inhibited by
      kinase-inactive mutants of CDK2 and CDC2. One obvious interpretation of these
      results is that like other cyclins, CDK-dependent phosphorylation of the cyclin A
      may be involved in cyclin A degradation. Our data indicated that CDK2 can
      phosphorylate cyclin A on Ser-154. Site-directed mutagenesis of Ser-154 abolished
      the phosphorylation by recombinant CDK2 in vitro and the majority of cyclin A
      phosphorylation in the cell. Activation of CDK2 and binding to SKP2 or p27(KIP1)
      were not affected by the phosphorylation of Ser-154. Surprising, in marked
      contrast to cyclin E, where phosphorylation of Thr-380 by CDK2 is required for
      proteolysis, degradation of cyclin A was not affected by Ser-154 phosphorylation.
      It is likely that the stabilization of cyclin A by the kinase-inactive CDKs was
      mainly due to a cell cycle effect. These data suggest an important difference
      between the regulation of cyclin A and cyclin E.

PMID- 10652301
TI  - Utrophin transcription is activated by an intronic enhancer.
AB  - The utrophin gene codes for a large cytoskeletal protein closely related to
      dystrophin. Its transcription is driven by a TATA-less promoter. Here we analyzed
      40 kilobases of the 5' end region of the utrophin gene searching for new utrophin
      regulatory elements in muscle cells. By transient transfection of utrophin
      genomic fragments in front of a reporter gene, we identified a new enhancer that
      maps downstream of the transcription start site within the second intron and co
      localizes with a DNase I-hypersensitive site. By deletion analysis it was mapped
      to a sequence of 128 base pairs that retains the whole activity. Linker scanning
      mutagenesis showed that most of the enhancer sequence is essential for its
      transcriptional activity. Binding analysis with nuclear cell extracts
      demonstrated that the enhancer regulatory elements, identified by mutagenesis,
      are protected from DNase I digestion. Because utrophin can functionally
      substitute dystrophin, the identification and characterization of new regulatory
      elements provide new targets for possible therapies of Duchenne muscular
      dystrophy aiming at the up-regulation of the utrophin expression in muscle cells.

PMID- 10652302
TI  - The transmembrane aspartates in presenilin 1 and 2 are obligatory for gamma
      secretase activity and amyloid beta-protein generation.
AB  - The discovery that a deficiency of presenilin 1 (PS1) decreases the production of
      amyloid beta-protein (Abeta) identified the presenilins as important mediators of
      the gamma-secretase cleavage of beta-amyloid precursor protein (APP). Recently,
      we found that two conserved transmembrane (TM) aspartates in PS1 are critical for
      Abeta production, providing evidence that PS1 either functions as a required
      diaspartyl cofactor for gamma-secretase or is itself gamma-secretase. Presenilin
      2 (PS2) shares substantial sequence and possibly functional homology with PS1.
      Here, we show that the two TM aspartates in PS2 are also critical for gamma
      secretase activity, providing further evidence that PS2 is functionally
      homologous to PS1. Cells stably co-expressing TM Asp --> Ala mutations in both
      PS1 and PS2 show further accumulation of the APP-derived gamma-secretase
      substrates, C83 and C99. The production of Abeta is reduced to undetectable
      levels in the conditioned media of these cells. Furthermore, endoproteolysis of
      the exogenous Asp mutant PS2 is absent, and endogenous PS1 C-terminal fragments
      are diminished to undetectable levels. Therefore, the co-expression of PS1 and
      PS2 TM Asp --> Ala mutants suppresses the formation of any detectable PS1 or PS2
      heterodimeric fragments and essentially abolishes the production of Abeta. These
      results explain the residual Abeta production seen in PS1-deficient cells and
      demonstrate the absolute requirement of functional presenilins for Abeta
      generation. We conclude that presenilins, and their TM aspartates in particular,
      are attractive targets for lowering Abeta therapeutically to prevent Alzheimer's
      disease.

PMID- 10652304
TI  - Regulation of Pap phase variation. Lrp is sufficient for the establishment of the
      phase off pap DNA methylation pattern and repression of pap transcription in
      vitro.
AB  - The pyelonephritis-associated pili (pap) operon in Escherichia coli is regulated
      by an epigenetic mechanism involving the formation of specific DNA methylation
      patterns characteristic of transcriptionally active (phase ON) and inactive
      (phase OFF) cells. The formation of pap DNA methylation patterns in vivo was
      previously shown to require the leucine-responsive regulatory protein (Lrp) and
      DNA adenine methylase (Dam). To monitor the binding of Lrp to pap DNA, an in
      vitro methylation protection assay was developed. Binding of Lrp to a Dam target
      site proximal to the papBA promoter (designated GATC(prox)) blocked methylation
      of this site and specifically repressed transcription. The DNA methylation
      pattern and transcription state are identical to those observed in vivo in phase
      OFF cells. To determine if binding of Lrp at GATC(prox) was necessary for
      repression of papBA transcription, we analyzed a pap mutation (pap-13) that
      reduced the affinity of Lrp for the GATC(prox) region. Binding of Lrp to pap-13
      DNA was shifted to a promoter distal Dam target site (designated GATC(dist)). Lrp
      blocked methylation of GATC(dist) in the pap-13 mutant, but did not repress papBA
      transcription. Together, these results show that binding of Lrp to the GATC(prox)
      region is sufficient for the establishment of the phase OFF DNA methylation
      pattern and repression of papBA transcription.

PMID- 10652303
TI  - Exogenously added human group X secreted phospholipase A(2) but not the group IB,
      IIA, and V enzymes efficiently release arachidonic acid from adherent mammalian
      cells.
AB  - Mammalian secreted phospholipases A(2) (sPLA2s) comprise a group of at least
      eight enzymes, including the recently identified group X sPLA2. A bacterial
      expression system was developed to produce human group X sPLA2 (hGX). Inhibition
      studies show that the sPLA2 inhibitor LY311727 binds modestly more tightly to
      human group IIA sPLA2 than to hGX and that a pyrazole-based inhibitor of group
      IIA sPLA2 is much less active against hGX. The phospholipid head group preference
      of vesicle-bound hGX was determined. hGX binds tightly to phosphatidylcholine
      vesicles, which is thought to be required to act efficiently on cells. Tryptophan
      67 hGX makes a significant contribution to interfacial binding to zwitterionic
      vesicles. As little as 10 ng/ml hGX releases arachidonic acid for cyclooxygenase
      2- dependent prostaglandin E(2) generation when added exogenously to adherent
      mammalian cells. In contrast, human group IIA, rat group V, and mouse group IB
      sPLA2s are virtually inactive at releasing arachidonate when added exogenously to
      adherent cells. Dislodging cells from the growth surface enhances the ability of
      all the sPLA2s to release fatty acids. Studies with CHO-K1 cell mutants show that
      binding of sPLA2s to glycosaminoglycans is not the basis for poor plasma membrane
      hydrolysis by group IB, IIA, and V sPLA2s.

PMID- 10652305
TI  - The ferrous dioxygen complex of the oxygenase domain of neuronal nitric-oxide
      synthase.
AB  - The mechanisms by which nitric-oxide synthases (NOSs) bind and activate oxygen at
      their P450-type heme active site in order to synthesize nitric oxide from the
      substrate L-arginine are mostly unknown. To obtain information concerning the
      structure and properties of the first oxygenated intermediate of the enzymatic
      cycle, we have used a rapid continuous flow mixer and resonance Raman
      spectroscopy to generate and identify the ferrous dioxygen complex of the
      oxygenase domain of nNOS (Fe(2+)O(2) nNOSoxy). We detect a line at 1135 cm(-1) in
      the resonance Raman spectrum of the intermediate formed from 0.6 to 3.0 ms after
      the rapid mixing of the ferrous enzyme with oxygen that is shifted to 1068 cm(-1)
      with (18)O(2). This line is assigned as the O-O stretching mode (nu(O-O)) of the
      oxygenated complex of nNOSoxy. Rapid mixing experiments performed with nNOSoxy
      saturated with L-arginine or N(omega)-hydroxy-L-arginine, in the presence or
      absence of (6R)-5,6, 7,8-tetrahydro-L-biopterin, reveal that the nu(O-O) line is
      insensitive to the presence of the substrate and the pterin. The optical spectrum
      of this ferrous dioxygen species, with a Soret band wavelength maximum at 430 nm,
      confirms the identification of the previously reported oxygenated complexes
      generated by stopped flow techniques.

PMID- 10652306
TI  - Identification of a binding site on the type II activin receptor for activin and
      inhibin.
AB  - Type II activin receptors (ActRII and ActRIIB) are single-transmembrane domain
      serine/threonine kinase receptors that bind activin to initiate the signaling and
      cellular responses triggered by this hormone. Inhibin also binds type II activin
      receptors and antagonizes many activin effects. Here we describe alanine scanning
      mutagenesis of the ActRII extracellular domain. We identify a cluster of three
      hydrophobic residues (Phe(42), Trp(60), and Phe(83)) that, when individually
      mutated to alanine in the context of the full-length receptor, cause the
      disruption of activin and inhibin binding to ActRII. Each of the alanine
      substituted ActRII mutants retaining activin binding maintains the ability to
      form cross-linked complexes with activin and supports activin cross-linking to
      the type I activin receptor ALK4. Unlike wild-type ActRII, the three mutants
      unable to bind activin do not cause an increase in activin signaling when
      transiently expressed in a corticotroph cell line. Together, our results
      implicate these residues in forming a critical binding surface on ActRII required
      for functional interactions with both activin and inhibin. This first
      identification of a transforming growth factor-beta family member binding site
      may provide a general basis for characterizing binding sites for other members of
      the superfamily.

PMID- 10652307
TI  - Regulation of vascular smooth muscle tone by N-terminal region of caldesmon.
      Possible role of tethering actin to myosin.
AB  - To assess the functional significance of tethering actin to myosin by caldesmon
      in the regulation of smooth muscle contraction, we investigated the effects of
      synthetic peptides, containing the myosin-binding sequences in the N-terminal
      region of caldesmon, on force directly recorded from single permeabilized smooth
      muscle cells of ferret portal vein. Two peptides were used, IK29C and MY27C,
      containing residues from Ile(25) to Lys(53) and from Met(1) to Tyr(27) of the
      human and chicken caldesmon sequence, respectively, plus an added cysteine at the
      C terminus. In cells clamped at pCa 6. 7, both peptides increased basal tone.
      Pretreatment of cells at pCa 6.7 with IK29C or MY27C decreased the amplitude of
      subsequent phenylephrine-induced contractions but not microcystin-racemic mixture
      induced contractions. In all cases the effects of the peptides were concentration
      dependent, and IK29C was more potent than MY27C, in agreement with their relative
      affinity toward myosin. The peptides were ineffective after the phenylephrine
      contraction was established. MY27C did not further increase the magnitude of
      contraction caused by a maximally effective concentration of IK29C, consistent
      with the two peptides having the same mechanism of action. Neither polylysine nor
      two control peptides containing scrambled sequences of IK29C, which do not bind
      myosin, had any effect on basal or phenylephrine-induced force. Our results
      suggest that IK29C and MY27C induce contraction by competing with the myosin
      binding domain of endogenous caldesmon. Digital imaging of fluoroisothiocyanate
      tagged IK29C confirmed the association of the peptide with intracellular
      filamentous structures. The results are consistent with a model whereby tethering
      of actin to myosin by caldesmon may play a role in regulating vascular tone by
      positioning the C-terminal domain of caldesmon so that it is capable of blocking
      the actomyosin interaction.

PMID- 10652308
TI  - Similarities in function and gene structure of cytohesin-4 and cytohesin-1,
      guanine nucleotide-exchange proteins for ADP-ribosylation factors.
AB  - Activation of ADP-ribosylation factors (ARFs), approximately 20-kDa GTPases that
      are inactive in the GDP-bound form, depends on guanine nucleotide-exchange
      proteins (GEPs) to accelerate GTP binding. A novel ARF GEP, designated cytohesin
      4, was cloned from a human brain cDNA library. Deduced amino acid sequence of the
      47-kDa protein contains the same structural components present in cytohesin -1, 
      2, and -3, including an approximately 200-amino acid Sec7 domain with an
      approximately 100-residue pleckstrin homology domain near the C terminus. The
      Sec7 domain sequence is 77% identical to those of other cytohesins. Structures of
      the cytohesin-4 and cytohesin-1 genes were remarkably similar, except for an
      extra 3-base pair (GAG) exon present in cytohesin-1. Two mRNAs with and without
      the 3-base pair sequence were found in brain in different ratios for cytohesin-1,
      -2, and -3 but not cytohesin-4. Recombinant cytohesin-4 stimulated guanosine 5'-3
      O-(thio)triphosphate binding by human ARF1 and ARF5 but not ARF6. Like other
      cytohesins and unlike the approximately 200-kDa ARF GEPs, it was not inhibited by
      brefeldin A. A cytohesin-4 mRNA of approximately 3.7 kilobases, abundant in
      leukocytes, was not detected in most tissues. Among separated populations of
      blood cells, approximately 90% of CD33(+) (monocytes), 80% of CD2(+) (NK/T), and
      10-20% of CD19(+) (B) cells contained cytohesin-4 mRNA by in situ hybridization.
      Thus, in gene structure and brefeldin A-insensitive GEP activity, cytohesin-4
      resembles other cytohesins, but its tissue distribution differs considerably,
      consistent with a different specific function.

PMID- 10652310
TI  - Simian virus 40 large T antigen binds a novel Bcl-2 homology domain 3-containing
      proapoptosis protein in the cytoplasm.
AB  - A 193-kDa SV40 large T antigen (T-Ag)-binding protein, designated p193, was
      identified and cloned. Inspection of the deduced amino acid sequence revealed the
      presence of a short motif similar to the Bcl-2 homology (BH) domain 3, suggesting
      that p193 may be a member of a family of apoptosis promoting proteins containing
      only BH3 motifs. In support of this, p193 expression promoted apoptosis in NIH
      3T3 cells. Deletion of the BH3 motif abolished p193 apoptosis activity. p193
      induced apoptosis was antagonized by co-expression of Bcl-X(L). Immune cytologic
      analysis indicated that p193 is localized to the cytoplasm of transfected cells.
      p193-induced apoptosis was also antagonized by co-expression of T-Ag, which
      resulted in the cytoplasmic localization of both proteins. The p193 binding site
      was mapped to an N-terminal region of T-Ag previously implicated in transforming
      activity. These results suggest that T-Ag possesses an antiapoptosis activity,
      independent of p53 sequestration, which is actuated by T-Ag/p193 binding in the
      cytoplasm.

PMID- 10652309
TI  - Novel carbohydrate binding site recognizing blood group A and B determinants in a
      hybrid of cholera toxin and Escherichia coli heat-labile enterotoxin B-subunits.
AB  - The B-subunits of cholera toxin (CTB) and Escherichia coli heat-labile
      enterotoxin (LTB) are structurally and functionally related. However, the
      carbohydrate binding specificities of the two proteins differ. While both CTB and
      LTB bind to the GM1 ganglioside, LTB also binds to N-acetyllactosamine-terminated
      glycoconjugates. The structural basis of the differences in carbohydrate
      recognition has been investigated by a systematic exchange of amino acids between
      LTB and CTB. Thereby, a CTB/LTB hybrid with a gain-of-function mutation resulting
      in recognition of blood group A and B determinants was obtained.
      Glycosphingolipid binding assays showed a specific binding of this hybrid B
      subunit, but not CTB or LTB, to slowly migrating non-acid glycosphingolipids of
      human and animal small intestinal epithelium. A binding-active glycosphingolipid
      isolated from cat intestinal epithelium was characterized by mass spectrometry
      and proton NMR as GalNAcalpha3(Fucalpha2)Galbeta4(Fucalpha3)Glc
      NAcbeta3Galbeta4Glc NAcbeta3Galbeta4Glcbeta1Cer. Comparison with reference
      glycosphingolipids showed that the minimum binding epitope recognized by the
      CTB/LTB hybrid was Galalpha3(Fucalpha2)Galbeta4(Fucalpha3)GlcNAc beta. The blood
      group A and B determinants bind to a novel carbohydrate binding site located at
      the top of the B-subunit interfaces, distinct from the GM1 binding site, as found
      by docking and molecular dynamics simulations.

PMID- 10652311
TI  - Molecular and functional characterization of protein 4.1B, a novel member of the
      protein 4.1 family with high level, focal expression in brain.
AB  - Brain-enriched isoforms of skeletal proteins in the spectrin and ankyrin gene
      families have been described. Here we characterize protein 4.1B, a novel homolog
      of erythrocyte protein 4.1R that is encoded by a distinct gene. In situ
      hybridization revealed high level, focal expression of 4.1B mRNA in select
      neuronal populations within the mouse brain, including Purkinje cells of the
      cerebellum, pyramidal cells in hippocampal regions CA1-3, thalamic nuclei, and
      olfactory bulb. Expression was also detected in adrenal gland, kidney, testis,
      and heart. 4.1B protein exhibits high homology to the membrane binding, spectrin
      actin binding, and C-terminal domains of 4.1R, including motifs for interaction
      with NuMA and FKBP13. cDNA characterization and Western blot analysis revealed
      multiple spliceoforms of protein 4.1B, with functionally relevant heterogeneity
      in the spectrin-actin and NuMA binding domains. Regulated alternative splicing
      events led to expression of unique 4. 1B isoforms in brain and muscle; only the
      latter possessed a functional spectrin-actin binding domain. By
      immunofluorescence, 4. 1B was localized specifically at the plasma membrane in
      regions of cell-cell contact. Together these results indicate that 4.1B
      transcription is selectively regulated among neuronal populations and that
      alternative splicing regulates expression of 4.1B isoforms possessing critical
      functional domains typical of other protein 4.1 family members.

PMID- 10652312
TI  - Sensing of extracellular cations in CasR-deficient osteoblasts. Evidence for a
      novel cation-sensing mechanism.
AB  - We isolated osteoblastic cell lines from wild-type (CasR(+/+)) and receptor null
      (CasR(-/-)) mice to investigate whether CasR is present in osteoblasts and
      accounts for their responses to extracellular cations. Osteoblasts from both
      CasR(+/+) and CasR(-/-) mice displayed an initial period of cell replication
      followed by a culture duration-dependent increase in alkaline phosphatase
      activity, expression of osteocalcin, and mineralization of extracellular matrix.
      In addition, a panel of extracellular cations, including aluminum and the CasR
      agonists gadolinium and calcium, stimulated DNA synthesis, activated a
      transfected serum response element-luciferase reporter construct, and inhibited
      agonist-induced cAMP in CasR(-/-) osteoblasts. The functional responses to these
      cations were identical in CasR(+/+) and CasR(-/-) osteoblasts. Thus, the absence
      of CasR alters neither the maturational profile of isolated osteoblast cultures
      nor their in vitro responses to extracellular cations. In addition, CasR
      transcripts could not be detected by reverse transcription-polymerase chain
      reaction with mouse specific primers in either CasR(+/+) or CasR(-/-)
      osteoblasts, and immunoblot analysis with a CasR-specific antibody was negative
      for CasR protein expression in osteoblasts. The presence of a cation-sensing
      response in osteoblasts from CasR(-/-) mice indicates the existence of a novel
      osteoblastic extracellular cation-sensing mechanism.

PMID- 10652313
TI  - NMR solution structure of complement-like repeat CR3 from the low density
      lipoprotein receptor-related protein. Evidence for specific binding to the
      receptor binding domain of human alpha(2)-macroglobulin.
AB  - We have used NMR methods to determine the structure of the calcium complex of
      complement-like repeat 3 (CR3) from the low density lipoprotein receptor-related
      protein (LRP) and to examine its specific interaction with the receptor binding
      domain of human alpha(2)-macroglobulin. CR3 is one of eight related repeats that
      constitute a major ligand binding region of LRP. The structure is very similar in
      overall fold to homologous complement-like repeat CR8 from LRP and complement
      like repeats LB1, LB2, and LB5 from the low density lipoprotein receptor and
      contains a short two-strand antiparallel beta-sheet, a one turn alpha-helix, and
      a high affinity calcium site with coordination from four carboxyls and two
      backbone carbonyls. The surface electrostatics and topography are, however, quite
      distinct from each of these other repeats. Two-dimensional (1)H,(15)N
      heteronuclear single quantum coherence spectra provide evidence for a specific,
      though relatively weak (K(d) approximately 140 microM), interaction between CR3
      and human alpha2-macroglobulin receptor binding domain that involves a contiguous
      patch of surface residues in the central region of CR3. This specific interaction
      is consistent with a mode of LRP binding to ligands that uses contributions from
      more than one domain to generate a wide array of different binding sites, each
      with overall high affinity.

PMID- 10652314
TI  - Cell type-specific storage of dopamine beta-monooxygenase.
AB  - Expression of dopamine beta-monooxygenase (DBM), the enzyme that converts
      dopamine into norepinephrine, is limited to adrenal chromaffin cells and a small
      population of neurons. We studied DBM trafficking to regulated granules by stably
      expressing rat DBM in AtT-20 corticotrope tumor cells, which contain regulated
      granules, and in Chinese hamster ovary (CHO) cells, which lack regulated
      granules. The behavior of exogenous DBM in both cell lines was compared with
      endogenous DBM in adrenal chromaffin cells. CHO cells secreted active DBM,
      indicating that production of active enzyme does not require features unique to
      neuroendocrine cells. Pulse-chase experiments indicated that early steps in DBM
      maturation followed a similar time course in AtT-20, CHO, and adrenal chromaffin
      cells. Use of a conformation-sensitive DBM antiserum indicated that acquisition
      of a folded structure occurred with a similar time course in all three cell
      types. Cell type-specific differences in DBM trafficking became apparent only
      when storage in granules was examined. As expected, DBM was stored in secretory
      granules in chromaffin cells; CHO cells failed to store DBM. Despite the fact
      that AtT-20 cells have regulated granules, exogenous DBM was not stored in these
      granules. Thus storage of DBM in secretory granules requires cell type specific
      factors.

PMID- 10652315
TI  - Initiation of spectrin dimerization involves complementary electrostatic
      interactions between paired triple-helical bundles.
AB  - The spectrin heterodimer is formed by the antiparallel lateral association of an
      alpha and a beta subunit, each of which comprises largely a series of homologous
      triple-helical motifs. Initiation of dimer assembly involves strong binding
      between complementary motifs near the actin-binding end of the dimer. In this
      study, the mechanism of lateral spectrin association at this dimer nucleation
      site was investigated using the analytical ultracentrifuge to analyze
      heterodimers formed from recombinant peptides containing two or four homologous
      motifs from each subunit (alpha20-21/beta1-2; alpha18-21/beta1-4). Both the two
      motif and four-motif dimer associations were weakened substantially with
      increasing salt concentration, indicating that electrostatic interactions are
      important for the dimer initiation process. Modeling of the electrostatic
      potential on the surface of the alpha20 and beta2 motifs showed that the side of
      the motifs comprising the A and B helices is the most favorable for association,
      with an area of positive electrostatic potential on the AB face of the beta2
      motif opposite negative potential on the AB face of the alpha20 motif and vise
      versa. Protease protection analysis of the alpha20-21/beta1-2 dimer showed that
      multiple trypsin and proteinase K sites in the A helices of the beta2 and alpha21
      motifs become buried upon dimer formation. Together, these data support a model
      where complementary long range electrostatic interactions on the AB faces of the
      triple-helical motifs in the dimer nucleation site initiate the correct pairing
      of motifs, i.e. alpha21-beta1 and alpha20-beta2. After initial docking of these
      complementary triple-helical motifs, this association is probably stabilized by
      subsequent formation of stronger hydrophobic interactions in a complex involving
      the A helices of both subunits and possibly most of the AB faces. The beta
      subunit A helix in particular appears to be buried in the dimer interface.

PMID- 10652316
TI  - Mapping of Eps15 domains involved in its targeting to clathrin-coated pits.
AB  - Clathrin-coated pit (CCP) formation occurs as a result of the targeting and
      assembly of cytosolic coat proteins, mainly the plasma membrane clathrin
      associated protein complex (AP-2) and clathrin, to the intracellular face of the
      plasma membrane. In the present study, the mechanisms by which Eps15, an AP-2
      binding protein, is targeted to CCPs was analyzed by following the intracellular
      localization of Eps15 mutants fused to the green fluorescent protein. Our
      previous results indicated that the N-terminal Eps15 homology (EH) domains are
      required for CCP targeting. We now show that EH domains are, however, not
      sufficient for targeting to CCPs. Similarly, neither the central coiled-coil nor
      the C-terminal AP-2 binding domains were able to address green fluorescent
      protein to CCPs. Thus, targeting of Eps15 to CCPs likely results from the
      collaboration between EH domains and another domain of the protein. An Eps15
      mutant lacking the coiled-coil domain localized to CCPs showing that Eps15
      dimerization is not strictly required. In contrast, Eps15 mutants lacking all AP
      2 binding sites showed a dramatic decrease in plasma membrane staining, showing
      that AP-2 binding sites, together with EH domains, play an important role in
      targeting Eps15 into CCPs. Finally, the effect of the Eps15 mutants on clathrin
      dependent endocytosis was tested by both immunofluorescence and flow cytometry.
      The results obtained showed that inhibition of transferrin uptake was observed
      only with mutants able to interfere with CCP assembly.

PMID- 10652317
TI  - The enhanced affinity for thiolate anion and activation of enzyme-bound
      glutathione is governed by an arginine residue of human Mu class glutathione S
      transferases.
AB  - A series of chimeric human Mu class glutathione S-transferases were designed to
      determine mechanisms by which they activate enzyme-bound glutathione (GSH) for
      reaction with electrophilic substrates. In view of evidence that the His(107)
      residue of hGSTM1a-1a is important for catalysis (Patskovsky, Y. V., Patskovska,
      L. N., and Listowsky, I. (1999) Biochemistry 38, 1193-1202), the cognate Arg(107)
      residue of the hGSTM2 subunit was replaced (R107N or R107H) and arginine residues
      were also incorporated into position 107 of hGSTM1 (H107R) and hGSTM4 (S107R)
      subunits. The major distinguishing kinetic properties invariably associated with
      enzymes containing an Arg(107) residue include an inverse dependence of k(cat) on
      viscosity and lower K(m(GSH values relative to enzymes with other residues at
      that position. Moreover, affinities for GSH thiolate anion binding are greater
      for enzymes containing Arg(107))), with K(d) values of 20-50 microM that are
      consistent with the K(m(GSH values (10-25 microM) obtained by steady-state
      kinetic analyses. Both thermodynamic and kinetic and data indicate that the
      Arg(107))) residue is specifically involved in enhancing the binding affinity of
      GSH thiolate anion relative to that of the protonated form. These enzymes
      therefore, can be more effective at lower GSH concentrations. Combined mutations
      indicate that both Arg(107) and Tyr(6) residues are required for thiolate anion
      formation and stabilization. The three-dimensional structure of ligand-free
      hGSTM2-2 determined by x-ray crystallography suggests that Arg(107) maintains an
      electrostatic interaction with the Asp(161) side chain (3 A apart), but is
      distant from the GSH-binding site. However, an alternative energetically
      favorable model places the guanidino group 4 A from the sulfur atom of bound GSH.
      It is suggested therefore, that in solution, motion of the positively charged
      arginine into the catalytic pocket could provide a counter ion to promote
      ionization of the sulfhydryl group of GSH, thereby accounting for the observed
      greater affinity of enzymes containing Arg(107) for binding of thiolate anion.

PMID- 10652318
TI  - The hsp90-related protein TRAP1 is a mitochondrial protein with distinct
      functional properties.
AB  - The hsp90 family of molecular chaperones was expanded recently due to the cloning
      of TRAP1 and hsp75 by yeast two-hybrid screens. Careful analysis of the human
      TRAP1 and hsp75 sequences revealed that they are identical, and we have cloned a
      similar protein from Drosophila. Immunofluorescence data show that human TRAP1 is
      localized to mitochondria. This mitochondrial localization is supported by the
      existence of mitochondrial localization sequences in the amino termini of both
      the human and Drosophila proteins. Due to the striking homology of TRAP1 to
      hsp90, we tested the ability of TRAP1 to function as an hsp90-like chaperone.
      TRAP1 did not form stable complexes with the classic hsp90 co-chaperones p23 and
      Hop (p60). Consistent with these observations, TRAP1 had no effect on the hsp90
      dependent reconstitution of hormone binding to the progesterone receptor in
      vitro, nor could it substitute for hsp90 to promote maturation of the receptor to
      its hormone-binding state. However, TRAP1 is sufficiently conserved with hsp90
      such that it bound ATP, and this binding was sensitive to the hsp90 inhibitor
      geldanamycin. In addition, TRAP1 exhibited ATPase activity that was inhibited by
      both geldanamycin and radicicol. Thus, TRAP1 has functions that are distinct from
      those of hsp90.

PMID- 10652319
TI  - Amino acid residues of S-modulin responsible for interaction with rhodopsin
      kinase.
AB  - S-modulin in frog or its bovine homologue, recoverin, is a 23-kDa EF-hand Ca(2+)
      binding protein found in rod photoreceptors. The Ca(2+)-bound form of S-modulin
      binds to rhodopsin kinase (Rk) and inhibits its activity. Through this
      regulation, S-modulin is thought to modulate the light sensitivity of a rod. In
      the present study, we tried to identify the interaction site of the Ca(2+)-bound
      form of S-modulin to Rk. First, we mapped roughly the interaction regions by
      using partial peptides of S-modulin. The result suggested that a specific region
      near the amino terminus is the interaction site of S-modulin. We then identified
      the essential amino acid residues in this region by using S-modulin mutant
      proteins: four amino acid residues (Phe(22), Glu(26), Phe(55), and Thr(92)) were
      suggested to interact with Rk. These residues are located in a small closed
      pocket in the Ca(2+)-free, inactive form of S-modulin, but exposed to the surface
      of the molecule in the Ca(2+)-bound, active form of S-modulin. Two additional
      amino acid residues (Tyr(108) and Arg(150)) were found to be crucial for the
      Ca(2+)-dependent conformational changes of S-modulin.

PMID- 10652320
TI  - Identification of basic residues in the heparin-binding exosite of factor Xa
      critical for heparin and factor Va binding.
AB  - We recently demonstrated that a template mechanism makes a significant
      contribution to the heparin-accelerated inactivation of factor Xa (FXa) by
      antithrombin at physiologic Ca(2+), suggesting that FXa has a potential heparin
      binding site. Structural data indicate that 7 of the 11 basic residues of the
      heparin-binding exosite of thrombin are conserved at similar three-dimensional
      locations in FXa. These residues, Arg(93), Lys(96), Arg(125), Arg(165), Lys(169),
      Lys(236), and Arg(240) were substituted with Ala in separate constructs in Gla
      domainless forms. It was found that all derivatives cleave Spectrozyme FXa with
      similar catalytic efficiencies. Antithrombin inactivated FXa derivatives with a
      similar second-order association rate constant (k(2)) in both the absence and
      presence of pentasaccharide. In the presence of heparin, however, k(2) with
      certain mutants were impaired up to 25-fold. Moreover, these mutants bound to
      heparin-Sepharose with lower affinities. Heparin concentration dependence of the
      inactivation revealed that only the template portion of the cofactor effect of
      heparin was affected by the mutagenesis. The order of importance of these
      residues for binding heparin was as follows: Arg(240) > Lys(236) > Lys(169) >
      Arg(165) > Lys(96) > Arg(93) >/= Arg(125). Interestingly, further study suggested
      that certain basic residues of this site, particularly Arg(165) and Lys(169),
      play key roles in factor Va and/or prothrombin recognition by FXa in
      prothrombinase.

PMID- 10652322
TI  - Parathyroid hormone-activated volume-sensitive calcium influx pathways in
      mechanically loaded osteocytes.
AB  - This paper documents for the first time a volume-sensitive Ca(2+) influx pathway
      in osteocytes, which transmits loading-induced signals into bone formation.
      Stretch loading by swelling rat and chicken osteocytes in hypo-osmotic solution
      induced a rapid and progressive increase of cytosolic calcium concentration,
      [Ca(2+)](i). The influx of extracellular Ca(2+) explains the increased
      [Ca(2+)](i) that paralleled the increase in the mean cell volume. Gadolinium
      chloride (Gd(3+)), an inhibitor of stretch- activated cation channels, blocked
      the [Ca(2+)](i) increase caused by hypotonic solutions. Also, the expression of
      alpha1C subunit of voltage-operated L-type Ca(2+) channels (alpha1C) is required
      for the hypotonicity-induced [Ca(2+)](i) increase judging from the effect of
      alpha1C antisense oligodeoxynucleotides. Parathyroid hormone (PTH) specifically
      potentiated the hypotonicity-induced [Ca(2+)](i) increase in a dose-dependent
      manner through the activation of adenyl cyclase. The increases induced by both
      PTH and hypotonicity were observed primarily in the processes of the osteocytes.
      In cyclically stretched osteocytes on flexible-bottomed plates, PTH also
      synergistically elevated the insulin-like growth factor-1 mRNA level.
      Furthermore, Gd(3+) and alpha1C antisense significantly inhibited the stretch
      induced insulin-like growth factor-1 mRNA elevation. The volume-sensitive calcium
      influx pathways of osteocytes represent a mechanism by which PTH potentiates
      mechanical responsiveness, an important aspect of bone formation.

PMID- 10652321
TI  - Truncation of the beta-catenin binding domain of E-cadherin precedes epithelial
      apoptosis during prostate and mammary involution.
AB  - A potential target of hormone action during prostate and mammary involution is
      the intercellular junction of adjacent secretory epithelium. This is supported by
      the long-standing observation that one of the first visible stages of prostate
      and mammary involution is the disruption of interepithelial adhesion prior to the
      onset of apoptosis. In a previous study addressing this aspect of involution, we
      acquired compelling evidence indicating that the disruption of E-cadherin
      dependent adhesion initiates apoptotic programs during prostate and mammary
      involution. In cultured prostate and mammary epithelial cells, inhibition of E
      cadherin-dependent aggregation resulted in cell death following apoptotic
      stimuli. Loss of cell-cell adhesion in the nonaggregated population appeared to
      result from the rapid truncation within the cytosolic domain of the mature, 120
      kDa species of E-cadherin (E-cad(120)). Immunoprecipitations from cell culture
      and involuting mammary gland demonstrated that this truncation removed the beta
      catenin binding domain from the cytoplasmic tail of E-cadherin, resulting in a
      non-beta-catenin binding, membrane-bound 97-kDa species (E-cad(97)) and a free
      cytoplasmic 35-kDa form (E-cad(35)) that is bound to beta-catenin. Examination of
      E-cadherin expression and cellular distribution during prostate and mammary
      involution revealed a dramatic reduction in junctional membrane staining that
      correlated with a similar reduction in E-cad(120) and accumulation of E-cad(97)
      and E-cad(35). The observation that E-cadherin was truncated during involution
      suggested that hormone depletion activated the same apoptotic pathway in vivo as
      observed in vitro. Based on these findings, we hypothesize that truncation of E
      cadherin results in the loss of beta-catenin binding and cellular dissociation
      that may signal epithelial apoptosis during prostate and mammary involution.
      Thus, E-cadherin may be central to homeostatic regulation in these tissues by
      coordinating adhesion-dependent survival and dissociation-induced apoptosis.

PMID- 10652323
TI  - Effects of aging on mitochondrial DNA copy number and cytochrome c oxidase gene
      expression in rat skeletal muscle, liver, and heart.
AB  - Mitochondrial DNA (mtDNA) deletions and mutations have been reported to occur
      with aging in various tissues. To determine the functional impact of these
      changes, we measured mtDNA copy number, mitochondria-encoded cytochrome c oxidase
      (COX) subunit I and III transcript levels, and COX enzyme activity in skeletal
      muscles (medial and lateral gastrocnemius and soleus), liver, and heart in 6- and
      27-month-old rats. Substantial age-related reductions of mtDNA copy number
      occurred in skeletal muscle groups (-23-40%, p < 0.03) and liver (-50%, p < 0.01)
      but not in the heart. The decline in mtDNA was not associated with reduced COX
      transcript levels in tissues with high oxidative capacities such as red soleus
      muscle or liver, while transcript levels were reduced with aging in the less
      oxidative mixed fiber gastrocnemius muscle (-17-22%, p < 0.05). Consistent with
      transcript levels, COX activity also remained unchanged in aging liver and heart
      but declined with age in the lateral gastrocnemius (-32%, p < 0.05). Thus, the
      effects of aging on mitochondrial gene expression are tissue-specific. A
      substantial age-related decline in mtDNA copy number proportional to tissue
      oxidative capacities is demonstrated in skeletal muscle and liver. mtDNA levels
      are in contrast preserved in the aging heart muscle, presumably due to its
      incessant aerobic activity. Reduced mtDNA copy number has no major effects on
      mitochondrial encoded transcript levels and enzyme activities in various tissues
      under these base-line study conditions. In contrast, maintenance of mitochondrial
      transcript levels that may be linked to oxidative metabolism and energy demand
      appears to be the main determinant of mitochondrial oxidative capacity in aging
      tissues.

PMID- 10652324
TI  - Integrin alpha(2)I domain recognizes type I and type IV collagens by different
      mechanisms.
AB  - The collagens are recognized by the alphaI domains of the collagen receptor
      integrins. A common structural feature in the collagen-binding alphaI domains is
      the presence of an extra helix, named helix alphaC. However, its participation in
      collagen binding has not been shown. Here, we have deleted the helix alphaC in
      the alpha(2)I domain and tested the function of the resultant recombinant protein
      (DeltaalphaCalpha(2)I) by using a real-time biosensor. The DeltaalphaCalpha(2)I
      domain had reduced affinity for type I collagen (430 +/- 90 nM) when compared
      with wild-type alpha(2)I domain (90 +/- 30 nM), indicating both the importance of
      helix alphaC in type I collagen binding and that the collagen binding surface in
      alpha(2)I domain is located near the metal ion-dependent adhesion site. Previous
      studies have suggested that the charged amino acid residues, surrounding the
      metal ion-dependent adhesion site but not interacting with Mg(2+), may play an
      important role in the recognition of type I collagen. Direct evidence indicating
      the participation of these residues in collagen recognition has been missing. To
      test this idea, we produced a set of recombinant alpha(2)I domains with
      mutations, namely D219A, D219N, D219R, E256Q, D259N, D292N, and E299Q. Mutations
      in amino acids Asp(219), Asp(259), Asp(292), and Glu(299) resulted in weakened
      affinity for type I collagen. When alpha(2) D219N and D292N mutations were
      introduced separately into alpha(2)beta(1) integrin expressed on Chinese hamster
      ovary cells, no alterations in the cell spreading on type I collagen were
      detected. However, Chinese hamster ovary cells expressing double mutated alpha(2)
      D219N/D292N integrin showed remarkably slower spreading on type I collagen, while
      spreading on type IV collagen was not affected. The data indicate that alpha(2)I
      domain binds to type I collagen with a different mechanism than to type IV
      collagen.

PMID- 10652325
TI  - Differential regulation of sentrinized proteins by a novel sentrin-specific
      protease.
AB  - Sentrin-1, also called SUMO-1, is a protein of 101 residues that is distantly
      related to ubiquitin and another ubiquitin-like protein, NEDD8. Here we report
      the cloning of a novel sentrin-specific protease, SENP1, which has no homology to
      the known de-ubiquitinating enzymes or ubiquitin C-terminal hydrolases. However,
      SENP1 is distantly related to the yeast Smt3-specific protease, Ulp1. A COS cell
      expression system was used to demonstrate the activity of SENP1 in vivo. When HA
      tagged sentrin-1 was co-expressed with SENP1, the higher molecular weight sentrin
      1 conjugates were completely removed. Surprisingly, the major sentrinized band at
      90 kDa remained intact. The disappearance of the high molecular weight sentrin-1
      conjugates also coincided with an increase in free sentrin-1 monomers. SENP1 is
      also active against proteins modified by sentrin-2, but not those modified by
      ubiquitin or NEDD8. In addition, sentrinized PML, a tumor suppressor protein that
      resides in the nucleus, was selectively affected by SENP1, whereas sentrinized
      RanGAP1, which is associated with the cytoplasmic fibrils of the nuclear pore
      complex, remained intact. The inability of SENP1 to process sentrinized RanGAP1
      in vivo is most likely due to its nuclear localization because SENP1 is active
      against sentrinized RanGAP1 in vitro. The identification of a nuclear-localized,
      sentrin-specific protease will provide a unique tool to study the role of
      sentrinization in the biological function of PML and in the pathogenesis of acute
      promyelocytic leukemia.

PMID- 10652326
TI  - Interactions of the sulfonylurea receptor 1 subunit in the molecular assembly of
      beta-cell K(ATP) channels.
AB  - We have investigated protein interactions involved in pancreatic beta-cell ATP
      sensitive potassium channel assembly. These channels, which are of key importance
      for control of insulin release, are a hetero-oligomeric complex of pore-forming
      Kir6.2 subunits and sulfonylurea receptor (SUR1) subunits with two nucleotide
      binding domains (NBD1 and NBD2). We divided SUR1 into two halves at Pro-1042.
      Expression of either the individual N- or C-terminal domain in a baculovirus
      expression system did not lead to glibenclamide binding activity, although
      studies with green fluorescent protein fusion proteins showed that both half
      molecules were inserted into the plasma membrane. However, significant
      glibenclamide binding activity was observed when the half-molecules were co
      expressed (even when NBD2 was deleted from the C-terminal half-molecule).
      Simultaneous expression of Kir6.2 resulted in enhanced glibenclamide binding
      activity. We conclude that the glibenclamide-binding site includes amino acid
      residues from both halves of the molecule, that there is strong interaction
      between different regions of SUR1, that NBD2 is not essential for glibenclamide
      binding, and that interactions between Kir6.2 and SUR1 participate in ATP
      sensitive potassium channel assembly. Investigation of NBD1-green fluorescent
      protein fusion protein distribution inside insect cells expressing C-terminal
      halves of SUR1 demonstrated strong interaction between NBD1 and NBD2. We also
      expressed and purified NBD1 from Escherichia coli. Purified NBD1 was found to
      exist as a tetramer indicating strong homomeric attractions and a possible role
      for NBD1 in SUR1 assembly.

PMID- 10652327
TI  - The role of homodimers in surfactant protein B function in vivo.
AB  - Surfactant protein B (SP-B) is detected in the airways as a sulfhydryl-dependent
      dimer (M(r) approximately 16,000). To test the hypothesis that formation of
      homodimers is critical for SP-B function, the cysteine residue reported to be
      involved in SP-B dimerization was mutated to serine (Cys(248) --> Ser) and the
      mutated protein was targeted to the distal respiratory epithelium of transgenic
      mice. Transgenic lines which demonstrated appropriate processing, sorting, and
      secretion of human SP-B monomer were crossed with SP-B +/- mice to achieve
      expression of human monomer in the absence of endogenous SP-B dimer (hSP-B(mon),
      mSP-B-/-). In two of three transgenic lines, hSP-B(mon), mSP-B-/- mice had normal
      lung structure, complete processing of SP-C proprotein, well formed lamellar
      bodies, and normal longevity. Pulmonary function studies revealed an altered
      hysteresis curve for hSP-B(mon), mSP-B-/- mice relative to wild type mice. Large
      aggregate surfactant fractions from hSP-B(mon), mSP-B-/- mice resulted in higher
      minimum surface tension in vitro compared with surfactant from wild type mice.
      Surfactant lipids supplemented with 2% hSP-B monomer resulted in slower
      adsorption and higher surface tension than surfactant with 2% hSP-B dimer. Taken
      together, these data indicate a role for SP-B dimer in surface tension reduction
      in the alveolus.

PMID- 10652328
TI  - Ablation of a critical surfactant protein B intramolecular disulfide bond in
      transgenic mice.
AB  - The 79-amino acid, mature SP-B peptide contains three intramolecular disulfide
      bonds shared by all saposin-like proteins. This study tested the hypothesis that
      the disulfide bond formed between cysteine residues 35 and 46 (residues 235 and
      246 of the SP-B proprotein) is essential for proper function of SP-B. To test the
      role of this bridge in SP-B function in vivo, a construct was generated in which
      cysteine residues 235 and 246 of the human SP-B proprotein were mutated to serine
      and cloned under the control of the 3.7-kilobase hSP-C promoter (hSP
      B(C235S/C246S)). In two transgenic mouse lines, expression of the mutant peptide
      in the wild-type murine SP-B background was invariably lethal in the neonatal
      period. In four additional lines, survival was inversely related to the level of
      transgene expression. To test the ability of the mutant peptide to functionally
      replace the wild-type protein, transgenic mice were crossed into the SP-B null
      background. No animals that expressed hSP-B(C235S/C246S) in the murine SP-B-/-
      background survived the neonatal period. hSP-B(C235S/C246S) proprotein
      accumulated in the endoplasmic reticulum and was not processed to the mature,
      biologically active peptide. The results of these studies demonstrate that the
      intramolecular bridge between residues 235 and 246 is critical for intracellular
      trafficking of SP-B and suggest that overexpression of mutant SP-B in the wild
      type background may be lethal.

PMID- 10652329
TI  - The transcriptional co-activator ADA5 is required for HAC1 mRNA processing in
      vivo.
AB  - Accumulation of unfolded proteins in the endoplasmic reticulum (ER) activates
      signaling pathways to induce transcription of a number of genes encoding ER
      protein chaperones and-folding catalysts. In Saccharomyces cerevisiae this
      transcriptional induction is mediated by an increase in the synthesis of the
      transcription factor Hac1p. The transmembrane receptor Ire1p/Ern1p containing a
      Ser/Thr protein kinase and endoribonuclease activity transmits the unfolded
      protein response (UPR) from the ER to the nucleus. Activation of Ire1p kinase
      induces its endoribonuclease activity to cleave unspliced HAC1 mRNA and generate
      exon fragments that are subsequently ligated by tRNA ligase (RLG1). Whereas
      unspliced HAC1 mRNA is poorly translated, spliced HAC1 mRNA is efficiently
      translated. Subunits of the yeast transcriptional co-activator complex SAGA also
      play a role in the UPR. Deletion of GCN5, ADA2, or ADA3 reduces, and deletion of
      ADA5 completely abolishes, the UPR. Although HAC1 mRNA requires only Ire1p and
      Rlg1p in vitro, we demonstrate that ADA5 is required for the IRE1/RLG1-dependent
      splicing reaction of HAC1 mRNA in vivo. In addition, Ada5p interacts with Ire1p.
      These results suggest that subcomponents of transcriptional co-activator
      complexes may be involved in RNA processing events.

PMID- 10652330
TI  - Modeling and alanine scanning mutagenesis studies of recombinant pokeweed
      antiviral protein.
AB  - The Phytolacca americana-derived naturally occurring ribosome inhibitory protein
      pokeweed antiviral protein (PAP) is an N-glycosidase that catalytically removes a
      specific adenine residue from the stem loop of ribosomal RNA. We have employed
      molecular modeling studies using a novel model of PAP-RNA complexes and site
      directed mutagenesis combined with bioassays to evaluate the importance of the
      residues at the catalytic site and a putative RNA binding active center cleft
      between the catalytic site and C-terminal domain for the enzymatic deadenylation
      of ribosomal RNA by PAP. As anticipated, alanine substitutions by site-directed
      mutagenesis of the PAP active site residues Tyr(72), Tyr(123), Glu(176), and
      Arg(179) that directly participate in the catalytic deadenylation of RNA resulted
      in greater than 3 logs of loss in depurinating and ribosome inhibitory activity.
      Similarly, alanine substitution of the conserved active site residue Trp(208),
      which results in the loss of stabilizing hydrophobic interactions with the ribose
      as well as a hydrogen bond to the phosphate backbone of the RNA substrate, caused
      greater than 3 logs of loss in enzymatic activity. By comparison, alanine
      substitutions of residues (28)KD(29), (80)FE(81), (111)SR(112), (166)FL(167) that
      are distant from the active site did not significantly reduce the enzymatic
      activity of PAP. Our modeling studies predicted that the residues of the active
      center cleft could via electrostatic interactions contribute to both the correct
      orientation and stable binding of the substrate RNA molecule in the active site
      pocket. Notably, alanine substitutions of the highly conserved, charged, and
      polar residues of the active site cleft including (48)KY(49), (67)RR(68),
      (69)NN(70), and (90)FND(92) substantially reduced the depurinating and ribosome
      inhibitory activity of PAP. These results provide unprecedented evidence that
      besides the active site residues of PAP, the conserved, charged, and polar side
      chains located at its active center cleft also play a critical role in the PAP
      mediated depurination of ribosomal RNA.

PMID- 10652331
TI  - The carboxyl-terminal tyrosine residue of protein-tyrosine phosphatase alpha
      mediates association with focal adhesion plaques.
AB  - The receptor protein-tyrosine phosphatase alpha (PTPalpha) is involved in the
      activation of c-Src kinase as well as in down-regulation of the insulin signal.
      To investigate the role of PTPalpha in activation of the Src kinase in more
      detail we tried to overexpress this phosphatase in NIH3T3 fibroblasts. Although
      PTPalpha has been overexpressed in rat embryonic fibroblasts and in embryonic
      carcinoma cells and should increase mitogenic responses we were not able to
      achieve a detectable overexpression. In contrast, expression of partially (C442S)
      or completely inactive (C442S,C732S) PTPalpha or of phosphatase active PTPalpha
      containing mutation Y781F or Y798F was possible. The level of expression,
      however, was reduced to background after several passages of lines expressing
      PTPalphaC442S,C732S and PTPalphaY781F. When employed in a focus formation assay,
      only infection with virus encoding PTPalphaY798F induced Src-dependent formation
      of foci. In immunofluorescence studies, PTPalphaC442S and PTPalphaY781F but not
      PTPalphaY798F colocalized with proteins found in focal adhesion plaques.
      Treatment of PTPalphaC442S-overexpressing cells with vanadate abolished this
      colocalization and led to proteolytic processing of the phosphatase. We conclude
      that tyrosine 798 in PTPalpha is important for localization at focal adhesion
      plaques. Inhibition of phosphatases by vanadate treatment releases PTPalpha from
      focal adhesions.

PMID- 10652332
TI  - Co-expression of Gbeta5 enhances the function of two Ggamma subunit-like domain
      containing regulators of G protein signaling proteins.
AB  - Regulators of G protein signaling (RGS) stimulate the GTPase activity of G
      protein Galpha subunits and probably play additional roles. Some RGS proteins
      contain a Ggamma subunit-like (GGL) domain, which mediates a specific interaction
      with Gbeta5. The role of such interactions in RGS function is unclear. RGS
      proteins can accelerate the kinetics of coupling of G protein-coupled receptors
      to G-protein-gated inwardly rectifying K(+) (GIRK) channels. Therefore, we
      coupled m2-muscarinic acetylcholine receptors to GIRK channels in Xenopus oocytes
      to evaluate the effect of Gbeta5 on RGS function. Co-expression of either RGS7 or
      RGS9 modestly accelerated GIRK channel kinetics. When Gbeta5 was co-expressed
      with either RGS7 or RGS9, the acceleration of GIRK channel kinetics was strongly
      increased over that produced by RGS7 or RGS9 alone. RGS function was not enhanced
      by co-expression of Gbeta1, and co-expression of Gbeta5 alone had no effect on
      GIRK channel kinetics. Gbeta5 did not modulate the function either of RGS4, an
      RGS protein that lacks a GGL domain, or of a functional RGS7 construct in which
      the GGL domain was omitted. Enhancement of RGS7 function by Gbeta5 was not a
      consequence of an increase in the amount of plasma membrane or cytosolic RGS7
      protein.

PMID- 10652333
TI  - Trp1, a candidate protein for the store-operated Ca(2+) influx mechanism in
      salivary gland cells.
AB  - The trp gene family has been proposed to encode the store-operated Ca(2+) influx
      (SOC) channel(s). This study examines the role of Trp1 in the SOC mechanism of
      salivary gland cells. htrp1, htrp3, and Trp1 were detected in the human
      submandibular gland cell line (HSG). HSG cells stably transfected with htrp1alpha
      cDNA displayed (i) a higher level of Trp1, (ii) a 3-5-fold increase in SOC
      (thapsigargin-stimulated Ca(2+) influx), determined by [Ca(2+)](i) and Ca(2+)
      activated K(+) channel current measurements, and (iii) similar basal Ca(2+)
      permeability, and inhibition of SOC by Gd(3+) but not by Zn(2+), as compared with
      control cells. Importantly, (i) transfection of HSG cells with antisense
      trp1alpha cDNA decreased endogenous Trp1 level and significantly attenuated SOC,
      and (ii) transfection of HSG cells with htrp3 cDNA did not increase SOC. These
      data demonstrate an association between Trp1 and SOC and strongly suggest that
      Trp1 is involved in this mechanism in HSG cells. Consistent with this suggestion,
      Trp1 was detected in the plasma membrane region, the proposed site of SOC, of
      acinar and ductal cells in intact rat submandibular glands. Based on these
      aggregate data, we propose Trp1 as a candidate protein for the SOC mechanism in
      salivary gland cells.

PMID- 10652334
TI  - Functional mapping of receptor specificity domains of glial cell line-derived
      neurotrophic factor (GDNF) family ligands and production of GFRalpha1 RET
      specific agonists.
AB  - The glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs)
      (GDNF, neurturin, artemin, and persephin) are critical regulators of
      neurodevelopment and support the survival of midbrain dopaminergic and spinal
      motor neurons in vitro and in animal disease models making them attractive
      therapeutic candidates for treatment of neurodegenerative diseases. The GFLs
      signal through a multicomponent receptor complex comprised of a high affinity
      binding component (GDNF-family receptor alpha-component (GFRalpha1-GFRalpha4))
      and the receptor tyrosine kinase RET. To begin characterization of GFL receptor
      specificity at the molecular level, we performed comprehensive homologue-scanning
      mutagenesis of GDNF, the prototypical member of the GFLs. Replacing short
      segments of GDNF with the homologous segments from persephin (PSPN) (which cannot
      bind or activate GFRalpha1.RET or GFRalpha2.RET) identified sites along the
      second finger of GDNF critical for activating the GFRalpha1.RET and GFRalpha2.RET
      receptor complexes. Furthermore, introduction of these regions from GDNF,
      neurturin, or artemin into PSPN demonstrated that they are sufficient for
      activating GFRalpha1. RET, but additional determinants are required for
      interaction with the other GFRalphas. This difference in the molecular basis of
      GFL-GFRalpha specificity allowed the production of GFRalpha1. RET-specific
      agonists and provides a foundation for understanding of GFL-GFRalpha.RET
      signaling at the molecular level.

PMID- 10652335
TI  - Stability-activity relationships of a family of G-tetrad forming oligonucleotides
      as potent HIV inhibitors. A basis for anti-HIV drug design.
AB  - Recently, we have demonstrated that T30695, a G-tetrad-forming oligonucleotide,
      is a potent inhibitor of human immunodeficiency virus, type I (HIV-1) integrase
      and the K(+)-induced loop folding of T30695 plays a key role in the inhibition of
      HIV-1 integrase (Jing, N., and Hogan, M. E. (1998) J. Biol. Chem. 273, 34992
      34999). Here we have modified T30695 by introducing a hydrophobic bulky group,
      propynyl dU, or a positively charged group, 5-amino dU, into the bases of T
      residues of the loops, and by substitution of the T-G loops by T-T loops.
      Physical measurements have demonstrated that the substitution of propynyl dU or 5
      amino dU for T in the T residues of the loops did not alter the structure of
      T30695, and these derivatives also formed an intramolecular G-quartet structure,
      which is an essential requirement for anti-HIV activity. Measured IC(50) and
      EC(50) values show that these substitutions did not induce an apparent decrease
      in the ability to inhibit HIV-1 integrase activity and in the inhibition of HIV-1
      replication in cell culture. However, the substitution of T-T loops for T-G loops
      induced a substantial decrease in both thermal stability and anti-HIV activity.
      The data analysis of T30695 and the 21 derivatives shows a significant,
      functional correlation between thermal stability of the G-tetrad structure and
      the capacity to inhibit HIV-1 integrase activity and between thermal stability of
      the G-tetrad structure and the capacity to inhibit HIV-1 replication, as assessed
      with the virus strains HIV-1 RF, IIIB, and MN in cell culture. This relationship
      between thermostability and activity provides a basis for improving the efficacy
      of these compounds to inhibit HIV-1 integrase activity and HIV-1 replication in
      cell culture.

PMID- 10652336
TI  - Identification of CD7 as a cognate of the human K12 (SECTM1) protein.
AB  - CD7 is a 40-kDa protein found primarily on T, NK, and pre-B cells; the function
      of the CD7 protein in the immune system is largely unknown. The K12 (SECTM1)
      protein was originally identified by its location just upstream of the CD7 locus.
      The K12 gene encodes a transmembrane protein of unknown function. In order to
      clone a K12-binding protein, we generated a soluble version of the human K12
      protein by fusing its extracellular domain to the Fc portion of human IgG(1).
      Flow cytometry experiments showed that the K12-Fc fusion protein bound at high
      levels to both human T and NK cells. Precipitation experiments using K12-Fc on
      (35)S-radiolabeled NK cells lysates indicated that the K12 cognate was an
      approximately 40-kDa protein. A human peripheral blood T cell cDNA expression
      library was screened with the K12-Fc protein, and two independent, positive cDNA
      clones were identified and sequenced. Both cDNAs encoded the same protein, which
      was CD7. Thus, K12 and CD7 are cognate proteins that are located next to each
      other on human chromosome 17q25. Additionally, we have cloned the gene encoding
      the mouse homologue of K12, shown that it maps near the mouse CD7 gene on
      chromosome 11, and established that the mouse K12 protein binds to mouse, but not
      human, CD7. Mouse K12-Fc inhibited in a dose-dependent manner concanavalin A
      induced proliferation, but not anti-TcRalpha/beta induced proliferation, of mouse
      lymph node T cells. Human K12-Fc stimulated the up-regulation of CD25, CD54, and
      CD69 on human NK cells in vitro.

PMID- 10652337
TI  - Expression of the AML-1 oncogene shortens the G(1) phase of the cell cycle.
AB  - The AML-1-encoded transcription factor, AML-1B, regulates numerous hematopoietic
      specific genes. Inappropriate expression of AML-1-family proteins is oncogenic in
      cell culture systems and in mice. To understand the oncogenic functions of AML-1,
      we established cell lines expressing AML-1B to examine the role of AML-1 in the
      cell cycle. DNA content analysis and bromodeoxyuridine pulse-chase studies
      indicated that entry into the S phase of the cell cycle was accelerated by up to
      4 h in AML-1B-expressing 32D.3 myeloid progenitor cells as compared with control
      cells or cells expressing E2F-1. However, AML-1B was not able to induce continued
      cell cycle progression in the absence of growth factors. The DNA binding and
      transactivation domains of AML-1B were required for altering the cell cycle.
      Thus, AML-1B is the first transcription factor that affects the timing of the
      mammalian cell cycle.

PMID- 10652338
TI  - Transcription activation by the orphan nuclear receptor, chicken ovalbumin
      upstream promoter-transcription factor I (COUP-TFI). Definition of the domain
      involved in the glucocorticoid response of the phosphoenolpyruvate carboxykinase
      gene.
AB  - Chicken ovalbumin upstream promoter-transcription factors (COUP-TFs), orphan
      members of the nuclear receptor superfamily, play a key role in the regulation of
      organogenesis, neurogenesis, and cellular differentiation during embryogenic
      development. COUP-TFs are also involved in the regulation of several genes that
      encode metabolic enzymes. Although COUP-TFs function as potent transcription
      repressors, there are at least three different molecular mechanisms of activation
      of gene expression by COUP-TFs. First, as we have previously shown, COUP-TF is
      required as an accessory factor for the complete induction of phosphoenolpyruvate
      carboxykinase gene transcription by glucocorticoids. This action is mediated by
      the binding of COUP-TF to the glucocorticoid accessory factor 1 (gAF1) and 3
      (gAF3) elements in the phosphoenolpyruvate carboxykinase gene glucocorticoid
      response unit. In addition, COUP-TF1 binds to DNA elements in certain genes and
      transactivates directly. Finally, COUP-TF1 serves as a coactivator through DNA
      bound hepatic nuclear factor 4. Here we show that the same region of COUP-TFI,
      located between amino acids 184 and 423, is involved in these three mechanisms of
      transactivation by COUP-TFI. Furthermore, we show that GRIP1 and SRC-1 potentiate
      the activity of COUP-TFI and that COUP-TFI associates with these coactivators in
      vivo using the same region required for transcription activation. Finally,
      overexpression of GRIP1 or SRC-1 does not convert COUP-TFI from a transcriptional
      repressor into a transcriptional activator in HeLa cells.

PMID- 10652339
TI  - Peroxisomal membrane protein Pmp47 is essential in the metabolism of middle-chain
      fatty acid in yeast peroxisomes and Is associated with peroxisome proliferation.
AB  - Pmp47 of the methylotrophic yeast Candida boidinii belongs to a mitochondrial
      family of solute transporters and is localized in peroxisomal membranes. Its
      human homolog, Pmp34, is also known. In this study, we characterized the role of
      Pmp47 in fatty acid metabolism and peroxisome proliferation using the PMP47
      deleted strain of C. boidinii (strain pmp47Delta). The wild-type strain grew well
      on a middle-chain fatty acid, laureate, as the single carbon source, and mild
      peroxisome proliferation was observed during its growth. The pmp47Delta strain
      could not grow on laureate but could grow on long-chain fatty acids including
      palmitate, myristate, and oleate. The levels of laureate oxidation activity in
      intact cells and in semi-permeabilized cells of strain pmp47Delta were lower than
      the respective level in the wild-type strain, although the level of laureate
      oxidation activity in the cell lysate and the level of lauroyl-CoA oxidation in
      semi-permeabilized cells of strain pmp47Delta were indistinguishable from the
      respective level in the wild-type strain. When lauroyl-CoA was provided in the
      cytosol of strain pmp47Delta through expression of Saccharomyces cerevisiae Faa2p
      (lauroyl-CoA synthetase) in which its peroxisome targeting signal was deleted,
      the growth of strain pmp47Delta on laureate was recovered to the level of growth
      of the wild-type strain. Laureate is converted to its CoA form in peroxisomes by
      the action of lauroyl-CoA synthetase. These results suggested that Pmp47 is
      involved in the transport of a small molecule (possibly ATP) required in the
      conversion of laureate to its CoA form in peroxisomes and that the absence of
      Pmp47 causes impairment of laureate metabolism, which results in the inability of
      pmp47Delta cells to grow on laureate. In addition, Pmp47 may be involved in
      peroxisome proliferation, because the pmp47Delta strain contained a reduced
      number of peroxisomes, as judged from the fluorescence analysis of cells
      expressing green fluorescent protein tagged with the peroxisome targeting signal
      1 (GFP-AKL).

PMID- 10652340
TI  - Purification and characterization of a neutral ceramidase from mouse liver. A
      single protein catalyzes the reversible reaction in which ceramide is both
      hydrolyzed and synthesized.
AB  - We report here a novel ceramidase that was purified more than 150, 000-fold from
      the membrane fraction of mouse liver. The enzyme was a monomeric polypeptide
      having a molecular mass of 94 kDa and was highly glycosylated with N-glycans. The
      amino acid sequence of a fragment obtained from the purified enzyme was
      homologous to those deduced from the genes encoding an alkaline ceramidase of
      Pseudomonas aeruginosa and a hypotheical protein of the slime mold Dictyostelium
      discoideum. However, no significant sequence similarities were found in other
      known functional proteins including acid ceramidases of humans and mice. The
      enzyme hydrolyzed various N-acylsphingosines but not galactosylceramide,
      sulfatide, GM1a, or sphingomyelin. The enzyme exhibited the highest activity
      around pH 7.5 and was thus identified as a type of neutral ceramidase. The
      apparent K(m) and V(max) values for C12-4-nitrobenzo-2-oxa-1, 3-diazole-ceramide
      and C16-(14)C-ceramide were 22.3 microM and 29.1 micromol/min/mg and 72.4 microM
      and 3.6 micromol/min/mg, respectively. This study also clearly demonstrated that
      the purified 94-kDa ceramidase catalyzed the condensation of fatty acid to
      sphingosine to generate ceramide, but did not catalyze acyl-CoA-dependent acyl
      transfer reaction.

PMID- 10652341
TI  - Examining the noncompetitive antagonist-binding site in the ion channel of the
      nicotinic acetylcholine receptor in the resting state.
AB  - 3-Trifluoromethyl-3-(m-[(125)I]iodophenyl)diazirine ([(125)I]TID) has been shown
      to be a potent noncompetitive antagonist (NCA) of the nicotinic acetylcholine
      receptor (AChR). Amino acids that contribute to the binding site for [(125)I]TID
      in the ion channel have been identified in both the resting and desensitized
      state of the AChR (White, B.H., and Cohen, J.B. (1992) J. Biol. Chem. 267, 15770
      15783). To characterize further the structure of the NCA-binding site in the
      resting state channel, we have employed structural analogs of TID. The TID
      analogs were assessed by the following: 1) their ability to inhibit [(125)I]TID
      photoincorporation into the resting state channel; 2) the pattern, agonist
      sensitivity, and NCA inhibition of [(125)I]TID analog photoincorporation into
      AChR subunits. The addition of a primary alcohol group to TID has no demonstrable
      effect on the interaction of the compound with the resting state channel.
      However, conversion of the alcohol function to acetate, isobutyl acetate
      (TIDBIBA), or to trimethyl acetate leads to rightward shifts in the concentration
      response curves for inhibition of [(125)I]TID photoincorporation into the AChR
      channel and a progressive reduction in the agonist sensitivity of [(125)I]TID
      analog photoincorporation into AChR subunits. Inhibition of [(125)I]TID analog
      photoincorporation by NCAs (e.g. tetracaine) as well as identification of the
      sites of [(125)I]TIDBIBA photoincorporation in the deltaM2 segment indicate a
      common binding locus for each TID analog. We conclude that relatively small
      additions to TID progressively reduce its ability to interact with the NCA site
      in the resting state channel. A model of the NCA site and resting state channel
      is presented.

PMID- 10652342
TI  - Cyclin D3 compensates for loss of cyclin D2 in mouse B-lymphocytes activated via
      the antigen receptor and CD40.
AB  - Cyclin D2 is the only D-type cyclin expressed in mature mouse B-lymphocytes, and
      its expression is associated with retinoblastoma protein (pRB) and pRB-related
      protein phosphorylation and induction of E2F activity, as B-cells enter the cell
      cycle following stimulation via surface IgM and/or CD40. Cyclin D-dependent
      kinase activity is required for cell proliferation, yet cyclin D2(-/-) mice have
      normal levels of mature B-lymphocytes. Here we show that B-lymphocytes from
      cyclin D2(-/-) mice can proliferate in response to anti-IgM and anti-CD40, but
      the time taken to enter S-phase is longer than for the corresponding cyclin
      D2(+/+) cells. This is due to the compensatory induction of cyclin D3, but not
      cyclin D1, which causes pRb phosphorylation on CDK4-specific sites. This is the
      first demonstration that loss of a D-type cyclin causes specific expression and
      functional compensation by another member of the family in vivo and provides a
      rationale for the presence of mature B-lymphocytes in cyclin D2(-/-) mice.

PMID- 10652343
TI  - Pancreatic beta cell-specific transcription of the pdx-1 gene. The role of
      conserved upstream control regions and their hepatic nuclear factor 3beta sites.
AB  - To identify potential transactivators of pdx-1, we sequenced approximately 4.5
      kilobases of the 5' promoter region of the human and chicken homologs, assuming
      that sequences conserved with the mouse gene would contain critical cis
      regulatory elements. The sequences associated with hypersensitive site 1 (HSS1)
      represented the principal area of homology within which three conserved
      subdomains were apparent: area I (-2694 to -2561 base pairs (bp)), area II (-2139
      to -1958 bp), and area III (-1879 to -1799 bp). The identities between the mouse
      and chicken/human genes are very high, ranging from 78 to 89%, although only
      areas I and III are present within this region in chicken. Pancreatic beta cell
      selective expression was shown to be controlled by mouse and human area I or area
      II, but not area III, from an analysis of pdx-1-driven reporter activity in
      transfected beta- and non-beta cells. Mutational and functional analyses of
      conserved hepatic nuclear factor 3 (HNF3)-like sites located within area I and
      area II demonstrated that activation by these regions was mediated by HNF3beta.
      To determine if a similar regulatory relationship might exist within the context
      of the endogenous gene, pdx-1 expression was measured in embryonic stem cells in
      which one or both alleles of HNF3beta were inactivated. pdx-1 mRNA levels induced
      upon differentiation to embryoid bodies were down-regulated in homozygous null
      HNF3beta cells. Together, these results suggest that the conserved sequences
      represented by areas I and II define the binding sites for factors such as
      HNF3beta, which control islet beta cell-selective expression of the pdx-1 gene.

PMID- 10652344
TI  - Regulation of dinitrogenase reductase ADP-ribosyltransferase and dinitrogenase
      reductase-activating glycohydrolase by a redox-dependent conformational change of
      nitrogenase Fe protein.
AB  - The nitrogenase-regulating enzymes dinitrogenase reductase ADP-ribosyltransferase
      (DRAT) and dinitrogenase reductase-activating glycohydrolase (DRAG), from
      Rhodospirillum rubrum, were shown to be sensitive to the redox status of the
      [Fe(4)S(4)](1+/2+) cluster of nitrogenase Fe protein from R. rubrum or
      Azotobacter vinelandii. DRAG had <2% activity with oxidized R. rubrum Fe protein
      relative to activity with reduced Fe protein. The activity of DRAG with oxygen
      denatured Fe protein or a low molecular weight substrate, N(alpha)-dansyl
      N(omega)-(1,N(6)-etheno-ADP-ribosyl)-arginine methyl ester, was independent of
      redox potential. The redox midpoint potential of DRAG activation of Fe protein
      was -430 mV versus standard hydrogen electrode, coinciding with the midpoint
      potential of the [Fe(4)S(4)] cluster from R. rubrum Fe protein. DRAT was found to
      have a specificity opposite that of DRAG, exhibiting low (<20%) activity with 87%
      reduced R. rubrum Fe protein relative to activity with fully oxidized Fe protein.
      A mutant of R. rubrum in which the rate of oxidation of Fe protein was
      substantially decreased had a markedly slower rate of ADP-ribosylation in vivo in
      response to 10 mM NH(4)Cl or darkness stimulus. It is concluded that the redox
      state of Fe protein plays a significant role in regulation of the activities of
      DRAT and DRAG in vivo.

PMID- 10652345
TI  - Molecular determinants of site-specific inhibition of human DNA topoisomerase I
      by fagaronine and ethoxidine. Relation to DNA binding.
AB  - DNA topoisomerase (top) I inhibition activity of the natural alkaloid fagaronine
      (NSC157995) and its new synthetic derivative ethoxidine (12-ethoxy
      benzo[c]phenanthridine) has been correlated with their molecular interactions and
      sequence specificity within the DNA complexes. Flow linear dichroism shows that
      ethoxidine exhibits the same inhibition of DNA relaxation as fagaronine at the 10
      fold lower concentration. The patterns of DNA cleavage by top I show linear
      enhancement of CPT-dependent sites at the 0.016-50 microM concentrations of
      fagaronine, whereas ethoxidine suppress both top I-specific and CPT-dependent
      sites. Suppression of top I-mediated cleavage by ethoxidine is found to be
      specific for the sites, including strand cut between A and T. Fagaronine and
      ethoxidine are DNA major groove intercalators. Ethoxidine intercalates DNA in A-T
      sequences and its 12-ethoxy-moiety (absent in fagaronine) extends into the DNA
      minor groove. These findings may explain specificity of suppression by ethoxidine
      of the strong top I cleavage sites with the A(+1), T(-1) immediately adjacent to
      the strand cut. Fagaronine does not show any sequence specificity of DNA
      intercalation, but its highly electronegative oxygen of hydroxy group (absent in
      ethoxidine) is shown to be an acceptor of the hydrogen bond with the NH(2) group
      of G base of DNA. Ability of fagaronine to stabilize top I-mediated ternary
      complex is proposed to be determined by interaction of its hydroxy group with the
      guanine at position (+1) of the DNA cleavage site and of quaternary nitrogen
      interaction with top I. The model proposed provides a guidance for screening new
      top I-targeted drugs in terms of identification of molecular determinants
      responsible for their top I inhibition effects.

PMID- 10652346
TI  - OUT, a novel basic helix-loop-helix transcription factor with an Id-like
      inhibitory activity.
AB  - Transcription factors belonging to the basic helix-loop-helix (bHLH) family are
      involved in various cell differentiation processes. We report the isolation and
      functional characterization of a novel bHLH factor, termed OUT. OUT, structurally
      related to capsulin/epicardin/Pod-1 and ABF-1/musculin/MyoR, is expressed mainly
      in the adult mouse reproductive organs, such as the ovary, uterus, and testis,
      and is barely detectable in tissues of developing embryos. Physical association
      of OUT with the E protein was predicted from the primary structure of OUT and
      confirmed by co-immunoprecipitation. However, unlike other bHLH factors, this
      novel protein failed to bind E-box or N-box DNA sequences and inhibited DNA
      binding of homo- and heterodimers consisting of E12 and MyoD in gel mobility
      shift assays. In luciferase assays, OUT inhibited the induction of E-box
      dependent transactivation by MyoD-E12 heterodimers. Deletion studies identified
      the domain responsible for the inhibitory action of OUT in its bHLH and C
      terminal regions. Moreover, terminal differentiation of C2C12 myoblasts was
      inhibited by exogenous introduction of OUT. These inhibitory functions of OUT
      closely resemble those of the helix-loop-helix inhibitor Id proteins. Based on
      these findings, we propose that this novel protein functions as a negative
      regulator of bHLH factors through the formation of a functionally inactive
      heterodimeric complex.

PMID- 10652347
TI  - Transcription factor-dependent loading of the E1 initiator reveals modular
      assembly of the papillomavirus origin melting complex.
AB  - Replication of bovine papillomavirus type 1 DNA absolutely requires the viral
      transcription factor E2 as well as the initiator E1, although E1 alone has all
      the activities expected of an initiator protein. E1 assembles on the DNA in a
      stepwise fashion and undergoes a transition in activities from site-specific DNA
      binding protein to mobile helicase. Complex assembly is assisted by the viral
      transcription factor E2 at two levels. E2 acts generally as a specificity factor,
      which through cooperative binding with E1 generates an initial E1 complex
      containing three E1 dimers bound to ori on one face of the DNA, E1-ori.
      Furthermore, E2 can promote the transition to an ori melting complex by
      recruiting additional E1 molecules to ori, effectively reducing the E1
      concentration required for ori melting. This reaction is dependent on an E2
      binding site positioned distal to the precursor E1-ori complex. The final origin
      melting complex has two subunits that each encircle the DNA and function
      independently to melt ori. The assembly pathway we describe has implication for
      understanding DNA melting and unwinding reactions, which are generally poorly
      understood.

PMID- 10652348
TI  - Enhancement of phototransduction protein interactions by lipid surfaces.
AB  - The G protein cascade of vision depends on two peripheral membrane proteins: the
      G protein, transducin (G(t)), and cGMP phosphodiesterase (PDE). Each has
      covalently attached lipids, and interacts with transduction components on the
      membrane surface. We have found that their surface interactions are critically
      dependent on the nature of the lipid. Membranes enhance their protein-protein
      interactions, especially if electrostatic attraction is introduced with
      positively charged lipids. These interactions are less enhanced on highly curved
      surfaces, but are most enhanced by unsaturated or bulky acyl chains. On
      positively charged membranes, G(t) assembles at a high enough density to form two
      dimensional arrays with short-range crystalline order. Cationic membranes also
      support extremely efficient activation of PDE by the GTPgammaS (guanosine 5'-O
      (thiotriphosphate)) form of Galpha(t) (Galpha(t)-GTPgammaS), minimizing
      functional heterogeneity of transducin and allowing activation with nanomolar
      Galpha(t)-GTPgammaS. Quantification of PDE activation and of the amount of
      Galpha(t)-GTPgammaS bound to PDE indicated that G(t) activates PDE maximally when
      bound in a 1:1 molar ratio. No cooperativity was observed, even at nanomolar
      concentrations. Thus, under these conditions, the one binding site for Galpha(t)
      GTPgammaS on PDE that stimulates catalysis must be of higher affinity than one or
      more additional sites which are silent with respect to activation of PDE.

PMID- 10652349
TI  - Identification of amino acid residues and protein kinases involved in the
      regulation of NFATc subcellular localization.
AB  - The subcellular localization of the transcription factor NFATc is tightly
      regulated by the calcium-regulated phosphatase calcineurin, which acts to
      directly dephosphorylate NFATc, causing its rapid translocation from the
      cytoplasm to the nucleus. The calcineurin-mediated nuclear localization of NFATc
      is opposed by poorly defined protein kinases that act either to directly
      antagonize nuclear import or, alternatively, to promote nuclear export. Here, we
      provide evidence that the cellular protein kinases JNK, ERK, p38, and CK2
      (formerly casein kinase II) are involved in the regulation of NFATc subcellular
      localization. We show that JNK, ERK, and p38 physically associate with the NFATc
      N-terminal regulatory domain and can directly phosphorylate functionally
      important residues involved in regulating NFATc subcellular localization, namely
      Ser(172) and the conserved NFATc Ser-Pro repeats. Moreover, we found that
      overexpression of JNK, ERK, or p38 is able to block ionomycin-induced NFATc
      nuclear translocation, whereas treatment of cells with both PD98059 and SB202190,
      which inhibit MAPK/SAPK signaling pathways, is sufficient to trigger NFATc
      nuclear localization. Finally, we show that CK2 also binds the N terminus of
      NFATc and phosphorylates functionally important amino acid residues, including a
      conserved amino acid motif located downstream of each of the NFATc Ser-Pro
      repeats that appears to be important for regulating NFATc nuclear export.
      Collectively, these studies identify functionally important amino acid residues
      and protein kinases involved in the regulation of NFATc subcellular localization.

PMID- 10652350
TI  - Smad and AML proteins synergistically confer transforming growth factor beta1
      responsiveness to human germ-line IgA genes.
AB  - Transcription of germ-line immunoglobulin heavy chain genes conditions them to
      participate in isotype switch recombination. Transforming growth factor-beta1
      (TGF-beta1) stimulates promoter elements located upstream of the IgA1 and IgA2
      switch regions, designated Ialpha1 and Ialpha2, and contributes to the
      development of IgA responses. We demonstrate that intracellular Smad proteins
      mediate activation of the Ialpha1 promoter by TGF-beta. TGF-beta type 1 receptor
      (ALK-5), activin type IB receptor (ALK-4), and the "orphan" ALK-7 trans-activate
      the Ialpha1 promoter, thus raising the possibility that other members of the TGF
      beta superfamily can also modulate IgA synthesis. Smads physically interact with
      the AML family of transcription factors and cooperate with them to activate the
      Ialpha1 promoter. The Ialpha1 element provides a canape of interspersed high and
      low affinity sites for Smad and AML factors, some of which are indispensable for
      TGF-beta responsiveness. While AML.Smad complexes are formed in the cytoplasm of
      DG75 and K562 cells constitutively, only after TGF-beta receptor activation,
      novel Smad3.Smad4.AML complexes are detected in nuclear extracts by EMSA with
      Ialpha1 promoter-derived probes. Considering the wide range of biological
      phenomena that AMLs and Smads regulate, the physical/functional interplay between
      them has implications that extend beyond the regulation of class switching to
      IgA.

PMID- 10652351
TI  - A naturally occurring sequence variation that creates a YY1 element is associated
      with increased cystic fibrosis transmembrane conductance regulator gene
      expression.
AB  - We have identified previously a novel complex mutant allele in the cystic
      fibrosis transmembrane conductance regulator (CFTR) gene in a patient affected
      with cystic fibrosis (CF). This allele contained a mutation in CFTR exon 11 known
      to cause CF (S549R(T>G)), associated with the first alteration described so far
      in the minimal CFTR promoter region (-102T>A). Studies on genotype-phenotype
      correlations revealed striking differences between patients carrying mutation
      (S549R(T>G)) alone, who had a severe disease, and patients carrying the complex
      allele (-102(T>A)+S549R(T>G)), who exhibited milder forms of CF. We thus
      postulated that the sequence change (-102T>A) may attenuate the effects of the
      severe (S549R(T>G)) mutation through regulation of CFTR expression. Analysis of
      transiently transfected cell lines with wild-type and -102A variant human CFTR
      directed luciferase reporter genes demonstrates that constructs containing the 
      102A variant (which creates a Yin Yang 1 (YY1) core element) increases CFTR
      expression significantly. Electrophoretic mobility shift assays indicate that the
      -102 site is located in a region of multiple DNA-protein interactions and that
      the -102A allele recruits specifically an additional nuclear protein related to
      YY1. The finding that the YY1-binding allele causes a significant increase in
      CFTR expression in vitro may allow a better understanding of the milder phenotype
      observed in patients who carry a severe CF mutation within the same gene.

PMID- 10652352
TI  - Transforming ability of MEN2A-RET requires activation of the phosphatidylinositol
      3-kinase/AKT signaling pathway.
AB  - The RET gene codes for a receptor tyrosine kinase that plays a crucial role
      during the development of both the enteric nervous system and the kidney. Germ
      line missense mutations at one of six codons specifying extracytoplasmic
      cysteines are responsible for two related cancer disorders as follows: multiple
      endocrine neoplasia type2A (MEN2A) and familial medullary thyroid carcinoma
      (FMTC). MEN2A and FMTC mutations result in a constitutive catalytic activity and
      as a consequence convert RET into a dominantly acting transforming gene. Although
      it has been shown that RET-MEN2 mutants activate several transduction pathways,
      their respective contribution to the neoplastic phenotype remains poorly
      understood. Over the past few years, it has become increasingly clear that the
      transforming ability of several viral and cellular oncoproteins depends on their
      capacity to activate phosphatidylinositol 3-kinase (PI3K). We now report that RET
      carrying a representative MEN2A mutation at Cys-634 (termed RET-MEN2A) activates
      PI3K and its downstream effector, the serine/threonine kinase AKT/protein kinase
      B. Previous studies have demonstrated that mutation of Tyr-1062, which is the
      intracellular docking site for Shc and Enigma on RET, abolishes the RET-MEN2A
      transforming activity. We provide evidence that mutation of Tyr-1062 abrogates
      the binding of the p85 regulatory subunit of PI3K to RET-MEN2A and the subsequent
      stimulation of the PI3K/AKT pathway. Furthermore, infection of rat fibroblasts
      with a retrovirus expressing a dominant-interfering form of PI3K suppresses RET
      MEN2A-dependent transformation, whereas overexpression of AKT enhances the RET
      MEN2A oncogenic potential. In summary, these data are consistent with the notion
      that RET-mediated cell-transforming effect is critically dependent on the
      activation of the PI3K/AKT pathway.

PMID- 10652353
TI  - Rho-associated kinase ROCK activates LIM-kinase 1 by phosphorylation at threonine
      508 within the activation loop.
AB  - LIM-kinase 1 (LIMK1) phosphorylates cofilin, an actin-depolymerizing factor, and
      regulates actin cytoskeletal reorganization. LIMK1 is activated by the small
      GTPase Rho and its downstream protein kinase ROCK. We now report the site of
      phosphorylation of LIMK1 by ROCK. In vitro kinase reaction revealed that the
      active forms of ROCK phosphorylated LIMK1 on the threonine residue and markedly
      increased its cofilin-phosphorylating activity. A LIMK1 mutant (T508A) with
      replacement of Thr-508 within the activation loop of the kinase domain by alanine
      was neither phosphorylated nor activated by ROCK. Replacement of Thr-508 by
      serine changed the ROCK-catalyzed phosphorylation residue from threonine to
      serine. A LIMK1 mutant with replacement of Thr-508 by two glutamates increased
      the kinase activity about 2-fold but was not further activated by ROCK. In
      addition, wild-type LIMK1, but not its T508A mutant, was activated by co
      expression with ROCK in cultured cells. These results suggest that ROCK activates
      LIMK1 in vitro and in vivo by phosphorylation at Thr-508. Together with the
      recent finding that PAK1, a downstream effector of Rac, also activates LIMK1 by
      phosphorylation at Thr-508, these results suggest that activation of LIMK1 is one
      of the common targets for Rho and Rac to reorganize the actin cytoskeleton.

PMID- 10652354
TI  - Mapping of subunit-subunit contact surfaces on the beta' subunit of Escherichia
      coli RNA polymerase.
AB  - The RNA polymerase core enzyme of Escherichia coli with the catalytic activity of
      RNA polymerization is assembled sequentially under the order: 2alpha --> alpha(2)
      --> alpha(2)beta --> alpha(2)betabeta'. The core enzyme gains the activities of
      promoter recognition and transcription initiation after binding the sigma
      subunit. The subunit-subunit contact surfaces of beta' subunit (1407 residues)
      were analyzed by testing complex formation between various beta' fragments and
      either the alpha(2)beta complex or the sigma(70) subunit. Results indicate that
      two regions, one central region between residues 515 and 842 and the other COOH
      terminal proximal region downstream from residue 1141, are involved in binding
      the alpha(2)beta complex; and the NH(2)-terminal proximal region between residues
      201 and 345 plays a major role in binding the sigma(70) subunit. However, both
      alpha(2)beta binding sites have weak activity of the sigma(70) subunit; likewise,
      the sigma(70) subunit-contact surface has weak binding activity of the
      alpha(2)beta complex. The sites involved in the catalytic function of RNA
      polymerization are all located within two spacer regions sandwiched between these
      three subunit-subunit contact surfaces.

PMID- 10652355
TI  - Pex8p, an intraperoxisomal peroxin of Saccharomyces cerevisiae required for
      protein transport into peroxisomes binds the PTS1 receptor pex5p.
AB  - We report the characterization of ScPex8p, which is essential for peroxisomal
      biogenesis in Saccharomyces cerevisiae. Cells lacking Pex8p are characterized by
      the presence of peroxisomal membrane ghosts and mislocalization of peroxisomal
      matrix proteins of the PTS1 and PTS2 variety to the cytosol. Pex8p is tightly
      associated with the lumenal face of the peroxisomal membrane. Consistent with its
      intraperoxisomal localization, Pex8p contains a peroxisomal targeting signal 1,
      and it interacts with the PTS1 receptor Pex5p. However, the Pex5p/Pex8p
      association is also observed upon deletion of the PTS1 of Pex8p, suggesting that
      Pex8p contains a second binding site for Pex5p. The pex8Delta mutant phenotype
      and the observed PTS1-independent interaction with the PTS1 receptor suggest that
      Pex8p is involved in protein import into the peroxisomal matrix. In pex8Delta
      cells, the PTS1 and PTS2 receptor still associate with membrane bound components
      of the protein import machinery, supporting the assumption that the Pex8p
      function in protein translocation follows the docking event.

PMID- 10652356
TI  - Regulation of protein kinase Ctheta function during T cell activation by Lck
      mediated tyrosine phosphorylation.
AB  - Protein kinase C theta (PKCtheta) is a novel Ca(2+)-independent PKC isoform,
      which is selectively expressed in skeletal muscle and hematopoietic cells,
      especially T cells. In T cells, it colocalizes with the T cell antigen receptor
      (TCR).CD3 complex in antigen-stimulated T cells and is involved in the
      transcriptional activation of the interleukin-2 gene. In the present study, we
      report that PKCtheta is tyrosine phosphorylated in Jurkat T cells upon TCR.CD3
      activation. The Src family protein-tyrosine kinase, Lck, was critical in TCR
      induced tyrosine phosphorylation of PKCtheta. Lck phosphorylated and was
      associated with the regulatory domain of PKCtheta both in vitro and in intact
      cells. This association was constitutive, but it was enhanced by T cell
      activation, with both Src-homology 2 and Src-homology 3 domains of Lck
      contributing to it. Tyrosine 90 (Tyr-90) in the regulatory domain of PKCtheta was
      identified as the major phosphorylation site by Lck. A constitutively active
      mutant of PKCtheta (A148E) could enhance proliferation of Jurkat T cells and
      synergized with ionomycin to induce nuclear factor of T cells activity. However,
      mutation of Tyr-90 into phenylalanine markedly reduced (or abolished) these
      activities. These results suggest that Lck plays an important role in tyrosine
      phosphorylation of PKCtheta, which may in turn modulate the physiological
      functions of PKCtheta during TCR-induced T cell activation.

PMID- 10652357
TI  - The transcription factor deltaEF1 is inversely expressed with type II collagen
      mRNA and can repress Col2a1 promoter activity in transfected chondrocytes.
AB  - The regulation of Col2a1, which encodes type II collagen, likely results from a
      balance of both positive and negative proteins. Here we present evidence that the
      transcription factor deltaEF1 participates in the negative regulation of Col2a1
      transcription. A deletion analysis suggested that a region between -100 and -307
      of the rat Col2a1 gene was required for activity in differentiating chick limb
      bud mesenchymal cells; however, mutation of a conserved E2 box site in this
      region actually increased promoter activity. Supershift analysis demonstrated
      that deltaEF1, a known transcriptional repressor, bound to the E2 box in a
      sequence-dependent manner. Chick limb bud mesenchymal cells, which do not express
      type II collagen, expressed abundant deltaEF1 mRNA, but, following
      differentiation in micromass culture, deltaEF1 mRNA expression was lost. Primary
      embryonic chick sternal chondrocytes, which express abundant type II collagen,
      displayed minimal levels of deltaEF1 mRNA. The inhibition of Col2a1 transcription
      following treatment of chick sternal chondrocytes with growth factors was
      accompanied by increased deltaEF1 expression. Overexpression of deltaEF1 in
      differentiated chondrocytes resulted in decreased expression of a reporter
      construct containing a collagen II promoter/enhancer insert; however, this
      negative regulation was not dependent on the proximal E2 box. This is the first
      report of a specific transcription factor involved in the negative regulation of
      Col2a1.

PMID- 10652358
TI  - Role of tyrosine phosphorylation in the regulation of the interaction of
      heterogenous nuclear ribonucleoprotein K protein with its protein and RNA
      partners.
AB  - The heterogeneous nuclear ribonucleoprotein K protein recruits a diversity of
      molecular partners and may act as a docking platform involved in such processes
      as transcription, RNA processing, and translation. We show that K protein is
      tyrosine-phosphorylated in vitro by Src and Lck. Treatment with
      H(2)O(2)/Na(3)VO(4), which induces oxidative stress, stimulated tyrosine
      phosphorylation of K protein in cultured cells and in intact livers. Tyrosine
      phosphorylation increased binding of Lck and the proto-oncoprotein Vav to K
      protein in vitro. Oxidative stress increased the association of K protein with
      Lck and Vav, suggesting that tyrosine phosphorylation regulates the ability of K
      protein to recruit these effectors in vivo. Translation-based assay showed that K
      protein is constitutively bound to many mRNAs in vivo. Native immunoprecipitated
      K protein-mRNA complexes were disrupted by tyrosine phosphorylation, suggesting
      that the in vivo binding of K protein to mRNA may be responsive to the
      extracellular signals that activate tyrosine kinases. This study shows that
      tyrosine phosphorylation of K protein regulates K protein-protein and K protein
      RNA interactions. These data are consistent with a model in which functional
      interaction of K protein is responsive to changes in the extracellular
      environment. Acting as a docking platform, K protein may bridge signal
      transduction pathways to sites of nucleic acid-dependent process such as
      transcription, RNA processing, and translation.

PMID- 10652359
TI  - Helicobacter pylori activates the histidine decarboxylase promoter through a
      mitogen-activated protein kinase pathway independent of pathogenicity island
      encoded virulence factors.
AB  - Helicobacter pylori infection of the gastric mucosa is accompanied by an
      activated histamine metabolism. Histamine plays a central role in the regulation
      of gastric acid secretion and is involved in the pathogenesis of gastroduodenal
      ulcerations. Histidine decarboxylase (HDC) is the rate-limiting enzyme for
      histamine production, and its activity is regulated through transcriptional
      mechanisms. The present study investigated the effect of H. pylori infection on
      the transcriptional activity of the human HDC (hHDC) promoter in a gastric
      epithelial cell line (AGS) and analyzed the underlying molecular mechanisms. Our
      studies demonstrate that H. pylori infection potently transactivated the hHDC
      promoter. The H. pylori-responsive element of the hHDC gene was mapped to the
      sequence +1 to +27 base pairs, which shows no homology to known cis-acting
      elements and also functions as a gastrin-responsive element. H. pylori regulates
      the activity of this element via a Raf-1/MEK/ERK pathway, which was activated in
      a Ras-independent manner. Furthermore, we found that H. pylori-induced
      transactivation of the hHDC promoter was independent of the cag pathogenicity
      island and the vacuolating cytotoxin A gene and therefore may be exerted through
      (a) new virulence factor(s). A better understanding of H. pylori-directed hHDC
      transcription can provide novel insights into the molecular mechanisms of H.
      pylori-dependent gene regulation in gastric epithelial cells and may lead to new
      therapeutic approaches.

PMID- 10652360
TI  - Reentry into the cell cycle of contact-inhibited vascular endothelial cells by a
      phosphatase inhibitor. Possible involvement of extracellular signal-regulated
      kinase and phosphatidylinositol 3-kinase.
AB  - Vascular endothelial cells are unique in that they exit from the cell cycle when
      they come into contact with each other. Although the phenomenon is called
      "contact inhibition," little is known about the cellular mechanisms involved.
      Here we show that the phosphatase inhibitor sodium orthovanadate (SOV) induced
      the reentry of contact-inhibited human umbilical vascular endothelial cells
      (HUVECs) into the cell cycle and that reentry was associated with activation of
      the extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3-kinase
      (PI 3-K)/Akt pathways. SOV stimulated [(3)H]thymidine uptake of contact-inhibited
      HUVECs in a time- and dose-dependent manner. SOV-induced increase in
      [(3)H]thymidine uptake was significantly inhibited by the mitogen-activated
      protein kinase kinase inhibitor PD98059 and by the PI 3-K inhibitor LY294002. SOV
      also stimulated the expression of cyclin D1, cyclin E, and cyclin A, and the
      activity of CDK2 kinase, whereas it decreased the expression of p27(kip1). In
      marked contrast, growth media alone did not induce these changes. Furthermore,
      these SOV-induced changes were abolished by pretreatment with PD98059 and
      LY294002. SOV stimulated phosphorylation of ERK and Akt in contact-inhibited
      HUVECs, while growth media alone did not. This phosphorylation was associated
      with inhibition of phosphatase activity in the cells. Finally, overexpression of
      high cell density-enhanced protein tyrosine phosphatase 1 inhibited c-fos and
      cyclin A promoter activity. Taken together, our results suggest that in contact
      inhibited HUVECs, increased phosphatase activity suppressed the ERK and PI 3
      K/Akt pathways, resulting in exit from the cell cycle by down-regulation of
      cyclin D1, cyclin E, and cyclin A and by up-regulation of p27(kip1).

PMID- 10652361
TI  - The amyloid precursor-like protein 2 associates with the major histocompatibility
      complex class I molecule K(d).
AB  - Amyloid precursor-like protein 2 (APLP2) is a member of a protein family related
      to the amyloid precursor protein, which is implicated in Alzheimer's disease.
      Little is known about the physiological function of this protein family. The
      adenovirus E3/19K protein binds to major histocompatibility complex (MHC) class I
      antigens in the endoplasmic reticulum, thereby preventing their transport to the
      cell surface. In cells coexpressing E3/19K and the MHC K(d) molecule, K(d) is
      associated with E3/19K and two cellular protein species with masses of 100 and
      110 kDa, termed p100/110. Interestingly, p100/110 are released from the complex
      upon the addition of K(d)-binding peptides, suggesting a role for these proteins
      in peptide transfer to MHC molecules. Here we demonstrate by microsequencing,
      reactivity with APLP2-specific antibodies, and comparison of biochemical
      parameters that p100/110 is identical to human APLP2. We further show that the
      APLP2/K(d) association does not require the physical presence of E3/19K. Thus,
      APLP2 exhibits an intrinsic affinity for the MHC K(d) molecule. Similar to the
      binding of MHC molecules to the transporter associated with antigen processing,
      complex formation between APLP2 and K(d) strictly depends upon the presence of
      beta(2)-microglobulin. Conditions that prolong the residency of K(d) in the
      endoplasmic reticulum lead to a profound increase of the association and a
      drastic reduction of APLP2 transport. Therefore, this unexpected interplay
      between these unrelated molecules may have implications for both MHC antigen and
      APLP2 function.

PMID- 10652362
TI  - The carboxyl terminus of the cystic fibrosis transmembrane conductance regulator
      binds to AP-2 clathrin adaptors.
AB  - The cystic fibrosis transmembrane conductance regulator (CFTR) undergoes rapid
      and efficient endocytosis. Since functionally active CFTR is found in purified
      clathrin-coated vesicles isolated from both cultured epithelial cells and intact
      epithelial tissues, we investigated the molecular mechanisms whereby CFTR could
      enter such endocytic clathrin-coated vesicles. In vivo cross-linking and in vitro
      pull-down assays show that full-length CFTR binds to the endocytic adaptor
      complex AP-2. Fusion proteins containing the carboxyl terminus of CFTR (amino
      acids 1404-1480) were also able to bind AP-2 but did not bind the Golgi-specific
      adaptor complex AP-1. Substitution of an alanine residue for tyrosine at position
      1424 significantly reduced the ability of AP-2 to bind the carboxyl terminus of
      CFTR; however, mutation to a phenylalanine residue (an amino acid found at
      position 1424 in dogfish CFTR) did not perturb AP-2 binding. Secondary structure
      predictions suggest that Tyr(1424) is present in a beta-turn conformation, a
      conformation disrupted by alanine but not phenylalanine. Together, these data
      suggest that the carboxyl terminus of CFTR contains a tyrosine-based
      internalization signal that interacts with the endocytic adaptor complex AP-2 to
      facilitate efficient entry of CFTR into clathrin-coated vesicles.

PMID- 10652363
TI  - Identification of RNA polymerase beta' subunit segment contacting the melted
      region of the lacUV5 promoter.
AB  - Identification of the RNA polymerase functional regions involved in interactions
      with promoter is a basis for understanding the mechanism of transcription
      initiation. We have used formaldehyde cross-linking to identify a region of
      Escherichia coli RNA polymerase beta' subunit contacting lacUV5 promoter in open
      complex. Treatment of open complex with formaldehyde results in cross-linking of
      beta' and sigma(70) subunits at positions -5 and -3 on the nontemplate strand of
      the promoter DNA. These cross-links reflect specific interactions between RNA
      polymerase and promoter established in open complex. The positions of
      formaldehyde cross-links in the beta' subunit were mapped to the N-terminal
      segment (Cys(198)-Met(237)), which is contiguous to the evolutionary conserved
      region B. The proximity of the beta' and sigma cross-links suggest that the N
      terminal region of the beta' subunit, interacting with single-stranded promoter
      DNA, can cooperate with the sigma subunit in the process of open complex
      formation.

PMID- 10652364
TI  - Prolactin-releasing peptide activation of the prolactin promoter is
      differentially mediated by extracellular signal-regulated protein kinase and c
      Jun N-terminal protein kinase.
AB  - Regulation of the mitogen-activated protein kinase (MAPK) family by prolactin
      releasing peptide (PrRP) in both GH3 rat pituitary tumor cells and primary
      cultures of rat anterior pituitary cells was investigated. PrRP rapidly and
      transiently activated extracellular signal-regulated protein kinase (ERK) in both
      types of cells. Both pertussis toxin, which inactivates G(i)/G(o) proteins, and
      exogenous expression of a peptide derived from the carboxyl terminus of the beta
      adrenergic receptor kinase I, which specifically blocks signaling mediated by the
      betagamma subunits of G proteins, completely blocked the PrRP-induced ERK
      activation, suggesting the involvement of G(i)/G(o) proteins in the PrRP-induced
      ERK activation. Down-regulation of cellular protein kinase C did not
      significantly inhibit the PrRP-induced ERK activation, suggesting that a protein
      kinase C-independent pathway is mainly involved. PrRP-induced ERK activation was
      not dependent on either extracellular Ca(2+) or intracellular Ca(2+). However,
      the ERK cascade was not the only route by which PrRP communicated with the
      nucleus. JNK was also shown to be significantly activated in response to PrRP.
      JNK activation in response to PrRP was slower than ERK activation. Moreover, to
      determine whether a MAPK family cascade regulates rat prolactin (rPRL) promoter
      activity, we transfected the intact rPRL promoter ligated to the firefly
      luciferase reporter gene into GH3 cells. PrRP activated the rPRL promoter
      activity in a time-dependent manner. Co-transfection with a catalytically
      inactive form of a MAPK construct or a dominant negative JNK, partially but
      significantly inhibited the induction of the rPRL promoter by PrRP. Furthermore,
      co-transfection with a dominant negative Ets completely abolished the response of
      the rPRL promoter to PrRP. These results suggest that PrRP differentially
      activates ERK and JNK, and both cascades are necessary to elicit rPRL promoter
      activity in an Ets-dependent mechanism.

PMID- 10652365
TI  - Expression of a human beta-globin transgene in mice with the CACC motif and
      upstream sequences deleted from the promoter still depends on erythroid Kruppel
      like factor.
AB  - Mice in which the erythroid Kruppel-like Factor (EKLF) gene is inactivated die in
      fetal life due to down-regulation of the beta-globin gene. Results have suggested
      that EKLF functions through the proximal CACC motif of the beta-globin promoter.
      For example, natural mutations of this element that fail to bind EKLF give
      reduced gene expression and the ability of EKLF to activate reporter genes in co
      transfection assays is dependent on an intact CACC. Here, removal of the CACC
      motif and upstream promoter sequences from the beta-globin gene resulted in
      reduced expression in transgenic mice. However, breeding onto an EKLF-/-
      background demonstrated that a CACC-less beta-globin transgene remains highly
      dependent on EKLF. Hence, although the beta-globin gene partly depends on the
      proximal CACC motif for expression, it is unlikely that the major mechanism of
      gene activation by EKLF is through this element. We also show that a lacZ
      reporter gene linked to the beta-globin promoter, with or without the CACC box
      present, is actually expressed higher in EKLF-/- fetuses than in wild type
      animals, suggesting that EKLF may be able to act as an inhibitor of transcription
      with certain transgene configurations.

PMID- 10652366
TI  - Mutational analysis of intrinsic regions of presenilin 2 that determine its
      endoproteolytic cleavage and pathological function.
AB  - To investigate the significance of endoproteolytic processing of presenilin 2
      (PS2) on its pathological function, we constructed PS2 cDNAs causing amino acid
      substitutions or deletions around the cleavage site. We found that a PS2 mutant
      (Del3) with a 20-amino acid deletion was not endoproteolytically processed, while
      other PS2s with amino acid substitutions and short deletions were cleaved.
      Overproduction of all the mutant proteins led to a compensatory decrease of
      endogenous PS1 fragments, but did not affect the amyloid beta peptide X-42/Abeta
      X-40 ratio without the familial Alzheimer's disease mutation. The Del3 mutant did
      not exhibit significant deficits in gamma-secretase activity. The turnover rate
      of the Del3 holoprotein was the same as that of full-length PS2. These data
      suggest that the determinants of the PS2 cleavage site reside within a large
      region and that the pathological function of PS2 is exerted by familial
      Alzheimer's disease mutations not related to the cleavage of holoproteins. We
      also found that PS2 with an 18-amino acid deletion at the C-terminal end was not
      processed. Its overexpression led neither to diminished accumulation of
      endogenous PS1 fragments nor to increased production of amyloid beta peptide X
      42. The C-terminal end of PS2 seems to possess the signal for entry into the
      processing pathway.

PMID- 10652367
TI  - Potent inhibition of the master chondrogenic factor Sox9 gene by interleukin-1
      and tumor necrosis factor-alpha.
AB  - The inflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor-alpha
      (TNF-alpha) strongly inhibit the expression of genes for cartilage extracellular
      matrix proteins. We have recently obtained genetic evidence indicating that the
      high mobility group domain containing transcription factor Sox9 is required for
      cartilage formation and for expression of chondrocyte-specific genes including
      the gene for type II collagen (Col2a1). We show here that IL-1 and TNF-alpha
      cause a marked and rapid decrease in the levels of Sox9 mRNA and/or protein in
      chondrocytes. A role for the transcription factor NFkappaB in Sox9 down
      regulation was suggested by the ability of pyrrolidine dithiocarbamate, an
      inhibitor of the NFkappaB pathway, to block the effects of IL-1 and TNF-alpha.
      This role was further supported by the ability of a dominant-negative mutant of
      IkappaBalpha to block the IL-1 and TNF-alpha inhibition of Sox9-dependent Col2a1
      enhancer elements. Furthermore, forced expression of the NFkappaB subunits p65 or
      p50 also inhibited Sox9-dependent Col2a1 enhancer. Because Sox9 is essential for
      chondrogenesis, the marked down-regulation of the Sox9 gene by IL-1 and TNF-alpha
      in chondrocytes is sufficient to account for the inhibition of the chondrocyte
      phenotype by these cytokines. The down-regulation of Sox9 may have a crucial role
      in inhibiting expression of the cartilage phenotype in inflammatory joint
      diseases.

PMID- 10652368
TI  - Molecular mechanism of decreased glutathione content in human immunodeficiency
      virus type 1 Tat-transgenic mice.
AB  - Human immunodeficiency virus (HIV) progressively depletes GSH content in humans.
      Although the accumulated evidence suggests a role of decreased GSH in the
      pathogenesis of HIV, significant controversy remains concerning the mechanism of
      GSH depletion, especially in regard to envisioning appropriate therapeutic
      strategies to help compensate for such decreased antioxidant capacity. Tat, a
      transactivator encoded by HIV, is sufficient to cause GSH depletion in vitro and
      is implicated in AIDS-associated Kaposi's sarcoma and B cell lymphoma. In this
      study, we report a decrease in GSH biosynthesis with Tat, using HIV-1 Tat
      transgenic (Tat+) mice. A significant decline in the total intracellular GSH
      content in liver and erythrocytes of Tat+ mice was accompanied by decreased gamma
      glutamylcysteine synthetase regulatory subunit mRNA and protein content, which
      resulted in an increased sensitivity of gamma-glutamylcysteine synthetase to
      feedback inhibition by GSH. Further study revealed a significant reduction in the
      activity of GSH synthetase in liver of Tat+ mice, which was linearly associated
      with their GSH content. Therefore, Tat appears to decrease GSH in vivo, at least
      partially, through modulation of GSH biosynthetic enzymes.

PMID- 10652369
TI  - The FYVE domain of early endosome antigen 1 is required for both
      phosphatidylinositol 3-phosphate and Rab5 binding. Critical role of this dual
      interaction for endosomal localization.
AB  - Early endosome antigen 1 (EEA1) is 170-kDa polypeptide required for endosome
      fusion. EEA1 binds to both phosphtidylinositol 3-phosphate (PtdIns3P) and to Rab5
      GTP in vitro, but the functional role of this dual interaction at the endosomal
      membrane is unclear. Here we have determined the structural features in EEA1
      required for binding to these ligands. We have found that the FYVE domain is
      critical for both PtdIns3P and Rab5 binding. Whereas PtdIns3P binding only
      required the FYVE domain, Rab5 binding additionally required a 30-amino acid
      region directly adjacent to the FYVE domain. Microinjection of glutathione S
      transferase fusion constructs into Cos cells revealed that the FYVE domain alone
      is insufficient for localization to cellular membranes; the upstream 30-amino
      acid region required for Rab5 binding must also be present for endosomal binding.
      The importance of Rab5 in membrane binding of EEA1 is underscored by the finding
      that the increased expression of wild-type Rab5 increases endosomal binding of
      EEA1 and decreases its dependence on PtdIns3P. Thus, the levels of Rab5 are rate
      limiting for the recruitment of EEA1 to endosome membranes. PtdIns3P may play a
      role in modulating the Rab5 EEA1 interaction.

PMID- 10652370
TI  - Calcineurin controls the expression of isoform 4CII of the plasma membrane Ca(2+)
      pump in neurons.
AB  - The expression of the CII splice variant of the plasma membrane Ca(2+) ATPase 4
      (PMCA4) was down-regulated in granule neurons when they were cultured under
      conditions of partial membrane depolarization (25 mM KCl), which are required for
      long term in vitro survival of the neurons. These conditions, which cause a
      chronic increase of the resting free Ca(2+) concentration in the neurons, have
      recently been shown to promote up-regulation of the PMCA2, 3, and 1CII isoforms.
      Whereas the chronic, i.e. >3 days, Ca(2+) increase was necessary for the up
      regulation of the PMCA1CII, 2, and 3, the down-regulation of the PMCA4CII mRNA
      was already evident 1-2 h after the start of culturing in 25 mM KCl. The
      immunosuppressant calcineurin inhibitor FK506 inhibited the down-regulation of
      the PMCA4CII at both the protein and the mRNA level but did not affect the
      changes of the other PMCA pumps. Direct evidence for the involvement of
      calcineurin in the down-regulation of the PMCA4CII was obtained by overexpressing
      a truncated, constitutively active, and Ca(2+)-independent form of calcineurin;
      under these conditions, depolarization was not required for the down-regulation
      of the PMCA4CII pump. De novo synthesis of (transcription) factors was required
      for the down-regulation of the PMCA4CII mRNA. Calcineurin, therefore, controls
      the neuronal transcription of PMCA4CII, a splice variant of the pump isoforms
      that is found almost exclusively in brain.

PMID- 10652371
TI  - Elastase in intestinal mucus enhances the cytotoxicity of Shiga toxin type 2d.
AB  - Shiga toxin variant type 2d (Stx2d) produced by some strains of Shiga toxin
      producing Escherichia coli is composed of an enzymatically active A subunit and a
      B (binding) pentamer. The cytotoxicity of Stx2d is increased (activated) 10-1000
      fold for Vero cells when the toxin is incubated with mucus obtained from the
      small intestine of mice. In this study we isolated an Stx2d activator and
      identified it as a mouse elastase with strong homology to human elastase IIIB.
      Moreover, commercially available porcine pancreatic elastase preparations also
      activated Stx2d cytotoxicity although with a lower specific activity than
      isolated mouse elastase. Elastase directly nicked the Stx2d A subunit to A(1) and
      A(2), an event that did not correlate with activation. However, elastase also
      reduced the size and changed the isoelectric point of the A(2) peptide, as
      determined by SDS-polyacrylamide gel electrophoresis and two-dimensional
      electrophoresis followed by Western immunoblot analysis. This elastase-mediated
      size and charge shift in the A(2) peptide of Stx2d occurred concurrently with
      activation of the toxin. Both the reduction in size of the Stx2d A(2) peptide by
      incubation with elastase as well as the associated activation of Stx2d
      cytotoxicity were fully inhibited by elastatinal, an elastase-specific inhibitor.

PMID- 10652372
TI  - Neuronal calcium activates a Rap1 and B-Raf signaling pathway via the cyclic
      adenosine monophosphate-dependent protein kinase.
AB  - Activity-dependent regulation of neuronal events such as cell survival and
      synaptic plasticity is controlled by increases in neuronal calcium levels. These
      actions often involve stimulation of intracellular kinase signaling pathways. For
      example, the mitogen-activated protein kinase, or extracellular signal-regulated
      kinase (ERK), signaling cascade has increasingly been shown to be important for
      the induction of gene expression and long term potentiation. However, the
      mechanisms leading to ERK activation by neuronal calcium are still unclear. In
      the present study, we describe a protein kinase A (PKA)-dependent signaling
      pathway that may link neuronal calcium influx to ERKs via the small G-protein,
      Rap1, and the neuronal Raf isoform, B-Raf. Thus, in PC12 cells, depolarization
      mediated calcium influx led to the activation of B-Raf, but not Raf-1, via PKA.
      Furthermore, depolarization also induced the PKA-dependent stimulation of Rap1
      and led to the formation of a Rap1/B-Raf signaling complex. In contrast,
      depolarization did not lead to the association of Ras with B-Raf. The major
      action of PKA-dependent Rap1/B-Raf signaling in neuronal cells is the activation
      of ERKs. Thus, we further show that, in both PC12 cells and hippocampal neurons,
      depolarization-induced calcium influx stimulates ERK activity in a PKA-dependent
      manner. Given the fact that both Rap1 and B-Raf are highly expressed in the
      central nervous system, we suggest that this signaling pathway may regulate a
      number of activity-dependent neuronal functions.

PMID- 10652373
TI  - More evidence of aniseikonia in pseudophakia from another expert, with a
      "seconding" of a warning to corneal, refractive and implant surgeons.

PMID- 10652374
TI  - A comment on grand rounds #55. A case of bilateral inferior rectus restriction
      after previous unilateral inferior rectus recession for thyroid eye disease.

PMID- 10652375
TI  - Scientific essay: [Bagolini's] Striated GLASSES: a reappraisal.

PMID- 10652377
TI  - Comment/Critique of the issue

PMID- 10652376
TI  - To "Faden" or not to "Faden": is that a question?!

PMID- 10652378
TI  - Correlation of postoperative extraocular muscle suture adjustment with its
      immediate effect on the strabismic deviation.
AB  - PURPOSE: To determine if any relationship exists between the amount of adjustment
      using this surgical technique and resulting changes in the strabismic deviation.
      METHODS: A prospective database obtained between the years 1991 and 1996 was used
      to obtain retrospective clinical information and data for this study. We found in
      the database 172 postoperatively adjusted muscles in 159 patients who could be
      included in this study. All patients had their muscles adjusted postoperatively
      within the first 24 hours after surgery. Information retrieved specific to this
      study included the post-surgical, pre-adjustment strabismic deviation, the amount
      and direction of the adjustment and the resulting deviation immediately after
      this postoperative adjustment. Statistical analysis was performed on the total
      and individual muscles, as well as the direction of adjustment, comparing pre- to
      post-adjustment binocular deviations. RESULTS: There was a significant overall
      relationship between the millimeters of postoperative adjustment and the amount
      of change in the binocular deviation (p<.0001). This relationship was more linear
      under 3.0 mm of postoperative adjustment. The effect of the amount of postop'
      adjustment when advancing the muscle was significantly greater than when
      recessing the muscle (p<.0001). There was more effect per mm of postop'
      adjustment of horizontal muscles than vertical muscles (p=.004). CONCLUSIONS:
      There is a linear correlation of postoperative extraocular muscle adjustment when
      advancing an adjustable muscle but this correlation is more variable for
      adjustments over 3.0 mm. The effect of adjustment per mm is greater when
      adjusting horizontal than vertical muscles. There is a poor correlation for
      further recession. Prediction Equations are provided to enhance clinical results
      of this technique.

PMID- 10652379
TI  - The use of (a)symmetry of the rest position of the eyes under general anesthesia
      or sedation-hypnosis in the design of strabismus surgery: A favorable pilot study
      in 51 exotropia cases.
AB  - BACKGROUND AND PURPOSE: Studies support techniques of intraoperative adjustment
      under general anesthesia, of eye muscle surgery, based upon the rest position
      (deviation) to improve surgical results. None, however, have examined the
      (a)symmetry, per se, of the rest position and its influence on surgical outcomes.
      METHODS: Retrospective/prospective patient chart data and photographs taken of
      patients under anesthesia were judged for (a)symmetry of deviation and correlated
      with (a)symmetry of surgery performed on 51 exotropic patients. Two groups were
      compared: "matched" (symmetrical surgery for symmetrical deviations and
      asymmetrical surgery for asymmetrical deviations) and "opposite" in which the
      reverse was performed. RESULTS: Sensory results were "statistically
      significantly" better (p=0.027), the need for postoperative adjustment of
      adjustable sutures was "statistically significantly" less (p=0.031) and the motor
      results tended to be improved (p=0.237) ("clinically/medically significant") when
      surgery was "matched" to the deviation under anesthesia. CONCLUSION: Use of the
      (a)symmetry of deviations under anesthesia can improve surgical results.
      Therefore, the final decision as to which muscles to operate on might best be
      delayed until the time of surgery when that (a)symmetry can be observed. This
      pilot study should be confirmed by a proper completely prospective randomized
      study.

PMID- 10652380
TI  - Rod monochromatism and blue cone monochromatism: pupillary, accommodative and
      convergence reactions to darkness.
AB  - PURPOSE: To elucidate the mechanism of paradoxical pupillary constriction to
      darkness (PPCD) and the clinical characteristics facilitating this phenomenon.
      METHODS: Six rod monochromats, three blue cone monochromats, with three obligate
      BCM carriers, and ten age matched controls were studied. Pupillary responses,
      refractions and eye positions were measured with an infrared refractometer, with
      and without background room lighting while being simultaneously recorded on VHS
      (infrared) video tape from onset of darkness. RESULTS: Only rod monochromats
      displayed typical paradoxical pupillary responses. Blue cone monochromats and
      obligate BCM carriers showed reduced pupillary contraction, compared to controls,
      but no paradoxical pupillary reaction. Changes neither in accommodation nor
      convergence were found during paradoxical pupillary constriction to darkness in
      our rod monochromats. CONCLUSIONS: Paradoxical pupillary constrictions to
      darkness were seen in rod monochromats but were found not to be age or gender
      related. This constriction was accompanied neither by accommodation nor
      convergence changes. No significant differences in pupillary responses to
      darkness were observed in BCMs nor their carriers, although pupillary dilation to
      darkness seemed slightly impaired as compared to normals.

PMID- 10652381
TI  - Grand rounds #56: A case of persistent dissociated vertical deviation despite
      elevation deficiency.

PMID- 10652382
TI  - Microstrabismus in monozygotic twins.
AB  - PURPOSE: To report microesotropia in twins as a unique example of the role of
      heredity in primary microstrabismus. METHODS: Clinical records of the
      examinations of monozygotic twins with primary microstrabismus were reviewed.
      RESULT: Microstrabismus with different clinical findings was present in
      monozygotic twins. The family history and personal history of the patients were
      not significant. CONCLUSION: Microstrabismus can be seen as primary ocular
      motility problem without previous infantile esotropia or anisometropia. Genetic
      factors as well as intrauterine environment and developmental factors may affect
      sensorimotor development of the infant and cause ocular motility problems. Both
      twins should be examined for ocular motility disorders even in the absence of
      complaints.

PMID- 10652383
TI  - Normal audiologic presentations in patients with acoustic neuroma: An evaluation
      using strict audiologic parameters.
AB  - Although several studies have previously reported on patients presenting with
      "normal" audiologic parameters in acoustic neuroma, the present study is, to our
      knowledge, the first to exclusively examine in detail cases involving
      exceptionally stringent objective audiometric features. Of 369 patients with
      acoustic neuroma who were operated on between April 1980 and April 1997 by our
      group, 10 had strictly normal hearing, defined as follows: (1) pure-tone average
      < 20 dB; (2) speech discrimination score > 90%; and (3) interaural differences
      </= 10 dB at every hertz level. A high level of audiologic functioning was found
      to significantly lower the sensitivity of auditory brainstem response in the
      detection of acoustic neuroma. Magnetic resonance imaging was the only
      preoperative test exhibiting 100% sensitivity in this setting. Thus, a high level
      of clinical suspicion appears warranted in any case involving unexplained
      unilateral audiovestibular symptoms-including those instances in which strictly
      normal hearing parameters exist and are associated with negative auditory
      brainstem response findings.

PMID- 10652384
TI  - Vestibular autorotation testing in patients with benign paroxysmal positional
      vertigo.
AB  - OBJECTIVES: The current gold standard for diagnosis of benign paroxysmal
      positional vertigo (BPPV) is the Dix-Hallpike maneuver. However, because of
      fatigability, the Dix-Hallpike is often falsely normal. The objective of this
      study was to evaluate the utility of vestibular autorotation testing in the
      diagnosis of BPPV. METHODS: The charts of 210 patients at a tertiary referral
      center for vertiginous disorders were reviewed. All patients underwent clinical
      evaluation, Dix-Hallpike testing, audiometry, electronystagmography, and
      vestibular autorotation testing. The vestibular autorotation results of patients
      with BPPV were compared with the findings in patients with non-BPPV vestibular
      disorders. The sensitivity and specificity of vestibular autorotation testing in
      diagnosing BPPV were calculated. RESULTS: Ninety-one patients (42.9%) had BPPV,
      76 patients (36.2%) had vertigo of uncertain cause, 28 (13.3%) had unilateral
      vestibular hypofunction, 9 patients (4.3%) had Meniere's disease, and 2 patients
      (1.0%) had perilymphatic fistula. Patients with BPPV were 3.32 times more likely
      to have a normal horizontal gain (95% CI = 1.54-7.19). A normal horizontal gain
      is 85% sensitive but only 36% specific for BPPV. Patients with BPPV were 1.9
      times more likely to have vertical phase lead (95% CI = 0.95-3.93). Patients with
      BPPV were 2.20 times more likely to have both normal horizontal gain and vertical
      phase lead (95% CI = 1.03-4.69) The sensitivity of the combination of normal
      horizontal gain and vertical phase lead on vestibular autorotation testing is 87%
      specific but only 25% sensitive in the diagnosis of BPPV. CONCLUSION: A normal
      horizontal gain or vertical phase lead on vestibular autorotation testing in a
      vertiginous patient is suggestive of but not exclusive to a diagnosis of BPPV.
      The combination of a normal horizontal gain and vertical phase lead on vestibular
      autorotation testing is highly suggestive of the diagnosis of BPPV. Adjuvant use
      of these parameters in vestibular autorotation testing may prove to be helpful in
      the diagnosis of BPPV.

PMID- 10652385
TI  - Virtual temporal bone: creation and application of a new computer-based teaching
      tool.
AB  - The human temporal bone is a 3-dimensionally complex anatomic region with many
      unique qualities that make anatomic teaching and learning difficult. Current
      teaching tools have proved only partially adequate for the needs of the aspiring
      otologic surgeon in learning this anatomy. We used a variety of computerized
      image processing and reconstruction techniques to reconstruct an anatomically
      accurate 3-dimensional computer model of the human temporal bone from serial
      histologic sections. The model is viewed with a specialized visualization system
      that allows it to be manipulated easily in a stereoscopic virtual environment.
      The model may then be interactively studied from any viewpoint, greatly
      simplifying the task of conceptualizing and learning this anatomy. The system
      also provides for simultaneous computer networking that can bring distant
      participants into a single shared virtual teaching environment. Future directions
      of the project are discussed.

PMID- 10652386
TI  - Allergic management of Meniere's disease: an outcome study.
AB  - The effect of allergy immunotherapy and elimination of suspected food allergens
      was evaluated in patients with Meniere's disease. A total of 137 patients with
      Meniere's disease for whom allergy treatment had been recommended were identified
      and were mailed and returned a symptoms questionnaire. One hundred thirteen had
      received allergy treatment; 24 did not have treatment and served as a control
      group. Information regarding history, signs and symptoms, allergy test results,
      and audiologic data were obtained by chart review. The 113 patients treated with
      desensitization and diet showed a significant improvement from pretreatment to
      posttreatment in both allergy and Meniere's symptoms. Ratings of frequency,
      severity, and interference with everyday activities of their Meniere's symptoms
      also appeared better after allergy treatment than ratings from the control group
      of untreated patients. Vertigo control results, by use of the American Academy of
      Otolaryngology-Head and Neck Surgery classification, categorized 47.9% as class A
      or B. Hearing was stable or improved in 61.4%. Patients with Meniere's disease
      can show improvement in their symptoms of tinnitus and vertigo when receiving
      specific allergy therapy. The inner ear may be the target, directly or
      indirectly, of an allergic reaction.

PMID- 10652387
TI  - Postmeningitic ossification in pediatric cochlear implantation.
AB  - OBJECTIVE: The goals of this study were to retrospectively review high-resolution
      CTs (HRCTs) of pediatric postmeningitic cochlear implant recipients and to
      correlate results with surgical findings. METHODS: HRCTs of 20 children (11
      months to 12 years old) who underwent implantation with multichannel devices were
      reviewed. Results were correlated with the degree of ossification observed at
      surgery. RESULTS: Ninety percent of subjects required drilling of ossified bone
      within the basal turn at surgery. HRCT of the cochleas suggested ossification
      within the basal turn in 45% (50% sensitivity). Ossification of the lateral
      semicircular canal on HRCT was present in 72% (77% sensitivity). Five of 6 cases
      without radiographic evidence of ossification had positive findings at surgery.
      CONCLUSION: Ossification is a common occurrence in postmeningitic deaf children.
      Ossification of the lateral semicircular canal on HRCT is a more sensitive
      measure for predicting ossification than evidence of cochlear involvement.
      Absence of ossification on HRCT is no guarantee of cochlear patency at the time
      of implantation.

PMID- 10652388
TI  - Effects of external beam radiation on the allograft dermal implant.
AB  - OBJECTIVE: The purpose of this study was to define the effects of external beam
      radiation (EBR) on AlloDerm (LifeCell Corp) through the analysis of graft
      thickness, fibroblast recellularization, and neovascularization as a function of
      time. METHODS AND MATERIAL: Thirty-six male Sprague-Dawley rats (n = 36) were
      randomly assigned to 1 of 4 groups (A, B, C, and D). AlloDerm was implanted
      subcutaneously into the hind legs of each rat, and 20 Gy of EBR was administered
      to one side. Grafts harvested 1, 2, 4, and 12 weeks after radiation were
      subjected to blinded histologic analysis. RESULTS: In groups A, B, and C, the
      irradiated grafts showed a significant decrease in recellularization versus
      nonirradiated (P < 0.001). At 12 weeks (group D), recellularization equalized,
      but neovascularization was significantly less (P = 0.048) in the irradiated
      group. Graft thickness was unaffected. CONCLUSIONS: In the rat model, EBR of the
      implanted AlloDerm graft hinders recellularization in the early posttreatment
      period. However, EBR did not adversely affect graft thickness, recellularization
      or ultimate graft survival.

PMID- 10652389
TI  - Tumor grade, microvessel density, and activities of malate dehydrogenase, lactate
      dehydrogenase, and hexokinase in squamous cell carcinoma.
AB  - Squamous cell carcinomas were evaluated with respect to tumor differentiation
      (through use of hematoxylin and eosin stain), microvessel density (through use of
      CD-34 immunocytochemical stain), and magnitudes of malate dehydrogenase (MDH),
      hexokinase, and lactate dehydrogenase (LDH) enzyme activities. Direct
      correlations were found between tumor grade, MDH activity, and microvessel
      density. Direct correlations were also found between hexokinase activity and MDH
      activity and microvessel density. Inverse correlations were found between LDH
      activity and both tumor grade and MDH activity. These results suggest that the
      high rate of glucose utilization (indicated by hexokinase activity) found in more
      poorly differentiated tumors has a higher component of aerobic oxidative
      metabolism (indicated by MDH activity) and a relatively lower contribution from
      anaerobic metabolism (indicated by LDH activity) than do the rates found in more
      differentiated tumors. It is also suggested that as the glycolytic rate
      increases, more pyruvate goes into the Krebs cycle than into lactate. The
      availability of glucose-derived pyruvate for oxidative metabolism would mean less
      of a dependency on glutamine as a carbon source in squamous cell carcinoma.

PMID- 10652390
TI  - Frey's syndrome and parotidectomy flaps: A retrospective cohort study.
AB  - Gustatory sweating, also known as Frey's syndrome, is a recognized phenomenon
      after parotidectomy. The incidence of clinically significant gustatory sweating
      may be dependent on the thickness of the skin flap that is elevated at the time
      of surgery. Dissection in the subcutaneous level or the deeper sub-superficial
      musculoaponeurotic system level are 2 commonly used techniques in the operation.
      Twenty-eight patients were prospectively evaluated for Frey's syndrome after
      superficial parotidectomy. Thirteen patients underwent subcutaneous and 15
      patients sub-superficial musculoaponeurotic system flap elevation. The overall
      incidence of gustatory sweating was determined, and a comparison of the two
      surgical techniques was assessed subjectively by patient interview-questionnaire
      and objectively evaluated with starch-iodine testing.

PMID- 10652391
TI  - Evaluation of a new procedure for nasal alar rim and valve collapse: nasal alar
      rim reconstruction.
AB  - OBJECTIVE: A new operative technique to improve nasal valve collapse by placement
      of cartilage struts along the alar rim was compared with the standard nasal valve
      cartilage graft (NVG) technique. METHODS AND PATIENTS: A retrospective study of
      consecutive patients with nasal valve collapse was performed at Stanford
      University Medical Center. Seventy-nine patients with nasal valve collapse
      underwent reconstruction with either the classic NVG technique or a newly
      developed nasal alar rim reconstructive (NARR) procedure. The mean age of the
      NARR group was 50.13 years (SD +/- 9.40), with 36 men (92.3%) and 3 women (7.7%).
      The mean age of the NVG group was 52. 14 years (SD +/- 10.83), with 36 men (90%)
      and 4 women (10%). MAIN OUTCOME MEASURES: These included functional and
      subjective evaluation of nasal valve collapse. RESULTS: Forty patients (50.6%)
      underwent the NVG technique, and 39 (49.4%) received the NARR procedure. The NVG
      technique revealed 0% worsened, 15.0% (6/40) unchanged, 25.0% (10/40) improved,
      and 60% (24/40) free of obstruction. The NARR procedure revealed 2.6% worsened,
      2.6% unchanged, 7.7% improved, and 87.1% free of obstruction. CONCLUSIONS: Nasal
      alar cartilage struts placed along the caudal alar rim offers sufficient support
      to the alar rim and valve area. This procedure appears to be as effective as
      currently available reconstructive alternatives, while being technically
      uncomplicated.

PMID- 10652392
TI  - Toronto Facial Grading System: interobserver reliability.
AB  - The Toronto Facial Grading System (TFGS) is an observer scale for rating facial
      nerve dysfunction. The TFGS scores aspects of resting symmetry, symmetry of
      voluntary movement, and synkinesis for each division of the face (subscores) and
      then provides calculated total scores and an overall composite score of facial
      function. The developers of the scale have validated its sensitivity for
      identifying small changes in facial dysfunction and the independence of the
      different components measured. Herein we report our results in a study of
      interobserver reliability using the TFGS. Twenty-five patients from the
      Massachusetts Eye and Ear Infirmary Facial Nerve Center with varying degrees of
      facial paresis, paralysis, and synkinesis were videotaped, and the video
      recordings were scored by 5 independent observers using the TFGS. Intraclass
      correlation coefficients (kappa) and 95% confidence intervals were calculated for
      subscores and for each total and composite score. Intraclass correlation
      coefficients ranged from 0.59 to 0.85, all considered substantial to near-perfect
      agreement between observers. We believe the TFGS is superior to other scales by
      virtue of its sensitivity, comprehensiveness, ease of use, and interobserver
      reliability. The TFGS presently appears to be the best option in those situations
      in which accurate and precise documentation of facial function is required.

PMID- 10652393
TI  - Bilateral simultaneous orbital decompression for Graves' orbitopathy with a
      combined endoscopic and Caldwell-Luc approach.
AB  - Graves' orbitopathy can lead to cosmetic deformity, orbital pain, and visual
      impairment. Surgical intervention can improve proptosis, cosmetic appearance of
      the eyelids, vision, and orbital pain with minimal morbidity. Ten patients with
      dysthyroid orbitopathy underwent concurrent bilateral orbital decompressions. Of
      these, 9 underwent simultaneous bilateral endoscopic and transantral
      decompressions, and 1 had only bilateral endoscopic decompressions. Medical
      management of keratopathy was attempted before surgery. All patients were
      previously treated with radioiodine and high-dose corticosteroids, and 2 patients
      had prior low-dose orbital irradiation. Preoperative and postoperative visual
      acuity, color vision testing, and measurement of proptosis were recorded for all
      patients. In addition, photographs and CT scans of the orbit and sinuses were
      done. After surgery, visual acuity improved in 8 patients and remained unchanged
      in 2 patients. Diplopia in the primary and downward gaze improved in 1 patient
      and remained unchanged in the 3 others who had it before surgery. Color vision
      deficits in the blue/yellow range were present in 8 patients before surgery and
      all reversed within 2 weeks after surgery. Proptosis decreased by an average of
      4.83 mm (range 4-7 mm) in patients undergoing the combined decompression and
      decreased by 4 mm in the 1 patient who had the endoscopic decompression only.
      Ethmoid sinusitis developed in 1 patient but resolved with oral antibiotics, and
      another patient had an asymmetric result requiring additional unilateral surgery,
      which corrected the asymmetry. Overall, this approach avoids external incisions
      and allows excellent visualization in the regions of the orbital apex and ethmoid
      roof, facilitating maximal decompression without the increased risk of bleeding
      or visual disturbances.

PMID- 10652394
TI  - Remifentanil-based anesthesia versus a propofol technique for otologic surgical
      procedures.
AB  - Otologic procedures require a still surgical field and are associated with a 50%
      incidence of emetic symptoms. Propofol reduces nausea and vomiting but not
      intraoperative movement. This study compares a remifentanil/propofol anesthetic
      to a propofol/fentanyl combination to determine which provides the best
      perioperative conditions for otologic microsurgery. Eighty healthy patients were
      randomly assigned to receive one of the anesthetic combinations. Demographic
      data, hemodynamic variables, movement, and bispectral index monitoring values in
      addition to anesthetic emergence, nausea, vomiting, pain, and other recovery
      variables were compared between groups with appropriate statistical methods. Both
      groups were similar. Times to eye opening (7.7 +/- 0.7 vs 12.4 +/- 1.2 minutes)
      and extubation (9.8 +/- 0.9 vs 12.4 +/- 1.0 minutes) were shorter with
      remifentanil. This group also had lower hemodynamic variables and movement (23%
      vs 65%) under anesthesia. Postoperative pain was mild in both groups, but
      remifentanil patients had more than the propofol group. All other postoperative
      parameters were similar. Remifentanil-based anesthesia produces better
      hemodynamic stability, less movement, and faster emergence after otologic
      surgery, with propofol's antiemetic effect, for the same cost.

PMID- 10652395
TI  - Outcomes of septoplasty.
AB  - A prospective nonrandomized study of consecutive patients presenting to the
      Massachusetts Eye and Ear Infirmary for septoplasty was conducted to evaluate
      patient-based outcome. Patients received statistically validated measures of
      general health status (Short Form-12) and nasal specific health (Nasal Health
      Survey) before and 6 and 12 months after surgery. Multiple perioperative patient-
      and surgeon-dependent treatment variables were also evaluated to determine the
      impact on outcome. A total of 161 patients were entered into the study, and 93
      were available for statistical analysis. At 9 months the mean follow-up (range 6
      12 months), both symptom and medication subscores of the Nasal Health Survey, and
      the total score demonstrated significant improvement (P < 0.05); 71% of patients
      had clinically significant improvement as determined by at least a 50% decrease
      in duration of nasal symptoms. Measures of general health did not differ
      significantly from normative values at baseline and did not change after surgical
      intervention. Predictor analysis revealed that female gender and a history of
      previous nasal surgery predicted worse outcome.

PMID- 10652396
TI  - Postoperative treatment of the patient with obstructive sleep apnea.
AB  - OBJECTIVE: The postoperative management of patients with obstructive sleep apnea
      syndrome (OSAS) has been based primarily on the potential loss of the airway. Our
      hypothesis is that not all patients with OSAS require placement in the intensive
      care unit after surgery. METHODS: We undertook a prospective, nonrandomized study
      (N = 38). Data included demographics, polysomnograms, body mass index (BMI), and
      postoperative course, including any complications within 72 hours. RESULTS: The
      average respiratory disturbance index was 66, and the average BMI was 29. The
      average preoperative and postoperative maximal arterial oxygen desaturation
      values were 82% and 94%, respectively. Patients with BMIs less than 35 did not
      have desaturation values below 90%. No complications occurred. DISCUSSION: Within
      the first 72 hours after surgery, no complications were observed in our study
      groups. Patients with BMIs greater than 35 were at increased risk for
      postoperative desaturations. The uncomplicated OSAS patient, one without
      significant comorbid factors, can be treated in a safe and prudent fashion
      outside of an intensive care unit.

PMID- 10652397
TI  - Botulinum toxin treatment for symptomatic Frey's syndrome.
AB  - Gustatory sweating, or Frey's syndrome, usually occurs after surgery or trauma to
      the parotid gland as a result of inappropriate parasympathetic cholinergic
      innervation of cutaneous sympathetic receptors. Numerous medical and surgical
      treatments have been proposed to prevent or treat this condition. The results,
      overall, have been unsatisfactory. Botulinum toxin is a relatively new treatment
      modality for Frey's syndrome. We review the literature and present our experience
      with 7 patients successfully treated with intradermal injections of botulinum
      toxin (Botox). Our technique and dosing are described. In all treated patients
      gustatory sweating ceased in the area injected with botulinum toxin. In 6
      patients, symptoms reappeared, and additional injections were needed up to 4
      times, at 6- to 8-month intervals. All patients now have been free of symptoms
      for a long period of time (mean 12.1 months). We strongly recommend intradermal
      injections of botulinum toxin as a safe, efficacious treatment for gustatory
      sweating.

PMID- 10652398
TI  - Assessment of auditory cortex activation with functional magnetic resonance
      imaging.
AB  - OBJECTIVE: The goal was to assess auditory cortex activation evoked by pure-tone
      stimulus with functional MRI. METHODS: Five healthy children, aged 7 to 10 years,
      were studied. Hearing evaluation was performed by pure-tone audiometry in a sound
      treated room and in the MRI scanner with the scanner noise in the background.
      Subjects were asked to listen to pure tones (500, 1000, 2000, and 4000 Hz) at
      thresholds determined in the MRI scanner. Functional image processing was
      performed with a cross-correlation technique with a correlation coefficient of
      0.5 (P < 0.0001). Auditory cortex activation was assessed by observing activated
      pixels in functional images. RESULTS: Functional images of auditory cortex
      activation were obtained in 3 children. All children showed activation in
      Heschl's gyrus, middle temporal gyrus, superior temporal gyrus, and planum
      temporale. The number of activated pixels in auditory cortexes ranged from 4 to
      33. CONCLUSIONS: Functional images of auditory cortex activation evoked by pure
      tone stimuli are obtained in healthy children with the functional MRI technique.

PMID- 10652399
TI  - Effect of long-term electrical stimulation on motor recovery and improvement of
      clinical residuals in patients with unresolved facial nerve palsy.
AB  - PURPOSE: This study investigated the efficacy of a pulsatile electrical current
      to shorten neuromuscular conduction latencies and minimize clinical residuals in
      patients with chronic facial nerve damage caused by Bell's palsy or acoustic
      neuroma excision. SUBJECTS: The study group included 12 patients (mean age 50.4
      +/- 12. 3 years) with idiopathic Bell's palsy and 5 patients (mean age 45.6 +/-
      10.7 years) whose facial nerves were surgically sacrificed. The mean time since
      the onset of paresis/paralysis was 3.7 years (range 1-7 years) and 7.2 years
      (range 6-9 years) for the Bell's and neuroma excision groups, respectively.
      METHOD AND PROCEDURES: Motor nerve conduction latencies, House-Brackmann facial
      recovery scores, and a 12-item clinical assessment of residuals were obtained 3
      months before the onset of treatment, at the beginning of treatment, and after 6
      months of stimulation. Patients were treated at home for periods of up to 6 hours
      daily for 6 months with a battery-powered stimulator. Stimulation intensity was
      kept at a submotor level throughout the study. Surface electrodes were secured
      over the most affected muscles. Groups and time factors were used in the analyses
      of the 3 outcome measures. RESULTS: No statistical differences were found between
      the two diagnostic groups with respect to any of the 3 outcome measures. Mean
      motor nerve latencies decreased by 1.13 ms (analysis of variance test,
      significant P = 0.0001). House-Brackmann scores were also significantly lower
      (Wilcoxon signed rank test, P = 0.0003) after treatment. Collective scores on the
      12 clinical impairment measures decreased 28.7 +/- 8.1 points after 6 months
      [analysis of variance test, significant P = 0.0005). Eight patients showed more
      than 40% improvement, 4 better than 30%, and 5 less than 10% improvement in
      residuals score. CONCLUSION: These data are consistent with the notion that long
      term electrical stimulation may facilitate partial reinnervation in patients with
      chronic facial paresis/paralysis. Additionally, residual clinical impairments are
      likely to improve even if motor recovery is not evident.

PMID- 10652400
TI  - Head and neck squamous cell carcinoma: better to be young.
AB  - Most head and neck squamous cell carcinoma patients are elderly, with few younger
      than 40 years. Controversy exists in the literature regarding outcomes for
      younger patients. The goal of this research project was to compare baseline
      features and outcomes for young patients (</=40 years), middle-aged patients (41
      64 years), and old patients (>/=65 years). To investigate the relationship
      between age and important presenting features and outcomes, 1160 recently
      diagnosed patients first treated at Washington University between 1980 and 1991
      were identified from an existing database. Full 5-year survival information was
      available for 1030 patients (89%). Overall, the 5-year survival rate was 46%
      (478/1030); young patients (65%, 26/40) had a significantly better survival rate
      than middle-aged (52%, 292/566) or old patients (38%, 160/424) (chi(2) = 24.5; P
      = 0. 001). Survival was also related to smoking, comorbidity, primary site, TNM
      stage, and nodal disease. Age remained a significant factor even after we
      controlled for these other factors. Young patients developed fewer recurrent and
      new primary tumors. We conclude that young patients have a much better overall
      prognosis than older patients. The reasons for this difference are unclear, but
      it appears that the impact of age goes beyond an actuarial effect.

PMID- 10652401
TI  - Oral appliances for the treatment of snoring and obstructive sleep apnea.
AB  - Oral appliances have been used by dentists for several decades to treat snoring
      and obstructive sleep apnea. Although these devices are regulated by the Food and
      Drug Administration, most have undergone only sparse clinical testing for
      efficacy and safety. Most otolaryngologists are not well-versed in their
      applicability as treatment options. This review summarizes the historical
      development of oral appliances, the types of available devices, the current
      literature regarding devices, and pertinent regulatory issues as they relate to
      the ongoing debate over appliance use and potential misuse.

PMID- 10652402
TI  - Powered surgical instruments for laryngeal surgery.

PMID- 10652403
TI  - Chest wall mass after pectoralis major myocutaneous flap reconstruction.

PMID- 10652404
TI  - Guillain-Barre syndrome presenting as bilateral vocal cord paralysis.

PMID- 10652405
TI  - Disseminated blastomycosis presenting as a neck mass.

PMID- 10652406
TI  - Evaluation of implant losses and skin reactions around extraoral bone-anchored
      implants: A 0- to 8-year follow-up.
AB  - This is an 8-year follow-up of a group of 214 patients who underwent surgical
      insertion of titanium implants in the mastoid process for the retention of bone
      anchored hearing aids and auricular prostheses. The skin reactions around the
      implants and the various factors dealing with implant loss were evaluated. The
      number of patients who never had any episode of adverse skin reactions during the
      8-year period is 70% and is about the same as previously reported. The frequency
      and degree of adverse skin reactions were noted to be decreasing with time. The
      young age group had the highest incidence of adverse skin reactions, and this
      high frequency is consistent with results of earlier reports. None of the
      remaining group of patients (30%) who had 1 or more episodes of adverse skin
      reactions lost their implants because of this problem; most implant losses were
      primarily the result of loss of integration. The probability of losing an implant
      because of adverse skin reactions is quite low; however, these skin reactions, if
      left untreated, may eventually lead to implant loss or withdrawal.

PMID- 10652407
TI  - Anterior approaches in juvenile nasopharyngeal angiofibromas with intracranial
      extension.
AB  - Although surgery is regarded as the mainstay of treatment for juvenile
      nasopharyngeal angiofibromas (JNAs), ancillary treatment modalities such as
      radiotherapy and on rare occasions chemotherapy are still recommended by many for
      intracranial extension with apparent radiologic involvement of the cavernous
      sinus and internal carotid artery. Further, most authors undertaking surgical
      excision of this subgroup of patients would recommend a lateral or combined
      frontal and lateral approach for its removal. In a series of 49 cases of JNA, 14
      were found during surgery to have intracranial extradural extension; the anterior
      approach was used for their removal. Although in these cases, on radiography the
      cavernous sinus often looked to be invaded and the internal carotid artery was
      displaced superolaterally, there was no difficulty in establishing a plane of
      dissection. Total removal was achieved in 11 of the 14 cases with a single-stage
      procedure. Of the 3 cases with residual tumor, only 1 occurred intracranially.
      Removal was achieved by a subtemporal approach in this case. For the extracranial
      residual tumors 1 required a midface degloving and the other, with a 1-cm
      residual tumor in the nasopharynx, has been treated conservatively for 6 years
      with no evidence of growth. No deaths or significant complications have occurred,
      and radiotherapy has not been required. We conclude that JNAs are tumors with a
      predilection for spread but that rarely invade dura, acting instead to displace
      it. We believe that surgery is the method of choice for treating these lesions
      and that an anterior surgical approach with microsurgical techniques should be
      used in the first instance. In the last 2 cases we preferred a midface degloving
      technique to avoid facial scarring and because this approach allows a widening of
      the surgical field if needed by the performance of bilateral maxillary free bone
      flaps. On the rare occasion that a lateral approach, with its attendant permanent
      conductive hearing loss, is found to be necessary for total tumor removal, this
      can be done as a staged procedure. This may be necessary when the tumor has
      spread lateral to the horizontal internal carotid artery.

PMID- 10652408
TI  - Usefulness of the C1 transverse process as a reference guide in the dissection of
      the upper lateral neck.
AB  - In this investigation we dissected 3 cadavers with the lateral cervical approach
      to assess the usefulness of the transverse process of the atlas (TPA) as a
      reference guide in the upper lateral neck. Our results indicate that all the
      important structures in this space can be identified systematically. Lateral to
      the TPA sits the posterior belly of the digastric muscle, the stylohyoid muscle,
      and the occipital artery. Anterior to the TPA, the styloid process can be
      exposed. The internal jugular vein and cranial nerves X, XI, and XII sit between
      the styloid process and the TPA. Superior to the TPA, tracing the carotid sheath
      upward, the carotid canal and jugular foramen can be reached. Anteroinferior to
      the jugular foramen, the hypoglossal nerve emerges from the cranial cavity
      through the hypoglossal canal. Posterior to the TPA, the suboccipital triangle
      can be recognized. Within the triangle, the vertebral artery and its accompanying
      venous complex can be identified.

PMID- 10652409
TI  - Electroneurographic facial muscle pattern in Bell's palsy.
AB  - To study the electroneurographic facial muscle pattern in Bell's palsy over time,
      electroneurographic recordings in the frontalis, orbicularis oculi, nasalis, and
      mentalis muscle regions were performed early (mean, day 11) and 1 and 3 months
      after the onset of the condition in 30 consecutive patients. The correlation
      between facial muscle electroneurographic recordings over time was also
      calculated. An additional aim was to assess whether further prognostic
      information could be obtained by electroneurographic recordings in more than one
      facial region. The recovery pattern was similar in all 4 facial regions.
      Initially, the correlation between the facial recordings was weak (r = 0.20
      0.27), but it was improved at follow-up examinations (r = 0.33-0.65). Favorable
      outcome in 23 of 24 patients (96%) could have been predicted by the initial
      nasalis and/or mentalis recordings. The gap between patients with favorable
      outcome and patients with unfavorable outcome increased when the average
      electroneurography values were calculated from 1, 2, and 4 muscle recordings (4%,
      8%, and 15%, respectively). Our results indicate that in Bell's palsy,
      electroneurographic examination of more than one facial muscle region may add
      prognostic information and that the degree of degeneration is initially different
      in the nerve branches.

PMID- 10652410
TI  - Nasal polyposis: role of subclinical delayed food hypersensitivity.
AB  - Nasal polyposis is a common problem in otolaryngology. The cause remains unclear,
      and treatment with medication and surgery is often unsatisfactory. We present our
      controlled study, which suggests a strong association between food allergy and
      nasal polyposis. The study was conducted in 2 parts. A postal survey of 900
      patients with nasal polyps showed 53 respondents (5.9%) had a known food allergy.
      In the prospective study, 80 nasal polyp patients and 36 control subjects
      completed intradermal tests for food allergy. Sixty-five nasal polyp patients
      (81%) and 4 control subjects (11%) had positive intradermal food test results.
      This is highly significant. We believe that food allergy may play a significant
      role in the pathogenesis of nasal polyposis and should be further studied.

PMID- 10652411
TI  - Schwannoma of the greater superficial petrosal nerve.

PMID- 10652412
TI  - Use of [F]-fluorodeoxyglucose positron emission tomography in monitoring response
      of recurrent neurotropic desmoplastic melanoma to radiotherapy.

PMID- 10652413
TI  - Giant external carotid artery pseudoaneurysm presenting as a parotid mass.

PMID- 10652414
TI  - Localized amyloid tumor of the nasopharynx.

PMID- 10652415
TI  - Epiglottic cyst.

PMID- 10652416
TI  - Postoperative cholesterol cyst of the mastoid.

PMID- 10652417
TI  - UICC study group on basic and clinical cancer research: Animal models for the
      natural history of cancer. Meeting held at Woods Hole, MA (USA), June 21-23,
      1999. International Union Against Cancer.

PMID- 10652418
TI  - fhit Alterations in endometrial carcinoma and hyperplasia.
AB  - The fhit (fragile histidine triad) gene on chromosome 3p14.2 is a candidate
      tumour-suppressor gene; its abnormal transcripts are detected in several human
      cancers. To define the role of the fhit gene in the development of endometrial
      cancer, we examined 39 endometrial carcinomas for the presence of fhit gene
      alterations. fhit transcripts were analyzed by RT-PCR and direct sequencing. Loss
      of fhit transcript was observed in 6/39 (15%) tumours. Aberrant fhit transcripts,
      with deletions and/or insertions, were observed in 7/39 (18%) tumours but not in
      any normal endometrium. Allelic losses at D3S1300 and D3S4103, both located
      within intron 5 of fhit, were detected in 6/25 (24%) and 5/22 (23%) informative
      cases respectively. Expression of fhit protein was detected by
      immunohistochemistry; fhit protein was strongly expressed in 8/8 proliferative
      phase and 5/5 secretory phase endometria, also in 5/5 atrophic endometria; and it
      was strongly expressed in 6/6 simple hyperplasias without atypia, 6/6 complex
      hyperplasias without atypia, and II/II complex hyperplasias with atypia. In
      contrast, loss or reduced expression of fhit protein was observed in 13/27 (48%)
      endometrial adenocarcinomas. The impaired expression of the fhit protein was
      significantly correlated with the histological grade of the tumours. The present
      data suggest that inactivation of the fhit gene is an important genetic event
      associated with the genesis of endometrial carcinoma, especially with tumours of
      higher histological grade, which are believed to emerge directly from an atrophic
      endometrium.

PMID- 10652419
TI  - Antibodies against oncoproteins E6 and E7 of human papillomavirus types 16 and 18
      in cervical-carcinoma patients from Russia.
AB  - Certain human papillomaviruses (HPV), mainly types 16 and 18, have been widely
      recognized as an essential etiologic factor for the development of carcinoma of
      the uterine cervix. The early HPV proteins E6 and E7 are consistently expressed
      in the tumor cells, and cervical-carcinoma patients can develop antibodies
      against these oncoproteins. For cervical-carcinoma patients from Eastern Europe
      and Russia, detailed information on HPV DNA prevalence and HPV-specific immune
      responses is limited. The presence of HPV DNA in 128 Russian cervical-carcinoma
      tissues was determined: HPV16 DNA was found in 78% of the cases, HPV18 DNA in
      14%, and no HPV-DNA in 10%. Using 4 recently developed sensitive and highly
      specific second-generation enzyme-linked immunosorbent assays, we also analyzed
      the prevalence of antibodies against HPV16 and -18 E6 and E7 proteins in sera
      from 95 cervical-carcinoma patients, from 61 female patients with non-HPV
      associated tumors and from 83 female healthy controls. The strong association of
      E6 and/or E7 antibodies with cervical carcinoma was confirmed, with 36%
      seropositives in this group against only 2% in the control groups. The detected
      antibodies are highly HPV-type-specific since all 26 HPV16-E6- or -E7-antibody
      positive patients had HPV16 DNA in their tumor and 6 out of the 8 HPV18-antibody
      positive patients had HPV18 DNA. Antibody responses to HPV16 E6 and E7 appear to
      be dependent on clinical stage of the disease, with 21% seropositives found in
      FIGO stage I, 42% in stage II and 53% in stage III. Antibody response to HPV16 E6
      is more frequent than to E7, especially in early stages.

PMID- 10652420
TI  - Evaluation of adult T-cell leukemia/lymphoma incidence and its impact on non
      Hodgkin lymphoma incidence in southwestern Japan.
AB  - The incidence of adult T-cell leukemia/lymphoma (ATL) and its impact on that of
      total non-Hodgkin lymphoma (NHL) were evaluated in Nagasaki, an area in
      southwestern Japan where human T-cell lymphotropic virus type I (HTLV-I) is
      endemic. The first study area comprised 4 towns located on the K Islands, which
      had a population of 26,870 in 1990. The overall HTLV-I seroprevalence estimated
      from the serologic survey of 18,485 subjects was 16.2%. By using the data from
      the Nagasaki Prefectural Cancer Registry (NPCR) and reviewing clinical and
      laboratory information, we identified 40 cases of ATL and 35 cases of other NHL
      diagnosed between 1985 and 1995. The crude annual incidence of ATL among 100,000
      HTLV-I carriers aged 30 or older was estimated at 137.7 for men and 57.4 for
      women, with a significant sex difference after adjustment for age (rate ratio =
      2.50, 95% confidence interval 1.32-4.73). The cumulative risk from 30 to 79 years
      of age was estimated at approximately 6.6% for men and 2.1% for women. Among the
      entire population, ATL accounted for 51 to 59% of the total NHL incidence,
      showing the strong impact of HTLV-I infection. The second study area comprised
      the whole of Nagasaki Prefecture (total population in 1990 = 1.56 million).
      Between 1985 and 1995, 989 cases of ATL and 1,745 cases of other NHL were
      registered in the NPCR. The world age-standardized annual incidence rate of ATL
      per 100,000 persons aged 30 or older was estimated at 10.5 for men and 6.0 for
      women, which accounted for approximately 37 to 41% of the total NHL incidence.

PMID- 10652421
TI  - Cancer incidence in Karachi, Pakistan: first results from Karachi Cancer
      Registry.
AB  - No cancer incidence data from Pakistan have been published in the 5 decades since
      independence. Incidence data for the period 1995-1997 from the population of the
      Karachi South district (1.7 million) are presented here. A total of 4,268 new
      cancer cases were registered during this period: 2,160 cases in males and 2,108
      cases in females. Overall, 95.3% of the incident cases were microscopically
      verified. The incidence rates for all cancers combined were 80.5 per 100,000
      (crude) and 136.7 per 100,000 (age- standardised rates [ASR]) for males and 91.8
      (crude) and 163.2 per 100,000 (ASR) for females. In males, lung cancer (ASR 20.3)
      was the most frequently recorded malignancy followed by oral cavity (ASR 13.8)
      and larynx cancer (ASR 8.6). In females, breast was the most common site of
      cancer, accounting for one third of female cancers (ASR 51.7), followed by oral
      cavity (ASR 14.1) and ovarian cancer (ASR 10.2). Karachi reports the highest
      incidence of breast cancer for any Asian population, except Jews in Israel.
      Tobacco smoking is estimated to be responsible for 40% of cancers in males and
      tobacco chewing for a further substantial proportion of head and neck cancers.

PMID- 10652422
TI  - Regulation of telomerase by alternate splicing of human telomerase reverse
      transcriptase (hTERT) in normal and neoplastic ovary, endometrium and myometrium.
AB  - Telomerase extends telomeric repeats at the ends of linear chromosomes, thereby
      prolonging the replicative capacity of cells. To investigate possible regulatory
      mechanisms of telomerase, we measured telomerase enzyme activity, human
      telomerase RNA (hTR) and human telomerase reverse transcriptase (hTERT) mRNA in
      normal and neoplastic ovary, endometrium and myometrium. Telomerase activity was
      detected in most malignancies and in normal endometrium but not in myometrial
      leiomyoma, normal myometrium or normal ovary. hTR was expressed in all tissue
      samples. hTERT mRNA was expressed in many tissue samples, and no tissue sample
      exhibited telomerase activity without expressing hTERT mRNA. However, the
      presence of hTR and hTERT mRNA was not sufficient for telomerase activity.
      Alternate splicing of hTERT produced mRNAs lacking critical reverse transcriptase
      (RT) motifs in both normal and neoplastic tissues. Only tissues expressing hTERT
      containing complete A and B RT motifs demonstrated telomerase activity. Finally,
      several normal ovarian tissues and myometrial leiomyomas lacked telomerase
      activity despite expressing hTR and hTERT containing complete A and B RT motifs.
      This was not seen in ovarian and myometrial malignancies, where the expression of
      hTR and hTERT containing complete A and B RT motifs was sufficient for telomerase
      activity. We conclude that in ovarian and uterine tissues, the presence of a
      functional telomerase complex is regulated at multiple levels, including hTERT
      transcription and alternative splicing of hTERT transcripts. The lack of
      telomerase activity in several normal but not malignant tissues expressing hTR
      and hTERT containing complete A and B RT motifs suggests that there are further
      mechanisms for suppressing telomerase activity downstream of hTERT transcription
      and mRNA splicing, and these mechanisms have been lost during neoplastic
      transformation.

PMID- 10652423
TI  - A region of common deletion in 22q13.3 in human glioma associated with
      astrocytoma progression.
AB  - Loss of heterozygosity for chromosome 22 (LOH 22) occurs in gliomas of all
      malignancy grades. Neurofibromatosis type 2 (NF2) patients are at increased risk
      of developing a glioma. However, the NF2 gene in 22q12.2 is not involved in
      glioma tumorigenesis. To detect additional regions on chromosome 22 that may
      harbor tumor suppressor genes important in glioma tumorigenesis, we determined
      LOH 22 profiles for 159 gliomas using 32 markers. LOH 22 was found in 46 tumors
      (29%). Thirteen tumors displayed partial LOH 22, from which we deduced a region
      of common deletion between markers D22S928 and D22S1169 in 22q13.3. LOH of at
      least this region was detected in 13% of the astrocytomas (As), in 20% of the
      anaplastic astrocytomas (AAs) and in 35% of the glioblastomas multiforme (GBMs).
      The significant increased frequency of LOH 22q13.3 in the highest malignancy
      grade (GBM vs. A and AA, p = 0.02) indicates that loss of this region is
      associated with astrocytoma progression.

PMID- 10652424
TI  - The role of tobacco, snuff and alcohol use in the aetiology of cancer of the
      oesophagus and gastric cardia.
AB  - While tobacco and alcohol are established risk factors for oesophageal squamous
      cell carcinoma, their roles in the aetiology of the increasingly common
      oesophageal adenocarcinoma remains uncertain. We tested the association between
      tobacco, snuff and alcohol use and the risk of oesophageal and cardia cancer in a
      nationwide, population-based case-control study in Sweden. Face-to-face
      interviews were conducted with 618 (81% of all eligible) patients (189
      oesophageal adenocarcinoma, 262 cardia adenocarcinoma and 167 oesophageal
      squamous-cell carcinoma) and 820 control subjects. Odds ratios (OR) were
      calculated by logistic regression with multivariate adjustments for potential
      confounding. The risk of oesophageal adenocarcinoma was not associated with snuff
      or alcohol use, and the association with smoking was weak or absent. Gastric
      cardia adenocarcinoma was dose-dependently associated with smoking (OR=4.2, 95%
      CI=2.5-7.0 among heavy smokers compared with never-smokers), but not with alcohol
      or snuff use. Oesophageal squamous-cell carcinoma was strongly associated with
      tobacco, moderately with alcohol, but not with snuff use; combined use of tobacco
      and alcohol entailed a strongly increased risk (OR=23.1, 95% CI=9.6-56.0 among
      heavy users compared with never-users). We conclude that tobacco smoking, a
      strong risk factor for oesophageal squamous-cell carcinoma and cardia
      adenocarcinoma, does not play an important role in the aetiology of oesophageal
      adenocarcinoma. None of the studied exposures can explain the increasing
      incidence of oesophageal adenocarcinoma.

PMID- 10652425
TI  - Expression of emmprin by oral squamous cell carcinoma.
AB  - A transmembrane glycoprotein recently identified on some tumor cells,
      extracellular matrix metalloproteinase inducer (EMMPRIN), has been shown to
      induce metalloproteinase (MMP) production by peritumor fibroblasts (PTF). We
      examined biopsy specimens of normal human oral mucosa and oral squamous cell
      carcinoma (SCC) for expression of EMMPRIN. In normal mucosa, EMMPRIN was
      expressed at the cell membrane throughout the epithelium with a slight
      enhancement along the basal cell layer. In oral SCC, EMMPRIN was expressed at the
      cell membrane throughout the entire lesion. Immunofluorescence microscopy
      localized EMMPRIN to the cell membrane in a highly invasive oral SCC cell line in
      agreement with our in vivo observations. Function-blocking antibodies to EMMPRIN
      significantly inhibited oral SCC cell migration on tenascin-C (TN-C) and
      fibronectin as well as invasion through a reconstituted basement membrane (RBM).
      We previously showed that soluble factors from SCC cells and PTF are required for
      deposition of a TN-C matrix. To determine whether EMMPRIN may modulate the
      release or expression of these soluble factors, we again used function-blocking
      antibodies. Antibodies to EMMPRIN completely inhibited the organization of TN-C
      matrices and partially reduced the deposition of FN matrices by oral SCC cell
      /PTF co-cultures. In addition, antibodies to EMMPRIN perturbed the expression of
      MMP-2. Moreover, antibodies to MMP-2 perturbed oral SCC cell invasion of an RBM
      by approx. 75%. Our results demonstrate that EMMPRIN is highly expressed in oral
      SCC, facilitates tumor cell motility, and mediates TN-C matrix deposition. Taken
      together, these results suggest that EMMPRIN may help regulate oral squamous cell
      carcinoma invasion.

PMID- 10652426
TI  - Seroepidemiology of human papillomavirus type 73: a sexually transmitted low-risk
      virus.
AB  - Human papillomavirus type 73 (HPV 73) has been detected in some invasive cervical
      cancers and has been cloned from a squamous-cell carcinoma of the esophagus, but
      the epidemiology of this infection and its associated risk of cancer is unknown.
      We investigated the seroepidemiology of this virus using virus-like particles.
      The IgG response to HPV 73 appeared to be HPV type-specific, since a comparison
      of HPV 73 antibody levels before and after infection with HPV 6, 11, 16, 18 or 33
      found no evidence of cross-induction of HPV 73 antibodies and since there was
      little correlation between the antibody levels to HPV 73 and the other 5
      investigated HPV types. In both a cross-sectional serosurvey that included 274
      women and a 7-year follow-up study that enrolled 98 women, HPV 73 seropositivity
      was found to be strongly dependent on the number of lifetime sexual partners [OR
      for > 4 vs. 0 to 1 partners: 6.0 (95%CI: 1.4-53.6) and 7.9 (95% CI: 2.8-28.3),
      respectively]. Finally, the risk for HPV 73 seropositive women to develop CIN was
      investigated in a prospective study nested in a cohort of 15,234 Swedish women.
      The population-based HPV 73 seroprevalence in Sweden was 14%. No excess risk for
      CIN was found (OR: 0.77). We conclude that HPV 73 is a mainly sexually
      transmitted, probably mostly transient, infection that does not confer any
      measurably increased risk for CIN development.

PMID- 10652427
TI  - Preserved foods in relation to risk of nasopharyngeal carcinoma in Shanghai,
      China.
AB  - A population-based case-control study was conducted in Shanghai, China, to
      investigate the association between dietary factors and risk of nasopharyngeal
      carcinoma (NPC). The study included 935 NPC patients aged 15 to 74 years and
      1,032 community controls. Exposures to salted fish and other protein-containing
      preserved food were associated with increased risk of NPC. Individuals who ate
      salted fish at least once a week had an 80% increase in risk of NPC relative to
      those who ate salted fish less than once a month (p = 0.07). Compared with those
      in the lowest quartile of protein-containing preserved foods, subjects in the
      highest quartile of intake experienced a statistically significant 78% increase
      in risk of NPC [odds ratio (OR) = 1.78, 95% confidence interval (CI) = 1.37
      2.31], with a dose-dependent relationship (p for linear trend < 0.001 ). A
      similar association between intake of preserved vegetables and NPC risk was
      observed (OR = 1.39, p for linear trend = 0.003). In contrast, high intake of
      oranges/tangerines was associated with a statistically significant reduction in
      risk of NPC (OR = 0.55, p for linear trend < 0.001). When we examined the joint
      effect of preserved food and oranges/tangerines on risk of NPC, subjects in the
      highest tertile of preserved food and the lowest tertile of orange/ tangerine
      intake had a 3-fold increase in risk (95% CI = 2.08-4.91) compared with those in
      the lowest tertile of preserved food and the highest tertile of orange/tangerine
      intake.

PMID- 10652428
TI  - Non-dietary risk factors for nasopharyngeal carcinoma in Shanghai, China.
AB  - A population-based case-control study was conducted in Shanghai, China, to
      investigate the associations between exposures to various non-dietary variables
      and risk of nasopharyngeal carcinoma (NPC). A total of 935 NPC patients and 1,032
      community controls were included. Active cigarette smoking was a moderate risk
      factor for NPC [odds ratio (OR) = 1.28, 95% confidence interval (CI) 1.02-1.61].
      Results were highly consistent between men and women. It is estimated that 12% of
      NPC cases in Shanghai, China, can be attributable to cigarette smoking. Among
      lifelong nonsmokers, there was a strong and statistically significant positive
      association between NPC risk and exposure to substantial secondhand smoke as a
      child or as an adult in women. However, the associations among lifelong
      nonsmoking men were weaker and not statistically significant. The gender
      differences in risk associated with passive smoking were either statistically
      significant or almost so. There were excess numbers of NPC patients compared with
      control subjects who had a history of chronic ear and nose disease (OR = 1.96,
      95% CI 1.56-2.46) and a family history of NPC (OR = 7.47, 95% CI 2.14-12.88).

PMID- 10652429
TI  - Cell cycle regulators in testicular cancer: loss of p18INK4C marks progression
      from carcinoma in situ to invasive germ cell tumours.
AB  - Cell cycle regulators govern cellular proliferation, modulate differentiation
      and, when defective, contribute to oncogenesis. Here, we examined expression of
      cyclins A, B1 and E, and cyclin-dependent kinase (CDK) inhibitors p18INK4C (p18),
      p21WAF1/Cip1 (p21) and p27KiP1 (p27), in normal human adult testis (n = 5), and
      53 testicular tumours, including 23 carcinomas in situ (CIS) and 30 germ cell
      tumours (GCTs). Immunohistochemical analysis revealed a correlation between
      proliferation and abundance of the cyclin proteins, and abundant p18 and the lack
      of p21 and p27 in normal spermatogenesis. Expression of p21 and/or p27 was
      induced in some differentiated structures seen in teratomas, and was
      recapitulated in cell culture, using human NTera2/D1 teratocarcinoma cells
      induced to differentiate into neurons. CIS lesions showed abundant p18, low
      cyclin E, and moderate p27, in contrast with most invasive seminomas and
      embryonal carcinomas with very low-to-negative p18, often elevated cyclin E, and,
      unexpectedly, sustained or increased p27. Our results suggest increased abundance
      of cyclin E, and particularly downmodulation or loss of p18INK4C as the features
      that correlate with progression from CIS to invasive germ cell tumours of the
      human testis.

PMID- 10652430
TI  - Losses of the tumor suppressor BIN1 in breast carcinoma are frequent and reflect
      deficits in programmed cell death capacity.
AB  - Oncogenic activation of MYC occurs often in breast carcinoma and is associated
      with poor prognosis. Loss or inactivation of mechanisms that restrain MYC may
      therefore be involved in tumor progression. In this study, we show that the MYC
      interacting adaptor protein BIN1 is frequently missing in malignant breast cells
      and that this loss is functionally significant. BIN1 was expressed in normal and
      benign cells and tissues but was undetectable in 6/6 estrogen receptor-positive
      or estrogen receptor-negative carcinoma cell lines examined. Similarly, complete
      or partial losses of BIN1 were documented in 30/50 (60%) cases of malignant
      breast tissue analyzed by immuno-histochemistry or RT-PCR. Abnormalities in the
      organization of the BIN1 gene were apparent in only a minority of these cases,
      suggesting that most losses were due to epigenetic causes. Nevertheless, they
      were functionally significant because ectopic BIN1 induced programmed cell death
      in malignant cells lacking endogenous BIN1 but had no effect on the viability of
      benign cells. We propose that loss of BIN1 may contribute to breast cancer
      progression by eliminating a mechanism that restrains the ability of activated
      MYC to drive cell division inappropriately.

PMID- 10652431
TI  - Inhibition of transforming activity of the ret/ptc1 oncoprotein by a 2-indolinone
      derivative.
AB  - ret-derived oncogenes are frequently and specifically expressed in thyroid
      tumors. In contrast to the ret receptor, ret oncoproteins are characterized by
      ligand-independent tyrosine-kinase activity and tyrosine phosphorylation. In this
      study, novel synthetic arylidene 2-indolinone compounds were evaluated as
      inhibitors of the ret/ptc1 tyrosine kinase. Four compounds inhibited ret/ptc1
      activity in immunokinase assay (IC50 27-42 microM) including one (1,3-dihydro-5,6
      dimethoxy-3-[(4-hydroxyphenyl) methylene)-2H-indol-2-one) (Cpd 1) that
      selectively inhibited the anchorage-independent growth of NIH3T3 transformants
      expressing the ret/ptc1 gene (NIH3T3ptc1 cells). Following exposure to Cpd 1, the
      transformed phenotype of NIH3T3ptc1 cells was reverted, within 24 hr, to a normal
      fibroblast-like morphology in adherent-cell culture. In these cells, the
      constitutive tyrosine phosphorylation of ret/ptc1, of the transducing adaptor
      protein shc and of a series of co-immunoprecipitated peptides became much
      reduced, as demonstrated by immunoprecipitation/Western-blot analyses. Data
      presented provide additional evidence that ret/ptc1 is directly implicated in
      malignant transformation, and demonstrate the ability of Cpd 1 to interfere in
      the signal transduction pathway constitutively activated by the ret/ptc1
      oncoprotein. These results confirm the interest of the arylidene 2-indolinone
      class of tyrosine-kinase inhibitors as tools for the study of ret signaling and
      the control of cell proliferation in ret- and ret/ptcs-associated diseases.

PMID- 10652432
TI  - Novel breast-tumor-associated MUC1-derived peptides: characterization in Db-/- x
      beta2 microglobulin (beta2m) null mice transgenic for a chimeric HLA-A2.1/Db
      beta2 microglobulin single chain.
AB  - The MUC1 protein was found to be up-regulated in a spectrum of malignant tumors.
      T-cell responses to the MUC1 extracellular tandem repeat array (TRA) were
      observed in murine models as well as in breast-carcinoma patients. In the present
      study, we evaluated the anti-tumor potential of HLA-A2.1-motif-selected peptides
      from non-TRA domains of the molecule. Peptide immunogenicity was examined in the
      Db-/- x beta2 microglobulin (beta2m) null mice transgenic for a modified HLA
      A2.1/Db-beta2 microglobulin single chain (HHD mice). Our results show the
      existence of 3 novel HLA-A2.1-restricted MUC1-derived cytotoxic T-lymphocyte
      (CTL) epitopes. These peptides are processed and presented by the HHD-transfected
      breast-tumor cell line MDA-MB-157. Moreover, CTL induced by these 3 peptides show
      higher lysis of target cells pulsed with breast-carcinoma-derived peptides than
      of targets pulsed with normal breast-tissue-derived peptides. These data suggest
      an important role for non-TRA MUC1-derived peptides as inducers of a MHC
      restricted CTL reaction to a breast-carcinoma cell line and patient-derived tumor
      extracts.

PMID- 10652433
TI  - Dependence of autocrine growth factor stimulation in platelet-derived growth
      factor-B-induced mouse brain tumor cells.
AB  - In human gliomas, platelet-derived growth factor (PDGF) ligand and receptor mRNA
      are often co-expressed, which suggests the presence of an autocrine loop. To
      further investigate the significance of PDGF stimulation in brain tumors, we used
      a previously developed mouse tumor model, in which malignant brain tumors of
      neuroepithelial origin were induced by injecting a murine retrovirus containing
      the human PDGF B-chain gene into the brains of neonatal mice. In the present
      investigation, we have characterized a cell line established from such an
      experimentally induced tumor in an INK4a-/- mouse. Cultured tumor cells expressed
      nestin and NG2 chondroitin sulfate proteoglycan and are thus most likely derived
      from an oligodendrocyte precursor cell. Tumor cells produced PDGF-B protein and
      displayed constitutively activated PDGF alpha receptors. Autocrine receptor
      activation could be blocked with the specific PDGF receptor tyrosine kinase
      inhibitor CGP 57148B, which led to almost complete inhibition of cell
      proliferation, which was much less affected by a PDGF B-chain aptamer that
      inhibits binding of PDGF-B to PDGF receptors and is unlikely to be able to pass
      through the plasma membrane. Our results imply an important role for PDGF
      autocrine stimulation in both initiation and progression of a subtype of gliomas.

PMID- 10652435
TI  - Antiproliferative effects of retinoic acid/interferon in cervical carcinoma cell
      lines: cooperative growth suppression of IRF-1 and p53.
AB  - Retinoids and interferons have been implicated in the growth regulation of
      cervical cancer cells. However, the molecular mechanisms are not fully defined.
      To analyze detailed mechanisms, HPV-positive (HeLa, CaSki), HPV-negative (C33A,
      HT-3) and non-cervical Cos-1 cell lines were treated with I microM all-trans
      retinoic acid (RA) and/or 10 ng/ml interferon-gamma (IFN-gamma). The growth of RA
      treated HeLa cells was less effectively suppressed than that of IFN-gamma-treated
      ones. A combination of RA and IFN-gamma leads to an additive antiproliferative
      effect on the cell growth. CaSki cell growth was also inhibited by IFN-gamma but
      was little stimulated by RA treatment, and the IFN effect was attenuated when IFN
      gamma was combined with RA. HPV-negative C33A and HT-3 cells, which are defective
      in p53 and Rb, and Cos- 1 cells were weakly or not responsive to all combined
      treatments. The molecular mechanism underlying the differential effects of RA/IFN
      on HeLa and C33A cells was investigated. Combined RA/IFN-gamma treatment caused a
      marked increase in the level of IFN regulatory factor-1 (IRF-1) in HeLa, whereas
      no induction of IRF-1 was observed in C33A, consistent with the findings that IFN
      signaling is functional in HeLa but is defective in C33A cells. The increase of
      p53 in HeLa cells might account for the down-regulation of HPV-18 E6 gene
      expression by RA/IFN-gamma. Furthermore, RA/IFN-gamma treatment resulted in the
      concurrent induction of p21WAF1 CDK inhibitor and dephosphorylation of Rb
      protein. Transient co-expression of IRF-1 and p53 led to the cooperative
      activation of the p21WAF1 promoter. Our results indicate that 2 transcription
      factors, increased in response to RA/IFN-gamma, cooperate functionally to
      regulate the cell cycle through the activation of a common p21WAF1 gene in HeLa
      cells.

PMID- 10652434
TI  - Osteoblast-derived TGF-beta1 modulates matrix degrading protease expression and
      activity in prostate cancer cells.
AB  - Tumor progression and metastasis may result in part from the selection of cell
      clones competent for survival, invasion and growth at secondary sites and
      characterized by loss of growth inhibitory responses, acquisition of increased
      adhesiveness and enhanced motility and protease expression. Transforming growth
      factor-beta1 (TGF-beta1) is produced by osteoblasts (OB) in a latent form and is
      activated by proteases in a cell-dependent manner. We show here that OB
      conditioned medium (OB CM) modulates Matrigel invasion of a bone metastatic
      prostate cancer cell line (PC3) and that this effect is blocked by antibody
      against TGF-beta1 and by uPA/plasmin inhibitors, suggesting that TGF-beta1 can
      modulate OB-mediated cell recruitment and that PC3 cells can activate TGF-beta1.
      TGF-beta1 induces uPA and PAI-1 secretion and promotes binding of uPA at the
      external plasma membrane with increased membrane-associated plasmin activity.
      Matrix metalloprotease-9 (MMP-9) is induced both in the medium and in the
      membrane associated form. Moreover, the balance between proteolytic activity and
      inhibition is crucial in the metastatic event. Indeed, the increment of PAI-1
      could have an important regulatory role on the extracellular proteolysis and
      might explain the decrease of net PA and gelatinolytic activities measured in the
      medium. In addition, PAI-1 plays a regulative role localizing matrix degradation
      in some specific sites, such as areas of cell-to-cell or cell-to-ECM contacts. In
      conclusion, TGF-beta1 enhances PC3 Matrigel invasion by a uPA/plasmin-dependent
      mechanism, also involving the MMP-9, and thus may play a central role in
      malignant prostate tumor progression as a result of stimulating bone matrix
      invasion.

PMID- 10652436
TI  - Long-term inhibitory effect of the orally active and pure antiestrogen EM-800 on
      the growth of human breast cancer xenografts in nude mice.
AB  - The antiproliferative effect of the new antiestrogen EM-800 has been studied
      during 40 weeks of treatment on human breast carcinoma ZR-75-1 xenografts in
      ovariectomized nude mice supplemented with estrone (0.5 microg, s.c. daily). At
      the daily 50 microg (approximately 2.5 mg/kg) oral dose, EM-800 caused a complete
      inhibition of the 680% stimulatory effect of estrone on the growth of the ZR-75-1
      human breast cancer xenografts. Complete response, defined as the complete
      disappearance of the tumors, was observed in 41% of tumors following treatment
      with the 50 microg dose of the antiestrogen, while a value of 26% was found in
      ovariectomized animals. The proportion of tumors showing progression at the end
      of 40 weeks of treatment decreased from 94% in the estrone-supplemented animals
      to 62%, 61% and 19% in the animals receiving the 5 microg, 20 microg and 50
      microg daily doses of the antiestrogen, respectively. None of the tumors that
      showed a complete or a partial response progressed at later time intervals. The
      50 microg daily dose of EM-800 nearly completely (93%) or completely (28% below
      the value in ovariectomized animals) reversed the stimulatory effect of estrone
      on uterine and vaginal weight, respectively. The disappearance of 41% of tumors
      in the group of animals that received the 50 microg daily dose of EM-800
      indicates that the antiestrogen induces cell death or apoptosis in ZR-75-1 human
      breast cancer cells and that its action is cytotoxic and not only cytostatic.

PMID- 10652437
TI  - An ovarian adenocarcinoma line derived from SV40/E-cadherin-transfected normal
      human ovarian surface epithelium.
AB  - Epithelial ovarian carcinomas are thought to originate in the ovarian surface
      epithelium (OSE), i.e., the mesothelium covering the ovary, but experimental
      evidence for this origin has been lacking. Contrary to most epithelia, where
      neoplastic progression is associated with a reduction of E-cadherin, this cell
      cell adhesion molecule is sparse in normal human OSE but its expression increases
      with the development of ovarian epithelial metaplasia and neoplasia.
      Concurrently, the tumors tend to acquire characteristics of the complex epithelia
      of the oviduct and uterus. The high proportion of ovarian cancers where such
      aberrant Mullerian differentiation occurs suggests that this change may confer a
      selective advantage on the transforming cells. We previously demonstrated that
      increased E-cadherin expression may be a cause, rather than a consequence, of
      such Mullerian differentiation. E-cadherin was transfected into SV40 large T
      antigen-immortalized, E-cadherin-negative cells derived from normal OSE.
      Constitutive expression of E-cadherin re-established normal epithelial markers
      that had been lost in culture, such as keratin, and induced markers of metaplasia
      and neoplasia, such as CA125. In the present study, SV40-immortalized, E-cadherin
      transfected cells, but not the E-cadherin-negative controls, were found to be
      anchorage-independent and to form transplantable, invasive s.c. and i.p.
      adenocarcinomas in 100% of injected SCID mice. Tumor cells injected i.p. seeded
      the mesenteries and omentum, invaded the liver and thigh musculature and produced
      ascites. The presence of SV40 large T antigen in the tumor cell nuclei confirmed
      their origin as transfected OSE cells. Our results demonstrate that ovarian
      adenocarcinomas can be derived by genetic manipulation of normal human OSE.

PMID- 10652438
TI  - Quercetin inhibits p21-RAS expression in human colon cancer cell lines and in
      primary colorectal tumors.
AB  - Immunocytochemical studies have revealed that 10 microM quercetin reduced the
      steady state levels of p21-ras proteins in both colon cancer cell lines and
      primary colorectal tumors. These findings were confirmed by Western blot and flow
      cytometric analysis showing that the inhibition of p21-ras expression by
      quercetin was time- and concentration-dependent. Twenty-four-hour treatment with
      10 microM quercetin reduced p21-ras levels to about 50% of control values.
      Quercetin was similarly effective in inhibiting the expression of K-, H-, and N
      ras proteins. Moreover, the effect of quercetin on ras oncogene expression was
      not dependent on the cell cycle position of colon cancer cells and appeared to be
      specific and not merely a consequence of overall inhibition of protein synthesis.
      Northern blot analysis revealed that quercetin produced in colon cancer cells an
      early (30 min) reduction of the steady state levels of K-, H-, and N-ras mRNAs.
      This reduction was also present after 6 hr of flavonoid treatment. These effects
      of quercetin suggest a possible chemopreventive role for this compound in
      colorectal carcinogenesis.

PMID- 10652439
TI  - Complex cadherin expression in human prostate cancer cells.
AB  - Changes in cell-cell interactions are critical in the process of cancer
      progression. Likewise, it has been shown that loss of expression of the cell
      adhesion molecule E-cadherin is associated with grade, stage, and prognosis in
      many carcinomas, including prostate cancer. Impaired E-cadherin-mediated
      interactions result in an invasive phenotype; however, the mere loss of cell-cell
      contact and communication is not the sole explanation for the observed
      correlation between loss of E-cadherin-mediated adhesion and poor clinical
      outcome. Using a degenerate cloning strategy for sequences that are highly
      conserved between the various cadherins, we found several other cadherins (N- and
      P-cadherin and cadherin-4, -6, and -11) to be expressed in human prostate cancer
      cells. Our data suggest that besides loss of E-cadherin function, also
      (upregulation of) expression of other cadherins is involved in the acquisition of
      an invasive and/or metastatic phenotype. Especially, changes in the expression of
      N-cadherin and cadherin-11 may play an important role in prostate cancer
      progression.

PMID- 10652440
TI  - Brain-immune connection: immuno-regulatory properties of CNS-resident cells.
AB  - Even though the immune privileged status of the central nervous system (CNS)
      limits access of systemic immune cells through the blood brain barrier (BBB), an
      immune response can occur in this compartment with or without major breach of the
      BBB. In this review, we consider properties of resident cells of the CNS, that
      participate in regulating the neural antigen (Ag)-directed immune responses
      implicated in autoimmune diseases such as multiple sclerosis (MS). Under such
      conditions, the CNS is usually viewed as the target or victim of the immune
      assault, because such immune responses are thought to be initiated and regulated
      within the systemic immune compartment. The CNS-endogenous cells may themselves,
      however, initiate, regulate and sustain an immune response. We consider the
      immune regulatory functions within the CNS in terms of events occurring within
      the CNS parenchyma (microglia, astroglia) and at the vascular interface. These
      regulatory functions involve antigen presentation to T cells and polarization of
      the cytokine response of these cells. Such responses may contribute not only to
      the overall tissue injury in primary immune disorders but also in a wide range of
      traumatic, ischemic and degenerative processes.

PMID- 10652441
TI  - Fractalkine modulates TNF-alpha secretion and neurotoxicity induced by microglial
      activation.
AB  - Among the chemokine family, fractalkine shows unusual properties: it exists as a
      membrane-bound and soluble protein, and both fractalkine and its receptor
      CX(3)CR1 are expressed predominantly in the central nervous system. In rat cell
      culture models, the chemokine fractalkine was expressed in neurons and microglia,
      but not in astrocytes and its receptor exclusively localized to microglial cells,
      where its expression was downregulated by treatment with the bacterial endotoxin
      (LPS). In microglial cultures, LPS (10 ng/ml) induced a marked increase in the
      release of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha).
      The effects of LPS on TNF-alpha secretion were partially blocked (30%) by
      fractalkine and the effects of fractalkine were reversed by a polyclonal anti
      fractalkine antibody. When microglial-associated fractalkine was neutralized by
      anti-fractalkine antibody, the LPS response was increased by 80%, suggesting
      tonic activation of microglial fractalkine receptors by endogenous fractalkine.
      The effects of the antibody were antagonized by the addition of fractalkine. LPS
      activated microglia were neurotoxic when added to neuronal hippocampal culture,
      producing 20% neuronal death, as measured by NeuN-positive cell counting. An anti
      fractalkine antibody produced neurotoxic effects of similar magnitude in this co
      culture system and also markedly potentiated the neurotoxic effects of LPS
      activated microglia (40% neuronal death). These results suggest that endogenous
      fractalkine might act tonically as an anti-inflammatory chemokine in cerebral
      tissue through its ability to control and suppress certain aspects of microglial
      activation. These data may have relevance to degenerative conditions such as
      multiple sclerosis, in which cerebral inflammatory processes may be activated.

PMID- 10652442
TI  - Expression of neuron specific phosphatase, striatal enriched phosphatase (STEP)
      in reactive astrocytes after transient forebrain ischemia.
AB  - We studied the distribution and change of striatal enriched phosphatase (STEP) in
      the gerbil hippocampus after transient forebrain ischemia. STEP was expressed in
      the perikarya and in neuronal processes; it was not detected in non-neuronal
      cells of control animals. After 5-min forebrain ischemia, STEP immunoreactivity
      (STEP-IR) was preserved for 2 days; it disappeared 4 and more days after ischemia
      with completion of delayed neuronal death (DND) in the CA1 subfield. Furthermore,
      only in the CA1 after ischemia, STEP was expressed in reactive astrocytes for 4
      to 28 days, showing different patterns of glial fibrillary acidic protein (GFAP)
      positive reactive astrocytes. After non-or less-than lethal ischemia, STEP
      expression in reactive astrocytes corresponded with the degree of neuronal
      degeneration. Immunoblot analysis of the CA1 subfield revealed the expression of
      three isoforms, STEP45, -56 and -61; their expression patterns changed with time
      after ischemia. These data suggest that neuronal STEP is preserved until cell
      degeneration after ischemia and that STEP is expressed in reactive astrocytes
      only after lethal ischemia, with different expression patterns for its isoforms.
      Of STEP45, -56 and -61, STEP61 was the most strongly expressed in the reactive
      astrocytes; both STEP45 and -61 were expressed in neurons and the expression of
      STEP56 was weak. STEP may play an important role not only in neurons but also in
      reactive astrocytes after ischemia, depending on neuronal degeneration.

PMID- 10652443
TI  - Tenascin-R inhibits regrowth of optic fibers in vitro and persists in the optic
      nerve of mice after injury.
AB  - Tenascin-R, an extracellular matrix constituent expressed by oligodendrocytes and
      some neuronal cell types, may contribute to the inhibition of axonal regeneration
      in the adult central nervous system. Here we show that outgrowth of embryonic and
      adult retinal ganglion cell axons from mouse retinal explants is significantly
      reduced on homogeneous substrates of tenascin-R or a bacterially expressed
      tenascin-R fragment comprising the epidermal growth factor-like repeats (EGF-L).
      When both molecules are presented as a sharp substrate border, regrowing adult
      axons do not cross into the tenascin-R or EGF-L containing territory. All in
      vitro experiments were done in the presence of laminin, which strongly promotes
      growth of embryonic and adult retinal axons, suggesting that tenascin-R and EGF-L
      actively inhibit axonal growth. Contrary to the disappearance of tenascin-R from
      the regenerating optic nerve of salamanders (Becker et al., J Neurosci 19:813
      827, 1999), the molecule remains present in the lesioned optic nerve of adult
      mice at levels similar to those in unlesioned control nerves for at least 63 days
      post-lesion (the latest time point investigated), as shown by immunoblot analysis
      and immunohistochemistry. In situ hybridization analysis revealed an increase in
      the number of cells expressing tenascin-R mRNA in the lesioned nerve. We conclude
      that, regardless of the developmental stage, growth of retinal ganglion cell
      axons is inhibited by tenascin-R and we suggest that the continued expression of
      the protein after an optic nerve crush may contribute to the failure of adult
      retinal ganglion cells to regenerate their axons in vivo.

PMID- 10652444
TI  - Microglial tissue plasminogen activator (tPA) triggers neuronal apoptosis in
      vitro.
AB  - Several CNS disorders feature microglial activation. Microglia are known to have
      both restorative and cytotoxic capabilities. Neuronal apoptosis has been noted
      after an acute insult such as ischemia. Microglia may participate in this event.
      We previously showed that conditioned medium (CM) harvested from peritoneal
      macrophages or from activated microglia triggered apoptosis in rat hippocampal
      neurons in culture. We wished to characterize the factor responsible for
      triggering neuronal death. Quiescent microglia produced CM that did not disrupt
      hippocampal neurons. Lipopolysaccharide-activated microglia produced CM which
      resulted in neuronal death. This effect was blocked by plasminogen activator
      inhibitor-1, by tPA STOP, and by co-incubation with tPA antibody. Recombinant
      human tPA exaggerated the neurotoxic effects of microglial CM, while tPA alone
      was toxic only at very high concentrations. This in vitro system, which probably
      excludes any significant impact of microglial free radicals, suggests that
      microglial tPA may contribute significantly to hippocampal neuronal death.

PMID- 10652445
TI  - Biochemical analysis of proteasomes from mouse microglia: induction of
      immunoproteasomes by interferon-gamma and lipopolysaccharide.
AB  - The 20S proteasome is a multicatalytic threonine protease and serves to process
      peptides that are subsequently presented as antigenic epitopes by MHC class I
      molecules. In the brain, microglial cells are the major antigen presenting cells
      and they respond sensitive to pathologic events. We used cultured mouse microglia
      and a microglial cell line, the BV-2 line, as a model to study the correlation
      between microglial activation parameters and structural plasticity of the 20S/26S
      proteasome. Lipopolysaccharide (LPS)- or interferon-gamma (IFN-gamma)-stimulated
      microglia or BV-2 cells exhibit properties of activated microglia such as high
      levels of TNFalpha and IL-6 release. In response to IFN-gamma or LPS, three
      constitutive beta subunits (beta1/Delta, beta2/MC14, beta5/MB1) were replaced by
      the immunoproteasome subunits ibeta1/LMP2, ibeta2/MECL-1, and ibeta5/LMP7,
      indicating that activated microglia adapts its proteasomal subunit composition to
      the requirements of an optimized MHC class I epitope processing. Induction of
      immunoproteasomes in BV-2 cells was solely provoked by IFN-gamma, but not by LPS.
      Moreover, LPS (but not IFN-gamma) triggered the expression of a novel protein of
      approximately 50 kD as part of the proteasome activator PA700, that is the
      substrate-recognizing and unfolding unit of the 26S proteasome. These results
      indicate that both the 20S core protease as well as the proteasome activator
      PA700 are targets of modulatory subunit replacements or transient association of
      regulatory components in the course of microglial activation.

PMID- 10652446
TI  - Tumour necrosis factor alpha mRNA expression in early multiple sclerosis lesions:
      correlation with demyelinating activity and oligodendrocyte pathology.
AB  - The precise role of tumour necrosis factor alpha (TNFalpha) in multiple sclerosis
      (MS) is still controversial. Most findings from the animal model experimental
      allergic encephalomyelitis have yet to be confirmed in multiple sclerosis. The
      aim of this study was to define the significance of TNFalpha with respect to the
      hallmark of MS, that is demyelination. Therefore, 78 lesion areas from diagnostic
      brain biopsies of 32 patients were analysed. Lesion demyelinating activity was
      classified by the presence of myelin degradation products in macrophages and
      macrophage activation markers. Non-radioactive in situ hybridisation was carried
      out to detect TNFalpha mRNA expressing cells. DNA fragmentation was visualised by
      TdT-mediated X-dUTP nick end labeling. A significantly higher number of cells
      expressed TNFalpha mRNA in active demyelinating lesions than in inactive or
      remyelinating lesions irrespective of the extent of the inflammatory infiltrate.
      TNFalpha mRNA expression correlated with the appearance of DNA fragmentation in T
      lymphocytes and oligodendrocytes within the lesions. In the periplaque white
      matter, expression of TNFalpha mRNA negatively correlated with oligodendrocyte
      numbers. These data support previous findings from animal models and in vitro
      experiments. Although not proving, the current study strongly suggests a
      pathogenic role of TNFalpha in demyelination in human multiple sclerosis and
      gives further support for TNFalpha-directed therapeutic strategies.

PMID- 10652447
TI  - Expression and function of the protein tyrosine phosphatase SHP-1 in
      oligodendrocytes.
AB  - Previous studies in this laboratory have shown that the SH-2 domain-containing
      protein tyrosine phosphatase SHP-1 is expressed in CNS glia and functions to
      modulate cytokine activities in these cells. The present study demonstrates that
      SHP-1 is expressed within multiple regions of the CNS in vivo, especially in
      white matter. Interestingly, we show that mice genetically lacking in SHP-1
      (motheaten mice) in the CNS displayed dysmyelination. We therefore examined the
      expression of SHP-1 in the myelin-forming oligodendrocytes. Oligodendrocytes
      present in either mixed glial cultures or pure cultures expressed high levels of
      SHP-1 in the cytoplasm of cell bodies and processes. Oligodendrocytes isolated
      from motheaten mice did not express SHP-1. To test possible functions for SHP-1
      in oligodendrocytes in controlling cytokine signaling, we compared the
      responsiveness of oligodendrocytes isolated from either motheaten or normal
      littermate mice with IL-6. IL-6 induced higher levels of STAT3 phosphorylation
      and STAT3-responsive c-fos gene expression in pure oligodendrocyte cultures of
      motheaten compared with normal littermate mice. These studies demonstrate that
      oligodendrocytes express SHP-1 and that SHP-1 functions to control IL-6
      signaling. SHP-1 may therefore be a critical regulator of oligodendrocyte
      differentiation in response to IL-6 family cytokines. Further, these findings may
      relate to dysmyelination in mice lacking SHP-1.

PMID- 10652449
TI  - Cyclooxygenase-2 is highly expressed in microglial-like cells in a murine model
      of prion disease.
AB  - Prion diseases, or transmissible spongiform encephalopathies, are a relatively
      rare group of chronic degenerative disorders afflicting both animals and humans,
      characterized by typical histopathological signs such as amyloid deposition,
      neuronal loss and spongiform changes. Despite the absence of a typical acute
      inflammatory response, the consistent microglial activation and astrocytosis,
      that are found in human pathologies as well as in animal models, suggests the
      existence of an ongoing inflammatory response in these neurodegenerative
      diseases. To investigate the role of cyclooxygenase-2 (COX-2) activity in the
      pathogenesis of chronic neurodegenerative diseases, we studied
      immunohistochemically the expression of this key enzyme in the formation of
      prostaglandins during inflammatory responses in a well characterized murine model
      of prion disease. We found that COX-2 is selectively up-regulated in glial cells
      presenting the typical morphology of activated microglia and that the number of
      COX-2-positive cells increases with the progression of the disease. The extensive
      microglial expression of COX-2, that is likely to be followed by a sustained
      enzymatic activity leading to the generation of prostaglandins as well as of
      oxygen free radicals, might have important effects on chronic neurodegeneration.
      Further functional experiments are required to elucidate the role of COX-2
      activity in the pathogenesis of chronic neurodegenerative diseases.

PMID- 10652448
TI  - Topical correlation of increased hippocampal glutamine synthetase
      immunoreactivity and glutamatergic terminal fields after entorhinal cortex
      lesion.
AB  - Many astrocyte functions are related to glutamatergic transmission and to other
      synaptic functions, such as glutamate uptake and glutamate metabolism. While many
      of these functions can be executed by perisynaptic astrocyte processes, it is not
      clear how these processes are formed. One of the factors guiding them to the
      synapse may be synaptically released glutamate. This would explain the topical
      correlation between laminated glutamatergic terminal fields and laminae most
      intensely labeled by a cytoplasmic astrocyte marker, anti-glutamine synthetase
      (GS). This hypothesis was tested by selectively increasing the glutamate content
      in one terminal field. The rat entorhinal cortex, the origin of the glutamatergic
      projection to the outer molecular layer (OML) of the hippocampal fascia dentata,
      was lesioned electrolytically. In line with the hypothesis, GS immunoreactivity
      was strongly increased in the OML at 6 and 8 days postlesion. Lesion of only the
      medial entorhinal cortex resulted in heavily increased GS immunoreactivity only
      in the central portion of the molecular layer (i.e., the corresponding terminal
      field). The laminae affected were always separated from neighboring fields by a
      straight and clear-cut line. Although many other factors are released in the
      terminal field after lesion, the results are consistent with a guiding role for
      glutamate. The lamina-specific effect suggests that the factor(s) involved have a
      very limited diffusion distance. The straight border line between affected and
      unaffected laminae, which cuts across astrocyte territories, can best be
      explained by ramification of only those processes of a given astrocyte that are
      contained within the lamina affected.

PMID- 10652450
TI  - The role of natural products in a modern drug discovery program.

PMID- 10652451
TI  - Reelin in brain development studies.

PMID- 10652452
TI  - How many leads from HTS? - Comment.

PMID- 10652453
TI  - Dimeric malarial drugs for enhanced activity.

PMID- 10652455
TI  - Computational methods for the prediction of 'drug-likeness'
AB  - Recently, one of the key trends in the pharmaceutical industry has been the
      integration of what have traditionally been considered 'development' activities
      into the early phases of drug discovery. The aim of this paradigm shift is the
      prompt identification and elimination of candidate molecules that are unlikely to
      survive later stages of discovery and development. In this review, the authors
      examine the growing role that is being played by computational methods in this
      filtering process, with a particular focus on the prediction of intestinal
      absorption and blood-brain barrier penetration.

PMID- 10652456
TI  - High-throughput gene expression analysis for drug discovery.
AB  - The ability to rapidly survey and compare gene expression levels between
      reference and test samples is moving the drug discovery process towards a more
      genomic orientation. The success of the Human Genome Project and related private
      genomics initiatives, combined with new technologies to probe, image and access
      expression data, are responsible for this transformation. This article reviews
      the history, status and future direction of high-throughput gene expression
      analysis. It describes classical approaches, explains the development of methods
      such as differential display for discovering novel genes, and discusses how
      microarray technology is exploiting collections of known sequences to pinpoint
      drug targets.

PMID- 10652457
TI  - Dynamic diversity in drug discovery: Putting small-molecule evolution to work.
AB  - From oligonucleotides to orangutans, nature has found darwinian evolution to be
      the most efficient means of optimizing populations of organisms - or molecules.
      Recently, several research groups have begun adapting darwinian evolution to the
      identification of small molecules with specific properties. Although still at an
      early stage, this new field of 'dynamic diversity' shows promise as a method for
      the identification of high-affinity ligands for biomolecules.

PMID- 10652458
TI  - Studying heart disease using the proteomic approach.
AB  - The pathogenic mechanisms underlying cardiac dysfunction in heart disease are
      still largely unknown. It is likely, though, that significant alterations in
      myocardial gene and protein expression underlie these disease processes and
      determine their progression and outcome. Most molecular studies of cardiac
      dysfunction have been carried out on specific cellular systems. However, the
      application of the proteomic approach to the study of heart disease has made it
      possible to characterize global alterations in protein expression. This promises
      new insights into the cellular mechanisms involved in cardiac dysfunction and is
      likely to result in the discovery of novel diagnostic markers and new therapeutic
      opportunities.

PMID- 10652459
TI  - Monitor: molecules and profiles.
AB  - Monitor provides an insight into the latest developments in drug discovery
      through brief synopses of recent presentations and publications together with
      expert commentaries on the latest technologies. There are two sections: Molecules
      summarizes the chemistry and the pharmacological significance and biological
      relevance of new molecules reported in the literature and on the conference
      scene; Profiles offers commentary on promising lines of research, emerging
      molecular targets, novel technology, advances in synthetic and separation
      techniques and legislative issues.

PMID- 10652460
TI  - Combinatorial chemistry.

PMID- 10652461
TI  - The potential of specific COX-2 inhibition.

PMID- 10652463
TI  - Innate immunity: from plants to humans.

PMID- 10652462
TI  - Atopy and asthma: genetic variants of IL-4 and IL-13 signalling.

PMID- 10652464
TI  - Organ-specific immune responses associated with infectious disease.
AB  - The immune response to infection can vary markedly in different organs of the
      same animal. In some organs, the infection can resolve with subsequent immunity
      to re-infection, whereas in other organs, pathogens can persist. Here, Christian
      Engwerda and Paul Kaye highlight the importance of defining organ-specific immune
      mechanisms for developing strategies that deal effectively with infectious
      diseases and their associated pathologies.

PMID- 10652465
TI  - Rheumatoid arthritis and p53: how oxidative stress might alter the course of
      inflammatory diseases.
AB  - Oxidative stress at sites of chronic inflammation can cause permanent genetic
      changes. The development of mutations in the p53 tumor suppressor gene and other
      key regulatory genes could help convert inflammation into chronic disease in
      rheumatoid arthritis and other inflammatory disorders.

PMID- 10652466
TI  - Structural features of MHC class I molecules that might facilitate alternative
      pathways of presentation.
AB  - Comparisons of the structures of different mouse MHC class I molecules define how
      polymorphic residues determine the unique structural motif and atomic anchoring
      of their bound peptides. Here, Ted Hansen and colleagues speculate that
      quantitative differences in how class I molecules interact with peptide, beta2
      microglobulin and molecular chaperones that facilitate peptide loading might
      determine their relative participation in different pathways of antigen
      presentation.

PMID- 10652467
TI  - Role of the common cytokine receptor gamma chain (gammac) in thymocyte selection.
AB  - During thymocyte development, T-cell receptor (TCR) alphabeta-mediated
      intracellular signals can elicit two entirely different cellular responses:
      positive selection (resulting in rescue from death and maturation or
      differentiation) and negative selection (induction of apoptosis). Here, Hiroshi
      Nakajima and colleagues discuss how survival signals that are dependent on the
      common cytokine receptor gamma chain (gammac) might affect the TCR-driven
      selection process in thymocytes, underscoring the potential role of cytokines in
      this process.

PMID- 10652468
TI  - The third function of the thymus.
AB  - Nonresponsiveness of mammalian T cells to self-antigens is not totally accounted
      for in terms of clonal deletion, T-cell anergy and T-cell ignorance: studies have
      shown that the T-cell repertoire of healthy individuals contains cells with the
      potential to cause autoimmune disease. This article describes a T-cell-mediated
      mechanism that prevents the realization of this potential and indicates how its
      failure can lead to the development of autoimmunity.

PMID- 10652470
TI  - T-cell clonality in immune responses.

PMID- 10652469
TI  - Modulating chemokines: more lessons from viruses.
AB  - Chemokines are crucial effector molecules involved in orchestrating the host
      inflammatory response against invading pathogens. Viruses have devised several
      strategies for exploiting or neutralizing chemokines or their receptors to
      further their own propagation or elude host defenses. Insight into strategies
      used by viruses to modulate chemokines might help generate novel approaches for
      treating viral diseases and chemokine-mediated inflammatory disorders.

PMID- 10652471
TI  - T-cell function in the human newborn.

PMID- 10652472
TI  - Reply to hassan and reen

PMID- 10652473
TI  - Of mice and MACs.

PMID- 10652474
TI  - Xenotransplanted neurons show potential to treat spinal injuries and Parkinson's
      disease.

PMID- 10652475
TI  - Fatty acid imbalance might lead to novel treatments for CF.

PMID- 10652476
TI  - Unravelling adenosine's effects on stroke.

PMID- 10652477
TI  - Does dysregulation of the Notch and wingless/Wnt pathways underlie the
      pathogenesis of Alzheimer's disease?
AB  - Alzheimer's disease is characterized by the presence of neurofibrillary tangles
      and senile neuritic plaques in the brain. Tangles are aggregates of paired
      helical filaments composed of the microtubule-associated protein, tau, in a
      hyperphosphorylated state. Senile plaques have a core of amyloid beta-peptide
      derived by proteolysis of the amyloid precursor protein. A major hurdle in
      defining the pathogenic mechanisms in Alzheimer's disease is to understand how
      both amyloid beta-peptide deposition and paired helical filament formation are
      biochemically linked. Recent genetic discoveries provide some clues, suggesting
      that components of two developmentally important signalling pathways, Notch and
      wingless, or the vertebrate homologue of wingless, Wnt, are involved.

PMID- 10652478
TI  - Aquaporins in health and disease.
AB  - The molecular basis of membrane water-permeability remained elusive until the
      recent discovery of the aquaporin water-channel proteins. The fundamental
      importance of these proteins is suggested by their conservation from bacteria
      through plants to mammals. Ten mammalian aquaporins have thus far been
      identified, each with a distinct distribution. In the kidney, lung, eye and
      brain, multiple water-channel homologs are expressed, providing a network for
      water transport in those locations. It is increasingly clear that alterations in
      aquaporin expression or function can be rate-limiting for water transport across
      certain membranes. Aquaporins are likely to prove central to the pathophysiology
      of a variety of clinical conditions from diabetes insipidus to various forms of
      edema and, ultimately, they could be a target for therapy in diseases of altered
      water homeostasis.

PMID- 10652479
TI  - Recent advances with recombinant bacterial vaccine vectors.
AB  - Bacille Calmette-Guerin (BCG), Listeria monocytogenes, Salmonellae and Shigellae
      have shown promise as vaccine vectors in experimental animal models. Although
      disappointing results in humans and non-human primates stalled the development of
      this vaccination strategy, interest in this approach was reinvigorated recently
      by the development of bacterial DNA-vaccine-vectors. The purpose of this review
      is to highlight the strengths and weaknesses of bacterial vaccine vectors, and to
      discuss the future prospects of these vaccine delivery systems.

PMID- 10652480
TI  - Antisense therapeutics: is it as simple as complementary base recognition?
AB  - Antisense oligonucleotides provide a simple and efficient approach for developing
      target-selective drugs because they can modulate gene expression sequence
      specifically. Antisense oligonucleotides have also become efficient molecular
      biological tools to investigate the function of any protein in the cell. As the
      application of antisense oligonucleotides has expanded, multiple mechanisms of
      oligonucleotides have been characterized that impede their routine use. Here, we
      discuss different mechanisms of action of oligonucleotides and the possible ways
      of minimizing non-antisense-related [corrected] effects to improve their
      specificity.

PMID- 10652481
TI  - Gene therapy strategies for colon cancer.
AB  - Colorectal cancer is the second most common cause of cancer mortality in Western
      countries. Gene therapy represents a novel approach to the treatment of
      colorectal cancer, and this review addresses the current strategies and ongoing
      clinical trials, including gene correction, immunomodulatory approaches and virus
      directed enzyme-prodrug systems. Although the pre-clinical results for these
      strategies have been encouraging, clinical trials have not yet reflected these
      data. However, gene therapy for colorectal cancer is still in the early stages of
      development, and its potential, particularly in combination with conventional
      cancer therapies, warrants further investigation.

PMID- 10652482
TI  - Animal models for autoimmune demyelinating disorders of the nervous system.
AB  - Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central
      nervous system (CNS) that takes a relapsing-remitting or a progressive course
      (reviewed in Refs 1,2). Its counterpart in the peripheral nervous system (PNS) is
      chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) (reviewed in
      Ref. 3). In addition, there are acute, monophasic disorders, such as the
      inflammatory demyelinating polyradiculoneuropathy termed Guillain-Barre syndrome
      (GBS) in the PNS, and acute disseminated encephalomyelitis (ADEM) in the CNS.
      Both MS and GBS are heterogeneous syndromes. In MS different exogenous assaults
      together with genetic factors can result in a disease course that finally fulfils
      the diagnostic criteria. In both diseases, axonal damage can add to a primarily
      demyelinating lesion and cause permanent neurological deficits. No single animal
      model exists that mimics all the features of human demyelinating diseases;
      rather, the available models reflect specific facets. Here, we focus on
      experimental autoimmune encephalomyelitis (EAE) and neuritis (EAN) as models in
      rat and mouse strains, and discuss their distinct histopathology and the roles
      played by different autoantigens.

PMID- 10652483
TI  - Malaria: new ideas, old problems, new technologies.

PMID- 10652484
TI  - Veterinary parasitology: developments in immunology, epidemiology and control.

PMID- 10652486
TI  - Bednets, size and culture on the Web

PMID- 10652485
TI  - Schistosomiasis vaccines: a devils' advocate view.

PMID- 10652487
TI  - Field studies of cytotoxic T lymphocytes in malaria infections: implications for
      malaria vaccine development.
AB  - The search for a cytotoxic T lymphocyte (CTL)-inducing malaria vaccine has moved
      forward from epitope identification to planning stages of safety and
      immunogenicity trials of candidate vaccines. Development of CTL-inducing vaccine
      candidates has taken center stage based on the observation that CTL-mediated
      protection might be the dominant mechanism by which sterile immunity is achieved
      in irradiated sporozoite immunization experiments in humans and laboratory
      animals. However, studies in naturally infected individuals living in endemic
      areas, as reviewed here by Michael Aidoo and Venkatachalam Udhayakumar, have
      revealed that CTL induction might be influenced by factors such as parasite
      variants, host genes, other infections and transmission patterns. The influence
      of these factors on CTL induction has been demonstrated individually and in
      various combinations in controlled animal experiments. However, in naturally
      infected humans, they are presented in a complex host-parasite-environment
      interaction, in a manner that is not easily achieved in laboratory-based
      experiments. Understanding these interactions is crucial for the development and
      testing of CTL-inducing vaccines for humans.

PMID- 10652489
TI  - Lymphocyte polyclonal activation: a pitfall for vaccine design against infectious
      agents.
AB  - In this article, Bernardo Reina-San-Martin, Alain Cosson and Paola Minoprio
      summarize the marked alterations in the immune system functions after infection
      that might account for the poor success of effective parasite vaccine
      development. Many of the studies on oligoclonal B- and T-cell responses to
      parasite antigens aiming at vaccination strategies would seem to ignore more
      general, and perhaps fundamental, aspects of parasite-immune system interactions.
      In essence, because of its consequences on immunopathology and parasite escape,
      the authors ascribe a central importance in the pathogenesis of parasitic
      diseases to the 'nonspecific' polyclonal lymphocyte activation that occurs during
      infection. Hence, novel targets and strategies for immune intervention should be
      considered.

PMID- 10652488
TI  - Pathways involved in environmental sensing in trypanosomatids.
AB  - Digenetic parasites, such as those of the order Kinetoplastida, must respond to
      extracellular and intracellular signals as they adapt to new environments within
      their different hosts. Evidence for signal transduction has been obtained for
      Trypanosoma brucei, T. cruzi and Leishmania, as reviewed here by Marilyn Parsons
      and Larry Ruben. Although the broad picture suggests similarities with the
      mammalian host, there are large gaps in our understanding of these processes;
      this probably contributes to a perception of differences. Nonetheless, current
      evidence suggests that the trypanosomatids might lack certain classes of
      signalling molecules found in other organisms.

PMID- 10652490
TI  - Websites of interest

PMID- 10652491
TI  - Schistosome population genetic structure: when clumping worms is not just
      splitting hairs.
AB  - Schistosomiasis is a major public health problem, affecting over 200 million
      people worldwide. Although Schistosoma mansoni has been studied rigorously in an
      attempt to provide a vaccine based on a number of candidate antigens, there has
      been a lack of complementary effort to determine the range and distribution of
      variation in representative molecules throughout natural populations. Here, Jason
      Curtis and Dennis Minchella highlight current (and suggest future) research
      efforts aimed at assessing genetic variation in schistosome populations, and call
      for a more robust consideration of schistosome population genetics.

PMID- 10652492
TI  - Reducing intestinal nematode infection: efficacy of albendazole and mebendazole.
AB  - The widespread use of mebendazole and albendazole for treating intestinal
      nematode infections in human populations is raising concerns that careful
      monitoring pro- cedures should be in place to identify any emergence of drug
      resistance. In this article, Andy Bennett and Helen Guyatt discuss whether
      benchmark parasitological drug efficacy rates can be defined for these
      anthelmintics, by analysing published data on cure rates and egg reduction rates
      in the treatment of Ascaris lumbricoides, Trichuris trichiura and hookworm.

PMID- 10652493
TI  - Distribution of African malaria mosquitoes belonging to the Anopheles gambiae
      complex.
AB  - The distribution of malaria vector mosquitoes, especially those belonging to
      species complexes that contain non-vector species, is important for strategic
      planning of malaria control programmes. Geographical information systems have
      allowed researchers to visualize distribution data on maps together with
      environmental parameters, such as rainfall and temperature. Here, Maureen
      Coetzee, Marlies Craig and David le Sueur review our current knowledge on the
      distribution of the members of the Anopheles gambiae complex.

PMID- 10652494
TI  - Transcription of the kinetoplastid spliced leader RNA gene.
AB  - In recent years, much has been learned about the cis-elements controlling
      transcription of the kinetoplastid spliced leader (SL) RNA gene. The SL RNA gene
      contains the first 39 nucleotides that are trans-spliced on to all nuclear
      derived mRNAs in these organisms. Transcription initiation is determined by two
      precisely spaced upstream elements and transcription termination is directed by
      the downstream poly-T tract, although the RNA polymerase responsible for SL RNA
      synthesis is still questioned. In this article, David Campbell, Nancy Sturm and
      Michael Yu review the field of kinetoplastid SL RNA gene transcription, address
      past proposals in light of current data and discuss some of the differences that
      appear in the literature.

PMID- 10652495
TI  - A call for collaboration.

PMID- 10652497
TI  - Reply

PMID- 10652496
TI  - The future of veterinary parasitology--a UK view.

PMID- 10652498
TI  - Signal transduction from the angiotensin II AT2 receptor.
AB  - Recent studies of genetically engineered animals have established a role for the
      angiotensin II (AT2) receptor in cardiovascular, renal and central functions, as
      well as in developmental processes. This review summarizes new insights into
      major AT2 signaling pathways--activation of protein phosphatases, the nitric
      oxide-cGMP system and phospholipase A2--which have been related to specific
      cellular responses or functions of this receptor.

PMID- 10652499
TI  - Transcriptional repression by nuclear hormone receptors.
AB  - Repression by nuclear receptors plays important roles in acute promyelocytic
      leukemia and other diseases. Nuclear receptor corepressor (N-CoR) and SMRT
      (silencing mediator of retinoic acid and thyroid hormone receptor) are
      corepressor proteins whose modular structure facilitates receptor interaction as
      well as transduction of repression signals involving histone deacetylation,
      alterations in chromatin structure and direct interactions with the basal
      transcription machinery. Interactions between nuclear receptors and corepressor
      complexes have multiple determinants. This allows regulation, and potentially
      therapeutic manipulation, of receptor, corepressor, cell-type and target-gene
      specificity.

PMID- 10652500
TI  - The beta cell in autoimmune diabetes: many mechanisms and pathways of loss.
AB  - Death of pancreatic beta cells is the final step in the pathogenesis of type 1
      diabetes before it becomes clinically apparent. Applying recent basic research
      about how cells die to the clinical problem of diabetes is a current opportunity
      and challenge. To date, perforin is the only factor definitely implicated in beta
      cell killing in the non-obese diabetic (NOD) mouse model, although some perforin
      deficient NOD mice develop diabetes. Our results suggest that other factors that
      cause beta-cell death remain to be identified.

PMID- 10652501
TI  - Implications of proopiomelanocortin (POMC) mutations in humans: the POMC
      deficiency syndrome.
AB  - The recent discovery of the contribution of proopiomelanocortin (POMC)-derived
      peptides to the regulation of energy homeostasis and exocrine gland secretion in
      mice aroused new interest in the complex function of the endocrine POMC network.
      In addition, the first mutations in the gene encoding POMC have been identified
      in two patients affected by adrenal insufficiency, early onset severe obesity and
      red hair pigmentation. Therefore, the focus of this brief review will be the
      detailed discussion of the implications of these new findings in the physiology
      of the human POMC ligand-receptor system.

PMID- 10652502
TI  - Aromatase as a therapeutic target in endometriosis.
AB  - In contrast to normal endometrium, the expression of aromatase is aberrant in
      endometriosis and is stimulated by prostaglandin E2 (PGE2). This results in local
      production of estrogen, which induces PGE2 formation and establishes a positive
      feedback cycle. Another abnormality in endometriosis--deficient 17 beta
      hydroxysteroid dehydrogenase (17 beta-HSD) type 2 expression--impairs the
      inactivation of estradiol (E2) to estrone (E1). These molecular aberrations
      collectively favor accumulation of increasing quantities of E2, and PGE2 in
      endometriosis. The clinical relevance of these findings was exemplified by the
      successful treatment of an unusually aggressive case of postmenopausal
      endometriosis with an aromatase inhibitor.

PMID- 10652503
TI  - Comparison of the European and USA practice guidelines for Osteoporosis.
AB  - The European Foundation for Osteoporosis and Bone Disease (EFFO), the Royal
      College of Physicians, the European Community and the National Osteoporosis
      Foundation of the USA (NOF) have recently published guidelines for the diagnosis
      and management of osteoporosis. All adopt case-finding strategies but the
      conceptual approach between the European and North American guidelines differs
      fundamentally. This gives rise to differences in the populations identified for
      assessment and treatment.

PMID- 10652504
TI  - Laccases are widespread in bacteria.

PMID- 10652505
TI  - Reinventing the wheel.

PMID- 10652507
TI  - The integration of SPR biosensors with mass spectrometry: possible applications
      for proteome analysis.
AB  - The successful integration of biospecific interaction analysis based on surface
      plasmon resonance and mass spectrometry produces a powerful technique that
      couples the benefits of sensitive affinity capture and characterization of
      binding events with the ability to characterize interacting molecules. A variety
      of biosensors has been used to capture proteins and peptides biospecifically on
      sensor surfaces, with subsequent analysis using mass spectrometry. Applying this
      type of analysis to proteomic studies could lead to ligand and protein-complex
      identification, and might provide clues leading to the identification of
      pathways.

PMID- 10652508
TI  - Continuous weak-affinity immunosensing.
AB  - A multitude of weak biological interactions, either working alone or in concert,
      occur frequently throughout biological systems. We have used this natural feature
      of readily reversible interactions as the basis for continuous immunosensing. In
      a model system, a set of weak monoclonal antibodies directed towards a
      carbohydrate epitope was studied with the aid of surface plasmon resonance.
      Because the system requires no regeneration, it can be used as a truly on-line
      immunosensing device. This principle should have wide application in all areas
      where there is a need for the continuous evaluation of a molecule.

PMID- 10652509
TI  - Human embryonic stem cell and embryonic germ cell lines.
AB  - Undifferentiated human embryonic stem (ES) cells and embryonic germ (EG) cells
      can be cultured indefinitely and yet maintain the potential to form many or all
      of the differentiated cells in the body. Human ES and EG cells provide an
      exciting new model for understanding the differentiation and function of human
      tissue, offer new strategies for drug discovery and testing, and promise new
      therapies based on the transplantation of ES and EG cell-derived tissues.

PMID- 10652510
TI  - Supported membranes on soft polymer cushions: fabrication, characterization and
      applications.
AB  - Soft biofunctional and biocompatible interfaces on solids designed by the
      deposition of ultrathin soft polymer films or supported membranes have numerous
      scientific and practical applications. These include the immobilization of
      glycolipids, membrane receptors and proteins to generate models of cell and
      tissue surfaces. Powerful surface-sensitive techniques can be applied to study
      protein-protein recognition processes at membranes and the control of cell
      adhesion by the interplay of specific 'lock-and-key' forces and universal
      interfacial forces. Potential practical applications include the design of smart
      biosensors based on electro-optical devices and the fabrication of biofunctional
      surfaces for the stimulation of cell proliferation and tissue growth, or for the
      suppression of apoptosis.

PMID- 10652511
TI  - Using photolabile ligands in drug discovery and development.
AB  - Photoactivatable ligands are important tools used in drug discovery and drug
      development. These ligands enable researchers to identify the targets of drugs,
      to determine the affinity and selectivity of the drug-target interaction, and to
      identify the binding site on the target. Examples are presented from three
      fundamentally different approaches: (1) photoaffinity labeling of target
      macromolecules; (2) photoactivation and release of 'caged ligands'; and (3)
      photoimmobilization of ligands onto surfaces.

PMID- 10652512
TI  - Single-nucleotide polymorphism analysis by MALDI-TOF mass spectrometry.
AB  - Single-nucleotide polymorphisms (SNPs) have great potential for use in genetic
      mapping studies, which locate and characterize genes that are important in human
      disease and biological function. For SNPs to realize their full potential in
      genetic analysis, thousands of different SNP loci must be screened in a rapid,
      accurate and cost-effective manner. Matrix-assisted laser desorption-ionization
      time-of-flight (MALDI-TOF) mass spectrometry is a promising tool for the high
      throughput screening of SNPs, with future prospects for use in genetic analysis.

PMID- 10652513
TI  - Molecular motors: the driving force behind mammalian left-right development.
AB  - The molecular motors dynein and kinesin are large protein complexes that convert
      the energy generated by ATP hydrolysis into directional movement along the
      microtubule cytoskeleton. They are required for a myriad of cellular processes,
      including mitotic spindle movement, axonal and vesicular transport, and ciliary
      beating. Recently, it has been shown that, in addition, they have a unique role
      during embryonic patterning: they are required to orient and establish the left
      right axis in early vertebrate development.

PMID- 10652514
TI  - Nucleocytoplasmic shuttling signals: two for the price of one.
AB  - It has been appreciated for some time that basic-amino-acid-type nuclear
      localization signals control nuclear uptake of proteins and that leucine-rich
      nuclear export signals mediate export back into the cytoplasm. The machinery that
      recognizes and escorts these well-defined protein transport signals through the
      nuclear pore complex has been identified and characterized. Does this mean that
      the nuclear transport field knows all it needs to about transport signals? Not
      quite, as several recent publications have expanded the membership of a growing
      family of transport signals, known as nucleocytoplasmic shuttling (NS) signals.
      All proteins currently known to contain this type of signal also associate with
      mRNA. This article reviews what is currently known about mediators of NS signal
      transport and discusses the link between NS signal-containing proteins and RNA
      export.

PMID- 10652515
TI  - Dosage compensation: making 1X equal 2X.
AB  - Animals that have XX females and XY or XO males have differing doses of X-linked
      genes in each sex. Overcoming this is the most immediate and vital aspect of
      sexual differentiation. A number of systems that accurately compensate for sex
      chromosome dosage have evolved independently: silencing a single X chromosome in
      female mammals, downregulating both X chromosomes in hermaphrodite Caenorhabditis
      elegans and upregulating the X chromosome in male Drosophila all equalize X
      linked gene expression. Each organism uses a largely non-overlapping set of
      molecules to achieve the same outcome: 1X = 2X.

PMID- 10652516
TI  - Turning on ARF: the Sec7 family of guanine-nucleotide-exchange factors.
AB  - ARF proteins are important regulators of membrane dynamics and protein transport
      within the eukaryotic cell. The Sec7 domain is approximately 200 amino acids in
      size and stimulates guanine-nucleotide exchange on members of the ARF class of
      small GTPases. The members of one subclass of Sec7-domain proteins are direct
      targets of the secretion-inhibiting drug brefeldin A, which blocks the exchange
      reaction by trapping a reaction intermediate in an inactive, abortive complex. A
      separate subclass of Sec7-domain proteins is involved in signal transduction and
      possess a domain that mediates membrane binding in response to extracellular
      signals.

PMID- 10652517
TI  - Differential sorting and post-secretory targeting of proteins in parasitic
      invasion.
AB  - Toxoplasma gondii uses a highly coordinated arsenal of three structurally and
      biochemically distinct secretory granules to invade and develop in a wide range
      of host cells. Proteins of these secretory granules are sorted to strategic
      subcellular locations using distinctive sorting signals and are then triggered
      differentially for exocytosis. These secreted proteins are subsequently targeted
      and inserted into membrane domains.

PMID- 10652518
TI  - Ceramide in the eukaryotic stress response.
AB  - Several extracellular agents and stress stimuli, such as tumour necrosis factor
      alpha, chemotherapeutic agents and heat, cause ceramide accumulation. They do
      this by regulating enzymes involved in its metabolism. Ceramide modulates a
      number of biochemical and cellular responses to stress, including apoptosis, cell
      cycle arrest and cell senescence.

PMID- 10652520
TI  - Reply to Vroomen and de Gelder.

PMID- 10652519
TI  - Crossmodal integration: a good fit is no criterion.

PMID- 10652521
TI  - Attentional modulation of visual motion perception.
AB  - How is the perception and processing of visual motion affected by attention? This
      review examines recent research in cognition, perception and neurophysiology that
      explores how ongoing behavioural tasks (and the attentional states they impose)
      modulate the processing of visual motion. Although traditional views hold that
      motion is processed in an obligatory, 'pre-attentive' manner, evidence for
      processing in a task-independent manner is scant. Recent studies of human
      perception that have measured motion priming, motion aftereffects, uncertainty
      effects, and motion-interaction effects indicate instead that even simple aspects
      of motion processing may be substantially affected by whether motion information
      in a task is used or ignored by the perceiver. Single-unit studies in brain areas
      sensitive to visual motion in monkeys, and functional imaging studies on humans,
      also indicate that task and attentional state affect activity levels in brain
      regions thought to be important in motion perception. This review brings together
      these converging findings of attentional modulation of motion perception and
      considers them in light of object-oriented theories of attention.

PMID- 10652522
TI  - Do the eyes have it? Cues to the direction of social attention.
AB  - The face communicates an impressive amount of visual information. We use it to
      identify its owner, how they are feeling and to help us understand what they are
      saying. Models of face processing have considered how we extract such meaning
      from the face but have ignored another important signal - eye gaze. In this
      article we begin by reviewing evidence from recent neurophysiological studies
      that suggests that the eyes constitute a special stimulus in at least two senses.
      First, the structure of the eyes is such that it provides us with a particularly
      powerful signal to the direction of another person's gaze, and second, we may
      have evolved neural mechanisms devoted to gaze processing. As a result, gaze
      direction is analysed rapidly and automatically, and is able to trigger reflexive
      shifts of an observer's visual attention. However, understanding where another
      individual is directing their attention involves more than simply analysing their
      gaze direction. We go on to describe research with adult participants, children
      and non-human primates that suggests that other cues such as head orientation and
      pointing gestures make significant contributions to the computation of another's
      direction of attention.

PMID- 10652523
TI  - Non-verbal numerical cognition: from reals to integers.
AB  - Data on numerical processing by verbal (human) and non-verbal (animal and human)
      subjects are integrated by the hypothesis that a non-verbal counting process
      represents discrete (countable) quantities by means of magnitudes with scalar
      variability. These appear to be identical to the magnitudes that represent
      continuous (uncountable) quantities such as duration. The magnitudes representing
      countable quantity are generated by a discrete incrementing process, which
      defines next magnitudes and yields a discrete ordering. In the case of continuous
      quantities, the continuous accumulation process does not define next magnitudes,
      so the ordering is also continuous ('dense'). The magnitudes representing both
      countable and uncountable quantity are arithmetically combined in, for example,
      the computation of the income to be expected from a foraging patch. Thus, on the
      hypothesis presented here, the primitive machinery for arithmetic processing
      works with real numbers (magnitudes).

PMID- 10652524
TI  - Acquiring generic knowledge.
AB  - Generic knowledge is knowledge about kinds of things. The existence of generic
      knowledge poses a difficult acquisition problem: how do we acquire knowledge
      about kinds of things if we have experience with only a limited number of
      examples of the kinds in question? The problem is exacerbated by the fact that we
      sometimes acquire generic knowledge on the basis of experience with only a single
      instance of the kind. In this review, it is argued that there is a formal system
      for common-sense conception that underlies the acquisition of an important class
      of generic knowledge. Generic knowledge acquired through the use of the formal
      system represents the stable knowledge we have about kinds of things. It
      complements, rather than replaces, the statistical and causal (mechanistic)
      knowledge acquired through the use of other learning mechanisms.

PMID- 10652525
TI  - The awesome power of yeast biochemical genomics.
AB  - A new genomic strategy for identifying the gene encoding any biochemical activity
      has recently been developed, in which an array of individual yeast strains
      expressing a genomic set of open reading frames fused to glutathione S
      transferase can be assayed for a biochemical activity of interest. Designated
      'biochemical genomics', this approach represents an innovative application of
      genomic information.

PMID- 10652527
TI  - Vertebrate evolution: recent perspectives from fish.
AB  - Recent progress in understanding the evolution of vertebrate genomes has been
      rapid, and previous notions that all such genomes could be regarded as equivalent
      in their gene content have been rendered outdated. This notion, often embodied in
      the representation that vertebrates possess four Hox complexes, still appears in
      contemporary textbooks of developmental biology. Recent data from the genomes of
      teleost fish show that this assumption is untrue and suggest that interesting
      situations might arise from the apparent proliferation of genes among fish.

PMID- 10652526
TI  - RAP, RAP, open up! New wrinkles for RAP1 in yeast.
AB  - RAP1 (repressor/activator protein 1) from budding yeast is well known for its
      involvement in gene activation and repression, telomere structure and function,
      and replication. Recent studies have examined additional roles for RAP1 in
      heterochromatin boundary-element formation, creation of hotspots for meiotic
      recombination, and chromatin opening. These studies provide new insight into the
      ability of this abundant DNA-binding protein to participate in a diverse array of
      functions taking place in a chromatin environment.

PMID- 10652528
TI  - Position-specific codon conservation in hypervariable gene families.

PMID- 10652529
TI  - Origin of replication of Thermotoga maritima.

PMID- 10652530
TI  - MIRs as agents of mammalian gene evolution.

PMID- 10652531
TI  - Organelle genes--do they jump or are they pushed?

PMID- 10652532
TI  - Identifying HOX paralog groups by the PBX-binding region.

PMID- 10652533
TI  - Insights into the functions of BRCA1 and BRCA2.
AB  - Since BRCA1 and BRCA2 were cloned five years ago, unraveling their normal
      functions has posed fascinating problems for cancer biologists. Both genes are
      novel, and little of their normal function was revealed by their sequence. Both
      genes contribute to homologous recombination and DNA repair, to embryonic
      proliferation, to transcriptional regulation and, for BRCA1, to ubiquitination.
      But questions regarding BRCA1 and BRCA2 biology remain, and their resolution is
      critical for clinical development. Why do ubiquitously expressed genes that
      participate in universal pathways lead, when mutant, specifically to breast and
      ovarian cancer? Why are the same genes required for embryonic proliferation and
      for tumor suppression?

PMID- 10652534
TI  - Functions of LIM-homeobox genes.
AB  - Homeobox genes play fundamental roles in development. They can be subdivided into
      several subfamilies, one of which is the LIM-homeobox subfamily. The primary
      structure of LIM-homeobox genes has been remarkably conserved through evolution.
      Have their functions similarly been conserved? A host of new data has been
      derived from mutational analysis in diverse organisms, such as nematodes, flies
      and vertebrates. These studies have revealed a prominent involvement of LIM
      homeodomain proteins in tissue patterning and differentiation, and their function
      in neural patterning is evident in all organisms studied to date. Here, we
      summarize the recent findings on LIM-homeobox gene function, compare the function
      of these genes from different organisms and describe specific co-factor
      requirements.

PMID- 10652535
TI  - The ADAM gene family: surface proteins with adhesion and protease activity.
AB  - An ADAM is a transmembrane protein that contains a disintegrin and
      metalloprotease domain and, therefore, it potentially has both cell adhesion and
      protease activities. Currently, the ADAM gene family has 29 members, although the
      function of most ADAM gene products is unknown. We discuss the ADAM gene products
      with known functions that act in a highly diverse set of biological processes,
      including fertilization, neurogenesis, myogenesis, embryonic TGF-alpha release
      and the inflammatory response.

PMID- 10652536
TI  - Eukaryotic DNA replication: a model for a fixed double replisome.
AB  - To duplicate their genomes, eukaryotic cells have to overcome some formidable
      chemical and topological hurdles, considering the number of nucleotides that have
      to be polymerized faithfully and the sheer physical size of the DNA molecules
      that have to be disentangled and partitioned in an orderly way. This article
      tackles one particular aspect of the process: the organization of the apparatus
      that advances the replicative growing forks along the DNA molecule. Here, I
      suggest a solution to the difficulty of separating the daughter molecules in an
      orderly way and propose an alternative to the current models, which reconciles
      the use of a single polarity of synthesis by the DNA polymerases with the need
      for parallel polymerization of two strands of opposite polarity.

PMID- 10652537
TI  - Genetic research and culturally specific risks: one size does not fit all.

PMID- 10652538
TI  - Ladislav tauc (1926-1999)

PMID- 10652539
TI  - Is CREB a key to neuronal survival?
AB  - A range of molecules control nerve-cell survival in the brain. Many of these
      molecules might be neuroprotective through activation of the transcription factor
      cAMP-response-element-binding protein (CREB). Activation of CREB, by
      phosphorylation of Ser133, occurs in brain-damage-resistant hippocampal dentate
      granule cells and is triggered by neuroprotective environmental stimulation. In
      addition, the Akt neuroprotective signaling pathway activates CREB, and CREB
      synthesis and phosphorylation promote the survival of many cells, including
      neurons, in vitro. Thus, CREB might be responsible for programmed nerve-cell
      survival. Studies investigating its role in the brain are now required to confirm
      these in vitro results, and the downstream survival genes, whose expression is
      activated by CREB in neurons, need to be identified.

PMID- 10652540
TI  - Dendritic spine formation and pruning: common cellular mechanisms?
AB  - The recent advent of novel high-resolution imaging methods has created a flurry
      of exciting observations that address a century-old question: what are biological
      signals that regulate formation and elimination of dendritic spines? Contrary to
      the traditional belief that the spine is a stable storage site of long-term
      neuronal memory, the emerging picture is of a dynamic structure that can undergo
      fast morphological variations. Recent conflicting reports on the regulation of
      spine morphology lead to the proposal of a unifying hypothesis for a common
      mechanism involving changes in postsynaptic intracellular Ca2+ concentration,
      [Ca2+]i: a moderate rise in [Ca2+]i causes elongation of dendritic spines, while
      a very large increase in [Ca2+]i causes fast shrinkage and eventual collapse of
      spines. This hypothesis provides a parsimonious explanation for conflicting
      reports on activity-dependent changes in dendritic spine morphology, and might
      link these changes to functional plasticity in central neurons.

PMID- 10652542
TI  - Reply

PMID- 10652541
TI  - Fast regulation of steroid biosynthesis: a further piece in the neurosteroid
      puzzle.

PMID- 10652543
TI  - Volume transmission.

PMID- 10652544
TI  - Reply

PMID- 10652545
TI  - Calpain and caspase: can you tell the difference?, by kevin K.W. WangVol. 23, pp.
      20-26

PMID- 10652546
TI  - Autoreceptors, membrane potential and the regulation of transmitter release.
AB  - It has been suggested that depolarization per se can control neurotransmitter
      release, in addition to its role in promoting Ca2+ influx. The 'Ca2+ hypothesis'
      has provided an essential framework for understanding how Ca2+ entry and
      accumulation in nerve terminals controls transmitter release. Yet, increases in
      intracellular Ca2+ levels alone cannot account for the initiation and termination
      of release; some additional mechanism is needed. Several experiments from various
      laboratories indicate that membrane potential has a decisive role in controlling
      this release. For example, depolarization causes release when Ca2+ entry is
      blocked and intracellular Ca2+ levels are held at an elevated level. The key
      molecules that link membrane potential with release control have not yet been
      identified: likely candidates are presynaptic autoreceptors and perhaps the Ca2+
      channel itself.

PMID- 10652547
TI  - Gap junctions, synchrony and seizures.
AB  - The old concept that the direct intercellular cytoplasmic connections between
      neurones participate in the coordination of neuronal activity has gained new
      relevance, owing to recent theoretical and experimental evidence, particularly
      with regard to neuronal synchronization and epileptogenesis. Computer simulations
      demonstrating that neurones synchronize and alter their firing patterns depending
      on gap-junctional communication, have provided insights into the interactions
      between electrotonic coupling and cellular and synaptic characteristics.
      Experimental manipulations of gap-junctional communication support its role in
      the generation and maintenance of synchronized neuronal firing and seizures.
      Hence, in addition to chemical transmission, direct electrotonic coupling might
      contribute to normal and abnormal physiological brain rhythms.

PMID- 10652548
TI  - Postsynaptic protein phosphorylation and LTP.
AB  - Prolonged changes in synaptic strength, such as those that occur in LTP and LTD,
      are thought to contribute to learning and memory processes. These complex
      phenomena occur in diverse brain structures and use multiple, temporally staged
      and spatially resolved mechanisms, such as changes in neurotransmitter release,
      modulation of transmitter receptors, alterations in synaptic structure, and
      regulation of gene expression and protein synthesis. In the CA1 region of the
      hippocampus, the combined activation of SRC family tyrosine kinases, protein
      kinase A, protein kinase C and, in particular, Ca2+/calmodulin-dependent protein
      kinase II results in phosphorylation of glutamate-receptor-gated ion channels and
      the enhancement of subsequent postsynaptic current. Crosstalk between these
      complex biochemical pathways can account for most characteristics of early-phase
      LTP in this region.

PMID- 10652550
TI  - Do tall trees scale physiological heights?

PMID- 10652549
TI  - Complex interactions between mGluRs, intracellular Ca2+ stores and ion channels
      in neurons.
AB  - Metabotropic glutamate receptors (mGluRs) can increase intracellular Ca2+
      concentration via Ins(1,4,5)P3- and ryanodine-sensitive Ca2+ stores in neurons.
      Both types of store are coupled functionally to Ca2+-permeable channels found in
      the plasma membrane. The mGluR-mediated increase in intracellular Ca2+
      concentration can activate Ca2+-sensitive K+ channels and Ca2+-dependent
      nonselective cationic channels. These mGluR-mediated effects often result from
      mobilization of Ca2+ from ryanodine-sensitive, rather than Ins(1,4, 5)P3
      sensitive, Ca2+ stores, suggesting that close functional interactions exist
      between mGluRs, intracellular Ca2+ stores and Ca2+-sensitive ion channels in the
      membrane.

PMID- 10652551
TI  - Wolbachia as a speciation agent.

PMID- 10652552
TI  - Testing the relative importance of positive and negative effects on community
      structure.

PMID- 10652553
TI  - Why egg yolk is yellow.

PMID- 10652554
TI  - Implications of paleorecords for ecosystem management.

PMID- 10652555
TI  - Population viability analyses in plants: challenges and opportunities.
AB  - This review of 95 plant population viability analyses (PVAs) reveals that most
      studies consider one species, only a few populations and are based on data
      collected for less than five years. Only five studies referred to themselves as
      PVAs. Plants offer numerous challenges, such as seed banks and periodic
      recruitment, but these can be answered with suitable data collection and
      modeling. New approaches, such as metapopulation models, inclusion of disturbance
      cycles, and integration of genetics and demography, are producing more realistic
      PVAs. Although exact solutions are fraught with limitations, plant PVAs can be
      useful in comparing management regimes, populations and microhabitats, and in
      using these results to guide conservation and management.

PMID- 10652556
TI  - Biological consequences of global warming: is the signal already apparent?
AB  - Increasing greenhouse gas concentrations are expected to have significant impacts
      on the world's climate on a timescale of decades to centuries. Evidence from long
      term monitoring studies is now accumulating and suggests that the climate of the
      past few decades is anomalous compared with past climate variation, and that
      recent climatic and atmospheric trends are already affecting species physiology,
      distribution and phenology.

PMID- 10652557
TI  - Recent mass invasion of the North American Great Lakes by Ponto-Caspian species.
AB  - The North American Great Lakes have been invaded and dramatically altered by more
      than 145 alien species. Many invasions have occurred during the past few decades
      because of the release of Eurasian ballast water from transoceanic ships. Current
      regulations require ships to exchange foreign ballast with highly saline water
      before entering the Great Lakes; this procedure should prevent colonization by
      strictly freshwater species, but species with broad salinity tolerance might
      survive transport in exchanged water. A recent series of invasions by euryhaline
      organisms from the Black and Caspian Seas region signals a new phase in the
      transformation of the Great Lakes - one that supports the concept of an
      'invasional meltdown'.

PMID- 10652558
TI  - The fall and rise of Dr Pangloss: adaptationism and the Spandrels paper 20 years
      later.
AB  - Twenty years have passed since Gould and Lewontin published their critique of
      'the adaptationist program' - the tendency of some evolutionary biologists to
      assume, rather than demonstrate, the operation of natural selection. After the
      'Spandrels paper', evolutionists were more careful about producing just-so
      stories based on selection, and paid more attention to a panoply of other
      processes. Then came reactions against the excesses of the anti-adaptationist
      movement, which ranged from a complete dismissal of Gould and Lewontin's
      contribution to a positive call to overcome the problems. We now have an
      excellent opportunity for finally affirming a more balanced and pluralistic
      approach to the study of evolutionary biology.

PMID- 10652559
TI  - The mid-domain effect: geometric constraints on the geography of species
      richness.
AB  - Geographic patterns of species richness are influenced by many factors, but the
      role of shared physiographical and physiological boundaries in relation to range
      size distributions has been surprisingly neglected, in spite of the fact that
      such geometric constraints lead to mid-domain richness peaks even without
      environmental gradients (the mid-domain effect). Relying on null models, several
      recent studies have begun to quantify this problem using simulated and empirical
      data. This approach promises to transform how we perceive geographic variation in
      diversity, including the long unresolved latitudinal gradient in species
      richness. The question is not whether geometry affects such patterns, but by how
      much.

PMID- 10652560
TI  - The relationship of cathepsin B and stefin A mRNA localization identifies a
      potentially aggressive variant of human prostate cancer within a Gleason
      histologic score.
AB  - Cathepsin B (CB) is involved in degradation of extracellular matrix proteins
      during tumor progression in human solid organ tumors (such as colorectal,
      bladder, and breast cancers), including human prostate cancer. Its activities are
      regulated by endogenous inhibitors (such as stefins or cystatins). Increased
      expression of cathepsin B message, protein, and membrane association have been
      linked to malignancy, but there are very few studies of their mRNA expression in
      prostate cancer using in situ hybridization techniques. Our objective was to
      determine the relationship of CB and stefin A (cystatin A) mRNA localization to
      the Gleason grading system for histologic scores in the hope of distinguishing
      aggressive and less aggressive variants of prostate cancer. We used a 25-base
      biotinylated oligonucleotide CB cDNA antisense probe to localize CB message and a
      27-base biotinylated oligonucleotide stefin A cDNA antisense probe to localize
      stefin A message. Prostate samples from 41 prostatectomy patients were collected
      along with their pre-surgery serum PSA levels and clinical stage of the disease.
      Sections prepared from frozen prostate tissue samples were hybridized with the CB
      and stefin A and control pBR 322 probes using techniques reported by Sinha et al.
      [1] and their distribution quantitated by an image analysis system. Prostate
      sections treated with RNAse before hybridization or incubated with the pBR 322
      control probe showed little or no reaction products, confirming that localization
      of CB and stefin A probes was specific. In prostate cancer, the reaction products
      were found in neoplastic and invasive cells and occasionally in stromal cells.
      The ratios of CB to stefin A were similar in normal prostate and benign prostatic
      hyperplasia (BPH) whereas they varied consistently within and between Gleason
      histologic scores for prostate cancer. These variations showed three localization
      patterns; namely, prostate cancers with higher levels of CB than stefin A, lower
      levels of CB than stefin A, and similar levels of CB and stefin A. All three
      patterns and ratios for CB and stefin A were found in prostate samples (22/41)
      represented by the Gleason histologic score 6 tumors. In these tumors, serum PSA
      levels ranged from 1 to 78 ng/ml and prostate cancers showed B, C, and D clinical
      stages. There was no correlation of CB/stefin A ratio and serum PSA values or
      clinical stage in a limited number of prostate cancer cases. Our data showed that
      there were prostate cancer cases within Gleason histologic scores which expressed
      high, similar, and low levels of CB when compared to stefin A. We postulate that
      prostate cancer cases showing higher levels of CB compared to stefin A probably
      represent an aggressive variant of this cancer within any one Gleason histologic
      score. If this is the case, aggressive variants of prostate cancer would occur
      within Gleason scores 3 to 10 even though higher scores are usually considered
      more aggressive forms of prostate cancers. Since our study is based upon a very
      limited number of frozen prostate samples, we emphasize that a larger series of
      archival prostate cancer samples along with their survival data should be
      analyzed to establish any relationship of CB/stefin A ratio and aggressive
      variants of this cancer. Therefore, our conclusion is tentative. Our study
      provides a partial explanation for differences in the clinical course of prostate
      cancer in patients. This is the first study to show that determination of CB and
      stefin A mRNA ratios may lead to identification of aggressive and less aggressive
      variants of prostate cancer within a Gleason histologic score.

PMID- 10652561
TI  - Determining the telomerase activity of exfoliated cells in intestinal lavage
      solution to detect colorectal carcinoma.
AB  - In order to make a definitive diagnosis of colorectal carcinoma, it is desirable
      to detect cancerous cells in stool samples. The detection of cancer gene products
      in stool samples, however, is said to be extremely difficult. The involvement of
      telomerase in the development of various malignancies has been reported. We
      therefore performed colonoscopy and thereby collected the intestinal lavage
      solution remaining in the lower portion of rectum to determine any possible signs
      of colorectal carcinoma. This fluid consisted of a combination of stool and
      exfoliated intestinal mucosa. We examined the telomerase activity of the
      intestinal lavage solution, collected from 19 colorectal carcinoma patients and
      from 11 volunteers (colonospically normal controls) based on the method of the
      telomeric repeat amplification protocol (TRAP) assay. All patients drank a
      polyethylene glycol-electrolyte lavage solution (PEG-ELS) before the examination.
      Sample solutions were collected by the colonoscope at the beginning of
      colonoscopy. Telomerase activity was thus found in 11 (57.9%) of the 19
      intestinal lavage solution samples. In contrast, all eleven samples from the
      colonoscopically normal subjects were negative. These findings thus suggest that
      measuring telomerase activity of exfoliated cells in intestinal lavage solution
      may thus be useful as a new diagnostic method for colorectal carcinoma.

PMID- 10652562
TI  - Apoptosis: a two-edged sword in aging.
AB  - It is now recognized that apoptosis plays an important role in many physiological
      processes, including aging and age-related diseases. Apoptosis plays both
      positive and negative roles in aging, and some of these roles are reviewed here.
      Of particular importance are the roles of apoptosis in reducing cancer incidence,
      and in promoting neurodegenerative disease. Therefore, the regulation of
      apoptosis is an inviting target for therapeutic interventions in aging and age
      related disease.

PMID- 10652563
TI  - Identification of novel human kallikrein-like genes on chromosome 19q13.3-q13.4.
AB  - The human kallikrein gene family is localized on chromosome 19q13.3-q13.4 and
      currently includes three members: KLK1 or pancreatic/renal kallikrein, KLK2 or
      human glandular kallikrein and KLK3 or prostate-specific antigen (PSA). The
      latter two genes are almost prostate-specific and they are used for diagnosis and
      monitoring of prostate cancer and more recently, in breast cancer applications.
      In this paper, we analyzed a 300Kb genomic DNA region around chromosome 19q13.3
      q13.4 in an effort to map known kallikrein or kallikrein-like genes and identify
      new kallikrein-like genes. Using the known kallikrein or kallikrein-like genes
      PSA, KLK2, enzyme and normal epithelial cell-specific 1 gene (NES1) as landmarks,
      we have identified another six novel genes of which, five have protein homologies
      and gene structure similarities with other kallikreins or kallikrein-like genes.
      We conclude, contrary to the current belief, that the human kallikrein gene locus
      contains a large number of kallikrein-like genes (at least thirteen). In this
      paper, we present a detailed description of the human kallikrein gene locus,
      encompassing the already known and newly identified genes. These new genes, like
      the already known kallikreins, may have utility for diagnosis, monitoring and
      therapeutics of various cancers including those of the breast, prostate and
      testis.

PMID- 10652564
TI  - The Brca1 and Brca2 proteins and tumor pathogenesis.
AB  - Germline alterations of the BRCA1 or BRCA2 genes result in susceptibility to
      breast and ovarian cancer. Protein-protein interaction studies, transcription
      activity and mouse knockout experiments have suggested that the Brca1 and Brca2
      proteins are of importance in DNA repair and maintenance of genome integrity,
      possibly due to the transactivation function of Brca1 or Brca2. Subsequently,
      tumors in individuals carrying germline mutation in either BRCA1 or BRCA2 gene
      show instability at chromosomal and gene level. Chromosomal and gene alterations
      are more pronounced in tumors from BRCA1 and BRCA2 mutation carriers than in
      sporadic tumors. Furthermore, BRCA1 and BRCA2 mutated breast tumors differ from
      sporadic tumors in respect to histological phenotype. Typically, a higher grade
      of malignancy is observed in familial tumors. This review summarizes the putative
      functions of the Brca1 and Brca2 proteins and pathogenesis in tumors of BRCA1 and
      BRCA2 mutation carriers.

PMID- 10652565
TI  - Inhibition of tumor necrosis factor-induced necrotic cell death by the zinc
      finger protein A20.
AB  - Tumor Necrosis Factor (TNF) is a cytokine that induces necrotic and apoptotic
      forms of cell death. The TNF-induced signalling mechanisms leading to necrosis or
      apoptosis are partially distinct, and are therefore likely to be regulated in a
      different way. The zinc finger protein A20 is a TNF-induced primary response gene
      that has been shown to inhibit TNF-induced apoptosis. However, its ability to
      inhibit the necrotic route of cell death as well as the underlying mechanism
      remains unknown. Here we show that stable expression of A20 or a fusion protein
      consisting of Green Fluorescent Protein (GFP) and A20 protects the TNF-sensitive
      fibroblast cell line L929 partially from TNF-induced necrotic cell death. TNF
      induced necrosis has been shown to involve the activation of several
      phospholipases, as well as an increased production of reactive oxygen radicals.
      The reduced TNF-sensitivity of A20-expressing L929 cells was correlated with a
      decrease of TNF-induced phospholipase A2 (PLA2), phospholipase C (PLC) and
      phospholipase D (PLD) activation. Furthermore, production of mitochondrial
      reactive oxygen intermediates was retarded by overexpression of A20. These
      results demonstrate that A20 not only inhibits TNF-induced apoptosis but also TNF
      induced necrosis, suggesting that it interferes with an early step in TNF
      signalling which is required for both types of cell death.

PMID- 10652566
TI  - Recombinant vaccinia virus expressing cytokine GM-CSF as tumor vaccine.
AB  - The efficacy of a recombinant vaccinia virus (rvv-GM-CSF) expressing the
      granulocyte macrophage colony stimulating factor (GM-CSF) as tumor vaccine was
      evaluated in the murine B16-F10 melanoma model. The vaccine was prepared by
      infection of irradiated tumor cells with rvv-GM-CSF. Control vaccine was B-16
      cells infected with a recombinant vaccinia virus expressing Escherichia coli beta
      galactosidase (rvv-lacZ). Pre-vaccination of naive C57BL/6 mice later inoculated
      with tumor cells and treatment of mice bearing tumors with GM-CSF vaccine
      inhibited tumor development and prolonged survival. Lung metastasis of B-16 was
      also inhibited by treatment with GM-CSF vaccine. The vaccine effects appeared to
      be tumor cell specific. The efficacy of the vaccine was comparable to a
      retroviral vaccine (MFG-muGM-CSF) in this system. The vaccine was also effective
      when rvv-GM-CSF was directly injected into the tumor. These data suggest that
      this vaccine approach has potential for use in cancer treatment, especially for
      patients with easily accessible tumors.

PMID- 10652567
TI  - Chemoprevention of mammary cancer with Se-allylselenocysteine and other
      selenoamino acids in the rat.
AB  - The present study examined the mammary cancer chemopreventive activity of Se
      methylselenocysteine, Se-propylselenocysteine and Se-allylselenocysteine in the
      rat methylnitrosourea (MNU) model. Each compound was supplemented in the diet at
      a level of 2 ppm Se for the entire duration of the experiment after MNU dosing.
      Se-Allylselenocysteine was the most active and caused a reduction in total tumor
      yield by 86%. Se-Methylselenocyteine and Se-propylselenocysteine were similar but
      less effective, and both produced a decrease of about 50% in tumorigenesis. All
      three compounds were very well absorbed through the gastrointestinal tract.
      However, more selenium was excreted in urine after gavaging with Se
      propylselenocysteine or Se-allylselenocysteine compared with Se
      methylselenocysteine. Analysis of selenium in the mammary gland and other organs
      showed that tissue selenium levels did not appear to be correlated with
      differences in chemopreventive activity. A lyase activity capable of catalyzing
      scission of the Se-alkyl group from the remainder of the amino acid was
      demonstrated. This activity was found to be high in liver and kidney, but
      relatively low in mammary gland and intestine. Minimal variations in enzyme
      activity towards each of the substrates were observed. Our results support the
      concept that Se-alkylselenoamino acids could be used as precursors for delivering
      the Se-alkyl moiety and that intrinsic chemical differences in the Se-alkyl
      substituent of the test compounds are likely to be important determinants of
      their biological effects.

PMID- 10652568
TI  - Warthin's tumour is not an Epstein-Barr virus related disease.
AB  - BACKGROUND: The histogenesis of Warthin's tumour (WT) is controversial. A
      possible role for Epstein-Barr virus (EBV) has been suggested. MATERIALS AND
      METHODS: Twenty formaldehyde-fixed, paraffin-embedded blocks of WT from the
      parotid gland were examined for the presence of EBV. In situ hybridisation was
      performed using EBV encoded small nuclear RNAs (EBER1/2) probes labelled with
      fluorescein isothiocyanate. An EBV-positive P3HR-1 cell line processed to
      paraffin wax was used as a positive control and a brain section as negative
      control. RESULTS: EBER1/2 could not be found in the neoplastic epithelial cells
      in any of the tumours nor in the adjacent normal parotid tissues. Individual
      positive lymphocytes were present in 7 tumours. CONCLUSIONS: These results
      indicated that EBV is not involved in the pathogenesis of WT.

PMID- 10652569
TI  - The use of liposomal anticancer agents to determine the roles of drug
      pharmacodistribution and P-glycoprotein (PGP) blockade in overcoming multidrug
      resistance (MDR).
AB  - Many attempts to circumvent P-glycoprotein (PGP)-based multidrug resistance (MDR)
      in cancer chemotherapy have utilized PGP blocking agents (also referred to as MDR
      modulators), which are co-administered with the anticancer drug. This approach is
      based on the premise that inhibiting PGP function will result in increased
      accumulation of many anticancer drugs in the tumor cells and restore full
      antitumor activity. However, co-administration of MDR modulators with anticancer
      drugs has often resulted in exacerbated toxicity of the anticancer drugs and
      limited chemosensitization of MDR tumors. These problems appear to be related to
      MDR modulator blockade of PGP excretory functions in healthy tissues, such as
      liver and kidney, which markedly reduces anticancer drug clearance properties.
      Two consequences of these pharmacokinetic interactions are: 1. Increased toxicity
      due to modulator-induced changes in biodistribution properties of the anticancer
      drug. 2. Problems interpreting preclinical and clinical data with respect to: a)
      Are therapeutic improvements due to altered pharmacokinetics or PGP modulation
      within the tumor cells? And, b) Does decreasing the anticancer drug dose to that
      which is equitoxic in the absence of the modulator potentially compromise tumor
      therapy due to decreased anticancer drug levels in the tumor tissue? Although
      many of the difficulties associated with co-administration of MDR modulators and
      anticancer drugs are manifested by toxicity effects, it is ultimately the ability
      to obtain effective antitumor activity against resistant tumors that will
      determine the utility of chemosensitization approaches. Liposomes appear to be
      well suited to solve many of the problems noted above that are associated with
      conventional anticancer drugs and MDR modulators. In view of these
      considerations, we have hypothesized that inadequate tumor delivery of anticancer
      agents and selectivity of PGP modulation are primarily responsible for the
      attenuated therapy of extravascular MDR solid tumors overexpressing PGP.
      Liposomal carriers have been utilized to provide tumor selective delivery of
      anticancer agents as well as to circumvent many toxicities associated with these
      agents by altering the pharmacodistribution properties of encapsulated drugs (1
      4). Given the pharmacokinetic changes induced by the MDR modulators on non
      encapsulated doxorubicin (DOX), we proposed that liposomes may limit these
      effects by virtue of their ability to reduce the exposure of encapsulated DOX to
      the kidneys and alter clearance of DOX in the liver (5,6). These tissues appear
      to be key factors involved in modulator-induced DOX pharmacokinetic changes (7).
      In conjunction with these toxicity buffering effects, the effect of PGP blockade
      on the cellular uptake of DOX in the tumor may be able to be selectively
      increased using liposomal carriers. This is based on the ability of small
      liposomes to passively extravasate in tumors (1,2,8,9) as well as their inability
      to accumulate in healthy susceptible tissues. By studying the toxicity and
      efficacy properties of liposome encapsulated DOX in combination with the MDR
      modulator PSC 833 we have been able to demonstrate that two factors play a major
      role in determining the effectiveness of chemosensitization approaches to
      overcome MDR; 1) optimizing selective localization of anticancer drug
      localization in tumor tissue and 2) effective blockade of PGP in tumor cells
      under conditions that do not compromise anticancer drug accumulation into the
      tumor. Failure to achieve both of these conditions simultaneously may be expected
      to result in substantially reduced therapy of MDR tumors.

PMID- 10652570
TI  - CHML suppresses cell growth and induces apoptosis in multiple human tumor lines.
AB  - In the present study, we have investigated the effect of cytotropic heterogeneous
      molecular lipid (CHML), a new anticancer agent, on growth suppression in a
      variety of human tumor cell lines. At a non-toxic concentration (a range from 25
      micrograms/ml to 100 micrograms/ml), CHML has shown to strongly inhibit tumor
      cell growth by using a typical colony survival assay. At a treatment of
      concentration of 50 micrograms/ml for 6 hours, CHML is able to suppress 50% of
      the tumor cell colony formation. At a concentration of 100 micrograms/ml (the
      therapeutic dosage in the clinical trial), more than 90% of the cells were killed
      in human breast carcinoma MCF-7, colorectal carcinoma RKO, kidney carcinoma G410,
      lung carcinoma and human myeloid leukemia ML-1 lines. In contrast, growth
      suppression of non-cancerous human skin fibroblasts by CHML was observed much
      less than that seen in tumor lines. These results indicate that CHML is an
      efficient inhibiting agent in tumor cell growth and is able to generate greater
      suppression in tumor cells than in noncancerous cells. With the use of DNA
      fragmentation assay, CHML was found to induce apoptosis in MCF-7, ML-1, H1299 and
      RKO lines after treatment at a concentration of 75 micrograms/ml for 8 hours.
      Following the CHML treatment, the tumor suppressor p53 protein elevated in RKO
      cells at 2 h posttreatment. The induction of p53 reached a peak at 4 hr and
      returned to normal level 16 hr later. Consistent with this result, Bax, which is
      regulated by p53 and is able to promote apoptosis, was also found to increase in
      a same kinetic manner as p53. These results suggest that the p53-pathway is
      activated by CHML and the activation of p53 may contribute to CHML-induced
      apoptosis in some tumor cells, such as MCF-7, RKO and ML-1. Considering that CHML
      is able to induce apoptosis in H1299 cells, which are of p53-negative status, it
      is speculated that CHML induces programmed cell death through both the p53
      dependent and- independent pathways.

PMID- 10652571
TI  - Inhibition of proliferation, invasion and adhesion of liver cancer cells by 5
      azacytidine and butyrate.
AB  - BACKGROUND: The prognosis for liver cancer is poor with current chemotherapeutic
      agents, for the most part, ineffective. We have recently shown that 5-azacytidine
      (5-azaC) and butyrate stimulate apoptosis in two human liver cancer cell lines
      (HepG2 and Hep3B). The purpose of our present study was to determine the effects
      of these agents on proliferation, invasion and adhesion of liver cancer cells,
      and to assess potential cellular mechanisms for these effects. MATERIALS AND
      METHODS: HepG2 and Hep3B cells were treated with either 5-azaC (8 microM), sodium
      butyrate (35 mM), 5-azaC + butyrate or vehicle (control); proliferation, cellular
      invasion and adherence were determined. Western blots were performed to assess
      expression levels of p21waf1, p27kip1 and p53. RESULTS: Treatment with 5-azaC
      alone inhibited invasion of Hep3B cells whereas butyrate alone inhibited invasion
      of HepG2 cells; the combination of 5-azaC + butyrate completely suppressed the
      invasion of both cell lines. Moreover, cellular adhesion and proliferation were
      inhibited in both cell lines by combination treatment. Levels of the Cdk
      inhibitor p21waf1 were increased in HepG2 cells after 5-azaC and in both cell
      lines after butyrate treatment; levels of p27kip1 were increased in both cell
      lines after either 5-azaC or butyrate treatment. CONCLUSIONS: Our results
      demonstrate that the combination of 5-azaC and butyrate effectively blocks
      proliferation, invasion and cellular adhesion of both HepG2 and Hep3B cells.
      Increases in the expression of the cell cycle inhibitory proteins, p21waf1 and
      p27kip1 suggest that these effects may be mediated through the induction of these
      inhibitory proteins. Agents such as 5-azaC and butyrate that target the cell
      cycle pathway may prove clinically useful in the adjuvant treatment of liver
      cancers.

PMID- 10652572
TI  - Folate binding protein peptide 191-199 presented on dendritic cells can stimulate
      CTL from ovarian and breast cancer patients.
AB  - Tumor associated lymphocytes (TAL) isolated from malignant ascites cultured in
      media containing interleukin-2 show antitumor responses. These antitumor
      responses are mediated by cytotoxic T lymphocytes (CTL) which recognize antigen
      in the context of MHC molecules using T cell receptors. CD8+ CTL recognize
      peptide epitopes processed from cellular proteins in the context of MHC class I
      molecules. These peptides have a restricted length of 8-11 amino acids. The
      folate binding protein (FBP) is overexpressed in over 90% of ovarian and 20-50%
      of breast cancers. We recently found that FBP is the source of antigenic peptides
      recognized by a number of these CTL-TAL. This indicated that FBP peptides are
      antigenic in vivo for ovarian and breast CTL-TAL. To define FBP immunogenicity, a
      peptide defining the epitope E39 (FBP, 191-199) was presented by PMBC derived
      dendritic cells (DC) from healthy donors isolated by the CD14 method to ovarian
      and breast CTL-TAL. Stimulation of ovarian and breast CTL-TAL by E39 pulsed DC
      (DC-E39), in the presence of IL-2, rapidly enhanced or induced E39 specific CTL
      activity. This E39-responder population consisted of cells expressing TCR V beta
      9, V beta 13, and V beta 17 families, based on the increase in the percentages of
      these families in DC-E39 versus DC-NP stimulated TAL. Characterization of
      immunogenic tumor antigens and of cytokine requirements for induction of
      functional antitumor effectors may be important for future cancer vaccine
      developments.

PMID- 10652573
TI  - A model using radiation and plasmid-mediated tumor necrosis factor-alpha gene
      therapy for treatment of glioblastomas.
AB  - The efficacy of radiotherapy for cancer is limited by the dose that can be safely
      delivered to the tumor without causing debilitating side effects. Previous
      studies have shown an additive or syngeneic reduction in the volume of malignant
      tumors when tumor necrosis factor-alpha (TNF-alpha) protein is administered prior
      to radiation. The major goal of the present investigation was to evaluate the
      efficacy of pGL1-TNF-alpha, a new plasmid construct that expresses human TNF
      alpha protein, together with radiotherapy in the C6 glioma/athymic mouse model.
      Subcutaneously growing tumors were injected with pGL1-TNF-alpha complexed with a
      cationic polyamine and radiation, singly and in combination, over an 8-day
      period. The maximum antitumor effect was achieved with the combination of
      polyamine-pGL1-TNF-alpha and radiation. Each modality used alone, including
      polyamine, modestly slowed tumor growth. In vitro evaluations of blood, spleen,
      and tumor indicated that the antitumor mechanisms of combination therapy may
      include, at least partly, the recruitment and activation of nonspecific effector
      cells. The results demonstrate that polyamine-pGL1-TNF-alpha can be safely and
      effectively administered together with radiation under the conditions used.

PMID- 10652574
TI  - Viscotoxin-free aqueous extracts from European mistletoe (Viscum album L.)
      stimulate activity of human granulocytes.
AB  - BACKGROUND: Extracts from European mistletoe (Viscum album L., VAL) are used for
      complementary cancer treatment. Viscotoxins (VT) and whole plant extracts with
      high amounts of the VT have been shown to stimulate functional activity of
      granulocytes. MATERIALS AND METHODS: We stimulated neutrophils from healthy
      donors in vitro with aqueous VT-free VAL extracts and mistletoe lectins (ML) in
      the presence of E.coli and studied phagocytosis (via incorporation of FITC
      labelled E.coli) and respiratory burst (via oxidation of dihydrorhodamine 123 to
      rhodamine 123) by flow cytometry. RESULTS: The VT-free VAL extract significantly
      stimulated granulocyte activity, and this effect correlated with the content of
      the ML, although the ML exerted no influence at relevant concentrations. Co
      incubation of the cells with VAL in the presence of VT further increased
      granulocyte response. CONCLUSIONS: From these data it is suggested that (1) a non
      VT non-ML component of the VAL extracts activated granulocytes and (2) different
      activation pathways may be involved in the stimulation by the whole plant extract
      and the VT.

PMID- 10652575
TI  - Expression of basement membrane antigens and matrix metalloproteinases 2 and 9 in
      cutaneous basal and squamous cell carcinomas.
AB  - BACKGROUND: Basement membrane (BM) antigens and matrix metalloproteinases (MMP)
      are involved in tumor invasion and metastasis. Basal (BCC) and squamous cell
      carcinomas (SCC) differ with respect to their biological behavior since the
      former are only locally aggressive whereas the latter have a metastatic
      potential. MATERIALS AND METHODS: We studied the immunohistochemical expression
      of several BM antigens and of MMP2 and MMP9, in 13 BCC, 13 SCC, and 8 in situ
      skin carcinomas. RESULTS: The expression of most BM antigens was reduced in the
      tumors in comparison with normal skin. Hemidesmosome- and lamina lucida
      associated antigens (plectin, NUT2, alpha 6/CD49f and laminin-5) were more
      decreased in BCC, whereas collagens type VII and IV were more decreased in SCC as
      compared with BCC; in BCC and SCC both collagens tended to be decreased on the
      leading edge of invasive tumor masses. In situ carcinomas showed a slightly
      diminished expression of alpha 6/CD49f integrin, plectin and NUT2. The expression
      of both MMP2 and MMP9 was increased in SCC as compared with BCC. CONCLUSION: Our
      findings further upheld the role of BM antigens and MMPs in the process of tumor
      aggressiveness. The reduced expression of collagen IV, combined with an increased
      expression of both MMP2 and MMP9 could account for the increased metastatic
      potential of SCC vs BCC through an increased invasion of the extracellular matrix
      and the vascular space.

PMID- 10652576
TI  - Induction of the human ARF protein by serum starvation.
AB  - The ARF protein encoded by the alternative transcript of the INK4a gene inhibits
      cell growth by stabilization of p53. ARF is induced by activated oncogenes sucll
      as c-myc, E1A and E2F-1. We show here that ARF protein expression is also induced
      by serum deprivation in the human tumor cell line MDA-MB-157 and in the SV40
      large T-immortalized keratinocyte line Rhek. This increase of expression was
      reversed by the addition of serum. ARF mRNA levels also increased after serum
      starvation, suggesting that ARF upregulation is mediated, at least in part, by
      increased transcription and/or mRNA stability. These results indicate that ARF
      responds not only to oncogenic hyper-proliferative signals but also to suboptimal
      growth conditions.

PMID- 10652577
TI  - Analysis of the TEL protein during tumour angiogenesis.
AB  - It has been proposed that breast cancer follows a programmed course of
      development that leads to an invasive phenotype that is associated with an
      increase in angiogenesis. Angiogenesis is a multistage process that requires, at
      its early stages, proliferation of endothelial cells, the break-down of their
      basement membranes, and their subsequent migration and organisation into new bud
      like vascular structures. The regulation of endothelial cell proliferation and
      migration during angiogenesis involves the ETS family of transcription factors.
      The TEL gene is a member of the ETS family and may play a role in vessel
      formation. Vascular endothelial growth factor (VEGF) is a specific growth factor
      in new vessel formation and in this study its regulatory effects on TEL protein
      phosphorylation are detailed. The TEL protein is found to be expressed during
      early endothelial cell tube formation in vitro. However, smaller vessels in
      either tumour or ovarian angiogenesis did not express the transcription factor;
      only the larger mature vessels were positive. Interestingly, TEL protein
      expression was lost in the invasive breast carcinoma studied, whilst in normal
      breast tissue, hyperplasia and ductal carcinoma in-situ, TEL protein expression
      was seen. The loss of expression of TEL protein in invasive mammary gland
      carcinoma may be an important factor in the pathogenesis of breast carcinoma.

PMID- 10652578
TI  - Meso-substituted cationic porphyrins interact with dsDNA and exhibit different
      localization patterns in radiation-induced fibrosarcoma cells.
AB  - Meso-substituted cationic porphyrins were examined for binding dsDNA. Subcellular
      localization time studies used Confocal Laser Scanning Microscopy of radiation
      induced fibrosarcoma (RIF) cells incubated with porphyrins. Binding studies
      revealed a reversible interaction between porphyrin and dsDNA that is a function
      of DNA shape. Binding was inhibited at high salt concentrations, and enhanced by
      heat and DNA denaturants such as dimethyl formamide (DMF). Trans dicationic
      porphyrin required more stringent binding conditions than cis dicationic and
      tetracationic porphyrins. Phenol extraction of porphyrin from the DNA-porphyrin
      complex demonstrates that cationic porphyrins do not damage dsDNA at high
      concentrations. Localization studies within a 24-hour range reveal different
      distribution patterns. Metal chelates of tetracationic porphyrin exhibited a
      cytoplasmic localization with the exception of the zinc chelate. Localization of
      other metal chelates appears to be redistributed to lysosomes and mitochondria
      between 3 and 6 hours post-incubation. HPPH used in PDT clinical trials localizes
      to the cytoplasmic compartment.

PMID- 10652579
TI  - Inhibition of farnesyl-protein-transferase in neuroblastoma cells by alpha
      hydroxyfarnesylphosphonate.
AB  - Oncogenic Ras is responsible for malignant transformation in a variety of tumors.
      Farnesylation of Ras by farnesyl-protein-transferase (FPTase) is necessary for
      membrane localization of Ras-proteins, a prerequisite for its biological
      activity. Although mutations in ras genes are rare in neuroblastoma inactivation
      of Ras by inhibition of the FPTase is of interest in neuroblastoma. In this
      tumor, amplification of N-myc is frequently observed and expression of N-myc is
      induced via Ras signaling. Farnesyl-protein-transferase of neuroblastoma cells is
      inhibited by alpha-hydroxyfarnesylphosphonate. In homogenates of the cell line SK
      N-AS an ID50 = 6.5 microM is estimated, in SK-N-SH the ID50 is 3.4 microM. The
      consequences of the inhibition of FPTase on the membrane localization was
      examined by immunoblots. Western blots of membrane proteins analysed with H-ras
      and N-ras specific antibodies revealed that H-ras protein is more sensitive to
      the inhibition of FPTase than N-ras protein. After culturing neuroblastoma cells
      for 24 hrs in the presence of 20 microM alpha-hydroxyfarnesylphosphonate H-ras
      protein completely dissappeared from the membrane fraction whereas N-ras protein
      was only affected by 50%. K-ras was not detectable on Western blots of three
      neuroblastoma cell lines. The experiments showed that FPTase inhibitors are
      effective in neuroblastoma cells but for complete inactivation of N-ras stronger
      conditions are required than for H-ras.

PMID- 10652580
TI  - Production of amyloid beta protein precursor as a proteinase inhibitor by human
      astrocytic tumors.
AB  - The production of amyloid beta protein precursor (APP), which is a potent
      inhibitor of matrix metalloproteinases and serine proteinases, in human
      astrocytic tumors (n = 17) and normal brain tissues (n = 3) was investigated. We
      found proteinase inhibitory activity at around 120 kD by trypsin reverse
      zymography in the culture media of explant cultures of anaplastic astrocytomas
      and glioblastomas, but not in those of astrocytomas and normal brain tissues.
      Immunohistochemistry using a monoclonal antibody against human APP demonstrated
      that APP was detectable mainly in tumor and endothelial cells. Semiquantative
      analysis of western blotting revealed that immunoreactivity for APP in the
      culture media of tumor explant cultures appeared to be increased associated with
      the malignancy of astrocytic tumors. These findings suggest that APP production
      may be related to the malignant progression of human astrocytic tumors.

PMID- 10652581
TI  - Presence of defensin in epithelial Langerhans cells adjacent to oral carcinomas
      and precancerous lesions.
AB  - We aimed to immunohistochemically study the localization of defensin (HNPs), a
      family of peptides with antimicrobial and cytotoxic activity, in oral tumor
      tissue. Therefore, tissue sections were embedded in paraffin, and defensin was
      immunostained by the streptavidin-biotin coupled peroxidase method. Langerhans
      cells were confirmed by indirect immunostaining with anti-S-100 protein
      polyclonal antibody. Melanocytes were stained with Fontana-Masson's stain.
      Neutrophils and intimal cells were stained by anti-defensin antibody. Langerhans
      cells in normal epithelium or dysplasic epithelium adjacent to squamous cell
      carcinoma and precancerous lesion were also stained. Defensins (HNPs) are
      nonspecific peptides that occur in neutrophils and protect against bacteria,
      fungi, and tumor cells. Since defensins are also found in epithelial Langerhans
      cells adjacent to tumor tissue, these peptides most likely have a role in tumor
      immunity.

PMID- 10652582
TI  - Immunophenotypical analysis and immunobiology of childhood brain tumors.
AB  - Cancer associated markers (CAMs) are the biochemical and immunological
      counterparts of the morphology of neoplasms. The expression of an
      immunocytochemically defined CAM is related to the tissue of origin and is not a
      random event. During the past two decades, the use of MoABs against oncofetal,
      neoplasm associated, cell lineage specific, endothelial, and cell proliferation
      related antigens in the diagnosis and biological assessment of prognosis in
      neoplastic disease gained increased importance. A sensitive direct correlation
      exists between the expression of certain molecules and the development of an
      invasive, highly malignant immunophenotype (IP) of neoplastic cells, allowing for
      the occurrence of angiogenesis and metastasis. Our systematic and detailed
      cellular IP analyses of 82 childhood brain tumors [34 medulloblastomas
      (MEDs)/primitive neuroectodermal tumors (PNETs), 42 astrocytomas (ASTRs), 5
      choroid plexus papillomas (CPPs) and 1 choroid plexus carcinoma (CPC)], was
      conducted using over 55 MoABs. An indirect, four-step, enzyme linked [alkaline
      phosphatase (AP) and peroxidase (PO)], biotin-streptavidin based, antigen
      detection technique was employed. (ABSTRACT TRUNCATED)

PMID- 10652583
TI  - Immunomodulating and antimetastatic activity of thymic peptides in BALB/c mice.
AB  - The immunomodulating and antimetastatic activity of a clinically approved low
      molecular weight, standardized thymic peptide (TP) preparation was evaluated in
      BALB/c-mice. Daily subcutaneous application of TP (7 consecutive days, 1 and 10
      micrograms per mouse) upregulated counts and activity of peripheral blood cells,
      as measured on day 14. To check the influence of TP on experimental liver
      metastases (liver colonization), RAW H10 lymphosarcoma cells were intravenously
      inoculated into BALB/c-mice. TP (1,10,100 micrograms/mouse) was subcutaneously
      administered daily for 7 consecutive days starting 24 hrs after tumor cell
      challenge. Liver colonization was investigated on day 14 after tumor cell
      inoculation and demonstrated a statistically significant (p < 0.05) reduction of
      experimental liver metastases for TP treated mice.

PMID- 10652584
TI  - The aspirin metabolite salicylate inhibits breast cancer cells growth and their
      synthesis of the osteolytic cytokines interleukins-6 and -11.
AB  - Some epidemiological studies have suggested that aspirin could be a
      chemopreventive agent against breast cancer. We tested the effects of the aspirin
      metabolite salicylate (SA) on four (Hs578T, MCF-7, MDA-MB-231, and T-47D) breast
      cancer cell (BCC) lines in vitro. Two features were studied: the proliferation of
      BCC and their production of the osteolytic cytokines interleukins-6 (IL-6) and 
      11 (IL-11) since BCC frequently metastasize to bone and induce tumor-induced
      osteolysis. SA, from 0.5 to 5 mM, caused BCC growth inhibition by up to 70% (IC50
      range 2.54 to 4.28 mM). At high concentrations, the drug induced apoptosis only
      (MDA-MB-231), or both apoptosis and primary necrosis (MCF-7). SA, as well as
      indomethacin (INDO), reduced the synthesis of IL-6 and -11, at both the protein
      and mRNA levels, in the two cell lines producing these cytokines (MDA-MB-231 and
      Hs578T). This latter effect seemed to be mediated by PGE2 since SA and INDO
      reduced PGE2 levels in MDA-MB-231 and Hs578T cells, PGE2 was not detected in MCF
      7 and T-47D cells and exogenous PGE2 increased IL-6 and -11 expression by MDA-MB
      231 cells. Collectively, our results suggest that SA could reduce the growth of
      breast tumors and inhibit to some extent the ability of BCC to induce osteoclast
      recruitment and osteolysis. These data indicate the need for further
      epidemiological and experimental studies.

PMID- 10652585
TI  - Epstein-Barr virus (EBV)-induced long-term proliferation of CD4+ lymphocytes
      leading to T lymphoblastoid cell lines carrying EBV.
AB  - We have previously demonstrated that Epstein-Barr virus (EBV) strain B95.8 can
      infect and initiate a partial transcriptional program in both CD4+ and CD8+
      lymphocytes (Guan, M. X., R.-D. Zhang, B. Wu, and E. E. Henderson. 1996. J.
      Virol. 70:7341-7346). Experiments were undertaken to determine whether EBV
      infection can alter the growth potential of T lymphocytes. Peripheral blood
      lymphocytes were separated into populations consisting of 99.8% CD4+ and 98.6%
      CD8+ T lymphocytes by FACS. Infection of these populations with EBV resulted in
      blastogenesis in both CD4+ and CD8+ populations. Clones were established from the
      CD4+ population in the presence of interleukin-2. Two of these clones expressed
      the T cell surface markers CD3 and CD4 and carried the EBV genome. One
      lymphoblastoid cell line (LCL) had a mixture of CD4+ and CD19+ cells. The T-LCLs
      harboring the EBV genome in circular form and transcribed mRNA transcripts
      corresponding to BZLF1, BRLF1, BMLF1, and EBER-1 and -2. Immunofluorescence
      demonstrated EBNA in the nucleus of T rosette-positive lymphoblasts with an
      absence of viral capsid antigen expression. In situ hybridization for EBER showed
      nuclear and cytoplasmic staining in B95.8 cells, whereas EBV-carrying T-LCLs only
      showed nuclear staining. These results demonstrate that EBV can both infect and
      induce growth transformation of T lymphocytes, supporting a direct role for EBV
      in AIDS-related, EBV-associated T cell lymphomas. A better understanding of the
      EBV transcriptional program during EBV-induced T cell transformation could
      directly lead to adoptive T cell therapeutic strategies and/or more effective
      antiviral chemotherapy for EBV-associated T cell lymphoma.

PMID- 10652586
TI  - Programmed cell death in colorectal carcinogenesis.
AB  - The most studied mechanism of malignant transformation has been cell
      proliferation. The relationship between programmed cell death (apoptosis), cell
      proliferation, and apoptosis regulatory genes (p53 and bcl-2), was studied in
      normal colonic epithelium, 26 sporadic adenomas both early and late, 25 FAP
      adenomas, and 34 carcinomas. We showed a decrease in programmed cell death and an
      increase in cell proliferation during the transition from adenoma to carcinoma.
      The increase of expression of p53 from early (10%) to late adenomas (87%)
      contrasted with the decrease of bcl-2 staining. Sixty-two per cent and 23% of
      carcinomas were reactive for p53 and bcl-2 respectively. Abnormal early
      activation of the bcl-2 gene, rather than late p53 gene mutation appears to be
      responsible for inhibition of apoptosis in colorectal carcinogenesis. bcl-2 was
      higher in FAP adenomas than in sporadic cases, and in carcinomas favouring the
      accumulation of long-living cells, which are more subject to mutation and thus
      cancerization.

PMID- 10652587
TI  - Quantification and distribution of neovascularization following microinjection of
      C6 glioma cells in rat brain.
AB  - BACKGROUND: It has been suggested that the switch to an angiogenic phenotype can
      separate the development of a tumor into two stages: the prevascular phase and
      the vascular phase. The purpose of the present work is to demonstrate the
      existence of an angiogenic switch in a longitudinal study of a brain tumor model
      during tumor growth by means of microvessel density measurements. MATERIALS AND
      METHODS: The study was performed on 32 rats bearing C6 glioma. At different
      stages of tumor growth, the histological aspects were described and sections were
      immunostained for factor VIII-related antigen in order to highlight microvessel
      endothelial cells. Microvessels were counted at 400 magnification for different
      areas (central non necrotic area, peripheral area, contralateral grey and white
      matter area), using image analysis software. RESULTS: Vessel density was
      significantly higher at the tumor-brain interface than in the center of the tumor
      or in the contralateral cortex. The vessel density remains stable in the tumor
      during the first 3 weeks after cell implantation, after which a clear increase of
      vessel density can be observed. CONCLUSION: The present study demonstrates the
      presence of an angiogenic switch which is concomitant with the development of
      necrosis and pseudopalisading pattern.

PMID- 10652588
TI  - Comparative chemopreventive activity of ibuprofen and N-(4-hydroxyphenyl)
      retinamide against the development and growth of rat mammary adenocarcinomas.
AB  - The chemopreventive effects of Ibuprofen on the development and growth of 7,12
      dimethylbenz(a)anthracene (DMBA) induced rat mammary tumors were examined. A well
      known breast cancer chemopreventive retinoid, N-(4-hydroxyphenyl) retinamide (4
      HPR) was also included in this study for comparison. At 7 days prior to receiving
      a single intragastric dose of 15 mg DMBA, rats were fed a control chow diet, as
      well as diets containing either 1000 mg/kg diet of Ibuprofen or 1.5 mmol/kg diet
      of 4-HPR. Ibuprofen and 4-HPR markedly increased tumor latency. At 112 days post
      DMBA intubation, tumor incidence was 86% in control rats as compared to 74% and
      62% in rats receiving Ibuprofen, and 4-HPR diets respectively (p < 0.05).
      Ibuprofen and 4-HPR reduced tumor burden and tumor volume almost to the same
      extent. The control rats had an average of 2.26 tumors/rat compared to 1.42 and
      1.46 tumors/rat in the Ibuprofen or 4-HPR groups respectively (p < 0.05).
      Similarly, average tumor volume was 3.25 cm3 in the control rats compared to 0.86
      cm3 and 0.83 cm3 in rats receiving Ibuprofen and 4-HPR diets respectively (p <
      0.05). These results suggest that Ibuprofen may have potential in the
      chemoprevention and treatment of breast cancer.

PMID- 10652589
TI  - Differentiation-inducing effect of thymidine on human neuroblastoma cells.
AB  - Human neuroblastoma cells (KP-N-RT(BMI) treated with thymidine underwent
      morphological differentiation, as revealed by the extension of neurites. The
      morphological differentiation was caused by deoxyadenosine as well, but not by
      thymine or deoxyribose. The neurite-extending effect of thymidine was
      counteracted by deoxycytidine, indicating that inhibition of ribonucleotide
      reductase was involved. Similar morphological change was indeed brought about by
      hydroxyurea, a specific inhibitor of the enzyme. Azidothymidine and
      dideoxythymidine were also effective in induction of neurite extension,
      suggesting that inhibition of DNA replication, rather than the reductase per se,
      is responsible for the induction of neurite extension. Supporting this notion,
      various inhibitors of DNA synthesis induced the morphological differentiation of
      the cells. Although a-amanitin and cycloheximide were suppressive, actinomycin D
      promoted the thymidine-induced neurite extension. Morphological changes caused by
      thymidine were similar to those induced by cyclic AMP, rather than retinoic acid.
      Intracellular cAMP content was however not increased by the thymidine treatment.

PMID- 10652590
TI  - Colorectal Kaposi's sarcoma in an HIV-negative male in association with
      ulcerative rectocolitis: a case report.
AB  - A rare case and the first reported in Italy of a classic form of colorectal
      Kaposi's sarcoma, associated with ulcerative rectocolitis, is presented.
      Following a total proctocolectomy, the patient was disease-free at four years.
      Some epidemiological risk factors such as sex, age, place of birth and both
      advanced malaria and immunodepressive therapies have also been evaluated. Thus
      far, only five similar cases have been reported in the literature. However, the
      epidemiological, clinical and prognostic features of this form of Kaposi's
      sarcoma must still be investigated.

PMID- 10652591
TI  - Different human papillomavirus genotypes in ano-genital lesions.
AB  - In order to verify the frequency and physical state of some viral strains of
      Human Papillomavirus (HPV) in anogenital lesions, two-hundred and four specimens
      were studied. HPV/DNA was detected by using non isotopic in situ hybridization
      method, HPV-DNA was found in 25 lesions. The integrated pattern of HPV types
      16/18 was found only in invasive carcinomas, the episomic one in all high risk
      lesions, never in invasive carcinomas. The low oncogenic risk genotypes 6/11 were
      detected only in condylomata acuminata, the high oncogenic risk genotypes 16/18
      were found not only in cervical intraepithelial and invasive lesions, but also in
      a condyloma acuminatum. Our findings confirm the importance of the viral
      genotypes in the evaluation of the risk for malignancy. Therefore, the detection
      of a high risk viral genotype, independently of its physical state, can evoke the
      ghost of the malignancy also in a low risk cervical lesion.

PMID- 10652592
TI  - Immunohistochemical expression of cathepsin D in laryngeal epithelial lesions:
      correlation with CD44 expression, p53 and Rb status and proliferation associated
      indices.
AB  - Clinical studies in several tumour types have shown a strong correlation between
      cathepsin D expression and tumour progression. Immunohistochemical staining for
      cathepsin D (clone D13A) was performed in paraffin embedded-tissues from 39
      invasive squamous cell carcinomas, 13 in situ carcinomas, 35 cases of dysplasia,
      10 papillomas and 17 cases of keratosis. The association between cathepsin D
      expression and CD44, p53, Rb proteins and proliferation indices (Ki-67, PCNA) was
      assessed by univariate analysis. Cathepsin D was highly positive in the groups of
      carcinomas compared to other lesions (p < 0.0001). A statistically significant
      correlation of cathepsin D expression with CD44 expression was observed in
      invasive cancers (p = 0.037). The relationship of cathepsin D immunoreactivity
      with p53, Rb and proliferation indices was insignificant. The results show that
      cathepsin D is expressed in a higher proportion of cancerous lesions of the
      larynx than in non cancerous or premalignant lesions, a fact which suggests that
      cathepsin D may be involved in laryngeal tumour cell growth process.

PMID- 10652593
TI  - Inhibition of attachment and chemotactic invasion of uterine endometrial cancer
      cells by a new vinca alkaloid, conophylline.
AB  - The effect of conophylline, a new vinca alkaloid that inhibits ras expression, on
      tumour cell adhesion and infiltration was evaluated using a human endometrial
      cancer cell line. When SNG-II, a highly differentiated human endometrial cancer
      cell line, was exposed to conophylline, the cells developed filamentous processes
      at concentrations which did not affect cell proliferation (0.03-0.3
      microgram/ml). After exposure to conophylline (0.3 microgram/ml), cells adherent
      to matrigel- and type IV collagen-coated wells respectively decreased to 26.9%
      and 33.3% of the number in the untreated control culture (p < 0.01). In an in
      vitro invasion assay using a Boyden chamber, infiltration of cells exposed to
      conophylline decreased to 19.4% (0.3 microgram/ml) (p < 0.01) of the control. In
      a wound assay, conophylline inhibited the movement of cells at 24 hr after
      wounding. Flow cytometric analysis revealed that expression of integrin beta 1
      was not altered by conophylline, but E-cadherin and CD44 were decreased. The
      expression of E-cadherin and CD44 could be changed by conophlline.

PMID- 10652594
TI  - Laminin-1-adherent cancer cells show increased proliferation and decreased
      apoptosis in vivo.
AB  - BACKGROUND: The growth rate of a tumor is dependent on both cell proliferation
      and cell loss. We have established subpopulations of human colon cancer cells
      with different in vivo growth rates by selecting the cells according to their
      adhesiveness to laminin-1 in vitro. MATERIALS AND METHODS: Laminin-1-adhesion
      selected colon cancer cells were injected into the cecal wall of nude mice. The
      tumors were examined 30 days later. Cell proliferation was assessed by
      proliferating cell nuclear antigen (PCNA) index and apoptotic cells were labeled
      by digoxigenin-11-dUTP using terminal deoxynucleotidyl transferase. RESULTS: The
      laminin-1-adherent cells, which formed larger tumors in vivo, showed increased
      proliferative activity and reduced apoptosis in comparison with the laminin-1
      nonadherent cells. CONCLUSION: Laminin-1 may enhance the malignant behavior of
      colon cancer cells by accelerating proliferation as well as by decreasing cell
      loss.

PMID- 10652595
TI  - Bcl-2 oncogene (B cell lymphoma/leukemia-2) levels correlate with systemic lupus
      erythematosus disease activity.
AB  - OBJECTIVE: Bcl-2 translocation or overexpression is found in many types of
      malignancy, possibly through alteration of the apoptosis mechanism. It has also
      been suggested that similar apoptotic alterations may be important in the
      pathogenesis of systemic lupus erythematosus (SLE). It is believed that a process
      of apoptosis at the stage of maturation or differentiation of lymphocytes may be
      related to the beginning of an autoimmune event, due to the non-elimination of
      autoreactive lymphocytes. The aim of this study is to test bcl-2 antigen
      expression in human SLE peripheral blood and to analyze its relationship with
      disease activity. MATERIALS AND METHODS: Serum levels of bcl-2 were studied by
      enzyme-linked immunoabsorbent assay in whole blood samples in 68 patients with
      SLE and its correlation with disease activity according to SLE disease activity
      index (SLEDAI). RESULTS: No significant differences were found in bcl-2 levels
      between all SLE patients and controls. We observed increased levels of bcl-2 in
      active SLE patients in relation to inactive (p = 0.0003) and controls (p = 0.02).
      Our results show a significant correlation between bcl-2 levels and SLEDAI values
      (R = 0.46, P < 0.001). CONCLUSIONS: These results suggest that bcl-2 levels are
      related to disease activity and that this protein may play a role in the
      pathogenesis of SLE.

PMID- 10652596
TI  - Latent forms of transforming growth factor-beta 2 (TGF-beta 2) in breast cyst
      fluid.
AB  - Transforming growth factor-beta (TGF-beta) is secreted by cells in high molecular
      weight, latent forms and the in vivo mechanisms for the activation remain largely
      an enigma. Women who have palpable breast cyst with intracystic Na/K < 3 may have
      a higher risk of developing breast cancer than those with intracystic Na/K > 3.
      Finding of significantly higher concentrations of TGF-beta 2 in the Na/K > 3
      group than Na/K < 3 group may explain the lower risk of breast cancer in the Na/K
      > 3 group. The aim of the present study was to characterise the latent forms of
      TGF-beta 2 in breast cyst fluid using HPLC, affinity chromatography, SDS-PAGE and
      immunostaining techniques. We found that TGF-beta 2 is present in high molecular
      weight, latent forms in breast cyst fluid: as a complex, probably with alpha 2
      macroglobulin and a 56 kD protein which is likely to be a precursor form of TGF
      beta 2.

PMID- 10652597
TI  - Different effects of the treatment with AGN 193836 and 9-cis-retinoic acid in
      breast cancer cells.
AB  - Retinoid effects have been well studied in different cellular models, and their
      in vitro action on breast cancer is well known. Much less is known about the
      function of the different retinoid receptors in mediating retinoid activity in
      this and other cellular models. In order to better understand these biological
      mechanisms, several synthetic compounds have been produced, that have specific
      binding affinity for selected nuclear receptors, and their effect has been
      evaluated and confronted with that of classic compounds able to bind to different
      receptors. The aim of this study was the evaluation of the biological activities
      in breast cancer cell lines of one of these new compounds, AGN 193836, with a
      very selective binding affinity (selective agonist retinoid) for one single
      retinoic acid receptor (RAR alpha), in respect to a classic retinoid able to bind
      to a broad spectrum of retinoic acid receptors (pan-agonist retinoid), 9cRA. Our
      results clearly indicate that the selective retinoid retains most of the
      biological activities of the pan-agonist compound, but its effect is probably
      aggravated by fewer side-effects in vivo: This evidences indicate that selective
      agonist retinoids are an interesting research field for the future, not only
      because of their speculative interest, but also in view of future clinical
      applications.

PMID- 10652598
TI  - Expression of different chemokines by human osteosarcoma cells in response to
      tumor necrosis factor-alpha.
AB  - We investigated the expression of different chemokines in the surnatants and
      inside the cells of four human osteosarcoma cell lines. HOS, U-2 OS, MG63 and
      Saos-2 cells were cultured for 24, 48, 72 hours both in basal conditions and
      after stimulus with TNF alpha. Human stromal cells were used as control. IL-8 and
      MCP-1 are present in higher concentration in the surnatants in contrast to RANTES
      which is present primarily inside the cells. IL-8 and MCP-1 are not totally
      expressed by all the human osteosarcoma cell lines in unstimulated conditions,
      but became detectable after TNF alpha treatment. In general, this cytokine
      stimulated the production and release of the three chemokines.

PMID- 10652599
TI  - Mutant p53 mediated induction of cell cycle arrest and apoptosis at G1 phase by 9
      hydroxyellipticine.
AB  - Wild-type p53 causes cell-cycle arrest at late G1 phase and induction of
      apoptosis by up- regulation of waf1 and bax, respectively. Although in many
      cancer cells p53 is frequently mutated and loses its functions, we have proposed
      that mutant p53 may be involved in the anticancer mechanism of 9-hydroxy
      ellipticine (9HE). It was shown using flow cytometry that 9HE (10 microM) caused
      induction of apoptosis in G1 phase of the cell cycle in mutant p53 (p53ala143,
      p53his175, orp53his273) transfected Saos-2 cells, but not in p53-deficient
      parental Saos-2 cells. Similar induction of apoptosis was observed 24-48 h after
      treatment with 9HE in mutant p53-containing SW480, SK-BR-3 and MKN-1, but not in
      p53-deficient KATO m cells. Using G1 phase cells isolated by centrifugal
      elutriation, it was confirmed that 9HE caused cell cycle arrest at G1 phase and
      subsequently induced G1 phase-restricted apoptosis. In accordance with the
      induction of arrest and apoptosis in G1 phase, 9HE caused up-regulation of waf1
      and bax mRNA in mutant p53-containing cells, but not in p53-deficient parental
      Saos-2 cells. In control experiments, adriamycin (ADR) showed neither G1
      restricted apoptosis nor elevation of bax mRNA. It is suggested that 9HE may
      cause G1 arrest and induction of G1 phase-restricted apoptosis by restoring the
      wild-type function of mutant p53 protein.

PMID- 10652600
TI  - Multiple recognition of various amphiphilic molecules by the multidrug resistance
      P-glycoprotein: molecular mechanisms and pharmacological consequences coming from
      functional interactions between various drugs.
AB  - P-glycoprotein (P-gp) is an active, ATP-dependent plasma membrane transporter
      which is responsible for the expulsion of various cytotoxic drugs with different
      chemical structures out of resistant (MDR) cells. It is also capable of
      transporting a number of other amphiphilic molecules, the so-called MDR-reversing
      agents, which belong to a very broad variety of chemical families. Moreover, P-gp
      can also play a role in steroid secretion and cellular detoxification by
      transporting various other substrates. In this review, we address the problem of
      the multiple recognition by P-gp of such a large number of amphiphilic molecules.
      This is both (i) from a basic viewpoint in order to discuss the underlying
      molecular mechanisms explaining how the general rule of substrate-enzyme
      specificity can be violated, and (ii) from a more applied pharmacological
      viewpoint to show in detail how the interaction of various drugs with P-gp leads
      to important consequences in terms of the relative effects of these drugs in the
      anticancer chemotherapy context, as well as for their pharmacokinetic
      distributions in the whole organism, rationalizing possible adverse drug
      reactions. In particular, we will present evidence that, independently of the
      technique used, the mutual interactions between P-gp transport substrates cannot
      always be reduced to simple competitive effects.

PMID- 10652601
TI  - Induction of cell death by ascorbic acid derivatives in human renal carcinoma and
      glioblastoma cell lines.
AB  - Sodium-L-ascorbate, L-ascorbic acid, D-isoascorbic acid, sodium 5,6-benzylidene-L
      ascorbate and sodium-6-beta-O-galactosyl-L-ascorbate, which produce ascorbyl
      radicals during the oxidative degradation, also induced cytotoxicity against
      cultured human renal carcinoma (TC-1) and glioblastoma multiform tumor (T98G)
      cell lines. On the other hand, L-ascorbic acid 2-phosphate magnesium and L
      ascorbic acid 2-sulfate dipotassium salt, which do not produce the ascorbyl
      radical, were inactive. This suggests the possible role of the ascorbyl radical
      for cell death induction. T98G cells were more resistant to ascorbate analogs
      than TC-1 and HL-60 cells, possibly due to higher intracellular glutathione
      concentrations. Ascorbate treatment induced rapid elevation of both intracellular
      concentration of cAMP and Ca2+ in HL-60 cells, but not in TC-1 and T98G cells.
      However, the elevation of cAMP by theophyline and N,2-dibutyryl adenosine 3,5
      cyclic monophosphate (dibutyryl cAMP) resulted in a decrease in the viable cell
      number. This suggests the possible role of cAMP for ascorbate-induced cell death.

PMID- 10652603
TI  - Quantification of apoptosis induction by doxorubicin in three types of human
      mammary carcinoma spheroids.
AB  - BACKGROUND: Apoptosis, also termed programmed cell death, is an active form of
      cellular degradation in contrast to the passive, inflammatory necrosis.
      Triggering apoptosis in tumor cells is a significant aim of chemotherapeutic
      treatment. MATERIALS AND METHODS: In this investigation the rate of apoptosis in
      human mammary carcinoma cell spheroids and monolayers was quantified following
      treatment with doxorubicin using various concentrations and incubation times.
      These data were compared with results of standardized clonogenicity assays,
      spheroid volume growth curves, and flowcytometric cell cycle analysis and BrdU
      labeling. RESULTS: Whereas spheroid volume growth and cellular clonogenicity were
      in excellent accordance with the well-established chemosensitivity of the three
      cell lines, the incidence of apoptosis did not reflect the different
      susceptibility of the cell lines to doxorubicin in a systematic way. On the other
      hand, theoretical considerations showed that the relatively low proportion of
      apoptosis can account for the relatively large decrease in spheroid volume, as
      observed in doxorubicin-treated T47D spheroids. CONCLUSIONS: The experimental
      data suggest that suppression of apoptosis is not an obligatory feature of multi
      drug resistant cell lines, and that resistance is rather correlated with an
      increase in DNA-synthesis.

PMID- 10652602
TI  - Lovastatin-induced inhibition of HL-60 cell proliferation via cell cycle arrest
      and apoptosis.
AB  - An inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase,
      lovastatin, induces growth arrest and cell death in a wide variety of malignant
      cells in vitro. We analyzed the effect of lovastatin on myeloid leukemic cell
      lines. Lovastatin significantly inhibited the proliferation of 7 cell lines among
      11 myeloid leukemic cell lines in a dose-dependent manner. In order to address
      the mechanism of antileukemic effect of lovastatin, cell cycle analysis was
      attempted in HL-60 cells, showing that lovastatin induced G1 arrest in HL-60
      cells following 72 h of drug exposure (1.5 microM, 5 microM and 10 microM) in a
      dose-dependent manner. Analysis of G1 regulatory proteins demonstrated that the
      protein levels of cyclin-dependent kinase (CDK) 2, CDK4, CDK6 and cyclin E were
      decreased after treatment with lovastatin (10 microM) in a time-dependent manner,
      but not cyclin D1. In addition, lovastatin increased the protein level of the
      cyclin-dependent kinase inhibitor (CDKI), p27, and markedly enhanced the binding
      of p27 with CDK2 and CDK4 more than CDK6 after 24 h exposure. At higher doses of
      lovastatin (50 mM, 100 mM, 200 mM), a significant apoptosis was observed as
      evidenced by FACS analysis with annexin V staining, which was associated with
      downregulation of Bcl-2 protein. These results suggest that lovastatin inhibits
      the proliferation of myeloid leukemic cells via G1 arrest in association with p27
      induction and is an effective inducer of apoptosis in HL-60 cells.

PMID- 10652604
TI  - Interleukin-2 induces the growth of human glioblastoma cells in culture.
AB  - The ability of the T cell growth factor interleukin-2 (IL-2) to support the
      proliferation of human glioblastoma cells in short-term cultures was evaluated. A
      morphological, cytochemical and immunocytochemical analysis was carried out at
      different times of treatment. In the presence of IL-2 growth of tumor cells was
      observed. On the contrary, in the absence of IL-2 only few colonies derived from
      tumor fragments were obtained and these were so after a long time. The
      immunocytochemical study revealed that IL-2 induces the expression of the IL-2
      receptor on human glioblastoma cells. In the presence of IL-2 proliferation of
      infiltrating lymphoid cells inside the tumor fragments was also observed.
      Morphological and cytochemical analysis of these cells revealed positivity for
      acid phosphatase (AP), dihydrofolate reductase (DHFR), dipeptydilaminopeptidase
      (DAP IV) and negativity for serine esterase. These data are in agreement with our
      previous study on activated lymphoid subsets. On the other hand, an absence of
      infiltrating lymphocytes was observed in cultures without IL-2. These results
      indicate that local treatment of human glioblastoma using IL-2 might produce
      tumor cell proliferation.

PMID- 10652605
TI  - Response of PC-3 prostate cancer cells to combination therapy using irradiation
      with glucocorticoids or doxorubicin.
AB  - OBJECTIVES: We evaluated the effects of irradiation, doxorubicin and
      dexamethasone on human PC-3 prostate cancer cells, investigating whether
      dexamethasone and doxorubicin can alter the irradiation cytotoxicity of PC-3
      cells. METHODS: We used the human PC-3 prostate cancer cells, analyzing cell
      growth with trypan blue exclusion, indices of the cell cycle with flow cytometry
      and apoptosis with flow cytometry and analysis of DNA fragmentation on simple
      agarose gel. RESULTS: Doxorubicin (100 nM) arrested cell cycle at the G2/M phase,
      decreased cell growth and produced apoptosis of PC-3 cells in a time-dependent
      manner. Dexamethasone (100 nM) increased the distribution of PC-3 cells at G0/G1
      phase in the cell cycle, exerting an inhibitory effect on the proliferation of PC
      3 cells after 48 and 72 hr, but it did not produce apoptosis. Irradiation (4 Gy)
      initially arrested cells at the G2/M phase in the cell cycle (24 hr) which was
      gradually overcome and the PC-3 cells were shifted into G0/G1 phase or apoptosis
      after 48 and 72 hr. Irradiation decreased the PC-3 cell growth by 40-50% after 48
      and 72 hr, respectively. Treatment with doxorubicin (100 nM) for 24, 48, and 72
      hr after irradiation potentiated irradiation cytotoxicity of PC-3 cells.
      Dexamethasone treatment 24 hr before and 24, 48 and 72 hr after irradiation
      increased the number of surviving PC-3 cells and partially neutralized the
      irradiation effects on cell cycle. CONCLUSION: Doxorubicin potentiated while
      dexamethasone partially reversed the irradiation cytotoxicity of PC-3 cells.
      These data may be of clinical importance for the treatment of hormone refractory
      prostate cancer.

PMID- 10652606
TI  - Current understanding of AIDS pathogenesis.
AB  - From the mid 1990s, considerable progress has been achieved in understanding the
      biology of the human immunodeficiency virus type 1 (HIV-1), and the pathogenesis
      of the acquired immunodeficiency syndrome (AIDS). However, these achievements are
      still not sufficient to indicate the reasons for failure of the host immune
      response in suppressing HIV-1 infection and why the immune system collapses at
      the end of the clinical latency period, followed by progression to the terminal
      course of the disease. A more complete view of the dynamics of AIDS pathogenesis
      may greatly facilitate the development of novel and ambitious therapeutic
      interventions, that are needed to counteract the onset of HIV-1 variants
      resistant to current antiretroviral treatments, to ensure affordable therapy
      programs for developing countries, and, in the long term, to eradicate the virus
      from patients and to confer protective immunity to HIV-1 infection.

PMID- 10652607
TI  - Evidence of a reduced DNA topoisomerase II mRNA expression after ionizing
      radiation.
AB  - DNA topoisomerase II (top2) is a nuclear enzyme which resolves the topological
      constraints during DNA metabolism and is the target of some of the most active
      drugs used in cancer chemotherapy. Top2 is regulated both transcriptionally and
      post-transcriptionally and its expression is coupled to cell cycle position. To
      explore the regulation of top2 after DNA damage, we studied the behavior of cell
      lines of the National Cancer Institute Anticancer Drug Screen, previously
      characterized for p53 status, in response to ionizing radiation. The kinetics of
      top2 mRNA expression were measured using quantitative hybridization. A profound
      and transient decrease of top2 mRNA after irradiation was detected within four
      hours in 30% of the 25 cell lines tested. This transient top2 decrease in mRNA
      expression occurred independently of the p53 status of the cell lines and was not
      associated with increased apoptotic DNA fragmentation. This observation indicates
      that a transient decrease in top2 mRNA expression may occur after DNA damage and
      suggests the need for preferential schedule when planning the use of top2
      inhibitors with ionizing radiation during combined radio-chemotherapy treatments.

PMID- 10652609
TI  - CD1a positive putative tumour infiltrating dendritic cells in human breast
      cancer.
AB  - CD1a molecules are expressed on dendritic cells (DC) during certain maturational
      phases coincident with the functions of antigen capture and processing. During
      these phases, CD1a is anchored to the cytoplasmic membrane through its
      cytoplasmic domain and the antigenic binding domain is projected from the cell
      surface. Membrane bound HLA Class I and II molecules are also expressed at
      relatively high levels on DC, but it is not known whether there is any
      interdependence between CD1 expression and that of the classical
      histocompatability molecules. Recent information concerning the structure,
      function and likely role of CD1 in presentation of hydrophobic lipid and
      carbohydrate antigens to the immune system is detailed. The potential relevance
      of the lipid presenting functions of CD1 molecules for the detection and
      recognition of tumour glycolipid antigens is hypothesised and discussed. CD1 a
      tumour infiltrating putative dendritic cells are discussed in terms of their
      density, separation, culture and possible function in breast cancers in the light
      of recent findings.

PMID- 10652608
TI  - 9-[2-(phosphonomethoxy)ethyl]-2,6-diaminopurine (PMEDAP)--a potential drug
      against hematological malignancies--induces apoptosis.
AB  - Antitumor activity of the acyclic nucleotide analogs PMEDAP, PMEA, and PMEG was
      studied on a model of a spontaneous T-cell lymphoma in inbred SD/cub rats.
      Significant therapeutic effects were recorded after a treatment with 16 daily
      doses of PMEDAP at 5 mg/kg applied to the vicinity of the growing lymphoma.
      Identical administration of PMEA, or PMEG at a daily dose of 0.1 mg/kg did not
      affect the survival of lymphoma-bearing animals compared with untreated controls.
      A decrease in the lymphoma weight during PMEDAP administration was accompanied by
      the suppression of mitotic activity in neoplastic cells and increased chromatin
      condensation as witnessed by karyological examinations. Electron-microscopy
      showed the morphology of apoptotic cells (shrunken cells with condensed
      chromatin, apoptotic bodies) in lymphoma cell suspensions. An increase of nuclear
      DNA fragmentation was found during PMEDAP administration compared with
      spontaneous DNA fragmentation of untreated control lymphomas. These results
      indicate that PMEDAP application induces apoptosis in in vivo growing lymphomas.
      The antitumor effect of PMEDAP lasts only during the administration of the drug.
      After its cessation progression of neoplasia was reestablished.

PMID- 10652610
TI  - Retinoic acid modulates RAR alpha and RAR beta receptors in human glioma cell
      lines.
AB  - To identify retinoic acid (RA) signalling pathways involved in growth and
      differentiation in cells of the glial lineage, two human glioma ceh lines were
      studied. The three RA receptors (RARs) mRNAs were constitutively expressed, and
      of the three RXRs, RXR beta appeared predominant. Western blotting analysis
      confirmed the constitutive expression of RAR alpha and RAR beta. Treatment with
      all-trans-RA induced morphological changes in the two cell lines, which
      progressed from their normal pattern of randomly oriented spindle-shaped cells to
      fibroblast-like glial cells. RA up-regulated RAR alpha and RAR beta mRNAs in both
      cell lines. Interestingly, RA treatment up-regulated RAR beta proteins but not
      RAR alpha proteins, suggesting post-transcriptional regulations of RAR
      transcripts in glioma cells.

PMID- 10652611
TI  - Drug resistant tumor cells have increased levels of tumor markers for invasion
      and metastasis.
AB  - The association between drug-resistance and three markers for invasive capacity:
      cathepsin D (Cath D), urokinase type plasminogen activator (uPA) and inhibitor of
      plasminogen activator type 1 (PAI-1) was examined in nine cervical and laryngeal
      carcinoma cell lines resistant to different cytostatics. The level of Cath D was
      measured by solid phase two-site immunoradiometric assay, while uPA and PAI-1
      concentrations were determined by use of ELISA. All drug resistant cell lines had
      increased concentration of cathepsin D. uPA levels were similar in parental and
      drug resistant cervical carcinoma cells, but significantly higher in all examined
      drug resistant laryngeal carcinoma cells. In cervical carcinoma cells, PAI-1
      concentrations were similar in parental and cisplatin resistant, but
      significantly higher in doxorubicin resistant cells. In laryngeal carcinoma
      cells, no increase in concentrations of PAI-1 was determined in the three from
      five resistant cell lines. There was no uPA in conditioned medium of parental or
      drug resistant cells. PAI-1 was detected in conditioned medium. Its levels were
      significantly increased in the medium of two cervical and three laryngeal drug
      resistant carcinoma cells. Thus, our results suggest that drug-resistance may be
      accompanied by increased levels of tumor associated proteases and/or its
      inhibitor.

PMID- 10652612
TI  - Induction of apoptosis in MCF-7 cells by indole-3-carbinol is independent of p53
      and bax.
AB  - The anticancer activity of indole-3-carbinol and the possible mechanisms involved
      were explored in human breast cancer cell lines MCF-7 and T47D. Treatment with
      indole-3-carbinol suppressed the growth of MCF-7 and T47D cells. MCF-7 cells were
      more sensitive to indole-3-carbinol than T47D cells. The growth suppression
      caused by indole-3-carbinol was found to be partially involved in its ability to
      induce apoptosis (programmed cell death) in MCF-7 cells. Western blot analysis
      demonstrated that wild-type p53 was not induced after treatment of MCF-7 cells
      with indole-3-carbinol. Northern blot analysis showed that treatment of MCF-7
      cells with indole-3-carbinol did not affect the expression of bax gene (one of
      the death genes). In the tissue culture medium, indole-3-carbinol was found to be
      partially converted to 3,3'-diindolylmethane. The experiments indicated that
      indole-3-carbinol suppressed MCF-7 cell growth in part by induction of apoptosis
      which was independent of p53 and bax expression and that the effect caused by
      indole-3-carbinol was partially due to its conversion to a more potent compound,
      3,3'-diindolylmethane, in vitro.

PMID- 10652613
TI  - The effects of telomerase inhibitors on lymphocyte function.
AB  - BACKGROUND: Telomerase is an enzyme that is present in both cancerous cells and
      lymphocytes. Telomerase inhibitors block tumor cell growth and are being
      considered for chemotherapy. This study tested whether telomerase inhibitors
      suppress growth of leukemic cell lines and blood lymphocytes (PBMC). RESULTS:
      Reverse transcriptase inhibitors azidothymidine (AZT) and 3'-deoxy-2:3'
      didehydrothymidine (d4T) decreased growth of all cells while dideoxyinosine (ddI)
      had no effect on Jurkat cells but increased growth of PBMC. The oligonucleotide
      (TTAGGG)3, which mimics the telomeric sequence, decreased growth of all cells.
      Inhibition by AZT, d4T and (TTAGGG)3 was manifested at 48-96 hours after addition
      to the cultures but not at 24 hours. The inhibition was partially to totally
      reversible upon inhibitor removal, indicating that the compounds were not
      cytotoxic but only suppressed cell growth temporarily. CONCLUSIONS:
      Immunosuppression may result from the use of telomerase inhibitors during
      chemotherapy but should only be temporary.

PMID- 10652614
TI  - Stimulation of human hematopoietic progenitor cells by the alkylphosphocholines
      hexadecylphosphocholine and hexadecyl-N,N,N-trimethyl-hexanolamine.
AB  - Hexadecylphosphocholine (HePC) represents a new class of membrane-active
      antitumoral compounds, the alkylphosphocholines. In vivo studies of HePC showed
      an increase in the total white blood count (WBC) in the highest dosage group in
      DMBA-induced breast carcinoma in the rat. In phase II studies most of 70 patients
      treated orally with HePC likewise showed a significant increase in WBC and a rise
      in platelet count. The present investigation on human bone marrow progenitor
      cells from 42 patients shows a dose-dependent and selective co-stimulatory effect
      of HePC on the G-CSF-dependent growth of bone marrow progenitor cells in
      progenitor cells from 22 patients. Hexadecyl-N,N,N-trimethyl-hexanolamine(HePC6),
      which has no, or only marginal antitumoral activity but comparable
      physicochemical properties to HePC, also stimulates the G-CSF-dependent colony
      formation in a dose-dependent manner. The molecular mode of action of the
      stimulating effect of HePC on G-CSF-dependent colony formation is not entirely
      understood. An inhibitory effect of HePC and ether lipids on protein kinase C
      (PKC) has been described. However, there also is evidence that etherlipids can
      stimulate PKC, which plays a crucial role in proliferation and survival of
      hematopoietic cells, under more physiological conditions. Therefore, the most
      likely explanation for the stimulating effect of HePC on G-CSF-dependent colony
      formation might be interference with signal transduction pathways.

PMID- 10652615
TI  - Cytotoxic intraepithelial lymphocytes in colorectal polyps and carcinomas.
AB  - The frequency of intraepithelial lymphocytes (IEL) was investigated in 255
      colorectal lesions: in 18 metaplastic polyps, in 159 tubular, serrated and
      villous adenomas, in 28 incipient adenocarcinomas and in 50 overt
      adenocarcinomas. > or = 21 IELs were found in 13.6% (12/88) of the adenomas with
      high grade dysplasia (HGD) but in none of the 18 metaplastic polyps, the 71
      adenomas with low grade dysplasia (LGD), or the 50 overt adenocarcinomas. CD3-T,
      MHCII and TIA1 cell antigens were positive in IELs from tubular adenomas, villous
      adenomas, incipient carcinomas and overt adenocarcinomas. In the normal
      colorectal mucosa and in metaplastic polyps, CD3-T was positive whereas MHCII and
      TIA 1 were not expressed. On the other hand, Fas cell antigen was expressed in
      the normal mucosa and in metaplastic polyps but it was downregulated in
      neoplastic lesions. The upregulation of CD3-T, MHC class II molecules, and TIA 1
      in IELs of neoplastic colorectal lesions suggests that they are activated and
      cytotoxic; however, they undergo apoptosis due to the downregulation of the FAS
      molecules.

PMID- 10652616
TI  - Protein content and number of nucleolar organizer regions are enhanced during
      phorbol ester-induced differentiation of cultured human megakaryocytic cells.
AB  - In order to investigate the protein synthesis in megakaryocyte polyploidization,
      phorbol myristate acetate (PMA, 5 x 10(-9) M), a differentiation marker known to
      induce megakaryocyte polyploidization, was added to human megakaryocytic cell
      lines (DAMI, HEL and K562) and the expression of platelet/megakaryocytic
      integrins, the numbers of nucleolar organizer regions (AgNORs) and the total
      protein content were estimated. Following exposure of PMA, the expression of the
      platelet membrane glycoprotein GPIIIa and thrombospondin and transferrin
      receptors was augmented in the three cell lines. The number of AgNORs shifted
      from 16.4 +/- 4.3, 24.4 +/- 2.5 and 13.6 +/- 3.1 for unstimulated cells to 20.0
      +/- 5.3, 38.7 +/- 7.9 and 16.8 +/- 2.3 for PMA-treated DAMI, HEL and K562 cells,
      respectively. Furthermore, after treatment with PMA, the numbers of AgNORs
      clusters or nucleoles increased significantly to 179%, 238% and 154% of controls
      in DAMI, HEL and K562 cell lines, respectively. Finally, addition of PMA culture
      for four days, significantly increased the protein contents to 153%, 171% and
      254% of controls for DAMI, HEL and K562 cell lines, respectively (p < 0.05 by t
      test). In conclusion, the increase in the total protein content and in the number
      of AgNORs by PMA, suggests that PMA-induced-megakaryocyte polyploidization occurs
      by enhanced protein production.

PMID- 10652617
TI  - Preventive effect of hesperidin against inflammation in CD-1 mouse skin caused by
      tumor promoter.
AB  - Our earlier studies have shown that the flavonoid hesperidin inhibits tumor
      promotion in a two stage skin tumorigenesis protocol in CD-1 mice. In this study
      hesperidin's significant protection (p < 0.0001) against 12-0
      tetradecanoylphorbol-13-acetate (TPA) induced edema in CD-1 mouse ear will be
      presented. Hesperidin also afforded significant protection against TPA induced
      hyperplasia in the dorsal skin through multiple application prior to TPA.
      Protection by hesperidin was 93% of the epidermal thickness and 100% of the
      vertical cell layers. The data also indicate the protective effect of hesperidin
      against TPA caused infiltration of neutrophils by 73%. These results suggest that
      hesperidin may possess potential as chemopreventive agent against tumor promoter
      induced inflammation and hyperplasia.

PMID- 10652618
TI  - Multidrug resistance-associated protein (MRP) mediated transport of daunomycin
      and leukotriene C4 (LTC4) in isolated plasma membrane vesicles.
AB  - Studies have been carried out to examine in vitro drug transport in plasma
      membrane vesicles isolated from HL60/ADR cells that overexpress MRP. The results
      demonstrate that glutathione (GSH) enhances transport of daunomycin. A greater
      increase in transport activity occurs when the reaction is carried out in the
      presence of both GSH and sodium chloride. Sodium chloride alone has no effect on
      daunomycin transport. It has also been observed that GSH in the presence of
      sodium chloride induces a major increase in the transport level of LTC4. Thus
      far, no metal ion other than sodium chloride has been found to be active in the
      drug transport system. Kinetic analysis reveals that GSH in the presence of
      sodium chloride greatly reduces Km and increases Vmax, for daunomycin. Additional
      studies show that ATPase activity in isolated plasma membrane from HL60/ADR cells
      is greatly enhanced in the presence of both GSH and sodium chloride. These
      results suggest the possibility that GSH and sodium chloride stimulate MRP
      mediated transport as a result of increased ATPase activity.

PMID- 10652619
TI  - Polymorphic tandem repeats in the thymidylate synthase gene is associated with
      its protein expression in human gastrointestinal cancers.
AB  - BACKGROUND: Thymidylate synthase (TS) is a target enzyme of 5-fluorouracil (5
      FU), and the TS gene has a polymorphic tandem repeated sequence in the 5'
      untranslated region. We investigated the polymorphism on the repeat length of the
      TS gene and its relation to the number of 5-fluoro-dUMP (FdUMP) binding sites in
      human gastrointestinal cancers. MATERIALS AND METHODS: Seventy adenocarcinoma
      samples were used. Twenty-one patients received UFT and 49 patients received no
      treatment before surgery. Tandem repeat length of TS gene was determined by PCR
      amplification of genomic DNA. The number of FdUMP binding sites were measured by
      3H-FdUMP binding assay. RESULTS: Double- (2R) and triple-repeated (3R) sequences
      of the TS gene were found in the cancer tissues. Three genotypes of TS were
      found: 2R/2R (n = 3), 2R/3R (n = 16) and 3R/3R (n = 51). The free TS level for
      the 3R/3R genotype was significantly higher than for the 2R/3R genotype in UFT
      (+) group. Similar genotype-dependent difference of TS level was observed in UFT
      (-) group. CONCLUSIONS: Our results suggest the link between TS genotype and TS
      protein expression. This link might offer an advantage for selection of patients
      to receive 5-FU-based chemotherapy.

PMID- 10652620
TI  - In vitro sensitivity to the liposomal preparation, DaunoXome in CLL.
AB  - In order to determine the efficacy of liposomal encapsulated daunorubicin
      (DaunoXome; DNX) in chronic Iymphocytic leukaemia, the sensitivities of cells
      from 10 patients with this disease were assessed and compared with that of free
      drug using the MTT assay. There was a marked variation in effect between patients
      for both drug preparations. Despite this, there was a small but significant
      enhancement of cytotoxicity afforded by the liposomal preparation (median 2.8
      fold, p < 0.01). The cells from 2 of the patients appeared to be resistant to
      free daunorubicin. However, incubation for 96 h in DNX appeared to circumvent
      this resistance. This increase in sensitivity for resistant cells could not be
      demonstrated in an MDR positive cell line (K562AR) suggesting that another
      mechanism of resistance may be involved. We conclude that it is feasible to
      assess sensitivity to DNX using the MTT assay in fresh cells from patients with
      CLL using a continuous drug exposure of 96 h. Furthermore, DNX appears more
      effective than free drug in this disease.

PMID- 10652621
TI  - The G and F contents in megakaryocyte cell lines after stimulation with phorbol
      myristate acetate.
AB  - Megakaryocyte polyploidization responds to platelet demand and results from the
      lack of cytoplasmic separation while the nucleus keeps dividing. In order to
      investigate the role of actin in the megakaryocyte polyploidization, phorbol
      myristate acetate (PMA, 5 x 10(-9) M), a differentiation marker known to induce
      megakaryocyte polyploidization, was added to human megakaryocytic cell lines
      (DAMI and HEL) and G, F and total actins were estimated by DNase I inhibition.
      After four days of culture in the presence of PMA, G actin contents in pg per
      10(6) cells were 13.0 pg +/- 2.8 and 1.0 pg +/- 0.1 for unstimulated DAMI and HEL
      cells. F actin contents per 10(6) cells were 5.8 pg +/- 1.5 and 0.1 pg +/- 0.0
      for DAMI and HEL cells. Addition of PMA for four days to culture significantly
      increased G actin contents (235% and 268% of controls) and F actin contents (234%
      and 394%), for DAMI and HEL cell lines, respectively (p < 0.05 by t-test). In
      contrast, G/F actin ratio was not affected (p < 0.05 by t-test) by PMA. DAMI
      cells from each ploidy classes were then sorted on an ELITE Coulter and assayed
      for actin content. While total actin, G actin and F actin per cell increased in
      polyploid cells cultured with PMA, there was a reduction in G, F and total actin
      contents per diploid equivalent when cells became polyploid. In conclusion,
      megakaryocyte polyploidization of these cell lines is not related to an unbalance
      between G and F actins but would be rather due at least partly to a defect in
      total actin production that could lead to a prevention of the formation of the
      constriction ring in telophase.

PMID- 10652622
TI  - In vivo antitumor activity of TT-232 a novel somatostatin analog.
AB  - The somatostatin analog TT-232 containing a 5 residue ring, was previously shown
      to inhibit the proliferation of a large number of cancer cell lines in vitro and
      reduce the size of tumors in animal models in vivo. Its action is accompanied by
      inhibition of tyrosine kinases and is characterized by the induction of
      programmed cell death. On the other hand, it was proved to be free of the
      endocrine effects of the natural compound. The aim of this study was to find the
      optimal dose and administration route for in vivo tumor therapy in an animal
      model. We have investigated the dose--and administration route-dependent
      antitumor activity of TT-232 on S-180 sarcoma tumor transplanted to inbred BDF1
      mice from SPF breeding. Long-term administration (i.p., s.c. and i.v. injections)
      was started either on the day subsequent to tumor transplantation or after the
      development of tumor. The antineoplastic potential of TT-232 was evaluated on the
      basis of survival and tumor growth inhibition. In long-term administration
      (injections twice a day for 2 weeks) a significant, but dose- and administration
      route-dependent therapeutic efficacy of TT-232 was observed. The optimum dose of
      TT-232 15 micrograms/kg which resulted in a 30-40% cure rate and 50-70% growth
      inhibition in S-180 sarcoma tumor. A moderate antitumor effect was achieved by TT
      232 when it was administered after the evelopment of tumor. Our study suggests
      that TT-232 can be a promising antitumor agent.

PMID- 10652623
TI  - Microvessel density, proliferating activity, p53 and bcl-2 expression in in situ
      ductal carcinoma of the breast.
AB  - BACKGROUND: Ductal carcinoma in situ (DCIS) of the breast represents a
      heterogeneous group of lesions that show important differences in biologic
      behavior. New vessel formation has been reported as a prognostic indicator in
      breast carcinoma, but little information is available about its significance in
      DCIS. This study was planned to examine angiogenesis in DCIS in relation to
      histologic subtype, proliferation activity, p53 and bcl-2 expression. MATERIALS
      AND METHODS: Paraffin sections from 24 cases of DCIS (9 comedo and 15 non comedo
      type) were studied immunohistochemically using polyclonal and monoclonal
      antibodies to von Willebrand factor, Ki-67, p53 (clone 1801) and bcl-2 proteins.
      The streptavidine-biotin technique with microwave antigen retrieval was employed.
      RESULTS: Most cases showed enhanced microvessel formation around ducts with DCIS
      compared to normal ducts. Comedo carcinomas (CCs) showed enhanced
      neovascularization compared to non comedo carcinomas (NCCs). Growth fraction
      determination with Ki-67 antibody showed that 78% of the CCs expressed high
      proliferating activity compared to 27% of the NCCs. p53 immunoexpression was
      noted in 78% of the CCs and 20% of the NCCs. Bcl-2 immunoreactivity was observed
      in 67% of the total cases in 58% of which there was no association with p53
      expression. However, an association was found between neovascularization and
      overexpression of Ki-67 and p53. CONCLUSIONS: This study suggests that
      neovascularization is an early phenomenon in breast neoplasia and is apparent as
      early as the in situ stage. CCs express a more aggressive immunophenotype,
      compared to the other DCIS subtypes, characterized by increased stromal
      interaction, high proliferating activity, p53 overexpression and a near lack of
      bcl-2 immunostaining.

PMID- 10652624
TI  - Purification and characterization of a Hodgkin's and B cell-associated
      glycoprotein.
AB  - A glycoprotein (BLA.36), expressed on the plasma membrane of Hodgkin's cells and
      also on normal and malignant B lymphocytes and histiocytes, was identified by
      reaction with a monoclonal antibody. BLA.36 was not detectable on other
      hematopoietic, carcinoma or melanoma cell lines. BLA.36 was purified to
      homogeneity by extracting proteins from a Hodgkin's cell line (HDLM-3), followed
      by immunoaffinity chromatography, utilizing immobilized anti-BLA.36 antibody, and
      gel filtration on Sephacryl S-100 in the presence of protein dissociating agents.
      The purified component yielded a single band on sodium dodecyl
      sulphate/polyacrylamide gel electrophoresis under both non-reducing and reducing
      conditions, and closely related three isotypes of similar molecular weight and
      with the apparent isoelectric points that ranged from 5.0 to 5.2 on two
      dimensional gel electrophoresis. The purified BLA.36 reacted with the original
      specific antibody, on both one- or two-dimensional gel electrophoresis,
      suggesting that antigenic determinant was not adversely affected during
      purification procedure. Competitive immunoprecipitation analyses and the
      determination of N-terminus sequence of the first 13 amino acid residues suggest
      that BLA.36 is unrelated to other known Hodgkin's or hematopoietic cell antigens.
      Finally, significance of BLA.36 expression on the growth of BLA.36-positive cell
      lines was studied. Blocking of BLA.36 with anti-BLA.36 antibody led to the in
      vitro growth-inhibition of BLA.36-positive cell lines. The antibody pre-absorbed
      with the purified BLA.36 was unable to exert growth-inhibition, demonstrating the
      specificity of reaction. In addition, the treatment of the BLA.36-positive cell
      lines with differentiation-inducing agent, alpha-interferon (alpha-IFN), down
      regulated BLA.36 expression and also showed in vitro growth-inhibition of BLA.36
      positive cell lines. Taken together, these results suggest a growth-related
      function of BLA.36.

PMID- 10652625
TI  - Growth inhibition and induction of specific hepatic phenotype expression by
      retinoic acid in HEPG2 cells.
AB  - Retinoic acid, the active metabolite of vitamin A, plays a role in the growth and
      differentiation of a variety of normal and malignant cells. In response to 5
      microM retinoic acid the human hepatoma-derived cell line HepG2 underwent
      significant growth inhibition (not associated with cell death), which reached a
      level of 80% in comparison with controls, after 12 days of continuous treatment.
      Retinoic acid also induced morphological changes in these cells, in particular
      the development of canalicular-like structures, indicating progression to a more
      differentiated phenotype. In addition, a reduced expression of alpha-fetoprotein
      was found. We suggest that our results may be important for the design of novel
      therapeutic approaches using RA for the treatment of liver tumors.

PMID- 10652626
TI  - Fas (APO-1, CD95) receptor expression and new options for immunotherapy in
      childhood medulloblastomas.
AB  - Central nervous system (CNS) tumors are the most common solid neoplasms in
      children. Medulloblastomas (MEDs) resemble embryonic neuroectodermal stem cells
      and their immature, uncommitted neuronal and glial progeny. Apoptosis is a basic
      physiological process wherein the cell initiates a sequence of events culminating
      in the fragmentation of its DNA, nuclear collapse, and finally, disintegration of
      the cell into small, membrane-bound apoptotic bodies. Expression of Fas (APO-1,
      CD95) receptor (FasR) and programmed or active cell death (PCD) was studied in
      childhood MEDs with varying stages of malignancy, and cell differentiation
      features. The majority of neoplastically transformed, neuroectodermal in origin
      cells, particularly in MEDs, express FasR, whereas normal cells in the CNS do
      not. FasR is a transmembrane glycoprotein, which belongs to the nerve growth
      factor/tumor necrosis factor (NGF/TNF) receptor superfamily. Apoptosis within
      childhood PNETs/MEDs is triggered by the binding of FasR to its natural ligand
      (FasL) or by cross-linking with anti-section i FasR antibodies. The resence of
      FasL has also been detected in childhood glial tumors. Therefore, a spontaneous,
      cellular immunophenotype (IP) regulatory, intratumoral apoptotic cell death
      (autocrine suicide) is possible in childhood brain tumors during neoplastic
      growth and progression. During our systematic immunocytochemical screening, we
      employed formalin fixed, paraffin-wax embedded tissue sections, as well as frozen
      sections of 34 primary human childhood PNETs/MEDs. The use of a sensitive,
      indirect, six step immunoperoxidase or alkaline phosphatase conjugated
      streptavidin-biotin antigen detection technique, modified by us, provided
      excellent immunocyto-chemical results. A systematic observation of the presence
      of apoptosis related markers (especially FasR) and cells in PCD was carried out.
      A strong expression (intensity of staining: "A"-the highest possible; number of
      stained neoplastic cells: +3 to +4, between 50% to 90%) of FasR, was detected
      employing 4 microns thick, formalin fixed, paraffin-wax embedded tissue slides.
      The panel of normal tissues employed as positive and negative tissue controls
      demonstrated presence of FasR in the prenatal thymus, mature tonsils and colon
      epithelium. Certainly, the coexpression of FasR, FasL, and other PCD-related
      proteins have also been reported in other human malignancies: breast cancer,
      colorectal carcinomas, large granular lymphocytic leukemia of T or NK cell
      origin, melanomas, lung, prostate, pancreas, and hepatocellular carcinomas. The
      coexpression of both FasR and FasL on several neoplastic cell types may represent
      an effective mechanism for tumor escape of the cellular immunological response of
      the host. It has been well established that brain tumors and melanomas produce
      their autocrine FasL, and even become capable of switching their signal
      transduction from the PCD pathway to a tumor growth, proliferative pathway. It
      seems that the therapeutical use of FasR-FasL (main apoptotic pathway) represents
      a new and exciting immunotherapeutical possibility in the treatment of primary
      childhood neuroectodermal tumors.

PMID- 10652627
TI  - Physicochemical conditions affecting the formation/stability of serum complexes
      and the determination of prostate-specific antigen (PSA).
AB  - Inaccurate determination of total prostate-specific antigen (t-PSA) mainly
      derives from inadequate estimation of this heterogeneous molecule and its
      complexes with serum protease inhibitors, such as the a,-antichymotrypsin (ACT)
      and alpha 2-macroglobulin (alpha 2M). While ACT-PSA complex is confirmed to be an
      important quantity for prostate cancer (PCa) diagnosis, alpha 2M-PSA complex is
      still an unmeasurable fraction. This study was performed to evaluate the
      phycicochemical conditions of PSA complex formation with serum protease
      inhibitors, focusing on ACT and alpha 2M. t-PSA and free prostate-specific
      antigen (f-PSA) levels were estimated with commercial immunoassays (Axsym/Abbott,
      Enzymun/Boehringer Mannheim, Elfa/ Biomerieux), while the formation of PSA
      complexes with ACT and alpha 2M with Western-blot electrophoresis. t-PSA values
      were unexpectedly lower after incubation of semen PSA for 4 days at 4 degrees C
      or at 37 degrees C in female serum and goat serum relevant to incubation in BSA
      buffer, possibly due to immunoreactivity loss in alpha 2M-PSA formation in the
      serum matrices. The transformation of PSA molecule into various measured and
      unmeasured forms after exposure to serum, especially suggested the inadequacy of
      serum matrices for f-PSA standard preparation. Loss of stability in PSA complexes
      was observed after dilution of prostate cancer (PCa) serum in aqueous buffer (BSA
      buffer), possibly due to dissociation of complex structure, the effect being
      mended by prior excess addition of ACT or alpha 2M. Optimum pH (approximately
      7.5) and temperature (37 degrees C) for serum protease inhibitors binding to PSA
      were these of human serum, the complex formation increasing with incubation time,
      but not with PSA concentration.

PMID- 10652628
TI  - Induction of epidermal growth factor receptor expression and mitogenesis by
      alcohol in human colon adenocarcinoma-derived Caco-2 cells.
AB  - Epidemiologic studies suggest that alcohol may be an inducing factor in human
      colon tumorigenesis. As colon cells are frequently under autocrine control by
      growth factors, involvement of the EGFR pathway in alcohol-related colon tumor
      progression was investigated in the human colon adenocarcinoma-derived cell line
      Caco-2 which shows EGFR distribution mainly in basolateral cell membranes. EGF
      treatment results in almost complete downregulation of the basolateral receptor.
      Low concentrations of ethanol (0.22 mM, 0.1%) however, lead to significantly
      increased EGFR mRNA and protein expression and a raised mitotic rate mainly in
      basolaterally treated cells. Alcohol-induced overexpression of EGFR is paralleled
      by increased cyclin D1 expression. This suggests a possible mechanism for low
      blood levels of alcohol to stimulate in vivo proliferation of colonocytes by
      elevating transcription of a growth factor receptor as well as by modifying
      expression of a cell cycle regulator.

PMID- 10652629
TI  - Effect of mitoxantrone liposomes on multidrug-resistant breast cancer cells.
AB  - A major obstacle in efficacy of breast cancer chemotherapy is the emergence of
      multidrug resistance. We investigated modulation of multidrug resistance by
      liposome-encapsulated mitoxantrone in a drug resistant human breast MCF7R cell
      line and the influence of liposome composition. Neutral high phase-transition
      temperature and anionic low phase-transition temperature phospholipid liposomes,
      reduced the resistance factor from 142 to 15 and 38, respectively. The higher
      cytotoxicity obtained with mitoxantrone-encapsulation was not necessarily related
      to higher intracellular uptake. Our data suggest that liposomes, according to
      their lipid composition, may alter the P-glycoprotein function by plasma membrane
      stabilization and modulate multidrug resistance in human cancer.

PMID- 10652630
TI  - Microbial conversion of methyl- and methoxy- substituted derivatives of 5H
      indolo[2,3-b]quinoline as a method of developing novel cytotoxic agents.
AB  - In furtherance of our structure-activity relationship studies on the antitumor
      activity of indolo[2,3-b]quinolines, novel cytotoxic derivatives bearing methyl
      groups at N-5, C-11, C-2 and/or C-9, as well as methoxy-groups at C-2 and/or C-9,
      were synthesized by the modified Graebe-Ullmann reaction. To elucidate the
      metabolic pathways of these compounds, zygomycete fungus Cunninghamella elegans
      ATCC 9245 (which is known to produce drug metabolites that are also formed in
      mammals) was used as a mimetic organism. Simultaneously, biotransformation of the
      same substrates was carried out with a microsomal fraction of rat liver. Three
      forms of microbial conversion were observed: hydroxylation of the aromatic ring
      or hydroxylation of the methyl group, and O-demethylation. The reaction proceeded
      regioselectively, and only positions C-2 and C-9 were affected in the indolo[2,3
      b]quinoline system. The products formed were found to be identical with the
      metabolites generated by rat liver microsomes. The metabolites obtained displayed
      a cytotoxic activity in vitro against colon adenocarcinoma SW-707 and lung
      carcinoma A-549 (ID50 in the range 0.27-3.04 microM), which was as strong as that
      of the substrates. In the course of the further metabolic pathway study of
      indolo[2,3-b]quinolines we found that metabolites with a hydroxyl group in the
      aromatic system were transformed to non-cytotoxic polymeric products by
      multicopper oxidases: human ceruloplasmin or fungal laccase (used as mimetic
      enzyme), whereas metabolites with a hydroxymethyl group did not undergo such
      bioconversion. The last mentioned compounds can be regarded as a novel type of
      cytotoxic indolo[2,3-b]quinoline derivatives formed in metabolic processes.

PMID- 10652631
TI  - TTT, a novel free radical spin trap, induces apoptosis in sarcoma Yoshida cells
      in vivo: comparative investigations of its cytotoxicity in vitro.
AB  - In light of our previous SAR studies on nitroxides acting as less toxic
      anticancer agents, antioxidants and radioprotectors, we designed and tested, in
      vivo an in vitro, a new triradical spin trap -N,N',N"-tris-(l-oxyl-2,2,6,6
      tetramethylpiperidine-4-yl)-1,3, 5-tnazine-2,4,6-triamine (TTT). The ability of
      TTT to act as an antitumor agent in vivo was investigated in pharmacological
      tests. The administration of TTT to rats bearing 3 day-old Sarcoma Yoshida
      (promotion phase of the disease) led to induction of apoptotic cell(s) death. Our
      results clearly indicated the suggested involvement of the free radical moiety of
      piperidine ring(s), thus indicating that the anticancer activity of nitroxide(s)
      may involve its intracellular redox reactions. To assess the relationship between
      the apoptotic effects of TTT in vivo and its possible cytotoxicity, we determined
      the relative antiproliferative and cytostatic potential of TTT in vitro as
      compared with this of the anticancer drugs: doxorubicin, aclarubicin and
      mitoxantrone, currently used in clinical practice in Poland. We found that TTT
      inhibits the growth and proliferation of two immortalized cell types-hamster B14
      cell line and mouse NIH 3T3 fibroblasts which we used as a model for neoplastic
      phenotype, in a dose-dependent manner.

PMID- 10652632
TI  - Immunohistochemical analysis of DNA mismatch-repair enzyme hMSH-2 and Ki-67 in
      breast carcinomas.
AB  - BACKGROUND: The human Mut-S-Homologon-2 (hMSH-2) gene product is a member of a
      highly conserved family of proteins involved in postrepiclation mismatch repair.
      MATERIALS AND METHODS: We have analyzed hMSH-2 expression in normal breast tissue
      (n = 10) and breast carcinomas (n = 30). hMSH-2 protein was investigated
      immunohistochemically on frozen sections using a specific mouse monoclonal
      antibody (clone FE11). hMSH-2 labelling pattern was compared with the staining
      pattern of the proliferation marker Ki-67. A hMSH-2-immunoreactivity score (hMSH
      2-IRS) for the semiquantitative analysis of hMSH-2 expression is presented.
      RESULTS: In normal breast tissue, we only found weak nuclear immunoreactivity for
      hMSH-2 in 70%, while the remaining 30% were hMSH-2 negative (mean hMSH-2- IRS:
      1.00; SD: +/- 0.82). All breast carcinomas analyzed revealed moderate to strong
      nuclear immunoreactivity (mean hMSH-2-IRS: 7.67; SD: +/- 3.55). hMSH-2 staining
      was heterogeneous, with visual differences between individual tumour cells.
      Expression of hMSH-2 protein was consistently and strongly upregulated in tumour
      cells of breast carcinomas as compared to normal breast tissue. No visual
      correlation in comparing the labelling patterns for hMSH-2 with the labeliing
      patterns for Ki-67 (mean percentage of Ki-67 positive tumour cells: 24.33%; SD:
      +/- 15.35) was observed in breast carcinomas. CONCLUSION: Our findings indicate
      that (a) hMSH-2 is expressed in normal human breast tissue; (b) expression of
      hMSH-2 may be of importance for the genetic stability of breast carcinomas in
      vivo.

PMID- 10652633
TI  - Cystosarcoma phyllodes of the breast: prognostic significance of proliferation
      and apoptosis associated genes.
AB  - BACKGROUND: Cystosarcoma phyllodes (CP) is a rare fibroepithelial tumor of the
      breast. So far no valuable prognostic factors are available for predicting the
      biological behaviour and often unexpected clinical outcome of this tumor.
      PATIENTS AND METHODS: Using immuno-histochemistry, Mib-1 evaluated proliferative
      activity and expression of p53, Bcl-2, c-erbB1, c-erbB2, cytokeratin and vimentin
      were analysed in 17 benign and 12 malignant CP. RESULTS: Cell proliferation was
      significantly higher in malignant tumors compared to benign ones both in the
      epithelial and mesenchymal parts. In the epithelial part Bcl-2 positive cells
      were found more frequently in benign than in malignant lesions. Positive
      immunoreactivity for p53 was seen in only one malignant case. The reaction was
      positive in the both epithelial and mesenchymal compartments. Expression of c
      erbB-proteins was not found in any case. The intermediate filament proteins
      indicate clearly the two components of the tumor. CONCLUSIONS: We concluded that
      increased proliferate activity and downregulation of Bcl-2 may be associated with
      dedifferentiation of cells and malignant progression. C-erbB-proteins are
      obviously not involved in carcinogenesis of CP.

PMID- 10652634
TI  - Oncoprotein coexpression in human aberrant crypt foci and minute polypoid lesions
      of the large bowel.
AB  - BACKGROUND: Genetic aberrations observed in the large bowel during the neoplastic
      progression have a cumulative effect and are responsible for the propagation of
      the multistep malignant process. In the present study we evaluated the
      immunoreactivity of c-fos, ras, bcl-2 and p53 in aberrant crypt foci (ACF) and
      minute polyps of the large bowel obtained from patients with colorectal cancer.
      METHODS: ACF and minute polyps were collected from macroscopically normal colonic
      mucosa. Protein immunoreactivity was detected on parafin sections utilizing the
      biotin-streptavidin method on 25 hyperplastic, 10 dysplastic ACF, 5 hyperplastic
      and 10 dysplastic adenomas. RESULTS: 41% of the lesions displayed positive ras
      immunoreactivity. bcl-2 immunoreactivity was positive in six minute polyps of
      which five were neoplastic. fos immunoreactivity was detected in five ACF and
      seven minute polyps, mainly in dysplastic lesions. Two neoplastic polyps were
      positive for p53 immunoreactivity. Coexpression of two or more oncoproteins was
      found with increasing frequency in dysplastic versus hyperplastic lesions and in
      polypoid lesions versus ACF. CONCLUSION: Abnormal expression and coexpression in
      oncoproteins can be identified in the earliest stages of colorectal tumorigenesis
      and may contribute to the progression of selected lesions during ACF-adenoma
      carcinoma sequence.

PMID- 10652635
TI  - Concentration and mindfulness meditations: unique forms of consciousness?
AB  - Electroencephalographic (EEG) recordings from 19 scalp recording sites were used
      to differentiate among two posited unique forms of mediation, concentration and
      mindfulness, and a normal relaxation control condition. Analyzes of all
      traditional frequency bandwidth data (i.e., delta 1-3 Hz; theta, 4-7 Hz; alpha, 8
      12 Hz; beta 1, 13-25 Hz; beta 2, 26-32 Hz) showed strong mean amplitude frequency
      differences between the two meditation conditions and relaxation over numerous
      cortical sites. Furthermore, significant differences were obtained between
      concentration and mindfulness states at all bandwidths. Taken together, our
      results suggest that concentration and mindfulness "meditations" may be unique
      forms of consciousness and are not merely degrees of a state of relaxation.

PMID- 10652636
TI  - The measurement of respiratory and metabolic parameters of patients and controls
      before and after incremental exercise on bicycle: supporting the effort syndrome
      hypothesis?
AB  - Hyperventilation (HV) occurring out of appropriate context, under some
      circumstances, can be potentially harmful to health. Nixon (1994) discusses
      convincingly the negative effects of long-term HV on the alkaloid buffering
      system and the potential challenge to a person's health status. Using capnography
      to measure respiration, percent expired CO2, to determine the anaerobic threshold
      during incremental exercise (the Effort Test), Nixon (1994) documented the onset
      of metabolic acidosis followed by alkalosis, secondary to the alkaloid buffering
      system response. Nixon (1994) hypothesized that recurring HV can lead to
      depletion of the alkaloid buffering system. By combining capnography, during the
      Effort Test, with analysis of blood gases and specific electrolytes, the effort
      syndrome hypothesis was further tested in the present study. Thirteen patients
      with various kinds of stress-related problems were compared with four control
      participants. Pretest blood gases, from capillary blood, were collected after 10
      minutes rest and 10 minutes of incremental exercise. Exhalation CO2, oxygen
      saturation, and traditional psychophysiological parameters were measured
      continuously during the experimental condition. Data from capillary blood and
      exhalation CO2 are reviewed. Change in patients' alkali buffering system supports
      the prediction made by Nixon (1994). The complexity of the data as well as
      methodological procedures of this study warrant a more sophisticated design, with
      more clearly defined functional analysis.

PMID- 10652637
TI  - Up-training loading responses in older adults.
AB  - This randomized, experimental-control group, multiple-observation study examined
      the ability of older adults to use center of pressure feedback to up-train the
      vertical loading response (LR) and the impact that such training had on changes
      in clinical tests of balance. Eleven community ambulators, aged at least 65
      years, with no recent history of falls were recruited by convenience sampling.
      Each group received 6 baseline sessions and 6 control/training sessions, followed
      by 1 posttest session. All sessions included visual cueing about stance
      equilibrium followed by 30 randomly timed dynamic, toes-up perturbations (8
      degrees, 66 degrees per second). Training consisted of verbal instructions with
      visual and auditory feedback of a 225 msec response window to shape an increase
      in total LR following perturbations. Subjects in the experimental group
      demonstrated a tendency to decrease vertical loading relative to baseline
      regardless of visual and verbal feedback encouraging strategies to increase it.
      Specifically, the T3 or 150-225 msec component of the response window showed a
      decline from session 7 to session 12. Up-training, however, appears to cause a
      faster rate of rise to the maintenance window, but this event probably occurs too
      late to correct for a loss of balance. No correlation was found between change in
      load values and change in performance on clinical balance tests.

PMID- 10652638
TI  - Perceived and physiological indicators of relaxation: as different as Mozart and
      Alice in chains.
AB  - The effects of listening to different types of music on perceived and
      physiological indicators of relaxation were evaluated. Fifty-six undergraduate
      students, 24 males and 32 females, mean age of 21, were randomly assigned to
      listen to classical, hard rock, self-selected relaxing music, or no music.
      Participants' relaxation level, skin temperature, muscle tension and heart rate
      were evaluated before and after exposure to a music condition. Analyses of
      variance using baseline measures as covariates indicated that skin temperature
      decreased for all conditions (p = 0.001) and the classical, self-selected
      relaxing music and no music groups reported significant increases in feelings of
      relaxation (p = 0.004). These results partially support the hypothesis that
      classical and self-selected relaxing music can increase perceptions of relaxation
      to a greater degree than listening to hard rock music. However, no differences
      were found between different types of music on physiological indicators of
      arousal. Implications for using music to reduce stress were discussed.

PMID- 10652639
TI  - The treatment of recalcitrant post-traumatic nightmares with autogenic training
      and autogenic abreaction: a case study.
AB  - Recurrent and frightening dreams are commonly experienced by patients who suffer
      from post-traumatic stress disorder after a motor vehicle accident. Such
      nocturnal episodes, if left untreated, can result in the experience of severe
      distress with physical, emotional, and psychophysiological concomitant. The
      present single-case study investigated the effects of the standard autogenic
      exercises and autogenic abreaction in reducing the frequency and severity of post
      traumatic nightmares in a survivor of a car crash. The patient was also
      instructed in two additional organ-specific formulas in order to improve her
      sleep. The results of the study showed that the interventions were successful in
      effectively treating the patient's distressing nightmares. Follow-up data
      suggested that the treatment effects persisted after the termination of therapy.
      Suggestions for future investigations are discussed.

PMID- 10652640
TI  - Established rheumatoid arthritis.
AB  - Currently the diagnosis of rheumatoid arthritis (RA) may be difficult; the ACR
      criteria appear most sensitive and specific in long-standing disease. Without
      clear definition or diagnostic criteria for early disease it is difficult to
      define late or established RA. The distinction between early and established RA
      has been further blurred by recent imaging studies that suggest even in what is
      currently termed early disease, there is evidence of joint damage. The natural
      history of RA suggests that most patients with clinic-diagnosed RA have a
      progressively disabling course, but evidence is growing that modern therapeutic
      strategies result in better long-term outcomes, especially when applied early in
      the disease course. In established disease, quantitative markers such as C
      reactive protein (CRP) give prognostic information, but in the pre-erosive, early
      phase of the disease the qualitative markers such as rheumatoid factor (RF) and
      shared epitope are crucial. As rheumatologists, our major aims must remain: (1)
      to diagnose the disease as early as possible; (2) to identify those patients with
      poor prognosis who will benefit most from targeted therapy; and (3) to aim for
      more intensive disease control irrespective of disease duration.

PMID- 10652641
TI  - Pathogenesis of joint damage in rheumatoid arthritis: evidence of a dominant role
      for interleukin-I.
AB  - Chronic arthritis is characterised by persistent joint inflammation and
      concomitant joint destruction. Although joint swelling is a major clinical
      feature, destruction of bone and cartilage may be dissociated from inflammation.
      It is therefore important to understand fully all elements of the destructive
      process. Tumour necrosis factor (TNF) and interleukin-I (IL-I) are considered
      pivotal cytokines in the process of human rheumatoid arthritis (RA), with a
      claimed cascade of TNF inducing most of the IL-I production. Studies in
      experimental models have revealed that TNF is indeed a pivotal cytokine in acute
      joint swelling, yet IL-I beta is the dominant cartilage destructive cytokine and
      its production may occur independently of TNF alpha. This was found with anti
      TNF/IL-I neutralising antibodies and the observations were recently supported by
      similar findings in arthritis models in TNF and IL-I knock-out mice. In RA, early
      clinical studies suggested a correlation between levels of IL-I beta and measures
      of joint damage. In vitro studies have also demonstrated regulatory effects of IL
      I beta on both cartilage degradation and cartilage invasion by synoviocytes. A
      randomised clinical trial has suggested a significant reduction in the rate of
      joint damage following IL-I beta inhibition by IL-I receptor antagonist. Clinical
      trials of TNF alpha blockade have demonstrated a marked reduction in the clinical
      manifestations of inflammation but, to date, an effect on the rate of joint
      damage awaits confirmation.

PMID- 10652642
TI  - The role of the hypothalamic-pituitary-adrenal axis in rheumatoid arthritis.
AB  - It has become clear that there is a bidirectional communication between the
      neuroendocrine and the immune system and that both systems influence each other
      and interact under physiological conditions and in response to inflammatory
      stimuli. The hypothalamic-pituitary axis plays an important role in regulating
      and controlling immune responses and dysfunction of the axis has been implicated
      in the pathogenesis of rheumatoid arthritis (RA). Corticotrophin-releasing
      hormone (CRH), one of the main hormones of the axis, is also released extra
      hypothalamically, peripherally at the site of inflammation and may modulate
      inflammatory responses locally. In this chapter we will discuss the role of the
      hypothalamic-pituitary-adrenal (HPA) axis and peripheral CRH, its influences on
      immune function and what is known about the possible pathogenetic role of the HPA
      axis and peripheral CRH in RA.

PMID- 10652643
TI  - Amyloid precursors and amyloidosis in rheumatoid arthritis.
AB  - Amyloidosis refers to the extracellular accumulation of amyloid fibrils, derived
      from a circulating precursor, in various tissue and organs. The most common form
      of amyloidosis worldwide is that which occurs secondary to chronic inflammatory
      disease, particularly rheumatoid arthritis. The precursor molecule is serum
      amyloid A (SAA), an acute phase reactant, which can be used as a surrogate marker
      of inflammation in many diseases. SAA has a number of immunomodulatory roles, can
      induce chemotaxis and adhesion molecule expression, has cytokine-like properties
      and can promote the upregulation of metalloproteinases. It enhances the binding
      of high density lipoprotein to macrophages and thus helps in the delivery of
      lipids to sites of injury for use in tissue repair. It is thus thought to be an
      integral part of the disease process. Moreover, elevated levels of SAA over time
      predispose to secondary amyloidosis. Pathogenic factors underlying this disease
      are outlined along with guidelines for diagnosis and management.

PMID- 10652644
TI  - Evaluation of established rheumatoid arthritis.
AB  - There are two major aspects to evaluate in patients with established RA, namely
      (i) the state or progress of the disease, and (ii) the effects of specific
      interventions. The evaluation should include reliable, valid and sensitive
      measures of disease activity, tissue damage and health status. It is important to
      recognise that measures of disease activity can be influenced by tissue damage as
      well. Also, in established RA, health status is likely to be influenced by both
      disease activity and tissue damage. Whether current rules concerning improvement
      or remission, which were developed in the context of early RA, can be applied to
      established disease has to be investigated. While use of radiographs is the
      current standard method of assessing damage in established RA, range-of-motion
      measures and muscle strength indices may be a more practical and an equally valid
      alternative. When selecting health status instruments one should carefully
      explore and pretest possible health status measures for specific clinical or
      study settings.

PMID- 10652645
TI  - Synovial tissue analysis in rheumatoid arthritis.
AB  - In rheumatoid arthritis, synovial tissue is easily accessible for systematic
      analysis. Blind needle biopsy is a simple and safe procedure, but is restricted
      to smaller tissue samples. Arthroscopic biopsy is also safe but is more
      complicated as it allows access to most sites in the joint and provides adequate
      tissue for extensive laboratory investigations. Synovial tissue analysis has been
      successfully applied to studies of disease mechanisms, response to treatment and
      prognosis. The immuno-histological features in synovial tissue have consistently
      reflected disease status. Synovial tissue analysis has been particularly
      informative in the study of novel therapeutic agents.

PMID- 10652646
TI  - Multidisciplinary patient care in rheumatoid arthritis: evolving concepts in
      nursing practice.
AB  - Multidisciplinary patient care is essential in the management of rheumatoid
      arthritis (RA), a chronic potentially disabling, multisystem disease. Concepts of
      multidisciplinary care continue to evolve. While all team members can make
      valuable contributions to patient care, this chapter focuses in particular on
      continuing and changing aspects of team management. Of the many disciplines
      associated with rheumatology, nursing has undergone the most radical change in
      recent years. New roles have been defined and the nursing profession is now
      emerging with additional skills to support patients and their families. Concepts
      of patient education also continue to evolve. As the beneficial effects of
      education are demonstrated, a patient education programme should be seen as
      essential to the management of rheumatoid arthritis. Finally, the importance of
      counselling skills is emphasised.

PMID- 10652647
TI  - Rheumatoid arthritis, disability and the workplace.
AB  - Rheumatoid arthritis is a common cause of disability worldwide. The nature of the
      disability impacts on all areas of life. This chapter focuses on the nature of
      the disability of rheumatoid arthritis with emphasis on work disability. The
      various approaches for minimising the disability and rehabilitating those with
      disability are discussed. The tools for the assessment of disability are
      described and their strengths and limitations outlined.

PMID- 10652648
TI  - Pharmacotherapeutic combination strategies with disease-modifying antirheumatic
      drugs in established rheumatoid arthritis.
AB  - Pharmacotherapy is still the cornerstone in the management of rheumatoid
      arthritis (RA). Due to several reasons the pharmacotherapeutic strategy has
      changed dramatically in the past decades. It has become clear that in most cases
      single treatment with disease modifying antirheumatic drugs (DMARDs) is
      insufficient to control the disease on the long term. This is the main reason why
      combinations of second-line agents are increasingly being used in the treatment
      of established RA. Many different ways of prescribing combination treatment and a
      large number of different combinations have been published. However definite
      conclusions which drugs to combine or what strategy to apply are difficult to
      make as solid studies which enable these conclusions are sparse. Several studies
      have shown that the best opportunity to achieve a good response is to use a set
      up approach, in addition different studies have shown that corticosteroids do
      have a profound effect on disease activity variables.

PMID- 10652649
TI  - Investigational treatments in rheumatoid arthritis.
AB  - The active search for new treatment modalities of established rheumatoid
      arthritis have created a dynamic period for rheumatology. Both promising
      pharmaceutical products and targeted interventions with products of the
      biotechnology industry are being developed. Leflunomide and the selective
      blockade of the cytokine tumour necrosis factor (TNF) have recently been
      registered in several countries and others will follow. Like all new therapeutic
      strategies much remains to be learned about the optimal use of these therapies
      and their possible limitations. The success of these interventions have shown
      that a complex disease such as rheumatoid arthritis that is refractory to
      conventional treatment can be modulated by new therapeutic strategies. This
      experience has also resulted in further searches for new drugs that influence
      those pathogenetic pathways affected by the interventions found to be effective.

PMID- 10652650
TI  - Bone marrow transplantation.
AB  - Some severe auto-immune diseases, including rheumatoid arthritis, require
      immunosuppression to save life or vital organ function. One major limiting factor
      in such immunosuppression is the unwanted and dangerous haematoablation occurring
      at the same time. It is now possible to give supralethal doses of
      haematoimmunoablative drugs, and to 'rescue' the patient with haematopoietic stem
      cell transplantation. There are case reports of patients with rheumatoid
      arthritis who have received bone marrow transplantation, now called
      haematopoietic stem cell transplantation (HSCT), for a conventional indication
      such as aplastic anaemia or malignancy, in whom a long lasting improvement of the
      arthritis was observed. However, not all cases have responded, and there are
      still many open questions concerning optimal treatment regimens. In addition,
      some animal model research has supported the concept of HSCT as a permanent
      treatment of auto-immune disease including arthritis. In the past three years,
      HSCT has been applied to treat auto-immune disease alone in around 180 patients,
      20 of whom having had rheumatoid arthritis and 13 juvenile arthritis. Early
      results are encouraging, but many issues require further clarification through co
      ordinated clinical trials. The evolution of this project, details of the early
      results, the remaining open questions and possible strategies to resolve these
      are the subject of this chapter.

PMID- 10652651
TI  - Management of therapy-resistant rheumatoid arthritis.
AB  - During the last two decades, newly introduced therapeutic strategies have
      resulted in satisfactory modification of the disease course in the majority of
      the patients with rheumatoid arthritis (RA). Nevertheless, a definite number of
      RA patients remain therapy-resistant, and for this group more aggressive
      treatment may be required for preventing permanent disability and progressive
      joint damage necessitating surgical procedures. Therefore, management of therapy
      resistant RA is one of the major challenges in modern rheumatology. RA patients
      who have not responded to conventional disease-modifying antirheumatic drug
      (DMARD) therapy are defined as refractory RA patients. However, a uniform
      description or definition for 'refractory' RA does not appear to be available. In
      this article we will deal with, and discuss, the term 'refractory RA' based on a
      MEDLINE database search using this term, currently available therapeutic options,
      data on therapy-resistant RA patients from an inception cohort of RA patients
      attending the Nijmegen University Hospital, management of extra-articular
      manifestations and future management strategies.

PMID- 10652652
TI  - Current concepts in triple arthrodesis.
AB  - When performed appropriately, good to excellent results may be obtained with
      triple arthrodesis in about 80% of patients. Postoperative pain relief, a
      plantigrade foot, and improved ambulatory ability are the desired surgical goals.
      Although there is a significant incidence of degenerative or compensatory
      arthritis in the remaining articulations, it is rarely of clinical significance.
      The surgical technique of triple arthrodesis is technically demanding. Rigid
      attention to detail is important to reduce surgical complications. It is
      important to understand the local anatomy to avoid injury to nerves, vessels, and
      tendons. Proper exposure of the joints facilitates cartilage removal and lowers
      the incidence of nonunion. Rigid compression fixation in an appropriate position
      provides the best possibility of a successful outcome. It is crucial to remember
      that a triple arthrodesis is an end-stage salvage procedure. With realistic
      expectations, the level of satisfaction will be higher for both patient and
      surgeon.

PMID- 10652653
TI  - Tibiotalocalcaneal arthrodesis with intramedullary interlocking nail fixation.
AB  - The use of intramedullary rod fixation for tibiotalocalcaneal fusion is gaining
      popularity. Many methods of fixation have been employed in the past, but
      intramedullary fixation has been shown to achieve higher fusion rates, provide
      fixation along the weight-bearing axis, and control rotational deformities. The
      authors describe the history, indications, technical considerations, and
      postoperative care of patients treated with fixation using an intramedullary rod
      with interlocking screws.

PMID- 10652654
TI  - Posterior tibial tendon dysfunction. Diagnosis, evaluation, and treatment.
AB  - Posterior tibial tendon dysfunction (PTTD) is a complex multifaceted condition
      that can affect the lower extremity. Rarely mentioned 20 years ago, today it is
      the subject of numerous articles, books, and is a topic at most scientific
      seminars relating to the foot and ankle. It is a muscle imbalance initiated by a
      rupture, avulsion, or chronic inflammation of the tibialis posterior tendon. With
      time, it progresses from a flexible to rigid flatfoot deformity. Left untreated,
      peritalar dislocation and degenerative joint disease may develop. This article
      discusses the diagnosis, evaluation, and treatment of PTTD.

PMID- 10652655
TI  - Arthroscopy of the ankle and subtalar joint.
AB  - Arthroscopy has become a useful diagnostic and therapeutic tool in foot and ankle
      surgery. There are a reasonable number of indications for its use in the ankle
      and a limited number for the subtalar joint. Procedures previously performed as
      open surgeries typically necessitate a lengthy recovery and were met with higher
      complication rates. Many of these procedures can now be performed through small
      incisions with the assistance of arthroscopy. This article reviews the
      pathologies amenable to arthroscopy as well as describes the indicated procedures
      and technical aspects of each.

PMID- 10652656
TI  - Late sequelae of calcaneal fractures.
AB  - Late problems following calcaneal fractures are a dilemma for both patients and
      physicians. Reconstructive procedures are of great use, however, it should be
      timed accordingly to improve the patient's symptoms. The key to successful
      reconstructive procedures is an understanding of the postfracture pathology and
      determination of all possible sources of pain and disability. Determination to
      specific areas is essential so that the correct procedures can be performed. When
      dealing with patients for reconstructive procedures of postfracture pathology
      there should be no guarantees given as to the success of salvage. Quite
      frequently multiple procedures may be necessary to achieve only satisfactory
      results.

PMID- 10652657
TI  - Isolated fusions of the hindfoot.
AB  - Increasingly, isolated arthrodeses are being used to successfully manage
      disorders of the hindfoot. Their relative simplicity makes these procedures an
      attractive alternative to the triple arthrodesis. Each joint fusion is not
      without certain pitfalls, and issues such as the location of the pain, origin,
      planal dominance, and multiple joint involvement must be taken into consideration
      when choosing a specific procedure. With proper patient selection and careful
      technique, the surgeon will find these procedures provide a valuable addition to
      his/her armamentarium.

PMID- 10652658
TI  - Treatment of the sequelae of pilon fractures.
AB  - Intra-articular fractures of the distal end of the tibia represent a wide
      spectrum of articular and metaphyseal damage and are relatively infrequent
      injuries. This article summarizes possible early and late complications involved
      in the treatment of pilon fractures. Diagnostic and treatment guidelines for
      these complications also are reviewed.

PMID- 10652659
TI  - The use of the hybrid external fixator system in the foot and ankle.
AB  - The proper techniques of external fixation are demanding regardless of the type
      of external fixator used. Attention to detail, including preoperative planning
      and strict postoperative care, is essential to maximize the advantages and
      minimize the disadvantages associated with external fixation.

PMID- 10652660
TI  - A new concept of ankle arthrodesis via arthroscopic technique.
AB  - Arthroscopic ankle arthrodesis is a modification of the standard ankle fusion.
      Ankle fusion via the use of the burr end impactor has proved to be as reliable as
      an open procedure. The key is to maximally distract the ankle with the external
      fixator. This procedure is technically simple and less traumatic to the patient.
      Complications with this type of procedure are no different than with other fusion
      procedures of the ankle. The reliability of this procedure in maintaining a
      congruent talo-tibial joint with ease of fusion and coaptation of bony surfaces,
      however, makes it preferable.

PMID- 10652661
TI  - Vancomycin-resistant Enterococci infected puncture wound to the foot. A case
      report.
AB  - Vancomycin is often administered empirically to patients with osteomyelitis,
      septic arthritis, septic throbophlebitis, infected burns, and cellulitis of the
      lower extremities when methicillin-resistant staphylococci are suspected, or when
      a staphylococcus organism is suspected in a penicillin-allergic patient.
      Physicians must be aware of the guidelines established regarding the use of
      Vancomycin to avoid bacterial resistance. Physicians also must be aware of the
      procedures that have been developed to help contain nasocomial outbreaks of
      Vancomycin-resistant Enterococci.

PMID- 10652662
TI  - Selective capsular shift technique for anterior and anterior-inferior
      glenohumeral instability.
AB  - Anterior and anterior-inferior glenohumeral instability is often successfully
      treated with nonoperative measures, especially in atraumatic instability. In the
      case of traumatic instability, especially when the labrum is detached from the
      anteroinferior glenoid rim, surgery is often necessary to stabilize the shoulder
      and restore function. An anatomic repair that addresses any capsular or labral
      defect is essential for a successful outcome, and the selective capsular shift
      technique offers the flexibility necessary to correct these deformities. Several
      equally important steps must be followed when treating anterior and anterior
      inferior glenohumeral instability. These include the correct diagnosis and
      indications for surgery; a technically successful surgical procedure; and
      diligent, physician-directed, closely monitored rehabilitation.

PMID- 10652663
TI  - Arthroscopic versus open Bankart repair for traumatic anterior shoulder
      instability.
AB  - After more than 15 years of experience, arthroscopic shoulder stabilization is
      becoming less controversial. Historically, recurrence rates following
      arthroscopic stabilization have been higher than with open stabilization.
      Although a negligible advantage may exist in terms of expedited postoperative
      rehabilitation and improved postoperative recovery of motion, critics suggest
      that its use in contact athletes be limited. The indications for arthroscopic
      stabilization are expanding, in part, because of improved understanding of the
      pathophysiology of shoulder instability. Understanding the mechanism of recurrent
      instability following arthroscopic stabilization offers clues to how physicians
      can prevent unsatisfactory results in the future. With newer instrumentation and
      the ability to thermally treat capsular tissue, coexisting pathology, such as
      capsular plastic deformation, rotator interval lesions, and unrecognized intra
      articular pathology, can now be addressed arthroscopically. The judicious use of
      these techniques is warranted until long-term study results become available.
      Ideal patients for arthroscopic Bankart repair have a discrete Bankart lesion; a
      robust, well-developed IGHL; no significant capsular laxity or intraligamentous
      injury; and an absence of concomitant intra-articular pathology. Additional
      findings on MR imaging or CT evidence of a discrete labral lesion and pure
      unidirectional anterior instability during EUA are also good prognostic
      indicators for arthroscopic Bankart repair. Arthroscopic criteria that render
      patients less appropriate for an arthroscopic repair include capsular injury,
      capsular laxity, a bony Bankart lesion, glenohumeral arthritis, and a rotator
      cuff tear. The authors' believe that either absent or patulous, poorly developed
      glenohumeral ligaments represent a poor prognostic indicator for a successful
      outcome following standard arthroscopic Bankart repair. Individuals with poor
      quality tissue are more predictably managed using open capsulorrhaphy. Patients
      with pathologic ligamentous laxity in the absence of a Bankart lesion or any
      apparent intraligamentous injury to the IGHL are also good candidates for
      treatment with an open capsulorrhaphy. Findings determined from a thorough
      physical examination, EUA, and the pathology appreciated during diagnostic
      arthroscopy help to appropriately choose the surgical procedure that effectively
      addresses pathology in patients who present with recurrent traumatic anterior
      instability. Patient preferences and surgical experience are important
      determinants of procedure selection, and current arthroscopic techniques lack the
      versatility to uniformly address the entire spectrum of pathology that may be
      associated with traumatic anterior shoulder instability. Surgeons should always
      be prepared to convert to an open-stabilization technique if the arthroscopic
      technique is deficient in addressing all pathology identified at the time of
      surgery.

PMID- 10652664
TI  - Arthroscopic Bankart repair. Operative technique and surgical pitfalls.
AB  - The arthroscopic management of patients with shoulder instability continues to
      evolve. The obvious benefits include a reduction of operative time, preservation
      of the subscapularis, improved visualization, and less blood loss. Newer
      techniques that allow the plastic deformation of the IGHLC to be addressed are
      emerging, which may yield results as successful as those of open Bankart repair.
      The ability to adequately tension the IGHLC may result in some loss of external
      rotation, which may improve results. Capsular tensioning must be critically
      analyzed at the time of surgery. Adequate stabilization with an arthroscopic
      approach should provide a convincing postoperative examination of stability. A
      careful examination after suture placement may indicate residual laxity that must
      be addressed. Finally, periods of immobilization are similar in open and
      arthroscopic techniques. The process of biologic healing is not accelerated by
      arthroscopic techniques, and early return to sport activities that may endanger
      the repair will likely result in early failure.

PMID- 10652665
TI  - Thermal versus suture treatment of symptomatic capsular laxity.
AB  - This article reviews the clinical results of unipolar thermal capsular shrinkage
      in 30 patients and compares that group to similar groups previously managed by
      laser-assisted capsulorrhaphy or by an arthroscopic capsular shift procedure.
      Patients were evaluated with respect to incidence of recurrent instability, the
      need for reoperation, and the ability to return to previous levels of activity or
      sports participation. Patients were rated as satisfactory or unsatisfactory based
      on criteria established by Neer. The results of this study suggest that thermal
      capsulorrhaphy with rotator interval plication is an effective treatment
      alternative for multidirectional instability, with results comparable to those
      previously reported with open and arthroscopic procedures.

PMID- 10652666
TI  - Repair of the rotator cuff. Mini-open and arthroscopic repairs.
AB  - The repair of rotator cuff tears by traditional open subacromial decompression
      and rotator cuff tendon reapproximation has proved successful in restoring
      function and decreasing pain, but open rotator cuff repair has some inherent
      disadvantages. Postoperative detachment of the deltoid repair has been reported
      and results in significant morbidity. The open technique may also require a
      longer period of limited motion resulting in greater stiffness. Arthroscopically
      assisted mini-open repairs and, more recently, completely arthroscopic repairs of
      the rotator cuff have been developed and increasingly are being applied. Both
      techniques avoid detachment of the deltoid. The mini-open and arthroscopic
      approaches to rotator cuff repair have the added benefit of arthroscopic
      evaluation of the glenohumeral joint. The mini-open technique has the advantage
      of allowing the direct visualization of the cuff repair and allows surgeons to
      place the stitches in an open fashion, which is familiar to all surgeons. The
      mini-open technique also allows the placement of tension-absorbing stitches in
      the rare cases that they are needed. Mini-open techniques also allow the choice
      of bone anchors or osseous tunnels for fixation. The completely arthroscopic cuff
      repair has several potential advantages over the open and mini-open cuff repair
      techniques; first is the decreased disruption of the soft tissues, which may
      result in less scarring and adhesions. The procedure is the most cosmetically
      appealing of the techniques. Reduced postoperative pain is also cited as an
      advantage but has been demonstrated only in a single, nonrandomized study.
      Finally, if technical difficulties arise, the conversion to a mini-open repair
      can be done easily. In a few studies, arthroscopic cuff repair techniques have
      shown promise as an alternative to mini-open or open repair, but these results
      have been at the hands of a few surgeons who have extensive experience in
      arthroscopy of the shoulder. In contrast, the mini-open procedure requires modest
      arthroscopic skills and has a documented history of success. Nevertheless,
      arthroscopic rotator cuff repair is a viable and effective technique in the hands
      of surgeons with adequate skills, and this procedure is likely to become more
      commonly performed in the future as shoulder arthroscopic skills and
      instrumentation improve.

PMID- 10652668
TI  - Superior labrum, anterior and posterior lesions. When and how to treat them.
AB  - The treatment of patients with SLAP lesions requires an understanding of the
      normal and abnormal anatomy of the superior labrum. SLAP lesions have a role in
      rotator cuff disease and glenohumeral instability. Operative repair with suture
      anchors has been detailed.

PMID- 10652667
TI  - Arthroscopic posterior capsular repair.
AB  - Posterior shoulder instability is associated with capsular laxity and well
      defined pathologic lesions of the gleno-labral concavity. Most arthroscopic
      techniques have concentrated on capsular shift or plication of capsular laxity.
      This article demonstrates that arthroscopic capsulolabral plication
      simultaneously can augment the glenolabral concavity to restore the glenoid
      depth, and can reduce excessive capsular laxity of the redundant posteroinferior
      capsule. This method has proven effective in treating posterior instability.

PMID- 10652669
TI  - Shoulder injuries in overhead athletes. The "dead arm" revisited.
AB  - The following statements summarize this article: Three distinct categories of
      Type 2 SLAP lesions exist: (1) anterior, (2) posterior, and (3) combined
      anteroposterior. Posterior Type 2 SLAP lesions have distinct clinical and
      anatomic features that distinguish them from anterior Type 2 SLAP lesions.
      Posterior and combined Type 2 SLAP lesions can be disabling to overhead-throwing
      athletes because of posterosuperior instability and anteroinferior pseudolaxity.
      The Jobe relocation test is positive with posterosuperior pain in patients with
      posterior or combined anterior-posterior Type 2 SLAP lesions and is negative in
      patients with anterior Type 2 SLAP lesions. Rotator cuff tears are frequently
      associated with posterior or combined anterior-posterior SLAP lesions, are lesion
      location specific, and typically begin from inside the joint as undersurface
      tears. Repair of posterior SLAP lesions can return overhead-throwing athletes to
      full overhead athletic functioning. The peel-back mechanism is a likely cause of
      posterior Type 2 SLAP lesions. To securely repair the posterosuperior labrum to
      resist torsional peel-back, sulure anchors must be placed posterior to the biceps
      at the corner of the glenoid. The repair must be protected against external
      rotation past 0 degree for 3 weeks to avoid undue premature torsional stresses on
      the repair from the peel-back mechanism. A tight posteroinferior capsule
      predisposes to Type 2 SLAP lesions in overhead athletes. Shoulders at risk for
      the dead arm syndrome have a marked loss of internal rotation caused by
      contracture of the posteroinferior capsule such that less than a 180 degrees arc
      of rotation is achieved with the arm abducted 90 degrees (the 180 degrees rule).
      Type 2 SLAP lesions that cause the dead arm syndrome in overhead-throwing
      athletes are most likely acceleration injuries that occur in late cocking rather
      than deceleration injuries in follow-through. Rehabilitation of athletes with the
      dead arm syndrome must include the entire kinetic chain. The root cause of the
      dead arm syndrome is the Type 2 SLAP lesion.

PMID- 10652670
TI  - Surgery, skin and syphilis. Daniel Turner's London (1667-1741).

PMID- 10652671
TI  - Management of heart failure in children.

PMID- 10652672
TI  - The Angio-Seal hemostatic puncture closure device. Concept and experimental
      results.
AB  - The Angio-Seal hemostatic puncture closure device is the culmination of
      development efforts dating from 1986. Development was driven to solve problems of
      delivering a multi-piece bioabsorbable puncture closure assembly through an
      introducer, the precise placement of the device in the vessel, the mastery of
      molding tiny absorbable polymer components, the manufacture of collagen
      hemostatic sponges having strong tear strength, and the testing of very large
      samples to establish safety and efficacy. Improvements included in the new 6F
      device to improve deployment reliability are also discussed.

PMID- 10652673
TI  - [Hemostatic closure of arterial puncture site using Angio-Seal after diagnostic
      heart catheterization or coronary intervention].
AB  - Conventional manual compression and subsequent application of pressure bandages
      is associated with prolonged immobility and significant patient discomfort.
      Routine anticoagulation as well as the use of new interventional devices and
      platelet inhibiting strategies lead to a higher incidence of local bleeding
      complications after diagnostic cardiac catheterization or coronary angioplasty.
      Immediate sheath removal increases patient comfort. The Angio-Seal system uses a
      biodegradable anchor and collagen plug for sealing of arterial puncture sites.
      Several studies showed the safety and efficacy of this device. Technical
      deployment success ranges between 88 and 100%. Significant reduction in time to
      hemostasis allows for earlier patient ambulation and shorter in-hospital stay
      compared to manual compression with peripheral complications not being increased.

PMID- 10652674
TI  - The Duett closure device: concept and experimental results.
AB  - Purpose of this paper is to investigate the hemostatic capabilities of a novel
      vascular sealing device consisting of a balloon catheter and procoagulant.
      Vascular sheaths were placed percutaneously in the femoral arteries of dogs. The
      sealing device was evaluated using the balloon catheter alone in 6 femoral
      arteries and with the addition of a procoagulant in 21 femoral arteries. The
      balloon catheter alone was successfully deployed in 6 of 6 femoral arteries
      achieving immediate hemostasis. In a second study in which the procoagulant was
      delivered following balloon placement, the sealing device was successfully
      deployed and hemostasis was achieved in 20 of 21 attempts (95%) despite removal
      of the balloon catheter. In a subset of fully anticoagulated animals, hemostasis
      was achieved in the sealing device-treated arteries at 6.5 +/- 3.4 minutes but in
      none of the controls (p < 0.001). This novel vascular sealing device successfully
      achieves rapid hemostasis in normal and anticoagulated dogs following
      percutaneous vascular procedures.

PMID- 10652676
TI  - Outpatient coronary stenting: femoral approach with vascular sealing.
AB  - Miniaturized devices and pressures for increased patient convenience and lowered
      cost have shortened length of stay for coronary interventions. A cohort of 60
      patients was recruited to assess the feasibility of outpatient stenting with
      vascular sealing. Patients with stable and unstable angina or myocardial
      infarction > 24 hours were considered for this strategy. Mean time to hemostasis,
      ambulation and discharge were 6.1, 256 and 296 minutes, respectively, for the 6F
      group, and 11.0, 351 and 489 minutes for the 7 to 8F group. No acute procedural
      complications occurred, and there were no ischemic complications at 24 hours or 1
      month. There was 1 pseudoaneurysm requiring surgical correction, but no other
      access site requiring treatment. The cost saved using the 6F approach is
      estimated at $478 and using the 8F approach, $437. Outpatient stenting using
      vascular sealing is feasible and safe, and may lead to significant nationwide
      cost reductions in the range of $40,000,000 yearly.

PMID- 10652675
TI  - Final report of the European multi-center registry using the Duett vascular
      sealing device.
AB  - Duett, a novel vascular sealing device, was first clinically used in July 1997. A
      European multi-center registry was established to evaluate the safety and
      procedural success of the Duett sealing device in a broad range of patients
      undergoing diagnostic or interventional endovascular procedures. At 25 European
      sites 1587 patients were enrolled. All patients (> or = 18 years) must have given
      informed consent for the use of the sealing device after a diagnostic and/or
      interventional endovascular procedure performed via a femoral arterial approach.
      Standard length (< or = 10 cm) 5 to 9 F introducer sheaths had to be used. An ACT
      of < or = 400 s, and any approved GP IIb/IIIa platelet receptor antagonist was
      permitted. Successful deployment could be achieved in 96.2% (1526/1587 patients)
      with complete hemostasis within 2 to 5 minutes in over 95% of the patients. The
      complication-free rate was 96.4%. Arterial occlusions were rare (4 patients) and
      successfully treated with surgical repair in 1 and with thrombolysis in 3
      patients. Pseudoaneurysms occurred in 34 patients, the majority (30/34) were
      successfully treated with ultrasound-guided compression or resolved
      spontaneously. The total rate of major complications was 2.6% (41/1587). The
      final results of the European registry demonstrate that the Duett sealing device
      can be used with a high procedural success following diagnostic and
      interventional endovascular procedures. The incidence of major complications is
      low and comparable to all other approved vascular closure devices and manual
      compression. CE-mark certification was approved at the end of 1998.

PMID- 10652677
TI  - [Surgical treatment of cardiovascular manifestations of Marfan's syndrome].
AB  - Patients with Marfan's syndrome suffer mainly from the cardiovascular
      manifestations of the disease, in particular the acute dissection or rupture of
      the dilated aorta. Due to improved diagnostic and early surgical intervention the
      life expectancy of these patients could be considerably improved. However,
      rupture is still the most frequent and dissection the second frequent cause of
      death. Life threatening complications of aortic dissection are pericardial
      effusion, aortic insufficiency and malperfusion syndrome, due to obstruction of
      aortic branches. Dissection of the ascending aorta is treated by implantation of
      a valved conduit with reimplantation of the coronary arteries. Some surgeons
      favor the complete replacement of the ascending aorta with preservation of the
      aortic valve, although long-term results show some development of aortic
      insufficiency after this procedure. Based on the experience of the last years,
      most surgeons prefer the prophylactic replacement of the aorta in Marfan
      patients, i.e. before complications have occurred. A special treatment algorithm
      helps to define the indication for the operative treatment in different
      manifestations of the disease. The low mortality of the elective replacement of
      the ascending aorta in contrast to replacement in emergency cases speaks in favor
      of the early operative treatment. For the long-term prognosis of the patient a
      closed and continuous cardiologic surveillance is mandatory. The patient should
      be close to a center with the necessary diagnostic tools and with sufficient
      experience with the medical and surgical treatment, in order to further improve
      the life expectancy in the future.

PMID- 10652678
TI  - [Aspects of radiation protection in cardiovascular brachytherapy].
AB  - In the scope of cardiovascular brachytherapy beta- as well as gamma-ray emitting
      radionuclides are used. The handling of radioactive sources is within the range
      of the radiation protection regulations (Strahlenschutzverordnung [StrlSch V]).
      According to EU guidelines an amendment of the StrlSch V is required by May 2000.
      The connected reduction of dose limits now should already be taken into
      consideration when planning irradiation facilities, likewise in cardiovascular
      brachytherapy. Temporary regulations for equipment that was already in operation
      before May 2000 are not planned in the new StrlSch V.

PMID- 10652679
TI  - [Transcoronary ablation of septal hypertrophy (TASH): supersedes it the surgery
      (myectomy)?].

PMID- 10652680
TI  - A national survey of regional poison control centers' management of occupational
      exposure calls.

PMID- 10652681
TI  - Glomus tumor: an unusual cause for return to work delay after back injury.

PMID- 10652682
TI  - Mercury toxicity due to use of a cosmetic cream.
AB  - The Arizona Department of Health Services performed an investigation to determine
      the health effects associated with the use of a mercury-containing beauty cream.
      A urine test for mercury was offered to cream users who contacted the Arizona
      Department of Health Services. Those with urine mercury levels > 20 micrograms/L
      were offered clinical evaluation. Eighty-nine urine specimens were submitted for
      testing. Of these, 66 showed an elevated urine mercury level (> 20 micrograms/L),
      and 55 people were evaluated in clinic. There were no major abnormalities found
      through physical examination or laboratory testing. Urine mercury levels declined
      from an initial mean of 170 micrograms/L to 32 micrograms/L at the final test
      (mean, 139 days later). The high urine mercury levels indicate that the use of
      this cosmetic cream constitutes a significant exposure. Neuropsychiatric symptoms
      were frequently reported, but few objective signs were noted.

PMID- 10652683
TI  - Aerosols generated during beryllium machining.
AB  - Some beryllium processes, especially machining, are associated with an increased
      risk of beryllium sensitization and disease. Little is known about exposure
      characteristics contributing to risk, such as particle size. This study examined
      the characteristics of beryllium machining exposures under actual working
      conditions. Stationary samples, using eight-stage Lovelace Multijet Cascade
      Impactors, were taken at the process point of operation and at the closest point
      that the worker would routinely approach. Paired samples were collected at the
      operator's breathing zone by using a Marple Personal Cascade Impactor and a 35-mm
      closed-faced cassette. More than 50% of the beryllium machining particles in the
      breathing zone were less than 10 microns in aerodynamic diameter. This small
      particle size may result in beryllium deposition into the deepest portion of the
      lung and may explain elevated rates of sensitization among beryllium machinists.

PMID- 10652684
TI  - Circulating natural killer cells in retired asbestos cement workers.
AB  - The effect of past exposure to asbestos on natural killer (NK) cell number and
      activity is uncertain. We measured NK cell number and activity in 1052 retired
      asbestos workers without symptomatic lung disease, lung cancer, or mesothelioma
      and with a long latency period from exposure; results were compared with those
      for 100 healthy age-matched controls. The exposed workers showed a decreased NK
      cell activity and increased NK cell number, yielding a 10.8 higher odds ratio for
      low NK activity per cell compared with controls (95% confidence interval 6.4 to
      18.4), which was due to both a decrease in NK cell activity and an increase in NK
      cell number. Asbestos exposure of 10 years or more increased the risk of low NK
      activity per cell. We conclude that exposure to asbestos is associated with
      diminished effectiveness of NK cells and a concomitant increase in the number of
      NK circulating cells.

PMID- 10652685
TI  - Why most workers with occupational repetitive trauma do not file for workers'
      compensation.
AB  - Despite the availability of no fault insurance for wage replacement and medical
      care costs, the majority of workers diagnosed with an occupational disease do not
      apply for workers' compensation. The objective of the study was to determine the
      reasons why workers diagnosed with work-related musculoskeletal disease did not
      apply for workers' compensation benefits. A cross-sectional study of 1598
      individuals diagnosed with neck, upper extremity, and low back work-related
      musculoskeletal disease from April to June 1996 was performed. All individuals
      were interviewed over the telephone using a standardized questionnaire. The
      questionnaire included questions about the precipitating event; demographics;
      health limitations; mood; pain level; and attitudes toward their health care
      provider, fellow workers, management, work environment, and filing for workers'
      compensation. Whenever possible, standardized questions from previous surveys
      were used. The interviewed individuals with work-related musculoskeletal disease
      were reported by health care practitioners as required by the state of Michigan's
      occupational disease reporting law. Workers reported during 12 weeks in the
      spring of 1996 by a Michigan health care professional as having a neck, back, or
      upper extremity musculoskeletal disorder were eligible to participate. Among the
      2703 reports received, 490 individuals could not be reached, 22 did not speak
      English, 12 had died or were too incapacitated by other medical conditions, and
      581 refused. We interviewed 59% of all eligible workers and 73% of all workers
      who were reachable and capable of responding in English. Only 25% of workers
      diagnosed with musculoskeletal disease filed a workers' compensation claim. The
      factors significantly associated with filing a claim were (1) increased length of
      employment (> 21 years: odds ratio [OR], 3.01, 95% confidence interval [CI], 1.31
      to 6.90); 11 to 20 years: OR, 2.34, 95% CI, 1.01 to 5.47; 6 to 10 years: OR,
      1.76, 95% CI, 0.73 to 4.25; 1 to 5 years: OR, 2.36, 95% CI, 1.03 to 5.42; < 1
      year: OR, 1.00; (2) lower annual income (< $40,000: OR, 1.75, 95% CI, 1.06 to
      2.88 vs > or = $80,000: OR, 1.00); (3) workers' dissatisfaction with coworkers
      (OR, 1.76, 95% CI, 1.01 to 3.06); (4) physician restrictions on activity (OR,
      2.16, 95% CI, 1.55 to 3.00); (5) type of physician providing treatment
      (specialist, including surgeon or orthopedist: OR, 3.63, 95% CI, 2.37 to 5.55);
      physical and occupational therapist: OR, 2.15, 95% CI, 1.35 to 3.43); family
      practitioner: OR, 1.33, 95% CI = 0.89 to 2.01; company physician: OR = 1.00); (6)
      off work > or = 7 days (OR, 14.85, 95% CI, 10.57 to 20.85); (7) decreased current
      health status (OR, 0.82, 95% CI, 0.70 to 0.96); and (8) increased severity of
      illness (OR, 1.24, 95% CI, 1.06 to 20.88). This study showed that only 25% of
      workers with a work-related musculoskeletal condition filed for workers'
      compensation and refutes the common perception that an individual with a work
      related problem is likely to file a workers' compensation claim. The strongest
      predictors of who would file were those factors associated with the severity of
      the condition. Other factors were increasing length of employment, lower annual
      income, and worker dissatisfaction with coworkers. Our study population consisted
      mainly of unionized autoworkers, and our findings may not be generalizable to the
      total workforce.

PMID- 10652686
TI  - Effectiveness of early physical therapy in the treatment of acute low back
      musculoskeletal disorders.
AB  - This study was designed to evaluate the effects of early physical therapy
      intervention on treatment outcomes for workers with acute low back injuries. A
      total of 3867 cases were randomly selected from the database of a large
      occupational health care provider. Cases were assigned to either the early
      therapy intervention group or one of the two comparison groups on the basis of
      their delay to physical therapy. The treatment outcomes for the three groups were
      compared. The results showed that patients in the early therapy intervention had
      more favorable outcomes than the two comparison groups. Specifically, patients in
      the early intervention group had fewer physician visits, fewer restricted
      workdays, fewer days away from work, and shorter case duration. These results
      provide a strong indication for the effectiveness of early therapy intervention.
      The financial implications of the findings is discussed.

PMID- 10652687
TI  - Psychosocial factors at work, smoking, sedentary behavior, and body mass index: a
      prevalence study among 6995 white collar workers.
AB  - This cross-sectional study examined whether psychosocial factors at work were
      associated with smoking, sedentary behavior, and body mass index. The study
      population was composed of 3531 men and 3464 women employed as white collar
      workers in 21 organizations. Data were collected at worksites. Psychological
      demands and decision latitude at work were measured with the Karasek 18-item
      questionnaire. Smoking, sedentary behavior, and mean body mass index were
      compared by quartiles of decision latitude and psychological demands and by job
      strain categories. Prevalence of smoking, mean number of cigarettes smoked per
      day, prevalence of sedentary behavior, and mean body mass index were not
      consistently associated with decision latitude, psychological demands, or high
      job strain. However, prevalence of smoking was elevated in women belonging to the
      highest quartile of psychological demands (odds ratio [OR], 1.2; 95% confidence
      interval [CI], 1.0 to 1.6) and in the active job strain groups in both men (OR,
      1.6; 95% CI, 1.2 to 2.1) and women (OR, 1.4; 95% CI, 1.0 to 2.0). Prevalence of
      sedentary behavior was elevated in men in the lowest quartile of decision
      latitude (OR, 1.3; 95% CI, 1.0 to 1.7), in the passive group (OR, 1.3; 95% CI,
      1.0 to 1.5), and in the high strain group (OR, 1.2; 95% CI, 1.0 to 1.6). In
      women, this prevalence was elevated in the third quartile of psychological demand
      (OR, 1.3; 95% CI, 1.1 to 1.6). These results provide only partial support for an
      association between some psychosocial factors at work and the prevalence of
      smoking and sedentary behavior.

PMID- 10652688
TI  - Worksite cardiovascular wellness programs as a route to substance abuse
      prevention.
AB  - This study addresses the question of worksites as an effective route to alcohol
      abuse prevention. Hypotheses tested include: (1) Cardiovascular disease risk
      reduction programs provide effective access for alcohol behavior change. (2)
      Proactive outreach and follow-up have more impact on health behavior change than
      health education classes. (3) Ongoing follow-up counseling produces the most
      behavior change. (4) Screening alone produces little change. The study population
      included 2000 employees, recruited through cardiovascular disease health
      screening, who were randomly assigned to individual outreach or classes
      interventions. Changes in the organization of work required more visible
      outreach, which produced demands for counseling services from many employees who
      were not in the original group targeted for outreach. After 3 years of
      intervention, rescreening results strongly supported hypotheses 1 and 2. Spill
      over effects from counseling produced plant-wide improvements, so that hypotheses
      3 and 4 were not confirmed. This demonstrates that highly visible outreach
      provides a cost-effective strategy for cardiovascular disease and alcohol
      prevention.

PMID- 10652689
TI  - Hearing loss among construction workers in Edmonton, Alberta, Canada.
AB  - Hearing acuity among electricians, plumbers and pipefitters, and boilermakers
      with > or = 20 years of union membership was compared with that of telephone
      workers. Automated pure tone audiometry was performed and a questionnaire was
      administered. Most construction workers were exposed to occupational noise and
      wore hearing protection. Median thresholds for electricians and telephone workers
      were comparable. Thresholds of plumbers and pipefitters were higher but
      comparable to expected values. Boilermakers had high levels of hearing loss.
      Thresholds at 4000 Hz among older workers were similar for all groups and were
      above expected values, suggesting a cohort effect. Audiometric screening seems to
      be warranted for some construction workers.

PMID- 10652690
TI  - Evaluation of a western blot test as a potential screening tool for occupational
      exposure to Mycobacterium tuberculosis in health care workers.
AB  - Health care workers (HCWs) have a higher than average risk for contracting
      Mycobacterium tuberculosis (MTB) infection and tuberculosis (TB). No markers of
      MTB-exposure are available, and TB risk assessment is performed by tuberculin
      screening, identifying individuals with acquired MTB infection. This study
      evaluated a western blot (WB) anti-M. bovis A60 complex antibody as a MTB
      exposure marker. WB reactivity was evaluated on 127 exposed and 28 non-exposed
      HCWs from four divisions of the Policlinico Hospital of Modena, and 140 non
      exposed bacille Calmette-Guerin-vaccinated controls. Excess of occupational TB
      risk according to the Occupational Safety and Health Administration (OSHA) was
      calculated in each division. WB-positivity (%) was: (1) significantly higher in
      exposed HCWs compared with non-exposed (72% vs 25%, P < 0.00001), (2) highly
      related (r = 0.99) to OSHA risk excess in all divisions, (3) higher than non
      exposed in HCWs with short (< 5 years) MTB-exposure (purified protein derivative
      [PPD], P > 0.18; WB, P < 0.04). PPD-positivity (%) was higher than controls only
      in HCWs with longer (> 5 years) MTB-exposure. The study suggests that the WB
      antibody might represent a more sensitive biological marker of MTB contact among
      exposed HCWs, related to the level of TB risk and detectable earlier than the PPD
      skin test, thus providing new tools for TB risk assessment in health care
      facilities.

PMID- 10652691
TI  - Lung cancer mortality among a cohort of men in a silicotic register.
AB  - To examine any association between silicosis and lung cancer, the clinic records
      of a cohort of 1502 silicotic workers diagnosed after 1981 were reviewed. All of
      the essential data, including occupational exposure, smoking habits, radiographic
      extent of silicosis, and vital status of each subject, were noted. The
      standardized mortality ratio for various causes of death was calculated. Thirty
      three patients died from lung cancer, giving a standardized mortality ratio of
      1.94 (95% confidence interval, 1.35 to 2.70). However, smoking accounted for most
      of the excess of lung cancer deaths among the silicotic workers in the cohort,
      and no consistent relationship between lung cancer mortality risk and either
      duration of exposure to silica dust or severity of silicosis was observed. There
      is no conclusive evidence in our data to support the hypothesis that lung cancer
      may be associated with silicosis.

PMID- 10652692
TI  - Consistency of occupational exposure history from pattern and model makers.
AB  - This study investigates the consistency of occupational histories reported by the
      same men in 1985 and again in 1988. Detroit-area pattern and model makers
      participating in a colorectal cancer screening program that was offered at 3-year
      intervals completed a career length occupational exposure questionnaire at each
      screening. Analysis of the data from the 243 men who participated in both
      screening programs provided the opportunity to examine the consistency with which
      these workers reported the extent of their exposure to 13 substances commonly
      found in their work environment. Workers were asked to provide a work history,
      and for each different pattern or model maker job they had held, to estimate the
      percentage of time they were exposed to the 13 substances. The data indicated
      that over the 3-year study period, pattern and model makers were highly
      consistent in reporting whether or not they were exposed to the 13 substances. In
      addition, their first estimates of the percentage of time they were exposed to
      each substance were within 10% of their second estimates more than 70% of the
      time. This concordance was somewhat diminished after excluding those who reported
      no exposure. These findings suggest that skilled tradesman can provide
      occupational exposure information that is likely to be useful for physicians in
      considering an occupational cause for a presenting health concern.

PMID- 10652693
TI  - Evaluation of occupational transmission of hepatitis A virus among wastewater
      workers.
AB  - To provide information concerning potential occupational transmission of
      hepatitis A virus (HAV) among wastewater workers in a large city in the United
      States, a cross-sectional survey was performed using a saliva test to detect
      antibodies to HAV (anti-HAV). Fifty-nine (20%) of 302 participants tested
      positive for anti-HAV. After controlling for the confounding effects of age and
      race, wastewater work was not significantly associated with an increase in the
      prevalence of anti-HAV (prevalence ratio = 1.3; 95% confidence interval 0.7 to
      2.4). Additionally, when examining only the wastewater workers, no statistically
      significant occupational risk factors for anti-HAV were identified. The results
      of this survey are consistent with the position of the Centers for Disease
      Control and Prevention regarding groups at risk for HAV infection.

PMID- 10652694
TI  - Motives for protective behavior against carcinogenic substances in the workplace:
      a pilot study among Dutch workers.
AB  - Exposure to carcinogenic substances in the workplace creates an increased risk of
      certain types of cancer among employees. In The Netherlands, more than one
      million of the total working population of 10 million are exposed to toxic
      substances in more than 100,000 Dutch companies. To motivate workers to comply
      with protective recommendations, it is important to know their reasons for
      complying or not complying. The goal of the present study was to analyze the
      differences between workers who show a relatively high degree of protective
      behavior and those who show a relatively low degree of such behavior. The beliefs
      of workers exposed to carcinogenic substances at four worksites were analyzed.
      Data on attitudes, perceptions of social support, and self-efficacy expectations
      toward compliance with protective behavior were collected among 164 workers. The
      results showed that non-compliant workers perceived fewer benefits, encountered
      less social support, and, most importantly, encountered more barriers to
      complying with safety recommendations. It is concluded that health education
      programs must address these specific items to motivate non-compliant workers to
      comply more fully with protective recommendations.

PMID- 10652695
TI  - Pre- and post-employment median nerve latency in pork processing employees.
AB  - There is some controversy regarding the relationship between development of
      median nerve dysfunction and employment activities. We performed nerve conduction
      studies of median nerve function on individuals before and after starting
      employment in the pork processing industry. After working an average of 64 days,
      employees (n = 45) showed significant prolongation of median motor and sensory
      nerve latency when comparing initial and final testing results in both dominant
      and non-dominant hands (P = < 0.01 to 0.03). A similar trend was found when
      testing a smaller group of employees (n = 17) who were already working (mean of 3
      days), though this did not generally reach statistical significance. This study
      supports the conclusion that prolongation of median motor and sensory nerve
      latency can occur within as little as 2 months after beginning employment in the
      pork processing industry.

PMID- 10652696
TI  - Incidence of cancer among welders and other shipyard workers with information on
      previous work history.
AB  - The incidence of cancer among 4480 shipyard workers, including 861 welders, was
      investigated for a potential relationship between exposure to welding fumes and
      lung cancer. A subcohort of 3150 workers with information on previous work
      history was studied separately. This investigation is a historical prospective
      cohort study. Environmental air samples were collected in 1973, 1977, and 1989.
      Information on smoking habits was surveyed in 1976 and 1984. The employment work
      histories were collected from the personnel register. There were 411 observed
      cancers of all sites versus 387.5 expected, and 45 cases of lung cancer versus
      51.3 expected. Nine cases of lung cancer were found among the welders versus 7.1
      expected. Among 310 former seamen with welding experience, there was 1 case of
      lung cancer versus 2.1 expected. These shipyard workers showed no excess risk of
      lung cancer. Tobacco smoking and asbestos exposure are potential confounders in
      the study. There was no clear relationship between exposure to welding fumes and
      lung cancer, but welders with the longest experience had a relative risk of 1.9
      for lung cancer. The differences in lung cancer incidence among the different
      shipyard workers could not be attributed to differences in recruitment patterns
      or previous work history.

PMID- 10652697
TI  - Morphological features of lymphatic and mesothelial communications in the broad
      ligament of the pig.
AB  - The broad ligament containing uterine, paraovarian, and oviduct lymphatics was
      examined in the pig in various phases of the estrous cycle using light, scanning
      and transmission electron microscopy. The architecture of these regions differed
      and was independent of the lymphangions of the precollector and collector
      lymphatic vessels. Lymphangions were separated from mesothelium by connective
      tissue and/or muscle layers; however, in the vicinity of the thin walled
      paraovarian sac, large lymphangions were often compressed between two epithelial
      layers. Numerous lymphatic lacunae were in direct contact with the peritoneal and
      paraovarian sac cavities. The mesothelial lining of the broad ligament and the
      external and internal epithelium of the pig paraovarian sac displayed two
      distinct cell types. Only smaller cuboidal cells with prominent microvilli
      extended above the lymphatic endothelium. The surfaces of these cells were
      discontinuous and showed: 1) lymphatic stomata, 2) small pores or fenestrae, 3) a
      superficial network of epithelial-free communications with underlying connective
      tissue to the paraovarian sac in the postovulatory period independent of the
      lymphatic vasculature, and 4) endothelial (instead of epithelial) cells with
      crevice-like discontinuities in large portions of the internal sac surface during
      the follicular phase of estrus. Numerous lymphatic stomata had orifices composed
      of flattened cuboidal cells while lymphatic endothelial cells were characterized
      by macula or zonula adherent connections formed within rims of various sizes (up
      to 50 microns in diameter). During estrus, there were circular (0.5-2.0 microns)
      and irregular (to 10 microns) interendothelial openings in stomatal orifices with
      migrating cells. These morphologic findings suggest that absorption and passage
      of fluid, particles and cells between cavities and the lymphatic lumen in areas
      of the paraovarian lymphatic plexus in the pig is feasible.

PMID- 10652698
TI  - Investigation of the mechanism of lymphocyte injection therapy in treatment of
      lymphedema with special emphasis on cell adhesion molecule (L-selectin).
AB  - We previously employed intraarterial lymphocyte injection therapy in conjunction
      with standard non-operative treatment of peripheral lymphedema of various
      etiologies. In this study, we further evaluated the clinical outcome of this
      therapy in 46 patients with unilateral lymphedema of the extremities. The results
      showed combined therapy (lymphocyte injection with compression) was effective in
      74% (34 of 46 patients) with dramatic reduction in lymphedema in 37% (17 of 46
      patients). In the most recent 5 patients treated, we examined the expression of
      cell adhesion molecule of the lymphocytes (L-selectin) before, during and after
      lymphocyte injection therapy to study the putative pathomechanism of this
      treatment method. The expression of L-selectin, a lymphocyte-specific adhesion
      molecule, increased in the autologous lymphocytes obtained by a blood cell
      separator and in the lymphocytes from the peripheral blood after injection.
      Moreover, the lymphocyte fraction, which was positive for L-selectin and negative
      for CD3, a T-cell marker, decreased after lymphocyte injection. We postulate that
      the lymphocytes of L-selectin (+) and CD (-) remain in the affected swollen limb
      and play a role in an ill-defined immunologic responsiveness that potentiates
      reduction in edema.

PMID- 10652699
TI  - Bioelectrical impedance analysis revisited.
AB  - Although total limb volume measurements are used to track the progress of
      lymphedema and its treatment, these measurements can be confounded by changes
      other than fluid excess namely muscle or fat gain. Bioelectrical impedance
      analysis (BIA) is a technique that specifically quantifies both total body fluid
      and extracellular fluid in extremities. Whereas BIA has potential as a quick,
      inexpensive, and quantitative technique to measure directly fluid gain or loss
      from lymphedema, it also has certain shortcomings that must be addressed before
      it can be validated. this paper examines the back-ground that explains why
      measuring total limb volume is insufficient to quantify the extent of peripheral
      lymphedema and explores the advantages and drawbacks of using BIA for this
      purpose.

PMID- 10652700
TI  - Effect of tumor necrosis factor-alpha and interleukin-2 on spleen lymphocyte
      migration in mouse skin.
AB  - Tumor necrosis factor-alpha (TNF-alpha) and interleukin-2 (IL-2) are reported to
      enhance lymphocyte binding to endothelial cells in vitro. We examined these two
      agents on lymphocyte migration in vivo. Spleen lymphocytes were radiolabeled with
      tritiated uridine (3H-UR) and then injected i.v. into mice. Each cytokine (TNF
      alpha or IL-2) or both cytokines were then injected intradermally on the back of
      mice. The results demonstrated that TNF-alpha stimulates lymphocyte migration in
      vivo in dose-dependent fashion. Kinetic analysis demonstrated that migration with
      TNF-alpha started at 3 h, peaked at 6 h, followed by a gradual decline back to
      baseline at 24 h. IL-2, on the other hand, was nearly inactive, and did not
      augment lymphocyte migration over and above that induced by TNF-alpha when both
      cytokines were injected together.

PMID- 10652701
TI  - Hair tourniquet syndrome: an unusual cause of perinatologic secondary lymphedema.

PMID- 10652702
TI  - [Need for rehabilitation and utilization].

PMID- 10652703
TI  - [Empirical determination of the need for rehabilitation].
AB  - In Germany, members of social insurance (e.g., pension) schemes have to apply for
      medical rehabilitation. Usually, the applications are the expression of a
      subjective demand. If the applications are granted this leads to the actual
      supply of medical rehabilitation services. Formerly, long waiting lists were
      common. These have been replaced by a new balance between demand (amount of
      applications), "offer" (capacity of rehabilitation clinics) and the amount of
      granted applications. In addition to these notions, the article develops the
      concept of need for rehabilitation services based on sociomedical indications.
      Consequently, the need for medical rehabilitation can--to a certain degree--be
      objectified. The concept of need should not be mixed up with that of demand: not
      every member of a social insurance scheme who objectively is in need of medical
      rehabilitation realizes the need, not everybody who realizes a need will apply
      for rehabilitation, and not all applications will be granted. The article gives
      an overview of different ways of needs assessment.

PMID- 10652704
TI  - [Demographic and curative factors of need for rehabilitation--possibilities and
      limits of simple time series models].
AB  - Regarding rehabilitation demands, macro-analytical time-series models outline a
      method for the estimation of effective rehabilitation needs and for explaining
      the magnitude of the requirements. Their range is limited, in so far as they are
      unable to clarify the rehabilitation requirement regarding individual micro-level
      behavioural aspects. For the moment the rehabilitation requirements are hidden
      units in the models. Differing macro-dimensions have been gradually included in
      the analysis. The demographic parameters of the potential patients in need of
      rehabilitation are the fundamental starting point. Rehabilitation requirements
      are increasingly modelled by the magnitude of the curative requirements. These
      are characterised in the rehabilitation as "preliminary or follow up". Two
      examples of simple time-series models in rehabilitation--for the development of
      rehabilitation demand--illustrate empirically, which possibilities and boundaries
      are set in view of demographic and curative requirements by the interpretative
      range of the macro-concepts. What is methodically interesting with it, is how the
      analytical borders of such time-series models can experience a recognisable
      theoretical broadening, through a projection in real logistical facts--here in
      the interaction between prognosis and retrospection.

PMID- 10652705
TI  - [Concept and measurement of need for rehabilitation--framework for a
      multidimensional investigational approach].
AB  - As before the concept and content regarding the need for rehabilitation have
      still not been sufficiently clarified. In particular, an operationalization of
      the underlying parameters, as the basis for their measurement is absent. Some
      exemplary research concepts have been introduced and their methodological
      implications have been put out. Resulting from this, up till now, in the most
      developed model, determining the need for rehabilitation has been developed as a
      latent multi-dimensional variable. A framework, as a starting point for a multi
      dimensional investigation regarding the need for rehabilitation has been
      introduced. According to this, the need for rehabilitation is a multidimensional,
      qualitative construct, that can not be directly observed and measured. The
      empirical investigation, which is based on this, limits the description of the
      need for rehabilitation to the various patterns of determinants, (description by
      a set of requirement factors and arranged factors) which result in different
      effects. Therefore different samples regarding the qualitative aspect do not mean
      the lesser or greater need for rehabilitation based on a continuum of
      measurement, but different qualitative forms which are visible in different
      effects.

PMID- 10652706
TI  - [Medical rehabilitation--quantitative developments and structural changes in the
      past and future].
AB  - Usually, only recent developments concerning application for, treatments and
      costs of inpatient rehabilitation are in focus and reported regularly to all
      those involved. This contribution, however, analyses the long-term development of
      data in the context of rehabilitation under the German statutory pension
      insurance scheme since 1968, seeking to gain insights relative to the present and
      future situation in the field of rehabilitation.

PMID- 10652707
TI  - [Need for rehabilitation and application behavior].
AB  - The need for rehabilitation is not absolute and given quality. Determination of
      the need for rehabilitation depends on various criteria, e.g., the case history
      and certain legally standardized medical prerequisites. Both the regulation of
      rehabilitation expenditures and different types of personal excess coverage may
      be interpreted as efforts on the part of social policy to introduce additional
      controls (i.e., alongside the medical prerequisites) of the need for
      rehabilitation. Since rehabilitation benefits are only granted in case the
      insured has applied for, the demand for personal excess coverage might cause a
      certain selection of financially powerful rehabilitees. Recent cost-cutting
      legislation, which inter alia included strict budgeting of rehabilitation
      expenditures and increased personal excess coverage, had entailed a considerable
      decline in the number of applications for rehabilitation in 1996 and 1997.
      Several pension insurance funds started questioning their insured to examine the
      general interest in using rehabilitation services. The results show a strong need
      for rehabilitation in the group of the older insured (aged 40 and over), however,
      only 35% to 40% of the insured in subjective need for rehabilitation intend to
      file an application for rehabilitation and an even smaller number of insured
      actually apply for rehabilitation. Major impediments to applying for
      rehabilitation mentioned are job uncertainty as well as the increased personal
      excess coverage under the recent austerity legislation.

PMID- 10652708
TI  - [Level of information and attitude to rehabilitation in the population].
AB  - The demand for rehabilitation services and benefits under the pension insurance
      scheme has repeatedly seen fluctuations, in particular in the wake of amendments
      in the statutory prerequisites and benefit scope. Since late 1996, the discussion
      on the rank of rehab benefits and massive regulatory activity of the law-maker
      have resulted in major declines in the numbers of applications received. In a
      nationwide survey, representative statements have therefore been collected on the
      level of awareness of and attitudes towards the field of medical rehabilitation
      in the population at large. The findings show that clearly reduced levels of
      demand for rehabilitation services and benefits, i.e. a nearly 50% drop, will
      have to be expected in the years ahead. Even among insures whose working capacity
      is endangered for health reasons, there is quite a number who would rather
      refrain from applying for rehabilitation. Reasons given in particular include
      excessive costs due to the additional user charges, doubt of successful
      participation, and fear of jeopardizing employment. Only about half of the
      general population is familiar with the actual amount of additional user charges
      in case of rehab participation, and an even lower share is aware of the
      exemptions possible. A considerable proportion of the population at large is
      afraid of adverse occupational consequences in case of participation in a
      rehabilitation measure, a proportion which however is much lower among persons
      with earlier actual participation.

PMID- 10652709
TI  - [Subjective need for rehabilitation, intention to apply and application for
      medical rehabilitation--results of a survey of federal insurance office].
AB  - The survey "Determinants in Applying for Medical Rehabilitation" intended to
      examine the interest of using rehabilitation services among workers in need of
      rehabilitation and clarify the reasons for the decline in applications for
      rehabilitation since 1995. For this reason 4400 blue collar workers of the
      regional pension fund (2% of the LVA population aged 40-59 years) were asked with
      a postal questionnaire. The response rate was 64%. In order to ensure the
      validity of the intentions stated, the pension fund verified how many workers
      actually filed an application for medical rehabilitation during the following
      twelve months. A quarter of the workers answering considered themselves in need
      for rehabilitation. Of these, 41% intended to file an application, 34% intended
      not to do so and 25% were undecided. The main reasons for intending to apply were
      encouragement by the GP and family members as well as the expectation of
      improving the working capacity. After one year, only 11% of the workers who
      claimed themselves to be in need for rehabilitation had filed an application for
      rehabilitation. This low number of applications from workers in subjective need
      for rehabilitation indicates a deficit in medical rehabilitation provision.

PMID- 10652710
TI  - [Subjective health, need for rehabilitation and utilization in a West-East
      comparison--results of a survey of insured clients of the federal insurance
      office for employees and the Saxony federal insurance office].
AB  - There were substantial changes within the rehabilitation framework due to new
      laws as well as internal need for more flexibility. In connection with this
      process, the BfA and the LVA Sachsen initiated a survey among their insured
      persons, the main points being the need for and use of rehabilitative care. The
      results of a West/East comparison are presented. A questionnaire was send to
      approximately 29,000 insured persons, the overall response rate was 43%. White
      collar workers in the East reported a better state of health compared with those
      in the West, with the most profound differences found in females. Subjective
      health status and subjective working capability were highly associated. The
      proportion of persons who reported a need for rehabilitation amounts to 24% among
      the insured with the LVA Sachsen (blue collar workers, East) and 12% among the
      white collar workers in the East. Independent of the state of health there was
      also an association between work stress and the need for rehabilitation. Persons
      from the East were less informed about rehabilitative care than persons from the
      West. Financial and workplace problems were among the major reasons not to apply
      for a rehabilitation measure even if there is a need. These reasons were
      mentioned more often in the East. In conclusion, there are substantial
      differences between West and East concerning the rehabilitative health sector. A
      prominent role is played by the employment situation.

PMID- 10652711
TI  - [Are there class-specific disadvantages in utilization of medical
      rehabilitation?].
AB  - Many studies prove the fact that the risk for morbidity and mortality is
      increased in lower social classes. Most chronical diseases also accumulate in
      lower classes. However, data are missing as to whether this social disadvantage
      also affects the use of medical rehabilitation, which could supply support in
      dealing with the consequences of such diseases. On the basis of questionnaire
      data of 3021 insures of the LVA pension insurance fund for workers, it was
      examined whether there are class specific differences in the need for medical
      rehabilitation and in the intention of insures to apply for such a measure and
      which kind of class specific barriers and attitudes may hinder the application.
      The results first of all confirm that insured of lower social classes are
      specially health strained and have a particular demand for rehabilitative offers.
      The insured, however, quite rarely rate themselves as requiring rehabilitation,
      whereas there is no significant class specific difference in the intention to
      apply for rehabilitation. There are significant differences in the attitudes
      which influence application for medical rehabilitation. Above all, there are
      economic considerations and job-related fears which hinder lower class insurees
      to apply for medical rehabilitation. This calls for action regarding
      implementation of special screenings and counselling.

PMID- 10652712
TI  - [Sex-specific predictors of utilization of cardiologic rehabilitation from the
      epidemiologic viewpoint].
AB  - Among men and women cardiovascular diseases are among the three main causes for
      early retirement and participation in rehabilitation programmes. Rehabilitation
      research has only recently taken notice of the potential effect of gender on the
      need and outcome of cardiac rehabilitation care. Findings from epidemiological
      studies suggest that sex differences exist at every stage of heart disease and
      therefore may also be important for the quality and quantity of gender specific
      rehabilitation needs. Based on results from epidemiological studies this article
      first describes some essential biomedical differences between men and women
      regarding coronary heart disease which should be taken into account when type and
      amount of rehabilitation programmes are discussed. Afterwards, some recent
      findings are presented which focus on gender specific aspects of the use and
      acceptance of rehabilitation procedures.

PMID- 10652713
TI  - [Need for rehabilitation from the viewpoint of the general practitioner].
AB  - In Germany, the general practitioner plays an important role in the allocation
      process of rehabilitative measures. A survey concerning the questions of need,
      demand and effectiveness of medical rehabilitation measures as seen from the
      general practitioner's perspective in Hamburg, Schleswig-Holstein und Halle/Saale
      (n = 956) in 1999 shows that general practitioners have a rather positive
      attitude towards rehabilitation in general. With regard to the different measures
      within the rehabilitation system they show a differentiated opinion. As they see
      a large percentage of over- and underuse of rehabilitation they would appreciate
      that their information on the patient would be more intensively taken into
      account in the allocation process.

PMID- 10652714
TI  - [Control of referral and duration of rehabilitation in federal insurance office
      provided rehabilitation].
AB  - Presented is a computer-based system for interactive assignment control, designed
      to cope with the increasing requirements in rehabilitation and health care
      concerning quality assurance, greater flexibility, as well as enhanced
      effectiveness and efficiency. Thanks to multi-factor control, medical,
      organizational and economic parameters can be taken into account selectively. In
      addition, an unbureaucratic approach to determining length of rehabilitation
      programme participation is described, which has been implemented successfully for
      the last three years.

PMID- 10652715
TI  - [Treatment dropout as failed utilization--development of a predictive model for
      inpatient psychosomatic rehabilitation].
AB  - Premature discontinuance of rehabilitative measures can be considered a revised
      decision by the patient concerning participation or a revised decision by the
      clinic concerning admittance. Such termination of therapy suggests that the
      individual need for rehabilitation (defined as the fit between the patient's need
      for rehabilitation and the treatment offered by the rehabilitation facility) is
      not (or no longer) present, at least at this point in time. Assuming that the
      individual need for rehabilitation actually existed when treatment was requested
      or approval for rehabilitative measures was granted, the question arises as to
      when and how the need changed in such a way that would prevent the treatment from
      continuing as planned and being concluded in a regular fashion. This question
      will be taken into focus in the present article by developing a model for the
      prediction and explanation of prematurely discontinued treatment. This model will
      give central significance to the intention to co-operate, which is considered a
      dependent variable by reference to individual symptoms and treatment related
      expectations. Furthermore, various factors of influence during the stay in the
      clinic are formulated, which, firstly, have a presumed effect on the intention to
      cooperate and, secondly, have an influence on whether the intention to
      prematurely terminate treatment develops from a specific intention to cooperate
      and whether this is then realized. The model is discussed with regard to its
      practicability and possibilities for operationalization.

PMID- 10652716
TI  - Pathogen-tick-host interactions: Borrelia burgdorferi and TBE virus.
AB  - Both tick-borne encephalitis (TBE) virus and Borrelia burgdorferi depend for
      their survival on a tick-borne transmission cycle involving diverse vertebrate
      hosts and ixodid (primarily Ixodes) tick species. Increasing evidence strongly
      suggests that a key factor in successful transmission is the ability of these
      pathogens to exploit the pharmacological properties of their vector tick's
      saliva. Proteins and other chemicals, secreted in tick saliva, control the
      vertebrate hosts' haemostatic, inflammatory and immune responses in order to
      facilitate blood-feeding. Such bioactive saliva molecules include immunoglobulin
      binding proteins, histamine-binding proteins, natural killer cell and interferon
      regulators, and complement inhibitors. By unravelling the contents of tick saliva
      and understanding their interactions with host and pathogen, we may identify new
      strategies for disease control.

PMID- 10652717
TI  - Tick-borne encephalitis virus: advances in molecular biology and vaccination
      strategy in the next century.

PMID- 10652718
TI  - Survival strategy of tick-borne encephalitis virus: cellular basis and
      environmental determinants.
AB  - Although TBE virus can be transmitted in the laboratory by a wide variety of
      ixodid tick species to a wide variety of vertebrate host species, nevertheless in
      nature endemic cycles of TBE virus depend principally on just two tick species,
      Ixodes ricinus in the western and I. persulcatus in the eastern Palaearctic. A
      complete transmission cycle, from tick to tick via vertebrates, occurs most
      efficiently between co-feeding ticks in the absence of a systemic viraemia. This
      non-systemic route depends on TBE virus replication within particular
      immunocompetent cells in the skin, and only certain vertebrate species, notably
      Apodemus mice, are susceptible to this. Amongst the potential tick vectors in
      Europe, only I. ricinus has the correct host relationships and appropriate
      natural life cycle to support such non-systemic transmission cycles. Within the
      wide European distribution of this tick-host relationship, only in certain places
      do larval and nymphal ticks feed together on the same hosts with sufficient
      coincidence to ensure TBE virus survival. The environmental factors that
      determine this seasonal coincidence are being identified with the help of
      remotely-sensed meteorological satellite imagery to create predictive risk maps
      of TBE foci.

PMID- 10652720
TI  - Some epidemiological data on TBE and Lyme borreliosis in Croatia.
AB  - TBE in Croatia was first discovered in 1953 but its mandatory reporting, as a
      distinct nosological entity, was instituted in 1987. Data presented here concern
      the 1989-1998 decade. During this period a total of 500 cases of TBE was
      recorded, ranging from 23 (1990) to 87 (1994) per year, with an average of 50
      cases annually. There is only one natural focus in the northern part of the
      country, between the rivers Sava and Drava. Alleged cases of TBE, as occurring
      out of the focus (Zadar and Pula), have not been certified. The seasonal
      distribution of TBE cases is typical, most cases occurring from May to July
      (75%). As for the age distribution of TBE, a substantial rise is seen after the
      age of 20, only some 3% of cases occurring in children younger than 10 years. The
      first documented cases of human Lyme borreliosis in Croatia were published in
      1986, its official compulsory reporting starting in 1991. Since then 1464 cases
      were recorded with an annual average of some 150 cases, varying from 93 (1992) up
      to 335 (1996). The age distribution is somewhat different from TBE, since the age
      group 0-9 years recruits 20% of all cases. Nevertheless, most of the diseased are
      of adult age. About 92% of the cases occur between May and August. The disease
      occurs mostly in the inland, above the 45th parallel, and only sporadically on
      the Adriatic coast.

PMID- 10652719
TI  - Main features of tick-borne encephalitis eco-epidemiology in Russia.
AB  - Tick-borne encephalitis (TBE) is a classic obligatorily transmissible viral
      infection with natural focality, which is widespread mainly in Eurasian forests
      of the temperate zone. Virus was discovered in the Russian Far East in 1937. Its
      main long-term reservoirs and vectors in natural foci are Ixodes persulcatus and
      I. ricinus ticks. Boundaries of the virus range and the location of natural foci
      within it are closely associated with the distribution pattern of these ticks.
      The largest categories of TBE range zoning are described. Each natural focus
      functions as a relatively autonomous parasitic system. The principal scheme of
      TBE virus circulation related to the development of three successive generations
      of the main vector is presented. The main parameter of epizootic activity and
      epidemic manifestation of natural foci and their long-term fluctuations in
      different regions are discussed. TBE morbidity in Russian and its dynamics during
      approximately 45 years are analysed.

PMID- 10652721
TI  - Estimating the prevalence of infectious agents using pooled samples: biometrical
      considerations.
AB  - Pooled testing of units is a common approach in the prevalence estimation of
      infectious agents, which leads to a reduction of total costs of diagnostic
      testing. We examine how the pool size affects the statistical properties of the
      prevalence estimator r. Exact formulae are used to determine bias and precision
      of r. It is shown that with moderate pool sizes the (upward) bias of r is
      negligible. If there is no diagnostic error, the random error of r increases
      slightly with higher pool sizes, whereas if sensitivity and specificity are lower
      than 1, pooling may markedly decrease the random error of r. Another reason why
      pooling may be beneficial (and even indispensable) is that it greatly reduces the
      huge bias that can result if the assumed values of the sensitivity and
      specificity of the diagnostic test are not equal to the true values. The
      numerical calculations show that, in case of prevalence rates of up to 5% and
      total sample sizes of n > or = 500, pool sizes of about 10 to 20 are generally
      satisfactory from a statistical view-point. The methodological advantages and
      disadvantages of more complicated pooling strategies involving repeated testing
      of units are discussed.

PMID- 10652722
TI  - Annual and seasonal variation of tick-borne encephalitis virus (TBEV) prevalence
      in ticks in selected hot spot areas in Germany using a nRT-PCR: results from 1997
      and 1998.
AB  - The prevalence of tick-borne encephalitis virus (TBEV) in Ixodes ricinus tick
      populations in endemic areas of Germany with the highest TBE risk is unknown.
      Annual and seasonal differences in TBEV prevalence have also not been studied.
      Against this background, in May 1997 we started a systematic virus surveillance
      programme in ticks collected in locations known to have a high incidence of
      autochthonous TBE cases. These were 5 locations in Baden-Wurttemberg (Black
      Forest) and 8 locations in Bavaria (surrounding Passau). Field-collected ticks
      were randomly assigned to pools of 10 adults or 20 nymphs, respectively. The tick
      pools were tested for the presence of TBEV-RNA using a newly developed, sensitive
      nested reverse transcriptase polymerase chain reaction assay (nRT-PCR). The
      primer pairs were selected from the 5'-terminal noncoding region, a highly
      conserved part of the virus. The specificity was tested by computer homology
      searches of sequences, as well as by sequencing of the first and the second
      amplificates, by Southern blot hybridisation with a DIG-labelled oligonucleotide
      probe, and by restriction enzyme analysis. The method has proved to be very
      sensitive, with a detection limit of 20 fg of TBEV RNA per PCR run, or a single
      positive tick. Based on biostatistical considerations a sample size of at least
      1000 ticks per estimation point was chosen. The estimated TBEV prevalence and
      confidence intervals (CI) were calculated from the nRT-PCR results of pooled
      samples (10 adults or 20 nymphs) using appropriate formulae for pooled testing.
      In order to identify the estimated TBEV prevalence as well as to assess the
      influence of annual and seasonal factors on TBEV prevalence, ticks were sampled
      twice a year (May and September) in 1997 and 1998 at exactly identical sites.
      These sites were selected because they were known to have had the highest
      incidence of autochthonous TBE cases during the previous 10 years. On sampling
      days, relevant local meteorological data were also noted. In total, 8500 I.
      ricinus ticks were investigated in this study, 4270 (3540 nymphs, 730 adults)
      from the Black Forest habitats, and 4230 (3680 nymphs, 550 adults) from the
      Bavarian locations. In the foci near Freiburg (Black Forest), the estimated virus
      prevalence was relatively high in the whole tick population, during 1997 with
      only slight seasonal differences [3.4% (confidence interval, CI, 2.3-4.8%) in May
      and 2.9% (CI 1.7-4.5%) in September]. In contrast, in 1998, in the same foci the
      estimated TBEV prevalence was considerably lower [1.1% (CI 0.5-2.0%) in May and
      0.6% (CI 0.2-1.4%) in September]. Thus, while the seasonal differences again
      remained low, the annual variation was marked. In the Bavarian foci in 1997, the
      estimated virus prevalence of the whole tick population studied was lower than in
      the Black Forest foci and the seasonal fluctuations were low: in May 1997 0.9%
      (CI 0.4-1.8%) of the ticks were positive, in September 1.1% (CI 0.5-1.9%). In
      1998, in May 2.0% (CI 1.1-3.3%) of the ticks were positive, and in September 1.1%
      (CI 0.5-2.1%). For the whole study period, every 50th to 100th I. ricinus nymph
      or adult in the Passau region was calculated to give a positive signal in the nRT
      PCR. The TBEV prevalence data indicate that residents and visitors of areas in
      Germany known for high endemic activity take a significant risk of contracting
      TBEV infection, if bitten by ticks. In addition, the data suggest that annual
      fluctuations may exist in the whole tick population studied. Seasonal
      fluctuations of the virus prevalence in ticks were small.

PMID- 10652723
TI  - Lyme borreliosis in Slovenia.
AB  - Basic epidemiological findings on Lyme borreliosis in Slovenia are presented.
      Data on vertebrate reservoir hosts are relatively modest. The presence of
      Borrelia burgdorferi sensu lato was demonstrated in about 20% of deer and 15-41%
      of examined small mammals. The presence of B. burgdorferi sensu lato was found by
      polymerase chain reaction in one half of 34 examined small mammals. Ixodes
      ricinus ticks have been found infected in all geographical regions of Slovenia
      examined till now. The highest infection rate was detected in the central part of
      Slovenia where almost 50% of adult ticks and one third of nymphs were positive by
      culture. The first isolation of B. burgdorferi sensu lato from material of
      Slovene patients succeeded in 1988 while the first isolates from ticks were
      obtained as late as 1993. The source material of human isolates has been skin,
      blood, cerebrospinal fluid, as well as synovial tissue and fluid. Thus far four
      Borrelia species were found by isolation to cause disease in humans: B. afzelii,
      B. garinii, B. burgdorferi sensu stricto, and B. bissettii. The majority of typed
      isolates belong to B. afzelii, but B. garinii slightly predominates among strains
      cultured from cerebrospinal fluid. Lyme borreliosis has been mandatory reportable
      in Slovenia for the last 11 years. It is the most common tick-borne disease and
      is present all over the country. The incidence has been increasing. In 1997
      155/100,000 cases were recorded; in some regions the incidence was even
      substantially higher. The disease affects both sexes (as a rule more often women
      than men) and all age groups. The incidence is the highest in persons 30-50 years
      of age, followed by children aged 6-15 years. Erythema migrans is by far the most
      common recorded manifestation.

PMID- 10652724
TI  - Chemoprophylaxis for Lyme borreliosis?
AB  - Chemoprophylaxis is a term which describes treatment with an antimicrobial
      chemotherapeutic before, during or shortly after an actual or suspected exposure
      to an infectious agent in order to prevent clinical disease, which may be severe
      or even fatal. Lyme borreliosis is considered the most frequent ixodid-tick
      transmitted human bacterial infection in the northern hemisphere. For several
      years there has been a debate on the prophylactic application of antimicrobial
      chemotherapeutics after an attached Ixodes tick was removed. Would this measure
      prevent a subsequent borrelia infection and would it be practical? People are
      exposed to tick-bites mostly during leisure spent in recreational areas which are
      often tick infested. The proportion of I. ricinus ticks infected with B.
      burgdorferi s. l. varies from area to area and in a given area also from year to
      year (infection rate up to a maximum of 55%). The transmission rate strongly
      depends on the duration of feeding, but it could be shown that the critical time
      of feeding is much shorter for European I. ricinus than for the North American I.
      scapularis or I. pacificus ticks. Nevertheless, even the low risk of
      complications despite the very good chance of treating erythema migrans
      successfully seems to justify prophylactic treatment for some investigators
      whilst others do not see an argument for this. Double blinded studies in the USA
      showed a relatively low frequency of illness after vector tick-bite and absence
      of disseminated disease manifestations. The efficacy of prophylactic antibiotic
      treatment after tick-bites is not established. Suggestions to examine removed
      ticks for borrelia in order to obtain indication for prophylactic antibiotic
      treatment will fail in practice because of high costs and uncertainty in
      verifying the transmission. Do we need blinded studies in central Europe on a
      representative number of cases, although it is known that Lyme borreliosis can be
      treated effectively even in its second and third stage and has never caused a
      fatal outcome? We conclude that only a reliable diagnosis of symptoms is the
      basis for a rational antibiotic treatment, and that instead of chemoprophylaxis
      for Lyme borreliosis after a vector tick-bite the wait and watch policy is
      recommended.

PMID- 10652725
TI  - Investigation of skin samples from red foxes (Vulpes vulpes) in eastern
      Brandenburg (Germany) for the detection of Borrelia burgdorferi s. l.
AB  - During earlier investigations a high prevalence of Borrelia (B.) burgdorferi s.
      l. in unfed Ixodes (I.) ricinus ticks in the Federal State of Brandenburg has
      been demonstrated. In the present study skin samples were obtained from 100 red
      foxes (Vulpes vulpes) from the districts where the highest B. burgdorferi
      prevalences had previously been found (i.e. Uckermark, Barnim, Markisch-Oderland,
      Oder-Spree). BSK- and MKP-medium including inhibitory substances were used for
      cultivation of spirochaetes. Non-motile spirochaete-like organisms were observed
      in 26% of the samples. Additionally, by subcultures it was not possible to obtain
      motile helical forms characteristic for B. burgdorferi. On tryptose agar, the
      bacteria which produced nonmotile forms appeared as corynebacterium-like
      colonies. Investigations by electron microscopy showed that the immobile spiral
      forms were giant whips (flagellae) which belonged to the contaminant flora. These
      forms proved to be negative for B. burgdorferi s. l. by the use of a nested-PCR.
      In a further study, the same skin samples were investigated for the presence of
      B. burgdorferi s. l.-DNA using a nested-PCR. Seven out of 100 samples were
      positive.

PMID- 10652727
TI  - The pigeon tick (Argas reflexus): its biology, ecology, and epidemiological
      aspects.
AB  - The European pigeon tick, Argas reflexus (F.), is in central Europe predominantly
      an urban pest parasitizing wild and domesticated pigeons, Columba livia. Under
      certain circumstances, however, it also bites humans, occasionally causing an IgE
      mediated type-I allergy. Control of A. reflexus is very difficult because of a
      number of remarkable morphological, physiological, and behavioural features of
      the tick. The present study aimed at elucidating the distribution and the
      frequency of occurrence of A. reflexus in Berlin and its possible vector role for
      Borrelia burgdorferi sensu lato (s. l.). Buildings reported by occupiers to be
      infested with A. reflexus were personally examined. In addition, the carrier
      status of this soft tick for B. burgdorferi (s. l.) was investigated in three
      German towns by an indirect immunofluorescence assay. A total of 188 Berlin
      buildings was found to be infested with A. reflexus between 1989 and 1998.
      Infestations were found in 17 out of the 21 districts, clustering in the inner
      city. There was only a single Borrelia-positive tick out of 800 sampled in
      Berlin, Leipzig, and Hannover using the genus specific antibody H9724. The same
      tick was PCR-negative for B. burgdorferi outer surface protein A. Neither these
      results nor those of other studies on the occurrence of antibodies against B.
      burgdorferi in pigeons suggest that field populations of A. reflexus and/or
      pigeons in central Europe harbour the causative agent of Lyme borreliosis.

PMID- 10652726
TI  - Lyme disease: pathogenesis and vaccine development.
AB  - Research of recent years on Lyme disease has greatly increased our understanding
      on antigenic structures and genotypic variability of the aetiological agent,
      Borrelia (B.) burgdorferi sensu lato, as well as on mechanisms underlying host
      parasite interactions and induction/mode of action of protective immune
      responses. A vaccine formula on the basis of the outer surface lipoprotein A
      (OspA), previously developed in our laboratory, has successfully been tested in a
      clinical trial involving nearly 10,000 subjects in the USA. The OspA vaccine is
      unique in that it protects the mammalian host from infection by eliminating
      spirochaetes from the vector, but does not cure an established disease. This is
      because spirochaetes express OspA exclusively in the tick, but not when
      transmitted into the vertebrate host. For Europe, a more complex vaccine formula
      is required in order to achieve full protection. This is due to the higher degree
      of heterogeneity of OspA molecules among isolates of B. burgdorferi in Europe and
      the inability of the monovalent vaccine to convey complete cross-protection.

PMID- 10652728
TI  - [Natural interferon-beta in the treatment of relapsing-remitting multiple
      sclerosis: a multicenter, randomized, MRI-based, phase II clinical trial].
AB  - OBJECTIVE: The ability of natural human interferon beta (n-hIFN beta) to reduce
      multiple sclerosis (MS) activity was investigated in 60 patients with relapsing
      remitting MS (RRMS). PATIENTS AND METHODS: Patients were randomized to receive
      either 9 MIU (33 micrograms) of n-hIFN beta by subcutaneous route, three times
      per week, on alternate days, during one year, or no treatment (control group)
      during the first six months and then switched to the same treatment for the
      following six months. Disease activity was monitored monthly by both magnetic
      resonance imaging (MRI) and clinical parameters. An intergroup analysis (first 6
      months of the study) showed fewer active lesions and lower exacerbation rate in
      the treatment group than in the control group. Similarly, there were more
      exacerbation-free patients in the treatment group during this time. RESULTS: When
      switched to treatment, the control group showed a significant reduction in the
      number of active lesions (p = 0.00001) and the exacerbation rate decreased by
      half. Exacerbation-free patients more than doubled (p = 0.006) and the median
      time to first exacerbation was significantly prolonged (96 vs > 180 days; p =
      0.019). Treatment was extended for 12 additional months at a dose of 6 MIU (22
      micrograms) once a week and disease activity persisted under control in 88% of
      patients. Treatment with n-hIFN beta was well tolerated, adverse events being
      mild and self-limiting. Sera were analyzed for anti-IFN beta antibodies and
      neutralizing activity was found in 12% of the patients after two years.
      CONCLUSION: The results of this phase II study show, that n-hIFN beta promotes a
      significant reduction of disease activity in RRMS as shown by both MRI and
      clinical variables, and that the treatment is well tolerated, with low
      antigenicity.

PMID- 10652729
TI  - [Predictive value of rapid tests of cognitive condition in traumatic head
      injury].
AB  - INTRODUCTION: Neuropsychological assessment after head injury (HI) is sometimes
      not possible because of the physical and/or cognitive condition of the patient,
      or the lack of neuropsychological specialists at the hospital. Therefore clinical
      scales and rapid tests are used to obtain information about the severity of the
      lesion and the general cognitive condition. OBJECTIVE: To determine whether the
      rapid clinical scales used to assess the severity of HI (Glasgow Coma Scale,
      GCS), presence or absence of post-traumatic amnesia (Galveston Orientation and
      Amnesia Test, GOAT) and general cognitive condition (Mini-Mental State
      Examination, MMSE, and Short Test of Mental Status, STMS) predict the cognitive
      condition one year after the head injury. PATIENTS AND METHODS: We made a
      prospective, longitudinal, observational study of 100 persons of both sexes with
      HI, assessed on admission by the Neurosurgical Department, and one year after the
      trauma in the Outpatient Clinic. Clinical scales were used to assess the severity
      of HI, cognitive screening tests, neuropsychological attention, linguistic,
      memory and practical constructive tests were also done. Statistical analysis was
      by simple regression. RESULTS: The GCS only explained a small percentage of the
      results obtained for immediate memory. The GOAT predicted the linguistic and
      verbal memory test performance. The MMSE and STMS explained a high proportion of
      the execution of neurophychological tasks (attention, linguistic, memory and
      practical construction) one year after the trauma. CONCLUSIONS: With the MMSE and
      STMS valid results may be obtained when it is not possible to carry out general
      neuropsychological assessment.

PMID- 10652730
TI  - [Detection of antibodies to beta-amyloid in carriers of E280A mutation in the
      presenilin-1 gene].
AB  - OBJECTIVE: To investigate some immune component that could contribute to the
      pathogenesis of Alzheimer's disease associated with the E280A mutation of the
      presenilin-1 gene (PS-1). PATIENTS AND METHODS: Serum antibodies against both
      cardiolipin and beta-amyloid peptides (beta 1-40 and beta 1-42) were quantitated
      by means of an indirect ELISA technique in carriers of the mutation, either
      healthy or with Alzheimer's disease, as well as in normal controls without the
      mutation. RESULTS: Out of 19 patients with Alzheimer's disease only 2 had
      increased values of antibodies to cardiolipin, namely: one with 14.58
      micrograms/ml of IgM and the other with 36.16 micrograms/ml of IgG. The remaining
      individuals revealed values under 10 micrograms/ml, considered normal, and there
      was no significant difference between the groups. Significant serum reactivity (p
      < 0.001) was detected against both beta-amyloid peptides in the mutation
      carriers, either with or without Alzheimer's disease, as compared to the control
      group. No correlation was detected between this antibody response and the mental
      or functional situation of the patients. CONCLUSION: beta-amyloid antibodies,
      present in the mutation carriers, may simply represent a marker of immune
      activation induced by beta-amyloid with no in vivo effect; however, despite the
      results, the possibility can not be ruled out of a pathogenic role of these
      antibodies in early onset Alzheimer's disease.

PMID- 10652731
TI  - [Hemifacial spasm, quality of life and depression].
AB  - INTRODUCTION: Quality of life, a concept which has become increasingly important
      in recent years, refers to a patient's perception of himself in relation to his
      illness and its treatment. This is compared with the concept of quantity of life
      or survival. This approach is in keeping with the concepts of health of the World
      Health Organization. Hemifacial spasm is a disorder of movement with a prevalence
      of 7.4 and 14.5 per 100,000 men and women respectively. OBJECTIVE: To evaluate
      the quality of life of patients with hemifacial spasm, study the occurrence of
      depression and ascertain whether it correlates with the severity, response to
      treatment and muscle groups involved. PATIENTS AND METHODS: We present a cohort
      of 57 patients (average age 53.4 years) with hemifacial spasm, in whom the
      disorder had been present for an average of 3.7 years. RESULTS: It was found that
      in these patients the quality of life and index of depression were worse when the
      severity of the disease was greater, response to treatment poorer and there was
      generalized hemifacial paralysis, (p < 0.00000) for each parameter. The
      deterioration in quality of life was correlated with depression (correlation 0.6)
      for the criteria of severity and muscle groups involved, but not with the
      response to treatment (correlation 0.3). CONCLUSION: Hemifacial spasm
      significantly alters the quality of life of patients and is associated with
      depression. This should be taken into account when treating such patients.

PMID- 10652732
TI  - [Neuropediatric clinical practice in a tertiary hospital of Basque Country].
AB  - INTRODUCTION: In our country, studies on the neuropediatric practice are scarce,
      in spite of their importance for planning of spending and resources, and
      definition of quality criteria. OBJECTIVE: To study the clinical workload of the
      main neuropediatric clinical problems. METHODS: Prospective, longitudinal,
      descriptive study of doctor-patient encounters, according to diagnosis, in the
      Child Neurology Division of a tertiaty hospital. RESULTS: 3,200 visits, of which
      83% were ambulatory. 24 ambulatory visits per 1,000 inhabitants younger than 15
      years, and year. Diagnosis demanding larger clinical activity for out-patients
      were: epilepsy/seizures (38%), mental retardation (17%), headaches (17%),
      hyperactivity/conduct disorders (12%), and cerebral palsy/permanent motor sequela
      (10%). Among in-patients: epilepsy/seizures (47%), mental retardation (10%),
      brain tumors/neurological complications of oncology disorders (8%), cerebral
      palsy/motor sequela (8%), and neurological complications of prematurity (7%).
      Among new out-patients, headaches is the most frequent diagnosis, followed by
      epilepsy; among new in-patients, epilepsy holds the first place, followed by
      neurological complications of prematurity and brain trauma. The index follow
      up/first visit is much larger for the real neurologic patient than for functional
      disorders so frequent among new referrals. CONCLUSIONS: The neuropediatric
      practice comprises essentially epilepsy, cognitive and conduct disorders, and
      headaches. Unfortunately, our practice is in part being defined by the pressure
      exerted by the primary medical care and by hospital management practices.

PMID- 10652733
TI  - [Different verbal behavior in children with attention deficit between 7 and 12
      years of age].
AB  - INTRODUCTION: According to factor brain organization of cognition model, it has
      been proposed that there are specific a shared underlie factors in the structure
      of each cognitive functions. OBJECTIVE: To determine if children with attention
      deficit disorder (ADD) have different verbal abilities than controls, and if
      verbal behaviors are related to inattention and hyperactive symptoms. PATIENTS
      AND METHODS: 32 children with attention deficit without hyperactivity (ADD/-H),
      28 children with attention deficit hyperactivity (ADD/+H), according to DSM-IV
      criteria and higher than 60-T-Score on an ADHD checklist, and 32 control children
      were selected. Age, sex, school achievement, and socioeconomic status were
      controlled. All children had a WISC-R performance intelligence quotient (PIQ) >
      80 and were 7-to-12-year old. Verbal test to assess comprehension, inferences,
      narrative, fluency, analogies and rapid naming were applied. RESULTS: Children
      from both ADD groups obtained significant lower WISC-R verbal intelligence
      quotient (VIQ), PIQ, full scale IQ (FSIQ), and phonologic fluency score than
      controls (ANOVA-Bonferroni's correction p < 0.005). ADD/+H children performed
      significant lower than controls in narrative and analogies (p < 0.005). An
      analysis of covariance (ANCOVA), using FSIQ as covariable, showed that phonologic
      verbal fluency continued presenting significant differences between control and
      ADD children. Inattention-hyperactivity checklist scores had significant inverse
      and mild correlations with inferences, items recalled in a narrative, phonologic
      verbal fluency, and analogies (r > -0.20, p < 0.05). There were significant and
      small correlations between inattention score and rapid naming errors, and between
      Inattention and rapid naming time (r > 0.20, p < 0.05). CONCLUSION: Our data
      found different verbal production, fluency and speed in ADD/+H and ADD/-H
      children. There were shared underlie relations between verbal abilities and
      behavioral symptoms.

PMID- 10652734
TI  - [Thalamic hematomas: etiology, clinical findings and prognosis].
AB  - INTRODUCTION: The appearance of new neuroimaging techniques has permitted study
      of large series of thalamic hematomas, amongst which differences have been
      observed according to the size and arterial territory affected. OBJECTIVE: To
      determine the existence or not of differences between thalamic hematomas,
      according to their arterial territory and size, with regard to the aetiology,
      clinical findings and short term prognosis. PATIENTS AND METHODS: A retrospective
      study was made of 60 patients admitted to hospital with the diagnosis of thalamic
      hematoma (between January 1987 and July 1997) classified according to
      localization as: anterior, dorsal, posterolateral, posteromedial and global, and
      according to size as: large (> 20 mm), and small (< 20 mm) in which we analyzed
      the aetiology, clinical signs and prognosis up to discharge from hospital.
      RESULTS: The commonest aetiology was found to be arterial hypertension (60%);
      with regard to the arterial territory involved we have observed different
      clinical and prognostic features but the number of patients in each group was too
      small to permit statistical analysis. Significant differences were shown with
      regard to the size of the hematoma: large hematomas more often extended to nearby
      structures, caused hydrocephalia, were associated with alteration in the level of
      consciousness, severe motor deficit, oculomotor changes, alteration in superior
      functions and hemianopsia, and had worse prognosis and increased mortality and
      dependence in everyday activity than small hematomas. CONCLUSION: According to
      their size, thalamic hematomas show statistically significant clinical and
      prognostic differences.

PMID- 10652735
TI  - [Neurophysiological assessment in patients with clinically defined multiple
      sclerosis with special reference to P300 wave study].
AB  - INTRODUCTION: In the cognitive sphere, alterations have been found in up to 65%
      of patients with multiple sclerosis (MS). Study of the P300 wave is a positive
      component of long latency related to cognitive function: amplitude with
      attention, and latency with the ability to process information. OBJECTIVE: To
      assess a study of the P300 wave in a group of patients with MS. PATIENTS AND
      METHODS: The P300 wave was studied in 26 patients, 22 women and 4 men, with
      definite clinical MS (on criteria of Poser et al), with normal motor and sensory
      conduction velocity studies. All patients had a battery of multi-modal evoked
      potentials (MEP), nuclear magnetic resonance imaging and immunological study of
      the cerebrospinal fluid. Seventeen patients had the exacerbation-remission (ER)
      and nine the primary progressive (PP) clinical forms of the disorder. RESULTS:
      The most markedly altered MEP were the visual and somatosensory evoked potentials
      (SSEP) of the patients with MS. When the types of clinical course were compared,
      the SSEP were statistically significant in the PP form, which may be explained by
      the greater spinal involvement of these patients. Comparative analysis of the
      P300 wave was done for 26 healthy patients of similar age and sex to that of the
      patients, and significant differences were found in P300 latency and amplitude
      between the MS and control groups. The patients who had had the disease for
      longer had significantly greater anomalies in the P300 waves. CONCLUSION: Study
      of the evolution of the P300 wave, which is cheap and easy to do, may be valuable
      in the evolutional assessment of cognitive changes in patients with MS.

PMID- 10652736
TI  - [Autonomic and somatic neuropathy in the diabetic patient: electric clinical
      analysis].
AB  - INTRODUCTION AND OBJECTIVE: Neuropathy is the more often complication in the
      diabetic patients. The relationship between somatic and autonomic neuropathy has
      not been studied on these patients, so we decided to compare both situations.
      PATIENTS AND METHODS: We have performed a comparative study among clinical
      elements, the nerve conduction study (NCS) and the autonomic cardiovascular
      function in 120 insulin dependent diabetics patients. We use clinical scales, the
      NCS and the heart rate variability study (HRVS) to know de autonomic
      cardiovascular function. RESULTS: Sensation was the clinical manifestation more
      compromised and there was not correlation between clinical manifestation and the
      HRVS. In the NCS the nerve conduction velocity was the element more affected and
      the nerve more compromised was the sural; there was good correlation between NCS
      and HRVS. Fifty per cent of patients had some degree of neuropathy, and the
      duration of the disease was an important factor on this damage. The clinical
      elements, the NCS and the HRVS together let us classified patients in: patients
      without neuropathy (10 cases), patients with somatic neuropathy (31 cases),
      patients with autonomic neuropathy (7 cases), patients with somatic-autonomic
      neuropathy (72 cases). CONCLUSIONS: To defined the diagnosis of cardiovascular
      autonomic neuropathy (CAN) is necessary the HRVS, the subclinical presentations
      of CAN are often without manifestation. There is a close relationship between the
      somatic and autonomic nerve damage, influenced by the duration of the disease.

PMID- 10652737
TI  - [Cerebral tumors as a cause of late onset epilepsy].
AB  - INTRODUCTION, PATIENTS AND METHODS: We made a study of 223 patients with
      epileptic seizures which started when the patient was aged over 25 years (late
      onset), who were admitted to the National Institute of Neurology and Neurosurgery
      of La Habana, Cuba, over a period of ten years. The patients were divided into
      three groups according to age: from 25 to 39, from 40 to 59 and over 60 years.
      They formed two etiological groups--tumour and non-tumour--to evaluate the
      possible relationship with clinical variables and the results of complementary
      tests. RESULTS: Of all the patients of groups 25 to 39 and 40 to 59 years. Over
      half the causes were of undefined cause. Of those in whom the cause was known,
      the most frequent cause of presentation was a tumour. Although vascular and
      degenerative causes were most frequent in the over 60 age group, cerebral tumours
      made up a significant percentage. We found that the presence of localizing signs
      on neurological examination or neuropsychological study and the occurrence of
      focal activity on the electroencephalogram were associated with the presence of a
      tumour, although their absence did not exclude this aetiology. There was no
      association with the type of seizures seen. CONCLUSION: Computerized axial
      tomography was very useful in the diagnosis of these tumours. However, a large
      percentage of patients required from two to four studies to establish the
      diagnosis.

PMID- 10652738
TI  - [The effect of gabapentin in bucco-facial allodynia. Experimental correlation of
      the trigeminal nerve].
AB  - INTRODUCTION: Trigeminal neuralgia is an unilateral alteration of the trigeminal
      nerve, characterized by recurrent paroxysms of pain in one or more of the nerve's
      branches. Trigger areas are described in points of the facial skin (allodynia).
      OBJECTIVE: To evaluate the effects of gabapentin (monotherapy) and associated
      with carbamazepine in allodynia of trigeminal neuralgia. PATIENTS AND METHODS:
      The effects of these drugs were studied in 14 patients with trigeminal allodynia
      and with 12 experimental cats, with microelectrodes of multiple connections in
      the central nervous system and in dental pulp to precipitate pain in injured
      zones, area of primary hyperalgesia, secondary hyperalgesia and allodynia zone.
      Unitary registrations and evoked potentials were evaluated in neuronal trigeminal
      organizations, encephalon, limic system and neocortex. RESULTS: The pairing of
      innocuous stimulus (allodynia) plus painful stimulus precipitate classic
      conditioned reflex. Unitary alteration and evoked potentials correlated with
      learning and memory were evaluated, involving the hippocampus in the results. The
      allodynia treatment obtains better results with the combined treatment than with
      the monotherapy. CONCLUSIONS: Allodynia can be the result of a neuronal
      sensitization due to the increment on intracellular calcium facilitating the
      exocytosis. Changes in the mechano-receptors of low threshold establish
      communication with nociceptive neurons by a presynaptic mechanism, considering
      new synaptic and morphologic contacts associated with learning and memory. The
      major effectiveness in the combined treatment is the base of an association of
      the gabaergic mechanism of gabapentin and the blockade of sodium and potassium
      ionic channels by the carbamazepine.

PMID- 10652739
TI  - [Behavioral phenotypes: cognitive and emotional explanation].
AB  - INTRODUCTION: We present a series of Behavioural phenotypes treated with
      neurocognitive and neuroemotional procedure. PATIENTS AND METHODS: A sample of 26
      cases were selected according to qualitative methodology from neuropediatric
      patients. The method was based on using the PASS theory of intelligence to
      approach the cognitive problem and the theory of masquerade behaviour as self
      defence to solve the emotional problem. Both theories have neurological bases.
      DN:CAS battery was utilized for assessment of cognitive processes. On the other
      hand, analysis of cases was carried out doing data analysis with video recorder
      device. RESULTS: All cases were considered responder cases although in different
      degree. The responder was defined as the patient which reached better
      intellectual achievement with respect to cognitive function and which gave up, at
      least partially, masquerade Behaviour with respect to emotional function.
      DISCUSSION: The Behaviour of the Behavioural phenotypes has neurological
      rationale. The PASS theory and the planning, in particular, supported by
      prefrontal cortex justifies consistently some behaviours. The masquerade
      Behaviour theory is explained by the fear emotional response mechanism which
      means emotion is a cerebral processing with neurological rationale. CONCLUSIONS:
      The Behavioural phenotypes are Behaviours and every Behaviour can be explained by
      neurological reasons both cognitive and emotional reasons. So, they can be
      treated by a cognitive and emotional procedure understood in the light of the
      neurology.

PMID- 10652740
TI  - [Neuropsychological findings in patients with middle temporal lobe epilepsy].
AB  - INTRODUCTION: Cognitive dysfunction in mesial temporal lobe epilepsy (MTLE) is
      still a controversial subject. Since refractory MTLE is considered a surgically
      remediable syndrome, the neuropsychological assessment to establish the presence
      of cognitive impairment in the surgical candidate became an important issue,
      given its possible relevance in predicting outcome after surgery. OBJECTIVE: Our
      aim was to study the cognitive profile of MTLE patients and to correlate the
      cognitive status with the presence or absence of hippocampal sclerosis. PATIENTS
      AND METHODS: Fifty patients with MTLE and 20 control subjects were matched by age
      and educational level. All subjects were studied with EEG, MRI scan, SPECT, and a
      comprehensive neuropsychological battery that included measures of language
      (naming and verbal fluency), visuospatial function (Block Design Test), memory
      (Signoret Battery), attention (Digit Span and Trail Making Test A) and executive
      abilities (Trail Making Test B and Wisconsin Card Sorting Test). RESULTS: MTLE
      patients, particularly those with hippocampal sclerosis, were found to have a
      considerable lower performance in learning (p < 0.01), naming (p < 0.05),
      attention (p < 0.05) and executive functions (p < 0.001). Among the MTLE patients
      a considerable number of subjects showed results within the normal range (n = 27)
      while others evidenced laterality specific cognitive impairments (n = 13).
      Material specific memory effects were seen in some patients but not all.
      CONCLUSIONS: Our results showed the neuropsychological heterogeneity of temporal
      lobe epilepsy, thus ruling out the existence of a single specific cognitive
      pattern of impairment in all MTLE patients, and suggesting the need of a thorough
      pre-surgical neuropsychological evaluation to be used with post-surgical
      prognosis purposes.

PMID- 10652741
TI  - [Neuropsychological findings in a case of porencephaly].
AB  - INTRODUCTION: At the present time porencephalia refers to the presence of deep,
      unilateral or bilateral cavities or excavations, frequently communicating with
      the subarachnoid space or lateral ventricles, which occur following brain
      destruction during the end of the foetal or beginning of the new-born period. The
      clinical features are various forms of cerebral paralysis (spastic hemiparesia,
      diplegia and tetraplegia), mental retardation and epileptic crises. To date there
      are few studies giving detailed analysis of the cognitive functions of affected
      persons. CASE REPORT: We studied the mental and cognitive state of an adult woman
      with massive porencephalic dilatation of the left lateral ventricle. The patient
      had a normal verbal intelligence quotient. Cortical function, including language,
      praxis and gnosis were maintained. She had alterations of memory, particularly
      verbal, and of frontal function. CONCLUSIONS: The deficits observed were not
      lateralized for neocortical functions, but were lateralized for memory. The
      neuropsychological pattern partly corresponded to subcortical deterioration due
      to the lesions of the white matter and basal ganglio.

PMID- 10652742
TI  - [Aggression and mental retardation associated with bilateral cortical and
      subcortical atrophy].
AB  - OBJECTIVE: We wish to show the relationship between the aggressivity and the
      bilateral frontal lesion. CLINICAL CASE: We describe a 18 years-old patient
      affected by a severe neurological and psychopathological disorder consisting of
      mental retardation and behavior alterations, especially expressed by mood
      changes, irritability and violent reactions with aggressivity. Three dimensional
      magnetic resonance study disclosed severe bilateral frontal lesion with the
      presence of very small cortical gyri and enlargement of the frontal zones of the
      lateral ventricles as well as atrophy of the anterior regions of the corpus
      callosum. CONCLUSION: The case reported shows the clear relationship between the
      bilateral frontal lesion and psychopathological disease, especially aggressivity
      and irritability.

PMID- 10652743
TI  - [Werdnig-Hoffmann disease. The first prenatal diagnosis in Cuba].
AB  - INTRODUCTION: Spinal muscular atrophy (SMA) is an autosomal recessive disorder
      characterized by the degeneration of cells of the spinal cord. The gene was
      localized on chromosome 5q13 and exists in two almost identical forms, which are
      distinguished by the change of base on exones 7 and 8. Mutations of the gene of
      survival motoreneuron (SMN) are the cause of illness. CLINICAL CASE: We report,
      for the first time in Cuba, the prenatal diagnosis of a type II SMA carrier,
      using molecular methods for direct detection of the mutation on exones 7 and 8 of
      the SMN gene, and haplo-identification with microsatellite markers of chromosome
      5q as an indirect method. A sample of amniotic liquid was taken at 18 weeks of
      gestation and the DNA extracted. No deletions were detected on exones 7 and 8 of
      the foetal DNA, which was therefore normal. CONCLUSIONS: Detection of deletions
      on the SMN gene is a method which permits detection of the condition (healthy or
      unhealthy) of the foetus, quickly and reliably, without requiring investigation
      of the entire family to obtain a result. The method does not require radio-active
      PCR, the results are clear and precise and may be obtained within 24 hours. It
      may also take the place of invasive methods such as muscle biopsy and electro
      myography and contribute to genetic assessment in families in which there is no
      DNA of the affected child.

PMID- 10652744
TI  - [Idiopathic hypophysitis in elderly patients. Report of 2 cases and review of
      literature].
AB  - INTRODUCTION: Hypophysis inflammatory tumors are a non frequent cause for
      hypopituitarism. The motive of outpatient visit is headache. It is more frequent
      in pregnancy and immediate post-labor women. The pathology shows a lymphocytic
      inflammatory infiltrated or granulomas with giant cells (these can be accompanied
      with an infectious or autoimmune systemic disease associated). CLINICAL CASES: We
      present two elderly female patients, without infectious or autoimmune pathology
      associated, with suggestive abnormalities of hypophysial adenoma by MRI. Both
      presented a suspecting clinical manifestation of intracranial expansive lesion
      (progressive intensive headaches, with partial compromise of the III left pair in
      the second one), noticing by laboratory a subclinical hormonal dysfunction.
      Surgery of tumoral exeresis was underwent in both patients, showing a
      granulomatous hypophysitis in one and a lymphocytic hypophysitis in the other.
      CONCLUSION: Hypophysis inflammatory tumors must be considered as a preoperative
      differential diagnosis of every hypophysial tumor without important hormonal
      dysfunction associated, mainly in women and what is more in pregnancy or lying-in
      women, taking into account that surgery of tumoral resection can worsen a
      subclinic hypophysial dysfunction.

PMID- 10652745
TI  - [Isolated hemi-ataxia as a sign of mesencephalic lacunar infarction].
AB  - INTRODUCTION: Lesions of the dento-rubro-thalamo-cortical pathway may cause
      homolateral or contralateral hemiataxia, depending on whether they are found
      above or below the decussation which occurs at the level of the inferior
      colliculus. Most mesencephalic infarctions causing hemiataxia also show
      oculomotor involvement with nuclear or fascicular lesions of the third cranial
      nerves. This was not seen in the case we report. CLINICAL CASE: We describe the
      case of a diabetic patient with a permanent right appendicular hemiataxia,
      without oculomotor involvement, caused by a lacunar infarct shown on MR imaging
      which was situated in the antero-external part of the left superior
      mesencephalum. CONCLUSIONS: This case helps to clarify the topography of the
      thalamic radiations of the mesencephalic calotte, including the decussated
      superior dento-rubro-thalamic pathway to the red nucleus. Involvement of this,
      situated in the mesencephalic lateral vascular territory causes contralateral
      hemiataxia.

PMID- 10652746
TI  - [Acute pseudobulbar paralysis: the use of diffusion techniques with magnetic
      resonance].
AB  - INTRODUCTION: Acute pseudobulbar palsy produced by bilateral cerebral infarctions
      is a rare syndrome, which includes among its symptoms mutism, severe dysphagia
      and diverse sensory-motor signs. CLINICAL CASES: We report two middle-aged
      patients who suddenly developed a severe dysarthria and dysphagia, which impeded
      their ability to speak and to feed themselves, with spasmodic laughing and crying
      and slight motor deficit ('pure' pseudobulbar palsy). The acute lesions, using
      conventional and diffusion-weighted magnetic resonance imaging, corresponded
      partially to the anterior choroidal artery (case 1: acute lesion in the left
      periventricular white matter and a subacute one in the right semioval centrum;
      case 2: acute lesions in the right frontal subcortical white matter and in the
      periventricular white matter adjacent to the left lateral ventricle). The
      favorable evolution of these patients in contrast to previously described
      patients with acute pseudobulbar palsy could indicate that the motor deficit is a
      prognostic factor for this syndrome. CONCLUSIONS: Diffusion-Weighted magnetic
      resonance imaging permits differentiation with high precision of the acute
      lesions in patients who present old ones. Sometimes multiple acute lacunar
      infarctions (MALI) are found to be responsible of the syndrome. Hypertension and
      diabetes are the risk factors for the small vessel disease underlying these MALI.

PMID- 10652747
TI  - [Giant cell arteritis, bilateral anterior ischemic optic neuropathy and
      anticardiolipin antibodies].
AB  - CLINICAL CASE: We report a case of giant cell arteritis (GCA) that developed
      acute bilateral amaurosis secondary to anterior ischemic optic neuropathy (AION),
      without other symptoms and with a normal erythrocyte sedimentation rate (ESR).
      Physical examination revealed painless and pulseless temporal arteries,
      ophthalmoscopic findings were blurring of margins, hyperaemia and elevation of
      both optic discs. Visual acuity was limited to hand motion perception and light
      darkness discrimination. Six months before of this syndrome, the patient was
      diagnosed of polymyalgia rheumatica and was maintained asymptomatic with 6 mg/day
      of deflazacort. Temporal artery biopsy was diagnostic. An elevated IgG type
      anticardiolipin antibodies (ACA) rate was detected in serum. The remaining
      laboratory studies were normal. CONCLUSIONS: In old people with uni or bilateral
      acute visual loss, even with normal erythrocyte sedimentation rate and without
      other symptoms associated, it is necessary to have a high index of suspicion in
      order to detect giant cell arteritis. This can facilitate an early diagnosis and
      immediate initiation of treatment with high doses of corticosteroids. An elevated
      level of IgG type anticardiolipin antibodies may be a risk factor to thrombotic
      complications, as anterior ischemic optic neuropathy, in patients with giant cell
      arteritis.

PMID- 10652748
TI  - [Sylvian arachnoid cysts, temporal lobe hypoplasia and epileptic encephalopathy].
AB  - CLINICAL CASE: The authors describe a 14 year-old boy with bilateral arachnoid
      cysts of the sylvian area and temporal lobe hypoplasia. Also showed vermis and
      brainstem hypoplasia. Clinically manifest a severe encephalopathy with
      tetraparesia, autism and late onset polymorphic epilepsy. He presented a
      favorable outcome with valproate and vigabatrine. To the best of our knowledge
      only one case like ours has been reported.

PMID- 10652749
TI  - [Anticoagulants: when, which, how much, until when: these are still the
      questions.II].
AB  - OBJECTIVE: To analyze the different presentations of ischemic cerebrovascular
      disease and develop algorithms for treatment in those different possible
      settings. DEVELOPMENT: We present an analysis of the publications in which the
      clinical, diagnostic and therapeutic features of aorto-emboli and cardio-emboli
      (patent foramen ovale, septal aneurysm, bacterial endocaritis, etc.) have been
      defined. We suggest an algorithm with general parameters for the use of
      anticoagulants in cerebrovascular disease. Subsequently we specifically consider
      the decision as to the moment to start anticoagulation, selection of the type of
      anticoagulant, dosage, route of administration and duration of the treatment.
      Because of the implications for treatment, we assess the therapeutic options when
      haemorrhagic infarcts occur. CONCLUSIONS: Based on studies in the literature
      showing benefit in individualized cerebrovascular disorders, and the anecdotic
      experiences of Drs. Miller Fisher, Caplan, Pessin and the writer, over the past
      40 years using anticoagulants in the different clinical settings described, some
      parameters for treatment are proposed. We emphasize that whilst patients with
      different types of cerebrovascular disease are all grouped together under the
      unifying term 'stroke', the various treatments evaluated will probably be shown
      to be inefficient or deleterious. The line of treatment suggested in this review
      is based on the definition of the different cerebrovascular scenarios according
      to their aetiology and mechanisms, so as to obtain the most suitable treatment in
      each case.

PMID- 10652750
TI  - [Vegetative states: a syndrome in search of a new name].
AB  - OBJECTIVES: 1. To critically analyze the concept of 'vegetative' state and a
      number of reasons that seem to justify the abandonment of this term. 2. To
      propose a new conceptual approach to the syndrome and, based on this approach, a
      new terminology. DEVELOPMENT: The concept of 'vegetative' state became popular in
      the medical literature, in the context of a 'neocorticalist' theory of
      consciousness. Its clear-cut simplicity and the prestige of its proponents
      contributed to this acceptance. However, this concept seems to be neurologically
      and philosophically inappropriate. In addition, in recent years a number of
      studies have shown that these states are frequently misdiagnosed, due mainly to
      their inherent complexity. Thus, the need for a new name for this syndrome has
      become increasingly evident. A conceptualization of the brain global functioning
      leads to a redefinition of these states. The 'syndrome of brain dismetafunction'
      is conceptually defined. This term does not have a pejorative connotation. It
      respects the inherent uncertainty associated to the subjective dimension of
      consciousness as well as to the prognosis of these states. It promotes an
      integrative approach to problems related to the diagnosis, treatment, and
      rehabilitation of these patients. CONCLUSION: It seems pertinent to propose the
      abandonment of the term 'vegetative' both as conceptually equivocal and as a term
      that may become a self-fulfilling prophecy. Moreover, a no less important reason
      to abandon this qualifier is the possibility of a more coherent conceptualization
      of this syndrome. As a consequence, this approach leads to a new terminology.

PMID- 10652751
TI  - [Intracranial hypertension].
AB  - INTRODUCTION: The characteristics of semirigid cavity confer to the skull and
      their content a special behavior, with regard to the other organs of the economy
      and they become the increases of pressure the interior in this space a threat
      against the appropriate evolution of the patients with intracranial pathologies
      of etiologies dissimilar. DEVELOPMENT: We make a study of the bibliography
      published on the topic, besides our personal approach with regard to the elements
      that we have been able to evaluate in our practices in clinic daily. We carried
      out a wide revision of the topic being exposed the physiopathological factors
      that intervene in to the maintenance of a homeostasis intracranial, the influence
      of the vital functions on this pressure and other aspects of importance. The
      clinical manifestations specify of this syndrome they are baskets after carrying
      out an analysis of their physiopathology. CONCLUSIONS: In this paper we exposes
      the methods for their menstruation as well as the importance of the use of these
      evidences in the establishment of an appropriate treatment. The modernized
      therapy of this entity, as well as the foundations of their application.

PMID- 10652752
TI  - [Recent advances in the treatment the nervous system disorders with interferon
      alpha].
AB  - INTRODUCTION: The interferons (IFN) have had considerable effect on the course of
      relapses and the natural course of the disability of patients with multiple
      sclerosis (MS). However, the effects of IFN in other neurological disorders are
      little known. OBJECTIVES: To review the literature on the experimental and
      clinical applications of the IFN in disorders of the nervous system excluding MS.
      DEVELOPMENT: We reviewed studies of the applications of the IFN in viral diseases
      (experimental and human rabies, herpes zoster, herpes virus, non-herpetic
      meningoencephalitic viruses, HTLV-I myelopathy, arbovirus in animals, subacute
      sclerosing panencephalitis (SSPE), progressive multifocal leukoencephalopathy);
      supposedly viral diseases (Reye's syndrome), continuous partial epilepsy
      (Kojewnikoff's syndrome); prion diseases (Creutzfeldt-Jakob disease);
      degenerative-hereditary diseases (amyotrophic lateral sclerosis, Alzheimer's
      disease, schizophrenia, Sturge-Weber-Dimitri syndrome); immuno-allergic disorders
      (experimental myasthenia gravis, chronic inflammatory demyelinating
      polyneuropathy-CIDP-); Landry-Guillain-Barre-Strohl syndrome, polyneuropathy
      associated with IgM monoclonal gammapathy; tumour disorders (benign and malignant
      primary tumours of the brain, metastatic tumours, meningeal carcinomatosis, extra
      intracranial haemangiomas, meningiomas), and other causes (cuban epidemic
      neuropathy, neuro-Beccet). CONCLUSIONS: Disorders of the nervous system in which
      IFN may be used in a clinical trial include: herpes zoster and herpes simplex
      infections, HTLV-I myelopathy; subacute sclerosing leukoencephalopathy,
      continuous partial epilepsy (Kojewnicoff's syndrome), intra-extracranial
      haemangiomas, CIDP, polyneuropathy associated with IgM gamma monoclonal disorder,
      malignant primary tumours, recurrent meningiomas, some cerebral metastases,
      Behcet's disease and schizophrenia.

PMID- 10652753
TI  - [Bioequivalence and generic drugs. I. Studies of bioequivalence, considering the
      theoretical basis, design and use].
AB  - OBJECTIVES: To describe the studies done before a generic drug is marketed.
      DEVELOPMENT: We reflect on the concept of bioequivalence and its limitations,
      then describe the parameters on which a study of bioequivalence is based and
      explain the statistical hypothesis of bioequivalence. Finally, we explain the
      process of a clinical trial of bioequivalence and how the results are analyzed,
      using a clinical trial as an example. We show how 'carry-over', formulation and
      period effects are analyzed; and also how bioequivalence may be evaluated by
      using different approximations: construction of the confidence interval,
      confidence hypothesis and nonparametric approximations. Finally, we mention the
      methods used to estimate the size of the sample required in a study of this kind.
      CONCLUSIONS: Studies of bioequivalence, even the simplest, have peculiarities of
      design and statistical basis which are markedly different from other clinical
      trials. When generic drugs are marketed it is important to know about the
      peculiarities and characteristics of the studies on which affirmation of the
      bioequivalence of these products is based.

PMID- 10652754
TI  - [Procedural learning and neurological disorders].
AB  - INTRODUCTION AND DEVELOPMENT: We review the current state of learning procedures
      in six neurological conditions: amnesia, Alzheimer-type dementia, Huntington's
      disease, Parkinson's disease, progressive supranuclear paralysis and cerebellar
      pathology. In each condition the conservation or deterioration of different types
      of ability is specified: motor and percepto-motor abilities were evaluated using
      different tests such as following a rotating disk or signal, the labyrinth test,
      percepto-motor adaptation test or tests using paradigms of time of serial
      reaction; percepto-cognitive abilities evaluated by 'mirror-reading' and
      cognitive abilities evaluated by the Tower of Hanoi, of Toronto, or of London.
      CONCLUSION: Most of the papers published describe conservation of learning
      procedures in amnesic syndromes, relatively conserved in Alzheimer's disease and
      relatively deteriorated in Huntington's disease, in progressive supranuclear
      paralysis and in cerebellar dysfunction.

PMID- 10652755
TI  - [Neuropsychological society of Catalana: past, present and future].

PMID- 10652756
TI  - [Treatment of the rise in arterial pressure during the acute phase of stroke.
      Recommendation of Catalan Societies of Arterial Hypertension and Neurology].
AB  - INTRODUCTION: Changes in arterial pressure (PA), especially arterial
      hypertension, are frequent during the acute phase of a stroke and the best
      therapeutic approach is controversial since although high blood pressure is
      associated with a poor prognosis, excessive or too rapid drop in blood pressure
      may also be associated with progression of the neurological deficit. OBJECTIVE:
      To reach agreement as to the correct therapeutic approach when the PA is high
      during the acute phase of a stroke, based on the published data and experience of
      a group of experts from the Catalan Societies of Neurology and Hypertension.
      METHODS: Review of the main recommendations published in the literature and
      discussion in joint study sessions. RESULTS: During the acute phase of a stroke
      moderate increases in blood pressure should not be treated. Antihypertensive
      treatment is recommended when the PA figures are of maintained levels of more
      than 220 mmHg of systolic or 120 mmHg of diastolic pressure in ischemic stroke,
      and over 180 mmHg of systolic or 105 mmHg of diastolic pressure in hemorrhagic
      stroke. CONCLUSIONS: Modifications of arterial pressure, especially of arterial
      hypertension, should be carefully treated during the acute phase of stroke,
      because of the risk of causing worsening of the neurological lesion. When
      treatment is indicated, it is best carried out in a Stroke Unite where this is
      possible.

PMID- 10652757
TI  - [Therapeutic benefits of monotherapy with lamotrigine].
AB  - OBJECTIVE: To analyze the overall therapeutic benefit (effect on seizures and
      quality of life) in 100 patients, aged 14-89 years, treated with lamotrigine
      (LTG) as primary (25) or secondary (75) monotherapy, followed up for between one
      and six years. PATIENTS AND METHODS: The patients were selected for treatment,
      under open observation, and not randomized at all. Thirty patients suffered from
      generalized seizures and 70 from partial crises, with progression to generalized
      tonic-clonic crises in 36 cases. The usual LTG serum level when bi-therapy was
      used was 2 to 4 mg and was similar with monotherapy. The predominant dosage of
      LTG (100 to 200 mg) was similar for monotherapy and for bi-therapy in those
      treated with valproate, as compared with 200-400 mg in most of those in whom the
      associated drug was carbamazepine (24), phenobarbital (14), phenytoin (6) or
      other drug, with a considerable reduction in dose (of 100 mg to 250 mg) when they
      were treated by monotherapy instead. RESULTS: Overall therapeutic benefit was
      obtained in 79 cases, partly due to suppression or reduction of the seisures, or
      maintenance free of them, but mainly due to correction of the side-effects,
      especially somnolence, attention disorders, obesity, tremor, ataxia, reduced
      global productivity, hyperlipidaemia and liver enzyme changes. CONCLUSION:
      Lamotrigine was more effective and better tolerated in smaller doses as
      monotherapy, and better than other drugs in reference to quality of life,
      especially by the supression of side-effects, demonstrating that it is valuable
      in obtaining overall improvement of the disease and its consequences.

PMID- 10652758
TI  - [The treatment of cerebrovascular disorders with anticoagulants and platelet
      aggregation inhibitors].
AB  - INTRODUCTION: The use of anticoagulants and platelet anti-aggregants is one of
      the basic features of the management of patients with cerebrovascular disease.
      DEVELOPMENT: The indications for the use of these agents have evolved from
      initial empirical use based on anecdotic evidence to current recommendations
      following multi-centre trials. Aspirin, ticlopidine, clopidogrel and warfarin are
      drugs of choice for secondary prevention of ischemic stroke (IS). Anticoagulants
      are used more in patients with IS of cardio-embolic origin. The use of anti
      aggregants/anticoagulation in acute IS has not been shown to be clearly effective
      and its use is limited to particular cases in which fibrinolytic treatment cannot
      be used. For satisfactory use of these drugs it is essential to correctly
      identify the type of IS and its progress over time. This article reviews the
      criteria established for the use of such treatment and describes the developing
      areas of multi-centre clinical trials.

PMID- 10652759
TI  - [Diagnosis and treatment of coagulation disorders].
AB  - INTRODUCTION: Approximately 5% of all cerebrovascular events (CVE), and 10% of
      those occurring in young patients, are due to hematological disorders.
      Hypercoagulability states are related to CVE in young patients, deep vein
      thrombosis, recurrent thromboses, pulmonary embolism, a family history of
      thrombosis and unusual venous and arterial thromboses. DEVELOPMENT: The
      conditions related to increased risk of thrombosis are: the congenital
      thrombophilias due to deficiency of protein C, protein S or antithrombin III,
      resistance to protein C activated by Leiden's factor V--cofactor of protein C
      with genetic mutation--; the primary antiphospholipid syndrome with
      anticardiolipin antibodies and lupus inhibitor; platelet disorders, deficit of
      heparin cofactor II, deficit of plasminogen and plasminogen tissue activator (t
      PA) and increase in the inhibitor of plasminogen tissue activator (PAI-I);
      alterations in factors of coagulation such as deficits of factor VII and factor
      XIII, mutation of prothrombin 20210-->A, increase in factor VIII.
      Hyperfibrinogenemia and hyperhomocysteinemia are also independent risk factors
      for CVE. CONCLUSION: The patients, especially young patients, with recurrent
      thrombosis or thrombosis of unknown origin should be assessed seeking clinical
      and serological signs of the primary antiphospholipid syndrome or other
      coagulopathies. Although we still have no results of controlled prospective
      studies regarding these conditions, long term anticoagulation is recommended on
      the findings of small-scale retrospective studies.

PMID- 10652760
TI  - [Thrombolytic therapy of cerebrovascular disorders].
AB  - OBJECTIVE: To analyze the available scientific evidence regarding treatment with
      thrombolytic agents in patients with cerebrovascular disease and present this in
      the context of daily practice. DEVELOPMENT: Publication of the NINDS study of
      treatment with t-PA for acute cerebral ischemia led to approval of this treatment
      for cerebrovascular disease. However, this therapy is associated with a
      significant frequency of hemorrhagic complications. We analyzed the most relevant
      studies on the use of thrombolytic drugs. The results of their intravenous and
      intra-arterial administration were compared with regard to the frequency of
      recanalization and hemorrhagic complications. We evaluated the results of
      physician's surveys on the use of t-PA since publication of the NINDS study.
      These results are interpreted in the context of the potentially generalized use
      of this treatment. CONCLUSIONS: Although in the NINDS study, administration of
      i.v. t-PA within three hours of an arterial occlusion resulted in a lower
      frequency of disability at three months, these results cannot be extrapolated to
      all medical settings. Until there is a more precise definition of the type of
      thrombolytic agent, dosage, route of administration, therapeutic window and
      concomitant use of other drugs, thrombolytic agents should preferably be used in
      centres specialized in the treatment of cerebrovascular disorders.

PMID- 10652761
TI  - [Diagnosis and treatment of symptomatic and asymptomatic carotid disease].
AB  - OBJECTIVE: Provide a management strategy for the evaluation and treatment of
      extracranial internal carotid artery disease. BACKGROUND: Despite 50 years that
      have elapsed since the first carotid artery endarterectomy, surgical indications
      in symptomatic and asymptomatic carotid artery disease remain controversial.
      DESIGN: The most important studies on the treatment of symptomatic and
      asymptomatic internal carotid artery disease were reviewed. Special scenarios
      were analyzed including: intraluminal thrombus, carotid artery occlusion,
      dissection, ulceration, fibromuscular dysplasia, re-stenosis post endarterectomy
      and carotid artery disease coexisting with coronary artery disease. The current
      status of carotid angioplasty was discussed briefly. CONCLUSIONS: A patient
      individualized approach based on the aforementioned studies and personal
      experience is provided. Endarterectomy is recommended in greater than 70% ICA
      symptomatic stenosis, in certain patients with 50 to 69% symptomatic stenosis,
      and exceptionally in asymptomatic patients, patients with associated coronary
      artery disease, ulceration, intraluminal thrombus and other less frequent
      scenarios.

PMID- 10652762
TI  - [Non-invasive evaluation of extracranial and intracranial vascular disease].
AB  - INTRODUCTION: Over the last 10 years the diagnosis of chronic and acute
      cerebrovascular disorders has been greatly improved. We have available now not
      only better anatomical imaging methods that allow a more precise localization and
      subtyping of the problem, but also physiological methods that look at the
      function and interaction between the brain's parenchyma and its perfusion.
      DEVELOPMENT: In this article the utility and clinical indications of
      ultrasonography (duplex and Transcranial Doppler) including the modern techniques
      of embolus detection are described. Also discussed are Magnetic resonance
      angiography, perfusion-diffusion magnetic resonance, computed tomographic
      angiography (angio-CT), single photon emission tomography (SPECT). Clinical
      examples of real cases exemplify the use of these techniques.

PMID- 10652763
TI  - [Diagnosis and treatment of intracerebral hemorrhage].
AB  - INTRODUCTION: Intracerebral hemorrhage (ICH) is the main hypertensive mechanism
      occurring as the consequence of structural changes in the small perforating
      vessels of the cerebral hemispheres and brain stem. DEVELOPMENT: These vascular
      lesions cause deeply situated hemorrhages in the cerebral hemispheres (basal grey
      nuclei and thalamus) and brain stem (pons); less common sites are in the
      subcortical white matter and cerebellum. There are many non-hypertensive causes
      of ICH including: amyloid cerebral angiopathy, vascular malformations,
      intracranial tumours, the use of anticoagulant and fibrinolytic agents,
      sympthomimetic drugs and vasculitis. These conditions usually cause hemorrhages
      situated in the subcortical white matter (lobar), some predominantly in the
      elderly (amyloid cerebral angiopathy) and others mainly in the young (vascular
      malformations and consumption of sympathomimetic drugs). Radiological diagnosis
      of ICH is easily made on computerized tomography (CT), and magnetic resonance
      (MR) gives additional data such as the stage of evolution of the hemorrhage and
      its possible causes (vascular malformations, underlying tumours). The therapeutic
      managements of ICH includes: immediate emergency treatment (the need for
      endotracheal intubation, control of the blood pressure) and the management of the
      conditions causing ICH (coagulation disorders, detection of toxic substances such
      as cocaine and other sympathomimetic agents); treatment of intracranial
      hypertension (hyperventilation, osmotic diuretics, barbiturate coma); the
      decision to proceed to surgery (reserved for patients with cerebellar bleeding
      accompanied by supratentorial hydrocephalus, lobar hemorrhage of intermediate
      size together with progressive neurological deterioration and signs of a space
      occupying lesion on CT, and ventriculostomy for thalamic or caudate nucleus
      bleeding with hydrocephalus.

PMID- 10652764
TI  - [Neurologic intensive care in patients with raised intracranial pressure].
AB  - INTRODUCTION: Intracranial hypertension is associated with a high mortality in
      patients with various encephalo-cranial disorders, so that it is important to
      recognize and treat the condition without delay. DEVELOPMENT: The main factors
      interacting to maintain normal intracranial pressure are the cerebral blood flow,
      arteriolar radius, cerebral perfusion pressure and plasma viscosity. Current
      treatment of raised intracranial pressure is aimed to restore these factors to
      normal, so as to maintain equilibrium between encephalic mass, cerebro-spinal
      fluid and blood volume. As well as traditional measures such as hyperventilation,
      administration of mannitol and barbiturates, today there are also new treatments
      available to the intensive care neurologist: hypertonic saline solutions,
      hypothermia, craniectomies and neuroprotective agents.

PMID- 10652765
TI  - [Characteristics and evolution of rehabilitation treatment in infantile cerebral
      paralysis].

PMID- 10652766
TI  - [Clinical characteristics of 50 patients with multiple sclerosis diagnosed in
      Santiago de Cuba].

PMID- 10652767
TI  - [Bilateral medial bulbar infarct: a case report].

PMID- 10652768
TI  - [Trigeminal neuralgia associated with Arnold Chiari malformation].

PMID- 10652769
TI  - [Lumbosacral plexopathy as a form of presentation of iliac arterial aneurysm].

PMID- 10652770
TI  - [Opsoclonus-myoclonus in a patient with AIDS: a good response to treatment with
      IV immunoglobulins].

PMID- 10652771
TI  - [On "Proposal for the application and scoring of the clock drawing test in
      Alzheimer's disease"].

PMID- 10652772
TI  - [Histiocytosis of the Langerhans cells with cerebellar and pyramidal involvement.
      Response to treatment with chemotherapy].

PMID- 10652773
TI  - [Tropical spastic paraparesis and mixed infection due to Treponema pallidum and
      HTLV-1].

PMID- 10652774
TI  - [Congenital vascular malformations in children].

PMID- 10652775
TI  - [Lactation and antiepileptic drugs].

PMID- 10652776
TI  - [Reflex epilepsy due to recitation].

PMID- 10652777
TI  - [Direct costs of cerebrovascular disease during the first year of follow-up].

PMID- 10652778
TI  - [Hemorrhagic infarct as a result of cerebral venous thrombosis as a complication
      of cirrhosis].

PMID- 10652779
TI  - [Usefulness of a diagnostic study of mental retardation].

PMID- 10652780
TI  - Cumulative subject and contributor indexes and tables of contents volumes 1-53.

PMID- 10652781
TI  - Further studies on the bioconversion of penicillin G into deacetoxycephalosporin
      G by resting cells of Streptomyces clavuligerus NP-1.
AB  - Resting cells of Streptomyces clavuligerus NP-1, which possess
      deacetoxycephalosporin C synthase activity, have been shown previously to perform
      oxidative ring expansion of penicillin G in the presence of iron, ascorbic acid,
      and alpha-ketoglutaric acid to form deacetoxycephalosporin G. Further studies on
      this bioconversion indicated that use of MOPS or HEPES buffer at pH 6.5 more than
      doubled the extent of the reaction observed with the previously used Tris-HCl at
      pH 7.4. Levels of bioconversion as high as 16.5% were achieved at low penicillin
      G concentrations. Previously, conversion yields were < 1%.

PMID- 10652782
TI  - Properties of the Macrophomina phaseolina endoglucanase (EGL 1) gene product in
      bacterial and yeast expression systems.
AB  - Functional expression of a beta-D-1,4 glucanase-encoding gene (egl1) from a
      filamentous fungus was achieved in both Escherichia coli and Saccharomyces
      cerevisiae using a modified version of pRS413. Optimal activity of the E. coli
      expressed enzyme was found at incubation temperatures of 60 degrees C, whereas
      the enzyme activity was optimal at 40 degrees C when expressed by S. cerevisiae.
      Enzyme activity at different pH levels was similar for both bacteria and yeast,
      being highest at 5.0. Yeast expression resulted in a highly glycosylated protein
      of approx 60 kDa, compared to bacterial expression, which resulted in a protein
      of 30 kDa. The hyperglycosylated protein had reduced enzyme activity, indicating
      that E. coli is a preferred vehicle for production scale-up.

PMID- 10652783
TI  - Analyte-receptor binding kinetics for different types of biosensors. A fractal
      analysis.
AB  - A fractal analysis is presented for analyte-receptor binding kinetics for
      different types of biosensor applications. Data taken from the literature may be
      modeled using a single-fractal analysis, a single- and a dual-fractal analysis,
      or a dual-fractal analysis. The latter two methods represent a change in the
      binding mechanism as the reaction progresses on the surface. Predictive
      relationships developed for the binding rate coefficient as a function of the
      analyte concentration are of particular value since they provide a means by which
      the binding rate coefficients may be manipulated. Relationships are presented for
      the binding rate coefficients as a function of the fractal dimension Df or the
      degree of heterogeneity that exists on the surface. When analyte-receptor binding
      is involved, an increase in the heterogeneity on the surface (increase in Df)
      leads to an increase in the binding rate coefficient. It is suggested that an
      increase in the degree of heterogeneity on the surface leads to an increase in
      the turbulence on the surface owing to the irregularities on the surface. This
      turbulence promotes mixing, minimizes diffusional limitations, and leads
      subsequently to an increase in the binding rate coefficient. The binding rate
      coefficient is rather sensitive to the degree of heterogeneity, Df, that exists
      on the biosensor surface. For example, the order of dependence on Df1 is 7.25 for
      the binding rate coefficient k1 for the binding of a Fab fragment of an
      antiparaquat monoclonal antibody in solution to an antigen in the form of a
      paraquat analog immobilized on a sensor surface. The predictive relationships
      presented for the binding rate coefficient and the fractal dimension as a
      function of the analyte concentration in solution provide further physical
      insights into the binding reactions on the surface, and should assist in
      enhancing biosensor performance. In general, the technique is applicable to other
      reactions occurring on different types of surfaces, such as cell-surface
      reactions.

PMID- 10652784
TI  - Preparation and preliminary characterization of exopolysaccharides by yeast
      Rhodotorula acheniorum MC.
AB  - The effects of various carbon and nitrogen sources on the synthesis of
      exopolysaccharides by Rhodotorula acheniorum MC were studied. The dynamic
      viscosity of cell-free culture broths during exopolysaccharide synthesis were
      measured. The highest values for the viscosity (10.14 MPa.s) and crude
      polysaccharide productivity (6.6 g/L) were obtained in a medium supplied with 5%
      sucrose. Ammonium sulfate was the most favorable nitrogen source for
      exopolysaccharide synthesis. The value of pH played a determinant role, and the
      obligatory condition for exopolysaccharide production was low (pH 1.7-2.0) during
      the fermentation. The chemical composition and sugar constituents of the crude
      exopolysaccharides were determined. Mannose was the main monosaccharide
      component, and its concentration was the highest (69.13%) in the crude
      exopolysaccharide synthesized in the medium that included 5% sucrose as a carbon
      source.

PMID- 10652785
TI  - Effects of acetate on the growth and fermentation performance of Escherichia coli
      KO11.
AB  - Escherichia coli KO11, in which the genes pdc (pyruvate decarboxylase) and adh
      (alcohol dehydrogenase) encoding the ethanol pathway from Zymomonas mobilis were
      inserted into the chromosome, has been shown to metabolize all major sugars that
      are constituents of hemicellulosic hydrolysates to ethanol, in anaerobic
      conditions. However, the growth and fermentation performance of this recombinant
      bacteria may be affected by acetic acid, a potential inhibitor present in
      hemicellulose hydrolysates in a range of 2.0-15.0 g/L. It was observed that
      acetate affected the growth of E. coli KO11, prolonging the lag phase and
      inducing loss of biomass production and reduction of growth rate. At lower pH
      levels, the sensitivity to acetic acid was enhanced owing to the increased
      concentration of the protonated species. On the other hand, the recombinant
      bacteria showed a high tolerance to acetic acid regarding fermentative
      performance. In Luria broth medium with glucose or xylose as a single sugar
      source, it was observed that neither yield nor productivity was affected by the
      addition of acetate in a range of 2.0-12.0 g/L, suggesting some uncoupling of the
      growth vs ethanol production.

PMID- 10652786
TI  - Molecular analysis and identification of the radC gene from the phototrophic
      bacterium Rhodobacter capsulatus B10.
AB  - The radC gene, whose product plays a role in the prokaryotic repair of DNA damage
      after UV and X-ray irradiation, was cloned and sequenced from the phototrophic
      bacterium Rhodobacter capsulatus B10. The gene codes for a protein of 214 amino
      acids with a molecular mass of 23,792 Da. The deduced amino acid sequence showed
      significant homology with the RadC proteins of Escherichia coli, Bacillus
      subtilis and Haemophilus influenzae. Northern blot analysis indicated that under
      both chemotrophic and phototrophic growth conditions the radC gene was relatively
      highly expressed and was induced about five-fold after UV-irradiation. Primer
      extension analysis revealed that transcription was initiated from the same
      position before and after UV treatment. Mutants (radC negative) have a low
      survival rate and a slower growth rate than the wild type.

PMID- 10652787
TI  - Comamonas acidovorans strain MC1: a new isolate capable of degrading the chiral
      herbicides dichlorprop and mecoprop and the herbicides 2,4-D and MCPA.
AB  - A gram-negative prototrophic bacterial species, strain MC1, was isolated from the
      vicinity of herbicide-contaminated building rubble and identified by 16S rDNA
      sequence analysis, its physiological properties, GC content, and fatty acid
      composition as Comamonas acidovorans. This strain displays activity for the
      productive degradation of the two enantiomers of dichlorprop [(RS)-2-(2,4
      dichlorophenoxy-)propionate; (RS)-2,4-DP] and mecoprop [(RS)-2-(4-chloro-2-methyl
      ) phenoxypropionate; (RS)-MCPP] in addition phenoxyacetate herbicides, i.e. 2,4
      dichlorophenoxyacetate (2,4-D) and 4-chloro-2-methylphenoxyacetate (MCPA), and
      various chlorophenols were utilized. Rates amounted to 1.2 mmoles/h g dry mass
      (2,4-D) and 2.7 mmoles/h g dry mass [(RS)-2,4-DP]. Degradation of (RS)-2,4-DP was
      not inhibited up to concentrations of 500 mg/l, nor of 2,4-D up to 200 mg/l. The
      optimum pH value of (RS)-2,4-DP degradation was around 8. The application of
      respective primers for PCR amplification revealed the presence of tfdB and tfdC
      genes.

PMID- 10652788
TI  - Bactericidal activities of essential oils of basil and sage against a range of
      bacteria and the effect of these essential oils on Vibrio parahaemolyticus.
AB  - Basil and sage essential oils were examined for bactericidal activity against a
      range of Gram-positive and Gram-negative bacteria by viable count determinations.
      Generally, Gram-positive bacteria showed higher resistance to basil and sage
      essential oils than Gram-negative bacteria. Vibrio species showed a high
      sensitivity to both essential oils. Stationary growth phase cells of selected
      bacteria showed higher resistance to these essential oils than exponential growth
      phase cells. Basil-resistant (b21) and sage-resistant (s20) strains of Vibrio
      parahaemolyticus were isolated. Both strains showed higher resistance to heat and
      H2O2 than parent strain. Conversely, heat-adapted V. parahaemolyticus also showed
      a higher resistance to these essential oils than nonadapted cells.

PMID- 10652789
TI  - [Pyrimidine receptor function in the central nervous system].
AB  - A spectroscopic method, using fluorescent Ca2+, K+ and Na+ ion indicators in
      combination with the use of fast-kinetic techniques on the time scale of 0.00004
      10 s has been applied to study mechanisms of P2 pyrimidoceptor-mediated signal
      transduction in brain homogenates. Effects of the known P2 receptor ligands (ATP,
      alpha, beta-methylene-ATP, UTP, UDP and uridine) and the P1 receptor ligand,
      adenosine, were compared by measuring the rates of transmembrane Ca2+, K+ and Na+
      ion fluxes in resealed plasmalemma fragments and nerve endings from the rat
      cerebral cortex. In homogenates containing resealed plasmalemma fragments,
      uridine (0.03-30 microM), but not adenosine, activated two phases of Ca2+ ion
      influx with onsets of a few ms and hundred ms in a concentration-dependent
      manner. Also, the activation of the fast-phase Ca2+ ion response by ATP, UDP and
      alpha, beta-methylene-ATP whereas that of the slow-phase by UTP and UDP were
      observed with 3 microM concentration of these P2 receptor ligands. In homogenates
      containing resealed nerve endings, the fast-phase Ca2+ ion response to uridine
      was absent. UTP, but not uridine and UDP (3 microM), activated a fast K+ ion
      influx with onset of < 1 ms. Adenosine (3 microM) evoked a slow Na+ ion influx
      with onset of > 0.1 s whereas the influx of Na+ ion to uridine was detectable
      below 0.01 s. Both nucleotides, ATP and UTP (3 microM), activated fluctuations of
      transmembrane Na+ ion influx and efflux. By contrast, UDP caused efflux of Na+
      ion in the subsecond range of time. Collectively these results suggest that
      transmembrane cation fluxes mediated by kinetically distinguishable P2U
      pyrimidoceptor subtypes are different.

PMID- 10652790
TI  - [Biological activity and structure of antitumor compounds from Plantago media L].
AB  - Tyrosine kinase inhibition and tumor growth inhibition activity of verbascoside
      and homoplantaginin are described. Both molecules proved to be equally
      significant inhibitors of isolated EGF-R tyrosine kinases, nevertheless their in
      vitro antiproliferative activity was variable in cellular assays. Their different
      inhibitory efficacies could be interpreted on the basis of conformational
      analysis and lipophilicity evaluation.

PMID- 10652791
TI  - [Molecular modeling studies of prolyl endopeptidase inhibitors].
AB  - Prolyl endopeptidase, a serine protease is considered to play an important role
      in the degradation of neuropeptides capable of changing the performance in
      learning and memory tasks in both animal and human. The inhibitors seem to be
      promising drug candidates to treat and prevent diseases with associated memory
      loss such as senile dementia. In the last decade advanced and improved new
      technologies have appeared to stimulate ideas in the design and synthesis of new
      drug molecules. The goal of this short communication is to review our results and
      observations, exemplified by our research on the inhibitors of prolyl
      endopeptidase. Among them qualitative and quantitative structure-activity
      relationship studies using conformational analyses, NMR measurements,
      pharmacophoric plots and CoMFA models are summarised.

PMID- 10652792
TI  - [The coupling of canine ventricular myocyte beta2-adrenoceptors to L-type calcium
      current].
AB  - To establish the functional coupling of beta adrenoceptor (beta AR) subtypes of
      beta 1AR and beta 2AR to L-type calcium current (ICaL), we investigated the non
      selective agonist isoproterenol (ISO), and the relatively selective beta 2AR
      agonists zinterol (ZIN) and salbutamol (SAL) on ICaL in isolated canine
      ventricular myocytes in the presence and absence of CGP 20712A (CGP) and atenolol
      (AT), selective beta 1AR antagonists, and ICI 118,551 (ICI) a selective beta 2AR
      antagonist. Peak ICaL was determined using "patch type" microelectrodes and whole
      cell voltage clamp. ISO (0.5 microM) increased ICaL maximally 3.5 +/- 0.67 fold.
      ZIN (10.0 microM) and SAL (10.0 microM) increased ICaL maximally 1.5 +/- 0.2 (n =
      5) fold and 1.4 +/- 0.1 (n = 5) fold, respectively. These effects were fully
      inhibited by CGP (0.3 microM) and AT (1.0 microM), inhibitors of beta 1AR but not
      by ICI (0.1 microM) a beta 2AR inhibitor. ZIN at relatively lower concentrations
      (< or = 0.1 microM) did not increase ICaL. CGP (0.3 microM) but not AT and ICI
      inhibited ICaL in the absence of beta AR agonists. CGP inhibition of ICaL was
      absent in the presence of forskolin (FK, 1.0 microM) that increases cAMP levels
      and ICaL by directly stimulating the adenylate cyclase. These indicate that none
      of the antagonists affect ICaL through an action downstream of beta AR.
      CONCLUSION: beta-adrenergic agonists increase ICaL via beta 1AR but not beta 2AR
      in canine ventricular myocytes.

PMID- 10652793
TI  - [Sudden infant death syndrome].

PMID- 10652794
TI  - [Molecular genetics of hereditary polyneuropathies].

PMID- 10652795
TI  - [The evaluation of the methodology in studies about diagnostic test in "Anales
      Espanola de Pediatria"].

PMID- 10652796
TI  - [Primary infection in vertically infected HIV-1 infants: biological
      characteristics of isolated virus, viral load and CD4 t-lymphocytes].
AB  - OBJECTIVE: Our aim was to study the relationship between virological and/or
      immunological markers during the first month of life in vertically HIV-1 infected
      infants without prior antiviral treatment. PATIENTS AND METHODS: Thirty HIV-1
      infected infants that had not received prior antiviral therapy, nor had their
      mother during pregnancy, were studied. Viral load was quantified using standard
      molecular assays. Viral isolation and phenotype were carried out by using viral
      co-cultures. Subpopulations of lymphocytes were determined by flow cytometry.
      RESULTS: We have found an inverse correlation between log10 CD4+ cells/mm3, as
      well as CD4+ percentage with log10 viral load, with a slope of -0.266 (CI95%: 
      0.459 to -0.074) and -6.648 (CI95%: -12.815 to -0.471), respectively. When the
      influence of viral phenotype on the log10 viral load or the percent of CD4+ T
      cells standardized according to age (Z-score) with the log10 of the viral load
      was determined, it was found that infants having syncytium inducing (SI) virus
      had 12.355% (CI95%: 2.336 to 22.373) less CD4+ cells and 4.530 standard
      deviations (IC95%: 0.448 to 8.613) than infants with non syncytium inducing (NSI)
      isolates. CONCLUSIONS: Our results suggest that a particular biological phenotype
      of viral isolates (SI and those with rapid/high replication) and high plasma
      viral loads have a statistically significant tendency to be associated. Viral
      load is the marker that shows the best inverse correlation with the level of CD4+
      cells normalized according to the infant's age. This correlation shows a
      different value in infants with SI and NSI isolates.

PMID- 10652797
TI  - [Reproducibility of the walking test in patients with cystic fibrosis].
AB  - OBJECTIVE: The walking test is a useful and objective method for evaluating the
      tolerance for exercise in patients with chronic bronchopulmonary diseases. Our
      objective was to check the reproducibility of this test and evaluate whether
      there are differences between tests of varying duration (2 and 6 minutes) in a
      group of patients with cystic fibrosis. PATIENTS AND METHODS: We utilized the
      walking test on 29 patients who were in a stable phase and under care in the
      Cystic Fibrosis Unit of our hospital. Two tests were carried out, one of 2
      minutes and the other of 6 minutes duration, both of which were repeated after a
      15-minute interval. RESULTS: The reproducibility of the walking test in this type
      of patient was very good and we found an excellent correlation between the two
      minute test and the six-minute test. We did not observe a training effect when
      the test was repeated. CONCLUSIONS: The two minute walking test has a high
      reproducibility and we propose this test, because it is shorter and more
      comfortable for pediatric patients with cystic fibrosis, in order to evaluate the
      evolution, progressive deterioration of the of the patient and the response to
      different types of treatments.

PMID- 10652798
TI  - [Prevalence of diagnosed asthma in pediatric population of Asturia. Regional work
      group on infantile asthma in primary care of Asturia].
AB  - OBJECTIVE: The aim of this study was to know the prevalence of physician
      diagnosed asthma and related epidemiological variable among children between 0
      and 13 years of age in Asturias (Spain). PATIENTS AND METHODS: A population based
      prevalence study was performed. A team of 44 researches evaluated the clinical
      records of children living in 24 different healthcare zones of Asturias. The
      total number of children included in the study was 27,511. Asthma during the
      infant period (0-23 months) and preschool age (2-5 years) was defined according
      to clinical criteria and asthma during school age (6-13 years) was established
      according to clinical criteria and pulmonary function. Prevalence of physician
      diagnosed asthma following these criteria, sex and age-class distribution and the
      prevalence of current asthma (presenting symptoms during the previous 12 months)
      were studied. The study is dated as of January 1, 1998. RESULTS: The child sample
      included in this study represents 23.9% of the Asturian pediatric population.
      Asthma was diagnosed in a total of 3,170 children, of these 243 were infants, 915
      preschoolers and 2,012 were of school age. Asthma prevalence calculated over the
      whole pediatric population was 11.5% with a breakdown by age groups of 7.6% for
      infants, 13.5% for preschoolers and 11.5% for school age children. Of all
      asthmatic children, 73.3% were symptomatic during the previous year. Males
      represented 61.5% of all asthmatic children. CONCLUSIONS: 1. Asthma prevalence is
      high with this illness being the number one health problem in children in
      Asturias. 2. The highest percentage of children suffering from asthma experienced
      symptoms during the previous year. 3. A predominance of this disease in males was
      confirmed.

PMID- 10652799
TI  - [The anal plug in the treatment of fecal incontinence in myelomeningocele
      patients: results of the first clinical trial].
AB  - OBJECTIVE: Ninety percent of patients with myelomeningocele are affected by
      urinary incontinence and more than 75% suffer fecal incontinence as well. For
      this reason, we carried out a clinical trial in order to demonstrate the
      performance of the anal plug. PATIENTS AND METHODS: The trial was carried out
      with 19 patients, 10 females and 9 males, between 3 and 26 years of age. Fecal
      incontinence was considered to be a problem in 94.7%. The anal plug used was made
      of polyurethane foam compressed by a polyvinyl alcohol foil that dissolves when
      exposed to warmth and moisture, expanding to its full size in 30-60 seconds. The
      anal plug is removed by pulling gently on a soft gauze string that is molded into
      the plug. RESULTS: The maximum time of having the anal plug in place was 12
      hours. The reason for removal was due to routine change in 57.9% of the cases and
      in 21% the product slipped out, mainly during the adaptation and training period.
      Application of the anal plug was found to be very easy by 73.6% of the patients.
      The general evaluation was excellent to good in 78.9% of the users and 89.5% of
      the patients wished to continue using the product. CONCLUSIONS: Having clinically
      evaluated the effectiveness of the anal plug, we can conclude that the use of
      this product provides clear physical and psychological benefits. To date, it is
      the only non-surgical treatment for fecal incontinence available to those
      patients who desire to carry out a complete social life.

PMID- 10652800
TI  - [Pubertal growth, final height and weight gain in girls diagnosed with IDDM
      during pre-pubertal period].
AB  - OBJECTIVE: Girls diagnosed of type 1 diabetes mellitus during the prepubertal
      stage may present reduced longitudinal growth and have a tendency to be
      overweight after puberty starts. Our objective was to evaluate the growth,
      pubertal growth spurt, final height and weight gain of diabetic girls diagnosed
      of insulin dependent diabetes during the prepubertal period. PATIENTS AND
      METHODS: We evaluated retrospectively the longitudinal growth and body mass index
      (BMI) of 17 girls diagnosed of type 1 diabetes before puberty, from the time of
      diagnosis until final height. The effects of age at diagnosis, evolution time,
      insulin therapy (conventional or intensified), insulin dose and metabolic control
      on growth were analyzed. RESULTS: The final height attained was 161 +/- 4 cm,
      which is within the target height range. The height at diagnosis (0.31 +/- 0.71)
      was normal in relationship to the reference population, showing a significant
      reduction upon reaching the final height (-0.18 +/- 0.77). The BMI was
      significantly increased when it was compared at final height (0.99 +/- 0.79) with
      the index obtained one year after the onset of diabetes (0.04 +/- 0.63). The
      insulin therapy regimen did not affect the evolution of the patients and no
      significant relationship existed between the age at diagnosis, duration of
      diabetes, daily insulin dosage or metabolic control and height or BMI.
      CONCLUSIONS: The final height of type 1 diabetic girls is reduced and adolescent
      diabetic girls have a tendency to be overweight. Metabolic control (for the range
      observed in these patients) or insulin dosage does not seem to affect the growth
      of diabetic girls.

PMID- 10652801
TI  - [Bone mass evolution in patients with precocious and advanced puberty treated
      with LHRH analogs].
AB  - OBJECTIVE: Our aim was to know the long-term effects of treatment with LHRH
      analogs on the bone mass of patients with precocious or advanced puberty.
      PATIENTS AND METHODS: Forty-six patients (11 boys and 35 girls) received a-LHRH
      throughout a 2-year period. The diagnoses were precocious or advance puberty
      alone or associated to other pathologies. The bone mass was indirectly estimated
      by measuring the cortical thickness (CT) and the metacarpal diameter (BD) of the
      2nd, 3rd, and 4th metacarpals, taking as a reference values the results of the
      longitudinal Aragonese study of the "Andrea Prader" Center. RESULTS: The CT was
      1.3 SD at the beginning and decreased to 0.3 SD (p < 0.002) by the end of therapy
      and continuing losing to reach 0.1 SD after withdrawal. The BA decreased from 0.8
      SD to 0.7 SD (p < 0.0002) and continued decreasing to reach 0.5 SD after
      withdrawal (p < 0.05). The BD went from -0.64 to -0.62 and to -0.9 SD (p < 0.04)
      after withdrawal. The longitudinal study of the same 18 cases gave similar
      results. No significant difference was found between sexes. CONCLUSIONS: In
      precocious or advance puberty, the bone age and the cortical thickness are
      increased. After two years of treatment with a-LHRH both decreased significantly
      and stabilized one year after its suppression. The BD does not change during the
      treatment, but continues losing value thereafter. This loss of bone mass, not
      well known in this pediatric situation, is probably related to estrogen
      deprivation and needs the attention of the physician in order to take possible
      preventative measures.

PMID- 10652802
TI  - [Risk factors for lung toxicity in pediatric cancer survivors].
AB  - OBJECTIVE: Our objectives were to determine the prevalence of alterations in lung
      function among pediatric cancer survivors with known risk factors and to
      establish clinical and imaging correlations, as well as to establish follow-up
      criteria. PATIENTS AND METHODS: Cancer survivors diagnosed at the Pediatric
      Oncology Unit between 1971 and 1997 who fulfilled at least one of the following
      criteria were eligible: 1) primary lung or thoracic wall neoplasm; 2) lung
      metastasis at diagnosis or later, or; 3) irradiation of mediastinum and/or lung
      fields. Assessment included respiratory symptomatology questionnaire, physical
      examination, forced spirometry, static lung volumes, maximal static respiratory
      pressures, single breath CO diffusing capacity, pulse oximetry and imaging
      studies. RESULTS: Thirty-five (14 females and 21 males) out of 41 survivors were
      assessed. Mean age at diagnosis, evaluation and follow-up were 9 (1-14), 18 (10
      28) and 9 (3-27) years, respectively. The diagnoses included pleuropulmonary
      blastoma (1), chest wall Ewing's sarcoma (1), Hodgkin's disease (18),
      nephroblastoma (7), yolk-sac tumor (2), acute leukemia2), non-Hodgkin's lymphoma
      (1), rhabdomyosarcoma (1), coriocarcinoma of the ovary (1) and osteosarcoma (1).
      Thirteen patients presented lung metastasis at diagnosis or later. All were
      administered chemotherapy. Irradiated fields were the mediastinum (dose 20-56 Gy)
      in 20 cases, the lung (8-30 Gy) in 6 and the spine (24 Gy) in one. Eight
      underwent thoracotomy. Fourteen percent were dyspneic when walking at the same
      rate as a person of the same sex and age (grade 2). Twenty percent had a
      restrictive ventilatory disorder, but none were obstructive. The presence of
      dyspnea had sensitivity, specificity, positive predictive values and negative
      predictive value for the diagnosis of restrictive ventilatory disorder of 67%,
      96%, 80% and 93%, respectively. Lung irradiation was associated with an increased
      risk for the development of restrictive disease. Excluding those who received
      lung irradiation, survivors under 6 years of age at diagnosis obtained lower
      spirometric values, lung volumes and DLCO values than survivors aged 6 years or
      older at diagnosis. There were no differences in pulmonary function values
      between survivors who received mediastinum irradiation and those who did not. The
      cumulative dose of cyclophosphamide significantly correlated with FVC, FEV1 and
      FRC. Pulse oximetry values were > or = 95% in all survivors. Maximal static
      respiratory pressures were within normal limits in all but one survivors whose
      other pulmonary function results were normal. Thirty-two percent (11 out of 34)
      had KCO (diffusing capacity adjusted to alveolar volume) values lower than 80% of
      reference values. Two survivors of nephroblastoma with pulmonary metastasis and
      who underwent lung irradiation had radiological signs of lung fibrosis.
      CONCLUSIONS: Pediatric cancer survivors who were administered intensive
      chemotherapy and/or lung irradiation are eligible for follow-up of lung function.
      Those diagnosed before 6 years of age and/or with moderate dyspnea are at high
      risk of having pulmonary restrictive disease. Imaging studies (chest X-ray) have
      a low sensitivity that prevents their use as a screening method in the follow-up
      of cancer survivors.

PMID- 10652803
TI  - [Recommendations for the identification of newborns. Commission of Identification
      of newborns of Spanish Academy of Pediatrics].

PMID- 10652805
TI  - [Brachial measurements as nutritional indicators in health term newborns].
AB  - OBJECTIVE: Our objective was to study the correlations between weight and length
      and weight index and brachial areas in healthy term newborns as indicators of
      nutritional status. PATIENTS AND METHODS: We studied 794 consecutive Caucasian
      newborns, 377 male and 417 females, with gestational ages of 39 +/- 09 weeks and
      adequate weights. We measured weight, length, weight/length index, body mass
      index and weight index. Measurements of the arm perimeter and tricipital skinfold
      were used to calculate the fatty, lean and total areas by two different methods.
      Mean, standard deviation and percentiles were utilized in the measurements. The
      Student's t-test was used to calculate differences and Pearson's test for
      correlations. RESULTS: We found that weight, length and weight/length indexes
      were higher in males than in females, except for the weight index. Brachial areas
      and parameter were higher in females, except for the lean area. We did not find
      significant differences between gender in brachial measurements calculated by the
      different methods. Among the males, we found a high degree of correlation between
      weight and the weight/length index (r = 0.963; p < 0.0001), and weight and total
      body area (r = 0.649; p < 0.0001). Similar data were obtained among females,
      where in addition a high correlation was found between the fat percentage and the
      body mass index (BMI, r = 0.223; p < 0.0001), as well as between brachial areas
      and BMI in both genders (p < 0.0001). CONCLUSIONS: In normal newborns, the
      brachial areas, taken as indicators of body composition, are statistically
      significantly correlated with the anthropometric parameters widely used to
      measure the nutritional status of newborns.

PMID- 10652804
TI  - [Creatine kinase BB activity in the serum and bronchial aspirate of preterm
      newborns with respiratory distress syndrome].
AB  - OBJECTIVE: The aim of this study was to test the utility of serum creatine kinase
      (CK) isoenzyme determinations as a marker of tissue injury in preterm newborns
      with respiratory distress syndrome (RDS). PATIENTS AND METHODS: Two groups of
      neonates were studied, 26 suffering from RDS who required mechanical ventilation
      and 20 healthy newborns with gestational ages, hours of life and birth weights
      similar to the first group. The activity of CK and its isoenzymes was determined
      in the bronchial aspirate and serum samples that were obtained before and 24
      hours after exogenous surfactant therapy. The isoenzymes were separated by
      electrophoresis on agarose gel and their activity expressed as a percentage of
      the total CK. Total proteins were quantified in the bronchial aspirate and CK
      enzymatic activity expressed in U/mg of protein x 10-3. RESULTS: The CK-BB
      isoenzyme was significantly increased (p < 0.001) in the serum of infants with
      RDS compared with the control group. In the bronchial aspirate, the isoenzymatic
      study showed that the CK-BB isoenzyme represented 98-100% of the total enzymatic
      CK activity. CONCLUSIONS: The study shows significant differences in the CK
      isoenzyme patterns of neonates with RDS compared to controls. An increase in
      serum levels of the CK-BB isoenzyme could be an effective marker of tissue injury
      in lung disease in the newborn.

PMID- 10652806
TI  - [Blepharophimosis, ptosis and epicanthus inversus syndrome plus sensorineural
      deafness].

PMID- 10652807
TI  - [Confusion of two cases of bipolar disorder with attention deficit hyperactivity
      disorder].

PMID- 10652808
TI  - [Congenital pulmonary lymphangiectasis and other associated anomalies: two case
      reports].

PMID- 10652809
TI  - [Acute epiglottitis. Study of 23 cases].

PMID- 10652810
TI  - [Refractory epilepsy].

PMID- 10652811
TI  - [Recommendations for basic, advanced and neonatal cardiopulmonary reanimation
      (III): advanced pediatric cardiopulmonary resuscitation. Spanish group of
      pediatric and neonatal cardiopulmonary resuscitation].

PMID- 10652812
TI  - [Prevalence of hepatitis A antibodies in 6-7 year-old children: follow-up study
      1990-1998].

PMID- 10652813
TI  - [Adolescents with clinical course suggestive of acquired immunodeficiency and non
      confirming conventional tests].

PMID- 10652814
TI  - [Viral myocarditis].

PMID- 10652815
TI  - [Infantile botulism].

PMID- 10652816
TI  - [Dioxin contamination risk for children].

PMID- 10652817
TI  - [Iron deficiency and celiac disease in children in Sahara].

PMID- 10652818
TI  - [Hyponatremic encephalopathy: avoidable complication of adenoidectomy].

PMID- 10652819
TI  - A quantitative study of the circulus arteriosus cerebri of the camel (Camelus
      dromedarius).
AB  - The afferent vessels of the circulus arteriosus cerebri in the camel were studied
      quantitatively. It was found that the diameters of the arteries did not differ
      significantly on the left and right sides. An interesting observation was that
      the basilar artery contributed to the blood supply of the brain in the camel, in
      contrast to the situation in other ruminants.

PMID- 10652820
TI  - The teeth of the horse: evolution and anatomo-morphological and radiographic
      study of their development in the foetus.
AB  - The aim of this work was to study the ontogenetic process in teeth from their
      early appearance in the ossifying matrix of the mandible and maxilla, in
      different foetuses of scalar ages. Radiographic examinations of the skull and
      mandible hemisections were performed and the latero-medial (LM) and dorsoventral
      (DV) projections for the skull and mandible were analysed. A high-definition film
      screen combination was used for this study. The exposure values ranged from 35
      kV/6 mAs to 58 kV/10 mAs, according to the size of the skulls and their degree of
      ossification. The first dental germ observed was the P3, at 138-140 days of
      pregnancy. At 146 days, P2 and P4 dental germs were visible. At 160-168 days, the
      dental germ of the first deciduous incisor tooth (I1) appeared; at 180-188 days
      of pregnancy the germ of the second (I2), and at 224 days the germ of the third
      (I3), were detectable. At 275 days the dental germ of the mandibular first molar
      tooth (M1) appeared, while the maxillary M1, which was not visible
      radiographically, was represented by a jelly-like amorphous body within its
      alveolar cavity.

PMID- 10652821
TI  - Sonographic observations of the peripheral vasculature of the equine thoracic
      limb.
AB  - Investigations of the equine peripheral vascular system have been constrained by
      the lack of a non-invasive method of examining the arteries and veins of the
      limbs of the conscious horse. Precise correlations were established between the
      gross anatomical features of the peripheral vessels and their B-mode sonographic
      appearance in each thoracic limb of 35 horses. A sonographic imaging protocol was
      established. Additional Doppler sonographic recordings defined the arterial
      waveforms and demonstrated that blood flow to the foot could be evaluated in the
      lateral proper digital artery, distal to the level of the coronary band. Valves
      (with 2-4 cusps) were identified in the lumina of the medial and lateral palmar
      common digital veins and those of the medial and lateral palmar proper digital
      veins. Spontaneous echo contrast, a smoke-like haze of echoic blood, was seen in
      the lateral and medial palmar common digital veins, the distal deep palmar venous
      arch and communicating branches, and the palmar proper digital veins, and
      occasionally seen in the distal deep palmar arterial arch and distal proper
      palmar digital arteries. The value of duplex sonography (B-mode and Doppler) for
      anatomical and physiological studies of the peripheral vasculature of the horse
      was clearly established. Such data could be applied to the investigation of
      diseases affecting the peripheral circulation.

PMID- 10652822
TI  - Ultrastructure of phagocytes from mammary glands of non-pregnant heifers.
AB  - Results of ultramicroscopic investigations of phagocytes isolated from non
      secreting and aberrantly secreting juvenile mammary glands of non-pregnant
      heifers are presented. The two types of phagocytes observed in cell suspensions
      obtained by lavage of mammary gland cavities were polymorphonuclear leukocytes
      and macrophages. Polymorphonuclear leukocytes were spherical or irregular in
      shape and contained segmented nuclei. Azurophilic and specific electron-dense
      granules, mitochondria, glycogen particles, phagosomes and phagolysosomes in
      cytoplasma and characteristic pseudopodia on the cell surface were observed. In
      addition to these normal polymorphonuclear leukocytes, degenerating cells,
      characterized by spherical nuclei, total absence of pseudopodia, merged nuclear
      segments and altered granules, other cellular organelles and plasmalemma were
      present. Two types of macrophages, i.e. vacuolized and non-vacuolized, could be
      distinguished. Typical of the non-vacuolized type was a kidney-shaped nucleus, a
      rich Golgi complex and a large amount of lysosomes in the cytoplasm. The
      vacuolized macrophages contained a large amount of electron-dense vacuoles in the
      cytoplasm. Unlike non-secreting glands, the cell suspensions collected from
      aberrantly secreting juvenile mammary glands contained only vacuolized
      macrophages. The vacuolization results from phagocytosis of corpuscular particles
      of aberrant milk plasma.

PMID- 10652823
TI  - Location of sympathetic postganglionic and sensory neurons innervating the testis
      in the male chicken.
AB  - Sympathetic postganglionic and sensory neurons were labelled by injections of
      horseradish peroxidase into the testis of the male chicken. The total number of
      labelled neurons in the paravertebral, prevertebral, dorsal root and nodose
      ganglia was 943 on average for five chickens. Sympathetic postganglionic neurons
      were located in the paravertebral ganglia T3-LS3 (10% of the total number of
      labelled neurons), especially in T6 and T7, and in the prevertebral ganglia
      adjacent to the adrenal glands and aorta (19%). They were found almost
      ipsilaterally. No labelled neurons were observed in the dorsal motor nucleus of
      the vagus. Sensory neurons were found bilaterally in the dorsal root ganglia T2
      LS3 (71%), especially in T5 to T7. Over a quarter of labelled sensory neurons
      were located in the contralateral dorsal root ganglia. In the nodose ganglia,
      only a few labelled sensory neurons were observed (much less than 1%). These
      results indicate that, unlike the ovary, the testis of the chicken tends to be
      innervated by ipsilaterally located sympathetic postganglionic and sensory
      neurons, with the sensory neurons being more numerous than the sympathetic
      postganglionic neurons.

PMID- 10652824
TI  - Morphology of the intestinal tract in the white rhinoceros (Ceratotherium simum).
AB  - The intestinal tract of the white rhinoceros (Ceratotherium simun) was dissected.
      We observed a simple structure for the small intestine, duodenum, jejunum and
      ileum, and a well-developed large intestine, cecum, colon and rectus. The cecum
      consisted of a small chamber, whereas the colon was much enlarged; notably larger
      than that of the domesticated horse, which belongs to the same order,
      Perissodactyla. This suggests that in the white rhinoceros the cecum may be
      functionally replaced by the well-developed colon which may act as the main
      fermentation tank in this animal.

PMID- 10652825
TI  - [Functional significance of musculature of the external nose in swine (Sus scrofa
      f. domestica)].
AB  - The origin and attachments of the muscles of the external nose were examined in
      17 pigs comprising both sexes and different age groups. The modification of the
      porcine nasal apex to the snout-disc leads to different functional aspects of the
      muscles of the external nose. Accordingly, all these muscles are attached to the
      snout-disc. Only the nasolabial levator and caninus muscles are also attached to
      the upper lip. In addition, the snout-disc includes an intrinsic muscle, the
      nasal muscle. With regard to morphological and functional aspects, the nostrils
      can be divided into two parts. The superficial part consists of muscle and
      connective tissue and is dilated by the cooperative contraction of all muscles of
      the external nose. In contrast, the second and cartilaginous part of the nostrils
      dilates less readily, through contraction of the rostrally located deep fibres of
      the levator nasolabial muscle. As an adaptation for rooting, a special supportive
      system for muscles of the external nose has developed in pigs, including osseous
      (eminentia canina) and muscular (muscular slip of the m. levator labii superioris
      attached to the nasal bone, species-specific development of the m. levator
      nasolabialis) structures. The observed cartilaginous connection between the
      ventral lateral nasal and the vomeronasal cartilages suggests another transport
      mechanism for odours into the vomeronasal organ. Due to this connection, movement
      of the snout-disc and the cartilages of the external nose could imply passive
      movement of the vomeronasal cartilage and therefore of the vomeronasal organ.

PMID- 10652826
TI  - Ultrastructural identification of small granule prolactin (PRL) cells in goat
      adenohypophysis by the colloidal-gold method.
AB  - We describe ultrastructural characteristics of PRL cells with small secretory
      granules, immunostained with ovine antiserum, in adult Murciano-Granadina milking
      goats during anoestrus, the last third of gestation and lactation. This cell
      subtype is considered to comprise a stable population that decreases numerically
      during gestation and lactation, and that may change during these stages to show
      large granules.

PMID- 10652827
TI  - The normal development of Mongolian gerbil foetuses and, in particular, the
      timing and sequence of the appearance of ossification centres.
AB  - To elucidate the normal development and growth of Mongolian gerbils, the timing
      and sequence of the appearance of ossification centres within foetuses were
      investigated. Average foetus body weight and tail length on the 15th day of
      pregnancy were found to be 0.042 g and 6.2 mm, respectively. For the 25th day of
      pregnancy, these measurements were 2.601 g and 29.4 mm, respectively. The body
      weight and tail length of foetuses increased significantly from the 20th day of
      pregnancy. Also, the first ossification centre of Mongolian gerbil foetuses
      appeared in the clavicle at the 17th day of pregnancy. The order in which
      ossification centres appeared in Mongolian gerbils resembles the pattern for rats
      and mice, except in some areas of the skull. Except for the clavicle, in which
      ossification centres appeared rather early, most ossification centres appeared in
      the last quarter of pregnancy. These results suggest that Mongolian gerbil foetal
      development is near completion by the last gestational stage. Also, ossification
      centres appear sooner in the skull and nasal bones than in other rodents.

PMID- 10652828
TI  - Effect of 7-nitroindazole, a selective neuronal nitric oxide synthase inhibitor,
      on parvalbumin immunoreactivity after cerebral ischaemia in the hippocampus of
      the Mongolian gerbil.
AB  - Previous studies have demonstrated that a loss of parvalbumin-immunoreactive (PV
      ir) neurones is observed in the hippocampus after transient cerebral ischaemia.
      However, whether the loss of parvalbumin (PV) immunoreactivity is related to the
      over-production of nitric oxide (NO) during cerebral ischaemia has not been
      evaluated. This study was designed to test the effect of 7-nitroindazole pre
      treatment (7-NI, 50 mg/kg), a selective neuronal NO synthase inhibitor, on PV
      immunoreactivity and its cellular activity following forebrain ischaemia. PV-ir
      neurones in the hippocampus of the control group were widely distributed in the
      pyramidal cell layer and stratum oriens of CA1 and CA3, and the granular cell
      layer of dentate gyrus. 7-NI pre-treatment completely suppressed the reduction of
      PV immunoreactivity in CA1 that was observed in the ischaemia-induced group.
      Subsequently, 7-NI pre-treatment also protected against the structural loss of
      microtubule-associated protein 2 (MAP2) immunoreactivity in CA1 after ischaemic
      insult. In addition, the Fos-defined neuronal activity of PV-ir neurones was
      slightly increased by the 7-NI pre-treatment 3 h after ischaemia. Based on these
      data, we conclude that the neuronal toxicity of NO may be involved in the loss of
      PV-ir neurones after cerebral ischaemia.

PMID- 10652829
TI  - Presence and distribution of neuroendocrine cells in the gastroenteropancreatic
      endocrine system of fallow deer foetuses.
AB  - The gastroenteropancreatic endocrine system was studied in 11- and 17-week-old
      fallow deer foetuses using an immunocytochemical technique. In the
      gastrointestinal tract, gastrin-, serotonin-, somatostatin- and cholecystokinin
      containing cells were found: their frequency and distribution were also
      determined. Anti-glucagon and anti-insulin antibodies did not stain any cells
      along the gut. In the pancreas, somatostatin-, pancreatic polypeptide-, insulin-
      and glucagon-immunoreactive cells were detected. The different distribution and
      number of neuroendocrine cells, in the two investigated stages of foetal life,
      are discussed. Data obtained in this study were compared with those published in
      a previous study on the gastrointestinal system of the adult fallow deer.

PMID- 10652830
TI  - Ultrastructural morphology of the gill of the hybrid striped bass (Morone
      saxatilis x M. chrysops).
AB  - The fine structure of the principal cell types found in the gill filaments and
      secondary, respiratory lamellae of the hybrid striped bass (Morone saxatilis x M.
      chrysops) was studied by transmission electron microscopy. Most of the cell types
      generally resembled those observed at this level of resolution in other
      euryhyaline, teleostean species, and the mucus cells, epithelial cells, and
      cartilage cells were non-distinctive. Pillar cells were atypically flattened
      within the lamellae. The extensive cytoplasmic tubular system of the chloride
      cells was more densely distributed and was less branched than reported for many
      other teleosts. The vascular endothelial cells of the marginal, lamellar blood
      vessels were particularly striking because of their prominent, electron-dense
      cytoplasmic granules. Although the physiological function and chemical
      composition of these granules remain obscure, their presence suggests an
      important role of secretion into the vascular lumen. These gill data from normal
      specimens of this sport and commercial, hybrid species constitute a useful basis
      for interpreting gill changes in diseased striped bass.

PMID- 10652831
TI  - Histochemical study of the distribution of nicotinamide adenine dinucleotide
      phosphate diaphorase (NADPHd)-positive neurons in the chicken caecum.
AB  - The distribution of nicotinamide adenine dinucleotide phosphate diaphorase
      (NADPHd)-positive neurones was investigated in the chicken caecum. Double
      staining combined NADPHd histochemistry with immunohistochemistry for neural
      nitric oxide synthase (nNOS) indicated that NADPHd-positive neurones also showed
      immunoreactivity for nNOS. NADPHd-positive nerve cell bodies were observed in
      both the myenteric and the submucous plexuses. Nerve fibres showing enzyme
      activity were mainly distributed in the circular muscle layer, but only a few
      fibres in the mucosal layer. Fine nerve fibres showing NADPHd activity were found
      running between germinal centres in the caecal tonsil. Quantitative analysis
      showed no significant differences in the number of enzyme-positive nerve cell
      bodies per ganglion of the myenteric and the submucous plexuses among three
      different caecal regions; proximal, middle and distal regions. Larger numbers of
      ganglia were detected in the submucous plexus than the myenteric plexus at all
      three regions. These data indicate that nitrergic neurones in the submucous
      plexus mainly project to the circular muscle layer in the chicken caecum. It is
      possible that nitrergic nerves regulate the motility of the chicken caecum.

PMID- 10652832
TI  - Morphometric study of the beta-cell volume of the canine pancreas with
      consideration of the axis of tissue transection.
AB  - The pancreatic beta-cell volume was assessed in 12 clinically normal crossbred
      dogs using immunohistochemical labelling for insulin and computer-assisted
      morphometric analysis. The beta-cell volume was less in the right lobe compared
      with the body and left lobe, but the beta-cell volume did not differ between the
      body and the left lobe as reported previously. The use of immunohistochemistry,
      computer-assisted morphometry, the inclusion here of extra-islet beta-cells and
      the exclusion of non-beta-endocrine cells in the investigation of the beta-cell
      volume may have contributed to this discrepancy. As most beta-cells form
      irregularly shaped three-dimensional bodies (islets of Langerhans), the effect of
      the plane of tissue transection (sagittal, transverse, oblique) on the
      calculation of the beta-cell volume was also examined. The beta-cell volume in
      the sagittal plane of the right lobe was lower than the volume in the oblique
      plane of the same lobe but was not different from the volume in the transverse
      plane. However, there were no differences in beta-cell volume in different planes
      in the body or left lobe. When quantifying beta-cell volume in health or disease,
      variation in the volume of beta-cells in different locations of the pancreas is
      an important consideration and the plane of transection may also influence
      results.

PMID- 10652833
TI  - [Functional morphology of the large intestinal mucosa of horses (Equus
      przewalskii f. caballus) with special regard to the epithelium].
AB  - The mucous membrane of the caecum and colon ascendens of adult horses was first
      studied using light and transmission electron microscopy. In the surface
      epithelium there was an inconspicuous constellation of organelles, otherwise
      there was a lot of mitochondria as a source of energy for absorptive
      performances. Moreover, enlarged intercellular spaces exist as an indication of
      an increased uptake of water and electrolytes. In the basal region of
      Lieberkuhn's crypts there were single enteroendocrine cells and numerous granules
      in the apical epithelial cytoplasm. The functional meaning of these granules is
      contrarily discussed in the literature. There was no epithelial activity of
      alkaline phosphatase. Against that a small positive reaction of adenosine
      triphosphatase was observed at the lateral plasmalemata of the epithelial cells.
      The sense of these findings with regard to the transport of substances in the
      equine large intestine is discussed.

PMID- 10652834
TI  - Histochemical study of the extensor digitorum longus and soleus muscles in
      alcoholic rats.
AB  - The extensor digitorum longus (EDL) and soleus (SOL) muscle fibres from albino
      rats submitted to experimental chronic alcoholism were evaluated in accordance
      with their metabolic and morphometric profiles. Twenty-seven male animals aged 4
      months and weighing approximately 400 g were used. The animals were divided into
      three groups: control, isocaloric and alcoholic and sacrifices were carried out
      after 5, 10 and 15 months. The muscles were dissected, removed, cross-sectioned
      in a cryostat and submitted to the NADH (nicotinamide adenine dinucleotide)
      reaction. The SO (slow-twitch-oxidative), FG (fast-twitch-glycolytic) and FOG
      (fast-twitch-oxidative-glycolytic) muscle fibre types exhibited a polygonal,
      triangular or rounded shape and did not present noteworthy modifications in
      either muscles during the study. The cross-sectional areas of the fibres from the
      studied muscles did not present significant differences during the observations.
      Fibre area behaved similarly in the alcoholic animals up to the 10th month, i.e.
      it was decreased, as also observed in the other groups. At 15 months, however,
      all fibres were increased, with a predominance of FG fibres in the SOL muscle.
      Changes in fibre population were observed mainly in the SOL muscle of alcoholic
      animals: SO fibres were initially increased in number but decreased after the
      10th month, and the opposite was observed for the population of FG fibres. FOG
      fibres increased linearly in number throughout the experiment. The statistical
      analysis showed nevertheless that the fibre population and cross-sectional area
      changes were not significant. In the alcoholic animals quantitative variations of
      muscle fibres were more evident in the SOL muscle, suggesting that the SOL muscle
      is more sensitive to the toxic action of ethanol. The results concerning the
      increased fibre diameter in alcoholic animals would be associated with muscle
      oedema induced directly or indirectly by the ethanol.

PMID- 10652835
TI  - Immunohistochemical localization of endometrial oestrogen and progesterone
      receptors in the cow.
AB  - The presence and distribution of oestrogen and progesterone receptors have been
      investigated by means of immunohistochemical procedures in the uterus of two
      groups of cows: the first group underwent superovulatory hormonal treatment while
      the second group was used as a control group. After the immunohistochemical study
      no differences regarding the presence and distribution of hormone receptors
      seemed to be apparent between the two groups, so it was concluded that the
      topographical distribution and staining intensity of hormone receptors seem to be
      unaffected by hormonal superovulatory treatment.

PMID- 10652836
TI  - Alternative imaging of the lung.
AB  - This article illustrates the roles of ultrasonography, scintigraphy, and computed
      tomography (CT) as alternative techniques for pulmonary imaging in small animals.
      The advantages and limitations of each modality, normal anatomic features, and
      technical considerations will be discussed. Selected applications will be
      examined and include pulmonary consolidation, neoplasia and other masses,
      atelectasis, pneumothorax, dystrophic mineralization, diffuse infiltrative
      disease, and pulmonary embolism. The use of ultrasound and CT-guided
      interventional procedures will also be briefly discussed.

PMID- 10652837
TI  - Bronchoscopy in small animal medicine: indications, instrumentation, and
      techniques.
AB  - Bronchoscopy is a useful tool in the evaluation and management of canine and
      feline respiratory diseases. Diagnostic indications include the evaluation of
      structural diseases (tracheobronchial collapse, stricture, intraluminal mass);
      inflammatory conditions (chronic bronchitis, pneumonia); and traumatic injuries.
      Several airway-sampling techniques are available with bronchoscopy;
      bronchoalveolar lavage has proved to be the most satisfactory specimen-collection
      technique. Therapeutic indications of bronchoscopy at this time in veterinary
      medicine are mainly limited to foreign body removal. As advances are made in
      veterinary bronchopulmonary medicine, other therapeutic applications of the
      bronchoscope may be realized.

PMID- 10652838
TI  - Diagnostic thoracoscopy.
AB  - Thoracoscopy is a minimally invasive diagnostic technique that provides access to
      the thoracic cavity for evaluation of intrathoracic pathology without surgical
      intervention. Intrathoracic structures can be visualized better with thoracoscopy
      than with an open thoracotomy. Indications for thoracoscopy include pleural
      effusion, pericardial effusion, intrathoracic masses, pneumothorax, primary
      pulmonary disease, and trauma. Thoracoscopy is technically similar to
      laparoscopy, using the same basic instrumentation and principles, but is easier
      to perform than laparoscopy. Patient preparation, anesthesia, and patient
      positioning are essentially the same for thoracoscopy as for a standard open
      thoracotomy. Thoracoscopy provides minimally invasive access to important
      diagnostic information with a very low incidence of complications.

PMID- 10652839
TI  - Collection and interpretation of respiratory cytology.
AB  - Advances in pulmonary cytological sampling have helped establish a more accurate
      diagnosis and better therapeutic choices for the respiratory patient. Choosing
      the appropriate test is necessary to maximize the potential diagnostic yield and
      should be based on the clinical presentation of the patient as well as the
      minimum database. This article describes several methods of collection of
      cytological samples for the canine and feline upper and lower respiratory tracts,
      defines normal respiratory cytology, and discusses normal cytological
      characterization of various respiratory diseases. Categorization of cytological
      findings may aid the clinician in narrowing the potential etiologies for the
      pulmonary disorder. The authors focus on cytological recovery and analysis from
      transtracheal wash (TTW), bronchial brushing, transthoracic lung aspiration
      (TTLA), bronchoalveolar lavage (BAL), and open chest biopsy. Indications,
      complications, and contraindications for each procedure are discussed. Variation
      in expected findings among BAL, TTW, TTLA, and bronchial brushings are described.
      Appropriate sampling technique, transport, and processing are also emphasized.

PMID- 10652840
TI  - Respiratory monitoring: arterial blood gas analysis, pulse oximetry, and end
      tidal carbon dioxide analysis.
AB  - The use of arterial blood gas analysis, pulse oximetry, and capnography has
      become commonplace in the assessment of veterinary patients. Blood gas analysis
      allows for the qualitative and quantitative assessment of both metabolic and
      respiratory acid-base problems, including the interrelationships between
      ventilation, oxygenation, and metabolic conditions. Blood gas analysis is a
      useful adjunct to clinical patient assessment and other diagnostics in
      determining appropriate therapy for specific and complex conditions. Both pulse
      oximetry and capnography are useful monitoring tools. However, they have
      technical limitations and cannot comprehensively evaluate patient oxygenation and
      ventilation. Pulse oximetry and capnography are not replacements for arterial
      blood gas analysis, but rather serve as adjunctive monitoring tools.

PMID- 10652841
TI  - Diagnosis of pulmonary hypertension.
AB  - Pulmonary hypertension may complicate a variety of congenital or acquired cardiac
      and pulmonary conditions. This vascular disorder results from conditions that
      lead to a chronic increase in left atrial pressure, increased pulmonary blood
      flow, or increased pulmonary vascular resistance. Definitive diagnosis requires
      cardiac catheterization and detection of systolic and mean pulmonary artery
      pressures exceeding 30 and 20 mm Hg, respectively. Clinical signs and historical
      complaints reflect underlying cardiac or pulmonary conditions, although syncope
      may be a predominant finding. Radiographic changes are nonspecific; however,
      right ventricular enlargement and enlarged pulmonary arteries should increase
      suspicion for the disorder. Estimates of pulmonary arterial pressure may be
      obtained through Doppler echocardiography. This requires detection of a high
      velocity regurgitant jet across the tricuspid or pulmonic valve. Further
      investigation is required to determine how pulmonary hypertension impacts therapy
      and prognosis for dogs and cats with cardiac and pulmonary diseases.

PMID- 10652842
TI  - Pulmonary function testing in small animals.
AB  - Pulmonary function testing (PFT) may be used to help provide objective
      information concerning the respiratory system in dogs and cats. Available
      techniques for PFT include spirometry, tidal breathing flow-volume loop analysis,
      barometric whole-body plethysmography, dynamic and static compliance, and lung
      and upper airway resistance. The information gained from PFT may help both in
      patient management and also in gaining understanding of the pathophysiology of
      the pulmonary system.

PMID- 10652843
TI  - Comparison of deterministic and stochastic SIS and SIR models in discrete time.
AB  - The dynamics of deterministic and stochastic discrete-time epidemic models are
      analyzed and compared. The discrete-time stochastic models are Markov chains,
      approximations to the continuous-time models. Models of SIS and SIR type with
      constant population size and general force of infection are analyzed, then a more
      general SIS model with variable population size is analyzed. In the deterministic
      models, the value of the basic reproductive number R0 determines persistence or
      extinction of the disease. If R0 < 1, the disease is eliminated, whereas if R0 >
      1, the disease persists in the population. Since all stochastic models considered
      in this paper have finite state spaces with at least one absorbing state,
      ultimate disease extinction is certain regardless of the value of R0. However, in
      some cases, the time until disease extinction may be very long. In these cases,
      if the probability distribution is conditioned on non-extinction, then when R0 >
      1, there exists a quasi-stationary probability distribution whose mean agrees
      with deterministic endemic equilibrium. The expected duration of the epidemic is
      investigated numerically.

PMID- 10652844
TI  - Feedback mechanisms between T helper cells and macrophages in the determination
      of the immune response.
AB  - The interactions between macrophages and T helper (Th) cells are a complex
      interplay of positive and negative signals. Some of the mathematical models of
      interactions between T helpers have indeed taken the influence of macrophages
      into account. In this work the macrophage is not considered as an extrinsic
      agent, that is duly directed by the T cells to be cytotoxic, nor is there
      consideration of T helper cell populations that are dominantly regulated by
      extrinsic properties of antigens per se, or by certain classes of presenting
      cells that preferentially select certain classes of lymphocytes or bias their
      commitment. Rather, a simplified model of feedback loops between Th cells and
      macrophages is formulated and analyzed. It is suggested how the mutual influence
      between Th and macrophages can determine the cytokine secretion pattern of these
      populations. The model provides a feedback scenario to account for experimental
      findings concerning reversal in the dominance of a specific cytokine profile in
      the course of some infections. A possible scenario accounting for the difference
      between the stability of Th1 and Th2 cytokine pattern is put forward. The model
      suggests explanations for the variability in the outcome of the immune response
      according to different body compartments. A rationale is presented that accounts
      for paradoxical findings indicating that Th1 cytokines are sometimes responsible
      for the downregulation of a Th1 dominated response.

PMID- 10652845
TI  - Combinatorics of giant hexagonal bilayer hemoglobins.
AB  - The paper discusses combinatorial and probabilistic models allowing to
      characterize various aspects of spacial symmetry and structural heterogeneity of
      the giant hexagonal bilayer hemoglobins (HBL Hb). Linker-dodecamer configurations
      of HBL are described for two and four linker types (occurring in the two most
      studied HBL Hb of Arenicola and Lumbricus, respectively), and the most probable
      configurations are found. It is shown that, for HBL with marked dodecamers, the
      number of 'normal-marked' pairs of dodecamers in homological position follows a
      binomial distribution. The group of symmetries of the dodecamer substructure of
      HBL is identified with the dihedral group D6. Under natural symmetry assumptions,
      the total dipole moment of the dodecamer substructure of HBL is shown to be zero.
      Biological implications of the mathematical findings are discussed.

PMID- 10652847
TI  - Are large complex ecosystems more unstable? A theoretical reassessment with
      predator switching.
AB  - Multi-species Lotka-Volterra models exhibit greater instability with an increase
      in diversity and/or connectance. These model systems, however, lack the likely
      behavior that a predator will prey more heavily on some species if other prey
      species decline in relative abundance. We find that stability does not depend on
      diversity and/or connectance in multi-species Lotka-Volterra models with this
      'predator switching'. This conclusion is more consistent with several empirical
      observations than the classic conclusion, suggesting that large complex
      ecosystems in nature may be more stable than previously supposed.

PMID- 10652846
TI  - Incorporating observability thresholds of tumors into the two-stage
      carcinogenesis model.
AB  - This paper discusses a general way of incorporating the growth kinetics of
      malignant tumors with the two-stage carcinogenesis model. The model is presented
      using time-homogeneous rate parameters. In that case, the differential equations
      comprising the model are straightforward to solve using standard numerical
      techniques and software. An extension of the method to time-dependent rate
      parameters is included in Appendix A. Allowing the rate parameters to be time
      dependent does incur computational cost. An expression is given for the expected
      time without visible tumor, a generalization of the expected time to an
      observable tumor that includes the possibility of tumor regression. The model is
      illustrated using incidental liver tumor data in control rats from NTP rodent
      carcinogenicity studies, using linear birth-death kinetics of tumors combined
      with a non-absorbing detection limit. The approach is also shown to be
      potentially useful with tumor observability thresholds having more complicated
      features.

PMID- 10652848
TI  - When the feasibility of an ecosystem is sufficient for global stability?
AB  - We show via a Liapunov function that in every model ecosystem governed by
      generalized Lotka-Volterra equations, a feasible steady state is globally
      asymptotically stable if the number of interaction branches equals n-1, where n
      is the number of species. This means that the representative graph for which the
      theorem holds is a 'tree' and not only an alimentary chain. Our result is valid
      also in the case of non-homogeneous systems, which model situations in which
      input fluxes are present.

PMID- 10652849
TI  - [Classification of oral cephalosporins. Expert group of the Paul Ehrlich Society
      for Chemotherapy (PEG)].

PMID- 10652850
TI  - [The analgesia asthma syndrome. Significance, diagnosis and therapy].

PMID- 10652851
TI  - [Nitric oxide (NO) and vascular oxidative stress. Importance in coronary disease,
      hypertension, diabetes mellitus and heart failure].

PMID- 10652852
TI  - [Consequences of measles vaccination. Further goals and extreme reality
      differentiated from each other. Interview by Marianne E Tippmann].

PMID- 10652853
TI  - [Medicine and adolescent health; why this new discipline, for whom and how?].

PMID- 10652854
TI  - [Adolescent sexuality: epidemiology, clinical approach and preventive measures].
AB  - The interest in sexuality of adolescents in medical practice is often mainly
      focussed on the onset of sexual intercourse and on the emergence of contraceptive
      needs, though the beginning of adolescence takes place much earlier with the
      first signs of puberty followed by the menarche. At the issue of this profound
      metamorphosis the adolescent needs to adapt herself to a modified, sexual body.
      Adolescence is also a time of identity development and of changes in
      relationships, which are influenced by gender role in family and perception
      related to gender during childhood. This article shows epidemiological data to
      consider and the main issues of gynaecologic consultation with the adolescent.
      The different stages of development depend on biological and environmental
      factors which either favour resilience or weaken the individual due to a lack of
      affection or to abusive relationships. Medical consultation for a gynaecological
      problem, questions on puberty and development or on contraception give medical
      professionals and especially gynaecologists a chance to address sexual issues
      naturally, to anticipate questions as well as contraceptive needs. The
      consultation with the adolescent includes also the screening for behaviour
      related to a lack of information or a personal or relational difficulty.

PMID- 10652855
TI  - [Sexual counseling during medical consultation with adolescents].
AB  - Family planning has been included in the activities of the Multidisciplinary Unit
      for Adolescent Health, from its opening. The patients can meet the counsellor for
      pure information; more often, they discuss many issues related to their personal
      and sexual life, to contraception or pregnancy, to fertility or sexually
      transmitted diseases, including HIV. All discussions take into account the
      developmental tasks of the adolescent as well as his cultural/ethnic background.
      The originality of this approach is that it is widely integrated in the
      activities of the Unit. For instance, specific situations and issues are
      regularly discussed during weekly multidisciplinary meetings bringing all the
      members of the staff together.

PMID- 10652856
TI  - [A clinical questionnaire for facilitating consultation with the adolescent].
AB  - The use of a self-administered questionnaire, filled in by the adolescent before
      the first encounter with a physician, represents an excellent screening tool. The
      questionnaire is highly confidential and its use is optional. This paper analyses
      the way the questionnaire was accepted and used by 361 young patients, during the
      first year of activity of the Multidisciplinary Unit for Adolescent Health in
      Lausanne. It shows the kind of problems which were reported by the adolescents,
      depending on their gender, their age and their reason for visit. The
      questionnaire serves several purpose: firstly, it outlines the global conception
      of health which forms the basis of the multidisciplinary approach used within the
      UMSA. Secondly, it constitutes a kind of guide for younger physicians training in
      adolescent medicine and allows them to screen in an appropriate period of time a
      large array of themes pertaining to health problems and symptoms, mental health,
      well-being, lifestyles and finally personal as well as environmental resources.
      Finally, it allows the young patient to disclose preoccupation or problems on
      very personal, intimate matters, which would be difficult to discuss openly in a
      first face to face interview. The experience gained during nine months shows that
      the questionnaire is very well accepted and useful. It's content will however be
      improved, since, in the opinion of both the patients and the staff, it still is
      too much focused on negative and problematic issues and not enough oriented
      towards resources and resilience.

PMID- 10652857
TI  - [Depression and suicidal risk in adolescents: detection, evaluation and
      management].
AB  - The frequency of depressive symptoms and disorders during adolescence, with its
      associated suicidal risks, constitutes a major public health problem. This paper
      discusses the problems linked with the assessment and diagnosis of various
      depressive disorders and underlines the fact that quite often, depression among
      adolescents is underestimated, so that its short and long term consequences,
      particularly in terms of suicidal conducts are completely overlooked. The
      discussion offers various approaches which should enable practising physician to
      better address this important issue.

PMID- 10652858
TI  - [The practitioner's office as a place for preventive measures for adolescents].
AB  - During adolescence, health care and health prevention activities are closely
      linked. In his office, every physician can have an impact on his young patients'
      health in different ways: screening for unmet health needs, increasing this
      adolescent's compliance in providing him with adequate information, discussing
      the consultant's behaviour and lifestyles, etc. Routine examinations (like before
      sports camp or entry into apprenticeship) represent excellent opportunities for
      such preventive activities. Finally, in this activity, the physician should
      evaluate and make use of his patient's resources; as well, he should not
      underestimate the impact of the adolescent's environment (climate in the family,
      social environment, working conditions, etc.).

PMID- 10652859
TI  - The ECHO outbreak of 1998.

PMID- 10652860
TI  - Hospice care in South Dakota: half-way there.

PMID- 10652861
TI  - State of South Dakota's child: 1999.
AB  - The Surgeon General's Year 2000 health goals for the nation are presented and
      data from South Dakota and the United States that measure progress toward
      achieving them are discussed. The percentage of low-birth weight babies (LBW) in
      South Dakota is lower than observed nationally, but, similar to the national
      trend, has increased in the past few years. Between 1996-1998, 1.1% of all
      newborns in the state weighed less than 1500 grams, and 5.7% weighed less than
      2500 grams. There has been continuing progress observed in the survival rate of
      the very low birth weight infant. In 1996 the state experienced a precipitous
      drop in its infant mortality rate (IMR) that has not been sustained in the past
      two years. The state's 1998 IMR of 9.0 per 1000 live births, however, is less
      than the mean rate of 10 that persisted over the previous decade. The IMR for
      white babies (5.7) has achieved the Year 2000 Goal. The rate of Sudden Infant
      Death in South Dakota is significantly higher (p < .001) than that observed
      nationally and speaks to the importance of placing babies on their backs to sleep
      and education regarding the risks associated with exposing a fetus and baby to
      smoking. The special topic of this year's report is breast-feeding. The benefits
      of breast-feeding to babies and mothers are described, as well as the need for it
      to be advocated by the health care community. This advocacy must emphasize breast
      feeding's importance, how women can be assisted as they begin to nurse, and how
      community efforts can be taken to enable breast-feeding continuation when women
      return to work following delivery.

PMID- 10652863
TI  - Epidemiology of physical and sexual abuse in young persons diagnosed with conduct
      disorder: a retrospective chart review.
AB  - The purpose of this study was to examine the existence of a history of physical
      and/or sexual abuse in adolescents diagnosed with Conduct Disorder. A
      retrospective chart review was undertaken at a Midwestern inpatient mental health
      facility. Files of adolescents diagnosed with Conduct Disorder, and who were
      admitted to this inpatient facility in 1995, were reviewed (n = 18). Fisher's
      exact probability tests were performed comparing the data gathered with
      statistics compiled by the U.S. Department of Health and Human Services (1998).
      The results suggest that the frequency of physical and sexual abuse is
      significantly greater than rates for the population at large. Implications for
      future research are discussed.

PMID- 10652862
TI  - Low molecular weight heparins in acute coronary syndrome.

PMID- 10652864
TI  - Perceiving musical tension in long chord sequences.
AB  - We attempted to predict perceived musical tension in longer chord sequences by
      hierarchic and sequential models based on Lerdahl and Jackendoff's and Lerdahl's
      cognitive theories and on Parncutt's sensory-psychoacoustical theory. Musicians
      and nonmusicians were asked to rate the perceived tension of chords which were
      drawn either from a piece composed for the study (Exp. 1) or from a Chopin
      Prelude (Exps. 2-4). In Exps. 3 and 4, several experimental manipulations were
      made to emphasize either the global or the local structure of the piece and to
      verify how these manipultions would affect the respective contribution of the
      models in the ratings. In all experiments, musical tension was only weakly
      influenced by global harmonic structure. Instead, it mainly seemed to be
      determined locally, by harmonic cadences. The hierarchic model of Lerdahl and
      Jackendoff provided the best fit to tension ratings, not because it accounted for
      global hierarchic effects, but because it captured the local effect of cadences.
      By reacting to these local structures, tension ratings fit quite well with a
      hierarchic model, even though the participants were relatively insensitive to the
      global structure of the pieces. As a main outcome, it is argued that musical
      events were perceived through a short perceptual window sliding from cadence to
      cadence along a sequence.

PMID- 10652865
TI  - Perceptual causality in the amodal completion of kinetic structures.
AB  - Perceptual causality as an amodal completion of kinetic structures was
      demonstrated. The experimental situation was as follows: a square appeared on the
      left, moved from left to right till it touched one side of a stationary rectangle
      (a perceptual screen), and disappeared; after a while, another square appeared at
      the other side of the rectangle and moved right. The first square moved faster
      than the second one. Sometimes, two moving objects were perceived, with an amodal
      launching effect: the first moving object seemed to collide with the second one
      behind the screen. When both the screen and the occluding interval were small,
      despite the discrepancy of velocities, a single moving object was perceived, but
      the object seemed to abruptly change its speed behind the screen. The perception
      of an amodal completion of movement raises some theoretical issues: the
      discrepancy between amodal completion of kinetic structures and that of static
      ones, the problem of perceptual identity, and figure-ground segregation in
      dynamic scene. The dilemma of the naive subject will also be discussed.

PMID- 10652866
TI  - Neither strong nor weak space constancy is coded in striate cortex.
AB  - Space constancy (the perception that the world remains stable despite eye
      movements) might be mediated by receptive fields with constant locations in the
      world rather than constant locations on the retina. In a strong form the
      hypothesis, receptive fields of single neurons would compensate for all eye
      movements, whereas in a weak form they would compensate only for the small
      movements of fixation that occur without retargeting. Early receptive field
      mapping confounded world-centered and retina-centered organizations by fixing the
      retina relative to the world. This paper links the strong and weak forms of
      constancy by relating previously isolated data, and illustrates the issues with a
      previously unpublished figure showing that striate receptive field have constant
      retinal locations. The first tests of space constancy in striate cortex
      contradicted the strong hypothesis; recent tests contradict the weak hypothesis,
      also. The results are consistent with modern theories of space constancy,
      differentiating between motor-oriented and perceptual functions of vision, and
      differentiating between constancy during pursuit and constancy across saccades.

PMID- 10652867
TI  - Central response selection is present during memory scanning, but hand-specific
      response preparation is absent.
AB  - Two experiments were performed to replicate the results of Ilan and Miller that
      response selection but no response-hand specific preparation is present during
      memory scanning. Letter-case determined which hand would respond, while memory
      set membership status determined whether the response was to be executed (go) or
      withheld (nogo). In Exp. 1, the LRP was observed as an index of response-hand
      specific preparation. In Exp. 2, the consistency effect derived from the response
      priming paradigm was observed as an index of more central response selection. The
      results replicate those of Ilan and Miller and suggest that central response
      selection is present during short-term memory scanning, but hand-specific
      response preparation is absent. Apparently, preliminary information is
      transmitted to the response selection stage during memory scanning, a finding
      that is inconsistent with serial stage models, but memory scanning interferes
      with hand-specific response preparation.

PMID- 10652868
TI  - [Traditional nursing instructor and teacher?].

PMID- 10652869
TI  - [New stakes in public health. Interview by J.F. Ploska.]].

PMID- 10652870
TI  - [Antidiabetic agents].

PMID- 10652871
TI  - [Caring for a patient with type 2 diabetes mellitus].

PMID- 10652872
TI  - [Education of the diabetic patient].

PMID- 10652873
TI  - [Interview with a teaching nurse].

PMID- 10652874
TI  - [Nutrition of diabetic patients].

PMID- 10652875
TI  - [The House of Diabetes in Marcq-en-Baroeul].

PMID- 10652876
TI  - [Tools for surveillance of diabetes mellitus].

PMID- 10652878
TI  - [Diabetes mellitus].

PMID- 10652877
TI  - [Emergency situations: hyperglycemia with ketonuria].

PMID- 10652879
TI  - [Temperature comfort and fever or searching for well-being].

PMID- 10652880
TI  - [Antiretrovirus therapies: tools to help comprehension and compliance].

PMID- 10652881
TI  - [The functions of a nurse anesthetist].

PMID- 10652882
TI  - Anaesthesia: past, present and future.

PMID- 10652883
TI  - Is spinal anaesthesia safe in pre-eclamptic toxaemia patients?
AB  - Thirty-three patients of pre-eclamptic toxaemia underwent caesarean section (CS)
      under general anaesthesia (n = 16) and spinal anaesthesia (n = 17). The Apgar
      score at 1, 5 and 10 minutes of the babies following spinal anaesthesia (SA) were
      only marginally better than that of general anaesthesia (GA; P > 0.05). The
      incidence of complication following GA (68.8%) were significantly (P < 0.05) more
      than that of SA (47.1%). Commonest complications following GA were intra
      operative hypertension (68.8%) followed by difficult intubation (25%), pulmonary
      oedema (12.8%), delayed recovery (12.8%) and mortality (4.3%). While following SA
      complications were intra-operative hypotension (47.1%), difficult SA (29.4%) and
      intra-operative vomiting (5.9%). The nature of complications following GA were
      more serious which may even lead to mortality (4.3%), whereas following SA it was
      less serious and easily manageable. Hence SA is not as unsafe as it is thought.

PMID- 10652884
TI  - Inguinal herniorrhaphy under local anaesthesia and spinal anaesthesia--a
      comparative study.
AB  - A prospective study was conducted at JIPMER, Pondicherry from September 1993 to
      June 1995. Fifty cases of inguinal herniorrhaphy were done under local
      anaesthesia (LA) and 60 cases under spinal anaesthesia (SA). The aim was to
      assess the safety and efficacy of inguinal herniorrhaphy under LA. The parameters
      studied were: (i) Efficacy of the anaesthesia, (ii) safety and postoperative
      course, and (iii) patient satisfaction. The LA group patients had better
      postoperative analgesia and earlier return to ambulation. They did not suffer the
      postspinal complications of headache and urinary retention. However, intra
      operative discomfort was significantly more in this group compared to the SA
      group.

PMID- 10652885
TI  - Victims of road accidents--assessment and management at field.

PMID- 10652886
TI  - Role of anaesthesiologist in the management of acute poisoning.

PMID- 10652887
TI  - Oxygen therapy.

PMID- 10652888
TI  - Peri-operative fluid therapy.

PMID- 10652889
TI  - Cancer pain--current modalities of management.

PMID- 10652890
TI  - Common postoperative complications.

PMID- 10652891
TI  - Evaluation of kidney functions and cyclosporine levels in renal transplant
      patients on Panimum Bioral in post transplant period.
AB  - A retrospective analysis of the patients being given Panimun Bioral
      (microemulsion cyclosporine) after renal transplantation was done at IKRDC,
      (Institute of Kidney Diseases & Research Centre), Ahmedabad. A total of 21
      patients were included for analysis. Patients were evaluated for various
      parameters e.g. weight, cyclosporine levels, S. Creatinine and BUN at three time
      schedules as 0 to > or = 30 days, > 30 to > or = 60 days and > 60 to 120 days
      after renal transplantation. The analysis of data obtained indicates the kidney
      function tests improved in these patients and therapeutically safe blood
      cyclosporine levels were achieved in all the three timeschedules.

PMID- 10652892
TI  - Will active ageing make the difference?

PMID- 10652893
TI  - 1999: the international year of the older persons.

PMID- 10652894
TI  - Comparison of therapeutic efficacy of nimesulide and diclofenac in patients with
      degenerative joint diseases.
AB  - The efficacy and tolerability profiles of nimesulide and diclofenac were
      evaluated in 180 patients suffering from various degenerative joint diseases. The
      clinical evaluations were performed at 0, 2 and 4 weeks. Nimesulide (100 mg)
      tablets were administered twice daily and diclofenac (50 mg) tablets were
      administered thrice daily. The principal efficacy parameters were the improvement
      in pain assessed through verbal scoring. Evaluation of tolerance was also
      established through similar method. Final judgment on efficacy was made by the
      physician. In all evaluations nimesulide showed improved efficacy parameters over
      diclofenac.

PMID- 10652895
TI  - Clinical and laboratory profile of diabetes in elderly.
AB  - India is amidst a demographic transition showing an ageing trend. This will
      increase non-communicable diseases including diabetes which is already showing an
      increasing trend. With scanty literature existing on elderly diabetics (> 60
      years of age), it was decided to study the clinico-laboratory and complication
      profile of this group of patients. Fifty consecutive elderly diabetics were
      studied and evaluated for ECG, chest x-ray, blood sugar, urea, creatinine, lipid
      profile, proteinuria, motor nerve conduction velocity and autonomic neuropathy.
      Duration of diabetes varied from one month to 28 years. Fifty-six per cent of the
      patients presented with classical symptoms of polyuria, polyphagia and
      polydipsia. Hypertension was present in 40% and cataract in 54% of the patients.
      Eighteen per cent were obese, 52% had evidence of peripheral neuropathy while 56%
      had autonomic neuropathy. Background diabetic retinopathy was present in 56%, pre
      proliferative retinopathy and maculopathy in 4% each; hypertensive retinopathy in
      10% of patients; 44% had microproteinuria and 8% had chronic renal failure.
      Hypercholesterolaemia was present in 64% and hypertriglyceridaemia in 42% of the
      patients with 26% having coronary artery disease. Sixty per cent were harbouring
      infections--20% had foot infections, 14% had tuberculosis and 10% had urinary
      tract infections. Ninety-two per cent of the patients were aware of their disease
      but 62% were not aware of the complications and of the need for strict dietary
      and drug compliance. There was a high prevalence of associated diseases viz,
      osteoarthritis, cataract, hypertension, hepatitis and parkinsonism. Therefore,
      this study brings out the need to have a holistic and multidisciplinary approach
      for management of elderly diabetics who constitute a heterogeneous group with
      distinct health care problems.

PMID- 10652896
TI  - Physiological and psychological effects of ageing in man.
AB  - A cross-sectional study involving men in various age groups was carried out to
      evaluate some of the physiological and psychological correlates responsible for
      functional alteration with advancement of age. Each group consisted of 20
      soldiers. Their resting physiological variables, lung function parameters,
      psychophysiological tests, and different mental functions were studied in
      thermoneutral laboratory. The results revealed the age related decline in various
      physiological and psychological functions.

PMID- 10652897
TI  - The eye in old age.

PMID- 10652898
TI  - Ageing: exploding the myths.

PMID- 10652899
TI  - Promotion of healthy ageing--the challenge of the next century.

PMID- 10652900
TI  - Practical issues in geriatric psychopharmacology.
AB  - In summary, clinicians must consider multiple changes in the absorption,
      distribution, metabolism, and elimination of psychotropic drugs among older
      patients. Lower starting doses (often one-quarter to one-half the usual adult
      dose) is advisable, with slow dosing adjustments (no sooner than every 5 to 7
      days) as needed. The time required to see steady-state therapeutic levels, or for
      elimination of most medications, are substantially longer in the elderly. One
      must consider the potential for drug-drug interactions, as well as anti
      cholinergic or other side-effects, when prescribing a regimen. Changes should be
      made slowly, changing only one variable at a time, in order to achieve best
      results.

PMID- 10652901
TI  - Ampullary carcinoma in the elderly.

PMID- 10652902
TI  - You can delay ageing.

PMID- 10652903
TI  - Population ageing: a public health challenge.

PMID- 10652904
TI  - Changing trends in hypertension.

PMID- 10652905
TI  - Hypertension in India--definition, prevalence and evaluation.
AB  - High blood pressure (BP) is an important cardiovascular risk factor. Hypertension
      experts still debate on the level of BP considered abnormal. The currently
      accepted dividing line is systolic BP > or = 140 mm Hg and/or diastolic BP > or =
      90 mm Hg based on epidemiological and intervention studies. In India,
      hypertension has become a major health problem. Epidemiological studies show a
      steadily increasing trend in hypertension prevalence over the last 40 years, more
      in urban than in the rural areas. This is converse to findings reported from
      developed countries where there is a significant decrease in its prevalence.
      Objectives of clinical evaluation of hypertensive individual are: To establish
      that BP is elevated, to seek evidence for a causal or contributory factor which
      may influence management, to assess target organ involvement and to assess
      relevant factors which will influence the particular mode of treatment to be
      adopted. Proper measurement techniques are important for diagnosis of
      hypertension. Canadian Coalition Guidelines are important in this regard. A
      basic, simple screening programme is the most appropriate policy for
      investigating the majority of hypertensive patients. Assessment of target organ
      involvement is important and can be obtained from history, physical examination
      or investigations. Studies of hypertension in general population have shown that
      secondary hypertension with high BP is present in 1.1% to 5.7% of subjects.
      Investigating all the hypertensive patients for secondary hypertension is not
      cost-effective and should be guided by history and clinical examination.

PMID- 10652906
TI  - Hypertensive heart disease.
AB  - Hypertensive heart disease (HHD) is a common problem in clinical practice. Left
      ventricular hypertrophy (LVH) is pathognomonic of HHD. Echo-Doppler study is the
      modality of choice to document cardiac involvement in hypertension. 'Radiology of
      chest and electrocardiography (ECG) are highly insensitive. Magnetic resonance
      imaging (MRI) produces similar results like echo but is not cost-effective. LVH
      is not merely related to haemodynamic load but several other factors are also
      involved in its genesis. LVH is a powerful and independent prognostic determinant
      for future cardiovascular and coronary events. LVH can be regressed by drugs but
      the aim in future should be prevention of LVH rather than its regression.

PMID- 10652907
TI  - Hypertension, insulin resistance and atherosclerosis.
AB  - Hypertension, in a sizable number of patients, though not all, is associated with
      and possibly caused by insulin resistance. The later is also associated with a
      cluster of other risk factors of atherosclerosis and coronary artery disease,
      namely, obesity, glucose intolerance with or without overt diabetes,
      hypercholesterolaemia, low high density lipoprotein (HDL), hypertriglyceridaemia,
      hypercoagulability, etc. Currently, all these disorders are together called
      insulin resistance syndrome (IRS) as insulin resistance is the common denominator
      of these abnormalities. The clinicians should identify the individuals who are at
      risk or already have manifestations of IRS, especially among the hypertensives,
      and direct their antihypertensive therapy to improve insulin sensitivity and to
      minimise atherosclerotic coronary heart disease.

PMID- 10652908
TI  - Hypertension and the kidneys--inter-relationship and therapeutic approach.
AB  - Over the last decade, a great body of evidence has pointed towards the role of
      kidneys in the genesis and maintenance of a hypertensive state. There exists a
      relationship between a rise in the blood pressure and a proportionate increase in
      the urinary excretion of sodium and water called the pressure-natriuresis curve.
      Chronic renal diseases are the most common causes of secondary hypertension
      accounting for 2-5% of all cases of secondary hypertension. The prevalence rate
      of renovascular hypertension based upon referral patterns range from 0.2% to 10%
      of hypertensive population. The data provided by the International Registries on
      end-stage renal disease have suggested that essential hypertension is an
      important cause of progressive renal damage. The pathological lesion observed in
      malignant hypertension is fibrinoid necrosis of the small arteries and
      arterioles. Amongst the armamentarium of antihypertensive drugs calcium channel
      antagonists and the angiotensin converting enzyme inhibitors have a role in
      limiting glomerular hypertension. The best modality to prevent and treat renal
      dysfunction in the presence of hypertension is an adequate and effective control
      of high blood pressure.

PMID- 10652909
TI  - Hypertension in elderly--an overview.
AB  - Hypertension (HT) is a common disease in elderly. It has different
      pathophysiologic, clinical and therapeutic implications in this age group. Due to
      loss of arterial wall elasticity with age, major vessels including aorta become
      stiff and less distensible. As age advances, these stiff vessels also lose beta
      adrenergic responsiveness with unchanged alpha adrenergic responsiveness. These
      together raise peripheral vascular resistance and aortic impedance which needs a
      powerful systolic ejection of left ventricle to maintain cardiac output. Result
      is rise in systolic blood pressure (SBP) and increase in left ventricular (LV)
      mass with compromised cardiac output and renal blood flow. Participation of renin
      angiotensin system and kidney in HT pathogenesis in elderly are minimum.
      Diagnosis of HT in elderly is made if SBP > 140 mm Hg and/or diastolic blood
      pressure (DBP) > 90 mm Hg or is taking antihypertensive medications. Isolated
      systolic hypertension (ISH) means SBP > 140 mm Hg with DBP < 90 mm Hg.
      Measurement of blood pressure (BP) is problematic, mainly due to pseudo HT,
      postural hypotension and white-coat HT. HT in absence of end organ changes
      suggest pseudo HT. Postural hypotension must be detected and treated.
      Systolodiastolic HT, carried over from middle age is the commonest type of HT in
      elderly. ISH is also common (10%). Atherosclerotic renovascular disease can cause
      secondary HT. Therapy is always needed in HT in elderly. Chance of coronary
      artery disease (CAD) and cerebrovascular accident (CVA) are quite high amongst
      elderly hypertensives. SBP is more dangerous than DBP. Benefits of therapy are
      more when compared to young. HT should be treated if SBP > 160 mm Hg and/or DBP >
      90 mm Hg. ISH needs therapy if SBP > 160 mm Hg. The benefits of therapy becomes
      less after 80 years. Treatment goal should be to keep BP below 140/90 mm Hg.
      Therapy should be gradual and stepwise. Na-restriction should be modest.
      Diuretics (e.g., thiazide 25 mg/day) are the drug of choice unless contra
      indicated. Beta blockers are inferior agents compared to diuretics unless angina
      or acute myocardial infarction (AMI) is present. Angiotensin converting enzyme
      (ACE) inhibitors are drug of choice only if congestive cardiac failure (CCF)
      and/or diabetes is present or other drugs are contra-indicated. Calcium entry
      blockers (CEB) are new but very good alternative to diuretics in elderly. Due to
      abnormal physiology, pharmacokinetics and drug interactions, side-effects are
      very common in elderly. They should be detected early and treated.

PMID- 10652910
TI  - Refractory hypertension--assessment and management.
AB  - The assessment of refractory hypertension consists of excluding causes such as
      invalid blood pressure measurement excessive salt intake, poor compliance with
      drugs, inadequate treatment, adverse drug effects and interactions, target organ
      damage (kidney) and secondary form of hypertension. The management plan includes
      control of salt and calories, adjusting the diuretic, re-evaluating the drug
      regimen, management of secondary hypertension and frequent evaluation and a good
      rapport with the patient.

PMID- 10652911
TI  - Principles of drug therapy in hypertension.
AB  - The most difficult diagnosis in medicine is the diagnosis of hypertension. Since
      this label encompasses many maladies both known (secondary hypertension), and the
      unknown, the office recording of blood pressure alone will not suffice to warrant
      treatment with drugs right away. There are more than 6 major guidelines in the
      world about the rules of the game of drug therapy in hypertension. The present
      preoccupation with newer drugs as first line antihypertensive drugs would ruin
      any economy, if the exchequer is to foot the bill. The stress in drug treatment
      has been the step-care mode of drug therapy where one starts with one drug in
      small doses, building the dose gradually, adding the next drug to get cumulative
      power to lower the pressure. Since the early seventies, the need to step-down
      therapy is being stressed wherein the doctor starts cutting down the drugs and
      the dosage, once he achieves the desired blood pressure levels. Diuretics and
      beta-blockers should be the first choice when drugs are indicated, unless there
      are positive indications for other drugs, or the first line drugs are contra
      indicated. Routine treatment with drugs is recommended by the American JNC for
      people with sustained blood pressure above 140/90 mm Hg, but the British
      recommendations put the cut off at the pressure level of 160/100 mm Hg. Indian
      patients respond to very small doses in the beginning. The Hypertension Optimal
      Treatment (HOT) study failed to demonstrate a significant difference between the
      3 randomised target blood pressure groups for the majority of cardiovascular
      events, although it did prove the theoretical hypothesis, that more vigorous
      treatment could certainly bring down the measured blood pressure to greater
      extent in 90% of patients I Greater importance will be given in the future for
      the non-pharmacological approaches, as well as to baseline blood pressure values,
      at which drug treatment should be started.

PMID- 10652912
TI  - A review of absorption characteristics of microemulsion cyclosporine products
      over the last 2 years in Indian subjects.
AB  - Microemulsion based cyclosporine has demonstrated better absorption with lesser
      pharmacokinetic variability. For the clinical use of any new microemulsion based
      product, bioequivalence testing with existing formulation is necessary. Panimun
      Bioral (Test) and Sandimmun Neoral (Reference) were evaluated in different
      transplant centers using both volunteers as well as renal transplant patients.
      All these centers have reported that both products are bioequivalent. These
      reports offer the physician an option to convert the patients to the Test product
      for economic reasons.

PMID- 10652913
TI  - Two-dimensional and three-dimensional imaging of gastric tumors using spiral CT.

PMID- 10652914
TI  - MR imaging of advanced gastric cancer: comparison of various MR pulse sequences
      using water and gadopentetate dimeglumine as oral contrast agents.
AB  - BACKGROUND: To evaluate clinical usefulness of oral contrast agents
      (gadopentetate dimeglumine and water) and to assess proper magnetic resonance
      (MR) imaging in evaluating advanced gastric cancer (AGC) by comparing different
      MR imaging techniques. METHODS: Fifteen patients with AGC were imaged with a 1.0
      T MR imager and body-array coil. All patients underwent surgery or laparascopic
      biopsy. Fast low-angle shot (FLASH), half-Fourier single-shot turbo spin-echo
      (HASTE), and true fast imaging with steady-state precession time (FISP) images
      were obtained after ingestion of 900 mL tap water in each patient, followed by
      postcontrast FLASH images after additional ingestion of gadopentetate dimeglumine
      (Gd-DTPA). Qualitative analysis including T-staging of AGC and scoring of imaging
      quality and quantitative analysis were performed prospectively. RESULTS: In image
      quality and diagnostic accuracy of T-staging, FLASH imaging showed results
      slightly superior to those of other imaging modalities, and there was no great
      difference between using water and Gd-DTPA as an oral contrast agent. As for
      cancer-to-gastric lumen contrast-to-noise ratio (CNR), HASTE and true FISP
      imaging were superior to FLASH imaging with Gd-DTPA (p < 0.0001). In cancer-to
      pancreas CNR, FLASH imaging without Gd-DTPA showed the best result. CONCLUSIONS:
      The use of Gd-DTPA as a positive contrast agent may not be imperative, and T1
      weighted FLASH imaging in combination with true FISP imaging with ingestion of
      tap water can be very useful in evaluating AGC with MR imaging.

PMID- 10652915
TI  - Value of the dynamic and delayed MR sequence with Gd-DTPA in the T-staging of
      stomach cancer: correlation with the histopathology.
AB  - BACKGROUND: To evaluate the usefulness of dynamic and delayed magnetic resonance
      (MR) imaging in the T-staging of stomach cancer and to compare the enhancement
      pattern of the cancerous lesion and the normal wall. METHODS: We performed MR
      imaging in 46 patients with stomach cancer (including four early gastric cancers
      and 42 advanced gastric cancers). Axial, sagittal, or coronal two-dimensional
      fast low-angle shot) MR images for the water-distended stomach were obtained with
      dynamic protocol, including precontrast images and images obtained 30, 60, 90,
      and 240-300 s after intravenous injection of the 0.1 mM Gd-DTPA/kg solution. We
      evaluated the thickness, interruption (or not) of the low signal intensity bands,
      and enhancement pattern of the cancerous wall and normal gastric wall. We
      prospectively evaluated the depth of cancer invasion, perigastric infiltration
      (extraserosal invasion), perigastric organ invasion, and regional lymph nodes and
      determined tumor staging on MR images. These MR evaluations including MR
      determined staging were correlated with the surgicopathologic findings. RESULTS:
      Stomach cancer was shown as having a thickened wall with a rapid enhancing
      pattern after intravenous Gd-DTPA administration. The mucosa (and/or submucosa)
      affected by stomach cancer showed an early enhancement pattern (30-90 s after Gd
      DTPA administration) in 43 of 46 patients (93%). The normal gastric mucosa
      demonstrated a delayed peak enhancement pattern (> 90 s after Gd-DTPA
      administration) in 29 of 46 patients (63%) and variable enhancement pattern in 17
      of 46 patients (37%). An interrupted low signal intensity band or highly enhanced
      tumorous lesion penetrating through the gastric wall was seen in 17 of 19 pT3
      patients (90%). Consistency between MR-determined staging and surgicopathologic
      staging occurred in three of four pT1 tumors (75%), 10 of 13 pT2 tumors (77%), 17
      of 19 pT3 tumors (90%), and eight of 10 pT4 tumors (80%); overall accuracy was
      83%. Overall accuracy of regional lymph node involvement, as determined by
      enhanced MR, was 52%; 24 of 46 node groups were positive. CONCLUSIONS: Dynamic
      and delayed MR imaging can be useful for predicting depth of cancer invasion,
      perigastric infiltration (extraserosal invasion), and perigastric organ invasion
      by gastric cancer.

PMID- 10652916
TI  - Detection of lymph-node metastases in patients with gastric carcinoma: comparison
      of three MR imaging pulse sequences.
AB  - BACKGROUND: To compare the diagnostic accuracy of magnetic resonance (MR) images
      obtained with three different pulse sequences for lymph-node metastases in
      patients with gastric cancer. METHODS: T1-weighted spin-echo (SE), breath-hold T2
      weighted fast SE, and triphasic gadolinium-enhanced dynamic gradient-recall-echo
      (GRE) MR images obtained in 16 patients with gastric carcinoma were
      retrospectively reviewed. Regional lymph nodes were assigned to four different
      groups, and image review was conducted on a lymph-node group-by-group basis; 64
      lymph-node groups were reviewed by two radiologists. Relative sensitivity,
      specificity, and accuracy were determined based on the findings with definitive
      surgery and follow-up imaging. Diagnostic accuracy was determined by means of
      receiver-operating-characteristic (ROC) analysis. RESULTS: Relative sensitivities
      for lymph-node metastases with T1-weighted SE, breath-hold T2-weighted fast SE,
      and dynamic GRE images were 61%, 94%, and 59%, respectively. Relative sensitivity
      with breath-hold T2-weighted fast SE images was significantly greater than that
      with T1-weighted SE (p < 0.05) and dynamic GRE (p < 0.05) images. Diagnostic
      accuracy determined by ROC analysis was marginally higher with breath-hold T2
      weighted fast SE (area under ROC curve [Az] = 0.87) than with T1-weighted SE (Az
      = 0.78, p = 0.08) and dynamic GRE (Az = 0.79, p = 0.12) images. CONCLUSION:
      Breath-hold T2-weighted fast SE sequence is useful in the detection of regional
      lymph-node metastases in patients with gastric carcinoma.

PMID- 10652917
TI  - Hydro-MRI for the visualization of gastric wall motility using RARE magnetic
      resonance imaging sequences.
AB  - BACKGROUND: Although different imaging techniques such as conventional X-ray,
      ultrasonography, and hydro-computed tomography are available for the imaging of
      the stomach, none can depict this organ in full size without radiation.
      Therefore, the study of the entire gastric wall motility of the stomach is
      difficult and in principle only performable with rapid magnetic resonance imaging
      (MRI) techniques. T1-weighted imaging sequences have been used for the dynamic
      study of gastric wall motility. This technique was combined with the oral intake
      of para- or superparamagnetic contrast agents to achieve sufficient intraluminal
      contrast. The technique described in the present study is based on a different
      contrast mechanism. METHODS: The stomach was filled with 500 mL of 10% of aqueous
      dextrose solution, and a strongly T2-weighted fast rapid acquisition with
      relaxation enhancement (RARE) type imaging sequence was used for data
      acquisition. No other contrast agents were applied. An ultrafast RARE imaging
      sequence with an asymmetric phase-encoding scheme was developed to achieve a high
      temporal and spatial resolution. The scanning time per image was approximately 1
      s. RESULTS: The stomach was imaged in full size. The concentric constrictor rings
      moved from the proximal part of the body toward the antrum. The mean duration for
      one contraction cycle was approximately 17.9 +/- 2.5 s, the mean contractile
      frequency was 3.4 +/- 0.5 s, and the mean spreading velocity was 65.5 +/- 3.6
      cm/min. CONCLUSIONS: The purpose of this study was to demonstrate a new technical
      approach for a noninvasive dynamic study of gastric motor function with hydro
      MRI. This robust method may have clinical application, e.g., in the diagnosis of
      gastroparesis, and may be extended to the rest of the gastrointestinal tract.

PMID- 10652918
TI  - Effects of butter and soybean oils on solid-phase gastric emptying in patients
      with functional dyspepsia.
AB  - BACKGROUND: To determine whether vegetable fats cause a slower or quicker rate of
      gastric emptying (GE) than animal fats, we evaluated the effect of animal butter
      and vegetable soybean oil on solid-phase GE in patients with functional
      dyspepsia. METHODS: Twenty-seven patients with functional dyspepsia were enrolled
      in this study. Radionuclide-labeled solid meals were used to evaluate GE. A study
      meal was composed of 206.8 kcal to 9.2 g protein, 45 g carbohydrate, and 10 g fat
      (formula 1, with animal butter: 26.2% saturated palmitic acid, 29.1% unsaturated
      oleic acid, 3.5% linoleic acid, and 0.5% linolenic acid; formula 2, with
      vegetable soybean oil: 11.0% saturated palmitic acid, 23.4% unsaturated oleic
      acid, 53.7% linoleic acid, and 7.8% linolenic acid). Each patient received
      formulas 1 and 2 as study meals on separate days. GE was represented by the
      gastric retention ratio of the study meal at 90 min (RR90): RR90 = residual
      radioactivity within the region of interest (ROI) covering the entire stomach at
      90 min divided by the initial radioactivity within the ROI at 0 min. RESULTS: The
      RR90 was 0.648 +/- 0.156 for formula 1 and 0.600 +/- 0.131 for formula 2. There
      was no significant difference for the RR99 between formulas 1 and 2 (paired
      Student's t test, p > 0.05). Of the 27 patients, 12 (44.4%) demonstrated an
      increased RR99 from formula 1 to formula 2, and the RR90 of remaining 15 (55.6%)
      patient decreased. In addition, neither the patients with increased RR90 nor
      those with decreased RR90 showed a difference of symptoms between the two study
      meals. CONCLUSION: Our data suggest that there is no difference between these two
      types of fat on gastric emptying.

PMID- 10652919
TI  - Amyloidosis of the alimentary canal: radiologic-pathologic correlation of CT
      findings.
AB  - BACKGROUND: The purpose of the study was to describe the computed tomographic
      (CT) findings of the alimentary canal and mesentery in amyloid infiltration of
      the gastrointestinal (GI) tract and to correlate the CT findings with histologic
      extent and distribution and with amyloid subtype. METHODS: Abdominal CT scans
      performed between 1988 and 1997 on patients with pathologically proven
      amyloidosis of the alimentary canal and mesentery. Histology was graded for
      extent of mucosal, submucosal, and muscularis propria involvement and for degree
      of interstitial and vascular distribution. CT findings were correlated with
      histologic extent, histologic distribution, and amyloid histochemical type.
      RESULTS: Twenty-three patients were included. Four (17%) had bowel wall
      thickening, which was associated with a higher submucosal extent and interstitial
      distribution than in patients with normal bowel by CT. Four (17%) patients had
      bowel wall dilatation without thickening, which was not associated with
      statistically significantly different histology than in patients with normal
      bowel by CT. There was no statistically significant correlation between CT
      findings and histochemical subtype. Mesenteric soft tissue infiltration was seen
      in two patients, and mesenteric adenopathy was seen in one patient. CONCLUSIONS:
      Normal bowel is a common abdominal CT finding in amyloidosis of the alimentary
      canal. When findings are present, GI wall thickening and/or bowel wall dilatation
      without wall thickening may be seen. Bowel wall thickening on CT correlates with
      submucosal extent and interstitial distribution of disease. Soft tissue
      infiltration and adenopathy are also occasionally seen.

PMID- 10652920
TI  - Sonographic diagnosis of intussusceptions in adults.
AB  - Differentiating bowel intussusception occurring in adults from other bowel
      diseases represents a diagnostic problem because this condition is not a common
      finding. Contrast radiography, computed tomography, magnetic resonance imaging,
      and abdominal ultrasonography are imaging techniques suitable for this diagnosis.
      Sonography is easy to perform, reproducible, and less invasive than the other
      techniques. The aim of the present study was to evaluate the diagnostic utility
      of abdominal sonography in four patients affected by bowel intussusception and to
      assess the advantages offered by this method.

PMID- 10652921
TI  - Idiopathic ileoileal intussusception in an adult with spontaneous reduction
      during enteroclysis: a case report.
AB  - We report a rare case of recurring idiopathic ileoileal intussusception in an
      adult. Diagnosis was established with abdominal computed tomography (CT) and
      enteroclysis, which led to a spontaneous reduction of the invagination. After a
      short period of physical improvement, a follow-up CT showed a recurrence. Surgery
      proved the diagnosis, but no predisposing factor was found.

PMID- 10652922
TI  - Primary aortoduodenal fistulas in minimally aneurysmal aortas: imaging diagnosis.
AB  - We report on the utility of computed tomography (CT) in making the diagnosis of
      primary aortoduodenal fistulas in two cases presenting with massive
      gastrointestinal hemorrhage. In both cases, the clinical presentation was
      insidious, no pulsatile abdominal mass was palpated, and endoscopy findings were
      inconclusive. CT showed minimally aneurysmal aortas communicating with larger
      areas of contained rupture and pseudoaneurysm stretching adjacent small bowel.

PMID- 10652923
TI  - Arteriovenous fistula secondary to iliac mycotic aneurysm: helical CT findings.
AB  - We describe the case of a 59-year-old man who presented a mycotic aneurysm of the
      common right iliac artery due to Streptococcus agalactiae and developed an
      arteriovenous fistula within the inferior vena cava secondary to spontaneous
      rupture of the aneurysm. The clinical syndrome, helical computed tomographic, and
      angiographic findings are described and discussed.

PMID- 10652924
TI  - Spiral CT virtual endoscopy of abdominal arteries: clinical applications.
AB  - Virtual endoscopy enables the creation of endoluminal views of the aorta and its
      branches by processing spiral computed tomographic (CT) images, thereby allowing
      the preoperative and postoperative evaluations of abdominal aortic aneurysms,
      aneurysms of the splenic, celiac, and common iliac arteries, and renal artery
      stenoses. Moreover, it is helpful for verifying the position of stents and
      endoprostheses from within the aortic lumen. This method is a promising addition
      to spiral CT.

PMID- 10652925
TI  - Free MRA of the abdomen: postprocessing dynamic gadolinium-enhanced 3D axial MR
      images.
AB  - Dynamic contrast-enhanced whole-abdomen axial images were obtained by using a fat
      suppressed, three-dimensional, breath-hold enhanced fast spoiled gradient-echo
      technique, configured for optimal evaluation for detection and characterization
      of liver lesions. We then evaluated the feasibility of using these images to
      reconstruct "free" abdominal magnetic resonance angiography, without additional
      cost or acquisition time, in 32 randomly chosen patients. The aorta, celiac
      trunk, superior mesenteric, hepatic, splenic, and renal arteries were clearly
      depicted.

PMID- 10652926
TI  - Clinical and MR imaging features of cryptoglandular and Crohn's fistulas and
      abscesses.

PMID- 10652927
TI  - Endorectal surface coil MR imaging as a staging technique for rectal carcinoma: a
      comparison study to rectal endosonography.
AB  - BACKGROUND: Preoperative staging of rectal cancer is critical for guiding therapy
      and prescribing the most appropriate treatment option. The purpose of this
      investigation was to compare the accuracy of endorectal surface coil magnetic
      resonance imaging (ERSCMRI) with endosonography (EUS) in staging rectal lesions.
      METHODS: Fourteen patients with rectal carcinoma, initially detected by barium
      enema or sigmoidoscopy underwent ERSCMRI and EUS. Subsequent resection of the
      lesions was performed, and the staging accuracies of these two modalities are
      compared. RESULTS: MR T-staging agreement with pathologic T-staging was similar
      to that of EUS, but MR enabled more accurate identification of nodal involvement.
      CONCLUSION: ERSCMRI produced greater overall accuracy in staging for rectal
      carcinoma than did EUS.

PMID- 10652928
TI  - CT fluoroscopy: technique and utility in guiding biopsies of transiently
      enhancing hepatic masses.
AB  - We evaluated a new percutaneous biopsy technique for rapid needle localization
      and biopsy of transiently enhancing focal hepatic masses. Three biopsies in three
      patients were completed on lesions 18-22 mm in diameter by using computed
      tomographic fluoroscopy during intravenous contrast enhancement of the liver. All
      three biopsies were diagnostic.

PMID- 10652929
TI  - Bronchogenic cyst appearing as a hepatic mass.
AB  - Because bronchogenic cysts may be found in or near any organ derived from the
      embryonic foregut, they sometimes pose considerable diagnostic difficulties. We
      describe the plain chest X-ray, computed tomographic, and angiographic findings
      in a patient with elevated CA 19-9 and upper quadrant abdominal pain due to a
      cystic tumor appearing as a hepatic mass. Surgery and histology showed a
      bronchogenic cyst located in the lower lobe of the right lung.

PMID- 10652930
TI  - Intraductal mucosal-spreading mucin-producing peripheral cholangiocarcinoma of
      the liver.
AB  - The computed tomographic (CT) appearance of a case of intraductal mucosal
      spreading mucin-producing peripheral cholangiocarcinoma of the liver is described
      in a patient presenting with acute pericardial tamponade due to rupture of the
      cystically dilated left intrahepatic ducts by mucin hypersecretion. CT showed
      cystic and tubular dilatation of the intrahepatic ducts of the left and caudate
      lobes, but there was no grossly visible tumor mass. Pathology showed a single
      layer of tall columnar tumor cells with short intraluminal papillary projections
      lining each bile duct; the ducts were markedly dilated because of excessive mucin
      secretion. There was no gross tumor mass in the bile ducts. The tumor spread
      diffusely and contiguously along the intrahepatic bile ducts, with minimal
      invasion to the bile duct wall. To our knowledge, there has been no report about
      mucosal-spreading peripheral cholangiocarcinoma of the liver.

PMID- 10652931
TI  - Fast T2-weighted liver MR imaging: comparison among breath-hold turbo-spin-echo,
      HASTE, and inversion recovery (IR) HASTE sequences.
AB  - BACKGROUND: To evaluate the diagnostic efficacy of fast T2-weighted magnetic
      resonance (MR) imaging sequences on image quality, hepatic lesion detection, and
      lesion conspicuity. METHODS: Three breath-hold, fast T2-weighted sequences with
      turbo-spin-echo (TSE), half-Fourier acquisition single-shot TSE (HASTE), and
      inversion recovery (IR) HASTE techniques were examined for 43 lesions in 20
      consecutive patients. Evaluation was performed qualitatively on image quality and
      lesion detectability and quantitatively on lesion conspicuity by using
      lesion/liver signal-intensity and contrast-to-noise ratios. RESULTS: Artifacts
      were significantly less present on the HASTE sequence (p < 0.01). Both TSE and
      HASTE sequences detected 39 lesions (91% each); the IR HASTE sequence detected 37
      (86%). IR HASTE sequence showed a significantly higher signal-intensity ratio
      than did the others (p < 0.01). CONCLUSIONS: Breath-hold TSE versus breath-hold
      HASTE or IR HASTE is still the most robust sequence in lesion detection, image
      quality, and lesion conspicuity. However, the HASTE sequence offers good lesion
      detection and image quality, and the IR HASTE has a better signal-intensity
      ratio.

PMID- 10652932
TI  - Fat detection in granular-cell renal cell carcinoma using chemical-shift gradient
      echo MR imaging: another renal tumor that contains fat.
AB  - Preoperative chemical-shift magnetic resonance images in a 56-year-old man
      suggested the presence of microscopic fat in the tumor. The surgical specimen
      showed a granular-cell renal cell carcinoma with papillary architecture,
      associated with abundant fat-containing foamy histiocytes in the interstitium.
      The radiologist should include this entity in the differential diagnoses of renal
      tumors that contain microscopic fat.

PMID- 10652934
TI  - [Perspectives based on a survey on anesthesiology activity in 1996].

PMID- 10652935
TI  - [Demography of anesthesiologists in the forthcoming years: a public health
      challenge].

PMID- 10652933
TI  - Malignant peripheral neuroectodermal tumor (MPNET) of the kidney.
AB  - BACKGROUND: Malignant peripheral neuroectodermal tumors (MPNETs) are primitive
      neuroblastic tumors that arise, unlike neuroblastomas, outside the autonomic
      nervous system. A renal origin has been described in very few cases. CASE REPORT:
      We report the case of a young male patient with a large MPNET of the right
      kidney, studied with ultrasound and computed tomography before surgical
      resection. The main radiologic features, the microscopic appearance and the
      typical immunohistochemical findings, are described and discussed.

PMID- 10652936
TI  - [Fastrach laryngeal mask and difficult intubation].
AB  - OBJECTIVE: To evaluate the success rate of intubation through the intubating
      laryngeal mask airway (LMA-Fastrach) in patients with predictive signs of
      difficult airway or after intubation failure. STUDY DESIGN: Open prospective
      study. PATIENTS: The study included 33 adults, 21 with predictive signs of
      difficult airway and 12 after intubation failure. METHODS: After induction of
      anaesthesia, the intubating LMA was inserted. Proper insertion was confirmed by
      easy bag ventilation and capnography. Intubation through the intubating LMA was
      then carried out with an armoured endotracheal tube. If intubation failed, a
      second attempt was carried out after a gentle manipulation of the intubating LMA.
      After two attempts, if intubation remained impossible, fibrescopic intubation
      through the intubating LMA was carried out. In case of failure the usual tracheal
      intubation algorithms were used. RESULTS: Tracheal intubation through the
      intubating LMA was successful in all patients, in 32 on the first attempt and in
      one on the second. Successful tracheal intubation was possible on the first
      attempt in 25 patients (76%), on the second in four (12%) and after fibrescopic
      intubation through the intubating LMA in the four remaining (12%). CONCLUSION:
      The results of this study confirm that tracheal intubation through the intubating
      LMA can be recommended in patients with a difficult airway, whether foreseen or
      not.

PMID- 10652937
TI  - [Pharmacodynamics and safety of mivacurium in infants and children under
      halothane-nitrous oxide anesthesia].
AB  - OBJECTIVES: To determine pharmacodynamic effects and safety of mivacurium in
      paediatric patients. STUDY DESIGN: Multicentric, prospective, open, non
      randomized study. PATIENTS: Forty-eight three-month-old to eight-year-old
      physical class ASA I or II children. METHOD: Anaesthesia was induced and
      maintained with halothane and nitrous oxide. Tracheal intubation was performed
      without a neuromuscular blocking agent. Neuromuscular blockade was measured with
      a strain force transducer after train-of-four stimulation of the ulnar nerve at
      the wrist every ten seconds. A single bolus dose of mivacurium (0.2 mg.kg-1) was
      injected during 15 seconds in patients allocated into three groups. Group 1:
      three to 12-month-old infants (n = 15), group 2: one- to three-year-old children
      (n = 16) and group 3: three- to eight-year-old children (n = 17). Onset and
      recovery parameters were measured in each patient. Heart rate and noninvasive
      arterial blood pressure were recorded every minute for five minutes after
      mivacurium injection. RESULTS: Following halothane administration for 29 and 32
      min, and a FEThalothane = 1 vol%, mivacurium (0.2 mg.kg-1) determined a 100%
      neuromusmcular blockade in all patients. The onset time was 71 +/- 34 s (mean +/-
      SD) in all patients and did not differ between groups. Time to 25% and 95%
      recovery of the first twitch and recovery index for all the patients were 12 +/-
      3 min, 19 +/- 5 min and 4 +/- 2 min respectively and did not differ between
      groups. No prolonged paralysis was observed. No significant changes of HR and BP
      occurred. CONCLUSIONS: Following 0.2 mg.kg-1 of mivacurium in patients aged
      between three months to eight years, a complete blockade occurs with a rapid
      onset time and a short duration of action, without significant cardiovascular
      effect.

PMID- 10652938
TI  - [Impact of initial antibiotic therapy on the course of resistance to
      fluoroquinolones and aminoglycosides in Gram-negative bacilli isolated from
      intensive care patients].
AB  - OBJECTIVE: To evaluate the effect of the initial antibiotic therapy associating a
      betalactam antibiotic (BLA) with either an aminoglycoside (AG) or a
      fluoroquinolone (FQ) on the development of resistance of gram-negative bacilli in
      an intensive care unit. STUDY DESIGN: Prospective bacteriological surveillance
      study. PATIENTS: The study included 51 patients experiencing a second infection
      with gram-negative organisms, eight days or more after a first infection. METHOD:
      The incidences of bacterial infection and the antimicrobial susceptibility have
      been assessed. RESULTS: The first-choice therapy was based either on BLA + AG
      (51%), or on BLA + FQ in the others (46%). The causative organisms were
      Enterobacteriaceae (57%) and Pseudomonas aeruginosa (31%). The second infection
      occurred 23 +/- 11 days after the first. The main organisms involved were
      Pseudomonas aeruginosa (51%) and Enterobacteriaceae (41%). In the group treated
      initially with an AG, only the antibiotic susceptibility for amikacin decreased
      significantly (72 vs 36%, p < 0.05). The latter was the most prescribed
      antibiotic (56%). In the FQ group, there was a significant decrease of
      susceptibility for ciprofloxacin, pefloxacin, netilmicin and tobramycin. The
      decrease was not significant for gentamicin and amikacin. CONCLUSIONS: In
      intensive care patients, the use of FQ in association with a BLA increases the
      resistance to AG and FQ. Therefore it seems preferable to administer an AG in
      association with a BLA. Amikacine should only be prescribed when justified for a
      given case.

PMID- 10652939
TI  - [Postoperative antero-external tibial compartment syndrome: co-responsibility of
      the operating table].
AB  - A 26-year-old, ASA1 patient underwent maxillofacial surgery under general
      anaesthesia, of 12-hour duration in the supine position. Postoperatively he
      developed rhabdomyolysis and acute renal failure. In the subsequent days, a
      bilateral leg compartment syndrome occurred with anterior tibial motor nerve
      injury requiring fasciotomies and excision of necrotic muscles. Several
      aetiological factors may have contributed to this accident: a long-lasting
      procedure, controlled hypotension and inappropriate position of the lower limbs.
      A laboratory study showed that the hardness of some new operating tables could be
      responsible for this complication. Some prophylactic measures are therefore
      required before the use of such devices.

PMID- 10652940
TI  - [Aortic diverticulum: differential diagnosis of traumatic lesions of the thoracic
      aorta].
AB  - We report the case of a 31-year-old patient with a chest trauma after a
      mountaineering accident. Contrast enhanced spiral computed tomography of the
      thorax showed a lesion of the aortic isthmus, suspected of being an aortic
      disruption. As the diagnosis of aortic rupture could not be formally established
      with computed tomography, a transoesophageal echocardiography and an aortic
      angiography were performed which showed a ductus diverticulum, representing one
      of the differential diagnoses of traumatic aortic disruption. A knowledge of this
      entity and its diagnostic criteria may avoid an unnecessary thoracotomy.

PMID- 10652941
TI  - [Effect of biflow-induced ventilation (BIFIV) on cerebral cortical blood flow in
      anesthesized rabbits with intracranial hypertension].
AB  - This study compared the effect of biflow-induced ventilation (BIFIV) and
      conventional mechanical ventilation (CMV) on cerebral cortical blood flow (CBF)
      of six anaesthetized rabbits with an intracranial pressure (ICP) at 45 mmHg.
      BIFIV did not improve CBF during increased ICP when compared to CMV.

PMID- 10652942
TI  - [Trends in hospital anesthesiology-resuscitation workforce in the forthcoming
      years. Is a crisis about to happen?].
AB  - Due to a drastic decrease, by governmental regulations, of the number of trainees
      in medical specialties, only 113 anaesthesiologists have been trained annually
      from 1988 to 1998, versus 440 annually from 1978 to 1988. If this training rate
      remains unchanged the manpower will decrease in 2010 to the 1980 level. In the
      opposite, the number of anaesthetics increased from 3.5 millions in 1980 to about
      8 millions in 1996. If governmental health care policy remains unchanged, a major
      shortage of anaesthesiologists is to be expected from 2010 on. This shortage will
      occur earlier if anaesthesiologists retire before the age of 65 years.

PMID- 10652943
TI  - [Medico-legal dimension of informed consent in medicine].
AB  - The practice of the medical arts is more and more becoming framed by laws and
      regulations. Concurrently, the civil liability in the medical field has also been
      deeply changed, in particular by reversing the charge of proof of the information
      given to the patient. After having been reminded of the place in the juridical
      arsenal of informed consent to a medical procedure, its value is discussed
      regarding the explanations given by the physicians. Guidelines for a forensic
      appraisal, with the aim of evaluating and appreciating the information received
      by the patient, are proposed. Recent judiciary decisions about refusal of care,
      especially blood transfusions, are discussed.

PMID- 10652944
TI  - [Left subclavian vein catheterization in cardiac arrest. Accidental insertion in
      the subclavian artery and aorta].

PMID- 10652945
TI  - [Consultation for infectious diseases in a private health care institution].

PMID- 10652946
TI  - [Implicit diagnosis...].

PMID- 10652947
TI  - [Assessment of severity and treatment of chloroquine poisoning].

PMID- 10652948
TI  - [Fatal poisoning caused by buflomedil].

PMID- 10652949
TI  - [Anesthesia in the obese patient].

PMID- 10652950
TI  - [Total intravenous anesthesia and ORL endoscopy].

PMID- 10652951
TI  - [Ambulatory anesthesia].

PMID- 10652952
TI  - Determinants of bone mass and bone geometry in adolescent and young adult women.
AB  - Bone mass and bone geometry are considered to have independent effects on bone
      strength. The purpose of this study was to obtain data on bone mass and geometry
      in young female populations and how they are influenced by body size and
      lifestyle factors. In a cross-sectional, observational study in six European
      countries, 1116 healthy Caucasian girls aged 11-15 and 526 women aged 20-23
      participated. Their radius was scanned at the ultradistal site and at a site
      approximately 30% of the radius length from the distal end with dual energy X-ray
      absorptiometry (DXA). The following parameters were assessed from the scans: bone
      mineral content (BMC), bone mineral density (BMD), cortical wall thickness (CWT),
      middistal diameter (D), cortical index (CI = 2CWT/D), and the Breaking Bending
      Resistance Index (BBRI = (D4 - [D-CWT]4)/D). Calcium intake was assessed by 3-day
      food records and physical activity by questionnaire. Body size parameters were
      measured by anthropometry. All parameters showed an increasing trend with
      pubertal stage and age, except for physical activity and calcium intake. BMC and
      BMD were relatively more dependent on body weight and age at menarche, whereas
      variation in D and the mechanical index BBRI was better explained by differences
      in height and grip strength. CI and CWT were relatively independent of variation
      in body size, whereas BMC and BBRI especially were explained for a substantial
      proportion (25-33% in the young adults) by body size parameters. Dietary intake
      of calcium and level of physical activity seem to contribute little to variation
      in bone parameters.

PMID- 10652953
TI  - Membranes and their constituents as promoters of calcium oxalate crystal
      formation in human urine.
AB  - We have proposed that membranes of cellular degradation products are a suitable
      substrate for the nucleation of calcium oxalate (CaOx) crystals in human urine.
      Human urine is generally metastable with respect to CaOx. To demonstrate that
      cellular membranes present in the urine promote nucleation of CaOx we removed
      these substrates by filtration or centrifugation and induced crystallization by
      adding sodium oxalate, before and after filtration or centrifugation. In a
      separate experiment, membrane vesicles isolated from rat renal tubular brush
      border were added into the filtered or centrifuged urine before crystal
      induction. Crystals were counted using a particle counter. Urine, the pellet, and
      retentate were analyzed for the presence of membranes, lipids, and proteins.
      Lipids were further separated into different classes, identified, and quantified.
      Both filtration and centrifugation removed lipids, proteins, and membrane
      vesicles, causing a reduction in lipid and protein contents of the urine. More
      crystals formed in whole than in filtered or centrifuged urine. The number of
      crystals significantly increased when filtered urine was supplemented with
      various urinary components such as the retentate and phospholipids, which are
      removed during filtration. We also determined the urinary metastable limit with
      respect to CaOx. Filtration and centrifugation were associated with increased
      metastable limit which was reduced by the addition of membrane vesicles. These
      results support our hypothesis that urine normally contains promoters of CaOx
      crystal formation and that membranes and their constituents are the most likely
      substrate for crystal nucleation in the urine.

PMID- 10652954
TI  - Changes in bone mineral, lean body mass and fat content as measured by dual
      energy X-ray absorptiometry: a longitudinal study.
AB  - Bone mineral density (BMD) and soft tissue composition were measured by dual
      energy X-ray absorptiometry (DXA) 3-4 years apart in 273 men and women aged 23
      90. We found different rates of BMD loss in different skeletal regions. There
      were also different rates of BMD loss in different regions within the hip.
      Average rates of loss for male subjects 50 years of age and above for BMD total
      body were 0.1%/year and for femoral neck 1.5%/year, whereas lumbar spine (L2-L4)
      increased by 0.4%/year. Average rates of loss for female subjects 50 years of age
      and above for BMD total body were 0.0%/year, femoral neck 0.9%/year, and lumbar
      spine (L2-L4) 0.1%/year.

PMID- 10652955
TI  - Serum CTX: a new marker of bone resorption that shows treatment effect more often
      than other markers because of low coefficient of variability and large changes
      with bisphosphonate therapy.
AB  - Serum CrossLaps is a new assay for measuring carboxy-terminal collagen crosslinks
      (CTX) in serum. This measurement is reported to be more specific to bone
      resorption than other measurements. However, the utility of this and other
      markers in monitoring patients on antiresorptive therapy depends on how often
      changes anticipated with therapy exceed changes attributable to random
      variability. In a study where subjects received either placebo or pamidronate, we
      calculated the minimum significant change (MSC), that is, the change that was
      sufficiently large that it was unlikely to be due to spontaneous variability. We
      also examined the changes in markers of bone turnover in subjects treated with
      pamidronate (APD) (30 mg i.v. in 500 ml D5W over 4 hours) to see how often
      observed changes in turnover after treatment exceeded the MSC. The MSC for serum
      CTX was 30.2%, and was significantly (P < 0.05) lower than the MSC for urinary
      NTX (54.0%), and not significantly different from the MSC of urinary DPD (20.6%).
      Ninety percent of subjects treated with APD had a decline in serum CTX that
      exceeded the MSC, compared with 74% for bone-specific alkaline phophatase (BSAP),
      57% for urinary N-telopeptide cross-links (NTX), and 48% for free
      deoxypyridinoline. Changes in serum CTX correlated reasonably well with changes
      in spine BMD after 2 years (r = 0.47), but this correlation did not quite reach
      statistical significance because of the small number of subjects. In conclusion,
      the serum CTX assay shows greater utility for assessing efficacy of
      antiresorptive treatment than some previously described markers.

PMID- 10652956
TI  - The decrease in serum bone-specific alkaline phosphatase predicts bone mineral
      density response to hormone replacement therapy in early postmenopausal women.
AB  - Hormone replacement therapy (HRT) prevents bone loss in postmenopausal women. Up
      to 20% of women demonstrate no increase in bone mineral density (BMD) on HRT. We
      examined whether early changes in serum bone alkaline phosphatase (B-ALP) predict
      long-term BMD changes in postmenopausal women on HRT. Ninety women within 1 year
      of menopause were randomly assigned to continuous or sequential
      estrogen/progestin (beta estradiol/norethisterone acetate) if naturally
      postmenopausal, or beta estradiol if within 1 month of surgical menopause. Spine,
      femoral neck BMD (DXA), and B-ALP were determined over 2 years. The mean percent
      BMD changes were 3.8%, 2.9%, 1.6% in the spine and 2.4%, 4.0%, 1.1% in the
      femoral neck in sequential, continuous, and estrogen alone treatment groups,
      respectively, significantly different from zero except for femoral neck BMD
      change in the estrogen alone group. HRT was associated with spine and femoral
      neck BMD loss in 17.4% and 25.3% of women, respectively. In estrogen/progestin
      treated women, baseline B-ALP correlated with spine BMD change (r = 0.42, P <
      0.01). At 3 months, B-ALP dropped significantly in the estrogen/progestin-groups
      with a maximal decrease at 12 months, but no change from baseline in the estrogen
      alone group. Using quartile analysis, women with the greatest drop in B-ALP (> or
      = 50%) at 6 months demonstrated the greatest gain in spine BMD at 2 years. A 40%
      decrease at 6 months in B-ALP had a 56% sensitivity, 83% specificity, 95%
      positive predictive value for spine BMD gain at 2 years. The decrease in B-ALP
      can be used to monitor BMD response to HRT.

PMID- 10652957
TI  - Cortisol decreases hepatocyte growth factor levels in human osteoblast-like
      cells.
AB  - Osteoporosis is a well-known side effect of long-term treatment with
      glucocorticoids. The hepatocyte growth factor (HGF) receptor is expressed by
      human osteoclasts and osteoblasts, and mouse osteoblasts also express HGF,
      indicating that HGF may regulate bone metabolism. Because HGF could be a
      candidate factor in the local paracrine signaling between osteoblasts and
      osteoclasts in bone, we decided to study whether human osteoblasts secrete HGF
      and whether glucocorticoids regulate the expression of HGF. HGF was easily
      detectable in the culture medium from human osteoblast-like cells (hOB). The HGF
      protein released into the culture medium was increased with increasing
      confluency. Hydrocortisone decreased the amount of HGF released into the culture
      medium from hOB in a dose-dependent manner with a maximal effect at 10(-6) M.
      Time-course studies revealed that hydrocortisone decreased the amount of HGF
      released into the culture medium significantly after 16 hours of stimulation (65
      +/- 2% of control culture). This effect of hydrocortisone was maximal after 24
      hours of stimulation (52 +/- 8% of control culture). In conclusion, HGF is
      produced by primary cultured hOB cells. Furthermore, the amount of HGF released
      into the culture medium is decreased by glucocorticoids. The biological
      significance of this finding remains to be demonstrated.

PMID- 10652958
TI  - Bone mineral densitometry substantially influences health-related behaviors of
      postmenopausal women.
AB  - Although bone mineral density measurements are helpful in predicting future risk
      for osteoporotic fractures, there is limited information available on how the
      results of bone densitometry influence a woman's use of therapeutic alternatives.
      To assess the role of bone mineral densitometry in influencing postmenopausal
      women to change health behaviors associated with osteoporosis, we prospectively
      followed, for an average of 2.9 years, 701 postmenopausal women over 50 years of
      age referred to an osteoporosis prevention program in a large metropolitan area.
      Assessments included bone mineral densitometry by dual-energy X-ray
      absorptiometry (with classification of skeletal health), medical history, use of
      hormone replacement therapy, calcium intake, caffeine intake, exercise, smoking
      habits, and fall precaution measures. Women classified at baseline with moderate
      low bone mass were twice as likely (33%), and women with severe low bone mass
      more than three times as likely (47%) to start hormone replacement therapy
      compared with women with a normal result (13%, P < 0.001). This was true
      regardless of whether they had taken hormone replacement therapy in the past.
      Below-normal BMD was a strong predictor of a woman's initiation of hormone
      replacement therapy (OR 4.2; 95% CI 2.7-6.4; P < 0.05) even after adjustment for
      age, education, history of osteoporosis or fracture, and medical condition
      related to osteoporosis. Women with moderate or severe low bone mass were also
      much more likely to start calcium supplements (81-90% versus 67%), increase
      dietary calcium (71-82% versus 60%), decrease use of caffeine (44-60% versus
      34%), start exercising (61-76% versus 52%), and quit smoking (22-24% versus 11%)
      relative to their behaviors prior to testing (P < 0.01). In conclusion,
      postmenopausal women report that the results of bone densitometry substantially
      influence the decision to begin hormone replacement therapy and calcium
      supplements, increase dietary calcium, decrease caffeine, increase exercise,
      decrease smoking, and take precautions to prevent falls. More studies are needed
      to measure the long-term effects of this influence.

PMID- 10652959
TI  - Osteoporosis after gastrectomy: bone mineral density of lumbar spine assessed by
      dual-energy X-ray absorptiometry.
AB  - Although osteoporosis is a common clinical disorder associated with gastric
      surgery, long-term effects of gastrectomy on bone metabolism are still unclear.
      The purpose of this study was to clarify the incidence and risk factors of
      osteoporosis after gastrectomy using univariate and multivariate analyses of
      quantitative measurements. The study included 59 patients who had undergone
      gastrectomy more than 5 years before. There were 38 men and 21 women, aged 37-81
      years, mean 64 years. Bone mineral density (BMD) of L2-L4 spine was measured
      using dual-energy X-ray absorptiometry (DXA). Absolute value of BMD (g/cm2) and
      age- and sex-matched BMD (%) were given. The mean BMD was 0.766 g/cm2, and the
      incidence of osteoporosis (BMD less than 0.70 g/cm2) was 37%: 18% in men and 71%
      in women. The mean age- and sex-matched BMD was 85.9%: 87.5% in men and 83.1% in
      women. Univariate and multivariate analyses revealed that BMD was significantly
      associated with the age and sex of patients, but was not influenced by the type
      of gastrectomy (partial versus total) and years after operation (< 20 versus 20
      <). Our study clarified the fact that postgastrectomy osteoporosis was frequent
      in the aged or female patients. BMD should be evaluated after gastrectomy,
      especially in the aged and in women.

PMID- 10652960
TI  - Short-term effect of vitamin K administration on prednisolone-induced loss of
      bone mineral density in patients with chronic glomerulonephritis.
AB  - Glucocorticoid-induced osteoporosis has been reported to be caused by enhanced
      bone resorption and suppressed bone formation. To clarify whether administration
      of vitamin K, which enhances bone formation, prevents prednisolone-induced loss
      of bone mineral density (BMD), a randomized, prospective, controlled study was
      conducted on 20 patients with chronic glomerulonephritis scheduled for treatment
      with prednisolone. All patients were initially treated with 0.8 mg/kg body
      weight/day of prednisolone (maximum of 40 mg) for 4 weeks, tapering to 20 mg/day
      over approximately 6 weeks. Ten patients received prednisolone alone (Group 1),
      and the other 10 patients received prednisolone plus 15 mg of menatetrenone,
      vitamin K, three times per day (Group 2). BMD of the lumbar spine measured by
      dual-energy X-ray absorptiometry (DXA) and biochemical markers of bone metabolism
      in blood and urine were evaluated before and 10 weeks after administration of
      prednisolone alone or with menatetrenone. In Group 1, treatment with prednisolone
      significantly reduced BMD of the lumbar spine from 1.14 +/- 0.12 to 1.10 +/- 0.11
      g/cm2 (P = 0.0029). Serum intact osteocalcin and procollagen type I C-peptide
      (PICP) concentrations, biochemical markers of bone formation, were markedly
      reduced. A biochemical marker of bone resorption, urinary excretion of
      deoxypyridinoline, was significantly reduced. In Group 2, prednisolone-induced
      reduction of BMD was prevented by menatetrenone administration (1.09 +/- 0.09 to
      1.07 +/- 0.07 g/cm2, P = 0.153). Menatetrenone prevented reduction of PICP
      concentration by prednisolone but not in serum intact osteocalcin concentration
      and urinary excretion of deoxypyridinoline. Thus, treatment with prednisolone
      resulted in loss of BMD of the lumbar spine associated with suppression of both
      bone formation and bone resorption. Menatetrenone is a useful agent in preventing
      prednisolone-induced loss of BMD.

PMID- 10652961
TI  - Odontoblast differentiation of human dental pulp cells in explant cultures.
AB  - In order to elucidate the mechanisms involved in human dentin formation, we
      developed a cell culture system to promote differentiation of dental pulp cells
      into odontoblasts. Explants from human teeth were cultured in Eagle's basal
      medium supplemented with 10% or 15% fetal calf serum, with or without beta
      glycerophosphate (beta GP). Addition of beta GP to the culture medium induced
      odontoblast features in the cultured pulp cells. Cells polarized and some of them
      exhibited a typical cellular extension. In some cases, cells aligned with their
      processes oriented in the same direction and developed junctional complexes
      similar to the terminal web linking odontoblasts in vivo. Fine structural
      analyses showed the presence of typical intracellular organelles of the
      odontoblast body, whereas the process contained only cytoskeleton elements and
      secretory vesicles. Polarized cells deposited onto the plastic dishes an abundant
      and organized type I collagen-rich matrix with areas of mineralization appearing
      thereafter. X-ray microanalysis showed the presence of calcium and phosphorus and
      the electron diffraction pattern confirmed the apatitic crystal structure of the
      mineral. High expression of alpha 1 (1) collagen mRNAs was detected in all
      polarized cells whereas dentin sialoprotein gene was mainly expressed in
      mineralizing areas. This cell culture system allowed for the differentiation of
      pulp cells into odontoblasts, at both the morphological and functional level.
      Moreover, these cells presented a spatial organization similar to the
      odontoblastic layer.

PMID- 10652962
TI  - Establishment and characterization of a culture system for enzymatically released
      rat dental pulp cells.
AB  - To establish a cell culture system that reflects the dentin formation in dental
      pulp tissue, we used dental pulp cells enzymatically isolated from rat incisor
      teeth. During the 20-day culture period, the cells exhibited various phenotypes
      of the odontoblast differentiation process, from the immature stage to the
      terminal mineralization stage. The cells began to form the mineralized nodules
      from day 10, and the nodules became larger by day 20. Alkaline phosphatase (ALP)
      positive cells surrounded the mineralized nodules. The ALP activity in the cell
      layers was maximal on day 5, and gradually decreased to day 20. The calcium
      content in the cell layers was very low by day 10, and significantly increased
      from day 15. Sulfated glycosamino-glycans (GAGs) contained in the cell layers
      increased by day 15, but the content then decreased by day 20. The dental pulp
      cells produced a small amount of osteocalcin that was released into the culture
      medium by day 10, and the amount secreted increased markedly from day 15. The
      expression of osteocalcin and parathyroid hormone/parathyroid hormone-related
      peptide (PTH/PTHrP) receptor mRNA was evident as early as day 5, and the
      expression of each gradually increased with the number of days in culture. Dentin
      matrix protein (Dmp1) mRNA gene transcripts were identified by use of the reverse
      transcription polymerase chain reaction (RT-PCR) in the cells throughout the
      culture period. The present results demonstrate that this culture system is
      useful for studying the differentiation process of the odontoblast-like cells.

PMID- 10652963
TI  - Expression of mRNAs for the alpha 1 subunit of voltage-gated calcium channels in
      human osteoblast-like cell lines and in normal human osteoblasts.
AB  - The activation of osteoblast calcium channels by many bone regulatory factors
      suggests an important role for intracellular calcium signaling in the control of
      bone remodeling. At least six different genes for the alpha 1 subunit of voltage
      gated calcium channels have been cloned including L-type (alpha 1S, alpha 1C, and
      alpha 1D) and non-L-type (alpha 1A, alpha 1B, and alpha 1E) isoforms. The goal of
      the present study was to identify which of these calcium channel isoforms are
      transcribed in human osteoblast-like cell lines (hFOB, MG-63, SAOS-2, TE-85, G
      292) and in cultures of normal human osteoblasts. Reverse transcriptase-PCR was
      used to amplify sequences corresponding to each of the alpha 1 subunits using
      isoform specific primers. The products of the PCR reaction were cloned and
      sequenced to verify their identify and used to probe southern blots of the PCR
      reactions. The results indicate that among the different types of osteoblast-like
      cells examined, two calcium channel isoforms were always expressed (alpha 1C and
      alpha 1A), three isoforms were variably expressed (alpha 1S, alpha 1D and alpha
      1B), and one isoform was not expressed in any of the osteoblast-like cells (alpha
      1E) but was easily detected in human brain controls. Our results indicate that
      mRNAs for multiple calcium channel alpha 1 subunits are expressed in human
      osteoblasts, including both L-type and non-L-type isoforms. In addition,
      significant heterogeneity exists between the different osteoblast cell models
      examined in the type and mRNA abundance of the different calcium channel
      isoforms.

PMID- 10652965
TI  - Acceleration of fresh fracture repair using the sonic accelerated fracture
      healing system (SAFHS): a review.
AB  - The Sonic Accelerated Fracture Healing System (SAFHS) is a relatively new
      fracture management tool which incorporates the application of a specifically
      modified diagnostic ultrasound unit to healing fractures with the intention of
      accelerating repair. In an animal fracture model, this device has been shown to
      accelerate the rate of biomechanical healing by a factor of 1.4-1.6. In two
      randomized, controlled trials in humans, the same unit has been shown to reduce
      the time frame of clinical and radiographic healing by 38%. In the two fracture
      regions investigated, tibial diaphysis and distal radius, this represented a 58
      day and 37 day reduction in healing time, respectively. Despite its effect on the
      entire process of fresh fracture repair, the effect of the SAFHS on the
      individual stages and processes involved has not been established. This paper
      reviews these stages and processes, and discusses the clinical and practical
      implications of the effect of the SAFHS on fracture repair and the need for
      further research into this modality.

PMID- 10652964
TI  - Posttranslational modifications of bone collagen type I are related to the
      function of rat femoral regions.
AB  - This study analyzes the relationship between the function of femoral regions in
      the rat and the extent of collagen type I posttranslational modifications, to
      assess whether the different functional roles, i.e., mechanical or metabolic, of
      the bone tissues are related to the molecular structure of the matrix. For this
      purpose, 18 female, 100-day-old Sprague-Dawley rats were sacrificed, under
      anesthesia, and their femurs were removed and dissected free of adhering tissue.
      The spongy bone of the proximal metaphysis and the diaphysis were then selected
      as regions exerting prevalently a mechanical function, and the spongy bone of the
      distal metaphysis was selected as mainly related to metabolic function. Bone
      prepared from these regions was used to extract and purify the major component of
      the matrix, type I collagen. The content of hydroxyproline, hydroxylysine,
      glycosylated hydroxylysine, and pyridinium crosslinks was evaluated and the
      amount of each compound was expressed as a molar ratio to hydroxyproline. The
      amount of glycosylated hydroxylysine and pyridinium crosslinks in the distal
      metaphysis are significantly different from the amounts measured both in the
      diaphysis and the proximal metaphysis. On the contrary, the amounts of the same
      compounds in the diaphysis and the proximal metaphysis are statistically the
      same. The amount of free hydroxylysine, however, appears to be different in the
      proximal metaphysis and in the diaphysis. The conclusion is that matrix
      composition differs among different skeletal regions according to the main
      function they exert.

PMID- 10652966
TI  - Mechanisms of development of heart failure in the hypertensive patient.
AB  - Hypertension is a major risk factor for the development of heart failure.
      Mechanisms which maintain normal function in the short term in the pressure
      overloaded heart have longer term deleterious effects. These include left
      ventricular (LV) hypertrophy and chronic activation of the adrenergic and renin
      angiotensin systems. beta-Blocking agents are capable of blocking the adrenergic
      system and, to some extent, the renin-angiotensin system. They are therefore
      attractive in treating hypertension, both for preventing the development of
      abnormalities and for reversing established LV dysfunction and hypertrophy.
      Trials in heart failure have shown that these agents prevent progressive
      myocardial dysfunction, prevent and reverse remodelling and improve intrinsic
      systolic function. Non-selective beta-blocking agents appear to offer greater
      anti-adrenergic effects than selective ones. However, more research is needed,
      including direct comparisons of different agents.

PMID- 10652967
TI  - Progression from hypertension to heart failure. Mechanisms and management.
AB  - Patients with hypertension are at increased risk of developing heart failure
      (HF), but the mechanisms by which hypertension leads to HF have not been
      clarified [although left ventricular hypertrophy (LVH) is clearly a predictor of
      an increased risk of HF]. Similarly, although antihypertensive therapy has been
      shown to reduce the risk of HF in hypertensive patients, it is not known how this
      benefit is produced and, currently, there is no clear evidence that any class of
      antihypertensive agent is more effective than any other in this respect. On
      theoretical grounds, beta-blockers would be expected to be ideal agents for the
      prevention of HF in hypertensive patients. In addition to control of blood
      pressure and regression of LVH, they have clear benefits on morbidity and
      mortality after myocardial infarction (MI), which probably plays a major role in
      the development of HF in hypertensive patients, and on the prognosis of HF
      itself. A reduction in long-term mortality after MI has been demonstrated only
      for non-selective beta-blockers. Carvedilol, a non-selective beta-blocker which
      also has other ancillary properties including alpha-1-receptor blockade and
      antioxidant effects and a favourable metabolic profile, may be an appropriate
      choice for the prevention of HF in hypertensive patients. This is reinforced by
      the salutary benefits of carvedilol for the reduction in the morbidity and
      mortality of HF itself.

PMID- 10652968
TI  - Prevention of heart failure.
AB  - Heart failure (HF) is a progressive process and the objective of treatment should
      be to prevent progression. Treatment should begin at the stage of asymptomatic
      left ventricular dysfunction (LVD), not only to reduce mortality but also to
      preserve exercise capacity and quality of life. To prevent clinical progression
      in patients with asymptomatic LVD or HF, left ventricular remodelling and
      dilatation must be prevented. The SOLVD prevention trial-the only clinical trial
      on the prevention of HF-showed that ACE inhibition significantly reduced the
      development of HF, but did not significantly reduce mortality. Plasma
      norepinephrine is elevated in patients with asymptomatic LVD, is further elevated
      in patients with overt HF, and is correlated with increased mortality. Inhibition
      of the sympathetic nervous system by administration of beta-blocking agents is
      therefore a logical treatment for patients with HF or asymptomatic LVD. Clinical
      trials have shown that beta-blocking agents increase left ventricular ejection
      fraction and reduce left ventricular dimensions in patients with HF, indicating
      regression of left ventricular remodelling. Almost all the patients in these
      studies were receiving an ACE inhibitor as part of their background medication,
      therefore the relative efficacy of beta-blocking agents and ACE inhibitors in the
      regression of remodelling is not known. CARMEN, a double-blind, randomised,
      parallel group study of carvedilol versus enalapril versus carvedilol + enalapril
      in 450 patients with mild HF, will provide this information.

PMID- 10652969
TI  - Reproductive choices in 2000: the relative safety of current oral contraceptives.

PMID- 10652970
TI  - The recent saga of cardiovascular disease and safety of oral contraceptives.
AB  - This review presents detailed risk estimates from relevant epidemiological and
      other studies on the comparative safety of second and third generation oral
      contraceptives (OC). Written with the intention of presenting a repository of the
      available information, it also discourses briefly into the symptomatology and
      diagnosis of diseases associated with OC use and presents some of the critical
      comments made about various epidemiological analyses. A general critique
      including observations and opinions of various investigators completes the
      review. We stress that our own opinions on the various studies, or an attempt to
      adjudge the relative safety of second and third generation OC, are not given
      since they form the substance of our second paper which completes this symposium.

PMID- 10652971
TI  - The public health implications of the 1995 'pill scare'.
AB  - The warning issued by the UK Committee on Safety Medicines in October 1995,
      followed by their 'Dear Doctor' letter of October 18, 1995, that oral
      contraceptive pills containing gestodene or desogestrel were associated with a
      higher risk of venous thromboembolism has had a negative impact on public heath.
      A significant number of women either switched brands or ceased contraception
      altogether following the announcement. National data suggest a strong association
      between the pill scare and a substantial increase in the number of unintended
      pregnancies, particularly significant among younger women, with use of oral
      contraception falling from 40 to 27% of under 16s between 1995-1996 and 1996
      1997. The resulting cost of the increase in births and abortions to the National
      Health Service has been estimated at about Pound Sterling 21 million for
      maternity care and from Pound Sterling 46 million for abortion provision. The
      level of risk should, in future, be more carefully assessed and advice more
      carefully presented in the interests of public health.

PMID- 10652972
TI  - The 'pill scare': the responses of authorities, doctors and patients using oral
      contraception.
AB  - In October 1995, the regulatory authority in the UK issued a warning about an
      increased risk of venous thromboembolism in women taking third-generation
      combined oral contraceptives. This was done before publication of the scientific
      papers involved, and resulted in a huge media 'pill scare'. The manner in which
      the information was released has been criticised, as many doctors did not receive
      their 'Dear Doctor' letter from the regulatory authority until after media
      reporting. The result of the scare has been a loss of confidence in the oral
      contraceptive pill in general, and a rise in abortion rates.

PMID- 10652973
TI  - Safety of modern oral contraception: the options for women: lessons to be
      learned.
AB  - The relatively short history of hormonal contraception has been marked by a
      series of 'pill scares', all of which--after creating panic among users--were
      proven to be unfounded in terms of public health impact. The latest pill scare,
      provoked by regulatory action in the United Kingdom and the Federal Republic of
      Germany in response to the publication of a series of articles indicating a
      doubling of risk of deep venous thrombosis in users of oral contraceptives
      containing third-generation progestins, seems finally settled: both the British
      and the German Drug Regulatory Authorities have now reverted their verdict. The
      damage unfortunately stays: hundreds of thousands of women have been compelled to
      abandon the pill of their choice, often deciding to drop contraception
      altogether, thereby exposing themselves to unwanted pregnancy and--in a number of
      cases--to pregnancy termination. This latest episode should be turned into
      something positive: we need to learn that, in the case of drugs in widespread
      use, before restrictive action is taken--and except for very rare and specific
      instances--the scientific community must carry out an exhaustive debate on the
      reality and importance of the observed effects. Although the public should, in
      each instance, be properly informed, it is only after this process has been
      completed that restrictive action should be taken. It is hoped that, after this
      last episode, all concerned have learned this simple principle and will accept
      being guided by it from now on.

PMID- 10652974
TI  - Avoiding problems in clinical practice after the pill scare.
AB  - The publications of 1995 and 1996 on the risk of venous thrombosis associated
      with the use of the combined oral contraceptive pill (COC) suggested that the
      risks were lower than previous estimates. The debate, which ensued, ensured that
      the safety of the COC with regard to arterial and venous disease was reassessed.
      This review details the importance of contraception for public health. It
      reassesses critically current prescribing practice in the light of the new
      publications on Factor V Leiden, arterial and venous disease. Methods of
      communicating information about the COC are assessed, and the difficulties of
      transmitting complex scientific data to health care professionals and the general
      public are debated. The importance of attempting to quantify the benefits and
      risks of the COC and explaining them in the context of other life events is
      emphasized.

PMID- 10652975
TI  - A clinician's response to the oral contraceptive thrombosis controversy.
AB  - The controversy involving new progestin oral contraceptives (OC) began in late
      1995, continued through 1996, and started to reach resolution in 1997. The
      fundamental question is whether OC containing desogestrel and gestodene have a
      different risk of thrombosis compared with OC containing older progestins.
      Correcting for preferential prescribing and the healthy user effect leads to the
      conclusion that all low-dose OC--regardless of progestin type--have an increased
      risk of venous thromboembolism. Low-dose OC do not increase the risk of
      myocardial infarction or stroke in healthy, non-smoking women less than 35 years
      of age. With effective patient screening for risk factors, the serious side
      effects of OC can be virtually eliminated.

PMID- 10652976
TI  - The role of selective prescribing in the increased risk of VTE associated with
      third-generation oral contraceptives.
AB  - In the early 1960s, it became apparent that oral contraception (OC) with
      oestroprogestogens increased the cardiovascular, venous thromboembolic (VTE),
      myocardial infarction (MI) and cerebrovascular accident (CVA) risk. The change in
      medical prescribing patterns, the reduction in ethinyloestradiol dosage and the
      use of less androgenic progestogens made prescribers confident that the risks
      would subsequently decrease. At the end of 1995 and early 1996, four publications
      called into question that optimism by showing that third-generation pills induced
      a two-fold increase in VTE risk compared with second-generation pills. A
      biological rationale was due to be announced later. Since then, re-analysis of
      the data has shown that the thrombotic risk factors are increased in third
      generation OC users but, more importantly, that those users (unlike those using
      second-generation pills) are the women who have not had the opportunity of
      revealing a latent thrombophilia and are, therefore, at a greater risk of
      expressing it during third-generation OC intake. When these data are considered,
      the difference between second- and third-generation OC users in terms of VTE risk
      is completely destroyed. In addition and although the risk factors (smoking in
      particular) are concentrated in third-generation OC users, the MI risk is less in
      those users than in second-generation pill users. This is particularly true in
      the presence of a risk factor such as smoking. No difference in risk has been
      observed for CVA in the general population between second- and third-generation
      OC users, but once more among smoking women the risk is lower with third
      generation OC.

PMID- 10652977
TI  - Biological coagulation findings in third-generation oral contraceptives.
AB  - An increased risk of venous thrombosis has been demonstrated in women receiving
      oral contraceptives (OCs). This risk has been primarily associated with the
      oestrogen content, but recent studies showed that the progestogen may also play a
      role. A higher risk was found with the so-called third-generation (desogestrel,
      gestodene) as compared with the second-generation progestogens (levonorgestrel).
      The risk was approximately two-fold. These unexpected results have been the
      subject of many debates, and bias--such as selection bias--has been suggested.
      The existence of bias cannot be completely excluded, but the thrombotic risk
      seems however to be slightly higher with the third-generation progestins.
      Haemostatic changes have been observed during OC intake. Both coagulation and
      fibrinolytic activity are increased: the beneficial profibrinolytic effect may
      counterbalance the deleterious procoagulant effect. This may explain that the
      absolute risk of venous thromboembolism is low during OC treatments. Some women
      who have pre-existing haemostatic abnormalities such as deficiency in
      antithrombin or activated protein C resistance with factor V Leiden, may be at a
      higher risk. The biological plausibility of the increased risk related to the
      third-generation progestogens has been explored. Theoretically, this could be due
      to an increased coagulation or to a lack of increased fibrinolysis as compared
      with second-generation progestogens. The only difference presently reported with
      third-generation OCs is a decreased sensitivity to activated protein C, possibly
      resulting in a hypercoagulability of greater magnitude. The selection bias
      suggested in epidemiological studies may also exist for the latter study, as
      women taking third- or second-generation OCs were not randomized. The possible
      increased risk related to third-generation OCs should not change the known
      general contra-indications. Practical guidelines are proposed for women with
      personal or family history of venous thromboembolism, and for those with a
      congenital cause of thrombophilia.

PMID- 10652978
TI  - Concordant and discordant effects on cardiovascular risks exerted by oestrogen
      and progestogen in women using oral contraception and hormone replacement
      therapy. ESHRE Capri Workshop Group.
AB  - The major indications for the clinical use of oestrogen and progestogen are oral
      contraception (OC) in young women, and hormonal replacement therapy (HRT) in
      menopause. Over the past few years, epidemiological data have associated the use
      of these hormones to different cardiovascular conditions such as myocardial
      infarction, cerebrovascular disease and venous thromboembolism. This review
      summarizes the data discussed and the conclusions achieved by the ESHRE Capri
      Workshop Group, recently published in Human Reproduction.

PMID- 10652979
TI  - Oral contraceptives and venous thromboembolic disease. Analyses of the UK General
      Practice Research Database and the UK Mediplus database.
AB  - The results of three independent studies of venous thromboembolic disease (VTE)
      and oral contraceptives are reviewed together with two further cohort/case
      control studies which we conducted using the MediPlus and General Practice
      Research Database (GPRD) databases. These latter studies jointly involved 395
      cases and uniquely examined the association between VTE and individual combined
      oral contraceptive (COC) formulations. The two studies yielded very similar
      results. Crude incidence rates for idiopathic VTE of 4.6 and 3.8 were found per
      10,000 exposed woman-years (EWY), in the MediPlus and GPRD studies respectively.
      Incidence rates increased markedly with age, and in both databases the rates
      amongst users of levonorgestrel products were lower than those amongst users of
      desogestrel and gestodene products. A case fatality rate of 3% and a mortality
      rate of 10 per million EWY were estimated. Odds ratios (OR) were calculated for
      confounding variables and different COC formulations. Both database studies
      indicated an excess of current smokers and women with high body mass indices
      amongst cases. There were significantly more cases with asthma in the GPRD study
      and cases who had been using their COC for less than a year. No statistically
      significant differences between COC formulations were found in the analyses where
      controls were matched to cases by practice and year of birth in both the MediPlus
      and GPRD studies. In the GPRD study we also ran a study where controls were
      matched by practice and within 5 year age bands. In this study the OR were
      consistently higher for the newer or 'third generation' products than when
      controls were matched by year of birth. However only the acne formulation/OC
      containing cyproterone acetate and 35 microg ethinyloestradiol yielded a
      significant OR of 2.3. It may be concluded that improvements in prescribing are
      paramount as the results strongly indicate that overweight women and those who
      smoke are at a greater risk of VTE. Further study is required to elucidate the
      possibility that asthma or its treatment may predispose to VTE, alone or in
      combination with other risk factors. However, neither the MediPlus nor GPRD
      studies indicate that any one COC formulation poses a greater risk of VTE than
      another.

PMID- 10652980
TI  - The Transnational Study on Oral Contraceptives and the Health of Young Women.
      Methods, results, new analyses and the healthy user effect.
AB  - The results of the Transnational Study on Oral Contraceptives and the Health of
      Young Women studies are reviewed, potential biases shown, and new analyses are
      presented. The initial finding was a slight increase in the risk of venous
      thromboboembolism (VTE) when users of third generation OC (containing the
      progestins desogestrel and gestodene) were compared with users of older (second
      generation) OC [odds ratio (OR) of 1.5; 95% confidence interval (CI) 1.0, 2.1].
      In order to account for potential biases in the study, new analyses were
      performed. A quadratic spline technique comparing first users of OC with never
      users found that risk of VTE is highest in the first year of OC use, but showed
      no difference between the two generations of OC upon adjustment. An analysis of a
      new dataset which now included full information on the past exposure history of
      all study subjects with a Cox regression model with time-dependent covariates
      produced an OR of 0.8 (0.5, 1.3) for the comparison of current users of third
      generation OC with current users of second generation OC. The results of the
      newer analyses with more refined techniques and with an enhanced dataset which
      includes data collected on the past exposures of all study subjects indicates
      that bias, particularly that introduced by healthy user cohorts, accounts for the
      results initially shown for VTE within the Transnational Study.

PMID- 10652981
TI  - Cardiovascular disease and combined oral contraceptives: reviewing the evidence
      and balancing the risks.
AB  - Cardiovascular risks have been a concern since combined oral contraceptives (OCs)
      were first introduced. In the past four years new, mostly reassuring information
      on the safety of modern, low oestrogen dose OCs has become available. However, in
      1995 the new information showed higher venous thromboembolism (VTE) risk for OCs
      containing desogestrel and gestodene compared with levonorgestrel- or
      norethindrone-containing OCs. The controversial responses by national
      authorities, their scientific and public health merits were hotly debated and
      many considered the differences in risk small and resulted from bias and/or
      confounding. We discuss these arguments and conclude they lack empirical support
      or cannot account for the 2-fold increased risk. The risk of ischaemic stroke and
      myocardial infarction (MI) associated with low oestrogen dose OCs are very small
      in women without cardiovascular risk factors, while increased risk of
      haemorrhagic stroke is confined to women >35 years of age. Applying the most
      recent risks to models of OC-attributable events and deaths, OC-attributable
      mortality in women <35 years is estimated to be <3 per million users annually,
      rising to about 10 per million users annually among smokers. In the context of
      external cause mortality (about 90 per million women of reproductive age annually
      in the UK) such risks appear small. Over the age of 35 years, OC-attributable
      mortality is a more important concern, particularly among smokers. In the absence
      of any appreciable OC-attributable mortality in young healthy women, the
      additional VTE risk for third compared with second generation OCs should be
      considered when women choose which OC to use.

PMID- 10652982
TI  - The aftermath of a pill scare: regression to reassurance.
AB  - In October 1995, following confidential exchanges of findings among investigators
      in several epidemiological studies, the UK Medicines Control Agency sent a 'Dear
      Doctor' letter to all clinical practitioners in the country. The letter alerted
      them to the possibility of an excess risk of venous thromboembolism among women
      taking combined oral contraceptives (OC) with the 'newer' progestins, notably
      desogestrel and gestodene. The communication provoked a major pill scare, not
      just in the United Kingdom but in other countries. The preliminary and
      unpublished findings from the four initial 1995-96 studies reported odds ratios
      (OR) ranging from 1.5 to 23 in the point estimates. These are very low relative
      risks but were communicated in a way that the public perceived as a 'doubling of
      the risks'. In the 3 years since the pill scare, additional research has been
      done. First, deliberate and careful analysis of some of the studies and
      replication of others have shown that the epidemiological investigations were
      affected by unavoidable systematic error. Three types of bias were demonstrated
      empirically, namely, prescription bias, referral bias and healthy user effect or
      attrition of susceptibles. All those biases would tend to drive OR spuriously
      upwards. Additional epidemiological studies have progressively shown lower ORs,
      some of them under the threshold of 1.0, i.e. 'no association'. Two major
      consensus assessments, one carried out by a World Health Organization Scientific
      Group and another undertaken by the International Federation of Fertility
      Societies, both attach little importance to differences between older (second
      generation) combined OC and newer ones (third generation). This paper is a
      synthesis of all published evidence since October 1995, at the time of the pill
      scare and in the 3 years since. In conclusion, all combined oral contraceptive
      pills are equally safe.

PMID- 10652983
TI  - The changing scene--an unnecessary pill crisis.
AB  - A number of case-control studies published in 1995/1996 have shown an apparent
      increase in the risk of venous thromboembolism (VTE) associated with the use of
      third-generation oral contraceptives (OC). However, it was discussed very early
      on that these studies were subject to a number of biases or residual confounding
      that would have increased the risk estimates for third-generation OC while
      lowering those for second-generation preparations. Six new studies or analyses
      were performed trying to take into account many of the methodological problems
      that were discussed for the initial studies: Two population-based database
      analyses in the UK and Germany, a new analysis of the General Practice Registry
      database (GPRD) in the UK, an analysis of a new database of the Transnational
      study, a re-analysis of the original Transnational study with a new technique,
      and a population-based study in Denmark. These studies could not confirm a higher
      VTE risk in users of third-generation OC compared with those using second
      generation OC. Data on the risk of arterial thromboembolism (ischaemic stroke and
      myocardial infarction) show no such difference between generations of OC, with a
      statistically significant reduction in the risk of acute myocardial infarction
      from first- to third-generation preparations in one major study. Some of the
      investigators concluded that there is very likely no increased risk of arterial
      thromboembolism associated with the use of low-dose oestrogen OC in young women
      who are properly screened for cardiovascular risk factors or for such conditions.
      These findings should be taken into account when interpreting the results of
      studies on the risk of VTE in women taking combined OC.

PMID- 10652984
TI  - Conclusions: the relative safety of modern oral contraceptives.
AB  - Published data on the relative safety of second and third generation oral
      contraceptives (OCs) is critically assessed. The original four studies published
      in 1995/1996 and their conclusions are examined in detail, including comments
      made by other investigators. Each study has advantages and flaws which are
      balanced in detail. Newer studies are then examined in the same manner. All
      recent papers indicate an equivalence of safety of second and third generation
      OCs, as the effects of various confounders and biases have been identified and
      analysed. We conclude that absolute risks are minor with both generations and
      that no reasons now exist to indicate any differences in their overall safety. We
      analyse finally how the pill crisis arose, and make suggestions about future
      reporting on OC safety.

PMID- 10652986
TI  - Cerebrospinal fluid lipoproteins are more vulnerable to oxidation in Alzheimer's
      disease and are neurotoxic when oxidized ex vivo.
AB  - Brain regional oxidative damage is thought to be a central mechanism in the
      pathogenesis of Alzheimer's disease (AD). Recent studies of cerebrospinal fluid
      (CSF) have suggested that increased lipid peroxidation of CSF and CSF
      lipoproteins also may occur in AD patients. In the present study, we determined
      the susceptibility of human CSF to ex vivo lipid peroxidation and tested the
      hypothesis that oxidized CSF lipoproteins may be neurotoxic. Whole CSF or a CSF
      lipoprotein fraction (d < 1.210 g/mL) was oxidized with 2,2'-azobis(2-amidino
      propane)dihydrochloride (AAPH), a hydrophilic free-radical generator. Kinetics of
      CSF lipid peroxidation were followed by a standard fluorescence product
      accumulation assay. Oxidation of AD CSF yielded significantly shorter fluorescent
      lag times than controls, indicating reduced antioxidant capacity. Electrophoretic
      mobilities of CSF apolipoproteins were specifically reduced upon oxidation of CSF
      with AAPH, suggesting that lipoproteins are primary targets of CSF lipid
      peroxidation. Cultured neuronal cells were exposed to physiological
      concentrations of isolated CSF lipoproteins oxidized with increasing
      concentrations of AAPH; the resulting neurotoxicity showed a significant linear
      AAPH concentration-response relationship. These results suggest that oxidized CSF
      lipoproteins may contribute to the pathogenesis of neurodegeneration in AD.

PMID- 10652987
TI  - Effect of the nonenzymatic glycosylation of high density lipoprotein-3 on the
      cholesterol ester transfer protein activity.
AB  - This study examines the relationship between high density lipoprotein-3 (HDL-3)
      glycation and cholesteryl ester transfer mediated by cholesteryl ester transfer
      protein (CETP). HDL-3 were glycated with various glucose concentrations (0-200
      mM) for 3 d at 37 degrees C with sodium cyanoborohydride as reducing agent and
      antioxidants. About 47% of the lysine residues were glycated in the presence of
      200 mM glucose, resulting in an increase in the cholesterol ester (CE) transfer
      of about 30%. Apparent kinetic parameters [expressed as maximal transfer
      (appT(max)) and CE concentration at half of T(max)(appK(H))] of CETP activity
      with glycated HDL-3 showed conflicting and paradoxical data: an increase in CETP
      activity associated with a decrease of CETP affinity. These alterations were not
      due to a change in HDL-3 lipid and protein composition nor to a peroxidative
      process but were associated with an increase in HDL-3 electronegativity and a
      decrease of HDL-3 fluidity. This study suggests that glycation modifies the
      apolipoprotein's conformation and solvation which are major determinants of
      interfacial properties of HDL-3. These modifications in turn affect CETP
      reactivity.

PMID- 10652985
TI  - Lipids in human milk.
AB  - I have reviewed recent (March 1995-December 1997) papers on human milk lipids
      including many on fatty acid (FA) composition. The effects of maternal diets on
      the profiles are apparent. However, more data on the composition of milk lipids
      are needed. It is noteworthy that so few papers on milk FA composition have
      reported analyses using high-resolution gas-liquid chromatography columns. Two of
      these were on milk from women in North America. The diets in North America are
      varied and the number of analyses few. We do not have a reliable data base
      showing the ranges of biologically important acids. Except for the gangliosides,
      few new data on the other lipids appeared during this period.

PMID- 10652988
TI  - Effect of eicosapentaenoic acid on the proliferation and incidence of apoptosis
      in the colorectal cell line HT29.
AB  - Fish oil has been shown to reduce the induction of colorectal cancer in animal
      models by a mechanism which may involve suppression of mitosis, increased
      apoptosis, or both. We used the human colonic adenocarcinoma cell line HT29 to
      explore the effects of the long-chain n-3 polyunsaturated fatty acid
      eicosapentaenoic acid (EPA) on cell proliferation and death in vitro. Cells were
      cultured in media containing EPA at 5, 10, and 15 microg/mL. Cell number and
      thymidine incorporation were used to quantify proliferation, and cell cycle
      effects were studied using flow cytometry. Gel electrophoresis, annexin-V
      binding, and morphological criteria were used to characterize apoptosis. Adherent
      cells and freely floating detached cells were treated as two distinct
      populations. In the presence of EPA at 10 and 15 microg/mL there was a marked
      reduction in the growth rate of adherent HT29 colonies, owing to an increased
      detachment of adherent cells. After treatment with 10 or 15 microg/mL EPA the
      proportion of adherent cells in S-phase increased, indicating either a block in
      late S-phase or early G2. Floating cells showed evidence of extensive DNA
      cleavage, but the proportion of floating cells with sub GO DNA content declined
      on treatment with 10 or 15 microg/mL EPA even though the number of floating cells
      increased. We conclude that EPA does not inhibit mitosis of adherent cells, but
      increases the rate at which they become detached from the substrate, probably at
      an early stage in the initiation of apoptosis. This mechanism may be analogous to
      "anoikis," or induction of apoptosis in response to loss of cell contact, and may
      contribute to the anticarcinogenic effects of fish oil in vivo.

PMID- 10652989
TI  - Effects of eicosapentaenoic acid and docosahexaenoic acid on plasma membrane
      fluidity of aortic endothelial cells.
AB  - We investigated the relative effects of n-3 eicosapentaenoic acid (EPA, 20:5n-3)
      and docosahexaenoic acid (DHA, 22:6n-3) on the plasma membrane fluidity of
      endothelial cells (EC) cultured from the thoracic aorta by determining
      fluorescence polarization of 1,6-diphenyl-1,3,5-hexatriene (DPH) and its cationic
      derivative trimethylamino-DPH (TMA-DPH). Fluidity assessed by TMA-DPH
      demonstrated no significant differences in plasma membranes of vehicle (dimethyl
      sulfoxide; DMSO)-, EPA-, and DHA-treated EC. Plasma membrane fluidity assessed by
      DPH polarization, however, was significantly higher in the order of DHA > EPA >
      DMSO. Total cholesterol content decreased significantly by 28.4 and 15.9% in the
      plasma membranes of DHA- and EPA-treated cells, respectively. Total phospholipid
      content remained unaltered in the plasma membranes of the three groups of cells;
      however, the molar ratio of total cholesterol to phospholipid decreased
      significantly only in the membranes of DHA-treated EC. The unsaturation index in
      the plasma membranes of EPA- and DHA-treated cells increased by 35.7 and 64.3%,
      respectively, compared with that in the plasma membranes of control cells. The
      activities of catalase and glutathione peroxidase in the whole-cell homogenates,
      and levels of lipid peroxides in either the whole-cell homogenates or in plasma
      membrane fractions were not altered in EPA- or DHA-treated EC. These results
      indicate that the influence of DHA is greater than that of EPA in increasing
      plasma membrane fluidity of vascular EC. We speculate that the greater effect of
      DHA compared to EPA is due to its greater ability to decrease membrane
      cholesterol content or the cholesterol/phospholipid molar ratio, or both, and
      also to its greater ability in elevating the unsaturation index in the plasma
      membranes of EC.

PMID- 10652990
TI  - Effect of peanut oil and randomized peanut oil on cholesterol and oleic acid
      absorption, transport, and distribution in the lymph of the rat.
AB  - Peanut oil was shown to be atherogenic in cholesterol-fed rats, rabbits, and
      monkeys. However, after randomization, a process in which the fatty acids in
      peanut oil are randomly rearranged, its atherogenicity was significantly reduced
      in cholesterol-fed rabbits and monkeys. The mechanism for this effect remains
      unknown. This study was designed to investigate whether the absorption, transport
      and distribution of dietary cholesterol and oleic acid in the lymph were altered
      in the presence of peanut oil or randomized peanut oil. Previous investigators
      collected lymph through the mesenteric duct for 6 h and analyzed lymph for
      cholesterol. In the present study, lymph fluids were collected at timed intervals
      for up to 8 h and then at 24 h via the thoracic duct. Cholesterol and oleic acid
      (fatty acid) were estimated not only in the whole lymph but also in lymph
      lipoprotein fractions and in major lipid fractions. A 24-h lymph collection will
      enhance accuracy as short-term fluctuations in lipid absorption will not affect
      the results. Thoracic duct lymph collection is quantitative compared to
      mesenteric duct lymph collection, which provides only a fraction of the total
      lymph. Rats were given a lipid emulsion containing either peanut oil or
      randomized peanut oil. The emulsion also contained cholesterol, oleic acid, and
      sodium taurocholate in saline and was given through a duodenal catheter. Results
      show that absorption, transport, and distribution of cholesterol and oleic acid
      in the lymph fluids were similar in both dietary groups. These results suggest
      that the atherogenicity of peanut oil may be due to other events taking place
      subsequent to the release of cholesterol-containing chylomicrons and very low
      density lipoprotein by the small intestinal epithelial cells into the blood or
      may be due to the triglyceride structure itself.

PMID- 10652992
TI  - Geometry of conjugated double bonds of CLA isomers in a commercial mixture and in
      their hepatic 20:4 metabolites.
AB  - Rats were fed a fat-free diet for 2 wk. After this period, while maintaining the
      animals on the same diet, the rats were given intragastrically 180 mg per day of
      a mixture of conjugated linoleic acids (CLA) as triacylglycerols. Gas
      chromatography mass spectrometry (GC-MS) analyses of this mixture, as well as
      hydrazine reduction and GC-MS and GC-Fourier transform infrared analyses of the
      resulting monoenes, revealed the presence of two major isomers, the 9c,11t- and
      the 10t,12c-18:2 accompanied by smaller amounts of the 8t, 10c and the 11c, 13t
      18:2 isomers. Minor quantities of cis,cis and trans,trans conjugated isomers also
      were detected. The total fatty acid methyl esters from the liver lipids were
      fractionated by reversed-phase high-performance liquid chromatography, and the
      fraction containing the 20:4 isomers was further fractionated by silver nitrate
      thin-layer chromatography. A band containing two 20:4 conjugated isomers was
      submitted to hydrazine reduction and the resulting monoenes analyzed by GC-MS as
      dimethyl-oxazoline derivatives. The two conjugated isomers were tentatively
      identified as 5c,8c, 11c, 13t-20:4 and 5c,8c,12t,14c-20:4. These could be formed
      by desaturation and elongation of the 9c,11t- and 10t,12c-18:2 present in the
      commercial CLA mixture.

PMID- 10652991
TI  - Dietary phospholipid alters biliary lipid composition in formula-fed piglets.
AB  - Plasma cholesterol, arachidonic acid (AA, 20:4n-6), and docosahexaenoic acid
      (DHA, 22:6n-3) are higher in breast-fed infants than in infants fed formula
      without cholesterol, AA, or DHA. This study investigated differences in plasma,
      hepatic, and bile lipids and phospholipid fatty acids, and expression of hepatic
      proteins involved in sterol metabolism that result from feeding formula with
      cholesterol with egg phospholipid to provide AA and DHA. For this study, three
      groups of piglets were evaluated: piglets fed formula with 0.65 mmol/L
      cholesterol, the same formula with 0.8% AA and 0.2% DHA from egg phospholipid,
      and piglets fed sow milk. Piglets fed the formula with phospholipid AA and DHA
      had higher plasma high density lipoprotein, but not apoprotein (apo) B
      cholesterol or triglyceride; higher bile acid and phospholipid concentrations in
      bile; and higher liver and bile phospholipid AA and DHA than piglets fed formula
      without AA and DHA (P < 0.05). Hydroxy methylglutaryl (HMG)-CoA reductase and 7
      alpha-hydroxylase, the rate-limiting enzymes of cholesterol and bile acid
      synthesis, respectively, and low density lipoprotein receptor mRNA levels were
      not different between piglets fed formula without and with phospholipid AA and
      DHA, but HMG-CoA reductase and 7alpha-hydroxylase mRNA were higher, and plasma
      apo B containing lipoprotein cholesterol was lower in all piglets fed formula
      than in piglets fed milk. These studies show that supplementing formula with AA
      and DHA from egg phospholipid alters bile metabolism by increasing the bile AA
      and DHA, and bile acid and phospholipid.

PMID- 10652993
TI  - Atorvastatin and simvastatin have distinct effects on hydroxy methylglutaryl-CoA
      reductase activity and mRNA abundance in the guinea pig.
AB  - The effects of atorvastatin and simvastatin on hydroxy methylglutaryl (HMG)-CoA
      reductase activity and mRNA abundance were studied in guinea pigs randomized to
      three groups: untreated animals and those treated with 20 mg/kg of atorvastatin
      or simvastatin. Guinea pigs were fasted for 0, 6, 12, or 18 h in an attempt to
      remove the drug from their systems. Reductase activity and mRNA levels were
      analyzed after each time point. Reductase inhibitor treatment resulted in 50-62%
      lower cholesterol concentrations compared to untreated guinea pigs (P < 0.0001),
      while plasma triacylglycerol (TAG) concentrations did not differ among groups.
      Plasma cholesterol and TAG were 50-70% lower after 18 h fasting in the three
      groups (P < 0.001). In the nonfasting state, simvastatin and atorvastatin
      treatment did not affect HMG-CoA reductase activity compared with untreated
      animals. However, after 6 h of fasting, simvastatin-treated guinea pigs had
      higher HMG-CoA reductase activity than untreated animals (P < 0.01), suggesting
      that the drug had been removed from the enzyme. In contrast, atorvastatin-treated
      guinea pigs maintained low enzyme activity even after 18 h of fasting. Further,
      HMG-CoA reductase mRNA abundance was increased by sevenfold after atorvastatin
      treatment and by twofold after simvastatin treatment (P < 0.01). These results
      suggest that simvastatin and atorvastatin have different half-lives, which may
      affect HMG-CoA reductase mRNA levels. The increase in reductase activity by
      simvastatin during fasting could be related to an effect of this statin in
      stabilizing the enzyme. In contrast, atorvastatin, possibly due to its longer
      half-life, prolonged inhibition of HMG-CoA reductase activity and resulted in a
      greater increase in mRNA synthesis.

PMID- 10652994
TI  - Synthesis of acetyl,docosahexaenoyl-glycerophosphocholine and its
      characterization using nuclear magnetic resonance.
AB  - Docosahexaenoic acid (DHA) circulates in mammals in lipoproteins and bound to
      serum albumin as a nonesterified fatty acid as well as esterified in
      lysophosphatidylcholine (lysoPC). 1-Lyso,2-DHA-glycerophosphocholine (GPC) is an
      unstable isomer because of a primary alcohol at the sn-1 position. To keep DHA at
      the sn-2 position of lysoPC, its usual position for the corresponding lysoPC to
      be acylated into PC in tissues, we synthesized 1-acetyl,2-DHA-GPC and confirmed
      its structure by use of nuclear magnetic resonance (NMR) spectroscopy in
      comparison with its positional isomer, 1-DHA,2-acetyl-GPC. 1-Lyso,2-DHA-GPC was
      prepared from 1-stearoyl,2-DHA-GPC by enzymatic hydrolysis and purified by high
      performance liquid chromatography. The isomerization of 1-lyso,2-DHA-GPC into 1
      DHA,2-lyso-GPC was obtained by keeping the former overnight at room temperature
      under nitrogen. Both lysoPC isomers were acetylated by acetic anhydride into 1
      acetyl,2-DHA-GPC and 1-DHA,2-acetyl-GPC, respectively, and the resulting
      phospholipids were fully characterized by NMR. In particular, the 1,2
      substitution pattern of the acetyl and DHA chains could be easily detected by 2D
      heteronuclear multibond correlation. We conclude that 1-acetyl,2-DHA-GPC might be
      considered as a stable form of 1-lyso,2-DHA-GPC for its delivery to tissues, if
      the latter exhibits acetyl hydrolase activity.

PMID- 10652995
TI  - Nondestructive NMR determination of oil composition in transformed canola seeds.
AB  - Magic-angle spinning (MAS) 13C nuclear magnetic resonance (NMR) spectroscopy is a
      convenient method for nondestructive, quantitative characterization of seed oil
      composition. We describe results for intact hybrid and transformed canola seeds.
      The MAS 13C NMR technique complements and agrees with gas chromatography results.
      The spectral resolution approaches that of neat, liquid oils. MAS 13C NMR data
      allow quantitative analysis of major oil components, including saturates and
      oleic, linoleic, and linolenic acyl chains. 13C NMR directly and quantitatively
      elucidates, triglyceride regiochemistry and acyl chain cis-trans isomers that
      cannot be quickly detected by other methods. MAS 13C NMR can serve as the primary
      method for development of near-infrared seed oil calibrations. These NMR methods
      are nondestructive and attractive for plant-breeding programs or other studies
      (e.g., functional genomics) where loss of seed viability is inconvenient.

PMID- 10652996
TI  - A rapid and quantitative method for total fatty acid analysis of fungi and other
      biological samples.
AB  - A quantitative method for the one-step esterification and determination of
      absolute amounts of polyunsaturated fatty acids in biotechnologically produced
      fungal mycelia is proposed. A system of two internal standards was used to
      quantify the total fatty acid content of the samples by gas chromatography. The
      degree of methylation of the analyzed fatty acids was calculated using the
      internal standards, and subsequently this quotient was used to validate the
      derivatization and extraction reactions. By utilizing this degree of methylation,
      the corrected amounts of the various fatty acids in the sample can be calculated.

PMID- 10652997
TI  - Experimental infection with bovine herpesvirus-4 enhances atherosclerotic process
      in rabbits.
AB  - An association of herpesvirus and atherosclerosis has been suggested by
      seroepidemiologic studies and detection of the virus in arterial tissues. To
      facilitate the studies of the pathogenic role of herpesvirus in atherosclerosis,
      we established a rabbit model of atherosclerosis with bovine herpesvirus type-4
      (BHV-4). Forty New Zealand White rabbits were randomly divided into six groups.
      Groups 1, 2, and 3 were inoculated iv with BHV-4 and control Groups 4, 5, and 6
      with normal saline. Groups 1 and 4 were fed a regular diet throughout the
      experiment; Groups 2 and 5 were fed a diet supplemented with 2% cholesterol for 3
      weeks starting at 3 weeks postinoculation; and Groups 3 and 6 with a diet
      supplemented with 2% cholesterol for 6 weeks starting at 3 days postinoculation.
      Extensive atherosclerotic lesions in Groups 2, 3, and 6, and small lesions in two
      rabbits in Group 1 were observed, but no obvious lesions were observed in Groups
      4 and 5. BHV-4 DNA was demonstrated by polymerase chain reaction and liquid
      hybridization in aortic sections, various tissue samples, and peripheral blood
      mononuclear cells of all infected rabbits. Our studies demonstrated that BHV-4
      can accelerate the atherosclerotic process in rabbits, and that experimental
      infection of rabbits with BHV-4 can be a useful atherosclerosis model.

PMID- 10652998
TI  - TNP-470, a potent angiogenesis inhibitor, amplifies human T lymphocyte activation
      through an induction of nuclear factor-kappaB, nuclear factor-AT, and activation
      protein-1 transcription factors.
AB  - TNP-470, an angiogenesis inhibitor derived from fumagillin, is foreseen as a
      promising anti-cancer drug. Its effectiveness to restrain tumor growth and its
      lack of major side effects have been demonstrated in several animal models and
      have led the drug to reach phase III clinical trials. Beside its antiangiogenesis
      activities, TNP-470 exhibits several effects on the immune system. We had shown
      previously that TNP-470 stimulated B lymphocyte proliferation through an action
      on T cells. In this study, we examined the cellular and molecular modifications
      induced by TNP-470 in normal human T lymphocytes. Transmission electron
      microscopic examination of PHA/TNP-470-treated T cells revealed significant
      morphologic modifications when compared with PHA-treated control T cells. TNP-470
      induced indeed an important and significant increase of the nuclear size as well
      as major nuclear chromatin decondensation. This observation indicated that TNP
      470 amplified T-cell activation and led us to investigate its effects on the
      activation of transcription factors involved in T-cell activation. Using
      electrophoretic mobility shift assays, we have demonstrated that TNP-470
      amplifies and extends the DNA-binding activity of nuclear factor-AT, nuclear
      factor-KB, and activation protein-1 in T cells. Furthermore, the angioinhibin
      significantly increased the secretion of IL-2 and IL-4. Our data demonstrate that
      TNP-470 amplifies the activation of T cells. This effect, whose molecular
      mechanisms remain to be elucidated, has to be taken into account in the
      assessment of the antitumor effect of the drug.

PMID- 10652999
TI  - Subsets of macrophages and dendritic cells in nonobese diabetic mouse pancreatic
      inflammatory infiltrates: correlation with the development of diabetes.
AB  - Islet-specific T cells are essential in the development of type I diabetes. The
      role of non-lymphoid cells is relatively unclear, although infiltration of
      dendritic cells and macrophages is the first sign of islet autoimmunity in
      diabetes-prone nonobese diabetic (NOD) mice. BDC2.5 is one of the autoreactive T
      cell clones isolated from NOD mice. Transfer of BDC2.5 T cells into young NOD
      mice accelerates diabetes development, whereas transgenic expression of the
      BDC2.5 T cell receptor on NOD T cells (BDC2.5 TCR-Tg NOD) markedly reduces
      diabetes development. We show that, although the same antigen-specificity is
      involved, both models differ significantly in insulitis. BDC2.5 TCR-Tg NOD mice
      develop an extensive, but non-aggressive, peri-insulitis by 3 weeks of age. In
      these large peri-islet infiltrates, resembling secondary lymphoid tissue, BM8+
      macrophages (Mphi) are virtually absent. In contrast, BDC2.5 T cell clone
      transfer results in an aggressive insulitis with small infiltrates, but
      relatively large numbers of BM8 Mphi. Infiltration of BM8+ Mphi therefore
      correlates with islet destruction. This is, however, not observed for all Mphi;
      Monts-4+ Mphi follow a reverse pattern and are present in higher numbers in
      BDC2.5 TCR-Tg than in transferred mice. ER-MP23+ Mphi are reduced in both
      transferred and transgenic mice compared with wild-type NOD. Thus, this study
      underlines and extends previous data suggesting that Mphi are implicated in both
      early and late phases in diabetes development. Furthermore, our data imply that
      subsets of non-lymphoid cells have different roles in diabetes development. It
      is, therefore, important to recognize this heterogeneity when interpreting both
      in vivo and in vitro studies concerning non-lymphoid cells in diabetes.

PMID- 10653000
TI  - Docosahexaenoic acid deficit is not a major pathogenic factor in peroxisome
      deficient mice.
AB  - Docosahexaenoic acid (DHA), a major component of membrane phospholipids in brain
      and retina, is profoundly reduced in patients with peroxisome biogenesis
      disorders (Zellweger syndrome). Supplementing newborn patients with DHA resulted
      in improved muscular tone and visual functions. The purpose of this study was to
      investigate (a) whether DHA levels were also reduced in newborn PEX5 knockout
      mice, the mouse model of Zellweger syndrome that we recently generated; (b)
      whether these levels could be normalized by supplying DHA; and (c) whether this
      results in longer survival. The DHA concentration in brain of newborn PEX5-/-
      mice was reduced by 40% as compared with levels in normal littermates; in liver,
      no differences were noticed. The daily administration of 10 mg of DHA-ethyl ester
      (EE) to pregnant heterozygous mothers during the last 8 days of gestation
      resulted in a normalization of brain DHA levels in Zellweger pups. However, no
      clinical improvement was observed in these pups, and the neuronal migration
      defect was unaltered. These data suggest that the accretion of DHA in the brain
      at the end of embryonic development is not only supported by the maternal supply
      but also depends on synthesis in the fetal brain. Furthermore, the DHA deficit
      does not seem to be a major pathogenic factor in the newborn Zellweger mice.

PMID- 10653001
TI  - Critical evaluation of ECV304 as a human endothelial cell model defined by
      genetic analysis and functional responses: a comparison with the human bladder
      cancer derived epithelial cell line T24/83.
AB  - Early reports indicated that ECV304 was a spontaneously-transformed line derived
      from a Japanese human umbilical vein endothelial cells (HUVEC) culture. Many
      morphological, immunochemical, and genetic studies provided further evidence that
      ECV304 was a valuable biomedical research tool and could be used to study
      processes that include angiogenesis in vitro and signal transduction by a variety
      of G protein-coupled receptors. However, several distinct differences between
      ECV304 and HUVEC are now apparent and recent reports have indicated genetic
      similarity between ECV304 and T24/83, a human bladder cancer cell line. To
      further assess the utility of ECV304 as a human endothelial cell model, we
      compared the functional responses of ECV304 and T24/83 to a range of G protein
      coupled receptor agonists. We also used DNA fingerprinting to karyotype both
      ECV304 and T24/83. Both ATP and uridine triphosphate (UTP) stimulated inositol
      phosphate metabolism in ECV304 without alteration of cAMP levels. Comparative
      data using selective P2Y receptor agonists indicated that this response, leading
      to calcium mobilization from intracellular stores, was predominantly mediated by
      the activation of P2Y2 receptors. Similar responses were recorded from both
      ECV304 and T24/83 cells. ECV304 expressed a relatively high basal activity of NOS
      that was reduced by L-NAME and stimulated by P2Y2 receptor agonists. In contrast,
      P2Y2 receptor activation did not induce prostaglandin synthesis in ECV304. Both
      ECV304 and T24/83 express receptors for adenosine, adrenaline, and calcitonin,
      which stimulate adenylate cyclase. Proliferation of ECV304 and T24/83 cells,
      measured by the incorporation of [3H]thymidine into DNA, was largely serum
      independent. This was in contrast to parallel experiments with porcine and bovine
      aortic endothelial cells that indicated a marked serum-dependent increase in DNA
      synthesis. Genetic analysis confirmed that ECV304 and T24/83 are identical.
      ECV304 displays some endothelial characteristics and is useful for the study of
      receptor pharmacology. However, ECV304 is not of HUVEC origin and is therefore an
      inappropriate cell line to study endothelial cell biology.

PMID- 10653002
TI  - Platelet-derived growth factors stimulate proliferation and extracellular matrix
      synthesis of pancreatic stellate cells: implications in pathogenesis of pancreas
      fibrosis.
AB  - At present, the cell-cell interactions and molecular mechanisms of pancreas
      fibrogenesis are largely unknown. The purpose of this study was to investigate
      paracrine stimulatory loops between platelets and pancreatic stellate cells
      (PSC). Human PSC were obtained by outgrowth from fibrotic human pancreas. Native
      platelet lysate (nPL) and transiently acidified platelet lysate (aPL) were added
      to cultured PSC (passage 4 to 7) in the absence of serum. The synthesis of
      collagen types I and III and c-fibronectin (cFN) was demonstrated on protein
      (immunofluorescence and quantitative immunoassay) and mRNA (Northern blot) level.
      Using sections of human pancreas with acute pancreatitis, platelet aggregates in
      capillaries were demonstrated by transmission electron microscopy. nPL, and to an
      even greater extent aPL, significantly increased the synthesis of collagen types
      I and III and of c-FN (120 microl/ml aPL increased collagen type I concentration
      in PSC supernatants by 1.99 +/- 0.17 times and c-FN of 2.49 +/- 0.28 times, mean
      +/- SD, n = 3). nPL and aPL also significantly stimulated cell proliferation
      (increased bromodeoxyuridine (BrdU) incorporation by 6.4 +/- 0.78 times and 10 +/
      0.29 times, respectively). By preincubating aPL with transforming growth factor
      beta (TGFbeta)- and platelet-derived growth factor (PDGF)-neutralizing antibodies
      and the TGFbeta-latency associated peptide, respectively, TGFbeta1 was identified
      as the main mediator stimulating matrix synthesis and PDGF as the responsible
      mitogen. Our data demonstrate that platelets contain fibrogenic mediators that
      stimulate proliferation (PDGF) and matrix synthesis (TGFbeta1) of cultured PSC.
      We suggest that platelets and PSC cooperate in the development of pancreas
      fibrosis.

PMID- 10653003
TI  - Microsatellite instability in the adenoma-carcinoma sequence of the stomach.
AB  - Sixty-three cases of stomach resections harboring both adenoma and carcinoma were
      analyzed for microsatellite instability (MSI). The cases included 28 carcinomas
      arising from adenoma (Type I) and 35 carcinomas with separate adenoma (Type II).
      The results of MSI assessed by 49 markers were the same for BAT-26 instability.
      The incidence of MSI was 21% in gastric adenoma and 30% in gastric carcinoma,
      which is significantly higher than gastric carcinoma without associated adenoma
      (p < 0.01). Five of eight (63%) cases of multiple carcinomas associated with
      adenoma showed MSI+ in adenoma and in one or more carcinoma lesion(s). Eight of
      thirteen (62%) MSI+ adenomas were associated with carcinoma, whereas 20 of 50
      (40%) MSI adenomas were associated with carcinoma. MSI+ adenomas of Type I showed
      a higher mutation rate of the TGF-beta RII gene than Type II (88% versus 40%).
      Gastric adenoma with TGF-beta RII gene mutation was more prone to transform into
      carcinoma (p = 0.03). This study revealed that gastric carcinoma arising from
      adenoma is frequently associated with a mismatch repair deficiency mechanism. In
      the gastric adenoma-carcinoma sequence, TGF-beta RII gene mutation occurred early
      in the adenoma stage and it persisted after malignant transformation.

PMID- 10653004
TI  - Loss of heterozygosity on chromosome 10 is more extensive in primary (de novo)
      than in secondary glioblastomas.
AB  - Glioblastomas develop de novo (primary glioblastomas) or through progression from
      low-grade or anaplastic astrocytoma (secondary glioblastomas). There is
      increasing evidence that these glioblastoma subtypes develop through different
      genetic pathways. Primary glioblastomas are characterized by EGFR and MDM2
      amplification/overexpression, PTEN mutations, and p16 deletions, whereas
      secondary glioblastomas frequently contain p53 mutations. Loss of heterozygosity
      (LOH) on chromosome 10 (LOH#10) is the most frequent genetic alteration in
      glioblastomas; the involvement of tumor suppressor genes, other than PTEN, has
      been suggested. We carried out deletion mappings on chromosome 10, using PCR
      based microsatellite analysis. LOH#10 was detected at similar frequencies in
      primary (8/17; 47%) and secondary glioblastomas (7/13; 54%). The majority (88%)
      of primary glioblastomas with LOH#10 showed LOH at all informative markers,
      suggesting loss of the entire chromosome 10. In contrast, secondary glioblastomas
      with LOH#10 showed partial or complete loss of chromosome 10q but no loss of 10p.
      These results are in accordance with the view that LOH on 10q is a major factor
      in the evolution of glioblastoma multiform as the common phenotypic end point of
      both genetic pathways, whereas LOH on 10p is largely restricted to the primary
      (de novo) glioblastoma.

PMID- 10653005
TI  - Anti-very late antigen-1 monoclonal antibody modulates the development of
      secondary lesion and T-cell response in experimental arthritis.
AB  - Rats injected in the hind paw with a mixture of Mycobacterium butirricum
      emulsified in mineral oil (FA) developed a severe polyarthritis that shared some
      immunological features with human rheumatoid arthritis. After this local
      administration, rats developed a secondary lesion (edema) in the contralateral
      paw, which is a hallmark of immune system activation. In vivo intravenous
      treatment with a monoclonal anti-very late antigen (VLA)-1 antibody (HA31/8)
      significantly reduced the edema formation in the contralateral paw. T cells
      isolated from contralateral paw draining lymph nodes of FA rats treated with
      HA31/8 showed a reduced cell proliferation in vitro, after stimulation with
      concanavalin A. Furthermore FACS analysis showed that the reduction in
      proliferation was concomitant to a reduction in the number of T cells positive to
      surface IL-2 receptor expression. Our data indicate that after in vivo treatment
      with a monoclonal anti-very late antigen-1 antibody, there is a beneficial effect
      on the development of the secondary lesion, which correlates to the reduced
      ability of T cells to proliferate in vitro as well as to a reduced surface
      expression of IL-2 receptor. The association of this antibody to other drugs
      interfering at other levels in rheumatoid arthritis may open a new therapeutic
      window.

PMID- 10653006
TI  - Teratomatous genotype detected in malignancies of a non-germ cell phenotype.
AB  - Originating from post-meiotic germ cells, mature ovarian teratomas (MOT) are
      genetically homozygous tumors within heterozygous hosts. MOT may be associated
      with malignant tumors of a non-germ cell phenotype (so-called malignant
      transformation). Based on the presence of in situ changes, some cases have been
      hypothesized to arise from teratomatous tissue. However, other malignancies
      associated with mature teratomas, such as sarcomas, may originate from either
      teratomatous elements or preexisting somatic ovarian tissue. Eight cases of MOT
      containing various histologic types of malignancy, including four squamous cell
      carcinomas, two sarcomas, one thyroid carcinoma, and one carcinoid tumor, were
      selected for study. Using selective tissue microdissection and PCR-based analysis
      of the extracted DNA, we compared the genotypic pattern of the mature
      teratomatous components to the associated malignant neoplasm with a random panel
      of highly informative genetic markers for different chromosomes. In all eight
      cases, genetic analysis of the malignant component revealed a homozygous
      genotype. In seven cases, the genetic profiles of mature teratomas and the
      associated malignant tumors were identical, suggesting a direct pathogenetic
      relationship between these lesions. In one case, the malignant component revealed
      homozygosity of different alleles compared with mature teratoma, suggesting
      independent teratomatous growth processes. This finding indicates that some
      ovarian malignancies of the non-germ cell phenotype arise in teratoma and fall
      into the spectrum of germ cell tumors.

PMID- 10653007
TI  - Structural alterations in the rat kidney after acute arsine exposure.
AB  - The mechanism of arsine (AsH3) toxicity is not completely understood. In this
      investigation, the toxicity of AsH3 and AsH3-produced hemolytic products was
      determined in primary culture of renal cortical epithelial cells and in the in
      situ isolated rat kidney. The objective of this study was to model kidney
      dysfunction caused by AsH3 exposure. The hypothesis was that unchanged AsH3 and
      AsH3-produced hemolysate that may contain arsenite (As(III)) as metabolite are
      both responsible for renal toxicity. Toxicity in isolated cells was determined by
      2, 3-bis[2-methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxa nilide inner
      salt (XTT) bioreduction, intracellular potassium (K+), and lactate dehydrogenase
      (LDH) leakage. Data from XTT bioreduction showed that most toxicity occurred at 1
      hour and was independent of the arsenic species. At 4 hours, the observed
      toxicity depended on the arsenic species and was generated by As(III). In the
      isolated cells, the As(III)-spiked hemolysate produced similar toxicities with
      regard to intracellular K and LDH. The AsH3-hemolysate only affected LDH at 1
      hour. Unchanged AsH3 was very toxic to the isolated rat kidney. In this system,
      after 10 minutes exposure to AsH3, the effects of toxicity were observed mainly
      in the glomerular and peritubular endothelial cells. Tubular epithelial cells
      also presented early signs of toxicity. The AsH3-hemolysate was not toxic after a
      1 -minute exposure. These data suggested that early cytotoxicity caused by
      unchanged AsH3 results in kidney dysfunction, produced by AsH3, and later by the
      formation of a hemolysate that may contain As(III). These data may be important
      in understanding the renal toxic effects after AsH3 intoxication.

PMID- 10653008
TI  - Heterogeneity of the angiogenic response induced in different normal adult
      tissues by vascular permeability factor/vascular endothelial growth factor.
AB  - Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) is an
      angiogenic cytokine with potential for the treatment of tissue ischemia. To
      investigate the properties of the new blood vessels induced by VPF/VEGF, we
      injected an adenoviral vector engineered to express murine VPF/VEGF164 into
      several normal tissues of adult nude mice or rats. A dose-dependent angiogenic
      response was induced in all tissues studied but was more intense and persisted
      longer (months) in skin and fat than in heart or skeletal muscle (< or =3 weeks).
      The initial response (within 18 hours) was identical in all tissues studied and
      was characterized by microvascular hyperpermeability, edema, deposition of an
      extravascular fibrin gel, and the formation of enlarged, thin-walled pericyte
      poor vessels ("mother" vessels). Mother vessels developed from preexisting
      microvessels after pericyte detachment and basement membrane degradation. Mother
      vessels were transient structures that evolved variably in different tissues into
      smaller daughter vessels, disorganized vessel tangles (glomeruloid bodies), and
      medium-sized muscular arteries and veins. Vascular structures closely resembling
      mother vessels and each mother vessel derivative have been observed in benign and
      malignant tumors, in other examples of pathological and physiological
      angiogenesis, and in vascular malformations. Together these data suggest that
      VPF/VEGF has a role in the pathogenesis of these entities. They also indicate
      that the angiogenic response induced by VPF/VEGF is heterogeneous and tissue
      specific. Finally, the muscular vessels that developed from mother vessels in
      skin and perimuscle fat have the structure of collaterals and could be useful
      clinically in the relief of tissue ischemia.

PMID- 10653009
TI  - Caspases mediate C2-ceramide-induced apoptosis of the human oligodendroglial cell
      line, MO3.13.
AB  - The signalling molecule ceramide participates in the sphingomyelin pathway and
      accumulates intracellularly in response to inflammatory mediators. Here we show
      that membrane permeable C2-ceramide is apoptogenic in the immortalised human
      oligodendroglial cell line MO3.13. Apoptosis (defined by cell shrinkage and
      chromatin condensation) is accompanied by caspase enzyme activation.
      Immunoblotting analysis of extracts from differentiated MO3.13 cells revealed the
      presence of caspase-3 proenzyme, activation by cleavage of pro-caspase-3 in cells
      treated with C2-ceramide and cleavage of the caspase substrates fodrin and
      rabaptin. Lysates also showed cleavage of a fluorogenic peptide substrate.
      Addition of the general caspase inhibitor BAF markedly attenuated apoptosis of
      MO3.13 oligodendroglia. A role for caspase-3-like enzymes in ceramide-induced
      apoptosis of oligodendroglia may have important implications for approaches to
      treatment of demyelinating diseases.

PMID- 10653010
TI  - Interleukin-12 promotes neurite outgrowth in mouse sympathetic superior cervical
      ganglion neurons.
AB  - To determine the role of cytokines in the nervous system, we examined the effect
      of interleukin-12(IL-12) on the nerve regeneration of mouse superior cervical
      ganglion cells (SCG). IL-12 enhanced the neurite outgrowth in a concentration
      dependent manner. Immunocytochemical studies demonstrated the expression of IL-12
      receptors in neuronal bodies and neurites. The mRNA expression of IL-12 receptors
      in SCG cells was confirmed by reverse transcription-polymerase chain reaction.
      Our data demonstrated the presence of IL-12 receptors in sympathetic neurons and
      suggest that IL-12 plays an important role in neuronal regeneration.

PMID- 10653011
TI  - Trophic actions of neurotrophin-3 on postnatal rat myenteric neurons in vitro.
AB  - A number of neurotrophic factors have been implicated in the prenatal development
      of the enteric nervous system. Although several of these factors continue to be
      expressed in the gut during postnatal life, their actions on postnatal enteric
      neurons are not understood. One such factor is the neurotrophin, NT-3. Both NT-3
      and its high affinity receptor, trk C, are expressed in the postnatal gut at a
      time when changes in the density of intestinal innervation are occurring. We have
      therefore examined the effects of NT-3 on postnatal myenteric neurons, using
      dissociated cell cultures of ganglia isolated from 6-8 day postnatal rat small
      intestine. Effects of NT-3 on neurite outgrowth and neuronal and glial cell
      numbers were measured after 2 days in vitro. The proportion of neurons was
      increased in NT-3 treated cultures, as was the proportion of neurons that
      extended processes. NT-3 treatment, at concentrations of between 0.1 ng and 10
      ng/ml, also resulted in a significant increase in mean total neurite length.
      These results indicate that NT-3 may play a role in the postnatal development of
      the enteric nervous system.

PMID- 10653012
TI  - Cilansetron acts at its site of absorption to antagonize the sensitivity of
      mesenteric afferent fibres to 5-hydroxytryptamine in the rat jejunum.
AB  - The present study compares the efficacy of cilansetron, a 5-hydroxytryptamine (5
      HT3)-receptor antagonist, delivered via intravenous and intraluminal routes, on
      the sensitivity of mesenteric afferent fibres supplying the proximal jejunum.
      Waveform analysis was performed to extract 5-HT sensitive single units from
      electrophysiological recordings of whole afferent nerve discharge. Dose effects
      of intravenous cilansetron (0.2-20 microg/kg) on the afferent response to 5-HT
      (10 microg) were examined to determine the threshold dose of cilansetron (2
      microg/kg). This dose applied intraluminally to the region of jejunum innervated
      by the afferents, resulted in a greater degree of antagonism of the 5-HT response
      than intravenous administration (47.8+/-7.9 vs. 76.9+/-4.7%, P = 0.008). We
      concluded that cilansetron is active at its site of absorption to antagonize 5
      HT3 receptors on vagal mucosal afferent terminals.

PMID- 10653013
TI  - The time locked theta response reflects interindividual differences in human
      memory performance.
AB  - Recent research indicates that an increase in theta band power is related to
      episodic memory performance. In this study with human subjects, the evoked (time
      locked) and induced (not time locked) theta response is analyzed in a recognition
      task. The results show a strong evoked theta response during an early retrieval
      period of up to 400 ms. Only for good memory performers theta is strictly time
      locked, indicating that theta peaks appear in preferred time windows after a
      target is presented. This effect--which coincides with a large P3--suggests that
      good performance requires a strict timing of different processing stages that
      correspond to cycles of theta activity.

PMID- 10653014
TI  - Nucleus reuniens thalami innervates gamma aminobutyric acid positive cells in
      hippocampal field CA1 of the rat.
AB  - The aim of the present study was to investigate whether the nucleus reuniens
      thalami (RE) innervates inhibitory cells in hippocampal field CA1. Therefore, we
      examined the RE-CA1 input at the ultrastructural level. RE axons were
      anterogradely labeled with biotin-conjugated dextran amine (BDA), in combination
      with pre-embedding gamma aminobutyric acid (GABA)-immunolabeling of neurons in
      CA1. We observed that part of the BDA-labeled axons formed asymmetrical (i.e.
      excitatory) synapses on GABA-positive dendrites. Based on these data, which are
      in line with our previously published electrophysiological observations (Dolleman
      Van der Weel, M.J., Lopes da Silva, F.H. and Witter, M.P., Nucleus reuniens
      thalami modulates activity in hippocampal field CA1 through excitatory and
      inhibitory mechanisms. J. Neurosci., 17 (1997) 5640-5650), we propose that RE-CA1
      input partially influences hippocampal transmission through activation of local
      inhibitory interneurons.

PMID- 10653015
TI  - N-methyl-D-aspartate receptor blockade enhances neuronal apoptosis induced by
      serum deprivation.
AB  - Neuronal apoptosis a hallmark of brain development could also be involved in
      neurodegenerative diseases. Glutamate toxicity is widely proposed as an important
      factor in the pathogenesis of neurological disorders. We show here that, in rat
      primary cortical cultures, the blockade of N-methyl-D-aspartate (NMDA) glutamate
      receptors exacerbated neuronal apoptosis induced by serum deprivation. This
      effect is observed at early stage of cultures (9 days in vitro (DIV)) and mildly
      decreases in more mature cultures (13 and 15 DIV). At the opposite, low
      concentrations of NMDA (5 microM) or glutamate (5 microM) prevented the neuronal
      apoptosis induced by trophic support withdrawal. In primary cortical cultures,
      the proapoptotic effect of trophic support removal can be modulated by NMDA
      receptors depending upon the magnitude of these glutamate receptor activation.

PMID- 10653016
TI  - Are amplitude and duration of anticipatory postural adjustments identically
      scaled to focal movement parameters in humans?
AB  - Anticipatory postural adjustments (APA), are known to precede the onset of
      voluntary movement. The aim of this study was to determine whether APA amplitude
      and duration are programmed identically according to the voluntary movement
      parameters. Subjects performed shoulder flexions at maximal and sub-maximal
      velocities, with and without an additional inertial load. APA amplitude and
      duration were plotted against kinetic energy and work of the forthcoming
      voluntary limb movement and showed a significant linear relation. When APA
      duration was plotted against mechanical work, two distinct APA duration values
      corresponded to a given value of work depending on the weight of the load, but
      this was not the case for APA amplitude. It is suggested that the APA amplitude
      and duration are scaled according to the same movement parameters, but not in the
      same way, APA duration being additionally sensitive to the postural effect which
      results from an additional weight.

PMID- 10653017
TI  - Endocannabinoids protect cerebral cortical neurons from in vitro ischemia in
      rats.
AB  - The endogenous cannabinoids (endocannabinoids) anandamide and 2
      arachidonylglycerol increased cell viability in cerebral cortical neuron cultures
      subjected to 8 h of hypoxia and glucose deprivation. This effect was observed at
      nanomolar concentrations, was reproduced by a non-hydrolyzable analog of
      anandamide, and was unaltered by CB1 or CB2 cannabinoid receptor antagonists.
      Like synthetic cannabinoids, endocannabinoids can protect neurons from hypoxic
      injury, and may represent endogenous neuroprotective molecules in cerebral
      ischemia.

PMID- 10653018
TI  - Potentiation of non-N-methyl-D-aspartate receptor-induced changes in blood
      pressure by substance P in rats.
AB  - Central release of substance P (SP) in the nucleus tractus solitarius (NTS) may
      potentiate the reflex responses evoked by baroreceptor afferent input to this
      medullary nucleus. The mechanism is not known but may involve modulation of
      responses produced by release of glutamate, the putative primary baroreceptor
      transmitter, at neurons within the NTS. The principal glutamate receptor subtype
      proposed to transmit baroreceptor afferent input at second-order neurons is the
      non-N-methyl-D-aspartate (NMDA) receptor. The present study examined the effects
      of microinjection of SP into barosensitive regions of the NTS on the depressor
      and bradycardic response induced by activation of non-NMDA receptors in the NTS
      by subsequent microinjection of (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4
      propionic acid (AMPA), a non-NMDA receptor agonist. Substance P potentiated the
      non-NMDA receptor-induced depressor response to AMPA in the NTS, evoking a
      significantly larger change in blood pressure over the same time period. These
      data suggest that SP may modulate a non-NMDA-miediated component of the
      baroreflex to influence the control of arterial blood pressure by increasing the
      sensitivity of the baroreceptor reflex.

PMID- 10653019
TI  - The industrial chemical Tinuvin 123 does not induce dopaminergic neurotoxicity in
      C57Bl/6 mice.
AB  - We have investigated the acute effects of systemic administration of Tinuvin 123
      on nigro-striatal dopaminergic neurons in the C57Bl/6 mouse. Tinuvin 123 was
      administered subcutaneously (s.c.) twice, 16 h apart, at doses of 0, 2, 20 or 200
      mg/kg body weight to a total of 48 male C57Bl/6 mice (12 animals/group). Seven
      days following the last dose the animals were decapitated and the brains removed.
      No deaths occurred during the study. There were no differences between the mean
      body weights of any of the experimental groups prior to or following Tinuvin 123
      treatment. Animals treated s.c. with 2 mg/kg Tinuvin 123 exhibited no changes in
      striatal dopamine or metabolite concentrations compared with vehicle-treated
      animals. Higher doses of Tinuvin 123 (20 and 200 mg/kg) resulted in a moderate
      loss of striatal dopamine (31 and 38%) but concentrations of the dopamine
      metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid and the
      neurotransmitters serotonin, aspartate, gamma aminobutyric acid and glutamate
      were unchanged. The total number of tyrosine hydroxylase-immunoreactive neurons
      in the entire substantia nigra were equivalent in the vehicle- and Tinuvin 123
      treated animals at all doses, thus no neuronal loss was demonstrated. In
      conclusion, this study demonstrates no evidence that systemic administered
      Tinuvin 123 induces dopaminergic neurotoxicity in C57Bl/6 mice.

PMID- 10653020
TI  - Levels of alpha- and beta-secretase cleaved amyloid precursor protein in the
      cerebrospinal fluid of Alzheimer's disease patients.
AB  - Alternative cleavage of the amyloid precursor protein (APP) results in generation
      and secretion of both soluble APP (sAPP) and beta-amyloid (Abeta). Abeta is the
      main component of the amyloid depositions in the brains of Alzheimer's disease
      (AD) patients. Using Western blotting, we compared the levels of alpha-secretase
      cleaved sAPP, beta-secretase cleaved sAPP and total sAPP, in cerebrospinal fluid
      (CSF) from 13 sporadic AD patients and 13 healthy controls. Our findings show
      significant amounts of beta-secretase cleaved sAPP in CSF. There was no
      statistically significant difference in the levels of beta-secretase cleaved sAPP
      between AD patients and controls. The levels of alpha-secretase cleaved sAPP and
      total sAPP were, however, found to be significantly lower in the AD patients than
      in the controls.

PMID- 10653021
TI  - Inhibition of carrageenan-induced edema by indomethacin or sodium salicylate does
      not prevent the increase of nerve growth factor in the rat hind paw.
AB  - It is known that the concentration of nerve growth factor (NGF) is increased in
      inflamed tissue, a phenomenon thought to induce long-lasting sensitization of
      afferent neurons. Although the effects of NGF may be of pathophysiological
      relevance, there is little known about the effects of non-steroidal anti
      inflammatory drugs on the inflammation-induced increase in NGF. In the present
      study, therefore, we used the non-steroidal anti-inflammatory drugs indomethacin
      and sodium salicylate in carrageenan-induced rat paw inflammation, in order to
      compare their anti-inflammatory action (determined as inhibition of edema) with
      their effects on the concentration of NGF in inflamed tissue. Carrageenan-induced
      inflammation increased the concentration of NGF in the paw 2-fold compared to non
      inflamed controls. Indomethacin (0.66-2 mg/kg) and sodium salicylate (100-300
      mg/kg) inhibited carrageenan-induced paw edema and indomethacin also inhibited
      the ex-vivo release of immunoreactive prostaglandin E2 from inflamed paw skin.
      However, at these doses, neither anti-inflammatory agent reduced the elevated
      levels of NGF. In contrast, a supramaximal dose of indomethacin (6 mg/kg)
      partially inhibited, and dexamethasone completely prevented the carrageenan
      induced increase in NGF. These results suggest that the anti-inflammatory potency
      of drugs as determined in the carrageenan edema model is not necessarily
      predictive for their ability to inhibit the NGF response. It seems possible,
      therefore, that even if anti-inflammatory treatment prevents the appearance of
      visible signs of inflammation, there may be still long-lasting effects of NGF on
      the phenotype of primary afferent neurons.

PMID- 10653022
TI  - Human brain cytochrome P450 1B1: immunohistochemical localization in human
      temporal lobe and induction by dimethylbenz(a)anthracene in astrocytoma cell line
      (MOG-G-CCM).
AB  - CYP1B1, a new member of human cytochrome P450 family 1, is involved in the
      xenobiotic detoxification metabolism and possibly activation of numerous
      procarcinogens and promutagens. Localization of CYP1B1 in human temporal lobe and
      its induction in astrocytoma cell line (MOG-G-CCM) by 7,12
      dimethylbenz(a)anthracene (DMBA) was investigated using antibodies against human
      CYP1B1. A single band of approximately 58 kDa size in both human temporal lobe
      and in MOG-G-CCM was detected by Western blot analysis. Treatment of MOG-G-CCM
      cells with DMBA resulted in approximately 2.8-fold induction of CYP1B1. CYP1B1
      immunoreactivity was detected at the blood-brain interface areas of the temporal
      lobe as evidenced by co-localization with CD34 antigen. These results suggest
      that this enzyme may be important in brain xenobiotic metabolism acting as an
      enzymatic barrier.

PMID- 10653023
TI  - Early accumulation of pathological PrP in the enteric nervous system and gut
      associated lymphoid tissue of hamsters orally infected with scrapie.
AB  - Infection of the central nervous system (CNS) is a defining feature of scrapie.
      Several findings suggest that scrapie agent invades the CNS via the splanchnic
      and vagus nerve after ingestion of infectivity. Here we address the involvement
      of the enteric nervous system (ENS) and gut-associated lymphoid tissue (GALT) in
      this pathogenetic process. Immunocytochemistry was used for the detection of
      pathological PrP in the duodenum and ileum of hamsters fed with 263K scrapie and
      sacrificed at different stages of incubation. The experiments revealed early
      infection of various GALT components and of submucosal and myenteric ENS ganglia.
      These results provide evidence for an important role of the ENS in scrapie
      neuroinvasion and for centripetal vagal spread of infection from the gut to the
      brain after oral uptake of agent.

PMID- 10653025
TI  - Cortical activation patterns during complex motor tasks in piano players and
      control subjects. A functional magnetic resonance imaging study.
AB  - We performed functional magnetic resonance imaging (MRI) in professional piano
      players and control subjects during an overtrained complex finger movement task
      using a blood oxygenation level dependent echo-planar gradient echo sequence.
      Activation clusters were seen in primary motor cortex, supplementary motor area,
      premotor cortex and superior parietal lobule. We found significant differences in
      the extent of cerebral activation between both groups with piano players having a
      smaller number of activated voxels. We conclude that, due to long-term motor
      practice a different cortical activation pattern can be visualized in piano
      players. For the same movements lesser neurons need to be recruited. The
      different volume of the activated ortical areas might therefore reflect the
      different effort necessary for motor performance in both groups.

PMID- 10653026
TI  - Hemodynamics in the carotid artery bifurcation: a comparison between numerical
      simulations and in vitro MRI measurements.
AB  - The presence of atherosclerotic plaques has been shown to be closely related to
      the vessel geometry. Studies on postmortem human arteries and on the experimental
      animal show positive correlation between the presence of plaque thickness and low
      shear stress, departure of unidirectional flow and regions of flow separation and
      recirculation. Numerical simulations of arterial blood flow and direct blood flow
      velocity measurements by magnetic resonance imaging (MRI) are two approaches for
      the assessment of arterial blood flow patterns. In order to verify that both
      approaches give equivalent results magnetic resonance velocity data measured in a
      compliant anatomical carotid bifurcation model were compared to the results of
      numerical simulations performed for a corresponding computational vessel model.
      Cross sectional axial velocity profiles were calculated and measured for the
      midsinus and endsinus internal carotid artery. At both locations a skewed
      velocity profile with slow velocities at the outer vessel wall, medium velocities
      at the side walls and high velocities at the flow divider (inner) wall were
      observed. Qualitative comparison of the axial velocity patterns revealed no
      significant differences between simulations and in vitro measurements. Even
      quantitative differences such as for axial peak flow velocities were less than
      10%. Secondary flow patterns revealed some minor differences concerning the form
      of the vortices but maximum circumferential velocities were in the same range for
      both methods.

PMID- 10653024
TI  - Anti-nociceptive effect induced by somatostatin released from sensory nerve
      terminals and by synthetic somatostatin analogues in the rat.
AB  - In rats anaesthetized with urethan and pretreated with pipecuronium bromide
      nocifensive reaction of blood pressure elevation evoked by intraarterial
      capsaicin injection was inhibited over 40 min by bilateral antidromic stimulation
      of the sensory fibres of the sciatic nerves. Rise in blood pressure, heart rate
      and respiratory frequency evoked by capsaicin were markedly diminished after
      smearing 1% mustard oil on the acutely denervated hindpaws indicating a release
      of mediators with anti-nociceptive action from cutaneous nociceptors. Intravenous
      injection of the putative mediator somatostatin (10 microg/kg) or its analogues
      RC-160 and TT-232, but not octreotide inhibited the cardiorespiratory and blood
      pressure responses evoked by topical cutaneous application of mustard oil or
      capsaicin instillation into the eye. It is concluded, that the endocrine and the
      anti-nociceptive effects of somatostatin are mediated through distinct receptor
      subtypes and therefore, TT-232, a novel heptapeptide analogue without endocrine
      action, is a promising analgesic compound.

PMID- 10653027
TI  - Moment distribution among human elbow extensor muscles during isometric and
      submaximal extension.
AB  - To understand better how the central nervous system (CNS) distributes a joint
      moment among muscles, moment distribution among the three heads of the triceps
      and the anconeus muscles during isometric elbow extension was quantified in vivo
      and noninvasively. Electrical stimulation was used to activate an individual
      muscle selectively at various contraction levels, and the relationship between
      the peak M-wave amplitude and peak elbow extension moment was established across
      various contraction levels for each muscle. The relationship was then used to
      calibrate the corresponding EMG signal and determine moment distribution among
      the muscles during voluntary isometric elbow extension. Results showed that
      moment distribution among muscles was not proportional to the muscles'
      physiological cross-sectional areas (PCSA) and the CNS favored uniarticular
      muscles for the isometric task performed: the uniarticular lateral and medial
      heads of the triceps were dominant (contributing approximately 70-90% of the
      total elbow extension moment) and the anconeus contributed significantly,
      especially at the lower levels of elbow extension moment (up to approximately 15%
      of the extension moment). In contrast, the two-joint long head of the triceps
      contributed significantly less than the uniarticular heads of the triceps. While
      the absolute contributions of all the muscles increased with the total elbow
      extension moment, the relative contributions of the muscles may increase or
      decrease with the elbow extension moment. Cross-validation using fresh data (not
      used in determining the moment distribution) showed close match between the
      measured and predicted elbow extension moment except for trials in which fatigue
      became significant.

PMID- 10653028
TI  - Muscle contributions to specific biomechanical functions do not change in forward
      versus backward pedaling.
AB  - Previous work had identified six biomechanical functions that need to be executed
      by each limb in order to produce a variety of pedaling tasks. The functions can
      be organized into three antagonistic pairs: an Ext/Flex pair that accelerates the
      foot into extension or flexion with respect to the pelvis, an Ant/Post pair that
      accelerates the foot anteriorly or posteriorly with respect to the pelvis, and a
      Plant/Dorsi pair that accelerates the foot into plantarflexion or dorsiflexion.
      Previous analyses of experimental data have inferred that muscles perform the
      same function during different pedaling tasks (e.g. forward versus backward
      pedaling) because the EMG timing was similar, but they did not present rigorous
      biomechanical analyses to assess whether a muscle performed the same
      biomechanical function, and if so, to what degree. Therefore, the objective of
      this study was to determine how individual muscles contribute to these
      biomechanical functions during two different motor tasks, forward and backward
      pedaling, through a theoretical analysis of experimental data. To achieve this
      objective, forward and backward pedaling simulations were generated and a
      mechanical energy analysis was used to examine how muscles generate, absorb or
      transfer energy to perform the pedaling tasks. The results showed that the
      muscles contributed to the same primary Biomechanical functions in both pedaling
      directions and that synergistic performance of certain functions effectively
      accelerated the crank. The gluteus maximus worked synergistically with the
      soleus, the hip flexors worked synergistically with the tibialis anterior, and
      the vasti and hamstrings functioned independently to accelerate the crank. The
      rectus femoris used complex biomechanical mechanisms including negative muscle
      work to accelerate the crank. The negative muscle work was used to transfer
      energy generated elsewhere (primarily from other muscles) to the pedal reaction
      force in order to accelerate the crank. Consistent with experimental data, a
      phase shift was required from those muscles contributing to the Ant/Post
      functions as a result of the different limb kinematics between forward and
      backward pedaling, although they performed the same biomechanical function. The
      pedaling simulations proved necessary to interpret the experimental data and
      identify motor control mechanisms used to accomplish specific motor tasks, as the
      mechanisms were often complex and not always intuitively obvious.

PMID- 10653029
TI  - Adaptation of muscle coordination to altered task mechanics during steady-state
      cycling.
AB  - The objective of this work was to increase our understanding of how motor
      patterns are produced during movement tasks by quantifying adaptations in muscle
      coordination in response to altered task mechanics. We used pedaling as our
      movement paradigm because it is a constrained cyclical movement that allows for a
      controlled investigation of test conditions such as movement speed and effort.
      Altered task mechanics were introduced using an elliptical chainring. The
      kinematics of the crank were changed from a relatively constant angular velocity
      using a circular chainring to a widely varying angular velocity using an
      elliptical chainring. Kinetic, kinematic and muscle activity data were collected
      from eight competitive cyclists using three different chainrings--one circular
      and two different orientations of an elliptical chainring. We tested the
      hypotheses that muscle coordination patterns (EMG timing and magnitude),
      specifically the regions of active muscle force production, would shift towards
      regions in the crank cycle in which the crank angular velocity, and hence muscle
      contraction speeds, were favorable to produce muscle power as defined by the
      skeletal muscle power-velocity relationship. The results showed that our
      hypothesis with regards to timing was not supported. Although there were
      statistically significant shifts in muscle timing, the shifts were minor in
      absolute terms and appeared to be the result of the muscles accounting for the
      activation dynamics associated with muscle force development (i.e. the delay in
      muscle force rise and decay). But, significant changes in the magnitude of muscle
      EMG during regions of slow crank angular velocity for the tibialis anterior and
      rectus femoris were observed. Thus, the nervous system used adaptations to the
      muscle EMG magnitude, rather than the timing, to adapt to the altered task
      mechanics. The results also suggested that cyclists might work on the descending
      limb of the power-velocity relationship when pedaling at 90 rpm and sub-maximal
      power output. This finding might have important implications for preferred
      pedaling rate selection.

PMID- 10653030
TI  - Is a joint moment-based cost function associated with preferred cycling cadence?
AB  - Eight experienced male cyclists (C), eight well-trained male runners (R), and
      eight less-trained male noncyclists (LT) were tested under multiple cadence and
      power output conditions to determine: (1) if the cadence at which lower extremity
      net joint moments are minimized (cost function cadence) was associated with
      preferred pedaling cadence (PC), (2) if the cost function cadence increased with
      increases in power output, and (3) if the association is generalizable across
      groups differing in cycling experience and aerobic power. Net joint moments at
      the hip, knee, and ankle were computed from video records and pedal reaction
      force data using 2-D inverse dynamics. The sum of the average absolute hip, knee,
      and ankle joint moments defined a cost function at each power output and cadence
      and provided the basis for prediction of the cadence which minimized net joint
      moments for each subject at each power output. The cost function cadence was not
      statistically different from the PC at each power output in all groups. As power
      output increased, however, the cost function cadence increased for all three
      subject groups (86 rpm at 100 W, 93 rpm at 150 W, 98 rpm at 200 W, and 96 rpm at
      250 W). PC showed little change (R) or a modest decline (C, LT) with increasing
      power output. Based upon the similarity in the mean data but different trends in
      the cost function cadence and PC in response to changes in power output as well
      as the lack of significant correlations between these two variables, it was
      concluded that minimiking net joint moments is a factor modestly associated with
      preferred cadence selection.

PMID- 10653031
TI  - Strain relief from the cerebral ventricles during head impact: experimental
      studies on natural protection of the brain.
AB  - Physical models of the parasagittal human skull/brain have been tested to
      investigate whether the cerebral ventricles provide natural protection of the
      brain by relieving strain during head rotation. A sophisticated model included
      anatomical structures, and a semicircular model consisted of a cylinder divided
      into two semicircles. Silicone gel simulated the brain and was detached from the
      vessel by a layer of liquid paraffin simulating the cerebrospinal fluid. Both
      models were run with and without an elliptical inclusion filled with liquid
      paraffin simulating a cerebral ventricle. The 2D models were exposed to angular
      acceleration by a pendulum impact causing 7600 rad/s2 peak rotational
      acceleration with 6 ms pulse duration. After rotating 100 degrees, the models
      were decelerated during 30 ms. The trajectory of grid markers was analyzed from
      high-speed video (1000 frames/s). Rigid-body displacement, shear strain and
      principal strain were determined from the displacement of three-point sets
      inferior and superior to the ventricle. For the subventricular (inferior) region
      in the sophisticated model, approximately 40% lower peak strain values were
      obtained in the model with ventricle than in the one without. Subcortical
      displacement was reduced by 12%. Corresponding strain reduction in the
      subcortical (superior) region was approximately 40% following the acceleration
      and 25% following the deceleration. Similar but less pronounced effects were
      found for the semicircular model. The lateral ventricles play an important role
      as strain relievers and provide natural protection against brain injury.

PMID- 10653032
TI  - Inertial properties and loading rates affect buckling modes and injury mechanisms
      in the cervical spine.
AB  - Cervical spine injuries continue to be a costly societal problem. Future
      advancements in injury prevention depend on improved physical and computational
      models which, in turn, are predicated on a better understanding of the responses
      of the neck during dynamic loading. Previous studies have shown that the
      tolerance of the neck is dependent on its initial position and its buckling
      behavior. This study uses a computational model to examine the mechanical factors
      influencing buckling behavior during impact to the neck. It was hypothesized that
      the inertial properties of the cervical spine influence the dynamics during
      compressive axial loading. The hypothesis was tested by performing parametric
      analyses of vertebral mass, mass moments of inertia, motion segment stiffness,
      and loading rate. Increases in vertebral mass resulted in increasingly complex
      kinematics and larger peak loads and impulses. Similar results were observed for
      increases in stiffness. Faster loading rates were associated with higher peak
      loads and higher-order buckling modes. The results demonstrate that mass has a
      great deal of influence on the buckling behavior of the neck, particularly with
      respect to the expression of higher-order modes. Injury types and mechanisms may
      be substantially altered by loading rate because inertial effects may influence
      whether the cervical spine fails in a compressive mode, or a bending mode.

PMID- 10653033
TI  - Bioprosthetic heart valve leaflet motion monitored by dual camera stereo
      photogrammetry.
AB  - Dual camera stereo photogrammetry (DCSP) was applied to investigate the leaflet
      motion of bioprosthetic heart valves (BHVs) in a physiologic pulse flow loop
      (PFL). A 25-mm bovine pericardial valve was installed in the aortic valve
      position of the PFL, which was operated at a pulse rate of 70 beats/min and a
      cardiac output of 5 l/min. The systolic/diastolic aortic pressure was maintained
      at 120/80 mmHg to mimic the physiologic load experienced by the aortic valve. The
      leaflet of the test valve was marked with 80 India ink dots to form a fan-shaped
      matrix. From the acquired image sequences, 3-D coordinates of the marker matrix
      were derived and hence the surface contour, local mean and Gaussian curvatures at
      each opening and closing phase during one cardiac cycle were reconstructed. It is
      generally believed that the long-term failure rate of BHV is related to the
      uneven distribution of mechanical stresses occurring in the leaflet material
      during opening and closing. Unfortunately, a quantitative analysis of the leaflet
      motion under physiological conditions has not been reported. The newly developed
      technique permits frame-by-frame mapping of the leaflet surface, which is
      essential for dynamic analysis of stress-strain behavior in BHV.

PMID- 10653034
TI  - Prediction of femoral fracture load using finite element models: an examination
      of stress- and strain-based failure theories.
AB  - Finite element (FE) models are often used to model bone failure. However, no
      failure theory for bone has been validated at this time. In this study, we
      examined the performance of nine stress- and strain-based failure theories, six
      of which could account for differences in tensile and compressive material
      strengths. The distortion energy, Hoffman and a strain-based Hoffman analog,
      maximum normal stress, maximum normal strain, maximum shear strain, maximum shear
      stress (tau(max)), Coulomb-Mohr, and modified Mohr failure theories were
      evaluated using automatically generated, computed tomographic scan-based FE
      models of the femur. Eighteen matched pairs of proximal femora were examined in
      two load configurations, one approximating joint loading during single-limb
      stance and one simulating impact from a fall. Mechanical testing was performed to
      assess model and failure theory performance in the context of predicting femoral
      fracture load. Measured and FE-computed fracture load were significantly
      correlated for both loading conditions and all failure criteria (p < or = 0.001).
      The distortion energy and tau(max) failure theories were the most robust of those
      examined, providing the most consistently strong FE model performance for two
      very different loading conditions. The more complex failure theories and the
      strain-based theories examined did not improve performance over the simpler
      distortion energy and tau(max) theories, and often degraded performance, even
      when differences between tensile and compressive failure properties were
      represented. The relatively strong performance of the distortion energy and
      tau(max) theories supports the hypothesis that shear/distortion is an important
      failure mode during femoral fracture.

PMID- 10653035
TI  - In vivo moment arm determination using B-mode ultrasonography.
AB  - The tendon excursion of the tibialis anterior (TA) muscle was measured in vivo
      using B-mode ultrasonography in seven subjects under three force levels (0, 30
      and 60% maximal voluntary contraction, MVC). For each force level, the TA moment
      arm (m) was determined by calculating the derivative of the tendon excursion
      relative to the ankle angle (a). A dynamometer controlled the ankle angle while
      force levels were monitored. The parametric model proposed by Miller and Dennis
      (1996), m = R sin(a + delta), where R is the largest moment arm and delta
      represents the offset angle of R from 90 degrees, was used in a least-squares fit
      of the relationship between moment arm and ankle angle. The R values at 0% MVC
      were significantly smaller than those at 30 and 60% MVC. The values of calculated
      moment arm at 0% MVC were not considered adequate estimates of the TA moment arm
      because of the possible confounding effect of the slackness of the relaxed muscle
      tendon unit in more dorsiflexed positions. The moment arm values at 30 and 60%
      MVC were believed to provide reliable estimates of those of TA since the
      application of tension probably reduced the effects of the slackness of the
      muscle-tendon unit and tendon elongation on tendon excursion measurement at these
      force levels. Since the ultrasonographic technique is an in vivo application of
      the tendon excursion technique and therefore takes the functional meaning into
      consideration, it can yield more significant moment arms than other in vivo or
      cadaver techniques.

PMID- 10653036
TI  - A mechanical model to determine the influence of masses and mass distribution on
      the impact force during running.
AB  - Simple spring-damper-mass models have been widely used to simulate human
      locomotion. However, most previous models have not accounted for the effect of
      non-rigid masses (wobbling masses) on impact forces. A simple mechanical model of
      the human body developed in this study included the upper and lower bodies with
      each part represented by a rigid and a wobbling mass. Spring-damper units
      connected different masses to represent the stiffness and damping between the
      upper and lower bodies, and between the rigid and wobbling masses. The simulated
      impact forces were comparable to experimentally measured impact forces. Trends in
      changes of the impact forces due to changes in touch-down velocity reported in
      previous studies could be reproduced with the model. Simulated results showed
      that the impact force peaks increased with increasing rigid or wobbling masses of
      the lower body. The ratio of mass distribution between the rigid and wobbling
      mass in the lower body was also shown to affect the impact force peak, for
      example, the impact force peak increased with increasing rigid contribution. The
      variation in the masses of upper body was shown to have a minimum effect on the
      impact force peak, but a great effect on the active force peak (the second peak
      in the ground reaction force). Future studies on the dynamics and neuro-muscular
      control of human running are required to take into consideration the influence of
      individual variation in lower body masses and mass distribution.

PMID- 10653037
TI  - Effect of optimization criterion on spinal force estimates during asymmetric
      lifting.
AB  - Optimization-based muscle force prediction models of the lumbar region are used
      in research and ergonomic practice, usually as a subroutine of a job analysis
      software package. Various optimization criteria have been put forward for use in
      rationally selecting a set of muscle forces to satisfy moment equilibrium,
      including the sum of cubed muscle contraction intensities and a double linear
      programming procedure for minimizing the spinal compression force and maximum
      muscle contraction intensity. A laboratory study was conducted to determine
      whether these two model formulations produce significantly different estimates of
      spinal forces for a dynamic asymmetric lift. Although statistically significant
      differences were found between the predictions of the two models, the difference
      in peak spinal compression force was only 1.1%.

PMID- 10653038
TI  - In vitro sodium fluoride exposure decreases torsional and bending strength and
      increases ductility of mouse femora.
AB  - Fluoride exposure in vivo can reduce the material strength of bone, an effect
      that has been attributed to a change in mineral structure. An in vitro model of
      fluoride exposure offers the potential to study directly the effects of fluoride
      on bone mineral. Previous investigators have reported that soaking bones in
      sodium fluoride in vitro reduces bone strength. However, long soaking times and
      the absence of physiological buffering ions from their treatment solutions may
      have caused mineral dissolution that contributed to the decrease in bone
      strength. Our objectives were to further characterize the effects of in vitro
      fluoride exposure on bone mechanical properties and to determine if the changes
      reported in previous studies of bovine cortical bone would be observed for whole
      rodent bones. We soaked 60 mouse femora in sodium fluoride solutions, with and
      without physiological buffering ions, and evaluated their torsional and bending
      properties. Fluoride soaked bones had a 30-fold increase in fluoride content and
      a 23% increase in water content compared to controls. These changes were
      associated with average reductions in ultimate load of 45%, reductions in
      rigidity of 70%, and increases in deformation to failure of 80%. The effect of
      fluoride was similar for bones treated in buffered and non-buffered solutions,
      and was observed in both torsion and bending. Our findings confirm those of
      previous studies and highlight the strong effect that in vitro fluoride exposure
      has on bone mechanical properties. The in vitro model of fluoride exposure offers
      a tool to further study the effects of ion substitution in bone.

PMID- 10653039
TI  - Theoretical solutions for internal bone remodeling of diaphyseal shafts using
      adaptive elasticity theory.
AB  - In this paper we considered the problem of internal bone remodeling induced by
      casting a broken femur. It is shown that, after the removal of the plastercast,
      the healing bone is either becoming more porous and less stiff or it is
      osteoporotic. The result is theoretical, based on a theory of internal bone
      remodeling proposed by Hegedus and Cowin (Journal of Elasticity 6, 1976, 337
      352).

PMID- 10653040
TI  - A new instrumentation system for training rowers.
AB  - A dry-land rowing system was developed to provide the coach and/or athlete with
      quantitative information about the athlete's kinetics and kinematics while the
      athlete trains. This system consists of a Concept II rowing ergometer
      instrumented with a force transducer and potentiometer, four electrogoniometers
      attached to the athlete's ankle, knee, hip, and elbow, and a data acquisition
      computer. The force transducer is used to quantify the athlete's pulling force.
      The potentiometer signal is used to locate the position of the handle. The
      electrogoniometers provide signals proportional to joint angles. A link segment
      model of the human body is used to locate joint centers based on limb lengths and
      joint angles. The computer is used to collect and process all the transducer
      signals, perform the link segment calculations and provide feedback to the coach
      or athlete in the form of a stick figure animation overlaid with kinematic and
      kinetic information. This system allows the coach and athlete to quickly study a
      rower's mechanics, to evaluate the effects that technique changes have on the
      power produced by the athlete, and to identify technique differences between
      athletes.

PMID- 10653041
TI  - An ex vivo model to study transport processes and fluid flow in loaded bone.
AB  - Load-induced fluid flow has been postulated to provide a mechanism for the
      transmission of mechanical signals (e.g. via shear stresses, enhancement of
      molecular transport, and/or electrical effects) and the subsequent elicitation of
      a functional adaptation response (e.g. modeling, remodeling, homeostasis) in
      bone. Although indirect evidence for such fluid flow phenomena can be found in
      the literature pertaining to strain generated potentials, actual measurement of
      fluid displacements in cortical bone is inherently difficult. This problem
      motivated us to develop and introduce an ex vivo perfusion model for the study of
      transport processes and fluid flow within bone under controlled mechanical
      loading conditions. To this end, a closed-loop system of perfusion was
      established in the explanted forelimb of the adult Swiss alpine sheep.
      Immediately prior to mechanical loading, a bolus of tracer was introduced
      intraarterially into the system. Thereafter, the forelimb of the left or right
      side (randomized) was loaded cyclically, via Schanz screws inserted through the
      metaphyses, producing a peak compressive strain of 0.2% at the middiaphysis of
      the anterior metacarpal cortex. In paired experiments with perfusion times
      totalling 2, 4, 8 and 16 min, the concentration of tracer measured at the
      middiaphysis of the cortex in cross section was significantly higher in the
      loaded bone than in the unloaded contralateral control. Fluorometric measurements
      of procion red concentration in the anterior aspect alone showed an enhancement
      in transport at early stages of loading (8 cycles, 2 min) but no effect in
      transport after higher number of cycles or increased perfusion times,
      respectively. This reflects both the small size of the molecular tracer, which
      would be expected to be transported rapidly by way of diffusive mechanisms alone,
      as well as the loading mode to which the anterior aspect was exposed. Thus, using
      our new model it could be shown that load-induced fluid flow represents a
      powerful mechanism to enhance molecular transport within the lacunocanalicular
      system of compact bone tissue. Based on these as well as previous studies, it
      appears that the degree of this effect is dependent on tracer size as well as the
      mechanical loading mode to which a given area of tissue is exposed.

PMID- 10653042
TI  - Improving the local solution accuracy of large-scale digital image-based finite
      element analyses.
AB  - Digital image-based finite element modeling (DIBFEM) has become a widely utilized
      approach for efficiently meshing complex biological structures such as trabecular
      bone. While DIBFEM can provide accurate predictions of apparent mechanical
      properties, its application to simulate local phenomena such as tissue failure or
      adaptation has been limited by high local solution errors at digital model
      boundaries. Furthermore, refinement of digital meshes does not necessarily reduce
      local maximum errors. The purpose of this study was to evaluate the potential to
      reduce local mean and maximum solution errors in digital meshes using a post
      processing filtration method. The effectiveness of a three-dimensional, boundary
      specific filtering algorithm was found to be mesh size dependent. Mean absolute
      and maximum errors were reduced for meshes with more than five elements through
      the diameter of a cantilever beam considered representative of a single
      trabecula. Furthermore, mesh refinement consistently decreased errors for
      filtered solutions but not necessarily for non-filtered solutions. Models with
      more than five elements through the beam diameter yielded absolute mean errors of
      less than 15% for both Von Mises stress and maximum principal strain. When
      applied to a high-resolution model of trabecular bone microstructure, boundary
      filtering produced a more continuous solution distribution and reduced the
      predicted maximum stress by 30%. Boundary-specific filtering provides a simple
      means of improving local solution accuracy while retaining the model generation
      and numerical storage efficiency of the DIBFEM technique.

PMID- 10653043
TI  - A paper by Jones et al. Alterations in the Young's modulus and volumetric
      properties of chondrocytes isolated from normal and osteoarthritic human
      cartilage (Journal of Biomechanics 32, 1999, 119-127)

PMID- 10653044
TI  - Infection in acute exacerbations of chronic bronchitis: a clinical perspective.
AB  - Acute exacerbations of chronic bronchitis (AECB) is an important cause of death
      and morbidity in developed countries and also has significant economic impact.
      The disease is characterized by increased dyspnoea, sputum volume and sputum
      purulence; the most commonly associated pathogens are Haemophilus influenzae,
      Streptococcus pneumoniae and Moraxella catarrhalis. H. influenzae and S.
      pneumoniae express virulence determinants that directly and indirectly impair
      mucociliary clearance and incite other consequences that are permissive to
      microbial persistence. Regarding the use of antibiotics, there is currently a
      lack of large-scale clinical trials that are sufficiently powerful to provide
      good evidence-based information. Nonetheless, antimicrobial chemotherapy has
      repeatedly been shown to confer benefit in patients with moderately severe
      features of AECB. Simple clinical criteria can be used to identify patients in
      whom there is a higher likelihood of treatment failure or mortality during AECB.
      These include significant cardiopulmonary co-morbidity, frequent exacerbations,
      advanced decline in lung function, malnutrition or other generalized debility,
      advanced age (>70 years) and concurrent treatment with corticosteroids. In such
      patients, an aggressive antimicrobial approach to AECB may be warranted in order
      to prevent clinical failure or representation. From a clinical perspective,
      appropriate drugs include those that are stable to beta-lactamases, are
      bactericidal against causative pathogens, penetrate diseased lung tissue in high
      concentrations and have a good safety profile.

PMID- 10653045
TI  - Asthma and asthma-like disorders.
AB  - Bronchial asthma is defined as a chronic inflammatory disease resulting in a
      reversible and variable bronchial obstruction. For the clinical diagnosis of the
      disease there are some key indicators but as there is no 'gold standard' a
      correct diagnosis will sometimes not be obtained. Examples are patients in a
      symptom-free stage, current medication interfering with the methods used,
      patients with asthma-like symptoms reporting lack of effect of bronchodilators
      and patients who are unable to perform a forced expiration in an airway function
      test. The prevalence of asthma is reported to be 5-10%. The prevalence of asthma
      like symptoms may be double this. The term 'asthma-like' has been used to an
      increasing extent during the last few years, which may indicate an increasing
      awareness of the fact that asthma-like symptoms are not always classical asthma.
      In this overview some disorders with asthma-like symptoms, especially in adults,
      are presented. The spectrum of differential diagnoses in a clinic may depend on
      which doctor/specialist the patient is consulting. In an asthma and allergy
      clinic it has been found that the most common differential diagnoses are chronic
      obstructive pulmonary disease (COPD), nonasthmatic cough and sensory hyper
      reactivity (SHR), a disorder which is sometimes mixed up with asthma due to
      similar symptoms (heavy breathing, cough, increased secretion, difficulty in
      getting air etc.) and similar trigger factors (smoke, strong scents, exercise,
      cold air etc.). Recently it has been suggested that a capsaicin inhalation test
      may be an objective test for identifying patients with SHR. In asthma effective
      treatment is available today but in asthma-like disorders, such as SHR, no
      effective therapy is available, underlining the need of further research for
      understanding the pathophysiological mechanisms.

PMID- 10653046
TI  - Patient factors and compliance with asthma therapy.
AB  - Compliance by patients to prescribed treatment regimens can be considered as the
      interface between effective therapy and effective disease management. Compliance
      can be affected by the nature of the relationship between the practitioner and
      the patient, and their attitudes towards each other. It has also been suggested
      that practitioner behaviour can influence patient behaviour and health status.
      However, each individual patient is influenced in his or her attitudes, and
      reactions to disease and its management, by a wide variety of patient-related
      factors. These include psychological variables such as mood, beliefs, and the
      knowledge, motivation and ability of the patient. Social factors may also play a
      role: these include age, marital and socioeconomic status and level of education.
      Results from a range of studies in patients with pulmonary or other diseases show
      that the psychosocial determinants of compliance are only poorly understood, and
      suggest that compliance cannot be predicted from patients' health status and that
      social factors are weak indicators only. Furthermore, it appears from available
      data that patients' beliefs about health issues are not as useful as indicators
      of likely compliance as was previously believed.

PMID- 10653047
TI  - Salmeterol reduces the need for inhaled corticosteroid in steroid-dependent
      asthmatics.
AB  - Previous results have demonstrated addition of long-acting beta2-adrenergic
      agonists to be beneficial in asthma patients already receiving inhaled
      corticosteroid. The purpose of this study was to determine, qualitatively as well
      as quantitatively, the steroid-sparing properties of salmeterol in stable asthma
      patients receiving maintenance inhaled corticosteroids (800-1600 microg day(-1)).
      In these patients, the daily dose of beclomethasone dipropionate was reduced by
      200 microg each week until asthma deteriorated, with the minimal acceptable dose
      (MAD) being defined as the dose one step above deterioration (sensitivity
      period). Following this, patients received three times the MAD for 2 weeks.
      Patients were randomized to receive either salmeterol 50 microg twice daily or
      placebo and the MAD was again determined (treatment period). Forced expiratory
      volume in 1 sec (FEV1) was measured each week. Morning and evening peak
      expiratory flow (PEF), symptom score and use of bronchodilator were recorded each
      day. Fifteen patients received salmeterol and 19 placebo. The MAD was
      significantly lower in the salmeterol group compared with placebo during the
      treatment period (P<0.01). A 50% reduction of the MAD was achieved by more
      patients treated with salmeterol than placebo (P = 0.001). Salmeterol caused a
      significantly greater reduction in daytime symptom score and use of as-needed
      beta2-agoinist therapy between sensitivity and treatment periods compared with
      placebo (P<0.05 for both). The results demonstrate, that the addition of
      salmeterol to corticosteroid treatment offers a clinically relevant potential for
      reduction of inhaled corticosteroid dose in steroid sensitive asthmatics.

PMID- 10653048
TI  - Evidence of mild respiratory disease in men with congenital absence of the vas
      deferens.
AB  - Cystic fibrosis (CF) is a severe disorder, whose main characteristics are, in
      addition to congenital absence of the vas deferens (CAVD), progressive lung
      disease, pancreatic insufficiency and elevated sweat chloride levels; CAVD
      without any other manifest clinical evidence is commonly suggested to be a form
      of CF with primarily genital expression. We undertook this study to test the
      hypothesis that men with a CAVD phenotype could be more CF-like than it is
      usually assumed. Each subject from a population of 42 patients suffering from
      CAVD was screened for a panel of 16 mutations plus the intron 8 5-thymidine
      allele of the CF gene (5T), and underwent a thorough clinical evaluation which
      included a detailed anamnesis, anthropometric data, chest and paranasal sinuses X
      rays, pulmonary function tests, sputum cultures, stool chymotrypsin
      determination, sweat test and, in a limited number of patients, Nasal Potential
      Difference (NPD) measurement. The genotype analysis detected one compound
      heterozygote, 23 heterozygotes and 15 individuals carrying the 5T allele; sweat
      chloride was positive in six, borderline in 11 and negative in 25 subjects; NPD
      was abnormal in 2/12 patients. Medical history and clinical examination were
      consistent with respiratory disease in 20 cases; there was radiological evidence
      of pulmonary hyperinflation in 37/39 and of sinus disease in 20/42 patients;
      Staphylococcus aureus was cultivated in the sputum of 9/36, Haemophilus
      influentiae in 3/36 subjects and three patients showed functional evidence of
      airway obstruction. These findings were equally distributed among sweat positive,
      borderline and negative patients. These results raise questions about the
      supposed benignancy of the CAVD condition. A close follow-up of men with CAVD
      could ascertain potential complications.

PMID- 10653049
TI  - Salmeterol/fluticasone propionate (50/500 microg) in combination in a Diskus
      inhaler (Seretide) is effective and safe in the treatment of steroid-dependent
      asthma.
AB  - This multicentre double-blind, double-dummy study compared the safety and
      efficacy of a new combination Diskus inhaler containing both salmeterol 50 microg
      and fluticasone propionate 500 microg (Seretide, GlaxoWellcome, France) with the
      same doses of the two drugs delivered via separate Diskus inhalers and with the
      same dose of fluticasone propionate alone. Patients were eligible for study entry
      if they had received an inhaled corticosteroid continuously for 12 weeks prior to
      run-in, and had received treatment with beclomethasone dipropionate or budesonide
      1500-2000 microg day(-1) or fluticasone propionate 750-1000 microg day(-1) for at
      least 4 weeks prior to run-in. In total, 503 patients receiving inhaled
      corticosteroids were randomized to 28 weeks' treatment with either
      salmeterol/fluticasone propionate (50/500 microg) via a single Diskus inhaler
      (combination) and placebo, or salmeterol 50 microg and fluticasone propionate 500
      microg administered via separate Diskus inhalers (concurrent), or fluticasone
      propionate 500 microg and placebo. All treatments were administered twice daily,
      mean morning peak expiratory flow rate (PEFR) and asthma symptoms were measured
      for the first 12 weeks and safety data were collected throughout the 28-week
      study. Over weeks 1 to 12, improvement in adjusted mean morning PEFR was 35 and
      33 l min(-1), respectively, in the combination and concurrent therapy treatment
      groups (12 and 10% increase from baseline, respectively). The mean difference
      between treatments was -3 l min(-1) (90% confidence interval -10.4 l min(-1))
      which was within the criteria for clinical equivalence. However, the combination
      therapy was statistically significantly superior to fluticasone propionate alone
      for mean morning PEFR (P<0.001) and other measures of lung function, whilst
      clinical equivalence of the combination and concurrent therapies was observed.
      All three treatments were well tolerated. In addition, there were no differences
      between the three treatments in either the c.hange in serum cortisol or urinary
      cortisol concentrations, which, for each treatment group, were no significantly
      different from baseline at the end of the treatment period. Thus, the combination
      of salmeterol and fluticasone propionate in a single inhaler is as well tolerated
      and effective in achieving asthma control in steroid-dependent patients as the
      separate administration of the two drugs, and both combination and concurrent
      therapy are superior to administration of the same dose of corticosteroid alone.

PMID- 10653050
TI  - Pulmonary damage after modest exposure to zinc chloride smoke.
AB  - Thirteen soldiers (11 men and two women) were exposed to zinc chloride smoke
      (ZCS) during a combat exercise. Even though their initial symptoms were modest, a
      prolonged follow up with lung function testing and blood samples was undertaken
      due to previous cases with fatal outcome after exposure to ZCS. Four weeks after
      exposure there were statistically significant declines from baseline values in
      lung diffusion capacity and total lung capacity of 16.2% and 4.3%, respectively.
      At the same time plasma levels of fibrinogen and zinc were significantly
      elevated, though mainly within the normal range. All variables showed a tendency
      towards normalization at follow up 8 weeks and 6 months after exposure. These
      findings indicate an unexpected quantifiable damage to lung parenchyma with a
      remarkable delay after modest exposure to zinc chloride smoke despite sparse
      initial symptoms. Exposure to high concentrations of ZCS may induce adult
      respiratory distress syndrome (ARDS) after a symptom free period of up to 12 days
      from exposure. Even though none of the soldiers in the present study developed
      ARDS the assessment of lung diffusion capacity and acute phase reactants is
      proposed as a supplement when monitoring patients after exposure to ZCS.

PMID- 10653051
TI  - Can urinary eicosanoids be a potential predictive marker of clinical response to
      thromboxane A2 receptor antagonist in asthmatic patients?
AB  - Thromboxane (TX) A2 is an important bronchoconstrictor in the pathogenesis of
      asthma. Seratrodast, known as AA-2414, is a new oral TXA2 receptor antagonist
      which is currently prescribed in asthma therapy in Japan. However its clinical
      effects have been very different in individual subjects. To assess whether the
      clinical efficacy of TXA2 antagonist is predictable on the basis of urinary
      arachidonic acid metabolites in urine of patients with asthma, an open and
      multicentre trial was conducted. Fifty adult asthmatic subjects (women/men =
      28/22) were enrolled [resting mean forced expiratory volume in 1 sec (FEV1)% was
      82%; range, 50-96%]. Urinary levels of 11-dehydro-TXB2, leukotriene (LT) E4, 2,3
      dinor-6-keto-prostaglandin F1alpha and creatinine in 3-h urine collected in the
      morning at the start of seratrodast (80 mg day(-1), once a day at evening for 4
      weeks) were measured. Responders were defined by improvements of asthma symptoms
      score and peak expiratory flow rate (PEFR). Of the 50 subjects, 45 completed this
      study. Eighteen patients were responders and the other 27 were nonresponders.
      There were no significant differences between the two groups in patients'
      characteristics, baseline lung functions, treatments and baseline urinary
      eicosanoids. The 11-dehydro-TXB2/LTE4 ratio of responders was significantly
      higher (P = 0.0091) than that of non-responders (mean +/- SE, 7.49+/-0.71 vs.
      5.09+/-0.67). Eleven patients out of 18 responders agreed to continue this drug
      for 6 months, the 11-dehydro-TXB2/LTE4 ratio decreased during this period, but
      not significantly. Our data demonstrated that responders and non-responders to
      TXA2 receptor antagonist existed in patients with asthma, and it suggests that
      the ratio of urinary eicosanoids might be a possible predictor of the effects of
      TXA2 receptor antagonist.

PMID- 10653052
TI  - The impact of pleurodesis in malignant effusion on respiratory function.
AB  - Pleurodesis of malignant pleural effusion provides for a substantially better
      quality of life compared to onging exudation with the need for repeated
      evacuation of fluid. Successful pleurodesis leads to permanent cessation of fluid
      production as a result of the formation of fibrous adhesion between the lung and
      costal pleura which in theory, however, might restrict lung mobility. In patients
      with poor lung function, or with need for bilateral pleurodesis, the apprehension
      of further impairment of lung function often arises. The aim of this study was to
      evaluate the effects of pleurodesis on lung function. Therefore 10 patients with
      malignant pleurisy with very limited tumour were investigated. They were without
      radiological signs of tumour infiltration in the lung parenchyma, without visible
      tumour growth in the pleural space during thoracoscopy and had undergone a
      successful one-sided pleurodesis. Respiratory function tests were performed at
      different times, 1-102 months after pleurodesis. The assessment consisted of:
      static and dynamic spirometry, exercise testing with blood gas determination and
      radiospirometry. Spirometric values were slightly low, but in general within the
      reference limits. Blood gas determination showed no signs of alveolar
      hypoventilation. Radiospirometry showed a slight attenuation of activity in the
      treated lung but similar turnover of gas of the treated vs. the untreated side.
      The study showed that pleurodesis in malignant pleurisy has only minor impact on
      respiratory function.

PMID- 10653053
TI  - Feasibility of spirometry and reversibility testing for the identification of
      patients with chronic obstructive pulmonary disease on asthma registers in
      general practice.
AB  - There is renewed interest in the diagnosis of chronic obstructive pulmonary
      disease (COPD) within primary care. Primary care physicians have difficulty
      distinguishing asthma from COPD. We tested the feasibility of using spirometry
      and if appropriate, reversibility testing, to identify patients with COPD on
      asthma registers in primary care. We carried out a cross-sectional study in three
      inner-city group practices in east London. Three hundred and twenty-eight
      patients aged 50 years and over on practice asthma registers were invited to
      attend for spirometry and, if appropriate, a trial of oral corticosteroids. The
      main outcome measures were: feasibility of carrying out spirometry; lung
      function; severity of COPD; prior diagnosis of COPD; response to a corticosteroid
      trial; quality of life. One hundred and sixty-eight of 328 (51%) patients
      attended for spirometry. According to British Thoracic Society criteria, 58 (34%)
      patients had normal spirometry at the time of assessment; 40 (24%) had active
      asthma and 57 (34%) had COPD. Thirteen patients (8%) were unable to perform
      spirometry. Of 57 patients with COPD 30 (53%) had mild, 15 (26%) had moderate and
      12 (21%) had severe disease. Twenty-three of 57 (40%) patients with COPD on
      spirometry had this diagnosis recorded prior to the study. New diagnoses of COPD
      were more likely in those with mild or moderate disease (P<0.05). Twenty-three of
      57 (40%) patients with COPD completed a corticosteroid trial: one showed
      significant reversibility of lung function. Spirometry was feasible and helped
      identify patients with COPD on asthma registers in these inner-city practices.
      Patients aged 50 years and over on asthma registers had a wide spectrum of lung
      function with considerable diagnostic misclassification. Some patients with
      normal lung function when tested may have had well controlled asthma. New
      diagnoses of COPD were mainly in those with mild or moderate disease.

PMID- 10653054
TI  - Influence of higher than conventional doses of oxitropium bromide on formoterol
      induced bronchodilation in COPD.
AB  - We examined the influence of higher than conventional doses of oxitropium bromide
      on formoterol-induced bronchodilation in patients with partially reversible
      stable COPD. Twenty outpatients inhaled one or two puffs of formoterol (12 microg
      puff(-1)), or placebo. Two hours after inhalation, a dose-response curve to
      inhaled oxitropium bromide (100 microg puff(-1)) or placebo was constructed using
      one puff, one puff, two puffs and two puffs, for a total cumulative dose of 600
      microg oxitropium bromide. Doses were given at 20-min intervals and measurements
      made 15 min after each dose. On six separate days, all patients received one of
      the following: (1) formoterol 12 microg + oxitropium bromide 600 microg, (2)
      formoterol 12 microg + placebo, (3) formoterol 24 microg + oxitropium bromide 600
      microg, (4) formoterol 24 microg + placebo, (5) placebo + oxitropium bromide 600
      microg, or (6) placebo + placebo. Both formoterol 12 microg and 24 microg induced
      a good bronchodilation (formoterol 12 microg, 0.19-0.20 l; formoterol 24 microg
      0.22-0.24 l). The dose-response curve of oxitropium, but not placebo, showed an
      evident increase in FEV1, with a further significant increase of respectively
      0.087 l and 0.082 l after the formoterol 12 microg and formoterol 24 microg pre
      treatment. This study shows that improved pulmonary function in patients with
      stable COPD may be achieved by adding oxitropium 400-600 microg to formoterol.
      There is not much difference in bronchodilation between combining oxitropium with
      formoterol 12 microg or 24 microg. In any case, formoterol 24 microg alone seems
      sufficient to achieve the same bronchodilation induced by oxitropium 600 microg
      alone in most patients.

PMID- 10653055
TI  - Nitric oxide metabolites in patients with asthma: induced sputum versus blood.
AB  - Nitric oxide (NO) plays an important role in physiological regulation of the
      airways. The monitoring of airway inflammation has being observed in bronchial
      asthma directly, by sputum examination, and indirectly, by measurements in
      peripheral blood. To investigate the diagnostic value of these two methods, we
      compared NO metabolites in induced sputum and serum obtained in patients with
      asthma and control subjects. Hypertonic saline induced sputum and serum were
      obtained in 13 patients with asthma and 10 control subjects. NO metabolite level
      was assayed by using modified Griess reaction. Eosinophil cationic protein (ECP)
      was measured by fluoroimmunoassay, and detected interleukin (IL)-5 by a sandwich
      ELISA. The accuracy of the tests was measured by plotting the data in receiver
      operating characteristic (ROC) curves and comparing the area under the curve for
      NO metabolites. Asthmatic patients, compared with control subjects, had
      significantly higher NO metabolites in induced sputum (1252.5+/-203.3 mol l(-1)
      vs. 557.2+/-101.5 mol l(-1), P<0.01) but not in serum. IL-5 in induced sputum was
      detected more frequently in patients with asthma than in control subjects [11/13
      (84.6%) vs. 1/10 (10%), P<0.01]. Asthmatic patients, compared with control
      subjects, had significantly higher ECP concentration in induced sputum (1270.0+/
      197.9 g l vs. 154.6+/-47.4 g l(-1), P<0.01). There were significant positive
      correlations between NO metabolites in induced sputum and eosinophils, ECP in
      induced sputum (r=0.58 P<0.05; r=0.64, P<0.01) in patients with asthma but not in
      serum. The area under the ROC curve showed that NO metabolites in induced sputum
      (0.78) are more accurate marker than NO metabolites in serum (0.53) (P<0.05).
      These findings suggest that NO metabolites in induced sputum is a more valuable
      indicator to monitor asthmatic airway inflammation than those in serum.

PMID- 10653056
TI  - Early house moves, indoor air, heating methods and asthma.
AB  - OBJECTIVES: To assess whether house moves or certain housing conditions are a
      risk factor for the development of childhood asthma. DESIGN: A case-control study
      of asthmatic and non-atopic children aged 4-16 years. SUBJECTS: One hundred
      children with confirmed asthma in a group general practice of 11000 patients in
      Plymouth, U.K. Each was matched by age and gender with a child with no history of
      wheeze, eczema or hay fever. MAIN OUTCOME MEASURES: House moves and main heating
      methods, prior to the age of onset of asthma in cases and controls. RESULTS:
      There was a non-significant association between early house moves and the
      subsequent development of asthma. No association was found with heating methods,
      except for ducted-air heating which, because of the small numbers involved could
      have occurred by chance. None of the other factors studied affecting indoor air
      showed an association. CONCLUSION: Moving house at an early age may increase the
      risk of developing asthma, or may be associated with other more important risk
      factors, such as increased general mobility and hence, exposure to viral
      infections. Heating methods or other factors likely to affect the indoor air
      quality in early life were not useful predictors of subsequent asthma in
      children.

PMID- 10653057
TI  - A confidential enquiry into certified asthma deaths in the North of England, 1994
      96: influence of co-morbidity and diagnostic inaccuracy.
AB  - To understand more fully the nature of events leading to asthmatic death, we
      conducted a confidential enquiry prospectively throughout 1994-96 among the
      surviving relatives and respective general practitioners of subjects whose deaths
      could be attributed to asthma, whether wholly or partly. We also reviewed
      relevant hospital records and autopsy reports, and we submitted all the gathered
      information to an enquiry panel for evaluation. The subjects were identified from
      death certificates issued in five districts of the Northern Health Region of
      England (population 1 million) on which asthma was recorded as the primary cause
      of death. The enquiry panel agreed that asthma had been a critical factor in
      causing death in only 33 of the 79 certified cases for which there were
      sufficient data. The level of concordance was substantially greater for subjects
      aged < 65 years (76%) than for those who were older (17%). In 16 of the 33 cases
      asthma alone appeared to be responsible for death, but in 17 cases a wide variety
      of additional, co-morbid, disorders appeared to have contributed. They included,
      during the 24 h preceding death, gastric aspiration, septicaemia, a single dose
      of a beta-blocker, the abuse of organic solvents or illicit drugs and possibly,
      an inadvertent exposure to horse allergen. More chronic causes of co-morbidity
      included ischaemic heart disease, chronic obstructive pulmonary disease (COPD),
      thoracic cage deformity and alcohol abuse. There were possible errors of
      judgement in two cases by the supervising physician (6%) and in three cases by
      the patient (9%). Poor compliance and psychosocial disruption probably exerted an
      additional adverse influence in nine cases (27%). We conclude: (1) that asthma
      death certification in subjects aged 65 years or more is very unreliable, (2)
      that for approximately half of the deaths in which asthma exerted a critical role
      there were critical co-morbid disorders and (3) that errors of judgement, poor
      compliance, or psychosocial disruption are likely to have exerted an additional
      adverse influence in an important minority of cases.

PMID- 10653058
TI  - Osteoporosis: epidemiology, diagnosis, and treatment.
AB  - Osteoporosis is an important health problem in the United States affecting
      approximately 24 million Americans, 15 to 20 million of whom are women over 45
      years of age. Bone fractures are the major cause of morbidity and mortality
      associated with osteoporosis. The most common fractures are those of the forearm,
      hip, and vertebral body, as well as the humerus, tibia, pelvis, and ribs.
      Osteoporosis-related injuries result in complications leading to prolonged
      hospitalization, decreased independence, increased incidence of depression, and a
      reduced quality of life. The disease takes an enormous personal and economic
      toll, with estimated costs in excess of $13.8 billion annually for direct medical
      treatment. The incidence of osteoporosis-related fractures is increasing and
      constitutes a major public health problem in the United States. With a few
      preventive measures such as identification of risk factors, careful examination,
      and a few simple diagnostic tests, prevention of osteoporosis during the teen and
      early adult years is far superior to any treatment for older individuals.
      Osteoporosis can be identified and an appropriate treatment strategy can be
      determined.

PMID- 10653059
TI  - Deactivating the implantable cardioverter-defibrillator: a biofixture analysis.
AB  - Automatic implantable cardioverter-defibrillators (ICDs) are becoming
      increasingly common, as is refusal of resuscitative efforts at the end of life,
      both by patients and surrogate decision-makers. While it is clear that a
      terminally ill patient who lacks decisional capacity may, through a surrogate,
      refuse cardiopulmonary resuscitation (CPR), is it appropriate for physicians to
      infer from such a refusal that the patient's ICD should be deactivated? A proper
      answer to this question requires consideration of the nature of consent to a do
      not-resuscitate (DNR) order, the context in which permission is given for the
      writing of the DNR order, and the ontologic status of implantable devices in
      general and ICDs in particular. We introduce the concept of "biofixtures" and
      suggest that a biofixture analysis is a novel way of approaching the difficult
      ethical issues that may confound the care of patients with implantable devices.

PMID- 10653060
TI  - Remodeling of the endocrine pancreas: the central role of amylin and insulin
      resistance.
AB  - BACKGROUND: Remodeling of the endocrine pancreas, caused by the deleterious
      effects of amylin as it is co-synthesized, co-packaged, and co-secreted with
      insulin, gives clinicians and researchers cause to ponder. METHODS: A literature
      search was done, and relevant publications and texts on amylin and islet amyloid
      polypeptide (IAPP) were reviewed. RESULTS: The mechanisms and clinical
      consequences attributed to the remodeling of the endocrine pancreas, along with
      proposals for reevaluating the methods of treating patients who have type 2
      diabetes are illustrated and discussed. CONCLUSIONS: In addition to controlling
      the devastating effects ofglucotoxicity, lipotoxicity, and hypertension, we
      should consider the newer hypoglycemic agents with regard to their effects on the
      remodeling of the endocrine pancreas. This remodeling results in structural and
      subsequent functional changes, causing continued elevations of hemoglobin A1C.
      Studies are indicated to determine whether amylin (IAPP) may be implicated in the
      remodeling of the arterial vessel wall, the glomerulus of the kidney, and the
      cardiac interstitium.

PMID- 10653061
TI  - Supernumerary breast tissue: historical perspectives and clinical features.
AB  - The presence of extra nipples and breasts, polythelia and polymastia
      respectively, is not uncommon. Such supernumerary breast tissue usually is found
      within the milk line extending from the axilla to pubic region. It was once
      thought that this condition was a symbol of increased fertility and femininity.
      Anne Boleyn was said to have a third breast. Ancient goddesses of fertility had
      row upon row of breasts on their chests. Polythelia is seen congenitally. Ectopic
      breast tissue and polymastia may not appear until enhanced by sex hormones during
      puberty or early pregnancy. The same pathology that can affect normally
      positioned breasts, including carcinoma, can occur in supernumerary breast
      tissue. Renal and other organ system anomalies are associated with supernumerary
      breast tissue. Further research is needed to establish the clinical significance
      of supernumerary breast tissue in light of its reported associated conditions.
      Appropriate treatment is yet to be refined.

PMID- 10653062
TI  - Perforation of the colon after blunt trauma.
AB  - Blunt rupture of the colon follows a direct blow to the abdomen. Physical
      findings suggesting peritoneal irritation are usually present early in the
      postinjury period and lead to further evaluation and operation. In unresponsive
      patients, physical findings may be masked, diagnosis delayed, and outcome
      compromised. Perioperative antibiotics and early celiotomy with complete intra
      abdominal exploration and primary repair of the colon injury usually provide
      excellent results.

PMID- 10653063
TI  - Rural acquired immunodeficiency syndrome in low and high prevalence areas.
AB  - BACKGROUND: Too little is understood about the spread of the acquired
      immunodeficiency syndrome (AIDS) in rural America. This study focuses on changes
      over 5 years in two low prevalence and two high prevalence human immunodeficiency
      virus (HIV) rural service areas. METHODS: An initial study conducted in 1993
      provided a base line for the study. Each site was revisited in the summer of
      1998. Data were analyzed by degree of rurality of the site, prevalence levels,
      and risk categories. RESULTS: Changes in the number of AIDS cases ranged from
      slow steady growth to increases of an epidemic magnitude. Some settings were
      characterized primarily by white homosexual men, and others had a more diverse
      population living in poverty. CONCLUSIONS: Populations receiving priority for
      national AIDS funding should be expanded to include rural America as a target
      group, and funding should provide the latitude for communities to match their
      local needs.

PMID- 10653064
TI  - Fulfillment of diagnostic criteria in Kawasaki disease.
AB  - BACKGROUND: The diagnosis of Kawasaki disease (KD) is made by fulfillment of
      clinical criteria. The dramatic effectiveness of intravenous immune globulin in
      this disease might lead to treatment of cases that do not meet those criteria.
      METHODS: A retrospective review was conducted of all cases of KD treated at
      Kosair Children's Hospital between January 1993 and July 1997. RESULTS: Fifty-six
      patients were identified. Demographic features were similar to reports from other
      regions of the country. Forty-eight children fulfilled criteria for typical or
      atypical KD and 8 (14%) did not. The latter children were not distinguished from
      those meeting criteria by standard laboratory test results. Echocardiographic
      abnormalities were found in 17 cases, including 3 with coronary artery aneurysms,
      but all abnormalities eventually resolved. CONCLUSIONS: The treatment of 14% of
      patients despite incomplete diagnostic criteria illustrates the tendency to be
      liberal in treatment decisions regarding KD. Whether this proportion of patients
      has a forme fruste of the illness that warrants treatment will await definitive
      biological markers for the syndrome.

PMID- 10653065
TI  - Immunization status of children born to human immunodeficiency virus (HIV)
      infected mothers in two Texas cities.
AB  - BACKGROUND: Because HIV-infected and HIV-exposed children are at risk of
      acquiring infectious diseases, they should be immunized. METHODS: We abstracted
      charts at pediatric HIV clinics in Dallas and San Antonio, matched the children
      to birth certificates and assessed up-to-date immunization status. RESULTS: Of
      the 178 children, 108 (61%) were up to date for the diphtheria-tetanus-pertussis
      (DTP), polio, and measles-mumps-rubella (MMR) series. In multivariate analysis,
      predictors of delayed immunization included maternal high-risk sexual partners
      and infant antiretroviral therapy. CONCLUSION: In this population of children
      born to HIV-infected mothers, immunizations were up to date in 61%, a figure that
      exceeds or equals immunization levels for other Texas children. Texas falls short
      of the recommended goal of 90% immunization for children of HIV-infected mothers
      and healthy children.

PMID- 10653066
TI  - Folate and vitamin B12-deficiency anemias in Vietnamese immigrants living in
      Southern California.
AB  - BACKGROUND: Although the occurrence of iron deficiency anemia and
      hemoglobinopathies in Vietnamese immigrants has been reported, folate and vitamin
      B12 deficiencies have not. Proper diagnosis and effective treatment is necessary
      to achieve a complete correction of anemia. METHODS: We retrospectively analyzed
      the records of Vietnamese immigrants seen in our medical clinic from 1991 to
      1993. Fifty-nine anemic patients (48 females and 11 males) had low levels of red
      blood cell (RBC) folate and/or serum vitamin B12. RESULTS: The patients' mean age
      was 37.7+/-17 years. Mean hemoglobin and hematocrit values were 11.4+/-0.7 g/dL
      and 34.4%+/-2.2%, respectively. Mean corpuscular volume (MCV) was normal in 40
      patients (68%) (mean, 89.1+/-5 fL) and low in 19 patients (32%) (mean, 69.7+/-6
      fL). Forty-four patients had low RBC folate levels (mean, 157.7+/-41.7 ng/mL).
      Twenty patients had low serum vitamin B12 levels (mean, 165.6+/-47 pg/mL).
      Fourteen patients had ferritin levels of <20%. CONCLUSIONS: Concomitant folate,
      vitamin B12, and iron deficiencies or hemoglobinopathies might have been
      responsible for either normal or low MCV in some of our anemic patients. In this
      ethnic group, RBC folate and serum vitamin B12 levels should be determined in all
      anemic patients.

PMID- 10653067
TI  - Can warfarin randomized trials be reproduced in 'real life'? Adherence to
      warfarin guidelines for intensity of anticoagulation in a university-based
      warfarin clinic.
AB  - BACKGROUND: Subjects in clinical trials may benefit from the increased attention
      and specific focus of the trial, thereby limiting the external validity of
      clinical trial results to clinical practice. Our study evaluated adherence to
      guidelines for intensity of anticoagulation in a large, university-based warfarin
      clinic to assess the generalizability of randomized clinical trials of warfarin
      efficacy to clinical practice. METHODS: We reviewed anticoagulation clinic
      records of 480 patients observed for up to 2 years to determine the amount of
      time anticoagulation was within the recommended therapeutic range. RESULTS: The
      most common indication for warfarin use was atrial arrhythmia (51.5%). Overall,
      anticoagulation was within the intended international normalized ratio (INR)
      target range on 57.8% of treatment days. Nontherapeutic treatment days were due
      more commonly to subtherapeutic INR values (27.6+/-25.7%) than supratherapeutic
      INR values (14.9+/-17.0%). This pattern was seen across all warfarin indications.
      CONCLUSION: These data are comparable to those reported from large randomized
      trials and thus support the generalizability of clinical trials of long-term
      warfarin anticoagulation to clinical practice.

PMID- 10653068
TI  - Spurious elevation of hemoglobin A1c by hereditary persistence of fetal
      hemoglobin.
AB  - We present the case of a 61- year-old black woman with a diagnosis of type 2
      diabetes and a falsely elevated hemoglobin A1c (HbA1c) due to hereditary
      persistence of fetal hemoglobin. Physicians and allied health care professionals
      are alerted to this potentially significant problem in the diagnosis and
      management of diabetes mellitus (DM), particularly in the wake of the Diabetes
      Complications and Control Trial when "strict" glycemic control assessed by HbA1c
      is now the standard of care.

PMID- 10653069
TI  - Diffuse alveolar hemorrhage syndrome due to 'silent' mitral valve regurgitation.
AB  - A variety of clinical diseases are associated with diffuse alveolar hemorrhage.
      Although mitral valve disease can cause hemoptysis, it rarely is associated with
      diffuse alveolar hemorrhage at presentation. A 49-year-old woman was admitted to
      the hospital with the abrupt onset of fever, anemia, dyspnea, azotemia, and
      diffuse alveolar infiltrates. Two-dimensional echocardiography done several
      months earlier to evaluate atypical chest pain had been unremarkable. Fiberoptic
      bronchoscopy 2 days after admission to the hospital revealed fresh blood
      throughout the tracheobronchial tree. The infiltrates resolved rapidly and
      completely during systemic steroid therapy only to reappear as the steroids were
      tapered, suggesting a beneficial therapeutic response. Results of serologic
      evaluation were negative. Transbronchial biopsies showed inflammation and
      hemosiderin-laden macrophages; no specific diagnosis was established. The patient
      was scheduled for open lung biopsy. The surgeon was concerned about the history
      of chest pain and requested placement of a pulmonary artery catheter, which
      revealed severe pulmonary hypertension. Transesophageal echocardiography and
      subsequent cardiac catheterization showed severe mitral regurgitation. Mitral
      valve replacement resulted in complete elimination of symptoms.

PMID- 10653070
TI  - Remission of facial and scalp hyperhidrosis with clonidine hydrochloride and
      topical aluminum chloride.
AB  - Axillary and palmar hyperhidrosis are featured prominently in the literature, but
      no previous studies have detailed a treatment regimen for specific excessive
      localized sweating of the face and scalp. In this report, a patient was treated
      for this condition with a combination of clonidine hydrochloride (0.3 mg to 0.4
      mg, with 0.25 mg to be taken at bedtime, to prevent daytime sedation) [corrected]
      and a topical solution of 20% aluminum chloride in anhydrous ethyl alcohol
      (Drysol). Over a period of 2 or 3 weeks, the patient achieved a complete
      remission of symptoms, while having only mild side effects. The treatment regimen
      also had the added advantage of lowering generalized anxiety.

PMID- 10653071
TI  - Rapid onset of stupor.
AB  - Catatonia is a syndrome with many causes that can be difficult to diagnose. In
      this report, we describe a case of rapid onset of stupor and loss of
      consciousness, subsequent evaluation, and treatment of catatonia in an HIV
      positive man.

PMID- 10653072
TI  - Metastatic small cell carcinoma to the testis.
AB  - Testicular neoplasms comprise 1% of all malignancies in men, with less than 3% of
      these malignancies due to metastatic disease. We report a case of a 51-year-old
      man with a history of left pneumonectomy done 2 years earlier for small cell
      carcinoma of the lung; the patient came to his primary care physician for routine
      follow-up. Physical examination was significant for a left testicular mass, which
      on final pathology was diagnosed as metastatic small cell carcinoma.

PMID- 10653073
TI  - Surreptitious superwarfarin ingestion with brodifacoum.
AB  - Physicians must have a high index of suspicion when patients have unexplained
      prolongation of the prothrombin time and bleeding in the absence of detectable
      warfarin. Several common rodenticides contain modified versions of warfarin that
      are not detectable in standard warfarin assays. We present a case of
      surreptitious brodifacoum ingestion in a patient who had years of unexplained
      bleeding and negative warfarin levels.

PMID- 10653074
TI  - Appendiceal diverticulitis.
AB  - We report the case of a 56-year-old man with episodic right lower quadrant
      abdominal pain. Preoperative evaluation included computed tomography (CT) showing
      a right lower quadrant phlegmon consistent with cecal diverticulitis or
      appendicitis. The patient was treated with a short course of bowel rest and
      antibiotics. Four weeks later, he had an appendectomy. The patient was found to
      have chronic appendiceal diverticulitis and recovered uneventfully.
      Histopathologic studies revealed herniated mucosa through the muscular layer
      associated with chronic inflammation and marked fibrosis. These findings
      represent appendiceal diverticulitis. Diverticulosis of the appendix is believed
      to be uncommon and roentgenologic diagnosis of appendiceal diverticular disease
      is rarely made. We discuss the diagnosis and CT findings of appendiceal
      diverticulitis and present a thorough review of the literature.

PMID- 10653075
TI  - Lack of mediastinal shift as a clue to delayed postpneumonectomy empyema.
AB  - Delayed postpneumonectomy empyema is uncommon. The condition is usually elusive
      and diagnosed late in the course of the disease, leading to increased morbidity.
      New air-fluid level on chest x-ray film or appearance of empyema necessitatis may
      enhance the index of suspicion and lead to early diagnosis, but in many cases no
      clinical or laboratory clues are apparent. We describe the case of a 60-year-old
      man with high fever and dyspnea 3(1/2) years after pneumonectomy. Diagnosis of
      postpneumonectomy empyema was delayed and finally suggested by the lack of
      expected mediastinal shift on chest film. Computed tomography (CT) of the chest
      showed a large quantity of fluid, which later proved to be empyema. The patient
      was treated successfully by continuous cavity irrigation with neomycin and
      systemic antibiotics. We conclude that in postpneumonectomy patients with septic
      fever, the only clue to diagnosis of delayed postpneumonectomy empyema may be
      hemithorax opacification without mediastinal shift, confirmed by CT-guided
      thoracocentesis. Therapy with cavity irrigation and systemic antibiotics seems
      appropriate.

PMID- 10653077
TI  - Heads up for healthy people 2010.

PMID- 10653076
TI  - Benzocaine-induced methemoglobinemia.
AB  - Methemoglobinemia is an uncommon but important complication associated with the
      use of topical anesthetics. We describe four cases of methemoglobinemia induced
      by topical benzocaine use. We review pathophysiology, early diagnosis, and
      therapy for this reversible yet potentially fatal condition. Physicians who use
      procedures involving the application of topical anesthetics need to be aware of
      this side effect to prevent significant morbidity and mortality.

PMID- 10653078
TI  - 2000-2010: the bone and joint decade.

PMID- 10653079
TI  - Long-term disability and return to work among patients who have a herniated
      lumbar disc: the effect of disability compensation.
AB  - BACKGROUND: Low-back problems are one of the most frequent reasons for disability
      compensation claims by workers. However, the effect of Workers' Compensation
      status on the long-term outcome for workers with sciatica has not been studied in
      detail, to our knowledge. Therefore, we believe that it is important to describe
      the long-term outcomes for patients who have herniation of a lumbar disc and
      sciatica according to the Workers' Compensation status at the time of the
      preoperative consultation. METHODS: We conducted a prospective, observational
      study of patients who had sciatica and were seeking care from specialist
      physicians in community-based practices throughout Maine. Among 440 eligible
      patients, 199 were receiving Workers' Compensation at the time of entry into the
      study (baseline) and 241 were not. Three hundred and twenty-six patients (74
      percent) completed questionnaires at the time of a four-year follow-up. The
      outcomes that we assessed included disability compensation and work status as
      well as relief from symptoms, functional status, and quality of life. RESULTS:
      Patients who were receiving Workers' Compensation at baseline were more likely to
      be young, male, and employed as laborers. They reported worse functional status;
      however, the clinical findings for these patients were similar to those for
      patients who were not receiving Workers' Compensation. Patients who had been
      receiving Workers' Compensation at baseline were more likely to be receiving
      disability benefits at the time of the four-year follow-up compared with those
      who had not (27 percent of 133 compared with 7 percent of 189; p<0.001); however,
      they were only slightly less likely to be working at the time of the four-year
      follow-up (80 percent of 133 compared with 87 percent of 190; p = 0.09).
      Operative management did not influence these comparisons, but it decreased
      symptoms and improved functional status. Patients who had been receiving Workers'
      Compensation at baseline also had significantly less relief from symptoms and
      improvement in quality of life than patients who had not been receiving Workers'
      Compensation (all p<0.001). In multivariate models, Workers' Compensation status
      at baseline was an independent predictor of whether the patient would be
      receiving disability benefits after four years (odds ratio, 3.5; 95 percent
      confidence interval, 1.7 to 7.6) but was not an independent predictor of whether
      the patient would be working on a job for pay at the time of the four-year follow
      up (odds ratio, 0.6; 95 percent confidence interval, 0.3 to 1.2). CONCLUSIONS:
      Even after adjustment for the initial treatment of the sciatica and for other
      clinical factors, patients who had been receiving Workers' Compensation at
      baseline were more likely to be receiving disability benefits and were less
      likely to report relief from symptoms and improvement in quality of life at the
      time of the four-year follow-up than patients who had not been receiving Workers'
      Compensation at baseline. Nonetheless, most patients returned to work regardless
      of their initial disability status, and those who had been receiving Workers'
      Compensation at baseline were only slightly less likely to be working after four
      years. Whether or not they had been receiving Workers' Compensation at baseline,
      patients who had been managed with an operation reported greater relief from
      symptoms and improvement in functional status at the time of the four-year follow
      up compared with patients who had been managed nonoperatively, even though the
      outcomes with regard to disability and work status in these two groups were
      comparable.

PMID- 10653080
TI  - Posterior-inferior capsular shift for the treatment of recurrent, voluntary
      posterior subluxation of the shoulder.
AB  - BACKGROUND: The treatment of recurrent posterior instability of the shoulder,
      especially when it is associated with voluntary subluxation, remains
      controversial, and operative correction generally is not advised. METHODS: The
      results of operative correction of recurrent posterior subluxation in a
      consecutive series of twenty-six shoulders in twenty-four patients were reviewed.
      Eighteen shoulders were on the dominant side. The average age of the patients was
      twenty-four years (range, fifteen to thirty-three years). All of the patients had
      involuntary as well as voluntary posterior instability, but none had a
      psychiatric disorder. Only five patients had sustained a definite injury that had
      initiated the instability. Seven shoulders had had previous operations. A program
      of nonoperative treatment for a duration of at least three months had failed to
      control the symptoms in all patients. The twenty-six shoulders were treated with
      a posterior-inferior capsular shift procedure, which included repair of a so
      called posterior Bankart lesion in seven shoulders. In addition, one of the
      shoulders had a posterior bone block and three shoulders (in two patients) had an
      osteotomy of the posterior part of the glenoid because of excessive glenoid
      retroversion. The outcome was assessed by means of a personal interview and a
      clinical examination, which included calculations of a score according to the
      system of Constant and Murley and the performance of the Simple Shoulder Test,
      and by means of a radiographic examination, with standardized radiographs and
      computerized tomography scanning. RESULTS: At an average of 7.6 years (range, 1.8
      to 14.6 years) after the operation, the patients estimated that the function of
      the shoulder was an average of 86 percent of that of a normal shoulder. The
      average relative score according to the system of Constant and Murley was 91
      percent. The subjective result was excellent for sixteen shoulders, good for
      eight, and fair for two. More than half of all of the patients were able to
      perform all activities of the Simple Shoulder Test, but eight patients (eight
      shoulders; 31 percent) still had discomfort at night. Five patients (21 percent)
      changed their profession because of the shoulder. All but one shoulder had a
      nearly normal active range of motion. The instability recurred in six (23
      percent) of the twenty-six shoulders; three recurrences were in shoulders that
      had had a primary operation, and three were in shoulders that had had an
      operation on the posterior aspect of the shoulder before the index procedure. The
      instability did not recur in four shoulders that had had previous operations on
      the anterior aspect of the shoulder. The subjective shoulder value, which was the
      patient's estimation of the value of the affected shoulder as a percentage of
      that of an entirely normal shoulder, was significantly higher for the stable
      shoulders (91 percent) than for the unstable shoulders (72 percent) (p<0.05). The
      relative score according to the system of Constant and Murley was also higher for
      the stable shoulders (93 percent) than for the unstable shoulders (87 percent),
      but the difference was not found to be significant, with the numbers available.
      The joints were found to be well centered radiographically, and only six
      shoulders showed minimum signs of osteoarthritis. Computerized tomography
      scanning revealed an average glenoid retroversion of 3.2 degrees (range, 17
      degrees of retroversion to 22 degrees of anteversion). When only the shoulders
      that had not had a posterior bone block or an osteotomy of the posterior aspect
      of the glenoid were considered, the average glenoid retroversion of those that
      had recurrent instability was 12.5 degrees, whereas it was only 6.2 degrees for
      those that remained stable (p<0.05). CONCLUSIONS: Overall, operative correction
      of voluntary posterior instability of the shoulder yielded very satisfactory
      intermediate-term clinical results. (ABSTRACT TRUNCATED)

PMID- 10653081
TI  - Shoulder arthroplasty with or without resurfacing of the glenoid in patients who
      have osteoarthritis.
AB  - BACKGROUND: The indications for resurfacing of the glenoid in patients who have
      osteoarthritis of the shoulder are not clearly defined; some investigators
      routinely perform hemiarthroplasty whereas others perform total shoulder
      arthroplasty. METHODS: Forty-seven patients (fifty-one shoulders) who were
      scheduled to have a shoulder arthroplasty for the treatment of degenerative
      osteoarthritis were randomly assigned, according to a random-numbers table, to
      one of two groups: replacement of the humeral head with resurfacing of the
      glenoid with a polyethylene component with cement (total shoulder arthroplasty
      [twenty-seven shoulders]) or replacement of the humeral head without resurfacing
      of the glenoid (hemiarthroplasty [twenty-four shoulders]). All patients received
      the same type of humeral component, and all operations were performed by or under
      the direct supervision of the same surgeon. The patients were followed for a mean
      of thirty-five months (range, twenty-four to seventy-two months) postoperatively.
      Evaluation was performed with use of the scoring systems of the University of
      California at Los Angeles and the American Shoulder and Elbow Surgeons. RESULTS:
      No difference was observed between the preoperative scores for the two groups of
      patients. Postoperatively, the mean scores with use of the University of
      California at Los Angeles system and the American Shoulder and Elbow Surgeons
      system were 23.2 points (range, 10 to 31 points) and 65.2 points (range, 15 to 94
      points), respectively, after hemiarthroplasty and 27.4 points (range, 9 to 34
      points) and 77.3 points (range, 3 to 100 points), respectively, after total
      shoulder arthroplasty. With the numbers available for study, no significant
      difference was found between the two operative groups with respect to the
      postoperative score. (Thirty-five subjects per group would be needed, assuming an
      effect size of 0.60 and a power of 0.80.) Total shoulder arthroplasty provided
      significantly greater pain relief (p = 0.002) and internal rotation (p = 0.003)
      than hemiarthroplasty did. Total shoulder arthroplasty also provided superior
      results in the specific areas of patient satisfaction, function, and strength,
      although none of these differences were found to be significant, with the numbers
      available. Total shoulder arthroplasty was associated with increased cost
      ($1177), operative time (thirty-five minutes), and blood loss (150 milliliters)
      per patient compared with hemiarthroplasty. To date, none of the total shoulder
      arthroplasties in the study group have been revised. Hemiarthroplasty yielded
      equivalent results for elevation and external rotation. Three of the twenty-five
      patients who had had a hemiarthroplasty needed a subsequent operation for
      resurfacing of the glenoid. The mean cost for the revision operations was
      $15,998. CONCLUSIONS: Total shoulder arthroplasty provided superior pain relief
      compared with hemiarthroplasty in patients who had glenohumeral osteoarthritis,
      but it was associated with an increased cost of $1177 per patient.

PMID- 10653082
TI  - The effect of a glenoid defect on anteroinferior stability of the shoulder after
      Bankart repair: a cadaveric study.
AB  - BACKGROUND: An osseous defect of the glenoid rim is sometimes caused by multiple
      recurrent dislocations of the shoulder. It is generally thought that a large
      defect should be treated with bone-grafting, but there is a lack of consensus
      with regard to how large a defect must be in order to necessitate this procedure.
      Some investigators have proposed that a defect must involve at least one-third of
      the glenoid surface in order to necessitate bone-grafting. However, it is
      difficult to determine (1) whether a defect involves one-third of the glenoid
      surface and (2) whether a defect of this size is critical to the stability of the
      shoulder after a Bankart repair. The purposes of the present study were (1) to
      create and quantify various sizes of osseous defects of the glenoid and (2) to
      determine the effect of such defects on the stability and motion of the shoulder
      after Bankart repair. METHODS: The glenoids from sixteen dried scapulae were
      photographed, and the images were scanned into a computer. The average shape of
      the glenoid was determined on the basis of the scans, and this information was
      used to design custom templates for the purpose of creating various sizes of
      osseous defects. Ten fresh-frozen cadaveric shoulders then were obtained from
      individuals who had been an average of seventy-nine years old at the time of
      death, and all muscles were removed to expose the joint capsule. With use of a
      custom multiaxis electromechanical testing machine with a six-degrees-of-freedom
      load-cell, the humeral head was translated ten millimeters in the anteroinferior
      direction with the arm in abduction and external rotation as well as in abduction
      and internal rotation. With a fifty-newton axial force constantly applied to the
      humerus in order to keep the humeral head centered in the glenoid fossa, the peak
      force that was needed to translate the humeral head a normalized distance was
      determined under eleven sequential conditions: (1) with the capsule intact, (2)
      after the creation of a simulated Bankart lesion, (3) after the capsule was
      repaired, (4) after the creation of an anteroinferior osseous defect with a width
      that was 9 percent of the glenoid length (average width, 2.8 millimeters), (5)
      after the capsule was repaired, (6) after the creation of an osseous defect with
      a width that was 21 percent of the glenoid length (average width, 6.8
      millimeters), (7) after the capsule was repaired, (8) after the creation of an
      osseous defect with a width that was 34 percent of the glenoid length (average
      width, 10.8 millimeters), (9) after the capsule was repaired, (10) after the
      creation of an osseous defect with a width that was 46 percent of the glenoid
      length (average width, 14.8 millimeters), and (11) after the capsule was
      repaired. RESULTS: With the arm in abduction and external rotation, the stability
      of the shoulder after Bankart repair did not change significantly regardless of
      the size of the osseous defect (p = 0.106). With the arm in abduction and
      internal rotation, the stability decreased significantly as the size of the
      osseous defect increased (p<0.0001): the translation force in shoulders in which
      the width of the osseous defect was at least 21 percent of the glenoid length
      (average width, 6.8 millimeters) was significantly smaller than the force in
      shoulders without an osseous defect. The range of external rotation in shoulders
      in which the width of the osseous defect was at least 21 percent of the glenoid
      length was significantly less than that in shoulders without a defect (p<0.0001)
      because of the pretensioning of the capsule caused by closing the gap between the
      detached capsule and the glenoid rim. The average loss of external rotation was
      25 degrees per centimeter of defect. CONCLUSIONS: An osseous defect with a width
      that is at least 21 percent of the glenoid length may cause instability and limit
      the range of motion of the shoulder after Bankart repair.

PMID- 10653083
TI  - Clinical outcome after primary triple arthrodesis.
AB  - BACKGROUND: To analyze the effects of multiple preoperative, intraoperative, and
      postoperative factors on the intermediate results of triple arthrodesis, we
      focused on preoperative deformity, preoperative diagnosis, degree of clinical and
      radiographic correction, and arthritis of the ankle. METHODS: Between 1987 and
      1995, 160 patients were managed with a total of 183 triple arthrodeses. Patients
      who had an infection or neuroarthropathy or who were managed with a revision
      arthrodesis were excluded from our study. Of the 160 patients, 111 (132 feet) who
      had been followed for a minimum of two years formed our study group. Each patient
      had an arthrodesis with rigid screw fixation and realignment of the joint
      surfaces without resection of wedges. The average duration of follow-up was 5.7
      years (range, 2.0 to 10.8 years). RESULTS: As seen radiographically, arthritis of
      the ankle was significantly more severe postoperatively than preoperatively
      (p<0.01), although patient satisfaction was not associated with the presence of
      arthritis. On a scale (not a visual analog) of 0 (not satisfied) to 10
      (completely satisfied), overall satisfaction averaged 8.3 points (range, 0 to 10
      points). The postoperative modified ankle-hindfoot score of the American
      Orthopaedic Foot and Ankle Society averaged 60.7 points (range, 0 to 94 points).
      There was a significant association (p = 0.001) between satisfaction of the
      patient and postoperative alignment. Ten patients had a total of eleven
      complications: four superficial wound problems, three nonunions, one case of
      superficial peroneal neuritis, one case of Charcot-like neuroarthropathy of the
      foot (in a patient in whom diabetes developed during the follow-up period), one
      rupture of the Achilles tendon, and one case of peroneal tenosynovitis. Of the
      111 patients, 101 (91 percent) stated that they would have the procedure again
      under similar circumstances, and this response was independent of the
      preoperative diagnostic or deformity group. CONCLUSIONS: Triple arthrodesis for
      the treatment of various deformities and etiologies is effective in relieving
      pain and improving functional deficits. Although a high prevalence of subsequent
      arthritis of the ankle was noted clinically and radiographically, we could detect
      no association between satisfaction of the patient and arthritis.

PMID- 10653084
TI  - Treatment of extrinsic flexion deformity of the toes associated with previous
      removal of a vascularized fibular graft.
AB  - BACKGROUND: Complications from vascularized fibular bone-grafting are infrequent.
      We saw six patients who had a painful flexion deformity of the great and lesser
      toes after a free vascularized fibular graft had been obtained from the
      ipsilateral leg. In this report, we discuss our management of these patients.
      METHODS: Painful flexion deformity of the toes that had developed in six adults
      after removal of a free vascularized fibular graft was treated by cutting of the
      flexor hallucis longus alone in three patients, by lengthening of the flexor
      hallucis longus alone in one, and by cutting of both the flexor hallucis longus
      and the flexor digitorum longus in two. RESULTS: After an average duration of
      follow-up of six years and eleven months, the flexion deformity of the great and
      lesser toes had decreased or disappeared, leading to improved or full extension
      of the digits. Preoperative and postoperative measurements of muscle strength for
      plantar flexion of the interphalangeal joints did not change appreciably.
      CONCLUSIONS: Cutting or lengthening of the flexor hallucis longus behind the
      ankle provides an adequate release of digital flexion deformities that occur
      after removal of a vascularized fibular bone graft.

PMID- 10653085
TI  - The effect of weight-bearing on the radiographic measurement of the position of
      the femoral head after total hip arthroplasty.
AB  - BACKGROUND: In most radiographic studies of polyethylene wear, investigators have
      used routine annual radiographs made with the patient in the supine position in
      order to measure penetration by the femoral head into the polyethylene liner.
      However, researchers have begun to question the effect of weight-bearing on the
      position of the head within the acetabular cup and, consequently, the effect of
      weight-bearing on measurements of penetration by the head. The purpose of the
      current study was to determine the effect of weight-bearing on the two
      dimensional radiographic position of the femoral head within the acetabular cup.
      METHODS: Thirty-seven patients (forty-seven hips) who had had a total hip
      arthroplasty had radiographs made at one of two separate institutions. A set of
      anteroposterior radiographs was made for each patient: one radiograph was made
      with the patient supine and one was made with the patient upright bearing full
      weight on the replaced hip. At one of the institutions, a third anteroposterior
      radiograph was made with the patient in the same upright position but not bearing
      weight on the replaced hip. All measurements of the two-dimensional position of
      the head were performed by a single observer with use of a previously published
      computerized measurement system. RESULTS: Data from both institutions revealed
      that measurements of the position of the head on radiographs made with the
      patient supine were strongly and significantly correlated with measurements of
      the position of the head on radiographs made with the patient bearing weight
      (r2>0.93, p<0.001 for both regressions). Examination of the differences between
      the measurements revealed no bias for one set of measurements to consistently
      underestimate or overestimate the values derived with use of the other method.
      Moreover, we found a nearly perfect relationship between the measurements of the
      position of the head on radiographs made with the patient standing and bearing
      weight and those on radiographs made with the patient standing but not bearing
      weight (r2 = 0.97, p<0.001, slope = 0.99, intercept = 0.02 millimeter).
      CONCLUSIONS: On the basis of these findings, there is no evidence that
      radiographs must be made with the patient bearing weight in order to accurately
      measure the position of the femoral head within the polyethylene liner.

PMID- 10653086
TI  - High tibial osteotomy with a calibrated osteotomy guide, rigid internal fixation,
      and early motion. Long-term follow-up.
AB  - BACKGROUND: We studied the results of sixty-four valgus-producing high tibial
      osteotomies performed with the use of a calibrated osteotomy cutting guide and
      rigid internal fixation, and followed by early motion, in fifty-six patients who
      had medial unicompartmental osteoarthritis and varus malalignment. Long-term
      studies have demonstrated that a high tibial osteotomy performed with staple
      fixation and followed by immobilization in a cast has an expected survival rate
      of approximately 85 percent at five years and 60 percent at ten years (in studies
      of ninety-five knees and 213 knees, respectively). To the best of our knowledge,
      there are no long-term reports on high tibial osteotomies performed with a
      calibrated osteotomy cutting guide and rigid internal fixation and followed by
      early motion. METHODS: The indications for high tibial osteotomy were medial
      unicompartmental osteoarthritis and varus malalignment. A lateral closing-wedge
      osteotomy was performed. The patients were reexamined to obtain a knee score, to
      make lateral radiographs of both knees, and to make a full-length anteroposterior
      radiograph (showing the entire lower extremity, including the hip and ankle) of
      the involved knee with the patient standing. RESULTS: Twenty-one knees were
      treated with a subsequent total knee arthroplasty at an average of sixty-five
      months after the high tibial osteotomy. The remaining forty-three knees had a
      good or excellent clinical result, with an average knee score of 94 points at an
      average of 8.5 years after the osteotomy. Survivorship analysis showed an
      expected rate of survival, with conversion to a total knee arthroplasty as the
      end point, of 85 percent at five years and 53 percent at ten years. No patient
      had patella baja postoperatively. There were six complications: four superficial
      wound infections, one superficial-vein thrombosis, and one delayed union (union
      occurred at five months). CONCLUSIONS: High tibial osteotomy has been criticized
      because of a high rate of complications, a loss of effectiveness with time, and
      the difficulty of conversion to a total knee arthroplasty secondary to patella
      baja. In our series, in which an osteotomy was performed with a calibrated
      osteotomy cutting guide and rigid internal fixation and was followed by early
      motion, the rate of complications was low and approximately two-thirds of the
      knees had a good or excellent clinical result at an average of 8.5 years.
      Conversion to a total knee arthroplasty was accomplished without difficulty in
      the patients who had this procedure. We highly recommend high tibial osteotomy
      with a calibrated osteotomy cutting guide, rigid internal fixation, and early
      motion for patients who wish to continue an active lifestyle.

PMID- 10653087
TI  - The protective effects of meniscal transplantation on cartilage. An experimental
      study in sheep.
AB  - BACKGROUND: Meniscal loss may result in arthritis. The aim of this study was to
      establish a simple operative method for meniscal transplantation in a large
      animal model and to determine whether meniscal transplantation provides
      protection of the articular surfaces, whether meniscal allografts have the same
      protective effect as meniscal autogenous grafts, and whether there is any
      rejection phenomenon associated with meniscal allografts. METHODS: Twenty-eight
      sheep were divided into four study groups, which were treated with (1) a sham
      operation (four sheep), (2) a meniscectomy (eight sheep), (3) a meniscal
      autogenous graft (eight sheep), or (4) a meniscal allograft (eight sheep). The
      meniscal transplant was secured with three suture anchors to the tibia. At four
      months after the operation, macroscopic and microscopic evaluations of the
      articular cartilage and the menisci of the sheep knees were performed in a
      blinded fashion. RESULTS: The group treated with the sham operation had no
      cartilage damage and had normal meniscal tissue. The meniscectomies resulted in
      significant macroscopic and microscopic damage to the articular cartilage in the
      medial compartment. The mean score (and standard error of the mean) for
      macroscopic damage to the cartilage in the group treated with the meniscectomy
      was 6.5+/-0.8 points compared with 3.9+/-0.7 points in the group treated with the
      autogenous graft and 4.3+/-0.6 points in the group treated with the allograft
      (p<0.05). The size of the area of damaged articular cartilage was reduced by
      approximately 50 percent in both groups treated with a meniscal transplant
      compared with the group treated with the meniscectomy (p<0.05). There were no
      significant differences between the group treated with the autogenous graft and
      that treated with the allograft. The histological appearance of the meniscal
      autogenous grafts was within normal limits. Interestingly, all of the allografts
      had evidence of fibrinoid degeneration with areas of hypocellularity and cloning
      of chondroid cells. CONCLUSIONS: These results suggest that meniscal
      transplantation provides noticeable although not complete protection against
      damage to the articular cartilage after a meniscectomy. The meniscal allografts
      were just as effective in providing this protection as were the meniscal
      autogenous grafts.

PMID- 10653088
TI  - Preoperative autologous donation for total joint arthroplasty. An analysis of
      risk factors for allogenic transfusion.
AB  - BACKGROUND: While autologous blood is commonly predonated to provide replacement
      of blood lost in orthopaedic procedures, few studies of patients managed with
      total joint replacement have addressed the problem of which patients are likely
      to benefit from an autologous blood-donation program. METHODS: A retrospective
      analysis of 489 consecutive patients who had had a total joint arthroplasty was
      performed to identify the risk factors for allogenic transfusion and to further
      define the indications for preoperative autologous blood donation. The operations
      included 247 total knee replacements (157 unilateral primary, thirty-two
      revision, and twenty-nine one-stage bilateral primary procedures) and 271 total
      hip replacements (163 primary and 108 revision procedures). Fifty-four percent
      (264) of the 489 patients donated a total of 527 units of blood (average, 2.0
      units per patient) preoperatively. RESULTS: One hundred and ninety-one patients
      (39 percent) required a transfusion of autologous blood or allogenic blood, or
      both. One hundred and thirty-one patients (27 percent) received autologous blood,
      and eighty-two patients (17 percent) received a transfusion of allogenic blood;
      twenty-two patients (4 percent) received both autologous and allogenic blood.
      Neither form of transfusion caused serious complications. Fifty-six percent (295)
      of the 527 units of autologous blood were discarded. Autologous donation
      significantly decreased the requirements for allogenic transfusion (relative
      risk, 0.1; p<0.0001). It also caused the level of hemoglobin to decrease an
      average of 12.2 grams per liter from the time before donation to the time before
      the operation (p<0.0001). Factors that increased the risk for allogenic
      transfusion were a revision knee or hip procedure or a one-stage bilateral
      primary knee replacement (relative risk, 5.7; p<0.0001), an initial hemoglobin
      level of less than 130 grams per liter (relative risk, 5.6; p<0.0001), and an age
      of sixty-five years or older (relative risk, 2.8; p = 0.02). None of the sixty
      seven patients who had a primary knee or hip arthroplasty and an initial
      hemoglobin level of 150 grams per liter or more required an allogenic
      transfusion. In addition, none of the sixty-three patients who had a primary
      arthroplasty, an initial hemoglobin level of between 130 and less than 150 grams
      per liter, and an age of less than sixty-five years required an allogenic
      transfusion. Eighty-three percent (115) of the 138 autologous units donated by
      the seventy patients in these two groups were discarded. These wasted units
      accounted for 39 percent of the 295 discarded units for the entire study sample.
      CONCLUSIONS: The efficiency of collection of autologous blood can be improved by
      identifying patients who have a very low risk of transfusion according to the
      type of arthroplasty, the initial level of hemoglobin, and age. Patients who have
      an initial hemoglobin level of at least 150 grams per liter or an initial
      hemoglobin level of between 130 and 150 grams per liter and an age of less than
      sixty-five years have a minimal risk of needing a transfusion during or after a
      primary total joint replacement. These patients should be apprised of their low
      risk so that they can make an informed decision regarding preoperative autologous
      donation.

PMID- 10653089
TI  - Distraction of hypertrophic callus in the treatment of segmental bone loss in the
      femur. A case report.

PMID- 10653090
TI  - Contralateral intrathoracic displacement of the humeral head. A case report.

PMID- 10653091
TI  - Long-term results of allograft replacement after total calcanectomy. A report of
      two cases.

PMID- 10653092
TI  - Subclinical slipped capital femoral epiphysis. Relationship to osteoarthrosis of
      the hip.

PMID- 10653093
TI  - Kienbock disease and negative ulnar variance.

PMID- 10653094
TI  - Kienbock disease and negative ulnar variance.

PMID- 10653095
TI  - Ultrasound--an alternative healing method for nonunions?
AB  - Several years ago, low-intensity pulsed ultrasound (frequency 1.5 MHz; signal
      burst width 200 micros; signal repetition frequency 1 KHz; intensity 30 mW/cm2)
      was shown to accelerate fresh fracture healing both clinically and
      experimentally. On the basis of a prescription use registry, this paper reports
      on the use of low-intensity pulsed ultrasound in the therapy of 951 delayed
      unions and 366 nonunions. The overall success rate for delayed unions was 91%
      (average healing time 129+/-2.7 days) and for nonunions 86% (average healing time
      152+/-5.3 days). Stratifying the data, it becomes clear that patient medication
      with calcium channel blockers, non-steroidal anti-inflammatory drugs, and
      steroids is a negative predictor for healing nonunions, as well as renal or
      vascular insufficiency. Patients who were smokers during ultrasound therapy had
      lower healing rates than those who never smoked. When comparing the patients of
      our own clinic treated with low-intensity ultrasound under study conditions which
      demonstrate that if healing was achieved it was an effect of the ultrasound
      therapy to the worldwide prescription use registry, no difference was seen in
      healing rate, healing time, or fracture age. Therefore, the results of these two
      populations support each other. Low-intensity pulsed ultrasound may provide a
      method of nonoperative treatment of great promise for healing disorders.
      Determination of ranking of this new method should be done within the near
      future.

PMID- 10653096
TI  - Operative treatment of mallet finger due to intra-articular fracture of the
      distal phalanx.
AB  - Treatment of a mallet finger due to an intra-articular fracture of the distal
      phalanx involving one-third or more of the articular surface is controversial.
      Thirty-three digits with such fractures were treated by open reduction and
      internal fixation with Kirschner wires. Of these 33 fractures, 13 were associated
      with subluxation of the distal phalanx. After an average follow-up period of 29
      months, the average loss of extension of the distal phalanx was 4 degrees, and
      the average flexion of the distal interphalangeal joint was 67 degrees.
      Radiographs of the distal joint in 27 digits appeared normal, while in the
      remaining 6 digits, slight degenerative changes were noted. In one there was a
      minor surgical complication. By using the operative technique described, a
      congruous reduction of the inta-articular fracture and satisfactory function were
      achieved.

PMID- 10653097
TI  - Magnetic resonance imaging as a screening procedure to avoid arthroscopy for
      meniscal tears.
AB  - The objective of this study was to evaluate the role of magnetic resonance
      imaging (MRI) as a screening procedure before arthroscopy of meniscal tears.
      Forty-one knees in 40 patients underwent MRI and arthroscopy. Compared with
      arthroscopy, the sensitivity, specificity, positive predictive value and negative
      predictive value for MRI for the nmedial meniscus were 100%, 77%, 71% and 100%,
      respectively, while the values for the lateral meniscus were 40%, 89%, 33% and
      91%, respectively. The overall accuracy for MRI of the medial and lateral menisci
      combined was 84%. On the basis of the high predictive value of negative MRI, we
      conclude that MRI is useful to exclude patients from unnecessary arthroscopy.

PMID- 10653098
TI  - Natural history of unreduced congenital dislocation of the hip in adults.
AB  - The natural history of 33 patients with 43 unreduced congenital dislocations of
      the hip was reviewed. The average age at the first consultation was 50 years.
      Four were men and 29 were women. Ten patients had bilateral and 23 unilateral
      complete dislocation. Average follow-up lasted 9.2 years. At the final follow-up
      23 hips and 18 knees were painful. Lumbago was observed in 6 of 15 patients under
      the age of 50 and in 14 of 18 patients over the age of 50 at the final follow-up.
      The average Harris hip scores at the first and final consultations were 69 and
      70, respectively. The average dislocation index was increased in the standing
      more than in the lying position. In unilaterally dislocated hips the average
      femorotibial angles in the ipsilateral and contralateral knees to the dislocated
      hip were 172 and 179 deg, respectively. Lumbar degenerative scoliosis of more
      than 5 deg was observed in 16 patients.

PMID- 10653099
TI  - Corrective osteotomy for malunion of the distal radius.
AB  - Forty-five patients were reviewed on average 5.7 years after corrective osteotomy
      for symptomatic distal radius malunion. Restoration of anatomy and function was
      assessed compared with the contralateral wrist. It was found that osteotomy of
      the distal radius alone did not completely restore normal anatomy and relieve
      symptoms, and in several cases a second operation was needed. Osteoarthritic
      changes in the radiocarpal and radioulnar joints were common, and they correlated
      with restriction in range of motion, but not with pain. Range of motion and grip
      power were reduced compared to the unaffected hand, but only loss of supination
      and ulnar deviation correlated with an unsatisfactory subjective result. The
      result was good or satisfactory in 33 of the 45 patients. We conclude that
      reconstructive procedures in patients with distal radius malunion may not
      completely restore normal function, and every effort should therefore be made to
      prevent malunion in the treatment of distal radius fractures.

PMID- 10653100
TI  - Anterior reconstructive spinal surgery with Zielke instrumentation for metastatic
      malignancies of the spine.
AB  - From March 1984 to April 1996, 60 consecutive patients with spinal metastasis
      underwent palliative surgery by anterior corpectomy and Zielke instrumentation.
      Their ages ranged from 21 to 76 years (mean 54 years). Thirty-two patients had
      metastasis to the thoracic spine, 20 to the lumbar spine, and 8 had both thoracic
      and lumbar metastases. The primary malignancies were lung cancer in 12 patients,
      colorectal cancer in 10, hepatoma in 9, thyroid cancer in 7, breast cancer in 3,
      and cancers of the stomach, kidney, nasopharynx, long bones, skin, and cervix in
      1 patient each. A primary carcinoma was never identified in 13 patients. In the
      present series, 4 patients died within 1 month, and 56 patients were followed-up.
      All maintained spinal stability postoperatively. Forty of 52 patients with severe
      pain obtained significant symptomatic relief for 3 months or more, and 33 of the
      46 paralyzed patients gained neural improvement. Sphincter dysfunction became
      better in 10 patients, and none became worse. We conclude that anterior
      corpectomy to decompress neural encroachment with instrumental reconstruction to
      stabilize the collapsed spine is a good adjunctive treatment in these highly
      selected patients.

PMID- 10653101
TI  - Dome-shaped proximal tibial osteotomy using percutaneous drilling for
      osteoarthritis of the knee.
AB  - We have improved a surgical technique for proximal tibial osteotomy that involves
      percutaneous drillings. We performed the modified dome-shaped proximal tibial
      osteotomy on 44 knees in 42 patients (8 men and 34 women) with an average age of
      66 years (range 50-78 years) for osteoarthritis of the knee. The mean follow-up
      period was 39 months (range 24-63 months). The varus angle was 4 degrees +/- 3.6
      degrees (mean +/- SD) preoperatively, and the valgus angle was 12 degrees +/- 3.3
      degrees postoperatively. Pain relief was obtained in all cases postoperatively.
      Transient pin tract infection occurred in one case, but it resolved completely
      following local irrigation. Intercondylar fracture of the upper fragment with no
      displacement was noted in two patients. They were treated with AO cancellous
      screw fixation, and improvement of pain was obtained in both cases. Osteotomy
      drill guide instruments are useful for accurately performing dome-shaped
      osteotomy. Our proximal tibial dome osteotomy with an external fixator allowed
      early motion and accurately maintained the angle of correction.

PMID- 10653102
TI  - Value of myofibrillar protein catabolic rate in Duchenne muscular dystrophy. A
      study after lower limb surgery.
AB  - Previous studies have shown a decreased progression of the course in Duchenne
      muscular dystrophy (DMD) patients treated by lower limb surgery in early
      childhood. The use of 3-methylhistidine (3-MH) excretion and 3-MH/creatinine
      excretion ratio as an appropriate indicator for the myofibrillar protein
      catabolic rate (MPCR) in muscle disorders is discussed controversially. To
      explore this issue we studied the renal excretion of (3-MH) over a period up to
      24 months (on average 20.8 +/- 1.4) after operation in 15 consecutive DMD
      patients with an average age at operation of 8.75 (+/- 2.43 years) to evaluate
      the myofibrillar protein catabolic rate. No significant change of the MPCR could
      be found in our population over the follow-up period. However, the formula for
      the calculation of the MPCR contains quantities which are not precisely known in
      DMD or assumed to be constant over the progressive course of DMD. Summarizing
      MPCR cannot be recommended for the assessment of therapeutic efficacy in DMD.

PMID- 10653103
TI  - Chondromyxoid fibroma of bone.
AB  - Chondromyxoid fibroma is a benign, although potentially aggressive tumor, with a
      cartilage-like matrix, accounting for approximately 1% of all bone tumors. It
      usually affects the metaphyseal region of long bones of patients in their first
      or second decade of life. An additional peak of incidence has been observed
      between 50 and 70 years of age. Three cases are presented here: 10-, 13-, and 52
      year-old patients, with lesions in the proximal tibia, the proximal humerus, and
      the proximal femur, respectively. The literature is reviewed in terms of clinical
      behavior, diagnostic procedures, prognostic factors, treatment, and outcome.
      Preferred treatment is complete local excision with tumor-free margins.
      Intralesional curettage with or without local adjuvants shows a local recurrence
      rate of approximately 25%. Radiation therapy may be useful in nonresectable cases
      but bears the well documented risk of radiation-induced malignancies.

PMID- 10653104
TI  - The kinematic total knee arthroplasty. A 10- to 15-year follow-up and survival
      analysis.
AB  - In 86 patients 102 consecutive cemented Kinematic total knee arthroplasties were
      reviewed 10-15 years after surgery to determine the clinical and radiographic
      results and to assess the survival rate. The average age of the 65 female and 21
      male patients at the time of surgery was 63 years. Forty-six knees were affected
      by rheumatoid arthritis (RA), 46 by osteoarthritis (OA), 7 by haemophilic
      arthropathy and 3 by osteonecrosis. One patient (1 knee) was lost to follow-up,
      and 31 patients (38 knees) died. Eleven knees had been revised for deep infection
      (4), wear (4), malposition (2) or persistent pain (1). Fifty-two knees were
      examined at an average follow-up period of 12 years. The mean Knee Society Score
      of 89 points was the same for RA and AO knees. Also, 92% of the knees caused no
      pain or only occasional mild pain. There were no cases of aseptic loosening of
      any component. Progressive radiolucent lines were not seen on the follow-up
      radiographs (43 knees, mean follow-up 12 years) The 10- and 14-year survival
      rates with revision as the end-point were 90% (confidence interval, CI: 81%-95%)
      and 82% (CI: 67%-92%), respectively. In the worst case scenario, with knees lost
      to follow-up and knees with moderate pain considered as failures, the 10- and 14
      year survival rates were 80% (CI: 69%-88%) and 62% (CI: 46%-77%), respectively.
      The Kinematic total knee arthroplasty yields equally good long-term results in
      patients with RA and those with OA. Deep infection and wear were the main reasons
      for revision.

PMID- 10653105
TI  - Transesophageal echocardiography and clinical features of fat embolism during
      cemented total hip arthroplasty. A randomized study in patients with a femoral
      neck fracture.
AB  - Forty patients suffering from a medial femoral neck fracture participated in a
      prospective, randomized study. In 20 patients, the femoral component was cemented
      using a contemporary technique. In the patient group operated on with the bone
      vacuum technique, the medullary cavity was drained during the insertion of the
      stem. The proximal draining hole was placed in the intertrochanteric region,
      along the prolongation of the linea aspera. The distal hole was placed 2 cm below
      the tip of the femoral component. Embolic phenomena were documented
      intraoperatively by continuous transesophageal echocardiographic imaging of the
      right atrium and ventricle. The clinical relevance of the emboli was noted
      simultaneously by recording hemodynamic and blood gas parameters. Patients of the
      control group showed severer and longer-lasting episodes of embolism than
      patients of the bone vacuum group. Ongoing emboli were first seen during the
      injection of the cement, and continued during stem insertion. Massive emboli of
      small particles could be verified in 19 patients (95%) of the control group and
      in 1 patient (5%) of the bone vacuum group (P < 0.05). During massive emboli, a
      distinct decrease in the arterial oxygen saturation and the end-expiratory carbon
      dioxide level was observed. The calculated average pulmonary shunt volume showed
      an increase after the insertion of the stem using the contemporary technique
      (36.5%; P < 0.05). These distinct hemodynamic changes were not observed in the
      bone vacuum group. This study was able to show a clearly reduced risk of
      pulmonary emboli using the bone vacuum cementing technique. The presence of pre
      existing disease greatly magnified the clinical relevance of fat embolism.

PMID- 10653106
TI  - Operative or conservative treatment of the acutely torn anterior cruciate
      ligament in middle-aged patients. A follow-up study of 133 patients between the
      ages of 40 and 59 years.
AB  - In all, 133 patients with an acute rupture of the anterior cruciate ligament
      (ACL) were reviewed (aged 40 to 59 years). Average follow-up was 29 +/- 10
      months. Thirty-one patients underwent conservative therapy, 35 patients were
      treated by primary suture, while in 67 the primary suture was augmented with the
      semitendinosus tendon. The patients with primary repair and semitendinosus tendon
      augmentation showed significantly better results according to OAK and Lysholm
      scores, the Lachman test, pivot-shift testing, and KT-1000 arthrometer
      measurements than those treated conservatively or with primary suture. The
      physical activity level was significantly higher in the patients with augmented
      ACL repair than in the conservatively treated patients. There was no significant
      difference between the patients with augmented ACL repair and conservative
      treatment in the assessment of range of motion, while the patients with primary
      suture had a significantly greater loss of flexion than those in the other two
      treatment groups. Increasing age was not found to have a negative effect on
      either operative or conservative treatment. The results indicate that patients
      between the ages of 40 and 59 years can be treated successfully by ACL surgery.

PMID- 10653107
TI  - Unexpected resection of soft-tissue sarcoma. More mutilating surgery, higher
      local recurrence rates, and obscure prognosis as consequences of improper
      surgery.
AB  - Sixteen referred patients were reviewed after excision of an unexpected soft
      tissue sarcoma of the extremities. Eight tumors were located in the muscle deep
      to the fascia, and 8 lesions exceeded the size of 5 cm. The lack of awareness by
      the primary physician towards the possibility of a malignant lesion was striking,
      although 11 of 16 tumors presented as a newly formed mass. No imaging studies
      were done in 11 patients. Fine needle biopsy was unsuccessfully performed in 3
      patients. Eleven lesions (63%) were high-grade. Resection margins were
      intralesional in 12 (75%) and marginal in 4 (25%) patients. Surgical oncologic
      rules were disregarded in 7 cases, including opening of probably uninvolved
      joints. Postoperative magnetic resonance imaging (MRI) scans showed a poor
      negative predictive value for residual tumor. Repeated resection, including three
      amputations, revealed residual tumor in 10 patients (63%). Four patients received
      adjuvant local radiation, with additional chemotherapy in 2 of them. At an
      average follow-up of 4.5 years (range 15-149 months), 4 patients (25%) had
      developed distant metastases with a local recurrence in 3 (19%). There was one
      tumor-related death (6%). Physicians' alertness towards the possible malignancy
      of an enlarging mass cannot be overemphasized. Evaluation by adequate imaging
      techniques, biopsy, and definitive resection and reconstruction should be
      performed by an oncologically trained orthopaedic surgeon. Inadequate primary
      excision leads to a high local recurrence rate and more mutilating surgery and
      obscures the long-term prognosis.

PMID- 10653108
TI  - Mechanical properties of a rat patellar tendon stress-shielded in situ.
AB  - The effects of stress deprivation on the mechanical properties of the patellar
      tendon (PT) were studied using 14 albino rats. The PT was stress-shielded with
      cerclages on one side, while the contralateral patellar tendon served as a sham
      operated control. After 10 weeks, paired load-strain as well as load-relaxation
      experiments were performed (11 and 3 specimen pairs, respectively). Mechanical
      tests showed, irrespective of the cerclage material used, that strain was
      increased significantly after stress-shielding (P < 0.02). The time constant
      significantly decreased in the stress-shielded specimens under 5 N loads, which
      may be considered 'physiological'. Tissue remodeling might explain the observed
      changes in the viscoelastic behaviour of the stress-shielded tendons. Loading,
      even in the physiological range of normal daily activity, may lead to an
      elongation of previously stress-shielded tendons or ligaments and consequently
      alter the behaviour of a joint.

PMID- 10653109
TI  - Mortality after total knee arthroplasty in patients with osteoarthrosis and
      rheumatoid arthritis.
AB  - Total knee arthroplasty (TKA) is a widely used procedure in the treatment of
      severe destruction of the knee joint because of osteoarthrosis (OA) or rheumatoid
      arthritis (RA). The aim of this study was to explore whether there is an
      increased mortality in patients after TKA with the underlying diagnosis OA or RA
      compared with the general population. We studied a consecutive series of 422
      primary TKAs with a hinged Blauth prosthesis in 330 patients (OA: 208 patients,
      175 women, 33 men; RA: 122 patients, 109 women, 13 men) with a mean follow-up of
      6 years (range 0-20 years). The mean age of the patients at the time of surgery
      was 70 years (range 29-87 years), being 72 years (range 46-87 years) for OA, and
      66 years (range 29-84 years) for RA. Age standardized mortality ratios (SMRs)
      were calculated for OA and RA. In patients with OA, the SMR was 1.03 (95% CI 0.76
      1.37) for women and 1.14 (95% CI 0.68-1.80) for men. SMRs of patients suffering
      from RA showed a clear shortening of the life span (women: 2.92, 95% CI 2.17
      3.85; men: 3.09, 95% CI 1.0-7.19). In spite of the risk of intra- and
      perioperative complications and further operative procedures necessary because of
      late complications, the implantation of a knee prosthesis per se does not
      necessarily significantly reduce the life expectancy in patients with OA.
      Patients with RA who require the implantation of a total knee prosthesis
      obviously represent a high-risk group with a high mortality rate.

PMID- 10653110
TI  - Electromyographically evident changes in skeletal muscles during tibial
      lengthening in dogs using the Ilizarov method.
AB  - Twenty-four beagle dogs underwent a lower leg lengthening on the right side of
      2.5 cm at a distraction rate of 2 times 0.5 mm per day using a circular fixator
      system. After a latency phase of 5 days and a distraction phase of 25 days, 12
      dogs (30-day dogs) underwent electromyography (EMG) of the gastrocnemius muscle
      on the lengthened and on the control side. The remaining half of the dogs
      underwent EMG after a consolidation phase of 25 days following the end of
      distraction (55-day dogs). During every EMG, at least 20 different muscle
      potentials were analyzed, and the duration, amplitude, and number of phases were
      determined of each individual potential. The 30-day dogs had significantly longer
      potential phases on the lengthened side and insignificantly smaller amplitudes
      compared with the control side. Furthermore, we observed a slightly larger number
      of polyphasic potentials on the distraction side. In the 55-day dogs, no
      significant differences were observed in the various parameters between the
      lengthened and the control side. Comparing 30- and 55-day dogs, the duration of
      the potentials on the distraction side was not significantly shorter in the 55
      day dogs, and the amplitude significantly higher. These findings could indicate
      combined neurogenous and myopathic alterations of the muscles during the early
      distraction phase which will be compensated during the later distraction period
      and the consolidation phase by reparative and reinnervation processes, leaving no
      lasting functional damage.

PMID- 10653111
TI  - Frozen shoulder: a sympathetic dystrophy?
AB  - Diagnostic and clinical features of the frozen shoulder syndrome and the Sudeck
      syndrome are similar in many aspects. Radioisotope bone scan shows an increased
      uptake in affected areas in both diseases, while native radiographs show a
      progressive demineralisation. Measurement of bone mineral density (BMD) by
      quantitative digital radiography objectified these local decalcification
      processes in an early stage of the frozen shoulder syndrome; 10 of 12 patients
      with primary frozen shoulder had BMD decreases greater 21% in the humeral head of
      the affected shoulder compared to the non-affected side. In the immobilised
      control group with degenerative changes of the rotator cuff, calcifying
      tendinitis and shoulder instability (n = 12) and in the group of healthy probands
      (n = 20), the difference between the affected and non-affected side (left and
      right humerus of the healthy probands) was only more than 21% in one case each.
      There are several references in the literature that assume frozen shoulder to be
      an algoneurodystrophic process; our observations support this hypothesis,
      possibly leading to earlier diagnoses and extended therapeutic management.

PMID- 10653112
TI  - Cone prosthesis for the hip joint.
AB  - The shape of the proximal segment of the femur must be taken into account when
      implanting femoral endoprostheses, especially those intended for cementless
      anchorage. Numerous femoral prostheses are available for the proximally broadly
      extending, "trumpet-shaped" morphology. However, the femur often has a narrow,
      more cylindrical configuration, as is frequently seen with dysplastic hip joints,
      but variants of the anatomical constitution or ethnic variants are also found.
      Conventional femoral prostheses with a proximal transverse oval or rectangular
      cross-section are often incorrectly positioned in those cases because they can
      fracture the narrow bones. In many instances, even a pathological anteversion
      attachment cannot be adequately corrected. The cone prosthesis is ideal for this
      morphology when pre-operative planning indicates good contact between the bone
      cortex and the middle third of the prosthetic stem. The tapered anchorage of the
      cone stem in the medullary cavity reamed to a cone shape promotes primary
      stability, which is a fundamental prerequisite for the osseointegration of a
      coarse blasted titanium implant. The sharp longitudinal ridges on the prosthetic
      stem, which tend to cut into the bone, ensure extensive rotational stability,
      which explains why thigh pain is not associated with the cone prosthesis. The
      cone prosthesis has proved its worth in 635 implants performed over 9 years, with
      highly satisfactory clinical and X-ray results. The surgical technique is
      relatively straightforward, and complications are rare. The patients' subjective
      satisfaction is particularly remarkable. The success of the operation lies in
      correct preoperative planning, which ensures that the morphology of the selected
      femur guarantees contact between the bone cortex and the middle third of the
      prosthetic stem.

PMID- 10653113
TI  - Open reduction and internal fixation in flexion-distraction injuries to the lower
      spine in children and adolescents involved in traffic accidents as car occupants.
      A report and literature review.
AB  - Flexion-distraction injuries of the spine are reported after traffic accidents in
      individuals wearing only lap seatbelts. We examine here this type of injury in
      one child and two adolescents who all were seated in the rear seat of cars
      involved in traffic accidents. All of the children were wearing regular three
      point safety belts not adjusted to children. They were all treated surgically.
      Two of the patients had no neurological impairment, while one patient suffered
      persistent complete paraplegia. In two patients intra-abdominal lesions required
      surgery. Flexion-distraction injuries in individuals with an immature skeleton,
      wearing standard three-point safety belts, have not been reported in the
      literature. The pathomechanism of the lesion in the lower spine may well involve
      damage to the intestines, particularly at the junction between the mobile intra
      abdominal and the fixed retroperitoneal part of the gut. Reduction and stable
      fixation preserve the anatomy of the lower spine, while unstable fixation methods
      do not secure reduction sufficiently to allow early mobilisation.

PMID- 10653114
TI  - Reduction of fat embolic risks in total hip arthroplasty using cannulated awls
      and rasps for the preparation of the femoral canal.
AB  - Fat embolic phenomena during cemented and non-cemented total hip arthroplasty
      occur even during the preparation of the femoral canal. This should be avoided in
      order to reduce the rate of fat embolic syndrome. In the present prospective
      study we demonstrate the benefit of cannulated awls and rasps in the reduction of
      fat embolic phenomena by means of transoesophageal echocardiography and extended
      cardiopulmonary monitoring. Two groups of 5 patients each with identical surgical
      procedures were treated either with cannulated (group 1) or with closed (group 2)
      awls and rasps. In group 1 no macroemboli but three embolic showers grades 1 and
      2 were seen. In contrast to these findings, three macroemboli and four embolic
      showers grades 1 and 3 were demonstrated in group 2. We recommend cannulated awls
      and rasps for the preparation of the femoral canal in cemented and non-cemented
      total hip arthroplasty. They are a simple and inexpensive aid to avoid fat
      embolic syndrome.

PMID- 10653115
TI  - Loosening pattern in a cementless custom-made hip stem: X-ray analysis, finite
      elements and photoelasticity measurements.
AB  - Thirty-three X-press cementless stems (Depuy) manufactured according to
      standardized X-rays were inserted from 1992 to 1994. The patients' mean age was
      49 (range 15-79) years with a mean follow-up of 32 (+/-6) months. A
      characteristic radiographic pattern of aseptic loosening with erosion of the
      medial cortex by the tip of the stem occurred in 28 patients and a valgus shift
      of the implant in 14 cases. A radiolucent line with increased sclerosis below the
      tip (zone Gruen 4) was observed in 17 cases. Four stems were revised due to
      histologically confirmed aseptic loosening. Biomechanical investigation of one of
      the revised stems with the typical pattern of valgus angulation and medial cortex
      erosion included photoelasticity and finite-element analysis. The
      intertrochanteric fit and fill obviously resulted in an unfavorable distribution
      of contact areas, including peaks of high stress on the medial tip of the stem.
      These experimental findings are even evident for a postulated rotational
      stability. The clinical and radiographic results of the cementless X-press stems
      do not seem to support the fixation concept of intertrochanteric fit and fill of
      femoral components.

PMID- 10653116
TI  - Nerve sheath ganglion of the ulnar nerve.
AB  - We report a case of a nerve sheath ganglion of the ulnar nerve at the canal of
      Guyon. This case involved a ganglion which was confined to the epineurium of the
      ulnar nerve. and it was completely excised without any damage to the nerve fiber.
      A nerve-sheath ganglion is rare, but it should be considered in the differential
      diagnosis of any tumor which is causing neural disturbance.

PMID- 10653117
TI  - A mould arthroplasty revision: a 43-year follow-up.
AB  - We present the outcome of a mould arthroplasty implanted for a congenital hip
      dysplasia in 1955 to revise a previous cup arthroplasty. This type of prosthesis,
      which has been developed on the basis of the concept of Smith-Peterson, by Prof.
      Marino-Zuco in Rome in the early 1940s, showed excellent results and was widely
      used until the advent of Charnley low-friction arthroplasty.

PMID- 10653118
TI  - Erdheim Chester disease: a rare cause of knee and leg pain.
AB  - A case of Erdheim Chester disease in a 51-year-old Turkish patient is described.
      Erdheim Chester disease is a rare form of lipoid granulomatosis. Knee and leg
      pain are the most common symptoms, and physicians working in orthopaedics and
      traumatology are the first to be consulted. Our patient demonstrated a typical
      bilateral, symmetric sclerosis of the metaphyseal region of long bones of the
      lower extremity, histologic examination revealed foamy, lipid-loaded histiocytes.
      The patient also suffered from arterial hypertension, diabetes insipidus and
      exophthalmos of the left eye. The diagnosis was confirmed by a bone biopsy, and
      the patient was treated with non-steroidal anti-inflammatory drugs,
      corticosteroids and vincristine.

PMID- 10653119
TI  - Bilateral Madelung's deformity without signs of dyschondrosteosis within five
      generations in a European family--case report and review of the literature.
AB  - The paper presents a European family showing bilateral Madelung's deformity
      within five consecutive generations. Females as well as males are affected
      alternately indicating autosomal dominant inheritance. Despite of a body height
      within the lower normal range in two patients the diagnosis of dyschondrosteosis
      could not be clearly established as further hints for dwarfism are missing. The
      etiology of Madelung's deformity may be difficult to establish. There seems to be
      the possibility of an inheritance independent from the complete syndroma of
      dyschondrosteosis. Therefore the genetic counselling will always be difficult and
      has to regard the wide variety of symptoms ranging from little pain and cosmetic
      disturbance to moderate pain and functional impairment.

PMID- 10653120
TI  - Disseminated hydatid disease causing paraplegia and destruction of the hip.
AB  - A patient who had had been treated by surgery for spinal echinococcosis in a
      Mediterranean country emigrated to northern Europe. After surgery, the
      echinococcosis disseminated and he developed chronic lytic and sinus-draining
      hydatid disease of the left hip and neuromuscular weakness of the left lower
      extremity. Seventeen years after the spinal surgery, he was referred to our hip
      service for a possible total hip replacement (THR) after receiving adequate
      chemotherapy against echinococcosis for nearly 3 years. Because of the poor
      results reported by others, we decided against THR; two of the four previous
      patients described in the current literature who had THR died due to
      complications.

PMID- 10653121
TI  - Polymorphism of the rabbit kappa kasein gene and its influence on performance
      traits.
AB  - The rabbit kappa-casein encoding gene has previously been shown to possess two
      alleles. The two alleles do not differ in their coding region and in the
      accumulation levels of mRNA. However they differ greatly with respect to their
      intronic regions. The rearranged regions in the first and fourth introns were
      found to be inverse and complementary LINE sequences. The A allele was found to
      be more frequent in different European breeds. Correlation of the kappa-casein
      genotype with the breeding capacity in a New Zealand White rabbit stock has been
      examined.

PMID- 10653122
TI  - Allelic differences in bovine kappa-CN gene which may regulate gene expression.
AB  - The most common kappa casein (kappa-CN) variants, kappa-CN A and kappa-CN B, are
      synthesised differentially in the lactating mammary gland of heterozygous animals
      (kappa-CN AB). In this study we evaluated several approaches for quantification
      of allele specific mRNA transcripts. The most consistent results were obtained
      using allele specific RT-PCR and capillary electrophoresis. On average, 13.4%
      more allele B specific than A specific transcripts were found. DNA sequencing of
      the proximal promoter region in several homozygous animals (kappa-CN AA, BB, EE)
      did not reveal any allele specific polymorphisms. Using the EMSA and DNase I
      footprinting we confirmed functional binding sites for three transcription
      factors (AP-2, NF1 and MGF) within the kappa-CN proximal promoter region.
      Sequence analysis of the 3'-UTR of the kappa-CN gene revealed seven allele
      specific sites. Two of these allelic differences were close to previously
      identified 3'-end regulatory sequences. In addition, allele specific differences
      in length between mRNAs of both variants were found. The two later findings
      suggest a possible post translational control determining content differences of
      kappa-CN in milk.

PMID- 10653124
TI  - Ploidy and morphological characteristics of Solanum tuberosum x Solanum phureja
      hybrids.
AB  - In attempt to induce doubled haploids in potato we studied interspecific hybrids
      between tetraploid Solanum tuberosum cultivars Igor, Jana, Vesna, Romano, Arinda,
      Fianna, Donald and Vital and Solanum phureja (clone IVP 48). Four out of eight
      cultivars produced 21 berries in total and 149 seedlings were obtained. Their
      ploidy was measured using flow cytometry. Analysis revealed 137 tetraploids, 10
      triploids and 2 haploids. One haploid, 6 triploids and most of the tetraploids
      produced tubers. Nine out of 10 triploids were produced in a cross between cv.
      Igor and S. phureja. The vigour of the haploid plant was weak and produced
      characteristic long light yellow tubers. Triploid plants were characterized by a
      dark violet coloration of the stem, which was the same as the coloration of the
      S. phureja. Tubers had violet skin colour of various intensities and deep eyes.
      The majority of the tetraploid plants (135) were phenotypically similar to the S.
      tuberosum, while two plants had a similar violet stem and tubers as the
      triploids. Triploids were interspecific hybrids and tetraploids were produced by
      spontaneous chromosome doubling from S. tuberosum gametes. Two tetraploid plants
      expressing violet coloration might have been interspecific hybrids formed from 2n
      S. phureja gametes. Further studies are needed to confirm these assumptions.

PMID- 10653123
TI  - Molecular cloning and partial characterisation of the mouse Cyp51 cDNA.
AB  - Northern analysis of the mouse testis and liver RNA show two types of lanosterol
      14alpha-demethylase (CYP51) transcripts, somatic and a testis-specific
      transcript. At least two CYP51 mRNAs are expressed in liver and testis, while the
      smallest transcript is expressed only in testis. The partial mouse Cyp51 cDNA
      (1052 bp) was obtained by RT-PCR cloning and was also found in expressed sequence
      tag (EST) clones. Bacterial artificial chromosome (BAC) clones containing mouse
      Cyp51 gene were also found. The coding part of the partial mouse CYP51 is 93.9%
      homologous to the rat and 87.9% to the human CYP51 cDNAs. There is less than 2%
      variation between the CYP51 EST clones to the RT-PCR cloned partial cDNA and BAC
      clones.

PMID- 10653125
TI  - Screening methods for cystic fibrosis transmembrane conductance regulator (CFTR)
      gene mutations in non-human primates.
AB  - We report here a comparison of isotopic and non-isotopic conformation analysis
      approach, for screening genomic DNA for coding variations in the cystic fibrosis
      transmembrane conductance regulator (CFTR) gene. A large pool of non-human
      primates was tested in order to detect naturally occuring CFTR carriers, for
      future testing of gene therapy of cystic fibrosis. We screened 25 of 27 CFTR
      exons in over 1,000 animals. We have detected numerous missense mutations and
      single nucleotide polymorphisms. We found that both methods are highly efficient
      for detection of variations in DNA sequence, but the non-radioactive approach is
      faster, less expensive and in some cases more sensitive.

PMID- 10653126
TI  - Molecular analysis of homeotic genes involved in barley development.
AB  - Ectopic expression of the barley homeobox gene BKn-3 conditions the development
      of epiphyllous flowers by de novo meristem formation. Various strategies are
      being described in an effort to identify genes whose products interact with the
      BKn-3 gene product or BKn-3 regulatory regions.

PMID- 10653127
TI  - Determination of aneuploids in hop (Humulus lupulus L.) using flow cytometry.
AB  - In order to study the possibility that high-resolution flow cytometry can be used
      for determination of aneuploids, different genotypes of Humulus lupulus were
      analyzed. Triploid cultivars are bred by hybridization between diploid and
      tetraploid lines, and as the result of this process, some aneuploids are
      occasionally also formed. We analyzed eight triploid cultivars and seven putative
      aneuploids. Triploid cultivars Cerera, Cicero, Celeia, Cekin, Blisk, Mt. Hood,
      Huller Bit. and Willamette (3x = 30) were measured for nuclear DNA content using
      Trifolium repens as reference. No significant differences among peak positions of
      triploid cultivars (having an average CV value per peak of 1.94%) were found.
      Measurement of nuclear DNA content was also performed for seven lines: 175/75,
      89/113, 89/154, 91/215, 175/17, 89/87 and 91/74 previously determined by
      chromosome counting to be aneuploids (CV per peak was 1.41%). A statistically
      lower DNA content was found for line 175/75 and higher values were measured for
      lines 89/154, 89/113 and 91/215. Repeated chromosome counting revealed that the
      number of chromosomes in line 175/75 was 29, while lines 89/154, 89/113 and
      91/215 possessed 31 chromosomes. The other lines were identified as triploids. We
      conclude that flow cytometry can be efficiently used for determination of
      aneuploidy in Humulus lupulus.

PMID- 10653128
TI  - Internalization kinetics of the gonadotropin-releasing hormone (GnRH) receptor.
AB  - This study quantified the agonist-induced endocytotic and recycling events of the
      mammalian gonadotropin releasing hormone receptor (GnRH-R) and investigated the
      role of the intracellular carboxyl (C)-terminal tail in regulating agonist
      induced receptor internalization kinetics. The rate of internalization for the
      rat GnRH-R was found to be exceptionally low when compared with G-protein coupled
      receptors (GPCRs) which possess a cytoplasmic C-terminal tail (thyrotropin
      releasing hormone receptor (TRH-R), catfish GnRH-R (cfGnRH-R) and GnRH/TRH-R
      chimeric receptor). These data provide evidence that the presence of a functional
      intracellular cytoplasmic C-terminal tail is essential for rapid internalization
      of the studied GPCRs.

PMID- 10653129
TI  - Evolutionary relationships among Europan newts (genus Triturus) as inferred from
      two mtDNA fragments.
AB  - European newts (genus Triturus) are widely studied, but their phylogeny is not
      yet unambiguously resolved. Fragments of mitochondrial DNA experiencing different
      rates of evolution (the ATPase and 12S rDNA genes) were sequenced in order to
      test a phylogenetic hypothesis derived from biochemical and behavioural data.
      Well supported branches of the existing phylogeny also gained support in our
      study. Within the subgenus Palaeotriton (the group of small-bodied newts) the
      monophyletic origin of the hypothesized T. boscai-T. italicus clade remained
      ambiguous, whereas strong support was gained for the sister-taxon relationship of
      T. vulgaris and T. montandoni. The position of T. vittatus within the subgenus
      Triturus as a sister taxon to the clade of big-bodied newts (T. marmoratus and T.
      cristatus superspecies) was also supported. However, the phylogenetic position of
      the medium-sized newt, T. alpestris could not be clarified.

PMID- 10653130
TI  - TGF-beta activates genes identified by differential mRNA display in pancreatic
      rudiments.
AB  - The effect of TGF-beta on gene activation in embryonic pancreatic rudiments was
      investigated using differential mRNA display. Several cDNA bands were augmented
      and some were suppressed in the presence of TGF-beta. Differentially expressed
      cDNAs were re-amplified, sequenced, and sequences compared to the GeneBank
      database. Glucagone and brain alpha-tropomyosin cDNAs were identified from the
      group of augmented cDNAs, and B-carboxypeptidase form the group of suppressed
      cDNAs. PCR experiments were confirmed with Northern blots. Obtained results are
      in accordance with immunohistochemical findings and render differential mRNA
      display a useful technique in identifying differentially expressed genes in
      embryonic pancreatic rudiments. Several unknown differentially expressed cDNA
      sequences obtained in our experiments remain to be identified.

PMID- 10653131
TI  - Genetic polymorphism of xenobiotic metabolising enzymes in Slovenian lung cancer
      patients.
AB  - Most carcinogenic substances require metabolic activation in order to become
      ultimate carcinogens. Genetic polymorphism of xenobiotic metabolising enzymes
      cytochromes P450 may therefore influence human cancer susceptibility. The aim of
      our study was to investigate if CYP1A1 gene polymorphism contributes to lung
      cancer susceptibility in Slovenian patients. Two polymorphic sites in CYP1A1 gene
      were analysed in DNA samples from 100 healthy controls and 199 lung cancer
      patients using genotyping approach. Our results indicate that CYP1A1 may be one
      of the factors determining susceptibility to squamous cell carcinoma of lung in
      Slovenian population. However the frequency of CYP1A1 polymorphisms is too low to
      be a potentially useful marker of increased lung cancer risk.

PMID- 10653132
TI  - Variable expression of Gorlin syndrome may reflect complexity of the signalling
      pathway.
AB  - Nevoid Basal Cell Carcinoma Syndrome (NBCCS) or Gorlin syndrome is an autosomal
      dominant disorder characterized by cancer predisposition and multiple
      developmental defects. Syndrome related disorders have been attributed to
      alterations of PTCH gene, which plays an important role in Shh signalling
      pathway. Unresolved complexities of the pathway impede understanding of
      mechanisms through which PTCH alterations lead to variable phenotype expression
      in Gorlin syndrome patients, while the role of chromosomal instability is not yet
      clear. To increase our understanding of NBCCS, every manifestation of the
      syndrome and associated genetic damage should be seriously considered. Therefore,
      several atypical NBCCS cases are presented in this paper.

PMID- 10653133
TI  - Angiotensin-converting enzyme gene polymorphism as a cardiovascular risk factor
      in children.
AB  - A family history of cardiovascular disease predicts cardiovascular risk in the
      next generation, which is either the result of inherited traits or certain living
      habits in some families. The aim of our study was to evaluate both variables and
      particularly the role of one of the possible genetic risk factors--angiotensin
      converting enzyme (ACE) gene polymorphism. History and anthropometric and
      biochemical parameters, ACE gene polymorphism and carotid wall thickness--intima
      media thickness (IMT) were studied in two groups of children: in children whose
      parents had a stroke before the age of 45 years and in children without a
      positive family history. The preliminary results of the present study failed to
      confirm our hypothesis that ACE gene polymorphism is a cardiovascular risk factor
      in children of parents with premature stroke.

PMID- 10653134
TI  - Heparin blocks functional innervation of cultured human muscle by rat motor
      nerve.
AB  - In vitro innervated human muscle is the only experimental model to study
      synaptogenesis of the neuromuscular junction in humans. Cultured human muscle
      never contracts spontaneously but will if innervated and therefore is a suitable
      model to study the effects of specific neural factors on the formation of
      functional neuromuscular contacts. Here, we tested the hypothesis that nerve
      derived factor agrin is essential for the formation of functional synapses
      between human myotubes and motoneurons growing from the explant of embryonic rat
      spinal cord. Agrin actions were blocked by heparin and the formation of
      functional neuromuscular contacts was quantitated. At a heparin concentration of
      25 microg/ml, the number of functional contacts was significantly reduced. At
      higher concentrations, formation of such contacts was blocked completely. Except
      at the highest heparin concentrations (150 microg/ml) neuronal outgrowth was
      normal indicating that blockade of neuromuscular junction formation was not due
      to neuronal dysfunction. Our results are in accord with the concept that binding
      of neural agrin to the synaptic basal lamina is essential for the formation of
      functional neuromuscular junctions in the human muscle.

PMID- 10653135
TI  - DD genotype of the angiotensin-converting enzyme gene and stroke in Slovenian
      population.
AB  - The angiotensin-converting enzyme (ACE) is a rate-limiting enzyme in the renin
      angiotensin system, the enzyme is involved in the vascular remodelling and
      atherosclerosis. Its significance in pathogenesis of ischemic cerebrovascular
      insults (CVI) is not known. We analysed 124 Slovenian patients with CVI and
      compared them with 161 healthy controls for I/D polymorphism. Under a recessive
      model (chi2 = 1.76, p = 0.1, OR = 1.40, 95% CI: 0.85-2.34) we found no
      significant difference in I/D genotypes between patients with CVI and controls.
      This study shows that in a group of Slovenian CVI patients the DD genotype is not
      an important risk factor for the development of stroke.

PMID- 10653137
TI  - Rapid extraction of DNA from archival clinical specimens: our experiences.
AB  - The analysis of DNA extracted from archival clinical specimens using polymerase
      chain reaction represents the basis of a variety of research and diagnostic
      protocols in medicine. However, the selection of optimal DNA extraction method is
      critical if such an analysis is to be successful. Recently, we have evaluated a
      number of rapid DNA extraction protocols in order to find the most suitable
      method for routine processing of the most common archival materials in
      pathological and cytological laboratories: paraffin-embedded tissues and
      Papanicolaou- or Giemsa-stained smears. Our results demonstrate that rapid DNA
      extraction methods have comparable DNA extraction efficiencies with standard DNA
      isolation protocols on archival clinical specimens with the exception of Giemsa
      stained smears.

PMID- 10653136
TI  - Deletion/insertion polymorphism in the angiotension-converting enzyme gene as a
      risk factor in the Slovenian patients with coronary heart disease.
AB  - The angiotensin-converting enzyme (ACE) plays by degradation of angiotensin I and
      bradykinin, an important role in modulations of smooth muscle proliferation and
      vascular tone. Typical plasma levels of ACE accompany the I/D polymorphism;
      however, a controversy exists as to whether the DD genotype of the ACE
      polymorphism affects the risk for the development of coronary heart disease
      (CHD). We compared the I/D polymorphism in 171 Slovenian CHD patients that were
      younger than 55 years with 134 healthy control individuals. The DD genotype is
      associated with a 2.3-fold increase in the risk for CHD.

PMID- 10653138
TI  - Seroprevalence of HIV-1 subtypes A-E among HIV-1 infected individuals from
      Slovenia.
AB  - To investigate the prevalence of HIV-1 subtypes A-E in Slovenia, 82 HIV-1
      infected individuals were tested for the presence of HIV-1 subtype specific
      antibodies using a research competitive peptide enzyme immuno assay supplied by
      Boehringer Mannheim. In 74 individuals unambiguous results were obtained. As in
      other European countries, the majority of Slovenian HIV-1 infected individuals
      (86.5%) were infected with subtype B. Infections with subtypes C, A, D and E were
      detected in 8.1%, 2.7%, 1.3% and 1.3% individuals, respectively.

PMID- 10653139
TI  - Evaluation of microsatellite markers for efficient assessment of high
      microsatellite instabile colorectal tumors.
AB  - Two hundred thirty randomly collected primary colorectal tumors were initially
      screened for microsatellite instability (MSI) with three highly informative
      microsatellite markers (BAT26, D2S123 and D5S346). Forty one (17.8%) tumors
      showed alterations in at least one marker. In further MSI analysis of these 41
      MSI tumors with additional 9 markers, 21 tumors (9.6% of 230 analyzed) exhibited
      MSI at more than 40% and the rest 20 (8.7% of 230 analyzed) tumors exhibited MSI
      at 8%-20% tested markers. These results support classification of MSI tumors into
      high MSI tumors (more than 40% unstable loci) and low MSI tumors (less than 20%
      unstable loci). Based on our results the combination of BAT26 and two out of four
      other highly informative markers (D2S123, D5S346, BAT25 or BAT40) is recommended
      for rapid and reliable assessment of high MSI tumors.

PMID- 10653140
TI  - Evidence that hereditary pancreatitis is genetically heterogeneous disorder.
AB  - Hereditary pancreatitis (HP) is an autosomal dominant disorder characterized by
      recurrent acute attacks of severe abdominal pain with an onset in early
      childhood. Many HP patients progress to complicated chronic pancreatitis and/or
      pancreatic cancer. Initially, a single mutation R117H in the cationic trypsinogen
      gene was detected in all affected members of five unrelated HP families. Further
      studies identified a second mutation (N21L) in two HP families without the R117H
      mutation. Before the association between cationic trypsinogen and HP was found,
      we detected a cystic fibrosis transmembrane conductance regulator (CFTR) gene
      mutation (L327R) in all affected individuals of a family with HP. We therefore
      performed a mutational analysis for R117H and N21L in cationic trypsinogen in
      this and three additional unrelated families with HP. The R117H mutation was
      detected in all 9 affected members of three HP families and in 3 asymptomatic but
      at-risk relatives. However, neither the R117H nor the N21L mutation in the
      cationic trypsinogen were found in the HP family with the L327R alteration in
      CFTR. The L327R allele segregates with the disease within this HP family and was
      not detected on 360 unrelated Caucasian non-CF chromosomes. Although close to 800
      different mutations have been detected in the CF gene of cystic fibrosis
      patients, L327R is a new alteration, not yet reported in connection with CF. The
      results of this study indicate that the CFTR gene may play a role in the etiology
      of minority of cases with HP and suggest that hereditary pancreatitis is
      genetically heterogeneous disease.

PMID- 10653141
TI  - Study of mutant and polyvariant mutant CFTR genes in patients with congenital
      absence of the vas deferens.
AB  - Congenital bilateral absence of the vas deferens (CBAVD) is a form of male
      infertility in which mutations in the cystic fibrosis transmembrane conductance
      regulator (CFTR) gene have been identified. Cystic fibrosis patients have
      mutations in both alleles of the gene while most CBAVD patients have mutations in
      only one allele. Frequently, the second CFTR allele is not mutant but
      polyvariant. We have studied CFTR gene mutations and polyvariant allele (TG)m(T)n
      in intron 8 in 37 patients with CBAVD. Ten (27%) compound heterozygotes and 16
      (43.3%) heterozygotes have been detected, while no alteration have been found in
      the coding and intronic bounderies regions in 11 (29.7%) patients. DeltaF508 was
      the most frequent mutation present in 15/74 (20.3%) alleles. Additional mutant
      alleles include: R117H (6.8%), R75Q (5.4%), D1270N (2.7%) and G576A (2.7%). We
      identified in total 14 different mutations and mutant variants, of which one
      E804V has not been reported previously. Of 37 alleles with not detectable
      alteration in the coding or splice site regions the (TG)12(T)5 allele has been
      found in 14 (37.8%) genes. If we consider that (TG)12(T)5 is believed per se to
      be a highly penetrant pathogenic allele connected with CBAVD, we have detected a
      disease causing alterations in 49/74 (66.2%) CFTR alleles of CBAVD patients.
      These results are extremely important for genetic counseling of couples indicated
      for in vitro fertilization.

PMID- 10653142
TI  - Lanosterol 14alpha-demethylase (CYP51)--a cholesterol biosynthetic enzyme
      involved in production of meiosis activating sterols in oocytes and testis--a
      minireview.
AB  - CYP51 is an evolutionarily conserved, housekeeping gene of the cytochrome P450
      superfamily which is involved in cholesterol biosynthesis in animals. The two
      intermediates of cholesterol biosynthetis pathway, sterol FF-MAS, produced by
      CYP51 and the following sterol T-MAS, accumulate in follicular fluid and in
      testis. CYP51 is expressed in all tissues in mammals with the highest level in
      the testis. In rat, expression peaks in postmeiotic male germ cells of the
      testis. Promoters of the human and rat CYP51 genes contain SRE and CRE elements
      which indicate two main regulatory routes--the sterol-dependent regulation and
      the cAMP-dependent regulation. While feedback regulation by sterols is
      characteristic for all genes involved in cholesterol biosynthesis and
      homeostasis, the cAMP-dependent regulation is unique, indicating that CYP51 may
      play tissue-specific roles distinct from cholesterol biosynthesis.

PMID- 10653143
TI  - Rhd and C/cE/e genotyping in Slovenian population.
AB  - The Rhesus (Rh) blood group system is, after ABO, clinically most important.
      Alloantibodies directed against Rh antigens are the major cause of a haemolytic
      disease of newborn (HDN) and of transfusion reactions. In search for novel
      methods for Rh genotyping we started to compare Rh genotypes identified from
      different tissues and Rh phenotypes. Genotypes determined from blood samples with
      PCR based RhD, C/c and E/e genotyping methods were compared with serologically
      identified phenotypes (N=32). With two exceptions the results of phenotyping and
      genotyping were in concordance. Two Rh serotypes from a Slovenian family that
      were unexpected according to the Mendelian laws were characterised genotypically.
      The two family members were suspected to have a chromosomal deletion on RH gene
      locus.

PMID- 10653144
TI  - Possible influence of genes located on chromosome 6 within or near to the major
      histocompatibility complex on development of essential hypertension.
AB  - Studies both in spontaneously hypertensive rats and in humans have suggested that
      genes within or near to the HLA complex on chromosome 6p may be associated and
      linked to the regulation of blood pressure. The aim of this study was to
      determine whether HLA alleles and their combinations contribute to increased
      blood pressure, as well as to identify chromosome region that may contain genes
      involved in the pathogenesis of essential hypertension. Our results suggest that
      presence of HLA-DRB1*0101/2 DQB1*0501/2 DQA1*0102 allelic combination represents
      risk factor for development of essential hypertension in Slovenians, while the
      risk is decreased in individuals possessing HLA-DRB1*1601/2 DQB1*0502 DQA1*0102
      or DRB3*. The linkage study indicates a possibility that at least one of the
      genes responsible for increased blood pressure is located near or within the HLA
      complex. A possible candidate is human endotelin-1 gene encoding a highly potent
      vasoactive peptide.

PMID- 10653145
TI  - Mutational analysis of 30 Slovenian cystic fibrosis patients compared to known
      Slovenian and European CF mutation spectra.
AB  - More than 800 mutations have been indentified in the CFTR gene. This vast
      mutation diversity makes the search for molecular defects in cystic fibrosis
      difficult. Out of 100 Slovenian CF families, we have screened 30, using DGGE and
      SSCP as mutation detection techniques, while the remaining 70 have been studied
      previously. Together our and the previous studies have been able to indentify 18
      CF mutations which cover 77.6% of the CF alleles in those families. The relative
      frequency of deltaF508 is 62.7% which is significantly higher than the average
      reported for the Mediterranean South European region (51.6%). At the same time,
      significant differences in mutation frequencies were found for the G542X, R1162X,
      W1282X, N1303K and 3905insT mutations. Several, otherwise rare mutations have
      been detected, such as: I148T, Q552X, 457TAT-->G, R1006H, 2907delTT, 3667ins4,
      A559T and G576A. An interesting fact is that A559T was so far found mostly in CF
      patients of African-American origin. These results imply that a high
      heterogeneity of CF mutations occurs within the small population of Slovenia,
      consisting only of 2 million inhabitants. In view of the spectrum and frequencies
      of detected mutations, Slovenian population expresses characteristics of
      Mediterranean and central European countries, and at the same time shows also
      distinctive differences and unique region specific CF mutations (Q685X, D192G,
      S4X).

PMID- 10653146
TI  - Nonradioactive northern blotting for the determination of acetylcholinesterase
      mRNA. Comparison to the radioactive technique.
AB  - A sensitive nonradioactive northern blotting for the detection of
      acetylcholinesterase mRNA in mammalian tissues is described and compared to its
      radioactive version. Best results were obtained if digoxigenin labeled RNA probe
      was used for hybridization and CDP-Star, a chemiluminescent alkaline phosphatase
      substrate, for detection. The described nonradioactive technique for
      acetylcholinesterase mRNA determination is as sensitive as the radioactive one,
      but requires no protection against radiation and is less time consuming. Because
      of higher stability of the labeled probe, nonradioactive technique is also more
      convenient from the standpoint of experimental planning.

PMID- 10653147
TI  - Effect of cultivation mode on a bioprocess for chromium yeast biomass enrichment.
AB  - Defined cultivation media for yeast growth which contained 278.8 mM of glucose
      and 0.1 mM of chromium(III) added as K2Cr(SO4)2 x 12 H2O was used in batch and
      combined batch/fed-batch cultivation mode. In fed batch cultivation mode the rate
      of substrate addition remained constant during growth of yeast and corresponded
      to a growth rate of 0.25 h(-1). In both cases the growth and yeast activity was
      followed by on line measurement of optical density, pH and pO2 at 30 degrees C.
      At the end of the bioprocess the concentration of protein in yeast biomass was
      determined off line by the biuret reaction. Total and organically bound chromium
      was detected by ETA-AAS. Different cultivation modes affected the total cell
      protein concentration of yeast grown in media supplemented with chromium. In
      batch process the protein content represented 25.7% of dry yeast biomass, in
      contrast in the mixed bioprocess this value was 16.9% one the same period of
      time. The influence of cultivation mode on chromium uptake was seen in total
      chromium accumulation which reached 8.68 +/- 0.16 micromol g(-1) d.wt. in batch
      and 1.92 +/- 0.04 micromol of chromium g(-1) of dry yeast biomass in combined
      batch/fed-batch cultivation mode. The opposite was observed for organically bound
      chromium. The 60% of total accumulated chromium was organically bound during
      yeast growth in combined batch/fed-batch mode. When yeast was grown in batch mode
      this value attained 13.5%. Results suggested that a combined batch/fed-batch mode
      of cultivation was more effective over a batch system in chromium
      biotransformation to organically bound chromium, regardless of the lower protein
      ratio determined in the yeast biomass.

PMID- 10653148
TI  - Stress mediated changes in expression of the pkaC gene, encoding the catalytic
      subunit of cAMP-dependent protein kinase, in Aspergillus niger.
AB  - The transcriptional regulation of the pkaC gene, encoding the catalytic subunit
      of cAMP-dependent protein kinase from Aspergillus niger, was analysed under
      different environmental conditions. Quantitative determination of pkaC transcript
      showed a significant decrease in concentration of specific mRNA immediately after
      a temperature, hypoosmotic and hyperosmotic shock followed by stimulated
      synthesis. The amount of pkaC mRNA as well as PKA enzymatic activity steadily
      decreased during the initial phase of growth in 15% sucrose medium while a slight
      increase was observed at the time of a change in morphology from bulbous cells to
      filamentous growth. Transcriptional alternation might be mediated by multiple
      putative stress elements in the promoter region of pkaC gene.

PMID- 10653149
TI  - Molecular cloning and chimerisation of CDI 315B monoclonal antibody.
AB  - A chimeric mouse-human antibody has been created that recognizes an antigen found
      on breast cancer cells and melanoma cells. Immunoglobulin constant domains of
      mouse monoclonal antibody CDI 315B Cgamma1 and CK, were substituted by the human
      Cgamma1 and Ckappa. The CDI 315B variable heavy and light chain regions were PCR
      amplified from hybridoma RNA and sequenced. Mouse variable VH and VL regions were
      joint to human IgG1 and kappa constant regions and subcloned into pcDNA3
      expression vectors. The Sp2/0 murine myeloma cells were transfected with
      expression vectors pcDNA3L and pcDNA3H and the reactivity of chimeric antibodies
      was tested by indirect ELISA using B16F1 murine melanoma cells as well as MCF7
      human breast cancer cells, as antigen.

PMID- 10653150
TI  - Recent advances in biohydrogen research.
AB  - A fundamental and principal difficulty of the future energy supply is that the
      formation of fossil fuels is much slower than the rate of their exploitation.
      Therefore the reserves which can be recovered in an energetically feasible manner
      are shrinking parallel with an increasing world-wide energy demand. Among the
      alternative energy carriers, hydrogen is preferred because it is easy to
      transport and store and it burns to environmentally friendly water vapour when
      utilized. Hydrogen can be produced in biological systems, however, our
      understanding of the molecular details is just emerging.

PMID- 10653151
TI  - Can hTNF-alpha be successfully produced and secreted in filamentous fungus
      Aspergillus niger?
AB  - A gene-fusion expression strategy was applied for the heterologous expression of
      hTNF-alpha in A. niger AB1.13. The TNF-alpha gene was fused with the A. niger
      glucoamylase GII form as a carrier-gene, behind its transcription control and
      secretion signal. The protein was expressed in the cells in the form of a
      glucoamylase-fusion protein, but was not present in the culture medium. From the
      expression of two hTNF-alpha analogues, LK 811 (Cys95/148) and LK 802 (Cys95/148,
      His107/108) respectively, we concluded that oligomerisation was not the critical
      point for secretion of hTNF-alpha in A. niger, but more probably improper folding
      already at the stage of monomer formation, or even incorrect processing of the
      molecule during the secretion pathway.

PMID- 10653152
TI  - The use of molecular biology to reprogram Streptomyces to make polyketide
      antibiotics more efficiently, and create novel secondary metabolites.
AB  - Recent advances in the molecular genetics of Streptomyces have increased our
      understanding of polyketide antibiotic biosynthesis, to the point where
      recombinant DNA approaches to generate novel structures are possible. Our
      understanding of how antibiotic pathways are regulated and integrated into
      central metabolism also provides the opportunity for strain manipulation to
      enhance productivity.

PMID- 10653153
TI  - Interaction trap experiment with CDC6.
AB  - CDC6 is an essential gene of yeast Saccharomyces cerevisiae. Although DNA
      sequence of the gene is available for a long time, biochemical function of Cdc6
      protein in the cell cycle remains unclear. Using the interaction trap experiment
      we were looking for proteins interacting specifically with Cdc6. Four gene
      products interacting with Cdc6 were detected. By sequence analysis we found that
      ECM11 codes for the protein involved in the cell wall synthesis, YNL201 codes for
      the protein of unknown function, probably involved in the carbon metabolism,
      YOR279 codes for protein of completely unknown function with no significant
      similarity with any known protein, and the interaction with Ty1
      retrotransposition element was also found. The strongest interaction with Cdc6
      bait measured as beta-galactosidase activity was observed with ECM11 and YNL201;
      YOR279 interacts slightly weaker. The weakest beta-galactosidase activity was
      obtained by Ty1A element. The strongest suppression of cdc6-1 mutation was
      observed by Ty1A element, the slight one with ECM11 and YNL201 but no suppression
      of thermosensitive mutation was detected for YOR279.

PMID- 10653154
TI  - Isolation, partial length sequence and expression of steroid inducible hps 70
      gene from Rhizopus nigricans.
AB  - Previous studies have shown that filamentous fungus Rhizopus nigricans responds
      to addition of different steroids into growth medium with induction of
      hydroxylation system and that some steroids provoke stress response. The purpose
      of this study was to investigate whether those steroids provoke induction of
      Hsp70 gene(s), well studied markers of stress response in different cells and
      organisms. The expression studies of fungal Hsp70 gene(s) using Northern blot
      analysis showed that fungal hsp70 mRNA was upregulated after treatment of mycelia
      with deoxycorticosterone and testosterone, but not after exposure to
      progesterone. In addition, expression of fungal Hsp70 mRNA was elevated after
      exposure of mycelia to heat shock (32 degrees C), ethanol, heavy metal (CuSO4),
      and oxidative stressor (H2O2), whereas treatment of mycelia with osmotic stressor
      (KCl) didn't have any influence on stress protein expression. The partial
      nucleotide sequence and deduced amino acid sequence homology search revealed that
      the cDNA clone (lambda hs20/2), isolated from cDNA library prepared from heat
      shock treated fungal mycelia, contained Hsp70 gene of DnaK subfamily.

PMID- 10653155
TI  - Equinatoxin II increases intracellular Ca2+ in NG 108-15 cells.
AB  - Equinatoxin II (EqT II) is a basic 20 kD protein isolated from the sea anemone
      Actinia equina. Intravenous injection of 3 LD50 of EqT II causes
      cardiorespiratory arrest. The aim of our study was to check the effects of EqT II
      on neuronal cells to assess the role of neuronal mechanisms in respiratory arrest
      after intravenous injection of the toxin. Effects of EqT II on mouse
      neuroblastoma x rat glioma NG108-15 cell were studied using confocal laser
      scanning microscopy and by Fura-2 fluorescence measurements. The results show
      that EqT II applied in nanomolar range increases intracellular Ca2+ activity
      significantly, which is possibly responsible for the morphological changes of
      NG108-15 cells after the exposure to 10 nM EqT II. Intracellular increase in Ca2+
      activity can not be prevented by use of the various pharmacological substances
      (e.g. Ca2+ channels blocker Verapamil and Bekanamycin). Swelling of the NG108-15
      cells after the exposure to the EqT II also can not be blocked with the sodium
      channel blocker tetrodotoxin. Increase in the intracellular Ca2+ activity is
      probably a result of Ca2+ entry through pores produced by the toxin, which has
      been shown by other authors on other cells and on phospholipid bilayer.
      Respiratory arrest after intravenous injection of the toxin can be caused by the
      action of the toxin on neuronal cells in medulla oblongata provided that EqT II
      can damage blood brain barrier thus enabling access to the neuronal cells. The
      results allow the conclusion that EqT II can affect normal calcium homeostasis
      and cell morphology of neuronal cells that can disturb cell physiology and its
      function thus affecting normal respiratory pattern.

PMID- 10653156
TI  - The effect of ammodytin L on frog neuromuscular junction.
AB  - Effects of myotoxic ammodytin L on frog neuromuscular junction were examined by
      morphological, enzymatic and electrophysiological studies. Electron micrographs
      of the frog neuromuscular junction revealed destruction of muscle fibers. Nerve
      terminals seemed to remain intact. The activity of the muscle specific enzymes in
      the bathing solution rose with time in a dose-dependent manner. Ammodytin L
      depressed the response of the neuromuscular preparation to acetylcholine.
      Measurements of electrically triggered isometric muscle contractions show that
      the toxin depresses the neuromuscular transmission both in the curarised and in
      the untreated frog neuromuscular preparation with marked difference between the
      time-courses of both effects, indicating that neurotoxic effect may also be
      involved.

PMID- 10653157
TI  - Limiting dilution analysis of human IL-2 producing T-cell precursors.
      Determination of hierarchical alloantigenic potential of human leukocyte antigens
      and evaluation of alloimune responses to single HLA-DP molecules.
AB  - Twenty nine healthy unrelated individuals were carefully selected and divided
      into three groups according to their HLA (Human Leukocyte Antigens) phenotypes. A
      sensitive and reproducible limiting dilution analysis (LDA) based bioassay using
      CTLL-20 cells for detection of human IL-2 was set up and used to assess the
      hierarchical impact of highly polymorphic HLA molecules on individual's
      alloreactivity. Our main interest was to evaluate the role of HLA-DP molecules in
      this process. By calculating frequencies of IL-2 producing helper T cell
      precursors (HTLp) and amounts of IL-2 produced in each experiment, we were able
      to confirm that HLA-DR molecules are the most potent alloantigens. In 29
      different combinations where a single HLA-DP mismatch between stimulating and
      responding cells was evaluated, some were reasonably tolerant, while the other
      ones evoked moderate to relatively strong alloimmune responses. Finally, two
      groups with statistically significant difference in alloimmune responses to
      stimulating HLA-DP molecules carrying D,E,A,V or G,G,P,M amino acid sequences at
      positions 84,85,86 and 87 in the sixth variable region F of the molecule could be
      formed, according to HTLp frequencies and amounts of IL-2 detected. Data
      presented are of great importance for the selection of unrelated as well as
      related bone marrow donors for haematological patients.

PMID- 10653158
TI  - Comparison of two monooxygenase systems with cytochrome P450 in filamentous
      fungus Rhizopus nigricans.
AB  - Besides the progesterone inducible steroid hydroxylase which catalyses the
      transformation of progesterone to 11alpha-hydroxyprogesterone the presence of
      another monooxygenase system in filamentous fungus Rhizopus nigricans (R.
      nigricans)--lanosterol demethylase was confirmed. Lanosterol demethylase was not
      inducible with progesterone. After subcellular fractionation both monooxygenase
      systems were found in microsomal fraction of fungus R. nigricans. To find out how
      to differentiate between the hydroxylase and demethylase systems the influence of
      inhibitors ketoconazole and metyrapone on both monooxygenase systems was studied.
      Both substances efficiently inhibited fungal steroid hydroxylase. Spectral
      studies used to characterize the interaction of inhibitors with cytochromes P450
      showed that both inhibitors bind to induced fungal preparations whereas in
      noninduced fungal preparations interaction with P450 was found only with
      ketoconazole. This indicated the difference in interaction of the two inhibitors
      on both monooxygenase systems present in fungus R. nigricans.

PMID- 10653159
TI  - Bacterial expression and refolding of different fragments of human CD14.
AB  - We have investigated bacterial expression of several fragments of CD14, a human
      cellular receptor for lipopolysaccharides (LPS). Despite binding of CD14 to the
      LPS, a vital constituent of bacterial outer membrane, we have succeeded in
      producing full length recombinant hCD14 in E. coli. High level of production of
      CD14 resulted in deposits of aggregated CD14 in bacteria in form of inclusion
      bodies, which made production of this protein possible. We have also produced N
      terminal fragments consisting of 134 and 152 residues, which comprise N-terminal
      domain with 2 and 3 leucine rich repeats, respectively and a fragment that
      contains only leucine rich repeats. Production of the N-terminal domain
      consisting of 69 residues could not be detected, probably due to the degradation
      of the produced protein within the bacteria. Full length CD14 and a fragment of
      152 residues from inclusion bodies were refolded, while the 134 residues fragment
      and the one with 10 leucine-rich repeats could not be refolded. Those results
      confirm that the minimal folding unit of CD14 must include N-terminal domain and
      at least 3 leucine rich repeats.

PMID- 10653160
TI  - Purification of cytochrome P450 from filamentous fungus Rhyzopus nigricans.
AB  - It has been reported in our previous studies that steroid hydroxylation system of
      Rhizopus nigricans involves cytochrome P450 and NADPH-cytochrome P450 reductase
      in the electron transport system. Both enzymes are membrane bound and are located
      in the microsomal preparations of progesterone induced fungal mycelia. In order
      to identify and characterize the cytochrome P450 component of fungal monoxygenase
      system, microsomal proteins from induced mycelia were subjected to HIGH Q anion
      exchange and MONO P (FPLC) anion exchange chromatography. Four fractions
      containing cytochrome P450 have been resolved on MONO P column. They exhibit CO
      difference spectra and type II difference spectra with ketoconazole.

PMID- 10653161
TI  - Early events in TNFa-p55 receptor interations--experiments with TNF dimers.
AB  - The first essential step in TNF signal transduction is believed to be clustering
      of the membrane bound receptors around the trimeric TNF molecule. To check if one
      receptor binding site would be enough to trigger the signal, we tried to prepare
      several types of TNF dimer. For this purpose, two TNF analogs bearing different
      cysteine mutations at the inner subunit binding surfaces were designed, expressed
      in E. coli and prepared in pure form. By mixing equimolar quantities of these
      analogs under appropriate conditions, two different types of dimer were prepared.
      The first, Dim/S2, proved to be composed mainly of a disulfide-linked dimer,
      which was still capable of trapping the third subunit of either of the precursor
      analogs, thus showing relatively high residual cytotoxicity. To avoid trimeric
      structures, Dim/S2 was further transformed into Dim/Iaa2 by alkylation of -SH
      groups of the newly introduced cysteines, allowing binding of only two TNF
      subunits through native contact surfaces. These dimers showed substantially
      reduced cytotoxicity on the L929 cell line. In addition, it appears that Dim/Iaa2
      is able to competitively inhibit cytotoxicity of native TNF, as assessed on the L
      M cell line.

PMID- 10653162
TI  - Identification and molecular cloning of cathepsin P, a novel human putative
      cysteine protease of the papain family.
AB  - A cDNA encoding a novel human putative member of the papain family of cysteine
      peptidases has been cloned. The protease, named cathepsin P, is synthesized as a
      preproprotein. The presumed propeptide of 38 amino acids is followed by a 242
      residue mature protein. The mature protease region is 30% identical to human
      papain-like cathepsins, with all the residues important for catalysis conserved.
      No similarity was observed in the propeptide region. On the contrary, the
      proenzyme shares 51-87% residues with some precursors of cysteine proteases from
      other species that have not yet been characterized. They all show a nearly
      completely conserved "CYTRED motif" in the propeptide region, not present in
      other members of the family, and could therefore constitute a distinct subfamily.

PMID- 10653163
TI  - Tissue expression and immunolocalization of a novel human cathepsin P.
AB  - The mRNA of a novel human cathepsin P is expressed at high levels in lung, liver
      and heart. Using antibodies raised against recombinant cathepsin P produced in
      Escherichia coli, a single protein band of 33 kDa was detected by immunoblotting
      an extract of human liver. By immunofluorescence, positive signals were observed
      in hepatocytes and Kupffer cells of liver, and the distal tubule cells of kidney
      showing mainly perimembranous distribution, indicating a role, as yet unknown,
      for this novel putative protease that is distinct from other cathepsins of the
      papain family.

PMID- 10653164
TI  - Cathepsin B and its inhibitor stefin A in brain tumors.
AB  - Cysteine protease cathepsin B (CatB) and its endogenous inhibitor stefin A (StA)
      play an important role in tumor progression. Increase of CatB expression and
      lower levels of its inhibitors were associated with tumor malignancy in brain
      tumors. In this study of 100 patients, CatB was localized by immunostaining to
      both, tumor and endothelial cells of primary brain tissue. Significant
      correlation with poor prognosis was found by univariate Cox's regression model.
      Intense overall immunostaining and immunostaining in endothelial cells alone were
      prognostic for survival (p=0.003 in both). When comparing CatB expression at mRNA
      level, we found considerable differences between center and periphery of a tumor
      as well as between different tumor samples. StA mRNA was only detected in benign,
      but not in malignant tissues. We suggest that screening of cysteine-protease
      genes expression can be applied in clinical prognosis of brain tumors.

PMID- 10653165
TI  - The effects of equinatoxin II on respiration--possible mechanism of the toxin
      lethality.
AB  - In rat an intravenous application (i.v.) of a lethal dose of the equinatoxin II
      (EqT II) provoked a respiratory arrest. It is not known whether the respiratory
      arrest is a result of a direct actions of the toxin on lung tissue, on
      neuromuscular junctions or the on the central nervous system. The influences of
      the toxin on the neuromuscular transmission and on muscular contraction were
      studied in isolated rat diaphragm. The effect of EqT II on end plate potentials
      of m. cutaneus pectoris was measured in the frog Rana esculenta. To monitor
      equinatoxin II effects on the central nervous system of a rat, the toxin was
      injected directly into the forth brain ventricle. The respiratory arrest was not
      the result of the toxin action on the neuromuscular junctions and peripheral
      nerves. The cessation of respiratory activity was most probably a result of
      equinatoxin II direct actions on lung tissue and on brain microcirculation.

PMID- 10653166
TI  - Molecular properties of central and peripheral histamine H1 and H2 receptors.
AB  - We identified and characterised histamine H1 and H2 receptor subtypes on rat
      cortical astrocytes in primary culture with radioligand binding studies and
      compared their molecular properties with peripheral (bovine vascular smooth
      muscle and endothelial cells) histamine H1 and H2 receptors. Our results showed
      the existence of a homogenous population of high affinity binding sites for 3H
      mepyramine (Bmax = 281 fmol/mg protein, K(D) = 3.5 +/- 0.7 nM) and 3H-tiotidine
      (Bmax = 59 fmol/mg protein, K(D) = 1.9 +/- 0.7 nM) on astrocytes, which was
      further confirmed by competition binding studies using various H1 and H2 specific
      agonists/antagonists. We showed differences in the density of receptors and
      differences in the affinities of competing drugs for the same histamine receptor
      subtype (H1 and H2) between the tissues used, which indicate different molecular
      properties of the central and peripheral histamine receptors.

PMID- 10653167
TI  - The relation between the rod-like inner structures and the shapes of the cells.
AB  - The shapes of the cells with simple rod-like inner structures are studied
      theoretically. Since the cell with inner structure can be bent, the possibility
      of non-axisymmetric shapes is considered. The equilibrium shape of the cell,
      obtained by minimizing the sum of the membrane bending energy and the bending
      energy of the rod, depends on the ratio between the bending constant of the
      membrane and the bending rigidity of the polymer rod. The dependence of the cell
      shape on the length of the rod and on the difference between inner and outer
      membrane layer areas is presented.

PMID- 10653168
TI  - Urothelial cell detachment and differentiation in urinary bladder.
AB  - In developing and in repairing bladder, proliferation of the transitional
      urothelium is followed by cell detachment--desquamation or apoptosis.
      Proliferation results in formation of terminally differentiated superficial cells
      and this process may be followed by checking the cells on the presence of
      differentiation markers. The formation of an asymmetric unit membrane (AUM)
      structure (plaque) on the cell surface is in correlation with urothelial
      differentiation. Thus, the microstructure of the luminal surface of the urinary
      bladder provides a very convenient differentiation biomarker. The surface of
      immature cells showed a pattern of microvilli. The progress of differentiation
      was associated with microvili arranged in rows finally forming the characteristic
      pattern of ridges in terminally differentiated cells. These results demonstrate
      that the characteristic surface pattern and the AUM plaque formation in the
      apical plasma membrane of superficial urothelial cells are associated with
      specific morphology, and patterns and thus help detect differentiation level of
      cell.

PMID- 10653170
TI  - The frequency dependence of phospholipid vesicle shapes in an external electric
      field.
AB  - Experiments show that phospholipid vesicles exposed to AC electric field undergo
      a shape transition from prolate to oblate ellipsoidal shape when the frequency of
      the field is increased. A theoretical model, based on the minimization of total
      free energy of the vesicle, was devised to explain this phenomenon. The model
      exhibits the same frequency-dependent prolate-to-oblate shape transition as
      observed in the experiment.

PMID- 10653169
TI  - Characterization of plasma membrane fraction from filamentous fungus Rhizopus
      nigricans.
AB  - In the filamentous fungus Rhizopus nigricans a steroid hydroxylating multienzyme
      system is inducible by progesterone and by several other steroids. The biological
      signal carried by progesterone might be mediated by receptors, located either in
      the plasma membrane or inside the cell. To elucidate the first possibility,
      plasma membrane fraction was examined for the presence of progesterone receptors.
      The isolation of plasma membrane from fungal homogenate containing different
      other membranes is difficult because of the rigid cell wall. Three different
      membrane fractions were prepared by differential centrifugation of the fungal
      homogenate and characterized by plasma membrane and mitochondrial membrane marker
      enzymes, H+-ATPase and mit-ATPase, respectively. The same fractions were examined
      for the presence of specific progesterone-binding molecules. Two of these
      fractions comprising the highest level of plasma membrane enzyme activity
      contained also the highest level of specific progesterone-binding compounds: 27,6
      fmol/mg protein and 18,8 fmol/mg protein. The correlation between plasma membrane
      marker enzyme activity and the amount of progesterone-binding proteins in plasma
      membrane fraction of Rhizopus nigricans might indicate the involvement of these
      molecules in the induction process.

PMID- 10653171
TI  - Rotation of giant phospholipid vesicles in an uniform shear flow.
AB  - Rotation of giant "point attached" phospholipid (POPC) vesicles in a shear flow
      was studied. The dependence of the angular velocity on the flow gradient was
      measured and the experimental results were compared to the predictions of a
      theoretical model. A good linear correlation between the angular velocity of the
      vesicle and the flow gradient, as predicted, was observed.

PMID- 10653172
TI  - Exogenously added growth factors have no effect on formation of cell junctions
      and cytoskeleton in urothelial cells in culture.
AB  - To elucidate the effects of epidermal growth factor-EGF and transforming growth
      factor-TGFbeta1 on cellular structure, especially on cell junctions and
      cytoskeleton, the distribution of ZO1, E-cadherin and desmoplakin as well as the
      organization of actin and keratin filaments have been examined
      immunohistochemically. In EGF-treated cultures as well as in TGFbeta1-treated
      cultures, the distribution of adhesion proteins looked similar. On the sites
      where cells made contacts, the presence of ZO1, E-cadherin and desmoplakin was
      revealed seen as a continuous line around cells. EGF as well as TGFbeta1
      treatment induced no difference in the presence and distribution of cytokeratin
      20; this marker of terminal differentiation was limited to superficial urothelial
      cells only. Also, the distribution of actin filaments was not significantly
      altered by any of the growth factors used. This indicates that neither cell
      junctions nor cytoskeleton of urothelial cells were affected by exogenously added
      growth factors. This may result from the influence of stroma on the formation of
      urothelium during the first days of culture of urinary bladder explants and the
      production of growth factors in the culture itself.

PMID- 10653173
TI  - Actin cytoskeleton and exocytosis in rat melanotrophs.
AB  - We monitored secretory activity of single rat melanotrophs by the patch-clamp
      membrane capacitance measurements (Cm). Secretory activity was stimulated by
      cytosol dialysis with a patch-pipette solution containing 1 microM [Ca2+]i. Actin
      cytoskeleton was disaggregated by pretreating cells with Clostridium spiroforme
      toxin, which specifically ADP-ribosylates cellular actin. The extent of
      cytoskeleton disaggregation was monitored by phalloidin immunostaining. The
      maximal rate of secretion increases two folds in toxin-treated cells in
      comparison to controls, whereas the extent of calcium-induced secretory response
      was similar to that obtained in the non-treated cells. The results show that the
      subcortical actin network attenuates the rate of secretory activity, which we
      interpret to reflect a barrier function of cytoskeleton for exocytosis.

PMID- 10653174
TI  - Lowering of the coronary flow in isolated rat heart by equinatoxin II depends
      upon extracellular Ca2+ concentration.
AB  - Equinatoxin II (EqT II) is a basic polypeptide toxin from the sea anemone Actinia
      equina (L.). Its LD50 in mice is 33 g/kg. The cause of death after intravenous
      application has been attributed to the circulatory failure resulting in the
      cardiotoxic effects. In Langendorff's rat and guinea-pig heart preparations EqT
      II caused dose dependent decrease in the coronary flow (CF). Morphologic changes
      of different cell cultures incubated with EqT II are the result of Ca2+ entry
      through the newly formed discrete pores. Pores in the cell membranes are composed
      of the toxin oligomeres. In the present study we tried to evaluate the dependence
      of vasoconstrictor effects of EqT II on isolated rat hearts upon the Ca2+
      concentration in the perfusion solution. EqT II did not affect the CF in the
      group without Ca2+. The strongest effect was observed in the group with 1.5 mM
      Ca2+ where the CF decreased to 7.7+/-7%. The results of our experiments indicate
      that the effects of EqT II on CF depend on Ca2+ concentration in the
      extracellular solution.

PMID- 10653175
TI  - Ca2+-sensitive and Ca2+-insensitive exocytosis in maize coleoptile protoplasts.
AB  - Ca2+ and osmotic driven extension of the surface area of maize coleoptile
      protoplasts was investigated using capacitance measurements and photolysis of the
      caged compound DM-nitrophen. Protoplasts responded to an elevation of cytoplasmic
      Ca2+ (Ca(i)) with a rapid burst in capacitance reaching a maximal increase of
      1.3+/-1.1% over the resting cell capacitance. Subsequent lowering of the osmotic
      potential in the external medium by 210 mosmol caused a further increase in Cm by
      26+/-6%. These data indicate two independent pathways for insertion of membrane
      into the plasma membrane. One is driven by Ca(i) and recruits membrane from a
      small pool. The osmotic evoked rise in surface area draws membrane from a much
      larger reservoir and may be driven by membrane tension.

PMID- 10653176
TI  - The contribution of lumbar sympathetic neurones activity to rat's skin blood flow
      oscillations.
AB  - Skin blood flow on the rat's paws using laser Doppler flowmeter, electrical
      activity of the heart (ECG) and respiration were measured simultaneously. The
      signals were recorded for 20 minutes, both before and after denervation, at core
      temperature 37 degrees C and 38.5 degrees C, that was maintained constant during
      the recordings. Spinal nerve fibres, at the level L3-L4, were transected.
      Experiments were performed on 15 adult Wistar rats under general anaesthesia. The
      oscillations in the measured signals were analysed in the time-frequency domain
      using wavelet transform. On the frequency region from 0.7 Hz to 5 Hz two
      characteristic peaks were observed in the skin blood flow spectrum. They
      correspond to the main peaks in the spectra of the ECG (around 3.3 Hz) and
      respiration (around 1.3 Hz). Several additional peaks were observed in the low
      frequency region, from 0.01 to 0.7 Hz, in all measured signals. In this frequency
      region the relative energy contribution of the blood flow oscillations decreased
      after denervation only in the denervated left hind paw. This difference was not
      statistically significant at 37 degrees C (p=0.098, Kruskal-Wallis test) but
      became statistically significant at 38.5 degrees C (p=0.017). Relative energy
      contribution of the low frequency region, from 0.01 to 0.7 Hz, decreased 2.5-fold
      in the blood flow of the denervated paw. Within this region the relative energy
      contribution decreased significantly in two intervals, from 0.01 to 0.08 Hz and
      from 0.08 to 0.2 Hz (p=0.023). In the higher frequency region, from 0.7 to 5 Hz,
      o statistically significant differences were obtained in any paws when compared
      before and after denervation at the same core temperature. We conclude that the
      activity of lumbar sympathetic neurones contributes to low frequency skin blood
      flow oscillations.

PMID- 10653177
TI  - Alternative statistical method for detecting changes in spontaneous activity of
      single olfactory receptor cells.
AB  - An statistical method for analysis of event data analysis, common in
      electrophysiological investigations of activities of olfactory receptor neurons,
      is proposed. The method is based on the analysis of the slopes of cumulative
      frequency distribution function. During the spontaneous activity the distribution
      function is linear which indicate that probability density distribution is
      uniform. During the chemical stimulation, the density of action potentials is
      either increased (excitation--E) or decreased (suppression--S), causing the
      observable change of the slope. The slope at each event is evaluated by piecewise
      linear regression. The type (E or S) and time of change of the slope can be
      determined, providing information for further statistical analyses. Graphically
      supported computer program (in S-PLUS) is available for interactive or routine
      use.

PMID- 10653178
TI  - Variation in JH synthesis rate in mature honeybees and its possible role in
      reprogramming of hypopharyngeal gland function.
AB  - Juvenile hormone (JH) synthesis was higher in followers than in dancers, which
      suggests that higher JH levels in followers might be an internal motivational
      stimulus to induce them to leave the hive to search for food. The positive
      correlation of in vitro JH synthesis rate and alpha-glucosidase activity in the
      hypopharyngeal gland suggests that JH is involved in the reprogramming of the
      hypopharyngeal gland from producing larval food (immature adults) to production
      of alpha-glucosidase in mature adults.

PMID- 10653179
TI  - Functional morphology of the inner ear and underwater audiograms of Proteus
      anguinus (Amphibia, Urodela).
AB  - Octavolateral sensory organs (auditory and lateral line organs) of cave
      salamander Proteus anguinus are highly differentiated. In the saccular macula of
      the inner ear the complex pattern of hair cell orientation and the large
      otoconial mass enable particle displacement direction detection. Additionally,
      the same organ, through air cavities within the body, enables detection of
      underwater sound pressure changes thus acting as a hearing organ. The cavities in
      the lungs and mouth of Proteus are a resonators that transmit underwater sound
      pressure to the inner ear. Behaviourally determined audiograms indicate hearing
      sensitivity of 60 dB (rel. 1 microPa) at frequencies between 1 and 10 kHz. The
      hearing frequency range was between 10 Hz and 10 kHz. The hearing sensitivities
      of depigmented Proteus and black Proteus were compared. The highest sensitivities
      of the depigmented animals (N=4) were at frequencies 1.3-1.7 kHz and it was 2 kHz
      in black animals (N=1). Excellent underwater hearing abilities of Proteus are
      sensory adaptations to cave habitat.

PMID- 10653180
TI  - Temporal and spectral properties of the songs of the southern green stink bug
      Nezara viridula (L.) from Slovenia.
AB  - Substrate born songs of the southern green stinkbug Nezara viridula (L.) from
      Slovenia were recorded and analysed. The male calling song is composed of narrow
      band regularly repeated single pulses and of broad-band frequency modulated
      pulses grouped into pulse trains. The female calling song is characterised by
      broad-band pulsed and narrow-band non-pulsed pulse trains. A frequency modulated
      pre-pulse precedes the narrow-band pulse train. A frequency-modulated post-pulse
      usually follows the pulse train of the male courtship song. The male calling song
      triggers broad-band pulse trains of the female courtship song. The female also
      produces a repelling low-frequency vibration that inhibits male calling and
      courtship. The male rival song is characterised by prolonged pulses with a
      typical frequency modulation.

PMID- 10653181
TI  - The amplitude of the electroolfactogram in catfish correlates with the proportion
      of responding ORNs.
AB  - We recorded simultaneously the electrophysiological responses of the olfactory
      organ [the electroolfactogram (EOG)] and action potential activity of single
      olfactory receptor neurons (ORNs) to amino acid stimuli in the brown bullhead
      catfish, Ameiurus nebulosus. To determine whether the amplitude of the EOG
      depends upon the number of responding ORNs, we tested two highly stimulatory
      (based on EOG recordings) amino acids [L-norvaline (L-nVal) and L-cysteine (L
      Cys)], two amino acids of intermediate potency [L-arginine (L-Arg) and L
      isoleucine (L-Ile)], and a poorly stimulatory amino acid [L-proline (L-Pro)].
      Forty-nine percent of the spontaneously active, single ORNs tested (n=142) were
      either suppressed or excited by amino acid stimuli. Of the ORNs tested with
      specific amino acids, 61% responded to 1 mM L-nVal (n=49), 57% responded to 1 mM
      L-Cys (n=30), 45% responded to L-Arg (n=31) and 36% responded to L-Ile (n=22)
      with either suppression or excitation. Only one ORN responded with suppression to
      10(-2) M L-Pro (n=10). These data suggest that the amplitude of the EOG in the
      brown bullhead catfish is correlated with the number of responsive ORNs (Spearman
      corr. coef. = 0.9; P<0.05).

PMID- 10653182
TI  - System for measuring isolated rat soleus muscle belly response to tetanic
      stimulation.
AB  - A novel system for simultaneous measurements of isotonic muscle contraction and
      transversal muscle belly displacement in the isolated rat soleus muscle was
      designed. The system simultaneously records tetanic contraction of the muscle and
      transversal displacements of the muscle belly. The tetanic rise times (TRT) and
      muscle belly displacement times (BDRT) were measured at different proton loads
      induced by CO2 at 1%, 5% and 30%. The measurements of muscle belly displacement
      enabled us to follow the water shift into the muscle tissue during the tetanic
      activity. Acidosis provoked by 30% CO2 irreversibly increased the BDRT, however
      the TRT were not changed.

PMID- 10653183
TI  - The ultrastructure of photoreceptor cells in the pineal organ of the blind cave
      salamander, Proteus anguinus (Amphibia, Urodela).
AB  - We studied ultrastructure of the photoreceptor cells in the pineal organ of
      blind, depigmented, neotenic cave salamander, Proteus anguinus. Unlike in epigean
      vertebrates the outer segments of most photoreceptor cells consists of
      concentrically arranged lamellae, however; in few cells, the outer segments
      contain 7-9 plasma membrane disks. In both types of photoreceptor cells the outer
      segments enclose lumps of vesicles of different sizes. The photoreceptor cells of
      Proteus anguinus are similar to those in other cavernicolous fish species.

PMID- 10653184
TI  - Taste(s) and olfaction(s) in fish: a review of specialized sub-systems and
      central integration.
AB  - Evidence from comparative morphology and electrophysiology suggests that both,
      olfaction and taste in fish serve different ecological roles. The lateral
      olfactory system (dorsolateral olfactory bulb glomeruli and lateral olfactory
      tract) and the external taste buds are probably specialized for food search and
      amino acid discrimination. The medial olfactory system (basomedial olfactory bulb
      glomeruli and medial olfactory tract) and the solitary chemosensory taste cells,
      however, may have their roles in intra- and interspecific interactions
      (discriminating pheromones by olfaction, bile components by both olfaction and
      taste). Whereas stimulation of the taste systems alone triggers reflexes,
      complex, conditional or conditioned behaviours are only released when the
      olfactory system is intact. This points at the importance of telencephalic and
      diencephalic integration of olfactory and taste inputs. Consequently, caution is
      appropriate concerning simplistic interpretations of deprivation experiments.

PMID- 10653185
TI  - The PDZ assembled "transducisome" of microvillar photoreceptors: the TRP/TRPL
      problem.
AB  - Two types of ion channels, TRP and TRPL, are activated upon light-absorption in
      rhabdomeral photoreceptor membranes of fly compound eyes. Whereas TRP is
      associated with other signaling proteins into a multiprotein complex
      (transducisome), the molecular organization of TRPL is discussed controversely.
      We analysed the TRPL content of blowfly rhabdomeral membranes and investigated by
      co-immunoprecipitation studies whether or not TRPL is part of the transducisome.
      Compared to TRP there are at least ten times less TRPL molecules present in the
      rhabdomeral membrane. A small fraction of the total TRPL present co
      immunoprecipitates with other proteins of the transducisome and vice versa. Our
      data suggest that a significant fraction of TRPL is not incorporated into the
      transducisome. This fraction may either form independent ion channels or bind to
      the transducisome transiently.

PMID- 10653186
TI  - Regeneration of the radial nerve in a dog influenced by electrical stimulation.
AB  - The effect of biphasic electric fields on nerve regeneration that follows injury
      to the left radial nerve of a dog was examined using electromyography (EMG). The
      left and right radial nerves were crushed with a serrated hemostat and the
      stimulating electrodes were positioned proximally and distally relative to the
      site of the injury. The left nerves received rectangular, biphasic current pulses
      (30 microA, 0.5 Hz) through the lesion for two months. The right radial nerves
      were treated as controls and regenerated without electrical stimulation. EMG
      activity was recorded intramuscularly from left and right musculus extensor
      digitorum (from Medical dictionary) communis (MEDC). Results obtained at the end
      of the two-month stimulation period showed a significant difference between the
      EMG activity of the stimulated and the unstimulated MEDC suggesting that the
      electrical treatment enhanced the nerve regeneration.

PMID- 10653187
TI  - The function of the cercal sensory system in escape behavior of the cave cricket
      Troglophilus neglectus Krauss.
AB  - Long cerci of cave crickets Troglophilus neglectus Krauss (Rhaphidophoridae,
      Orthoptera) are, in contrast to other investigated species, oriented
      perpendicularly to the ground. Behavioural experiments indicated that cave
      crickets detect wind direction and respond to stimulation by jumping away from
      the stimulus. Directed wind puffs deflect filiform sensory hairs on the cerci,
      trigger physiological responses of their sensory neurons and change activity of
      interneurons that control the escape direction. Two local interneuron pairs, one
      non-spiking and one spiking, were identified using intracellular recording and
      subsequent dye injection techniques. The non-spiking interneuron responds to the
      puffs from sides with a large depolarization and to the puffs from the front and
      back of the animal with a small depolarization. After stimulation from the
      ipsilateral side the spiking interneuron responds with a burst of spikes at the
      onset of stimulation and, after stimulation from the contralateral side, it
      responds with a burst of spikes at the onset and at the end of the stimulation.

PMID- 10653188
TI  - Green stink bug Nezara viridula detects differences in amplitude between
      courtship song vibrations at stem and petiolus.
AB  - Green stink bug Nezara viridula courtship songs are transmitted through plants as
      substrate vibrations. The amplitude of the vibrations is different at different
      distances from the source of vibration and at different locations on the plant.
      Amplitudes of the local vibration were measured on stem and petioli of the bean
      plant (Phaseolus vulgaris) with a Laser-Doppler vibrometer. Differences of the
      amplitudes of vibration between adjacent points around the nodes were large
      enough to release differential nerve activities of vibration receptor cells of
      different legs. There was no correlation between the signal amplitude and the
      distance from the singing bug, however; the differences in amplitudes of
      vibrations between the stem and the adjacent petioli of leaves potentially
      permitted direction finding in the green stink bug males.

PMID- 10653189
TI  - Coding principles in fish olfaction as revealed by single unit, EOG and
      behavioral studies.
AB  - At present, the principles of coding and codes for individual odorants are not
      known; however, several coding properties and their limitations emerged. The
      olfactory code for different odorants must be different to enable olfactory
      discrimination. We studied elements of the olfactory code that are accessible to
      combined microelectrode and behavioral techniques. A random sample of
      spontaneously active olfactory receptor neurons (ORNs) responded to a 15
      component mixture of amino acids with suppression, excitation and no change in
      their activity in the ratio of 6:1:8; ORNs responded to L-arginine (L-Arg) in the
      ratio of 5:5:60 and to L-cysteine (L-Cys) in the ratio of 10:1:27. ORNs provide
      information that enables nearly an unlimited behavioral discrimination of single
      odorants. Underwater electro-olfactogram (EOG) recordings from the olfactory
      organ measure the odorant-induced summed dc potential change from all the
      olfactory receptor neurons. In behavioral studies, the more (most) stimulatory
      component of the binary (ternary) mixture determined in EOG recordings was its
      better-perceived component; however, discrimination conditioning--repeated
      presentation of the conditioned mixture and its more stimulatory component alone-
      enabled the discrimination of the conditioned binary and ternary mixtures from
      their more (most) stimulatory components. In large multimixtures (13 components),
      where one amino acid is the more potent EOG stimulus than the other less
      stimulatory but equipotent components, catfish discriminated all single
      components from the conditioned multimixture. These results indicate that the
      multi-mixture is not detected as its most stimulatory component. Catfish also do
      not learn to discriminate a 13 component multimixture from a 12 component
      multimixture comprising 12 of the same components. Taken together, these findings
      indicate that the capacity for parallel transfer of mixture component information
      is limited in the catfish olfactory system. The finding of a limited capacity of
      multimixture component detection in catfish also supports the hypothesis of
      across nerve pattern coding of odorants and eliminates the sole existence of
      entirely specialized olfactory receptor neurons and labeled lines.

PMID- 10653190
TI  - Vibratory songs of hybrids from Brazilian and Slovenian populations of the green
      stink bug Nezara viridula.
AB  - Males and females of the green stink bug Nezara viridula produce species and sex
      specific vibrational signals. The songs of bugs from geographically isolated
      population differ in their temporal characteristics. Hybrids were produced
      between the bugs from Brazilian and Slovenian populations in order to examine the
      levels of genetic inheritance of their vibratory songs. Hybrid males and females
      produced songs which are distinctly different from parental songs and these
      differences can be attributable to genetic factor. The results show that in some
      parameters the hybrid songs are intermediate between the parental types. Several
      song parameters are apparently sex-linked. It remains to be established whether
      observed genetically determined differences in vibratory songs also indicate that
      cryptic species exist within the taxon N. viridula.

PMID- 10653191
TI  - Pure tone audiogram and speech audiometry in patients with hereditary motor and
      sensory neuropathy.
AB  - The goal of our work was to determine hearing thresholds in patients with hearing
      impairment due to hereditary motor and sensory neuropathy (HMSN I). In assessment
      of auditory function we used two methods: pure tone and speech audiometry. Pure
      tone audiometry was performed using air and bone conducted signals. Speech
      comprehension was defined with a test battery of monosyllabic words unknown to
      the patient. By comparing the results of these methods we were able to
      differentiate whether the hearing loss was of cochlear or retrocochlear origin.
      We tested 5 patients with HMSN I associated with difficulty in speech
      understanding. The tests showed mild to severe elevation of pure tone thresholds
      but no speech perception in any of tested patients. We suggest that this type of
      hearing impairment be due to the disorder of the auditory nerve function--a
      neuropathy of the auditory nerve as part of HMSN.

PMID- 10653192
TI  - Brainstem auditory evoked potentials and cochlear microphonics in the HMSN family
      with auditory neuropathy.
AB  - The aim of this work was to assess the hearing impairment in patients with
      hereditary motor and sensory neuropathy (HMSN). Elevation of pure tone thresholds
      in the presence of preserved inner ear function as suggested by cochlear
      microphonics (CM), absent or markedly abnormal brainstem auditory evoked
      potentials (BAEP), and elevation of speech perception out of proportion to the
      pure tone loss were found in the patients. From 28 members of a Gypsy family, we
      examined two siblings aged 31 and 30 years and their nephew aged 20 years, all
      suffering from HMSN that was associated with auditory neuropathy. All three
      affected members with difficulty of understanding speech had following
      investigations: pure tone and speech audiograms, BAEP, cochlear microphonics, and
      nerve conduction studies (NCV). RESULTS: the older two siblings had a flat 80 dB
      audiogram, whereas the younger one has flat 20 dB audiogram on the Lt. ear and 30
      dB audiogram on the Rt. ear. All had no speech comprehension and no BAEP. Two
      patients had preserved cochlear microphonics on one ear. Peripheral nerves were
      electrically not elicitable, however, at the beginning of the disease nerve
      conduction was slow. CONCLUSION: in all three affected members with distinct
      clinical picture of HMSN their hearing impairment was proved to be due to severe
      auditory neuropathy in the presence of preserved inner ear function.

PMID- 10653193
TI  - The reversible displacement of the passive diastolic p-V curve in the isolated
      guinea pig left ventricle.
AB  - We studied viscoelastic behaviour of the isolated diastolic guinea pig left
      ventricle (LV), manifested in changes of the hysteresis loop of the pressure
      volume (p-V) diagram, produced by acute volume loading. Specifically, we
      investigated how the width of the hysteresis depends on the way LV volume
      loading, and whether changes in the hysteresis width are reversible. Each of 11
      LV was instrumented with a catheter for injection and withdrawal of saline, and a
      micromanometer (Millar, 2F) to measure LV pressure. LV were loaded by the
      computer controlled injection of saline in 6-8 sequential injection steps of 100
      microl each with a pause of 5 s, followed by a similar withdrawal pattern. In
      protocol A (N = 5), a 100 microl higher maximal LV volume (LVVmax) was reached
      during injection than in the control run, and in protocol B (N = 6), the time
      spent at LVVmax was longer (20 vs. 5 s pause). In both protocols a reproducible
      displacement of the passive p-V curve during volume unloading was observed,
      reflected in the increase of the hysteresis width by 23+/-8% in protocol A, and
      12+/-3% in protocol B. Reversible displacement of the passive diastolic p-V curve
      after large aperiodic volume change suggests participation of reversible
      phenomena, like extracellular fluid filtration, and may in part provide an answer
      to the phenomenon of preconditioning.

PMID- 10653194
TI  - Hereditary motor and sensory neuropathy associated with auditory neuropathy in a
      Gypsy family.
AB  - In a Slovene Gypsy family of 19 subjects from four generations three patients
      with clinical characteristics compatible with hereditary motor and sensory
      neuropathy - Lom (HMSNL). were found They had severe distal and milder proximal
      muscle atrophy and weakness with areflexia of myotatic jerks. Two had facial
      weakness at the time when already wheelchair bound. All sensory modalities were
      affected distally in the limbs. Sluggish pupillary responses to light and
      convergence were found. They had skeletal abnormalities. One patient had
      polydactily on the hand. Nerve conduction studies were compatible with
      demyelinative polyneuropathy. Nerve biopsy showed mainly axonal loss without
      hypertrophic changes. Auditory neuropathy was diagnosed in all of them. None of
      the patients had duplication of 17p1.2-12 or point mutations in the Protein zero.
      Peripheral myelin protein and Connexin32 genes. Similar disorder that mapped to
      8q24 was previously described in some Bulgarian and Italian Gypsy families.
      Members of our family may suffer from the same hereditary disease and may carry
      the same ancestor mutation, which was in the past spread in European Gypsy
      populations.

PMID- 10653195
TI  - Non-invasive beat-to-beat determination of changes in the small artery compliance
      after smoking.
AB  - We investigated the response of the small arterial compliance on smoking in 5
      occasional smokers before, during and after inhaling the first cigarette in the
      day. For this purpose we used a non-invasive method based on interpretation of
      the oscillometric signal from the finger cuff coupled to the signal from
      photoplethysmograph. This system enables on-line determination of the finger
      artery compliance as function of transmural pressure (p(tm)) between 0 and 120 mm
      Hg, where each heart beat is presented by a set of compliance values in the range
      of the pulse pressure reduced by the cuff pressure. This procedure allowed
      construction of time course of the arterial compliance. When comparing the
      compliance value at ptm of 40 mm Hg, we found its fluctuations around the steady
      value during the rest and immediate lowering of the compliance after smoking,
      accompanied by the increase of blood pressure and heart rate.

PMID- 10653196
TI  - Weight bearing area during gait in normal and dysplastic hips.
AB  - The size and the shape of the weight bearing area in adult human hips depend on
      the forces acting in the hip and therefore change during the body motion. In this
      work the size and the shape of the weight bearing area in several phases of gait
      are estimated. The forces acting in the hip were determined through laboratory
      measurements and analyzed by mathematical models. The dysplastic hips are
      distinguished from the normal ones by a smaller center-edge angle of Wiberg while
      the time course of the forces acting in the hip is assumed to be the same in both
      cases. It is shown how radial articular stress is distributed over the weight
      bearing area in both cases. In normal human hips the weight bearing area occupies
      a rather large portion of the acetabulum-femoral head contact area while in
      dysplastic hips stress distribution is unfavourably concentrated in a smaller
      weight bearing area.

PMID- 10653197
TI  - Relaxation of epicardial strains after volume changes in the isolated guinea pig
      left ventricle.
AB  - Cardiac muscle is a porous viscoelastic material, exhibiting stress relaxation
      and hysteresis after being passively stretched. We investigated whether these
      material properties are also manifested in relaxation of epicardial segment
      lengths of the passive diastolic left ventricle (LV). For this purpose LV
      pressure and biaxial epicardial strains were measured simultaneously in isolated
      guinea pig hearts, arrested in diastole and instrumented to manipulate LV volume.
      Our study confirmed the existence of epicardial strain relaxation in both axial
      and circumferential directions, though it was much less expressed than LV
      pressure relaxation. Since the volume calculated from the segment lengths also
      revealed relaxation phenomena, our findings suggest that epicardial strain
      relaxation was connected with exchange of fluid from the LV cavity into the
      tightened epicardial vessels and back and not with the transformation of the LV
      shape.

PMID- 10653198
TI  - Modification of skeletal muscle AChE expression by a novel method of stimulus
      application to the peripheral nerve.
AB  - We have developed a new method for chronic application of electrical stimuli to
      the rat peripheral nerve in vivo. This method has the following advantages: (1)
      the amplitude, duration and pattern of stimulation can be adjusted before and
      during the course of experiment, (2) the set-up allows the animal to move freely
      during the experiment, and (3) the set-up is constructed from inexpensive, of-the
      shelf components that can be reused several times. The new method was used to
      study the influence of the pattern of muscle activation on acetylcholinesterase
      (AChE) regulation in extensor digitorum longus (EDL) and tibialis anterior (TA),
      fast skeletal muscles. Northern blot analysis of the chronically stimulated, fast
      EDL and TA revealed a rapid decrease of AChE mRNA level to a level typical for a
      slow, skeletal muscle.

PMID- 10653199
TI  - Changes in blood pH, lactate concentration and pulmonary ventilation during
      incremental testing protocol on cycle ergometer.
AB  - We investigated mutual changes in the blood lactate concentration ([LA]), blood
      pH and pulmonary ventilation (VE) to obtain insight into the regulation of pH at
      different levels of the exercise intensity. For this purpose the ratio VE/[LA]
      (1/min/mmol/l) was determined at each particular pH corresponding to exercise
      intensity in seven healthy subjects on the cycle ergometer during incremental
      exercise test. Changes in VE/[LA] ratio were found to exhibit three phases. In
      the first phase, the ratio increased without significant changes in [LA] and pH
      until it reached certain individual peak value. In the second phase, VE/[LA]
      decreased because increases in [LA] were considerably bigger than those of VE.
      Decreases in blood pH followed those of VE/[LA], nevertheless differences existed
      among subjects depending on how successful individual subjects regulated their
      blood pH. In the third phase with the VE/[LA] values stabilized between 15 and 22
      and pH values between 7.32 and 7.26, whereas differences between subjects became
      negligible. Similar trends to VE/[LA] were observed in case of the Onset of Blood
      Lactate Accumulation (OBLA) throughout the test at pH values below 7.32, as was
      manifested by the correlation coefficient. We conclude that blood pH regulation
      due to respiratory compensation of the lactate acidosis is more successful in
      subjects with better endurance (higher OBLA) but only when [LA] is slightly
      increased or at slight acidosis.

PMID- 10653200
TI  - Otoacoustic emissions in central auditory disorders.
AB  - Otoacoustic emissions are sounds produced by outer hair cells of cochlea. It is
      known that they may be useful in assessing hearing loss. The aim of our study was
      to evaluate their diagnostic capability in separating sensory from neural hearing
      impairment. Transiently evoked otoacoustic emissions (TOAE) and distortion
      product emissions (DP) were measured in 14 patients with sensorineural hearing
      loss. The results showed DP to be present in 12 patients and in 8 of them TOAE
      were detected despite the mild to severe hearing loss, thus indicating the lesion
      should be retrocochlear. The recording of otoacoustic emissions appears to be a
      technique for precise etiological diagnosis of hearing impairment.

PMID- 10653201
TI  - Long-term benzodiazepine therapy does not result in brain abnormalities.
AB  - Studies on the association between long-term benzodiazepine use and brain
      abnormalities have yielded conflicting results. The computed tomographic (CT)
      scans of 20 long-term users of benzodiazepine (65% men; mean age +/- SD [range],
      42 +/- 12.1 years [23-59]; mean daily benzodiazepine dose [diazepam equivalents],
      19.5 +/- 16.2 mg [2.5-70]; mean cumulative benzodiazepine exposure, 55.2 g [1.8
      198]) were compared with 36 age- (+/-3 years) and sex-matched controls. Controls
      were prospectively recruited from 96 patients attending a neurology clinic and
      were interviewed to screen for alcohol and substance use disorders and other
      conditions possibly leading to brain atrophy. Three neuroradiologists blindly
      assessed each CT scan for atrophy and measured ventricles (V1, V2, V3), sulci,
      fissures, cisterns, and folia. Reliability among observers ranged from 0.92 to
      <0.1, in which case deleting one observer increased all reliabilities to >0.45.
      No difference in atrophy was found between benzodiazepine users and controls. V1
      measures were significantly higher for benzodiazepine users than for controls
      (mean +/- SD, 12.1 +/- 1.3 vs. 11.1 +/- 2.0;p = 0.02), but measures of third and
      fourth largest sulci were significantly higher in controls than in benzodiazepine
      users. Right third and fourth largest sulci (mean +/- SD), respectively, were the
      following: controls, 0.72 +/- 0.4 and 0.74 +/- 0.7; benzodiazepine users, 0.51 +/
      0.3 and 0.46 +/- 0.3 (p < 0.02). Left third and fourth largest sulci,
      respectively, were the following: controls, 0.77 +/- 0.6 and 0.65 +/-0.3;
      benzodiazepine users, 0.53 +/- 0.3 and 0.5 +/- 0.3 (p < 0.02). Long-term
      benzodiazepine therapy does not result in brain abnormalities that can be
      demonstrated on CT scans.

PMID- 10653202
TI  - Comparison of the frequency of behavioral disinhibition on alprazolam,
      clonazepam, or no benzodiazepine in hospitalized psychiatric patients.
AB  - Several case reports have suggested that treatment with the benzodiazepine
      alprazolam can result in behavioral disinhibition. To address this question, the
      authors reviewed the medical records (blinded to all pharmacologic treatments the
      patients received) of 323 psychiatric inpatients treated with alprazolam (108
      patients), clonazepam (111 patients), or no benzodiazepine (104 patients) between
      January 1989 and June 1990. During benzodiazepine treatment, there were no
      significant differences among the three groups on the following measures: (1)
      acts of self-injury (alprazolam, 1.9%; clonazepam, 1.8%; no benzodiazepine,
      2.9%); (2) assaults on staff or other patients (alprazolam, 0%; clonazepam, 0.9%;
      no benzodiazepine, 1.0%); (3) need for seclusion or restraints (alprazolam, 3.7%;
      clonazepam, 6.3%; no benzodiazepine, 4.8%); (4) increased need for observation by
      hospital staff (alprazolam, 8.3%; clonazepam, 7.2%; no benzodiazepine, 6.7%); and
      (5) decrease in patient privileges (alprazolam, 11.1%; clonazepam, 12.6%; no
      benzodiazepine, 11.5%). The results indicate that in an inpatient psychiatric
      population, the frequency of behavioral disturbances with alprazolam, clonazepam,
      or no benzodiazepine does not differ. This suggests that alprazolam does not
      possess unique disinhibitory activity. Second, these data suggest that
      disinhibition may not be an important clinical problem associated with
      benzodiazepine use. The design of the study does not allow one to establish a
      relationship between the prescription of the benzodiazepine and worsening
      behaviors, and the findings need to be interpreted conservatively because it was
      a retrospective review of a heterogeneous population. However, it is noteworthy
      that the incidence of adverse events was low even in this high-risk population,
      and because the patients were in the hospital and under constant observation, the
      objective assessment of so-called paradoxical reactions was undertaken in a
      controlled setting.

PMID- 10653203
TI  - A double-blind, placebo-controlled trial of abecarnil and diazepam in the
      treatment of patients with generalized anxiety disorder.
AB  - In a multicenter, double-blind trial, 310 patients who had received a diagnosis
      of generalized anxiety disorder were treated for 6 weeks with either abecarnil,
      diazepam, or placebo at mean daily doses of 12 mg of abecarnil or 22 mg of
      diazepam administered three times daily. Patients who were improved at 6 weeks
      could volunteer to continue double-blind treatment for a total of 24 weeks. The
      maintenance treatment phase allowed the comparison of taper results for the three
      treatments at several study periods (0-6 weeks, 7-12 weeks, and more than 12
      weeks). Slightly more diazepam (77%) and placebo (75%) patients completed the 6
      week study than abecarnil patients (66%). At intake and baseline, after a 1-week
      placebo washout, the patient was required to have a Hamilton Rating Scale for
      Anxiety score of > or =20. Major adverse events for both abecarnil and diazepam
      were drowsiness, dizziness, fatigue, and coordination difficulties. Clinical
      improvement data showed that both abecarnil and diazepam produced statistically
      significantly more symptom relief than did placebo after 1 week of treatment. At
      6 weeks treatment (using last observation carried forward analysis), however,
      only diazepam still differed significantly (p < 0.01) from placebo. High placebo
      response (56% moderate to marked global improvement) at 6 weeks, as well as a
      slightly lower nonsignificant improvement rate observed with abecarnil, a partial
      y-aminobutyric acid (GABA) agonist, when compared with diazepam, a full GABA
      agonist, most likely contributed to our findings. Finally, taper results showed
      that only diazepam and not abecarnil caused the presence of temporary
      discontinuation symptoms, but only in patients who had been treated for at least
      12 weeks.

PMID- 10653204
TI  - Clonazepam and sertraline: absence of drug interaction in a multiple-dose study.
AB  - Thirteen subjects (seven men, six women) completed a placebo-controlled,
      randomized, double-blind, crossover study to determine whether an interaction
      occurs between clonazepam and sertraline. Ten days of once-daily doses of either
      clonazepam 1 mg and placebo (CZ + PL) or clonazepam 1 mg and sertraline 100 mg
      (CZ + SR) were administered; there was an 11-day washout period. Sertraline did
      not significantly affect the pharmacokinetics of clonazepam (p > 0.13).
      Clonazepam apparent oral clearance, volume of distribution, and half-life were
      3.9 +/- 0.2 L/hr, 233 +/-11 L, and 40.5 +/- 0.3 hours, respectively. The kinetics
      of the inactive metabolite 7-aminoclonazepam were marginally affected by
      sertraline, with a 21% decrease in the elimination half-life (p = 0.03) relative
      to CZ + PL and no significant difference between treatments in area under the
      curve or metabolite ratio. Card sorting (CS), digit-symbol substitution test
      (DSST), nurse-rated sedation scale (NRSS), and self-rated sedation scores were
      assessed four times daily on days -1 (PL + PL), 1, 4, 7, and 10. There were no
      differences between treatments in area under the effect curve or maximum observed
      effect for CS, DSST, or NRSS. Maximum impairment on all assessment days was low,
      with a less than 10% change from the drug-free values for CS and DSST. Despite
      higher clonazepam concentrations, predose (time 0) psychomotor and sedation
      scores did not differ among days -1, 1, 4, 7, and 10 or between treatments. These
      results in healthy volunteers indicate that sertraline does not affect the
      pharmacokinetics or pharmacodynamics of clonazepam.

PMID- 10653205
TI  - Double-blind, placebo-controlled study with reboxetine in inpatients with severe
      major depressive disorder.
AB  - The efficacy and tolerability of reboxetine, a unique selective noradrenaline
      reuptake inhibitor, were compared with those of placebo in a 6-week, randomized,
      double-blind study of hospitalized patients with a DSM-III-R diagnosis of major
      depressive disorder. Fifty-two patients (25 in the placebo group, 27 in the
      reboxetine group) were included in the efficacy analysis. Sixteen (64%) of those
      in the placebo group and four (15%) in the reboxetine group were withdrawn during
      the study because of lack of efficacy. Improvement in the mean Hamilton Rating
      Scale for Depression (HAM-D) total score at last assessment was significantly
      greater in the reboxetine group than in the placebo group (p < 0.001). Similarly,
      the response rate to treatment, defined as > or =50% reduction in HAM-D total
      score, was 74% for patients who received reboxetine compared with 20% for those
      who received placebo (p < 0.001). A significantly greater response with
      reboxetine than with placebo was seen as early as day 10 of treatment (p =
      0.006). The therapeutic efficacy of reboxetine was substantiated by improvement
      in mean scores on the Zung Self-Rating Scale and on the Clinical Global
      Impression Severity of Illness and Global Improvement scales. Reboxetine was well
      tolerated, and only one patient in each group withdrew because of adverse events.
      Dry mouth, insomnia, blurred vision, sweating, and constipation were recorded
      more frequently in the reboxetine group than in the placebo group. There was a
      tendency toward orthostatic changes in the systolic blood pressure, but this was
      not clinically significant. This study demonstrated that reboxetine is
      significantly more effective than placebo in the treatment of hospitalized
      patients with severe major depressive disorder and is well tolerated.

PMID- 10653206
TI  - Fluvoxamine-Clozapine drug interaction: inhibition in vitro of five cytochrome
      P450 isoforms involved in clozapine metabolism.
AB  - Administration of fluvoxamine to patients receiving clozapine therapy may
      increase the steady-state serum concentrations of clozapine by a factor of 5 to
      10. The authors undertook in vitro studies to disclose the mechanism behind this
      clinically important interaction. In a human liver microsome preparation,
      fluvoxamine showed a concentration-dependent inhibition of clozapine N
      demethylation. Fluvoxamine was much less effective as an inhibitor of clozapine N
      oxidation. Fluvoxamine also inhibited in a concentration-dependent manner the
      activity of all five cytochrome P450 (CYP) isoforms previously determined to be
      capable of catalyzing the demethylation of clozapine. Fluvoxamine inhibited
      CYP1A2 and 2C19 with the highest affinities (Ki values of 0.041 and 0.087 microM,
      respectively). The Ki values for CYP2C9 and 2D6 were 2.2 and 4.9 microM,
      respectively, whereas the Ki for CY3A4 was 24 microM. Assuming a hepatic tissue
      concentration of fluvoxamine in the range of 4 to 7 microM under therapeutic
      conditions, a clinically significant inhibition of all but CYP3A4 is expected in
      relation to clozapine N-demethylation. No significant effect of fluvoxamine on
      clozapine N-oxidation is to be expected under therapeutic conditions. Because of
      the large interindividual variability of the quantity of the various CYP isoforms
      in liver tissue, it is not possible to predict the fluvoxamine-induced increase
      in the plasma concentration of clozapine of an individual patient.

PMID- 10653207
TI  - Cytochrome P450 2D6 and treatment of codeine dependence.
AB  - Oral opioid analgesics such as codeine are used extensively worldwide and are
      frequently misused. Codeine is a substrate of CYP2D6, a genetically polymorphic
      P450 enzyme, and is metabolized to the more potent drug morphine. CYP2D6 activity
      can be inhibited by fluoxetine, and the inhibition of morphine formation may help
      individuals reduce their use of codeine. Fourteen long-term users of oral opiates
      (principally codeine) were assessed for an open-label pilot treatment study of
      fluoxetine 20 mg/day combined with a brief behavioral intervention and structured
      tapering of the opiate. Eight subjects entered and completed the 8-week
      treatment. Opiate use decreased by 30% to 100% of baseline use (p < 0.0001) in
      parallel with a decrease in CYP2D6 activity. Fluoxetine may have a role in the
      treatment of opiate dependence by decreasing opiate-reinforcing properties.

PMID- 10653208
TI  - Carbamazepine-nefazodone interaction in healthy subjects.
AB  - The pharmacokinetic interaction between nefazodone and carbamazepine was
      investigated in 12 healthy male volunteers. Subjects received nefazodone 200 mg
      twice daily for 5 days, and blood sample collection was performed on day 5 for 0-
      to 48-hour pharmacokinetic analysis. A 4-day wash-out phase then followed from
      days 6 to 9. Carbamazepine 200 mg was administered once daily from days 10 to 12,
      and then 200 mg was given twice daily from days 13 to 44. A 0- to 48-hour
      pharmacokinetic analysis was performed on day 38. Nefazodone 200 mg twice daily
      was added to the dosing regimen from days 40 to 44, and a subsequent 0- to 48
      hour pharmacokinetic analysis was performed on day 44. Coadministration of
      nefazodone increased steady-state plasma area under the concentration-time curve
      (AUC) of carbamazepine from 60.77 (+/-8.44) to 74.98 (+/-12.88) microg x hr/mL (p
      < 0.001) and decreased the active carbamazepine-10,11-epoxide metabolite AUC
      concentration from 7.10 (+/-1.16) to 5.71 (+/-0.52) microg x hr/mL (p < 0.005).
      During the combination, the steady-state AUC of nefazodone decreased from 7,326
      (+/-3,768) to 542 (+/-191) ng x hr/mL, and the AUCs of its metabolites
      (hydroxynefazodone, meta-chlorophenylpiperazine, and triazoledione) decreased
      significantly as well (p < 0.001). Coadministration of nefazodone 200 mg twice
      daily and carbamazepine 200 mg twice daily was found to be safe and well
      tolerated; however, the increased plasma exposure to carbamazepine may warrant
      monitoring of plasma carbamazepine concentrations with the combination. However,
      higher doses (>400 mg/day) of carbamazepine could yield more extensive induction,
      affecting tolerability of the combination. No change in the initial nefazodone
      dose is necessary, and subsequent dose adjustments should be made on the basis of
      clinical effects; however, the repercussion of carbamazepine induction of
      nefazodone metabolism on the antidepressant efficacy has yet to be studied.

PMID- 10653209
TI  - Efficacy of quetiapine in Parkinson's patients with psychosis.
AB  - Eleven patients with Parkinson's disease (PD) and acute psychosis received
      flexible doses of quetiapine between 25 and 300 mg/day based on clinical response
      and tolerance. Ten patients were receiving dopaminergic agents at baseline.
      Serial efficacy ratings (Brief Psychiatric Rating Scale, Clinical Global
      Impressions Scale), neuromuscular symptom assessments (Abnormal Involuntary
      Movement Scale, Simpson-Angus Scale, Unified Parkinson's Disease Rating Scale
      [UPDRS]), and adverse events monitoring were performed for up to 52 weeks. The
      patients had moderate hallucinations and/or delusions at baseline before the
      initiation of quetiapine. Nine of the 11 patients completed at least 12 weeks of
      treatment. Quetiapine was well tolerated in all but one patient, who became dizzy
      within the first week and withdrew from the study. Ten patients presented with
      moderate visual hallucinations. Quetiapine was markedly effective in controlling
      visual hallucinations in six of these patients. Symptoms of paranoia or delusions
      were less responsive to quetiapine. Four patients withdrew because of adverse
      events or comorbid medical problems, two withdrew because of a lack of efficacy,
      and five completed 52 weeks of treatment. The introduction of quetiapine did not
      exacerbate parkinsonian symptoms. Motor dysfunction, as measured by the UPDRS,
      revealed a slow, gradual worsening consistent with the progression of PD.
      Atypical antipsychotic medications such as quetiapine have a reduced likelihood
      of causing adverse drug-induced parkinsonism and therefore a possible role in
      treating psychotic symptoms in patients with PD.

PMID- 10653210
TI  - Laboratory measures of methylphenidate effects in cocaine-dependent patients
      receiving treatment.
AB  - Two experiments examined the effects of methylphenidate in male and female
      patients enrolled in an outpatient treatment program for primary cocaine
      dependence. The first study was a component of a double-blind efficacy trial
      wherein 57 patients were first tested in a human laboratory for their initial
      responsiveness to medication. Patients were randomly assigned to receive either
      placebo or methylphenidate treatment and received their first dose in the human
      laboratory environment before continuing in outpatient treatment. Methylphenidate
      was given as a 20-mg sustained-release dose (twice daily) plus an additional 5-mg
      immediate-release dose combined with the morning dose. Methylphenidate increased
      heart rate and subjective ratings; however, the subjective effects were primarily
      of a "dysphoric" nature, and significant effects were limited to increases in
      anxiety, depression, and anger on the Profile of Mood States; shaky/jittery
      ratings on a visual analog scale; and dysphoria on the lysergic acid diethylamide
      (LSD) scale of the Addiction Research Center Inventory. Methylphenidate did not
      increase cocaine craving nor ratings suggesting abuse potential (i.e., Morphine
      Benzedrine Group or drug-liking scores, etc.). None of the drug effects observed
      in the human laboratory was of clinical concern, and no subject was precluded
      from continuing in the outpatient study. After outpatient treatment completion,
      12 patients were brought back into a second double-blind human laboratory study
      in which three doses (15, 30, and 60 mg) of immediate-release methylphenidate
      were administered in an ascending series preceded and followed by placebo.
      Methylphenidate produced dose-related increases in heart rate, subjective ratings
      of shaky/jittery, and LSD/dysphoria without significantly altering cocaine
      craving or stimulant euphoria ratings. These results suggest that stimulant
      substitution-type approaches to the treatment of cocaine dependence are not
      necessarily contraindicated because of cardiovascular toxicity or medication
      abuse potential. However, they also suggest that the subjective effects of
      methylphenidate may not be positive enough for an adequate replacement approach.

PMID- 10653211
TI  - Naltrexone-induced nausea in patients treated for alcohol dependence: clinical
      predictors and evidence for opioid-mediated effects.
AB  - Naltrexone, an opiate antagonist, is well tolerated by most alcoholic patients;
      however, a subset reports significant nausea that can limit the effectiveness of
      this therapy. The goal of this study was to identify risk factors for naltrexone
      precipitated nausea to assist in the development of management strategies to
      maximize the overall effectiveness of naltrexone. On the basis of the hypothesis
      that alterations in the endogenous opioid system occur with repeated stimulation
      of endogenous opioids by alcohol, the authors predicted that the recency and
      intensity of alcohol use would be related to the risk of naltrexone-induced
      nausea. One hundred twenty alcohol-dependent subjects participated in an open
      label trial of naltrexone. After 5 to 30 days of abstinence, subjects received an
      initial naltrexone dose of 25 mg followed by a dose of 50 mg daily thereafter for
      10 weeks. New-onset adverse effects were rated mild, moderate, or severe after 1
      week of naltrexone. Logistic regression analyses were used to predict moderate to
      severe nausea during the first week of therapy from pretreatment patient
      characteristics. Moderate to severe nausea was reported by 18 subjects (15%) and
      was linked to poorer medication compliance and heavier drinking during treatment.
      Risk of nausea was significantly predicted by age, gender, intensity of drinking,
      duration of abstinence, and the interaction of abstinence duration and intensity
      of drinking. At shorter durations of abstinence, lighter drinkers were more
      likely to experience nausea than heavier drinkers. However, the risk of nausea
      declined with longer periods of abstinence, particularly for lighter drinkers.
      Younger age and female gender were associated with higher rates of nausea. These
      results support the hypothesis that recency and intensity of alcohol use are
      related to opiate antagonist-precipitated nausea and suggest that long-term
      alcohol use may result in alterations in the endogenous opioid system. Potential
      strategies to minimize the risk of nausea in vulnerable individuals are
      discussed.

PMID- 10653212
TI  - Comparison of central and peripheral pharmacologic effects of biperiden and
      trihexyphenidyl in human volunteers.
AB  - In this double-blind, randomized study, indices of central (memory, sedation) and
      peripheral (salivation, ratio of R-R interval on electrocardiogram) muscarinic
      function were evaluated in 14 healthy volunteers who received trihexyphenidyl,
      biperiden, and placebo. Additionally, serum drug levels were obtained 2 hours
      after oral administration. All subjects participated in three study sessions.
      During each session, subjects received two doses of biperiden (4 mg),
      trihexyphenidyl (5 mg), or placebo, and four series of tests were administered.
      The tests included the determination of cardiac response to standing (R-R ratio),
      mouth salivation, finger-tapping speed, digit span (forward and backward), a
      selective reminding task, and visual analog scales (VAS). On the VAS, subjects
      rated biperiden as significantly more sedating than either trihexyphenidyl or
      placebo, and both biperiden and trihexyphenidyl were associated with more
      dizziness than was placebo. Saliva production was significantly reduced by both
      trihexyphenidyl and biperiden compared with placebo. Digit span performance was
      significantly decreased in only the backward direction. The selective reminding
      task revealed highly significant decrements in the number of words recalled and
      consistent long-term retrieval after both biperiden and trihexyphenidyl. Delayed
      recall was significantly decreased by both active drugs. Both trihexyphenidyl and
      biperiden caused a significant increase in the R-R ratio comparison with placebo.
      With the exception of the VAS measurement of sedation, the effects caused by
      biperiden and trihexyphenidyl did not differ. The results of this study do not
      support the hypothesis that the side effect profile of biperiden is significantly
      different from that of trihexyphenidyl.

PMID- 10653213
TI  - Efficacy of kava extract for treating anxiety: systematic review and meta
      analysis.
AB  - Synthetic anxiolytic drugs are effective for treating anxiety, but they are
      burdened with adverse effects. Constraints on resources and time often render
      therapies such as psychologic interventions impracticable. Thus, an effective
      oral medication with few adverse effects would be a welcome addition to the
      therapeutic repertoire. This systematic review and meta-analysis was aimed at
      assessing the evidence for or against the efficacy of kava extract as a
      symptomatic treatment for anxiety. Systematic literature searches were performed
      in the computerized databases MEDLINE, EMBASE, BIOSIS, AMED, CISCOM, and the
      Cochrane Library (all from their respective inception to June 1998). The search
      terms used were kava, kawa, kavain, Piper methysticum, and Rauschpfeffer (German
      term for Piper methysticum). Experts on the subject were contacted to provide
      further information. There were no restrictions regarding the language of
      publication. Double-blind, randomized, placebo-controlled trials of oral kava
      extract for the treatment of anxiety were included. All publications were blinded
      before assessment by a person not involved in the study. Data were extracted in a
      standardized, predefined fashion independently by the two reviewers. The
      methodologic quality of all trials was assessed. Superiority of kava extract over
      placebo was suggested by all seven reviewed trials. The meta-analysis of three
      trials suggests a significant difference in the reduction of the total score on
      the Hamilton Rating Scale for Anxiety in favor of kava extract (weighted mean
      difference, 9.69; 95% confidence interval, 3.54-15.83). These data imply that
      kava extract is superior to placebo as a symptomatic treatment for anxiety.
      Therefore, kava extract is an herbal treatment option for anxiety that is worthy
      of consideration.

PMID- 10653214
TI  - Effectiveness of gabapentin for the treatment of behavioral disorders in
      dementia.
AB  - Twelve patients with moderate to severe dementia and severe behavioral disorders
      were treated with open-label gabapentin (200-1,200 mg/day) for 8 weeks in a
      prospective case-series design. Patients were nonresponders to previous trials of
      neuroleptics. Behaviors were measured at 2-week intervals with the
      Neuropsychiatric Inventory (NPI), the Cohen-Mansfield Agitation Inventory (CMAI),
      and the Clinical Global Impression Scale (CGI). Gabapentin was generally well
      tolerated in this population. Although 42% of patients experienced adverse events
      such as gait instability and sedation, only two patients discontinued treatment
      prematurely because of adverse events. Average patient scores for the CMAI and
      the NPI remained unchanged after gabapentin. On the CGI, two patients were much
      improved, three were minimally improved, six were unchanged, and one was
      minimally worse. Gabapentin may have a role in treating a subgroup of dementia
      patients with severe behavioral disorders who have not responded to neuroleptics.

PMID- 10653215
TI  - Effects of clozapine on substance use in patients with schizophrenia and
      schizoaffective disorder: a retrospective survey.
AB  - Substance use disorders, particularly those involving alcohol, marijuana, and
      cocaine, are highly prevalent among patients with schizophrenia and contribute
      markedly to its overall morbidity. Unfortunately, standard (typical)
      antipsychotic medications do not seem to reduce substance use in patients with
      schizophrenia and may even increase it. Recently, however, a few anecdotal case
      reports and two previous small "N" surveys have found that clozapine, an atypical
      antipsychotic medication, seems to decrease substance use in patients treated
      with this drug for their psychoses. The authors report data from a retrospective
      survey of substance use in 58 patients treated with clozapine who had a history
      of comorbid schizophrenia (or schizoaffective disorder) and substance use
      disorder. Of these 58 patients, 43 were being treated with clozapine at the time
      of the survey; the remaining 15 patients had discontinued clozapine before the
      survey. The survey involved chart review and clinician interview to assess change
      in substance use and global clinical symptoms while receiving treatment with
      clozapine. More than 85% of the patients who were active substance users at the
      time of initiation of treatment with clozapine decreased their substance use over
      the course of clozapine administration. For patients who continued treatment with
      clozapine up to the present, the decrease in substance use was strongly
      correlated with a decrease in global clinical symptoms. Data from this
      retrospective survey further support the previous observations that clozapine
      reduces substance use among patients with schizophrenic disorders. Moreover, the
      data suggest the need for prospective controlled studies of the effects of
      clozapine on substance use in this population.

PMID- 10653216
TI  - Cognitive improvement after benzodiazepine discontinuation.

PMID- 10653217
TI  - Prolonged upper airway instability in the parenteral use of benzodiazepine with
      levomepromazine.

PMID- 10653218
TI  - Mirtazapine: an inhibitor of cortisol secretion that does not influence growth
      hormone and prolactin secretion.

PMID- 10653219
TI  - Serotonin syndrome during treatment with paroxetine and risperidone.

PMID- 10653220
TI  - Efficacy of paroxetine in depression is influenced by a functional polymorphism
      within the promoter of the serotonin transporter gene.

PMID- 10653221
TI  - Abnormal monoamine metabolism in cerebrospinal fluid in a case of serotonin
      syndrome.

PMID- 10653222
TI  - Rifampin-induced selective serotonin reuptake inhibitor withdrawal syndrome in a
      patient treated with sertraline.

PMID- 10653223
TI  - Olanzapine serum concentrations lowered by concomitant treatment with
      carbamazepine.

PMID- 10653224
TI  - Attention deficit-hyperactivity disorder may be a risk factor for treatment
      emergent tardive dyskinesia induced by risperidone.

PMID- 10653225
TI  - Naltrexone for individuals with comorbid bipolar disorder and alcohol dependence.

PMID- 10653226
TI  - St. John's Wort: three cases of possible mania induction.

PMID- 10653227
TI  - The dawn of a new century: reflections on surgical issues.

PMID- 10653228
TI  - History of endoscopy: what lessons have we learned from the past?

PMID- 10653229
TI  - Laparoscopic vs open surgery: a preliminary comparison of quality-of-life
      outcomes.
AB  - BACKGROUND: The purported advantages of laparoscopic surgery over conventional
      open techniques are less pain and faster return to normal functional status. Very
      few studies have included validated measures of quality of life as end points.
      This study prospectively assessed the health status outcomes of patients
      undergoing four types of laparoscopic and open operations. METHODS:
      Preoperatively, patients undergoing elective inguinal hernioplasty, esophageal
      surgery, cholecystectomy, and splenectomy completed the SF-36, a well-tested,
      validated health-status instrument. This instrument measures physical functioning
      (PF), role-physical (RP), role-emotional (RE), bodily pain (BP), vitality (VT),
      mental health (MH), social functioning (SF), and general health (GH) health
      status domains. Patients then underwent either laparoscopic or open surgery.
      Patients were reassessed with the instrument > or =6 weeks after surgery. A total
      of 100 patients underwent these procedures. RESULTS: Compared to preoperative
      values, median SF-36 scores for laparoscopic cholecystectomy patients were
      improved in the domains of PF (85 vs 95, p = 0.01), BP (42 vs 75, p = 0.002), and
      VT (47.5 vs 70, p = 0.04); open cholecystectomy patients did not show
      statistically significant improvements over preoperative values. In addition,
      laparoscopic cholecystectomy patients had a better score than open
      cholecystectomy patients in the BP domain (75 vs 41, p = 0.05). Laparoscopic
      esophageal surgery patients had better scores than open surgery patients in the
      domains of RP (100 vs 0, p = 0.02) and VT (65 vs 52.5, p = 0.05). Compared to
      preoperative values, laparoscopic splenectomy patients had an improved score in
      GH (52 vs 77, p = 0.02) and better scores than open splenectomy patients in PF
      (90 vs 45, p = 0.05) and BP (84 vs 55.5, p = 0.01). Compared to preoperative
      values, open mesh hernioplasty patients showed improved scores in PF (70 vs 92.5,
      p = 0.03) and MH (72 vs 84, p = 0.05). Laparoscopic hernioplasty did not produce
      improved scores compared to either preoperative values or open hernioplasty.
      CONCLUSIONS: Laparoscopic surgery has demonstrably better quality-of-life
      outcomes than open surgery for cholecystectomy, splenectomy, and esophageal
      surgery. However, open hernioplasty has at least as good, if not better, health
      status outcomes than laparoscopic repair.

PMID- 10653230
TI  - Could age be an indication for laparoscopic colectomy in colorectal cancer?
AB  - BACKGROUND: The incidence of colorectal carcinoma increases in the elderly.
      Regardless of age as an isolated factor, postoperative complications represent
      the main factor in increasing hospital mortality. METHODS: The aim of this study
      was to compare the short-term results (first 30 postoperative days) after
      laparoscopically assisted colectomy (LAC) and open segmental colectomy (OC) in
      colorectal carcinoma between two groups of patients, older than 70 and younger
      than 70 years of age. In the study from November 1993 to June 1998, 255 patients
      were evaluated to participate. RESULTS: Peristalsis, oral intake, and discharge
      from the hospital occurred earlier in LAC than in OC treated patients, in the two
      age groups. The mean operative time was significantly longer in the LAC than in
      the OC patients in the two age groups. No differences were observed in morbidity
      between LAC and OC in the group younger than 70 years of age. However, the
      overall morbidity was significantly lower in the LAC group in patients older than
      70 years. One patient in the LAC group older than 70 years died. CONCLUSION:
      These results suggest that laparoscopically assisted colectomy may be
      particularly indicated in elderly patients.

PMID- 10653231
TI  - Laparoscopically assisted distal gastrectomy for early gastric cancer: is it
      superior to open surgery?
AB  - BACKGROUND: The purpose of this study was to compare clinical outcomes between
      laparoscopically assisted and open distal gastrectomy for early gastric cancer.
      METHODS: The records of 21 patients who underwent laparoscopically assisted
      distal gastrectomy (LG) for preoperative diagnosis of intramucosal gastric
      carcinoma between January 1996 and August 1998 were reviewed and compared with
      those of 31 open distal gastrectomy patients during the same period. RESULTS:
      Age, gender, and size and histologic differentiation of the lesions were matched.
      Those located at the body of the stomach (p = 0.011) and those macroscopically
      depressed (p = 0.049) were subjected more frequently to open surgery.
      Laparoscopically assisted gastrectomy required significantly longer operative
      time (p < 0.001) with less extensive lymph node dissection (p < 0.001). However,
      time to start of walking (p = 0.032), time to flatus (p = 0.002), duration of
      postoperative fever (p = 0.027), and postoperative hospital stay (p = 0.001) were
      significantly shorter in the LG group, and this group had a lower white blood
      cell count on the first postoperative day (p = 0.010). Blood loss and time to
      oral intake were comparable between the groups. Complications included one
      conversion to open surgery, one leakage, and one stenosis in the LG group, and
      two leakages and an atelectasis in the OG group. CONCLUSIONS: Although LG
      requires longer surgical time, this retrospective study suggests that it is
      superior to open surgery in terms of faster postoperative recoveries, shorter
      hospital stays, and cosmetic outcomes.

PMID- 10653232
TI  - Minimizing ports to improve laparoscopic cholecystectomy.
AB  - BACKGROUND: Minimizing the number and scope of ports used to perform laparoscopic
      cholecystectomy attempts to build on the improvements in postoperative pain
      control, rapid return to activity and work, patient satisfaction, and cosmetic
      result achieved by the laparoscopic method. METHODS: We studied 141 patients in
      two sequential studies: the first a prospective randomized trial with 41
      patients, and the second an examination of the more minimal procedure in 100
      patients. In the randomized trial, patients underwent laparoscopic
      cholecystectomy with three ports: three 5-mm ports or two 10-mm ports and one 5
      mm port. The 100 patients underwent the three 5-mm port procedure. RESULTS: In
      the randomized trial, differences were not statistically significant. However, on
      the average, the group with three 5-mm ports required less medication over less
      time, had less postoperative pain, and took less time to return to activity than
      the second group with larger ports. A statistically significant difference was
      found in incisional pain between the smaller group (21 patients) with two 10-mm
      ports and one 5-mm port and the larger group (100 patients) with three 5-mm
      ports, whether the measure was overall incisional pain (p = 0.014) or a
      comparison based on specific ports (p = 0.001). The percentage of cases requiring
      port enlargement to remove the gallbladder was not significantly different
      between the groups. There were no conversions to an open procedure, no fourth
      trocars added, and no complications. No patient required overnight
      hospitalization. CONCLUSIONS: Reducing the number and size of ports in
      laparoscopic cholecystectomy sustains or enhances the improvements initiated by
      performing laparoscopic rather than open cholecystectomy. In a comparison of
      microlaparoscopic procedures, patients undergoing the procedure with the shorter
      incisions experienced significantly less pain.

PMID- 10653233
TI  - Cost containment and totally extraperitoneal laparoscopic herniorrhaphy.
AB  - BACKGROUND: Surgeons who favor the laparoscopic repair of groin hernias are under
      pressure to contain the additional hospital costs associated with this technique,
      which is not universally acknowledged to be superior to less expensive open
      repairs. The purpose of this study was to compare costs and quality for TEP
      (total extraperitoneal) herniorrhaphy performed with and without balloon
      dissection and disposable cannulas. METHODS: We studied 92 TEP patients. The
      first 36 patients (group 1) were repaired using balloon dissection and disposable
      cannulas. The next 37 patients (group 2) were repaired with nondisposable access
      cannulas, without balloon dissection and with disposable working ports. The final
      19 patients (group 3) were repaired just as in group 2 except that all cannulas
      were nondisposable. RESULTS: The demographic data and complications were
      comparable for all three groups. The average hospital cost per case for group 1
      procedures was $2,099; for group 2, it was $1,920; and for group 3, it was
      $1,607. Costs for patients decreased comparably but for different reasons. Also
      reviewed were 20 patients who underwent Lichtenstein repairs during the study
      period. The average hospital cost for these repairs was $1,556. This group was
      not randomized with TEP groups, and the selection criteria were different; hence,
      data comparing the Lichtenstein and TEP procedures were not analyzed
      statistically. CONCLUSION: Costs can be significantly reduced and quality
      maintained when performing TEP herniorrhaphy without balloon dissection using
      nondisposable cannulas.

PMID- 10653234
TI  - Influence of CO2 pneumoperitoneum during laparoscopic surgery on cancer cell
      growth.
AB  - BACKGROUND: CO2 pneumoperitoneum provides a new surgical environment to treat
      malignant disease. The purpose of this study was to investigate the influence of
      CO2 pneumoperitoneum during laparoscopic surgery on cancer cell growth. METHODS:
      WiDr human colon cancer cells were incubated for 3 h under the following two
      conditions: 100% CO2 at 10 mmHg, and 95% air/5% CO2 (control). Cell proliferation
      was assessed by the WST-1 assay and BrdU assay. Tumor growth was assessed by
      subcutaneous injection into 20 nude mice. Cellular damage was measured by lactate
      dehydrogenase (LDH) assay. RESULTS: The number of WiDr cells under
      pneumoperitoneal conditions decreased in the first 24 h. However, no significant
      difference was observed in the proliferation rate and tumor growth of the viable
      cells. LDH release of the CO2 pneumoperitoneal group was higher than that of the
      controls. CONCLUSIONS: Our data indicate that CO2 pneumoperitoneum does not
      promote cancer cell proliferation but instead has a toxic effect on cancer cells.

PMID- 10653235
TI  - Endosonographic examination of gastrointestinal anastomoses with suspected
      locoregional tumor recurrence.
AB  - BACKGROUND: Endoscopic ultrasound is considered one of the best tools for the
      preoperative staging of esophageal, gastric, and rectal carcinoma. Depending on
      the individual investigator, the sensitivity of preoperative tumor staging by
      endosonography of the upper gastrointestinal tract (GEUS) is 80-92% for gastric
      carcinoma and 86-95% for esophageal carcinoma. However, the sensitivity and
      specificity of endosonography for the staging of lymph node metastases is less
      accurate. The accuracy of rectal endosonography (REUS) is approximately 90% for
      tumor assessment and approximately 80% for the detection of lymph node
      metastases. In this study, we address the question of whether endosonography
      enables the surgeon to distinguish scar tissue, which is rather homogeneous and
      echo-rich, from changes such as an anastomositis or a locoregional tumor
      recurrence, which are typically non-inhomogeneous and echo-poor. METHODS: During
      a 24-months period, we studied patients enrolled in a special tumor follow-up
      care program by either upper gastrointestinal (GEUS, n = 37 patients) or rectal
      endosonography (REUS, n = 49 patients) for exclusion of a locoregional tumor
      recurrence. In each patient, local tumor recurrence was suspected because of
      either medical history, clinical examination, or other diagnostic procedures.
      RESULTS: As in previous studies, our retrospective analysis revealed that
      endosonography has a high sensitivity in the detection of local tumor recurrences
      (>90%) for both GEUS and REUS. CONCLUSION: Endosonography is a highly accurate
      means of detecting local tumor recurrence.

PMID- 10653236
TI  - Feasibility of therapeutic pneumoperitoneum in a large animal model using a
      microvaporisator.
AB  - BACKGROUND: Multimodal therapy is used increasingly in advanced gastrointestinal
      tumors. Potential benefits of using an intraoperative adjuvant therapy during
      laparoscopy for cancer have been documented in animal studies. The aim of this
      study was to develop a device that could deliver such an intraoperative drug
      therapy. METHODS: We developed a micropump suitable for minimally invasive
      surgery procedures that allowed microdroplets of therapeutic substance to be
      distributed into the pneumoperitoneum (CO2), creating a "therapeutic
      pneumoperitoneum." A closed-loop control system regulates drug delivery according
      to the gas flow. In vitro, the micropump is able to aerosolize various aqueous
      and ethanol solutions, including cytostatic and bacteriostatic drugs and adhesion
      modulating agents. The size of the microdroplets has been optimized to prevent
      visual artifacts. RESULTS: The micropump was tested in an animal model (pig). The
      system was inserted into a 5-mm trocar. After insufflation of a 12-mm CO2
      pneumoperitoneum, laparoscopic sigmoid colon resections could be performed with
      no special difficulties. No fog developed, and no system-related complication was
      observed. At autopsy, the active principle was distributed to all exposed
      peritoneal surfaces. CONCLUSIONS: As opposed to conventional peritoneal washing,
      therapeutic pneumoperitoneum reaches the entire peritoneal surface, allowing an
      optimal drug distribution. Drug diffusion into the tissues is enhanced by the
      intraperitoneal pressure. Precise determination of the instantaneous and total
      drug quantity is possible. Therefore, this drug delivery system has several
      advantages over conventional irrigation. Its potential domains of application are
      locoregional cancer therapy, prevention of port-site recurrences,
      immunomodulation, analgesia, peritonitis, and prevention of postoperative
      adhesions.

PMID- 10653238
TI  - Long-term results after laparoscopic unroofing of solitary symptomatic congenital
      liver cysts.
AB  - BACKGROUND: Reports about laparoscopic management of symptomatic nonparasitic
      liver cysts are increasing, proving the procedure feasible and safe. However,
      late results of endoscopic unroofing currently are not available. The primary aim
      of the study was to offer long-term results with a follow-up of more than 5
      years. Two diagnostic pitfalls are presented. METHODS: Preoperatively, diagnosis
      was established by sonography, computed tomography (CT) scan, echinococcus
      serology, and tumor-marker measurement. The outcome of 12 laparoscopic
      fenestrations in 11 patients with symptomatic solitary liver cysts is presented.
      Nine patients were reexamined after a median observation time of 3.1 years
      (range, 0.6-6.4 years) by clinical investigation and ultrasonography, CT scan, or
      magnetic resonance imaging (MRI), respectively. RESULTS: All operations could be
      finished laparoscopically, and no death occurred. Simultaneous cholecystectomy
      was performed in six cases. All patients experienced immediate relief of
      symptoms. Postoperatively, no complications were observed except one patient with
      unilateral brachial vein thrombosis. Histologically, we discovered one hydatide
      cyst and one cystadenoma underlying the cystic disorder leading to further
      therapy. At follow-up, one of the remaining seven patients (14.3%) suffered
      symptomatic recurrence and successfully underwent reoperation endoscopically.
      CONCLUSIONS: The results of this study confirm the outcome reported previously
      after short- and intermediate-term follow-up showing that laparoscopic management
      of symptomatic solitary nonparasitic liver cysts is permanently successful in a
      large majority of cases when diagnosis is correct.

PMID- 10653237
TI  - Laparoscopic closure of perforated duodenal ulcer.
AB  - BACKGROUND: Medical treatment of peptic ulcer is highly successful, and the
      eradication of Helicobacter pylori (H. pylori) reduces ulcer recurrence. However,
      the incidence of perforated duodenal ulcer and its associated mortality have not
      been reduced by modern methods of therapy. Laparoscopic simple closure and
      omental plug by suturing, fibrin glue, and stapler have been successful. METHODS:
      Over a 1-year period (1996-97), 21 patients with perforated duodenal ulcer were
      operated on in our hospital by laparoscopic simple closure and omental patch. The
      mean age was 36.4 +/- 11.8 years (range, 18-61). Twenty patients were male
      (93.7%). The mean duration of pain was 9.1 +/- 11.7 hs (range, 2-48). Three
      patients had a previous history of duodenal ulcer (14.3%), and another three
      (14.3%) patients had a history of nonsteroidal antiinflammatory drug (NSAID)
      intake. Erect chest radiograph showed that 19 patients had air under the
      diaphragm (90.5%). Sixteen patients (76.2%) had frank pus in the abdomen, and
      five patients had a minimal peritoneal reaction (23.8%). RESULTS: The mean
      operative time was 71.6 +/- 24.6 mins (range, 40-120), and the mean hospital stay
      was 5.2 +/- 1.6 days (range, 3-9). The mean time to resume oral fluids was 3.1 +/
      0.8 days (range, 2-4). Only one patient was reoperated due to leakage identified
      by gastrographin swallow. CONCLUSIONS: This procedure is safe and efficient;
      however, further study of its long-term effectiveness and comparability to
      existing therapy is still needed.

PMID- 10653239
TI  - Newly designed retraction devices for intestine control during laparoscopic
      aortic surgery: a comparative study in an animal model.
AB  - BACKGROUND: Recent clinical studies have demonstrated the feasibility of
      laparoscopic surgery for aortic occlusive and aneurysmal disease. However,
      transperitoneal aortic access is compromised by poor exposure in the operative
      field from uncontrolled bowel. The retractors that are currently available are
      inadequate for this task. The development of new retractors would help to
      facilitate laparoscopic aortic surgery. METHODS: Six female piglets (28-30 kg) in
      each group underwent laparoscopy with pneumoperitoneum (12 mmHg). Exposure of the
      infrarenal aorta and cross-clamping were undertaken through a transperitoneal
      approach. Two paddles inserted in a polyester bilayer (mobile device, group A) or
      a mesh net fixed to the abdominal wall (fixed device, group B) were used to
      retain the bowel. Aortotomy and suturing were performed to mimic a vascular
      procedure. After bleeding was controlled, the intraabdominal pressure (IAP) was
      lowered to 6 mmHg, and retraction was assessed for 30 min. The main outcome
      measures were time to deploy the retractors, time to perform the vascular
      procedure, time to withdraw the devices, and total procedural time. Blood loss
      and frequency of retraction failure were also recorded. RESULTS: Mean time to
      deploy the device was 22 +/- 12 min in group A and 36 +/- 34 min in group B
      (n.s.). Vascular surgery time averaged 60 +/- 24 min in group A and 68 +/- 16 min
      in group B (n.s.). The times to withdraw the nets were 3.6 +/- 1.2 min and 13.5
      +/- 8.2 min, respectively (p < 0.05). Total surgery time was 155 +/- 41 min vs
      174 +/- 49 min (n.s.). There were six retraction failures, five in group A and
      one in group B. When lower IAP was used, there was only one failure in each study
      group. Mean blood loss was <150 ml in both groups. There were no major
      complications. CONCLUSIONS: Both methods provided adequate exposure of the
      infrarenal aorta. Vascular surgery time and blood loss were similar for both
      groups. The movable device proved more usable and, at lower IAP, more effective.
      The results of this study demonstrate effective bowel retraction for laparoscopic
      aortic surgery.

PMID- 10653240
TI  - Laparoscopic-assisted abdominoperineal resection for low rectal adenocarcinoma.
AB  - BACKGROUND: Laparoscopic-assisted resection for colorectal lesions is feasible,
      but most reported series are heterogeneous and noncomparative. The aim of this
      study was to investigate whether laparoscopic-assisted resection was better than
      open abdominoperineal resection for low rectal adenocarcinoma. METHODS: Twenty
      five (study group) of 59 consecutive patients who were considered suitable were
      selected for laparoscopic-assisted abdominoperineal resection based on the
      availability of informed consent, laparoscopic instruments, and experienced
      surgeons. The results in these patients were compared with the other 34 patients
      operated on by the open method (control group). RESULTS: The median follow-up
      times for the study and control groups were 30.1 and 28.3 months, respectively.
      The operation time was significantly longer (t-test, p < 0.001), while operative
      blood loss (Mann-Whitney U test, p = 0.02), postoperative analgesic requirement
      (Mann-Whitney U test, p = 0.02), time to resume normal diet (Mann-Whitney U test,
      p = 0.04), and total hospital stay (Mann-Whitney U test, p = 0.02) were
      significantly less in the study than in the control group. The oncological
      clearance, complication rate, disease-free interval, and survival were comparable
      in the two groups. CONCLUSIONS: Laparoscopic-assisted abdominoperineal resection
      allowed earlier postoperative recovery, with equal oncological clearance,
      morbidity, mortality, disease-free interval, and survival.

PMID- 10653241
TI  - The effect of high-definition imaging on surgical task efficiency in minimally
      invasive surgery: an experimental comparison between three-dimensional imaging
      and direct vision through a stereoscopic TEM rectoscope.
AB  - BACKGROUND: In 1995, when we first used a high-definition television (HDTV) video
      system during a laparoscopic cholecystectomy in Tuebingen, we were surprised by
      the excellence of the spatial impression achieved by an image with improved
      resolution. Although any improvement in vision systems entails a trade-off among
      cost, quality, and complexity, high-definition imaging may well become an
      essential part of 3-D video systems. The aim of this experimental study was to
      assess the impact of high definition on surgical task efficiency in minimally
      invasive surgery and to determine whether it is preferable to use a 3-D system or
      a 2-D system with perfect resolution and color--for instance, HDTV or the three
      chip charge-coupled device (3CCD). METHODS: We compared a 3-D video system with
      the vision through a stereoscopic rectoscope for transanal endoscopic
      microsurgery (TEM). Because its stereoscopic direct vision is not restricted to
      either shutter technology or video resolution, TEM optics represents the state of
      the art. For objective comparison, inanimate phantom models with suturing tasks
      were set up. The setups allowed the approach of parallel instruments as in TEM
      operations or via a laparoscopic approach, with oblique instruments coming
      laterally. Both types of procedure were carried out by highly experienced
      laparoscopic surgeons as well as those inexperienced in endoscopic surgery. These
      volunteers worked under 3-D video vision and/or TEM vision. Altogether, the model
      tasks were performed by 54 different persons. RESULTS: The evaluation did not
      show a significant (p > 0.05) difference in performance time in all models, but
      there was a clear trend showing the benefit of a higher resolution. CONCLUSION:
      We found a tendency for both endoscopically inexperienced and experienced
      surgeons to benefit from the use of a system with improved resolution (direct
      vision) rather than a 3-D shutter video system.

PMID- 10653242
TI  - Four-year experience with pleural abrasion using a rotating brush during video
      assisted thoracoscopy.
AB  - BACKGROUND: Due to the high recurrence rate in primary spontaneous pneumothorax
      (PSP), surgical therapy is currently a well-accepted method of treating this
      condition. There is no general agreement about the best time for surgical
      intervention (i.e., after the first or second episode) or the optimal surgical
      approach,--i.e., tube thoracocenteses, thoracotomy, or video-assisted
      thoracoscopy (VATS) with or without pleurectomy or pleurodesis. The aim of this
      study was to verify the efficacy of VATS and mechanical brush pleurodesis using a
      rotating electrical brush system. METHODS: We treated 47 patients with PSP
      between June 1993 and June 1997. Follow-up ranged from 20 to 56 months. There
      were 38 male and nine female patients with a mean age of 26 years. Emergency
      thoracocenteses due to tension pneumothorax became necessary in three patients.
      All patients were treated by VATS and mechanical brush pleurodesis. Wedge
      resection was done if bullae or blebs were present (68.1%). RESULTS: Operating
      time was 20-60 min (mean, 35). There were no intraoperative complications and no
      conversions to conventional surgery. In the first few postoperative days,
      postoperative pain was controlled with nonsteroidal antirheumatic drugs and
      additional morphines. Drainage time was 3-7 days (mean, 4). Hospitalization time
      was 4-8 days (mean, 5). The recurrence rate was 2.1% (one patient). No
      postoperative bleeding or wound infection occurred in any of our patients.
      CONCLUSIONS: VATS combined with mechanical brush pleurodesis using the electrical
      brush system is a highly effective and safe treatment for patients with recurrent
      primary spontaneous pneumothorax.

PMID- 10653243
TI  - Subjective evaluation of the therapeutic value of laparoscopic adhesiolysis: a
      retrospective analysis.
AB  - BACKGROUND: Adhesions are believed to be one of the principal causes of chronic
      pelvic pain. Although there may be some discrepancy between the degree of
      adhesions and the severity of the symptoms, surgical adhesiolysis is still
      considered to be useful for the relief of pain. METHODS: A total of 187 patients
      who underwent laparoscopic adhesiolysis at the Medical University of Ulm,
      Germany, within a 2-year period were asked to rank their discomfort on a visual
      pain scale before surgery and up to 1 1/2 years postoperatively. RESULTS: In this
      retrospective study, we found that nearly one-third of patients suffered from
      functional irritations that were either ameliorated or completely relieved by
      laparoscopic adhesiolysis. When other causes of chronic pain (such as
      endometriosis) are excluded, the results show that most patients benefited from
      laparoscopic adhesiolysis. CONCLUSIONS: It appears that laparoscopic adhesiolysis
      is an effective therapeutic measure to relieve chronic pelvic pain. Therefore,
      adhesiolysis should be performed in all patients with chronic or intermittent
      pain, and a complete lysis of adhesions should be planned. However, since pelvic
      pain may have organic or functional causes other than adhesions, complete
      adhesiolysis in patients with persistent pelvic pain may be of only limited
      importance.

PMID- 10653245
TI  - Visual identification of the cystic duct-CBD junction during laparoscopic
      cholecystectomy (visual cholangiography): an additional step for prevention of
      CBD injuries.
AB  - Despite advances in technical skills, common bile duct (CBD) injury during
      laparoscopic cholecystectomy is not an uncommon major complication. We describe a
      technical step that can be taken during the dissection of the triangle of Calot
      to allow the junction between the cystic duct and CBD to be clearly visualized.
      This is a safe and simple maneuver that mimics the one done in open surgery. Its
      routine application serves as an additional safety measure to prevent injury to
      the common bile duct.

PMID- 10653244
TI  - Ultrasonic coagulator for video-assisted internal mammary artery harvest.
AB  - BACKGROUND: The Harmonic Scalpel (HS; Ethicon Endo-Surgery, Cincinnati, OH, USA)
      is an ultrasonic coagulator that generates less heat than electrocautery. We
      compared canine internal mammary arteries (IMAs) harvested using the HS or
      electrocautery and reviewed the early clinical outcome after thoracoscopic IMA
      takedown with the HS. METHODS: Using HS and bipolar electrocautery (BE), 51 and
      49 IMA branches, respectively, in six mongrel dogs were divided. The divided
      branches were subjected to a pressure tolerance test. The impact of coagulation
      on the main trunk was investigated microscopically. Thoracoscopic IMA harvesting
      with the HS was performed in 41 patients. Seven human IMA segments including 10
      branches were examined microscopically. Postoperative angiography of 40 IMA
      grafts (97.6%) was performed. RESULTS: All the IMA branches withstood
      intraluminal pressures up to 250 mmHg. With BE, coagulation reached the
      adventitia of the main trunk in six segments (12.2%), but the HS caused no
      injury. Thoracoscopic IMA harvesting with excellent hemostasis was achieved using
      only the HS in all 41 patients. The main trunks of the human IMA segments were
      microscopically intact, and postoperative angiography demonstrated that the IMA
      grafts were intact. CONCLUSION: The HS appears to be a reliable coagulator for
      thoracoscopic IMA harvesting with minimal damage.

PMID- 10653246
TI  - The Vale knot: an intracorporeal slipknot.
AB  - Mastering intracorporeal ligation and suturing is an essential skill for the
      performance of most advanced endoscopic surgical procedures. Although many
      disposable instruments have become available for various tasks necessitating the
      construction of sutures and knots; issues of performance, safety, and cost
      efficiency remain to be settled. The authors believe that training should aim at
      the development of manual skills that could realize the clinical and cost
      efficiency benefits of using conventional surgical tasks in the endoscopic
      setting.

PMID- 10653247
TI  - Subfascial hemorrhage after endoscopic perforator vein ligation: control with
      balloon tamponade.

PMID- 10653248
TI  - Intraoperative cholangiography and bile duct injury in laparoscopic
      cholecystectomy.

PMID- 10653249
TI  - Bile leakage resulting from clip displacement of the cystic duct stump.

PMID- 10653250
TI  - A new anomaly at the center of the heart?

PMID- 10653251
TI  - Is there another type of biventricular atrioventricular connection?
AB  - In evaluating a 9-year-old girl, we encountered the following cardiac anomalies:
      a left atrioventricular valve (the morphologic left atrium on the left side,
      connected with the morphologic left ventricle); concordant atrioventricular
      connections; a right atrioventricular valve (a morphologic right atrium on the
      right side, connected with the morphologic right ventricle); concordant
      atrioventricular connection; a "central" atrioventricular valve (separating the
      morphologic right atrium from the morphologic left ventricle); and discordant
      atrioventricular connection with intact interatrial and interventricular septa. A
      right-to-left shunt passed through the central valvular structure, which was
      situated at the atrioventricular septum. This was the only means of mixing
      pulmonary and systemic blood. We suggest that this case presents a newly
      recognized cardiac anomaly.

PMID- 10653252
TI  - Cardiac arrhythmia at high altitude: the progressive effect of aging.
AB  - To evaluate the effects of aging on cardiac rhythm at high altitude, I wore a
      Holter monitor at age 75 during a climb to 5,100 m on Mt. Kilimanjaro, then
      compared findings with those from my climb to 5,895 m at age 65. Holter leads
      were placed to identify left or right ventricular source of ectopy, and on the
      2nd ascent arterial oxygen saturation was monitored by finger oximetry. Sea-level
      testing revealed no evidence of cardiac disease. During ascent from 4,710 to
      5,100 m, when arterial oxygen saturation reached 70%, heart rate was higher (123
      vs 116 beats per minute), and frequency of left ventricular premature complexes
      was greater (56 vs 50 per hour) than on the earlier ascent. Nine 3- to 5-complex
      runs of left ventricular tachycardia were recorded during climbing, resting, or
      sleeping, and there was 1 run of 14 complexes at 250 beats per minute during the
      climb near 5,100 m. These observations suggest that aging increases sympathetic
      response or sensitivity, or both, to hypoxia during exercise, and even during
      sleep. Also, our focus should perhaps be on sympathetic stimulation rather than
      on pulmonary hypertension as a cause of arrhythmia in unacclimatized older
      persons at high altitude.

PMID- 10653253
TI  - Proximal clamping levels in abdominal aortic aneurysm surgery.
AB  - In the surgical treatment of abdominal aortic aneurysm, the single proximal cross
      clamp can be placed at 3 alternative aortic levels: infrarenal, hiatal, and
      thoracic. We performed this retrospective study to evaluate the advantages and
      disadvantages of the 3 main aortic clamping locations. Eighty patients presented
      at our institution with abdominal aortic aneurysms from March 1993 through May
      1998. Fifty of these patients had intact aneurysms and underwent elective
      surgery, and 30 had ruptured aneurysms that necessitated emergency surgery.
      Proximal aortic clamping was applied at the infrarenal level in 24 patients (22
      from the intact aneurysm group, 2 from the ruptured group), at the hiatal level
      in 34 patients (22 intact, 12 ruptured), and at the thoracic level (descending
      aorta) via a limited left lateral thoracotomy in 22 patients (6 intact, 16
      ruptured). Early mortality rates (within 30 days) were 4% (2 of 50 patients)
      among patients with intact aneurysms and 40% (12 of 30 patients) among those with
      ruptured aneurysms. In the 2 patients from the intact aneurysm group, proximal
      aortic clamps were applied at the hiatal level. In the ruptured aneurysm group,
      proximal aortic clamps were placed at the thoracic level in 10 patients, the
      infrarenal level in 1, and the hiatal level in 1. According to our study, the
      clinical status of the patient and the degree of operative urgency--as determined
      by the extent of the aneurysm--generally dictate the proximal clamp location.
      Patients who present with aneurysmal rupture or hypovolemic shock benefit from
      thoracic clamping, because it restores the blood pressure and allows time to
      replace the volume deficit. Infrarenal placement is advantageous in patients with
      intact aneurysms if there is sufficient space for the clamp between the renal
      arteries and the aortic aneurysm. In patients with juxtarenal aneurysms, hiatal
      clamping enables safe and easy anastomosis to the healthy aorta. Clamping at this
      level also helps prevent late anastomotic aneurysm formation, which is frequently
      encountered after inadvertent anastomosis of the graft to a diseased portion of
      the aorta. Further studies are needed in order to confirm these results.

PMID- 10653254
TI  - Minimally invasive closed mitral commissurotomy.
AB  - Today, technical advances have decreased the risk of cardiopulmonary bypass to
      the point that closed mitral commissurotomy is performed infrequently in most
      cardiac centers and is considered hazardous. We describe a modified technique for
      closed mitral commissurotomy, improved in terms of safety and efficacy, and
      adapted for situations in which resources are limited. This operation was
      performed in 12 symptomatic patients with severe mitral stenosis whose valves
      were judged suitable for closed mitral commissurotomy or balloon valvuloplasty.
      After modified closed commissurotomy, the mitral valve areas of these patients
      were increased substantially, from 1.8 to 3.1 cm2. There was no new incidence of
      mitral regurgitation. We conclude that closed mitral commissurotomy is a safe
      alternative to open mitral commissurotomy, provided that patient selection
      criteria are strictly followed.

PMID- 10653255
TI  - Cyanoacrylate glue as an alternative to an additional suture line in the repair
      of type A aortic dissection.
AB  - We describe the use of cyanoacrylate glue in conjunction with gelatin-resorcinol
      formalin glue for the treatment of type A aortic dissection. Instead of placing
      an additional suture line 2-3 cm from the edges of the aortic stumps to create a
      large pocket for gluing, we have been using a cyanoacrylate adhesive for
      approximating the walls of the true and false lumina without the risk of tearing
      them. Moreover, the simplicity and quickness of the procedure enables application
      of the cyanoacrylate glue even deeper into the aortic arch, creating a wider area
      for gluing the dissected layers.

PMID- 10653256
TI  - Technical aspects of implanting the St. Jude Toronto stentless porcine valve.
AB  - Stentless xenograft aortic valves were designed to provide superior hemodynamic
      characteristics and durability, in comparison with stented tissue valves. The
      senior author (MJR) has implanted 46 St. Jude Toronto stentless porcine valves-
      with excellent hemodynamic results and no aortic insufficiency--since this valve
      was released by the Food and Drug Administration in November 1997. Because the
      implantation technique is significantly different from that of implanting a
      stented valve, and because proper implantation is critical for proper valve
      function and avoidance of aortic insufficiency, we discuss our technique in some
      detail.

PMID- 10653257
TI  - Sickle cell disease and aortic valve replacement: use of cardiopulmonary bypass,
      partial exchange transfusion, platelet sequestration, and continuous
      hemofiltration.
AB  - Sickle cell disease in patients undergoing open heart procedures presents a
      multitude of challenges to the medical staff. With improved techniques of
      cardiopulmonary bypass, surgery, and anesthesia for treating patients with sickle
      cell disease, perfusionists will likely encounter patients with this genetic
      disorder on a more frequent basis. A 40-year-old black woman was admitted to our
      institution with recurrent Staphylococcus epidermidis and sepsis. She underwent
      transesophageal echocardiography and cardiac catheterization and was subsequently
      diagnosed with severe aortic insufficiency. The aortic valve was replaced.
      Herein, we report our experience in the preoperative, perioperative, and
      postoperative management of this patient. We present a concise update on the
      current literature and techniques used by others in similar cases, and we provide
      a brief section on future considerations to assist fellow practitioners in
      recognizing this disease and meeting the accompanying challenges.

PMID- 10653258
TI  - Coronary artery bypass and superior vena cava syndrome.
AB  - Superior vena cava syndrome is the obstruction of the superior vena cava or its
      main tributaries by benign or malignant lesions. The syndrome causes edema and
      engorgement of the vessels on the face, neck, and arms, nonproductive cough, and
      dyspnea. We discuss the case of a 48-year-old obese diabetic woman who was
      admitted with unstable angina. She had previously been diagnosed with superior
      vena cava syndrome. Urgent coronary artery bypass grafting was necessary Although
      thousands of coronary artery bypasses are performed every year, there are not
      many reports on patients with superior vena cava syndrome who successfully
      undergo cardiopulmonary bypass and coronary artery grafting with an internal
      mammary artery as the conduit. The results of the case and alternative
      recommended methods are discussed.

PMID- 10653259
TI  - Alternative surgical management of post-infarction septal rupture: a case report.
AB  - Weaning a patient from cardiopulmonary bypass after repair of a postinfarction
      ventricular septal defect in the face of severe right ventricular failure is
      likely to be fatal. The use of a ventricular assist device may seem to be the
      only available option. We present an alternative surgical approach that we
      carried out in a 72-year-old woman. The right ventricular preload was decreased
      by adding a bidirectional cavopulmonary anastomosis to the septal rupture repair.

PMID- 10653260
TI  - Left ventricular rupture after mitral valve replacement in a patient with
      osteogenesis imperfecta tarda.
AB  - We describe the case of a patient with osteogenesis imperfecta tarda (Lobstein's
      syndrome) and mitral valve insufficiency. The course after mitral valve
      replacement was complicated by rupture of the left ventricular posterior wall,
      which caused massive bleeding and sudden death. The pathologic findings and the
      operative problems are discussed.

PMID- 10653261
TI  - Cardiac valvular papillary fibroelastoma: a report of 2 cases.
AB  - Papillary fibroelastomas are rare cardiac valve tumors with potential for life
      threatening complications such as stroke or sudden death. We report 2 cases of
      papillary fibroelastoma that were found by echocardiography. The 1st tumor arose
      from the mitral valve in a patient who presented after multiple transient
      neurologic events. The 2nd tumor arose from the aortic valve and was found
      incidentally during coronary artery bypass grafting. Both patients underwent
      successful surgical removal of the tumor.

PMID- 10653262
TI  - Embolization of Gianturco coil into the pulmonary artery requiring emergency
      surgical intervention.
AB  - We report the case of a 20-month-old girl who underwent Gianturco coil
      embolization to a patent ductus arteriosus in May 1997. The coil migrated to the
      pulmonary artery. After unsuccessful attempts to retrieve it with snares and
      forceps, we engaged the coil with an end-hole balloon catheter and pulled it down
      to the right ventricle. There it became entangled in the tricuspid valvular
      apparatus and could not be moved farther. Due to concerns about sequelae, the
      patient was referred for surgery. Following a mid-sternotomy under
      cardiopulmonary bypass, we removed the coil and ligated the patent ductus
      arteriosus. The patient made an uneventful recovery. A brief review of the
      literature is presented.

PMID- 10653263
TI  - Late patency of recycled internal mammary artery: verification by Doppler
      echocardiography and coronary angiography.
AB  - We report the case of a 57-year-old man who had presented with exertional angina
      early in 1997 and had subsequently undergone myocardial revascularization with
      the use of both internal mammary arteries. Two months after surgery, the patient
      was readmitted to the hospital with unstable angina. Coronary angiography
      revealed a 90% occlusion of the left internal mammary artery anastomosis, which
      was attached to the left anterior descending coronary artery. At reoperation, the
      left internal mammary artery was detached from the left anterior descending
      coronary artery, probed and injected with papaverine, checked for patency, and
      regrafted to the same coronary artery. Recycling of the left internal mammary
      artery was facilitated by the harvesting and routing technique that had been used
      during the previous operation. At the patient's 1-year follow-up visit, both
      Doppler echocardiography and coronary angiography showed patency of the recycled
      graft. We conclude that recycling of the left internal mammary artery is a safe
      and effective option in selected patients who require reoperation after
      myocardial revascularization.

PMID- 10653264
TI  - Hypoxia due to patent foramen ovale in the absence of pulmonary hypertension.
AB  - In most patients with a patent foramen ovale, blood flows from the left atrium to
      the right atrium in the absence of pulmonary hypertension. Our report describes a
      patient with a patent foramen ovale in whom flow occurred from the right atrium
      to the left atrium in the absence of pulmonary hypertension. We discuss
      hemodynamic findings and present a brief review of the pertinent medical
      literature regarding this phenomenon. We also discuss the role of transesophageal
      echocardiography in the diagnosis of this condition and in the elucidation of the
      underlying mechanisms, and we suggest several mechanisms that may explain the
      occurrence of this phenomenon in our patient.

PMID- 10653265
TI  - Pseudoaneurysm of the left ventricle: a rare sequela to mitral valve
      endocarditis.
AB  - Pseudoaneurysms of the left ventricle are a very unusual sequela to mitral valve
      endocarditis. We report the case of a 62-year-old woman who developed
      postendocarditis submitral left-ventricular pseudoaneurysm, which was diagnosed
      by means of transesophageal echocardiography. The mitral valve was replaced with
      a prosthesis, and the mouth of the pseudoaneurysm was closed with a patch. We
      discuss the possible mechanism of development of this unusual sequela to mitral
      valve endocarditis and emphasize the diagnostic value of transesophageal
      echocardiography.

PMID- 10653267
TI  - Six-year survival of unoperated ventricular septal rupture following myocardial
      infarction.
AB  - We present the case of a patient who survived for 6 years without surgical repair
      of a ventricular septal rupture that followed an acute myocardial infarction. To
      the best of our knowledge, only 3 other cases have been reported in which the
      patient survived for more than 5 years.

PMID- 10653266
TI  - Posttraumatic infrarenal abdominal aortic pseudoaneurysm.
AB  - Posttraumatic abdominal aortic pseudoaneurysm is a rare lesion. To date, fewer
      than 30 cases have been reported in the literature, with most of those cases
      involving the suprarenal aorta. Infrarenal posttraumatic abdominal aortic
      pseudoaneurysm following abdominal trauma has been reported in only 6 other
      cases. We observed such a lesion in a 62-year-old man 15 years after blunt
      abdominal trauma inflicted in a car accident. Back pain was the presenting
      symptom. Resection and Dacron graft interposition were performed without
      postoperative morbidity.

PMID- 10653268
TI  - Odynophagia in a woman with known coronary artery disease and ischemia on
      electrocardiogram.
AB  - Esophageal intramural hematoma can mimic other causes of chest pain. When the
      patient is known to have coronary artery disease, the diagnosis may be difficult.
      Moreover, the course may be complicated and may harm the patient if antiplatelet
      drugs, thrombolytics, and anticoagulants are used. The presence of odynophagia
      should alert the clinician to the possibility of an esophageal origin, even in a
      patient with known coronary artery disease. We present a case in which early
      recognition of the clinical presentation prevented potential iatrogenic
      complications.

PMID- 10653270
TI  - Abnormal blood lipids. Foreword

PMID- 10653269
TI  - Large inferoposterior wall pseudoaneurysm of the left ventricle with a thrombus
      after myocardial infarction.

PMID- 10653271
TI  - Primary and secondary prevention using lipid-lowering therapies.
AB  - The observation that coronary heart disease was greatest in those individuals
      with the highest cholesterol levels resulted in the development of interventions
      to lower cholesterol to improve coronary risk status. Some individuals will
      achieve target lipid levels with diet and lifestyle modification alone.
      Therefore, diet and lifestyle modification is the preferred initial treatment.
      For more aggressive management of those who do not respond to diet and lifestyle
      modification or who have documented coronary heart disease, lipid-lowering drugs,
      extensively tested in large, multicenter, randomized clinical trials are
      preferred. Initially, questions arose about adverse effects of lipid-lowering
      drugs, but continued use has demonstrated that these drugs are both safe and
      efficacious. The need remains, however, for clinicians to monitor each patient's
      response to lipid-lowering diets, lifestyle modification efforts, and drugs and
      evaluate whether beneficial effects outweigh the cost and potential for adverse
      effects.

PMID- 10653272
TI  - Pharmacology department: pharmacologic approaches to abnormal blood lipids.
AB  - There are currently four classes of drugs available to treat dyslipidemia:
      niacin, bile acid-binding resins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)
      reductase inhibitors, and fibric acid derivatives. Each acts at a unique point in
      a complex set of interrelated lipid metabolic pathways. The mechanism of action
      and adverse effects of these four classes are reviewed briefly. The efficacy of
      antioxidants and the importance of compliance issues are described.

PMID- 10653273
TI  - Coronary risk factors: influences on the lipid profile.
AB  - Risk factors for cardiovascular disease have been defined by various groups and
      experts for decades. Unfortunately, the lack of consensus among these groups and
      the periodic changes in risk factor listings have led to confusion among health
      care professionals. Because so many risk factors inter-relate, it is difficult to
      isolate the effect of a specific risk factor on the lipid profile. In an effort
      to eliminate some of the confusion, this article describes the known effects of
      physical inactivity, obesity, cigarette smoking, age, hypertension, and diabetes
      mellitus on lipids and lipoproteins. A summary of the known results is displayed
      in a table. Because of the complexity of the atherosclerotic disease process and
      the multifactorial influences on lipid metabolism, this remains an exciting and
      challenging area for research.

PMID- 10653274
TI  - Diet controversies in lipid therapy.
AB  - Increasing awareness of the relationship between diet and disease has prompted a
      notable increase in nutrition research. The focus of many of these studies
      continues to be on amount and type of fat in the diet. At the same time, a great
      deal of attention is being directed at other dietary components and their mode of
      action. The results are promising. More definitive answers must await future
      clinical trial data. However, the total dietary approach, including compliance
      measures, remains the foundation on which other nutrition recommendations should
      be based.

PMID- 10653275
TI  - Abnormal blood lipids: is it environment or is it genes?
AB  - Genetic and environmental factors contribute to the development and progression
      of atherosclerotic coronary heart disease processes. Major independent risk
      factors for coronary heart disease, including adverse levels of plasma lipids and
      lipoproteins, are also influenced by genetic and potentially modifiable
      environmental factors. Recent advances in molecular biology have resulted in the
      identification of specific genes associated with lipid disorders. The complex
      gene-environment interplay that contributes to interindividual variation in
      components of the lipid profile is also partially clarified. This article
      provides an overview of available data on the genetic and environmental
      influences on lipids and lipoproteins with emphasis on implications for clinical
      practice and future research.

PMID- 10653276
TI  - Cholesterol management: an opportunity for nurse case managers.
AB  - There is compelling scientific evidence that the modification of cardiovascular
      risk factors, including hypercholesterolemia, can reduce the incidence of
      myocardial infarction, effectively extend survival, decrease the need for
      interventional procedures, and improve quality of life in persons with and
      without known cardiovascular disease. Unfortunately, neither the publication of
      results from clinical trials of cholesterol lowering alone nor the 1993 National
      Cholesterol Education Program Adult Treatment Panel (NCEP-ATPII) updated
      guidelines for the treatment of hypercholesterolemia have resulted in widespread
      changes in cholesterol management and control. Systematic nurse case management
      of dyslipidemias in patients with or at high risk for the development of coronary
      heart disease has the potential to improve compliance with NCEP-ATPII guidelines.
      In cooperation with physicians, nurses have the opportunity to address a major
      public health problem with the potential to eventually affect the more than 11
      million people with coronary heart disease.

PMID- 10653277
TI  - Women, coronary heart disease, and dyslipidemia: does gender alter detection,
      evaluation, or therapy?
AB  - Gender-based differences in the prevalence, presentation, and treatment of
      coronary heart disease (CHD) defines an important area of controversy and
      research. Gender-based differences include age at onset of CHD, typical
      presentation of CHD symptoms, relative importance of coronary risk factors, and
      the potential relationship of ovarian function and estrogen status to the
      development of CHD. The American Heart Association reported in 1998 that the
      leading cause of death for American women is cardiovascular disease, with CHD
      responsible for the majority of total deaths. This article discusses the
      implication of elevated blood lipids in women. Special emphasis is placed on the
      role of hormone replacement therapy, an issue unique to women.

PMID- 10653278
TI  - Hypertriglyceridemia and low high-density lipoprotein: risks for coronary artery
      disease?
AB  - Elevated total cholesterol and LDL cholesterol have been well established as risk
      factors for coronary heart disease (CHD). Several large clinical trials have
      demonstrated that lipid lowering decreases the incidence and mortality that
      results from CHD. However, a high percentage of subjects in these studies did not
      receive benefit from LDL lowering. Many experts believe that other lipid
      disorders may play a significant role in the atherogenic process, including
      elevated triglyceride levels alone or in association with a low level of HDL. Do
      elevated triglyceride levels pose an increased risk for CHD? This article
      describes the research done evaluating this question, as well as the influences
      of lifestyle changes and pharmacologic interventions on these dyslipidemias.

PMID- 10653279
TI  - Novel risk factors for coronary heart disease: emerging connections.
AB  - In only 50% of cases of coronary heart disease (CHD) is the cause attributable to
      the established risk factors of hypertension, cigarette smoking, and elevated
      total and low-density lipoprotein (LDL) cholesterol levels. This finding has led
      to research examining other markers for CHD that may have a causal link to the
      atherothrombotic process. Several of these "emerging" risk factors are reviewed
      in this article: lipoprotein(a); small dense LDL particle size;
      hyperhomocysteinemia; and inflammatory, infectious, and hemostatic factors.
      Evaluation of each of these factors includes a review of the epidemiologic
      evidence, examination of the pathologic mechanism(s) by which the factor might
      participate in atherothrombosis, and the clinical utility of screening. Finally,
      and most relevant for the practicing clinician, the following is addressed: Does
      evidence exist that selective modification of these risk factors is associated
      with net clinical benefit?

PMID- 10653280
TI  - Biology of Alzheimer's disease.

PMID- 10653281
TI  - Genes and mechanisms involved in beta-amyloid generation and Alzheimer's disease.
AB  - Alzheimer's disease is characterized by the invariable accumulation of senile
      plaques that are predominantly composed of amyloid beta-peptide (Abeta). Abeta is
      generated by proteolytic processing of the beta-amyloid precursor protein
      (betaAPP) involving the combined action of beta- and gamma-secretase. Cleavage
      within the Abeta domain by alpha-secretase prevents Abeta generation. In some
      very rare cases of familial AD (FAD), mutations have been identified within the
      betaAPP gene. These mutations are located close to or at the cleavage sites of
      the secretases and pathologically effect betaAPP processing by increasing Abeta
      production, specifically its highly amyloidogenic 42 amino acid variant
      (Abeta42). Most of the mutations associated with FAD have been identified in the
      two presenilin (PS) genes, particularly the PS1 gene. Like the mutations
      identified within the betaAPP gene, mutations in PS1 and PS2 cause the increased
      generation of Abeta42. PS1 has been shown to be functionally involved in Notch
      signaling, a key process in cellular differentation, and in betaAPP processing. A
      gene knock out of PS1 in mice leads to an embryonic lethal phenotype similar to
      that of mice lacking Notch. In addition, absence of PS1 results in reduced gamma
      secretase cleavage and leads to an accumulation of betaAPP C-terminal fragments
      and decreased amounts of Abeta. Recent work may suggest that PS1 could be the
      gamma-secretase itself, exhibiting the properties of a novel aspartyl protease.
      Mutagenesis of either of two highly conserved intramembraneous aspartate residues
      of PS1 leads to reduced Abeta production as observed in the PS1 knockout. A
      corresponding mutation in PS2 interfered with betaAPP processing and Notch
      signaling suggesting a functional redundancy of both presenilins. In this issue,
      some of the recent work on the molecular mechanisms involved in Alzheimer's
      disease (AD) as well as novel diagnostic approaches and risk factors for AD will
      be discussed. In the first article, we like to give an overview on mechanisms
      involved in the proteolytic generation of Amyloid beta-peptide (Abeta), the major
      pathological player of this devastating disease. In the second part of this
      article recent results will be described, which demonstrate an unexpected
      biological and pathological function of an AD associated gene.

PMID- 10653282
TI  - The function of presenilin-1 in amyloid beta-peptide generation and brain
      development.
AB  - Several mutations in genes that cause the familial form of Alzheimer's Disease
      (FAD) have been identified. All mutations in the three FAD genes, i.e., amyloid
      precursor protein (APP), presenilin 1 (PS-1), and presenilin 2 (PS-2) cause an
      increased production of a longer, more amyloidogenic form of the amyloid peptide
      corroborating strongly the idea that abnormal processing of APP is central to the
      pathogenesis. In PS-1 deficient mice, 80% less amyloid peptide was produced.
      Instead, membrane associated carboxyterminal fragments generated by (alpha- and
      beta-secretase accumulated suggesting that PS-1 is involved in the gamma
      secretase activity cleaving the transmembrane domain of APP after alpha- and beta
      secretase cleavage has occured. The clinical mutations in PS-1 which increase the
      production of betaA41-42 therefore seem to cause a "selective" gain of its normal
      function. During cortical plate development in PS-1-deficient mice, neurons do
      not terminate their movement at the outer margin of the cortical plate, but enter
      the marginal zone and subarachnoid space. These focal heterotopias closely
      resemble those occuring, e.g., in human lissencephaly type II. The extracellular
      matrix of the cortical plate and marginal zone was altered as a consequence of a
      loss of Cajal-Retzius (CR) neurons from the marginal zone. The pathogenesis of
      this neuronal migration disorder is associated with a reduction and
      redistribution of notch- immunoreactivity in CR- and cortical plate neurons, a
      cell surface receptor operative in cell fate selection, which similar to APP is
      cleaved in its transmembrane domain during activation by a gamma-secretase like
      protease.

PMID- 10653283
TI  - The physiological role of presenilins in cellular differentiation: lessons from
      model organisms.
AB  - Mutations in the human presenilin genes cause the most frequent and aggressive
      forms of Alzheimer's Disease. They results in an increase of the 42 amino acid
      variant of amyloid beta peptide that rapidly aggregates into neurotoxic plaques.
      In addition, lack of presenilin activity prevents the proteolytic cleavage of the
      Notch receptor of intercellular signaling. The biological role of presenilins is
      evolutionary conserved in animals. This review summarizes recent results obtained
      from animal models to understand presenilin activity and malfunction.

PMID- 10653284
TI  - Clinical features of Alzheimer's disease.
AB  - The preclinical stage of Alzheimer's disease is inconspicuous and there are -
      almost by definition - no reliable and valid symptoms and signs which would allow
      a very early diagnosis before the manifestation of irreversible deficits. For a
      clinical diagnosis of dementia, cognitive impairment has to be severe enough to
      compromise the activities of daily living. In the mild dementia stage,
      difficulties with declarative memory are usually prominent; depressive symptoms
      are not infrequent, but the patient usually manages to live alone. Supervision is
      needed in the moderate dementia stage, when other cognitive domains are affected
      in a more obvious manner and non-cognitive disturbances of thought, perception,
      affect, and behavior put increasing stress on the caregivers. Complete dependence
      of the patients, who frequently develop neurological disturbances, is typical of
      the late stage of illness. The life expectancy of patients with a clinical
      diagnosis of Alzheimer's disease is significantly reduced, but to date there is
      hope that the period of relative well-being and not of suffering can be prolonged
      with modern symptomatic treatment interventions.

PMID- 10653285
TI  - Intracellular biology of Alzheimer's disease amyloid beta peptide.
AB  - Strong evidence links excess production of a small peptide and the pathogenesis
      of Alzheimer's disease (AD). Originally this peptide, beta-amyloid 42 (Abeta42),
      was assumed to be released by a pathogenic event; it is now well established that
      Abeta42 is released from cells during normal cellular metabolism of the Alzheimer
      amyloid precursor protein. Recently, in a series of surprising reports it was
      discovered that Abeta42 is produced intracellularly, and what might have been
      regarded first as a strange abnormality of a few selected cell lines has now been
      recognized as an important cellular pathway for Abeta production. Moreover, the
      differences between secretory and intracellular Abeta production might hold the
      clues for brain specificity and cellular mechanisms of AD pathogenesis.

PMID- 10653286
TI  - Stability of performance on neuropsychological tests in patients with
      schizophrenia.
AB  - This study evaluated the stability of performance on neuropsychological tests in
      a group of 14 schizophrenic patients. These patients were first tested as
      inpatients and later on as outpatients. The patients' results are also compared
      with matched normal controls and with standardized norms. The patients' test
      results were stable over time and no change in performance was found for the
      patients as a group, suggesting that these aspects of the patients' functioning
      were of a trait quality. The patient group had significantly poorer results on a
      majority of the tests compared with the controls. The variation of the level of
      cognitive functioning among the patients, however, was great. In clinical
      practice today, neuropsychological examinations are often included in the
      diagnostic procedure, and their results also have impact on treatment planning.
      However, the possibility to generalize the findings is reduced as a consequence
      of the low number of patients in the study.

PMID- 10653287
TI  - Corpus callosum size in schizophrenia--a magnetic resonance imaging analysis.
AB  - Previous MRI studies have shown differences in corpus callosum size between
      schizophrenic patients and controls. The corpus callosum (CC), as the main
      interhemispheric fiber tract, plays an important role in interhemispheric
      integration and communication. Though MRI studies suggest smaller CC in
      schizophrenia, there are still conflicting findings. Using in vivo magnetic
      resonance imaging, it was investigated whether the midsagittal area of CC differs
      between twenty-three right-handed male schizophrenic patients and twenty-three
      matched controls. Total CC area, five subregions of CC, total brain volume, gray
      and white matter were measured. No differences between schizophrenic patients and
      controls were found regarding all CC measurements, total brain volume, and gray
      matter tissue. However, a significant reduction of white matter tissue in the
      patient group emerged. There was no correlation between CC morphology and
      clinical variables such as age of onset, length of illness or symptom severity.
      Interestingly, five schizophrenic patients with a positive family history of
      schizophrenia showed significant reduction of the subregion C3, associated with a
      reduced total brain and gray and white matter volume. Significant reduction in
      the CC and its subregions was not confirmed in this group of patients with
      schizophrenia. In the subgroup of schizophrenic patients with a positive family
      history of schizophrenia, a significant reduction of the subregion corresponding
      to a part of the trunk of the CC was found.

PMID- 10653288
TI  - Growth factors in distraction osteogenesis. Immuno-histological pattern of TGF
      beta1 and IGF-I in human callus induced by distraction osteogenesis.
AB  - Although growth factors have been demonstrated during bone healing, their
      presence has not yet been confirmed in callus distraction. Therefore, in 3
      patients we searched for cytokines during callus distraction. Bone biopsies were
      immuno-histochemically stained for TGF-beta1, IGF-I, TGF-beta type II receptor,
      IGF receptor, and proliferating cell nuclear antigen (PCNA). Histologically we
      found immature woven bone in the middle of the callus zone and increasing
      calcification and lamellar bone in the re-modelling zone. Osteoblasts and
      fibroblast-like cells in the middle zone, and osteoblasts in all zones stained
      for TGF-beta and its receptor. The number of positive staining cells related to
      proliferous activity as assessed both by PCNA, and by bone density in
      radiographs. IGF-I could be detected everywhere. In conclusion, growth factors
      are present in bone formation and in areas of re-modelling during callotasis.
      Their relation to proliferous activity and radiographic density supports their
      involvement in osteogenesis.

PMID- 10653289
TI  - Classification of lesions of the medial patello-femoral ligament in patellar
      dislocation.
AB  - The remnants of the medial patello-femoral ligament (MPFL) of 67 knees, 18 with
      acute patellar dislocation and 49 with chronic patellar dislocation, were
      studied. The MPFL injuries of the acute cases were categorised into 2 groups: an
      avulsion tear type and a substantial tear type. The chronic cases were put into 3
      groups: those with loose femoral attachment (9 knees), those with scar tissue
      formation or abnormal scar branch formation (29 knees), and those with no
      evidence or continuity of the ligament (absent type) (11 knees). It is concluded
      that incompetence of the medial patello-femoral ligament is a major factor in the
      occurrence of recurrent patellar dislocation and/or an unstable patella following
      an acute patellar dislocation.

PMID- 10653290
TI  - Measurement of cartilage thickness in the human knee-joint by magnetic resonance
      imaging using a three-dimensional gradient-echo sequence.
AB  - We studied human specimens and compared data on cartilage thickness measurements
      with magnetic resonance imaging by using an image analysing system with
      corresponding histological sections in the middle of each sector. The findings
      are based on 768 measurements in 26 knee joints. Overall, there was very good
      magnetic resonance/anatomic correlation (r=0.88). The poorest correlation was in
      the sectors of the femur (r=0.69). The correlation seemed not to be dependent on
      the grade of osteoarthritic cartilage lesions. Despite good correlation rates,
      the mean magnetic resonance/anatomic difference (absolute values) was 0.41 mm
      (standard deviation (SD) 0.34 mm) or 18.08% (SD 18.9%). Imaging techniques need
      to be improved if the assessment of cartilage thickness by this means is to be of
      clinical relevance.

PMID- 10653291
TI  - Increased muscle stiffness after anterior cruciate ligament reconstruction-
      memory on injury?
AB  - Residual impairment of knee function was tested in 25 patients 6 to 12 months
      after successful unilateral reconstruction of the anterior cruciate ligament. The
      control group comprised 25 healthy individuals. Jumping onto one foot from a
      height of 20 cm was taken as a prototype of similar everyday activities. We
      measured maximum flexion of the knee during the landing phase of the jump, and
      the degree of knee flexion at the time of maximum deceleration of the knee
      against gravity during jumping using the three-dimensional optical motion
      analysis system-ELITE. In the group of patients, measured parametres were
      significantly smaller on the operated side than on the unaffected side. These two
      measured values were significantly smaller on both legs in group of patients as
      compared to the values in the control group. The results of our study indicate
      that functional disturbance persisted for 6 to 12 months after anterior cruciate
      reconstruction. This may be due to the changed muscle activation pattern of the
      knee causing increased stiffness of knee muscles. It seems that re-programming of
      the central nervous system occurred in order to protect the injured lower
      extremities from another injury.

PMID- 10653292
TI  - Efficacy of the axially loaded pivot shift test for the diagnosis of a meniscal
      tear.
AB  - Although magnetic resonance imaging (MRI) has improved the diagnostic accuracy of
      meniscal pathology, the authors believe that physical examination remains
      essential to the evaluation of knee pathology. In this study, the diagnostic
      accuracy of five clinical tests for meniscal pathology was prospectively
      evaluated in 160 patients, who thereafter underwent arthroscopy. 69% (109 knees)
      of the knees tested had associated ACL deficiency. There were 144 meniscal
      lesions in 130 of the 160 knees which were examined. The sensitivity of the tests
      was lower than the specificity. Conventional tests such as McMurray and Apley
      tests showed a low accuracy rate of 45% and 28% respectively. The diagnostic
      value of the axially loaded pivot shift test was significantly higher, indicating
      that this remains a useful diagnostic aid.

PMID- 10653293
TI  - Abductor weakness and stresses around acetabular components of total hip
      arthroplasty: a finite element analysis.
AB  - Abductor weakness, and the resulting Trendelenburg gait, after total hip
      arthroplasty is believed to be associated with a poor long-term outcome. We have
      constructed a two-dimensional finite element analysis using load cases to mimic
      this abductor weakness. The finite element analysis demonstrates slightly
      increased stresses, particularly at the bone-cement interface in the DeLee
      Charnley zone I, which does not seem sufficient to explain the adverse effect of
      abductor weakness.

PMID- 10653294
TI  - The short term outcome of elderly patients with hip fractures.
AB  - A prospective outcome study was performed of 100 hip fracture patients at an
      urban medical center in the United States. After hospitalization 19% were
      discharged to a rehabilitation facility and 59% were discharged home. At a mean
      follow-up of 8 months, 81% of patients lived at home, compared to 89% who lived
      at home prior to the fracture. At follow-up 71% of the patients were able to walk
      outside with one cane or no aids at all, and 81% were able to perform basic
      activities of daily living. Half of all patients did not require any home
      assistance at follow-up. Ten patients had died at follow-up. The goal of
      operatively treating the patient with a hip fracture is fixation of the fracture
      with a return to the patient's pre-fracture functional ability. This study
      illustrates that patients with hip fractures can be effectively treated and
      discharged home or to a short-term rehabilitation facility with restoration of
      their pre-fracture functional status.

PMID- 10653295
TI  - Stabilisation of acute femoral fractures in Paget's disease.
AB  - Eleven cases of acute femoral fractures in patients with Paget's disease are
      presented following stabilisation with the solid AO femoral nail. In three cases
      with severe deformity of the femur, reaming was required to enable implant
      insertion. No corticotomies were required. The median operation time was 55 (35
      65) min. There was no operative mortality and no patient developed signs of acute
      respiratory distress syndrome/fat embolism. Skeletal stability was achieved in
      all cases. The reconstruction proximal locking option (spiral blade) was utilised
      in ten of the eleven cases. In all cases a 9 mm nail was inserted. One patient
      (pagetic sarcoma) died 23 months after surgery. Ten of the eleven fractures
      healed uneventfully. The mean time to union was 32 (26-42) weeks.

PMID- 10653296
TI  - Prosthetic reconstruction of the femur for primary bone sarcoma.
AB  - The survival of patients and implants, complications and functional outcome were
      reviewed in 25 consecutive femoral endoprosthetic reconstructions for treatment
      of primary bone sarcoma. The diagnosis was chondrosarcoma in 11, osteosarcoma in
      10, MFH in 3 and Ewing's tumour in 1. Median follow up was 64 months (34 to 219)
      and median age at operation was 29 years (10 to 70). Twelve remained disease free
      at review. One had amputation for local recurrence and another was alive with
      metastases. 11 patients died at a median of 13 months (5 to 128); 8 from
      metastatic disease and 3 from other causes. Four implants were revised, at a
      median of 95 months (53 to 136); two for fractures of the stem and two for
      aseptic loosening. Three implants had radiological evidence of loosening at a
      median of 43 months (34 to 49). Fourteen patients had significant complications.
      The median functional score using the Musculoskeletal Tumour Society system was
      68%. In our experience, prosthetic reconstruction of the femur does not
      compromise survival, although there is a significant complication rate.

PMID- 10653297
TI  - Endoprosthetic replacement of the distal tibia and ankle joint for aggressive
      bone tumours.
AB  - Below knee amputation remains the treatment of choice for most patients with
      aggressive tumours of the distal tibia. We report the clinical and functional
      outcome of limb preserving surgery and endoprosthetic reconstruction of the
      distal tibia and ankle joint in five patients who declined amputation. The mean
      age was 32 years. Two had osteosarcoma, one Ewing's sarcoma, leiomyosarcoma and
      Giant cell tumour. Three patients developed significant complications including
      local recurrence, wound dehiscence and infection, and fibula impingement. Despite
      these complications the patients declined amputation even in the presence of
      significant discomfort. Early function was excellent in all patients but
      deteriorated with time. The patients still maintained an Enneking Score of more
      than 50%. Some patients are unwilling to undergo amputation for aggressive
      tumours of the distal tibia. For these, excision and reconstruction with
      endoprosthesis allow early functional recovery but there is significant medium
      term morbidity and functional deterioration.

PMID- 10653298
TI  - Use of a delayed cortical bone graft to treat diaphyseal defects in the forearm.
AB  - The technique of delayed autogenous cortical bone grafting was used in 17
      patients (6 women, 11 men, with an average age of 22 years) to treat diaphyseal
      defects resulting mainly from closed or compound fractures complicated by
      infection and bone tissue loss. Bones affected were the humerus in 1 case, the
      radius in 7 cases, the ulna in 4 cases, the radius and ulna in 2 cases, the first
      metacarpal in 1 case, and the femur in 2 cases. The average length of the defect
      was 5.7 cm and the graft, prepared from the anteromedial aspec of the tibia, was
      at least 1.5 cm longer than the defect. The graft application was combined with
      rigid internal fixation using an AO 3.5 mm DCP plate in most cases and this
      permitted early active movement. Union occurred without the need for any
      additional grafting procedure in 14 patients and within an average of 23 weeks.
      In most cases there was an increase in the thickness of the graft probably as a
      result of osteo-induction, with consequent restoration of the original diameter
      of the recipient bone diaphysis. The most frequent complication was infection (4
      cases), and this was controlled by means of debridement, cleaning and
      antibiotics. A delayed graft provides mechanical support, incorporates quickly
      and is therefore a reasonable alternative method for treating diaphyseal defects
      of long bones, particularly in the upper limb.

PMID- 10653299
TI  - The lateral impaction of the shoulder.
AB  - 17 patients had radiographic demonstration of injury to the clavicle, scapula and
      ribs from an impact delivered to the lateral shoulder. The study included 13
      males and 4 females whose ages ranged from 18 to 83 years (average 45 years).
      Most injuries were sustained in falls or motor vehicle accidents. Analysis of
      these cases suggests a biomechanical hypothesis concerning the transmission of
      the impact forces within the shoulder girdle. According to this hypothesis, the
      impaction force applied to the lateral shoulder is transmitted from outside
      inward following two paths. The anterior and superior path passes through the
      acromio-clavicular joint, the clavicle, the costo-clavicular joint and the sterno
      clavicular joint. The posterior and inferior path is transmitted within the gleno
      humeral joint, the scapula and the scapulo-thoracic joint. Major impacting force
      is required to disrupt the anterior and posterior arches of the shoulder girdle.
      When both of these supporting structures are damaged, the patient is at risk for
      more serious injuries, including disruption of the thorax, shoulder joint,
      brachial plexus and neck.

PMID- 10653300
TI  - Fractures due to hypocalcemic convulsion.
AB  - We report on two cases of patients in whom hypocalcemic seizures during
      hemodialysis led to right scapular body fracture in one and bilateral femoral
      neck fractures in the other.

PMID- 10653301
TI  - Symptomatic bucket handle tear of the lateral meniscus after knee arthroplasty.
AB  - We report on a 67-year-old women who had pain after a knee arthroplasty in the
      region of the lateral meniscus. The arthroscopy showed the remainder of the
      posterior horn of the lateral meniscus, which luxated as a bucket handle tear
      into the joint. The resection led to an immediate relief. This case show the
      importance of meticulous removal of the entire menisci during bicondylar surface
      replacement.

PMID- 10653302
TI  - Pitfalls in electrodiagnosis.
AB  - This review describes some of the factors that may lead to erroneous
      interpretations of electromyographic and nerve conduction studies. Such errors
      may be due either to technical or to biological factors, and it is imperative
      that the consequent limitations of the methods be considered in a diagnostic
      setting. Electrodiagnostic findings should always be interpreted in the clinical
      context, and since they are rarely specific for a particular disorder or
      pathology, it is necessary to satisfy several criteria to make a specific
      diagnosis. The aim of electromyographic examination is to ascertain whether
      weakness is due to a neurogenic lesion or to myopathy. It is, however, not
      sufficient to show the presence of denervation activity since this may occur in
      either condition. Therefore the motor unit potentials from both weak and
      nonaffected muscles should be examined quantitatively. Nerve conduction studies
      are carried out to ascertain whether motor or sensory myelinated fibers are lost,
      and whether the primary pathology is due to demyelination or axonal loss or to
      both. The nerve conduction velocity is of primary importance in this distinction.
      However, loss of large myelinated fibers leads to slowing of conduction; in some
      instances the conduction velocity may be normal if only a few large fibers are
      spared. In addition collateral sprouting in chronic conditions may lead to
      apparent sparing of motor fibers. Hence an erroneous diagnosis may be made of a
      sensory neuropathy if additional electromyography or other tests are not carried
      out. Conduction studies investigate only large myelinated fibers, and therefore
      in some instances there is discordance between the morphology and physiology.
      Acquired demyelinating neuropathies are sometimes associated with focal slowing
      of conduction or with conduction block. The demonstration of conduction block is
      important, but several requirements must be fulfilled in terms of technique,
      clinical context, and temporal development in order to avoid errors.

PMID- 10653303
TI  - Risk factors for levodopa-induced dyskinesias in Parkinson's disease.
AB  - To identify putative risk factors for levodopa-induced dyskinesias we studied the
      effect of several clinical variables on the occurrence of dyskinesias in a series
      of 168 consecutive patients with Parkinson's disease treated for at least 6
      months with levodopa. Of these, 108 (64%) developed dyskinesias after a mean
      duration of levodopa treatment of 51.4 +/- 43.3 months. Patients tended to suffer
      dyskinesias on the side of the body first affected by Parkinson's disease. The
      overall probability of developing dyskinesias increased with levodopa treatment
      duration, about 10% per year during the first 7 years. Univariate and
      multivariate logistic regression analysis identified the age at onset of
      Parkinson's disease (OR 0.923; 95% CI 0.883-0.964) and the initial levodopa dose
      (mean dose of the first 6 months of treatment; OR 1.004; 95% CI 1.002-1.006) as
      the main independent predictors. Survival curves showed that onset of Parkinson's
      disease at age 50 years or before (logrank, P < 0.05) and initial levodopa
      treatment with more than 600 mg/day (logrank, P < 0.05) were associated with a
      higher risk for the appearance of dyskinesias.

PMID- 10653304
TI  - Development of weakness in patients with chronic inflammatory demyelinating
      polyneuropathy and only sensory symptoms at presentation: a long-term follow-up
      study.
AB  - This long-term follow-up study examined patients with chronic inflammatory
      demyelinating polyneuropathy (CIDP) and only sensory symptoms at first
      presentation, with emphasis on the development of motor symptoms and long-term
      disability. From all CIDP patients referred to our Department between 1987 and
      1995, seven had only sensory symptoms at first clinical presentation. These were
      investigated according to a standard protocol, including a quantified clinical
      neurological examination and nerve conduction studies. The mean duration of the
      disease before weakness developed was 3.1 years, but varied considerably (0.8-6.3
      years). At follow-up, weakness developed in five patients and persisted in three
      of them. Five patients were not seriously incapacitated by their disease (Rankin
      1 or 2), four of them being in remission now and one showing a very slow
      progression of disease. Two patients were moderately disabled (Rankin 3); one had
      severe persistent sensory ataxia and only weakness during relapses and one had
      stepwise progression and moderate weakness. Motor nerve conduction studies
      revealed that the most notable worsening in the entire group of patients was a
      decrease in distal compound muscle action potential amplitudes, indicating the
      development of distal conduction block or axonal degeneration. These findings
      show that CIDP with only sensory symptoms is a transient clinical stage that
      precedes the appearance of weakness in about 70% of patients. The long-term
      prognosis does not differ from that of patients with CIDP who have weakness at
      the beginning of the disease.

PMID- 10653305
TI  - Polymorphisms in the glutamate transporter gene EAAT2 in European ALS patients.
AB  - Amyotrophic lateral sclerosis (ALS) is a progressive neurological disorder
      characterised by degeneration of upper and lower motor neurons. Whilst the
      primary pathogenic trigger is unknown in most cases, evidence is mounting to
      implicate a role for glutamate-mediated neurotoxicity in the disorder. Recent
      studies have shown reduced levels of the mainly astroglial glutamate transporter
      EAAT2 in ALS motor cortex and spinal cord and multiple abnormal EAAT2 mRNA
      species in ALS brain tissue. One cause of the low EAAT2 levels may be that point
      mutations in the EAAT2 gene, EAAT2, result in an abnormal unstable protein. To
      test this hypothesis we analysed EAAT2 in 128 sporadic and 23 familial European
      ALS cases. No variants within the coding sequence of EAAT2 to affect the protein
      sequence nor in the consensus splice sites of the flanking intronic sequences
      were found in any cases, similar to findings in other reports. Frequent
      polymorphisms within the flanking intronic sequences of both exons 2 and 4 were
      seen but at similar frequencies in controls. Mechanisms other than mutations
      within the coding region of EAAT2 must therefore be responsible for the low
      levels of EAAT2 seen in most cases of ALS.

PMID- 10653306
TI  - How do general practitioners diagnose and manage patients with transient
      monocular loss of vision of sudden onset?
AB  - Symptoms of transient loss of vision in one eye differ widely. They may have
      different causes and therefore carry a different prognosis. We studied the
      influence of differences between characteristics of transient monocular blindness
      on the diagnosis and management by general practitioners (GPs). A postal
      questionnaire, was sent to 1600 GPs in The Netherlands along with four case
      vignettes describing a case history of a 56-year-old man with transient monocular
      disturbances of vision of sudden onset. We introduced random permutations in the
      following four elements of the history: partial or complete visual field
      involved, blurring or blacking out of vision, attacks lasting minutes or hours,
      and patients having covered either eye during the attack or not. Respondents were
      asked about the probable diagnosis and the preferred management. For each of the
      16 permutations about 50 responses were obtained (overall response rate 54%).
      Ischemic transient monocular blindness (ITMB) was chosen as the most likely
      diagnosis in 49%. In 12% primary ocular disease was suspected. Involvement of the
      complete visual field, blacking out of vision, and short attacks were identified
      as independent predictors of a diagnosis of ITMB. A diagnosis of ITMB would have
      resulted in referral to a specialist in 72% of patients. Antithrombotic treatment
      would have been initiated in only 36% of ITMB patients. GPs consider brief
      attacks with complete blacking out of vision most typical for retinal ischemia.
      They refer only three-quarters of patients with probable ITMB to a specialist and
      start antithrombotic medication in only one-third of these patients. Therefore
      further education with regard to transient monocular blindness is needed.

PMID- 10653307
TI  - Fluorodopa uptake and glucose metabolism in early stages of corticobasal
      degeneration.
AB  - Fluorodopa (FDOPA) and fluorodeoxyglucose (FDG) PET was performed in six patients
      in early stages of corticobasal degeneration (CBD) and compared to Parkinson's
      disease (PD) patients with a similar degree of bradykinesia and rigidity and to
      healthy controls. Statistical parametric mapping analysis comparing CBD to
      controls showed metabolic decrease in premotor, primary motor, supplementary
      motor, primary sensory, prefrontal, and parietal associative cortices, and in
      caudate and thalamus contralateral to the side of clinical signs. Except for the
      prefrontal regions a similar metabolic pattern was observed when CBD was compared
      to PD. Putamen FDOPA uptake was decreased in both CBD and PD. Caudate FDOPA
      uptake in CBD patients was decreased contralateral to clinical signs when
      compared to controls, but was higher than in PD. In early stages of CBD, FDOPA
      and FDG PET patterns differed from those observed in PD. In CBD the asymmetry in
      FDOPA uptake was less pronounced than that of clinical signs or metabolic
      impairment.

PMID- 10653308
TI  - Negative sural nerve biopsy in neurolymphomatosis.
AB  - Patients with non-Hodgkin's lymphoma occasionally develop widespread invasion of
      peripheral nerves by tumor cells or neurolymphomatosis (NL). Clinically this
      usually results in asymmetrical, progressive, and painful polyneuropathy.
      Diagnosis rests on the identification of tumor cells in peripheral nerves. To
      avoid false-negative biopsy findings in patients with malignant lymphomatous
      infiltration of peripheral nerves it has been recommended to biopsy clinically
      involved nerves. We present two patients with histologically confirmed NL in whom
      sural the nerve biopsy finding was negative despite clinical and
      neurophysiological evidence of involvement of the sural nerve a. The clinical
      features of NL are reviewed. Some patients with neurolyphomatosis have only focal
      or proximal involvement of nerves, requiring the biopsy of an affected part of
      these nerves. Magnetic resonance imaging may be useful in identifying affected
      nerves.

PMID- 10653309
TI  - Cerebral blood flow and metabolic changes produced by repetitive magnetic brain
      stimulation.
AB  - We evaluated cerebral variation in oxyhemoglobin, deoxyhemoglobin, and cytochrome
      oxidase before and after transcranial magnetic and electrical stimulation in ten
      healthy volunteers using near-infrared spectroscopy. Immediately after magnetic
      but not after electric stimulation a significant increase in oxyhemoglobin and a
      decrease in cytochrome oxidase were observed (P < 0.05). Our data suggest that
      repetitive transcranial magnetic stimulation induces metabolic activation of the
      cerebral cortex together with an increase in cerebral blood flow.

PMID- 10653310
TI  - Detection of anterior horn lesions by MRI in central European tick-borne
      encephalomyelitis.
AB  - We report a case of central European tick-borne encephalitis with cervical
      myelitis presenting clinically as a lower motor neuron syndrome of the upper
      limbs with proximal asymmetrical pareses and atrophies. There were no sensory
      deficits nor signs of lesions of the spinal pathways or signs of encephalitis or
      meningitis. The affected motor fibers of the upper limbs were electrically
      inexcitable, but sensory findings were normal. Electromyography of the paralyzed
      muscles revealed pathological denervation activity without voluntary activation.
      The initial magnetic resonance imaging (MRI) showed a large hyperdense lesion in
      the anterior part of the cervical cord from C3 to T1. Despite the fact that MRI
      changes disappeared completely within 6 weeks the patient showed only little
      improvement in the paralyzed muscles after 6 months. To our knowledge, these MRI
      changes in patients with tick-borne encephalitis, consistent with an isolated
      anterior horn lesion, have never been reported previously. The course may have
      been aggravated by an initial antibiotic treatment with cephalosporins.

PMID- 10653311
TI  - Emotion-related cerebral asymmetry: hemodynamics measured by functional
      ultrasound.
AB  - This study assessed the use of transcranial Doppler ultrasound in detecting
      selective changes in cerebral blood flow velocity during emotional processes. The
      role of the respective hemispheres in emotional processing is controversial.
      Cerebral control of emotional processing has previously been investigated by
      analysis of patients with unilateral brain damage, experiments with selective
      stimulation of only one hemisphere, and more recently by imaging techniques
      measuring local cerebral blood flow. We investigated mean flow velocity
      continuously and simultaneously in both the right and left middle cerebral
      arteries (MCAs) in 16 healthy right-handed young subjects at rest and during the
      performance of three tasks: task 1: 15 slides with nonemotional content; task 2:
      15 slides with negative emotional content; task 3: 15 slides with nonemotional
      content with different content from that in task 1. The three tasks produced
      significantly different effects on the right and left hemispheres. During the two
      nonemotional tasks the increase in mean flow velocity over basal values was
      similar in the two MCAs (task 1: left MCA = 3.27 +/- 1.9%; right MCA = 3.63 +/-
      2.1%; task 3: left MCA = 2.42 +/- 0.7%; right MCA = 2.56 +/- 1.3%); the negative
      emotional task was accompanied by a significantly higher increase in the right
      (11.31 +/- 1.6%) than in the left MCA (4.72 +/- 3.7%; analysis of variance two
      way interaction: side of recording x task, F = 43.6, P < 0.001). These results
      show the possibility of obtaining specific functional information from bilateral
      transcranial Doppler ultrasound and suggest the involvement of the right
      hemisphere in emotional processing.

PMID- 10653312
TI  - Studies of the candidate genes in X-linked congenital cerebellar hypoplasia.
AB  - A gene for X-linked congenital cerebellar hypoplasia was recently localized to
      chromosome Xp11.21-q24. This region comprises several brain-specific genes
      responsible for various neurological disorders, including the proteolipid protein
      (PLP), doublecortin, and PAK3 genes. We screened these genes for mutations in
      patients with X-linked congenital cerebellar hypoplasia and found no pathogenic
      nucleotide changes or gene dose alterations. These findings allow the ruling out
      of PLP, doublecortin, and PAK3 as the disease-causing genes in this hereditary
      neurological syndrome.

PMID- 10653313
TI  - The sensitivity of thin-slice fast spin echo, fast FLAIR and gadolinium-enhanced
      T1-weighted MRI sequences in detecting new lesion activity in multiple sclerosis.
AB  - Fast fluid-attenuated inversion-recovery (FLAIR) and proton density/T2-weighted
      fast spin echo (FSE) brain images with 3-mm slices were acquired monthly for 7
      months in 37 multiple sclerosis patients. New and enlarging lesions were counted
      and compared according to the site of lesions seen with each sequence. In
      addition, the number of new enhancing lesions seen on gadolinium-enhanced T1
      weighted brain magnetic resonance imaging at the same time points was counted.
      All sequences used 3-mm contiguous axial slices. Overall, 126 new or enlarging
      lesions were seen on FSE and 135 on fast FLAIR (P = 0.25, Wilcoxon signed ranks
      test). Regional comparisons revealed significantly more fast FLAIR lesions only
      in the cortical/subcortical areas. There was a total of 295 new enhancing lesions
      over the same period -- a gain in the number of 'active lesions' of 234% seen
      with FSE and 218% with FLAIR. It is concluded that serial thin slice fast FLAIR
      is only slightly superior to FSE in detecting new and enlarging multiple
      sclerosis lesions but the difference is not sufficient to recommend that FLAIR
      should replace FSE in short-term, exploratory trials in MS using monthly
      scanning. Gadolinium-enhanced imaging is more then twice as sensitive as either
      FSE or fast FLAIR to new multiple sclerosis lesion activity, and enhancing
      lesions should provide the primary outcome measure in such studies.

PMID- 10653314
TI  - Depression in Parkinson's disease: brainstem midline alteration on transcranial
      sonography and magnetic resonance imaging.
AB  - Recent studies using transcranial sonography (TCS) have provided evidence of
      alterations in the mesencephalic midline structures in patients with unipolar
      depression and depression in Parkinson's disease (PD), suggesting an involvement
      of the basal limbic system in primary and secondary mood disorders. This study
      tested the hypothesis of brainstem midline abnormality in depression and
      investigated 31 PD patients by magnetic resonance imaging (MRI) and TCS. Signal
      intensity of the pontine and mesencephalic brainstem midline was rated on T2
      weighted images and measured by relaxometry. In addition, two blinded
      investigators assessed the echogenicity of the brainstem midline by TCS. The
      severity of motor symptoms and depression were graded independently using
      standard research scales. Rating of signal intensity and T2 relaxometry of the
      pontomesencephalic midline structures revealed significant difference between
      depressed and nondepressed PD patients (P < 0.05). This corresponded to a
      significant reduction in mesencephalic midline echogenicity of depressed PD
      patients on TCS images. No correlation was found between raphe signal intensity,
      T2 relaxation times, or TCS echogenicity and the severity of motor symptoms or
      depression. This study is the first to show changes in signal intensity and T2
      relaxation time of the pontomesencephalic midline structures on MRI in depressed
      PD patients confirming previous TCS findings. As these midline structures
      comprise fiber tracts and nuclei of the basal limbic system, the findings may
      support the hypothesis of an alteration in the basal limbic system in mood
      disorders.

PMID- 10653315
TI  - Cytokine production in patients carrying multiple sclerosis-linked HLA-DR
      alleles.

PMID- 10653316
TI  - Encephalomyopathy with multiple mitochondrial DNA deletions and multiple
      symmetric lipomatosis: further evidence of a possible association.

PMID- 10653317
TI  - Meningioma associated with McCune-Albright syndrome.

PMID- 10653318
TI  - Ischemic stroke in a 29-year-old man with left atrial spontaneous echoes and
      polycythemia vera.

PMID- 10653319
TI  - Combined acute disseminated encephalomyelitis and acute motor axonal neuropathy
      after vaccination for hepatitis A and infection with Campylobacter jejuni.

PMID- 10653320
TI  - Muscle injury in Guillain-Barre syndrome: a case report.

PMID- 10653321
TI  - Manifestations and treatment of Schimke immuno-osseous dysplasia: 14 new cases
      and a review of the literature.
AB  - Schimke immuno-osseous dysplasia (SIOD) is a rare autosomal recessive spondylo
      epiphyseal dysplasia. The characteristic features of SIOD include 1) short
      stature with hyperpigmented macules and an unusual facies, 2) proteinuria with
      progressive renal failure, 3) lymphopenia with recurrent infections, and 4)
      cerebral ischaemia. Although 25 patients have been reported with this disorder,
      the clinical course and phenotype of SIOD are not well characterized. This report
      summarizes the clinical findings, course and treatment of reported patients and
      includes 14 additional patients with SIOD. We emphasize the high incidence of
      cerebral ischaemia and ocular abnormalities, define the high incidence of thyroid
      dysfunction and blood cytopenia, and confirm the absence of effective and durable
      medical therapies. CONCLUSION: Schimke immuno-osseous dysplasia is a multi-system
      autosomal recessive disorder with variable expression that affects the skeletal,
      renal, immune, vascular, and haematopoietic systems. Medical therapy is limited
      especially for more severely affected individuals.

PMID- 10653322
TI  - Congenital absence of the trachea.
AB  - Congenital absence of the trachea is a rare cause of severe neonatal respiratory
      distress. Experimental studies show that it is probably caused by disorders in a
      system of folds in the tracheo-oesophageal space rather than abnormalities of a
      tracheo-oesophageal septum. A literature review disclosed 82 cases of tracheal
      agenesis, which showed male predominance and an association with prematurity and
      polyhydramnios. In 90% of cases associated congenital malformations were present,
      most frequently affecting the cardiovascular or gastro-intestinal systems and the
      genito-urinary tract. Clinical signs of tracheal agenesis or atresia are
      respiratory insufficiency, often with severe respiratory distress, absence of
      audible crying and difficult or impossible endotracheal intubation. At present,
      curative repair and survival are impossible unless there is enough proximal or
      distal trachea to create a tracheostoma. Important ongoing research is aimed at
      tissue-engineered cartilage for surgical repair of tracheal defects. CONCLUSION:
      Tracheal agenesis, although very rare, can be recognised from a characteristic
      clinical pattern. Mostly associated congenital malformations are present.
      Research into tissue-engineering might lead to possibilities for definitive
      surgical repair of tracheal agenesis or atresia; however, until curative repair
      becomes possible, prolonged ventilation via the oesophageal tube does not seem to
      be worthwhile.

PMID- 10653323
TI  - Persistent acquired lobar overinflation complicating bronchopulmonary dysplasia.
AB  - Persistent acquired lobar overinflation (PALO) may complicate bronchopulmonary
      dysplasia (BPD). From infants admitted to the regional neonatal intensive care
      unit or who had been followed up at the chronic lung disease clinic in Liverpool
      over a 6.5-year period, 11 children with BPD and PALO were identified and details
      of their neonatal and subsequent outcome obtained. Their median gestational age
      was 29 weeks (range 24-33) and median birth weight was 1317 g (range 676-1968 g).
      All had received ventilatory support for severe neonatal respiratory distress
      syndrome for a median of 26 days (range 5-86). The median age the acquired lobar
      overinflation was detected was 82 days (range 45424 days). Nine patients required
      continued neonatal or paediatric intensive care re-admission for deteriorating
      respiratory function. Six children have subsequently died at a median age of 9.5
      months (range 6.5-20). Five patients underwent bronchoscopy, four suggesting the
      presence of bronchomalacia. Three patients had ventilation-perfusion scans all
      showing that the overinflated lobe had no mismatch defect unlike other areas of
      the lung. CONCLUSION: The place of specific therapies for persistent acquired
      lobar overinflation is unclear. Surgery to remove the overinflated lobe in such
      cases may be inappropriate and the outcome of this complication of
      bronchopulmonary dysplasia appears to be poor.

PMID- 10653324
TI  - Diagnosis and molecular analysis of an atypical case of holocarboxylase
      synthetase deficiency.
AB  - Holocarboxylase synthetase (HCS) deficiency is a disorder of biotin metabolism
      characterised by metabolic ketoacidosis and skin lesions due to reduced
      activities of multiple biotin-dependent carboxylases. The onset of this disease
      is usually between the neonatal and infantile period. Here we report the
      molecular analysis of an atypical case of HCS deficiency, where the patient
      developed his first episode of acidosis at age 8 years and had an exceptionally
      slow response to biotin therapy. A homozygous mutation was identified at the + 5
      position of the splice donor site in intron 10 of the HCS gene (IVs10 + 5(g-
      >a)), resulting in abnormal splicing of HCS mRNA. A moderate decrease in the
      amount of normal HCS mRNA may account for the atypical, late-onset phenotype of
      this patient. Conclusion Molecular analysis is a useful tool for understanding
      the phenotypic variations in holocarboxylase synthetase deficiency.

PMID- 10653325
TI  - Novel mutations, no detectable mRNA and familial genetic analysis of the Wiskott
      Aldrich syndrome protein gene in six Japanese patients with Wiskott-Aldrich
      syndrome.
AB  - The Wiskott-Aldrich syndrome (WAS) is a primary X-linked immunodeficiency disease
      caused by mutations of the Wiskott-Aldrich syndrome protein (WASP) gene. The
      present molecular studies of six Japanese WAS patients identified five different
      mutations of WASP, including two novel mutations (45delG, 395insGGAGAT), the
      latter appearing to have occurred de novo. Familial carriers were detected by
      polymerase chain reaction-single strand conformational polymorphism analysis,
      restriction enzyme digestion and direct sequencing of PCR products. Neither mRNA
      nor the protein product were detectable in any of the patients, while various
      amounts of WASP protein were expressed in carriers, normal controls,
      haematopoietic cell lines of all lineages and in one patient after receiving
      allogeneic bone marrow transplantation. Conclusion Genetic and protein analysis
      is useful in the definite diagnosis and follow up of Wiskott-Aldrich syndrome
      patients and in carrier detection, especially of atypical or sporadic patients.

PMID- 10653326
TI  - Pubertal development and growth after total-body irradiation and bone marrow
      transplantation for haematological malignancies.
AB  - Pubertal development after total-body irradiation (TBI) was investigated in 40
      children (21 boys) treated with allogeneic bone marrow transplantation (BMT) for
      haematological malignancies at a mean age of 11.3 years. The mean age at the last
      visit was 19.0 years. Twenty-five patients (15 boys) were prepubertal at BMT.
      Data on secondary sexual characteristics, the pituitary-gonadal axis and
      longitudinal growth were retrospectively collected from the medical records. In
      boys not receiving additional testicular irradiation (n = 19), penile growth and
      pubic hair development was normal and all had serum testosterone levels within
      the adult range. The majority of them, however, had incidental elevations of LH,
      suggesting minor Leydig cell damage. Testicular volume at last measurement was
      small (mean: 10.5 ml) and serum FSH levels were elevated in all boys, with
      normalisation in only one, suggesting severe impairment of reproductive gonadal
      function. Of the ten girls who received BMT before puberty, six had a spontaneous
      onset of puberty and menarche; the four other girls needed hormonal substitution
      therapy. Recovery of gonadal function after cessation of substitution was seen in
      one girl, who became pregnant but had a spontaneous abortion. Decrease in height
      SDS was seen in the majority of patients and was positively correlated with male
      gender and lower age at the time of BMT. CONCLUSION: Careful monitoring of both
      gonadal function and growth after bone marrow transplantation and total body
      irradiation is warranted in order to detect disturbances early and ensure normal
      pubertal development in children treated for haematological malignancies.

PMID- 10653327
TI  - Primary infantile hypomagnesaemia: outcome after 21 years and treatment with
      continuous nocturnal nasogastric magnesium infusion.
AB  - Primary infantile hypomagnesaemia is an infrequent cause of neonatal
      hypocalcaemic seizures but one that responds well to magnesium supplementation.
      We describe a 22-year-old male, first reported at 4 months of age, who is
      currently free of neurological deficit but has suffered from intermittent
      hypomagnesaemic tetany and chronic diarrhoea due to large oral magnesium
      supplements. Hypothesizing that modest hypercalcaemia might prevent the tetany,
      we conducted a trial of 5 microg/day 1,25(OH)2D3 over 5 days. Despite the
      resultant increase in calcium, he developed tetany with the reduction of
      magnesium intake and decline of serum magnesium from 0.63 to 0.39 mmol/l (normal
      >0.65 mmol/l). After 1,25(OH)2D3 was stopped and the parenteral magnesium
      injections suspended, 33% of his usual oral supplement was given instead by
      continuous nasogastric infusion and serum magnesium rose to 0.60 mmol/l. This
      regimen was better tolerated because of decreased gastrointestinal side-effects
      and freedom from parenteral injections. We observed that 1,25(OH)2D3 supplements
      do not promote magnesium retention nor does the resultant hypercalcaemia prevent
      hypomagnesaemic tetany. CONCLUSION: Continuous nocturnal nasogastric infusion may
      be considered in lieu of parenteral therapy in primary infantile hypomagnesaemia.

PMID- 10653328
TI  - Neonatal renal venous thrombosis in Germany between 1992 and 1994: epidemiology,
      treatment and outcome.
AB  - Renal venous thrombosis (RVT) occurs mainly in the neonatal period and bears a
      dismal prognosis for individual kidney function. There is no generally accepted
      therapeutic regimen as controlled clinical trials are lacking. Over the last few
      years, thrombolytic therapy has been successfully employed by single centres. The
      present study set out to gather up-to-date information on the incidence, therapy
      and outcome of neonatal RVT as part of a prospective nation wide survey on
      neonatal thrombosis in Germany to serve as a basis for therapeutic trials in the
      future. Between 1992 and 1994 the minimum incidence of symptomatic neonatal RVT
      in Germany was 2.2 per 100,000 live births (95% confidence interval 1.4-3.3). Out
      of 35 cases, RVT occurred in 15 premature babies (incidence 13 per 100,000 live
      births (95% confidence interval 5.9-24.8). Ten babies had associated caval
      occlusion. Therapy was supportive in 8, low dose heparin was used in 14, full
      heparinization in 9 and thrombolytic therapy in 4 children. On follow-up after a
      median time of 11.5 months, renal atrophy was present in 26 out of 39 affected
      kidneys. CONCLUSION: Neonatal renal venous thrombosis still leads to irreversible
      kidney damage in the majority of cases. Because of the low incidence a multi
      national multi-centre therapeutic trial over a long period has to be considered
      in order to determine the optimal therapeutic approach.

PMID- 10653329
TI  - Erythrocyte fatty acid composition in term infants fed human milk or a formula
      enriched with a low eicosapentanoic acid fish oil for 4 months.
AB  - When term infants are fed standard formula that does not contain long-chain
      polyunsaturated fatty acids (LC-PUFA), they still show lower levels of
      docosahexaenoic acid (DHA) in red blood cell (RBC) phospholipids by several weeks
      or months postnatally. This study was designed in order to evaluate a potential
      alternative for supplementing term infant formulas with DHA by adding a high
      DHA/low-eicosapentanoic acid fish oil to levels similar to that in human milk
      (0.3%). A total of 37 term infants were included in the study at 3 days of life.
      DHA concentrations remained stable between inclusion and 4 months of life at
      around 8% of the RBC phospholipids in the LC-PUFA enriched formula-fed group
      whereas it decreased significantly in the standard formula-fed group. In the
      human milk-fed group, RBC DHA concentrations at 4 months of age were
      significantly lower than that at birth and were significantly correlated with the
      duration of breast feeding (r = 0.85; P = 0.0002). A significant decrease of
      arachidonic acid between inclusion and 4 months of age was observed in the
      enriched formula-fed group and reached a mean value at 4 months, which was
      significantly lower than that observed in the human milk or standard formula-fed
      groups (P<0.0001). CONCLUSION: Supplementing term formulas with a high
      docosahexaenoic acid/low-eicosapentanoic acid fish oil up to 4 months of age is
      efficient in improving docosahexaenoic acid status, however it increases the risk
      of impaired n-6 fatty acid status.

PMID- 10653330
TI  - Odd-numbered long-chain fatty acids in propionic acidaemia.
AB  - In patients with propionic acidaemia (PA), the increased intracellular
      concentration of propionyl-CoA leads to a relative abundance of odd-numbered long
      chain fatty acids (OLCFAs) in body lipids. We investigated the relative amount of
      OLCFA in erythrocyte membrane lipids over a period of 1-8 years in five patients
      with early onset PA and present their clinical outcome. After extraction from
      erythrocyte membrane lipids and esterification, fatty acids were analysed by
      capillary column gas chromatography. The sum of the OLCFA 15- and 17- carbon
      saturated and 17-carbon monounsaturated fatty acids (C15:0, C17:0, C17:1) was
      calculated and expressed as a percentage of the total C14-C22 fatty acids in the
      sample. Three patients (pccBC-complementation group) presented with a stable
      clinical course and showed OLCFA values usually below 1.9% (median % +/- SD:
      1.4+/-0.5, 1.6+/-0.5, 1.8+/-0.5). Two patients (pccA-complementation group) had a
      more severe course of the disease and showed higher medians and a broader range
      of OLCFA levels (2.2+/-1.2 and 2.2+/-0.8). CONCLUSION: Our study shows that odd
      numbered long-chain fatty acid concentrations are increased in patients with
      propionic acidaemia and are higher in those with a more severe clinical course.
      The value of odd-numbered long-chain fatty acids in the assessment of the
      phenotypic severity and in the management of propionic acidaemia remains to be
      proven in a prospective long-term study with more patients of differing
      phenotype.

PMID- 10653331
TI  - Injuries in young athletes.
AB  - Most injuries in children's sports are minor and self-limiting, suggesting that
      children and youth sports are safe. A child's skeletal system shows pronounced
      adaptive changes to intensive sports training. Sports injuries affect both
      growing bone and soft tissues and could result in damage of the growth mechanisms
      with subsequent life-lasting damage. During growth there are significant changes
      in the biomechanical properties of bone. In young athletes, as bone stiffness
      increases and resistance to impact diminishes, sudden overload may cause bones to
      bow or buckle. Epiphyseal injuries are usually due to shearing and avulsion
      forces, although compression also plays a significant role. Given the remarkable
      healing potential of bone in youngsters, fractures that initially united with
      some deformity can completely remodel and appear totally normal in later life.
      CONCLUSION: As the risk of injuries sustained by young athletes can be
      significant, it is essential that training programmes take into account their
      physical and psychological immaturity, so that growing athletes can adjust to
      their own body changes.

PMID- 10653332
TI  - Postoperative Mycobacterium avium osteomyelitis confirmed by polymerase chain
      reaction.
AB  - An 18-year-old male with Escobar syndrome developed Mycobacterium avium
      osteomyelitis after corrective osteotomy. After three surgical interventions the
      infection reappeared a fourth time. Repeated attempts at microbiological
      diagnosis of the granulomatous lesions by microscopy and culture for conventional
      bacteria and Mycobacteria did not reveal any organism. The diagnosis of
      Mycobacterium avium finally was achieved by polymerase chain reaction. Extensive
      immunological work-up did not reveal signs of immunodeficiency. The patient was
      treated successfully by a combined surgical and chemotherapeutic approach
      consisting of clarithromycin, ethambutol and ciprofloxacin. CONCLUSION:
      Polymerase chain reaction may be especially useful for clinical situations with a
      low bacterial load, especially for fastidious and slow growing pathogens like
      Mycobacteria. In our patient a combination of surgical therapy with a triple
      regimen containing clarithromycin proved successful for treatment of a localised
      infection with M. avium in a supposedly immunocompetent host.

PMID- 10653333
TI  - Brown tumour as a complication of secondary hyperparathyroidism in severe long
      lasting vitamin D deficiency rickets.
AB  - Brown tumour is a localised form of fibrous-cystic osteitis associated with
      primary or secondary hyperparathyroidism. Despite the fact that secondary
      hyperparathyroidism occurs in vitamin D deficiency rickets, no cases of rickets
      with brown tumour have so far been described. We present a 2.9-year-old girl who
      had brown tumour of the mandible due to severe vitamin D deficiency rickets.
      Treatment with vitamin D3 corrected the hyperparathyroidism rapidly which was
      followed by gradual regression in tumour size. CONCLUSION: Brown tumour can
      develop in severe, long-standing vitamin D deficiency rickets and responds to
      vitamin D treatment.

PMID- 10653334
TI  - Accelerated phase in partial albinism with immunodeficiency (Griscelli syndrome):
      genetics and stem cell transplantation in a 2-month-old girl.
AB  - A 2-month-old girl presented with fever, hepatosplenomegaly, pancytopenia,
      hypertriglyceridaemia and silvery-greyish hair, suggesting the diagnosis of
      Griscelli syndrome (partial albinism with immunodeficiency). This diagnosis was
      confirmed by the characteristic agglomeration of melanin in the hair shaft and
      accumulation of melanosomes in melanocytes of the skin. The patient was
      homozygous for polymorphic markers around the myosin-Va gene on chromosome 15q21,
      which co-localize to the Griscelli disease locus. Natural-killer cells were in
      the lower range. The stimulation of lymphocytes with antigen and mitogen was
      normal. The patient's accelerated phase, characterized by haemophagocytosis was
      treated with prednisolone, rabbit anti-thymocyte globulins, and intrathecal
      methotrexate. Remission was maintained with cyclosporin A until HLA-compatible
      peripheral blood stem cell transplantation from her mother. CONCLUSION: The
      silvery-greyish hair associated with fever, pancytopenia and
      hypertriglyceridaemia is the clue to early diagnosis of Griscelli syndrome and
      important to prevent death before stem cell transplantation.

PMID- 10653335
TI  - Vallecular cyst: an uncommon cause of stridor in newborn infants.
AB  - Vallecular cyst, a rare but generally benign lesion in the larynx, may cause
      stridor and even life-threatening airway obstruction in early infancy. We
      retrospectively studied 14 cases of newborn infants with vallecular cyst. There
      was no gender predilection and most cases were full-term and appropriate for
      gestational age. The clinical presentations included stridor, chest wall
      retraction, feeding difficulties and failure to thrive. Laryngomalacia was the
      most common associated anomaly. Flexible laryngoscopy was sufficient for
      diagnosing the vallecular cyst and larygmalacia. Maintenance of airway patency,
      nutritional support, and de-roofing of the cyst were the mainstays of management.
      CONCLUSION: Vallecular cyst should be included in the differential diagnosis of
      stridor in newborn infants. Respiratory and feeding difficulties in these
      patients can be dramatically improved after appropriate surgical removal of the
      cyst.

PMID- 10653336
TI  - Familial neonatal SIDS revealing carnitine-acylcarnitine translocase deficiency.
AB  - A patient with a severe phenotype of carnitine-acylcarnitine translocase
      deficiency (CATR)(McKusick 212138) is reported. Prior to birth, a defect in beta
      oxidation was suspected because of neonatal death of six siblings. Dietary
      treatment during neonatal adaptation and the subsequent six months of life and a
      trial of carnitine supplementation are reported. The rapidity with which long
      chain fatty acid metabolites can accumulate and induce secondary carnitine
      deficiency within a few hours after birth in an infant with CATR is noteworthy.
      CONCLUSION: High rates of glucose suppressed neonatal lipolysis in this infant,
      but did not seem sufficient to avoid secondary carnitine deficiency as in severe
      forms of CATR. Therefore simultaneous use of insulin and glucose may be necessary
      to control neonatal lipolysis. Carnitine supplementation and the possible adverse
      effects of MCT systematically administrated, should be further assessed in
      patients with CATR.

PMID- 10653337
TI  - Carotenoid supply in breast-fed and formula-fed neonates.
AB  - Carotenoids have various biological functions including their role as
      antioxidants. For humans fruits and vegetables are the only source of
      carotenoids. In the first months breast milk and/or formula preparations are the
      only nutrition for infants. To study the influence of nutrition on the plasma
      carotenoid profile in newborns, breast milk, different formula preparations, and
      the plasma of breast-fed (BF) and formula-fed (FF) newborns were analyzed by high
      performance liquid chromatography. The method used allowed beta-carotene, alpha
      carotene, lycopene, and beta-cryptoxanthine to be detected and all four were
      found in breast milk. In colostrum carotenoids were up to five times higher than
      in mature breast milk (P<0.05). In contrast, not all carotenoids could be found
      in formula preparations. Beta-carotene was detected in four out of eight, and
      beta-cryptoxanthine in three out of eight formula preparations. Lycopene and
      alpha-carotene were not detectable in any of the formula preparations. Four
      formula preparations did not contain any carotenoids. FF infants had different
      plasma carotenoid profiles compared to BF infants. beta-carotene was
      significantly lower in FF infants [14 (0-32) microg/l, median and interquartile
      ranges] than in infants after birth [24 (19-310) microg/l, P<0.05], and BF
      infants [32 (22-63) microg/l, P<0.05]. While newborns after birth had measurable
      plasma concentrations of lycopene (16 [14-18] microg/l) and of alpha-carotene [5
      (0-8) microg/l), these carotenoids were no longer detectable in FF infants after
      day 14. CONCLUSION: FF and BF infants show significant biochemical differences in
      plasma carotenoid concentrations.

PMID- 10653338
TI  - Presence of metabolic cardiovascular syndrome in obese children.
AB  - The aim of the present study was to investigate the aggregation of cardiovascular
      risk factors (hyperinsulinaemia, impaired glucose tolerance, dyslipidaemia, and
      hypertension) in 180 (77 female, 103 male) obese and 239 control children. Blood
      glucose, serum insulin and lipid levels were determined from blood samples taken
      after an overnight fast. Oral glucose tolerance tests were performed and blood
      glucose concentrations were monitored. The body mass index, body fat (on the
      basis of skinfold measurements), lean body mass and waist/hip ratio were
      calculated and blood pressure was measured five times in all subjects. It was
      shown that only 14.4% of obese children were free from any risk factors, in
      contrast to 79.1% of the control children. Four risk factors (metabolic
      cardiovascular syndrome) were found in 8.9% of the obese children (8.7% in males
      and 9.1% in females) while none could be detected in controls. Considerable
      differences were also detected in the prevalence of one, two or three risk
      factors between control and obese children. Patients with the metabolic
      cardiovascular syndrome could not be characterized by any of the investigated
      anthropometric characteristics, but the duration of obesity was significantly
      longer in these children. CONCLUSION: Potential risk factors for cardiovascular
      diseases already tend to cluster in childhood and they are strongly associated
      with obesity. Our observations suggest that the development of the metabolic
      cardiovascular syndrome has its origin in childhood.

PMID- 10653339
TI  - Diagnostic approach to primary ciliary dyskinesia: a review.
AB  - Primary ciliary dyskinesia (PCD) is a heterogeneous disease with impaired
      mucociliary transport leading to respiratory disorders, hearing impairment and
      male infertility. PCD can be diagnosed by clinical features together with
      functional and structural analysis of the cilia. To prevent bronchiectasis with a
      marked reduction in quality of life, early diagnosis is essential. The rarity of
      PCD and the costs of ultrastructural analysis of cilia require a rational
      diagnostic concept. We therefore reviewed the literature and compared clinical
      manifestations as well as functional and structural analyses of the cilia in 28
      patients (23 children, 5 adults) investigated between 1990 and 1998. All were
      thoroughly examined for other possible diseases before biopsy, and ten patients
      (35.7%; eight children, two adults) were diagnosed as having PCD. From the
      literature review and our findings we conclude that ciliary investigation is
      indicated (a) in patients who remain suspected of having PCD despite thorough
      clinical examination and exclusion of other disorders such as cystic fibrosis,
      allergy, immunologic disorders and alpha1-antitrypsin deficiency; (b) in patients
      with situs inversus suffering from chronic and/or recurrent airway infections;
      and (c) in patients with neonatal respiratory distress syndrome of "unknown"
      cause (i.e. after exclusion of hyaline membrane disease, aspiration syndromes,
      neonatal pneumonia, and pneumothorax as well as cardiovascular and metabolic
      diseases). CONCLUSION: The combination of extensive clinical examination with
      functional and ultrastructural analysis of the cilia results in a high degree of
      accuracy in diagnosing PCD.

PMID- 10653340
TI  - Buccal cell DNA analysis in premature and term neonates: screening for mutations
      of the complete coding region for the cystic fibrosis transmembrane conductance
      regulator.
AB  - Traditionally, cystic fibrosis (CF) is diagnosed either by measuring sweat
      electrolyte levels or by screening for mutations using genomic DNA isolated from
      leucocytes. The aim of this work was to develop a modified fast and non-invasive
      tool for the collection of cell samples and the genetic analysis of the entire
      coding region for the cystic fibrosis transmembrane conductance regulator (CFTR)
      in newborns, especially premature infants. Cell samples were taken by scraping
      the buccal mucus with tiny dental brushes, followed by DNA isolation and mutation
      analysis using SSCP-heteroduplex (single-strand conformation polymorphism)
      screening and sequencing. We have demonstrated that buccal cell DNA collected
      from premature and term newborns yields sufficient DNA (at least 60 ng) to
      perform a mutation screening of the complete CFTR coding region, independently of
      the patients' weight (mean 2200 g) or gestational age (mean 35 weeks). The high
      stability of the samples at room temperature admits the possibility of dry
      shipment of samples collected elsewhere to the diagnostic laboratory. CONCLUSION:
      This fast, non-invasive sampling and DNA isolation method allows for early
      diagnosis of CF, initiation of therapy and minimisation of parental uncertainty
      and offers a technique for mutation analysis in any other monogenic disorder.

PMID- 10653341
TI  - Low serum inhibin B levels as a marker of testicular damage after treatment for a
      childhood malignancy.
AB  - The aim of this study was to evaluate the role of inhibin B and the determination
      of its concentration to diagnose testicular damage after treatment for a
      childhood malignancy. Thirty-seven males treated for Hodgkin disease (n = 11) or
      non-Hodgkin lymphoma (n = 26) were examined at a mean age of 16.9+/-2.9 years.
      Mean age at the stop of therapy was 11.3+/-3.0 years and in most cases the
      chemotherapy regimen included gonadal damaging alkylating agents. Thirty-three
      normal males (mean age 17.9+/-4.1 years) were examined as controls. Serum samples
      were collected for determination of inhibin B, follicle-stimulating hormone
      (FSH), luteinizing hormone (LH), and testosterone. Median inhibin values were
      significantly lower in patients than in controls (96.0 vs. 225.0 pg/ml, P<0.0001)
      and a strong negative correlation was found between inhibin B and FSH (r = -0.86,
      P<0.0001), a weak correlation with LH (r = -0.32, P<0.05) and no correlation with
      testosterone. In post-pubertal patients (i.e., over 16 years) a positive
      correlation was found between testicular size and inhibin level (r = 0.53,
      P<0.05), but not between testicular size and testosterone level. Pathological low
      levels (values that differed by more than 2 SD from the mean value of control
      subjects) were found in 20 patients for inhibin B and 8 for testosterone (P<0.01)
      and pathological high values in 19 patients for FSH and 3 for LH. CONCLUSION:
      This study confirms the role that inhibin B plays in the regulation of FSH
      secretion and provides further evidence of the utility of its evaluation as a
      direct indicator of male gonadal dysfunction.

PMID- 10653342
TI  - Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency and early-onset liver
      cirrhosis in two siblings.
AB  - We present the clinical, pathological, biochemical, and molecular results on an
      infant girl with long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency and
      data on her deceased elder brother for whom this condition was retrospectively
      diagnosed. Clinical signs were liver enlargement and elevated liver enzymes,
      failure to thrive, and neurological disease (coma, seizures) triggered by an
      infectious stress. In the second child hepatic failure and status epilepticus
      developed during the onset of a rotavirus gastroenteritis. A barbituric coma was
      induced, but hypotonia and lack of eye pursuit persisted after suppression of
      antiepileptic drugs. She ultimately died of heart failure. Unlike previously
      reported cases, both of these patients had early-onset cirrhosis, and severe
      neurological disease was observed in the second child. CONCLUSION: Liver
      cirrhosis and brain damage may be underestimated in cases of long-chain 3
      hydroxyacyl-coenzyme A dehydrogenase deficiency and may occur early in life.

PMID- 10653343
TI  - Sclerosing cholangitis associated to cryptosporidiosis in liver-transplanted
      children.
AB  - Three children of a series of 461 pediatric liver transplant recipients developed
      diffuse cholangitis associated with intestinal cryptosporidium carriage. All
      three received immunosuppression consisting of tacrolimus and prednisone.
      Cryprosporidium carriage was treated with paramomycin, while immunosuppression
      was decreased according to graft tolerance. No other infectious pathogens were
      found, and no vascular problems were detected. Bile duct anastomosis was
      reoperated in all three, but biliary cirrhosis developed in one patient,
      requiring retransplantation. All three patients are alive and well, and free of
      intestinal parasites on follow-up. CONCLUSION: Cryptosporidium intestinal
      infection may play a role in some cases of otherwise unexplained cholangiopathies
      in pediatric liver transplant recipients. This may lead to significant morbidity,
      including need for retransplantation.

PMID- 10653344
TI  - The relationship between European paediatricians and commerce: ethical principles
      in paediatrics working group recommendations. Confederation of European Societies
      of Paediatrics (CESP).
AB  - It is important that doctors have an ethically proper relationship with
      commercial interests. The relationship between paediatricians, paediatric
      societies and industry is probably healthy. To further the interests of patients
      it is important that it remains so. CONCLUSION: This mentionship would be
      undermined if: there was a perceived conflict of interests between
      paediatricians, their patients and industry; paediatricians were seen to endorse
      companies whose marketing and other practices were unethical. It will be enhanced
      if: paediatricians did not receive individual gain from industry; industrial
      support for educational and research activities, whether to individuals or
      institutions, is open, proportionate and accountable.

PMID- 10653345
TI  - A child with abnormal features and expressive dysphasia.

PMID- 10653346
TI  - A girl with poor school performance.

PMID- 10653347
TI  - An infant with chronic diarrhoea and failure to thrive.

PMID- 10653348
TI  - The effectiveness of single and multiple applications of triple dye on umbilical
      cord separation time.

PMID- 10653349
TI  - Cosmetic sequelae of thoraco-amniotic shunting.

PMID- 10653350
TI  - One hundred courses of high frequency oscillatory ventilation: what have we
      learned?

PMID- 10653351
TI  - Myocarditis associated with parvovirus B19 infection in two siblings with merosin
      deficient congenital muscular dystrophy.

PMID- 10653352
TI  - The infection risk of oesophageal dilatations.

PMID- 10653353
TI  - Transient heart block in a newborn due to maternal antipsychotic treatment during
      pregnancy.

PMID- 10653354
TI  - Gefiltin in zebrafish embryos: sequential gene expression of two neurofilament
      proteins in retinal ganglion cells.
AB  - Neurogenesis is correlated with the progressive synthesis of diverse neuronal
      intermediate filaments (IF) proteins. This apparent developmental regulation of
      IF protein gene expression suggests that specific neurofilament proteins impart
      unique structural attributes that support the staged growth of the neuron. In the
      teleost visual pathway, the sequential expression of two IF genes, plasticin and
      gefiltin, is linked to the age of retinal ganglion cells (RGCs) and to the
      regeneration of optic axons after nerve injury. Given this pattern of plasticin
      and gefiltin expression, we hypothesized that the two proteins would be
      sequentially expressed in zebrafish retina during development. We analyzed the
      pattern of gefiltin expression during zebrafish development and compared it to
      our previous determination of plasticin expression (Canger et al. 1998). Gefiltin
      is expressed after plasticin, during the later stages of retinal development when
      axons grow past the optic chiasm and innervate their targets. Thus, during RGC
      development, expression of plasticin and gefiltin resembles that with optic nerve
      regeneration. Outside of the visual pathway, gefiltin is predominantly expressed
      in the central nervous system whereas plasticin is primarily expressed in the
      peripheral nervous system. These results suggest that the expression of these
      genes is regulated in a neuron-specific manner. In addition, since plasticin and
      gefiltin are co-expressed during RGC development, these findings suggest a more
      complex mechanism of transcriptional regulation which orchestrates the sequential
      expression of these genes.

PMID- 10653355
TI  - Dynamic and tissue-specific expression of eIF4E during zebrafish embryogenesis.
AB  - The regulation of protein synthesis is critical to diverse cellular processes and
      plays a pivotal role in regulating gene expression during embryogenesis. The cap
      binding protein eIF4E is a translational factor whose activity appears to be both
      ubiquitous and central to the regulation of protein synthesis in all cell-types.
      As a cell-cycle regulator, mesoderm inducer and proto-oncogene, the amount and
      activity of the translational factor eIF4E must be under strict control, but the
      range of its expression and its concentration as a function of position and time
      in the developing embryo are unknown. Consequently, we have initiated studies to
      elucidate the expression of the eIF4E gene and its role in the regulating
      embryonic development. We have cloned a zebrafish gene encoding eIF4E, zeIF4E,
      and measured its developmental expression. Unexpectedly, we found that the zeIF4E
      gene produces two alternatively spliced transcripts that potentially encode
      different forms of the initiation factor. Molecular analyses and in situ
      hybridization reveal a potential role for eIF4E in regulating protein synthesis
      during vertebrate oogenesis, gastrulation, and erythropoiesis. The dynamic and
      asymmetric expression of eIF4E during zebrafish embryogenesis reveals that this
      ostensibly general translation factor may act as a tissue-specific translational
      enhancer.

PMID- 10653356
TI  - Changes in FGF and FGF receptor expression in low-frequency-stimulated rat
      muscles and rat satellite cell cultures.
AB  - This study compares effects of chronic electrical stimulation on the expression
      levels of FGF-1, FGF-2 and their receptors (FGFRI, FGFR4) in rat tibialis
      anterior (TA) muscle of hypothyroid rat, as well as in satellite cell cultures
      derived from normal rat TA and soleus (SOL) muscles. In 5-day (5-d)-stimulated
      hypothyroid TA muscle, FGF-1 and FGF-2 mRNA levels were threefold elevated over
      control. FGFR1 and FGFR4 mRNAs were twofold and 1.5-fold elevated, respectively.
      In longer stimulated muscles, FGF-1 and FGFR4 mRNAs returned to basal levels,
      whereas FGF-2 mRNA remained elevated. FGFR1 mRNA decreased to control levels in
      10-d stimulated muscles, but increased again after 20 days of stimulation. SOL-
      and TA-derived satellite cell cultures were stimulated for 5 days. At this time
      point, changes in myosin heavy chain isoforms were detectable consisting of
      increases in MHCI mRNA and decreases in MHCIIb and MHCIId mRNA. The comparison
      between 5-d-stimulated hypothyroid TA muscle and 5-d-stimulated TA- and SOL
      derived satellite cell cultures revealed differences in the expression of FGF-1
      and FGF-2, but similar expression levels of FGFR1 and FGFR4. Even though FGF-1
      and FGF-2 mRNAs were elevated in the satellite cell cultures, their increases
      were less pronounced than in the stimulated hypothyroid muscle. Taking into
      consideration that skeletal muscle contains muscle fibres and various non-muscle
      tissues, e.g. blood vessels, these results suggest that the latter contribute to
      the observed increases in FGF-1 and FGF-2 expression in stimulated muscle.

PMID- 10653357
TI  - Expression patterns of gap junctional proteins connexin 32 and 43 suggest new
      communication compartments in the gastrulating rabbit embryo.
AB  - A central problem in embryological research is the identification of mechanisms
      by which control over the development of a viable individual is maintained. An
      important role in this process is attributed to intercellular communication the
      preconditions of which were examined in the present study. Using a range of
      monoclonal antibodies, the expression patterns of the gap junctional proteins
      connexin 32 (Cx32) and connexin 43 (Cx43) were examined in whole-mount
      preparations and cryosections of gastrulating rabbit embryos between 6.0 and 7.5
      days post conception. Distinct distribution patterns for Cx32 and Cx43,
      respectively, were found: Cx32 was exclusively expressed in the hypoblast and
      yolk sac epithelium (the lower layer of the embryo) whereas Cx43-expression was
      limited to the epiblast (in the upper layer) and its derivatives. Moreover, the
      dynamics of the Cx32 and Cx43 expression patterns indicate the existence of
      smaller tissue compartments within the three embryonic cell layers present at the
      beginning of gastrulation (epiblast, mesoderm and hypoblast). The most striking
      one of these smaller compartments is a belt-like area within the lower layer
      which straddles the epiblast-trophoblast border seen in the upper layer of the
      embryonic disc. The significance of these compartments for initiating and
      maintaining the gastrulation process is discussed.

PMID- 10653358
TI  - Basonuclin in murine corneal and lens epithelia correlates with cellular
      maturation and proliferative ability.
AB  - Basonuclin is a zinc finger protein with highly restricted tissue distribution.
      It has been found in abundance only in keratinocytes of stratified epithelia and
      the germ cells of the testis and ovary. We studied the expression pattern of
      basonuclin in relation to cellular proliferation and differentiation in murine
      corneal and lens epithelia, two self-renewing tissues in the eye which contain
      cells that proliferate throughout life. Mouse corneal and lens epithelial cells
      at various stages of development were labeled with BrdU for 90 min to detect
      cells in S phase and to establish proliferative rates. Whole eyes of mouse or rat
      were processed for frozen sections and cellular basonuclin was detected by either
      a rabbit antimouse- or a rabbit anti-human-basonuclin antibody. Basonuclin was
      expressed in virtually all cells in the basal layer of corneal epithelium and in
      the pre-equatorial lens epithelium, the respective proliferative compartments of
      adult corneal and lens epithelia. Basonuclin expression in corneal epithelium
      began at post-natal life day 4, first in a few cells and then spread to virtually
      all basal cells at day 20. Basonuclin was consistently absent in limbal
      epithelium. Lens basonuclin, which was detected earlier than that of the cornea,
      was confined to the pre-equatorial epithelium and was absent in equatorial cells
      that expressed p57KIP2, an early differentiation marker for these cells. An
      important distinction between corneal and lens basonuclin is that the former is
      predominantly nuclear whereas the latter cytoplasmic.

PMID- 10653359
TI  - A novel member of murine Polycomb-group proteins, Sex comb on midleg homolog
      protein, is highly conserved, and interacts with RAE28/mph1 in vitro.
AB  - The Polycomb group of (PcG) genes were originally described in Drosophila, but
      many PcG genes have mammalian homologs. Genetic studies in flies and mice show
      that mutations in PcG genes cause posterior transformations caused by failure to
      maintain repression of homeotic loci, suggesting that PcG proteins have conserved
      functions. The Drosophila gene Sex comb on midleg (Scm) encodes an unusual PcG
      protein that shares motifs with the PcG protein polyhomeotic, and with a
      Drosophila tumor suppressor, lethal(3)malignant brain tumor (l(3)mbt). Expressed
      sequence tag (EST) databases were searched to recover putative mammalian Scm
      homologs, which were used to screen murine cDNA libraries. The recovered cDNA
      encodes two mbt repeats and the SPM domain that characterize Scm, but lacks the
      cysteine clusters and the serine/threonine-rich region found at the amino
      terminus of Scm. Accordingly, we have named the gene Sex comb on midleg homolog 1
      (Scmh1). Like their Drosophila counterparts, Scmh1 and the mammalian polyhomeotic
      homolog RAE28/mph1 interact in vitro via their SPM domains. We analyzed the
      expression of Scmh1 and rae28/mph1 using northern analysis of embryos and adult
      tissues, and in situ hybridization to embryos. The expression of Scmh1 and
      rae28/mph1 is well correlated in most tissues of embryos. However, in adults,
      Scmh1 expression was detected in most tissues, whereas mph1/rae28 expression was
      restricted to the gonads. Scmh1 is strongly induced by retinoic acid in F9 and
      P19 embryonal carcinoma cells. Scmh1 maps to 4D1-D2.1 in mice. These data suggest
      that Scmh1 will have an important role in regulation of homeotic genes in
      embryogenesis and that the interaction with RAE28/mph1 is important in vivo.

PMID- 10653360
TI  - MR imaging of inflammatory joint diseases of the foot and ankle.
AB  - Pain affecting the foot and ankle is a common complaint frequently attributable
      to inflammatory joint diseases. Although conventional radiography is regarded as
      the initial step in the diagnostic investigation, MR imaging may contribute to
      further evaluation of these patients due to the direct visualization of the
      inflammatory soft tissue formed in the disease and its effects on bone, cartilage
      and para-articular structures. The high spatial resolution of MR imaging combined
      with tissue characterization often allows initial detection of inflammatory joint
      abnormalities at a stage that precedes radiographic evaluation. The typical MR
      appearance of certain inflammatory joint disorders may be helpful in narrowing
      the wide differential diagnosis. Furthermore, MR imaging can be used for an exact
      assessment of the extent of the disorder as well as its complications. Accurate
      diagnostic information can guide the clinician in further diagnostic tests and
      implementation of proper therapeutic treatment.

PMID- 10653361
TI  - Internal derangements of the shoulder: decision tree and cost-effectiveness
      analysis of conventional arthrography, conventional MRI, and MR arthrography.
AB  - PURPOSE: In a patient with internal derangement of the shoulder, the diagnostic
      method of choice is controversial. Conventional arthrography can diagnose most
      rotator cuff tears accurately; however, in many institutions MR arthrography is
      usually necessary to diagnose labral tears. We utilized decision tree methodology
      to compare the cost-effectiveness of conventional arthrography and conventional
      MRI with a hypothetical algorithm in which a patient underwent arthrography,
      performed with admixed gadolinium, which if negative, was followed by MRI.
      DESIGN: The use of double-contrast arthrography alone, conventional MRI alone,
      and gadolinium-enhanced MRI used as an adjunct to conventional arthrography were
      modeled for the diagnosis of full-thickness rotator cuff tears (RCT), partial
      RCTs, labral tears, and the absence of cuff/labral tears using decision analysis
      methodology. English language medical publications were searched to determine the
      base probabilities for the accuracy of the diagnostic tests. The outcome
      utilities ranged from -1 to +1 to reflect the value of correct diagnostic
      evaluation. Charges for diagnostic tests and appropriate surgical treatments were
      based on 1997 Medicare reimbursement rates for professional fees and hospital
      charges in an outpatient setting. Sensitivity analyses were performed to evaluate
      the effects of uncertainty regarding the prevalence of each disease state and the
      accuracy of several diagnostic tests. RESULTS: In the base-case analysis, the
      average effectiveness of double-contrast arthrography alone, MRI alone and
      arthrography selectively followed by MRI were 0.6610, 0.6715, and 0.7204,
      respectively. The average costs for each of these strategies were $1090, $2033,
      and $2339, respectively. CONCLUSION: Arthrography performed with admixed diluted
      gadolinium, which if negative is immediately followed by MRI, was somewhat more
      expensive than conventional MRI. However, because of much greater effectiveness,
      cost-effectiveness was significantly higher for our proposed algorithm.
      Conventional arthrography without gadolinium, although less expensive, had
      severely limited effectiveness.

PMID- 10653362
TI  - Stress fractures of the lateral metatarsal bones in metatarsus adductus foot
      deformity: a previously unrecognized association.
AB  - OBJECTIVE: To document a distinctive pattern of stress fractures in the lateral
      metatarsal bones of patients with metatarsus adductus foot deformity. DESIGN AND
      PATIENTS: Conventional radiographs and available medical records were reviewed in
      11 patients (6 women, 5 men; ages 25-61 years) with stress fractures of the
      lateral (fourth or fifth) metatarsal bones and metatarsus adductus. Evaluation
      included the number and location of fracture(s), forefoot adduction angle, and
      qualitative assessment of bone mineral density. Conditions that might predispose
      patients to metatarsal fractures, including direct trauma, osteoporosis, and
      neuropathic osteoarthropathy were also recorded. RESULTS: A total of 22 stress
      fractures were demonstrated, 17 of which involved the lateral metatarsals. A
      solitary fracture was present in six patients, while multiple fractures were
      evident in five patients. The sites of involvement were the fifth metatarsal
      (n=10), fourth metatarsal (n=7), third metatarsal (n=3), second metatarsal (n=1),
      and first metatarsal (n=1) bones. The locations of the stress fractures were in
      the proximal one-third of the metatarsal bones in 19 instances (86%) and in the
      middle one-third in three instances (14%). Forefoot adduction angle measured
      between 21 degrees and 37 degrees (normal range 8 degrees -14 degrees).
      CONCLUSION: Patients with metatarsus adductus may be at increased risk for stress
      fractures involving the lateral metatarsal bones, likely owing to the presence of
      altered biomechanics that place greater loads across the lateral aspect of the
      foot.

PMID- 10653364
TI  - Posteromedial subtalar coalition: imaging appearances in three cases.
AB  - OBJECTIVE: To define the imaging appearances in three cases of posteromedial
      subtalar coalition. DESIGN: Three patients who presented with hindfoot pain were
      found to have non-osseous coalition involving the posteromedial hindfoot. This
      entity is distinct from conventional middle facet coalition as the sustentaculum
      is uninvolved. RESULTS: Plain radiographs, available in two cases, demonstrated
      subtle irregularity of the posterior facet. MRI (three cases) demonstrated a
      mixed bony and cartilaginous mass lying posterior to the sustentaculum. There was
      trabecular oedema within the mass and adjacent talus, and narrowing of the space
      between the middle and posterior facets. Prominence and dilatation of the
      posterior tibial veins with tenosynovitis of the adjacent tibialis posterior
      tendon was seen. CT demonstrated the bony mass but did not detect the adjacent
      bony oedema. CONCLUSION: Posteromedial subtalar coalition may present with
      hindfoot pain and stiffness. The presence of a pseudarthrosis posterior to a
      normal middle facet is characteristic. The abnormality can be difficult to detect
      on plain radiographs.

PMID- 10653363
TI  - Fat-suppressed fast spin-echo mid-TE (TE[effective]=34) MR images: comparison
      with fast spin-echo T2-weighted images for the diagnosis of tears and anatomic
      variants of the glenoid labrum.
AB  - OBJECTIVE: To compare the sensitivity, specificity, and accuracy of fat
      suppressed fast spin-echo (FSE) mid-TE (TE[effective]=34) images with fat
      suppressed FSE T2-weighted images for the diagnosis of labral abnormalities.
      DESIGN AND PATIENTS: The study included 27 consecutive patients who had axial fat
      suppressed FSE T2-weighted and fat-suppressed FSE mid-TE MR images, and had
      labral abnormalities diagnosed at arthroscopy. The acquisition time was about 5
      min for each sequence, but the mid-TE sequence allowed a higher spatial
      resolution than the T2-weighted images (256x256 versus 256x192). Twenty-eight age
      matched patients with arthroscopically normal labra were included as a control
      group. The labrum was graded on the MR images as normal or abnormal separately by
      two musculoskeletal radiologists who were masked to the history and arthroscopic
      results. The surgical findings were used as the gold standard for calculating the
      sensitivity, specificity, and accuracy for interpreting the correct location of a
      labral abnormality. The sensitivity, specificity, and accuracy for the two
      sequences were compared with a McNemar test, and significance defined as P<0.05.
      RESULTS: For observer 1, the sensitivity for labral abnormalities was 0.59 on the
      T2-weighted images, and 0.78 on the mid-TE images (P=0.12). The specificity was
      0.54 for the T2-weighted, and 0.64 for the mid-TE images (P=0.51). The accuracy
      was 0.56 for the T2-weighted, and 0.71 for the mid- TE images (P=0.08). For
      observer 2, the sensitivity/specificity/accuracy was 0.67/0.93/0.80 for the T2
      weighted, and 0.70/0.86/0.78 for the mid-TE images (all P>0.5). CONCLUSION: In
      this small study there is no statistically significant difference for
      demonstrating labral abnormalities between FSE T2-weighted images, and higher
      resolution fat-suppressed FSE mid-TE (TE[effective]=34) images obtained with a
      similar acquisition time. Although there was a general trend toward higher
      sensitivity and accuracy with the mid-TE sequence, particularly for one of the
      two observers, a larger study is needed to determine whether this is the
      preferred single axial pulse sequence for conventional MR imaging of the labrum.

PMID- 10653365
TI  - Precision and intersite correlation of bone densitometry at the radius, tibia and
      femur with peripheral quantitative CT.
AB  - OBJECTIVE: To compare the in situ precision of peripheral quantitative CT (pQCT)
      at the radius, tibia and femur, and to analyze the intersite correlation, in
      order to determine whether measurements at the lower extremity reproduce results
      at the radius or are of additional informative value. DESIGN AND MATERIAL: pQCT
      measurements were performed in 86 elderly cadavers (mean age 80.5 years) at
      trabecular and cortical locations in the radius, tibia and femur, determining
      densitometric (bone mineral content and density) as well as geometric parameters
      (cross-sectional area, cortical thickness, polar moment of inertia and others).
      In 14 cadavers, repeated measurements were obtained at all sites on four
      different days. RESULTS AND CONCLUSIONS: At cortical sites, the precision for the
      densitometric and geometric variables ranged from 0.4% to 4.3%, and was similar
      for the radius, tibia and femur. At trabecular locations, the reproducibility of
      the density measurements ranged from 1.8% to 2.5% at the radius, and from 3.2% to
      5.9% at the femur and tibia. The intersite correlation of the total bone mineral
      content ranged from 0.87 and 0.97 at cortical sites, and from 0.63 to 0.85 at
      trabecular locations. The trabecular density showed a higher similarity between
      the tibia and femur (r=0.68-0.78) than between the radius and the lower extremity
      (r=0.41-0.45). The results demonstrate a substantial heterogeneity of trabecular
      bone in elderly individuals and advocate measurements directly at the site of
      clinical or scientific interest.

PMID- 10653366
TI  - Proliferative myositis in a child.
AB  - A case of proliferative myositis in the lumbar paraspinal muscles in a 14-year
      old boy is presented. Imaging investigations including plain radiograph,
      ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), bone scan
      and positron emission tomography (PET) were suggestive of an inflammatory process
      such as myositis ossificans. The diagnosis was made by incisional biopsy. More
      pronounced edema, more muscle fiber necrosis and a higher cellularity were found
      compared to adult cases. The karyotype of the lesion was normal. Clinically, the
      mass disappeared spontaneously. After 24 months, asymptomatic bridging
      ossification between the third and fourth lumbar vertebrae was noted.

PMID- 10653367
TI  - Recurrent, multiple, calcified soft tissue metastases from osteogenic sarcoma
      without pulmonary involvement.
AB  - Osteosarcoma (osteogenic sarcoma) metastasizes primarily to the lung. With the
      introduction of neoadjuvant chemotherapy as part of the treatment, the overall
      and disease-free survival rates have dramatically improved. In this case report,
      a young man with multiple soft tissue and bone metastases, including a rare large
      bone-forming retroperitoneal metastasis, is described. Despite the extensive
      extrapulmonary metastases, the patient did not develop pulmonary metastases in
      the 4 years following initial presentation of the primary tumour.

PMID- 10653368
TI  - Intramuscular metastasis from malignant melanoma: MR findings.
AB  - We present a rare case of intramuscular metastasis from malignant melanoma. The
      lesion showed intermediate to high signal intensity on T1-weighted magnetic
      resonance (MR) images and mixed signal intensities containing high and low
      signals on T2-weighted images. The signal intensity on T1-weighted images, which
      is due to the paramagnetic effect of melanin, is a characteristic MR finding of
      this entity.

PMID- 10653369
TI  - Progressive destructive vertebral sarcoid leading to surgical fusion.
AB  - Skeletal sarcoidosis is rare. This report describes a 31-year-old African
      American man who presented with a destructive osteolytic lesion of C2 and another
      lesion in a rib. The lesion at C2 was treated with corpectomy and bone graft.
      Four months later the lesion recurred and a new lesion was discovered in the
      cervical vertebral column. The patient declined surgery for instability for
      another 3 months, choosing to remain in a halo. Seven months following the
      initial operation, a technetium bone scan showed spread of the disease to the
      calvarium and thoracic and lumbar vertebrae. The patient had no symptoms
      referable to these sites. The patient agreed to have his neck fused at this
      point. For the next 10 months, the patient was on steroids and a further new
      lesion appeared at L5 without localizing signs or symptoms. The patient declined
      further evaluation over the next 12 months and is now considered lost to follow
      up.

PMID- 10653370
TI  - Analyzing risk factors of renal transplant outcome.

PMID- 10653371
TI  - Successful hepatic grafting after partial portal vein ligation in the rat:
      complete reversal of hemodynamic abnormalities.
AB  - BACKGROUND: Partial portal vein ligation (PPVL) is an established approach in the
      study of prehepatic portal hypertension in animals. The effect of orthotopic
      liver transplants (OLT) on hemodynamics in PPVL animals has not been investigated
      to date. The aim of this study was to develop a model of OLT in PPVL rats and to
      investigate its hemodynamic consequences. METHODS: Three groups of male Lewis
      rats were investigated (1) control animals (n=7), (2) PPVL (n=9), and (3)
      PPVL/OLT (n=16). Three weeks after PPVL, 9 animals were taken for hemodynamic
      measurements. OLT was performed in the remaining 16 PPVL rats (PPVL/OLT), and, 4
      weeks later, hemodynamic measurements were made. Blood biochemical analysis was
      performed at different time points in all 3 groups. RESULTS: The PPVL animals
      presented with hyperdynamic systemic circulation, extensive collateral
      vascularization in the hilar region, and portal-systemic shunting (portal
      systemic shunting; 35.3+/-5.5%). In the PPVL/OLT group, 15 rats survived for 4
      weeks (survival: 93.8%, 15 of 16). Of these PPVL/OLT rats, 3 died during the
      blood sampling protocol. In 3 PPVL/OLT rats, abnormal liver function and
      histology were found and deranged systemic and hepatic hemodynamics persisted
      after OLT. In the remaining 9 PPVL/OLT rats, systemic and hepatic hemodynamics
      had returned to normal at 4 weeks and portal systemic shunting was markedly
      reduced (2.5+/-0.9%). Liver function was in the normal range. CONCLUSIONS: (1)
      The possibility of performing OLT in PPVL rats with a high rate of survival has
      been confirmed. (2) In the majority of cases, complete reversal of hemodynamic
      abnormalities in the PPVL animals occurs after OLT (3). PPVL/OLT represents a new
      and important model in OLT research.

PMID- 10653372
TI  - Reconstruction of the intestinal lymphatic drainage after small bowel
      transplantation.
AB  - BACKGROUND: The surgical procedure of small bowel transplantation normally
      results in complete disruption of the graft's lymphatic drainage. The present
      study was undertaken to determine the impact of lymphatic reconstruction (LR) on
      the outcome of intestinal grafting, using a microsurgical model that immediately
      restores lymphatic drainage. MATERIALS: Brown Norway (RT1n) intestinal grafts
      were orthotopically transplanted into Lewis (RT1(1)) rats either with LR (+LR) or
      without LR (-LR). Recipients were randomly allocated into the following groups:
      no treatment or cyclosporine (CsA) at a dose of 2, 5, or 10 mg/kg/day
      subcutaneously from postoperative day (POD) 0 to 6. RESULTS: There was
      morphological regeneration of lymphatics in the -LR group between 1-3 weeks as
      previously reported, whereas normal lymph flow was immediately restored in the
      +LR group. All untreated and CsA(2 mg)-treated allografts were rapidly rejected
      in both the +LR and -LR groups. In the groups treated with approximately 5 mg of
      CsA, five of six -LR animals died of chronic rejection between 38 and 86 days
      (mean survival time +/- SD: 76.7+/-21 days), while all +LR animals survived until
      death on POD 100 (P < 0.05). Histological features of mucosal damage found in -LR
      grafts were absent in the +LR grafts. All of the animals treated with 10 mg of
      CsA survived indefinitely. Sequential histology revealed mild rejection in -LR
      and +LR grafts on POD 45, but +LR animals had significantly higher body weight
      gains (POD 50: -LR: 117+/-12% vs. +LR: 136+/-4%, P < 0.01). LR did not affect
      donor cell migration and nutritional parameters. CONCLUSION: LR improves the long
      term results of small bowel transplantation resulting in better survival rates,
      less mucosal damage due to chronic graft rejection, and greater weight gain. We
      conclude that impairment of lymph flow may contribute to poor outcomes when
      standard surgical techniques are used for small bowel transplantation.

PMID- 10653373
TI  - Cardioprotective effect of diadenosine tetraphosphate (AP4A) preservation in
      hypothermic storage and its relation with mitochondrial ATP-sensitive potassium
      channels.
AB  - BACKGROUND: The preconditioning effect of diadenosine tetraphosphate (AP4A) was
      reported in ischemia/reperfused hearts, but its effect in heart preservation was
      unknown. According to the possible role of mitochondrial ATP-sensitive potassium
      channel (mK(ATP) channel) in the effect of ischemic preconditioning, the
      contribution of mK(ATP) channel to the effect of AP4A was tested. METHODS:
      Isolated rat hearts were arrested and preserved by Eurocollin's (EC) solution at
      4 degrees C for 8 hr. AP4A (80 microM) or AP4A with the 5-hydroxydecanoic acid
      (100 microM), a selective inhibitor of the mK(ATP) channel, was added into the EC
      solution. The preischemic and postischemic cardiac functions were evaluated on a
      buffer-perfused Langendorff apparatus before storage and after 20 min of
      reperfusion. RESULTS: AP4A administration improved the recovery of poststorage
      cardiac functions (the rate-pressure production, left ventricular systolic
      pressure, heart rate, coronary flow rate, and derivative of left ventricular
      systolic pressure; P<0.05) and reduced the leakage of lactate dehydrate and
      creatine kinase during reperfusion, compared with EC alone. Those effects of AP4A
      were completely reversed by 5-hydroxydecanoic acid administration in combination
      subjects. CONCLUSION: AP4A administration protects the heart through opening of
      the mK(ATP) channel during hypothermic preservation. Thus, addition of AP4A into
      cardioplegia may be a novel method of ischemic preconditioning in the
      transplantation context.

PMID- 10653374
TI  - Effect of warm ischemia time and organ perfusion technique on liver microvascular
      preservation in a non-heart-beating rat model.
AB  - BACKGROUND: Current organ shortage has led to a reconsideration of non-heart
      beating cadaveric donation. METHODS: We assessed the effectivity of dual, i.e.,
      arterial and portal-venous versus exclusive, arterial gravity perfusion for
      procurement of rat livers after 30 min and 60 min of cardiac arrest, analyzing
      the rate and homogeneity of microvascular perfusion by in situ fluorescence
      microscopy. RESULTS: After 30 min of cardiac arrest, a nearly 100% recovery of
      acinar perfusion with a sinusoidal density not significantly different from that
      of normal, nonischemic livers was achieved by dual gravity perfusion.
      Prolongation of cardiac arrest to 60 min caused an almost 50% deficit of acinar
      and sinusoidal perfusion (P<0.05) with a concomitant 2-3-fold increase of
      heterogeneity of hepatic microperfusion. Regardless of the warm ischemic time
      period, dually perfused livers exhibited significantly (P<0.05) higher rates of
      both acinar and sinusoidal perfusion with increased homogeneity of
      microcirculation when compared with exclusive arterial perfusion. CONCLUSION:
      These data underline the need and benefit of dual perfusion as well as the
      limitation of warm ischemic tolerance to 30 min for safe liver procurement of non
      heart-beating donors.

PMID- 10653375
TI  - Specific immunosuppression by postoperative infusion of allogeneic spleen cells:
      requirement of donor major histocompatibility complex expression and graft-versus
      host reactivity.
AB  - BACKGROUND: Donor leukocytes may exert positive immunoregulatory effects on
      allograft acceptance. Most recent studies have focused on pretreatment protocols.
      In this study, the effect of postoperative infusion of donor leukocytes on graft
      survival and the phenotypic and functional requirements for infused cells were
      investigated in fully major histocompatibility complex (MHC)-mismatched rat heart
      transplant models. METHODS: LEW (RT1l) heart grafts were implanted
      heterotopically into abdomens of LEW.1W (RT1u), and different types of cells were
      infused postoperatively. Immunohistochemistry was used to evaluate
      histopathological changes of grafts. RESULTS: In the absence of any
      immunosuppressive agents, a single dose of viable donor spleen cells (SC), but
      not bone marrow cells, was able to prolong heart allograft survival to about 21
      days, while they were rejected promptly at day 7 in controls. Infusion of T cell
      depleted donor SC, irradiated donor SC or third-party (BN) SC showed no effect on
      graft survival. Compared with resting cells, neither in vitro nor in vivo
      prestimulation of infused donor SC improved graft survival. Clinical signs of
      graft-versus-host reaction were not observed in all above groups. Histology
      showed remarkable reduction in the severity of graft infiltrate and interleukin-2
      receptor-positive cells in grafts of cell-treated animals. Postoperative infusion
      of SC of F1 generation between different strain combinations showed two
      requirements for infused cells to be effective: (1) expression of donor-type MHC
      antigens and (2) strong alloreactivity against the host MHC antigens. CONCLUSION:
      Postoperative infusion of viable donor SC can lead to allospecific down
      regulation of alloreactivity by a graft-versus-host-associated effect.

PMID- 10653376
TI  - An association between cytomegalovirus infection and chronic rejection after
      liver transplantation.
AB  - BACKGROUND: Previous studies suggest a link between cytomegalovirus (CMV)
      infection and chronic rejection. Since these studies, more sophisticated
      diagnostic methods with high sensitivity and specificity for CMV have been
      developed and effective therapy/prophylaxis for CMV is now available. We sought
      CMV prospectively by polymerase chain reaction of serum and urine and by
      conventional methods in a group of 33 patients undergoing 57 transplants during
      1993 or 1994, selected from a larger series. There were 13 grafts lost to chronic
      rejection. The remaining 44 grafts that did not develop chronic rejection served
      as controls and comprised 15 successful primary grafts, 15 second transplants, 8
      third transplants, and 6 primary grafts that were lost for reasons other than
      chronic rejection. RESULTS: The combination donor CMV antibody negative with
      recipient antibody positive and the duration of CMV infection >30 days were
      associated with an increased relative risk of chronic rejection. In contrast, the
      presence of CMV infection alone, symptomatic CMV infection, the detection of CMV
      by PCR of serum or urine, and the peak/cumulative viral load were not predictive.
      CMV infection occurred earlier in those undergoing a second transplant for
      chronic rejection than for those undergoing a second transplant for other
      reasons. In addition, a human leukocyte antigen B mismatch was associated with
      prolonged CMV infection. CONCLUSION: These data are consistent with the
      hypothesis that prolonged subclinical cytomegalovirus infection is associated
      with an increased risk of chronic rejection.

PMID- 10653377
TI  - Proportion of glomerulosclerosis in procurement wedge renal biopsy cannot alone
      discriminate for acceptance of marginal donors.
AB  - BACKGROUND: The shortage of available kidneys for renal transplantation could be
      addressed, to some extent, by expanding the criteria for acceptance of marginal
      donors. The study of these criteria is limited by the selection of grafts
      actually retrieved and transplanted, therefore reduced to a study of risk
      factors. We have evaluated the potential of procurement renal biopies as an
      instrument for acceptance or refusal of donor kidneys for transplantation.
      METHODS: This was a prospective study of a consecutive series of 200 donors.
      Biopsies were performed by wedge technique at the donor operation and were
      evaluated for proportion of glomerulosclerosis, vascular and tubular changes, and
      interstitial fibrosis. The study included 387 renal grafts with a representative
      biopsy, transplanted, and followed-up for survival and functional evaluation; 24
      hr creatinine clearance at 1 and 3 weeks, and 3, 6, 12, 18, and 24 months.
      RESULTS: Factors associated with initial graft function included cold ischemia
      time, number of DR mismatches, tubular changes, although donor age showed the
      strongest correlation with short- and long-term level of graft function. DR
      mismatches and retransplantation appeared to be the only significant risk factors
      for graft loss. The proportion of glomerulosclerosis (mean 8%, range 0-48%)
      correlated with graft function in the simple regression analysis. However, when
      age was taken into account glomerulosclerosis did not correlate significantly
      with graft function. Furthermore, glomerulosclerosis as high as 25% or more had
      an acceptable 3-year graft survival rate of 74.7%. CONCLUSION: Procurement biopsy
      provides only limited information for the decision whether or not to accept a
      kidney donor.

PMID- 10653378
TI  - The prevalence of human papillomavirus DNA in benign keratotic skin lesions of
      renal transplant recipients with and without a history of skin cancer is equally
      high: a clinical study to assess risk factors for keratotic skin lesions and skin
      cancer.
AB  - DNA of the epidermodysplasia-verruciformis associated subgroup of HPV (EV-HPV) is
      frequently detected in biopsies of premalignant lesions and nonmelanoma skin
      cancers of renal transplant recipients. The prevalence of EV-HPVs, however, has
      never been systematically studied in benign keratotic skin lesions of patients
      with or without a history of skin cancer. This study included 42 renal transplant
      recipients with and 36 without a history of skin cancer. A total of 176 skin
      biopsies were tested for the presence of EV-HPV DNA, using a nested polymerase
      chain reaction (PCR). METHOD: EV-HPV typing was done by comparison of the
      sequence of the amplified PCR products with the sequence of all known EV-HPVs.
      The natural history of the development of keratotic skin lesions was studied. The
      number of keratotic skin lesions rapidly increased after transplantation. This
      increase was most pronounced in patients who developed skin cancer. The
      prevalence of EV-HPV DNA in benign keratotic skin lesions was equally high in
      patients with and without a history of skin cancer, i.e., 55 and 53% in the two
      groups, respectively. A large variety of EV-HPV types was found, but of these
      none were predominantly present in either patient groups. A higher prevalence of
      EV-HPV DNA was found in benign skin lesions from sun-exposed sites, but only in
      patients with a history of skin cancer. The association between the number of
      keratotic skin lesions and the development of skin cancer strongly supports the
      hypothesis that EV-HPVs play a role in cutaneous oncogenesis. The equally high
      prevalence of EV-HPV infection in patients with and without a history of skin
      cancer, however, may indicate that besides EV-HPV infection, other factors, such
      as sun exposure may also be important.

PMID- 10653379
TI  - Simultaneous kidney-pancreas transplantation without antilymphocyte induction.
AB  - BACKGROUND: The introduction of potent new immunosuppressive agents may allow
      simultaneous kidney-pancreas transplantation to be performed without
      antilymphocyte induction. METHODS: We analyzed 30 simultaneous kidney-pancreas
      transplantations receiving tacrolimus, mycophenolate mofetil, and steroids
      without without antilymphocyte induction. Eighteen patients underwent pancreas
      transplantation with portal-enteric (P-E) drainage and the remaining 12 had
      systemic bladder (S-B) drainage. Target 12 hr trough tacrolimus levels for the
      first 3 months after simultaneous kidney-pancreas transplantation were 15-20
      ng/ml. The oral mycophenolate mofetil dose was 2-3 g/day begun immediately
      posttransplant in two to four divided doses. Steroids were tapered according to
      protocol. RESULTS: All patients experienced immediate function of both kidney and
      pancreas grafts. One-year actuarial patient, kidney, and pancreas graft survival
      rates are 93, 93, and 90%, respectively. Nine patients (30%) had a total of 13
      rejection episodes (12 biopsy proven) including 4 within 2 weeks, 6 between 2
      weeks and 3 months, and 3 beyond 3 months after simultaneous kidney-pancreas
      transplantation. Three rejection episodes were treated with steroids alone and 10
      were treated with antilymphocyte therapy (5 OKT3 and 5 ATGAM). A total of seven
      patients (23%) received antilymphocyte therapy. Three patients (10%) had more
      than one rejection episode. Two pancreas grafts (7%) and one kidney graft (3%)
      were lost from rejection. Four patients (13%) developed cytomegalovirus
      infection, but none had tissue-invasive cytomegalovirus. At present, 22 surviving
      patients (81%) remain on triple immunosuppression with tacrolimus, mycophenolate
      mofetil, and prednisone with excellent dual graft function. CONCLUSION:
      Tacrolimus, mycophenolate mofetil, and prednisone immunosuppression without
      without antilymphocyte induction is safe and effective after simultaneous kidney
      pancreas transplantation.

PMID- 10653380
TI  - Immunologic and nonimmunologic factors: different risks for cadaver and living
      donor transplantation.
AB  - BACKGROUND: There is a debate about the relative contribution of immunologic
      (rejection) and nonimmunologic (limited nephron mass) factors in long-term graft
      survival. METHODS: Using multivariate analysis, we studied the association of the
      following variables with outcome: delayed graft function (DGF), acute rejection,
      recipient race (black vs. nonblack), donor age (<50 vs. > or =50), donor race,
      and donor and recipient gender. Because of the association between DGF and
      rejection, recipients were grouped as follows: DGF, rejection; DGF, no rejection;
      no DGF, rejection; no DGF, no rejection. Data were analyzed on 1199 first kidney
      transplants in adults (752 living donor, 447 cadaver donor) done between January
      1, 1985 and December 31, 1996. Two analyses were done: first, all transplants;
      second, only those with > or =1 year survival. For both, there was no difference
      in risk factors if death with function was or was not censored. RESULTS: For all
      cadaver transplant recipients, risk factors were acute rejection, DGF plus
      rejection, black recipient race, and donor age > or =50. For living donor
      recipients, only acute rejection was a risk factor. When only 1-year graft
      survivors were considered, risk factors were the same: for cadaver recipients,
      risk factors were acute rejection, DGF plus rejection, black recipient race, and
      donor age > or =50; for living donor recipients the risk factor was rejection.
      CONCLUSION: We found immunologic factors (rejection with or without DGF) to be
      significant in both living donor and cadaver donor transplants. Nonim. munologic
      factors (donor age, recipient race) were significant only in cadaver donor
      transplants.

PMID- 10653381
TI  - Clinical utility of monitoring sialyl Lewis(X) (CD15S) antigen on peripheral
      lymphocytes for the diagnosis and treatment of rejection after renal
      transplantation.
AB  - BACKGROUND: In organ transplantation, the grafts must be carefully monitored, but
      it is often difficult to make a quick and accurate diagnosis of unusual changes.
      Extensive research has failed to identify a useful marker for rejection. We
      investigated the clinical utility of sialyl Lewis(X) (CD15s) monitoring in 17
      renal transplant patients with acute rejection. METHODS: The expression of CD15s
      on peripheral lymphocytes was examined using flow cytometry in renal transplant
      recipients with rejection (n=17), without rejection (n=23), recipients infected
      with cytomegalovirus (n=7), recipients with other diseases (n=7), and healthy
      volunteers (n=18). CD15s expression was compared with histological findings, and
      was also examined before and after steroid pulse therapy to investigate the
      effects of steroids on CD15s antigen expression on the surface of the peripheral
      lymphocytes. RESULTS: CD15s was strongly expressed in all patients with
      rejection, but was not expressed in any of the patients without rejection or in
      any healthy volunteers. Histologically, cell infiltration into the rejected graft
      was moderate or severe in all patients with strong expression of CD15s. In
      contrast, no or only mild infiltration was observed in patients with weak
      expression of CD15s. In addition, 14 of 17 patients (14/17, 82%) with strong
      CD15s expression improved upon administration of steroid pulse therapy, although
      there was no benefit from steroids in any of the patients with weak expression of
      CD15s. CONCLUSIONS: The CD15s antigen is expressed strongly on the peripheral
      lymphocytes at the time of rejection. It is interesting that the efficacy of
      steroid therapy in the patients with elevated creatinine could be predicted by
      CD15s expression on the peripheral lymphocytes before graft biopsy. There have
      been only few reports showing the relationship between CD markers and the
      efficacy of the treatment in patients with elevated creatinine. We report that
      the detection of CD15s on the peripheral lymphocytes by flow cytometry was an
      easy, helpful, and noninvasive means for the diagnosis and treatment of patients
      with elevated creatinine after renal transplantation.

PMID- 10653382
TI  - Tuberculosis in orthotopic liver transplant patients: increased toxicity of
      recommended agents; cure of disseminated infection with nonconventional regimens.
AB  - BACKGROUND: Because increased hepatotoxicity was observed with first line
      antituberculous agents using four drug standard induction therapy in orthotopic
      liver transplant patients, we evaluated the efficacy and adverse effects of a
      novel continuation regimen for the treatment of tuberculosis in orthotopic liver
      transplant patients at a University Hospital in New York City. METHODS: The
      hospital records of all patients who were referred to Mount Sinai Hospital
      (n=924) and who underwent orthotopic liver transplant between September 1988 and
      May 1998 were reviewed. Data were collected from patient records. Nine orthotopic
      liver transplant patients (0.97%) developed tuberculosis over a 9.5-year period.
      A total of seven of nine (78%) patients had disseminated tuberculosis including
      two patients with meningitis. All mycobacterial isolates were sensitive to
      isoniazid, rifampin, pyrazinamide, and ethambutol. Standard induction therapy
      with three or four drugs was given for 2 months (mean). Hepatotoxicity related to
      the standard induction regimen developed in five of six (83.3%) patients. Liver
      biopsy during induction therapy revealed drug induced hepatitis in five of six
      (88%) patients and rejection in three of six (50%) patients. Continuation
      regimens consisted mainly of ethambutol and ofloxacin; mean length of therapy 9
      months. RESULTS: Overall mortality was 33.3% (three of nine patients) over a 4.5
      year follow-up period. Tuberculosis associated mortality was 22.2%. One patient
      died before therapy, another died with concomitant bacterial sepsis during
      induction therapy. Six of seven patients are alive and disease free. One patient
      died of recurrent hepatitis C and graft failure without evidence of tuberculous
      infection at death. Another patient retransplanted for chronic rejection, remains
      disease free at 1 year. The mean follow-up for six patients that completed
      treatment was 3.75 years (2.5-5.3 years). Six patients are free of tuberculosis.
      CONCLUSIONS: Our experience reveals that orthotopic liver transplant patients
      have poor tolerance for conventional therapy due to inherent toxicity of these
      agents and their concomitant bouts of organ rejection. Our nonconventional
      therapy yielded remarkably good results in that six patients, all with
      disseminated disease, were well after mean 3.5 years of follow-up. Consideration
      should be given to this novel follow-up therapy in patients without cavitary
      pulmonary disease who develop hepatotoxicity during induction.

PMID- 10653383
TI  - Thrombocytopenia in liver transplant recipients: predictors, impact on fungal
      infections, and role of endogenous thrombopoietin.
AB  - BACKGROUND: Thrombocytopenia is a frequent and potentially serious complication
      in liver transplant recipients. The role of endogenous thrombopoietin level in
      posttransplant thrombocytopenia, has not been fully defined in liver transplant
      recipients. Additionally, there is accumulating evidence to suggest that
      platelets play a important role in antimicrobial host defense. METHODS: There
      were 50 consecutive liver transplant recipients studied. Variables predictive of
      thrombocytopenia, its impact on infectious morbidity and outcome, and serial
      thrombopoietin (TPO) serum concentration were assessed. RESULTS: The median
      pretransplant platelet count was 67 x 10(3)/cmm. After the liver transplantation,
      the median nadir platelet count was 33 x 10(3)/cmm and was reached a mean of 6
      days after the transplant. A lower pretransplant platelet count (r= +.068,
      P=.0001), lower serum albumin before the transplants (r=+0.39, P=.014), longer
      operation time (r=0.27, P=.05), higher intraoperative packed red cells (r=0.28,
      P=.049) and fresh frozen plasma transfusions (r=0.42, P=.004), higher bilirubin
      at Day 7 (r=-.386, P=.005), and higher serum creatinine at Day 7 after the
      transplants (r=-.031, P=.025) correlated significantly with a lower nadir in
      platelets after the transplant. Nadir in platelet count was significantly lower
      in nonsurvivors compared with survivors (16 vs. 36 x 10(3)/cmm, P=.0001). Forty
      three percent (9 of 21) of the patients with nadir platelet counts of < or =30 x
      10(3)/cmm had a major infection within 30 days of the transplant compared with
      17% (5 of 29) with nadir platelet counts > 30 x 10(3)/cmm (P=.04). Fungal
      infections occurred in 14% of the patients with nadir platelet counts of < or =30
      x 10(3)/cmm versus 0% in those with nadir platelet counts of > 30 x 10(3)/cmm
      (P=.06); all patients with fungal infections had nadir platelet counts of < or
      =30 x 10(3)/cmm before fungal infection. Nadir in platelet count preceded the
      first major infection by a median of 7 days. Pretransplant TPO level did not
      differ between survivors (mean 103 pg/ml) or nonsurvivors (mean 144 pg/ml). After
      the transplantation, TPO levels increased in both groups. TPO level peaked at Day
      7 and subsequently declined in survivors. Nonsurvivors had persistent
      thrombocytopenia despite a progressive rise in TPO level; TPO level was
      significantly higher at Day 7 (P=.02), Day 9 (P=.0019), and Day 14 (P=.04) in
      nonsurvivors compared with survivors. CONCLUSION: Persistent thrombocytopenia
      portended a poor outcome in liver transplant recipients and was not related to
      low TPO levels. Thrombocytopenia preceded infections and identified a subgroup of
      liver transplant patients susceptible to early major infections; its precise role
      in fungal infections warrants validation in larger studies.

PMID- 10653384
TI  - Combined immunosuppression with cyclosporine (neoral) and SDZ RAD in non-human
      primate lung transplantation: systematic pharmacokinetic-based trials to improve
      efficacy and tolerability.
AB  - BACKGROUND: We studied the efficacy and tolerability of combined
      immunosuppressive therapy with cyclosporine A microemulsion (Neoral) plus the
      macrolide SDZ RAD 40-0 (2-hydroxyethyl) rapamycin (RAD) in a stringent cynomolgus
      monkey lung graft model in comparison with cyclosporine or SDZ RAD monotherapy.
      METHODS: Thirty-nine cynomolgus monkeys received mixed lymphocyte reaction (MLR)
      mismatched unilateral lung transplants. Immunosuppressants were administered
      orally as single daily doses. The observation period was 28 days and follow-up
      included serial trough blood drug concentrations measured by high performance
      liquid chromatography/mass spectrometry, blood analyses, chest radiographs, open
      lung biopsies, as well as tissue drug concentrations and graft histology at
      necropsy. RESULTS: Graft biopsies in monkeys treated with vehicle (n=4), Neoral
      (day 1-7: 150 mg/kg/day; day 8-28: 100 mg/kg/day; n=6; mean +/- SE trough level
      (MTL): 292+/-17 ng/ml) or SDZ RAD monotherapy (1.5 mg/kg/day; n=6; MTL: 15+/-1
      ng/ml) showed severe rejection. Coadministration in two transplant monkeys of
      Neoral (150/100 mg/kg/day) and SDZ RAD (1.5 mg/kg/day) caused their early death.
      In both animals, SDZ RAD blood levels were more than 5-fold higher than under
      monotherapy (MTL: 82+/-18 ng/ml). Simultaneous administration (n=6) of Neoral
      (150/100 mg/kg/day; MTL: 217+/-16 ng/ml) and SDZ RAD (0.3 mg/kg/day; MTL: 24+/-2
      ng/ml) improved graft outcome (mild rejection). Side effects included renal
      failure (n=2) and seizures (n=1). Three monkeys survived to day 28. In this group
      the MTL for cyclosporin was 143+/-13 and for RAD 38+/-3. Staggered treatment
      completely prevented rejection in four of six grafts. However, five of six
      monkeys had moderate to severe diarrhea. In a concentration-controlled trial of
      simultaneously administered Neoral and SDZ RAD in transplant monkeys (target SDZ
      RAD MTL: 20-40 ng/ml; cyclosporine MTL: 100-200 ng/ml) all six monkeys survived
      with improved drug tolerability and an average biopsy score of mild rejection.
      CONCLUSION: Combination of orally administered SDZ RAD and Neoral showed
      excellent immunosuppressive efficacy in a stringent lung transplant model. The
      drug interaction and the narrow therapeutic index of this drug combination
      required careful dose adjustments to optimize tolerability and efficacy.

PMID- 10653385
TI  - NOF-11: a one-year pediatric randomized double-blind comparison of neoral versus
      sandimmune in orthotopic liver transplantation.
AB  - BACKGROUND: Although cyclosporine (CsA) has been a mainstay in liver
      transplantation immunosuppression the original formulation [Sandimmune (SIM)] has
      variable absorption, particularly in children. Neoral is a new formulation of CsA
      that may have improved biovailability that would be advantageous in children.
      This study was undertaken to assess the pharmacokinetics (PK) and effects on
      outcome of Neoral versus Sandimmune (SIM) in primary pediatric liver transplant
      recipients. METHODS: Thirty-two patients were randomized to receive Neoral (17
      patients) or SIM (15 patients) in the early posttransplant period (days 1-7) in a
      double-blind fashion. Intravenous CsA was instituted immediately posttransplant
      followed by Neoral or SIM as soon as the patient was tolerating oral fluids (days
      1-7). PK were compared after the first dose (1-7 days), 3 weeks, and 6 and 12
      months posttransplant. In addition, side effects, effect of age and food on
      absorption, and rejection episodes were assessed by intent to treat analysis.
      Notable characteristics of this study include the use of a central laboratory for
      all sample analyses and the assessment of renal function using radioisotopic
      evaluation of glomerular filtration rates. RESULTS: At baseline the two groups
      were comparable. Neoral resulted in higher peak levels of CsA and total drug
      exposure with comparable time to peak drug levels at days 1-7 and week 3. This
      trend was maintained at 6 and 12 months. Time on i.v. CsA was reduced in the
      Neoral group (8.4 vs. 11.1 days) and the weight adjusted daily dose of SIM
      required to achieve target trough levels was about 2-fold more than Neoral from
      day 22 onward. In addition, biopsy proven and treated and steroid-resistant
      rejection episodes were fewer in the Neoral group (6 vs. 12; P=0.01 and 1 vs. 8:
      P=0.004, respectively). Side effects were comparable in both treatment groups.
      CONCLUSIONS: Neoral was well tolerated and had greater biovailability than SIM
      without any increase in the incidence of side effects. In addition fewer episodes
      of rejection were observed with Neoral versus SIM. We conclude that Neoral is the
      CsA formulation of choice for use in pediatric liver transplant recipients.

PMID- 10653386
TI  - Beneficial effects of pentoxifylline pretreatment in non-heart-beating donors in
      rats.
AB  - BACKGROUND: Pentoxifylline (PTX) pretreatment of recipients was shown to protect
      against liver graft failure from ischemia-reperfusion injury after orthotopic rat
      liver transplantation. It has also been shown that PTX protects against
      normothermic ischemia-reperfusion injury to the liver in lobar ischemia model in
      the rat. Whether PTX can benefit the liver procured from non-heart-beating donors
      (NHBDs) with up to 9 hr of cold ischemia is unknown. METHODS: Donor and recipient
      rats were pretreated with intraperitoneal PTX (50 mg/kg) 1 hr before cardiac
      arrest and transplantation, respectively. Grafts were transplanted 0, 30, and 60
      min after cardiac arrest with additional 1 and 9 hr of cold ischemia in both PTX
      pretreated or untreated (control) groups (10 rats per group). PTX (25 mg/kg/day)
      was continuously given to the surviving rats for 5 days postoperatively.
      Recipient survival rates, serum enzyme levels, and histopathological examination
      of postreperfusion liver biopsies were all analyzed. RESULTS: The survival rates,
      serum enzyme levels, and postreperfusion histology were significantly improved in
      groups pretreated with PTX compared to the controls. CONCLUSION: Donor and
      recipient PTX pretreatment significantly improves the viability of the liver
      grafts procured from NHBDs.

PMID- 10653387
TI  - Serological markers of recurrent beta cell destruction in diabetic patients
      undergoing pancreatic transplantation.
AB  - BACKGROUND: Besides alloimmunity to transplanted pancreatic tissue, recurrent
      autoimmune beta cell destruction is an additional limitation to successful
      clinical pancreatic allografts in type 1 diabetic patients. METHODS: We studied
      the prevalence of autoantibodies to glutamate decarboxylase (GAD) 65 and tyrosine
      phosphatase (IA-2) in 68 C-peptide-negative diabetic patients receiving
      pancreatic allografts. Sera from patients were obtained immediately before
      grafting. A second blood sample was analyzed at the time of graft failure in
      patients who returned to hyperglycemia and during the same follow-up period in
      those who experienced a functional pancreatic allograft. Patients were classified
      according to clinical outcome into chronic graft failure (group A, n=20), acute
      graft failure and/or arterial thrombosis (n=7), or functional pancreatic graft
      (group C, n=41). Sera from patients were screened for the presence of specific
      autoantibodies using an islet cell autoantibody assay, a combi-GAD and IA-2 test,
      and individual GAD and IA-2 assays. RESULTS: Patients from group A had
      significantly higher combi-test values than patients from group C (13+/-16 vs.
      4.5+/-12 units, P<0.02) and higher anti-GAD65 antibody (Ab) levels (0.19+/-0.3
      vs. 0.04+/-0.13 units, P<0.01) immediately before grafting. After graft failure
      in group A, both anti-GAD65 and anti-IA-2 Ab levels increased from baseline, but
      only the increase in anti-IA-2 Ab levels reached statistical significance (0.28+/
      0.12 vs. 15+/-34, P=0.03). When compared with group C, patients from group A had
      higher anti-GAD65 Abs (0.29+/-0.35 vs. 0.05+/-0.16, P<0.001) after graft failure.
      Interestingly, the number of double-Ab-positive patients rose from 5% to 35% in
      group A, whereas it remained at 5% in group C. In pancreatic transplants with
      bladder drainage, the presence of anti-GAD65 and/or anti-IA2 Abs was not
      associated with a reduction in urinary amylase levels. This suggests that a loss
      of endocrine function was not associated with exocrine failure in patients from
      group A. CONCLUSIONS: We can conclude from the present study that peripheral
      autoimmune markers are useful in diabetic patients receiving pancreatic
      allografts.

PMID- 10653388
TI  - Enhancement of susceptibility to Fas-mediated apoptosis of TH1 cells by
      nonmitogenic anti-CD3epsilon F(ab')2.
AB  - BACKGROUND: Anti-CD3epsilon F(ab')2 are nonmitogenic for naive T cells but can
      induce apoptosis of antigen-activated T cells in vitro and in vivo. We studied
      the mechanisms by which nonmitogenic anti-CD3epsilon F(ab')2 antibodies induce T
      cell death. METHODS: OVA-responsive T cell lines were generated by immunization
      in vivo and restimulation in vitro. Fas or Fas ligand (FasL) expression was
      tested by surface staining with specific mAbs. The apoptotic DNA and cell cycle
      phase were tested by staining DNA with propidium iodide. Interferon-gamma was
      measured by ELISA, whereas interleukin (IL)-2 and IL-4 were detected by
      bioassays. RESULTS: Restimulation with anti-CD3epsilon F(ab')2 induced apoptosis
      of antigen-activated wild-type T cells, but not Fas or FasL-defective T cells.
      Anti-CD3epsilon F(ab')2 induced death of cells expressing high levels of Fas and
      FasL, and preferentially deleted T helper (Th)1 cells but spared Th2 cells.
      Soluble anti-CD3epsilon F(ab')2 did not regulate Fas or induce FasL expression,
      indicating that the ability of anti-CD3epsilon F(ab')2 to induce T cell apoptosis
      depends on a distinct mechanism. T cells in S/G2 were found relatively resistant
      to Fas-mediated apoptosis, but anti-CD3epsilon F(ab')2 rendered those T cells
      exquisitely sensitive to Fas-mediated apoptosis. CONCLUSIONS: Anti-CD3epsilon
      F(ab')2 induces apoptosis of cycling CD4+ T cells through activation of the
      Fas/FasL pathway. Anti-CD3epsilon F(ab')2 does not regulate Fas or FasL
      expression but induces susceptibility to Fas-mediated apoptosis of cycling T
      cells. Anti-CD3epsilon F(ab')2 can induce death of polarized Th1 cells, but not
      Th2 cells, thus potentially skewing the repertoire of antigen-activated T cells
      toward the Th2 phenotype. These features predict that nonmitogenic anti
      CD3epsilon F(ab')2-like antibodies can be useful to prevent or reverse pathogenic
      immune responses mediated by Th1 cells.

PMID- 10653389
TI  - Effect of interleukin-10 on human anti-porcine xenogeneic cellular response in
      vitro.
AB  - BACKGROUND: Pigs are being used as an alternative source of tissues for humans
      and we are interested in the xenotransplantation of fetal pig islet-like cell
      clusters (ICC) into type 1 diabetic patients. Interleukin-(IL) 10 is a Th2
      cytokine with immunosuppressive properties that down-regulate the cell-mediated
      response. In this study, we evaluated the effects of recombinant human IL-10 on
      human anti-pig xenogeneic cellular response in mixed lymphocyte culture (MLC) and
      in mixed islet lymphocyte culture (MILC). METHODS: Human peripheral blood
      mononuclear cells as responder cells were cultured in one-way MLC with pig and
      human peripheral blood mononuclear cells as stimulant cells in xeno and allo-MLC,
      respectively, and also with fetal pig ICCs in MILC. IL-10 was added at the time
      of culture. RESULTS: The addition of IL-10 significantly inhibited the xeno-MLC
      (human anti-pig) in a dose-dependent manner, the percentage inhibition being 36,
      60, and 73% at 1, 10, and 50 ng/ml, respectively. Inhibition in xeno-MLC was
      significantly lower than that of the allo-MLC (human anti-human) at all
      concentrations used, the percentage inhibition of the latter being 58, 84, and
      92% at 1, 10, and 50 ng/ml, respectively. Further, the addition of IL-10 also
      significantly inhibited the proliferation of human peripheral blood mononuclear
      cells when they were cocultured with fetal pig ICCs, the inhibition being 59, 72,
      and 80% at 1, 10, and 50 ng/ml, respectively. IL-10 was not toxic to ICCs as
      determined by 3H-thymidine incorporation over 5 days culture. Preincubation of IL
      10 with the pig stimulant cells or the human responder cells did not confer
      additional benefit in the inhibition of xeno-MLC. IL-10 needs to be present at
      the start or at an early stage (within 4 hr) in the xeno-MLC because if the
      addition of IL-10 was delayed by 4 hr, the effect was lost. Next, the production
      of cytokines was examined in MLC and MILC. In xeno-MLC, levels (pg/ml) of tumor
      necrosis factor-alpha (TNF-alpha) (163+/-17), interferon-gamma (IFN-gamma) (278+/
      60), IL-5 (24+/-10), IL-6 (2959+/-923), and IL-10 (17+/-2) were produced in
      greater amounts than autologous controls (P<0.05). The levels of TNF-alpha, IFN
      gamma, IL-6, and IL-10 but not IL-5 were significantly (P<0.05) lower in xeno-MLC
      than those produced in allo-MLC. All of these cytokines were also produced in
      MILC when human peripheral blood mononuclear cells (PBMC) were cocultured with
      ICCs, levels (pg/ml) being TNF-alpha (308+/-47), IFN-gamma (93+/-17), IL-5 (6.2+/
      3), IL-6 (5649+/-421), and IL-10 (122+/-18). No detectable levels of IL-2 and IL
      4 were produced in the MLC and in MILC. Addition of IL-10 significantly inhibited
      the production of TNF-alpha, IFN-gamma, IL-5, and IL-6 by 76, 96, 100, and 93%,
      respectively, in xeno-MLC. Addition of IL-10 also significantly (P<0.05)
      inhibited the production of TNF-alpha, IFN-gamma, IL-5, and IL-6 by 88, 91, 100,
      and 96%, respectively, in MILC. Exogenous addition of IL-2 was partially able to
      reverse the effect of IL-10 although addition of TNF-alpha had no effect on xeno
      and allo-MLC. Synergism was seen between IL-10 and cyclosporine in the inhibition
      of xeno and allo-MLC. CONCLUSION: Taken together, the results demonstrated that
      IL-10 has an immunomodulatory role to play in the inhibition of cellular immune
      responses associated with the xenotransplantation of fetal pig ICCs.

PMID- 10653390
TI  - Gene transfer of immunomodulatory peptides correlates with heme oxygenase-1
      induction and enhanced allograft survival.
AB  - BACKGROUND: Decapeptides derived from human HLA class I sequences have been shown
      to prolong allograft survival. The mechanism of action of these peptides has been
      uncertain, because they act in an MHC unrestricted manner. Recently, it was found
      that these peptides bind heme oxygenase 1 (HO-1). In the present study, we sought
      to determine whether local delivery of these peptides through gene transfer could
      extend allograft survival, and to explore the underlying mechanisms. METHODS:
      C57BL/6 neonatal hearts were transplanted to CBA/J recipients and the peptide, or
      plasmid DNA encoding the peptide, was injected directly into the allograft at the
      time of the transplant. RESULTS: Direct injection of 1 microg of the B2702
      peptide into the allograft did not prolong survival (13.3+/-0.8 vs. 13.4+/-0.8
      days for untreated controls), but injection of 400 microg of peptide did extend
      survival (22.0+/-0.6). Injection of plasmid DNA encoding the B2702 peptide was
      superior to peptide delivery, extending graft survival to 30.8+/-1.5 days.
      Similar results were obtained using another plasmid encoding the rationally
      designed peptide BC1 (28.5+/-1.7), whereas no significant prolongation was
      observed using a plasmid encoding the control peptide B2705 (16.5+/-1.0). To
      explore the hypothesis that these peptides exert their immunosuppressive effect
      by altering HO-1 activity, animals were treated with iron protoporphyrin, an
      inducer of HO-1 activity, or tin protoporphyrin, an inhibitor of HO-1. Treatment
      with iron protoporphyrin alone extended graft survival (24.5+/-1.6) and did not
      alter the benefit in survival seen with BC1 gene transfer (28.0+/-0.8). In
      contrast, treatment with tin protoporphyrin abolished the benefit of BC1 gene
      transfer (17.0+/-0.6). CONCLUSIONS: These results demonstrate that plasmid
      mediated gene transfer is an effective means for delivering immunosuppressive
      peptides to extend allograft survival. The experiments suggest that these
      peptides may act by increasing HO-1 activity and support a role for HO-1 in
      immune regulation and allograft survival.

PMID- 10653391
TI  - In vivo osteogenic durability of cultured bone in porous ceramics: a novel method
      for autogenous bone graft substitution.
AB  - BACKGROUND: Bone marrow cells differentiate into bone-forming osteoblasts when
      cultured in medium supplemented with 15% fetal bovine serum, ascorbic acid, beta
      glycerophosphate, and dexamethasone. METHODS: To investigate in vivo osteoblastic
      activity and bone matrix formation by cultured bone marrow cells, Fischer rat
      marrow cells were cultured for 2 weeks in porous hydroxyapatite (HA) and then
      subcutaneously implanted into 7-week-old male syngeneic rats. The implants were
      harvested after 8 and 52 weeks for biochemical and histological analyses.
      RESULTS: At both times, formation of lamellar bone accompanied by regeneration of
      marrow were seen in many of the HA pores. When a fluorochrome (calcein) was
      administered at 50 weeks after implantation, it was detected in the pores of
      implants harvested at 52 weeks. Osteoclastic resorption followed by new bone
      formation was seen in some pores at 52 weeks, indicating that bone remodeling was
      continuing. The alkaline phosphatase activity of implants harvested at 52 weeks
      was comparable to that at 8 weeks, whereas the osteocalcin content of the
      implants harvested at 52 weeks was about twice that at 8 weeks. CONCLUSION: These
      results demonstrated that there was persistent in vivo osteogenic and
      hematopoietic activity in the prefabricated bone/HA constructs, and indicated
      that normal bone tissue was regenerated after grafting of the constructs, which
      were brittle before implantation. Tissue engineering using HA and cultured marrow
      cells culture may provide an alternative method of bone transplantation for
      patients with skeletal disorders, although further in vivo and in vitro
      experiments are needed.

PMID- 10653392
TI  - Cytokine-mobilized peripheral blood progenitor cells for allogeneic
      reconstitution of miniature swine.
AB  - BACKGROUND: Because of the relative ease of acquisition, increased yield, and
      improved engraftment characteristics, mobilized peripheral blood progenitor
      (stem) cells (PBSCs) have recently become the preferred source for hematopoietic
      stem cell transplantation. In our laboratory, procurement of a megadose of PBSCs
      is necessary for on-going studies evaluating non-myelosuppressive transplant
      regimens for the induction of mixed chimerism and allograft tolerance. To exploit
      hematopoietic growth factor synergy, we have sought to combine growth factors
      with proven utility to improve PBSC mobilization and maximize our PBSC
      procurement through an automated collection procedure. METHODS: Mobilization
      characteristics of PBSCs were determined in 2-5-month-old miniature swine.
      Animals received either swine recombinant stem cell factor (pSCF, 100 microg/kg)
      and swine recombinant interleukin 3 (pIL-3, 100 microg/kg), administered
      intramuscularly for 8 days, or pSCF, pIL-3, and human recombinant granulocyte
      colony stimulating factor (hG-CSF), at 10 microg/kg. Leukapheresis was performed
      beginning on day 5 of cytokine treatment and continued daily for 3 days. RESULTS:
      Collection of PBSCs from cytokine-mobilized animals via an automated
      leukapheresis procedure demonstrated a 10-fold increase in the number of total
      nucleated cells (TNC) (20-30 x 10(10) TNC) compared to bone marrow harvesting (2
      3 x 10(10) total TNC). A more rapid rise in white blood cells (WBCs) was seen
      after administration of all three cytokines compared to pSCF and pIL-3 alone. An
      increase in colony-forming unit granulocyte-macrophage frequency measured daily
      from peripheral blood during cytokine treatment, was seen with the addition of hG
      CSF to pSCF/pIL-3 correlating well with the rise in WBCs. Similarly, the addition
      of hG-CSF demonstrated a notable increase in the median progenitor cell yield
      from the 3-day leukapheresis procedure. Cytokine-mobilized PBSCs were capable of
      hematopoietic reconstitution. PBSCs mobilized with pSCF/pIL-3 were infused into
      an SLA-matched recipient conditioned with cyclophosphamide (50 mg/kg) and total
      body irradiation 1150 cGy. Neutrophil and platelet engraftment occurred on days 5
      and 7, respectively, with minimal evidence of graft-versus-host disease. Complete
      donor chimerism has been demonstrated 331 days after transplant. CONCLUSIONS: Our
      preliminary results show that in this well-defined miniature swine model,
      recombinant swine cytokine combinations (pSCF, pIL-3 with or without hG-CSF)
      successfully mobilize a high yield of progenitor cells for allogeneic
      transplantation. Furthermore, these cytokine-mobilized PBSCs demonstrate the
      potential to reconstitute hematopoiesis and provide long-term engraftment in
      miniature swine.

PMID- 10653393
TI  - Protection by vascular endothelial growth factor against sinusoidal endothelial
      damage and apoptosis induced by cold preservation.
AB  - BACKGROUND: It is well known that sinusoidal endothelial cell (SEC) damage during
      cold preservation of liver tissue is closely involved in early graft failure. The
      objective of this study was to investigate the involvement of apoptosis in the
      SEC damage induced by cold preservation and to demonstrate the protective effect
      of vascular endothelial growth factor (VEGF) on SEC injury, including apoptotic
      changes. METHODS: Isolated SECs and liver tissue of Wistar rats were cold
      preserved in University of Wisconsin (UW) solution, and the protective effect of
      VEGF was then investigated. Isolated SECs were cultured for 24 hr, and divided
      into the following 3 groups: Group A, in which the cells were cultured for an
      additional 27 hr, Group B, in which the cells were cold-preserved in UW solution
      for 3 hr, and then recultured for 24 hr, and Group C, in which 20 ng/ml of VEGF
      was added to both the culture medium and the UW solution of cells cultured
      according to the Group B protocol. Each group of SECs was morphologically
      examined using the phase contrast microscopic method and the transmission
      electron microscopic method (TEM), and quantitatively analyzed using the WST-1
      assay. Rat livers were cold-preserved in UW solution and divided into the VEGF(+)
      group and the VEGF(-) group, depending on whether VEGF was added or not. Each
      group of livers were analyzed by scanning electron microscopic method (SEM) after
      24 hr of preservation. The hyaluronic acid uptake rate (HUR) was also determined
      after 6 hr of preservation. After 24 hr of preservation and 6 hr of reperfusion,
      tissues were examined by TEM and by the terminal deoxynucleotidyl transferase d
      uridine triphosphate nick end labeling (TUNEL) assay. RESULTS: The phase contrast
      microscopic method and the WST-1 assay showed a protective effect of VEGF against
      the injury to isolated SECs during cold preservation and subsequent reculturing.
      Apoptosis was detected immediately by TEM after isolation of SECs, and the number
      of apoptotic cells increased with the incubation time. This increase was
      accelerated after cold preservation. The scanning electron microscopic method and
      the hyaluronic acid uptake rate showed a protective effect of VEGF against SEC
      damage in the cold-preserved livers. In the liver tissue, the TEM and the TUNEL
      assay detected apoptosis of SECs only after cold preservation and subsequent
      reperfusion. VEGF suppressed the apoptosis of SECs induced by cold preservation
      in both isolated cells and liver tissue. CONCLUSIONS: We demonstrated that SEC
      damage in the cold preservation of liver tissue was caused mainly by apoptosis,
      which required subsequent reperfusion. Moreover, isolated SECs showed spontaneous
      occurrence of apoptotic changes during culture, and these changes were
      accelerated by the preceding cold preservation. This is the first report to
      demonstrate the apoptotic changes of SECs seen here were inhibited by VEGF.

PMID- 10653394
TI  - Interaction of anti-HLA antibodies with pig xenoantigens.
AB  - BACKGROUND: Many patients with renal failure are condemned to long-term dialysis
      with little prospect of transplantation because they are highly sensitized with
      immunoglobulin G (IgG) directed against class I human leukocyte antigens (HLA) of
      virtually all donors. Xenotransplantation could represent an attractive solution
      providing their alloantibodies (alloAb) do not recognize porcine motifs. Hitherto
      there has been no in vivo demonstration of any cross-reactivity and the objective
      of this work was to investigate this problem using a technique of extracorporeal
      pig kidney perfusion as a model of clinical xenografting. METHODS: Pig kidneys
      were perfused ex vivo with plasma from both a group of highly sensitized patients
      and healthy individuals. Sequential plasma samples were analyzed for the titer of
      anti-Galalpha1-3Gal antibody (Ab) (major natural xenoreactive Ab) by enzyme
      linked immunosorbent assay and anti-HLA class I Ab against a cell panel. At the
      end of perfusion, kidneys were perfused with a citric acid buffer to elute bound
      Ab. RESULTS: Galalpha1-3Gal Ab were shown to decrease rapidly in the plasma (in
      less than 10 min) and then reached a plateau. A fractional decrease in anti-HLA
      Ab was also found in some of the perfused plasma samples. Anti-Gal Ab were
      readily detected in all citric acid perfusates and anti-HLA Ab in 8 of 10. The
      HLA specificities of eluted Ab were mainly concordant with the originally
      designated specificities for each patient. CONCLUSION: Anti-HLA class I Ab
      presumably cross-react with pig class I homologues. However, some plasma samples
      did not cross-react, suggesting that negatively cross-matched pig kidneys could
      be identified in the pig population for xenotransplantation in these patients.
      Further studies are required to precisely describe these cross-reactivities and
      to understand their functional significance in xenotransplantation.

PMID- 10653395
TI  - Liver transplant recipient sera derived soluble HLA mediates allele specific CTL
      apoptosis.
AB  - BACKGROUND: Significant levels of donor soluble human leukocyte antigen (HLA)
      class I (sHLA) are present in patients after transplants. We investigated the
      possibility that sHLA may inhibit cytolytic T lymphocyte (CTL) activity by
      inducing apoptosis of the CTL, thereby serving as a mechanism for specific
      tolerance. METHODS: sHLA-A2 and A3 were isolated from the sera of liver
      transplant recipients by affinity chromatography. T cell bulk lines directed
      against HLA-A2 and HLA-A3 were generated by stimulation with HLA-A2, A3+
      peripheral blood leukocytes and B-lymphoblastoid cells. Induction of T cell
      apoptosis by sHLA was analyzed by adding sHLA to allospecific CTL 4 or for 24 hr
      before flow cytometric analysis of propidium iodide and fluorescein
      isothiocyanate-conjugated annexin V stained cells. T cell receptor (TCR)
      engagement by sHLA was demonstrated using a monoclonal antibody specific for the
      TCR. RESULTS: sHLA-A3 inhibited CTL activity of a HLA-A3 T cell line by 53%,
      whereas sHLA-A2 had no effect. sHLA-A3 also increased T cell death by 77% over
      the control, whereas sHLA-A2 had no significant effect. However, sHLA-A2 induced
      21% apoptosis of an anti-HLA-A2 T cell line, whereas sHLA-A3 caused only 3%
      apoptosis. The antibody complexed form of sHLA was ineffective in the induction
      of apoptosis. Preincubation of the T cells with anti-T cell receptor monoclonal
      antibody protected the T cells from sHLA-induced apoptosis, indicating that sHLA
      TCR engagement is necessary for this process to occur. CONCLUSION: TCR-mediated
      apoptosis of alloreactive CTL may serve as a mechanism by which sHLA can modulate
      the immune response.

PMID- 10653396
TI  - Role of antibody-independent complement activation in rejection of porcine bone
      marrow cells in mice.
AB  - BACKGROUND: Although complement activation has been shown to be important in the
      rejection of solid organs in some xenogeneic species combinations, its role in
      the rejection of xenogeneic marrow engraftment is unknown. METHODS: The effect of
      complement depletion with cobra venom factor on porcine bone marrow cell (BMC)
      engraftment was examined in 3 Gy-irradiated C.B-17 severe combined
      immunodeficiency mice receiving 10(8) pig BMC. RESULTS: At 26 days after
      transplantation, the percentages of swine class I+, myeloid, and CD2+ cells in
      marrow, spleen, and peripheral blood, and the numbers of porcine myeloid
      progenitor cells in marrow, were increased in cobra venom factor-treated
      recipients compared with simultaneous control recipients. Consistent with the in
      vivo results, preheating serum (56 degrees C for 30 min) reduced the inhibitory
      effect of severe combined immunodeficiency mouse serum on the proliferation of
      pig BMC in vitro. CONCLUSION: Murine complement is capable of resisting
      xenogeneic hematopoietic engraftment through an antibody-independent mechanism.

PMID- 10653397
TI  - Reactivation of type 1 diabetes in patients receiving human fetal pancreatic
      tissue transplants without immunosuppression.
AB  - BACKGROUND: Insulin-dependent (type 1) diabetes is a cell-mediated autoimmune
      disease. Successful transplantation of human fetal pancreatic tissue into type 1
      diabetic patients must address both autoimmunity and allograft rejection. We
      investigated whether humoral and cellular responses to islet antigens could be
      demonstrated in the peripheral blood of type 1 diabetic subjects receiving human
      fetal pancreatic tissue transplants. METHODS: We investigated peripheral blood
      mononuclear cell (PBMC) responses, using cellular immunoblotting, and
      autoantibody responses to islet proteins, before transplantation and at 3-month
      intervals after transplantation. Our study population included nine long-term
      type 1 diabetes patients (mean disease duration of 21 years) receiving human
      fetal pancreatic tissue subcutaneously into the abdominal wall without
      immunosuppression. RESULTS: Before transplantation, all nine subjects tested
      negative for islet cell autoantibody (ICA), and seven of nine subjects tested
      positive for glutamic acid decarboxylase autoantibody (GADAb). After
      transplantation, all subjects became ICA(+), and the two patients who were GADAb(
      ) before transplantation, became GADAb(+) after transplantation. Maximum PBMC
      reactivity to separated human fetal pancreatic proteins was observed in four
      patients at 3 months, in one patient at 6 months, in two patients at 9 months,
      and in one patient at 12 months after transplantation. One subject, who had PBMC
      reactivity to multiple islet proteins before transplantation, continued to
      respond to multiple islet proteins throughout the study. CONCLUSIONS: We conclude
      that the development in the peripheral blood of ICA, GADAb, and PBMC reactivity
      to human fetal pancreatic proteins in the transplant recipients is most
      consistent with reactivation of the type 1 diabetes disease process.

PMID- 10653398
TI  - Conversion to neoral for neurotoxicity after primary adult liver transplantation
      under tacrolimus.
AB  - BACKGROUND: Neurological complications after orthotopic liver transplantation
      (OLTX) have remained a major concern in a small proportion of patients. The
      etiology of these complications is often thought to be multifactorial: the
      influence of calcineurin inhibitors is occasionally thought to play an important
      role. When neurotoxicity occurs after OLTX under tacrolimus, it is usually a
      minor complication and responds readily to a reduction in the dosage of or a
      temporary withdrawal of tacrolimus. However, neurotoxic complications
      occasionally do not respond to this conventional process. Neoral is a
      microemulsion formulation of cyclosporine. It has more consistent pharmacokinetic
      parameters and improved bioavailability when compared with conventional
      cyclosporine. The aim of the present report was to evaluate the role of Neoral in
      OLTX recipients with neurotoxic complication who failed to respond to a reduction
      in the dosage of tacrolimus. METHOD: Between August 1995 and November 1997, 330
      adults (age >18 years) received primary OLTX under tacrolimus-based
      immunosuppression (mean age 52.6+/-11.4 years). There were 190 men and 140 women.
      Twenty-three (7%) patients (mean age 53.2+/-11.8 years; 17 men, 6 women) were
      converted to Neoral (mean 35+/-41 days after OLTX). These patients were followed
      until June 1998 (mean follow-up 22.7+/-7.8 months). RESULTS: Four (17.4%)
      patients died during the follow-up period, and two patients underwent
      retransplantation. Neurological symptoms improved in all patients who survived.
      Adequate trough concentrations were achieved in all patients with p.o. Neoral.
      Nine (39%) patients experienced rejection episodes after conversion. Six (26.1%)
      patients were converted back to tacrolimus because of ongoing rejection (n=3),
      retransplantation (n=2), or persistent nausea and vomiting (n=1) without
      recurrence of the original neurological complication. CONCLUSION: Neurological
      complications after OLTX disorders that occur under tacrolimus and that fail to
      respond to a reduction in the dosage can be treated safely by conversion to
      Neoral. However, the rate of rejection is up to 39%, and patients can often be
      converted back to tacrolimus without recurrence of the original neurological
      complication.

PMID- 10653399
TI  - Pulmonary hypertension associated with pulmonary occlusive vasculopathy after
      allogeneic bone marrow transplantation.
AB  - BACKGROUND: Pulmonary vasculature abnormalities, including pulmonary veno
      occlusive disease, have been demonstrated in marrow allograft recipients.
      However, it is often difficult to make a correct diagnosis of pulmonary lesions.
      METHODS: An open lung biopsy was performed on a patient who developed severe
      pulmonary hypertension after bone marrow transplantation for T-cell lymphoma.
      RESULTS: An open lung biopsy specimen demonstrated pulmonary arterial occlusion
      due to intimal fibrosis and veno-occlusion. The most striking alteration was
      partial to complete occlusion of the small arteries by fibrous proliferation of
      the intima. CONCLUSION: High-dose preparative chemotherapy and radiation before
      transplantation are thought to have contributed to the development of
      vasculopathy in this patient, because arterial occlusion by intimal fibrosis and
      atypical veno-occlusion are often associated with lung injury due to
      chemoradiation. An open lung biopsy is essential for diagnosing pulmonary
      vascular disease presenting signs compatible with posttransplantation pulmonary
      hypertension.

PMID- 10653400
TI  - Outcomes of laparoscopic donor nephrectomy in obese patients.
AB  - The applicability of laparoscopic donor nephrectomy (LDN) has not been assessed
      in the obese donor. We hypothesized that obesity is not a technical
      contraindication to LDN. From May 1998 to February 1999, 40 patients underwent
      LDN at the Georgetown Transplant Institute with the transperitoneal technique.
      Prophylaxis against deep venous thrombosis consisted of venous compression
      stockings, low-molecular weight heparin in obese patients, and early ambulation.
      The following variables were examined: donor sex, age, weight, height, related
      versus nonrelated donation, body mass index (BMI; wt/ht2), operating room time,
      estimated blood loss, length of stay, time out of work, and complications. BMI>31
      indicates morbid obesity, BMI>27 indicates >20% over ideal body weight, and
      normal BMI is 25. The patients were divided into nonobese (BMI< or =31) and obese
      groups (BMI>31). The two groups do not differ in outcome after LDN. Our data
      indicate that obesity is not associated with increased morbidity or mortality
      after LDN.

PMID- 10653402
TI  - Donor treatment with phentolamine mesylate improves machine preservation dynamics
      and early renal allograft function.
AB  - BACKGROUND: It has been suggested that pharmacologic conditioning of the donor
      before organ procurement may protect the renal allograft from injuries associated
      with the cold ischemic period. We compared the administration of two vasoactive
      agents before organ procurement to: (1) determine their influence on machine
      perfusion characteristics and (2) determine their impact on delayed graft
      function (DGF) in transplanted renal allografts. METHODS: Between January 1997
      and December 1998, 150 kidneys were procured from heart-beating donors and
      preserved in our laboratory by machine perfusion (MP) or cold storage (CS). The
      following vasoactive agents were randomly administered to the donor 5 min before
      aortic cross clamp: phentolamine mesylate (PM) or hydralazine (H). The control
      groups received no donor conditioning. Kidneys were grouped as follows: (1)
      MP+PM, (2) MP+H, (3) MP, (4) CS+PM, (5) CS+H, (6) CS. 10 mg PM/50 kg donor weight
      was administered to the PM groups and 20 mg H/50 kg donor weight was administered
      to the H groups. DGF was defined as the need for dialysis within the first 7 days
      after the transplant. RESULTS: MP+PM increased renal flow by 12% and decreased
      renal resistance by 18% compared with the MP+H group, and increased renal flow by
      23% and decreased renal resistance by 30% compared with the MP group. Moreover,
      the MP+PM group was associated with improved early allograft function.
      CONCLUSIONS: Donor treatment with PM immediately before aortic cross-clamp is
      associated with improved machine perfusion dynamics (renal flow and renal
      resistance) and lower incidence of DGF compared with donor treatment with H or no
      treatment. Moreover, MP of renal allografts was associated with improved early
      function compared with CS grafts.

PMID- 10653401
TI  - Development of cytomegalovirus resistance to ganciclovir after oral maintenance
      treatment in a renal transplant recipient.
AB  - The emergence of a resistant strain is a theoretical threat after extensive use
      of antiviral drugs. We report the emergence of a ganciclovir-resistant
      cytomegalovirus (CMV) strain in a kidney transplant recipient during oral
      ganciclovir maintenance treatment. The patient was treated by oral ganciclovir
      for 2 months after successful treatment of CMV primary infection by intravenous
      ganciclovir. He developed a new episode of CMV infection with no clinical
      response to intravenous ganciclovir. The CMV isolate exhibited both phenotypic
      and genotypic resistance to ganciclovir. The CMV isolate was constituted of a
      mixture of strains, with and without a mutation at codon 460 of the UL97 gene.
      The clinical condition improved when mycophenolate mofetil (MMF) was
      discontinued, and a short course of intravenous globulin was added to
      ganciclovir. The emergence of the CMV strain could be secondary to more potent
      immunosuppression provide by MMF or subtherapeutic level obtained during oral
      ganciclovir treatment. We believe that ganciclovir resistance must be part of the
      differential diagnosis when a patient relapses or fails to respond to ganciclovir
      treatment.

PMID- 10653403
TI  - Differential expression of alpha-GAL epitopes (Galalpha1-3Galbeta1-4GlcNAc-R) on
      pig and mouse organs.
AB  - BACKGROUND: Expression of the alpha-gal epitope in mice can be completely
      eliminated by disruption of the alpha1,3 galactosyltransferase gene. As an
      initial step for assessing the feasibility of this approach in the pig, it was of
      interest to compare the expression of alpha-gal epitopes in pig and mouse organs.
      METHODS: Membranes from pig and mouse organ homogenates were analyzed for alpha
      gal epitope expression by Western blots, enzyme-linked immunosorbent assay
      (ELISA), immunostaining of tissues, and ELISA inhibition assay. RESULTS:
      Immunostaining of Western blots with human anti-Gal detected alpha-gal epitopes
      on glycoproteins from pig organs but not on glycoproteins from the corresponding
      mouse organs. ELISA with membrane homogenates and immunostaining of tissue
      sections demonstrated a much higher binding of human anti-Gal to alpha-gal
      epitopes on pig membranes than on mouse membranes. ELISA inhibition assay with
      monoclonal anti-Gal indicated that alpha-gal epitope expression in pig organs is
      up to 500-fold higher than in mouse organs. CONCLUSION: Expression of alpha-gal
      epitopes in pig organs is many fold higher than in mouse organs. The abundance of
      these epitopes in pigs raises the question of whether pigs can properly develop
      without expression of alpha-gal epitopes.

PMID- 10653404
TI  - Usefulness of direct sequencing in the detection of microchimerism in liver
      transplant recipients.

PMID- 10653405
TI  - The ophthalmologist and the global impact of the AIDS epidemic LV Edward Jackson
      Memorial Lecture.

PMID- 10653406
TI  - Ocular lesions associated with HIV infection in India: a series of 100
      consecutive patients evaluated at a referral center.
AB  - PURPOSE: To document the ocular disorders seen in patients known to be infected
      with human immunodeficiency (HIV) virus at a referral eye clinic in India.
      METHODS: The first 100 individuals known to be HIV-positive at a referral eye
      clinic between 1993 and 1998 were enrolled in a prospective study. They underwent
      complete ocular and systemic evaluation. RESULTS: Most of the patients (76%) were
      in the 20-to 40-year age group. Heterosexual exposure to commercial sex workers
      was the most common risk factor (70%) for HIV infection. Cytomegalovirus (CMV)
      retinitis (17%) and HIV retinopathy (15%) were the most common HIV-associated
      ophthalmic lesions. Pulmonary tuberculosis (67%) and oropharyngeal candidiasis
      (66%) were the most commonly associated systemic infections. Ocular involvement
      was most common in children who contracted the disease through perinatal
      transmission (66.7%) and in homosexual patients (60%). Ocular involvement was
      comparatively less common in patients who contracted the disease through blood
      transfusions (33%) or exposure to commercial sex workers (24.3%). CONCLUSIONS:
      This study shows that the spectrum of ocular lesions associated with HIV
      infection in India is different from that seen elsewhere in the world. The
      prevalence of CMV retinitis and HIV retinopathy is lower in India, and there have
      been no cases of ocular Kaposi sarcoma. Adnexal infections, albeit rare, were
      seen in our series. The nonavailability and cost of therapy influenced the visual
      prognosis in these patients.

PMID- 10653407
TI  - Evaluation of central serous chorioretinopathy with optical coherence tomography.
AB  - PURPOSE: To evaluate central serous chorioretinopathy with optical coherence
      tomography during the acute phase and after resolution of the acute phase.
      METHODS: In a prospective study, 23 consecutive eyes of 23 patients (19 men, four
      women; mean age +/- SD, 46.0+/-8.1 years; range, 29 to 60 years) with central
      serous chorioretinopathy were examined with optical coherence tomography during
      the acute phase and after resolution of the retinal detachment. After the initial
      examination, the patients were reexamined for 3 to 6 months (mean, 4.7+/-1.1
      months). Cross-sectional retinal images through the center of the fovea were
      obtained from all eyes by optical coherence tomography. The retinal thickness at
      the center of the fovea was measured. The difference between the retinal
      thickness during the acute phase and after resolution of the retinal detachment
      was statistically analyzed using the Wilcoxon test. We also examined a grayish
      white lesion that corresponded to the leakage point in fluorescein angiography in
      four eyes. RESULTS: In the acute phase, neurosensory retina was thickened within
      the area of serous retinal detachment in all 23 eyes. The detached retina was
      thicker than the reattached retina after resolution of the retinal detachment in
      all eyes. The retinal thickness at the center of the fovea during the acute phase
      (range, 157 to 236 microm; mean +/- SD, 196.9+/-22.6 microm) was significantly
      thickened compared with that after resolution (range, 105 to 152 microm; mean +/-
      SD, 124.8+/-10.7 microm; P<.0001, Wilcoxon test). In the acute phase, areas of
      low reflectivity localized within the detached retina were observed in 18 of the
      23 eyes. In the area of the grayish-white lesion, optical coherence tomography
      showed a moderately reflective mass bridging the detached neurosensory retina and
      retinal pigment epithelium in the four eyes; the outer layer of the detached
      retina was more highly reflective in these eyes. The retinal pigment epithelium
      was focally detached beneath the subretinal reflective mass in three of the four
      eyes. CONCLUSIONS: In all eyes studied, neurosensory retina was thickened within
      the area of serous retinal detachment in the acute phase of central serous
      chorioretinopathy. The grayish-white lesion seems to be a fibrinous exudate that
      accumulates in the subretinal space and infiltrates into the outer retina.

PMID- 10653408
TI  - Optical coherence tomography of orange-red subretinal lesions in eyes with
      idiopathic polypoidal choroidal vasculopathy.
AB  - PURPOSE: To study the cross-section images of orange-red lesions in eyes with
      idiopathic polypoidal choroidal vasculopathy and compare their protrusions
      quantitatively with those of serous retinal pigment epithelium detachment.
      METHODS: Optical coherent tomography images scanning remarkable orange-red
      lesions in eyes with idiopathic polypoidal choroidal vasculopathy and serous
      retinal pigment epithelium detachment in age-related macular degeneration or
      central serous chorioretinopathy were prospectively recorded. The correlation
      between the base diameter and the height of the lesions was analyzed. RESULTS:
      Optical coherence tomography images show prominent anterior protrusion of the
      orange-red lesions. The ratio of the height to the base diameter of the orange
      red lesions in eyes with idiopathic polypoidal choroidal vasculopathy is 0.32+/
      0.05, and it is significantly larger than lesions in eyes with serous retinal
      pigment epithelium detachment (0.18+/-0.05, P< .001). CONCLUSION: The orange-red
      lesions in eyes with idiopathic polypoidal choroidal vasculopathy have a more
      sharply peaked shape than serous retinal pigment epithelium detachment as a
      subretinal structure, suggesting polypoidal vascular lesions in eyes with
      idiopathic polypoidal choroidal vasculopathy are situated beneath the Bruch
      membrane and covered anteriorly with both the retinal pigment epithelium and the
      Bruch membrane.

PMID- 10653409
TI  - Scanning laser ophthalmoscope fundus perimetry before and after laser
      photocoagulation for clinically significant diabetic macular edema.
AB  - PURPOSE: To prospectively evaluate functional and funduscopic changes after laser
      treatment in patients with diabetic retinopathy and clinically significant
      macular edema by scanning laser ophthalmoscope fundus perimetry. METHODS: Thirty
      eyes of 30 patients with clinically significant macular edema as a result of
      diabetic retinopathy were prospectively examined before and at least 3 months
      after focal laser treatment with automatic fundus threshold perimetry using the
      scanning laser ophthalmoscope. Thresholds of light sensitivity were compared with
      age-corrected normal values and correlated with corrected visual acuity and
      subjective appraisal of visual function. RESULTS: In 30 eyes, fundus perimetry
      lasted for 10.5+/-2.7 (mean+/-SD) minutes with 322+/-67 stimulus presentations
      for each eye. Whereas eight eyes remained stable (< +/-1 dB change), 15 improved
      concerning mean deviation (MD) (3.1+/-1.7 dB) after focal laser treatment.
      Stability of fixation remained the same after focal laser treatment (0.75+/-0.57
      degree). Laser scars showed marked loss of function (MD > 13 dB). CONCLUSIONS:
      Although light sensitivity was reduced in areas of macular edema, there was no
      correlation between the amount of edema and visual function. Fundus perimetry
      allows the creation of exact maps of retinal dysfunction before and after laser
      treatment. It may help in making management decisions in diabetic and nondiabetic
      patients by offering a sensitive parameter in addition to visual acuity.

PMID- 10653410
TI  - Indocyanine green angiography in the diagnosis of retinal arterial macroaneurysms
      associated with submacular and preretinal hemorrhages: a case series.
AB  - PURPOSE: To report the use of indocyanine green angiography in the diagnosis of
      retinal arterial macroaneurysms associated with preretinal and subretinal
      hemorrhage. METHODS: Retrospective case series. Indocyanine green angiograms of
      five consecutive patients with dense preretinal, intraretinal, and subretinal
      hemorrhages in which the cause of hemorrhage was still in question after clinical
      evaluation and fluorescein angiography. RESULTS: In five eyes of five patients,
      indocyanine green angiography demonstrated acquired retinal arterial
      macroaneurysms as the cause of hemorrhage. Each diagnosis was confirmed after the
      hemorrhages spontaneously resolved or were surgically removed. CONCLUSIONS:
      Indocyanine green angiography is useful in the diagnosis of acquired retinal
      arterial macroaneurysms when fluorescein angiography is inconclusive because of
      preretinal, intraretinal, or subretinal hemorrhage. Establishing the diagnosis of
      retinal arterial macroaneurysm can influence the management of patients with
      submacular and premacular hemorrhage.

PMID- 10653411
TI  - Indocyanine green angiographic features of choroidal rupture and choroidal
      vascular injury after contusion ocular injury.
AB  - PURPOSE: To report features of choroidal rupture and choroidal vascular injury
      after contusion ocular injury on indocyanine green angiography. METHODS: In a
      prospective study, nine patients (nine eyes) with choroidal rupture after ocular
      contusion underwent initial fluorescein angiography and indocyanine green
      angiography within 19 days after trauma. Eyes that had a distinct abnormality of
      the retinal pigment epithelium were excluded from this study. Subtraction
      indocyanine green angiography was also performed. Follow-up fluorescein
      angiographic and indocyanine green angiographic findings were also studied.
      RESULTS: Initial ophthalmoscopic examination revealed subretinal hemorrhage in
      all nine eyes. In five of the nine eyes, choroidal rupture was not seen on
      initial ophthalmoscopic or fluorescein angiographic examination because it was
      hidden beneath the subretinal hemorrhage, but it was detected on subsequent
      examinations. In the remaining four eyes, choroidal rupture was observed by
      ophthalmoscopy at the time of initial examination, and these eyes exhibited
      hyperfluorescent streaks on fluorescein angiography in the region of the
      subretinal hemorrhage. On initial indocyanine green angiography of all nine eyes,
      observed hypofluorescent streaks became more obvious with time. For each eye,
      there were more hypofluorescent streaks on indocyanine green angiography than
      hyperfluorescent streaks on fluorescein angiography. In one eye, the location of
      indocyanine green leakage nearly coincided with the location of a
      hyperfluorescent streak on fluorescein angiography. In this case, crescentic
      streaks of hypofluorescence were seen on the temporal side of the subretinal
      hemorrhage on indocyanine green angiography, although choroidal rupture was not
      observed in that region by ophthalmoscopy or fluorescein angiography. In two of
      the nine eyes, indocyanine green angiography and the subtraction technique
      demonstrated disturbance of flow into choroidal vessels, especially at the
      choroidal rupture site. CONCLUSION: After ocular contusion injury, various
      features of choroidal rupture and choroidal vascular injury were observed on
      indocyanine green angiography. This technique may contribute to the diagnosis of
      choroidal rupture and to the understanding of the clinical course after injury.

PMID- 10653412
TI  - Deadly weapon-related open-globe injuries: outcome assessment by the ocular
      trauma classification system.
AB  - PURPOSE: To describe mechanisms and injury characteristics influencing visual
      outcomes in eyes with open-globe injuries caused by deadly weapons and to apply
      the classification system introduced by the Ocular Trauma Classification Group.
      METHODS: Two-hundred-twenty-eight eyes of 212 consecutive patients, who were
      mostly injured in military confrontation, were analyzed. Mechanism and injury
      characteristics were evaluated for predicting visual outcome according to the
      recently studied classification system as well as other variables pertinent to
      this specific clinical setting of severe eye trauma. Final visual acuities were
      defined as favorable (5/200 or better) or unfavorable (less than 5/200, including
      enucleation). RESULTS: The mean age of patients was 23 years, and the mean follow
      up was 5.7 months. The predictors for favorable visual outcome were type B, grade
      1, zone I, and relative afferent pupillary defect-negative injuries. The
      predictors for unfavorable outcome were type A, grade 5, zone III, and relative
      afferent pupillary defect-positive injuries. Land mine and hand grenade injuries
      had the worst outcome among causative agents. Proliferative vitreoretinopathy,
      comprising 30.4% of postoperative failures, was the most common complication.
      CONCLUSION: Deadly weapon-related open-globe injuries, especially those
      associated with land mines and hand grenades, have devastating visual results.
      Evaluation of trauma mechanism and injury characteristics according to the Ocular
      Trauma Classification System seems to predict visual outcomes in this series of
      severe open-globe injuries.

PMID- 10653413
TI  - Postoperative analgesia by reinjections of local anesthetic through an indwelling
      retrobulbar catheter.
AB  - PURPOSE: To evaluate an indwelling retrobulbar catheter for repeatable
      postoperative retrobulbar injections of local anesthetics for titratable
      analgesia after intraocular surgery. METHODS: The prospective study included all
      124 patients (124 eyes) who consecutively underwent retinal or
      cyclocryocoagulation (n = 22), pars plana vitrectomy, or retinal detachment
      surgery (n = 102), and who were operated on by the same surgeon with local
      anesthesia within a period of 12 months. Using commercially available retrobulbar
      needles with a diameter of 0.60 mm or 0.80 mm and a length of 38 mm, 5 ml of
      mepivacaine 2% with hyaluronidase were injected. Through the same needle, a 28
      gauge commercially available flexible catheter was introduced into the
      retrobulbar space, the needle was withdrawn, and the catheter was fixed in place.
      When the patients started to feel pain after surgery, 2 ml of mepivacaine 2% or 2
      ml of bupivacaine 0.75% were reinjected through the catheter. The catheter was
      removed 24 to 72 hours after surgery. RESULTS: Because of increasing pain in the
      postoperative period, 93 patients (93 of 124, or 75%) received a reinjection
      4.2+/-2.0 hours after the preoperative injection. Seventy patients received a
      second reinjection after an additional 2.7+/-1.9 hours, and 42 patients received
      a third reinjection 3.1+/-2.0 hours later. After each reinjection, the patients
      became pain free. Removal of the catheter after surgery was unremarkable.
      CONCLUSIONS: An indwelling retrobulbar catheter for repeatable postoperative
      injection of short-acting local anesthetics is useful and effective for
      titratable postoperative analgesia after intraocular surgery, and it allows
      patients to avoid the side effects of systemic analgesics and sedatives.

PMID- 10653414
TI  - Experimental evaluation of two current-generation automated microkeratomes: the
      Hansatome and the Supratome.
AB  - PURPOSE: To compare flap dimensions, cut quality, and blade deterioration after
      reuse in an experimental setting using two current-generation microkeratomes for
      laser-assisted in situ keratomileusis. METHODS: Two pivoting-head principle
      microkeratomes, the Hansatome and the Supratome, were used to perform a corneal
      flap in 50 freshly enucleated pig cadaver eyes, with an intended thickness of 160
      microm. Provided stainless steel blades were used from one to five times. Flap
      diameter was measured by planimetry and thickness calculated using ultrasonic
      pachymetry at three different locations. Scanning electron microscopy of stromal
      beds and blades' cutting edges were performed to assess the cut and blade
      deterioration after repeated use. RESULTS: Mean flap central thickness
      (Hansatome/Supratome) was 151 microm (SD 18)/192 microm (SD 32). Progressive
      thinning/thickening of the flap was observed in the direction toward the hinge (P
      = .003/P = .021). Mean vertical flap diameters of 8.9 mm (SD 0.3)/8.0 mm (SD 0.4)
      differed significantly (P = .001). No correlation was found between thickness and
      diameter (r = 0.03, P = .935/r = 0.12, P = .603). At scanning electron
      microscopy, smooth cuts were observed with both keratomes using a new blade.
      Periodical chatter lines at keratectomy edge were present and were more
      pronounced after blade reuse. Cut quality, blade deterioration, and small tissue
      remnants on the blade surface were noted with repeated blade use, especially
      using the Supratome. CONCLUSIONS: Local flap thickness and flap diameter
      variations are inherent to the instrument used. Comparable cut-surface quality
      can be obtained with new blades. Although cut and blade deterioration appears to
      be minor after two reuses, the presence of tissue remnants on the blade surface
      still limits its reuse.

PMID- 10653415
TI  - Comparison of changes in manifest refraction and corneal power after
      photorefractive keratectomy.
AB  - PURPOSE: To determine which corneal curvature values most closely correlate to
      change in manifest refraction after excimer laser photorefractive keratectomy.
      METHODS: In a prospective study at the Cullen Eye Institute, excimer laser
      photorefractive keratectomy was performed on 27 eyes of 27 patients (mean age,
      38.07+/-6.65 years). Preoperative refractive errors ranged from -2.25 diopters to
      -8.75 diopters (mean, -5.74+/-2.09 diopters). Preoperatively and 1 month
      postoperatively, we determined the spherical equivalent of the subjective
      manifest refraction (corrected for a 12-mm vertex distance) and measured corneal
      power using standard keratometry (Bausch & Lomb Keratometer; Rochester, New York)
      and computerized videokeratography (EyeSys Corneal Analysis System; Premier Laser
      Systems Inc, Houston, Texas). We collected 15 corneal values: standard
      keratometry and 14 computerized videokeratography values calculated using the
      axial, instantaneous, and refractive formulas. All calculations were performed
      with 1.3375 and 1.376 for the refractive index of the cornea. For each of the
      corneal values, we subtracted the change in corneal power from the change in
      manifest refraction and calculated for this difference the means, SDs,
      correlations, and regressions. RESULTS: Mean differences between change in
      refraction and change in corneal power were lower when for a refractive index of
      1.376 than for 1.3375, were lowest for the most central measurement points, and
      displayed a high SD. A value of 1.408 for the refractive index would be required
      to optimize the correlation between change in manifest refraction and effective
      refractive power of the central 3 mm of the cornea. CONCLUSIONS: For individual
      patients who have undergone photorefractive keratectomy, changes in corneal
      values determined by computerized videokeratography or by standard keratometry do
      not reliably predict change in manifest refraction.

PMID- 10653416
TI  - Scanning laser polarimetry of the normal human retinal nerve fiber layer: a
      quantitative analysis.
AB  - PURPOSE: To provide a quantitative comparison of retardation values obtained with
      the scanning laser polarimeter (Nerve Fiber Layer Analyzer; Laser Dignostic
      Technologies, San Diego, California) in normal subjects, with the known
      histologic properties of the human retinal nerve fiber layer. METHODS: Scanning
      laser polarimetry was performed on 48 normal subjects. The retardation values
      obtained from each eye were processed to remove reflections from the optic nerve
      head vasculature and to derive peripapillary polar retardation profiles. The
      location of the maximum and minimum retardation values superior and inferior to
      the disk was determined. Retardation values were also determined along lines
      running radially from the center of the optic disk to through the points of
      maximal retardation. RESULTS: Retardation values were greater in the superior and
      inferior quadrants of the peripapillary retinal nerve fiber layer compared with
      the nasal and temporal quadrants. Superiorly, peak retardation values were nasal
      to the vertical meridian by 22.9 degrees (SD, 17.5) in right eyes and by 15.7
      degrees (SD, 17.7) in left eyes. Inferiorly, the peak showed a closer
      correspondence with the vertical meridian, lying nasal to this by 0.8 degrees
      (SD, 14.9) in right eyes and temporal to this by 2.8 degrees (SD, 15.4) in left
      eyes. Radial analysis showed that the peak retardation occurred approximately
      (0.5 to 0.7 disk diameters from the optic disk margin) at the superior and
      inferior aspect of the disk. The degree of modulation of retardation around the
      optic disk was less than would be expected from the variation in peripapillary
      nerve fiber layer thickness seen histologically. CONCLUSION: The location of the
      peak retardation values shows reasonable agreement with the angular location of
      the peak values of nerve fiber layer thickness published for humans. By contrast,
      the modulation of retardation values around the disk and the change with
      eccentricity from the optic disk center differ from the anatomic data. The Nerve
      Fiber Layer Analyzer appears to measure a correlate of nerve fiber layer
      thickness, but it is important that any discrepancies between the retardation and
      anatomic data are recognized in the clinical interpretation of polarimetric data.

PMID- 10653417
TI  - Cardiovascular and cerebrovascular mortality associated with ocular
      pseudoexfoliation.
AB  - PURPOSE: In recent years, several studies have shown the presence of vascular,
      cardiac, and other organ pseudoexfoliative material in patients with ocular
      pseudoexfoliation. The purpose of this study was to determine whether an
      association exists between ocular pseudoexfoliation and cardiovascular,
      cerebrovascular, or all-cause mortality. METHODS: This retrospective study
      included 472 residents of Olmsted County, Minnesota, who were diagnosed with
      pseudoexfoliation syndrome or pseudoexfoliative glaucoma at Mayo Clinic from 1976
      through 1995. Of these 472 cases, 151 subsequently died from 1976 through 1997.
      Cause of death for these patients, as determined by the National Center for
      Health Statistics was compared with the entire Rochester, Minnesota, population
      using Kaplan-Meier analysis. RESULTS: Of the 472 patients with ocular
      pseudoexfoliation, 358 (76%) were female and 114 (24%) were male. The mean age at
      diagnosis was 74 years, with a SD of 10 years and a range from 39 to 106 years.
      Cardiovascular disease resulted in 40 deaths, with a 15-year cumulative
      probability of cardiovascular mortality of 22%, compared with an expected 20% (no
      significant difference with P = .19). Cerebrovascular disease resulted in 26
      deaths with a 15-year cumulative probability of cerebrovascular mortality of 12%,
      compared with an expected 10% (no significant difference with P = .38). Finally,
      the 15-year observed all-cause cumulative mortality was 53% versus an expected
      rate of 59% (significant difference with P = .0002). CONCLUSIONS: No association
      was found between ocular pseudoexfoliation and cardiovascular or cerebrovascular
      mortality. All-cause mortality was significantly less in patients with ocular
      pseudoexfoliation.

PMID- 10653418
TI  - Does that drug work? Pitfalls in studies on the efficacy and safety of glaucoma
      medications.

PMID- 10653419
TI  - Successful treatment of severe wrinkled corneal flap after laser in situ
      keratomileusis with deionized water.
AB  - PURPOSE: To investigate a case of severe wrinkled corneal flap after laser in
      situ keratomileusis (LASIK) successfully treated by hydrating the flap with
      deionized water and applying a bandage contact lens. METHODS: A 39-year-old woman
      presented with corneal flap wrinkles 24 hours after undergoing LASIK in her left
      eye. Under the operating microscope the flap was refloated and hydrated with
      sterile deionized water for 2 minutes without stretching or ironing the flap. A
      bandage contact lens was then applied for 24 hours. Sterile deionized water was
      used topically every 2 hours for 1 day. RESULTS: Twenty-four hours after
      treatment with sterile deionized water and a bandage contact lens, the cornea was
      smooth and wrinkle free. CONCLUSIONS: Hydration with deionized water may offer
      advantages over isotonic solutions in treating a wrinkled corneal flap after
      LASIK.

PMID- 10653420
TI  - Conjunctival intraepithelial neoplasia presenting as corneal ulcer.
AB  - PURPOSE: To report a case of conjunctival intraepithelial neoplasia presenting as
      corneal ulcer. METHOD: Case report of a 28-year-old man who presented with sudden
      onset of pain, redness, and watering in the right eye. Examination of right
      cornea revealed deep stromal infiltrate inferonasally. Adjacent to the infiltrate
      and straddling the inferonasal limbus, a reddish well-defined sessible lesion
      with prominent blood vessels was seen. After corneal scraping for microbiological
      evaluation, the patient was treated with frequent instillation of ciprofloxacin
      hydrochloride 0.3% eyedrops. RESULTS: Corneal scraping revealed no
      microorganisms. Infiltrate resolved promptly after excision of the lesion.
      Histopathologic evaluation of the excised lesion revealed conjunctival
      intraepithelial neoplasia. CONCLUSIONS: This case highlights the fact that
      conjunctival intraepithelial neoplasia at the limbus may present as corneal
      ulcer. This ulcer could have occurred secondary to a dellen formation and
      epithelial breakdown predisposing to a corneal ulcer.

PMID- 10653421
TI  - Combined intraepithelial squamous neoplasia and atypical fibroxanthoma of the
      cornea and limbus.
AB  - PURPOSE: To investigate a case of an unusual neoplasm of the cornea and limbus.
      METHODS: A 59-year-old man presented with a highly vascularized, nodular mass
      involving the left cornea and limbus. An excisional biopsy and, subsequently, a
      superficial lamellar keratectomy and multiple conjunctival biopsies were
      performed. At the 6-month follow-up examination, repeat conjunctival biopsies
      were performed. RESULTS: Histopathologic examination of the corneal specimen
      showed a high-grade intraepithelial squamous neoplasia (in situ carcinoma)
      overlying an atypical fibroxanthoma. CONCLUSION: We report the clinical and
      histologic appearance of a corneal/limbal neoplasm consisting of an
      intraepithelial squamous neoplasia and an atypical fibroxanthoma.

PMID- 10653422
TI  - Congenital trigeminal anesthesia in two siblings and their long-term follow-up.
AB  - PURPOSE: To alert ophthalmologists to congenital trigeminal anesthesia as a cause
      of corneal scarring and amblyopia and its effective treatment with
      tarsorrhaphies. METHODS: Case reports. A 2-month-old infant presented with
      bilateral corneal erosions and complete corneal anesthesia. Her sister presented
      at age 3 years with a corneal ulcer and corneal hypoesthesia (sensation markedly
      decreased). The father and paternal grandmother of the siblings also had corneal
      hypoesthesia. RESULTS: Further investigation of the infant revealed bilateral
      hearing loss, swallowing difficulties, and decreased sensation in the trigeminal
      nerve distribution. A diagnosis of congenital trigeminal anesthesia was made. The
      corneal erosions of the patient resolved with bilateral two-thirds width
      tarsorrhaphies. The girl continues to do well now at 10 years of age with ocular
      lubrication and superficial corneal scar removal. Her older sister initially
      required antibiotic ointment for her corneal ulcer but now requires only ocular
      lubrication for congenital trigeminal anesthesia. CONCLUSION: This study
      describes the earliest reported use of tarsorrhaphies in an infant with
      congenital trigeminal anesthesia. The presence of this condition in her sister
      and relatives makes it one of the few reports of congenital trigeminal anesthesia
      in more than two generations. Early recognition of this condition is essential in
      the preservation of useful vision.

PMID- 10653423
TI  - Cicatrizing conjunctivitis associated with paraneoplastic lichen planus.
AB  - PURPOSE: To report two cases of cicatrizing conjunctivitis associated with
      paraneoplastic lichen planus. METHODS: Case reports. RESULTS: Two patients were
      examined because of redness and discomfort in both eyes. A 63-year-old woman with
      follicular, small-cleaved cell lymphoma had cicatrizing conjunctivitis,
      stomatitis, vulvitis, and skin lesions. A 25-year-old man with malignant thymoma
      had cicatrizing conjunctivitis, erosive stomatitis, and penile papules.
      Histopathologic studies of conjunctiva and skin biopsy specimens in the first
      patient and labial biopsy specimens in the second revealed lichen planus.
      CONCLUSION: Paraneoplastic lichen planus is a possible cause of cicatrizing
      conjunctivitis associated with inflammatory skin and mucous membrane disease.

PMID- 10653424
TI  - Detection of HPV-20, HPV-23, and HPV-DL332 in a solitary eyelid syringoma.
AB  - PURPOSE: To report evidence of many human papillomavirus types occurring in a
      solitary syringoma clinically appearing as a papilloma. METHODS: A 57-year-old
      man presented with a 10-year history of an upper eyelid tumor. Histopathology,
      human papillomavirus-nested polymerase chain reaction, human papillomavirus-DNA
      cloning into vector pCR2.1, sequencing, and computer-assisted evaluation were
      performed. RESULTS: Histopathology demonstrated a solitary benign syringoma. HPV
      20 and HPV-23 were present in one clone each, and HPV-5-related HPV-DL332 was
      present in 9 clones. CONCLUSION: Many human papillomavirus types may be detected
      in an ocular syringoma.

PMID- 10653425
TI  - Anterior uveitis as the initial sign of adult Kawasaki syndrome (mucocutaneous
      lymph node syndrome).
AB  - PURPOSE: To report anterior uveitis as the initial sign of adult Kawasaki
      syndrome (mucocutaneous lymph node syndrome). METHODS: Case report. RESULTS:
      Kawasaki syndrome was diagnosed in an 18-year-old woman with reduction of vision
      caused by anterior uveitis, fever, erythemateous cutaneous rash, conjunctival
      injection, and cervical lymph adenopathy, after medical examination including
      serologic tests. Aspirin and intravenous immunoglobulin were given, resulting in
      improvement of the condition. CONCLUSION: Slit-lamp examination should be useful
      in the evaluation of patients with suspected Kawasaki syndrome, differentiating
      this condition from streptococcal and staphylococcal toxin-mediated diseases,
      viral infections, and drug reactions, not commonly associated with anterior
      uveitis.

PMID- 10653426
TI  - Migraine and tension headache in high-pressure and normal-pressure glaucoma.
AB  - PURPOSE: To analyze the association of normal-pressure glaucoma and migraine.
      METHODS: In a prospective study, 154 patients with glaucoma (56 normal-pressure
      subgroup and 98 high-pressure glaucoma subgroup), 55 patients with ocular
      hypertension, and 75 control subjects were analyzed by means of a standardized
      questionnaire based on International Headache Society criteria. RESULTS:
      According to the questionnaire, 46 patients (17%) were classified as suffering
      from migraine and 20 (7%) from tension headache (episodic and chronic). The
      prevalence of headache, migraine, and tension headache did not vary significantly
      among control subjects, patients with ocular hypertension, and patients with
      glaucoma, but migraine was significantly more common in patients with normal
      pressure glaucoma (28%) compared with control subjects (12%; P<.05) and patients
      with high-pressure glaucoma (10%; P<.01). CONCLUSION: The results suggest an
      association of normal-pressure glaucoma and migraine and a potential, common
      vascular etiology of both diseases.

PMID- 10653427
TI  - Arteriovenous adventitial sheathotomy for the treatment of macular edema
      associated with branch retinal vein occlusion.
AB  - PURPOSE: To report arteriovenous adventitial sheathotomy for treatment of macular
      edema associated with branch retinal vein occlusion. METHODS: Case reports with
      review. Five eyes of five patients with best-corrected visual acuity of less than
      20/200 secondary to branch retinal vein occlusion had pars plana vitrectomy and
      arteriovenous adventitial sheathotomy and were followed postoperatively for a
      mean of 6.5 years (range, 5 to 7 years). RESULTS: In four of five eyes, the best
      corrected visual acuity improved to 20/30 to 20/70. In the remaining eye, visual
      acuity remained at finger counting secondary to macular ischemia. CONCLUSION:
      Arteriovenous adventitial sheathotomy may be beneficial for select patients with
      poor vision secondary to branch retinal vein occlusion.

PMID- 10653428
TI  - Multiple retinal arteriolar occlusions associated with coexisting primary
      antiphospholipid syndrome and factor V Leiden mutation.
AB  - PURPOSE: To investigate a case of a young woman with both primary
      antiphospholipid syndrome and factor V Leiden mutation who developed multiple
      retinal arteriolar occlusions. METHOD: Case report of a 25-year-old woman with
      history and laboratory tests confirming the diagnosis of both primary
      antiphospholipid syndrome and factor V Leiden mutation who presented with blurred
      vision in both eyes. RESULTS: Multiple retinal arteriolar occlusions were
      observed in both of her eyes. The patient was treated first with heparin and then
      with warfarin. CONCLUSIONS: Primary antiphospholipid syndrome and factor V Leiden
      mutation, as well as other forms of thrombophilia, should be considered in the
      differential diagnosis of unexplained retinal vascular occlusions. The
      coexistence of several thrombophilic disorders may carry a particularly high risk
      for thrombotic manifestations.

PMID- 10653429
TI  - Central retinal artery occlusion associated with head or neck pain revealing
      spontaneous internal carotid artery dissection.
AB  - PURPOSE: To report two cases of head or neck pain and central retinal artery
      occlusion associated with spontaneous dissection of the ipsilateral internal
      carotid artery. METHODS: Case reports. RESULTS: We describe two cases of sudden
      visual loss caused by central retinal artery occlusion. Both cases were preceded
      by ipsilateral headaches or neck pain and tinnitus. The patient had no other
      neurological signs or history of trauma. In both cases, cerebral angiography
      revealed ipsilateral internal carotid artery dissection. CONCLUSION: Ipsilateral
      headache or neck pain with tinnitus preceding central retinal artery occlusion is
      highly suggestive of internal carotid artery dissection. Early diagnosis and
      treatment may reduce the risk of hemispheric stroke.

PMID- 10653430
TI  - Orbital ganglioglioma arising from ectopic neural tissue.
AB  - PURPOSE: To report a case of neonatal orbital ganglioglioma originating from
      ectopic neural tissue. METHOD: Case report. RESULTS: An African-American male
      presented at birth with proptosis and expansion of the left orbit. A discrete
      soft-tissue mass was located inferolateral to the globe, which proved to be a
      ganglioglioma. CONCLUSION: The tumor is presumed to have originated from ectopic
      neural tissue in the orbit. Although infrequent, this tumor should be included in
      the differential diagnosis of neonatal orbital neoplasms.

PMID- 10653431
TI  - Retinal vascular occlusion and deficiencies in the protein C pathway.

PMID- 10653432
TI  - Retinal vascular occlusion and deficiencies in the protein C pathway.

PMID- 10653433
TI  - The emerging role of magnetic resonance angiography in the management of patients
      with third nerve palsy.

PMID- 10653434
TI  - Modified sutureless sclerotomies in pars plana vitrectomy.

PMID- 10653435
TI  - Efficacy of unilateral versus bilateral temporal artery biopsies for the
      diagnosis of giant cell arteritis.

PMID- 10653436
TI  - Suppression of rat and mouse lymphocyte function by urban air particulates
      (Ottawa dust) is reversed by N-acetylcysteine.
AB  - Epidemiology studies have demonstrated increased pulmonary morbidity such as
      allergy and infection with episodes of high particulate air pollution (size range
      0.1-10 microm diameter, PM10), but the mechanism(s) for this association is not
      yet well defined. The present study was undertaken to evaluate the effects of EHC
      93 urban particles (Ottawa dust) on immune functions of peripheral blood
      mononuclear cells (PBMCs) and splenocytes from male Fischer 344 rats and C57Bl/6
      mice. Immune function endpoints evaluated included cell viability, lymphocyte
      blastogenesis stimulated by T-cell mitogen (concanavalin A, Con A) or B-cell
      mitogens [lipopolysaccharide (LPS) or LPS/dextran sulfate], intracellular Ca2+
      concentration, interleukin 2 (IL-2) production, and expression of receptors for
      transferrin (TfR) and IL-2 (IL-2R). In addition, the effect of N-acetylcysteine
      (NAC), an antioxidant, on the toxicity of EHC-93 particles was evaluated. Total
      EHC-93 particles, water leachate of EHC-93, and washed EHC-93 suppressed
      proliferation of PBMCs and splenocytes to T- and B-cell mitogens. Treatment of
      splenocytes with EHC-93 particles did not alter intracellular Ca2+ concentration
      or mitogen-induced expression of TfR and IL-2R expression, but increased IL-2
      production assayed by enzyme-linked immunosorbent assay (ELISA). In spite of an
      increase in IL-2 production, exogenous IL-2 when added to cultures was able to
      reverse the suppression of Con A-induced lymphocyte proliferation by EHC-93
      particles. Furthermore, the suppressive effect of EHC-93 particles on mitogen
      induced lymphocyte proliferation was completely abolished by addition of the
      antioxidant NAC to cultures, suggesting a possible role of oxidative factors for
      the toxicity of EHC-93 particles.

PMID- 10653437
TI  - Increased concentration of arachidonic acid in erythrocyte membranes in
      chronically lead-exposed men.
AB  - Animals intoxicated by lead present alterations in the fatty acid composition of
      red blood cells (RBC). Since this altered fatty acid composition of membranes may
      be a general reflection of lead toxicosis, we have examined 12 clinically healthy
      lead-exposed male subjects for fatty acid composition of RBC membranes along with
      blood lead, serum calcium, and serum iron concentrations. Twelve unexposed age
      matched male subjects were used as controls. Significantly increased levels of
      arachidonic acid (AA) were found as compared to matching healthy controls in the
      RBC of the lead-exposed subjects. The increase of AA correlated in a dose
      dependent manner with elevation in lead, and with serum iron, while a negative
      correlation was found between AA and serum calcium. The known ability of lead to
      substitute for calcium, which is essential in activating phospholipase A2 for AA
      release from membrane phospholipids, may be the main reason for increased AA in
      RBC membranes.

PMID- 10653438
TI  - Neurotoxicity of ethyl methacrylate in rats.
AB  - Ethyl methacrylate (ethyl 2-methyl-2-propenoate, EMA) has been implicated in the
      development of neurologic impairment following occupational exposure. The
      potential of EMA to produce neurotoxicity was investigated in adult male Sprague
      Dawley rats in two experiments. In the first experiment, animals were
      administered 100, 200, 400, or 800 mg/kg by daily intraperitoneal (i.p.)
      injections for 60 d. Control rats received daily i.p. injections of 1 ml
      saline/kg. Clinical observations, spontaneous motor activity, and performance in
      the Morris water maze were assessed. Alterations in clinical parameters in the
      higher dose groups included lethargy, impaired breathing, decreased weight gain,
      and increased mortality. Alterations in motor activity were observed at 100
      mg/kg, a dose that did not cause alterations in clinical parameters, body weight
      gain, or mortality. There was also a dose-dependent impairment in performance in
      the Morris water maze. In the second experiment, animals were administered EMA in
      drinking water at concentrations of 0.1, 0.2, or 0.5% for 60 d. Control rats were
      administered tap water. Animals were perfused at the termination of exposure and
      samples of brain, spinal cord, and sciatic nerve were prepared for histological
      examination. Spongiform alterations were observed in fiber tracts of the
      forebrain, brainstem, and spinal cord. Clusters of axonal swellings were
      scattered throughout the dorsal, ventral, and lateral columns of the spinal cord,
      and typically involved internodal segments of two or three neighboring axons.
      Shrunken axons with separated myelin lamellae and large axons with thinner than
      normal myelin sheaths were apparent in the sciatic nerve. The patterns of
      alterations in the white matter of the spinal cord and the sciatic nerve are
      consistent with myelinopathy, but additional experiments are necessary to confirm
      whether oligodendroglia and Schwann cells are the primary sites of injury. In
      addition to the alterations associated with myelin, there was a decrease in the
      density of neurons in the ventral horn of the spinal cord. While the observed
      effects of EMA on the nervous system of rats are consistent with neurologic
      symptoms of workers exposed to EMA, additional experiments are necessary to
      determine if the level and route of exposures associated with occupational use
      produce these impairments in experimental animals.

PMID- 10653439
TI  - Systemic indicators of inorganic arsenic toxicity in four animal species.
AB  - The effect of arsenic compounds depends on the chemical form and is specific for
      certain organs. The lack of specific biological indicators for the effects of
      each arsenic species makes it difficult to differentiate their toxicity. Five
      prospective biological indicators of systemic toxicity were examined at time
      points ranging from 15 min to 24 h using male Sprague-Dawley rats, B6C3F1 mice,
      Golden-Syrian hamsters, and Hartley guinea pigs, following intraperitoneal dosing
      with 0.1 and 1 mg/kg sodium arsenite. Rats and mice were also dosed with 1 mg/kg
      sodium arsenate. Total blood arsenic levels were determined in all animal species
      to show that exposure occurred and as an index of the severity of the change is
      an indicator of toxicity. Total blood arsenic levels were increased in all animal
      species. This increase was dose, arsenic species, and animal dependent. Renal
      pyruvate dehydrogenase activity was significantly decreased at early time points
      in mice, hamsters, and guinea pigs, and at later time points in rats dosed with
      arsenite. Rats and mice dosed with arsenate also exhibited PDH decrease at early
      time points. Blood hematocrit and glucose were increased in the rat and guinea
      pig, respectively, after arsenite administration. Creatinine and urea nitrogen
      were found to be unresponsive to arsenic in most animal species. Data suggested
      that the mouse and secondly the hamster appear to be the most appropriate animal
      models for the study of acute arsenic toxicity.

PMID- 10653440
TI  - Diuretics and the therapy of hypertension.

PMID- 10653441
TI  - Diuretic complications.
AB  - BACKGROUND: Diuretics are widely used and generally safe, but like any
      therapeutic agents, they may cause side effects. METHODS: A review of recent
      literature pertaining to diuretic usage was performed, with emphasis on specific
      reports of side effects. Reports of large-scale hypertension trials employing
      diuretics were also examined for descriptions of diuretic-related complications.
      RESULTS: All diuretics promote excretion of sodium. Depending upon the site and
      mode of action, some diuretics increase excretion of potassium, chloride,
      calcium, bicarbonate, or magnesium. Some can reduce renal excretion of
      electrolyte-free water, calcium, potassium, or protons. Consequently, electrolyte
      and acid-base disorders commonly accompany diuretic use. Except for the mildly
      natriuretic collecting duct agents, which are used mainly to limit potassium
      excretion, all diuretics can cause volume depletion with prerenal azotemia. Loop
      agents and distal convoluted tubule agents, such as the thiazides, produce
      hypokalemic, hypochloremic, metabolic alkalosis that responds to potassium
      chloride replacement. Carbonic anhydrase inhibitors produce less hypokalemia and
      volume depletion but commonly induce metabolic acidosis that is often
      symptomatic. The potassium-sparing agents also limit proton excretion, and
      spironolactone may produce metabolic acidosis. Hyperkalemia is a leading
      complication of the potassium-sparing agents, especially in patients with an
      underlying tendency for hyperkalemia. Thiazide diuretics, in particular, have
      been linked to glucose intolerance, which may be an effect of hypokalemia rather
      than the diuretic itself. Whether diuretic-induced hypokalemia increases
      cardiovascular risk is controversial. Loop agents and thiazides may lead to
      hyponatremia, which, in the case of thiazides, may cause permanent neurologic
      damage. Dose-related reversible or irreversible ototoxicity may complicate
      treatment with loop agents. Nephrocalcinosis, nephrolithiasis, hypomagnesemia,
      and hyperuricemia can potentially complicate treatment with some diuretic agents.
      Reported idiosyncratic reactions to diuretics include interstitial nephritis,
      noncardiogenic pulmonary edema, pancreatitis, and myalgias. CONCLUSIONS:
      Potential side effects of a diuretic can often be anticipated from its mode of
      action on the kidney. These complications may be mitigated with careful
      monitoring, dosage adjustment, and replacement of electrolyte losses. Other side
      effects are idiosyncratic and cannot be prevented.

PMID- 10653442
TI  - Treatment of edematous disorders with diuretics.
AB  - Generalized edema results from alterations in renal sodium homeostasis that
      ultimately result in an expansion of extracellular fluid volume and accumulation
      of interstitial fluid. The common edematous disorders include congestive heart
      failure, cirrhosis, nephrotic syndrome, and renal insufficiency. The
      abnormalities of sodium homeostasis contributing to edema formation in each
      condition are discussed. Management of volume homeostasis, with an emphasis on
      the role of diuretic therapy, is reviewed.

PMID- 10653443
TI  - Pharmacology of diuretics.
AB  - The diuretics in our therapeutic armamentarium have predictable effects based on
      their nephron sites of action. All but spironolactone must reach the lumen or
      urinary side of the nephron to exert their effects. Thus, in settings of
      decreased renal function, doses must be increased to deliver more diuretic into
      the urine. In other edematous disorders, such as congestive heart failure (CHF)
      and cirrhosis, adequate amounts of diuretic reach the site of action if renal
      function is satisfactory. Diminished response in these conditions is caused by a
      decrease in the sensitivity of the nephron to the diuretic, the mechanism of
      which is unknown. Rather than using large single doses of diuretic in CHF and
      cirrhosis, multiple doses and/or combinations of diuretics should be used.
      Therefore, thiazide diuretics coupled with loop diuretics are most logical
      because they affect different nephron sites and the thiazide counteracts distal
      nephron hypertrophy that may occur with loop diuretics alone. Ample studies have
      shown that such combinations can result in a truly synergistic response. Using
      pharmacokinetics and pharmacodynamics of diuretics, we can design therapeutic
      regimens in which satisfactory control of fluid and electrolyte homeostasis can
      be achieved in the vast majority of patients.

PMID- 10653444
TI  - Physiology of renal sodium transport.
AB  - A wealth of studies performed with a spectrum of methods spanning simple
      clearance studies to the molecular identification of ion transporters has
      increased our understanding of how approximately 1.7 kg of NaCl and 180 L of H2O
      are absorbed by renal tubules in man and how the urinary excretion is fine-tuned
      to meet homeostatic requirements. This review will summarize our current
      understanding. In the proximal nephron, approximately 60 to 70% of the filtered
      Na+ and H2O is absorbed together with approximately 90% of the filtered HCO3-.
      The exact quantities are determined by many regulatory factors, such as
      glomerulotubular balance, angiotensin II, endothelin, sympathetic innervation,
      parathyroid hormone, dopamine, acid base status and others. The essential
      components of absorption are luminal membrane Na+/H+ exchange and the basolateral
      (Na+ + K+)-ATPase. In the thick ascending limb of the loop of Henle, 20 to 30% of
      the filtered NaCl is absorbed via Na+2Cl-K+ cotransport driven by the basolateral
      (Na+ + K+)-ATPase. No H2O is absorbed at this nephron site. The transport rate is
      determined by the Na+ load and by several hormones and neurotransmitters,
      including prostaglandins, parathyroid hormone, glucagon, calcitonin, arginine
      vasopressin (AVP), and adrenaline. In the distal tubule, some 5 to 10% of the
      filtered load is absorbed via Na+Cl- cotransport in the luminal membrane driven
      by the basolateral (Na+ + K+)-ATPase. The rate of transport is again determined
      by the delivered load and by several hormones and neurotransmitters. One of the
      tasks of the collecting duct is to control the absorption of approximately 10 to
      15% of the filtered H2O, regulated by AVP, and just a few percent of the filtered
      Na+, controlled by aldosterone and natriuretic hormone. The water absorption
      proceeds through the luminal membrane via aquaporin 2 and through the basolateral
      membrane via aquaporin 3 channels and is driven by the osmotic gradient built up
      by the counter current concentrating system. The Na+ absorption occurs via Na+
      channels present in the luminal membrane driven by the basolateral (Na+ + K+)
      ATPase. With no pharmacological interference, urinary excretion of Na+ can vary
      between less than 0.1% and no more than 3% of the filtered load, and that of H2O
      can vary between 0.3 and 15%.

PMID- 10653445
TI  - Lymphocytic intracellular calcium in a patient with complicated verapamil
      overdose.
AB  - Overdose with calcium channel blockers (CCBs) may lead to serious complications.
      CCBs act by blocking calcium entry into the cell, thus lowering intracellular
      calcium ([Ca2+]i). [Ca2+]i during CCB overdose has not yet been reported. We
      measured [Ca2+]i in lymphocytes of a patient with acute verapamil overdose with a
      complex clinical picture. A 59-year-old woman was admitted after a suicidal
      ingestion of 7200 mg of a sustained-release verapamil preparation. She presented
      with hypotension, complete atrioventricular block, stupor, hypokalemia, and
      hyperglycemia. Acute oliguric renal failure, acute pancreatitis, and the adult
      respiratory distress syndrome further complicated her medical course. Treatment
      was supportive and she recovered completely. Intracellular calcium ([Ca2+]i) was
      measured in the patient's lymphocytes using a spectrofluorometer with the calcium
      sensitive dye Fura-2-acetoxymethyl ester. Thirty nine hours after the ingestion,
      [Ca2+]i was low at 52 nM (compared with 80 nM in a healthy control subject).
      Lymphocytic [Ca2+]i did not respond to stimulation with phytohemagglutinin (PHA).
      Fourteen days after the verapamil overdose, after the patient had recovered
      completely, lymphocytic [Ca2+]i was still low at 55 nM. At this time, there was
      an incomplete response to PHA in the lymphocytes. Three months after the
      ingestion, [Ca2+]i was normal, with a normal response to PHA. Verapamil overdose
      may run a complex clinical course, but full recovery is to be hoped for with full
      supportive care. Cellular intoxication, as reflected by low lymphocytic [Ca2+]i,
      is prolonged and lags behind the clinical recovery by weeks.

PMID- 10653446
TI  - Disseminated fat necrosis with asymptomatic pancreatitis: a case report and
      review of the literature.
AB  - A 62-year-old man with multiple nontender skin nodules is presented. Some of
      these nodules discharged a purulent looking fluid. At presentation, the patient
      did not have any other complaints. No infectious, neoplastic, or immunologic
      origin could be found for the nodular rash. Biochemical profile, imaging, and
      skin biopsy confirmed the diagnosis of disseminated fat necrosis (DFN)
      accompanying asymptomatic pancreatitis. The process involved the mesenteric,
      subcutaneous, and intramedullary fat. The skin lesions were surgically treated.
      Mesenteric and intramedullary fat necrosis were watched closely. A year later,
      the patient was readmitted with a diagnosis of pancreatitis. Subcutaneous and
      intramedullary necrosis were completely resolved at this time, and only
      mesenteric fat necrosis prevailed. The clinical syndrome of DFN, its etiology,
      pathophysiology, treatment, and prognosis are discussed.

PMID- 10653447
TI  - Emerging and reemerging issues in infectious diseases: hepatitis C. Proceedings
      of a meeting. Washington, DC, USA. December 8, 1998.

PMID- 10653449
TI  - Natural history of hepatitis C.
AB  - It is now widely accepted that 85% or more of individuals with acute hepatitis C
      virus (HCV) infection progress to chronic hepatitis, and chronic hepatitis C is a
      known risk factor for cirrhosis and hepatocellular carcinoma (HCC). However,
      there has been much controversy about the inevitability of developing cirrhosis
      and HCC and the time frames in which they are likely to occur. Natural history
      studies have provided varying estimates of the risk of progression in chronic
      hepatitis C. Part of this variation may be a result of viral-specific, host,
      and/or environmental factors, but much of it undoubtedly is a result of the
      difficulties of doing natural history studies in this disease: acute onset is
      rarely identified, chronic infection is often asymptomatic, and the duration of
      disease is prolonged. Three types of studies--prospective, retrospective, and
      retrospective-prospective (nonconcurrent prospective)--have attempted to
      determine the clinical outcomes of chronic HCV infection and have provided widely
      varying estimates. The combined population data indicate that the disease
      progresses slowly over approximately 30 years, on average. Approximately 20% of
      infected individuals will progress to fibrosis and cirrhosis. Of these,
      approximately 20% will progress to HCC. The likelihood of progression appears to
      be independent of genotype or viral load but increases with alcohol intake, male
      sex, age over 40 years at infection, and coinfection with human immunodeficiency
      virus (HIV) or hepatitis B virus (HBV). Results of ongoing nonconcurrent studies
      are needed to determine disease progression in the third, fourth, and fifth
      decades of infection and to better define the factors that affect progression.

PMID- 10653448
TI  - Epidemiology of hepatitis C in the United States.
AB  - Although hepatitis C virus (HCV) infection is the most common chronic blood-bome
      infection in the United States, the annual incidence of new infections has
      decreased by more than 80% since 1989 to approximately 36,000 new infections by
      1996. The Third National Health and Nutrition Examination Survey (NHANES III)
      revealed that an estimated 3.9 million US citizens (1.8%) have been infected with
      HCV. Of these, approximately 2.7 million persons are chronically infected with
      HCV. Population-based studies indicate that 40% of chronic liver disease is HCV
      related. Chronic hepatitis C results in an estimated 8,000 to 10,000 deaths each
      year. Because the prevalence of HCV infection is approximately threefold higher
      among persons now between 30 and 49 years of age, the number of deaths resulting
      from HCV-related liver disease could increase substantially during the next 10 to
      20 years, as this cohort reaches the ages at which complications from chronic
      liver disease typically occur. Most people who develop chronic infection may not
      even be aware that they have been infected, because acute disease is commonly
      benign. However, infected persons can transmit the disease to others and are at
      risk for developing chronic liver disease. HCV is transmitted primarily through
      direct percutaneous exposures to blood. In the United States, blood transfusion
      accounted for a substantial proportion of HCV infections before 1990, when
      routine testing began, but now accounts for only a small percentage. Injection
      drug use is currently the major risk factor for acute HCV infection. Prevention
      and control of HCV infection in the United States must focus not only on
      reduction of transmission in groups at high risk of infection (e.g., injection
      drug users) but also on the early identification of persons with chronic
      infection.

PMID- 10653450
TI  - Discovery of non-A, non-B hepatitis and identification of its etiology.
AB  - The discovery of hepatitis C was the direct result of the landmark discoveries of
      hepatitis B virus (HBV) and hepatitis A virus (HAV) and their serologies.
      Screening tests for HAV and HBV made it possible in the mid-1970s to examine
      cases of transfusion-associated hepatitis (TAH) and to demonstrate that only
      approximately 25% resulted from HBV and that none were related to HAV.
      Consequently, approximately 75% of TAH became classified as non-A, non-B
      hepatitis (NANBH). Subsequently, chimpanzee studies demonstrated that NANBH was a
      result of a transmissible agent Although it has been difficult to convince
      clinicians that NANBH was a serious disease because the overt manifestations are
      generally mild, it gradually became apparent that the NANBH agent often resulted
      in chronic hepatitis and sometimes evolved into cirrhosis. The NANBH agent
      remained a virologic enigma for the next decade until researchers at the Chiron
      Corporation used an ambitious molecular approach on large volumes of high-titer
      infectious chimpanzee plasma from the Centers for Disease Control and Prevention
      (CDC). They extracted RNA, cloned it into an expression vector, and screened the
      expressed product with presumed immune sera. A single positive clone was found in
      the millions screened, and, within a year, the entire genome was sequenced and
      the agent was identified as a novel flavivirus--the hepatitis C virus (HCV).
      Retrospective analysis of pedigreed samples at the National Institute of Health
      (NIH) showed that 70% to 90% of NANBH cases were HCV related. The impact of HCV
      blood donor screening has been enormous. The single-antigen first-generation
      enzyme immunoassay (EIA-1) prevented 40,000 HCV infections within the first year,
      and the second-generation assay (EIA-2) has actually reduced new transfusion
      related HCV infections to almost zero.

PMID- 10653451
TI  - Hepatitis C virus genotypes and quasispecies.
AB  - Genetic heterogeneity is a hallmark of the hepatitis C virus, as a result largely
      of the infidelity of viral RNA-dependent RNA polymerase. Random nucleotide
      substitutions are introduced at a very high rate. The existence of genotypes was
      confirmed by statistical and mathematical techniques, and the relation of the
      genotypes to each other has been determined. There are six major genotypes, each
      with multiple subtypes. Isolates of the same genotype have an average sequence
      homology of 95%, but different genotypes have sequence similarity of
      approximately 65% on average. The nucleotide sequence in portions of the
      hepatitis C viral genome, including the 5' noncoding region, part of the core
      gene, and other nonstructural proteins, is highly conserved. Genotype analysis
      typically utilizes these highly conserved regions. There are many techniques for
      determining viral genotype, and in general, concordance between techniques is
      good. Methods most commonly used for assigning hepatitis C virus (HCV) genotypes
      in clinical practice include restriction fragment length polymorphism analysis
      and the reverse hybridization line probe assay (LiPA; Innogenetics, Ghent,
      Belgium). The worldwide distribution of HCV genotypes has been determined; some
      genotypes are highly characteristic of certain areas. The most common subtypes, 1
      and 2, are less genetically diverse than the others and are more widely
      distributed. The impact of genotype on disease course is controversial, but
      recent data suggest that there is a genotype-dependent differential response to
      therapy. Quasispecies refers to evolution of a highly related but genetically
      heterogeneous population of HCV isolates. The pathobiological and clinical
      implications of HCV quasispecies are poorly understood.

PMID- 10653452
TI  - Evaluation of fibrosis and hepatitis C.
AB  - Prognosis of hepatitis C is determined primarily by the extent and progression of
      fibrosis. Fibrosis, or the accumulation of extracellular matrix, is reversible,
      whereas cirrhosis is not. A large-scale clinical trial showed that extensive
      fibrosis may go undetected with little or no clinical signs or symptoms. The mean
      interval from time of infection to development of cirrhosis was approximately 30
      years, although cirrhosis may occur in as little as 10 to 15 years or more than
      50 years. Viral factors, including genotype and viral RNA levels, predict the
      response to therapy but do not independently correlate with rate of fibrosis.
      Host factors that are known to increase the likelihood of fibrosis include older
      age at infection, male gender, and alcohol intake. Other host factors, possibly
      the immune phenotype, are thought to be very important in determining rate of
      fibrosis, yet these factors have not yet been identified. At present, there is no
      substitute for liver biopsy to assess fibrosis, and there is a compelling need to
      develop noninvasive markers, because none currently exist. The Metavir system, a
      five-stage scale used for the evaluation of the extent of fibrosis, is the most
      carefully validated method for scoring fibrosis. Remarkable progress has been
      made in understanding the cellular and molecular basis of fibrosis. For example,
      it is now known that hepatic stellate cells are the major source of extracellular
      matrix after their activation, which connotes a conversion from a resting,
      vitamin A-rich cell to one that is proliferative, fibrogenic, and contractile.
      Future research should focus on better understanding the cellular basis of
      fibrosis and its natural history as treatments for hepatitis C continue to
      improve.

PMID- 10653453
TI  - Diagnostic testing for hepatitis C: practical considerations.
AB  - Although knowledge of the molecular biology of the hepatitis C virus is rapidly
      evolving, current therapeutic strategies remain suboptimal for most patients with
      chronic hepatitis C. It is hoped that with information derived from virologic
      variables, therapy can be tailored to individual patients, offering them the
      greatest likelihood of response or preventing the unnecessary use of costly and
      occasionally unpleasant medications when treatment failure is deemed probable.
      Genotyping and quantitation of hepatitis C virus have provided great insights
      into the pathogenesis of chronic hepatitis C. Retrospective studies have
      demonstrated that hepatitis C virus genotyping and viral burden may play some
      role in disease progression and response to therapy. With the widespread
      availability of these tests, it is important to try to develop a rational plan
      for their use that will provide information in a manner that is both cost
      effective and relevant to clinical decision making for the individual patient. At
      this point, the utility of measuring hepatitis C virus RNA levels and genotyping
      in making decisions about treatment regimens or monitoring therapy in daily
      clinical practice is continually evolving.

PMID- 10653454
TI  - Cost-effectiveness of screening patients for hepatitis C.
AB  - This review discusses the benefits and drawbacks of public health screening for
      hepatitis C, its cost effectiveness, and the various strategies to identify
      individuals infected with the hepatitis C virus (HCV). Of the estimated 4 million
      people infected with hepatitis C in the United States, approximately 50% are
      unaware of their infection. Both the high incidence and recent improvements in
      the treatment of hepatitis C make it likely that a screening program for this
      disease would be beneficial to patients, their families, and to the public.
      Testing for anti-HCV antibody is now widely available, automated, sensitive
      (>95%), and relatively inexpensive (approximately $80 per test). Interferons and
      the introduction of ribavirin into the treatment armamentarium have improved the
      effectiveness of therapy. Lifestyle modifications can be made to decrease the
      risk of transmission, and patients can be counseled to avoid alcohol consumption
      and receive hepatitis A and hepatitis B vaccinations, if appropriate. An
      additional benefit of early detection is that family members can be alerted to
      the risk factors for hepatitis C. Such education increases overall public
      awareness of the disease and may improve prevention efforts. Several national
      agencies within the United States and in Europe have issued guidelines for
      hepatitis C screening. Each of these calls for screening of high-risk
      populations, which include individuals who have received blood products and
      intravenous drug users. Targeted screening and improved treatment outcomes will
      likely show identification of those with hepatitis C to be cost effective in the
      future.

PMID- 10653455
TI  - Analogy of human immunodeficiency virus to hepatitis C virus: the human
      immunodeficiency model.
AB  - The human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome
      (AIDS) for many years overshadowed hepatitis C, which we now know is in some ways
      an even bigger problem. Important differences also exist between these two
      viruses and the diseases they cause, and we must be cautious about drawing too
      close an analogy. However, there are some striking similarities, and many lessons
      have been learned from HIV research over the past two decades. Parallels with HIV
      include persistence of the virus, genetic diversity during replication in the
      host, and the utility of combination treatment that is just now being appreciated
      with HCV infection. In the last few years, targeted antiviral drugs, such as
      protease inhibitors, have had an impressive effect on HIV-related morbidity and
      mortality. Similarities in the HIV and HCV genomes suggest that such drugs may
      also be useful in treating hepatitis.

PMID- 10653456
TI  - Hepatitis C--virology and future antiviral targets.
AB  - The hepatitis C virus is a single-stranded RNA virus with a genome approximately
      9,000 nucleotides in length. The genome consists of a single, large open reading
      frame (ORF) and 5' and 3' untranslated regions. The highly conserved 5'
      untranslated region is 341 nucleotides in length with a complex secondary
      structure and may function as an internal ribosomal entry site (IRES). The 3'
      untranslated region is approximately 500 nucleotides in length and contains a
      hypervariable region, followed by a poly(U) sequence and a highly conserved 98
      nucleotide element with a stable secondary structure. The ORF codes form a single
      polyprotein that is processed into as many as 10 polypeptides, including a capsid
      protein (core), two envelope proteins (E1 and E2), and nonstructural proteins
      (NS2, NS3, NS4, and NS5). Potentially suitable antiviral targets include the
      IRES, protease, helicase, and RNA polymerase. In vitro studies show that
      antisense oligonucleotides can inhibit the production of structural HCV proteins
      and may be therapeutically useful if the problems of stability and delivery can
      be solved. The binding of HCV envelope proteins to CD81, a potential receptor for
      viral entry into hepatocytes, has recently been described and also raises the
      possibility of agents to block the binding to CD81 or the entry of the virus into
      cells.

PMID- 10653457
TI  - Viral kinetics and mathematical models.
AB  - Mathematical models can provide insights into the dynamics of viral diseases.
      Methods that were introduced to analyze human immunodeficiency virus dynamics in
      vivo can be modified to give insights into hepatitis C virus (HCV) dynamics, the
      mechanisms of action of interferon, and the consequences of giving different
      dosages of interferon. Patients received doses of 5, 10, or 15 mIU of interferon
      daily for 14 days followed by maintenance therapy of 5 mIU daily until day 90.
      HCV-RNA levels in serum dropped rapidly over the first 1 to 2 days of therapy.
      Comparing the kinetics of this response with mathematical models suggests that
      interferon acts by blocking the production or release of HCV virions from
      infected cells. The analysis further indicates that a daily dose of 5 mIU blocks
      approximately 80% of HCV production, and doses of 10 and 15 mIU block
      approximately 95% of HCV production. The serum level of HCV is approximately
      constant before treatment is initiated. Our model suggests that in order to
      maintain this constant level, on average, approximately 1 trillion virions are
      produced and cleared daily in an untreated HCV-infected person. The acute, rapid
      clearance of HCV, which occurs over the first 2 days of therapy, is followed by a
      slower phase of serum HCV decline. The rate of the second-phase decline may
      reflect the rate at which HCV-producing cells are killed, possibly by immune
      responses. Additional studies are needed to evaluate more fully the kinetics of
      the second-phase decline as well as its dose dependence and its predictive power
      with regard to eradication of HCV.

PMID- 10653458
TI  - Chronic hepatitis C viral infection in patients with normal serum alanine
      aminotransferases.
AB  - A substantial proportion of patients with chronic hepatitis C virus (HCV)
      infection (HCV RNA positive) have persistently normal serum alanine
      aminotransferases (ALT). These patients currently pose a therapeutic dilemma, as
      it is not clear how best to deal with them. Response rates to interferon are low,
      and in some cases interferon therapy has been associated with an increase in
      serum aminotransferases. Therefore, the NIH Consensus Conference recommended
      against treating them with interferon. Although most patients with persistently
      normal serum ALT levels have mild disease on liver biopsy, the consensus panel
      did think it appropriate to do liver biopsies in these subjects. Few data are
      available on therapy with the combination of interferon and ribavirin for such
      patients. At Saint Louis University, 24 patients with normal ALT were treated
      with interferon/ribavirin. Preliminary analysis of the results shows that 33% of
      the patients had a sustained response 24 weeks after therapy. Thus, uncertainties
      remain about patients with chronic HCV infection and persistently normal serum
      ALT with the currently available therapies. However, if a more effective and
      better tolerated therapy were to become available, such patients might best be
      treated to eliminate the chronic viral infection.

PMID- 10653459
TI  - Hepatitis C therapy in treatment-naive patients.
AB  - Until recently, interferon was the only approved therapy for previously untreated
      patients with chronic hepatitis C. Unfortunately, the majority of patients do not
      respond to this regimen, and rates of sustained virologic response were a
      disappointingly low 15% to 20%. Clearly, more effective treatment for this
      infection was needed. The nucleoside analogue ribavirin is now approved for
      administration in combination with interferon to treatment-naive individuals with
      hepatitis C (HCV) infection as well as HCV-positive patients who have relapsed
      after interferon monotherapy. Results of a recent US multicenter trial in
      treatment-naive patients with chronic hepatitis C demonstrate that combination
      therapy with interferon plus ribavirin produces sustained virologic response
      rates that are two to three times higher than those obtained with interferon
      alone. Rates of sustained virologic response (defined as undetectable serum HCV
      RNA levels 24 weeks after completion of treatment) were 6% vs 31% after 24 weeks
      of interferon alone vs interferon plus ribavirin, respectively. For 48 weeks of
      treatment, rates of sustained virologic response were 13% and 38% with
      monotherapy and combination therapy, respectively. These results, which are
      consistent with those obtained in smaller preliminary trials and in a recently
      completed international multicenter trial, suggest that combination therapy with
      interferon and ribavirin may be preferable to monotherapy as first-line treatment
      for patients with chronic HCV infection.

PMID- 10653460
TI  - Management of interferon relapsers.
AB  - Relapse in patients who have evidenced an initial response to a course of
      interferon monotherapy for chronic hepatitis C virus (HCV) infection has been a
      major frustration. At least 70% of responders will relapse after a 6-month course
      of treatment and more than 50% will relapse after a 12-month course of treatment,
      usually within the first 3 to 6 months after treatment discontinuation. At most,
      half of patients relapsing after an initial 6-month course will have a sustained
      response to a second, 12-month course of interferon monotherapy. A more promising
      second-line regimen is the combination of interferon plus ribavirin. A recent
      multicenter international trial has shown that this regimen results in a
      sustained virologic response rate of nearly 50%, fully 10-fold higher than the
      sustained response rate observed with a second 6-month course of interferon alone
      (49% vs 5%, respectively). In patients with non-1 genotype and viral levels no
      greater than 2 million copies/mL, the likelihood of sustained response to the
      second course of combination therapy was 100%. Biochemical and virologic
      responses (normalization of liver enzymes and disappearance of HCV RNA from the
      serum) were frequently accompanied by histologic improvement. HCV-RNA levels < or
      = 2 million copies/mL and non-1 viral genotype predicted treatment response,
      whereas age, gender, body weight, source of infection, type of interferon used
      for the first round of treatment, and elapsed time since first treatment had no
      effect. Based on these data, combination therapy with interferon and ribavirin is
      now considered the treatment of choice for relapsers. It is not clear whether 12
      months of combination therapy might have produced even better rates of viral
      eradication in relapsed patients.

PMID- 10653461
TI  - Available options for treatment of interferon nonresponders.
AB  - In the great majority of patients, hepatitis C virus (HCV) infection is not self
      limiting. Approximately 70% to 85% of patients exposed to HCV will go on to
      develop chronic hepatitis. Among those who undergo treatment with interferon
      alpha, only 15% to 20% can be expected to respond to a 12- to 18-month course of
      therapy. With the addition of ribavirin to interferon monotherapy, the likelihood
      of sustained response (defined as normal alanine aminotransferase levels and
      negative HCV RNA persisting 6 months after the end of therapy) increases to
      approximately 40%. The fact remains, however, that there is still a substantial
      proportion of patients who will fail to respond to treatment. Without viral
      eradication, cirrhosis and hepatocellular carcinoma persist as long-term risks.
      Several options are available for the treatment of patients who fail to respond
      to interferon monotherapy. These include interferon dose escalation, whether by
      administering higher doses or administering them more frequently; changing to a
      different form of interferon; retreatment with a combination of interferon and
      ribavirin; adjunctive therapies, of which the best studied is phlebotomy to
      decrease hepatic iron stores; use of long-term, low-dose "maintenance"-type
      therapy; and watchful waiting with frequent follow-up. In the absence of long
      term, large-scale clinical trials to support these modalities, physicians must
      exercise their best clinical judgment and individualize treatment to suit the
      patient's condition, needs, and preferences.

PMID- 10653462
TI  - Principles of interferon induction therapy.
AB  - Several strategies have been devised to enhance the number of patients with
      hepatitis C virus (HCV) infection who achieve a sustained response to interferon
      alpha therapy. Induction therapy uses higher than usual doses of interferon,
      given on a daily, rather than three times per week basis, for a defined period.
      The goal is to minimize fluctuations in interferon levels, preventing viral
      rebound in periods when drug levels are low. The optimal interferon-alpha-2b dose
      for acute viral clearance is probably 10 MIU. Studies of HCV viral kinetics after
      interferon-alpha dosing have shown a biphasic response to drug. In the initial 24
      to 48 hours after a dose of interferon, there is an extremely rapid, interferon
      dose-dependent decrease in viral titer. This reflects inhibition of viral
      production and/or release. The second lower phase of viral decrease then ensues,
      which is highly variable between patients. It is thought to reflect the death
      rate of infected hepatocytes. Brisk decrease during the second phase of viral
      kinetics is the best predictor of HCV-RNA clearance by 3 months. Second-phase
      viral decrease correlates with histologic activity on liver biopsy and
      pretreatment serum transaminase levels. Hepatitis C virus genotype differences
      are important, as well, because genotypes 2 and 3 are cleared by interferon more
      readily than the more resistant genotype 1.

PMID- 10653463
TI  - Cost-effectiveness of treatments for chronic hepatitis C.
AB  - With increasing concern by consumers, employers, health-care payers, and policy
      makers, interest has grown in determining the economic efficiency of drugs.
      Consequently, numerous pharmacoeconomic studies have sought to estimate the
      marginal cost-effectiveness of initial interferon treatment for chronic hepatitis
      C. The effects of treating patients with histologically mild chronic hepatitis C
      for 6 months with interferon was compared with no interferon treatment using a
      computer simulation model. Data were obtained from five prospective trials,
      natural history studies from the literature, and actual cost data for hepatitis C
      patients. After applying the currently recommended annual discount rate (3%), the
      computer model projects a $400 reduction in lifetime cost of care and a 1.5-year
      increase in life expectancy associated with interferon treatment. Economic
      savings derived from preventing future cases of cirrhosis and hepatocellular
      carcinoma more than offset the initial treatment cost. By preventing future liver
      complications in responders, interferon treatment should prolong life expectancy
      and reduce costs. When compared with other well-accepted medical interventions,
      interferon treatment should be considered "cost-effective." Economic rationales
      should not restrict the availability of interferon for patients with hepatitis C.

PMID- 10653464
TI  - Hepatitis C virus and human immunodeficiency virus: clinical issues in
      coinfection.
AB  - The prevalence of hepatitis C virus (HCV) and human immunodeficiency virus (HIV)
      coinfection ranges from nearly 30% to over 50%, depending on the population.
      Shared modes of transmission and the success of current antiretroviral regimens
      have contributed to the emergence of HCV as a significant pathogen in the HIV
      positive population. HIV coinfection appears to worsen HCV infection, with
      studies showing more severe fibrosis, a higher frequency of cirrhosis, and
      increased deaths from liver disease. HIV coinfection may also increase the rate
      of maternal-fetal transmission of HCV. Similarly, studies suggest a more rapid
      progression to AIDS or death for HCV genotypes 1a and 1b than for other genotypes
      in HIV-infected patients with hemophilia. Highly active antiretroviral therapy
      (HAART), such as HIV protease inhibitors, has no effect on HCV infection and may
      transiently increase ALT, AST, and hepatitis C viral load. Hepatotoxicity
      associated with HAART may or may not be related to the presence of HCV and may
      depend on the specific agents used. Data suggest that treating chronic hepatitis
      C in HIV-co-infected patients can decrease fibrosis, increase T-cell
      responsiveness to HCV antigens, and decrease the rate of fatal hepatomas.
      Interferon alpha may provide sustained biochemical or virologic responses in
      HIV/HCV-coinfected patients. The combination of interferon-alpha and ribavirin
      may also be a treatment option but is more complex, and additional research is
      needed. Treating HCV infection in HIV/HCV-coinfected individuals may help lower
      the hepatitis C viral load and permit treatment with protease inhibitors.

PMID- 10653465
TI  - Management of hepatitis C in the hemophilia patient.
AB  - Patients with hemophilia who received clotting factor concentrates before the
      availability of heat-treated factors in the mid-1980s were almost universally
      infected with hepatitis C virus (HCV). Until recently, the clinical impact of
      chronic hepatitis C was largely overshadowed by human immunodeficiency virus
      (HIV) infection in this risk group. With recent advances in treating HIV
      infection, there is greater emphasis on the morbidity and mortality associated
      with chronic hepatitis C in the hemophilic population. A recent study from the
      United Kingdom demonstrated that mortality from chronic liver disease in
      hemophilic patients was 16.7 times greater than in the general population, and
      death resulting from liver cancer, 5.6 times greater. Before the advent of
      protease inhibitors, which can alter the natural history of HIV infection, co
      infection with HIV appeared to accelerate the course of chronic hepatitis C.
      Levels of HCV RNA were dramatically increased after HIV seroconversion, and liver
      failure was found in 9% of patients, exclusively among those co-infected with
      HIV. HCV genotypes generally reflect the predominant genotype of the donor
      population, but multiple genotypes may be present. Liver biopsy may be performed
      safely via the percutaneous or transjugular route in hemophilic patients with
      chronic hepatitis C, although there is an increased cost because of the expense
      of factor replacement. Response to interferon in this population has been similar
      to that expected in the general population. Large trials are underway to evaluate
      the role of combination therapy with interferon and ribavirin for the treatment
      of patients with hemophilia and hepatitis C.

PMID- 10653466
TI  - Hepatitis C and renal failure.
AB  - Chronic hepatitis C virus (HCV) infection is common among patients with chronic
      renal failure. This chronic viral infection can result in significant morbidity
      and mortality. Liver failure from chronic hepatitis C is one of the leading
      causes of death among long-term survivors of renal transplantation. HCV infection
      also can be a cause of glomerulonephritis and nephrotic syndrome. Recognition of
      these conditions is important to optimize the management of these patients.

PMID- 10653467
TI  - The alcoholic patient with hepatitis C virus infection.
AB  - Chronic alcoholism in patients with chronic hepatitis C hastens disease
      progression toward development of cirrhosis and hepatocellular carcinoma.
      Approximately 30% of alcoholic patients with liver disease are infected with the
      hepatitis C virus (HCV), the primary risk factor being a history of injection
      drug use. The histologic pattern in alcoholics is typically indistinguishable
      from nonalcoholic patients similarly infected with chronic hepatitis C. The
      mechanism(s) involved in alcohol-induced enhancement of chronic hepatitis C have
      not entirely been established but may involve increased viral replication, iron
      overload, and immune suppression. Still to be determined is the minimum amount of
      daily alcohol intake, if any, that can be ingested without enhancing progressive
      liver injury. However, chronic hepatitis C patients undergoing treatment with
      interferon must abstain from any alcohol intake, because the efficacy of
      interferon therapy is significantly lower in those who continue to drink. Future
      research efforts are needed in order to further delineate the epidemiology and
      pathogenesis of chronic hepatitis C in the alcoholic patient.

PMID- 10653468
TI  - Hepatitis C and the correctional population.
AB  - The hepatitis C epidemic has extended well into the correctional population where
      individuals predominantly originate from high-risk environments and have high
      risk behaviors. Epidemiologic data estimate that 30% to 40% of the 1.8 million
      inmates in the United States are infected with the hepatitis C virus (HCV), the
      majority of whom were infected before incarceration. As in the general
      population, injection drug use accounts for the majority of HCV infections in
      this group--one to two thirds of inmates have a history of injection drug use
      before incarceration and continue to do so while in prison. Although correctional
      facilities also represent a high-risk environment for HCV infection because of a
      continued high incidence of drug use and high-risk sexual activities, available
      data indicate a low HCV seroconversion rate of 1.1 per 100 person-years in
      prison. Moreover, a high annual turnover rate means that many inmates return to
      their previous high-risk environments and behaviors that are conducive either to
      acquiring or spreading HCV. Despite a very high prevalence of HCV infection
      within the US correctional system, identification and treatment of at-risk
      individuals is inconsistent, at best. Variable access to correctional health-care
      resources, limited funding, high inmate turnover rates, and deficient follow-up
      care after release represent a few of the factors that confound HCV control and
      prevention in this group. Future efforts must focus on establishing an accurate
      knowledge base and implementing education, policies, and procedures for the
      prevention and treatment of hepatitis C in correctional populations.

PMID- 10653469
TI  - A history of the first uncoupling protein, UCP1.
AB  - The lack of energy conservation in brown adipose tissue mitochondria when
      prepared by conventional methods was established in the 1960s and was correlated
      with the thermogenic function of the tissue. In order to observe energy
      conservation, two requirements had to be met: the removal of the endogenous fatty
      acids and the addition of a purine nucleotide. These two factors have been the
      essential tools that led to the discovery of the energy dissipation pathway, the
      uncoupling protein UCP1. The activity is regulated by these two ligands. Purine
      nucleotides bind from the cytosolic side of the protein and inhibit transport.
      Fatty acids act as seconds messengers of noradrenaline and increase the proton
      conductance. This review presents a historical perspective of the steps that led
      to the discovery of UCP1, its regulation, and our current view on its mechanism
      of transport.

PMID- 10653470
TI  - Contribution to the identification and analysis of the mitochondrial uncoupling
      proteins.
AB  - This review is primarily focused on the contribution of our laboratory to study
      of the mitochondrial uncoupling UCPs. The initial stage was the description of a
      32-kDa membranous protein specifically induced in brown adipose tissue
      mitochondria of cold-adapted rats. This protein was then shown by others to be
      responsible for brown fat thermogenesis and was referred to as the uncoupling
      protein-UCP (recently renamed UCP1). cDNA and genomic clones of UCP1 were
      isolated and used to investigate the topology and functional organization of the
      protein in the membrane and the mechanisms of control of UCP1 gene transcription.
      Orientation of the transmembrane fragments was proposed and specific amino acid
      residues involved in the inhibition of UCP1 by purine nucleotides were identified
      in recombinant yeast. A potent enhancer mediating the response of the UCP1 gene
      to retinoids and controlling the specific transcription in brown adipocytes was
      identified using transgenic mice. More recently, we identified UCP2, an UCP
      homolog widely expressed in human and rodent tissues we also collaborated to
      characterize the plant UCP. Although the biochemical activities and physiological
      roles of the novel UCPs are not well understood, these recent data stimulate
      research on mitochondrial carriers, mitochondrial bioenergetics, and energy
      expenditure.

PMID- 10653471
TI  - Uncoupling protein--a useful energy dissipator.
AB  - The structure/function relationship in the uncoupling proteins (UCP) is reviewed,
      stressing UCP from brown adipose tissue (UCP1) since, so far, nearly no
      biochemistry is known for the UCP variants UCP2, UCP3, and UCP4. The transport
      for H+ and Cl- and its dependence on fatty acids in reconstituted vesicles is
      described. The inhibition and binding of nucleotides to UCP1, in particular, the
      pH dependence and two-stage binding are analyzed. A model for the role of fatty
      acid in H+ transport is shown. The role of specific residues in UCP1 is analyzed
      by directed mutagenesis in a yeast expression system. The different regulation by
      the cellular energy potential of UCP1 versus UCP3 is discussed.

PMID- 10653472
TI  - Anion carriers in fatty acid-mediated physiological uncoupling.
AB  - Physiological aspects of uncoupling of oxidation and phosphorylation are reviewed
      in the context of involvement of mitochondrial anion carriers. It is assumed that
      the carriers facilitate electrophoretic translation of fatty acid anion, RCOO-,
      from the inner to the outer leaflet of the mitochondrial membrane, whereas back
      movement of the protonated fatty acid, RCOOH, from the outer to the inner leaflet
      represents flip-flop of RCOOH via the phospholipid bilayer of the membrane. The
      RCOO- transport seems to be catalyzed by the ATP/ADP and aspartate/ glutamate
      antiporters, dicarboxylate carrier, and uncoupling proteins (UCP1, UCP2, UCP3L,
      UCP3s, and plant UCP). The fatty acid uncoupling is shown to be involved in the
      thermoregulatory heat production in animals and plants exposed to cold, as well
      as in performance of respiratory functions other than ATP synthesis, i.e.,
      formation of useful substances, decomposition of unwanted substances, and
      antioxidant defense. Moreover, partial uncoupling might take part in optimization
      of the rate of ATP synthesis in aerobic cells.

PMID- 10653473
TI  - The mechanisms of fatty acid-induced proton permeability of the inner
      mitochondrial membrane.
AB  - Nonesterified long-chain fatty acids have long been known as uncouplers of
      oxidative phosphorylation. They are efficient protonophores in the inner
      mitochondrial membrane but not so in artificial phospholipid membranes. In the un
      ionized form, they undergo a rapid spontaneous transbilayer movement (flip-flop).
      However, the transbilayer passage of the dissociated (anionic) form is hindered
      by the negatively charged hydrophilic carboxylic group. In the inner
      mitochondrial membrane, the transfer of fatty acid anions is mediated by the
      adenine nucleotide translocase, the dicarboxylate carrier, and the
      glutamate/aspartate carrier. As a result, the passage of protons and electric
      charges is a concerted effect of the spontaneous flip-flop of the undissociated
      (protonated) form in one direction and carrier-facilitated transfer of the
      ionized (deprotonated) form in the other direction. In addition, fatty acids also
      promote opening of the mitochondrial permeability transition pore, presumably due
      to their interaction with one of its constituents, the adenine nucleotide
      translocase, thus forming an additional route for dissipation of the proton
      gradient. Structural prerequisites for these proton-conducting mechanisms are (1)
      a weakly ionized carboxylic group and (2) a hydrocarbon chain of appropriate
      length without substituents limiting its mobility and hydrophobicity.

PMID- 10653474
TI  - Fatty acid interaction with mitochondrial uncoupling proteins.
AB  - The phenomena of fatty acid interaction with mitochondrial integral membrane
      proteins, namely uncoupling proteins (UCPs), are reviewed to emphasize the fatty
      acid cycling mechanism that has been suggested to explain the UCP function. Fatty
      acid-induced uncoupling is suggested to serve in bioenergetic systems, to set the
      optimum efficiency, and to tune the degree of coupling of oxidative
      phosphorylation. Fatty acid interaction with the "classic" uncoupling protein
      (UCP1) from mitochondria of thermogenic brown adipose tissue (BAT) is well known.
      UCP1 is considered to mediate purine nucleotide-sensitive uniport of monovalent
      unipolar anions, including anionic fatty acids. The return of protonated fatty
      acid leads to H+ uniport and uncoupling. Experiments supporting this mechanism
      are also reviewed for plant uncoupling mitochondrial protein (PUMP) and ADP/ATP
      carrier. The fatty acid cycling mechanism is predicted, as well for the recently
      discovered uncoupling proteins, UCP2 and UCP3.

PMID- 10653475
TI  - Uncoupling protein 3: its possible biological role and mode of regulation in
      rodents and humans.
AB  - The recently discovered uncoupling protein 3 (UCP3) is highly homologous to the
      mitochondrial inner membrane protein UCP1, which generates heat by uncoupling the
      respiratory chain from oxidative phosphorylation. The thermogenic function of
      UCP1 protects against cold and regulates the energy balance in rodents. We review
      in vitro studies investigating the uncoupling activity of UCP3 and in vivo
      studies, which address UCP3 gene expression in brown adipose tissue and skeletal
      muscle under various metabolic conditions. The data presented are, for the most,
      consistent with an uncoupling role for UCP3 in regulatory thermogenesis. We also
      discuss mediators of UCP3 regulation and propose a potential role for
      intracellular fatty acids in the mechanism of UCP3 modulation. Finally, we
      hypothesize a role for UCP3 in the metabolic adaptation of the mitochondria to
      the degradation of fatty acids.

PMID- 10653476
TI  - UCP1: the original uncoupling protein--and perhaps the only one? New perspectives
      on UCP1, UCP2, and UCP3 in the light of the bioenergetics of the UCP1-ablated
      mice.
AB  - The availability of a UCP1-ablated mouse has enabled critical studies of the
      function of UCP1, UCP2, and UCP3. Concerning UCP1, its presence in brown-fat
      mitochondria is associated with innate uncoupling, high GDP-binding capacity, and
      GDP-inhibitable Cl- permeability and uncoupling--but the high fatty acid
      sensitivity found in these mitochondria is observed even in the absence of UCP1.
      The absence of UCP1 leads to low cold tolerance but not to obesity. UCP1 ablation
      also leads to an augmented expression of UCP2 and UCP3 in brown adipose tissue,
      making this tissue probably the one that boasts the highest expression of these
      UCPs. However, these very high expression levels are not associated with any
      inherent uncoupling, or with a specific GDP-binding capacity, or with a GDP
      sensitive Cl- permeability, or with any effect of GDP on mitochondrial membrane
      potential, or with an increased basal metabolism of cells, or with the presence
      of norepinephrine- or fatty acid-induced thermogenesis in cells, and not with a
      cold-acclimation recruited, norepinephrine-induced thermogenic response in the
      intact animal. Therefore, it can be discussed whether any uncoupling effect is
      associated with UCP2 or UCP3 when they are endogenously expressed and,
      consequently, whether (loss of) uncoupling (thermogenic) effects of UCP2 or UCP3
      can be invoked to explain metabolic phenomena, such as obesity.

PMID- 10653477
TI  - Mitochondrial uncoupling: role of uncoupling protein anion carriers and
      relationship to thermogenesis and weight control "the benefits of losing
      control".
AB  - Uncoupling proteins, a subgroup of the mitochondrial anion transporter
      superfamily, have been identified in prokaryotes, plants, and mammalian cells.
      Evolutionary conservation of these molecules reflects their importance as
      regulators of two critical mitochondrial functions, i.e., ATP synthesis and the
      production of reactive oxygen species (ROS). Although the amino acid sequences of
      the three mammalian uncoupling proteins, UCP1, UCP2 and UCP3, are very similar,
      each homolog is the product of a unique gene and important differences have been
      demonstrated in their tissue-specific expression and regulation. UCP1 and UCP3
      appear to be key regulators of energy expenditure, and hence, nonshivering
      thermogenesis, either in brown adipose tissue (UCP1) or skeletal muscle (UCP3).
      UCP2 is expressed more ubiquitously, although generally at low levels, in many
      tissues. There is conflicting evidence about its importance as a regulator of
      resting metabolic rate. However, evidence suggests that this homolog might
      modulate the mitochondrial generation of ROS in some cell types, including
      macrophages and hepatocytes. While the induction of various uncoupling protein
      homologs provides adaptive advantages, both to the organism (e.g., thermogenesis)
      and to individual cells (e.g., reduced ROS), increased uncoupling protein
      activity also increases cellular vulnerability to necrosis by compromising the
      mitochondrial membrane potential. This narrow "risk-benefit" margin necessitates
      tight control of uncoupling protein activity in order to preserve cellular
      viability and much remains to be learned about the regulatory mechanisms
      involved.

PMID- 10653478
TI  - Brown adipose tissue thermogenesis during aging and senescence.
AB  - We have found that cold- and norepinephrine-induced brown adipose tissue (BAT)
      nonshivering thermogenesis (NST) is significantly lower in old male Fischer 344
      rats and is associated with the decreased ability of these animals to maintain
      homeothermy. This decline in BAT thermogenesis is not as great in females.
      Although the mechanism(s) underlying this gender difference in the age-related
      decrease in brown fat NST are not completely elucidated, they do not appear to
      reflect decreased sympathetic neural activity of BAT in the older males vs.
      females. Rather, our investigations, strongly suggest that the blunted cold
      induced heat production of BAT reflects less functional BAT. The fact that the
      older animals have less functional BAT than do their younger counterparts may
      predispose them to the accumulation of excess body fat. Our studies have also
      found that near the end of the natural life of these rats, they enter a state of
      senescence that can be identified by spontaneous rapid body weight loss,
      resulting from decreased food intake. In this state, the rats are considerably
      more susceptible to cold than are comparably aged presenescent (body weight
      stable) rats of the same chronological age. The greater hypothermia exhibited by
      the senescent vs. presenescent rats during cold exposure is associated with a
      significant reduction in the amount of functional brown fat and in the amount of
      heat each brown fat cell can generate. It is the intent of this review to discuss
      the findings of these investigations.

PMID- 10653479
TI  - Mitochondrial proton leak and the uncoupling proteins.
AB  - An energetically significant leak of protons occurs across the mitochondrial
      inner membranes of eukaryotic cells. This seemingly wasteful proton leak accounts
      for at least 20% of the standard metabolic rate of a rat. There is evidence that
      it makes a similar contribution to standard metabolic rate in a lizard. Proton
      conductance of the mitochondrial inner membrane can be considered as having two
      components: a basal component present in all mitochondria, and an augmentative
      component, which may occur in tissues of mammals and perhaps of some other
      animals. The uncoupling protein of brown adipose tissue, UCP1, is a clear example
      of such an augmentative component. The newly discovered UCP1 homologs, UCP2,
      UCP3, and brain mitochondrial carrier protein 1 (BMCP1) may participate in the
      augmentative component of proton leak. However, they do not appear to catalyze
      the basal leak, as this is observed in mitochondria from cells which apparently
      lack these proteins. Whereas UCP1 plays an important role in thermogenesis, the
      evidence that UCP2 and UCP3 do likewise remains equivocal.

PMID- 10653480
TI  - Plant uncoupling mitochondrial protein activity in mitochondria isolated from
      tomatoes at different stages of ripening.
AB  - In the present study we have observed a higher state of coupling in respiring
      mitochondria isolated from green as compared to red tomatoes (Lycopersicon
      esculentum, Mill.). Green tomato mitochondria produced a membrane potential
      (deltapsi) high enough to phosphorylate ADP, whereas in red tomato mitochondria,
      BSA and ATP were required to restore deltapsi to the level of that obtained with
      green tomato mitochondria. This supports the notion that such uncoupling in red
      tomato mitochondria is mediated by a plant uncoupling mitochondrial protein
      (PUMP; cf. Vercesi et al., 1995). Nevertheless, mitochondria from both green and
      red tomatoes exhibited an ATP-sensitive linoleic acid (LA)-induced deltapsi
      decrease providing evidence that PUMP is also present in green tomatoes. Indeed,
      proteoliposomes containing reconstituted green or red tomato PUMP showed LA
      uniport and LA-induced H+ transport. It is suggested that the higher
      concentration of free fatty acids (PUMP substrates) in red tomatoes could explain
      the lower coupling state in mitochondria isolated from these fruits.

PMID- 10653481
TI  - Time-course of oxidation of lipids in human cerebrospinal fluid in vitro.
AB  - Oxidative mechanisms play an important role in the pathogenesis of Alzheimer's
      disease, Parkinson's disease and other neurodegenerative diseases. To assess
      whether the oxidation of brain lipoproteins plays a role in the development of
      these pathologies, we investigated whether the lipoproteins of human
      cerebrospinal fluid (CSF) are susceptible to oxidative modification in vitro. We
      studied oxidation time-course for up to 100 h of human CSF in the absence
      (autooxidation) or presence of exogenous oxidants. Autooxidation of diluted CSF
      was found to result in a slow accumulation of lipid peroxidation products. The
      time-course of lipid hydroperoxide accumulation revealed three consecutive
      phases, lag-phase, propagation phase and plateau phase. Qualitatively similar
      time-course has been typically found in human plasma and plasma lipoproteins.
      Autooxidation of CSF was accelerated by adding exogenous oxidants, delayed by
      adding antioxidants and completely inhibited by adding a chelator of transition
      metal ions. Autooxidation of CSF also resulted in the consumption of endogenous
      ascorbate, alpha-tocopherol, urate and linoleic and arachidonic acids. Taking
      into account that (i) lipid peroxidation products measured in our study are known
      to be derived from fatty acids, and (ii) lipophilic antioxidants and fatty acids
      present in CSF are likely to be located in CSF lipoproteins, we conclude that
      lipoproteins of human CSF are modified in vitro during its autooxidation. This
      autooxidation appears to be catalyzed by transition metal ions, such as Cu(II)
      and Fe(III), which are present in native CSF. These data suggest that the
      oxidation of CSF lipoproteins might occur in vivo and play a role in the
      pathogenesis of neurodegenerative diseases.

PMID- 10653482
TI  - Antioxidants and herbal extracts protect HT-4 neuronal cells against glutamate
      induced cytotoxicity.
AB  - Antioxidant therapy has been shown to be beneficial in neurological disorders
      including Alzheimer's disease and cerebral ischemia. Glutamate-induced
      cytotoxicity in HT-4 neuronal cells has been previously demonstrated to be due to
      oxidative stress caused by depletion of cellular glutathione (GSH). The present
      study demonstrates that a wide variety of antioxidants inhibit glutamate-induced
      cytotoxicity in HT-4 neuronal cells. Low concentrations of alpha-tocopherol and
      its analogs were highly effective in protecting neuronal cells against
      cytotoxicity. Purified flavonoids and herbal extracts of Gingko biloba (EGb 761)
      and French maritime pine bark (Pycnogenol) were also effective. We have
      previously shown that pro-glutathione agents can spare GSH and protect cells from
      glutamate insult in a C6 glial cell model. The protective effects of nonthiol
      based antioxidants tested in the HT-4 line were not mediated via GSH level
      modulation. In contrast, protective effects of thiol-based pro-glutathione agents
      alpha-lipoic acid (LA) and N-acetyl cysteine (NAC) corresponded with a sparing
      effect on GSH levels in glutamate-treated HT-4 cells. Glutamate-induced
      cytotoxicity in HT-4 cells is a useful model system for testing compounds or
      mixtures for antioxidant activity.

PMID- 10653483
TI  - Increased hepatic lipid soluble antioxidant capacity as compared to other organs
      of streptozotocin-induced diabetic rats: a cyclic voltammetry study.
AB  - It has been suggested that oxidative stress plays an important role in the
      chronic complications of diabetes. The experimental findings regarding the
      changes in tissue antioxidant enzymes and lipid peroxidation of diabetic tissues
      have been inconsistent. Previous studies in our laboratory demonstrated that the
      reducing power of a specific tissue correlates with its low molecular weight
      antioxidant (LMWA) capacity. In the present study, the overall LMWA capacity
      (reducing equivalents) of plasma and tissues of streptozotocin (STZ)-induced
      diabetic rats (1-4 weeks) and insulin treated diabetic rats were measured by
      cyclic voltammetry. Levels of water and lipid soluble LMWA capacity progressively
      decreased in the diabetic plasma, kidney, heart and brain, while the diabetic
      liver, at 2, 3 and 4 weeks after STZ injection, showed a significant increase in
      the overall lipid soluble LMWA capacity (p < 0.001). Subsequently, analysis of
      specific components by high pressure liquid chromatography (electrochemical
      detection) showed decreased levels of ascorbic acid in plasma, kidney, heart and
      brain of diabetic animals. The alpha-tocopherol level dropped in all tissues,
      except for the liver in which there was a significant increase (p < 0.01 and p <
      0.001 at 2-4 weeks). Lipid peroxidation was assessed by conjugated diene levels,
      which increased significantly in all diabetic tissues except the liver. Insulin
      treatment that was started after 3 weeks of diabetes and continued for 3 weeks
      showed no change in the conjugated dienes and in the overall LMWA capacity in all
      organs. Our results suggest a unique behavior of the liver in the STZ-induced
      diabetic rats to the stress and indicate its higher capacity to cope with
      oxidative stress as compared to other organs.

PMID- 10653484
TI  - Myocardial protection by protykin, a novel extract of trans-resveratrol and
      emodin.
AB  - Protykin is an all-natural, high potency standardized extract of trans
      resveratrol (20%) and emodin (10%) derived from the dried rhizome of Polygonum
      cuspidatum. Previous studies have demonstrated free radical scavenging and anti
      inflammatory activities of resveratrol. Since free radicals play a crucial role
      in the pathogenesis of myocardial ischemia/reperfusion injury, we examined
      whether Protykin could preserve the heart during ischemic arrest. Sprague-Dawley
      rats were divided into two groups: experimental group was gavaged Protykin (100
      mg/kg body wt) dissolved in corn oil for three weeks, while the control group was
      gavaged corn oil alone. After three weeks, rats were sacrificed, isolated hearts
      perfused via working mode, were made globally ischemic for 30 min followed by 2 h
      of reperfusion. Left ventricular functions were continuously monitored and
      malonaldehyde (MDA) (presumptive marker for oxidative stress) formation were
      estimated. At the end of each experiment, myocardial infarct size was measured by
      TTC staining method. Peroxyl radical scavenging activity of Protykin was
      determined by examining its ability to remove peroxyl radical generated by 2,2'
      azobis (2-amidinopropane) dihydrochloride, while hydroxy radical scavenging
      activity was tested with its ability to reduce 7-OH*-coumarin-3-carboxylic acid.
      The results of our study demonstrated that the Protykin group provided
      cardioprotection as evidenced by improved post-ischemic left ventricular
      functions (dp, dp/dt(max)) and aortic flow as compared to control group. This was
      further supported by the reduced infarct size in the Protykin group. Formation of
      MDA was also reduced by Protykin treatment. In vitro studies demonstrated that
      Protykin possessed potent peroxyl and hydroxyl radical scavenging activities. The
      results of this study indicate that Protykin can provide cardioprotection,
      presumably by virtue of its potent free radical scavenging activity.

PMID- 10653485
TI  - Chroman amide and nicotinyl amide derivatives: inhibition of lipid peroxidation
      and protection against head trauma.
AB  - A series of chroman amide and nicotinyl amide derivatives was designed and
      synthesized for the treatment of traumatic and ischemic CNS injury. Five
      compounds were significantly more potent inhibitors of lipid peroxidation in
      vitro than the reference antioxidant, trolox (p < 0.01). Quantitative structure
      activity studies demonstrated that the inhibitory action was related to the
      ability to donate electrons, charge on hydroxy group and E(LUMO), to scavenging
      radicals and to the lipophilicity log P, which determines penetration of membrane
      lipids. ESR study indicated the ability of 12 to scavenge the hydroxyl radicals.
      The most promising compound, [(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1
      benzopyran-2yl)ca rbonyl]-3'-(aminoethyl) indole (12), inhibited ex vivo lipid
      peroxidation in a head injury model and showed potent in vivo neuroprotective
      efficacy. Improvement of neurological recovery within 1 h of injury (grip test
      score) by as much as 200% was observed together with significant anti-anoxia
      activity. Compound 12 was a potent antagonist of methamphetamine-induced
      hypermotility resulting from dopamine release in the mouse brain. These results
      support the importance of cerebroprotective radical-scavenging agents for the
      treatment of traumatic injury and anoxia as well as provide additional evidence
      for the role of oxygen radicals and dopamine in brain damage.

PMID- 10653486
TI  - Studies of free radical-mediated cryoinjury in the unicellular green alga Euglena
      gracilis using a non-destructive hydroxyl radical assay: a novel approach for
      developing protistan cryopreservation strategies.
AB  - The development of cryoconservation methods for the long-term storage of algal
      cultures is important for the ex situ preservation of biological diversity and
      the maintenance of genetic stability within this group of important organisms.
      However, as many unicellular algae are recalcitrant to cryogenic storage, this
      study aims to evaluate the role of oxidative stress in cryoinjury. A non
      invasive, non-destructive assay method previously applied to animal cells has
      been developed to evaluate free radical mediated oxidative stress in Euglena
      gracilis exposed to different cryopreservation treatments. The procedure employs
      dimethyl sulphoxide as a probe for the hydroxyl radical. Adopting this approach
      it was possible to identify those components of the cryopreservation protocol
      which were the most damaging. These were identified as preparative centrifugation
      and sub-zero freezing treatments. Poststorage survival in E. gracilis was
      significantly (P < 0.05) enhanced when the chelating agent desferrioxamine was
      included in the recovery medium whilst methane production was significantly (P <
      0.004) reduced, suggesting that the additive was capable of ameliorating
      oxidative stress. The potential of using novel, exogenous antioxidant treatments
      developed for medical applications and applying them to enhance cryopreservation
      tolerance in recalcitrant unicellular algae is discussed.

PMID- 10653487
TI  - Elevated plasma homocysteine elicits an increase in antioxidant enzyme activity.
AB  - Elevated plasma homocysteine is considered to be a risk factor for cardiovascular
      disease. The mechanisms for this effect are not fully understood but there is
      some evidence for a role for reactive oxygen species (ROS). This study was
      conducted to explore the effects of elevated plasma total homocysteine (tHcy)
      concentration on activity of antioxidant enzymes in the circulation. The study
      group consisted of 10 patients with inherited defects of homocysteine metabolism,
      from whom 41 blood samples were collected over a period of six months. Blood
      samples were also collected from 13 of their obligate heterozygous parents. For
      data analysis samples were classified as those with plasma tHcy < 20 microM or >
      20 microM. The activity of erythrocyte superoxide dismutase (SOD) and plasma
      glutathione peroxidase (GSHPx) was elevated in samples with plasma tHcy > 20
      microM. Moreover, a significant correlation was demonstrated between plasma GSHPx
      activity, plasma glutathione peroxidase protein and plasma tHcy. III vitro
      studies confirmed that this observation was not due to a simple chemical
      enhancement of enzyme activity. Homocysteine protected GSHPx from loss of
      activity following incubation at 37 degrees C. A similar effect was seen with
      another thiol-containing amino acid, cysteine. Results suggest that elevated
      plasma tHcy represents an oxidative stress, resulting in an adaptive increase in
      activity of antioxidant enzymes in the circulation.

PMID- 10653488
TI  - The antioxidant activities of seasonings used in Asian cooking. Powerful
      antioxidant activity of dark soy sauce revealed using the ABTS assay.
AB  - Scavenging of the ABTS (2,2'-azinobis[3-ethylbenzothiazoline-6-sulphonate])
      derived nitrogen-centred radical cation (ABTS*+) was used to compare the total
      antioxidant activities of several seasonings used in Asian cooking. The results
      were expressed as Trolox equivalent antioxidant capacity (TEAC). The TEAC
      activities of dark soy sauces were found to be exceptionally high. In evaluating
      the TEAC of commercial products, attention must be paid to the addition of
      preservatives by manufacturers to the seasonings tested. Sodium benzoate (a
      preservative added to several seasonings) did not react significantly with
      ABTS*+, but the sulphite content of certain white wines may have led to an over
      estimation of their TEAC.

PMID- 10653489
TI  - Growth characteristics of fibroblasts isolated from the trunk and distal aspect
      of the limb of horses and ponies.
AB  - OBJECTIVE: To determine if there is a difference in in vitro growth of
      fibroblasts isolated from the trunk and distal aspect of the limb of horses and
      ponies. To determine the effects of a corticosteroid and monokine on in vitro
      growth of fibroblasts isolated from the trunk and distal aspect of the limb of
      horses and ponies. STUDY DESIGN: Growth of fibroblasts from tissues harvested
      from the trunk and limb were compared from horse and pony samples grown in
      control media and control media with triamcinolone or monokine added. ANIMALS OR
      SAMPLE POPULATION: Dermal and subcutaneous tissue from 22 horses and 17 ponies of
      various ages and breeds. METHODS: Fibroblast growth was assessed by tritiated
      thymidine uptake using standard cell culture techniques. The effect of a monokine
      or triamcinolone plus control media were compared with control media for
      fibroblast growth. RESULTS: Fibroblast growth from tissues isolated from the
      horse limb was significantly less than growth from the horse trunk and the limb
      and trunk of ponies. Monokine was more effective than triamcinolone in
      suppressing fibroblast growth from tissues isolated from the trunk and limb in
      both horses and ponies. CONCLUSIONS: There are growth differences in fibroblasts
      isolated from the limb of horses compared with those isolated from the trunk and
      from the limb and trunk of ponies. CLINICAL RELEVANCE: The difference in
      fibroblast growth from tissues isolated from the trunk and limb of horses and
      ponies may provide evidence for the difference reported in the healing
      characteristics of limb wounds in horses and ponies. Influencing fibroblast
      growth may provide a key to controlling the development of exuberant granulation
      tissue in horses and ponies.

PMID- 10653490
TI  - The effect of compacted cancellous bone grafting on the healing of subchondral
      bone defects of the medial femoral condyle in horses.
AB  - OBJECTIVE: To compare the quality of second-intention healing and that of
      compacting sternally harvested cancellous bone into subchondral bone defects of
      the medial femoral condyle in horses. STUDY DESIGN: A controlled experiment using
      a surgical technique that minimizes soft tissue trauma, customized for
      consistency among horses. ANIMALS OR SAMPLE POPULATION: Ten horses, aged 2 to 5
      years, free of hindlimb lameness and with radiographically normal stifles.
      METHODS: After a 12.7-mm-diameter x 19-mm-deep defect was created into randomly
      selected medial femoral condyles, bone and cartilage healing was evaluated over a
      6-month period in control horses (n = 5) and horses receiving a compacted
      cancellous bone graft (n = 5). Healing was evaluated using lameness assessment,
      radiographic and microradiographic interpretation, arthroscopic appearance,
      percent bone fill, proteoglycan content, and histology. RESULTS: Six months after
      surgery, there was no significant difference between grafted and ungrafted
      defects with respect to lameness, radiographic score, or percent bone fill.
      Histologically, grafted defects were characterized by the presence of dead graft
      and secondary cyst formation in four defects. Ungrafted defects filled with
      fibrous tissue and no cyst formation were identified. CONCLUSIONS: Grafted
      defects do not heal better than ungrafted defects, and lameness was not affected
      by surgical technique. CLINICAL SIGNIFICANCE: Cartilage healing is similar in
      grafted and ungrafted defects in the equine medial femoral condyle at 6 months,
      suggesting that surgical debridement alone of cystic structures remains the
      treatment of choice.

PMID- 10653491
TI  - Keratinocyte growth factor enhances early gut adaptation in a rat model of short
      bowel syndrome.
AB  - OBJECTIVE: To evaluate the effects of keratinocyte growth factor (KGF) on
      intestinal adaptation after resection of 85% of the small intestine and consider
      its potential application in short bowel syndrome (SBS). STUDY DESIGN:
      Experimental study using a known model of SBS. ANIMAL POPULATION: Thirty male
      Sprague Dawley rats. METHODS: Four groups of animals were designated. Two groups
      underwent 85% resection of the small intestine, while the other two groups were
      sham-operated, undergoing transection and reanastomosis. Resected and sham
      operated groups then received either 3 mg/kg KGF or vehicle subcutaneously daily
      for 3 days. Gut adaptation was evaluated by measurements of mucosal cellularity
      and biochemical activity in duodenal, jejunal, and ileal segments. RESULTS:
      Significant small intestinal growth after bowel resection alone was confirmed in
      resected versus sham-operated rats. KGF further augmented this growth in the
      resected animals. Mucosal wet weight of the small intestine increased with
      resection and was further increased (by 20% or more) with KGF administration.
      Mucosal thickness, villus length, and crypt depth exhibited similar patterns of
      response. The KGF-induced increase in mucosal morphology was accompanied by
      increased mucosal DNA and protein content, followed by a trend toward increased
      mucosal enzyme activity. Histology demonstrated an increase in goblet cells in
      KGF-treated animals. In situ hybridization analysis demonstrated that KGF
      markedly increased mucosal expression of intestinal trefoil protein (ITF) mRNA.
      CONCLUSIONS: KGF enhances gut growth, differentiation, and gene regulation during
      adaptation in rat small intestine after massive resection. CLINICAL RELEVANCE:
      KGF may be beneficial in the management of veterinary and human patients
      undergoing massive intestinal resection.

PMID- 10653492
TI  - Finite element method evaluation: articulations and diagonals in an 8-pin type 1B
      external skeletal fixator.
AB  - OBJECTIVE: To determine the mechanical properties of articulations and diagonals
      in an 8-pin type 1b external skeletal fixator (ESF). STUDY DESIGN: Finite element
      method-computer simulation. METHODS: The control type 1b ESF was supplemented
      with different articulations and diagonals. The parameters of frame angle,
      articulation diameter, and pin- or connector-based fastening were altered. The
      configurations were loaded for axial compression, torsion, and craniocaudal and
      mediolateral bending as single loads and as a combination. Three-dimensional
      linear and rotational gap strain and Von Mises stress maxima were determined.
      RESULTS: For 90 degrees , 60 degrees , and 30 degrees frame angles and 0.48-cm
      diameter articulations and diagonals, the best configurations, based on lower gap
      strain combined with decreased or minimally increased stress maxima for the
      combined load, were single or double diagonals or four horizontal articulations.
      Combining double diagonals with double wide horizontal articulations further
      lowered gap strain. For a 90 degrees frame angle and 0.32-cm-diameter
      articulations and diagonals, the superior configurations, showing the lowest gap
      strain combined with decreased or minimally increased stress maxima for the
      combined load, were double diagonals, four horizontal, or wide double horizontal
      articulations. The 0.48-cm articulations and diagonals provided lower or similar
      gap strain than 0.32-cm articulations and diagonals. The connector-to-connector
      version of these superior configurations provided slightly lower or similar gap
      strain and stress maxima than the pin-to-pin version. Only pin-to-pin-fastened
      double diagonals provided better stress maxima than the corresponding connector
      to-connector version. CONCLUSIONS: Supplementing a type 1b ESF with double
      diagonals and wide double articulations results in the greatest increase in
      stability at the fracture gap for complex fractures or in the initial phase of
      bone healing.

PMID- 10653493
TI  - An in vitro biomechanical investigation of an equine interlocking nail.
AB  - OBJECTIVE: To determine the mechanical properties of Equine Interlocking Nail
      (EIN; JD Wheat Veterinary Orthopedic Research Laboratory, University of
      California, Davis) stabilized osteotomized tibiae and compare these variables
      with estimated in vivo loads. STUDY DESIGN: In vitro biomechanical investigation.
      ANIMALS: Twelve adult equine cadaveric tibiae. SAMPLE POPULATION: EIN-stabilized
      tibiae were tested monotonically under compression, 3- and 4-point bending, and
      torsion. Mechanical properties were compared with estimated in vivo loads.
      RESULTS: EIN-tibial composite mean compressive yield load (11 kN) and bending
      moment (216 Nm) were greater than loads expected postoperatively in vivo;
      however, the mean torsional yield load (156 Nm) was less than that expected in
      vivo. CONCLUSIONS: EIN-stabilized tibiae had compressive and bending strengths
      greater than those expected to maintain stability during walking in adult horses.
      Torsional yield strength did not appear sufficient to provide stability during
      walking in vivo. CLINICAL RELEVANCE: The EIN is not a feasible method of fracture
      repair for adult equine tibial fractures at this time, because its mechanical
      properties appear inadequate to withstand the postoperative torsional loads
      encountered during walking. Because this method of fracture repair may offer
      biological advantages, further modification of an interlocking nail for adult
      horses appears warranted.

PMID- 10653494
TI  - Evaluation of a bioresorbable hyaluronate-carboxymethylcellulose membrane for
      prevention of experimentally induced abdominal adhesions in horses.
AB  - OBJECTIVE: To evaluate the efficacy of a bioresorbable hyaluronate
      carboxymethylcellulose membrane (HA-membrane) for prevention of experimentally
      induced abdominal adhesions in horses. STUDY DESIGN: Experimental study. ANIMAL
      POPULATION: Twelve healthy adult horses. METHODS: The effect of an HA-membrane on
      adhesion formation was evaluated in 12 healthy horses using an established model
      of serosal trauma to induce adhesions. A ventral median celiotomy and two jejunal
      resections and end-to-end anastomoses were performed. Two separate jejunal areas
      were abraded, and three 2-0 chromic gut sutures placed in the abraded areas. In
      treated horses (n = 6), HA-membranes were applied to the jejunum to completely
      cover the anastomoses and abraded areas of jejunum. Nontreated horses (n = 6)
      served as controls. All horses were killed 10 days after surgery. The abdominal
      cavity was evaluated for adhesion formation. The frequency of intra-abdominal
      adhesions between groups was compared with a chi2 test with statistical
      significance set at P < .05. RESULTS: All control horses had intra-abdominal
      adhesions; fibrous adhesions were associated with both jejunal abrasion sites in
      5 horses. One treated horse developed adhesions. There were significantly fewer
      adhesions in the HA-membrane-treated group (P < .0034). CONCLUSIONS: In this
      experimental model, application of an HA-membrane to a localized area of serosal
      trauma reduced the frequency of intra-abdominal adhesion formation. CLINICAL
      RELEVANCE: Application of an HA membrane may decrease the frequency of adhesions
      in horses at an increased risk of postoperative adhesion formation.

PMID- 10653495
TI  - Effects of analgesia of the distal interphalangeal joint or palmar digital nerves
      on lameness caused by solar pain in horses.
AB  - OBJECTIVE: To determine if pain of the dorsal margin of the sole in horses can be
      attenuated by anesthesia of either the distal interphalangeal (DIP) joint or the
      palmar digital (PD) nerves. STUDY DESIGN: A unilateral forelimb lameness was
      induced by creating solar pain. Response to administration of local anesthetic or
      saline solution into the DIP joint and to administration of local anesthetic
      around the PD nerves was evaluated. ANIMALS: Six horses. METHODS: Lameness was
      induced by creating pressure on the dorsal margin of the sole by screwing set
      screws into a nut welded to the inside of each branch of a shoe. Gaits were
      evaluated before and after application of set-screws and after a local anesthetic
      or saline solution was administered into the DIP joint and, in a second trial,
      after a local anesthetic was injected around the PD nerves. Gaits recorded on
      videotape were evaluated, and lameness scores were assigned to each gait.
      RESULTS: Lameness scores were high after application of set-screws and remained
      high after saline solution was administered into the DIP joint. Scores decreased
      significantly (P < or = .05) after a local anesthetic was administered into the
      DIP joint or around the PD nerves. CONCLUSIONS: Analgesia of the DIP joint or the
      PD nerves desensitizes at least a portion of the sole. CLINICAL RELEVANCE: Pain
      arising from the sole should not be excluded as a cause of lameness when lameness
      is attenuated by analgesia of the DIP joint or PD nerves.

PMID- 10653496
TI  - Relative stiffness and stress of type I and type II external fixators: acrylic
      versus stainless-steel connecting bars--a theoretical approach.
AB  - OBJECTIVE: To compare the stiffness and pin stresses of three sizes of external
      fixator systems with stainless-steel and acrylic connecting bars. STUDY DESIGN:
      Finite element analysis. METHODS: Small, medium, and large external fixator
      systems of type I and type II configurations were modeled for finite element
      analysis. Each model was evaluated with a standard stainless-steel and three
      different diameters of acrylic connecting bar. Displacements and stresses were
      calculated for the loading modes of axial compression, medio-lateral bending,
      cranio-caudal bending, and torsion. The location of the pin experiencing maximum
      stress was determined for all configurations and loading modes. RESULTS: Acrylic
      column diameters of 9.53 mm for the small external fixator system and 15.9 mm for
      the medium external fixator system provide equivalent stiffness and maximum pin
      stresses to those provided by the standard stainless-steel connecting bars (3.2-
      and 4.8-mm diameter, respectively). The largest diameter acrylic column tested
      (31.75-mm) produced lower stiffness and higher maximum pin stresses than the
      standard stainless-steel connecting bar (11.1-mm diameter). CONCLUSIONS: When
      applying a small or medium external fixator, an acrylic column of 9.53-mm or 15.9
      mm diameter, respectively, can be used. For a large external fixator system, an
      acrylic column of diameter >31.75 mm is required. CLINICAL RELEVANCE: The sizes
      of acrylic connecting bars for use in small and medium external fixator systems
      have been determined. Large systems should incorporate the standard stainless
      steel connecting bar.

PMID- 10653497
TI  - Surgical treatment of lumbosacral instability caused by discospondylitis in four
      dogs.
AB  - OBJECTIVE: To describe a surgical technique involving distraction and
      stabilization of the lumbo-sacral vertebral segment using an external skeletal
      fixator in dogs with lumbosacral instability caused by discospondylitis. STUDY
      DESIGN: Retrospective clinical study. ANIMALS: Four client-owned dogs. METHODS:
      Medical records of all dogs diagnosed with discospondylitis from 1994 to 1997
      were identified and reviewed. Four dogs with lumbosacral discospondylitis
      requiring surgical treatment were then specifically studied. Surgical technique,
      clinical signs, preoperative diagnostic investigation, radiographic findings, and
      the results of short-term and long-term reevaluations were recorded. RESULTS:
      Twelve dogs with discospondylitis were identified, 4 of which had lumbosacral
      discospondylitis. These 4 dogs underwent surgical distraction and stabilization
      because they failed to respond to medical treatment. Three dogs received a
      cancellous bone graft between L7 and S1 and had rapid interbody fusion of this
      vertebral segment. The dog that did not receive a graft did not have interbody
      fusion at the time of fixator removal. This did not affect the final clinical
      outcome. Lumbosacral pain and neurological deficits present before surgery
      rapidly subsided after the procedure. All dogs received concurrent antibiotic
      treatment for a minimum of 4 weeks. All dogs were clinically normal at the time
      of fixator removal and all continued to do well during the follow-up period (8-48
      months; mean, 27.5 months). CONCLUSION AND CLINICAL RELEVANCE: Lumbosacral
      discospondylitis may not respond well to conservative treatment because of the
      mobility of the affected space. Surgical treatment involving distraction and
      stabilization to obtain intervertebral fusion is very effective in treating
      lumbosacral instability caused by discospondylitis.

PMID- 10653498
TI  - Perioperative stress response in the dog: effect of pre-emptive administration of
      medetomidine.
AB  - OBJECTIVE: To determine the effect of medetomidine on the stress response induced
      by ovariohysterectomy in isoflurane-anesthetized dogs. STUDY DESIGN: Prospective
      randomized study. ANIMALS: Twelve healthy adult female purpose-bred dogs,
      weighing 16.8 to 25 kg. METHODS: Two treatments were randomly administered to
      each of twelve dogs at weekly intervals: (1) Saline injected IM followed in 15
      minutes by isoflurane anesthesia (ISO) induced by mask and maintained at an end
      tidal concentration of 1.8% for 60 minutes; and (2) Medetomidine, 15 ug/lkg IM
      followed in 15 minutes by isoflurane anesthesia (ISO&MED) induced by mask and
      maintained at an end-tidal concentration of 1.0% for 60 minutes. One week after
      completion of these two treatments, all dogs were ovariohysterectomized. six
      receiving each treatment (SURG and SURG&MED). Central venous blood samples (10
      mL) were obtained immediately before medetomidine or saline (baseline) and at 30,
      75, and 195 minutes and 24 hours after administration of medetomidine or saline
      in ISO and ISO&MED. In SURG and SURG&MED, samples were obtained immediately prior
      to injection of medetomidine or saline (baseline) and at 30 (before skin
      incision), 45 (after severence of the ovarian ligament), 75 (after skin closure),
      105 (30 minutes after skin closure, dog recovered and in sternal recumbency),
      135, 195, 375 minutes, and 24 hours after the initial sample. Samples were
      analyzed for epinephrine, norepinephrine, adrenocorticotrophic hormone (ACTH),
      cortisol, insulin, and glucose. Data were analyzed by analysis of variance and
      where significant differences were found, a least significant difference test was
      applied. RESULTS: Premedication with medetomidine prevented or delayed the stress
      response induced by ovariohysterectomy in isoflurane-anesthetized dogs.
      CONCLUSIONS: The stress response induced by ovariohysterectomy, although
      significant, is of short duration. Medetomidine safely and effectively reduced
      surgically-induced stress responses. CLINICAL RELEVANCE: Surgically induced
      stress responses can be obtunded or prevented by administration of medetomidine.

PMID- 10653499
TI  - The recovery of horses from inhalant anesthesia: a comparison of halothane and
      isoflurane.
AB  - OBJECTIVE: Recovery is one of the more precarious phases of equine general
      anesthesia. The quality and rate of recovery of horses from halothane and
      isoflurane anesthesia were compared to determine differences in the
      characteristics of emergence from these commonly used inhalant anesthetics.
      EXPERIMENTAL DESIGN: Prospective, randomized blinded clinical trial. SAMPLE
      POPULATION: A total of 96 Thoroughbred and 3 Standardbred racehorses admitted for
      elective distal forelimb arthroscopy. METHODS: All horses were premedicated with
      intravenous xylazine, induced with guaifenesin and ketamine, and maintained on a
      large animal circle system fitted with an out of the circle, agent specific
      vaporizer. Recoveries were managed by a blinded scorer with a standardized
      protocol. A 10 category scoring system was used to assess each horse's overall
      attitude, purposeful activity, muscle coordination, strength and balance from the
      time of arrival in recovery to standing. Times to extubation, sternal recumbency
      and standing were recorded. Median recovery scores and mean times to extubation,
      sternal and standing were compared using the Mann-Whitney U test and student's t
      test, respectively. RESULTS: The median score for horses recovering from
      halothane was lower (20.0; range, 10 to 57) than that for horses recovering from
      isoflurane (27.5; range, 10 to 55). Horses in the two groups were extubated at
      similar mean times (halothane, 11.3 +/- 5.5 and isoflurane, 9.5 +/- 5.2 minutes)
      but horses recovering from isoflurane achieved sternal recumbency (halothane,
      37.7 +/- 12.1 and isoflurane, 24.7 +/- 8.8 minutes) and stood (halothane, 40.6 +/
      12.9 and isoflurane, 27.6 +/- 9.6 minutes) sooner than those recovering from
      halothane. CONCLUSIONS: The recovery of horses from isoflurane anesthesia was
      more rapid but less composed than that from halothane. CLINICAL RELEVANCE: The
      quality of recovery following isoflurane was worse than after halothane
      anesthesia using the criteria chosen for this study. However, the range of
      recovery scores was similar for both groups and all horses recovered without
      significant injury.

PMID- 10653500
TI  - Determination of the minimum anesthetic concentration and cardiovascular dose
      response for sevoflurane in chickens during controlled ventilation.
AB  - OBJECTIVE: To determine the minimum anesthetic concentration for sevoflurane and
      effects of various multiples of minimum anesthetic concentration on arterial
      pressure and heart rate during controlled ventilation in chickens. STUDY DESIGN:
      Prospective experimental study. ANIMALS: Seven healthy chickens, 6 to 8 months
      old, weighing 1.6 to 3.4 kg. METHODS: A rebreathing, semiclosed anesthetic
      circuit was used. Anesthesia was induced by mask with sevoflurane in oxygen. Each
      chicken was endotracheally intubated, then controlled ventilation was started and
      the end-tidal CO2 partial pressure was maintained at 30 to 40 mm Hg. Body
      temperature was maintained at 39.5 degrees to 41.0 degrees C. The inspired and
      end-tidal sevoflurane concentration were monitored with a multigas monitor.
      Minimum anesthetic concentration was determined as the minimal end-tidal
      sevoflurane concentration which prevented gross purposeful movement in response
      to clamping a toe for 1 minute. After the determination, the cardiovascular
      effects of sevoflurane at 1.0, 1.5, and 2.0 times the minimum anesthetic
      concentration were determined. RESULTS: The minimum anesthetic concentration for
      sevoflurane was 2.21% + 0.32% (mean +/- SD). Mean arterial pressure and heart
      rate at minimum anesthetic concentration were 84 +/- 13 mm Hg and 150 +/- 58
      beats/min, respectively. There was a dose-dependent decrease in arterial
      pressure. The heart rate did not change significantly over the range 1 to 2 x
      minimum anesthetic concentration. No cardiac arrhythmias developed throughout the
      experiments. CONCLUSIONS AND CLINICAL RELEVANCE: The minimum anesthetic
      concentration for sevoflurane in chickens was within the range of minimum
      alveolar concentration reported in mammals. When the concentration of sevoflurane
      is increased during controlled ventilation in chickens, decrease in arterial
      pressure should be expected.

PMID- 10653501
TI  - Perioperative management of calves undergoing implantation of a left ventricular
      assist device.
AB  - OBJECTIVE: To describe perioperative management of calves that underwent left
      lateral thoracotomy, aortic cross-clamping, partial left heart bypass and
      implantation of a left ventricular assist device. SAMPLE POPULATION: A total of
      43 healthy castrated male calves, weighing 121 +/- 24 kg. RESULTS: Diazepam (mean
      +/- SD, 0.26 +/- 0.07 mg/kg), ketamine (5.9 +/- 2.17 mg/kg) and isoflurane were
      used in the anesthetic management of calves undergoing implantation of a left
      ventricular assist device in the descending thoracic aorta. Other adjunctive
      agents administered were fentanyl (11 +/- 5.4 microg/kg), lidocaine (4.9 +/- 3.19
      mg/kg), bupivacaine (0.75%) and butorphanol (0.49 +/- 0.13 mg/kg). None of the
      calves regurgitated at induction or during intubation. A tube was used to drain
      the rumen and prevent bloat during the procedure. Partial left heart bypass was
      used to perfuse the caudal half of the body during the period of aortic cross
      clamp and device implantation. Initial mean systemic blood pressure was 96 +/- 25
      mm Hg, and pressures measured in the auricular artery increased during aortic
      cross-clamping and bypass. Vasoconstrictor therapy was required to treat caudal
      arterial hypotension during the procedure in 9 calves. Mean systemic arterial
      pressures returned to baseline values by the end of the anesthetic period.
      Initial mean pulmonary arterial pressures (PAP) were 22 +/- 3 mm Hg. A
      significant but transient increase in pulmonary arterial pressure occurred after
      both heparin and protamine administration. CONCLUSIONS: The described anesthetic
      protocol was effective for thoracotomy and implantation of an intra-aortic left
      ventricular assist device in normal calves. Partial left ventricular bypass was a
      useful adjunct during the period of aortic cross clamp. The doses of heparin and
      protamine administered were effective. Responsibility to monitor oxygenation of
      the cranial half of the animal continues during the bypass period as hypoxemia
      due to pulmonary dysfunction will not be detected by the perfusionist.

PMID- 10653502
TI  - How do we communicate stereotypes? Linguistic bases and inferential consequences.
AB  - The linguistic expectancy bias is defined as the tendency to describe expectancy
      consistent information at a higher level of abstraction than expectancy
      inconsistent information. The communicative consequences of this bias were
      examined in 3 experiments. Analyses of judgments that recipients made on the
      basis of linguistically biased information generated by transmitters indicated
      that behavior in expectancy-consistent messages was attributed more to
      dispositional and less to situational factors than behavior in expectancy
      inconsistent messages. Moreover, this effect was mediated by the level of
      linguistic abstraction of the messages. These findings provide direct evidence
      for the hypothesis that recipients are sensitive to variations in linguistic
      abstraction in spontaneous language use because of stereotypes. Results are
      discussed with respect to the interpersonal aspects of stereotyping.

PMID- 10653503
TI  - How far do we go beyond the information given? The impact of knowledge activation
      on interpretation and inference.
AB  - In a series of 4 studies, the inferential scope of assimilative knowledge
      accessibility effects was investigated. Evidence was found for the hypothesis
      that both the breadth and evaluative extremity of activated knowledge affect the
      range of evaluative inferences made during the interpretation of ambiguous
      targets. The scope of knowledge accessibility effects was larger when broad and
      extreme traits were primed than when narrow and moderate traits were primed. The
      contribution of the extremity component to this effect was stronger than the
      impact of the breadth component. Furthermore, the authors demonstrated that
      descriptive overlap between priming and target stimuli is not a necessary
      precondition for such interpretation effects to occur. Descriptive
      inapplicability may be compensated for when priming stimuli are sufficiently
      broad or extreme.

PMID- 10653504
TI  - The relation between self-discrepancies and emotion: the moderating roles of self
      guide importance, location relevance, and social self-domain centrality.
AB  - In 5 studies, the authors investigated the effects of self-guide importance,
      domain centrality to self-definition, and self-domain relevance of testing
      location on relationships between actual-ideal (AI) and actual-ought (AO)
      discrepancies and emotions. Although no unique relationships occurred for self
      discrepancies, moderating effects were found for social self-domains. Location
      relevance overshadowed other moderator effects. In less relevant locations, AI
      discrepancies were smaller and AO discrepancy-emotion relationships were
      moderated by self-guide importance. For more important self-domains, AI
      discrepancies were smaller and AO discrepancies were unrelated to agitation. For
      less important self-domains, agitation was related to the AO discrepancy and self
      guide importance interaction. By suggesting that different self-regulatory
      strategies minimize the consequences of AI and AO discrepancies, evidence for
      distinct ideal and ought self-regulation is provided.

PMID- 10653505
TI  - Habits as knowledge structures: automaticity in goal-directed behavior.
AB  - This study tested the idea of habits as a form of goal-directed automatic
      behavior. Expanding on the idea that habits are mentally represented as
      associations between goals and actions, it was proposed that goals are capable of
      activating the habitual action. More specific, when habits are established (e.g.,
      frequent cycling to the university), the very activation of the goal to act
      (e.g., having to attend lectures at the university) automatically evokes the
      habitual response (e.g., bicycle). Indeed, it was tested and confirmed that, when
      behavior is habitual, behavioral responses are activated automatically. In
      addition, the results of 3 experiments indicated that (a) the automaticity in
      habits is conditional on the presence of an active goal (cf. goal-dependent
      automaticity; J. A. Bargh, 1989), supporting the idea that habits are mentally
      represented as goal-action links, and (b) the formation of implementation
      intentions (i.e., the creation of a strong mental link between a goal and action)
      may simulate goal-directed automaticity in habits.

PMID- 10653506
TI  - When are we better than them and they worse than us? A closer look at social
      discrimination in positive and negative domains.
AB  - This article argues that in-group favoritism occurs on positive and negative
      dimensions only when the dimensions of comparison provide an appropriate and
      meaningful basis for self-other definition, that is, when traits comparatively
      and normatively fit in-group-out-group categorizations. Three studies are
      reported in which groups were evaluated on positive or negative traits that
      varied in their degree of normative fit to in-group and out-group identity. In
      line with predictions, fit rather than stimulus valence was the crucial
      determinant of (a) in-group favoritism and (b) absolute level of differentiation
      between groups. Implications of the findings for explanations of positive
      negative asymmetry and broader understandings of intergroup discrimination are
      discussed.

PMID- 10653507
TI  - Error management theory: a new perspective on biases in cross-sex mind reading.
AB  - A new theory of cognitive biases, called error management theory (EMT), proposes
      that psychological mechanisms are designed to be predictably biased when the
      costs of false-positive and false-negative errors were asymmetrical over
      evolutionary history. This theory explains known phenomena such as men's
      overperception of women's sexual intent, and it predicts new biases in social
      inference such as women's underestimation of men's commitment. In Study 1 (N =
      217), the authors documented the commitment underperception effect predicted by
      EMT. In Study 2 (N = 289), the authors replicated the commitment bias and
      documented a condition in which men's sexual overperception bias is corrected.
      Discussion contrasts EMT with the heuristics and biases approach and suggests
      additional testable hypotheses based on EMT.

PMID- 10653508
TI  - Decision-induced focusing in social dilemmas: give-some, keep-some, take-some,
      and leave-some dilemmas.
AB  - Previous research on asymmetric social dilemmas has suggested that public good
      dilemmas evoke different choice behaviors than do resource dilemmas. The authors
      propose that these differences reflect a differential focus that is dependent on
      the way decisions are generally presented in the dilemma types. In agreement with
      this, the results of 2 experimental studies suggest that, in public good
      dilemmas, group members are less focused on the consequences of their actions for
      the final outcome distribution when deciding how many endowments they give to the
      public good than when deciding how many endowments they keep for themselves. In
      resource dilemmas, group members are less focused on the final outcome
      distribution when deciding how many endowments they leave in the collective
      resource than when deciding how many endowments they take.

PMID- 10653509
TI  - Studying the dynamics of emotional expression using synthesized facial muscle
      movements.
AB  - Synthetic images of facial expression were used to assess whether judges can
      correctly recognize emotions exclusively on the basis of configurations of facial
      muscle movements. A first study showed that static, synthetic images modeled
      after a series of photographs that are widely used in facial expression research
      yielded recognition rates and confusion patterns comparable to posed photos. In a
      second study, animated synthetic images were used to examine whether schematic
      facial expressions consisting entirely of theoretically postulated facial muscle
      configurations can be correctly recognized. Recognition rates for the synthetic
      expressions were far above chance, and the confusion patterns were comparable to
      those obtained with posed photos. In addition, the effect of static versus
      dynamic presentation of the expressions was studied. Dynamic presentation
      increased overall recognition accuracy and reduced confusions between unrelated
      emotions.

PMID- 10653510
TI  - Temperament and personality: origins and outcomes.
AB  - This article reviews how a temperament approach emphasizing biological and
      developmental processes can integrate constructs from subdisciplines of
      psychology to further the study of personality. Basic measurement strategies and
      findings in the investigation of temperament in infancy and childhood are
      reviewed. These include linkage of temperament dimensions with basic affective
      motivational and attentional systems, including positive affect/approach, fear,
      frustration/anger, and effortful control. Contributions of biological models that
      may support these processes are then reviewed. Research indicating how a
      temperament approach can lead researchers of social and personality development
      to investigate important person-environment interactions is also discussed.
      Lastly, adult research suggesting links between temperament dispositions and the
      Big Five personality factors is described.

PMID- 10653511
TI  - Dispositional emotionality and regulation: their role in predicting quality of
      social functioning.
AB  - Individual differences in emotionality and regulation are central to conceptions
      of temperament and personality. In this article, conceptions of emotionality and
      regulation and ways in which they predict social functioning are examined. Linear
      (including additive) and nonlinear effects are reviewed. In addition, data on
      mediational and moderational relations from a longitudinal study are presented.
      The effects of attention regulation on social functioning were mediated by
      resiliency, and this relation was moderated by negative emotionality at the
      first, but not second, assessment. Negative emotionality moderated the relation
      of behavior regulation to socially appropriate/prosocial behavior. These results
      highlight the importance of examining different types of regulation and the ways
      in which dispositional characteristics interact in predicting social outcomes.

PMID- 10653512
TI  - The child is father of the man: personality continuities from childhood to
      adulthood.
AB  - This article presents findings about continuities in personality development that
      have been uncovered in the Dunedin study, an investigation of a cohort of
      children studied from age 3 to 21. At age 3, children were classified into
      temperament groups on the basis of observations of their behavior. In young
      adulthood, data were collected from study members themselves, from people who
      knew them well, and from official records. Undercontrolled 3-year-olds grew up to
      be impulsive, unreliable, and antisocial, and had more conflict with members of
      their social networks and in their work. Inhibited 3-year-olds were more likely
      to be unassertive and depressed and had fewer sources of social support. Early
      appearing temperamental differences have a pervasive influence on life-course
      development and offer clues about personality structure, interpersonal relations,
      psychopathology, and crime in adulthood.

PMID- 10653514
TI  - Paracelsus: herald of modern toxicology.

PMID- 10653513
TI  - Nature over nurture: temperament, personality, and life span development.
AB  - Temperaments are often regarded as biologically based psychological tendencies
      with intrinsic paths of development. It is argued that this definition applies to
      the personality traits of the five-factor model. Evidence for the endogenous
      nature of traits is summarized from studies of behavior genetics, parent-child
      relations, personality structure, animal personality, and the longitudinal
      stability of individual differences. New evidence for intrinsic maturation is
      offered from analyses of NEO Five-Factor Inventory scores for men and women age
      14 and over in German, British, Spanish, Czech, and Turkish samples (N = 5,085).
      These data support strong conceptual links to child temperament despite modest
      empirical associations. The intrinsic maturation of personality is complemented
      by the culturally conditioned development of characteristic adaptations that
      express personality; interventions in human development are best addressed to
      these.

PMID- 10653515
TI  - Placental transfer and pharmacokinetics of a single dermal dose of [14C]methyl
      parathion in rats.
AB  - The pharmacokinetics and placental transfer of a single dermal 10.0 mg
      (10microCi)/kg dose of uniformly phenyl-labeled [14C] methyl parathion (0,0
      dimethyl 0-4-nitrophenyl phosphorothioate) were investigated in pregnant Sprague
      Dawley rats at 14-18 days of gestation. Three rats were killed at each time
      interval: 1, 2, 4, 12, 24, 48, 72, and 96 h after dosing. Radioactivity
      disappeared biexponentially from the administration sites, which retained 50% and
      3% of the dose after 1 h and 96 h, respectively. Most of the absorbed
      radioactivity was excreted in the urine (91%). Only 3% of the 14C was recovered
      in the feces. One h after the administration, radioactivity was detected in all
      tissues, including fetal tissue. The peak maternal plasma concentration of
      radioactivity (ng methyl parathion equivalent/ml) was 1005 at 2 h, compared to
      318 ng for fetal plasma at 12 h. The maximum concentrations of radioactivity (ng
      methyl parathion equivalent/g), detected in most tissues within 12 h of dosing,
      were, in descending order: adipose tissue (67,532), kidney (1,571), spleen
      (1,256), spinal cord (1,004), heart (729), liver (706), brain (546), placenta
      (389), and fetus (256). The metabolism studies showed that methyl parathion,
      detected by HPLC, was the major compound identified in plasma and tissues. The
      maximum concentration detected was in plasma, at 513 ng/ml, and in the following
      tissues (ng/g fresh tissue): kidney (819), fetus (668), placenta (394), liver
      (375), and brain (282). The metabolite methyl paraoxon was detected in maternal
      brain and liver at maximum concentrations (ng/g fresh tissue) of 135 and 64 after
      12 h and 4 h respectively, while p-nitrophenol was only detected in liver at a
      maximum concentration of 21 ng/g 72 h after dosing. Pharmacokinetic studies
      showed that methyl parathion disappeared monoexponentially from plasma and
      tissues. The half-life of elimination of methyl parathion from plasma was 11 h
      corresponding to a constant rate value of 0.06 h(-1). The results indicate that
      skin and placenta are poor barriers against methyl parathion permeability,
      resulting in a rapid and extensive dermal absorption of this insecticide and
      extensive placental transfer. This is indicated by the relative residence (R(R))
      of methyl parathion in the plasma, which was largest in the placenta followed by
      the fetus. This study suggests that pregnant women and fetuses may be at risk of
      cholinergic toxicity following dermal exposure to methyl parathion.

PMID- 10653516
TI  - Physiologically based pharmacokinetic modeling of the temperature-dependent
      dermal absorption of chloroform by humans following bath water exposures.
AB  - The kinetics of chloroform in the exhaled breath of human volunteers exposed skin
      only via bath water (concentrations < 100 ppb) were analyzed using a
      physiologically based pharmacokinetic (PBPK) model. Significant increases in
      exhaled chloroform (and thus bioavailability) were observed as exposure
      temperatures were increased from 30 to 40 degrees C. The blood flows to the skin
      and effective skin permeability coefficients (Kp) were both varied to reflect the
      temperature-dependent changes in physiology and exhalation kinetics. At 40
      degrees C, no differences were observed between males and females. Therefore, Kps
      were determined (approximately 0.06 cm/hr) at a skin blood flow rate of 18% of
      the cardiac output. At 30 and 35 degrees C, males exhaled more chloroform than
      females, resulting in lower effective Kps calculated for females. At these lower
      temperatures, the blood flow to the skin was also reduced. Total amounts of
      chloroform absorbed averaged 41.9 and 43.6 microg for males and 11.5 and 39.9
      microg for females exposed at 35 and 40 degrees C, respectively. At 30 degrees C,
      only 2/5 males and 1/5 females had detectable concentrations of chloroform in
      their exhaled breath. For perspective, the total intake of chloroform would have
      ranged from 79-194 microg if the volunteers had consumed 2 liters of water orally
      at the concentrations used in this study. Thus, the relative contribution of
      dermal uptake of chloroform to the total body burdens associated with bathing for
      30 min and drinking 2 liters of water (ignoring contributions from inhalation
      exposures) was predicted to range from 1 to 28%, depending on the temperature of
      the bath.

PMID- 10653517
TI  - Biotransformation and male rat-specific renal toxicity of diethyl ethyl- and
      dimethyl methylphosphonate.
AB  - Dimethyl methylphosphonate (DMMP) is a widely used chemical. Diethyl
      ethylphosphonate (DEEP) has been proposed as a replacement for DMMP in several
      applications. A long-term carcinogenesis study with DMMP in rats and mice showed
      a significant increase in the incidence of kidney tumors after 2 years of
      exposure in male but not in female rats and both sexes of mice. DMMP is not
      genotoxic. Due to these findings, a role of alpha(2u)-globulin accumulation in
      organ-specific tumorigenicity may be possible. alpha(2u)-Globulin is a low
      molecular-weight protein synthesized in male rats under androgen control. Several
      male rat specific renal carcinogens have been shown to bind to alpha(2u)-globulin
      and to impair the renal degradation of this protein. This impairment results in
      alpha(2u)-globulin accumulation in the kidney, lysosomal overload, cell death,
      cell proliferation, and finally, renal tumor induction. To further characterize
      the toxicology of DMMP and DEEP, we investigated the biotransformation of these
      compounds and their ability to induce alpha(2u)-globulin accumulation in kidney.
      Biotransformation of both DMMP and DEEP were studied in male and female rats
      after single oral doses of 50 and 100 mg/kg. 31P-NMR and GC/MS showed that
      unchanged DMMP was excreted with urine; methyl phosphonate was identified as the
      only metabolite in urine. Unchanged DEEP was also excreted with urine; in
      addition, ethyl ethylphosphonate and ethylphosphonate were urinary metabolites.
      The majority of the applied dose of both compounds was recovered in urine within
      24 h indicating rapid absorption and excretion. No sex-differences in rates of
      formation or excretion of metabolites were seen. To investigate alpha(2u)
      globulin accumulation in the kidney after DMMP and DEEP, male and female Fischer
      344 rats were administered DMMP or DEEP daily for five consecutive days by
      gavage. DMMP doses were 500- and 1,000-mg/kg body weight (bw); due to marked
      toxicity, daily DEEP dose of 50 and 100 mg/kg had to be used. Control rats
      received corn oil only and positive controls received five doses of 500-mg/kg bw
      trimethylpentane (TMP). Relative kidney weights were increased in male rats dosed
      with DMMP, DEEP, and TMP. alpha(2u)-Globulin in kidney cytosol was separated and
      quantified by capillary electrophoresis and by SDS-PAGE and Western blotting. In
      DMMP-, DEEP-, and TMP-treated rats, dose-dependent increases in the alpha(2u)
      globulin content were observed by both methods in male, but not female rats. The
      increase of alpha(2u)-globulin accumulation was accompanied by the formation of
      protein droplets in the proximal tubules of male rats. These data demonstrate
      that the sex specific increase in kidney tumors by DMMP in male rats may be due
      to alpha(2u)-globulin accumulation and that similar toxic effects are to be
      expected from DEEP.

PMID- 10653518
TI  - Long-term toxicity and carcinogenicity study of cyclamate in nonhuman primates.
AB  - Twenty-one monkeys (cynomolgus, rhesus, African green) were fed cyclamate (100
      mg/kg and 500 mg/kg) in the diet five times per week from a few days after birth
      and continuing for up to 24 years. Malignant tumors were diagnosed in three 24
      year-old cyclamate monkeys; these were metastatic colon carcinoma (rhesus; 500
      mg/kg), metastatic hepatocellular carcinoma (cynomolgus; 500 mg/kg), and a small,
      well differentiated adenocarcinoma of the prostate (cynomolgus; 100 mg/kg).
      Benign tumors were found at necropsy in three females; these were adenoma of the
      thyroid gland (rhesus; 100 mg/kg) and two cases of leiomyoma of the uterus
      (rhesus; 100 mg/kg and 500 mg/kg). No tumors were detected in an age-matched
      control group of 16 monkeys. Examination of the testes revealed complete
      testicular atrophy in one of the old cyclamate monkeys, and focal germ cell
      aplasia (Sertoli-only tubules) in two other cyclamate monkeys. Focal
      spermatogenic interruption (maturation arrest) at various germ cell levels mixed
      with normal spermatogenesis was observed in both the cyclamate-treated and the
      control monkeys, all of which were over 20 years old. Measurements of terminal
      cyclohexylamine concentrations showed that three of the males dosed with
      cyclamate at 500 mg/kg were high converters, with plasma concentrations
      comparable to the levels that produce testicular atrophy in rats. However, only
      one of the three high converters showed histologic evidence of irregular
      spermatogenesis. The overall conclusion is that the testicular abnormalities and
      the sporadic cases of different malignancies found after more than 20 years of
      dosing do not provide clear evidence of a toxic or carcinogenic effect of sodium
      cyclamate in monkeys.

PMID- 10653519
TI  - Activation of neutrophil calcium-dependent and -independent phospholipases A2 by
      organochlorine compounds.
AB  - The production of reactive oxygen species by organochlorine pesticides has been
      implicated in the toxicity and carcinogenicity of these compounds; however, the
      mechanism by which these agents stimulate the production of oxygen radicals is
      unknown. Phospholipase A2 (PLA2)-mediated release of arachidonic acid has been
      shown to play an essential role in superoxide anion (O2-) production in
      neutrophils exposed to various physiologic and pharmacologic agents. Therefore,
      studies were performed to determine if the organochlorine pesticides, lindane and
      dieldrin, activate neutrophils to produce O2- by a mechanism that requires PLA2.
      Production of O2- and 3H-AA release increased with similar kinetics and
      concentration-response relations in neutrophils activated with either dieldrin or
      lindane. Significant release of 3H-AA was seen in neutrophils stimulated with
      dieldrin or lindane in calcium-free medium and in the presence of the
      intracellular calcium chelator BAPTA-AM, suggesting that these agents stimulate a
      PLA2 that does not require calcium for activation. In addition, both O2-
      production and 3H-AA release were inhibited in a concentration-dependent manner
      by BEL, a mechanism-based inhibitor of calcium-independent PLA2. These data
      suggest that dieldrin and lindane stimulate O2- production by a mechanism that
      involves PLA2. However, release of 3H-AA was not abrogated completely by BEL nor,
      in the case of dieldrin, preserved entirely in the absence of calcium. This
      suggests that more than one isoform of PLA2 is activated by dieldrin and by
      lindane, and that one isoform is calcium-dependent.

PMID- 10653520
TI  - Effect of ceramide on intracellular glutathione determines apoptotic or necrotic
      cell death of JB6 tumor cells.
AB  - Selective induction of cell death is a means to remove unwanted cell populations
      from a tissue or organ. Understanding the signaling events responsible for
      mediating cell death by cytokines, such as tumor necrosis factor-alpha (TNFalpha)
      are key to the development of pharmacologic inducers of this response. Ceramide
      has been implicated as a secondary messenger for TNFalpha-induced cell death, but
      many of the intracellular effects of ceramide are not fully understood. Recent
      reports suggest that ceramide signaling may involve oxidative stress. To explore
      the relationship between TNF sensitivity and ceramide signaling, two genetic
      variants of mouse JB6 RT101 epidermal tumor cells, one resistant and one
      sensitive to TNFalpha-induced cytotoxicity, were treated with C2-ceramide.
      Treatment with 20 microM ceramide induced apoptosis and this was quickly followed
      by oncotic necrosis in the TNFalpha-sensitive JB6 (TNFs) cells. The same
      concentration of ceramide induced apoptosis, but not oncotic necrosis of the
      TNFalpha resistant JB6 (TNFr) cells. The basal level of glutathione was
      significantly higher in TNFr cells than in TNFs cells. Treatment with 20 microM
      ceramide decreased cellular glutathione in TNFs cells by 50%, in contrast to an
      insignificant decrease in the TNFr cells. A significant increase in reactive
      oxygen was noted in TNFs cells treated with 10 or 20 microM ceramide.
      Furthermore, pretreatment with the antioxidant N-acetylcysteine or with
      glutathione monoethylester delayed the onset of ceramide-induced oncotic
      necrosis, but did not inhibit apoptosis. Our results suggest that the severity of
      the decrease in glutathione appears to determine whether cells undergo just
      apoptosis or also oncotic necrosis. They also suggest that ceramide-induced
      oncotic necrosis is modulated by a decline in cellular glutathione and an
      elevation of reactive oxygen. These results suggest that a decrease in cellular
      redox potential determines susceptibility to ceramide-dependent killing pathways.

PMID- 10653521
TI  - Characterization of nitric oxide production following isolation of rat
      hepatocytes.
AB  - Freshly isolated suspensions of rat parenchymal liver cells (hepatocytes) produce
      large amounts of nitrite following isolation. Nitrite production was inhibited by
      the inducible nitric oxide synthase (iNOS) inhibitor aminoguanidine, as well as
      the transcription inhibitor actinomycin D. Increases in iNOS mRNA, protein, and
      activity levels correlated with the formation of nitrite. iNOS mRNA was first
      detectable 2 h after the onset of hepatocyte incubations and peaked at 4 h. These
      results indicate that nitrite formation is a result of the large scale production
      of nitric oxide (NO) by hepatocytes in response to the time-dependent induction
      of iNOS. NO production by hepatocytes was attenuated by pretreatment of rats with
      the Kupffer cell inhibitor, gadolinium chloride. Also, the addition of the
      endotoxin neutralizing agent, polymyxin B; the protein kinase inhibitor,
      staurosporine, and antioxidants to perfusion buffers and hepatocyte suspensions
      also decreased nitrite formation. Collectively, our results suggest that iNOS is
      induced in hepatocytes in response to the stresses generated during collagenase
      isolation procedures. The response appears to be triggered by a complex
      interaction between several different factors including Kupffer cell activation,
      reactive oxygen species generation, and endotoxin contamination of collagenase
      preparations.

PMID- 10653522
TI  - Acute, multiple-dose, and genetic toxicology of AR177, an anti-HIV
      oligonucleotide.
AB  - AR177 (Zintevir) is a 17-mer oligonucleotide that has been shown to have anti-HIV
      activity and to be a potent HIV-1 integrase inhibitor in vitro, and is among the
      first oligonucleotides to enter human clinical trials. Acute and multiple-dose
      intravenous toxicity studies were performed in mice, and genetic toxicity studies
      were performed in vitro and in vivo in order to determine the toxicity profile of
      AR177. The acute toxicity study in mice showed that AR177 had an LD50 of > or =
      1.5 g/kg body weight. The multipledose toxicity study in mice showed that AR177
      caused male-specific mortality, and changes in serum chemistry, hematology, and
      histology at doses of 250 and 600 mg/kg. Clinical chemistry findings included
      changes in liver function, and decreased erythrocyte values at 250 and 600 mg/kg.
      Histopathologic findings included vacuolization of reticuloendothelial cells in
      phagocytic cells in lymphoid tissue, liver, lungs, heart and uterus, and
      extramedullary hematopoeisis in the spleen. Renal toxicity was exhibited as
      nephropathy and tubular necrosis in the two high-dose groups of males. A no
      effect dose was not established. AR177 did not exhibit genetic toxicity in any of
      three mutagenic assays. In combination with previously reported toxicity studies
      of AR177 in monkeys, this study showed that the toxicity of AR177 is species
      specific.

PMID- 10653523
TI  - DNA damage induced by 3,3'-dimethoxybenzidine in liver and urinary bladder cells
      of rats and humans.
AB  - 3,3'-Dimethoxybenzidine (DMB), a congener of benzidine used in the dye industry
      and previously found to be carcinogenic in rats, was evaluated for its genotoxic
      activity in primary cultures of rat and human hepatocytes and of cells from human
      urinary bladder mucosa, as well as in liver and bladder mucosa of intact rats. A
      similar modest dose-dependent frequency of DNA fragmentation was revealed by the
      alkaline elution technique in metabolically competent primary cultures of both
      rat and human hepatocytes exposed for 20 h to subtoxic DMB concentrations ranging
      from 56 to 180 microM. Replicating rat hepatocytes displayed a modest increase in
      the frequency of micronucleated cells after a 48-h exposure to 100 and 180 microM
      concentrations. In primary cultures of human urinary bladder mucosa cells exposed
      for 20 h to 100 and 180 microM DMB, the Comet assay revealed a clear-cut increase
      of DNA fragmentation. In rats given one-half LD50 of DMB as a single oral dose,
      the GSH level was reduced in both the liver and urinary bladder mucosa, whereas
      DNA fragmentation was detected only in the bladder mucosa. Taken as a whole,
      these results suggest that DMB should be considered a potentially genotoxic
      chemical in both rats and humans; the selective effect on the rat urinary bladder
      might be the consequence of pharmacokinetic behavior.

PMID- 10653524
TI  - Glutathione oxidation and mitochondrial depolarization as mechanisms of
      nordihydroguaiaretic acid-induced apoptosis in lipoxygenase-deficient FL5.12
      cells.
AB  - Nordihydroguaiaretic acid (NDGA) induces apoptosis in a variety of cell lines.
      The mechanism(s) of this effect is not known, although the focus has been on the
      ability of NDGA to inhibit lipoxygenase (LOX) activities. In the present study,
      NDGA-induced apoptosis was studied in a murine hematopoietic cell line, FL5.12.
      Although this cell line lacks detectable LOX protein or activities, NDGA (10
      microM) was able to induce apoptosis. There was a massive loss of mitochondrial
      membrane potential by 4 h after the addition of NDGA, suggesting that this
      organelle might be targeted by NDGA. A pro-oxidant NDGA effect has been suggested
      as playing a role in apoptosis. This was supported by the findings that
      glutathione disulfide levels were increased by 4 h following treatment with 10
      microM NDGA, that pretreatment with N-acetylcysteine completely blocked the NDGA
      induced loss of membrane potential and apoptosis, and that lipid peroxidation was
      enhanced in cells treated with NDGA. However, no evidence of increased levels of
      reactive oxygen could be seen in NDGA-treated cells loaded with
      dichlorofluorescin diacetate or dihydrorhodamine and analyzed by flow cytometry.
      Bcl-X(L) protein levels were unaffected by NDGA treatment. Caspase-3 was rapidly
      activated with a peak at 8 h after FL5.12 cells were treated with NDGA. Ac-DEVD
      CHO (25 microM) and boc-asp-FMK (20 microM) both inhibited caspase-3 enzyme
      activity by 97% 8 h after NDGA treatment. Boc-asp-FMK, a more general caspase
      inhibitor, delayed NDGA-induced apoptosis while Ac-DEVD-CHO, a more specific
      inhibitor of caspase-3, had no effect. These results suggest that NDGA-induced
      apoptosis happens through reactions that depolarize mitochondria, oxidize
      glutathione and lipids, but do not generate significant amounts of free reactive
      oxygen species.

PMID- 10653525
TI  - Subchronic physostigmine pretreatment in marmosets: absence of side effects and
      effectiveness against soman poisoning with negligible postintoxication
      incapacitation.
AB  - Subchronic pretreatment with physostigmine (PHY) (0.0125 mg/kg/h) leading to a
      blood acetylcholinesterase inhibition of about 30% caused no side effects when
      applied to marmoset monkeys. This was evident on behavioral parameters and on EEG
      and cortical visual evoked response. Furthermore, this treatment regime, followed
      by atropine as postintoxication therapy, protected the marmosets against
      lethality after a 2 x LD50 dose of soman with negligible postintoxication
      incapacitation. These findings suggest that a symptom-free pretreatment with
      subchronic PHY could protect man sufficiently against severe soman intoxication.

PMID- 10653526
TI  - Chronic toxicity and reversibility of antifertility effect of immunization
      against gonadotropin-releasing hormone in male rats and rabbits.
AB  - The chronic systemic toxicity of immunization with gonadotropin-releasing
      hormone, conjugated to tetanus toxoid (GnRH-TT), was investigated in male rats
      and rabbits in order to start Phase I clinical trials. Groups of rats and rabbits
      were immunized with GnRH-TT dissolved in aqueous adjuvant. The antigen was
      administered at weeks 0, 4, and 8, followed by boosters to maintain high antibody
      titers. At termination (8-9 months after first immunization), twenty rats and ten
      rabbits exhibiting the highest mean anti-GnRH titers and all the controls were
      selected for complete toxicological evaluation. In the rat study, a castrated
      control group was included for comparison with the immunized group. The
      hematological and serum chemistry parameters of immunized rats and rabbits were
      not affected in a significant manner. Most of the changes in serum chemistry of
      immunized rats were also found in castrated rats, indicating that the changes are
      most likely due to the withdrawal of androgenic support. The weights of the
      testes, epididymides, and sex accessory glands were lower in all immunized
      animals. There was significant atrophy of the germinal epithelium, which,
      however, sustained a population of Sertoli cells, spermatogonia, and pachytene
      spermatocytes. Other morphological changes in the prostate, seminal vesicles,
      pituitary, and mammary gland reflected the effect of androgen withdrawal. The
      decrease in the weight of liver, kidney, and heart seen in the immunized rats was
      also present in castrated rats and was not associated with any histopathological
      changes. The reversibility of immunization-induced infertility was investigated
      by mating the rats with normal females. Four months after the start of
      immunization, 9 out of 10 immunized rats were infertile whereas by nine months,
      all rats had regained fertility. Thus, it is concluded that immunization with
      GnRH-TT had no systemic toxicological effects in the adult male rats and rabbits
      for the period studied. The results also indicated that the GnRH-TT immunization
      had an antifertility effect in male rats. Fertility was restored following
      cessation of immunization and decline in anti-GnRH antibody titers.

PMID- 10653527
TI  - Developmental toxicity studies in rats and rabbits with 3,5,6-trichloro-2
      pyridinol, the major metabolite of chlorpyrifos.
AB  - 3,5,6-Trichloro-2-pyridinol (TCP), the primary metabolite of chlorpyrifos and
      chlorpyrifos-methyl, was evaluated for potential developmental toxicity. Groups
      of 32-34 bred female Fischer 344 rats were given 0, 50, 100, or 150 mg TCP/kg/day
      by gavage on gestation days 6-15; the fetuses were evaluated on gestation day 21.
      Similarly, groups of 16 inseminated female New Zealand White rabbits were given
      0, 25, 100, or 250 mg TCP/kg/day by gavage on gestation days 7-19, and fetuses
      were evaluated on gestation day 28. No clinical signs of toxicity attributed to
      TCP were noted in either species. In rats, at 150 mg/kg/day, maternal effects
      included slight decreases in feed consumption, significantly depressed body
      weight gain (25% relative to controls) resulting in significantly lower maternal
      terminal body weights, and increased relative liver weight. At 100 mg/kg/day,
      maternal body weight gain in rats was depressed approximately 22%. Among rabbits,
      maternal effects were limited to the group given 250 mg/kg/day, which lost an
      average of approximately 70 g during the treatment period (vs. 140 g in the
      controls). There were no effects on fetal weight or viability, nor were there
      significant increases in any fetal alteration in either species. A slightly
      higher (not statistically significant) than usual incidence of central nervous
      system anomalies occurred in rabbits, but these anomalies were found in both
      treated and control groups in this study as well as contemporaneous studies of
      unrelated compounds. This, and the fact that these anomalies were not seen with
      the parent compound, chlorpyrifos, suggest that their origin was spontaneous.
      Thus, TCP was not considered fetotoxic or teratogenic in either rats or rabbits,
      even at dose levels that produced maternal toxicity.

PMID- 10653528
TI  - Trichloroethylene inhibits development of embryonic heart valve precursors in
      vitro.
AB  - Previous epidemiological studies with humans and laboratory studies with chickens
      and rats linked trichloroethylene (TCE) exposure to cardiac defects. Although the
      cardiac defects in humans and laboratory animals produced by TCE are diverse, a
      majority of them involves valvular and septal structures. Progenitors of the
      valves and septa are formed by an epithelial-mesenchymal cell transformation of
      endothelial cells in the atrioventricular (AV) canal and outflow tract areas of
      the heart. Based on these studies, we hypothesized that TCE might cause cardiac
      valve and septa defects by specifically perturbing epithelial-mesenchymal cell
      transformation. We tested this hypothesis using an in vitro chick-AV canal
      culture model. This study shows that TCE affected several elements of epithelial
      mesenchymal cell transformation. In particular, TCE blocked the endothelial cell
      cell separation process that is associated with endothelial activation. Moreover,
      TCE inhibited mesenchymal cell formation throughout the concentration range
      tested (50-250 ppm). In contrast, TCE had no effect on the cell migration rate of
      the fully formed mesenchymal cells. Finally, the expression of 3 proteins
      (selected as molecular markers of epithelial-mesenchymal cell transformation) was
      analyzed in untreated and TCE-treated cultures. TCE inhibited the expression of
      the transcription factor Mox-1 and extracellular matrix (ECM) protein fibrillin
      2. In contrast, TCE had no effect on the expression of alpha-smooth muscle actin.
      These data suggest that TCE may cause cardiac valvular and septal malformations
      by inhibiting endothelial separation and early events of mesenchymal cell
      formation in the heart.

PMID- 10653529
TI  - Comparative pathogenesis of haloacetic acid and protein kinase inhibitor
      embryotoxicity in mouse whole embryo culture.
AB  - Haloacetic acids (HAs) are embryotoxic contaminants commonly found in drinking
      water. The mechanism of HA embryotoxicity has not been defined, but may be
      mediated in part by protein kinase C (PKC) inhibition. This study was conducted
      to evaluate the pathogenesis of HA embryotoxicity, and to compare these data with
      those from specific (Bis I) and non-specific (staurosporine) inhibitors of PKC.
      Embryos were incubated for varying times with several HAs, Bis I, staurosporine,
      or Bis V (a negative control). Cell cycle analysis was performed by flow
      cytometry following nuclear staining with propidium iodide; apoptosis was
      evaluated by fluorescence microscopy following LysoTracker staining. At
      concentrations producing 100% embryotoxicity with no embryolethality, only
      staurosporine perturbed the cell cycle. However, flow cytometry revealed
      accumulation of sub-G1 events (an apoptotic indicator) across time with
      bromochloroacetic acid, dichloroacetic acid, and staurosporine, but not
      dibromoacetic acid, Bis I, or Bis V. Sub-G1 events were particularly prominent in
      the head region, and remained at control levels in the heart. LysoTracker
      staining confirmed a similar pattern of apoptosis in the intact embryo; BCA and
      DCA produced intense staining in the prosencephalon, with virtually no staining
      in the heart. These data indicate that while cell-cycle perturbation may not
      mediate the pathogenesis of HA embryotoxicity, these agents do induce embryonic
      apoptosis. In addition, the lack of Bis I-induced apoptosis indicates that PKC
      inhibition is unlikely to be the sole mediator of HA embryotoxicity.

PMID- 10653530
TI  - Lack of effects of nose-only inhalation exposure on testicular toxicity in male
      rats.
AB  - Reductions in testicular mass, sperm motility, and mating frequency have been
      attributed to the stresses caused by confinement of Sprague-Dawley male rats in
      nose-only inhalation exposure tubes. Testicular changes, including an increase in
      testicular atrophy, have been detected at an increased incidence in male rats
      used in inhalation studies as compared with rats of the same age and strain used
      in oral toxicity studies. This study was designed to determine whether nose-only
      exposure of male rats caused testicular toxicity under conditions of cooling of
      the exposure room and appropriate acclimation to the exposure tubes. In order to
      acclimate the rats to the nose-only inhalation exposure apparatus, all male rats
      were placed in the exposure tubes for at least four successively increasing time
      intervals (15, 30, 45, and 60 min) on 4 separate days, with a rest period of
      approximately 48 h between the first and second acclimation. Twenty male rats
      were exposed nose-only to filtered air for approximately 2 h per day for 28 days
      before cohabitation and continuing throughout a 14-day cohabitation period. To
      reduce thermal stress, the exposure room temperature was maintained at 64 to 70
      degrees F. Twenty control rats were housed in the same room as the exposed rats
      but were not placed in exposure tubes. End points monitored were body weight,
      testicular weight, sperm count, sperm motility, and histopathology of the testes,
      epididymides, prostate, and seminal vesicles. The control rats gained weight more
      rapidly than the exposed rats. All the rats in both groups mated successfully,
      and testicular weights, normalized to body weight, were similar for both groups.
      More importantly, there were no microscopic changes that could be considered an
      adverse effect on the reproductive tissues in the male rats placed in exposure
      tubes. Thus, nose-only exposure for up to 2 h per day for a total of 42 days did
      not cause adverse effects on the reproductive organs, fertility, or reproductive
      performance of male rats under the conditions of this study.

PMID- 10653531
TI  - Lack of carcinogenicity of chlorpyrifos insecticide in a high-dose, 2-year
      dietary toxicity study in Fischer 344 rats.
AB  - Chlorpyrifos (CPF) was administered daily in the feed to evaluate toxicity and
      oncogenicity potential in male and female Fischer 344 rats, according to U.S. EPA
      guidelines. Doses for the 2-year study were based on findings in a 13-week
      feeding study in which lower body weights, urinary perineal staining, adrenal
      cortical vacuolization, and inhibition (slightly more than 60%) of brain
      cholinesterase (ChE) occurred at 15 mg/kg/day. The high dose in the subsequent 2
      year study was 10 mg/kg/day, with lower doses of 0, 0.05, 0.1, or 1.0 mg/kg/day
      chosen to define dose-response patterns. Rats given 10 mg/kg/day for 2 years were
      healthy and there was no evidence of premature deaths. Mild toxicity occurred
      only in rats given 10 mg/kg/day and consisted of perineal urine soiling in
      females and a 6-8% body-weight decrease in males. Males given 10 mg/kg/day also
      had increased adrenal weights and vacuolation of the adrenal zona fasciculata.
      ChE was considered a measure of exposure. Plasma, RBC, and brain ChE activities
      were inhibited in rats given 10 mg/kg/day, and the plasma and RBC ChE activities
      were inhibited in rats given 1.0 mg/kg/day. Chronic exposure to 0.1 mg/kg/day was
      considered a threshold exposure level for inhibition of plasma ChE. Rats given 10
      mg/kg/day, considered a maximum-tolerated dose, had approximately 60% chronic
      inhibition of brain ChE. This group had similar numbers and types of neoplasms as
      control rats. Consequently, CPF was not carcinogenic at dose levels up to 10
      mg/kg/day.

PMID- 10653532
TI  - Effects of aldose reductase inhibitors on antioxidant defense in rat and rabbit
      liver.
AB  - Aldose reductase has been implicated in the etiology of diabetic complications,
      atherosclerosis, and ischemia-reperfusion injury. Aldose reductase inhibitors are
      known to have species-dependent differences in biotransformation enzyme
      induction. Whether aldose reductase inhibitors, which have antioxidant potential,
      alter the oxidative stress pathway is unknown. This study has determined whether
      four daily ip treatments of either low (10 mg/kg) or high (50 mg/kg) doses of AL
      1576 or AL-4114 alter the activities of the antioxidant defense enzymes catalase,
      glutathione reductase, glutathione peroxidase, superoxide dismutase, and the
      concentrations of reduced and oxidized glutathione in livers of normal rats and
      rabbits. There was no change in the concentration of thiobarbituric acid reactive
      substances in either rat or rabbit livers, indicating that lipid peroxidation was
      not increased by any treatment. Hepatic catalase, superoxide dismutase, and
      glutathione peroxidase activities and concentrations of reduced and oxidized
      glutathione were not significantly altered in rat, though glutathione reductase
      activity was increased after high doses of both drugs. However, in rabbit liver,
      glutathione reductase activity decreased in a dose-dependent manner after AL-4114
      treatment, while superoxide dismutase and glutathione peroxidase activities
      decreased only after the low dose of AL-4114. Although AL-4114 and AL-1576 did
      not directly generate increased lipid peroxidation within normal rat and rabbit
      livers, some of the enzymes responsible for oxidative defense were altered,
      particularly in rabbit livers.

PMID- 10653533
TI  - Manganese-bilirubin effect on cholesterol accumulation in rat bile canalicular
      membranes.
AB  - Manganese-bilirubin (Mn-BR)-induced cholestasis in rats is associated with
      altered lipid composition of various hepatic subcellular fractions. Increased
      bile canalicular (BCM) cholesterol content in Mn-BR cholestasis and the
      intracellular source of the accumulating cholesterol were investigated. To label
      the total hepatic cholesterol pool, male Sprague-Dawley rats were given ip 3H
      cholesterol, followed 18 h later by 2-14C-mevalonic acid (a precursor of
      cholesterol synthesis). To induce cholestasis, manganese (Mn, 4.5 mg/kg) and
      bilirubin (BR, 25 mg/kg) were injected iv; animals were killed 30 min after BR
      injection; canalicular and sinusoidal membranes, microsomes, mitochondria, and
      cytosol were isolated. Total cholesterol content of each fraction was determined
      by spectrophotometric techniques as well as radiolabeled techniques. In Mn-BR
      cholestasis, the total cholesterol concentrations of BCM and cytosol were
      significantly increased. Also, the contribution of 14C-labeled cholesterol (newly
      synthesized cholesterol) was enhanced in all isolated cellular fractions. The
      results are consistent with the hypothesis that accumulation of newly synthesized
      cholesterol in BCM is involved in Mn-BR cholestasis. An enhanced rate of
      synthesis of cholesterol, however, does not appear to be the causal event, as the
      activity of HMG-CoA reductase (rate-limiting enzyme in cholesterol synthesis),
      assessed in vitro, was decreased following Mn-BR treatment. Treatment with the Mn
      BR combination may affect other aspects of intracellular cholesterol dynamics.

PMID- 10653534
TI  - MD/PhD's in science.

PMID- 10653535
TI  - Bigger is better?

PMID- 10653536
TI  - Management of severe lower abdominal or inguinal pain in high-performance
      athletes. PAIN (Performing Athletes with Abdominal or Inguinal Neuromuscular Pain
      Study Group).
AB  - The purpose of this study was to gain insight into the pathophysiologic processes
      of severe lower-abdominal or inguinal pain in high-performance athletes. We
      evaluated 276 patients; 175 underwent pelvic floor repairs. Of the 157 athletes
      who had not undergone previous surgery, 124 (79%) participated at a professional
      or other highly competitive level, and 138 patients (88%) had adductor pain that
      accompanied the lower-abdominal or inguinal pain. More patients underwent related
      adductor releases during the later operative period in the series. Evaluation
      revealed 38 other abnormalities, including severe hip problems and malignancies.
      There were 152 athletes (97%) who returned to previous levels of performance. The
      syndrome was uncommon in women and the results were less predictable in
      nonathletes. A distinct syndrome of lower-abdominal/adductor pain in male
      athletes appears correctable by a procedure designed to strengthen the anterior
      pelvic floor. The location and pattern of pain and the operative success suggest
      the cause to be a combination of abdominal hyperextension and thigh
      hyperabduction, with the pivot point being the pubic symphysis. Diagnosis of
      "athletic pubalgia" and surgery should be limited to a select group of high
      performance athletes. The consideration of other causes of groin pain in the
      patient is critical.

PMID- 10653537
TI  - Rupture of the pectoralis major muscle. Outcome after repair of acute and chronic
      injuries.
AB  - We retrospectively studied 17 cases of distal pectoralis major muscle rupture to
      compare the results of repair in acute and chronic injuries and to compare
      operative and nonoperative treatment. Thirteen patients underwent surgery (six
      acute injuries [less than 2 weeks after injury] and seven chronic injuries) and
      four had nonoperative management. The mean age of the patients at injury was 29,
      and 10 of the 17 injuries were the result of weight lifting. Follow-up ranged
      from 18 months to 6 years (mean, 28 months). All patients subjectively rated
      strength, pain, motion, function with strenuous sporting activities, cosmesis,
      and overall satisfaction. Objectively, patients were examined for range of
      motion, deformity, atrophy, and strength. Isokinetic strength testing was
      performed in eight patients: six treated operatively (three acute and three
      chronic) and two treated nonoperatively. Overall subjective ratings were 96% in
      the acute group, 93% in the chronic group, and only 51% in the nonoperative
      group. Isokinetic testing showed that patients operated on for acute injuries had
      the highest adduction strength (102% of the opposite side) compared with patients
      with chronic injuries (94%) or nonoperative treatment (71%). There were no
      statistically significant subjective or objective differences in outcome between
      the patients treated operatively for acute or chronic injuries, but these
      patients fared significantly better than patients treated nonoperatively.

PMID- 10653538
TI  - Operative treatment of ulnar collateral ligament injuries of the elbow in
      athletes.
AB  - Over a 6-year period, the senior author (JRA) performed 91 ulnar collateral
      ligament reconstructions (N = 78) or repairs (N = 13). All patients were male and
      between the ages of 15 and 39 years (average, 21.6). Thirty-seven patients (41%)
      were professional baseball players, 41 (45%) were collegiate baseball players,
      and 7 (7.7%) were high school or recreational players. Subcutaneous ulnar nerve
      transposition with stabilization of the nerve with fascial slings of the flexor
      pronator mass was performed in all patients, and additional procedures were
      performed in 27 patients (29.7%), including 22 excisions of posteromedial
      olecranon osteophytes. Average follow-up was 35.4 months. Ten patients had
      preoperative ulnar nerve symptoms, nine of whom had complete resolution of
      symptoms after surgery. Complications occurred in eight patients. The average
      time from surgery to initiation of the interval throwing program was 3.4 months,
      and the average time to return to competitive throwing was 9.8 months. Sixty
      seven patients (74%) were available for follow-up; of these, 53 (79%) had
      returned to their previous levels of competition or to a higher level.
      Reconstruction of the ulnar collateral ligament, with transposition and
      stabilization of the ulnar nerve and appropriate rehabilitation, was found to be
      effective in correcting medial instability of the elbow and allowed most athletes
      to return to previous levels of play in less than 1 year.

PMID- 10653539
TI  - Primary stability of press-fit-implanted osteochondral grafts. Influence of graft
      size, repeated insertion, and harvesting technique.
AB  - The aim of this study was to evaluate the fixation strength of press-fit
      implanted osteochondral grafts with respect to graft size (length and diameter),
      the effect of repeated insertion after pullout, and harvesting technique.
      Experiments were performed using the Osteochondral Autograft Transfer System on
      porcine femoral condyles. Failure loads of 10-mm-long grafts (mean, 47 N) were
      significantly lower than failure loads of 15-mm-long grafts (mean, 93 N) and 20
      mm-long grafts (mean, 110 N) (all grafts, 11 mm in diameter). Reinsertion of the
      15-mm-long grafts after initial pullout resulted in a significant reduction of
      failure loads (mean, 93 N versus 44 N). Failure loads of 8-mm-diameter grafts
      (mean, 41 N) were significantly lower than those of 11-mm-diameter grafts (mean,
      92 N) (all 15 mm long). Levering of the tubular chisel during graft harvest
      significantly decreased press-fit stability as compared with simple turning of
      the chisel (mean, 32 N versus 52 N) (8-mm diameter and 15-mm length). These
      results suggest that primary fixation strength of press-fit-inserted
      osteochondral grafts depends on the size of the grafts and that repeated pullout
      and reinsertion of grafts as well as a nonoptimal harvesting technique (levering)
      will reduce primary stability.

PMID- 10653540
TI  - The stabilizing sling for the long head of the biceps tendon in the rotator cuff
      interval. A histoanatomic study.
AB  - A histoanatomic study of the rotator cuff interval was done in 13 cadaveric
      specimens to investigate the relation of its ligamentous structures to the long
      head of the biceps tendon, with a special focus on revealing a stabilizing
      function. After macroscopic evaluation, the lateral half of the rotator cuff
      interval capsule was cut into three sections: medial, middle, and lateral. These
      sections were embedded in methacrylate, and then serial sections were made and
      stained for polarized light microscopy. The superior glenohumeral ligament was
      seen to form a fold having the macroscopic appearance of a U-shaped anterior
      suspension sling for the long head of the biceps tendon. Microscopic evaluation
      revealed an important role of the fasciculus obliquus in the roof of this sling.
      Fibers of the supraspinatus tendon join the posterosuperior part of the sling.
      The subscapularis tendon is not involved in this suspensory mechanism. As a
      result of these observations, we determined that the superior glenohumeral
      ligament and the fasciculus obliquus are the most important ligamentous
      reinforcements of a stabilizing sling for the long head of the biceps tendon in
      the rotator cuff interval. Their histologic appearance indicates they function to
      protect the long head of the biceps against anterior shearing stress. A lesion of
      this sling might lead to anterior instability of the biceps tendon.

PMID- 10653541
TI  - Biomechanical analysis of a posterior cruciate ligament reconstruction.
      Deficiency of the posterolateral structures as a cause of graft failure.
AB  - We hypothesized that posterior cruciate ligament reconstructions are often
      compromised by associated injuries to the posterolateral structures. Therefore,
      we evaluated a posterior cruciate ligament reconstruction in isolated and
      combined injury models using a robotic/universal force-moment sensor testing
      system. The resulting knee kinematics and the in situ forces in the native and
      reconstructed posterior cruciate ligament were determined under four external
      loading conditions. In the isolated injury model, reconstruction reduced
      posterior tibial translation to within 1.5+/-1.3 to 2.4+/-1.4 mm of the intact
      knee at 30 degrees and 90 degrees under a 134-N posterior tibial load. In the
      combined injury model, deficiency of the posterolateral structures increased
      posterior tibial translation of the reconstructed knee by 6.0+/-2.7 mm at 30
      degrees and 4.6+/-1.5 mm at 90 degrees of flexion. External rotation increased up
      to 14 degrees while varus rotation increased up to 7 degrees. In situ forces in
      the posterior cruciate ligament graft also increased significantly (by 22% to
      150%) for all loading conditions. Our results demonstrate that a graft that
      restores knee kinematics for an isolated posterior cruciate ligament deficiency
      is rendered ineffective and may be overloaded if the posterolateral structures
      are deficient. Therefore, surgical reconstruction of both structures is
      recommended in the setting of a combined injury.

PMID- 10653542
TI  - Natural history of a hamstring tendon autograft used for anterior cruciate
      ligament reconstruction in a sheep model.
AB  - The purpose of this study was to describe the histologic structure of the
      intraarticular segment of a semitendinosus tendon autograft used for anterior
      cruciate ligament reconstruction over the first year after surgery. We performed
      an anterior cruciate ligament reconstruction in a single hindlimb of 11 sheep
      using a doubled semitendinosus tendon autograft secured to the femur with an
      endoscopic button and polyester tape and to the tibia with sutures tied around a
      screw. The histologic structure of the intraarticular segment of the graft at 4,
      8, 12, 24, and 52 weeks after surgery was compared with that of the normal
      semitendinosus tendon and anterior cruciate ligament. The random collagen fiber
      orientation progressed to a longitudinal orientation from the peripheral to the
      central areas of the graft over the initial 12 weeks after surgery. A uniform
      sinusoidal crimp pattern similar to that seen in the normal anterior cruciate
      ligament was identified under polarized light in nearly one-half of each graft by
      24 weeks. Further maturation was noted at 52 weeks. Graft necrosis was not
      evident at any time period. This study showed that semitendinosus tendon
      autografts transform into a histologic structure similar to that of the normal
      anterior cruciate ligament over the initial year after surgery, as has been
      described for patellar tendon grafts.

PMID- 10653543
TI  - The effect of nonphysiologically high initial tension on the mechanical
      properties of in situ frozen anterior cruciate ligament in a canine model.
AB  - An experimental study was performed in 32 adult beagle dogs to clarify the effect
      of nonphysiologically high initial tension on the mechanical and histologic
      properties of in situ frozen anterior cruciate ligaments. Both anterior cruciate
      ligaments in each dog underwent the in situ freeze-thaw treatment. The tibial
      insertion of the ligament was then made free from the tibia along with a
      cylindrical bone block. In the right knee, an initial tension of 20 N was applied
      on the anterior cruciate ligament by translocating the bone block in the distal
      direction. In the left knee, this bone block was anatomically reduced. Each bone
      block was firmly fixed with an interference screw. Ten animals were sacrificed at
      6 weeks and 10 at 12 weeks. The tensile strength and the tangent modulus in the
      highly tensioned knee were significantly less than those in the physiologically
      tensioned knee at 12 weeks. Histologically, cell nuclei appeared to be spindle
      shaped in the physiologically tensioned knee, while oval nuclei and focal
      degenerative changes with a number of vacuoles were occasionally found in the
      matrix in the highly tensioned knee. This study demonstrated that a
      nonphysiologically high tension significantly deteriorates the mechanical
      properties of the in situ frozen anterior cruciate ligament compared with
      physiologic tension.

PMID- 10653544
TI  - The prevalence of spondylolysis in the Spanish elite athlete.
AB  - The diagnosis of spondylolysis is a major cause of concern for patients and their
      families, especially when the patients are young athletes with promising futures
      in their sports. In this study, 3152 case histories of high-level athletes were
      evaluated to determine which sports had a higher prevalence of spondylolysis. The
      overall percentage of spondylolysis among athletes in this study (8.02%) was not
      very much higher than that among the general population, which varies between 3%
      and 7%. However, when each sport was considered separately we found much higher
      values for some sports, with the highest percentages occurring in throwing sports
      (26.67%), artistic gymnastics (16.96%), and rowing (16.88%). The analysis of the
      biomechanical movements involved in the sports with greater prevalence of
      spondylolysis has led us to include the element of torsion against resistance as
      another possible causative factor for spondylolysis that should be added to the
      already known causative mechanisms, lumbar hyperextension and rotation. We have
      divided the sports into three risk groups according to the prevalence of
      spondylolysis shown and the characteristics of the sample, and we recommend
      systematic radiological examination of the lumbar spine in athletes considered to
      be at greater risk of developing spondylolysis.

PMID- 10653545
TI  - Osteochondritis dissecans of the patellofemoral joint.
AB  - Osteochondritis dissecans of the patellofemoral joint is an uncommon condition
      that may be the cause of anterior knee pain or crepitus. We present the clinical
      features of 37 patients with osteochondritis dissecans lesions of the
      patellofemoral joint (24 on the patella, 13 on the trochlear groove), including
      two patients with medial trochlear groove lesions, which have not, to our
      knowledge, been previously reported. The osteochondral lesions involved the
      convex articular surfaces. The median age of patients when first examined was 15
      years, and 54% of patients had open epiphyses. These lesions were more common in
      male patients than in female patients (four-to-one ratio). Osteochondritis
      dissecans of the patellofemoral joint can be overlooked unless quality
      radiographs are viewed with care and, at arthroscopy, both the patella and
      trochlear groove are assessed. Treatment depends on the symptoms, site, and
      nature of the lesion and the patient's age. Nonoperative management includes
      patellar taping and vastus medialis obliquus muscle exercises. Operative
      intervention is indicated for patients with mechanical symptoms and includes
      arthroscopy, consisting of chondroplasty and removal of loose bodies, and lateral
      retinacular release. In this study treatment generally improved the symptoms, but
      patients with articular cartilage loss had persistent patellofemoral crepitus and
      discomfort.

PMID- 10653546
TI  - The lateral notch sign associated with acute anterior cruciate ligament
      disruption.
AB  - We prospectively studied all of the patients with anterior cruciate ligament
      disruptions who sought treatment at the senior author's office during a 36-month
      period. Plain radiographs identified depressions measuring 2 mm or more in the
      lateral femoral condyle (lateral notch sign) in 9 of 120 knees (7.5%) with acute
      anterior cruciate ligament disruption and in 2 of 44 knees (4.5%) with chronic
      pivot shift instability. The depression ranged from 2 to 6 mm deep and from 20 to
      25 mm long. The mean age for acutely injured patients with lateral notch signs
      was 17.2 years, 6 years younger than the mean age of the group with acutely
      injured anterior cruciate ligaments as a whole. Ten of the 11 patients (91%) with
      lateral notch signs were men, and all 6 patients with depressions shallower than
      prior descriptions of the notch sign were men. In contrast, 67% (N = 110) of the
      entire group of patients who had anterior cruciate ligament disruption were men.
      Ten of the 11 patients (91%) with the lateral notch signs and 4 of the 6 patients
      (66%) with minimal depressions also had lateral meniscus tears, while 58 of 147
      patients (39%) without lateral femoral condyle depression had lateral meniscus
      tears. Previous reports that the lateral notch is a sign of chronic anterior
      cruciate ligament deficiency with recurrent pivot shifts are not supported by the
      number of prospectively recognized acute lateral femoral notch signs in this
      series. We found the presence of radiographic changes in the lateral femoral
      condyle to have statistically significant correlations with young age, male sex,
      lateral meniscus tears in general and anterior-horn lateral meniscus tears
      specifically, and lateral femoral chondral lesions.

PMID- 10653547
TI  - The anterior intermeniscal ligament of the knee. An anatomic study.
AB  - The purpose of this study was to identify the presence of the anterior
      intermeniscal ligament of the knee and to study its attachment patterns and
      relationships to other anatomic structures within the knee. Fifty unpaired
      cadaveric knees were dissected. An identifiably distinct anterior intermeniscal
      ligament was found in 47 specimens (94%). The average length was 33 mm and the
      average midsubstance width was 3.3 mm. The average perpendicular distance from
      the anterior intermeniscal ligament to the anterior margin of the tibial
      insertion of the anterior cruciate ligament was 7.8 mm (range, 2.0 to 13.5). The
      anterior intermeniscal ligament was the primary attachment for the anterior horn
      of the medial meniscus in 12 knees (24%); 7 knees (14%) had no tibial insertion
      and 5 knees (10%) had only a fine fascial tibial connection. Successful
      arthroscopic evaluation, surgical repair, and meniscal allograft reconstruction
      can be enhanced by a precise knowledge of the anterior intermeniscal ligament
      anatomy, especially when identifying the various insertion patterns of the
      anterior horn of the medial meniscus. A correct understanding of these patterns
      is helpful for avoiding patient injury during surgical procedures (particularly
      arthroscopic ACL reconstructions) performed in close proximity to the anterior
      intermeniscal ligament of the knee.

PMID- 10653548
TI  - Chronic Achilles tendon overuse injury: complications after surgical treatment.
      An analysis of 432 consecutive patients.
AB  - We analyzed the complications after surgical treatment of Achilles tendon overuse
      injuries in 432 consecutive patients. The patients underwent a clinical
      examination 2 weeks, and 1, 2, and 5 months after the surgery. If a complication
      appeared, the patient was followed up clinically for at least 1 year. There were
      46 (11%) complications in the 432 patients: 14 skin edge necroses, 11 superficial
      wound infections, 5 seroma formations, 5 hematomas, 5 fibrotic reactions or scar
      formations, 4 sural nerve irritations, 1 new partial rupture, and 1 deep vein
      thrombosis. Fourteen patients with a complication had reoperations: four patients
      for skin edge necrosis, two for superficial wound infection, two for seroma
      formation, one for hematoma formation, two for fibrotic reaction or scar
      formation, two for sural nerve irritation, and one for a new partial rupture.
      About every 10th patient treated surgically for chronic Achilles tendon overuse
      injury suffered from a postoperative complication that clearly delayed recovery.
      However, the majority of patients with a complication healed and returned to
      their preinjury levels of activity. To reduce this morbidity, it is essential
      that the surgeon be continuously aware of the possibility of postoperative
      complications and use proper surgical techniques.

PMID- 10653549
TI  - Injury risk factors among telemark skiers.
AB  - We performed a population survey of telemark skiers over two ski seasons to
      determine specific risk factors for injury. The survey inquired about the skier's
      sex, experience, equipment used, injuries, and number of days skied in each
      season. The respondents completed the surveys whether or not they were injured
      while skiing. We received 677 responses from telemark skiing clubs, with 19,962
      skier-days of data. The number of self-reported injuries was 178, for an overall
      self-reported injury rate of 8.9 per 1000 skier-days. Knee injuries (N = 48) were
      the most common injury (27%), followed by thumb (N = 32, 18%) and shoulder (N =
      21, 12%) injuries. Specific risk factors for injury were identified with
      multivariate regression and survival analysis. The skill level of the skier had a
      significant injury-sparing effect, as did the use of plastic telemark boots. The
      protective effect of the plastic boots was likely due to the increased stability
      they provided compared with traditional leather boots. There were fewer knee
      injuries with the recently available releasable bindings for telemark skis. Sex
      and age had no significant impact on injury rates in this study population. As
      all reported deaths associated with telemark sking were due to environmental
      hazards, skiers must continue to pay close attention to these hazards in the
      backcountry.

PMID- 10653550
TI  - The effects of hyaluronan on tissue healing after meniscus injury and repair in a
      rabbit model.
AB  - To assess the effect of hyaluronan on meniscus injury and repair, we had 35
      mature New Zealand White rabbits undergo bilateral meniscus injury and repair (19
      in the peripheral region, and 16 in the inner region). A longitudinal tear was
      created in the medial meniscus and repaired with horizontally placed nylon
      sutures. The left knee joint received intraarticular injections of hyaluronan 1
      week after surgery and once a week for 5 weeks. The right knees were injected
      with phosphate-buffered saline (the carrier vehicle of the hyaluronan). Twelve
      weeks after repair, tears in the peripheral region showed gross and histologic
      evidence of healing, with no difference between the vehicle- and hyaluronan
      treated menisci. Biochemically, the ratio of reducible collagen cross-links in
      the hyaluronan-treated menisci was significantly higher than in the vehicle
      treated menisci, indicating greater level of collagen remodeling. Biomechanically
      the vehicle- and hyaluronan-treated menisci demonstrated similarly high tearing
      load and fracture toughness. In the inner region, poor healing response was
      observed grossly and histologically in both treatment groups. Water content in
      the hyaluronan-treated menisci was significantly lower than in the vehicle
      treated menisci, indicating a lower level of swelling. Hyaluronan treatment
      stimulated collagen remodeling in the peripheral region and inhibited swelling of
      the meniscus repaired in the inner region.

PMID- 10653551
TI  - The relative incidence of anterior cruciate ligament injury in men and women at
      the United States Naval Academy.
AB  - The purpose of this study was to evaluate the relative risk of anterior cruciate
      ligament injury in female versus male midshipmen at the United States Naval
      Academy. From 1991 to 1997, we recorded the incidence of anterior cruciate
      ligament injury during intercollegiate athletics, intramural athletics, and
      military training. The subjects were male and female varsity athletes, coed
      intramural athletes, and participants in military training consisting of the
      obstacle course and instructional wrestling. All patient data were collected at
      the time of injury. Records filed at the intramural sports office, along with a
      questionnaire completed by coaches and trainers, were used to estimate midshipmen
      exposures. Results showed that in intercollegiate soccer, basketball, and rugby,
      women had a relative injury risk of 3.96 compared with men. In coed soccer,
      basketball, softball, and volleyball, the women's relative injury risk was 1.40
      compared with men. In military training, women had a relative injury risk of 9.74
      compared with men. In comparing overall annual anterior cruciate ligament injury
      rates among midshipmen, we found that women had a relative injury risk of 2.44
      compared with men. We concluded that female midshipmen have an increased relative
      risk of anterior cruciate ligament injury as compared with men in intercollegiate
      athletics, basic military training, and throughout their service academy career.
      This increase was not statistically significant at the intramural level of
      athletics.

PMID- 10653552
TI  - Structural properties of the intact and the reconstructed coracoclavicular
      ligament complex.
AB  - Numerous procedures have been described for the operative management of
      acromioclavicular joint injuries, but surprisingly little information is
      available on the ultimate mechanical behavior of the native coracoclavicular
      ligament complex or on the various methods of reconstruction. We tested 19 fresh
      frozen cadaveric bone-ligament-bone preparations of the coracoclavicular ligament
      in uniaxial tension at 25 mm/min until failure. Seven specimens were left intact,
      six had the trapezoid ligament sectioned, and six had the conoid ligament
      sectioned. Reconstruction of the coracoclavicular ligament was achieved using
      coracoacromial ligament transfers, woven polyester slings, suture anchors, and
      Bosworth screws; all reconstructions were also tested to failure. The intact
      coracoclavicular ligament failed by avulsion or midsubstance tear at 500 (+/-134)
      N, with a stiffness of 103 (+/-30) N/mm and elongation to failure of 7.7 (+/-1.9)
      mm. There was no significant difference between the contributions of the conoid
      or trapezoid ligaments in this loading configuration. Coracoclavicular slings and
      suture anchors provided strength similar to that of the coracoclavicular
      ligament, but with significantly greater deformations (14 to 26 mm). Screw
      fixation resulted in comparable stiffness and superior strength to the
      coracoclavicular ligament, but only if bicortical purchase was obtained.
      Coracoacromial ligament transfers were the weakest and least stiff, and
      augmentation with another form of coracoclavicular fixation is recommended. These
      results provide a useful baseline for comparison of the initial performance of
      reconstructive techniques with the performance of the native coracoclavicular
      ligament.

PMID- 10653553
TI  - Malleolar bursitis in figure skaters. Indications for operative and nonoperative
      treatment.
AB  - Figure skaters are unique athletes who must train for extended periods of time
      performing motions and routines that create excessive compressive and shear
      forces between their malleoli and boots. As a result, they are susceptible to the
      development of a painful adventitious malleolar bursitis. Most often these
      patients will relate a recent increase in their training schedule or the purchase
      of a new pair of skating boots. This condition usually responds favorably to
      nonoperative measures including stretching of the boot over the affected area and
      protective padding placed around the inflamed bursa. If the swelling is marked,
      then an aspiration, subsequent injection with cortisone, and a compressive wrap
      may be indicated. This treatment regimen will enable the majority of figure
      skaters to continue skating. If the symptoms continue or increase despite
      nonoperative measures, then cessation of skating for a brief period must be
      considered. If this is not a viable option for the skater, surgical excision of
      the bursa may be warranted. If septic bursitis occurs, immediate surgical
      debridement and intravenous antibiotics are indicated. A Staphyloccocus aureus
      organism is most often responsible and should be treated with appropriate
      antibiotics. These patients may return to skating when there is no sign of
      further infection, the soft tissues have fully healed, and there is no sign of
      residual inflammatory bursa, usually at 4 to 6 weeks after surgery.

PMID- 10653554
TI  - Fatal rhabdomyolysis with bilateral gluteal, thigh, and leg compartment syndrome
      after the Army Physical Fitness Test. A case report.

PMID- 10653555
TI  - Coracoid impingement. A case report and review of the literature.

PMID- 10653556
TI  - Acute compartment syndrome of the thigh associated with exercise.

PMID- 10653557
TI  - Current trends in anterior cruciate ligament reconstruction. Part II. Operative
      procedures and clinical correlations.
AB  - Surgical management of the anterior cruciate ligament-deficient knee has evolved
      from primary repair to extracapsular augmentation to anterior cruciate ligament
      reconstruction using biologic tissue grafts. The technique of anterior cruciate
      ligament reconstruction has improved over the last few decades with the aid of
      knowledge gained from basic science and clinical research. The biology and
      biomechanics of anterior cruciate ligament reconstruction were analyzed in the
      previously published first part of this article. In this second part, current
      operative concepts of anterior cruciate ligament reconstruction as well as
      clinical correlations are discussed. The latest information regarding anterior
      cruciate ligament reconstruction is presented with a goal of demonstrating the
      correlation between the application of basic science knowledge and the
      improvement of clinical outcomes.

PMID- 10653558
TI  - Association between the menstrual cycle and anterior cruciate ligament injuries
      in female athletes.

PMID- 10653559
TI  - Effect of a patellar realignment brace on patients with patellar subluxation and
      dislocation. Evaluation with kinematic magnetic resonance imaging.

PMID- 10653560
TI  - Sacral stress fracture in an elite college basketball player after the use of a
      jumping machine.

PMID- 10653561
TI  - Recreational physical activity and the risk of cholecystectomy in women.

PMID- 10653562
TI  - From Shakespeare to Defoe: malaria in England in the Little Ice Age.
AB  - Present global temperatures are in a warming phase that began 200 to 300 years
      ago. Some climate models suggest that human activities may have exacerbated this
      phase by raising the atmospheric concentration of carbon dioxide and other
      greenhouse gases. Discussions of the potential effects of the weather include
      predictions that malaria will emerge from the tropics and become established in
      Europe and North America. The complex ecology and transmission dynamics of the
      disease, as well as accounts of its early history, refute such predictions. Until
      the second half of the 20th century, malaria was endemic and widespread in many
      temperate regions, with major epidemics as far north as the Arctic Circle. From
      1564 to the 1730s the coldest period of the Little Ice Age malaria was an
      important cause of illness and death in several parts of England. Transmission
      began to decline only in the 19th century, when the present warming trend was
      well under way. The history of the disease in England underscores the role of
      factors other than temperature in malaria transmission.

PMID- 10653563
TI  - Could a tuberculosis epidemic occur in London as it did in New York?
AB  - In early 1999, more than 160 senior physicians, public health officials, and
      nurses met to discuss London's tuberculosis (TB) control program. The program was
      examined against the public health response of New York City's Bureau of
      Tuberculosis Control during a 1988 to 1992 epidemic. This article outlines TB
      epidemiology and control in New York City 10 years ago and in London today to
      assess whether the kind of epidemic that occurred in New York could occur in
      London.

PMID- 10653564
TI  - Japanese encephalitis immunization in South Korea: past, present, and future.
AB  - Japanese encephalitis (JE), once a major public health problem in South Korea,
      has declined since the 1980s, as a result of improved living conditions, a
      mosquito eradication program, and a national JE vaccination program, which
      includes annual booster vaccine for all children less than or equal to 15 years
      of age. Increased immunity has greatly reduced illness and death; however,
      vaccine adverse effects are increasing, and a National Compensation Program for
      Vaccine Injury was begun in 1995. This article reviews past successes, current
      problems, and future direction of the JE vaccination program in South Korea.

PMID- 10653565
TI  - Coccidioidomycosis in New York State.
AB  - Coccidioidomycosis, a systemic fungal disease caused by Coccidioides immitis, is
      endemic in the southwestern United States and in parts of Mexico and Central and
      South America. Only sporadic cases have been reported in areas (including New
      York) where the disease is not endemic. We used hospital discharge records and
      state mycology laboratory data to investigate the characteristics of C. immitis
      infections among New York State residents. From 1992 to 1997, 161 persons had
      hospital discharge diagnoses of coccidioidomycosis (ICD9 Code 114.0 - 114.5,
      114.9). From 1989 to 1997, 49 cultures from patients were confirmed as C.
      immitis; 26 of these patients had traveled to disease-endemic areas. Fourteen of
      16 isolates had multilocus genotypes similar to those of Arizona isolates, which
      corroborates the travel-related acquisition of the disease. Our results indicate
      that coccidioidomycosis may be more common in New York residents than previously
      recognized. Increased awareness among health-care providers should improve timely
      diagnosis of coccidioidomycosis and prevention of associated illnesses and deaths
      among patients in nondisease-endemic areas.

PMID- 10653566
TI  - Dengue surveillance in Florida, 1997-98.
AB  - Recent dengue outbreaks in the Caribbean and Central and South America and the
      presence of competent mosquito vectors increase the likelihood of future
      autochthonous transmission in Florida. During April 1997 to March 1998, a
      laboratory-based active surveillance program detected 18 cases of dengue
      involving all four dengue serotypes. All patients reported recent travel to
      countries with indigenous dengue transmission. These results demonstrate that
      dengue infections are imported into Florida at a much higher rate than reflected
      by previous passive surveillance; therefore, the risk for local dengue
      transmission may be increasing.

PMID- 10653567
TI  - Norwalk-like calicivirus genes in farm animals.
AB  - Viruses closely related to Norwalk-like viruses (NLVs) were recently found in
      stored stool samples from two calves (United Kingdom and Germany) and four pigs
      (Japan), sparking discussions about the potential for zoonotic transmission. To
      investigate if NLVs are commonly present in farm animals, pooled stool samples
      from 100 pig farms, 48 chicken farms, 43 dairy cow herds, and 75 veal calf farms
      from the Netherlands were assayed by reverse transcription- polymerase chain
      reaction amplification, using primers specific for the detection of NLVs from
      humans. NLV RNA was detected in 33 (44%) of the specimens from veal calf farms
      and two (2%) specimens from pig farms. Our data show that NLV infections until
      recently thought to be restricted to humans occur often in calves and sometimes
      in pigs. While zoonotic transmission has not been proven, these findings suggest
      that calves and pigs may be reservoir hosts of NLVs.

PMID- 10653569
TI  - Candida dubliniensis fungemia: the first four cases in North America.
AB  - We report the first four North American cases of Candida dubliniensis fungemia,
      including the first isolation of this organism from the bloodstream of an HIV
      infected person. All isolates were susceptible in vitro to commonly used
      antifungal drugs. This report demonstrates that C. dubliniensis can cause
      bloodstream infection; however, the incidence of disease is not known.

PMID- 10653568
TI  - Molecular genetic evidence of a novel morbillivirus in a long-finned pilot whale
      (Globicephalus melas).
AB  - A long-finned pilot whale with morbilliviral disease was stranded in New Jersey.
      An immunohistochemical stain demonstrated morbilliviral antigen. Reverse
      transcriptase-polymerase chain reaction for morbillivirus P and N genes was
      positive. Novel sequences most closely related to, but distinct from, those of
      dolphin and porpoise morbilliviruses suggest that this virus may represent a
      third member of the cetacean morbillivirus group.

PMID- 10653570
TI  - Integronlike structures in Campylobacter spp. of human and animal origin.
AB  - Resistance to antimicrobial agents used to treat severe Campylobacter spp.
      gastroenteritis is increasing worldwide. We assessed the antimicrobial resistance
      patterns of Campylobacter spp. isolates of human and animal origin. More than
      half (n = 32) were resistant to sulphonamide, a feature known to be associated
      with the presence of integrons. Analysis of these integrons will further our
      understanding of Campylobacter spp. epidemiology.

PMID- 10653571
TI  - Burkholderia pseudomallei traced to water treatment plant in Australia.
AB  - Burkholderia pseudomallei was isolated from environmental specimens 1 year after
      an outbreak of acute melioidosis in a remote coastal community in northwestern
      Australia. B. pseudomallei was isolated from a water storage tank and from spray
      formed in a pH-raising aerator unit. Pulsed-field gel electrophoresis confirmed
      the aerator and storage tank isolates were identical to the outbreak strain,
      WKo97.

PMID- 10653572
TI  - Molecular typing of multidrug-resistant Salmonella Blockley outbreak isolates
      from Greece.
AB  - During 1998, a marked increase (35 cases) in human gastroenteritis due to
      Salmonella Blockley, a serotype rarely isolated from humans in the Western
      Hemisphere, was noted in Greece. The two dominant multidrug-resistance phenotypes
      (23 of the 29 isolates studied) were associated with two distinct DNA
      fingerprints, obtained by pulsed-field gel electrophoresis of genomic DNA.

PMID- 10653573
TI  - Risk factors for carriage of Neisseria meningitidis during an outbreak in Wales.
AB  - In a school outbreak of meningococcal disease in Wales, we compared risk factors
      for the carriage of Neisseria meningitidis B15 P1.16 with carriage of any
      meningococci. Students had throat swabs and completed a questionnaire. Sixty
      (7.9%) carried meningococci; risk for carriage was higher in those >14 years of
      age.

PMID- 10653574
TI  - Salmonellosis in the Republic of Georgia: using molecular typing to identify the
      outbreak-causing strain.
AB  - In May 1998, three large outbreaks of salmonellosis, affecting 91 persons, were
      identified in the Republic of Georgia. Eighteen Salmonella Typhimurium strains
      were characterized by arbitrary primed polymerase chain reaction and pulsed-field
      gel electrophoresis; the results suggested that all cases were part of a single
      outbreak caused by a distinct clonal strain.

PMID- 10653575
TI  - First report of Q fever in Oman.
AB  - Although serologic evidence suggests the presence of Q fever in humans and
      animals in Saudi Arabia and the United Arab Emirates, acute Q fever has not been
      reported on the Arabian Peninsula. We report the first two cases of acute Q fever
      in Oman.

PMID- 10653576
TI  - The philosophic origins of science and the evolution of the two cultures.

PMID- 10653577
TI  - Isolation of a dengue type 1 virus from a soldier in West Africa (Cote d'Ivoire)

PMID- 10653579
TI  - Population-based study of invasive Kingella kingae infections.

PMID- 10653578
TI  - Carbapenem-hydrolyzing metallo-beta-lactamase from a nosocomial isolate of
      Pseudomonas aeruginosa in France.

PMID- 10653580
TI  - Involving ornithologists in the surveillance of vancomycin-resistant enterococci.

PMID- 10653581
TI  - RNA is closely associated with human mast cell secretory granules, suggesting a
      role(s) for granules in synthetic processes.
AB  - The distribution of ribosomes in mature human mast cells, a major granulated
      secretory cell, does not resemble that in other secretory cells, such as
      pancreatic acinar cells and plasma cells. By routine ultrastructural analysis,
      ribosomes in human mast cells are often close to, attached to, or even appear to
      be within secretory granules. To document better these relationships, we used
      multiple electron microscopic imaging methods, based on different principles, to
      define RNA, ribosome, and granule relationships in mature human mast cells. These
      methods included EDTA regressive staining, RNase digestion, immunogold labeling
      of ribonucleoproteins or uridine, direct binding or binding after ultrastructural
      in situ hybridization of various polyuridine probes to polyadenine in mRNA, and
      ultrastructural autoradiographic localization of [3H]-uridine incorporated into
      cultured human mast cells. These different labeling methods demonstrated
      ribosomes, RNA, U1SnRNP (a small nuclear RNP specific for alternative splicing of
      mRNA), mRNA, and uridine to be associated with secretory granules in human mast
      cells, implicating granules in a larger synthetic role in mast cell biology.

PMID- 10653582
TI  - Nonrandom distribution of metaphase AgNOR staining patterns on human acrocentric
      chromosomes.
AB  - The metaphase nucleolar organizer regions (NORs) contain ribosomal genes
      associated with proteins such as upstream binding factor (UBF) and RNA polymerase
      I (RPI). These genes are clustered in 10 loci of the human acrocentric
      chromosomes (13, 14, 15, 21, and 22). Some NOR-associated proteins, termed AgNOR
      proteins, can be specifically stained by silver. In this study we took advantage
      of technical advances in digital imaging, image restoration techniques, and
      factorial correspondence analysis (FCA) to study the different AgNOR staining
      patterns of metaphase chromosomes in human lymphocytes. Three predominant
      patterns could be distinguished: pair (47%), stick-like (28%), and unstained
      (18%) structures. By studying the frequency of occurrence of each pattern on
      different chromosomes, two groups could be defined. Chromosomes 13, 14, and 21
      carried predominantly pair or stick-like AgNOR structures, whereas chromosomes 15
      and 22 mainly carried pair AgNOR structures or remained unstained. We suggest
      that the different AgNOR shapes reflect both the number of ribosomal genes
      carried by each chromosome and the differential recruitment of active ribosomal
      genes in each NOR cluster. This is the first study showing a nonrandom
      distribution of AgNOR shape among acrocentric chromosomes.

PMID- 10653583
TI  - Immunocytochemical localization of Shc and activated EGF receptor in early
      endosomes after EGF stimulation of HeLa cells.
AB  - After binding of epidermal growth factor (EGF), the EGF receptor (EGFR) becomes
      autophosphorylated via tyrosine. The ligand-activated receptor is internalized by
      endocytosis and subsequently degraded in the lysosomal pathway. To follow EGFR
      activation after EGF stimulation, we generated antisera to the EGFR
      phosphotyrosine sites pY992 and pY1173. The SH2 region of Shc binds to both these
      sites. Both antisera identified EGFR after EGF binding and did not crossreact
      with the unactivated receptor. The intracellular distribution of phosphorylated
      EGFR after ligand binding was traced by two-color immunofluorescence confocal
      microscopy and immunoelectron microscopy. Before EGF stimulation EGFR was
      primarily located along the cell surface. When internalization of activated EGFR
      was inhibited by incubation with EGF on ice, Y992- and Y1173-phosphorylated EGFR
      were located along the plasma membrane. Ten minutes after internalization at 37C,
      Y992- and Y1173-phosphorylated EGFR were almost exclusively located in early
      endosomes, as shown by co-localization with EEA1. Immunoelectron microscopy
      confirmed that phosphorylated EGFR was located in intracellular vesicles
      resembling early endosomes. After EGF stimulation, the adaptor protein Shc
      redistributed to EGFR-containing early endosomes. Our results indicate that EGFR
      activation of Shc via tyrosine-phosphorylated Y992 and Y1173 occurred in early
      endocytic compartments, and support a role for membrane trafficking in
      intracellular signaling.

PMID- 10653584
TI  - Behavior of smooth muscle cells during arterial ductal closure at birth.
AB  - To determine which part of the smooth muscle cells (SMCs) of the ductus
      arteriosus (DA) contribute to duct closure after birth, we looked for areas in
      which SM2 myosin heavy chain (MHC) mRNA expression, which is associated with
      contraction of smooth muscle, and apoptosis could be detected in the DA during
      development. In situ hybridization revealed that the SM2 MHC mRNA was strongly
      positive in the longitudinally oriented SMCs and inner layer of the circularly
      oriented SMCs just before birth. Apoptotic cells were detected in the SMCs of the
      DA from 1 day after birth. Histochemical analysis using terminal deoxynucleotidyl
      transferase-mediated dUTP-digoxigenin nick end-labeling (TUNEL) revealed
      significant numbers of TUNEL-positive nuclei in the longitudinally oriented SMCs
      and the inner layer of the circularly oriented SMCs. Masson-stained sections
      showed that the TUNEL-positive area in the DA was replaced by connective tissue
      from 1 day after birth. These results suggest that the increase in the SM2 MHC
      mRNA expression and the induction of apoptosis are present at the same site in
      the media of the DA. Therefore, the SMCs in this area may play an important role
      in duct constriction and remodeling of the vessel wall after birth.

PMID- 10653585
TI  - Localization of mitochondrial 60-kD heat shock chaperonin protein (Hsp60) in
      pituitary growth hormone secretory granules and pancreatic zymogen granules.
AB  - We used quantitative immunogold electron microscopy and biochemical analysis to
      evaluate the subcellular distribution of Hsp60 in rat tissues. Western blot
      analysis, employing both monoclonal and polyclonal antibodies raised against
      mammalian Hsp60, shows that only a single 60-kD protein is reactive with the
      antibodies in brain, heart, kidney, liver, pancreas, pituitary, spleen, skeletal
      muscle, and adrenal gland. Immunogold labeling of tissues embedded in the acrylic
      resin LR Gold shows strong labeling of mitochondria in all tissues. However, in
      the anterior pitutary and in pancreatic acinar cells, Hsp60 also localizes in
      secretory granules. The labeled granules in the pituitary and pancreas were
      determined to be growth hormone granules and zymogen granules, respectively,
      using antibodies to growth hormone and carboxypeptidase A. Immunogold labeling of
      Hsp60 in all compartments was prevented by preadsorption of the antibodies with
      recombinant Hsp60. Biochemically purified zymogen granules free of mitochondrial
      contamination are shown by Western blot analysis to contain Hsp60, confirming the
      morphological localization results in pancreatic acinar cells. In kidney distal
      tubule cells, low Hsp60 reactivity is associated with infoldings of the basal
      plasma membrane. In comparison, the plasma membrane in kidney proximal tubule
      cells and in other tissues examined showed only background labeling. These
      findings raise interesting questions concerning translocation mechanisms and the
      cellular roles of Hsp60.

PMID- 10653586
TI  - Involvement of caspase-3 and GD3 ganglioside in ceramide-induced apoptosis in
      Farber disease.
AB  - Farber's disease (FD) is a rare genetic disorder caused by ceramidase deficiency,
      which results in ceramide accumulation in lung, liver, colon, skeletal muscle,
      cartilage, and bone. Although this disease has been symptomatically
      characterized, little is known about its molecular pathogenetic process. Because
      recent studies reported that ceramide accumulation induces GD3 ganglioside
      formation and apoptosis, we investigated, in tissue obtained via colonoscopy from
      seriously involved patients, the possible involvement of ceramide in FD
      colonocyte destruction. Histochemical and TUNEL analyses of paraffin-embedded
      sections revealed that 45 +/- 4.3% of FD colonocytes showed morphological signs
      of apoptosis compared with the 8 +/- 2.3% of constitutive epithelial cell death.
      Importantly, immunohistochemical study for pro-apoptotic factors showed that GD3
      accumulation co-localized with active caspase-3 and cleaved K18 in FD colon
      tissue. These findings provide evidence for a role of the apoptotic ceramide
      pathway in the pathogenesis of FD.

PMID- 10653587
TI  - Changes in ErbB2 (her-2/neu), ErbB3, and ErbB4 during growth, differentiation,
      and apoptosis of normal rat mammary epithelial cells.
AB  - Studies were undertaken to examine the natural role of ErbB2, ErbB3, and ErbB4
      during the development of normal rat mammary epithelial cells (MECs) in vivo and
      in vitro. Immunohistochemical analysis demonstrated that mammary gland terminal
      end buds expressed abundant ErbB2 and ErbB4 but limited ErbB3 in pubescent rats,
      whereas luminal epithelial cells in nulliparous rats expressed ErbB2, ErbB3,
      and/or ErbB4. During pregnancy, ductal epithelial cells and stromal cells
      expressed abundant ErbB3 but limited ErbB2. Although ErbB2 and ErbB3 were
      downregulated throughout lactation, both receptors were re-expressed during
      involution. In contrast, ErbB4 was downregulated throughout pregnancy, lactation,
      and involution. Immunoblotting and immunoprecipitation studies confirmed the
      developmental expression of ErbB2 and ErbB3 in the mammary gland and the co
      localization of distinct ErbB receptors in the mammary gland of nulliparous rats.
      In agreement with our in vivo findings, primary culture studies demonstrated that
      ErbB2 and ErbB3 were expressed in functionally immature, terminally
      differentiated and apoptotic MECs, and downregulated in functionally
      differentiated MECs. ErbB receptor signaling was required for epithelial cell
      growth, functional differentiation, and morphogenesis of immature MECs, and the
      survival of terminally differentiated MECs. Finally, ErbB4 expression did not
      interfere with functional differentiation and apoptosis of normal MECs.

PMID- 10653588
TI  - Ruthenium hexaammine trichloride chemography for aggrecan mapping in cartilage is
      a sensitive indicator of matrix degradation.
AB  - We developed a new quantitative histochemical method for mapping aggrecan content
      in articular cartilage and applied it to models of cartilage degradation.
      Ruthenium hexaammine trichloride (RHT) forms co-precipitates with aggrecan, the
      main proteoglycan component of cartilage, and was previously found to be a good
      fixative in aiding the maintenance of chondrocyte morphology. We show that these
      RHT-aggrecan precipitates generate a positive chemographic signal on
      autoradiographic emulsions, in the absence of any radioactivity in the tissue
      section, via a process similar to the autometallographic process used previously
      for localization of trace metals ions in tissues. By exploiting the inherent
      depth-dependence of aggrecan concentration in adult articular cartilage, we
      demonstrated that the density of silver grains produced by RHT-derived
      chemography on autoradiographic emulsions correlated with locally measured
      aggrecan concentration as determined by the dimethylmethylene blue assay of
      microdissected tissue from these different depths of cartilage. To explore the
      benefits of this new method in monitoring tissue degradation, cartilage explants
      were degraded during culture using interleukin-1 (IL-1) or digested after culture
      using chondroitinase and keratinase. The RHT chemographic signal derived from
      these samples, compared to controls, showed sensitivity to loss of aggrecan and
      distinguished cell-mediated loss (IL-1) from degradation due to addition of
      exogenous enzymes. The RHT-derived chemographic grain density represents an
      interesting new quantitative tool for histological analysis of cartilage in
      physiology and in arthritis.

PMID- 10653589
TI  - Brush border myosin I (BBMI): a basally localized transcript in human jejunal
      enterocytes.
AB  - To extend our recent observation that villin mRNA, encoding an apical
      microvillous protein, is dichotomously localized in the basal region of human
      enterocytes, we examined the localization of mRNAs for brush border myosin I
      (BBMI) and intestinal fimbrin (I-fim). In situ hybridization indicated that BBMI
      mRNA localized to the basal region of human enterocytes, whereas the mRNA for I
      fim distributed diffusely. To facilitate study of potential mechanisms of mRNA
      targeting, we cloned a full-length cDNA for BBMI including its 5'- and 3'
      untranslated regions (UTRs). This cDNA shares 86% sequence identity with bovine
      BBMI and 85% with rat BBMI. Sequence analysis revealed no obvious similarity
      between the 3'-UTRs of BBMI and villin. This study provides evidence of novel
      sorting pathways for intestinal microvillous cytoskeletal proteins.

PMID- 10653590
TI  - Pararosaniline fixation for detection of co-stimulatory molecules, cytokines, and
      specific antibody.
AB  - Integral immunohistochemical analysis of immune responses in frozen sections
      requires that, in addition to constitutively expressed membrane CD markers, less
      stable determinants can be reliably visualized. Therefore, we compared the
      commonly used acetone fixation method with pararosaniline fixation for six
      determinant categories. These categories included selected constitutively
      expressed markers, inducible co-stimulatory molecules, pro- and anti-inflammatory
      cytokines (including the novel cytokine IL-18, also known as IGIF and IL-1gamma),
      antigen-specific antibody in plasma cells, bacterial peptidoglycan, and lysosomal
      acid phosphatase activity. Human spleen and mouse spleen activated by agonistic
      anti-CD40 antibody or TNP-Ficoll immunization were analyzed in parallel with
      brain tissue from multiple sclerosis (MS) patients and marmoset monkeys with
      experimental autoimmune encephalomyelitis (EAE), an animal model for MS. Fixation
      with pararosaniline resulted in better morphology of all tissues and inhibited
      endogenous alkaline phosphatase activity in brain tissue. Most determinants could
      be reliably detected. Staining sensitivity and intensity were markedly increased
      for selected determinant-tissue combinations, e.g., for IL-4 in human spleen and
      CD40 in human and mouse spleen. These data show that pararosaniline is a useful
      alternative to acetone, resulting in superior morphology and specific staining
      for selected determinant-tissue combinations. This provides additional
      flexibility for in situ analysis of immune reactivity.

PMID- 10653591
TI  - Parvalbumin is expressed in normal and pathological human parathyroid glands.
AB  - The parathyroid glands are of major importance in calcium homeostasis. Small
      changes in the plasma calcium (Ca2+) concentration induce rapid changes in
      parathyroid hormone (PTH) secretion to maintain the extracellular Ca2+ levels
      within the physiological range. Extracellular Ca2+ concentration is continuously
      measured by a G-protein-coupled Ca2+-sensing receptor, which influences the
      expression and secretion of PTH. The mechanism of signal transduction from
      receptor sensing to PTH secretion is not well understood, but changes in PTH
      secretion are tightly linked to changes in the cytosolic Ca2+ concentration.
      Using immunohistochemistry and Western blot analysis, we detected the EF Ca2+
      binding protein parvalbumin (PV) in normal and in hyperplastic and adenomatous
      human parathyroid glands. The strongest PV signal was present in chief cells and
      water clear cells, whereas in oxyphilic cells only a weak signal was observed.
      Immunohistochemistry and in situ hybridization of the PTH indicated a co
      localization of PV and PTH in the same cell types. Because changes in the
      cytosolic Ca2+ concentration are believed to influence the process of PTH
      secretion, a possible role of PV as a modulator of this Ca2+ signaling is
      envisaged.

PMID- 10653592
TI  - Co-expression of the squamous cell carcinoma antigens 1 and 2 in normal adult
      human tissues and squamous cell carcinomas.
AB  - Squamous cell carcinoma antigen (SCCA) serves as a serological marker for
      advanced squamous cell carcinomas (SCCs) and as an indicator of therapeutic
      response. Recent molecular studies show that the SCCA is transcribed by two
      almost identical tandemly arrayed genes, SCCA1 and SCCA2. These genes are members
      of the high molecular weight serine proteinase inhibitor (serpin) superfamily.
      Although SCCA1 and SCCA2 are 92% identical at the amino acid level, they have
      distinct biochemical properties. Paradoxically, SCCA1 is an inhibitor of papain
      like cysteine proteinases, such as cathepsins L, S, and K, whereas SCCA2 inhibits
      chymotrypsin-like serine proteinases, cathepsin G, and mast cell chymase. Using a
      new set of discriminatory monoclonal antibodies (MAbs) and polymerase chain
      reaction (PCR) assay, we showed that SCCA1 and SCCA2 were co-expressed in the
      suprabasal layers of the stratified squamous epithelium of the tongue, tonsil,
      esophagus, uterine cervix and vagina, Hassall's corpuscles of the thymus, and
      some areas of the skin. SCCA1 and SCCA2 also were detected in the pseudo
      stratified columnar epithelium of the conducting airways. Examination of squamous
      cell carcinomas of the lung and head and neck showed that SCCA1 and SCCA2 were co
      expressed in moderately and well-differentiated tumors. Moreover, there was no
      differential expression between these SCCA "isoforms" in normal or malignant
      tissues. In contrast to previous studies, these data indicated that the
      expression of SCCA1 and SCCA2 was not restricted to the squamous epithelium and
      that these serpins may coordinately regulate cysteine and serine proteinase
      activity in both normal and transformed tissues.

PMID- 10653593
TI  - Apoptosis in rat gastric antrum: evidence that regulation by food intake depends
      on nitric oxide synthase.
AB  - The turnover of the epithelium of the gastrointestinal tract is regulated by a
      balance between cell multiplication and cell loss. We examined the effects of
      starvation on apoptosis in endocrine and other epithelial cells of rat
      antropyloric mucosa. Apoptosis was determined by the TUNEL reaction combined with
      immunocytochemical staining for gastrin and somatostatin. Apoptotic cell
      morphology was determined by bisbenzimide staining for DNA. Both gastrin and
      somatostatin cells showed a significantly lower apoptotic index than the general
      epithelium. This agrees with the longer turnover kinetics of gastric endocrine
      cells. On starvation, the apoptotic index of the general epithelium and of the
      gastrin but not of the somatostatin, cells increased significantly. This was
      prevented by the nitric oxide synthase (NOS) inhibitor L-NAME but not by its
      inactive stereoisomer D-NAME. Immunoreactive neuronal NOS was present in
      somatostatin cells, in nonendocrine cells predominating in the surface and pit
      epithelium, and in rare nerve fibers. Endothelial cell NOS was present in
      vessels, whereas the inducible isoform was barely detectable. Thus, endogenous
      NOS isoforms participate in regulating antropyloric epithelial apoptosis during
      starvation. The close paracrine relation between somatostatin cells and gastrin
      cells suggests that the former regulates apoptosis of the latter through release
      of NO.

PMID- 10653594
TI  - High-density hapten labeling and HRP conjugation of oligonucleotides for use as
      in situ hybridization probes to detect mRNA targets in cells and tissues.
AB  - Oligonucleotides that carry a detectable label can be used to probe for mRNA
      targets in in situ hybridization experiments. Oligonucleotide probes (OPs) have
      several advantages over cDNA probes and riboprobes. These include the easy
      synthesis of large quantities of probe, superior penetration of probe into cells
      and tissues, and the ability to design gene- or allele-specific probes. One
      significant disadvantage of OPs is poor sensitivity, in part due to the
      constraints of adding and subsequently detecting multiple labels per
      oligonucleotide. In this study, we compared OPs labeled with multiple detectable
      haptens (such as biotin, digoxigenin, or fluorescein) to those directly
      conjugated with horseradish peroxidase (HRP). We used branching phosphoramidites
      to add from two to 64 haptens per OP and show that in cells, 16-32 haptens per OP
      give the best detection sensitivity for mRNA targets. OPs were also made by
      directly conjugating the same oligonucleotide sequences to HRP. In general, the
      HRP-conjugated OPs were more sensitive than the multihapten versions of the same
      sequence. Both probe designs work well both on cells and on formaldehyde-fixed,
      paraffin-embedded tissues. We also show that a cocktail of OPs further increases
      sensitivity and that OPs can be designed to detect specific members of a gene
      family. This work demonstrates that multihapten-labeled and HRP-conjugated OPs
      are sensitive and specific and can make superior in situ hybridization probes for
      both research and diagnostic applications.

PMID- 10653595
TI  - Localization of monoamine oxidase A and B in human pancreas, thyroid, and adrenal
      glands.
AB  - We studied monoamine oxidase (MAO) A and B localization in human pancreas,
      thyroid gland, and adrenal gland by immunohistochemistry. The primary antibodies
      used were mouse monoclonal anti-human MAO-A (6G11/E1) and anti-human MAO-B
      (3F12/G10/2E3). Samples were obtained from six routine autopsy cases and fixed in
      2% paraformaldehyde. Exocrine pancreas showed a widespread distribution of MAO-A,
      whereas MAO-B was present only in centroacinar cells and epithelial cells of
      pancreatic ducts. In endocrine pancreas, MAO-A was observed in around 50% of
      islet cells, whereas MAO-B was less abundant and was restricted to the periphery
      of islets. Thyroid gland showed strong MAO-A immunoreactivity in all cell types
      and was MAO-B-negative. In adrenal gland, the capsule displayed MAO-A but not MAO
      B immunoreactivity, whereas the cortex showed widespread MAO-A staining but was
      MAO-B-negative in interstitial cells. Finally, in the medulla only a few
      scattered cells showed either MAO-A or MAO-B immunoreactivity. To our knowledge,
      these data represent the first study of the cellular distribution of MAO-A and
      MAO-B in the three human tissues included.

PMID- 10653596
TI  - Novel application of tyramide signal amplification (TSA): ultrastructural
      visualization of double-labeled immunofluorescent axonal profiles.
AB  - Fluorescent immunocytochemistry (FICC) allows multiple labeling approaches when
      enzyme-based techniques are difficult to combine, such as in double-labeling
      experiments targeting small-caliber axonal segments. Nevertheless, the conversion
      of FICC to a product visible at the electron microscopic (EM) level requires
      labor-intensive procedures, thus justifying the development of more user-friendly
      conversion methods. This study was initiated to simplify the conversion of FICC
      to EM by employing the unique properties of tyramide signal amplification (TSA),
      which allowed the simultaneous targeting of a fluorescent tag and biotin label to
      the same antigenic site. Briefly, one of two antigenic sites typically co
      localized in damaged axonal segments was visualized by the application of a
      fluorescent secondary antibody, with the other tagged via a biotinylated
      antibody. Next, an ABC kit was used, followed by the simultaneous application of
      fluorophore-tyramide and biotin-tyramide. After temporary mounting for
      fluorescent digital photomicroscopy, sections were incubated in ABC and reacted
      with diaminobenzidine before EM analysis. Double-labeling fluorescent
      immunocytochemistry with TSA clearly delineated damaged axonal segments. In
      addition, these same axonal segments yielded high-quality EM images with discrete
      electron-dense reaction products, thereby providing a simple and reproducible
      means for following fluorescent analysis with EM.

PMID- 10653597
TI  - The Ki-67 protein: from the known and the unknown.
AB  - The expression of the human Ki-67 protein is strictly associated with cell
      proliferation. During interphase, the antigen can be exclusively detected within
      the nucleus, whereas in mitosis most of the protein is relocated to the surface
      of the chromosomes. The fact that the Ki-67 protein is present during all active
      phases of the cell cycle (G(1), S, G(2), and mitosis), but is absent from resting
      cells (G(0)), makes it an excellent marker for determining the so-called growth
      fraction of a given cell population. In the first part of this study, the term
      proliferation marker is discussed and examples of the applications of anti-Ki-67
      protein antibodies in diagnostics of human tumors are given. The fraction of Ki
      67-positive tumor cells (the Ki-67 labeling index) is often correlated with the
      clinical course of the disease. The best-studied examples in this context are
      carcinomas of the prostate and the breast. For these types of tumors, the
      prognostic value for survival and tumor recurrence has repeatedly been proven in
      uni- and multivariate analysis. The preparation of new monoclonal antibodies that
      react with the Ki-67 equivalent protein from rodents now extends the use of the
      Ki-67 protein as a proliferation marker to laboratory animals that are routinely
      used in basic research. The second part of this review focuses on the biology of
      the Ki-67 protein. Our current knowledge of the Ki-67 gene and protein structure,
      mRNA splicing, expression, and cellular localization during the cell-division
      cycle is summarized and discussed. Although the Ki-67 protein is well
      characterized on the molecular level and extensively used as a proliferation
      marker, the functional significance still remains unclear. There are indications,
      however, that Ki-67 protein expression is an absolute requirement for progression
      through the cell-division cycle.

PMID- 10653598
TI  - T-cell recognition of melanoma-associated antigens.
AB  - In this review, we summarize the significant progress that has been made in the
      identification of melanoma-associated antigens (MAA) recognized by cytotoxic T
      lymphocytes (CTL). These antigens belong to three main groups: tumor-associated
      testis-specific antigens (e.g. , MAGE, BAGE, and GAGE); melanocyte
      differentiation antigens (e.g., tyrosinase, Melan-A/MART-1); and mutated or
      aberrantly expressed molecules (e.g, CDK4, MUM-1, beta-catenin). Although strong
      CTL activity may be induced ex vivo against most of these antigens, often in the
      presence of excess cytokines and antigen, a clear understanding of the functional
      status of CTL in vivo and their impact on tumor growth, is still lacking. Several
      mechanisms are described that potentially contribute to tumor cell evasion of the
      immune response, suggesting that any antitumor efficacy achieved by immune
      effectors may be offset by factors that result ultimately in tumor progression.
      Nevertheless, most of these MAA are currently being investigated as immunizing
      agents in clinical studies, the conflicting results of which are reviewed.
      Indeed, the therapeutic potential of MAA has still to be fully exploited and new
      strategies have to be found in order to achieve an effective and long-lasting in
      vivo immune control of melanoma growth and progression.

PMID- 10653599
TI  - Heterogeneity in expression of human leukocyte antigens and melanoma-associated
      antigens in advanced melanoma.
AB  - The study of tumor immunology has led to many innovative therapeutic strategies
      for the treatment of melanoma. The strategies are primarily dependent on melanoma
      associated antigen peptide vaccination or T-cell-based therapy. These
      immunotherapies are totally reliant on proper copresentation of human leukocyte
      antigen class I molecules in sufficient quantity and the presence and
      availability of melanoma-associated antigenic peptides. Altered expression of
      either HLA class I molecules or melanoma antigens is known to occur. These
      defects lead to altered manufacture and copresentation of HLA class I molecules
      with melanoma-associated antigens to T-cells. Defects in any one combination can
      lead to loss of recognition of melanoma cells and their subsequent destruction by
      cytotoxic T-lymphocytes. Thus, these immunotherapy strategies can be thwarted by
      defects or heterogeneity of expression of human leukocyte antigen class I or of
      melanoma-associated antigens.

PMID- 10653600
TI  - Cancer and anticancer therapy-induced modifications on metabolism mediated by
      carnitine system.
AB  - An efficient regulation of fuel metabolism in response to internal and
      environmental stimuli is a vital task that requires an intact carnitine system.
      The carnitine system, comprehensive of carnitine, its derivatives, and proteins
      involved in its transformation and transport, is indispensable for glucose and
      lipid metabolism in cells. Two major functions have been identified for the
      carnitine system: (1) to facilitate entry of long-chain fatty acids into
      mitochondria for their utilization in energy-generating processes; (2) to
      facilitate removal from mitochondria of short-chain and medium-chain fatty acids
      that accumulate as a result of normal and abnormal metabolism. In cancer
      patients, abnormalities of tumor tissue as well as nontumor tissue metabolism
      have been observed. Such abnormalities are supposed to contribute to
      deterioration of clinical status of patients, or might induce cancerogenesis by
      themselves. The carnitine system appears abnormally expressed both in tumor
      tissue, in such a way as to greatly reduce fatty acid beta-oxidation, and in
      nontumor tissue. In this view, the study of the carnitine system represents a
      tool to understand the molecular basis underlying the metabolism in normal and
      cancer cells. Some important anticancer drugs contribute to dysfunction of the
      carnitine system in nontumor tissues, which is reversed by carnitine treatment,
      without affecting anticancer therapeutic efficacy. In conclusion, a more complex
      approach to mechanisms that underlie tumor growth, which takes into account the
      altered metabolic pathways in cancer disease, could represent a challenge for the
      future of cancer research.

PMID- 10653601
TI  - Cyclosporin A decreases the degradation of type I collagen in rat gingival
      overgrowth.
AB  - Cyclosporin A (CsA) is used as an immunosuppressive agent and its prominent side
      effect is the induction of fibrous gingival overgrowth. The purpose of this study
      was to investigate the effect of CsA on the type I collagen metabolism in the
      gingiva of rats fed a powdered diet either containing or lacking CsA.
      Immunohistochemical analysis revealed that type I collagen was more prevalent in
      the connective tissue of CsA-treated gingiva than in those of control rats on
      days 15, 30, and 55 after the start of feeding. Total RNAs were isolated from
      mandibular molar gingiva on days 0, 3, 8, 15, 30, and 55. Quantitative analysis
      of mRNA by reverse transcriptase-polymerase chain reaction revealed that the CsA
      treated groups showed a gradual decrease in expression of type I collagen and
      collagenase mRNAs, 0.4% and 18.0% on day 55 compared with those on day 0,
      respectively. In the control groups, type I collagen and collagenase mRNAs also
      decreased to 19.7% and 63.0%, respectively, however, both mRNA expressions were
      significantly lower in the CsA-treated group than in the controls. An electron
      microscopic analysis of fibroblasts was performed to count the number of cells
      with collagen fibrils in the cytoplasm, a marker of phagocytosis of collagen by
      fibroblasts. The collagen fibrils were detected in 4.7% +/- 2.7% and 24.3% +/-
      13.7% of fibroblasts in the overgrown gingiva treated with CsA rat for 8 days and
      30 days, but in 57.0% +/- 5.3% and 81.3% +/- 9.2% of fibroblasts in the each
      control group gingiva, respectively. Furthermore, in vitro analysis was performed
      to measure the phagocytosis of cultured fibroblasts by flow cytometry using
      collagen-coated latex beads. Fibroblasts isolated from CsA-treated gingiva on day
      8 and day 30 contained 5.7% +/- 0.6% and 9.9% +/- 1.5% phagocytic cells, whereas
      control fibroblasts contained 50.3% +/- 5.5% and 33.3% +/- 4.9% phagocytic cells,
      respectively. The inhibition rate of phagocytic activity was similar between in
      vivo and in vitro assays. These findings suggest that the decrease of the
      collagen degradation due to the lower phagocytosis and the lower collagenase mRNA
      expression are closely associated with the increase of type I collagen
      accumulation in CsA-treated rat gingiva.

PMID- 10653602
TI  - Endothelial cell regulation of nitric oxide production during hypoxia in coronary
      microvessels and epicardial arteries.
AB  - Nitric oxide (NO) synthesized by endothelial cell nitric oxide synthase (eNOS)
      elicits vasodilation of resistance-sized coronary microvessels. Since coronary
      blood flow increases during hypoxia, we tested the hypotheses that: (1) hypoxia
      results in increased blood flow through increased NO production mediated by the
      upregulation of both eNOS mRNA and protein and (2) the regulation of NO
      production in response to hypoxia differs in microvascular endothelial cells and
      nonresistance, epicardial endothelial cells. Monocultures of vascular endothelium
      from resistance (approximately 100 micro) and nonresistance epicardial arteries
      were established and characterized. Nitric oxide was quantitated using a
      chemiluminescence method. Hypoxia (pO(2) = 10 mmHg) significantly increased NO
      production in both cell lines, with less NO produced in microvascular
      endothelium. Western blots demonstrated that hypoxia caused a time-dependent
      increase in eNOS protein in both lines, with an average 2.5-fold increase in
      nonresistance, epicardial endothelial cells compared to an average 1.7-fold
      increase in protein from microvascular endothelium. Total mRNA recovery increased
      2.4 +/- 0.6-fold within 30 min of hypoxia in nonresistance, epicardial
      endothelial cells with no increase in microvascular endothelial cells. Although
      hypoxia increased NO production in both populations of endothelial cells, the
      increase in NO production and eNOS protein in microvascular endothelium was less
      compared to nonresistance, epicardial endothelial cells. Furthermore, there was
      no significant upregulation of total mRNA for eNOS in microvascular endothelium.
      The data indicate that increased NO production in microvascular endothelium
      during hypoxia may be through translational or posttranslational modifications of
      the enzyme, whereas transcriptional upregulation may account for the increased NO
      production in nonresistance, epicardial endothelial cells. Oxygen-sensitive
      response mechanisms that modulate NO production may be different in endothelium
      from different coronary artery vascular beds.

PMID- 10653603
TI  - Downregulation of CXCR-2 but not CXCR-1 expression by human keratinocytes by UVB.
AB  - Interleukin-8 (IL-8) belongs to the CXC chemokine family. IL-8 exerts its
      biological activities by binding to specific cell surface receptors, CXCR-1 and
      CXCR-2. Both receptors bind IL-8 with high affinity but they have different
      affinities for MGSA/Groalpha and NAP-2. It has been shown that the expression of
      epidermal CXCR-2 is increased in psoriasis, suggesting that activation of KC
      mediated by CXCR-2 contributes to the characteristic epidermal changes observed
      in psoriasis. In order to examine the mechanism(s) by which UVB therapy is
      effective for several dermatoses including psoriasis, we sought to examine if UVB
      would modulate the expression of CXCR-1 and CXCR-2 in human keratinocytes (KC).
      Constitutive expression of CXCR-1 and CXCR-2 mRNA was detected by RT-PCR in
      normal cultured human KC. After 100 or 300 J/m(2) irradiation, a decrease in CXCR
      2 mRNA was detectable from 12 h after irradiation; this downregulation was
      observed until 48 h after irradiation. In contrast, the CXCR-1 mRNA level was
      unchanged. Immunohistochemical studies and flow cytometry analysis confirmed the
      suppressive effect of UVB on the expression of CXCR-2 protein in cultured human
      keratinocytes. Immunohistochemical studies on two minimal erythema doses (2MED)
      exposed and 2MED-unexposed skin from healthy volunteers revealed that CXCR-2
      staining occurred over the whole layer of the epidermis but at 24 h after 2MED
      irradiation, the positive staining of CXCR-2 was decreased. A faint CXCR-1
      staining was observed in the lower part of the epidermis both in unexposed and
      exposed skins. Our results indicate that UVB-induced growth inhibition of KC in
      hyperproliferative skin disorders may, in part, be related to downregulation of
      CXCR-2.

PMID- 10653604
TI  - Posttranslational modifications of the KI-67 protein coincide with two major
      checkpoints during mitosis.
AB  - Ki-67 is a nuclear protein present in all proliferating cells that are in the
      active part of the cell division, but not in resting cells. This feature is
      extensively used in tumor diagnostics to estimate the growth fraction of a given
      cell population. We now demonstrate that the spatial and temporal regulation of
      the Ki-67 protein during the cell cycle is associated with mitosis-specific
      phosphorylation. These posttranslational modifications of the Ki-67 protein are
      accompanied by a characteristic redistribution of the protein from the interior
      of the nucleus to the periphery of the condensed chromosomes and vice versa.
      Phosphorylation could be suppressed by activating cell-cycle checkpoints that
      control the entry into mitosis through the activity of the cyclin B/cdc2 complex.
      In vitro experiments confirm that the presence of the cdc2 kinase and its
      regulatory subunit cyclin B is required for the phosphorylation of the Ki-67
      protein. We further demonstrated that the Ki-67 protein is a new member of the
      family of MPM-2 reactive phosphoproteins, which includes both structural and
      functional proteins that are necessary for the control and timing of mitosis.
      Phosphorylation and dephosphorylation of the Ki-67 protein are therefore
      controlled by key regulatory structures of the cell cycle and occur at two
      hallmark events within the cell cycle: the breakdown and the reorganization of
      the nucleus during mitosis.

PMID- 10653605
TI  - Differential induction of tumor necrosis factor alpha and manganese superoxide
      dismutase by endotoxin in human monocytes: role of protein tyrosine kinase,
      mitogen-activated protein kinase, and nuclear factor kappaB.
AB  - A mutant Escherichia coli lipopolysaccharide (LPS) lacking myristoyl fatty acid
      markedly stimulates the activity of manganese superoxide dismutase (MnSOD)
      without inducing tumor necrosis factor alpha (TNFalpha) production by human
      monocytes (Tian et al., 1998, Am J Physiol 275:C740.), suggesting that induction
      of MnSOD and TNFalpha by LPS are regulated through different signal transduction
      pathways. The protein tyrosine kinase (PTK)/mitogen-activated protein kinase
      (MAPK) pathway plays an important role in the LPS-induced TNFalpha production. In
      the current study, we determined the effects of PTK inhibitors, genistein and
      herbimycin A, on the induction of MnSOD and TNFalpha in human monocytes.
      Genistein (10 microg/ml) and herbimycin A (1 microg/ml) markedly inhibited LPS
      induced protein tyrosine phosphorylation, phosphorylation and nuclear
      translocation of MAPK (p42 ERK, extracellular signal-regulated kinase), and
      increases in the steady state level of TNFalpha mRNA as well as TNFalpha
      production. In contrast, at similar concentrations, genistein and herbimycin A
      had no effect on the LPS-induced activation of nuclear factor kappaB (NFkappaB)
      and induction of MnSOD (mRNA and enzyme activity) in human monocytes. In
      addition, inhibition of NFkappaB activation by gliotoxin and pyrrodiline
      dithiocarbamate, inhibited LPS induction of TNFalpha and MnSOD mRNAs. These
      results suggest that (1) while PTK and MAPK are essential for the production of
      TNFalpha, they are not necessary for the induction of MnSOD by LPS, and (2) while
      activation of NFkappaB alone is insufficient for the induction of TNFalpha mRNA
      by LPS, it is necessary for the induction of TNFalpha as well as MnSOD mRNAs.

PMID- 10653607
TI  - Nitric oxide induces dose-dependent CA(2+) transients and causes temporal
      morphological hyperpolarization in human neutrophils.
AB  - We exposed adherent neutrophils to the nitric oxide (NO)-radical donors S-nitroso
      N-acetylpenicillamine (SNAP), S-nitrosoglutathione (GSNO), and sodium
      nitroprusside (SNP) to study the role of NO in morphology and Ca(2+) signaling.
      Parallel to video imaging of cell morphology and migration in neutrophils,
      changes in intracellular free Ca(2+) ([Ca(2+)](i)) were assessed by ratio imaging
      of Fura-2. NO induced a rapid and persistent morphological hyperpolarization
      followed by migrational arrest that usually lasted throughout the 10-min
      experiments. Addition of 0.5-800 microM SNAP caused concentration-dependent
      elevation of [Ca(2+)](i) with an optimal effect at 50 microM. This was probably
      induced by NO itself, because no change in [Ca(2+)](i) was observed after
      treatment with NO donor byproducts, i.e. D-penicillamine, glutathione, or
      potassium cyanide. Increasing doses of SNAP (>/=200 microM) attenuated the Ca(2+)
      response to the soluble chemotactic stimulus formyl-methionyl-leucyl
      phenylalanine (fMLP), and both NO- and fMLP-induced Ca(2+) transients were
      abolished at 800 microM SNAP or more. In kinetic studies of fluorescently labeled
      actin cytoskeleton, NO markedly reduced the F-actin content and profoundly
      increased cell area. Immunoblotting to investigate the formation of nitrotyrosine
      residues in cells exposed to NO donors did not imply nitrosylation, nor could we
      mimic the effects of NO with the cell permeant form of cGMP, i.e., 8-Br-cGMP.
      Hence these processes were probably not the principal NO targets. In summary, NO
      donors initially increased neutrophil morphological alterations, presumably due
      to an increase in [Ca(2+)](i), and thereafter inhibited such shape changes. Our
      observations demonstrate that the effects of NO donors are important for
      regulation of cellular signaling, i.e., Ca(2+) homeostasis, and also affect cell
      migration, e.g., through effects on F-actin turnover. Our results are discussed
      in relation to the complex mechanisms that govern basic cell shape changes,
      required for migration.

PMID- 10653606
TI  - 24R,25-(OH)(2)D(3) mediates its membrane receptor-dependent effects on protein
      kinase C and alkaline phosphatase via phospholipase A(2) and cyclooxygenase-1 but
      not cyclooxygenase-2 in growth plate chondrocytes.
AB  - Recent studies have shown that 24R,25-(OH)(2)D(3) mediates its effects on growth
      plate chondrocytes via membrane receptors. This study examined the roles of
      phospholipase A(2) (PLA(2)) and cyclooxygenase (Cox) in the mechanism of action
      of 24R, 25-(OH)(2)D(3) in resting zone chondrocytes in order to determine whether
      the activity of one or both enzymes provides a regulatory checkpoint in the
      signaling pathway resulting in increased protein kinase C (PKC) activity. We also
      determined whether constitutive or inducible Cox is involved. Cultures were
      incubated with 24R, 25-(OH)(2)D(3) for 90 min to measure PKC or for 24 h to
      measure physiological responses ([(3)H]-thymidine incorporation, alkaline
      phosphatase-specific activity, [(35)S]-sulfate incorporation). Based on RT-PCR
      and Northern blot analysis, resting zone chondrocytes express mRNAs for both Cox
      1 and Cox-2. Levels of mRNA for both proteins were unchanged from control levels
      after a 24-h incubation with 24R,25-(OH)(2)D(3). To examine the role of Cox, the
      cultures were also treated with resveratrol (a specific inhibitor of Cox-1), NS
      398 (a specific inhibitor of Cox-2), or indomethacin (a general Cox inhibitor).
      Cox-1 inhibition resulted in effects on proliferation, differentiation, and
      matrix production typical of 24R, 25-(OH)(2)D(3). In contrast, inhibition of Cox
      2 had no effect, indicating that 24R,25-(OH)(2)D(3) exerts its effects via Cox-1.
      Inhibition of Cox-1 also blocked 24R,25-(OH)(2)D(3)-dependent increases in PKC.
      Activation of PLA(2) with melittin inhibited 24R, 25-(OH)(2)D(3)-dependent
      stimulation of PKC, and inhibition of PLA(2) with quinacrine stimulated PKC in
      response to 24R, 25-(OH)(2)D(3). Inclusion of resveratrol reduced the melittin
      dependent inhibition of PLA(2) and caused an increase in quinacrine-stimulated
      PLA(2) activity. Metabolism of arachidonic acid to leukotrienes is not involved
      in the response to 24R, 25-(OH)(2)D(3) because inhibition of lipoxygenase had no
      effect. The effect of 24R,25-(OH)(2)D(3) was specific because 24S,25-(OH)(2)D(3),
      the biologically inactive stereoisomer, failed to elicit a response from the
      cells. These results support the hypothesis that 24R, 25-(OH)(2)D(3) exerts its
      effects via more than one signaling pathway and that these pathways are
      interrelated via the modulation of PLA(2). PKC regulation may occur at multiple
      stages in the signal transduction cascade.

PMID- 10653608
TI  - The levels and kinetics of oxygen tension detectable at the surface of human
      dermal fibroblast cultures.
AB  - Low oxygen tension has recently been shown to stimulate cell growth and clonal
      expansion, as well as synthesis and transcription of certain growth factors and
      extracellular matrix components. These results have been obtained by exposing
      cell cultures to a hypoxic environment. Using an oxygen probe, we have now
      studied how experimental conditions affect the oxygen tension detectable at the
      cell surface. Dissolved oxygen tension was directly related to the height of the
      medium above the cell surface (r = 0.8793, P = 0.021), but was constant when no
      cells were present in the flask (r = -0. 9732, P = 0.001). In both human dermal
      fibroblasts and NIH/3T3 cultures, oxygen tension decreased linearly as cell
      density increased (r = -0.835, P < 0.0001; r = -0.916, P < 0.0001, respectively).
      When human dermal fibroblasts were exposed to 2% O(2), maximum hypoxic levels (0
      mmHg) were achieved within approximately 15 min, and the recovery time was within
      a similar time frame. The addition of rotenone, an inhibitor of cellular
      respiration, blocked this decrease in oxygen tension at the cell surface,
      suggesting that cellular consumption of oxygen is responsible for the decline.
      Finally, we examined the cell-surface oxygen tension in control and acutely
      wounded human skin equivalents (HSE), consisting of a keratinocyte layer over a
      type I collagen matrix containing fibroblasts. We found that oxygen tension
      dropped significantly (P < 0.0001) in acutely wounded areas of HSE as compared to
      unwounded areas of HSE and that this drop was prevented by the addition of
      mitomycin C. These results indicate that cell-surface oxygen tension is
      indirectly related to cell density, and that the amount of detectable oxygen at
      the cell surface is a function of cell density, the oxygen tension in the
      incubator, and increased cellular activity, as occurs after injury.

PMID- 10653609
TI  - Participation of type II protein kinase A in the retinoic acid-induced growth
      inhibition of SH-SY5Y human neuroblastoma cells.
AB  - To examine the role of protein kinase A (EC 2.7.1.37) isozymes in the retinoic
      acid-induced growth inhibition and neuronal differentiation, we investigated the
      changes of protein kinase A isozyme patterns in retinoic acid-treated SH-SY5Y
      human neuroblastoma cells. Retinoic acid induced growth inhibition and neuronal
      differentiation of SH-SY5Y cells in a dose- and time-dependent manner. Neuronal
      differentiation was evidenced by extensive neurite outgrowth, decrease of N-Myc
      oncoprotein, and increase of GAP-43 mRNA. Type II protein kinase A activity
      increased by 1.5-fold in differentiated SH-SY5Y cells by retinoic acid treatment.
      The increase of type II protein kinase A was due to the increase of RIIbeta and
      Calpha subunits. Since type II protein kinase A and RIIbeta have been known to
      play important role(s) in the growth inhibition and differentiation of cancer
      cells, we further investigated the role of the increased type II protein kinase A
      by overexpressing RIIbeta in SH-SY5Y cells. The growth of RIIbeta-overexpressing
      cells was slower than that of parental cells, being comparable to that of
      retinoic acid-treated cells. Retinoic acid treatment further increased the
      RIIbeta level and further inhibited the growth of RIIbeta-overexpressing cells,
      showing strong correlation between the level of RIIbeta and growth inhibition.
      However, RIIbeta-overexpressing cells did not show any sign of neuronal
      differentiation and responded to retinoic acid in the same way as parental cells.
      These data suggest that protein kinase A participates in the retinoic acid
      induced growth inhibition through the up-regulation of RIIbeta/type II protein
      kinase A.

PMID- 10653610
TI  - Effect of aging on the mechanisms of PTH-induced calcium influx in rat intestinal
      cells.
AB  - We have investigated the effects of aging on parathyroid hormone (PTH) modulation
      of intracellular calcium homeostasis and their relationship to signal
      transduction pathways in isolated rat duodenal cells (enterocytes). PTH (10(-8)
      10(-9) M) increased enterocyte (45)Ca(2+) influx and intracellular Ca(2+)
      concentration ([Ca(2+)](i)) to a greater extent (twofold and 50%, respectively)
      in aged (24 months) than in young (3 months) animals. The [Ca(2+)](i) response of
      old cells to the hormone was slower, lacking the early phase of changes in
      cytosolic Ca(2+). Ca(2+) influx induced by PTH was prevented by the protein
      kinase A antagonist Rp-cAMPS in both young and aged enterocytes, whereas neomycin
      and compound U73122, inhibitors of PLC-catalyzed phosphoinositide hydrolysis,
      abolished hormone-dependent Ca(2+) influx in young but had no effect on aged
      cells. Higher basal adenylyl cyclase (AC) activity and cAMP content were detected
      in old enterocytes. PTH increased the absolute levels of cAMP in aged cells and
      AC activity of microsomes isolated therefrom to a greater extent (>/= twofold)
      than in young enterocytes/membranes. In young cells, the hormone also induced a
      rapid and transient release of inositoltrisphosphate (IP(3)) and diacylglycerol
      (neomycin-sensitive) at 45 sec, and a delayed phase of DAG at 5 min (neomycin
      insensitive). The early formation of IP(3) and DAG was blunted in aged animals.
      These results suggest that both the PLC and adenylyl cyclase cascades are
      involved in PTH stimulation of Ca(2+) influx in duodenal cells. During aging,
      however, only the cAMP pathway is operative, mediating a potentiation of the
      effects of the hormone. Additional studies are required to establish the relative
      role of PTH-dependent messenger systems in the regulation of intestinal calcium
      absorption and age-related abnormalities.

PMID- 10653611
TI  - Agonist-induced changes in cell shape during regulated secretion in rat
      pancreatic acini.
AB  - The actin cytoskeleton plays an important role in the mediation of exocytosis and
      the determination of cell shape. Experimentally induced changes in cell shape
      have been shown to affect stimulated secretion in pancreatic acini. In this
      study, we have examined whether physiologic agonists induce changes in acinar
      cell shape to modulate secretion. Computer-enhanced video microscopy,
      immunofluorescence confocal microscopy, and quantitative Western blotting were
      used to study cell shape changes and cytoskeletal dynamics in rat pancreatic
      acini. Amylase assays were performed to study the effect of the actin-myosin
      cytoskeletal antagonists latrunculin A, BDM, and ML-9 on secretion. We found that
      pancreatic acini underwent a prominent and reversible shape change in response to
      the physiologic secretory agonist cholecystokinin. This was accompanied by an
      apical activation of myosin II as well as a basolateral redistribution of both
      actin and myosin II. Cytoskeletal antagonists inhibited this shape change and
      attenuated stimulated amylase secretion. Therefore, in addition to acting as a
      barrier at the apex, the actin-myosin cytoskeleton may also function to modulate
      cell shape to further regulate stimulated secretion.

PMID- 10653612
TI  - Radical psychology institutionalized: a history of the Journal Psychologie &
      Maatschappij [psychology & society].
AB  - Starting out as a newsletter for radical psychologists, the Dutch journal
      Psychologie & Maatschappij (Psychology & Society) moved in the past decade toward
      the theoretical mainstream within psychology. In this paper, the major changes in
      the journal are described and analyzed, as well as the features that did not
      change: an emphasis on theory and history, an interdisciplinary approach, and an
      emphasis on discussion. The main transformations were from psychology as
      instrumental toward the goals of the progressive movement in the Netherlands,
      then to extreme criticism of all scientific and professional psychological
      activities, and finally to adherence to the most advanced approaches within
      academic psychology.

PMID- 10653613
TI  - The Harvard study of values: mirror for postwar anthropology.
AB  - In 1949, social scientists at Harvard University began a long-range,
      multidisciplinary research project called the Comparative Study of Values in Five
      Cultures. The topic of values had been hotly debated since the 1920s, a debate
      that was renewed with vigor in the postwar period. When Clyde Kluckhohn, an
      anthropologist well known for his work among the Navajos, designed the Values
      Study research, he thus focused on a topic of much interest. This essay describes
      how this little-known project had roots in the debate on values and cut a
      trajectory through a quickly changing intellectual environment.

PMID- 10653615
TI  - Briefly noted

PMID- 10653614
TI  - Gestalt psychology in Italy.
AB  - Graz gestalt psychology was introduced into Italy after World War I with Vittorio
      Benussi's emigration to Padua. His earliest adherent, Cesare Musatti, defended
      Graz theory, but after Benussi's premature death became an adherent of the Berlin
      gestalt psychology of Wertheimer-Kohler-Koffka. He trained his two most important
      students, Fabio Metelli and Gaetano Kanizsa, in orthodox Berlin theory. They
      established rigid "schools" in Padua and Trieste. The structure of Italian
      academics allowed for such strict orthodoxy, quite unlike the situation in
      America, where scientific objectivity mitigated against schools. In the 1960s,
      some of the students of Metelli and Kanizsa (above all Bozzi) initiated a realist
      movement-felt in Kanizsa's late work-that was quite independent of that of J. J.
      Gibson. Finally, more recently, Benussi and Graz theorizing have been embraced
      again, sentimentally, as a predecedent to Kanizsa-Bozzi.

PMID- 10653616
TI  - News and notes

PMID- 10653617
TI  - Low stray ELF magnetic field exposure system for in vitro study.
AB  - An exposure facility for wide application to cell exposure to an ELF (extremely
      low frequency) magnetic field was developed. It is suitable for conducting
      experiments under a high-intensity, variable-frequency magnetic field, on the
      biological effects of the ELF magnetic field in an in vitro study. The exposure
      system consists of Merritt's 4-square coil as a basic component to generate the
      required magnetic field intensity of 10 mT at 50 Hz with spatial field uniformity
      less than +/-3% in a 400 mm cube. Concentric compensation coils are adopted to
      eliminate the effects of stray fields on sham (control) samples in the vicinity
      of the exposure system. The uniformity of the magnetic field in the exposure
      coil, the increase in the power supply capacity due to the existence of
      compensation coils, and the stray field estimation were investigated carefully.
      After fabricating the system, performance tests were carried out and all the
      characteristics were found to be satisfactory. In addition, the ideal
      configuration for a concentric coil system was proposed.

PMID- 10653618
TI  - Evaluation of the potential promoting effect of 60 Hz magnetic fields on N-ethyl
      N-nitrosourea induced neurogenic tumors in female F344 rats.
AB  - The present study investigated the possible effect of 60 Hz magnetic fields (MFs)
      as promoters of neurogenic tumors initiated transplacentally by a chemical
      carcinogen, N-ethyl-N-nitrosourea (ENU). In a preliminary study, 5 mg of ENU was
      shown to induce 30 to 40% neurogenic tumors in F344 rats offspring after 420 days
      of observation. In the present study, 400 female rats were divided into eight
      different groups (50 animals/group) and exposed in utero (on day 18 of gestation)
      to a single intravenous dose of either Saline (Group I), or ENU, 5 mg/kg (Group
      II to VIII). Dams in group II were given no further treatment while dams in
      Groups III to VII were exposed to 5 different intensities of MFs forty eight
      hours later. Animals in group III were sham exposed (<0.02 microT) while groups
      IV to VII were exposed to 2, 20, 200, and 2000 microT, respectively. Dams in
      Group VIII were injected intraperitoneally with 12-O-tetradecanoylphrobol-13
      acetate (TPA; 10 micrograms/kg) from day 19 until delivery, and then their female
      offspring continued to be injected every 15 days, starting at day 14 after birth
      until sacrifice (positive controls). Accordingly, this study included three
      different types of controls: Internal controls (Groups II and III) and positive
      control (Group VIII). Body weight, mortality and clinical observations were
      evaluated in all groups of animals during in-life exposure. Necropsy was
      performed on all exposed and control animals that died, were found moribund or
      sacrificed at termination of the study. Histopathological evaluation was done for
      all brains, spinal cords, cranial nerves, major organs (lungs, liver, spleen,
      kidneys, pituitary, thyroid and adrenals) and all gross lesions observed during
      necropsy. All clinical observations and pathological evaluations were conducted
      under "blinded" conditions. The findings from this ENU/MFs promotion study
      clearly demonstrate that, under our defined experimental conditions, exposure to
      60 Hz linear (single axis) sinusoidal, continuous wave MFs had no effect on the
      survival of female F344 rats or on the number of animals bearing neurogenic
      tumors. These results suggest that MFs have no promoting effect on neurogenic
      tumors in the female F344 rats exposed transplacentally to ENU.

PMID- 10653619
TI  - Changes in paroxysmal brainwave patterns of epileptics by weak-field magnetic
      stimulation.
AB  - In order to assess the effects of weak-field magnetic stimulation on brain
      electrical activity in epileptics, three patients suffering from mesial temporal
      lobe epilepsy (MTLE) were exposed to DC magnetic fields of 0.9 and 1.8 millitesla
      (mT). The EEG activity was recorded simultaneously from intracranial electrodes
      inserted through the foramen ovale (FO) and scalp electrodes. Significant
      enhancement of interictal epileptiform activity was observed in two patients,
      while in one patient, magnetic stimulation resulted in the cessation of
      interictal spike/wave trains.

PMID- 10653620
TI  - Electromagnetic fields enhance the stress response at elevated temperatures in
      the nematode Caenorhabditis elegans.
AB  - We have studied the effect of extremely low frequency electromagnetic fields (ELF
      EMF) in the presence of a second stressor (mild heat shock) on the expression of
      a lacZ reporter gene under the control of hsp16 or hsp70 promoters in two
      transgenic strains of C. elegans. The expression of the reporter gene was studied
      by scoring animals with induced beta-galactosidase activity after staining in
      toto or by biochemical quantitation of the enzyme activity, respectively. In our
      experimental setup we were able to expose the animals to 50 Hz magnetic flux
      density of 0-150 microT and at the same time control temperature with high
      precision (+/-0.1 degrees C). Experimental conditions were defined for which EMF
      strongly enhances the expression of the reporter gene.

PMID- 10653621
TI  - Effects of 100 mT time varying magnetic fields on the growth of tumors in mice.
AB  - The effects of 100-mT, 0.8-Hz square-wave magnetic fields on the growth of
      chemically induced tumors in mice were investigated. Tumors were initiated using
      one injection of benzo(a)pyrene (either 0.2 mg or 2.0 mg/animal). Male and female
      mice (Balb/c, C3H and C57/bl/6 strains) were exposed for 8 h/day from the onset
      of tumor until death or until the tumor volume reached a predetermined volume.
      Statistically significant decrease in the rate of tumor growth and increase in
      survival were observed in all cases. Results are discussed in terms of previous
      published work and of possible mechanisms.

PMID- 10653622
TI  - Effects of PEMF on a murine osteosarcoma cell line: drug-resistant (P
      glycoprotein-positive) and non-resistant cells.
AB  - After pulsed exposure of Dunn osteosarcoma cells (nonresistant cells) to
      Adriamycin (ADR) at increasing concentrations and single-cell cloning of
      surviving cells, ADR-resistant cells were obtained. These resistant cells
      expressed P-glycoprotein and had resistance more than 10 times that of their
      nonresistant parent cells. Compared to the nonresistant cells not exposed to
      pulsing electromagnetic fields (PEMF) in ADR-free medium, their growth rates at
      ADR concentrations of 0.01 and 0.02 micrograms/ml, which were below IC50, were
      83.0% and 61.8%, respectively. On the other hand, in the nonresistant cells
      exposed to PEMF (repetition frequency, 10 Hz; rise time, 25 microsec, peak
      magnetic field intensity, 0.4-0.8 mT), the growth rate was 111.9% in ADR-free
      medium, 95.5% at an ADR concentration of 0.01 micrograms/ml, and 92.2% at an ADR
      concentration of 0.02 micrograms/ml. This promotion of growth by PEMF is
      considered to be a result of mobilization of cells in the non-proliferative
      period of the cell cycle due to exposure to PEMF. However, at ADR concentrations
      above the IC50, the growth rate tended to decrease in the cells not exposed to
      PEMF. This may be caused by an increase in cells sensitive to ADR resulting from
      mobilization of cells in the non-proliferative period to the cell cycle. The
      growth rate in the resistant cells exposed to PEMF was significantly lower than
      that in the non-exposed resistant cells at all ADR concentrations, including ADR
      free culture (P</=0.0114). Therefore, this study suggests that PEMF promotes the
      growth of undifferentiated cells but progressively suppresses the growth of more
      differentiated cells, i.e., PEMF controls cell growth depending on the degree of
      cell differentiation. This study also shows the potentiality of PEMF as an
      adjunctive treatment method for malignant tumors.

PMID- 10653623
TI  - Possible cocarcinogenic effects of ELF electromagnetic fields may require
      repeated long-term interaction with known carcinogenic factors.
AB  - Literature on cancer-related biological effects of extremely low frequency (ELF)
      magnetic fields (MF) is discussed in the light of the current understanding of
      carcinogenesis as a multistep process of accumulating mutations. Different animal
      models and study designs have been used to address possible cocarcinogenic
      effects of MFs. Based on a comparison of the results, we propose a hypothesis
      that MF exposure may potentiate the effects of known carcinogens only when both
      exposures are chronic. We also discuss possible mechanisms of MF effects on
      carcinogenesis and the adequacy of the classical two-step initiation/promotion
      animal experiments for simulating human exposure to the complex mixture of
      environmental carcinogens. We conclude that experiments designed according to the
      two-step concept may not be sufficient for studying the possible role of MF in
      carcinogenesis. Possible further animal studies are more likely to be productive
      if they include models that combine chronic exposure to MFs with long-term
      exposures to known carcinogens.

PMID- 10653624
TI  - Morphologic responses of osteoblast-like cells in monolayer culture to ELF
      electromagnetic fields.
AB  - Osteoblast-like cells (MC 3T3-E1) were exposed for 24 h, immediately after
      plating, to a 60 Hz, 0.7 mT rms magnetic flux density, sufficient to induce an
      electric field of 0.5 mV/m rms, in order to investigate the influence of ELF
      field exposure on cell morphology. Using phase contrast images of the live cells,
      computerized image-analysis permitted rapid and objective quantification of cell
      length, width, area, perimeter, circularity and angular orientation. While the
      field-exposed cells were consistently smaller than sham treated cells, the
      morphologic alterations were not significantly different in the exposed cell
      population when cell orientation was not considered. When analyzed with respect
      to cell orientation, cells oriented parallel to the induced electric field
      (orthogonal to the applied magnetic field) demonstrated a significant decrease in
      cell length and an increase in roundness. These results confirm and extend
      previous studies on the morphologic adaptation of cells to low level ELF
      electromagnetic fields. The results suggest that the observed responses most
      likely depend on the induced electric field, with a field intensity threshold
      well below 1 mV/m. Further, these results provide important clues to the specific
      mechanism by which such low level fields may be capable of influencing cell
      behavior, and help to explain some of the difficulties in obtaining robust
      responses in in vitro EMF experiments.

PMID- 10653625
TI  - The arithmetic mean of ratio-normalized experiments overestimates the true E/C
      ratio.
AB  - Biological assays often suffer from large systematic variation between sets of
      experiments. This variation is sometimes countered by normalizing the results of
      an "exposed" (E) experiment to that of a simultaneously performed "control" (C).
      We demonstrate that the arithmetic mean of such ratios overestimates the "true"
      E/C ratio. Fortunately, the overestimation may be calculated from experimentally
      accessible information, and it is generally possible to correct for this factor
      using formulas presented in this paper. We have studied the impact of this effect
      on a set of studies in the bioelectromagnetics literature and find that, although
      most results are weakened by the correction, few are significantly altered. Some
      of the papers used for our literature study are controversial; we believe that
      the present study may strengthen the quoted results by removing doubts about the
      statistical treatment of E/C ratios. Both false positives and negatives are
      possible if the proper correction is not made to the arithmetic mean of a set of
      E/C data. Realistic examples of erroneous statistical conclusions demonstrate
      that this is a real concern for E/C data which are marginal in both magnitude
      (mean < 2) and variance (standard deviation > 0.5).

PMID- 10653626
TI  - DC-ELF characterization of random mixtures of piecewise nonlinear media.
AB  - Biological tissues are ensembles of linear and nonlinear, symmetric and
      asymmetric constituents. As far as their electromagnetic characterization is
      concerned, they can be modeled as microscopic mixtures of the corresponding
      material media. Any medium volume can be properly discretized in a finite number
      of cells which can be modeled as an equivalent three dimensional network of
      lumped components, in order to characterize its electromagnetic behavior at
      wavelengths much longer than the relevant average linear size of the constitutive
      cells. Therefore, any mixture and the corresponding tissue can be characterized
      in terms of its effective conductance at extremely low frequency, with respect to
      a reference set of electrodes (ports of the equivalent network). When the above
      procedure is implemented for evaluating any of the aforesaid conductances, a
      resulting nonlinear characteristic should be expected. In reality, it may happen
      that the effect of the constitutive nonlinearities and the related asymmetries
      are smeared out by the randomness of the interconnections of the lumped
      components, leading at a macroscopic level to an isotropic constant equivalent
      conductance, i.e., to an isotropic constant equivalent conductivity of the
      mixture. The closed form analysis of a random network of nonlinear (piecewise
      linear) resistors offers a simple but clear cut example of such a property. This
      result, if extrapolated to biological media, suggests a new hint for explaining
      why there is no inconsistency between the typical electric characterization of
      biological tissues as almost linear macroscopic media, by means of their
      effective conductivity and permittivity, and the nonlinearities of the
      biochemical processes occurring in the tissue cells. In fact, the nonlinearities
      may not be observable by means of macroscopic electrical measurements because of
      the randomized spatial orientation and location of the processes.

PMID- 10653627
TI  - The effect of sterol structure on membrane lipid domains reveals how cholesterol
      can induce lipid domain formation.
AB  - Detergent-insoluble membrane domains, enriched in saturated lipids and
      cholesterol, have been implicated in numerous biological functions. To understand
      how cholesterol promotes domain formation, the effect of various sterols and
      sterol derivatives on domain formation in mixtures of the saturated lipid
      dipalmitoylphosphatidylcholine (DPPC) and a fluorescence quenching analogue of an
      unsaturated lipid was compared. Quenching measurements demonstrated that several
      sterols (cholesterol, dihydrocholesterol, epicholesterol, and 25
      hydroxycholesterol) promote formation of DPPC-enriched domains. Other sterols and
      sterol derivatives had little effect on domain formation (cholestane and
      lanosterol) or, surprisingly, strongly inhibit it (coprostanol, androstenol,
      cholesterol sulfate, and 4-cholestenone). The effect of sterols on domain
      formation was closely correlated with their effects on DPPC insolubility. Those
      sterols that promoted domain formation increased DPPC insolubility, whereas those
      sterols that inhibit domain formation decreased DPPC insolubility. The effects of
      sterols on the fluorescence polarization of diphenylhexatriene incorporated into
      DPPC-containing vesicles were also correlated with sterol structure. These
      experiments indicate that the effect of sterol on the ability of saturated lipids
      to form a tightly packed (i.e., tight in the sense that the lipids are closely
      packed with one another) and ordered state is the key to their effect on domain
      formation. Those sterols that promote tight packing of saturated lipids promote
      domain formation, while those sterols that inhibited tight packing of saturated
      lipids inhibited domain formation. The ability of some sterols to inhibit domain
      formation (i.e., act as "anti-cholesterols") should be a valuable tool for
      examining domain formation and properties in cells.

PMID- 10653628
TI  - Replication protein A interactions with DNA. III. Molecular basis of recognition
      of damaged DNA.
AB  - Human replication protein A (RPA) is a heterotrimeric single-stranded DNA-binding
      protein (subunits of 70, 32, and 14 kDa) that is required for cellular DNA
      metabolism. RPA has been reported to interact specifically with damaged double
      stranded DNA and to participate in multiple steps of nucleotide excision repair
      (NER) including the damage recognition step. We have examined the mechanism of
      RPA binding to both single-stranded and double-stranded DNA (ssDNA and dsDNA,
      respectively) containing damage. We show that the affinity of RPA for damaged
      dsDNA correlated with disruption of the double helix by the damaged bases and
      required RPAs ssDNA-binding activity. We conclude that RPA is recognizing single
      stranded character caused by the damaged nucleotides. We also show that RPA binds
      specifically to damaged ssDNA. The specificity of binding varies with the type of
      damage with RPA having up to a 60-fold preference for a pyrimidine(6-4)pyrimidone
      photoproduct. We show that this specific binding was absolutely dependent on the
      zinc-finger domain in the C-terminus of the 70-kDa subunit. The affinity of RPA
      for damaged ssDNA was 5 orders of magnitude higher than that of the damage
      recognition protein XPA (xeroderma pigmentosum group A protein). These findings
      suggest that RPA probably binds to both damaged and undamaged strands in the NER
      excision complex. RPA binding may be important for efficient excision of damaged
      DNA in NER.

PMID- 10653629
TI  - Beta-sheet proteins with nearly identical structures have different folding
      intermediates.
AB  - The folding mechanisms of two proteins in the family of intracellular lipid
      binding proteins, ileal lipid binding protein (ILBP) and intestinal fatty acid
      binding protein (IFABP), were examined. The structures of these all-beta-proteins
      are very similar, with 123 of the 127 amino acids of ILBP having backbone and
      C(beta) conformations nearly identical to those of 123 of the 131 residues of
      IFABP. Despite this structural similarity, the sequences of these proteins have
      diverged, with 23% sequence identity and an additional 16% sequence similarity.
      The folding process was completely reversible, and no significant concentrations
      of intermediates were observed by circular dichroism or fluorescence at
      equilibrium for either protein. ILBP was less stable than IFABP with a midpoint
      of 2. 9 M urea compared to 4.0 M urea for IFABP. Stopped-flow kinetic studies
      showed that both the folding and unfolding of these proteins were not monophasic,
      suggesting that either multiple paths or intermediate states were present during
      these processes. Proline isomerization is unlikely to be the cause of the
      multiphasic kinetics. ILBP had an intermediate state with molten globule-like
      spectral properties, whereas IFABP had an intermediate state with little if any
      secondary structure during folding and unfolding. Double-jump experiments showed
      that these intermediates appear to be on the folding path for each protein. The
      folding mechanisms of these proteins were markedly different, suggesting that the
      different sequences of these two proteins dictate different paths through the
      folding landscape to the same final structure.

PMID- 10653630
TI  - Rational modification of protein stability by the mutation of charged surface
      residues.
AB  - Continuum methods were used to calculate the electrostatic contributions of
      charged and polar side chains to the overall stability of a small 41-residue
      helical protein, the peripheral subunit-binding domain. The results of these
      calculations suggest several residues that are destabilizing, relative to
      hydrophobic isosteres. One position was chosen to test the results of these
      calculations. Arg8 is located on the surface of the protein in a region of
      positive electrostatic potential. The calculations suggest that Arg8 makes a
      significant, unfavorable electrostatic contribution to the overall stability. The
      experiments described in this paper represent the first direct experimental test
      of the theoretical methods, taking advantage of solid-phase peptide synthesis to
      incorporate approximately isosteric amino acid substitutions. Arg8 was replaced
      with norleucine (Nle), an amino acid that is hydrophobic and approximately
      isosteric, or with alpha-amino adipic acid (Aad), which is also approximately
      isosteric but oppositely charged. In this manner, it is possible to isolate
      electrostatic interactions from the effects of hydrophobic and van der Waals
      interactions. Both Arg8Nle and Arg8Aad are more thermostable than the wild-type
      sequence, testifying to the validity of the calculations. These replacements led
      to stability increases at 52.6 degrees C, the T(m) of the wild-type, of 0.86 and
      1.08 kcal mol(-)(1), respectively. The stability of Arg8Nle is particularly
      interesting as a rare case in which replacement of a surface charge with a
      hydrophobic residue leads to an increase in the stability of the protein.

PMID- 10653631
TI  - Improving the catalytic activity of a thermophilic enzyme at low temperatures.
AB  - Enzymes from thermophilic organisms often are barely active at low temperatures.
      To obtain a better understanding of this sluggishness, we used DNA shuffling to
      mutagenize the trpC gene, which encodes indoleglycerol phosphate synthase, from
      the hyperthermophile Sulfolobus solfataricus. Mutants producing more active
      protein variants were selected by genetic complementation of an Escherichia coli
      mutant bearing a trpC deletion. Single amino acid changes and combinations of
      these changes improved growth appreciably. Five singly and doubly altered protein
      variants with changes at the N- and C-termini, or at the phosphate binding site,
      were purified and characterized with regard to their kinetics of enzymatic
      catalysis, product binding, cleavage by trypsin, and inactivation by heat.
      Turnover numbers of the purified variant proteins correlated with the
      corresponding growth rates, showing that the turnover number was the selected
      trait. Although the affinities for both the substrate and the product decreased
      appreciably in most protein variants, these defects were offset by the
      accumulation of high levels of the enzyme's substrate. Rapid mixing of the
      product indoleglycerol phosphate with the parental enzyme revealed that the
      enzyme's turnover number at low temperatures is limited by the dissociation of
      the enzyme-product complex. In contrast, representative protein variants bind and
      release the product far more rapidly, shifting the bottleneck to the preceding
      chemical step. The turnover number of the parental enzyme increases with
      temperature, suggesting that its structural rigidity is responsible for its poor
      catalytic activity at low temperatures. In support of this interpretation, the
      rate of trypsinolysis or of thermal denaturation is accelerated significantly in
      the activated protein variants.

PMID- 10653633
TI  - Asp-99 donates a hydrogen bond not to Tyr-14 but to the steroid directly in the
      catalytic mechanism of Delta 5-3-ketosteroid isomerase from Pseudomonas putida
      biotype B.
AB  - Delta 5-3-ketosteroid isomerase (KSI) catalyzes the allylic isomerization of
      Delta 5-3-ketosteroids at a rate approaching the diffusion limit by an
      intramolecular transfer of a proton. Despite the extensive studies on the
      catalytic mechanism, it still remains controversial whether the catalytic residue
      Asp-99 donates a hydrogen bond to the steroid or to Tyr-14. To clarify the role
      of Asp-99 in the catalysis, two single mutants of D99E and D99L and three double
      mutants of Y14F/D99E, Y14F/D99N, and Y14F/D99L have been prepared by site
      directed mutagenesis. The D99E mutant whose side chain at position 99 is longer
      by an additional methylene group exhibits nearly the same kcat as the wild-type
      while the D99L mutant exhibits ca. 125-fold lower kcat than that of the wild
      type. The mutations made at positions 14 and 99 exert synergistic or partially
      additive effect on kcat in the double mutants, which is inconsistent with the
      mechanism based on the hydrogen-bonded catalytic dyad, Asp-99 COOH...Tyr-14
      OH...C3-O of the steroid. The crystal structure of D99E/D38N complexed with
      equilenin, an intermediate analogue, at 1.9 A resolution reveals that the
      distance between Tyr-14 O eta and Glu-99 O epsilon is ca. 4.2 A, which is beyond
      the range for a hydrogen bond, and that the distance between Glu-99 O epsilon and
      C3-O of the steroid is maintained to be ca. 2.4 A, short enough for a hydrogen
      bond to be formed. Taken together, these results strongly support the idea that
      Asp-99 contributes to the catalysis by donating a hydrogen bond directly to the
      intermediate.

PMID- 10653632
TI  - Dissection of malonyl-coenzyme A decarboxylation from polyketide formation in the
      reaction mechanism of a plant polyketide synthase.
AB  - Chalcone synthase (CHS) catalyzes formation of the phenylpropanoid chalcone from
      one p-coumaroyl-CoA and three malonyl-coenzyme A (CoA) thioesters. The three
      dimensional structure of CHS [Ferrer, J.-L., Jez, J. M., Bowman, M. E., Dixon, R.
      A., and Noel, J. P. (1999) Nat. Struct. Biol. 6, 775-784] suggests that four
      residues (Cys164, Phe215, His303, and Asn336) participate in the multiple
      decarboxylation and condensation reactions catalyzed by this enzyme. Here, we
      functionally characterize 16 point mutants of these residues for chalcone
      production, malonyl-CoA decarboxylation, and the ability to bind CoA and acetyl
      CoA. Our results confirm Cys164's role as the active-site nucleophile in
      polyketide formation and elucidate the importance of His303 and Asn336 in the
      malonyl-CoA decarboxylation reaction. We suggest that Phe215 may help orient
      substrates at the active site during elongation of the polyketide intermediate.
      To better understand the structure-function relationships in some of these
      mutants, we also determined the crystal structures of the CHS C164A, H303Q, and
      N336A mutants refined to 1.69, 2.0, and 2.15 A resolution, respectively. The
      structure of the C164A mutant reveals that the proposed oxyanion hole formed by
      His303 and Asn336 remains undisturbed, allowing this mutant to catalyze malonyl
      CoA decarboxylation without chalcone formation. The structures of the H303Q and
      N336A mutants support the importance of His303 and Asn336 in polarizing the
      thioester carbonyl of malonyl-CoA during the decarboxylation reaction. In
      addition, both of these residues may also participate in stabilizing the
      tetrahedral transition state during polyketide elongation. Conservation of the
      catalytic functions of the active-site residues may occur across a wide variety
      of condensing enzymes, including other polyketide and fatty acid synthases.

PMID- 10653635
TI  - Roles of histidine 784 and tyrosine 639 in ribose discrimination by T7 RNA
      polymerase.
AB  - On the basis of their recently described T7 RNA polymerase-T7 promoter crystal
      structure, Cheetham et al. [(1999) Nature 399, 80] propose that discrimination of
      the hydrogen bonding character of the elongating NTP ribose 2'-substituent
      involves a hydrogen bond to histidine 784. This would contradict a previous
      conclusion, based on the characterization of mutant RNAPs, that discrimination of
      the hydrogen bonding character of the ribose 2'-substituent depends solely on the
      hydroxyl group of tyrosine 639. To resolve this point, we prepared and
      characterized histidine 784 point mutants. We find that while these mutations
      reduce the activity of the polymerase, they do not significantly reduce the level
      of ribose discrimination. Furthermore, a mutant with alanine at position 784
      preferentially utilizes NTPs with 2'-substituents capable of acting as hydrogen
      bond donors or acceptors (2'-OH and 2'-NH(2)) over NTPs with substituents that
      lack such properties (2'-F and 2'-H). In contrast, mutation of tyrosine 639 to
      phenylalanine eliminates discrimination of ribose 2'-group hydrogen bonding
      character. The effects on ribose discrimination of mutating tyrosine 639 to
      phenylalanine are independent of the side chain at position 784. These results
      indicate that histidine 784 is not involved in discrimination of the ribose 2'
      group of the elongating NTP. The ability of T7RNAP tyrosine 639, which is
      conserved in both RNA and DNA polymerases, to select for rNTPs appears to be due
      to the fact that in RNAPs this tyrosine is available to hydrogen bond to the
      ribose 2'-OH, while in DNAPs it is hydrogen bonded to a glutamic acid.

PMID- 10653634
TI  - The major cyclic trimeric product of indole-3-carbinol is a strong agonist of the
      estrogen receptor signaling pathway.
AB  - Indole-3-carbinol (I3C), a component of Brassica vegetables, is under study as a
      preventive agent of cancers of the breast and other organs. Following ingestion,
      I3C is converted to a series of oligomeric products that presumably are
      responsible for the in vivo effects of I3C. We report the effects of the major
      trimeric product, 5,6,11,12,17,18-hexahydrocyclonona[1,2-b:4,5-b':7,8-b'
      ']triindole (CTr), on the estrogen receptor (ER) signaling pathways. Tumor
      promoting effects of high doses of I3C may be due to activation of aryl
      hydrocarbon receptor (AhR)-mediated pathways; therefore, we also examined the
      effects of CTr on AhR activated processes. We observed that CTr is a strong
      agonist of ER function. CTr stimulated the proliferation of estrogen-responsive
      MCF-7 cells to a level similar to that produced by estradiol (E(2)) but did not
      affect the growth of the estrogen-independent cell line, MDA-MD-231. CTr
      displaced E(2) in competitive-binding studies and activated ER-binding to an
      estrogen responsive DNA element in gel mobility shift assays with EC(50)s of
      about 0.1 microM. CTr activated transcription of an E(2)-responsive endogenous
      gene and exogenous reporter genes in transfected MCF-7 cells, also with high
      potency. CTr failed to activate AhR-mediated pathways, consistent with the low
      binding affinity of CTr for the AhR reported previously. Comparisons of the
      conformational characteristics of CTr with other ER ligands indicated a
      remarkable similarity with tamoxifen, a selective ER antagonist used as a breast
      cancer therapeutic agent and suggest an excellent fit of CTr into the ligand
      binding site of the ER.

PMID- 10653636
TI  - Sequence- and stereospecific conformational rearrangement of styrene oxide
      adducts located at A x C mismatched base pairs.
AB  - The solution structures of R- and S-alpha-(N(6)-adenyl)-styrene oxide adducts
      mismatched with cytosine at position X(7) in d(CGGACAXGAAG) x d(CTTCCTGTCCG),
      incorporating codons 60, 61 (underlined), and 62 of the human N-ras
      protooncogene, were determined. These were the R- and S(61,3)C adducts. The
      structures for these mismatched adducts differed from the sequence isomeric R-
      and S(61,2)C adducts [Painter, S. L., Zegar, I. S., Tamura, P. J., Bluhm, S.,
      Harris, C. M., Harris, T. M., and Stone, M. P. (1999) Biochemistry 38, 8635
      8646]. The results reveal that the structural consequences of cytosine mispairing
      opposite the R- and S-alpha-SO adducts differ as a function of DNA sequence. The
      thermodynamic stability of both the R- and S(61,3)C mismatched adducts was
      dependent upon pH. At neutral pH, the R- and S(61,3)C adducts exhibited
      significant structural perturbation and had lower T(m) values, as compared to the
      R- and S(61,2)C adducts. In both instances, this was attributed to reorientation
      about the C6-N(6) bond, such that the N(6)H proton faced away from the Watson
      Crick face of the purine base and into the major groove. The conformation about
      the N(6)-C(alpha)-C(beta)-O torsion angle was predicted from rMD calculations to
      be stabilized by a N/O gauche-type interaction between the styrenyl hydroxyl
      moiety and adenine N(6) at the lesion site. For the R(61,3)C adduct, the styrenyl
      moiety remained oriented in the major groove and faced in the 3'-direction. In
      the properly base-paired R(61,3) adduct, it had faced in the 5' direction. For
      the S(61,3)C adduct, the styrene ring was inserted into the duplex, approximately
      perpendicular to the helical axis of the DNA. It faced in the 5'-direction. In
      the properly base-paired S(61,3) adduct, it had faced in the 3'-direction. The
      results were correlated with site-specific mutagenesis experiments in vivo. The
      latter revealed that the R- and S(61,3)-alpha-styrene oxide adducts were
      nonmutagenic. This may be a consequence of the greater structural perturbation
      associated with formation of the cytosine mismatch at neutral pH for the R- and
      S(61,3) adducts as compared to the S(61,2) adduct that exhibited low levels of A 
      -> G mutations.

PMID- 10653637
TI  - Origins of deuterium kinetic isotope effects on the proton transfers of the
      bacteriorhodopsin photocycle.
AB  - Deuterium kinetic isotope effects (KIE) were measured, and proton inventory plots
      were constructed, for the rates of reactions in the photocycles of wild-type
      bacteriorhodopsin and several site-specific mutants. Consistent with earlier
      reports from many groups, very large KIEs were observed for the third (and
      largest) rise component for the M state and for the decay of the O state,
      processes both linked to proton transfers in the extracellular region. The proton
      inventory plots (ratio of reaction rates in mixtures of H(2)O and D(2)O to that
      in H(2)O vs mole fraction of D(2)O) were approximately linear for the first and
      second M rise components and for M decay, as well as for O decay, indicating that
      the rates of these reactions are limited by simple proton transfer. Uniquely, the
      third rise component of M (and in the D96N mutant also a fourth rise component)
      exhibited a strongly curved proton inventory plot, suggesting that its rate,
      which largely accounts for the rate of deprotonation of the retinal Schiff base,
      depends on a complex multiproton process. This curvature is observed also in the
      E194Q, E204Q, and Y57F mutants but not in the R82A mutant. From these findings,
      and from the locations of bound water in the extracellular region in the crystal
      structure of the protein [Luecke, Schobert, Richter, Cartailler, and Lanyi (1999)
      J. Mol. Biol. 291, 899-911], we suspect that the effects of deuterium
      substitution on the formation of the M state originate from cooperative
      rearrangements of the extensively hydrogen-bonded water molecules 401, 402, and
      406 near Asp-85 and Arg-82.

PMID- 10653638
TI  - Structure determination and binding kinetics of a DNA aptamer-argininamide
      complex.
AB  - The structure of a DNA aptamer, which was selected for specific binding to
      arginine, was determined using NMR spectroscopy. The sequence forms a hairpin
      loop, with residues important for binding occurring in the loop region. Binding
      of argininamide induces formation of one Watson-Crick and two non-Watson-Crick
      base pairs, which facilitate generation of a binding pocket. The specificity for
      arginine seems to arise from contacts between the guanidino end of the arginine
      and phosphates, with atoms positioned by the shape of the pocket. Complex binding
      kinetics are observed suggesting that there is a slow interconversion of two
      forms of the DNA, which have different binding affinities. These data provide
      information on the process of adaptive recognition of a ligand by an aptamer.

PMID- 10653639
TI  - Crystal structure of rabbit phosphoglucose isomerase, a glycolytic enzyme that
      moonlights as neuroleukin, autocrine motility factor, and differentiation
      mediator.
AB  - The multifunctional protein phosphoglucose isomerase, also known as neuroleukin,
      autocrine motility factor, and differentiation and maturation mediator, has
      different roles inside and outside the cell. In the cytoplasm, it catalyzes the
      second step in glycolysis. Outside the cell, it serves as a nerve growth factor
      and cytokine. We have determined the three-dimensional structure of rabbit muscle
      phosphoglucose isomerase complexed with the competitive inhibitor D-gluconate 6
      phosphate by X-ray crystallography at 2.5 A resolution. The structure shows that
      the enzyme is a dimer with two alpha/beta-sandwich domains in each subunit. The
      location of the bound D-gluconate 6-phosphate inhibitor leads to the
      identification of residues involved in substrate specificity (Ser209, Ser159,
      Thr214, Thr217, and Thr211). The results of previously published kinetic studies
      suggest that a lysine and a histidine are involved in the catalytic mechanism.
      The crystal structure suggests active site residues Lys518 and His388 might be
      these residues. In addition, the positions of amino acid residues that are
      substituted in the genetic disease nonspherocytic hemolytic anemia suggest how
      these substitutions can result in altered catalysis or protein stability.

PMID- 10653640
TI  - Structure and dynamics of an acid-denatured protein G mutant.
AB  - NMR studies of protein denatured states provide insights into potential
      initiation sites for folding that may be too transient to be observed
      kinetically. We have characterized the structure and dynamics of the acid
      denatured state of protein G by using a F30H mutant of G(B1) which is on the
      margin of stability. At 5 degrees C, F30H-G(B1) is greater than 95% folded at pH
      7.0 and is greater than 95% unfolded at pH 4.0. This range of stability is useful
      because the denatured state can be examined under relatively mild conditions
      which are optimal for folding G(B1). We have assigned almost all backbone (15)N,
      H(N), and H(alpha) resonances in the acid-denatured state. Chemical shift,
      coupling constant, and NOE data indicate that the denatured state has
      considerably more residual structure when studied under these mild conditions
      than in the presence of chemical denaturants. The acid-denatured state populates
      nativelike conformations with both alpha-helical and beta-hairpin
      characteristics. To our knowledge, this is the first example of a denatured state
      with NOE and coupling constant evidence for beta-hairpin character. A number of
      non-native turn structures are also detected, particularly in the region
      corresponding to the beta1-beta2 hairpin of the folded state. Steady-state ?(1)H
      (15)N? NOE results demonstrate restricted backbone flexibility in more structured
      regions of the denatured protein. Overall, our studies suggest that regions of
      the helix, the beta3-beta4 hairpin, and the beta1-beta2 turn may serve as
      potential initiation sites for folding of G(B). Furthermore, residual structure
      in acid-denatured F30H-G(B1) is more extensive than in peptide fragments
      corresponding to the beta1-beta2, alpha-helix, and beta3-beta4 regions,
      suggesting additional medium-to-long-range interactions in the full-length
      polypeptide chain.

PMID- 10653641
TI  - Solution structure of the CBM10 cellulose binding module from Pseudomonas
      xylanase A.
AB  - Plant cell wall hydrolases generally have a modular structure consisting of a
      catalytic domain linked to one or more noncatalytic carbohydrate-binding modules
      (CBMs), whose common function is to attach the enzyme to the polymeric substrate.
      Xylanase A from Pseudomonas fluorescens subsp. cellulosa (Pf Xyn10A) consists of
      a family 10 catalytic domain, an N-terminal family IIa cellulose-binding module,
      and an internal family 10 cellulose-binding module. The structure of the 45
      residue family 10 CBM has been determined in solution using NMR. It consists of
      two antiparallel beta-sheets, one with two strands and one with three, with a
      short alpha-helix across one face of the three-stranded sheet. There is a high
      density of aromatic residues on one side of the protein, including three aromatic
      residues (Tyr8, Trp22, and Trp24), which are exposed and form a flat surface on
      one face, in a classical polysaccharide-binding arrangement. The fold is closely
      similar to that of the oligonucleotide/oligosaccharide-binding (OB) fold, but
      appears to have arisen by convergent evolution, because there is no sequence
      similarity, and the presumed binding sites are on different faces.

PMID- 10653642
TI  - Trp22, Trp24, and Tyr8 play a pivotal role in the binding of the family 10
      cellulose-binding module from Pseudomonas xylanase A to insoluble ligands.
AB  - Aromatic amino acids are believed to play a pivotal role in carbohydrate-binding
      proteins, by forming hydrophobic stacking interactions with the sugar rings of
      their target ligands. Family 10 cellulose-binding modules (CBM10s), present in a
      number of cellulases and xylanases expressed by Pseudomonas fluorescens subsp.
      cellulosa, contain two tyrosine and three tryptophan residues which are highly
      conserved. To investigate whether these amino acids play an important role in the
      interaction of CBM10 from P. fluorescens subsp. cellulosa xylanase A (Pf Xyn10A)
      with cellulose, each of these residues was changed to alanine in CBM10 expressed
      as a discrete module or fused to the catalytic domain of Pf Xyn10A (CBM10-CD),
      and the capacity of the mutant proteins of CBM10-CD to bind the polysaccharide
      was evaluated. The data showed that W22A, W24A, and Y8A bound very weakly to
      cellulose compared to the wild-type protein, while Y12A retained its capacity to
      interact with the glucose polymer. When the W7A mutation was introduced into
      CBM10 the protein domain did not accumulate in Escherichia coli. In contrast, the
      W7A mutant of CBM10-CD was efficiently expressed in E. coli, although the protein
      bound very weakly to cellulose. NMR spectra of wild-type CBM10, W22A, and W24A
      were very similar, suggesting that the mutations did not significantly affect the
      protein fold. Titration of wild-type CBM10, W22A, and W24A with N
      bromosuccinimide indicated that Trp22 and Trp24 were on the surface of the
      protein, while Trp7 was buried. Collectively, these data indicate that Trp22,
      Trp24, and Tyr8 play a direct role in the binding of Pf Xyn10A CBM10 to
      cellulose. The results are discussed in the light of the three-dimensional
      structure of CBM10 [Raghothama, S., Simpson, P. J., Szabo, L., Nagy, T., Gilbert,
      H. J., and Williamson, M. P. (2000) Biochemistry 39, 978-984].

PMID- 10653643
TI  - Halophilic adaptation: novel solvent protein interactions observed in the 2.9 and
      2.6 A resolution structures of the wild type and a mutant of malate dehydrogenase
      from Haloarcula marismortui.
AB  - Previous biophysical studies of tetrameric malate dehydrogenase from the
      halophilic archaeon Haloarcula marismortui (Hm MalDH) have revealed the
      importance of protein-solvent interactions for its adaptation to molar salt
      conditions that strongly affect protein solubility, stability, and activity, in
      general. The structures of the E267R stability mutant of apo (-NADH) Hm MalDH
      determined to 2.6 A resolution and of apo (-NADH) wild type Hm MalDH determined
      to 2.9 A resolution, presented here, highlight a variety of novel protein-solvent
      features involved in halophilic adaptation. The tetramer appears to be stabilized
      by ordered water molecule networks and intersubunit complex salt bridges "locked"
      in by bound solvent chloride and sodium ions. The E267R mutation points into a
      central ordered water cavity, disrupting protein-solvent interactions. The
      analysis of the crystal structures showed that halophilic adaptation is not aimed
      uniquely at "protecting" the enzyme from the extreme salt conditions, as may have
      been expected, but, on the contrary, consists of mechanisms that harness the high
      ionic concentration in the environment.

PMID- 10653644
TI  - Insights into the molecular relationships between malate and lactate
      dehydrogenases: structural and biochemical properties of monomeric and dimeric
      intermediates of a mutant of tetrameric L-[LDH-like] malate dehydrogenase from
      the halophilic archaeon Haloarcula marismortui.
AB  - L-Malate (MalDH) and L-lactate (LDH) dehydrogenases belong to the same family of
      NAD-dependent enzymes. LDHs are tetramers, whereas MalDHs can be either dimeric
      or tetrameric. To gain insight into molecular relationships between LDHs and
      MalDHs, we studied folding intermediates of a mutant of the LDH-like MalDH (a
      protein with LDH-like structure and MalDH enzymatic activity) from the halophilic
      archaeon Haloarcula marismortui (Hm MalDH). Crystallographic analysis of Hm MalDH
      had shown a tetramer made up of two dimers interacting mainly via complex salt
      bridge clusters. In the R207S/R292S Hm MalDH mutant, these salt bridges are
      disrupted. Its structural parameters, determined by neutron scattering and
      analytical centrifugation under different conditions, showed the protein to be a
      tetramer in 4 M NaCl. At lower salt concentrations, stable oligomeric
      intermediates could be trapped at a given pH, temperature, or NaCl solvent
      concentration. The spectroscopic properties and enzymatic behavior of monomeric,
      dimeric, and tetrameric species were thus characterized. The properties of the
      dimeric intermediate were compared to those of dimeric intermediates of LDH and
      dimeric MalDHs. A detailed analysis of the putative dimer-dimer contact regions
      in these enzymes provided an explanation of why some can form tetramers and
      others cannot. The study presented here makes Hm MalDH the best characterized
      example so far of an LDH-like MalDH.

PMID- 10653645
TI  - Energetic contributions of four arginines to phosphate-binding in thymidylate
      synthase are more than additive and depend on optimization of "effective charge
      balance".
AB  - In thymidylate synthase, four conserved arginines provide two hydrogen bonds each
      to the oxygens of the phosphate group of the substrate, 2'-deoxyuridine-5'
      monophosphate. Of these, R23, R178, and R179 are far removed from the site of
      methyl transfer and contribute to catalysis solely through binding and
      orientation of ligands. These arginines can be substituted by other residues,
      while still retaining more than 1% activity of the wild-type enzyme. We compared
      the kinetics and determined the crystal structures of dUMP complexes of three of
      the most active, uncharged single mutants of these arginines, R23I, R178T, and
      R179T, and of double mutants (R23I, R179T) and (R178T, R179T). The dramatically
      higher K(m) for R178T compared to the other two single mutants arises from the
      effects of R178 substitution on the orientation of dUMP; 10-15-fold increases in
      for R23I and R178T reflect the role of these residues in stabilizing the closed
      conformation of TS in ternary complexes. The free energy for productive dUMP
      binding, DeltaG(S), increases by at least 1 kcal/mol for each mutant, even when
      dUMP orientation and mobility in the crystal structure is the same as in wild
      type enzyme. Thus, the four arginines do not contribute excess positive charge to
      the PO(4)(-2) binding site; rather, they ideally complement the charge and
      geometry of the phosphate moiety. More-than-additive increases in DeltaG(S) seen
      in the double mutants are consistent with quadratic increases in DeltaG(S)
      predicted for deviations from ideal electrostatic interactions and may also
      reflect cooperative binding of the arginines to the phosphate oxygens.

PMID- 10653646
TI  - Regulation of plasmin activity by annexin II tetramer.
AB  - Annexin II tetramer (AIIt) is a major Ca(2+)-binding protein of the endothelial
      cell surface which has been shown to stimulate the tissue plasminogen activator
      (t-PA)-dependent conversion of plasminogen to plasmin. In the present report, we
      have examined the regulation of plasmin activity by AIIt. The incubation of
      plasmin with AIIt resulted in a 95% loss in plasmin activity. SDS-PAGE analysis
      established that AIIt stimulated the autoproteolytic digestion of plasmin heavy
      and light chains. The kinetics of AIIt-stimulated plasmin autoproteolysis were
      first-order, suggesting that binding of plasmin to AIIt resulted in the
      spontaneous autoproteolysis of the bound plasmin. AIIt did not affect the
      activity of other serine proteases such as t-PA or urokinase-type plasminogen
      activator. Furthermore, other annexins such as annexin I, II, V, or VI did not
      stimulate plasmin autoproteolysis. Increasing the concentration of AIIt on the
      surface of human 293 epithelial cells increased cell-mediated plasmin
      autoproteolysis. Thus, in addition to stimulating the formation of plasmin, AIIt
      also promotes plasmin inactivation. These results therefore suggest that AIIt may
      function to provide the cell surface with a transient pulse of plasmin activity.

PMID- 10653647
TI  - 8-oxodGTP incorporation by DNA polymerase beta is modified by active-site residue
      Asn279.
AB  - To understand how the active site of a DNA polymerase might modulate the coding
      of 8-oxo-7,8-dihydrodeoxyguanine (8-oxodG), we performed steady-state kinetic
      analyses using wild-type DNA polymerase beta (pol beta) and two active-site
      mutants. We compared the coding of these polymerases by calculating the ratio of
      efficiencies for incorporation of dATP and dCTP opposite 8-oxodG and for
      incorporation of 8-oxodGTP opposite dA and dC. For wild-type pol beta, there is a
      2:1 preference for incorporation of dCTP over dATP opposite 8-oxodG using a 5'
      phosphorylated 4-base gap substrate. Mutation of either Asn279 or Arg283 to
      alanine has almost no effect on the ratio. 8-OxodGTP is preferentially
      incorporated opposite a template dA (24:1) by wild-type pol beta; mutation of
      Asn279 to alanine results dramatic change whereby there is preferential
      incorporation of 8-oxodGTP opposite dC (14:1). This suggests that interactions of
      8-oxodGTP with Asn279 in the polymerase active site may alter the conformation of
      8-oxodGTP and therefore alter its misincorporation.

PMID- 10653648
TI  - Rate of deactivation of nitric oxide-stimulated soluble guanylate cyclase:
      influence of nitric oxide scavengers and calcium.
AB  - Soluble guanylate cyclase (sGC) is highly activated by nitric oxide (NO) and is
      the known mediator of the effects of NO on a variety of physiological processes.
      The rates at which sGC is activated and deactivated are therefore of wide
      interest since they determine the duration of a tissue's response to NO. The
      effect of NO on smooth muscle dissipates in 1-2 min, suggesting that both
      activation and deactivation are fast. In vitro measurements show that the
      activation of sGC occurs in less than a second, while the deactivation takes
      several hours at 20 degrees C. However, recent reports indicate that Mg-GTP,
      oxyhemoglobin, and reducing and oxidizing agents could deactivate the cyclase in
      several seconds to minutes, though the effectiveness of each of these agents is
      in dispute. We investigated the lifetime of NO-sGC in the cytosol of retina by
      monitoring its enzymatic activity at 20 degrees C. Our results show that Mg-GTP,
      the substrate of NO-sGC, has no influence on the deactivation. Similarly,
      reducing agents glutathione and dithiothreitol shortened the half-life of NO-sGC
      only by about 30%. The greatest effect on the deactivation was caused by
      scavengers of NO: oxyhemoglobin reduced the half-life of NO-sGC from 106 min to
      18 s; another NO scavenger, 2-(4-carboxyphenyl)-4,4,5, 5-tetramethylimidazoline-1
      oxyl-3-oxide (CPTIO), reduced it to 42 s (20 degrees C). Similarly rapid
      deactivation was observed with the enzyme from bovine lung, immunoprecipitated
      enzyme from bovine retina, and heme-deficient enzyme from bovine retina
      reconstituted with heme. On the other hand, YC-1, an activator of sGC, stabilized
      the activated enzyme, preventing NO dissociation, as was evident from the
      inability of oxyhemoglobin or CPTIO to deactivate NO-sGC. Calcium, which is known
      to inhibit NO-sGC, also inhibited the effects of oxyhemoglobin and CPTIO, slowing
      down the deactivation of the enzyme. Lithium, which is also known to inhibit NO
      sGC, had no effect on the deactivation rate of the enzyme. These results, taken
      together, suggest that two factors with major impact on the lifetime of NO-sGC
      are the proximity to NO scavengers and the calcium concentration in the cell.

PMID- 10653649
TI  - An apoptotic model for nitrosative stress.
AB  - Nitric oxide overproduction has been implicated in the pathogenesis of many
      disorders, including artherosclerosis, neurodegenerative diseases, inflammatory
      and autoimmune diseases, and cancer. The common view holds that nitric oxide
      induced cellular injury is caused by oxidative stress. This theory predicts that
      interactions between reactive nitrogen species and reactive oxygen species
      produce powerful oxidants that initiate cell death programs. Cytokine-treated
      murine macrophages are the prototype of this form of cellular injury. Here we
      report that generation of reactive nitrogen species upon
      lipopolysacharide/interferon-gamma stimulation of RAW 264.7 cells is largely
      divorced from production of reactive oxygen species, and that oxidative stress is
      not principally responsible for cell death (in this model). Rather, the death
      program is induced mainly by a nitrosative challenge, characterized by the
      accrual of nitrosylated proteins without a major alteration in cellular redox
      state. Moreover, interactions between reactive oxygen and nitrogen species may
      alter the balance between pathways that yield nitrite and nitrate, without
      impacting the level of S-nitrosylation or extent of cell death. Our results thus
      (1) provide new insights into NO-related metabolic pathways, (2) demonstrate that
      apoptotic injury can be caused by nitrosative mechanisms, and (3) establish a
      model for nitrosative stress in mammalian cells.

PMID- 10653650
TI  - Kinetics of peptide binding to the class II MHC protein I-Ek.
AB  - Class II MHC glycoproteins bind short (7-25 amino acid) peptides in an extended
      type II polyproline-like conformation and present them for immune recognition.
      Because empty MHC is unstable, measurement of the rate of the second-order
      reaction between peptide and MHC is challenging. In this report, we use
      dissociation of a pre-bound peptide to generate the active, peptide-receptive
      form of the empty class II MHC molecule I-Ek. This allows us to measure directly
      the rate of reaction between active, empty I-Ek and a set of peptides that vary
      in structure. We find that all peptides studied, despite having highly variable
      dissociation rates, bind with similar association rate constants. Thus, the rate
      limiting step in peptide binding is minimally sensitive to peptide side-chain
      structure. An interesting complication to this simple model is that a single
      peptide can sometimes bind to I-Ek in two kinetically distinguishable
      conformations, with the stable peptide-MHC complex isomer forming much more
      slowly than the less-stable one. This demonstrates that an additional free-energy
      barrier limits the formation of certain specific MHC-peptide complex
      conformations.

PMID- 10653651
TI  - Importance of the carboxy-terminal 25 amino acid residues of lung collectins in
      interactions with lipids and alveolar type II cells.
AB  - Surfactant proteins A and D (SP-A and SP-D) are structurally related members of
      the collectin family found in the alveolar compartment of the lung. SP-A binds
      dipalmitoylphosphatidylcholine (DPPC) and galactosylceramide (GalCer), induces
      liposome aggregation, and regulates the uptake and secretion of surfactant lipids
      by alveolar type II cells in vitro. SP-D binds phosphatidylinositol (PI) and
      glucosylceramide. The purpose of this study was to identify a critical stretch of
      primary sequence in the SP-A region Cys(204)-Phe(228) and the SP-D region
      Cys(331)-Phe(355) that is involved in protein-specific lipid and type II cell
      interactions. Chimeras ad1 and ad2 were constructed with rat SP-A/SP-D splice
      junctions at Cys(218)/Gly(346) and Lys(203)/Cys(331), respectively. Chimera ad1
      but not ad2 retained DPPC liposome binding activity. Both chimeras retained
      significant binding to GalCer liposomes. Chimera ad1 did not bind to PI, whereas
      chimera ad2 acquired a significant PI binding. Both chimeras failed to induce
      liposome aggregation and to interact with alveolar type II cells. In addition,
      monoclonal antibody 1D6 that blocks specific SP-A functions did not recognize
      either chimera. From these results, we conclude that (1) the SP-A region Leu(219)
      Phe(228) is required for liposome aggregation and interaction with alveolar type
      II cells, (2) the SP-A region Cys(204)-Cys(218) is required for DPPC binding, (3)
      the SP-D region Cys(331)-Phe(355) is essential for minimal PI binding, and (4)
      the epitope for mAb 1D6 is located at the region contiguous to the SP-A region
      Leu(219)-Phe(228).

PMID- 10653653
TI  - Characterization of two high-density lipoprotein binding sites on porcine
      hepatocyte plasma membranes: contribution of scavenger receptor class B type I
      (SR-BI) to the low-affinity component.
AB  - Two HDL(3) high- and low-affinity binding sites are present on the human hepatoma
      cell line (HepG(2)). Recently, we have suggested that the high-affinity binding
      sites might modulate the endocytosis of HDL through the low-affinity binding
      sites [Guendouzi, K. (1998) Biochemistry 37, 14974-14980], highlighting the
      physiological importance of this family of HDL high-affinity binding sites. The
      present data demonstrate the presence of HDL(3) high-affinity (K(d) = 0.37
      microg/mL, B(max) = 260 ng/mg of protein) and low-affinity (K(d) = 86.2
      microg/mL, B(max) = 14 300 ng/mg of protein) binding sites on purified porcine
      hepatocyte plasma membranes. By contrast, free apoA-I was strictly specific to
      the high-affinity sites (K(d) = 0.2 microg/mL and B(max) = 72 ng/mg of protein).
      Competition experiments between (125)I-labeled HDL(3) and either LDL, oxidized
      LDL, or anti-SR-BI IgG as competitors show that SR-BI is mostly responsible (70%
      displacement) for the binding of HDL(3) to the low-affinity binding sites. By
      contrast, the same competition experiments using (125)I-labeled free apoA-I
      clearly excluded SR-BI as the high-affinity binding receptor. We conclude that
      the binding of HDL onto hepatocyte plasma membranes involves: (1) two low
      affinity binding receptors, one being SR-BI; (2) one family of high-affinity
      binding sites unrelated to SR-BI.

PMID- 10653652
TI  - Charged membrane surfaces impede the protein-mediated transfer of
      glycosphingolipids between phospholipid bilayers.
AB  - A lipid transfer protein that facilitates the transfer of glycolipids between
      donor and acceptor membranes has been investigated using a fluorescence resonance
      energy transfer assay. The glycolipid transfer protein (23-24 kDa, pI 9.0)
      catalyzes the high specificity transfer of lipids that have sugars beta-linked to
      either a ceramide or a diacylglycerol backbone, such as simple glycolipids and
      gangliosides, but not the transfer of phospholipids, cholesterol, or cholesterol
      esters. In this study, we examined the effect of different charged lipids on the
      rate of transfer of anthrylvinyl-labeled galactosylceramide (1 mol %) from a
      donor to acceptor vesicle population at neutral pH. Compared to neutral donor
      vesicle membranes, introduction of negatively charged lipid at 5 or 10 mol % into
      the donor vesicles significantly decreased the transfer rate. Introduction of the
      same amount of negative charge into the acceptor vesicle membrane did not impede
      the transfer rate as effectively. Also, positive charge in the donor vesicle
      membrane was not as effective at slowing the transfer rate as was negative charge
      in the donor vesicle. Increasing the ionic strength of the buffer with NaCl
      significantly reversed the charge effects. At neutral pH, the transfer protein
      (pI congruent with 9.0) is expected to be positively charged, which may promote
      association with the negatively charged donor membrane. Based on these and other
      experiments, we conclude that the transfer process follows first-order kinetics
      and that the off-rate of the transfer protein from the donor vesicle surface is
      the rate-limiting step in the transfer process.

PMID- 10653654
TI  - The amino-terminal nine amino acid sequence of poliovirus capsid VP4 protein is
      sufficient to confer N-myristoylation and targeting to detergent-insoluble
      membranes.
AB  - The confinement of membrane proteins by lipid-lipid interactions into specialized
      detergent-insoluble membrane (DIM) microdomains has been proposed as a general
      mechanism to recruit selectively lipid-modified proteins and specific
      transmembrane proteins. Poliovirus capsid VP4 protein and its precursors are
      myristoylated at the NH(2)-terminal Gly residue. To determine whether poliovirus
      uses DIMs during its replicative cycle, we isolated DIMs from poliovirus-infected
      HeLa cells and identified the presence of capsid proteins and their precursors,
      proteinases 2A and 3C, and other viral proteins involved in poliovirus RNA
      replication such as protein 2C and the polymerase 3D. The morphology of these
      DIMs was similar to that of the previously described rosette-like vesicles
      associated with replication complexes isolated from poliovirus-infected cells. To
      examine the possible role of the myristoyl moiety in the targeting of poliovirus
      structural proteins to DIMs, we generated a chimeric protein consisting of the
      nine amino-terminal amino acids from VP4 fused to the amino terminus of the green
      fluorescent protein (GFP). The selected VP4 sequence was sufficient to confer N
      myristoylation and targeting to DIMs to the GFP chimera. Mutations within this
      sequence known to affect both myristoylation and poliovirus assembly abrogated
      the targeting of the GFP chimera. These results indicate that the myristoylated
      amino-terminal nonapeptide from poliovirus VP4 protein constitutes a signal for
      incorporation into DIMs.

PMID- 10653655
TI  - Exchanging cofactors in the core antennae from purple bacteria: structure and
      properties of Zn-bacteriopheophytin-containing LH1.
AB  - The core light-harvesting LH1 complex of Rhodospirillum rubrum consists of an
      assembly of membrane-spanning alpha and beta polypeptides, each of which binds
      one bacteriochlorophyll (BChl) a molecule. In this work, we describe a technique
      that allows the replacement of the natural, Mg BChl a cofactors present in this
      protein by Zn-bacteriopheophytin (Zn-Bpheo). This technique makes use of the well
      characterized, reversible dissociation of LH1 induced by the detergent beta
      octylglucoside. Incubation of partially dissociated LH1 with exogeneous pigments
      induces an equilibrium between the protein-bound BChl and the exogeneous pigment.
      This results in the binding of chemically modified pigments to LH1, in amounts
      which depend on the pigment composition and concentration of the exchange buffer.
      This method can yield information on the relative affinities of the LH1 protein
      binding sites for the different pigments BChl and Zn-Bpheo and can also be used
      to obtain fully reassociated LH1 proteins, with a variable content of modified
      pigment, which may be precisely monitored. Absorption and FT-Raman spectroscopy
      indicate that this exchange procedure leads to LH1 proteins containing modified
      pigments, but retaining a binding site structure identical to that of native LH1.
      Furthermore, examination of the binding curves suggests that there are two
      distinguishable binding sites, probably corresponding to the two polypeptides,
      with very different properties. One of these two binding sites shows a marked
      preference for Zn-Bpheo over BChl, while the other binding site appears to prefer
      BChl.

PMID- 10653656
TI  - Protonation states and pH titration in the photocycle of photoactive yellow
      protein.
AB  - Photoactive yellow protein (PYP) undergoes a light-driven cycle of color and
      protonation states that is part of a mechanism of bacterial phototaxis. This
      article concerns functionally important protonation states of PYP and the
      interactions that stabilize them, and changes in the protonation state during the
      photocycle. In particular, the chromophore pK(a) is known to be shifted down so
      that the chromophore is negatively charged in the ground state (dark state) even
      though it is buried in the protein, while nearby Glu46 has an unusually high
      pK(a). The photocycle involves changes of one or both of these protonation
      states. Calculations of pK(a) values and protonation states using a semi
      macroscopic electrostatic model are presented for the wild-type and three
      mutants, in both the ground state and the bleached (I(2)) intermediate state.
      Calculations allowing multiple H-bonding arrangements around the chromophore also
      have been carried out. In addition, ground-state pK(a) values of the chromophore
      have been measured by UV-visible spectroscopy for the wild-type and the same
      three mutants. Because of the unusual protonation states and strong electrostatic
      interactions, PYP represents a severe test of the ability of theoretical models
      to yield correct calculations of electrostatic interactions in proteins. Good
      agreement between experiment and theory can be obtained for the ground state
      provided the protein interior is assumed to have a relatively low dielectric
      constant, but only partial agreement between theory and experiment is obtained
      for the bleached state. We also present a reinterpretation of previously
      published data on the pH-dependence of the recovery of the ground state from the
      bleached state. The new analysis implies a pK(a) value of 6.37 for Glu46 in the
      bleached state, which is consistent with other available experimental data,
      including data that only became available after this analysis. The new analysis
      suggests that signal transduction is modulated by the titration properties of the
      bleached state, which are in turn determined by electrostatic interactions.
      Overall, the results of this study provide a quantitative picture of the
      interactions responsible for the unusual protonation states of the chromophore
      and Glu46, and of protonation changes upon bleaching.

PMID- 10653657
TI  - Nitrogenase reduction of carbon disulfide: freeze-quench EPR and ENDOR evidence
      for three sequential intermediates with cluster-bound carbon moieties.
AB  - Freeze-quenching of nitrogenase during reduction of carbon disulfide (CS(2)) was
      previously shown to result in the appearance of a novel EPR signal (g = 2.21,
      1.99, and 1.97) not previously associated with any of the oxidation states of the
      nitrogenase metal clusters. In the present work, freeze-quench X- and Q-band EPR
      and Q-band (13)C electron nuclear double resonance (ENDOR) spectroscopic studies
      of nitrogenase during CS(2) reduction disclose the sequential formation of three
      distinct intermediates with a carbon-containing fragment of CS(2) bound to a
      metal cluster inferred to be the molybdenum-iron cofactor. Modeling of the Q-band
      (35 GHz) EPR spectrum of freeze-trapped samples of nitrogenase during turnover
      with CS(2) allowed assignment of three signals designated "a" (g = 2.035, 1.982,
      1.973), "b" (g = 2.111, 2.002, and 1.956), and "c" (g = 2.211, 1. 996, and
      1.978). Freezing samples at varying times after initiation of the reaction
      reveals that signals "a", "b", and "c" appear and disappear in sequential order.
      Signal "a" reaches a maximal intensity at 25 s; signal "b" achieves maximal
      intensity at 60 s; and signal "c" shows maximal intensity at 100 s. To
      characterize the intermediates, (13)CS(2) was used as a substrate, and freeze
      trapped turnover samples were examined by Q-band (13)C ENDOR spectroscopy. Each
      EPR signal ("a", "b", and "c") gave rise to a distinct (13)C signal, with
      hyperfine coupling constants of 4.9 MHz for (13)C(a), 1. 8 MHz for (13)C(b), and
      2.7 MHz for (13)C(c). Models for the sequential formation of intermediates during
      nitrogenase reduction of CS(2) are discussed.

PMID- 10653658
TI  - Time-resolved site-directed spin-labeling studies of bacteriorhodopsin: loop
      specific conformational changes in M.
AB  - A spin-label at site 101 in the C-D loop of bacteriorhodopsin was previously
      found to detect a conformational change during the M --> N transition [Steinhoff,
      H. -J., Mollaaghababa, R., Altenbach, C., Hideg, K., Krebs, M. P., Khorana, H.
      G., and Hubbell, W. L. (1994) Science 266, 105-107]. We have extended these time
      resolved electron paramagnetic resonance studies in purple membranes by analyzing
      conformational changes detected by a spin-label at another site in the C-D loop
      (103), and at sites in the A-B loop (35), the D-E loop (130), and the E-F loop
      (160). In addition, we have investigated the motion detected by a spin-label at
      site 101 in a D96A mutant background that has a prolonged M intermediate. We find
      that among the examined sites, only spin-labels in the C-D loop detect a
      significant change in the local environment after the rise of M. Although the
      D96A mutation dramatically prolongs the lifetime of the M intermediate, it does
      not perturb either the structure of bacteriorhodopsin or the nature of the light
      activated conformational change detected by a spin-label at site 101. In this
      mutant, a conformational change is detected during the lifetime of M, when no
      change in the 410 nm absorbance is observed. These results provide direct
      structural evidence for the heterogeneity of the M population in real time, and
      demonstrate that the motion detected at site 101 occurs in M, prior to Schiff
      base reprotonation.

PMID- 10653660
TI  - Cofactor and substrate binding to vanadium chloroperoxidase determined by UV-VIS
      spectroscopy and evidence for high affinity for pervanadate.
AB  - The vanadate cofactor in vanadium chloroperoxidase has been studied using UV-VIS
      absorption spectroscopy. A band is present in the near-UV that is red-shifted as
      compared to free vanadate and shifts in both position and intensity upon change
      in pH. Mutation of vanadate binding residues has a clear effect on the spectrum.
      Substrate-induced spectral effects allow direct measurement of separate kinetics
      steps for the first time for vanadium haloperoxidases. A peroxo intermediate is
      formed upon addition of H(2)O(2), which causes a decrease in the absorption
      spectrum at 315 nm, as well as an increase at 384 nm. This peroxo form is very
      stable at pH 8.3, whereas it is less stable at pH 5.0, which is the optimal pH
      for activity. Upon addition of halides to the peroxo form, the native spectrum is
      re-formed as a result of halide oxidation. Stopped-flow experiments show that
      H(2)O(2) binding and Cl(-) oxidation occur on the millisecond to second time
      scale. These data suggest that the oxidation of Cl(-) to HOCl occurs in at least
      two steps. In the presence of H(2)O(2), the affinity for the vanadate cofactor
      was found to be much higher than previously reported for vanadate in the absence
      of H(2)O(2). This is attributed to the uptake of pervanadate by the apo-enzyme.
      Human glucose-6-phosphatase, which is evolutionarily related to vanadium
      chloroperoxidase, is also likely to have a higher affinity for pervanadate than
      vanadate. This could explain the enhanced insulin mimetic effect of pervanadate
      as compared to vanadate.

PMID- 10653659
TI  - Binding of troponin I and the troponin I-troponin C complex to actin-tropomyosin.
      Dissociation by myosin subfragment 1.
AB  - Troponin I (TnI) is the component of the troponin complex, TnI, TnC, TnT, that is
      responsible for inhibition of actomyosin ATPase activity. Using the fluorescence
      of pyrene-labeled tropomyosin (Tm), we probed the interaction of TnI and TnIC
      with Tm on the reconstituted muscle thin filament. The results indicate that TnI
      and TnIC(-Ca(2+)) bind specifically and strongly to actin-Tm with a stoichiometry
      of 1 TnI or 1 TnIC/1 Tm/7 actin, in agreement with previous results. The binding
      of myosin heads (S1) to actin-Tm at low levels of saturation caused TnI and TnIC
      to dissociate from actin-Tm. These results are interpreted in terms of the S1
      binding state allosteric-cooperative model of the actin-Tm thin filament,
      closed/open. Thus, TnI and TnIC(-Ca(2+)) bind to the closed state of actin-Tm and
      their binding is greatly weakened in the S1-induced open state, indicating that
      they act as allosteric inhibitors. The fluorescence change and the stoichiometry
      indicate that the TnI-binding site is composed of regions from both actin and Tm
      probably in the vicinity of Cys 190.

PMID- 10653661
TI  - Folding defects caused by single amino acid substitutions in a subunit are not
      alleviated by assembly.
AB  - Significant stabilization of a protein often occurs when it is assembled into an
      oligomer. Bacteriophage P22 contains 420 monomers of coat protein that are
      stabilized by the assembly and maturation processes. The effects of eight single
      amino acid substitutions in coat protein that each cause a temperature-sensitive
      folding defect were investigated to determine if the conformational differences
      previously observed in the monomers could be alleviated by assembly or
      maturation. Several techniques including differential scanning calorimetry, heat
      induced expansion, urea denaturation, and sensitivity to protease digestion were
      used to explore the effects of the amino acid substitutions on the conformation
      of coat protein, once assembled. Each of the amino acid substitutions caused a
      change in the conformation as compared to wild-type coat protein, observed by at
      least one of the probes used. Thus, neither assembly nor expansion entirely
      corrected the conformational defects in the monomeric subunits of the folding
      mutants.

PMID- 10653662
TI  - Potent and selective inhibition of zinc aminopeptidase A (EC 3.4.11.7, APA) by
      glutamyl aminophosphinic peptides: importance of glutamyl aminophosphinic residue
      in the P1 position.
AB  - Through the development of a new chemical strategy, aminophosphinic peptides
      containing a pseudoglutamyl residue (Glu Psi(PO2-CH2)Leu-Xaa) in the N-terminal
      position were synthesized and evaluated as inhibitors of aminopeptidase A (APA).
      The most potent inhibitor developed in this study, Glu Psi(PO2-CH2)Leu-Ala,
      displayed a Ki value of 0.8 nM for APA, but was much less effective in blocking
      aminopeptidase N (APN) (Ki = 31 microM). The critical role of the glutamyl
      residue in this phosphinic peptide, both in potency and selectivity, is
      exemplified by the P1 position analogue, Ala Psi(PO2-CH2)Leu-Ala, which exhibited
      a Ki value of 0.9 microM toward APA but behaved as a rather potent inhibitor of
      APN (Ki = 25 nM). Glu Psi(PO2-CH2)Leu-Xaa peptides are poor inhibitors of
      angiotensin converting enzyme (Ki values higher than 1 microM). Depending on the
      nature of the Xaa residue, the potency of these phosphinic peptides toward
      neutral endopeptidase 24-11 varied from 50 nM to 3 microM. In view of the in vivo
      role of APA in the formation of brain angiotensin III, one of the main effector
      peptides of the renin angiotensin system in the central nervous system, highly
      potent and selective inhibitors of APA may find important therapeutic
      applications soon.

PMID- 10653663
TI  - Evidence for P-N bond scission in phosphoroamidate nerve agent adducts of human
      acetylcholinesterase.
AB  - Acetylcholinesterases (AChEs) form conjugates with certain highly toxic
      organophosphorus (OP) agents that become gradually resistant to reactivation.
      This phenomenon termed "aging" is a major factor limiting the effectiveness of
      therapy in certain cases of OP poisoning. While AChE adducts with phosphonates
      and phosphates are known to age through scission of the alkoxy C-O bond, the
      aging path for adducts with phosphoroamidates (P-N agents) like the nerve agent
      N,N-dimethylphosphonocyanoamidate (tabun) is not clear. Here we report that
      conjugates of tabun and of its butyl analogue (butyl-tabun) with the E202Q and
      F338A human AChEs (HuAChEs) age at similar rates to that of the wild-type enzyme.
      This is in marked contrast to the large effect of these substitutions on the
      aging of corresponding adducts with phosphates and phosphonates, suggesting that
      a different aging mechanism may be involved. Both tabun and butyl-tabun appear to
      be similarly accommodated in the active center, as suggested by molecular
      modeling and by kinetic studies of phosphylation and aging with a series of
      HuAChE mutants (E202Q, F338A, F295A, F297A, and F295L/F297V). Mass spectrometric
      analysis shows that HuAChE adduct formation with tabun and butyl-tabun occurs
      through loss of cyanide and that during the aging process both of these adducts
      show a mass decrease of 28 +/- 4 Da. Due to the nature of the alkoxy substituent,
      such mass decrease can be unequivocally assigned to loss of the dimethylamino
      group, at least for the butyl-tabun conjugate. This is the first demonstration
      that AChE adducts with toxic P-N agents can undergo aging through scission of the
      P-N bond.

PMID- 10653664
TI  - Identification of an essential tyrosine residue in nitroalkane oxidase by
      modification with tetranitromethane.
AB  - The flavoprotein nitroalkane oxidase from Fusarium oxysporum catalyzes the
      oxidation of nitroalkanes to the respective aldehydes or ketones with production
      of nitrite and hydrogen peroxide. The enzyme is irreversibly inactivated by
      incubation with tetranitromethane, a tyrosine-directed reagent, at pH 7.3. The
      inactivation is time-dependent and shows first-order kinetics for two half-lives
      of inactivation. Further inactivation can be achieved upon a second addition of
      tetranitromethane. A saturation kinetic pattern is observed when the rate of
      inactivation is determined versus the concentration of tetranitromethane,
      indicating that a reversible enzyme-inhibitor complex is formed before
      irreversible inactivation occurs. Values of 0.096 +/- 0.013 min(-1) and 12.9 +/-
      3.8 mM were determined for the first-order rate constant for inactivation and the
      dissociation constant for the reversibly formed complex, respectively. The
      competitive inhibitor valerate protects the enzyme from inactivation by
      tetranitromethane, suggesting an active-site-directed inactivation. The UV
      visible absorbance spectrum of the inactivated enzyme is perturbed with respect
      to that of the native enzyme, suggesting that treatment with tetranitromethane
      resulted in nitration of the enzyme. Comparison of tryptic maps of nitroalkane
      oxidase treated with tetranitromethane in the presence and absence of valerate
      shows a single peptide differentially labeled in the inactivated enzyme. The
      spectral properties of the modified peptide are consistent with nitration of a
      tyrosine residue. The amino acid sequence of the nitrated peptide is L-L-N-E-V-M
      C-(NO(2)-Y)-P-L-F-D-G-G-N-I-G-L-R. The possible role of this tyrosine in
      substrate binding is discussed.

PMID- 10653665
TI  - Phosphorylation of recombinant human ATP:citrate lyase by cAMP-dependent protein
      kinase abolishes homotropic allosteric regulation of the enzyme by citrate and
      increases the enzyme activity. Allosteric activation of ATP:citrate lyase by
      phosphorylated sugars.
AB  - Recombinantly expressed human ATP:citrate lyase was purified from E. coli, and
      its kinetic behavior was characterized before and after phosphorylation. Cyclic
      AMP-dependent protein kinase catalyzed the incorporation of only 1 mol of
      phosphate per mole of enzyme homotetramer, and glycogen synthase kinase-3
      incorporated an additional 2 mol of phosphate into the phosphorylated protein.
      Isoelectric focusing revealed that all of the phosphates were incorporated into
      only one of the four enzyme subunits. Phosphorylation resulted in a 6-fold
      increase in V(max) and the conversion of citrate dependence from sigmoidal,
      displaying negative cooperativity, to hyperbolic. The phosphorylated recombinant
      enzyme is more similar to the enzyme isolated from mammalian tissues than
      unphosphorylated enzyme with respect to the K(m) for citrate, CoA, and ATP, and
      the specific activity. Fructose 6-phosphate was found to be a potent activator
      (60-fold) of the unphosphorylated recombinant enzyme, with half-maximal
      activation at 0.16 mM, which results in a decrease in the apparent K(m) for
      citrate and ATP, as well as an increase in the V(max) of the reaction. Thus,
      human ATP:citrate lyase activity is regulated in vitro allosterically by
      phosphorylated sugars as well as covalently by phosphorylation.

PMID- 10653666
TI  - Mechanism of the antichaperone activity of protein disulfide isomerase:
      facilitated assembly of large, insoluble aggregates of denatured lysozyme and
      PDI.
AB  - Protein disulfide isomerase (PDI), a folding catalyst and chaperone can, under
      certain conditions, facilitate the misfolding and aggregation of its substrates.
      This behavior, termed antichaperone activity [Puig, A., and Gilbert, H. F.,
      (1994) J. Biol. Chem. 269, 25889] may provide a common mechanism for aggregate
      formation in the cell, both as a normal consequence of cell function or as a
      consequence of disease. When diluted from the denaturant, reduced, denatured
      lysozyme (10-50 microM) remains soluble, although it does aggregate to form an
      ensemble of species with an average sedimentation coefficient of 23 +/- 5 S
      (approximately 600 +/- 100 kDa). When low concentrations of PDI (1-5 microM) are
      present, the majority (80 +/- 8%) of lysozyme molecules precipitate in large,
      insoluble aggregates, together with 87 +/- 12% of the PDI. PDI-facilitated
      aggregation occurs even when disulfide formation is precluded by the presence of
      dithiothreitol (10 mM). Maximal lysozyme-PDI precipitation occurs at a constant
      lysozyme/PDI ratio of 10:1 over a range of lysozyme concentrations (10-50
      microM). Concomitant resolubilization of PDI and lysozyme from these aggregates
      by increasing concentrations of urea suggests that PDI is an integral component
      of the mixed aggregate. PDI induces lysozyme aggregation by noncovalently cross
      linking 23 S lysozyme species to form aggregates that become so large
      (approximately 38,000 S) that they are cleared from the analytical
      ultracentrifuge even at low speed (1500 rpm). The rate of insoluble aggregate
      formation increases with increasing PDI concentration (although a threshold PDI
      concentration is observed). However, increasing lysozyme concentration slows the
      rate of aggregation, presumably by depleting PDI from solution. A simple
      mechanism is proposed that accounts for these unusual aggregation kinetics as
      well as the switch between antichaperone and chaperone behavior observed at
      higher concentrations of PDI.

PMID- 10653667
TI  - Mitral valve prolapse: the merchant of venice or much ado about nothing?

PMID- 10653668
TI  - Circadian, circaseptan and circannual periodicity of cardiac arrest.

PMID- 10653669
TI  - Concerning gender and therapy after acute myocardial infarction: are there
      differences between men and women?

PMID- 10653670
TI  - Cardioversion of chronic atrial fibrillation-towards a more aggressive approach.

PMID- 10653671
TI  - The Brugada syndrome: do we need more than the 12-lead ECG?

PMID- 10653672
TI  - Defining acute myocardial infarction by ST segment deviation.

PMID- 10653673
TI  - Dilated cardiomyopathy, are a few drinks allowed?

PMID- 10653674
TI  - Heparin and angiogenic therapy.

PMID- 10653675
TI  - Optimizing the initial 12-lead electrocardiographic diagnosis of acute myocardial
      infarction.
AB  - AIMS: The optimum definition of ST elevation for diagnosis of acute myocardial
      infarction, with respect to both the minimum height and the minimum numbers of
      leads, is unknown. Furthermore, only 50% of patients with acute myocardial
      infarction present with ST elevation. We thus quantified the sensitivity and
      specificity of different ST elevation criteria for diagnosis of acute myocardial
      infarction, and determined whether models incorporating multiple QRST features in
      addition to ST elevation, could improve detection of acute myocardial infarction.
      METHODS AND RESULTS: The study population comprised 1190 subjects: 1041
      consecutive patients presenting with chest pain (335 with acute myocardial
      infarction) and 149 controls without chest pain. Subjects were randomly divided
      into a training set (587) and a validation set (603). ECG prediction models for
      acute myocardial infarction incorporating different ST elevation criteria and/or
      additional QRST features (Q waves, ST depression, T wave inversion, bundle branch
      block, axes deviations, and left ventricular hypertrophy) were developed in
      training set patients using forward stepwise multiple logistic regression. Models
      were then prospectively tested in the validation set patients. The optimum ST
      elevation model (based on > or =1 mm ST elevation in > or = 1 inferior/lateral
      leads, or > or =2 mm ST elevation in > or =1 anteroseptal leads) correctly
      classified 83.1% of subjects (55.8% sensitivity, 94. 0% specificity). The choice
      of ST elevation definition had marked influence on the sensitivity (45.4-68.6%)
      and specificity (81.2-98. 1%) for diagnosis of acute myocardial infarction. The
      addition of multiple QRST variables only marginally improved overall
      classification but did result in high specificity (92.6-96.1%). CONCLUSION:
      Different definitions of 'significant' ST elevation led to marked variations in
      sensitivity and specificity for diagnosis of acute myocardial infarction.
      Multiple QRST features in addition to ST elevation only marginally improved
      overall classification.

PMID- 10653676
TI  - Mortality trends in men and women with acute myocardial infarction in coronary
      care units in Israel. A comparison between 1981-1983 and 1992-1994. For the
      SPRINT and the Israeli Thrombolytic Survey Groups.
AB  - AIMS: To assess trends in the management and subsequent outcome in men and women
      in two cohorts of consecutive patients with acute myocardial infarction
      hospitalized in coronary care units in Israel, in the pre-reperfusion and the
      reperfusion eras. METHODS AND RESULTS: We compared trends in the in-hospital
      management, and 30-day and 1-year mortality in men and women in two cohorts of
      patients hospitalized with acute myocardial infarction in coronary care units in
      Israel, in the pre-reperfusion and the reperfusion eras. The first cohort of 5839
      consecutive patients (4315 men, 74%) was from the Secondary Prevention
      Reinfarction Israeli Nifedipine Trial (SPRINT) registry of 1981-1983; the second
      cohort of 1940 patients (1429 males, 74%) derived from two prospective nationwide
      surveys conducted in all coronary care units in Israel in January/February 1992
      and 1994. The demographic and clinical characteristics of patients with acute
      myocardial infarction in both periods were comparable. Patients in 1992-94
      received aspirin, angiotensin-converting enzyme inhibitors, beta-blockers and
      nitrates more frequently than in 1981-83. Thrombolysis, coronary angiography,
      angioplasty and bypass grafting were not used in 1981-83, whereas in 1992-94
      these procedures were used in 45%, 28%, 11% and 4% of men, respectively, and in
      39%, 20%, 9% and 3% of women, respectively. The 30-day age-adjusted mortality
      declined, in men, from 17.0% in 1981-83 to 10.8% in 1992-94 (multivariate
      adjusted odds ratio [OR]=0. 69; 95% confidence interval [CI] 0.55 to 0.87), and
      the cumulative 1-year age-adjusted mortality declined from 24.6% to 16.9%
      (adjusted hazard ratio [HR]=0.70%; 95% CI 0.60 to 0.81). In women, the decline in
      mortality rates were of similar magnitude, from 24.0% to 15.1% (OR=0.70; 95% CI
      0.52 to 0.94), and from 33.6% to 21.0% (HR=0.67; 95% CI 0.55 to 0.81),
      respectively. In both sexes, the decline in mortality was more marked in patients
      reperfused by thrombolysis and/or mechanical revascularization, but was also
      evident in non-reperfused patients. CONCLUSIONS: Despite higher mortality in both
      periods in women compared to men, the prognosis of men and women with acute
      myocardial infarction improved considerably during the last decade, with a
      similar decline in 1-year mortality of approximately 30%. The implementation in
      daily practice of new therapeutic modalities proven to be effective in clinical
      trials after acute myocardial infarction, probably played a major role in this
      favourable outcome in both sexes.

PMID- 10653677
TI  - Increased digitalis-like immunoreactive substances in patients with hypertrophic
      cardiomyopathy.
AB  - AIMS: Although increased digitalis-like immunoreactive substances have been found
      in cases of hypertension and heart failure, no information is available about
      digitalis-like immunoreactive substances in patients with hypertrophic
      cardiomyopathy. We investigated digitalis-like immunoreactive substances in the
      plasma and biopsied specimens of patients with hypertrophic cardiomyopathy.
      METHODS AND RESULTS: In 40 patients with hypertrophic cardiomyopathy (27 with the
      non-obstructive type and 13 with the obstructive type), the plasma concentration
      of digitalis-like immunoreactive substances was studied by fluorescence
      polarization immunoassay. Right ventricular endomyocardial biopsy specimens were
      analysed immunohistochemically, using a monoclonal antibody against digoxin. An
      increase in digitalis-like immunoreactive substances of more than 0.2 ng. ml(
      1)in plasma was found in six of 27 patients with non-obstructive hypertrophic
      cardiomyopathy (22.2%) and five of 13 with obstructive hypertrophic
      cardiomyopathy (38.4%). Under light microscopy, positive staining against the
      antibody was observed heterogeneously on some cardiocytes. In non-obstructive
      hypertrophic cardiomyopathy, digitalis-like immunoreactive substances in the
      plasma correlated with the left atrial dimension and inversely with the cardiac
      index. In obstructive hypertrophic cardiomyopathy, plasma and myocardial
      digitalis-like immunoreactive substances were positively correlated; they also
      correlated with left ventricular end-diastolic pressures. Under electron
      microscopy, digitalis-like immunoreactive substances were detected at the
      sarcolemma in the free wall, T-tubules, intercalated discs and Z-bands of
      cardiocytes. CONCLUSIONS: Increased digitalis-like immunoreactive substances in
      plasma and cardiocytes, which may have been caused by pressure and/or volume
      overload, were found in patients with hypertrophic cardiomyopathy. Digitalis-like
      immunoreactive substances may act on the sarcolemma of cardiocytes and be
      transported into the cytoplasm.

PMID- 10653678
TI  - Comparison of long-term outcome of alcoholic and idiopathic dilated
      cardiomyopathy.
AB  - AIMS: The outcome of alcoholic cardiomyopathy is thought to be better than
      idiopathic dilated cardiomyopathy if patients abstain from alcohol. The aim of
      this study was to compare the long-term clinical outcome of alcoholic and
      idiopathic dilated cardiomyopathy. METHODS AND RESULTS: Of 134 patients with
      dilated cardiomyopathy and normal coronary angiography, 50 had alcoholic
      cardiomyopathy; they were compared serially to 84 patients with idiopathic
      dilated cardiomyopathy. Left ventricular end-diastolic diameter, left ventricular
      ejection fraction and cardiac index, severity of ventricular arrhythmias,
      measurement of heart rate variability and results of signal-averaged ECG were
      similar in both groups. Although alcohol withdrawal was strongly recommended but
      observed in only 70% of patients with alcoholic cardiomyopathy, both groups had
      similar outcome in terms of cardiac death after follow-up treatment of 47+/-40
      months. Multivariate analysis in the entire cohort demonstrated that increased
      pulmonary capillary wedge pressure (P=0. 003), alcoholism and lack of abstinence
      during follow-up (P=0.006) and decreased standard deviation of all normal-to
      normal RR intervals (P=0.02) were independent predictors of cardiac death.
      CONCLUSION: In contrast with previous studies, patients with alcoholic
      cardiomyopathy did not have a better outcome than patients with idiopathic
      dilated cardiomyopathy. Alcoholism without abstinence was a strong predictor of
      cardiac death. This suggests that a more aggressive approach to alcohol cessation
      is needed in these patients.

PMID- 10653679
TI  - Diurnal, weekly and seasonal variation of sudden death. Population-based analysis
      of 24,061 consecutive cases.
AB  - AIMS: Several studies have reported circadian and seasonal variations in acute
      cardiovascular disease. In addition, a weekly variation has been observed in
      acute myocardial infarction. The aim of our study was to determine the circadian
      weekly, and seasonal variations of sudden death utilizing population-based data.
      METHODS AND RESULTS: We analysed the emergency medical system data of Berlin
      (West) from 1987-1991 with respect to all consecutive sudden deaths in subjects
      >18 years (n=24 061). There was a marked circadian variation of sudden death,
      with a minimum between 0 and 6 h and a maximum between 6 and 12 h (P<0.0001) for
      every day of the week. A minimum of events occurred on Sundays (n=3143), and a
      maximum on Mondays (n=3721), corresponding to a relative increase of 18.3%
      (P<0.0001). The increase was more pronounced (23.6%) in patients < or =65 than in
      patients >65 (15.7%). In addition, we found a significant seasonal variation
      (P<0.0001) in events, with a maximum during winter (December to February,
      n=6493), and a minimum during summer (June to August, n=5472), corresponding to a
      relative difference of 18.7%. The seasonal variation was more pronounced in
      patients >65 years. CONCLUSION: The present analyses demonstrate marked
      variations in the occurrence of sudden death with peaks during morning hours, on
      Mondays, and during winter months. The findings suggest that the onset of sudden
      death may be associated with endogenous rhythms and external factors including
      climatic conditions.

PMID- 10653680
TI  - Sudden death in patients and relatives with the syndrome of right bundle branch
      block, ST segment elevation in the precordial leads V(1)to V(3)and sudden death.
AB  - BACKGROUND: The syndrome with an electrocardiographic pattern of right bundle
      branch block, ST segment elevation in leads V(1)to V(3)and sudden death is
      genetically determined and caused by mutations in the cardiac sodium channel. The
      inheritance of the disease is autosomal dominant. Sudden death may, however,
      occur from a variety of causes in relatives and patients with this syndrome.
      PATIENTS AND METHODS: Twenty-five Flemish families with this syndrome with a
      total of 334 members were studied. Affected members were recognized by means of a
      typical electrocardiogram either occurring spontaneously or after the intravenous
      administration of antiarrhythmic drugs. Sudden deaths in these families were
      classified as related or not to the syndrome by analysis of the data at the time
      of the event, mode of inheritance of the disease, and data provided by survivors.
      Results Of the 25 families with the syndrome, 18 were symptomatic (at least one
      sudden death related to the syndrome) and seven were asymptomatic (no sudden
      deaths related to the syndrome). In total, there were 42 sudden cardiac deaths
      (12% incidence). Twenty-four sudden deaths were related to the syndrome and all
      occurred in symptomatic families. Eighteen sudden deaths (43% of total sudden
      deaths) were not related to the syndrome (nine cases) or were of unclear cause
      (nine cases). Three of them occurred in two asymptomatic families and the
      remaining 15 in five symptomatic families. Twenty-four of the 50 affected members
      (47%) suffered (aborted) sudden death and 18 of the 284 unaffected members (6%).
      This difference in the incidence of sudden death was statistically significant
      (P<0.0001). Patients with (aborted) sudden death caused by the syndrome were
      younger than patients with sudden death of other or unclear causes (38+/-4 years
      vs 59+/-3 years respectively, P=0.0003). CONCLUSIONS: In families at high risk of
      sudden death because of genetically determined diseases, the main cause of sudden
      death remains the disease. However, almost the half of sudden deaths are caused
      by unrelated diseases or are of unclear cause. Accurate classification of the
      causes of sudden death is mandatory for appropriate analysis of the causes of
      death when designing preventive treatments.

PMID- 10653681
TI  - Is there a place for the late cardioversion of atrial fibrillation? A long-term
      follow-up study of patients with post-thyrotoxic atrial fibrillation.
AB  - AIMS: As atrial fibrillation is associated with significant mortality and
      morbidity, restoration of sinus rhythm is desirable. However, previous data
      suggest that cardioversion should be restricted to patients in whom the
      fibrillation is of limited duration (<1-2 years) because of high relapse rates.
      It may be the frequent association with cardiac disease, rather than the duration
      of fibrillation itself, which determined the high relapse of earlier studies. The
      aim of this study was to investigate rates of cardioversion, maintenance of sinus
      rhythm and predictors of subsequent relapse in a homogeneous group of patients
      without evidence of any co-existent cardiac disease. METHODS AND RESULTS: We
      report on a retrospective series of 106 patients with thyrotoxicosis-induced
      fibrillation but no other heart disease: 87% had been in atrial fibrillation for
      >12 months (median duration 28.5, interquartile range 15-47 months).
      Cardioversion was attempted using disopyramide and then electric shock. Ninety
      eight patients were successfully cardioverted: at late follow-up, 80.6+/-37
      months (mean+/-SD), 67% were in sinus rhythm. CONCLUSION: Although a relationship
      between the duration of fibrillation and maintenance of sinus rhythm was found,
      the high proportion remaining in sinus rhythm, compared with other series,
      suggests this influence may be less important than the presence or absence of
      structural heart disease.

PMID- 10653683
TI  - Serum leptin levels in heart failure patients may be altered differently
      according to clinical stage.

PMID- 10653682
TI  - Serum leptin concentration in heart failure patients: does the literature reflect
      reality?

PMID- 10653685
TI  - A reply.

PMID- 10653684
TI  - AT1-receptor blockers.

PMID- 10653686
TI  - Natriuretic peptides in clinical practice.

PMID- 10653688
TI  - ESC News and Appointments.

PMID- 10653687
TI  - A reply.

PMID- 10653689
TI  - RING domains: master builders of molecular scaffolds?
AB  - Intense interest in the RING domain has arisen because of its widespread
      occurrence and involvement in human disease. Several intriguing characteristics
      evident from the study of this cysteine-rich, zinc-binding domain have made it
      difficult to establish a single defining biochemical function for RINGs. These
      proteins are found throughout the cell and mediate diverse cellular processes,
      e.g. oncogenesis, apoptosis, development and viral infection. Recent developments
      indicate that RING-mediated protein interactions are critical for transcriptional
      repression and for ubiquitination. These data are in addition to previously
      established functions for RINGs in RNA processing, cell-cycle control and
      peroxisomal biogenesis, to name a few. At first glance, there appears to be
      little to link such disparate actions. Collectively, these results suggest that
      RINGs function in formation and architecture of large protein complexes that
      contribute to diverse cellular processes. Here, new developments, in the context
      of previous results, are discussed in an attempt to establish a unifying theory
      for RING function.

PMID- 10653690
TI  - Evidence for helical unwinding of an RNA substrate by the RNA enzyme RNase P: use
      of an interstrand disulfide crosslink in substrate.
AB  - To gain an understanding of structural changes induced in substrates by
      Escherichia coli ribonuclease P (RNase P), we have incorporated an interstrand
      disulfide crosslink proximal to the cleavage site in a model substrate. RNase P
      is able to process the reduced, non-crosslinked form of this substrate as well as
      a substrate in which the free thiol molecules have been alkylated with
      iodoacetamide. However, the oxidized, crosslinked form is cleaved at a
      significantly lower rate. Therefore, helical unwinding of the analog of the
      aminoacyl stem of the substrate near its site of cleavage may be necessary for
      efficient processing by E. coli RNase P.

PMID- 10653691
TI  - Functional conservation of RNA polymerase II in fission and budding yeasts.
AB  - The complementary DNAs of the 12 subunits of fission yeast (Schizosaccharomyces
      pombe) RNA polymerase II were expressed from strong promoters in Saccharomyces
      cerevisiae and tested for heterospecific complementation by monitoring their
      ability to replace in vivo the null mutants of the corresponding host genes. Rpb1
      and Rpb2, the two largest subunits and Rpb8, a small subunit shared by all three
      polymerases, failed to support growth in S. cerevisiae. The remaining nine
      subunits were all proficient for heterospecific complementation and led in most
      cases to a wild-type level of growth. The two alpha-like subunits (Rpb3 and
      Rpb11), however, did not support growth at high (37 degrees C) or low (25 degrees
      C) temperatures. In the case of Rpb3, growth was restored by increasing the gene
      dosage of the host Rpb11 or Rpb10 subunits, confirming previous evidence of a
      close genetic interaction between these three subunits.

PMID- 10653692
TI  - Hydration of [d(CGC)r(aaa)d(TTTGCG)](2).
AB  - We have studied the hydration and dynamics of RNA C2'-OH in a DNA. RNA hybrid
      chimeric duplex [d(CGC)r(aaa)d(TTTGCG)](2). Long-lived water molecules with
      correlation time tau(c) larger than 0.3 ns were found close to the RNA adenine H2
      and H1' protons in the hybrid segment. A possible long-lived water molecule was
      also detected close to the methyl group of 7T in the RNA-DNA junction but not to
      the other two thymine bases (8T and 9T). This result correlates with the
      structural studies that only DNA residue 7T in the RNA-DNA junction adopts an O4'
      endo sugar conformation (intermediate between B-form and A-form), while the other
      DNA residues including 3C in the DNA-RNA junction, adopt C1'-exo or C2'-endo
      conformations (in the B-form domain). Based on the NOE cross-peak patterns, we
      have found that RNA C2'-OH tends to orient toward the O3' direction, forming a
      possible hydrogen bond with the 3'-phosphate group. The exchange rates for RNA
      C2'-OH were found to be around 5-20 s(-1), compared to 26.7(+/-13.8) s(-1)
      reported previously for the other DNA.RNA hybrid duplex. This slow exchange rate
      may be due to the narrow minor groove width of [d(CGC)r(aaa)d(TTTGCG)](2), which
      may trap the water molecules and restrict the dynamic motion of hydroxyl protons.
      The distinct hydration patterns of the RNA adenine H2 and H1' protons and the DNA
      7T methyl group in the hybrid segment, as well as the orientation and dynamics of
      the RNA C2'-OH protons, may provide a molecular basis for further understanding
      the structure and recognition of DNA.RNA hybrid and chimeric duplexes.

PMID- 10653693
TI  - Reconstitution of the KRAB-KAP-1 repressor complex: a model system for defining
      the molecular anatomy of RING-B box-coiled-coil domain-mediated protein-protein
      interactions.
AB  - The KRAB domain is a 75 amino acid residue transcriptional repression module
      commonly found in eukaryotic zinc-finger proteins. KRAB-mediated gene silencing
      requires binding to the corepressor KAP-1. The KRAB:KAP-1 interaction requires
      the RING-B box-coiled coil (RBCC) domain of KAP-1, which is a widely distributed
      motif, hypothesized to be a protein-protein interface. Little is known about RBCC
      mediated ligand binding and the role of the individual sub-domains in recognition
      and specificity. We have addressed these issues by reconstituting and
      characterizing the KRAB:KAP-1-RBCC interaction using purified components. Our
      results show that KRAB binding to KAP-1 is direct and specific, as the related
      RBCC domains from TIF1alpha and MID1 do not bind the KRAB domain. A combination
      of gel filtration, analytical ultracentrifugation, chemical cross-linking, non
      denaturing gel electrophoresis, and site-directed mutagenesis techniques has
      revealed that the KAP-1-RBCC must oligomerize likely as a homo-trimer in order to
      bind the KRAB domain. The RING finger, B2 box, and coiled-coil region are
      required for oligomerization of KAP-1-RBCC and KRAB binding, as mutations in
      these domains concomitantly abolished these functions. KRAB domain binding
      stabilized the homo-oligomeric state of the KAP-1-RBCC as detected by chemical
      cross-linking and velocity sedimentation studies. Mutant KAP-1-RBCC molecules
      hetero-oligomerize with the wild-type KAP-1, but these complexes were inactive
      for KRAB binding, suggesting a potential dominant negative activity. Substitution
      of the coiled-coil region with heterologous dimerization, trimerization, or
      tetramerization domains failed to recapitulate KRAB domain binding. Chimeric KAP
      1-RBCC proteins containing either the RING, RING-B box, or coiled-coil regions
      from MID1 also failed to bind the KRAB domain. The KAP-1-RBCC mediates a highly
      specific, direct interaction with the KRAB domain, and it appears to function as
      an integrated, possibly cooperative structural unit wherein each sub-domain
      contributes to oligomerization and/or ligand recognition. These observations
      provide the first principles for RBCC domain-mediated protein-protein interaction
      and have implications for identifying new ligands for RBCC domain proteins.

PMID- 10653694
TI  - Two active-site tyrosyl residues of protein TrwC act sequentially at the origin
      of transfer during plasmid R388 conjugation.
AB  - Protein TrwC is the relaxase-helicase responsible for the initiation and
      termination reactions of DNA processing during plasmid R388 conjugation. Site
      directed mutagenesis was used to change to phenylalanine each of a set of four
      conserved tyrosyl residues in the sequence of the N-terminal relaxation domain of
      the protein. Simultaneous mutation of both Y18 and Y26 was required to abolish in
      vitro cleavage and strand-transfer reactions catalyzed by protein TrwC on
      oligonucleotides containing the nic site. Thus, both Y18 and Y26 could be
      involved independently in the formation of oligonucleotide-protein covalent
      complexes that constitute presumed intermediates of these reactions. This
      hypothesis was confirmed by the observation of Y18 and Y26-specific peptide
      oligonucleotide adducts after protease digestion of TrwC and mutant derivatives.
      Finally mutation Y18F, but not mutation Y26F, abolished nic-cleavage of a
      supercoiled DNA containing the R388 origin of transfer (oriT). These data allowed
      the construction of a model for conjugative DNA processing in which Y18
      specifically catalyzes the initial cleavage reaction, while Y26 is used for the
      second strand-transfer reaction, which terminates conjugation. The model suggests
      a control mechanism that can be effective at each conjugative replication cycle.

PMID- 10653695
TI  - Evidence for DNA bending at the T7 RNA polymerase promoter.
AB  - Phage T7 RNA polymerase is the only DNA-dependent RNA polymerase for which we
      have a high-resolution structure of the promoter-bound complex. Recent studies
      with the more complex RNA polymerases have suggested a role for DNA wrapping in
      the initiation of transcription. Here, circular permutation gel retardation
      assays provide evidence that the polymerase does indeed bend its promoter DNA. A
      complementary set of experiments employing differential phasing from an array of
      phased A-tracts provides further evidence for both intrinsic and polymerase
      induced bends in the T7 RNA polymerase promoter DNA. The bend in the complex is
      predicted to be about 40-60 degrees and to be centered around positions -2 to +1,
      at the start site for transcription, while the intrinsic bend is much smaller
      (about 10 degrees ). These results, viewed in the light of a recent crystal
      structure for the complex, suggest a mechanism by which binding leads directly to
      bending. Bending at the start site would then facilitate the melting necessary to
      initiate transcription.

PMID- 10653696
TI  - Molecular characterisation of two structurally distinct groups of human homers,
      generated by extensive alternative splicing.
AB  - Homer proteins bind specifically to the C termini of the metabotropic glutamate
      receptor mGluR1alpha/a and mGluR5, play a role in their targeting and modulate
      their synaptic properties. We have discovered that extensive alternative splicing
      generates a family of 17 Homer proteins. These fall into two distinct groups of
      12 "long" Homers, which all have a coiled-coil domain at their C termini, and
      five "short" Homers, which lack such a domain. All Homers contain the N-terminal
      sequence responsible for their binding to mGluR1alpha/a receptors and can be co
      localised with the recombinantly expressed mGluR1alpha/a protein in HEK-293
      cells. The existence of the long and the short variants of each of the Homer-1,
      Homer-2 and Homer-3 proteins reflects the fundamental principles of Homer
      functions.

PMID- 10653697
TI  - Drosophila ACT88F indirect flight muscle-specific actin is not N-terminally
      acetylated: a mutation in N-terminal processing affects actin function.
AB  - Many eukaryotic proteins are co and post-translationally modified at their N
      termini by removal of one or two amino acid residues and N(alpha)-acetylation.
      Actins show two different forms of N-terminal processing dependent on their N
      terminal sequence. In class II actins, which include muscle actins, the common
      primary sequence of Met-Cys-Asp-actin is processed to acetyl-Asp-actin. The
      functional significance of this in vivo is unknown. We have studied the indirect
      flight muscle-specific actin, ACT88F, of Drosophila melanogaster. Our results
      show that ACT88F is N-terminally processed in vivo as a class II actin by removal
      of the first two amino acid residues (Met and Cys), but that uniquely the N
      terminus is not acetylated. In addition we show that ACT88F is methylated,
      probably at His73. Flies carrying the mod(-) mutation fail to complete post
      translational processing of ACT88F. We propose that the mod gene product is
      normally responsible for removing N-acetyl-cysteine from actin. The biological
      significance of this process is demonstrated by observations that retention of
      the N-acetyl-cysteine in ACT88F affects the flight muscle function of mod(-)
      flies. This suggests that the extreme N terminus affects actomyosin interactions
      in vivo, a proposal we have examined by in vitro motility assays of ACT88F F
      actin from mod(-) flies. The mod(-) actin only moves in the presence of
      methylcellulose, a viscosity-enhancing agent, where it moves at velocities
      slightly, but significantly, reduced compared to wild-type. These data confirm
      that N-acetyl-cysteine at the N terminus affects actomyosin interactions,
      probably by reducing formation of the initial actomyosin collision complex, a
      process known to involve the actin N terminus.

PMID- 10653698
TI  - Solution structure of Cobalt(III)hexammine complexed to the GAAA tetraloop, and
      metal-ion binding to G.A mismatches.
AB  - The solution structure of a 22 nt RNA hairpin and its complex with
      Co(NH(3))(6)(3+) bound to the GAAA tetraloop has been determined by NMR
      spectroscopy. Co(NH(3))(6)(3+) has a similar geometry to Mg(H(2)O)(6)(2+) and can
      be used as a probe for binding sites of completely solvated magnesium ions. The
      hairpin contains tandem G.A mismatches, similar to the P5abc region of a group I
      intron, and is closed by a GAAA tetraloop. The tandem G.A mismatches are imino
      hydrogen bonded in contrast with the sheared G.A mismatches found in a different
      context in the crystal structure of the P4-P6 domain. Chemical shift changes of
      the imino protons upon titration of the RNA hairpin with Mg(2+) and with
      Co(NH(3))(6)(3+) were used to identify ion-binding sites. Paramagnetic resonance
      broadening upon titration with Mn(2+) was also used. The titration curves gave
      dissociation binding constants for the magnesium ions in the millimolar range,
      similar to the binding in the major groove of RNA at tandem G.U base-pairs.
      Although the largest chemical shift change occurred at an imino proton of one of
      the G.A base-pairs, no nuclear Overhauser enhancement cross-peaks between the
      cobalt ligand and neighboring RNA protons were seen, presumably due to the high
      mobility of the Co(NH(3))(6)(3+) at this site. Nuclear Overhauser enhancement
      cross-peaks between Co(NH(3))(6)(3+) and the GAAA tetraloop were observed, which
      allowed the determination of the structure of the tetraloop binding site. The
      Co(NH(3))(6)(3+) is bound in the major groove of the GAAA tetraloop with hydrogen
      bonds to guanine base N7 and to phosphate oxygen atoms of the tetraloop.

PMID- 10653699
TI  - Structural comparison of the PhoB and OmpR DNA-binding/transactivation domains
      and the arrangement of PhoB molecules on the phosphate box.
AB  - PhoB is a transcriptional activator that binds to the phosphate box in the
      promoters of the phosphate genes of Escherichia coli. PhoB contains two
      functional domains, an N-terminal phosphorylation domain and a C-terminal DNA
      binding/transactivation domain. Here, the three-dimensional structure of the DNA
      binding/transactivation domain has been determined by NMR. It consists of an N
      terminal four-stranded beta-sheet, a central three helical bundle and a C
      terminal beta-hairpin. The second and third helices form a helix-turn-helix (HTH)
      variant containing a longer turn than the corresponding turn of the classical HTH
      motif. The overall architecture is very close to that of the OmpR DNA
      binding/transactivation domain, however, the conformation of the long turn region
      of PhoB, a putative interaction site for the RNA polymerase sigma subunit, is
      entirely different from that of the corresponding turn of OmpR, which interacts
      with the alpha subunit. In addition, the third helix of PhoB is three amino acid
      residues longer than the corresponding helix of OmpR. The binding site of PhoB is
      a TGTCA sequence and the phospahte box contains the two binding sites. NMR
      studies of the complexes of the PhoB DNA-binding/transactivation domain bound to
      several different DNA molecules have revealed that two PhoB molecules bind in a
      tandem array on the phosphate box. In each complex of PhoB the third helix of the
      DNA-binding/transactivation domain is likely to recognize the TGTCA sequence from
      the major groove of DNA and the C-terminal beta-hairpin contacts on the minor
      groove of the 3' site out of the TGTCA sequence in a non-specific manner. The
      long turn region facing outward is likely to interact with the sigma subunit.

PMID- 10653700
TI  - High-resolution structure of bovine pancreatic trypsin inhibitor with altered
      binding loop sequence.
AB  - A mutant of bovine pancreatic trypsin inhibitor (BPTI) has been constructed and
      expressed in Escherichia coli in order to probe the kinetic and structural
      consequences of truncating the binding loop residues to alanine. In addition to
      two such mutations (Thr11Ala and Pro13Ala), it has a conservative Lys15Arg
      substitution at position P(1) and an unrelated Met52Leu change. In spite of the
      binding loop modification, the affinity for trypsin is only 30 times lower than
      that of the wild-type protein. At pH 7.5 the protein can be crystallized on the
      time-scale of hours, yielding very stable crystals of a new (tetragonal) form of
      BPTI. Conventional source X-ray data collected to 1.4 A at room temperature
      allowed anisotropic structure refinement characterized by R=0.1048. The structure
      reveals all 58 residues, including the complete C terminus, which is in a salt
      bridge contact with the N terminus. The Cys14-Cys38 disulfide bridge is observed
      in two distinct chiralities. This bridge, together with an internal water
      molecule, contributes to the stabilization of the binding loop. The Ala mutations
      have only an insignificant and localized effect on the binding loop, which
      retains its wild-type conformation (maximum deviation of loop C(alpha) atoms of
      0.7 A at Ala13). Four (instead of the typical three) additional water molecules
      are buried in an internal cleft and connected to the surface via a sulfate anion.
      Three more SO(4)(2-) anions are seen in the electron density, one of them located
      on a 2-fold axis. It participates in the formation of a dimeric structure between
      symmetry-related BPTI molecules, in which electrostatic and hydrogen bonding
      interactions resulting from the mutated Lys15Arg substitution are of central
      importance. This dimeric interaction involves direct recognition loop-recognition
      loop contacts, part of which are hydrophobic interactions of the patches created
      by the alanine mutations. Another 2-fold symmetric interaction between the BPTI
      molecules involves the formation of an antiparallel intermolecular beta-sheet
      that, together with the adjacent intramolecular beta-hairpin loops, creates a
      four-stranded structure.

PMID- 10653701
TI  - NMR solution structure of the inserted domain of human leukocyte function
      associated antigen-1.
AB  - The interaction between the leukocyte function-associated antigen-1 (LFA-1) and
      the intercellular adhesion molecule is thought to be mediated primarily via the
      inserted domain (I-domain) in the alpha-subunit. The activation of LFA-1 is an
      early step in triggering the adhesion of leukocytes to target cells decorated
      with intercellular adhesion molecules. There is some disagreement in the
      literature over the respective roles of conformational changes in the I-domain
      and of divalent cations (Mg(2+), Mn(2+)) in the activation of LFA-1 for
      intercellular adhesion molecule binding. X-ray crystallographic structures of the
      I-domains of LFA-1 and Mac-1 in the presence and absence of cations show
      structural differences in the C-terminal alpha-helix; this change was proposed to
      represent the active and inactive conformations of the I-domain. However, more
      recent X-ray results have called this proposal into question. The solution
      structure of the Mg(2+) complex of the I-domain of LFA-1 has been determined by
      NMR methods, using a model-based approach to nuclear Overhauser enhancement
      spectroscopy peak assignment. The protein adopts the same structure in solution
      as that of the published I-domain X-ray structures, but the C-terminal region,
      where the X-ray structures are most different from each other, is different again
      in the solution structures. The secondary structure of this helix is well formed,
      but NMR relaxation data indicate that there is considerable flexibility present,
      probably consisting of breathing or segmental motion of the helix. The
      conformational diversity seen in the various X-ray structures could be explained
      as a result of the inherent flexibility of this C-terminal region and as a result
      of crystal contacts. Our NMR data are consistent with a model where the C
      terminal helix has the potential flexibility to take up alternative
      conformations, for example, in the presence and absence of the intercellular
      adhesion molecule ligand. The role of divalent cations appears from our results
      not to be as a direct mediator of a conformational change that alters affinity
      for the ligand. Rather, the presence of the cation appears to be involved in some
      other way in ligand binding, perhaps by acting as a bridge to the ligand and by
      modulation of the charge of the binding surface.

PMID- 10653702
TI  - Orienting domains in proteins using dipolar couplings measured by liquid-state
      NMR: differences in solution and crystal forms of maltodextrin binding protein
      loaded with beta-cyclodextrin.
AB  - Protein function is often regulated by conformational changes that occur in
      response to ligand binding or covalent modification such as phosphorylation. In
      many multidomain proteins these conformational changes involve reorientation of
      domains within the protein. Although X-ray crystallography can be used to
      determine the relative orientation of domains, the crystal-state conformation can
      reflect the effect of crystal packing forces and therefore may differ from the
      physiologically relevant form existing in solution. Here we demonstrate that the
      solution-state conformation of a multidomain protein can be obtained from its X
      ray structure using an extensive set of dipolar couplings measured by triple
      resonance multidimensional NMR spectroscopy in weakly aligning solvent. The
      solution-state conformation of the 370-residue maltodextrin-binding protein (MBP)
      loaded with beta-cyclodextrin has been determined on the basis of one-bond (15)N
      H(N), (15)N-(13)C', (13)C(alpha)-(13)C', two-bond (13)C'-H(N), and three-bond
      (13)C(alpha)-H(N) dipolar couplings measured for 280, 262, 276, 262, and 276
      residues, respectively. This conformation was generated by applying hinge
      rotations to various X-ray structures of MBP seeking to minimize the difference
      between the experimentally measured and calculated dipolar couplings. Consistent
      structures have been derived in this manner starting from four different crystal
      forms of MBP. The analysis has revealed substantial differences between the
      resulting solution-state conformation and its crystal-state counterpart (Protein
      Data Bank accession code 1DMB) with the solution structure characterized by an
      11(+/-1) degrees domain closure. We have demonstrated that the precision achieved
      in these analyses is most likely limited by small uncertainties in the
      intradomain structure of the protein (ca 5 degrees uncertainty in orientation of
      internuclear vectors within domains). In addition, potential effects of
      interdomain motion have been considered using a number of different models and it
      was found that the structures derived on the basis of dipolar couplings
      accurately represent the effective average conformation of the protein.

PMID- 10653703
TI  - The transition state in the folding-unfolding reaction of four species of three
      disulfide variant of hen lysozyme: the role of each disulfide bridge.
AB  - The effects of lacking a specific disulfide bridge on the transition state in
      folding were examined in order to explore the folding-unfolding mechanism of
      lysozyme. Four species of three-disulfide variant of hen lysozyme (3SS-lysozyme)
      were prepared by replacing two Cys residues with Ala or Ser: C6S/C127A,
      C30A/C115A, C64A/C80A and C76A/C94A. The recombinant hen lysozyme was studied as
      the standard reference containing four authentic disulfide bridges and the extra
      N-terminal Met: the recombinant hen lysozyme containing the extra N-terminal.
      Folding rates were measured by monitoring the change in fluorescence intensity
      associated with tri-N-acetyl-d-glucosamine binding to the active site of refolded
      lysozyme. It was confirmed that the folding rate of the recombinant hen lysozyme
      containing the extra N-terminal was the same as that of wild-type lysozyme, and
      that the folding rate was little affected by the presence of tri-N-acetyl-d
      glucosamine (triNAG). The folding rate of C64A/C80A was found to be the fastest
      and almost the same as that of the recombinant hen lysozyme containing the extra
      N-terminal, and that of C30A/C115A the second, and that of C6S/C127A the third.
      The folding rate of C76A/C94A was particularly slow. On the other hand, the
      unfolding rates which were measured in the presence of triNAG showed the
      dependence on the concentration of triNAG. The intrinsic unfolding rate in the
      absence of triNAG was determined by extrapolation. Also in the unfolding rate,
      C76A/C94A was markedly slower than the others. It was found from the analysis of
      binding constants of triNAG to C64A/C80A during the unfolding process that the
      active site of C64A/C80A partly unfolds already prior to the unfolding
      transition. On the basis of these kinetic data, we suggest that C64A/C80A folding
      transition can occur with leaving the loop region around SS3 (C64-C80) flexible,
      while cross-linking by SS4 (C76-C94) is important for the promotion of folding,
      because it is an indispensable constraint on the way towards the folding
      transition state.

PMID- 10653704
TI  - Limitation of bacterial growth by dissolved organic matter and iron in the
      Southern ocean.
AB  - The importance of resource limitation in controlling bacterial growth in the high
      nutrient, low-chlorophyll (HNLC) region of the Southern Ocean was experimentally
      determined during February and March 1998. Organic- and inorganic-nutrient
      enrichment experiments were performed between 42 degrees S and 55 degrees S along
      141 degrees E. Bacterial abundance, mean cell volume, and [(3)H]thymidine and
      [(3)H]leucine incorporation were measured during 4- to 5-day incubations.
      Bacterial biomass, production, and rates of growth all responded to organic
      enrichments in three of the four experiments. These results indicate that
      bacterial growth was constrained primarily by the availability of dissolved
      organic matter. Bacterial growth in the subtropical front, subantarctic zone, and
      subantarctic front responded most favorably to additions of dissolved free amino
      acids or glucose plus ammonium. Bacterial growth in these regions may be limited
      by input of both organic matter and reduced nitrogen. Unlike similar experimental
      results in other HNLC regions (subarctic and equatorial Pacific), growth
      stimulation of bacteria in the Southern Ocean resulted in significant biomass
      accumulation, apparently by stimulating bacterial growth in excess of removal
      processes. Bacterial growth was relatively unchanged by additions of iron alone;
      however, additions of glucose plus iron resulted in substantial increases in
      rates of bacterial growth and biomass accumulation. These results imply that
      bacterial growth efficiency and nitrogen utilization may be partly constrained by
      iron availability in the HNLC Southern Ocean.

PMID- 10653705
TI  - Bacterial primary colonization and early succession on surfaces in marine waters
      as determined by amplified rRNA gene restriction analysis and sequence analysis
      of 16S rRNA genes.
AB  - The nearly universal colonization of surfaces in marine waters by bacteria and
      the formation of biofilms and biofouling communities have important implications
      for ecological function and industrial processes. However, the dynamics of
      surface attachment and colonization in situ, particularly during the early stages
      of biofilm establishment, are not well understood. Experimental surfaces that
      differed in their degrees of hydrophilicity or hydrophobicity were incubated in a
      salt marsh estuary tidal creek for 24 or 72 h. The organisms colonizing these
      surfaces were examined by using a cultivation-independent approach, amplified
      ribosomal DNA restriction analysis. The goals of this study were to assess the
      diversity of bacterial colonists involved in early succession on a variety of
      surfaces and to determine the phylogenetic affiliations of the most common early
      colonists. Substantial differences in the representation of different cloned
      ribosomal DNA sequences were found when the 24- and 72-h incubations were
      compared, indicating that some new organisms were recruited and some other
      organisms were lost. Phylogenetic analyses of the most common sequences recovered
      showed that the colonists were related to organisms known to inhabit surfaces or
      particles in marine systems. A total of 22 of the 26 clones sequenced were
      affiliated with the Roseobacter subgroup of the alpha subdivision of the division
      Proteobacteria (alpha-Proteobacteria), and most of these clones were recovered at
      a high frequency from all surfaces after 24 or 72 h of incubation. Two clones
      were affiliated with the Alteromonas group of the gamma-Proteobacteria and
      appeared to be involved only in the very early stages of colonization (within the
      first 24 h). A comparison of the colonization patterns on the test surfaces
      indicated that the early bacterial community succession rate and/or direction may
      be influenced by surface physicochemical properties. However, organisms belonging
      to the Roseobacter subgroup are ubiquitous and rapid colonizers of surfaces in
      coastal environments.

PMID- 10653706
TI  - Enhancement of secretion and extracellular stability of staphylokinase in
      Bacillus subtilis by wprA gene disruption.
AB  - Staphylokinase (SAK), a polypeptide secreted by Staphylococcus aureus, is a
      plasminogen activator with a therapeutic potential in thrombosis diseases. A
      Bacillus subtilis strain which is multiply deficient in exoproteases was
      transformed by an expression plasmid carrying a promoter and a signal sequence of
      subtilisin fused in frame with the sak open reading frame. However, the amount of
      SAK secretion was marginal (45 mg/liter). In contrast, disruption of the wprA
      gene, which encodes a subtilisin-type protease, strongly promoted the production
      of SAK in the stationary phase (181 mg/liter). In addition, the extracellular
      stability of mature SAK was dramatically enhanced. These data indicate a
      significant role of the wprA gene product in degrading foreign proteins, both
      during secretion and in the extracellular milieu.

PMID- 10653707
TI  - Characterization of 4-hydroxyphenylacetate 3-hydroxylase (HpaB) of Escherichia
      coli as a reduced flavin adenine dinucleotide-utilizing monooxygenase.
AB  - 4-Hydroxyphenylacetate 3-hydroxylase (HpaB and HpaC) of Escherichia coli W has
      been reported as a two-component flavin adenine dinucleotide (FAD)-dependent
      monooxygenase that attacks a broad spectrum of phenolic compounds. However, the
      function of each component in catalysis is unclear. The large component (HpaB)
      was demonstrated here to be a reduced FAD (FADH(2))-utilizing monooxygenase. When
      an E. coli flavin reductase (Fre) having no apparent homology with HpaC was used
      to generate FADH(2) in vitro, HpaB was able to use FADH(2) and O(2) for the
      oxidation of 4-hydroxyphenylacetate. HpaB also used chemically produced FADH(2)
      for 4-hydroxyphenylacetate oxidation, further demonstrating that HpaB is an
      FADH(2)-utilizing monooxygenase. FADH(2) generated by Fre was rapidly oxidized by
      O(2) to form H(2)O(2) in the absence of HpaB. When HpaB was included in the
      reaction mixture without 4-hydroxyphenylacetate, HpaB bound FADH(2) and
      transitorily protected it from rapid autoxidation by O(2). When 4
      hydroxyphenylacetate was also present, HpaB effectively competed with O(2) for
      FADH(2) utilization, leading to 4-hydroxyphenylacetate oxidation. With sufficient
      amounts of HpaB in the reaction mixture, FADH(2) produced by Fre was mainly used
      by HpaB for the oxidation of 4-hydroxyphenylacetate. At low HpaB concentrations,
      most FADH(2) was autoxidized by O(2), causing uncoupling. However, the coupling
      of the two enzymes' activities was increased by lowering FAD concentrations in
      the reaction mixture. A database search revealed that HpaB had sequence
      similarities to several proteins and gene products involved in biosynthesis and
      biodegradation in both bacteria and archaea. This is the first report of an
      FADH(2)-utilizing monooxygenase that uses FADH(2) as a substrate rather than as a
      cofactor.

PMID- 10653708
TI  - Quinolobactin, a new siderophore of Pseudomonas fluorescens ATCC 17400, the
      production of which is repressed by the cognate pyoverdine.
AB  - Transposon mutant strain 3G6 of Pseudomonas fluorescens ATCC 17400 which was
      deficient in pyoverdine production, was found to produce another iron-chelating
      molecule; this molecule was identified as 8-hydroxy-4-methoxy-quinaldic acid
      (designated quinolobactin). The pyoverdine-deficient mutant produced a
      supplementary 75-kDa iron-repressed outer membrane protein (IROMP) in addition to
      the 85-kDa IROMP present in the wild type. The mutant was also characterized by
      substantially increased uptake of (59)Fe-quinolobactin. The 75-kDa IROMP was
      produced by the wild type after induction by quinolobactin-containing culture
      supernatants obtained from the pyoverdine-negative mutant or by purified
      quinolobactin. Conversely, adding purified wild-type pyoverdine to the growth
      medium resulted in suppression of the 75-kDa IROMP in the pyoverdine-deficient
      mutant; however, suppression was not observed when Pseudomonas aeruginosa PAO1
      pyoverdine, a siderophore utilized by strain 3G6, was added to the culture.
      Therefore, we assume that the quinolobactin receptor is the 75-kDa IROMP and that
      the quinolobactin-mediated iron uptake system is repressed by the cognate
      pyoverdine.

PMID- 10653709
TI  - Degradation of n-hexadecane and its metabolites by Pseudomonas aeruginosa under
      microaerobic and anaerobic denitrifying conditions.
AB  - A strategy for sequential hydrocarbon bioremediation is proposed. The initial
      O(2)-requiring transformation is effected by aerobic resting cells, thus avoiding
      a high oxygen demand. The oxygenated metabolites can then be degraded even under
      anaerobic conditions when supplemented with a highly water-soluble alternative
      electron acceptor, such as nitrate. To develop the new strategy, some phenomena
      were studied by examining Pseudomonas aeruginosa fermentation. The effects of
      dissolved oxygen (DO) concentration on n-hexadecane biodegradation were
      investigated first. Under microaerobic conditions, the denitrification rate
      decreased as the DO concentration decreased, implying that the O(2)-requiring
      reactions were rate limiting. The effects of different nitrate and nitrite
      concentrations were examined next. When cultivated aerobically in tryptic soy
      broth supplemented with 0 to 0.35 g of NO(2)(-)-N per liter, cells grew in all
      systems, but the lag phase was longer in the presence of higher nitrite
      concentrations. However, under anaerobic denitrifying conditions, even 0.1 g of
      NO(2)(-)-N per liter totally inhibited cell growth. Growth was also inhibited by
      high nitrate concentrations (>1 g of NO(3)(-)-N per liter). Cells were found to
      be more sensitive to nitrate or nitrite inhibition under denitrifying conditions
      than under aerobic conditions. Sequential hexadecane biodegradation by P.
      aeruginosa was then investigated. The initial fermentation was aerobic for cell
      growth and hydrocarbon oxidation to oxygenated metabolites, as confirmed by
      increasing dissolved total organic carbon (TOC) concentrations. The culture was
      then supplemented with nitrate and purged with nitrogen (N(2)). Nitrate was
      consumed rapidly initially. The live cell concentration, however, also decreased.
      The aqueous-phase TOC level decreased by about 40% during the initial active
      period but remained high after this period. Additional experiments confirmed that
      only about one-half of the derived TOC was readily consumable under anaerobic
      denitrifying conditions.

PMID- 10653711
TI  - Glycine betaine, carnitine, and choline enhance salinity tolerance and prevent
      the accumulation of sodium to a level inhibiting growth of Tetragenococcus
      halophila.
AB  - Natural-abundance (13)C-nuclear magnetic resonance was used to probe the
      intracellular organic solute content of the moderately halophilic bacterium
      Tetragenococcus halophila. When grown in complex growth media supplemented or not
      with NaCl, T. halophila accumulates glycine betaine and carnitine. Unlike other
      moderate halophiles, T. halophila was not able to produce potent osmoprotectants
      (such as ectoines and glycine betaine) through de novo synthesis when cultured in
      defined medium under hyperosmotic constraint. Addition of 2 mM carnitine, glycine
      betaine, or choline to defined medium improved growth parameters, not only at
      high salinity (up to 2.5 M NaCl) but also in media lacking NaCl. These compounds
      were taken up when available in the surrounding medium. The transport activity
      occurred at low and high salinities and seems to be constitutive. Glycine betaine
      and carnitine were accumulated by T. halophila in an unmodified form, while
      exogenously provided choline led to an intracellular accumulation of glycine
      betaine. This is the first evidence of the existence of a choline-glycine betaine
      pathway in a lactic acid bacterium. An assay showed that the compatible solutes
      strikingly repressed the accumulation of glutamate and slightly increased the
      intracellular potassium level only at high salinity. Interestingly,
      osmoprotectant-treated cells were able to maintain the intracellular sodium
      concentration at a relatively constant level (200 to 300 nmol/mg [dry weight]),
      independent of the NaCl concentration of the medium. In contrast, in the absence
      of osmoprotectant, the intracellular sodium content increased sharply from 200 to
      2,060 nmol/mg (dry weight) when the salinity of the medium was raised from 1 to 2
      M. Indeed, the imported compatible solutes play an actual role in regulating the
      intracellular Na(+) content and confer a much higher salt tolerance to T.
      halophila.

PMID- 10653710
TI  - Identification of and spatio-temporal differences between microbial assemblages
      from two neighboring sulfurous lakes: comparison by microscopy and denaturing
      gradient gel electrophoresis.
AB  - The microbial assemblages of Lake Ciso and Lake Vilar (Banyoles, northeast Spain)
      were analyzed in space and time by microscopy and by performing PCR-denaturing
      gradient gel electrophoresis (DGGE) and sequence analysis of 16S rRNA gene
      fragments. Samples obtained from different water depths and at two different
      times of the year (in the winter during holomixis and in the early spring during
      a phytoplankton bloom) were analyzed. Although the lakes have the same climatic
      conditions and the same water source, the limnological parameters were different,
      as were most of the morphologically distinguishable photosynthetic bacteria
      enumerated by microscopy. The phylogenetic affiliations of the predominant DGGE
      bands were inferred by performing a comparative 16S rRNA sequence analysis.
      Sequences obtained from Lake Ciso samples were related to gram-positive bacteria
      and to members of the division Proteobacteria. Sequences obtained from Lake Vilar
      samples were related to members of the Cytophaga-Flavobacterium-Bacteroides
      phylum and to cyanobacteria. Thus, we found that like the previously reported
      differences between morphologically distinct inhabitants of the two lakes, there
      were also differences among the community members whose morphologies did not
      differ conspicuously. The changes in the species composition from winter to
      spring were also marked. The two lakes both contained sequences belonging to
      phototrophic green sulfur bacteria, which is consistent with microscopic
      observations, but these sequences were different from the sequences of cultured
      strains previously isolated from the lakes. Euryarchaeal sequences (i.e.,
      methanogen- and thermoplasma-related sequences) also were present in both lakes.
      These euryarchaeal group sequences dominated the archaeal sequences in Lake Ciso
      but not in Lake Vilar. In Lake Vilar, a new planktonic population related to the
      crenarchaeota produced the dominant archaeal band. The phylogenetic analysis
      indicated that new bacterial and archaeal lineages were present and that the
      microbial diversity of these assemblages was greater than previously known. We
      evaluated the correspondence between the abundances of several morphotypes and
      DGGE bands by comparing microscopy and sequencing results. Our data provide
      evidence that the sequences obtained from the DGGE fingerprints correspond to the
      microorganisms that are actually present at higher concentrations in the natural
      system.

PMID- 10653712
TI  - Naphthalene degradation and incorporation of naphthalene-derived carbon into
      biomass by the thermophile Bacillus thermoleovorans.
AB  - The thermophilic aerobic bacterium Bacillus thermoleovorans Hamburg 2 grows at 60
      degrees C on naphthalene as the sole source of carbon and energy. In batch
      cultures, an effective substrate degradation was observed. The carbon balance,
      including naphthalene, metabolites, biomass, and CO(2), was determined by the
      application of [1-(13)C]naphthalene. The incorporation of naphthalene-derived
      carbon into the bulk biomass as well as into specified biomass fractions such as
      fatty acids and amino acids was confirmed by coupled gas chromatography-mass
      spectrometry (GC-MS) and isotope analyses. Metabolites were characterized by GC
      MS; the established structures allow tracing the degradation pathway under
      thermophilic conditions. Apart from typical metabolites of naphthalene
      degradation known from mesophiles, intermediates such as 2, 3
      dihydroxynaphthalene, 2-carboxycinnamic acid, and phthalic and benzoic acid were
      identified for the pathway of this bacterium. These compounds indicate that
      naphthalene degradation by the thermophilic B. thermoleovorans differs from the
      known pathways found for mesophilic bacteria.

PMID- 10653713
TI  - Natural mediators in the oxidation of polycyclic aromatic hydrocarbons by laccase
      mediator systems.
AB  - The oxidation of polycyclic aromatic compounds was studied in systems consisting
      of laccase from Trametes versicolor and so-called mediator compounds. The
      enzymatic oxidation of acenaphthene, acenaphthylene, anthracene, and fluorene was
      mediated by various laccase substrates (phenols and aromatic amines) or compounds
      produced and secreted by white rot fungi. The best natural mediators, such as
      phenol, aniline, 4-hydroxybenzoic acid, and 4-hydroxybenzyl alcohol were as
      efficient as the previously described synthetic compounds ABTS [2,2'-azino-bis-(3
      ethylbenzothiazoline-6-sulfonic acid)] and 1-hydroxybenzotriazole. The oxidation
      efficiency increased proportionally with the redox potentials of the phenolic
      mediators up to a maximum value of 0.9 V and decreased thereafter with redox
      potentials exceeding this value. Natural compounds such as methionine, cysteine,
      and reduced glutathione, containing sulfhydryl groups, were also active as
      mediator compounds.

PMID- 10653714
TI  - Interspecific transfer of Streptomyces giant linear plasmids in sterile amended
      soil microcosms.
AB  - The interspecific transfer of two giant linear plasmids was investigated in
      sterile soil microcosms. Plasmids pRJ3L (322 kb) and pRJ28 (330 kb), both
      encoding mercury resistance, were successfully transferred in amended soil
      microcosms from their streptomycete hosts, the isolates CHR3 and CHR28,
      respectively, to a plasmidless and mercury-sensitive strain, Streptomyces
      lividans TK24. Transconjugants of S. lividans TK24 were first observed after 2 to
      3 days of incubation at 30 degrees C, which corresponded to the time taken for
      the formation of mycelia in soil. Transfer frequencies were 4.8 x 10(-4) and 3.6
      x 10(-5) CFU/donor genome for pRJ3L and pRJ28, respectively. Transconjugants were
      analyzed by pulsed-field gel electrophoresis for the presence of plasmids, and
      plasmid identity was confirmed by restriction digests. Total genomic DNA digests
      confirmed that transconjugants were S. lividans TK24. The mercury resistance
      genes were shown to be on the plasmid in the transconjugants by hybridization
      analysis and were still functional. This is the first demonstration of transfer
      of giant linear plasmids in sterile soil microcosms. Giant linear plasmids were
      detected in many Streptomyces spp. isolated from mercury-contaminated sediments
      from Boston Harbor (United States), Townsville Harbor (Australia), and the Sali
      River (Tucuman, Argentina). Mercury resistance genes were shown to be present on
      some of these plasmids. Our findings that giant linear plasmids can be
      transferred between Streptomyces spp. and are common in environmental
      Streptomyces isolates suggest that these plasmids are important in gene transfer
      between streptomycetes in the environment.

PMID- 10653715
TI  - Broad-host-range shuttle vectors for screening of regulated promoter activity in
      viridans group streptococci: isolation of a pH-regulated promoter.
AB  - Viridans group streptococci are major constituents of the normal human oral flora
      and are also identified as the predominant pathogenic bacteria in native valve
      infective endocarditis. Little information is available regarding the regulation
      of gene expression in viridans group streptococci, either in response to changes
      in the oral environment or during development of endocarditis. We therefore
      constructed a set of broad-host-range vectors for the isolation of promoters from
      viridans group streptococci that are activated by specific environmental stimuli
      in vitro or in vivo. A genomic library of Streptococcus gordonii strain CH1 was
      constructed in one of the new vectors, and this library was introduced into a
      homologous bacterium by using an optimized electroporation protocol for viridans
      group streptococci. Because viridans group streptococci entering the bloodstream
      from the oral cavity encounter an increase in pH, we selected promoters
      upregulated by this specific stimulus. One of the selected promoter sequences
      showed homology to the promoter region of the hydA gene from Clostridium
      acetobutylicum, the expression of which is known to be regulated by the
      environmental pH. The isolation of this pH-regulated promoter shows that S.
      gordonii can sense an increase in the environmental pH, which serves as a signal
      for bacterial gene activation. Furthermore, this demonstrates the usefulness of
      these new selection vectors in research on adaptive gene expression of viridans
      group streptococci and possibly also of other gram-positive bacteria.

PMID- 10653716
TI  - Dissimilatory metal reduction by the facultative anaerobe Pantoea agglomerans
      SP1.
AB  - Anaerobic enrichments with acetate as the electron donor and Fe(III) as the
      terminal electron acceptor were obtained from sediments of Salt Pond, a coastal
      marine basin near Woods Hole, Mass. A pure culture of a facultatively anaerobic
      Fe(III) reducer was isolated, and 16S rRNA analysis demonstrated that this
      organism was most closely related to Pantoea (formerly Enterobacter) agglomerans,
      a member of the family Enterobacteriaceae within the gamma subdivision of the
      Proteobacteria. This organism, designated strain SP1, can grow by coupling the
      oxidation of acetate or H(2) to the reduction of a variety of electron acceptors,
      including Fe(III), Mn(IV), Cr(VI), and the humic substance analog 2,6
      anthraquinone disulfonate, but not sulfate. To our knowledge, this is the first
      mesophilic facultative anaerobe reported to couple acetate oxidation to
      dissimilatory metal reduction.

PMID- 10653717
TI  - Peptide nucleic acid-mediated PCR clamping as a useful supplement in the
      determination of microbial diversity.
AB  - Peptide nucleic acid (PNA)-mediated PCR clamping (H. Orum, P. E. Nielsen, M.
      Egholm, R. H. Berg, O. Buchardt, and C. Stanley, Nucleic Acids Res. 21:5332-5336,
      1993) was introduced as a novel procedure to selectively amplify ribosomal DNAs
      (rDNAs) which are not frequently found in clone libraries generated by standard
      PCR from complex microbial consortia. Three different PNA molecules were used;
      two of these molecules (PNA-ALF and PNA-EUB353) overlapped with one of the
      amplification primers, whereas PNA-1114F hybridized to the middle of the
      amplified region. Thus, PCR clamping was achieved either by competitive binding
      between the PNA molecules and the forward or reverse primers (competitive
      clamping) or by hindering polymerase readthrough (elongation arrest). Gene
      libraries generated from mixed rDNA templates by using PCR clamping are enriched
      for clones that do not contain sequences homologous to the appropriate PNA
      oligomer. This effect of PCR clamping was exploited in the following two ways:
      (i) analysis of gene libraries generated by PCR clamping with PNA-ALF together
      with standard libraries reduced the number of clones which had to be analyzed to
      detect all of the different sequences present in an artificial rDNA mixture; and
      (ii) PCR clamping with PNA-EUB353 and PNA-1114F was used to selectively recover
      rDNA sequences which represented recently described phylogenetic groups (NKB19,
      TM6, cluster related to green nonsulfur bacteria) from an anaerobic,
      dechlorinating consortium described previously. We concluded that PCR clamping
      might be a useful supplement to standard PCR amplification in rDNA-based studies
      of microbial diversity and could be used to selectively recover members of
      undescribed phylogenetic clusters from complex microbial communities.

PMID- 10653718
TI  - The Streptococcus thermophilus autolytic phenotype results from a leaky prophage.
AB  - Streptococcus thermophilus autolytic strains are characterized by a typical bell
      shaped growth curve when grown under appropriate conditions. The cellular
      mechanisms involved in the triggering of lysis and the bacteriolytic activities
      of these strains were investigated in this study. Lactose depletion and organic
      solvents (ethanol, methanol, and chloroform) were shown to trigger a premature
      and immediate lysis of M17 exponentially growing cells. These factors and
      compounds are suspected to act by altering the cell envelope properties, causing
      either the permeabilization (organic solvents) or the depolarization (lactose
      depletion) of the cytoplasmic membrane. The autolytic character was shown to be
      associated with lysogeny. Phage particles, most of which were defective, were
      observed in the culture supernatants after both mitomycin C-induced and
      spontaneous lysis. By renaturing sodium dodecyl sulfate-polyacrylamide gel
      electrophoresis, a bacteriolytic activity was detected at 31 kDa exclusively in
      the autolytic strains. This enzyme was detected during both growth and
      spontaneous lysis with the same intensity. We have shown that it was prophage
      encoded and homologous to the endolysin Lyt51 of the streptococcal temperate
      bacteriophage phi01205 (M. Sheehan, E. Stanley, G. F. Fitzgerald, and D. van
      Sinderen, Appl. Environ. Microbiol. 65:569-577, 1999). It appears from our
      results that the autolytic properties are conferred to the S. thermophilus
      strains by a leaky prophage but do not result from massive prophage induction.
      More specifically, we propose that phagic genes are constitutively expressed in
      almost all the cells at a low and nonlethal level and that lysis is controlled
      and achieved by the prophage-encoded lysis proteins.

PMID- 10653719
TI  - Estimation of the yield coefficient of Pseudomonas sp. strain DP-4 with a low
      substrate (2,4-dichlorophenol [DCP]) concentration in a mineral medium from which
      uncharacterized organic compounds were eliminated by a non-DCP-degrading
      organism.
AB  - The yield coefficient (YC) of Pseudomonas sp. strain DP-4, a 2, 4-dichlorophenol
      (DCP)-degrading organism, was estimated from the number of CFU produced at the
      expense of 1 unit amount of DCP at low concentrations. At a low concentration of
      DCP, the YC can be overestimated in pure culture, because DP-4 assimilated not
      only DCP but also uncharacterized organic compounds contaminating a mineral salt
      medium. The concentration of these uncharacterized organic compounds was
      nutritionally equivalent to 0.7 microg of DCP-C ml(-1). A mixed culture with non
      DCP-degrading organisms resulted in elimination of ca. 99.9% of the
      uncharacterized organic compounds, and then DP-4 assimilated only DCP as a
      substrate. In a mixed culture, DP-4 degraded an initial concentration of 0.1 to
      10 microg of C ml of DCP(-1) and the number of CFU of DP-4 increased. In the
      mixed culture, DCP at an initial concentration of 0.07 microg of C ml(-1) was
      degraded. However, the number of CFU of DP-4 did not increase. DCP at an
      extremely low initial concentration of 0.01 microg of C ml(-1) was not degraded
      in mixed culture even by a high density, 10(5) CFU ml(-1), of DP-4. When glucose
      was added to this mixed culture to a final concentration of 1 microg of C ml(-1),
      the initial concentration of 0.01 microg of C ml of DCP(-1) was degraded. These
      results suggested that DP-4 required cosubstrates to degrade DCP at an extremely
      low initial concentration of 0.01 microg of C ml(-1). The YCs of DP-4 at the
      expense of DCP alone decreased discontinuously with the decrease of the initial
      concentration of DCP, i.e., 1.5, 0.19, or 0 CFU per pg of DCP-C when 0.7 to 10,
      0.1 to 0.5, or 0.07 microg of C ml of DCP(-1) was degraded, respectively. In this
      study, we developed a new method to eliminate uncharacterized organic compounds,
      and we estimated the YC of DP-4 at the expense of DCP as a sole source of carbon.

PMID- 10653720
TI  - Characterization and role of the branched-chain aminotransferase (BcaT) isolated
      from Lactococcus lactis subsp. cremoris NCDO 763.
AB  - In Lactococcus lactis, which is widely used as a starter in the cheese industry,
      the first step of aromatic and branched-chain amino acid degradation is a
      transamination which is catalyzed by two major aminotransferases. We have
      previously purified and characterized biochemically and genetically the aromatic
      aminotransferase, AraT. In the present study, we purified and studied the second
      enzyme, the branched-chain aminotransferase, BcaT. We cloned and sequenced the
      corresponding gene and used a mutant, along with the luciferase gene as the
      reporter, to study the role of the enzyme in amino acid metabolism and to reveal
      the regulation of gene transcription. BcaT catalyzes transamination of the three
      branched-chain amino acids and methionine and belongs to class IV of the
      pyridoxal 5'-phosphate-dependent aminotransferases. In contrast to most of the
      previously described bacterial BcaTs, which are hexameric, this enzyme is
      homodimeric. It is responsible for 90% of the total isoleucine and valine
      aminotransferase activity of the cell and for 50 and 40% of the activity towards
      leucine and methionine, respectively. The original role of BcaT was probably
      biosynthetic since expression of its gene was repressed by free amino acids and
      especially by isoleucine. However, in dairy strains, which are auxotrophic for
      branched-chain amino acids, BcaT functions only as a catabolic enzyme that
      initiates the conversion of major aroma precursors. Since this enzyme is still
      active under cheese-ripening conditions, it certainly plays a major role in
      cheese flavor development.

PMID- 10653721
TI  - Dynamics of bacterial community composition and activity during a mesocosm diatom
      bloom.
AB  - Bacterial community composition, enzymatic activities, and carbon dynamics were
      examined during diatom blooms in four 200-liter laboratory seawater mesocosms.
      The objective was to determine whether the dramatic shifts in growth rates and
      ectoenzyme activities, which are commonly observed during the course of
      phytoplankton blooms and their subsequent demise, could result from shifts in
      bacterial community composition. Nutrient enrichment of metazoan-free seawater
      resulted in diatom blooms dominated by a Thalassiosira sp., which peaked 9 days
      after enrichment ( approximately 24 microg of chlorophyll a liter(-1)). At this
      time bacterial abundance abruptly decreased from 2.8 x 10(6) to 0.75 x 10(6) ml(
      1), and an analysis of bacterial community composition, by denaturing gradient
      gel electrophoresis (DGGE) of PCR-amplified 16S rRNA gene fragments, revealed the
      disappearance of three dominant phylotypes. Increased viral and flagellate
      abundances suggested that both lysis and grazing could have played a role in the
      observed phylotype-specific mortality. Subsequently, new phylotypes appeared and
      bacterial production, abundance, and enzyme activities shifted from being
      predominantly associated with the <1.0-microm size fraction towards the >1.0
      microm size fraction, indicating a pronounced microbial colonization of
      particles. Sequencing of DGGE bands suggested that the observed rapid and
      extensive colonization of particulate matter was mainly by specialized alpha
      Proteobacteria- and Cytophagales-related phylotypes. These particle-associated
      bacteria had high growth rates as well as high cell-specific aminopeptidase, beta
      glucosidase, and lipase activities. Rate measurements as well as bacterial
      population dynamics were almost identical among the mesocosms indicating that the
      observed bacterial community dynamics were systematic and repeatable responses to
      the manipulated conditions.

PMID- 10653723
TI  - Genetically modified Vibrio harveyi strains as potential bioindicators of
      mutagenic pollution of marine environments.
AB  - For biodetection of mutagenic pollution of marine environments, an organism
      naturally occurring in these habitats should be used. We found that marine
      bacterium Vibrio harveyi may be an appropriate bioindicator of mutagenic
      pollution. For positive selection of mutants, we developed a simple method for
      isolation of V. harveyi mutants resistant to neomycin. We constructed genetically
      modified V. harveyi strains that produce significantly more neomycin-resistant
      mutants upon treatment with low concentrations of mutagens than the wild-type
      counterpart. The sensitivity of the mutagenicity test with the V. harveyi strains
      is at least comparable to (if not higher than) that of the commonly used Ames
      test, which uses Salmonella enterica serovar Typhimurium strains. Therefore, we
      consider that the V. harveyi strains described in this report could be used as
      potential bioindicators of mutagenic pollution of marine environments.

PMID- 10653722
TI  - Expression of the Staphylococcus hyicus lipase in Lactococcus lactis.
AB  - The extracellular Staphylococcus hyicus lipase was expressed under the control of
      different promoters in Lactococcus lactis and Bacillus subtilis. Its expression
      at high and moderate levels is toxic for the former and the latter hosts,
      respectively. In L. lactis, the lipase was expressed at a high level, up to 30%
      of the total cellular proteins, under the control of the inducible promoter
      PnisA. About 80% of the lipase remained associated with the cells. Close to half
      of this amount remained associated with the inner side of the cytoplasmic
      membrane as unprocessed pre-pro-lipase. The other half was trapped by the cell
      wall and partially degraded at the N-terminal end. This result suggests that
      extracellular proteases degrade the lipase. Surprisingly, the kinetics and the
      pattern of lipase degradation were different in the two L. lactis subspecies, L.
      lactis subsp. cremoris and L. lactis subsp. lactis. The extracellular proteolytic
      systems that degrade lipase are thus different in these closely related
      subspecies. The incorrect export of the lipase is not due to an inappropriate
      leader peptide but may be due to an inefficiency of several steps of lipase
      secretion. We propose that (i) the S. hyicus lipase may require a special
      accessory system to be correctly exported or (ii) the kinetics of lipase
      synthesis may be a critical factor for proper folding.

PMID- 10653724
TI  - Bacteriocin production with Lactobacillus amylovorus DCE 471 is improved and
      stabilized by fed-batch fermentation.
AB  - Amylovorin L471 is a small, heat-stable, and hydrophobic bacteriocin produced by
      Lactobacillus amylovorus DCE 471. The nutritional requirements for amylovorin
      L471 production were studied with fed-batch fermentations. A twofold increase in
      bacteriocin titer was obtained when substrate addition was controlled by the
      acidification rate of the culture, compared with the titers reached with constant
      substrate addition or pH-controlled batch cultures carried out under the same
      conditions. An interesting feature of fed-batch cultures observed under certain
      culture conditions (constant feed rate) is the apparent stabilization of
      bacteriocin activity after obtaining maximum production. Finally, a mathematical
      model was set up to simulate cell growth, glucose and complex nitrogen source
      consumption, and lactic acid and bacteriocin production kinetics. The model
      showed that bacterial growth was dependent on both the energy and the complex
      nitrogen source. Bacteriocin production was growth associated, with a
      simultaneous bacteriocin adsorption on the producer cells dependent on the lactic
      acid accumulated and hence the viability of the cells. Both bacteriocin
      production and adsorption were inhibited by high concentrations of the complex
      nitrogen source.

PMID- 10653725
TI  - Molecular characterization of Irish Salmonella enterica serotype typhimurium:
      detection of class I integrons and assessment of genetic relationships by DNA
      amplification fingerprinting.
AB  - Salmonella enterica is among the principal etiological agents of food-borne
      illness in humans. Increasing antimicrobial resistance in S. enterica is a cause
      for worldwide concern. There is concern at present in relation to the increasing
      incidence of human infection with antimicrobial agent-resistant strains of S.
      enterica serotype Typhimurium, in particular of phage type DT104. Integrons
      appear to play an important role in the dissemination of antimicrobial resistance
      genes in many Enterobacteriaceae including S. enterica. In this study the
      antimicrobial susceptibilities and phage types of 74 randomly collected strains
      of S. enterica serotype Typhimurium from the Cork region of southern Ireland,
      obtained from human, animal (clinical), and food sources, were determined. Each
      strain was examined for integrons and typed by DNA amplification fingerprinting
      (DAF). Phage type DT104 predominated (n = 48). Phage types DT104b (n = 3), -193
      (n = 9), -195 (n = 6), -208 (n = 3), -204a (n = 2), PT U302 (n = 1), and two
      nontypeable strains accounted for the remainder. All S. enterica serotype
      Typhimurium DT104 strains were resistant to ampicillin, chloramphenicol,
      streptomycin, Sulfonamide Duplex, and tetracycline, and one strain was
      additionally resistant to trimethoprim. All DT104 strains but one were of a
      uniform DAF type (designated DAF-I) and showed a uniform pattern of integrons
      (designated IP-I). The DT104b and PT U302 strains also exhibited the same
      resistance phenotype, and both had the DAF-I and IP-I patterns. The DAF-I pattern
      was also observed in a single DT193 strain in which no integrons were detectable.
      Greater diversity of antibiograms and DAF and IP patterns among non-DT104 phage
      types was observed. These data indicate a remarkable degree of homogeneity at a
      molecular level among contemporary isolates of S. enterica serotype Typhimurium
      DT104 from animal, human, and food sources in this region.

PMID- 10653726
TI  - Role of the spore coat layers in Bacillus subtilis spore resistance to hydrogen
      peroxide, artificial UV-C, UV-B, and solar UV radiation.
AB  - Spores of Bacillus subtilis possess a thick protein coat that consists of an
      electron-dense outer coat layer and a lamellalike inner coat layer. The spore
      coat has been shown to confer resistance to lysozyme and other sporicidal
      substances. In this study, spore coat-defective mutants of B. subtilis
      (containing the gerE36 and/or cotE::cat mutation) were used to study the relative
      contributions of spore coat layers to spore resistance to hydrogen peroxide
      (H(2)O(2)) and various artificial and solar UV treatments. Spores of strains
      carrying mutations in gerE and/or cotE were very sensitive to lysozyme and to 5%
      H(2)O(2), as were chemically decoated spores of the wild-type parental strain.
      Spores of all coat-defective strains were as resistant to 254-nm UV-C radiation
      as wild-type spores were. Spores possessing the gerE36 mutation were
      significantly more sensitive to artificial UV-B and solar UV radiation than wild
      type spores were. In contrast, spores of strains possessing the cotE::cat
      mutation were significantly more resistant to all of the UV treatments used than
      wild-type spores were. Spores of strains carrying both the gerE36 and cotE::cat
      mutations behaved like gerE36 mutant spores. Our results indicate that the spore
      coat, particularly the inner coat layer, plays a role in spore resistance to
      environmentally relevant UV wavelengths.

PMID- 10653727
TI  - Increased levels of markers of microbial exposure in homes with indoor storage of
      organic household waste.
AB  - As part of environmental management policies in Europe, separate collection of
      organic household waste and nonorganic household waste has become increasingly
      common. As waste is often stored indoors, this policy might increase microbial
      exposure in the home environment. In this study we evaluated the association
      between indoor storage of organic waste and levels of microbial agents in house
      dust. The levels of bacterial endotoxins, mold beta(1-->3)-glucans, and fungal
      extracellular polysaccharides (EPS) of Aspergillus and Penicillium species were
      determined in house dust extracts as markers of microbial exposure. House dust
      samples were collected in 99 homes in The Netherlands selected on the basis of
      whether separated organic waste was present in the house. In homes in which
      separated organic waste was stored indoors for 1 week or more the levels of
      endotoxin, EPS, and glucan were 3.2-, 7.6-, and 4. 6-fold higher, respectively
      (all P < 0.05), on both living room and kitchen floors than the levels in homes
      in which only nonorganic residual waste was stored indoors. Increased levels of
      endotoxin and EPS were observed, 2.6- and 2.1-fold (P < 0.1), respectively, when
      separated organic waste was stored indoors for 1 week or less, whereas storage of
      nonseparated waste indoors had no effect on microbial agent levels (P > 0.2). The
      presence of textile floor covering was another major determinant of microbial
      levels (P < 0.05). Our results indicate that increased microbial contaminant
      levels in homes are associated with indoor storage of separated organic waste.
      These increased levels might increase the risk of bioaerosol-related respiratory
      symptoms in susceptible people.

PMID- 10653728
TI  - Role of rpoS in acid resistance and fecal shedding of Escherichia coli O157:H7.
AB  - Acid resistance (AR) is important to survival of Escherichia coli O157:H7 in
      acidic foods and may play a role during passage through the bovine host. In this
      study, we examined the role in AR of the rpoS-encoded global stress response
      regulator sigma(S) and its effect on shedding of E. coli O157:H7 in mice and
      calves. When assayed for each of the three AR systems identified in E. coli, an
      rpoS mutant (rpoS::pRR10) of E. coli O157:H7 lacked the glucose-repressed system
      and possessed reduced levels of both the arginine- and glutamate-dependent AR
      systems. After administration of the rpoS mutant and the wild-type strain (ATCC
      43895) to ICR mice at doses ranging from 10(1) to 10(4) CFU, we found the wild
      type strain in feces of mice given lower doses (10(2) versus 10(3) CFU) and at a
      greater frequency (80% versus 13%) than the mutant strain. The reduction in
      passage of the rpoS mutant was due to decreased AR, as administration of the
      mutant in 0.05 M phosphate buffer facilitated passage and increased the frequency
      of recovery in feces from 27 to 67% at a dose of 10(4) CFU. Enumeration of E.
      coli O157:H7 in feces from calves inoculated with an equal mixture of the wild
      type strain and the rpoS mutant demonstrated shedding of the mutant to be 10- to
      100-fold lower than wild-type numbers. This difference in shedding between the
      wild-type strain and the rpoS mutant was statistically significant (P </= 0.05).
      Thus, sigma(S) appears to play a role in E. coli O157:H7 passage in mice and
      shedding from calves, possibly by inducing expression of the glucose-repressed
      RpoS-dependent AR determinant and thus increasing resistance to gastrointestinal
      stress. These findings may provide clues for future efforts aimed at reducing or
      eliminating this pathogen from cattle herds.

PMID- 10653729
TI  - A protein disulfide isomerase gene fusion expression system that increases the
      extracellular productivity of Bacillus brevis.
AB  - We have developed a versatile Bacillus brevis expression and secretion system
      based on the use of fungal protein disulfide isomerase (PDI) as a gene fusion
      partner. Fusion with PDI increased the extracellular production of heterologous
      proteins (light chain of immunoglobulin G, 8-fold; geranylgeranyl pyrophosphate
      synthase, 12-fold). Linkage to PDI prevented the aggregation of the secreted
      proteins, resulting in high-level accumulation of fusion proteins in soluble and
      biologically active forms. We also show that the disulfide isomerase activity of
      PDI in a fusion protein is responsible for the suppression of the aggregation of
      the protein with intradisulfide, whereas aggregation of the protein without
      intradisulfide was prevented even when the protein was fused to a mutant PDI
      whose two active sites were disrupted, suggesting that another PDI function, such
      as chaperone-like activity, synergistically prevented the aggregation of
      heterologous proteins in the PDI fusion expression system.

PMID- 10653730
TI  - Endosymbiotic microbiota of the bamboo pseudococcid Antonina crawii (Insecta,
      Homoptera).
AB  - We characterized the intracellular symbiotic microbiota of the bamboo
      pseudococcid Antonina crawii by performing a molecular phylogenetic analysis in
      combination with in situ hybridization. Almost the entire length of the bacterial
      16S rRNA gene was amplified and cloned from A. crawii whole DNA. Restriction
      fragment length polymorphism analysis revealed that the clones obtained included
      three distinct types of sequences. Nucleotide sequences of the three types were
      determined and subjected to a molecular phylogenetic analysis. The first sequence
      was a member of the gamma subdivision of the division Proteobacteria (gamma
      Proteobacteria) to which no sequences in the database were closely related,
      although the sequences of endosymbionts of other homopterans, such as psyllids
      and aphids, were distantly related. The second sequence was a beta-Proteobacteria
      sequence and formed a monophyletic group with the sequences of endosymbionts from
      other pseudococcids. The third sequence exhibited a high level of similarity to
      sequences of Spiroplasma spp. from ladybird beetles and a tick. Localization of
      the endosymbionts was determined by using tissue sections of A. crawii and in
      situ hybridization with specific oligonucleotide probes. The gamma- and beta
      Proteobacteria symbionts were packed in the cytoplasm of the same mycetocytes (or
      bacteriocytes) and formed a large mycetome (or bacteriome) in the abdomen. The
      spiroplasma symbionts were also present intracellularly in various tissues at a
      low density. We observed that the anterior poles of developing eggs in the
      ovaries were infected by the gamma- and beta-Proteobacteria symbionts in a
      systematic way, which ensured vertical transmission. Five representative
      pseudococcids were examined by performing diagnostic PCR experiments with
      specific primers; the beta-Proteobacteria symbiont was detected in all five
      pseudococcids, the gamma-Proteobacteria symbiont was found in three, and the
      spiroplasma symbiont was detected only in A. crawii.

PMID- 10653731
TI  - Genetic variation among endosymbionts of widely distributed vestimentiferan
      tubeworms.
AB  - Vestimentiferan tubeworms thriving in sulfidic deep-sea hydrothermal vents and
      cold seeps are constrained by their nutritional reliance on chemoautotrophic
      endosymbionts. In a recent phylogenetic study using 16S ribosomal DNA, we found
      that endosymbionts from vent and seep habitats form two distinct clades with
      little variation within each clade. In the present study, we used two different
      approaches to assess the genetic variation among biogeographically distinct
      vestimentiferan symbionts. DNA sequences were obtained for the noncoding,
      internal transcribed spacer (ITS) regions of the rRNA operons of symbionts
      associated with six different genera of vestimentiferan tubeworms. ITS sequences
      from endosymbionts of host genera collected from different habitats and widely
      distributed vent sites were surprisingly conserved. Because the ITS region was
      not sufficient for distinguishing endosymbionts from different habitats or
      locations, we used a DNA fingerprinting technique, repetitive-extragenic
      palindrome PCR (REP-PCR), to reveal differences in the distribution of repetitive
      sequences in the genomes of the bacterial endosymbionts. Most of the
      endosymbionts displayed unique REP-PCR patterns. A cladogram generated from these
      fingerprints reflected relationships that may be influenced by a variety of
      factors, including host genera, geographic location, and bottom type.

PMID- 10653732
TI  - Inhibition of Streptococcus mutans NS adhesion to glass with and without a
      salivary conditioning film by biosurfactant- releasing Streptococcus mitis
      strains.
AB  - The release of biosurfactants by adhering microorganisms as a defense mechanism
      against other colonizing strains on the same substratum surface has been
      described previously for probiotic bacteria in the urogenital tract, the
      intestines, and the oropharynx but not for microorganisms in the oral cavity. Two
      Streptococcus mitis strains (BA and BMS) released maximal amounts of
      biosurfactants when they were grown in the presence of sucrose and were harvested
      in the early stationary phase. The S. mitis biosurfactants reduced the surface
      tensions of aqueous solutions to about 30 to 40 mJ m(-2). Biochemical and
      physicochemical analyses revealed that the biosurfactants released were
      glycolipids. An acid-precipitated fraction was extremely surfactive and was
      identified as a rhamnolipidlike compound. In a parallel-plate flow chamber, the
      number of Streptococcus mutans NS cells adhering to glass with and without a
      salivary conditioning film in the presence of biosurfactant-releasing S. mitis BA
      and BMS (surface coverage, 1 to 4%) was significantly reduced compared with the
      number of S. mutans NS cells adhering to glass in the absence of S. mitis. S.
      mutans NS adhesion in the presence of non-biosurfactant-releasing S. mitis BA and
      BMS was not reduced at all. In addition, preadsorption of isolated S. mitis
      biosurfactants to glass drastically reduced the adhesion of S. mutans NS cells
      and the strength of their bonds to glass, as shown by the increased percentage of
      S. mutans NS cells detached by the passage of air bubbles through the flow
      chamber. Preadsorption of the acid-precipitated fraction inhibited S. mutans
      adhesion up to 80% in a dose-responsive manner. These observations indicate that
      S. mitis plays a protective role in the oral cavity and protects against
      colonization of saliva-coated surfaces by cariogenic S. mutans.

PMID- 10653733
TI  - A gene encoding a novel multidomain beta-1,4-mannanase from Caldibacillus
      cellulovorans and action of the recombinant enzyme on kraft pulp.
AB  - Genomic walking PCR was used to obtained a 4,567-bp nucleotide sequence from
      Caldibacillus cellulovorans. Analysis of this sequence revealed that there were
      three open reading frames, designated ORF1, ORF2, and ORF3. Incomplete ORF1
      encoded a putative C-terminal cellulose-binding domain (CBD) homologous to
      members of CBD family IIIb, while putative ORF3 encoded a protein of unknown
      function. The putative ManA protein encoded by complete manA ORF2 was an enzyme
      with a novel multidomain structure and was composed of four domains in the
      following order: a putative N-terminal domain (D1) of unknown function, an
      internal CBD (D2), a beta-mannanase catalytic domain (D3), and a C-terminal CBD
      (D4). All four domains were linked via proline-threonine-rich peptides. Both of
      the CBDs exhibited sequence similarity to family IIIb CBDs, while the mannanase
      catalytic domain exhibited homology to the family 5 glycosyl hydrolases. The
      purified recombinant enzyme ManAd3 expressed from the cloned catalytic domain
      (D3) exhibited optimum activity at 85 degrees C and pH 6.0 and was extremely
      thermostable at 70 degrees C. This enzyme exhibited high specificity with the
      substituted galactomannan locust bean gum, while more substituted galacto- and
      glucomannans were poorly hydrolyzed. Preliminary studies to determine the effect
      of the recombinant ManAd3 and a recombinant thermostable beta-xylanase on oxygen
      delignified Pinus radiata kraft pulp revealed that there was an increase in the
      brightness of the bleached pulp.

PMID- 10653734
TI  - Cytochrome c(3) mutants of Desulfovibrio desulfuricans.
AB  - To explore the physiological role of tetraheme cytochrome c(3) in the sulfate
      reducing bacterium Desulfovibrio desulfuricans G20, the gene encoding the
      preapoprotein was cloned, sequenced, and mutated by plasmid insertion. The
      physical analysis of the DNA from the strain carrying the integrated plasmid
      showed that the insertion was successful. The growth rate of the mutant on
      lactate with sulfate was comparable to that of the wild type; however, mutant
      cultures did not achieve the same cell densities. Pyruvate, the oxidation product
      of lactate, served as a poor electron source for the mutant. Unexpectedly, the
      mutant was able to grow on hydrogen-sulfate medium. These data support a role for
      tetraheme cytochrome c(3) in the electron transport pathway from pyruvate to
      sulfate or sulfite in D. desulfuricans G20.

PMID- 10653736
TI  - Biocatalytic synthesis of vanillin.
AB  - The conversions of vanillic acid and O-benzylvanillic acid to vanillin were
      examined by using whole cells and enzyme preparations of Nocardia sp. strain NRRL
      5646. With growing cultures, vanillic acid was decarboxylated (69% yield) to
      guaiacol and reduced (11% yield) to vanillyl alcohol. In resting Nocardia cells
      in buffer, 4-O-benzylvanillic acid was converted to the corresponding alcohol
      product without decarboxylation. Purified Nocardia carboxylic acid reductase, an
      ATP and NADPH-dependent enzyme, quantitatively reduced vanillic acid to vanillin.
      Structures of metabolites were established by (1)H nuclear magnetic resonance and
      mass spectral analyses.

PMID- 10653735
TI  - Development of catechol 2,3-dioxygenase-specific primers for monitoring
      bioremediation by competitive quantitative PCR.
AB  - Benzene, toluene, xylenes, phenol, naphthalene, and biphenyl are among a group of
      compounds that have at least one reported pathway for biodegradation involving
      catechol 2,3-dioxygenase enzymes. Thus, detection of the corresponding catechol
      2,3-dioxygenase genes can serve as a basis for identifying and quantifying
      bacteria that have these catabolic abilities. Primers that can successfully
      amplify a 238-bp catechol 2,3-dioxygenase gene fragment from eight different
      bacteria are described. The identities of the amplicons were confirmed by
      hybridization with a 238-bp catechol 2,3-dioxygenase probe. The detection limit
      was 10(2) to 10(3) gene copies, which was lowered to 10(0) to 10(1) gene copies
      by hybridization. Using the dioxygenase-specific primers, an increase in catechol
      2, 3-dioxygenase genes was detected in petroleum-amended soils. The dioxygenase
      genes were enumerated by competitive quantitative PCR with a 163-bp competitor
      that was amplified using the same primers. Target and competitor sequences had
      identical amplification kinetics. Potential PCR inhibitors that could coextract
      with DNA, nonamplifying DNA, soil factors (humics), and soil pollutants (toluene)
      did not impact enumeration. Therefore, this technique can be used to accurately
      and reproducibly quantify catechol 2, 3-dioxygenase genes in complex environments
      such as petroleum-contaminated soil. Direct, non-cultivation-based molecular
      techniques for detecting and enumerating microbial pollutant-biodegrading genes
      in environmental samples are powerful tools for monitoring bioremediation and
      developing field evidence in support of natural attenuation.

PMID- 10653737
TI  - Selective removal of nitrogen from quinoline and petroleum by Pseudomonas ayucida
      IGTN9m.
AB  - Enrichment culture experiments employing soil and water samples obtained from
      petroleum-contaminated environments succeeded in the isolation of a pure culture
      possessing the ability to utilize quinoline as a sole nitrogen source but did not
      utilize quinoline as a carbon source. This culture was identified as Pseudomonas
      ayucida based on a partial 16S rRNA gene sequence, and the strain was given the
      designation IGTN9m. Examination of metabolites using thin-layer chromatography
      and gas chromatography-mass spectrometry suggests that P. ayucida IGTN9m converts
      quinoline to 2-quinolinone and subsequently to 8-hydroxycoumarin. Resting cells
      of P. ayucida IGTN9m were shown to be capable of selectively removing about 68%
      of quinoline from shale oil in a 16-h treatment time. These results suggest that
      P. ayucida IGTN9m may be useful in petroleum biorefining for the selective
      removal of organically bound nitrogen from petroleum.

PMID- 10653738
TI  - Application of neural computing methods for interpreting phospholipid fatty acid
      profiles of natural microbial communities.
AB  - The microbial community compositions of surface and subsurface marine sediments
      and sediments lining burrows of marine polychaetes and hemichordates from the
      North Inlet estuary (near Georgetown, S.C. ) were analyzed by comparing ester
      linked phospholipid fatty acid (PLFA) profiles with a back-propagating neural
      network (NN). The NNs were trained to relate PLFA inputs to sediment type outputs
      (e.g., surface, subsurface, and burrow lining) and worm species (e.g., Notomastus
      lobatus, Balanoglossus aurantiacus, and Branchyoasychus americana). Sensitivity
      analysis was used to determine which of the 60 PLFAs significantly contributed to
      training the NN. The NN architecture was optimized by changing the number of
      hidden neurons and calculating the cross-validation error between predicted and
      actual outputs of training and test data. The optimal NN architecture was found
      to be four hidden neurons with 60-input neurons representing the 60 PLFAs, and
      four output neurons coding for both sediment types and worm species. Comparison
      of cross-validation results using NNs and linear discriminant analysis (LDA)
      revealed that NNs had significantly fewer incorrect classifications (2.7%) than
      LDA (8.4%). For the NN cross-validation, both sediment type and worm species had
      3 incorrect classifications out of 112. For the LDA cross-validation, sediment
      type and worm species had 7 and 12 incorrect classifications out of 112,
      respectively. Sensitivity analysis of the trained NNs revealed that 17 fatty
      acids explained 50% of variability in the data set. These PLFAs were highly
      different among sediments and burrow types, indicating significant differences in
      the microbiota.

PMID- 10653740
TI  - In situ determination of sulfide turnover rates in a meromictic alpine lake.
AB  - A push-pull method, previously used in groundwater analyses, was successfully
      adapted for measuring sulfide turnover rates in situ at different depths in the
      meromictic Lake Cadagno. In the layer of phototrophic bacteria at about 12 m in
      depth net sulfide consumption was observed during the day, indicating active
      bacterial photosynthesis. During the night the sulfide turnover rates were
      positive, indicating a net sulfide production from the reduction of more-oxidized
      sulfur compounds. Because of lack of light, no photosynthesis takes place in the
      monimolimnion; thus, only sulfide formation is observed both during the day and
      the night. Sulfide turnover rates in the oxic mixolimnion were always positive as
      sulfide is spontaneously oxidized by oxygen and as the rates of sulfide oxidation
      depend on the oxygen concentrations present. Sulfide oxidation by
      chemolithotrophic bacteria may occur at the oxicline, but this cannot be
      distinguished from spontaneous chemical oxidation.

PMID- 10653739
TI  - Culture-dependent and culture-independent characterization of microbial
      assemblages associated with high-temperature petroleum reservoirs.
AB  - Recent investigations of oil reservoirs in a variety of locales have indicated
      that these habitats may harbor active thermophilic prokaryotic assemblages. In
      this study, we used both molecular and culture-based methods to characterize
      prokaryotic consortia associated with high-temperature, sulfur-rich oil
      reservoirs in California. Enrichment cultures designed for anaerobic
      thermophiles, both autotrophic and heterotrophic, were successful at temperatures
      ranging from 60 to 90 degrees C. Heterotrophic enrichments from all sites yielded
      sheathed rods (Thermotogales), pleomorphic rods resembling Thermoanaerobacter,
      and Thermococcus-like isolates. The predominant autotrophic microorganisms
      recovered from inorganic enrichments using H(2), acetate, and CO(2) as energy and
      carbon sources were methanogens, including isolates closely related to
      Methanobacterium, Methanococcus, and Methanoculleus species. Two 16S rRNA gene
      (rDNA) libraries were generated from total community DNA collected from
      production wellheads, using either archaeal or universal oligonucleotide primer
      sets. Sequence analysis of the universal library indicated that a large
      percentage of clones were highly similar to known bacterial and archaeal isolates
      recovered from similar habitats. Represented genera in rDNA clone libraries
      included Thermoanaerobacter, Thermococcus, Desulfothiovibrio, Aminobacterium,
      Acidaminococcus, Pseudomonas, Halomonas, Acinetobacter, Sphingomonas,
      Methylobacterium, and Desulfomicrobium. The archaeal library was dominated by
      methanogen-like rDNAs, with a lower percentage of clones belonging to the
      Thermococcales. Our results strongly support the hypothesis that sulfur-utilizing
      and methane-producing thermophilic microorganisms have a widespread distribution
      in oil reservoirs and the potential to actively participate in the biogeochemical
      transformation of carbon, hydrogen, and sulfur in situ.

PMID- 10653741
TI  - beta-cyanoalanine production by marine bacteria on cyanide-free medium and its
      specific inhibitory activity toward cyanobacteria.
AB  - In screening the culture broth of marine bacteria collected at Yap (Micronesia),
      Palau (Belau), and Okinawa (the southwest islands of Japan) for antimicroalgal
      activity, 37 out of 2,594 bacterial isolates tested were found to produce
      anticyanobacterial substances against Oscillatoria amphibia NIES-361. One strain,
      C-979, identified as a Vibrio sp., was selected and cultured in 2.4 liters of
      marine broth 2216 to identify the bioactive compound produced by the strain. The
      purified very hydrophilic compound (16.4 mg) was determined to be beta-cyano-L
      alanine (L-CNAla) by instrumental analyses and the application of the advanced
      Marfey method. L-CNAla did not inhibit the growth of bacteria, yeast, or
      eukaryotic microalgae, but some cyanobacteria were found to be sensitive to L
      CNAla at a concentration of 0.4 to 25 microg/ml. The effect of L-CNAla on some
      other environmental organisms, including invertebrates and a macroalgae, is
      discussed. CNAla production in marine broth was examined by thin-layer
      chromatography for the 37 bacterial isolates which produced an anticyanobacterial
      substance. The broth of 36 of these strains contained CNAla, suggesting the wide
      distribution of CNAla production by marine bacteria. This is the first report on
      bacteria that produce CNAla without a supply of the cyanide ion in the medium.

PMID- 10653742
TI  - Development of a selective medium for isolation of Helicobacter pylori from
      cattle and beef samples.
AB  - Helicobacter pylori has been isolated from the human stomach with media
      containing only minimal selective agents. However, current research on the
      transmission and sources of infection requires more selective media due to the
      higher numbers of contaminants in environmental, oral, and fecal samples. The
      objective of this study was to develop and evaluate detection techniques that are
      sufficiently selective to isolate H. pylori from potential animal and food
      sources. Since H. pylori survives in the acidic environment of the stomach, low
      pH with added urea was studied as a potential selective combination. H. pylori
      grew fairly well on H. pylori Special Peptone plating medium supplemented with 10
      mM urea at pH 4. 5, but this pH did not sufficiently inhibit the growth of
      contaminants. Various antibiotic combinations were then compared, and a
      combination consisting of 10 mg of vancomycin per liter, 5 mg of amphotericin B
      per liter, 10 mg of cefsulodin per liter, 62,000 IU of polymyxin B sulfate per
      liter, 40 mg of trimethoprim per liter, and 20 mg of sulfamethoxazole per liter
      proved to be highly selective but still allowed robust colonies of H. pylori to
      grow. This medium was highly selective for recovering H. pylori from cattle and
      beef samples, and it is possible that it could be used to enhance the recovery of
      this bacterium from human and environmental samples, which may be contaminated
      with large numbers of competing microorganisms.

PMID- 10653743
TI  - Sexuality and genetic identity in the Agaricus section Arvenses.
AB  - Twelve wild collections and one commercial strain were used to characterize
      breeding systems and to develop molecular identities in the Arvenses section of
      the genus Agaricus, which includes the "horse mushroom" A. arvensis. Two
      morphotypes were identified based on macro- and micromorphological features.
      However, not all collections could be delimited by conventional taxonomic
      characters. Sequencing of the small subunit intergenic spacer (ITS) region (368
      to 370 bp) of the rRNA genes clearly resolved the 13 collections into two
      clusters consistent with the identified morphotypes. Single-spore progenies and
      mating type testers were established and used to test intra- and interstock
      compatibility. The two compatibility groups identified were consistent with ITS
      clusters. Compatibility group I stocks readily interbred within the constraints
      of a unifactorial heterothallic system with a multiallelic mating type factor.
      Compatibility group II had a more restricted breeding pattern, and interactions
      were difficult to predict on the basis of mating type. Morphological data, ITS
      sequences, and the ability to interbreed suggest that these collections are part
      of a complex of interrelated species. Single-spore, homokaryotic isolates from
      both compatibility groups were able to fruit in compost culture, and two of the
      collections may represent natural homokaryotic fruiting. We conclude that species
      from the section Arvenses have versatile unifactorial heterothallic life cycles
      that permit both interbreeding and homokaryotic fruiting.

PMID- 10653744
TI  - Morphologic, host specificity, and molecular characterization of a Hungarian
      Cryptosporidium meleagridis isolate.
AB  - This study was undertaken in order to characterize Cryptosporidium meleagridis
      isolated from a turkey in Hungary and to compare the morphologies, host
      specificities, organ locations, and small-subunit RNA (SSU rRNA) gene sequences
      of this organism and other Cryptosporidium species. The phenotypic differences
      between C. meleagridis and Cryptosporidium parvum Hungarian calf isolate
      (zoonotic genotype) oocysts were small, although they were statistically
      significant. Oocysts of C. meleagridis were successfully passaged in turkeys and
      were transmitted from turkeys to immunosuppressed mice and from mice to chickens.
      The location of C. meleagridis was the small intestine, like the location of C.
      parvum. A comparison of sequence data for the variable region of the SSU rRNA
      gene of C. meleagridis isolated from turkeys with other Cryptosporidium sequence
      data in the GenBank database revealed that the Hungarian C. meleagridis sequence
      is identical to a C. meleagridis sequence recently described for a North Carolina
      isolate. Thus, C. meleagridis is a distinct species that occurs worldwide and has
      a broad host range, like the C. parvum zoonotic strain (also called the calf or
      bovine strain) and Cryptosporidium felis. Because birds are susceptible to C.
      meleagridis and to some zoonotic strains of C. parvum, these animals may play an
      active role in contamination of surface waters not only with Cryptosporidium
      baileyi but also with C. parvum-like parasites.

PMID- 10653745
TI  - A novel genetically engineered pathway for synthesis of poly(hydroxyalkanoic
      acids) in Escherichia coli.
AB  - A new pathway to synthesize poly(hydroxyalkanoic acids) (PHA) was constructed by
      simultaneously expressing butyrate kinase (Buk) and phosphotransbutyrylase (Ptb)
      genes of Clostridium acetobutylicum and the two PHA synthase genes (phaE and
      phaC) of Thiocapsa pfennigii in Escherichia coli. The four genes were cloned into
      the BamHI and EcoRI sites of pBR322, and the resulting hybrid plasmid, pBPP1,
      conferred activities of all three enzymes to E. coli JM109. Cells of this
      recombinant strain accumulated PHAs when hydroxyfatty acids were provided as
      carbon sources. Homopolyesters of 3-hydroxybutyrate (3HB), 4-hydroxybutyrate
      (4HB), or 4-hydroxyvalerate (4HV) were obtained from each of the corresponding
      hydroxyfatty acids. Various copolyesters of those hydroxyfatty acids were also
      obtained when two of these hydroxyfatty acids were fed at equal amounts: cells
      fed with 3HB and 4HB accumulated a copolyester consisting of 88 mol% 3HB and 12
      mol% 4HB and contributing to 68.7% of the cell dry weight. Cells fed with 3HB and
      4HV accumulated a copolyester consisting of 94 mol% 3HB and 6 mol% 4HV and
      contributing to 64.0% of the cell dry weight. Cells fed with 3HB, 4HB, and 4HV
      accumulated a terpolyester consisting of 85 mol% 3HB, 13 mol% 4HB, and 2 mol% 4HV
      and contributing to 68.4% of the cell dry weight.

PMID- 10653746
TI  - Effect of increased yeast alcohol acetyltransferase activity on flavor profiles
      of wine and distillates.
AB  - The distinctive flavor of wine, brandy, and other grape-derived alcoholic
      beverages is affected by many compounds, including esters produced during
      alcoholic fermentation. The characteristic fruity odors of the fermentation
      bouquet are primarily due to a mixture of hexyl acetate, ethyl caproate (apple
      like aroma), iso-amyl acetate (banana-like aroma), ethyl caprylate (apple-like
      aroma), and 2-phenylethyl acetate (fruity, flowery flavor with a honey note). The
      objective of this study was to investigate the feasibility of improving the aroma
      of wine and distillates by overexpressing one of the endogenous yeast genes that
      controls acetate ester production during fermentation. The synthesis of acetate
      esters by the wine yeast Saccharomyces cerevisiae during fermentation is ascribed
      to at least three acetyltransferase activities, namely, alcohol acetyltransferase
      (AAT), ethanol acetyltransferase, and iso-amyl AAT. To investigate the effect of
      increased AAT activity on the sensory quality of Chenin blanc wines and
      distillates from Colombar base wines, we have overexpressed the alcohol
      acetyltransferase gene (ATF1) of S. cerevisiae. The ATF1 gene, located on
      chromosome XV, was cloned from a widely used commercial wine yeast strain of S.
      cerevisiae, VIN13, and placed under the control of the constitutive yeast
      phosphoglycerate kinase gene (PGK1) promoter and terminator. Chromoblot analysis
      confirmed the integration of the modified copy of ATF1 into the genome of three
      commercial wine yeast strains (VIN7, VIN13, and WE228). Northern blot analysis
      indicated constitutive expression of ATF1 at high levels in these yeast
      transformants. The levels of ethyl acetate, iso-amyl acetate, and 2-phenylethyl
      acetate increased 3- to 10-fold, 3.8- to 12-fold, and 2- to 10-fold,
      respectively, depending on the fermentation temperature, cultivar, and yeast
      strain used. The concentrations of ethyl caprate, ethyl caprylate, and hexyl
      acetate only showed minor changes, whereas the acetic acid concentration
      decreased by more than half. These changes in the wine and distillate composition
      had a pronounced effect on the solvent or chemical aroma (associated with ethyl
      acetate and iso-amyl acetate) and the herbaceous and heads-associated aromas of
      the final distillate and the solvent or chemical and fruity or flowery characters
      of the Chenin blanc wines. This study establishes the concept that the
      overexpression of acetyltransferase genes such as ATF1 could profoundly affect
      the flavor profiles of wines and distillates deficient in aroma, thereby paving
      the way for the production of products maintaining a fruitier character for
      longer periods after bottling.

PMID- 10653747
TI  - Spatial changes in the bacterial community structure along a vertical oxygen
      gradient in flooded paddy soil cores.
AB  - Molecular ecology techniques were applied to assess changes in the bacterial
      community structure along a vertical oxygen gradient in flooded paddy soil cores.
      Microsensor measurements showed that oxygen was depleted from 140 microM at the
      floodwater/soil interface to nondetectable amounts at a depth of approximately
      2.0 mm and below. Bacterial 16S rRNA gene (rDNA)-based community fingerprint
      patterns were obtained from 200-microm-thick soil slices of both the oxic and
      anoxic zones by using the T-RFLP (terminal restriction fragment length
      polymorphism) technique. The fingerprints revealed a tremendous shift in the
      community patterns in correlation to the oxygen depletion measured with depth.
      16S rDNA clone sequences recovered from the oxic or anoxic zone directly
      corresponded to those terminal restriction fragments which were highly
      characteristic of the respective zone. Comparative sequence analysis of these
      clones identified members of the alpha and beta subclasses of Proteobacteria as
      the abundant populations in the oxic zone. In contrast, members of clostridial
      cluster I were determined to be the predominant bacterial group in the oxygen
      depleted soil. The extraction of total RNA followed by reverse transcription-PCR
      of the bacterial 16S rRNA and T-RFLP analysis resulted for both oxic and anoxic
      zones of flooded soil cores in community fingerprint patterns similar to those
      obtained by the rDNA-based analysis. This finding suggests that the microbial
      groups detected on the rDNA level are the metabolically active populations within
      the oxic and anoxic soil slices examined.

PMID- 10653748
TI  - An improved spectrophotometric method to study the transport, attachment, and
      breakthrough of bacteria through porous media.
AB  - This study reports an improved spectrophotometric method for studying bacterial
      (Pseudomonas fluorescens UPER-1) transport and attachment in saturated porous
      media (silica sand). While studying the effect of ionic strength by the
      traditional packed-column spectrophotometric method, we encountered an artifact.
      The absorbance of a well-stirred bacterial suspension was found to decrease with
      time in the presence of high concentrations of sodium and potassium phosphate
      salts (> or = 10(-2) M) as the cells continued to age in a resting stage. Our
      results show that collision efficiency and a bed ripening index will be in error
      by as much as 20% if breakthrough is measured by the traditional
      spectrophotometric technique. We present an improved experimental technique that
      will minimize the artifact and should substantially advance the understanding of
      bacteria transport in porous media.

PMID- 10653749
TI  - Carbon dioxide and nisin act synergistically on Listeria monocytogenes.
AB  - This paper examines the synergistic action of carbon dioxide and nisin on
      Listeria monocytogenes Scott A wild-type and nisin-resistant (Nis(r)) cells grown
      in broth at 4 degrees C. Carbon dioxide extended the lag phase and decreased the
      specific growth rate of both strains, but to a greater degree in the Nis(r)
      cells. Wild-type cells grown in 100% CO(2) were two to five times longer than
      cells grown in air. Nisin (2.5 microg/ml) did not decrease the viability of
      Nis(r) cells but for wild-type cells caused an immediate 2-log reduction of
      viability when they were grown in air and a 4-log reduction when they were grown
      in 100% CO(2). There was a quantifiable synergistic action between nisin and
      CO(2) in the wild-type strain. The MIC of nisin for the wild-type strain grown in
      the presence of 2.5 microg of nisin per ml increased from 3.1 to 12.5 microg/ml
      over 35 days, but this increase was markedly delayed for cultures in CO(2). This
      synergism between nisin and CO(2) was examined mechanistically by following the
      leakage of carboxyfluorescein (CF) from listerial liposomes. Carbon dioxide
      enhanced nisin-induced CF leakage, indicating that the synergistic action of
      CO(2) and nisin occurs at the cytoplasmic membrane. Liposomes made from cells
      grown in a CO(2) atmosphere were even more sensitive to nisin action. Liposomes
      made from cells grown at 4 degrees C were dramatically more nisin sensitive than
      were liposomes derived from cells grown at 30 degrees C. Cells grown in the
      presence of 100% CO(2) and those grown at 4 degrees C had a greater proportion of
      short-chain fatty acids. The synergistic action of nisin and CO(2) is consistent
      with a model where membrane fluidity plays a role in the efficiency of nisin
      action.

PMID- 10653750
TI  - Characterization of a foldase, protein disulfide isomerase A, in the protein
      secretory pathway of Aspergillus niger.
AB  - Protein disulfide isomerase (PDI) is important in assisting the folding and
      maturation of secretory proteins in eukaryotes. A gene, pdiA, encoding PDIA was
      previously isolated from Aspergillus niger, and we report its functional
      characterization here. Functional analysis of PDIA showed that it catalyzes the
      refolding of denatured and reduced RNase A. pdiA also complemented PDI function
      in a Saccharomyces cerevisiae Deltapdi1 mutant in a yeast-based killer toxin
      assay. Levels of pdiA mRNA and PDIA protein were raised by the accumulation of
      unfolded proteins in the endoplasmic reticulum. This response of pdiA mRNA levels
      was slower and lower in magnitude than that of A. niger bipA, suggesting that the
      induction of pdiA is not part of the primary stress response. An increased level
      of pdiA transcripts was also observed in two A. niger strains overproducing a
      heterologous protein, hen egg white lysozyme (HEWL). Although overexpression of
      PDI has been successful in increasing yields of some heterologous proteins in S.
      cerevisiae, overexpression of PDIA did not increase secreted yields of HEWL in A.
      niger, suggesting that PDIA itself is not limiting for secretion of this protein.
      Downregulation of pdiA by antisense mRNA reduced the levels of microsomal PDIA
      activity by up to 50%, lowered the level of PDIA as judged by Western blots, and
      lowered the secreted levels of glucoamylase by 60 to 70%.

PMID- 10653751
TI  - Immunolocalization of dinitrogenase reductase produced by Klebsiella pneumoniae
      in association with Zea mays L.
AB  - The endophytic lifestyle of Klebsiella pneumoniae is described, including the
      production of dinitrogenase reductase by bacteria residing in maize root tissue.
      The green fluorescent protein (GFP) was used to detect the colonization of maize
      by K. pneumoniae strains 2028 and 342. These strains were found to reside in
      intercortical layers of the stem and within the region of maturation in the root.
      The production of dinitrogenase reductase by GFP-tagged bacteria was visualized
      using immunolocalization. This activity was only apparent when bacteria were
      supplied with an exogenous carbon source. The results suggest that maize provides
      a suitable habitat for K. pneumoniae and that this species is capable of
      producing nitrogenase under the appropriate plant cultivation conditions.

PMID- 10653752
TI  - Bacterial cell surface display of an enzyme library for selective screening of
      improved cellulase variants.
AB  - The bacterial surface display method was used to selectively screen for improved
      variants of carboxymethyl cellulase (CMCase). A library of mutated CMCase genes
      generated by DNA shuffling was fused to the ice nucleation protein (Inp) gene so
      that the resulting fusion proteins would be displayed on the bacterial cell
      surface. Some cells displaying mutant proteins grew more rapidly on carboxymethyl
      cellulose plates than controls, forming heterogeneous colonies. In contrast,
      cells displaying the nonmutated parent CMCase formed uniform tiny colonies. These
      variations in growth rate were assumed to result from altered availability of
      glucose caused by differences in the activity of variant CMCases at the cell
      surface. Staining assays indicate that large, rapidly growing colonies have
      increased CMCase activity. Increased CMCase activity was confirmed by assaying
      the specific activities of cell extracts after the expression of unfused forms of
      the variant genes in the cytoplasm. The best-evolved CMCases showed about a 5-
      and 2.2-fold increase in activity in the fused and free forms, respectively.
      Sequencing of nine evolved CMCase variant genes showed that most amino acid
      substitutions occurred within the catalytic domain of the enzyme. These results
      demonstrate that the bacterial surface display of enzyme libraries provides a
      direct way to correlate evolved enzyme activity with cell growth rates. This
      technique will provide a useful technology platform for directed evolution and
      high-throughput screening of industrial enzymes, including hydrolases.

PMID- 10653753
TI  - Purification and molecular characterization of a tripeptidase (PepT) from
      Lactobacillus helveticus.
AB  - A tripeptidase (PepT) from a thermophilic dairy starter strain of Lactobacillus
      helveticus was purified by four chromatographic steps. PepT appeared to be a
      trimeric metallopeptidase with a molecular mass of 150 kDa. PepT exhibited
      maximum activity against hydrophobic tripeptides, with the highest activity for
      Met-Gly-Gly (K(m), 2.6 mM; V(max), 80.2 micromol. min(-1). microg(-1)). Some of
      the hydrophobic dipeptides were slowly hydrolyzed, distinguishing the
      Lactobacillus PepT from its counterpart in mesophilic Lactococcus lactis. No
      activity against tetrapeptides or amino acid p-nitroanilide derivatives was
      observed. The pepT gene and its flanking regions were isolated by PCR and
      sequenced by cyclic sequencing. The sequence analyses revealed open reading
      frames (ORFs) 816 bp (ORF1) and 1,239 bp (ORF2) long. ORF2 encoded a 47-kDa PepT
      protein which exhibited 53% identity with the PepT from L. lactis. The mRNA
      analyses indicated that pepT conforms a novel operon structure with an ORF1
      located upstream. Several putative -35/-10 regions preceded the operon, but only
      one transcription start site located downstream of the first putative -10 region
      was identified. An inverted repeat structure with DeltaG of -64.8 kJ/mol was
      found downstream of the PepT-encoding region.

PMID- 10653754
TI  - Bacterial activity in the rhizosphere analyzed at the single-cell level by
      monitoring ribosome contents and synthesis rates.
AB  - The growth activity of Pseudomonas putida cells colonizing the rhizosphere of
      barley seedlings was estimated at the single-cell level by monitoring ribosomal
      contents and synthesis rates. Ribosomal synthesis was monitored by using a system
      comprising a fusion of the ribosomal Escherichia coli rrnBP1 promoter to a gene
      encoding an unstable variant of the green fluorescent protein (Gfp). Gfp
      expression in a P. putida strain carrying this system inserted into the
      chromosome was strongly dependent on the growth phase and growth rate of the
      strain, and cells growing exponentially at rates of > or = 0.17 h(-1) emitted
      growth rate-dependent green fluorescence detectable at the single-cell level. The
      single-cell ribosomal contents were very heterogeneous, as determined by
      quantitative hybridization with fluorescently labeled rRNA probes in P. putida
      cells extracted from the rhizosphere of 1-day-old barley seedlings grown under
      sterile conditions. After this, cells extracted from the root system had
      ribosomal contents similar to those found in starved cells. There was a
      significant decrease in the ribosomal content of P. putida cells when bacteria
      were introduced into nonsterile bulk or rhizosphere soil, and the Gfp monitoring
      system was not induced in cells extracted from either of the two soil systems.
      The monitoring system used permitted nondestructive in situ detection of fast
      growing bacterial microcolonies on the sloughing root sheath cells of 1- and 2
      day-old barley seedlings grown under sterile conditions, which demonstrated that
      it may be possible to use the unstable Gfp marker for studies of transient gene
      expression in plant-microbe systems.

PMID- 10653755
TI  - Cotransformation of Trichoderma harzianum with beta-glucuronidase and green
      fluorescent protein genes provides a useful tool for monitoring fungal growth and
      activity in natural soils.
AB  - Trichoderma harzianum was cotransformed with genes encoding green fluorescent
      protein (GFP), beta-glucuronidase (GUS), and hygromycin B (hygB) resistance,
      using polyethylene glycol-mediated transformation. One cotransformant (ThzID1-M3)
      was mitotically stable for 6 months despite successive subculturing without
      selection pressure. ThzID1-M3 morphology was similar to that of the wild type;
      however, the mycelial growth rate on agar was reduced. ThzID1-M3 was formed into
      calcium alginate pellets and placed onto buried glass slides in a nonsterile
      soil, and its ability to grow, sporulate, and colonize sclerotia of Sclerotinia
      sclerotiorum was compared with that of the wild-type strain. Wild-type and
      transformant strains both colonized sclerotia at levels above those of indigenous
      Trichoderma spp. in untreated controls. There were no significant differences in
      colonization levels between wild-type and cotransformant strains; however, the
      presence of the GFP and GUS marker genes permitted differentiation of introduced
      Trichoderma from indigenous strains. GFP activity was a useful tool for
      nondestructive monitoring of the hyphal growth of the transformant in a natural
      soil. The green color of cotransformant hyphae was clearly visible with a UV
      epifluorescence microscope, while indigenous fungi in the same samples were
      barely visible. Green-fluorescing conidiophores and conidia were observed within
      the first 3 days of incubation in soil, and this was followed by the formation of
      terminal and intercalary chlamydospores and subsequent disintegration of older
      hyphal segments. Addition of 5-bromo-4-chloro-3-indolyl-beta-D-glucuronic acid (X
      Gluc) substrate to recovered glass slides confirmed the activity of GUS as well
      as GFP in soil. Our results suggest that cotransformation with GFP and GUS can
      provide a valuable tool for the detection and monitoring of specific strains of
      T. harzianum released into the soil.

PMID- 10653756
TI  - Distribution of Nitrosomonas europaea and Paracoccus denitrificans immobilized in
      tubular polymeric gel for nitrogen removal.
AB  - To improve the cooperative removal of nitrogen by Nitrosomonas europaea and
      Paracoccus denitrificans, we controlled their distribution in a tubular gel. When
      ethanol was supplied inside the tubular gel as an electron donor, their
      distributions overlapped in the external region of the gel. By changing the
      electron donor from ethanol to gaseous hydrogen, the distribution of P.
      denitrificans shifted to the inside of the tube and was separated from that of N.
      europaea. The separation resulted in an increase of the oxidation rate of ammonia
      by 25%.

PMID- 10653757
TI  - In situ analysis of sulfate-reducing bacteria related to Desulfocapsa
      thiozymogenes in the chemocline of meromictic Lake Cadagno (Switzerland).
AB  - Comparative sequence analysis of a 16S rRNA gene clone library from the
      chemocline of the meromictic Lake Cadagno (Switzerland) retrieved two clusters of
      sequences resembling sulfate-reducing bacteria within the family
      Desulfovibrionaceae. In situ hybridization showed that, similar to sulfate
      reducing bacteria of the family Desulfobacteriaceae, bacteria of one cluster with
      similarity values to the closest cultured relatives of between 92.6 and 93.1%
      resembled free cells or cells loosely attached to other cells or debris. Bacteria
      of the second cluster closely related to Desulfocapsa thiozymogenes DSM7269 with
      similarity values between 97. 9 and 98.4% were generally associated with
      aggregates of different small-celled phototrophic sulfur bacteria, suggesting a
      potential interaction between the two groups of bacteria.

PMID- 10653758
TI  - Cloning and sequencing of an alkaline protease gene from Bacillus lentus and
      amplification of the gene on the B. lentus chromosome by an improved technique.
AB  - A gene encoding an alkaline protease was cloned from an alkalophilic bacillus,
      and its nucleotide sequence was determined. The cloned gene was used to increase
      the copy number of the protease gene on the chromosome by an improved gene
      amplification technique.

PMID- 10653759
TI  - Phosphate inhibits acetotrophic methanogenesis on rice roots.
AB  - The contribution of acetate- and H(2)/CO(2)-dependent methanogenesis to total
      CH(4) production was determined in excised washed rice roots by radiolabeling,
      methyl fluoride inhibition, and stable carbon isotope fractionation. Addition of
      > or = 20 mM phosphate inhibited methanogenesis, which then was exclusively from
      H(2)/CO(2). Otherwise, acetate contributed about 50 to 60% of the total
      methanogenesis, demonstrating that phosphate specifically inhibited acetotrophic
      methanogens on rice roots.

PMID- 10653760
TI  - Influence of osmotic and nutritional stress on physiology of Penicillium
      fellutanum in removal of phosphocholine and modification of phospho-1-O-[N
      peptidyl-(2-aminoethanol)] phosphodiesters of peptidophosphogalactomannan
      species.
AB  - Addition of 3 M NaCl to 72-h cultures of Penicillium fellutanum in 2 mM phosphate
      resulted in an increase in percentage of extracellular
      peptidophosphogalactomannan III (pP(x)GM(iii)) and a decrease in that of
      pP(x)GM(ii). The magnitude of (31)P nuclear magnetic resonance signals at 1.47
      and 1.33 ppm of phospho-1-O-[N-peptidyl-(2-aminoethanol)] phosphodiesters
      pP(x)GM(ii) and pP(x)GM(iii) decreased compared with controls. The data suggest
      that serine, glycine, and threonine residues from the 3-kDa peptide and from
      galactofuranosyl-6-O-phospho-1'-O-[N-peptidyl-(2-aminoethanol)] residues were the
      precursors of the needed choline-derived osmolytes.

PMID- 10653761
TI  - Effect of catalase on hydrogen peroxide penetration into Pseudomonas aeruginosa
      biofilms.
AB  - The penetration of hydrogen peroxide into biofilms formed by wild-type and
      catalase-deficient Pseudomonas aeruginosa strains was measured using
      microelectrodes. A flowing stream of hydrogen peroxide (50 mM, 1 h) was unable to
      penetrate or kill wild-type biofilms but did penetrate and partially kill
      biofilms formed by an isogenic strain in which the katA gene was knocked out.
      Catalase protects aggregated bacteria by preventing full penetration of hydrogen
      peroxide into the biofilm.

PMID- 10653762
TI  - Diversity of infectious pancreatic necrosis virus strains isolated from fish,
      shellfish, and other reservoirs in Northwestern Spain.
AB  - A comparison was done of 231 strains of birnavirus isolated from fish, shellfish,
      and other reservoirs in a survey study that began in 1986 in Galicia
      (northwestern Spain). Reference strains from all of the infectious pancreatic
      necrosis virus serotypes were included in the comparison, which was done by
      neutralization tests and agarose and polyacrylamide gel electrophoresis of the
      viral genome. The neutralization tests with antisera against the West Buxton,
      Spajarup (Sp), and Abild (Ab) strains showed that most of the Galician isolates
      were European types Sp and Ab; however, many isolates (30%) could not be typed.
      Results from agarose gels did not provided information for grouping of the
      strains, since all were found to have genomic segments of similar sizes. Analysis
      of polyacrylamide gels, however, allowed six electropherogroups (EGs) to be
      differentiated on the basis of genome mobility and separation among segments, and
      a certain relationship between EGs and serotypes was observed. A wide diversity
      of electropherotypes was observed among the Galician isolates, and as
      neutralization tests showed, most of the isolates were included in EGs
      corresponding to European types Ab and Sp. Only 6.5% of the isolates had the
      electropherotype characteristic of American strains.

PMID- 10653763
TI  - Selective and sensitive method for PCR amplification of Escherichia coli 16S rRNA
      genes in soil.
AB  - A set of PCR primers targeting 16S rRNA gene sequences was designed, and PCR
      parameters were optimized to develop a robust and reliable protocol for selective
      amplification of Escherichia coli 16S rRNA genes. The method was capable of
      discriminating E. coli from other enteric bacteria, including its closest
      relative, Shigella. Selective amplification of E. coli occurred only when the
      annealing temperature in the PCR was elevated to 72 degrees C, which is 10
      degrees C higher than the optimum for the primers. Sensitivity was retained by
      modifying the length of steps in the PCR, by increasing the number of cycles, and
      most importantly by optimizing the MgCl(2) concentration. The PCR protocol
      developed can be completed in less then 2 h and, by using Southern hybridization,
      has a detection limit of ca. 10 genomic equivalents per reaction. The method was
      demonstrated to be effective for detecting E. coli DNA in heterogeneous DNA
      samples, such as those extracted from soil.

PMID- 10653764
TI  - Pathovars of Pseudomonas syringae causing bacterial brown spot and halo blight in
      phaseolus vulgaris L. are distinguishable by ribotyping.
AB  - Ribotyping was evaluated as a method to differentiate between Pseudomonas
      syringae pv. phaseolicola and pv. syringae strains causing bacterial brown spot
      and halo blight diseases in Phaseolus vulgaris L. Ribotyping, with restriction
      enzymes BglI and SalI and using the Escherichia coli rrnB operon as the probe,
      differentiated 11 and 14 ribotypes, respectively, and a combination of data from
      both procedures yielded 19 combined ribotypes. Cluster analysis of the combined
      ribotypes differentiated the pathovars phaseolicola and syringae, as well as
      different clonal lineages within these pathovars. The potential of ribotyping to
      screen for correlations between lineages and factors such as geographical region
      and/or bean varieties is also reported.

PMID- 10653766
TI  - Effect of flagella on initial attachment of Listeria monocytogenes to stainless
      steel.
AB  - At 22 degrees C a flagellin mutant of Listeria monocytogenes was found to attach
      to stainless steel at levels 10-fold lower than wild-type cells, even under
      conditions preventing active motility. At 37 degrees C, when flagella are not
      produced, attachment of both strains was identical. Therefore, flagella per se
      facilitate the early stage of attachment.

PMID- 10653765
TI  - A selective medium and a specific probe for detection of Vibrio vulnificus.
AB  - A selective medium (VVM) and a specific 16S rRNA gene (rDNA) probe (V3VV) for the
      detection of Vibrio vulnificus were developed. The medium contains D-(+)
      cellobiose as the main carbon source and electrolytes (MgCl(2)-6H(2)O and KCl),
      which stimulate bacterial growth. Polymyxin B, colistin, and moderate alkalinity
      and salinity provide selectivity properties. V. vulnificus grows on VVM as flat,
      bright yellow colonies. Other Vibrio species tested either did not grow or showed
      green-bluish colonies, with the exception of V. campbelli, V. carchariae, and V.
      navarrensis. There is a higher colony count on VVM agar than on cellobiose
      colistin agar or on modified cellobiose-polymyxin B-colistin agar. The specific
      probe was evaluated by colony hybridization and dot blot hybridization with PCR
      amplified 16S rDNA using collection strains and environmental isolates. No strain
      studied other than V. vulnificus showed positive hybridization with this
      oligonucleotide. The combined use of VVM agar and the V3VV probe provided the
      recovery of V. vulnificus from mixed bacterial suspensions and spiked mussels.

PMID- 10653767
TI  - Determination of Escherichia coli contamination with chromocult coliform agar
      showed a high level of discrimination efficiency for differing fecal pollution
      levels in tropical waters of Kampala, Uganda.
AB  - Escherichia coli, total coliforms, fecal coliforms, and sulfite-reducing
      anaerobic spore formers from different polluted sites in a tropical environment
      were determined in order to test for their indication ability for fecal
      contamination. Quantification of E. coli contamination with Chromocult coliform
      agar proved to be efficient and feasible for determining fecal pollutions in the
      investigated area within 24 h. The other microbial parameters showed a lower
      ability to differentiate sites and cannot be recommended for monitoring fecal
      pollution in the studied tropical surface waters.

PMID- 10653768
TI  - Survival of Bifidobacterium longum immobilized in calcium alginate beads in
      simulated gastric juices and bile salt solution.
AB  - Bifidobacterium longum KCTC 3128 and HLC 3742 were independently immobilized
      (entrapped) in calcium alginate beads containing 2, 3, and 4% sodium alginate.
      When the bifidobacteria entrapped in calcium alginate beads were exposed to
      simulated gastric juices and a bile salt solution, the death rate of the cells in
      the beads decreased proportionally with an increase in both the alginate gel
      concentration and bead size. The initial cell numbers in the beads affected the
      numbers of survivors after exposure to these solutions; however, the death rates
      of the viable cells were not affected. Accordingly, a mathematical model was
      formulated which expressed the influences of several parameters (gel
      concentration, bead size, and initial cell numbers) on the survival of entrapped
      bifidobacteria after sequential exposure to simulated gastric juices followed by
      a bile salt solution. The model proposed in this paper may be useful for
      estimating the survival of bifidobacteria in beads and establishing optimal
      entrapment conditions.

PMID- 10653769
TI  - Observation of soft contact lens disinfection with fluorescent metabolic stains.
AB  - A rapid fluorescent staining method using a tetrazolium dye and propidium iodide
      for the in-use assessment of disinfection of Pseudomonas aeruginosa biofilms on
      soft contact lenses showed that 11 to 13% of cells on lenses remained actively
      respiring and recoverable by culture methods after 30 min of exposure to 3%
      hydrogen peroxide.

PMID- 10653770
TI  - The mechanochemistry of molecular motors.
AB  - A theory of molecular motors is presented that explains how the energy released
      in single chemical reactions can generate mechanical motion and force. In the
      simplest case the fluctuating movements of a motor enzyme are well described by a
      diffusion process on a two-dimensional potential energy surface, where one
      dimension is a chemical reaction coordinate and the other is the spatial
      displacement of the motor. The coupling between chemistry and motion results from
      the shape of the surface, and motor velocities and forces result from diffusion
      currents on this surface. This microscopic description is shown to possess an
      equivalent kinetic mechanism in which the rate constants depend on externally
      applied forces. By using this equivalence we explore the characteristic
      properties of several broad classes of motor mechanisms and give general
      expressions for motor velocity versus load force for any member of each class. We
      show that in some cases simple plots of 1/velocity vs. 1/concentration can
      distinguish between classes of motor mechanisms and may be used to determine the
      step at which movement occurs.

PMID- 10653771
TI  - Simulations of ion permeation through a potassium channel: molecular dynamics of
      KcsA in a phospholipid bilayer.
AB  - Potassium channels enable K(+) ions to move passively across biological
      membranes. Multiple nanosecond-duration molecular dynamics simulations (total
      simulation time 5 ns) of a bacterial potassium channel (KcsA) embedded in a
      phospholipid bilayer reveal motions of ions, water, and protein. Comparison of
      simulations with and without K(+) ions indicate that the absence of ions
      destabilizes the structure of the selectivity filter. Within the selectivity
      filter, K(+) ions interact with the backbone (carbonyl) oxygens, and with the
      side-chain oxygen of T75. Concerted single-file motions of water molecules and
      K(+) ions within the selectivity filter of the channel occur on a 100-ps time
      scale. In a simulation with three K(+) ions (initially two in the filter and one
      in the cavity), the ion within the central cavity leaves the channel via its
      intracellular mouth after approximately 900 ps; within the cavity this ion
      interacts with the Ogamma atoms of two T107 side chains, revealing a favorable
      site within the otherwise hydrophobically lined cavity. Exit of this ion from the
      channel is enabled by a transient increase in the diameter of the intracellular
      mouth. Such "breathing" motions may form the molecular basis of channel gating.

PMID- 10653773
TI  - Mechanical unfolding of a beta-hairpin using molecular dynamics.
AB  - Single-molecule mechanical unfolding experiments have the potential to provide
      insights into the details of protein folding pathways. To investigate the
      relationship between force-extension unfolding curves and microscopic events, we
      performed molecular dynamics simulations of the mechanical unfolding of the C
      terminal hairpin of protein G. We have studied the dependence of the unfolding
      pathway on pulling speed, cantilever stiffness, and attachment points. Under
      conditions that generate low forces, the unfolding trajectory mimics the
      untethered, thermally accessible pathway previously proposed based on high
      temperature studies. In this stepwise pathway, complete breakdown of backbone
      hydrogen bonds precedes dissociation of the hydrophobic cluster. Under more
      extreme conditions, the cluster and hydrogen bonds break simultaneously.
      Transitions between folding intermediates can be identified in our simulations as
      features of the calculated force-extension curves.

PMID- 10653772
TI  - Continuum solvent model calculations of alamethicin-membrane interactions:
      thermodynamic aspects.
AB  - Alamethicin is a 20-amino acid antibiotic peptide that forms voltage-gated ion
      channels in lipid bilayers. Here we report calculations of its association free
      energy with membranes. The calculations take into account the various free-energy
      terms that contribute to the transfer of the peptide from the aqueous phase into
      bilayers of different widths. The electrostatic and nonpolar contributions to the
      solvation free energy are calculated using continuum solvent models. The
      contributions from the lipid perturbation and membrane deformation effects and
      the entropy loss associated with peptide immobilization in the bilayer are
      estimated from a statistical thermodynamic model. The calculations were carried
      out using two classes of experimentally observed conformations, both of which are
      helical: the NMR and the x-ray crystal structures. Our calculations show that
      alamethicin is unlikely to partition into bilayers in any of the NMR
      conformations because they have uncompensated backbone hydrogen bonds and their
      association with the membrane involves a large electrostatic solvation free
      energy penalty. In contrast, the x-ray conformations provide enough backbone
      hydrogen bonds for the peptide to associate with bilayers. We tested numerous
      transmembrane and surface orientations of the peptide in bilayers, and our
      calculations indicate that the most favorable orientation is transmembrane, where
      the peptide protrudes approximately 4 A into the water-membrane interface, in
      very good agreement with electron paramagnetic resonance and oriented circular
      dichroism measurements. The calculations were carried out using two alamethicin
      isoforms: one with glutamine and the other with glutamate in the 18th position.
      The calculations indicate that the two isoforms have similar membrane
      orientations and that their insertion into the membrane is likely to involve a 2
      A deformation of the bilayer, again, in good agreement with experimental data.
      The implications of the results for the biological function of alamethicin and
      its capacity to oligomerize and form ion channels are discussed.

PMID- 10653774
TI  - Stereochemical requirements for receptor recognition of the mu-opioid peptide
      endomorphin-1.
AB  - A series of diastereoisomers of endomorphin-1 (EM1, Tyr(1)-Pro(2)-Trp(3)-Phe(4)
      NH(2)) have been synthesized and their potency measured using the guinea pig
      ileum assay. [D-Phe(4)]EM1 possessed 1/10 the potency of EM1, while potencies of
      [D-Tyr(1)]EM1 and [D-Trp(3)]EM1 were 50- and 100-fold lower, respectively.
      Drastic loss of activity occurred in the [D-Pro(2)]EM1 peptide. The structural
      determinants for the inactivity and reduced potency of the diastereoisomers were
      investigated using NMR spectroscopy and conformational analysis. Simulations of
      trans-[D-Pro(2)]EM1 using NOE-derived distance constraints afforded well-defined
      structures in which Tyr and Trp side chains stack against the proline ring. The
      inactivity of [D-Pro(2)]EM1 was explained by structural comparison with EM1 (,
      FEBS Lett. 439:13-20). The two peptides showed an opposite orientation of the
      Trp(3) residue with respect to Tyr(1), thus suggesting a role of Pro(2) as a
      stereochemical spacer in orienting Trp(3) and Phe(4) toward regions suitable for
      mu-receptor interaction. The agonist activity of [D-Tyr(1)]EM1 and [D-Trp(3)]EM1
      was attributed to their ability to adopt low-energy conformations that mimic
      those of EM1. The requirements for mu-receptor activation were examined further
      by comparing EM1 with the mu-peptide [D-Ala(2), MePhe(4), Gly-ol]-enkephalin
      (DAMGO). Conformations of DAMGO with a Tyr(1)-MePhe(4) phenyl ring separation of
      approximately 12 A were found to mimic Tyr(1)-Phe(4) of EM1, thus suggesting
      overlapping binding modes between these two peptides.

PMID- 10653775
TI  - Two time constants for the binding of proteins to DNA from micromechanical data.
AB  - Recent experimental advances allow the direct measurement of the force/extension
      behavior for DNA in the presence of strongly binding proteins. Such experiments
      reveal information about the cooperative mechanism of protein binding. We have
      studied the irreversible binding of such proteins to DNA using a simple
      simulation and present a method for estimating quantitative rate constants for
      the nucleation and growth of linear domains of proteins bound to DNA. Such rate
      constants also give information about the relative energetics of the two binding
      processes. We discuss our results in the context of recent data for the DNA-recA
      ATPgammas system, for which the nucleation time is 4.7 x 10(4) min per recA
      binding site and the total growth rate of each domain is 1400 recA/min.

PMID- 10653776
TI  - Differences between apo and three holo forms of the intestinal fatty acid binding
      protein seen by molecular dynamics computer calculations.
AB  - It is commonly believed that binding affinity can be estimated by consideration
      of local changes of ligand and protein. This paper discusses a set of molecular
      dynamics simulations of intestinal fatty acid binding protein addressing the
      protein's response to presence or absence of different ligands. A 5-ns simulation
      was performed of the protein without a ligand, and three simulations (one 5-ns
      and two 2-ns) were performed with different fatty acids bound. The results
      indicate that, although the basic protein structure is unchanged by the presence
      of the ligand, other properties are significantly affected by ligand binding. For
      example, zero-time covariance patterns between protein, bound waters, and ligand
      vary between the different simulations. Moreover, the interaction energies
      between ligand and specific residues indicate that different ligands are
      stabilized in different ways. In sum, the results suggest that binding
      thermodynamics within this system will need to be calculated not from a subset of
      nearby protein:ligand interactions, but will depend on a knowledge of the motions
      coupling together water, protein, and ligand.

PMID- 10653777
TI  - An electrostatic mechanism closely reproducing observed behavior in the bacterial
      flagellar motor.
AB  - A mechanism coupling the transmembrane flow of protons to the rotation of the
      bacterial flagellum is studied. The coupling is accomplished by means of an array
      of tilted rows of positive and negative charges around the circumference of the
      rotor, which interacts with a linear array of proton binding sites in channels.
      We present a rigorous treatment of the electrostatic interactions using minimal
      assumptions. Interactions with the transition states are included, as well as
      proton-proton interactions in and between channels. In assigning values to the
      parameters of the model, experimentally determined structural characteristics of
      the motor have been used. According to the model, switching and pausing occur as
      a consequence of modest conformational changes in the rotor. In contrast to
      similar approaches developed earlier, this model closely reproduces a large
      number of experimental findings from different laboratories, including the
      nonlinear behavior of the torque-frequency relation in Escherichia coli, the
      stoichiometry of the system in Streptococcus, and the pH-dependence of swimming
      speed in Bacillus subtilis.

PMID- 10653778
TI  - Modeling the kinetics of acylation of insulin using a recursive method for
      solving the systems of coupled differential equations.
AB  - This paper describes a theoretical method for solving systems of coupled
      differential equations that describe the kinetics of complicated reaction
      networks in which a molecule having multiple reaction sites reacts irreversibly
      with multiple equivalents of a ligand (reagent). The members of the network
      differ in the number of equivalents of reagent that have reacted, and in the
      patterns of sites of reaction. A recursive algorithm generates series,
      asymptotic, and average solutions describing this kinetic scheme. This method was
      validated by successfully simulating the experimental data for the kinetics of
      acylation of insulin.

PMID- 10653779
TI  - Adjustments for the display of quantized ion channel dwell times in histograms
      with logarithmic bins.
AB  - Dwell-time histograms are often plotted as part of patch-clamp investigations of
      ion channel currents. The advantages of plotting these histograms with a
      logarithmic time axis were demonstrated by, J. Physiol. (Lond.). 378:141-174),
      Pflugers Arch. 410:530-553), and, Biophys. J. 52:1047-1054). Sigworth and Sine
      argued that the interpretation of such histograms is simplified if the counts are
      presented in a manner similar to that of a probability density function. However,
      when ion channel records are recorded as a discrete time series, the dwell times
      are quantized. As a result, the mapping of dwell times to logarithmically spaced
      bins is highly irregular; bins may be empty, and significant irregularities may
      extend beyond the duration of 100 samples. Using simple approximations based on
      the nature of the binning process and the transformation rules for probability
      density functions, we develop adjustments for the display of the counts to
      compensate for this effect. Tests with simulated data suggest that this procedure
      provides a faithful representation of the data.

PMID- 10653780
TI  - Molecular dynamics simulations of the d(CCAACGTTGG)(2) decamer: influence of the
      crystal environment.
AB  - Molecular dynamics (MD) simulations of the DNA duplex d(CCAACGTTGG)(2) were used
      to study the relationship between DNA sequence and structure. Two crystal
      simulations were carried out; one consisted of one unit cell containing two
      duplexes, and the other of two unit cells containing four duplexes. Two solution
      simulations were also carried out, one starting from canonical B-DNA and the
      other starting from the crystal structure. For many helicoidal parameters, the
      results from the crystal and solution simulations were essentially identical.
      However, for other parameters, in particular, alpha, gamma, delta, (epsilon -
      zeta), phase, and helical twist, differences between crystal and solution
      simulations were apparent. Notably, during crystal simulations, values of helical
      twist remained comparable to those in the crystal structure, to include the
      sequence-dependent differences among base steps, in which values ranged from 20
      degrees to 50 degrees per base step. However, in the solution simulations, not
      only did the average values of helical twist decrease to approximately 30 degrees
      per base step, but every base step was approximately 30 degrees, suggesting that
      the sequence-dependent information may be lost. This study reveals that MD
      simulations of the crystal environment complement solution simulations in
      validating the applicability of MD to the analysis of DNA structure.

PMID- 10653782
TI  - Clustering of macroions in solutions of highly asymmetric electrolytes.
AB  - In this paper, we present results of computer simulations for a primitive model
      of asymmetric electrolyte solutions containing macroions, counterions and in a
      few cases, also co-ions. The results show that the valency of counterions plays
      an important role in shaping the net interaction between the macroions. For
      solutions with monovalent counterions, the macroions are distributed at larger
      distances, and in solutions with divalent counterions, the macroions come closer
      to each other and share a layer of counterions, whereas, in solutions with
      trivalent counterions, the macroions form clusters. These clusters dissolve upon
      dilution or addition of a simple electrolyte. These findings suggest a mechanism
      whereby the nonuniform distribution of macroions observed experimentally in
      charged systems may occur.

PMID- 10653781
TI  - Molecular dynamics study of the nature and origin of retinal's twisted structure
      in bacteriorhodopsin.
AB  - The planarity of the polyene chain of the retinal chromophore in
      bacteriorhodopsin is studied using molecular dynamics simulation techniques and
      applying different force-field parameters and starting crystal structures. The
      largest deviations from a planar structure are observed for the C(13)==C(14) and
      C(15)==N(16) double bonds in the retinal Schiff base structure. The other
      dihedral angles along the polyene chain of the chromophore, although having lower
      torsional barriers in some cases, do not significantly deviate from the planar
      structure. The results of the simulations of different mutants of the pigment
      show that, among the studied amino acids of the binding pocket, the side chain of
      Trp-86 has the largest impact on the planarity of retinal, and the mutation of
      this amino acid to alanine leads to chromophore planarity. Deletion of the methyl
      C(20), removal of a water molecule hydrogen-bonded to H(15), or mutation of other
      amino acids to alanine did not show any significant influence on the distortion
      of the chromophore. The results from the present study suggest the importance of
      the bulky residue of Trp-86 in the isomerization process, in both ground and
      excited states of the chromophore, and in fine-tuning of the pK(a) of the retinal
      protonated Schiff base in bacteriorhodopsin. The dark adaptation of the pigment
      and the last step of the bacteriorhodopsin photocycle imply low barriers against
      the rotation of the double bonds in the Schiff base region. The twisted double
      bonds found in the present study are consistent with the proposed mechanism of
      these ground state isomerization events.

PMID- 10653783
TI  - Density functional theory for the nonspecific binding of salt to
      polyelectrolytes: thermodynamic properties.
AB  - The thermodynamics of the nonspecific binding of salt to a polyelectrolyte
      molecule is studied using a density functional approach. The polyelectrolyte
      molecule is modeled as an infinite, inflexible, and impenetrable charged cylinder
      and the counterions and co-ions are modeled as charged hard spheres of equal
      diameter. The density functional theory is based on a hybrid approach where the
      hard-sphere contribution to the one-particle correlation function is evaluated
      nonperturbatively and the ionic contribution to the one-particle correlation
      function is evaluated perturbatively. The advantage of the approach is that
      analytical expressions are available for all the correlation functions. The
      calculated single ion preferential interaction coefficients, excess free energy,
      and activity coefficients show a nonmonotonic variation as a function of polyion
      charge in the presence of divalent ions. These properties display considerable
      departure from the predictions of the nonlinear Poisson-Boltzmann (NLPB)
      equation, with qualitative differences in some cases, which may be attributed to
      correlation effects neglected in the NLPB theory.

PMID- 10653784
TI  - A model for photoreceptor-based magnetoreception in birds.
AB  - A large variety of animals has the ability to sense the geomagnetic field and
      utilize it as a source of directional (compass) information. It is not known by
      which biophysical mechanism this magnetoreception is achieved. We investigate the
      possibility that magnetoreception involves radical-pair processes that are
      governed by anisotropic hyperfine coupling between (unpaired) electron and
      nuclear spins. We will show theoretically that fields of geomagnetic field
      strength and weaker can produce significantly different reaction yields for
      different alignments of the radical pairs with the magnetic field. As a model for
      a magnetic sensory organ we propose a system of radical pairs being 1)
      orientationally ordered in a molecular substrate and 2) exhibiting changes in the
      reaction yields that affect the visual transduction pathway. We evaluate three
      dimensional visual modulation patterns that can arise from the influence of the
      geomagnetic field on radical-pair systems. The variations of these patterns with
      orientation and field strength can furnish the magnetic compass ability of birds
      with the same characteristics as observed in behavioral experiments. We propose
      that the recently discovered photoreceptor cryptochrome is part of the
      magnetoreception system and suggest further studies to prove or disprove this
      hypothesis.

PMID- 10653785
TI  - Calculation of hydrodynamic properties of globular proteins from their atomic
      level structure.
AB  - The solution properties, including hydrodynamic quantities and the radius of
      gyration, of globular proteins are calculated from their detailed, atomic-level
      structure, using bead-modeling methodologies described in our previous article (,
      Biophys. J. 76:3044-3057). We review how this goal has been pursued by other
      authors in the past. Our procedure starts from a list of atomic coordinates, from
      which we build a primary hydrodynamic model by replacing nonhydrogen atoms with
      spherical elements of some fixed radius. The resulting particle, consisting of
      overlapping spheres, is in turn represented by a shell model treated as described
      in our previous work. We have applied this procedure to a set of 13 proteins. For
      each protein, the atomic element radius is adjusted, to fit all of the
      hydrodynamic properties, taking values close to 3 A, with deviations that fall
      within the error of experimental data. Some differences are found in the atomic
      element radius found for each protein, which can be explained in terms of protein
      hydration. A computational shortcut makes the procedure feasible, even in
      personal computers. All of the model-building and calculations are carried out
      with a HYDROPRO public-domain computer program.

PMID- 10653786
TI  - Evaluation of the number of agonist molecules needed to activate a ligand-gated
      channel from the current rising phase.
AB  - We propose a new method for calculating the number of agonist binding sites (n)
      in ligand-gated receptor channels from the initial phase of the current. This
      method is based on the fact that the relation between the current (I) and its
      first-time derivative (I') at the beginning of the current reflects the number of
      transitions that lead to channel opening. We show that, for constant agonist
      concentration, the above relationship at t --> 0 provides the number of steps
      leading to channel opening. When the agonist concentration is not constant but
      rather increases linearly with time, the corresponding value can be obtained
      using a slightly modified procedure. The analytical results were compared with
      computer simulations and a good match between the two was obtained. The
      theoretical procedure was then validated experimentally using the nicotinic
      receptor, because, for this receptor, the number of binding sites is well
      established. Indeed, the expected number of two binding sites was obtained. The
      method was then tested for the quisqualate-type glutamate receptor channel from
      the opener muscle of crayfish. The number of this receptor's binding sites is not
      fully resolved. Our results suggest that, for this glutamate receptor as well,
      two binding sites must be occupied to open the channel.

PMID- 10653787
TI  - NMR study of volatile anesthetic binding to nicotinic acetylcholine receptors.
AB  - New lines of evidence suggest that volatile anesthetics interact specifically
      with proteins. Direct binding analysis, however, has been largely limited to
      soluble proteins. In this study, specific interaction was investigated between
      isoflurane, a clinically important volatile anesthetic, and membrane-bound
      nicotinic acetylcholine receptors (nAChRs) from Torpedo electroplax, using (19)F
      nuclear magnetic resonance spectroscopy and gas chromatography. The receptors
      were reconstituted into 1, 2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) lipid
      vesicles. After correcting for nonspecific partitioning into the lipid, the
      equilibrium dissociation constant, K(d), of isoflurane binding to nAChR at 15
      degrees C was found to be 0.36 +/- 0.03 mM. This value is within the clinically
      relevant concentration range of the agent. Based on the receptor concentrations
      in the vesicle suspension assayed by the bicinchoninic acid method and the
      fraction of bound isoflurane, X(b), determined by gas chromatography, an estimate
      of an average of 9-10 specifically bound isoflurane molecules can be made for
      each receptor, or two for each subunit. Upon binding, the transverse relaxation
      time constant (T(2)) of (19)F resonance of isoflurane is decreased by nearly
      three orders of magnitude, indicating a dramatic reduction in the mobility of
      specifically bound isoflurane. Kinetic analysis reveals that the off rate of
      binding, k(-1), is 1.7 x 10(4) s(-1). The on rate, k(+1), can thus be calculated
      to be approximately 4.8 x 10(7) M(-1) s(-1), suggesting a nearly diffusion
      limited association. This is in contrast to anesthetic binding to a soluble
      protein, bovine serum albumin (BSA), where k(+1) and k(-1) are at least an order
      of magnitude slower. It is concluded that the presence of lipids may be critical
      for the correct evaluation of binding kinetics between volatile anesthetics and
      neuronal receptors.

PMID- 10653788
TI  - The influence of surface charges on the conductance of the human connexin37 gap
      junction channel.
AB  - The single-channel conductance of the hCx37 homotypic gap junction channel does
      not saturate with transjunctional voltages up to +/-75 mV, nor does it depend
      linearly on the intracellular electrolyte concentration. The average maximum
      unitary conductances measured in KCl were 175 pS (30 mM), 236 pS (55 mM), 343 pS
      (110 mM), and 588 pS (270 mM) in the presence of 0.1 mM MgCl(2). The unexpectedly
      high unitary conductance at low salt concentrations can be explained by fixed
      charge groups within or near the channel orifice. Fixed cytoplasmic surface
      charges (3.4 e) positioned adjacent (15 A) to the channel pore adequately model
      the data (surface charge density of 0.24 e/(nm)(2)). In other experiments, high
      Mg(2+) reduced the unitary conductance of hCx37 homotypic gap junction channels
      more than predicted by screening alone, consistent with specific effects of
      Mg(2+) on the channel.

PMID- 10653789
TI  - Complex voltage-dependent behavior of single unliganded calcium-sensitive
      potassium channels.
AB  - study and characterization of unliganded openings is of central significance for
      the elucidation of gating mechanisms for allosteric ligand-gated ion channels.
      Unliganded openings have been reported for many channel types, but their low open
      probability can make it difficult to study their kinetics in detail. Because the
      large conductance calcium-activated potassium channel mSlo is sensitive to both
      intracellular calcium and to membrane potential, we have been able to obtain
      stable unliganded single-channel recordings of mSlo with relatively high opening
      probability. We have found that the single-channel gating behavior of mSlo is
      complex, with multiple open and closed states, even when no ligand is present.
      Our results rule out a Monod-Wyman-Changeux allosteric mechanism with a central
      voltage-dependent concerted step, and they support the existence of quaternary
      states with less than the full number of voltage sensors activated, as has been
      suggested by previous work involving measurements of gating currents.

PMID- 10653791
TI  - Rapid kinetic analysis of multichannel records by a simultaneous fit to all dwell
      time histograms.
AB  - A method is presented for rapidly extracting single-channel transition rate
      constants from patch-clamp recordings containing signals from several channels.
      The procedure is based on a simultaneous fit of the observed dwell-time
      distributions for all conductance levels, using a maximum likelihood approach.
      This algorithm allows estimation of single-channel rate constants in cases where
      more advanced methods may be impractical because of their extremely long
      computational time. A correction is included for the limited time resolution of
      the recording system, according to theory developed by Roux and Sauve (Biophys.
      J. 48:149-158, 1985), by accounting for the impact of undetected transitions on
      the dwell-time distributions, and by introducing an improved practical
      implementation of a fixed dead time for the case of more than one channel. This
      feature allows application of the method to noisy data, after filtering. A
      computer program implementing the method is tested successfully on a variety of
      simulated multichannel current traces.

PMID- 10653790
TI  - A point mutation in domain 4-segment 6 of the skeletal muscle sodium channel
      produces an atypical inactivation state.
AB  - We compared wild-type rat skeletal muscle NaChs (micro1) and a mutant NaCh
      (Y1586K) that has a single amino acid substitution, lysine (K) for tyrosine (Y),
      at position 1586 in the S6 transmembrane segment of domain 4. In Y1586K,
      macroscopic current decay is faster, the V(1/2) of the activation curve is
      shifted in the depolarized direction, and the fast-inactivation curve is less
      steep compared with mu1. After an 8-ms depolarization pulse, Y1586K recovers from
      inactivation much more slowly than mu1. The recovery is double exponential,
      suggesting recovery from two inactivation states. Varying the depolarization
      protocols isolates entry into an additional, "atypical" inactivation state in
      Y1586K that is distinct from typical fast or slow inactivation. Substitution of
      positively charged arginine (R) at Y1586 produces an inactivation phenotype
      similar to that of Y1586K. Substitution by negatively charged aspartic acid (D)
      or uncharged alanine (A) at Y1586 produces an inactivation phenotype similar to
      mu1. Our results suggest that the positive charge of lysine (K) produces the
      atypical inactivation state in Y1586K. We propose that a conformational change
      during depolarization alters the relative position of the 1586K residue in the D4
      S6 segment and that atypical inactivation in Y1586K occurs via an electrostatic
      interaction in or near the inner pore region.

PMID- 10653792
TI  - Distribution of halothane in a dipalmitoylphosphatidylcholine bilayer from
      molecular dynamics calculations.
AB  - We report a 2-ns constant pressure molecular dynamics simulation of halothane, at
      a mol fraction of 50%, in the hydrated liquid crystal bilayer phase of
      dipalmitoylphosphatidylcholine. Halothane molecules are found to preferentially
      segregate to the upper part of the lipid acyl chains, with a maximum probability
      near the C(5) methylene groups. However, a finite probability is also observed
      along the tail region and across the methyl trough. Over 95% of the halothane
      molecules are located below the lipid carbonyl carbons, in agreement with
      photolabeling experiments. Halothane induces lateral expansion and a concomitant
      contraction in the bilayer thickness. A decrease in the acyl chain segment order
      parameters, S(CD), for the tail portion, and a slight increase for the upper
      portion compared to neat bilayers, are in agreement with several NMR studies on
      related systems. The decrease in S(CD) is attributed to a larger accessible
      volume per lipid in the tail region. Significant changes in the electric
      properties of the lipid bilayer result from the structural changes, which include
      a shift and broadening of the choline headgroup dipole (P-N) orientation
      distribution. Our findings reconcile apparent controversial conclusions from
      experiments on diverse lipid systems.

PMID- 10653793
TI  - Effect of pH on the interfacial tension of lipid bilayer membrane.
AB  - The dependence of the interfacial tension of a lipid bilayer on the pH of the
      aqueous solution has been studied. A theoretical equation is derived to describe
      this dependence. Interfacial tension measurements of an egg phosphatidylcholine
      bilayer were carried out. The experimental results agreed with those derived from
      the theoretical equation obtained close to the isoelectric point within a range
      of three pH units. A maximum corresponding to the isoelectric point appears both
      in the theoretical equation and in the experimental data.

PMID- 10653794
TI  - Effect of phospholipid composition on an amphipathic peptide-mediated pore
      formation in bilayer vesicles.
AB  - To better understand the influence of phospholipid acyl-chain composition on the
      formation of pores by cytotoxic amphipathic helices in biological membranes, the
      leakage of aqueous contents induced by the synthetic peptide GALA (WEAALAEALAE
      ALAEHLAEALAEALEALAA) from large unilamellar phospholipid vesicles of various
      compositions has been studied. Peptide-mediated leakage was examined at pH 5.0
      from vesicles made of phosphatidylcholine (PC) and phosphatidylglycerol (PG) with
      the following acyl-chain compositions: 1-palmitoyl-2-oleoyl (PO), 1,2-dioleoyl
      (DO), 1, 2-dielaidoyl (DE), and 1,2-dipetroselinoyl (DPe). A mathematical model
      predicts and simulates the final extents of GALA-mediated leakage of 1
      aminonaphthalene-3,6,8-trisulfonic acid (ANTS) and p-xylene-bis-pyridinium
      bromide (DPX) from 1-palmitoyl-2-oleoyl-phosphatidylcholine/1-palmitoyl-2-oleoyl
      phospha tidylglycerol (POPC/POPG) and 1, 2-dielaidoyl-sn-glycero-3
      phosphocholine/1, 2-dielaidoyl-phosphatidylglycerol (DEPC/DEPG) liposomes at pH
      5.0 as a function of peptide concentration in the bilayer, by considering that
      GALA pores responsible for this leakage have a minimum size of 10 +/- 2 monomers
      and are formed by quasiirreversible aggregation of the peptide. With the
      phospholipid acyl-chain compositions tested, GALA-induced ANTS/DPX leakage
      follows the rank order POPC/POPG approximately DEPC/DEPG > DPePC/DPePG >
      DOPC/DOPG. Results from binding experiments reveal that this reduced leakage from
      DOPC/DOPG vesicles cannot be explained by a reduced binding affinity of the
      peptide to these membranes. As shown by monitoring the leakage of a fluorescent
      dextran, an increase in the minimum pore size also does not explain the reduction
      in ANTS/DPX leakage. The data suggest that surface-associated GALA monomers or
      aggregates are stabilized in bilayers composed of phospholipids containing a cis
      unsaturation per acyl chain (DO and DPe), while transbilayer peptide insertion is
      reduced. GALA-induced ANTS/DPX leakage is also decreased when the vesicles
      contain phosphatidylethanolamine (PE). This lends further support to the
      suggestion that factors stabilizing the surface state of the peptide reduce its
      insertion and subsequent pore formation in the bilayer.

PMID- 10653795
TI  - Vectorial budding of vesicles by asymmetrical enzymatic formation of ceramide in
      giant liposomes.
AB  - Sphingomyelin is an abundant component of eukaryotic membranes. A specific
      enzyme, sphingomyelinase can convert this lipid to ceramide, a central second
      messenger in cellular signaling for apoptosis (programmed cell death),
      differentiation, and senescence. We used microinjection and either Hoffman
      modulation contrast or fluorescence microscopy of giant liposomes composed of 1
      stearoyl-2-oleoyl-sn-glycero-3-phosphocholine (SOPC), N-palmitoyl-sphingomyelin
      (C16:0-SM), and Bodipy-sphingomyelin as a fluorescent tracer (molar ratio
      0.75:0.20:0.05, respectively) to observe changes in lipid lateral distribution
      and membrane morphology upon formation of ceramide. Notably, in addition to rapid
      domain formation (capping), vectorial budding of vesicles, i.e., endocytosis and
      shedding, can be induced by the asymmetrical sphingomyelinase-catalyzed
      generation of ceramide in either the outer or the inner leaflet, respectively, of
      giant phosphatidylcholine/sphingomyelin liposomes. These results are readily
      explained by 1) the lateral phase separation of ceramide enriched domains, 2) the
      area difference between the adjacent monolayers, 3) the negative spontaneous
      curvature, and 4) the augmented bending rigidity of the ceramide-containing
      domains, leading to membrane invagination and vesiculation of the bilayer.

PMID- 10653796
TI  - Membrane partitioning of the cleavage peptide in flock house virus.
AB  - Membrane translocation of the ssRNA genome of nodaviruses has been proposed to be
      mediated by direct lipid-protein interactions between a postassembly
      autocatalytic cleavage product from the capsomere and the target membrane. We
      have recently shown that the 21-residue Met-->Nle variant of the N-terminal
      helical domain (denoted gamma(1)) of the cleavage peptide in flock house
      nodavirus increases membrane permeability to hydrophilic solutes and can alter
      both membrane structure and function, suggesting the possibility of peptide
      triggered disruption of the endosomal membrane as a prelude to viral uncoating in
      the host cytoplasm. Elucidation of partitioning energetics would allow an
      assessment of the likelihood of this mechanism. We report herein complete
      thermodynamic characterization of the partitioning of gamma(1) to phospholipids
      by lipid-peptide titrations following changes in ellipticity, fluorescence
      signature, or calorimetric response. These experiments revealed a partitioning
      energy comparable to natural membrane-active peptide toxins, suggesting that the
      proposed mechanism may be possible. Additionally, a novel switch in the balance
      of partitioning forces was found: when the lipid headgroup was changed from
      zwitterionic to negatively charged, membrane association of the peptide became
      completely entropy-driven.

PMID- 10653797
TI  - Detection of peptide-lipid interactions in mixed monolayers, using isotherms,
      atomic force microscopy, and fourier transform infrared analyses.
AB  - To improve the understanding of the membrane uptake of an amphipathic and
      positively charged vector peptide, we studied the interactions of this peptide
      with different phospholipids, the nature of whose polar headgroups and physical
      states were varied. Three lipids were considered: dipalmitoylphosphatidylcholine
      (DPPC), dipalmitoylphosphatidylglycerol (DPPG), and dioleoylphosphatidylglycerol
      (DOPG). The approach was carried out by three complementary methods: compression
      isotherms of monolayers and atomic force microscopy observations associated with
      Fourier transform infrared investigations. From analysis of the compression
      isotherms, it was concluded that the peptide interacts with all lipids and with
      an expansion of the mean molecular area, implying that both components form
      nonideal mixtures. The expansion was larger in the case of DOPG than for DPPC and
      DPPG because of an alpha to beta conformational transition with an increase in
      the peptide molar fraction. Atomic force microscopy observations showed that the
      presence of small amounts of peptide led to the appearance of bowl-like particles
      and that an increase in the peptide amounts generated the formation of filaments.
      In the case of DOPG, filaments were found at higher peptide molar fractions than
      already observed for DOPC because of the presence of negatively charged lipid
      headgroups.

PMID- 10653799
TI  - Cholesterol crystalline polymorphism and the solubility of cholesterol in
      phosphatidylserine.
AB  - There is a marked hysteresis between the heating and cooling polymorphic phase
      transition of anhydrous cholesterol. At a scan rate of 0.05 degrees C/min the
      difference in transition temperatures between heating and cooling scans is
      approximately 10 degrees C. This phenomenon also occurs with mixtures of
      cholesterol with phosphatidylserine and can result in an underestimation of the
      amount of crystalline cholesterol in a sample that has not been cooled
      sufficiently. With 1-palmitoyl-2-oleoyl phosphatidylserine and 1-stearoyl-2
      oleoyl phosphatidylserine the cholesterol crystallites form while the lipid
      remains in the L(alpha) phase. Sonication of dimyristoyl phosphatidylserine with
      a 0.4 mol fraction cholesterol results in the loss of cholesterol crystallite
      diffraction, but only a partial loss of the polymorphic transition detected by
      calorimetry. We therefore conclude that the thermal history of the sample can
      have profound effects on the appearance of the polymorphic phase transition of
      cholesterol by differential scanning calorimetry. Depending on the morphology of
      the vesicles, diffraction methods may underevaluate the amount of cholesterol
      crystallites present.

PMID- 10653798
TI  - Unbinding-binding transition induced by molecular snaps in model membranes.
AB  - We have used a lamellar phase made of a nonionic surfactant, dodecane and water,
      as a model membrane to investigate its interactions with macromolecular
      inclusions bringing together two membranes, i.e., acting as macromolecular snaps.
      In systems devoid of inclusions, the interlamellar distance depends on the total
      volume fraction of membranes Phi. We show that, in presence of a transmembrane
      protein, or of several de novo designed peptides of different length and
      composition, the lamellar phase undergoes a binding transition. Under such
      conditions, the interlamellar distance is no longer proportional to Phi(-1), but
      rather to the surface concentration of snaps within the membrane. It also appears
      that, in the presence of the hydrophobic segment of peptide snaps, the length of
      the inclusions must be at least equal to the hydrophobic length of the membrane
      to be active. Experimental results have been precisely fitted to a model of
      thermally stabilized membranes, decorated with snaps. However, in the presence of
      inclusions, the parameter describing the interactions between membranes, has to
      take into account the length of the inclusion to preserve good predictive
      capabilities.

PMID- 10653800
TI  - Trans interactions between galactosylceramide and cerebroside sulfate across
      apposed bilayers.
AB  - The two glycosphingolipids galactosylceramide (GalC) and its sulfated form,
      cerebroside sulfate (CBS), are present at high concentrations in the multilayered
      myelin sheath and are involved in carbohydrate-carbohydrate interactions between
      the lipid headgroups. In order to study the structure of the complex of these two
      glycolipids by Fourier transform infrared (FTIR) spectroscopy, GalC dispersions
      were combined with CBS dispersions in the presence and absence of Ca(2+). The
      FTIR spectra indicated that a strong interaction occurred between these
      glycolipids even in the absence of Ca(2+). The interaction resulted in
      dehydration of the sulfate, changes in the intermolecular hydrogen bonding
      interactions of the sugar and other oxygens, decreased intermolecular hydrogen
      bonding of the amide C==O of GalC and dehydration of the amide region of one or
      both of the lipids in the mixture, and disordering of the hydrocarbon chains of
      both lipids. The spectra also show that Ca(2+) interacts with the sulfate of CBS.
      Although they do not reveal which other groups of CBS and GalC interact with
      Ca(2+) or which groups participate in the interaction between the two lipids,
      they do show that the sulfate is not directly involved in interaction with GalC,
      since it can still bind to Ca(2+) in the mixture. The interaction between these
      two lipids could be either a lateral cis interaction in the same bilayer or a
      trans interaction between apposed bilayers. The type of interaction between the
      lipids, cis or trans, was investigated using fluorescent and spin-label probes
      and anti-glycolipid antibodies. The results confirmed a strong interaction
      between the GalC and the CBS microstructures. They suggested further that this
      interaction caused the CBS microstructures to be disrupted so that CBS formed a
      single bilayer around the GalC multilayered microstructures, thus sequestering
      GalC from the external aqueous phase. Thus the CBS and GalC interacted via a
      trans interaction across apposed bilayers, which resulted in dehydration of the
      headgroup and interface region of both lipid bilayers. The strong interaction
      between these lipids may be involved in stabilization of the myelin sheath.

PMID- 10653801
TI  - Membrane fusion mediated by coiled coils: a hypothesis.
AB  - A molecular model of the low-pH-induced membrane fusion by influenza
      hemagglutinin (HA) is proposed based upon the hypothesis that the conformational
      change to the extended coiled coil creates a high-energy hydrophobic membrane
      defect in the viral envelope or HA expressing cell. It is known that 1) an
      aggregate of at least eight HAs is required at the fusion site, yet only two or
      three of these HAs need to undergo the "essential" conformational change for the
      first fusion pore to form (Bentz, J. 2000. Biophys. J. 78:000-000); 2) the
      formation of the first fusion pore signifies a stage of restricted lipid flow
      into the nascent fusion site; and 3) some HAs can partially insert their fusion
      peptides into their own viral envelopes at low pH. This suggests that the
      committed step for HA-mediated fusion begins with a tightly packed aggregate of
      HAs whose fusion peptides are inserted into their own viral envelope, which
      causes restricted lateral lipid flow within the HA aggregate. The transition of
      two or three HAs in the center of the aggregate to the extended coiled coil
      extracts the fusion peptide and creates a hydrophobic defect in the outer
      monolayer of the virion, which is stabilized by the closely packed HAs. These HAs
      are inhibited from diffusing away from the site to admit lateral lipid flow, in
      part because that would initially increase the surface area of hydrophobic
      exposure. The other obvious pathway to heal this hydrophobic defect, or some
      descendent, is recruitment of lipids from the outer monolayer of the apposed
      target membrane, i.e., fusion. Other viral fusion proteins and the SNARE fusion
      protein complex appear to fit within this hypothesis.

PMID- 10653802
TI  - Translational diffusion of globular proteins in the cytoplasm of cultured muscle
      cells.
AB  - Modulated fringe pattern photobleaching (MFPP) was used to measure the
      translational diffusion of microinjected fluorescein isothiocyanate (FITC)
      labeled proteins of different sizes in the cytoplasm of cultured muscle cells.
      This technique, which is an extension of the classical fluorescence recovery
      after photobleaching (FRAP) technique, allows the measurement of the
      translational diffusion of macromolecules over several microns. Proteins used had
      molecular masses between 21 and 540 kDa. The results clearly indicated that the
      diffusivity of the various proteins is a decreasing function of their
      hydrodynamic radius. This decrease is more rapid with globular proteins than with
      FITC-labeled dextrans (, Biophys. J. 70:2327-2332), most likely because, unlike
      globular proteins, dextrans are randomly coiled macromolecules with a flexible
      structure. These data do not exclude the possibility of a rapid diffusion over a
      short distance, unobservable with our experimental set-up, which would take place
      within the first milliseconds after bleaching and would correspond to the
      diffusion in restricted domains followed by impeded diffusion provoked by the
      network of microtubules, microfilaments, and intermediate filaments. Thus our
      results may complement rather than contradict those of Verkman and collaborators
      (, J. Cell Biol. 138:1-12). The biological consequence of the size-dependent
      restriction of the mobility of proteins in the cell cytoplasm is that the
      formation of intracellular complexes with other proteins considerably reduces
      their mobility.

PMID- 10653804
TI  - Measurement of nucleotide exchange rate constants in single rabbit soleus
      myofibrils during shortening and lengthening using a fluorescent ATP analog.
AB  - The kinetics of displacement of a fluorescent nucleotide, 2'(3')-O-[N[2
      [[Cy3]amido]ethyl]carbamoyl]-adenosine 5'-triphosphate (Cy3-EDA-ATP), bound to
      rabbit soleus muscle myofibrils were studied using flash photolysis of caged ATP.
      Use of myofibrils from this slow twitch muscle allowed better resolution of the
      kinetics of nucleotide exchange than previous studies with psoas muscle
      myofibrils (, Biophys. J. 73:2033-2042). Soleus myofibrils in the presence of Cy3
      EDA-nucleotides (Cy3-EDA-ATP or Cy3-EDA-ADP) showed selective fluorescence
      staining of the A-band. The K(m) for Cy3-EDA-ATP and the K(d) for Cy3-EDA-ADP
      binding to the myofibril A-band were 1.9 microM and 3.8 microM, respectively,
      indicating stronger binding of nucleotide to soleus cross-bridges compared to
      psoas cross-bridges (2.6 microM and 50 microM, respectively). After flash
      photolysis of caged ATP, the A-band fluorescence of the myofibril in the Cy3-EDA
      ATP solution under isometric conditions decayed exponentially with a rate
      constant of 0.045 +/- 0.007 s(-1) (n = 32) at 10 degrees C, which was about seven
      times slower than that for psoas myofibrils. When a myofibril was allowed to
      shorten with a constant velocity, the nucleotide displacement rate constant
      increased from 0.066 s(-1) (isometric) to 0.14 s(-1) at 20 degrees C with
      increasing shortening velocity up to 0.1 myofibril length/s (V(max), the
      shortening velocity under no load was approximately 0. 2 myofibril lengths/s).
      The rate constant was not significantly affected by an isovelocity stretch of up
      to 0.1 myofibril lengths/s. These results suggest that the cross-bridge kinetics
      are not significantly affected at higher strain during lengthening but depend on
      the lower strain during shortening. These data also indicate that the interaction
      distance between a cross-bridge and the actin filament is at least 16 nm for a
      single cycle of the ATPase.

PMID- 10653803
TI  - Three-dimensional reconstruction of thin filaments containing mutant tropomyosin.
AB  - Interactions of the components of reconstituted thin filaments were investigated
      using a tropomyosin internal deletion mutant, D234, in which actin-binding pseudo
      repeats 2, 3, and 4 are missing. D234 retains regions of tropomyosin that bind
      troponin and form end-to-end tropomyosin bonds, but has a length to span only
      four instead of seven actin monomers. It inhibits acto-myosin subfragment 1
      ATPase (acto-S-1 ATPase) and filament sliding in vitro in both the presence and
      absence of Ca(2+) (, J. Biol. Chem. 272:14051-14056) and lowers the affinity of S
      1.ADP for actin while increasing its cooperative binding. Electron microscopy and
      three-dimensional reconstruction of reconstituted thin filaments containing
      actin, troponin, and wild-type or D234 tropomyosin were carried out to determine
      if Ca(2+)-induced movement of D234 occurred in the filaments. In the presence and
      absence of Ca(2+), the D234 position was indistinguishable from that of the wild
      type tropomyosin, demonstrating that the mutation did not affect normal
      tropomyosin movement induced by Ca(2+) and troponin. These results suggested
      that, in the presence of Ca(2+) and troponin, D234 tropomyosin was trapped on
      filaments in the Ca(2+)-induced position and was unable to undergo a transition
      to a completely activated position. By adding small amounts of rigor-bonded N
      ethyl-maleimide-treated S-1 to mutant thin filaments, thus mimicking the myosin
      induced "open" state, inhibition could be overcome and full activation restored.
      This myosin requirement for full activation provides support for the existence of
      three functionally distinct thin filament states (off, Ca(2+)-induced, myosin
      induced; cf.;, J. Mol. Biol. 266:8-14). We propose a further refinement of the
      three-state model in which the binding of myosin to actin causes allosteric
      changes in actin that promote the binding of tropomyosin in an otherwise
      energetically unfavorable "open" state.

PMID- 10653805
TI  - The effect of polyethylene glycol on the mechanics and ATPase activity of active
      muscle fibers.
AB  - We have used polyethylene glycol (PEG) to perturb the actomyosin interaction in
      active skinned muscle fibers. PEG is known to potentiate protein-protein
      interactions, including the binding of myosin to actin. The addition of 5% w/v
      PEG (MW 300 or 4000) to active fibers increased fiber tension and decreased
      shortening velocity and ATPase activity, all by 25-40%. Variation in [ADP] or
      [ATP] showed that the addition of PEG had little effect on the dissociation of
      the cross-bridge at the end of the power stroke. Myosin complexed with ADP and
      the phosphate analog V(i) or AlF(4) binds weakly to actin and is an analog of a
      pre-power-stroke state. PEG substantially enhances binding of these states both
      in active fibers and in solution. Titration of force with increasing [P(i)]
      showed that PEG increased the free energy available to drive the power stroke by
      about the same amount as it increased the free energy available from the
      formation of the actomyosin bond. Thus PEG potentiates the binding of myosin to
      actin in active fibers, and it provides a method for enhancing populations of
      some states for structural or mechanical studies, particularly those of the
      normally weakly bound transient states that precede the power stroke.

PMID- 10653806
TI  - Direct inhibition of microtubule-based kinesin motility by local anesthetics.
AB  - Local anesthetics are known to inhibit neuronal fast anterograde axoplasmic
      transport (FAAT) in a reversible and dose-dependent manner, but the precise
      mechanism has not been determined. FAAT is powered by kinesin superfamily
      proteins, which transport membranous organelles, vesicles, or protein complexes
      along microtubules. We investigated the direct effect of local anesthetics on
      kinesin, using both in vitro motility and single-molecule motility assays. In the
      modified in vitro motility assay, local anesthetics immediately and reversibly
      stopped the kinesin-based microtubule movement in an all-or-none fashion without
      lowering kinesin ATPase activity. QX-314, a permanently charged derivative of
      lidocaine, exerted an effect similar to that of lidocaine, suggesting that the
      effect of anesthetics is due to the charged form of the anesthetics. In the
      single-molecule motility assay, the local anesthetic tetracaine inhibited the
      motility of individual kinesin molecules in a dose-dependent manner. The
      concentrations of the anesthetics that inhibited the motility of kinesin
      correlated well with those blocking FAAT. We conclude that the charged form of
      local anesthetics directly and reversibly inhibits kinesin motility in a dose
      dependent manner, and it is the major cause of the inhibition of FAAT by local
      anesthetics.

PMID- 10653807
TI  - Cryoatomic force microscopy of filamentous actin.
AB  - Cryoatomic force microscopy (cryo-AFM) was used to image phalloidin-stabilized
      actin filaments adsorbed to mica. The single filaments are clearly shown to be
      right-handed helical structures with a periodicity of approximately 38 nm. Even
      at a moderate concentration ( approximately 10 microg/ml), narrow, branched rafts
      of actin filaments and larger aggregates have been observed. The resolution
      achieved is sufficient to resolve actin monomers within the filaments. A closer
      examination of the images shows that the branched rafts are composed of up to
      three individual filaments with a highly regular lateral registration with a
      fixed axial shift of approximately 13 nm. The implications of these higher-order
      structures are discussed in terms of x-ray fiber diffraction and rheology of
      actin gels. The cryo-AFM images also indicate that the recently proposed model of
      left-handed F-actin is likely to be an artifact of preparation and/or low
      resolution AFM imaging.

PMID- 10653808
TI  - Charge motions during the photocycle of pharaonis halorhodopsin.
AB  - Oriented gel samples were prepared from halorhodopsin-containing membranes from
      Natronobacterium pharaonis, and their photoelectric responses to laser flash
      excitation were measured at different chloride concentrations. The fast component
      of the current signal displayed a characteristic dependency on chloride
      concentration, and could be interpreted as a sum of two signals that correspond
      to the responses at high-chloride and no-chloride, but high-sulfate,
      concentration. The chloride concentration-dependent transition between the two
      signals followed the titration curve determined earlier from spectroscopic
      titration. The voltage signal was very similar to that reported by another group
      (Kalaidzidis, I. V., Y. L. Kalaidzidis, and A. D. Kaulen. 1998. FEBS Lett. 427:59
      63). The absorption kinetics, measured at four wavelengths, fit the kinetic model
      we had proposed earlier. The calculated time-dependent concentrations of the
      intermediates were used to fit the voltage signal. Although no negative electric
      signal was observed at high chloride concentration, the calculated
      electrogenicity of the K intermediate was negative, and very similar to that of
      bacteriorhodopsin. The late photocycle intermediates (O, HR', and HR) had almost
      equal electrogenicities, explaining why no chloride-dependent time constant was
      identified earlier by Kalaidzidis et al. The calculated electrogenicities, and
      the spectroscopic information for the chloride release and uptake steps of the
      photocycle, suggest a mechanism for the chloride-translocation process in this
      pump.

PMID- 10653809
TI  - Sensory rhodopsin II from the haloalkaliphilic natronobacterium pharaonis: light
      activated proton transfer reactions.
AB  - In the present work the light-activated proton transfer reactions of sensory
      rhodopsin II from Natronobacterium pharaonis (pSRII) and those of the channel
      mutants D75N-pSRII and F86D-pSRII are investigated using flash photolysis and
      black lipid membrane (BLM) techniques. Whereas the photocycle of the F86D-pSRII
      mutant is quite similar to that of the wild-type protein, the photocycle of D75N
      pSRII consists of only two intermediates. The addition of external proton donors
      such as azide, or in the case of F86D-pSRII, imidazole, accelerates the
      reprotonation of the Schiff base, but not the turnover. The electrical
      measurements prove that pSRII and F86D-pSRII can function as outwardly directed
      proton pumps, whereas the mutation in the extracellular channel (D75N-pSRII)
      leads to an inwardly directed transient current. The almost negligible size of
      the photostationary current is explained by the long-lasting photocycle of about
      a second. Although the M decay, but not the photocycle turnover, of pSRII and
      F86D-pSRII is accelerated by the addition of azide, the photostationary current
      is considerably increased. It is discussed that in a two-photon process a late
      intermediate (N- and/or O-like species) is photoconverted back to the original
      resting state; thereby the long photocycle is cut short, giving rise to the large
      increase of the photostationary current. The results presented in this work
      indicate that the function to generate ion gradients across membranes is a
      general property of archaeal rhodopsins.

PMID- 10653810
TI  - Low-resolution molecular structures of isolated functional units from arthropodan
      and molluscan hemocyanin.
AB  - Synchrotron x-ray scattering measurements were performed on dilute solutions of
      the purified hemocyanin subunit (Bsin1) from scorpion (Buthus sindicus) and the N
      terminal functional unit (Rta) from a marine snail (Rapana thomasiana). The model
      independent approach based on spherical harmonics was applied to calculate the
      molecular envelopes directly from the scattering profiles. Their molecular shapes
      in solution could be restored at 2-nm resolution. We show that these units
      represent stable, globular building blocks of the two hemocyanin families and
      emphasize their conformational differences on a subunit level. Because no
      crystallographic or electron microscopy data are available for isolated
      functional units, this study provides for the first time structural information
      for isolated, monomeric functional subunits from both hemocyanin families. This
      has been made possible through the use of low protein concentrations (< or = 1
      mg/ml). The observed structural differences may offer advantages in building very
      different overall molecular architectures of hemocyanin by the two phyla.

PMID- 10653811
TI  - A designed four-alpha-helix bundle that binds the volatile general anesthetic
      halothane with high affinity.
AB  - The structural features of volatile anesthetic binding sites on proteins are
      being examined with the use of a defined model system consisting of a four-alpha
      helix bundle scaffold with a hydrophobic core. Previous work has suggested that
      introducing a cavity into the hydrophobic core improves anesthetic binding
      affinity. The more polarizable methionine side chain was substituted for a
      leucine, in an attempt to enhance the dispersion forces between the ligand and
      the protein. The resulting bundle variant has an improved affinity (K(d) = 0.20
      +/- 0.01 mM) for halothane binding, compared with the leucine-containing bundle
      (K(d) = 0.69 +/- 0.06 mM). Photoaffinity labeling with (14)C-halothane reveals
      preferential labeling of the W15 residue in both peptides, supporting the view
      that fluorescence quenching by bound anesthetic reports both the binding
      energetics and the location of the ligand in the hydrophobic core. The rates of
      amide hydrogen exchange were similar for the two bundles, suggesting that
      differences in binding affinity were not due to changes in protein stability.
      Binding of halothane to both four-alpha-helix bundle proteins stabilized the
      native folded conformations. Molecular dynamics simulations of the bundles
      illustrate the existence of the hydrophobic core, containing both W15 residues.
      These results suggest that in addition to packing defects, enhanced dispersion
      forces may be important in providing higher affinity anesthetic binding sites.
      Alternatively, the effect of the methionine substitution on halothane binding
      energetics may reflect either improved access to the binding site or allosteric
      optimization of the dimensions of the binding pocket. Finally, preferential
      stabilization of folded protein conformations may represent a fundamental
      mechanism of inhaled anesthetic action.

PMID- 10653812
TI  - Do parallel beta-helix proteins have a unique fourier transform infrared
      spectrum?
AB  - Several polypeptides have been found to adopt an unusual domain structure known
      as the parallel beta-helix. These domains are characterized by parallel beta
      strands, three of which form a single parallel beta-helix coil, and lead to long,
      extended beta-sheets. We have used ATR-FTIR (attenuated total reflectance-fourier
      transform infrared spectroscopy) to analyze the secondary structure of
      representative examples of this class of protein. Because the three-dimensional
      structures of parallel beta-helix proteins are unique, we initiated this study to
      determine if there was a corresponding unique FTIR signal associated with the
      parallel beta-helix conformation. Analysis of the amide I region, emanating from
      the carbonyl stretch vibration, reveals a strong absorbance band at 1638 cm(-1)
      in each of the parallel beta-helix proteins. This band is assigned to the
      parallel beta-sheet structure. However, components at this frequency are also
      commonly observed for beta-sheets in many classes of globular proteins. Thus we
      conclude that there is no unique infrared signature for parallel beta-helix
      structure. Additional contributions in the 1638 cm(-1) region, and at lower
      frequencies, were ascribed to hydrogen bonding between the coils in the loop/turn
      regions and amide side-chain interactions, respectively. A 13-residue peptide
      that forms fibrils and has been proposed to form beta-helical structure was also
      examined, and its FTIR spectrum was compared to that of the parallel beta-helix
      proteins.

PMID- 10653813
TI  - Voltammetry of a flavocytochrome c(3): the lowest potential heme modulates
      fumarate reduction rates.
AB  - Iron-induced flavocytochrome c(3), Ifc(3), from Shewanella frigidimarina
      NCIMB400, derivatized with a 2-pyridyl disulfide label, self-assembles on gold
      electrodes as a functional array whose fumarate reductase activity as viewed by
      direct electrochemistry is indistinguishable from that of Ifc(3) adsorbed on gold
      or graphite electrodes. The enhanced stability of the labeled protein's array
      permits analysis at a rotating electrode and limiting catalytic currents fit well
      to a Michaelis-Menten description of enzyme kinetics with K(M) = 56 +/- 20
      microM, pH 7.5, comparable to that obtained in solution assays. At fumarate
      concentrations above 145 microM cyclic voltammetry shows the catalytic response
      to contain two features. The position and width of the lower potential component
      centered on -290 mV and corresponding to a one-electron wave implicates the
      oxidation state of the lowest potential heme of Ifc(3) as a defining feature in
      the mechanism of fumarate reduction at high turnover rates. We propose the
      operation of dual pathways for electron transfer to the active site of Ifc(3)
      with the lowest potential heme acting as an electron relay on one of these
      pathways.

PMID- 10653814
TI  - Solvent effects on the conformation of the transmembrane peptide gramicidin A:
      insights from electrospray ionization mass spectrometry.
AB  - The binding of sodium ions to the transmembrane channel peptide gramicidin A has
      permitted the use of electrospray ionization mass spectrometry to study its
      conformation in different solvent environments. The mass spectra of the peptide
      in the various solvents suggest that different conformations of gramicidin A
      differ in their ability to bind metal ions. The data are consistent with
      monomeric behavior of gramicidin A in trifluoroethanol and dimethyl sulfoxide
      solutions, but reveal the presence of noncovalent intermolecular interactions in
      ethanol solution through the observation of heterodimers formed between the
      naturally occurring variants of the peptide. The addition of 50% v/v of water to
      the ethanolic solution causes changes in the circular dichroism spectrum of the
      peptide, suggestive of a shift in the equilibrium mixture of conformers present
      toward monomeric species, a result supported by its mass spectrum. The structure
      of gramicidin A in trifluoroethanol has also been investigated by hydrogen
      exchange measurements monitored by mass spectrometry. The observation of
      significant protection against exchange suggests that the monomeric peptide is
      highly structured in trifluoroethanol. The results indicate that mass
      spectrometry has the potential to probe the conformational behavior of neutral
      hydrophobic peptides in environments that mimic their functional states.

PMID- 10653815
TI  - Electron paramagnetic resonance study of the migratory ant Pachycondyla marginata
      abdomens.
AB  - Electron paramagnetic resonance was used to investigate the magnetic material
      present in abdomens of Pachycondyla marginata ants. A g congruent with 4.3
      resonance of high-spin ferric ions and a very narrow g congruent with 2 line are
      observed. Two principal resonance broad lines, one with g > 4.5 (LF) and the
      other in the region of g congruent with 2 (HF), were associated with the
      biomineralization process. The resonance field shift between these two lines, HF
      and LF, associated with magnetic nanoparticles indicates the presence of cluster
      structures containing on average three single units of magnetite-based
      nanoparticles. Analysis of the temperature dependence of the HF resonance
      linewidths supports the model picture of isolated magnetite nanostructures of
      approximately 13 nm in diameter with a magnetic energy of 544 K. These particles
      are shown to present a superparamagnetic behavior at room temperature. The use of
      these superparamagnetic particle properties for the magnetoreception process of
      the ants is suggested.

PMID- 10653817
TI  - Torque-speed relationship of the flagellar rotary motor of Escherichia coli.
AB  - The output of a rotary motor is characterized by its torque and speed. We
      measured the torque-speed relationship of the flagellar rotary motor of
      Escherichia coli by a new method. Small latex spheres were attached to flagellar
      stubs on cells fixed to the surface of a glass slide. The angular speeds of the
      spheres were monitored in a weak optical trap by back-focal-plane interferometry
      in solutions containing different concentrations of the viscous agent Ficoll.
      Plots of relative torque (viscosity x speed) versus speed were obtained over a
      wide dynamic range (up to speeds of approximately 300 Hz) at three different
      temperatures, 22.7, 17.7, and 15.8 degrees C. Results obtained earlier by
      electrorotation (, Biophys. J. 65:2201-2216) were confirmed. The motor operates
      in two dynamic regimes. At 23 degrees C, the torque is approximately constant up
      to a knee speed of nearly 200 Hz, and then it falls rapidly with speed to a zero
      torque speed of approximately 350 Hz. In the low-speed regime, torque is
      insensitive to changes in temperature. In the high-speed regime, it decreases
      markedly at lower temperature. These results are consistent with models in which
      torque is generated by a powerstroke mechanism (, Biophys. J. 76:580-587).

PMID- 10653816
TI  - cAMP regulated membrane diffusion of a green fluorescent protein-aquaporin 2
      chimera.
AB  - To study the membrane mobility of aquaporin water channels, clones of stably
      transfected LLC-PK1 cells were isolated with plasma membrane expression of GFP
      AQP1 and GFP-AQP2, in which the green fluorescent protein (GFP) was fused
      upstream and in-frame to each aquaporin (AQP). The GFP fusion did not affect AQP
      tetrameric association or water transport function. GFP-AQP lateral mobility was
      measured by irreversibly bleaching a spot (diameter 0.8 microm) on the membrane
      with an Argon laser beam (488 nm) and following the fluorescence recovery into
      the bleached area resulting from GFP translational diffusion. In cells expressing
      GFP-AQP1, fluorescence recovered to >96% of its initial level with t(1/2) of 38
      +/- 2 s (23 degrees C) and 21 +/- 1 s (37 degrees C), giving diffusion
      coefficients (D) of 5.3 and 9.3 x 10(-11) cm(2)/s. GFP-AQP1 diffusion was
      abolished by paraformaldehyde fixation, slowed >50-fold by the cholesterol
      binding agent filipin, but not affected by cAMP agonists. In cells expressing GFP
      AQP2, fluorescence recovered to >98% with D of 5.7 and 9.0 x 10(-11) cm(2)/s at
      23 degrees C and 37 degrees C. In contrast to results for GFP-AQP1, the cAMP
      agonist forskolin slowed GFP-AQP2 mobility by up to tenfold. The cAMP slowing was
      blocked by actin filament disruption with cytochalasin D, by K(+)-depletion in
      combination with hypotonic shock, and by mutation of the protein kinase A
      phosphorylation consensus site (S256A) at the AQP2 C-terminus. These results
      indicate unregulated diffusion of AQP1 in membranes, but regulated AQP2 diffusion
      that was dependent on phosphorylation at serine 256, and an intact actin
      cytoskeleton and clathrin coated pit. The cAMP-induced immobilization of
      phosphorylated AQP2 provides evidence for AQP2-protein interactions that may be
      important for retention of AQP2 in specialized membrane domains for efficient
      membrane recycling.

PMID- 10653818
TI  - Sequence dependence of energy transfer in DNA oligonucleotides.
AB  - The sequence, temperature, concentration, and solvent dependence of singlet
      energy transfer from normal DNA bases to the 2-aminopurine base in synthesized
      DNA oligomers were investigated by optical spectroscopy. Transfer was shown
      directly by a variable fluorescence excitation band at 260-280 nm. Adenine (A) is
      the most efficient energy donor by an order of magnitude. Stacks of A adjacent to
      2AP act as an antenna for 2AP excitation. An interposed G, C, or T base between A
      and 2AP effectively blocks transfer from A to 2AP. Base stacking facilitates
      transfer, while base pairing reduces energy transfer slightly. The efficiency is
      differentially temperature dependent in single- and double-stranded oligomers and
      is highest below 0 degrees C in samples measured. An efficiency transition occurs
      well below the melting transition of a double-stranded decamer. The transfer
      efficiency in the duplex decamer d(CTGA[2AP]TTCAG)(2) is moderately dependent on
      the sample and salt concentration and is solvent dependent. Transfer at
      physiological temperature over more than a few bases is improbable, except along
      consecutive A's, indicating that singlet energy transfer is not a major factor in
      the localization of UV damage in DNA. These results have features in common with
      recently observed electron transfer from 2AP to G in oligonucleotides.

PMID- 10653819
TI  - Study by (23)Na-NMR, (1)H-NMR, and ultraviolet spectroscopy of the thermal
      stability of an 11-basepair oligonucleotide.
AB  - 23Na-NMR, (1)H-NMR, and ultraviolet (UV) spectroscopy have been used to study the
      thermal stability of the double helix structure of an 11-basepair
      oligonucleotide. The denaturation curves obtained by (23)Na-NMR and UV are
      analyzed using a two-state model. The melting temperature and DeltaH(0) obtained
      are identical within experimental error, suggesting that modifications in the
      ionic atmosphere, probed by (23)Na-NMR, and the modifications in the basepair
      stacking, probed by UV, occur at the same temperature. Additional dynamical
      information on the denaturation process has been obtained by (1)H-NMR: slow
      exchange is observed between the thymine methyl resonances, and the disappearance
      of imino protons shows that a single basepair opening does not contribute
      significantly to proton exchange.

PMID- 10653820
TI  - A unified theory of the B-Z transition of DNA in high and low concentrations of
      multivalent ions.
AB  - We showed recently that the high-salt transition of poly[d(G-C)]. poly[d(G-C)]
      between B-DNA and Z-DNA (at [NaCl] = 2.25 M or [MgCl(2)] = 0.7 M) can be ascribed
      to the lesser electrostatic free energy of the B form, due to better immersion of
      the phosphates in the solution. This property was incorporated in cylindrical DNA
      models that were analyzed by Poisson-Boltzmann theory. The results are
      insensitive to details of the models, and in fair agreement with experiment. In
      contrast, the Z form of the poly[d(G-m5C)] duplex is stabilized by very small
      concentrations of magnesium. We now show that this striking difference is
      accommodated quantitatively by the same electrostatic theory, without any
      adjustable parameter. The different responses to magnesium of the methylated and
      nonmethylated polymers do not come from stereospecific cation-DNA interactions:
      they stem from an experimentally derived, modest difference in the
      nonelectrostatic component of the free energy difference (or NFED) between the Z
      and B forms. The NFED is derived from circular DNA measurements. The differences
      between alkaline earth and transition metal ions are explained by weak
      coordination of the latter. The theory also explains the induction of the
      transition by micromolar concentrations of cobalt hexammine, again without
      specific binding or adjustable parameters. Hence, in the case of the B-Z
      transition as in others (e.g., the folding of tRNA and of ribozymes), the effect
      of multivalent cations on nucleic acid structure is mediated primarily by
      nonspecific ion-polyelectrolyte interactions. We propose this as a general rule
      for which convincing counter-examples are lacking.

PMID- 10653821
TI  - Circulation online only : february 1, 2000

PMID- 10653822
TI  - Intracoronary radiation : it keeps on glowing.

PMID- 10653823
TI  - Laminar shear stress upregulates the complement-inhibitory protein clusterin : a
      novel potent defense mechanism against complement-induced endothelial cell
      activation.
AB  - BACKGROUND: The complement system is implicated in the pathogenesis of
      atherosclerosis. Complement has been shown to activate endothelial cells (ECs) by
      inducing a proinflammatory response. Physiological levels of shear stress exert
      potent antiatherosclerotic effects. Therefore, we investigated whether shear
      stress antagonizes the effects of complement on ECs. METHODS AND RESULTS:
      Incubation of ECs with nonlytic concentrations of complement serum (CS: 0.2 U/mL
      for 6 hours) resulted in an upregulation of interleukin-8 (IL-8) (165+/-12%) and
      monocyte chemoattractant protein-1 (MCP-1) mRNA expression (267+/-34%).
      Preexposure of ECs for 18 hours with laminar shear stress (15 dyne/cm(2))
      abrogated CS-induced IL-8 release to 106+/-10% (P<0.001) and reduced CS-induced
      MCP-1 expression (170+/-31%; P<0.05). To examine the mechanism of the protective
      effect of shear stress, expression of the complement-inhibitory protein clusterin
      was analyzed under shear exposure. Shear stress increased clusterin mRNA (225+/
      76%, 6 hours) and protein expression (164+/-22%, 18 hours). Specific inhibition
      of clusterin by transfection with antisense oligonucleotides reversed the
      protective effect of shear stress on CS-induced MCP-1 and IL-8 upregulation
      (P<0.05 versus sense-transfected cells). Moreover, clusterin overexpression
      inhibited CS-induced EC activation. CONCLUSIONS: Shear stress abrogates the
      complement-induced proinflammatory response of ECs by upregulation of the
      complement-inhibitory protein clusterin. Upregulation of clusterin may contribute
      to the potent antiatherosclerotic effects of shear stress by preventing
      endothelial activation through the complement cascade.

PMID- 10653824
TI  - First clinical experience with the DeBakey VAD continuous-axial-flow pump for
      bridge to transplantation.
AB  - BACKGROUND: A shortage of donor organs and increased numbers of deaths of
      patients on the waiting list for cardiac transplantation make mechanical
      circulatory support for a bridge to transplantation a standard clinical
      procedure. Continuous-flow rotary blood pumps offer exciting new perspectives.
      METHODS AND RESULTS: Two male patients (ages 44 and 65 years) suffering from end
      stage left heart failure were implanted with a DeBakey VAD axial-flow pump for
      use as a bridge to transplant. In the initial postoperative period, the mean pump
      flow was 3.9+/-0.5 L/min, which equals a mean cardiac index (CI) of 2.3+/-0.2 L.
      min(-1). m(-2). In both patients, the early postoperative phase was characterized
      by a completely nonpulsatile flow profile. However, with the recovery of heart
      function 8 to 12 days after implantation, increasing pulse pressures became
      evident, and net flow rose to 4.5+/-0.6 L/min, causing an increase of mean CI up
      to 2.7+/-0.2 L. min(-1). m(-2). Patients were mobilized and put through regular
      physical training. Hemolysis stayed in the physiological range and increased only
      slightly from 2. 1+/-0.8 mg/dL before surgery to 3.3+/-1.8 mg/dL 6 weeks after
      implantation. CONCLUSIONS: The first clinical implants of the DeBakey VAD axial
      flow pump have demonstrated the device to be a promising measure of bridge-to
      transplant mechanical support.

PMID- 10653825
TI  - Three-year clinical and angiographic follow-up after intracoronary radiation :
      results of a randomized clinical trial.
AB  - BACKGROUND: Although several early trials indicate treatment of restenosis with
      radiation therapy is safe and effective, the long-term impact of this new
      technology has been questioned. The objective of this report is to document
      angiographic and clinical outcome 3 years after treatment of restenotic stented
      coronary arteries with catheter-based (192)Ir. METHODS AND RESULTS: A double
      blind, randomized trial compared (192)Ir with placebo sources in patients with
      previous restenosis after coronary angioplasty. Over a 9-month period, 55
      patients were enrolled; 26 were randomized to (192)Ir and 29 to placebo. At 3
      year follow-up, target-lesion revascularization was significantly lower in the
      (192)Ir group (15. 4% versus 48.3%; P<0.01). The dichotomous restenosis rate at 3
      year follow-up was also significantly lower in (192)Ir patients (33% versus 64%;
      P<0.05). In a subgroup of patients with 3-year angiographic follow-up not
      subjected to target-lesion revascularization by the 6-month angiogram, the mean
      minimal luminal diameter between 6 months and 3 years decreased from 2.49+/-0.81
      to 2.12+/-0.73 mm in (192)Ir patients but was unchanged in placebo patients.
      CONCLUSIONS: The early clinical benefits observed after treatment of coronary
      restenosis with (192)Ir appear durable at late follow-up. Angiographic restenosis
      continues to be significantly reduced in (192)Ir-treated patients, but a small
      amount of late loss was observed between the 6-month and 3-year follow-up time
      points. No events occurred in the (192)Ir group to suggest major untoward effects
      of vascular radiotherapy. At 3-year follow-up, vascular radiotherapy continues to
      be a promising new treatment for restenosis.

PMID- 10653826
TI  - Cost-effectiveness of platelet glycoprotein IIb/IIIa inhibition with eptifibatide
      in patients with non-ST-elevation acute coronary syndromes.
AB  - BACKGROUND: In the PURSUIT trial, eptifibatide significantly reduced the 30-day
      incidence of death and myocardial infarction relative to placebo in 9461 patients
      with an acute coronary syndrome (unstable angina or non-Q-wave myocardial
      infarction). METHODS AND RESULTS: We conducted a 2-part prospective economic
      substudy of the 3522 US patients enrolled in PURSUIT: (1) an empirical intention
      to-treat comparison of medical costs (hospital plus physician) up to 6 months
      after hospitalization and (2) a lifetime cost-effectiveness analysis. The base
      case cost-effectiveness ratio was expressed as the 1996 US dollars required to
      add 1 life-year with eptifibatide therapy. The 2 treatment arms had equivalent
      resource consumption and medical costs (exclusive of the cost of the eptifibatide
      regimen) during the index (enrollment) hospitalization (P=0.78) and up to 6
      months afterward (P=0.60). The average wholesale price of the eptifibatide
      regimen was $1217, but a typical hospital discounted price was $1014. The
      estimated life expectancy from randomization in the US patients was 15.96 years
      for eptifibatide and 15.85 years for placebo, an incremental difference of 0.111.
      The incremental cost-effectiveness ratio for eptifibatide therapy in US PURSUIT
      patients was $16 491 per year of life saved. This result was robust through a
      wide range of sensitivity analyses. The cost-utility ratio for eptifibatide
      (using time trade-off defined utilities) was $19 693 per added quality-adjusted
      life-year. CONCLUSIONS: Based on the results observed in the US PURSUIT patients,
      the routine addition of eptifibatide to standard care for non-ST-elevation acute
      coronary syndrome patients is economically attractive by conventional standards.

PMID- 10653827
TI  - Relationships between homocysteine, factor VIIa, and thrombin generation in acute
      coronary syndromes.
AB  - BACKGROUND: It has been suggested by clinical, epidemiological, and experimental
      in vitro studies that homocysteine potentiates thrombin generation. This
      prothrombotic effect however has not previously been demonstrated in patients
      presenting with acute coronary syndromes (ACS). METHODS AND RESULTS: Patients
      with ACS (n =117) presenting with confirmed acute myocardial infarction (MI) (n
      =57) or unstable angina pectoris (UAP) (n =60) were consecutively recruited
      together with patients (n =18) in whom the presenting chest pain was not of
      cardiac origin (NCP), included as controls. Plasma samples were collected on
      admission and before clinical intervention. Homocysteine was assayed by high
      performance liquid chromatography, and both Factor VIIa and prothrombin fragment
      F1+2 were analyzed by ELISA. There were significant elevations in F1+2 in MI
      (P<0.001) and UAP (P=0.003), and modest elevations in Factor VIIa in UAP (P<0.05)
      compared with NCP but no differences in homocysteine levels among those groups.
      On dividing patients with ACS into quartiles of homocysteine, there was a
      stepwise increase in F1+2 (P<0.0001) and of Factor VIIa (P<0.05). There were
      significant correlations in ACS between homocysteine and F1+2 (r=0.46, P<0.0001),
      homocysteine and Factor VIIa (r=0.24, P<0.01), and F1+2 and Factor VIIa (r=0.41,
      P<0.0001). There was no correlation between homocysteine and either F1+2 (r=
      0.15, P=0.57) or Factor VIIa (r=0. 22, P=0.37) in the NCP patients. CONCLUSIONS:
      Elevated plasma homocysteine is associated with and may cause elevated Factor
      VIIa and thrombin generation in patients presenting with ACS. These findings
      suggest an explanation for the prothrombotic effect of homocysteine in ACS.

PMID- 10653828
TI  - Effects of metoprolol CR in patients with ischemic and dilated cardiomyopathy :
      the randomized evaluation of strategies for left ventricular dysfunction pilot
      study.
AB  - BACKGROUND: Metoprolol provides clinical benefits in patients with congestive
      heart failure (CHF). In this study, we investigated the effects of controlled
      release metoprolol (metoprolol CR) on clinical status, on left ventricular (LV)
      volumes and function, and on neurohumoral activation in a large number of
      patients with CHF of mixed causes. METHODS AND RESULTS: Four hundred twenty-six
      patients with symptomatic CHF were randomized to receive metoprolol CR or placebo
      for 24 weeks. Metoprolol CR did not affect 6-minute walk distance, New York Heart
      Association functional class, or quality of life. However, there was a
      significant improvement in measures of LV function with an attenuation in the
      increase in LV end-diastolic (+23+/-65 mL [placebo] versus +6+/-61 mL, P=0.01)
      and LV end-systolic (+19+/-55 mL [placebo] versus -2+/-51 mL, P<0.001) volumes
      after 24 weeks of therapy. LV ejection fraction was unchanged (-0.05% or -0.005)
      in the placebo group but increased by 2. 4% in the metoprolol CR-treated patients
      (P=0.001). Patients receiving metoprolol CR had a greater decrease in angiotensin
      II (P=0.036) and renin (P=0.032) levels but an increase in N-terminal atrial
      natriuretic peptide and brain natriuretic peptide levels (P<0. 01). There were
      fewer deaths in the group receiving beta-blockers (3. 4% versus 8.1%), and there
      was a similar number of patients experiencing the composite outcomes of death or
      any hospitalization. CONCLUSIONS: When added to ACE inhibitors, angiotensin II
      receptor antagonists, or both, the use of metoprolol CR improves ventricular
      function, reduces activation of the renin-angiotensin systems, and results in
      fewer deaths.

PMID- 10653829
TI  - Immunoglobulin adsorption in patients with idiopathic dilated cardiomyopathy.
AB  - BACKGROUND: Idiopathic dilated cardiomyopathy (IDC) frequently is a progressive
      disease without causative therapy options. Following the hypothesis that in
      certain patients autoantibodies against cardiac structures may induce, maintain,
      or promote the progression of the disease, we investigated whether the
      elimination of these autoantibodies through immunoadsorption would improve
      cardiac function. METHODS AND RESULTS: This prospective case-control study
      included 34 patients with IDC. Each patient presented with moderate to severe
      heart failure and evidence of autoantibodies directed against beta(1)
      adrenoceptors (beta(1)-AABs). Seventeen patients received standard medical
      therapy (control group), whereas 17 were also treated with immunoadsorption
      (treatment group) to eliminate beta(1)-AABs. A 1-year follow-up included
      echocardiographic assessment of left ventricular ejection fraction and internal
      diameters, beta(1)-AAB levels, and clinical status every 3 months. Within 1 year,
      the mean+/-SD left ventricular ejection fraction rose from 22.3+/-3.3% to 37.9+/
      7.9% (P=0.0001) in the treatment group, with a relative increase of 69.9%.
      However, in the control group, no overall increase was seen (from 23.8+/-3.0% to
      25.2+/-5.9%, P=0. 3154). Left ventricular diameter in diastole decreased by 14.5%
      from 74.5+/-7.1 to 63.7+/-6.0 mm in the treatment group (P=0.0001) and by 3.8%
      (P=0.2342) in the control group. In the treatment group, the NYHA functional
      rating improved after immunoadsorption (P=0.0001). beta(1)-AABs did not increase
      anew. CONCLUSIONS: In IDC, the use of immunoadsorption is superior to the use of
      standard medical therapy. It significantly improves cardiac performance and
      clinical status.

PMID- 10653830
TI  - Effects of continuous positive airway pressure on sleep apnea and ventricular
      irritability in patients with heart failure.
AB  - BACKGROUND: Patients with heart failure and systolic dysfunction may develop
      disordered breathing during sleep. Repeated episodes of apnea and hypopnea may
      result in desaturation and arousals, which could adversely affect left
      ventricular function. The purpose of this study was to determine the short-term
      effects of continuous positive airway pressure (CPAP) on sleep-disordered
      breathing and its consequences in heart failure patients. METHODS AND RESULTS:
      The author prospectively studied 29 male patients whose initial polysomnograms
      showed 15 or more episodes of apnea and hypopnea per hour (apnea-hypopnea index,
      AHI). Twenty-one patients had predominately central and 8 patients obstructive
      sleep apnea. All were treated with CPAP during the subsequent night. In 16
      patients, CPAP resulted in virtual elimination of disordered breathing. In these
      patients, the mean AHI (36+/-12 [SD] versus 4+/-3 per hour, P=0.0001), arousal
      index due to disordered breathing (16+/-9 versus 2+/-2 per hour, P=0.0001), and
      percent of total sleep time below saturation of 90% (20+/-23% to 0.3+/-0.7%,
      P=0.0001) decreased, and lowest saturation (76+/-8% versus 90+/-3%, P=0.0001)
      increased with CPAP. In 13 patients who did not respond to CPAP, these values did
      not change significantly. In patients whose sleep apnea responded to CPAP, the
      number of hourly episodes of nocturnal premature ventricular contractions (66+/
      117 versus 18+/-20, P=0.055) and couplets (3.2+/-6 versus 0.2+/-0.21, P=0.031)
      decreased. In contrast, in patients whose sleep apnea did not respond to CPAP,
      ventricular arrhythmias did not change significantly. CONCLUSIONS: In 55% of
      patients with heart failure and sleep apnea, first-night nasal CPAP eliminates
      disordered breathing and reduces ventricular irritability.

PMID- 10653831
TI  - Alcohol potentiates orthostatic hypotension : implications for alcohol-related
      syncope.
AB  - BACKGROUND: Alcohol consumption may be linked to syncopal events. The mechanisms
      by which alcohol may induce syncope are unknown. Impairment of the response to
      orthostatic stress may be involved. Using a double-blind, randomized, placebo
      controlled study, we tested the hypothesis that short-term alcohol intake causes
      orthostatic hypotension because of an impairment in the vasoconstrictor response
      to orthostatic stress. METHODS AND RESULTS: We examined the effects of alcohol on
      blood pressure, heart rate, and forearm vascular resistance (FVR) during
      orthostatic stress achieved by stepwise increases in lower-body negative pressure
      (LBNP) in 14 healthy young volunteers. During the placebo session, blood pressure
      did not change significantly during LBNP at -5, -10, and -20 mm Hg. A significant
      decrease in blood pressure was evident only at -40 mm Hg. In contrast, blood
      pressure fell significantly at all levels of LBNP during the alcohol session.
      Compared with placebo, alcohol potentiated the hypotensive responses to LBNP,
      particularly at -40 mm Hg, when the decrease in systolic blood pressure after
      alcohol intake (-14 mm Hg) was double that after placebo intake (-7 mm Hg). FVR
      increased with LBNP after placebo. However, after alcohol intake, FVR did not
      increase during LBNP despite the potentiated decrease in blood pressure. FVR
      responses during LBNP were reduced during alcohol compared with placebo
      consumption (P=0.04). CONCLUSIONS: Short-term alcohol consumption elicits
      hypotension during orthostatic stress because of impairment of vasoconstriction.
      These findings have implications for the understanding of the hemodynamic effects
      of alcohol and, in particular, for understanding syncopal events that occur in
      association with alcohol intake.

PMID- 10653832
TI  - N-Type calcium channels control sympathetic neurotransmission in human heart
      atrium.
AB  - BACKGROUND: Because knowledge about the type of calcium channels involved in
      action potential-induced norepinephrine release from the human peripheral
      sympathetic nervous system is sparse, we investigated which types of calcium
      channels are functionally important in the sympathetic nerves of human cardiac
      tissue. METHODS AND RESULTS: In superfused segments of human right atrial
      appendages, the type of calcium channels that control [(3)H]norepinephrine
      release evoked by transmural electrical stimulation was determined.
      [(3)H]norepinephrine release was almost abolished by 0.2 micromol/L omega
      conotoxin GVIA (a selective blocker of N-type channels) but was not modified by
      0.1 micromol/L omega-agatoxin IVA (a selective blocker of P- and Q-type
      channels). Mibefradil (a T-type and N-type calcium channel blocker) at
      concentrations of 0.3 to 3 micromol/L reduced the evoked tritium overflow in a
      frequency- and calcium-dependent manner, whereas 0.1 to 10 micromol/L amlodipine,
      diltiazem, and verapamil (selective blockers of L-type channels) were
      ineffective. CONCLUSIONS: Norepinephrine release from cardiac sympathetic nerves
      is triggered by Ca(2+) influx via N-type but not L- and P/Q-type calcium
      channels. The inhibitory effect of mibefradil on norepinephrine release at
      clinically relevant concentrations is probably due to its blocking action on N
      type Ca(2+) channels. This property of mibefradil is unique among the calcium
      channel blockers that have been or still are therapeutically applied and may
      considerably contribute to its slight negative chronotropic effect in vivo.

PMID- 10653833
TI  - Intracoronary adenovirus-mediated delivery and overexpression of the beta(2)
      adrenergic receptor in the heart : prospects for molecular ventricular
      assistance.
AB  - BACKGROUND: Genetic modulation of ventricular function may offer a novel
      therapeutic strategy for patients with congestive heart failure. Myocardial
      overexpression of beta(2)-adrenergic receptors (beta(2)ARs) has been shown to
      enhance contractility in transgenic mice and reverse signaling abnormalities
      found in failing cardiomyocytes in culture. In this study, we sought to determine
      the feasibility and in vivo consequences of delivering an adenovirus containing
      the human beta(2)AR cDNA to ventricular myocardium via catheter-mediated
      subselective intracoronary delivery. METHODS AND RESULTS: Rabbits underwent
      percutaneous subselective catheterization of either the left or right coronary
      artery and infusion of adenoviral vectors containing either a marker transgene
      (Adeno-betaGal) or the beta(2)AR (Adeno-beta(2)AR). Ventricular function was
      assessed before catheterization and 3 to 6 days after gene delivery. Both left
      circumflex- and right coronary artery-mediated delivery of Adeno-beta(2)AR
      resulted in approximately 10-fold overexpression in a chamber-specific manner.
      Delivery of Adeno-betaGal did not alter in vivo left ventricular (LV) systolic
      function, whereas overexpression of beta(2)ARs in the LV improved global LV
      contractility, as measured by dP/dt(max), at baseline and in response to
      isoproterenol at both 3 and 6 days after gene delivery. CONCLUSIONS: Percutaneous
      adenovirus-mediated intracoronary delivery of a potentially therapeutic transgene
      is feasible, and acute global LV function can be enhanced by LV-specific
      overexpression of the beta(2)AR. Thus, genetic modulation to enhance the function
      of the heart may represent a novel therapeutic strategy for congestive heart
      failure and can be viewed as molecular ventricular assistance.

PMID- 10653834
TI  - Induction of a myocardial adrenomedullin signaling system during ischemic heart
      failure in rats.
AB  - BACKGROUND: Increased plasma adrenomedullin (ADM) levels have been reported in
      congestive heart failure (HF). The present study was designed to investigate
      myocardial regulation of the different components of the ADM signaling system
      (ADM, ADM receptor, and receptor-activity-modifying protein-2, RAMP-2) during
      ischemic HF in rats and to identify the cells in the myocardium displaying ADM
      like immunoreactivity (ADM-ir). Furthermore, the effects of endothelin (ET)
      receptor antagonism on expression of the myocardial ADM system during HF were
      investigated. METHODS AND RESULTS: Northern blot analysis revealed increased ADM
      mRNA expression in the nonischemic left ventricle, with maximal levels 28 days
      after induction of myocardial infarction (1.5-fold, P<0.05) compared with the
      sham group. Parallel elevations of myocardial ADM receptor and RAMP-2 mRNA levels
      were also observed (2.3- and 1.5-fold increase, respectively; P<0.05). In
      addition, high levels of ADM mRNA were seen in the ischemic region.
      Immunohistochemical analysis revealed a substantial increase of ADM-ir in
      microvascular endothelium and perivascular interstitial cells of myocardial
      tissue contiguous to the ischemic region. In addition, radioligand binding
      studies demonstrated a 1.6-fold increase of specific ADM binding sites in the
      failing left ventricle (P<0.05). Intervention with the mixed ET(A)/ET(B) receptor
      antagonist bosentan (100 mg. kg(-1). day(-1) PO) for 15 days prevented the
      increase of RAMP-2 mRNA. CONCLUSIONS: The study demonstrates a concerted
      induction of several components of the myocardial ADM signaling system during
      postinfarction failure and that the vessels are the main source of myocardial
      ADM. Our observations indicate a role for ADM as an autocrine/paracrine factor
      during ventricular remodeling after myocardial infarction.

PMID- 10653835
TI  - Chronic N(G)-nitro-L-arginine methyl ester-induced hypertension : novel molecular
      adaptation to systolic load in absence of hypertrophy.
AB  - BACKGROUND: Chronic N(G)-nitro-L-arginine methyl ester (L-NAME), which inhibits
      nitric oxide synthesis, causes hypertension and would therefore be expected to
      induce robust cardiac hypertrophy. However, L-NAME has negative metabolic effects
      on protein synthesis that suppress the increase in left ventricular (LV) mass in
      response to sustained pressure overload. In the present study, we used L-NAME
      induced hypertension to test the hypothesis that adaptation to pressure overload
      occurs even when hypertrophy is suppressed. METHODS AND RESULTS: Male rats
      received L-NAME (50 mg. kg(-1). d(-1)) or no drug for 6 weeks. Rats with L-NAME
      induced hypertension had levels of systolic wall stress similar to those of rats
      with aortic stenosis (85+/-19 versus 92+/-16 kdyne/cm). Rats with aortic stenosis
      developed a nearly 2-fold increase in LV mass compared with controls. In
      contrast, in the L-NAME rats, no increase in LV mass (1. 00+/-0.03 versus 1.04+/
      0.04 g) or hypertrophy of isolated myocytes occurred (3586+/-129 versus 3756+/
      135 microm(2)) compared with controls. Nevertheless, chronic pressure overload
      was not accompanied by the development of heart failure. LV systolic performance
      was maintained by mechanisms of concentric remodeling (decrease of in vivo LV
      chamber dimension relative to wall thickness) and augmented myocardial calcium
      dependent contractile reserve associated with preserved expression of alpha- and
      beta-myosin heavy chain isoforms and sarcoplasmic reticulum Ca(2+) ATPase (SERCA
      2). CONCLUSIONS: When the expected compensatory hypertrophic response is
      suppressed during L-NAME-induced hypertension, severe chronic pressure overload
      is associated with a successful adaptation to maintain systolic performance; this
      adaptation depends on both LV remodeling and enhanced contractility in response
      to calcium.

PMID- 10653837
TI  - Activation of mitochondrial ATP-dependent potassium channels by nitric oxide.
AB  - BACKGROUND: Nitric oxide (NO) has been implicated as a mediator of "second
      window" ischemic preconditioning, and mitochondrial ATP-dependent K(+)
      (mitoK(ATP)) channels are the likely effectors. The links between NO and
      mitoK(ATP) channels are unknown. METHODS AND RESULTS: We measured mitochondrial
      redox potential as an index of mitoK(ATP) channel opening in rabbit ventricular
      myocytes. The NO donor S-nitroso-N-acetyl-DL-penicillamine (SNAP, 0.1 to 1
      mmol/L) oxidized the mitochondrial matrix dose-dependently without activating
      sarcolemmal K(ATP) channels. SNAP-induced oxidation was blocked by the selective
      mitoK(ATP) channel blocker 5-hydroxydecanoate and by the NO scavenger 2-(4
      carboxyphenyl)-4,4', 5,5'-tetramethylimidazole-1-oxyl-3-oxide. SNAP-induced
      mitochondrial oxidation was detectable either by photomultiplier tube recordings
      of flavoprotein fluorescence or by confocal imaging. SNAP also enhanced the
      oxidative effects of diazoxide when both agents were applied together. Exposure
      to 1 mmol/L 8Br-cGMP failed to mimic the effects of SNAP. CONCLUSIONS: NO
      directly activates mitoK(ATP) channels and potentiates the ability of diazoxide
      to open these channels. These results provide novel mechanistic links between NO
      induced cardioprotection and mitoK(ATP) channels.

PMID- 10653836
TI  - Upregulation of COX-2 during cardiac allograft rejection.
AB  - BACKGROUND: The hypothesis that cyclooxygenase-2 (COX-2) is involved in the
      myocardial inflammatory response during cardiac allograft rejection was
      investigated using a rat heterotopic abdominal cardiac transplantation model.
      METHODS AND RESULTS: COX-2 mRNA and protein in the myocardium of rejecting
      cardiac allografts were significantly elevated 3 to 5 days after transplantation
      compared with syngeneic controls (n=3, P<0.05). COX-2 upregulation paralleled in
      time and extent the upregulation of iNOS mRNA, protein, and enzyme activity in
      this model. COX-2 immunostaining was prominent in macrophages infiltrating the
      rejecting allografts and in damaged cardiac myocytes. Prostaglandin (PG) levels
      in rejecting allografts were also higher than in native hearts. Because NO has
      been reported to modulate PG synthesis by COX-2, additional transplants were
      performed using animals treated with a selective COX-2 inhibitor (SC-58125) and a
      selective inhibitor of the inducible nitric oxide synthase (iNOS) N-aminomethyl-L
      lysine. At posttransplant day 5, inhibitor administration resulted in a
      significant reduction of COX-2 mRNA expression (3764+/-337 versus 5110+/-141
      arbitrary units, n=3, P<0.05) and iNOS enzymatic activity (1.7+/-0.4 versus
      22.8+/-14. 4 nmol/mg protein, n=3, P<0.01) compared with vehicle-treated
      allogeneic transplants. Allograft survival in treated animals was increased
      modestly from 5.4 to 6.4 days (P<0.05). However, apoptosis of cardiac myocytes
      (TUNNEL method) was only marginally reduced relative to vehicle controls in
      treated graft recipients. The intensity of allograft rejection was also similar
      in the treated and untreated allografts. CONCLUSIONS: The data indicates that COX
      2 expression is enhanced in parallel with iNOS in the myocardium during cardiac
      allograft rejection.

PMID- 10653838
TI  - Essential hypertension : part II: treatment.

PMID- 10653839
TI  - Delivery strategies to achieve therapeutic myocardial angiogenesis.
AB  - The use of recombinant genes or growth factors to enhance myocardial collateral
      blood vessel function may represent a new approach to the treatment of
      cardiovascular disease. Proof of concept has been demonstrated in animal models
      of myocardial ischemia, and clinical trials are underway. Currently, it is
      unknown which is the safest and most effective delivery strategy to induce
      clinically important therapeutic angiogenic responses in ischemic myocardium.
      Most strategies for transcatheter delivery of angiogenic factors have used an
      intracoronary route, which may have limitations because of imprecise localization
      of genes or proteins and systemic delivery to noncardiac tissue. The effect of
      direct intraoperative intramyocardial injection of angiogenic factors on
      collateral function has been reported in experimental models, and angiogenesis is
      being studied after direct intramyocardial injection of angiogenic peptides or
      plasmid vectors during open heart surgery in patients. Catheter-based
      transendocardial injection of angiogenic factors may provide equivalent benefit
      without the need for surgery. Intrapericardial delivery of angiogenic factors may
      offer a theoretical advantage of prolonged exposure of either coronary or
      myocardial tissue to the administered drug as result of a reservoir function of
      the pericardium. In this article, we review the different modes of administration
      for therapeutic myocardial angiogenesis therapy.

PMID- 10653840
TI  - Images in Cardiovascular Medicine. Aberrant right subclavian artery mimics aortic
      dissection.

PMID- 10653842
TI  - Homocysteine levels in London Indian Asians.

PMID- 10653841
TI  - Critical pathways : a review. Committee on Acute Cardiac Care, Council on
      Clinical Cardiology, American Heart Association.

PMID- 10653843
TI  - US Inspector General recoups millions in audits, fraud, and abuse investigations.

PMID- 10653844
TI  - Study predicts 55 million people uninsured by the year 2008.

PMID- 10653845
TI  - Mobile telephone study underway.

PMID- 10653846
TI  - Identical atherosclerotic lesions in identical twins.

PMID- 10653847
TI  - Janus kinase 3 (Jak3) is essential for common cytokine receptor gamma chain
      (gamma(c))-dependent signaling: comparative analysis of gamma(c), Jak3, and
      gamma(c) and Jak3 double-deficient mice.
AB  - The common cytokine receptor gamma chain (gamma(c)) is an essential receptor
      component for IL-2, IL-4, IL-7, IL-9 and IL-15, and thereby gamma(c)-deficient
      mice exhibit impaired T cell and B cell development. The Janus family tyrosine
      kinase 3 (Jak3) is known to be associated with gamma(c), and the reported
      phenotypes of gamma(c)-deficient (gamma(c)(-)) and Jak3-deficient (Jak3(-)) mice
      are similar, indicating that Jak3 is an essential transducer of gamma(c)
      dependent signals. Nevertheless, certain differences have been suggested related
      to the range of actions of gamma(c) and Jak3. To clarify whether gamma(c)
      dependent cytokines can partially transduce their signals without Jak3, we
      compared lymphocyte development in gamma(c)(-), Jak3(-), and gamma(c) and Jak3
      double-deficient (gamma(c)(-)Jak3(-)) mice in the same genetic background. With
      the exception that T and B cells in Jak3(-) mice express high levels of gamma(c),
      the defects in thymocyte and peripheral T cell and B cell development are
      indistinguishable among gamma(c)(-), Jak3(-) and gamma(c)(-)Jak3(-) mice.
      Interestingly, although Bcl-2 induction was previously suggested to be Jak3
      independent, IL-7 cannot induce Bcl-2 expression in CD4 single-positive (SP)
      thymocytes in either gamma(c)(-) or Jak3(-) mice nor can IL-7 rescue CD4 SP
      thymocytes from dexamethasone-induced cell death in gamma(c)(-) or Jak3(-) mice.
      These results indicate that Jak3 is absolutely essential for gamma(c)-dependent T
      cell and B cell development, and for gamma(c)-dependent prevention of thymocyte
      apoptosis.

PMID- 10653848
TI  - Expression of IL-10 receptors on epithelial cells from the murine small and large
      intestine.
AB  - The appearance of chronic intestinal inflammation in IL-10 knockout mice suggests
      IL-10 may inhibit adverse responses to luminal antigen. Moreover, this
      inflammation is associated with an increase in class II MHC molecule expression
      on intestinal epithelial cells. Thus, the role of IL-10 regulation in epithelial
      cell function was investigated. Using RT-PCR, it was shown that intestinal
      epithelial cells express mRNA for both subunits of the IL-10 receptor-signaling
      complex. In addition, biotinylated IL-10 was shown to bind to both cultured and
      freshly isolated intestinal epithelial cells prepared from the small or large
      intestine. This binding appeared specific as it was blocked by neutralizing
      antibodies to IL-10 but not the isotype control. Moreover, an excess of native IL
      10 also inhibited the binding of radiolabeled IL-10. To evaluate whether IL-10
      mediated any functions through this receptor, epithelial cells were cultured with
      IL-10 alone or with IFN-gamma plus IL-10. IL-10 alone had no detectable effects
      on epithelial cell growth or their expression of class II MHC molecules but it
      did antagonize the effect of IFN-gamma on the viability of cultured cells. In
      addition, IL-10 blocked the IFN-gamma-induced expression of class II MHC
      molecules on cultured epithelial cells. These results suggest that IL-10 binds to
      a specific receptor on intestinal epithelial cells and may regulate the
      contribution of epithelial cells to the inflammatory and immune response in the
      digestive tract.

PMID- 10653849
TI  - The role of alpha(4) and LFA-1 integrins in selectin-independent monocyte and
      neutrophil migration to joints of rats with adjuvant arthritis.
AB  - Monocytes and neutrophils are chronically recruited to joints in rheumatoid
      arthritis. In the joints of rats with adjuvant arthritis, this is mediated, in
      part, by selectin-dependent and selectin-independent mechanisms. To define the
      selectin-independent mechanisms, (51)Cr-labeled blood monocytes, (111)In-labeled
      neutrophils and function blocking mAb to the selectins and integrins were
      utilized. Integrins contributed to the selectin-independent monocyte migration to
      arthritic joints with 58-70% inhibition of this recruitment by anti-alpha(4) or
      anti-LFA-1 mAb, relative to selectin blockade alone. alpha(4) plus P-selectin
      blockade was as effective as combined blockade of alpha(4), P-, E- and L
      selectin, mediating approximately 83% of the overall monocyte migration to the
      joints. In contrast, LFA-1 was the predominant selectin-independent mechanism for
      neutrophil recruitment to the joints. LFA-1 together with P-selectin had
      essential roles in the talar joint. In dermal inflammation in the arthritic rats,
      LFA-1 accounted for most (69%) of the selectin-independent monocyte migration to
      the chemoattractant C5a(desArg) (zymosan-activated serum), whereas LFA-1 and Mac
      1 both contributed to selectin-independent neutrophil recruitment to C5a(desArg).
      alpha(4) integrin and P-selectin in concert mediated monocyte recruitment to
      lipopolysaccharide and IFN-gamma lesions (81%). Thus: (1) either alpha(4) or LFA
      1 can mediate monocyte migration to arthritic joints in the absence of selectin
      function and alpha(4) together with P-selectin is particularly important; (2) LFA
      1 is the predominant mechanism of selectin-independent migration of neutrophils
      to inflamed joints; and (3) in arthritic rats, selectin-independent migration of
      monocytes and neutrophils to dermal inflammation is mediated by alpha(4) or LFA-1
      or both LFA-1 and Mac-1, depending on the leukocyte type, and inflammatory
      stimulus.

PMID- 10653850
TI  - IL-12 synergizes with IL-18 or IL-1beta for IFN-gamma production from human T
      cells.
AB  - IL-18 is a proinflammatory cytokine that plays an important role in NK cell
      activation and T(h)1 response. IL-18 has a structural homology to IL-1,
      particularly IL-1beta. IL-18R, composed of IL-1R-related protein (IL-18Ralpha)
      and IL-1R accessory protein-like (IL-18Rbeta), belongs to the IL-1R family.
      Furthermore, IL-18R at least partly shares the signal transducing system with IL
      1R. Thus, the IL-18-IL-18R system has a striking similarity to the IL-1-IL-1R
      system. For this reason, we regarded it important to investigate whether, like IL
      18, IL-1beta synergizes with IL-12 in inducing IFN-gamma production from human T
      cells and plays an important role in the T(h)1 response. Here we show that IL-12
      and IL-1beta synergistically induce T cells to proliferate and produce IFN-gamma
      without their TCR engagement. IL-12 stimulation induced an increase in the
      proportion of T cells positive for IL-18R. Then, IL-12-stimulated T cells
      responded to IL-18 or IL-1beta by their proliferation and IFN-gamma production,
      although levels of IL-1beta-induced responses were lower. CD4(+)CD45RA(+) T
      cells, although they constitutively expressed IL-18Rbeta mRNA, did not express IL
      18Ralpha mRNA. Phytohemagglutinin (PHA) stimulation alone induced IL-18Ralpha
      mRNA without affecting the expression of IL-18Rbeta mRNA. T(h)1-inducing
      conditions (PHA, IL-12 and anti-IL-4) further increased this expression. We also
      show that T(h)1 cells but not T(h)2 cells have increased expression of IL-18R and
      IL-1R, and produce IFN-gamma in response to IL-18 and/or IL-1beta.

PMID- 10653851
TI  - Transduction of a murine dominant negative activation transcription factor 1
      increases cell surface expression of the class I MHC on a human epidermoid tumor
      cell line.
AB  - The transcription of the MHC class I genes is regulated by interaction of cis
      elements, located in the 5' genomic flanking regions, with sequence-specific
      trans-factors. We have identified a cis-regulatory element, 5'-TGACGCG-3', of the
      H-2D(d) gene. This cyclic adenosine-3',5'-monophosphate regulatory element (CRE)
      like sequence, named H-2 binding factor 1 (H-2 BF1) binding motif, is highly
      conserved among species. In addition, we found that homo- and heterodimers of
      activation transcription factor 1 (ATF-1) and CRE binding protein (CREB)
      associate with the H-2 BF1 binding motif and activate transcription of the H
      2D(d) gene. Here we demonstrate that a homologue of ATF-1, originally isolated
      and designated ATF-1DN, acts as a dominant repressor, blocking the ability of
      wild-type ATF-1 and CREB to bind to the H-2 BF1 probe in electrophoretic mobility
      shift assays (EMSA). We have utilized this molecule to analyze the participation
      of the H-2 BF1 complexes, consisting of the H-2 BF1 binding motif and ATF-1/CREB
      trans-factors, in the physiological regulation of MHC class I expression in
      tissue culture cells. A human epidermoid carcinoma cell line, A431, was
      transfected with ATF-1DN and clones expressing the gene transcripts were
      selected. When analyzed in the EMSA, nuclear proteins prepared from these clones
      exhibited a decreased shift of the H-2 BF1 probe corresponding to the levels of
      the ATF-1DN gene expression. Additionally, MHC class I expression of cells with
      reduced H-2 BF1 activity was significantly higher than in control cells lacking
      ATF-1DN. These findings indicate that in these carcinoma cells, the H-2 BF1
      complexes negatively regulate the constitutive expression of MHC class I.

PMID- 10653852
TI  - Regulation of mast cell signaling through high-affinity IgE receptor by CD45
      protein tyrosine phosphatase.
AB  - The transmembrane tyrosine phosphatase CD45 regulates the activity of src family
      protein tyrosine kinases (PTK) and thereby influences the signaling via such
      receptors as T and B cell antigen receptors associated with these PTK. However,
      its implication in signaling through the mast cell receptor with high affinity
      for IgE (FcepsilonRI) is less clear, although Lyn, a member of the src family,
      plays an important role in FcepsilonRI-mediated signaling. To define a role for
      CD45 in FcepsilonRI signal transduction, we established CD45 high expressing rat
      basophilic leukemia cell lines (RBL-CD45H) and cell lines expressing trace
      amounts of CD45 (RBL-CD45L). We demonstrate that although all RBL-CD45L cell
      lines degranulate following IgE- and antigen-induced FcepsilonRI aggregation, the
      response is significantly reduced at a low dose of antigen. The cells show a
      delayed and slowed Ca(2+) mobilization even though at a higher dose where the
      cells degranulate to a similar extent as RBL-CD45H. This diminished Ca(2+)
      response is restored by reconstitution of RBL-CD45L with a chimeric molecule
      containing the cytoplasmic phosphatase domains of rat CD45. Furthermore, tyrosine
      phosphorylation of FcepsilonRI, association of FcepsilonRI with Lyn and PTK
      activity associated with FcepsilonRI, all of which are enhanced upon FcepsilonRI
      aggregation in RBL-CD45H, are impaired in RBL-CD45L. Finally, we show that
      FcepsilonRI is physically associated with CD45 in RBL-CD45H prior to receptor
      aggregation. Thus, we propose that, although not indispensable in mast cell
      degranulation, CD45 positively regulates the signaling through FcepsilonRI by
      promoting the activation of FcepsilonRI-associated Lyn.

PMID- 10653853
TI  - Serrate1-induced notch signalling regulates the decision between immunity and
      tolerance made by peripheral CD4(+) T cells.
AB  - Signals derived from antigen-presenting cells (APC) influence the functional
      differentiation of CD4(+) T cells. We report here that Serrate1 (Jagged1), a
      ligand for the Notch1 receptor, may contribute to the differentiation of
      peripheral CD4(+) T cells into either helper or regulatory cells. Our findings
      demonstrate that antigen presented by murine APC overexpressing human Serrate1
      induces naive peripheral CD4(+) T cells to become regulatory cells. These cells
      can inhibit primary and secondary immune responses, and transfer antigen-specific
      tolerance to recipient mice. Our results show that Notch signalling may help
      explain 'linked' suppression in peripheral tolerance, whereby tolerance induced
      to one epitope encompasses all epitopes on that antigen during the course of an
      immune response.

PMID- 10653854
TI  - IL-6 inhibits the proliferation of fibroblastic synovial cells from rheumatoid
      arthritis patients in the presence of soluble IL-6 receptor.
AB  - IL-6 and tumor necrosis factor (TNF)-alpha have been proven to play an important
      role in the development of rheumatoid arthritis (RA). It is well known that TNF
      alpha induces IL-6 production from synovial cells as well as their proliferation.
      The effect of IL-6 on synovial cells, however, is not clear. An in vitrostudy was
      performed to determine the effect of IL-6 on the proliferation of synovial cells.
      Fibroblastic synovial cells isolated from the synovial tissues of eight RA
      patients were employed after the third to sixth passages. IL-6 in the presence of
      soluble IL-6 receptor (sIL-6R) inhibited the proliferation of synovial cells in a
      dose-dependent manner in seven cases without increasing the number of necrotic or
      apoptotic cells, while TNF-alpha increased synovial cell proliferation in all
      cases. The inhibitory effect of IL-6 was observed only in the presence of sIL-6R
      although small amounts of IL-6R were detected in these cells by RT-PCR analysis.
      However, anti-IL-6R or anti-gp130 mAb treatment increased spontaneous growth of
      synovial cells in all eight cases, suggesting that endogenous IL-6 and a small
      amount of IL-6R expressed in synovial cells suppressed their growth without
      exogenous IL-6 or sIL-6R. In addition, the IL-6-sIL-6R complex reduced the TNF
      alpha-induced proliferation of synovial cells while TNF-alpha induced their IL-6
      production. These data suggest that IL-6 may act as a negative feedback factor
      for TNF-alpha-induced synovial cell growth.

PMID- 10653855
TI  - Soluble human MHC class I molecules induce soluble Fas ligand secretion and
      trigger apoptosis in activated CD8(+) Fas (CD95)(+) T lymphocytes.
AB  - In the present study, we have evaluated the apoptotic effect of soluble human MHC
      class I (sHLA-I) antigens on CD8(+) T lymphocytes. sHLA-I antigens and beta(2)
      microglobulin-free HLA class I heavy chains, isolated from serum, induced
      apoptosis on phytohemagglutinin-activated CD8(+) T lymphocytes in autologous and
      allogeneic combinations. The extent of CD8(+) T cell apoptosis depends on the
      degree of activation, time of incubation with sHLA-I antigens and amount of sHLA
      I antigens added to the cultures. Apoptosis is induced by the interaction of Fas
      (CD95)(+) cells with soluble Fas ligand which is released following binding of
      sHLA-I antigens to CD8 molecules. These results suggest that sHLA-I antigens may
      regulate immune responses by inducing apoptosis in activated CD8(+) T cells.

PMID- 10653856
TI  - Tuning T cell activation threshold and effector function with cross-reactive
      peptide ligands.
AB  - We have generated a panel of cross-reactive T cells by immunizing SJL mice (I
      A(s)) with Q144 peptide, an analog of an autoantigenic peptide (W144) of myelin
      proteolipid protein (PLP) 139-151 (HSLGKWLGHPDKF) in which W was replaced by Q at
      position 144. Following immunization with Q144, T cells were expanded in vitro
      with W144, which is a cross-reactive, suboptimal ligand, for Q144-specific T
      cells. The T cell clones responded to both ligands and grew normally on the
      peptide W144, but were hyperstimulated when activated by Q144 in vitro. This
      hyperstimulation results in a heteroclitic proliferative response with secretion
      of additional cytokines not induced by W144. Thus expansion of T cells by a
      suboptimal cross-reactive ligand effectively lowers the activation threshold so
      that the immunizing antigen becomes a hyperstimulating ligand for the clones.
      Surprisingly, when the T cell clones are grown on the hyperstimulating ligand
      Q144, some adapt by increasing their activation threshold. This desensitization
      results in a loss of response to a number of cross-reactive ligands and the
      appearance of a more specific T cell response. Long-term culture with the
      hyperstimulating ligand is sometimes associated with down-regulation of CD4
      expression. These results provide an explanation for the common finding of T cell
      heteroclicity, and suggest that although the specificity and hierarchy of the
      response of T cells to peptides is determined by the TCR, activation threshold
      and effector functions are modified by exposure to cross-reactive ligands. This
      observation has implications for the development and regulation of autoimmune
      disease.

PMID- 10653857
TI  - Ly49A expression on T cells alters T cell selection.
AB  - Ly49 receptors are inhibitory receptors expressed on subsets of both NK cells and
      NK1.1(+) T cells. The function of these receptors on NK cells is believed to be
      important in maintaining self-tolerance, yet their role on T cells is unclear. In
      this report we investigated how an Ly49A transgene alters T and NK cell
      development in an in vivo environment, where a ligand for Ly49A is expressed.
      Ly49A transgenic mice that co-expressed an MHC ligand for Ly49A, H-2D(d),
      developed a severe inflammatory disorder that resulted in death within the first
      weeks of age. T cells expressing forbidden TCR V(beta) chains were found both in
      the thymus and periphery of transgenic mice, while non-transgenic littermates had
      successfully deleted these T cell subsets. These data indicate that the
      expression of Ly49A on T cells could alter T cell selection and allow survival of
      potentially self-reactive T cells.

PMID- 10653858
TI  - IFN-gamma-independent IgG2a production in mice infected with viruses and
      parasites.
AB  - After infection with some viruses and intracellular parasites, antibody
      production is restricted to IgG2a. We first observed that, whereas live viruses
      such as lactate dehydrogenase-elevating virus (LDV) or mouse adenovirus induced
      mostly an IgG2a response, a large proportion of antibodies produced against
      killed viruses were IgG1. This IgG1 antiviral response was suppressed when live
      virions were added to inactivated viral particles. These results indicate that
      the IgG2a preponderance is related to the infectious process itself rather than
      to the type of antigen involved. Since IFN-gamma is known to stimulate IgG2a
      production by activated B lymphocytes and to be secreted after infection, we
      examined the role of this cytokine in the antibody isotypic distribution caused
      by LDV. Most IgG2a responses were relatively unaffected in mice deficient for the
      IFN-gamma receptor or treated with anti-IFN-gamma antibody. A similar IFN-gamma
      independent IgG2a secretion was observed after infection with the parasites
      Toxoplasma gondii and Trypanosoma cruzi. However, the IFN-gamma-independent IgG2a
      production triggered by infection still required the presence of functional T(h)
      lymphocytes. Therefore, signal(s) other than IFN-gamma secretion may explain the
      T(h)-dependent isotypic bias in antibody secretion triggered by viruses and
      parasites.

PMID- 10653859
TI  - Refluxtions on esophageal cancer: can we swallow the changes?

PMID- 10653860
TI  - Outcome of patients receiving radiation for cancer of the esophagus: results of
      the 1992-1994 Patterns of Care Study.
AB  - PURPOSE: A Patterns of Care Study examined the records of patients with
      esophageal cancer (EC) treated with radiation in 1992 through 1994 to determine
      the national practice processes of care and outcomes and to compare the results
      with those of clinical trials. PATIENTS AND METHODS: A national survey of 63
      institutions was conducted using two-stage cluster sampling, and specific
      information was collected on 400 patients with squamous cell (62%) or
      adenocarcinoma (37%) of the thoracic esophagus who received radiation therapy
      (RT) as part of primary or adjuvant treatment. Patients were staged according to
      a modified 1983 American Joint Committee on Cancer staging system. Fifteen
      percent of patients had clinical stage (CS) I disease, 40% had CS II disease, and
      30% had CS III disease. Twenty-six percent of patients underwent esophagectomy.
      Seventy-five percent of patients received chemotherapy; 84% of these received
      concurrent chemotherapy and radiation (CRT). RESULTS: Significant variables for
      overall survival in multivariate analysis include the use of esophagectomy (risk
      ratio [RR] = 0.62), the use of chemotherapy (RR = 0.63), Karnofsky performance
      status (KPS) greater than 80 (RR = 0.61), CS I or II disease (RR = 0.66), and
      facility type (RR = 0.72). Age, sex, and histology were not significant.
      Preoperative CRT resulted in a nonsignificantly higher 2-year survival rate
      compared with definitive CRT alone (63% v 39%; P =.11), whereas 2-year survival
      by planned treatment rather than treatment given was 47.7% for preoperative CRT
      and 35.4% for definitive CRT (P =.23). Definitive CRT compared with definitive RT
      alone resulted in significantly higher 2-year survival (39% v 20.6%; P =.027) and
      lower 2-year local regional failure (30% v 57.9%; P =. 0031). CONCLUSION: This
      study confirms the value of CRT in EC treatment. It indicates that the results
      obtained in practice settings nationwide are similar to those obtained in
      clinical trials and that KPS and the 1983 clinical staging system are useful
      prognostic indicators. The suggested value of esophagectomy and superiority of
      preoperative CRT over CRT alone in this study should be tested in a randomized
      trial.

PMID- 10653861
TI  - Randomized trial of omeprazole or ranitidine versus placebo in the prevention of
      chemotherapy-induced gastroduodenal injury.
AB  - PURPOSE: Anticancer drugs may induce acute mucosal injury to stomach and
      duodenum. This study was planned to evaluate the efficacy of omeprazole or
      ranitidine in preventing such an injury. PATIENTS AND METHODS: Two hundred twenty
      eight cancer patients with normal stomach and duodenum or with less than three
      erosions, who were selected to be treated with cyclophosphamide, methotrexate,
      and fluorouracil (90 breast carcinoma patients) or fluorouracil alone (138 colon
      carcinoma patients), were randomly assigned to treatment with omeprazole 20 mg,
      ranitidine 300 mg, or one placebo tablet a day. Seven days after the second
      course of chemotherapy (CT), the patients underwent a further
      esophagogastroduodenoscopy to evaluate the mucosal injury. Endoscopic findings
      were quantified on the basis of an arbitrary score, and the occurrence of
      epigastric pain or heartburn was assessed weekly. RESULTS: A significant
      difference was found among the three groups (P =.0032), as well as between pre-
      and postCT endoscopic findings (P =.00001). Endoscopic scores after CT were
      significantly higher than pretreatment scores in the placebo (P =.003) and
      ranitidine (P =.003) groups but not in the omeprazole group (P =.354). Acute
      ulcers were significantly less frequent in patients receiving omeprazole or
      ranitidine than in those receiving placebo (P =.0001 and P =.0315, respectively).
      Epigastric pain and/or heartburn were significantly less frequent in patients
      receiving omeprazole (P =.00124) or ranitidine (P =.038) than in those receiving
      placebo. CONCLUSION: Omeprazole is effective in preventing chemotherapy-induced
      gastroduodenal injury. Ranitidine is effective in reducing the frequency of
      ulcers and upper gastrointestinal symptoms but is not effective in preventing the
      global endoscopic worsening caused by chemotherapy. The different efficacy of
      omeprazole and ranitidine can be explained by their different pharmacodynamics.

PMID- 10653862
TI  - LMCE3 treatment strategy: results in 99 consecutively diagnosed stage 4
      neuroblastomas in children older than 1 year at diagnosis.
AB  - PURPOSE: To tailor postinduction therapy for stage 4 neuroblastoma in children
      who are older than 1 year at diagnosis according to status after induction.
      PATIENTS AND METHODS: From March 1987 to December 1992, 99 patients who were
      consecutively admitted were included in the Lyon-Marseille-Curie East of France
      (LMCE)3 strategy. After induction with the French Society of Pediatric Oncology
      NB87 regimen and surgery, patients who were in complete remission immediately
      proceeded to consolidation therapy with vincristine, melphalan, and fractionated
      total-body irradiation (VMT). All other patients underwent a postinduction
      strategy before VMT, either an additional megatherapy regimen or further
      chemotherapy with etoposide/carboplatin. RESULTS: The progression-free survival
      (PFS) is 29% at 7 years from diagnosis, which compares favorably with that of a
      similar cohort of 72 patients previously reported by our group (LMCE1; PFS of 20%
      at 5 years and 8% at 14 years, P =.004). In the multivariate analysis, only age
      younger than 3 years at diagnosis (P =.0085) and achievement of complete or very
      good partial remission after NB87 and surgery (P =.00024) remained significant.
      The PFS of the 87 patients who were included in the postinduction strategy was
      significantly better than that of the comparable 62 patients on the LMCE1 study
      (32% v 11% at 7 years; P =.005). CONCLUSION: The progressive improvements in the
      LMCE results over the last 10 years suggest that improvements in supportive care
      measures and increases in each component of this strategy (induction,
      postinduction, consolidation) may all contribute to increased survival rates.

PMID- 10653863
TI  - Favorable biology and outcome of stage IV-S neuroblastoma with supportive care or
      minimal therapy: a Children's Cancer Group study.
AB  - PURPOSE: Stage IV-S neuroblastoma is a metastatic disease associated with
      spontaneous regression and good survival, but 10% to 20% of infants die from
      early complications. The purpose of this study was to evaluate outcome and
      prognostic factors in infants with stage IV-S neuroblastoma treated prospectively
      with supportive care only or, in symptomatic patients, with low-dose cytotoxic
      therapy. PATIENTS AND METHODS: Eighty eligible infants were studied for response
      and survival with supportive care or, for symptomatic patients, cyclophosphamide
      5 mg/kg/d for 5 days with or without hepatic radiation of 4.5 Gy over 3 days.
      Staging was reviewed centrally, and MYCN gene copy number, Shimada
      histopathologic classification, serum ferritin levels, and bone marrow
      immunocytology were determined. RESULTS: Stage IV-S and International
      Neuroblastoma Staging System stage 4S were 98% concordant. MYCN was not amplified
      in any of the tumors tested (n = 58), and Shimada histopathologic classification
      was favorable in 96% (n = 68/71). The 5-year event-free survival (EFS) rate for
      all infants was 86% and the survival rate was 92%. Supportive care was the only
      treatment provided for 44 (55%) of 80 infants, and their 5-year survival rate was
      100%, compared with 81% survival for those requiring cytotoxic therapy for
      symptoms (P =.005). Five of six deaths were in infants younger than 2 months of
      age at diagnosis and were due to complications of extensive abdominal involvement
      with respiratory compromise or disseminated intravascular coagulation. Although
      age </= 3 months at diagnosis was significant for EFS (P =. 043), it was less
      significant for survival (P =.077). The only other significant factor predictive
      for improved survival was favorable Shimada histopathologic classification. Sites
      of metastatic involvement (liver, skin, or bone marrow) and surgical resection of
      the primary tumor were not significant for survival. CONCLUSION: This study
      confirms the favorable biologic features and excellent survival of infants with
      stage IV-S neuroblastoma with minimal therapy. Infants younger than 2 months old
      at diagnosis with rapidly progressive abdominal disease may benefit from earlier
      and more intensive treatment.

PMID- 10653864
TI  - Long-term risk of second malignancy in survivors of Hodgkin's disease treated
      during adolescence or young adulthood.
AB  - PURPOSE: To quantify the long-term risk of second primary cancers (SCs) in
      patients diagnosed with Hodgkin's disease (HD) during adolescence or young
      adulthood. PATIENTS AND METHODS: The risk of SCs was assessed in 1,253 patients
      diagnosed with HD before the age of 40 years and treated in two Dutch cancer
      centers between 1966 and 1986. The median follow-up duration was 14.1 years.
      RESULTS: In all, 137 patients developed SCs, compared with 19.4 cases expected on
      the basis of incidence rates in the general population (relative risk [RR] = 7.0;
      95% confidence interval, 5.9 to 8.3). The 25-year actuarial risk of SC overall
      was 27.7%. The RR of solid tumors increased greatly with younger age at the first
      treatment of HD, not only for breast cancer but also for all other solid tumors,
      with RRs of 4.9, 6.9, and 12.7 for patients first treated at ages 31 to 39 years,
      21 to 30 years, and </= 20 years, respectively. Among patients first treated at
      the age of 20 years or younger, the RR of developing a solid tumor before the age
      of 40 years was significantly greater than the RR of solid tumor development at
      ages 40 to 49 years (RR = 27.9 v RR = 4.2; P =.0001). Patients who received
      salvage chemotherapy had significantly greater risk of solid cancers other than
      breast cancer than did patients whose treatment was restricted to initial
      radiotherapy or initial combined-modality treatment (RR = 9.4 and 4.7,
      respectively; P =. 004). CONCLUSION: After more than 20 years of follow-up, the
      risk of solid tumors is still much greater in survivors of HD than in the
      population at large. Reassuringly, the greatly increased risk of solid tumors in
      patients who were young (</= 20 years of age) at the first treatment seems to
      decrease as these patients grow older. Our data suggest that chemotherapy may
      increase the risk of solid tumors from radiotherapy.

PMID- 10653865
TI  - Risk of second malignancy after Hodgkin's disease in a collaborative British
      cohort: the relation to age at treatment.
AB  - PURPOSE: To assess long-term site-specific risks of second malignancy after
      Hodgkin's disease in relation to age at treatment and other factors. PATIENTS AND
      METHODS: A cohort of 5,519 British patients with Hodgkin's disease treated during
      1963 through 1993 was assembled and followed-up for second malignancy and
      mortality. Follow-up was 97% complete. RESULTS: Three hundred twenty-two second
      malignancies occurred. Relative risks of gastrointestinal, lung, breast, and bone
      and soft tissue cancers, and of leukemia, increased significantly with younger
      age at first treatment. Absolute excess risks and cumulative risks of solid
      cancers and leukemia, however, were greater at older ages than at younger ages.
      Gastrointestinal cancer risk was greatest after mixed-modality treatment
      (relative risk [RR] = 3.3; 95% confidence interval [CI], 2.1 to 4.8); lung cancer
      risks were significantly increased after chemotherapy (RR = 3. 3; 95% CI, 2.4 to
      4.7), mixed-modality treatment (RR = 4.3; 95% CI, 2.9 to 6.2), and radiotherapy
      (RR = 2.9; 95% CI, 1.9 to 4.1); breast cancer risk was increased only after
      radiotherapy without chemotherapy (RR = 2.5; 95% CI, 1.4 to 4.0); and leukemia
      risk was significantly increased after chemotherapy (RR = 31.6; 95% CI, 19.7 to
      47.6) and mixed-modality treatment (RR = 38.1; 95% CI, 24.6 to 55. 9). These
      risks were generally greater after treatment at younger ages: for patients
      treated at ages younger than 25 years, there were RRs of 18.7 (95% CI, 5.8 to
      43.5) for gastrointestinal cancer after mixed-modality treatment, 14.4 (95% CI,
      5.7 to 29.3) for breast cancer after radiotherapy, and 85.2 (95% CI, 45.3 to
      145.7) for leukemia after chemotherapy (with or without radiotherapy).
      CONCLUSION: Age at treatment has a major effect on risk of second malignancy
      after Hodgkin's disease. Although absolute excess risks are greater for older
      patients, RRs of several important malignancies are much greater for patients who
      are treated when young. The increased risk of gastrointestinal cancers may relate
      particularly to mixed-modality treatment, and that of lung cancer to chemotherapy
      as well as radiotherapy; there are also well-known increased risks of breast
      cancer from radiotherapy and leukemia from chemotherapy. The roles of specific
      chemotherapeutic agents in the etiology of solid cancers after Hodgkin's disease
      require detailed investigation.

PMID- 10653866
TI  - Molecular and clinical features of non-Burkitt's, diffuse large-cell lymphoma of
      B-cell type associated with the c-MYC/immunoglobulin heavy-chain fusion gene.
AB  - PURPOSE: t(8;14)(q24;q32) and/or c-MYC/immunoglobulin heavy-chain (IGH) fusion
      gene have been observed not only in Burkitt's lymphoma (BL) but also in a
      proportion of non-BL, diffuse large-cell lymphoma of B-cell type (DLCL). We
      explored molecular features of DLCL with c-MYC/IGH fusion and the impact of this
      genetic abnormality on clinical outcome of DLCL. PATIENTS AND METHODS: A total of
      203 cases of non-BL DLCL were studied. Genomic DNA extracted from tumor tissues
      was subjected to long-distance polymerase chain reaction (LD-PCR) using
      oligonucleotide primers for exon 2 of c-MYC and for the four constant region
      genes of IGH. RESULTS: Twelve cases (5.9%) showed positive amplification; one had
      a c-MYC/Cmicro, nine had a c-MYC/Cgamma, and two had a c-MYC/Calpha fusion
      sequence. Restriction and sequence analysis of the LD-PCR products, ranging from
      2.3 to 9.4 kb in size, showed that breakage in the 12 cases occurred within a 1.5
      kb region that included exon 1 of c-MYC in combination with breakpoints at the
      switch regions of IGH (10 of 12). In 10 cases, Myc protein encoded by the fusion
      genes demonstrated mutations and/or deletions. Six cases had additional molecular
      lesions in BCL-2 or BCL-6 and/or p53 genes. The age range of the 12 patients was
      44 to 86 years, with a median age of 65.5 years. Five patients had stage I/II
      disease, and seven had stage III/IV disease. Lactate dehydrogenase was elevated
      in nine of 11 subjects. Seven showed involvement of the gastrointestinal tract.
      All patients were treated by surgery and/or chemoradiotherapy; six died of the
      disease within 1 year, resulting in the poorest 1- and 2-year survival rates
      among DLCL subgroups. CONCLUSION: The c-MYC/IGH fusion gene of DLCL is identical
      to that of the sporadic type of BL (sBL). DLCL with c-MYC/IGH shares clinical
      features with sBL but is characterized further by an older age distribution.

PMID- 10653867
TI  - Phase II multicenter study of brief single-agent methotrexate followed by
      irradiation in primary CNS lymphoma.
AB  - PURPOSE: To assess, in a multi-institutional setting, the impact on relapse,
      survival, and toxicity of adding two cycles of intravenous methotrexate to
      cranial irradiation for immunocompetent patients with primary CNS lymphoma.
      PATIENTS AND METHODS: Forty-six patients with a median age of 58 years and
      Eastern Cooperative Oncology Group performance status 0 to 3 were entered onto
      this phase II study. The protocol consisted of methotrexate 1 g/m(2) on days 1
      and 8 followed by cranial irradiation on day 15. A whole-brain dose of 45 Gy was
      followed by a boost of 5.4 Gy. Intrathecal chemotherapy and spinal irradiation
      were given only to patients for whom cytologic examination of CSF was positive
      for CNS lymphoma. The median follow-up time was 36 months, with a minimum
      potential follow-up of 12 months. RESULTS: Median survival was 33 months, with 2
      year probability of survival 62% +/- 15% (95% confidence interval). Twenty
      patients have relapsed. The predominant site of relapse was the brain. Neither
      performance status nor age was found to influence survival. Six patients
      developed a dementing illness at a median of 16 months after treatment, and three
      of these died as a consequence. CONCLUSION: A brief course of intravenous
      methotrexate before cranial irradiation is associated with 2-year and median
      survival rates superior to those reported for radiotherapy alone and similar to
      more intensive combined-modality regimens. Neurotoxicity remains an important
      competing risk for these patients.

PMID- 10653868
TI  - High-dose therapy with autologous bone marrow support as consolidation of
      remission in follicular lymphoma: long-term clinical and molecular follow-up.
AB  - PURPOSE: To evaluate the long-term results of high-dose therapy (HDT) in
      follicular lymphoma, with specific emphasis on the prognostic significance of
      polymerase chain reaction (PCR)-detectable Bcl-2/IgH rearrangements. PATIENTS AND
      METHODS: Between June 1985 and October 1995, 99 patients with follicular lymphoma
      received HDT as consolidation of second or subsequent remission. Bone marrow was
      treated in vitro with anti-B-cell antibodies and complement. RESULTS: Sixty-five
      patients remained alive, 49 treatment-failure free, with a median follow-up of
      5.5 years (range, 1.5 to 12.5 years). Four "early" and 10 "late" deaths occurred
      from treatment-related causes; seven of the latter were due to secondary
      myelodysplasia (s-MDS) or secondary acute myeloblastic leukemia. Overall, 12
      (12%) of the 99 patients developed s-MDS or acute myeloblastic leukemia. Kaplan
      Meier estimates of freedom from recurrence (FFR) and survival rates at 5 years
      were 63% (95% confidence interval [CI], 52% to 72%) and 69% (95% CI, 58% to 78%),
      respectively. For all 99 patients, in multivariate analysis, absence of the Bcl
      2/IgH rearrangement at the time of diagnosis (hazards ratio [HR], 0.39; P =.04)
      and three or fewer treatment episodes before HDT (HR, 0.03; P =.001) were
      significant prognostic factors for improved survival. For patients bearing Bcl
      2/IgH rearrangements, in univariate and multivariate analyses, absence of a PCR
      detectable Bcl-2/IgH rearrangement during follow-up was associated with a
      significantly lower risk of recurrence (adjusted HR, 0.13; P <.001) and death
      (HR, 0.25; P =.02), whereas the PCR status of the reinfused bone marrow did not
      correlate with outcome. CONCLUSION: Prolonged FFR can be achieved in patients
      with follicular lymphoma after HDT, but as yet there is no survival advantage
      compared with conventional treatment. These results confirm that elimination of
      cells bearing the Bcl-2/IgH rearrangement is highly desirable and should be
      attempted. The incidence of s-MDS is of increasing concern in this setting.

PMID- 10653869
TI  - Randomized trial of bone marrow versus lenograstim-primed blood cell allogeneic
      transplantation in patients with early-stage leukemia: a report from the Societe
      Francaise de Greffe de Moelle.
AB  - PURPOSE: To compare hematologic recovery in patients receiving allogeneic blood
      cell transplantation (BCT) with those receiving allogeneic bone marrow
      transplantation (BMT). PATIENTS AND METHODS: One hundred eleven patients with
      leukemia in the early stages and with HLA-matched sibling donors were randomized
      in this study. One hundred one underwent transplantation. Standard procedures for
      collection and transplantation were used. Patients did not receive prophylactic
      granulocyte colony-stimulating factor after undergoing transplantation. In
      addition to clinical end points being established, a prospective and comparative
      economic evaluation of the first 6 months after transplantation was performed.
      RESULTS: Groups were balanced for patient, donor, and transplant characteristics.
      Blood cell collection led to the collection of a higher number of CD34(+) and
      CD3(+) cells than did bone marrow collection (P < 10(-6)) without reported side
      effects for the donor. Patients in the BCT group reached platelet counts of 25
      and 50 x 10(9) platelets/L 8 and 11 days earlier than did the BMT group (P < 10(
      4) and P < 10(-5)), respectively. This resulted in fewer platelet transfusions
      during the first 180 days after transplantation (P =.002) for the former group.
      The time to reach neutrophil counts of 0.5 and 1 x 10(9) neutrophils/L was 6 and
      7 days shorter, respectively, in the BCT group than in the BMT group (P < 10(
      5)). This quicker hematologic recovery was associated with a shorter length of
      hospitalization and a decrease in total cost of procedure during the first 6
      months. CONCLUSION: This study establishes that allogeneic BCT results in quicker
      hematologic recovery but is associated with a higher occurrence of chronic graft
      versus-host disease.

PMID- 10653870
TI  - Results of treatment with hyper-CVAD, a dose-intensive regimen, in adult acute
      lymphocytic leukemia.
AB  - PURPOSE: To evaluate the efficacy and toxicity of Hyper-CVAD (fractionated
      cyclophosphamide, vincristine, doxorubicin, and dexamethasone), a dose-intensive
      regimen, in adult acute lymphocytic leukemia (ALL). PATIENTS AND METHODS: Adults
      with newly diagnosed ALL referred since 1992 were entered onto the study;
      treatment was initiated in 204 patients between 1992 and January 1998. No
      exclusions were made because of older age, poor performance status, organ
      dysfunction, or active infection. Median age was 39.5 years; 37% were at least 50
      years old. Mature B-cell disease (Burkitt type) was present in 9%, T-cell disease
      in 17%. Leukocytosis of more than 30 x 10(9)/L was found in 26%, Philadelphia
      chromosome-positive disease in 16% (20% of patients with assessable metaphases),
      CNS leukemia at the time of diagnosis in 7%, and a mediastinal mass in 7%.
      Treatment consisted of four cycles of Hyper-CVAD alternating with four cycles of
      high-dose methotrexate (MTX) and cytarabine therapy, together with intrathecal
      CNS prophylaxis and supportive care with antibiotic prophylaxis and granulocyte
      colony-stimulating factor therapy. Maintenance in patients with nonmature B-cell
      ALL included 2 years of treatment with mercaptopurine, MTX, vincristine, and
      prednisone (POMP). RESULTS: Overall, 185 patients (91%) achieved complete
      remission (CR) and 12 (6%) died during induction therapy. Estimated 5-year
      survival and 5-year CR rates were 39% and 38%, respectively. The incidence of CNS
      relapse was low (4%). Compared with 222 patients treated with vincristine,
      doxorubicin, and dexamethasone (VAD) regimens, our patients had a better CR rate
      (91% v 75%, P <.01) and CR rate after one course (74% v 55%, P <.01) and better
      survival (P <.01), and a smaller percentage had more than 5% day 14 blasts (34% v
      48%, P =.01). Previous prognostic models remained predictive for outcome with
      Hyper-CVAD therapy. CONCLUSION: Hyper-CVAD therapy is superior to our previous
      regimens and should be compared with established regimens in adult ALL.

PMID- 10653871
TI  - Factors predicting for efficacy and safety of docetaxel in a compassionate-use
      cohort of 825 heavily pretreated advanced breast cancer patients.
AB  - PURPOSE: To identify predictive factors for efficacy and safety in advanced
      breast cancer (ABC) patients treated in the French compassionate-use docetaxel
      program. PATIENTS AND METHODS: A total of 825 ABC patients treated with docetaxel
      (100 mg/m(2) every 3 weeks) were source-reviewed and analyzed for prognostic
      factors associated with overall response rate (ORR), time to treatment failure
      (TTF), overall survival (OS), febrile neutropenia, mucositis, and severe fluid
      retention syndrome by univariate and multivariate analysis. RESULTS: The ORR was
      22.9% (95% confidence interval, 20.2% to 26.2%). The median TTF and OS were 4.0
      and 9.8 months, respectively. By multivariate analysis, secondary anthracycline
      resistant disease was significantly associated (P <. 05) with lower ORR and
      shorter TTF and OS, whereas anthracycline-refractory disease was associated with
      shorter OS. Poor performance status was associated with lower ORR, shorter TTF,
      and shorter OS. Liver dysfunction (transaminase levels > 1.5 times the upper
      limit of normal [ULN] and alkaline phosphatase [AP] level > three times ULN) and
      time since first relapse less than 24 months were associated with shorter TTF and
      OS. Other significant correlations included the following: elevated CA 15-3 serum
      level with lower ORR; more than two involved sites, and minor transaminase and AP
      level abnormalities with shorter OS; and no previous chemotherapy for ABC with
      shorter TTF. According to multivariate analysis, ORR, TTF, and OS were not
      decreased in patients with liver metastases but without liver dysfunction.
      CONCLUSION: Docetaxel activity was maintained in heavily pretreated ABC patients
      and in those with liver metastasis; docetaxel must be used cautiously, however,
      in patients with liver dysfunction in whom high morbidity risk necessitates
      strict adherence to dose-adaptation guidelines.

PMID- 10653872
TI  - Survival in early breast cancer patients is favorably influenced by a natural
      humoral immune response to polymorphic epithelial mucin.
AB  - PURPOSE: Polymorphic epithelial mucin (PEM or MUC1) is being studied as a vaccine
      substrate for the immunotherapy of patients with adenocarcinoma. The present
      study analyzes the incidence of naturally occurring MUC1 antibodies in early
      breast cancer patients and relates the presence of these antibodies in
      pretreatment serum to outcome of disease. MATERIALS AND METHODS: We measured
      immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies to MUC1 with an
      enzyme-linked immunoassay (PEM.CIg), which uses a MUC1 triple-tandem repeat
      peptide conjugated to bovine serum albumin, in pretreatment serum samples
      obtained from 154 breast cancer patients (52 with stage I disease and 102 with
      stage II) and 302 controls. The median disease-specific survival time of breast
      cancer patients was 74 months (range, 15 to 118 months). A positive test result
      was defined as MUC1 IgG or IgM antibody levels equal to or greater than the
      corresponding rounded-up median results obtained in the total breast cancer
      population. RESULTS: A positive test result for both MUC1 IgG and IgM antibodies
      in pretreatment serum was associated with a significant benefit in disease
      specific survival in stage I and II (P =.0116) breast cancer patients. Positive
      IgG and IgM MUC1 antibody levels had significant additional prognostic value to
      stage (P =.0437) in multivariate analysis. Disease-free survival probability did
      not differ significantly. However, stage II patients who tested positive for MUC1
      IgG and IgM antibody and who relapsed had predominantly local recurrences or
      contralateral disease, as opposed to recurrences at distant sites in the patients
      with a negative humoral response (P =.026). CONCLUSION: Early breast cancer
      patients with a natural humoral response to MUC1 have a higher probability of
      freedom from distant failure and a better disease-specific survival. MUC1
      antibodies may control hematogenic tumor dissemination and outgrowth by aiding
      the destruction of circulating or seeded MUC1-expressing tumor cells. Vaccination
      of breast cancer patients with MUC1-derived (glyco)peptides in an adjuvant
      setting may favorably influence the outcome of disease.

PMID- 10653873
TI  - Early start of adjuvant chemotherapy may improve treatment outcome for
      premenopausal breast cancer patients with tumors not expressing estrogen
      receptors. The International Breast Cancer Study Group.
AB  - PURPOSE: The proper time to commence adjuvant chemotherapy after primary surgery
      for breast cancer is unknown. An analysis of the International (Ludwig) Breast
      Cancer Study Group (IBCSG) Trial V at a median follow-up of 11 years suggested
      that early initiation of adjuvant chemotherapy might improve outcome for
      premenopausal, node-positive patients whose tumors did not express any estrogen
      receptor (ER). PATIENTS AND METHODS: We investigated the relationship between
      early initiation of adjuvant chemotherapy, ER status, and prognosis in 1,788
      premenopausal, node-positive patients treated on IBCSG trials I, II, and VI. The
      disease-free survival for 599 patients (84 with ER-absent tumors) who commenced
      adjuvant chemotherapy within 20 days (early initiation) was compared with the
      disease-free survival for 1,189 patients (142 with ER-absent tumors) who started
      chemotherapy 21 to 86 days after surgery (conventional initiation). The median
      follow-up was 7.7 years. RESULTS: Among patients with ER-absent tumors, the 10
      year disease-free survival was 60% for the early initiation group compared with
      34% for the conventional initiation group (226 patients; hazard ratio [HR], 0.
      49; 95% confidence interval [CI], 0.33 to 0.72; P =.0003). This difference
      remained statistically significant in a Cox multiple regression analysis
      controlling for study group, number of positive nodes, tumor size, age, vessel
      invasion, and institution (HR, 0.60; 95% CI, 0.39 to 0.92; P =.019). Conversely,
      early initiation of chemotherapy did not significantly improve disease-free
      survival for patients with tumors expressing ER (1,562 patients; multiple
      regression HR, 0.93; 95% CI, 0.79 to 1.10; P =.40). CONCLUSION: In premenopausal
      patients with ER-absent tumors, early initiation of systemic chemotherapy after
      primary surgery might improve outcome. Further confirmatory studies are required
      before any widespread modification of current clinical practice. In premenopausal
      patients with tumors expressing some ER, gains from early initiation are unlikely
      to be clinically significant.

PMID- 10653874
TI  - Clinical progression of breast cancer malignant behavior: what to expect and when
      to expect it.
AB  - PURPOSE: Seemingly localized breast cancer is a heterogeneous mix of truly
      localized cancers and cancers with occult metastases. Our purpose is to determine
      the parameters of metastatic proclivity for the different clinical presentations
      of operable breast cancer and to present quantitative prognostic information
      useful to both doctors and patients. PATIENTS AND METHODS: A series of regionally
      treated breast cancer patients was analyzed to determine the likelihood and time
      of the appearance of clinical metastases for different clinical subgroups.
      Patients operated on at the University of Chicago from 1927 to 1987 for
      clinically regionally localized breast cancer, who received no systemic therapy
      as a part of their initial treatment, were included. Overall survival and distant
      disease-free survival in this mature series are analyzed. RESULTS:
      Metastagenicity, the metastatic proclivity of a tumor, increases with both tumor
      size and nodal involvement. This is also true for virulence, which is the rate at
      which these metastases appear. Each clinical group has a cured population, even
      those with extensive nodal involvement. A table provides a tool for determining
      the proportion of risk expended in each clinical group as a function of the
      distant disease-free survival. Whereas the likelihood of metastasis increases
      with tumor size and nodal involvement, the time to their appearance decreases.
      CONCLUSIONS: Breast cancer metastagenicity and virulence are heterogeneous even
      within clinically similar groups of operable breast cancer patients. Tumor
      progression is correlated with increasing tumor size and nodal involvement.
      Markers are needed to identify individual tumor virulence and metastagenicity.

PMID- 10653875
TI  - Plasma D-dimer levels in operable breast cancer patients correlate with clinical
      stage and axillary lymph node status.
AB  - PURPOSE: To investigate the relationship between preoperative plasma D-dimer
      levels and extent of tumor involvement in operable breast cancer patients.
      PATIENTS AND METHODS: A total of 140 preoperative plasma specimens were obtained
      from women scheduled to undergo diagnostic breast biopsies. Ninety-five patients
      in the initial group went on to undergo axillary lymph node dissection. Of the
      140 patients from whom plasma samples were obtained, 102 were subsequently
      diagnosed with invasive breast carcinoma, nine were subsequently diagnosed with
      ductal carcinoma-in-situ, and 20 were subsequently diagnosed with benign breast
      disease. Plasma D-dimer levels were quantitated using a commercially available
      immunoassay kit (DIMERTEST; American Diagnostica, Greenwich, CT). The
      relationships between plasma D-dimer and other prognostic variables (tumor size,
      estrogen receptor, progesterone receptor, nuclear grade, histologic grade,
      lymphovascular invasion, and clinical stage grouping) were then examined using
      univariate and multivariate linear and logistic regression analyses. RESULTS:
      Median plasma D-dimer levels were significantly higher in patients with invasive
      carcinoma than those patients with either benign breast disease or carcinoma-in
      situ (P =.0001). A significant relationship existed between the presence of
      elevated D-dimer (> 100 ng/mL) and involved axillary lymph nodes (chi(2) test; P
      =.001). Elevated D-dimer levels predicted positive lymph node involvement in both
      univariate regression (P =.0035) and multivariate linear regression (P =.012)
      models. In addition, elevated D-dimer levels predicted the presence of
      lymphovascular invasion in univariate logistic regression (P =. 0025) and
      multivariate logistic regression analysis (P =.0053). Quantitative D-dimer levels
      were highly correlated with clinical stage grouping (analysis of variance test; P
      =.002). CONCLUSION: Plasma D-dimer levels were markers of lymphovascular
      invasion, clinical stage, and lymph node involvement in operable breast cancer.
      This correlation suggests that detectable fibrin degradation, as measured by
      plasma D-dimer, is a clinically important marker for lymphovascular invasion and
      early tumor metastasis in operable breast cancer.

PMID- 10653876
TI  - Adenovirus-mediated p53 gene transfer in sequence with cisplatin to tumors of
      patients with non-small-cell lung cancer.
AB  - PURPOSE: To determine the safety and tolerability of adenovirus-mediated p53
      (Adp53) gene transfer in sequence with cisplatin when given by intratumor
      injection in patients with non-small-cell lung cancer (NSCLC). PATIENTS AND
      METHODS: Patients with advanced NSCLC and abnormal p53 function were enrolled
      onto cohorts receiving escalating dose levels of Adp53 (1 x 10(6) to 1 x 10(11)
      plaque-forming units [PFU]). Patients were administered intravenous cisplatin 80
      mg/m(2) on day 1 and study vector on day 4 for a total of up to six courses (28
      days per course). Apoptosis was determined by the terminal deoxynucleotidyl-
      transferase-dUTP nick-end labeling assay. Evidence of vector-specific sequences
      were determined using reverse-transcriptase polymerase chain reaction. Vector
      dissemination and biodistribution was monitored using a series of assays
      (cytopathic effects assay, Ad5 hexon enzyme-linked immunosorbent assay, vector
      specific polymerase chain reaction assay, and antibody response assay). RESULTS:
      Twenty-four patients (median age, 64 years) received a total of 83 intratumor
      injections with Adp53. The maximum dose administered was 1 x 10(11) PFU per dose.
      Transient fever related to Adp53 injection developed in eight of 24 patients.
      Seventeen patients achieved a best clinical response of stable disease, two
      patients achieved a partial response, four patients had progressive disease, and
      one patient was not assessable. A mean apoptotic index between baseline and
      follow-up measurements increased from 0.010 to 0.044 (P =.011). Intratumor
      transgene mRNA was identified in 43% of assessable patients. CONCLUSION:
      Intratumoral injection with Adp53 in combination with cisplatin is well
      tolerated, and there is evidence of clinical activity.

PMID- 10653877
TI  - Comparison of survival and quality of life in advanced non-small-cell lung cancer
      patients treated with two dose levels of paclitaxel combined with cisplatin
      versus etoposide with cisplatin: results of an Eastern Cooperative Oncology Group
      trial.
AB  - PURPOSE: Treatment with cisplatin-based chemotherapy provides a modest survival
      advantage over supportive care alone in advanced non-small-cell lung cancer
      (NSCLC). To determine whether a new agent, paclitaxel, would further improve
      survival in NSCLC, the Eastern Cooperative Oncology Group conducted a randomized
      trial comparing paclitaxel plus cisplatin to a standard chemotherapy regimen
      consisting of cisplatin and etoposide. PATIENTS AND METHODS: The study was
      carried out by a multi-institutional cooperative group in chemotherapy-naive
      stage IIIB to IV NSCLC patients randomized to receive paclitaxel plus cisplatin
      or etoposide plus cisplatin. Paclitaxel was administered at two different dose
      levels (135 mg/m(2) and 250 mg/m(2)), and etoposide was given at a dose of 100
      mg/m(2) daily on days 1 to 3. Each regimen was repeated every 21 days and each
      included cisplatin (75 mg/m(2)). RESULTS: The characteristics of the 599 patients
      were well-balanced across the three treatment groups. Superior survival was
      observed with the combined paclitaxel regimens (median survival time, 9.9 months;
      1-year survival rate, 38.9%) compared with etoposide plus cisplatin (median
      survival time, 7.6 months; 1-year survival rate, 31.8%; P =. 048). Comparing
      survival for the two dose levels of paclitaxel revealed no significant
      difference. The median survival duration for the stage IIIB subgroup was 7.9
      months for etoposide plus cisplatin patients versus 13.1 months for all
      paclitaxel patients (P =.152). For the stage IV subgroup, the median survival
      time for etoposide plus cisplatin was 7.6 months compared with 8.9 months for
      paclitaxel (P =.246). With the exceptions of increased granulocytopenia on the
      low-dose paclitaxel regimen and increased myalgias, neurotoxicity, and, possibly,
      increased treatment-related cardiac events with high-dose paclitaxel, toxicity
      was similar across all three arms. Quality of life (QOL) declined significantly
      over the 6 months. However, QOL scores were not significantly different among the
      regimens. CONCLUSION: As a result of these observations, paclitaxel (135 mg/m(2))
      combined with cisplatin has replaced etoposide plus cisplatin as the reference
      regimen in our recently completed phase III trial.

PMID- 10653878
TI  - Overexpression of Her-2 in patients with poorly differentiated carcinoma or
      poorly differentiated adenocarcinoma of unknown primary site.
AB  - PURPOSE: To determine the frequency of Her-2 overexpression in patients with
      poorly differentiated carcinoma or poorly differentiated adenocarcinoma of
      unknown primary site. PATIENTS AND METHODS: Tumor specimens from 100 patients
      with poorly differentiated carcinoma or poorly differentiated adenocarcinoma were
      stained for the Her-2 protein using the Dako immunohistochemical method. Clinical
      and pathologic characteristics of patients with and without Her-2 overexpression
      were compared. RESULTS: Staining for Her-2 overexpression was successful in 94 of
      100 patients. Ten (11%) of 94 tumor specimens overexpressed Her-2. Eight of 10
      overexpressors had poorly differentiated adenocarcinoma, and all overexpressors
      had predominant tumor location above the diaphragm, usually in the mediastinum or
      lungs. CONCLUSION: Her-2 overexpression occurs in a minority of patients with
      poorly differentiated carcinoma/adenocarcinoma of unknown primary site. Because
      most overexpressors had poorly differentiated adenocarcinoma, further evaluation
      of patients with adenocarcinoma of unknown primary site is necessary to determine
      the frequency of Her-2 overexpression in this common subgroup. Evaluation of the
      efficacy of trastuzumab in Her-2 overexpressors with carcinoma of unknown primary
      site is indicated.

PMID- 10653879
TI  - Alterations of chromosome arms 1p and 19q as predictors of survival in
      oligodendrogliomas, astrocytomas, and mixed oligoastrocytomas.
AB  - PURPOSE: A recent report suggests that alterations of chromosome arms 1p and 19q
      are associated with chemotherapeutic response and overall survival in anaplastic
      oligodendroglioma patients treated with procarbazine, lomustine, and vincristine
      chemotherapy. We set out to further clarify the diagnostic and prognostic
      implications of these alterations in a broader set of diffuse gliomas, including
      astrocytic neoplasms and low-grade oligodendrogliomas. PATIENTS AND METHODS:
      Fluorescence in situ hybridization (FISH) signals from DNA probes mapping to 1p
      and 19q common deletion regions were enumerated in 162 diffuse gliomas (79
      astrocytomas, 52 oligodendrogliomas, and 31 mixed oligoastrocytomas), collected
      as part of an ongoing prospective investigation of CNS tumors. RESULTS: The
      oligodendroglial phenotype was highly associated with loss of 1p (P =.0002), loss
      of 19q (P <.0001), and combined loss of 1p and 19q (P <.0001). Combined loss of
      1p and 19q was identified as a univariate predictor of prolonged overall survival
      among patients with pure oligodendroglioma (log-rank, P =.03) and remained a
      significant predictor after adjusting for the effects of patient age and tumor
      grade (P <.01). This favorable association was not evident in patients with
      astrocytoma or mixed oligoastrocytoma. CONCLUSION: Combined loss of 1p and 19q is
      a statistically significant predictor of prolonged survival in patients with pure
      oligodendroglioma, independent of tumor grade. Given the lack of this association
      in patients with astrocytic neoplasms and the previously demonstrated
      chemosensitivity of oligodendrogliomas, a combined approach of histologic and
      genotypic assessment could potentially improve existing strategies for patient
      stratification and management.

PMID- 10653880
TI  - Cognitive function as a predictor of survival in patients with recurrent
      malignant glioma.
AB  - PURPOSE: To determine the contribution of cognitive function in predicting the
      survival of patients with recurrent malignant brain tumors. PATIENTS AND METHODS:
      A total of 80 patients with recurrent glioblastoma multiforme or anaplastic
      astrocytoma were seen for baseline evaluations before beginning a phase I or
      phase II clinical trial. Each patient received a battery of nine brief tests
      measuring cognitive function, ability to perform activities of daily living
      (ADLs), and quality of life (QOL). Tests were given monthly after treatment was
      begun. RESULTS: Performance on a test of verbal memory was independently and
      strongly related to survival after accounting for age, Karnofsky performance
      status score, histology, and time since diagnosis. Models incorporating three of
      nine and all nine tests in the battery accounted for significantly more variance
      in survival than did the clinical variables alone. Measures of QOL and ADLs
      (bathing, feeding, and so on) were not independently related to survival,
      although they provide clinical information that is important for patient care.
      CONCLUSION: These results indicate that a multifaceted assessment of cognition,
      QOL, and patient function is practical for brain tumor patients in clinical
      trials and can provide information regarding the relative risks versus benefits
      of new treatment regimens that supplements the information from the usual
      clinical variables.

PMID- 10653881
TI  - Surveillance for recurrent head and neck cancer using positron emission
      tomography.
AB  - PURPOSE: Earlier detection of head and neck cancer recurrence may improve
      survival. We evaluated the ability of [(18)F]fluorodeoxyglucose positron emission
      tomography (FDG-PET) to detect recurrence in a prospective trial using sequential
      PET scans. PATIENTS AND METHODS: Serial posttherapy FDG-PET was prospectively
      performed in 44 patients with stage III or IV head and neck cancer. PET was
      performed twice during the first posttreatment year (at 2 and 10 months after
      therapy) and thereafter as needed. After therapy, patients were grouped, based on
      tissue biopsies, into those who achieved a complete response (CR) and those who
      had residual disease (RD). Patients who achieved a CR were further grouped into
      those without evidence of disease and those who had recurrence by 1 year after
      completion of therapy. Disease status as determined by physical examination (PE),
      PET, and correlative imaging was compared. RESULTS: Eight patients were lost to
      follow-up and six had RD after therapy. Of the remaining 30 patients with a CR,
      16 had recurrence in the first year after therapy. Five of these 16 patients had
      recurrence detected by PET only, four by PET and correlative imaging only, five
      by PE and PET only, and two by PE, correlative imaging, and PET. Only PET
      detected all recurrences in the first year. PET performed better than correlative
      imaging (P =.013) or PE (P =.002) in the detection of recurrence. CONCLUSION: PET
      can detect head and neck tumor recurrence when it may be undetectable by other
      clinical methods. FDG-PET permits highly accurate detection of head and neck
      cancer recurrence in the posttherapy period.

PMID- 10653882
TI  - Phase I and pharmacologic study of irinotecan administered as a 96-hour infusion
      weekly to adult cancer patients.
AB  - PURPOSE: We conducted a phase I and pharmacologic study of a weekly 96-hour
      infusion of irinotecan to determine the maximum-tolerated dose, define the
      toxicity profile, and characterize the clinical pharmacology of irinotecan and
      its metabolites. PATIENTS AND METHODS: In 26 adult patients with solid tumors,
      the duration and dose rate of infusion were escalated in new patients until
      toxicity was observed. RESULTS: In 11 patients who were treated with irinotecan
      at 12.5 mg/m(2)/d for 4 days weekly for 2 of 3 weeks, dose-limiting grade 3
      diarrhea occurred in three patients and grade 3 thrombocytopenia occurred in two
      patients. The recommended phase II dose is 10 mg/m(2)/d for 4 days given weekly
      for 2 of 3 weeks. At this dose, the steady-state plasma concentration (Css) of
      total SN-38 (the active metabolite of irinotecan) was 6.42 +/- 1.10 nmol/L, and
      the Css of total irinotecan was 28.60 +/- 17.78 nmol/L. No patient experienced
      grade 3 or 4 neutropenia during any cycle. All other toxicities were mild to
      moderate. The systemic exposure to SN-38 relative to irinotecan was greater than
      anticipated, with a molar ratio of the area under the concentration curve (AUC)
      of SN-38 to irinotecan of 0.24 +/- 0.08. One objective response lasting 12 months
      in duration was observed in a patient with metastatic colon cancer. CONCLUSION:
      The recommended phase II dose of irinotecan of 10 mg/m(2)/d for 4 days weekly for
      2 of 3 weeks was extremely well tolerated. Further efficacy testing of this
      pharmacologic strategy of administering intermittent low doses of irinotecan is
      warranted.

PMID- 10653883
TI  - Research on complementary/alternative medicine for patients with breast cancer: a
      review of the biomedical literature.
AB  - PURPOSE: This article reviews English-language articles published in the
      biomedical literature from 1980 to 1997 that reported results of clinical
      research on complementary and alternative medical treatments (CAM) of interest to
      patients with breast cancer. METHODS: We searched 12 electronic databases and the
      bibliographies of the retrieved papers, review articles, and books on CAM and
      breast cancer. The retrieved articles were grouped by end point: breast cancer
      (eg, tumor size, survival), disease-related symptoms, side effects of treatment,
      and immune function. Within each end point, we organized the articles by modality
      and assessed study design, findings, and qualitative aspects. RESULTS: Of the
      more than 1,000 citations retrieved, 51 fit our criteria for review. Of the
      articles reviewed, 17 were randomized clinical trials; three of these were trials
      of cancer-directed interventions, two of which involved the same treatment
      (melatonin). Seven articles described observational studies, and the remainder
      were reports of phase I or II trials. Relatively few CAM modalities reportedly
      used by many breast cancer patients were mentioned in articles retrieved by this
      process. Most articles had shortcomings. CONCLUSION: Although many studies had
      encouraging results, none showed definitively that a CAM treatment altered
      disease progression in patients with breast cancer. Several modalities seemed to
      improve other outcomes (eg, acupuncture for nausea, pressure treatments for
      lymphedema). If CAM studies are well-founded, well-designed, and meticulously
      conducted, and their hypotheses, methods, and results are reported clearly and
      candidly, research in this controversial area should acquire credibility both in
      the scientific community and among advocates of unconventional medicine.

PMID- 10653884
TI  - Phase I clinical trial design in cancer drug development.
AB  - The past decade has seen the publication of a number of new proposals for the
      design of phase I trials of anticancer agents. The purpose of these proposals has
      been to address ethical concerns about treating excessive numbers of patients at
      subtherapeutic doses of a new agent and to increase the overall efficiency of the
      process while enhancing the precision of the recommended phase II dose. In early
      1998, a workshop of phase I investigators was held under the sponsorship of
      Bristol-Myers Squibb Pharmaceutical Research Institute (Wallingford, CT) to
      review the experience to date with novel phase I methodologies, with a particular
      focus on their efficiency and safety. This report summarizes the material
      presented. It was concluded that for phase I trials of antineoplastics
      (cytotoxics), which begin at 0.1 mouse-equivalent LD10 doses, evidence to date
      suggests that the historic approach of using a modified Fibonacci escalation and
      three patients per dose level is not necessary and is seldom used. One patient
      per dose level and more rapid escalation schemes, both empirically based and
      statistically based, are commonly used with apparent safety. There remain
      questions, however: Which of the dose escalation schemes is optimal? Are there
      alternatives to toxicity as a phase I end point, and will these end points be
      reliable in defining active doses? Answering these questions in a reasonable time
      frame will be important if new anticancer agents are not to suffer undue delays
      in phase I evaluation.

PMID- 10653885
TI  - Side effects of chemotherapy. Case 1. Radiation recall dermatitis from
      gemcitabine.

PMID- 10653886
TI  - Side effects of chemotherapy. Case 2. Radiation recall reaction induced by
      gemcitabine.

PMID- 10653887
TI  - Side effects of chemotherapy. Case 3. Acute interstitial pneumonitis related to
      gemcitabine.

PMID- 10653888
TI  - Doc, how much time do I have?

PMID- 10653889
TI  - Allogeneic transplantation for low-grade lymphoma: long-term follow-up.

PMID- 10653890
TI  - The intrinsic electrostatic potential and the intermediate ring of charge in the
      acetylcholine receptor channel.
AB  - A ring of aligned glutamate residues named the intermediate ring of charge
      surrounds the intracellular end of the acetylcholine receptor channel and
      dominates cation conduction (Imoto et al. 1988). Four of the five subunits in
      mouse-muscle acetylcholine receptor contribute a glutamate to the ring. These
      glutamates were mutated to glutamine or lysine, and combinations of mutant and
      native subunits, yielding net ring charges of -1 to -4, were expressed in Xenopus
      laevis oocytes. In all complexes, the alpha subunit contained a Cys substituted
      for alphaThr244, three residues away from the ring glutamate alphaGlu241. The
      rate constants for the reactions of alphaThr244Cys with the neutral 2
      hydroxyethyl-methanethiosulfonate, the positively charged 2-ammonioethyl
      methanethiosulfonate, and the doubly positively charged 2-ammonioethyl-2'
      ammonioethanethiosulfonate were determined from the rates of irreversible
      inhibition of the responses to acetylcholine. The reagents were added in the
      presence and absence of acetylcholine and at various transmembrane potentials,
      and the rate constants were extrapolated to zero transmembrane potential. The
      intrinsic electrostatic potential in the channel in the vicinity of the ring of
      charge was estimated from the ratios of the rate constants of differently charged
      reagents. In the acetylcholine-induced open state, this potential was -230 mV
      with four glutamates in the ring and increased linearly towards 0 mV by +57 mV
      for each negative charge removed from the ring. Thus, the intrinsic electrostatic
      potential in the narrow, intracellular end of the open channel is almost entirely
      due to the intermediate ring of charge and is strongly correlated with alkali
      metal-ion conductance through the channel. The intrinsic electrostatic potential
      in the closed state of the channel was more positive than in the open state at
      all values of the ring charge. These electrostatic properties were simulated by
      theoretical calculations based on a simplified model of the channel.

PMID- 10653891
TI  - Voltage dependence of slow inactivation in Shaker potassium channels results from
      changes in relative K(+) and Na(+) permeabilities.
AB  - Time constants of slow inactivation were investigated in NH(2)-terminal deleted
      Shaker potassium channels using macro-patch recordings from Xenopus oocytes. Slow
      inactivation is voltage insensitive in physiological solutions or in simple
      experimental solutions such as K(+)(o)//K(+)(i) or Na(+)(o)//K(+)(i). However,
      when [Na(+)](i) is increased while [K(+)](i) is reduced, voltage sensitivity
      appears in the slow inactivation rates at positive potentials. In such solutions,
      the I-V curves show a region of negative slope conductance between approximately
      0 and +60 mV, with strongly increased outward current at more positive voltages,
      yielding an N-shaped curvature. These changes in peak outward currents are
      associated with marked changes in the dominant slow inactivation time constant
      from approximately 1.5 s at potentials less than approximately +60 mV to
      approximately 30 ms at more than +150 mV. Since slow inactivation in Shaker
      channels is extremely sensitive to the concentrations and species of permeant
      ions, more rapid entry into slow inactivated state(s) might indicate decreased
      K(+) permeation and increased Na(+) permeation at positive potentials. However,
      the N-shaped I-V curve becomes fully developed before the onset of significant
      slow inactivation, indicating that this N-shaped I-V does not arise from
      permeability changes associated with entry into slow inactivated states. Thus,
      changes in the relative contributions of K(+) and Na(+) ions to outward currents
      could arise either: (a) from depletions of [K(+)](i) sufficient to permit
      increased Na(+) permeation, or (b) from voltage-dependent changes in K(+) and
      Na(+) permeabilities. Our results rule out the first of these mechanisms.
      Furthermore, effects of changing [K(+)](i) and [K(+)](o) on ramp I-V waveforms
      suggest that applied potential directly affects relative permeation by K(+) and
      Na(+) ions. Therefore, we conclude that the voltage sensitivity of slow
      inactivation rates arises indirectly as a result of voltage-dependent changes in
      the ion occupancy of these channels, and demonstrate that simple barrier models
      can predict such voltage-dependent changes in relative permeabilities.

PMID- 10653893
TI  - The spark and its ember: separately gated local components of Ca(2+) release in
      skeletal muscle.
AB  - Amplitude, spatial width, and rise time of Ca(2+) sparks were compared in frog
      fast-twitch muscle, in three conditions that alter activation of release channels
      by [Ca(2+)]. A total of approximately 17,000 sparks from 30 cells were evaluated.
      In cells under voltage clamp, caffeine (0.5 or 1 mM) increased average spark
      width by 28%, rise time by 18%, and amplitude by 7%. Increases in width were
      significant even among events of the same rise time. Spontaneous events recorded
      in permeabilized fibers with low internal [Mg(2+)] (0.4 mM), had width and rise
      times greater than in reference, and not significantly different than those in
      caffeine. The spark average in reference rides on a continuous fluorescence
      "ridge" and is continued by an "ember," a prolongation of width approximately 1
      microm and amplitude <0.2, vanishing in approximately 100 ms. Ridge and ember
      were absent in caffeine and in permeabilized cells. Exposure of voltage-clamped
      cells to high internal [Mg(2+)] (7 mM) had effects opposite to caffeine, reducing
      spark width by 26% and amplitude by 27%. In high [Mg(2+)], the ember was visible
      in individual sparks as a prolongation of variable duration and amplitude up to
      1.2. Based on simulations and calculation of Ca(2+) release flux from averaged
      sparks, the increase in spark width caused by caffeine was interpreted as
      evidence of an increase in radius of the release source-presumably by recruitment
      of additional channels. Conversely, spark narrowing suggests loss of contributing
      channels in high Mg(2+). Therefore, these changes in spark width at constant rise
      times are evidence of a multichannel origin of sparks. Because ridge and ember
      were reduced by promoters of Ca(2+)-dependent activation (caffeine, low [Mg(2+)])
      and became more visible in the presence of its inhibitors, they are probably
      manifestations of Ca(2+) release directly operated by voltage sensors.

PMID- 10653892
TI  - Voltage-dependent structural interactions in the Shaker K(+) channel.
AB  - Using a strategy related to intragenic suppression, we previously obtained
      evidence for structural interactions in the voltage sensor of Shaker K(+)
      channels between residues E283 in S2 and R368 and R371 in S4 (Tiwari-Woodruff,
      S.K., C.T. Schulteis, A.F. Mock, and D. M. Papazian. 1997. Biophys. J. 72:1489
      1500). Because R368 and R371 are involved in the conformational changes that
      accompany voltage-dependent activation, we tested the hypothesis that these S4
      residues interact with E283 in S2 in a subset of the conformational states that
      make up the activation pathway in Shaker channels. First, the location of residue
      283 at hyperpolarized and depolarized potentials was inferred by substituting a
      cysteine at that position and determining its reactivity with hydrophilic,
      sulfhydryl-specific probes. The results indicate that position 283 reacts with
      extracellularly applied sulfhydryl reagents with similar rates at both
      hyperpolarized and depolarized potentials. We conclude that E283 is located near
      the extracellular surface of the protein in both resting and activated
      conformations. Second, we studied the functional phenotypes of double charge
      reversal mutations between positions 283 and 368 and between 283 and 371 to gain
      insight into the conformations in which these positions approach each other most
      closely. We found that combining charge reversal mutations at positions 283 and
      371 stabilized an activated conformation of the channel, and dramatically slowed
      transitions into and out of this state. In contrast, charge reversal mutations at
      positions 283 and 368 stabilized a closed conformation, which by virtue of the
      inferred position of 368 corresponds to a partially activated (intermediate)
      closed conformation. From these results, we propose a preliminary model for the
      rearrangement of structural interactions of the voltage sensor during activation
      of Shaker K(+) channels.

PMID- 10653894
TI  - The noncompetitive inhibitor WW781 senses changes in erythrocyte anion exchanger
      (AE1) transport site conformation and substrate binding.
AB  - WW781 binds reversibly to red blood cell AE1 and inhibits anion exchange by a two
      step mechanism, in which an initial complex (complex 1) is rapidly formed, and
      then there is a slower equilibration to form a second complex (complex 2) with a
      lower free energy. According to the ping-pong kinetic model, AE1 can exist in
      forms with the anion transport site facing either inward or outward, and the
      transition between these forms is greatly facilitated by binding of a
      transportable substrate such as Cl(-). Both the rapid initial binding of WW781
      and the formation of complex 2 are strongly affected by the conformation of AE1,
      such that the forms with the transport site facing outward have higher affinity
      than those with the transport site facing inward. In addition, binding of Cl(-)
      seems to raise the free energy of complex 2 relative to complex 1, thereby
      reducing the equilibrium binding affinity, but Cl(-) does not compete directly
      with WW781. The WW781 binding site, therefore, reveals a part of the AE1
      structure that is sensitive to Cl(-) binding and to transport site orientation,
      in addition to the disulfonic stilbene binding site. The relationship of the
      inhibitory potency of WW781 under different conditions to the affinities for the
      different forms of AE1 provides information on the possible asymmetric
      distributions of unloaded and Cl(-)-loaded transport sites that are consistent
      with the ping-pong model, and supports the conclusion from flux and nuclear
      magnetic resonance data that both the unloaded and Cl(-)-loaded sites are very
      asymmetrically distributed, with far more sites facing the cytoplasm than the
      outside medium. This asymmetry, together with the ability of WW781 to recruit
      toward the forms with outward-facing sites, implies that WW781 may be useful for
      changing the conformation of AE1 in studies of structure-function relationships.

PMID- 10653895
TI  - Differential occurrence of reluctant openings in G-protein-inhibited N- and P/Q
      type calcium channels.
AB  - Voltage-dependent inhibition of N- and P/Q-type calcium channels by G proteins is
      crucial for presynaptic inhibition of neurotransmitter release, and may
      contribute importantly to short-term synaptic plasticity. Such calcium-channel
      modulation could thereby impact significantly the neuro-computational repertoire
      of neural networks. The differential modulation of N and P/Q channels could even
      further enrich their impact upon synaptic tuning. Here, we performed in-depth
      comparison of the G-protein inhibition of recombinant N and P/Q channels,
      expressed in HEK 293 cells with the m2 muscarinic receptor. While both channel
      types display classic features of G-protein modulation (kinetic slowing of
      activation, prepulse facilitation, and voltage dependence of inhibition), we
      confirmed previously reported quantitative differences, with N channels
      displaying stronger inhibition and greater relief of inhibition by prepulses. A
      more fundamental, qualitative difference in the modulation of these two channels
      was revealed by a modified tail-activation paradigm, as well as by a novel
      "slope" analysis method comparing time courses of slow activation and prepulse
      facilitation. The stark contrast in modulatory behavior can be understood within
      the context of the "willing-reluctant" model, in which binding of G-protein
      betagamma subunits to channels induces a reluctant mode of gating, where stronger
      depolarization is required for opening. Our experiments suggest that only N
      channels could be opened in the reluctant mode, at voltages normally spanned by
      neuronal action potentials. By contrast, P/Q channels appear to remain closed,
      especially over these physiological voltages. Further, the differential
      occurrence of reluctant openings is not explained by differences in the rate of G
      protein unbinding from the two channels. These two scenarios predict very
      different effects of G-protein inhibition on the waveform of Ca(2+) entry during
      action potentials, with potentially important consequences for the timing and
      efficacy of synaptic transmission.

PMID- 10653897
TI  - Deletion of the S3-S4 linker in the Shaker potassium channel reveals two
      quenching groups near the outside of S4.
AB  - When attached outside the voltage-sensing S4 segment of the Shaker potassium
      channel, the fluorescent probe tetramethylrhodamine (TMRM) undergoes voltage
      dependent fluorescence changes (DeltaF) due to differential interaction with a pH
      titratable external protein-lined vestibule (Cha, A., and F. Bezanilla. 1998. J.
      Gen. Physiol. 112:391-408.). We attached TMRM at the same sites [corresponding to
      M356C and A359C in the wild-type (wt) channel] in a deletion mutant of Shaker
      where all but the five amino acids closest to S4 had been removed from the S3-S4
      linker. In the deletion mutant, the maximal DeltaF/F seen was diminished 10-fold,
      and the DeltaF at M356C became pH independent, suggesting that the protein-lined
      vestibule is made up in large part by the S3-S4 linker. The residual DeltaF
      showed that the probe still interacted with two putative quenching groups near
      the S4 segment. One group was detected by M356C-TMRM (located outside of S3 in
      the deletion mutant) and reported on deactivation gating charge movement when
      applying hyperpolarizing voltage steps from a holding potential of 0 mV. During
      activating voltage steps from a holding potential of -90 mV, the fluorescence
      lagged considerably behind the movement of gating charge over a range of
      potentials. Another putative quenching group was seen by probes attached closer
      to the S4 and caused a DeltaF at extreme hyperpolarizations (more negative than 
      90 mV) only. A signal from the interaction with this group in the wt S3-S4 linker
      channel (at L361C) correlated with gating charge moving in the hyperpolarized
      part of the Q-V curve. Probe attached at A359C in the deletion mutant and at
      L361C in wt channel showed a biphasic DeltaF as the probe oscillated between the
      two groups, revealing that there is a transient state of the voltage sensor in
      between, where the probe has maximal fluorescence. We conclude that the voltage
      sensor undergoes two distinct conformational changes as seen from probes attached
      outside the S4 segment.

PMID- 10653898
TI  - [Refined chromosome assignment of human novel H-RalGDS gene on chromosome 9q34.1
      by using radiation hybrid genebridge 4 panel].
AB  - OBJECTIVE: Refined chromosome assignment of a novel Ras-related H-RalGDS gene
      (the human homology of rat RalGDS, Ral guanine nucleotide dissociation stimulator
      recently cloned and characterized by our laboratory) by using human/rodent
      radiation somatic cell hybrid panel GB4. METHODS: According to the sequence of
      the 3'-untranslated region of H-RalGDS cDNA, forward and reverse primers were
      designed and used to amplify the human/rodent somatic radiation hybrid Genebridge
      4 panel. The PCR result of each cell line of the panel was scored in a certain
      way and put into the related internet site of WI/MIT Radiation Hybrid Mapper for
      RH mapping and comprehensive analysis. RESULTS: The H-RalGDS gene was
      successfully localized to the framework of chromosome 9. After referring to
      literature and further integrated mapping analysis of the physical, genetic
      linkage and cytological mappings, the gene was assigned precisely between the
      markers SURF5 and RPL7A which had already been assigned to human chromosome
      9q34.1. CONCLUSION: The localization of H-RalGDS not only contributed much to the
      construction of refined gene map and cytogenetic map within the region of
      chromosome 9q34, but also made clear that RH mapping of human novel genes is a
      simple, convenient and reliable method which can provide even more genetic
      information of genes within chromosomal regions.

PMID- 10653896
TI  - Modulation of the Shaker K(+) channel gating kinetics by the S3-S4 linker.
AB  - In Shaker K(+) channels depolarization displaces outwardly the positively charged
      residues of the S4 segment. The amount of this displacement is unknown, but large
      movements of the S4 segment should be constrained by the length and flexibility
      of the S3-S4 linker. To investigate the role of the S3-S4 linker in the
      ShakerH4Delta(6-46) (ShakerDelta) K(+) channel activation, we constructed S3-S4
      linker deletion mutants. Using macropatches of Xenopus oocytes, we tested three
      constructs: a deletion mutant with no linker (0 aa linker), a mutant containing a
      linker 5 amino acids in length, and a 10 amino acid linker mutant. Each of the
      three mutants tested yielded robust K(+) currents. The half-activation voltage
      was shifted to the right along the voltage axis, and the shift was +45 mV in the
      case of the 0 aa linker channel. In the 0 aa linker, mutant deactivation kinetics
      were sixfold slower than in ShakerDelta. The apparent number of gating charges
      was 12.6+/-0.6 e(o) in ShakerDelta, 12.7+/-0.5 in 10 aa linker, and 12.3+/-0.9 in
      5 aa linker channels, but it was only 5.6+/-0.3 e(o) in the 0 aa linker mutant
      channel. The maximum probability of opening (P(o)(max)) as measured using noise
      analysis was not altered by the linker deletions. Activation kinetics were most
      affected by linker deletions; at 0 mV, the 5 and 0 aa linker channels' activation
      time constants were 89x and 45x slower than that of the ShakerDelta K(+) channel,
      respectively. The initial lag of ionic currents when the prepulse was varied from
      -130 to -60 mV was 0.5, 14, and 2 ms for the 10, 5, and 0 aa linker mutant
      channels, respectively. These results suggest that: (a) the S4 segment moves only
      a short distance during activation since an S3-S4 linker consisting of only 5
      amino acid residues allows for the total charge displacement to occur, and (b)
      the length of the S3-S4 linker plays an important role in setting ShakerDelta
      channel activation and deactivation kinetics.

PMID- 10653899
TI  - [Exclusive mapping on polydactyly with markers on chromosome 7 and 2 in a Chinese
      kindred].
AB  - OBJECTIVE: This study was aimed at mapping polydactyly related genes in a Chinese
      kindred. METHODS: Linkage analysis was performed using 7 markers on chromosome 7
      and 1 marker on chromosome 2. RESULTS: Pairwise linkage analysis showed no
      linkage between the markers and polydactyly related gene in the kindred.
      CONCLUSION: The polydactyly related gene in this kindred may be located on a new
      locus.

PMID- 10653900
TI  - [Molecular cytogenetics study in a case with unbalanced chromosome
      translocation].
AB  - OBJECTIVE: To analyze the chromosome structural aberration in a case of
      unbalanced chromosome translocation by fluorescence in situ hybridization
      technique. METHODS: The 1,18 whole chromosome specific painting probe were used
      to confirm chromosome abnormality suggested by high resolution G-banding
      examination. RESULTS: An unbalanced translocation t(1;18)(q42;q22) was detected
      in the patient, which caused partial trisomy of 1q42-qter and partial monosomy of
      18q22-qter. CONCLUSION: The identified translocation suggested a potential site
      for congenital heart disease.

PMID- 10653901
TI  - [The promoter sequence of human nitric-oxide-synthase gene: functional study].
AB  - OBJECTIVE: Endothelial nitric oxide synthase (ecNOS) catalyzes the NADPH and O(2)
      to nitric oxide(NO). This study aimed at the regulation mechanism of the
      transcription of ecNOS gene. METHODS: The promoter regions of ecNOS gene were
      analyzed by gel mobility shift assay and DNase I footprinting assay using nuclear
      extract from endothelial cells. RESULTS: Three regions were protected by
      protein/transcription-factors. One of these regions, (-106 to -88) was
      demonstrated to be SP1 binding consensus sequence which was extremely rich in GC
      content. The other two regions, (-79 to -64) and (-58 to -44), covered the CTCF
      binding regions, but showed various binding modes. CONCLUSION: The protected
      regions are bound either with aggregated SP1/SP1- like proteins or with new
      transcription factor which have not been reported yet.

PMID- 10653902
TI  - [Analysis of chromosomal karyotypes in 300 fetal blood samples during the second
      and third trimesters of gestation].
AB  - OBJECTIVE: To analyze the fetal chromosomal karyotypes from the blood samples
      obtained by cordocenteses during the second and third trimesters, and to
      investigate the types of chromosomal abnormalities, as well as the relationship
      between the abnormal karyotypes and the indications of prenatal diagnosis.
      METHODS: Cordocenteses were performed in 300 pregnant women with different
      indications for prenatal diagnosis during the 18 to 38 gestational weeks, and
      fetal chromosomal karyotypes were examined. RESULTS: Twenty three chromosomal
      abnormalities(7.7%) were checked out. In the second trimester, there were 15
      abnormalities in 174 samples(8. 6%); whereas in the third trimester, it was 8 out
      of 126(6.3%), P=0. 77. Trisomy, the leading abnormality, consisted of
      60.9%(14/23) of all abnormalities and 9 out of 14 were trisomy 21, which was 39.
      1%(9/23). In those aged over 35 years, trisomy 21 was detected in 5 of 92(5.4%),
      and in the age under 35 years, it was 4 out of 208(1. 9%), P=0.26. Thirty three
      women had the history of giving a birth of trisomy 21 previously, this time,
      however, no one was recurrent. Highest chromosomal aberration rate, 26.3%(5/19),
      was detected in the fetuses with intrauterine growth retardation(IUGR), and all
      were trisomy. Balanced translocation was found in 5 fetuses (1 associated with
      Robertsonian translocation), which was 21.7%(5/23). CONCLUSION: During the second
      and third trimesters, the rate of chromosomal abnormality is 7.7% in those
      fetuses who have maternal indications for prenatal diagnosis. trisomy, especially
      trisomy 21, is the most common abnormal karyotype found in these periods and in
      advanced maternal age, as well as in severe IUGR.

PMID- 10653903
TI  - [Delineation of 6q deletions in breast carcinoma cell lines by fluorescence in
      situ hybridization].
AB  - OBJECTIVE: To detect and delineate 6q deletions in ten breast carcinoma cell
      lines. METHODS: Fluorescence in situ hybridization(FISH) with 37 YAC probes
      hybridizing from 6q12 to 6q27 and a centromeric probe of chromosome 6 as internal
      control. RESULTS: In five cell lines, large deletions extending from 6q12 to 6q27
      were found, while a small deletion involving 6q25-6q27 was identified in one cell
      line. In two cell lines containing different cell populations, deletions of 6q
      occurred in cells with polysomy 6, but not in cells with disomy 6. In addition,
      an overpresentation of 6q21-q22.2 was detected in one cell line. CONCLUSION: 6q25
      q27 seems to be the commonly deleted region in breast cancers and 6q deletions
      might be secondary changes.

PMID- 10653904
TI  - [DNA polymorphism of Pvu II site in the lipoprotein lipase gene in patients with
      type 2 diabetes mellitus].
AB  - OBJECTIVE: To study the relationship between the lipoprotein lipase(LPL) gene and
      type 2 diabetes mellitus (DM) and its lipid metabolism. METHODS: PCR-RFLP method
      was used to determine the DNA polymorphism of 6th intron at LPL gene in 127 DM
      patients and 125 controls. RESULTS: The allele frequencies in case and control
      groups were 69.3%, 63.6% for "P+" and 30.7%, 36.4% for "P-", respectively; the
      frequencies of genotypes were 48.0%, 44.8% for P+/P+, 42.5%, 37. 6% for P+/P- and
      9.45%, 17.6% for P-/P-, respectively. There was no significant difference in
      frequencies of genotypes or alleles between the two groups. The LPL Pvu II
      polymorphism in Chinese population was similar to that in Japanese population,
      and was different from that in European and American population. CONCLUSION: The
      LPL-Pvu II-RFLP in Chinese population is not significantly associated with type 2
      diabetes mellitus. The significant difference of Pvu II-RFLP among various races
      was observed.

PMID- 10653905
TI  - [The relationship of polymorphism of angiotensinogen and angiotensin converting
      enzyme with essential hypertension].
AB  - OBJECTIVE: In order to investigate the candidate genes for essential
      hypertension(EH), the authors determined the frequencies of M235T allele
      variation in exon 2 of angiotensinogen(AGT) gene and angiotensin converting
      enzyme (ACE) gene in 95 normotensives and 87 hypertensives in Chinese. METHODS:
      Polymerase chain reaction combined with restriction enzyme digestion was used to
      detect the variation AGT gene while PCR was used to determine ACE gene
      polymorphism. RESULTS: T235 allele frequency was significantly higher in
      hypertensive patients than in controls (0.45 vs 0.33, P<0. 05) and it was
      noticeably higher in male hypertensives. The frequency of ACE D allele in the EH
      patients with family history was higher than that in controls(0.59 vs
      0.41,P<0.05). CONCLUSION: The variation of AGT gene was involved in the
      pathogenesis of hypertension, especially in male. The ACE D allele was associated
      with EH with family history.

PMID- 10653906
TI  - [Induction of apoptosis in ovarian carcinoma cells by HSP70 antisense
      oligodeoxynucleotides].
AB  - OBJECTIVE: To investigate the role of HSP70 in the proliferation and survival of
      ovarian carcinoma cells by inhibiting HSP70 expression with HSP70 antisense
      oligomer. METHODS: Morphological changes of apoptotic cells were investigated by
      light microscopy. DNA fragmentation was analysed by agarose gel electrophoresis.
      Kinetics of induction of apoptosis and cell cycle were analysed by flow
      cytometry. RESULTS: The HSP70 antisense oligomer treated ovarian carcinoma cells
      showed apparent inhibition of proliferation and characteristic morphological
      changes of apoptosis. Also, a ladder-like pattern of DNA fragments was
      demonstrated on agarose gel electrophoresis. HSP70 antisense-oligomer induced
      apoptosis of ovarian carcinoma cells mainly in G(1)/S phase in 8.3% to 41% at 1
      to 20micromol/L. The apoptosis-inducting effect of HSP70 antisense oligomer was
      in a dose- and time-dependent manner. CONCLUSION: HSP70 antisense oligomer could
      not only inhibit the proliferation but also induce the apoptosis in ovarian
      carcinoma cells.

PMID- 10653907
TI  - [Correlation of inactivation of CDKN2/p16 gene by methylation and lung cancers].
AB  - OBJECTIVE: To study the relationship between methylation state of CDKN2/p16 gene
      and lung cancers. METHODS: Genomic DNA was digested with methylation-sensitive
      enzymes and Southern blotting was used to analyses the methylation state of
      CDKN2/p16 gene in 89 cases of lung cancer. RESULTS: Twenty-one out of 89 lung
      cancers(23.6%) shown methylation of CDKN2/p16 gene, and 17 of them occurred in 42
      P16 negative cases with a rate of 40.5%(17/42). CONCLUSION: Methylation of
      CDKN2/p16 gene 5' CpG island is probably an important mechanism of gene
      inactivation; it may take part in the onset and process of lung cancer.

PMID- 10653908
TI  - [Loss of imprinting of insulin-like growth factor II gene in acute myeloid
      leukemia].
AB  - OBJECTIVE: To investigate the status of insulin- like growth factor-2(IGF-2) gene
      imprinting in acute myeloid leukemia(AML). METHODS: Selection of heterozygous
      cases for Apa I polymorphism within exon 9 of IGF-2 gene and further analysis of
      loss of imprinting(LOI) were done in 26 AML patients by polymerase chain
      reaction(PCR), reverse transcription PCR (RT-PCR) and restriction fragment length
      polymorphism(RFLP) technique. RESULTS: Eleven cases of AML patients were
      identified as heterozygous for IGF-2(11/26); 8 heterozygous patients showed
      biallelic expression of IGF-2, indicating loss of IGF-2 imprinting. CONCLUSION:
      The frequent LOI of IGF-2 may play a role in the development of acute myeloid
      leukemia.

PMID- 10653909
TI  - [Chinese Han population data obtained from fluorescently detected STR loci
      vWA31A, TH01, F13A01, FES, TPOX and CSF1PO].
AB  - OBJECTIVE: This paper was designed to evaluate 6 short tandem repeats(STR) loci
      for their use in forensic personal identification. METHODS: The allele
      frequencies and genotype frequencies at 6 tetranucleotide STR loci were
      determined in a sample of 132 unrelated individuals from a Chinese population of
      Han nationality in Guangzhou. The PCR products were analysed on 4% denaturing
      PAGE and detected using fluorescently labeled primers in an automated 377
      sequencer(PE). The resultant allele frequencies were compared with other
      population or race databases. RESULTS: All the 6 loci (vWA31A, TH01, F13A01,FES,
      TPOX, CSF1PO) met Hardy-Weinberg equilibrium. No random association of alleles
      among the 6 loci was noted. Except locus vWA31A, the observed heterozygosities at
      other 5 loci were significantly lower than those reported in Caucasian and Black
      population studies. The calculated DP=0.99999,PE=0.9708,pM=1.059 times 10(-5).
      CONCLUSION: The data obtained can be used in human identity and paternity
      testing, and in other genetic researches and population investigation.

PMID- 10653910
TI  - [Quick RNA extraction from specified morphological region in frozen sections and
      its RT-PCR application].
AB  - OBJECTIVE: To establish a method for quick RNA extraction from specified
      histological region in frozen sections so as to avoid cross RNA contamination
      among different types of cells/tissues and to achieve specific RT-PCR
      amplification. METHODS: Prepare serial frozen sections 5microm in thickness for
      histological and immunocytochemical examination. Based on the results, make one
      or two pieces of 20 microm section and select a specified region for quick RNA
      extraction and RT-PCR analysis. RESULTS: RNA extraction can be finished within an
      hour and the data of RT-PCR obtained within 6 hours. Besides the high
      performance, this method can efficiently exclude pseudo positive or pseudo
      negative results caused by inter-cellular RNA contamination. CONCLUSION: This
      method is an important complement to the current techniques for RNA extraction
      and RT-PCR.

PMID- 10653911
TI  - [A convenient method of recovering DNA from agarose electrophoretic gels].
AB  - OBJECTIVE: Construct a simple unit to efficiently recover DNA from agarose
      electrophoretic gels. METHODS: With the use of 1.5ml microcentrifuge tube, 1 ml
      tip, nylon web membrane and dialysis membrane, the authors made a clever yet
      simple DNA recovering gadget, tested this gadget by using it to recover specific
      electrophoretic DNA bands of lambdaDNA/EcoR I+Hind III markers, and then examined
      the recovery ratio through agarose gel electrophoresis. A restriction enzyme's
      digestion product was taken as another sample to test the recovered product's
      quality by means of DNA ligation and subsequent agarose gel electrophoresis.
      RESULTS: Under such electroelution conditions as with an electrophoretic buffer
      of 1xTBE, a voltage grade of 3V/cm and an elution time of 0.5h, the final
      recovery ratio of 564bp DNA was up to 80%, and that of 21227bp DNA was about 30%.
      Judged either by the agarose gel electrophoresis performance or by the DNA
      ligation result, the recovered DNA proved to be of excellent quality. CONCLUSION:
      It is an easy, quick, efficient and cheap method of recovering DNA from agarose
      electrophoretic gels. The recovering unit can be a permanent one, provided that
      the dialysis membrane in this unit is changed for recovering different DNA
      samples.

PMID- 10653912
TI  - [Detection of Prader-Willi syndrome by methylation-specific PCR].
AB  - OBJECTIVE: Using a faster and more efficient method to diagnose Prader-Willi
      syndrome(PWS). METHODS: Differential DNA methylation at several sites in the PWS
      critical region where the maternal homologue is unmethylated and
      transcriptionally active. Methylation-specific PCR(MSPCR) is based on sodium
      bisulfite treatment of DNA, which converts unmethylated but not methylated
      cytosine residues to uracil, and PCR primers specific for the maternal and the
      paternal allele. Methylation analysis by Southern blot is made to validate the
      MSPCR result. RESULTS: Bisulfite-modified DNA from PWS patients amplified only
      with methylated allele-specific primer pair showed only maternal 174bp PCR
      product. MSPCR and PW71B methylation studies showed an abnormal pattern
      consistent with the clinical diagnosis of PWS. Untreated DNA does not produce a
      PCR product. CONCLUSION: MSPCR can be used to detect all presently testable
      causes of PWS (deletion, uniparental disomy, and imprinting mutation) in an
      efficient first step for stepwise diagnostic testing, compared with either
      Southern blot analysis which is more timeconsuming, or fluorescence in situ
      hybridization(FISH) which can not detect uniparental disomy or imprinting
      mutation.

PMID- 10653913
TI  - Molecular evolution of the Newcastle disease virus matrix protein gene and
      phylogenetic relationships among the paramyxoviridae.
AB  - Matrix (M) gene sequences for recent field isolates and older reference Newcastle
      disease viruses (NDV) were examined to determine phylogenetic relationships and
      population trends among these viruses. Overall, the M gene has a majority of
      synonymous nucleotide sequence substitutions occurring among NDV isolates.
      However, several predicted amino acid changes in the M protein of specific NDV
      isolates have occurred that correlate to phylogenetic relationships. Nucleotide
      substitutions in these codons have a greater number of nonsynonymous base
      changes. The NDV isolates arising since the 1970s belong to a population of
      viruses that expanded worldwide at an exponential rate. These viruses may have
      their origins in free-living birds, are present worldwide, and continue to
      circulate causing disease in poultry. A specific NDV lineage composed of virulent
      isolates obtained in the US prior to 1970 appears to no longer exists among free
      living birds or commercial poultry. However, "vaccine-like" viruses are common in
      the US and continue to circulate among commercial poultry. Based on M protein
      amino acid sequences, NDV separates as a clade most closely related to
      morbilliviruses and not with their current designated category, the rubulaviruses
      among the Paramyxoviridae. Consequently, avian paramyxoviruses should have their
      own taxonomic subfamily among the Paramyxovirinae.

PMID- 10653914
TI  - Dynamics of dominance of a dipeptide insertion in reverse transcriptase of HIV-1
      from patients subjected to prolonged therapy.
AB  - A small proportion (0.8%) of individuals of a cohort of HIV-1 infected patients
      subjected to prolonged therapy with nucleoside analogues included a recently
      recognised dipeptide insertion in their RT (Ser-Ser or Ser-Gly between RT codons
      69 and 70). To study the dynamics of dominance of genomes with this genetic
      change, sequential HIV-1 isolates from two patients were analyzed with regard to
      consensus sequences and complexity of mutant spectra. The two patients displayed
      completely different, complex evolutionary patterns leading to temporary
      dominance of dipeptide insertions. In one patient, a virus very closely related
      to an ancestor virus from the same patient overtook the population at late times,
      displacing genomes encoding a Ser-Ser insertion. In another patient the
      sequential dominance of genomes with Ser-Ser insertion-->no insertion-->Ser-Gly
      insertion was observed. These three types of genomes coexisted in the mutant
      spectrum of one HIV-1 isolate. Complexity was also reflected in the shape of
      phylogenetic trees derived with genomes from the mutant spectrum at each time
      point. The results suggest that HIV-1 genomes encoding a dipeptide insertion
      between RT codons 69 and 70 do not show a clear selective advantage over other
      genomes lacking the insertion. Such an absence of a clear selective advantage
      will favor that such genomes encoding this RT insertion become dominant only in a
      transient fashion, and following disparate kinetics in different patients.

PMID- 10653915
TI  - Evidence for integration of Glyptapanteles indiensis polydnavirus DNA into the
      chromosome of Lymantria dispar in vitro.
AB  - Polydnaviruses replicate within calyx cells of the female ovaries of certain
      species of parasitic wasps and are required for the successful parasitization of
      lepidopteran hosts. These viruses, which have unusual double-stranded circular
      DNA segmented genomes, are integrated as proviruses into the genomes of their
      associated wasp hosts and are believed to be transmitted vertically through
      germline tissue. Here, by combined Southern hybridization, polymerase chain
      reaction (PCR) assays and viral sequence analyses we provide evidence that DNA
      originating from two distinct double-stranded circular segments of the
      polydnavirus genome from the braconid Glyptapanteles indiensis (GiPDV) integrates
      in vitro into the genome of cells derived from the natural host, Lymantria
      dispar. The G. indiensis polydnavirus DNA, as a result of its unique ability to
      be integrated in part into the chromosome of cells derived from its lepidopteran
      host, has potential to be developed as an in vitro cell transformation system.

PMID- 10653917
TI  - Characterization of antiviral activity of lactoferrin against hepatitis C virus
      infection in human cultured cells.
AB  - We recently found that bovine lactoferrin (bLF), a milk glycoprotein belonging to
      the iron transporter family, prevented hepatitis C virus (HCV) infection in human
      hepatocyte PH5CH8 cells, that are susceptible to HCV infection, and demonstrated
      that the anti-HCV activity of bLF was due to the interaction of bLF and HCV. In
      this study we further characterized the anti-HCV activity of bLF and the
      mechanism by which bLF prevents HCV infection. We found that bLF inhibited viral
      entry to the cells by interacting directly with HCV immediately after mixing of
      bLF and HCV inoculum. The anti-HCV activity of bLF was lost by heating at 65
      degrees C, and other milk proteins (mucin, beta-lactoglobulin and casein) did not
      prevent HCV infection, indicating that bLF prevented HCV infection in a rather
      specific manner. Furthermore, we found that bovine lactoferricin, a basic N
      terminal loop of bLF that is an important region for antibacterial activity, did
      not exhibit any anti-HCV activity, suggesting that some other region is involved
      in anti-HCV activity. We confirmed that prevention of HCV infection by bLF was a
      general phenomenon, because bLF inhibited HCV infection with all five inocula
      examined, and bLF inhibited HCV infection in human MT-2C T-cells, that were
      susceptible to HCV infection. In addition, infection with hepatitis G virus,
      which is distantly related to HCV, was prevented also by bLF. In conclusion,
      lactoferrin is a natural glycoprotein which effectively protects against HCV
      infection in hepatocytes and lymphocytes by neutralizing the virus.

PMID- 10653916
TI  - Inhibition of the bovine papillomavirus E2 protein activity by peptide nucleic
      acid.
AB  - The bovine papillomavirus type-1 E2 protein is the master regulator of the
      papillomavirus transcription and replication, the activity of which is regulated
      through sequence-specific DNA binding. Peptide nucleic acid (PNA) is a nucleic
      acid analogue, which associates with high affinity to complementary DNA, RNA or
      PNA, yielding in formation of stable complexes. The potential use of PNA as a
      sequence-specific inhibitor of the E2 protein activity is studied in this report.
      We demonstrate that replacement of one or both DNA strands with the complementary
      PNA reduced drastically the affinity of the BPV-1 E2 protein to its target site
      in the direct as well as in competitive binding as shown by in vitro gel-shift
      assays. We demonstrate that PNA could specifically bind to the double stranded E2
      binding site by forming the complex with DNA oligonucleotide. In addition, PNA
      was able to bind specifically to the E2 binding site within the supercoiled
      plasmid DNA. Such binding of PNA to the E2 binding site within the origin of
      replication specifically abolished the activity of the E2 protein in the
      initiation of DNA replication in vivo.

PMID- 10653918
TI  - Characterisation of PCV-2 isolates from Spain, Germany and France.
AB  - The new isolated circovirus variant PCV-2 is discussed to be the etiological
      agent of a new emerging swine disease with a variable morbidity and high
      lethality, postweaning multisystemic wasting syndrome (PMWS). PMWS has been
      diagnosed in North America and West Europe. Clinical signs include dyspnea, loss
      of weight, lymph node enlargement and lymphocyte depletion in lymphoid tissues.
      This report describes the characterisation of PCV-2 isolates from animals
      affected with PMWS from Germany, Spain and France. We could demonstrate the
      presence of circovirus by electron microscope, in situ hybridisation and PCR. PCR
      revealed incidence of PCV-2 in many tissues of one infected animal with the
      exception of heart and nervous system. The phylogenetic analysis of all PCV-2
      isolates yet published in the database, showed relationship of isolates from
      Spain, Germany and France, with three sequences from Canada determined recently
      and two isolates from Taiwan, while other North American sequences display a
      separate cluster. PCR screening of randomly collected organ samples from German
      pigs not affected with PMWS, revealed a rate of infection with PCV-1 of 5% and
      with PCV-2 of 26.8%, while blood samples showed a lower incidence.

PMID- 10653919
TI  - DNA sequencing and phylogenetic analysis of the protease gene of ovine adenovirus
      3 suggest that adenoviruses of sheep belong to two different genera.
AB  - Until now, the only published ovine adenovirus DNA sequence was the complete
      genome of ovine adenovirus isolate 287 (OAV287) which, compared to other
      mammalian adenoviruses, possesses strikingly unique genomic organisation and
      should properly be classified into a new adenovirus genus. The protease gene
      sequence of ovine adenovirus type 3 (OAdV-3) was determined and analysed. The
      results of phylogenetic analysis of the 205 residue long protein demonstrated
      that OAdV-3 belongs to the genus Mastadenovirus, and is surprisingly closely
      related to bovine adenovirus type 2. In spite of the common host origin, the
      evolutionary distance between OAdV-3 and OAV287 proved to be great suggesting
      that sheep, similarly to cattle and fowl, might be infected by distantly related
      adenoviruses belonging to different genera.

PMID- 10653920
TI  - Mapping target site selection for the non-specific nuclease activities of
      retroviral integrase.
AB  - To identify the parts of retroviral integrase that interact with its DNA
      substrates, we compared the patterns of target site usage by chimeric enzymes and
      protein fragments in assays that reveal integrase's non-specific nuclease
      activities. The central region of 12 chimeric proteins between the human
      immunodeficiency virus type 1 and visna virus integrases was found to be
      responsible for selecting non-viral target DNA sites when small alcohols provide
      the attacking nucleophilic OH group during non-specific alcoholysis assays.
      Testing deletion derivatives of the integrase protein in this assay, which has
      similarities to the DNA joining reaction that occurs during retroviral
      integration, defined a smaller central domain that is sufficient for activity.
      Thus, this core domain likely contains both the host DNA site and the nucleophile
      site. Surprisingly, the region of integrase responsible for selecting non-viral
      target DNA sites when the viral DNA end is the attacking nucleophile could not
      similarly be mapped with the standard oligonucleotide joining assay. We therefore
      tested the proteins in a more sensitive assay that displays preferred sites of
      viral DNA insertion in a plasmid DNA target. All 12 chimeras yielded novel
      patterns compared with the wild-type enzymes in this assay, although local
      insertion patterns indicated that the central domain plays an important role in
      target site selection. Together, these data suggest that other protein regions
      must be involved when the attacking nucleophilic group is provided by viral DNA.
      Because specific recognition of viral DNA ends was previously mapped to the
      central domain, two different regions of integrase must interact with retroviral
      DNA.

PMID- 10653921
TI  - Analysis of proteins encoded in the bipartite genome of a new type of parvo-like
      virus isolated from silkworm - structural protein with DNA polymerase motif.
AB  - Bombyx mori densonucleosis virus type 2 (BmDNV-2) is a small, spherical virus
      containing two complementary single-stranded linear DNA molecules (VD1, VD2).
      BmDNV-2 is a new type of virus with a unique, yet unspecified replication
      mechanism which is different from that of parvoviruses (Bando, H., Choi, H., Ito,
      Y., Nakagaki, M. , Kawase, S., 1992. Structural analysis on the single-stranded
      genomic DNAs of the virus newly isolated from silkworm: the DNA molecules share a
      common terminal sequence, Arch. Virol. 124, 187-193; Bando, H., Hayakawa, T.,
      Asano, S., Sahara, K., Nakagaki, M. , Iizuka, T., 1995. Analysis of the genetic
      information of a DNA segment of a new virus from silkworm, Arch. Virol., 140,
      1147-1155; Hayakawa, T., Asano, S., Sahara, K., Iizuka, T., Bando, H., 1997.
      Detection of replicative intermediate with closed terminus of Bombyx
      densonucleosis virus. Arch. Virol. 142, 1-7). Recent analyses on the genomic
      information of BmDNV-2 identified open reading frames which code for three
      tentative nonstructural proteins and four (VP1 to 4) of the six known structural
      proteins (Bando, H., Hayakawa, T., Asano, S., Sahara, K., Nakagaki, M., Iizuka,
      T., 1995. Analysis of the genetic information of a DNA segment of a new virus
      from silkworm, Arch. Virol., 140, 1147-1155; Nakagaki et al., in preparation). In
      this report we demonstrate that the two largest ORFs, VD1-ORF1 and VD2-ORF1, code
      for the two remaining structural proteins. In addition, computer-assisted
      analysis revealed that the structural protein encoded in VD1-ORF1 contains
      sequences conserved among various DNA polymerases, and showed an evolutionary
      relationship with the DNA polymerases involved in protein-primed replication.

PMID- 10653922
TI  - An accessory open reading frame (orf-x) of jaagsiekte sheep retrovirus is
      conserved between different virus isolates.
AB  - Jaagsiekte sheep retrovirus (JSRV) is the etiological agent of a contagious lung
      tumour of sheep known as sheep pulmonary adenomatosis (syn: ovine pulmonary
      carcinoma, jaagsiekte). JSRV exhibits a simple genetic organization,
      characteristic of the type D and type B retroviruses, with the canonical
      retroviral sequences gag, pro, pol and env encoding the structural proteins of
      the virion. An additional open reading frame (orf-x), of approximately 500 bp
      overlapping pol, is present in the only two complete sequences of JSRV published
      to date. Since very little information is available on the biology of JSRV it is
      important to establish if orf-x is conserved between different virus isolates. In
      this study we analysed the orf-x region of JSRV isolates collected from the
      United Kingdom, Italy, Spain and South Africa. In addition we also analysed the
      presence of orf-x in JSRV-related endogenous sequences (enJSRVs) present in the
      sheep genome. Orf-x was highly conserved in all the exogenous isolates (n=10) and
      in most of the endogenous sequences (n=8). Thus orf-x may be an accessory gene of
      JSRV and haves a biological function which might be advantageous to JSRV.
      Phenetic analysis conducted on the complete orf-x nucleotide sequences seems to
      highlight the presence of three distinct groups statistically well supported by
      bootstrapping: i) exogenous JSRV sequence from the UK; ii) exogenous JSRV
      sequences from Southern Europe and iii) the exogenous South African strain plus
      all the endogenous sequences analyzed and collected from Australia, Italy, UK and
      South Africa.

PMID- 10653923
TI  - Dyslipidemia and coronary artery disease.
AB  - Atherosclerotic vascular diseases are expected to remain the major cause of
      mortality and morbidity globally well into the 21st century. Preventive measures
      by lifestyle changes (diet, exercise, smoking cessation, prevention of obesity
      and diabetes) will play an important role in retarding the onset of these
      diseases. A strategy aimed at identifying high risk individuals - those with
      established coronary artery disease or other vascular diseases - will provide the
      most cost effective means of preventing cardiovascular events. The high risk
      strategy is aimed at identification of healthy subjects with multiple
      cardiovascular risk factors, identification of those with diabetes,
      identification of those with genetic lipoprotein disorders and initiation of
      treatment with medications if necessary. Categorical risk factors should be
      treated because of the lifetime increase in cardiovascular risk.

PMID- 10653924
TI  - Coronary artery disease and women: applying the guidelines for risk factor
      management.
AB  - Coronary artery disease (CAD) is the leading cause of death for women. In large
      part because of increased age at presentation and a greater frequency of
      concomitant morbidities, women who develop CAD have a poorer prognosis than do
      men. Although the long term outcome of revascularization procedures is good, the
      associated procedural morbidity and mortality in women is high. More emphasis
      should be placed on the primary and secondary prevention of CAD in women.
      Although women respond well to risk factor modification, including lipid-lowering
      therapies, recent data indicate that their awareness of risk factors and
      prevention strategies is poor. Physician risk factor assessment and adherence to
      current guideline recommendations are essential in preventing the development or
      progression of CAD in women.

PMID- 10653925
TI  - Medical therapy versus revascularization: the atorvastatin versus
      revascularization treatment AVERT trial.
AB  - Although previous studies have shown that angioplasty improves exercise
      performance and reduces symptoms better than standard medical therapy in low
      risk, stable patients with coronary disease, none of these studies used
      aggressive cholesterol-lowering medical therapy. In addition, the event rate of
      death from myocardial infarction and other coronary events was found to be
      slightly higher in patients who had undergone angioplasty. The Atorvastatin
      versus Revascularization Treatment (AVERT) trial was the first study designed to
      compare the efficacy of aggressive cholesterol-lowering therapy versus
      percutaneous transluminal coronary angioplasty in low risk, stable patients with
      coronary artery disease. Results favour the use of aggressive lipid lowering over
      percutaneous transluminal coronary angioplasty in patients with mild to moderate
      coronary disease. Treatment with atorvastatin significantly reduced low density
      lipoprotein cholesterol levels, and was associated with a 36% reduction in
      ischemic events and a significant delay in time to first ischemic event.

PMID- 10653926
TI  - Is hormone replacement therapy cardioprotective? Decision-making after the heart
      and estrogen/progestin replacement study.
AB  - Coronary artery disease (CAD) is the major cause of death in women.
      Postmenopausal status is associated with a twofold increase of risk for
      cardiovascular events, in part because of detrimental changes in plasma
      lipoproteins and endothelial function. Hormone replacement therapy (HRT) has
      beneficial effects on plasma lipids, flow-mediated vasodilation and fibrinolysis
      that could be expected to have positive effects on the incidence of
      cardiovascular events in many postmenopausal women. However, oral HRT also has
      procoagulant effects and clearly increases the risk of venous thromboembolism.
      The prothrombotic effects of oral estrogen are not a major concern for the
      majority of healthy women and major studies including the Framingham Heart Study
      and the Nurses' Health Study showed that HRT use is associated with protection
      from cardiovascular disease. In contrast, the Heart and Estrogen/progestin
      Replacement Study (HERS) failed to show a beneficial effect of oral HRT on
      cardiovascular events in older women with advanced CAD. In such women, the acute
      prothrombotic effects of oral estrogen may outweigh the long-term
      antiatherosclerotic effects of HRT. Until the results of other randomized
      controlled studies are complete, advice regarding HRT should be based on
      anticipated benefits on CAD risk factors versus the overall risk of both venous
      and arterial thrombosis.

PMID- 10653927
TI  - Low density lipoprotein cholesterol: is lower better?
AB  - Low density lipoprotein cholesterol (LDL-C) reduction leads to significant
      decreases in coronary events, as well as in most large trials performed recently,
      cardiovascular and total mortality. The lowest risk of coronary events occurs
      among people with the lowest LDL-C levels. Achieving a target LDL-C level less
      than 2.5 mM in individuals at high risk of a coronary event often necessitates
      the use of lipid-lowering drugs, primarily statins. Review of the major clinical
      trials involving statins reveals that LDL-C reduction is associated with a
      significant reduction in coronary events in men and women, older individuals,
      those with various other risk factors and those with either coronary artery
      disease or a high risk of developing it. The greatest clinical benefits have been
      associated with the greatest LDL-C reductions, although the incremental benefit
      is less at lower levels. Ongoing studies will help determine optimal new
      treatment targets for LDL-C.

PMID- 10653928
TI  - Advocates on your behalf.

PMID- 10653929
TI  - From the Heart and Stroke Foundation of Canada. Canadian excellence in research.

PMID- 10653930
TI  - What's new on the net. The revolution.

PMID- 10653931
TI  - Effects of long term resistance training on left ventricular morphology.
AB  - OBJECTIVES: To assess the effects of long term (mean +/- SD 10+/-5 years, range
      three to 25 years) resistance training on left ventricular (LV) dimensions and
      mass. METHODS AND RESULTS: The study participants were 21 elite male power
      lifters (age 33.4+/-5.9 years) and 10 sedentary male control subjects (age 30.9+/
      4.2 years). Two-dimensionally guided transthoracic M-mode echocardiograms were
      obtained at rest to quantify LV diastolic cavity dimension, posterior wall
      thickness, ventricular septal wall thickness and LV mass. Long term resistance
      training was not associated with an alteration in LV diastolic cavity dimension
      (resistance trained 54. 4+/-4.3 mm versus control 51.8+/-5.6 mm), ventricular
      septal wall thickness (resistance trained 9.7+/-1.0 mm versus control 10.1+/-0.7
      mm), posterior wall thickness (resistance trained 9.6+/-1.5 mm versus control
      9.3+/-1.4 mm) or LV mass (resistance trained 200. 3+/-32.5 g versus control
      186.5+/-39.6 g). In addition, no resistance-trained athlete was found to have an
      LV mean wall thickness above clinical normal limits (12 mm or less). CONCLUSION:
      Contrary to common beliefs, long term resistance training as performed by elite
      male power-lifters does not alter LV morphology.

PMID- 10653932
TI  - Radiofrequency ablation of atrial tachycardia originating from the triangle of
      Koch.
AB  - Atrial tachycardia (AT) originating in the triangle of Koch is reported rarely
      and presents a potential risk of atrioventricular (AV) block during
      radiofrequency (RF) catheter ablation. Eight patients with AT in the triangle of
      Koch undergoing RF ablation are presented. There were five women and three men,
      ranging in age from 32 to 74 years. One patient had bicuspid aortic valve
      disease, and the other seven patients had no structural heart disease. At
      electrophysiological study, AT was inducible in all eight patients. In one
      patient, AV nodal re-entrant tachycardia was also inducible. The site of AT was
      located by recording the earliest atrial activation during AT and successful RF
      ablation. Fluoroscopy confirmed the corresponding site to the region of the
      triangle of Koch. The earliest atrial activation was 35+/-9 ms before the surface
      P wave, and was recorded at the apex of the triangle of Koch near the bundle of
      His in six patients and midway between the bundle of His and coronary sinus os in
      two patients. At the successful RF application site, His potential was not
      recorded in any patient. The mean AV ratio was 5:1 (range 1:1 to 12:1). RF
      ablation at the successful site resulted in accelerated junctional rhythm in four
      of the eight patients and successfully terminated AT in all eight patients, with
      first-degree AV block in one patient. In conclusion, AT from the triangle of Koch
      is a distinct entity and RF ablation can be successfully performed; however, a
      potential risk of AV block remains.

PMID- 10653933
TI  - Induction of heat shock protein 72 protects against organ damage in essential
      hypertension: A hypothesis.
AB  - Over 12 consecutive years, hyperthermia was induced by immersion in hot baths
      1576 times in one subject with a long history of labile hypertension. In year 13
      (1996), following hyperthermia induction, peripheral lymphocytes were analyzed by
      Western blot analysis for heat shock protein 72 (HSP72) gene expression. It was
      demonstrated that rectal and oral fevers maintained for 15 mins at 38.2 C and 38.
      6 C or higher, respectively, triggered HSP72 expression. Because this subject
      showed no evidence of organ damage secondary to hypertension, and because both
      hyperthermia and acute hypertension upregulate HSP72 expression, a role for HSP72
      in protection against the adverse effects of essential hypertension disease is
      proposed and discussed.

PMID- 10653934
TI  - Developing guidelines for allocating catheterization laboratory resources:
      lessons from an Ontario Consensus Panel. Consensus Panel on Cardiac
      Catheterization Laboratory Services in Ontario and the Steering Committee of the
      Cardiac Care Network of Ontario.
AB  - In March 1997, the Ontario Ministry of Health asked the Cardiac Care Network of
      Ontario (CCN) to develop guidelines for allocating cardiac catheterization
      laboratory resources. A consensus panel of providers and planners used findings
      from the literature and expert opinion to recommend guidelines for the operation
      of cardiac catheterization laboratories and criteria to be considered when
      allocating additional cardiac catheterization laboratory resources. This article
      summarizes the consensus panel's major findings that may be of value to other
      jurisdictions, including need identification, clinical practice, system issues,
      location criteria and cost considerations. The article reflects the advice given
      to the Ontario Ministry of Health by the CCN and is not an official position
      paper of the Canadian Cardiovascular Society.

PMID- 10653935
TI  - Modifications of the isolated frog heart preparation in Carl Ludwig's Leipzig
      Physiological Institute: relevance for cardiovascular research.
AB  - Carl Ludwig was the first physiologist to systematically study isolated organs
      (heart, muscle, kidney, liver, lung). In his Leipzig Physiological Institute, the
      isolated perfused frog heart preparation was established in 1866 by Elias Cyon.
      This preparation was subsequently subjected to various modifications, and many
      important observations were made by scientists such as Joseph Coats, Henry
      Pickering Bowditch, Luigi Luciani, Michael Joseph Rossbach, Hugo Kronecker and
      Otto Frank. The influence of filling pressure on contraction amplitude, the all
      or-none law of the heart, the absolute refractory period, postextrasystolic
      potentiation, the staircase ('Treppe') phenomenon and the dependence of heart
      function on oxidative metabolism were discovered. The negative chronotropic and
      inotropic effects of vagus nerve stimulation were also first documented, and a
      model to induce arrhythmias was established. The isolated frog heart preparation
      became a widely used standard model for teaching and for basic cardiovascular
      research. Sidney Ringer discovered the essential role of calcium ions for heart
      function. Otto Loewi discovered the chemical transduction mechanism of the vagus
      with acetylcholine as transmitter. In more recent times, the cyclical changes in
      cAMP and cGMP that occur during the cardiac cycle were first described in the
      frog heart by Wollenberger and associates. Thus, the isolated perfused frog heart
      established and modified in Carl Ludwig's Leipzig Physiological Institute led not
      only to the discovery of basic phenomena, but also to observations that became
      the basis for concepts to be developed and elaborated later. Furthermore, the
      isolated perfused frog heart was the starting point for the development of the
      isolated mammalian heart in the retrogradely perfused, nonworking mode in the
      heart-lung modification and in the working heart preparation.

PMID- 10653936
TI  - Intracardiac extension of intravenous leiomyomatosis in a pregnant woman: A case
      report and review of the literature.
AB  - Intravenous leiomyomatosis is an uncommon clinical entity characterized by the
      growth of a benign, smooth muscle tumour within the venous system. Intracardiac
      extension of this tumour is rare, and approximately 35 cases have been reported
      in the literature. The second case of massive intracardiac extension of
      intravenous leiomyomatosis is reported in a pregnant patient diagnosed after the
      unusual presentation of seizure activity. Tumours were successfully removed from
      the right internal iliac vein, inferior vena cava, and right atrium and ventricle
      in a single-stage operation using cardiopulmonary bypass and circulatory arrest.
      Concomitant total abdominal hysterectomy and bilateral salpingo-oophorectomy were
      performed. Nine months after diagnosis, the patient was evaluated for recurrent
      disease. A review of the literature from 1994 to 1998 is presented.

PMID- 10653938
TI  - A new year - A new millennium

PMID- 10653937
TI  - Double vessel occlusions after balloon angioplasty treated by stenting and
      subsequently by abciximab infusion.
AB  - Stent thrombosis is a serious complication after percutaneous coronary
      intervention. A patient is presented with a double vessel occlusion after balloon
      angioplasty and subsequent stenting. He was then managed by abciximab therapy
      alone. Control angiography showed complete resolution of the thrombotic
      occlusions. His subsequent clinical course was uneventful.

PMID- 10653939
TI  - Factors affecting oral feeding with severe traumatic brain injury.
AB  - Safe and adequate nutrition, vital to the recovery from a traumatic brain injury,
      can be severely compromised by the presence of dysphagia. This study identified
      injury severity and swallowing factors that were associated with impaired oral
      intake in patients with severe brain injury. An admitting Glasgow Coma Scale
      (GSC) 3-5; a Rancho Los Amigos Scale of Cognitive Functioning (RLA) Level II; a
      computed tomography (CT) scan exhibiting midline shift, brainstem involvement, or
      brain pathology requiring emergent operative procedures; or ventilation time
      >/=15 days identified patients at highest risk for abnormal swallowing,
      aspiration, and delay in initiation of oral feeding and achievement of total oral
      feeding. When combined in multivariate models, RLA Level, CT scan, ventilation
      time and aspiration emerged as significant independent predictors of impaired
      oral intake.

PMID- 10653940
TI  - Fiberoptic endoscopic evaluation of swallowing in patients with acute traumatic
      brain injury.
AB  - Dysphagia and aspiration in intensive care unit patients with acute traumatic
      brain injury (TBI) is a frequent and potentially life-threatening problem. Any
      diagnostic technique used with this population, therefore, must be able to be
      performed in a timely and efficient manner while providing objective information
      on the nature of the swallowing problem. The purpose of the present study was to
      investigate the utility of using the fiberoptic endoscopic evaluation of
      swallowing (FEES) technique to diagnosis pharyngeal stage dysphagia and determine
      aspiration status in patients who presented with acute TBI. A total of 47
      subjects were assessed with FEES. Thirty of 47 (64%) subjects swallowed
      successfully and were able to take an oral diet: 2 of 30 (7%) thickened liquids
      and puree consistencies, 8 of 30 (27%) a soft diet, and 20 of 30 (67%) a regular
      diet. Seventeen of 47 (36%) subjects exhibited pharyngeal stage dysphagia with
      aspiration and were not permitted an oral diet based on objective results
      provided by FEES. Of the 17 subjects who aspirated, 9 of 17 (53%) exhibited
      silent aspiration. Younger subjects (mean age 34 years, 3 months) aspirated
      significantly less often than older subjects (mean age 51 years, 8 months). No
      significant age difference was observed for gender or between overt and silent
      aspirators. It was concluded that FEES is an objective and sensitive tool that
      can be used successfully to diagnose pharyngeal stage dysphagia, determine
      aspiration status, and make recommendations for oral or nonoral feeding in
      patients with acute TBI.

PMID- 10653941
TI  - Causes and complications associated with swallowing disorders in traumatic brain
      injury.
AB  - A major complication commonly seen in persons with severe brain injury is
      swallowing dysfunction. The neuropathology leading to impaired swallowing is
      discussed. In addition, Other risk factors associated with dysfunctional
      swallowing, such as tracheostomy and the need for prolonged ventilatory support,
      are discussed. Within the intensive care environment, the consequences of
      impaired swallowing leading to aspiration-a major cause of pneumonia-are
      discussed.

PMID- 10653942
TI  - The metabolic response to acute traumatic brain injury and implications for
      nutritional support.
AB  - An overview of the metabolic response to acute traumatic brain injury is
      presented. The consequences of hypermetabolism, hypercatabolism, and an altered
      immune function are discussed. Once a person with acute traumatic brain injury
      develops this hyperdynamic state, the resultant excessive protein breakdown
      ensues. This can lead to malnutrition. The feeding methods used to prevent
      malnutrition are discussed, along with the proper alimentation to provide to
      diminish the hyperdynamic state and improve immune function.

PMID- 10653943
TI  - The role of fiberoptic endoscopy in dysphagia rehabilitation.
AB  - The clinical bedside swallow evaluation and videofluoroscopy routinely have been
      used for dysphagia management. This article explores clinical issues for
      dysphagia management in the population with brain injury in the acute
      rehabilitation setting. Citing the dysphagia, cognitive, and other relevant
      issues present in the population with brain injury, the use of fiberoptic
      endoscopy to address dysphagia assessment and intervention is presented. Factors
      for decision making, a retrospective review of recent studies, and relevant cases
      are discussed.

PMID- 10653944
TI  - Dysphagia after head trauma: the effect of cognitive-communicative impairments on
      functional outcomes.
AB  - This article discusses the impact of cognitive-communicative and behavior
      problems on oral intake. Data on the swallowing outcomes of a group of patients
      in an acute rehabilitation facility are presented. These data illustrate the
      relationships among severity of dysphagia, admission and discharge Functional
      Independence Measure (FIM) scores, admission and discharge cognitive FIM scores
      and length of stay. Two case studies that describe the effect of cognitive
      communicative disorders on dysphagia are provided.

PMID- 10653945
TI  - Case studies in dysphagia after pediatric brain injury.
AB  - The course of pediatric traumatic brain injury is not homogeneous because the
      underlying neuropathology can be so variable. Assessment, intervention, and
      recovery are examined among five individuals whose neuroradiologic imaging
      differed grossly on initial and early presentations after head trauma. Knowledge
      of the neuropathology in an overarching sense can be informative to a clinician's
      management of different swallowing problems after brain injury.

PMID- 10653946
TI  - Narratives in rehabilitation.

PMID- 10653947
TI  - Venous thrombosis in traumatic brain injury

PMID- 10653961
TI  - Morphology and physiology of auditory and vibratory ascending interneurones in
      bushcrickets.
AB  - Auditory/vibratory interneurones of the bushcricket species Decticus albifrons
      and Decticus verrucivorus were studied with intracellular dye injection and
      electrophysiology. The morphologies of five physiologically characterised
      auditory/vibratory interneurones are shown in the brain, subesophageal and
      prothoracic ganglia. Based on their physiology, these five interneurones fall
      into three groups, the purely auditory or sound neurones: S-neurones, the purely
      vibratory V-neurones, and the bimodal vibrosensitive VS-neurones. The S1-neurones
      respond phasically to airborne sound whereas the S4-neurones exhibit a tonic
      spike pattern. Their somata are located in the prothoracic ganglion and they show
      an ascending axon with dendrites located in the prothoracic, subesophageal
      ganglia, and the brain. The VS3-neurone, responding to both auditory and
      vibratory stimuli in a tonic manner, has its axon traversing the brain, the
      suboesophageal ganglion and the prothoracic ganglion although with dendrites only
      in the brain. The V1- and V2-neurones respond to vibratory stimulation of the
      fore- and midlegs with a tonic discharge pattern, and our data show that they
      receive inhibitory input suppressing their spontaneous activity. Their axon
      transverses the prothoracic ganglion, subesophageal ganglion and terminate in the
      brain with dendritic branching. Thus the auditory S-neurones have dendritic
      arborizations in all three ganglia (prothoracic, subesophageal, and brain)
      compared to the vibratory (V) and vibrosensitive (VS) neurones, which have
      dendrites almost only in the brain. The dendrites of the S-neurones are also more
      extensive than those of the V-, VS-neurones. V- and VS-neurones terminate more
      laterally in the brain. Due to an interspecific comparison of the identified
      auditory interneurones the S1-neurone is found to be homologous to the TN1 of
      crickets and other bushcrickets, and the S4-neurone also can be called AN2. J.
      Exp. Zool. 286:219-230, 2000.

PMID- 10653962
TI  - Enzyme activities involved in lipid metabolism during embryonic development of
      Macrobrachium borellii.
AB  - The activities of the enzymatic systems involved in the activation and
      degradation of fatty acids, and in the synthesis of triacylglycerols and
      phospholipids were studied in vitro using total cellular homogenate and
      subcellular fractions of eggs of the shrimp Macrobrachium borellii at different
      developing stages. Egg development was divided into seven stages based on
      morphological features of the embryo. Palmitoyl-CoA ligase activity increased as
      the embryo developed and showed its maximum at stage V. An increase in the
      synthesis of triacylglycerols and diacylglycerols was also observed at this
      stage. Diacylglycerylethers were synthesized more actively during the first
      stages of development. The higher specific activity observed in total homogenate
      than in microsomal fraction suggested that their synthesis was not exclusively
      microsomal. Phospholipid synthesis was very active all along development,
      reflecting active membrane biosynthesis. The highest activity of the cytosolic
      triacylglycerol lipase was observed at stage V. Fatty acid degradation, measured
      as mitochondrial beta-oxidation activity, did not vary significantly during
      development. We conclude that both the anabolic and catabolic processes
      concerning lipid metabolism are very active, with values similar to those
      described for adult hepatopancreas, revealing the major role of lipids during
      shrimp embryogenesis energetics, and that the highest activities of lipid
      synthesis-hydrolysis take place at stage V when embryos are under active
      organogenesis. J. Exp. Zool. 286:231-237, 2000.

PMID- 10653963
TI  - Betaine aldehyde dehydrogenase kinetics partially account for oyster population
      differences in glycine betaine synthesis.
AB  - Betaine aldehyde dehydrogenase (BADH), the terminal enzyme of the glycine betaine
      synthetic pathway was purified 245-fold from the mitochondria of Atlantic and
      Chesapeake Bay oyster populations acclimated to 350 mosm, using ammonium sulfate
      precipitation, anion exchange, and affinity chromatography. BADH from both
      populations functions at its maximum rate at 50-55 degrees C over a broad pH
      range (7.5-9). BADH activity is also modulated by increased [Na(+)] and [K(+)].
      Although BADH from both populations has a similar V(max), BADH from Bay oysters
      has a substantially lower affinity for its substrate, betaine aldehyde, (K(m) =
      0.36 mM), than BADH from Atlantic oysters (K(m) = 0.1 mM). Despite kinetic
      differences, BADH from both Atlantic and Chesapeake Bay oysters have the same
      molecular weight based on electrophoretic analysis. These differences in BADH
      enzyme kinetics between the two oyster populations probably partially explain the
      lower glycine betaine synthesis rates and concentrations in Chesapeake Bay
      oysters. J. Exp. Zool. 286:238-249, 2000.

PMID- 10653964
TI  - Choline dehydrogenase kinetics contribute to glycine betaine regulation
      differences in chesapeake bay and atlantic oysters.
AB  - Choline dehydrogenase (CD), the first enzyme of the glycine betaine synthetic
      pathway, was measured in a mitochondrial lysate from gill tissue from Atlantic
      and Chesapeake Bay oysters acclimated to both 350 and 750 mosm. CD from both
      populations functions at its maximum rate at 30 degrees C and pH 8.75. Although
      CD from both populations has a similar affinity for its substrate, choline (K(m)
      = 15.7 mM), CD V(max) from Atlantic oysters is twice that from Bay oysters. In
      addition, the CD K(m )doubles and the V(max) increases four-fold in both oyster
      populations acclimated to 750 mosm. CD activity is competitively inhibited by
      both betaine aldehyde and glycine betaine. The differences in CD kinetics between
      the two oyster populations help to account for the lower glycine betaine
      synthesis rates and concentrations in Chesapeake Bay oysters. CD cannot function
      rapidly enough to saturate the enzyme, betaine aldehyde dehydrogenase (BADH),
      immediately downstream, and, therefore, CD kinetics limit the rate of glycine
      betaine synthesis in oysters. J. Exp. Zool. 286:250-261, 2000.

PMID- 10653965
TI  - Rhythmic sensitization of nematocyst discharge in response to vibrational
      stimuli.
AB  - Sea anemones capture prey by discharging nematocysts and other cnidae. Discharge
      of microbasic p-mastigophore (mpm) nematocysts is regulated in part by hair
      bundle mechanoreceptors on tentacles arising from multicellular complexes
      consisting of supporting cells and a sensory neuron. Anemone hair bundles detect
      movements of prey and then sensitize cnidocytes (cnida-containing cells) to
      discharge mpm nematocysts in response to contact between the prey and tentacle.
      Data from a simple bioassay based on counting nematocysts discharged into test
      probes, indicate that approximately twice as many nematocysts discharge into test
      probes touched to tentacles after sensitization than before sensitization. We
      here report that sub-second bursts of vibrational stimuli at key frequencies (51,
      55, 65, or 74 Hz; Watson GM, Mire P, Hudson RR. 1998. J Exp Zool 281:582-593)
      sensitize discharge for at least 90 sec. Very few complete cycles of vibration
      are sufficient to sensitize discharge. However, as the number of cycles of
      vibration is increased, discharge is sensitized in rhythmic patterns. Computer
      analysis of the data by fast Fourier transforms indicates discharge to vibrations
      at 65 Hz is sensitized every 6.75 cycles. At 51 Hz discharge is sensitized every
      2.00 cycles. At 74 Hz, discharge is sensitized in a polyrhythm occurring every
      4.26, 3.76, 2.46, and 2. 10 cycles, respectively. At 55 Hz, discharge is
      sensitized in a polyrhythm occurring every 6.09, 3.20, 2.91, and 2.0 cycles,
      respectively. Apparently, cells in the neuronal pathway interconnecting anemone
      hair bundles with cnidocytes count cycles of vibration and then sensitize
      discharge or not according to the tally. J. Exp. Zool. 286:262-269, 2000.

PMID- 10653966
TI  - Expression of lbx1 involved in the hypaxial musculature formation of the mouse
      embryo.
AB  - Somites are the source of hypaxial musculature including skeletal muscles of the
      limb, tongue, and trunk. To get insight into the function of mouse Lbx1 homeobox
      gene in early somitic mesoderm differentiation, in situ hybridization analyses
      were performed. At the 4-6 somite stage (8 dpc), Lbx1 was first expressed in the
      lateral portion of the epithelial somite and dermomyotomal epithelium. This was
      in contrast to the expression of myf-5 in the medial region of the somite. The
      lateral expression of Lbx1 in somitic mesoderm then occurred regionally along the
      anterior-posterior body axis. Later, at 10 dpc (stage 1 of limb bud development),
      Lbx1-positive migrating cells originated in the lateral dermomyotomal lips at
      occipital, forelimb, and hindlimb levels. They also expressed Pax-3 and c-met,
      known as markers of the migrating limb muscle precursor cells. In stage 4
      hindlimb bud (11.5 dpc), the dorsal and ventral muscle precursor populations
      expressed Lbx1. In stage 8 forelimb buds (12.5 dpc), Lbx1 expression was reduced
      in the proximal muscle masses, where the high expression of myogenin accompanying
      muscle differentiation was detected. These results suggest that mouse Lbx1 might
      be involved in the commitment or determination of a muscle cell subpopulation
      during hypaxial musculature development. J. Exp. Zool. 286:270-279, 2000.

PMID- 10653967
TI  - Aposymbiotic culture of the sepiolid squid Euprymna scolopes: role of the
      symbiotic bacterium Vibrio fischeri in host animal growth, development, and light
      organ morphogenesis.
AB  - The sepiolid squid Euprymna scolopes forms a bioluminescent mutualism with the
      luminous bacterium Vibrio fischeri, harboring V. fischeri cells in a complex
      ventral light organ and using the bacterial light in predator avoidance. To
      characterize the contribution of V. fischeri to the growth and development of E.
      scolopes and to define the long-term effects of bacterial colonization on light
      organ morphogenesis, we developed a mariculture system for the culture of E.
      scolopes from hatching to adulthood, employing artificial seawater, lighting that
      mimicked that of the natural environment, and provision of prey sized to match
      the developmental stage of E. scolopes. Animals colonized by V. fischeri and
      animals cultured in the absence of V. fischeri (aposymbiotic) grew and survived
      equally well, developed similarly, and reached sexual maturity at a similar age.
      Development of the light organ accessory tissues (lens, reflectors, and ink sac)
      was similar in colonized and aposymbiotic animals with no obvious morphometric or
      histological differences. Colonization by V. fischeri influenced regression of
      the ciliated epithelial appendages (CEAs), the long-term growth of the light
      organ epithelial tubules, and the appearance of the cells composing the ciliated
      ducts, which exhibit characteristics of secretory tissue. In certain cases,
      aposymbiotic animals retained the CEAs in a partially regressed state and
      remained competent to initiate symbiosis with V. fischeri into adulthood. In
      other cases, the CEAs regressed fully in aposymbiotic animals, and these animals
      were not colonizable. The results demonstrate that V. fischeri is not required
      for normal growth and development of the animal or for development of the
      accessory light organ tissues and that morphogenesis of only those tissues coming
      in contact with the bacteria (CEAs, ciliated ducts, and light organ epithelium)
      is altered by bacterial colonization of the light organ. Therefore, V. fischeri
      apparently makes no major metabolic contribution to E. scolopes beyond light
      production, and post-embryonic development of the light organ is essentially
      symbiont independent. J. Exp. Zool. 286:280-296, 2000.

PMID- 10653968
TI  - Marking zebrafish, Danio rerio (cyprinidae), using scale regeneration.
AB  - Tagging or marking small laboratory-bred fish species is not an easy task. This
      also holds for the zebrafish, Danio rerio, which is widely used throughout the
      world as a model organism for genetics, developmental biology, etc. We present a
      simple marking technique based on scale regeneration. A comparative morphological
      study of various types of zebrafish scales indeed shows that regenerated scales
      are easily distinguishable from nonregenerated ones. We propose to take advantage
      of this typical morphology to mark a single or several individuals. This
      technique, based on a natural biological process, is easy to perform and does not
      enhance fish mortality in laboratory breeding conditions. It permits assembly of
      several specimens in a single tank with the possibility of identifying each of
      them by regenerated-scale coding. Nevertheless, a prerequisite is that the
      species does not lose and regenerate scales in large numbers in laboratory
      breeding conditions. To check this, 5,200 scales were removed from a large region
      of the left flank in 100 zebrafish and the number and position of regenerated
      scales were statistically analysed. Our results indicate that (1) laboratory-bred
      zebrafish have only a few regenerated scales (7.48%), (2) the probability of
      finding a regenerated scale is similar whatever its position in a row (antero
      posterior axis), but (3) it differs from one row to another (scales from the back
      are more frequently lost than those from the pectoral region). This paper
      presents a procedure to mark small breeding colonies of zebrafish using scale
      regeneration with the number and position of the scales to be removed with high
      probability of marking success. J. Exp. Zool. 286:297-304, 2000.

PMID- 10653969
TI  - Changes in intestinal and hepatic thyroid hormone deiodination during spontaneous
      metamorphosis of the sea lamprey, Petromyzon marinus.
AB  - We measured microsomal low-K(m) outer-ring deiodination (ORD) and inner-ring
      deiodination (IRD) activities for thyroxine (T(4)) and 3, 5,3'-triiodothyronine
      (T(3)) in intestine and liver in nonmetamorphosing (undersized) larvae,
      immediately premetamorphic larvae, animals in stages 1-7 of metamorphosis, and
      immediately postmetamorphic sea lampreys (Petromyzon marinus). For intestine:
      T(4)ORD activity was relatively low in nonmetamorphosing larvae, increased in
      premetamorphic individuals, was highest in stages 1 and 2 and was very low during
      stages 3-7; T(4)IRD activity was negligible until stage 3 but increased 4.7-fold
      through stages 3 to 7 such that T(4)IRD activity was 14 times T(4)ORD activity at
      stage 6; T(3)ORD activity was undetectable; T(3)IRD activity was not measured
      through stages 3-7 but correlated with T(4)IRD activity at other stages. For
      liver: deiodination was only measured up to stage 2 and in postmetamorphic
      animals; in contrast to intestine, T(4)ORD activity fell to low levels at stage 2
      and was low during postmetamorphosis; T(4)IRD and T(3)IRD activities were very
      low and uninfluenced by developmental stage; T(3)ORD activity was undetectable.
      We conclude that (1) deiodination activity is usually much higher in intestine
      than in liver, (2) intestinal ORD and IRD activities change reciprocally so that
      ORD predominates in early metamorphosis but IRD predominates in mid and late
      metamorphosis, and (3) changes in intestinal deiodination may contribute to the
      characteristic depression of plasma T(4) and T(3) levels during spontaneous
      metamorphosis. J. Exp. Zool. 286:305-312, 2000.

PMID- 10653970
TI  - Alteration of the sex determining system resulting from structural change of the
      sex chromosomes in the frog Rana rugosa.
AB  - Rana rugosa in Japan is divided into four geographical races on the basis of the
      karyotype of the sex chromosomes: one in which heteromorphic sex chromosomes
      occur in the female sex (ZW/ZZ-system), another in which they are present in
      males (XX/XY-system), and the remaining two in which no heteromorphism is seen in
      either sex. The last two inherit the XX/XY sex determining system. Y and Z
      chromosomes in the former two are of the same karyotype as the no. 7 chromosomes
      seen in one of the latter two, whereas X and W are caused by two inversions that
      occurred in the original Xs (no. 7). In this study, we first attempted to detect
      the structural difference between the resulting X and W by examining their
      chiasma formation. The chiasma distribution between X and W was closely similar
      to that between two Xs, suggesting that the W and X are identical in structure.
      Regarding the change from XX/XY- to ZW/ZZ-system, the simplest explanation is
      that the putative female-determining gene(s) on the W grew functionally stronger
      by inversions. Next, we examined the sex of triploids having two Xs and one Z.
      The data showed that the triploids with two original Xs and a Z were all male,
      whereas most of those with two resulting Xs and a Z developed into females as
      expected. We speculated that the female-determining gene(s) on the resulting X
      grew mildly stronger functionally by position effect, whereas those on the W grew
      much stronger for some other reason (e.g., duplication). J. Exp. Zool. 286:313
      319, 2000.

PMID- 10653971
TI  - Establishment of fetal gonad/mesonephros coculture system using EGFP transgenic
      mice.
AB  - In developing mouse embryos, the Sertoli cells, Leydig cells, and seminiferous
      cords are differentiated in the XY gonads. The migration of mesonephric cells
      into the gonads is required during the developmental stage for seminiferous cord
      formation in the male gonads. In previous experiments, an organ coculture system
      has been used to examine morphologically developing gonads. However, by the
      process used in this system for fixing and staining the gonad/mesonephros
      complexes for examination, the kinetics of cell migration and the character of
      migrating cells cannot be observed. In the present study, we established an
      improved organ coculture system, using transgenic mice ubiquitously expressing
      Enhanced Green Fluorescent Protein (EGFP). In this system, time-dependent
      morphological changes in male-specific migration were observable in the
      gonad/mesonephros complex. The cell migration occurred at around 20 hr of
      coculture and began to spread at 25 hr with increases in the number of migrating
      cells occurring at 45 hr of coculture. No degenerative changes were detected at
      the end of coculture. Our results indicate that the present coculture system is
      very useful for investigating the mechanism of cell migration, as well as the
      characteristics of the migrating cells, in developing gonads. J. Exp. Zool.
      286:320-327, 2000.

PMID- 10653972
TI  - Fluid flow-induced tyrosine phosphorylation and participation of growth factor
      signaling pathway in osteoblast-like cells.
AB  - To investigate how mechanical loading stimulates bone cells, we subjected murine
      osteoblast-like cells, MC3T3E1, to fluid flow generated by shaking culture
      dishes. Since we had previously found that egr-1 mRNA is up-regulated by the
      flow, and that the regulation involves tyrosine kinase, we examined which
      proteins are tyrosine-phosphorylated by flow. Western blotting and
      immunoprecipitation of cell lysates showed tyrosine phosphorylation enhancement
      of many proteins, including ERK2 and Shc, and activation of ERK1/2. Although
      these responses did not occur in serum-free media, addition of EGF or bFGF
      recovered the responses. AG1478, an inhibitor of EGF receptor kinase activity,
      abolished tyrosine phosphorylation enhancement, ERK1/2 activation, and egr-1 mRNA
      accumulation induced by the flow of EGF-containing serum-free media. These
      results suggest that growth factor signaling pathways are involved in these
      responses. Repetition of fluid flow induced repeatedly up-regulation of egr-1
      mRNA. Such events may also occur in bone under mechanical loading.

PMID- 10653973
TI  - [8-(Diethylamino)octyl-3,4,5-trimethoxybenzoate, HCl], the inhibitor of
      intracellular calcium mobilization, blocked mitogen-induced T cell proliferation
      by interfering with the sustained phase of protein kinase C activation.
AB  - The physiological role of IP(3)-dependent Ca(2+) release in T cell activation was
      in question due to the contradictory findings that [8-(Diethylamino)octyl-3,4,5
      trimethoxybenzoate, HCl] (TMB-8), an inhibitor of intracellular Ca(2+)
      mobilization, blocked T cell proliferation, curtailing specifically the level of
      released Ca(2+) did not affect T cell activation and T cell line lacking IP(3)
      receptor was defective in IL-2 production in response to TCR/CD3 ligand. In the
      present study we found that TMB-8 inhibited Concanavalin A (Con A)- but not
      PMA/Ionomycin-induced T cell proliferation in a reversible and dose-dependent
      manner. The kinetic study revealed that TMB-8 exerted the inhibitory effect at a
      very early step of T cell activation. The Ca(2+) ionophore ionomycin augmented
      instead of overcoming the inhibitory effect of TMB-8, although the same doses of
      ionomycin alone had no effect on Con A-induced T cell proliferation. PMA the
      metabolically stable, but not diacylglycerol (DAG) the metabolically labile,
      activator of protein Kinase C (PKC) completely overcome the antiproliferative
      effect of TMB-8. A specific DAG lipase inhibitor RHC80267 also overcome the
      effect of TMB-8. Taken together, these results showed that the process of Ca(2+)
      release through IP(3) receptor, not the released Ca(2+), is essential for the
      sustained phase of PKC activation during T cell proliferation.

PMID- 10653974
TI  - Mechanism of action of superactive vitamin D analogs through regulated receptor
      degradation.
AB  - We and others have previously shown that selected vitamin D analogs potentiate
      the vitamin D receptor (VDR) mediated transcription much more efficiently than
      the natural hormone itself. Here we show that the transcriptionally active 20-epi
      analogs, namely KH 1060 and MC 1288, protect VDR against degradation more
      efficiently than calcitriol at 10(-10) M concentration (VDR t(1/2) > 48 h, 17 h,
      and 10 h, respectively). The conformationally epi-like analog EB 1089 did not
      significantly alter the half-life of VDR (10.3 h), but retained the VDR levels
      over longer periods of time than calcitriol. The transcriptionally weak analog GS
      1558, on the other hand, enhanced VDR degradation even more than what was
      observed with the unliganded receptor (t(1/2) 4.5 h and 5 h, respectively).
      Inhibition of proteasome activity by the inhibitor MG-132 resulted in a marked
      increase in the VDR levels in cells treated with the vehicle or GS 1558 (2.5-fold
      and 2.7-fold, respectively), more than twice the levels observed in the presence
      of calcitriol or EB 1089 (1.2-fold and 1.1-fold, respectively). MG-132 treatment
      did not increase the VDR levels in cells treated with KH 1060 or MC 1288. The
      electrophoretic mobility shift assay (EMSA) with nuclear extracts from MG-132
      treated cells revealed formation of a high-molecular-weight RXRbeta-VDR-VDRE
      complex, which also contained Sug1. In the presence of calcitriol, 34% of total
      VDR in its DNA binding state was present in this complex. The 20-epi analogs
      effectively prevented the formation of this complex, since, in this case, only
      16% of total VDR was found in this complex. These results suggest that KH 1060
      and MC 1288 induce a VDR conformation, which prevents binding of proteins
      mediating receptor degradation. As a result, the regulation of VDR degradation
      differs from that found with the calcitriol-VDR complex resulting in superactive
      transcriptional action of the analogs.

PMID- 10653975
TI  - Differential nuclear localization and nuclear matrix association of the splicing
      factors PSF and PTB.
AB  - A monoclonal antibody raised against nuclear matrix proteins detected a protein
      of basic pI in human nuclear matrix protein samples of various cellular origin.
      The ubiquitously occurring (common) nuclear matrix protein was identified as
      splicing factor PSF (PTB associated splicing factor). The interaction between the
      splicing factors PSF and PTB/hnRNP I was confirmed by co-immunoprecipitation from
      nuclear salt extracts. However, the nuclear localization of PSF and PTB and their
      distribution in subnuclear fractions differed markedly. Isolated nuclear matrices
      contained the bulk of PSF, but only minor amounts of PTB. In confocal microscopy
      both proteins appeared in speckles, the majority of which did not co-localize.
      Removing a large fraction of the soluble PTB structures by salt extraction
      revealed some colocalization of the more stable PTB fraction with PSF. These
      PTB/PSF complexes as well as the observed PSF-PTB interaction may reflect the
      previously reported presence of PTB and PSF in spliceosomal complexes during RNA
      processing. The present data, however, point to different cellular distribution
      and nuclear matrix association of the majority of PSF and PTB.

PMID- 10653976
TI  - Mitogen-activated protein phosphorylation in endothelial cells exposed to
      hyperosmolar conditions.
AB  - The effect of hyperosmolarity on the induction of the mitogen-activated protein
      kinases (MAPK) was studied in bovine aortic endothelial cell (EC). Different
      types of agents were used to differentiate the effects of osmolarity from other
      variables. Hypertonic treatment with physiologically relevant levels of NaCl (350
      mOsm/kg H(2)O) significantly increased the level of expression of p38 within 2
      min, and ERK-1/2 and JNK after 10 min. The inductions peaked between 30 and 60
      min and returned to baseline levels within 2 h. A similar pattern of induction
      occurred with ionic contrast agent. p38 induction by glucose and mannitol showed
      a similar pattern, although the level of ERK-1/2 phosphorylation was not as
      robust, and JNK was not induced by glucose. Urea did not affect the level of
      induction of the MAPK isoforms. It is concluded that MAPK plays an important role
      in hyperosmolality-induced signal transduction. Different osmotic agents induce
      MAPK expression differently. No MAPK induction with urea implies that cell
      shrinkage may be an important component of hyperosmolality-induced MAPK
      phosphorylation.

PMID- 10653977
TI  - Function, oligomerization, and conformation of tumor-associated p53 proteins with
      mutated C-terminus.
AB  - Mutations that affect the oligomerization domain (OD) of the p53 tumor suppressor
      may be of particular interest because of the remarkable contradiction between the
      conservation of the OD and its relative functional resistance to amino acid
      substitutions, and because of recent hints that cellular protein factors may
      interact with the OD. Both point to the possibility that this domain fulfills
      tasks beyond oligomerization. We report that the tumor-associated mutants 330H,
      334V, and 337C are defective for homo-oligomerization by three criteria.
      Accordingly, 330H and 337C failed to bind to a p53 recognition motif in gel-shift
      assays and to stimulate reporter genes efficiently in transient transfections.
      334V retained some activity in both assays despite being oligomerization
      defective. The ability of the mutants to induce apoptosis correlated with their
      performance in the DNA binding and transactivation assays. However, mutants 330H
      and 337C were able to provoke cell death when overexpressed, which in combination
      with their failure to transactivate genes suggests competence for the induction
      of transactivation-independent apoptosis at high protein levels. Although 334V
      and 337C failed to homo-oligomerize, they were able to hetero-oligomerize with a
      p53 with wild-type OD, and 334V was able to interfere with transactivation by wt
      p53. All mutants showed a reduced reactivity with antibody PAb421 and a distinct
      calpain cleavage pattern indicative of conformational alterations. In conclusion,
      tumor-associated OD mutants of p53 can be functionally competent to different
      degrees despite of being oligomerization defective.

PMID- 10653978
TI  - Activation of p38 mitogen-activated protein kinase and mitochondrial Ca(2+)
      mediated oxidative stress are essential for the enhanced expression of grp78
      induced by the protein phosphatase inhibitors okadaic acid and calyculin A.
AB  - We have reported that treatment with okadaic acid, a potent protein phosphatase
      inhibitor, has the ability to enhance the synthesis of the 78-kDa glucose
      regulated protein (GRP78). This article reports our investigation of another
      protein phosphatase inhibitor, calyculin A, demonstrating the signaling pathways
      elicited by the protein phosphatase inhibitors that lead to the induction of
      grp78. Our data showed that the induction process is abolished by SB203580, a
      specific inhibitor of p38 mitogen-activated protein kinase (p38(MAPK)).
      Phosphorylation-activation of p38(MAPK) in the treated cells was indicated by its
      own phosphorylation, as shown by double Western blotting analyses and directly
      confirmed by the in vitro kinase assay using MAPK-activated protein kinase-2, a
      well-known downstream effector of p38(MAPK), as a substrate. The involvement of
      p38(MAPK) in this process is further substantiated by using transient
      transfection assays with a plasmid, pGRP78-Luc, which contains a 0.72-kbp stretch
      of the grp78 promoter. By exploiting the same transfection assay, we demonstrated
      that the up-regulation of the grp78 promoter by the protein phosphatase
      inhibitors is suppressed in the presence of the cytoplasmic calcium chelator
      bis(aminophenoxy)ethane N,N'-tetraacetic acid, the mitochondria calcium uniporter
      inhibitor ruthenium red as well as the antioxidants N-acetyl cysteine and
      pyrrolidinedithiocarbamate. Taken together, our results lead us to conclude that
      treatment with the protein phosphatase inhibitors would activate the signaling
      pathways involving p38(MAPK) and mitochondrial calcium-mediated oxidative stress
      and that these pathways must act in concert in order to confer the induction of
      grp78 by okadaic acid and calyculin A.

PMID- 10653979
TI  - The proteasome controls the expression of a proliferation-associated nuclear
      antigen Ki-67.
AB  - The proteasome is a protease complex responsible for rapid, selective, and
      irreversible removal of regulatory proteins, as well as many other cellular
      proteins. In this study, we have demonstrated that a proliferation-associated
      nuclear protein Ki-67 depended on the proteasome for its rapid degradation. A
      proteasome-specific inhibitor lactacystin augmented Ki-67 protein levels in
      pancreatic cancer BxPC-3 cells while repressed the level of steady-state Ki-67
      mRNA. Inhibition of the proteasome also led to accumulation of two CDK inhibitors
      p27(kip1) and p21(cip1) in the BxPC-3 cells. Failed reduction of Ki-67 protein
      and enhanced levels of the two CDK inhibitors are likely contributing factors for
      the suppressed BxPC-3 proliferation after proteasome inhibition.

PMID- 10653980
TI  - Role of insulin-like growth factor-I in regulating estrogen receptor-alpha gene
      expression.
AB  - The role of insulin-like growth factor-I (IGF-I) in regulating estrogen receptor
      alpha (ER-alpha) gene expression and activity was investigated in the human
      breast cancer cell line MCF-7. Treatment of cells with 40 ng/ml IGF-I resulted in
      a 60% decrease in ER-alpha protein concentration by 3 h, and the amount of ER
      alpha remained suppressed for 24 h. A multiple-dose ligand-binding assay
      demonstrated that the decrease in ER-alpha protein corresponded to a similar
      decrease of 50% in estradiol-binding sites with no effect on the binding affinity
      of ER-alpha. The dissociation constant of the estradiol-ER-alpha complex in the
      absence of IGF-I (K(d) = 3 x 10(-10) +/- 0.5 x 10(-10) M) was similar to the
      dissociation constant in the presence of IGF-I (K(d) = 6 x 10(-10) +/- 0.3 x 10(
      10) M). The decrease in ER-alpha protein concentration was paralleled by an 80%
      decrease in the steady-state amount of ER-alpha mRNA by 3 h. The IGF-I induced
      decrease in ER-alpha mRNA was due to the inhibition of ER-alpha gene
      transcription. When an 128-base pair ER-alpha-promoter-CAT construct was
      transfected into MCF-7 cells, treatment with IGF-I resulted in a 40% decrease in
      CAT activity. In contrast to the effects on ER-alpha, treatment with IGF-I
      induced two endogenous estrogen-regulated genes, progesterone receptor and pS2,
      by 4- and twofold, respectively. The pure antiestrogen ICI-164, 384 blocked this
      induction, suggesting that ER-alpha mediates the effects of IGF-I. Transient co
      transfections of wild-type ER-alpha and an estrogen response element-CAT reporter
      into COS-1 cells demonstrated that IGF-I increased reporter gene activity. This
      effect was also blocked by ICI 164,384. Protein kinase A and phosphatidylinositol
      3-kinase inhibitors blocked the IGF-I effects on ER-alpha expression and
      activity, suggesting that these kinases may be involved in the cross-talk between
      the IGF-I and ER-alpha pathways.

PMID- 10653981
TI  - Identification of a cell type-specific silencer in the first exon of the His-1
      gene.
AB  - The His-1 gene is developmentally expressed in the murine choroid plexus but is
      silenced in the adult brain. To test the hypothesis that the gene contains cis
      acting elements that contribute to this repression, we have analyzed segments of
      the proximal promoter for negative regulatory sequences by transient transfection
      analysis. The activity of the proximal promoter was moderately influenced by
      positively and negatively acting sequences located from -335 to -168 and -617 to 
      335, respectively. A strong His-1-positive regulatory element (HPRE, +18 to +29)
      was essential for maximal promoter activity and could also enhance the activity
      of the heterologous SV40 promoter in an orientation-dependent manner. The HPRE
      contains homology to the neuronal restrictive silencer element (NRSE) but
      interacted with nuclear proteins that were distinct from the NRSE-binding factor
      (NRSF). By contrast, a potent negative regulatory sequence (HNRE) was identified
      in the first exon that repressed either the His-1 or SV40 promoters by greater
      than 80%. This negative regulatory sequence interacted with nuclear proteins from
      cells that contain a silent His-1 gene but showed no interaction with nuclear
      proteins from cells that actively transcribe the endogenous gene. HNRE-mediated
      repression was orientation independent; most of this activity was mapped to a
      minimal 26-bp sequence. These findings suggest that the first exon of the His-1
      gene contains a cell type-specific silencer that contributes to the regulation of
      His-1 transcription.

PMID- 10653982
TI  - Increased ecto-metallopeptidase activity in cells undergoing apoptosis.
AB  - Release from the cell surface of a variety of growth factors, cytokines, and
      proteases follows exposure to genetically stressful agents capable of inducing
      apoptosis and necrosis. Increased ectoprotease activity is responsible for their
      release. We show that increased activity of several metalloproteases on the HeLa
      cell surface occurs after stresses due to UVC, actinomycin D, cycloheximide, and
      cisplatinum, which induce the release of transforming growth factor-alpha
      (TGFalpha) and other bioactive molecules. The ectoprotease activities increase
      preferentially on apoptotic cells, while little change occurs in viable cells.
      Gross decreases, except for the putative TGFalphaase activity, accompany
      necrosis. These changes may contribute to tissue repair and the absence of an
      inflammatory reaction to apoptotic cell death. They appear to be due to
      preferential enzyme activation or to retention by cells undergoing significant
      categorical decreases in protein content.

PMID- 10653983
TI  - Identification and cloning of a human urea transporter HUT11, which is
      downregulated during adipogenesis of explant cultures of human bone.
AB  - Bipotential cells in human trabecular bone explant cultures that express
      osteoblast characteristics are able to undergo adipogenesis in the presence of 3
      isobutyl-1-methylxanthine plus dexamethasone (Nuttall et al. [1998] J Bone Miner
      Res 13:371-382). The initial studies of these bipotential cells in explant
      cultures have been extended to examine differential gene expression during
      osteoblast/adipocyte transdifferentiation. Using differential display, we have
      identified a gene expressed in trabecular bone explant cultures that is
      downregulated as these cells differentiate from an osteoblast to an adipocyte
      phenotype. Homology searching identified this gene as the human urea transporter
      HUT11. The expression and downregulation of HUT11 have been observed in multiple
      patient bone explant cultures. The size of the bone explant-derived HUT11 mRNA is
      approximately 4.4 kb, which is identical to the largest splice variant reported.
      In this article, we report the cloning and sequencing of this gene from primary
      human osteoblasts. In addition, we report tissue distribution for the bone
      explant-derived form of HUT11 mRNA and show a reciprocal relationship between the
      expression of HUT11 and the nuclear hormone receptor peroxisome proliferator
      activated receptor gamma 2, which is a marker of adipocyte differentiation.
      Because the control of osteoblast/adipocyte transdifferentiation is unknown,
      selective downregulation of HUT11 during adipogenesis suggests that HUT11
      expression may be a marker of the switch from an osteoblast to an adipocyte
      phenotype. Understanding the role of HUT11 in osteoblasts may provide insights
      into the mechanism controlling osteoblast and adipocyte differentiation.

PMID- 10653984
TI  - 5-methoxytryptophol preserves hepatic microsomal membrane fluidity during
      oxidative stress.
AB  - Lipid peroxidation is a degenerative chain reaction in biological membranes that
      may be initiated by exposure to free radicals. This process is associated with
      changes in the membrane fluidity and loss of several cell membrane-dependent
      functions. 5-methoxytryptophol (ML) is an indole isolated from the mammalian
      pineal gland. The purpose of this study was to investigate the effects of ML (0.
      01mM-10mM) on membrane fluidity modulated by lipid peroxidation. Hepatic
      microsomes obtained from rats were incubated with or without ML (0.01-10 mM).
      Then lipid peroxidation was induced by FeCl(3), ADP, and NADPH. Membrane fluidity
      was determined using fluorescence spectroscopy. Malonaldehyde (MDA) +4
      hydroxyalkenals (4-HDA) concentrations were estimated as an indicator of the
      degree of lipid peroxidation. With oxidative stress, membrane fluidity decreased
      and MDA+4-HDA levels increased. ML (0.01-3 mM) reduced membrane rigidity and the
      rise in MDA+4-HDA formation in a concentration-dependent manner. 10 mM ML
      protected against lipid peroxidation but failed to prevent the membrane rigidity.
      In the absence of oxidative reagents, ML (0.3-10 mM) decreased membrane fluidity
      whereas MDA+4-HDA levels remained unchanged. This indicates that ML may interact
      with membrane lipids. The results presented here suggest that ML may be another
      pineal indoleamine (in addition to melatonin) that resists membrane rigidity due
      to lipid peroxidation.

PMID- 10653985
TI  - Regulation of the human bradykinin B2 receptor expressed in sf21 insect cells: a
      possible role for tyrosine kinases.
AB  - The functional regulation of the human bradykinin B2 receptor expressed in sf21
      cells was studied. Human bradykinin B2 receptors were immunodetected as a band of
      75-80 kDa in membranes from recombinant baculovirus-infected cells and visualized
      at the plasma membrane, by confocal microscopy, using an antibody against an
      epitope from its second extracellular loop. B2 receptors, detected in membranes
      by [(3)H-bradykinin] binding, showed a Kd of 0.66 nmol/L and an expression level
      of 2.57 pmol/mg of protein at 54 h postinfection. In these cells, bradykinin
      induced a transient increase of intracellular calcium ([Ca(2+)](i)) in fura 2-AM
      loaded sf21 cells, and promoted [(35)S]-GTP(gamma)S binding to membranes. The
      effects of bradykinin were dose dependent (with an EC(50) of 50 nmol/L for
      calcium mobilization) and were inhibited by N-alpha-adamantaneacetyl-D-Arg
      [Hyp(3),Thi(5,8),D-phe(7)]-Bk, a specific B2 receptor antagonist. When the B2
      antagonist was applied at the top of the calcium transient, it accelerated the
      decline of the peak, suggesting that calcium mobilization at this point was still
      influenced by receptor occupation. No calcium mobilization was elicited by 1
      micromol/L (Des-Arg(9))-Bk, a B1 receptor agonist that did not inhibit the
      subsequent action of 100 nmol/L bradykinin. No effect of bradykinin was detected
      in uninfected cells or cells infected with the wild-type baculovirus. Bradykinin
      induced [Ca(2+)](i) mobilization was increased by genistein and tyrphostin A51.
      These tyrosine kinase inhibitors did not modify basal levels of [Ca(2+)](i).
      Homologous desensitization of the B2 receptor was observed after repeated
      applications of bradykinin, which resulted in attenuated changes in intracellular
      calcium. In addition, genistein promoted an increased response to a third
      exposure to the agonist when applied after washing the cells that had been
      previously challenged with two increasing doses of bradykinin. Genistein did not
      affect the calcium mobilization induced by activation of the endogenous
      octopamine G protein-coupled receptor or by thapsigargin. The B2 receptor,
      detected by confocal microscopy in unpermeabilized cells, remained constant at
      the surface of cells stimulated with bradykinin for 10 min, in the presence or
      absence of genistein. Agonist-promoted phosphorylation of the B2 receptor was
      markedly accentuated by genistein treatment. Phosphoaminoacid analysis revealed
      the presence of phosphoserine and traces of phosphothreonine, but not
      phosphotyrosine, suggesting that the putative tyrosine kinase(s), activated by
      bradykinin, could act in a step previous to receptor phosphorylation.
      Interestingly, genistein prevented agonist-induced G protein uncoupling from B2
      receptors, determined by in vitro bradykinin-stimulated [(35)S]-GTP(gamma)S
      binding, in membranes from bradykinin pretreated cells. Our results suggest that
      tyrosine kinase(s) regulate the activity of the human B2 receptor in sf21 cells
      by affecting its coupling to G proteins and its phosphorylation.

PMID- 10653986
TI  - Circular YAC vectors containing short mammalian origin sequences are maintained
      under selection as HeLa episomes.
AB  - pYACneo, a 15.8-kb plasmid, contains a bacterial origin, G418-resistance gene,
      and yeast ARS, CEN, and TEL elements. Three mammalian origins have been cloned
      into this circular vector: 343, a 448-bp chromosomal origin from a transcribed
      region of human chromosome 6q; X24, a 4.3-kb element containing the hamster DHFR
      origin of bidirectional replication (oribeta), and S3, a 1.1-kb human anti
      cruciform purified autonomously replicating sequence. The resulting constructs
      have been transfected into HeLa cells, and G418-resistant subcultures were
      isolated. The frequency of G418-resistant transformation was 1.7-8.7 times higher
      with origin-containing YACneo than with vector alone. After >45 generations under
      G418 selection, the presence of episomal versus integrated constructs was
      assessed by fluctuation assay and by PCR of supercoiled, circular, and linear
      genomic cellular DNAs separated on ethidium bromide-cesium chloride gradients. In
      stable G418-resistant subcultures transfected with vector alone or with
      linearized constructs, as well as in some subcultures transfected with circular
      origin-containing constructs, resistance was conferred by integration into the
      host genome. However, several examples were found of G418-resistant transfectants
      maintaining the Y.343 and the YAC.S3 circular constructs in a strictly episomal
      state after long-term culture in selective medium, with 80-90% stability per cell
      division. The episomes were found to replicate semiconservatively in a
      bromodeoxyuridine pulse-labeling assay for </=130 cell generations after
      transfection. Furthermore, after </=172 cell generations rescued episomal DNA
      could be isolated intact and unrearranged, and could be used to retransform
      bacteria. These versatile constructs, containing mammalian origins, have the
      capacity for further modification with human telomere or large putative
      centromere elements, in an effort to move towards construction of a human
      artificial chromosome.

PMID- 10653987
TI  - Interactive binding at cytochrome P-450 of cell growth regulatory bioamines,
      steroid hormones, antihormones, and drugs.
AB  - The virtually universal family of P-450 isozymes contribute to the regulation of
      cell growth by modulating the levels of steroids and other lipid messengers for
      cytoplasmic and nuclear processes, including gene expression. In microsomes from
      rat liver cells, the concentration ( approximately 1 nmole/mg protein) of
      cytochromes P-450 approximates that of intracellular binding sites (K(d) 1.0-50
      microM) for histamine. The potencies of certain therapeutic drugs to inhibit
      catalytic activity of, and histamine binding to, cytochromes P-450 in vitro were
      previously shown by us to be predictive of relative propensities to modulate
      tumor growth in rodents. Also, we demonstrated that growth-regulating polyamines
      potently interact with histamine at P-450. We now show that several classes of
      steroid hormones, antiestrogens, and antiandrogens, as well as various
      arylalkylamine drugs, all potently inhibit (3)H-histamine binding to cytochrome P
      450 (K(i) values: testosterone 0.28 microM, progesterone 0.56 microM, flutamide
      1.7 microM, tamoxifen 9.0 microM). Furthermore, all the various hormone and drug
      ligands are mutually inhibitory in their binding to cytochrome P-450; e.g., K(i)
      values of androstenedione and progesterone, to inhibit imipramine binding to P
      450 (determined by spectral analysis), are 11 nM and 26 nM, respectively. The
      K(i) value of imiprimine to inhibit binding of androstenedione to P-450 is 3.5
      microM. We estimate the total P-450 content in microsomes to be greater in male
      than in female rats and correlated with the number of binding sites for
      histamine, but not for steroids and drugs that appear to be more selective for P
      450 isozymes. Thus, for at least some isozymes, the homeostatic role of the
      monooxygenases may be governed by histamine, modulated by endogenous ligands, and
      perturbed by many foreign molecules.

PMID- 10653988
TI  - Expression of Ca(2+) channel subunits during cardiac ontogeny in mice and rats:
      identification of fetal alpha(1C) and beta subunit isoforms.
AB  - Functional cardiac L-type calcium channels are composed of the pore-forming
      alpha(1C) subunit and the regulatory beta(2) and alpha(2)/delta subunits. To
      investigate possible developmental changes in calcium channel composition, we
      examined the temporal expression pattern of alpha(1C) and beta(2) subunits during
      cardiac ontogeny in mice and rats, using sequence-specific antibodies. Fetal and
      neonatal hearts showed two size forms of alpha(1C) with 250 and 220 kDa.
      Quantitative immunoblotting revealed that the rat cardiac 250-kDa alpha(1C)
      subunit increased about 10-fold from fetal days 12-20 and declined during
      postnatal maturation, while the 220-kDa alpha(1C) decreased to undetectable
      levels. The expression profile of the 85-kDa beta(2) subunit was completely
      different: beta(2) was not detected at fetal day 12, rose in the neonatal stage,
      and persisted during maturation. Additional beta(2)-stained bands of 100 and 90
      kDa were detected in fetal and newborn hearts, suggesting the transient
      expression of beta(2) subunit variants. Furthermore, two fetal proteins with
      beta(4) immunoreactivity were identified in rat hearts that declined during
      prenatal development. In the fetal rat heart, beta(4) gene expression was
      confirmed by RT-PCR. Cardiac and brain beta(4) mRNA shared the 3 prime region,
      predicting identical primary sequences between amino acid residues 62-519,
      diverging however, at the 5 prime portion. The data indicate differential
      developmental changes in the expression of Ca(2+) channel subunits and suggest a
      role of fetal alpha(1C) and beta isoforms in the assembly of Ca(2+) channels in
      immature cardiomyocytes.

PMID- 10653989
TI  - Introduction to current directions

PMID- 10653990
TI  - MMPI-2 validity scales in child custody evaluations: clinical versus statistical
      significance.
AB  - The MMPI-2 is commonly used in the psychological assessment of parents within
      child custody evaluations. Due to the interface of mental health practitioners
      with non-mental-health professionals in the context of child custody cases,
      careful attention must be paid to the potential misunderstanding or misuse of
      data from psychological testing. While traditional clinical lore has maintained
      an expectation of clinically significant defensiveness on the MMPI-2 with this
      population, the research data does not support this view. Despite empirical
      findings that identify patterns of elevations on the MMPI-2 validity scales with
      parents involved in child custody disputes, these patterns have been demonstrated
      to reach statistical but not clinical significance. That is, MMPI-2 profiles that
      contain elevations on scales L or K that either invalidate or notably suppress
      clinical scales are not to be expected in the child custody population. False
      causal attributions contributing to the potential mischaracterization or loss of
      important data related to personality functioning within this population are
      identified and discussed. Potential dangers associated with such false causal
      attributions are reviewed.

PMID- 10653991
TI  - Gender differences in evaluating social-sexual conduct in the workplace.
AB  - Qualitative interviews exploring gender differences in perceptions of sexual
      harassment were conducted with 100 full-time St. Louis area employees. Women more
      than men reported that telling dirty/sexual jokes was a non-harassing behavior,
      qualified behaviors as harassing when they happened in the workplace, and
      considered behaviors as non-harassing when the man's intentions were not harmful.
      Men more than women reported that requesting a date was a non-harassing behavior,
      qualified behaviors as harassing when the woman did not welcome the behavior, and
      considered behaviors as non-harassing when they did not violate workplace norms.
      Logistic regression analysis predicted the respondent gender with 86% accuracy.
      Finally, concept mapping suggested that when women think about harassers they are
      concerned with power and social aptitude, while men seem to be more concerned
      about the responsibility and psychological adjustment of perpetrators of sexual
      harassment. When women think about victims of harassment they are concerned with
      a woman's assertiveness and work effectiveness, while men are more concerned with
      the psychological state of the woman and how provocative she is when they think
      about victims of sexual harassment.

PMID- 10653992
TI  - Identifying inmates at risk for disciplinary infractions: a comparison of two
      measures of psychopathy.
AB  - Poythress, Edens, and Lilienfeld (1998) recently reported a moderately strong
      correlation between Hare's (1991) Psychopathy Checklist-Revised (PCL-R) and a
      newly developed self-report measure of psychopathy, the Psychopathic Personality
      Inventory (PPI) of Lilienfeld and Andrews (1996), in an ethnically diverse sample
      of 50 inmates from a youthful offender prison. The present study reports follow
      up data regarding disciplinary infractions in this sample and examines the
      utility of the PCL-R and PPI for identifying those at risk for institutional
      misbehavior. Generally modest, but statistically significant, correlations were
      obtained between both measures and indices of aggressive institutional behavior.
      Multiple regression analyses revealed that both measures accounted for common
      variance in the criterion but that neither accounted for significant unique
      variance. Results are discussed in terms of the clinical utility of these
      measures in populations of young offenders.

PMID- 10653993
TI  - Patient consent for release of sensitive information from their medical records:
      an exploratory study.
AB  - The disclosure of sensitive information concerning mental health, drug and
      alcohol use, and communicable diseases requires express patient consent under
      federal and state laws. This paper presents the results of a retrospective
      medical record abstraction of hospital consent-to-treatment and release-of
      information forms, examining whether the forms are present in the records, and,
      if so, whether they are signed by patients. The results suggest that patients who
      have sensitive information in their medical records or pay out of pocket for
      their care are less likely to consent to disclosure of their records. We discuss
      the implications of these results and recommend further research to understand
      patients' perceptions of medical confidentiality and the processes used for
      securing consent to hospital treatment.

PMID- 10653994
TI  - Young people's experience of the Canadian youth justice system: interacting with
      police and legal counsel.
AB  - Young people's knowledge and experience of the youth justice system was examined
      to explore self-reported factors that influenced their decisions regarding
      assertion versus waiver of rights to silence and legal counsel. Participants were
      50 adolescents from Toronto, Canada ranging in age from 12 to 18 (mean age=15.6
      years). Results of semi-structured interviews indicated that while over 60% of
      participants recalled being told of their rights to silence and counsel, three
      quarters did not contact a lawyer at the police station and half of those asked
      by police answered their questions. Findings suggest that the awareness of due
      process rights is not sufficient to mitigate the atmosphere of coercion that
      characterizes the police station. Implications and limitations of the study are
      discussed.

PMID- 10653995
TI  - Development and preliminary validation of a semi-structured interview for the
      screening of law enforcement candidates.
AB  - A standard practice among most law enforcement agencies is to include
      psychological screening in the selection of job candidates. Although the use of
      personality tests in predicting job performance of law enforcement officers has
      received empirical support (e.g., the Minnesota Multiphasic Personality
      Inventory, the Inwald Personality Inventory), there is a conspicuous absence of
      data regarding the reliability and validity of interview procedures. The present
      study represents the first step in the development of a standardized, semi
      structured interview for use in the screening of law enforcement personnel. This
      interview, the Law Enforcement Candidate Interview, was constructed using content
      areas drawn from measures used in the screening of law enforcement personnel
      (e.g., Inwald Personality Inventory) and assessment of personality functioning
      (Structured Clinical Interview for DSM-III-R Personality Disorders). This
      interview was then administered by two doctoral students to a group of law
      enforcement academy cadets (n=34). A modest degree of inter-rater reliability was
      achieved, although internal consistency was somewhat lacking. Interview scores
      were correlated with measures of academy performance (final grade-point average
      and peer and supervisor ranking of academy performance). Results of these
      analyses suggest the LECI is a modest predictor of academy performance. Potential
      uses of the LECI and future research indications are outlined.

PMID- 10653996
TI  - The effect of multiple childhood sexual assaults on mock-jurors' perceptions of
      repressed memories.
AB  - The effect of multiple childhood sexual assaults on the believability of a
      repressed memory of the assault was assessed using mock jurors. Participants read
      a fictional civil trial summary about a child sexual assault case presented in
      one of three reporting conditions: (a) immediate condition-the alleged victim
      testified immediately after the assault(s); (b) repressed condition-the alleged
      victim reported the assault(s) 20 years later, after remembering it/them for the
      first time; or (c) no-repressed condition-the alleged victim reported the
      assault(s) 20 years later, but the memory of the assault(s) had been present for
      those years. The number of assaults was either one or 30. The results showed that
      for all reporting conditions 30 alleged assaults led to relatively more decisions
      for the plaintiff than the defendant, and greater believability of the plaintiff.
      The increases in decisions rendered and believability were also generally true
      for the immediate condition compared to when there was a delay in reporting. The
      results are discussed in terms of mock jurors' perceptions of child sexual
      assault, both those reported immediately and those reported after many years.

PMID- 10653997
TI  - Deaf murderers: clinical and forensic issues.
AB  - Data are reported on 28 deaf individuals who were convicted, pled guilty, or have
      been charged and awaiting trial for murder. The unique forensic issues raised by
      these cases are discussed, and their clinical picture presented. A significant
      percentage of these deaf murderers and defendants had such severely limited
      communication skills in both English and American Sign Language that they lacked
      the linguistic ability to understand the charges against them and/or to
      participate in their own defense. As such, they were incompetent to stand trial,
      due not to mental illness or mental retardation, but to linguistic deficits. This
      form of incompetence poses a dilemma to the courts that remains unresolved. This
      same linguistic disability makes it impossible for some deaf suspects to be
      administered Miranda Warnings in a way comprehensible to them. This paper
      identifies the reasons for the communication problems many deaf persons face in
      court and offers remedial steps to help assure fair trials and police
      interrogations for deaf defendants. The roles and responsibilities of psychiatric
      and psychological experts in these cases are discussed. Data are provided on the
      etiology of the 28 individuals' hearing losses, psychiatric/psychological
      histories, IQs, communication characteristics, educational levels, and victim
      characteristics.

PMID- 10653998
TI  - Facilitated communication: rejected in science, accepted in court-a case study
      and analysis of the use of FC evidence under Frye and Daubert.
AB  - This article traces the phenomenon of facilitated communication (FC) from its
      introduction to the United States in 1990 to its use in recent court proceedings.
      FC is an alleged breakthrough technique that enables nonverbal individuals with
      developmental disabilities to communicate via a form of assisted typing.
      Widespread use of FC resulted in miraculous communications and surprising
      allegations of abuse. The growing importance and notoriety of FC attracted the
      interest of the scientific community which rejected the technique after numerous
      controlled studies were undertaken. Despite the rejection of FC by the scientific
      community, however, some courts have accepted this unproven technique by evading
      their state's test of scientific admissibility. It is asserted that court
      decisions admitting FC evidence are pretextural, and it is argued that FC should
      not be admitted into court proceedings. In addition, this report analyzes the
      future of FC in those states that have adopted the newer Daubert standard for
      scientific evidence.

PMID- 10654000
TI  - Size is important (and so are quality and style)

PMID- 10653999
TI  - Challenging a flexible neuropsychological battery under Kelly/Frye: a case study.
AB  - The ability of the flexible neuropsychological battery approach to withstand a
      challenge under California's evidentiary standard, Kelly/Frye, was tested in an
      actual trial. Despite repeating many criticisms offered by the literature (e.g.,
      no malingering measures, unknown accuracy rates, ignoring statistical
      limitations, not using age norms), the battery was allowed in "for the weight of
      the evidence," rather than being excluded as unreliable.

PMID- 10654001
TI  - The use of yellow fever virus modified by in vitro cultivation for human
      immunization. J. Exp. Med. 65, 787-800 (1937)

PMID- 10654002
TI  - Genetically engineered HSV in the treatment of glioma: a review.
AB  - Central nervous system malignancies, particularly glioblastoma multiforme, pose
      significant problems for the development of novel therapeutics. In the absence of
      advances with standard surgical and chemotherapeutic approaches, the utilisation
      of genetically engineered viruses, both as direct oncolytic agents as well as for
      the delivery of foreign proteins, represents a significant advance in the
      experimental approach to management of patients with these incurable tumours.
      Among other viruses, HSV offers an opportunity to directly influence the
      replication of tumour cells within the central nervous system. Because of its
      propensity to replicate in neuronal tissue as well as its large coding capacity,
      it provides an experimental model for the development of novel therapeutics. The
      status of these experimental approaches will be summarised in this review.

PMID- 10654003
TI  - Does SV40 infection contribute to the development of human cancers?
AB  - A large number of recent studies have reported the detection of simian virus 40
      (SV40) nucleotide sequences in a number of unrelated human cancers which include
      paediatric and adult brain tumours, pleural mesotheliomas, bronchopulmonary
      carcinomas and osteosarcomas. Most of the data have been gathered by the use of
      PCR assays. These observations imply that SV40 is circulating in human
      communities by person-to-person transmission and that the virus is capable of
      wide dissemination in the infected individual. These claims must be regarded with
      skepticism for a variety of reasons. There are several inconsistencies in the
      reported data; for example, there is a wide variation (0-23%) in the frequency of
      SV40 sequences in normal tissues. The results of PCR assays have been difficult
      to confirm by less error-prone and independent assays and the relationship of the
      virus to the tumour cell is not characterised. The SV40 sequences reported from
      humans are essentially identical to those of wild-type SV40; it is difficult to
      conceive that a highly species-specific polyomavirus like SV40 would cross the
      species barrier, become a human infection, and acquire pathogenic potential for
      the new host without significant adaptive change in its genome. The available
      evidence, although not extensive, does not indicate that SV40 is circulating in
      human communities. It is premature to discuss or speculate on the potential role
      of SV40 in the development of human cancer until the presence of SV40 in cancers
      and in human communities is established unequivocally, the risk factors for SV40
      infection are elucidated, and the effect of SV40 exposure on the development of
      specific cancers is examined in the context of other known risk factors for those
      cancers.

PMID- 10654004
TI  - Monitoring of viral susceptibility: new challenges with the development of
      influenza NA inhibitors.
AB  - With the clinical development of anti-viral agents, monitoring for the continued
      susceptibility of wild-type strains has become important in disease management.
      Various methods have been used to monitor viral susceptibility; the advantages
      and disadvantages of which depend on the virus, the target and the scale of the
      research being undertaken. The plaque-reduction assay is valuable for measuring
      susceptibility of most viruses but is not ideal for large-scale monitoring. Yield
      reduction, measuring specific virus antigens, and dye-uptake assays, measuring
      virus cytopathic effects, are more suitable for high-throughput requirements, but
      the IC(50) value (the concentration that inhibits 50% of virus) varies with the
      viral inoculum. Surveillance of influenza susceptibility to
      rimantadine/amantadine in the clinic has predominantly used EIA-based assays,
      since plaquing of influenza clinical isolates is variable. With development of
      the influenza NA inhibitors it became apparent that current cell-based assays
      were unsuitable for monitoring susceptibility to this new class of drugs.
      Variability may result from virus spread directly from cell to cell in culture by
      passing the NA function. Furthermore, mutations selected in the HA, while not
      apparently contributing to phenotypic resistance in vivo, may result in cell
      culture based resistance, and may mask NA resistance in cell culture by modifying
      receptor-binding specificity. One important distinction between NA inhibitors and
      other antiviral enzyme inhibitors is that both target enzyme and inhibitor work
      extracellularly. NA assays are therefore most representative of the in vivo
      situation for monitoring susceptibility, supported by HA sequencing. As the
      clinical use of NA inhibitors escalates, a major change will be required in
      approaches used to monitor susceptibility of influenza isolates in virology
      laboratories world-wide.

PMID- 10654006
TI  - Publisher's announcement

PMID- 10654005
TI  - Human parechoviruses--biology and clinical significance.
AB  - A new genus of the family Picornaviridae, Parechovirus, has recently been
      recognised on the basis of distinctive biological and molecular properties. In
      particular: parechoviruses exhibit characteristic effects on the host cell;
      cleavage of the capsid protein VP0, required for maturation of the virus particle
      in most other picornaviruses, does not occur; there is a unique extension, which
      is highly basic in character, to the N-terminus of the capsid protein VP3; and
      the 2A protein, in common with those of only two other known picornaviruses, is a
      homologue of a family of cellular proteins involved in the control of cell
      proliferation. The type member of the Parechovirus genus is a frequent human
      pathogen, formerly known as echovirus 22, which has been renamed human
      parechovirus 1. The genus also includes the closely related virus, human
      parechovirus 2 (formerly echovirus 23). Human parechoviruses generally cause
      mild, gastrointestinal or respiratory illness, but more serious consequences of
      infection, such as myocarditis and encephalitis have been reported. Most
      infections occur in young children. Ljungan virus, a newly identified virus of
      rodents, shares a number of molecular features with the human parechoviruses,
      raising important questions about the evolution of parechoviruses and their
      introduction into the human population.

PMID- 10654007
TI  - A phase I dose escalation study of multicyclic, dose-intensive chemotherapy with
      peripheral blood stem cell support for small cell lung cancer.
AB  - A phase I dose-escalation study of multicyclic, ifosfamide, carboplatin, and
      etoposide (ICE) with sequential reinfusion of peripheral blood stem cells (PBSCs)
      was conducted to determine the maximum-tolerated dose (MTD) of ICE. Twenty-four
      patients with SCLC (LD: 6, ED: 18) were treated with ifosfamide (3000-9000 mg/m2,
      24-h infusion), carboplatin (300-400 mg/m2), and etoposide (300 mg/m2) followed
      by subcutaneous filgrastim (75 microg/day) from day 4 to the day of PBSC
      collection. PBSC were harvested when the WBC count reached >/=5 x 109/l. The
      leukapheresis product was cryopreserved and reinfused on day 4 of the next cycle,
      which was started 48 h after the last PBSC collection. The ifosfamide dose was
      escalated as follows: 3000 mg/m2 (level 1), 5000 mg/m2 (level 2), 7000 mg/m2
      (level 3), 9000 mg/m2 (level 4). Patients with LD were treated with concurrent
      radiotherapy at 1.5 Gy twice daily for the initial 3 weeks to a total dose of 45
      Gy and MTD, defined separately. Patients were evaluated for hematologic and non
      hematologic toxicity, actual dose intensities, as well as response to therapy.
      The maximum-tolerated dose (MTD) was defined as the dose level at which more than
      5 days of grade 4 myelo- suppression or non-hematologic toxicity greater than
      grade 3 developed in two thirds of the patients. For ED cases, MTD was level 4
      and the recommended dose of ifosfamide was 7000 mg/m2. For LD cases, the
      recommended dose of ifosfamide was 5000 mg/m2. The dose limiting toxicity of
      multicyclic ICE was hemato- logic toxicity and CNS toxicity which manifested as
      ataxia. Tumor responses were seen in all patients, with 14 patients showing a
      complete response. The actual total dose-intensity at the recommended dose level
      was 2.2 and 1.74, for ED and LD, respectively, compared with previously reported
      ICE regimens. PBSC support for dose-intensive ICE regimen permitted dose
      escalation of ifosfamide with a mean interval of 16-17 days. We conclude that
      this regimen is well tolerated, with acceptable hematological and non
      hematological toxicity. Bone Marrow Transplantation (2000) 25, 5-11.

PMID- 10654008
TI  - Cytokine-mobilized allogeneic peripheral blood stem cell transplants in children
      result in rapid engraftment and a high incidence of chronic GVHD.
AB  - Between October 1995 and October 1998, 24 children aged 9 months to 17 years
      (median 11 years) underwent cytokine-mobilized allogeneic peripheral blood stem
      cell (PBSC) transplantation for treatment of hematological disorders. All of the
      transplants were the first allogeneic transplant for the recipient. Twenty
      patients were transplanted for hematological malignancies (ALL = 8, AML = 6, CML
      = 4, MDS = 2) and four patients were transplanted for non-malignant disease
      (thalassemia major = 2, Wiskott-Aldrich syndrome = 1, Kostmann's syndrome = 1).
      Nineteen donors were HLA-identical siblings, four were HLA-matched or single
      antigen mismatched parents, and one was a syngeneic transplant. Donors aged 8 to
      38 years (median 15 years, 14 donors <18 years) received G-CSF 10 microg/kg/day
      subcutaneously beginning 4 days before PBSC collection and were submitted to one
      to three leukapheresis collections. The median CD34+ cell yield was 7.8 x 106
      cells/kg recipient body weight. All patients achieved an ANC >0.5 x 109/l after a
      median of 13 days (range 10-21). Twenty-three patients eventually achieved
      platelet transfusion independence. One patient died on day 63 without ever
      achieving platelet transfusion independence. Four patients received platelet
      transfusions to maintain a platelet count well above 20 x 109/l due to bleeding
      complications. Of the 19 evaluable patients, the median time to a non-transfused
      platelet count of 20 x 109/l was 12 days (range 0-44). Ten of 23 at-risk patients
      developed acute GVHD grades II to IV, with grades III to IV in four patients.
      Twelve of 19 patients followed for at least 100 days have developed chronic GVHD
      (extensive = 2, limited = 10) with an actuarial risk of chronic GVHD of 75% at 1
      year. The Kaplan-Meier estimate of event-free survival is 65% at 2 years. Four
      patients died (GVHD = 3, VOD = 1), three patients relapsed, and one patient with
      thalassemia major had a late graft failure with autologous recovery. Based upon
      our experience, allogeneic PBSCT is safe for both pediatric donors and recipients
      and engraftment of neutrophils and platelets is rapid. Bone Marrow
      Transplantation (2000) 25, 13-18.

PMID- 10654009
TI  - High-dose cyclophosphamide + carboplatin and interleukin-2 (IL-2) activated
      autologous stem cell transplantation followed by maintenance IL-2 therapy in
      metastatic breast carcinoma - a phase II study.
AB  - While high-dose chemotherapy and stem cell transplantation is associated with
      higher complete response rates than conventional chemotherapy in patients with
      metastatic breast cancer (MBC), its role in conferring a survival advantage is
      unproven. We report the results of a prospective phase II trial of 33 patients
      accrued between 1996 to 1998 with chemosensitive MBC, who received
      cyclophosphamide (Cy) 2000 mg/m2/day and carboplatin (Cb) 600 mg/m2/day for 3
      consecutive days, followed by infusion of peripheral blood stem cells cultured in
      IL-2 for 24 h on day 0 as adoptive immunotherapy. Low-dose interleukin-2 (IL-2)
      was administered from day 0 to +4 and/or +7 to +11, +14 to +18, +21 to +25, then
      5 days per month for 11 months to augment a graft-versus-tumor effect. The
      results of this study were compared to those of a historical control group
      treated with an identical high-dose Cb + Cy regimen with SCT but without IL-2
      treatment. Only gastrointestinal (GI) toxicity was more frequent in the IL-2
      cohort (P = 0.0031). At a median follow-up of 18.6 months, the median progression
      free survival (PFS) is 9 months (2.4-40) and the median OS has not been reached
      yet. The Kaplan-Meier estimated 2 year PFS is 35%, compared with 17% in the
      control arm (P = 0.73), and the estimated 2 year OS is 78%, compared with 61% in
      the control arm (P = 0.22). Multivariate analysis showed that ER status was an
      independent predictor for OS and PFS, and less chemotherapy prior to HDCSCT
      predicted for a better PFS. These results show that augmenting HDC with IL-2
      activated SCT is well-tolerated. Whether a therapeutic advantage is achievable in
      patients with MBC remains to be determined. Bone Marrow Transplantation (2000)
      25, 19-24.

PMID- 10654010
TI  - Multiple myeloma: the number of reinfused plasma cells does not influence outcome
      of patients treated with intensified chemotherapy and PBPC support.
AB  - Multiple myeloma (MM) is characterized by the expansion of tumor plasma cells in
      bone marrow (BM), but neoplastic cells have been consistently detected in
      peripheral blood (PB). Peripheral blood progenitor cell (PBPC) collections have
      been widely used to support high-dose therapy for MM patients. A flow cytometric
      technique has been used to detect plasma cells in PB and PBPC harvests. High CD38
      expression identified these cells, and their nature was confirmed by the
      coexpression of specific antigens, such as CD138 and cytoplasmic immunoglobulins.
      Malignant plasma cell reinfusion could negatively affect response rate and
      survival, as demonstrated in other hematological malignancies. To address this
      issue, the relationship between the number of reinfused plasma cells, response to
      chemotherapy and event-free survival (EFS) have been analyzed. Sixty-four MM
      patients were treated with intensified chemotherapy at diagnosis. They were
      mobilized with cyclophosphamide and G-CSF, and then treated with melphalan 100
      mg/m2 (MEL100) followed by PBPC support. A second course was given after 2
      months, and a third to patients not in complete remission. There was no
      correlation between the number of reinfused plasma cells and response rate after
      this intensified chemotherapy: patients attaining complete remission received 3.6
      x 106/kg CD38+ cells, while those with a partial or no response received 5.6 and
      2.9 x 106/kg CD38+ cells. Similarly, there was no correlation between the number
      of reinfused plasma cells and EFS. Patients receiving less than 4.85 x 106/kg
      CD38+ cells experienced a median EFS of 34.2 months as opposed to 36.4 months for
      those receiving more than 4.85 x 106/kg CD38+ cells (P = 0.7). Recurrence of the
      disease is consistently observed in MM: our data suggest that in vivo residual
      tumor cells, rather than reinfused plasma cells are more likely to be responsible
      for relapse. Bone Marrow Transplantation (2000) 25, 25-29.

PMID- 10654011
TI  - Autologous stem cell transplantation for advanced Hodgkin's disease in children.
      Spanish group for BMT in children (GETMON), Spain.
AB  - This study evaluates the outcome of myeloablative chemo-radiotherapy and
      autologous stem cell transplantation (ASCT) in children with Hodgkin's disease
      (HD). Twenty children aged 5 to 18 years (median 10.8 years) at diagnosis, with
      relapsed, refractory or very poor prognosis HD, underwent ASCT in eight hospitals
      of our country. Status at transplant was: second complete remission (CR2): n =
      12; further CR (CR >2): n = 3, partial remission (PR): n = 2, relapse: n = 2 and
      first CR (CR1): n = 1. Eighteen patients received chemotherapy-based conditioning
      regimens: cyclophosphamide, carmustine and etoposide (CBV): 11 (55%), carmustine,
      etoposide, cytarabine and melphalan (BEAM): 5, other: 2; and two patients were
      conditioned with TBI/Cy. Peripheral blood (PB) was the source of progenitor cells
      in 12 patients, BM in seven, and BM plus PB, in one. All patients engrafted. One
      patient died of sepsis and multiorgan failure at day 28 after transplantation.
      All four patients with measurable disease (PR or relapse) at transplantation
      attained complete remission. Five patients relapsed 5-34 months after transplant
      (median: 11 months). Eighteen children remain alive with a median survival time
      of 40 months. The projected 5-year overall survival and event-free survival (EFS)
      rates were 0.95 and 0.62. High-dose therapy with stem cell rescue can lead to
      durable remissions in children with advanced HD. Bone Marrow Transplantation
      (2000) 25, 31-34.

PMID- 10654012
TI  - Role of high-dose therapy and initial response in survival of poor-risk patients
      with aggressive non-Hodgkin's lymphoma: a retrospective series on 126 patients
      from a single center.
AB  - It is now established that a subgroup of non-Hodgkin's lymphoma (NHL) patients
      probably benefit from high-dose therapy (HDT). We therefore retrospectively
      analyzed survival of 126 consecutive patients with large cell lymphoma (LCL) and
      high-intermediate (HI) or high-risk (H) age-adjusted international prognostic
      index (Aa-IPI). They received either standard chemotherapy (CT) (66 patients), or
      HDT (60 patients). Distribution of the Aa-IPI scores showed no statistical
      significant difference between the two treatment groups. Complete response (CR)
      rate was 51% for the whole series, with 41% and 62% for the standard CT group and
      HDT group, respectively. With a median follow-up of 63 months (range, 16 to 159),
      the 5-year overall survival (OS) and event-free survival (EFS) for all patients
      was 52% and 43%, respectively. There was a statistical significant difference in
      terms of survival towards the HDT group: OS at 76% vs 31%, EFS at 64% vs 24%.
      Patients who achieved CR with front-line therapy had a 5-year OS at 70%, while it
      was 34% for patients who were not in CR. These results are comparable to those
      reported in the literature, and strongly suggest that both initial CR achievement
      and HDT as front-line treatment are predictive factors for prolonged survival of
      patients with poor-risk LCL. Bone Marrow Transplantation (2000) 25, 35-40.

PMID- 10654013
TI  - Second allogeneic hematopoietic stem cell transplantation as treatment for
      leukemia relapsing following a first transplant.
AB  - We report 27 patients with relapsed acute or chronic leukemia who underwent a
      second hematopoietic stem cell transplant (HSCT) from a related or unrelated
      donor. Seventeen patients were diagnosed with acute myelogenous leukemia (AML),
      six with acute lymphocytic leukemia (ALL) and four with chronic myeloid leukemia
      (CML). Ages ranged from 22 to 49 years (median 37); 13 patients were female and
      14 male. Relapse was diagnosed between 1 and 45 months after the first HSCT.
      Sixteen patients who relapsed had received an autologous transplant initially and
      11 an allogeneic transplant. Ten patients relapsed within 6 months and 17
      patients later than 6 months. Chemotherapy was used as reinduction for relapse
      after HSCT in 16 patients who had received an autologous transplant and in three
      who had received an allogeneic transplant, since the latter did not respond to
      reduction of immunosuppression to induce a graft-versus-leukemia (GVL) reaction.
      Five of these 19 patients (26%) achieved complete remission (CR), seven patients
      did not respond to chemotherapy and seven achieved a partial remission (PR). The
      stem cell source for the second HSCT included bone marrow (n = 12) and PBSC (n =
      4) from genotypically identical unrelated donors, PBSC (n = 7) and bone marrow (n
      = 3) from related donors. Currently eight of the 27 patients are alive and
      disease-free after the second HSCT. One patient is alive and disease-free after
      two allogeneic transplants (day +1538), eight patients, who relapsed after an
      autologous transplant followed by an allogeneic transplant (days +248 to +1140),
      acute myeloid leukaemia (n = 6) and chronic myeloid leukemia (n = 2) are alive
      and disease-free. The overall disease-free survival is 30% (8/27). The overall
      disease-free survival of autologous transplant patients subsequently undergoing
      an allogeneic transplant is 43% (P = 0.049). It is suggested that a second HSCT
      is possible for patients with leukemia relapse following the first autologous
      transplant. A second transplant might also be offered to patients relapsing after
      the first allogeneic HSCT. Bone Marrow Transplantation (2000) 25, 41-45.

PMID- 10654014
TI  - Decreased graft-versus-host disease after haplotype mismatched bone marrow
      allografts in miniature swine following interleukin-2 treatment.
AB  - Graft-versus-host disease (GVHD) is an important complication of bone marrow
      transplantation after transplants between HLA-mismatched donor/recipient pairs.
      In mice, giving IL-2 post transplant decreases GVHD in this setting. We studied
      high-dose IL-2 therapy in pigs. Transplants were carried out after conditioning
      with fractionated total body radiation and cyclophosphamide. Fourteen pigs
      received a fully mismatched bone marrow transplant (six with IL-2; eight without
      IL-2), and six received a single haplotype class II mismatched transplant (three
      with IL-2; three without IL-2). GVHD was evaluated by skin histology. All fully
      mismatched recipients had severe GVHD (grade 2-3) and died within 13 to 51 days
      whether or not they received IL-2. Pigs receiving a one haplotype class II
      mismatched transplant without IL-2 developed severe skin GVHD lasting for 8-45
      days; all died within 57 days. Similar pigs receiving IL-2 post transplant had no
      or only mild skin GVHD for less than 15 days; two are long-term survivors. Bone
      Marrow Transplantation (2000) 25, 47-52.

PMID- 10654015
TI  - Immune reconstitution and outcome after unrelated cord blood transplantation: a
      single paediatric institution experience.
AB  - We report the outcome of 12 children who underwent unrelated cord blood
      transplant (U-CBT) in a single institution between February 1997 and July 1998.
      The 1 year event-free survival was 67% (95% CI of 26%). Four children died with
      infectious complication as cause of death in three cases. Immune reconstitution
      was studied during first year post transplant by assaying total lymphocyte
      counts, B cells, NK cells and T cell subsets in the eight disease-free surviving
      patients. We observed a prompt recovery of CD19+ cell number which was greater
      than 500/microl at 9 months for all patients except the one with severe cGVHD. B
      cells constituted the predominant lymphocyte subset at 6 and 9 months post
      transplant with normal or elevated B cell numbers according to normal paediatric
      range. We noted normal serum immunoglobulin levels at 6 months post transplant
      for IgA and IgM and at 9 months for IgG. The CD3+ cell count and particularly the
      CD3+CD8+ T cell subset remained depressed until 12 months post transplant. Six
      months after unrelated CBT, seven out of eight patients had less than 100
      CD3+CD8+ cells/microl. CD3+CD4+ cell recovery was less impaired with all children
      achieving an absolute count of CD3+CD4+ cells greater than 200/microl during the
      first year in a median of 5 months. The percentage of NK cells was elevated
      during the first 6 months after CBT but their absolute count remained within the
      normal range. Bone Marrow Transplantation (2000) 25, 53-57.

PMID- 10654016
TI  - Fever and neutropenia in pediatric hematopoietic stem cell transplant patients.
AB  - The objective of this study was to identify patterns of fever and neutropenia in
      pediatric patients undergoing initial hospitalization for hematopoietic stem cell
      transplantation. A retrospective review of 75 HSCTs over a 4-year period at a
      single institution was performed, of which 68% were allogeneic and 32% were
      autologous. Stem cell sources included bone marrow (29%), PBSC (52%) and
      umbilical cord blood (16%). Fever occurred in 74 (98%) of the episodes.
      Unexplained fever (FUO) occurred in 43%. Bacteremia without an anatomic focus
      occurred in 29%, while CVC associated infections occurred in 17%. In 49% of
      transplants at least one blood culture was positive. The incidence of bacteremia
      was higher in allogeneic HSCTs (58%) than in autologous transplants (29%). Gram
      positive bacteria accounted for 71% of the isolates. Lower rates of bacteremia
      were observed in patients receiving oral fluoroquinolone prophylaxis. The median
      duration of fever was 12.5 days and time to engraftment 14 days. Regression
      analysis demonstrated that duration of fever was strongly associated with time to
      engraftment, and that time to engraftment was associated with source of cells and
      number of CD34+ cells/kg administered. Recipients of autologous PBSC had the
      shortest durations of fever and time to engraftment, while recipients of
      allogeneic umbilical cord blood had the longest. Bone Marrow Transplantation
      (2000) 25, 59-65.

PMID- 10654017
TI  - High prevalence of diarrhea but infrequency of documented Clostridium difficile
      in autologous peripheral blood progenitor cell transplant recipients.
AB  - Autologous peripheral blood progenitor cell (PBPC) transplant recipients
      frequently receive multiple antibiotics for neutropenic fever in addition to high
      dose chemotherapy. Although there are many possible causes for diarrhea in this
      population, empiric therapy for possible C. difficile colitis is common in some
      centers. This study sought to define the frequency of diarrhea and of a positive
      C. difficile toxin assay in PBPC transplant recipients. Data were collected on 80
      patients enrolled in a randomized trial of two different antibiotic regimens
      during PBPC transplant. Data included the presence or absence of diarrhea, all
      microbiologic studies performed during the transplant admission, and all
      antimicrobials administered during the transplant admission. Of 80 patients
      enrolled, 61 (76.3%) developed diarrhea. Only 3/61 (4.9%) had a positive C.
      difficile toxin assay. A total of 122 C. difficile toxin assays were performed;
      for each positive C. difficile assay, 41 stool samples were analyzed. Twenty
      courses of oral metronidazole (18/20 empiric) and 10 courses of oral vancomycin
      (8/10 empiric) were given. A total of 25 of 61 patients with diarrhea (41%)
      received therapy for possible C. difficile. Diarrhea is common during autologous
      PBPC transplant but a positive C. difficile assay is uncommon. The practice of
      empiric therapy for C. difficile in this population in a non-outbreak setting
      should be re-evaluated. Bone Marrow Transplantation (2000) 25, 67-69.

PMID- 10654018
TI  - Assessing permeability alterations of the blood-bone marrow barrier due to total
      body irradiation: in vivo quantification with contrast enhanced magnetic
      resonance imaging.
AB  - Our aim was to quantify irradiation-induced permeability alterations of the blood
      bone marrow barrier (BMB) with dynamic contrast enhanced magnetic resonance
      imaging (MRI). The standard small molecular contrast agent, gadoterate meglumine,
      and a new macromolecular contrast agent, carboxymethyldextran-Gd-DOTA (CMD-Gd
      DOTA), were compared. Twenty New Zealand white rabbits underwent MRI of the bone
      marrow before and 1-2 days after total body irradiation (TBI). Dynamic,
      repetitive T1-weighted MRI was performed before and after injection of either
      0.05 mmol/kg BW CMD-Gd-DOTA (n = 10) or 0.5 mmol/kg BW gadoterate (n = 10). Bone
      marrow contrast enhancement was quantified as delta signal intensity: DeltaSI =
      |(SIpost - SIpre) / SIpre| * 100%. All MRI data were compared with the
      histopathologic BMB ultrastructure. Dynamic bone marrow DeltaSI data steadily
      increased after CMD-Gd-DOTA injection, while blood DeltaSI data slightly
      decreased. This bone marrow contrast enhancement, indicative of contrast agent
      extravasation, was significantly higher and prolonged in the irradiated group as
      compared to non-irradiated controls (P < 0.05) and corresponded to irradiation
      induced alterations of the BMB ultrastructure seen on electron microscopy. By
      contrast, DeltaSI data of non-irradiated and irradiated marrow were not
      significantly different following gadoterate injection (P > 0.05). We conclude
      that irradiation-induced alterations in BMB permeability could be reliably
      assessed with dynamic MRI, using the new macromolecular contrast agent CMD-Gd
      DOTA. Bone Marrow Transplantation (2000) 25, 71-78.

PMID- 10654019
TI  - Central nervous system dysfunction as the first manifestation of multiple organ
      dysfunction syndrome in stem cell transplant patients.
AB  - Development of CNS dysfunction in the setting of hematopoietic stem cell
      transplant (HSCT) has been previously shown to predict for subsequent second
      organ dysfunction and death. In this paper, we describe the characteristics of
      this isolated CNS dysfunction, and its relationship to multiple organ dysfunction
      syndrome (MODS) after HSCT. Twenty-one of 186 patients undergoing HSCT developed
      CNS dysfunction as their first organ dysfunction a mean of 22.8 +/- 0.9 days
      after the start of the preparative regimen. Compared with 137 patients who
      developed no organ dysfunction, patients presenting with CNS dysfunction were
      more likely to have undergone allogeneic HSCT (P = 0.001) and to have received a
      total body irradiation-based regimen (P = 0.001), and were less likely to have
      been transplanted for lymphoma (P = 0.008). Patients who developed CNS
      dysfunction were more likely to die than those with no organ dysfunction (P < 0.
      001). Of the 21 patients who developed CNS dysfunction, 48% resolved their
      dysfunction by a mean of 4.6 days later without progression to second organ
      dysfunction, and 90% of these patients survived to day 100. Fifty-two percent of
      patients with CNS dysfunction progressed to second organ dysfunction (pulmonary
      or hepatic) a mean of 5.5 days later, and only 36% survived to day 100 (P =
      0.02). The patients who progressed to second organ dysfunction and those who did
      not were not different in terms of type of HSCT (allogeneic vs autologous), stem
      cell source (blood vs bone marrow), age, diagnosis or preparative regimen.
      Development of CNS dysfunction in the setting of HSCT, as with other organ
      dysfunctions (such as hepatic veno-occlusive disease), probably represents an
      early manifestation of a systemic disorder predisposing for MODS, increasing the
      risk of transplant-related mortality. Early systemic therapies directed at
      modulating this systemic disorder are probably indicated. Bone Marrow
      Transplantation (2000) 25, 79-83.

PMID- 10654020
TI  - Three to six year follow-up of normal donors who received recombinant human
      granulocyte colony-stimulating factor.
AB  - One hundred and one donors who had received filgrastim (rhG-CSF) for the purpose
      of donating either granulocytes or peripheral blood stem cells (PBSC) for their
      relatives more than 3 years ago were contacted. All donors had received daily rhG
      CSF at a median dose of 16 microg/kg/day (range 3-16) for a median of 6 days
      (range 3-15 days). All collection procedures were completed and short-term side
      effects of rhG-CSF were mild in the majority of the donors. At a median time
      interval of 43.13 months (range 35-73), the donors were contacted to assess
      whether adverse effects related to rhG-CSF administration had occurred. Prior to
      rhG-CSF two donors had cancer, one had a myocardial infarction, one was hepatitis
      C virus positive, one had a history of sinusitis, one had Graves' disease and two
      had arterial hypertension. None worsened with the rhG-CSF administration but the
      donor with a history of infarction had an episode of angina following apheresis,
      and the donor with Graves' disease had a stroke 15 months after rhG-CSF. Two
      pregnancies occurred after the rhG-CSF administration and one donor was 2-3 weeks
      pregnant during rhG-CSF treatment. Three pregnancies resulted in two normal
      births and one in a spontaneous abortion of a pregnancy which occurred more than
      2 years following rhG-CSF. In the time following rhG-CSF administration two
      donors developed cancer (breast and prostate cancer) at a follow-up of 70 and 11
      months, respectively. One donor developed lymphadenopathy 38 months after the rhG
      CSF, which spontaneously resolved. Blood counts were obtained in 70 donors at a
      median follow up of 40.4 months (range 16.8-70.8). Hematocrit was 43% (median,
      range 36.8-48), white blood cells were 5.7 x 109/l (median, range 3-14),
      granulocytes 3.71 x 109/l (median, range 1. 47-10.36), lymphocytes 1.67 x 109/l
      (median, range 0.90-3.96), monocytes 0.46 x 109/l (median, range 0.07-0.87) and
      platelet counts were 193.0 x 109/l (median, range 175.0-240.0). This study
      indicates that short-term administration of rhG-CSF to normal donors for the
      purpose of mobilizing the PBSC or granulocytes appears safe and without any
      obvious adverse effects more than 3 years after the donation. Bone Marrow
      Transplantation (2000) 25, 85-89.

PMID- 10654021
TI  - The detection of wt-1 transcripts is not associated with an increased leukemic
      relapse rate in patients with acute leukemia after allogeneic bone marrow or
      peripheral blood stem cell transplantation.
AB  - We studied the role of wt-1 as a minimal residual disease (MRD) marker in 46
      patients with acute leukemia (AL) (1st CR n = 24; 2nd CR n = 9, in relapse n =
      13) after allogeneic bone marrow or peripheral blood stem cell transplantation.
      Prior to allogeneic transplant, wt-1 transcripts were detected by PCR in 38 of 46
      patients (83%) with AL. After transplant, in 14 of 38 patients (37%) wt-1
      transcripts were detected in at least one PCR assay at a median of 12 months post
      transplant (range 1-89 months). Twelve of the 38 patients relapsed after
      transplant, but only seven of the 12 were wt-1 positive after transplant. In five
      relapsing patients the wt-1 test remained negative 0 to 3 months prior to
      relapse. On the other hand, only seven of 14 patients with a positive test for wt
      1 after transplant, relapsed consecutively. In 17 of the 46 study patients
      chromosomal abnormalities had been found prior to transplant (AML-M4eo with inv16
      n = 7, AML-M2 with t(8;21) n = 3, AML-M3 with t(15;17) n = 1, AML-M5 with t(4;11)
      n = 1, ALL with t(9;22) n = 5). In these 17 patients, we analyzed the wt-1
      transcript simultaneously with a specific chimeric transcript characteristic for
      the corresponding chromosomal abnormality. In 32 of 45 samples (71%) the results
      for the MRD marker and wt-1 transcript were concordant, but differed in 13
      patients. We conclude that detection of wt-1 transcripts does not predict
      leukemic relapse reliably and is therefore not a suitable MRD marker in patients
      with acute leukemia after allogeneic BM or PBSC transplantation. Bone Marrow
      Transplantation (2000) 25, 91-96.

PMID- 10654022
TI  - Purging in BCR-ABL-positive acute lymphoblastic leukemia using immunomagnetic
      beads: comparison of residual leukemia and purging efficiency in bone marrow vs
      peripheral blood stem cells by semiquantitative polymerase chain reaction.
AB  - Twenty autologous bone marrow (BM) and 25 peripheral blood stem cell (PBSC)
      grafts were collected from a total of 40 consecutive patients with BCR-ABL+ acute
      lymphoblastic leukemia (ALL) in first (n = 37) or second (n = 3) complete
      morphological remission and subsequently purged with a cocktail of anti-CD19, 
      CD10, AB4 MoAbs and immunomagnetic beads (IMB). Residual BCR-ABL-positive cells
      before purging were detected in 19 of 20 BM grafts at a median of 4 (range 0-6)
      logs and in 17 of 25 evaluable PBSC grafts at a median of 1 (range 0-3) log above
      the limit of detection assessed by a semiquantitative limiting log10-dilution RT
      PCR (P < 0.0001). IMB purging depleted a median of 2.5 (range 1-4) log of
      residual BCR-ABL+ cells from BM and a median of 1 (range 0-2) log from PBSC
      grafts, achieving RT-PCR negativity in 1/20 BM and 12/25 PBSC grafts after
      purging. Cell recoveries were 62% and 86% (P < 0.0001) of MNC and 74% and 97% (P
      = 0.065) of CD34+ cells after BM and PBSC purging, respectively. BM purging was
      superior using the triple MoAb cocktail which depleted 2.64 +/- 0.4 log (n = 14)
      compared to 1.6 +/- 0.4 log (n = 5) using the MoAb cocktail not including AB4 (P
      = 0. 02). We conclude that unpurged BM grafts contain 2-3 log more residual BCR
      ABL+ cells than unpurged PBSC grafts and that purging efficacy is superior in BM
      compared to PBSC grafts, but median titers in purged BM grafts still exceed those
      in purged PBSC grafts. Bone Marrow Transplantation (2000) 25, 97-104.

PMID- 10654023
TI  - Fulminant hepatitis B following bone marrow transplantation in an HBsAg-negative,
      HBsAb-positive recipient; reactivation of dormant virus during the
      immunosuppressive period.
AB  - It is widely accepted that seroconversion of HBsAg to HBsAb indicates clearance
      of hepatitis B virus. We describe a 50-year-old man with chronic myelocytic
      leukemia who developed lethal hepatitis B 22 months after allo-BMT. He had been
      negative for HBsAg and positive for HBsAb before BMT. Hepatitis B virus latently
      existing in the liver cells before BMT proliferated during the immunosuppressed
      period causing fatal hepatitis. Recipients with positive HBsAb should be
      considered to have the potential for active hepatitis B to emerge after BMT. Bone
      Marrow Transplantation (2000) 25, 105-108.

PMID- 10654024
TI  - A case of hemolytic uremic syndrome improved with nitric oxide.
AB  - Hemolytic uremic syndrome (HUS) after transplantation is difficult to treat, and
      there is no consensus regarding optimal mode of treatment. We attached
      transdermal isosorbide tape as a nitric oxide (NO) donor to patients with HUS
      after bone marrow transplantation (BMT). This was very effective in ameliorating
      the hemolysis and increasing platelet numbers. We report here the successful use
      of an isosorbide in a patient with HUS after transplantation. Bone Marrow
      Transplantation (2000) 25, 109-110.

PMID- 10654025
TI  - Allogeneic hematopoietic stem cell transplantation for advanced mycosis
      fungoides: evidence of a graft-versus-tumor effect.
AB  - Allogeneic hematopoietic stem cell transplantation should be considered as a
      therapeutic option for patients with generalized erythoderma or tumor stage MF.
      Indeed, the only curative option for MF may be an allogeneic transplant. Bone
      Marrow Transplantation (2000) 25, 111-113.

PMID- 10654026
TI  - Late and localized extramedullary relapse of a light chain kappa myeloma after
      syngeneic bone marrow transplantation.
AB  - We report the case of a 54-year-old female patient with stage IIIA kappa light
      chain myeloma (MM) who relapsed 7 years after syngeneic bone marrow
      transplantation (BMT). The relapse occurred as a voluminous soft tissue
      plasmacytoma in the leg, developing after local trauma. The patient was
      successfully treated with local radiotherapy and has remained progression-free
      for more than 2 years. This case represents one of the longest survivors, in
      complete remission, after syngeneic transplantation for MM. The presentation of
      recurrent disease as localized plasmacytoma with extramedullary growth is unusual
      in the post-transplant setting. Bone Marrow Transplantation (2000) 25, 115-117.

PMID- 10654027
TI  - Allogeneic PBPC transplantation: an effect on incidence and distribution of
      chronic graft-versus-host disease without long-term survival benefit?

PMID- 10654028
TI  - First report of Epstein-Barr virus lymphoproliferative disease after cord blood
      transplantation.

PMID- 10654029
TI  - Assessment of dental students' competence.

PMID- 10654030
TI  - Recent developments in understanding temporomandibular joint disorders. Part 1:
      Bone marrow abnormalities of the mandibular condyle.
AB  - Improvements in diagnostic imaging of the temporomandibular joint in the past 20
      years have shown that disk displacement is the most frequent abnormality in
      patients with joint pain and dysfunction. The aetiology of the pain is poorly
      understood. Recent studies with magnetic resonance imaging have demonstrated a
      number of other changes in the TMJ. In this paper I review the possible
      significance of alterations in the condylar bone marrow and its relationship to
      osteonecrosis.

PMID- 10654031
TI  - A new method for the automated alignment of dental radiographs for digital
      subtraction radiography.
AB  - OBJECTIVES: To provide a robust and convenient method by which radiographic
      images can be spatially aligned for digital radiographic subtraction without the
      use of manually selected reference points. METHODS: An automated method for image
      alignment is described which begins with the extraction of a large number of edge
      features (1500 or more pixels) from each of two radiographic images taken of the
      same anatomical region of a given patient. The features in the first radiograph
      are paired, pixel by pixel, with those in the second radiograph using a nearest
      neighbor criterion. The edge features in the first radiograph are aligned with
      those in the second radiograph by performing an affine transformation that is
      consistent with the projection geometry for a plantar parallel X-ray beam.
      Transformation parameters are determined which provide the smallest spatial
      alignment error between the two sets of equivalent features. These parameters are
      found by a closed-form analytic solution, thus enabling a computationally
      efficient implementation. The final transformation is then applied to the entire
      first image resulting in a close spatial match to the second image. The
      performance of three dentists using the automatic method was compared with their
      performance using a manual method of alignment for eight pairs of images.
      RESULTS: The root mean squared error in image alignment for the automatic method
      was 14% lower than that with manual alignment. The variability for the automatic
      method was half that of the maximal method as measured by the residual error. The
      automatic method was also three times faster than the manual method. CONCLUSIONS:
      This method could make digital subtraction more accessible to researchers and
      practising dentists. Batch mode implementation could enable the processing of
      large volumes of data. Restriction to a region of interest and improved feature
      extraction could further improve performance.

PMID- 10654032
TI  - Interaction between noise and file compression and its effect on the recognition
      of caries in digital imaging.
AB  - OBJECTIVES: To determine the interaction between image noise and file
      compression, with special emphasis on the accuracy of caries diagnosis. METHODS:
      Fifty-nine bitewing radiographs of patients were taken simultaneously with
      Ektaspeed Plus (Eastman-Kodak, Rochester, NY, USA) film without lead foil and the
      Digora storage phosphor system (Soredex, Helsinki, Finland). Three different
      levels of Gaussian noise were added to the original digital images which were
      then compressed with JPEG 53. Seven observers evaluated the presence and depth of
      caries lesions on selected approximal surfaces on a 5-point scale. The results of
      JPEG 27 compression from a previous study were also included. ROC analysis was
      used together with multivariate analysis of variance (MANOVA). RESULTS: JPEG 27
      and 53 reduced the file size down to 7% and 4.6% of the original respectively.
      ROC curve analysis showed no significant difference between image conditions
      (original, JPEG 27, and JPEG 53) at the same noise level. JPEG 27 and 53 had
      larger Az scores than their original counterparts at the same noise level.
      However, MANOVA showed that for depth estimation of enamel lesions JPEG 53
      resulted in a higher observer error. CONCLUSIONS: Both JPEG 53 and 27 could
      reduce some of the adverse effect of noise from the image by removing high
      spatial frequencies. JPEG 53, resulting in a compression ratio of 1:21, does not
      compromise the diagnostic performance in general. JPEG 53 compression may however
      affect the ability to detect enamel lesions.

PMID- 10654033
TI  - Physical properties of a photostimulable phosphor system for intra-oral
      radiography.
AB  - OBJECTIVES: To determine physical properties of the Digora digital intra-oral
      radiographic system (Soredex Orion Corporation, Helsinki, Finland) for different
      calibration settings and beam energies. METHODS: The line spread function (LSF)
      and the modulation transfer function (MTF) were determined from radiographs of a
      slit. Noise power spectra (NPS) were determined from radiographs exposed to
      homogeneous radiation fields at 10, 50 and 100% of the calibration exposure for
      three tube potentials. All calculations were performed using relative values of
      exposure comprised of gray level, the signal at the photomultiplier tube and the
      amplified signal in order to confirm agreement between these different
      approaches. Noise equivalent quanta (NEQ) were calculated from the one
      dimensional NPSs and the MTF. Detective quantum efficiencies (DQE) were
      determined from the NEQs and representative values of the photon fluence. Signal
      to-noise ratios (SNR) were calculated for different signal contrasts applying the
      NEQs. RESULTS: The MTF of the system exhibited typical characteristics and falls
      to a value close to zero at the Nyquist frequency of about 7 cycles/mm. Noise as
      expressed by the NPS was found to be relatively low, i.e. about 10(-5) to 10(-6)
      mm2 depending on exposure and frequency. There was no significant difference
      between data obtained at different beam energies. The NEQ and hence the DQE were
      relatively high. DQE decreased with increased exposure. For exposures in the
      clinical range of the DQE reached a peak value of about 25%. SNRs are favorable.
      CONCLUSION: The physical properties of the Digora intra-oral system indicate that
      it is suitable for digital intra-oral radiography.

PMID- 10654034
TI  - Measurement of the volume of oral tumors by three-dimensional spiral computed
      tomography.
AB  - OBJECTIVE: To determine the precision and accuracy of in vitro measurements of
      the volume of oral tumors with three-dimensional (3D) spiral computed tomography
      (CT) and their precision in vivo. METHODS: Two simulated tumors made of modelling
      compound mixed with contrast medium were positioned medial to the mandibles of
      five cadaver heads and examined with subsecond spiral CT. Two observers
      delineated the simulated tumors twice in axial, coronal and sagittal views and
      then measured the volume from multiplanar reconstructed images. The software
      tools automatically displayed the simulated tumors in 3D-reconstructed images
      with the volumetric measurements. The simulated tumors were removed and their
      volume measured by water displacement. The volume of 15 oral tumors associated
      with the mandible were measured in vivo with the same imaging methods and the
      precision analysed. RESULTS: There were no statistically significant differences
      between or within observers or between imaging and physical measurements in
      vitro, nor between inter- and intra-observer measurements in vivo (P > 0.05).
      CONCLUSION: Volumetric measurements from 3D-reconstructed CT are reliable and
      accurate in vitro and reliable in vivo. The method is potentially useful for the
      management of oral neoplasms.

PMID- 10654035
TI  - Evaluation of a new F speed dental X-ray film. The effect of processing solutions
      and a comparison with D and E speed films.
AB  - OBJECTIVE: To compare the properties of a new speed group F intra-oral X-ray film
      with those of three well established types both from groups D and E, and evaluate
      the impact of six commercially available processing solutions. METHODS: Four
      types of dental X-ray film, Flow (Flow X-ray, West Hempstead, NY, USA), speed
      group F, Ektaspeed Plus (Eastman Kodak, Rochester NY, USA) and M2 Comfort
      (AgfaGevaert, Morstel, Belgium), both speed group E, and Ultra-speed (Eastman
      Kodak), speed group D, were exposed under standardised conditions and processed
      in six different processing solutions. Base plus fog density, characteristic
      curves, film density, speed, average gradient, contrast and latitude and spatial
      resolution were calculated. RESULTS: The choice of processing chemistry affected
      radiographic characteristics including speed grouping. The new F film was
      consistently the fastest. M2 Comfort could achieve F speed and Ultra-speed
      achieved E speed using Automat XR chemicals. The speed of Ektaspeed Plus was
      independent of the automatic processing solution used. Ultra-Speed film had the
      lowest base plus fog density and the widest latitude. Film contrast was similar
      irrespective of the film and solution combination. CONCLUSIONS: The choice of
      processing chemistry can affect radiographic characteristics. The new F film
      reduces patient exposure by one-half compared with E speed film with no detriment
      to image quality.

PMID- 10654036
TI  - Accuracy of implant treatment planning utilizing template-guided reformatted
      computed tomography.
AB  - OBJECTIVES: To evaluate the magnitude of error in transferring the planned
      position of implants from reformatted CT scans to a surgical template. METHODS:
      The deviation between the position of the apex of the proposed implant in
      paraxial CT reformats and on the corresponding study cast was measured in 77
      prospective sites in five maxillas and nine mandibles. RESULTS: The transfer
      error was 0.6 (s.d. 0.4) mm in the maxilla and 0.3 (s.d. 0.4) mm in the mandible.
      CONCLUSIONS: The transfer errors detected in this investigation are not
      clinically relevant. Other factors involved in transferring positional and
      angular measurements from reformatted CT to the surgical site may result in more
      significant errors.

PMID- 10654037
TI  - Precision and accuracy of measurements in digital panoramic radiography.
AB  - OBJECTIVES: To evaluate the precision and accuracy of digital measurements in
      digital panoramic radiography. METHODS: A series of 70 digital panoramic
      radiographs were obtained of a dry skull in seven different positions with
      metallic pins and spheres fixed to the mandible. Three replicate measurements
      were performed with the mouse-driven cursor by one reader at 1:1 and 2:1
      magnification. Precision was assessed with the reliability index (R) and
      Malony/Rastogi test and the effect of magnification on accuracy by paired
      Wilcoxon test. RESULTS: Vertical measurements were less reproducible than
      horizontal measurements. There were significant differences in assessments
      between images at 1:1 and 2:1 magnification (P < 0.05). The maximum variation in
      mean difference was 0.4% of actual object length for pins and 1.2% for spheres.
      The difference did not exceed 0.1 mm. R was lower for 2:1 magnification and
      consistently lower for spheres compared with pins. CONCLUSION: The most reliable
      measurements were obtained of linear objects in the horizontal plane. Digital
      measurements are sufficiently accurate for clinical use.

PMID- 10654059
TI  - "Sweetness"

PMID- 10654038
TI  - A comparison of the diagnostic utility of two image receptors for panoramic
      radiography.
AB  - OBJECTIVE: To compare the diagnostic utility of two screen-film systems for
      panoramic radiography, one based on green and the other on ultraviolet light.
      MATERIALS AND METHODS: Two hundred consecutive adult patients with teeth in all
      four quadrants requiring panoramic radiographs were randomly allocated to one of
      two groups. One group was imaged with OGA L (CEA AB, Strangnas, Sweden) film
      using Lanex Regular (Eastman Kodak, Rochester, NY, USA) screens (the Lanex
      group). The other group was imaged using Ultra-Vision (Dupont UK Limited,
      Hertfordshire, UK) film and screens (the Ultra-vision group). Two different
      panoramic machines were used, a Planmeca (Planmeca OY, Helsinki, Finland) and
      Cranex (Soredex Orion Corporation, Helsinki, Finland). The radiographs were
      evaluated by two radiographers for overall quality and any faults recorded. Two
      dental radiologists evaluated the crestal and apical areas of every standing
      tooth on a 4-point scale. The likelihood of getting a high-quality image with the
      different films was modelled using logistic regression, adjusting for the
      radiologist and the area of the tooth being examined. Inter- and intra-examiner
      agreement was calculated using Kappa and weighted Kappa where appropriate.
      RESULTS: The radiographers recorded no significant differences in positioning
      errors between the two groups of film. However, the films produced on the Cranex
      were less likely to be recorded as excellent. The radiologists' interexaminer
      agreement for the lower molars and upper incisors was only moderate at best
      (kappa = 0.56). No significant differences were found between the likelihood of
      the two types of film providing a high-quality image. Crestal areas were more
      likely to be scored well than apical areas. CONCLUSION: There were no differences
      in ease of discerning apical and crestal areas between the two screen-film
      systems. There was only poor to moderate agreement between the two radiologists.
      Ultra-Vision can be recommended as an alternative to existing rare earth systems
      for panoramic radiography.

PMID- 10654060
TI  - The efficacy of perturbation training in nonoperative anterior cruciate ligament
      rehabilitation programs for physical active individuals.
AB  - BACKGROUND AND PURPOSE: Treatment techniques involving perturbations of support
      surfaces may induce compensatory muscle activity that could improve knee
      stability and increase the likelihood of returning patients to high-level
      physical activity. The purpose of this study was to determine the efficacy of
      augmenting standard nonoperative anterior cruciate ligament (ACL) rehabilitation
      programs with a perturbation training program. SUBJECTS: Twenty-six patients with
      acute ACL injury or ruptures of ACL grafts participated in the study. Subjects
      had to have a unilateral ACL injury, be free of concomitant multiple ligament or
      meniscal damage requiring surgical repair, and pass a screening examination
      designed to identify patients who had the potential to return to high-level
      physical activity with nonoperative treatments. Subjects also had to be regular
      participants in level I activities (eg, soccer, football, basketball) or level II
      activities (eg, racquet sports, skiing, construction work). METHODS: Subjects
      were randomly assigned to either a group that received a standard rehabilitation
      program (standard group) or a group that received the standard program augmented
      with a perturbation training program (perturbation group). Treatment outcome was
      determined from scores on the Knee Outcome Survey's Activities of Daily Living
      Scale (ADLS) and Sports Activity Scale, a global rating of knee function, scores
      on a series of single-limb hop tests, measurements of maximum isometric
      quadriceps femoris muscle force output, and the group frequency of unsuccessful
      rehabilitation. Unsuccessful rehabilitation was defined as the occurrence of an
      episode of giving way of the knee or failure to maintain the functional status of
      a rehabilitation candidate on retesting. RESULTS: More subjects had unsuccessful
      rehabilitation in the standard group compared with the perturbation group. There
      was a within-group x time interaction for the ADLS, global rating of knee
      function, and crossover hop test scores. These scores decreased from posttraining
      to the 6-month follow-up for the standard group. CONCLUSION AND DISCUSSION:
      Although both the standard program and the perturbation training program may
      allow subjects to return to high-level physical activity, the perturbation
      training program appears to reduce the risk of continued episodes of giving way
      of the knee during athletic participation and allows subjects to maintain their
      functional status for longer periods.

PMID- 10654061
TI  - Investigation of trunk and extremity movement associated with passive head
      turning in newborns.
AB  - BACKGROUND AND PURPOSE: Physical therapist examination of pediatric clients or
      clients with neurological conditions often includes the observation of
      stereotypical movement patterns such as the asymmetrical tonic neck reflex and
      righting reactions. The purpose of this study was to investigate whether
      extremity and trunk responses to passive head turning could be documented in
      newborn infants. SUBJECTS AND METHODS: Forty-two newborns with no known medical
      problems were videotaped within 5 days of birth while an investigator turned
      their heads left and right. Videotapes were stopped at 5-second intervals to
      record the direction of head turn with the rest of the body obscured. A second
      investigator recorded trunk and extremity position with the head obscured.
      RESULTS: The direction of head turning affected upper- and lower-extremity
      position, with extension stronger on the face side. The direction of trunk
      convexity was also affected by head position, with the trunk convex to the side
      to which the face was turned. CONCLUSION AND DISCUSSION: Extremity responses and
      trunk responses to passive head turning can be documented corresponding to
      patterns reported for the asymmetrical tonic neck reflex and righting reflexes in
      neonates with no known medical problems more frequently than would occur by
      chance.

PMID- 10654062
TI  - Detrimental effects of short-term glucocorticoid use on the rat diaphragm.
AB  - BACKGROUND AND PURPOSE: The purpose of this study was to determine the effect of
      short-term, high doses of glucocorticoids on both body and diaphragm weights as
      well as contractile characteristics of the rat diaphragm. SUBJECTS: Adult, female
      Sprague-Dawley rats were divided into 2 groups: a control group (n=16) and a
      prednisolone group (n=16). METHODS: The prednisolone group received prednisolone
      at a dosage of 5 mg/kg, and the control group received sham saline injections for
      5 days. Animals were weighed prior to and after completion of the drug injection
      period. At the completion of the drug injection period, the animals were
      sacrificed, and the diaphragm, soleus, and extensor digitorum longus muscles were
      removed and weighed. A small strip of the costal diaphragm was connected to a
      force transducer, and the following contractile characteristics were measured:
      maximal specific isometric tetanic tension, peak isometric twitch specific
      tension, one-half relaxation time, and time to peak tension. RESULTS: Both body
      and diaphragm weights decreased by 15% in the prednisolone group as compared with
      the control group. Maximal specific isometric tetanic tension was reduced 13% in
      the prednisolone group as compared with the control group. There was no
      difference in any twitch contractile characteristics between the 2 groups.
      CONCLUSION AND DISCUSSION: These data support the hypothesis that glucocorticoid
      treatment over a 5-day period results in a decrease in specific tension as well
      as diaphragm and body weight. These results may have implications for the
      treatment of patients receiving high doses of glucocorticoids for acute medical
      conditions.

PMID- 10654063
TI  - Alberta infant motor scale: reliability and validity when used on preterm infants
      in Taiwan.
AB  - BACKGROUND AND PURPOSE: The goal of this study was to examine the reliability and
      validity of measurements obtained with the Alberta Infant Motor Scale (AIMS) for
      evaluation of preterm infants in Taiwan. SUBJECTS: Two independent groups of
      preterm infants were used to investigate the reliability (n=45) and validity
      (n=41) for the AIMS. METHODS: In the reliability study, the AIMS was administered
      to the infants by a physical therapist, and infant performance was videotaped.
      The performance was then rescored by the same therapist and by 2 other therapists
      to examine the intrarater and interrater reliability. In the validity study, the
      AIMS and the Bayley Motor Scale were administered to the infants at 6 and 12
      months of age to examine criterion-related validity. RESULTS: Intraclass
      correlation coefficients (ICCs) for intrarater and interrater reliability of
      measurements obtained with the AIMS were high (ICC=.97-.99). The AIMS scores
      correlated with the Bayley Motor Scale scores at 6 and 12 months (r=.78 and.90),
      although the AIMS scores at 6 months were only moderately predictive of the motor
      function at 12 months (r=.56). CONCLUSION AND DISCUSSION: The results suggest
      that measurements obtained with the AIMS have acceptable reliability and
      concurrent validity but limited predictive value for evaluating preterm Taiwanese
      infants.

PMID- 10654064
TI  - Central causes of dizziness.

PMID- 10654065
TI  - Inputs from intrinsic primary afferent neurons to nitric oxide synthase
      immunoreactive neurons in the myenteric plexus of guinea pig ileum.
AB  - Nitric oxide synthase (NOS) immunoreactivity occurs in two groups of neurons in
      the guinea pig small intestine: descending interneurons that are also
      immunoreactive for choline acetyltransferase (ChAT), and inhibitory motor neurons
      that lack ChAT immunoreactivity. Interneurons that are involved in local reflexes
      would be expected to have inputs from intrinsic primary afferent (sensory)
      neurons, most of which are calbindin-immunoreactive. We examined this possibility
      using triple staining for NOS, ChAT and calbindin immunoreactivity and
      investigated the relationships between calbindin-immunoreactive varicosities and
      the cell bodies of NOS-immunoreactive neurons, using high-resolution confocal
      microscopy and electron microscopy. By confocal microscopy, we found that the
      cell bodies of ChAT/NOS interneurons received 84 +/- 23 (mean +/- SD) direct
      appositions from calbindin-immunoreactive varicosities and that the cell bodies
      of NOS-inhibitory motor neurons received 82 +/- 20 appositions. Electron
      microscopic examination of the relations of 265-calbindin-immunoreactive
      varicosities, at distances within the resolution of the confocal microscope (300
      nm), to 30 NOS-immunoreactive nerve cells indicated that 84% formed close
      contacts or synapses and 16% were separated from neurons by thin glial cell
      processes. Thus, each NOS-immunoreactive nerve cell receives about 70 synaptic
      inputs or close contacts from the calbindin-immunoreactive varicosities of
      intrinsic primary afferent neurons. It is concluded that there are monosynaptic
      reflex connections in which intrinsic primary afferent neurons synapse directly
      with motor neurons and di- or poly-synaptic reflexes in which ChAT- and NOS
      immunoreactive neurons are interneurons, interposed between intrinsic primary
      afferent neurons and NOS-inhibitory neurons.

PMID- 10654066
TI  - Transneuronal labeling of neurons in the adult rat central nervous system
      following inoculation of pseudorabies virus into the colon.
AB  - Transneuronal tracing with pseudorabies virus (PRV) was used to identify sites in
      the central nervous system involved in the neural control of colon function. PRV
      immunoreactive (IR) cells were primarily localized to the caudal lumbosacral (L6
      S1) and caudal thoracicrostral lumbar (T13-L1) spinal segments with the
      distribution varying according to survival time (72-96 h). In the lumbosacral
      spinal cord at all time points examined, significantly (P < or = 0.005) greater
      numbers of PRV-IR cells were present in the region of the sacral parasympathetic
      nucleus (SPN) of the S1 spinal segment compared to that of the L6 segment. These
      studies also revealed morphologically distinct cell types with a differential
      distribution (probably interneurons and preganglionic parasympathetic neurons) in
      the region of the SPN in the L6-S1 spinal segments following colon inoculation.
      PRV-labeled neurons were located at various levels of the neuraxis and at many
      sites had a distribution similar to that following injection of virus to other
      urogenital organs. However, some unique sites in the dorsal motor nucleus of the
      vagus, nucleus of the solitary tract, nucleus ambiguus and area postrema were
      also identified. To determine if labeling in these caudal medullary sites was
      mediated by spinal or vagal pathways, the colon was inoculated with PRV in
      animals with a complete spinal cord (T8) transection (5-7 days prior). Following
      spinal transection, PRV-infected cells were detected in the same caudal medullary
      regions; however, labeling in other regions (e.g., Barrington's nucleus) was
      eliminated or significantly reduced. These studies have yielded several novel
      observations concerning the central neural control of colonic function: (1) the
      preganglionic efferent and primary afferent innervation of the colon arises
      primarily from the S1 spinal segment; (2) the distribution of PRV-infected
      neurons in the central nervous system following colon inoculation was similar to
      that following PRV inoculation of other urogenital organs; (3) Barrington's
      nucleus, which has been identified previously as the pontine micturition center,
      may have a role in colonic function; and (4) PRV infection in Barrington's
      nucleus following colon inoculation is mediated by bulbospinal pathways whereas
      labeling in caudal medullary regions is mediated, at least in part, by vagal
      pathways.

PMID- 10654067
TI  - True enamel covering in teeth of the Australian lungfish Neoceratodus forsteri.
AB  - Lungfish are a unique order of sarcopterygian fish cleidographically positioned
      between tetrapods and fish. An uninterrupted 400-million-year-old fossil record
      has documented lungfish skeletal elements to remain virtually unchanged since the
      Early Devonian. In the current study we investigated the enamel layer of lungfish
      teeth in order to determine whether there was evidence for higher vertebrate
      "true" enamel in the Australian lungfish. Juvenile lungfish from the Brisbane
      River were processed for light and electron microscopy and analyzed for
      parameters indicative of true enamel formation. Using anti-amelogenin primary
      antibodies for immunodetection and Western blots, enamel protein epitopes were
      detected in developing lungfish teeth. Using transmission electron microscopy and
      electron diffraction analysis, long and parallel-oriented hydroxyapatite crystals
      were observed in lungfish outer tooth coverings. Our findings indicate that
      Australian lungfish teeth are covered by a layer of true enamel. Based on the
      lungfish fossil record we conclude that features of true enamel formation may be
      as old as 400 million years. Based on taxonomic classification we confirm that
      true enamel is found not only in tetrapods but also in the sarcopterygian clade
      of the Gnathostomata.

PMID- 10654068
TI  - Nanoscale topography of the basement membrane underlying the corneal epithelium
      of the rhesus macaque.
AB  - This paper quantitatively defines the nanoscale topography of the basement
      membrane underlying the anterior corneal epithelium of the macaque. Excised
      corneal buttons from macaques were placed in 2.5 mM ethylenediaminetetraacetate
      (EDTA) for 2.5 h, after which the epithelium was carefully removed to expose the
      underlying basement membrane. The integrity of the remaining basement membrane
      was verified using fluorescent microscopy in conjunction with antibody staining
      directed against laminin and collagen type IV as well as transmission electron
      microscopy. Characterization of the surface of the basement membrane was
      performed using transmission electron microscopy, high-resolution, low-voltage
      scanning electron microscopy, and atomic force microscopy. Quantitative data were
      obtained with all three imaging techniques and compared. The basement membrane
      has a complex topography consisting of tightly cross-linked fibers intermingled
      with pores. The mean elevation of features measured by transmission electron
      microscopy, scanning electron microscopy, and atomic force microscopy was 149 +/-
      60 nm, 191 +/- 72 nm, and 147 +/- 73 nm, respectively. Mean fiber diameter as
      measured by SEM was 77 +/- 44 nm and pore diameter was 72 +/- 40 nm, with pores
      occupying approximately 15% of the total surface area. Similar feature types and
      dimensions were also found for Matrigel, a commercially available basement
      membrane-like complex, supporting that a minimum of artifact was introduced by
      corneal preparative procedures to remove the overlying epithelium. Topographic
      features amplified the surface area over which cell-substratum interactions occur
      by an estimated 400%. The three-dimensional structure of the basement membrane
      exhibits a rich complex topography of individual features, consisting of pores
      and fibers with dimensions ranging from 30 to 400 nm. These nanoscale substratum
      features may modulate fundamental cell behaviors such as adhesion, migration,
      proliferation, and differentiation.

PMID- 10654069
TI  - Immunohistochemical analysis of Bcl-2 and Bax expression in relation to cell
      turnover and epithelial differentiation markers in the non-lactating human
      mammary gland epithelium.
AB  - The expression of the apoptosis-related proteins Bcl-2 and Bax was investigated
      by immunohistochemistry in the normal non-lactating human mammary gland in
      relation to cell proliferation and apoptosis. In order to characterize individual
      Bax/Bcl-2-immunoreactive cells, the epithelial markers cytokeratin 14 and 19 and
      the macrophage marker CD 68 were used. Secretory-like differentiation of
      epithelial cells was characterized by histochemistry and lectin staining of
      surface glycoconjugates. Cell proliferation was exclusively found in glandular
      epithelial cells with broad contact to the ductular lumen, whereas nuclei with
      apoptosis-related DNA fragmentation were seen predominantly in basally located
      glandular epithelial cells and in myoepithelial cells. Weak immunoreactivity for
      Bcl-2 and Bax was present throughout all epithelia, suggesting a balance between
      pro- and antiapoptotic effects in the majority of epithelial cells. However,
      specific cells showed a strong staining for Bax or Bcl-2. The strongly Bcl-2
      immunoreactive epithelial cells were not identical with proliferating cells, but
      they resembled them in configuration and in the luminal intraepithelial position.
      In contrast, the strongly Bax-positive epithelial cells had no or only a narrow
      contact to the ductular lumen. The different patterns of Bax/Bcl-2
      immunoreactivity in specific glandular epithelial cells suggest that there are
      also different grades of susceptibility towards apoptotic stimuli in individual
      glandular epithelial cells. We conclude that specific Bax/Bcl-2 expression
      patterns could reflect particular cell differentiation states, and that the
      strongly Bcl-2-positive cells in part could represent epithelial stem cells.

PMID- 10654070
TI  - Pituitary adenylate cyclase-activating polypeptide in intrinsic and extrinsic
      nerves of the rat pancreas.
AB  - Pituitary adenylate cyclase-activating polypeptide (PACAP) is the latest member
      of the vasoactive intestinal polypeptide (VIP) family of neuropeptides present in
      nerve fibres in many peripheral organs. Using double immunohistochemistry, with
      VIP as a marker for intrinsic innervation and calcitonin-gene related peptide
      (CGRP) as a marker for mainly extrinsic innervation, the distribution and
      localization of PACAP were studied in the rat pancreas. PACAP was demonstrated in
      nerve fibres in all compartments of the pancreas and in a subpopulation of
      intrapancreatic VIP-containing ganglion cells. PACAP and VIP were co-stored in
      intra- and interlobular nerve fibres innervating acini, blood vessels, and in
      nerve fibres within the islets of Langerhans. No PACAP immunoreactivity was
      observed in the islet cells. Another population of PACAP-immunoreactive nerve
      fibres co-localized with CGRP innervated ducts, blood vessels and acini.
      PACAP/CGRP-positive nerve fibres were also demonstrated within the islets.
      Neonatal capsaicin reduced the PACAP-38 concentration by approximately 50%, and
      accordingly a marked reduction in PACAP/CGRP-immunoreactive nerve fibres in the
      exocrine and endocrine pancreas was observed. Bilateral subdiaphragmatic vagotomy
      caused a slight but significant decrease in the PACAP-38 concentration compared
      with controls. In conclusion, PACAP-immunoreactive nerve fibres in the rat
      pancreas seem to have dual origin: extrinsic, most probably sensory fibres co
      storing CGRP; and intrinsic, constituting a subpopulation of VIP-containing nerve
      cell bodies and fibres innervating acinar cells and islet cells. Our data provide
      a morphological basis for the reported effects of PACAP in the pancreas and
      suggest that PACAP-containing nerves in the rat pancreas may have both efferent
      and sensory functions.

PMID- 10654071
TI  - Expression of the common alpha-subunit mRNA of glycoprotein hormones during the
      chick pituitary organogenesis, with special reference to the pars tuberalis.
AB  - The expression of a common alpha-subunit mRNA of glycoprotein hormones was
      examined in the pituitary of chick embryos at various stages of development by in
      situ hybridization with a digoxigenin-labeled quail alpha-subunit cRNA probe. As
      a comparison with the expression of alpha-subunit mRNA, the onset of luteinizing
      hormone (LH) immunoreactivity was examined by immunohistochemical staining with a
      chicken LH antiserum. Both alpha-subunit mRNA and LH immunoreactivity began to
      appear in the basal-posterior region of the Rathke's pouch at embryonic day (E)
      3.5. At E4.5 when the cephalic and caudal lobes of the pars distalis could be
      distinguished in the Rathke's pouch, intense signal for alpha-subunit mRNA was
      restricted to the cephalic lobe, consisting of a high columnar epithelium. At E6,
      gonadotrophs that were ovoid in shape, expressed intense signal for alpha-subunit
      mRNA, and revealed intense immunoreactivity for LH, were first detected in the
      cephalic lobe. At this stage, alpha-subunit mRNA expression became weak in the
      undifferentiated columnar cells of the cephalic lobe. At E8, the pars tuberalis
      primordium located close to the median eminence was formed at the lateral-apical
      end of the cephalic lobe. The primordium expressed intense signal for alpha
      subunit mRNA. Gonadotrophs showing immunoreactivity for LH were densely
      distributed throughout the cephalic and caudal lobes in 8-day-old embryos. The
      pars tuberalis primordium expressing alpha-subunit mRNA progressively extended
      along the median eminence with embryonal age and reached the rostoral end by E14.
      Thus, both primordia of the pars distalis and pars tuberalis expressed intense
      signal for the common alpha-subunit mRNA. This subunit may play a role in the
      cytodifferentiation of the adenohypophysis.

PMID- 10654072
TI  - Effect of cholecystokinin-2 receptor blockade on rat stomach ECL cells. A
      histochemical, electron-microscopic and chemical study.
AB  - The ECL cells in the oxyntic mucosa of rat stomach produce histamine and
      chromogranin A-derived peptides such as pancreastatin. The cells respond to
      gastrin via cholecystokinin-2 (CCK2) receptors. A CCK2 receptor blockade was
      induced by treatment (for up to 8 weeks) with two receptor antagonists, YM022 and
      YF476. Changes in ECL-cell morphology were examined by immunocytochemistry and
      electron microscopy, while changes in ECL cell-related biochemical parameters
      were monitored by measuring serum pancreastatin and oxyntic mucosal
      pancreastatin, and histamine concentrations, and histidine decarboxylase (HDC)
      activity. The CCK2 receptor blockade reduced the ECL-cell density only
      marginally, if at all, but transformed the ECL cells from slender, elongated
      cells with prominent projections to small, spherical cells without projections.
      The Golgi complex and the rough endoplasmic reticulum were diminished. Secretory
      vesicles were greatly reduced in volume density in the trans Golgi area.
      Circulating pancreastatin concentration and oxyntic mucosal HDC activity were
      lowered within a few hours. Oxyntic mucosal histamine and pancreastatin
      concentrations were reduced only gradually. The CCK2 receptor blockade was found
      to prevent the effects of omeprazole-evoked hypergastrinaemia on the ECL-cell
      activity and density. In conclusion, gastrin, acting on CCK2 receptors, is needed
      to maintain the shape, size and activity of the ECL cells, but not for
      maintaining the ECL-cell population.

PMID- 10654073
TI  - PDGF receptor kinase blocker AG1295 attenuates interstitial fibrosis in rat
      kidney after unilateral obstruction.
AB  - The current study was designed to investigate possible effects of the platelet
      derived growth factor (PDGF) receptor kinase blocker AG1295 on the development of
      interstitial fibrosis in rats with unilateral ureteral obstruction (UUO),
      monitored by ED-A+ fibronectin expression, the number of macrophages, and the
      presence of myofibroblasts as visualized by immunohistochemistry with monoclonal
      antibodies (mAb) IST9, mAb ED1, and mAb 1A4, respectively; interstitial fibrosis
      was quantified by Sirius-Red staining and computer-aided image analysis. Without
      AG1295 treatment, the Sirius-Red stained area of the control kidneys comprised
      6.8 +/- 1.3% of the totally inspected area and increased to 19.0 +/- 1.9% in
      animals by 14 days and to 23.4 +/- 1.7% by 21 days after UUO. The number of
      macrophages increased from 4.3 +/- 1.1 in controls to 16.6 +/- 2.6 in animals at
      14 days and to 23.2 +/- 4.4 at 21 days after UUO. This was accompanied by an
      increase in both ED-A+ fibronectin deposition and alpha-smooth muscle actin
      expression. Treatment with AG1295 (12 mg/kg body weight, daily i.p.)
      significantly reduced interstitial fibrosis as verified by a smaller Sirius-Red
      stained area (15.7 +/- 1.9% in animals at 14 days and 17.0 +/- 0.7% at 21 days
      after UUO) and also by a reduced number of macrophages (12.8 +/- 1.4 in animals
      at 14 days and 15.5 +/- 3.8 at 21 days after UUO), and by the ED-A+ fibronectin
      deposition and the number of cells positive for alpha-smooth muscle actin. The
      study indicates that the PDGF receptor kinase blocker AG1295 is able to decrease
      interstitial fibrosis in the rat UUO model significantly. The diminution of early
      fibrosis mediators, i.e., macrophages, ED-A+ fibronectin, and myofibroblast
      phenotype, points to a modulated fibrosis process via a blockade of PDGF actions.

PMID- 10654074
TI  - Distribution of P2X receptor subtypes in the rat female reproductive tract at
      late pro-oestrus/early oestrus.
AB  - Using immunohistochemistry techniques, we have examined the female reproductive
      organs of the rat in late pro-oestrus/early oestrus for the presence of purine
      nucleotide P2X1-7 receptors. In contrast to the male genital organs and the
      urinary tract, P2X1 receptors were present weakly, if at all, on smooth muscle
      membranes, except in blood vessels, whereas P2X2 immunoreactivity in smooth
      muscle was present in ovary and uterus as well as in blood vessels. Neither P2X1
      nor P2X2 receptors were present in fallopian tubes. P2X5 receptors were seen in
      the differentiating cell layers of the stratified squamous vaginal epithelium and
      also in the very early stages of ovarian follicular development; P2X6 receptors
      were present in secondary follicles. P2X7 receptors, markers for programmed cell
      death, were present in the keratinised vaginal epithelium and also in the
      exfoliating superficial endometrial cells. The possible biological significance
      of these signalling molecules in the female reproductive tract is discussed.

PMID- 10654075
TI  - Cytological changes during bioluminescence production in dissociated photocytes
      from the ophiuroid Amphipholis squamata (Echinodermata).
AB  - Bioluminescence in the ophiuroid Amphipholis squamata is produced by photocytes
      located within the spinal ganglia of arm spines. Ganglionic cells were
      dissociated (pronase digestion) and photocytes separated from other cell types by
      using a continuous density Percoll gradient. Aliquots from a stock suspension of
      photocytes in artificial sea water were stimulated to produce light by using KCl
      or acetylcholine and fixed for ultrastructural observation at different times of
      the luminous process. Preluminescent, luminescent, and postluminescent photocytes
      contained various intracytoplasmic structures, such as Golgi, flat and distended
      rough endoplasmic reticulum cisternae, bundles of fibrils, and up to six types of
      membrane-bounded vesicles. These structures either co-occurred or succeeded one
      another during the process of light production, indicating that they were most
      probably participating in the luminescence reaction. Two types of vesicles,
      sharing some ultrastructural features, probably represented the microsources of
      the photocytes. One type occurred almost exclusively in luminescent photocytes,
      and the other almost exclusively in postluminescent photocytes, suggesting that
      one may be transformed into the other. The latter type of vesicle contained
      densely packed fibro-tubular units, giving a characteristic paracrystalline
      appearance to postluminescent photocytes.

PMID- 10654076
TI  - Quantitative morphological analysis of embryonic cockroach (Periplaneta
      americana) brain neurons developing in vitro.
AB  - Neurons dissociated from the brain of embryonic cockroaches (Periplaneta
      americana) can be maintained in culture for several weeks. The survival as well
      as the progressive organization of the neurons into a complex network was studied
      during a 5-week period under different culture conditions. About 10% of the
      dissociated cells adhered to the culture dish. This figure remained constant
      throughout the culture. The cell diameter ranged from 10 to 20 microns and did
      not change significantly over time in culture. Whereas only a few cells exhibited
      neurites at the start of the culture, the number of cells exhibiting neurites
      increased to reach about 99% after 2 weeks. The different cells were then
      connected to each other, forming a network, which became more and more complex.
      The number of cells per cluster as well as the length and the diameter of the
      "connectives" that linked the different clusters were found to increase with
      time. The morphology of individual neurons within the network was visualized
      after intracellular injection of biocytin. Labeling with antibodies raised
      against serotonin or GABA indicated that neurons were able to differentiate and
      to acquire specific neurotransmitter fates. The serotonergic phenotype was found
      to appear progressively throughout the culture, in parallel with the formation of
      the network. Cell density, addition of fetal calf serum, and ecdysone were shown
      to influence the development of the network.

PMID- 10654077
TI  - Topographic mapping of the axons of the femoral chordotonal organ neurons in the
      cricket Gryllus bimaculatus.
AB  - Central projections of the femoral chordotonal organ (FCO) neurons in the cricket
      Gryllus bimaculatus were investigated by selectively staining small numbers of
      axons. The FCOs in all legs consist of partly fused ventral and dorsal scoloparia
      in the proximal femur. The ventral scoloparium neurons can be reliably divided
      into two groups: the ventral group neurons (VG), which are arranged in a
      sequentially smaller manner distally, and dorsal group neurons (DG), which simply
      aggregate in the proximal region near the dorsal scoloparium. All axons of the
      FCO projected to the ipsilateral half of the respective thoracic ganglion. The VG
      axons possessed dorso-lateral branches in the motor association neuropile and
      antero-ventral branches dorso-lateral to the anterior ventral association centre.
      However, the more proximally the somata were situated, the more medially the main
      neurites terminated. The DG axons showed some variations: some axons of the
      distally located neurons possessed dorso-lateral branches and terminated on the
      boundary region of the mVAC, while the other axons terminated exclusively in the
      medical ventral association centre (mVAC), including the ventral part, which
      receives auditory sensory neuron projections. All axons of the dorsal scoloparium
      neurons projected exclusively into the dorsal part of the mVAC; however, the
      ventrally located neurons projected more ventrally than did the dorsally located
      neurons. The above characteristics were nearly identical in the pro- and
      metathoracic FCOs. These results suggest that the cricket FCO axons are roughly
      organized in a somatotopic map and are broadly differentiated in their function.

PMID- 10654078
TI  - Characterization of an extremely motile cellular network in the rotifer
      Asplanchna spp. Structure, kinetics, and the cytoskeleton.
AB  - The pseudocoelomic body cavity of the rotifer Asplanchna spp. contains free cells
      that form a highly dynamic, three-dimensional polygonal network of filopodia.
      Using video-enhanced differential interference contrast microscopy, we have
      qualitatively and quantitatively characterized the motion types involved with
      network motility: (1) filopodial junctions are displaced laterally at 10.52 +/-
      0.46 microns/s; (2) free-ending filopodia form and extend at rates of 8.77 +/-
      0.40 microns/s, until they retract again at 7.23 +/- 0.87 microns/s; (3)
      filopodial strands fuse either laterally or tip to the lateral side. The
      combination of these motion types results in enlargements, diminutions, and
      extinctions of filopodial polygons, and in the formation of new polygons.
      Moreover, there is intense and fast (5.11 +/- 0.28 microns/s) particle transport
      within the filopodial strands. The organization of the cytoskeleton in filopodia
      was examined by electron microscopy and by labeling with fluorescent-tagged
      phalloidin. Filopodia contain several microtubules that are often organized in a
      bundle. Moreover, F-actin is present within the filopodia. To characterize which
      of these cytoskeletal systems is involved with cell and organelle motility, we
      have examined cell dynamics after incubations with colchicine or cytochalasin D.
      The results of these pharmacological experiments provide evidence that
      microtubules are required for both cell and organelle motility, but that actin
      filaments contribute to these phenomena and are required for the structural
      maintenance of slender filopodia.

PMID- 10654079
TI  - The mitotic centromeric protein MEI-S332 and its role in sister-chromatid
      cohesion.
AB  - Faithful segregation of sister chromatids during cell division requires properly
      regulated cohesion between the sister centromeres. The sister chromatids are
      attached along their lengths, but particularly tightly in the centromeric
      regions. Therefore specific cohesion proteins may be needed at the centromere.
      Here we show that Drosophila MEI-S332 protein localizes to mitotic metaphase
      centromeres. Both overexpression and mutation of MEI-S332 increase the number of
      apoptotic cells. In mei-S332 mutants the ratio of metaphase to anaphase figures
      is lower than wild type, but it is higher if MEI-S332 is overexpressed. In
      chromosomal squashes centromeric attachments appear weaker in mei-S332 mutants
      than wild type and tighter when MEI-S332 is overexpressed. These results are
      consistent with MEI-S332 contributing to centromeric sister-chromatid cohesion in
      a dose-dependent manner. MEI-S332 is the first member identified of a predicted
      class of centromeric proteins that maintain centromeric cohesion.

PMID- 10654080
TI  - Meiotic events at the centromeric heterochromatin: histone H3 phosphorylation,
      topoisomerase II alpha localization and chromosome condensation.
AB  - Mechanisms of chromosome condensation and segregation during the first meiotic
      division are not well understood. Resolution of recombination events to form
      chiasmata is important, for it is chiasmata that hold homologous chromosomes
      together for their oppositional orientation on the meiotic metaphase spindle,
      thus ensuring their accurate segregation during anaphase I. Events at the
      centromere are also important in bringing about proper attachment to the spindle
      apparatus. This study was designed to correlate the presence and activity of two
      proteins at the centromeric heterochromatin, topoisomerase II alpha (TOP2A) and
      histone H3, with the processes of chromosome condensation and individualization
      of chiasmate bivalents in murine spermatocytes. We tested the hypothesis that
      phosphorylation of histone H3 is a key event instigating localization of TOP2A to
      the centromeric heterochromatin and condensation of chromosomes as spermatocytes
      exit prophase and progress to metaphase. Activity of topoisomerase II is required
      for condensation of chromatin at the end of meiotic prophase. Histone H3 becomes
      phosphorylated at the end of prophase, beginning with its phosphorylation at the
      centromeric heterochromatin in the diplotene stage. However, it cannot be
      involved in localization of TOP2A, since TOP2A is localized to the centromeric
      heterochromatin throughout most of meiotic prophase. This observation suggests a
      meiotic function for TOP2A in addition to its role in chromatin condensation. The
      use of kinase inhibitors demonstrates that phosphorylation of histone H3 can be
      uncoupled from meiotic chromosome condensation; therefore other proteins, such as
      those constituting metaphase-promoting factor, must be involved. These results
      define the timing of important meiotic events at the centromeric heterochromatin
      and provide insight into mechanisms of chromosome condensation for meiotic
      metaphase.

PMID- 10654081
TI  - The topological organization of chromosomes 9 and 22 in cell nuclei has a
      determinative role in the induction of t(9,22) translocations and in the
      pathogenesis of t(9,22) leukemias.
AB  - The neighborhood relationships of chromosomes can be of great importance for
      basic cellular processes such as gene expression or translocation induction. In
      this study, the topological organization of chromosomes 9 and 22 was investigated
      in cell nuclei of G0-phase lymphocytes. We found that the territories of both
      chromosomes are predominantly located in the central region of cell nuclei. In
      addition to this, chromosomes 9 and 22 were frequently associated in pairs
      detected as false-positive ABL-BCR fusions. Both effects might substantially
      increase the probability of interaction between chromosomes. Because of this,
      exchange aberrations were studied in chromosomes 9 and 22 of human lymphocytes
      irradiated by neutrons. The rate of aberration induction between these
      chromosomes was 11 times higher than the expected frequency based on the
      fractional molecular weight of these chromosomes. We show that the increased rate
      of exchange between chromosomes 9 and 22 induced by neutrons corresponds to the
      neighborhood relationships of both chromosomes. Similar topological
      characteristics of ABL and BCR genes were found in several cell lines: T- and B
      lymphocytes. HL60 cells and bone marrow cells. This finding suggests that the
      specific chromatin structure mentioned might be responsible for the high rate of
      induction of t(9;22)-positive leukemias in the human population.

PMID- 10654082
TI  - Cytogenetic and molecular characterization of a highly repeated DNA sequence in
      the peach potato aphid Myzus persicae.
AB  - Electrophoresis following digestion of Myzus persicae genomic DNA with HindIII
      showed the presence of a prominent band of approximately 200 bp whereas a faint
      electrophoretic band corresponding to DNA fragments of about 3000 bp was observed
      after digestion with ApaI. In situ digestion with restriction enzymes, followed
      by in situ nick translation, showed that ApaI targets are localized at the
      nucleolus organizer-bearing X telomeric region, whereas HindIII restriction sites
      are clustered in intercalary C-positive areas on the same X chromosome.
      Fluorescent in situ hybridization (FISH) carried out by using digoxygenin-labeled
      HindIII repeats as probe fully confirmed overlapping between the hybridization
      sites of this probe and the AT-rich intercalary heterochromatic bands on the X
      chromosome. These findings, together with published data, allow us to conclude
      that the M. persicae genome possesses three classes of C-positive
      heterochromatin: (i) a GC-rich argentophilic band located on one telomere of the
      X chromosome that contains ApaI targets; (ii) AT-rich intercalary bands located
      on the X chromosome containing clustered HindIII fragments; (iii) AT-rich
      telomeric bands located on autosomes, consisting of HaeIII repeats. Molecular
      analysis has shown that the length of the HindIII repeat consensus sequence is
      189 bp with an AT content of 67%. Southern blotting with HindIII monomers
      revealed a regular ladder of bands composed of multimers of basic length that are
      characteristic of satellite DNAs. The HindIII repeat displays other features
      typical of eukaryotic satellite arrays such as overlapping with heterochromatic
      bands and a high degree of sequence similarity among monomers (84%-94%). A
      similarity plot showed that sequences were particularly variable in the 50-100 bp
      region whereas they proved to be highly conservative in the first 50 bp, thus
      suggesting that this portion of the repeat might be functionally important.

PMID- 10654083
TI  - Distribution and evolution of mobile elements in the virilis species group of
      Drosophila.
AB  - The distributions of Penelope and Ulysses, two transposable elements that can
      induce hybrid dysgenesis, were studied in several species groups of Drosophila.
      No significant hybridization to Penelope and Ulysses probes was detected by
      Southern blot analyses of species outside the virilis group. In contrast, both
      element families have had a long residence in all species of the virilis species
      group, as indicated by their strong presence in the heterochromatic chromocenter.
      Except for D. kanekoi, D. lummei, and some strains of D. virilis, species of the
      group carry full-sized, and at least potentially functional, copies of both
      element families. Consistent with the occurrence of recent transposition,
      Penelope and Ulysses elements are located at different chromosomal sites in
      different geographical strains of the same species. A total of 79 Penelope and 47
      Ulysses euchromatic insertion sites were localized to chromosomal subsections in
      species of the virilis group. Highly significant deviations from independence of
      the distributions of Penelope and Ulysses and previously established inversion
      breakpoints were documented, suggesting that these transposable elements may have
      played an important role in genomic reorganization and evolution of the virilis
      species group, which is especially rich in karyotypic variation.

PMID- 10654084
TI  - A LINE2 repetitive DNA sequence from the cichlid fish, Oreochromis niloticus:
      sequence analysis and chromosomal distribution.
AB  - We report the cloning and characterization of a long interspersed nucleotide
      element (LINE) from a cichlid fish, Oreochromis niloticus, and show the
      distribution of this element, called CiLINE2 for cichlid LINE2, in the
      chromosomes of this species. The identification of an open reading frame in
      CiLINE2 with amino acid sequence similarity to reverse transcriptases encoded by
      LINE-like elements in Caenorhabditis elegans, Platemys spixii, Schistosoma
      mansoni, Gallus gallus (CRI), Drosophila melanogaster (I factor), and Homo
      sapiens (LINE2), as well as the structure of the element, suggest it is a member
      of this family of non-long terminal repeat-containing retrotransposons. Search of
      a DNA sequence database identified sequences similar to CiLINE2 in four other
      fish species (Haplotaxodon microlepis, Oreochromis mossambicus, Pseudotropheus
      zebra, and Fugu rubripes). Southern blot hybridization experiments revealed the
      presence of sequences similar to CiLINE2 in all Tilapiini species analyzed from
      the genera Oreochromis, Tilapia, and Sarotherodon, and gave an estimated copy
      number of about 5500 for the haploid genome of O. niloticus. Fluorescent in situ
      hybridization showed that CiLINE2 sequences were organized in small clusters
      dispersed over all chromosomes of O. niloticus, with a higher concentration near
      chromosome ends. Furthermore, the long arm of chromosome 1 was strikingly
      enriched with this sequence. The distribution of LINE2-related elements might
      underlie the difference in chromosome banding patterns observed between cold
      blooded vertebrates and mammals.

PMID- 10654085
TI  - Substrate specificity and gene expression of the amino-acid permeases in
      Saccharomyces cerevisiae.
AB  - All known amino-acid permeases (AAPs) in Saccharomyces cerevisiae belong to a
      single family of homologous proteins. Genes of 15 AAPs were overexpressed in
      different strains, and the ability to take up one or more of the 20 common L
      alpha-amino acids was studied in order to obtain a complete picture of the
      substrate specificity for these permeases. Radiolabelled amino-acid uptake
      measurements showed that Agp1p is a general permease for most uncharged amino
      acids (Ala, Gly, Ser, Thr, Cys, Met, Phe, Tyr, Ile, Leu, Val, Gln and Asn).
      Gnp1p, which is closely related to Agp1p, has a somewhat less-broad specificity,
      transporting Leu, Ser, Thr, Cys, Met, Gln and Asn, while Bap2p and Bap3p, which
      are also closely related to Agp1p, are able to transport Ile, Leu, Val, Cys, Met,
      Phe, Tyr and Trp. All four permeases are transcriptionally induced by an
      extracellular amino acid, but differ in expression with respect to the nitrogen
      source. On a non-repressive nitrogen source, AGP1 is induced, while GLN1, BAP2
      and BAP3 are not. Except for Dip5p, which is a transporter for Glu, Asp, Gln,
      Asn, Ser, Ala and Gly, the rest of the permeases exhibit narrow specificity.
      Tat2p can take up Phe, Trp and Tyr; Put4p can transport Ala, Gly and Pro; while
      Can1p, Lyp1p and the previously uncharacterized Alp1p are specific for the
      cationic amino acids. These findings modify the prevalent view that S. cerevisiae
      only contains one general amino-acid permease, Gap1p, and a number of permeases
      that are specific for a single or a few amino acids.

PMID- 10654086
TI  - The budding yeast cohesin gene SCC1/MCD1/RHC21 genetically interacts with PKA,
      CDK and APC.
AB  - Cohesin is a protein that plays a key role in the cohesion and separation of
      sister chromatids. During the duplication of chromatids, cohesin holds sister
      chromatids together until the onset of anaphase, and thereby prevents the
      premature separation of sister chromatids which would otherwise jeopardize the
      faithful segregation of chromosomes. To investigate the molecular mechanisms of
      sister chromatid cohesion, we have isolated multicopy suppressors of a
      temperature-sensitive (ts) mutation in the SCC1/MCD1/RHC21 gene which encodes a
      component of the cohesin complex in budding yeast. Isolation of multicopy
      suppressors of rhc21-sk16 and further genetic analyses revealed that several
      distinct biological pathways are involved in the regulation of SCC1/MCD1/RHC21
      function. Firstly, PDE2 and BCY1, each of which inhibits the activity of protein
      kinase A (PKA), suppressed the temperature sensitivity of the rhc21-sk16 mutant.
      Secondly, PDE2 suppressed the temperature sensitivity of the cdc16-1 mutant.
      These results suggest that SCC1/MCD1/RHC21 is negatively regulated by the PKA
      pathway via the anaphase promoting complex (APC). Thirdly, ZDS1, a multicopy
      suppressor of cdc28-1N, and its homologue ZDS2 were isolated as multicopy
      suppressors of rhc21-sk16. Furthermore, the rhc21-sk16 mutant did not grow in the
      presence of the cdc28-1N mutation. Hence, SCC1/MCD1/RHC21 is positively regulated
      by the mitotic CDK, CDC28. Finally, SCC1/MCD1/RHC21 was found to interact
      genetically with CDC20, an activator of APC. Overexpression of CDC20 suppressed
      the temperature sensitivity of rhc21-sk16, and rhc21-sk16 was shown to be
      synthetically lethal with cdc20-1. In addition, the growth of the rhc21-sk16
      mutant was inhibited by overproduction of the anaphase inhibitor Pds1p, whose
      degradation is mediated by Cdc20p in APC-dependent proteolysis. The functional
      relationships between SCC1/MCD1/RHC21 and PKA, CDK or APC are discussed.

PMID- 10654087
TI  - Use of sulfite resistance in Saccharomyces cerevisiae as a dominant selectable
      marker.
AB  - Two S. cerevisiae genes were found to exhibit dominant phenotypes useful for
      selecting transformants of industrial and laboratory strains of S. cerevisiae.
      FZF1-4, which confers sulfite resistance, was originally isolated and identified
      as RSU1-4, but the two genes are shown here to be allelic. Cysteine 57 in wild
      type Fzf1p was found to be replaced by tyrosine in Fzf1-4p. Multicopy SSU1, which
      also confers sulfite resistance, was found to be somewhat less efficient. In both
      cases, a period of outgrowth in non-selective medium following transformation was
      found to be necessary. The number of transformants obtained was found to be
      strain-dependent, and also to depend on the sulfite concentration used during
      selection. Undesirable background growth of non-transformants was not observed at
      cell densities as high as 2.5 x 10(7)/plate. In two ura3 laboratory strains where
      selection for URA3 was applied independently of that for sulfite, the
      transformation efficiency for sulfite resistance was about 50% that for uracil
      prototrophy.

PMID- 10654088
TI  - Complex group-I introns in nuclear SSU rDNA of red and green algae: evidence of
      homing-endonuclease pseudogenes in the Bangiophyceae.
AB  - The green alga Scenedesmus pupukensis and the red alga Porphyra spiralis contain
      large group-IC1 introns in their nuclear small subunit ribosomal RNA genes due to
      the presence of open reading frames at the 5' end of the introns. The putative
      555 amino-acid Scenedesmus-encoded protein harbors a sequence motif resembling
      the bacterial S9 ribosomal proteins. The Porphyra intron self-splices in vitro,
      and generates both ligated exons and a full-length intron RNA circle. The
      Porphyra intron has an unusual structural organization by encoding a potential
      149 amino-acid homing-endonuclease-like protein on the complementary strand. A
      comparison between related group-I introns in the Bangiophyceae revealed homing
      endonuclease-like pseudogenes due to frame-shifts and deletions in Porphyra and
      Bangia. The Scenedesmus and Porphyra introns provide new insights into the
      evolution and possible novel functions of nuclear group-I intron proteins.

PMID- 10654089
TI  - Photoperiod-sensitive cytoplasmic male sterility in wheat: nuclear-mitochondrial
      incompatibility results in differential processing of the mitochondrial orf25
      gene.
AB  - An alloplasmic wheat line with the cytoplasm of Aegilops crassa expresses
      photoperiod-sensitive cytoplasmic male sterility (PCMS). Southern- and Northern
      hybridization analyses showed that this line contains alterations in both the
      gene structure and transcription patterns of the mitochondrial gene orf25. In
      this study, the nucleotide sequence around the orf25 gene of Ae. crassa (CR
      orf25) and common wheat (AE-orf25) was determined, and we found that the upstream
      region of CR-orf25 had been replaced by that of rps7 of common wheat (AE-rps7)
      through recombination. A novel open reading frame (orf48) is present upstream of
      CR-orf25. In these three genes, transcription was initiated from the consensus
      promoter motif of plant mitochondrial genes located in the upstream regions.
      Processing enzymes in Ae. crassa and common wheat cleave the respective precursor
      mRNAs, namely CR-orf25 and AE-rps7, at sites similar to that of the premature
      mitochondrial 26S rRNA. In contrast, the precursor mRNA is not effectively
      processed at the target sequence of CR-orf25 in the alloplasmic wheat line.
      Because major transcripts of the euplasmic CR-orf25 and AE-rps7 genes would
      result in a truncated orf48 product, one possibility is that the orf48 protein
      might disturb mitochondrial function at a specific stage and hence affect the
      expression of the PCMS trait.

PMID- 10654090
TI  - Volvox germline-specific genes that are putative targets of RegA repression
      encode chloroplast proteins.
AB  - In Volvox carteri, regA acts as a master gene to suppress all germ cell functions
      in somatic cells. Its product, RegA, has features of a transcriptional repressor.
      Here we report cDNA sequences representing 15 nuclear genes with properties
      expected of RegA targets: they are expressed strongly in germ cells and in regA-,
      but not regA+, somatic cells. Two of them encode polypeptides with no
      recognizable features, but ten (like three previously sequenced ones) encode
      chloroplast proteins of known function, and the remaining three encode putative
      chloroplast proteins of unknown function. This suggests that RegA blocks
      reproductive development in somatic cells by preventing chloroplast biogenesis,
      thereby making it impossible for the cells to grow enough to reproduce.

PMID- 10654091
TI  - Insertional mutagenesis in Coprinus cinereus: use of a dominant selectable marker
      to generate tagged, sporulation-defective mutants.
AB  - We have constructed a dominant selectable marker, PHT1, for transformation of the
      basidiomycete Coprinus cinereus. PHT1 consists of a bacterial hygromycin B
      resistance gene fused to the promoter and terminator regions of the C. cinereus
      beta-tubulin gene. We found in transformation experiments that PHT1 confers
      hygromycin B resistance to all strains of C. cinereus tested, that it integrates
      without apparent bias into the genome, and that it is stable through meiotic
      crosses. We used a plasmid containing this marker, pPHT1, for restriction enzyme
      mediated integration (REMI) and found that this technique could increase
      transformation efficiencies more than seven-fold. In REMI experiments using KpnI,
      the integrated DNA was flanked by intact KpnI sites in 53% of the cases examined,
      single-copy insertions represented 60% of the integration events, and most
      multicopy insertions were oriented head-to-tail. A screen of REMI-generated
      transformants yielded sporulation-defective mutants at a frequency of 1.2%.
      Genetic analysis showed that in six of nine mutants examined, the defect in spore
      formation is most likely a direct result of the pPHT1 insertion, and in three of
      these mutants a single pPHT1 locus was shown to cosegregate with the sporulation
      defect. We used semi-random PCR to isolate the genomic DNA adjacent to one pPHT1
      insertion in a sporulation-defective mutant and found that we had disrupted the
      C. cinereus spo11 gene. Thus, REMI, in combination with pPHT1, is a powerful tool
      for the dissection of the meiotic process in C. cinereus.

PMID- 10654092
TI  - Complementary mating types of Mucor circinelloides show electrophoretic karyotype
      heterogeneity.
AB  - Electrophoretic karyotypes of ten strains of Mucor circinelloides f. lusitanicus
      were generated by contour-clamped homogeneous electric field (CHEF) gel
      electrophoresis. Most of the strains analyzed showed polymorphisms, but a
      different main karyotype pattern could be correlated with each mating type.
      Genome structure was further analyzed by gene assignment to the chromosome-sized
      DNAs. Nonradioactive hybridization techniques identified the chromosomal
      localization of seven cloned genes. The hybridization patterns confirmed the
      similarity between the mating-type (-) strains and showed some heterogeneity
      among the mating-type (+) strains. Linkage was found between genes pyrF and chs3
      in all the strains, between the gene leuA and the rDNA in all mating-type (-)
      strains and ATCC 1216b (+), and between chs2 and the rDNA in CBS 969.68 (+). This
      is the first time that gene linkage in M. circinelloides has been reported, but
      in some cases the linkage relationships obtained are strain-dependent.

PMID- 10654093
TI  - Early diagnosis of Alzheimer dementia based on clinical and biological factors.
AB  - Alzheimer's disease (AD) is common in elderly individuals; it causes distress for
      the patients and their relatives as well as large costs for the society. With the
      advent of symptomatic treatment at present and probable etiology-based cures in
      the future, it will be possible to relieve and put an end to these negative
      effects. Therefore, it is necessary to diagnose the disease as early as possible.
      In this review, we briefly summarize the state-of-the-art concerning various
      available clinical and biochemical methods for identifying AD. Increasing age,
      heritage, and presence of ApoE e4 allele have been confirmed as risk factors for
      AD as well as some putative factors (e.g., low education, hypertension,
      hypotension) based on epidemiological recent research. Selective impairment of
      episodic memory has been found to be a preclinical marker for future development
      of AD based on convergent data from asymptomatic AD-related mutation carriers,
      longitudinal studies of patients with mild cognitive impairment (MCI), and
      epidemiological studies of incident AD cases. Neurophysiological methods are
      inexpensive and useful for the identification of changes in brain dysfunction in
      AD and new promising methods are under development. Using magnetic resonance
      imaging (MRT), structural measurements of brain atrophy and specific brain
      structures such as the hippocampus have been reported to detect dementia
      development early in the course of disease. Similarly, functional measurements of
      brain activity (e.g., blood flow) have revealed that hypometabolism in bilateral
      parietotemporal brain areas early in the disease course. Finally, biochemical
      studies have demonstrated that certain proteins (e.g., tau the A beta 1-42/43
      metabolite of the amyloid precursor protein) may be associated with the disease
      process in AD, although the specificity of these markers remains to be
      established. It is concluded that still no single marker of AD exists, which
      makes it necessary to rely on data from multiple sources in order to arrive at
      the best possible diagnosis of AD.

PMID- 10654094
TI  - Reanalysis of the first case of Alzheimer's disease.
AB  - When a disease becomes as important as Alzheimer's dementia, there is a natural
      interest in its medical history and in the origin of the underlying disease
      concept. Key to understanding Alois Alzheimer's views on the disease, which was
      named after him, are the histological sections of the cases he saw. This
      histological material was rediscovered in Munich in 1992 and 1997 (Neurogenetics
      1997, 1:73-80; 1998, 1:223-228). An extensive neuropathological and molecular
      genetic analysis of the tissue is currently being carried out. The present
      article summarizes the history of the rediscovery and provides an analysis of the
      neuropathology of Alois Alzheimer's first case, Auguste D.

PMID- 10654095
TI  - Neuropathology of Alzheimer's disease: what is new since A. Alzheimer?
AB  - Alzheimer's disease results from severe cytoskeletal alterations in only a few
      neuronal types within the human central nervous system. These intraneuronal
      changes take the form of neurofibrillary tangles and neuropil threads. Beginning
      in predisposed induction sites in the allocortex, the lesions follow a
      predictable sequence as they engulf other territories of the cerebral cortex and
      a specific set of subcortical nuclei. Some components of the brain are
      devastated, while others remain intact until the end phase of the disease.
      Assessment of the location of the afflicted neurons and the severity of the
      lesions allows the distinction of stages in the development of the disease. The
      degenerative process begins with the emergence of the first lesions, at whatever
      age it occurs. The illness remains subclinical for years, and proceeds
      inexorably, gradually laying waste to higher order limbic system centers.
      Clinical symptoms are observed only late in the course of the disease, and their
      appearance is usually concurrent with the encroachment of the destructive process
      upon neocortical association areas. The sequence of destruction bears a striking
      resemblance to the inverse sequence of cortical myelination. Late myelinating
      areas and layers develop the disease-related changes earlier and at higher
      densities than those which are myelinated early. The brain of the human adult is
      heavily laden with intraneuronal deposits of lipofuscin and neuromelanin pigment.
      The average density of neuronal pigmentation in given cortical areas mirrors the
      density of cytoskeletal lesions that develop in the course of the disease.
      Pigment-laden neuronal types giving rise to a single long, thin, unmyelinated or
      sparsely myelinated axon are particularly prone to developing Alzheimer's disease
      related cytoskeletal changes.

PMID- 10654096
TI  - The biological and pathological function of presenilin proteins--simple cell
      systems and a worm in Alzheimer's disease research.
AB  - Alzheimer's disease (AD) is the most common form of dementia. In a small number
      of cases AD is genetically inherited. Mutations are associated with so far three
      genes. These genes encode the beta-amyloid precursor protein (beta APP), as well
      as presenilin (PS) 1 and -2. Mutations in all three genes affect the generation
      of amyloid beta-peptide (A beta), which is the major component of senile plaques.
      Mutations in the PS genes occur much more frequently as those associated with the
      beta APP gene and can cause the earliest onset of AD ever recorded. PS genes are
      not only involved in familial AD but also play a functional role in the general
      production of A beta. Therefore PS proteins are key molecules, which will allow
      us to understand fundamental aspects of the molecular mechanisms involved in AD.
      Here we will summarize the pathological as well as biological function of PS and
      demonstrate that simple systems, such as cultured cells and the worm
      Caenorhabditis elegans can be used for modern AD research.

PMID- 10654097
TI  - Retrogenesis: clinical, physiologic, and pathologic mechanisms in brain aging,
      Alzheimer's and other dementing processes.
AB  - Data from clinical, electrophysiologic, neurophysiologic, neuroimaging and
      neuropathologic sources indicates that the progression of brain aging and
      Alzheimer's disease (AD) deterioration proceeds inversely to human ontogenic
      acquisition patterns. A word for this process of degenerative developmental
      recapitulation, "retrogenesis", has been proposed. These retrogenic processes
      provide new insights into the pathologic mechanism of AD deterioration. An
      understanding of retrogenic phenonmena can also result in insights into the
      applicability of retrogenic pathologic mechanisms for non-AD dementing disorders.
      Management strategies based upon retrogenesis have recently been proposed.
      Retrogenic pathophysiology also points to previously unexplored pharmacologic
      approaches to dementia prevention and treatment.

PMID- 10654098
TI  - Risk factors and differential diagnosis of Alzheimer's disease.
AB  - Due to demographic changes the frequency of dementia is increasing dramatically.
      About 50-60% of patients with dementia are clinically associated with AD, which
      is a multifactorial and long-term disease both in clinical and preclinical
      aspects. Various genetic and non-genetic risk factors play a role in influencing
      age of onset and disease progression.

PMID- 10654099
TI  - Alzheimer's disease: past, present, and future.
AB  - As we look to a world where more individuals will suffer from dementia, it is
      important to reflect on our past accomplishments as we work to create a better
      future. Attempts to develop better medications for Alzheimer's disease focus on
      symptomatic treatments for both cognitive and behavioral symptoms. Some progress
      has been made in the areas through use of cholinesterase inhibitors and novel
      neuroleptics. Quality of life is a central concept to improving our interventions
      and to developing more effective treatments based on our understanding of
      pathogenesis. In the past, almost hundred years since the pioneering work in Emil
      Kraepelin's laboratory that we are celebrating in this series of papers, we have
      come far but we have further to go.

PMID- 10654100
TI  - In vivo PET imaging and postmortem studies suggest potentially reversible and
      irreversible stages of brain metabolic failure in Alzheimer's disease.
AB  - In vivo brain imaging of patients with Alzheimer's disease (AD) using positron
      emission tomography (PET) demonstrates progressive reductions in resting-state
      brain glucose metabolism and blood flow (markers of synaptic activity) in
      relation to dementia severity, more so in association than primary cortical
      regions. During cognitive or psychophysical stimulation, however, blood flow and
      metabolism in the affected brain regions can increase to the same extent in
      mildly demented AD patients as in age-matched controls, despite reduced resting
      state values. The extent of activation declines with dementia severity and is
      markedly reduced in severely demented patients. Thus, there appears to be an
      initial functionally-responsive stage in AD, which direct brain analysis suggests
      is accompanied by reversible down-regulation because of reduced synaptic energy
      demand of enzymes mediating mitochondrial oxidative-phosphorylation. A later
      irreversible stage of AD is accompanied by marked synaptic loss, accumulation of
      intracellular neurofibrillary tangles, reduced general transcriptional capacity,
      and death of neurons.

PMID- 10654101
TI  - Molecular pathogenesis of prion diseases.
AB  - Prion diseases such as Creutzfeldt-Jakob disease in humans, scrapie in sheep, and
      BSE in cattle are transmissible and fatal neurodegenerative diseases. The
      infectious agent of these diseases has been designated as "prion". It consists
      mainly and perhaps exclusively of a conformational variant of a physiological
      glycoprotein, the cellular prion, protein, PrPC, which is a copper-binding
      protein of the cell surface. In spite of the wealth of biochemical and
      biophysical information, the conformational transition from PrPC to PrPSc, the
      infectious isoform of the prion protein, is not well understood. Nerve cell loss
      in prion diseases may be caused by neurotoxic effects of the prion protein.
      Certain properties of the prion protein such as the apparent form of its
      glycosylation and conformational properties reflected by the preferential site of
      digestion with proteinase K are associated with particular phenotypes of prion
      disease. The appearance of a new variant of Creutzfeldt-Jakob disease in humans,
      which is most likely caused by the consumption of BSE-infected food in the UK, is
      cause for major concern particularly since there is no known effective treatment
      of prion diseases.

PMID- 10654102
TI  - The Lewy body variant of Alzheimer's disease: clinical, pathophysiological and
      conceptual issues.
AB  - In 1923, Friedrich H. Lewy described dementia with Lewy bodies in a large
      proportion of his patients with paralysis agitans which had co-incident plaques
      and neurofibrillary tangles. The potential contribution of Lewy bodies to a
      dementia syndrome with fluctuating course, visual hallucinations, Parkinsonian
      features and neuroleptic hypersensitivity was rediscovered many decades later.
      The comorbidity of Alzheimer's and Parkinson's disease is not uncommon as both
      diseases show an exponential increase with advancing age and their coincidence is
      of great clinical importance. The combination of a cholinergic deficit--which is
      particularly severe due to the double pathology targeting the basal nucleus of
      Meynert--and a dopaminergic deficit requires cholinergic and cautious
      dopaminergic treatment. Excessive dopamine (L-dopa), antidopaminergic
      (neuroleptic) or anticholinergic treatment (anti-Parkinson or neuroleptic
      medication) may further complicate the condition, worsen extrapyramidal,
      psychotic or cognitive disturbances and even lead to a neuroleptic malignant
      syndrome.

PMID- 10654103
TI  - Investigations on oxidative stress and therapeutical implications in dementia.
AB  - Alzheimer's disease (AD) is a progressive dementia affecting a large proportion
      of the aging population. The histopathological changes in AD include neuronal
      cell death and formation of amyloid plaques and neurofibrillary tangles (NFTs)
      NFTs are composed of hyperphosphorylated tau protein, and senile plaques contain
      aggregates of the beta-peptide. There is also evidence that brain tissue in
      patients with AD is exposed to oxidative stress during the course of the disease.
      Advanced glycation endproducts (AGEs), which are formed by a non-enzymatic
      reaction of glucose with long-lived protein deposits, are potentially toxic to
      the cell, are present in brain plaques in AD, and its extracellular accumulation
      in AD may be caused by an accelerated oxidation of glycated proteins. The
      microtubuli-associated protein tau is also subject to intracellular AGE
      formation. AGEs participate in neuronal death causing direct (chemical) radical
      production: Glycated proteins produce nearly 50-fold more radicals than non
      glycated proteins, and indirect (cellular) radical production: Interaction of
      AGEs with cells increases oxidative stress. During aging cellular defence
      mechanisms weaken and the damages to cell constituents accumulate leading to loss
      of function and finally cell death. The development of drugs for the treatment of
      AD remains at a very unsatisfying state. However, pharmacological approaches
      which break the vicious cycles of oxidative stress and neurodegeneration offer
      new opportunities for the treatment of AD. Theses approaches include AGE
      inhibitors, antioxidants, and anti-inflammatory substances, which prevent radical
      production. AGE inhibitors might be able to stop formation of AGE-modified beta
      amyloid deposits, antioxidants are likely to scavenge intracellular and
      extracellular superoxide radicals and hydrogen peroxide before these radicals
      damage cell constituents or activate microglia, and anti-inflammatory drugs
      attenuating microglial radical and cytokine production.

PMID- 10654104
TI  - The neuropathology of schizophrenic diseases: historical aspects and present
      knowledge.
AB  - In the first half of the century, histological abnormalities in the cortex and
      thalamus of schizophrenics were described. These findings, however, remained
      controversial and finally were widely forgotten. More recently, a large number of
      structural imaging studies convincingly showed subtle structural changes such as
      ventricular enlargement, cortical sulcal enlargement, and smaller hippocampi in a
      considerable proportion of schizophrenic patients. Many studies reported minor
      tissue abnormalities in limbic structures. Since the limbic system is
      anatomically and functionally interposed between the neocortical association
      areas and phylogenetically old hypothalamic and brain stem systems, limbic
      dysfunction may lead to a dissociation between cognitive activities and basic
      emotional reactions, thus, explaining some aspects of the psychopathology of
      schizophrenia. Reduced cortical asymmetry, lack of gliosis, and other findings
      support the idea of a disorder of early brain development; however, a progressive
      component also might be inherent.

PMID- 10654105
TI  - The course of schizophrenia in the light of modern follow-up studies: the ABC and
      WHO studies.
AB  - In schizophrenia most of the social consequences emerge in the prodromal phase of
      the illness and before treatment is initiated. Further course is determined by
      the level of social development at illness onset and by age- and sex-related
      illness behavior. Despite the sex difference in age at onset the disease process
      seems to be the same in both sexes, since social course in men and women
      converges in the long run. Although great variation in outcome between the
      patients is to be observed at each cross-section, the medium and long-term
      symptom-related course of schizophrenia shows a high degree of stability at the
      individual level.

PMID- 10654106
TI  - Deficit syndromes in schizophrenic patients 15 years after their first
      hospitalisation: preliminary results of a follow-up study.
AB  - This study is a follow-up study on broadly defined schizophrenic disorders.
      Patients were assessed standardized at the time of their first hospitalization
      (admission and discharge) and reassessed in an standardized manner 15 years
      later. The aim of the analyses presented here was to evaluate the frequency of
      patients with markedly expressed negative symptoms in terms of deficit syndrome
      and to analyze which of the variables assessed at the time of first
      hospitalization were predictive concerning deficit syndromes at follow-up.
      Results indicate that nearly one third of patients have developed a deficit
      syndrome 15 years after their first hospitalization. These patients are
      characterized by severe impairments in important areas of life, such as
      partnership or employment. Furthermore, apart from more pronounced negative
      symptoms, these patients also have more paranoid-hallucinatory symptoms than
      schizophrenic patients without deficit syndromes. Predictive signs for non
      development of a deficit syndrome 15 years later were good global functioning,
      female gender, pronounced depressive symptoms and good treatment response
      concerning negative and paranoid-hallucinatory symptoms at first hospitalization.
      A longer duration of symptoms prior to first hospitalization, lack of a
      partnership, pronounced negative symptoms at admission and at discharge were
      predictive of developing a deficit syndrome. Results are discussed with regard to
      the literature and to methodological limitations.

PMID- 10654107
TI  - Neurotransmitter interactions in schizophrenia-therapeutic implications.
AB  - The search for new and improved antipsychotic agents has increased in intensity
      during the past five years. The era of searching for non-toxic copies of
      clozapine has been followed by several different lines of research, some of which
      pursue the traditional dopamine track, although at a higher level of
      sophistication, whereas others focus on other neurotransmitters, such as
      serotonin and glutamate. Emerging knowledge about the interactions between
      different neurotransmitters in complex neurocircuits opens up possibilities for
      achieving antipsychotic activity by interfering with many different
      neurotransmitters. Most intriguing is the finding in animal experimental models,
      indicating that it should be possible to alleviate psychotic conditions by
      stabilizing rather than paralyzing neurocircuits, thus avoiding the risk of motor
      and mental side effects of the currently used drugs. Among these new classes,
      dopaminergic stabilizers and 5-HT2A receptor antagonists appear to offer the most
      promise at present. In a longer perspective, drugs interfering with glutamate
      function via different mechanisms may also turn out to be useful, especially in
      the control of negative symptoms.

PMID- 10654108
TI  - Developmental malformations in cerebral structures of schizophrenic patients.
AB  - In recent years neuroimaging techniques have revealed various cerebral and
      structural variances in patients with schizophrenic psychoses. The best
      established findings are the enlargement of the lateral ventricles and discrete
      structural deficits in temporobasal structures of the cortex. Neuropathological
      investigations have detected subcortical as well as cortical variances.
      Subcortically, the volume of the striatum and the globus pallidus have been found
      to be enlarged in schizophrenics. Among the cortical deviations, the
      cytoarchitectonic disturbances of the rostral entorhinal region have been well
      documented and are especially important. According to neuropathological criteria,
      they are derived from disturbances of prenatal cell migration within the central
      nervous system. Well documented are the architectonic changes in the rostral
      cingulate gyrus which is itself connected with the entorhinal region via the
      Papez circuit. These findings are supported and supplemented by the results of
      epidemiological studies which indicate a disturbance of brain development during
      the second trimester of the prenatal period. Viral infections (Influenza A2) of
      mothers during this critical period appear to play an especially important role.
      Nevertheless, the interaction between a genetic predisposition and exogenous
      noxious agents in such cases still needs to be clarified in our understanding of
      the etiology of schizophrenic psychoses.

PMID- 10654109
TI  - Structural neuroimaging in schizophrenia. An integrative view of neuromorphology.
AB  - The use of structural magnetic resonance imaging (MRI) in studies of
      schizophrenia has resulted in a more detailed picture of anatomic areas which may
      be altered in this syndrome. Thus far, there have been over 130 studies of
      schizophrenia using MRI and, taken together, they present a clear picture of a
      group of disorders with altered brain structure. Their major finding is a
      confirmation of the older pneumoencephalography and computertomography studies
      showing an enlargement of lateral ventricles and a volume reduction seen in the
      temporal lobe. When structural studies are carried out in other cortical and
      subcortical regions, however, the volume reduction is not so uniform, but rather
      restricted to certain areas in a given patient. In addition medication effects
      can be seen especially in the caudate nucleus which tend to increase in volume
      after long-term neuroleptic drug usage and again normalize under the atypical
      drug clozapine. These data are consistent with a neurodevelopmental model of
      schizophrenia and with some kind of progressive neurodegenerative process. This
      review suggests that an integrative model with initial developmental errors may
      underlie the majority of cases of schizophrenia, but that cases of chronic
      schizophrenia appear to involve progressive neurodegeneration. In assessing the
      scatter in available data, it appears that there is no consistent neuropathology
      across all cases of schizophrenia and preferential areas of dysfunction can be
      determined. Thus, there seems a collection of subtle neurodevelopmental errors
      which can lead to various forms of schizophrenia and that at least some types of
      schizophrenia most probably also involve a neurodegenerative process which could
      in fact be a consequence of the initial developmental defect.

PMID- 10654110
TI  - Family and genetic studies on the relationship of schizophrenia to affective
      disorders.
AB  - Schizophrenia is a genetically influenced disease with a broad and heterogeneous
      phenotype transmitted in families. Of particular interest is the familial-genetic
      relationship between schizophrenia and affective disorders. Taking advantage of
      refined epidemiological methods, the dichotomy between both groups of disorders
      is not less consistently found than expected. Recently, linkage studies
      identified multiple candidate regions for susceptibility genes for each of both
      disorders. Several of these candidate regions for schizophrenia are overlapping
      with candidate regions for bipolar disorder. Thus, the hypothesis of an
      etiological dichotomy of schizophrenia and affective disorders faces a new
      challenge.

PMID- 10654111
TI  - The role of immune function in schizophrenia: an overview.
AB  - Immune alterations in schizophrenia have been described for decades. However,
      modern immunological methods and new insights into the highly developed and
      functionally differentiated immune system allows an integrative view of both, the
      older and also recent findings of immunological abnormalities in schizophrenia.
      Both, the unspecific and the specific arm of the immune system seem to be
      involved in the dysfunction of the immune system in schizophrenia. The unspecific
      "innate" immune system shows signs of an overactivation in unmedicated
      schizophrenic patients, as increased monocytes and gamma delta-cells point to.
      Increased levels of Interleukin-6 (IL-6) and the activation of the IL-6 system in
      schizophrenia might also be the result of the activation of
      monocytes/macrophages. On the contrary, several parameters of the specific
      cellular immune system are blunted, e.g. the decreased T-helper-1 (TH-1) related
      immune parameters in schizophrenic patients both, in vitro and in vivo. It seems
      that a TH-1-TH-2 imbalance with a shift to the TH-2 system is associated with
      schizophrenia. During antipsychotic therapy with neuroleptics, the specific TH-1
      related immune answer becomes activated, but also the B-cell system and the
      antibody production increases.

PMID- 10654113
TI  - Dopamine- and serotonin-receptors in schizophrenia: results of imaging-studies
      and implications for pharmacotherapy in schizophrenia.
AB  - Considerable progress has been achieved over the past 15 years in uncovering the
      biological basis of major psychiatric disorders. Since psychopharmacological
      treatment is thought to act on the underlying biological basis of the disease,
      brain imaging techniques enable us to understand the mechanism of action of such
      compounds. Positron emission tomography (PET) as well as single photon emission
      computerized tomography (SPECT) are important tools used to determine patterns of
      brain dysfunction and to uncover the mechanism of action for antipsychotic
      compounds. These techniques allow us to determine striatal D2 receptor as well as
      cortical 5-HT2A receptor occupancy rates which are linked, at least partly, to
      clinical efficacy as well as side effect rates. In general it has been shown that
      atypical antipsychotics have a lower striatal D2 receptor occupancy rate than
      typical antipsychotics, parallelling the more favorable extrapyramidal side
      effects of atypical antipsychotics, and as a group effect they have a high 5-HT2A
      occupancy compared to low rates for typical agents. However, there is no
      association between striatal D2 receptor occupancy rates and antipsychotic
      efficacy but 5-HT2A occupancy rates are associated with favorable treatment for
      depressive symptoms within schizophrenia and improvement of cognitive function.
      The availability of ligands for measurement of extrastriatal D2 receptors or
      different 5-HT receptors (e.g. 5-HT1A) will further shed light on the
      pathophysiology of schizophrenia as well as possible psychopharmacological
      treatment perspectives.

PMID- 10654114
TI  - Relationship between dopaminergic and serotonergic neuronal activity in the
      frontal cortex and the action of typical and atypical antipsychotic drugs.
AB  - Clozapine, iloperidone, quetiapine, olanzapine, risperidone and ziprasidone
      represent the new generation of antipsychotic drugs, successors to the typical
      antipsychotic drugs such as chlorpromazine and haloperidol. The first group of
      agents are usually referred to as atypical antispychotics because they produce
      significantly fewer extrapyramidal symptoms than do the typical neuroleptics at
      clinically equivalent doses. These drugs also show advantages in treating
      positive symptoms, especially in patients whose positive symptoms fail to respond
      to the typical antipsychotic drugs. They also have advantages for treating
      negative symptoms, cognitive dysfunction and mood stabilization. There are
      variations to the extent to which the atypical antipsychotics show these
      advantages with regard to efficacy and side effects. The mechanism of action of
      these drugs is a matter of keen interest. We review here the evidence that some,
      or all, of these advantages are related to their actions at serotonin and
      dopamine receptors.

PMID- 10654115
TI  - Atypical neuroleptics: a new approach in the treatment of negative symptoms.
AB  - The results of controlled studies on the efficacy of novel/atypical neuroleptics
      in negative symptoms are presented. The data show that these drugs are more
      favorable in the treatment of negative symptoms in acute schizophrenic patients
      than the classical neuroleptics such as haloperidol and chlorpromazine.
      Apparently, the greater efficacy in negative symptoms can only partially be
      explained by indirect effects via better extrapyramidal tolerability, better
      effects on productive psychotic symptoms etc., and is to a certain degree due to
      a direct effect of the atypical neuroleptic on negative symptoms. This view is
      confirmed by results from one trial studying the efficacy of an atypical
      neuroleptic in patients suffering from chronic schizophrenia with stable,
      predominant negative symptoms. Parallel to the evaluation of the novel/atypical
      neuroleptics in negative symptoms, great progress in the methodology of clinical
      trials in this field has been made.

PMID- 10654116
TI  - Principles and results of family therapy in schizophrenia.
AB  - There is growing evidence that social factors contribute significantly to the
      course and outcome in schizophrenia. In particular, the relationship between high
      EE and schizophrenic relapse has been documented by many investigators. Since
      1980, several psychoeducational family management programs have been evaluated
      showing a significant reduction in relapse when compared to standard psychiatric
      care. To prevent tardive dyskinesia, alternative medication strategies have been
      introduced, e.g. low dose and targeted medication. In the Munich treatment study
      the combined effects of behavioral family management (BFM) and standard dose (SD)
      or targeted neuroleptic medication TM) on relapse and social functioning of the
      patient as well as coping and burden of the family have been investigated. N = 51
      patients with 73 relatives were randomly assigned to the two groups (BFMSD = 27,
      BFMTM = 24). Relapse rates at 18 month were: BFSD = 3.9%, BFMTM = 33.8%. In
      summary, psychoeducational family management in combination with standard dose
      medication proved to be highly effective in preventing relapse in schizophrenia.
      These results are in line with findings of anglo-american studies and call for a
      more widespread application of these new psychosocial approaches in order to
      provide the best services available for the chronically ill schizophrenic patient
      and their families.

PMID- 10654112
TI  - Cognitive dysfunction in schizophrenia: unifying basic research and clinical
      aspects.
AB  - Seeking to unite psychological and biological approaches, this paper links
      cognitive and cellular hypotheses and data about thought and language
      abnormalities in schizophrenia. The common thread, it is proposed, is a
      dysregulated suppression of associations (at the behavioral and functional neural
      systems level), paralleled by abnormalities of inhibition at the cellular and
      molecular level, and by an abnormal anatomical substrate (reduced MRI gray matter
      volume) in areas subserving language. At the level of behavioral experiments and
      connectionist modeling, data suggest an abnormal semantic network connectivity
      (strength of associations) in schizophrenia, but not an abnormality of network
      size (number of associates). This connectivity abnormality is likely to be a
      preferential processing of the dominant (strongest) association, with the neglect
      of preceding contextual information. At the level of functional neural systems,
      the N400 event-related potential amplitude is used to index the extent of
      "search" for a semantic match to a word. In a short stimulus-onset-asynchrony
      condition, both schizophrenic and schizotypal personality disorder subjects
      showed, compared with controls, a reduced N400 amplitude to the target words that
      were related to cues, e.g. cat-dog, a result compatible with behavioral data.
      Other N400 data strongly and directly suggest that schizophrenics do not
      efficiently utilize context.

PMID- 10654117
TI  - Validity of the Child Behaviour Checklist in a Norwegian sample.
AB  - The purpose of the study was to test the applicability of the Child Behaviour
      Checklist for assessing behaviour problems and competencies in Norwegian children
      and adolescents. Information was obtained by mailing checklists to parents of
      random sampled children and adolescents in a mixed rural/semirural area and the
      urban Oslo area. High-scoring children and random samples of normal-scoring
      children in two different age groups were clinically assessed in the second part
      of the study. The results support the predictive validity of the CBCL as judged
      by its ability to distinguish between children with psychiatric disorders and
      psychiatrically non-disordered children. Differences pertaining to sex, age, SES,
      and degree of urbanisation confirm findings of earlier studies across cultures.

PMID- 10654118
TI  - Validating the Ontario Child Health Scale in a UK population.
AB  - The Ontario Child Health Scale (OCHS) was one of the first scales to seek to
      assess a broad range of formally defined psychiatric disorders using a checklist
      format. The performance of the teacher version of this instrument is reported in
      a UK population of children attending a special educational provision for
      emotionally and behaviourally disordered (EBD) pupils. Against DSM-IV criteria
      the instrument proved to have retained its convergent and discriminant validity,
      although it was somewhat less effective in detecting internalizing disorders and
      discriminating oppositional defiance from other behavioural disorders. Overall
      the results confirm the usefulness of this instrument as a screening tool in a UK
      population.

PMID- 10654119
TI  - The Conners-28 teacher questionnaire in clinical and nonclinical samples of Greek
      children 6-12 years old.
AB  - It is accepted practice in child psychiatry to use more than one source of
      information in assessing behavioural problems in children and adolescents.
      Employing standardized tools for these assessments allows cross-cultural
      comparisons and better interchange of the findings. Achenbach's Child Behavior
      Checklist (CBCL) and Teacher's Report Form (TRF) are two widely accepted
      instruments that were standardized in Greece within the framework of the European
      Network for the Study of Hyperkinetic Disorder. We studied the Conners-28 teacher
      questionnaire in a Greek community sample of primary schoolchildren aged 6-12
      years. The factor structure showed to be similar to that originally reported from
      the USA. Discrimination between the referred and nonreferred sample was high,
      especially for the Inattentive-passive scale. Conners-28 scores were highly
      correlated with the TRF (scored by the same informant), much less so with the
      CBCL (scored by a different informant). Our study demonstrates the usefulness and
      applicability of the Conners-28 item questionnaire.

PMID- 10654120
TI  - Psychosocial factors and adequacy of services for children in children's homes.
AB  - Risk and protective factors of psychosocial development in children in different
      residential care settings need to be further studied internationally, in order to
      develop working methods for social and health care services. Standardized methods
      of the CBCL, TRF, and CGAS, were used to evaluate psychosocial functioning of
      children in children's homes in Finland. Further, data on sociodemographic
      situations and traumatic events in their lives were assembled. The percentage of
      behavioural and emotional problems within clinical or borderline range in the
      different ratings was 55-80%. Combined traumatization, sexual abuse, school
      difficulties, male sex, older age (> 11 years) and older age at first and on
      going placement (> 7 years), as well as difficulties in relationships with
      parents are likely to be associated with more severe behaviour problems and lower
      general functioning. The results of this study show that children and adolescents
      in social service residential settings are a highly vulnerable group and that
      these children have extensive mental health needs.

PMID- 10654121
TI  - Adolescence-limited versus life-course-persistent criminal behaviour in
      adolescent psychiatric inpatients.
AB  - A nation-wide sample of 1072 Norwegian adolescent psychiatric inpatients were
      followed up 15-33 (mean 23.8) years after hospitalisation, by record linkage to
      the National Register of Criminality. Defining criminal behaviour as entry into
      the criminal registry, 481 patients (45%) had an adolescent criminal debut,
      entering the registry before the age of 21. Of these, 130 (27%) had no criminal
      record after the age of 21 and were consequently considered as adolescence
      limited criminal offenders, as opposed to the remaining 351 (73%) individuals who
      continued their criminal behaviour beyond the age of 21 and were considered as
      life-course-persistent criminal offenders. On the basis of hospital records, all
      patients were rediagnosed according to DSM-IV and scored on factors hypothesised
      to have predictive power as to persistence of criminal behaviour. We found that
      79.6% of the male, and 58.8% of the female adolescent delinquents went on to life
      course-persistent criminality. In females, intravenous use of illegal drugs, and
      being discharged from the hospital elsewhere than to the family home, were strong
      and independent predictors of life-course-persistent criminal behaviour. In
      males, the following were significant and independent predictors of life-course
      persistent criminality: a high number of conduct disorder criteria fulfilled,
      comorbidity of psychoactive substance use disorder, and having attended
      correctional school.

PMID- 10654122
TI  - Youth suicide in an international context.
AB  - Mortality statistics are examined for 10- to 19-year-old males and females to
      examine whether the widely-claimed high rates and upward trends in suicide among
      young men in England and Wales during recent years are applicable to this group.
      Various definitions of suicide are considered. A consistent increase in rates
      between 1980 and 1994 was found in England and Wales for 15- to 19-year-old males
      (and for younger males although not for females) but this was less dramatic than
      has been reported for a slightly wider age band. Comparisons between these
      profiles of young deaths and those for Finland, Germany, Hungary, Ireland and
      Norway indicated that, regardless of definition, rates of suicide for those under
      20 years are lower in England and Wales than any of the other countries studied.
      Trends, nonetheless, showed varying patterns. While the upward trend among 15- to
      19-year-old males in England and Wales was of similar order to that found in
      Finland or Norway, it represented a far less marked rise than in Ireland and was
      in contrast to the declining rates found in Germany and Hungary. Methods used in
      deaths recorded as suicide differed by country but there were few consistent
      trends.

PMID- 10654123
TI  - Do inpatients on adolescent units recover? A study of outcome and acceptability
      of treatment.
AB  - BACKGROUND: The study investigated progress made by adolescent inpatients during
      their stay on an adolescent unit and at a 6-18 month follow-up. It also
      investigated patient views of treatment provided on the unit. METHOD: Evaluation
      of outcome involved the collection of outcome ratings from patients, unit staff
      and referrers. For the purposes of analysis, patients were categorised on
      admission according to whether they were admitted to the unit for assessment or
      for treatment. The mean length of stay of those admitted for assessment was 2.8
      weeks whilst the mean length of stay of patients admitted for treatment was 14.4
      weeks. Acceptability of treatment was examined using patient evaluations of the
      range of interventions experienced. RESULTS: Outcome ratings were generally
      favourable, although those obtained from referrers varied according to the rating
      method used. The majority of patients who made progress during their inpatient
      stay had either maintained or made further progress at follow-up. Patients whose
      condition remained unchanged during their stay tended to remain unchanged at
      follow-up. Patients were generally positive about their experience. CONCLUSIONS:
      It is possible to investigate outcome in an adolescent unit. The results are
      encouraging and indicate that this form of treatment can be effective and
      acceptable.

PMID- 10654124
TI  - Social-cognitive abilities in children with lesser variants of autism: skill
      deficits or failure to apply skills?
AB  - The present study re-examined the ability of children with lesser variants of
      autism (classified as PDD-NOS) to infer emotions of other people and to describe
      others in terms of inner, psychological characteristics. It also explores the
      hypothesis that these children may have the skill to infer mental states of other
      people, but fail to use these skills spontaneously. Children with lesser variants
      of autism and normal control children matched for age, sex and intelligence were
      given three structured emotional role-taking tasks and asked to give two
      spontaneous descriptions of peers. The results showed that both groups did not
      differ with respect to their ability to infer other people's emotions in the
      structured role-taking tasks. In contrast, significant differences were found on
      the free person descriptions: the children with PDD-NOS used fewer inner,
      psychological characteristics to describe peers.

PMID- 10654125
TI  - Further evidence for a low body weight in male children and adolescents with
      Asperger's disorder.
AB  - The study explores the common clinical impression and previously reported finding
      by Hebebrand et al. (7) of reduced body weight in male children and adolescents
      with Asperger's disorder (AD). Body weight and height of 36 consecutively
      admitted male patients with AD were retrospectively assessed for the calculation
      of body mass indices (BMI, kg/m2). The BMIs were transformed to percentile ranks
      and plotted into BMI-centiles representative for the German population. In
      addition, comorbid psychopathology was assessed to explore a possible
      relationship between associated psychopathology and body weight. The mean BMI
      centile of all patients was 34.7 +/- 31.8 and, thus, differed significantly from
      the mean centile of an age- and gender-matched psychiatric control group, which
      was 52.7 +/- 28.3. Thirteen patients had a BMI below the 10th centile and five
      even below the third. Three of the latter presented with disturbed eating
      behaviour. Altogether four patients showed disturbed eating behaviour. They had a
      significantly lower mean BMI-centile than the rest of the group. The BMI-centiles
      of patients with other additional psychopathology did not differ significantly
      from the mean percentile of the whole cohort. The results clearly show an
      increased risk for underweight and disturbed eating behaviour in patients with
      Asperger's disorder which should be evaluated in further studies.

PMID- 10654126
TI  - Treating children and adults: whose body is it anyway?
AB  - This essay, about the concept of treatment, is written by a psychiatrist who is
      monitoring extreme treatment situations, namely surgical treatment of epilepsy.
      It challenges the implicit assumption that persons consulting doctors necessarily
      want to be treated. A child may not be privy to, or wish to be party to, a
      treatment. The child, or the parent on behalf of the child, may not agree to the
      course of action that is in its best interest. One problem of treatment concerns
      who owns the body that is to be treated. Ultimately, the body belongs to the
      state and is merely tenanted by the child and managed by a parent on the state's
      behalf. But the body must, somehow, be owned if its sickness is to be
      acknowledged. The lack of real autonomy provides for the possibility of abuse
      including abusive therapies. "Abuse" is applicable only to abuse of trust.
      Autonomy is granted or conceded by parents and by the state but is never
      complete. Autonomy is confirmed by taking informed decisions about what will
      happen to the body. Treatment is a cost/benefit deal in which the precise aim to
      be achieved has to be described and accepted before treatment begins.

PMID- 10654127
TI  - Psychopharmacological preferences of Polish child and adolescent psychiatrists.

PMID- 10654128
TI  - Design and subjects of a Finnish epidemiological study on psychiatric disorders
      in childhood.
AB  - In an epidemiological multi-centre study, parents filled in the Rutter Parent
      Questionnaire (RA2) and teachers filled in the Rutter Teacher Questionnaire (RB2)
      for almost 6000 children. The children filled in the Children's Depression
      Inventory (CDI). The subjects well represented the entire population of 8-9-year
      old children in Finland. The material and design of the study as well as the
      basic demographic characteristics are presented.

PMID- 10654129
TI  - Behavioural and emotional symptoms in 8-9-year-old children.
AB  - We present epidemiological data from a multi-centre study on psychiatric symptoms
      among 6017 8-9-year-old children representing a total annual birth cohort (N =
      60007) in Finland. The results are based on three questionnaires: the Rutter
      Parent Scale (RA2), the Rutter Teacher Scale (RB2), the Children's Depression
      Inventory (CDI). The proportion of children that scored above the cutoff points,
      indicating probable psychiatric disturbance, were 11.2% for the RA2, 13.9% for
      the RB2 and 6.9% for the CDI. Twenty-four percent of the subjects scored above
      the cutoff point on at least one of the questionnaires. Low family social status
      and disrupted family relations correlated strongly with high rates of symptoms in
      the children.

PMID- 10654130
TI  - Psychiatric disorders in 8-9-year-old children based on a diagnostic interview
      with the parents.
AB  - Using three questionnaires, the Rutter Parent Questionnaire (RA2), The Rutter
      Teacher Questionnaire (RB2) and the Children's Depression Inventory (CDI), we
      screened 8-9-year-old children representing a total annual birth cohort (N =
      60007) in Finland. In a second stage we interviewed the parents of 119 screen
      negative, and 316 screen positive children by using a structured parent
      interview. At the population level the overall prevalence rate for psychiatric
      disturbance was 21.8%, higher among boys (29.8%) than among girls (12.8%). Nine
      percent of the children were in urgent need of treatment and, in addition, 25%
      were in need of assessment. The prevalence of different levels of disturbance
      was: reactive 9.5%; neurotic 18.4%; borderline 3.1%; and other severe disorders
      2.3%. The prevalence of different diagnostic groups were: anxiety disorder 5.2%;
      depressive disorder 6.2%; specific fears 2.4%; defiant and conduct disorder 4.7%;
      and attention-deficit hyperactivity-disorder 7.1%. The prevalence for the most
      common single first Axis-I DSM-III-R diagnoses were: attention-deficit
      hyperactivity-disorder 7%; dysthymia 4.6%; adjustment disorder with mixed
      disturbance of emotion and conduct 3.4%; oppositional defiant disorder 2.7%;
      specific fear 1.7%; anxiety disorder 1.5%; enuresis nocturnal 1.5%; and
      depression 1.4%. Only 3.1% of the children had visited health professionals for
      psychiatric problems during the previous three months. Only a minority of the
      children with psychiatric disturbances had ever consulted health professionals
      for their problems. Of all the children, 7.5% had a severe psychiatric
      disturbance that had lasted for more than 3 years.

PMID- 10654131
TI  - Emotional and behavioural symptoms in 8-9-year-old children in relation to family
      structure.
AB  - The association between family structure and behavioural and emotional symptoms
      in prepubertal children was studied in an epidemiological survey conducted in
      Finland. Five thousand eight hundred thirteen children aged 8 and 9 years were
      screened using the Rutter Parent Questionnaire (RA2) for parents and the Rutter
      Teacher Questionnaire (RB2) for teachers. Information concerning family type,
      birth order and sibship size were obtained from the parents. The majority of the
      children (84%) in the sample lived with both their biological parents, 10% with a
      single parent, and around 5% with a biological parent and a stepparent. Around 1%
      of the children lived outside their original home. The prevalence of behavioural
      and emotional symptoms was lowest in children living with both their biological
      parents and highest among children living outside their original home according
      to both parents' and teachers' reports. Children living with a parent and a
      stepparent had problems more often at home, but less often at school than
      children living with a single parent. Living with a single father was associated
      with having more externalizing, school-related problems, while living with a
      stepfather was associated with having more internalizing, home related problems.
      Having younger siblings seemed to be associated with fewer problems at school,
      and being the youngest child with having less problems both at home and at
      school.

PMID- 10654132
TI  - Children's behavioural/emotional problems: a comparison of parents' and teachers'
      reports for elementary school-aged children.
AB  - This study assessed the agreement between parents and teachers concerning
      behavioural/emotional symptoms of children. 5671 children born in 1981 (mean age
      8.5 years at the time of study) were studied using the Rutter Parent
      Questionnaire (RA2) and the Rutter Teacher Questionnaire (RB2). Boys had more
      behavioural symptoms on both scales, 3.6% of the boys and 2.3% of the girls were
      deviant on both scales. Agreement between parents and teachers on single
      behaviours was better for deviant girls than for deviant boys. The factors
      constructed from the Rutter scale items (separately of each scale) represented
      externalizing, internalizing and hyperactivity behaviours. For all children,
      moderate correlations between parents' and teachers' ratings were found in
      externalizing behaviour and hyperactivity. Correlations of the factors were
      clearly higher for deviant girls than for deviant boys. Scoring high on one of
      the scales increased the probability of scoring high on the second scale. The
      discussion focuses on factors that may affect agreement between parents and
      teachers when behavioural symptoms are assessed.

PMID- 10654133
TI  - Psychiatric disorders, performance level at school and special education at early
      elementary school age.
AB  - We assessed the relationship between psychological deviance and performance level
      at school among 8-year-old children. The use of special education among children
      with psychiatric disorders was also studied. In Stage 1, 5813 children were
      studied using the Rutter Parent Questionnaire (RA2), the Rutter Teacher
      Questionnaire (RB2) and the Children's Depression Inventory (CDI). In Stage 2, a
      subsample (n = 424) of these children were interviewed, using the Isle of Wight
      Interview. In Stage 1, more children defined as low achievers (LAs) came from low
      SES families than did average (NAs) and high achievers (HAs). They also had more
      psychiatric symptoms, and they scored above the cutoff (13 points on the RA2,
      nine points on the RB2 and 17 points on the CDI) more commonly than other
      children. In Stage 2, two thirds of children who received special education had
      some psychiatric disorder. The probability of a child with psychiatric disorder
      obtaining some extra tutoring or special education was 3.1-fold when compared
      with children without psychiatric disorders. Depressive children and children
      with attention deficit disorders most commonly had extra tutoring (4.8-fold) when
      compared with children without psychiatric disorders. The probability of getting
      special education was highest for attention deficit disorders (6.2-fold),
      thereafter for anxiety (3.1-fold), and for oppositional/conduct disorders (2.8
      fold).

PMID- 10654134
TI  - Behavioural/emotional symptoms among 8-9-year-old children with somatic symptoms
      or illnesses as reported by their teacher.
AB  - The aim of this study was to assess children's behavioural/emotional symptoms at
      school and to compare these symptoms of somatically healthy children with those
      of children with somatic illnesses or symptoms. The Rutter Teacher Questionnaire
      (RB2) was used for measuring psychiatric symptoms in 5813 children aged 8-9
      years. The parents reported the somatic symptoms and illnesses of their children
      during the previous 12 months. One hundred and sixty one children had a marked or
      serious chronic illness, 292 had a mild chronic illness, and 92 had one or
      several symptoms. The findings suggest that boys with a marked or serious chronic
      somatic illness are prone to manifest psychiatric symptoms in their interactions
      with peers and teachers at school and that boys with a mild chronic illness have
      less psychiatric symptoms than healthy boys.

PMID- 10654135
TI  - Are twins' behavioural/emotional problems different from singletons'?
AB  - We compared twins with singletons in the National Epidemiological Child
      Psychiatric Study, which included 122 twins and 5455 singletons, born in 1981 and
      selected at random. Behavioural and emotional symptoms were assessed in 1989 on
      the basis of questionnaires filled in by the parents (Rutter Parent
      Questionnaire) (RA2), teachers (Rutter Teacher Questionnaire) (RB2) and the
      children themselves (Children's Depression Inventory) (CDI). Parents' reported
      proportions of probable behavioural/emotional disorders did not differ between
      the twin and singleton girls, but among the twin boys there was a nonsignificant
      trend of being more often probably disturbed. Twins were reported to be less
      disturbed than singletons according to the teachers' assessments. No difference
      was found between twins and singletons in their self-reports. When analysing
      parents' reported values of various sum scores, the twin boys obtained slightly
      higher scores than singletons, while twin girls scored significantly lower on
      total and emotional disturbances. Twin boys obtained lower mean scores than
      singletons for probable disorder in the teachers' evaluations, the differences
      arising mostly in the emotional area. The same type of trend, however
      nonsignificant, was found among the teachers' evaluations of girls. No
      significant difference was found in the mean scores for hyperactivity. This large
      population-based sample suggests that twins may have a lower rate of behavioural
      problems in childhood than singletons, a finding that has to be taken into
      account in behavioural genetic studies.

PMID- 10654136
TI  - Smoking and drinking habits in adolescence--links with psychiatric disturbance at
      the age of 8 years.
AB  - Smoking and drinking habits were studied among 1098 14-15-year-old adolescents
      using a mailed questionnaire. The subjects were drawn from a representative
      population of 5813 randomly selected 8-year-old children previously studied in
      the National Epidemiological Child Psychiatry Study in Finland in 1989. The
      questionnaire included items on the adolescents' smoking habits and alcohol
      consumption. Regular smoking was more common among boys (and girls) who, in
      childhood, had been rated by their parents (Rutter Parent Questionnaire) (RA2) as
      disturbed, 14.6% (30.3%), than among the nondisturbed, 6.6% (8.4%). Similarly,
      more of the previously disturbed (according to the RA2) adolescent boys drank
      alcohol regularly, 19.7%, as compared to the nondisturbed boys, 9.3%. Among
      girls, regular alcohol consumption was more common among those who previously had
      behavioural or mixed type problems (according to the RA2), 70.7%, as compared to
      those who previously had emotional or no problems, 12.2%. More of the previously
      depressed girls smoked regularly, 45.1%, than those who had not been depressed,
      7.9%. Behavioural and emotional problems in childhood seemed to predispose to
      smoking and drinking in adolescence. The parents were more sensitive than the
      teachers in recognising the long-lasting problems of their children.

PMID- 10654137
TI  - Psychiatric symptoms in children with intellectual disability.
AB  - In a sample of almost 6000 8-year-old children, we found that 1.5% attended
      special schools for the educationally subnormal, or training schools. Psychiatric
      symptoms were studied by means of three screening instruments: the Rutter Parent
      Questionnaire (RA2) for the parents, the Rutter Teacher Questionnaire (RB2) for
      the teachers, and the Children's Depression Inventory (CDI) for the children. The
      prevalence rate of children identified as possibly suffering from a psychiatric
      disturbance was 32.2% according to the RA2. The corresponding prevalence rate for
      the RB2 was 34.2%. According to the CDI 11.0% had depressive disturbance. All
      types of disturbances were more frequent among the intellectually disabled
      children as compared to the nondisabled children. The differences were
      statistically significant for emotional and mixed types of disturbance on the
      RA2, and for emotional and conduct types of disturbance on the RB2.

PMID- 10654138
TI  - Teacher-rated psychiatric problems in 8-year-old children and parental quality of
      previous day-care.
AB  - In this study behavioural/emotional problems in 95 8-year-old schoolchildren were
      assessed by using the Rutter Parent Questionnaire (RB2) for teachers and related
      to earlier day-care periods. A relatively low proportion of behavioural/emotional
      problems was found among those children whose parents reported only moderate
      dissatisfaction with the first day-care period. Behavioural/emotional problems
      were associated with high numbers of day-care periods and short day-care periods.
      The proportion of problems was high among children with a moderate mean length of
      periods as compared with those with no day-care short periods or very long
      periods. The differences in behavioural/emotional problems were related to the
      degree of parental satisfaction with the quality, as well as to the continuity of
      day-care. However, the results of logistic regression analysis found no
      significant associations related to stability when the background factors were
      controlled for. These results may reflect the consequences of continuity versus
      discontinuity in the relationships between children, parents and caregivers.

PMID- 10654139
TI  - Four-year course of teacher-reported internalising, externalising and comorbid
      syndromes in preadolescent children.
AB  - The aim of this study was to elucidate the nature of comorbidity between
      internalising and externalising syndromes and its meaning in the course of these
      syndromes from 8 to 12 years of age in a school setting. The children in the
      cohort (N = 1320) were born in 1981. They were first surveyed in second grade (N
      = 1284) and followed up in sixth grade (N = 906). Teachers were the informants,
      and the study was carried out by means of a questionnaire. Data from both points
      of time were available on 861 subjects. The Rutter Teacher Questionnaire (RB2)
      measured behavioural and emotional symptoms at Time 1, and the Teacher Report
      Form (TRF) at Time 2. Comorbidity was more prevalent in boys than girls.
      Childhood comorbidity predicted externalising syndrome and comorbidity, but not
      internalising syndrome in early adolescence. It changed the course of boys'
      internalising syndromes to an externalising direction over time. The data suggest
      a gender difference in the pattern of comorbidity. When comorbidity was
      partialled out, it was very rare for internalising and externalising syndromes to
      develop into contrasting syndromes over time. The recovery rate for childhood
      comorbidity was poor. Special attention should be paid to making schools
      recognise and help these children.

PMID- 10654140
TI  - Metaiodobenzylguanidine scintigraphy of the heart: what have we learnt
      clinically?

PMID- 10654141
TI  - Evaluation of [11C]GB67, a novel radioligand for imaging myocardial alpha 1
      adrenoceptors with positron emission tomography.
AB  - Dysfunction of the sympathetic nervous system underlies a number of myocardial
      disorders. Positron emission tomography (PET) offers a way of assessing receptor
      function non-invasively in humans, but there are no PET radioligands for
      assessing myocardial alpha-adrenoceptors. GB67, a structural and pharmacological
      analogue of the alpha 1-adrenoceptor antagonist prazosin, was labelled with
      positron-emitting carbon-11 (t1/2 = 20.4 min) by 11C-methylation of N
      desmethylamido-GB67 (GB99). [11C]GB67 was injected intravenously into conscious
      rats. Serial arterial blood samples were taken. Rats were killed and tissues
      removed to determine radioactivity. The percentages of unchanged [11C]GB67 and
      its radioactive metabolites in plasma and tissues were assessed by HPLC. Plasma
      clearance of radioactivity was rapid. Myocardial uptake was maximal at 1-2 min
      and decreased slowly during 60 min. Predosing with adrenoceptor antagonists
      demonstrated selectivity for myocardial alpha 1-adrenoceptors. GB67 and prazosin
      blocked uptake of radioactivity; the non-selective antagonist, phentolamine,
      partially blocked uptake; the alpha 2-adrenoceptor antagonist, RX 821002, only
      blocked uptake at high dose and the beta-adrenoceptor antagonist, CGP 12177, had
      no effect. Additionally, injection of prazosin at 20 min after radioligand
      displaced radioactivity. In vivo competition curves obtained by injecting
      [11C]GB67 with varying amounts of either unlabelled GB67 or its precursor GB99
      were fitted to a competitive binding model to provide estimates of the maximum
      number of binding sites (Bmax) and half saturation doses (K) for myocardium.
      Assuming a tissue protein content of 10%, the values of Bmax [approximately 13
      pmol.(g tissue)-1[ were similar to those ]50-170 fmol.(mg protein)-1] reported
      for myocardial alpha 1-adrenoceptors assessed in vitro. Both GB67 and its
      precursor GB99 had high affinity for alpha 1-adrenoceptors [KGB67 = 1.5 nmol.(kg
      body weight)-1, KGB99 = 4.8 nmol.(kg body weight)-1]. HPLC demonstrated four
      radioactive metabolites in plasma. [11C]GB67 was 80% of the radioactivity at 5
      min and 50% at 45 min. No radioactive metabolites were detected in myocardium up
      to 60 min after injection. [11C]GB67 was assessed in two male human volunteers.
      PET demonstrated high myocardial uptake. The profile of radioactive metabolites
      in plasma was comparable to that in the rat, although metabolism was slower in
      humans. Thus, [11C]GB67 is a promising radioligand for assessing alpha 1
      adrenoceptors in human myocardium with PET.

PMID- 10654142
TI  - Imaging active lymphocytic infiltration in coeliac disease with iodine-123
      interleukin-2 and the response to diet.
AB  - Coeliac disease is diagnosed by the presence of specific antibodies and a jejunal
      biopsy showing mucosal atrophy and mononuclear cell infiltration. Mucosal cell
      mediated immune response is considered the central event in the pathogenesis of
      coeliac disease, and untreated coeliac patients show specific features of T-cell
      activation in the small intestine. Here we describe the use of iodine-123
      interleukin-2 scintigraphy in coeliac patients as a non-invasive tool for
      detection of lymphocytic infiltration in the small bowel and its use for therapy
      follow-up, and we demonstrate the specificity of binding of labelled-IL2 to
      activated lymphocytes by ex-vivo autoradiography of jejunal biopsies. 123I-IL2
      was administered i.v. [74 MBq (2 mCi)], and gamma camera images were acquired
      after 1 h. Ten patients were studied with 123I-IL2 scintigraphy at diagnosis and
      seven were also investigated after 12-19 months of gluten-free diet. Results were
      expressed as target-to-background radioactivity ratios in six different bowel
      regions before and after the diet. At the time of diagnosis all patients showed a
      significantly higher bowel uptake of 123I-IL2 than normal subjects (P < 0.003 in
      all regions). A significant correlation was found between jejunal radioactivity
      and the number of IL2R + ve lymphocytes per millimetre of jejunal mucosa as
      detected by immunostaining of jejunal biopsy (r2 = 0.66; P = 0.008).
      Autoradiography of jejunal biopsies confirmed that labelled-IL2 only binds to
      activated T-lymphocytes infiltrating the gut mucosa. After 1 year of the diet,
      bowel uptake of 123I-IL2 significantly decreased in five out of six regions (P <
      0.03), although two patients still had a positive IL2 scintigraphy in one region.
      We conclude that 123I-IL2 scintigraphy is a sensitive non-invasive technique for
      assessing in vivo the presence of activated mononuclear cells in the bowel of
      patients affected by coeliac disease. Unlike jejunal biopsy, this method provides
      information from the whole intestine and gives a non-invasive measure of the
      effectiveness of the gluten-free diet.

PMID- 10654143
TI  - Blood metabolism of [methyl-11C]choline; implications for in vivo imaging with
      positron emission tomography.
AB  - [methyl-11C]choline (11C-choline) is a radioligand potentially useful for
      oncological positron emission tomography (PET). As a first step towards the
      development of a kinetic model for quantification of 11C-choline uptake, blood
      metabolism of 11C-choline during PET imaging was studied in humans. High
      performance liquid chromatography (HPLC) and thin-layer chromatography (TLC) were
      used for the analysis of 11C-choline and its radioactive metabolites. Prior to
      human PET imaging we studied ex vivo the biodistribution and metabolism of
      intravenously administered 11C-choline in rats. Our results revealed that the
      radioactivity accumulated particularly in kidney, lung, adrenal gland and liver.
      Chromatographic analysis showed that the level of unmetabolized 11C-choline in
      rat plasma decreased from 42% +/- 20% (mean +/- SD) at 5 min to 21% +/- 10% at 15
      min after injection. In accordance with these findings, in humans the
      unmetabolized 11C-choline represents 62% +/- 19% of the total radioactivity in
      arterial plasma at 5 min after injection and 27% +/- 12% at 15 min. In human
      venous plasma the corresponding values were 85% +/- 12% and 48% +/- 12% at 5 and
      10 min, respectively. The major metabolite observed in both human and rat plasma
      was identified as 11C-betaine. In human arterial plasma this maximally
      represented 82% +/- 9% of the total radioactivity at 25 min after radiotracer
      injection. By 20 min after injection, the 11C-choline and 11C-betaine in human
      arterial plasma reached a plateau, and their fractional activities remained
      nearly constant thereafter. Although most of the circulating 11C-choline in blood
      is transported to tissues, it does not disappear totally from blood within the
      first 40 min after tracer injection.

PMID- 10654144
TI  - Effect of exercise induced hyperlactatemia on the biodistribution and metabolism
      of iodine-123-15(p-iodophenyl)-3-R,S-methyl pentadecanoic acid in normal
      volunteers.
AB  - We have evaluated the biodistribution and metabolism of iodine-123-15-(p
      iodophenyl)-3-R,S-methyl pentadecanoic acid (BMIPP) in the presence of increased
      lactate levels induced by short-term heavy exercise. Five healthy male subjects
      received 159 MBq (+/- 13 MBq) 123I-BMIPP at rest and a week later after they
      performed a maximal exercise test using a bicycle ergometer. Planar and
      tomographic images were obtained with a dual-head gamma camera up to 4 h after
      administration of the tracer. Multiple blood samples were taken at different time
      points for blood clearance, substrate concentration measurements and for HPLC
      analysis of metabolites. The exercise test did not alter plasma glucose and non
      esterified fatty acid concentrations, but blood lactate increased from 1.12
      mmol/l at rest to 9.26 mmol/l with maximal exercise. After exercise, BMIPP showed
      a significantly faster plasma clearance than at rest and the production of PIPA,
      the end metabolite of BMIPP oxidation, was reduced. Activity in the heart was
      similar after exercise and at rest on planar images 15 min after injection (4.83
      +/- 0.50% ID vs 4.80 +/- 0.43% ID, P = NS), although the myocardium-to-cavity
      activity ratio, as determined on the SPET images 20 min after tracer injection,
      was slightly increased after the exercise test (4.20 +/- 0.63 vs 3.78 +/- 1.34 at
      rest, P = NS). Significantly increased activity was observed in a leg muscle
      region of interest after exercise (4.98 +/- 0.50% ID vs 3.93 +/- 0.44% ID at
      rest, P = 0.02). Between early and late images, tracer washout from the
      myocardium increased from 20.72% at rest to 36.72% after exercise (P < 0.05), but
      was unchanged for liver and leg muscles. The metabolic and physiological
      alterations induced by exercise do not degrade image quality of BMIPP
      scintigraphy. On the contrary, exercise-induced hyperlactatemia seems to enhance
      myocardium-to-cavity activity ratios on SPET images, although this effect does
      not reach statistical significance in this small group of normal subjects. These
      findings further support the robustness of BMIPP SPET in varied metabolic
      environments.

PMID- 10654145
TI  - Assessment of tissue viability after frostbite injury by technetium-99m-sestamibi
      scintigraphy in an experimental rabbit model.
AB  - Frostbite causes injury to the tissue by direct ice-crystal formation at the
      cellular level with cellular dehydration and microvascular occlusion. Muscle that
      initially appears viable on reperfusion may subsequently become necrotic because
      of microcirculatory collapse. Since muscle is a sensitive tissue in frostbite
      injury, we used technetium-99m-sestamibi limb scintigraphy to assess tissue
      viability in an experimental rabbit model. Twelve rabbits were used for this
      investigation. The right hind limb of the rabbits was immersed to the ankle joint
      in a container filled with 90% ethanol at -25 degrees C for 10 min. Frostbitten
      limbs were allowed to thaw in air at room temperature. Imaging and pathological
      examination of the affected limbs were performed 2 h, 24 h, 48 h and 72 h after
      freezing. In 2-h images, initial hypoperfusion was seen that corresponded to
      circulatory collapse. In 24-h images, there was hyperperfusion (so-called period
      of temporary reperfusion), corresponding to circulatory restoration. In 48-h
      images, a second hypoperfusion corresponded to viable but ischaemic tissue. In 72
      h images, there was non-perfusion of the limb that correlated with the
      pathologically determined diagnosis of necrosis. All scintigraphic patterns
      correlated with pathological findings. We suggest that these scintigraphic
      patterns in soft tissue may be helpful in distinguishing between frank infarction
      and reversible ischemia and therefore may be useful in selecting early
      therapeutic or surgical interventions to salvage bone and soft tissue. Further
      studies are needed to show the usefulness of 99mTc sestamibi scintigraphy in
      clinical frostbite cases.

PMID- 10654146
TI  - Technetium-99m hexamethylpropylene amine oxime leucocyte scintigraphy in the
      differential diagnosis of cerebral abscesses.
AB  - The diagnosis of brain abscess is often difficult, as the clinical symptoms are
      not specific. Computed tomography (CT) and magnetic resonance imaging (MRI) are
      highly sensitive, but different cerebral lesions, especially neoplasms, can have
      the same ring-like contrast enhancement. Brain abscess is a severe illness
      requiring rapid diagnosis to choose the most appropriate therapy. Technetium-99m
      hexamethylpropylene amine oxime (HMPAO)-labelled leucocyte scintigraphy is
      commonly used to detect an inflammatory process. The aim of this study was to
      present the results obtained with leucocyte scintigraphy in 65 patients with
      intracranial mass lesions and clinical findings compatible to or suggestive of
      brain abscess. The final diagnosis, based on surgery, clinical findings and
      stereotatic puncture, was brain abscess in 17 patients, primary brain neoplasm in
      22, brain metastasis in 16, lymphoma in 2, cysticercosis in 2, hematoma in 2 and
      cerebral infarction in 4. 99mTc-HMPAO leucocyte scintigraphy was positive in all
      abscess cases. The scan was negative in the rest of the patients examined, with
      the exception of one lesion, which was finally diagnosed as a tumour (1 false
      positive). All patients who did not have false-negative scans were treated with
      steroids. The sensitivity, specificity and diagnostic accuracy of leucocyte
      scintigraphy was 100%, 97.8% and 98.4%, respectively. In conclusion, in our
      experience, leucocyte scintigraphy is a valuable aid in the differential
      diagnosis between abscess and neoplasm.

PMID- 10654147
TI  - Reproducibility of serial peri-ictal single-photon emission tomography difference
      images in epilepsy patients undergoing surgical resection.
AB  - Peri-ictal single-photon emission tomography (SPET) difference images co
      registered to magnetic resonance imaging (MRI) visualize regional cerebral blood
      flow (rCBF) changes and help localize the epileptogenic area in medically
      refractory epilepsy. Few reports have examined the reproducibility of SPET
      difference image results. Epilepsy patients having two peri-ictal and at least
      one interictal SPET scan who later underwent surgical resection were studied.
      Localization accuracy of peri-ictal SPET difference images results, interictal
      electroencephalography (EEG), and ictal EEG from the first (seizure 1) and second
      (seizure 2) seizure, as well as MRI and positron emission tomography (PET)
      findings, were compared using surgical resection site as the standard. Thirteen
      patients underwent surgical resection (11 temporal lobe and 2 extratemporal).
      SPET results from seizure 1 were localized to the surgical site in 12/13 (92%)
      patients, while SPET results from seizure 2 were localized in 13/13 (100%)
      patients. All other modalities were less accurate than the SPET results
      interictal EEG--seizure 1 6/13 (46%); ictal EEG--seizure 1 5/13 (38%); interictal
      intracranial EEG--seizure 2 4/9 (44%); ictal intracranial EEG--seizure 2 results
      8/9 (89%); MRI 6/13 (46%); PET 9/13 (69%)[. SPET results were reproducible in
      12/13 (92%) patients. SPET difference images calculated from two independent peri
      ictal scans appear to be reproducible and accurately localize the epileptogenic
      area. While SPET difference images visualize many areas of rCBF change, the
      quantification of these results along with consideration of injection time
      improves the diagnostic interpretation of the results.

PMID- 10654148
TI  - The value of gallium-67 and thallium-201 whole-body and single-photon emission
      tomography images in dialysis-related beta 2-microglobulin amyloid.
AB  - The aim of this study was to investigate the value of gallium-67 and thallium-201
      whole-body and single-photon emission tomography (SPET) images in long-term
      dialysis patients in whom dialysis-related beta 2-microglobulin amyloid (beta 2
      MA) was clinically suspected. Twenty-three patients who had received dialysis for
      at least 10 years were included in the study. A technetium-99m methylene
      diphosphonate (MDP) whole-body scan was performed in all of the patients. If
      there was any MDP accumulation in the articular and/or peri-articular region,
      67Ga and 201Tl whole-body and SPET images were then acquired. If any 67Ga and/or
      201Tl uptake was observed, a CT-guided biopsy was done. In those patients who had
      articular and/or peri-articular uptake of 99mTc MDP, 67Ga and/or 201Tl and who
      were pathologically proven to have beta 2-MA, 99mTc MDP, 67Ga and 201Tl whole
      body scans and SPET were carried out again, both 3 months and 1 year after
      initiation of treatment. This served to evaluate the therapeutic effect and
      allowed comparison with the clinical findings. Of the 23 patients, eight had
      abnormal 99mTc MDP uptake. Among these eight, six had intense 99mTc MDP, 67Ga and
      201Tl uptake in the articular and peri-articular regions before medication. Three
      months after the start of treatment, there were very marked decreases in uptake
      on both the 67Ga and 201Tl scans but less obvious changes in uptake of 99mTc-MDP.
      In comparison with the other clinical manifestations such as limitation in range
      of motion, the more the painful disability improved, the less was the uptake on
      both 67Ga and 201Tl scans. There were virtually no differences in uptake pattern
      between the three scans of each radiopharmaceutical obtained for each patient in
      both 3 months and 1 year after initial of treatment. It is concluded that 99mTc
      MDP whole-body bone scan can both detect active and pre-existing inactive
      deposits of beta 2-MA. 67Ga and 201Tl scans are helpful to differentiate active
      from inactive deposits of beta 2-MA and to evaluate the therapeutic effect on
      these patients. SPET images are usually needed to distinguish articular and
      periarticular lesions from bone lesions.

PMID- 10654149
TI  - Value of ultrasound-guided fine-needle aspiration biopsy of thyroid nodules in an
      endemic goitre area.
AB  - The aim of this study was to determine the value, advantages and limitations of
      ultrasound-guided fine-needle aspiration biopsy (US-FNAB) in an endemic goitre
      area. US-FNAB was performed on all outpatients who presented with hypoechoic
      and/or hypofunctional and/or growing nodules. A total of 4518 US-FNABs were
      performed and 718 patients from this series underwent surgery. Cytological
      results of the primarily performed US-FNAB of these patients were compared
      retrospectively with the histological results. US-FNAB results were grouped as
      (1) non-malignant (n = 303), (2) non-malignant follicular proliferation (n =
      177), (3) malignancy cannot be ruled out (n = 133), (4) malignant (n = 61), (5)
      inadequate (n = 34), and (6) sampling error; biopsy of a non-malignant nodule (n
      = 10). Nodules as small as 5 mm in diameter could be biopsied, gaining
      representative material. US-FNAB found a malignant or suspicious cytology in 65
      out of 87 cases with malignant histology (74.71%). Diagnosis of early tumour
      stages was often possible: 12 of 18 thyroid carcinomas biopsied and smaller than
      10 mm in diameter had malignant or suspicious cytology (groups 3 and 4). US-FNAB
      was performed incorrectly within non-malignant nodules in ten patients (1.39%)
      with multinodular goitre (ten papillary carcinomas, nine smaller than 10 mm).
      Regarding the cytology of groups 1 and 2 as benign and those of groups 3 and 4 as
      malignant, US-FNAB performance was as follows: sensitivity 87.84%, specificity
      78.50%, negative predictive values 98.13%, positive predictive values 33.51% and
      accuracy 79.53%. Biopsies with inadequate material were obtained in 4.73% of all
      biopsies. No major adverse effects occurred. Re-biopsies in 61 cases did not
      alter the cytological outcome in those cases where adequate material was
      obtained. US-FNAB is a valuable method in the pre-operative assessment of thyroid
      nodules in order to select patients for surgery, as malignancy can often be
      detected even in early tumour stages. However, even with ultrasonographic
      guidance, the minimal tumour size detectable by US-FNAB is around 5 mm. The
      cytological interpretation in cases with regression and microfollicular
      proliferation also sets limits on the method. However, patients with non
      malignant cytologies can be followed up safely by sonography due to the high NPV
      of US-FNAB as long as thyroid nodules do not become larger. Re-biopsies seem to
      be of limited value as long as adequate material was obtained by US-FNAB.

PMID- 10654150
TI  - Use of fluorine-18 fluorodeoxyglucose positron emission tomography in the
      detection of silent metastases from malignant melanoma.
AB  - Correct staging is crucial for the management and prognosis of patients with
      malignant melanoma. The aim of this prospective study was to compare staging by
      whole-body positron emission tomography using fluorine-18 fluorodeoxyglucose (18F
      FDG) with staging by conventional methods. Thirty-eight patients with malignant
      melanoma of clinical stage II (local recurrence, in-transit and regional lymph
      node metastases) or III (metastases to other sites than in stage II) were
      included in the study. The results of the PET scans were compared with those
      obtained by clinical examination, computed tomography, ultrasound, radiography,
      and liver function tests and histology or clinical follow-up. With 18F-FDG PET we
      found for all foci a sensitivity of 97% and a specificity of 56%, compared with
      62% and 22%, respectively, when using routine methods. For intra-abdominal foci,
      the sensitivity and specificity were 100% for both 18F-FDG PET and routine
      methods. Corresponding figures for pulmonary/intrathoracic foci were 100% and
      33%, respectively. Of the patients included in this study, 34% would not have
      been staged correctly by conventional methods alone. We conclude from this study
      that 18F-FDG PET is a sensitive method superior to conventional methods for
      detecting widespread metastases from malignant melanoma. Mutilating surgery of no
      benefit can thereby be avoided. 18F-FDG PET is useful as a supplement to clinical
      examination in melanoma staging.

PMID- 10654151
TI  - Dosimetry of rhenium-188 diethylene triamine penta-acetic acid for endovascular
      intra-balloon brachytherapy after coronary angioplasty.
AB  - To examine the possibility of using rhenium-188 diethylene triamine penta-acetic
      acid (DTPA) for endovascular intra-balloon brachytherapy after angioplasty, dose
      distribution around the balloon was calculated and validated by film dosimetry.
      Medical internal radiation dosimetry (MIRD) was calculated assuming that the
      balloon had ruptured and that the contents had been released into the systemic
      circulation. 188Re-perrhenate eluate from the 188W/188Re generator was
      concentrated using an ion column and used to label DTPA. The dose distribution
      around the angioplasty balloon (20 mm length, 3 mm diameter cylinder) was
      estimated by Monte Carlo simulation using the EGS4 code. The time required for
      17.6 Gy to be absorbed at 1 mm from the balloon's surface following application
      of 3700 MBq/ml of 188Re was found to be 278 s. Fifty percent of the energy was
      deposited in the first millimetre of the vessel wall from the balloon's surface.
      The calculated radiation absorbed dose agreed with that measured by film
      dosimetry, which was performed using a water phantom, with errors ranging from
      9.4% to 17%. Upon balloon rupture the total amount of 188Re-DTPA was presumed to
      enter the systemic circulation. The resulting radiation absorbed dose was
      calculated using the MIRDOSE3 program and residence times obtained from dogs and
      amounted to 0.0056 mGy/MBq to the whole body and 4.56 mGy/MBq to the urinary
      bladder. The absorbed dose of 188Re-DTPA to the whole body was one-tenth of that
      of 188Re-perrhenate. A window-based program was developed to calculate the
      exposure time and the radiation dose absorbed as a function of the 188Re
      concentration and the arbitrary distance from the balloon to the surrounding
      tissues. We conclude that 188Re-DTPA is easy to prepare, safe to use and suitable
      for intra-balloon brachytherapy after coronary angioplasty.

PMID- 10654152
TI  - Performance evaluation of PET scanners: testing of geometric arc correction by
      off-centre uniformity measurement.
AB  - The aim of this study was to demonstrate the necessity of an off-centre
      uniformity measurement during performance evaluation and acceptance testing of a
      positron emission tomography (PET) system. To this end, the effect of different
      methods of geometric arc correction on image uniformity was considered. The arc
      correction routine of the system software of a particular PET scanner family was
      tested in computer simulations, phantom measurements and a patient study. Various
      methods of geometric arc correction--nearest neighbour interpolation, linear
      interpolation and cubic smoothing spline interpolation--were applied to the same
      data. Uniformity was evaluated both visually and quantitatively using intensity
      profiles and regions of interest. The arc correction routine of the PET scanner
      family produced significant ring artefacts and led to overestimation of tracer
      uptake by up to 15%. Since uniformity measurements are usually performed using a
      cylindrical phantom at the centre of the transverse field of view, these
      artefacts are not detected. In conclusion, the standards for performance
      evaluation of a PET scanner should be extended by inclusion of an off-centre
      uniformity measurement at the edge of the transverse field of view. On the basis
      of our comparison of different methods for geometric arc correction, we suppose
      that cubic smoothing spline interpolation might improve the relation between
      statistical noise reduction and spatial resolution as compared with conventional
      linear interpolation.

PMID- 10654153
TI  - How to perform a comprehensive search for FDG-PET literature.
AB  - In this study, a comprehensive, unbiassed search strategy for identifying
      literature on fluorine-18 fluorodeoxyglucose positron emission tomography (FDG
      PET) in Medline, Embase and Current Contents was developed, with specific search
      strategies for each database, using MeSH terms as well as free text words for PET
      and FDG. To examine which text words apply to FDG, we evaluated the ways of
      spelling FDG in a random sample of FDG-PET articles (n = 100). These words were
      used as free text words in the two databases and overlap was determined. PET
      publications were identified using the text words "positron emission tomography"
      and "pet$" combined with the respective MeSH terms for each database. To compare
      the yield of the combined FDG-PET strategy in each database, the retrieved
      citations were downloaded to Pro-Cite 4.0. Finally, we added search terms for
      lung cancer, breast cancer, melanoma, head and neck cancer and lymphoma to our
      strategy and to a short strategy (consisting of the text words "positron emission
      tomography" and "fdg"). In order to measure the yield and precision (positive
      predictive value, PPV) of our search strategy and compare it with the short one,
      we screened the title and abstract of the retrieved citations. Reviewing a random
      sample of the FDG-PET literature yielded 56 different ways of spelling FDG. We
      confined the list to 11 text words, without missing articles. Of the publications
      retrieved by these text words, only 4% were indexed by the MeSH term
      "Fludeoxyglucose F18" in Medline and 29% by the MeSH-term "Fluorodeoxyglucose
      F18" in Embase. Only 51% of PET articles were indexed by the MeSH term
      "Tomography, emission-computed" in Medline and 40% by the MeSH term "Positron
      emission tomography" in Embase. The combined search strategy for identifying
      studies on FDG and PET resulted in 2865 publications in Medline and 2646 in
      Embase. Medline identified 1662 publications not found by Embase; Embase
      identified 1422 publications not found by Medline. Compared with the short
      strategy, our search strategy yielded on average 52% more publications (94%, 41%
      and 20% more in Medline, Embase and Current Contents, respectively). The PPV of
      our strategy (percent of publications that were really on PET, FDG and the
      specified subject) was 70%, compared with 76% using the short strategy.
      Regardless of the strategy used, Embase yielded more publications and was also
      slightly more specific than Medline. With the recommended strategy, FDG-PET
      publications can be identified more efficiently. We have shown the importance of
      searching more than one database and emphasize the use of both MeSH terms and
      text words in a search strategy. Standardization of the spelling of FDG and
      indexing of articles on FDG would substantially simplify searching.

PMID- 10654154
TI  - Standardization of cerebral PET imaging in clinical neurological diagnostics.

PMID- 10654156
TI  - Scientific publishing in the new millennium.

PMID- 10654155
TI  - Highlights of the annual meeting of the European Association of Nuclear Medicine,
      Barcelona 1999. Scientific-based functional imaging and therapy for the next
      millennium.

PMID- 10654157
TI  - Milestones in nuclear medicine.

PMID- 10654158
TI  - Lactitol tolerance in healthy Thai adults.
AB  - The hydrogen breath analysis test was performed in healthy Thai adults to
      determine lactitol tolerance. The study was conducted in 39 individuals (11 males
      and 28 females) aged 18-41 years. All volunteers agreed to participate in this
      study after the risks and benefits had been fully explained. Subjects were
      requested not to consume milk, milk products, or high-vegetable diets for a day
      and to fast from 10 p.m. of the day preceding the test day. After consumption of
      the test diet (12 and 20 g of lactose or lactitol, respectively, in 250 mL
      water), the subjects recorded the severity of symptoms for 24 hours. Breath
      samples were collected after fasting and after consumption of the test diet at 30
      min intervals over the 7-hour study period. Breath samples were analyzed for
      hydrogen using gas chromatography. After consumption of 12 g lactose, the
      prevalence of lactose malabsorbers was established. The increment of a peak
      breath hydrogen level of > or = 20 ppm above the baseline level was used as an
      indicator of lactose malabsorption. The lactose malabsorbers were further
      classified as lactose tolerance or lactose intolerance according to the
      gastrointestinal symptoms observed. All 39 healthy Thai adults could be
      classified into 3 groups as follows: 9 (23%) lactose absorbers (LA), 15 (38.5%)
      lactose mal-absorber/tolerance (LMT), and 15 (38.5%) lactose mal
      absorber/intolerance (LMI). Using the hydrogen breath test, 67% of the subjects
      were identified as lactitol intolerance after the consumption of 12 g lactitol.
      The lactitol intolerance comprised 53.8% of LMI, 34.6% of LMT, and 11.5% of LA.
      Among all subjects, one third of LA (33%), two thirds of LMT (60%), and 93% of
      LMI were lactitol intolerant. In addition, gastrointestinal symptoms such as
      flatulence and abdominal pain were most pronounced in LMI. Diarrhea was also a
      prominent manifestation after consumption of 12 g lactitol. Therefore, it was
      finally decided that 20 g lactose or lactitol were not given to LMI because of
      the risk of gastrointestinal symptoms. After high doses (20 g) of lactose and
      lactitol consumption, most LMT developed more symptoms than did LA and the main
      symptom was diarrhea. Consumption of 20 g lactose resulted in fewer symptoms than
      20 g lactitol in both LA and LMT. On the basis of the hydrogen breath test, most
      LA tolerated 12 g lactitol without gastrointestinal symptoms except some
      flatulence whereas most LMT and LMI did not. Twenty g lactitol was not tolerated
      by both LA and LMT because there was diarrhea among the subjects, especially in
      LMT. Although the hydrogen breath analysis test is the best method for
      identification of lactose malabsorption, it is not the best method to identify
      lactitol intolerance. A hydrogen concentration of 15 ppm above the baseline level
      was found to be the best cut-off point to indicate lactitol intolerance although
      sensitivity was 85% and specificity only 38% in this study. It was further
      concluded that there is a greater susceptibility to lactitol in human lactose
      malabsorbers than in lactose absorbers. Our findings might be relevant for the
      limited use of lactitol in Thailand.

PMID- 10654159
TI  - Anthocyanins are potent antioxidants in model systems but do not reduce
      endogenous oxidative DNA damage in human colon cells.
AB  - Anthocyanins are common colored plant flavonoids, occurring as glycosides of the
      respective anthocyanidin-chromophores. Like other flavonoids, anthocyanidins are
      also expected to have antioxidative and anti-mutagenic properties in vivo,
      although only few data are available. To gain more knowledge on possible
      protective mechanisms in mammalian cells, we have compared their extracellular
      and intracellular antioxidative potential in vitro and in human colon tumor
      cells. We used Aronia melanocarpa Elliot anthocyanin (AA) concentrates, fractions
      thereof, concentrates from Elderberry, Macqui, and Tintorera fruits, as well as
      pure compounds. In vitro, antioxidative properties of the samples were studied
      with the ferric reducing ability assay (FRA assay). As a measure of intracellular
      oxidative/antioxidative effects, H2O2-induced strand breaks as well as oxidized
      DNA bases were determined in human tumor HT29 clone 19A cells using a
      microgelelectrophoresis assay (comet test). Major results were that isolated
      compounds (aglycons and glycosides) and complex plant samples are powerful
      antioxidants in vitro. In fact their activities by far exceeded those of Trolox
      and vitamin C in the FRA assay. Also, H2O2-induced DNA strand breaks were reduced
      in cells treated with the complex plant extracts. In contrast, endogenous
      generation of oxidized DNA bases was not prevented. In summary, the intracellular
      steady state of oxidized DNA bases is not altered by anthocyanins or
      anthocyanidins. This finding raises questions with respect to the cancer
      preventive potential of anthocyanidins within specific tissues, such as the
      colon. Extracellularly, however, the compounds are potent antioxidants. This
      points to their potential for providing systemic protection in vivo, e.g., by
      scavenging oxidants in the blood stream and in the colon. Notably, both aglycons
      and glycosides have equally strong antioxidant activity.

PMID- 10654160
TI  - Validation of a self-administered 3-day estimated dietary record for use in the
      elderly.
AB  - AIM OF THIS STUDY: was to assess the validity of a 3-day estimated dietary
      record, especially developed for the longitudinal study on nutrition and health
      status in an aging population (aged > or = 60 years) in Giessen, Germany.
      METHODS: The dietary record comprises 146 food items. Portion sizes of the foods
      consumed were estimated by means of household measures and corresponding
      dimensions. The validity of the dietary record was evaluated by means of nitrogen
      excretion in the 24 h urine in 14 women and 9 men, and by comparing energy intake
      and basal metabolic rate determined by indirect calorimetry in 238 women and 105
      men. RESULTS: Neither in women nor in men were any differences found between
      calculated nitrogen intake (13.4 +/- 2.2 g and 15.0 +/- 2.0 g, respectively) and
      nitrogen excretion (12.9 +/- 2.1 g and 15.7 +/- 3.0 g, respectively). The ratio
      between reported energy intake and basal metabolic rate was 1.62 +/- 0.46 in
      women and 1.53 +/- 0.46 in men. Regarding energy intake, 7.6% of the females and
      16.2% of the males were classified as under-reporters. They show a significantly
      higher body weight and BMI than the adequate reporters. CONCLUSION: The results
      have proved the new 3-day estimated dietary record as suitable to determine
      energy and nutrient supply of the elderly.

PMID- 10654161
TI  - Investigations on the intestinal availability of native thiamin in selected foods
      and feedstuffs.
AB  - The aim of the present study was to investigate the precaecal digestibility as a
      quantitative measure for the intestinal availability of naturally occurring
      thiamin from selected foods and feedstuffs. Therefore, three experiments were
      conducted to examine the following foods and feedstuffs: Eggs, bananas, white
      cabbage, corn, milk, fish, barley, soybeans, rice, wheat bran, brewer's yeast,
      rye and soybean meal. The foods and food processing procedures were made with
      regard to their relevance in human and animal nutrition. For all experiments male
      pigs with an initial live weight between 33 and 40 kg were fitted with an end-to
      end ileo-rectal anastomosis with preserved ileo-caeco-colicvalve. Three weeks
      after surgery, the digestibility trials were carried out from week 4 to week 9
      and week 12 to week 17 after surgery. The animals were fed the individual
      experimental diets for a period of 12 days while digesta were collected twice a
      day quantitatively during the final 5 days of this period. Precaecal
      digestibility for thiamin from all tested foods and feedstuffs was within a range
      from 73% to 94% with the highest values from boiled soybeans, boiled rice and
      barley, and the lowest value from steamed fish. In comparison with the animal
      products the plant products show on average a nearly equal precaecal
      digestibility for thiamin (87.3% versus 83.5%). Moreover, all tested foods and
      feedstuffs exhibit a relatively good intestinal availability of thiamin.

PMID- 10654162
TI  - Estrone in food: a factor influencing the development of obesity?
AB  - BACKGROUND: Estrone is a relatively abundant hormone widely distributed in
      tissues of animal and plant origin. It is a mild estrogen that induces increases
      in body weight in experimental animals. The relative abundance of estrone esters
      in animal tissues suggests that it may also be found in foods, from which it may
      alter the mechanisms of body weight control. AIM OF THE STUDY: To measure the
      total estrone content in food and to determine whether this may affect body
      weight. METHODS: In the first part of the study, a method was devised for the
      measurement of total estrone content in food. This was applied to the analysis of
      estrone content in a variety of food. Finally, hyperlipidic diets (18.6 MJ/kg)
      with a total estrone content 0.89 +/- 0.21 mumol/kg (control group) and 1.37 +/-
      0.13 mumol/kg (laced with estrone fatty esters) were given to rats during 15
      days, in order to determine the influence of dietary estrone on the body mass.
      Zucker lean (Fa/?) rats weighing initially 200-215 g were used. The total estrone
      (essentially as fatty esters) content of food was investigated by combining a
      dried methanol extraction with saponification and measurement of the free estrone
      evolved through radioimmunoassay. RESULT: The content of estrone was zero in some
      vegetables, but significant in fruits, meats, and especially fats, both of plant
      and animal origin. The application of these analyses to a standard recommended
      diet for humans may result in intakes of more than 1 mumol of estrone per day, a
      figure comparable to the estrogen production by women. When rats were exposed to
      a raised estrone content in a fat-rich diet, they significantly increased their
      body weights, doubling their rate of growth (1.99 g/day) compared with controls
      (0.81 g/day), but maintaining their plasma composition and the proportions of
      lipid, water, and protein in their carcasses. CONCLUSION: The widely distributed
      estrone esters in food and their relatively high concentrations may result in
      high free hormone intakes in humans. The continued and massive intake of estrone
      may enhance tissue deposition and lead to obesity.

PMID- 10654163
TI  - Effect of thalidomide and structurally related compounds on corneal angiogenesis
      is comparable to their teratological potency.
AB  - Neovascular diseases are the leading causes of blindness in humans. Although
      several promising compounds have been isolated, pharmacological treatment remains
      difficult. Thalidomide has inhibitory effects on angiogenesis in the corneal
      micropocket assay. However, the results vary considerably depending on the
      administration route and animal model. The aim of this study, therefore, was to
      investigate thalidomide and two of its derivatives, supidimide and EM12, in the
      rabbit corneal micropocket assay. Using both basic fibroblast growth factor and
      vascular endothelial growth factor for initiation of the neovascular response, we
      were able to show a significant inhibition of neovascularisation with all three
      substances. EM12, the most teratogenic derivative analysed, was demonstrated to
      be the most potent inhibitor of angiogenesis in this model. Thalidomide and
      supidimide did not show systemic side effects in the applied dosage. An equal
      dosage of EM12, however, resulted in significant weight loss of the animals, but
      did not increase angiogenic activity compared with lower doses. Together with
      earlier findings, these data support a strong correlation between the
      antiangiogenic potential and the teratogenic activity of thalidomide and
      structurally related compounds.

PMID- 10654164
TI  - Electrophysiological abnormalities in age-related macular degeneration.
AB  - BACKGROUND: Results from psychophysical tests indicate that in age related
      macular degeneration (ARMD) retinal function is globally impaired. Observations
      in single ARMD cases showing abnormalities of the electrooculogram (EOG) and
      electroretinogram (ERG) encouraged us to systematically examine ARMD patients by
      means of electrophysiological tests to confirm a global retinal dysfunction in
      ARMD. METHODS: Sixty-six patients with ARMD were examined clinically and by means
      of EOG, ERG, triple scotopic ERG, and fluorescein angiography (FA). RESULTS: EOG
      data were considerably reduced in ARMD. Scotopic a- and b-waves of the ERG were
      mildly affected. The bright flash response showed reduced b-waves with normal
      implicit times. The amplitude of the oscillatory potential OP2 was significantly
      reduced and photopic responses were also pathologic compared with an age-matched
      control group. Geographic atrophy and pigment epithelium detachment showed
      specific abnormalities in the ERG, whereas in soft drusen EOG changes were more
      conspicuous. CONCLUSIONS: In addition to data from psychophysical tests the
      results from electrophysiological examinations indicated a global reduction of
      retinal function in ARMD which seemed to be present not only in the macula but
      also elsewhere in the retina.

PMID- 10654165
TI  - Pars plana vitrectomy, endolaser coagulation of the retina and the ciliary body
      combined with silicone oil endotamponade in the treatment of uncontrolled
      neovascular glaucoma.
AB  - PURPOSE: Neovascular glaucoma develops on a background of ischemic ocular
      pathologies, such as diabetic eye diseases or central retinal vein occlusion.
      Development of neovascular membranes in the chamber angle leads to elevated
      intraocular pressure (IOP). Since cyclodestructive therapy or drainage surgery
      often fails, we have examined intense antiproliferative surgery as a treatment
      for advanced neovascular glaucoma. PATIENTS AND METHODS: Thirty-two patients with
      uncontrolled neovascular glaucoma (mean IOP 45.5 mmHg) subsequent to central
      retinal vein occlusion or advanced diabetic retinopathy underwent
      antiproliferative surgery, which comprised pars plana vitrectomy, panretinal
      laser treatment and direct laser coagulation of the ciliary processes, followed
      by silicone oil tamponade. Patients were followed up for a minimum of 1 year and
      as long as 3 years. RESULTS: One week following surgery the IOP was normal,
      ranging from 8 to 21 mmHg, in 52% of eyes (15/29). After 3 months the IOP was
      normal in 50% (16/32); after 6 months, in 59% (16/27); and after 1 year, in 72%
      (18/25). Of the 10 eyes that lost all sight after the surgery, 7 eyes had a
      history of central retinal vein occlusion. Hypotony was observed in 6% of the
      eyes (2/32) 3 months after surgery; after 6 months hypotony was present in 15%
      (4/27), and after 1 year hypotony was present in 12% (3/25). CONCLUSIONS: The
      theoretical premise of our surgical intervention (antiproliferative surgery) is
      that laser treatment interrupts the self-enhancing pathway of retinal ischemia,
      release of proliferative factors and increase in intraocular pressure. The
      silicone oil endotamponade prevents postoperative complications and supports the
      rapid regression of rubeosis iridis by separating the anterior from the posterior
      segment.

PMID- 10654166
TI  - Cellular transport of subretinal material into choroidal and scleral blood
      vessels: an electron microscopic study.
AB  - BACKGROUND: The fate of indigestible material injected into the subretinal space
      of rats was investigated. METHODS: The non-toxic dye Monastral Blue (MB), which
      cannot be digested within the lysosomal compartment, was injected transsclerally
      into the subretinal space of Long Evans and Wistar rats. After 5 and 12 days
      respectively the eyes were enucleated and examined by light and electron
      microscopy. Cryo sections were made of eyes 5 days after MB injection for the
      application of immunohistochemical techniques using markers for epithelial cells
      (cytokeratin) and macrophages (ED 1). RESULTS: Retina, choroid and sclera were
      not altered in their morphology in the circumference of the MB-containing bubble
      generated by subretinal injection. After both 5 and 12 days no injected material
      was found extracellularly in the subretinal space. Especially high amounts of MB
      were found, in particular 5 days after injection, in lysosomes and melanosomes of
      RPE cells as well as in cells between choroidal melanocytes. Cells containing MB
      were seen in contact with choroidal and scleral blood vessels. These MB
      containing cells in the choroid and in the sclera were positive for macrophage
      antibodies. CONCLUSION: Subretinal injection was confirmed as a suitable method
      for placing fluids into the subretinal space without affecting the morphology of
      the retina. Subretinal injected material was shown to be incorporated into
      lysosomes and melanosomes of RPE cells. The injected material was subsequently
      transported through Bruch's membrane to be finally removed from the eye via
      choroidal and scleral veins, the process involving macrophages.

PMID- 10654167
TI  - Comprehensive assessment of retinal, choroidal and retrobulbar haemodynamics
      during blood gas perturbation.
AB  - BACKGROUND: A study was performed to evaluate the effect of isoxic hypercapnia on
      ocular haemodynamics using colour Doppler imaging (CDI), scanning laser Doppler
      flowmetry (SLDF) and ocular blood flow (OBF) tonography. METHODS: Measurements
      were taken for one eye of each of 14 healthy subjects (mean age 27 +/- 6 years)
      during breathing of room air and then during isoxic hypercapnia (breathing CO2
      and room air). Using CDI, blood flow velocities and resistance indices were
      determined for the ophthalmic artery (OA), central retinal artery (CRA) and short
      posterior ciliary arteries (SPCAs). Using SLDF a 10 x 10 pixel frame was used to
      measure blood flow, volume and velocity in each quadrant of the peripapillary
      retina. Pulsatile ocular blood flow (POBF) was measured using the OBF tonograph.
      RESULTS: Using CDI, peak systolic and end diastolic velocities increased and
      resistance index decreased significantly in the SPCAs during hypercapnia. Using
      SLDF, blood flow, volume and velocity increased significantly during hypercapnia
      in the superior temporal quadrant of the peripapillary retina. No significant
      difference was observed between baseline and hypercapnia for POBF. CONCLUSIONS:
      Isoxic hypercapnia resulted in an increase in peripapillary retinal and SPCA
      blood flow parameters as determined by SLDF and CDI respectively. This implies
      the presence of autoregulatory activity in these vasculatures. These findings may
      be of significance in the pathogenesis of ocular disease such as glaucoma where
      autoregulation is thought to be compromised.

PMID- 10654168
TI  - Development of laser-induced retinal damage in the rabbit.
AB  - BACKGROUND: Laser lesions may induce retinal damage that is larger than expected
      from the size of the coagulated area. This study was designed to follow the
      development of laser-induced reduction in retinal function and to correlate it
      with structural changes. METHODS: Pigmented rabbits were treated in one eye with
      225 argon laser lesions. The ERG responses were recorded at different times after
      treatment. The effect of the laser treatment upon the functional integrity of the
      retina was assessed from the ERG responses. Structural damage was examined by
      light microscopy. RESULTS: Shortly (1-2 h) after laser treatment, the ERG
      responses were reduced by about 50%. ERG deficit continued to develop and reached
      a maximal level about 24 h after treatment. Thereafter, slow recovery was
      observed but permanent deficit, relative to the initial laser effect, was seen
      even 30 days after treatment. Histological observations indicated extensive
      serous retinal detachment between laser lesions that developed within 24 h after
      treatment. At 30 days post-treatment, lesioned areas were completely destroyed
      and heavily pigmented. The retina between lesions was attached to the pigment
      epithelium but exhibited different degrees of structural damage. CONCLUSIONS: The
      immediate laser damage is confined to the coagulated areas while secondary
      functional damage develops within 24 h and probably reflects serous retinal
      detachment between lesions. The serous retinal detachment completely resolves
      with time but may induce permanent structural abnormalities in non-coagulated
      retinal areas that is reflected in a functional deficit larger than the initial
      laser effect.

PMID- 10654169
TI  - Physiological features of primary cultures and subcultures of human retinal
      pigment epithelial cells before and after cryopreservation for cell
      transplantation.
AB  - BACKGROUND: One striking disadvantage of in vitro culturing of human retinal
      pigment epithelial (RPE) cells is the loss of epithelial differentiation and
      specific cell function during culture. This may be one of the main reasons for
      the failure of RPE cell transplantation. The aim of this study was to evaluate
      cell culture conditions ensuring the maintenance of differentiation and function
      of RPE cells after subcultivation and storage in liquid nitrogen. METHODS:
      Enzymatically isolated cells were seeded onto coated culture dishes, cultured
      with a specially formulated improved growth medium until confluence and then
      cryopreserved in liquid nitrogen for 16-66 months. HLA class I and II typing was
      performed before cryopreservation and after thawing. Expression of Ca2+ channels
      in primary, first-passage and cryopreserved RPE cells was studied using the patch
      clamp technique. RESULTS: After cryopreservation no loss of any HLA antigen was
      detectable in 12 of 14 cell strains studied. Patch-clamp experiments demonstrated
      that high-threshold L-type Ca2+ channels, which are typical for freshly isolated
      cells, could be detected in first-passage and cryopreserved RPE cells only when
      improved culture conditions were employed, not in conventionally cultured cells.
      The characteristics of these channels showed little change in subcultured cells
      compared to primary cultures. CONCLUSION: This is the first study showing the
      maintenance of adult human RPE-specific cell differentiation and characteristics
      in vitro after primary culture and after cryopreservation using improved cell
      culture methods. The optimization and quality control of cell culture is an
      important prerequisite for successful cell transplantation.

PMID- 10654170
TI  - Understanding the origin of visual percepts elicited by electrical stimulation of
      the human retina.
AB  - BACKGROUND: The success of a retinal prosthesis for patients with outer retinal
      degeneration (ORD) depends on the ability to electrically stimulate retinal cells
      other than photoreceptors. Experiments were undertaken in human volunteers to
      ascertain whether electrical stimulation of cells other than photoreceptors will
      result in the perception of light. METHODS: In two subjects, two areas of laser
      damage (argon green and krypton red) were created in an eye scheduled for
      exenteration due to recurrent cancer near the eye. In the operating room prior to
      exenteration, under local anesthesia, a hand-held stimulating device was inserted
      via the pars plana and positioned over the damaged areas and normal retina.
      Subjects' psychophysical responses to electrical stimulation were recorded.
      RESULTS: In both subjects, electrical stimulation produced the following
      perceptions. Normal retina: dark oval (subject 1), dark half-moon (subject 2);
      krypton red laser-treated retina: small, white light (both subjects); argon green
      laser treated retina: thin thread (subject 1), thin hook (subject 2). Histologic
      evaluation of the krypton red-treated retina showed damage confined to the outer
      retinal layers, while the argon green-treated area evinced damage to both the
      outer and the inner nuclear layers. CONCLUSION: The perception produced by
      electrical stimulation was dependent on the retinal cells present. Electrical
      stimulation of the krypton red-ablated area best simulated the electrically
      elicited visual perceptions of our blind, ORD patients, suggesting that the site
      of stimulation in blind patients is the inner retinal neurons.

PMID- 10654171
TI  - Morphometric study of the displacement of retinal ganglion cells subserving cones
      within the human fovea.
AB  - BACKGROUND: A study was carried out to measure the displacement of retinal
      ganglion cells subserving the cones within the human fovea. METHODS: Four human
      retinas were examined along the nasal or vertical hemi-meridians. Total
      displacement was estimated by adding the displacement due to fibres of Henle and
      bipolar cells, measured as the lateral extension of the Henle fibres and of the
      obliquely running fibre bundles within the inner nuclear layer, respectively.
      RESULTS: At the foveal border (0.5-0.8 mm or 1.8-2.9 deg eccentricity) the mean
      offset due to fibres of Henle and mean total lateral displacement was at a
      maximum of 0.32 +/- 0.03 mm and 0.37 +/- 0.03 mm, respectively. A steep decrease
      of displacement was found outside the foveal border out to an eccentricity of 2.0
      2.5 mm. We were able to plot displacement along the vertical meridian in relation
      to eccentricity with good correlation between three eyes. The data were used to
      establish different mathematical functions describing the relation between
      eccentricity and displacement. These functions were applied to previously
      presented data on densities of retinal ganglion cells and cones. CONCLUSIONS: The
      present estimates of displacement within the human central fovea offer the
      possibility of analysis of quantitative relations between cones and retinal
      ganglion cells. Our data provide predictive guidance by establishing that vitreo
      retinal procedures causing damage to retinal ganglion cells up to 1 mm from the
      foveal centre could have implications for loss of information generated within
      the fovea.

PMID- 10654172
TI  - Grid laser treatment in macular branch retinal vein occlusion.
AB  - BACKGROUND: Macular branch retinal vein occlusion (MBRVO) is a subgroup of branch
      retinal vein occlusion in which the occlusion is limited to a small venous vessel
      draining a sector of the macular region. The present study aimed to evaluate
      prospectively whether grid laser treatment is useful in improving the visual
      acuity of eyes affected by MBRVO with significant macular edema. METHODS: Ninety
      nine patients affected by MBRVO of recent onset were prospectively studied during
      a 24-month period; eyes were randomly assigned to the control group, the early
      grid laser treatment group or the delayed grid laser treatment group. Clinical
      and angiographic features were recorded during the whole follow-up; parameters
      such as visual acuity and macular edema were carefully evaluated, the latter even
      by means of stereophotography. RESULTS: With respect to the baseline mean visual
      acuity values, a statistically significant improvement was noted at the 3-month
      follow-up and at the 1-year follow-up. No additional improvement was noted at the
      2-year follow-up. No statistically significant difference was found between the
      treated groups and the control group. CONCLUSIONS: We hypothesize that the abrupt
      ischemic damage subsequent to MBRVO is the main factor causing the central
      function impairment. Grid laser treatment is not able to reduce the macular edema
      more than the natural evolution, and does not improve visual acuity.

PMID- 10654173
TI  - Motility and binocularity outcomes in vitrectomy versus scleral buckling in
      retinal detachment surgery.
AB  - BACKGROUND: Ocular motility defects and loss of binocularity are well-recognised
      problems following retinal detachment surgery. It is presumed that scleral
      buckling is primarily responsible for these effects. The increasing use of
      vitrectomy in the management of retinal detachment might be expected to reduce
      the incidence of these defects. METHOD: Two groups of patients presenting with
      primary uncomplicated rhegmatogenous retinal detachments were examined following
      a single surgical repair. The first group underwent vitrectomy (n = 17), the
      second group, scleral buckling/external surgical techniques (n = 23). RESULTS:
      Heterotropia was present in 24% (n = 4) of the vitrectomy group and 30% (n = 7)
      of the "external" group, with suppression reported clinically in 8 of these and
      diplopia by the other 3. While ocular movements were frequently full (vitrectomy
      59%, external 61%), restricted vertical movements were observed in 35% of the
      vitrectomy group and 26% of the external group, with horizontal and general
      restrictions being rare (6% and 13% respectively). True motor fusion was more
      common for the external group (44%) than the vitrectomies (24%), while
      superimposition was more frequent in the vitrectomies (64%; external 39%). The
      latter was achieved only with correcting prisms in 18% of vitrectomies and 9% of
      the external group. The remainder did not demonstrate any potential for
      binocularity. Visual symptoms were more frequent among the vitrectomy group, with
      aniseikonia and torsion significantly more common. CONCLUSIONS: The findings
      confirm that ocular motility problems are not exclusive to scleral buckling, with
      the incidence being similar in both groups. Slinging of the extraocular muscles
      and the accompanying dissection, resulting in the 'fat adherence syndrome', must
      be considered as contributory factors. The visual deficits which inevitably occur
      as the result of retinal detachment seem to play a more major role in the
      disruption of binocularity in these cases.

PMID- 10654174
TI  - Vasoproliferative retinal tumors associated with peripheral chorioretinal scars
      in presumed congenital toxoplasmosis.
AB  - BACKGROUND: The purpose of this retrospective clinical study was to demonstrate
      vascularization of peripheral hyperplastic chorioretinal scars in presumed
      congenital toxoplasmosis by choroidal vessels and secondly to report
      vasoproliferative tumors of the sensory retina seen in association with such
      lesions. METHODS: Retrospective study of a cohort of 13 patients with peripheral
      hypertrophic chorioretinal scars, including fluorescein angiography (eight eyes)
      and indocyanine green angiography (seven eyes). Congenital toxoplasmosis was
      serologically confirmed in seven cases and suspected on clinical grounds in six
      cases. RESULTS: Sixteen eyes exhibited a peripheral complex scar with a posterior
      atrophic and an anterior hypertrophic part. These scars were vascularized from
      the choroid. In eight of these eyes an additional vasoproliferative tumor was
      seen within or adjacent to the scar and in one fellow eye a vasoproliferative
      retinal tumor was found as well. These eyes experience visual loss, resulting
      from vitritis and exudative/traction retinal detachment. Regression of exudation
      was seen in five of seven cryocoagulated or endophotocoagulated tumors.
      CONCLUSION: Peripheral hypertrophic scars in presumed congenital toxoplasmosis
      can be vascularized from the choroid. A vasoproliferative tumor of the sensory
      retina, secondary to presumed congenital toxoplasmosis scars, can cause vitritis
      and exudative/traction retinal detachment. Early coagulation of this lesion may
      prevent a poor outcome.

PMID- 10654175
TI  - Subretinal fibrosis and choroidal neovascularization in Vogt-Koyanagi-Harada
      syndrome.
AB  - BACKGROUND: To describe clinical findings of subretinal fibrosis and choroidal
      neovascularization in patients with Vogt-Koyanagi-Harada (VKH) syndrome. METHODS:
      We retrospectively reviewed 75 medical records of patients with VKH seen at the
      National Eye Institute, Bethesda, Maryland between 1978 and 1996. Recorded data
      included age, gender, race, duration of disease, extraocular manifestations, best
      corrected visual acuity, slit-lamp biomicroscopy, retinal examination, retinal
      photographs and fluorescein angiograms. We sought features that correlated with
      the visual outcome. RESULTS: Thirty of 75 (40%) patients developed subretinal
      fibrosis. Eleven patients (14.7%) had choroidal neovascularization. Presence of
      subretinal fibrosis was associated with a longer duration of the disease (42.6 vs
      19.1 months, P = 0.07). Patients with subretinal fibrosis had worse visual acuity
      than those without subretinal fibrosis (26.2 vs 57.3 ETDRS letters read, P <
      0.001) after adjusting for duration of disease (P = 0.021), degree of vitreous
      haze (P = 0.074), and use of immunosuppressive therapy (P = 0.008). CONCLUSIONS:
      Presence of subretinal fibrosis in patients with VKH is associated with a poor
      visual prognosis. The diagnosis of choroidal neovascularization and subretinal
      fibrosis presents a challenge in the management of this disease.

PMID- 10654177
TI  - [Hearing loss caused by New Year's fireworks. Survey of incidence of blast and
      explosion trauma in Germany during the 1998/99 New Year's celebration].

PMID- 10654176
TI  - Detection of mRNA for proteins involved in retinol metabolism in iris pigment
      epithelium.
AB  - BACKGROUND: To investigate in iris pigment epithelium (IPE) the expression of
      mRNA for proteins involved in retinol metabolism we used a semi-quantitative
      reverse transcription polymerase chain reaction (RT-PCR) technique. METHODS: RNA
      was prepared from freshly isolated bovine IPE and retinal pigment epithelium
      (RPE) cells and reverse transcribed. The expression of mRNA for cellular
      retinaldehyde binding protein (CRALBP), p63 (RPE63), the presumed retinal pigment
      epithelial membrane receptor for retinoids, and 11-cis-dehydrogenase (11cisRDH)
      was determined by RT-PCR using specific primers. Semi-quantitative expression
      data were obtained by using a series of fivefold dilution of each cDNA with a
      fixed number of PCR cycles. RESULTS: Bovine IPE and RPE cells express mRNA for
      CRALBP, 11cisRDH, and RPE63. The mRNA expression for CRALBP and 11cisRDH is high
      and equal in both cell types. However, RPE63 mRNA expression in IPE cells is
      relatively low compared with the expression in RPE cells. CONCLUSIONS: The
      presence of mRNA for CRALBP, RPE63, and 11cisRDH suggests that IPE cells may be
      able to metabolize retinol.

PMID- 10654178
TI  - [New knowledge about acoustic neurinoma. Congress notes of the "Third
      International COnference on Acoustic Neurinoma and other CPA tumors", Rome, 12-17
      June 1999].

PMID- 10654179
TI  - [Occupation and cancer of the head-neck area].
AB  - Head- and neck-cancer is a multifactorial disease. Besides major risk factors
      like alcohol and tobacco consumption, occupational factors play a significant
      role. At present it is estimated that in western industrial nations about 4 to
      10% of all head- and neck-cancer cases are caused by occupational exposures.
      Combined exposures to occupational and non-occupational risk factors as well as
      the interaction of different occupational agents may have a synergistic effect on
      the cancer risk. It is very likely that the cancer risk due to occupational
      factors is modulated by host factors like DNA repair capacity and enzymatically
      controlled activation and inactivation of carcinogens.

PMID- 10654180
TI  - [Outcome of hyperbaric oxygen therapy in therapy refractory tinnitus].
AB  - Although many studies are available concerning the treatment of sudden deafness
      using hyperbaric oxygenation, only a few of these deal with tinnitus. The aim of
      the present study was to evaluate the therapeutic use of hyperbaric oxygenation
      in cases of tinnitus. A total of 193 patients, having undergone primary
      intravenous hemorheologic therapy, were treated with hyperbaric oxygenation.
      Tinnitus was evaluated before, after ten sessions and after 15 sessions using a
      tinnitus questionnaire. Additionally, an audiometric examination was performed.
      Measurable improvements of the tinnitus occurred in 22% of the patients, whereas
      a moderate improvement was seen in 17% of cases. 10.4% showed an excellent
      improvement and tinnitus disappeared completely in two patients. The improvement
      rate decreased in those cases where the time from onset of tinnitus exceeded 40
      days. In conclusion, hyperbaric oxygenation seems to be a moderately effective
      additional treatment in the therapy of tinnitus after primary hemorheologic
      therapy, provided the time from onset of tinnitus is less than 1 month.

PMID- 10654181
TI  - [Radiosurgery of acoustic neurinoma as a minimally invasive alternative to
      microsurgery].
AB  - From April 1992 to July 1998 stereotactic radiosurgery (Gamma Knife) was used to
      treat 1382 patients; 181 had acoustic neurinomas and were followed up, 44 of them
      for at least 4 years (48-75 months, median 60). With no mortality control of
      growth tumor was achieved in all cases but one. It was possible to preserve
      useful hearing in more than half of the patients (60%). In two patients
      complications due to the radiation with enlargement of the cystic component were
      observed. One patient needed additional microsurgical decompression. Three
      patients suffered transient incomplete facial palsy (one permanent, HBI III), and
      two patients complained of mild trigeminal neuropathy. One suffered from
      hydrocephalus and a shunting procedure was necessary. The neurological state
      improved in 23 patients (52%); five complained of new or worsened deficits.
      Radiosurgery is an effective alternative treatment for acoustic neurinomas with
      exceptionally low mortality and morbidity. With respect to preserving cranial
      nerve function the results are just as good as those of microsurgical resection.
      Short duration of hospitalization and quick return to normal activities make
      radiosurgery quite cost effective.

PMID- 10654182
TI  - [Use of open MRI in head-neck surgery].
AB  - The vertical open MRI (Signa SP, 0, 5 Tesla) is ideal for interventional
      diagnosis and therapy. From our point of view indications in Otorhinolaryngology
      are biopsies of tumours which are difficult to access such as the petrous apex
      and the petroclival region, the parapharyngeal space and neck and the orbit.
      Furthermore the open MRI is useful in the surgery of paranasal sinuses, in the
      evaluation of tissue-resection and helpful in detection of the anatomy of
      delicate structures as the internal carotid artery, the skull-base and the orbit.
      Also navigation in open MRI is possible for example with a flash-point-system.
      The advantage to conventional navigation systems is the possibility of real-time
      imaging, which allows detection of tissue shift occurring during the procedure.
      We report about our experience with ten biopsies of the petrous apex and the
      petroclival junction and two biopsy of the parapharyngeal space and the neck.
      Further experience was gained with MR guided placement of afterloading tubes into
      large neck metastases in three cases and microscopic surgery of paranasal sinuses
      in five cases. In all operative procedures an excellent resolution was found
      especially for soft tissue structures as for example blood vessels. With the aid
      of special pointer systems or artefacts by surgical instruments all relevant
      anatomical structures could be detected intraoperatively, concerning normal and
      pathologic tissue. Thus open MRI proved to be a helpful instrument in these
      operative procedures.

PMID- 10654183
TI  - [Effect of primary radiochemotherapy on cellular and subcellular immunologic
      parameters].
AB  - PURPOSE: It is well known that chemotherapy and radiotherapy in other tumor sites
      than head and neck cause immunomodulating effects. The purpose of this trial was
      to assess the influence of radiochemotherapy in head and neck on cellular and
      subcellular immunity. PATIENTS AND METHODS: In a phase II/III-trial fifty
      patients with advanced squamous cell carcinoma of the head and neck were treated
      by simultaneously accelerated radiochemotherapy with Carboplatin (70 mg/sqm).
      Total radiation dose was 66 Gy/35 days. The following immunological parameters
      were investigated at several time points during therapy: total lymphocytes, total
      T-lymphocytes, CD4+ lymphocytes, CD8+ lymphocytes, monocytes, natural killer
      cells, interleukin-2-receptor-positive T-cells, MHC class II-positive B-cells,
      monocytes and T-cells, CD4/CD8-ratio; Cytokines: II-1, soluble II-1-receptor
      antagonist, II-2, soluble II-2-receptor, II-3, II-4, II-6, soluble II-6-receptor,
      II-8, interferon-alpha, granulocytes-macrophages-colony-stimulating-factor, tumor
      necrosis factor-alpha, soluble intercellular adhesion molecule-1. In addition,
      responses to the in vitro stimulation of lymphocytes by mitogens was tested.
      RESULTS: During therapy lymphocyte subpopulation counts decreased significantly
      but reversibly. Simultaneously, the function of lymphocytes was significantly but
      reversibly reduced. Also, II-8-concentration decreased significantly whereas
      concentrations of II-6 and soluble II-1-receptor antagonist significantly
      increased. CONCLUSIONS: The accelerated radiochemotherapy with Carboplatin
      induces a severe impairment of cellular immunity, followed by compensatory
      cytokine reaction.

PMID- 10654184
TI  - [Hyper-IgE syndrome with ENT manifestations. Overview and case report of
      successful therapy with high dosage i.v. immunoglobulin].
AB  - Hyperimmunoglobulin E syndrome (Hiob syndrome or Buckley syndrome) is a rare
      disorder of the immune system that can show characteristic manifestations in the
      head and neck. Typical symptoms are fever, recurrent urticarial rashes,
      lymphadenitis, and bacterial infections of the skin and various parenchymatous
      organs. Diagnosis is established by elevated serum IgE concentrations with the
      absence of any signs of allergy or parasitic disease. We present our clinical
      experiences in managing of a 29-year old woman whose hyper IgE syndrome was
      diagnosed initially during of the treatment of lymphatic hyperplasia of the base
      of the tongue although she had typical symptoms of hyper IgE syndrome for some
      years. High-dose intravenous immunoglobulin therapy (IVIG) was found to be well
      tolerated and effective. More than one year after a single course of immunoglobin
      therapy symptoms markedly improved. Current knowledge and therapeutic options in
      hyper IgE syndrome are discussed. We recommend that IVIG be considered as one of
      the first choices in the treatment of hyper IgE syndrome.

PMID- 10654185
TI  - [Traumatic tympanic membrane perforation].

PMID- 10654186
TI  - [Metastasizing oropharyngeal tumor. Extramedullary plasmacytoma].

PMID- 10654187
TI  - [Throat pain after chopping wood. Penetrating trauma of the soft tissues of the
      neck caused by a metal splinter].

PMID- 10654188
TI  - [The Heermann "cartilage palisade tympanoplasty"].

PMID- 10654189
TI  - Inhibitors of intracellular chloride regulation induce cisplatin resistance in
      canine osteosarcoma cells.
AB  - The objective of this study was to examine the role of ion transport mechanisms
      in clinical anticancer drug resistance. Reduction in intracellular accumulation
      of cisplatin is believed to be an early change in cisplatin-resistant cells, and
      may be dependent on the concentration of intracellular chloride (Cl-) ions and
      intracellular pH. The primary aim of this study was to describe the modifying
      effects of NHMA (5-N,N hexamethylene; amiloride), a Na+/H+ antiport inhibitor,
      and/or SITS (4-acetamido-4';isothiocyanostilbene-2,2'-disulfonic acid), a HCO3
      /Cl- transport inhibitor, in bicarbonate-containing or bicarbonate-free media on
      cisplatin (cis-diamminedichloroplatinum(II); CDDP) toxicity between known
      cisplatin-sensitive (COS31) and cisplatin-resistant (COS31/rCDDP) canine
      osteosarcoma cells. This study has shown that cell survival can be influenced by
      the inhibition of the Na(+)-dependent HCO3-/Cl- exchanger using SITS. The
      addition of SITS increases the intracellular Cl- concentration in canine
      osteosarcoma cells cultured in a bicarbonate-containing media. In a bicarbonate
      free media, the addition of SITS results in a decrease in the cytotoxic action of
      cisplatin.

PMID- 10654190
TI  - Effects of simultaneous treatment with hydroxyapatite and coffee cherry, the
      residue left after the removal of coffee beans, on spontaneous mammary
      tumourigenesis and related parameters in SHN mice.
AB  - We have found that the chronic administration of the diet containing 5%
      hydroxyapatite (HAP) derived from bovine or swine bone or drinking water
      containing 0.5% extract of coffee cherry (CC), the residue left after the removal
      of coffee beans, induced a marked inhibition of spontaneous mammary
      tumourigenesis in SHN mice, while the effects decreased with age. In the present
      study, the combined effects of HAP and CC on mammary tumourigenesis and related
      parameters were examined. The inhibitory effects of HAP or CC alone on the
      development and/or the growth of mammary tumours were reduced by HAP + CC.
      Decreased food and water intake and retarded body growth caused by CC were
      ameliorated by HAP. Enhancement by HAP or CC of the excretion of the urine
      components was mostly nullified by HAP + CC. Parameters such as normal mammary
      gland growth and uterine adenomyosis on which neither HAP nor CC had an effect
      also did not respond to HAP + CC. These findings suggest that the target is
      important when administering natural products in combination if the agents are to
      manifest their effects, additive, synergistic, antagonistic or otherwise.

PMID- 10654191
TI  - Inhibition of chemokine-induced chemotaxis of monkey leukocytes by mu-opioid
      receptor agonists.
AB  - It is recognized that chemotaxis and phagocytosis constitute the first line of
      defense in the immune system, and chemokines function mainly as chemoattractants
      for phagocytic cells, recruiting monocytes and neutrophils from the blood to
      sites of infection. In this study, chemotaxis of monkey leukocytes was evaluated
      using human chemokines IL-8 (interleukin-8), MIP-1 beta and RANTES as the
      chemoattractants, and the effects of micro-opioid receptor agonists, morphine,
      DAMGO, methadone and endomorphine, on the efficiency of chemotaxis were examined.
      It was found that human chemokines served well as chemoattractants for monkey
      leukocytes, and similar to the human system, chemokine-induced chemotaxis of
      monkey leukocytes was inhibited in the presence of micro-opioid receptor
      agonists. The inhibition could be reversed by naloxone, a specific micro-opioid
      receptor antagonist. These studies further support the value of the monkey model
      for drug abuse studies in humans, as well as suggest that opioids such as
      morphine may alter immune functions through micro-opioid receptors on leukocytes.

PMID- 10654192
TI  - Particle-mediated gene transfer of murine interleukin-12 cDNA suppresses the
      growth of Lewis lung carcinoma.
AB  - We evaluated the effectiveness of the Helios gene gun system, a recently
      developed, commercially available gene gun device. Following skin transfection
      with beta-galactosidase or interleukin-12 cDNA using the gene gun, beta
      galactosidase expression was detected exclusively in the epidermal cell layer,
      and transgene expression of IL-12 cDNA was maximal 2 days post-transfection and
      remained detectable for at least 5 additional days. Furthermore, particle
      mediated delivery of IL-12 cDNA into epidermal cells overlying an intradermal
      tumor resulted in a significant suppression of tumor growth of Lewis lung
      carcinoma. Appreciable levels of IFN-gamma production were readily detected at
      the skin transfection site, and were induced from splenocytes and lymph node
      cells in the IL-12 treated mice. These results show that in vivo delivery of IL
      12 cDNA into skin by the Helios gene gun device can have a useful routine
      application for cancer therapy research.

PMID- 10654193
TI  - Image cytophotometric DNA analysis of cystadenolymphomas.
AB  - Warthin's tumour of the parotid gland is generally a benign lesion, consisting of
      an epithelial and a lymphoid component with unclear histogenetic relationship, 17
      cases of Warthin's tumour were investigated for ploidy related parameters by the
      image analysis system CAS200. All cases investigated were euploid. A diploid DNA
      pattern (Auer type I) was detected in 7/17 (41%) cases both in the epithelial and
      lymphoid component of the same tumour. In addition to a diploid cell fraction a
      tetraploid cell component was found in 7/17 (41%) cases, coincidentally, in the
      epithelial and lymphoid component (Auer type II). Euploidy in all investigated
      cases is in agreement with the generally benign nature of Warthin's tumours. The
      similarity of the DNA pattern (Auer type) in the genetically unrelated epithelial
      and lymphoid components in most cases (84%) is suggested to be related to a
      similar functional state of these two components and is discussed in relation to
      the histogenesis of cystadenolymphomas.

PMID- 10654194
TI  - Tumor site-dependent differential modulation of systemic immunity in RENCA
      bearing mice.
AB  - Renal cell carcinoma (RCC) is a highly metastatic cancer which is known to be
      immunogenic and responsive to immunotherapies using cytokines. The effect of
      tumor site (organ microenvironment) on the biologic behavior of murine RCC cell
      line (RENCA) was examined by observing systemic immunomodulations. Reduction of
      the spleen size observed in tumor bearing mice correlated with a significant
      decrease in splenic nucleated cell numbers. In the mice bearing RENCA cell tumors
      in the renal subcapsule, a significant increase of splenic T cell blastogenesis
      against Con-A (234% of naive control) was observed with reduction of NK activity
      (45% of naive control). The changes in T cell blastogenesis and NK activity
      observed in subcutis (s.c.) inoculated RENCA tumor bearers were less significant.
      However, macrophage functioning and proportions in the spleen were significantly
      increased only in s.c. tumor bearers. Data indicated tumor site-dependent
      differential modulation of systemic immunity in RENCA bearing mice which suggests
      that immunotherapy for RCC should consider not only the tumor but also the
      tumor's microenvironment.

PMID- 10654195
TI  - Influence of anti-allergic agents on in vivo expression of co-stimulatory
      molecules in normal mice.
AB  - The co-stimulatory signal provided by the interaction between CD28 and its
      ligands, CD80 and CD86, is critical for T cell activation. Engagement of CD40 and
      CD40L is also essential for IgE synthesis and secretion. In the present study, we
      examined the influence of anti-allergic drugs on co-stimulatory molecule (CD40,
      CD80 and CD86) expression in normal mouse splenocytes by flow cytometry.
      Treatment of BALB/c mice with azelastine (AZ) at a dose of 50.0
      micrograms/kg/day, which is the most effective therapeutic dose, for two weeks
      scarcely affected the expression of co-stimulatory molecules CD40, CD80 and CD86
      on splenocytes, whereas a three-week treatment strongly suppressed the expression
      of these molecules. We also examined the influence of terfenadine (TR) on co
      stimulatory molecule expression. The expression of molecules on splenocytes was
      inhibited when donor mice were treated orally with 2.0 mg/kg/day of TR for three
      weeks. However, it was not inhibited during a two-week period treatment. These
      results suggest that the attenuating effects of anti-allergic agents on the
      diseases may be explained, in part, by their inhibitory action of co-stimulatory
      molecule expression.

PMID- 10654196
TI  - Primary malignant melanoma of the esophagus: report of two cases and review of
      the literature.
AB  - We reported two cases of primary malignant melanoma of the esophagus, treated
      with interpositioning of the left colon subcutaneously over the sternum. We also
      reviewed the world literature on this rare but fatal disease.

PMID- 10654197
TI  - Chemoprevention of cancer: an ongoing saga.
AB  - The trivial adage "an ounce of prevention..." is certainly appropriate in
      oncology; cancer has and continues to have an enormous impact on morbidity,
      suffering, socioeconomics and mortality. Curative therapy is elusive--cancer
      remains a mainly lethal disease, which makes the objective of prevention even
      more important and attractive. Sober estimates put the potentially avoidable or
      preventable cancers in the Western World at 80% (1): the effects of smoking and
      alcohol, being overweight, diet promiscuity and other lifestyle choices are well
      known, yet at the individual level, corrective measures are disappointingly
      ignored. Lately, this issue is being further weakened by our acceptance of
      inherited susceptibility--why change our habits and indulgences, if we can not
      escape our genetic destiny? However, there is a massive and growing amount of
      information on chemoprevention which needs to be carefully evaluated, in the hope
      that someday, we should be able to avoid or at least delay cancer by the use of
      natural or synthetic compounds which intervene in the early precancerous process.

PMID- 10654198
TI  - Possible role of HHV-6 in the enhanced severity of HSV-1 keratitis.
AB  - Rabbits were divided into three groups and infected with Human Herpesvirus Type 6
      (HHV-6) or Herpes Simplex Virus Type 1 (HSV 1). Infected eyes were swabbed and
      cultured every alternate day. At day 15 postinfection (PI), rabbits were
      sacrificed, trigeminal ganglia (TG) and corneas were analyzed for the presence or
      absence of viral DNA. The severity of keratitis was much greater in the eyes
      inoculated by both viruses and cultures from these animals were HSV-1 positive
      for 15 days PI as compared to 9 days PI for rabbits infected with HSV-1 alone.
      The corneas from infected eyes and the corresponding TGs from animals infected
      with HSV-1 were positive for HSV-1 DNA. HHV-6 DNA was recoverable from corneas of
      infected eyes, but not from the corresponding TGs. Although preliminary, these
      observations indicate that HHV-6 may enhance the HSV-1 expression in animals with
      dual infections.

PMID- 10654199
TI  - Tumor tissue recycling--a new combination treatment for solid tumors:
      experimental and preliminary clinical research.
AB  - Although H&H combination treatment (high active TIL and high sensitive drugs) as
      previously described to solid tumor patients is more efficient than single-agent
      treatments such as TIL adoptive immunotherapy, it has a short-term efficiency for
      the immune response to metastatic cancers. Currently, a new version of the
      combination of active and adoptive immune response was established. TILs, tumor
      vaccines and high sensitive drugs. The experimental results demonstrated that
      TILs from 49 cases (65%) were more than 1,000 expansion-fold and only 6 cases
      (24%) less than 500 fold. The peaks of TIL 3H-TdR cytotoxicity test from 35 of 64
      TIL specimens were kept from 40 to 56 days. TIL phenotypes studied here indicated
      CD3 80 +/- 21%, CD4 37 +/- 21%, CD8 44 +/- 18% and HLA DR 69 +/- 24% after IL2
      induction, in contrast, to CD3 20 +/- 12%, CD4 10 +/- 7%, CD8 11 +/- 3% and HLA
      DR 30 +/- 16% before induction. Thirty two of 75 cases were assayed using the
      chemosensitivity test. The distribution of positive rates for the
      chemosensitivity test were slightly different in different tumors regarding
      tissues in liver, lung, ovary, breast, and melanoma, 2 cases with melanoma all
      showed negative results. The results of a tumor vaccine using TNF-alpha gene
      transduction demonstrated that the expression of HLA Class I and HLA Class II
      were dramatically increased 87% and 43%. After implanting tumor cells via
      transduced TNF-alpha retroviral vector into 6-12 week old BALB/c nude mice, only
      one subject of nine nude mice had a tumor weight of 2.67 g, but the control group
      all displayed tumors with a weight of 3.24 +/- 0.56 g. Preliminarily clinical
      trials also showed that the new version was obviously a promising combination.

PMID- 10654200
TI  - Maintaining spontaneous breathing efforts during mechanical ventilatory support.

PMID- 10654201
TI  - Bronchodilators and mechanical ventilation in COPD patients. Emptying, pumping or
      both?

PMID- 10654202
TI  - Anionic bases for continuous forms of renal replacement therapy (CCRT) in the
      ICU.

PMID- 10654203
TI  - Should we measure plasma volume in intensive care medicine?

PMID- 10654204
TI  - Bronchodilator delivery by metered-dose inhaler in mechanically ventilated COPD
      patients: influence of tidal volume.
AB  - OBJECTIVE: The delivery of bronchodilator drugs with metered-dose inhaler (MDI)
      and a spacer in mechanically ventilated patients has become a widespread
      practice. However, the various ventilator settings that influence the efficacy of
      MDI are not well established. The tidal volume (VT) during drug delivery has been
      suggested as one of the factors that might increase the effectiveness of this
      therapy. To test this, the effect of two different VT on the bronchodilation
      induced by beta 2-agonists administered with MDI and a spacer in a group of
      mechanically ventilated patients with chronic obstructive pulmonary disease
      (COPD) was examined. METHODS: Nine patients with COPD, mechanically ventilated on
      volume-controlled mode, were prospectively randomised to receive six puffs of
      salbutamol (S, 100 micrograms/puff) either with a VT of 8 ml/kg (normal VT, 582
      +/- 85) or with a VT of 12 ml/kg (high VT, 912 +/- 137). With both modes
      inspiratory flow was identical. S was administered with an MDI adapted to the
      inspiratory limb of the ventilator circuit using an aerosol cloud enhancer
      spacer. After a 6-h washout, patients were crossed-over to receive S by the
      alternative mode of administration. Static and dynamic airway pressures, minimum
      (Rint) and maximum (Rrs) inspiratory resistance, the difference between Rrs and
      Rint (delta R), static end-inspiratory respiratory system compliance (Cst,rs),
      intrinsic positive end-expiratory pressure (PEEPi) and heart rate (HR) were
      measured before and at 15, 30 and 60 min after S. RESULTS: S caused a significant
      decrease in dynamic and static airway pressures, PEEPi, Rint and Rrs. These
      changes were not influenced by VT and were evident at 15, 30 and 60 min after S.
      With normal and high VT, Cst,rs, delta R and HR did not change after S.
      CONCLUSIONS: We conclude that S delivered with an MDI and a spacer device induces
      significant bronchodilation in mechanically ventilated patients with COPD, the
      magnitude of which is not affected by at least a 50% increase in VT. These
      results do not support the VT manipulations when bronchodilators are administered
      in adequate doses during controlled mechanical ventilation.

PMID- 10654205
TI  - Effects of prone position on alveolar recruitment and oxygenation in acute lung
      injury.
AB  - OBJECTIVE: To investigate the effects of prone position (PP) on alveolar
      recruitment and oxygenation in acute respiratory failure. DESIGN: Prospective
      physiologic study. SETTING: Medical ICU two in a university hospital. PATIENTS:
      Twelve adult patients intubated and mechanically ventilated with medical primary
      acute lung injury/adult respiratory distress syndrome (ALI/ARDS) in whom PP was
      indicated. MEASUREMENTS AND RESULTS: We constructed the static inflation volume
      pressure curves (V-P) of the respiratory system in the 12 patients and
      differentiated between lung and chest wall in ten of them. We determined the
      difference between end-expiratory lung volume on positive end-expiratory pressure
      (PEEP) and relaxation volume of the respiratory system on zero PEEP (delta FRC).
      The recruited alveolar volume was computed as the delta FRC times the ratio of
      static elastance of the respiratory system to the lung. These measurements
      together with arterial blood gases determination were made in supine position
      (SP1), after 1 h of PP and after 1 h of supine repositioning (SP2) at the same
      level of PEEP. The PaO2/FIO2 ratio improved from SP1 to PP (136 +/- 17 vs 204 +/-
      24 mm Hg; p < 0.01). An PP-induced alveolar recruitment was found in five
      patients. The change in oxygenation correlated to the recruited volume. The
      static elastance of the chest wall decreased from 4.62 +/- 0.99 cmH2O/l in SP1 to
      6.26 +/- 0.54 cmH2O/l in PP (p < 0.05) without any correlation to the change in
      oxygenation. CONCLUSIONS: Alveolar recruitment may be a mechanism of oxygenation
      improvement in some patients with acute hypoxemic respiratory failure. No
      correlation was found between change in oxygenation and chest wall elastic
      properties.

PMID- 10654206
TI  - ARDS in patients with thermal injury.
AB  - OBJECTIVE: To determine the time to onset of the adult respiratory distress
      syndrome (ARDS) in patients with thermal injury requiring mechanical ventilation.
      Secondarily, to consider the burn-related risk factors, demographics, incidence,
      and mortality for ARDS in this population. DESIGN: Retrospective chart review;
      ARDS defined according to the American-European Consensus Conference and the Lung
      Injury Severity Score definitions. SETTING: Regional, tertiary referral, adult
      burn unit in a university teaching hospital. PATIENTS AND PARTICIPANTS: Patients
      with thermal injury requiring mechanical ventilation, admitted between 1 January
      1991 and 28 February 1995. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Of 469
      consecutive admissions, 126 (26.9%) received intubation and mechanical
      ventilation. ARDS was defined according to the American-European Consensus and
      Lung Injury Severity Score (score > 2.5) definitions. The mean time to onset of
      ARDS from admission to the burn unit was 6.9 +/- 5.2 and 8.2 +/- 10.7 days when
      defined by the American-European Consensus and Lung Injury Severity Score
      definitions respectively (p = 0.41). Of the intubated patients, 53.6 and 45.2%
      developed ARDS according to the American-European Consensus and Lung Injury
      Severity Score definitions, respectively (p = 0.19). Using multivariate logistic
      analysis, only age proved to be an independent risk factor for the development of
      ARDS (p = 0.03), although there was a trend toward an increased incidence of
      inhalation injury in patients with ARDS. Mortality was not significantly greater
      (41.8 vs 32.2%) in those with ARDS compared to those without (p = 0.27).
      CONCLUSIONS: According to the American-European Consensus Conference and the Lung
      Injury Severity Score definitions, ARDS is common in the adult burn population
      and has a delayed onset compared to most critical care populations. We found age
      to be a major predisposing factor for ARDS.

PMID- 10654207
TI  - Changing a hydrophobic heat and moisture exchanger after 48 hours rather than 24
      hours: a clinical and microbiological evaluation.
AB  - OBJECTIVE: Complications following ventilation with dry and cold gases may be
      prevented by the use of artificial noses or heat and moisture exchangers, which
      are a solution to both the problems of humidification and heat preservation. The
      aim of the present study was to determine whether changing hydrophobic heat and
      moisture exchangers (HMEs) every 48 h rather than 24 h would affect their
      efficacy to preserve the heat and moisture of inspiratory gases. The impact of a
      prolonged use of the HME on its microbial colonization was also assessed. DESIGN:
      Prospective observational study. SETTING: ICU of a university hospital. PATIENTS:
      Twelve patients requiring controlled mechanical ventilation for more than 2 days
      were evaluated. INTERVENTIONS: The patients were ventilated with a heat and
      moisture exchanger (HME) (Maxipleat Filter, Europe Medical, France). The
      hydrophobic HME was placed between the Y-piece and the connecting tube and
      changed after 48 h of continuous use. Temperature (degree C), relative humidity
      (%) and absolute humidity (mgH2O/l) were obtained using the capacitive sensor
      principle. Bacterial colonization (tracheal secretions and ventilator side of the
      HME) were obtained on days 1 and 2. MEASUREMENTS AND RESULTS: After 48 h of
      ventilation with the same HME, tracheal tube occlusion was never observed. Using
      the same hydrophobic HME for 48 h rather than 24 h did not affect its technical
      performance: temperature at 24 h: 32.5 +/- 1.3 degrees C, at 48 h: 32.7 +/- 1.8
      degrees C; relative humidity (RH) at 24 h: 99.0 +/- 1.4%, at 48 h: 99.0 +/- 1.4%;
      absolute humidity (AH) at 24 h: 34.0 +/- 2.4 mgH2O/l, at 48 h: 34.4 +/- 3.5
      mgH2O/l. Peak and mean airway pressures did not change over the 48-h study
      period, with identical tidal and minute volumes in the study patients. Total
      respiratory heat losses were not modified during the 48-h study period (at 24 h:
      152 +/- 47 cal/min, at 48 h: 149 +/- 65 cal/min). Evaporative and convective heat
      losses were not modified either. On day 1, eight patients had positive cultures
      of their tracheal secretions at a colony count of 10(3) or higher cfu/ml. After
      48 h of use of the same HME, only six patients had a positive culture of their
      tracheal secretions. Cultures from the ventilator sides of the HMEs were all
      sterile (12/12) after 48 h of use. CONCLUSIONS: Changing the hydrophobic HME
      after 48 h rather than 24 h did not affect its technical performance in terms of
      heat and water preservation of ventilatory gases. There is also some indirect
      evidence of very little, if any, change in HME resistance. No bacterial
      colonization of the ventilator sides of the HMEs was observed after 48 h of use.
      However, other large clinical trials should be undertaken to confirm the safety
      of extending the time between HME changes.

PMID- 10654208
TI  - The use of different buffers during continuous hemofiltration in critically ill
      patients with acute renal failure.
AB  - OBJECTIVE: To determine the impact of different hemofiltration (HF) replacement
      fluids on the acid-base status and cardiovascular hemodynamics in patients with
      acute renal failure (ARF) and continuous veno-venous hemofiltration (CVVH).
      DESIGN: Prospective, cohort study. SETTING: Intensive Care Unit of the Heinrich
      Heine University Hospital, Dusseldorf, Germany. SUBJECT AND METHODS: One hundred
      and thirty-two critically ill patients with acute renal failure and continuous
      veno-venous HF were studied. Fifty-two patients were subjected to lactate-based
      (group 1), and 32 to acetate-based hemofiltration (group 2) while 48 (group 3)
      were treated with bicarbonate-based buffer hemofiltration fluid. Fifty-seven had
      a septic, and 75 a cardiovascular, origin of the ARF. Creatinine, blood urea
      nitrogen (BUN), serum bicarbonate, arterial pH, lactate and Apache II scores were
      noted daily. MAIN RESULTS: The mean CVVH duration was 9.8 +/- 8.1 days, mortality
      was 65%. No difference was present between the groups under investigation with
      regard to the main clinical parameters. Lactate- and bicarbonate-based
      hemofiltration led to significantly higher serum bicarbonate and arterial pH
      values as compared to the acetate-based hemofiltration. Serum bicarbonate values
      at 48 h after the initiation of CVVH treatment were 25.7 +/- 3.8 mmol/l (p <
      0.001) in group 1, 20.6 +/- 3.1 mmol/l in group 2 and 23.3 +/- 3.9 mmol/l (p <
      0.001) in group 3. While a lack of increase in serum bicarbonate and arterial pH
      was correlated to poor prognosis in lactate- and bicarbonate-based
      hemofiltration, no such observation was made in acetate-based hemofiltration.
      Cardiovascular hemodynamics were superior in patients treated with lactate- and
      bicarbonate-based buffer solution as compared to those treated with acetate-based
      buffer solution. CONCLUSIONS: The degree of correction of acidosis during
      hemofiltration was determined by patient outcome in patients treated with lactate
      and bicarbonate-based buffer solutions, but not in patients receiving acetate
      buffered solution. Bicarbonate and lactate-based buffer solutions were found to
      be superior to acetate-based replacement fluid.

PMID- 10654209
TI  - Does indocyanine green accurately measure plasma volume independently of its
      disappearance rate from plasma in critically ill patients?
AB  - OBJECTIVE: To determine whether plasma volume determined by the indocyanine green
      (ICG) dilution method (PV-ICG) is equally accurate independently of its
      disappearance rate from plasma in the critically ill. DESIGN: Retrospective
      clinical investigation. SETTING: Intensive care unit of a university teaching
      hospital. PATIENTS AND METHODS: 192 adult patients were initially enrolled. The
      PV-ICG and the initial distribution volume of glucose (IDVG) were calculated
      utilizing a one-compartment model by simultaneous administration of ICG 25 mg and
      glucose 5 g on the first day of measurement in each patient. Twenty-one patients
      were excluded from the study because of a higher PV-ICG/IDVG ratio (> 0.45)
      indicating apparent overestimation of the PV-ICG associated with the generalized
      protein capillary leakage. The remaining 171 patients were divided into four
      groups according to the magnitude of their disappearance rate of ICG from plasma
      (Ke-ICG). RESULTS: Convergence was assumed consistently in each ICG or glucose
      decay curve, even in the lower Ke-ICG less than 0.10/min. The relationship
      between the two volumes was not statistically different among groups.
      CONCLUSIONS: The results suggest that the measurement of the PV-ICG can be
      equally accurate independently of its disappearance rate from plasma unless there
      is generalized protein capillary leakage.

PMID- 10654210
TI  - Plasma levels of the three endothelial-specific proteins von Willebrand factor,
      tissue factor pathway inhibitor, and thrombomodulin do not predict the
      development of acute respiratory distress syndrome.
AB  - OBJECTIVE: To determine if the plasma levels of three endothelial-specific
      proteins, von Willebrand factor (vWF), tissue factor pathway inhibitor (TFPI) and
      thrombomodulin (TM) may be useful in predicting the development of acute
      respiratory distress syndrome (ARDS). DESIGN: Blood samples were obtained from
      normal healthy volunteers and on the first day from patients at risk for ARDS and
      those with ARDS. Daily sequential measurements of vWF and TFPI were performed in
      two patients. SETTING: Normal subjects were employees at Saint Louis University
      Hospital, St. Louis, Missouri. Patients at risk and those with ARDS were patients
      admitted to the medical and surgical floors and the intensive care units at St.
      Louis University Hospital. PATIENTS AND PARTICIPANTS: Plasma levels of vWF, TFPI
      and TM were measured in 27 normals, and on day 1 in 15 patients at risk for ARDS
      and 18 patients with ARDS from different etiologic factors. MEASUREMENTS AND
      RESULTS: Plasma levels of vWF were significantly elevated in the at-risk (p <
      0.01) and ARDS group (p < 0.001) as compared to normals but did not differ
      significantly between the two groups (p > 0.05). Plasma levels of TFPI were not
      significantly different between the normal and the at-risk group (p > 0.05);
      however, they were significantly elevated in ARDS as compared with at-risk and
      normal groups (p < 0.001). Levels of TM were significantly increased in the at
      risk group as compared to normals (p < 0.01) but were not significantly different
      from the ARDS group (p > 0.05). Eight patients at risk progressed to develop
      ARDS. A vWF level of > 300% in patients at risk was 62% sensitive and 71%
      specific for predicting the development of ARDS with a positive predictive value
      of only 34%. TFPI levels were normal in 7 of the 8 patients who developed ARDS. A
      TM level of > 100 ng/ml in patients at risk was 50% sensitive and 57% specific
      with a positive predictive value of merely 8% for development of ARDS. There was
      no significant difference in the mean plasma levels of the three proteins on day
      1 in patients at risk who developed ARDS as compared with those who did not
      develop ARDS. There was also no difference in mean plasma levels of the three
      proteins in patients with ARDS from sepsis as compared with ARDS from other
      etiologies. Plasma levels of vWF and TFPI correlated significantly. CONCLUSION:
      Plasma levels of vWF, TFPI and TM did not appear to serve as useful markers for
      predicting ARDS in patients at risk.

PMID- 10654211
TI  - Septic shock without documented infection: an uncommon entity with a high
      mortality.
AB  - OBJECTIVES: To determine whether patients with clinically identified infection
      have the same outcome as patients with apparent sepsis but no identified
      infectious source. DESIGN: Retrospective analysis of patient data. PATIENTS: All
      patients treated with septic shock in a 31-bed intensive care unit (ICU) over a 3
      year period. RESULTS: Data from 227 patients were analysed. Eighty-seven percent
      had a clinically identified source of infection. ICU mortality was higher in
      septic shock patients without a clinically identified source of infection than in
      those with an identified source of infection (86% versus 66%, p < 0.05).
      CONCLUSIONS: A small number of patients presenting with septic shock have no
      clinically identified infection. These patients have a higher mortality rate than
      patients in whom an infection is identified.

PMID- 10654212
TI  - Skin lesions in the ICU.
AB  - OBJECTIVE: The objective of this study is to identify the dermatological
      disorders (DDs) responsible for the most common skin lesions in the ICU, their
      incidence and their impact on mortality, degree of severity and length of stay in
      the ICU. DESIGN AND SETTING: We performed a 2-year prospective study in a general
      medical and surgical ICU including, exceptionally, paediatric cases. PATIENTS: We
      included all patients who presented skin lesions upon admission or developed them
      during their ICU stay. RESULTS: Forty-six patients (10% of all admissions) were
      enrolled, with 51 DDs. SAPS II score (43) and mean length of stay (19 days) were
      significantly higher than in the general group of ICU admissions. Differences in
      mortality rates (26% versus 29%) were not statistically significant. CONCLUSIONS:
      DDs are entities that should be borne in mind in the critically ill patient;
      their incidence is by no means negligible and makes careful examination of the
      skin mandatory both on admission and during a patient's ICU stay.

PMID- 10654213
TI  - Intravenous nicardipine for severe hypertension in pre-eclampsia--effects of an
      acute treatment on mother and foetus.
AB  - OBJECTIVES: To assess the efficacy in lowering blood pressure, and the safety for
      mother and foetus of an acute nicardipine therapy in severe pre-eclampsia.
      DESIGN: Prospective clinical study. SETTING: One university hospital obstetric
      unit. PATIENTS: Twenty consecutive adult pre-eclamptic patients with severe
      hypertension. INTERVENTION: Nicardipine, 1 microgram/kg per min, was given
      intravenously to lower the mean arterial pressure (MAP) by at least 15%. Then,
      the dosage was reduced by 1/3, and the final dosage was determined to maintain
      MAP at 20-30% below the initial value, by increasing or decreasing the infusion
      rate by 0.5 mg/h. MEASUREMENTS AND RESULTS: Maternal MAP and heart rate (HR) were
      assessed every 5 min for 1 h. Foetal HR (FHR) was recorded throughout the study
      period and assessed for Fischer score. Gestational age, Apgar scores, birth
      weight, capillary filling time and the duration of stay in the paediatric
      intensive care unit (ICU) were used to evaluate the short-term perinatal outcome.
      A 15-30% decrease in MAP occurred within 15-20 min in all patients. An increase
      in HR was noted, and two patients had severe tachycardia. Maternal side effects
      included flushing, headache, nausea and dizziness. FHR showed a transient
      decrease in acceleration episodes and occurrence of decelerations. No nicardipine
      related foetal distress occurred. Four infants born during the study period did
      well at birth and had a good outcome. CONCLUSIONS: Acute nicardipine therapy can
      induce severe maternal tachycardia. No severe foetal or neonatal adverse effects
      occurred. This dose scheme requires comparison with alternative therapeutic
      options.

PMID- 10654214
TI  - The role of endothelin-1 in pressure autoregulation of cerebral blood flow in
      rats.
AB  - OBJECTIVE: To investigate the role of the endothelin system in pressure
      autoregulation of cerebral blood flow (CBF) in rats. DESIGN: We tested pressure
      autoregulation by increasing cerebral perfusion pressure (CPP; mean arterial
      pressure-intracranial pressure) with norepinephrine (0.08 microgram.kg-1.min-1
      for 30 min) twice in ten anesthetized normocapnic rats. The first test was
      performed without (control test) and the second test after administration of the
      combined endothelin ETA/B receptor antagonist, bosentan, i.v. (30 mg/kg; drug
      test). CBF was measured by the hydrogen clearance technique. RESULTS: During the
      control test, norepinephrine infusion increased CPP by 21 +/- 2 (23 +/- 2%) mmHg
      (mean +/- SEM; p < 0.001) and CBF by 3.6 +/- 3.1 (6 +/- 8%) ml/100 g/min (p =
      0.5, Fig. 1); during the drug test, norepinephrine infusion increased CPP by 18
      +/- 1 (20 +/- 2%) mmHg (p < 0.001) and CBF by 15.8 +/- 4.1 (46 +/- 13%) ml/100
      g/min (p = 0.004). Mean arterial pressure was not affected by bosentan infusion
      (p = 0.2). PaCO2 levels were stable during the tests (40.2 +/- 1.4 mmHg).
      CONCLUSIONS: The endothelin system is involved in cerebral pressure
      autoregulation in a rodent model in vivo. The role of this system under
      pathophysiologic conditions such as subarachnoid hemorrhage, where basal vascular
      tone and its regulation may be altered, remains to be defined.

PMID- 10654215
TI  - Alteration of anion gap during almost total plasma replacement with synthetic
      colloids in piglets.
AB  - In ten piglets (body weight 8.2-11.6 kg), acid base, electrolyte and anion gap
      changes were investigated during almost total plasma replacement with
      hydroxyethyl starch (HES) and modified fluid gelatin (GEL) in saline solution
      using a cell saver autotransfusion technique. During the study, there were only
      moderate acid base changes, but marked disturbances in anion balance. At study
      end, the mean chloride concentration was significantly higher (mmol/l: normal
      values 97-108, HES 116 +/- 1.5, GEL 108 +/- 1.1, p < 0.01) and the mean anion gap
      was significantly lower in the HES group in comparison to the GEL group (mmol/l:
      normal values 5-14, HES 3 +/- 1.7, GEL 11.9 +/- 0.9, p < 0.01). It is concluded
      that plasma replacement with electroneutral HES, but not with negatively charged
      GEL, can lower the anion gap irrespective of the underlying disease. This can be
      misleading when the anion gap is used for differential diagnosis of metabolic
      acidosis in patients after large volume infusion of synthetic colloids.

PMID- 10654216
TI  - Vancomycin assay performance in patients with acute renal failure.
AB  - OBJECTIVE: Fluorescence polarization immunoassays (FPIA) have been reported to
      overestimate vancomycin serum concentrations compared to high-performance liquid
      chromatography (HPLC) or enzyme multiplied immunoassay technique (EMIT) in
      patients with chronic renal disease. The assay manufacturer has modified the FPIA
      to remedy this overestimation. The purpose of this study was to compare the assay
      performance of two FPIAs to EMIT in acute renal failure patients receiving
      vancomycin and continuous venovenous hemofiltration. DESIGN: Open-label trial.
      SETTING: Intensive care unit in a university affiliated hospital. PATIENTS AND
      PARTICIPANTS: 15 serum and ultrafiltrate samples were obtained from 14 critically
      ill patients (mean +/- SD; 57 +/- 12 years; 8 males/6 females). MEASUREMENTS AND
      RESULTS: Vancomycin concentrations were determined by a polyclonal FPIA (pFPIA)
      performed on the TDx system, a monoclonal FPIA (mFPIA) performed on the AxSYM
      system and EMIT. The coefficient of variation for all assays was < 5%. The mean
      difference +/- SDd between mFPIA vs EMIT and pFPIA vs EMIT assays in serum were: 
      0.08 +/- 1.55 and 1.24 +/- 2.11 mg/l, respectively. The limits of agreement
      between the mFPIA vs EMIT and pFPIA vs EMIT assays in serum were: -3.18 to 3.03
      and -2.99 to 5.46 mg/l, respectively. CONCLUSIONS: Our data demonstrate that the
      manufacturer's changes to the pFPIA have reduced overestimation. The mFPIA
      appears to be an acceptable assay for measuring vancomycin serum concentrations
      in acute renal failure patients and does not significantly overestimate these
      concentrations.

PMID- 10654217
TI  - Safety and efficacy of a sustained inflation for alveolar recruitment in adults
      with respiratory failure.
AB  - OBJECTIVE: To assess the safety and efficacy of a sustained inflation, used as a
      lung volume recruitment maneuver in ventilated patients with hypoxemic
      respiratory failure. DESIGN: Prospective data collection as part of a quality
      assurance program following introduction of a lung volume recruitment guideline
      in the intensive care unit. SETTING: Academic medical-surgical critical care
      unit. PATIENTS: Hypoxemic patients with bilateral pulmonary infiltrates. Patients
      with chronic obstructive pulmonary disease, pulmonary barotrauma and hemodynamic
      instability were excluded. INTERVENTIONS: A sustained inflation using a pressure
      of 30 to 45 cmH2O was applied for 20 s. The pressure was determined as the lesser
      of 45 cmH2O or the peak pressure while ventilated at a tidal volume of 12 ml/kg.
      Intra-arterial blood pressure and pulse oximetry were monitored continuously.
      MEASUREMENTS AND RESULTS: Significant improvement in oxygenation occurred in the
      majority of patients within 10 min. The mean oxygen saturation improved from 86.9
      +/- 5.5 to 94.3 +/- 2.3% (p < 0.01). No significant adverse effects were noted:
      hypotension and mild oxygen desaturation occurred in some patients during the 20
      s inflation, reversing rapidly after inflation was terminated. No barotrauma
      occurred. CONCLUSIONS: A sustained inflation is a safe, clinically applicable
      method of lung volume recruitment which improves oxygenation in selected patients
      and may have a role in ventilatory management.

PMID- 10654218
TI  - Acute neuromuscular respiratory failure after ICU discharge. Report of five
      patients.
AB  - OBJECTIVE: To describe a syndrome of acute neuromuscular respiratory failure (NM
      ARF) caused by ICU-acquired acute myopathy and neuropathy. DESIGN: Case series.
      SETTING: General Regional University Hospital in Brescia, Italy. PATIENTS: Five
      adult patients with NM-ARF after prolonged ICU stay and successful weaning from
      the ventilator and ICU discharge. INTERVENTIONS: None. MEASUREMENTS: Clinical
      signs of NM-ARF, electroneurography and electromyography (ENMG) of peripheral
      nerves and muscles, and functional assessment of respiratory muscles. RESULTS: NM
      ARF was diagnosed at the time of (one case), or 1-3 days after, ICU discharge.
      Limb weakness alarmed the physicians, while the signs of the NM-ARF were
      initially undetected. In the first observed case the acute respiratory failure
      was near fatal, and necessitated ICU readmission, while in the other cases 2
      weeks of aggressive chest physiotherapy permitted resolution of the respiratory
      failure. History, clinical course and ENMG indicated the diagnosis of critical
      illness myopathy and neuropathy (CRIMYNE). Three patients recovered fully, while
      two had persisting evidence of axonal polyneuropathy several months after the
      onset. CONCLUSIONS: Critically ill patients with prolonged ICU stay, sepsis and
      MOF are at great risk of developing CRIMYNE, which in turn may be responsible for
      NM-ARF. This latter complication may arise after resolution of the respiratory
      and cardiac dysfunctions and successful weaning from the ventilator. As NM-ARF
      may cause unplanned ICU readmission or even unexpected death, strict clinical
      surveillance and monitoring of respiratory muscle function is recommended after
      discharge to the general ward of patients with proven NM-ARF. Early intensive
      chest physiotherapy can resolve the condition.

PMID- 10654219
TI  - Lack of significant treatment effect of plasma exchange in the treatment of drug
      induced toxic epidermal necrolysis?
AB  - OBJECTIVE: Comparison of outcome in patients with toxic epidermal necrolysis
      (TEN) in patients who received plasma exchange (PE) compared with the results in
      two other centres that used almost identical treatment protocols but without PE.
      DESIGN: Retrospective comparative case series with two recently published case
      series serving as controls. SETTING: National burns intensive care unit (ICU) and
      Department of Transfusion Medicine at Linkoping University Hospital, Sweden.
      PATIENTS: 8 consecutive patients admitted with TEN who received PE during 1987
      1997. INTERVENTIONS: Neither prophylactic antibiotics nor cortisone were used.
      The patients were given a median of 5.5 PE treatments (range 1-8). RESULTS: Eight
      patients with a median (range) age of 45 years (5-89) and with a median skin
      involvement total body surface area (TBSA) of 38% (12-100) were treated. The
      length of stay in the burns ICU was 15 (13-25) days and the time from onset of
      the cutaneous signs until complete re-epithelialisation was 24 days (13-55) for
      the seven survivors. Five patients fulfilled the diagnostic criteria of sepsis.
      One patient with extensive ischaemic cardiac disease developed septic shock and
      died (mortality 12.5%). Two patients developed side effects from PE. CONCLUSIONS:
      To our knowledge, this is the largest series yet presented using PE in the
      treatment of TEN. Our results, in patients with less cutaneous involvement,
      similar causative agents, and similar demographic data as in the other two
      studies (controls), were no different as far as mortality, length of stay, or
      time to re-epithelialisation were concerned. This finding does not support the
      use of PE in the treatment of TEN.

PMID- 10654220
TI  - Bleeding after intermittent or continuous r-hirudin during CVVH.
AB  - OBJECTIVE: To demonstrate bleeding complications encountered in patients after
      cardiac surgery on continuous venovenous haemofiltration (CVVH) treated with
      continuous versus intermittent r-hirudin for heparin-induced thrombocytopenia
      (HIT) type II. DESIGN: Case description. SETTING: Cardiothoracic intensive care
      unit at a university hospital. PATIENTS: 5 consecutive patients with proven HIT
      type II on CVVH after major cardiac surgery. INTERVENTIONS: Recombinant hirudin
      (r-hirudin) was given continuously at a dose of 0.01 mg/kg per h in three
      patients or in repeated bolus administration of 0.05 mg/kg in two patients.
      MEASUREMENTS AND RESULTS: Since the ecarin clotting time assay was not available
      at that time to monitor hirudin effects on coagulation, the activated partial
      thromboplastin time (normal range 26-38 s, target range 50-60 s) was used. The
      continuously treated patients suffered from major bleeding complications.
      Therefore, the regimen was changed to repeated bolus administration, reducing the
      incidence of bleeding complications probably due to a threefold diminished
      cumulative hirudin dose per day in comparison to continuous administration.
      CONCLUSIONS: If ecarin clotting time, the most suitable monitor for hirudin
      activation, is not available, we would prefer to give r-hirudin in repeated
      boluses to avoid major bleeding complications in cardiac surgery patients on
      CVVH.

PMID- 10654221
TI  - C1-esterase inhibitor in graft failure after lung transplantation.
AB  - Graft failure after lung transplantation may occur immediately after
      transplantation due to reperfusion injury or later due to rejection and
      infection. Although the pathological mechanisms are not completely known, the
      clinical findings are similar to the adult respiratory distress syndrome. In this
      condition, the blood coagulation contact system and the complement system are
      activated, leading to a capillary leak syndrome. Activation of the contact as
      well as the complement system is regulated by a common inhibitor, C1-esterase
      inhibitor (C1-INH). We report on two patients who received high doses of C1-INH
      for 2 days during graft failure either due to reperfusion injury immediately
      after transplantation or due to an acute rejection 2 months after double-lung
      transplantation. In both cases of graft failure, a capillary leak syndrome
      occurred with pleural effusions of 7 l to more than 10 l per day. In case 1
      disturbance of gas exchange during severe reperfusion injury could not be treated
      effectively with other treatment modalities like nitric oxide ventilation or
      surfactant administration. With the use of C1-INH, pleural effusions reduced
      within 12 h, leading to normal graft function within 4 days. In the second
      recipient, acute rejection forced the use of extracorporeal membrane oxygenation
      (ECMO) within 24 h despite immunosuppressive therapy. After administration of C1
      INH, pleural effusions reduced from 19 l per day to 300 ml within 3 days of
      treatment. ECMO was discontinued after C1-INH treatment and the patient extubated
      2 weeks later. This experience indicates that C1-INH may play a role in the
      management of capillary leak syndrome after lung transplantation.

PMID- 10654222
TI  - Usefulness of transesophageal echocardiography to detect Staphylococcus aureus
      infected superior vena cava thrombosis.

PMID- 10654223
TI  - Acute respiratory distress syndrome precipitated by transjugular intrahepatic
      porto-systemic shunting for severe hepatic veno-occlusive disease. Is it due to
      pulmonary leucostasis?

PMID- 10654224
TI  - Unusual complication after percutaneous dilatational tracheostomy:
      pneumoperitoneum with abdominal compartment syndrome.

PMID- 10654225
TI  - A vote for inhaled adrenaline in the treatment of severe upper airway obstruction
      caused by piercing of the tongue in hereditary angioedema.

PMID- 10654226
TI  - Mediastinal neurofibroma as a cause of unilateral diaphragm paralysis in von
      Recklinghausen's disease.

PMID- 10654227
TI  - Generalized muscle rigidity in a neonate following intrathecal fentanyl during
      caesarean delivery.

PMID- 10654228
TI  - ARDS due to Yersinia enterocolitica sepsis in a patient with thalassemia major.

PMID- 10654229
TI  - Metoclopramide improves gastric motility.

PMID- 10654230
TI  - An international review of HES.

PMID- 10654231
TI  - ECLS in pertussis: does it have a role?

PMID- 10654232
TI  - Harmonization of medico-legal autopsy rules. Committee of Ministers. Council of
      Europe.

PMID- 10654233
TI  - Sequence analysis of alleles at a microsatellite locus D14S299 (wg1c5) and
      population genetic comparisons.
AB  - In order to increase the discriminating power of DNA analysis in personal
      identification, we evaluated the forensic utility of the microsatellite locus
      D14S299 (wg1c5) in the Japanese population and also in the Chinese and Caucasian
      populations. Twelve different alleles were identified in length by gel
      electrophoresis with silver staining. The major alleles in Japanese were
      sequenced and designated as the numbers of the variable repeats (GGAT or GGAA).
      There were five variable regions and extensive homoplasy was found. However, the
      allele fragment lengths were in 4 bp increments and no "interalleles" were found.
      The estimated heterozygosity and the polymorphism information content (PIC) were
      0.726 and 0.689, respectively in Japanese. Those in Chinese (0.743 and 0.704)
      were similar to those in Japanese, while those in Caucasians (0.812 and 0.781)
      were much higher. After adjacent alleles were combined to yield at least five
      entries, statistical analysis was performed. The power of discrimination (PD) was
      0.887 in Japanese, 0.895 in Chinese and 0.935 in Caucasians and no significant
      deviations from the Hardy-Weinberg equilibrium were found in the three
      populations. We retyped all apparently homozygous samples using an alternative
      pair of flanking primers and found them to be true homozygotes. D14S299 appears
      to be a useful STR locus for forensic practice.

PMID- 10654234
TI  - Neuron-specific enolase as an effective immunohistochemical marker for injured
      axons after fatal brain injury.
AB  - Recently, it has been reported that a diagnosis of diffuse axonal injury in cases
      with a short survival period can be made with the use of immunolabelling for beta
      amyloid precursor protein (APP). We examined whether immunostaining for neuron
      specific enolase (NSE) can also be a useful marker for the detection of axonal
      injury in its early stages. Sections of the corpus callosum from 19 cases of head
      injury and from 9 cases of no head injury were immunostained for NSE and stained
      by the standard Holmes' silver method. For comparison, serial sections from
      several cases were immunostained for APP. Immunostaining for NSE as well as for
      APP, labelled injured axons in head injury cases with as early as 1.5 h survival
      where Holmes' staining failed to detect any changes of axons. Since NSE and APP
      labelled only injured axons but not normal axons, the results were readily
      interpretable. These findings indicate that NSE should be an effective marker for
      the detection of axonal injury in its early stages.

PMID- 10654235
TI  - Allele typing of short tandem repeats by capillary electrophoresis.
AB  - Capillary electrophoresis with laser-induced fluorescence was applied to the
      analysis of six STRs and the amelogenin sex test with the purpose of verifying
      accuracy and precision of the sizing method with the GS500 internal standard.
      Sequenced dye-labeled, PCR-amplified alleles from amelogenin, HumVWA31, HumTH01,
      HumF13A01, HumFIBRA, D21S11 and HumCSF1PO loci were run several times on the same
      capillary and on multiple capillaries and the offset of computer-measured
      fragment sizes from the expected molecular weights was calculated and analysed.
      All loci except D21S11 showed a poor degree of accuracy. Precision results from
      run-to-run and day-to-day injections displayed a maximum standard deviation (SD)
      > 0.15 nt for HumVWA31, HumF13A01, D21S11 and HumFIBRA, although the maximum
      range of calculated sizes in multiple runs was lower than 1 basepair. No
      variation in precision was observed according to the quality of the DNA template.
      Allele typing by comparison with allelic ladders for each locus is recommended.

PMID- 10654236
TI  - Three-dimensional (3-D) imaging in post-mortem examinations: elucidation and
      identification of cranial and facial fractures in victims of homicide utilizing 3
      D computerized imaging reconstruction techniques.
AB  - The analysis of cranial and facial fractures in skeletal remains of homicidal
      victims can prove challenging for forensic anthropologists and forensic
      pathologists in postmortem examination. In such cases, the use of 3-D
      computerized imaging to elucidate the fractures and patterns of injuries can
      provide strong medical evidence that is very useful during litigation and at
      trial. The authors describe 3-D reconstructions of the skull performed as part of
      forensic postmortem examination in a recent victim of homicide.

PMID- 10654237
TI  - Y-STR haplotyping in two Hungarian populations.
AB  - A set of seven Y-chromosomal STR loci (DYS19, DYS389-I, DYS389-II, DYS390,
      DYS391, DYS392, DYS393) with the addition of the bilocal marker DYS385 was used
      to generate male-specific haplotype databases for two Hungarian population
      samples, Caucasians from the Budapest area and Romanies from Baranya county. At
      the locus DYS385 three types of intermediate sized alleles were detected in six
      males. The presence of a (GA) dinucleotide, probably due to an (AA) deletion in
      the second (GAAA) repeat of the polymorphic repeat region leads to an
      intermediate allelle 17.2. The intermediate alleles 17.-1 and 18.-1 with the
      consensus repeat structure of (GAAA)17 and (GAAA)18, respectively, were found to
      lack a T in the same (T)7 stretch located within the 3' flanking region of each
      allele. The forensic efficiency values for the Romany population were
      significantly lower than those found in the Central Hungarian and other non
      isolated Causasian populations, which may imply a possible common paternal
      ancestry of some haplotypes in the Romany sample. With pairwise comparisons of
      inter-population molecular variance, the two populations analyzed here and an
      Italian population sample, could be clearly distinguished using the seven
      monoclonal Y-STRs. A sizing precision of < or = 0.14 nucleotide standard
      deviation was obtained with capillary electrophoresis carried out on an ABI Prism
      310 Genetic Analyzer. Objective and accurate genotyping is thus possible using an
      internal size standard with a high density of fragments.

PMID- 10654239
TI  - Homicidal poisoning with halothane.
AB  - A double homicide by smothering with halothane-moistened towels is described and
      the blood and tissue concentrations of halothane are discussed in comparison to
      the literature.

PMID- 10654238
TI  - Identification of victims of the 1998 Taoyuan Airbus crash accident using DNA
      analysis.
AB  - In February 1998 a civilian aeroplane carrying 196 individuals crashed in Taiwan
      and killed another 6 people on the ground. Although there were dental and medical
      records, fingerprints, photographic evidence and personal effects to identify
      some of the victims, DNA analysis was required to further identify severely
      damaged remains. From the 202 people known to have perished in the plane crash, a
      total of 685 fragments of human remains were subjected to DNA analysis. The
      analysis was carried out using nine microsatellite loci, plus amelogenin to
      cluster the 685 fragments into 202 groups, accounting for all the victims. To
      establish genetic relatedness of the victims to other victims and living
      relatives, additional DNA loci were used. In this case the paternity index was
      increased by using HLA DQA1 plus Polymarker. The same 16 DNA loci were used to
      test blood samples from 201 relatives to establish parent/child and sibling
      relationships. With the exception of 19 victims identified by non-genetic
      evidence, 183 victims were successfully identified by DNA typing with relatively
      high values of paternity index by the direct or indirect comparison of relatives.
      The 202 victims were from 37 different families, ranging in size from 2 to 13
      members and 74 individuals known to be unrelated to any other victim. The DNA
      from living relatives was used to identify one member of a family group, from
      which other victims of the family could be identified. ABO blood group
      information was further used to confirm genetic relatedness within families. A
      comparison of the DNA profiling results to the ABO blood group of the victims
      showed no discrepancies with the exception of two mutations in the FGA locus. In
      cases of severely damaged victims from a plane crash, DNA analysis proved to be
      the best choice to identify victims.

PMID- 10654240
TI  - Proficiency testing for psychoactive substances in Italy.
AB  - This paper describes the general design and main results of the Italian
      proficiency testing program for the analysis of psychoactive substances in urine,
      a long-term initiative created in 1995 on an educational basis and characterized
      by an innovative internet-based service for data exchange between laboratories
      and the organizing body. Batches of six urine samples, validated by reference
      laboratories, are sent every 3 months to participating laboratories, which may
      choose which classes of substances to test from those planned by the program
      panel and, within those classes, which type of analytical commitment to work on:
      identification of just one class (Option 1), identification of single substances
      (Option 2), or identification and quantification of single substances (Option 3).
      Comprehensive periodical reports and annual reports are provided to participants
      with evaluation of their performance and an annual workshop is organized to
      discuss technical-scientific topics related to clinical, forensic and analytical
      toxicology. About 200 laboratories currently participate in the program and a
      total of 67,059 analyses have been carried out since 1995. The mean percentage of
      correct results was 96.8%, with a yearly improvement of about 0.4%. The best
      average false positive and false negative rates were obtained for methadone (0.2%
      and 2.1% respectively) and cocaine (0.3% and 2.2%). The worst average false
      positive rates were obtained for amphetamines and opiates (3.2% and 5.0%) and
      worst average false negative rates for amphetamines, barbiturates and
      cannabinoids (17.4%, 30.7% and 19.9%).

PMID- 10654241
TI  - Population genetic data for HumF13B, HumLPL and HumHPRTB in southeast Poland.
AB  - Allele frequencies for the three short tandem repeat systems HumF13B, HumLPL and
      HumHPRTB were determined in a population sample from southeast Poland. PCR
      products were separated by electrophoresis on denaturing polyacrylamide gels,
      followed by silver staining. A total of six alleles for HumF13B, seven for HumLPL
      and eight alleles for HumHPRTB were detected and no deviations from Hardy
      Weinberg equilibrium were observed. The allele frequency data for the three
      systems were compared with other Caucasian populations.

PMID- 10654242
TI  - Fluorescence-based amplification of the STR loci D18S535, D1S1656 and D12S391 in
      a population sample from Aragon (north Spain).
AB  - Population data were generated for the STR loci D18S535, D1S1656 and D12S391 in a
      population sample of unrelated healthy individuals born and living in Aragon
      (North Spain). The three loci were amplified using a fluorescence-based PCR
      method and were typed automatically. No deviation from Hardy-Weinberg
      expectations were observed. The three loci proved to be highly discriminating and
      valuable polymorphisms for forensic analyses.

PMID- 10654243
TI  - Nine STR markers plus amelogenin (AmpFlSTR Profiler Plus): a forensic study in an
      Austrian population.
AB  - Genetic efficiency data of nine short tandem repeat (STR) loci were determined by
      multiplex PCR using fluorescently labeled primers and subsequent analysis by
      capillary electrophoresis (ABI 310). For each locus 7-14 alleles were detected.
      The combined matching probability is about 1 x 10(-11). No deviations from Hardy
      Weinberg equilibrium were observed.

PMID- 10654244
TI  - [Significance of the time course of ST segment elevation just after reperfusion
      therapy for acute myocardial infarction].
AB  - The significance of the time course of ST segment elevation just after
      reperfusion therapy for acute myocardial infarction was investigated in 25
      consecutive patients with acute myocardial infarction and ST elevation. The most
      elevated ST lead from the standard electrocardiogram on admission was
      continuously monitored as the ST trend for 72 hr including during the reperfusion
      procedure. The culprit artery was totally occluded and reperfused without flow
      delay. Left ventriculograms were obtained after reperfusion and 3-4 weeks later.
      The most elevated ST level before reperfusion was measured as the maximal level
      and the ST level 30 min after reperfusion as the reperfused level. The patients
      were divided into 2 groups, group ST > or = 50% (n = 12) with a decrease of less
      than 50% of the maximal ST level and group ST < 50% (n = 13) with a decrease of
      50% or over 50%. Regional left ventricular wall motion of infarct site, end
      diastolic left ventricular volume and ejection fraction were compared between the
      acute and chronic phase left ventriculograms in each group. In group ST > or =
      50%, no significant change was detected in both regional and global ejection
      fraction, whereas end-diastolic left ventricular volume enlarged significantly in
      the chronic phase (acute 80 +/- 25 ml/m2 to chronic 95 +/- 17 ml/m2, p < 0.01).
      In group ST < 50%, regional and global ejection fraction both improved
      significantly (SD/chord: acute -2.2 +/- 1.5 to chronic -1.4 +/- 0.4, p < 0.001;
      ejection fraction: acute 50 +/- 14% to chronic 57 +/- 13%, p < 0.01) but end
      diastolic left ventricular volume remained the same in the chronic phase. The
      peak creatine kinase level and the frequency of ST re-elevation at reperfusion
      were significantly higher in group ST > or = 50% than in group ST < 50% (creatine
      kinase: group ST > or = 50% 5,496 +/- 2,219 IU/l, group ST < 50% 1,913 +/- 1,180
      IU/l, p < 0.0001; ST re-elevation: group ST > or = 50% 83%, group ST < 50% 38%, p
      < 0.05), although the time from onset of myocardial infarction to reperfusion,
      the maximal ST level, the degree of collateral development, and the frequency of
      pre-infarction angina were not different between the 2 groups. Rapid resolution
      of ST elevation after reperfusion is a useful marker of the improvement of left
      ventricular function in acute myocardial infarction.

PMID- 10654245
TI  - [Influence of diabetes mellitus and complications on long-term outcome of
      coronary artery bypass surgery].
AB  - The influence of diabetes mellitus and complications on the long-term outcome of
      coronary artery bypass graft surgery (CABG) was investigated in 192 consecutive
      patients who underwent elective CABG between January 1992 and March 1996. Of
      these, 102 patients were diabetic and 90 were nondiabetic. Preoperative and
      postoperative left ventricular ejection fraction, number of grafts, use of
      arterial conduit, and frequency of perioperative infarction were all similar in
      the 2 groups. During a mean follow-up of 3.2 years, diabetics showed higher
      cardiac mortality than nondiabetics (15% vs 3%, p = 0.01). Cardiac event-free
      survival was also low in diabetics, and this difference increased throughout the
      period (91% vs 99% at 2 years, 74% vs 90% at 4 years in diabetics and
      nondiabetics, respectively, by Kaplan-Meier analysis, p = 0.008). Multivariate
      Cox regression analysis revealed postoperative low ejection fraction and diabetes
      mellitus as independent predictors of late cardiac death. Major causes of cardiac
      death in diabetics were sudden death, pump failure and acute myocardial
      infarction. Additionally, subgroup analysis in diabetics using the Cox regression
      model identified postoperative low ejection fraction, female gender and diabetic
      nephropathy as independent predictors of late cardiac death. Thus, patients with
      diabetes have a worse clinical outcome after CABG, especially when associated
      with low ejection fraction, female gender and diabetic nephropathy. Intensive
      management of heart failure, prevention of myocardial infarction and specific
      strategy for female patients are all essential to improve the long-term outcome
      of diabetics after CABG.

PMID- 10654246
TI  - Effects of aging on aortic diameters and distensibility in Marfan's syndrome:
      comparison with healthy subjects.
AB  - The relationships between age, aortic diameter, and aortic distensibility were
      examined in patients with Marfan's syndrome. Aortic diameters were measured at
      the sinus of Valsalva, the ascending aorta, the aortic arch, and the abdominal
      aorta in 20 patients (aged 5-63 years) with Marfan's syndrome and 30 age-matched
      normal control subjects. The aortic distensibility was calculated as follows:
      aortic distensibility = 2 (change in aortic diameter)/(diastolic aortic diameter)
      (systolic pressure-diastolic pressure). Aortic diameter increased with age in
      both groups. The diameters of the sinus of Valsalva and the ascending aorta were
      greater in the Marfan group than in the control group, and increased even after
      adolescence in patients with Marfan's syndrome. Aortic distensibility was the
      highest at the abdominal aorta and the lowest at the sinus of Valsalva in both
      groups. Aortic distensibility decreased with age in both groups, but aortas were
      less distensible in the Marfan group than in the control group at all ages. The
      sinus of Valsalva and the ascending aorta dilate abnormally after adolescence in
      patients with Marfan's syndrome. However, aortic elastic properties in patients
      with Marfan's syndrome were abnormal even in childhood.

PMID- 10654247
TI  - [Calcification in culprit lesions of coronary artery disease].
AB  - Coronary calcification, a type of coronary atherosclerosis, has recently been
      closely examined in clinical cardiology because its presence may influence the
      selection of interventional therapy. In addition, plaque instability is one of
      the most important factors in the mechanism of acute coronary syndrome, and
      calcium deposit is frequently detected in advanced lesions. However, little is
      known about the clinical significance of coronary calcification. The incidence of
      calcium deposits was investigated in the culprit lesions (culprit coronary
      calcification) of patients with serious coronary artery disease to discover any
      cardioprotective effect. Initial coronary angiography was performed in 179
      consecutive patients with acute myocardial infarction with Q wave on
      electrocardiography (AMI group; male 139, female 40, mean age 60.2 +/- 10 yr) and
      in 119 consecutive patients with stable effort angina pectoris (SAP group; male
      78, female 41, mean age 63.8 +/- 8 yr) for which balloon plasty or bypass surgery
      was necessary from 1990 to 1997. Culprit coronary calcification was defined
      positive if the calcification deposit was present cinefluoroscopically within 5
      mm from the culprit point. The culprit point was defined as the narrowest point
      after successful intracoronary thrombolytic therapy or the latest point to be
      dilated during a balloon inflation in direct or rescue percutaneous transluminal
      coronary angioplasty in the AMI group, and the narrowest point of the culprit
      lesion in the SAP group. There was no statistical difference in clinical
      background between the 2 groups other than male dominance in the AMI group and
      high incidence of family history of ischemic heart disease in the SAP group (p <
      0.05). Culprit coronary calcification in patients over 50 years old was less
      frequently positive in the AMI group than the SAP group (26% vs 66%, p < 0.005,
      respectively). In younger patients under 50 years old, the incidence of culprit
      coronary calcification was low (14-15%) in both groups. Culprit coronary
      calcification was frequently positive in the right or the left anterior
      descending coronary artery in the SAP group (p < 0.005). There was no incidental
      sex difference of culprit coronary calcification. This comparison suggests that
      if a plaque contains cinefluoroscopically visible calcification, it may be
      regarded as less vulnerable or having a history of chronic process of
      atherosclerosis which results in protecting plaque rupture.

PMID- 10654248
TI  - [Electrocardiographic left ventricular hypertrophy without echocardiographic
      abnormalities evaluated by myocardial perfusion and fatty acid metabolic
      imaging].
AB  - The pathophysiologic process in patients with electrocardiographic left
      ventricular hypertrophy with ST, T changes but without echocardiographic
      abnormalities was investigated by myocardial perfusion imaging and fatty acid
      metabolic imaging. Exercise stress 99mTc-methoxy-isobutyl isonitrile (MIBI)
      imaging and rest 123I-beta-methyl-p-iodophenyl pentadecanoic acid (BMIPP) imaging
      were performed in 59 patients with electrocardiographic hypertrophy including 29
      without apparent cause including hypertension and echocardiographic hypertrophy,
      and 30 with essential hypertension. Coronary angiography was performed in 6
      patients without hypertension and 4 with hypertension and biopsy specimens were
      obtained from the left ventricular apex from 6 patients without hypertension.
      Myocardial perfusion and 123I-BMIPP images were classified into 3 types: normal,
      increased accumulation of the isotope at the left ventricular apex (high uptake)
      and defect. Transient perfusion abnormality and apical defect observed by 123I
      BMIPP imaging were more frequent in patients without hypertension than in
      patients with hypertension (32% vs 17%, p = 0.04671 in perfusion; 62% vs 30%, p =
      0.0236 in 123I-BMIPP). Eighteen normotensive patients with apical defect by 123I
      BMIPP imaging included 3 of 10 patients with normal perfusion at exercise, 6 of
      10 patients with high uptake and 9 of 9 patients with perfusion defect. The
      defect size revealed by 123I-BMIPP imaging was greater than that of the perfusion
      abnormality. Coronary stenoses were not observed and myocardial specimens showed
      myocardial disarray with hypertrophy. Moreover, 9 patients with hypertension and
      apical defects by 123I-BMIPP showed 3 different types of perfusion. Many patients
      without hypertension show a pathologic process similar to hypertrophic
      cardiomyopathy. Perfusion and 123I-BMIPP imaging are useful for the
      identification of these patients.

PMID- 10654249
TI  - New multifunctional percutaneous transluminal coronary angioplasty catheter
      device capable of balloon inflation, local drug delivery and coronary perfusion.
AB  - A new percutaneous transluminal coronary angioplasty catheter with multiple
      functions of balloon inflation, local drug delivery and coronary perfusion has
      been devised. The device consists of an inflatable lumen, a drug delivery lumen,
      and a perfusion (or guide wire) lumen. A drug can be infused from the port
      located distal to the inflated balloon during continuous blood perfusion via the
      perfusion lumen. Fluorescence-labeled heparin and peroxidase administered using
      the device permeated into denuded vessel tissues during ongoing perfusion and
      remained there for over 24 hr. This prototype device indicates the potential
      therapeutic implications of the concepts of the device.

PMID- 10654250
TI  - [Toxoplasma pericarditis without immunosuppressant disorder detected by
      polymerase chain reaction of pericardial fluid: a case report].
AB  - There have been several case reports, a total of 22 up to the present, of
      toxoplasma pericarditis. Out of them, in only a few cases the diagnosis was
      properly made with a proof of the microscopic presence of Toxoplasma gondii. This
      is the first report of toxoplasma pericarditis in which the presence of
      Toxoplasma gondii was detected by polymerase chain reaction of pericardial
      effusion. In addition, the previous reports will be reviewed, and compared to
      this present case. A 29-year-old woman, without immunosuppressant disorder,
      suffering from fever and orthopnea was admitted to our hospital. Blood chemistry
      findings indicated mild liver dysfunction and inflammation. Chest radiography
      showed cardiac enlargement. Electrocardiography showed sinus tachycardia and ST
      elevation. Echocardiography revealed a massive pericardial effusion.
      Pericardiocentesis demonstrated 638 ml of bloody fluid. Cytologic study of the
      fluid was class II for malignancy, and polymerase chain reaction to tuberculosis
      was negative. However, a high titer of the anti-toxoplasma antibody of 1: 20,480
      (passive hemagglutination) indicated pericarditis caused by Toxoplasma gondii.
      Subsequently, Toxoplasma gondii was identified in the pericardial effusion by
      polymerase chain reaction. Clinical symptoms improved after pericardiocentesis,
      but 2 months later pericarditis recurred. Treatment was started with 800 mg
      acetylspiramycin daily but failed to improve the symptoms. Because of the
      development of pleuritis, treatment was changed to sulfadoxine 1,000
      mg/pyrimethamine 50 mg. After the treatment with them, her symptoms improved.
      Only 22 cases of toxoplasma pericarditis have been reported worldwide and 15 of
      those cases were without immunosuppressant disorder. The usual symptoms at the
      onset of pericarditis without immunosuppressant disorder are fever, dyspnea and
      chest pain. Seven patients developed cardiac tamponade. Pericardiocentesis was
      performed in 8 cases and the pericardial fluid was hemorrhagic in 6. Pericardial
      thickening was detected in 5 cases. The diagnosis of toxoplasma infection is very
      difficult, because asymptomatic infection of Toxoplasma gondii is very common.
      Pericarditis is a disease difficult to confirm the etiology. Detection of
      Toxoplasma gondii in pericardial effusion by the polymerase chain reaction is
      very useful for its diagnosis.

PMID- 10654251
TI  - Color flow signal in the left atrium as a mirror image artifact suggesting one
      leaflet constriction of the St. Jude Medical valve: a case report.
AB  - Color Doppler echocardiography detected an abnormal color flow signal originating
      from the prosthetic mitral valve and extending to the left atrium during diastole
      in an 84-year-old woman with St. Jude Medical valve replacement. The flow was
      away from the transducer and almost identical to the left ventricular inflow
      signal except for the direction. Cinefluoroscopy showed one of the leaflets fixed
      at systole whereas the other leaflet was mobile. After reinforcement of
      anticoagulant therapy, this abnormal color flow signal disappeared and motion of
      both leaflets normalized. This color flow signal, presumably a mirror image
      artifact of the left ventricular inflow caused by the immobilized leaflet, could
      be a sign of one leaflet constriction in patients with St. Jude Medical valve
      replacement.

PMID- 10654252
TI  - [A 77-year-old man with continuous heart murmur].

PMID- 10654253
TI  - Loud harsh holosystolic murmur in a middle-aged man.

PMID- 10654254
TI  - Fluctuating mutation bias and the evolution of base composition in Drosophila.
AB  - The idea that the pattern of point mutation in Drosophila has remained constant
      during the evolution of the genus has recently been challenged. A study of the
      nucleotide composition focused on the Drosophila saltans group has evidenced
      unsuspected nucleotide composition differences among lineages. Compositional
      differences are associated with an accelerated rate of amino acid replacement in
      functionally less constrained regions. Here we reassess this issue from a
      different perspective. Adopting a maximum-likelihood estimation approach, we
      focus on the different predictions that mutation and selection make about the
      nonsynonymous-to-synonymous rate ratio. We investigate two gene regions, alcohol
      dehydrogenase (Adh) and xanthine dehydrogenase (Xdh), using a balanced data set
      that comprises representatives from the melangaster, obscura, saltans, and
      willistoni groups. We also consider representatives of the Hawaiian picture
      winged group. These Hawaiian species are known to have experienced repeated
      bottlenecks and are included as a reference for comparison. Our results confirm
      patterns previously detected. The branch ancestral to the fast-evolving
      willistoni/saltans lineage, where most of the change in GC content has occurred,
      exhibits an excess of synonymous substitutions. The shift in mutation bias has
      affected the extent of the rate variation among sites in Xdh.

PMID- 10654255
TI  - Phylogenetics of Perissodactyla and tests of the molecular clock.
AB  - Two mitochondrial genes, the protein-coding cytochrome c oxidase subunit II
      (COII) gene and a portion of the 12S rRNA gene, were used for phylogenetic
      investigation of the mammalian order Perissodactyla. The primary objective of the
      study was to utilize the extensive fossil record of perissodactyls for
      calibrating molecular clocks and comparing estimates of divergence times using
      both genes and two fossil calibration points. Secondary objectives included
      clarification of previously unresolved relationships within Tapiridae and
      comparison of the results of separate and combined analyses of two genes.
      Analyses included several perissodactyl lineages representing all three families
      (Tapiridae, Equidae, and Rhinocerotidae), most extant genera, all four species of
      tapirs, two to four species of rhinoceros, and two species of Equus. The
      application of a relatively recent fossil calibration point and a relatively
      ancient calibration point produced greatly different estimates of evolutionary
      rates and divergence times for both genes, even though a relative rates test did
      not find significant rate differences among taxa. A likelihood-ratio test,
      however, rejected a molecular clock for both genes. Neither calibration point
      produced estimates of divergence times consistent with paleontological evidence
      over a range of perissodactyl radiations. The combined analysis of both genes
      produces a well-resolved phylogeny with Perissodactyla that conforms to
      traditional views of interfamilial relationships and supports monophyly of
      neotropical tapirs. Combining the data sets increases support for most nodes but
      decreases the support for a neotropical tapir clade because the COII and 12S rRNA
      data sets are in conflict for tapir relationships.

PMID- 10654256
TI  - Evolution of cis-acting elements in 5' flanking regions of vertebrate actin
      genes.
AB  - Regulation of the vertebrate actin multigene family involves the recognition of
      various regulatory sequences (cis-acting elements) that specify the distinct
      tissue type and developmental program of expression for each actin paralogue,
      which implies that the distribution of cis-acting elements may be unique for each
      paralogue gene. To elucidate the evolution of these unique distribution patterns,
      we improved a method to scan for cis-acting elements in the 5' flanking
      regulatory region of genes and used it to analyze five cis-acting elements (SRE,
      MyoD binding site, Elk-1 binding site, positive and negative YY1 binding sites)
      of six actin paralogue genes (beta and gamma cytoplasmic actins, alpha and gamma
      smooth muscle actins, and alpha skeletal and alpha cardiac actins) among various
      vertebrates. It was shown that although an element(s) may exist in all paralogue
      genes of the same species, its numbers, compositions, and distribution patterns
      or even sequences vary remarkably among paralogues, which contributes to their
      different tissue- and developmental-specific expression. However, each pair of
      coexpressed paralogues has some certain similarity in distribution patterns.
      Furthermore, among various orthologues of actin genes derived from diverse
      vertebrates, the sequences, numbers, and distribution patterns of these cis
      acting elements are highly conserved or even identical in the long run of
      phylogeny of vertebrates. Taken together, the results described above strongly
      indicate that not only the structures of actins but also their expression
      patterns are essential in both the phylogeny and the physiology of vertebrates.
      The distribution patterns of cis-acting elements of various actin genes can be
      regarded as indicators of both horizontal (paralogues) and vertical (orthologous)
      evolution of actins.

PMID- 10654257
TI  - Expression of the dentin matrix protein 1 gene in birds.
AB  - The emergence of jawed vertebrates was predicated on the appearance of several
      innovations, including tooth formation. The development of teeth requires the
      participation of several specialized genes, in particular, those necessary for
      the formation of hard tissues--dentin, enamel, and cementum. Some vertebrates,
      most conspicuously birds, secondarily lost the tooth-forming ability. To
      determine the fate of some of the tooth-forming genes in the birds, we tested a
      domestic fowl cDNA library for the expression of the dentin matrix protein 1
      (DMP1) gene. The library was prepared from the poly(A+) RNA isolated from the
      jaws of 11- to 13-day-old embryos and the testing was carried out by the
      polymerase chain reaction with degenerate primers designed on the basis of the
      available mammalian and reptile sequences. A chicken homologue of the DMP1 gene
      identified by this approach was shown to be expressed in the jaws and long bones,
      the same two tissues as in mammals. The chicken DMP1 gene has an exon/ intron
      organization similar to that of its mammalian and reptile counterparts. The
      chicken gene contains three short highly conserved segments, the rest of the gene
      being poorly alignable or not alignable with its mammalian or reptilian
      homologues. The distribution of similarities and dissimilarities along the gene
      is indicative of a mode of evolution in which only short segments are kept
      constant, while the rest of the gene is relatively free to vary as long as the
      proportion of certain amino acid residues is retained in the encoded polypeptide.
      The DMP1 gene may have been retained in birds because of its involvement in bone
      formation.

PMID- 10654258
TI  - Phylogeny of the restriction endonuclease-like superfamily inferred from
      comparison of protein structures.
AB  - To date all attempts to derive a phyletic relationship among restriction
      endonucleases (ENases) from multiple sequence alignments have been limited by
      extreme divergence of these enzymes. Based on the approach of Johnson et al.
      (1990), I report for the first time the evolutionary tree of the ENase-like
      protein superfamily inferred from quantitative comparison of atomic coordinates
      of structurally characterized enzymes. The results presented are in harmony with
      previous comparisons obtained by crystallographic analyses. It is shown that
      lambda-exonuclease initially diverged from the common ancestor and then two
      "endonucleolytic" families branched out, separating "blunt end cutters" from "5'
      four-base overhand cutters." These data may contribute to a better understanding
      of ENases and encourage the use of structure-based methods for inference of
      phylogenetic relationship among extremely divergent proteins. In addition, the
      comparison of three-dimensional structures of ENase-like domains provides a
      platform for further clustering analyses of sequence similarities among different
      branches of this large protein family, rational choice of homology modeling
      templates, and targets for protein engineering.

PMID- 10654259
TI  - Gene expression, amino acid conservation, and hydrophobicity are the main factors
      shaping codon preferences in Mycobacterium tuberculosis and Mycobacterium leprae.
AB  - Mycobacterium tuberculosis and Mycobacterium leprae are the ethiological agents
      of tuberculosis and leprosy, respectively. After performing extensive comparisons
      between genes from these two GC-rich bacterial species, we were able to construct
      a set of 275 homologous genes. Since these two bacterial species also have a very
      low growth rate, translational selection could not be so determinant in their
      codon preferences as it is in other fast-growing bacteria. Indeed, principal
      components analysis of codon usage from this set of homologous genes revealed
      that the codon choices in M. tuberculosis and M. leprae are correlated not only
      with compositional constraints and translational selection, but also with the
      degree of amino acid conservation and the hydrophobicity of the encoded proteins.
      Finally, significant correlations were found between GC3 and synonymous distances
      as well as between synonymous and nonsynonymous distances.

PMID- 10654260
TI  - Rates of conservative and radical nonsynonymous nucleotide substitutions in
      mammalian nuclear genes.
AB  - To understand the process and mechanism of protein evolution, it is important to
      know what types of amino acid substitutions are more likely to be under selection
      and what types are mostly neutral. An amino acid substitution can be classified
      as either conservative or radical, depending on whether it involves a change in a
      certain physicochemical property of the amino acid. Assuming Kimura's two
      parameter model of nucleotide substitution, I present a method for computing the
      numbers of conservative and radical nonsynonymous (amino acid altering)
      nucleotide substitutions per site and estimate these rates for 47 nuclear genes
      from mammals. The results are as follows. (1) The average radical/conservative
      rate ratio is 0.81 for charge changes, 0.85 for polarity changes, and 0.49 when
      both polarity and volume changes are considered. (2) The radical/conservative
      rate ratio is positively correlated with the nonsynonymous/synonymous rate ratio
      for charge changes or when both polarity and volume changes are considered. (3)
      Both the conservative/synonymous rate ratio and the radical/synonymous rate ratio
      are lower in the rodent lineage than in the primate or artiodactyl lineage,
      suggesting more intense purifying selection in the rodent lineage, for both
      conservative and radical nonsynonymous substitutions. (4) Neglecting
      transition/transversion bias would cause an underestimation of both radical and
      conservative rates and the ratio thereof. (5) Transversions induce more dramatic
      genetic alternations than transitions in that transversions produce more amino
      acid altering changes and among which, more radical changes.

PMID- 10654261
TI  - Molecular evolution in a multisite nearly neutral mutation model.
AB  - A simple nearly neutral mutation model of protein evolution was studied using
      computer simulation assuming a constant population size. In this model, a gene
      consists of a finite number of codons and there is no recombination within a
      gene. Each codon has two replacement and one silent sites. The fitness of a gene
      was determined multiplicatively by amino acids specified by codons (the
      independent multicodon model). Nucleotide diversity at replacement sites
      decreases as selection becomes stronger. A reduction of nucleotide diversity at
      silent sites also occurs as selection intensifies but the magnitude of the
      reduction is not a monotone function of the intensity of selection. The
      dispersion index is close to one. The average value of Tajima's and Fu and Li's
      statistics are negative and their absolute values increases as selection
      intensifies. However, their powers of detecting selection under the present model
      were not high unless the number of sites is large or mutation rate is high. The
      MK test was shown to detect intermediate selection fairly well. For comparison,
      the house-of-cards model was also investigated and its behavior was shown to be
      more sensitive to changes of population size than that of the independent
      multicodon model. The relevance of the present model for explaining protein
      evolution was discussed comparing its prediction and recent DNA data.

PMID- 10654262
TI  - Intron conservation in a UV-specific DNA repair gene encoded by chlorella
      viruses.
AB  - Large dsDNA-containing chlorella viruses encode a pyrimidine dimer-specific
      glycosylase (PDG) that initiates repair of UV-induced pyrimidine dimers. The PDG
      enzyme is a homologue of the bacteriophage T4-encoded endonuclease V. The pdg
      gene was cloned and sequenced from 42 chlorella viruses isolated over a 12-year
      period from diverse geographic regions. Surprisingly, the pdg gene from 15 of
      these 42 viruses contain a 98-nucleotide intron that is 100% conserved among the
      viruses and another 4 viruses contain an 81-nucleotide intron, in the same
      position, that is nearly 100% identical (one virus differed by one base). In
      contrast, the nucleotides in the pdg coding regions (exons) from the intron
      containing viruses are 84 to 100% identical. The introns in the pdg gene have 5'
      AG/GTATGT and 3'-TTGCAG/AA splice site sequences which are characteristic of
      nuclear-located, spliceosomal processed pre-mRNA introns. The 100% identity of
      the 98-nucleotide intron sequence in the 15 viruses and the near-perfect identity
      of an 81-nucleotide intron sequence in another 4 viruses imply strong selective
      pressure to maintain the DNA sequence of the intron when it is in the pdg gene.
      However, the ability of intron-plus and intron-minus viruses to repair UV-damaged
      DNA in the dark was nearly identical. These findings contradict the widely
      accepted dogma that intron sequences are more variable than exon sequences.

PMID- 10654263
TI  - Molecular data from the 16S rRNA gene for the phylogeny of Pectinidae (Mollusca:
      Bivalvia).
AB  - The phylogenetic relationships among the species belonging to the family
      Pectinidae are still an issue of debate. The mitochondrial DNA sequences from the
      large ribosomal RNA gene may be of great value for systematic and phylogenetic
      studies within families. Partial sequences of the 16S rRNA gene were obtained for
      the scallop species Adamussium colbecki, Aequipecten opercularis, Chlamys glabra,
      C. islandica, C. varia, and Pecten jacobeus and compared with the published
      sequence of Pecten maximus. The present molecular data show that Chlamys are
      polyphyletic and do not support the assignment of these species to the two
      subfamilies Chlamydinae and Pectininae. Moreover, the minimal genetic distance
      between P. maximus and P. jacobeus suggests that they could belong to the same
      species.

PMID- 10654264
TI  - Testing the extent of sequence similarity among viroids, satellite RNAs, and
      hepatitis delta virus.
AB  - A Monte Carlo method was used to test the extent of sequence similarity among
      viroids, satellite RNAs, and hepatitis delta virus. This analysis revealed that
      there is insufficient sequence similarity among these pathogens to support the
      hypothesis that they have a common evolutionary origin. Furthermore, while
      definite patterns of sequence similarity were observed among some viroids, there
      was a clear lack of overall similarity, indicating that a monophyletic origin for
      even this group cannot be reliably supported from sequence data alone.

PMID- 10654265
TI  - Ethics regarding living-donor organ transplantation.
AB  - During the last two decades, an intensive discussion has taken place in the field
      of medical ethics, which has lead to a reawakening of interest in the subject of
      living-donor organ transplantation and a re-evaluation of the moral problems
      related to it. In this process, traditional professional ethics have, to a large
      extent, been replaced by more complex modes of moral reasoning. The ethical
      principle of respect for the autonomy of persons has proven to be of prime
      importance in this field.

PMID- 10654266
TI  - Living-donor kidney transplantation.
AB  - The number of living donations is increasing in Europe and especially in Germany.
      The reasons seem to be a continuous shortage of cadaveric organs, better results
      after living related and living unrelated donation, and a high willingness in the
      population to donate. Various legal prerequisites have to be fulfilled in
      different countries. In general, careful donor evaluation is necessary to avoid
      excessive risk in the donor. Nephrectomy for transplantation can be performed via
      various approaches; microinvasive surgical techniques have been introduced, but
      are not yet established. Immunosuppression in living related donation is no
      different from that in cadaveric transplantations. In conclusion, living donation
      seems to be an adequate alternative to cadaveric donation. Moreover, results are
      twice as good as cadaveric donation with regard to long-term function.

PMID- 10654267
TI  - Living-donor liver transplantation in children.
AB  - INTRODUCTION: Living-related liver transplantation (LRLT) for paediatric
      recipients was developed 10 years ago to overcome the high mortality on the
      waiting list. Since then, liver transplantation programs around the world have
      begun to employ this method with encouraging results. This review describes the
      actual status of LRLT in children, aspects of donor selection, donor risks, and
      surgical technique, as well as an update of the results of the leading LRLT
      programs in the world. The donor operation has matured to the stage of being a
      standardised, teachable procedure with a low risk of morbidity or mortality.
      However, there is a percentage of potential donations that have to be declined
      for medical or socio-psychological reasons. LRLT provides grafts of excellent
      quality and short cold ischemic times. A major advantage is the fact that the
      optimal moment for the transplantation procedure can be chosen. Together with
      split-liver techniques, LRLT has a positive effect on the general situation of
      the paediatric waiting list for liver transplantation, with a reduction of pre
      transplant mortality to nearly 0%.

PMID- 10654268
TI  - Living-donor liver transplantation in adults.
AB  - End-stage liver disease is being treated by liver transplantation. Despite
      legislative and social efforts, the number of cadaveric organs suitable for liver
      transplantation has not grown to match the increasing demand. The insufficient
      number of grafts results in high mortality for patients on the waiting list and
      prolonged waiting times with increasing morbidity. Following the success of
      living related-donor segmental liver transplantation in children, an amended
      concept has been applied to the adult patients. The early experience with this
      technique, the process concerning the selection of the donor for the recipient,
      the risks of the donor, and the future evolution of living related-donor liver
      transplantation are the topics of this article.

PMID- 10654269
TI  - Living-donor pancreas and small-bowel transplantation.
AB  - BACKGROUND: In contrast to renal and liver transplantation, only a limited number
      of pancreas and intestinal live-donor transplants have so far been reported.
      PATIENTS: The vast majority of live segmental pancreas transplants have been
      performed at the University of Minnesota. From 1979 to 1993, a total of 78
      solitary pancreas transplants--28 after kidney and 49 pancreas transplants alone-
      were performed and, from 1994 to August 1999, 27 simultaneous pancreas/kidney
      transplants. For the first intestinal transplant, a segment of ileum from the
      mother was used in Boston in 1964. In 1970, 170 cm of jejuno-ileum from a human
      leukocyte antigen (HLA)-identical sister was removed and transplanted in New
      York. In 1988, an intestinal transplant from a haplo-type-identical sister was
      performed at Kiel University, Germany. In the 1990s, a few more intestinal
      transplants from live donors were reported to the registry. RESULTS: No death
      occurred among pancreas or intestinal donors. Altogether, seven pancreas donors
      required splenectomy and several donors required drainage of abscesses or fluid
      collections. Three of the 78 pancreas donors and at least two of the 27
      pancreas/kidney donors required insulin post-donation. Twenty-seven of the
      solitary segmental pancreas transplants failed for technical reasons. Graft
      survival of technically successful pancreas transplants was 68% after 1 year and
      38% after 10 years. Patient and renal allograft survival of combined
      kidney/pancreas transplants after 1 year was 100%, while 1-year pancreas survival
      was 84%. The first recipient of a live-donor intestinal transplant died only 12 h
      after surgery. The second case lived for 79 days and was able to eat for 6 weeks.
      A patient transplanted in 1988 lived for 4 years mainly on oral nutrition. Many
      of the live-donor intestinal transplants carried out in the 1990s became long
      term survivors. CONCLUSION: Pancreas and small-bowel transplantation using organs
      from live donors is possible in experienced centers, with no donor mortality and
      excellent survival rates for recipients and grafts. Since abnormal glucose
      tolerance post-donation cannot be excluded with certainty and since, for the time
      being, there is no pancreas or small-bowel shortage in Europe, live donation of
      these organs should be restricted mainly to highly sensitized patients with a
      cross-match-negative relative or HLA-identical donor-intestinal recipient
      combinations.

PMID- 10654270
TI  - Detection of telomerase activity in esophageal squamous cell carcinoma and normal
      esophageal epithelium.
AB  - BACKGROUND/AIMS: Relatively little has been reported about the telomerase
      activity of esophageal squamous cell carcinoma or normal esophageal epithelium.
      In this study, we have evaluated whether telomerase activity is a useful marker
      for detecting malignancies in the esophagus. PATIENTS/METHODS: Esophageal
      carcinomas and normal esophageal tissues adjacent to carcinomas were obtained
      from 52 surgically treated, unselected patients, and normal esophageal epithelium
      from 11 non-cancerous patients were obtained by means of biopsy. The telomeric
      repeat amplification protocol (TRAP) assay was used for detection of telomerase
      activity in these samples. The incidence of detection of telomerase activity in
      esophageal carcinoma was compared with that of telomerase activity in normal
      esophageal epithelium. Moreover, the clinicopathological characteristics of
      telomerase-positive tumors were compared with those of telomerase-negative
      tumors. RESULTS: Of the 52 carcinomas, 40 (77%) had detectable telomerase
      activity. However, telomerase activity was detected in 45 of 52 (87%) normal
      tissue samples adjacent to carcinomas and in 8 of 11 (73%) normal esophageal
      epithelium from non-cancerous patients. In esophageal cancer, no significant
      difference was detected in the clinicopathological findings between the
      telomerase-positive and -negative cases. CONCLUSION: These results indicate that
      not only esophageal squamous cell carcinomas but also normal esophageal
      epithelium show strong telomerase activity. Thus, telomerase activity may not be
      a good marker for the detection of carcinoma in the esophagus.

PMID- 10654271
TI  - Minimally invasive video-assisted parathyroidectomy--selective approach to
      localized single gland adenoma.
AB  - BACKGROUND: The valid operative standard for primary hyperparathyroidism (pHPT)
      consists of cervicotomy and presentation of all parathyroid glands. This
      operative technique features the macroscopic identification of the responsible
      adenoma. It also has the advantage of detecting multiglandular disease. The
      increasing sensitivity of preoperative localization methods and the possibility
      of intra-operative measurement of parathyroid hormone prepared the way for
      minimally invasive procedures. METHODS: All patients with pHPT were examined by
      cervical sonography and sestamibi scintigraphy of the parathyroid glands.
      Patients eligible for the described procedure had to comply to the following
      inclusion criteria: biochemical evidence of pHPT, localization of one
      unequivocally enlarged parathyroid gland on two corresponding imaging results; no
      former surgery or radiation to the neck; no multinodular goiter; no suspected
      carcinoma of the thyroid; and no secondary or recurrent hyperparathyroidism. We
      used an operative technique first described by Miccoli in 1997. Before
      preparation and at 2, 10 and 15 min after exstirpation of the parathyroid
      adenoma, peripheral blood was drawn. The operation was terminated when a 50%
      decrease of preoperative PTH levels was reached. RESULTS: During a 12-month
      period (1 December 1997 to 30 November 1998), 13 patients with pHPT of a total of
      59 patients (22%) with hyperparathyroidism (pHPT and sHPT) were operated on
      employing this minimally invasive procedure. In three patients, the operative
      technique had to be converted to the conventional procedure due to superior
      adenomas in two cases and a dorsoesophageal adenoma in one case. The procedure
      could thus be successfully completed in ten patients. The overall failure rate
      was zero in all patients with regard to the underlying disease. There was one
      temporary, recurrent laryngeal-nerve palsy. The mean overall length of the
      hospital stay was 3 days. CONCLUSION: The minimally invasive video-assisted
      parathyroidectomy for localized single-gland adenoma is a new and attractive
      surgical therapy option for primary hyperparathyroidism due to improved patient
      comfort, shortened length of hospital stay and favorable cosmetic results. This
      may lead to one-day surgery and, therefore, to a reduction of overall costs.

PMID- 10654272
TI  - Respiratory symptoms and dysphagia in patients with gastroesophageal reflux
      disease: a comparison of medical and surgical therapy.
AB  - BACKGROUND: Gastroesophageal reflux disease (GERD) is a common condition and may
      frequently lead to dysphagia and respiratory symptoms. The aim of this study was
      to investigate the effects of medical and surgical therapy to control these
      symptoms. METHODS: Eighty GERD patients with either dysphagia or respiratory
      symptoms were studied by means of a detailed symptom questionnaire, upper
      gastrointestinal endoscopy, esophageal manometry, 24-h esophageal pH monitoring
      and a barium esophagogram. All patients had been receiving medical therapy with
      proton-pump inhibitors and cisapride for 6 months. After withdrawal of medical
      therapy and relapse of GERD, 62 patients decided to undergo anti-reflux surgery
      (laparoscopic Nissen fundoplication in 19 and laparoscopic partial posterior
      fundoplication in 43 patients). Symptoms were assessed prior to treatment, at 6
      months following medical therapy and 6 months after surgery. RESULTS: Heartburn
      and esophagitis were effectively treated by medical and surgical therapy.
      Dysphagia was improved in all patients following surgery but only in 27% of
      patients following medical therapy. Improvement of respiratory symptoms was found
      in 86% of patients following surgery but only in 14% following medical therapy.
      Improvement of regurgitation was registered only following surgical therapy.
      CONCLUSIONS: Since medical treatment is likely to fail in GERD patients with
      complex symptoms such as dysphagia, regurgitation and respiratory symptoms, the
      need for surgery arises in these patients and may be the only successful
      treatment in the long term.

PMID- 10654273
TI  - Hyperthyroidism after surgery for primary hyperparathyroidism.
AB  - BACKGROUND: The coexistence of hyperthyroidism and primary hyperparathyroidism
      (pHPT) has been reported. We have questioned whether hypercalcemia or surgical
      trauma contribute to transient hyperthyroidism following parathyroid surgery.
      METHODS: Twenty-six pHPT and eleven breast cancer patients were compared
      regarding pre-, peri- and postoperative thyrotropin (TSH), free thyroxine (T4)
      and free triiodothyronine (T3) concentrations. Thyroglobulin concentration,
      occurrence of autonomous thyroid nodules, and variables reflecting surgical
      trauma were compared in pHPT patients with and without postoperative
      hyperthyroidism. RESULTS: Postoperatively, eleven pHPT patients demonstrated T4
      and T3 concentrations above normal, and nine developed symptoms of mild
      thyrotoxicosis. A parallel rise in TSH and T4 concentrations was seen during both
      parathyroid and breast cancer surgery. Compared with patients with no
      postoperative hyperthyroidism, patients with postoperative hyperthyroidism showed
      a parallel rise in mean thyroglobulin and T4/T3 concentrations as well as higher
      thyroglobulin concentrations. However, there was no difference in variables
      assessing surgical trauma nor in occurrence of autonomous thyroid nodules. The
      peri-operative rise in TSH was preceded by a decrease in calcium. CONCLUSION:
      Transient hyperthyroidism after parathyroid surgery is not infrequent. The
      condition seems to be self-limiting, since symptoms invariably subsided without
      treatment. Manipulation of the thyroid gland is most likely the major
      contributing factor to postoperative hyperthyroidism. However, it may not be the
      sole explanation, since our data suggest a more multifactorial scenario.

PMID- 10654274
TI  - Management of peritoneal-surface malignancy: the surgeon's role.
AB  - BACKGROUND: Peritoneal surface malignancy can result from seeding of
      gastrointestinal cancer or abdominopelvic sarcoma; it can also occur as a primary
      disease, for example, peritoneal mesothelioma. In the past, this clinical
      situation was treated only with palliative intent. METHODS: An aggressive
      approach to peritoneal surface malignancy involves peritonectomy procedures,
      perioperative intraperitoneal chemotherapy and knowledgeable patient selection.
      The clinical assessments necessary for valid clinical judgements include the
      cancer histopathology (invasive vs expansive progression), the preoperative
      abdominal and pelvic computed tomogram, the peritoneal cancer index and the
      completeness of cytoreduction score. Proper patient selection is mandatory for
      optimizing the results of treatment. RESULTS: In a series of phase-II studies,
      appendiceal tumors with peritoneal seeding was the paradigm for success with a
      75% long-term survival in properly selected patients. Carcinomatosis from colon
      cancer had an overall 5-year survival of 20% but with selected patients this
      reached 50%. Also, sarcomatosis patients overall had only a 10% 5-year survival
      but selected patients had a 75% survival. In all malignancies, early aggressive
      treatment of minimal peritoneal surface dissemination showed the greatest
      benefit. CONCLUSIONS: The surgeon must accept responsibility for knowledgeable
      management of peritoneal surface dissemination of cancer. A curative approach has
      been demonstrated in large phase-II studies. Adjuvant studies with perioperative
      intraperitoneal chemotherapy in diseases where peritoneal surface spread occurs
      are indicated.

PMID- 10654275
TI  - Treatment of acute liver failure: hybrid liver support. A critical overview.
AB  - Hybrid liver support systems, which combine living cells of the liver in an
      extracorporeal circuit, have entered the first clinical trials in patients with
      acute liver failure. The goal of the different developments is to provide within
      a few hours a biological support of the patient's failing liver. Different
      technical solutions can be found to provide a sufficient functional mass of liver
      cells to the patient. Within this article, the biotechnical and clinical
      backgrounds of these developments are discussed, initial clinical results are
      summarized and an evaluation of this method as experimental treatment is given.

PMID- 10654276
TI  - Microcirculatory basis for the design of artificial blood.
AB  - Artificial blood or blood substitutes are being developed using molecular
      solutions of modified free hemoglobin. When these products are used and the red
      blood cell mass is reduced below the transfusion trigger, there is a condition of
      extreme hemodilution which is characterized by a significant reduction of blood
      viscosity and NO production, reflex vasoconstriction, decreased functional
      capillary density, and impaired microvascular function. This combination of
      events may be lethal because decreased NO availability may also increase the
      intrinsic oxygen consumption of the tissue. Current developments in the
      understanding of the physiology of the microcirculation in extreme hemodilution,
      and the physical events associated with the substitution of red blood cells with
      molecular hemoglobin solutions show that a viable "artificial blood" can be
      obtained from a new formulation of the product, where viscosity is such that when
      introduced in the circulation the resulting viscosity of blood is close to
      normal, the dissociation curve is left shifted and the concentration of
      hemoglobin is in the range of 3-5 g Hb/dl. This formulation redistributes viscous
      losses in the circulation causing higher capillary pressure which maintains
      functional capillary density, a key parameter in tissue survival. Furthermore the
      increased plasma viscosity increases shear stress in the microcirculation,
      enhancing the production shear dependent vasodilators, thus counteracting the
      vasoconstrictor effects due to NO scavenging by free hemoglobin solutions. A
      principal feature of this formulation is that it maintains microvascular function
      when the transfusion trigger is passed and the circulation is subjected to
      extreme hemodilution.

PMID- 10654277
TI  - A web-based research tool for functional genomics of the microcirculation: the
      leukocyte adhesion cascade.
AB  - OBJECTIVE: Currently, microvascular data are almost exclusively deposited in
      scholarly journals. With the increasing availability of molecular data and the
      construction of genomic databases, a need arises to organize physiological data
      in a more accessible format. The microcirculation is a functional system that
      spans all organ systems and shares certain characteristics of organization with
      metabolic pathways, which have successfully been organized around genomic
      information for several prokaryotes. Here, we present a web-based research and
      teaching tool (http:@hsc.Virginia.EDU/medicine/basic-sci/biomed/l ey/) that
      covers a small aspect of microcirculatory physiology, the leukocyte adhesion
      cascade. METHODS: Currently, the site is organized in a flat-text mode with
      hypertext links to GenBank, Medline, and online journals where available.
      RESULTS: The web-based research and education tool is useful for graduate student
      education, and as a research resource for genetic researchers interested in gene
      function and for physiologists and biomedical engineers interested in the
      molecular basis of the leukocyte adhesion cascade. Our effort is intended to be a
      beginning toward a distributed database for the microcirculation
      (microcirculation physiome. see http://www.bme.jhu.edu/news/microphys).
      CONCLUSIONS: We invite all microvascular researchers to provide annotations and
      comments to make the research and teaching tool more useful to the scientific
      community.

PMID- 10654278
TI  - T-lymphocytes contribute to hepatic leukostasis and hypoxic stress induced by gut
      ischemia-reperfusion.
AB  - Although neutrophils have been implicated in the hepatic injury elicited by gut
      ischemia/reperfusion (I/R), the contribution of other leukocyte populations to
      this injury process remains unclear. The objective of this study was to determine
      whether lymphocytes contribute to gut I/R-induced microvascular dysfunction and
      inflammatory responses in the liver. Intravital videomicroscopy was used to
      monitor leukocyte recruitment, the number of nonperfused sinusoids and pyridine
      nucleotide (NADH) autofluorescence in livers of wild-type, SCID, and interferon
      gamma (IFN-gamma) knockout mice exposed to 15 min of gut ischemia and 1 h of
      reperfusion. In wild-type mice, gut I/R elicited significant increases in the
      number of stationary leukocytes, nonperfused sinusoids, NADH autofluorescence
      (indicating hypoxia), and elevated plasma alanine aminotransferase (ALT) and TNF
      alpha levels. All of these responses were profoundly attenuated in SCID mice,
      while only some of the responses (in the midzonal region) were blunted in IFN
      gamma knockout mice. Reconstitution (24 h before ischemia) of the circulating
      lymphocyte pool with T-cell enriched splenocytes, but not T cell deficient (from
      nude mice), CD4+ T-cell depleted splenocytes or splenocytes derived from IFN
      gamma knockout mice, allowed the SCID mice to respond to gut I/R in a manner
      similar to wild-type mice. Some of the responses were restored following
      reconstitution with CD8+ T-cell depleted splenocytes. These findings implicate
      CD4+ T-lymphocytes and IFN-gamma in the hepatic microvascular dysfunction and
      inflammatory cell accumulation elicited by gut I/R.

PMID- 10654280
TI  - Quantitative image analysis of F-actin in endothelial cells.
AB  - OBJECTIVE: Filamentous actin (F-actin) plays a central role in maintaining
      endothelial barrier function. Thrombin and histamine, two inflammatory mediators
      that increase endothelial permeability, can alter F-actin production and
      distribution. In this study, we use a newly developed image analysis technique to
      show that these two inflammatory mediators differentially alter F-actin
      structure. METHODS: Human umbilical vein endothelial cells were grown to
      confluence and treated with either histamine (1 microM), thrombin (1 microM) or
      the agonist's vehicle. The endothelium was stained with BODIPY-phallodin, and
      digitized images were taken of the treated cells. The digitized images of
      individual human umbilical vein endothelial cells (HUVEC) were imported into a F
      actin image analysis program (FAAP) and converted to layers, each one pixel
      thick. The program then determined the mean gray level (which corresponded to the
      amount of F-actin) in each layer starting from the outside of the cell (layer 1)
      and progressing in one pixel layer increments towards the center of the cell
      (layer 32). RESULTS: Both inflammatory mediators increased endothelial F-actin
      production, however, the distribution of the actin was different. Thrombin
      increased the presence of stress fibers, while also decreasing peripheral banding
      actin. In contrast, histamine had no effect on peripheral actin compared to
      control, but did increase the presence of F-actin stress fibers. CONCLUSIONS:
      These results establish that thrombin and histamine alter endothelial F-actin
      production in different locations within the cell, which can be quantified using
      an image analysis program.

PMID- 10654279
TI  - In vivo assessment of synovial microcirculation and leukocyte-endothelial cell
      interaction in mouse antigen-induced arthritis.
AB  - OBJECTIVE: The microcirculation and leukocyte-endothelial cell interaction in
      synovial tissue of an inflamed joint are known to play a crucial role in the
      pathogenesis of rheumatoid arthritis. The aim of this study was to characterize
      the in vivo changes in the microvasculature and in leukocyte-endothelial cell
      interactions in the mouse synovial tissue using intravital fluorescence
      microscopy in three stages of antigen-induced arthritis. The expression of E- and
      P-selectin and ICAM-1 were also studied using immunohistochemistry. METHODS:
      Antigen-induced arthritis (AiA) was produced in Balb/c mice. The severity of
      arthritis at three different phases was quantified using a clinical and
      histological score. For the intravital fluorescence microscopy measurements, the
      patella tendon was partially resected for visualization of the intraarticular
      synovial tissue of the knee joint. The number of rolling and adherent leukocytes,
      functional capillary density (FCD) and RBC velocity were quantitatively measured
      in synovial microvessels. Expression of ICAM-1, E- and P-selectin was assessed by
      immunohistochemistry. RESULTS: There was a significant increase in the leukocyte
      rolling fraction in postcapillary venules in the acute phase of AiA (from 0.26 +/
      0.05 in controls to 0.45 +/- 0.04 8 d after AiA induction). The number of
      leukocytes adherent to the endothelium was significantly elevated in all phases
      of arthritis (from 121 +/- 27 in controls to 376 +/- 62 mm2 63 d after AiA
      induction). Functional capillary density was significantly enhanced in the acute
      (332 +/- 15 cm/cm2) and intermediate phases (320 +/- 15 cm/cm2) compared to
      control values (227 +/- 15 cm/cm2). Arthritis resulted in a distinct increase in
      the expression of ICAM-1 on the synovial endothelium in all phases of AiA. E- and
      P-selectin expression were detected only in the acute phase. CONCLUSION: Our
      model provides new insights into the microcirculatory changes which occur in the
      synovial tissue of an arthritic joint.

PMID- 10654281
TI  - Endothelin mediates a component of the enhanced myogenic responsiveness of
      arterioles from hypertensive rats.
AB  - OBJECTIVE: To determine if the enhanced pressure-induced constriction of
      arterioles isolated from hypertensive rats is mediated by the endothelium.
      METHODS: We utilized isolated, cannulated first-order arterioles (80 to 110
      microns, i.d.) from the rat cremaster muscle of spontaneously hypertensive (SHR)
      and normotensive (WKY) rats. Arteriolar diameter was measured in response to
      changes in intraluminal pressures as well as various pharmacological agents in
      the presence and absence of an intact endothelial cell lining. RESULTS: All
      arterioles developed intrinsic tone (approximately 74% of passive). Pressure
      diameter relationships over a pressure range of 30 to 170 cm H2O demonstrated
      that the myogenic response of arterioles derived from both WKY and SHR was not
      dependent upon an intact endothelium. However, at higher pressures (> 170 cm H2O)
      the ability of the denuded arteriole from the SHR to maintain a constricted
      diameter was completely abolished. Treatment of arterioles from the SHR having
      intact endothelium with diclofenac (10(-5) M; 30 min) to inhibit the effect of
      cyclooxygenase had no effect on the high pressure constriction. In contrast,
      application of BQ-123 (10(-7) M; 30 min), an ET-A receptor blocker used to
      inhibit vascular smooth muscle responses to endothelin, completely abolished the
      arteriolar constriction at higher pressures. CONCLUSIONS: Therefore, in the
      hypertensive, arteriolar vasomotor responses to changes in intraluminal pressure
      is due to at least two mechanisms; one that is intrinsic to vascular smooth
      muscle (i.e., myogenic) and a second that involves an endothelial cell release of
      endothelin.

PMID- 10654282
TI  - A new in vivo microvascular preparation of the hamster ovary.
AB  - Ovarian function in the cycling female is intimately related to and dependent
      upon significant microvascular regulation and restructuring. To enable
      investigation of the microvascular determinants of ovarian function, we present
      an in vivo preparation of the golden hamster ovary. The preparation does not
      compromise the ovarian vascular supply. The viability and responsiveness of the
      preparation were confirmed by quantifying arteriolar responses to vasoactive
      agents in 17 hamsters. Small surface arterioles (mean diameter 15-16 microns)
      responded with statistically significant changes in diameter to adenosine and
      oxygen and showed significant, dose-dependent constriction in response to
      norepinephrine and the NO synthase inhibitor L-NAME. Other key findings included
      extremely high microvascular permeability that varied with the day of the estrous
      cycle and functionally significant architectural features of the utero-ovarian
      vascular network. Potential applications of the preparation include elucidation
      of the role of the microvasculature in follicular development and luteal
      regression, investigation of utero-ovarian crossregulation, and development of a
      model for the study of ovarian angiogenesis and vascular regression.

PMID- 10654283
TI  - The Mississippi Stroke Education Consortium: a state-based template to promote
      stroke awareness, prevention and emergency treatment.
AB  - The Mississippi Stroke Education Consortium (MSEC) is a state-based volunteer
      advocacy group founded in 1994 consisting of specific policy-setting
      organizations dedicated to decreasing the impact of stroke on Mississippi's
      inhabitants through a continuous educational process targeting both laypersons
      and healthcare professionals.

PMID- 10654284
TI  - The relationship of migraine and stroke.
AB  - Migraine, a common disorder of uncertain pathogenesis, is linked to ischemia in a
      variety of ways. In some cases the relationship is coincidental. In others,
      migraine may be causally related to stroke, although the mechanism of migrainous
      stroke, if not due to arterial dissection, is unclear. In young women, additional
      risk factors for stroke such as cigarette smoking, use of combined oral
      contraceptives and anticardiolipin antibody immunoreactivity may potentiate
      migraine, especially migraine with aura, as a stroke risk factor. The complexity
      of the relationship is highlighted in certain genetic conditions such as cerebral
      autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy
      and mitochondrial encephalopathy with lactic acidosis and stroke in which
      migraine and stroke are both prominent clinical features.

PMID- 10654285
TI  - Evolution of neuronetworks.
AB  - Since the 1970s, the care of critically ill neurologic and neurosurgical patients
      has emerged as a developing subspecialty. Management of these patients involves
      an enormous amount of data generation and analysis. Review of the history of
      neuroepidemiology and neurocritical care demonstrates the inevitability of their
      present unwiedly burden of information. Compelling advantages of computerization
      in direct patient care include aid in data acquisition, analysis and remote
      access. Infrastructure and resources used to collect data on individual patients
      may be augmented to archive data in clinical databases. Several investigators
      have initiated information management projects including automation of beside
      clinical documentation, development of systems for remote access to information
      and patient registries to study the natural history and outcome of specific
      neurological conditions. These are steps toward the development of integrated
      systems to aid in patient monitoring, data management, continuous quality
      improvement and the generation of hypotheses for further clinical investigation.
      Improvements in information management technology will allow increased efficiency
      in an era where information generation continues to increase exponentially.

PMID- 10654287
TI  - A brief cognitive screening battery for dementia in the community.
AB  - Screening community samples for dementia often necessitates administering a
      cognitive test battery by trained personnel. Because diagnostic examinations are
      expensive, a useful screening battery must be highly specific in addition to
      having high sensitivity. The Monogahela Valley Independent Elders Survey (MoVIES)
      includes a random sample of community-dwelling participants at least 65 years of
      age who were screened using an extensive test battery of cognitive tests that
      required over 30 min to administer. Classification and Regression Trees (CART)
      was used to identify a subset of the battery that could be administered quickly
      and which maintained high levels of sensitivity and specificity for a diagnosis
      of dementia. The Short and Sweet Screening Instrument (SASSI) is a brief battery
      consisting of three standard cognitive tests that can be administered in
      approximately 10 min. Compared to the full battery, it was more sensitive (94%
      vs. 90%) and had comparable specificity (91% vs. 92%) for dementia in this
      sample.

PMID- 10654286
TI  - Clinical correlates of ventricular and sulcal size on cranial magnetic resonance
      imaging of 3,301 elderly people. The Cardiovascular Health Study. Collaborative
      Research Group.
AB  - To identify potential risk factors for and clinical manifestations of ventricular
      and sulcal enlargement on cranial magnetic resonance imaging (MRI), 3,301
      community-dwelling people 65 years or older without a history of stroke or
      transient ischemic attack underwent extensive standardized evaluations and MRI.
      In the multivariate model, increased age and white matter grade on MRI were the
      dominant risk factors for ventricular and sulcal grade. For ventricular grade,
      other than race, for which non-Blacks had higher grades, models for men and women
      shared no other factors. For sulcal grades, models for men and women shared
      variables reflecting cigarette smoking and diabetes. Clinical features were
      correlated more strongly with ventricular than sulcal grade and more strongly for
      women than men. Significant age-adjusted correlations between ventricular grade
      and the Digit-Symbol Substitution Test were found for men and women. Prospective
      studies will be needed to extend findings of this cross-sectional analysis.

PMID- 10654288
TI  - Possible reason for the higher incidence of spontaneous intracerebral hemorrhage
      among Hispanics than non-Hispanic whites in New Mexico.

PMID- 10654289
TI  - The cladribine trial in secondary progressive MS: response.

PMID- 10654290
TI  - Tumour phospholipid metabolism.
AB  - Following the impetus of early clinical and experimental investigations, in vivo
      and in vitro MRS studies of tumours pointed in the eighties to the possible
      significance of signals arising from phospholipid (PL) precursors and catabolites
      as novel biochemical indicators of in vivo tumour progression and response to
      therapy. In the present decade, MRS analyses of individual components
      contributing to the 31P PME (phosphomonoester) and PDE (phosphodiester)
      resonances, as well as to the 1H 'choline peak', have reinforced some of these
      expectations. Moreover, the absolute quantification of these signals provided the
      basis for addressing more specific (although still open) questions on the
      biochemical mechanisms responsible for the formation of intracellular pools of PL
      derivatives in tumours, under different conditions of cell proliferative status
      and/or malignancy level. This article is aimed at providing an overview on: (a)
      quantitative MRS measurements on the contents of phosphocholine (PCho),
      phosphoethanolamine (PEtn) and their glycerol derivatives glycerol 3
      phosphocholine (GPC) and glycerol 3-phosphoethanolamine (GPE)[ in human tumours
      and cells (with particular attention to breast and brain cancer and lymphomas),
      as well as in normal mammalian tissues (including developing organs and rapidly
      proliferating tissues); (b) possible correlations of MRS parameters like
      PEtn/PCho and PCho/GPC ratios with in vitro cell growth status and/or cell
      tumorigenicity; and (c) current and new hypotheses on the role and interplay of
      biosynthetic and catabolic pathways of the choline and ethanolamine cycles in
      modulating the intracellular sizes of PCho and PEtn pools, either in response to
      mitogenic stimuli or in relation to malignant transformation.

PMID- 10654291
TI  - Continuous saturation EPI with diffusion weighting at 3.0 T.
AB  - This paper presents a steady-state method of arterial spin labelling using
      continuous saturation in conjunction with echo-planar imaging (EPI), which has
      been implemented at 3 T. The continuous saturation technique has the advantage of
      having high sensitivity compared to transient labelling techniques, when long
      repetition times are used. It is also easy to implement and requires minimal data
      to be acquired for quantitation. Like other arterial spin labelling techniques,
      continuous saturation is potentially prone to overestimation of perfusion rates
      due to the effect of tagged blood in vessels within the image slice. Using a
      simple model of the vasculature, the degree of diffusion weighting required to
      suppress the arterial signal has been determined, with the results indicating
      that a value of 2 s/mm2 is adequate. Histogram analysis of the experimental data
      has been used to evaluate the effect of diffusion weighting. Using a b-value of 2
      s/mm2, the mean perfusion-related signal change in grey matter on continuous
      saturation was found to be 1.5 +/- 0.2%, yielding a mean perfusion rate of 87 +/-
      9 ml/100 g/min. Brain activation studies using the diffusion weighted continuous
      saturation technique gave a mean increase in perfusion of 36 +/- 12% in activated
      motor cortex.

PMID- 10654292
TI  - Quantitative 13C NMR studies of metabolic compartmentation in the adult mammalian
      brain.
AB  - We review the information obtained by 13C NMR methods on the metabolic
      compartmentation of the adult mammalian brain with emphasis on its quantitative
      aspects. Classical radiotracer evidence and more recent 13C NMR results support
      the presence in the brain of at least two glutamate pools, small and large,
      associated with two kinetically different tricarboxylic acid cycles localized in
      glia and neurons, respectively. Neuronal and glial cycles interact closely,
      utilizing common substrates like glucose and oxygen and exchanging a variety of
      metabolites including glutamate, glutamine and GABA. A model for the cerebral
      metabolism of (1,2-13C2) acetate has made it possible to calculate fluxes through
      both cycles and evaluate the exchanges of glutamate, glutamine and GABA under
      different physiopathological conditions. Calculated flux values through the
      neuronal and glial tricarboxylic acid cycles are 1.0 and 0.4 mumol/min g,
      respectively. In the adult normoxic brain, the small and large glutamate pools
      account for approximately 10% and 90% of cerebral glutamate with estimated
      turnover times of 1.25 and 5.8/min, respectively. Net transfers of neuronal
      glutamate and GABA to the glial compartment are calculated to be 0.1 and 0.04
      mumol/min g while transfer of glial glutamine to the neuronal compartment is
      estimated as 0.1 mumol/min g. Pyruvate recycling in the adult brain occurs mainly
      in the synaptic terminals with a calculated flux of 0.3 mumol/min g. These flux
      values are altered severely in pathological states such as hypothyroidism or
      ischemia.

PMID- 10654293
TI  - In vitro proton and phosphorus NMR spectroscopic analysis of murine (C57Bl/6J)
      brain development.
AB  - We report for the first time in vitro proton and phosphorus NMR spectroscopic
      analyses of murine brain development from fetal to adult stages. Chloroform
      methanol extracts from C57B16/J mouse brain, at ages ranging from 15 days in
      utero (F15) to adult, permitted the simultaneous investigation of both cytosolic
      and membrane phospholipid compartments. The protein content of murine brain was
      determined and used for quantitation of individual metabolite levels. Proton NMR
      spectroscopy revealed that NAA, considered a neuronal marker, is undetectable at
      F15. Glutamate, GABA and creatine, however, are present at this time. All four
      compounds reach maximum levels at 21 days postnatal (P21). Choline and alanine
      levels are at their peak in fetal brain and progressively fall as the brain
      develops. Phosphorus NMR spectroscopy shows that phosphatidylcholine,
      phosphatidylinositol, sphingomyelin, and phosphatidylserine increase steadily
      from F15 to P21.

PMID- 10654294
TI  - Non-invasive observation of acetyl-group buffering by 1H-MR spectroscopy in
      exercising human muscle.
AB  - The observation of a previously unidentified peak in localized 1H magnetic
      resonance (MR) spectra of human muscle during and after a work load is reported.
      Basic NMR properties of this resonance, as well as physiologic circumstances of
      its observation, suggest that it is due to the acetyl group of acetylcarnitine.
      The relatively large pool of muscular carnitine acts as a buffering system
      stabilizing the ratio of acetylated to free coenzyme A. Free carnitine can be
      acetylated to a large extent whenever a mismatch occurs between the fluxes
      through pyruvate dehydrogenase and the TCA cycle. Results of initial applications
      of 1H MR spectroscopy in several muscles and under different exercise regimens
      are in agreement with earlier invasive measurements of acetylcarnitine. It is
      demonstrated that the detailed dynamics of acetyl group formation are now likely
      to be observable non-invasively in humans by localized 1H magnetic resonance
      spectroscopy on standard MR imaging systems, and that acetylcarnitine buffering
      as a function of exercise type, oxygenation states, diet and pathology could thus
      be studied repeatedly and in various muscle groups with much improved temporal
      resolution.

PMID- 10654295
TI  - [Three-dimensional CT diagnosis of cerebrovascular pathology].

PMID- 10654296
TI  - [Spinal lipoma in children: analysis of magnetic resonance image for upward
      displacement of medullary-conus on 44 consecutive surgical cases].
AB  - Medullary conus-untethering operation was conducted on 52 infants with spinal
      lipoma. Magnetic resonance (MR) image was used in order to evaluate the
      untethering results in 44 out of these 52 patients who could be followed-up after
      Osaka Medical Center & Research Institute for Maternal & Child Health was opened.
      Talking into account the changes in vertebral body during the growth period of
      infants, the authors studied the upward displacement of the conus-lipoma
      interface by four fractional MR sagittal image, using the vertebral body
      intervertebral disc space as the baseline. Upward displacement was confirmed in
      27 of 44 (61.4%). The mean, median and trimmed mean of upward displacement were
      1.78 +/- 0.80, 2.0, 1.70 fractions, respectively. Sixteen (59.3%) were caudal
      type, 10 (37.0%) were transitional type and 1 (3.7%) was dorsal type. By type of
      spinal lipoma, upward displacement was observed in 16 of 23 caudal type patients
      (69.6%), 10 of 16 transitional type patients (62.5%) and 1 of 5 dorsal type
      patients (20%). While the rate of upward displacement was almost equal between
      the caudal and transitional type, that of dorsal type was lower. However,
      statistical analysis for the difference in population percentage of the three
      groups showed that significant difference existed only in the caudal type group.

PMID- 10654297
TI  - [Inter-examiner reliability of nerve conduction measurements].
AB  - A total of 122 patients were performed motor and sensory nerve conduction studies
      of the upper limb by two examiners (1. doctor, 2. medical technician) to know the
      inter-examiner reliability of nerve conduction measurements. Subjects contained
      normal individuals and various types of neuropathy patients. Motor nerve
      conduction studies were carried out in the median nerve, and antidromic sensory
      nerve conduction studies were performed in the median and ulnar nerves. F-wave
      latency of the median nerve and sensory conduction velocity between finger and
      wrist of the median and ulnar nerves presented the equal mean value between two
      examiners. A relatively good correlation between two examiners was pointed out in
      the distal motor latency and F-wave latency. Inappropriate measurements were
      caused by the differences in the site of placement of stimulating or recording
      electrodes and effects of submaximum stimuli or stimulus spread to other nerves.
      In sensory nerve conduction studies, especially in the ulnar nerve, careful
      attention should be paid to avoid the influence of motor artifact in giving
      supramaximum stimuli. Amplitude measurements showed larger inter-examiner
      difference than latency or velocity measurements. We reported the present
      condition of measurement reliability. We should do our best to minimize the
      error.

PMID- 10654298
TI  - [Immunohistochemical evaluation of intracranial recurrent meningiomas:
      correlation of topoisomerase II alpha expression and cell proliferative
      potential].
AB  - Most of meningiomas belong to benign tumor. But inspite of Simpson grade I
      surgical resection, it had been reported that a part of these cases recurred
      after initial operation. In discussing tumor recurrence in meningioma, it is
      important to evaluate not only the extent of surgical resection and malignancy
      but also cell proliferative potential, which had been studied
      immunohistochemically by using BudR, PCNA and MIB-1. Recently, it is known that
      topoisomerase (Topo) II alpha expression becomes remarkable in tumorigenesis. The
      correlation with cell proliferative potential has been reported. In this paper we
      evaluated the relationship of cell proliferative potential and tumor recurrence
      immunohistochemically by using Topo II alpha and MIB-1 monoclonal antibody in the
      21 recurrent cases of meningiomas and hemangiopericytomas. As a result, mean Topo
      II alpha staining index (SI) and MIB-1 SI initial surgical resection were 2.29%
      and 3.41%, respectively, at recurrence these SIs had risen at 4.3% and 6.25%,
      respectively. As to the interval from initial surgical resection to recurrence,
      in the cases which recurred under 3 years Topo II alpha SI and MIB-1 SI were
      3.13% and 5.00%, on the other hand, in the cases which recurred later than 3
      years were 1.16% and 1.30%, respectively. Topo II alpha SI and MIB-1 SI 1 of
      former cases were higher than latter cases. Furthermore good correlation between
      the Topo II alpha SI and MIB-1 SI was found. It is concluded that Topo II alpha
      expression was as well available for the marker of cell proliferative potential
      and for one of the predicting factors for tumor recurrence in meningioma and
      hemangiopericytoma as MIB-1 SI.

PMID- 10654299
TI  - [Increased sensory nerve action potential amplitudes after plasma exchanges in a
      patient with acute sensory neuropathy].
AB  - Acute sensory neuropathy (ASN) is characterized by rapidly progressive sensory
      ataxia and areflexia without motor weakness. The disease has been thought to be
      due to dorsal root ganglionitis which leads to secondary sensory nerve axonal
      degeneration. In contrast, we here report a patient with ASN, in whom results of
      nerve conduction study pointed to a direct involvement of the sensory nerve
      axons. A 33-year-old man was admitted to our hospital because of a few days
      history of progressive numbness in his extremities and unsteadiness of gait. The
      results of motor nerve conduction studies were normal. Amplitudes of sensory
      nerve action potentials (SNAPs) decreased within a few days after admission,
      whereas sensory nerve conduction velocities were preserved. Cerebrospinal fluid
      examination showed an elevated protein level without pleocytosis. He was
      diagnosed as having ASN, and was treated with four times of plasma exchange which
      rapidly restored SNAP amplitudes to normal. However, a few days after the plasma
      exchanges, SNAP amplitudes decreased again. Second series of plasma exchanges one
      month after admission transiently increased SNAP amplitudes again but not to
      normal range. These electrophysiologic changes were not associated with clinical
      improvement. A sural nerve biopsy one month after admission revealed axonal
      degeneration. These findings suggest that our patient's sensory impairment is
      caused by reversible sensory axonopathy due to humoral factors that can be
      removed by plasma exchange, as well as acute irreversible ganglionopathy which
      may lead to secondary axonal degeneration as shown by sural nerve biopsy.

PMID- 10654300
TI  - [Rhythmic involuntary movement of the neck in a patient with brainstem
      encephalitis].
AB  - A 36-year-old Japanese woman was admitted to our hospital, because of facial
      palsy, ophthalmoplegia, cerebellar ataxia, and rhythmic myoclonus of the neck.
      About a few weeks before admission, she developed symptoms of common cold and
      general fatigue. Her laboratory data were unremarkable, and her CSF was normal.
      Serum levels of antibodies to gangliosides were within normal limits. Her MRIs of
      the brain and neck were normal. Both somatosensory evoked cortical potential
      study and auditory evoked brainstem response study were normal. She was diagnosed
      as postinfectious brainstem encephalitis, and the administration of
      corticosteroid was started. After the treatment, her symptoms improved. To our
      knowledge, it is rare to see myoclonus to the neck without palatal tremor in
      patients with brainstem encephalitis.

PMID- 10654301
TI  - [The dissecting aortic aneurysm associated with polymyalgia rheumatica: a case
      report].
AB  - We report a patient with a dissecting aortic aneurysm associated with polymyalgia
      rheumatica (PMR). The patient is a 55-year-old Japanese man without a history of
      hypertension, diabetes mellitus and syphilis. He was admitted to an emergency
      hospital because of severe back pain, and was diagnosed as having a dissecting
      aneurysm of the descending aorta. After the admission, he began to notice severe
      muscle pain in his bilateral shoulder. Although his back pain gradually improved,
      his muscle pain progressively worsened, and his lower extremities were also
      involved. Then, he was introduced to our hospital. On neurological examination,
      he was alert and oriented. His cranial nerves were all intact. There was no
      muscle weakness nor sensory disturbance. Laboratory studies revealed that his
      erhythrocyte sedimentation rate was extremely high without elevation of the serum
      level of creatine phoshpokinase, rheumatoid factors and c-reactive protein. He
      was diagnosed as having PMR, and oral administration of prednisolone++ was
      started. Within several days, his muscle pain dramatically disappeared. As is
      known, there is a close relationship between PMR and temporal arteritis of giant
      cell arteritis. In general, PMR is a benign disease and responds well to steroid
      therapy, and prevalence of the giant cell arteritis is low in Japanese people.
      However, it should be kept in mind that the dissecting aneurysm is a relevant,
      severe complication of PMR because arteritis can be latently present in PMR.

PMID- 10654302
TI  - [Acquired pendular nystagmus after pontine hemorrhage].
AB  - A 60-year-old hypertensive woman had a pontine hemorrhage that caused slight
      right hemiplegia, deep sensory disturbance on her right side and dysarthria.
      Three months after the stroke, she was transferred to our hospital for
      rehabilitation. Approximately 6 months later, she gradually began to complain of
      the visual oscillation. Continual, unceasing conjugate vertical/rotatory eye
      movements were observed. Fixation was momentary at best because of an inability
      to dampen the spontaneous eye movements. Electrooculography (EOG) showed
      bilateral vertical/rotatory sinusoidal eye movements of 2.5 Hz frequency and 10-
      to 35-degree amplitude. Both vertical and horizontal optokinetic nystagmus were
      absent. Caloric stimulation did not evoke any responses bilaterally. There were
      no rhythmical movements at similar frequencies in other parts of the body such as
      palatal myoclonus. MRI revealed not only hematoma mainly at the dorsal pontine
      tegmentum but also hypertrophy of the inferior olive nucleus, suggesting
      disruption of the central tegmental tract. Lesions of this tract may be one cause
      of pendular nystagmus. Several drug therapies were investigated for the
      nystagmus. There was no response to baclofen 15 mg. Trihexyphenidyl 4 mg was
      discontinued because of drug-induced hallucinations. Tiapride 600 mg and
      phenobarbital 90 mg were each slightly effective in reducing both frequency and
      amplitude of nystagmus. Treatment with clonazepam 1 mg resulted in the striking
      disappearance of nystagmus. She was aware of this and no longer experienced
      oscillopsia. Despite the visual benefit, however, the patient did not wish to
      continue this drug because of drowsiness and muscle relaxation. The potential
      long-term therapeutic application of clonazepam should be further investigated.
      To our knowledge, there have been no reports of successful treatment in acquired
      pendular nystagmus with clonazepam. Therefore, based on this favorable
      experience, it is suggested that clonazepam should be added to the list of
      potential therapies for pendular nystagmus.

PMID- 10654303
TI  - [Two cases of sporadic juvenile Parkinson's disease caused by homozygous deletion
      of Parkin gene].
AB  - Parkin gene, which is one of the causes of familial Parkinson's disease, was
      cloned in 1998, and it was found that mutations of this gene induces familial
      Parkinson's disease of autosomal recessive form (AR-JP). Clinical studies have
      revealed that almost cases of AR-JP are consanguineous or hereditary. However, AR
      JP may also be caused by marriage between two carriers. We therefore investigated
      the existence of a homozygous deletion in the parkin gene in 10 patients with
      juvenile Parkinson's disease with the onset of age younger than 40 years without
      consanguinity or heredity. A large delection of the gene was found in 2 of the 10
      patients with sporadic Parkinson's disease, and both of these deletion were exon
      4. The present study clearly suggests that juvenile Parkinson's disease in Japan
      may be caused by abnormalities in parkin gene regardless of family history or
      consanguinity.

PMID- 10654304
TI  - [Dural arteriovenous fistula of the transverse sigmoid sinus after transvenous
      embolization of the carotid cavernous fistula].
AB  - We report a case of dural arteriovenous fistula of the transverse-sigmoid sinus
      after transvenous embolization of the carotid cavernous fistula. A 72-year-old
      woman presented with left exophthalmos, chemosis, bruit and left abducens nerve
      palsy in June 1996. Bilateral external and internal carotid angiograms revealed
      the dural arteriovenous fistula of the cavernous sinus. We embolized the dural
      arteriovenous fistula using a transvenous approach via the left inferior petrosal
      sinus. Angiograms demonstrated the complete disappearance of the dural
      arteriovenous fistula. Two years and six months later, she complained of tinnitus
      at the retroauricular region. Left external carotid angiograms showed a dural
      arteriovenous fistula of the transverse-sigmoid sinus fed by occipital, posterior
      auricular, middle meningeal and superficial temporal arteries. We embolized the
      dural arteriovenous fistula using a transarterial approach. Her symptoms
      disappeared but the dural arteriovenous fistula did not disappear completely. We
      discussed the clinical features and etiology of this case.

PMID- 10654305
TI  - [A case of primary brain-stem injury recovered from persistent vegetative state
      after L-dopa administration].
AB  - A 51-year-old male was transferred to our hospital just after traffic accident.
      On admission, the patient was comatose (Glasgow Coma Scale of 6) and showed a
      left hemiparesis with a left oculomotor nerve palsy. Computed tomography
      demonstrated a traumatic subarachnoid hemorrhage without mass lesion. Magnetic
      resonance imaging showed high intensity lesions on the left dorsolateral midbrain
      and the right cerebral peduncle. The distribution of lesions implied diffuse
      axonal injury involving dopaminergic systems such as the substantia nigra and the
      ventral tegmental area. After several months of conservative management, the
      patient showed no recovery and was diagnosed as persistent vegetable state. The
      administration of L-dopa was then started and the patient showed remarkable
      neurological improvement. Therefore the patient's neurological status was thought
      to be modified with primary brain stem injury and accompanying traumatic
      Parkinson's syndrome. It is important to understand "pseudo" persistent
      vegetative state in the management of patients showing prolonged consciousness
      disturbance. L-dopa should be considered as the drugs of pharmacological
      intervention for the patients of masked parkinsonism behind "pseudo" persistent
      vegetative state whose dopaminergic systems might have been damaged.

PMID- 10654306
TI  - [A juvenile case of chronic inflammatory demyelinating polyradiculoneuropathy
      with severe onion bulb-like change mimicking hereditary neuropathy].
AB  - A 15-year-old male developed symmetrical weakness of the limb muscles. He had not
      had any previous developmental disorders except delayed initiation of walking.
      Flexion contraction of ankle joint and pes cavus deformity were seen. The
      cerebrospinal fluid protein concentration was elevated. Nerve conduction study
      showed severe conduction block and temporal dispersion. A sural nerve biopsy
      revealed remarkable onion bulb-like changes and perivascular infiltration of
      inflammatory cells. After high-dose corticosteroid treatment, he showed
      improvement in muscle strength. Although there were no abnormalities of genes
      related to hereditary neuropathy, the atypical findings of severe demyelinating
      changes of peripheral nerves mimicked hereditary neuropathy.

PMID- 10654307
TI  - [A case of sphenoid sinus mucocele associated with progressive optic neuropathy].

PMID- 10654308
TI  - [Primary malignant lymphoma of the brain].

PMID- 10654309
TI  - [A 73-year-old woman with familial Parkinson's disease].
AB  - We report a 73-year-old Japanese woman with familial Parkinson's disease. The
      patient was well until her 67 years of the age, when she noted rest tremor in her
      right hand. Soon after her gait became short stepped. She visited our clinic on
      October 6, 1992 when she was 68 years old. She was alert and well oriented
      without dementia. She showed masked face, small voice, small stepped gait,
      retropulsion, resting tremor in her right hand, rigidity in the neck, and
      bradykinesia. She was treated with 400 mg/day of levodopa-carbidopa, which
      improved her symptoms, however, she developed wearing off phenomenon 3 years
      after the initiation of levodopa treatment. On August 26, 1998, she developed
      abdominal pain, diarrhea, and vomiting. She was admitted to another hospital,
      where abdominal plain x-ray revealed an evidence of intestinal obstruction
      (ileus). She was treated with nasogastric suction and intravenous fluid. Her
      condition did not improve and she was transferred to our hospital on August 29,
      1998. Her family history revealed no consanguineous marriage. She had two elder
      brothers and three elder sisters. One of her brothers had been diagnosed as
      Parkinson's disease. Her husband also suffered from Parkinson's disease, however,
      her parents apparently did not have Parkinson's disease. On admission, she
      appeared to be drowsy. Her blood pressure was 102/70 mmHg, body temperature 36.2
      degrees C. The lungs were clear and no cardiac murmur was present. Abdomen was
      flat and bowel sound was audible. No abnormal mass was palpable. Neurologic
      examination revealed mild consciousness disturbance, masked face, and small
      voice. No motor paralysis was noted. Muscle tone was hypotonic. No abnormal
      involuntary movement was noted. Abnormal laboratory findings on admission were as
      follows; WBC 11,300/microliter, amylase 1,373 IU/l, CK 446 IU/l, BUN 50 mg/dl,
      creatinine 1.17 mg/dl, CRP 22.7 mg/ dl, Na 134 mEq/l, K 3.1 mEq/l, and Cl 81
      mEq/l. A chest x-ray film revealed pneumonic shadows in both lower lung fields.
      She was treated by nasointestinal suction, intravenous fluids, and chemotherapy
      for her infection. Her BP started to drop on September 2 and she developed
      cardiac arrest on the same day. She was discussed in a neurological CPC. The
      chief discussant arrived at the conclusion that the patient had a form of
      autosomal dominant familial Parkinson's disease. As parents did not have
      Parkinson's disease, some of the participants raised the possibility of autosomal
      recessive inheritance. But the age of onset was too late for autosomal recessive
      inheritance. Majority thought that the mode of inheritance was autosomal dominant
      with low penetrance. alpha-Synuclein mutation causes an autosomal dominant
      familial Parkinson's disease, but this type is very rare in non-Greek populations
      and the penetrance is high. Chromosome 2-linked autosomal dominant familial
      Parkinson's disease shows low penetrance. There are many other autosomal dominant
      forms of familial Parkinson's disease linked to yet unknown chromosome loci.
      Majority thought that this patient also had a form of Lewy-body positive
      autosomal dominant familial Parkinson's disease of unknown chromosome locus. Post
      mortem examination revealed ischemic intestinal lesion with strangulation. This
      was thought to be the cause of her death. In the central nervous system, the
      brain appeared to be normal by inspection. In the coronal sections, the
      substantia nigra and the locus coeruleus showed marked depigmentation. Histologic
      examination revealed marked neuronal loss and Lewy body formation in the
      remaining neurons. Pathologic examination was consistent with Parkinson's
      disease. Mutational analysis for the parkin gene was negative.

PMID- 10654310
TI  - Confirmation of G. von Bekesy's theory of paradoxical wave propagation along the
      cochlear partition by means of bone-conducted auditory brainstem responses.
AB  - In order to investigate the propagation time of the traveling wave in the cochlea
      after bone-conduction stimulation of the inner ear, bone-conducted auditory
      brainstem responses (ABRs) were recorded in 6 normally hearing subjects after
      masking the basal cochlear region using high-pass filtered noise. As in air
      conducted ABRs, Jewett V wave latency is delayed corresponding to the propagation
      time of the traveling wave front traversing the desynchronized hair cell region.
      These results support the theory of paradoxical wave propagation proposed by von
      Bekesy in 1952, who postulated that wave motion always starts from the stiffest
      part of the basilar membrane, independent of the location of the vibrating force.
      In addition, we also found a latency delay of the Jewett V wave of bone-conducted
      ABRs in 8 patients with high-frequency hearing loss which corresponded to the
      severity of their hearing impairment.

PMID- 10654311
TI  - Lack of calbindin-D28k does not affect hearing level or survival of hair cells in
      acoustic trauma.
AB  - Calbindin is a cytosolic calcium-binding protein abundant in the hair cells of
      the inner ear and in distinct neurons of the auditory pathway. It is suggested to
      speed the return of potentially toxic calcium levels to normal. In this study, we
      show the basic hearing functions and the result of noise trauma from the
      calbindin null mutant mice generated by gene targeting. Auditory brainstem evoked
      response and distortion product otoacoustic emissions appear similar as in the
      control group. A moderate noise-induced trauma produced a similar loss of hair
      cells in calbindin null mutant mice than in wild-type controls. The result
      suggests that although calbindin is abundant in hair cells, it is not essential
      for the main hearing function and it does not provide physiological protection
      against a moderate noise-induced inner ear trauma in mice.

PMID- 10654312
TI  - Age-related hearing changes and effects of exotoxin on inner ear function in
      aging rat. A frequency-specific auditory brainstem response study.
AB  - Frequency-specific auditory brainstem responses to tone bursts (2-31.5 kHz) and
      tuning curves were recorded in 8 male rats during their entire life. No
      significant threshold elevation occurred during the 1st year. Mean age at onset
      of hearing loss was 20 months, with individual variations ranging from 14 up to
      23 months. In most animals, threshold elevations were limited to 20 and 31.5 kHz.
      At age of 18-23 months, 3 rats were treated with Pseudomonas aeruginosa exotoxin
      A. After instillation, threshold elevation occurred at all frequencies, followed
      by near-total recovery at low frequencies, but only partial reversibility at high
      frequencies. It is concluded that aging-related hearing changes in Sprague-Dawley
      albino rats start at different ages, particularly comprising high frequencies and
      encroaching on the middle and low areas with increasing age.

PMID- 10654313
TI  - Immunohistochemical localization of proliferating cells and epidermal growth
      factor receptors in mouse olfactory epithelium.
AB  - We investigated age-related changes in proliferating cells and epidermal growth
      factor receptors (EGFRs) in mouse olfactory epithelium using an
      immunohistochemical method with the antiproliferating cell nuclear antigen (PCNA)
      antibody and the antihuman EGFRs antibody. Many PCNA-positive cells occurred in
      the surface and basal layers of the olfactory epithelium in the embryonal and
      neonatal mice. However, only some PCNA-positive cells occurred in the basal layer
      of adult mice, and only a few presented in the basal layer of aged mice. EGFRs
      were observed in all layers of the olfactory epithelium at the embryonal and
      neonatal stages, but were not identified in the olfactory epithelium at the adult
      or aged stages. We believe that a decrease in EGFRs in the olfactory epithelium
      induces the inhibition of cell proliferation, with the resultant atrophy of the
      olfactory epithelium.

PMID- 10654314
TI  - Microradiographic study of retrieved craniofacial osseointegrated implants.
AB  - In this study 18 screw-shaped extraoral osseointegrated implants retrieved from
      10 patients were analyzed. The reasons for retrieval were: unexplained pain (n =
      4); inability to cope with the implants (n = 2); fracture of the central screw (n
      = 2); skin penetration problems (n = 1), and trauma (n = 1). Retrieved implants
      were trephined with a border of surrounding bone, fixed, embedded in epon
      plastic, ground and processed for microradiography. The study group comprised 6
      males and 4 females with a mean age of 53.4 (range 9-81) years. All implants were
      clinically stable at the time of removal, and the mean osseointegration time was
      3 (range 1-5) years. Six implants were removed from the temporal bone, 5 from the
      frontal bone, and 7 from the maxilla. By microradiography, it was found that all
      retrieved implants were surrounded by a lamellar type of bone with haversian
      systems, vascular channels, osteocyte lacunae, and in some specimens regeneration
      and resorption areas. Bone metal contact was estimated to vary between 27 and
      83%. Bone metal contact was lower in the frontal bone compared to the temporal
      bone or maxilla, and was further reduced after preoperative irradiation. Longer
      osseointegration time increased bone metal contact, as did increased age up to 60
      years. It is concluded that extraoral osseointegrated implants in humans may
      integrate morphologically as well as clinically. By microradiography it was
      possible to define bone metal contact in the region of implant installation.

PMID- 10654316
TI  - Nasal mucosal swelling and reactivity during a menstrual cycle.
AB  - INTRODUCTION: Nasal stuffiness is a great problem for many women in the later
      part of pregnancy. OBJECTIVE: This study was performed to evaluate whether
      oestrogen causes nasal congestion and/or a hyperreactive reaction of the nasal
      mucosa. MATERIAL AND METHODS: Ten healthy fertile women were examined during
      menstruation. Nasal mucosal congestion was studied with rhinostereometry and
      acoustic rhinometry. The nasal mucosa was challenged with 3 doses of histamine
      solution to study nasal reactivity. Measurements were made 3 times during
      menstruation. To find the exact time of ovulation, when oestrogen reaches its
      peak value, intravaginal ultrasound tests were done and blood samples taken, to
      determine the oestrogen and progesterone levels. RESULTS: The nasal mucosa became
      hyperreactive to histamine in connection with ovulation, when the blood level of
      oestrogen reached its peak. This does not occur during the menstrual or the
      luteal phase. No significant alteration was found in the baseline position during
      the menstruation. CONCLUSION: There is a connection between high oestrogen level
      and nasal mucosal reactivity.

PMID- 10654315
TI  - Intranasal histamine challenge in normal subjects and allergic rhinitis before
      and after intranasal budesonide studied with rhinostereometry and
      micromanipulator-guided laser Doppler flowmetry.
AB  - Ten healthy subjects and 10 patients suffering from allergic rhinitis to birch
      pollen were investigated with the combination of rhinostereometry and laser
      Doppler flowmetry, thus simultaneously measuring changes in mucosal swelling and
      microcirculation, following intranasal histamine challenge. Compared to normals,
      the allergies had a higher degree of congestion and a lower increase in perfusion
      and velocity of flow. In the allergies there was a decrease in CMBC
      (concentration of moving blood cells) that was not seen in normals. The decrease
      in CMBC seen in allergies could be attributed to an increase in vascular
      permeability producing an interstitial edema, a well-known effect of histamine.
      After treatment with 1 week of intranasal steroid, most of the differences in the
      reaction pattern between normals and allergies had disappeared.

PMID- 10654317
TI  - Implications of endoscopic endonasal surgery for the treatment of postoperative
      maxillary mucoceles.
AB  - Recently, endoscopic endonasal surgery has been widely used to treat chronic
      sinusitis with good results being reported by many investigators. Endoscopic
      endonasal surgery is a technique available not only for chronic sinusitis but
      also for other sinus diseases including postoperative maxillary mucoceles. In
      this report, the indications and limitations of endoscopic endonasal surgery for
      the treatment of postoperative maxillary mucoceles are discussed based on our
      experience treating 26 such mucoceles at our clinic. The indications for
      endoscopic endonasal surgery include mucoceles in close contact with the lateral
      wall of the inferior nasal meatus and those mucoceles that can be widely opened
      to the middle nasal meatus. The following cases could not be treated by
      endoscopic endonasal surgery: mucoceles that were localized in areas distant from
      the nasal cavity, mucoceles in which the lateral wall of the inferior nasal
      meatus was bony and intensely thickened, and mucoceles that could not be
      sufficiently opened to the middle nasal meatus.

PMID- 10654318
TI  - Direct carotid cavernous fistula after submucous resection of the nasal septum.
AB  - A carotid cavernous fistula (CCF) is an abnormal arteriovenous anastomosis
      between the carotid artery and the cavernous sinus. Etiologies of this condition
      reported in the literature so far include facial trauma, rupture of an
      intracavernous aneurysm of the carotid artery, Ehler-Danlos syndrome and
      fibromuscular dysplasia of the cerebral arteries. Such fistulae were reported as
      complications of rhinoplasty, transsphenoidal surgery, embolization of cavernous
      sinus meningioma, and rhinocerebral mucormycosis. CCF may also occur
      spontaneously in children or as a congenital malformation. However, to our
      knowledge, submucous resection of the nasal septum has not been reported before
      to cause direct carotid-cavernous fistula. CT and angiographic findings are
      presented and a review of the literature for reported causes of CCF is made as
      well as a brief discussion of the possible pathophysiology.

PMID- 10654319
TI  - Periodic alternating nystagmus and congenital nystagmus: similarities in possibly
      inherited cases.
AB  - In this paper, 2 patients, a daughter with periodic alternating nystagmus and a
      mother with congenital fixation nystagmus, are presented, and the similarities of
      the two disorders are discussed, not only in the eye movements, but also in their
      underlying abnormalities. The literature was reviewed, and the link between
      periodic alternating and congenital fixation nystagmus, which had been suggested
      based on circumstantial evidence, may be confirmed by our cases. The possible
      evidence of inheritance suggests that the two disorders share common
      abnormalities in visual processing.

PMID- 10654320
TI  - ABO-incompatible pediatric kidney transplantation in a single-center trial.
AB  - We have performed ten pediatric kidney transplantations from living-related ABO
      incompatible donors. All patients underwent preoperative plasmapheresis with or
      without immunoadsorption to reduce isoagglutinin. Primary immunosuppression
      consisted of methyl-prednisolone, cyclosporin or tacrolimus, azathioprine, anti
      lymphocyte globulin, and/or deoxyspergualin. At transplantation splenectomy was
      simultaneously performed in all patients. Median follow-up is 65 months (range 4
      95 months). The patient and graft survival rates are 100% to date. Post
      transplantation isoagglutinin titers did not increase more than 1:32, except for
      1 patient, without uncontrollable vascular rejection episodes. Despite the heavy
      immunosuppressive regimen, cytomegalovirus infection occurred in only three
      patients, who were successfully treated with ganciclovir and cytomegalovirus high
      titer gamma globulin. Our small series clearly shows that the preoperative
      reduction of isoagglutinin, splenectomy, and strict immunosuppressive therapy
      lead to successful long-term results in children.

PMID- 10654321
TI  - Renal replacement therapies in pediatric multiorgan dysfunction syndrome.
AB  - Both peritoneal dialysis (PD) and continuous hemodiafiltration (CHDF) techniques
      are used in children who develop acute renal failure as part of multiorgan
      dysfunction syndrome (MODS). An important goal of renal support in MODS is
      treatment and prevention of fluid overload. This report describes an experience
      with PD and CHDF in children with MODS and presents an analysis of fluid balance
      for each modality. Medical records of patients with MODs treated with PD/CHDF
      were reviewed. Fluid balance was studied only in patients with documented fluid
      overload treated with PD/CHDF for more than 24 h. Successful fluid control was
      defined as more fluid output than input over the course of PD/CHDF. CHDF was used
      in 37 patients, median age 47 months (range 0.2-284 months), for a mean of 110 h
      (range 4-733 h). PD was initiated in 25 patients, median age 4 months (range 0.1
      156 months), for a mean of 145 h (range 7-992 h). Successful fluid control was
      achieved in 17 of 26 (65%) CHDF patients and in 5 of 14 (36%) PD patients (P <
      0.01, chi-squared). In conclusion, CHDF is more effective than PD in treating and
      preventing fluid overload in children with MODS.

PMID- 10654322
TI  - Vitamin E alleviates the oxidative stress of erythropoietin in uremic children on
      hemodialysis.
AB  - The efficacy of combined therapy with recombinant human erythropoietin (rhEPO)
      and vitamin E versus rhEPO alone in the treatment of anemia was examined in
      children (n = 10, aged 15.2 +/- 3.2 years) on chronic hemodialysis at the restart
      of rhEPO therapy after a 4-week interval. The results confirmed that rhEPO
      induced oxidative stress of the red blood cells as observed during the first
      rhEPO therapy. Vitamin E (15 mg/kg per day per os) was introduced after 2 weeks
      of rhEPO monotherapy, when the signs of acute oxidative stress appeared. The
      level of oxidized glutathione (GSSG) increased from 8.9 +/- 3.1 to 26.7 +/- 5.7
      nmol/g hemoglobin (Hb) by that time. After 2 weeks of simultaneous vitamin E
      treatment, there was a significant difference in GSSG values compared with rhEPO
      monotherapy (10.1 +/- 3.9 vs. 56.7 +/- 15.8 nmol/g Hb, P < 0.001). A considerable
      decrease was observed in the previously high ratio of GSSG/reduced glutathione
      (GSH), an indicator of oxidative stress, and the level of carboxyhemoglobin,
      indicating hemolysis. A significant increase in Hb and hematocrit (P < 0.01) was
      achieved within 2 weeks of starting the combined therapy, while similar results
      occurred only at the 8th and 5th weeks without vitamin E. Antioxidant vitamin E
      supplementation improved the therapeutic effect of rhEPO in patients with chronic
      renal failure on hemodialysis.

PMID- 10654323
TI  - Concurrent centrifugation plasmapheresis and continuous venovenous
      hemodiafiltration.
AB  - Continuous venovenous hemofiltration/hemodiafiltration (CVVH/D) is commonly used
      to provide renal replacement therapy for critically ill patients who are
      hemodynamically unstable. Occasionally, the addition of plasmapheresis therapy is
      necessary for some conditions, including immune-mediated acute renal failure,
      sepsis, fulminant hepatic failure, and thrombotic thrombocytopenic
      purpura/hemolytic uremic syndrome. Most tertiary care facilities provide
      centrifugation plasmapheresis instead of membrane plasmapheresis, because of the
      requirement for both therapeutic plasma exchange and pheresis of cellular blood
      products. We report a new technique where centrifugation plasmapheresis and CVVHD
      (P-CVVHD) are combined and used concurrently. Blood from the patient was
      concurrently filtered utilizing a Hospal BSM 22 machine with a Multiflow 60
      hemofilter and a Cobe Spectra continuous cell separator in a parallel
      configuration. P-CVVHD is technically possible and can be used for long periods
      of time with limited risks. There may be advantages to P-CVVHD compared with
      discontinuous combined CVVH/D and plasmapheresis therapy.

PMID- 10654324
TI  - Intraperitoneal pressure and hernias in children on peritoneal dialysis.
AB  - Abdominal wall hernias have been increasingly recognized in patients on
      continuous ambulatory peritoneal dialysis (CAPD). They are also more frequent in
      children than in adults. The aim of this study was to determine the influence of
      intraperitoneal pressure (IPP) on the development of hernias in children on CAPD,
      and if there was a difference between IPP in children and adults. We studied 14
      children aged 11.2 +/- 3.2 years, body weight 31.1 +/- 9.4 kg, who had undergone
      CAPD for 16.2 +/- 14.4 months. Also, 10 adults were studied, aged 48 +/- 18
      years, body weight 62.4 +/- 13.9 kg, on the CAPD program for 35 +/- 27 months.
      The IPP was measured via a column of dialysate in the peritoneal dialysis line,
      immediately before the drainage of the peritoneal cavity. The pressure was
      measured with the patients in the supine position, at the level of the umbilical
      cicatrix with the zero point located on the mean axillary line. IPP was measured
      at inspiration and at expiration, and the mean of these two measurements was
      calculated. The children were divided in two groups: group 1 (n = 7) without
      hernias and group 2 (n = 7) with hernias (5 umbilical and 2 inguinal). The IPP of
      all children was 9.5 +/- 2.9 cm H2O. The IPP was 8.1 +/- 2.6 and 10.9 +/- 2.6 cm
      H2O in groups 1 and 2, respectively (P = 0.003). The instilled volume for test
      was similar in both groups. The IPP of the adults was 13.8 +/- 2.8 cm H2O, which
      was significantly greater than that of the children (P = 0.001). In conclusion,
      hernia is a common complication in children on CAPD and its prevalence is
      affected by IPP. Other associated factors may be the presence of anatomically
      weak sites in the abdominal wall of the children, since IPP is lower in children
      than in adults.

PMID- 10654325
TI  - Townes-Brocks syndrome and renal dysplasia: a novel mutation in the SALL1 gene.
AB  - A 14-year-old African-American boy had chronic renal failure and Townes-Brocks
      syndrome (TBS). There were no affected family members. Features were imperforate
      anus, rectoperineal fistula, triphalangeal thumb, bifid thumb, rocker bottom
      feet, bilateral ear tags, satyr ear, sensorineural hearing loss, hypospadias,
      bilateral renal hypoplasia, and progressive chronic renal failure. Renal and
      urological anomalies in TBS include renal hypoplasia, renal dysplasia, unilateral
      renal agenesis, horseshoe kidney, posterior urethral valves, uretero-vesical
      reflux, and meatal stenosis. TBS is caused by a dominantly inherited defect in
      the gene encoding the SALL1 putative transcription factor, a protein possibly
      required for urological, renal, limb, ear, brain, and liver development. This
      patient had a novel mutation in this gene. The extent of renal involvement in
      patients with TBS should be evaluated for optimum treatment and prediction of
      prognosis.

PMID- 10654326
TI  - Thrombocytopenia and absent radii (TAR) syndrome associated with horseshoe
      kidney.
AB  - The TAR syndrome is an inherited disorder characterized by limb abnormalities,
      especially absent radii, and hypomegakaryocytic thrombocytopenia. Previous
      reports have included two infants with genitourinary abnormalities. We report a
      newborn with bilaterally absent radii and foreshortened ulnae, hypoplastic
      humeri, a left clubfoot, a ventricular septum defect, and persistent
      thrombocytopenia. This constellation of abnormalities is consistent with the TAR
      syndrome. In addition, he had a horseshoe kidney with parenchyma of normal
      appearance. This is the first report of horseshoe kidney in association with the
      TAR syndrome.

PMID- 10654327
TI  - Effect of thiazide on established furosemide-induced nephrocalcinosis in the
      young rat.
AB  - A previous study on furosemide-induced nephrocalcinosis (NC) showed only partial
      resolution of the calcifications after discontinuation of the diuretic. We
      investigated whether treatment with chlorothiazide (CTZ) will expedite the
      resolution of established furosemide-induced NC. Seventy-eight weanling male
      Sprague-Dawley rats were divided into eight groups. Three groups were studied for
      1 week: A, control; B, furosemide 40 mg/kg per 24 h; C, CTZ 100 mg/kg per 24 h.
      Five groups were studied for 5 weeks: D, control; E, F, G, furosemide 40 mg/kg
      per 24 h for 1 week followed by 4 weeks of observation (E), CTZ 50 mg/kg per 24 h
      (F), and CTZ 100 mg/kg per 24 h (G) and; and CTZ 100 mg/kg per 24 h (H) for 5
      weeks. At the end of each study period urine and blood were collected, one kidney
      was studied histologically and the contralateral ashed for quantitative calcium
      (Ca) analysis. Animals in group B developed NC with a kidney Ca content of 1,844
      +/- 203 micrograms/g dry tissue compared with group A 248 +/- 86 (P < 0.05) and
      group C 256 +/- 56 (P < 0.05). There were no differences among the three groups
      with regard to creatinine clearance, urine phosphate (P) or Ca excretion,
      although the latter tended to be lower in group C. Animals in group E showed a
      reduction in the magnitude of NC, with kidney Ca of 550 +/- 398 micrograms/g dry
      tissue, which was lower than in group B (P < 0.05) but still higher than in
      groups D (140 +/- 27) (P < 0.05) or H (162 +/- 63) (P < 0.05). Kidney Ca content
      in groups F (497 +/- 142) and G (489 +/- 271 micrograms/g dry tissue) was similar
      to that in group E. There were no differences among the five groups with regard
      to creatinine clearance or urine P excretion. Urine Ca excretion was
      significantly lower in groups F and G than groups D and E. We conclude that once
      established, NC caused by furosemide is not affected by CTZ therapy in spite of
      the anticalciuric property of the latter.

PMID- 10654328
TI  - Distal myopathy in nephropathic cystinosis.
AB  - In long-standing nephropathic cystinosis complications are observed in various
      organs. Distal myopathy was first described in detail in 1994. The prevalence was
      calculated to be 24%. We studied seven patients with nephropathic cystinosis with
      neurophysiological techniques. Only two patients complained of a distal muscle
      weakness but all showed signs of myopathy on electromyography, which was more
      pronounced in the distal muscles. Motor and sensory nerve conduction parameters
      were within normal ranges. One patient with the juvenile form of nephropathic
      cystinosis also had myopathy. We conclude that distal myopathy can be detected in
      nephropathic cystinosis even in the absence of clinically overt muscle weakness.
      Cystine-depleting therapy with cysteamine is recommended for all patients with
      cystinosis, even after renal transplantation, and the effect on the myopathy
      should be studied.

PMID- 10654329
TI  - Cyclic voiding cystourethrography in the diagnosis of occult vesicoureteric
      reflux.
AB  - Cyclic voiding cystourethrography (CVC) enhances the detection of vesicoureteric
      reflux (VUR). We investigated whether more-severe VUR may be overlooked, and
      whether older children are at risk of having their VUR missed with the
      conventional single-cycle study. Three hundred and seventy patients, 168 boys and
      202 girls aged 1 month to 16 years, consecutively admitted over 1 year for
      suspicion of VUR, underwent two complete cycles of filling and voiding CVC. One
      hundred and four subjects, 33 boys and 71 girls, were older than 3 years (mean
      age 5.7 years, range 3.2-16 years). Sixty-six refluxing ureters from 51 patients
      were identified in the first cycle and 61 refluxing ureters from 45 patients were
      identified only with the second cycle. Four instances of grade IV VUR in 4
      patients and three of grade V VUR in 3 patients were overlooked completely in the
      first cycle. Seven episodes of VUR < or = grade III from 5 patients diagnosed in
      the first cycle were upgraded to > or = grade IV at the second cycle. The
      presence of VUR was identified only in the second cycle in 35 of 74 subjects aged
      < or = 3 years and in 10 of 22 aged > 3 years (not significant). Of the 10
      children aged > 3 years, 2, who had diagnosis only at the second cycle, had > or
      = grade IV VUR. More-severe VUR may be overlooked or down-graded in a single
      cycle study. Two-cycle CVC is also useful in children older than 3 years.

PMID- 10654330
TI  - Nocturnal enuresis: correction of renal function by desmopressin and diclofenac.
AB  - Sixty-two children with nocturnal enuresis (43 boys, 19 girls aged 6-15 years)
      were treated with either desmopressin (Adiuretin-SD) (n = 32) or sodium
      diclofenac (n = 30). Desmopressin was effective in 85% of children and diclofenac
      in 33%. In children with primary nocturnal enuresis, the glomerular filtration
      rate was normal, whereas diuresis and solute excretion during the night were
      increased. Compared with healthy children, the nightly excretion of sodium was
      elevated by 43.7% and magnesium by 58.4%. A high correlation was found between
      the free water reabsorption and solute clearance (P < 0.001) in children with
      nocturnal enuresis. Changes in kidney function in nocturnal enuresis appear to be
      due to a decrease in the water and ion reabsorption in the thick ascending limb
      of Henle's loop because of a changed regulation of ion transport in this part of
      the nephron. Administration of desmopressin or a decrease in prostaglandin
      production after diclofenac administration restores the ion and water transport
      in the kidney, which results in the disappearance of nocturnal enuresis. The
      results indicate a role of changes in regulation of ion transport in renal
      tubules in the pathogenesis of one of the forms of primary nocturnal enuresis.

PMID- 10654331
TI  - Suppressed urinary excretion of aquaporin-2 in an infant with primary polydipsia.
AB  - We observed severe overhydration in an 18-month-old Japanese girl with primary
      polydipsia. The secretion of antidiuretic hormone (ADH) was decreased, and
      urinary excretion of aquaporin-2, a vasopressin-sensitive water channel protein,
      was suppressed under basal conditions, but the response of aquaporin-2 to ADH was
      essentially preserved. These findings suggest that the water channel itself was
      intact and that overhydration resulting from polydipsia was responsible for the
      decreased ADH secretion and suppression of the water channel protein.

PMID- 10654332
TI  - Membranous nephropathy and orbital malignant tumor.
AB  - A 7-year-old girl with membranous nephropathy is reported who suffered 16 months
      later from an orbital rhabdomyosarcoma. Proteinuria disappeared at the time of
      the remission of the tumor. Membranous nephropathy as paraneoplastic syndrome is
      exceptional in children, since only two other cases associated with a solid tumor
      have been reported in the literature.

PMID- 10654333
TI  - Hyperparathyroidism during growth hormone treatment: a role for puberty?
AB  - We describe three adolescent patients on chronic hemodialysis with a pubertal
      growth spurt who developed severe hyperparathyroidism during recombinant human
      growth hormone treatment. Parathyroid hormone levels were raised in parallel with
      the increase in linear growth in all patients. In two patients,
      hyperparathyroidism was successfully controlled with an increase in calcitriol
      dosage. In the third patient, growth hormone had to be withdrawn. We discuss the
      possibility that puberty is a risk factor for the development of
      hyperparathyroidism during growth hormone therapy.

PMID- 10654334
TI  - Botryoid Wilms tumor: case report and review of literature.
AB  - A rare case of botryoid Wilms tumor is presented. The main clinical
      manifestations were persistent low-grade fever, malaise, and proteinuria
      associated with microhematuria. Ultrasonography revealed an echogenic mass in the
      right kidney, and a contrast-enhanced mass was found in the dilated collecting
      system by contrast-enhanced computed tomography. The surgically resected tumor
      was a polypoid, light-yellow, glistening mass that occupied a large part of the
      renal pelvis and originated from the pelvicaliceal wall. Part of the tumor
      extended to the proximal ureter, resulting in hydronephrosis in the involved
      kidney. No parenchymal lesion was observed. Microscopic examination revealed
      epithelial, stromal, and blastemal components, which indicated Wilms tumor.
      Infection had occurred in the hydronephrotic kidney, which presumably had caused
      the major presenting symptoms. The prognosis of our patient and previously
      reported cases of botryoid Wilms tumor was good compared with that of typical
      Wilms tumor, since the botryoid type can be detected at an early stage.

PMID- 10654335
TI  - Association of systemic lupus erythematosus and hemolytic uremic syndrome in a
      child.
AB  - We describe a 10-year-old girl with systemic lupus erythematosus (SLE) who first
      presented with hemolytic uremic syndrome (HUS). Diagnoses were based on the
      classic HUS triad, including the observation of fragmented red blood cells, and
      on the American College of Rheumatology criteria for SLE. Plasma exchange may
      have been effective against both HUS and SLE in this patient, as it was
      associated with improvement of platelet counts, renal function, and serological
      findings.

PMID- 10654336
TI  - A practical primary care approach to hematuria in children.
AB  - Although hematuria is a common finding in the unselected population of children,
      the approach to evaluation is quite variable. Changes in the practice of primary
      care medicine in the United States mandate an approach to common office problems
      that is practical and realistic. This review addresses three areas: the current
      approach to evaluation of hematuria in children, a classification of children
      with hematuria into four distinct and easily identified clinical categories, and
      the development of an algorithm for application in the primary care setting. Each
      category is discussed relative to the more-common etiologies of hematuria, with
      recommendations for appropriate evaluation as well as suggestions of an
      appropriate referral to the nephrologist. An algorithm is proposed that provides
      a practical, systematic approach to the problem without the requirement for a
      specific diagnosis in every patient. The proposed classification and approach to
      the evaluation of children with hematuria should help simplify and clarify a
      potentially complex process.

PMID- 10654337
TI  - Enterohemorrhagic Escherichia coli infections: following transmission routes.
AB  - Infections with enterohemorrhagic Escherichia coli (EHEC) are the major cause of
      hemolytic-uremic syndrome (HUS), the most-common cause of acute renal failure in
      childhood. The mortality rate of HUS (0%-5% in most recent series and 10%-30% in
      individual reports) and residual chronic renal sequelae (in up to 50% of patients
      in long-term follow-up studies) emphasize the seriousness of HUS for public
      health. Several studies have described possible sources of EHEC infection.
      However, in the majority of cases the pathogen cannot be identified in food or
      animals and the routes of transmission remain unclear. In this review article the
      hypothesized routes of transmission are summarized. The medical data bases
      "Medline" and "Current contents" were screened for the years January 1966 through
      November 1998. The difficulties in following the chain of EHEC infection are
      discussed. A precise evaluation of the environmental aspects of the patient is a
      precondition for further analysis.

PMID- 10654338
TI  - Intraperitoneal administration of erythropoietin.

PMID- 10654339
TI  - Fetal urine indices as indicators of kidney function.

PMID- 10654340
TI  - The etiology of renal failure in south-east Anatolia.

PMID- 10654341
TI  - Nephrotic syndrome following hepatitis B vaccination.

PMID- 10654342
TI  - A 10-year-old girl was found to have asymptomatic proteinuria upon routine
      urinary screening at school.

PMID- 10654343
TI  - The link between physics and chemistry in track modelling.
AB  - The physical structure of a radiation track provides the initial conditions for
      the modelling of radiation chemistry. These initial conditions are not perfectly
      understood, because there are important gaps between what is provided by a
      typical track structure model and what is required to start the chemical model.
      This paper addresses the links between the physics and chemistry of tracks, with
      the intention of identifying those problems that need to be solved in order to
      obtain an accurate picture of the initial conditions for the purposes of
      modelling chemistry. These problems include the reasons for the increased yield
      of ionisation relative to homolytic bond breaking in comparison with the gas
      phase. A second area of great importance is the physical behaviour of low-energy
      electrons in condensed matter (including thermolisation and solvation). Many of
      these processes are not well understood, but they can have profound effects on
      the transient chemistry in the track. Several phenomena are discussed, including
      the short distance between adjacent energy loss events, the molecular nature of
      the underlying medium, dissociative attachment resonances and the ability of low
      energy electrons to excite optically forbidden molecular states. Each of these
      phenomena has the potential to modify the transient chemistry substantially and
      must therefore be properly characterised before the physical model of the track
      can be considered to be complete.

PMID- 10654344
TI  - Tumor therapy and track structure.
AB  - The elevated relative biological effectiveness (RBE) of heavy ions like carbon is
      the main reason for their use in radiotherapy and is due to the microscopic
      distribution of dose inside each particle track. High local doses produce lesions
      that are expected to have a diminished possibility of repair. Thus, RBE depends
      on track structure and on the biological repair capacity of the tissue that is
      affected by the irradiation. For tumor treatment planning with heavy ions, the
      beam quality and the tissue sensitivity have to be taken into account. Using the
      dependence of radial dose distribution on particle energy and atomic number on
      the physical side and x-ray dose response for the repair capacity on the
      biological side, the response to particle irradiation can be calculated in the
      local effect model (LEM) and used for treatment planning. This article traces the
      route from electron emission as the basis of track structure to the RBE
      calculation and the application in treatment planning.

PMID- 10654345
TI  - Interaction of photons with molecules--cross-sections for photoabsorption,
      photoionization, and photodissociation.
AB  - A survey is given of recent progress in measurements of photoabsorption,
      photoionization, and photodissociation cross-sections of molecules in the
      wavelength range of photons in the vacuum ultraviolet (VUV), where the optical
      oscillator-strengths of most molecules are predominantly distributed. Some
      remarks are presented on molecules in the condensed phase. Particular emphasis is
      placed on the current understanding of spectroscopy and dissociation dynamics of
      molecules in the superexcited states which are produced through the interaction
      of photons in this wavelength range. In the VUV range, most of the observed super
      excited states are assigned to high-Rydberg states which are vibrationally
      (and/or rotationally), doubly, or inner-core excited, and converge to each of the
      ion states.

PMID- 10654346
TI  - The track structures of ionizing particles and their application to radiation
      biophysics. II. Results for various organisms irradiated with protons, deuterons
      and alpha-particles.
AB  - Using knowledge of the track structure generated by ionizing particles together
      with details of the organisms being irradiated, the application of a new
      analytical method to two biophysical models to explain the inactivation of cells
      by radiation has been developed. It is shown that both models are equally
      successful in predicting experimental results and that good agreement is found
      with the data for single-strand phage, Bacillus subtilis spores, various strains
      of Escherichia coli, haploid and diploid yeast, and human diploid fibroblasts.
      The only significant discrepancy arose with T1-phage, for which a tentative
      explanation is offered. The differences in inherent radiosensitivity between
      organisms, after allowance is made for differences in target size, are attributed
      to differences in enzymatic repair systems and in the packing of the DNA.

PMID- 10654347
TI  - Effect of lithium on thyroidal 131iodine uptake, its clearance, and circulating
      levels of triiodothyronine and thyroxine in lead-treated rats.
AB  - The influence of lead acetate (50 mg per kg body weight) on the 131iodine (131I)
      biokinetics (uptake and retention) in rat thyroid and serum levels of
      triiodothyronine (T3) as well as thyroxine (T4) was evaluated as a function of
      time and in combination with lithium treatment. The 2-h and 24-h uptake of 131I
      in the thyroid was stimulated significantly by lead treatment. The 24-h uptake
      showed a maximum stimulation after 4 months of lead treatment. Lithium
      supplementation, however, showed the opposite effect by reducing the iodine
      uptake whereby the maximum decrease was noticed after 2 months of treatment.
      Further, simultaneous lead and lithium treatment resulted in an even more
      pronounced increase of 2-h 131I uptake with a maximum after 3 months. However,
      the 24-h uptake after 3 months and 4 months of treatment did not differ
      significantly from the lead treated reference groups. The thyroidal biological
      half-life of 131I (Tbiol) was found to have clearly increased following the
      lead/lithium treatment. Interestingly, the combined lead/lithium treatment
      applied for 4 months caused a further growth of Tbiol, thus reflecting an
      increased retention of 131I. A maximum increase of Tbiol was seen after 2 months
      of combined treatment. A progressive decline of the circulating T3 and T4 levels
      following lead or lithium treatment was noticed and was more pronounced after
      combined treatment.

PMID- 10654348
TI  - Relative risks of radiation-associated cancer: comparison of second cancer in
      therapeutically irradiated populations with the Japanese atomic bomb survivors.
AB  - In this paper the radiation-associated relative risks of second primary cancer
      incidence in groups treated for first primary cancer by radiotherapy are compared
      with radiation-associated relative risk estimates in the Japanese atomic bomb
      survivor cancer incidence data. For four cancer sites, namely lung cancer, bone
      cancer, ovarian cancer and leukaemia, the relative risks in the comparable (age
      at exposure, time since exposure, sex matched) subsets of the Japanese data are
      significantly greater than those in the majority of second cancer studies. Even
      when the differences between the relative risks in the Japanese atomic bomb
      survivors and the medical series do not approach conventional levels of
      statistical significance, relative risks tend to be higher in the Japanese data
      than in the second cancer studies. At least for leukaemia, the discrepancy
      between the Japanese and second cancer risks can be largely explained by cell
      sterilisation effects. There are few indications of modification of radiation
      associated second cancer relative risk among those treated with adjuvant
      chemotherapy, nor are there strong indications of modification of radiation
      associated relative risk by heritable genetic factors. If anything, there is
      evidence that second cancer relative excess risks are lower among those patients
      with cancer-prone disorders than among non-susceptible patients. However, the
      higher underlying cancer risk in some of these medically exposed populations
      should also be considered, in particular for those with cancer-prone conditions,
      so that the absolute excess risk is sometimes higher than in the Japanese data.

PMID- 10654349
TI  - Does transforming growth factor beta 1 play a role in the pathogenesis of chronic
      allograft rejection?
AB  - To investigate the potential role of Transforming Growth Factor beta 1 (TGF beta
      1) in the pathogenesis of chronic allograft rejection, we studied TGF beta 1
      expression in a rat aortic allograft model. mRNA and protein expression of total
      and endogenously active TGF beta 1 were analysed in infra-renal orthotopic aortic
      syngeneic and allogeneic grafts and matched with the histological appearances of
      the grafts, 2, 4 and 12 weeks post-transplantation. Serum levels of TGF beta 1
      were also measured. The level of TGF beta 1 m RNA and protein expression appeared
      highest 2 and 4 weeks following transplantation in both syngeneic and allogeneic
      grafts, with significantly elevated levels of mRNA expression in the 2 week
      allograft specimens. These time-points correlate histologically with maximal
      inflammatory cell infiltration of the grafts. By 12 weeks post-transplantation,
      TGF beta 1 mRNA expression is reduced in allogeneic grafts compared to syngeneic
      grafts. However, detectable levels of total and endogenously active TGF beta 1
      protein levels in the allografts exceed those measured in the syngeneic grafts at
      this time point. These results demonstrate the complex expression pattern of this
      growth factor during the progression of chronic rejection and suggest an
      aetiological link between TGF beta 1 and the process of accelerated graft
      atherosclerosis.

PMID- 10654350
TI  - The effects of FK409 on pulmonary ischemia-reperfusion injury in dogs.
AB  - FK409 is the first spontaneous nitric oxide (NO) donor known to increase plasma
      cyclic guanosine 3',5'monophosphate levels. In this study, we evaluated the
      effect of FK409 on pulmonary ischemia-reperfusion injury in an in situ warm
      ischemia canine model. Fourteen dogs were divided into two groups, and the FK409
      treated group was given 5 micrograms/kg per min FK409. Warm ischemia was induced
      for 3 h. The arterial partial pressure of oxygen (PaO2), arterial oxygen
      saturation (SaO2), cardiac output (CO), left pulmonary vascular resistance (L
      PVR), and endothelin-I (ET-I) were measured. A histologic study was performed,
      and polymorphonuclear neutrophils (PMNs) were also counted. The PaO2, SaO2, and L
      PVR levels and PMNs after 30 min of reperfusion, ET-I after 2 h of reperfusion,
      and the 7-day survival rate were significantly (P < 0.05) better in the FK409
      treated group than in the control group. The histologic damage was reduced in the
      FK409-treated group compared to the control group. FK409 appears to have a
      protective effect in ischemia-reperfusion injury of the lung.

PMID- 10654351
TI  - Effects of portal vein clamping time on rat liver microcirculation following
      extended cold preservation and transplantation.
AB  - Orthotopic rat liver transplantation (ORLT) following extended cold preservation
      in University of Wisconsin (UW) solution has been shown to induce alterations of
      the hepatic microcirculation, mainly characterized by areas of no-reflow. The
      present study was performed to determine whether these alterations were related
      to the portal vein clamping time (PVCT), shown to be the main determinant of
      survival after ORLT. The hepatic microcirculation was evaluated using the
      multiple-indicator dilution curve (MIDC) technique after ORLT following 24-hour
      cold ischemia in UW solution. Two groups of rats were studied: one with PVCTs of
      less than 14 min (survival conditions) and one with PVCTs of more than 18 min
      (nonsurvival conditions). Four hours after ORLT, only long PVCTs were associated
      with small, but significant, nonperfused areas, about 10% of the liver not being
      perfused by water; however, in both survival and nonsurvival conditions, the
      sinusoidal sieving function was well-maintained in perfused areas. In addition,
      liver viability parameters and hepatocyte function were similarly and minimally
      altered. The hepatic microcirculation is minimally altered 4 h after ORLT
      following extended cold preservation in UW solution, whatever the survival
      condition. Although only found after long PVCTs, the low magnitude of areas of no
      reflow should not be associated with lethal injury of the transplanted liver, a
      finding further supporting the concept that survival after ORLT following 24-hour
      cold preservation in UW solution is mainly influenced by extrahepatic factors.

PMID- 10654352
TI  - Deoxyspergualin delays xenograft rejection in the guinea pig-to-C6-deficient rat
      heart transplantation model.
AB  - This study aimed to investigate the effects of 15-deoxyspergualin (DSG),
      tacrolimus (FK 506) and cyclosporin A (CyA), alone or in combination, on delayed
      xenograft rejection (DXR). We used the guinea-pig-to-C6-deficient (C6-)-PVG-rat
      heart transplantation model, since in this strain combination, hyperacute
      rejection is avoided. In C6- control rats, the guinea pig xenografts survived for
      39.2 +/- 6.3 h (mean +/- SD). Splenectomy alone resulted in a xenograft survival
      of 71.8 +/- 7.8 h, but the addition of CyA or FK 506 did not further improve
      graft survival (73.6 +/- 3.0 h and 72.0 +/- 17.6 h, respectively). In contrast,
      DSG treatment increased graft survival to a mean of 99.8 +/- 9.2 h. When CyA or
      FK 506 was combined with DSG, no additional effects were observed (105 +/- 24.3 h
      and 95.1 +/- 5.6 h, respectively). DSG alone or in combination with FK 506 or CyA
      resulted in a significant reduction in the serum IgM levels and reduced the
      deposits of IgM and IgG in rejected grafts. However, all xenografts were still
      heavily infiltrated by ED1 + macrophages, regardless of the treatment used. Thus,
      DSG treatment resulted in moderate prolongation of xenograft survival in C6-
      rats. The effect seems to be related to suppression of xenoreactive antibody
      production. To prolong xenograft survival further, strategies that inhibit
      macrophage infiltration seem required.

PMID- 10654353
TI  - The clinical significance of conversion of complement-dependent cytotoxic T cell
      crossmatch test after renal transplantation.
AB  - The purpose of this study was to investigate the clinical relevance of conversion
      of post-transplant T cell crossmatch between kidney donor and recipient. This
      study comprises 892 cadaveric renal transplantations performed on 874 adult
      patients between August 1991 and December 1997. Recipient selection was based on
      a negative complement-dependent cytotoxic T cell crossmatch test with current (<
      or = 2 months old) serum. For this study, on day 0 and day 14 after
      transplantation, serum samples were collected for later crossmatching. On day 14
      after transplantation, the crossmatch had converted to positive in 76
      transplantations (8.5%). Acute rejection occurred in 50% of the converters and
      22% of the non-converters (P < 0.005), and graft survival was significantly
      poorer (P < 0.025), being 85 vs 94% at 1 and 68 vs 83% at 5 years, respectively.
      In patients with delayed graft function, 1-year graft survival was 77% in the
      converters and 91% in the non-converters (P < 0.05). Conversion of T cell
      crossmatch, especially in connection with delayed graft function, identifies a
      subgroup of patients at high risk of severe rejection and poor graft survival.

PMID- 10654354
TI  - Measurement of blood serum cyclosporine levels using capillary "fingerstick"
      sampling: a validation study.
AB  - Capillary blood sampling as a means of monitoring blood cyclosporine levels has
      replaced venipuncture in some medical centers. As the validity of capillary
      venipuncture for analysis of cyclosporine has not been documented, we sought to
      validate the capillary blood collection technique by comparing it with serum
      samples collected simultaneously by venous phlebotomy. Forty paired capillary-
      and venous samples were collected from 36 cardiac transplantation patients and
      analyzed, using a polyclonal immunoassay. The values obtained were compared using
      regression correlation. The correlation coefficient for all 40 samples was 0.859.
      However, we discovered that the first 7 capillary specimens were processed
      incorrectly. The correlation coefficient for the other 33 samples was 0.995 (99%
      confidence interval 0.987-0.998). The excellent correlation between serum samples
      obtained from capillary sampling and from venous sampling, together with the ease
      of obtaining capillary blood specimens, make "fingerstick" sampling the method of
      choice for monitoring cyclosporine levels in infants and children.

PMID- 10654355
TI  - Auxiliary liver transplantation: how to improve regeneration of the native liver
      by surgery.
AB  - The technical factors which could influence regeneration of the native liver (NL)
      in auxiliary liver transplantation (ALT) for fulminant hepatic failure (FHF) are
      not well known. We studied NL regeneration according to the location of graft
      anastomosis in the recipient's portal system (superior mesenteric vein versus
      portal vein), and graft weight (50% reduced-size versus full-size graft) in a rat
      model of ALT with 80% reduction of the NL, and graft arterialization. NL
      regeneration was significantly more obvious when the graft was anastomosed on the
      recipient's superior mesenteric vein, thus establishing venous flow to the NL
      from the pancreas, the spleen, and the stomach, and when a full-size graft was
      used. The influence of portal venous flow on NL regeneration, assessed by 3H[
      thymidine incorporation, was measurable as early as day 2. Both technical
      variables in combination resulted in significantly greater regeneration (ratio
      weight of NL/body weight at day 30: 2.32 +/- 0.68% versus 1.21 +/- 0.63%
      respectively, P = 0.02). Early preservation of portal flow to the NL is advisable
      to maximize NL regeneration in ALT. In any case, this regeneration is not impeded
      by the use of large auxiliary grafts.

PMID- 10654356
TI  - Development of bronchiolitis obliterans syndrome despite blood chimerism in human
      lung transplant recipients.
AB  - Bronchiolitis Obliterans Syndrome (BOS) remains the overwhelming obstacle to the
      success of lung transplantations (LTx). The presence of donor-specific
      microchimerism (DSM) and its association with lung allograft function is not well
      defined. To investigate the relationship between chimerism and BOS, blood was
      obtained from 21 LTx recipients. Genomic DNA was isolated from patient blood, and
      PCR-based techniques were used to identify recipient and donor HLA-DR. Fifty
      percent of the LTx recipients with BOS exhibited DSM at "T1" time post
      transplant, and 40% at one year follow-up (T2). However, 54% exhibited DSM in the
      BOS-free group at T1, and 44% at T2. Of the BOS-free, DSM-positive patients at
      T1, 29% developed BOS by T2. In contrast, 50% of BOS-free DSM-negative patients
      50% developed BOS (P > 0.05). Double LTx had a higher prevalence of DSM (73%) and
      a lower prevalence of BOS (46%) than single LTx (50% and 80% respectively, P >
      0.05). One-HLA-DR-antigen-matched LTx recipients show a low prevalence of DSM
      compared to non-matched (P < 0.05). This study demonstrates that the development
      of BOS in LTx recipients could also occur in the presence of blood chimerism.

PMID- 10654357
TI  - Eurotransplant randomized multicenter kidney graft preservation study comparing
      HTK with UW and Euro-Collins.
AB  - The aim was to evaluate the effect of HTK compared to UW and Euro-Collins (EC) on
      the initial graft function and long term graft survival in two prospective
      randomized studies. Only kidneys from heart-beating, kidney-only or kidney +
      heart donors were eligible for entry. Initial non-function (INF) was defined as
      the absence of life-sustaining renal function, requiring dialysis treatment on
      two or more occasions, during the first week after transplantation. To evaluate
      the contribution of the preservation solutions on INF in relation to other
      factors, a multivariate, 2-step logistic regression model was used. Randomization
      was performed between July 1990 and September 1992. The UW-HTK study comprised
      342 donors and 611 transplants (UW: 168 donors and 297 transplants, HTK: 174
      donors and 314 transplants). In the EC-HTK study 317 donors and 569 transplants
      were included (EC: 155 donors and 277 transplants, HTK: 162 donors and 292
      transplants). INF occurred in 33% of either HTK-(n = 105) or UW-(n = 99)
      preserved kidneys (P = NS), and in 29% of the HTK-(n = 85) and in 43% of the EC
      (n = 119) preserved kidneys (P = 0.001). Multivariate analysis showed no
      significant influence of the preservation solution on the incidence of INF in the
      UW-HTK study, but factors contributing to INF were donor age, cause of death,
      retransplantation, and cold ischemic period. The EC-HTK study showed a
      significantly higher risk of INF, using EC as preservation, in addition to cold
      ischemic period and donor quality. The 3-year graft survival of HTK-preserved
      kidneys was 73%, compared to 68% for UW-preserved kidneys in the UW-HTK study (P
      = NS); while the 3-year graft survival of HTK preserved kidneys was 70% compared
      to 67% for EC-preserved kidneys in the EC-HTK study (P = NS). We can conclude
      that HTK is comparable to UW in its preservative abilities, using kidneys from
      heart-beating kidney-only donors, whereas EC as renal preservation solution
      should be avoided.

PMID- 10654358
TI  - Tauroursodeoxycholate ameliorates reperfusion injury after pig liver
      transplantation.
AB  - Reperfusion injury is a serious problem after clinical liver transplantation,
      often leading to dys- or even non-function of grafts. The present study was
      designed to determine whether the hydrophilic bile salt tauroursodeoxycholate
      (TUDC), known to be hepatoprotective in cholestatic liver disease, mitigates
      reperfusion injury in an in vivo pig liver transplantation model. Liver
      transplantation was performed in 12 pigs after a preservation time of 8 h. TUDC
      was administered to donor and recipient animals, and saline to controls. Blood
      was drawn at different time points for determination of liver enzymes. Bile
      samples were collected, and bile flow (BF), and bile salt secretion rate (BSSR)
      determined. Samples of liver tissue and bile ducts were taken for assessment by
      light and electron microscopy. Liver enzymes were significantly lower in the TUDC
      group. BF and BSSR were significantly higher. Microscopy revealed better
      preservation of bile duct architecture of the TUDC-infused animals. We can
      conclude that infusions of TUDC in pig livers ameliorate reperfusion injury in
      vivo. The molecular basis for this finding may be the membrane stabilizing effect
      of TUDC. Further studies are warranted to clarify its effect.

PMID- 10654359
TI  - Oral absorption of tacrolimus in children with intestinal failure due to short or
      absent small bowel.
AB  - We describe two children with intestinal failure due to short or absent small
      bowel who underwent isolated liver transplantation for liver disease related to
      parenteral nutrition. Both received reduced-size liver grafts whilst awaiting a
      suitable small bowel donor. Immunosuppressive therapy was based on oral
      tacrolimus and intravenous steroids. Therapeutic levels of tacrolimus were
      achieved at low dosage of 0.14-0.28 mg/kg per day. Median and mean blood
      tacrolimus levels were 9.9 and 13.7 ng/ml (range 4.9-42.3 ng/ml) in case 1 and
      5.8 and 7.2 ng/ml (range 1-30 ng/ml) in case 2 before small bowel
      transplantation, respectively. Following small bowel transplantation, levels were
      17.1 and 20.1 ng/ml (range 9.2-30 ng/ml), with oral doses of 0.54-1.35 mg/kg per
      day. Both children died of adenovirus pneumonia, with functioning grafts. Our
      experience demonstrates that effective levels of immunosuppression can be
      achieved by oral administration of tacrolimus in children with short or absent
      small bowel.

PMID- 10654360
TI  - Dual renal transplant from a non-heart beating donor.
AB  - In September 1998, a 48 year old male underwent bilateral renal transplantation
      from a 51 year old non-heart beating donor (NHBD) with ischemic heart disease.
      The grafts exhibited delayed graft function, otherwise short term results have
      been good, with a three month serum creatinine of 80 mumol/l, three month GFR of
      79 ml/min per 1.73 m2 BSA, and no episodes of acute rejection. We advocate dual
      transplantation when sub-optimal NHBD kidneys are otherwise in danger of being
      discarded.

PMID- 10654361
TI  - PCR confirmation of microchimerism and diagnosis of graft versus host disease
      after liver transplantation.

PMID- 10654362
TI  - Current scientific understanding of urinary tract infections in women: an
      overview.

PMID- 10654363
TI  - The bowel microflora: an important source of urinary tract pathogens.
AB  - The large bowel is home to a complex microbial community that is present
      throughout the life of the human host. Relatively few microbial species detected
      in faeces in relatively low numbers have been implicated as major aetiological
      agents of urinary tract infections. The impact of these few species on human
      health is considerable, especially when recurrent urinary tract infections are
      considered, and ways must be found to reduce their pathogenic activities. One
      approach may be to learn about the ecology of the bowel ecosystem and devise ways
      by which the numbers of enterobacteria, in particular, can be restricted. This,
      in turn, would decrease the dose of potential urinary tract pathogens present in
      the faeces.

PMID- 10654364
TI  - The development of bacterial biofilms on indwelling urethral catheters.
AB  - The biofilm mode of growth has been implicated in the majority of human bacterial
      infections. In the urinary tract, notable biofilm-associated infections include
      prostatitis, chronic cystitis, struvite urolithiasis, and catheter-associated
      infections. Biofilms protect the causative organisms from host defences and
      antimicrobial therapy. Biofilm formation has traditionally been considered to
      result from adhesion and capsule formation by adherent microorganisms. Recent
      work has shown that a large number of genes are activated during this process,
      some of which have been associated with twitching motility, quorum sensing, and
      slow growth. In this paper, we review some of the recent work on biofilm biology
      and highlight its role in urinary tract infections, particularly those associated
      with urinary catheters.

PMID- 10654365
TI  - The urinary tract response to entry of pathogens.
AB  - The urinary tract response to the entry of pathogens is complex and involves
      multiple aspects of the immune system. Herein we have divided them into cytokine,
      immunoglobulin, and cellular responses. Our current understanding suggests that
      interleukin 6 (IL-6) and IL-8 are the major contributors to the cytokine
      response. Both IL-6 and IL-8 are produced locally and systemically as part of the
      initiation of an inflammatory reaction. The cellular response becomes clinically
      apparent by the appearance of polymorphonuclear neutrophils (PMNs) in the urine.
      The contribution of gamma delta T-lymphocytes is beginning to be appreciated due
      to the use of gene-knockout mice in studies of urinary tract infection (UTI). B
      lymphocytes are important because antibody response to UTI is important. In
      addition to the classic systemic antibody response, a local antibody response
      dominated by secretory immunoglobulin A (sIgA) has been shown to play a major
      role in the host response to UTI. Efforts to create a vaccine against UTI have
      focused on stimulation and intensification of this local sIgA production.
      Investigation continues to define the role of these responses, explain how they
      interact, and elucidate other aspects of the immune response to UTI that are yet
      unknown. Ultimately, this work aims to provide more effective treatment and
      prevention of UTI in those susceptible to invasions of the urinary tract by
      pathogens. Comprehension of how these responses interact may lead to a better
      understanding of UTI susceptibility and promote new and innovative types of
      treatment.

PMID- 10654366
TI  - Potential preventive strategies and therapies in urinary tract infection.
AB  - There are perhaps five strategies either presently advocated or under
      investigation for prevention of recurrent urinary tract infection (UTI):
      antibiotics, including natural peptides; functional foods; vaccines; probiotics;
      and miscellaneous, including avoidance of spermicides and maintenance of good
      hygiene. It is not possible to state the proportion of patients using antibiotics
      versus foods such as cranberry or using alternative approaches such as avoidance
      of spermicides. The majority of women who are referred to specialists will be
      prescribed long-term, low-dose antibiotics. However, given the magnitude of the
      problem, it is safe to state that large numbers of women are at least
      experimenting with alternative remedies such as drinking of cranberry juice or
      ingestion of herbal remedies with a view to enhancing their immune response.
      Vaccine development remains a long way from human use and has yet to be developed
      for organisms other than Escherichia coli. The use of probiotics of restore the
      normal vaginal flora and provide a competitive bacterial barrier to pathogens is
      close to becoming available as an alternative preventive approach. The next
      decade should see the introduction of new methods for reduction of the high
      incidence of UTI and better management of recurring urogenital infections.

PMID- 10654367
TI  - Urinary tract infection: a moving target.
AB  - Urinary tract infection is an old problem that continues to present new
      challenges. The purpose of this special edition is to pull together new basic
      scientific information regarding the pathogenesis of infection and to review the
      state of the art in the evaluation and treatment of urinary tract infection in
      some of the more complex or challenging clinical settings. The goal has been more
      than a summarization of current knowledge; the intent has been to highlight areas
      of uncertainty, thereby emphasizing the need for further investigation. Herein we
      briefly mention four clinical settings for urinary tract infection that, in our
      opinion, present important new or evolving challenges and are particularly
      fertile areas for further work.

PMID- 10654368
TI  - Treatment of urinary tract infection: what's old, what's new, and what works.

PMID- 10654369
TI  - Controversies in childhood urinary tract infections.
AB  - Management of childhood urinary tract infections is conceptually straightforward,
      but controversies persist. Specimens must be collected carefully or culture
      results can be difficult to interpret. Urine culture remains the diagnostic
      standard but does not substitute for careful urinalysis. Radiography studies are
      designed to define abnormalities predisposing patients to pyelonephritis and to
      assess the extent of renal involvement during infection, but there is no
      agreement on the most appropriate combination of studies. Circumcision reduces
      the incidence of urinary infections in male infants. Vaginal reflux may have an
      impact on recurrent infections, especially after courses of antibiotics. The
      importance of vesicoureteral reflux remains controversial because renal scarring
      appears to be related more to infection than to reflux itself. A strong argument
      can be made for the avoidance of prophylactic antibiotic therapy, even in
      patients with reflux. Increased attention to early diagnosis and treatment may be
      responsible for a decreasing incidence in renal failure from reflux nephropathy
      in children.

PMID- 10654370
TI  - Issues in urinary tract infections in the elderly.

PMID- 10654371
TI  - Issues surrounding the prevention and management of device-related infections.
AB  - The use of biomaterial devices in all aspects of modern medicine has increased
      exponentially in the past three decades. Device-related infections constitute one
      of the main impediments to their long-term use. We discuss the pathogenesis,
      prevention, and management of catheter-associated urinary tract infection
      (CAUTI). The recent innovations in biomaterial design and surface coatings
      intended to prevent colonization of the device surface are presented. Despite
      these significant advances, the ability to protect these surfaces beyond the
      short term presents a continued challenge to investigators.

PMID- 10654372
TI  - Fungal infections of the urinary tract.
AB  - Funguria, fungal urinary tract infections, are most commonly caused by Candida
      species but may also be caused by Cryptococcus neoformans, Aspergillus species,
      and the endemic mycoses. Candiduria presents as an increasingly common nosocomial
      infection, which may involve all anatomic levels of the urinary tract, resulting
      in a spectrum of disease varying from asymptomatic candiduria to clinical sepsis.
      Although several successful systemic or local therapeutic options exist for the
      eradication of candiduria, knowledge of the pathogenesis and natural history of
      candiduria has lagged. This has resulted in confusion among practitioners as to
      when antifungal therapy is indicated. Treatment guidelines have recently been
      formulated and are described herein.

PMID- 10654374
TI  - Goethe almost died of urosepsis.
AB  - In the year of 1805, Goethe almost died of urosepsis. His urological problems
      were not diseases arising from full health but a new variation in a life
      accompanied by illnesses. Some sources date the first colics he experienced to
      the year 1795 and others say 1805. The most dramatic period in the course of his
      illness was in February, when he suffered from fever of such an extent that one
      could speak of urosepsis. Recovery took place slowly and was accompanied by minor
      relapses. Nothing about this is written down in his work. On the advice of his
      doctors, Goethe undertook a cure in Lauchstadt in July and August. The report of
      his consultant, Professor Johann Christian Reil, on his problems in the field of
      urology remained undiscovered until 1937. Professor Reil recommended treatment
      with thermae carolinae, aqua calcis, soap soda crystallisata, herbae
      subastringentes, and uva ursi, among other measures. With increasing age,
      Goethe's colics disappeared. The passing of a stone has never been described.
      Whereas Goethe hinted about medical problem other than those reported herein, the
      urological problems discussed in this article were left unmentioned. Nonetheless,
      literature that deals with Goethe's diseases is interesting from the aspect of
      both the history of medicine and the history of culture.

PMID- 10654373
TI  - Pathogenesis and management of recurrent urinary tract infections in women.

PMID- 10654375
TI  - The biological aging is our inescapable fate--but can we modify it?
AB  - The quest for postponing ageing has been in the mind of man since the earliest
      civilisations and the ancient symbols (healing water, herbs, sleep and the snake)
      are also found in the attempts undertaken today. Maximum life span, however, has
      not changed much due to these efforts. The rate of increase has been estimated to
      be about 10 year per million years. Mean life span has, on the other hand,
      increased dramatically, due to major environmental improvements, from about 30 to
      80 years. Much of this increase is due to decrease in childhood and early
      adulthood mortality and has occurred during the last 130 years. Whether and to
      what extent this increase will continue is not clear. The complexity of the human
      genome is discussed together with current knowledge of gene technology and
      ethical problems in this context. Life extension in primitive animals with much
      simpler genomes, and inheritable diseases with premature ageing in man are used
      as examples for how new knowledge can be gained in this field. Transgenic animals
      and knockout mice are used as examples for progress in gene technology. It is
      emphasised that at present the best possibilities to ameliorate the effects of
      the ageing processes are having a healthy lifestyle, which includes a balanced
      diet, avoiding being overweight, drinking some red wine and doing a moderate
      amount of physical exercise.

PMID- 10654376
TI  - Ageing in Europe--challenges and consequences.
AB  - This article outlines the five key social and economic policy challenges
      presented by the ageing population of the European Union (EU). These challenges
      are the maintenance of economic security in old age, preserving intergenerational
      solidarity, combating the social exclusion created by age discrimination,
      providing long-term care in the context of changes in family and residence
      patterns, and enabling older people to participate in society as full citizens.
      The nature of each of these challenges is discussed and priorities pinpointed.
      The discussion of policy challenges is preceded by an outline of the demographic
      context of the EU: the combination of declining fertility and increasing
      longevity. This also includes a discussion of the links between demography and
      policy. The conclusion of the article considers the current threat to the
      European model of social policy and suggests ways in which the gerontological
      community might contribute to its defence.

PMID- 10654377
TI  - Intergenerational family relations and social support.
AB  - A parallel process to the aging of societies in the Western world occurs in
      changing family structures and network compositions. The shape of families is
      shifting from horizontal to vertical, where the size of generations is becoming
      smaller but the number of living generations is increasing. Recently there is an
      increased emphasis in the study of intergenerational relations on the
      interdependence of generations. The "aging of the aged", though, means the need
      for more care and support. It is well documented that there is continued high
      involvement of families in care giving. However, as the age structure of the
      society and the family change so does the availability and ability for care of
      its networks. The presentation will, thus, discuss and analyze the following
      three issues: First, a theoretical perspective on family intergenerational
      relationships will be presented, based on social exchange theory and the
      intergenerational solidarity model. Empirical findings will focus on grandparent
      grandchild relations and on immigrant families, stressing the importance of
      ethnicity. Second, care giving and support to frail elderly family members, in
      different types of living arrangements, will be described and analyzed, as a
      major topic in research and policy. Third, the relations and impact of family
      solidarity, support and care on the quality of life of the older people will be
      discussed.

PMID- 10654378
TI  - Dementia: epidemiology, intervention and concept of care.
AB  - Dementia is going to be one of the major challenges of the next century for our
      societies due to the enormous burden on the health care systems. Dementia is the
      major cause of death and the most important risk factor for disability and entry
      into a nursing home in elderly people. Moreover, because of the progress in the
      treatment of Alzheimer's disease, in particular with the cholinesterase
      inhibitors, demented people will be more often and detected earlier by general
      practitioners and families. Thus, dementia will become progressively more a
      public problem than a private one. This tendency could be increased by the
      unemployment problem among young adults which obliges their parents to support
      them, neglecting then their own parents' problems. A possible way to win this
      challenge is prevention. Intervention on several risk factors of dementia in the
      elderly is possible. The Syst-Eur trial demonstrated recently that treatment of
      systolic high blood pressure could decrease the risk of dementia by 50%. Other
      vascular risk factors, depression, aluminium in drinking water, and active life
      are other good candidates for preventive intervention. Finally, secondary
      prevention by treatment among people with mild cognitive impairment will be
      another interesting way of delaying the onset of the disease and decrease it's
      prevalence.

PMID- 10654379
TI  - Ageing and the cardiovascular system.
AB  - Heart disease is the most common cause of death in elderly people. Cardiovascular
      aging is a continuous and irreversible process. It has a decline rate that varies
      among individuals and can be modulated by three conceptually different
      influences, namely, physiological changes due to the passage of time, adaptive
      sequeles of previous diseases or surgery in younger life, and influence of the
      individual lifestyle or their own cardiovascular risk factors. The main practical
      consequences of aging processes are a progressive change in the morphological,
      functional, and semiological characteristics of the cardiovascular system and an
      increase in the number of age-related cardiovascular disorders. The main
      morphological cardiovascular changes with aging happen in the structure of
      cardiac tissue and chambers, in the conduction system, and in the coronary
      arteries. But the cardiac function at rest in healthy elderly persons is adequate
      to meet the body's need. A normal or almost normal cardiac output in the elderly
      is to be maintained by increasing the stroke volume and the ejection fraction due
      to an augmented cardiac filling (preload). Atypical clinical pictures are very
      common in elderly patients with cardiovascular disease. For example, non-cardiac
      symptoms are the often presenting features. Concerning the treatment of
      cardiovascular diseases in the elderly, the clinician needs to consider age
      related factors as multimorbidity and disabilities, the possible side effects
      and/or interactions due to pharmacodynamic or/and pharmacocinetic changes. And he
      has to take into account the social and financial situation of his patient.

PMID- 10654380
TI  - Occurrence of chronic diseases and their impact on physical disability over the
      whole spectrum of aging: from 65 to over 100 years of age.
AB  - The aging of the Italian population is an emerging public health priority. In
      2025 Italy is expected to have the highest world median age with nearly half of
      the population over 50 years old. To avoid an unbearable burden of disease and
      disability on future generations, we must identify areas for intensive disease
      and disability prevention programs. Preliminary results from the PRO.V.A study
      show that disability is associated with conditions that are potentially
      preventable as chronic diseases and falls or are treatable as chronic pains.
      Moreover, it is of extreme interest to identify and understand biological and
      environmental secrets of successful aging as the AKEA study tries to do and the
      ways of overcoming disabilities in the extreme limits of life more and more
      possible to reach.

PMID- 10654381
TI  - Sarcopenia, hypermetabolism, and aging.
AB  - Sarcopenia is a constant in aging. Observed over long periods, it can reach 1%
      per year. But it is such a tenuous phenomenon that it cannot be observed over
      short periods at steady state. The aging phenomenon mainly hits fibers, Type II
      but on aged muscle thin, normal, and hypertrophic fibers cohabit with sclerosis
      and fat increases. Sarcopenia is difficult to study, due to the lack of simple
      clinical, biochemical, or imaging measures. Anthropometric data are largely
      dependent on water content. DEXA gives better information on appendicular muscle
      loss. Measures of strength analyze functional outcomes of sarcopenia. Sarcopenia
      appears largely multifactorial. Hormonal changes, e.g., drop in growth hormone,
      menopause, and andropause, explain impaired protein synthesis. Disuse (sedentary,
      bed rest) may explain chronical protein lysis. But the main factors for muscle
      lysis imply life events and occurring diseases. Cytokines (IL6, TNF alpha) and
      stress hormones (cortisol) induce quick protein lysis in muscle. Rapid and
      intensive successive aggressions during life cannot be compensated by slowed
      synthesis. Harmful consequences of sarcopenia explain many disabilities of old
      age: loss of strength, inducing itself loss of mobility, falls, equilibrium
      disorders, poor ADL: loss of nutritional reserves (protein and glycogen)
      impairing capacities of immune response. Muscle loss spoils vital functions as
      respiration. Treatment remains rather limited to resistance exercise. Although,
      these results are thin, they are the only ones to be validated in all the elderly
      even the frail or the old. However it is not efficient during the evolution of an
      inflammatory process. The powerful action of cytokine and cortisol on muscular
      hypermetabolism must be incited for early treatment of any infectious or
      inflammatory event. Nutritional supplementation has no efficiency in the absence
      of malnutrition and without exercise. Although mobility impairments mainly due to
      sarcopenia are the first cause of disablement in the elderly, we lack information
      on etiology, evolution, and measurement of sarcopenia. We also lack controlled
      therapeutical studies.

PMID- 10654382
TI  - [Age and aging as incomplete architecture of human ontogenesis].
AB  - The focus is on the basic biological-genetic and social-cultural architecture of
      human development across the life span. The starting point is the frame provided
      by past evolutionary forces. A first conclusion is that for modern times and the
      relative brevity of the time windows involved in modernity, further change in
      human functioning is primarily dependent on the evolution of new cultural forms
      of knowledge rather than evolution-based changes in the human genome. A second
      conclusion concerns the general architecture of the life course. Three governing
      lifespan developmental principles coexist. First, because long-term evolutionary
      selection evince a negative age correlation, genome-based plasticity and
      biological potential decrease with age. Second, for growth aspects of human
      development to extend further into the life span, culture-based resources are
      required at ever increasing levels. Third, because of age-related losses in
      biological plasticity and negative effects associated with some principles of
      learning (e.g., negative transfer), the efficiency of culture is reduced as
      lifespan development unfolds. Joint application of these principles suggests that
      the lifespan architecture becomes more and more incomplete with age. Three
      examples are given to illustrate the implications of the lifespan architecture
      outlined. The first is a general theory of development involving the
      orchestration of three component processes and their age-related dynamics:
      Selection, optimization, and compensation. The second example is theory and
      research on lifespan intelligence that distinguishes between the biology-based
      mechanics and culture-based pragmatics of intelligence and specifies distinct age
      gradients for the two categories of intellectual functioning. The third example
      considers the goal of evolving a positive biological and cultural scenario for
      the last phase of life (fourth age). Because of the general lifespan architecture
      outlined, this objective becomes increasingly difficult to achieve. In fact, for
      other reasons (such as the obsolescence created by rapid technological change)
      the 21st century can be considered as the century of the permanently incomplete
      mind. The advent of intervention genetics creates a new scenario with promise and
      despair. Promise because of the possibility to complete the biological-genetic
      architecture of the life course through a priori and a posteriori genetic
      engineering, despair because of a new schism created by the risk of dissociation
      of the time course of genetic intervention and cultural evolution. For the first
      time in history, humankind is truly in charge of it's biocultural "natural"
      destiny.

PMID- 10654383
TI  - [Violence against the aged within the family: results of studies by the "Bonner
      HsM (treating vs. mistreating) Study].
AB  - Central aspects of intra-familiar violence and of their causes are discussed. The
      first results of the study "Handeln statt Misshandeln" (HSM, Action against
      Violence) are presented. Data were collected in Bonn, Germany, by the means of a
      postal questionnaire. Approximately 10 percent of old people reported experiences
      of violence in their families during the past five years. Most often mental
      violence and financial deceit were mentioned. Experiences of violence mainly
      caused psychological and emotional problems. If at all, victims searched for
      support in their immediate social network. Persons who were married or of bad
      physical health had often experiences of violence. Significant difference between
      victims and non-victims were detected for experiences of violence, the victims'
      subjective well-being, the quality of the families' external relations and the
      victims' socio-economic status.

PMID- 10654384
TI  - [Tasks, burdens and borderline situations in old age. General discussion].
AB  - In this four-part review article, an update covering the geropsychological
      research since 1988 in German speaking countries is given as follows: Cognitive
      development in old age (part I), personality development in old age (part II),
      social relations in old age (part III), age-related tasks, burdens, and border
      situations (part IV). In part IV of the update presented in this issue, research
      contributing to a competence perspective of old age and aging is summarized under
      four main headings: (1) Independence, everyday life, and everyday competence; (2)
      aging in spatial, physical, and technical environments; (3) health and coping
      with illness; (4) coping with death and dying. The article ends with a general
      discussion considering as well the findings of our survey addressing
      gerontologists from German speaking countries.

PMID- 10654385
TI  - [Letter to the editor on the editorial: "Social work with the aged--Balance,
      crisis and prospectives" by T. Kllie and R. Schmidt: Gerontologie und Geriatrie,
      31:301-303 (1998)].

PMID- 10654386
TI  - [Letter to the editor on the article "The Minimal Geriatric Data Set of BAG of
      the Clinical-Geriatric Establishment as instrument of Stationary Geriatrics" by
      M. Bochert et al. Gerontologie Geriatrie 32;11-23].

PMID- 10654387
TI  - [Transvenous closure of atrial septal defects--experimental therapy or
      established treatment method].

PMID- 10654388
TI  - [T-wave alternans in microwave frequency as a new indicator of disordered
      ventricular repolarization: pathophysiology, methodology, clinical results].
AB  - Primary prevention of sudden cardiac death is hampered by the inability to
      accurately identify high risk patients. Various noninvasive methods such as
      determination of left ventricular function or heart rate variability as well as
      invasive electrophysiologic testing are currently used for risk stratification.
      Noninvasive measurement of microvolt T wave alternans (TWA) is a promising new
      method to assess repolarization abnormalities; in experimental studies, TWA was
      associated with an increased incidence of ventricular tachyarrhythmias. Since the
      occurrence of TWA is heart rate-dependent, it is measured either during atrial
      pacing or during exercise stress testing. The first clinical validation of the
      method was performed in patients undergoing invasive EP testing to assess
      prediction of inducibility of ventricular tachyarrhythmias. A first prospective
      validation of the noninvasive method was performed in patients surviving out-of
      hospital cardiac arrest fitted with an ICD. Further studies have shown a good
      concordance between invasive and noninvasive TWA determination. The occurrence of
      TWA in this population was of predictive value with respect to arrhythmia
      recurrence. Recently published data confirm the value of TWA assessment with
      respect to identification of patients with congestive heart failure at high risk
      of malignant ventricular tachyarrhythmias. The use of this method in post
      myocardial infarction risk stratification is currently under prospective
      evaluation.

PMID- 10654389
TI  - [Left ventricular remodeling: pathophysiological mechanisms and therapeutic
      recommendations].
AB  - Hospital mortality from acute myocardial infarction has decreased in the last two
      decades. Left ventricular dysfunction therefore have been mainly due to ischemia.
      After extensive myocardial infarction, there are processes of adaptation
      (remodeling) which result in altered geometry of the left ventricle. The effects
      of this on neurohormonal systems (organ regulation), on the changed ratio of
      myocyte mass and collagen content owing to reactive and reparative fibrosis
      (organ texture) and on the molecular and cellular mechanisms (organ structure)
      are of crucial importance. Depending on the structural changes, the myocardial
      contractility decreases. This is associated with an activation of the circulating
      renin-angiotensin-aldosterone system (RAAS). The fundamental knowledge available
      has led to the therapeutic use of ACE inhibitors in the post-infarct period. This
      treatment enabled a sustained reduction of mortality in several large-scale
      randomized studies. The effect of early administration in patients with clinical
      signs of heart failure and/or left ventricular dysfunction was very much greater
      compared to unselected controls. Only 17 and 13 patients had to be treated after
      selection in order to save one life in the AIRE and TREACE Study respectively
      (NNT: number needed to treat), whereas e.g. in the ISIS-4 study 200 unselected
      patients had to be treated. In clinical practice, however, this life-saving
      therapy is only used in every second patient requiring treatment. With
      consideration of an individual form of treatment (anterior infarction, large
      infarct area, reinfarction, clinical signs of heart failure as well as arterial
      hypertension and diabetes mellitus), a greater acceptance of evidence-based
      guidelines is thus desirable. Treatment with a high dose may be expected to be of
      additional benefit.

PMID- 10654390
TI  - [Costs of coronary heart diseases over the remaining life time in coronary heart
      disease cases--an analysis of the current status of coronary heart disease cases
      in Germany from the social perspective].
AB  - Cardiovascular diseases are the major cause of death not only in Germany.
      Coronary heart diseases result in substantial disability and loss of productivity
      and contribute to escalating costs of health care. OBJECTIVE: It was our
      objective to estimate the costs of CHD for the German population from the
      perspective of the society. The characteristic of this approach is the
      calculating of costs until the approximated end of life. METHODS: In the study,
      all health care costs concerning CHD in Germany were allocated to age, sex,
      health care sector and primary diagnosis on the basis of comprehensive data on
      morbidity, mortality, direct and indirect costs. For the estimate of indirect
      costs the human capital approach was taken. Considered as cases were all patients
      hospitalized in the reference year (1996). The costs of this cohort in 1996 and
      up to their protected end of life were estimated. It was taken into account that,
      in comparison to the general population, life expectancy of cases with risk
      factors or CHD would have been reduced. In calculating indirect costs, gender and
      age specific unemployment rates were considered. All future costs were discounted
      by 4% from the reference year onward. RESULTS: Direct costs are approximately 39
      billion DM discounted at 4%, indirect costs total 73 billion DM. The average cost
      per case (including morbidity and mortality) until the approximated end of life
      is nearly 125,000 DM. CONCLUSION: In our cost analysis, the indirect costs are
      higher than the direct costs. For the future, it will be important to estimate
      the costs of prevalent cases until the end of life and to compare the influence
      of different interventions on these parameters and on the whole budget of the
      social security system.

PMID- 10654391
TI  - [Value and safety of ambulatory electrophysiologic study].
AB  - One-hundred-thirty patients underwent 53 electrophysiological studies including
      programmed atrial and ventricular stimulation and 96 atrial overdrive
      stimulations on an outpatient basis. The indications for electrophysiological
      study were disabling palpitation, syncope, or presyncope, intracardiac conduction
      disturbance, and bradyarrhythmia. In one patient the efficacy of oral
      antiarrhythmic drug therapy was evaluated by repeat electrophysiological study.
      Atrial overdrive stimulation was performed in patients with atrial flutter or
      atrial tachycardia. On the basis of the result of electrophysiological testing,
      25 patients were believed not to require any treatment, 16 patients received new
      drug therapy, 7 patients underwent catheter ablation in a second session, 2
      patients had either a pacemaker or an ICD implanted, and 1 patient continued to
      receive the drug therapy that had been tested. Atrial overdrive stimulation
      resulted in a regular sinus rhythm in 66 patients (69%). Except for one patient
      in whom atrial flutter could not be terminated, atrial fibrillation was induced
      in the remaining 30 patients. After the procedure, patients were monitored for 30
      min in case of overdrive stimulation, and for approximately 3 h after
      electrophysiological study or 6 h if additional coronary angiography had been
      performed. Severe complications were not observed. In 10 cases minor hematoma
      occurred at the puncture site without serious sequelae.--Outpatient
      electrophysiological study as well as atrial overdrive stimulation are feasible
      and safe in a selected group of patients.

PMID- 10654392
TI  - Radiographic characteristics of Cook detachable and Gianturco coils as well as
      clinical results of transcatheter closure of the patent ductus arteriosus.
AB  - PURPOSE: To describe the radiographic appearance of the Gianturco and the Cook
      detachable coils and present the clinical results in patients who underwent
      transcatheter closure of patent ductus arteriosus. MATERIALS AND METHODS: Between
      January 1994 and June 1997, eighty-two patients underwent closure of patent
      ductus arteriosus (PDA) using either Gianturco or Cook detachable coils. The
      chest x-ray and echocardiography of all patients were reviewed and the following
      parameters were evaluated: 1) the size of the heart (cardiothoracic ratio), 2)
      the position and the type of the coils in the postero-anterior and the lateral
      projection, 3) the number of coils used, 4) the existence of residual ductal
      flow, 5) Doppler velocity in the left pulmonary artery. RESULTS: Complete
      occlusion was achieved in 94%, and cardio-thoracic ratio regressed from 0.57 to
      0.53 (p < 0.01), after a mean follow-up of 1.2 years. The identification of the
      different coils on the chest radiograph was successful in only 47% of cases,
      difficulties arising especially, when multiple coils were used. In 55 patients
      (67%) the coil position was judged to be optimal, in 27 patients (33%)
      suboptimal. The latter correlates with the presence of residual shunt. Multiple
      coils correlated more with a left pulmonary artery flow velocity exceeding 1.5
      m/s. CONCLUSION: Coil-occlusion of patent ductus arteriosus is effective and
      leads to reduced cardio-thoracic ratio. Radiographic coil identification is
      possible but may be difficult if multiple coils are deployed. Suboptimal coil
      position led more often to residual PDA shunt. Multiple coils are more commonly
      associated with increased LPA velocities, but hemodynamic significant obstruction
      to flow is rare.

PMID- 10654393
TI  - [Interventional catheter occlusion of the atrial septal defect of the secundum
      type--experiences with "CardioSeal" and "Angel Wings"].
AB  - Between July 1996 and July 1998, 34 patients (female n = 16, male n = 18) were
      scheduled for catheter--interventional occlusion (ASDO) of an atrium septum
      defect of secundum type (ASD II). Median age was 7.9 years (2.5-54.6), weight
      23.1 kg (9-97). 9 defects were closed with "Angel Wings" (AW) and 25 ASD
      occlusions were attempted with "CardioSeal" (CS). 30 patients had simple ASD II,
      3 persisting foramen ovale with suspected paradoxal cerebral embolization and 1
      significant residual shunt at atrial level after corrective heart surgery for
      interrupted aortic arch type B. ASDO was successful in 31/34 cases (91%). One CS
      was removed surgically due to significant left to right shunt after release and
      two CS devices were withdrawn back into the sheath. Median ASD diameter was 11.9
      mm (6-16), balloon occlusive diameter was 15 mm (6-20) and median left to right
      shunt was 40% (6-64%). On follow up minimal left to right shunt was seen in 5/31
      patients (16%). In selected patients catheter--interventional ASDO may be a good
      alternative to surgical ASD closure.

PMID- 10654394
TI  - [Dissection of the sinus valsalvae aortae as a complication of coronary
      angioplasty].
AB  - The localized dissection of the aortic sinus of valsalvae is a rare complication
      of coronary angioplasty involving mainly the right coronary artery. In all
      previously published case reports (n = 10), a coronary dissection provided the
      entry door with subsequent retrograde progression of the dissection into the
      aortic root. In our case of a 75 year old female patient with symptomatic three
      vessel disease, a chronic occlusion of a proximal RCA could not be passed by a
      coronary guide wire. During the procedure an aneurysm of the aortic sinus
      occurred near the ostium of the RCA. The patient was referred for immediate
      aortocoronary bypass surgery. The inspection of the aortic sinus showed, as the
      entry of the dissection, a small puncture hole, adjacent to the ostium of the
      RCA, probably caused by the stiff 0.014 coronary guide wire, and no retrograde
      dissection of the right coronary artery. The localized dissection could easily be
      fixed by a prolene suture during the bypass surgery procedure with an
      uncomplicated postoperative course. If the entry of the dissection is within the
      coronary artery, forced contrast injections and balloon inflations promote its
      propagation and should be avoided. If the entry could be sealed by an
      intracoronary stent and the aneurysm remained localized, confirmed by
      echocardiographic controls, the aneurysm tends to resolve spontaneously in the
      first month without need for surgery. A progression of the aneurysm into the
      ascending aorta or a failure of an entry sealing with a stent is an indication
      for urgent surgical treatment.

PMID- 10654395
TI  - [Acute pericardial tamponade in cardiac echinococcosis].
AB  - An echinococcal cyst of the heart is a rare cause of acute cardiac tamponade. We
      report on a 24 year old male from the Kosovo who was brought in an emergency
      state from a provincial hospital complaining of severe dyspnea, thoracic pain,
      dizziness, and a short period of unconsciousness. Surgical decompression had to
      be performed urgently, because the pericardium could not be punctuated due to the
      position of the hydatid cyst. The differential diagnosis was cardiac tumor or
      echinococcal cyst. Because of a negative result of a test for anti-echinococcal
      antibodies (indirect haemagglutination) and no eosinophilia (5%), the diagnosis
      of hydatid cyst was at first discarded. Later on, the test for anti-echinococcal
      antibodies became positive and a marked eosinophilia (59%) was manifest. In
      combination with a typical appearance in the echocardiograph and NMR, the
      diagnosis of a cardiac hydatid cyst was made. After preoperative treatment with
      albendazole, the cyst was sterilized with a 20% NaCl solution and the contents
      evacuated. The therapy with albendazole was continued. When last seen eight
      months after the first incidence, the patient was well except some degree of
      dyspnea on exertion. As a differential diagnosis of a cardiac tumor, a hydatid
      cyst should be taken into account in patients from an area where Echinococcus
      granulosus is endemic. A negative test on antiechinococcal antibodies and the
      absence of eosinophilia do not rule out echinococcosis.

PMID- 10654396
TI  - Patterns in metazoan parasite communities of some oyster species.
AB  - Metazoan parasite communities of Crassostrea gigas and Ostrea edulis from Great
      Britain, Crassostrea virginica from Mexico, and Saccostrea commercialis from
      Australia are described and summarized in terms of species composition, species
      richness, total number of individuals and dominance. Metazoan parasite
      communities in all host species were composed of turbellarians and the
      metacercarial stage of digeneans, with the exception of S. commercialis where
      only metacercariae were found. Arthropods, including one copepod and one mite
      species, were present only in British oyster species. All metazoan parasite
      communities of oysters had few species and low density of individuals. Richest
      communities were found in C. virginica at both component and infracommunity
      level. The least diverse component community occurred in S. commercialis.
      Infracommunities in O. edulis and S. commercialis never exceeded one species per
      host. The host response against parasites is suggested as the principal factor
      responsible for depauperate parasite communities of oysters. Environmental
      factors characteristic of tropical latitudes are likely to have enhanced both the
      number of species and the densities of parasites per host in the infracommunities
      of C. virginica.

PMID- 10654397
TI  - Helminth parasites of the wild rabbit Oryctolagus cuniculus near Malham Tarn,
      Yorkshire, UK.
AB  - Between 1992 and 1996, 95 rabbits from the immediate locality of Malham Tarn,
      North Yorkshire, UK were examined for the presence of helminth parasites. All the
      examinations took place in late September or October. Three species of nematodes,
      Graphidium strigosum, Passalurus ambiguus and Trichostrongylus retortaeformis and
      two species of cestodes, Taenia pisiformis and Cittotaenia pectinata were
      identified. There were no associations between helminth species richness and year
      of sampling, host weight or sex. A logistic model was fitted to the prevalence
      data from these helminths as was an over-dispersed Poisson model to the worm
      burden data. Graphidium strigosum was the most frequently identified species with
      an average prevalence of 78%. The mean prevalence and intensity of Graphidium
      infection were significantly effected by sampling year. The lower than normal
      rainfall recorded at the Tarn during the years 1995 and 1996 may have be one
      reason for this pattern. The worm burden of G. strigosum was significantly
      positively associated with rabbit body weight. The intensity of infection with P.
      ambiguus was significantly higher in female rabbits. There was a significant non
      linear relationship between P. ambiguus worm burden and rabbit weight (P = 0.002)
      with worm burdens being highest in the 1000 g to 1499 g weight cohort.
      Trichostrongylus retortaeformis was only identified in 1994 and male rabbits
      harboured significantly higher worm burdens than females (48 vs. 7, P = 0.022).
      Over the five years, the average Taenia pisiformis prevalence was 31% and there
      was a significant positive association between worm burden and rabbit weight (P =
      0.001). Cittotaenia pectinata had a prevalence of 37% over the whole study period
      with no interactions between prevalence or intensity and body weight, year of
      sampling or rabbit sex. All five helminths showed an overdispersed distribution
      with k values less than 1.

PMID- 10654398
TI  - A molecular perspective on the genera Paragonimus Braun, Euparagonimus Chen and
      Pagumogonimus Chen.
AB  - The status of the genera Euparagonimus Chen, 1963 and Pagumogonimus Chen, 1963
      relative to Paragonimus Braun, 1899 was investigated using DNA sequences from the
      mitochondrial cytochrome c oxidase subunit I (CO1) gene (partial) and the nuclear
      ribosomal DNA second internal transcribed spacer (ITS2). In the phylogenetic
      trees constructed, the genus Pagumogonimus is clearly not monophyletic and
      therefore not a natural taxon. Indeed, the type species of Pagumogonimus, P.
      skrjabini from China, is very closely related to Paragonimus miyazakii from
      Japan. The status of Euparagonimus is less obvious. Euparagonimus cenocopiosus
      lies distant from other lungflukes included in the analysis. It can be placed as
      sister to Paragonimus in some analyses and falls within the genus in others. A
      recently published morphological study placed E. cenocopiosus within the genus
      Paragonimus and probably this is where it should remain.

PMID- 10654399
TI  - The effect of excess dietary manganese on uninfected and Ascaridia galli infected
      chicks.
AB  - The effect of dietary manganese from two different sources on chicks (uninfected
      and infected with Ascaridia galli) was studied. Chick diet was supplemented with
      0.9 g Mn2+ kg-1 food either in the form of MnSO4.H2O or 2Gly. MnCl2.2H2O for 20
      days. Chicks were divided into six groups: group 0, control; group 1, control +
      MnSO4.H2O; group 2, control + 2Gly.MnCl2.2H2O; group 3, infected with A. galli;
      group 4, infected with A. galli + MnSO4.H2O; and group 5, infected with A. galli
      + 2Gly.MnCl2.2H2O. Body weight, mortality, worn burden, and liver manganese
      content were investigated. Excess dietary manganese increased weights and
      manganese level, but mortality and worm burden were unaffected. A greater
      bioavailability of manganese from 2Gly.MnCl2.2H2O was established.

PMID- 10654400
TI  - Larval toxocariasis and its clinical manifestation in childhood in the Slovak
      Republic.
AB  - Results are presented of 90 children aged 1-15 years hospitalized with
      toxocariasis. Blood count analysis and laboratory examination were done by
      routine clinical laboratory methods. Anti-Toxocara antibodies were detected in
      the serum of patients using an ELISA method. Demographic analysis of the
      children's families exposed to the risk of disease allowed estimation of age
      specific rates for clinical toxocariasis. The probability of toxocaral infection
      and the intensity of its clinical manifestations in children are determined by
      the epidemiology of this zoonosis and by the risk factors in the family. The
      presence of high titres of specific IgG antibodies in all age categories
      correlates with the clinical manifestations of toxocariasis. The highest
      admission rate is in the age categories of 3-5 years (43.3%) and 6-10 years
      (36.7%). Laboratory findings show that the most conspicuous changes occur in the
      age category 1-5 years. The high percentage of seropositive dog-keeping and puppy
      breeding families and the possibility of infection with repeated doses of larvae
      stimulate eosinophilia, which prevails in children under the age of five years.
      We present the percentage of patients whose parameters showed deviations from the
      reference values for a particular age category. Analyses of laboratory indices
      and of clinical manifestations will contribute to the accuracy of diagnosis and
      effectiveness of treatment of this disease.

PMID- 10654401
TI  - Mating behaviour of Echinostoma trivolvis and E. paraensei in concurrent
      infections in hamsters.
AB  - Young adults of Echinostoma trivolvis and E. paraensei were recovered from
      hamsters previously infected with metacercarial cysts. Some worms of each species
      were exposed for 1 h to 3-H-tyrosine to label sperm and transplanted singly to
      uninfected hamsters with several unlabelled worms of the same or opposite species
      or both species. After 5 days, recovered worms were processed for paraffin
      sectioning and autoradiography. The resulting slides were observed for the
      location of radioactive sperm in the seminal receptacles of donor (labelled) and
      recipient (unlabelled) worms. When E. trivolvis was the donor with the recipient
      E. paraensei, self-insemination took place, but only one interspecies mating
      occurred out of 72 possible recipient worms. When E. paraensei served as the
      donor, self-insemination again occurred, but no cross-insemination was observed
      among the 59 E. trivolvis recipient worms. When single donor worms had a choice
      of either species of recipient worms, no interspecies mating took place, but both
      self- and cross-insemination occurred in the normal, unrestricted behaviour found
      in single species mating studies. Rates of both self- and cross-insemination were
      higher in concurrent infections of both recipient species than in single species
      mating studies. After transplant, both species localized in their natural habitat
      within the small intestine, with 1/3 overlapping in the duodenum, making
      interspecies mating a possibility. The correlation between mating and
      electrophoretic studies on the genetic relationship between 37-collar-spined
      echinostomes is discussed.

PMID- 10654402
TI  - Nematocide activity of 6,7-diarylpteridines in three experimental models.
AB  - The in vitro nematocide activity of seventeen 6,7-diarylpteridines has been
      tested using three different experimental models, Caenorhabditis elegans,
      Nippostrongylus brasiliensis and Heligmosomoides polygyrus. The method of
      evaluation of inhibition in the secretion of acetylcholinesterase by H. polygyrus
      seems to be the most indicated to avoid false positives. The in vivo activities,
      against Trichinella spiralis, of the most in vitro active pteridines have been
      assayed. All pteridine derivatives bearing 6,7-di-p-bromophenyl substituents have
      shown in vitro nematocide activities in the three experimental models used.
      Amongst all the pteridines tested in vivo, only 2,4-pteridinedithione derivatives
      exhibited moderate activity.

PMID- 10654403
TI  - The effect of transportation and confinement stress on egg production by
      Dicrocoelium dendriticum in sheep.
AB  - The effect of transportation and confinement stress on Dicrocoelium dendriticum
      egg production was investigated. Sheep passing a minimum of 200 eggs g-1 of
      faeces were selected from a naturally infected flock. A group of six ewes (group
      A) was transferred to the laboratory premises and kept indoors for 28 days, while
      another group (B) of six ewes remained on pasture and was used as a control.
      Faecal examinations and egg counting were performed weekly, on all sheep, from
      one week before to 28 days after the transportation of the animals. Comparison of
      faecal egg counts between groups revealed higher (P < 0.01) counts in transported
      sheep sampled on days 7, 14 and 28 of the trial. Furthermore, egg counts obtained
      from sheep that were transferred remained consistently high while the ones from
      sheep that remained on pasture showed significant variation. Therefore, it is
      concluded that stress-inducing factors, such as transportation and confinement
      may enhance egg production of D. dendriticum.

PMID- 10654404
TI  - Comparison of adult liver flukes from highland and lowland populations of
      Bolivian and Spanish sheep.
AB  - A morphological study of adult liver flukes and eggs from sheep in a human
      fascioliasis endemic zone in the Northern Bolivian Altiplano showed that they
      belong to the species Fasciola hepatica. An exhaustive morphometric comparison
      with a F. hepatica population from Spanish sheep was made using image analysis
      and an allometric model: (y2m-y2)/y2 = c(y1m-y1)/y1[b, where y1 = body surface or
      body length, y2 = one of the measurements analyzed, y1m, y2m = maximum values
      towards which y1 and y2 respectively tend, and c, b = constants. Only slight
      allometric differences in worms were observed despite the geographic distance
      between both Spanish and Bolivian sheep populations and the very high altitude of
      the Bolivian Altiplano.

PMID- 10654405
TI  - Sexual development of Taenia solium in hamsters from rodent-derived cysticerci.
AB  - In order to determine whether Taenia solium can be maintained in the laboratory
      using rodents as definitive hosts, six nude rats, 20 immunosuppressed Mongolian
      gerbils and 20 immunosuppressed Syrian hamsters were each inoculated through a
      stomach tube with three cysticerci recovered from SCID mice. No adult worms of T.
      solium were found in the intestinal tract of any of these 46 rodents. In
      addition, five immunosuppressed Syrian hamsters were fed with the same number of
      cysticerci enclosed in rodent muscles from SCID mice. Two of these hamsters were
      found to be infected 40 days post-infection, each harbouring a sexually developed
      worm in the intestinal tract. Although no eggs were produced, prepatent
      infections may be possible if a longer time was allowed for worm development.
      Moreover, the maintenance of the life cycle of T. solium in the laboratory using
      the rodent model can be established.

PMID- 10654406
TI  - Mating interactions between Schistosoma haematobium and S. mansoni.
AB  - Schistosoma haematobium and S. mansoni are two medically important schistosomes,
      commonly occurring sympatrically in Africa and so potentially able to infect the
      same human host. Experiments were designed to study the mating behaviour of these
      two species in mixed infections in hamsters. Analysis of the data obtained showed
      that both heterospecific and homospecific pairs readily form. No significant
      difference was seen between the two species in their ability in forming pairs,
      however, S. mansoni showed a greater homospecific mate preference. Analysis of
      the data using the Mantel-Haenszel test suggests that mating competition does
      occur between S. haematobium and S. mansoni, the former being the more dominant
      species. Both species appeared to be able to change mate, with S. haematobium
      showing a greater ability in taking S. mansoni females away from S. mansoni males
      when introduced into a pre-established S. mansoni infection highlighting the
      competitiveness of S. haematobium. The significance of the results is discussed
      in relation to the epidemiological consequences occurring in Senegal, and other
      areas where both species are sympatric.

PMID- 10654407
TI  - A retrospective study of ocular toxocariasis in Japan: correlation with antibody
      prevalence and ophthalmological findings of patients with uveitis.
AB  - To classify the clinical characteristic of ocular toxocariasis in Japan, the
      prevalence of antibodies to Toxocara antigens was examined in patients with
      uveitis of unknown aetiology. From 1982 to 1993, serum specimens of 383 cases and
      intraocular fluid samples of 22 cases were serologically screened for Toxocara
      infection with five immunodiagnostic tests. Fifty-five sera and 11 intravitreous
      fluid samples were estimated to have significantly high antibody levels against
      larval excretory-secretory (ES) antigens of T. canis. Eight cases were positive
      in both serum and vitreous fluid, and three were positive only in the vitreous
      fluid. Among the 58 antibody positive samples, 20 cases were omitted due to a
      lack of detailed description of ocular findings. The remaining 38 cases are
      described in this study. Of these 38 cases, 34 (89%) were older than 20 years of
      age. Ocular lesions were located in the posterior fundus in 11 cases, in the
      peripheral fundus in 18 cases, and in both areas in seven cases. Of the eight
      cases in which papillary oedema or redness was observed, chorioretinal lesions
      were also present in seven of them. Tractional retinal detachment was present in
      five cases. These observations suggest that ocular toxocariasis in Japan has a
      different clinical profile compared with those in the other countries, and
      indicate a need for revised classification of ocular toxocariasis.

PMID- 10654408
TI  - ELISA and immunoblot using purified glycoproteins for serodiagnosis of
      cysticercosis in pigs naturally infected with Taenia solium.
AB  - The establishment of reliable serological methods for cysticercosis in pigs is
      important for the surveillance, control and prevention of taeniosis/cysticercosis
      in humans as well as in pigs to prevent economic loss. Both ELISA and immunoblot
      using glycoproteins (GPs) purified by a single step of preparative iso-electric
      focusing, which are highly useful for human cysticercosis, have been applied for
      a serological study in pigs naturally infected with Taenia solium. All sera from
      pigs showed similar responses to those in human cysticercosis. Therefore, it is
      expected that both ELISA and immunoblots using GPs would be useful in
      differentiating infected pigs from uninfected ones.

PMID- 10654409
TI  - Effects of Echinostoma caproni infections on metallic ions in the intestinal
      mucosa of ICR mice.
AB  - Inductively coupled plasma atomic emission spectrometry (ICP-AES) was used to
      study metallic ions in the intestinal mucosa of ICR mice infected with
      Echinostoma caproni and the mucosa of uninfected control mice. Infected mucosa (n
      = 9 with about 100 mg wet weight per sample) were examined at 2 weeks p.i. in
      mice that were infected with about 25 worms per host. Uninfected mucosa (n = 9
      with about 100 mg wet weight per sample) were examined in the same time frame as
      the infected mucosa. Five metals were measured in the mucosa by ICP-AES analysis,
      as follows: calcium, potassium, magnesium, sodium and zinc. There were no
      significant differences (Student's t-test, P > 0.05) in the concentrations of
      calcium, potassium or zinc in infected versus uninfected mucosa. The
      concentration of sodium was significantly greater (P < 0.05) in the mucosa of
      infected versus uninfected mucosa, but the situation was reversed in regard to
      magnesium.

PMID- 10654410
TI  - Antibacterial and antiandrogen flavonoids from Sophora flavescens.
AB  - Sixteen flavanones, three flavanonols, and four pterocarpans were isolated from
      the MeOH extract of the roots of Sophora flavescens. Twelve of these were new
      compounds, including eight prenylflavanones (1-8), one prenylflavanonol (9) and
      three novel pterocarpane derivatives (10-12). Their structures were elucidated
      using NMR and mass spectral methods. Some of these compounds have irregular C10
      prenyl moieties at C-8 of the flavanone skeleton. These compounds exhibited
      significant antibacterial activities against the Gram-positive bacteria
      Staphylococcus aureus, Bacillus subtilis, S. epidermidis, and Propionibacterium
      acnes. They also exhibited antiandrogen activities.

PMID- 10654411
TI  - New annonaceous acetogenins from Rollinia mucosa.
AB  - Four new compounds, a mixture of 20,23-cis-2,4-trans-bullatalicinone (1) and
      20,23-cis-2,4-cis-bullatalicinone (2), rollimusin (3), and rolliacocin (4), along
      with eight known acetogenins, were isolated from an ethyl acetate extract of the
      unripe fruits of Rollinia mucosa. The structures and stereochemistry of 1-4 were
      determined on the basis of spectral data and chemical evidence.

PMID- 10654413
TI  - New triterpenoid saponins and sapogenins from Saponaria officinalis.
AB  - Five new triterpenoid saponins, named saponariosides I-M, were isolated from the
      whole plants of Saponario officinalis. Their structures were established as
      saponarioside I (1) 3-O-beta-D-xylopyranosyl-16 alpha-hydroxygypsogenic acid 28-O
      alpha-D-galactopyranosyl-(1-->6)-beta-D- glucopyranosyl-(1-->3)[-beta-D
      glucopyranoside[, saponarioside J (3) 3-O-beta-D-xylopyranosylolean-11,13(18)
      diene-23,28-dioic acid 28-O-beta-D-glucopyranosyl-(1-->3)-beta-D-glucopyranosyl
      (1-->6)[- beta-D-glucopyranoside[, saponarioside K (4) 3,4-seco-16 alpha
      hydroxygypsogenic acid 28-O-beta-D-glucopyranosyl- (1-->3)-beta-D-glucopyranosyl
      (1-->6)[-beta-D-glucopyranoside[, saponarioside L (5) 3-O-beta-D
      xylopyranosylgypsogenic acid 28-O-beta-D-glucopyranosyl-(1-->3)-beta-D
      glucopyranosyl-(1-->6)[-beta- D- glucopyranoside[, and saponarioside M (6) 3-O
      beta-D-glucopyrano-sylgypsogenic acid 28-O-beta-D-glucopyranosyl-(1-->2)-beta-D
      glucopyranosyl-(1--6)-beta-D- glucopyranoside[ by NMR studies and chemical
      degradations. The aglycons of saponariosides J (3) and K (4) are new sapogenins.

PMID- 10654412
TI  - DNA polymerase beta inhibitors from Baeckea gunniana.
AB  - Crude plant extracts were surveyed for their ability to inhibit DNA polymerase
      beta. A methyl ethyl ketone extract prepared from Baeckea gunniana was identified
      as a potent inhibitor of the enzyme. Bioassay-guided fractionation of the
      extract, using an assay to monitor the inhibitory potential of individual
      fractions toward DNA polymerase beta, led to the isolation of four active ursane
      and oleanane triterpenoids (1-4). Inhibitory principle 1 is a new natural
      product, and 2 is a novel compound. Their structures were established as 3 beta
      hydroxyrus-12,19(29)-dien-28-oic acid (1) and 3 beta-hydroxyrus-18,20(30)-dien-28
      oic acid (2) by spectroscopic analysis and by comparison with the data for the
      structurally related compound ursolic acid (4). Also isolated as a DNA polymerase
      beta inhibitor was oleanolic acid (3). Compounds 1-4 had IC50 values of 5.3-8.5
      microM as inhibitors of polymerase beta in the presence of bovine serum albumin
      (BSA) and 2.5-4.8 microM in the absence of BSA.

PMID- 10654414
TI  - DNA polymerase beta inhibitors from Tetracera boiviniana.
AB  - Bioassay-guided fractionation of an active methyl ethyl ketone extract of
      Tetracera boiviniana, using a sensitive assay to monitor DNA polymerase beta
      inhibition, resulted in the isolation of three known triterpenoids, betulinic
      acid (1), 3-cis-p-coumaroyl maslinic acid (2), and 3-trans-p-coumaroyl maslinic
      acid (3). Compounds 1-3 inhibited DNA polymerase beta with IC50 values of 14, 15,
      and 4.2 microM in the presence of bovine serum albumin (BSA) and 6.5, 7.5, and
      2.0 microM in the absence of BSA, respectively. Further, compounds 1-3
      potentiated the effects of bleomycin in cultured P-388D1 cells.

PMID- 10654415
TI  - A new biflavonoid from Calophyllum panciflorum with antitumor-promoting activity.
AB  - A new biflavonoid named pancibiflavonol (1) was isolated from an EtOH extract of
      the stem bark of Calophyllum panciflorum, along with six known biflavonoids, and
      its structure was elucidated by spectroscopic methods. These biflavonoids all
      exhibited significant inhibitory activity against 12-O-tetradecanoylphorbol-13
      acetate-induced Epstein-Barr virus early antigen activation in Raji cells.

PMID- 10654417
TI  - Oceanapiside, an antifungal bis-alpha,omega-amino alcohol glycoside from the
      marine sponge Oceanapia phillipensis.
AB  - The structure of oceanapiside, an antifungal alpha, omega-bis-aminohydroxylipid
      glycoside from the temperate marine sponge Oceanapia sp., was elucidated by a
      combination of 2D NMR, chemical degradation/correlation, and MALDI MS-MS
      spectrometry. Oceanapiside exhibits antifungal activity against Candida glabrata
      at 10 micrograms/mL (MIC).

PMID- 10654416
TI  - Two novel anti-emetic principles of Alpinia katsumadai.
AB  - Two novel diarylheptanoids named katsumadain A (1) and katsumadain B (2) were
      isolated from the seeds of Alpinia katsumadai, and their structures were
      determined by spectroscopic analysis. Both katsumadains A (1) and B (2) showed
      anti-emetic activities on copper sulfate-induced emesis in young chicks.

PMID- 10654418
TI  - A new vitamin E (alpha-tocomonoenol) from eggs of the Pacific salmon Oncorhynchus
      keta.
AB  - A novel alpha-tocomonoenol 3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyl-12
      tridecenyl )-2H-1- benzopyran-6-ol[ having an unusual methylene unsaturation at
      the isoprenoid-chain terminus of alpha-tocopherol was isolated from the
      lipophilic fraction of chum salmon eggs. The structure of this marine-derived
      tocopherol (MDT) was established by spectral analyses. The peroxyl radical
      trapping activities of MDT and alpha-tocopherol were compared in aqueous
      phosphatidylcholine liposomal suspension and in methanolic solution at 37 degrees
      C. The antioxidant activity of MDT was found to be identical to that of alpha
      tocopherol under the experimental conditions of measurement.

PMID- 10654419
TI  - Serinol-derived malyngamides from an Australian cyanobacterium.
AB  - Serinol derivatives 4a and 4b were isolated from an Australian blue-green alga
      and characterized by spectroscopic means. Their absolute stereochemistry was
      established by chemical methods.

PMID- 10654420
TI  - Lyngbyastatin 2 and norlyngbyastatin 2, analogues of dolastatin G and
      nordolastatin G from the marine cyanobacterium Lyngbya majuscula.
AB  - Lyngbyastatin 2 (1) and norlyngbyastatin 2 (2), new cytotoxic analogues of
      dolastatin G (3) and nordolastatin G (4), respectively, have been isolated as
      constituents from a Guamanian variety of the marine cyanobacterium Lyngbya
      majuscula. Structure elucidation of these cyclic depsipeptides relied on
      extensive application of 2D NMR techniques. The finding of these new metabolites
      further supports the proposal that many compounds originally isolated from the
      sea hare Dolabella auricularia are most likely of cyanobacterial origin.

PMID- 10654421
TI  - Revision of the stereochemistry of batzelladine F. Approaches to the tricyclic
      hydroxyguanidine moiety of batzelladines G, H, and I.
AB  - The polycyclic guanidine alkaloids batzelladines F-I isolated from a Jamaican
      sponge of the genus Batzella in 1997 are of potential value for the treatment of
      AIDS because they induce p56lck-CD4 dissociation at micromolar concentrations.
      Comparison of the spectral data for both the synthetic syn and anti tricyclic
      left-hand portions of batzelladine F establishes that the natural product has the
      syn rather than the anti stereochemistry originally assigned. Approaches to the
      tricyclic hydroxyguanidine moiety of batzelladines G-I are described.

PMID- 10654422
TI  - Surface roughness of preparations for backscattered electron-scanning electron
      microscopy: the image differences and their Monte Carlo simulation.
AB  - Patterns and levels of mineralisation in the biological hard tissues have been
      studied using the backscattered electron (BSE) mode in the scanning electron
      microscope (SEM). To prevent gross topographic detail overwhelming changes in
      signal from composition, samples are embedded in polymethylmethacrylate (PMMA)
      and a flat block surface produced by polishing or micromilling. This study was
      undertaken to establish the degree of residual topography achieved in these
      finishing processes. A sample of human rib was embedded in PMMA and prepared, as
      for examination in the SEM, by polishing on graded abrasives and pre- and,
      finally, ultramilling. After each preparation step, the block face was imaged
      using a confocal reflection microscope surface mapping facility. The recorded
      topographies were used in a Monte Carlo simulation to model the surface interface
      and thus, for each of the sample preparation techniques, to calculate predicted
      variations in BSE signal. The latter were compared with experimental data derived
      under standard operating conditions in the SEM. Micromilling produced block faces
      with typical peak-trough relief of 80 nm, while hand polishing left occasional
      scratches 1.5 microns deep with a general undulation of 150-250 nm. Monte Carlo
      simulations of a rough surface of bone using these data predicted that additional
      contrast levels of 5% could be expected from micromilled surfaces and > 10% for
      hand polished samples of bone. Thus, micromilling is the best preparation method
      for bone, since this tissue develops a collagen orientation-related relief on
      polishing, which may be largely responsible for the (incorrect) supposition that
      lamellation in bone is related to changes in net degree of mineralisation.

PMID- 10654423
TI  - Cryo-planing for cryo-scanning electron microscopy.
AB  - In the past decade, investigators of cryo-planing for low-temperature scanning
      electron microscopy (cryo-SEM) have developed techniques that enable observations
      of flat sample surfaces. This study reviews these sample preparation techniques,
      compares and contrasts their results, and introduces modifications that improve
      results from cryo-planing. A prerequisite for all successful cryo-planing
      required a stable attachment of the specimen to a holder. In most cases, clamping
      with a screw mechanism and using indium as space-filler sufficed. Once this
      problem was solved, any of three existing cryo-planing methods could be used to
      provide successful results: cryo-milling, microtomy in a cold room, and cryo
      ultramicrotomy. This study introduces modifications to the cryo-planing technique
      that produces flat surfaces of any desired plane through a specimen. These flat
      surfaces of frozen, fully hydrated samples can be used to improve observations
      from cryo-SEM as well as to enhance results from x-ray microanalysis and
      (digital) image analysis. Cryo-planing results of chrysanthemum (Dendranthema x
      grandiflorum Tzvelev) stems, hazel (Corylus avelane L.) stems, and repeseed
      (Brassica napus L.) pistils are presented to illustrate the use of the planing
      method on fibrous, hard, and delicate materials, respectively.

PMID- 10654424
TI  - Influence of topography and specimen preparation on backscattered electron images
      of bone.
AB  - Backscattered electron (BSE) images of bone exhibit graylevel contrast between
      adjacent lamellae. Mathematical models suggest that interlamellar contrast in BSE
      images is an artifact due to topographic irregularities. However, little
      experimental evidence has been published to support these models, and it is not
      clear whether submicron topographical features will alter BSE graylevels. The
      goal of this study was to determine the effects of topography on BSE image mean
      graylevels and graylevel histogram widths using conventional specimen preparation
      techniques. White-light interferometry and quantitative BSE imaging were used to
      investigate the relationship between the BSE signal and specimen roughness.
      Backscattered electron image graylevel histogram widths correlated highly with
      surface roughness in rough preparations of homogeneous materials. The
      relationship between BSE histogram width and surface roughness was specimen
      dependent. Specimen topography coincided with the lamellar patterns within the
      bone tissue. Diamond micromilling reduced average surface roughness when compared
      with manual polishing techniques but did not significantly affect BSE graylevel
      histogram width. The study suggests that topography is a confounding factor in
      quantitative BSE analysis of bone. However, there is little quantitative
      difference between low-to-moderate magnification BSE images of bone specimens
      prepared by conventional polishing or diamond micromilling.

PMID- 10654425
TI  - Scanning electron microscopy studies of protein-functionalized atomic force
      microscopy cantilever tips.
AB  - Protein-functionalized atomic force microscopy (AFM) tips have been used to
      investigate the interaction of individual ligand-receptor complexes. Herein we
      present results from scanning electron microscopy (SEM) studies of protein
      functionalized AFM cantilever tips. The goals of this study were (1) to examine
      the surface morphology of protein-coated AFM tips and (2) to determine the
      stability of the coated tips. Based on SEM images, we found that bovine serum
      albumin (BSA) in solution spontaneously adsorbed onto the surface of silicon
      nitride cantilevers, forming a uniform protein layer over the surface. Additional
      protein layers deposited over the initial BSA-coated surface did not
      significantly alter the surface morphology. However, we found that avidin
      functionalized tips were contaminated with debris after a series of force
      measurements with biotinylated agarose beads. The bound debris presumably
      originated from the transfer of material from the agarose bead. This observation
      is consistent with the observed deterioration of functional activity as measured
      in ligand-receptor binding force experiments.

PMID- 10654426
TI  - Sperm cell mediated transgenesis: a review.
AB  - Transgenesis would be greatly streamlined if sperm cells could be used as
      transgene vectors. Attempts to 'force' sperm cells to take up transgenes may be
      more worthy of further study than 'autouptake' attempts. However, thorough proof
      of its effectiveness will be required if sperm cell-mediated gene transfer is to
      be accepted, given the evolutionary implications associated with the possibility
      of sperm cells being able to transfer exogenous DNA.

PMID- 10654427
TI  - An efficient method for in vitro fertilization in rabbits.
AB  - This experiment was carried out to study a simple and efficient method for in
      vitro production of rabbit embryos. Newly ejaculated rabbit spermatozoa were used
      to fertilize superovulated oocytes after capacitation in vitro with four
      different media: (A) isotonic defined medium (DM)+heparin, (B) DM only,(C) DM+
      high ionic strength defined medium (HIS), and (D) DM supplemented with 10mM
      NaHCO3 (mDM) +HIS supplemented with 10mM NaHCO3 (mHIS). The presumptive zygotes
      were cultured in M199 supplemented with 10% FCS, 1.25mM Na Pyruvate and 0.1mM
      EDTA (mM199). The cleavage rates after 24h of incubation were 29.3%, 32.1%,
      64.9%, and 91.6% respectively, and the rates of blastocyst formation after 72h
      were 0, 27.3%, 58.4% and 85.2%, respectively. The results in the (D) treatment
      were significantly better than the other three treatments (p<0.01). Developmental
      potential of in vivo and in vitro derived zygotes was also compared using the
      mM199. The percentages of blastocyst and hatching blastocyst in the two groups
      were 92.5% and 87.2% after 84h, and 84.9% and 83.7% after 108h, respectively, and
      the two groups were not significantly different (p>0.05). The developmental
      progress of the two groups was nearly synchronous towards the end of culture.
      When IVF embryos from 2- to 4-cell stage were transferred into recipients, the
      pregnancy rate did not differ from in vivo fertilization, but the rate of live
      young from IVF was significantly lower than from in vivo. The results of this
      experiment showed that ejaculated rabbit sperm could be capacitated efficiently
      after treatment of mDM and mHIS, and rabbit IVF embryos achieved great
      development in mM199 in vitro.

PMID- 10654428
TI  - Standardization and conversion of marker polymorphism measures.
AB  - Large scale gene mapping efforts in domestic animals have generated and mapped a
      large number of genetic markers that are useful for mapping quantitative trait
      and disease loci and for DNA diagnostic purposes such as parentage testing.
      Marker polymorphism is an important criterion for selecting genetic markers in
      planning experiment for mapping quantitative trait loci or for DNA diagnostic
      purposes. Current formulations of marker polymorphism measures are functions of
      marker allele frequencies. In this study, two measures of marker polymorphism
      that are available from gene mapping studies and do not require allele
      frequencies were proposed and analyzed: the observed polymorphic information
      content (PIC) and the observed family information content (FIC). The observed FIC
      was more stable than the observed PIC because the observed FIC is unaffected by
      the variation in the frequency of heterozygous parents. However, both FIC and PIC
      are dependent on the gene mapping design. The effective number of alleles is
      recommended as a tool to standardize marker polymorphism measures so that
      polymorphism of different markers can be compared on an equal basis, and to
      obtain a new polymorphism measure (such an exclusion probability) from an
      existing measure (such as FIC). The usage of the effective number of alleles to
      standardize FIC, PIC and exclusion probabilities is illustrated using genetic
      markers in a published linkage map.

PMID- 10654429
TI  - Expression of beta-galactosidase and pig leptin gene in vitro by recombinant
      adenovirus.
AB  - Adenovirus has been used in vivo and in vitro as a vector to carry a foreign gene
      for gene transfer. Two kinds of replication defective human recombinant
      adenovirus vectors were used in this study, the first containing beta
      galactosidase reporter gene (AdCMVLac-Z) and the second carrying a gene for
      porcine leptin gene (AdCMVpLeptin). AdCMVLac-Z was tested for its ability to
      transfer DNA into pig kidney and pituitary cells. These cells expressed Lac-Z
      transiently 48 hours after the infection. In addition, when the pig kidney cells
      expressing the Lac-Z were replated with low density for the formation of colonies
      from each cell, colonies of blue cells expressing Lac-Z were observed. These
      results demonstrate that human recombinant adenovirus can be used as a
      transducing viral vector for inducing long-term expression in pig kidney cells.
      We also constructed a recombinant adenovirus (AdCMVpLeptin) which contained a pig
      leptin gene for the expression of pig leptin in vitro in the 293 human kidney
      cell line. 293 cells transfected with AdCMVpLeptin produced both a 15 KDa of a
      secretory form of porcine leptin and an 18 KDa long form containing signal
      peptide. Our study demonstrated that the recombinant adenovirus system offers a
      method for gene transfer and expression in pig cells.

PMID- 10654430
TI  - SSCP analysis at the bovine CSN3 locus discriminates six alleles corresponding to
      known protein variants (A, B, C, E, F, G) and three new DNA polymorphisms (H, I,
      A1).
AB  - A high resolution SSCP protocol was developed for simultaneous discrimination of
      the known CSN3 alleles A, B, C, E, F and G. Furthermore, three new DNA
      polymorphisms were identified in different Bos taurus and Bos indicus breeds or
      crosses. Mendelian segregation was shown for two of these polymorphisms (named
      CSN3*H and 1), and the third (named CSN3*A1) was found in unrelated animals, thus
      indicating the presence of three additional alleles at the bovine CSN3 locus. DNA
      sequencing revealed single mutations that led to a Thr/Ile substitution in amino
      acid position 135 for CSN3*H and to a Ser/Ala substitution in position 104 of the
      deduced amino acid sequence of CSN3*1 (GenBank accession numbers AF105260 and
      AF121023) compared to CSN3*A. In CSN3*A1, a silent mutation in the third codon
      position of Pro150 was found (GenBank accession number AF092513).

PMID- 10654431
TI  - Tetracycline-controlled expression of glycosylated porcine interferon-gamma in
      mammalian cells.
AB  - Tetracycline-controlled expression plasmids that allow inducible expression of
      proteins in mammalian cells (Gossen & Bujard, 1992), have been used to express
      porcine interferon-gamma in the RK-13 rabbit kidney cell line. Following neomycin
      selection, stable clones produced recombinant, glycosylated porcine interferon
      gamma (rGPoIFN-gamma) only after removal of tetracycline (Tc). Southern blot
      analysis of one clone showed that approximately 50 copies of IFN-gamma cDNA were
      present in the cell genome. In the absence of Tc, stable clones secreted large
      amounts of rGPoIFN-gamma (up to 16 microg/ml) into the medium supplemented with
      10% FCS and high glucose concentration. Molecular weight comparison of 35S
      Methionine, labelled rGPoIFN-gamma with natural leukocytic IFN-gamma after
      immunoprecipitation, revealed 4 major glycoforms with apparent Mr of 27,000;
      25,000; 20,000 and 18,500, that are almost identical in both IFN-gamma species.
      In both cases, all 4 glycoforms resolved into 2 polypeptide monomers with
      apparent Mr of 16,500 and 14,500 upon deglycosylation with N-glycosydase F. The
      biological activity of rGPoIFN-gamma was in the same range as that of natural
      leukocytic PoIFN-gamma (2 x 10(6) U/mg). Eventually, this recombinant mammalian
      IFN-gamma should constitute a very useful substitute for leukocyte PoIFN-gamma in
      in vitro or in vivo experiments.

PMID- 10654432
TI  - Mapping of two tumor suppressor genes in the pig.
AB  - Mutations in the breast cancer 1, early onset (BRCA1) gene confer an increased
      risk of breast and ovarian cancer in humans. The human MAD (mothers against
      decapentaplegic, Drosophila) homolog 4 (MADH4) locus is a target for deletion in
      pancreatic and other cancers. Given the role of the pig in biomedical studies,
      pig orthologs of BRCA1 and MADH4 were identified and localized in the porcine
      genome.

PMID- 10654433
TI  - The end of a millennium.

PMID- 10654434
TI  - Dental restoration review praised.

PMID- 10654435
TI  - GDC fee increase protested.

PMID- 10654436
TI  - NHS direct and access to dental care.
AB  - NHS Direct - the nurse-led 24-hour telephone helpline - is the flagship
      initiative of the 'New NHS'. The scheme is already available to over 19 million
      people, and is planned to serve 60% of England by the end of 1999 and the whole
      of the country by the end of 2000. It is intended to revolutionise how and when
      people access the NHS, particularly out-of-hours. The present government has
      recently also signalled that NHS Direct should play a key role in rebuilding
      accessibility to NHS dentistry. Yet many dentists are unaware of its existence,
      and within the profession there has been little debate regarding its actual or
      likely future impact on how people access dental care. This article briefly
      describes the concept and early experiences of NHS Direct, and speculates about
      its potential impact on how people access dental care.

PMID- 10654437
TI  - Pseudomonas aeruginosa septicaemia from an oral source.
AB  - Oral colonisation with aerobic Gram-negative bacilli (AGNB) is abnormal and
      usually indicates a medically compromised state in the host. It has been
      postulated that oral colonisation with AGNB may predispose a patient to serious
      systemic infection, but proof of this assertion is lacking. This report describes
      an elderly patient who had oral colonisation of Pseudomonas aeruginosa and
      developed septicaemia from an identical strain of this bacterium.

PMID- 10654438
TI  - Continued apexogenesis of immature permanent incisors following trauma.
AB  - Two cases of trauma to immature teeth are described which differed significantly
      in their initial severity. However, both subsequently presented with continued
      apical root formation. In the two cases a histological examination after tooth
      removal confirmed continued apical development of the traumatised immature teeth
      distant to their respective coronal portions. These cases highlight the
      resilience of the root sheath of Hertwig to trauma.

PMID- 10654440
TI  - Complications and maintenance.

PMID- 10654439
TI  - Short and sticky options in the treatment of the partially dentate patient.
AB  - As we move into the twenty-first century, patterns of dental disease in adults
      are changing. Surveys of adult dental health indicate that more people are
      keeping their teeth for longer in life. In many cases, the ravages of dental
      disease and the cumulative effect of a lifetime of restorative dentistry lead to
      gradual tooth loss. For many of these patients, restoration of a complete
      dentition may not be feasible nor desirable. In recent years, functionally
      oriented treatment planning has become acceptable in light of recent research
      findings. Using this approach, treatment efforts and resources are directed
      principally at retaining the 'strategic' part of the dentition in the long term,
      ie, the anterior and premolar teeth. This paper describes, with the aid of
      treated cases, a means of combining a shortened dental arch strategy with resin
      bonded bridgework. With the aid of recent research in this area of clinical
      practice, some suggestions as to the use of the technique are also described.

PMID- 10654441
TI  - The cariostatic potential of cheese: cooked cheese-containing meals increase
      plaque calcium concentration.
AB  - OBJECTIVE: Eating cheese by itself increases plaque calcium concentration - which
      is probably one mechanism of the well-established action of cheese in reducing
      experimental caries. The objective of the present study was to determine whether
      consumption of cheese as part of a cooked, mixed meal (ie as it is habitually
      consumed) is able to increase plaque calcium concentration. DESIGN: Plaque
      samples were obtained from 16 adult volunteers before and 5 minutes after
      consumption of either a 15 g cube of cheese, one of two cheese-containing test
      meals, or one of two control meals. Each subject tested each of the four meals on
      a separate occasion. Plaque calcium concentration was measured using atomic
      absorption spectrophotometry. RESULTS: The test meals increased plaque calcium
      concentrations to a significantly greater magnitude than the control meals (P <
      0.05). A non-significant trend was observed towards a larger magnitude of change
      in plaque calcium concentration in the 8 subjects with the lowest, compared with
      the 8 subjects with the highest baseline concentration. CONCLUSION: The findings
      suggest that cheese-containing meals increase plaque calcium concentration and
      thus probably protect against dental caries.

PMID- 10654442
TI  - Smokers and drinkers awareness of oral cancer: a qualitative study using focus
      groups.
AB  - OBJECTIVE: To examine the perceptions and understanding of oral cancer among
      older male drinkers and smokers in the north east of England. DESIGN: Qualitative
      research using focus group discussions led by an experienced moderator. SETTING:
      Residents of the north east of England in their community. SUBJECTS: Male alcohol
      drinkers and tobacco smokers over the age of 44 years and by socio-economic
      grouping. RESULTS: There is a lack of knowledge and understanding of the risk of
      oral cancer in this whole at-risk population sample. Even those who have direct
      contact with the disease profess ignorance. Information on health is perceived as
      confusing or distrusted. Much of this is linked to a fatalistic approach to
      serious illness. CONCLUSIONS: There appears to be a large information gap to
      bridge, and we need to further understand the target group for oral cancer health
      promotion; and to use that knowledge to design effective health promotion
      initiatives.

PMID- 10654443
TI  - A survey of oral implantology teaching in the university dental hospitals and
      schools of the United Kingdom and Eire.
AB  - AIM: To provide an overview of the currently available academic teaching and
      clinical training in oral implantology at the university dental schools and
      hospitals of the United Kingdom and Eire. METHOD: A questionnaire was sent to the
      dean or director of dental studies and forwarded to the respective units involved
      in the academic teaching and clinical training of oral implantology. The setting
      was the university dental hospitals, and dental schools of the UK and Eire.
      Information was collected between July 1997 and March 1999. The main outcome
      measures were course availability, duration and emphasis for undergraduate and
      postgraduate study in the clinical discipline of oral implantology. The units or
      departments responsible for training and teaching were identified and formal
      degree courses were distinguished from non-degree courses. RESULTS: All
      institutions replied to the survey. All university dental schools provide
      undergraduate training in oral implantology in accordance with the guidelines
      provided by the General Dental Council. However, the courses vary with regard to
      the departments involved and the level of student participation. Thirteen centres
      provide informal postgraduate training with the duration ranging from one to
      eighteen days. Just eight centres provide formal academic graduate training based
      on oral implantology leading to recognised degrees. CONCLUSION: All university
      dental schools provide undergraduate teaching in oral implantology. Most centres
      also provide informal postgraduate training based on oral implantology. However,
      opportunities for academic graduate training, leading to recognised
      qualifications in this subject, appear limited at present.

PMID- 10654444
TI  - Establishment of a myelodysplastic syndrome (MDS)/secondary AML-derived T
      lymphoid cell line K2-MDS.
AB  - We have established a T lymphoid cell line, K2-MDS, from the peripheral blood
      mononuclear cells (PBMC) of a patient with acute myeloblastic leukemia (AML)
      transformed myelodysplastic syndrome (MDS). K2-MDS cells are positive for the
      expression of CD4, CD5, CD13, CD25, CD71, CD95, HLA-DR and cytoplasmic CD3.
      Southern blotting analysis shows T cell receptor (TCR) beta chain genes
      rearrangements, whereas immunoglobulin heavy chain (IgH) genes are not
      rearranged. Further, the patient PBMC contains TCR beta chain genes
      rearrangements in the same manner as K2-MDS cells. The data indicate that K2-MDS
      is a T lymphoid cell line derived from a myelodysplastic clone in the patient
      PBMC. This new MDS-derived cell line K2-MDS may be a useful in vitro model for
      studies on the pathogenetic mechanisms leading to MDS.

PMID- 10654445
TI  - Malignant hematopoietic cell lines: in vitro models for the study of
      myelodysplastic syndromes.
AB  - The myelodysplastic syndromes (MDS) are clonal myeloid disorders characterized by
      bone marrow cell dysplasia and ineffective hematopoiesis leading to peripheral
      refractory cytopenias. The course of the disease ranges from a chronic status
      with progressively impaired hematopoiesis to rapid evolution to acute myeloid
      leukemia (AML). A panel of continuous malignant hematopoietic cell lines has been
      established from the whole spectrum of MDS variants and also from the different
      stages of the diseases, namely from the MDS phase or the overt leukemia post-MDS
      phase. Ten cell lines were derived from the various MDS subtypes; 17 cell lines
      were established from patients with leukemia (mainly AML) post-MDS. While most
      cell lines display myelocytic, monocytic or erythroid features, some cell lines
      carry lymphoid characteristics (precursor B-cell, B-cell, or T-cell), With regard
      to these lymphoid MDS-derived cell lines, more detailed authentication (prove of
      derivation from the assumed patient) and verification (prove of the malignant
      nature of the cell line and derivation from the assumed neoplastic cells) are
      required to validate the cell lines as true in vitro representatives of MDS and
      to exclude any cross-contamination with other cells or immortalization of normal
      bystander cells. On the other hand, lymphoid MDS-derived cell lines may attest to
      the clonal nature of MDS which may afflict progenitor cells giving rise to
      lymphoid or myelomonocytoid cells. Many of the MDS-derived cell lines carry
      cytogenetic and molecular genetic abnormalities typically associated with MDS:
      gain or loss of all or parts of chromosomes 5, 7, 8 and 20 (-5/5q-, -7/7q-, + 8,
      20q-); alterations of oncogenes and tumor suppressor genes (IRF-1, p15, p16, p53,
      RAS, RB). In summary, the present panel of cell lines provides continuously
      growing cells and thus unlimited cell material for use as in vitro paradigms
      covering the whole spectrum of MDS-related hematopoetic malignancies. Properly
      authenticated and verified MDS-derived cell lines which should be made freely
      available will represent important research tools for the study of MDS biology.

PMID- 10654446
TI  - The regulation of telomerase activity in hematopoietic cells.

PMID- 10654447
TI  - Polyamine-depletion induces p27Kip1 and enhances dexamethasone-induced G1 arrest
      and apoptosis in human T lymphoblastic leukemia cells.
AB  - Glucocorticoid-induced apoptosis is preceded by G1 arrest and supposed to be up
      regulated by polyamine-depletion, which also induces G1, arrest. In CEM leukemia
      cells, dexamethasone showed an antileukemic effect by inducing G1 arrest and
      apoptosis. DFMO, which depleted cellular polyamines by inhibiting ornithine
      decarboxylase, induced G1 arrest but without apoptosis, though it enhanced
      dexamethasone-induced G1 arrest and apoptosis. The G1 arrest was associated with
      hypophosphorylation of pRb. Dexamethasone inhibited the increase of mutated p53
      expression but had little effect on p2Wafl/Cip1 expression. The p27Kip1, level
      was increased by dexamethasone or and DFMO in line with the kinetics of G1
      arrest. Therefore, the up-regulation of dexamethasone-induced apoptosis by
      polyamine-depletion may be associated with additive down-regulation of G1
      progression via the p27Kip1-pRb pathtway.

PMID- 10654448
TI  - Efficacy of N-acetylcysteine and all-trans retinoic acid in restoring in vitro
      effective hemopoiesis in myelodysplastic syndromes.
AB  - We evaluated the in vitro effect on clonogenic potential (CFU-GM) and apoptosis
      in myelodysplastic syndromes (MDS) progenitors of an anti-oxidant (N
      acetylcysteine, NAC) and/or a differentiating (all-trans retinoic acid, ATRA)
      agent. NAC significantly reduced apoptosis, both NAC and ATRA induced an increase
      in CFU-GM, but NAC seemed to be particularly effective in the high risk (HR) MDS.
      NAC + ATRA conferred a significant advantage in terms of CFU-GM with respect to
      NAC and ATRA alone. Tumor Necrosis Factor-alpha (TNF-alpha) levels decreased
      after incubation with NAC in the MDS samples. This study shows that ineffective
      hemopoiesis in MDS could benefit from both NAC and ATRA, suggesting that anti
      oxidant treatment may play a role in guaranteeing MDS cell survival, predisposing
      them towards differentiation.

PMID- 10654449
TI  - Oxidative stress and the myelodysplastic syndromes.

PMID- 10654450
TI  - From sideroblastic anemia to the role of mitochondrial DNA mutations in
      myelodysplastic syndromes.
AB  - A primary mitochondrial defect may be pivotal in the pathogenesis of acquired
      idiopathic sideroblastic anemia (AISA). The mitochondrial respiratory chain is
      involved in mitochondrial iron uptake and supply of ferrous iron (Fe2+) for heme
      synthesis. Mitochondrial DNA (mtDNA) comes into play because several subunits of
      the respiratory chain are encoded by the mitochondrial genome. We have identified
      heteroplasmic mutations of mtDNA, which may not only impair mitochondrial iron
      metabolism and heme synthesis, but through impairment of mitochondrial energy
      production may have much broader implications for MDS pathogenesis. For example,
      increased apoptosis and genetic instability may be phenomena linked to
      mitochondrial dysfunction.

PMID- 10654451
TI  - Increased CD38 expression is associated with favorable prognosis in adult acute
      leukemia.
AB  - CD38 is expressed in acute lymphoblastic leukemia (ALL) and acute myelogenous
      leukemia (AML) blasts and its prognostic significance is unknown. We investigated
      CD38 expression in 304 AML and 138 ALL patients. CD38 was lower in AML-M3
      compared to other FAB subtypes (5% vs. 41%; P < 0.001), but was similar among ALL
      subtypes (56.6%; P = 0.69). Ph + ALL and AML with t(15; 17) patients showed lower
      CD38 expression than the other cytogenetic groups. Overall survival favored AML
      and ALL patients with higher CD38 levels. Multivariate analysis revealed CD38
      expression to be an independent outcome predictor in AML, but not in ALL.

PMID- 10654452
TI  - CD38: an 'orphan' protein that may be finding a home?

PMID- 10654453
TI  - Absolute number of circulating CD34+ cells is abnormally low in refractory
      anemias and extremely high in RAEB and RAEB-t; novel pathologic features of
      myelodysplastic syndromes identified by highly sensitive flow cytometry.
AB  - We scored absolute numbers of circulating CD34+ cells by a highly sensitive
      triple-color flow cytometric analysis using CD45 monoclonal antibody, CD34
      monoclonal antibody and propidium iodide. Forty-one patients with MDS (RA: 27,
      RARS: 1, RAEB: 6, RAEB-t: 3,CMML: 4), 12 patients with aplastic anemia (AA) and
      36 age-adjusted normal subjects were studied. RA had significantly decreased
      numbers of cells expressing CD34 (0.21 +/- 0.29 x 10(6)/l) compared with normal
      subjects (0.81 +/- 0.36 x 10(6)/l)(P < 0.001). This low number of CD34+ cells in
      RA resembles the case of AA (0.39 +/- 0.73 x 10(6)/l). In light-scatter analysis,
      the CD34+ cells of RA patients were distributed mainly in low forward scatter
      (FSC) (lymphocyte region). In contrast, the CD34+ cell counts were extremely high
      in patients with RAEB (46.54 +/- 71.37 x 10(6)/l) and RAEB-t (57.00 +/- 52.36 x
      10(6)/l) (P < 0.001) and the CD34+ cells were observed in high FSC (blast
      region).CMML patients showed moderately increased numbers of CD34+ cells (3.69 +/
      4.64 x 10(6)/l). Thus, there was a distinct difference in cell size and number
      of circulating CD34+ cells between RA and RAEB/RAEB-t. In univariate and
      multivariate analysis, a high CD34+ cell count (> or = 1.0 x 10(6)/l) was a poor
      prognostic factor. This method allows one to distinguish RA from other MDS
      subtypes more reliably than by morphology alone and provides early signs of
      progression to acute leukemia.

PMID- 10654454
TI  - Pulmonary leukostasis mimicking pulmonary embolism.
AB  - We report a case of a 32-year-old woman who presented with shortness of breath
      and pleuritic chest pain, and mismatched perfusion defects on a ventilation
      perfusion scan suspicious for pulmonary embolism. However, subsequent data
      revealed the diagnosis of acute myelogenous leukemia with hyperleukocytosis and
      associated pulmonary leukostasis. Unfortunately, the patient died despite urgent
      leukopheresis. Autopsy examination revealed extensive infiltration of leukemic
      cells in all major organs with no evidence of pulmonary embolism. This case
      highlights the clinical, radiographic and histologic features of pulmonary
      leukostasis, and reminds the clinician that not all ventilation-perfusion
      mismatching is due to thromboembolic disease.

PMID- 10654455
TI  - The management of severe acetabular bone loss using structural allograft and
      acetabular reinforcement devices.
AB  - The cases of 37 acetabular reconstructions in 35 patients with major structural
      pelvic bone loss were reviewed. At an average follow-up of 7.1 years, patients
      rated their results as excellent in 12 cases (32.4%), good in 22 (59.5%), fair in
      2 (5.4%), and poor in 1 (2.7%). Thirty-four cases (91.9%) were classified as a
      clinical success. Thirty-six allografts (97.3%) had radiographic evidence of full
      incorporation. Of the unrevised hips, 1 (2.7%) was classified as definitely
      loose, 2 (5.4%) as probably loose, and 4 (10.8%) as possibly loose. One revision
      of an acetabular component was required because of late sepsis. This is the first
      reported series on the use of acetabular reinforcement devices with solid bulk
      allograft covering more than 50% of the socket. The allograft is protected in the
      early postoperative period, superior migration of the cup is virtually eliminated
      as a complication, and the incidence of aseptic loosening is greatly diminished.

PMID- 10654456
TI  - Acetabular revision arthroplasty using so-called jumbo cementless components: an
      average 7-year follow-up study.
AB  - The optimal technique for acetabular revision surgery in the face of major bone
      stock deficiency remains controversial. One subset of these problem cases
      consists of hips that are amenable to reconstruction using a large, hemispherical
      cementless acetabular component, the so-called jumbo acetabular component. We
      report the intermediate-term experience of 24 hips in 24 patients who underwent
      an uncemented acetabular revision using a hemispherical acetabular component of >
      or = 66 mm diameter. In 16 hips, the femoral component was replaced as well. Of
      the 18 hips in patients alive after 5 years, 15 were assessed at a mean follow-up
      of 7.0 years (range, 5.0-10.3 years). The mean final Harris Hip Score was 86
      points (range, 45-100 points). No acetabular component had been revised, and none
      were loose radiographically. In this difficult group, a bimodal distribution
      resulted. The complication rate was high. In those without infection, the results
      were excellent.

PMID- 10654457
TI  - The effect of intraoperative intravenous fixed-dose heparin during total joint
      arthroplasty on the incidence of fatal pulmonary emboli.
AB  - All patients who underwent primary total knee arthroplasty (TKA), revision TKA,
      primary total hip arthroplasty (THA), and revision THA between January 1, 1990,
      and December 31, 1996, were retrospectively reviewed to determine the incidence
      of fatal pulmonary emboli. All TKA patients received 1,000 U of intravenous
      heparin sodium before the tourniquet was inflated and an additional 500 U of
      intravenous heparin sodium before the inflation of the second tourniquet during
      bilateral TKA. All THA patients received 1,000 U of intravenous heparin sodium at
      the time of the skin incision and 500 U of intravenous heparin sodium before
      preparation of the femoral canal. The overall incidence of fatal pulmonary emboli
      was extremely low (TKA, 0.096%; THA, 0.16%). With this regimen of intravenous
      intraoperative heparin, postoperative aspirin, thromboembolic disease hose, and
      early ambulation, there is no risk of postoperative bleeding, it is inexpensive,
      and there is no concern on how long to keep the patients on this regimen
      postoperatively. We recommend this regimen for the prevention of fatal pulmonary
      emboli after total joint arthroplasty.

PMID- 10654458
TI  - A comparison of 4 intraoperative methods to determine femoral component rotation
      during total knee arthroplasty.
AB  - A total of 100 consecutive posterior cruciate-retaining total knee arthroplastics
      were performed in 81 patients with an average age of 69 years by 1 surgeon.
      Diagnoses included osteoarthritis in 93 knees and rheumatoid arthritis in 7
      knees. The femoral alignment necessary to create a rectangular flexion gap was
      determined and compared with Whiteside's line, the transepicondylar axis, and a
      line in 3 degrees of external rotation relative to the posterior condyles of the
      femur. The transepicondylar axis most consistently recreated a balanced flexion
      space, whereas 3 degrees of external rotation off the posterior condyles was
      least consistent, especially in valgus knees.

PMID- 10654459
TI  - Outcome of total hip arthroplasty in small-proportioned patients.
AB  - In a prospective, consecutive series, 41 total hip arthroplasties were performed
      in 27 small-proportioned patients with small femoral dimensions. The 17 female
      and 10 male patients averaged 23.6 years (range, 14-47 years), and the mean
      height and weight were 157 cm (range, 132-183 cm) and 53.5 kg (range, 36-84 kg).
      The most common preoperative diagnosis was juvenile rheumatoid arthritis in 18
      patients (28 hips). Most patients were severely disabled in their daily activity,
      and 68% of the patients were classified as Charnley functional class C. The
      femoral implants consisted primarily of the proximally porous-coated miniature
      Anatomic Medullary Locking femoral component (AML/CDH, Depuy, Warsaw, IN) in 33
      hips in 22 patients (average stem diameter, 9.5 mm; range, 8-12.0 mm). A porous
      ingrowth acetabular cup fixed with screws was used in all procedures. At an
      average follow-up of 51 months, Harris Hip Scores improved significantly from 34
      points (range, 0-65 points) preoperatively to 85 points (range, 33-100 points)
      after arthroplasty. There were no intraoperative complications. There was 1
      revision because of femoral implant loosening. Three cementless femoral
      components showed evidence of nonprogressive subsidence. One patient had
      significant bilateral acetabular component polyethylene wear and underwent
      revision. All other femoral and acetabular components were radiographically
      stable. The relief of pain and improvement of function were dramatic. The
      miniature AML/CDH femoral component, combined with an uncemented acetabular cup,
      provides a promising, off-the-shelf alternative in small-proportioned patients.

PMID- 10654460
TI  - Factors contributing to rapid wear and osteolysis in hips with modular acetabular
      bearings made of hylamer.
AB  - There have been several reports of osteolysis associated with rapid wear of
      Hylamer. A detailed analysis of retrieved implants and tissues can identify
      factors contributing to rapid wear and osteolysis. The mean linear wear rate of
      12 liners was 0.49 mm/y, and 11 of 12 hips had progressive retroacetabular
      osteolysis. The average patient age was 50 years, and the mean implantation time
      was 50 months. All liners were sterilized by gamma irradiation in air. There was
      an 11-month difference in the average shelf-life of the 3 liners that were white
      and those that were darker in color. The volumetric wear rate of the white liners
      was 30% less than that of the others, suggesting a difference in the wear
      resistance of the liners as a function of shelf life. The mean average surface
      roughness (Ra) and the mean maximum surface roughness (R(max)) of the femoral
      heads were increased 3-fold and 50-fold compared with typical values for unused
      femoral heads. Evidence of 3-body wear, such as metal particles embedded in the
      liners, was commonly present. The pattern of backside liner deformation and
      burnishing was consistent with relative motion between the liner and the shell.
      In addition to generating Hylamer wear particles, repetitive axial motion between
      the liner and shell could generate fluid pressure, which transmitted through
      holes in the acetabular shell could cause or contribute to the development of
      retroacetabular osteolysis. Hylamer particles of variable shape and size,
      consistent with generation by several wear modes, were isolated from
      periprosthetic tissues.

PMID- 10654461
TI  - Dall-Miles plating for periprosthetic B1 fractures of the femur.
AB  - Eight patients (9 fractures) who have been treated with Dall-Miles plating in
      this unit between April 1996 and October 1997 for ipsilateral periprosthetic
      fractures around total hip replacement (7 cases) and total knee replacement (2
      cases) have been reviewed. Four were men, and 4 were women. The average age at
      the time of operation was 77 years (range, 65-89 years). The average follow-up
      period was 14.6 months (range, 6-24 months). Three fractures healed
      satisfactorily with no evidence of malunion (3 of 9). The final result was
      unsatisfactory in the other 6 fractures. The femoral component had been inserted
      in a varus position in all the failures but was in a neutral position in the 3
      successes. Procedures other than Dall-Miles plating might be more appropriate in
      the management of periprosthetic fractures in which the femoral component is in a
      varus position.

PMID- 10654462
TI  - Primary total hip arthroplasty in patients with ankylosing spondylitis.
AB  - The results of total hip arthroplasty in a group of patients with ankylosing
      spondylitis are described. Ninety-five arthroplasties were performed in 56 men
      and 2 women whose average age at operation was 38.9 years (standard deviation
      [SD], 11.6; range, 19.2-78.8). They were followed for an average of 135.4 months
      (SD, 81.6; range, 24.4-331.2). We encountered 4 deep infections necessitating the
      removal of prostheses. Two of 3 dislocations were anterior dislocations. Nineteen
      arthroplasties were revised at an average of 162.0 months (SD, 49.6; range, 55.1
      250.5) after the primary surgery; 9 of them had only the acetabular component
      revised because of aseptic loosening. Hyperextension of the hips is a common
      phenomenon that can lead to surgical error and predispose the prosthesis to
      anterior dislocation.

PMID- 10654463
TI  - The reliability and validity of the Vancouver classification of femoral fractures
      after hip replacement.
AB  - This study assessed the reliability and validity of a new classification system
      for fractures of the femur after hip arthroplasty. Forty radiographs were
      evaluated by 6 observers, 3 experts and 3 nonexperts. Each observer read the
      radiographs on 2 separate occasions and classified each case as to its type (A,
      B, C) and subtype (B1, B2, B3). Reliability was assessed by looking at the
      intraobserver and interobserver agreement using the kappa statistic. Validity was
      assessed within the B group by looking at the agreement between the radiographic
      classification and the intraoperative findings. Our findings suggest that this
      classification system is reliable and valid. Intraobserver agreement was
      consistent across observers, ranging from 0.73 to 0.83. There was a negligible
      difference between experts and nonexperts. Interobserver agreement was 0.61 for
      the first reading and 0.64 for the second reading by kappa analysis, indicating
      substantial agreement between observers. Validity analysis revealed an observed
      agreement kappa value of 0.78, indicating substantial agreement. This study has
      shown that this classification is reliable and valid.

PMID- 10654464
TI  - Partially hydroxyapatite-coated stemmed acetabular cup and nonstructural bone
      graft in the management of severe acetabular deficiency.
AB  - We evaluated the use of a stemmed acetabular cup with morcellized allograft in
      the treatment of severe acetabular deficiency requiring reconstruction at
      arthroplasty. There were 29 hips, of which 22 were revision operations (18
      aseptic, 4 postinfective) and 7 were complex primary hip replacements. All
      patients had severe acetabular deficiency as classified by the American Academy
      of Orthopaedic Surgeons: type IIB, 3; type IIIa, 18; type IIIB, 8. The patients
      had a mean follow-up of 46 months (range, 14-74 months). The hip center of
      rotation improved from a mean preoperative, side-to-side difference of 11.5 mm to
      2.5 mm postoperatively (P < .001 ). The medial bone stock improved from a mean
      preoperative value of 1.5 mm to 11 mm postoperatively (P < .001). The Harris Hip
      Score improved from a mean preoperative score of 42 points to a postoperative
      score of 84 points (P < .001 ). There was 1 case of failure resulting from
      sepsis. The early results with this method of reconstruction of severe acetabular
      deficiency show encouraging restoration of bone stock, with no cases of aseptic
      loosening until the last follow-up.

PMID- 10654465
TI  - Determining the necessity for routine pathologic examinations in uncomplicated
      total hip and total knee arthroplasties.
AB  - Total hip and total knee arthroplasties (n = 951) were retrospectively reviewed
      to determine the cost-effectiveness of routine pathologic examination of surgical
      specimens in primary total hip and total knee replacements. Discrepancies between
      the postoperative diagnosis and the final pathologic diagnoses were recorded. Of
      the 951 cases reviewed, 27 (2.8%) noted conflicting postoperative and pathologic
      diagnosis. In all cases, the discrepancy was between a postoperative diagnosis of
      osteoarthritis and pathologic diagnosis of avascular necrosis. No new cases of
      neoplasia or inflammatory arthropathy were noted based on the pathologic
      interpretation. Sixteen of these discrepancies (5.1%) and were noted in total hip
      arthroplasties, and 11 (1.7%) were noted in total knee arthroplasties. In no case
      was postoperative medical or surgical treatment altered. Based on this review,
      strong consideration should be given to the elimination of routine pathologic
      evaluation of surgical specimens during primary joint arthroplasty, leaving this
      pathologic evaluation optional, at the discretion of the orthopaedic surgeon,
      rather than mandatory.

PMID- 10654466
TI  - Migration of polyethylene wear debris in one type of uncemented femoral component
      with circumferential porous coating: an autopsy study of 5 femurs.
AB  - This autopsy study analyzed the migration of polyethylene wear debris adjacent to
      uncemented femoral components with circumferential porous coating. Five femoral
      specimens retrieved at autopsy from 3 patients were investigated. Two stems were
      40% porous coated, 2 were 80% porous coated, and 1 was 100% porous coated. The
      implants' time in situ ranged from 53 to 132 months (average, 94.8 months). All
      patients were followed clinically and radiographically until death.
      Radiographically, 3 of the stems were bone ingrown with proximal bone loss, 1
      stem was mainly fibrous encapsulated, and 1 stem was completely fibrous
      encapsulated. Histologic examination of bone adjacent to the middle and distal
      sections of the femoral implant revealed no polyethylene wear debris or
      granulation tissue in any of the specimens. In 2 bone-ingrown cases, a small
      number of polyethylene particles and small areas of granulation tissue were
      present at the proximal level. This granulation tissue, however, did not cause
      major osteolysis. The findings in this study imply that circumferential porous
      coating of cementless femoral components could prevent distal migration of
      polyethylene wear debris along the bone-implant interface in both bone-ingrown
      and fibrous-encapsulated femoral implants.

PMID- 10654467
TI  - Anthropometric measurements to design total knee prostheses for the Indian
      population.
AB  - An anthropometric computed tomography scan study was undertaken to design femoral
      components in 86 knees (47 osteoarthritic Indians-21 men, 26 women) who matched
      standards suggested by the Indian Council of Medical Research, 1990. Patients
      were classified into 3 random groups based on anteroposterior diameter (<55 mm,
      55-59 mm, >59 mm). Most Indian men (86.8%) could have the femoral component
      satisfactorily replaced by available designs. A statistically significant number
      of women (60.4%, P < .001) had femoral anteroposterior diameters smaller than the
      smallest available (55 mm) femoral component. Splaying in mediolateral dimension
      (> 10 mm) in a given anteroposterior size was noted in all 3 groups. This pilot
      study representative of the Indian population can be used to manufacture
      prosthetic inventories suitable for most of the Asian-Pacific population having
      smaller anthropometric measurements than Western populations.

PMID- 10654468
TI  - Diversity of proximal femoral medullary canal.
AB  - To analyze the endosteal dimensions of the proximal femoral medullary canal, we
      studied 50 cadaver femora using computed tomography and a border detection method
      from 20 mm above the lesser trochanter, the osteotomy level, down to the isthmus.
      We documented the presence of a dense calcar septum in 96% of femora studied. In
      addition to mediolateral, anteroposterior, and neck-oriented dimensions, we
      calculated canal flare indices (CFIs) between the osteotomy level and the isthmus
      and metaphyseal canal flare indices (MCFIs) between the osteotomy level and the
      level 20 mm below the lesser trochanter midpoint to describe the shape of the
      endosteal cavity. With respect to the canal opening, the anteroposterior and
      mediolateral planes parallelled each other over the entire region as indicated by
      the high correlation (r = .7, P < .001) between the CFIs in these directions. The
      prediction of one dimension from another was unreliable in the metaphyseal
      region, where bone ingrowth is supposed to occur in a femoral prosthesis. The
      MCFI seemed to be the best parameter to distinguish the various types of proximal
      femoral canal shapes. We have described the variability of the proximal femoral
      endosteal dimensions in detail and find that the wide variation in the shape and
      size of the proximal femoral medullary canal means that it is almost impossible
      to achieve 100% cortical contact with the stem, especially in the metaphysis.

PMID- 10654469
TI  - The anatomic basis for the concept of lateralized femoral stems: a frontal plane
      radiographic study of the proximal femur.
AB  - We determined the range of sizes for a system of monoblock femoral prostheses
      that would provide adequate (a term defined in the text) fill in the frontal
      plane and restore femoral offset and leg length. We performed an anatomic study,
      based on measurements in 200 anteroposterior pelvic radiographs. If diaphyseal
      filling implants are to be used, 9 sizes are sufficient to obtain excellent canal
      filling and restoration of femoral offset in >80% of cases, assuming that the
      level of neck osteotomy can vary over a 1-cm range. When using metaphyseal
      filling implants, only a limited adjustment can be obtained from the level of
      neck osteotomy. A system limited to 8 sizes approximates the anatomy of the
      femoral canal with satisfactory precision in 73% of cases. If such a system is
      provided with only a single neck shaft angle for each stem size, it does not
      allow restoration of the biomechanical center of the hip in >67% of cases. A
      system of 8 sizes of 1 neck/shaft angle and a 22-mm modular head restores the
      anatomy in only 49% of cases. Approximating the frontal anatomy of 85% of femora
      with an implant filling the metaphysis requires at least 15 sizes distributed in
      3 metaphyseal configurations, each supplied with 2 different neck shalt angles.

PMID- 10654470
TI  - The TRAC PS mobile-bearing prosthesis: design rationale and in vivo 3-dimensional
      laxity.
AB  - We present a posterior stabilized mobile-bearing prosthesis, TRAC PS, which has
      congruent contact from full extension to full flexion, allows for freedom of
      internal-external rotation, and has an automatic posterior shift in tibiofemoral
      contact on the tibia to maximize the quadriceps lever arm in flexion. TRAC PS has
      2 radii of curvature in the sagittal plane, 1 for the distal femoral condyles and
      1 for the posterior femoral condyles, as does the normal knee. The distal and
      posterior femoral condyles articulate congruently in the inner tracks or the
      outer tracks of the polyethylene bearing, respectively. Anterior or posterior
      sliding of the femoral condyles on the bearing or of the bearing on the tibial
      tray cannot occur, providing inherent anterior and posterior stability. Three
      dimensional knee laxity testing was performed on 17 patients from 12 months to 25
      months after total knee arthroplasty with the TRAC PS and on 18 healthy control
      subjects of similar ages. Normal ligament balancing and normal internal-external
      rotational laxity were achieved with the TRAC PS prosthesis. Anterior and
      posterior laxity in the patients with TRAC PS was significantly reduced compared
      with that of the control subjects.

PMID- 10654471
TI  - The effect of cement restrictors on the occlusion of the humeral canal: an in
      vitro comparative study of 2 devices.
AB  - An in vitro study investigated the efficacy of cement restrictor devices on
      cement containment and penetration within the humerus. Eight pairs of preserved
      humeri were prepared using advanced cementing technique followed by insertion of
      1 of 2 cement restrictors. Low-viscosity cement was injected followed by sham
      humeral stem insertion. Each specimen was sectioned into transverse 10-mm slices.
      Slices were photographed and digitized to quantify the cement/stem and canal
      cross-sectional area. Cement penetration was determined from the ratio of cement
      area to canal area. A significant increase in cement penetration was observed
      among slices from distal to proximal for both restrictors (P = .02). There was no
      significant difference in cement penetration, leakage, or migration between
      restrictors. Five of the 8 specimens migrated, with means of 21.5 +/- 25.0 mm and
      24.0 +/- 36.0 mm for the polyethylene and silicone restrictors. Leakage or
      migration resulted in a significant decrease in cement penetration with the
      polyethylene restrictors (P = .001). In the silicone restrictor group, migration
      resulted in decreased cement penetration (P = .04). When using advanced cementing
      techniques, intramedullary restrictors allow improved cement penetration;
      however, they do not ensure cement containment.

PMID- 10654472
TI  - Viability of femoral heads treated with resurfacing arthroplasty.
AB  - There is a general conception that resurfacing arthroplasty causes femoral head
      osteonecrosis and subsequent failure of the implant. This study histologically
      analyzed 25 resurfaced femoral heads up to 12 years postoperatively and found
      that osteonecrosis was not induced by the procedure.

PMID- 10654473
TI  - Ipsilateral total shoulder arthroplasty and total elbow replacement arthroplasty:
      a caveat.
AB  - Shoulder and elbow replacement arthroplasty both achieve a high degree of success
      in patients with inflammatory arthritis. When both arthroplastics are performed
      on the same side, a stress riser can occur in the humeral diaphysis between the
      tips of the 2 humeral components. When the shoulder arthroplasty is performed
      first, a short-stemmed humeral component is advised. If a long-stemmed humeral
      component at either joint is already in place, the cement column for the
      subsequent arthroplasty should extend to and include the cement column of the
      extant component.

PMID- 10654474
TI  - Acute periprosthetic fracture of the acetabulum associated with osteolytic pelvic
      lesions: a report of 3 cases.
AB  - Three cases of acute acetabular fracture around uncemented porous-coated
      acetabular components associated with osteolytic lesions of the pelvis are
      reported. In each case, the fracture occurred through an area of severe
      osteolysis that contributed to the structural failure of the pelvis. None of the
      fractures were associated with significant trauma, and none of the implants
      demonstrated evidence of loosening before the fracture. When marked pelvic
      osteolysis develops around the acetabular component of a total hip arthroplasty,
      the possibility of pelvic fracture must be considered. Total hip arthroplasty
      patients with osteolysis should be followed with radiographs at regular and
      frequent intervals. When osteolysis progresses, early intervention should be
      strongly considered because appropriate treatment may prevent fracture
      occurrence.

PMID- 10654475
TI  - Use of a Dall-Miles plate and cables for the fixation of a periprosthetic tibial
      fracture.
AB  - Although tibial periprosthetic fractures are uncommon, they are likely to be
      encountered more frequently with the increased use of total knee arthroplasty,
      and they present a challenging management problem. Here we present our solution
      to this problem, which provided a safe, effective means of fracture management,
      while maintaining the prosthesis.

PMID- 10654476
TI  - Clinical and radiographic evaluation of the Charnley versus the Spectron hip
      prosthesis.

PMID- 10654477
TI  - Women in thoracic surgery: an ancient tradition and a new milestone.

PMID- 10654478
TI  - Rheologic considerations in organ preservation.

PMID- 10654479
TI  - Focal angiogen therapy using intramyocardial delivery of an adenovirus vector
      coding for vascular endothelial growth factor 121.
AB  - BACKGROUND: Adenovirus (Ad) vector-mediated gene therapy strategies have emerged
      as promising modalities for the "biological revascularization" of tissues. We
      hypothesized that direct intramyocardial, as opposed to intracoronary,
      administration of an Ad vector coding for the vascular endothelial growth factor
      121 cDNA (Ad(GV)VEGF121.10) would provide highly focal Ad genome levels, and
      increases in VEGF, ideal for inducing localized therapeutic angiogenesis.
      METHODS: Persistence and regional distribution of the vector were assessed by
      TaqMan real-time quantitative polymerase chain reaction technology and enzyme
      linked immunosorbent assay, after intramyocardial Ad(GV)VEGF121.10 in the rat,
      and either intramyocardial or intracoronary (circumflex territory) vector in
      Yorkshire swine. Based on these results, we assessed the focal nature of the
      improved cardiac blood flow in a previously reported porcine myocardial ischemia
      model. RESULTS: Intramyocardial delivery of Ad(GV)VEGF121.10 in the rat resulted
      in local persistence of the Ad genome that decreased 1,000-fold over 3 weeks,
      with peak myocardial VEGF expression 24 to 72 h after vector delivery. After
      intramyocardial Ad(GV)VEGF121.10 in the circumflex distribution of pigs, Ad
      vector genome and VEGF protein levels were more than 1,000-fold and more than 90
      fold higher, respectively, in this distribution than in other myocardial regions.
      In comparison, intracoronary injection yielded maximum myocardial Ad genome and
      VEGF levels 33-fold and 9-fold lower, respectively, than that after
      intramyocardial delivery. Angiograms obtained 28 days after intramyocardial
      Ad(GV)VEGF121.10 demonstrated rapid circumflex reconstitution via collaterals
      localized to the region of vector administration. CONCLUSIONS: These studies
      demonstrate that direct intramyocardial administration of Ad(GV)VEGF121.10
      results in focal genome and VEGF levels, including focal angiogenesis, sufficient
      to normalize blood flow to the ischemic myocardium, findings that are relevant to
      designing human trials of gene therapy-mediated cardiac angiogenesis.

PMID- 10654480
TI  - Repair of anterior leaflet mitral valve prolapse: chordal replacement versus
      chordal shortening.
AB  - BACKGROUND: To determine the optimal method of repair for severe, segmental
      anterior leaflet prolapse, we analyzed outcome of 121 patients who underwent
      chordal shortening (n = 46) and chordal replacement (n = 75) from 1988 to 1996.
      METHODS: Chordae were replaced with expanded polytetrafluoroethylene sutures.
      Patients had an annuloplasty with either chordal replacement or shortening.
      Follow-up was 100% complete (mean, 3.7 years). RESULTS: Mean age was 62.1 years,
      86 were men, and 60 patients had isolated valve repair. There was one hospital
      death and 14 late deaths for a 5-year actuarial survival of 86.4%+/-4.5%. Sixteen
      patients underwent reoperation, 5 in the replacement group and 11 in the
      shortening group. Mechanism of valve failure in the replacement group was native
      chordae rupture (n = 4) and neochordae dehiscence (n = 1). With chordal
      shortening, repair failure was attributed to rupture of shortened chordae (n =
      8), leaflet prolapse with and without annuloplasty ring dehiscence (n = 2), and
      native chordae elongation (n = 1). Risk of reoperation because of repair failure
      at 3.5 years was 1.4% in the chordal replacement group and 14.8% in the chordal
      shortening group (p = 0.02). CONCLUSIONS: Chordal replacement is superior to
      chordal shortening, providing a predictable method for correction of mitral
      regurgitation with a low incidence of reoperation.

PMID- 10654481
TI  - Multicenter review of preoperative risk factors for stroke after coronary artery
      bypass grafting.
AB  - BACKGROUND: Stroke complicates the postoperative course in 1% to 6% of patients
      undergoing coronary revascularization. There has been no large scale mandatory
      database reporting on the incidence of stroke after coronary revascularization.
      METHODS: A multicenter regional database from the Bureau of Health Care Research
      Information Services, New York State Department of Health, on 19,224 patients who
      underwent coronary revascularization in 31 hospitals within New York State during
      1995 was analyzed to determine the risk factors for postoperative stroke.
      RESULTS: The incidence of postoperative stroke was 1.4% (n = 270). Hospital
      mortality for patients who had a stroke was 24.8%, compared with 2.0% for the
      rest of the patient population. Postoperative stroke increased the hospital
      length of stay threefold (27.9+/-1.9 versus 9.1+/-0.9 days, p<0.0001).
      Multivariable logistic regression identified the following variables to be
      significantly associated with a postoperative stroke: calcified aorta (p<0.0001;
      odds ratio [OR], 3.013), prior stroke (p = 0.0003; OR, 1.909), age (p<0.0001; OR,
      1.522 per 10 years), carotid arterial disease (p = 0.002; OR, 1.590), duration of
      cardiopulmonary bypass (p = 0.0004; OR, 1.27 per 60 minutes), renal failure (p =
      0.0062; OR, 2.032), peripheral vascular disease (p = 0.0157; OR, 1.62), cigarette
      smoking (p = 0.0197; OR, 1.621), and diabetes mellitus (p = 0.0158; OR, 1.373).
      CONCLUSIONS: Postoperative stroke increases mortality and length of stay after
      coronary revascularization. Several risk factors can be identified, and some of
      these factors are potentially amenable to intervention, either before or during
      coronary revascularization, and should also influence patient selection.

PMID- 10654482
TI  - Hirudin as anticoagulant for cardiopulmonary bypass: importance of preoperative
      renal function.
AB  - BACKGROUND: Recombinant hirudin is an alternative anticoagulant for
      cardiopulmonary bypass in patients with heparin-induced thrombocytopenia type II.
      Although there is no neutralizing agent for recombinant hirudin, its fast renal
      elimination enables quick cessation of bleeding after cardiopulmonary bypass. The
      aim of the study was to compare anticoagulant effects of recombinant hirudin in
      regards to renal function in patients with heparin-induced thrombocytopenia type
      II. METHODS: Twenty-one patients (mean age, 65 years, and range, 35 to 82 years)
      underwent different complex cardiovascular procedures using recombinant hirudin
      as the anticoagulant for cardiopulmonary bypass. Postoperative blood loss,
      transfusion requirements, and hemostatic variables were compared between patients
      with a creatinine level lower than 1.5 mg/dL (group 1, normal renal function; n =
      17 patients) and those with a creatinine level greater than 1.5 mg/dL (group 2,
      impaired renal function; n = 4 patients). RESULTS: The patients in group 1 showed
      no increased tendency toward postoperative bleeding. In contrast, all 4 patients
      in group 2 required reexploration for increased postoperative bleeding. They had
      higher activated partial thromboplastin times and transfusion requirements
      postoperatively. CONCLUSIONS: If recombinant hirudin is used as the anticoagulant
      for cardiopulmonary bypass in patients with heparin-induced thrombocytopenia type
      II and impaired renal function, the risk of postoperative bleeding is increased.

PMID- 10654483
TI  - Perspectives of a cardiac surgery resident in-training on off-pump coronary
      bypass operation.
AB  - BACKGROUND: Contemporary residency training in the cardiac component of
      cardiothoracic operation is focused mainly on attaining technical proficiency in
      coronary artery revascularization. Most trainees in cardiothoracic operation are
      required to perform 35 cases of coronary revascularization in order to fulfill
      the minimum requirements for certification by the American Board of Thoracic
      Surgery. Although experience in minimally invasive coronary revascularization is
      not required for board certification in cardiothoracic operation, it is
      recognized by both trainees and program directors as an important component of
      contemporary training in less-invasive surgical approaches (LISA) for coronary
      artery disease. The objective of this study was to describe the training of
      residents in off-pump coronary revascularization in an accredited training
      program. METHODS: A retrospective analysis of a single resident's experience in
      minimally invasive coronary revascularization over an 18 month period in a 2-year
      residency program in cardiothoracic operation was carried out. RESULTS: Of the
      166 total cases of coronary bypass operation, the resident performed 61 cases
      (37% of the total) off-pump as primary surgeon with attending supervision.
      Patients undergoing off-pump coronary bypass had an average of 2.4 grafts (range
      1 to 5) and conventional coronary artery surgeon (on cardiopulmonary bypass)
      performed by the resident had an average of 4 grafts (range 2 to 5). The
      marginal/circumflex system was bypassed in patients that required
      revascularization of the marginal/circumflex system, which was 56% (n = 36 of 62)
      in the off-pump group and 90% for the conventional group using cardiopulmonary
      bypass. The conversion rate from off-pump technique to conventional coronary
      bypass using cardiopulmonary bypass was 3.2% in this series. CONCLUSIONS:
      Technical innovations and evolution of techniques to better stabilize the heart
      for off-pump coronary revascularization have made the procedure both effective
      and safe. Our experience has shown that cardiothoracic residents can be taught
      the skills necessary to perform coronary revascularization off cardiopulmonary
      bypass. There are currently no standards for the training of cardiothoracic
      residents in off-pump coronary artery operation. We propose that at least 50
      cases be performed under supervision by a trained surgeon to obtain adequate
      credentials in minimally invasive coronary revascularization.

PMID- 10654484
TI  - Performance of 21-mm size perimount aortic bioprosthesis in the elderly.
AB  - BACKGROUND: Aortic valve replacement in elderly patients with a small aortic
      annulus may pose difficult problems in terms of prosthesis selection. We have
      evaluated the hemodynamic performance of the 21-mm Carpentier-Edwards Perimount
      bioprosthesis implanted in elderly patients. METHODS: From July 1996 to June
      1998, 19 patients (17 women and 2 men, mean age 76+/-4 years and mean body
      surface area 1.73+/-0.13 m2), had aortic valve replacement with a 21-mm
      Carpentier-Edwards Perimount bioprosthesis. The hemodynamic performance of the
      valve was evaluated in 16 patients, who completed at least a 6-month follow-up
      interval, with transthoracic color-Doppler echocardiography with particular
      reference to peak and mean transprosthetic gradients, effective orifice area
      index, and regression of left ventricular mass index. RESULTS: There were no late
      deaths and no major postoperative complications. At a mean follow-up of 12+/-7
      months, compared to discharge, all patients showed clinical improvement with a
      significant reduction of peak gradient (from 23+/-4 to 21+/-6 mm Hg, p = 0.04)
      and left ventricular mass index (from 181+/-23 to 153+/-20 g/m2; p<0.001),
      whereas mean gradient (from 13+/-3 to 13+/-4 mm Hg, p = not significant) and
      effective orifice area index (from 1.12+/-0.34 to 1.13+/-0.28 cm2/m2, p = not
      significant) remained substantially unchanged. CONCLUSIONS: The use of a 21-mm
      Carpentier-Edwards Perimount bioprosthesis is associated with low transprosthetic
      gradients and significant reduction in left ventricular hypertrophy after aortic
      valve replacement. The results of our study suggest that a 21-m Carpentier
      Edwards Perimount bioprosthesis should be considered a valid option in elderly
      patients with aortic valve disease and a small aortic annulus.

PMID- 10654485
TI  - Role of myocardial revascularization in postinfarction ventricular septal
      rupture.
AB  - BACKGROUND: Postinfarction ventricular septal rupture requires urgent closure.
      The role of systematic coronarography and coronary revascularization needs
      clarification. METHODS: Fifty-four patients who underwent patch closure of
      postinfarction ventricular septal defect were reviewed. A coronarography had been
      systematically and myocardial revascularization selectively (when significant
      coronary artery stenosis existed) performed. RESULTS: No patient died or
      deteriorated during coronarography. Twenty-six patients showed no coronary artery
      disease besides the infarct-related artery, and 28 had associated disease.
      Threatened myocardial territories were revascularized usually with venous grafts
      (mean number of distal anastomosis, 2.5). Operative mortality was 19% and 32% (p
      = 0.36) and late mortality 43% and 53% (p = 0.75) in patients without and in
      patients with associated coronary artery disease, respectively. Survival curve in
      both group was similar, at least up to 8 years after operation. CONCLUSIONS:
      Myocardial revascularization controlled the added risk of associated coronary
      artery disease in the postoperative period and in median term. A coronarography
      should be performed in all patients who can be stabilized hemodynamically and
      myocardial revascularization performed in case of significant stenosis.

PMID- 10654486
TI  - Early and follow-up angiography in minimally invasive coronary bypass without
      mechanical stabilization.
AB  - BACKGROUND: This study was undertaken to assess the early and late outcome of
      coronary anastomosis constructed on a beating heart without the help of
      mechanical stabilization. METHODS: All consecutive patients (51) from January
      1996 to September 1997 who had bypass done by one surgeon using a left
      minithoracotomy (39) or median sternotomy (12) on a beating heart with occlusive
      local snares without mechanical stabilization underwent follow-up angiography
      early (100%) (within 6 hours) and late (63.5%) at a mean of 9.6+/-4.48 months
      (range, 3.3 to 19.1 months). RESULTS: The cumulative late patency was 95.4% (83
      of 87 patients), with two early and two late occlusions. There was no early or
      late mortality or perioperative myocardial infarction. Two patients (3.9%)
      developed recurrent angina. Four anastomotic irregularities (4 of 32 patients,
      12.6%) have cleared up on follow-up angiography. There was no evidence of late
      stenosis at the snare sites used for local occlusion. CONCLUSIONS: Minimally
      invasive coronary bypass is safe and effective. Early angiographic abnormalities
      should be interpreted with caution and we could not demonstrate any long-term
      deleterious effects of local snaring.

PMID- 10654487
TI  - Preoperative immunoglobulin treatment in patients with Werlhof's disease
      undergoing cardiac operation.
AB  - BACKGROUND: Patients with Werlhof's disease and undergoing a cardiac surgical
      procedure with cardiopulmonary bypass are at increased risk for bleeding
      complications. We report the usefulness of preoperative immunoglobulin treatment
      in selected patients. METHODS: Between May 1995 and July 1998, 10 patients with
      Werlhof's disease underwent a cardiac surgical procedure with cardiopulmonary
      bypass in our department. Five patients with mean platelet counts of less than
      80x10(9)/L received immunoglobulin therapy preoperatively (group 1). The other 5
      patients with mean platelet counts higher than 80x10(9)/L were not so treated
      (group 2). RESULTS: In group 1, mean platelet count increased from 54x10(9)/L 5
      days before operation to 112x10(9)/L after immunoglobulin treatment (p = 0.018)
      and did not fall to less than 60x10(9)/L postoperatively. Patients in group 1
      received 16 units of packed red blood cells and 5 units of platelet concentrate.
      Patients in group 2 required 24 units of packed red blood cells, 5 units of
      platelet concentrate, and 23 units of fresh frozen plasma. Only 1 patient (group
      2) had a surgical bleeding complication that required reexploration. Mean
      drainage loss was 1,100 mL in group 1 and 1,210 mL in group 2. CONCLUSIONS: Our
      data demonstrate that immunoglobulin treatment of patients with Werlhof's disease
      and mean platelet counts of less than 80x10(9)/L significantly augments platelet
      counts preoperatively. It may be useful in selected patients.

PMID- 10654488
TI  - Coronary artery bypass grafting with gastroepiploic artery composite graft.
AB  - BACKGROUND: To achieve better results after coronary artery bypass grafting
      (CABG), arterial conduits are the first choice in multiple CABG for younger
      patients. We present here the early results of CABG with gastroepiploic artery
      (GEA) composite graft with free radial artery (RA) to revascularize right
      coronary artery or left circumflex artery in addition to internal thoracic artery
      to left anterior descending artery. METHODS: Between July 1997 and June 1998, 13
      patients received CABG with GEA (larger caliber than 2.0 mm) composite graft. We
      have assessed the early results. RESULTS: There was no postoperative death or
      major morbidity. Postoperative angiogram was performed in 11 patients and all
      conduits were patent. Postoperative exercise stress test was done in 13 cases and
      showed no ischemia. CONCLUSIONS: Multiple CABG with arterial conduit can be
      performed by this procedure. The free RA functioned from secondary branches
      derived from proximal GEA. In conclusion, this procedure seems to be safe and
      effective, and both long-term patency and better quality of life may be expected.

PMID- 10654489
TI  - Surgical outcome of traumatic rupture of the thoracic aorta.
AB  - BACKGROUND: The aim of this study was to point out the results of different
      techniques of spinal cord protection in surgically-treated patients with
      traumatic thoracic aorta (TTA). METHODS: A multicentric study was carried out
      involving 182 patients with TTA. Four patients died before surgery. Two patients
      were operated on without any investigation and 2 had no aortic tear at
      thoracotomy. The remaining 174 patients had aortic isthmus disruption and were
      included in the study. The mean age was 32.3+/-14.29 years with 126 men (72.4%)
      and 48 women (27.6%). Road accidents were causal in 163 patients (93.66%);
      polytraumatism was frequent. A standard chest roentgenogram led to a diagnosis
      which was confirmed with aortography in 94.8% of cases. Surgical repair of
      visceral lesions was performed in 52 patients (29.9%) for traumatic spleen,
      liver, diaphragm, mesentery, and gut. These operations were done before or after
      aortic operation in 21.3% and 8.6% of cases, respectively. Thirty-three patients
      (19%) died and 9 (5.2%) had paraplegia. Sixty-nine patients had clamp and sew
      technique (group 1). Ninety-three patients had different types of extracorporeal
      circulation (group 2), and 12 patients had Gott shunt (group 3). No difference
      appeared between the 3 groups according to mortality and paraplegia. But the sex
      ratio, age, visceral lesions, craniocerebral lesions, the type of aortic repair,
      and cross-clamp time were discriminative. RESULTS: The univariate analysis point
      out age, cross-clamp time, hemothorax, and anatomical type of aortic injury as
      the risk factors of death. This was confirmed by a multivariable test which
      retained age, cross-clamp time, and hemothorax as risk factors. When not
      diagnosed in time, TTA is serious and has a bad prognosis. In spite of a high
      mortality and morbidity, the surgical management has improved. Immediate
      operation and medullar protection are the stumbling block in this operation.
      CONCLUSIONS: Operation can be delayed in some cases, but one must take care of
      hemodynamic instability. This calls for a repair of the serious associated
      lesions first, or of a quick performing of a thoracotomy for ruptured aorta. The
      question remains, is it better to protect the spinal cord with the lower aortic
      perfusion and avoid the simple cross-clamp? Clinical studies give few answers to
      this question, and the best answer has not yet been given, as we lack prospective
      studies in this field.

PMID- 10654490
TI  - Intermittent antegrade warm blood cardioplegia for CABG: extended interval of
      cardioplegia.
AB  - BACKGROUND: Intermittent delivery of warm cardioplegia provides a bloodless
      surgical field, but it is clinically important to evaluate the periods of
      normothermic ischemia. The aims of this study are to compare intermittent
      antegrade warm blood cardioplegia (IAWBC) with intermittent antegrade cold blood
      cardioplegia (IACBC) groups in terms of myocardial protection, and also to
      evaluate whether the length of ischemic time in the IAWBC group has an effect on
      myocardial dysfunction. METHODS: This study is based on a retrospective review of
      patients who underwent elective coronary artery bypass surgery: 162 consecutive
      patients with IAWBC and 107 consecutive patients with IACBC. RESULTS: The
      creatinine kinase peak was smaller in the IAWBC group compared with the IACBC
      group (p<0.0001). The cardiac index after cardiopulmonary bypass was higher in
      the IAWBC group (p<0.02), and the amount of inotropic support required to wean
      from cardiopulmonary bypass was less in the IAWBC group compared with the IACBC
      group (p<0.0001). CONCLUSIONS: IAWBC with 30 minutes of ischemia provides to be
      clinically acceptable myocardial protection for coronary bypass surgery.

PMID- 10654491
TI  - Drew-Anderson technique attenuates systemic inflammatory response syndrome and
      improves respiratory function after coronary artery bypass grafting.
AB  - BACKGROUND: Cardiopulmonary bypass causes inflammatory reactions leading to organ
      dysfunction postoperatively. This study was undertaken to determine whether using
      patients' own lungs as oxygenator in a bilateral circuit (Drew-Anderson
      Technique) could reduce systemic inflammatory response to cardiopulmonary bypass,
      improving patients clinical outcome following coronary artery bypass grafting.
      METHODS: A prospective randomized controlled trial involving 30 patients, divided
      in two groups of 15 patients each, undergoing elective coronary artery bypass
      grafting, was undertaken. In the Drew-group bilateral extracorporeal circulation
      using patient's lung as oxygenator was performed. The other patients served as
      control group, where standard cardiopulmonary bypass procedure was used. RESULTS:
      Pro-inflammatory and anti-inflammatory mediators were measured. Peak
      concentrations of proinflammatory interleukin-6, interleukin-8, were
      significantly lower in 15 patients undergoing Drew-Anderson Technique compared
      with the concentrations measured in 15 patients treated with standard
      cardiopulmonary bypass technique. Differences in patient recovery were analyzed
      with respect to time of intubation, blood loss, intrapulmonary shunting,
      oxygenation, and respiratory index. In patients undergoing uncomplicated coronary
      artery bypass grafting procedures bilateral extracorporeal circulation using the
      patients' own lung as oxygenator provided significant biochemical and clinical
      benefit in comparison to the standard cardiopulmonary bypass procedure.
      CONCLUSIONS: This prospective randomized clinical study has demonstrated that
      exclusion of an artificial oxygenator from cardiopulmonary bypass circuit
      significantly decreases the activation of inflammatory reaction, and that
      interventions that attenuate this response may result in more favorable clinical
      outcome.

PMID- 10654492
TI  - LV-powered coronary sinus retroperfusion reduces infarct size in acutely ischemic
      pigs.
AB  - BACKGROUND: We developed a prosthetic left ventricle (LV) to coronary sinus (CS)
      shunt (LVCSS) that is autoregulating and provides LV-powered retrograde perfusion
      of the coronary sinus. METHODS: Each of 20 Yorkshire pigs underwent 1 hour of
      left anterior descending diagonal artery occlusion followed by 3 hours of
      reperfusion. The controls (n = 5) did not have shunt treatment. The LVCSS group
      (n = 9) underwent shunt treatment during the ischemic period. The LVCSS with
      partial coronary sinus occlusion (PCSO) group (LVCSS+PCSO, n = 6) underwent shunt
      treatment and PCSO during the ischemic period. Vital staining and planimetry
      techniques were used to determine the area at risk for infarction and the area of
      necrosis. RESULTS: The area at risk was not significantly different among groups.
      The area of necrosis was decreased by 53% in the LVCSS group and by 73% in the
      LVCSS+PCSO group when compared to controls (p<0.01 among all groups).
      CONCLUSIONS: The LVCSS reduces infarct size in pigs after acute coronary artery
      occlusion. The addition of PCSO to LVCSS further improves myocardial salvage.

PMID- 10654493
TI  - Emergency coronary artery bypass graft surgery in abciximab-treated patients.
AB  - BACKGROUND: Although the platelet antiaggregant abciximab is frequently used with
      percutaneous coronary interventions, results of emergency coronary artery bypass
      graft operations in patients recently treated with abciximab are poorly
      characterized. METHODS: During a 29-month period, 12 patients required emergency
      coronary artery bypass grafting within 12 hours (mean, 1.9 hours) of abciximab
      therapy. Our full standard heparin dose regimen was used (mean heparin dose,
      53,000 U per patient). Each patient received a single platelet transfusion dose
      after protamine administration, and further blood products were transfused as
      necessary. Clinical outcome and transfusion requirements were compared with
      predicted results based on risk-adjusted historical patients. RESULTS: No
      patients died and none were returned to the operating room for coagulopathy
      related bleeding. Per patient transfusion requirements were as follows: red blood
      cells, 3.6 units; apheresis platelets, 1.4 units; and fresh frozen plasma, 1.5
      units. As compared with predicted values, there was no excessive incidence of
      mortality, stroke, or red blood cell transfusion requirements. CONCLUSIONS:
      Emergency coronary artery bypass graft operations using full-dose heparin can be
      performed successfully in acutely ischemic abciximab-treated patients.
      Prophylactic transfusion of platelets after protamine administration appears to
      be useful.

PMID- 10654494
TI  - Cardiac surgery in patients with end-stage renal disease: 10-year experience.
AB  - BACKGROUND: End-stage renal disease is known to be an important risk factor
      complex for cardiac operations performed with cardiopulmonary bypass. METHODS: To
      investigate the influence of preoperative status on perioperative mortality and
      morbidity, we retrospectively analyzed data from 65 patients (20 women and 45 men
      with a mean age of 58.8+/-10.0 years [+/-standard deviation]) with end-stage
      renal disease who were on dialysis and who underwent a cardiac surgical procedure
      between 1988 and 1998. RESULTS: Fifty-one percent of the patients had isolated
      coronary artery bypass grafting, 35% had replacement or reconstruction of one
      valve or two valves, and 14% underwent combined coronary artery bypass grafting
      and valve replacement. The perioperative mortality rate was 13.8% with 78% (7 of
      9) of deaths occurring in patients having a valve procedure. Six of the 9
      patients who died had compromised left ventricular function preoperatively, and
      all 9 were in New York Heart Association class III or IV. Mean preoperative
      duration of dialysis was longer (80+/-70 months) in the 9 patients who died
      compared with that in the surviving 56 patients (45+/-49 months) (p = 0.05). We
      found dyspnea at rest, duration of dialysis of 60 months or more, combined
      procedures (coronary artery bypass grafting and valve operation), and New York
      Heart Association class IV to be associated with a higher relative risk for
      perioperative death. Neither angina pectoris nor isolated coronary artery bypass
      grafting was associated with increased relative risk for perioperative death.
      However, after a cardiac operation, mortality in patients with end-stage renal
      disease was substantially higher than in those with normal renal function.
      CONCLUSIONS: These data are comparable with those in the literature and possibly
      suggest that both indications and referral for surgical intervention have been
      delayed in patients who have end-stage renal disease combined with coronary
      artery disease, valve disease, or both. The delay may contribute to the
      relatively high perioperative mortality.

PMID- 10654495
TI  - Arginine vasopressin in the treatment of 50 patients with postcardiotomy
      vasodilatory shock.
AB  - BACKGROUND: The barroreflex-mediated secretion of arginine vasopressin has been
      found to be defective in a variety of vasodilatory shock states, such as
      postcardiotomy shock, and administration of the hormone markedly improves
      vasomotor tone and blood pressure. The high incidence of vasodilatory shock in
      patients undergoing left ventricular assist device (LVAD) implantation makes this
      population an ideal model in which to assess the risks and benefits of
      vasopressin. METHODS: The medical records of the 102 patients receiving LVADs at
      Columbia-Presbyterian Medical Center from January 1995 to August 1998 were
      reviewed. Fifty patients were eligible for study based on a history of arginine
      vasopressin administration in the operating room or intensive care unit within 24
      hours of implantation. RESULTS: Despite LVAD implantation and the administration
      of vasopressors, patients were hypotensive with a mean arterial pressure less
      than 60 mm Hg. The administration of vasopressin (0.09+/-0.05 U/min) increased
      mean arterial pressure (58+/-13 to 75+/-14 mm Hg; p<0.001) while reducing
      norepinephrine administration (11.7+/-13 to 7.9+/-6.0 mcg/min; p = 0.023). There
      was no significant change in LVAD flow. The incidence of compromised regional
      perfusion was not different between LVAD patients who received vasopressin as
      compared to hemodynamically stable LVAD patients who did not receive vasopressin.
      CONCLUSIONS: We have demonstrated vasopressin at low doses to be a safe and an
      effective vasopressor in 50 patients with postcardiotomy vasodilatory shock.

PMID- 10654496
TI  - Heart preservation in HTK solution: role of coronary vasculature in recovery of
      cardiac function.
AB  - BACKGROUND: Poor myocardial tolerance to prolonged cold ischemia remains a major
      concern in heart transplantation. In this study, we estimated superiority of
      Histidine-Tryptophan-Ketoglutarate (HTK) over University of Wisconsin (UW) as a
      cardiac preservation solution. METHODS: Isolated rat hearts were mounted on a
      Langendorff apparatus to estimate the baseline cardiac function. The hearts were
      arrested and stored at 4 degrees C in UW and HTK solution for 8 hours, and then
      reperfused. The aortic flow, coronary flow, cardiac output, rate pressure
      product, and left ventricular dp/dt in the HTK group recovered significantly more
      than the UW group. The values of myocardial total adenine nucleotides and the
      adenosine triphosphate to adenosine diphosphate ratio were higher in the HTK than
      in the UW group. We also examined coronary vascular responsiveness using left
      coronary arteries dissected from the rat hearts before flushing, before storage,
      after storage, and after reperfusion. RESULTS: The maximal relaxation response to
      acetylcholine was significantly higher in the HTK than in the UW group after
      reperfusion, although there were no significant differences at each stage before
      reperfusion. In addition, the endothelium-independent relaxation response to
      sodium nitroprusside in the HTK group was also well preserved after reperfusion.
      CONCLUSIONS: These results indicate that HTK is superior to UW solution for
      cardiac preservation. HTK protects coronary vasculature during preservation,
      which together with reperfusion might lead to improved functional cardiac
      recovery following preservation.

PMID- 10654497
TI  - Radial artery harvest: comparison of ultrasonic dissection with standard
      technique.
AB  - BACKGROUND: The radial artery (RA) is used increasingly for myocardial
      revascularization. Having an ultrasonic dissector available in our unit, we began
      to use it for RA harvest with the impression that harvest spasm might be less for
      the new technique. METHODS: We compared RA harvest using standard techniques (21
      RA) with ultrasonic dissection (41 RA) in which all branches were divided between
      clips with scissors in the former and bleeding branches were clipped in the
      latter. RESULTS: Harvest times were not different. Conventional technique used
      74+/-18 (mean +/- standard deviation) clips versus 3.2+/-4.3 clips (p<0.001). In
      situ free flow was 17.2+/-20.7 mL/min for conventional technique versus 52.5+/
      48.1 for ultrasonic (p<0.001). Free flow after the proximal anastomosis to the
      left internal thoracic artery was 38.5+/-60.4 mL/min for conventional technique
      and 50.7+/-29.6 for ultrasonic (p = 0.008). Free flow 10 minutes after
      intraluminal papaverine was 78.5+/-45.9 mL/min for usual technique versus 102.8+/
      51.7 for ultrasonic (p = 0.016). No patient required reoperation for bleeding.
      CONCLUSIONS: Ultrasonic dissection of the RA is associated with decreased RA
      spasm, good hemostasis, no additional harvest time, and has become our standard
      technique.

PMID- 10654498
TI  - Biocompatibility of silicone-coated oxygenator in cardiopulmonary bypass.
AB  - BACKGROUND: This study was designed to analyze the biocompatibility of silicone
      coated oxygenators using inflammatory response as the outcome measure, and to
      investigate whether the silicone-coated oxygenators perform better in terms of
      postoperative organ dysfunction. METHODS: The 32 patients who underwent
      cardiopulmonary bypass (CPB) were divided into 3 groups: group A (n = 10),
      heparin-coated circuit with silicone-coated oxygenator; group B (n = 11), whole
      heparin-coated circuit; and group C (n = 11), whole untreated circuit. The plasma
      concentrations of the proinflammatory markers, made of inflammatory cytokines
      (tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, interleukin-8),
      terminal complement complex (C5b-9), and polymorphonuclear elastase (PMN-E), were
      measured by enzyme-linked immunosorbant assay. RESULTS: All proinflammatory
      markers were significantly lower in groups A and B than in group C, especially
      C5b-9 and PMN-E concentrations, which were significantly lower in group A than in
      group B. The alveolar-arterial oxygen gradients (A-aDO2) and the respiratory
      index were significantly better in group A than in group C. In group B, however,
      only the A-aDO2 was significantly better than in group C. The duration of
      intubation and the length of stay in the intensive care unit stay were
      significantly shorter in groups A and B than in group C. CONCLUSIONS: Silicone
      coated oxygenators are biocompatible and prevent postoperative organ dysfunction.

PMID- 10654499
TI  - A new technique for debridement in rheumatic valvular disease: the rasping
      procedure.
AB  - BACKGROUND: Valve repair is superior to valve replacement in terms of
      postoperative risk. However, the conventional techniques used for valve repair in
      patients with rheumatic valvular disease have not resulted in a good long-term
      outcome. METHODS: We developed a novel "rasping procedure" using an electric
      rasper for debridement in rheumatic valvular diseases. Between April 1986 and
      December 1996, the rasping procedure was performed on the aortic valve (A
      rasping) of 24 patients who exhibited moderate stenosis with mild regurgitation.
      Between June 1992 and December 1996, this procedure was performed on the mitral
      valve (M-rasping) of 12 patients who exhibited mitral stenosis with mild
      regurgitation. RESULTS: Among the 24 patients on whom A-rasping was performed, 4
      patients did not show any improvement after the A-rasping procedure, and required
      valve replacement. In each of the remaining 20 cases, the transvalvular pressure
      gradient decreased, and regurgitation disappeared, or was reduced to a trivial
      level. In all 12 patients on whom M-rasping was performed, the transvalvular
      pressure gradient significantly decreased, orifice area significantly increased,
      and the regurgitation disappeared. Postoperative echocardiographic examinations
      were performed during a mean follow-up period of 110 months in the patients who
      received A-rasping, and that of 50 months in the patients who received M-rasping.
      A significant change in the valve requiring subsequent surgery was not seen in
      any of the patients. CONCLUSIONS: The rasping procedure is an effective technique
      for excising rheumatic valvular hypertrophic lesions. It resulted in good
      intermediate to long-term outcome.

PMID- 10654500
TI  - The combination of propranolol and magnesium does not prevent postoperative
      atrial fibrillation.
AB  - BACKGROUND: Atrial fibrillation is a common complication of cardiovascular
      surgery. Beta-blockers have been shown to decrease the incidence of postoperative
      atrial fibrillation. However, the use of magnesium is more controversial. It was
      our hypothesis that adjunctive magnesium sulfate would improve the efficacy of
      beta-blockers alone in the prevention of postoperative atrial fibrillation.
      METHODS: We prospectively randomized 167 coronary artery bypass patients (mean
      age 61+/-10 years, 115 men) to receive propranolol alone (20 mg four times daily)
      or propranolol and magnesium (18 g over 24 hours). Magnesium was begun
      intraoperatively, and propranolol was started on admission to the intensive care
      unit. RESULTS: Using an intention-to-treat analysis, the incidence of
      postoperative atrial fibrillation was 19.5% in the propranolol-treated patients
      and 22.4% in propranolol + magnesium-treated patients (p = 0.65). Because
      combination therapy resulted in an excess of postoperative hypotension, which
      required withholding doses of propranolol, an on-treatment analysis was also
      performed. In this analysis, the incidence of atrial fibrillation was still not
      significantly different (18.5% in propranolol-treated patients and 10.0% in
      propranolol + magnesium-treated patients, p = 0.20). CONCLUSIONS: Adjunctive
      magnesium sulfate, in combination with propranolol, does not decrease the
      incidence of postoperative atrial fibrillation.

PMID- 10654501
TI  - Surgical management of the straddling mitral valve in the biventricular heart.
AB  - BACKGROUND: The straddling mitral valve in the biventricular heart is a rare
      condition that may complicate biventricular repair. METHODS: Treatment and
      outcomes in 5 consecutive patients who underwent primary repair between 1992 and
      1997 were reviewed. Their ages at repair ranged from 2 months to 8 years. Three
      patients had a double-outlet right ventricle with a subaortic (n = 2) or
      subpulmonary (n = 1) ventricular septal defect. Two patients had transposition of
      the great arteries (S,D,D), a ventricular septal defect, and left ventricular
      outflow tract obstruction. The attachments of the papillary muscles of the
      straddling mitral valves were located on the right ventricular aspect of the
      ventricular septum. Four patients underwent baffle partitioning of the
      ventricular cavity. The baffle suture line was used to secure the chordae
      tendineae crossing the ventricular septal defect, or was intentionally omitted at
      the papillary muscle. The right ventricular outflow tract was reconstructed with
      patch augmentation, an extracardiac conduit, or an arterial switch operation. One
      patient with transposition who had a giant papillary muscle to the straddling
      mitral valve associated with abnormal insertion of the tricuspid valve on the
      conal septum underwent univentricular repair. RESULTS: There were no early or
      late postoperative deaths. There was no mitral valve dysfunction, left
      ventricular outflow tract obstruction, or heart block in the 4 patients who
      underwent biventricular repair. CONCLUSIONS: Although there are several
      exceptional situations in which ventricular partitioning may result in early and
      late complications, a straddling mitral valve does not preclude biventricular
      repair.

PMID- 10654503
TI  - Effect of cardiopulmonary bypass on pulmonary gas exchange: a prospective
      randomized study.
AB  - BACKGROUND: Conventional coronary artery bypass surgery is associated with
      postoperative pulmonary dysfunction. Inflammation due to cardiopulmonary bypass
      has been regarded as one of the main causes. In this study, we investigated the
      effect of coronary revascularization with or without cardiopulmonary bypass on
      pulmonary function. METHODS: Fifty-two patients (40 male, mean age 60.1 years)
      were prospectively randomized to undergo coronary revascularization via median
      sternotomy, with or without normothermic cardiopulmonary bypass. Alveolar
      arterial oxygen gradients were measured before and after induction of anesthesia,
      postoperatively in the intensive care unit during mechanical ventilation and 6
      hours after tracheal extubation. The techniques of anesthesia and mechanical
      ventilation were standardized throughout. RESULTS: Patient characteristics were
      similar in the two groups. The alveolar-arterial oxygen gradients increased
      progressively throughout the perioperative period, with no significant
      differences in the two groups at any time during the study. CONCLUSIONS:
      Myocardial revascularization with or without cardiopulmonary bypass caused a
      similar degree of pulmonary dysfunction, as assessed by alveolar-arterial oxygen
      gradient. Our study suggests that the deterioration in pulmonary gas exchange
      associated with cardiac surgery is due to factors other than the use of
      cardiopulmonary bypass.

PMID- 10654502
TI  - Intraoperative echocardiographic detection of regurgitant jets after valve
      replacement.
AB  - BACKGROUND: Paravalvular jets, documented by intraoperative transesophageal
      echocardiography, have prompted immediate valve explantation by others, yet the
      significance of these jets is unknown. METHODS: Twenty-seven patients had
      intraoperative transesophageal two-dimensional color Doppler echocardiography,
      performed to assess the number and area of regurgitant jets after valve
      replacement, before and after protamine. Patients were grouped by first time
      versus redo operation, valve position and type. RESULTS: Before protamine, 55
      jets were identified (2.04+/-1.4 per patient) versus 29 jets after (1.07+/-1.2
      per patient, p = 0.0002). Total jet area improved from 2.0+/-2.2 cm2 to 0.86+/
      1.7 cm2 with protamine (p<0.0001). In all patients jet area decreased (average
      decrease, 70.7%+/-27.0%). First time and redo operations had similar improvements
      in jet number and area (both p>0.6). Furthermore, mitral and mechanical valves
      each had more jets and overall greater jet area when compared to aortic and
      tissue valves, respectively. CONCLUSIONS: Following valve replacement, multiple
      jets are detected by intraoperative transesophageal echocardiography. They are
      more common and larger in the mitral position and with mechanical valves.
      Improvement occurs with reversal of anticoagulation.

PMID- 10654504
TI  - Excellence and low case volume: an example of the inapplicability of volume-based
      credentialing.
AB  - BACKGROUND: Health care reform, public disclosure of hospital and surgeon
      specific results, plus changes in reimbursement patterns have raised the specter
      of volume-based credentialing. METHODS: Using The Society of Thoracic Surgeons
      Cardiac Database, we examined the data for all coronary artery bypass graft-only
      patients (n = 615) operated on by us from July 1991 to June 1997. RESULTS: The
      observed mortality was 0.33% and the observed-to-expected ratio was 0.12
      (p<0.005). Morbidity was low as well. CONCLUSIONS: Excellent results can be
      obtained for patients undergoing coronary artery bypass grafting in the presence
      of both low surgeon and low hospital case volume.

PMID- 10654505
TI  - Myocardial tactile stiffness during acute reduction of coronary blood flow.
AB  - BACKGROUND: Evaluation of regional myocardial contractile function is of clinical
      importance. We have developed a new tactile sensor system for accurate
      measurement of myocardial stiffness in situ. We found that the myocardial
      stiffness measured by this sensor, which we call tactile stiffness, can be a very
      useful index for accurate quantification of regional myocardial function. In this
      study, we used a coronary stenosis model to investigate regional myocardial
      tactile stiffness under conditions of reduced coronary blood flow. METHODS: The
      myocardial tactile stiffness, coronary blood flow, and ventricular pressure and
      volume, of five open chest mongrel dogs weighing 15 to 17 kg, were measured.
      After measuring the baseline myocardial stiffness, coronary arterial stenosis was
      induced with a balloon occluder. RESULTS: Reducing the coronary flow to 50% and
      25% of the baseline level reduced the end-systolic tactile stiffness
      significantly from 2.20+/-0.16 g/mm2 to 2.05+/-0.20 g/mm2 (p<0.05) and from
      2.21+/-0.16 g/mm2 to 1.96+/-0.18 g/mm2 (p<0.01), respectively. Reducing the flow,
      to 50% and 25%, increased the end-diastolic stiffness significantly from 1.29+/
      0.15 g/mm2 to 1.39+/-0.14 g/mm2 (p<0.01) and from 1.30+/-0.16 g/mm2 to 1.46+/
      0.14 g/mm2 (p<0.05), respectively. CONCLUSIONS: We consider that the regional
      myocardial tactile stiffness will be a useful index sensitive enough to detect
      changes in regional contractile function under conditions of reduced coronary
      blood flow.

PMID- 10654506
TI  - Global myocardial revascularization without cardiopulmonary bypass using
      innovative techniques for myocardial stabilization and perfusion.
AB  - BACKGROUND: In off-pump coronary bypass grafting (CABG), invasiveness is reduced
      but technically perfect anastomosis is jeopardized by cardiac motion and the need
      to hurry to reduce the time of ischemia. Also, a major cause of postoperative
      morbidity and mortality is ungrafted circumflex coronary artery disease. We have
      devised a means of overcoming these shortcomings and performing multivessel CABG.
      The objective of this study was to assess the safety and efficacy of our
      technique. METHODS: One hundred patients with severe triple-vessel disease
      underwent multivessel off-pump CABG. For cardiac stabilization, a combination of
      local pericardial stabilization sutures and lifting and rotating the heart by
      means of posterior pericardial sutures were used. For myocardial perfusion, a
      technique of retrograde coronary sinus perfusion by arterial blood from the
      ascending aorta was used. RESULTS: Each patient received an average of 3.8 grafts
      (range 3 to 5). Complications included conversion to cardiopulmonary bypass (CPB)
      in 1 patient and a perioperative myocardial infarction in the same patient. In
      all other patients we were able to perform a satisfactory grafting in all
      territories with no operative mortality. Rapid recovery allowed 95% of our
      patients to resume normal activity within 1 month. A predischarge graft angiogram
      in 35 patients showed 97.8% patency. CONCLUSIONS: These results suggest that off
      pump CABG with our techniques is effective and safe. Early clinical outcome and
      excellent patency rates suggest its more widespread use in selected cases.

PMID- 10654507
TI  - Late outcomes of open heart surgery in patients 70 years or older.
AB  - BACKGROUND: The purpose of this study is to examine the long-term survival and
      quality of life, including the influence of comorbidities, in patients 70 years
      of age and over after open heart surgery. METHODS: This was a retrospective study
      of 401 consecutive patients, who were 70 years of age or older at the time of
      surgery. Survival and quality of life of these patients were measured at 6- to 8
      year follow-up. RESULTS: The 5-year survival rate was 85%, and was comparable
      with the age- and gender-matched West Virginia population. Survival declined with
      increasing preexisting comorbidities. Of the 176 respondents completing the
      quality of life (SF-36) survey, most scores were similar to or substantially
      better than the US population normative scores for individuals 70 years of age or
      older. CONCLUSIONS: Survival rates vary by presence or absence of specific
      comorbid conditions. Quality of life in the appropriately selected elderly after
      open heart surgery appears to be similar to the US population normative scores.

PMID- 10654508
TI  - Perfusion-assisted direct coronary artery bypass: selective graft perfusion in
      off-pump cases.
AB  - BACKGROUND: Hemodynamic instability during multivessel off-pump coronary artery
      bypass grafting can lead to hypotension, progressive myocardial ischemia, further
      hypotension, and the need for urgent cardiopulmonary bypass. METHODS: In 10
      patients undergoing off-pump coronary artery bypass grafting, a novel technique
      of pressure-controlled blood delivery has been used that allows the immediate
      restoration of arterial blood to distal coronary beds after distal coronary
      anastomosis. This technique utilizes a servo-controlled pump to allow delivery of
      blood at systemic or suprasystemic pressures, and provides the option for
      infusion of supplemental additives for myocardial resuscitation, myocardial
      vasodilation, and enhancement of myocardial performance. RESULTS: Myocardial
      perfusion was successfully enhanced via one or two grafts in all 10 patients with
      an average graft flow of 98+/-8 mL/min. In 3 patients, a 27% increase in
      perfusion pressure led to a 59% increase in perfusate flow. All patients were
      hemodynamically stable after initiation of selective graft perfusion.
      CONCLUSIONS: Based on this preliminary patient series, the selective perfusion of
      grafted vessels seems to facilitate multivessel off-pump coronary artery bypass
      grafting by promoting rapid recovery of grafted segments, by enhanced hemodynamic
      stability during subsequent anastomoses, and by providing increased flexibility
      in the sequence of grafting.

PMID- 10654509
TI  - Preservation of the pulmonary valve complex in tetralogy of fallot: how small is
      too small?
AB  - BACKGROUND: Surgical repair of congenital lesions associated with right
      ventricular outflow tract obstruction frequently requires the destruction of
      pulmonary valve (PV) components including the valve annulus. The resultant
      pulmonary insufficiency may lead to late functional deterioration of right
      ventricular performance. Acute right ventricular dysfunction has been associated
      with poor pulmonary runoff, tricuspid valve regurgitation, and pulmonary
      hypertension. Preservation of PV competence may prevent both early and late right
      ventricular failure. However, the recent trend towards earlier repair of
      tetralogy of Fallot (TOF) may preclude preservation of the PV in favor of a
      transannular patch. We reviewed our experience with surgical repair of TOF to
      determine if age and/or body size affected the ability to repair the PV. METHODS:
      We reviewed the clinical records of 50 consecutive children who underwent
      surgical repair of TOF by one surgeon. The latter 27 patients underwent repair
      with an intention to preserve their pulmonary valve. In total, 28 patients
      underwent repair with preservation of their pulmonary valve, and form the basis
      of this study. Serial echocardiographic assessments were performed early (3 to 6
      months) and late (12 months) after surgery. RESULTS: Pulmonary valve preservation
      was possible in the majority of children (89%) in whom it was intended. Pulmonary
      valve competence was observed in 68% of children, with only 5 (16%) children
      demonstrating severe insufficiency at follow-up. Residual right ventricular
      outflow tract obstruction was present in only 1 child who underwent repair with
      pulmonary valve preservation at greater than 2 years of age. CONCLUSIONS: Our
      data suggest that earlier repair of TOF does not preclude preservation of the
      pulmonary valve and may indeed facilitate repair. The pulmonary valve remains
      competent at 12 months, with acceptable gradients, and should participate in
      somatic growth. Pulmonary valve preservation during repair of TOF may prevent
      free pulmonary insufficiency, progressive right ventricular dilation, and the
      need for future prosthetic pulmonary valve replacement.

PMID- 10654510
TI  - Right atrioventricular extracardiac conduit as a fontan modification: late
      results.
AB  - BACKGROUND: The right ventricle, when incorporated in the Fontan circulation,
      might enlarge and function as a pump to the pulmonary circulation. Experience has
      shown that over the long-term, this operation can be associated with major
      difficulties. METHODS: The late results, (13+/-6 years) after right
      atrioventricular connection as a Fontan modification, were reviewed in 14
      patients with tricuspid atresia (11), ventricular septal-defect with small right
      ventricle (2), and double inlet left ventricle (1) to assess the long-term
      survival, the right ventricular size, and the need and timing of reoperations.
      Operations used a valved conduit (7), a valveless Dacron (E.L. Bard, Haverhill,
      PA) tube (5) and a direct right atrium-right ventricle anastomosis (2). RESULTS:
      Death occurred in 5 by 8+/-5 years. Conduit obstruction occurred in 10 by 9+/-3
      years equally in patients with valved (6 of 7) compared to patients with
      valveless conduits (4 of 5) and irrespective of right ventricular size (3 of 4
      with enlarged right ventricle versus 4 of 6 with small ventricle). Patients with
      direct atrioventricular anastomosis had no obstruction. Reoperation was performed
      in 9 but failed to relieve the obstruction in 4 because of external compression
      (4) with or without thrombosis (1). CONCLUSIONS: Right atrioventricular
      connection as a Fontan modification can provide good early palliation, but is a
      poor long-term solution, as it is associated with a high incidence and
      difficulties in relieving the obstruction.

PMID- 10654511
TI  - Long-term follow-up of pediatric cardiac patients requiring mechanical
      circulatory support.
AB  - BACKGROUND: The present study examines the long-term outcome of pediatric
      patients with cardiac disease who required mechanical circulatory support with
      extracorporeal membrane oxygenation or ventricular assist devices. METHODS:
      Telephone interviews and questionnaires were administered to parents and
      physicians of pediatric cardiac patients who were in-hospital survivors after
      requiring mechanical circulatory support, with either extracorporeal membrane
      oxygenation or ventricular assist devices. Data was collected regarding these
      patients' general health, cardiac status, and neurologic outcome, and compared
      between the two modes of support. RESULTS: Follow-up was available for 26
      patients supported with extracorporeal membrane oxygenation (25 survivors, 96%)
      and 11 patients supported with ventricular assist devices (10 survivors, 91%);
      median follow-up 42 months, 11 to 92 months). More than 80% of survivors were in
      New York Heart Association class I or II. Of 31 patients for whom neurologic
      assessment data was available, moderate to severe neurologic impairment was more
      common for extracorporeal membrane oxygenation supported patients [13 of 21, 59%)
      than for ventricular assist device supported patients (2 of 10, 20% p = 0.03).
      Neurologic impairment was associated with small patient size and the use of
      circulatory arrest during cardiac surgical repair, but was not associated with in
      hospital neurologic complications, carotid cannulation, or presupport cardiac
      arrest. CONCLUSIONS: The long-term survival and cardiac functional status of
      pediatric cardiac patients requiring mechanical circulatory support is favorable.
      Extracorporeal membrane oxygenation supported patients demonstrate higher rates
      of neurologic impairment than patients supported with ventricular assist devices.
      Poor neurologic outcomes are associated with institution of support in younger
      patients with more complex congenital heart disease.

PMID- 10654512
TI  - Pulmonary vascular changes induced by congenital obstruction of pulmonary venous
      return.
AB  - BACKGROUND: Pulmonary venous obstruction (PVO) induces pulmonary arterial
      hypertension, as well as pulmonary venous hypertension, and jeopardizes the
      repair of cardiac lesions. METHODS: Four cases of congenital mitral stenosis and
      4 cases of cor triatriatum (Lucas type A), ages ranging from 2 months to 16
      years, were histologically examined on pulmonary vasculature. Histometrical
      analysis was performed on medial thickness and intimal changes of both pulmonary
      arteries and veins. For comparison, the examination of pulmonary vasculature in
      ventricular septal defect (VSD) cases was also performed. RESULTS: Medial
      thickening and intimal fibrosis, in both pulmonary arteries and veins with
      widespread lymphangiectasia, were characteristic vascular changes of PVO cases.
      Medial thickness of pulmonary arteries was correlated with preoperative pulmonary
      arterial pressure (PAP) (r = 0.77, p = 0.03 for systolic PAP), and greater than
      that of VSD cases. Medial thickness of pulmonary veins was also greater in PVO
      cases. Intimal fibrosis of pulmonary arteries and veins was seen extensively at
      the advanced ages, whereas no plexiform lesions or more advanced stages of
      pulmonary vascular disease were present. CONCLUSIONS: Congenital PVO induced
      progressive medial thickening and intimal fibrosis in pulmonary arteries and
      veins accompanied by lymphangiectasia. However, no plexiform lesions or more
      advanced stages of pulmonary vascular disease were present, which may explain the
      reversibility of pulmonary hypertension due to congenital PVO.

PMID- 10654513
TI  - Lowering reperfusion pressure reduces the injury after pulmonary ischemia.
AB  - BACKGROUND: Controlled reperfusion with a modified solution limits pulmonary
      injury following ischemia. Our initial studies infused this modified reperfusate
      at a pressure of 40 to 50 mm Hg to insure distribution. However, perhaps a lower
      pressure, which is closer to the normal physiologic pressure in the lung, would
      improve results by decreasing sheer stress. METHODS: Fifteen adult pigs underwent
      2 hours of lung ischemia by clamping the left bronchus and pulmonary artery. Five
      (group 1) then underwent uncontrolled reperfusion by removing the vascular clamps
      and allowing unmodified blood to reperfuse the lung at a pulmonary artery
      pressure of 20 to 30 mm Hg. The other 10 pigs underwent controlled reperfusion by
      mixing blood from the femoral artery with a crystalloid solution, and infusing
      this modified reperfusate into the ischemic lung through the pulmonary artery for
      10 minutes before removing the arterial clamp. In 5 (group 2), the modified
      solution was infused at a pressure of 40 to 50 mm Hg, and in 5 (group 3) 20 to 30
      mm Hg. Lung function was assessed 60 minutes after reperfusion and expressed as
      percentage of control. RESULTS: Compared to uncontrolled reperfusion (group 1),
      controlled reperfusion at a pressure of 40 to 50 mm Hg (group 2) significantly
      improved postreperfusion pulmonary compliance (77% versus 86%; p<0.001 versus
      group 1), and arterial/alveolar ratio (a/A) ratio (27% versus 52%; p<0.001 versus
      group 1); as well as decreased pulmonary vascular resistance (PVR) (198% versus
      154%; p<0.001 versus group 1), lung water (84.3% versus 83.5%; p<0.001 versus
      group 1), and myeloperoxidase (0.35 versus 0.23 optical density/min/mg protein).
      Reducing the pressure of the modified reperfusate to 20 to 30 mm Hg further
      improved postreperfusion compliance (92%+/-1%; p<0.001 versus groups 1 and 2) and
      a/A ratio (76%+/-1%; p<0.001 versus groups 1 and 2); and lowered PVR (133%+/-2%;
      p<0.001 versus groups 1 and 2), lung water (82.7%+/-0.1%; p<0.001 versus groups 1
      and 2), and myeloperoxidase (0.16%+/-0.01%; p<0.001 versus groups 1 and 2).
      CONCLUSIONS: After 2 hours of pulmonary ischemia, a severe lung injury occurs
      following uncontrolled reperfusion, controlled reperfusion with a modified
      solution reduces this reperfusion injury, and lowering the pressure of the
      modified reperfusate to more physiologic levels (20 to 30 mm Hg) further reduces
      the reperfusion injury improving pulmonary function.

PMID- 10654514
TI  - What is the optimal distal resection margin for esophageal carcinoma?
AB  - BACKGROUND: Whereas a proximal resection margin of 12 cm is recommended for
      complete resection of esophageal cancer, the extent of distal resection is
      unclear. METHODS: We examined distal resection margins in a consecutive series of
      patients who underwent esophagectomy for squamous cell carcinomas (n = 50),
      primary esophageal adenocarcinomas (n = 100), and adenocarcinomas of the cardia
      (n = 39), in whom all macroscopic tumor was judged to be completely resected.
      RESULTS: Microscopic tumor was found at a 3-cm distal resection margin for one
      multifocal squamous cell carcinoma. Positive distal resection margins were seen
      in 12% (12 of 100 patients) of primary esophageal adenocarcinomas (median, 2 cm
      versus 4 cm if negative; p = 0.002, Wilcoxon) and 28% (11 of 39 patients) of
      cardia adenocarcinomas (median, 1 cm versus 3 cm if negative; p = 0.02,
      Wilcoxon). Although pathologic stage was shown to be the only significant
      predictor of overall survival (Hazard ratio [HR] 1.8; 95% confidence interval 1.2
      to 2.6; p = 0.007), there was a trend toward reduced postoperative survival for
      patients with histologically positive distal resection margins, in particular for
      patients with cardia adenocarcinomas (median, 15.4 months versus 5.7 months if
      negative; p = 0.0001). CONCLUSIONS: To achieve consistently negative distal
      resection margins, we recommend resection of at least 5 cm of macroscopically
      normal foregut below the distal margin of the primary tumor.

PMID- 10654515
TI  - Exhaled nitric oxide correlates with experimental lung transplant rejection.
AB  - BACKGROUND: Increased nitric oxide production accompanies acute lung allograft
      rejection. Transforming growth factor-beta1 is an immunosuppressive cytokine
      capable of ameliorating acute rejection. The purpose of this study was to
      determine whether exhaled nitric oxide (eNO) concentrations correlated with the
      degree of acute rejection. METHODS: A model of acute lung transplant rejection in
      the rat was developed, and concentrations of eNO were measured at the time of
      animal sacrifice. In group 1 (partial immunosuppression), donor lungs were
      pretreated with transforming growth factor-beta1 before implantation. In group 2
      (fulminant acute rejection), no immunosuppression was used. In group 3 (full
      immunosuppression), recipients received cyclosporine. Group 4 were normal rats.
      RESULTS: When measured from both lungs, eNO concentrations were 4.97+/-0.68
      versus 6.73+/-2.90 ppb for groups 1 and 2, respectively (p = 0.58). When measured
      selectively from transplanted left lungs, eNO concentrations were 8.61+/-0.97
      versus 42.14+/-7.27 ppb, respectively (p<0.001). In groups 3 and 4, eNO
      concentrations were 1.02+/-0.21 and 1.51+/-0.74 ppb, respectively. CONCLUSIONS:
      Exhaled nitric oxide is elevated in fulminant acute rejection, is reduced after
      partial immunosuppression using transforming growth factor-beta1 gene therapy,
      and is in the normal range in cyclosporine-treated animals. The measurement of
      eNO correlates with the degree of acute lung allograft rejection and may serve as
      a noninvasive measure of acute lung transplant rejection in the clinical setting.

PMID- 10654516
TI  - Conservative treatment for postintubation tracheobronchial rupture.
AB  - BACKGROUND: Postintubation tracheobronchial rupture is usually responsible for
      unstable intraoperative or postoperative conditions, and its management is
      discussed. We insist on conservative treatment as a viable alternative after late
      diagnosis of postintubation tracheobronchial rupture. METHODS: We conducted a
      retrospective study including 14 consecutive patients treated between April 1981
      and July 1998. RESULTS: Twelve tracheobronchial ruptures occurred after
      intubation for general surgery and two after thoracic surgery. In all cases, the
      tear consisted of a linear laceration of the posterior membranous wall of the
      tracheobronchial tree ranging from 2 to 6 cm. One death occurred in a very weak
      patient unfit to undergo a redo operation for surgical repair. Seven patients
      were treated conservatively and cured without sequelae. Six patients underwent
      surgical repair, of whom 2 were diagnosed and repaired intraoperatively.
      CONCLUSIONS: Aggressive surgical repair is not always mandatory after delayed
      diagnosis of iatrogenic tracheobronchial rupture. Conservative treatment must
      often be considered, except after lung resection.

PMID- 10654517
TI  - Thoracoscopic resection of ectopic parathyroid glands.
AB  - BACKGROUND: The vast majority of parathyroid glands in hyperparathyroidism can be
      resected through a cervical approach. In approximately 2% of the cases, the
      ectopic gland is in the mediastinum in a location that requires a thoracic
      approach. METHODS: We report 7 such cases that were resected using video-assisted
      thoracic surgery to avoid the need for an open surgical procedure. RESULTS: All
      glands were successfully identified preoperatively and subsequently resected.
      Hospital stay averaged less than 3 days with only one minor complication.
      CONCLUSIONS: Ectopic mediastinal parathyroid glands may be safely and accurately
      resected using video-assisted thoracic surgery to avoid open approaches.

PMID- 10654518
TI  - Sodium nitroprusside mitigates oleic acid-induced acute lung injury.
AB  - BACKGROUND: Acute lung injury (ALI) is associated with pulmonary hypertension,
      intrapulmonary shunting, and increased microvascular permeability, leading to
      altered oxygenation capacity. Oleic acid (OA) creates a significant ALI that
      physiologically mimics human adult respiratory distress syndrome (ARDS). It has
      been hypothesized that pulmonary vasodilatation may improve ALI. Studies in our
      laboratory using this model and nitric oxide (NO) have shown that NO inhalation
      is detrimental and worsens the effects of OA. We studied the effect of
      pretreatment with a potent vasodilator, sodium nitroprusside (SNP), on ALI
      induced by OA in an isolated lung model. We hypothesized that pretreatment with
      SNP will worsen pulmonary hypertension and oxygenation in OA-induced ALI, similar
      to the effects seen with inhaled NO in this model. METHODS: Rabbit heart lung
      blocks were isolated, flushed in vivo, harvested, immediately perfused with whole
      blood, and ventilated with 50% oxygen. Pulmonary artery pressure was determined
      every 15 seconds for 90 minutes of perfusion. Oxygenation was determined by blood
      gas analysis of pulmonary venous effluent at 0, 20, 40, 60, and 90 minutes after
      initiation of OA infusion. Four groups were studied: saline control (SC), oleic
      acid control (OAC; 20-minute infusion of 50% OA/ethanol into pulmonary
      circulation), SNP control (NPC; 10 microg/ kg/min SNP infused without subsequent
      OA infusion), and SNP treatment (NPRx); 10 microg/kg/min SNP infused before
      OA/ethanol. Pulmonary artery pressure (PAP), oxygenation (arterio-venous oxygen
      difference [AVO2], compliance (CPL), and wet/dry lung weight were determined.
      RESULTS: No significant differences were found between the NPRx group and SC.
      Pretreatment with SNP eliminated the detrimental effects of OA infusion.
      CONCLUSIONS: Contrary to our hypothesis, pretreatment with SNP eliminates the
      decrease in oxygenation and increase in lung weight, and ameliorates pulmonary
      hypertension in our isolated lung model of OA-induced ALI.

PMID- 10654520
TI  - Extended resections for bronchogenic carcinoma invading the superior vena cava
      system.
AB  - BACKGROUND: Extended resection of non-small-cell lung cancer (NSCLC) involving
      the superior vena cava (SVC) system is infrequently performed and oncologic
      benefits are still uncertain. METHODS: From 1983 to 1996, 25 patients underwent
      resection of the SVC system for T4, NSCLC. RESULTS: A total of 12 pneumonectomies
      (48%), ten lobectomies (40%), and three wedge resections (12%) were performed.
      Seven patients had complete resection of the SVC with graft interposition, 12
      patients underwent tangential resection of the SVC, and 1 patient had a
      pericardial patch; 5 patients underwent resection of right innominate and
      subclavian veins without vessel reconstruction. The lymph node status was N0 in 8
      patients (32%), N1 in 3 (12%) and N2 in 14 patients (56%). Five patients (20%)
      underwent incomplete resection. Nine patients (36%) developed postoperative
      complications (36%) that were fatal in 3 patients (12%). At the completion of the
      study, 10 patients were still alive. The median survival was 11.5 months and the
      5-year actuarial survival rate was 29%, with 4 patients alive at 5 years.
      CONCLUSIONS: The resection of the SVC system for direct involvement by T4, NSCLC
      can be performed in selected patients with an acceptable postoperative mortality.
      Even though no significant prognostic factors were observed, the patients who
      required a lobectomy with limited lymph node involvement seemed to benefit the
      most from surgery.

PMID- 10654519
TI  - Effects of mast cell membrane stabilizing agents in a rat lung ischemia
      reperfusion model.
AB  - BACKGROUND: The aim of this study was to test the hypothesis that agents which
      stabilize the mast cell membrane may modulate the phenotype of the vascular wall
      in a lung ischemia-reperfusion model, including altering expression of
      endothelial and leukocyte adhesion receptors and the inducible nitric oxide
      synthase (NOS-2). METHODS: Three sets of rats were given either intravenous
      saline (group A), ketotifen (group B), or cromolyn (group C), respectively. The
      left pulmonary artery was ligated temporarily and reopened after 2 hours of
      ischemia. Then, after a 2-hour period of reperfusion, the left lung was excised.
      ICAM-1 and NOS-2 were measured at the protein level by Western blotting, and cGMP
      levels were measured by enzyme-linked immunosorbent assay in the lung tissue
      specimens for each drug group. RESULTS: ICAM-1 expressions, determined as the
      intensity of a given band on the Western blot, were 197+/-59 in group B and 195+/
      83 in group C versus 369+/-114 in group A (p = 0.002 for analysis of variance).
      In contrast with ICAM-1, NOS-2 expression was increased by ketotifen or cromolyn
      treatment (464+/-82 in group B and 507+/-93 in group C, compared with 377+/-44
      for group A, p = 0.007). The finding of increased NOS-2 expression in groups B
      and C is consistent with the observed increase in tissue cGMP levels in the same
      groups (1.92+/-0.9 pmol/mL for group A versus 7.8+/-3.5 pmol/mL for group B, and
      12.4+/-5.8 pmol/mL for group C, p = 0.0004). CONCLUSIONS: These data establish
      that mast cell stabilizing agents modulate the vascular phenotype in the setting
      of pulmonary ischemia and reperfusion by decreasing ICAM-1 expression, augmenting
      expression of NOS-2, and increasing tissue cGMP levels. As decreasing ICAM-1
      expression and increasing cGMP levels have proven useful to limit proinflammatory
      mechanisms of tissue injury, mast cell stabilizing agents may provide a new
      therapeutic option to improve organ function in the setting of reperfusion.

PMID- 10654521
TI  - Ischemic preconditioning enhances recovery of isolated rat lungs after
      hypothermic preservation.
AB  - BACKGROUND: Ischemic preconditioning, an endogenous protection mechanism, occurs
      in many organs, including lungs. The efficacies of differing ischemic durations
      in protecting the lung are unknown. We compared the ability of three
      preconditioning protocols to protect rat lungs during storage. METHODS: Function
      was measured in five groups of perfused, ventilated rat lungs. Group 1 lungs
      underwent control perfusion (60 minutes) without storage. Groups 2 through 5
      underwent the following prestorage protocols: group 2, 20 minutes of perfusion;
      group 3, 10 minutes of perfusion, 5 minutes of cessation of ventilation and
      perfusion (ischemia), and 5 minutes of reperfusion; group 4, 5 minutes of
      perfusion, 10 minutes of ischemia, and 5 minutes of reperfusion; and group 5, 2
      periods of 5 minutes of ischemia and 5 minutes of reperfusion. Lungs were then
      flushed with, and immersed (6 hours) in modified bicarbonate buffer (4 degrees
      C). Lung function was reassessed during 40 minutes of reperfusion (37 degrees C).
      Subsequently we examined preconditioning by stopping ventilation or perfusion
      separately. RESULTS: After reperfusion, lungs in group 2 had a compliance of
      0.015+/-0.002 mL/cm H2O (mean +/- SE, n = 10), significantly lower than lungs in
      group 1 (0.063+/-0.002 mL/cm H2O). Ischemic preconditioning was protective, with
      lungs in groups 3, 4, and 5 having compliances greater (p<0.05) than those in
      group 2. Preconditioning by cessation of ventilation alone was also effective.
      CONCLUSIONS: Preconditioning attenuates deterioration in lung compliance on
      reperfusion to a degree dependent on the protocol used.

PMID- 10654522
TI  - Postintubation tracheal tear repair by cervicotomy and longitudinal tracheotomy.
AB  - BACKGROUND: Membranous tracheal lacerations are a serious complication of
      endotracheal intubation. Smaller tears are often better managed with a
      conservative treatment. Larger ruptures, especially when associated with
      important manifestations, need an early surgical repair. METHODS: In the last 3
      years, three female patients with a posterior tracheal wall laceration, related
      to endotracheal intubation, underwent surgical procedure in our institution. All
      tracheal tears were repaired with a running suture through a small cervical
      collar incision and longitudinal tracheotomy. RESULTS: All surgical procedures
      were effective and lasted less than 1 hour. Patients were discharged on average
      after 5 days. Endoscopic follow-up showed a perfect repair of the tear without
      signs of tracheal stenosis. CONCLUSIONS: This is a reliable, quick, and safe
      approach to a rare but insidious complication of general anesthesia. It avoids
      lateral and posterior dissection of the trachea, reducing the risk of a recurrent
      laryngeal nerve injury.

PMID- 10654523
TI  - Sex-associated differences in survival of patients undergoing resection for lung
      cancer.
AB  - BACKGROUND: The increasing incidence of lung cancer among women prompted us to
      assess whether sex-associated differences exist in the presentation and survival
      of patients who undergo major lung resection for lung cancer. METHODS: We
      performed a retrospective review of patients who had major lung resection for
      lung cancer from January 1980 to June 1998. RESULTS: There were 265 men and 186
      women. Women were younger (60.7+/-0.8 versus 63.6+/-0.6 years; p = 0.005).
      Adenocarcinoma was more common among women (48% versus 40%; p = 0.001).
      Pathologic stages for men were: I = 43%, II = 26%, IIIA = 25%, IIIB or IV = 6%,
      and for women: I = 52%, II = 20%, IIIA = 22%, IIIB or IV = 6% (p = 0.146). Median
      survival was better for women (41.8 versus 26.9 months; p = 0.006). This was due
      both to a difference in stage at presentation and to a better median survival
      rate for adenocarcinoma compared with squamous cell cancer. The data suggest an
      association between sex and survival, although this failed to reach statistical
      significance. Sex influenced survival with a relative risk for women of 0.67 (95%
      confidence interval 0.35 to 1.29; p = 0.231 adjusted for stage, cell type, age,
      and spirometry). CONCLUSIONS: There are sex-associated differences in the
      presentation and possibly in the survival of patients with lung cancer. This
      finding has possible implications regarding the selection of patients for therapy
      and for the design of randomized therapeutic trials.

PMID- 10654524
TI  - Needle thoracic sympathectomy for essential hyperhidrosis: intermediate-term
      follow-up.
AB  - BACKGROUND: Essential hyperhidrosis is a condition with excessive sweating
      localized to certain part of the body. A definitive cure can be obtained by upper
      thoracic sympathectomy. METHOD: Between June and October 1997, 117 patients with
      essential hyperhidrosis underwent needle thoracoscopic sympathectomy. Of the 94
      patients, 42 were men and 52 women. Their ages ranged from 14 to 63 years, with a
      mean age of 23 years. RESULTS: There were no mortality or life-threatening
      complications. Symptomatic improvement was found in 95.7%. Compensatory
      hyperhidrosis was found in 71.2% of the patients, but in these compensatory
      hyperhidrosis were mostly tolerable. CONCLUSIONS: This therapeutic procedure is
      minimally invasive and very effective. Further development of the new device and
      surgical technique are expected to follow.

PMID- 10654525
TI  - Antineural and antinuclear autoantibodies are of prognostic relevance in non
      small cell lung cancer.
AB  - BACKGROUND: Autoantibodies against nervous system structures have been proven to
      be a prognostic factor in small cell lung cancer. However, little is known about
      humoral autoimmunity in non-small cell lung cancer (NSCLC) and its prognostic
      significance. METHODS: We examined antineural antibodies (AnAb) and antinuclear
      antibodies (ANA) in the sera of 61 patients with NSCLC (histologically: 29
      adenocarcinoma, 32 squamous cell carcinoma). Twenty-one patients had stage I
      NSCLC, 11 stage II, and 29 patients stage III. Autoantibody detection was done by
      immunofluorescence test; Western blotting was used as a confirmation test.
      RESULTS: Of the NSCLC patients, 27.8% were antineural antibody positive, and
      32.7% had ANA. No differences were found between the histological groups. AnAb
      positive patients showed a better survival in all patients (p = 0.005). There was
      also a higher survival of ANA-positive patients, but this was only significant in
      stage III (p = 0.0025). Cox regression analysis showed that antineural and
      antinuclear antibodies are a stage-independent prognostic factor in NSCLC.
      CONCLUSIONS: Antineural and antinuclear autoantibodies are a stage-independent
      prognostic factor in patients with NSCLC and may represent an effective immune
      response to the tumor.

PMID- 10654526
TI  - Heterotopic pancreas of the esophagus masquerading as Boerhaave's syndrome.
AB  - Heterotopic pancreas (HP) of the esophagus is rare. We report a patient with HP
      of the esophagus and review the presentation, treatment, and results of the nine
      previously reported cases. Two patients had cancer. This high incidence raises
      concerns that HP of the esophagus may be premalignant. Because surveillance
      endoscopy is not possible, all known or suspected esophageal HP should be treated
      surgically.

PMID- 10654527
TI  - Inadvertent suture through the chest tube: a simple solution to a frustrating
      problem.
AB  - Although an uncommon complication, inadvertent suturing of the chest tube to the
      chest wall during closure of a thoracotomy, unfortunately can happen. This
      frustrating situation likely leads to a rethoracotomy and cutting of the suture
      in order to release the chest tube. In this report, we propose a fast and easy
      solution to this problem.

PMID- 10654528
TI  - Symptomatic accessory cardiac bronchus.
AB  - Symptomatic accessory cardiac bronchus is rare. A 52-year-old woman with an
      accessory bronchus, who had had frequent episodes of hemosputum for 6 years,
      suffered from empyema complicated by a right lower lung abscess infected with
      Pseudomonas aeruginosa. Resection of the anomalous cardiac bronchus after open
      drainage of the pleural cavity was successful.

PMID- 10654529
TI  - Low-molecular-weight heparin for prosthetic heart valves: treatment failure.
AB  - There is no adequate substitute therapy for patients with prosthetic heart
      valves, in whom anticoagulation with warfarin or unfractionated heparin must be
      withheld. In the literature there are several reports describing successful
      treatment with low-molecular-weight heparin in patients with prosthetic heart
      valves. We report two cases of low-molecular-weight heparin treatment failure
      resulting in thrombosed prosthetic heart valves with stormy clinical
      presentations, who underwent successful valve replacements.

PMID- 10654530
TI  - Pneumothorax necessitans presenting as a presternal pneumothoracocele.
AB  - A 31-year-old woman who is an intravenous drug abuser developed sternoclavicular
      joint infection with mediastinal and subcutaneous tissue abscesses that
      communicated through an erosion in the manubrium caused by osteomyelitis. Air
      entrapment from a subsequent apical pneumothorax formed a localized anterior
      "pneumothoracocele." We referred to this condition as "pneumothorax necessitans,"
      and we suggest including it in the differential diagnosis of anterior chest wall
      masses.

PMID- 10654531
TI  - Bifid sternum: neonatal surgical treatment.
AB  - The sternal cleft is a rare congenital anomaly resulting from a fusion failure of
      the sternum, generally observed at birth and asymptomatic. Surgery is indicated
      to protect the heart and major vessels from trauma, to improve respiratory
      dynamics, and for aesthetic reasons. We observed 2 neonates for a superior and
      medial thoracic mass. The defect involved the upper two thirds of the sternum.
      The surgical operation for both patients consisted in the primary closure of the
      defect.

PMID- 10654532
TI  - Right pulmonary artery left atrium communication.
AB  - A 12-year-old boy presented with central cyanosis, clubbing, and ejection
      systolic murmur in the left second and third intercostal space. Chest
      roentgenogram showed a round opacity on the right border of cardiac silhouette.
      Echocardiography revealed a communication between right pulmonary artery and left
      atrium, which was later confirmed on selective pulmonary cineangiography.
      Successful surgical ligation without cardiopulmonary bypass resulted in the cure
      of the disease.

PMID- 10654533
TI  - Aortic pseudoaneurysm after ligation of aneurysmal saphenous vein graft.
AB  - After an aneurysmal saphenous vein graft was ligated and divided at reoperation,
      the proximal stump continued to enlarge, rather than occluding by thrombosis,
      producing an aortic pseudoaneurysm that compressed adjacent cardiac structures.
      Oversewing the aortosaphenous junction of ligated vein graft remnants will
      prevent this complication.

PMID- 10654534
TI  - Left upper lobe bronchus reimplantation for nonpenetrating thoracic trauma.
AB  - Trauma to the tracheobronchial tree has been diagnosed and treated with
      increasing frequency over the last several decades. However, most reports have
      dealt with management of injuries to the trachea and main stem bronchi, as
      approximately 80% of blunt tracheobronchial injuries occur within this area. With
      few exceptions, injury to the lobar bronchi has resulted in thoracotomy and
      lobectomy. We describe a patient with an injury to the left upper lobe bronchus
      who presented with delayed obstruction of the airway by fibrogranulation tissue.
      A successful segmental resection of the bronchial occlusion with reimplantation
      was performed, thereby preserving the patient's otherwise normal left upper lobe.
      This case demonstrates that resection and reimplantation of an injured lobar
      bronchus are feasible, even in a delayed setting.

PMID- 10654536
TI  - Operative treatment of truncus arteriosus communis coexisting with tricuspid
      atresia.
AB  - The coexistence of tricuspid atresia and common arterial trunk is extremely rare.
      We present a successful three-stage surgical treatment of this defect. The first
      stage included disconnection of the pulmonary arteries from the common trunk,
      atrial septectomy and systemic-to-pulmonary shunt; the second stage, a hemi
      Fontan procedure; and the third stage, a fenestrated Fontan completion. The child
      is now 8 years old and is developing well.

PMID- 10654535
TI  - Treatment of giant aortic aneurysm with tracheal compression and sternal erosion
      without circulatory arrest.
AB  - Treatment of huge aneurysms involving the ascending aorta and the aortic arch
      with compression of the surrounding structures represents a surgical challenge.
      The case of a patient affected by respiratory insufficiency and sternal erosion
      caused by chronic giant aortic aneurysm is reported. The use of a stepwise
      approach and selective cerebral arterial perfusion ensured successful operative
      management, avoiding circulatory arrest and enabling an expeditious postoperative
      recovery.

PMID- 10654537
TI  - Primary tracheal schwannoma.
AB  - We report a case of a primary tracheal schwannoma causing symptoms of airway
      obstruction in a 33-year-old man. Bronchoscopy and computerized tomography
      demonstrated a polypoid intratracheal mass obstructing 90% of the lumen. Tracheal
      resection with primary anastomosis was performed. Histologic analysis revealed a
      benign neurogenic tumor of Schwann cell origin.

PMID- 10654539
TI  - Metastatic atrial myxoma to the skin at 15 years after surgical resection.
AB  - Metastasis from atrial myxoma is uncommon. We report on a patient who developed
      metastasis of the left atrial myxoma to the skin at 15 years after surgical
      resection. The primary lesion had not recurred. The myxoma has the potential for
      metastatic growth.

PMID- 10654538
TI  - Successful resection of ductus arteriosus aneurysm in infancy.
AB  - We report a case of thrombosed patent ductus arteriosus aneurysm in an infant.
      The aneurysm was detected accidentally on chest roentgenogram and presented as
      globular soft tissue density mass in left posterosuperior mediastinum. Resection
      of the aneurysm was performed without cardiopulmonary bypass. Two years after
      operation the patient is well and growing normally.

PMID- 10654540
TI  - Bridge to recovery with a left ventricular assist device for fulminant acute
      myocarditis.
AB  - Acute fulminant myocarditis frequently causes circulatory collapse that is
      resistant to conventional therapy. We describe a case in which a patient with
      histologically confirmed viral myocarditis was supported by a left ventricular
      assist device (LVAD) as a bridge to recovery. The LVAD was successfully weaned 3
      weeks later.

PMID- 10654541
TI  - Esophagectomy after pneumonectomy: a surgical challenge.
AB  - Esophagectomy after pneumonectomy has been reported rarely, and the surgical
      approach presents a challenge. We report a case of a transthoracic esophagectomy
      in a 54-year-old man who had undergone right pneumonectomy for non-small cell
      lung cancer 16 years previously.

PMID- 10654542
TI  - Adenocarcinoma in a mid-esophageal diverticulum.
AB  - The incidence of esophageal adenocarcinoma has been increasing compared with
      squamous cell carcinoma. The most common location of adenocarcinoma of the
      esophagus is the distal one third. Cancer developing in an esophageal
      diverticulum is uncommon, but tumors of squamous cell origin in esophageal
      diverticula have been reported previously. We describe an adenocarcinoma in a
      midesophageal diverticulum and review malignancies occurring in esophageal
      diverticula.

PMID- 10654543
TI  - Aberrant right subclavian artery aneurysm.

PMID- 10654544
TI  - Improved exposure of isolated perimembranous ventricular septal defects.
AB  - We describe an alternative step in the transatrial approach to the repair of
      ventricular septal defects. We temporarily detach the chorda of the obscuring
      tricuspid valve from its attachment to the septum to expose the ventricular
      septal defect.

PMID- 10654545
TI  - A new, safe, and easy technique of atrial septal defect creation.
AB  - We created an atrial septal defect (ASD) using a Ferris-Smith-Kerrison bone punch
      under transesophageal echocardiographic monitoring for infants with complex
      congenital heart diseases, eg, transposition of the great arteries. We describe a
      safe and easy technique of ASD creation instead of Blalock-Hanlon operation.

PMID- 10654546
TI  - Facile location of the saphenous vein during endoscopic vessel harvesting.
AB  - Endoscopic techniques are used more frequently to harvest the saphenous vein for
      cardiac and peripheral vascular procedures. To identify the saphenous vein
      through an initial small access incision can be difficult. We describe the use of
      a portable intraoperative ultrasound system to expeditiously identify the
      saphenous vein during endoscopic harvesting, particularly in obese patients.

PMID- 10654547
TI  - Modifying a venovenous extracorporeal membrane oxygenation circuit to reduce
      recirculation.
AB  - Lung rest is the primary goal of venovenous extracorporeal membrane oxygenation
      for severe acute respiratory failure. To achieve this there has to be adequate
      extracorporeal flow. This can be achieved by a two-cannula technique in most
      cases. In some cases, extra flow is either not achievable or causes excessive
      recirculation. We report 8 patients in whom we achieved adequate blood and oxygen
      delivery using a three-cannula technique. Five patients survived (62.5%).

PMID- 10654548
TI  - Atrial fibrillation after cardiac operation: risks, mechanisms, and treatment.
AB  - Atrial fibrillation (AF) is a common complication of cardiac operations that
      leads to increased risk for thromboembolism and excessive health care resource
      utilization. Advanced age, previous AF, and valvular heart operations are the
      most consistently identified risk factors for this arrhythmia. Dispersion of
      repolarization leading to reentry is believed to be the mechanism of
      postoperative AF, but many questions regarding the pathophysiology of AF remain
      unanswered. Treatment is aimed at controlling heart rate, preventing
      thromboembolic events, and conversion to sinus rhythm. Multiple investigations
      have examined methods of preventing postoperative AF, but the only firm
      conclusions that can be drawn is to avoid beta-blocker withdrawal after operation
      and to consider beta-blocker therapy for other patients who may tolerate these
      drugs. Preliminary investigations showing sotalol and amiodarone to be effective
      in preventing postoperative AF are encouraging, but early data have been limited
      to selective patient populations and have not adequately evaluated safety. Newer
      class III antiarrhythmic drugs under development may have a role in the treatment
      of postoperative AF, but the risk of drug-induced polymorphic ventricular
      tachycardia must be considered. Nonpharmacologic interventions under
      consideration for the treatment of AF in the nonsurgical setting, such as
      automatic atrial cardioversion devices and multisite atrial pacing, may
      eventually have a role for selected cardiac surgical patients.

PMID- 10654549
TI  - Neuroendocrine neoplasia of the lung.

PMID- 10654550
TI  - Early Italian contributions to cavopulmonary shunt procedures.

PMID- 10654551
TI  - Would pH-stat strategy generate nitric oxide during hypothermic perfusion?

PMID- 10654552
TI  - Thymectomy for elderly myasthenia gravis patients.

PMID- 10654553
TI  - Lateral thoracotomy closure technique.

PMID- 10654554
TI  - Bypass grafts in Takayasu's disease.

PMID- 10654555
TI  - Axillary cannulation.

PMID- 10654556
TI  - Octogenarians and cardiac surgery.

PMID- 10654557
TI  - New method of myocardial revascularization with the radial artery.

PMID- 10654558
TI  - Reduction of wall changes in sheathed grafts.

PMID- 10654560
TI  - Pericardial patch for atrial septal defect closure.

PMID- 10654559
TI  - Cerebral perfusion and transcranial Doppler.

PMID- 10654561
TI  - Determination of gamma-hydroxybutyrate (GHB) in biological specimens by gas
      chromatography--mass spectrometry.
AB  - A simple liquid-liquid extraction procedure for the analysis of gamma
      hydroxybutyrate (GHB) in biological fluids without conversion to its lactone,
      gamma-butyrolactone, is described. Following derivatization to its di-TMS
      derivative, GHB was detected using gas chromatography-electron impact mass
      spectrometry. Diethylene glycol was used as the internal standard. The limit of
      quantitation in 1 mL of blood was 1 mg/L, and a linear response was observed over
      the concentration range 1 to 100 mg/L. Coefficients of variation for both intra
      assay precision and interassay reproducibility ranged between 3.9 and 12.0%. GHB
      was detected in the blood of a sexual assault victim (3.2 mg/L), in the blood of
      two driving (DUI) cases (33 and 34 mg/L), and in the blood and urine of two
      nonfatal GHB-overdose cases (blood 130 and 221 mg/L; urine 1.6 and 2.2 g/L). The
      observed clinical symptoms ranged from confusion, disorientation, vomiting, and
      nystagmus to ataxia, sinus bradycardia, unconsciousness, and apnea.

PMID- 10654562
TI  - Elimination half-life of acetone in humans: case reports and review of the
      literature.
AB  - Two instances of finding abnormally high concentrations of acetone in urine (0.10
      g/dL and 0.052 g/dL) without any measurable amounts of ethanol (<0.005 g/dL) or
      isopropanol (<0.005 g/dL) prompted a survey of the elimination kinetics of
      isopropanol and its metabolite acetone in humans. In a hospital patient who had
      ingested denatured alcohol, the elimination half-life (t(1/2)) of acetone during
      detoxification was 27 h and not 3-5 h as reported by other workers. Several other
      literature reports of individuals who had ingested isopropanol as well as
      controlled studies after administration of moderate amounts of acetone and/or
      isopropanol support the notion of a long elimination half-life of 17-27 h for
      acetone compared with a t(1/2) of 1-3 h for isopropanol.

PMID- 10654563
TI  - Rapid analysis of amphetamine, methamphetamine, MDA, and MDMA in urine using
      solid-phase microextraction, direct on-fiber derivatization, and analysis by GC
      MS.
AB  - A rapid, sensitive, and solvent-free procedure for the simultaneous determination
      of amphetamine, methamphetamine, 3,4-methylenedioxyamphetamine (MDA), and 3,4
      methylenedioxymethamphetamine (MDMA) in urine was developed using solid-phase
      microextraction (SPME) and gas chromatography-mass spectrometry (GC-MS) in the
      selected ion monitoring mode. A headspace vial containing the urine sample, NaOH,
      NaCl, and amphetamine-d3 as the internal standard was heated at 100 degrees C for
      20 min. A polydimethylsiloxane fiber was maintained in the vial headspace for 10
      min in order to adsorb the amphetaminic compounds, which were subsequently
      derivatized by exposing the fiber to trifluoroacetic anhydride for 20 min in the
      headspace of another vial maintained at 60 degrees C for 20 min. The
      trifluoroacetyl derivatives were desorbed in the GC injection port for 5 min.
      Several parameters were considered during the method optimization process. These
      included a comparison of SPME with or without headspace, the required
      derivatization procedure, and the influence of temperature on the headspace
      extraction and derivatization methods. The optimized method was validated for the
      four compounds tested. Calibration curves showed linearity in the range 50-1000
      ng/mL (r = 0.9946-0.9999). Recovery data were 71.89-103.24%. The quantitation
      limits were 10 ng/mL for amphetamine and methamphetamine and 20 ng/mL for MDA and
      MDMA. All of these data recommend the applicability of the method for use in the
      analytical routine of a forensic laboratory.

PMID- 10654564
TI  - Structural elucidation of an uncommon phenylethylamine analogue in urine
      responsible for discordant amphetamine immunoassay results.
AB  - The present paper describes investigations following the analysis of a urine
      specimen containing important amounts of an unknown substance detected by gas
      chromatography-mass spectrometry (GC-MS) analysis. FPIA analysis was positive
      (cutoff 0.3 mg/L) and Triage 8 rapid test was negative (cutoff 1 mg/L) for
      amphetamines. Considering the GC-MS spectrum, two different molecules, for
      example, N-ethyl-1-(3,4-methylenedioxyphenyl)ethylamine (1) or N-ethyl-4
      methoxyamphetamine (2), have been suspected. Synthesis of these two compounds was
      carried out together with spectral (MS, 1H and 13C NMR, IR, UV) and
      chromatographic (GC) characterization as well as determination of immunological
      cross reactivities (FPIA and Triage 8). The unknown compound present in the urine
      specimen has been finally identified as N-ethyl-4-methoxyamphetamine (2), an
      uncommon amphetamine analogue.

PMID- 10654565
TI  - Tetrachloroethylene and trichloroethylene fatality: case report and simple
      headspace SPME-capillary gas chromatographic determination in tissues.
AB  - We describe a simple, precise, and sensitive assay of tetrachloroethylene and
      trichloroethylene in tissues, suitable both for emergency cases and forensic
      medicine. The method employs headspace solid phase microextraction-capillary gas
      chromatography and electron capture detection. The case is relative to a 45-year
      old woman discovered unconscious in a laundry area. The concentrations of the
      solvents in tissues were determined and compared to other previously published
      fatalities.

PMID- 10654566
TI  - Elimination of the interferences by keto-opiates in the GC-MS analysis of 6
      monoacetylmorphine.
AB  - A simple procedure to eliminate the interference from keto-opiates in the
      analysis of 6-monoacetylmorphine (6-MAM) by gas chromatography-mass spectrometry
      is described. The pretreatment of urine samples with sodium bisulfite followed by
      solid-phase extraction results in the elimination of the bisulfite addition
      products formed from the reaction of the bisulfite ions with the carbonyl carbon
      of the keto-opiates. This simple procedure results in the accurate quantitation
      of 6-MAM at a concentration of 4 ng/mL in the presence of keto-opiates up to
      10,000 ng/mL.

PMID- 10654567
TI  - Identification of the general unknown. Application of mass selective detectors in
      forensic toxicology.
AB  - One of the basic aims of forensic toxicology is the identification of previously
      unknown drugs and poisons. This is frequently achieved using the combination of
      gas chromatography and benchtop quadrupole or ion trap mass spectrometers. The
      influence of matrix loading on the mass spectral quality was tested, and it was
      found that a realistic amount of matrix changed the pattern of the spectra
      obtained by the ion trap mass spectrometer. Disturbed mass spectra led to
      unsuitable suggestions from the library search and thus rendered the
      identification of the "general unknown" more difficult. On the other hand, higher
      selectivity and lower detection limits favored the ion trap technology for target
      analysis because of the capability of MS-MS.

PMID- 10654568
TI  - Rapid method for the solid-phase extraction and GC-MS analysis of flunitrazepam
      and its major metabolites in urine.
AB  - Recently, flunitrazepam (Rohypnol) has become an increasingly popular drug of
      abuse among young adults, who take it for its euphoric effects. In other cases,
      the drug has been used by rapists for its sedative and hypnotic effects that can
      induce a catatonialike trance and memory loss in potential victims; as a result,
      it has been nicknamed the "date-rape drug". For these reasons, the Drug
      Enforcement Administration recently considered adding the drug (a.k.a. "Roofies")
      to the same category as heroin and LSD. A selective and sensitive technique has
      been developed for extracting, detecting, and identifying flunitrazepam and its
      two major metabolites (7-aminoflunitrazepam and N-desmethylflunitrazepam) in
      human urine. Using a solid-phase extraction cartridge containing a "mixed-mode"
      bonded silica gel (Bond Elut Certify), flunitrazepam and its metabolites were
      selectively isolated from other urine components and quantitated and identified
      by gas chromatography-tandem mass spectrometry with a benchtop ion mass
      spectrometer. The extraction method is rapid, reproducible, and precise, and it
      has a broad linear working range. The overall extraction efficiency was found to
      be more than 90% for the parent drug as well as the two major metabolites.

PMID- 10654569
TI  - Quantitative screening for benzodiazepines in blood by dual-column gas
      chromatography and comparison of the results with urine immunoassay.
AB  - A dual-column retention index method is described for quantitative gas
      chromatographic (GC) screening of 26 benzodiazepine drugs and metabolites in the
      blood using DB-5 and DB-17 capillary columns and electron capture detection. The
      method involves a one-step, small-scale liquid-liquid extraction with ethyl
      acetate and derivatization with N-methyl-N-(tert
      butyldimethylsilyl)trifluoroacetamide with 1% tert-butyldimethylsilyl chloride.
      The results from the GC screening of 514 postmortem blood samples were compared
      to those obtained from urine immunoassay (Syva ETSplus with a 200-ng/mL cutoff).
      Both methods gave a negative result in 284 cases and a positive result in 149
      cases. In 48 cases, urine was negative by immunoassay but blood was positive by
      GC. The opposite situation (blood negative, urine positive) was detected only in
      four cases. In 29 cases, an invalid result was obtained by urine by immunoassay:
      26 blood samples of those cases were negative and three samples positive by GC.
      In postmortem forensic toxicology, the present GC method seems to be a good
      alternative to the common combination of urinary immunoassay followed by
      quantitative analysis of blood by chromatography.

PMID- 10654570
TI  - A comparison of sodium hydroxide and sodium sulfide digestion of mouse hair in
      the recovery of radioactivity following systemic administration of [3H]-nicotine
      and [3H]-flunitrazepam.
AB  - Pigmented (C57BI) and nonpigmented (balb/c) mice, 25 days of age, were treated
      intraperitoneally with [3H]-nicotine (4 mg/kg, 555 dpm/ng) or [3H]-flunitrazepam
      (1 mg/kg, 2200 dpm/ng) daily for three days. After 21 days, shaved back hair was
      digested at 37 degrees C for 24 h with either 1 M sodium hydroxide or 1 M sodium
      sulfide. With both drugs, sodium sulfide extraction removed the same amount of
      radioactivity as sodium hydroxide from nonpigmented hair. However, sodium sulfide
      removed significantly more radioactivity from pigmented hair than did sodium
      hydroxide. In pigmented hair, sodium sulfide solubilized 35% and 74% of the
      flunitrazepam- and nicotine-associated radioactivity, respectively. Of this, 12%
      and 43%, respectively, could be partitioned into ethyl acetate. Microscopic
      examination of residual pellets after digestion demonstrated a more thorough
      dissolution of the hair shaft with sodium sulfide with only melanosomes
      remaining. The results demonstrate the significant interaction of flunitrazepam
      and nicotine with melanins and the utility of sodium sulfide in increasing drug
      recovery.

PMID- 10654572
TI  - Use of solid-phase microextraction (SPME) for the determination of methadone and
      its main metabolite, EDDP, in plasma by gas chromatography-mass spectrometry.
AB  - A simple, rapid method for the determination of methadone and its metabolite 2
      ethylene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) in plasma using solid-phase
      microextraction (SPME) and gas chromatography-mass spectrometry is proposed. A
      100-microm polydimethylsiloxane film fiber was exposed by immersion for 30 min in
      a diluted plasma solution (1:4 with buffer pH 9) containing both compounds and an
      internal standard (proadifen). Calibration curves were linear over the
      concentration range 50-2000 ng/mL. The analysis time was 45 min per sample. The
      determination of methadone and EDDP was subject to no interference. The
      performance of SPME was compared with that of liquid-liquid extraction, obtaining
      lower limits of detection for EDDP. The method using the two extraction
      procedures was applied to 10 plasma samples from methadone-treated patients.

PMID- 10654571
TI  - Cocaine, cocaine metabolite, and ethanol concentrations in postmortem blood and
      vitreous humor.
AB  - The use of postmortem cocaine and metabolite concentrations is a complex subject.
      This study was undertaken to determine (1) the usefulness of vitreous humor as a
      specimen, compared with blood, to quantitate cocaine and cocaine metabolites; (2)
      whether there is a preferential site of disposition for cocaethylene between
      vitreous humor and blood; and (3) if the presence of cocaethylene influences the
      concentration of benzoylecgonine in postmortem specimens. Cocaine,
      benzoylecgonine, and cocaethylene were quantitated in blood and vitreous humor by
      gas chromatography-mass spectrometry, and ethanol was quantitated by gas
      chromatography in 62 medical examiner cases. No differences were found between
      mean concentrations of vitreous cocaine 0.613 mg/L (standard deviation [SD] 0.994
      mg/L), cocaethylene 0.027 mg/L (SD 0.59 mg/L), and ethanol 0.092 g/dL (SD 0.13
      g/dL) compared to blood cocaine 0.489 mg/L (SD 1.204 mg/L), cocaethylene 0.022
      mg/L (SD 0.055 mg/L), and ethanol 0.058 g/dL (SD 0.91 g/dL), respectively.
      However, a statistical difference was found between mean benzoylecgonine
      concentrations in vitreous 0.989 mg/L (SD 1.597 mg/L) and blood 1.941 mg/L (SD
      2.912 mg/L) (p = 0.0004). Regression analysis demonstrated that linear
      relationships were present between concentrations of vitreous and blood cocaine
      (r = 0.854) and benzoylecgonine (r = 0.763). However, the correlation
      coefficients were lower for cocaethylene (r = 0.433) and ethanol (r = 0.343).
      There were variations between the concentrations of cocaine and metabolites both
      in terms of magnitude and also direction of change. Mean concentrations of
      benzoylecgonine in blood and vitreous were higher in cases where ethanol was
      absent, 2.593 mg/L (SD 3.195 mg/L) and 1.431 mg/L (SD 2.021 mg/L), compared to
      when ethanol was present, 1.199 mg/L (SD 2.396 mg/L) and 0.469 mg/L (SD 0.553
      mg/L). This study demonstrates that vitreous humor may be used to quantitate
      cocaine and cocaine metabolites; however, because the concentrations of
      cocaethylene in vitreous humor and blood were not well correlated, vitreous humor
      may not be a reliable specimen for measuring cocaine and cocaine metabolite
      concentrations.

PMID- 10654573
TI  - Saliva/plasma ratio of methadone and EDDP.

PMID- 10654574
TI  - Delta9-tetrahydrocannabivarin (THCV) as a marker of cannabis use: is the
      methodology forensically acceptable?

PMID- 10654575
TI  - Cytokine-cytokine interactions and the brain.
AB  - Cytokine-cytokine interactions play a role in health and are crucial during
      immunological and inflammatory responses in disease. Cytokine interactions can
      result in additive, antagonist, or synergistic activities in maintaining
      physiological functions such as feeding, body temperature, and sleep, as well as
      in anorectic, pyrogenic, and somnogenic neurological manifestations of acute and
      chronic disease. These interactions involve signaling homology, convergence of
      signaling pathways, and/or positive or negative feedbacks within and among
      cytokine systems. The interplay of cytokines with neurotransmitters,
      peptides/neuropeptides, and hormones also influence cytokine action in the brain.
      Interactive chemical cascades involving cytokines are consistent with the
      homeostatic physiological mechanisms and with the multi-humoral, pleiotropic, and
      redundant processes that occur during acute and chronic disease.

PMID- 10654576
TI  - Recent techniques for tracing pathways in the central nervous system of
      developing and adult mammals.
AB  - Over the last 20 years, the choice of neural tracers has increased manyfold, and
      includes newly introduced anterograde tracers that allow quantitation of single
      axon morphologies, and retrograde tracers that can be combined with intracellular
      fills for the study of dendritic arbors of neurons which have a specific
      projection pattern. The combination of several different tracers now permits the
      comparison of multiple connections in the same animal, both quantitatively and
      qualitatively. Moreover, the finding of new virus strains, which infect neural
      cells without killing them, provides a tool for studying multisynaptic
      connections that participate in a circuit. In this paper, the labeling
      characteristics, mechanism of transport and advantages/disadvantages of use are
      discussed for the following recently introduced neural tracers: carbocyanine
      dyes, fluorescent latex microspheres, fluorescent dextrans, biocytin, dextran
      amines, Phaseolus vulgaris leucoagglutinin, cholera toxin and viruses. We also
      suggest the choice of specific tracers, depending on the experimental animal, age
      and type of connection to be studied, and discuss quantitative methodologies.

PMID- 10654577
TI  - Autoregulation of the interleukin-1 system and cytokine-cytokine interactions in
      primary human astrocytoma cells.
AB  - Cytokines are proposed to play important roles in brain tumor biology. Previous
      studies reported on interleukin-1beta (IL-1beta) production and IL-1 receptor
      type I (IL-1RI, signaling receptor) expression in human astrocytomas, and on IL
      1beta action in astrocytoma cell lines. However, all studies that have tested the
      direct action of cytokines have used exclusively astrocytoma cell lines, which do
      not recapitulate the in situ astrocytoma. Here, we demonstrate that astrocytoma
      cells obtained shortly after tumor neurosurgical resection respond to the direct
      application of human IL-1beta with a significant upregulation of IL-1alpha, IL
      1beta, IL-1RI, and tumor necrosis factor-alpha (TNF-alpha) mRNAs. IL-1 receptor
      antagonist (IL-1Ra, an endogenous inhibitor that blocks IL-1alpha and IL-1beta
      actions) mRNA was not upregulated. Application of heat-inactivated IL-1beta had
      no effect on any cytokine component examined, demonstrating specificity of
      action. On the other hand, IL-1beta application did not modulate any cytokine
      component in acutely resected and dissociated primitive neuroectodermal tumor
      cells. The data have implications for a positive autoregulatory IL-1beta feedback
      system and synergistic IL-1beta <=> TNF-alpha interactions, which can be involved
      in the growth of pilocytic astrocytomas. The results together with our previous
      studies also support the notion that IL-1Ra or a compound with similar cytokine
      inhibitory activity could be useful for brain immunotherapy of astrocytomas.

PMID- 10654578
TI  - Growth factor effects on survival and development of calbindin immunopositive
      cultured septal neurons.
AB  - Alzheimer's disease (AD) is a neurodegenerative disease characterized by
      dementia, senile plaques, fibrillary tangles, and a reduction of cholinergic
      neurons in areas of the brain, including the septal nucleus. Certain growth
      factors may promote the long-term survival of this subpopulation of neurons at
      risk. This study was undertaken to characterize growth factors' long-term effects
      on survival and development of neurons expressing the calcium-binding protein
      calbindin. In order to accomplish this, embryonic day 16 rat septal neurons were
      grown in bilaminar culture with astrocytes and in the absence of serum. These
      cultures were chronically treated with estrogen (Es), insulin-like growth factors
      I/II (IGF-I, IGF-II), basic fibroblast growth factor (bFGF), and nerve growth
      factor (NGF). Insulin-like growth factor II significantly increased the number of
      neurons immunoreactive for calbindin by 155%, suggesting either an increase in
      the survival of this subpopulation or an increase in the percentage of cells
      expressing calbindin. Chronic treatment with NGF, IGF-II, and Es significantly
      increased the number of primary neuritic processes on calbindin-positive neurons,
      whereas NGF and Es caused significant increases in the number of secondary
      processes and in the total lengths of the neuritic processes. Thus, effects of
      IGF-II, estrogen, and NGF on survival and maintenance of this neuronal
      subpopulation may be dependent on alterations in neurons which are immunopositive
      for calbindin.

PMID- 10654579
TI  - A role of nitric oxide as an inhibitor of gamma-aminobutyric acid transaminase in
      rat brain.
AB  - The present study has been aimed to investigate the effect of nitric oxide (NO)
      on the concentration of gamma-aminobutyric acid (GABA) in rat brain. The
      concentrations of GABA and glutamate and the activities of glutamic acid
      decarboxylase (GAD) and gamma-aminobutyric acid transaminase (GABA-T) were
      determined in groups of animals 5 and 30 min after intraperitoneal injection of a
      NO-increasing dose (1,000 mg/kg) of its precursor, L-arginine and a dose (50
      mg/kg) of N-nitro-L-arginine methyl ester (L-NAME) that inhibits NO synthesis
      from L-arginine. L-arginine-induced elevation of NO concentration was accompanied
      by an increased concentration of GABA in the brain. GABA-T activity was inhibited
      in these animals. NO-decreasing action of L-NAME coincided with a reduction in
      the concentration of GABA and an enhancement of GABA-T activity. Both L-arginine
      and L-NAME did not alter the activity of GAD and the concentration of glutamate.
      An interpretation of these data suggests that NO has a GABA-T-inhibiting role in
      the brain.

PMID- 10654580
TI  - Immunohistochemical estimation of rat brain somatostatin on avoidance learning
      impairment induced by thiamine deficiency.
AB  - In rats, on the 25th day after the start of a thiamine-deficient (TD) diet,
      impairment of avoidance learning was significantly induced in proportion to the
      decrease somatostatin (SST) fluorescence intensity in the cortex, amygdala,
      thalamus, hypothalamus, and hippocampus, including the CA1, CA2, and dentate
      gyrus (DG). Only a single injection of thiamine HCl (0.5 mg/rat, subcutaneous) on
      the 14th day after the start of a TD diet improved the amnesia to the level of
      the pair-fed control and prevented the decrease in the SST level. Whereas these
      reversal effects of thiamine treatment were not found when the treatment was
      given on the 21st day after the start of a TD diet. These results indicate that,
      after a certain degree of thiamine deficiency, TD-induced behavioral effects
      might be reversible, but some neuronal fibers might be irreversibly damaged,
      probably due to the reduction of thiamine-dependent enzymes in brain
      mitochondria. The results also suggest the possibility that SST in the brain may
      be closely related to the avoidance learning impairment induced by TD.

PMID- 10654581
TI  - Cholesterol and triglyceride levels in the serum of muricidal male Wistar rats:
      indices of mitochondrial benzodiazepine receptors?
AB  - Cholesterol and triglyceride levels were studied in the serum of aggressive
      muricidal and non-muricidal male Wistar rats. The muricidal behavior was either
      spontaneous or induced by a long-term isolation or by adrenalectomy. Cholesterol
      levels were slightly higher in the whole population of muricidal rats; this was
      mainly observed in spontaneously and in adrenalectomized muricidal rats, as
      compared to non-muricidal rats of the same series. As regards triglyceride
      levels, they were significantly higher in the whole population of muricidal rats,
      mainly in isolation- and adrenalectomy-induced muricidal rats; the ratio of
      triglycerides to body weight was higher in the serum of muricidal rats of all
      series. The possible significance of these results is discussed in light of the
      data of the literature and related to the functional role of either mitochondrial
      benzodiazepine receptors or serotonin.

PMID- 10654582
TI  - Regional distribution of gonadotropin-releasing hormone-like, beta-endorphin
      like, and methionine-enkephalin-like immunoreactivities in the central nervous
      system of the goat.
AB  - Regional distribution of gonadotropin-releasing hormone (GnRH)-like-, beta
      endorphin (beta-end)-like-, and methionine-enkephalin (met-enk)-like
      immunoreactivity was quantified across various regions of the central nervous
      system (CNS) of male and female goats by using highly specific radioimmunoassays.
      All the animals were sacrificed during the months of March through June (non
      breeding season). Although the distribution of these three neuropeptides was
      similar to other mammalian species, species-specific gender differences in the
      levels of neuropeptides were noticed in the goat CNS. Highest levels of GnRH-like
      immunoreactivities were found in the hypothalamus. The hypothalamus of male goats
      exhibited significantly higher levels of GnRH-like immunoreactivities compared to
      female goats. Other regions exhibiting GnRH-like immunoreactivities included
      olfactory bulbs, preoptic and supraoptic regions, and mamillary bodies. Both beta
      end- and met-enk immunoreactivities were detected in all selected regions of goat
      CNS, but highest levels of these opioid peptide-like immunoreactivities were
      limited to the forebrain regions of the goat. The supraoptic area of the female
      goats contained significantly higher levels of beta-end-like immunoreactivities
      than that of the male goats. Met-enk-peptide-like immunoreactivity also exhibited
      gender-specific differences in its content in some regions of the CNS. The male
      goats exhibited significantly higher levels of met-enk-like immunoreactivity in
      both the striatal and hypothalamic regions of the brain.

PMID- 10654583
TI  - Differential paired-pulse effects of gabazine and bicuculline in rat hippocampal
      CA3 area.
AB  - Field potentials were evoked in hippocampal area CA3 of anaesthetised rats by
      commissural stimulation, in order to study the effect of the prototypic gamma
      aminobutyric acid (GABA)A antagonists gabazine (SR-95531; GBZ) and bicuculline
      methiodide (BMI) on paired-pulse interaction. Prominent paired-pulse inhibition
      of the orthodromic population spike (PS2) was observed when the interpulse
      interval (IPI) was < or = 40 ms, while facilitation occurred at IPIs >100 ms.
      Paired-pulse facilitation was lost at 500 ms. The antidromic population spike
      (PS1) presented paired-pulse facilitation at low-IPI, which decayed exponentially
      at increasing IPI. When the recording micropipettes contained millimolar
      concentrations of either GBZ, or BMI, single stimuli evoked repetitive
      (epileptiform) orthodromic PS2, of higher amplitude, while the antidromic PS1 was
      only weakly influenced. BMI reduced, but GBZ enhanced the low-IPI paired-pulse
      inhibition of the orthodromic PS2. Furthermore, BMI blunted paired-pulse
      facilitation of the antidromic PS1 at low-IPI, while GBZ caused strong paired
      pulse inhibition of PS1 at IPI < or = 60 ms. The differential effects of GBZ and
      BMI on paired-pulse interaction might reflect different mechanisms of action of
      these compounds.

PMID- 10654585
TI  - Nicotine attenuates stress-induced changes in plasma amino acid concentrations
      and locomotor activity in rats.
AB  - It is known that stressor stimuli (both systemic and processive) and nicotine
      activate central nervous system. Surprisingly, numerous studies have demonstrated
      an increase in nicotine self-administration among smokers when exposed to stress
      in order to reduce the stress-related tension. Therefore, in the present study,
      we decided to investigate the influence of nicotine on both behavioral (i.e., on
      locomotor activity) and metabolic (i.e., on the level of amino acids in the
      plasma) changes following water immersion restraint stress in rats. As expected,
      the stress produced evident decline in locomotor activity of the rats (p < 0.001)
      and in the levels of all plasma amino acids studied (p < 0.05). Nicotine alone
      also significantly reduced locomotor activity (p < 0.05) and the levels of some
      plasma amino acids. However, when administered to rats subjected to water
      immersion and restraint, nicotine attenuated both stress-induced decrease in
      locomotor activity (p < 0.05) and in some plasma amino acids. Thus, this study
      demonstrated that the mode of action of nicotine is strongly dependent on the
      level of initial brain activity, which provide new evidence for arousal
      modulation model of nicotine action.

PMID- 10654584
TI  - Activation of 5-HT2A/2C receptors within the nucleus accumbens increases local
      dopaminergic transmission.
AB  - This study was designed to assess the involvement of the 5-hydroxytryptamine (5
      HT)2A/2C receptor subtypes in the regulation of in vivo dopamine release in the
      rat nucleus accumbens (NAC). Extracellular dopamine (DA) in the NAC was measured
      using intracerebral microdialysis coupled with an HPLC-EC system. 5-HT2A/2C
      receptor agonist, (+/-)-1-(4-lodo-2,5-dimethoxyphenyl)-2-aminopropane (DOI) and
      antagonists, LY-53,857 and ketanserin, were all administered via a dialysis probe
      into the NAC. The results showed that perfusion with DOI at concentrations of 10,
      50, 100, and 300 microM elicited a significant and concentration-dependent
      increase in extracellular DA. DA levels returned to control values within 40-60
      min after terminating DOI perfusion. The increased DA induced by perfusion with
      100 microM DOI was sensitive to sodium channel blockade with tetrodotoxin, and
      antagonized by co-perfusion with either LY-53,857 (25 and 50 microM) or
      ketanserin (50 microM). Perfusion with 50 microM LY-53,857 alone failed to alter
      basal levels of DA. The results suggest that local application of DOI increases
      DA release via a receptor-mediated process, and are consistent with the concept
      that activation of 5-HT2A/2C receptors within the NAC can augment dopaminergic
      transmission in this region although these receptors are not involved in the
      regulation of basal accumbal DA release.

PMID- 10654587
TI  - Azimuthal directional sensitivity of prepulse inhibition of the pinna startle
      reflex in decerebrate rats.
AB  - Previous studies have indicated that the auditory midbrain, the inferior
      colliculus, is important for both sound localization and mediation of prepulse
      inhibition of the startle reflex. The present study investigated the azimuthal
      directional sensitivity of prepulse inhibition of the pinna startle reflex in
      decerebrate rats. The pinna startle reflex was measured by recording multi-unit
      action potentials from the cervicoauricular muscles. The startling noise burst
      (94 dB SPL) was produced by a stationary speaker at 0 degrees azimuth, and the
      non-startling prepulse noise burst (46 dB SPL) was produced by a movable speaker
      whose direction was changed in the frontal azimuthal plane. The interval between
      the onset of the prepulse sound and the onset of the startling sound was 100 ms.
      The pinna reflex to the startling sound was strongly inhibited by the prepulse
      sound, and the inhibited startle response exhibited a flat azimuthal directional
      curve. In addition to further confirming that the neural pathways mediating
      prepulse inhibition are located in the brainstem, the present results indicate
      that interaural disparities of binaural inputs used for sound localization are
      not capable of modulating prepulse inhibition of the startle reflex.

PMID- 10654586
TI  - Altered sensitivity of dopamine autoreceptors in rat accumbens 1 and 7 days after
      intermittent or continuous cocaine withdrawal.
AB  - Using slice preparations, we investigated the effects of chronic cocaine
      treatment on dopamine autoreceptor sensitivity in the nucleus accumbens core.
      Cocaine (40 mg/kg/day) was given for 14 days, either by continuous subcutaneous
      infusion (osmotic minipumps) or single daily injections. One or 7 days after
      cocaine withdrawal, we used fast scan cyclic voltammetry (10 Hz sampling rate) to
      measure inhibition of electrically evoked dopamine release by quinpirole (3-300
      nM). Continuous cocaine infusion increased quinpirole sensitivity on day 1 of
      withdrawal, particularly at low concentrations of quinpirole, but this effect was
      no longer evident by day 7. Intermittent cocaine injections had no effect on day
      1 of withdrawal but by day 7 there was a quinpirole subsensitivity. On either
      withdrawal day, the baseline peak dopamine release or uptake half-life exhibited
      no treatment group differences. It is suggested that these cocaine dosing regimes
      cause differential and dynamic changes in dopamine autoreceptor sensitivity
      during the early withdrawal phase.

PMID- 10654588
TI  - Safety evaluation of phytosterol esters. Part 5. Faecal short-chain fatty acid
      and microflora content, faecal bacterial enzyme activity and serum female sex
      hormones in healthy normolipidaemic volunteers consuming a controlled diet either
      with or without a phytosterol ester-enriched margarine.
AB  - A study was conducted in 12 healthy males and 12 healthy females (mean age 36
      years, mean body mass index 24 kg/m2), to determine the effect of a margarine
      enriched with phytosterol esters on faecal short-chain fatty acids (SCFAs) and
      faecal bacterial enzyme activities, viable faecal microflora count, female sex
      hormones and serum cholesterol concentrations. The study design was a two-period,
      parallel dosing, randomized, placebo-controlled dietary study. Under controlled
      dietary conditions, participants consumed 40 g of the control margarine for 21
      and 28 consecutive days for males and females, respectively. This was followed
      immediately by the second part of the study where subjects were equally and
      randomly allocated to consume daily 40 g of either the control or the test
      margarine, containing 8.6 g vegetable oil phytosterols (a mixture of beta
      sitosterol, campesterol and stigmasterol), also for 21 or 28 days. All females
      were shown to have a regular menstrual cycle and were on an established method of
      contraception not involving oral contraceptives. When compared with the control
      group values, the test group showed a significant reduction in serum total and
      LDL cholesterol concentrations of 18 and 23% (P < 0.001; P < 0.001) respectively,
      in faecal lactic acid concentration (P = 0.039) and in serum progesterone levels
      (P = 0.021). There were no other significant treatment effects. Within each group
      a number of significant changes occurred compared to baseline. In the test group,
      faecal lactic acid concentration and the ratio of acetic acid:total SCFA; and the
      ratio of butyric acid:total SCFA, in the control group were both significantly
      reduced (P = 0.016). Compared to baseline, azo-reductase activity was
      significantly reduced in the control group (P = 0.047). Total faecal aerobes (P =
      0.028), lactobacilli (P = 0.003) and staphylococci (P = 0.025) content was also
      significantly reduced in the control group, while in the test group only
      lactobacilli content was reduced (P = 0.019). Of the significant findings
      reported in this study, none was considered to be of biological importance except
      the beneficial reduction in serum total and LDL-cholesterol concentrations. The
      daily consumption of a margarine enriched with 8.6 g vegetable oil phytosterols
      did not affect the bacterial profile or the metabolic activities of the gut
      microflora, nor did it result in biologically relevant effects on serum female
      sex hormone levels. The margarine enriched with the vegetable oil phytosterols
      was well tolerated by both male and female volunteers.

PMID- 10654589
TI  - Metabolites of diallyl disulfide and diallyl sulfide in primary rat hepatocytes.
AB  - The objectives of this study were to analyse and identify the metabolites of
      diallyl disulfide (DADS) and diallyl sulfide (DAS) in primary rat hepatocytes
      prepared by collagenase perfusion. According to the results, allyl mercaptan (AM)
      and allyl methyl sulfide (AMS) were the metabolites of DADS. The highest amount
      of AMS (0.93 +/- 0.08 microg/ml at 90 min) was much less than that of AM (46.2 +/
      6.6 microg/ml at 60 min). Combined with the Purge and Trap using a gas
      chromatography-mass spectrometry (GC-MS) system, it is very useful to detect the
      trace amounts of metabolites in primary rat hepatocytes. Results also showed that
      AMS was a metabolite of DAS. The highest amount of AMS in the extracellular fluid
      of hepatocytes was 0.63 +/- 0.16 microg/ml at 30 min of incubation.

PMID- 10654590
TI  - Binding capacity of various fibre to pesticide residues under simulated
      gastrointestinal conditions.
AB  - The purpose of this study was to compare the effect of the nature and quantity of
      various dietary fibre (cellulose, hemicellulose, pectin, lignin) in diets on the
      binding capacity to pesticides azinphos-methyl (AZM), chlorpropham (CLP),
      chlorothalonil (CKL), permethrin (PER) as estimated by solubility under
      conditions of pH and temperature simulating those in the gastrointestinal tract
      (incubated at pH 2 for 30 min at 37 degrees C, then at pH 7 for 60 min). The
      ratios of fibre to pesticides were determined in omnivorous diets. In this model,
      the binding capacity of lignin was equal to hemicellulose for PER, AZM and CLP,
      but it was significantly higher for CKL. Hemicellulose bound more CKL, AZM and
      CLP than did cellulose. Although pectin appreciably decreased all pesticides, its
      effect was lower than other fibres with one exception--cellulose-CKL. In the
      presence of equal amounts of fibre, lignin exerted the most significant effect on
      pesticide solubility. Hemicellulose and cellulose bind to the same extent PER and
      AZM. The effect of pectin was significant only on CKL and AZM when compared to
      the control.

PMID- 10654591
TI  - Sphinganine/sphingosine ratio in plasma and urine as a possible biomarker for
      fumonisin exposure in humans in rural areas of Africa.
AB  - This study was conducted in the Transkei region of the Eastern Cape and KwaZulu
      Natal province, South Africa and in the Bomet district, western Kenya. The
      sphinganine (Sa)/sphingosine (So) ratios in the plasma and urine of male and
      female volunteers consuming a staple diet of home-grown maize in Transkei, were
      0.34 +/- 0.36 (mean +/- standard deviation) (n = 154) and 0.41 +/- 0.72 (n =
      153), respectively and in plasma samples from KwaZulu-Natal it was 0.44 +/- 0.23
      (n = 26). In Kenya, the ratios in plasma and urine were 0.28 +/- 0.07 (n = 29)
      and 0.34 +/- 0.20 (n = 27), respectively. Mean total fumonisin level in home
      grown maize, randomly collected in Transkei from the same region where the human
      volunteers lived, was 580 ng/g (n = 40), as compared to the KwaZulu-Natal
      province, where no fumonisin (n = 17) were detected (< 10 ng/g) in the home-grown
      maize. In Kenya, only one of seven samples was contaminated with 60 ng/g
      fumonisins. No significant differences were found in the Sa/So ratios between
      males and females within the regions nor between the different regions (P >
      0.05). It is possible that the ratio is not sensitive enough to act as a
      biomarker for fumonisin exposure in humans at these levels of contamination in
      maize. This is the first report on Sa/So ratios determined in rural populations
      in Africa consuming home-grown maize as their staple diet.

PMID- 10654592
TI  - Effect of urinary pH on the progression of urinary bladder tumours.
AB  - Systemic alkalosis has been postulated to enhance tumorigenesis, whereas systemic
      acidosis has been implicated to exert a favourable influence on tumour control
      and regression. In the present study the urinary pH was influenced by feeding
      acid-forming or base-forming diets, and the effect of alkaline or acid urine on
      the early and late progression phase of urinary bladder carcinogenicity was
      investigated in male Wistar rats. Bladder lesions were initiated by N-butyl-N-(4
      hydroxybutyl) nitrosamine (0.05% BBN in the drinking water during 4 weeks) and
      promoted by sodium bicarbonate (3.4% NaHCO3 in the diet during 15 or 25 weeks).
      After short- (15 week) and more long-term (25 week) promotion with NaHCO3, groups
      of 20 rats were fed a diet containing the acidifying salt ammonium chloride (2.1%
      NH4Cl) or the control diet. All surviving rats were killed after a total study
      duration of 52 weeks. Additional control groups were, after initiation, fed diets
      containing NaHCO3 and killed after 15 wk or 25 wk of promotion, or at the end of
      the study. In rats fed diets with added salts, water intake and the amount of
      urine produced were increased and the urinary density was decreased compared to
      rats fed control diet. During NaHCO3 feeding, urinary pH and sodium concentration
      were increased. During NH4Cl feeding, urinary pH was decreased and urinary
      chloride and calcium concentrations were increased. Initiation by BBN followed by
      treatment with NaHCO3 caused a high incidence of papillary/nodular hyperplasia,
      papillomas and carcinomas of the bladder epithelium. These lesions progressed
      with time or longer duration of NaHCO3 promotion. A tumour protective effect of
      urinary acidification by NH4Cl was not found. In fact, both acidification and
      prolonged alkalinization tended to aggravate the malignancy of bladder
      carcinomas.

PMID- 10654593
TI  - Threshold for classification as a skin sensitizer in the local lymph node assay:
      a statistical evaluation.
AB  - For more than 15 years, the murine local lymph node assay (LLNA) has undergone
      development, evaluation and validation as an alternative approach to the
      predictive identification of skin sensitizing chemicals. The criteria by which
      sensitizing chemicals are distinguished from those without significant skin
      sensitising hazard were developed empirically and were based on experience rather
      than a mathematical formula or statistical method. The current practice is to
      classify, as skin sensitizers, those chemicals which at one or more test
      concentrations stimulate a threefold or greater increase in the proliferative
      activity in draining lymph node cells. Despite the apparent confirmation of the
      utility of this approach from the extensive data available, there has not
      previously been any attempt to substantiate the accuracy of this criterion. In
      this present investigations, data from 134 chemicals tested in the LLNA and in
      the guinea pig and/or for which there exists clear evidence relating to human
      skin sensitization potential, have been subjected to a rigorous statistical
      evaluation using Receiver Operating Characteristic (ROC) curves. Whether the
      analysis is based on a comparison with guinea pig or human data, the results
      indicate that the empirically derived threefold threshold is an acceptable
      practical value for hazard identification.

PMID- 10654594
TI  - The application of in vitro data in the derivation of the acceptable daily intake
      of food additives.
AB  - The acceptable daily intake (ADI) for food additives is commonly derived from the
      NOAEL (no-observed-adverse-effect level) in long-term animal in vivo studies. To
      derive an ADI a safety or uncertainty factor (commonly 100) is applied to the
      NOAEL in the most sensitive test species. The 100-fold safety factor is
      considered to be the product of both species and inter-individual differences in
      toxicokinetics and toxicodynamics. Although in vitro data have previously been
      considered during the risk assessment of food additives, they have generally had
      no direct influence on the calculation of ADI values. In this review 18 food
      additives are evaluated for the availability of in vitro toxicity data which
      might be used for the derivation of a specific data-derived uncertainty factor.
      For the majority of the food additives reviewed, additional in vitro tests have
      been conducted which supplement and support the short- and long-term in vivo
      toxicity studies. However, it was recognized that these in vitro studies could
      not be used in isolation to derive an ADI; only when sufficient in vivo
      mechanistic data are available can such information be used in a regulatory
      context. Additional short-term studies are proposed for the food additives which,
      if conducted, would provide data that could then be used for the calculation of
      data-derived uncertainty factors.

PMID- 10654595
TI  - Mice lacking HSP90beta fail to develop a placental labyrinth.
AB  - The 90 kDa heat-shock proteins (HSP90s) play important roles during stress
      situations as general chaperones and under physiological conditions in the
      conformational activation of specific protein substrates. Vertebrates express two
      cytosolic HSP90s (HSP90alpha and HSP90beta) ubiquitously. We have mutated the
      Hsp90beta gene in murine embryonic stem cells and generated Hsp90beta mutant
      mice. Heterozygous animals were phenotypically normal. Interestingly, homozygous
      embryos developed normally until embryonic day 9.0/9.5. Then, although Hsp90beta
      is expressed ubiquitously, they exhibited phenotypic abnormalities restricted to
      the placenta. The mutant concepti failed to form a fetal placental labyrinth and
      died a day later. Fusion between the allantois and the chorionic plate occurred,
      allantoic blood vessels invaded the chorion, but then did not expand. Mutant
      trophoblast cells failed to differentiate into trilaminar labyrinthine
      trophoblast. Despite conspicuous similarities between HSP90alpha and HSP90beta at
      the molecular level, our data suggest that HSP90beta has a key role in placenta
      development that cannot be performed by the endogenous HSP90alpha alone. Analysis
      of chimeric concepti consisting of mutant embryos and tetraploid embryos or ES
      cells revealed that wild-type allantois was able to induce mutant trophoblast to
      differentiate. In contrast, trophoblast wild type at the Hsp90beta locus was
      unable to differentiate when in contact with mutant allantois. Therefore, the
      primary defect caused by the Hsp90beta mutation resided in the allantois. The
      allantois mesoderm is thought to induce trophoblast differentiation. Our results
      show that Hsp90beta is a necessary component of this induction process.

PMID- 10654596
TI  - Netrin 1 is required for semicircular canal formation in the mouse inner ear.
AB  - The morphogenetic development of the mammalian inner ear is a complex multistep
      process, the molecular and cellular details of which are only beginning to be
      unraveled. We show here that mouse netrin 1, known to be involved in axon
      guidance and cell migration in the central nervous system, also plays a critical
      morphogenetic role during semicircular canal formation. netrin 1 is expressed at
      high levels in the otic epithelium, in cells that will come together to form a
      fusion plate, a prerequisite for the formation of semicircular canals. In netrin
      1 mutant mice, fusion plate formation is severely affected resulting in a reduced
      anterior semicircular canal and the complete lack of the posterior and lateral
      canals. Our results suggest that netrin 1 facilitates semicircular canal
      formation through two different mechanisms: (1) it participates in the detachment
      of the fusion plate epithelia from the basement membrane, and (2) it stimulates
      proliferation of the periotic mesenchymal cells which then push the epithelial
      cell walls together to form the fusion plate.

PMID- 10654597
TI  - The axr6 mutants of Arabidopsis thaliana define a gene involved in auxin response
      and early development.
AB  - The indolic compound auxin regulates virtually every aspect of plant growth and
      development, but its role in embryogenesis and its molecular mechanism of action
      are not understood. We describe two mutants of Arabidopsis that define a novel
      gene called AUXIN-RESISTANT6 (AXR6) which maps to chromosome 4. Embryonic
      development of the homozygous axr6 mutants is disrupted by aberrant patterns of
      cell division, leading to defects in the cells of the suspensor, root and
      hypocotyl precursors, and provasculature. The homozygous axr6 mutants arrest
      growth soon after germination lacking a root and hypocotyl and with severe
      vascular pattern defects in their cotyledons. Whereas previously described
      mutants with similar developmental defects are completely recessive, axr6
      heterozygotes display a variety of morphological and physiological alterations
      that are most consistent with a defect in auxin physiology or response. The AXR6
      gene is likely to be important for auxin response throughout the plant, including
      early development.

PMID- 10654598
TI  - Acceleration of trophoblast differentiation by heparin-binding EGF-like growth
      factor is dependent on the stage-specific activation of calcium influx by ErbB
      receptors in developing mouse blastocysts.
AB  - Heparin-binding EGF-like growth factor (HB-EGF) is expressed in the mouse
      endometrial epithelium during implantation exclusively at sites apposed to
      embryos and accelerates the development of cultured blastocysts, suggesting that
      it may regulate peri-implantation development in utero. We have examined the
      influence of HB-EGF on mouse trophoblast differentiation in vitro and the
      associated intracellular signaling pathways. HB-EGF both induced intracellular
      Ca2+ signaling and accelerated trophoblast development to an adhesion-competent
      stage, but only late on gestation day 4 after ErbB4, a receptor for HB-EGF,
      translocated from the cytoplasm to the apical surface of trophoblast cells. The
      acceleration of blastocyst differentiation by HB-EGF was attenuated after
      inhibition of protein tyrosine kinase activity or removal of surface heparan
      sulfate, as expected. Chelation of intracellular Ca2+ blocked the ability of HB
      EGF to accelerate development, as did inhibitors of protein kinase C or
      calmodulin. The absence of any effect by a phospholipase C inhibitor and the
      requirement for extracellular Ca2+ suggested that the accrued free cytoplasmic
      Ca2+ did not originate from inositol phosphate-sensitive intracellular stores,
      but through Ca2+ influx. Indeed, N-type Ca2+ channel blockers specifically
      inhibited the ability of HB-EGF to both induce Ca2+ signaling and accelerate
      trophoblast development. We conclude that HB-EGF accelerates the differentiation
      of trophoblast cells to an adhesion-competent stage by inducing Ca2+ influx,
      which activates calmodulin and protein kinase C. An upstream role for ErbB4 in
      this pathway is implicated by the timing of its translocation to the trophoblast
      surface.

PMID- 10654599
TI  - Addition of the BMP4 antagonist, noggin, disrupts avian inner ear development.
AB  - Bone morphogenetic protein 4 (BMP4) is known to regulate dorsoventral patterning,
      limb bud formation and axis specification in many organisms, including the
      chicken. In the chick developing inner ear, BMP4 expression becomes localized in
      two cell clusters at the anterior and posterior edges of the otic epithelium
      beginning at stage 16/17 and is expressed in presumptive sensory tissue at later
      stages. This restricted spatiotemporal pattern of expression occurs just prior to
      the otocyst's transition to a more complex three-dimensional structure. To
      further analyze the role of BMP4 in avian otic morphogenesis, cells expressing
      BMP4 or its antagonist, noggin, were grown on agarose beads and implanted into
      the periotic mesenchyme surrounding the chick otocyst. Although the BMP4
      producing cells had no effect on the mature inner ear structure when implanted
      alone, noggin-producing cells implanted adjacent to the BMP4 cell foci prevented
      normal semicircular canal development. Beads implanted at the anterior BMP4 focus
      eliminated the anterior and/or the horizontal canals. Noggin cells implanted at
      the posterior focus eliminated the posterior canal. Canal loss was prevented by
      co-implantation of BMP4 cell beads next to noggin beads. An antibody to the chick
      hair cell antigen (HCA) was used to examine sensory cell distribution, which was
      abnormal only in the affected tissues of noggin-exposed inner ears. These data
      suggest a role for BMP4 in the accurate and complete morphological development of
      the semicircular canals.

PMID- 10654600
TI  - Activation of knot (kn) specifies the 3-4 intervein region in the Drosophila
      wing.
AB  - Hedgehog (Hh) plays an important role in Drosophila wing patterning by inducing
      expression of Dpp, which serves to organize the wing globally across the A-P
      axis. We show here how Hh signalling also plays a direct role in patterning the
      medial wing through the activation of the Hh-target gene, knot (kn). kn is
      expressed in Hh-responsive cells near the A-P compartment boundary, where its
      expression is dependent on fu, a component of Hh signalling. kn is required for
      the proper positioning of veins 3 and 4 and to prevent ectopic venation between
      them. Furthermore, the expansion anteriorly of the normal kn expression domain
      causes an associated anterior shift in the position of vein 3 in the resultant
      wing. Ectopic expression of kn elsewhere in the wing imaginal disc results in the
      failure to properly activate the vein initiation genes, rho and Dl. Expression of
      the gene encoding the EGF-receptor (EGFR), which is required for vein initiation
      and subsequent differentiation, is normally depressed in the 3-4 intervein
      region. This downregulation of EGFR in the medial portion of the imaginal disc is
      dependent on kn activity and ectopic expression of kn inactivates EGFR elsewhere
      in the wing primordium. We propose kn expression in Hh-responsive cells of the
      wing blade anlagen during the late third instar creates a zone of cells in the
      medial wing in which vein primordia cannot be induced. The primordia for veins 3
      and 4 are laid down adjacent to the kn-imposed vein-free zone, presumably by a
      signalling factor (such as Vn) also synthesized in the medial region of the wing.

PMID- 10654601
TI  - Sry induces cell proliferation in the mouse gonad.
AB  - Sry is the only gene on the Y chromosome that is required for testis formation in
      mammals. One of the earliest morphological changes that occurs as a result of Sry
      expression is a size increase of the rudimentary XY gonad relative to the XX
      gonad. Using 5'-bromo-2'-deoxyuridine (BrdU) incorporation to label dividing
      cells, we found that the size increase corresponds with a dramatic increase in
      somatic cell proliferation in XY gonads, which is not detected in XX gonads. This
      male-specific proliferation was observed initially in the cells of the coelomic
      epithelium and occurred in two distinct stages. During the first stage,
      proliferation in the XY gonad was observed largely in SF1-positive cells and
      contributed to the Sertoli cell population. During the second stage,
      proliferation was observed in SF1-negative cells at and below the coelomic
      epithelium and did not give rise to Sertoli cells. Both stages of proliferation
      were dependent on Sry and independent of any other genetic differences between
      male and female gonads, such as X chromosome dosage or other genes on the Y
      chromosome. The increase in cell proliferation began less than 24 hours after the
      onset of Sry expression, before the establishment of male-specific gene
      expression patterns, and before the appearance of any other known male-specific
      morphological changes in the XY gonad. Therefore, an increase in cell
      proliferation in the male coelomic epithelium is the earliest identified effect
      of Sry expression.

PMID- 10654603
TI  - Formation of the avian primitive streak from spatially restricted blastoderm:
      evidence for polarized cell division in the elongating streak.
AB  - Gastrulation in the amniote begins with the formation of a primitive streak
      through which precursors of definitive mesoderm and endoderm ingress and migrate
      to their embryonic destinations. This organizing center for amniote gastrulation
      is induced by signal(s) from the posterior margin of the blastodisc. The mode of
      action of these inductive signal(s) remains unresolved, since various origins and
      developmental pathways of the primitive streak have been proposed. In the present
      study, the fate of chicken blastodermal cells was traced for the first time in
      ovo from prestreak stages XI-XII through HH stage 3, when the primitive streak is
      initially established and prior to the migration of mesoderm. Using replication
      defective retrovirus-mediated gene transfer and vital dye labeling, precursor
      cells of the stage 3 primitive streak were mapped predominantly to a specific
      region where the embryonic midline crosses the posterior margin of the epiblast.
      No significant contribution to the early primitive streak was seen from the
      anterolateral epiblast. Instead, the precursor cells generated daughter cells
      that underwent a polarized cell division oriented perpendicular to the
      anteroposterior embryonic axis. The resulting daughter cell population was
      arranged in a longitudinal array extending the complete length of the primitive
      streak. Furthermore, expression of cVg1, a posterior margin-derived signal, at
      the anterior marginal zone induced adjacent epiblast cells, but not those lateral
      to or distant from the signal, to form an ectopic primitive streak. The cVg1
      induced epiblast cells also exhibited polarized cell divisions during ectopic
      primitive streak formation. These results suggest that blastoderm cells located
      immediately anterior to the posterior marginal zone, which secretes an inductive
      signal, undergo spatially directed cytokineses during early primitive streak
      formation.

PMID- 10654602
TI  - Retinoic acid synthesis and hindbrain patterning in the mouse embryo.
AB  - Targeted disruption of the murine retinaldehyde dehydrogenase 2 (Raldh2) gene
      precludes embryonic retinoic acid (RA) synthesis, leading to midgestational
      lethality (Niederreither, K., Subbarayan, V., Dolle, P. and Chambon, P. (1999).
      Nature Genet. 21, 444-448). We describe here the effects of this RA deficiency on
      the development of the hindbrain and associated neural crest. Morphological
      segmentation is impaired throughout the hindbrain of Raldh2-/- embryos, but its
      caudal portion becomes preferentially reduced in size during development.
      Specification of the midbrain region and of the rostralmost rhombomeres is
      apparently normal in the absence of RA synthesis. In contrast, marked alterations
      are seen throughout the caudal hindbrain of mutant embryos. Instead of being
      expressed in two alternate rhombomeres (r3 and r5), Krox20 is expressed in a
      single broad domain, correlating with an abnormal expansion of the r2-r3 marker
      Meis2. Instead of forming a defined r4, Hoxb1- and Wnt8A-expressing cells are
      scattered throughout the caudal hindbrain, whereas r5/r8 markers such as kreisler
      or group 3/4 Hox genes are undetectable or markedly downregulated. Lack of
      alternate Eph receptor gene expression could explain the failure to establish
      rhombomere boundaries. Increased apoptosis and altered migratory pathways of the
      posterior rhombencephalic neural crest cells are associated with impaired
      branchial arch morphogenesis in mutant embryos. We conclude that RA produced by
      the embryo is required to generate posterior cell fates in the developing mouse
      hindbrain, its absence leading to an abnormal r3 (and, to a lesser extent, r4)
      identity of the caudal hindbrain cells.

PMID- 10654604
TI  - Ultrabithorax and the control of cell morphology in Drosophila halteres.
AB  - The Drosophila haltere is a much reduced and specialised hind wing, which
      functions as a balance organ. Ultrabithorax (Ubx) is the sole Hox gene
      responsible for the differential development of the fore-wing and haltere in
      Drosophila. Previous work on the downstream effects of Ubx has focused on the
      control of pattern formation. Here we provide the first detailed description of
      cell differentiation in the haltere epidermis, and of the developmental processes
      that distinguish wing and haltere cells. By the end of pupal development, haltere
      cells are 8-fold smaller in apical surface area than wing cells; they differ in
      cell outline, and in the size and number of cuticular hairs secreted by each
      cell. Wing cells secrete only a thin cuticle, and undergo apoptosis within 2
      hours of eclosion. Haltere cells continue to secrete cuticle after eclosion.
      Differences in the shape of wing and haltere cells reflect differences in the
      architecture of the actin cytoskeleton that become apparent between 24 and 48
      hours after puparium formation. We show that Ubx protein is not needed later than
      6 hours after puparium formation to specify these differences, though it is
      required at later stages for the correct development of campaniform sensilla on
      the haltere. We conclude that, during normal development, Ubx protein expressed
      before pupation controls a cascade of downstream effects that control changes in
      cell morphology 24-48 hours later. Ectopic expression of Ubx in the pupal wing,
      up to 30 hours after puparium formation, can still elicit many aspects of haltere
      cell morphology. The response of wing cells to Ubx at this time is sensitive to
      both the duration and level of Ubx exposure.

PMID- 10654605
TI  - SHH-N upregulates Sfrp2 to mediate its competitive interaction with WNT1 and WNT4
      in the somitic mesoderm.
AB  - Dorsoventral polarity of the somitic mesoderm is established by competitive
      signals originating from adjacent tissues. The ventrally located notochord
      provides the ventralizing signals to specify the sclerotome, while the dorsally
      located surface ectoderm and dorsal neural tube provide the dorsalizing signals
      to specify the dermomyotome. Noggin and SHH-N have been implicated as the
      ventralizing signals produced by the notochord. Members of the WNT family of
      proteins, on the other hand, have been implicated as the dorsalizing signals
      derived from the ectoderm and dorsal neural tube. When presomitic explants are
      confronted with cells secreting SHH-N and WNT1 simultaneously, competition to
      specify the sclerotome and dermomyotome domains within the naive mesoderm can be
      observed. Here, using these explant cultures, we provide evidence that SHH-N
      competes with WNT1, not only by upregulating its own receptor Ptc1, but also by
      upregulating Sfrp2 (Secreted frizzled-related protein 2), which encodes a
      potential WNT antagonist. Among the four known Sfrps, Sfrp2 is the only member
      expressed in the sclerotome and upregulated by SHH-N recombinant protein. We
      further show that SFRP2-expressing cells can reduce the dermomyotome-inducing
      activity of WNT1 and WNT4, but not that of WNT3a. Together, our results support
      the model that SHH-N at least in part employs SFRP2 to reduce WNT1/4 activity in
      the somitic mesoderm.

PMID- 10654606
TI  - Nab proteins mediate a negative feedback loop controlling Krox-20 activity in the
      developing hindbrain.
AB  - The developing vertebrate hindbrain is transiently subdivided along the anterior
      posterior axis into metameric units, called rhombomeres (r). These segments
      constitute units of lineage restriction and display specific gene expression
      patterns. The transcription factor gene Krox-20 is restricted to r3 and r5, and
      is required for the development of these rhombomeres. We present evidence that
      Krox-20 transcriptional activity is under the control of a negative feedback
      mechanism in the hindbrain. This regulatory loop involves two closely related
      proteins, Nabl and Nab2, previously identified as antagonists of Krox-20
      transcriptional activity in cultured cells. Here we show that in the mouse
      hindbrain, Nab1 and Nab2 recapitulate the Krox-20 expression pattern and that
      their expression is dependent on Krox-20 function. Furthermore, misexpression of
      Nab1 or Nab2 in zebrafish embryos leads to alterations in the expression patterns
      of several hindbrain markers, consistent with an inhibition of Krox-20 activity.
      Taken together, these data indicate that Krox-20 positively regulates the
      expression of its own antagonists and raise the possibility that this negative
      feedback regulatory loop may play a role in the control of hindbrain development.

PMID- 10654607
TI  - Identification and characterization of hydra metalloproteinase 2 (HMP2): a meprin
      like astacin metalloproteinase that functions in foot morphogenesis.
AB  - Several members of the newly emerging astacin metalloproteinase family have been
      shown to function in a variety of biological events, including cell
      differentiation and morphogenesis during both embryonic development and adult
      tissue differentiation. We have characterized a new astacin proteinase, hydra
      metalloproteinase 2 (HMP2) from the Cnidarian, Hydra vulgaris. HMP2 is translated
      from a single mRNA of 1.7 kb that contains a 1488 bp open reading frame encoding
      a putative protein product of 496 amino acids. The overall structure of HMP2 most
      closely resembles that of meprins, a subgroup of astacin metalloproteinases. The
      presence of a transient signal peptide and a putative prosequence indicates that
      HMP2 is a secreted protein that requires post-translational processing. The
      mature HMP2 starts with an astacin proteinase domain that contains a zinc binding
      motif characteristic of the astacin family. Its COOH terminus is composed of two
      potential protein-protein interaction domains: an "MAM" domain (named after
      meprins, A-5 protein and receptor protein tyrosine phosphatase mu) that is only
      present in meprin-like astacin proteinases; and a unique C-terminal domain (TH
      domain) that is also present in another hydra metalloproteinase, HMP1, in
      Podocoryne metalloproteinase 1 (PMP1) of jellyfish and in toxins of sea anemone.
      The spatial expression pattern of HMP2 was determined by both mRNA whole-mount in
      situ hybridization and immunofluorescence studies. Both morphological techniques
      indicated that HMP2 is expressed only by the cells in the endodermal layer of the
      body column of hydra. While the highest level of HMP2 mRNA expression was
      observed at the junction between the body column and the foot process,
      immunofluorescence studies indicated that HMP2 protein was present as far
      apically as the base of the tentacles. In situ analysis also indicated expression
      of HMP2 during regeneration of the foot process. To test whether the higher
      levels of HMP2 mRNA expression at the basal pole related to processes underlying
      foot morphogenesis, antisense studies were conducted. Using a specialized
      technique named localized electroporation (LEP), antisense constructs to HMP2
      were locally introduced into the endodermal layer of cells at the basal pole of
      polyps and foot regeneration was initiated and monitored. Treatment with
      antisense to HMP2 inhibited foot regeneration as compared to mismatch and sense
      controls. These functional studies in combination with the fact that HMP2 protein
      was expressed not only at the junction between the body column and the foot
      process, but also as far apically as the base of the tentacles, suggest that this
      meprin-class metalloproteinase may be multifunctional in hydra.

PMID- 10654608
TI  - Targeted disruption of the murine junD gene results in multiple defects in male
      reproductive function.
AB  - JunD is one of three mammalian Jun proteins that contribute to the AP-1
      transcription factor complex. Distinct regulation and functions have been
      proposed for each Jun member, but less is known about the biological functions of
      each of these proteins in vivo. To investigate the role of JunD, we have
      inactivated the murine gene by replacement with a bacterial lacZ reporter gene.
      Embryonic JunD expression was initially detected in the developing heart and
      cardiovascular system. Subsequent broadening phases of JunD expression were
      observed during embryonic development and expression in the adult was widespread
      in many tissues and cell lineages. Mutant animals lack JunD mRNA and protein and
      showed no evidence of upregulation of c-Jun and JunB mRNA levels. In contrast to
      the other two Jun members, homozygous JunD-/- mutant animals were viable and
      appeared healthy. However, homozygous JunD-/- animals showed a reduced postnatal
      growth. Furthermore, JunD-/- males exhibited multiple age-dependent defects in
      reproduction, hormone imbalance and impaired spermatogenesis with abnormalities
      in head and flagellum sperm structures. No defects in fertility were observed in
      JunD-/- female animals. These results provide evidence for redundant functions
      for members of the Jun family during development and specific functions for JunD
      in male reproductive function.

PMID- 10654609
TI  - Segmental expression of Hoxb2 in r4 requires two separate sites that integrate
      cooperative interactions between Prep1, Pbx and Hox proteins.
AB  - Direct auto- and cross-regulatory interactions between Hox genes serve to
      establish and maintain segmentally restricted patterns in the developing
      hindbrain. Rhombomere r4-specific expression of both Hoxb1 and Hoxb2 depends upon
      bipartite cis Hox response elements for the group 1 paralogous proteins, Hoxal
      and Hoxbl. The DNA-binding ability and selectivity of these proteins depend upon
      the formation of specific heterodimeric complexes with members of the PBC
      homeodomain protein family (Pbx genes). The r4 enhancers from Hoxb1 and Hoxb2
      have the same activity, but differ with respect to the number and organisation of
      bipartite Pbx/Hox (PH) sites required, suggesting the intervention of other
      components/sequences. We report here that another family of homeodomain proteins
      (TALE, Three-Amino acids-Loop-Extension: Prep1, Meis, HTH), capable of dimerizing
      with Pbx/EXD, is involved in the mechanisms of r4-restricted expression. We show
      that: (1) the r4-specific Hoxb1 and Hoxb2 enhancers are complex elements
      containing separate PH and Prep/Meis (PM) sites; (2) the PM site of the Hoxb2,
      but not Hoxb1, enhancer is essential in vivo for r4 expression and also
      influences other sites of expression; (3) both PM and PH sites are required for
      in vitro binding of Prepl-Pbx and formation and binding of a ternary Hoxbl-Pbxla
      (or 1b)-Prepl complex. (4) A similar ternary association forms in nuclear
      extracts from embryonal P19 cells, but only upon retinoic acid induction. This
      requires synthesis of Hoxbl and also contains Pbx with either Prepl or Meisl.
      Together these findings highlight the fact that PM sites are found in close
      proximity to bipartite PH motifs in several Hox responsive elements shown to be
      important in vivo and that such sites play an essential role in potentiating
      regulatory activity in combination with the PH motifs.

PMID- 10654610
TI  - Embryonic origins of spleen asymmetry.
AB  - The spleen is a vertebrate organ that has both hematopoietic and immunologic
      function. The embryonic origins of the spleen are obscure, with most studies
      describing the earliest rudiment of the spleen as a condensation of mesodermal
      mesenchyme on the left side of the dorsal mesogastrium. The development of spleen
      handedness has not been described previously, presumably because of the
      difficulty in assaying spleen position in the embryo and the lack of early, organ
      specific molecular markers. Here we show that expression of the homeobox gene
      Nkx2-5 serves as a marker for spleen precursor tissue. Pre-splenic tissue is
      initially located in symmetric domains on both sides of the embryo but, during
      subsequent development, only the left side goes on to form the mature spleen.
      Therefore, the final location of the spleen on the left side of the body axis
      appears to result from preferential development of the spleen precursor cells on
      the left side of the embryo. Our studies indicate that the spleen and heart
      become asymmetric via different cellular mechanisms. Nkx2-5 may function locally
      as part of the laterality cascade, downstream of nodal and Pitx2, or it may
      direct asymmetric morphogenesis after laterality has been determined.

PMID- 10654611
TI  - Signalling by FGF8 from the isthmus patterns anterior hindbrain and establishes
      the anterior limit of Hox gene expression.
AB  - Current evidence suggests that the anterior segment of the vertebrate hindbrain,
      rhombomere 1, gives rise to the entire cerebellum. It is situated where two
      distinct developmental patterning mechanisms converge: graded signalling from an
      organising centre (the isthmus) located at the midbrain/hindbrain boundary
      confronts segmentation of the hindbrain. The unique developmental fate of
      rhombomere 1 is reflected by it being the only hindbrain segment in which no Hox
      genes are expressed. In this study we show that ectopic FGF8 protein, a candidate
      for the isthmic organising activity, is able to induce and repress gene
      expression within the hindbrain in a manner appropriate to rhombomere 1. Using a
      heterotopic, heterospecific grafting strategy we demonstrate that rhombomere 1 is
      able to express Hox genes but that both isthmic tissue and FGF8 inhibit their
      expression. Inhibition of FGF8 function in vivo shows that it is responsible for
      defining the anterior limit of Hox gene expression within the developing brain
      and thereby specifies the extent of the rl territory. Previous studies have
      suggested that a retinoid morphogen gradient determines the axial limit of
      expression of individual Hox genes within the hindbrain. We propose a model
      whereby activation by retinoids is antagonised by inhibition by FGF8 in the
      anterior hindbrain to set aside the territory from which the cerebellum will
      develop.

PMID- 10654613
TI  - The dyad gene is required for progression through female meiosis in Arabidopsis.
AB  - In higher plants the gametophyte consists of a gamete in association with a small
      number of haploid cells, specialized for sexual reproduction. The female
      gametophyte or embryo sac, is contained within the ovule and develops from a
      single cell, the megaspore which is formed by meiosis of the megaspore mother
      cell. The dyad mutant of Arabidopsis, described herein, represents a novel class
      among female sterile mutants in plants. dyad ovules contain two large cells in
      place of an embryo sac. The two cells represent the products of a single division
      of the megaspore mother cell followed by an arrest in further development of the
      megaspore. We addressed the question of whether the division of the megaspore
      mother cell in the mutant was meiotic or mitotic by examining the expression of
      two markers that are normally expressed in the megaspore mother cell during
      meiosis. Our observations indicate that in dyad, the megaspore mother cell enters
      but fails to complete meiosis, arresting at the end of meiosis 1 in the majority
      of ovules. This was corroborated by a direct observation of chromosome
      segregation during division of the megaspore mother cell, showing that the
      division is a reductional and not an equational one. In a minority of dyad
      ovules, the megaspore mother cell does not divide. Pollen development and male
      fertility in the mutant is normal, as is the rest of the ovule that surrounds the
      female gametophyte. The embryo sac is also shown to have an influence on the
      nucellus in wild type. The dyad mutation therefore specifically affects a
      function that is required in the female germ cell precursor for meiosis. The
      identification and analysis of mutants specifically affecting female meiosis is
      an initial step in understanding the molecular mechanisms underlying early events
      in the pathway of female reproductive development.

PMID- 10654612
TI  - Left-right asymmetric expression of BbPtx, a Ptx-related gene, in a lancelet
      species and the developmental left-sidedness in deuterostomes.
AB  - The long-standing question of how asymmetric development or asymmetric body
      structures in lancelets (amphioxus) are phylogenetically related to the body plan
      of other animals is still untouched. Three anterior structures, the preoral pit,
      club-shaped gland and mouth, are remarkable asymmetric features in developing
      lancelets that all open on the left side of the body. A Ptx-related gene, BbPtx
      is the first identified transcription factor gene with an asymmetrical expression
      pattern in lancelets similar to that in vertebrates, and thus it may provide a
      clue for the above question. Expression of the BbPtx gene is first detected at
      the dorsal margin of the blastopore in early mid-gastrulae and then becomes
      restricted to the left anterodorsal wall of the primitive gut and to the
      developing left somitocoelomic system. Expression continues on the left side in
      the developing preoral pit, club-shaped gland and mouth as well as in the
      mesoderm at the caudal end. Unlike D-Ptx1 in Drosophila, BbPtx is not coexpressed
      with a fork head gene in lancelets; instead the two genes are expressed in a
      complementary fashion on the left side of the embryo. The expression pattern of
      BbPtx is not compatible with the calcichordate hypothesis of Jefferies, in which
      the proposed ancestor of chordates rotated its tail 90 degrees counterclockwise
      in relation to the head/trunk. The expression of both BbPtx and vertebrate Pitx2
      in tissues derived from the coelom implies that the left-right asymmetric
      development has a common origin between cephalochordates and vertebrates.
      Considering the development of the coelom in deuterostomes, however, left-right
      asymmetric development involving Pitx2-related genes is rather likely to be a
      primitive character shared among deuterostomes.

PMID- 10654614
TI  - Recent developments in the virus therapy of cancer.
AB  - Cancer is one of the leading causes of death in the United States. Although there
      has been significant progress in the areas of cancer etiology, diagnostic
      techniques, and cancer prevention, adequate therapeutic approaches for many
      cancers have lagged behind. One promising line of investigation is the virus
      therapy of cancer. This approach entails the use of viruses, such as
      retroviruses, adenovirus, and vaccinia virus, to modify tumor cells so that they
      become more susceptible to being killed by the host immune response,
      chemotherapeutic agents, or programmed cell death. This review discusses recent
      advances in the virus therapy of cancer from both basic science and clinical
      perspectives. Given the potential of viruses to kill tumor cells directly or
      transduce desired gene products to allow a vigorous host antitumor immune
      response, the virus therapy of cancer holds great promise in the treatment of
      cancer.

PMID- 10654615
TI  - Tumor necrosis factor-alpha-induced insulin resistance in adipocytes.
AB  - Recent studies examining the link between insulin resistance and the development
      of obesity and noninsulin-dependent diabetes mellitus are consistent with the
      involvement of tumor necrosis factor-alpha (TNF-alpha) as a central mediator. In
      insulin resistant obese mouse models, neutralization of TNF-alpha in circulation
      has been demonstrated to restore insulin-mediated glucose uptake. Adipose tissue
      has been shown to be a site for synthesis of TNF-alpha, with the degree of
      adiposity directly correlated with the level of synthesis. Studies conducted on
      obese human patients have demonstrated a correlation between levels of TNF-alpha,
      the extent of obesity, as well as the level of hyperinsulinemia observed.
      Mechanistic studies in cell culture have suggested that TNF-alpha functions to
      render cells insulin resistant through regulation of the synthesis of the insulin
      responsive glucose transporter as well as through interference with insulin
      signaling. This review will address these issues and additionally introduce the
      reader to the molecular aspects of TNF-alpha, its receptors as well as TNF-alpha
      initiated signaling cascades, that are necessary to understand the function of
      this cytokine in the regulation of adipose tissue metabolism.

PMID- 10654616
TI  - Pyruvate: metabolic protector of cardiac performance.
AB  - Pyruvate, a metabolic product of glycolysis and an oxidizable fuel in myocardium,
      increases cardiac mechanical performance and energy reserves, especially when
      supplied at supraphysiological concentrations. The inotropic effects of pyruvate
      are most impressive in hearts that have been reversibly injured (stunned) by
      ischemia/reperfusion stress. Glucose appears to be an essential co-substrate for
      pyruvate's salutary effects in stunned hearts, but other fuels including lactate,
      acetate, fatty acids, and ketone bodies produce little or no improvement in
      postischemic function over glucose alone. In contrast to pharmacological
      inotropism by catecholamines, metabolic inotropism by pyruvate increases cardiac
      energy reserves and bolsters the endogenous glutathione antioxidant system.
      Pyruvate enhancement of cardiac function may result from one or more of the
      following mechanisms: increased cytosolic ATP phosphorylation potential and Gibbs
      free energy of ATP hydrolysis, enhanced sarcoplasmic reticular calcium ion uptake
      and release, decreased cytosolic inorganic phosphate concentration, oxyradical
      scavenging via direct neutralization of peroxides and/or enhancement of the
      intracellular glutathione/NADPH antioxidant system, and/or closure of
      mitochondrial permeability transition pores. This review aims to summarize
      evidence for each of these mechanisms and to consider the potential utility of
      pyruvate as a therapeutic intervention for clinical management of cardiac
      insufficiency.

PMID- 10654617
TI  - Pluripotent hemopoietic stem cells in mice and humans.
AB  - Although it has been reported previously that pluripotent hemopoietic stem cells
      (P-HSCs) express c-kit, the receptor for stem cell factor (steel factor), we and
      other groups have recently shown that P-HSCs do not express c-kit. In this
      review, we provide evidence that c-kit<low P-HSCs in mice have long-term
      reconstituting activity (LTRA > 2 years) and the capacity to form colony-forming
      units in spleen (CFU-S) on Day 16, although c-kit(low) HSCs or c-kit+ HSCs have
      LTRA less than 1.5 years and the capacity to form CFU-S on Day 14 or on Day 10,
      respectively. In addition, we have found that there is a major histocompatibility
      complex (MHC) restriction between P-HSCs and stromal cells; normal P-HSCs can
      proliferate and differentiate efficiently in collaboration with MHC class I
      compatible (but not MHC class I-incompatible) stromal cells. In humans, we also
      show that c-kit<low P-HSCs can differentiate into c-kit(low) cells, then c-kit+
      cells in vitro.

PMID- 10654618
TI  - Regional fat deposition in the legs is useful as a presumptive marker of
      antiatherogenesity in Japanese.
AB  - To examine the pathological role of regional fat deposition in development of
      metabolic and cardiovascular disorders, regional fat distribution was evaluated
      using metabolites and hormones as measures of obesity-related disorders. The
      subjects enrolled were 100 sex-matched inpatients, who were admitted, regardless
      of their body mass index values, for further examination of unusual results from
      periodic medical screening tests, and for examination of obesity-induced
      complications and treatment of obesity. Body fat distribution was analyzed using
      dual energy X-ray absorptiometry (DEXA). Analysis of parameters regarding fat
      distribution showed that gender was one of the determinants affecting correlation
      between fat distribution and metabolites of fasting plasma glucose (FPG),
      hemoglobin A1c (HbA1c), total cholesterol (TC), or triglyceride (TG). However,
      regardless of gender, both leg trunk fat (L/Tr) and arm trunk fat (A/Tr) ratios
      negatively correlated with a total body fat (% total fat) ratio, whereas the
      intercept value of female regression line in L/Tr was greater than that in males,
      but not in A/Tr. Percentage total fat, L/Tr, and A/Tr in males correlated
      significantly with FPG, TC, TG, low-density lipoprotein (LDL), very low density
      lipoprotein (VLDL), atherogenic index (A.I.), and apoB/A1 only low density
      lipoprotein (LDL) was significantly correlated solely to L/Tr and A/Tr. These
      results indicate that regional fat distribution in males may not be a major
      determinant for development of metabolic disorders in obese patients. Unlike male
      regional fat distribution, female L/Tr correlated significantly not only with TC,
      TG, and LDL, but also with FPG and HbA1c, although both of the latter 2 glucose
      related parameters in males showed no correlation with any parameters of fat
      deposition. The remaining female parameters of fasting plasma insulin, VLDL,
      A.I., and ApoB/A1 correlated with each of the three parameters of fat deposition,
      as similarly shown in males. The powerful and negative correlation was thus
      evident, particularly in females, between leg fat deposition and parameters of
      glucose and lipid metabolites. The resulting information provides a novel insight
      that regional fat deposition at the legs is useful as a marker for metabolic and
      cardiovascular disorders associated with obesity.

PMID- 10654619
TI  - Influence of aging and caloric restriction on activation of Ras/MAPK,
      calcineurin, and CaMK-IV activities in rat T cells.
AB  - The signaling cascade mediated by Ras (p21ras) and MAPK (mitogen-activated
      protein kinase) and calcium/calmodulin regulating enzymes, calcineurin (CaN) and
      CaMK-IV, are considered to be essential for T-cell growth and function. In the
      present study, the effect of aging and caloric restriction (CR) on the induction
      of Ras and MAPK activation by concanavalin A (ConA) was studied. Splenic T cells
      were isolated from young (4-6 months) and old (22-24 months) rats that had free
      access to food (control group), and from caloric restricted old (22-24 months)
      rats that beginning at 6 weeks of age were fed 60%(40% caloric restriction) of
      the diet consumed by the control rats. We found that the induction of Ras
      activity in T cells isolated from control old rats was lower (P<0.001) than that
      in control young rats. However, the levels of Ras activity in T cells isolated
      from CR old rats were similar to the levels in the age-matched control rats. The
      induction of MAPK activity in T cells isolated from control old rats and CR old
      rats was significantly less than in T cells isolated from control young rats, and
      caloric restriction significantly (P<0.05) reduced the age-related decline in
      MAPK activation. We also measured the induction of CaN and CaMK-IV activities by
      ConA in T cells from control young and old and CR old rats. The induction of both
      CaN and CaMK-IV activity decreased with age. Caloric restriction significantly
      (P<0.05) reduced the age-related decline in CaN activity, but had no significant
      effect on CaMK-IV activity. The changes in Ras/MAPK activation and in CaN and
      CaMK-IV activity with age or with CR were not associated with alterations in
      their corresponding protein levels. Thus, caloric restriction has a differential
      effect on the activation of the upstream signaling molecules that are altered
      with age.

PMID- 10654620
TI  - Carotenoid supplementation reduces erythema in human skin after simulated solar
      radiation exposure.
AB  - Excessive exposure to solar radiation, especially ultraviolet A (UVA: 320-400 nm)
      and ultraviolet B (UVB: 290-320 nm) radiation, may induce UV-carcinogenesis and
      erythema in the skin. Although the protective effects of carotenoids against skin
      lesions are still unclear, beta-carotene has been proposed as an oral sun
      protectant. The purpose of this study was to determine the magnitude of the
      protective effects of oral alpha- and beta-carotene supplementation for 24 weeks
      on UVA- and UVB-induced erythema in humans. While being exposed to UVA and UVB
      radiation, 22 subjects (11 men and 11 women) were supplemented with natural
      carotenoids for 24 weeks. Each day for the first 8 weeks, subjects were given 30
      mg of natural carotenoids containing 29.4 mg of beta-carotene, 0.36 mg of alpha
      carotene, and traces of other carotenoids in vegetable oil. The natural
      carotenoid dose was progressively raised by 30-mg increments, at every 8 weeks,
      from 30 mg to 90 mg. Small areas (1 cm2) of the skin were exposed to increasing
      doses of UV light (16-42 mJ/cm2) to determine the minimal erythema dose (MED).
      MED was defined as a uniform pink color with well-defined borders. MED readings
      were obtained by visual inspection 24 hr postirradiation. Blood samples taken
      during supplementation were used to determine alpha- and beta-carotene serum
      levels and for a lipid peroxidation analysis. During natural carotenoid
      supplementation, the MED of solar simulator radiation increased significantly
      (P<0.05). After 24 weeks of supplementation, serum beta-carotene levels were
      increased from 0.22 microg/ml (95% CI; 0.16-0.27) to 1.72 microg/ml (95% CI;1.61
      1.83). Similarly, alpha-carotene serum levels increased from 0.07 microg/ml (95%
      CI;0.048-0.092) to 0.36 microg/ml (95% CI; 0.32-0.40). Serum lipid peroxidation
      was significantly (P<0.05) inhibited in a dose-dependent manner during natural
      carotenoid supplementation. The present data suggest that supplementation with
      natural carotenoids may partially protect human skin from UVA- and UVB-induced
      erythema, although the magnitude of the protective effect is modest.

PMID- 10654621
TI  - Zinc deficiency exacerbates loss in blood-brain barrier integrity induced by
      hyperoxia measured by dynamic MRI.
AB  - Using dynamic Magnetic Resonance Imaging (dMRI), blood-brain barrier (BBB)
      permeability (k(PSrho)) and tissue interstitial leakage space (v(e)) were
      evaluated in zinc-deficient (ZnDF) male weanling Wistar rats following 3 days
      exposure to hyperoxia (85% O2). Temporal monitoring of T1-weighted MR image
      changes, following a bolus intravenous injection of gadolinium-DTPA, allowed
      estimation of BBB integrity. Three-day exposure of hyperoxia caused a marginal
      loss of BBB integrity, reflected in a slight increase in kPSrho and v(e),
      observed in both the animals fed adequate zinc (ZnAL) and pair-fed controls
      (ZnPF). However, zinc deficiency resulted in a significant increase in both
      kPSrho and v(e), indicating a severely disturbed BBB. In addition MR-visible free
      water was elevated in ZnDF brains following hyperoxia treatment indicating that a
      loss of BBB integrity may be associated with neuronal edema. The diminished BBB
      integrity may be free-radical mediated as the ratio of oxidized to reduced
      glutathione (GSSG:GSH) was significantly elevated.

PMID- 10654622
TI  - Proarrhythmia of azimilide and other class III antiarrhythmic agents in the
      adrenergically stimulated rabbit.
AB  - The ventricular proarrhythmic actions of five class III antiarrhythmic agents
      were compared in the Carlsson rabbit model. In adrenergically stimulated
      anesthetized rabbits, azimilide, clofilium, dofetilide, sematilide, and d,l
      sotalol caused premature ventricular contractions and nonsustained and sustained
      ventricular tachyarrhythmias (NSVT and SVT) at pharmacologically equivalent
      intravenous doses that increased QTc intervals 20% (ED20). There were no
      significant differences between agents in the percentage of rabbits with serious
      arrhyhthmias at the ED20 doses of 5.2, 0.033, 0.015, 0.66, and 2.8 mg/kg i.v.,
      respectively. Proarrhythmia was dose-dependent. Linear regression analysis of
      arrhythmia score versus log dose estimated the NSVT doses as 6.2, 0.055, 0.0089,
      1.5, and 5.7, respectively. Analysis of arrhythmia states during a 10-min window
      after infusion when QTc prolongation was 20% showed that the compounds differed
      significantly in the proportion of time treated rabbits spent in SVT and combined
      NSVT and SVT. Rabbits treated with azimilide spent significantly less time in SVT
      and combined NSVT and SVT, followed in order of increasing time by d,l-sotalol,
      sematilide, clofilium, and dofetilide.

PMID- 10654623
TI  - A model that reproduces syndromes associated with human multiple myeloma in
      nonirradiated SCID mice.
AB  - A human myeloma line was used to create a model of human multiple myeloma in vivo
      that would reproduce the pathophysiology of the disease, including the cachexia
      associated with cancer. Unirradiated severe combined immunodeficient (SCID) mice
      were used as surrogate hosts for in vivo experiments that allowed the effects of
      autocrine (human) verus paracrine (murine) cytokines on the development of
      myeloma to be studied. Serum levels of human paraprotein increased over time and
      with the number of cells transplanted. Transplanted mice developed major
      syndromes, cachexia and paralysis (due to invasion of bones by myeloma cells),
      associated with multiple myeloma. Analyses of serum samples obtained from
      transplanted mice revealed that when the mice were terminal, total serum protein
      decreased on average by 20%, whereas serum triglycerides decreased on average by
      50%. These data indicate the mice were cachectic, which was confirmed by
      necropsy. The mice had low but measurable levels of both human and murine
      interleukin (IL)-6, soluble IL-6 receptor, and murine IL-10 in their sera. The
      presence of these cytokines and the IL-6 receptor in sera are also
      characteristics of human myeloma in patients. Since human cells do not respond to
      murine IL-6, it was possible to demonstrate clearly the importance of autocrine
      IL-6 in establishing myeloma in situ. By reproducing both the hallmarks of a
      cancer as well as the accompanying paraneoplastic syndromes, this model should be
      useful in designing more effective therapies for both the primary cancer as well
      as the accompanying secondary diseases.

PMID- 10654624
TI  - Ileal lipid infusion stimulates jejunal synthesis of apolipoprotein A-IV without
      affecting mRNA levels.
AB  - We examined the effect of ileal infusions of lipid emulsion on mRNA levels and
      biosynthesis of apolipoprotein A-IV (apo A-IV) in jejunal Thiry-Vella fistulas in
      rats. The rats were surgically prepared with jejunal Thiry-Vella fistulas; after
      recovery they were deprived of food, equipped with ileal infusion cannulas, then
      given 8 hr ileal infusions of fatty acid/monoglyceride emulsions. Mucosal
      synthesis and transcript levels of apo A-IV in the Thiry-Vella loop were then
      measured. Lipid infusion produced a two-fold stimulation in incorporation of 3H
      leucine into apo A-IV-specific protein, but had no significant effect on apo A-IV
      mRNA levels. These results support the hypothesis that a lipid-elicited, distal
      gut-derived, systemic signal stimulates the production of apo A-IV by a post
      transcriptional mechanism.

PMID- 10654625
TI  - Microfilament network is needed for the endocytosis of water channels and not for
      apical membrane insertion upon vasopressin action.
AB  - In the current study, a novel role for the microfilaments in vasopressin-induced
      water transport in toad urinary bladders, a popular model for the mammalian
      collecting duct, was established. Vasopressin-induced water transport was not
      affected by cytochalasin D (CD, 20 microM) or latrunculin B (Lat B, 0.5-2
      microM), microfilament-disrupting reagents, suggesting that the initial
      trafficking of vesicles containing water channels and insertion of membranes into
      the apical membrane are microfilament-independent. After the removal of
      vasopressin, bladders treated with CD or Lat B continued to transport water at
      least 2-3-fold greater than those that received the vehicle. Furthermore, the
      enhanced water transport was inhibited by HgCl2 (1 mM), a potent inhibitor of
      water channel-mediated water flow, suggesting that the enhanced water flow was
      through water channels. In addition, Lat B and CD inhibited vasopressin-induced
      endocytosis of horseradish peroxidase (HRP), a fluid endocytotic marker. These
      results suggested that although microfilaments are not needed for the initial
      trafficking of water channels to the apical side, the microfilament network is
      essential for the retrieval of water channels following their insertion into
      apical membranes.

PMID- 10654626
TI  - Feeding reduces activity of growth hormone-releasing hormone and somatostatin
      neurons.
AB  - Secretion of growth hormone (GH) is synchronized among castrate male cattle
      (steers) around feeding when access to feed is restricted to a 2-hr period each
      day. Typically, concentrations of GH increase before and decrease after feeding.
      Our objectives were to determine whether i) concentrations of GH decrease in
      blood after start of feeding; ii) activity of immunoreactive growth hormone
      releasing hormone (GHRH-ir) neurons decreases in the arcuate nucleus (ARC) after
      feeding; iii) activity of immunoreactive somatostatin (SS-ir) neurons in the
      periventricular nucleus (PeVN) and ARC increase after feeding; and iv) GHRH
      stimulates release of GH to a similar magnitude at 0900 and at 1300 hr, in steers
      fed between 1000 and 1200 hr. Blood samples were collected at 20-min intervals
      from 0700 to 1300 hr. Groups of steers were euthanized at 0700, 0900, 1100, and
      1300 hr (n = 5 per group). Dual-label immunohistochemistry was performed on free
      floating sections of hypothalami using antibodies directed against Fos and Fos
      related antigens (Fos/FRA) as a marker of neuronal activity in immunoreactive
      GHRH and SS neurons. Concentrations of GH were high before and decreased after
      feeding. The percentage of SS-ir neurons containing Fos/FRA-ir in the PeVN was
      50% lower (P<0.01) at 1100 hr and 36% lower (P<0.05) at 1300 hr than at 0900 hr.
      There was no change in percentage of SS-ir neurons containing Fos/FRA-ir in the
      ARC. The percentage of GHRH-ir neurons containing Fos/FRA-ir in the ARC was 66%
      lower (P<0.05) at 1100 hr and 65% lower (P<0.05) at 1300 hr than at 0700 hr. In
      contrast, the number of GHRH-ir neurons increased from 0700 to 1300 hr. GHRH
      induced release of GH was suppressed at 1300 hr compared with 0900 hr. In
      conclusion, reduced basal and GHRH-induced secretion of GH after feeding was
      associated with decreased activity of GHRH neurons in the ARC and decreased
      activity of SS neurons in the PeVN.

PMID- 10654627
TI  - Mediators and mechanisms of radiation nephropathy.
AB  - Normal tissue radiation injury occurs after sufficient irradiation, thus limiting
      the curative potential of x-ray therapy. In the kidney, radiation injury results
      in fibrosis and, ultimately, renal failure. The mediators of fibrosis in
      radiation nephropathy have received scant attention. Therefore, we evaluated the
      sequential presence of alpha smooth muscle actin (alphasma), fibrin, collagen,
      and TGFbeta1 in a porcine model of radiation nephropathy using 9.8 Gy single-dose
      local kidney irradiation. During the 24-week study, there was progressive and
      significant collagen accumulation in glomeruli and in interstitium. In glomeruli,
      this was associated with significant mesangial alphasma expression by 2 weeks
      after irradiation, a further rise at 4 weeks, and then a gradual fall to
      baseline. Glomerular fibrin deposition was significant by 4 weeks after
      irradiation, and remained elevated thereafter. There was little or no glomerular
      TGFbeta1 expression at any time point. Tubular fibrin deposition was significant
      at 4 weeks after irradiation but declined thereafter. There was little or no
      tubulo-interstitial alphasma expression at any time after irradiation. At 6 weeks
      after irradiation, there was a significant peak of tubular epithelial TGFbeta1
      expression that declined thereafter. The early glomerular injury is evident as
      mesangial alphasma expression but is not proceeded by TGFbeta1 expression. There
      is sustained glomerular fibrin deposition with deposition of fibrin in tubular
      lumens, suggesting that tubular fibrin derives and flows out from injured
      glomerular tufts. We conclude that i) alphasma expression is an early marker of
      glomerular radiation injury, presaging scarring; ii) fibrin deposition is
      involved in glomerular and tubular radiation injury; and iii) TGFbeta1 is not an
      early event in radiation nephropathy, and not apparent in glomeruli in this
      model, but may correlate with later tubulo-interstitial fibrosis. Thus, the
      mediators of scarring in this model differ according to time after injury and
      also according to the affected tissue compartment.

PMID- 10654628
TI  - A pilot study of antibiotic cycling in a hematology-oncology unit.
AB  - OBJECTIVE: To determine the safety and treatment efficacy of cycling antibiotic
      regimens for prophylaxis or treatment of patients with profound neutropenia.
      DESIGN: A prospective, nonrandomized, observational trial. SETTING: A 20-bed
      adult hematology-oncology inpatient unit at a university referral hospital.
      PATIENTS: Hospitalized adult patients with chemotherapy- or radiation-induced
      neutropenia (absolute neutrophil count less than 500 cells/mm3). INTERVENTION:
      Between July 1994 and January 1996, 295 hospitalized patients were evaluated on
      an intent-to-treat basis for the cycling protocol. Of these, 271 were eligible
      and assigned to one of four antibiotic regimens being used at the time of
      enrollment: (1) ceftazidime+vancomycin; (2) imipenem; (3) aztreonam+cefazolin;
      (4) ciprofloxacin+clindamycin. Data on infection rates and types, and antibiotic
      resistance patterns, toxicity, and effectiveness were collected. RESULTS: Twenty
      four patients were excluded. Of the 271 evaluable patients, 123 (42%) were able
      to complete treatment on the assigned regimen. Of the 148 patients (50%) unable
      to do so, the reasons for failure included persistent fever (79%), breakthrough
      bacteremia (14%), and drug toxicity (7%). The antibiotic susceptibility profiles
      over the study period showed no increase in resistance. However, there was a
      marked increase in enterococcal infections. CONCLUSIONS: Our data show no
      significant increase in side effects or decrease in efficacy while cycling
      antibiotics among neutropenic patients and thus support further study of its
      role.

PMID- 10654629
TI  - Pharmacodynamic modeling of risk factors for ciprofloxacin resistance in
      Pseudomonas aeruginosa.
AB  - OBJECTIVE: To determine risk factors for ciprofloxacin resistance in Pseudomonas
      aeruginosa. METHODS: Patients with cultures (any site) positive for P aeruginosa,
      susceptible to ciprofloxacin, between January 1993 and December 1996 were
      identified using a computerized database. Factors predictive of emergence of
      ciprofloxacin resistance in P aeruginosa strains isolated from the same cultured
      site, within 21 days of the initial culture, were determined. Factors considered
      included length of stay prior to initial P aeruginosa culture, isolation site,
      initial minimum inhibitory concentration (MIC), antibiotic area under the 24-hour
      concentration curve (AUC24), total area under the 24-hour inhibitory
      concentration curve ([AUIC24] AUC24/MIC summed for all active drugs),
      antibiotic(s) used as dichotomous variables (yes/no), and use of monotherapy or
      combination therapy. RESULTS: Of 635 patients, 43 (7%) subsequently had
      ciprofloxacin-resistant P aeruginosa isolated. Four significantly differing
      patient groups were identified: group 1, P aeruginosa isolates from all sites
      other than the respiratory tract, treated with any drugs; group 2, respiratory
      tract isolates treated with drugs other than ciprofloxacin; group 3, respiratory
      tract isolates treated with ciprofloxacin at AUIC24 >110 (microg x
      h/mL)/microg/mL; and group 4, respiratory tract isolates treated with
      ciprofloxacin at AUIC24 < or =110 (microg x h/mL)/microg/mL. The observed
      percentage resistant was a continuous function of prior length of stay in all
      four groups. Respiratory tract isolates had higher rates of ciprofloxacin
      resistance (12%) than isolates from other infection sites (4%). Respiratory tract
      isolates exposed to ciprofloxacin at AUIC24 < or =110 (microg x h/mL)/microg/mL
      had the highest resistance (17%). At AUIC24 >110 (microg x h/mL)/microg/mL,
      resistance was decreased to 11%, a rate similar to that seen in respiratory
      isolates not exposed to ciprofloxacin (7%). CONCLUSIONS: Application of
      pharmacokinetic and pharmacodynamic principles to dosing of ciprofloxacin may
      reduce the risk of ciprofloxacin resistance to the level seen in isolates exposed
      to other agents.

PMID- 10654630
TI  - Antimicrobial cycling: lessons learned from the aminoglycoside experience.
AB  - Several discrete strategies have been suggested to prevent or reduce microbial
      resistance to antimicrobials, including optimal use of the agents (also known as
      good stewardship); control, removal, or restriction of antimicrobials; use of
      antimicrobials in combination; and rotational or cyclic use of antimicrobials.
      The latter strategy is attractive because it periodically removes from the
      institutional environment certain classes or specific agents that could induce or
      select resistance. Hospitalwide studies of aminoglycoside substitution employed
      from the late 1970s through the early 1990s, although not originally intended to
      test cycling or rotation of aminoglycosides, serendipitously provided data that
      may be useful in designing future studies. In particular, one 10-year study at
      the Minneapolis Veterans' Affairs Medical Center (MVAMC) rotated amikacin and
      gentamicin use over cycles of 12 to 51 months' duration. Significantly reduced
      resistance to gentamicin was found when amikacin was used, but resistance to
      gentamicin returned with the first gentamicin recycle. This was followed by
      reintroduction of amikacin a second time with decreased resistance to gentamicin
      and, finally, a second reintroduction of gentamicin without resistance to it
      recurring. Thus, some evidence of proof of principal can be garnered, albeit
      subject to considerable criticism. Critical examination of the design of the
      aminoglycoside rotation study and the unforeseen pitfalls is provided as a 13
      element guidance list for design of future rotational studies. Rotational usage
      practices are likely to be most appropriate for drugs active against gram
      negative bacilli because of the wide choices available for rotation. Future
      availability of new agents active against resistant gram-positive organisms will
      present the opportunity to cycle these agents as vancomycin substitutes. Careful
      monitoring of clinical outcomes and resistance will be required. Multicenter
      controlled trials that follow carefully designed protocols are most likely to
      produce statistically significant and clinically meaningful results.

PMID- 10654631
TI  - Potential role of pharmacokinetics, pharmacodynamics, and computerized databases
      in controlling bacterial resistance.
AB  - Bacterial resistance to antibiotics continues to be a problem, in spite of
      increased knowledge of resistance mechanisms. Due to the multifactorial nature of
      bacterial resistance, studies that evaluate the association between antimicrobial
      exposure and emergence of resistance may fail to find a relationship unless other
      factors, in particular the association between patient-pathogen pharmacokinetics
      (PK) and pharmacodynamics (PD) and the emergence of bacterial resistance, are
      evaluated as well. It has been hypothesized that, in conjunction with good
      infection control practices, cycling of antimicrobial agents may prove to be
      effective in reducing resistance emergence. There is some indication that there
      may be a relationship between the level of antibiotic exposure and the
      probability of emergence of bacterial resistance. As shown in our companion
      article in this supplement, factors associated with ciprofloxacin resistance in
      Pseudomonas aeruginosa included increased length of stay prior to isolation,
      exposure to ciprofloxacin, and respiratory tract site of bacterial isolation.
      However, in patients who received ciprofloxacin therapy, when exposure was at an
      area under the 24-hour inhibitory concentration curve (AUIC24)>110 (microg x
      h/mL)/microg/mL, resistance was decreased to 11%, a rate similar to that seen in
      respiratory isolates not exposed to ciprofloxacin (7%). While the length of time
      the patient spends in the hospital and the site of infection cannot be
      controlled, by using PK and PD principles for dosing of ciprofloxacin, the
      emergence of ciprofloxacin resistance in P aeruginosa may be reduced. Prospective
      antibiotic-cycling studies may help to determine not only the impact of
      antibiotic cycling on the institution's antibiogram but also, through the use of
      PK and PD principles, may help to determine appropriate dosing schedules for
      antibiotics in order to reduce the probability of emergence of bacterial
      resistance.

PMID- 10654632
TI  - The microbial genetics of antibiotic cycling.
AB  - Cycling of currently available antibiotics to reduce resistance is an attractive
      concept. For cycling strategies to be successful, their implementation must have
      a demonstrable impact on the prevalence of resistance determinants already
      dispersed throughout the hospital and associated healthcare facilities. While
      antibiotic use in hospitals clearly constitutes a stimulus for the emergence of
      resistance, it is by no means the only important factor. The incorporation of
      resistance determinants into potentially stable genetic structures, including
      bacteriophages, plasmids, transposons, and the more newly discovered movable
      elements termed integrons and gene cassettes, forces some degree of skepticism
      about the potential for such strategies in institutions where resistance
      determinants are already prevalent. In particular, the expanding role of
      integrons may pose an ultimate threat to formulary manipulations such as cycling.
      Despite these concerns, the crisis posed by antimicrobial resistance warrants
      investigation of any strategy with the potential for reducing the prevalence of
      resistance. Over the next decade, new studies with carefully designed outcomes
      should determine the utility of antibiotic cycling as one control measure for
      nosocomial resistance.

PMID- 10654633
TI  - Antibiotic cycling and marketing into the 21st century: a perspective from the
      pharmaceutical industry.
AB  - Before the development of the first antimicrobial agents, bacteria already had
      demonstrated an ability to adapt to stress in the environment, resulting in the
      development of resistance that often makes the prevailing antibiotic treatment
      ineffective. The response to antimicrobial resistance in the medical community
      has been to use new or alternative antibiotics not previously used against the
      resistant bacteria. The pharmaceutical industry has responded to the resistance
      problem by producing newer antibiotics, either as modifications of currently
      existing compounds or as combinations of compounds that may inhibit or bypass the
      bacterial resistance mechanisms. The development of new antibiotics is a lengthy
      and costly process. To be successful, the pharmaceutical industry must anticipate
      the changing needs of the medical community, as well as the dynamic process of
      antimicrobial resistance. The marketing of new antimicrobial agents must be
      adaptable to the potential environmental pressures that induce bacterial
      resistance in order to ensure the longevity of the agents.

PMID- 10654634
TI  - Strategies for study of the role of cycling on antimicrobial use and resistance.
AB  - Resistant bacteria usually are seen first in the intensive care unit and other
      acute-care areas. Thus, strategies to control these organisms often are first
      tested in these healthcare settings. Frequent among these strategies are attempts
      to improve antimicrobial use. One proposed method to decrease resistance in
      special settings like the intensive care unit is the cycling or rotation of
      antimicrobials. This intervention must be evaluated in the context of other
      concomitant attempts to improve antimicrobial usage and must take into account
      other factors influencing resistance. Until such studies are done, the value of
      cycling and other efforts to limit prescribers' choices of drugs in endemic
      settings will be unclear. Studies to evaluate cycling will have to be of large
      scale to produce useful data. It is unlikely that many hospitals or healthcare
      systems will have sufficient resources on their own to develop studies of
      sufficient power to be applied widely. Thus, cooperative studies to provide data
      on this important issue should be an international priority.

PMID- 10654635
TI  - Tempus fugit: TB and the 20th century.

PMID- 10654636
TI  - When bad news is good news. Tuberculosis in the Philippines.

PMID- 10654637
TI  - Tuberculosis in the urban poor settlements in the Philippines.
AB  - SETTING: Urban poor settlements in the Philippines. OBJECTIVE: To determine the
      magnitude of the tuberculosis problem in urban poor settlements in comparison
      with urban areas studied in the Nationwide Tuberculosis Prevalence Survey. STUDY
      DESIGN AND METHOD: A multistage cluster survey of BCG scar, tuberculin test,
      chest radiography and sputum examination for bacillary disease, in urban poor
      areas. RESULTS: The prevalences of culture-positive and smear-positive
      tuberculosis were 17.5 +/- 2.3 (95% CI 13.3-22.4) and 7.9 +/- 2.3 per thousand
      (95% CI 2.611.5), respectively. Extrapolated to the total population, the rates
      in the urban poor settlements were 12.4 +/- 1.7 (95% CI 9.6-16.2) and 5.6 +/- 1.6
      per thousand population (95% CI 1.3-8.3), respectively. The prevalence of active
      pulmonary tuberculosis in subjects aged 10 years or more was 66 +/- 5.6/1000 (95%
      CI 55-77). The BCG vaccination rate was 72%. The overall prevalence of
      tuberculosis infection was 66%, and 39% in those aged 5-9 years, corresponding to
      an annual risk of infection (ARI) of 6.5%. CONCLUSION: The problem of
      tuberculosis was substantial in the urban poor settlements, and was appreciably
      worse than that in the general urban population.

PMID- 10654638
TI  - The role of core groups in transmitting Mycobacterium tuberculosis in a high
      prevalence community in Southern Mexico.
AB  - SETTING: A community in Southern Mexico with a high prevalence of tuberculosis.
      OBJECTIVE: To characterize the transmission dynamics in a region with a DOTS
      based tuberculosis control program. DESIGN: Community-based screening of chronic
      coughers between 1 March 1995 and 31 August 1996. Individuals with acid-fast
      bacilli (AFB) in their sputum were enrolled, interviewed, and had mycobacterial
      cultures and fingerprinting performed. In-depth interviews were conducted on all
      persons with DNA fingerprinting. RESULTS: AFB smears were performed on 1424
      individuals, 124 of whom were microbiologically confirmed. Of the 95 cases for
      whom bacterial DNA fingerprints were available, 38 were in clusters. The largest
      cluster involved seven individuals who were members of a social network centered
      on a series of unlicensed bars. CONCLUSION: This population-based molecular
      epidemiologic study showed that a focus of transmission within a social network
      accounted for one fourth of transmission which rapidly progressed to disease.
      These observations raise questions about the potential benefit of targeted
      tuberculosis control interventions in health jurisdictions approaching WHO
      defined DOTS benchmarks.

PMID- 10654639
TI  - Transmission of tuberculosis in an endemic urban setting in Brazil.
AB  - SETTING: Two out-patient facilities in Sao Paulo, Brazil. OBJECTIVE: To study the
      transmission pattern of tuberculosis (TB) among human immunodeficiency virus
      (HIV) infected and uninfected persons in a setting endemic for TB. DESIGN: A
      prospective study comparing HIV-seropositive and -seronegative TB patients
      identified consecutively between 1 March 1995 and 1 April 1997. The patients were
      stratified according to their Mycobacterium tuberculosis isolate IS6110 RFLP
      patterns. Risk factors were sought for infection with an RFLP cluster pattern
      strain, inferred to represent recent transmission. RESULTS: Fifty-eight (38%) of
      151 HIV-seropositive patients and 36 (25%) of 142 HIV-seronegative patients were
      infected with M. tuberculosis isolates that belonged to cluster patterns (OR
      1.84, 95% CI 1.08-3.13). Multidrug-resistant (MDR) strains were isolated from 19
      patients, all of whom were HIV seropositive; 12 (63%) of these, and 46 (35%) of
      132 drug-susceptible isolates had cluster patterns (OR 3.20, 95% CI 1.08-9.77).
      CONCLUSION: In a TB-endemic urban setting in Brazil, the proportion of cases
      resulting from recent transmission appears to be greater among HIV-seropositive
      than among HIV-seronegative patients. A large proportion of MDR-TB (63%) cases
      was caused by strains that had cluster RFLP patterns, suggesting recent
      transmission of already resistant organisms. This type of knowledge regarding TB
      transmission may help to improve locally appropriate TB control programs.

PMID- 10654640
TI  - Sex differences in the epidemiology of tuberculosis in San Francisco.
AB  - SETTING: Worldwide differences in sex-specific tuberculosis case rates remain
      fundamentally unexplained. OBJECTIVE: To explore various factors that may explain
      sex differences in tuberculosis incidence rates for San Francisco from 1991-1996.
      DESIGN: A retrospective epidemiologic analysis of sex-specific tuberculosis
      incidence rates in San Francisco from 1991-1996. Stratified analyses were
      performed on age at diagnosis, racial/ethnic group, human immunodeficiency virus
      (HIV) status, and place of birth. Molecular fingerprinting with IS6110 data was
      used to study sex differences in the incidence of disease for recently
      transmitted and reactivated cases of tuberculosis. RESULTS: In the study period,
      the male to female incidence rate ratio was 2.1 (95% CI 1.9-2.3). Stratified
      analyses revealed differences in sex-specific rates after the age of 14 and the
      highest male:female ratios were seen in the US-born, white, and black
      populations. High ratios were also observed for cases with clustered
      fingerprints, similar to those observed for the US-born population. In sub
      populations with predominantly reactivated cases of tuberculosis, ratios were
      also above unity after adolescence, but the effect was less pronounced.
      CONCLUSION: The ongoing transmission of tuberculosis in the US-born population is
      one of the factors that explains the difference in sex-specific rates of disease
      in San Francisco. Observed differences in tuberculosis rates between the sexes
      may be due to a difference in transmission dynamics rather than diagnosis or
      reporting biases.

PMID- 10654641
TI  - Tuberculosis trends in Central Serbia in the period 1956-1996.
AB  - OBJECTIVE: To estimate tuberculosis incidence and mortality trends in Central
      Serbia (excluding Kosovo and Vojvodina provinces) in the period 1956-1996.
      DESIGN: The incidence and mortality data of tuberculosis in Central Serbia in the
      period 1956-1996 were analysed based on the annual reports of the Institute for
      Lung Diseases and Tuberculosis in Belgrade and the official data of the Republic
      Health Institute. RESULTS: During the period under observation, tuberculosis
      incidence decreased from 324.0 to 34.8/100 000 population, fitting the
      exponential model (y = 389.066e-(0.0689); F = 847.60; P = 0.000). Mortality rates
      decreased from 76.0 in 1956 to 0.9/100000 in 1982. Over the whole period (1956
      1996) the decrease in mortality rates fitted the exponential model (y = 66.83e
      (0.0922); F = 150.95; P = 0.000). The increase in mortality rates in the period
      1982-1996 fitted cubic model (y = 7.647 - 2.674x + 0.359x(2)-0.013x(3); F =
      12.17; P = 0.001). CONCLUSION: Decreasing trends in tuberculosis incidence are
      the result of good control programmes. Changes in mortality trends are related to
      migration from war zones and poor economic conditions which hinder the detection
      and treatment of tuberculosis.

PMID- 10654642
TI  - Screening tuberculosis suspects using two sputum smears.
AB  - SETTING: Ntcheu district hospital, Malawi. OBJECTIVE: To assess a screening
      strategy for tuberculosis (TB) suspects using two sputum smears. DESIGN: A
      strategy of screening all TB suspects with two sputum smears for 6 months (1 July
      31 December 1998) was compared with the period 1 January to 30 June 1998 during
      which the strategy of screening TB suspects with three sputum smears was in use.
      All chest radiographs of patients with negative sputum smears were assessed, and
      in those with pulmonary cavities and extensive disease a third sputum smear was
      examined. Data were collected from the laboratory sputum register and the TB
      register. The two 6-month periods were compared. RESULTS: In the laboratory
      register, using a two-sputum strategy, 186 (16%) of 1152 TB suspects were smear
      positive, a result that was no different than when the three-sputum strategy was
      used, where 173 (16%) of 1106 TB suspects were smear-positive. The clinical
      pattern of TB using the different screening strategies was similar, with 58% of
      registered patients smear-positive with the two-sputum strategy and 54% smear
      positive with the three-sputum strategy. In the first 6 months 3177 sputum smears
      were examined compared to 2266 smears in the second 6 months, a 29% reduction in
      the number of smears examined. The cost of consumables using the strategy of
      three sputum smears was USD $731 compared with USD $521 using the strategy of two
      sputum smears. C O N C L U S I O N S: Screening TB suspects using two sputum
      smears is as effective as screening using three sputum smears, and is associated
      with less laboratory work and savings in costs.

PMID- 10654643
TI  - Mycobacterium tuberculosis and human immunodeficiency virus co-infection in
      intravenous drug users on admission to prison.
AB  - BACKGROUND: Intravenous drug users (IDUs) and prisoners are groups of great
      interest in human immunodeficiency virus (HIV) infection and tuberculosis (TB)
      epidemiology. AIM: To determine predictors and temporal trends of the co
      infection of Mycobacterium tuberculosis and HIV in IDUs on admission to prison.
      PATIENTS AND METHODS: Between 1 January 1991 and 31 December 1997, 796 IDUs or
      former IDUs were studied. Socio-demographic and penitentiary variables were
      evaluated. HIV-positive patients with > or =5 mm induration on tuberculin test
      were deemed co-infected. Analysis of factors associated with co-infection was
      based on a logistic regression model. RESULTS: Of the incoming prisoners, 44.0%
      were infected by M. tuberculosis, 43.8% by HIV and 20.1% were co-infected. Co
      infection predictors were: 1) total prison time served previously (none, OR 1; <2
      years, OR 2.44, 95% CI 1.28-4.64; > or =2 years, OR 4.94, 95% CI 2.56-9.55); 2)
      age (16-25 years, OR 1; 25-29 years, OR 3.14, 95% CI 1.71-5.75; >29 years, OR
      3.67, 95% CI 1.96-6.86); 3) tattoos (OR 1.56, 95% CI 0.98-2.49), 4) syringe
      sharing (OR 2.43, 95% CI 1.57-3.77) and 5) ex-IDU status (OR 1.87, 95% CI 1.23
      2.82). No statistically significant variation in the annual co-infection tendency
      was observed (OR 1.10, 95% CI 0.98-1.22). CONCLUSIONS: The high prevalence of co
      infection that was detected was associated with risk factors that could be
      amended by public health intervention.

PMID- 10654644
TI  - Prevalence and risk factors for positive tuberculin skin tests among active drug
      users at a syringe exchange program.
AB  - OBJECTIVES: To evaluate the prevalence and predictors of tuberculin skin test
      (TST) reactions > or =10 mm among active injection drug users (IDUs) at a syringe
      exchange program in New York City. METHODS: From August 1995 to January 1996,
      participants were offered TB screening, an interview, and received $15.00 upon
      returning for skin test interpretation. RESULTS: 610/650 (94%) consented to
      screening. Of the 566 (93%) who returned for skin test readings, skin test data
      were available for 564 (99.8%); 14% (95% CI 11.6-17.4) had TSTs > or =10 mm. When
      the > or =5 mm threshold for interpretation of TST among HIV-infected persons was
      used, the prevalence of TST positivity increased by only 1%. In univariate
      analysis, the prevalence of TST > or =10 mm increased with age and with
      increasing years of IDU (both P = 0.001). Because of a strong correlation between
      age and duration of IDU, two logistic regression models were examined. In the
      model with age alone, a history of self-reported TST positivity (OR 8.88; 95% CI
      4.9-16.09; P = 0.0001) and increasing age (OR per 10 years increase in age, 1.69;
      95% CI 1.24-2.29; P = 0.0008) were independent predictors of TSTs > or =10 mm. In
      the model with duration of IDU, a history of TST positivity (OR 8.82; 95% CI 4.74
      16.41; P = 0.0001) and duration of IDU (OR per 10 years of IDU, 1.46; 95% CI 1.10
      1.94; P = 0.0081) were independent predictors of TST > or =10 mm. CONCLUSIONS:
      Use of the reduced cutoff point for TST positivity from 10 mm to 5 mm did not
      significantly affect the prevalence of positive TSTs in this cohort of active
      drug users. Increased prevalence of TB infection with age suggests a high annual
      incidence of TB infection in this population, and the increased risk of TB
      infection with increasing duration of IDU suggests that the duration spent in IDU
      environments may increase infection risk.

PMID- 10654645
TI  - Factors predicting non-completion of tuberculosis treatment among HIV-infected
      patients in Barcelona (1987-1996).
AB  - OBJECTIVE: To determine the predictive factors of non-completion of tuberculosis
      (TB) treatment among patients infected with the human immunodeficiency virus
      (HIV). DESIGN: Between 1987 and 1996, 2201 HIV-infected TB patients were detected
      by the Barcelona Tuberculosis Prevention and Control Programme. Patients who
      completed treatment were compared to those who abandoned. Bivariate analysis was
      made by chi(2) test to compare qualitative variables. Associations were measured
      by means of odds ratios (OR) with 95% confidence intervals (CI). Variables
      showing a statistically significant association were analysed at multivariate
      level by means of a logistic regression model. RESULTS: Treatment was carried to
      completion by 1065 patients (48.4%), 289 (13.1%) abandoned, 648 (29.5%) died
      during treatment, and 142 (6.5%) moved out of the city. Final outcome could not
      be established in 57 (2.5%). Intravenous drug users (IDU) represented 76.2% of
      patients. The rate of non-completion between 1987 and 1992 was 26.3% and for 1993
      1996 it was 15.1%, a decrease of 42.6%. Living in neighbourhoods of a low socio
      economic level (OR 1.61; 95% CI 1.222.13), homelessness (OR 3.56; 95% CI 2.01
      6.31), history of TB (OR 1.61; 95% CI 1.12-2.33), and having presented with a
      current TB episode in 1987-1992 (OR 1.42; 95% CI 1.01-2.00), were risk factors
      for abandoning TB treatment. CONCLUSIONS: Social and health factors together
      influence non-completion of TB treatment in HIV-infected patients, while health
      interventions can improve treatment completion.

PMID- 10654646
TI  - Effectiveness of infection control measures in controlling a nosocomial outbreak
      of multidrug-resistant tuberculosis among HIV patients in Italy.
AB  - SETTING: Between October 1992 and February 1994, 33 cases of multidrug-resistant
      tuberculosis (MDR-TB) were diagnosed among patients infected by the human
      immunodeficiency virus (HIV) and hospitalised in an HIV ward in Milan, Italy.
      This outbreak was part of a much larger outbreak, begun in another hospital and
      probably transferred through a patient. OBJECTIVE: To evaluate risk factors for
      transmission and the effectiveness of infection control measures. DESIGN: 1)
      Active follow-up of exposed patients, 2) cohort study among HIV-infected patients
      exposed to MDR-TB cases before and after the implementation of control measures,
      3) screening of close contacts of MDR-TB cases, and 4) molecular typing by
      restriction fragment length polymorphism (RFLP) analysis. RESULTS: The risk of
      MDR-TB was higher in patients with lower CD4+ lymphocyte percentages and longer
      duration of exposure. No difference in the daily risk was observed for in
      patients vs day-hospital patients or by room distance from an infectious case. Of
      the 90 patients exposed before the implementation of infection control measures
      (i.e., October 1992-June 1993) 26 (28.9%) developed MDR-TB, whereas none of the
      44 patients exclusively exposed after implementation developed MDR-TB, despite
      the continuing presence of infectious MDR-TB cases in the ward. CONCLUSION:
      Simple control measures were effective in significantly reducing nosocomial
      transmission among patients.

PMID- 10654647
TI  - Rapid screening of Mycobacterium tuberculosis for susceptibility to rifampicin
      and streptomycin.
AB  - OBJECTIVE: To investigate rapid detection of drug-resistant tuberculosis using
      the genotypic Inno-LiPA Rif TB assay and a novel, low-cost, bacteriophage-based
      susceptibility assay. DESIGN: The performance of the microwell phage replication
      assay (MPRA) on 18 isolates from suspected multidrug-resistant tuberculosis
      patients was compared to the LiPA assay performed directly on sputum specimens.
      Mutations in the rpoB gene identified by LiPA that confer resistance to
      rifampicin (RMP) were confirmed by DNA sequencing, while susceptibilities were
      confirmed by the proportion method and BACTEC. A further 19 isolates undergoing
      routine screening for both RMP and streptomycin susceptibility were included for
      comparison. RESULTS: Susceptibility to RMP was determined for 17/18 (94.4%)
      sputum specimens tested by LiPA. Correlation between MPRA, molecular and
      conventional methods was 100% for the detection of RMP susceptibility. However,
      for susceptibility to streptomycin one discrepant result was found: an isolate
      susceptible to streptomycin by the proportion method was found resistant by MPRA
      to 2 microg/ml of streptomycin. Similarly, an isolate initially resistant by MPRA
      upon re-testing was found susceptible in agreement with the conventional method.
      CONCLUSION: LiPA enables rapid detection of drug-resistant infection, while MPRA
      offers simple, low-tech testing of drug susceptibilities that may be appropriate
      for application in low-income countries.

PMID- 10654648
TI  - Usefulness of pleural complement activation products in differentiating
      tuberculosis and malignant effusions.
AB  - OBJECTIVE: To determine whether measurement of the complement activation products
      SC5b-9 and C3a-desArg in pleural fluid can reliably differentiate tuberculous
      from malignant pleural effusions. DESIGN: Twenty-four patients with tuberculous
      pleuritis, 29 with malignant pleural effusion, and 30 control subjects with
      transudates were enrolled in the study. SCSb-9 and C3a-desArg were measured in
      pleural fluid using commercial ELISA tests, and their performances were evaluated
      using receiver operating characteristic (ROC) analysis. RESULTS: Patients with
      tuberculous pleuritis had higher mean levels of pleural SC5b-9 (5052 microg/L)
      and C3a-desArg (7436 microg/L) than those with malignant effusions (1048 and 2835
      microg/L, respectively), whereas only SC5b-9 concentrations in the latter were
      comparable with controls. The area under the ROC curve (AUC) was 0.84 for SC5b-9
      and 0.81 for C3a-desArg. Pleural SC5b-9 showed an accuracy of 80.8%, compared
      with 78.8% for C3a-desArg, when cut-off points of 1500 and 4500 microg/L,
      respectively, were used. Using a stepwise logistic regression model, the
      combination of pleural SCSb-9 > or =1500 microg/L, age < or =35 years, and
      pleural monocyte percentage > or =90% provided the highest accuracy for
      tuberculous pleurisy (88.5%, AUC 0.95). CONCLUSION: This pilot study suggests
      that pleural SC5b-9 is clinically useful for differentiating tuberculous and
      malignant pleural effusions.

PMID- 10654649
TI  - Comparison of respiratory symptoms questionnaires.
AB  - SETTING: Comparisons in performance of questionnaires are of interest in
      international comparisons of prevalences and risk factors, after translation and
      development of new questionnaires. Factors such as sex, age, educational level
      and smoking habits may influence the performance of questionnaires. OBJECTIVE: 1)
      To discuss questionnaire comparisons in general, using as an example a Norwegian
      respiratory symptoms questionnaire compared with a translation of the British
      Medical Research Council questionnaire on chronic bronchitis; and 2) to examine
      whether reliability differs in subgroups. DESIGN: A population sample of 935
      residents of Hordaland County, Norway, completed two questionnaires in a short
      interval of time. Agreement and Cohen's kappa were calculated. RESULTS:
      Prevalences were significantly different between the two questionnaires for most
      symptoms. Agreement decreased from non-smokers through ex-smokers to smokers,
      whereas the kappa statistic increased. Agreement increased as the educational
      level increased, whereas the kappa statistic declined. No significant age and sex
      effects on agreement and kappa were observed. CONCLUSION: Small changes in the
      phrasing of a question can have considerable effect on prevalence estimates.
      Reliability statistics are prevalence dependent. Reliability may differ according
      to smoking habit and educational level. Questionnaires should be tested in the
      population that they are to be used in.

PMID- 10654650
TI  - Microcolony detection for rapid diagnosis of Mycobacterium tuberculosis
      infection.

PMID- 10654651
TI  - Molecular approach to identifying route of Mycobacterium tuberculosis
      transmission in a village.

PMID- 10654652
TI  - Further consequences of thioacetazone-induced cutaneous reactions.

PMID- 10654653
TI  - Pathologies of brain attentional networks.
AB  - In the last decade, it has been possible to trace the areas of the human brain
      involved in a variety of cognitive and emotional processes by use of imaging
      technology. Brain networks that subserve attention have been described. It is now
      possible to use these networks as model systems for the exploration of symptoms
      arising from various forms of pathology. For example, we can use the orienting
      network to understand the effects of lesions that produce neglect of sensory
      information either by brain damage or by restricting transmitter input. Frontal
      attention networks may provide similar understanding of pathologies at higher
      levels of cognition. Evidence relating these networks to attention deficit and
      hyperactivity disorder (ADHD) is considered.

PMID- 10654654
TI  - The cognitive-energetic model: an empirical approach to attention-deficit
      hyperactivity disorder.
AB  - Attention Deficit/Hyperactivity Disorder (ADHD) is a childhood psychiatric
      disorder which when carefully defined, affects around 1% of the childhood
      population [Swanson JM, Sergeant JA, Taylor E, Sonuga-Barke EJS, Jensen PS,
      Canwell DP. Attention-deficit hyperactivity disorder and hyperkinetic disorder.
      Lancet 1998;351:429-433]. The primary symptoms: distractibility, impulsivity and
      overactivity vary in degree and association in such children, which led DSM IV to
      propose three subgroups. Only one of these subgroups, the combined subtype:
      deficits in all three areas, meets the ICD-10 criteria. Since the other two
      subtypes are used extensively in North America (but not in Europe), widely
      different results between centres are to be expected and have been reported.
      Central to the ADHD syndrome is the idea of an attention deficit. In order to
      investigate attention, it is necessary to define what one means by this term and
      to operationalize it in such a manner that others can test and replicate
      findings. We have advocated the use of a cognitive-energetic model [Sanders, AF.
      Towards a model of stress and performance. Acta Psychologica 1983;53: 61-97]. The
      cognitive-energetic model of ADHD approaches the ADHD deficiency at three
      distinct levels. First, a lower set of cognitive processes: encoding, central
      processing and response organisation is postulated. Study of these processes has
      indicated that there are no deficits of processing at encoding or central
      processing but are present in motor organisation [Sergeant JA, van der Meere JJ.
      Convergence of approaches in localizing the hyperactivity deficit. In Lahey BB,
      Kazdin AE, editors. Advancements in clinical child psychology, vol. 13. New York:
      Plenum press, 1990. p. 207-45; Sergeant, JA, van der Meere JJ. Additive factor
      methodology applied to psychopathology with special reference to hyperactivity.
      Acta Psychologica 1990;74:277-295]. A second level of the cognitive-energetic
      model consists of the energetic pools: arousal, activation and effort. At this
      level, the primary deficits of ADHD are associated with the activation pool and
      (to some extent) effort. The third level of the model contains a management or
      executive function system. Barkley [Barkley RA, Behavioral inhibition, sustained
      attention, and executive functions: constructing a unifying theory of ADHD.
      Psychological Bulletin 1997;121:65-94] reviewed the literature and concluded that
      executive function deficiencies were primarily due to a failure of inhibition.
      Oosterlaan, Logan and Sergeant [Oosterlaan J, Logan GD, Sergeant JA. Response
      inhibition in ADHD, CD, comorbid ADHD + CD, anxious and normal children: a meta
      analysis of studies with the stop task. Journal of Child Psychology and
      Psychiatry 1998;39:411-426] demonstrated that this explanation was not specific
      to ADHD but also applied to children with the associated disorders of
      oppositional defiant and conduct disorder. Other executive functions seem to be
      intact, while others, are deficient. It is argued here that the cognitive
      energetic model is a useful guide for determining not only ADHD deficiencies and
      associated disorders but also linking human cognitive neuroscience studies with
      neurobiological models of ADHD using animals [Sadile AG. Multiple evidence of a
      segmental defect in the anterior forebrain of an animal model of hyperactivity
      and attention deficits. Neuroscience and Biobehavioral Reviews, in press;
      Sagvolden T, Sergeant JA. Attention-deficit hyperactivity disorder: from brain
      dysyfunctions to behaviour. Behavioural Brain Research 1998;94:1-10]. A plea for
      an integrated attack on this research problem is made and the suggestion that
      conceptual refinement between levels of analysis is essential for further
      fundamental work to succeed is offered here.

PMID- 10654655
TI  - Functional frontalisation with age: mapping neurodevelopmental trajectories with
      fMRI.
AB  - The aim of this study was to investigate whether previously observed
      hypofrontality in adolescents with attention deficit-hyperactivity disorder
      (ADHD) during executive functioning [Rubia K, Overmeyer S, Taylor E, Brammer M,
      Williams S, Simmons A, Andrew C, Bullmore ET. Hypofrontality in attention deficit
      hyperactivity disorder during higher order motor control: a study using fMRI. Am
      J Psychiatry 1999;156(6):891-896] could be attributed to delayed maturation of
      frontal cortex. Brain activation of 17 healthy subjects, 9 adolescents and 8
      young adults, during performance of a motor response inhibition task and a motor
      timing task was measured using functional magnetic resonance imaging (fMRI). The
      effect of age on brain activation was estimated, using the analysis of variance
      and regression, at both voxel and regional levels. In the delay task, superior
      performance in adults was paralleled by a significantly increased power of
      response in a network comprising prefrontal and parietal cortical regions and
      putamen. In the stop task, alternative neuronal routes--left hemispheric
      prefrontal regions in adults and right hemispheric opercular frontal cortex and
      caudate in adolescents--seem to have been recruited by the two groups for
      achieving comparable performances. A significant age effect was found for the
      prefrontal activation in both task, confirming the hypothesis of a
      dysmaturational pathogenesis for the hypofrontality in ADHD.

PMID- 10654656
TI  - Dopamine genes and ADHD.
AB  - Family, twin, and adoption studies have documented a strong genetic basis for
      ADHD/HKD, but these studies do not identify specific genes linked to the
      disorder. Molecular genetic studies can identify allelic variations of specific
      genes that are functionally associated with ADHD/HKD, and dopamine genes have
      been the initial candidates based on the site of action of the stimulants drugs,
      which for a half century have provided the primary pharmacological treatment for
      ADHD/HKD. Two candidate dopamine genes have been investigated and reported to be
      associated with ADHD/HKD: the dopamine transporter (DAT1) gene [Cook et al.,
      American Journal of Human Genetics 1995;56:993-998, Gill et al., Molecular
      Psychiatry 1997;2:311-313] and the dopamine receptor D4 (DRD4) gene [LaHoste et
      al., Molecular Psychiatry 1996;1:121-124: Smalley et al., 1998;3:427-430; Swanson
      et al., Molecular Psychiatry 1998;3:38-41]. Speculative hypotheses [Swanson and
      Castellanos, NIH Consensus Development Conference: Diagnosis and Treatment of
      Attention Deficit Hyperactivity Disorder, November 1998. p. 37-42] have suggested
      that specific alleles of these dopamine genes may alter dopamine transmission in
      the neural networks implicated in ADHD/HKD (e.g. that the 10-repeat allele of the
      DAT1 gene may be associated with hyperactive re-uptake of dopamine or that the 7
      repeat allele of the DRD4 gene may be associated with a subsensitive postsynaptic
      receptor). These and other variants of the dopamine hypothesis of ADHD will be
      discussed.

PMID- 10654657
TI  - Clinical psychopharmacology of AD/HD: implications for animal models.
AB  - A working knowledge of the clinical psychopharmacology of the psychostimulants in
      AD/HD is essential to the development of valid animal models of the disorder. The
      clinical pharmacokinetics and pharmacodynamics of D-amphetamine (D-AMP) and
      methylphenidate (MPH) have been well-studied. The plasma half-life of these
      compounds in children is approximately 5 h, with an onset of therapeutic action
      within a half-hour, and peak action at 1-3 h. The effective dose range for D-AMP
      in children is 0.2-0.5 mg/kg, and for MPH 0.3-1.0 mg/kg. In humans,
      psychostimulants bring about reductions in activity level and impulsivity, and
      improvement in attention span. Enhancement of executive processes mediated in the
      pre-frontal cortex in humans (especially tolerance for delay) is believed to
      mediate these therapeutic effects. There are no long-term remedial effects of the
      drug on behavior-i.e. symptoms return when the drugs are withdrawn. When used in
      the therapeutic dose range, there is no evidence of the development of
      significant tolerance or sensitization. These and other clinical findings to be
      discussed must guide and constrain the development of animal models of stimulant
      drug effects in AD/HD.

PMID- 10654658
TI  - Behavioral validation of the spontaneously hypertensive rat (SHR) as an animal
      model of attention-deficit/hyperactivity disorder (AD/HD).
AB  - A good model of a disorder is one that: (a) mimics, although in a simpler form
      than the full-blown clinical case, the fundamentals of the behavioral
      characteristics, in this case of people with Attention-Deficit/Hyperactivity
      Disorder (AD/HD;face validity); (b) conforms with a theoretical rationale for the
      disorder (construct validity); and (c) is able to predict aspects of behavior,
      genetics and neurobiology previously uncharted in the clinics (predictive
      validity). This article discusses the Spontaneously Hypertensive Rat (SHR) and
      some other putative animal models of AD/HD. It is argued that although other
      strains and species may be hyperactive and/or show attention deficits following
      genetic, environmental or pharmacological interventions, the SHR is presently the
      only strain shown to have the major behavioral symptoms of AD/HD. This does not
      mean that investigating other models cannot give valuable information.

PMID- 10654659
TI  - WKHA rats with genetic hyperactivity and hyperreactivity to stress: a review.
AB  - WKHA rats are a homozygous strain of hyperactive rats developed by successive
      selected inbreedings, starting from a cross of spontaneously hypertensive (SHR)
      rats with their normotensive control strain, WKY. WKHA express hyperactivity in a
      novel environment, as do SHRs, however their blood pressure is normotensive, thus
      they are potentially a more promising model of hyperactivity than the SHR. WKHA
      became homozygous in 1990 (20 strict brother/sister inbreedings), and they are
      currently in the F36 generation. Studies in collaboration with numerous
      colleagues have allowed us to describe a limited behavioral and neurochemical
      profile of WKHA rats. Their most prominent behaviors include hyperactivity in a
      novel environment, and a marked hyperreactivity to stress, both of which are also
      characteristic of SHRs. They differ from SHRs in other respects: WKHA are less
      aggressive, habituate more readily to a novel environment, and are less
      exploratory in a familiar environment than the SHR. Neurochemical studies have
      revealed changes in brain monoamine function in WKHA rats, particularly in
      frontal cortical norepinephrine and dopamine uptake, and they show marked changes
      in neuroendocrine responses in the hypothalamic/pituitary/adrenal axis, as well
      as altered POMC peptides in the pituitary anterior and posterior lobes. Molecular
      genetic studies by colleagues in Bordeaux have identified a quantitative trait
      locus for the hyperactivity/hyperreactivity trait of WKHA rats.

PMID- 10654660
TI  - The acallosal mouse strain I/LnJ: a putative model of ADHD?
AB  - ADHD has been sometimes associated to a defective interhemispheric cross-talk
      caused by hypoplasia of the corpus callosum. The inbred mouse strain I/LnJ shows
      total callosal agenesis with complete penetrance, and behavioral features which
      resemble ADHD. In conditioned learning tasks, as well as in paradigms of
      spontaneous behavior. I/LnJ mice, as compared to other inbred strains, show lower
      learning scores, impulsiveness, and significantly higher locomotor activity,
      albeit with considerable individual variations. In order to disentangle the
      influences of the genetic background from the effects of the callosal agenesis,
      we undertook crossing studies between I/LnJ and C57BL/6 mice, obtaining hybrids
      with missing corpus callosum. In comparison to normal C57BL/6 mice, acallosal
      hybrids exposed to a novel open-field showed a different locomotor pattern, with
      less short stops and more center crossing during the beginning of the session. In
      a metabolic mapping study, the tendency of acallosals to stay off the walls was
      found to be associated to lower 2-deoxyglucose uptake in the left striatum and
      cerebral cortex, while the number of short stops was correlated to the bilateral
      levels of 2-deoxyglucose uptake in the frontal and parietal cortex. The results
      hint at a right hemisphere dominance in impulsiveness and hyperactivity, boosted
      by the lack of callosal connections.

PMID- 10654661
TI  - Coloboma mouse mutant as an animal model of hyperkinesis and attention deficit
      hyperactivity disorder.
AB  - Hyperkinesis and developmental behavioral deficiencies are cardinal signs of
      attention-deficit hyperactivity disorder. In mice, the mutation coloboma (Cm)
      corresponds to a contiguous gene defect that results in phenotypic abnormalities
      including spontaneous hyperactivity, head-bobbing, and ocular dysmorphology. In
      addition, coloboma mutant mice exhibit delays in achieving complex neonatal motor
      abilities and deficits in hippocampal physiology, which may contribute to
      learning deficiencies. The hyperkinesis is ameliorated by low doses of the
      psychostimulant D-amphetamine and can be rescued genetically by a transgene
      encoding SNAP-25, located within the Cm deletion. Together with syntaxin and
      synaptobrevin/VAMP, SNAP-25 constitutes a core protein complex integral to
      synaptic vesicle fusion and neurotransmitter release. Despite the ubiquitous role
      of SNAP-25 in synaptic transmission, and uniformly decreased expression in the
      mutants, coloboma mice show marked deficits in Ca2+-dependent dopamine release
      selectively in dorsal but not ventral striatum. This suggests that
      haploinsufficiency of SNAP-25 reveals a specific vulnerability of the
      nigrostriatal pathway which regulates motor activity and may provide a model for
      impaired striatal input into executive functions encoded by the prefrontal cortex
      associated with ADHD.

PMID- 10654662
TI  - Non-selective attention in a rat model of hyperactivity and attention deficit:
      subchronic methylphenydate and nitric oxide synthesis inhibitor treatment.
AB  - The involvement of dopamine (DA) and nitric oxide (NO) in the process of non
      selective attention (NSA) to environmental stimuli has been investigated in the
      juvenile Spontaneously Hypertensive rat (SHR). To this aim the frequency and
      duration of rearing episodes in a novelty situation, which is thought to monitor
      NSA, have been measured in male SHR and Wistar-Kyoto (WKY) control rats following
      subchronic treatment with methylphenidate (MP; 3 mg/kg) or the nitric oxide
      synthase (NOS) inhibitor L-Nitro-arginine-methylester (L-NAME; 1 mg/kg) or
      vehicle daily for two weeks. Different groups were tested at 0.5 h or 24 h after
      the last injection in a Lat-maze. Tests were repeated twice at a 24 h interval
      and lasted 10 min each. Upon first exposure, there was a differential drug effect
      only in the SHR. In fact, MP and L-NAME yielded a shift to the left and to the
      right, i.e. towards episodes of lower or higher duration, respectively. This
      shift was more pronounced in the group tested 0.5 h after the last injection. In
      contrast, both drugs produced a significant lengthening of the rearing episodes
      in the SHR only in comparison with the vehicle-treated rats over days of testing.
      Therefore both MP and L-NAME appear to shear a similar effect on non-selective
      attention, although the effect of L-NAME is somewhat paradoxical. The latter is
      likely to be due to increased arginine selective uptake due to negative feedback
      with the NO production. The consequent increased arginine availability displaces
      the NOS inhibitor, thus leading to increased NO production. In conclusion,
      dopamine and nitric oxide play a role in non-selective attention by synaptic and
      extrasynaptic mechanisms, respectively, in a rat model of hyperactivity and
      attention-deficits.

PMID- 10654663
TI  - Paradoxical effects of D-amphetamine in infant and adolescent mice: role of
      gender and environmental risk factors.
AB  - The psychostimulant D-amphetamine (AMPH) increases generalised activity in adult
      subjects, while exerting a paradoxical "calming effect" in children with
      Attention-deficit Hyperactivity Disorder (AD/HD). A number of animal models have
      been developed to characterise the neurobiological basis of this AMPH action. In
      this line, the present review summarises recent work on the effects of AMPH on
      behavioural and physiological parameters in developing mice with a special
      emphasis on the role of gender and environmental risk factors. Behavioural and
      neuroendocrine responses to AMPH administration (0, 1, or 3 mg/kg, IP) and their
      relation to changes in the environment, represented by social stimuli, were
      studied in infant CD-1 mouse pups of both sexes at three different developmental
      ages (3, 8, or 18 postnatal (pnd) days). Mouse pups were assessed either in
      baseline condition or following 24 h maternal deprivation. AMPH exerted a
      paradoxical effect on CORT secretion only in maternally deprived subjects while
      affecting behaviour mainly in deprived female subjects, which showed a
      generalised shift to the left in the dose-response curve to this drug. Unwanted
      perseverative motor effects and possible dependence states represent side effects
      of AMPH administration. Further knowledge on these aspects comes from another set
      of studies where a shortened conditioned place preference (CPP) paradigm was
      employed to assess the reinforcing properties of AMPH (0, 1, 3.3, or 10 mg/kg) in
      developing mice on 14-17, 21-24, and 28-31 pnd. Data indicate that AMPH-CPP
      develops early, mice being able, already at two weeks of age, to acquire a place
      preference that relies on adult-like sensory, motor, and associative capacities.
      AMPH-CPP appears earlier in females, compared to males. A detailed analysis of
      acute D-amphetamine effects evidenced that the drug produces a dose-dependent
      increase in locomotor activity and in several responses (including stereotypes).
      These effects appear much larger at both post weaning stages than in preweanlings
      and are significantly more pronounced in females than in males. Overall these
      data suggest that AMPH action is dependent on the baseline level of activity and
      indicate a strong role of gender in the effects of this drug measured early on
      during development, with females showing greater sensitivity to this drug. A
      better understanding of AMPH action during the early ontogenetic phases,
      particularly its interaction with environmental factors, might extend our
      knowledge on the neurobiological basis of AD/HD, possibly improving the clinical
      efficacy of psychostimulant drugs.

PMID- 10654664
TI  - An integrative neuroanatomical perspective on some subcortical substrates of
      adaptive responding with emphasis on the nucleus accumbens.
AB  - Neuroanatomical substrates associated in the literature with adaptive responding
      are discussed, with a focus on the nucleus accumbens. While it is emphasized that
      the accumbens exhibits multiple levels of complex organization, a fairly complete
      list of brief descriptions of recent studies devoted specifically to the
      accumbens shell and core subterritories is presented in tabular format. The
      distinct patterns of connectivity of the accumbens core and shell and structures
      related to them by connections are described. Multiple inputs, outputs and
      abundant reciprocity of connections within the ventral parts of the basal ganglia
      are emphasized and the implications for "through-put" of impulses is considered.
      It is noted, at least on neuroanatomical grounds, that there is ample reason to
      expect feed forward processing from shell and structures with which it is
      associated to core and structures with which it is associated. Furthermore, the
      potential for additional feed forward processing involving several forebrain
      functional anatomical systems, inlcuding the ventral striatopallidum, extended
      amygdala and magnocellular basal forebrain complex is considered. It is intended
      that from the considerations recorded here a conceptual framework will begin to
      emerge that is amenable to further experimental substantiation as regards how
      multiple basal forebrain systems and the cortices to which they are related by
      connections work together to fashion a unitary object--the adaptive response.

PMID- 10654665
TI  - Central histaminergic system and cognition.
AB  - The neurotransmitter histamine is contained within neurons clustered in the
      tuberomammillary nuclei of the hypothalamus. These cells give rise to widespread
      projections extending through the basal forebrain to the cerebral cortex, as well
      as to the thalamus and pontomesencephalic tegmentum. These morphological features
      suggest that the histaminergic system acts as a regulatory center for whole-brain
      activity. Indeed, this amine is involved in the regulation of numerous
      physiological functions and behaviors, including learning and memory, as
      indicated by extensive research reviewed in this paper. Histamine effects on
      cognition might be explained by the modulation of the cholinergic system.
      However, interactions of histamine with any transmitter system, and/or a putative
      intrinsic procognitive role cannot be excluded. Furthermore, although
      experimental evidence indicates that attention-deficit hyperactivity disorder
      symptoms arise from impaired dopaminergic and noradrenergic transmission, recent
      research suggests that histamine is also involved. The possible relevance of
      histamine in disorders such as age-related memory deficits, Alzheimer's disease
      and attention-deficit hyperactivity disorder is worth of consideration, and
      awaits validation with clinical trials that will prove the beneficial effects of
      histaminergic drugs in the treatment of these diseases.

PMID- 10654666
TI  - Heterogeneity of the mesotelencephalic dopamine fibers: physiology and
      pharmacology.
AB  - The mesotelencephalic dopamine (DA) system is heterogeneous with respect to
      nuclei, terminal loci, DA receptor subtypes, electrophysiological characteristics
      and response patterns, and neuropharmacological response to a range of agents.
      The majority of mesocortical and mesolimbic DA neurons originate in the ventral
      tegmental area. Mesostriatal DA neurons originate in substantia nigra pars
      compacta. DA neurons originating from the retrorubal field primarily innervate
      subcortical limbic and neostriatal loci. Mesostriatal terminal loci have
      relatively low densities of D3 and D4 receptors, compared to mesolimbic and
      mesocortical loci. The D1 and D2 receptors appear more homogeneously distributed.
      Electrophysiologically, mesostriatal DA neurons show more regularity in firing
      pattern (fewer bursting events), and a lower basal firing rate than mesolimbic or
      mesocortical neurons. Neuropharmacologically, mesocortical DA neurons are less
      responsive to intravenous d-amphetamine, (+)apomorphine, and chronic
      antipsychotic drug treatment. Mesocortical DA neurons are also relatively
      insensitive to iontophoretically applied DA, a finding congruent with their
      reported relative lack of somatodendritic autoreceptors. Neurochemically,
      mesoaccumbens DA neurons are more sensitive to systemic administration of drugs
      with addictive liability.

PMID- 10654667
TI  - Epigenetic cues in midbrain dopaminergic neuron development.
AB  - Midbrain dopaminergic (DA) neurons subserve complex and varied neural functions
      in vertebrate CNS. Their progenitors give rise to DA neurons by the action of two
      extracellular inducers, Sonic Hedgehog and FGF8. After this first commitment, the
      function of selectively activated transcription factors, like the orphan steroid
      nuclear receptor Nurr1, is required for DA final determination. Subsequently, DA
      function is selectively modulated by specific interaction with the developing
      striatal target tissue. Committed and determined DA neurons express the key genes
      involved in DA neurotransmission at different times in development. Synthesis and
      intracellular accumulation of DA is achieved shortly after expression of Nurr1,
      while high affinity uptake, responsible for ending the neurotransmission, takes
      place after a few days. Cell contacts between the presynaptic DA neurons and
      target striatal neurons are apparently necessary for the fine modulation of DA
      function, in vivo and in vitro.

PMID- 10654668
TI  - Structure and function of dopamine receptors.
AB  - Dopamine (DA) is the most abundant catecholamine in the brain. The involvement
      and importance of DA as a neurotransmitter in the regulation of different
      physiological functions in the central nervous system (CNS) is well known.
      Deregulation of the dopaminergic system has been linked with Parkinson's disease,
      Tourette's syndrome, schizophrenia, attention deficit hyperactive disorder (ADHD)
      and generation of pituitary tumours. This review focuses on the pharmacological
      and biochemical features shared by the dopamine receptors. We address their
      coupling to secondary messenger pathways and their physiological function based
      upon studies using pharmacological tools, specific brain lesions and, more
      recently, genetically modified animal models.

PMID- 10654669
TI  - The nucleus accumbens motor-limbic interface of the spontaneously hypertensive
      rat as studied in vitro by the superfusion slice technique.
AB  - The behavioral disturbances of attention-deficit hyperactivity disorder (ADHD)
      have been attributed to dysfunction of the mesolimbic dopaminergic (DA)
      projection from the ventral tegmental area of the midbrain. DA released from
      terminals in the nucleus accumbens (interface between limbic and motor areas of
      the brain) draws attention to unexpected, behaviorally significant events and
      provides the motivational drive for reward-related behavior. An in vitro
      superfusion technique was used to show that depolarization (25 mM K+)-induced
      release of DA from nucleus accumbens slices of spontaneously hypertensive rats
      (SHR, animal model for ADHD) was significantly lower than that of Wistar-Kyoto
      controls (WKY). Evidence also suggested that DA autoreceptor efficacy was
      increased at low endogenous agonist concentrations. D2 receptor blockade by the
      antagonist, sulpiride, caused a significantly greater increase in the
      electrically stimulated release of DA from nucleus accumbens slices of SHR
      compared to WKY. This suggested that presynaptic regulation of DA release had
      been altered in SHR to cause down-regulation of the DA system. This could have
      occurred at an early stage of development in an attempt to compensate for
      abnormally high DA concentrations. The reduction in DA transmission could have
      left the adult SHR with impaired DA reward/reinforcement mechanisms, resulting in
      the behavioral disturbances characteristic of ADHD.

PMID- 10654670
TI  - Sex differences in dopamine receptors and their relevance to ADHD.
AB  - Gender differences in ADHD may be attributable to gender differences in dopamine
      receptor density. Striatal male D2 receptor density increases 144+/-26% between
      25 and 40 days (the onset of puberty), while female D2 receptor density increases
      only 31+/-7%. Male receptor density is then sharply eliminated by 55% by
      adulthood. Periadolescent females show little overproduction and pruning of
      striatal D1 and D2 receptors, though adult density is similar to males. The rise
      of male, but not female, striatal dopamine receptors parallels the early
      developmental appearance of motor symptoms of ADHD and may explain why prevalence
      rates are 2-4 fold higher in men than women. Pruning of striatal dopamine
      receptors coincides with the estimated 50-70% remission rate by adulthood.
      Transient lateralized D2, dopamine receptors (left > right) in male striatum may
      increase vulnerability to ADHD. More persistent attentional problems may be
      associated with the overproduction and delayed pruning of dopamine receptors in
      prefrontal cortex. Differences in D1 receptor density in nucleus accumbens may
      have implications for increased substance abuse in males.

PMID- 10654671
TI  - Neuroprotective effects of estradiol in mesencephalic dopaminergic neurons.
AB  - There is a gender difference, or male predominance, in Parkinson's disease and
      attention deficit hyperactivity disorder (ADHD). Although the reason why it is
      predominantly the male who suffers from the diseases is still unknown, the female
      steroid hormone may be involved in the pathogenesis. Estrogen is a female sex
      hormone with a steroid structure. Like other steroid hormones, it binds to
      specific receptors in the nuclei and regulates gene transcription (genomic
      effects). In addition to the genomic effects, it can act as an antioxidant, a
      process not mediated by the estrogen receptor (nongenomic effects). Further,
      estrogen can have a novel action through a specific receptor located in the
      plasma membrane. In the central nervous system, estrogen provides neuroprotection
      mediated through multiple mechanisms. In this article, we review several possible
      mechanisms for the neuroprotective effects including antiapoptotic protection by
      estrogens as transcription factors, protection against oxidative stress by
      estrogens acting as antioxidants, and neurotrophic cross talk through the signal
      cascade shared with neurotrophic factors.

PMID- 10654673
TI  - Network operations revealed by brain metabolic mapping in a genetic model of
      hyperactivity and attention deficit: the naples high- and low-excitability rats.
AB  - Genetic rat models are important for research on the neural networks of attention
      and emotionality. Naples-High Excitability (NHE) rats and Naples Low-Excitability
      (NLE) rats were investigated with random-bred (NRB) rats as controls. These rat
      lines were named for their respective behavior on spatial novelty tasks.
      Quantitative cytochrome oxidase (CO) histochemistry has been demonstrated to
      reflect long-lasting changes in tissue metabolic capacity. CO metabolic
      differences between the NLE and NHE were found in the granular cell layer of the
      outer blade of the dentate gyrus. In addition, NLE showed greater CO activity
      than NRB in medial frontal cortex, and lower activity in perirhinal cortex
      (dorsal region). NHE showed greater CO activity than NRB in entorhinal cortex
      (superficial layers) and lower activities in perirhinal cortex and cortical
      amygdala. These data support the hypothesis that NLE/NHE rats may be an
      appropriate model for studying genetically altered limbic regions related to
      impaired emotional processing. The results support the involvement of limbic
      circuits in attentive processes and impulsiveness, and support the use of the NLE
      and NHE strains as animal models of Attention Deficit Hyperactivity Disorder
      (ADHD) in children.

PMID- 10654672
TI  - Remodeling of neural networks in the anterior forebrain of an animal model of
      hyperactivity and attention deficits as monitored by molecular imaging probes.
AB  - Remodeling of neural networks in the anterior forebrain of an animal model of
      hyperactivity and attention deficits as monitored by molecular imaging probes.
      These studies report on the remodeling of neural networks which are likely to be
      the consequences of the segmental defect in the anterior forebrain of an animal
      model of hyperactivity and attention-deficit, the juvenile prehypertensive male
      spontaneously hypertensive rat (SHR). Molecular biology and microscope imaging
      techniques were used such as: (i) dopamine (DA) D-1 and D-2 receptors by
      radioligand binding studies; (ii) the Ca2+/Calmodulin-dependent protein kinase II
      (CaMKII); (iii) transcription factors (TF) such as c-FOS by Immunocytochemistry;
      and (iv) the respiratory chain enzyme cytochrome-oxidase (C.O.), as markers of
      neuronal activity in the anterior forebrain of SHR and Wistar Kyoto normotensive
      (WKY) controls rats. Microcomputer-assisted high-resolution image analysis using
      DA receptor binding and C.O., as probes revealed by cross-correlations among
      different regions within brain an altered cross-talk in the anterior forebrain of
      the SHR as compared to the controls. In particular, an altered cross-talk was
      also observed within the amygdala complex in the SHR by CaMKII and c-FOS
      expression. Therefore, the hypothesized segmental defect in the anterior
      forebrain of the SHR produces network consequences leading to behavioral
      alteration in the attentional activity and emotional domains. Subchronic
      treatment with metilphenidate (MP) that is known to block the reuptake of
      biogenic amines (mainly DA) produced network remodeling which are known to be
      paralleled by behavioral modifications in the attentive activity and emotional
      domains. Imperspective, the results from this model system that features the main
      aspects of attention-deficit hyperactivity disorder (ADHD), can be useful for the
      understanding of the neural substrates of hyperactivity and attention deficits
      and possibly for an early diagnosis and appropriate treatment of ADHD children.

PMID- 10654674
TI  - Multiple evidence of a segmental defect in the anterior forebrain of an animal
      model of hyperactivity and attention deficit.
AB  - Molecular biology and microscope imaging techniques were used to map putative
      neural substrates of hyperactivity and attention deficit in an animal model, the
      juvenile prehypertensive male spontaneously hypertensive rat (SHR). We have
      studied in anterior forebrain sections of SHR and Wistar-Kyoto Normotensive (WKY)
      controls the spatial distribution of neural markers such as: (i) dopamine (DA) D
      1 and D-2 receptor families by radioligand binding studies; (ii) the
      Ca2+/calmodulin-dependent protein kinase II (CaMKII); and (iii) the transcription
      regulators of gene expression (TFs) c-FOS and JUN-B by Immunocytochemistry (ICC).
      Microcomputer-assisted high-resolution image analysis showed in the SHR a higher
      density of DA D-1 receptors and a lower density of D-3 autoreceptors paralleled
      by a reduced number of elements positive for CaMKII and TFs in a restricted
      segment of the anterior forebrain that included the most rostral portions of the
      caudate-putamen, pole and shell of the nucleus accumbens and olfactory tubercle.
      The differential rostro-caudal distribution of D-1 receptors and D-3
      autoreceptors is discussed in the light of current hypotheses of DA
      mesocorticolimbic system functioning. In addition, the segmental defect was
      partially reversed by subchronic treatment with a DA re-uptake blocker,
      Methylphenidate (MPH; 3 mg/kg) and by environmental stimulation during the fifth
      and sixth postnatal week. The findings are consistent with the role of genetic
      determinants and environmental factors in the phenotypic expression of
      hyperactivity and attention deficit.

PMID- 10654675
TI  - Technical advances in ear reconstruction with autogenous rib cartilage grafts:
      personal experience with 1200 cases.
AB  - Through the author's experience with 1200 cases during a 25-year period, this
      article presents technical improvements in ear reconstruction and proposes and
      discusses possible directions for further technical advancement. This article
      presents the rationale for the author's current methods of managing total ear
      repair. Throughout the article, the author stresses and demonstrates cartilage
      sparing techniques that are designed to minimize the amount of cartilage used in
      a repair to preserve maximum chest wall integrity. This article also presents the
      latest method of framework fabrication, showing differences in construction
      between younger and older patients; a new method that constructs a tragus as an
      integral part of the framework; a method that maintains ear projection with a
      scalp-banked cartilage wedge; and a method that solves the always frustrating low
      hairline by presurgical laser treatment. In addition, the concept of creating
      autogenous frameworks by tissue engineering is pursued and discussed in practical
      clinical terms. A survey of 1000 microtia patients indicates that surgically
      constructed ears remain durable, withstand trauma well, and provide consistent
      emotional relief and psychological benefits through the repair.

PMID- 10654676
TI  - Treatment of large complex cranial bone defects by using hydroxyapatite ceramic
      implants.
AB  - Hydroxyapatite ceramic implants were used in the reconstruction of very large and
      complex-form cranial bone defects in nine patients. The bone defects were the
      result of craniectomy after infections and other complications such as severe
      brain edema, after neurosurgery, and as a result of trauma, subdural hemorrhage,
      and surgery for brain tumor. The size, shape, and curvature of the hydroxyapatite
      ceramic implants were determined based on high-precision, full-scale models
      fabricated through a laser lithographic molding method by using computed
      tomographic data. The use of this method allowed the fabrication of
      hydroxyapatite ceramic implants of shapes that accurately matched the area of
      bone defect, allowing for a minimum of adjustment during the operation even with
      a complex-form implantation. Not only were good cranial contour reconstructed and
      aesthetically satisfactory results obtained in the cases treated by incorporating
      this series of techniques, but neurologic conditions present in some cases were
      also improved to some extent. The postoperative course has been steady for all
      nine patients, with no blood transfusions required during or after the operations
      and no implants requiring removal because of infection or other postoperative
      complications. The average length of postoperative hospitalization for the nine
      cases was 11.7 days, remarkably short considering the clinical conditions.

PMID- 10654677
TI  - Eustachian tube cartilage and medial movement of lateral pharyngeal wall on
      phonation.
AB  - Several authors have demonstrated the importance of medial movement of the
      lateral pharyngeal wall in velopharyngeal closure upon phonation. However, it
      remains controversial what muscle is responsible for lateral pharyngeal wall
      movement and where is the main site of this movement. The purpose of this study
      was to address the above two unanswered questions. In 22 subjects (12 normal
      volunteers, 10 patients with cleft palate), lateral pharyngeal wall movement upon
      phonation was evaluated by using rapid magnetic resonance imaging (MRI). Before
      rapid MRI, their lateral pharyngeal wall movements were classified into three
      groups: the poor, moderate, and good, according to the findings of
      nasopharyngoscopy. Inward displacement of the eustachian tube cartilages upon
      phonation, which was quantified as distance ratio in the transverse plane of MR
      images, was compared with nasopharyngoscopic findings. In addition, the level of
      lateral pharyngeal wall movement was observed in the plane 5 mm lateral to the
      mid-sagittal plane of MR images. Inward displacement of the eustachian tube
      cartilage in the transverse plane of MR images was coincident with medial
      movement of lateral pharyngeal wall observed by nasopharyngoscopy in all 22
      subjects. By using one-way analysis of variance, a statistically significant
      correlation was found between nasopharyngoscopic classification and distance
      ratio. The sagittal plane of MR images revealed that the main site of movement
      occurred at the level of the hard palate and above. It is concluded that medial
      movement of the lateral pharyngeal wall consists of inward displacement of the
      eustachian tube cartilage, which is caused by contraction of the levator veli
      palatini muscle, and that the primary site of this movement is at the level of
      the hard palate and above, where the eustachian tube, but not the superior
      constrictor muscle, exists.

PMID- 10654678
TI  - Prelaminated free flap reconstruction of complex central facial defects.
AB  - This article is a review of five patients who underwent reconstruction of nasal
      and paranasal facial defects with prelaminated forearm free flaps. The defects
      resulted from thermal injury, gunshot wound, excision of tumor, and arteriovenous
      malformation (n = 2). The forearm flaps were based on the radial artery (n = 4)
      and ulnar artery (n = 1) and were prelaminated with grafts of skin and cartilage.
      All flaps were successfully transferred to the face, but revisions were needed to
      separate the subunits and improve appearance. A prelaminated free flap should be
      considered for a patient requiring reconstruction of a complex central facial
      defect.

PMID- 10654679
TI  - Oromandibular reconstruction with the radial-forearm osteocutaneous flap:
      experience with 60 consecutive cases.
AB  - One of the more difficult problems in reconstructive surgery of the head and neck
      is replacement of bone and soft tissue lost because of injury, osteomyelitis, or
      malignancy. The radial-forearm osteocutaneous flap is an accepted choice for
      oromandibular reconstruction. This study was undertaken to review one center's
      experience with 60 consecutive cases of oromandibular reconstruction with the
      radial-forearm osteocutaneous flap. Records of the 38 men and 22 women (mean age,
      60 years; range, 26 to 86 years) were reviewed for tumor location, defect and
      bone length, flap failure rate, recipient- and donor-site complications, length
      of surgery, and hospital stay. Cancer resection was the reason for 97 percent of
      reconstructions; 33 percent of flaps were used to reconstruct a lateral defect of
      the mandible, 40 percent a lateral-central defect, and 27 percent a lateral
      central-lateral defect. Mean skin flap size was 55 cm2 (range, 15 to 117 cm2) and
      mean bone length, 9.4 cm (range, 5 to 14 cm). The microvascular success rate was
      98.3 percent. Complications included fracture of the donor radius (15 percent),
      nonunion of the mandible (5 percent), and hematoma (8.3 percent). These results
      are comparable to results reported in the literature with other radial forearm
      flaps. The free radial osteocutaneous flap is a safe and reliable choice for
      mandibular reconstruction. It offers sufficient bone to reconstruct large defects
      and can provide adequate pedicle length for vessel anastomosis to the
      contralateral side of the neck. The above attributes make the radial forearm
      osteocutaneous flap one of the "first line" flap choices for oromandibular
      reconstruction.

PMID- 10654680
TI  - Multiple-segment osteotomy in maxillofacial surgery.
AB  - Multiple-segment osteotomy is defined as an osteotomy that divides the tooth
      bearing arch of the maxilla or mandible into three or more segments. Combining
      large-segment orthognathic surgery and unitooth or small-segment surgery is an
      effective approach for dealing with a wide range of dentofacial deformities with
      occlusal problems. The indications for a multiple-segment osteotomy included
      dentofacial deformities and malocclusions requiring stable correction within a
      short overall treatment period. From 1991 to 1997, a total of 85 patients had
      multiple-segment osteotomy orthognathic procedures performed at Chang Gung
      Memorial Hospital. The indications for surgery were maxillary
      protrusion/deformity (31 patients), mandibular prognathism (51 patients), and
      noncleft maxillary retrusion (three patients). The types of osteotomies performed
      were Le Fort I, anterior segmental osteotomies of the maxilla or the mandible,
      palatal split, posterior segment, and unitooth or double-tooth segments. Follow
      up ranged from 6 months to 7 years; stability was seen in movements, with only
      three complications (one partial gingival loss and two inferior mental
      paresthesias). No osteotomized segments were lost. The average overall treatment
      time was approximately 15 months, including 3 to 6 months of preoperative and 9
      to 12 months of postoperative orthodontic treatment. This is at least 6 months
      shorter than traditional orthognathic surgery. Experience with 85 consecutive
      patients has shown that the results are good and the procedure is safe, with
      minimal complications.

PMID- 10654681
TI  - The inverted nipple: its grading and surgical correction.
AB  - Inverted nipples have been treated by various methods by many authors, but the
      relationship between the grade of the deformity and the appropriate surgical
      procedure is not clearly described. One hundred seven inverted nipples in 60
      patients were treated from 1993 to 1997. They were divided into three groups by
      the authors' system of grading. The grade was made by preoperative evaluation of
      severity of inversion and was confirmed by the surgical findings. In grade I, the
      nipple is easily pulled out manually and maintains its projection quite well.
      Grade I nipples are believed to have minimal fibrosis; thus, manual traction and
      a single, buried purse-string suture are enough for the correction. The majority
      of inverted nipples belong to grade II, i.e., the nipples can be pulled out but
      cannot maintain projection and tend to go back again. These nipples are thought
      to have moderate fibrosis beneath the nipple. Blunt dissections for surgical
      release were carried out until the inversion did not recur after releasing the
      traction. The lactiferous ducts could be identified and preserved, permitting
      proper release of fibrotic bands in the grade II group. The purse-string suture
      was used. In grade III, to which the least number of inverted-nipple cases
      belong, the nipple can hardly be pulled out manually. Severe fibrosis made it
      impossible to reach optimal release of the fibrotic band with the preservation of
      the ducts. The fibrotic bands are widely dissected, and the lactiferous ducts are
      cut, especially in the central portion. Two or three deepithelialized dermal
      flaps may be used to make up for soft-tissue deficiency; a purse-string suture is
      also used. This grading system will be useful for patient classification and
      analysis, systematic planning, and application of the proper surgical procedures.

PMID- 10654682
TI  - Importance of the pedicle length measurement in reduction mammaplasty.
AB  - Various measurements are still considered to be important for making decisions
      regarding the approach in reduction mammaplasty, even though the vast majority of
      techniques used are based on an inferior pedicle. This study was performed to
      analyze the variability of the suprasternal notch-to-nipple and nipple-to
      inframammary fold distance measurements when using the inferior pedicle
      technique. In 92 patients, 184 breasts having various volumes were measured
      preoperatively, and the variability of the measurements of the suprasternal notch
      to-nipple and nipple-to-inframammary fold distance was analyzed. The values of
      the distance from the suprasternal notch to nipple were dispersed over a wide
      range with a trimodal distribution, with peaks at the intervals of 23 to 27 cm,
      28 to 33 cm, and 34 to 45 cm. In contrast, the values of the nipple-to
      inframammary fold distance showed a normal distribution pattern, with the peak at
      14 cm. The distance from the suprasternal notch to nipple has a fair relationship
      to the inframammary fold-to-nipple distance, the latter being concentrated in a
      smaller range (r = 0.51). The former is often used to decide whether a free
      nipple graft should be performed. However, the relative consistency of the latter
      measurement has led to the conclusion that the free-nipple graft technique need
      never be considered.

PMID- 10654683
TI  - Repeat reduction mammaplasty.
AB  - Repeat reduction mammaplasty is an uncommonly performed procedure. Currently, no
      clear operative guidelines of management exist. Sixteen patients (28 breasts)
      with a mean age of 29 years (range, 13 to 52 years) underwent repeat breast
      reduction over an 11-year period. Before the first reduction, the mean notch to
      nipple distance was 29.6 cm (range, 24 to 38 cm) and mean nipple to inframammary
      crease distance was 15.5 cm (range, 12 to 18 cm). The mean mass of tissue excised
      was 615 g per breast. A number of different pedicles were used (six inferior,
      five superior, four superomedial, one unknown). All patients subsequently
      developed pseudoptosis. The nipple to inframammary crease distance was a mean of
      11.4 cm (having initially been set at 7 cm) before the second procedure. At the
      second operation, two patients (three breasts) had their initial pedicles
      transected and the nipple-areola complex moved, and both patients developed
      vascular compromise of the nipple-areola complex (two breasts). Where the same
      pedicle was used in the second operation (five patients, 10 breasts), one patient
      developed unilateral nipple-areola complex necrosis. In eight patients, because
      of the development of pseudoptosis, the nipple was in a satisfactory position,
      and therefore only an inferior wedge of tissue required excision. This was
      performed without nipple-areola complex compromise, irrespective of the initial
      pedicle. The mean mass of tissue excised in the second operation was 325 g per
      breast (range, 120 to 620 g). Fourteen patients were available for follow-up
      after a mean of 5.1 years (range, 3 months to 11.7 years) following the repeat
      reduction mammaplasty. In the repeat breast reduction, where nipple-areola
      complex transposition is planned, the initial pedicle should be reused to
      maintain nipple-areola complex perfusion. Where the initial pedicle is not known,
      a free nipple graft may be the safest option. In patients with pseudoptosis, in
      whom the nipple does not require transposition, an inferior wedge of tissue can
      be safely excised, irrespective of the initial pedicle.

PMID- 10654684
TI  - An approach to the repair of partial mastectomy defects.
AB  - In many cases, breast deformity caused by partial mastectomy can be reduced or
      corrected by plastic surgery. Partial breast reconstruction is best performed
      immediately after the partial mastectomy using an approach determined by the size
      of the breast and the defect. Small defects in large breasts usually need no
      reconstruction. For larger defects in large breasts, breast reshaping (similar to
      reduction mammaplasty) combined with a contralateral breast reduction is usually
      the best option. For medium-sized or smaller breasts with small to moderate-sized
      defects, local flaps from the subaxillary region are very useful. If the defect
      is too large for correction with local tissue, a latissimus dorsi myocutaneous
      flap is usually the best choice. Using these techniques, patients can achieve
      aesthetically better outcomes from breast-conservation therapy, even when larger
      tumors are being treated or when wider margins are taken to reduce the risk of
      tumor recurrence. By working together with an oncologic surgeon and facilitating
      the removal of larger tumors, the plastic surgeon can widen the indications for
      both breast-conservation therapy and breast reconstruction at the same time.

PMID- 10654685
TI  - Local recurrence risk after skin-sparing and conventional mastectomy: a 6-year
      follow-up.
AB  - In this study, the records of all patients at the University of Texas M. D.
      Anderson Cancer Center with T1 or T2 breast cancer who were treated between March
      of 1986 and November of 1990 with mastectomy followed by immediate breast
      reconstruction were reviewed for the presence of recurrent disease. Patients with
      in situ disease were not included. Patients were included in the study if a local
      recurrence occurred (regardless of the length of follow-up) or if a follow-up of
      6 years or longer could be obtained. Patients were grouped according to the use
      or nonuse of skin-sparing mastectomy, by tumor stage, and by nuclear grade of the
      tumor. The series included 154 patients, of whom 114 had skin-sparing
      mastectomies and 40 had nonskin-sparing mastectomies. The local recurrence rate
      in the skin-sparing mastectomy group was 7.0 percent, whereas in the nonskin
      sparing mastectomy group it was 7.5 percent. The sample size in the nonskin
      sparing mastectomy group was too small for meaningful statistical analysis, but
      the data suggest that there is no clinically important difference in recurrence
      rates between the two groups. We conclude that the use of skin-sparing technique
      for early breast cancer patients does not significantly increase the risk of
      tumor recurrence after mastectomy.

PMID- 10654686
TI  - Transarticular bony defects after trauma and sepsis: arthrodesis using
      vascularized fibular transfer.
AB  - Ten male patients with previously infected bony defects involving both sides of
      an articulation underwent arthrodesis using a vascularized fibular transfer. The
      average age of these patients was 38 years (range, 20 to 60 years). The size of
      the bony defect averaged 9 cm (range, 3 to 21 cm). The ankle was involved in five
      patients, the knee in two patients, the wrist in two patients, and the elbow in
      one patient. Nine cases represented septic pseudarthroses (eight after trauma and
      one after attempted ankle arthrodesis). One patient had a defect across the wrist
      after debridement of a chronic infection. The patients were followed for an
      average of 71 months (range, 26 to 144 months). Nine patients healed after the
      index vascularized fibular transfer, and one patient (ankle arthrodesis) required
      a second cancellous bone-grafting procedure for delayed union at the junction of
      the fibula with the talus. Four of seven patients with lower limb involvement had
      residual leg length discrepancies averaging 5 cm (range, 3 to 8 cm), and one had
      a persistent 20-degree internal rotation deformity. Two of the patients with
      upper limb involvement had stiff digits. Five of the nine previously employed
      patients returned to their former occupation (including heavy labor in four
      cases). Complications included two wound separations, one case of instability of
      the donor ankle after removal of a large fibular graft (related in part to a
      prior injury), and one fracture at the junction of the fibular graft with the
      local bone 10 months after the index procedure, which united after plate fixation
      and application of autogenous cancellous bone graft. Arthrodesis using a transfer
      of vascularized fibular bone represents a viable option for limb salvage in the
      face of an infected transarticular bony defect.

PMID- 10654688
TI  - Effect of nerve repair after unilateral partial facial paralysis on craniofacial
      growth and development.
AB  - The effect of partial transection, coaptation, and freezing of the left facial
      nerve on craniofacial growth and development was investigated. Twelve-day-old New
      Zealand White rabbits were randomly assigned to four groups: control group (n =
      15), nerve ablation group (n = 15) with a surgically induced partial facial
      paralysis, nerve coaptation group (n = 15) with a surgically induced partial
      facial paralysis treated by immediate microsurgical nerve coaptation, and nerve
      freezing group (n = 13) with a freezing-induced partial facial paralysis. All
      animals were operated on at the age of 12 days; follow-up evaluations were
      performed at the ages of 2 months (end-point prepubertal growth) and 6 months
      (full grown). Computerized dorsoventral roentgencephalometric analysis and
      computer tomographic three-dimensional volumetric measurements were performed at
      both ages. Roentgencephalometric analysis revealed that the growth disturbances
      of the nerve ablation group and the nerve coaptation group were analogous. In
      contrast, in the nerve freezing group, hardly any growth disturbances as compared
      with the control group were seen. The CT volume measurements revealed a
      significant left-right difference in maxillary volume at the ages of 2 and 6
      months in the nerve coaptation group as compared with the control group. Muscle
      histomorphometric analysis revealed a shift in muscle fiber composition in the
      nerve coaptation group and the nerve freezing group, with an increase of type I
      fibers at the cost of type IIA fibers. This shift was significantly less
      pronounced in the latter than in the former. Nerve histomorphometric analysis
      revealed a significant increase in the number of nerve fibers in the nerve
      coaptation group as compared with the control group. In the nerve freezing group,
      the increase in the number of nerve fibers was not significantly different as
      compared with the control group and the nerve coaptation group. Both the
      equivalent diameter and the myelin area were equally reduced in the nerve
      coaptation and nerve freezing groups. Thus, the nerve coaptation group and the
      nerve freezing group did not differ significantly in the extent of nerve
      recovery, although they differed in the extent of muscle recovery. The extent of
      muscle recovery, in turn, was related to the extent of abnormal craniofacial
      growth and development. Indeed, the growth and development were hardly abnormal
      in the nerve freezing group and as abnormal as after untreated paralysis in the
      nerve coaptation group. Therefore, factors related to nerve regeneration, other
      than those assessed by nerve histomorphology, were considered to be responsible
      for these differences between both groups. The duration of the denervation time
      was regarded to be considerably shorter in the nerve freezing group than in the
      nerve coaptation group, resulting in the observed improved muscle recovery. The
      difference in the degree of axonal malalignment between both groups was
      considered to be negligible, because of the tolerance toward axonal malalignment
      at neonatal age.

PMID- 10654687
TI  - Basic fibroblast growth factor and transforming growth factor beta-1 expression
      in the developing dura mater correlates with calvarial bone formation.
AB  - Numerous studies have found dura mater-calvarial mesenchyme interactions during
      calvarial bone induction; however, the exact molecular mechanisms governing these
      inductive events remain unknown. Recent studies have implicated basic fibroblast
      growth factor (FGF-2) and transforming growth factor-beta1 (TGF-beta1) in
      regulating bone formation. The purpose of this study was, therefore, to
      investigate the expression of FGF-2 and TGF-beta1 during calvarial bone formation
      in rats. Eight rats were killed on embryonic days 14, 18, and 20 and neonatal day
      1 (n = 32). Four animals at each time point were analyzed by in situ
      hybridization, and the remainder were analyzed by immunohistochemistry. The
      results indicated that the dura mater underlying the developing calvarial bone
      strongly expressed FGF-2 and TGF-beta1 mRNA at all time points examined. In
      contrast, minimal growth factor expression was noted in the overlying calvarial
      mesenchyme until embryonic day 18, but it increased significantly with increasing
      age. Importantly, FGF-2 and TGF-beta1 mRNA expression in the dura mater
      underlying the developing calvarium preceded and was significantly greater than
      expression in the calvarium mesenchyme (p < 0.05). Interestingly, minimal
      expression of FGF-2 and TGF-beta1 mRNA was noted for all time points in the dura
      mater underlying the posterior frontal suture and within the posterior frontal
      suture connective tissue (p < 0.01 when compared with the dura mater underlying
      the developing calvarium). Immunohistochemical findings closely paralleled mRNA
      expression, with intense staining for FGF-2 and TGF-beta1 in the dura mater
      underlying the developing calvarial mesenchyme. Increasing FGF-2 and TGF-beta1
      staining was noted within calvarial osteoblasts with increasing age, particularly
      in cells located near the endocranial surface (i.e., in contact with the
      developing dura mater). These findings, together with the known biologic
      functions of FGF-2 and TGF-beta1, implicate these growth factors in the
      regulation of calvarial bone growth by the developing dura mater. The possible
      mechanisms of this interaction are discussed.

PMID- 10654689
TI  - The effects of cisplatinum and vincristine on peripheral nerve regeneration.
AB  - Current treatment modalities for extremity sarcoma often include tumor
      extirpation plus neoadjuvant therapy. Limb-sparing surgery may require
      reconstruction of critical nerve defects. Neurotoxic side effects from adjuvant
      chemotherapy have been reported and raise concerns regarding the effects of
      chemotherapy on nerve regeneration. In an attempt to define the effects of
      adjuvant chemotherapy on peripheral nerve regeneration, cisplatin and vincristine
      were administered to rats following isografting of the posterior tibial nerve.
      Parameters used to assess peripheral nerve regeneration included walking track
      analysis and histomorphology. Sixty 250-g Sprague-Dawley rats were randomly
      allocated into one of three treatment groups. Each animal underwent a 15-mm
      reversed interposition nerve isograft from 30 donor rats into the right posterior
      tibial nerve. Ten animals served as control. The remaining animals were divided
      into two groups of 25 animals each. One group received cisplatin (75 mg/m2) and
      the other group received vincristine (1 mg/m2). Chemotherapy was administered at
      4-week cycles for a total of six cycles (24 weeks). Walking track analysis was
      performed monthly. Nerve specimens were harvested from the grafted segment and
      the distal posterior tibial nerve for histomorphology. Walking track analysis
      demonstrated no statistical difference in print length between the control and
      chemotherapeutic groups at the conclusion of the study. The number of axons per
      square millimeter and nerve fiber density were not statistically different
      between control and chemotherapeutic groups. In the rodent posterior tibial nerve
      model, postoperative adjuvant therapy does not significantly alter functional
      outcome in peripheral nerve regeneration. The practice of immediate nerve
      grafting after tumor extirpation, despite planned postoperative chemotherapy, is
      supported.

PMID- 10654690
TI  - The influence of systemic growth hormone administration on the healing time of
      skin graft donor sites in a pig model.
AB  - A more rapid healing of skin graft donor sites has often been observed during
      ultimoratio therapies with growth hormone in adults who have suffered extremely
      severe burns. The purpose of this animal experimental study was to examine the
      influence of systemic growth hormone administration on the healing time of skin
      graft donor sites under standardized conditions in pigs. The animals were 14 (7
      experimental and 7 control) male, sexually mature, German domestic pigs, in which
      30 skin graft donor sites 8 cm x 4 cm and 0.6 mm deep were created. Fifteen each
      of the skin graft donor sites were bandaged with the same material [hydrocolloid
      bandage (Varihaesive E) and PVP-iodine gauze (Braunovidon Gaze)]. The test period
      was 15 days for each pig, whereby recombinant growth hormone (0.5 IU/kg body
      weight per day) was applied subcutaneously in the experimental group. The
      bandages were changed under brief narcosis every 2 days, during which one skin
      punch biopsy was taken per skin graft donor site, and blood samples were drawn
      for determination of the serum IGF-1 values. Photographic documentation was also
      recorded. The biopsies were examined histologically (hematoxylin and eosin stain)
      and immunohistochemically (collagen IV and VII, and laminin), whereby
      histologically the start of keratinization was assessed as a healing criterion.
      The serum IGF-1 values in the growth hormone group were statistically
      significantly higher than in the control group. Immunohistochemically, a complete
      basal membrane was observed in both the experimental and the control group after
      the 7th or 8th day. A clearly elevated serum IGF-1 level correlated in the growth
      hormone group with the skin graft donor sites healing. It could thus be
      demonstrated both clinically and histologically that systemic application of
      growth hormone results in a statistically significantly more rapid healing of the
      skin graft donor sites by 2 days earlier than in the control group.

PMID- 10654691
TI  - In vivo study of electrolyte exchanges through membranes of saline-filled breast
      implants.
AB  - Saline-filled breast implants are currently used in breast reconstruction and
      augmentation. Free diffusion of electrolytes through these implants has been
      questioned recently and is of potentially high importance. Many questions are
      still unanswered about this phenomenon. Eighteen prostheses were reviewed and
      tested for diffusion and exchange of electrolytes and glucose in vivo. None of
      these implants demonstrated major variation of the inner contents from the
      original saline used to fill them, emphasizing the real innocuousness of such
      implants in terms of possible ionic pooling. Extrapolation of these results to
      all implants made by different manufacturers is not possible according to the
      sample size in the present study.

PMID- 10654692
TI  - Brain abscess as a complication of orthognathic surgery: diagnosis, management,
      and pathophysiology.
AB  - We present what we believe is the first case of a brain abscess resulting from
      orthognathic surgery reported in the literature. Although recent advances have
      significantly improved the treatment of brain abscesses, delays in diagnosis lead
      to persistent high rates of mortality. Often, the initial symptoms are vague and
      nonspecific. Commonly, the neurologic status of the patient deteriorates
      significantly before suspicion is raised and a CT scan is obtained. This case
      report is intended to benefit all practitioners who participate in the
      perioperative care of orthognathic surgery patients. Although the occurrence of a
      brain abscess is rare, it is hoped that this case will heighten the awareness of
      clinicians to this potential complication.

PMID- 10654693
TI  - Replantation and a history of migraine headaches: ergo(t) a warning.

PMID- 10654694
TI  - Congenital upper auricular detachment.
AB  - A rare case of unilateral congenital ear deformity has been presented. The
      deformity is characterized by detachment and posterior rotation of the right
      upper auricle in an otherwise grossly normal auricle. We believe that this
      deformity may be related to defective mesenchymal fusion or accretion between the
      auricular hillocks of the hyoid and mandibular arches. Satisfactory correction
      was achieved by auricular repositioning with two triangular flaps.

PMID- 10654695
TI  - The role of plastic surgery in the management of airway obstruction.
AB  - A patient with the rare genetic disease of mitochondrial oxidative
      phosphorylation is presented. The phenotypic presentation included localized,
      idiosyncratic lipodystrophy that caused life-threatening respiratory obstruction.
      Plastic surgical excision and suction-assisted lipoplasty of huge deposits of fat
      and skin led to marked improvement in patient posture and ventilation. This rare
      disorder, stages of treatment, and salient references are discussed.

PMID- 10654696
TI  - Simple method of designing a bilobed flap.
AB  - In the present study, we devised a new method of designing bilobed flaps. This
      method makes the flap easy to draw and has the merits of diffusing the tension on
      the flap and minimizing the dog-ear. We used this flap in 16 patients with face
      and head skin defects and obtained good results.

PMID- 10654697
TI  - Use of a temporoparietal fascia-covered silastic implant in nose reconstruction
      after foreign body removal.
AB  - A total of 47 consecutive patients with paraffinoma of the nose underwent surgery
      for paraffinoma removal and insertion of temporoparietal fascia-covered Silastic
      implants between January of 1990 and June of 1996. There are several advantages
      to our procedure, and we obtained satisfactory outcomes with it. A bilateral alar
      rim incision was sufficient for our procedure. The Silastic implant could be
      sculptured easily, was not absorbed, and produced excellent cosmetic results. The
      fascia was highly bioadaptable and survived beneath the dermis through
      revascularization, even in the places where the paraffin material remained. The
      fascia reinforced the thinned skin that resulted after paraffinoma removal and,
      therefore, prevented exposure of the Silastic implant. The telangiectasia of
      paraffinoma of the nose improved in some patients after surgery.

PMID- 10654698
TI  - The influence of Maria Curie's discovery of radium in 1898 on plastic surgery.

PMID- 10654699
TI  - Nipple reconstruction with the double-opposing tab flap.

PMID- 10654700
TI  - The evolution of the Hughes tarsoconjunctival flap for the lower eyelid
      reconstruction.
AB  - The Hughes tarsoconjunctival flap was initially described in 1937. This flap is
      best used for reconstructing full-thickness defects involving the central portion
      of the lower eyelid. The evolution of this flap over the last 60 years is
      outlined. Several important modifications are presented; these modifications lead
      to decreased donor-site morbidity and improved recipient site outcome.

PMID- 10654701
TI  - The cosmetic plastic surgeon in the millennium: are we competitive enough?

PMID- 10654702
TI  - Breast augmentation: compression--a very important factor in preventing capsular
      contracture.
AB  - The incidence of capsular contracture is reduced when smooth-surfaced, saline
      filled implants are placed subpectorally, avoiding contamination and the presence
      of blood. In addition, since the authors began using compression, they have not
      had one single capsular contracture requiring surgery. The authors' technique,
      their preoperative and postoperative regimens, an explanation of how they use
      compression, and the scientific and mathematical explanation of why compression
      could be the most important factor in preventing capsular compression are
      described. Of more than 1700 augmentations performed in our private clinic, only
      830 could be included in the study. The patients were followed clinically for 1
      year, after which time they completed a questionnaire, the results of which
      showed the authors that capsular contracture had not developed.

PMID- 10654703
TI  - Augmentation mammaplasty in male-to-female transsexuals.
AB  - Hormonal therapy and gender-confirming surgery are the treatments of choice in
      appropriately selected male-to-female transsexuals. Penectomy and vaginoplasty
      are the paramount surgical requests of the male transsexual, but breast
      enlargement greatly increases subjective feelings of femininity. There are only
      limited reports on augmentation mammaplasty in male transsexuals, and hardly any
      attention has been paid to the differences between the female mammary anatomy and
      its male counterpart. The basic anatomic and surgical considerations of
      augmentation mammaplasty for 201 male-to-female transsexuals who were operated on
      from 1979 to 1997 are reviewed and discussed. They include the differences
      between male and female anatomy and how to feminize the male chest, the results
      of hormonal therapy and the proper timing of surgery, the choice of implant size
      and surgical approach, the results that may be expected after surgery, and the
      implications of all mentioned on the long-term outcome and follow-up after
      augmentation mammaplasty. Because the referring doctor may not check on the
      breasts or may not be trained to examine augmented breasts for pathologic
      conditions, the mammaplastic surgeon has an obligation to ensure the proper
      follow-up of these patients.

PMID- 10654704
TI  - Witch's chin: a progressive, three-step technique.
AB  - Witch's chin is an unpleasant aesthetic defect characterized by ptosis of
      premental tissue and a deep submental fold, which may be exaggerated by
      hyperprojection of the mandible. These three elements determine the different
      degrees of deformity; therefore, the ideal treatment should be directed to one,
      two, or all three of them. Despite unanimity on the surgical approach of the
      defect, a large variety of techniques have been proposed by various authors. The
      need to use a technique suitable for different clinical pictures, characterized
      by a progressive surgical aggression, as usually performed in this practice, has
      led to standardize a technique to correct witch's chin, by means of three
      progressive steps, depending on the degree of deformity. The advantage of this
      procedure is that once a good result has been achieved, the subsequent steps may
      be omitted. The technique has been successfully performed in five patients, and
      the mean follow-up is 12 months. Figures from two representative cases are
      presented.

PMID- 10654705
TI  - The effect of increased plastic surgeon supply on fees for aesthetic surgery: an
      economic analysis.
AB  - The size of the plastic surgery workforce has important effects on the financial
      environment of the specialty. Economic theory predicts that increasing the area
      supply of surgeons performing aesthetic surgery will result in lower fees for
      their services. This study tested that theory in the actual aesthetic surgery
      marketplace. The study examined the ratio of plastic surgeons to the general
      population of several states. It then traced the aesthetic surgery fees resulting
      from different densities of area plastic surgeons. This information was
      economically analyzed to project the fee effects of possible future changes in
      the number of practicing plastic surgeons. For the states of New York,
      California, and Texas, there is a proportional decrease in fees as the density of
      plastic surgeons increases. For example, New York has 34 percent more plastic
      surgeons proportionally than Texas, and its fees are 30 percent lower in real
      dollars. Economic analysis can project the fee effects of changing the supply of
      surgeons performing aesthetic surgery. The analysis reveals that a 30 percent
      national increase in the supply of plastic surgeons would lower fees by
      approximately 32 percent. Similarly, if the number of plastic surgeons increases
      by 50 percent, fees will decrease by approximately 53 percent. However, these fee
      effects can be mitigated by expanding the demand for aesthetic surgery. In
      conclusion, the size of the plastic surgery workforce has profound effects on the
      fees paid for aesthetic surgery, and the magnitude of these effects can be
      understood, predicted, and optimized using the tools of economics.

PMID- 10654706
TI  - The value of tear film breakup and Schirmer's tests in preoperative
      blepharoplasty evaluation.
AB  - The authors published their article on the value of tear film breakup and
      Schirmer's tests in preoperative blepharoplasty evaluation in 1989. The purpose
      of this update is to expand the original article in light of refinements and
      experiences in subsequent years. It was concluded in the 1989 article that the
      abnormal tear film breakup and Schirmer's tests were not good predictors of
      possible postblepharoplasty dry eye complications. It was concluded in the review
      that the anatomy and the history including scleral show, lagophtholmus, negative
      vector, snap test, previous surgery, increased blinking, dryness, grittiness and
      pain were more important predictors of postoperative dry eye problems than the
      ocular tests. The authors' opinion remains so, and they do less preoperative tear
      film testing and place more emphasis on the history and the anatomy as predictors
      of potential problems. In this follow-up to the 1989 article, the authors include
      a survey from several surgeons as to how they evaluate their patients for
      elective aesthetic blepharoplasty, which in large measure confirms the authors'
      practice.

PMID- 10654707
TI  - The AntiDoctor.

PMID- 10654708
TI  - Plastic surgeons or thugs?

PMID- 10654709
TI  - Workforce issues.

PMID- 10654710
TI  - Functional outcome after surgery for trigonocephaly.

PMID- 10654711
TI  - Commentary on speech outcome and maxillary growth in patients with unilateral
      complete cleft lip/palate operated on at 6 versus 12 months of age.

PMID- 10654712
TI  - Oral diapneusia: a peculiar variety of oral mucosal fibrous hyperplasia.

PMID- 10654713
TI  - Readjustment of the degree of lift following frontalis sling operation in ptosis:
      a new and simple method.

PMID- 10654714
TI  - A technical tip for needle guides in otoplasty.

PMID- 10654715
TI  - The intramuscular needle plastic cap as soft-tissue protector during wire
      traction.

PMID- 10654716
TI  - Changes in physical symptoms and body image after reduction mammaplasty: response
      to a discussion.

PMID- 10654718
TI  - Posterior interosseous flap based on a septal perforator, in the absence of the
      distal artery.

PMID- 10654717
TI  - Reevaluating the need for routine drainage in reduction mammaplasty.

PMID- 10654719
TI  - Disposable gloves in the treatment of pressure sores.

PMID- 10654720
TI  - A case of giant keloid in the female genitalia.

PMID- 10654721
TI  - Conception following penile reconstruction.

PMID- 10654722
TI  - A method for correcting prominent axillary folds.

PMID- 10654723
TI  - The vermilion myomucosal flap for the treatment of oral commissure gunshot wound
      deformities.

PMID- 10654724
TI  - The World War II Italian Battalion surgeon--St. Louis University connection.

PMID- 10654725
TI  - Uvular transposition: a new method of cleft palate repair.
AB  - This prospective study was done to determine whether a new cleft palate repair
      utilizing uvular transposition improved speech outcome as measured objectively by
      a speech pathologist. In the uvular transposition procedure, the palate was
      lengthened with tissue from the uvula by a double-opposing Z-plasty; an
      intravelar veloplasty was performed, and two-thirds of the mass of the uvula was
      transposed to the nasal surface of the soft palate. This procedure facilitates
      velopharyngeal closure by significantly lengthening the palate, anatomically
      reconstructing the muscles of the palate, and decreasing the palatal excursion
      necessary to achieve closure. Sixty-two children with a cleft palate were treated
      with this procedure performed by the senior surgeon between the years of 1988 and
      1995. These children were then enrolled in cleft lip and palate clinic at age 2
      to 3 years and blindly evaluated yearly by a single speech pathologist who
      specialized in pediatric speech pathology. Postoperative clinical follow-up
      ranged from 36 to 112 months (mean, 56.8 months). Perceptual nasal emission was
      found to be normal in 59 of the 62 patients (95 percent). Nasometry was performed
      in all 62 of these patients, and the mean score was 15.7 percent, well within the
      accepted normal range of 25 or less at our institution. Only two of these
      children (3 percent) required a pharyngeal flap for velopharyngeal insufficiency.
      These findings suggest that the uvula transposition cleft palate repair may
      result in good normalization of speech with negligible rates of velopharyngeal
      insufficiency.

PMID- 10654726
TI  - Velopharyngeal motion after sphincter pharyngoplasty: a videonasopharyngoscopic
      and electromyographic study.
AB  - Sphincter pharyngoplasty is a surgical procedure for managing velopharyngeal
      insufficiency after palatal closure. This procedure is intended to create an
      active diaphragm for velopharyngeal closure. The purpose of this study was to
      evaluate velopharyngeal motion after sphincter pharyngoplasty, by using selective
      electromyography and simultaneous videonasopharyngoscopy. Twenty-five patients
      who were subjected to sphincter pharyngoplasty from 1985 to 1996 were reviewed.
      All conditions were evaluated by using electromyography with simultaneous
      videonasopharyngoscopy. The following velopharyngeal muscles were examined:
      superior constrictor pharyngeus, palatopharyngeus, and levator veli palatini. The
      palatopharyngeus was included in the superiorly based surgical flaps inserted at
      the posterior pharyngeal wall. Twenty-three patients (92 percent) showed complete
      velopharyngeal closure. The two patients with residual velopharyngeal
      insufficiency showed a defect size of 20 and 25 percent. None of the patients
      showed electromyographic activity at the superiorly based flaps, indicating
      absence of activity of the palatopharyngeus muscles. However, all patients showed
      normal electromyographic activity at the superior constrictor pharyngeus and the
      levator veli palatini. Videonasopharyngoscopy demonstrated that lateral
      pharyngeal wall movements, which ranged from 25 to 40 percent, were related to
      strong electromyographic activity at the superior constrictor pharyngeus. It is
      concluded that the superiorly based pharyngeal flaps of the sphincter
      pharyngoplasty do not seem to create an active diaphragm for velopharyngeal
      closure. Moreover, the observed sphinctering seems to be passive, caused by the
      contraction of the superior constrictor pharyngeus.

PMID- 10654727
TI  - Upper lip measurements at the time of surgery and follow-up after modified
      rotation-advancement flap repair in unilateral cleft lip patients.
AB  - The purpose of this prospective study was to determine whether unilateral cleft
      lip repaired by the rotation-advancement flap will grow short on the repaired
      side. This study involved 56 patients with nonsyndromic unilateral cleft lip (31
      with complete and 25 with incomplete cleft lip) who underwent a rotation
      advancement flap repair by a single surgeon between 1989 and 1997. Eleven
      patients were lost to follow-up. Forty-five patients have been followed for a
      varying period of between 8 and 84 months (mean = 37 months). The upper lip was
      measured immediately after the lip repair and follow-up using calipers. The
      growth ratios of vertical, horizontal, and nostril sill dimensions were compared
      between the cleft side and the noncleft side of the same face. Statistical
      analysis was performed to compare the growths between the cleft and noncleft
      sides. There was not a significant difference in the growth ratios of vertical
      (Wilcoxon signed rank test, p = 0.85) and horizontal dimensions (Student's t
      test, p = 0.18) between the cleft and noncleft sides. There was, however, a
      statistically significant difference in the growth ratios of nostril sill width
      between the cleft and noncleft sides (Student's t test, p = 0.02). Our findings
      indicated that a repaired unilateral cleft retained the vertical and horizontal
      dimensions determined at the time of the initial repair.

PMID- 10654728
TI  - The innervated gracilis musculocutaneous flap for total tongue reconstruction.
AB  - A functional neotongue following total glossectomy requires both soft-tissue bulk
      and reconstruction of muscle function. We used innervated transverse gracilis
      musculocutaneous flaps to reconstruct total glossectomy defects in eight
      patients. The obturator nerve to the gracilis muscle was approximated to the
      hypoglossal nerve to reinnervate the gracilis muscle by using microsurgical
      technique. The cutaneous paddle of the gracilis flap easily supplies sufficient
      bulk to replace the total glossectomy defect. Follow-up of patients ranged from 3
      to 47 months. All patients were able to resume oral feeding. Electromyographic
      studies performed on one patient showed reinnervation of the flap with active
      elevation of the posterior pharynx. Ultimately, seven patients died because of
      recurrence of their disease. The innervated gracilis musculocutaneous flap may
      benefit patients who have a total glossectomy by allowing them to achieve a more
      functional recovery.

PMID- 10654729
TI  - Patterns of maxillofacial injuries in powered watercraft collisions.
AB  - Because of the widespread popularity of water sports, plastic and reconstructive
      surgeons can expect to manage an increasing number of injuries associated with
      these activities, particularly those related to powered watercraft vehicles.
      Although seat belts for motorists and helmets for motorcyclists may be
      efficacious, such devices currently do not serve a similar role in powered
      watercraft sports. In this study, a retrospective chart review of 194 consecutive
      patients who presented to the University of Miami/Jackson Memorial Hospital
      (Level I trauma center) as a result of powered watercraft collisions is
      presented. The purpose of this investigation was to assess the incidence, cause,
      demographics, and available management options for head and neck injuries
      secondary to powered watercraft. Identified were 194 patients who presented
      because of watersports-related injuries during the period January 1, 1991,
      through December 31, 1996. From this group, 81 patients (41.8 percent) sustained
      injuries directly attributable to powered watercraft collisions, including 41
      personal watercraft collisions (50.6 percent), 39 boat collisions (48.1 percent),
      and 1 airboat collision (1.2 percent). The patient population, as expected,
      tended to be young and male with an average age of 29 years (range, 8 to 64 years
      old). Interestingly, 41 of the patients (50.6 percent) who presented to this
      trauma center as a result of powered watercraft collisions also sustained
      associated head and neck trauma. Of 74 injuries 24 were facial fractures (32.4
      percent), 18 were facial lacerations (24.3 percent), 14 were closed head injuries
      (18.9 percent), 8 were skull fractures (10.8 percent), 4 were scalp lacerations
      (5.4 percent), 4 were C-spine fractures (5.4 percent), 1 was an ear laceration
      (1.4 percent), and 1 was a fatality (1.4 percent). Le Fort fractures were the
      most commonly identified facial fracture in this series. The number of these
      injuries seen in hospital emergency rooms will most likely increase in the future
      as the popularity of water-related recreational activities becomes even more
      widespread. Based on these findings, it is strongly recommended that future
      efforts be directed toward the prevention of these injuries through patient
      education and the eventual development of efficacious and safe protective
      equipment.

PMID- 10654730
TI  - Facial asymmetry: three-dimensional analysis using laser surface scanning.
AB  - This study evaluates six different techniques with respect to their ability to
      quantitatively describe facial asymmetry in three dimensions. Three-dimensional
      facial images were acquired using a Cyberware 3030RGB laser surface scanner.
      Image processing was performed on a Silicon Graphics Indigo computer workstation.
      The following techniques for facial asymmetry analysis were developed: asymmetry
      in the location of anthropometric landmarks, Euclidean distance matrix analysis
      (EDMA), scalar measurement of the lower ciliary margin and palpebral fissure
      area, clearance vector mapping, and determination of the volume of asymmetry.
      Techniques were applied and validated in three anthropometric models: a perfectly
      symmetrical plastic head model and a plaster head model with and without a
      unilateral cheek augmentation. In each of the anthropometric test models, each
      analytical technique was validated by means of static anthropometric facial
      models and was evaluated for intraobserver and interobserver reliability.
      Asymmetries in the location of anthropometric landmarks can be accurately
      determined to within 2 mm in x, y, and z directions of the Cartesian space. EDMA
      is a useful technique in describing both size and shape changes of discrete areas
      of the face. Measurement of the lower ciliary margin and palpebral fissure area
      is reliable. Clearance vector mapping is especially useful in quantifying facial
      surface asymmetries in facial areas where anthropometric landmarks are scarce.
      Volume of asymmetry is potentially useful in those patients for whom the use of
      injections or implants of known volume may be helpful in correcting unilateral
      facial deficiencies.

PMID- 10654731
TI  - Surgical planning of computer-assisted repositioning osteotomies.
AB  - Repositioning osteotomies are frequently used in orthopedic surgery and
      traumatology to correct malpositions. Computed tomography (CT),
      stereolithographic models, and x-rays are used in planning. However, the
      precision achieved in the planning phase is usually not translated to patients.
      The Surgical Segment Navigator (SSN) is a navigation system that allows computer
      assisted correction of malpositions. It consists of an infrared positioning
      device, two dynamic reference frames (DRF), an infrared pointer, and an infrared
      camera. All data are displayed numerically and graphically on the monitor of the
      SSN workstation. The Laboratory Unit for Computer-Assisted Surgery (LUCAS) is
      used for planning surgery in the laboratory. LUCAS requires only a native CT
      scan. A preparatory operation to implant bone markers that will be visible in x
      rays and a further planning CT scan showing the bone markers, which were
      necessary with previous systems, are not required for the LUCAS and SSN system.
      This significantly reduces the radiation exposure of the patient and the costs of
      surgical planning. Measuring anatomical landmarks in the surgical site, which is
      time-consuming and reduces accuracy, is not required with the SSN system because
      the position of the infrared transmitters is known during surgical planning on
      the LUCAS workstation. This makes the surgical approach faster and much more
      precise. The surgical planning data are transferred to the surgical site using a
      data file and an individual surface pattern that fits the surface of the
      navigated bone segment. The data file is exported from the LUCAS-workstation to
      the SSN workstation. The planned spatial displacement of the infrared
      transmitters is saved in this file. The individual surface pattern carries the
      infrared transmitters. This pattern is the mechanical interface between infrared
      transmitters and navigated bone segment. The individual surface pattern can be
      polymerized directly on a small stereolithographic model of the navigated bone
      segment. The surface pattern can also be generated as negative form from a CT
      data set using a computer-assisted design/manufacture system. In summary, LUCAS
      and SSN allow for the computer-assisted correction of malpositions and
      positioning of artificial joints and implants. In principle, the systems can be
      used in all fields of surgery.

PMID- 10654732
TI  - An integrated approach for increasing the survival of autologous fat grafts in
      the treatment of contour defects.
AB  - Autologous fat grafting as a technique to correct soft-tissue defects is a
      controversial subject. The high percentage of fat resorption and the resulting
      need for additional grafting considerably reduce the value of this method. The
      purpose of this study was to evaluate the clinical application of tissue
      culturing methodology in the handling of the lipocyte aspirate in an endeavor to
      improve the survival rate and therefore the take of the grafted lipocytes. The
      method consists of syringe aspiration of the lipocytes from the donor site,
      isolation of intact lipocytes by gentle centrifugation, suspension of the
      aspirate in an enriched cell culture medium, and injection of the cell suspension
      into preformed subdermal tunnels. A number of media were tested and shown to
      prolong the survival of lipocytes ex vivo using fluorescent acridine orange
      stain. Implementing the integrated cell culture techniques increased the
      lipocytes' viability, as indicated in clinical evaluation in which the amount of
      graft take ranged between 50 and 90 percent. The results of 15 patients with
      varied types of cases who were operated on using this new methodology show that
      the tissue defect was filled and remained so in postoperative follow-ups of 6 to
      24 months. A three-dimensional CAT scan-aided evaluation method was developed and
      used in one of four case histories presented herein.

PMID- 10654733
TI  - Analysis of risk factors associated with rupture of silicone gel breast implants.
AB  - Despite many recent studies on breast implant rupture, there is no general
      consensus on causation or incidence. Existing studies have not reported a
      multivariate analysis of risk factors associated with breast implant rupture.
      Most studies lack adequate sample size to study the effect of implant type,
      manufacturer, and other patient-related factors that might affect rupture. This
      study addresses all of these shortcomings. Patients undergoing implant removal by
      a single surgeon between 1990 and 1996 were examined for rupture and for 16
      potential risk factors. The association between rupture and various factors was
      analyzed by univariate and multivariate analyses. A total of 842 patients
      underwent removal of 1619 implants. Increasing age of implant [p < 0.0001;
      adjusted odds ratio (OR), 1.20; 95% confidence interval (CI), 1.15 to 1.23],
      retroglandular location (p = 0.0002; OR, 1.93; CI, 1.37 to 2.71), Baker
      contracture grades III and IV (p = 0.005; OR, 1.52; CI, 1.14 to 2.03), and
      presence of local symptoms (p = 0.05; OR, 1.37; CI, 1.00 to 1.89) were associated
      with rupture. When different implant types were compared with smooth gel
      implants, after adjustment, double-lumen (p < 0.0001; OR, 0.33; CI, 0.22 to 0.50)
      and polyurethane-covered implants (p < 0.0002; OR, 0.33; CI, 0.20 to 0.57) had
      significantly lower rupture rates. When various manufacturers were compared with
      Dow Corning after adjusting for other factors, rupture rates were significantly
      lower for McGhan (p < 0.0001; OR, 0.41; CI, 0.26 to 0.65), whereas higher for
      Surgitek (p < 0.019; OR, 1.52; CI, 1.05 to 2.18). Significant risk factors for
      breast implant rupture were identified: older implants, retroglandular implant
      location, implant contracture, local symptoms, certain implant type, and certain
      manufacturer. Although the results of this study are based on a nonrandomized
      explant population from a single surgeon's practice, knowledge of these risk
      factors will permit better interpretation of future data on rupture. The
      knowledge will enable the medical community to better advise their breast implant
      population regarding durability and appropriate time for removal or replacement.

PMID- 10654734
TI  - Lymphatic mapping and sentinel lymph node biopsy in patients with melanoma of the
      lower extremity.
AB  - Lymphatic mapping and sentinel lymph node biopsy is a new technique used in the
      surgical treatment of patients with malignant melanoma. The purpose of this study
      was to evaluate the results of this approach for patients with melanoma of the
      lower extremity. Between May of 1994 and June of 1997 at the H. Lee Moffitt
      Cancer Center and Research Institute, 85 consecutive patients with clinical stage
      I and II melanoma of the lower extremity underwent lymphatic mapping and sentinel
      lymph node biopsy. These nodes were identified in all 85 patients by
      intraoperative lymphatic mapping with both radiolymphoscintigraphy and a vital
      blue dye injection. Eleven patients (12.9 percent) had histologically positive
      sentinel lymph nodes, and 10 patients underwent inguinal complete lymph node
      dissections. All 10 patients had no further histologically positive lymph nodes
      confirmed by subsequent complete dissection. Among 74 patients with
      histologically negative sentinel lymph nodes, only 2 patients (2.7 percent)
      developed inguinal nodal metastases during a mean follow-up period of 21.8 months
      (range, 13.5 to 58.3 months). The sensitivity of lymphatic mapping and sentinel
      lymph node biopsy in this series was 100 percent and the specificity was 97.3
      percent. Therefore, we conclude that the use of lymphatic mapping and sentinel
      lymph node biopsy can accurately stage patients with melanoma of the lower
      extremity and provide a rational surgical approach for these patients.

PMID- 10654735
TI  - Influence of recipient vessels on free tissue transplantation of the extremities.
AB  - A retrospective analysis of the records of 107 free flap transplants in 94
      patients operated on between May of 1992 and September of 1997 at the Center for
      Microsurgery of Extremities, Nopparatrajathanee Hospital, was conducted to study
      the risk factors leading to free flap failure. These factors were periods of
      operation to reflect the experience of the surgeon, locations of the defects,
      anastomotic techniques, and the use of vein grafts. Chi-square, Fisher's exact
      test, and multiple logistic regression analysis were used to determine the
      significance of the data. The overall vascular complication rate was 28 percent
      (30 of 107 transplants) and the re-exploration rate was 13 percent (14 of 107
      transplants), the flap salvage rate was 50 percent (7 of 14 flaps), whereas the
      overall failure rate was 15 percent (16 of 107 transplants). The significant
      factors that caused free flap failure were the experience of the surgeon and the
      use of vein grafts. The most important experience was in the choice and
      preparation of the recipient vessel. When the surgeon gained more experience in
      the past 2 years (from October of 1995 to September of 1997), the success rate
      improved significantly. Moreover, the use of vein grafts no longer affected the
      outcome. Therefore, in this investigation the most important factor that improved
      the outcome of free tissue transplantation in the extremities was the experience
      of the surgeon in choosing and preparing the recipient vessels.

PMID- 10654736
TI  - The anatomy of the extended peroneal venous system.
AB  - The fibula has deservedly become a workhorse flap for vascularized bone grafts.
      As with most flaps, much is known regarding idiosyncrasies of its arterial
      supply, and the corresponding venous system has generally been assumed to be
      comparable. Because this donor site has become increasingly versatile, a detailed
      anatomic study that would verify this latter assertion should be important.
      Therefore, venous mapping specifically of the peroneal venae comitantes was
      completed in 29 fresh lower limbs. In every specimen, paired venae comitantes of
      large caliber indeed paralleled the course of the peroneal artery. All were of
      quality satisfactory for microanastomoses, which should provide reassurance that
      preoperative evaluation of the peroneal venous system is not routinely indicated.
      However, anatomic variations proved to be the norm. The two venae comitantes did
      not necessarily coalesce into a single common peroneal vein [6 of 29 (21
      percent)]. Usually, the lateral peroneal vein was the larger and continued
      proximally either alone (17 percent) or as the common peroneal vein (66 percent)
      to form the lateral tibioperoneal vena comitans. Thus, the venous pedicle of a
      fibula flap could be lengthened up to its confluence with the popliteal vein, a
      maneuver that potentially could obviate the need for a vein graft at least on the
      venous side. Although anomalies of the peroneal artery could preclude use of the
      fibula altogether, there appeared to be no such contraindications from a venous
      standpoint, despite the fact that the venous anatomy was unique in every
      individual. Some important similarities in patterns, though, do exist. For
      example, a common peroneal vein was formed by the juncture of the lateral
      peroneal vein and some combination of branches joining the lateral posterior
      tibial vein and medial peroneal vein in 63 percent of all limbs. Because
      exceptions are the rule, the choice of donor vein and venous pedicle length best
      remains an intraoperative decision dependent on the presenting anatomy.

PMID- 10654737
TI  - Outcome comparison in traumatic lower-extremity reconstruction by using various
      composite vascularized bone transplantation.
AB  - Lower-extremity injury may present as a composite soft-tissue and bone defect,
      resulting directly from trauma or subsequent debridements. These composite
      defects often require vascularized osteocutaneous flaps for an effective, staged
      reconstruction. Among various donor sites, the vascularized fibular flap is
      generally considered the best option because of its inherent advantages. However,
      when the fibular flap is not available, iliac and rib flaps become the
      alternative choices. The purpose of this retrospective study was to compare the
      functional results of the alternatively chosen bone flaps (iliac and rib flaps)
      with those of the fibular flaps.

PMID- 10654738
TI  - A systematic approach for improvement of the donor sites of fasciocutaneous
      flaps.
AB  - Fasciocutaneous flaps as a group have been maligned more often for fear of
      potential donor-site morbidity than any concern for reliability. Typically, this
      is related to limitations imposed by the skin graft necessary to close most such
      donor sites, as admittedly has been required for the majority (52 percent) of our
      313 flaps over the past 2 decades. Nevertheless, 48 percent did not require skin
      grafts, reflecting the adoption of strategies that evolved to minimize this
      shortcoming. These included use of fascia-only flaps, primary closure with small
      composite flaps, direct closure possible by use of rotation or advancement flaps
      or a second flap, or a delayed closure utilizing either pretransfer or
      posttransfer tissue expansion. Donor-site complications were actually fewest when
      a skin graft or primary closure was possible and occurred at the same rate
      regardless of body region. However, because the skin-grafted donor site was
      always a cosmetic compromise, a systematic approach to circumvent its use
      whenever possible is emphasized as a valuable tool to enhance the role of
      fasciocutaneous flaps as a vascularized flap alternative.

PMID- 10654739
TI  - Nerve decompression at the wrist in patients with Charcot-Marie-Tooth disease.
AB  - Studies evaluating the effects of nerve release in patients with Charcot-Marie
      Tooth disease have been extremely limited to date. This series attempts to
      evaluate the clinical and electrophysiologic effect of nerve release at the wrist
      in a series of patients with this disease. Five patients with documented Charcot
      Marie-Tooth disease of the upper extremity were followed clinically and had nerve
      conduction testing both before and after surgery. This study shows that there was
      an improvement in both sensory and motor testing after release in a significant
      proportion of patients (p < 0.05). All patients documented improvement in their
      sensory latency response postoperatively (100 percent) and most showed
      improvement in motor latency responses (87 percent). More importantly, however,
      there seems to be an even greater clinical improvement in preoperative complaints
      (e.g., paresthesia and pain) in the majority of the extremities that underwent
      surgery with all patients experiencing initial relief and the majority showing no
      recurrence (63 percent) at last follow-up. From these results, this relief can be
      variable, but has lasted for a significant duration postoperatively in the
      majority, necessitating careful consideration for surgery as a legitimate option
      for patients with Charcot-Marie-Tooth.

PMID- 10654740
TI  - Regional differentiation of rat cranial suture-derived dural cells is dependent
      on association with fusing and patent cranial sutures.
AB  - A significant body of literature supports a role for the dura mater underlying
      cranial sutures in the regulation of sutural fate. These studies have implicated
      regional differentiation of the dura mater based on association with fusing and
      patent rat cranial sutures. The purpose of these experiments was to isolate and
      characterize dural cells associated with fusing (posterior frontal) and patent
      (sagittal) rat cranial sutures. Six-day-old rats were killed, and the dura mater
      underlying the posterior frontal and sagittal sutures was harvested. Dural cells
      were briefly trypsinized and allowed to reach confluence. Two litters (10 animals
      per litter) were used for each set of experiments. Cells were harvested after the
      first and fifth passages for analysis of vimentin and desmoplakin expression
      (characteristic of human meningeal cells), cellular proliferation, density at
      confluence (a measure of cellular contact inhibition), and alkaline phosphatase
      production. In addition, bone nodule formation and collagen I production were
      analyzed in first passage cells. The results indicate that suture-derived dural
      cells can be established and that these cells coexpress vimentin and desmoplakin.
      In addition, it is demonstrated that first-passage sagittal suture-derived dural
      cells proliferate significantly faster and have decreased cellular contact
      inhibition than posterior frontal suture-derived cells (p < 0.01). Finally, it is
      shown that suture-derived dural cells have osteoblast-like properties, including
      alkaline phosphatase production, collagen I expression, and bone nodule formation
      in vitro. The possible mechanisms by which regional differentiation of suture
      derived dural cells occur are discussed.

PMID- 10654741
TI  - Transdermal photopolymerization of poly(ethylene oxide)-based injectable
      hydrogels for tissue-engineered cartilage.
AB  - Transdermal photopolymerization, a minimally invasive method for implantation,
      was used to subcutaneously place a mixture of polymer and isolated chondrocytes
      to regenerate cartilage tissue in vivo. Semi-interpenetrating networks of varying
      proportions of poly(ethylene oxide)-dimethacrylate and poly(ethylene oxide) and
      primary bovine articular chondrocytes were implanted in athymic mice. Four mice
      (12 implants) were harvested at 2, 4, and 7 weeks. Chondrocytes survived
      implantation and photopolymerization and formed neocartilage containing 1.5 to
      2.9% wet weight collagen and 4 to 7% glycosaminoglycan. Thirty-five percent of
      the total collagen was type II collagen. Histologic analysis exhibited tissue
      structure resembling neocartilage, and safranin O staining demonstrated
      glycosaminoglycan distribution throughout the hydrogels. This study demonstrates
      the potential use of transdermal photopolymerization for minimally invasive
      subcutaneous implantation of hydrogels and chondrocytes for in vivo cartilage
      regeneration.

PMID- 10654742
TI  - De novo induction of island capsule flap by using two silastic sheets: Part 1.
      Generation.
AB  - A new experimental model for de novo generation of an axial pattern island flap
      has been designed in a rat model. The purpose of this study was to make a
      sufficient vascular carrier, as an island capsule flap, with only vascular
      pedicles and addition of collagen fibers induced by foreign-body reaction. The
      femoral arteriovenous bundle was isolated and sandwiched between two 2.5 x 1.5 cm
      Silastic sheets. Eight weeks later, as a delay procedure, femoral vessels were
      ligated at the distal end of the Silastic sheets and the four margins of the
      sheets were divided except for the vascular pedicle. This capsule flap was raised
      as a secondary island flap connected only by its vascular pedicle, then it was
      sutured back in place. Ten days after the delay procedure, the upper Silastic
      sheet was removed and a full-thickness skin graft was performed on the capsular
      island flap. Animals were killed at 80 days. A total of 40 axial pattern
      capsulocutaneous flaps from 20 Sprague-Dawley rats were successfully achieved.
      Pathologic study revealed neovascularization, and abundantly impregnated vascular
      structures near the pedicle were observed with randomly developed collagen
      fibers. The skin graft took 100 percent on this newly formed capsular flap;
      therefore, the capsule structure was able to survive on its own and support skin
      grafts. This experiment, by using an isolated femoral artery and vein as the main
      pedicle, led to the formation of a capsule flap through a normal foreign body
      reaction between two Silastic sheet implants. This new flap can be used as a
      reliable vascular carrier for various needs with minimal donor morbidity.

PMID- 10654743
TI  - Effect of hyperbaric oxygen and medicinal leeching on survival of axial skin
      flaps subjected to total venous occlusion.
AB  - This study evaluates the effect of hyperbaric oxygen and medicinal leeching on
      axial skin flaps subjected to total venous occlusion. Axial epigastric skin flaps
      (3 x 6 cm) were elevated on their vascular pedicles in 40 male Wistar rats. Total
      venous occlusion was achieved by division of all veins draining the skin flap.
      Arterial inflow was left intact. Animals were randomly assigned to one of five
      groups: sham (n = 8); control, total venous occlusion only (n = 8); occlusion
      with hyperbaric oxygen (n = 8); occlusion with leeching (n = 8); occlusion with
      leeching and hyperbaric oxygen (n = 8). The hyperbaric oxygen protocol consisted
      of 90-minute treatments, twice daily, with 100% O2 at 2.5 atmospheres absolute
      for 4 days. The leeching protocol consisted of placing medicinal leeches on the
      congested flaps for 15 minutes, once daily, for 4 days. Laser Doppler
      measurements of flap perfusion were recorded preoperatively, postoperatively, and
      on postoperative days 1 and 3. The percentage of flap necrosis was evaluated on
      postoperative day 3. Mean percentage necrosis and mean laser Doppler readings
      were compared between both groups. The flaps in the sham group demonstrated 99
      percent survival, whereas the flaps in the occlusion-only group demonstrated 100
      percent necrosis. The flaps in the occlusion with oxygen, the occlusion with
      leeching, and the occlusion with oxygen and leeching groups demonstrated 1, 25,
      and 67 percent survival, respectively. Sham laser Doppler readings remained
      within normal limits. Laser Doppler readings in the occlusion-only and the
      occlusion with oxygen groups decreased to negligible levels on postoperative day
      1, and on postoperative day 3 no perfusion was demonstrated. In both the
      occlusion with leeching and the occlusion with leeching and oxygen groups, there
      was also a significant decrease in laser Doppler measurements after surgery, but
      perfusion remained stable throughout the remainder of the study. This study
      demonstrates that hyperbaric oxygen alone is not an effective treatment for skin
      flaps compromised by total venous occlusion. The combination of leeching and
      hyperbaric oxygen treatment of total venous occlusion results in a significant
      increase in flap survival above that found with leeching alone. It appears that
      hyperbaric oxygen is effective because of the venous outflow provided by leeching
      as demonstrated by laser Doppler flow readings.

PMID- 10654744
TI  - Blockade of platelet endothelial cell adhesion molecule-1 (PECAM-1) protects
      against ischemia-reperfusion injury in muscle flaps at microcirculatory level.
AB  - Several lines of evidence show that platelet endothelial cell adhesion molecule-1
      (PECAM-1), a component of endothelial cell junctions, is required for leukocyte
      transmigration through endothelial cell monolayers. Polymorphonuclear leukocytes
      play an important role in ischemia-reperfusion injury. We sought to determine
      whether administering an anti-PECAM-1 antibody would prevent or attenuate
      ischemia-reperfusion injury in a rat cremaster muscle flap injury model. Eighteen
      male Sprague-Dawley rats were divided into three groups. Group I (control):
      Cremaster muscle island flaps were dissected for baseline measurements of eight
      indicators: numbers of rolling, sticking, and transmigrating neutrophils, numbers
      of rolling and sticking lymphocytes, number of perfused capillaries, endothelial
      edema, and vessel permeability. Group II: The prepared cremaster flap was
      subjected to 4 hours of ischemia and 24 hours of reperfusion. Group III: The
      muscle flap was subjected to ischemia and reperfusion as in group II, and anti
      PECAM-1 antibodies (1 mg/kg) were injected subcutaneously 15 minutes before
      reperfusion. Blood vessels were observed in vivo under an intravital microscopy
      system. Microvascular permeability was made visible with injected fluorescein
      isothiocyanate-labeled albumin and evaluated with Kontron Elektronik computer
      software. The ischemia-reperfusion-alone group (group II) presented a 225-percent
      increase in the activation of sticking leukocytes (2.4 +/- 0.4 to 7.8 +/- 0.8, p
      < 0.05) (p < 0.01). This leukocyte activation was reduced by 83 percent following
      anti-PECAM-1 monoclonal antibody treatment (1.3 +/- 0.5 per 100 microm) (p <
      0.01). At 24 hours, endothelial injury in group II was confirmed by a 4-fold
      increase in the number of transmigrating leukocytes into the interstitial space
      (7.6 +/- 1.2 per field versus 1.9 +/- 0.4 per field in controls). This phenomenon
      was reduced by 85 percent following anti-PECAM-1 monoclonal antibody treatment
      (1.1 +/- 0.2 per field) (p < 0.01). Analysis showed that the number of flowing
      capillaries was 67 percent lower in group II (6.8 +/- 0.3 to 2.2 +/- 0.7, p <
      0.01). Anti-PECAM-1 antibody treatment caused a 2.5-fold increase in this number
      (5.6 +/- 0.5, p < 0.01). Microcirculatory permeability index showed a 180-percent
      increase in group II (p < 0.05) when compared with baseline values. This
      increased albumin leakage was effectively attenuated by antibody treatment (p <
      0.05). Blocking the action of PECAM-1 in vivo by administering monoclonal
      antibodies significantly attenuated ischemia-reperfusion injury, presumably by
      inhibiting transendothelial migration of neutrophils and by increasing capillary
      perfusion at a muscle flap microcirculatory level.

PMID- 10654745
TI  - Effect of vascular delay on viability, vasculature, and perfusion of muscle flaps
      in the rabbit.
AB  - The delay procedure is known to augment pedicled skin or muscle flap survival. In
      this study, we set out to investigate the effectiveness of vascular delay in two
      rabbit muscle flap models. In each of the muscle flap models, a delay procedure
      was carried out on one side of each rabbit (n = 20), and the contralateral muscle
      was the control. In the latissimus dorsi flap model, two perforators of the
      posterior intercostal vessels were ligated. In the biceps femoris flap model, a
      dominant vascular pedicle from the popliteal artery was ligated. After the 7-day
      delay period, the bilateral latissimus dorsi flaps (based on the thoracodorsal
      vessels) and the bilateral biceps femoris flaps (based on the sciatic vessels)
      were elevated. Animals were divided into three groups: part A, assessment of
      muscle flap viability at 7 days using the tetrazolium dye staining technique (n =
      7); part B, assessment of vascular anatomy using lead oxide injection technique
      (n = 7); and part C, assessment of total and regional capillary blood flow using
      the radioactive microsphere technique (n = 6). The results in part A show that
      the average viable area of the latissimus dorsi flap was 96 +/- 0.4 percent (mean
      +/- SEM) in the delayed group and 84 +/- 0.7 percent (mean +/- SEM) in the
      control group (p < 0.05, n = 7), and the mean viable area of the biceps femoris
      flap was 95 +/- 2 percent in the delayed group and 78 +/- 5 percent in the
      control group (p < 0.05, n = 7). In part B, it was found that the line of
      necrosis in the latissimus dorsi flap usually appeared at the junction between
      the second and third vascular territory in the flap. Necrosis of the biceps
      femoris flap usually occurred in the third territory, and occasionally in both
      the second and the third territories. In Part C, total capillary blood flow in
      delayed flaps (both the latissimus dorsi and biceps femoris) was significantly
      higher than that in the control flaps (p < 0.05). Increased regional capillary
      blood flow was found in the middle and distal regions, compared with the control
      (p < 0.05, n = 6). In conclusion, ligation of either the dominant vascular
      pedicle in the biceps femoris muscle flap or the nondominant pedicle in the
      latissimus dorsi muscle flap in a delay procedure 1 week before flap elevation
      improves capillary blood flow and muscle viability. Vascular delay prevents
      distal flap necrosis in two rabbit muscle flap models.

PMID- 10654746
TI  - Total eyelid reconstruction with free dorsalis pedis flap after deep facial burn.
AB  - A case of severe facial and corneal burns with complete loss of upper and lower
      eyelids is reported together with the acute management and surgical options for
      total eyelid defects secondary to thermal injury. An acutely burned man with 78
      percent total burn surface area presented with complete exposure of the left
      cornea. Because of the severe thermal injury, no facial tissues were available as
      donor sources for reconstructing the eyelid. A free dorsalis pedis flap was used
      to cover the exposed cornea after bilateral conjunctival advancement flaps, with
      septal cartilage graft for structural support. A conjunctivodacryocystorhinostomy
      was performed at the time of the coverage. The patient was unable to perform an
      exact visual acuity test; however, his gross vision was intact.

PMID- 10654747
TI  - Angiolipoma of the finger masquerading as flexor tenosynovitis.

PMID- 10654748
TI  - Penile reconstruction: combined use of an innervated forearm osteocutaneous flap
      and big toe pulp.
AB  - The use of a radial forearm flap has become the most popular method to
      reconstruct a phallus in recent years. This method of reconstruction, however, is
      plagued with problems such as urethral fistula and loss of phallic girth as a
      result of tissue atrophy, rendering a phallic contour that is cosmetically
      unsatisfactory. We had the opportunity of modifying the technique of penile
      reconstruction using a forearm osteocutaneous flap to minimize these problems.
      Specifically, a segment of the big toe pulp is used to reconstruct a glans penis.
      Sensory restoration in the "glans" and "penile shaft" is restored by coapting the
      digital and the antebrachial nerves to the penile nerve remnants. A segment of
      flexor carpi radialis muscle is included in the design of a forearm flap to
      reinforce the coaptation site of the urethral tract. An arteriovenous shunt is
      incorporated in the shaft as a mechanism to elicit erection of the penis by
      compressing the root of the neophallus. We had used these technical modifications
      in a 51-year-old man who had undergone penile amputation because of cancer. The
      cosmetic appearance and erotic and tactile sensation in the shaft and glans were
      proper and satisfactory at the end of fourth year after the surgery. The coital
      function was also satisfactory.

PMID- 10654749
TI  - A new technique for microvascular anastomosis: external metallic circle.
AB  - Vessel anastomosis is the most critical step in free tissue transfers and
      replantation surgery. We report on a new microvascular anastomosis technique that
      uses a metallic circle around the anastomotic circumference. Sutures are first
      passed inside the circle and tied outside and over the circle so as to stretch
      open the anastomotic site. By retraction of vessel ends, the circle is totally
      exteriorized and thus there is no contact with blood. In 48 rats, the external
      circle method was compared with the conventional technique for constructing end
      to-end anastomosis between carotid arteries (1 to 1.2 mm) and femoral veins (1 to
      1.5 mm). The external circle method proved to be superior to the conventional end
      to-end technique in speed of execution for both arterial and venous anastomoses.
      Patency rates at the third week were significantly higher in the venous group
      using the metallic circle (100 percent versus 70.8 percent, p < 0.05). This new
      method may be applicable in clinical microvascular surgery.

PMID- 10654750
TI  - Radial forearm free flap: hybrid version.
AB  - The hybrid version of the radial forearm free flap provides an alternative method
      for reconstruction in the head and neck. It is versatile and has certain
      theoretical and practical advantages, including high-flow venous drainage, long
      venous pedicle, lymphatic drainage, and the avoidance of venous anastomosis or
      venous transpositional graft. In those situations when the availability of veins
      is reduced after a radical neck dissection or the quality of vein is poor because
      of previous irradiation, the hybrid free flap is the method of choice for
      microvascular reconstruction in the head and neck region.

PMID- 10654751
TI  - Donor-site morbidity comparison between endoscopically assisted and traditional
      harvest of free latissimus dorsi muscle flap.
AB  - Endoscopically assisted harvest of free latissimus dorsi muscle flaps is being
      used more frequently in reconstructive microsurgery because it requires a smaller
      incision and leaves a more acceptable scar in the donor site. Donor-site
      morbidity was compared between groups of 22 latissimus dorsi muscles harvested
      using the endoscopically assisted technique and 26 using the traditional
      technique. The results revealed no statistically significant differences in the
      amount of intraoperative bleeding, the incidence of postoperative hematoma and
      seroma, and the incidence of donor-site wound infection as assessed by the
      surgeon. However, a patient questionnaire revealed that even though it did not
      reach a statistically significant difference, endoscopically assisted harvest of
      the latissimus dorsi muscle had less pain and allowed earlier and better movement
      of the upper extremity of the donor site. The patients' attitudes and feelings
      about the scar and overall satisfaction were also higher in the endoscopic group,
      which demonstrated a statistically significant difference.

PMID- 10654752
TI  - A comparison between subgaleal and subperiosteal brow lifts.
AB  - The author has thought for a long time that the endoscopic subperiosteal brow
      lift has a better long-term result than the bicoronal subgaleal brow lift;
      therefore, he stopped doing subgaleal bicoronal brow lifts in 1995 in favor of
      the endoscopic subperiosteal approach. To discover if this impression could be
      objectively verified, the author undertook a retrospective study of 120 patients
      who had a brow lift. They were divided into four groups, depending on the type of
      operation, and were compared with each other by means of a new digitalized
      analyzing tool. Measurements of the vertical height from the midpupil to the top
      of the brow, from the medial canthus to the top of the brow, and from the lateral
      canthus to the top of the brow were made. Preoperative measurements were compared
      with postoperative measurements taken after 1 year. No significant difference
      existed between the preoperative and postoperative values in the patients who had
      a subgaleal brow lift. In the patients who had a subperiosteal brow lift, there
      was a mean increase of 7 mm in the vertical height of the brow 1 year after the
      operation.

PMID- 10654753
TI  - Multiple, combined plications of the SMAS-platysma complex: breaking down the
      face-aging vectors.
AB  - After analyzing how facial tissues are affected during the aging process, 36
      rhytidoplasties were performed by plicating the superficial musculoaponeurotic
      system (SMAS)-platysma complex. Also, additional procedures were performed to
      improve the aesthetic result. Patients were followed for 3 to 33 months (median,
      13 months); their ages ranged from 42 to 72 years (median, 53 years). Because the
      facial soft tissues present specific anatomic particularities and the force
      vector determinants for facial ptosis are many and varied, specific plications
      were combined to obtain the desired results during a rhytidoplasty. Combinations
      of six different types of plications are described; some of them are used
      individually by various authors to manage the SMAS-platysma complex. Major
      complications did not occur, despite extensive cutaneous undermining, and
      morbidity was similar to that of other techniques that handle the SMAS. The
      results were satisfactory for all patients, and clinical improvement was noted in
      all cases. On the basis of these results, using combined plication to manage the
      SMAS-platysma complex during a rhytidoplasty is recommended. The opposing vectors
      should be considered when planning the combination of plications.

PMID- 10654754
TI  - Famciclovir as antiviral prophylaxis in laser resurfacing procedures.
AB  - Latent herpes simplex virus (HSV types I and II) may be reactivated by laser
      resurfacing procedures, presenting serious postoperative complications in
      approximately 9 percent of patients. Perioperative prophylactic administration of
      nucleoside analog antiviral agents has been shown to decrease the duration and
      severity of postsurgical herpes infection and to prevent recurrence. This study
      was conducted to assess the efficacy of famciclovir in preventing orofacial
      herpes virus reactivation and primary infection in patients undergoing laser
      resurfacing. HSV history was obtained from a total of 121 patients undergoing the
      procedure. Antiviral prophylaxis with famciclovir was begun 1 to 2 days before
      surgery and continued for 5 days after surgery. Patients with no history of
      orofacial herpes (n = 94) received 125 mg of famciclovir twice daily. Those with
      a history of orofacial herpes (n = 27) received 250 mg of famciclovir twice
      daily. Postsurgical HSV infection rates in patients receiving famciclovir
      prophylaxis were compared with those from a similar historical control group of
      HSV-positive patients (n = 127) who received no prophylaxis. In patients
      receiving famciclovir prophylaxis, one patient (1.1 percent) in the HSV-negative
      history group and no patients in the HSV-positive history group had postsurgical
      herpes infection. Famciclovir significantly reduced postsurgical herpes infection
      when compared with the 9.4 percent rate of herpes reactivation in patients who
      received no prophylaxis (p = 0.003). This study suggests that twice-daily
      famciclovir prophylaxis markedly reduces orofacial herpes virus infection in
      patients undergoing laser resurfacing.

PMID- 10654755
TI  - Cellulite treatment: a myth or reality: a prospective randomized, controlled
      trial of two therapies, endermologie and aminophylline cream.
AB  - Cellulite is a common phenomenon that particularly affects the thighs and
      buttocks of women. Little scientific evidence exists to support any of the many
      advertised treatments for it. A total of 52 of 69 women, who were divided into
      three groups, completed a 12-week, randomized, controlled trial in which the
      effectiveness of two different treatments for cellulite was assessed. The
      patients acted as their own controls. The treatments investigated were twice
      daily application of aminophylline cream and twice-weekly treatment with
      Endermologie ES1. Group 1 (double blind) received aminophylline to one
      thigh/buttock and a placebo cream to the other. Group 2 (singly blind) received
      Endermologie to one thigh/buttock. Group 3 received Endermologie to both sides
      and used the same cream regimen as group 1. Results were assessed subjectively by
      the patient and by clinical examination and photographic assessment by the
      surgeon (before and after the trial). Morphologic assessment included body mass
      index, thigh girth at two points, and thigh fat depth measurement by ultrasound.
      No statistical difference existed in measurements between legs for any of the
      treatment groups (paired t test, p > 0.4). The best subjective assessment, by the
      patients themselves, revealed that only 3 of 35 aminophylline-treated legs and 10
      of 35 Endermologie-treated legs had their cellulite appearance improved. The
      authors do not believe that either of these two treatments is effective in
      improving the appearance of cellulite.

PMID- 10654756
TI  - Treatment of alar cartilage malposition using the cartilage disc graft technique.
AB  - Patients with a bifid, cephalically rotated, contour-deformed, bulky,
      overprojected, pinched-tip, alar-dislocated, and/or alar-tethered nose had
      primary and secondary rhinoplasties using complete lateral alar cartilage
      mobilization, modification, and repositioning and the cartilage disc tip-graft
      technique. This technique avoids the pitfalls of classic in situ subtraction
      rhinoplasty and provides a better way to correct the nasal shape without causing
      airway obstruction. This technique was performed in 30 patients in the past 6
      years who had primary or secondary rhinoplasties, with satisfactory results.

PMID- 10654757
TI  - Refinements in extracorporal septoplasty.
AB  - Septal deviations interfere with nasal airflow and contribute to deformities in
      the external appearance of the nose. An aesthetically and functionally
      satisfactory correction of severe septal deformities or "crippled" septal plates
      often requires a temporary intraoperative removal of the septal cartilage for
      appropriate remodeling. This article describes refinements to the previously
      described technique of extracorporal septoplasty; these refinements have proven
      useful and have made the procedure safer in the hands of less experienced
      surgeons. The refinements simplify the straightening methods for the explanted
      septal plate, achieving a stable and median fixation of the replanted septum
      while maintaining a satisfactory contour of the nasal dorsum. A milling cutter is
      used to straighten the irregularities of the explanted septal plate and to thin
      broadly based anterior nasal spines. When necessary, microplates are added to
      stabilize the osteotomized and medialized anterior nasal spine. The final
      positioning of the replanted septal plate is greatly enhanced by a rein stitch,
      transosseous sutures, and multiple quilt stitches. Additionally, direct fixation
      of the replanted septum to the edges of the upper lateral cartilages further
      improves the stability of the reconstruction. Finally, particular care should be
      taken to avoid residual irregularities of the nasal dorsum; it they occur, these
      irregularities can be covered with a thin cartilaginous splint or a layer of
      dehydrated fascia lata or autologous temporal fascia. A total of 436 patients who
      underwent rhinoseptoplasties at the authors' department during a 1-year period
      were reviewed. Of these patients, 108 presented with severe septal deviations and
      underwent an extracorporal septoplasty using the refined techniques described
      herein. Despite the complexity of the procedure, the patients' satisfaction rates
      were high, independent of the operating surgeon.

PMID- 10654758
TI  - New approach to the gummy smile.
AB  - The authors present a multidisciplinary approach to the gingival smile in which
      its three components are evaluated. These components are the dynamic component of
      the lip (repose versus smiling) and the two static elements of the gum and
      maxilla. Once an appropriate diagnosis has been made, the authors act on the
      gingiva for delayed passive eruption, on the maxilla for long face syndrome, and
      on the lip with lip-elongation techniques. When delayed passive eruption is
      associated with hyperfunction of the lip elevators, an intraoral approach with an
      incision at the level of the upper labial frenulum and dissection from the
      anterior nasal spine to the anterior maxillary fossae, in addition to gingival
      remodeling, is recommended to reduce gingival exposure.

PMID- 10654759
TI  - The lower muscular balance of the face used to lift labial commissures.
AB  - One of the weak points in face lifts is their failure to fully correct the ptosis
      of the labial commissures. This article illustrates a new technique to optimize
      this commissural repositioning in face lifts by using the muscular balances of
      the lower half of the face. There is, in effect, a third type of muscular
      balance, which acts on the commissural modiolus and is created by the opposing
      forces of the levator muscles (notably the zygomaticus major and the levator
      anguli oris) and the depressor muscles (principally the depressor anguli oris).
      Rarely a purely cutaneous problem, labial commissural ptosis is more a part of
      mediofacial ptosis affecting the entire soft tissue. I have used the malar
      subperiosteal face lift technique, the only approach that allows the centrofacial
      features to be lifted as a whole block, since late 1996 and have treated a series
      of more than 30 patients affected with mediofacial ptoses involving the malar
      eminences, the nasolabial folds, and the labial commissures. Retensioning the
      levator muscles was combined with wholesale subperiosteal release of the
      depressor muscles, notably the depressor anguli oris. Patient follow-up has
      lasted between 6 and 20 months. In all instances, this use of the lower facial
      muscular balances allowed optimal repositioning of the labial commissure. In
      particularly outstanding cases, unilateral release of the depressor muscles was
      used to correct facial asymmetry at the level of the lip commissures and thereby
      restore harmony and alignment. In 10 of our cases, this slackening of the
      depressor muscles was also used in conjunction with a peripheral face lift; the
      resulting heightening of the commissures was, in these cases, perhaps less
      spectacular, but it invariably contributed to the rejuvenation of the face.

PMID- 10654760
TI  - Mandibular contouring: a surgical technique for the asymmetrical lower face.
AB  - Correcting facial asymmetry is a difficult problem for plastic surgeons. From
      1991 to 1996, the authors treated 53 cases of mandibular angle resection, 13 of
      which were of patients with an asymmetrical lower face. On the basis of these
      experiences, the authors highlight two important points in dealing with the
      asymmetrical lower face. The first is accurate resection of each side of the
      face. A cloth pattern was used to improve the accuracy of the procedure and to
      make the final result match the preoperative design regarding amount and shape.
      The second concerns soft-tissue change after the operation. Satisfactory results
      are obtained by the accurate resection of the bone coupled with the correct
      management of the surrounding soft tissue. The amount of bone to be resected was
      determined not simply by cephalometry, but by both cephalometry and external
      appearance. Postoperative cephalometry is not always symmetrical, and it is
      important that the final external appearance be harmonious and symmetrical. Using
      the above method, results have been satisfactory to both the surgeons and the
      patients, with the exception of three patients who had residual asymmetry. No
      permanent sensory loss or motor nerve palsy was observed, and no infections
      occurred.

PMID- 10654761
TI  - The role of plastic surgery in congenital cutis laxa: a 10-year follow-up.
AB  - The clinical features and the plastic surgery management of a 23-year-old woman
      with cutis laxa are presented. Two rhytidectomies were performed in this patient
      within 1 year. The first was associated with a SMAS flap; the second employed a
      prehairline incision. The evolution of the aging facial appearance 10 years after
      the last face lift was evaluated and compared with the preoperative situation.
      Repeated face lifts seem to be an interesting way to manage patients with cutis
      laxa. Unlike patients with other disorders of the connective tissue, those with
      cutis laxa have no vascular fragility and heal well. The role of plastic surgery
      and the clinical features and timing for operation are reviewed and discussed.

PMID- 10654762
TI  - Blindness as a complication of subcutaneous nasal steroid injection.
AB  - Blindness as a result of steroid injection into areas adjacent to the eyes,
      namely the interior of the nose and eyelids, has been described in the
      otolaryngologic and ophthalmologic literature but at no time in the plastic
      surgery literature. We describe a case of permanent visual loss at the time of
      injection of a long-acting steroid to the dorsum of the nose for postrhinoplasty
      scarring. We suggest that before steroid injection for elective procedures, the
      patient be informed of all possible consequences of complications even if their
      occurrence is very rare.

PMID- 10654763
TI  - Breast implant overfill, optimal fill, and the standard of care.

PMID- 10654764
TI  - Outcome studies and practice guidelines in plastic surgery.

PMID- 10654765
TI  - Management of inferior turbinate hypertrophy.

PMID- 10654766
TI  - Repair of nasal-septal perforations.

PMID- 10654767
TI  - Nasal packing in rhinoplasty and septorhinoplasty: it is wiser to avoid.

PMID- 10654768
TI  - Keloids: time to dispel the myths?

PMID- 10654769
TI  - A rubber band: the cheapest drain.

PMID- 10654770
TI  - Free vascularized fibula transfer: who was first?

PMID- 10654771
TI  - Periareolar subcuticular pursestring suture.

PMID- 10654772
TI  - Umbilicoplasty.

PMID- 10654773
TI  - Revisitation of the vascular anatomy of the lumbrical and interosseous muscles.

PMID- 10654774
TI  - The role of interleukin-1alpha and collagenase in chronic wounds.

PMID- 10654775
TI  - Noninvasive liposculpture: an association of external ultrasound delivery with
      endermosuctioning massage.

PMID- 10654776
TI  - The treatment of lymphedema.

PMID- 10654777
TI  - Intraoperative intermittent lower-extremity massage for the surgeon with proven
      medical benefit.

PMID- 10654778
TI  - What price advertising?

PMID- 10654779
TI  - Quality-of-life outcomes after cosmetic surgery.

PMID- 10654780
TI  - Integument flaps incorporating the nutrifying arteries of cutaneous nerves and/or
      cutaneous veins.

PMID- 10654781
TI  - Polidocanol for refractory seroma.

PMID- 10654782
TI  - The role of transverse thoracic muscle in sternal wound dehiscence.

PMID- 10654783
TI  - Chorionic Villus Sampling Birth Defects Registry.

PMID- 10654784
TI  - Application of high-temperature simulated distillation to the residuum oil
      supercritical extraction process in petroleum refining
AB  - The gas chromatographic method of high-temperature simulated distillation (HTSD)
      is described, and the results are presented for the application of HTSD to the
      characterization of petroleum refinery feed and products from solvent
      deasphalting operations. Results are presented for refinery residual feed,
      deasphalted oil, and asphaltene fractions from the residual oil supercritical
      extraction process. Asphaltene removal from petroleum residuum using solvent
      deasphalting results in the improved quality and high recovery of deasphalted oil
      product for use as lube oil, fluid catalytic cracking, or hydrocracker
      feedstocks. The HTSD procedure presented here proves valuable for characterizing
      the fractions from the deasphalting process to obtain the percentage yield with
      boiling point data over the range from approximately 36 degrees C (97 degrees F)
      to 733 degrees C (1352 degrees F), which covers the boiling range of n-paraffins
      of carbon number C5 to C108.

PMID- 10654785
TI  - Studies on neurosteroids X. Determination of pregnenolone and
      dehydroepiandrosterone in rat brains using gas chromatography-mass spectrometry
      mass spectrometry.
AB  - An assay method for pregnenolone and dehydroepiandrosterone in rat brains is
      developed using gas chromatography (GC)-electron ionization-mass spectrometry
      (MS)-MS. The extract of the rat brain homogenate containing deuterated internal
      standard with organic solvent is purified by silica gel minicolumn
      chromatography. The obtained fraction is derivatized into methyloxime, treated
      with dimethylisopropylsilylimidazole, and then subjected to GC-MS-MS. The method
      is applied to the determination of these steroids in the gray matter and
      olfactory bulbs of rat brains, which are divided into control and acute stressed
      specimens. Although pregnenolone in both regions of the rat brains increases more
      than three times after stress, dehydroepiandrosterone in both regions is not so
      clearly influenced by stress.

PMID- 10654786
TI  - Quantitation of caffeine by capillary zone electrophoresis with end-column
      amperometric detection at a carbon microdisk array electrode.
AB  - Capillary zone electrophoresis is employed for the determination of caffeine
      using end-column amperometric detection with a carbon fiber microdisk array
      electrode at a constant potential of 1.45 V versus a saturated calomel electrode.
      The optimum conditions of separation and detection are 0.1 52mM NaH2PO4-0.648mM
      Na2HPO4 for the buffer solution, 20 kV for the separation voltage, 5 kV for the
      injection voltage, and 10s for the injection time. The limit of detection is 2.9
      x 10(-4)mM or 1.2 fmol (signal-to-noise ratio = 2). The relative standard
      deviation is 0.68% for the migration time and 2.3% for the electrophoretic peak
      current. The method is applied to determining caffeine in human serum and a cola
      drink.

PMID- 10654787
TI  - A high-performance liquid chromatographic method for the determination of
      monofluoroacetate.
AB  - A simple isocratic high-performance liquid chromatographic (HPLC) method for the
      quantitative analysis of monofluoroacetic acid (MFA), the toxic substance of
      Dichapetalum cymosum, in plant material, rumen contents (gastric contents), and
      liver samples is described. A suitable HPLC column that gives optimum
      sensitivity, accuracy, precision, and separation of MFA is identified. A C-610
      organic acid analysis column at ambient temperature with 0.02M H3PO4 as an eluent
      and ultraviolet detection at 210 nm is utilized to quantitate MFA. Using this
      method, the average percentage recovery in plant material, bovine liver, and
      rumen samples is 94.8%, and a detection limit of 12 microg/L is achievable.

PMID- 10654788
TI  - Supercritical fluid extraction and gas chromatography or electroanalysis of metal
      chelates from different sample matrices
AB  - The supercritical fluid extraction of Pb(DDC)2 and MoO2(acac)2 complexes is
      performed. The previously formed complexes are used in order to simplify the
      extraction process. In the extraction cell, 9.0 mg of Pb(DDC)2 or 30.0 mg of
      MoO2(acac)2 is added. With these two complexes, a study of static and dynamic
      extraction as a function of pressure (1000-2500 psi), temperature (40-160 degrees
      C), and presence of modifier (methanol) is performed. Under the best conditions,
      5.6 mg of Pb(DDC)2 (2.3 mg of Pb2+) is recovered. The parameters are 2500 psi of
      pressure, 160 degrees C of temperature, 0.5 mL methanol (placed in a 10-mL
      extraction cell), 60.0 min of static extraction, and 2.0 min of dynamic
      extraction. It is necessary to add 3.0 mL of methanol to enhance efficiency on
      the MoO2(acac)2 complex recovery. Quantitative extractions of MoO2(acac)2 (9.0 mg
      of MoVI) are obtained when the experiments are carried out under 1000-2500 psi of
      pressure, 140 degrees C, and times no longer than 10.0 min. Then, the study is
      carried out forming the in situ complexes. For this purpose, metallic ion and
      ligand are added. Under these conditions, the Pb2+ recovery decreases from 2.3 to
      1.9 mg, and the MoVI recovery decreases from 9.0 to 1.0 mg. When 1.9 mg of Pb2+
      and 1.0 mg of MoVI or less is placed in the extraction cell, the recoveries are
      always 100%. The Pb2+ extracts are directly accomplished using gas chromatography
      flame ionization detection (GC-FID), and the MoVI extracts are analyzed using GC
      FID and catalytic adsorption voltammetry. The quantitation of pure extracts is
      carried out by constructing calibration curves with complex solutions and sample
      solutions using the standard addition method. This method is applied by
      determination of Pb2+ in sodium alginate extracted from algae and blood, urine,
      and human milk from patients with diagnosed plumbunemy. MoVI is determined in
      irrigation water and pasture of animal intake.

PMID- 10654789
TI  - Determination of edible bird's nest and its products by gas chromatography.
AB  - A specific gas chromatographic (GC) detection method for edible bird's nest (EBN)
      based on identifying the composition of the oligosaccharide chain combined with
      glycoprotein in EBN is developed. Five monoses (D-mannitose, D-galactose, N
      acetyl-D-galactosamine, N-acetyl-D-glucosamine, and N-acetyl neuraminate) that
      constitute the oligosaccharide chain are detected using GC and GC-mass
      spectrometry techniques; their characteristic GC spectrum can reliably be
      regarded as EBN's fingerprint. The peak-area ratios in GC spectrum of those five
      monoses are found to be fixed; therefore, the GC technique developed in this work
      can conveniently be used to determine various raw EBNs and their products both
      qualitatively and quantitatively, distinguishing between fake and genuine EBN
      rapidly.

PMID- 10654790
TI  - High-performance liquid chromatographic determination of pyrazinamide in human
      plasma, bronchoalveolar lavage fluid, and alveolar cells.
AB  - A technique is presented for the measurement of pyrazinamide in human plasma,
      bronchoalveolar lavage, and alveolar cells by reversed-phase column
      chromatography. The assay utilizes acetazolamide as an internal standard,
      ultraviolet detection at 268 nm, and an acetonitrile-based mobile phase.
      Preparation of plasma samples requires a simple deproteinization step, resulting
      in the development of sharp peaks with retention times of 8.4 and 17 minutes for
      pyrazinamide and acetazolamide, respectively. Bronchoalveolar lavage and alveolar
      cell suspensions require an acid extraction with ethyl acetate, evaporation to
      dryness, and reconstitution. This method provides specific, rapid, and reliable
      determinations of drug concentrations and therefore is suitable for
      pharmacological studies, particularly those that are designed to quantitate the
      intrapulmonary concentrations of pyrazinamide.

PMID- 10654791
TI  - Elution characteristics of natural cyclodextrins on porous graphitic carbon
AB  - The retention behavior of natural alpha-, beta-, and gamma-cyclodextrins on a
      porous graphitic carbon (PGC) stationary phase is investigated. Unusual retention
      properties for reversed-phase chromatographic conditions are observed with
      acetonitrile-methanol and water-methanol mixtures as mobile phases. It is assumed
      that the retention process is governed not only by the standard solvophobic
      effect but also by specific interactions described as "CD-PGC" effect. The
      retention factor versus the volumetric methanol fraction in the mobile phase show
      second-order curves expressing this double mechanism hypothesis. van't Hoff plots
      demonstrate the contribution of these two retention processes. The retention
      factor of each natural cyclodextrin is shown to depend on the mobile phase
      property to act as a proton acceptor, according to the solvent selectivity
      classification described by Snyder. The "CD-PGC" effect is interpreted as an
      equilibrium between different interactions: cyclodextrin-PGC stationary phase,
      London dispersion forces, and cyclodextrin-mobile phase hydrogen bonding. The
      balance of these interactions may monitor the orientation of the cyclodextrin
      molecule facing the carbon surface, which is therefore suspected to be the major
      parameter of this retention mechanism.

PMID- 10654792
TI  - Primary oesophageal motility disorders: how primary are they?
AB  - The normal regulation of oesophageal peristalsis is complex. Nitric oxide
      containing inhibitory neurons and cholinergic excitatory nerve fibres play the
      key roles. In the so-called primary oesophageal motility disorders, the
      coordination of oesophageal contractions and lower oesophageal sphincter function
      is disturbed (achalasia, diffuse oesophageal spasm), or the amplitudes of
      peristaltic contractions are abnormally high (nutcracker oesophagus). This
      article focuses on the pathophysiology of achalasia and nutcracker oesophagus.
      There is evidence that achalasia and nutcracker oesophagus should not be
      considered parts of one and the same range of diseases.

PMID- 10654793
TI  - Studies of autonomic function in patients with achalasia and nutcracker
      oesophagus.
AB  - BACKGROUND: Post-mortem studies in patients with achalasia reveal degenerative
      changes in the vagus and its dorsal motor nuclei suggesting the possibility of
      widespread autonomic dysfunction. AIMS: To study a broad range of autonomic
      function in patients with achalasia and nutcracker oesophagus and in asymptomatic
      volunteers. SUBJECTS: Patients with a manometric diagnosis of achalasia and
      nutcracker oesophagus and age- and sex-matched asymptomatic volunteers. METHODS:
      Subjects underwent measurement of: (1) pupil cycle time estimation; (2) heart
      rate response to the Valsalva manoeuvre, standing and deep breathing; (3)
      systolic blood pressure response to standing; (4) diastolic response to sustained
      handgrip; (5) spectral analysis of heart rate variability; and (6) heart rate and
      blood pressure during the Valsalva manoeuvre. RESULTS: No significant differences
      were found between patients with achalasia and asymptomatic volunteers. Patients
      with nutcracker oesophagus, however, had longer pupil cycle times (1.2 (0.9-1.4)
      s versus 0.9 (0.8-1.2) s, P= 0.02) and had attenuation of both the rise in the
      low frequency peak of heart rate variability and the fall in the high frequency
      peak on standing (rise in low frequency peak - patients 26.6 (10.4-52.3)% to 42.2
      (15.5-54.0)%, P = 0.46, volunteers 16.9 (8.4-37.2)% to 47.4 (21.1-66.3)%, P =
      0.03; fall in high frequency peak - patients 18.1 (0.9-43.3)% to 10.1 (0.5
      26.6)%, P= 0.46, volunteers 24.8 (8.5-44.4)% to 9.3 (2.6-35.6)%, P= 0.03). The
      rise in blood pressure during the Valsalva manoeuvre was also attenuated in
      patients with nutcracker oesophagus compared with asymptomatic volunteers (6.9
      (1.0-9.3) mmHg versus 12.9 (11 -23.0) mmHg, P < 0.01). CONCLUSIONS: Whereas tests
      of cardiovascular and pupillary autonomic function are normal in patients with
      achalasia, patients with nutcracker oesophagus show defects in both
      parasympathetic and sympathetic function.

PMID- 10654794
TI  - A single centre's 20 years' experience of columnar-lined (Barrett's) oesophagus
      diagnosis.
AB  - BACKGROUND: The pattern of oesophageal carcinoma type has been changing for some
      time in a number of countries, with adenocarcinoma becoming more frequent
      OBJECTIVE: To investigate the prevalence of columnar-lined (Barrett's) oesophagus
      and oesophageal adenocarcinoma in Barrett's oesophagus during a 20-year period in
      a single centre. METHODS: All upper gastrointestinal endoscopy and histology
      reports for the period January 1977 to December 1996 inclusive were reviewed.
      Data were analysed from patients who had histologically proven Barrett's
      oesophagus. The data were analysed as a single cohort and in five-year bands
      according to the date of diagnosis. RESULTS: Of 44,721 endoscopies, 636 Barrett's
      oesophagus cases were diagnosed; 508 (323 males 185 females; M:F ratio 1.7) were
      histologically proven. The frequency of Barrett's oesophagus detection increased
      steadily from 0.2% to 1.6% of all endoscopies per five-year band. The M:F ratio
      and the mean ages at diagnosis (61 years, range 60-63 for males and 69 years,
      range 68-79 for females) remained constant throughout. Barrett's oesophagus was
      diagnosed at a younger age in males (peak 60-69 years) compared to females (peak
      70-79 years). The male oesophageal adenocarcinoma incidence (11.1%) was almost
      twice that in females (6.5%). In the majority (81%), the initial diagnosis of
      oesophageal adenocarcinoma and Barrett's oesophagus was made concurrently.
      CONCLUSIONS: The increasing Barrett's oesophagus frequency may reflect an
      increasing incidence or recognition of this condition or both. Barrett's
      oesophagus males are more likely to develop oesophageal adenocarcinoma than
      females.

PMID- 10654795
TI  - The effect of the anastomotic size on gastric emptying after hemigastrectomy with
      Billroth II reconstruction.
AB  - OBJECTIVE: To determine if the size of the gastrojejunal anastomosis after
      Billroth II reconstruction was the rate-limiting factor in gastric emptying in
      the postoperative period. METHODS: Twelve mongrel dogs were randomized to have
      either 1.5 cm or 5 cm gastrojejunal anastomoses prior to Billroth II
      hemigastrectomy. Each dog had three solid and three liquid radiolabelled emptying
      studies pre- and postoperatively. Data were collected using a gamma camera. For
      liquid studies, images were obtained at 0 min, 2 min, 4 min, 6 min, 8 min, 10
      min, 20 min, 30 min, 40 min, 50 min and 60 min. For solid studies, images were
      obtained at 0 min, 5 min, 10 min, 20 min, 30 min, 40 min, 50 min, 60 min, 70 min,
      80 min, 90 min, 100 min, 110 min and 120 min. Means were compared by analysis of
      variance using the repeated measures option. RESULTS: Postoperative liquid
      emptying was significantly faster in the first 10 min with both 1.5 cm and 5 cm
      anastomoses compared with preoperative scans in the same animals (45% versus 20%
      and 48% versus 29%, respectively). On the other hand, solid gastric emptying was
      much slower postoperatively with the 1.5 cm anastomosis compared with
      preoperative scans (29% versus 65%) as well as compared with postoperative 5 cm
      anastomosis (29% versus 62%) at the end of 120 min. CONCLUSIONS: Our model
      suggests that the gastric emptying of solids is affected by the size of the
      gastrojejunal anastomosis and not by the diameter of the efferent limb of the
      small intestine following Billroth II reconstruction.

PMID- 10654796
TI  - Relationship between Helicobacter pylori, gastric parietal cell antibodies and
      heat shock proteins.
AB  - BACKGROUND: The relationship between Helicobacter pylori and autoimmune (type A)
      gastritis is unclear. Infections may trigger autoimmune phenomena but the
      underlying mechanisms are unknown. AIM: To determine the relationships between H.
      pylori infection and gastric parietal cell antibodies (PCA), and PCA and heat
      shock protein (HSP) antibody. METHODS: Fifty-five serum samples positive for PCA,
      22 males and 33 females (median age 61 years, range 29-108 years) were compared
      with 60 control samples negative for PCA, 24 males and 36 females (median age, 48
      years, range 11-91 years). H. pylori infection and HSP65K antibodies were
      determined by enzyme-linked immunosorbent assay. CagA and VacA status were
      determined by Western blotting. RESULTS: The prevalence of H. pylori was higher
      in PCA-positives than controls, 29/55 [53%, 95% confidence interval (CI) 39-66%]
      versus 13/60 (22%, 95% CI 12-34); P= 0.0009. Age was not a confounding factor.
      Odds ratio for PCA seropositivity if H. pylori-positive was 4.0 (1.79-9.07), P=
      0.003. There was an interaction between age and H. pylori, particularly in
      younger patients. CagA strains were less common in PCA-positives than controls,
      10/29 (35%, 95% CI 19-54) versus 9/13 (69%, 39-91), P< 0.05. HSP65K antibodies
      were elevated in H. pylori infection but to a similar degree for both PCA
      positives and controls. CONCLUSION: H. pylori, particularly CagA-negative
      strains, are associated with autoimmune gastritis and may be implicated in the
      pathogenesis of autoimmune (type A) gastritis, particularly in younger persons.

PMID- 10654797
TI  - Antral gastric permeability to antigens in mice is altered by infection with
      Helicobacter felis.
AB  - OBJECTIVE: Gastric inflammation is observed not only during Helicobacter pylori
      infection but also after eradication of the bacterium. The hypothesis that an
      altered gastric permeability could be involved was tested using a model of mice
      infected with Helicobacter felis. DESIGN: The antral and corpus gastric
      permeability during infection and after eradication of bacteria was studied.
      METHODS: Gastric fragments from the antrum and corpus of healthy mice, mice
      infected with H. felis, or mice after bacterial eradication, were mounted in
      Ussing chambers, and fluxes of sodium (JNa), mannitol (JMan) and horseradish
      peroxidase (HRP) under intact (JHRPi) and degraded (JD) form were measured.
      RESULTS: In healthy mice, JNa, JMan, JHRPi and JD, respectively, were greater in
      the antrum (6.5 +/- 0.5 microEq/h.cm2; 0.137 +/- 0.016 micromol/h.cm2; 30.4 +/-
      7.4 ng/h.cm2 and 852 +/- 173 ng/h.cm2) than in the corpus (5.0 +/- 0.3
      microEq/h.cm2; 0.085 micro 0.013 micromol/h.cm2; 9.5 +/- 2.8 ng/h.cm2 and 434 +/-
      139 ng/h.cm2). In H. felis-infected mice, HRP fluxes in the antrum were increased
      (JHRPi = 182 +/- 86, JD = 948 +/- 94 ng/h.cm2) as compared to controls (JHRPi =
      10.3 +/- 2.6, JD = 458 +/- 98 ng/h.cm2). Bacterial eradication led to the
      reduction of intact (JHRPi = 53 +/- 26 ng/h.cm) but not of degraded (JD = 844 +/-
      213 ng/h.cm) HRP fluxes. After eradication, degraded HRP fluxes returned to
      normal in mice without inflammation (JD = 558 +/- 36 ng/h.cm2) but not in those
      with persistent inflammation (JD = 987 +/- 310 ng/h.cm2). CONCLUSIONS: The
      results suggest that during H. felis infection, bacterial colonization and
      inflammation lead to an increased gastric permeability along the direct and
      degradative pathways, respectively. Such an increased antigenic load could
      contribute to the perpetuation of gastric inflammation after bacterial
      eradication, and possibly to food protein sensitization.

PMID- 10654798
TI  - Night-time quiescence and morning activation in the human colon: effect on
      transit of dispersed and large single unit formulations.
AB  - OBJECTIVES: Controlling the delivery of drugs to different regions of the colon
      remains an elusive goal. The aim of this study was to define the diurnal
      variation in colonic transit and show how this influences the colonic
      distribution and residence time of different formulations given either in the
      morning or evening. METHODS: Colonic transit of small particulates and a large
      capsule was measured during nocturnal sleep and daytime wakefulness. Eighteen
      healthy volunteers participated in a randomised crossover study. 111In-labelled
      resin (150-300 microm) and a large 99mTc-labelled non-disintegrating capsule (22
      x 8 mm) were swallowed at either 0800h or 1700h. MAIN OUTCOME MEASURES: The
      geometric centre of isotope (range 1-9) was calculated from serial scintiscans
      allowing comparison of overnight and daytime transit. RESULTS: Transit of resin
      was delayed in the overnight compared to daytime 8 h periods (change in geometric
      centres (GCs), mean +/- SEM, 0.59 +/- 0.14 vs 1.46 +/- 0.39 respectively, P <
      0.02). Maximal resin movement occurred immediately after awakening, prior to
      breakfast, in 9/18 studies (P < 0.05). The capsule was more distal than the resin
      at the end of the study 15 h after dosing (P < 0.001). There was marked inter
      individual variability in distribution of both resin and capsule at 15 h, the
      range of GCs being 2.8-9 and 2.2-9, respectively. CONCLUSION: Sleep delays
      colonic transit and large capsules travel faster than dispersed small particles.
      However, substantial inter-individual variability in transit makes targeting
      specific regions of the human colon unreliable with either dispersed or single
      unit formulations.

PMID- 10654799
TI  - Clinical utility of simultaneous measurement of serum high-sensitivity des-gamma
      carboxy prothrombin and Lens culinaris agglutinin A-reactive alpha-fetoprotein in
      patients with small hepatocellular carcinoma.
AB  - OBJECTIVE: To evaluate the diagnostic efficacy of simultaneous measurements of
      high-sensitivity des-gamma-carboxy prothrombin (H-DCP) and Lens culinaris
      agglutinin A-reactive alpha-fetoprotein (AFP-L3) in small hepatocellular
      carcinoma (HCC). METHODS: Sixty-one patients with small HCCs < or = 2 cm in
      diameter and 134 controls (chronic hepatitis: 59 cases; cirrhosis: 75 cases) were
      examined. H-DCP was measured by electrochemiluminescence immunoassay (cut-off 40
      mAU/ml (milli-arbitrary units/ml) and AFP-L3% (percentage of AFP-L3/total AFP) by
      lectin-affinity electrophoresis coupled with the antibody-affinity blotting
      method (cut-off 10%). Fifty-six patients were histologically diagnosed and the
      remaining five patients were diagnosed clinically. RESULTS: Of 61 patients, 27
      (44.3%) were positive for H-DCP and 14 (23.0%) were positive for AFP-L3. There
      was no correlation between H-DCP and AFP-L3%. Nineteen patients (31.1%) had
      positive H-DCP alone. Six patients (9.8%) had positive AFP-L3 alone, and in eight
      patients (13.1%) both markers were positive. In combination assay, 33 of 61
      patients (54.1%) were positive for either marker; specificity and accuracy were
      97.8% and 84.1%, respectively. There was a tendency for the AFP-L3% to be
      elevated in patients with moderately or poorly differentiated HCC (P= 0.0564) and
      multiple HCC nodules (P= 0.0316), while the H-DCP showed no elevation related to
      the tumour type. CONCLUSION: The detection rate of small HCC was improved by
      combination assay with H-DCP and AFP-L3%. Our results indicate that the markers
      are complementary and useful for the diagnosis and evaluation of small HCC when
      measured simultaneously.

PMID- 10654800
TI  - The role of cAMP-MAPK signalling in the regulation of human hepatocellular
      carcinoma growth in vitro.
AB  - OBJECTIVE: We have previously identified that primary human hepatocellular
      carcinoma (HCC) is associated with altered guanine nucleotide regulatory protein
      (G-protein) expression concomitant with decreased adenylyl cyclase (AC) and
      increased mitogen activated protein kinase (MAPK) activity in vivo. This study
      aims to address the potential link between Gs protein regulation of AC activity/
      cyclic adenosine monophosphate (cAMP) production and the subsequent downstream
      regulation of MAPK activity and mitogenesis. DESIGN: Pharmacological agents which
      selectively interact with specific target proteins involved in signal
      transduction via the Gs-AC-cAMP-MAPK signalling pathway were employed in cultured
      human HCC cell lines in these studies. These agents allow us to address the role
      of individual components of these pathways in the regulation of mitogenesis in
      HCC. METHODS: These studies utilized three distinct human HCC cell lines (HepG2,
      Hep3B and SKHep) in the absence and presence of agents that alter AC-cAMP
      dependent signalling. De novo DNA synthesis was determined as a marker of altered
      cellular proliferation, and MAPK activity was determined as the ability to
      catalyse myelin basic protein (MBP) phosphorylation. RESULTS: 8-Bromo-cAMP (8-Br
      cAMP; a cell-permeable cAMP analogue) and forskolin (AC activator) dose
      dependently decreased thymidine incorporation in all three cell lines. In
      addition, serum-stimulated [3H] thymidine incorporation was significantly
      decreased in HepG2, Hep3B and SKHep cell lines following treatment with either 8
      Br-cAMP or forskolin. By contrast, MDL12330A (MDL; irreversible AC inhibitor)
      enhanced thymidine incorporation in all three cell lines. Treatment with either 8
      Br-cAMP or forskolin significantly decreased serum-stimulated MAPK activity.
      CONCLUSIONS: These data suggest that cAMP acts as an anti-mitogenic agent in
      these hepatic tumorigenic cell lines in vitro such that inhibition of AC activity
      promotes MAPK activity and cellular mitogenesis in HCC.

PMID- 10654801
TI  - The incidence and characteristics of some paraneoplastic syndromes of
      hepatocellular carcinoma in Nigerian patients.
AB  - OBJECTIVE: To determine whether paraneoplastic syndromes of hepatocellular
      carcinoma such as erythrocytosis, hypoglycaemia, hypercholesterolaemia and
      hypercalcaemia are found in Nigerian patients with this tumour, and, if present,
      to determine their incidence and characteristics. DESIGN: Consecutive patients
      with a diagnosis of hepatocellular carcinoma seen over a 10-year period at Ile
      Ife, Nigeria, underwent haematocrit (100 patients), plasma glucose (65),
      cholesterol (65) and calcium studies (30). Shortage of laboratory reagents did
      not allow all the 100 patients to be tested for plasma glucose, cholesterol and
      calcium. METHODS: Haematocrit was determined by the microhaematocrit method, and
      the glucose oxidase-peroxidase, Liebermann-Burchard and O-cresolphthalein
      complexone methods were employed for the estimation of plasma glucose,
      cholesterol and calcium respectively. RESULTS: The haematocrit values ranged from
      19 to 63% with a mean of 34.51% (SD 7.72). Only 1 out of 100 patients (1%) had
      erythrocytosis (haematocrit 63%). Sixty-five patients had their plasma glucose
      determined. The range of values for fasting plasma glucose (FPG) was 1-8.4 mmol/l
      with a mean of 4.3 (SD 1.6). Hypoglycaemia occurred in 18 patients (27.7%)(14
      males, 4 females). The mean liver span for patients with FPG > 5.0 mmol/l was
      16.87 cm (SD 3.03), while the value for those with FPG < 3.0 mmol/l was 22.0 cm
      (SD 6.14, P < 0.05). Plasma cholesterol was determined in 65 patients and the
      range of values was 2.1 -18.1 mmol/l with a mean of 5.65 (SD 2.42).
      Hypercholesterolaemia occurred in 16 patients (24.6%) (15 males, 1 female). The
      range of plasma calcium obtained in 30 patients was 1.6-3.15 mmol/l with a mean
      of 2.36 (SD 0.32). Three patients (10%) (all males) had hypercalcaemia.
      CONCLUSION: While erythrocytosis has a low incidence, hypoglycaemia and
      hypercholesterolaemia are important paraneoplastic syndromes of hepatocellular
      carcinoma in Nigerian patients. The study confirms that the larger the liver
      mass, the greater the tendency towards hypoglycaemia. Also, the paraneoplastic
      syndromes studied occurred predominantly in hepatocellular carcinomas with
      cirrhosis.

PMID- 10654802
TI  - In patients with cirrhosis, serum albumin determination should be carried out by
      immunonephelometry rather than by protein electrophoresis.
AB  - OBJECTIVE: Serum albumin is a key parameter for prognosis in cirrhosis. We
      compared levels of serum albumin determined by both protein electrophoresis and
      immunonephelometry, with special reference to the Child-Pugh classification.
      DESIGN AND METHODS: One hundred and thirty-one patients, including 39 with
      cirrhosis, were included prospectively during 2 months. The aetiology of
      cirrhosis was mainly alcoholism (67%) and hepatitis C virus (HCV) (18%). Serum
      albumin was determined simultaneously by electrophoresis (Hydrasys SEBIA
      following protein determination by the biuret reaction) and by immunonephelometry
      (BECKMAN Nephelometer). Values were compared by non-parametric tests. RESULTS:
      For the whole population, electrophoretic and immunonephelometric values
      correlated (p = 0.85; P < 0.0001), but electrophoresis significantly
      overestimated serum albumin by a median 1.6 g/l (P < 0.0001) with a large spread
      in values (range, -3.9 to 12.7). Median overestimation in cirrhosis was 2.6 g/l
      (P < 0.0001; range, -2.0 to 10.2) and 1.0 g/l (P < 0.0001; range, -3.9 to 12.7)
      in patients without cirrhosis (difference, P < 0.02). For 6/39 (15.4%) patients
      with cirrhosis, this overestimation led to an underestimation in the Child-Pugh
      classification. CONCLUSION: In our experience, electrophoresis can lead to serum
      albumin values which are significantly different compared to those obtained by
      immunonephelometry. This discrepancy may lead to an incorrect Child-Pugh
      classification. Therefore, in the follow-up of cirrhotic patients, serum albumin
      should be determined by immunonephelometry.

PMID- 10654803
TI  - Endoscopic resection of two granular cell tumours of the oesophagus.
AB  - Granular cell tumour of the oesophagus is rare and usually single. It is
      diagnosed by endoscopic appearance, results of endosonography, and histological
      examination of biopsy specimens. Although histological examination is required
      for diagnosis, it is difficult occasionally to obtain tumour samples by forceps
      because granular cell tumour is usually located in the submucosal layer. We
      report the case of a Japanese man with two granular cell tumours of the
      oesophagus. One lesion was diagnosed as a granular cell tumour by histological
      examination of a biopsy specimen, but the other was not. Endoscopic resection was
      performed to obtain the diagnosis and treat the lesions since some granular cell
      tumours are potentially malignant. Both tumours were completely resected
      endoscopically, and the diagnosis of granular cell tumour could be established by
      histological examination of resected tissue. Endoscopic resection is thus useful
      in the diagnosis and treatment of granular cell tumour of the oesophagus.

PMID- 10654804
TI  - A particularly aggressive combined glucagonoma and gastrinoma syndrome.
AB  - Duodeno-pancreatic biochemically polyfunctional endocrine tumour is a well known
      entity. Usually, only one hormone is responsible for the clinical features. We
      report a case of aggressive combined glucagonoma and gastrinoma tumour without
      metastases, causing respectively diabetic ketoacidosis and fulminant peptic
      ulcer, and death. Occasional patients can present with clinical features of both
      glucagonoma and gastrinoma. Diabetic patients exhibiting migratory skin lesions
      should be suspected of glucagonoma. In addition, a multidisciplinary approach to
      such patients including dermatologists, surgeons, radiologists and endoscopists
      is mandatory.

PMID- 10654806
TI  - Post-surgical shunt hepatopulmonary syndrome in a case of non-cirrhotic portal
      hypertension: lack of efficacy of shunt reversal.
AB  - Hepatopulmonary syndrome, a consequence of significant liver disease and portal
      hypertension, is thought to be secondary to the effects of vasoactive substances,
      normally inactivated in the liver, on the pulmonary vasculature. We report a
      patient with preserved hepatic function who underwent a decompressive surgical
      porto-systemic shunt for non-cirrhotic portal hypertension. This patient
      developed hepatopulmonary syndrome with dyspnoea and oxygen desaturation 2 years
      post-surgical shunt. Over the next 7 years, the patient's respiratory function
      became increasingly impaired although hepatic function remained preserved.
      Because of the hypothesized role of porto-systemic shunting in the aetiology of
      this syndrome, the surgical shunt was successfully reversed angiographically. No
      improvement in dyspnoea or oxygen saturation occurred and liver transplantation
      was undertaken. Six months post-transplant, the patient has decreased his oxygen
      requirements and is free of dyspnoea. Our experience supports the causal role of
      porto-systemic shunting in the pathogenesis of hepatopulmonary syndrome but
      suggests that merely decreasing the extent of porto-systemic shunting is not
      beneficial. Liver transplantation remains the only reliable therapeutic modality
      available to these patients.

PMID- 10654805
TI  - Overlapping syndrome of autoimmune hepatitis and primary sclerosing cholangitis
      associated with pyoderma gangrenosum and ulcerative colitis.
AB  - We describe the case of a 18-year-old male patient who first presented with
      decompensated cirrhosis, fever and generalized lymphadenopathy. He had abnormal
      results for liver biochemical tests, with a hepatitic-like picture and high titre
      of antinuclear antibodies. According to the scoring system proposed by the
      International Autoimmune Hepatitis Group he had 'definite' autoimmune hepatitis
      and responded well to immunosuppressive treatment. One year later he developed
      pyoderma gangrenosum which was successfully treated with cyclosporine. Two years
      later he experienced bloody diarrhoea as a first presentation of ulcerative
      colitis. At that time both the cholestatic biochemical picture and the
      cholangiographic appearances of the biliary tree were consistent with primary
      sclerosing cholangitis. Despite the addition of azathioprine and ursodeoxycholic
      acid to his treatment regime he developed recurrent episodes of cholangitis and
      intractable pruritus for which he underwent successful liver transplantation.

PMID- 10654807
TI  - Cholecystostomy: an unusual approach to stenting of a distal common bile duct
      stricture.
AB  - Strictures, both benign and malignant, of the distal common bile duct (CBD) are
      reasonably common, and if stented are usually approached endoscopically via the
      duodenum, or transhepatically via an intrahepatic and then common hepatic duct.
      We describe a case of endoscopic stenting of a distal CBD stricture over a wire
      passed percutaneously through the gallbladder, cystic duct and into the duodenum.
      To our knowledge, this has not been previously described.

PMID- 10654808
TI  - Oesophageal ulceration associated with ingestion of mefenamic acid capsules.

PMID- 10654809
TI  - Internet developments and their significance for healthcare.
AB  - This paper reviews some recent developments in the technology of the Internet,
      and shows how they may affect the way in which healthcare is provided. Starting
      with a brief technical history of the Internet, the paper discusses some of the
      technical developments that have taken place or been proposed in recent years,
      and speculates on the realities of their adoption within the next five years. The
      paper also discusses trends in public accessibility to the Internet and the
      development of Internet services. Finally, the impact of the technological
      developments on the way in which new healthcare services may be provided is
      discussed. Our conclusions are that the growth rate in Internet access and the
      improvements in performance resulting from the new technologies will make the
      Internet the focus of many new healthcare developments, in particular in the
      areas of telemedicine and in communication between patient and healthcare
      professionals. Increasingly, the Internet will be used to convey more 'real-time'
      information.

PMID- 10654810
TI  - Beyond the Ingelfinger Rule: the intellectual property ethics after the end of
      biomedical journals' monopoly.
AB  - According to the so-called Ingelfinger Rule (IR), biomedical journals do not
      accept for publication papers which have already been publicized elsewhere. This
      rule was subjected to fierce criticism which was mainly based on the fact that
      authors transfer the intellectual rights of their work to the journals. With the
      emergence of the Internet, the scientific community has a golden opportunity to
      re-evaluate the IR concept. Scientists no longer have to depend on the debatable
      benefits (i.e. publicity and review) stemming from journal publications; rather
      they can be free to explore novel communication opportunities and, subsequently,
      to tackle the emerging intellectual property issues. This approach should take
      into account the tight bond between applied research and the world economy, the
      need for teamwork instead of individual effort for effective scientific research,
      and the added value of journal publications. Based on such an analysis, it would
      appear that the inherent characteristics of the Internet promote a re-assessment
      of the intellectual property theory on three levels: the cognitive (the way in
      which knowledge is made up from its building blocks), the morphological (the use
      of hypertext) and finally the sociological (the formation of virtual scientific
      communities). It is concluded that publishing on the Internet necessitates a
      different approach to the question of intellectual property based on the primal
      values of science. This can be achieved only if the scientific community embraces
      and nourishes the academic nature of the Internet as well as laying down the
      rules to control the dissemination of ideas without the intervention of non
      scientific third parties.

PMID- 10654811
TI  - Rx medication information for the public and the WWW: quality issues.
AB  - Misuse of prescription medications is a serious problem largely due to lack of
      information. Lay users are making use of resources available on the World Wide
      Web in order to bridge this information gap. It has already been noted though
      that health and medicine oriented sites present serious shortcomings with regard
      to quality and reliability of their content. In this review, checklists were used
      to determine to which extent the criteria suggested for quality evaluation of on
      line health information are observed by sites offering information on Rx
      medications to the public. Also evaluated was the sites' comprehensiveness in
      coverage of important subject specific topics. The reviewed sites met
      inadequately the proposed quality criteria and presented significant variations
      in their coverage of the subject. Evaluation of information accuracy remains an
      unresolved problem in quality assessment, while techniques for automated review
      and retrieval are urgently needed. In the meantime, though, quality guidelines
      could prove more useful in getting valuable feedback from information providers
      and lay users alike, improving quality of information at its point of production.

PMID- 10654812
TI  - Internet agents for telemedicine services.
AB  - Telemedicine can be defined as telematic support of collaboration between distant
      medical professionals, co-operating on shared resources of various kinds.
      Attention should be paid to telematics and informatics concepts, especially those
      oriented towards collaboration. In particular, the recent agent paradigm seems
      suitable for the analysis, design and development of telemedicine services
      because of its commitment to intercommunication and sharing of resources. The
      present paper is an introduction to the agent paradigm from its theoretical basis
      to the technological issues, and describes an agent-based approach to
      telemedicine, specifically applied to telepathology applications. The system is
      based on an agent-based model and template (JAMES) using Java, which has been
      used to implement a prototype multipurpose telepathology application based on a
      federated agency architecture.

PMID- 10654814
TI  - A retrieval system for the selection and statistical analysis of clinical data.
AB  - Within the last years computer-aided clinical documentation has provided
      researchers and administrators with very large volumes of data for research. User
      friendly retrieval tools are needed when processing these clinical databases.
      Clinical researchers require applications by means of which steps in selection
      and analysis can be performed in an iterative process. During the deduction of
      statistical parameters from routinely collected data a number of problems occur
      that do not appear in the analysis of data gathered within clinical studies.
      Unlike clinical studies, routine data have complex structures and must first be
      formatted and above all temporally synchronized. In this paper we will describe
      the medical retrieval system ArchiMed developed at the Vienna General Hospital. A
      main objective in the design of this system was to support a joint evaluation of
      data from clinical studies and routinely collected data. The retrieval system
      comprises the main functions: Selection of Patients; Selection and Joining of
      Variables; and Statistical Analysis.

PMID- 10654813
TI  - The virtual mole clinic: preliminary results from the Plymouth skin cancer
      screening study using telemedicine.
AB  - This study evaluated a skin cancer screening service between primary and
      secondary care in Plymouth using a store and forward telemedicine system. The
      primary objective was to minimize the time from a patient presenting to a GP with
      a suspicious lesion to the lesion being assessed and diagnosed by a plastic
      surgeon. This study retrospectively assessed the practical, technical and
      operational aspects of incorporating telemedicine into everyday practice and
      patient satisfaction. Both the GP practice and plastic surgeons were equipped
      with the appropriate technology for creating, transmitting and accessing an
      electronic telemedicine record (ETR) via an ISDN 2 line. Patients with suspicious
      lesions accessed the GP via Mole Check Clinics. The GP captured and transmitted
      an ETR consisting of digital images and relevant clinical data. In a virtual mole
      clinic, the plastic surgeon accessed and reviewed the ETR. The expert opinion was
      entered directly into the ETR and transmitted to the GP within 48 hours. All
      patients were offered a face-to-face consultation at a real mole clinic within 7
      days. Outcomes demonstrated patient and clinician satisfaction and the ability to
      deliver high quality diagnostic images and resulting expert opinion. This study
      informed a larger study for future applications of telemedicine.

PMID- 10654815
TI  - Using intelligent search for finding medical sites.
AB  - In this paper we present an intelligent search tool, which we developed in order
      to automate search and evaluation of websites. We used TFIDF heuristics to
      determine term frequency and decision trees to evaluate the quality of sites.
      Training set for the decision tree contained manually evaluated websites. Each
      website was described by the combination of various attributes, complexity
      metrics and the evaluation. The intelligent search tool is equipped with a user
      friendly interface, which enables people to exploit the tool to its limits with
      minimum effort, in their quest for information. For testing purposes, we looked
      for sites with telemedical content. The set of sites, which was the result of
      using the intelligent search tool, has been evaluated by a group of students.

PMID- 10654816
TI  - The role of electronic journals in reducing publication bias.
AB  - Publication bias poses a threat to the validity of medical research. It is
      unlikely that conventional paper journals can solve the problem of selective
      publication of studies with striking results because of their space limitation
      and need to be newsworthy. Peer-reviewed electronic journals without limitation
      of space might provide a solution to this paradox. To maintain the integrity of
      medical publication, editorial policy needs to be changed to accept clinical
      trials for publication, based only on the methodological criteria and not on the
      impact of their findings.

PMID- 10654817
TI  - Insulin-like growth factor I treatment for end-stage renal disease at the end of
      the millennium.

PMID- 10654818
TI  - Clinical use of growth factors in chronic renal failure.
AB  - Erythropoietin has been demonstrated to improve the quality of life in patients
      with chronic renal failure, and growth hormone has been approved for use in
      children with chronic renal failure and short stature as a growth promoting
      agent. Growth factors also have great therapeutic potential to improve glomerular
      function in the setting of chronic renal failure. Further studies are required to
      delineate the role of insulin-like growth factor I in the setting of end-stage
      chronic renal failure.

PMID- 10654819
TI  - The role of osteoprogenitors in vascular calcification.
AB  - Calcification is a component of vascular disease that usually occurs in concert
      with atheroma formation but through distinct pathophysiological processes. Vessel
      wall osteoprogenitor cells known as calcifying vascular cells can form bone
      matrix proteins and calcified nodules, analogous to osteoblastic differentiation
      in bone. These cells have been isolated from the tunica media of bovine and human
      arteries, and both in-vitro tissue culture models and mouse models of vascular
      calcification have been established. Studies of the effects of diabetes mellitus,
      hyperlipidemia, estrogens and glucocorticoids on calcifying vascular cell
      function provide insight into the relationship between common human disease
      states and vascular calcification.

PMID- 10654820
TI  - Expression of 25-hydroxyvitamin D3-1alpha-hydroxylase along the nephron: new
      insights into renal vitamin D metabolism.
AB  - Renal synthesis of the active form of vitamin D, 1,25-dihydroxyvitamin D3
      [1,25(OH)2D3], is a pivotal step in calcium and phosphate homeostasis. Production
      of 1,25(OH)2D3 is catalyzed by the mitchondrial cytochrome P450, 25
      hydroxyvitamin D3-1alpha-hydroxylase (1alpha-HYD). As a consequence of the tight
      regulation of vitamin D metabolism during normal physiology, studies of the
      expression and regulation of 1alpha-HYD have proved remarkably difficult.
      However, the recent cloning of the gene for 1alpha-HYD has enabled a more
      comprehensive analysis of the tissue distribution of 1alpha-HYD, as well as the
      mechanisms involved in controlling 1,25(OH)2D3 production. In particular, an
      understanding of site-specific expression and regulation of 1alpha-HYD along the
      nephron might help to elucidate a more versatile role for 1,25(OH)2D3 in renal
      physiology.

PMID- 10654821
TI  - Prostaglandin receptors: their role in regulating renal function.
AB  - Renal cyclooxygenase-1 and cyclooxygenase-2 actively metabolize arachidonate to
      metabolism five primary prostanoids: prostaglandin E2, prostaglandin F2a,
      prostaglandin I2, thromboxane A2, and prostaglandin D2. These lipid mediators
      interact with a family of distinct G-protein-coupled prostanoid receptors
      designated EP, FP, IP, TP, and DP, respectively, which exert important regulatory
      effects on renal function. The intrarenal distribution of these prostanoid
      receptors has been mapped and the consequences their activation are being
      characterized. The FP, TP, and EP1 receptors preferentially couple to increased
      cell Ca2+. EP2, EP4, DP, and IP receptors stimulate cyclic adenosine
      monophosphate, whereas the EP3 receptor preferentially couples to Gi, inhibiting
      cyclic adenosine monophosphate generation. EP1 and EP3 messenger RNA expression
      predominate in the collecting duct and thick limb, respectively, where their
      stimulation reduces sodium chloride and water absorption, promoting natriuresis
      and diuresis. Interestingly, only a mild change in renal water handling is seen
      in the EP3 receptor knockout mouse. Although only low levels EP2 receptor
      messenger RNA are detected in kidney and its precise intrarenal localization is
      uncertain, mice with targeted disruption of the EP2 receptor display salt
      sensitive hypertension, suggesting it also plays an important role in salt
      excretion. In contrast, EP4 messenger RNA is readily detected in the glomerulus
      where it may contribute to the regulation of renin release and decrease
      glomerular resistance. TP receptors are also highly expressed in the glomerulus,
      where they may increase glomerular vascular resistance. The IP receptor messenger
      RNA is most highly expressed in the afferent arteriole and it may also modulate
      renal arterial resistance and renin release. At present there is little evidence
      for DP receptor expression in the kidney. Together these receptors act as
      physiologic buffers that protect the kidney from excessive functional changes
      during periods of physiologic stress. Loss of the combined effects of these
      receptors contributes to the side effects seen in the setting of nonsteroidal
      anti-inflammatory drug administration, whereas selective antagonists for these
      receptors may provide new therapeutic approaches in disease.

PMID- 10654822
TI  - Endothelin and renal vascular fibrosis: of mice and men.
AB  - The present review focuses on recent data regarding the role of endothelin as a
      mediator of renal vascular fibrosis. Following a brief description of the
      endothelin system, the question of whether endothelin is involved in hypertensive
      mechanisms is examined in experimental, genetic and transgenic animal models.
      Evidence is provided that implicates endothelin as an important factor of the
      development of tissue fibrosis and end-organ damage associated with hypertension,
      with particular emphasis on renal vascular fibrosis. Data indicating that
      endothelin interacts with other vasoconstrictor systems, such as angiotensin II,
      are also considered. Finally, results from preliminary clinical studies using
      endothelin receptor antagonists to treat cardiac and renal pathologies are
      briefly discussed.

PMID- 10654823
TI  - The role of homeobox genes in kidney development.
AB  - Homeodomain-containing transcription factors are essential for a variety of
      processes in vertebrate development, including organogenesis. They have been
      shown to regulate cell proliferation, pattern segmental identity and determine
      cell fate decisions during embryogenesis. During nephrogenesis, homeobox genes
      play an important role at multiple developmental stages, from the early events in
      intermediate mesoderm to terminal differentiation of glomerular and tubular
      epithelia. Increasingly sophisticated genetic approaches will probably reveal
      additional functions for this class of transcription factors in the developing
      kidney and lead to the identification of critical downstream target genes.

PMID- 10654824
TI  - Modelling the effects of vascular stress in mesangial cells.
AB  - It has recently been shown that mesangial cells are subjected to multiple forms
      of mechanical strain (fluid shear, hydrostatic pressure, and triaxial stretch) as
      a result of forces exerted by the vasculature. Nevertheless, the exact nature and
      the relative response to these stimuli have not been clarified. Although it is
      now well established that cyclic stretching of mesangial cells in culture results
      in the overproduction of extracellular matrix, indicating how intraglomerular
      hypertension may lead to glomerular scar formation, the contribution of different
      intracellular signalling mechanisms and extracellular mediators of the response
      are only now being identified. Recent studies point to a role for high glucose
      concentrations, transforming growth factor beta and its receptors, vascular
      endothelial growth factor, and connective tissue growth factor as important
      mediators, or modifiers of the response to mechanical strain. Although evidence
      exists for a role for protein kinase C, recent studies also implicate the mitogen
      activated protein kinases along with enhanced DNA-binding activity of AP-1 as
      part of the signalling cascade altering matrix synthesis and cell proliferation
      in response to stretch. Finally, recent studies examining the effects of
      oscillating hyperbaric pressure demonstrate similarities, as well as differences,
      in comparison to those of cyclic stretch.

PMID- 10654825
TI  - Stress-responsive signal transduction mechanisms in glomerular cells.
AB  - Mechanical stresses appear to play a key role in the progression of glomerular
      diseases that are characterized by increased transcapillary hydraulic pressure.
      Glomerular mesangial cells proliferate and produce extracellular matrix proteins
      in vivo in such diseases. Mesangial cell responses to pulsatile mechanical
      stimuli have been studied extensively in vitro during the past few years.
      Mechanical signals are sensed at the cell membrane and propagated through the
      cytoplasm, and result in the activation of transcription factors that elicit
      production of prosclerotic cytokines and matrix proteins, and cell proliferation.
      Endothelial cells are exposed to shear and pulsatile stress and show some similar
      responses in other vascular beds.

PMID- 10654826
TI  - The antihypertensive and renal effects of angiotensin II receptor antagonists:
      remaining questions.

PMID- 10654827
TI  - Bibliography. Current world literature. Hormones, autacoids, neurotransmitters
      and growth factors.

PMID- 10654828
TI  - Bibliography. Current world literature. Circulation and hemodynamics.

PMID- 10654829
TI  - Identifying and assessing the null hypothesis.

PMID- 10654830
TI  - The Behavioral Model for Vulnerable Populations: application to medical care use
      and outcomes for homeless people.
AB  - OBJECTIVES: (1) To present the Behavioral Model for Vulnerable Populations, a
      major revision of a leading model of access to care that is particularly
      applicable to vulnerable populations; and (2) to test the model in a prospective
      study designed to define and determine predictors of the course of health
      services utilization and physical health outcomes within one vulnerable
      population: homeless adults. We paid particular attention to the effects of
      mental health, substance use, residential history, competing needs, and
      victimization. METHODS: A community-based probability sample of 363 homeless
      individuals was interviewed and examined for four study conditions (high blood
      pressure, functional vision impairment, skin/leg/foot problems, and tuberculosis
      skin test positivity). Persons with at least one study condition were followed
      longitudinally for up to eight months. PRINCIPAL FINDINGS: Homeless adults had
      high rates of functional vision impairment (37 percent), skin/leg/foot problems
      (36 percent), and TB skin test positivity (31 percent), but a rate of high blood
      pressure similar to that of the general population (14 percent). Utilization was
      high for high blood pressure (81 percent) and TB skin test positivity (78
      percent), but lower for vision impairment (33 percent) and skin/leg/foot problems
      (44 percent). Health status for high blood pressure, vision impairment, and
      skin/leg/foot problems improved over time. In general, more severe homeless
      status, mental health problems, and substance abuse did not deter homeless
      individuals from obtaining care. Better health outcomes were predicted by a
      variety of variables, most notably having a community clinic or private physician
      as a regular source of care. Generally, use of currently available services did
      not affect health outcomes. CONCLUSIONS: Homeless persons are willing to obtain
      care if they believe it is important. Our findings suggest that case
      identification and referral for physical health care can be successfully
      accomplished among homeless persons and can occur concurrently with successful
      efforts to help them find permanent housing, alleviate their mental illness, and
      abstain from substance abuse.

PMID- 10654831
TI  - Healthcare use by homeless persons: implications for public policy.

PMID- 10654832
TI  - Rigor at the expense of relevance equals rigidity: where to next in the study of
      medical care utilization?

PMID- 10654833
TI  - The impact of utilization management on readmissions among patients with
      cardiovascular disease.
AB  - OBJECTIVE: To determine if prospective utilization reviews that lead to reduced
      hospital length of stay (LOS) relative to days requested by an attending
      physician affect the likelihood of readmission for privately insured patients
      with cardiovascular disease. DATA SOURCES: Data obtained from a private insurance
      company on utilization management decisions from 1989 through 1993. During this
      five-year period, 39,117 inpatient reviews were conducted, 4,326 (11.1 percent)
      on patients with cardiovascular disease. We selected for analysis all 4,326
      reviews performed on patients with cardiovascular disease. STUDY DESIGN: We used
      proportional hazard analysis (Cox regression) to investigate the relationship
      between LOS reductions relative to days requested by a patient's attending
      physician and the likelihood of readmission within 60 days of discharge. Separate
      analyses were performed for medical and procedural admissions. PRINCIPAL
      FINDINGS: There were 2,813 requests for medical admission, and 1,513 requests for
      procedural admission. Requests for admission were rarely denied. Length of stay
      was reduced relative to that requested by the treating physician for 17 percent
      and 19 percent of medical and procedural admissions, respectively. Cumulative 60
      day readmission rates were 9.5 percent for medical admissions and 12.3 percent
      for procedural admissions. We found no relationship between LOS reduction and the
      likelihood of readmission for medical admissions. However, patients admitted for
      procedures who had their length of stay reduced by two or more days were 2.6
      times as likely to be readmitted within 60 days as those who had no reduction in
      their length of stay (95% CI: 1.3-5.1; p < .005). CONCLUSIONS: Utilization
      management (UM) rarely denies requests for inpatient treatment of cardiovascular
      disease. The association between LOS reduction and the likelihood of readmission
      for patients admitted for cardiovascular procedures raises concern that UM may
      adversely affect clinical outcome for some patients. Further research is needed
      to definitively elucidate any relationship that might exist between utilization
      review decisions and quality of care.

PMID- 10654834
TI  - The direct and indirect effects of cost-sharing on the use of preventive
      services.
AB  - OBJECTIVE: To test empirically a model for estimating the direct and indirect
      effects of different forms of cost-sharing on the utilization of recommended
      clinical preventive services. DATA SOURCES/SETTINGS: Stratified random sample of
      10,872 employees, 18-64 years, who had belonged to their plan for at least one
      year, from seven large companies that were members of the Pacific Business Group
      on Health (PBGH) in 1994. DATA COLLECTION: The 1994 PBGH Health Plan Value Check
      Survey. 1994 PBGH data on requirements for employee out-of-pocket patient cost
      sharing for 52 different health plans. DESIGN: Five equations were derived to
      estimate the direct and indirect effects of two forms of cost-sharing (copayments
      and coinsurance/deductibles) in two forms of managed care (HMOs and PPO/indemnity
      plans) on four clinical preventive services: mammography screening, cervical
      cancer screening, blood pressure screening, and preventive counseling. Probit
      models were used to estimate elasticities for the indirect and direct effects.
      PRINCIPAL FINDINGS: Both forms of cost-sharing in both plan types had negative
      and significant indirect effects on preventive counseling (from -1 percent to -7
      percent). The direct effect of cost-sharing was negative for preventive
      counseling (-5 percent to -9 percent) and Pap smears (from -3 percent to -9
      percent) in both HMOs and PPOs, and for mammography only in PPOs (-3 percent to 
      9 percent). The results of the effects on blood pressure screening are
      inconclusive. CONCLUSIONS: Both the direct and indirect effects of cost-sharing
      negatively affected the receipt of preventive counseling in HMOs and PPOs. As
      predicted, the direct negative effect of cost-sharing was greater than the
      indirect effect for Pap smears and mammography. Eliminating cost-sharing for
      these services may be important to increasing their utilization to recommended
      levels.

PMID- 10654835
TI  - Associations among hospital capacity, utilization, and mortality of US Medicare
      beneficiaries, controlling for sociodemographic factors.
AB  - OBJECTIVE: To explore whether geographic variations in Medicare hospital
      utilization rates are due to differences in local hospital capacity, after
      controlling for socioeconomic status and disease burden, and to determine whether
      greater hospital capacity is associated with lower Medicare mortality rates. DATA
      SOURCES/STUDY SETTING: The study population: a 20 percent sample of 1989 Medicare
      enrollees. Measures of resources were based on a national small area analysis of
      313 Hospital Referral Regions (HRR). Demographic and socioeconomic data were
      obtained from the 1990 U.S. Census. Measures of local disease burden were
      developed using Medicare claims files. STUDY DESIGN: The study was a cross
      sectional analysis of the relationship between per capita measures of hospital
      resources in each region and hospital utilization and mortality rates among
      Medicare enrollees. Regression techniques were used to control for differences in
      sociodemographic characteristics and disease burden across areas. DATA
      COLLECTION/EXTRACTION METHODS: Data on the study population were obtained from
      Medicare enrollment (Denominator File) and hospital claims files (MedPAR) and
      U.S. Census files. PRINCIPAL FINDINGS: The per capita supply of hospital beds
      varied by more than twofold across U.S. regions. Residents of areas with more
      beds were up to 30 percent more likely to be hospitalized, controlling for
      ecologic measures of socioeconomic characteristics and disease burden. A greater
      proportion of the population was hospitalized at least once during the year in
      areas with more beds; death was also more likely to take place in an inpatient
      setting. All effects were consistent across racial and income groups. Residence
      in areas with greater levels of hospital resources was not associated with a
      decreased risk of death. CONCLUSIONS: Residence in areas of greater hospital
      capacity is associated with substantially increased use of the hospital, even
      after controlling for socioeconomic characteristics and illness burden. This
      increased use provides no detectable mortality benefit.

PMID- 10654837
TI  - Measuring hospital efficiency: a comparison of two approaches.
AB  - OBJECTIVE: To compare the results of scoring hospital efficiency by means of two
      new types of frontier models, Data Envelopment Analysis (DEA) and stochastic
      frontier regression (SFR). STUDY SETTING: Financial records of Florida acute care
      hospitals in continuous operation over the period 1982-1993. STUDY DESIGN:
      Comparable DEA and SFR models are specified, and these models are then estimated
      to obtain the efficiency indexes yielded by each. The empirical results are
      subsequently examined to ascertain the extent to which they serve the needs of
      hospital policymakers. DATA COLLECTION: A longitudinal or panel data set is
      assembled, and a common set of output, input, and cost indicators is constructed
      to support the estimation of comparable DEA and SFR models. PRINCIPAL FINDINGS:
      DEA and SFR models yield convergent evidence about hospital efficiency at the
      industry level, but divergent portraits of the individual characteristics of the
      most and least efficient facilities. CONCLUSIONS: Hospital policymakers should
      not be indifferent to the choice of the frontier model used to score efficiency
      relationships. They may be well advised to wait until additional research
      clarifies reasons why DEA and SFR models yield divergent results before they
      introduce these methods into the policy process.

PMID- 10654836
TI  - Does reengineering really work? An examination of the context and outcomes of
      hospital reengineering initiatives.
AB  - OBJECTIVE: To examine the effect of reengineering on the competitive position of
      hospitals. Although many promises have been made regarding outcomes of process
      reengineering, little or no research has examined this issue. This article
      provides an initial exploration of the direct effects of reengineering on the
      competitive cost position of hospitals and the modifying effects of
      implementation factors. DATA SOURCES/STUDY SETTING: Obtained for primary data
      from a 1996/1997 national survey of hospital restructuring and reengineering
      sponsored by the American Hospital Association and the Leonard Davis Institute
      for Health Economics. Responses from approximately 30 percent of all U.S. acute
      care hospitals with 100 or more inpatient beds in metropolitan service areas were
      combined with American Hospital Association annual survey and InterStudy HMO data
      in this study. STUDY DESIGN: A first-difference multivariate regression was
      utilized to examine the effects of reengineering and other explanatory variables
      on the change in the cost position of a hospital's expenses per adjusted patient
      day relative to its market's costs per adjusted patient day. DATA
      COLLECTION/EXTRACTION METHODS: The survey of hospital restructuring and
      reengineering was mailed to hospital chief executive officers. The CEOs
      identified reengineering and restructuring hospital activities over the previous
      five years. The extensiveness and components of reengineering and internal
      restructuring were identified and used in the empirical analysis. PRINCIPAL
      FINDINGS: Results suggest that reengineering without integrative and coordinative
      efforts may damage an organization's cost position. The use of steering
      committees, project teams, codification of the change process, and executive
      involvement in core changes modifies the results of reengineering to improve an
      organization's competitive position. CONCLUSIONS: In a national sample of
      hospitals, reengineering alone was not found to improve the relative cost
      competitive position. Organizations attempting to improve their cost
      competitiveness must consider the way in which change is implemented. This
      research suggests that the process of change may be as important as the change
      instrument. Additional research is needed to explore differences between early
      and late adopters.

PMID- 10654838
TI  - Relationships between alterations in glutathione metabolism and the disposition
      of inorganic mercury in rats: effects of biliary ligation and chemically induced
      modulation of glutathione status.
AB  - Influences of biliary ligation and systemic depletion of glutathione (GSH) or
      modulation of GSH status on the disposition of a low, non-nephrotoxic i.v. dose
      of inorganic mercury were evaluated in rats in the present study. Renal and
      hepatic disposition, and the urinary and fecal excretion, of inorganic mercury
      were assessed 24 h after the injection of a 0.5-micromol/kg dose of mercuric
      chloride in control rats and rats pretreated with acivicin (two 10-mg/kg i.p.
      doses in 2 ml/kg normal saline, 90 min apart, 60 min before mercuric chloride),
      buthionine sulfoximine (BSO; 2 mmol/kg i.v. in 4 ml/kg normal saline, 2 h before
      mercuric chloride) or diethylmaleate (DEM; 3.37 mmol/kg i.p. in 2 ml/kg corn oil,
      2 h before mercuric chloride) that either underwent or did not undergo acute
      biliary ligation prior to the injection of mercury. Among the groups that did not
      undergo biliary ligation, the pretreatments used to alter GSH status systemically
      had varying effects on the disposition of inorganic mercury in the kidneys,
      liver, and blood. Biliary ligation caused the net renal accumulation of mercury
      to decrease under all pretreatment conditions. By contrast, biliary ligation
      caused significant increases in the hepatic burden of mercury in all pretreatment
      groups except in theacivicin-pretreated group. Blood levels of mercury also
      increased as a result of biliary ligation, regardless of the type of pretreatment
      used. The present findings indicate that biliary ligation combined with methods
      used to modulate GSH status systemically have additive effects with respect to
      causing reductions in the net renal accumulation of mercury. Additionally, the
      findings indicate that at least some fraction of the renal accumulation of
      inorganic mercury is linked mechanistically to the hepato-biliary system.

PMID- 10654839
TI  - Inactivation of Coprinus cinereus peroxidase by 4-chloroaniline during turnover:
      comparison with horseradish peroxidase and bovine lactoperoxidase.
AB  - The peroxidase from Coprinus cinereus (CPX) catalyzed oxidative oligomerization
      of 4-chloroaniline (4-CA) forming several products: N-(4-chlorophenyl)
      benzoquinone monoamine (dimer D), 4,4'-dichloroazobenzene (dimer E); 2-(4
      chloroanilino)-N-(4-chlorophenyl)-benzoquinone (trimer F); 2-amino-5
      chlorobenzoquinone-di-4-chloroanil (trimer G); 2-(4-chloroanilino)-5
      hydroxybenzoquinone-di-4-chloroanil (tetramer H) and 2-amino-5-(-4-chlroanilino)
      benzoquinone-di-4-chloroanil (tetramer 1). In the presence of 4-CA and H2O2, CPX
      was irreversibly inactivated within 10 min. Inactivation of CPX in the presence
      of H2O2 was a time-dependent, first-order process when the concentration of 4-CA
      was varied between 0 and 2.5 mM. The apparent dissociation constant (Ki) for CPX
      and 4-CA was 0.71 mM. The pseudo-first order rate constant for inactivation
      (k(inact)), was 1.15 x 10(-2) s(-1). Covalent incorporation of 20 mole 14C-4-CA
      per mole of inactivated CPX was observed. The partition ratio was about 2200 when
      either 4-CA or H2O2 was used as the limiting substrate. These results show that 4
      CA is a metabolically activated inactivator (i.e. a suicide substrate).
      Unmodified heme and hydroxymethyl heme were isolated from native, 4-CA
      inactivated and H2O2-incubated CPX. Inactivation resulted in significant losses
      in both heme contents. Analysis of tryptic peptides from 4-CA-inactivated CPX by
      MALDI-TOF/ MS and UV-VIS spectrophotometry suggested that trimer G and tetramer H
      were the major 4-CA derivatives that were covalently bound, including to a
      peptide (MGDAGF-SPDEVVDLLAAHSLASQEGLNSAIFR) containing the heme binding site.
      These studies show that heme destruction and covalent modification of the
      polypeptide chain are both important for the inactivation of CPX. These results
      were compared with similar studies on 4-CA-inactivated horseradish peroxidase
      (HRP) and bovine lactoperoxidase (LPO) during the oxidation of 4-CA.

PMID- 10654840
TI  - Effect of inducers of DT-diaphorase on the toxicity of 2-methyl- and 2-hydroxy
      1,4-naphthoquinone to rats.
AB  - It has previously been shown that rats pre-treated with butylated hydroxyanisole
      (BHA), a well-known inducer of the enzyme DT-diaphorase, are protected against
      the toxic effects of 2-methyl-1,4-naphthoquinone but are made more susceptible to
      the harmful action of 2-hydroxy-1,4-naphthoquinone. In the present experiments,
      the effects of BHA have been compared with those of other inducers of DT
      diaphorase. Rats were dosed with BHA, butylated hydroxytoluene (BHT), ethoxyquin
      (EQ), dimethyl fumarate (DMF) or disulfiram (DIS) and then challenged with a
      toxic dose of the naphthoquinones. All the inducers protected against the
      haemolytic anaemia induced by 2-methyl-1,4-naphthoquinone in rats, with BHA, BHT
      and EQ being somewhat more effective than DMF and DIS. A similar order of
      activity was recorded in the relative ability of these substances to increase
      hepatic activities of DT-diaphorase, consistent with a role for this enzyme in
      facilitating conjugation and excretion of this naphthoquinone. In contrast, all
      the compounds increased the haemolytic activity of 2-hydroxy-1,4-naphthoquinone.
      DMF and DIS were significantly more effective in this regard than BHA, BHT and
      EQ. DMF and DIS also caused a much greater increase in levels of DT-diaphorase in
      the intestine, suggesting that 2-hydroxy-1,4-naphthoquinone is activated by this
      enzyme in the gut. BHA, BHT and EQ had no effect on the nephrotoxicity of 2
      hydroxy-1,4-naphthoquinone, but the severity of the renal lesions was decreased
      in rats pre-treated with DMF and DIS. The results of the present experiments show
      that modulation of tissue levels of DT-diaphorase may not only alter the severity
      of naphthoquinone toxicity in vivo, but may also change the relative toxicity of
      these substances to different target organs.

PMID- 10654841
TI  - Effect of pre-treatment with dichloroacetic or trichloroacetic acid in drinking
      water on the pharmacokinetics of a subsequent challenge dose in B6C3F1 mice.
AB  - Dichloroacetate (DCA) and trichloroacetate (TCA) are prominent by-products of
      chlorination of drinking water. Both chemicals have been shown to be hepatic
      carcinogens in mice. Prior work has demonstrated that DCA inhibits its own
      metabolism in rats and humans. This study focuses on the effect of prior
      administration of DCA or TCA in drinking water on the pharmacokinetics of a
      subsequent challenge dose of DCA or TCA in male B6C3F1 mice. Mice were provided
      with DCA or TCA in their drinking water at 2 g/l for 14 days and then challenged
      with a 100 mg/kg i.v. (non-labeled) or gavage (14C-labeled) dose of DCA or TCA.
      The challenge dose was administered after 16 h fasting and removal of the
      haloacetate pre-treatment. The haloacetate blood concentration-time profile and
      the disposition of 14C were characterized and compared with controls. The effect
      of pre-treatment on the in vitro metabolism of DCA in hepatic S9 was also
      evaluated. Pre-treatment with DCA caused a significant increase in the blood
      concentration-time profiles of the challenge dose of DCA. No effect on the blood
      concentration-time profile of DCA was observed after pre-treatment with TCA. Pre
      treatment with TCA had no effect on subsequent doses of DCA. Pre-treatment with
      DCA did not have a significant effect on the formation of 14CO2 from radiolabeled
      DCA. In vitro experiments with liver S9 from DCA-pre-treated mice demonstrated
      that DCA inhibits it own metabolism. These results indicate that DCA metabolism
      in mice is also susceptible to inhibition by prior treatment with DCA, however
      the impact on clearance is less marked in mice than in F344 rats. In contrast,
      the metabolism and pharmacokinetics of TCA is not affected by pre-treatment with
      either DCA or TCA.

PMID- 10654842
TI  - Effects of bogus feedback on intelligence test performance.
AB  - French-Canadian high school students (N = 196) completed different forms of the
      Wonderlic Personnel Test (WPT; E. F. Wonderlic, 1983) on two occasions. Before
      the second test, they received negative or positive bogus feedback about their
      initial performance. Most students (n = 158) were informed that the WPT measured
      intelligence, and the instruction was issued before either the first (n = 42) or
      the second test (n = 116). In the latter case, WPT validity either was not
      mentioned (n = 36) or was described as high or low (ns = 39 and 41,
      respectively). WPT performance improved on the second test, but it was not
      related to feedback in any of the instruction conditions. Reasons for these
      results and their practical implications are discussed.

PMID- 10654843
TI  - The role of self-esteem in affiliation.
AB  - The role of self-esteem in a person's decision to initially affiliate with
      someone and subsequently maintain that affiliation was examined. A sample of 221
      pairs of participants ("observers" and their "affiliates") were administered the
      Rosenberg Self-Esteem Scale (M. Rosenberg, 1979), the Social Desirability Scale
      (D. Crowne & D. Marlowe, 1964), and a general interest questionnaire. The
      observers and most of their affiliates were undergraduate students enrolled at a
      southwestern U.S. university. Both at initial contact and during maintained
      affiliation, the observers with high self-esteem scores tended to affiliate with
      persons who scored significantly lower on self-esteem, and observers with low
      self-esteem scores tended to affiliate with persons who scored significantly
      higher on self-esteem. The authors concluded that a person's level of self-esteem
      may play an important role in his or her choices of affiliates.

PMID- 10654844
TI  - Perception of parental acceptance in women with binge eating disorder.
AB  - The authors contribute to the validating literature for binge eating disorder
      (BED) by examining perceptions of parents and satisfaction with life among obese
      women with and without BED. Participants were female patients, recruited through
      a private medical clinic, who were assigned to groups on the basis of body mass
      index (BMI) and scores on the Questionnaire on Eating and Weight Patterns (QEWP;
      R. L. Spitzer et al., 1992). Groups consisted of (a) obese women with BED (n =
      32), (b) obese women who had no eating disorders (n = 51), and (c) nonobese women
      with no eating disorders (n = 30). All participants completed the Parental
      Acceptance/Rejection Questionnaire (PARQ; R. P. Rohner, 1986), the Satisfaction
      with Life Scale (SWLS; J. Fischer & K. Corcoran, 1994), and the Beck Depression
      Inventory (BDI; A. T. Beck & R. A. Steer, 1987). Obese women with BED perceived
      their fathers as more rejecting than did women in the other groups. Moreover,
      obese women with BED perceived their fathers as significantly more rejecting than
      their mothers. The BED group indicated lower satisfaction with life and higher
      levels of depression than the groups without eating disorders. These findings
      further validate the diagnostic category of BED. Obese women with BED appear to
      be a distinct subgroup of the obese population. The results indicate a need for
      further assessment of the father-daughter relationship in connection to BED and
      other eating disorders.

PMID- 10654845
TI  - University students' learning approaches in three cultures: an investigation of
      Biggs's 3P model.
AB  - The relationship of various learning approaches to students' academic
      achievement, abilities, and other characteristics was examined in a sample of
      university students in Hong Kong, mainland China, and the United States. The
      theoretical framework for this project was J. B. Biggs's (1987) theory of student
      learning approaches. The participants completed the Study Process Questionnaire
      (based on Biggs's theory) and provided a variety of demographic information. The
      participants' achievement scores and self-rated scores on analytical, creative,
      and practical abilities were also obtained. Results indicated that scores on
      certain subscales of the Study Process Questionnaire statistically predicted
      participants' achievement beyond their self-rated abilities. In addition, certain
      learning approaches were significantly related to the participants' ages, gender,
      parents' education levels, and their travel and work experiences. Implications of
      these findings are discussed as they relate to teaching and learning.

PMID- 10654846
TI  - Depressed and nondepressed students: differences in interpersonal perceptions.
AB  - The purpose of this research was to study the patterns of interpersonal behavior
      of depressed students. Depressed participants rated themselves lower than non
      depressed controls on assertiveness and initiation of interactions and
      significantly higher than controls on concern about what others think,
      introversion, and submissiveness. Depressed participants also scored
      significantly higher than controls on measures of dependency, self-criticism, and
      the need to please others. Ratings of depressed participants by their roommates
      were not correlated with depressed participants' self-reports. In contrast, most
      subscale self-ratings and roommate ratings for the nondepressed participants and
      their roommates were significantly correlated.

PMID- 10654847
TI  - The measurement of locus of control: assessing more than meets the eye?
AB  - Ambiguities in the conceptions and measurement of locus of control were
      investigated in this study. Specifically, some psychometric properties of several
      widely used measures of perceived behavior-outcome contingency, interpersonal
      power, and social self-efficacy were assessed. To different degrees, the results
      indicated that all three measures of perceived behavior-outcome contingency
      lacked convergent and discriminant validity. Implications for interpreting past
      research, directions for future investigations, and limitations of the present
      study are discussed.

PMID- 10654848
TI  - Functional and dysfunctional impulsivity, depression, and suicidal ideation in a
      prison population.
AB  - D. Lester (1993) was not able to show any association between dysfunctional
      impulsivity and suicidal ideation, but he did find a negative correlation between
      suicidal ideation and functional impulsivity. The correlation was weak and was
      not significant when depression was controlled for. Given the fact that college
      students were the participants in that study, the low correlations may have
      resulted from insufficient variance in the data. In the current study, data were
      collected from prisoners (half of whom had recently attempted suicide);
      correlations among the variables were stronger (but still quite low) than the
      correlations found in Lester's study. As expected, the association between
      dysfunctional impulsivity and suicidal ideation was stronger than that between
      functional impulsivity and suicidal ideation. However, consistent with Lester's
      study, these correlations were not significant when depression was controlled
      for. Results indicate that a direct association between impulsivity and suicidal
      ideation is unlikely.

PMID- 10654849
TI  - An empirical application of transaction-costs theory to organizational design
      characteristics.
AB  - The environmental uncertainty component of transaction-costs theory was used to
      predict the organizational structural characteristics of size (number of
      employees) and horizontal differentiation (number of vice presidents) using
      financial and management information from the COMPACT DISCLOSURE data base (which
      contains the most recent annual and periodic reports for more than 12,000 public
      companies). Organizations were categorized as low- or high-uncertainty industries
      according to Dess and Beard's (1984) Dynamism Scale, and net sales volume was
      controlled. As predicted, high-uncertainty companies had significantly higher
      horizontal differentiation than low-uncertainty firms, a finding that supports
      the transaction-costs expectation that organizations may require more departments
      or personnel to cope with increasing uncertainty. Surprisingly, low-uncertainty
      firms were found to have significantly more employees than high-uncertainty
      organizations, which is the opposite of what transaction-costs theory predicts.
      Possible explanations for this unexpected finding and further potential
      limitations are discussed.

PMID- 10654850
TI  - Beyond intimacy: conceptualizing sex differences in same-sex friendships.
AB  - This study was designed to replicate and extend prior findings that same-sex
      friendships of women and men are equally important but that women's friendships
      are more intimate. A group of adolescents and a group of adults were asked to
      complete an anonymous questionnaire regarding the quality of their close
      friendships, the degree to which they would support a close friend in times of
      difficulty, and the degree to which they would celebrate with a friend in times
      of success. Results demonstrated that both females and males saw and spoke with
      their close friends and were equally willing to confront and trust their close
      friends. Females, however, reported more desire to spend time with a close friend
      in times of difficulty and to celebrate with a close friend who had just
      experienced a positive event. Results are discussed in terms of the differing
      functions of women's and men's same-sex friendships and women's greater general
      interest in and attention to transitions in the lives of other individuals.

PMID- 10654851
TI  - Predicting occupational personality test scores.
AB  - The relationship between students' actual test scores and their self-estimated
      scores on the Hogan Personality Inventory (HPI; R. Hogan & J. Hogan, 1992), an
      omnibus personality questionnaire, was examined. Despite being given descriptive
      statistics and explanations of each of the dimensions measured, the students
      tended to overestimate their scores; yet all correlations between actual and
      estimated scores were positive and significant. Correlations between self
      estimates and actual test scores were highest for sociability, ambition, and
      adjustment (r = .62 to r = .67). The results are discussed in terms of employers'
      use and abuse of personality assessment for job recruitment.

PMID- 10654852
TI  - The value of normal clinical data.
AB  - As optometric practitioners, we all gather and then analyze large quantities of
      clinical data every day. We understand that some of these data will be normal (or
      negative), and some will be abnormal (or positive); some will even be
      questionable (unreliable or suspicious). However, all clinical data used to
      prevent, diagnose, treat, and/or rehabilitate our patients are important;
      therefore, patients--as well as third-party payors--should be reminded of this
      fact.

PMID- 10654853
TI  - Anti-HIV drugs allow immune system to rebound, fight CMV.

PMID- 10654854
TI  - Improvements in clinical and functional vision and quality of life after second
      eye cataract surgery.
AB  - PURPOSE: To determine whether there is a need for second eye cataract surgery or
      whether cataract surgery in one eye provides sufficiently adequate vision.
      METHODS: The vision of 43 patients was assessed using a battery of clinical
      vision tests, performance-based functional vision tests, and quality of life
      questionnaires, both before and a few months after cataract surgery. Twenty-five
      patients underwent second eye surgery and 18 patients underwent first-eye
      surgery. To determine whether cataract surgery returned vision to normal levels,
      a control group of 25 subjects of a similar age with normal, healthy eyes was
      also assessed. RESULTS: Overall, greater improvements occurred in most aspects of
      vision after first eye surgery than after second eye surgery. However, second eye
      surgery provided similar improvements in mobility orientation and self-reported
      night driving to those after first eye surgery, and substantially greater
      improvements in stereoacuity and reductions in anisometropia. CONCLUSIONS: The
      study provides additional evidence to support the need for second eye cataract
      surgery. Second eye surgery may be particularly important to improve mobility
      orientation and the avoidance of falls.

PMID- 10654855
TI  - Eye movements and reading with plus-lens magnifiers.
AB  - PURPOSE: This study aimed to determine the eye movement parameter(s) that is
      primarily affected when fully sighted subjects use plus-lens magnifiers for
      reading. METHODS: Two forms of plus-lens magnifier were used: hand-held and
      spectacle-mounted. Eye movements were recorded using an infrared limbal
      reflection system as subjects read passages of text with and without the
      magnifiers. Data were compared for a young age group and an elderly (education
      matched) age group. RESULTS: For both age groups, a sawtooth pattern of eye
      movements was observed and reading speed was significantly (p = 0.0001) reduced
      when using the magnifiers compared with reading without. Forward saccade length
      decreased significantly (p = 0.0001) and time for retrace increased significantly
      (p = 0.0001), but fixation durations were unaffected. The form of magnifier had
      no significant effect on reading speed or eye movement parameters. CONCLUSIONS:
      The reduction in reading speed that occurred when using the plus-lens magnifiers
      was primarily a result of decreased forward saccade length.

PMID- 10654856
TI  - Reading with eccentric fixation is faster in inferior visual field than in left
      visual field.
AB  - PURPOSE: People with central field loss tend to fixate so that information falls
      in the inferior or left visual field. Studies of reading from a page of text
      suggest that using inferior field is advantageous relative to using left visual
      field. In this study, we investigated whether reading without eye movements in
      normal peripheral vision is better when text is presented in inferior or left
      visual field. METHODS: Reading rates were determined for retinally stabilized
      rapid serial visual presentation sentences of seven letter sizes, presented at 5
      degrees in inferior and left visual field of six normal observers. RESULTS: When
      print size is appropriately magnified for peripheral viewing, reading speed in
      inferior field is faster than in left visual field. There is no significant
      difference between inferior and left visual field in the print size required to
      reach maximum reading speed. CONCLUSIONS: For reading tasks not involving eye
      movements, there is an advantage in eccentrically fixating such that text falls
      in inferior rather than left visual field.

PMID- 10654857
TI  - Responses of contact lens wearers to a dry eye survey.
AB  - The purpose of this study was to examine ocular symptoms that have been
      associated with dry eye among contact lens wearers. A dry eye questionnaire was
      administered at random to 83 contact lens wearers at a private practice in
      Toronto, Ontario. On average, the most frequent ocular symptom among those
      queried was dryness and the least frequent was soreness. There was a significant
      shift (p < 0.0001; paired t-test) toward increased symptoms in the evening
      compared with the morning. Blurry, changeable vision was also a frequent and
      noticeable symptom. However, most subjects reported that their ocular symptoms
      were not severe enough for them to stop work or hobbies or to remove their
      contact lenses. Our results show that the symptoms of ocular dryness and
      discomfort are relatively common among contact lens wearers, and that they worsen
      toward the end of the day. These findings suggest that lens care practitioners
      should examine their patients who wear contact lenses toward the end of the day
      to best identify symptomatic patients.

PMID- 10654858
TI  - Associated phoria in relation to stereopsis with random-dot stereograms.
AB  - In the present work, we use random-dot stereograms to test a possible
      relationship between associated phoria and stereopsis. We determined, using a
      modified constant-stimulus method, the disparity range that indicates the maximum
      range at which stereoscopic correspondence can be achieved. A total of 27
      observers took part in the experiment. The value of the disparity range as a
      function of the associated phoria (measured with a Mallet unit) seems to indicate
      that greater associated phoria (fixation disparity) correlates with a
      deterioration in stereoscopic vision, reducing the disparity range and therefore
      the space region in which stereoscopic vision can be attained.

PMID- 10654859
TI  - Health policy and eye care services in Jamaica.
AB  - PURPOSE: To test the hypothesis that access to and amount of eye care services in
      Jamaica are inadequate and that this is related to insufficient eye care
      personnel and legal limitations on optometric practice in Jamaica. METHODS: An
      eye care provider survey, a consumer survey, and a literature search were used
      for data collection. The consumer sample consisted of 500 subjects (aged 16 to 84
      years or older) recruited from a stratified random sample of food markets in
      Jamaica. The provider sample consisted of 10 ophthalmologists and 10
      optometrists, randomly selected from licensing rosters. Adequacy of amount of eye
      care services was measured by comparing the frequency of eye examinations in
      Jamaica with professional practice guidelines. Access was measured by the eye
      provider to population ratio compared with calculated need for adequate care.
      RESULTS: Only 38.6% of the study population had received an eye examination
      within 3 years and only 23.4% reported having eye examinations at least once
      every 3 years. Over 43% had never received an eye examination. The total eye care
      provider/population ratio was only 2.04/100,000 and only 1.32/100,000 when
      optometrists are excluded. CONCLUSION: Access to and amount of eye care services
      are severely inadequate in Jamaica. Outdated optometric laws governing the
      activities of eye care professionals compounds the problem.

PMID- 10654861
TI  - STD prevention: effectively reaching the core and a bridge population with a four
      component intervention.

PMID- 10654860
TI  - Evidence of declining STD prevalence in a South African mining community
      following a core-group intervention.
AB  - OBJECTIVES: To reduce the prevalence of curable sexually transmitted diseases
      (STDs) in a South African mining community through provision of STD treatment
      services, including periodic presumptive treatment and prevention education to a
      core group of high-risk women living in areas around the mines. METHODS: Women at
      high risk for STDs attended a mobile clinic monthly for examination and
      counseling, and were treated presumptively for bacterial STDs with a directly
      observed 1-g dose of azithromycin. Gonococcal and chlamydial infection rates were
      measured by urine ligase chain reaction, and genital ulcers were assessed by
      clinical examination. Changes in STD prevalence among local miners were assessed
      through comparison of prevalence in two cross-sectional samples of miners taken 9
      months apart, and through routine disease surveillance at mine health facilities.
      RESULTS: During the first 9 months of the intervention, 407 women used the
      services. Baseline prevalence of Neisseria gonorrhoeae and/or Chlamydia
      trachomatis in women was 24.9%; 9.7% of these women had clinical evidence of
      genital ulcer disease (GUD). The proportion of women with incident gonococcal or
      chlamydial infections at the first monthly return visit (69% follow-up rate) was
      12.3%, and genital ulcers were found in 4.4% of these women. In the miner
      population, the prevalence of N gonorrhoeae and/or C trachomatis was 10.9% at
      baseline and 6.2% at the 9-month follow-up examination (P<0.001). The prevalence
      of GUD by clinical examination was 5.8% at baseline and 1.3% at follow-up
      examination (P< 0.001). Rates of symptomatic STDs seen at mine health facilities
      decreased among miners in the intervention area compared with miners living
      farther from the site and with less exposure to the project. DISCUSSION:
      Provision of STD treatment services to a core group of high-risk women may
      significantly reduce their burden of disease, and may contribute to a reduction
      in community STD prevalence. In the absence of sensitive and affordable screening
      tests for STDs in women, periodic presumptive treatment coupled with prevention
      education is a feasible approach to providing STD services in this population.

PMID- 10654862
TI  - Social network methods for endemic foci of syphilis: a pilot project.
AB  - BACKGROUND: Social network methods have improved our understanding of sexually
      transmitted disease transmission dynamics, and may be of use in routine field
      operations for partner notification. GOAL: To augment traditional syphilis
      control activities with social network methods in an Atlanta area with high
      syphilis morbidity. STUDY DESIGN: Disease investigators conducted interviews,
      used network diagrams to prioritize their work, and relied on network connections
      for finding hard-to-reach persons. RESULTS: A total of 396 contacts were elicited
      from 48 infected and 50 uninfected persons. The cumulative prevalence of syphilis
      was 12.6%, and 24 persons infected with HIV were identified. Network methods
      disclosed a large, interconnected group (276 persons) characterized by high
      network centrality and the substantial presence of small, interactive subgroups
      (microstructures). CONCLUSION: The network approach is a feasible field
      technique, and can identify core groups involved in the intense transmission of
      syphilis. The targeted, network-based approach may be useful in attempts to
      eliminate syphilis.

PMID- 10654863
TI  - A critical piece by whatever name.

PMID- 10654865
TI  - Herpes simplex type 2 infection in the developing world: is it time to address
      this disease?

PMID- 10654864
TI  - Human immunodeficiency virus infection and genital ulcer disease in South Africa:
      the herpetic connection.
AB  - BACKGROUND AND OBJECTIVES: While genital ulcers are a risk factor in HIV
      infection, the association of specific agents of genital ulcer disease (GUD) with
      HIV infection may vary. GOAL: To determine the etiology of GUD in HIV-infected
      and HIV-uninfected men attending sexually transmitted disease (STD) clinics in
      Durban, Johannesburg, and Cape Town, South Africa, and the association of
      previous and current sexually transmitted infections with HIV infection in men
      with ulcerative and nonulcerative STDs. STUDY DESIGN: A cross-sectional study of
      558 men with genital ulcers and 602 men with urethritis. RESULTS: Patients with
      GUD were more likely to be infected with HIV than patients with urethritis (39.4%
      versus 21.4%, P< or =0.001). Herpes simplex virus 2 (HSV-2) was the most common
      agent identified in ulcer specimens (35.9%), and was detected in a significantly
      higher proportion of ulcer specimens from HIV-infected patients than in specimens
      from HIV-uninfected patients (47.4% versus 28.2%, P< or =0.001). Patients
      infected with HIV-1 were significantly more likely to have HSV-2 infection, as
      measured by the presence of the antibody to glycoprotein G-2, than patients not
      infected with HIV (63.1% versus 38.5%, P< or =0.001). Patients infected with HIV
      1 were also significantly more likely to have initial HSV-2 infection than HIV
      uninfected patients with GUD (50.0% versus 31.6%, P = 0.007). Haemophilus ducreyi
      was detected in 31.7% of ulcer specimens; prevalence did not vary by HIV
      infection status. Treponema pallidum DNA was detected significantly less
      frequently in ulcer specimens from patients infected with HIV than in specimens
      from patients not infected with HIV (10.2% versus 26%, P< or =0.001); no
      association was found between HIV-infection status and fluorescent treponemal
      antibody absorption test seroreactivity, even when men with M-PCR-positive
      syphilis lesions were excluded from the analyses. CONCLUSION: The authors found
      that HSV-2 is a more common etiology of GUD than has been suggested by previous
      studies conducted in South Africa; serologic evidence of HSV-2 infection and
      current cases of genital herpes are strongly associated with HIV infection among
      men who present to STD clinics with GUD or urethritis.

PMID- 10654866
TI  - Medical care expenditures for genital herpes in the United States.
AB  - BACKGROUND: Approximately 45 million Americans have serologic evidence of HSV-2
      infection and HSV-2 seroprevalence in the United States has increased 30% over
      the past two decades. Despite rapid increases in HSV-2 prevalence, the last
      estimate of the U.S. national direct medical cost for genital herpes (GH) was
      completed in 1985. The objective of this study is to assess the U.S. direct
      medical expenditures for GH and its complications to assist policy makers in
      allocating limited STD resources efficiently. METHODS: We estimated the number of
      GH-related clinical visits and pharmacy claims from several national and state
      sources, estimated the average direct medical cost per visit from two
      administrative claims databases, and calculated the U.S. national direct medical
      costs for GH by applying the average direct medical cost per visit to the number
      of clinical visits and pharmacy claims. RESULTS: The U.S. national number of GH
      related clinical visits was estimated to be 499,655 and there were approximately
      2,056,1180 pharmacy claims annually. Of those clinical visits, private office
      based physician and public STD clinic visits alone accounted for 89%. The U.S.
      national direct medical costs were estimated at $166 million annually for 1992
      1994, which represents $207 million in 1999 dollars. Of the total cost, medical
      care accounted for 36% and drug treatment for 64%. CONCLUSIONS: The medical costs
      of pharmacy claims and office-based physician visits account for the majority of
      the medical expenditures for GH. Our estimates, based on the best available data
      on medical expenditure, indicate that GH is a major public health problem with a
      substantial economic burden.

PMID- 10654867
TI  - Factors associated with condom use for oral sex among female brothel-based sex
      workers in Singapore.
AB  - BACKGROUND AND OBJECTIVE: The prevalence of oral sex increased from 27.1% in 1992
      to 81.1% in 1997, with a concomitant increase in pharyngeal gonorrhea, among
      female sex workers in Singapore. The extent of condom use for oral sex among them
      is unknown. GOAL: To determine the prevalence of and factors associated with
      consistent condom use during oral sex. STUDY DESIGN: A cross-sectional study of
      225 women randomly selected from the surveillance scheme register of female
      brothel-based sex workers with a history of oral sex documented in their medical
      records. RESULTS: Slightly more than half (56.9%) consistently used condoms for
      oral sex compared to 97% for vaginal sex. Condom use was significantly higher
      among middle than high class sex workers (adjusted rate ratio: 1.52, 95% CI: 1.01
      2.29) and those with negotiation skills (adjusted rate ratio: 1.95, 95% CI: 1.32
      2.07). CONCLUSION: Sex workers should be taught skills to negotiate condom use
      for oral sex.

PMID- 10654868
TI  - Prevalence and tetM subtype of tetracycline-resistant Neisseria gonorrhoeae in
      Ohio, 1994.

PMID- 10654869
TI  - Vaccines against sexually transmitted infections: promise and problems of the
      magic bullets for prevention and control.

PMID- 10654870
TI  - HIV prevalence in patients with syphilis, United States.
AB  - BACKGROUND: Among persons with a sexually transmitted disease (STD), the
      proportion who are also infected with HIV is a major factor influencing the
      public health impact of that STD on HIV transmission. GOAL: To assess HIV
      infection in persons with syphilis in the United States. STUDY DESIGN: A
      systematic literature review was conducted of U.S. studies with HIV
      seroprevalence data in patients with syphilis. RESULTS: Thirty studies were
      identified and analyzed. The median HIV seroprevalence in men and women infected
      with syphilis was 15.7% (interquartile range [IQR]: 13.6-21.8%), among men was
      27.5% (23.1-29.6%), and among women was 12.4% (8.3-20.5%). Median odds ratios for
      men and women, men only, and women only were 4.5, 8.5, and 3.3, respectively.
      Seroprevalences among men who have sex with men (MSM) and injecting drug users
      (IDU) ranged from 64.3-90.0% and 22.5-70.6%, respectively. CONCLUSIONS: Despite
      substantial variability, HIV seroprevalence is high among patients with syphilis
      in the United States, identifying them as a critical target group for HIV
      prevention efforts.

PMID- 10654871
TI  - More of the same is not validation.

PMID- 10654872
TI  - Role of NO in hemodialysis hypotension.

PMID- 10654873
TI  - Intraoperative continuous renal replacement therapy in orthotopic liver
      transplantation.

PMID- 10654874
TI  - High dose chemotherapy and hematopoietic progenitor cell reinfusion in the
      treatment of solid tumors.

PMID- 10654875
TI  - Pharmacokinetics of bisoprolol and its effect on dialysis refractory
      hypertension.
AB  - The efficacy, safety, and pharmacokinetics of bisoprolol were investigated
      following oral administration once daily for 12 weeks in hyperreninemic patients
      with dialysis-refractory hypertension. Mean blood pressure rapidly fell from 132
      to 112 mmHg in the 5.0-mg/day (n = 6) and from 142 to 128 mmHg in the 2.5-mg/day
      patients (n = 5), which were accompanied by a fall in plasma renin activity. On
      nondialysis days, Cmax and T1/2 were significantly higher in patients than in
      healthy control subjects. However, Cmax in the 2.5-mg/day patients was almost
      equal to that in healthy control subjects receiving 5.0 mg/day of bisoprolol.
      Plasma bisoprolol was dialyzable. During the course of the study, dialysis
      hypotension and bradycardia occurred in two patients receiving 5.0 mg/day of
      bisoprolol. In conclusion, a daily dose of 2.5 mg bisoprolol seems to be an
      adequate and relatively effective dose in our patients with dialysis-refractory
      hypertension.

PMID- 10654877
TI  - Development of a urea concentration gradient between muscle interstitium and
      plasma during hemodialysis.
AB  - In this pilot study, muscle interstitial urea concentrations during hemodialysis
      (HD) were determined with a microdialysis technique and the results were compared
      with plasma water urea concentrations. Three patients were investigated during a
      total of five treatments. Under predialysis steady-state conditions, no
      difference was observed. During treatment, the muscle interstitial urea
      concentration was on average 19% higher (range 13-28%, n=4) than the plasma urea
      concentration after 17+/-3 min, 29% higher (25-31%, n=3) after 53+/-10 min, 40%
      higher (26-50%, n=3) after 117+/-6 min, 31% higher (26-34%, n= 3) after 179+/-5
      min, and 31% higher (27-36%, n=4) after 231+/-5 min. The gradient declined after
      the conclusion of HD, muscle interstitial concentrations being on average 16% (9
      26%, n=4) higher than plasma urea concentrations 9+/-2 min after treatment, and
      8% (6-10%, n=3) 25+/-3 min after treatment. Thus, a urea concentration gradient
      with a higher concentration in muscle interstitium than in plasma, developed
      during HD, and dissipated gradually after treatment. This is consistent with
      blood flow-dependent urea sequestration in muscle tissue, causing
      intercompartment disequilibrium of urea during HD, and its consequent
      redistribution after treatment contributing to postdialysis urea rebound.

PMID- 10654876
TI  - Which organic acids does hemofiltrate contain in the presence of acute renal
      failure?
AB  - It is not generally possible to measure most organic acids in the serum of
      critically ill patients, due to rapid metabolism and methodological problems.
      Only the regular measurement of lactic acid and the arterial ketone body ratio
      (acetoacetate/beta-hydroxybutyrate, AKBR) have been introduced in clinical
      practice, but these parameters can represent only a part of the disturbed
      metabolism. In pediatric patients, a chromatographical urine analysis has been
      established for detection of inborn errors of metabolism, which allows the
      determination of more than 50 organic acids simultaneously (gas chromatographic
      (GC) analysis in combination with mass spectrometry (MS)]. In continuous
      treatment of acute renal failure, hemofiltrate is always available, but it
      contains only low protein concentrations and after the filtration process,
      metabolism is rapidly stopped. The sieving coefficient of lactic acid is nearly
      one in hemofiltration. The aim of our study was to compare results of the regular
      and CG/MS methods in blood and hemofiltrate for lactic acid, and to find other
      organic acids of possible clinical importance. We investigated serum (lactic
      acid) and hemofiltrate of 40 critically ill patitens, similar to the urine
      analysis method for infants. All patients suffered from acute renal failure and
      were treated by continuous veno-venous hemofiltration (CVVH). The conditions of
      treatment were standardized (spontaneous ultrafiltration in the first hour), and
      the material (blood/hemofiltrate) was taken one hour after the beginning of
      extracorporeal circulation. Statistical methods included correlation analysis,
      nonparametric ANOVA with Wilcoxon scores (ranks of data), and stepwise
      discriminant analysis. Regular and GC/MS methods in hemofiltrate showed a good
      correlation for lactic acid. The best correlation with lactic acid was found for
      4-hydroxy-phenyllactic acid (n=20, r=0.866), 2-hydroxy-valeric acid (n=22,
      r=0.7491) and 2-hydroxybutyric acid (n=32, r=0.5148). Age, sex, diagnosis, and
      APACHE II score play a subordinate role, but the presence of glyceric and citric
      acid possibly have prognostic importance [nonparimetric ANOVA with Wilcoxon
      scores (ranks of data)], as does the combination of 3-hydroxypropionic acid,
      glyceric acid, and threonic-acid-4-lacton (stepwise discriminant analysis). It
      can be concluded that in acute renal failure, the measurement of lactic acid and
      AKBR can reflect only a small part of disturbed metabolism. Hemofiltrate can be a
      useful medium in describing metabolic processes in critically ill patients with
      acute renal failure. Some inherited metabolic diseases in infants
      (phenylketonuria, maple syrup disease) and ketoacidosis show similar metabolic
      modifications.

PMID- 10654878
TI  - Rotary cell culture system (RCCS): a new method for cultivating hepatocytes on
      microcarriers.
AB  - The Rotary Cell Culture System (RCCS) is a new technology for growing anchorage
      dependent or suspension cells in the laboratory. The RCCS is a horizontally
      rotated, bubble free disposable culture vessel with diffusion gas exchange. The
      system provides a reproducible, complex 3D in vitro culture system with large
      cell masses. During cell growing the rotation speed can be adjusted to compensate
      for increased sedimentation rates. The unique environment of low shear forces,
      high mass transfer, and microgravity, provides very good cultivating conditions
      for many cell types, cell aggregates or tissue particles in a standard tissue
      culture laboratory. The system enables to culture HepG2 cells on Cytodex 3
      microcarriers (mcs) to high densities. We inoculated 2 x 10(5)/ml HepG2 cells and
      200 mg Cytodex 3 mcs in 50 ml Williams E medium (incl. 10% FCS) allowing them to
      attach to the mcs in the rotating vessel (rotation rate 14-20 rpm). HepG2 cells
      readily attached to the mcs while the vessel was rotating. Attachment of HepG2 to
      the mcs was about 50% after 24 hrs and 100 % within 48 hrs. After 72 hrs of
      rotary culturing small aggregates of Hep G2 on mcs were built. HepG2 cells and
      the aggregates rotated with the vessel and did not settle within the vessel or
      collide with the wall of the vessel. We conclude that this new RCCS is an
      excellent technology for culturing HepG2 cells on Cytodex 3 mcs. The system is
      easy to handle and enables to culture anchorage dependent cells to high densities
      in a short period.

PMID- 10654879
TI  - Design of the solar cell system for recharging the external battery of the
      totally-implantable artificial heart.
AB  - The solar cell as the advanced alternative energy resource was found to be
      acceptable for increasing battery running time of the totally-implantable
      artificial heart. A sample of the wireless charging system with solar cell base
      gives a maximum battery running time around 9 hours and some physical and
      psychological freedom to the patient. This improvement will assist the
      application of the implantable artificial heart for a longer period of time and
      with added convenience to the recipient.

PMID- 10654880
TI  - Numerical solution for blood flow in a centrifugal ventricular assist device.
AB  - A very small centrifugal pump, fully supported by magnetic bearings, is being
      developed for use as a ventricular assist device to be implanted in humans. In
      this paper, we apply computational fluid dynamics to model the blood flow to aid
      in the design of the ventricular assist device. The flow of blood through the
      pump has been modeled using computational fluid dynamics (CFD) software that is
      commercially available from AEA Technology, UK. The flow regions modeled in
      version 3 of the Continuous Flow Ventricular Assist Device (CF3) are the fully
      shrouded four bladed impeller and the two clearance regions around the impeller
      that are bounded by the pump hub and shroud. This paper describes the geometry
      and computational grids developed for the flow regions, and the equations of
      motion for the blood flow are developed. The overall numerically-evaluated flow
      rates and head rise have similar trends to the flow parameters experimentally
      measured, indicating that future pump designs can be effectively modeled
      numerically before being constructed and tested. Numerical solutions are
      presented and compared with experimentally-obtained overall pump performance
      results. These solutions are used to predict shear stress levels to be
      experienced by the blood flowing through the pump, and it is predicted that
      hemolysis will be insignificant. The solutions also indicate no regions of flow
      stagnation that can be a source of thrombosis in pumps. The calculations provide
      a viable design method to achieve improved efficiency in future versions of this
      pump.

PMID- 10654881
TI  - The role of usable length in the compliance measurement of vascular prostheses.
AB  - In this study we investigated the dependence of the mechanical properties and in
      particular of the radial compliance of a vascular prosthesis as a function of its
      usable length. Radial compliance was measured at 60 bpm and in the pressure range
      80-120 mmHg. Starting from compliance measurements a simple model was used to
      calculate the pulse wave velocity and the reflection coefficients between 6 mm
      and 8 mm grafts (knitted and woven) with iliac and subclavean artery of similar
      diameter. The results provide an indication of the influence of usable length on
      the compliance and diameter mismatch at the anasthomosis between graft and host
      artery.

PMID- 10654882
TI  - Development of a new biodegradable intravascular polymer stent with simultaneous
      incorporation of bioactive substances.
AB  - OBJECTIVE: Due to the thrombogenicity and permanent implant nature of metallic
      stents, bioresorable synthetic polymers have been proposed for stents and local
      drug delivery systems. Bioresorbable polyesters like poly(D,L-lactide)
      demonstrated excellent biocompatibility in various tissues. This paper describes
      a novel method for the molding of these polymers. The specific CESP-process
      (Controlled Expansion of Saturated Polymers) is characterised by the use of the
      plasticizer carbon dioxide and allows the incorporation of bioactive substances
      at physiologic temperatures into the polymer bulk and the production of complex
      designed implants. METHODS: The CESP-process is characterised by the exposure of
      an amorphous polymer to an inert gas at high pressure with a significant lower
      glass transition point. The plasticizing effect makes it possible to process
      polylactides at a temperature close to room temperature. The low process
      temperature constitutes a key advantage for thermally sensitive polymers and
      allows the incorporation of thermally sensitive pharmaceutical additives. To
      obtain some preliminary information on the biocompatibility, in vitro cell
      toxicity testing as well as drug release assessment was performed. RESULTS:
      Different polymer sheets were produced using the CESP-process. Cytotoxicity was
      not observed in any molded polymer material. According to the mechanical and
      biocompatibility results Poly(D,L-lactide) (P-DL-LA) was investigated in the CESP
      process. Finite element analysis was used to test the possible geometry of an
      adequate stent. A helical design was chosen and a stent-prototype was produced
      using the CESP-process. Peroxidase activity as an incorporated marker enzyme
      could be measured over 6 weeks. Different drug release profiles were obtained due
      to various pore sizes of the polymer. CONCLUSIONS: The new CESP-process can be
      used to process biodegradable polymers and to mold different stent geometries
      without inducing cytotoxic effects to the material. Furthermore, this procedure
      permits the simultaneous incorporation of bioactive substances during the molding
      process. Drug release kinetics can be regulated by different pore sizes of the
      material.

PMID- 10654883
TI  - Postprostatectomy urinary incontinence: the case for artificial urinary sphincter
      implantation.

PMID- 10654884
TI  - Collagen injection or artificial sphincter for postprostatectomy incontinence:
      collagen.

PMID- 10654885
TI  - Sex assignment in cases of ambiguous genitalia and its outcome.

PMID- 10654886
TI  - Transurethral radiofrequency therapy for benign prostatic hyperplasia using a
      novel saline-liquid conductor: the virtual electrode.

PMID- 10654887
TI  - Improving cystine stone therapy: an in vitro study of dissolution.
AB  - OBJECTIVES: To perform an in vitro study analyzing the possibilities in
      therapeutic strategies for an effective treatment of cystine stones. METHODS:
      Artificial stones made of cystine [Bon(n)-Stones] with a ball-shaped size of 0.9
      cm in diameter were used. Chemolysis of artificial cystine stones with different
      solvents (artificial urine, physiologic sodium chloride solution, acetylcysteine,
      tris-(hydroxymethylene)-aminomethane [THAM], and combinations of these) was
      investigated. An experimental arrangement with computer-assisted online
      measurement of data simulating the physiologic conditions in the upper urinary
      tract at varying pH values was used. RESULTS: All solutions showed a statistical
      improvement in the solubility of cystine stones compared with artificial urine
      and physiologic sodium chloride solution. The combination of THAM (pH 10) and 2%
      acetylcysteine was most effective (1 3.91 +/- 1.73 mg/hr) and demonstrated a 41 
      fold higher ability to dissolve cystine calculi compared with artificial urine.
      CONCLUSIONS: Our data indicate that local chemolysis with special solutions is an
      effective treatment modality in cystine stone therapy.

PMID- 10654888
TI  - Clinical significance of gross hematuria and its evaluation in patients receiving
      anticoagulant and aspirin treatment.
AB  - OBJECTIVES: To investigate the results of evaluations in patients presenting with
      gross hematuria while receiving anticoagulant or aspirin treatment and to compare
      the source of bleeding in these respective groups. METHODS: We retrospectively
      studied all patients admitted because of gross hematuria while receiving warfarin
      or aspirin treatment between 1990 and 1998. The degree of anticoagulation was
      evaluated in patients taking anticoagulation medication. Almost all patients were
      evaluated by cystoscopy and either excretory urography or ultrasound. RESULTS:
      Patients taking warfarin had a normal evaluation almost twice as often as those
      taking aspirin: 38% versus 22%, respectively. The leading pathologic findings in
      both groups were a bleeding benign prostate and a tumor in the urinary tract, in
      similar proportions. Overall, a tumor was diagnosed in one quarter of patients,
      and other treatable pathologic findings were diagnosed about half the time. In
      the 11 patients receiving excessive anticoagulation medication, two tumors were
      found (18%). Hemorrhagic cystitis was diagnosed in 12 patients. All 12 were
      taking aspirin. CONCLUSIONS: A normal evaluation was more prevalent in the
      warfarin group. A tumor was diagnosed in about one quarter of the patients. The
      prevalence of hemorrhagic cystitis in patients taking aspirin may point to a
      specific bleeding diathesis in the urothelium of these patients. In light of
      these findings, a full evaluation is warranted in patients receiving aspirin or
      warfarin therapy, and the presence of excessive anticoagulation should not impede
      a full evaluation.

PMID- 10654889
TI  - Renal ablative cryosurgery in selected patients with peripheral renal masses.
AB  - OBJECTIVES: To present the preliminary results of renal ablative cryosurgery in
      selected patients. METHODS: Seven patients were treated, all of whom had small
      peripheral tumors and chose not to undergo partial or radical nephrectomy. Four
      patients underwent a rib-sparing flank incision; the remaining three underwent
      laparoscopy. All tumors were biopsied before cryoablation. Intraoperative
      ultrasound was used to monitor the cryolesion. RESULTS: There were no
      intraoperative complications. The estimated blood loss averaged 111 mL. To date,
      6 of the 7 patients have undergone at least one follow-up computed tomography
      scan (14.2 months average follow-up); all these scans demonstrated partial
      resolution of the lesion. Clinically, the patients tolerated the procedure
      without any renal complications or significant changes in creatinine.
      CONCLUSIONS: This limited clinical trial has demonstrated the feasibility of
      treating small peripherally located renal tumors with cryosurgery with minimal
      morbidity and a favorable outcome. Further studies are necessary to determine the
      long-term efficacy of this treatment modality.

PMID- 10654890
TI  - Smoking and alcohol use may be risk factors for poorer outcome in patients with
      clear cell renal carcinoma.
AB  - OBJECTIVES: To correlate the clinical outcomes of 148 patients with clear cell
      renal carcinoma treated at a single institution with a variety of other factors.
      METHODS: Cases were derived from a consecutive series of nephrectomy specimens
      obtained from 1980 to 1994. A retrospective review of clinical records was
      performed, with tobacco use, alcohol use, recurrence, and survival noted.
      RESULTS: The median age of the patients was 62 years. The median follow-up was
      4.4 years. Of 148 patients, 82% had localized disease (MO), and 18% had suspected
      metastases (M1) at the time of nephrectomy. Of 121 patients without metastases at
      diagnosis, T classification was assessed for 117: 48 (41%) had T1 disease, 18
      (15%) T2, 46 (39%) T3, and 5 (4%) T4. The Fuhrman grade was 1 or 2 in 51% of
      patients and 3 or 4 in 45%. Both clinical stage and grade were significantly
      associated with overall survival (P <0.0001 and P = 0.0028, respectively) and
      recurrence-free survival (P = 0.0002 and P = 0.0011, respectively). Smoking and
      alcohol use history was determined in 70% and 63% of patients, respectively. In
      patients with Stage M0, smokers had a significantly worse overall survival rate
      compared with nonsmokers (P = 0.039). Also, in patients with Stage M0, a trend
      toward a worse recurrence-free survival rate was noted in alcohol users compared
      with those who never used alcohol regularly (P = 0.06). CONCLUSIONS: The
      prognosis of clear cell renal carcinoma depends on the pathologic stage at
      diagnosis and the Fuhrman grade. Smoking is a known risk factor for developing
      renal cancer and may be associated with increased mortality from clear cell
      carcinoma in patients with Stage M0. Also, regular alcohol use may decrease the
      recurrence-free survival rate.

PMID- 10654891
TI  - Potential role of nephrectomy in the treatment of metastatic renal cell
      carcinoma: a retrospective analysis.
AB  - OBJECTIVES: To examine the outcomes of patients with newly diagnosed metastatic
      renal cell carcinoma (RCC) who underwent initial nephrectomy as a component of
      therapy, because the role of nephrectomy in the treatment of patients with
      metastatic RCC is uncertain. METHODS: A retrospective review of 63 patients who
      underwent radical nephrectomy with or without additional surgical procedures in
      the setting of metastatic RCC was performed. Pretreatment characteristics and the
      type of surgery were examined as predictors of outcome, and the type of systemic
      therapy received (if any) and overall survival were determined. RESULTS: The
      median patient age was 59 years (range 39 to 79). Thirty-two patients had a
      single metastatic site, with the most common sites being the lung (n = 33),
      lymphatics (n = 32), and bone (n = 19). Seventeen patients (27%) also underwent
      vena cavotomy during surgery. Two patients died perioperatively. Thirty-nine
      (62%) patients underwent systemic therapy after surgery, and 6 patients (9.5%)
      were rendered free of disease and elected not to receive systemic treatment. The
      median survival was 17.8 months. CONCLUSIONS: Primary renal surgery may be
      beneficial for selected patients with metastatic RCC, and most patients will be
      able to receive postoperative systemic therapy.

PMID- 10654892
TI  - "BPSA," a specific molecular form of free prostate-specific antigen, is found
      predominantly in the transition zone of patients with nodular benign prostatic
      hyperplasia.
AB  - OBJECTIVES: The biologic mechanism for the increased proportion of noncomplexed
      ("free") prostate-specific antigen (PSA) found in the serum of patients with
      benign prostate disease is unknown. We recently reported that most of the PSA
      found in benign, hyperplastic, and cancerous prostatic tissue is in the free
      form. To determine whether specific molecular forms of free PSA are associated
      differentially with normal, hyperplastic, or cancerous prostatic tissue, we have
      further characterized the free PSA in each type of prostatic tissue. METHODS: PSA
      was purified by immunoaffinity chromatography from matched prostatic tissue
      samples of peripheral zone cancer (PZ-C), PZ noncancer (PZ-N), and transition
      zone (TZ) tissue from 10 large-volume (greater than 50 g) and 8 small-volume
      (less than 25 g) radical prostatectomy specimens. Eight TZ specimens obtained
      during transurethral resection of the prostate for benign prostatic hyperplasia
      (BPH) were also analyzed. The different molecular forms of PSA were further
      resolved by high-performance hydrophobic interaction chromatography. Clipped
      forms of PSA were identified by N-terminal amino acid sequencing. RESULTS: More
      than 99% of the PSA in prostatic tissues was in the free, noncomplexed form.
      Specimens from the prostate TZ were found to contain elevated levels of an
      altered form of PSA, which we designated BPSA. Purified BPSA contained a
      distinctive cleavage at lysine 182. The median percent BPSA (%BPSA) was 11.4 in
      the TZ of specimens with nodular BPH compared with a %BPSA of 4.1 in the TZ of
      specimens without nodular BPH (P <0.0014). The median %BPSA levels of the PZ-N
      and PZ-C tissues ranged from 3.2 to 4.9 and were not significantly different from
      one another or from the %BPSA level of TZ tissues without nodular BPH.
      CONCLUSIONS: We have identified a specific molecular form of clipped free PSA,
      called BPSA, that is increased within the prostatic TZ of patients exhibiting
      nodular BPH. Higher levels of percent free PSA in serum have been found to
      correlate strongly with prostate volume, which in turn is closely associated with
      the progressive enlargement of nodular BPH tissue within the TZ of the prostate.
      Thus, it is possible that a proportion of the serum percent free PSA found in
      patients with BPH may be composed of BPSA released into the serum.

PMID- 10654893
TI  - Men's attitudes regarding genetic testing for hereditary prostate cancer risk.
AB  - OBJECTIVES: Little is known about the attitudes of men unselected for a family
      history for prostate cancer concerning genetic testing for prostate cancer risk
      or genetic testing for inherited cancer predisposition. To explore this, we
      examined the interest in molecular testing for hereditary prostate cancer (HPC)
      predisposition among a self-selected cohort of 342 men presenting for prostate
      cancer screening. METHODS: Participants were surveyed concerning their attitudes
      about DNA testing for HPC predisposition and knowledge of prostate cancer
      associated risk factors, including heredity. RESULTS: Of the participants
      completing the survey, 92% expressed interest in learning about DNA testing, and
      89% stated that they would undergo DNA analysis for HPC predisposition, if
      available. Twenty-eight percent of respondents failed to demonstrate an adequate
      understanding of the concept of "inherited tendency." The demonstrated level of
      understanding of this concept did not differ by the respondent's family history,
      although it varied by race. An interest in learning about or undergoing testing
      did not vary by race, family history, or demonstrated understanding of the
      concept of inherited risk. CONCLUSIONS: Among men presenting for routine prostate
      cancer screening, interest in learning about testing for HPC predisposition and
      in having such testing performed may be high. The data also provide evidence
      that, in a population of men unselected for family history, interest in molecular
      testing for this common, male-specific cancer may parallel the high interest
      level demonstrated among women in DNA testing for inherited breast and ovarian
      cancer risk.

PMID- 10654894
TI  - Pretreatment prostate-specific antigen as an outcome predictor of targeted
      transurethral microwave thermotherapy.
AB  - OBJECTIVES: To evaluate pretreatment serum prostate-specific antigen (PSA) as an
      outcome predictor of targeted microwave thermotherapy. METHODS: Seventy-one
      patients with lower urinary tract symptoms of benign prostatic hyperplasia
      underwent targeted transurethral microwave thermotherapy using the Targis system.
      Outcomes 12 months after treatment were evaluated by the International Prostate
      Symptom Score (IPSS), peak urinary flow rate (Qmax), and quality-of-life (QOL)
      score. The ability of PSA to predict outcomes was evaluated by linear and
      logistic regression and receiver operating characteristic curve analysis.
      RESULTS: Higher pretreatment PSA levels were significantly predictive of an
      absolute IPSS change of -7.5 or less for patients with moderate baseline symptoms
      or - 15 or less for those with severe baseline symptoms; an absolute Qmax change
      of 5 mL/s or greater; an absolute QOL score change of -3 or less; an IPSS at 12
      months of 7 or less; a Qmax at 12 months of greater than 12 mL/s; and a QOL score
      at 12 months of 1 or less. Nevertheless, even without taking pretreatment PSA
      into account, most patients benefitted substantially from targeted microwave
      thermotherapy. Thus, 74%, 71%, and 79% of all eligible patients improved 50% or
      more in IPSS, Qmax, and QOL score, respectively, at 12 months compared with
      baseline. No significant association between PSA and either prostate or
      transition zone volume could be demonstrated. CONCLUSIONS: Most patients benefit
      substantially from targeted microwave thermotherapy. However, higher PSA levels
      are significantly predictive of more favorable outcomes. This association may
      reflect patient-to-patient differences in the relative abundance of PSA-producing
      epithelial cells in the transition zone of the prostate.

PMID- 10654895
TI  - Patient-reported urinary continence and sexual function after anatomic radical
      prostatectomy.
AB  - OBJECTIVES: After radical prostatectomy, the rates for recovery of urinary
      continence and sexual function reported by experienced surgeons are much higher
      than the patient-reported outcomes from other centers. It is uncertain whether
      this represents differences in surgical technique or in the collection of data.
      This study was performed to determine patient-reported rates of continence and
      potency after radical prostatectomy performed by an experienced surgeon at a high
      volume referral center for the treatment of localized prostate cancer. METHODS:
      Sixty-four men with localized prostate cancer who were potent preoperatively and
      who had sexual partners underwent anatomic radical prostatectomy between March
      1997 and January 1998. A validated disease-targeted quality-of-life survey that
      assesses function and bother in two organ systems (urinary and sexual) was
      administered preoperatively and at 3, 6, 12, and 18 months postoperatively.
      RESULTS: Urinary continence, which was defined as wearing no pads, gradually
      improved during the first 12 months after surgery, and at 1 2 and 18 months, 93%
      of the patients were dry. Throughout the study, 93% to 98% of the patients
      characterized their urinary bother as none or small. Potency, defined as the
      ability to have unassisted intercourse with or without the use of sildenafil,
      improved gradually, and by 18 months, 86% of patients were potent and 84%
      considered sexual bother as none or small. Although one third of patients at 18
      months were using sildenafil intermittently, only 2 patients were not able to
      have intercourse without its use. CONCLUSIONS: Patient-reported rates of
      continence and potency after radical prostatectomy performed by an experienced
      surgeon are high.

PMID- 10654896
TI  - Use of intraoperative video documentation to improve sexual function after
      radical retropubic prostatectomy.
AB  - OBJECTIVES: To determine whether arbitrary minor variances in surgical technique
      can have a major impact on the recovery of sexual function after radical
      retropubic prostatectomy. METHODS: The surgical procedures of 62 potent men were
      videotaped prospectively. Eighteen months after the study was initiated, the
      videotapes were reviewed and specific steps in the surgical procedure correlated
      with patient-reported potency rates. RESULTS: Four steps were identified that
      appeared to correlate with the recovery of sexual function: over-sewing back
      bleeders from the proximal dorsal vein on the anterior surface of the prostate,
      division of the striated sphincter when placing urethral sutures, division of the
      posterior striated sphincter, and hemostasis at the end of the case. CONCLUSIONS:
      We believe that retrospective review of intraoperative videotapes has great
      promise. Because many surgeons use different techniques, it is likely that each
      individual may be able to identify other important arbitrary variations that may
      improve their patients' outcomes. Similarly, for surgeons with less than optimal
      outcomes, the review of early successful cases may enable them to identify ways
      that modification of their surgical technique can improve the outcome of future
      patients. To the best of our knowledge, the use of retrospective review of
      intraoperative videotapes has not been commonly used in any other surgical field.

PMID- 10654898
TI  - Ultrasound-based stereotactic guidance of precision conformal external beam
      radiation therapy in clinically localized prostate cancer.
AB  - OBJECTIVES: Use of external beam radiation fields that conform to the shape of
      the target improves biochemical control in prostate cancer by facilitating dose
      escalation through increased sparing of normal tissue. By correcting potential
      organ motion and setup errors, ultrasound-directed stereotactic localization is a
      method that may improve the accuracy and effectiveness of current conformal
      technology. The purpose of this study was to quantify the precision of the
      transabdominal ultrasound-based approach using computed tomography (CT) as a
      standard. METHODS: Thirty-five consecutive men participated in a prospective
      comparison of daily CT and ultrasound-guided localization at Fox Chase Cancer
      Center. Daily CT prostate localization was completed before the delivery of each
      final boost field. In the CT simulation suite, transabdominal ultrasound-based
      stereotactic localization was also performed. The main outcome measure was a
      three-dimensional comparison of prostate position as determined by CT versus
      ultrasound. RESULTS: Sixty-nine daily CT and ultrasound prostate position shifts
      were recorded for 35 patients. The magnitude of difference between the CT and
      ultrasound localization ranged from 0 to 7.0 mm in the anterior/posterior, 0 to
      6.4 mm in the lateral, and 0 to 6.7 mm in the superior/inferior dimension. The
      corresponding directed average disagreements were extremely small:
      anterior/posterior, -0.09 +/- 2.8 mm SD; lateral, -0.16 +/- 2.4 mm SD; and
      superior/inferior, -0.03 +/- 2.3 mm SD). Analysis of the paired CT-ultrasound
      shifts revealed a high correlation between the two modalities in all three
      dimensions (anterior/ posterior r = 0.88; lateral r = 0.91; and superior/inferior
      r = 0.87). CONCLUSIONS: Ultrasound-directed stereotactic localization is safe and
      as accurate as CT scanning in targeting the prostate for conformal external beam
      radiation therapy. The application of this technology to current conformal
      techniques will allow the reduction of treatment margins in all dimensions. This
      should diminish treatment-related morbidity and facilitate further dose
      escalation, resulting in improved cancer control.

PMID- 10654897
TI  - Cost comparison of radical prostatectomy and transperineal brachytherapy for
      localized prostate cancer.
AB  - OBJECTIVES: To compare perioperative costs associated with radical retropubic
      prostatectomy (RRP) to transperineal brachytherapy (BXRT) with iodine-125 (125I)
      seeds in the treatment of localized prostate cancer. METHODS: Actual costs per
      case for the perioperative period were compiled prospectively for 583 consecutive
      patients undergoing RRP or BXRT between January 1, 1997 and October 30, 1998
      using a hospital-wide cost accounting system. The total cost per case included
      both technical and professional components. The technical costs included those
      incurred for anesthesiology, laboratory medicine, medicine, pharmacy, nursing,
      radiology, 125I seeds, and BXRT technicians. Professional costs included fees
      from anesthesiology, laboratory, medicine, urology, radiation oncology, and
      physics. Cases were divided into three groups for analysis: group 1, RRP (n =
      404); group 2, BXRT with planning ultrasound performed in the office setting
      before implantation (n = 107); and group 3, BXRT with planning ultrasound
      performed in the operating room at the time of implantation (n = 72). Results are
      reported as relative cost ratios, with RRP assigned a relative cost of 1.0.
      RESULTS: The total relative perioperative cost for BXRT exceeded that for RRP by
      85% to 105%. Technical cost, exclusive of 125I seeds, was substantially lower for
      BXRT (relative cost 0.36 to 0.42) but was more than offset by the cost of the
      seeds when comparing total cost with RRP. Performance of the planning ultrasound
      in the operating room (group 3) increased the total cost by 20%. The categorical
      technical costs for both BXRT groups were significantly lower for anesthesiology,
      laboratory medicine, medicine, pharmacy, and nursing but were significantly
      higher for radiology. The total professional costs were similar for all groups.
      CONCLUSIONS: Perioperative costs of BXRT with 125I seeds are substantially higher
      than RRP in the treatment of localized prostate cancer, primarily because of the
      cost of the seeds.

PMID- 10654899
TI  - Salvage cryotherapy for recurrent prostate cancer after radiation therapy: the
      Columbia experience.
AB  - OBJECTIVES: Cryotherapy of the prostate represents a potential treatment for
      localized recurrent prostate cancer after radiation therapy. We report our
      experience and evaluate the predictive factors for prostate-specific antigen
      (PSA) recurrence. METHODS: Between October 1994 and April 1999, 43 patients
      underwent salvage cryoablation. All patients had biopsy-proven recurrent prostate
      cancer without seminal vesicle invasion, negative bone scans, and negative lymph
      node dissection. Patients had received 3 months of combined hormonal therapy
      before cryosurgery. Biochemical recurrence-free survival (bRFS) was defined as a
      PSA value less than 0.1 ng/mL. RESULTS: Complications included incontinence (9%),
      obstruction (5%), urethral stricture (5%), rectal pain (26%), urinary infection
      (9%), scrotal edema (12%), and hematuria (5%). The mean follow-up was 21.9 months
      (range 1.2 to 54). Twenty-six patients (60%) reached a serum PSA nadir less than
      0.1 ng/mL, 16 (37%) had a PSA less than 4 ng/mL, and 1 (3%) had a PSA less than
      10 ng/mL. The bRFS rate was 79% at 6 months and 66% at 12 months. The bRFS rate
      was higher for patients who had an undetectable postcryotherapy PSA than for
      patients who did not reach a PSA less than 0. 1 ng/mL (73% versus 30%, P =
      0.0076). Using multivariate analysis, a PSA nadir greater than 0.1 ng/mL was an
      independent predictor of PSA recurrence. CONCLUSIONS: Current salvage cryotherapy
      of the prostate can result in undetectable serum PSA levels with low morbidity.
      Our data support the current safety and efficacy profile. We believe that
      cryotherapy is a viable option in the treatment of patients who have biopsy
      proven local failure after radiation therapy for prostate cancer. Further
      refinements in technique and equipment may enhance cryosurgical results.

PMID- 10654900
TI  - Importance of high radiation doses (72 Gy or greater) in the treatment of stage
      T1-T3 adenocarcinoma of the prostate.
AB  - OBJECTIVES: To analyze the effect of total radiation dose on the outcome of
      patients treated with external beam radiotherapy for early-stage prostate cancer.
      METHODS: The records of a total of 738 patients with localized prostate cancer
      treated with external beam radiotherapy (RT) and no androgen deprivation at our
      institution between July 1986 and February 1999 were reviewed. Two risk groups
      were defined: favorable (Stage T1-T2, pretreatment prostate-specific antigen
      [PSA] level 10.0 ng/mL or less, and biopsy Gleason score 6 or less) and
      unfavorable (Stage T3 lesion or pretreatment PSA level greater than 10.0 ng/mL or
      biopsy Gleason score 7 or greater). The median RT dose was 70.0 Gy (range 57.6 to
      78.0), with 192 patients (26%) receiving at least 72.0 Gy. The mean follow-up was
      45 months. RESULTS: The 5-year biochemical relapse-free survival (bRFS) rate was
      58%. The 5-year bRFS rate for patients who received radiation doses of 72 Gy or
      greater versus less than 72 Gy was 85% and 54%, respectively (P <0.001). On
      multivariate analysis of factors affecting bRFS rates, the number of follow-up
      PSA levels (P <0.001), tumor stage (P <0.001), pretreatment PSA (P <0.001),
      biopsy Gleason score (P <0.00 1), and RT dose (P = 0.001) were the only
      independent predictors of outcome. For favorable tumors, the 5-year bRFS rate for
      patients who received radiation doses of 72 Gy or greater versus less than 72 Gy
      was 98% and 81 %, respectively (P = 0.023). For unfavorable tumors, the 5-year
      bRFS rate for patients who received radiation doses of 72 Gy or greater versus
      less than 72 Gy was 75% and 41 %, respectively (P = 0.001). CONCLUSIONS: Patients
      receiving radiation doses of 72 Gy or higher had a significantly better outcome.
      The improvement was seen in all subgroups of patients. If these results are
      confirmed, radiation doses exceeding 72 Gy should be considered the standard of
      care. Inc.

PMID- 10654901
TI  - Complications after prostate brachytherapy in the Medicare population.
AB  - OBJECTIVES: Prostate brachytherapy is gaining in popularity among patients and
      physicians for the treatment of clinically localized prostate cancer. Although
      several major centers have published their results and morbidity data, nationwide
      data concerning complications have not been available. This study reports
      complications after prostate brachytherapy for men in the Medicare population.
      METHODS: All men in the Medicare population who underwent prostate brachytherapy
      in 1991 were identified. All inpatient, outpatient, and physician (Part B)
      Medicare claims for these men from 1991 to 1993 were then analyzed to determine
      outcomes. RESULTS: In 1991, 2124 men in the Medicare population underwent
      prostate brachytherapy. A total of 176 men (8.3%) underwent a surgical procedure
      for bladder outlet obstruction during the follow-up period, including
      transurethral resection of the prostate in 141 men. Seven men (0.3%) underwent a
      colostomy for complications secondary to radiation, and 4 men (0.2%) had an
      artificial urinary sphincter placed after prostate brachytherapy. Penile
      prostheses were placed in 14 men (0.6%) in the first 24 to 36 months after
      prostate brachytherapy. A diagnosis of urinary incontinence was carried by 140
      men (6.6%) after the procedure; 179 men (8.4%) carried a diagnosis of erectile
      dysfunction after their procedure. A diagnosis consistent with rectal injury
      secondary to radiation appeared in 116 men (5.5%) after prostate brachytherapy.
      CONCLUSIONS: Prostate brachytherapy is being promoted as an effective treatment
      option for clinically localized prostate cancer that offers a low risk of
      complications. The low rate of urinary incontinence, bladder outlet obstruction,
      and erectile dysfunction was confirmed by analyzing a nationwide cohort of men.
      Rectal complications were also consistent with those described in published
      studies. The limitations of claim information in determining patient outcomes,
      however, must be kept in mind when evaluating these data.

PMID- 10654902
TI  - Transdermal estrogen in the treatment of hot flushes in men with prostate cancer.
AB  - OBJECTIVES: To assess the effectiveness and tolerability of transdermal estrogen
      in men with hot flushes after hormonal therapy for prostate cancer. METHODS:
      Twelve men with moderate to severe hot flushes were randomized to receive either
      low-dose (0.05 mg) or high-dose (0.10 mg) estrogen patches applied twice weekly
      for 4 weeks. After a 4-week washout period in which no treatment was given, each
      patient received the alternative dose for 4 weeks. Treatment response was
      assessed by daily logs and questionnaires completed every 4 weeks that included a
      visual analog assessment. Serum luteinizing hormone, follicle-stimulating
      hormone, testosterone, and estradiol levels were also measured every 4 weeks
      during the study. RESULTS: There was a significant reduction in the overall
      severity of the hot flushes seen in patients with both the low and high-dose
      estrogen patch. A significant reduction in the daily frequency of the hot flushes
      was seen with the high-dose patch only. Overall, 10 (83%) of 12 men reported
      either mild, moderate, or major improvement in symptoms with either the low or
      high-dose patch. Mild, painless breast swelling or nipple tenderness was noted in
      2 (17%) and 5 (42%) of 12 men treated with the low and high-dose estrogen patch,
      respectively. FSH levels decreased significantly with both the low and high-dose
      patch. Estradiol levels increased from 12.1 to 16.4 pg/mL and 26.9 pg/mL with the
      low and high-dose patch, respectively. There was no significant change in serum
      testosterone or luteinizing hormone levels. CONCLUSIONS: Transdermal estrogen
      appears to be a promising, well-tolerated therapy for men with hot flushes after
      endocrine treatment for prostate cancer. Further study in larger groups of
      patients is necessary to assess the relative effectiveness and morbidity of this
      treatment.

PMID- 10654903
TI  - Adjuvant treatment of clinical stage I seminoma: is a single course of
      carboplatin sufficient?
AB  - OBJECTIVES: Adjuvant radiotherapy produces excellent disease-free rates in
      clinical Stage I seminoma. However, concern is growing about side effects and
      late hazards of this treatment. Carboplatin has been suggested to supplant
      radiotherapy. To date, there is little experience with this drug in the adjuvant
      treatment of seminoma. In particular, it is unclear whether one or two courses
      should be administered. METHODS: In a nonrandomized study, 125 patients with pure
      clinical Stage I seminoma were given adjuvant carboplatin treatment (400 mg/m2).
      Ninety-three patients received one course and 32 two courses. The median follow
      up time was 48 months. To assess gonadal toxicity, serial measurements of
      follicle-stimulating hormone (FSH) levels were done. To assess myelotoxicity,
      platelet counts at 3 and 4 weeks after treatment were monitored. RESULTS: There
      were no relapses after two courses of carboplatin. After one course of
      carboplatin, eight relapses occurred (8.6%; 95% confidence interval [CI] 3.79% to
      16.2%). All the relapses were located in the para-aortic region, and all the
      patients were rescued with cisplatin-based chemotherapy. The median time to
      recurrence was 16 months. The 5-year actuarial progression-free survival rate
      after one course was 91.1% (95% CI 85.25% to 97.01%). Younger patients (age
      groups: less than 30 years and 31 to 38 years) had relapses more frequently (P =
      0.038) than those in the older age group (greater than 38 years). After 3 weeks,
      32% of the patients had platelet counts below 150/nL. The median FSH level
      increased immediately after treatment, reaching a peak of 13.6 U/L. After 20
      months, the median FSH level had returned to the normal range. CONCLUSIONS: One
      adjuvant course of carboplatin was associated with low myelotoxicity and low
      gonadal toxicity; however, the recurrence rate was almost 9% and thus
      unsatisfactory. After two courses of carboplatin, no relapse was observed. Thus,
      the two-course regimen of carboplatin appears to be equivalent to radiotherapy,
      and because of its favorable toxicity profile, this regimen should be
      investigated in randomized trials.

PMID- 10654904
TI  - Effect of microsurgical subinguinal varicocele ligation to treat pain.
AB  - OBJECTIVES: The traditional treatment for a painful varicocele consists of
      conservative measures followed by varicocelectomy. We report our results with
      microsurgical subinguinal varicocele ligation to treat pain. METHODS: From 1996
      to 1999, a total of 119 men underwent subinguinal microsurgical varicocele
      ligation for painful varicocele. The diagnosis of varicocele was based on the
      findings of both physical examination and color Doppler ultrasound. Patients
      described pain with testicular discomfort as scrotal heaviness or a dull ache.
      While waiting for the operation (range 3 to 5 weeks), all the patients underwent
      a preoperative trial of conservative management for pain. RESULTS: Of 119 men, 82
      (69 %) were available for follow-up 3 months postoperatively. Of those 82
      patients, 72 (88%) reported complete resolution of pain, 4 patients (5%) partial
      resolution, 5 patients (6%) no change, and 1 patient (1%) epididymal discomfort
      that resolved with conservative measures. Of the 9 patients with partial or no
      change, 2 patients had reflux recurrence as seen on color Doppler ultrasound.
      CONCLUSIONS: Subinguinal microsurgical varicocele ligation is an effective
      treatment for painful varicocele when performed in selected patients.

PMID- 10654905
TI  - Intracavernous alprostadil alfadex is more efficacious, better tolerated, and
      preferred over intraurethral alprostadil plus optional actis: a comparative,
      randomized, crossover, multicenter study.
AB  - OBJECTIVES: To compare the efficacy, safety, and patient preference of
      intracavernously administered alprostadil alfadex and intraurethrally
      administered alprostadil. METHODS: A crossover, randomized, open-label
      multicenter study of 111 patients with erectile dysfunction of at least 6 months'
      duration compared the efficacy, safety, and patient preference of intracavernosal
      alprostadil (EDEX/Viridal) with MUSE plus optional ACTIS. All patients underwent
      an in-office dose titration with either drug before undertaking an at-home
      treatment phase. The most frequently used doses during the at-home phase were 40
      microg (44.1% of men) and 1000 microg (86.8% of men) for EDEX and MUSE,
      respectively; the mean doses were 26.1 microg and 922.5 microg for EDEX and MUSE,
      respectively. RESULTS: More EDEX than MUSE administrations resulted in an
      erection sufficient for sexual intercourse (82.5% versus 53.0%); significantly
      more patients using EDEX achieved at least one erection sufficient for sexual
      intercourse (92.6% versus 61.8%; P <0.0001); and EDEX use resulted in a
      significantly greater percentage of patients attaining at least 75% of erections
      sufficient for sexual intercourse (75% versus 36.8%; P <0.0001). Penile pain was
      the most common side effect for both medications: 20.0% versus 30.5% (in-office)
      and 33.8% versus 25.0% (at-home) for EDEX and MUSE, respectively. Similar numbers
      of adverse events were reported with either treatment during the at-home phase.
      Patient and partner satisfaction was greater with EDEX, and more patients
      preferred this therapy, choosing to continue it during a patient preference
      period at the end of the study. CONCLUSIONS: Since intracavernous injection
      therapy was more efficacious, better tolerated, and preferred by the patients and
      their partners, it should be offered as the first-choice treatment if oral
      therapy fails or is contraindicated.

PMID- 10654906
TI  - The mucosal collar revisited.
AB  - OBJECTIVES: The mucosal collar was designed to achieve a cosmetically normal
      appearing, circumcised phallus during hypospadias surgery. The original technique
      has been modified and refined since its introduction by Firlit in 1987. Herein,
      we provide a detailed description of the procedure as it is now performed.
      METHODS: From 1987 to 1998, more than 500 mucosal collars were created by the
      senior author as a routine component of the hypospadias repair. RESULTS: The
      mucosal collar produced a cosmetically normal-appearing, circumcised phallus in
      all cases. No associated morbidities attributable to the collar occurred.
      CONCLUSIONS: The mucosal collar is a simple procedure to master and reproducibly
      yields a normal-appearing, circumcised phallus. The techniques used for
      urethroplasty are independent of the creation of the collar and will never
      preclude its use. We believe that the cosmetic outcome is unequaled by other
      techniques and that the collar should be used in all hypospadias surgery,
      regardless of the type of repair.

PMID- 10654907
TI  - Clinical results of fetal obstructive uropathy treated by vesicoamniotic
      shunting.
AB  - OBJECTIVES: To report the clinical results of 5 fetuses after a vesicoamniotic
      shunting procedure (VASP). METHODS: Between 1995 and 1998, 5 patients (two with
      prune belly syndrome, one with a cloacal anomaly, one with urethral stenosis, and
      one with a sacrococcygeal teratoma) underwent VASP using a double-basket
      catheter. We used the following selection criteria: a fetus without chromosomal
      defects, with oligohydramnios, and with a predicted good renal function from
      sequential or single fetal urinalysis (sodium concentration, chloride
      concentration, and osmolarity at less than 100 mEq/L, less than 90 mEq/L, and
      less than 210 mOsm, respectively). RESULTS: The mean gestational age was 20.8 +/-
      6.9 weeks at diagnosis, 24.2 +/- 6.0 weeks at VASP, and 30.6 +/- 6.2 weeks at
      delivery. In our study, 2 of 5 patients survived. One of the patients with prune
      belly syndrome was 18 months old at last follow-up, with hydrocephalus and a
      creatinine level of 0.2 mg/dL. The patient with the cloacal anomaly was 4 years
      old at last follow-up and had signs of clonic convulsion. However, psychomotor
      development was delayed in both. Of the 3 patients who died, 2 died after birth,
      and the autopsy determined death was due to pulmonary insufficiency. The patient
      with urethral stenosis died in utero. CONCLUSIONS: Although the principal purpose
      of VASP is to prevent pulmonary hypoplasia and dysfunctional kidneys, VASP was
      not always effective, as the outcomes were poor in most of our patients. A
      greater standardization of patient selection and a large cohort study in the
      future should be considered to assess VASP.

PMID- 10654908
TI  - Surgical complications of bladder augmentation: comparison between various
      enterocystoplasties in 133 patients.
AB  - OBJECTIVES: Ileal and sigmoid augmentation are equally effective at increasing
      bladder capacity and compliance. Therefore, knowledge of the incidence of major
      complications, including perforation, small bowel obstruction (SBO), anastomotic
      complications, calculus formation, and indications for revision may be useful in
      choosing the ideal segment. We compared the complications of ileocystoplasty and
      two types of sigmoidocystoplasty that required reoperative surgery. METHODS:
      Between 1981 and 1997, 158 patients with a mean age of 11 years (range 2 to 25)
      underwent augmentation cystoplasty. Ileum or sigmoid colon was used in 133
      patients, who were the subjects of this study. The mean follow-up was 64 months
      (range 6 to 185). Indications included neurogenic bladder (n = 100), bladder
      exstrophy (n = 12), cloacal exstrophy (n = 6), posterior urethral valves (n = 3),
      and miscellaneous (n = 12). Ileum was used in 65 patients and sigmoid colon in
      68. Of these, 48 underwent conventional colocystoplasty and 20 seromuscular
      colocystoplasty lined with urothelium (SCLU). Seventy-nine percent required
      additional procedures to achieve continence or facilitate catheterization, which
      included bladder neck procedures in 56% or continent stomas alone in 23%.
      RESULTS: There were no deaths or complications of bowel anastomosis. Overall,
      continence was achieved in 95%. Spontaneous bladder perforation was highest in
      patients with neurogenic bladder. Calculi developed more frequently in patients
      with continent stomas (P = 0.04) and in patients with bladder/cloacal exstrophy
      (32%) than in patients with neurogenic bladder (P = 0.01). Additional procedures
      and route of catheterization did not increase the risk of perforation. One
      patient with SCLU with known hypercalciuria developed bladder calculi.
      CONCLUSIONS: Sigmoid colon showed a trend of a lower rate of SBO with no
      difference in perforation or stone formation compared with ileum. Primary
      diagnoses of bladder or cloacal exstrophy and continent stomas are risk factors
      for the development of calculi. SCLU has a low rate of surgical complications and
      no incidence of perforation or SBO thus far; therefore, we advocate the use of
      SCLU when feasible, and sigmoid as the preferred bowel segment for augmentation
      cystoplasty.

PMID- 10654909
TI  - Use of ureteroscopy and holmium:yttrium-aluminum-garnet laser in the treatment of
      an infundibular stenosis.
AB  - An infundibular stenosis is defined by a dilated calyx draining through a
      narrowed infundibulum into a nondistended renal pelvis. We describe the use of
      ureteroscopy and the holmium:yttrium-aluminum-garnet (YAG) laser to successfully
      treat an infundibular stenosis in a 27-year-old woman who presented with left
      flank pain. The holmium:YAG laser is well suited for this application. It can be
      applied with precise control of the direction and depth of the cut. The
      retrograde approach avoids the morbidity of a percutaneous nephrostomy and is
      well suited for treating an anterior infundibular stenosis.

PMID- 10654910
TI  - Open technique for nerve-sparing retroperitoneal lymphadenectomy.
AB  - INTRODUCTION: Retroperitoneal lymphadenectomy (RPLND) is indicated in patients
      with testicular cancer of all stages for staging, prognostic, and therapeutic
      purposes. Modification of the classic RPLND to incorporate nerve sparing has
      reduced the morbidity associated with this procedure with respect to ejaculation
      and fertility. TECHNICAL CONSIDERATIONS: Performance of nerve-sparing RPLND
      requires an understanding of the anatomy of the sympathetic chains, their
      branches, and their relationship to the major structures of the retroperitoneum.
      The key element of this procedure is the prospective identification of the
      postganglionic nerves, which arise from the lumbar sympathetic chains and form an
      anastomosing network anterior to the aorta and surrounding the origin of the
      inferior mesenteric artery. Precise dissection of these nerves allows complete
      skeletonization of the great vessels and removal of all lymphatic tissue, without
      compromising cancer control. CONCLUSIONS: Nerve-sparing RPLND is the procedure of
      choice for patients with testicular cancer in whom surgical therapy of the
      retroperitoneum is indicated. The procedure is associated with minimal morbidity
      and results in preservation of ejaculation in virtually all patients with low
      stage disease and in selected patients with advanced disease or after
      chemotherapy.

PMID- 10654912
TI  - Retroperitoneal mass and hydronephrosis.

PMID- 10654911
TI  - Laparoscopic retroperitoneal lymph node dissection.
AB  - INTRODUCTION: Retroperitoneal lymph node dissection (RPLND) is the most accurate
      method for evaluating the presence of retroperitoneal metastases from clinical
      Stage I nonseminomatous testicular tumors. We have introduced laparoscopy to
      reduce the morbidity of open RPLND, which is too high for a diagnostic procedure.
      As the next step, we replaced open surgery with the laparoscopic approach for
      Stage IIb tumors to remove residual tumor after chemotherapy. TECHNICAL
      CONSIDERATIONS: One prerequisite for laparoscopic RPLND is free access to the
      retroperitoneum, which can be achieved by wide dissection of the colon and
      duodenum. The borders of the dissection are the same as with open surgery, and
      complete dissection can be achieved. Bipolar coagulation and the harmonic scalpel
      have proved very helpful in achieving adequate hemostasis, a crucial point.
      Venous lesions can be sealed with fibrin glue. CONCLUSIONS: Laparoscopic RPLND is
      superior to open surgery with regard to morbidity and complication rates, and
      operative times are equal once enough experience has been collected. The
      diagnostic accuracy is the same for both methods, and tumor control is not
      compromised by the laparoscopic approach. The only drawback of laparoscopy is the
      long and steep learning curve.

PMID- 10654913
TI  - Intrathoracic herniation of the kidney.

PMID- 10654914
TI  - Effects of sildenafil on cAMP and cGMP levels in isolated human cavernous and
      cardiac tissue.
AB  - OBJECTIVES: To further investigate the mechanism of action of sildenafil, a
      selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific
      phosphodiesterase 5 (PDE5), that has been proved to be effective in the treatment
      of male erectile dysfunction. We assessed the effects of sildenafil on the in
      vitro formation of cGMP and cyclic adenosine monophosphate (cAMP) in isolated
      human corpus cavernosum and cardiac muscle. METHODS: Isolated segments of human
      corpus cavernosum and cardiac muscle were exposed to increasing concentrations of
      sildenafil. The dose-dependent accumulation of cGMP and cAMP was determined in
      the tissue samples by means of radioimmunoassays. Responses of the isolated
      tissue preparations to sildenafil were compared with those obtained with the
      reference compounds sodium nitroprusside, forskolin, and milrinone. RESULTS: In
      the concentration range 0.01 to 1 microM, there was only a minor effect of
      sildenafil on cGMP levels in isolated human cavernous and cardiac tissues. In
      contrast, sildenafil was found to increase cAMP significantly in both cavernous
      and cardiac tissue in physiologic and supraphysiologic concentrations. The
      stimulation of cAMP by sildenafil was more pronounced in cavernous than in
      cardiac tissue. Concentrations of cGMP in the cardiac strips were unaltered by
      milrinone; cAMP was stimulated starting at a concentration of 0.05 microM. In the
      range of 0.1 to 1.0 microM, the in vitro effect of sildenafil on cAMP levels in
      the cardiac samples was almost equivalent to that of milrinone. CONCLUSIONS: Our
      findings provide a potential mechanism for the cardiovascular side effects that
      have been reported with sildenafil use, highlighting the fact that a "cross-talk"
      between cGMP and cAMP-dependent signal transduction pathways might exist in human
      cavernous and cardiac muscle that may be of pharmacologic significance.

PMID- 10654915
TI  - Soluble Fas in serum from patients with renal cell carcinoma.
AB  - OBJECTIVES: Fas/APO- 1 is an apoptosis-signaling cell-surface receptor belonging
      to the tumor necrosis factor receptor family. The Fas-Fas ligand system plays an
      important role in cytotoxic T-lymphocyte-mediated or natural killer cell-mediated
      cytotoxicity against tumor cells. Soluble Fas (sFas), generated by alternative
      splicing, has been reported to antagonize the interaction of cell-surface Fas
      with Fas ligand. This study examined the level of sFas in the serum of patients
      with renal cell carcinoma (RCC) and investigated the correlation between the sFas
      level and clinicopathologic parameters of RCC. METHODS: Using reverse
      transcriptase-polymerase chain reaction, we examined the production of sFas
      messenger RNA (mRNA) from the cultured human RCC cell lines ACHN and OUR-10 and
      from surgical specimens. We also measured sFas levels in the serum of 31 patients
      with RCC before and after nephrectomy using an sFas-specific enzyme-linked
      immunosorbent assay. RESULTS: mRNA of sFas was identified both in cultured ACHN
      cells and human RCC tissues, although mRNA of wild-type Fas was exclusively
      predominant. The level of sFas in the serum of patients with RCC was
      significantly higher than that of normal controls, but sFas was not detectable in
      the supernatant of cultured renal cancer cells. Preoperative and postoperative
      serum sFas levels did not clearly correlate with the patients' age or sex or with
      histologic stage, grade, or cell type of RCC. The serum sFas level in patients
      with RCC correlated with tumor size. In 24 of the 31 cases, radical nephrectomy
      reduced the serum sFas level within 3 months. CONCLUSIONS: Our results suggest
      that the elevated serum sFas level in patients with RCC might not be derived from
      the tumor itself but might reflect an immune response to the tumor burden. Serum
      sFas may be a useful indicator of tumor burden in patients with RCC.

PMID- 10654916
TI  - Prospects for hepatitis B virus eradication and control of hepatocellular
      carcinoma.
AB  - Hepatitis B virus infection is the most common cause of chronic hepatitis, liver
      cirrhosis and hepatocellular carcinoma worldwide. In areas hyperendemic for HBV
      infection, the related complications occur mostly during adulthood. However,
      nearly half of all primary infection in chronic carriers occurs in the perinatal
      period through maternal transmission, the other half arising from horizontal
      transmission mainly through intrafamilial spread or injection using unsterilized
      needles. A universal vaccination programme is better than immunization for at
      risk groups. Hepatitis B vaccination should be integrated into the Expanded
      Programme on Immunization in children. Universal immunization against hepatitis B
      virus has proved to be effective in reducing the hepatitis B carrier rate to one
      tenth of the prevalence before the vaccination programme in highly endemic areas,
      and the incidence of hepatocellular carcinoma in children has also been shown to
      be significantly reduced. Continued efforts to implement universal vaccination
      programmes worldwide will very likely reduce the incidence of hepatitis B virus
      related diseases, particularly liver cirrhosis and hepatocellular carcinoma.

PMID- 10654917
TI  - Hepatitis C virus and hepatocellular carcinoma.
AB  - The sequential development of cirrhosis and hepatocellular carcinoma (HCC) in
      patients with transfusion-associated hepatitis was a clue leading to the
      identification of hepatitis C virus (HCV) as a risk factor for HCC. The incidence
      of HCV-related liver cancer is increasing in many developed countries: tumours
      arise in older patients, are almost invariably associated with cirrhosis and
      often have a less aggressive course than is seen in HCC related to other
      aetiological factors. Most HCCs grow as a single hepatic nodule for several years
      before generating satellite or distant tumour nodules. Tumour progression and
      hepatic failure are the leading causes of death. HCV might promote cancer through
      cirrhosis, which is per se an important risk factor for this tumour. HCV might
      also have oncogenic properties by interacting with cellular genes that regulate
      cell growth and differentiation. The primary prevention of HCC through
      vaccination against HCV is not yet available. The treatment of patients with
      chronic hepatitis C with interferon might attenuate the risk of HCC.

PMID- 10654918
TI  - New approaches to the investigation of focal hepatic lesions.
AB  - In the past few years, tremendous advances have been made in the fields of
      magnetic resonance imaging, computed tomography and ultrasonography. These
      include the development of novel contrast agents and new approaches to image
      acquisition and processing. This review provides an overview of the state-of-the
      art of imaging investigation of focal hepatic lesions and highlights some of the
      most exciting emerging technologies.

PMID- 10654919
TI  - Aflatoxin and liver cancer.
AB  - This chapter reviews the data that have been accumulated implicating aflatoxin
      ingestion as an important risk factor in the aetiology of hepatocellular
      carcinoma (HCC). Numerous epidemiological studies have observed a correlation
      between areas of high aflatoxin exposure and a high incidence of HCC. The use of
      experimental models and specific biomarkers for aflatoxin exposure, such as
      urinary metabolites or aflatoxin adducts, have validated these findings. Ongoing
      clinical trials in Qidong, China, have indicated that oltipraz, a chemopreventive
      agent, can lower the biologically effective dose of aflatoxins by decreasing the
      metabolism of aflatoxin to its carcinogenic form and increasing the
      detoxification pathways of these metabolites. Intervention with chemicals such as
      these, alongside hepatitis B virus immunization programmes and improved storage
      conditions of staple foods, are prevention measures that can be undertaken to
      reduce the incidence of HCC in high-risk regions.

PMID- 10654921
TI  - Liver transplantation for malignant disease.
AB  - For many patients with malignant disease of the liver, liver transplantation
      offers the only opportunity for clinical cure or prolonged palliation. As a
      result of organ scarcity, patients are increasingly selected on the basis of
      tumour stage and with the predictable likelihood of prolonged survival in mind.
      Consequently, 3- and 5-year survival rates of 72% and 68% respectively have been
      described for patients transplanted with hepatocellular carcinoma for tumours
      measuring less than 5 cm in diameter or up to three in number. Moreover, many
      centres are developing adjuvant and neo-adjuvant therapeutic protocols to
      minimize the risks of disease recurrence following transplantation for
      malignancy. In this chapter, we review the current knowledge in relation to
      transplantation for hepatocellular carcinoma, fibrolamellar hepatocellular
      carcinoma, cholangiocarcinoma, metastatic neuroendocrine tumours, secondary solid
      tumours and other rarer malignancies.

PMID- 10654920
TI  - Surgical treatment of malignant liver tumours.
AB  - Surgical resection is the mainstay of treatment for malignant liver tumours and
      offers the only chance of cure. Advances in radiological imaging, surgical
      technique and peri-operative management have enabled liver resection to be
      performed safely. Partial hepatectomy is indicated for the treatment of
      hepatocellular carcinoma and hepatic metastases from colorectal cancer. In
      addition, it may be utilized for selected patients with liver metastases from
      other primary tumours. Total hepatectomy with transplantation may be of benefit
      in some patients with unresectable neuroendocrine metastases or small
      hepatocellular carcinomas. The role of cryosurgery has not been precisely
      defined, and it needs to be compared with other palliative therapies such as
      ethanol injection and hepatic artery embolization.

PMID- 10654922
TI  - Non-surgical treatment for liver metastases.
AB  - The liver is a common site for developing metastatic disease. Although any
      malignancy can spread to the liver, the direct passage of blood from the
      gastrointestinal tract to the liver via the portal circulation results in a high
      rate of liver metastasis from gastrointestinal tract tumours. Various
      radiographical tests including computed tomography and magnetic resonance imaging
      can detect the majority of liver metastases. Surgical resection if feasible is
      the treatment of choice since it produces a 5-year survival rate of about 30%.
      However, the majority of the patients relapse after hepatic resection, 50%
      relapsing in the liver. Systemic chemotherapy produces response rates of 15-30%
      with a median survival of 10-12 months. It is estimated that 30,000 patients each
      year in the USA are candidates for regional hepatic therapy. Hepatic arterial
      chemotherapy, hepatic artery embolization, chemoembolization, cryosurgery,
      ethanol injection of the tumour and radiation therapy are being investigated as
      potential treatment options for such patients.

PMID- 10654923
TI  - Locoregional treatments for hepatocellular carcinoma.
AB  - Improvements in diagnostic techniques have enhanced our understanding of the
      natural history of hepatocellular carcinoma (HCC). This has facilitated a proper
      evaluation of the available treatment options for this neoplasm through both
      phase II studies and randomized controlled trials. Surgical resection and liver
      transplantation constitute the first two radical options, and when they are
      contra-indicated, patients may benefit from percutaneous ethanol injection or
      thermal ablation by radiofrequency current. These options may also achieve a
      complete response and constitute the last potentially radical therapies for small
      HCC. In contrast, for large multinodular tumours, the available treatment options
      have not been shown to improve survival. Arterial embolization with or without
      associated chemotherapy has been widely used. However, randomized controlled
      trials have failed to show a survival benefit, emphasizing the need to develop
      new treatment strategies.

PMID- 10654924
TI  - Screening for hepatocellular carcinoma.
AB  - Screening for hepatocellular carcinoma has become widely practised in the
      management of patients with end-stage liver disease. However, the theoretical
      basis for this practice is largely lacking. Issues such as the selection of the
      target population and the correct method of confirming positive screening tests
      have yet to be resolved. Complicating the assessment of screening strategies is
      the poor literature on comparing different forms of therapy. Nonrandomized,
      uncontrolled studies that do not account for lead-time bias make it frequently
      impossible to know whether an applied treatment has really improved survival.
      Despite these difficulties, screening is reality, and strategies have to be
      devised to efficiently screen patients, find small tumours and apply effective
      treatments. Some practical strategies are discussed.

PMID- 10654925
TI  - Monitoring response to treatment in liver tumours.
AB  - New imaging techniques offer better ways of measuring response to treatment and
      remain central to the formal assessment of response in clinical trials and
      routine clinical practice. Increasing tumour size is consistently associated with
      progressive disease. However, there is evidence that the designation 'partial
      response', as determined by conventional imaging techniques, may not always
      accurately reflect the degree of treatment-induced tumour necrosis. Thus,
      responses classified as partial on imaging grounds have, in some cases, been
      shown to be complete pathological responses after surgical resection, implying
      that residual tumour and necrotic/fibrotic tumour remnants cannot always be
      accurately distinguished by imaging. In this situation, serological tumour
      markers such as alphafetoprotein may be useful in measuring the true degree of
      response. While radiological imaging is likely to remain the main method of
      assessing response in phase II trials of drugs for the treatment of liver cancer,
      it may in some instances be useful to apply additional parameters such as
      alphafetoprotein level.

PMID- 10654926
TI  - A review of gene therapy for the treatment of central nervous system tumors.
AB  - The transfer of genes into tumors of the central nervous system has been touted
      as a novel treatment. However, several scientific and technological hurdles will
      have to be resolved before such strategies become useful clinical tools. This
      review summarizes the current knowledge in the field. Some of the gene delivery
      vectors employed both preclinically and clinically are those based on
      retroviruses, herpes simplex viruses, adenoviruses, adeno-associated viruses, and
      reoviruses. Cells such as fibroblasts and neural progenitor cells may also
      provide therapeutic value. These vectors are used to deliver into the tumor cell
      a variety of anticancer genes, such as those that activate chemotherapy agents,
      increase tumor immunogenicity, modulate tumor apoptosis and/or angiogenesis. One
      of the issues confronting such therapeutic strategies revolves around the blood
      brain-barrier that may limit the penetration of vectors and genes form the
      circulation into the tumor. Results from a variety of clinical trials are
      becoming available. While the safety of this treatment strategy appears to have
      been established, therapeutic efficacy has been lacking. Additional refinements
      in the basic technology of vector construction and further understanding of the
      basic biology of gene transfer and expression will help in establishing gene
      therapy as clinically useful against brain tumors.

PMID- 10654927
TI  - DNA replication and cancer.
AB  - Current knowledge of the mechanisms of DNA replication and their implications in
      oncogenesis is reviewed. Progress in this area will continue to provide new tools
      in the clinical characterization and treatment of a variety of neoplasms.

PMID- 10654928
TI  - Soluble immune mediators in POEMS syndrome with pulmonary hypertension: case
      report and review of the literature.
AB  - POEMS syndrome is a plasma cell dyscrasia that presents with numerous
      complications, one of which is rarely pulmonary hypertension. Here we present a
      case of POEMS syndrome with pulmonary hypertension who improved with steroids and
      six rounds of plasmapheresis done over 1 month, and we document the baseline
      immune mediator status and the changes associated with the therapeutic
      intervention. Serum levels of soluble immune mediators such as interleukin (IL)
      5, IL-8, IL-10, and eotaxin were normal at baseline and throughout therapy,
      whereas those of tumor necrosis factor (TNF)-alpha, soluble TNF-receptor type I
      (sTNF-RI), IL-6, interferon (IFN)-gamma, IL-2, and sIL-2R, which were abnormally
      high at baseline normalized with steroids and plasmapheresis. Serum levels of sIL
      6R, which were abnormally low at baseline, increased to normal after therapy. The
      latter results pinpoint not only potential mediators of the systemic
      manifestations of POEMS syndrome with pulmonary hypertension but also relevant
      markers in patient follow-up. In this respect, IL-6 has been involved in the
      pathogenesis of multiple myeloma and Castleman's disease, and the interplay
      between abnormally high levels of IL-6 and abnormally low levels of its soluble
      receptor, deficiencies that corrected with therapy in this patient, appears to be
      particularly relevant to the pathogenic manifestations of POEMS syndrome with
      pulmonary hypertension. These findings are discussed in the context of our
      current knowledge of the pathogenesis of pulmonary hypertension and of potential
      new therapeutic modalities for POEMS syndrome with pulmonary hypertension.

PMID- 10654929
TI  - The role for transforming growth factor-beta (TGF-beta) in human cancer.
AB  - Uncontrolled cellular proliferation is a hallmark of cancer. Thus, a relevant and
      important question is how cancer cells have escaped from normal growth regulatory
      mechanisms to become malignant and, further, what events favor progression and
      metastasis. Growth regulatory proteins of the transforming growth factor-beta
      family (TGF-beta) are one of the few classes of endogenous inhibitors of cell
      growth. Contrary to the first notion that these proteins may be downregulated in
      cancer cells to promote their growth, generally it has been otherwise found that
      there is a marked increase in the expression of TGF-beta mRNA and protein in
      human cancers (in vivo), including those of the pancreas, colon, stomach, lung,
      endometrium, prostate, breast, brain, and bone. Furthermore, in many of these
      cancers high expression correlates with more advanced stages of malignancy and
      decreased survival. The increased expression of TGF-beta is usually accompanied
      by a loss in the growth inhibitory response to TGF-beta. For example, certain
      tumor cells in culture (i.e., colon carcinoma and glioblastoma multiforme)
      demonstrate a progressive loss of the growth inhibitory response to TGF-beta that
      varies directly with the malignant stage of the original tumor, and the most
      aggressive forms actually switch to being autocrine and/or paracrine growth
      stimulated by TGF-beta. The study of the molecular events associated with the
      escape of tumor cells from growth regulation by TGF-beta has provided insight
      into mechanisms underlying carcinogenesis. The mechanisms for upregulation of TGF
      beta are unknown. However, once malignant cells lose their growth inhibitory
      response to TGF-beta and produce massive amounts of these proteins, the increased
      expression of TGF-beta provides a selective advantage for tumor cell survival as
      TGF-betas are also angiogenic and have potent immunosuppressive effects,
      including specifically inhibiting tumoricidal natural and lymphocyte-activated
      killer cells. In light of the significant role for TGF-betas in regulating cell
      growth, it is not surprising that in more recent years studies have shown that
      specific genetic alterations involved in the signaling pathway for TGF-beta
      mediated growth inhibition have occurred in many human cancers. Specific defects
      in TGF-beta receptors, TGF-beta-related-signal transduction/gene activation, and
      TGF-beta-regulated cell cycle proteins, have all been implicated in the
      oncogenesis of many human cancers. In this context, components of the TGF-beta
      growth response pathway are considered to be tumor suppressor genes, as absence
      (or malfunction) of one or more receptors or signaling proteins would have the
      potential to cause loss of growth regulation. More recently, the
      posttranslational reduction of levels of the cyclin-dependent kinase inhibitor
      (CKI), p27kip1, which mediates TGF-beta growth inhibition, provides an additional
      means for cancer cells to escape negative growth regulation by TGF-beta. This
      review provides background information on TGF-beta and updates the status of our
      knowledge of the role for TGF-beta in specific human malignancies. Understanding
      the molecular events involved in TGF-beta function in normal cells and its lack
      of function in tumor cells should identify novel therapeutic targets in human
      cancers.

PMID- 10654930
TI  - Crystal structure of a fibrillarin homologue from Methanococcus jannaschii, a
      hyperthermophile, at 1.6 A resolution.
AB  - Fibrillarin is a phylogenetically conserved protein essential for efficient
      processing of pre-rRNA through its association with a class of small nucleolar
      RNAs during ribosomal biogenesis. The protein is the antigen for the autoimmune
      disease scleroderma. Here we report the crystal structure of the fibrillarin
      homologue from Methanococcus jannaschii, a hyperthermophile, at 1.6 A resolution.
      The structure consists of two domains, with a novel fold in the N-terminal region
      and a methyltransferase-like domain in the C-terminal region. Mapping temperature
      sensitive mutations found in yeast fibrillarin Nop1 to the Methanococcus
      homologue structure reveals that many of the mutations cluster in the core of the
      methyltransferase-like domain.

PMID- 10654931
TI  - Prion properties of the Sup35 protein of yeast Pichia methanolica.
AB  - The Sup35 protein (Sup35p) of Saccharomyces cerevisiae is a translation
      termination factor of the eRF3 family. The proteins of this family possess a
      conservative C-terminal domain responsible for translation termination and N
      terminal extensions of different structure. The N-terminal domain of Sup35p
      defines its ability to undergo a heritable prion-like conformational switch,
      which is manifested as the cytoplasmically inherited [PSI(+)] determinant. Here,
      we replaced the N-terminal domain of S.cerevisiae Sup35p with an analogous domain
      from Pichia methanolica. Overexpression of hybrid Sup35p induced the de novo
      appearance of cytoplasmically inherited suppressor determinants manifesting key
      genetic and biochemical traits of [PSI(+)]. In contrast to the conventional
      [PSI(+)], 'hybrid' [PSI(+)] showed lower mitotic stability and preserved their
      suppressor phenotype upon overexpression of the Hsp104 chaperone protein. The
      lack of Hsp104 eliminated both types of [PSI(+)]. No transfer of prion state
      between the two Sup35p variants was observed, which reveals a 'species barrier'
      for the [PSI(+)] prions. The data obtained show that prion properties are
      conserved within at least a part of this protein family.

PMID- 10654932
TI  - A recessive C-terminal Jervell and Lange-Nielsen mutation of the KCNQ1 channel
      impairs subunit assembly.
AB  - The LQT1 locus (KCNQ1) has been correlated with the most common form of inherited
      long QT (LQT) syndrome. LQT patients suffer from syncopal episodes and high risk
      of sudden death. The KCNQ1 gene encodes KvLQT1 alpha-subunits, which together
      with auxiliary IsK (KCNE1, minK) subunits form IK(s) K(+) channels. Mutant KvLQT1
      subunits may be associated either with an autosomal dominant form of inherited
      LQT, Romano-Ward syndrome, or an autosomal recessive form, Jervell and Lange
      Nielsen syndrome (JLNS). We have identified a small domain between residues 589
      and 620 in the KvLQT1 C-terminus, which may function as an assembly domain for
      KvLQT1 subunits. KvLQT1 C-termini do not assemble and KvLQT1 subunits do not
      express functional K(+) channels without this domain. We showed that a JLN
      deletion-insertion mutation at KvLQT1 residue 544 eliminates important parts of
      the C-terminal assembly domain. Therefore, JLN mutants may be defective in KvLQT1
      subunit assembly. The results provide a molecular basis for the clinical
      observation that heterozygous JLN carriers show slight cardiac dysfunctions and
      that the severe JLNS phenotype is characterized by the absence of KvLQT1 channel.

PMID- 10654933
TI  - Targeted expression of baculovirus p35 caspase inhibitor in oligodendrocytes
      protects mice against autoimmune-mediated demyelination.
AB  - The mechanisms underlying oligodendrocyte (OLG) loss and the precise roles played
      by OLG death in human demyelinating diseases such as multiple sclerosis (MS), and
      in the rodent model of MS, experimental autoimmune encephalomyelitis (EAE),
      remain to be elucidated. To clarify the involvement of OLG death in EAE, we have
      generated transgenic mice that express the baculovirus anti-apoptotic protein p35
      in OLGs through the Cre-loxP system. OLGs from cre/p35 transgenic mice were
      resistant to tumor necrosis factor-alpha-, anti-Fas antibody- and interferon
      gamma-induced cell death. cre/p35 transgenic mice were resistant to EAE induction
      by immunization with the myelin oligodendrocyte glycoprotein. The numbers of
      infiltrating T cells and macrophages/microglia in the EAE lesions were
      significantly reduced, as were the numbers of apoptotic OLGs expressing the
      activated form of caspase-3. Thus, inhibition of apoptosis in OLGs by p35
      expression alleviated the severity of the neurological manifestations observed in
      autoimmune demyelinating diseases.

PMID- 10654934
TI  - 14-3-3 proteins block apoptosis and differentially regulate MAPK cascades.
AB  - 14-3-3 family members are dimeric phosphoserine-binding proteins that participate
      in signal transduction and checkpoint control pathways. In this work, dominant
      negative mutant forms of 14-3-3 were used to disrupt 14-3-3 function in cultured
      cells and in transgenic animals. Transfection of cultured fibroblasts with the
      R56A and R60A double mutant form of 14-3-3zeta (DN-14-3-3zeta) inhibited serum
      stimulated ERK MAPK activation, but increased the basal activation of JNK1 and
      p38 MAPK. Fibroblasts transfected with DN-14-3-3zeta exhibited markedly increased
      apoptosis in response to UVC irradiation that was blocked by pre-treatment with a
      p38 MAPK inhibitor, SB202190. Targeted expression of DN-14-3-3eta to murine
      postnatal cardiac tissue increased the basal activation of JNK1 and p38 MAPK, and
      affected the ability of mice to compensate for pressure overload, which resulted
      in increased mortality, dilated cardiomyopathy and massive cardiomyocyte
      apoptosis. These results demonstrate that a primary function of mammalian 14-3-3
      proteins is to inhibit apoptosis.

PMID- 10654936
TI  - Mechanism of rescue of common p53 cancer mutations by second-site suppressor
      mutations.
AB  - The core domain of p53 is extremely susceptible to mutations that lead to loss of
      function. We analysed the stability and DNA-binding activity of such mutants to
      understand the mechanism of second-site suppressor mutations. Double-mutant
      cycles show that N239Y and N268D act as 'global stability' suppressors by
      increasing the stability of the cancer mutants G245S and V143A-the free energy
      changes are additive. Conversely, the suppressor H168R is specific for the R249S
      mutation: despite destabilizing wild type, H168R has virtually no effect on the
      stability of R249S, but restores its binding affinity for the gadd45 promoter.
      NMR structural comparisons of R249S/H168R and R249S/T123A/H168R with wild type
      and R249S show that H168R reverts some of the structural changes induced by
      R249S. These results have implications for possible drug therapy to restore the
      function of tumorigenic mutants of p53: the function of mutants such as V143A and
      G245S is theoretically possible to restore by small molecules that simply bind to
      and hence stabilize the native structure, whereas R249S requires alteration of
      its mutant native structure.

PMID- 10654935
TI  - FHL2, a novel tissue-specific coactivator of the androgen receptor.
AB  - The control of target gene expression by nuclear receptors requires the
      recruitment of multiple cofactors. However, the exact mechanisms by which nuclear
      receptor-cofactor interactions result in tissue-specific gene regulation are
      unclear. Here we characterize a novel tissue-specific coactivator for the
      androgen receptor (AR), which is identical to a previously reported protein
      FHL2/DRAL with unknown function. In the adult, FHL2 is expressed in the
      myocardium of the heart and in the epithelial cells of the prostate, where it
      colocalizes with the AR in the nucleus. FHL2 contains a strong, autonomous
      transactivation function and binds specifically to the AR in vitro and in vivo.
      In an agonist- and AF-2-dependent manner FHL2 selectively increases the
      transcriptional activity of the AR, but not that of any other nuclear receptor.
      In addition, the transcription of the prostate-specific AR target gene probasin
      is coactivated by FHL2. Taken together, our data demonstrate that FHL2 is the
      first LIM-only coactivator of the AR with a unique tissue-specific expression
      pattern.

PMID- 10654937
TI  - Core histone N-termini play an essential role in mitotic chromosome condensation.
AB  - We have studied the role of core histone tails in the assembly of mitotic
      chromosomes using Xenopus egg extracts. Incubation of sperm nuclei in the
      extracts led to the formation of mitotic chromosomes, a process we found to be
      correlated with phosphorylation of the N-terminal tail of histone H3 at Ser10.
      When the extracts were supplemented with H1-depleted oligosomes, they were not
      able to assemble chromosomes. Selective elimination of oligosome histone tails by
      trypsin digestion resulted in a dramatic decrease in their ability to inhibit
      chromosome condensation. The chromosome assembly was also inhibited by each of
      the histone tails with differing efficiency. In addition, we found that
      nucleosomes were recruiting through the flexible histone tails some chromosome
      assembly factors, different from topoisomerase II and 13S condensin. These
      findings demonstrate that histone tails play an essential role in chromosome
      assembly. We also present evidence that the nucleosomes, through physical
      association, were able to deplete the extracts from the kinase phosphorylating
      histone H3 at Ser10, suggesting that this kinase could be important for
      chromosome condensation.

PMID- 10654938
TI  - A small amphipathic alpha-helical region is required for transcriptional
      activities and proteasome-dependent turnover of the tyrosine-phosphorylated
      Stat5.
AB  - Cytokines induce the tyrosine phosphorylation and associated activation of signal
      transducers and activators of transcription (Stat). The mechanisms by which this
      response is terminated are largely unknown. Among a variety of inhibitors
      examined, the proteasome inhibitors MG132 and lactacystin affected Stat4, Stat5
      and Stat6 turnover by significantly stabilizing the tyrosine-phosphorylated form.
      However, these proteasome inhibitors did not affect downregulation of the
      tyrosine-phosphorylated Stat1, Stat2 and Stat3. With Stat5 isoforms, we have
      observed that tyrosine-phosphorylated carboxyl-truncated forms of Stat5 proteins
      were considerably more stable than phosphorylated wild-type forms of the protein.
      Also, the C-terminal region of Stat5 could confer proteasome-dependent
      downregulation to Stat1. With a series of C-terminal deletion mutants, we have
      defined a relatively small, potentially amphipathic alpha-helical region that is
      required for the rapid turnover of the phosphorylated Stat5 proteins. The region
      is also required for transcriptional activation, suggesting that the functions
      are linked. The results are consistent with a model in which the transcriptional
      activation domain of activated Stat5 is required for its transcriptional activity
      and downregulation through a proteasome-dependent pathway.

PMID- 10654939
TI  - The organized chromatin domain of the repressed yeast a cell-specific gene STE6
      contains two molecules of the corepressor Tup1p per nucleosome.
AB  - In yeast alpha cells the a cell-specific genes STE6 and BAR1 are packaged as gene
      sized chromatin domains of positioned nucleosomes. Organized chromatin depends on
      Tup1p, a corepressor that interacts with the N-terminal regions of H3 and H4. If
      Tup1p functions to organize or stabilize a chromatin domain, the protein might be
      expected to be present at a level stoichiometric with nucleosomes. Chromatin
      immunoprecipitation assays using Tup1p antibodies showed Tup1p to be associated
      with the entire genomic STE6 coding region. To determine stoichiometry of Tup1p
      associated with the gene, a yeast plasmid containing varying lengths of the STE6
      gene including flanking control regions and an Escherichia coli lac operator
      sequence was constructed. After assembly into chromatin in vivo in Saccharomyces
      cerevisiae, minichromosomes were isolated using an immobilized lac repressor. In
      these experiments, Tup1p was found to be specifically associated with repressed
      STE6 chromatin in vivo at a ratio of about two molecules of the corepressor per
      nucleosome. These observations strongly suggest a structural role for Tup1p in
      repression and constrain models for organized chromatin in repressive domains.

PMID- 10654940
TI  - The Bbp1p-Mps2p complex connects the SPB to the nuclear envelope and is essential
      for SPB duplication.
AB  - In budding yeast, microtubules are organized by the spindle pole body (SPB),
      which is embedded in the nuclear envelope via its central plaque structure. Here,
      we describe the identification of BBP1 in a suppressor screen with a conditional
      lethal allele of SPC29. Bbp1p was detected at the central plaque periphery of the
      SPB and bbp1-1 cells were found to be defective in SPB duplication. bbp1-1 cells
      extend their satellite into a duplication plaque like wild-type cells; however,
      this duplication plaque then fails to insert properly into the nuclear envelope
      and does not assemble a functional inner plaque. This function in SPB duplication
      is probably fulfilled by a stable complex of Bbp1p and Mps2p, a nuclear envelope
      protein that is also essential for duplication plaque insertion. In addition, we
      found that Bbp1p interacts with Spc29p and the half-bridge component Kar1p. These
      interactions are likely to play a role in connecting the SPB with the nuclear
      envelope and the central plaque with the half-bridge.

PMID- 10654941
TI  - Serum-stimulated, rapamycin-sensitive phosphorylation sites in the eukaryotic
      translation initiation factor 4GI.
AB  - The eukaryotic translation initiation factor 4G (eIF4G) proteins play a critical
      role in the recruitment of the translational machinery to mRNA. The eIF4Gs are
      phosphoproteins. However, the location of the phosphorylation sites, how
      phosphorylation of these proteins is modulated and the identity of the
      intracellular signaling pathways regulating eIF4G phosphorylation have not been
      established. In this report, two-dimensional phosphopeptide mapping demonstrates
      that the phosphorylation state of specific eIF4GI residues is altered by serum
      and mitogens. Phosphopeptides resolved by this method were mapped to the C
      terminal one-third of the protein. Mass spectrometry and mutational analyses
      identified the serum-stimulated phosphorylation sites in this region as serines
      1108, 1148 and 1192. Phosphoinositide-3-kinase (PI3K) inhibitors and rapamycin,
      an inhibitor of the kinase FRAP/mTOR (FKBP12-rapamycin-associated
      protein/mammalian target of rapamycin), prevent the serum-induced phosphorylation
      of these residues. Finally, the phosphorylation state of N-terminally truncated
      eIF4GI proteins acquires resistance to kinase inhibitor treatment. These data
      suggest that the kinases phosphorylating serines 1108, 1148 and 1192 are not
      directly downstream of PI3K and FRAP/mTOR, but that the accessibility of the C
      terminus to kinases is modulated by this pathway(s).

PMID- 10654942
TI  - A recurrent RNA-binding domain is appended to eukaryotic aminoacyl-tRNA
      synthetases.
AB  - Aminoacyl-tRNA synthetases of higher eukaryotes possess polypeptide extensions in
      contrast to their prokaryotic counterparts. These extra domains of poorly
      understood function are believed to be involved in protein-protein or protein-RNA
      interactions. Here we showed by gel retardation and filter binding experiments
      that the repeated units that build the linker region of the bifunctional glutamyl
      prolyl-tRNA synthetase had a general RNA-binding capacity. The solution structure
      of one of these repeated motifs was also solved by NMR spectroscopy. One repeat
      is built around an antiparallel coiled-coil. Strikingly, the conserved lysine and
      arginine residues form a basic patch on one side of the structure, presenting a
      suitable docking surface for nucleic acids. Therefore, this repeated motif may
      represent a novel type of general RNA-binding domain appended to eukaryotic
      aminoacyl-tRNA synthetases to serve as a cis-acting tRNA-binding cofactor.

PMID- 10654943
TI  - Male sterility and enhanced radiation sensitivity in TLS(-/-) mice.
AB  - TLS (also known as FUS) is an RNA-binding protein that contributes the N-terminal
      half of fusion oncoproteins implicated in the development of human liposarcomas
      and leukemias. Here we report that male mice homozygous for an induced mutation
      in TLS are sterile with a marked increase in the number of unpaired and mispaired
      chromosomal axes in pre-meiotic spermatocytes. Nuclear extracts from TLS(-/-)
      testes lack an activity capable of promoting pairing between homologous DNA
      sequences in vitro, and TLS(-/-) mice and embryonic fibroblasts exhibit increased
      sensitivity to ionizing irradiation. These results are consistent with a role for
      TLS in homologous DNA pairing and recombination.

PMID- 10654944
TI  - The controlling role of ATM in homologous recombinational repair of DNA damage.
AB  - The human genetic disorder ataxia telangiectasia (A-T), caused by mutation in the
      ATM gene, is characterized by chromosomal instability, radiosensitivity and
      defective cell cycle checkpoint activation. DNA double-strand breaks (dsbs)
      persist in A-T cells after irradiation, but the underlying defect is unclear. To
      investigate ATM's interactions with dsb repair pathways, we disrupted ATM along
      with other genes involved in the principal, complementary dsb repair pathways of
      homologous recombination (HR) or non-homologous end-joining (NHEJ) in chicken
      DT40 cells. ATM(-/-) cells show altered kinetics of radiation-induced Rad51 and
      Rad54 focus formation. Ku70-deficient (NHEJ(-)) ATM(-/-) chicken DT40 cells show
      radiosensitivity and high radiation-induced chromosomal aberration frequencies,
      while Rad54-defective (HR(-)) ATM(-/-) cells show only slightly elevated
      aberration levels after irradiation, placing ATM and HR on the same pathway.
      These results reveal that ATM defects impair HR-mediated dsb repair and may link
      cell cycle checkpoints to HR activation.

PMID- 10654946
TI  - Supplemental Therapeutic Oxygen for Prethreshold Retinopathy Of Prematurity (STOP
      ROP), a randomized, controlled trial. I: primary outcomes.
AB  - OBJECTIVE: To determine the efficacy and safety of supplemental therapeutic
      oxygen for infants with prethreshold retinopathy of prematurity (ROP) to reduce
      the probability of progression to threshold ROP and the need for peripheral
      retinal ablation. METHODS: Premature infants with confirmed prethreshold ROP in
      at least 1 eye and median pulse oximetry <94% saturation were randomized to a
      conventional oxygen arm with pulse oximetry targeted at 89% to 94% saturation or
      a supplemental arm with pulse oximetry targeted at 96% to 99% saturation, for at
      least 2 weeks, and until both eyes were at study endpoints. Certified examiners
      masked to treatment assignment conducted weekly eye examinations until each study
      eye reached ophthalmic endpoint. An adverse ophthalmic endpoint for an infant was
      defined as reaching threshold criteria for laser or cryotherapy in at least 1
      study eye. A favorable ophthalmic endpoint was regression of the ROP into zone
      III for at least 2 consecutive weekly examinations or full retinal
      vascularization. At 3 months after the due date of the infant, ophthalmic
      findings, pulmonary status, growth, and interim illnesses were again recorded.
      RESULTS: Six hundred forty-nine infants (325 conventional and 324 supplemental)
      were enrolled from 30 centers over 5 years. Five hundred ninety-seven (92.0%)
      infants attained known ophthalmic endpoints, and 600 (92%) completed the
      ophthalmic 3-month assessment. The rate of progression to threshold in at least 1
      eye was 48% in the conventional arm and 41% in the supplemental arm. After
      adjustment for baseline ROP severity stratum, plus disease, race, and gestational
      age, the odds ratio (supplemental vs conventional) for progression was.72 (95%
      confidence interval:.52, 1.01). Final structural status of all study eyes at 3
      months of corrected age showed similar rates of severe sequelae in both treatment
      arms: retinal detachments or folds (4.4% conventional vs 4.1% supplemental), and
      macular ectopia (3.9% conventional vs 3.9% supplemental). Within the prespecified
      ROP severity strata, ROP progression rates were lower with supplemental oxygen
      than with conventional oxygen, but the differences were not statistically
      significant. A post hoc subgroup analysis of plus disease (dilated and tortuous
      vessels in at least 2 quadrants of the posterior pole) suggested that infants
      without plus disease may be more responsive to supplemental therapy (46%
      progression in the conventional arm vs 32% in the supplemental arm) than infants
      with plus disease (52% progression in conventional vs 57% in supplemental).
      Pneumonia and/or exacerbations of chronic lung disease occurred in more infants
      in the supplemental arm (8.5% conventional vs 13.2% supplemental). Also, at 50
      weeks of postmenstrual age, fewer conventional than supplemental infants remained
      hospitalized (6.8% vs 12.7%), on oxygen (37.0% vs 46.8%), and on diuretics (24.4%
      vs 35. 8%). Growth and developmental milestones did not differ between the 2
      arms. CONCLUSIONS: Use of supplemental oxygen at pulse oximetry saturations of
      96% to 99% did not cause additional progression of prethreshold ROP but also did
      not significantly reduce the number of infants requiring peripheral ablative
      surgery. A subgroup analysis suggested a benefit of supplemental oxygen among
      infants who have prethreshold ROP without plus disease, but this finding requires
      additional study. Supplemental oxygen increased the risk of adverse pulmonary
      events including pneumonia and/or exacerbations of chronic lung disease and the
      need for oxygen, diuretics, and hospitalization at 3 months of corrected age.
      Although the relative risk/benefit of supplemental oxygen for each infant must be
      individually considered, clinicians need no longer be concerned that supplemental
      oxygen, as used in this study, will exacerbate active prethreshold ROP.

PMID- 10654945
TI  - Impaired germinal center reaction in mice with short telomeres.
AB  - Reduction of germinal center reactivity is a landmark of immunosenescence and
      contributes to immunological dysfunction in the elderly. Germinal centers (GC)
      are characterized by extensive clonal expansion and selection of B lymphocytes to
      generate the pool of memory B cells. Telomere maintenance by telomerase has been
      proposed to allow the extensive proliferation undergone by B lymphocytes in the
      GC during the immune response. We show here that late generation mTR(-/-) mice,
      which lack the mouse telomerase RNA (mTR) and have short telomeres, present a
      dramatic reduction in GC number following antigen immunization. Upon immunization
      with an antigen, wild-type splenocyte telomeres are elongated and this is
      accompanied by a high expression of the telomerase catalytic subunit in the
      spleen GC. In contrast, telomerase-deficient mTR(-/-) splenocytes show telomere
      shortening after immunization, presumably due to cell proliferation in the
      absence of telomerase. All together, these results demonstrate the importance of
      telomere maintenance for antibody-mediated immune responses and support the
      notion that telomere elongation detected in wild-type spleens following
      immunization is mediated by telomerase.

PMID- 10654947
TI  - Detection of pathogen transmission in neonatal nurseries using DNA markers as
      surrogate indicators.
AB  - OBJECTIVE: Nosocomial infections are a major problem confronting neonatal
      intensive care units (NICUs). This study was conducted to determine if DNA
      markers designed from the cauliflower mosaic virus (CaMV 35S DNA) can serve as
      surrogate indicators of nosocomial pathogen transmission in NICUs. METHODS:
      Regions of cauliflower CaMV 35S promoter DNA were designed to serve as surrogate
      markers of microbial transmission pathways. Each of 6 pods within the NICU under
      study houses 8 newborn infants. DNA marker was placed on the telephone handle in
      only 1 of the 6 NICU pods (study pod). Bedside caregivers were blinded as to when
      placebo or marker were placed in the pod. Thirty-two samples were collected from
      predetermined sites within each pod at 0, 4, 8, 24, and 48 hours and 7 days after
      DNA placement. Similar sites were sampled in each of the 6 pods. Additional
      samples were collected concurrently from areas of the NICU segregated from direct
      patient care. Polymerase chain reactions were performed on collected samples, and
      products were analyzed by agarose gel electrophoresis. RESULTS: One thousand
      three hundred samples of the environment and hands of personnel were collected
      and analyzed. Within the study pod, 58% of sites tested positive for the DNA
      marker throughout all time points; positive sites peaked at 8 hours (78%) and
      declined to 23% positive at 7 days. The other 5 pods had a mean of 18% of sites
      positive throughout the 7 days and exhibited a similar decline throughout time.
      The most consistently positive sites within all pods were the blood gas
      analyzers, computer mice, telephone handles, medical charts, ventilator knobs,
      door handles, radiant warmer control buttons, patient monitors, and personnel
      hands. In areas outside the pods, the nurse's station, resident physician
      charting area, changing room, and staff break room had a mean of 50% positive
      sites throughout all time points. CONCLUSIONS: DNA markers proved useful as safe,
      surrogate indicators of microorganism transmission within and outside pods in the
      NICU. We speculate that utilization of these techniques in the hospital
      environment will provide important information about transmission of pathogens in
      the NICU, assist in developing and enforcing cleaning procedures, and permit
      testing of educational intervention programs targeting a decrease in nosocomial
      infections.nosocomial infection, neonatal intensive care, DNA marker, polymerase
      chain reaction, infection control.

PMID- 10654948
TI  - Cerebrospinal fluid findings in aseptic versus bacterial meningitis.
AB  - BACKGROUND: Aseptic meningitis is often reported to be characterized by a
      mononuclear cell predominance in the cerebrospinal fluid (CSF), whereas bacterial
      meningitis is characterized by a polymorphonuclear (PMN) cell predominance. In
      contrast, other studies suggest that PMNs can be the most prevalent cell in early
      aseptic meningitis followed by a shift to mononuclear cells within 24 hours.
      These contradictory reports may lead to uncertainty in the diagnosis and
      treatment of meningitis. OBJECTIVES: To assess 1) the characteristics of the CSF
      differential in aseptic versus bacterial meningitis, 2) the influence of duration
      of illness on the CSF differential, and 3) the role of the CSF differential in
      discriminating between aseptic versus bacterial meningitis. METHODS: A
      retrospective chart review was conducted of all cases of meningitis in children
      >30 days of age hospitalized during the peak months for enteroviral meningitis
      (April to October) between 1992 to 1997. Cases of aseptic meningitis were defined
      as having at least 20 white blood cells/mm(3) and the absence of bacterial growth
      on culture. Patients were excluded if they received antibiotic therapy within the
      previous 5 days. Cases of bacterial meningitis were defined as having a positive
      culture of the CSF or the presence of a CSF pleocytosis with positive cultures of
      the blood. CSF variables including white blood cell differential and time from
      the onset of symptoms to the performance of a lumbar puncture were analyzed. PMNs
      were considered to be predominant when the percentage of neutrophils added to
      juvenile forms was >50% of cells. RESULTS: One hundred fifty-eight cases of
      meningitis were reviewed: 138 were aseptic and 20 were bacterial. The patients
      ranged in age from 30 days to 18 years; 61% were male. Fifty-seven percent of
      cases of aseptic meningitis had a PMN predominance. The percentage of PMNs in the
      CSF in patients with aseptic meningitis was not statistically different for
      patients who had a lumbar puncture performed either within or beyond 24 hours of
      the onset of symptoms. Fifty-one percent of the 53 patients with aseptic
      meningitis and duration of illness >24 hours had a PMN predominance. The ability
      of a PMN predominance to differentiate between aseptic and bacterial meningitis
      was assessed. The sensitivity of a PMN predominance for aseptic meningitis is 57%
      whereas the specificity is 10%. The positive predictive value of a PMN
      predominance for aseptic disease is 81% but the negative predictive value is 3%.
      Alternative definitions of PMN predominance from 60% to 90% were not useful as a
      clinical indicator of bacterial disease. CONCLUSIONS: The majority of children
      with aseptic meningitis have a PMN predominance in the CSF. The PMN predominance
      is not limited to the first 24 hours of illness. Because the majority of children
      with a PMN predominance during enteroviral season will have aseptic disease, a
      PMN predominance as a sole criterion does not discriminate between aseptic and
      bacterial meningitis.

PMID- 10654950
TI  - School difficulties at adolescence in a regional cohort of children who were
      extremely low birth weight.
AB  - OBJECTIVES: To compare measures of psychometric assessment and school
      difficulties in a cohort of extremely low birth weight (ELBW) teenagers and term
      controls, and to determine whether there is stability in psychometric measures
      between age 8 and the teen years. STUDY DESIGN: Longitudinal follow-up;
      geographically defined region. PARTICIPANTS: 150 of 169 (89%) ELBW survivors born
      between 1977 and 1982 and 124 of 145 (86%) sociodemographically matched term
      controls between 12 and 16 years of age. Psychometric measures: Wechsler
      Intelligence Scale for Children-Revised, Wide Range Achievement Test-Revised, and
      a validated parent questionnaire. RESULTS: Neurosensory impairments were present
      in 28% of ELBW and 1% of controls. The mean Wechsler Intelligence Scale for
      Children-Revised scores were ELBW: 89 +/- 19 and controls: 102 +/- 13. ELBW
      children did less well on Wide Range Achievement Test-Revised Reading, Spelling,
      and Arithmetic measures with mean scores in the range from 75 to 85. ELBW
      children <750 g were more disadvantaged, compared with those >/=750 g. A
      significantly higher proportion of ELBW children were receiving special
      educational assistance and/or had repeated a grade (ELBW: 58%; controls: 13%;
      odds ratio: 9.0). Paired analysis of within-cohort data at age 8 and teen years
      showed that for both cohorts Arithmetic scores declined, but there were small
      improvements in other measures, predominantly in the term children. CONCLUSIONS:
      Differences of 13 to 18 points in psychometric measures in ELBW teens compared
      with controls are both statistically significant and clinically relevant.
      Decreasing birth weight was associated with increased risk on all measures. The
      high utilization of special educational resources has economic implications, and
      the incremental cost attributable to being extremely premature needs to be
      determined.

PMID- 10654949
TI  - Links between early adrenal function and respiratory outcome in preterm infants:
      airway inflammation and patent ductus arteriosus.
AB  - OBJECTIVE: To investigate the relationship of cortisol concentrations during the
      first week of life to patent ductus arteriosus (PDA), markers of lung
      inflammation, and respiratory outcome in very low birth weight infants. METHODS:
      Newborns <1,500 g birth weight were prospectively enrolled at 2 centers. Serum
      cortisol was measured 3 times during days 2 to 7 of life. Tracheal lavage was
      performed on intubated infants and analyzed for interleukin-1beta, -6, and -8,
      and for total protein, albumin, and alpha-1 protease inhibitor. Infants receiving
      prenatal glucocorticoids were excluded. RESULTS: We obtained 337 cortisol values
      from 125 infants. Infants treated for PDA had lower cortisol values after day 2.
      One hundred thirty-three tracheal fluid samples were obtained on matching days
      from 71 intubated infants. Cortisol correlated inversely with tracheal
      interleukins and proteins. Lower cortisol values during the second half of the
      week correlated with longer duration of supplemental oxygen therapy and with
      subsequent development of chronic lung disease at 28 days and at 36 weeks.
      CONCLUSION: Infants with lower cortisol values in the first week of life had an
      increased incidence of PDA, increased lung inflammation, and an increased
      incidence of chronic lung disease. These findings suggest that early adrenal
      insufficiency may underlie the previously observed association of increased lung
      inflammation and PDA with adverse respiratory outcome in this population.

PMID- 10654951
TI  - Influence of congenital heart disease on mortality after noncardiac surgery in
      hospitalized children.
AB  - OBJECTIVE: To evaluate the incremental risk of congenital heart disease on
      mortality after noncardiac surgery in children. DESIGN: We reviewed the clinical
      information network database of the University Hospital Consortium for the period
      January 1, 1993, through December 31, 1996, and identified 191 261 patients <18
      years old having 1 or more noncardiovascular surgical procedures. Of these
      patients, 6.5% had a diagnosis of congenital heart disease. Patients having
      ambulatory surgery are excluded from this database. Short-term (1-, 2-, and 3
      day) and 30-day mortality were compared, as well as mortality for neonates,
      infants (31 days to 1 year), and older children (1-17 years); mortality for the
      100 most common surgical procedures, mortality for 10 relatively minor surgical
      procedures, and mortality in subgroups of patients with minor versus severe
      cardiac diagnoses. RESULTS: Short-term and 30-day mortality was increased in the
      patients with congenital heart disease patients (30-day mortality odds ratio 3.5;
      95% confidence limit, 3.2-3.9). Mortality was also increased in patients with
      congenital heart disease in the 2 youngest age groups, for the 100 most common
      operations, and for 10 relatively minor operations. Children with more severe
      heart disease diagnoses had higher mortality than did children carrying less
      serious cardiac diagnoses. CONCLUSION: A diagnosis of congenital heart disease
      adds significant incremental risk of mortality in children requiring inpatient
      noncardiovascular surgery. This outcome difference is present for both minor and
      major surgical procedures, and regardless of whether mortality is measured at 1,
      3, or 30 days. The incremental risk is greatest in neonates and infants where the
      presence of congenital heart disease is associated with a 2-fold increase in
      mortality from noncardiac surgery.

PMID- 10654952
TI  - Child and adolescent illness falsification.
AB  - OBJECTIVE: To review the current state of knowledge on factitious illness in
      children and adolescents to help clarify the relationship of this phenomenon to a
      range of somatizing disorders in children and factitious disorder by proxy.
      DESIGN: The literature of the past 30 years was reviewed for cases describing
      children <18 years old who have intentionally falsified symptoms of illness,
      without known parental involvement. Cases in which a parent was involved, the
      child acknowledged a credible motive, the deception was identified after age 18,
      or which appeared in foreign languages were excluded. Data on age, gender,
      factitious symptoms, method, duration of deception, and outcome of confrontation,
      where available, were gathered from case studies. RESULTS: Forty-two cases of
      illness falsification by children were identified, with a mean age of 13.9, and a
      range from 8 to 18 years. The majority of patients were female (71%), and the
      gender imbalance was greater for the older children. The most commonly reported
      falsified or induced conditions were fevers, ketoacidosis, purpura, and
      infections, and the fabrications ranged from false symptom-reporting to active
      injections, bruising, and ingestions. The mean duration of the falsifications was
      almost 16 months before detection. Many of the children admitted to their
      deceptions when confronted, and some had positive outcomes at follow-up. The
      descriptions of some of these children as bland, depressed, and fascinated with
      health care were remarkably similar to adults with factitious disorders.
      CONCLUSIONS: Medical conditions fabricated by children may go undetected for a
      variety of reasons, or diagnosed as somatization. Further study of children who
      falsify symptoms may in some cases help identify earlier experiences of
      Munchausen by proxy abuse or covert parental coaching of illness falsification,
      and provide more effective interventions. Better understanding and identification
      of these children is likely to help prevent the development of more chronic adult
      factitious disorders.

PMID- 10654953
TI  - The role of interpretation processes and parental discussion in the media's
      effects on adolescents' use of alcohol.
AB  - OBJECTIVE: The process that connects media use with alcohol-related beliefs and
      behaviors has not been well documented. To address this issue, we examined
      adolescents' viewing patterns, beliefs about alcohol and media messages, and
      parental discussion of media messages in the context of a theoretical model of
      message interpretation processes. Measures included the degree to which
      adolescents found portrayals desirable, realistic, and similar to their own
      lives; the degree to which they wanted to be like (identify with) the portrayals;
      and the degree to which they associated positive outcomes with drinking alcohol
      (expectancies). DESIGN: Cross-sectional survey. SETTING: Two public high schools
      in the California central coastal area that include a diverse population in terms
      of ethnic origin, income level, and education level. PARTICIPANTS: Ninth-grade
      students (n = 252) and 12th-grade students (n = 326). OUTCOME MEASURES: Students
      reported the number of days within the past week watching various genres of
      television content, along with perceptions of realism of content, desirability of
      portrayals, identification with portrayals, expectancies toward alcohol use,
      personal norms for alcohol use, desire for products with alcohol logos, current
      alcohol use, frequency of parental reinforcement, and counter-reinforcement of
      television messages. Associations were examined via hierarchical multiple
      regression analysis. RESULTS: Effects of media exposure on drinking behavior,
      controlling for grade level, ethnicity, gender, household income, and education
      levels were primarily positive and indirect, operating through a number of
      intervening beliefs, especially expectancies (beta =.59; r(2) =.33). Direct
      associations, primarily with exposure to late-night talk shows (beta =.12; r(2)
      =.01), were small. Parental discussion also affected behavior indirectly,
      operating through expectancies, identification, and perceived realism. The appeal
      of products with alcohol logos, which was higher among the younger students (t =
      3.44) and predicted by expectancies (beta =. 37; r(2) =.13), sports viewing (beta
      =.17; r(2) =.03) and late-night talk shows (beta =.10; r(2) =.01), predicted
      actual drinking behavior (beta =.22; r(2) =.04). Drinking behavior was higher
      among the older students (t = -2.515). CONCLUSIONS: Adolescents make drinking
      decisions using a progressive, logical decision-making process that can be
      overwhelmed by wishful thinking. The potential risk of frequent exposure to
      persuasive alcohol portrayals via late-night talk shows, sports, music videos,
      and prime-time television for underage drinking is moderated by parental
      reinforcement and counter-reinforcement of messages. Interventions need to
      acknowledge and counter the appeal of desirable and seemingly realistic alcohol
      portrayals in the media and alert parents to their potential for unintended
      adverse effects.

PMID- 10654955
TI  - Can peak expiratory flow predict airflow obstruction in children with asthma?
AB  - STUDY OBJECTIVES: A recent trend in the treatment of asthma has been the
      widespread, independent use of peak expiratory flow (PEF). We examined whether
      PEF monitoring creates inaccuracies in assessment of children with moderate to
      severe asthma. METHODS: We compared the negative predictive value of PEF in
      relation to the forced expiratory volume in 1 second (FEV(1)), and to the forced
      expiratory flow between 25% and 75% of the vital capacity (FEF(25-75%)) at
      different levels of air trapping as determined by the residual volume over total
      lung capacity ratio (RV/TLC). RESULTS: The study included 244 patients, ages 4 to
      18 years with all classes of asthma severity, with FEV(1) ranging from 28% to
      134% of predicted value. We analyzed 367 sets of pulmonary function tests
      performed throughout a 3-year period. Thirty percent of patients with a normal
      PEF value had an abnormal FEV(1) or FEF(25-75%). As air trapping increased, the
      ability of a normal PEF to predict normal FEV(1) and FEF(25-75%) readings fell
      from 83% to 53%. The negative predictive value was significantly lower for
      patients with RV/TLC ratio >30 compared with patients with RV/TLC <30.
      CONCLUSIONS: The results of this study suggest that it might be possible to
      identify children for whom the PEF is likely to give false-negative results. As
      air trapping increases, it causes the PEF to give misleading reassurance of
      normal pulmonary function. Furthermore, poor predictiveness of PEF is obtained
      when values 80% of predicted for age are considered normal.

PMID- 10654954
TI  - Changes in mesenteric blood flow response to feeding: conventional versus fiber
      optic phototherapy.
AB  - OBJECTIVE: To evaluate whether fiberoptic phototherapy influences the
      postprandial increase in mesenteric blood flow velocity similarly to conventional
      phototherapy in preterm infants. PATIENTS AND METHODS: With the use of Doppler
      color ultrasonography, blood flow velocity in the superior mesenteric artery was
      measured both preprandially and postprandially in 19 preterm infants during and
      after conventional phototherapy, and in 20 preterm infants during and after fiber
      optic phototherapy. The mean arterial blood pressure/mean flow velocity ratio was
      calculated as an estimate of relative vascular resistance of the superior
      mesenteric artery. RESULTS: The study shows that conventional phototherapy blunts
      the postprandial mesenteric blood flow response to feeding in preterm infants.
      Furthermore, it shows that the postprandial increase in intestinal blood flow is
      not attenuated when fiber-optic phototherapy is administered, and that such
      postprandial increase of blood flow is significantly greater than in infants
      receiving conventional phototherapy. During and after fiber-optic phototherapy, a
      significant reduction in postprandial relative vascular resistance was found;
      such reduction was significantly greater than during conventional phototherapy.
      CONCLUSIONS: Fiber-optic phototherapy is preferable to conventional phototherapy
      for the treatment of hyperbilirubinemia in preterm infants because it does not
      affect the physiologic postprandial redistribution of blood flow from the
      periphery to the gastrointestinal system as does conventional phototherapy.

PMID- 10654956
TI  - Use assessment of self-administered epinephrine among food-allergic children and
      pediatricians.
AB  - BACKGROUND AND OBJECTIVES: Food allergy is a common cause of anaphylaxis, and
      early treatment with epinephrine can be life-saving. We sought to determine the
      ability of families with food allergic children and pediatricians to properly use
      self-injectable epinephrine. METHODS: We enrolled families of consecutive, food
      allergic pediatric patients newly referred to our allergy practice but previously
      prescribed epinephrine and a sampling of pediatricians. Parents or teenage
      patients answered a structured questionnaire concerning use of self-injectable
      epinephrine and demonstrated the use of devices with which they were familiar.
      Demonstrations were scored in a standard manner. RESULTS: One hundred one
      families of food-allergic children (mean age of patients, 6.4 years) were
      enrolled. Self-injectable epinephrine was prescribed (mean of 2.7 years
      previously) primarily by pediatricians (n = 46) and allergists (n = 49). Patients
      were prescribed EpiPen (n = 93), EpiE-Z Pen (n = 11), and Ana-Kit (n = 3). Eighty
      six percent of the families responded that they had the device with them "at all
      times," but only 71% of this group had epinephrine at the visit. Among those with
      the epinephrine, 10% had devices beyond the labeled expiration date. Thus, only
      55% of the 101 families had unexpired epinephrine on-hand at the time of the
      survey. Among children in school, 77% had the medication available in school, and
      81% stated that the school knew the indications for administration. Only 32% of
      the participants correctly demonstrated the use of the device. Twenty-nine
      attending pediatricians were enrolled (mean 14 yrs in practice; mean 4
      epinephrine prescriptions/year). Familiarity with the devices was as follows:
      EpiPen (86%), EpiE-Z Pen (17%) and Ana-Kit (7%). Only 24% generally gave patients
      written materials concerning indications. Overall, 18% were familiar with and
      able to demonstrate correct use of at least 1 device (21% correctly demonstrated
      Epi-Pen). Seventeen pediatric residents were enrolled; 65% were familiar with the
      EpiPen; 36% demonstrated it correctly and only 1 resident was familiar with Ana
      Kit. CONCLUSIONS: Many parents of severely food-allergic children, and food
      allergic teenagers cannot correctly administer their self-injectable epinephrine
      and may not have the medication readily available. Pediatricians are not familiar
      with these devices and may fail to review their use with patients. Improved
      patient and physician education is needed to ensure proper use of this life
      saving medication.

PMID- 10654957
TI  - Evaluation of a state health insurance program for low-income children:
      implications for state child health insurance programs.
AB  - BACKGROUND: The State Child Health Insurance Program (SCHIP) is the largest
      public investment in child health care in 30 years, targeting 11 million
      uninsured children, yet little is known about the impact of health insurance on
      uninsured children. In 1991, New York State implemented Child Health Plus
      (CHPlus), a health insurance program that became a model for SCHIP: OBJECTIVE: To
      examine changes in access to care, utilization of services, and quality of care
      among children enrolled in CHPlus. DESIGN: A pre-post design was used to evaluate
      the health care experiences of children in the year before enrollment in CHPlus
      and during the year after CHPlus enrollment. SETTING: New York State, stratified
      into 4 regions: New York City, urban counties around New York City, upstate urban
      counties, and upstate rural counties. PARTICIPANTS: A total of 2126 children (0
      12.99 years of age) who enrolled in CHPlus in 1992-1993. DATA COLLECTION: Parents
      were interviewed by telephone, and primary care medical charts were reviewed for
      694 children (0-3. 99 years of age). ANALYSIS: Access, utilization, and quality
      of care measures for each child were compared for the year before and the year
      after CHPlus enrollment, controlling for age, geographic region, previous
      insurance coverage, and CHPlus plan type (indemnity or managed care). RESULTS:
      Enrollment in CHPlus was associated with fewer children lacking a medical home
      (5% before CHPlus vs 1% during CHPlus), with the greatest change occurring in New
      York City (11% vs 1%), where access before CHPlus was lowest. CHPlus was also
      associated with increased primary care visits: by 25% for preventive visits, by
      52% for acute visits, and by 42% for total visits. The number of specialists seen
      during CHPlus was more than twice as high than before CHPlus. CHPlus was not
      associated with changes in emergency department utilization, although
      hospitalizations, which were not covered by CHPlus, were 36% lower during CHPlus
      coverage. Use of public health departments for immunizations declined by 64%,
      with more immunizations delivered in the medical home during CHPlus coverage. One
      third of parents reported improved quality of health care for their child as a
      result of CHPlus, and virtually none noted worse quality of care. CONCLUSIONS:
      This statewide health insurance program for low-income children was associated
      with improved access, utilization, and quality of care, suggesting that SCHIP has
      the potential to improve health care for low-income American children.

PMID- 10654958
TI  - Late abnormal findings on high-resolution computed tomography after Mycoplasma
      pneumonia.
AB  - BACKGROUND: The clinical course of Mycoplasma pneumonia is typically mild and
      self-limited. There are, however, several case reports of severe complication
      following this illness with considerable morbidity and mortality. OBJECTIVES:
      This study was conducted to investigate, using high-resolution computed
      tomography (HRCT), the long-term pulmonary structural abnormalities after
      Mycoplasma pneumonia and to identify risk factors (chest radiograph findings,
      antibody titers, and host factors) that might increase the likelihood of
      developing the sequelae. METHODS: Thirty-eight children requiring hospitalization
      attributable to Mycoplasma pneumonia were recruited by the retrospective
      examination of hospital records. They underwent HRCT after an interval of 1.0 to
      2. 2 years. A control group of 17 children with the history of Mycoplasma upper
      respiratory infection was also studied after a similar interval. RESULTS:
      Abnormal HRCT findings were present in 37% (14/38) of the pneumonia group,
      compared with 12% (2/17) of the control group. The abnormalities in the pneumonia
      group, which appeared alone or in combination, included mosaic perfusion (n =
      12), bronchiectasis (n = 8), bronchial wall thickening (n = 4), decreased
      vascularity (n = 1), and air trapping on expiratory scan (9 of 29 tested). The
      area affected by these abnormalities, usually involving 2 or more lobes,
      corresponded in all cases to the location of the infiltrate on chest radiograph
      at the time of pneumonia. Between subjects with abnormal HRCT (n = 14) and normal
      HRCT (n = 24) in the pneumonia group, significant differences were observed in
      age at the time of pneumonia (mean +/- standard deviation: 5.3 +/- 2. 0 years vs
      7.7 +/- 3.4 years) and peak antimycoplasma antibody titer (geometric mean [range
      of 1 standard deviation]; 1:7943 [3126-19 953] vs 1:3093 [832-11 482]).
      CONCLUSIONS: We conclude that a considerable proportion of children with history
      of Mycoplasma pneumonia have abnormal findings on HRCT, suggestive of small
      airway obstruction and that younger age and higher antibody titer at the time of
      pneumonia may be risk factors for these sequelae.

PMID- 10654959
TI  - The incidence of necrotizing enterocolitis after introducing standardized feeding
      schedules for infants between 1250 and 2500 grams and less than 35 weeks of
      gestation.
AB  - OBJECTIVE: To evaluate the incidence of necrotizing enterocolitis (NEC) after
      implementing standardized feeding schedules. METHOD: This was a cohort study,
      which retrospectively reviewed the incidence of NEC for a 3-year period before
      implementing feeding schedules and prospectively evaluated the incidence of NEC
      for a 3-year period after implementing feeding schedules in infants with birth
      weights between 1250 and 2500 g and <35 weeks' gestation. The feeding schedules
      were comprised of 3 parts. First, no group was fed within the first 24 hours of
      life. Feeds were started between 24 to 72 hours of life based on birth weight.
      Second, the initial feed was full-strength breast milk or half-strength formula.
      Half-strength formula was changed to full-strength formula on the fourth day for
      all groups. Third, the daily feeding volume increase was no greater than 20 mL/kg
      for all groups. RESULTS: In the 477 infants before the feeding schedules, there
      were 23 (4.8%) cases of definite NEC defined as pneumatosis on abdominal film or
      NEC confirmed at the time of surgery, and in the 466 infants after the feeding
      schedules, there were 5 (1.1%) cases of NEC. Before the feeding schedules, those
      who developed NEC started feeds sooner 1.5 +/- 1.5 (+/- standard deviation [SD])
      days versus 3.0 +/-.7 (+/-SD) days, reached full feeds sooner 4.0 +/- 1.8 (+/-
      SD) days versus 9.8 +/-.5 (+/-SD) days and were more likely to have been started
      on formula than those who developed NEC after implementing the feeding schedules.
      The mean time for NEC to occur after the feeding schedules increased from 5.9 +/-
      4.1 (+/-SD) days to 19.4 +/- 16.3 (+/- SD) days, although not statistically
      significant. The number of mothers who received prenatal steroids increased after
      the feeding schedules. The number of infants with NEC, however, significantly
      decreased whether their mothers were pretreated with steroids. The risk of NEC
      was reduced 84% after the introduction of feeding schedules as determined by
      multiple logistic regression analysis and adjusting for confounding by birth
      weight, white race, prenatal steroid exposure, day of life of first feed, day of
      life to reach full feeds, and breast milk. CONCLUSION: The incidence of NEC was
      significantly decreased after the implementation of standardized feeding
      schedules, which was independent of birth weight, prenatal steroid exposure,
      breast milk, day of life of first feed, and the number of days to reach full
      feeds.

PMID- 10654960
TI  - The discrepancy between maturation of visual-evoked potentials and cognitive
      outcome at five years in very preterm infants with and without hemodynamic signs
      of fetal brain-sparing.
AB  - OBJECTIVE: After intrauterine growth restriction we found at the age of 6 months
      an acceleration of neurophysiologic maturation. However, at later ages impaired
      cognitive outcome has been reported. Therefore, we investigated in children with
      and without fetal hemodynamic adaptation to intrauterine growth restriction
      whether the accelerated neurophysiologic maturation in infancy might be
      associated with impaired cognitive outcome at preschool age. DESIGN: At 5 years
      of age cognitive function was assessed using the Revision of the Amsterdam
      Children's Intelligence Test in 73 preterm infants (26-33 weeks) who were
      prospectively followed from the antenatal period up to the age of 5 years.
      Maternal educational level was used as a background variable to estimate the
      confounding effects of socioeconomic status on cognitive function. Fetal Doppler
      studies were performed and the umbilical artery pulsatility index (PI) divided by
      the middle cerebral artery PI ratio (U/C ratio) was calculated. A U/C ratio
      >0.725 was considered as an indication of fetal cerebral hemodynamic adaptation
      to a compromised placental perfusion, ie, fetal brain-sparing. Visual-evoked
      potentials (VEPs) were recorded at 6 months and 1 year of age. In addition, data
      on neurologic status at 3 years were available. RESULTS: Mean IQ score was
      significantly lower for children born with a raised U/C ratio (87 +/- 16)
      compared with children with a normal U/C ratio (96 +/- 17). VEP latencies
      decreased significantly in infants with a normal U/C ratio, whereas no decrease
      was found in infants with a raised U/C ratio. Variables contributing
      significantly to the variance of cognitive function were: U/C group, VEP latency
      maturation, level of maternal education, and neurodevelopmental outcome at 3
      years. The linear regression model explained 33% of the variance in cognitive
      function. CONCLUSIONS: Both being born with a raised U/C ratio and an
      acceleration of VEP latencies are negatively associated with cognitive outcome at
      5 years of age. Fetal brain-sparing, although a seemingly beneficial adaptive
      mechanism for intact neurologic survival, is, however, later associated with a
      poorer cognitive outcome.

PMID- 10654962
TI  - Exogenous apotransferrin and exchange transfusions in hereditary iron overload
      disease.
AB  - OBJECTIVE: To investigate whether apotransferrin administration and exchange
      transfusion can improve outcome in patients with the recently described recessive
      congenital iron overload disease, presenting with intrauterine growth
      retardation, severe lactic acidosis, aminoaciduria, and hemosiderosis of the
      liver that so far has been treatment-resistant and lethal. METHODOLOGY: Because
      the patients have hypotransferrinemia, hyperferritinemia, increased transferrin
      saturation, and bleomycin detectable iron in plasma, we designed a treatment
      regime aiming at decreasing free iron and iron overload. The serum transferrrin
      concentration was increased to adult level (2-5 g/L) by intravenous
      apotransferrin administrations and thereafter exchange transfusion was performed.
      RESULTS: Two patients were treated. In patient 1, the transferrin saturation
      decreased from a baseline value of 100% and remained normal after the third
      exchange transfusion, and in patient 2, a reversible beneficial effect was seen
      on transferrin saturation and bleomycin-detectable iron. However, both infants
      died later of the disease, at 10 and 8 weeks of age, respectively. CONCLUSIONS:
      Exogenous apotransferrin administration proved to be safe and might deserve
      evaluation in other neonatal diseases with presence of free iron in plasma.

PMID- 10654961
TI  - Granulocyte colony-stimulating factor serum and urine concentrations in
      neutropenic neonates before and after intravenous administration of recombinant
      granulocyte colony-stimulating factor.
AB  - BACKGROUND: Recombinant granulocyte colony-stimulating factor (rG-CSF) has been
      suggested as a treatment for certain varieties of neonatal neutropenia, but
      little is known about the pharmacologic disposition of rG-CSF in that population.
      METHODS: Ten neutropenic neonates were treated with rG-CSF, 10 micrograms/kg
      intravenously once daily for 3 to 5 days. Serum and urine samples were obtained
      before rG-CSF dosing and at intervals thereafter for G-CSF quantification by
      enzyme-linked immunosorbent assay. RESULTS: Five of the neutropenic neonates
      (termed group 1) were not infected but likely had hyporegenerative neutropenia (4
      were born after pregnancy-induced hypertension/intrauterine growth restriction,
      and 1 had Rh hemolytic disease). Five other infants (group 2) had neutropenia
      accompanying bacterial sepsis and shock. Before receiving the first dose of rG
      CSF, endogenous G-CSF serum and urine concentrations were relatively low in group
      1, averaging 130 pg/mL (range: 48-209) in serum and 53 pg/mL (range: 15-141) in
      urine. Serum concentrations immediately before the final dose were much higher
      (range: 81-24 835 pg/mL), whereas urine concentrations were unchanged (range: <7
      pg/mL-126 pg/mL). In group 2 patients, before receiving the first-dose of rG-CSF,
      endogenous concentrations were very high, averaging 59 575 pg/mL (range: 20 028
      98 280) in serum and 3189 pg/mL (range: 23-4770) in urine. Predose serum
      concentrations before the final dose (range: 427-14 460 pg/mL) were lower than
      before the first dose. The area under the concentration curve after the first
      dose of rG-CSF administration in group 1 was significantly lower than after the
      first dose in group 2, but no difference in area under the concentration curve
      was observed between groups 1 and 2 after the last dose of rG-CSF. SPECULATION:
      The principal means of clearing G-CSF from the serum is by saturable binding to
      specific G-CSF receptors (G-CSF-Rs). Therefore, the very high G-CSF serum and
      urine concentrations of group 2 patients before the first rG-CSF dose implies
      that their G-CSF-Rs were saturated before the dose was given. We speculate that
      if G-CSF-Rs are saturated with endogenous G-CSF, treatment with rG-CSF will add
      little or nothing to the granulocytopoietic effort. On this basis, we judge that
      neonates with septic shock and neutropenia are unlikely to derive benefit from rG
      CSF administration.

PMID- 10654963
TI  - Unintentional pediatric superwarfarin exposures: do we really need a prothrombin
      time?
AB  - OBJECTIVE: To determine whether routine follow-up coagulation studies are useful
      in children with accidental exposures to rodenticides containing superwarfarin
      compounds. DESIGN: Retrospective review of poison center charts involving
      pediatric superwarfarin exposures occurring in two 2-year periods. SETTING: An
      American Association of Poison Control Centers-certified regional poison control
      center with an annual call volume of 55 000 calls per year from a 2-state area
      with a combined population of 4 million people. OUTCOME MEASURES: Prothrombin
      times and/or international normalized ratios and reported clinical signs of
      excessive anticoagulation after exposure. RESULTS: Of 542 children in 4 years of
      data collection, follow-up prothrombin times and/or international normalized
      ratios measurements did not detect any significant coagulation abnormalities. No
      child developed bleeding complications. No child required or received antidotal
      treatment with vitamin K. CONCLUSION: Normal preschool-aged children with
      unintentional acute exposures to superwarfarin rodenticides do not require any
      routine follow-up laboratory studies and do not require any medical intervention.

PMID- 10654964
TI  - Nocturnal pulse oximetry as an abbreviated testing modality for pediatric
      obstructive sleep apnea.
AB  - OBJECTIVE: To determine the utility of pulse oximetry for diagnosis of
      obstructive sleep apnea (OSA) in children. METHODS: We performed a cross
      sectional study of 349 patients referred to a pediatric sleep laboratory for
      possible OSA. A mixed/obstructive apnea/hypopnea index (MOAHI) greater than or
      equal to 1 on nocturnal polysomnography (PSG) defined OSA. A sleep laboratory
      physician read nocturnal oximetry trend and event graphs, blinded to clinical and
      polysomnographic results. Likelihood ratios were used to determine the change in
      probability of having OSA before and after oximetry results were known. RESULTS:
      Of 349 patients, 210 (60%) had OSA as defined polysomnographically. Oximetry
      trend graphs were classified as positive for OSA in 93 and negative or
      inconclusive in 256 patients. Of the 93 oximetry results read as positive, PSG
      confirmed OSA in 90 patients. A positive oximetry trend graph had a likelihood
      ratio of 19.4, increasing the probability of having OSA from 60% to 97%. The
      median MOAHI of children with a positive oximetry result was 16.4 (7.5, 30.2).
      The 3 false-positive oximetry results were all in the subgroup of 92 children who
      had diagnoses other than adenotonsillar hypertrophy that might have affected
      breathing during sleep. A negative or inconclusive oximetry result had a
      likelihood ratio of.58, decreasing the probability of having OSA from 60% to 47%.
      Interobserver reliability for oximetry readings was very good to excellent (kappa
      =.80). CONCLUSIONS: In the setting of a child suspected of having OSA, a positive
      nocturnal oximetry trend graph has at least a 97% positive predictive value.
      Oximetry could: 1) be the definitive diagnostic test for straightforward OSA
      attributable to adenotonsillar hypertrophy in children older than 12 months of
      age, or 2) quickly and inexpensively identify children with a history suggesting
      sleep-disordered breathing who would require PSG to elucidate the type and
      severity. A negative oximetry result cannot be used to rule out OSA.

PMID- 10654965
TI  - What can We learn from STOP-ROP and earlier studies?

PMID- 10654966
TI  - Twice-daily oral penicillin for treatment of streptococcal pharyngitis: less is
      best.

PMID- 10654967
TI  - Oxygen therapy, oxygen toxicity, and the STOP-ROP trial.

PMID- 10654968
TI  - Hereditary hemochromatosis in siblings: diagnosis by genotyping.

PMID- 10654969
TI  - Hemosiderosis in a normal child secondary to oral iron medication.

PMID- 10654970
TI  - In situ hybridization detection of human herpesvirus 6 in brain tissue from fatal
      encephalitis.
AB  - A 23-month-old girl died after 2 days' illness with rash, fever, and convulsions.
      Neuropathologic findings were consistent with viral hemorrhagic encephalitis in
      pontine tegmentum and medial thalamic areas. Human herpesvirus 6 (HHV-6) DNA was
      detected in pontine nuclei by in situ hybridization. In addition, polymerase
      chain reaction for HHV-6 of serum and paraffin-embedded pontine tissue was
      positive, and serology indicated an acute primary infection. This is the first
      case showing HHV-6 DNA in the brain cells of an immunocompetent patient with
      acute encephalitis.

PMID- 10654971
TI  - Rhabdomyolysis associated with infection by Mycoplasma pneumoniae: a case report.
AB  - BACKGROUND: Mycoplasma pneumoniae is responsible for approximately 20% of the
      cases of community-acquired pneumonia. The onset of respiratory symptoms is
      gradual and systemic complaints such as headache, malaise, arthalgias, and low
      grade fever are frequently prominent. Extrapulmonary manifestations of M
      pneumoniae are common and hematologic (thrombocytopenia, splenomegaly,
      disseminated intravascular coagulation, hemolytic anemia), dermatologic (Stevens
      Johnson syndrome), gastrointestinal (vomiting, diarrhea, pancreatitis), renal
      (interstitial nephritis, glomerulonephritis), cardiac (pericarditis, myocarditis,
      pericardial effusion) and central nervous system (meningitis, transverse
      myelitis, polyradiculopathy, cerebellar ataxia, sensorineural hearing loss)
      complications can occur. OBSERVATION: We describe the case of an adolescent girl
      with massive rhabdomyolysis associated with an infection caused by M pneumoniae.
      We briefly review the differential diagnosis of a patient presenting with acute
      rhabdomyolysis and discuss the use of a new polymerase chain reaction-based assay
      for direct detection of M pneumoniae in throat swab specimens. CONCLUSION:
      Clinicians should be aware of a possible association between rhabdomyolysis and
      infection with M pneumoniae and should consider testing for M pneumoniae when
      they are presented with a patient with idiopathic rhabdomyolysis. The new
      polymerase chain reaction-based assay for detection of M pneumoniae is a more
      accurate and more efficient method than traditional culture.

PMID- 10654972
TI  - Liver failure attributable to hepatitis A virus infection in a developing
      country.
AB  - In young children hepatitis A virus (HAV) infections are usually subclinical
      events. However, HAV is also associated with progressive hepatic failure and even
      death in some patients. This study was undertaken to characterize the course of
      hepatitis A-related acute liver failure in children from a developing country
      where hepatitis A is endemic and produces significant morbidity. Patients <15
      years of age with confirmed hepatitis A, seen at the Aga Khan University Hospital
      between January 1991 and August 1998 were identified using the patient registry.
      Of the 2735 patients seen with hepatitis A, 232 were admitted to the hospital. Of
      these 30 patients developed progressive hepatic dysfunction and liver failure.
      During this period, 45 children were admitted with liver failure attributable to
      other causes. Of the patients admitted with hepatitis A-related liver failure, 25
      (83.3%) were encephalopathic at presentation and 36.7% of the patients died. The
      prothrombin time was the most significant predictor of survival. There was a
      significant difference between those who survived and those who died on
      discriminant analysis with respect to age, grade of hepatic encephalopathy,
      duration of hospitalization, prothrombin time, and duration of jaundice when
      taken as a group. There is a striking prevalence of liver dysfunction progressing
      to hepatic failure among children seen at a hospital in Karachi, Pakistan. This
      study demonstrates the significant morbidity and mortality that can attend HAV
      infections in children in a developing country despite tertiary medical
      facilities. The risk of HAV and its sequelae could probably be effectively
      reduced in these settings with improved sanitation and universal immunization.

PMID- 10654973
TI  - Congenital cutaneous candidiasis: clinical presentation, pathogenesis, and
      management guidelines.
AB  - We describe a term infant with congenital cutaneous candidiasis (CCC), and review
      all cases in the English literature that reported birth weight and outcome.
      Presence of an intrauterine foreign body was a predisposing factor for
      development of CCC and subsequent preterm birth. The most common presentation of
      CCC in neonates weighing >1000 g was a generalized eruption of erythematous
      macules, papules, and/or pustules that sometimes evolved to include vesicles and
      bullae. Extremely low birth weight, premature neonates weighing <1000 g most
      often presented with a widespread desquamating and/or erosive dermatitis (10 of
      15 [67%]), and were at greater risk for systemic infection with Candida spp (10
      of 15 [67%]) and death (6 of 15 [40%] than those weighing >1000 g (5 of 48 [10%];
      4 of 48 [8%], respectively). Systemic antifungal therapy is recommended for
      neonates with burn-like dermatitis attributable to Candida spp, or positive
      blood, urine, and/or cerebrospinal fluid cultures. Systemic treatment also should
      be considered for all infants with CCC who have respiratory distress in the
      immediate neonatal period and/or laboratory signs of sepsis such as an elevated
      leukocyte count with an increase in immature forms or persistent hyperglycemia
      and glycosuria.

PMID- 10654974
TI  - The pediatrician and childhood bereavement. American Academy of Pediatrics.
      Committee on Psychosocial Aspects of Child and Family Health.
AB  - Pediatricians should understand and evaluate children's reactions to the death of
      a person important to them by using age-appropriate and culturally sensitive
      guidance while being alert for normal and complicated grief responses.
      Pediatricians also should advise and assist families in responding to the child's
      needs. Sharing, family support, and communication have been associated with
      positive long-term bereavement adjustment.

PMID- 10654975
TI  - Provision of educationally-related services for children and adolescents with
      chronic diseases and disabling conditions. American Academy of Pediatrics.
      Committee on Children with Disabilities.
AB  - Children and adolescents with chronic diseases and disabling conditions often
      need related services. As medical home professionals, pediatricians can assist
      children, adolescents, and their families with the complex federal, state, and
      local laws, regulations, and systems associated with these services. Expanded
      roles for pediatricians in Individual Family Service Plan, Individualized
      Education Plan, and 504 Plan development and implementation are recommended. The
      complex range of federal, state, and local laws, regulations, and systems for
      special education and related services for children and adolescents in public
      schools is beyond the scope of this statement. Readers are referred to the policy
      statement "The Pediatrician's Role in Development and Implementation of an
      Individual Education Plan (IEP) and/or an Individual Family Services Plan"(1) by
      the American Academy of Pediatrics for additional background materials.

PMID- 10654976
TI  - Personal watercraft use by children and adolescents. American Academy of
      Pediatrics. Committee on Injury and Poison Prevention.
AB  - The use of personal watercraft (PWC) has increased dramatically during the past
      decade as have the speed and mobility of the watercraft. A similar dramatic
      increase in PWC-related injury and death has occurred simultaneously. No one
      younger than 16 years should operate a PWC. The operator and all passengers must
      wear US Coast Guard-approved personal flotation devices. Other safety
      recommendations are suggested for parents and pediatricians.

PMID- 10654977
TI  - Prevention and management of pain and stress in the neonate. American Academy of
      Pediatrics. Committee on Fetus and Newborn. Committee on Drugs. Section on
      Anesthesiology. Section on Surgery. Canadian Paediatric Society. Fetus and
      Newborn Committee.
AB  - This statement is intended for health care professionals caring for neonates
      (preterm to 1 month of age). The objectives of this statement are to: 1. Increase
      awareness that neonates experience pain; 2. Provide a physiological basis for
      neonatal pain and stress assessment and management by health care professionals;
      3. Make recommendations for reduced exposure of the neonate to noxious stimuli
      and to minimize associated adverse outcomes; and 4. Recommend effective and safe
      interventions that relieve pain and stress.

PMID- 10654978
TI  - Fatal hypermagnesemia in a child treated with megavitamin/megamineral therapy.
AB  - We report a case of fatal hypermagnesemia resulting from the unsupervised use of
      high doses of magnesium oxide administered as part of a regimen of megavitamin
      and megamineral therapy to a child with mental retardation, spastic quadriplegia,
      and seizures. The treatment regimen was given at the recommendation of a
      dietician working as a private nutritional consultant without the involvement or
      notification of the child's pediatrician. Hypermagnesemia is an uncommon but
      serious side effect of the use of magnesium containing compounds. These compounds
      are widely used as laxatives and dietary supplements, and serious side effects
      are uncommon when used in appropriate dosages and with adequate supervision. The
      use of alternative medical therapies, including megavitamin/megamineral therapy,
      is widespread. Many patients use alternative medicine or seek care from
      alternative medicine practitioners without the recommendation or knowledge of
      their primary physicians. Despite unproved benefit, many alternative therapies
      may be safe. However, unsupervised use of generally safe treatments can result in
      serious side effects. This case report serves to illustrate the characteristic
      pathophysiologic changes of severe hypermagnesemia, an entity rarely seen in
      pediatric practice, and more importantly, it alerts primary care and subspecialty
      pediatricians to be aware of and monitor the use of alternative medical therapies
      in their patients.

PMID- 10654979
TI  - The impact of dosing frequency on the efficacy of 10-day penicillin or
      amoxicillin therapy for streptococcal tonsillopharyngitis: A meta-analysis.
AB  - OBJECTIVE: The recommended dosing frequency of oral penicillin for the treatment
      of acute streptococcal tonsillopharyngitis has long been 3 to 4 times daily. In
      1994, treatment guidelines included twice-daily (BID) dosing for the first time,
      a recommendation that could significantly increase the ease of compliance. This
      meta-analysis was performed to determine whether overall cure rates differed
      between BID or once-daily (QD) versus more frequent dosing schedules in the
      treatment of streptococcal tonsillopharyngitis. DATA SOURCES: Candidate studies
      for this meta-analysis included all clinical trials of therapy for streptococcal
      tonsillopharyngitis published through August 1998 and identified using Medline,
      Dissertation Abstracts, conference proceedings, and bibliographies of all
      retrieved articles. STUDY SELECTION: A study was eligible for inclusion if it was
      a randomized clinical trial that compared the efficacies of different dosing
      frequencies of 10-day penicillin or amoxicillin in the treatment of streptococcal
      tonsillopharyngitis. Of the 30 articles initially identified, 6 studies met
      eligibility criteria. OUTCOME MEASURE: The measure of interest was the difference
      in proportion cured between the BID or QD dosing group and the comparison group
      with more frequent dosing. RESULTS: The results of this analysis suggest that BID
      dosing of 10-day penicillin is as efficacious as more frequent dosing regimens in
      the treatment of streptococcal tonsillopharyngitis. This result also holds true
      in a subgroup analysis confined to pediatric cases and does not vary with total
      daily dose of the regimen. QD dosing of penicillin is associated with a cure rate
      that is 12 percentage points lower than more frequent dosing (95% confidence
      interval: 3-21). In contrast, this decreased efficacy is not found with QD dosing
      of amoxicillin. CONCLUSIONS: This meta-analysis supports current recommendations
      for BID dosing of penicillin in treating streptococcal tonsillopharyngitis. QD
      penicillin is associated with decreased efficacy and should not be used.
      Simplified regimens of amoxicillin of shorter duration or of less frequent dosing
      should be further investigated.

PMID- 10654980
TI  - Urinary tract infection in febrile infants younger than eight weeks of Age.
AB  - OBJECTIVE: To assess the usefulness of laboratory parameters, including
      peripheral white blood cell (WBC) count, C-reactive protein (CRP) concentration,
      erythrocyte sedimentation rate (ESR), and microscopic urinalysis (UA), for
      identifying febrile infants younger than 8 weeks of age at risk for urinary tract
      infection (UTI), and comparison of standard UA and hemocytometer WBC counts for
      predicting the presence of UTI. METHODS: A total of 162 febrile children <8 weeks
      of age were enrolled in this prospective study. All underwent clinical evaluation
      and laboratory investigation, including WBC count and differential; ESR; CRP;
      blood culture; a lumbar puncture for cell count and differential, glucose level,
      protein level, Gram stain, and culture; and a UA and urine culture. All urine
      specimens were obtained by suprapubic aspiration and microscopically analyzed
      with standard UA as well as with hemocytometer WBC counts. Quantitative urine
      cultures were performed. Sensitivity, specificity, accuracy, likelihood ratios,
      and receiver operating characteristic (ROC) curves were determined for each of
      the screening tests. RESULTS: There were 22 positive urine culture results of at
      least 100 colony-forming unit/mL. Eighteen of these 22 patients were males, and
      all were uncircumcised. There were significant differences for pyuria >/=5
      WBCs/hpf, pyuria >/=10 WBC/microL, CRP >20 mg/L, and ESR >30 mm/hour between
      culture-positive and culture-negative groups (P <.05). The ROC area for
      hemocytometer WBC count, standard UA, peripheral WBC count, ESR, and CRP
      concentration were.909 +/-.045,.791 +/-.065,.544 +/-.074,. 787 +/-.060, and.822
      +/-.036, respectively. The ROC curve analysis indicates that the CRP, ESR, and
      standard UA were powerful but imperfect tools with which to discriminate for UTI
      in potentially infected neonates. Hemocytometer WBC counts had the highest
      sensitivity, specificity, accuracy, and likelihood ratios for identifying very
      young infants with positive urine culture results. For all assessments,
      hemocytometer WBC counts were significantly different, compared with the standard
      urinalysis. ESR, CRP, and peripheral WBC counts were not helpful in identifying
      UTI in febrile infants. CONCLUSION: UTI had a prevalence of 13.6% in febrile
      infants <8 weeks of age. The CRP, ESR, and standard UA were imperfect tools in
      discriminating for UTI, and the sensitivity of these laboratory parameters was
      relatively low. Hemocytometer WBC count was a significantly better predictor of
      UTI in febrile infants.

PMID- 10654981
TI  - Impact of dietary fat and fiber intake on nutrient intake of adolescents.
AB  - OBJECTIVE: To evaluate the impact of fat and fiber intake on energy and nutrient
      intake of 15-year-old adolescents. STUDY DESIGN: Twenty-four-hour dietary recalls
      were collected on a random sample of 15-year-olds. Subjects were then categorized
      into groups based on fat and fiber intake, with 319 students meeting criteria for
      1 of 4 dietary intake quadrants: low fat, low fiber; low fat, high fiber; high
      fat, low fiber; and high fat, high fiber. Students with medium fat or fiber
      intakes were excluded from the study. Low-fat and high-fat intake were defined as
      <30% and >40% of total energy intake, respectively. Low- and high-fiber intake
      were defined as <15 g/day and >20 g/day, respectively. RESULTS: Low-fat and high
      fiber intake had a minimal impact on energy intake and did not adversely affect
      nutrient intake. High-fiber intake was associated with greater likelihood of
      adequate intake of vitamins A, B6, B12, and C; niacin; thiamin; riboflavin;
      folacin; magnesium; iron; zinc; phosphorus; and calcium. High-fat intake was
      associated with greater likelihood of adequate vitamin B12 intake. Significant
      differences in fat and fiber intake distributions were found for ethnic
      background and gender, with more non-white than white students in the high-fat
      groups and more males than females in the high-fiber groups. CONCLUSIONS: A low
      fat and high-fiber diet meeting current nutrition recommendations does not
      adversely affect energy or nutrient intake, increases nutrient density of the
      diet, and increases the likelihood of adequate intake for several key nutrients.

PMID- 10654982
TI  - Absence of growth retardation in children with perennial allergic rhinitis after
      one year of treatment with mometasone furoate aqueous nasal spray.
AB  - OBJECTIVE: Intranasal corticosteroids are used widely for the treatment of
      allergic rhinitis because they are effective and well tolerated. However, their
      potential to suppress growth of pediatric subjects with allergic rhinitis
      continues to be a concern, particularly in light of reports of growth suppression
      after treatment with intranasal beclomethasone dipropionate or intranasal
      budesonide (see the article by Skoner et al in this month's issue). A 1-year
      study of prepubertal patients between 3 and 9 years of age with perennial
      allergic rhinitis was conducted to assess the effects on growth of mometasone
      furoate aqueous nasal spray (MFNS), a new once-daily (QD) intranasal
      corticosteroid with negligible bioavailability. METHODS: This was a randomized,
      placebo-controlled, double-blind, multicenter study. Ninety-eight subjects were
      randomized to treatment with either MFNS 100 microg QD or placebo for 1 year.
      Each subject's height was required to be between the 5th and 95th percentile at
      baseline, and skeletal age at screening was required to be within 2 years of
      chronological age, as determined by left wrist x-rays. Washout periods for
      medications that affect either childhood growth or allergic rhinitis symptoms
      were established based on estimated period of effect, and these medications were
      prohibited during the study. However, short courses of either oral prednisone
      lasting no longer than 7 days or low-potency topical dermatologic corticosteroids
      lasting no longer than 10 days were permitted if necessary. Height was measured
      with a calibrated stadiometer at baseline and at 4, 8, 12, 26, 39, and 52 weeks,
      and the primary safety variable was the change in standing height. The rate of
      growth was also calculated for each subject as the slope (linear regression) of
      the change in height from baseline using data from all visits of subjects who had
      at least 2 visits. Hypothalamic-pituitary-adrenocortical- (HPA)-axis function was
      assessed via cosyntropin stimulation testing at baseline and at 26 and 52 weeks.
      All analyses were based on all randomized subjects (intent-to-treat principle).
      The change from baseline in standing height was analyzed by a 2-way analysis of
      variance that extracted sources of variation attributable to treatment, center,
      and treatment-by-center interaction. RESULTS: Demographic characteristics were
      similar at baseline. Eighty-two subjects completed the study (42 in the MFNS
      group and 40 in the placebo group), and 93% of subjects achieved at least 80%
      compliance with therapy. After 1 year of treatment, no suppression of growth was
      seen in subjects treated with MFNS, and mean standing heights were similar for
      both treatment groups at all time points. For the primary safety variable (change
      in height from baseline), both treatment groups were similar at all time points
      except for weeks 8 and 52. Subjects treated with MFNS had a slightly greater mean
      increase in height than subjects treated with placebo at these time points: the
      change in height was 6.95 cm versus 6.35 cm at the 1-year time point. However,
      the rate of growth (.018 cm/day) averaged for all time points over the course of
      the study was similar for both treatment groups. Additional analyses found that
      MFNS did not retard growth in any sex or age subgroup of subjects. The use of
      exogenous corticosteroids other than the study drug was also similar among the 2
      treatment groups. Results from cosyntropin stimulation testing confirmed the
      absence of systemic effects of MFNS. The change from baseline in the difference
      between prestimulation and poststimulation levels was similar for both treatment
      groups after 1 year of treatment, with no evidence of HPA-axis suppression in
      MFNS-treated subjects at any time point. Incidences of treatment-related adverse
      events were similar for both treatment groups, with 16% of MFNS-treated subjects
      reporting adverse events, compared with 22% of placebo-treated subjects.
      CONCLUSIONS: (ABSTRACT TRUNCATED)

PMID- 10654983
TI  - Detection of growth suppression in children during treatment with intranasal
      beclomethasone dipropionate.
AB  - OBJECTIVE: Intranasal beclomethasone dipropionate (BDP) has generally been
      considered to have no systemic activity at recommended doses, but the potential
      for long-term effects on growth has not previously been evaluated. This study was
      undertaken to assess the effects of 1 year of treatment with intranasal BDP on
      growth in children. STUDY DESIGN: In this double-blind, randomized, parallel
      group study, 100 prepubertal children 6 to 9 years old with perennial allergic
      rhinitis were treated with aqueous BDP 168 microg twice daily (n = 51) or placebo
      (n = 49) for 1 year. Subjects' baseline heights were required to be between the
      5th and 95th percentile, and skeletal age as determined by left wrist radiograph
      was required to be within 2 years of chronological age. Washout periods for
      medications known to affect growth, including other forms of corticosteroids,
      were established, and these medications were prohibited during the study.
      However, short courses of oral prednisolone lasting no more than 7 days, and
      short courses of dermatologic corticosteroids lasting no more than 10 days, were
      allowed. Height was measured with a stadiometer after 1, 2, 4, 6, 8, 10, and 12
      months of treatment. The hypothalamic-pituitary-adrenocortical axis was assessed
      by measurements of 8 AM basal cortisol concentrations and response to. 25 mg
      cosyntropin stimulation. The primary safety parameter was the rate of change in
      standing height. Statistical analyses were based on all randomized subjects who
      received at least 1 dose of medication (intent-to-treat principle). The rate of
      change in standing height was analyzed for all subjects who entered the study and
      for those completing the full 12 months of treatment (n = 80). The rate of change
      in standing height over the 1-year study was calculated as the slope of a linear
      regression line fitted to each subject's height measurements over time. Because
      there was a statistically significant between-group difference in standing height
      at baseline, an analysis of covariance was performed for all analyses of standing
      height data. RESULTS: Of the 100 subjects enrolled, 90 completed the study. The 2
      treatment groups were generally comparable at baseline; however, at baseline,
      mean age and mean height were significantly greater in the BDP treatment group
      that the in placebo treatment group. In both analyses, overall growth rate was
      significantly slower in BDP-treated subjects than placebo-treated subjects. The
      mean change in standing height after 1 year was 5.0 cm in the BDP-treated
      subjects compared with 5.9 cm in the placebo-treated subjects. The difference in
      growth rates was evident as early as the 1-month treatment visit, suggesting that
      the effect on growth occurred initially. The growth-suppressive effect of BDP
      remained consistent across all age and gender subgroups, and among subjects with
      and without a previous history of corticosteroid use. Use of additional exogenous
      corticosteroids during the study was similar in both groups and did not affect
      the results. Because there was a baseline imbalance in height, a supplemental
      analysis of the differences in prestudy growth rates was performed. This analysis
      found no baseline imbalance in prestudy growth rates. To determine whether the
      difference in growth rates during the study could be attributed to preexisting
      growth rates, a z score analysis was performed. The heights of both groups were
      normalized at baseline and at the end of the study using the US National Center
      for Health Statistics data for mean and standard deviations of height. This
      analysis confirmed that the difference in growth rates between the 2 groups was
      primarily attributable to the treatment rather than to any preexisting difference
      in growth. Additional analyses confirmed that the results were not influenced by
      outlier values. No significant between-group difference were found in the
      hypothalamic-pituitary-adrenocortical axis assessments. No unusual adverse events
      were observed. (ABSTRACT

PMID- 10654984
TI  - Effect of cisapride on the QT interval in infants with gastroesophageal reflux.
AB  - OBJECTIVE: We prospectively studied the effect of cisapride per se on QT interval
      in young infants (3-6 months) with gastroesophageal reflux (GER) in a controlled
      setting. STUDY DESIGN: The infants diagnosed with GER and deemed to require
      therapy with cisapride were divided into 2 groups. Group A comprised infants with
      GER who underwent an electrocardiogram (ECG) before initiation of therapy with
      cisapride in the dose of 1 mg per kg per 24 hours, divided into 3 doses. They
      were reweighed after 7 to 10 days, and the dose was adjusted for their new
      weight. A repeat ECG was performed after approximately 2 weeks (12-18 days) of
      therapy. The QT interval was measured in each ECG and then the corrected QT
      interval was calculated by Bazett's formula. Group B comprised infants with GER
      who had already been on therapy with cisapride for over 1 month. All infants in
      group B received cisapride in an approximate dose of 1 mg per kg per 24 hours (.8
      1.1 mg/kg/24 hours) given in 3 divided doses. They underwent only 1 ECG, ie, at 1
      to 4 months after initiation of therapy. The measurement of the actual dose of
      cisapride was demonstrated to every parent and a marked measuring syringe was
      provided. The following categories of infants were not included: those with any
      underlying cardiopulmonary, renal, or hepatic problem; those with a history of
      apnea; those using a macrolide antibiotic or azole antifungal at any stage during
      the study; and infants hospitalized for any reason during the course of the
      study. RESULTS: Cisapride therapy in the dose of 1 mg/kg/day frequently resulted
      in a slight increase in the QT interval (pretreatment: 390 +/- 18 milliseconds;
      posttreatment: 400 +/- 20 milliseconds) but the increase was still below the
      accepted upper limit of 440 milliseconds and not statistically significant. Even
      with prolonged therapy, the pattern of change in QT interval was similar to that
      with therapy for 2 weeks. Overall, 2 of 100 (2%) infants developed a prolongation
      of corrected QT interval beyond the normal range (456 and 486 milliseconds).
      Neither infant had evidence of any arrhythmia or conduction defect on ECG. No
      additional factor could be identified in either infant to explain prolongation of
      the QT interval. CONCLUSION: Our experience suggests that cautious cisapride
      therapy in young infants in a modest dose does not result in arrhythmias or
      conduction defects. We recommend that: 1) the dose of cisapride in infants be
      <1.2 mg/kg/day and preferably between.8 and 1 mg/kg/day; 2) the right measure of
      the dose be actually demonstrated to the parents; and 3) parents be provided a
      list of drug interactions with cisapride. One should think twice before denying
      the use of an effective drug simply because of the need for closer monitoring and
      extra time spent for parent education.

PMID- 10654985
TI  - Intestinal transplantation for short gut syndrome attributable to necrotizing
      enterocolitis.
AB  - BACKGROUND: Necrotizing enterocolitis (NEC) is a life-threatening condition of
      the neonatal age, which frequently requires surgical intervention. After
      extensive bowel resection, a small proportion of these patients may develop
      chronic short gut syndrome (SGS) and require chronic total parenteral nutrition
      (TPN) use. Intestinal transplantation has been performed in these patients as a
      life-saving option. This study reviews our experience with intestinal
      transplantation for SGS attributable to NEC emphasizing the mode of presentation,
      natural history, timing, and outcome. METHODS: A retrospective chart review was
      performed for all pediatric patients who underwent small bowel transplantation
      for NEC at the University of Miami between August 1994 and March 1999. RESULTS:
      Eleven transplants were performed for 10 patients with NEC (8 male and 2 female;
      median age: 1.75 years [range: 10 months to 10. 1 years]). Procedures performed
      were isolated intestinal transplants (n = 2), combined liver-intestinal
      transplants (n = 6), and multivisceral transplants (n = 3). All patients were
      born prematurely with median birth weight of 1.640 kg (range: 810 g to 2. 730
      kg). They developed NEC in the first few days of life and subsequently underwent
      an average of 5 surgeries per patient before transplant. Transplant was indicated
      for liver failure in 8 patients and recurrent central line sepsis in 2 others. At
      present, 6 patients are alive with an overall 1-year and 3-year actuarial
      survival of 60% and a median follow-up of 29 months (range: 9-46 months). Six
      children have been weaned off TPN after a median time of 71 days (range: 19-131)
      from transplantation. All survivors are at home with functional grafts.
      CONCLUSION: Intestinal transplantation provided a reasonable outcome in patients
      with NEC-associated SGS who had already developed life-threatening complications
      related to TPN. Intestinal transplantation replaced the diseased intestine and
      liver, enfranchised patients from TPN, and conferred improved quality of life.
      These patients should be actively considered for intestinal transplantation and
      referred to a transplant center as soon as possible.

PMID- 10654986
TI  - Long-term developmental outcomes in patients with deformational plagiocephaly.
AB  - OBJECTIVES: To determine whether there was an increased rate of later
      developmental delay in school-aged children who presented as infants with
      deformational plagiocephaly without obvious signs of delay at the time of initial
      evaluation. METHODS: A retrospective medical record review of 254 patients
      evaluated at the Craniofacial Center of the Children's Hospital and Regional
      Medical Center in Seattle, Washington, from 1980 through 1991 was completed.
      Consenting patient families were interviewed via telephone to determine what, if
      any, special medical or educational problems had occurred for the children who
      had had plagiocephaly in infancy or their siblings with normal head shapes.
      RESULTS: A total of 181 families from the medical record review could be notified
      about the study and 63 families agreed to participate in a telephone interview.
      The sample of participants for the telephone interview was random to and
      representative of the group as a whole. The families reported that 25 of the 63
      children (39.7%) with persistent deformational plagiocephaly had received special
      help in primary school including: special education assistance, physical therapy,
      occupational therapy, speech therapy generally through an Individual Education
      Plan. Only 7 of 91 siblings (7.7%), serving as controls, required similar
      services (chi(2) = 21.24). Delays could not be specifically anticipated at the
      time of the diagnosis of deformational plagiocephaly from any simple set of
      factors including treatment with helmet therapy, although effected males with
      reported uterine constraint were at the highest risk for subsequent school
      problems. CONCLUSIONS: Infants with deformational plagiocephaly comprise a high
      risk group for developmental difficulties presenting as subtle problems of
      cerebral dysfunction during the school-age years. There is a need for additional
      research on the long-term developmental problems in infants with deformational
      plagiocephaly. plagiocephaly, facial asymmetry, torticollis, developmental delay.

PMID- 10654987
TI  - Incidence and costs of 1987-1994 childhood injuries: demographic breakdowns.
AB  - OBJECTIVES: Injuries pose a threat to health and well-being and are a major
      source of medical spending in the United States for children and youth 0 to 21
      years of age. This study provides national estimates of the incidence of fatal
      and nonfatal childhood injuries and comprehensive cost estimates by age, gender,
      race, family income, metropolitan residence, and place of incident. METHODS:
      Eight years of National Health Interview Survey data (1987 to 1994) were used to
      estimate nonfatal injury incidence rates among children and youth 21 years of age
      and younger. The survey documents all medically attended or temporarily disabling
      injuries within the 2 weeks before the interview. Injuries were defined as
      diagnoses 800-995 in the International Classification of Diseases, Ninth
      Revision, excluding late effects cases. Fatality counts came from 1994 Vital
      Statistics. Estimates of the costs of injuries (1994 US dollars) included medical
      spending, lost future work, and lost quality of life. Medical payments included
      spending on hospital and professional services, rehabilitation, prescriptions,
      home health care, and medical equipment. Lost future work and lost quality of
      life consisted of the present value of work that children will be unable to do as
      adults if they are killed or permanently disabled combined with the pain and
      suffering that children and their families experience because of the injury. Cost
      estimates excluded parental income losses from work missed, property damage,
      legal costs, and insurance claims-adjustment costs related to permanent
      disability and death. RESULTS: INCIDENCE. A total of 3,073 injury episodes for
      3,058 children were obtained from 8 years of National Health Interview Survey
      data. This represents 20.6 million children in the United States who were injured
      each year, or approximately 25 per 100 children. This translates to 56,000
      nonfatal injury episodes each day that require medical attention or limit
      children's activity. For fatal injuries, the rate was 38 children per 100,000.
      The nonfatal injury rate for males (mean: 30; 95% confidence interval [CI]:
      29,31) was higher than the rate for females (mean: 20; 95% CI: 19,21); the fatal
      injury rate for males was more than twice that of females. Injury rates increased
      with age. Children 0 to 9 years of age had the lowest rate of nonfatal injury.
      Rates for nonfatal injury among children 0 to 4 years of age were lower (mean:
      20; 95% CI: 18,21) than those for the 5 to 9 age group (mean: 22; 95% CI: 20,
      23). However, the rate for fatal injuries (21 per 100,000) among the 0 to 4 age
      group was higher than the 5 to 9 age group (9 per 100,000). Nonfatal injury rates
      for children 10 years of age and older were higher, with the highest estimated
      injury rates in late adolescence (15-19 years; mean: 31; 95% CI: 29,33). Nonfatal
      injuries occurred at higher rates among white children (mean: 27; 95% CI: 26,28)
      than black children (mean: 19; 95% CI: 17,21) or children from other racial
      backgrounds (mean: 13; 95% CI: 10,16). The reverse was true for fatal injuries,
      with higher fatality rates among black children (59 per 100,000). Children in
      families with incomes under $5,000 had the highest rate of nonfatal injury (mean:
      31; 95% CI: 27,35), followed by those in the $35,000 to $49,999 income range
      (mean: 25; 95% CI: 23,27). The rate of nonfatal injuries in the other income
      brackets were fairly similar, with those in the highest income bracket having the
      lowest rate (mean: 14; 95% CI: 13,15). Fatality rates by family income were not
      available. The nonfatal injury rate in nonmetropolitan areas (mean: 10; 95% CI:
      9,11) was higher than in metropolitan areas (mean: 8; 95% CI: 7,8); the same was
      true for fatal injury rates (33 per 100,000 in nonmetropolitan areas vs 25 in
      metropolitan areas). Males consistently had higher injury rates than females
      across all places of injury. Youth 15 years of age and older had higher rates for
      injuries that occur on the public roads, in recreatio

PMID- 10654988
TI  - Polymorphonuclear elastase as a diagnostic marker of acute pyelonephritis in
      children.
AB  - OBJECTIVE: Experimental evidence suggests that neutrophils and their metabolites
      play an important role in the pathogenesis of pyelonephritis. The aim of this
      study was to investigate the diagnostic value of polymorphonuclear elastase-a(1)
      antitrypsin complex (E-a(1)-Pi) for the detection of acute pyelonephritis in
      children. METHODS: Eighty-three patients, 29 boys and 54 girls, 25 days to 14
      years of age, with first-time symptomatic urinary tract infection were
      prospectively studied. Fifty-seven healthy children served as controls.
      Dimercaptosuccinic acid (DMSA) scan and voiding cystourethrography were performed
      in all patients. Plasma and urinary E-a(1)-Pi, C-reactive protein (CRP),
      erythrocyte sedimentation rate (ESR), neutrophil count, urinary N-acetyl-beta
      glucosaminidase (NAG), N-acetyl-beta-glucosaminidase b (NAG b), and creatinine
      levels were measured in all patients on admission and 3 days after the
      introduction of antibiotics. The same markers were also measured in the control
      subjects. RESULTS: Planar DMSA scintigraphy demonstrated changes of acute
      pyelonephritis in 30 of 83 children (group A). It was normal in the remaining 53
      children (group B). The sex and age distributions were not significantly
      different between the 2 groups, as well as between the patients and the control
      subjects (group C). Nineteen of the 53 children with a normal DMSA had body
      temperature >/=38 degrees C, whereas all but 4 children with abnormal DMSA had
      temperature >/=38 degrees C. Therefore, the temperature was significantly
      different between these 2 groups. The sensitivity and specificity of fever (>/=38
      degrees C) as an indicator of renal involvement based on isotopic findings were
      86% and 64%, respectively. Given the significant number of the febrile children
      with normal DMSA scintiscans, group B was subdivided into B(1) with 19 febrile
      children (14 boys and 5 girls) and B(2) with 34 children whose body temperature
      was below 38 degrees C (8 boys and 26 girls). The sex and age distribution was
      significantly different between groups B(1) and B(2). The mean age of group B(1)
      was.78 years (range: 28 days to 9 years; median:.25 years; standard deviation:
      2.1). All but 1 child in this group were younger than 1 year of age. In contrast,
      in group B(2), there were only 4 infants, the remaining 30 children were older
      than 2.5 years (mean age: 6 years; median: 7 years; standard deviation: 3.5;
      range: 34 days to 12 years). The mean duration of fever before hospital admission
      was 2.8 days for group A and 1.8 days for group B(1). This difference was not
      statistically significant. Similarly, body temperature was not significantly
      different between these 2 groups. The distribution of plasma E-a(1)-Pi values was
      normal in the control subjects. The sensitivity and specificity of plasma E-a(1)
      Pi, as an indicator of renal involvement, were 96% and 50%, respectively, taking
      the 95th percentile of the reference range as a cutoff value. However,
      considering as a cutoff value the level of 72 microg/dL (95th percentile of group
      B(2)), its sensitivity and specificity were 74% and 86%, respectively. Plasma E
      a(1)-Pi levels were significantly elevated in group A compared with group B and
      in both groups, the plasma E-a(1)-Pi values were significantly higher than in the
      control subjects. A significant difference also was noticed between group A and
      each of the subgroups B(1) and B(2) and also between the subgroups themselves.
      Plasma E-a(1)-Pi concentrations correlated significantly with neutrophil count in
      groups A (r =.3), B (r =.4), and B(2) (r =.46), but the correlation was not
      significant in group B(1.) ESR levels showed, among the different groups, similar
      differences with those of E-a(1)-Pi values. Unlike E-a(1)-Pi, CRP levels were
      comparable between groups A and B(1), which both consisted of febrile children.
      Neutrophil count was not significantly different between subgroups B(1) and B(2).
      (ABSTRACT TRUNCATED)

PMID- 10654989
TI  - A pilot study of posttraumatic stress and nonadherence in pediatric liver
      transplant recipients.
AB  - BACKGROUND: Symptoms of posttraumatic stress disorder (PTSD) were described in
      survivors of life-threatening diseases, the trauma being the experiences
      associated with the disease or its treatment. Their prevalence in liver
      transplant recipients is unknown. Based on clinical observations, we hypothesize
      that a significant proportion of pediatric liver transplant recipients suffers
      from PTSD symptoms. We further hypothesize that nonadherence (noncompliance) to
      medical management may, in some cases, be associated with these symptoms.
      Traumatized patients, according to this hypothesis, will avoid taking their
      medications, because these serve as painful reminders of the disease. OBJECTIVES:
      To determine the prevalence of PTSD symptoms in a sample of pediatric liver
      transplant recipients. To determine whether symptoms of PTSD are associated with
      nonadherence in these patients. To describe the clinical presentation of PTSD and
      the management of severe nonadherence in patients who suffer from this disorder.
      METHODS: Nineteen pediatric liver transplant recipients and their caretakers were
      interviewed, using the UCLA Post Traumatic Stress Disorder Reaction Index
      (PTSRI). Data were obtained on a few demographic parameters and perception of
      disease threat. Adherence was evaluated by 2 methods: 1) a clinician panel
      (taking into account the clinical sequelae of severe nonadherence); and 2)
      computation of the standard deviations (SDs) of consecutive determinations of
      blood levels of Tacrolimus (a higher SD means higher variability between
      individual measures and is therefore an indicator of nonadherence). As an
      illustration of the general phenomenon, we describe 3 cases of liver transplant
      recipients who were nonadherent and who suffered from PTSD. RESULTS: Six of 19
      patients had positive scores on all 3 components of the PTSRI (PTSD patients).
      Three of these, and none of the others, were considered significantly nonadherent
      by the panel. Therefore, nonadherence was significantly associated with the
      existence of symptoms from all 3 domains of PTSD (Fisher's exact test) in our
      sample. In particular, a high avoidance score on the PTSRI was highly correlated
      with panel-determined nonadherence. Further, SD of medication levels were
      significantly higher in PTSD patients, compared with the rest of our sample. No
      significant differences were found in perception of disease threat or demographic
      variables between PTSD patients and the rest of our sample. The 3 cases that we
      describe became adherent to their medications when symptoms of PTSD subsided
      during the course of therapy. CONCLUSIONS: Clinically significant nonadherence,
      determined by 2 different methods, was associated with the full spectrum of PTSD
      symptoms in this sample. It was especially associated with a high avoidance
      score, which suggests that avoidance of reminders of the disease (eg,
      medications) may be a mechanism of nonadherence. Screening for and management of
      these symptoms, therefore, may improve adherence. This novel concept may be
      applicable to other patient populations. However, more data are needed before any
      definite conclusions can be drawn.

PMID- 10654990
TI  - Taking issue: the lawyerization of American mental health.

PMID- 10654993
TI  - Treating high-cost users of behavioral health services in a health maintenance
      organization.

PMID- 10654994
TI  - Long-acting stimulants for the treatment of attention-deficit disorder in cocaine
      dependent adults.

PMID- 10654995
TI  - Managed care and unmet need for mental health and substance abuse care in 1998.

PMID- 10654996
TI  - Patterns of hospital costs for depression in general hospital wards and
      specialized psychiatric settings.

PMID- 10654997
TI  - A son's suicide, a father's grief.

PMID- 10655000
TI  - Model commitment law revised to improve patient treatment. 1953.

PMID- 10655001
TI  - Commentary & analysis: the Draft Act Governing Hospitalization of the Mentally
      Ill: its genesis and its legacy.
AB  - As a follow-up to the preceding article first published in the February 1953
      issue, Paul Appelbaum, M.D., offers a commentary and analysis on the revised
      Draft Act Governing Hospitalization of the Mentally Ill. He includes its
      psychiatric context in the five-year period between 1951 and 1955 and later
      developments related to involuntary commitment.

PMID- 10655002
TI  - The effect of copayments on drug and alcohol treatment following inpatient
      detoxification under managed care.
AB  - OBJECTIVE: The study examined the rate and duration of outpatient substance abuse
      treatment following inpatient detoxification under managed care. METHODS: Seven
      years of claims data from a large behavioral health care carve-out plan were used
      to identify patients. Rates and duration of formal substance abuse treatment
      following detoxification were calculated, and regression models were used to
      explore factors that may affect participation in treatment. RESULTS: Seventy-nine
      percent of the detoxification patients received formal substance abuse treatment,
      the majority within the week following discharge. Formal follow-up care lasted an
      average of ten weeks, with visits occurring on average about once a week. When
      other variables likely to influence participation in substance abuse treatment
      were controlled for, the level of outpatient copayments significantly affected
      the rate of participation in treatment. CONCLUSIONS: These findings indicate that
      the rate of participation in outpatient treatment after detoxification is high,
      but room for improvement remains. The results suggest that reducing copayment
      levels is one mechanism for increasing the likelihood that individuals with
      severe drug and alcohol problems will receive subsequent treatment. The need for
      such treatment is underscored by the severity of illness of those who undergo
      detoxification and the societal costs of untreated substance use disorders.

PMID- 10655003
TI  - Knowledge of mental health benefits and preferences for type of mental health
      providers among the general public.
AB  - OBJECTIVE: The study explored knowledge of mental health benefits and preferences
      for providers among the general public. METHODS: Analysis was based on a
      telephone survey of 1,358 adults randomly sampled throughout Michigan in 1997
      1998. RESULTS: A large proportion of the respondents were uninformed about their
      mental health benefits. One-quarter of the sample were unsure if their health
      plan even included mental health services. Forty-three percent of the sample
      believed that mental health benefits were equal to benefits provided for general
      medical services. In answer to a survey question that summarized payment
      restrictions for psychiatric services and counseling under Medicare, nearly a
      quarter of older respondents indicated that they would not seek care even when
      needed. In the overall sample, the majority of respondents said they would
      initially seek care from their primary care physician for a mental health
      problem, although responses varied by age. Persons over age 65 were significantly
      more likely to seek assistance from their primary care doctor than were younger
      persons. CONCLUSIONS: The general public lacks information about important mental
      health benefits, and this lack of information may represent a barrier in their
      seeking care when needed. Given the overriding preference for primary care
      providers to treat mental health problems, particularly among older adults,
      mental health issues should be given more attention at all levels of primary care
      education.

PMID- 10655004
TI  - Preferred terms for users of mental health services among service providers and
      recipients.
AB  - OBJECTIVE: The terms used to refer to recipients of psychiatric services continue
      to be controversial. Terms in current use include "patient," "client,"
      "consumer," and "survivor." In this study mental health service recipients and
      providers were surveyed about their preferences among these terms, and responses
      were analyzed to identify factors associated with various preferences. METHODS: A
      total of 550 service providers and 427 recipients at four sites in Ontario-two
      provincial psychiatric hospitals, a private mental health center, and a
      psychiatric unit of a general hospital-participated in a brief anonymous survey.
      RESULTS: Among service providers, 68.4 percent preferred the term "patient," 26.5
      percent preferred "client," and.5 percent preferred "consumer." Logistic
      regression analysis showed that service providers' preferences were associated
      with age and gender. Among service recipients, 54.8 percent preferred the term
      "patient," 28.8 percent preferred "client," 7 percent preferred "survivor," and
      2.8 percent preferred "consumer." Service recipients' preferences were associated
      with site, self-reported diagnosis, and employment status. CONCLUSION: The study
      results indicate lack of universality in preferences for terms for users of
      mental health services and suggest the need for dialogue about preferred terms
      between service providers and recipients.

PMID- 10655005
TI  - Shorter hospital stays and more rapid improvement among patients with
      schizophrenia and substance disorders.
AB  - OBJECTIVE: Length of stay and treatment response of inpatients with acute
      schizophrenia were examined to determine whether differences existed between
      those with and without comorbid substance-related problems. METHODS: The sample
      comprised 608 patients with a diagnosis of schizophrenia or schizoaffective
      disorder treated on hospital units with integrated dual diagnosis treatment. They
      were rated on admission and discharge by a psychiatrist using a structured
      clinical instrument. Patients with no substance-related problems were compared
      with those with moderate to severe problems using t tests, chi square tests, and
      analysis of variance. RESULTS: When analyses controlled for age, gender, and
      other clinical variables, dually diagnosed patients were found to have improved
      markedly faster compared with patients without a dual diagnosis. Their hospital
      stays were 30 percent shorter on both voluntary and involuntary units. They also
      showed somewhat greater symptomatic improvement and no increase in 18-month
      readmission rates. On admission the dual diagnosis group was more likely to be
      younger, male, and homeless and more likely to be a danger to self and others.
      Severity of psychosis was the same at admission for the two groups, but the
      dually diagnosed patients were rated as less psychotic at discharge. CONCLUSIONS:
      Dually diagnosed patients with schizophrenia appear to stabilize faster during
      acute hospitalization than those without a dual diagnosis. The authors
      hypothesize that substance abuse may temporarily amplify symptoms or that these
      patients may have a higher prevalence of better-prognosis schizophrenia. The
      availability of integrated dual-focus inpatient treatment and a well-developed
      outpatient system may also have helped these patients recover more rapidly.

PMID- 10655006
TI  - Predicting medication noncompliance after hospital discharge among patients with
      schizophrenia.
AB  - OBJECTIVE: The study sought to identify predictors of noncompliance with
      medication in a cohort of patients with schizophrenia after discharge from acute
      hospitalization. METHODS: Adult psychiatric inpatients with schizophrenia or
      schizoaffective disorder for whom oral antipsychotics were prescribed (N=213)
      were evaluated at hospital discharge and three months later to assess medication
      compliance. Comparisons were made between patients who reported stopping their
      medications for one week or longer and patients who reported more continuous
      medication use. RESULTS: Of the 213 patients, about a fifth (19.2 percent) met
      the criterion for noncompliance. Medication noncompliance was significantly
      associated with an increased risk of rehospitalization, emergency room visits,
      homelessness, and symptom exacerbation. Compared with the compliant group, the
      noncompliant group was significantly more likely to have a history of medication
      noncompliance, substance abuse or dependence, and difficulty recognizing their
      own symptoms. Patients who became medication noncompliant were significantly less
      likely to have formed a good therapeutic alliance during hospitalization as
      measured by inpatient staff reports and were more likely to have family members
      who refused to become involved in their treatment. CONCLUSIONS: Patients with
      schizophrenia at high risk for medication noncompliance after acute
      hospitalization are characterized by a history of medication noncompliance,
      recent substance use, difficulty recognizing their own symptoms, a weak alliance
      with inpatient staff, and family who refuse to become involved in inpatient
      treatment.

PMID- 10655007
TI  - Social functioning of patients with schizophrenia in high-income welfare
      societies.
AB  - OBJECTIVE: The study assessed the level of reintegration into the community of
      patients with schizophrenia in Oslo, Norway, a country with a well-developed
      social welfare system and low unemployment rates. METHODS: Eighty-one patients
      with a DSM-III-R diagnosis of schizophrenia treated in 1980 and in 1983 in a
      short-term ward of a psychiatric hospital were followed up after seven years.
      Seventy-four of 76 patients alive at follow-up agreed to participate. Social
      functioning was measured by the Strauss-Carpenter Level of Functioning Scale and
      the Social Adjustment Scale. RESULTS: At follow-up 78 percent of patients lived
      independently, 47 percent were socially isolated, and 94 percent were unemployed.
      Thirty-four percent had lost employment in the follow-up period. A poor outcome
      in terms of social functioning and community reintegration was associated with
      loss of employment. A good outcome was predicted by short periods of inpatient
      hospitalization, high levels of education, being married, male gender, and not
      having a late onset of psychosis. CONCLUSIONS: The level of homelessness among
      these patients with schizophrenia was encouragingly low, which may have been
      expected in a high-income welfare society. However, insufficient efforts were
      aimed at social and instrumental rehabilitation, and the level of unemployment
      was alarmingly high.

PMID- 10655008
TI  - Self-esteem as an outcome measure in studies of vocational rehabilitation for
      adults with severe mental illness.
AB  - OBJECTIVE: Self-esteem is widely used as an outcome variable in studies of
      psychiatric rehabilitation, based on the assumption that improved functional
      status leads to higher self-esteem. Little is known, however, about the
      determinants of self-esteem among adults with severe mental illness. The utility
      of a popular measure of global self-esteem-the Rosenberg Self-Esteem Scale-as an
      outcome measure was examined in this population. METHODS: A total of 143
      participants enrolled in a study of vocational rehabilitation were assessed at
      baseline and six, 12, and 18 months later using measures of self-esteem,
      symptoms, life satisfaction, work status, housing status, and total income.
      RESULTS: Scores on the Rosenberg Self-Esteem Scale did not vary with work status
      or other functional outcomes but instead were strongly related to measures of
      life satisfaction and affective symptoms. CONCLUSIONS: The hypothesis that
      working leads to improved self-esteem for people with severe mental illness was
      not supported. For this population, self-esteem, as measured by the Rosenberg
      Self-Esteem Scale, appears to be a relatively stable trait that reflects general
      life satisfaction and affective symptoms rather than objective functional status.

PMID- 10655010
TI  - Using quality improvement teams to improve documentation in records at a
      community mental health center.
AB  - OBJECTIVE: A community mental health center sought a system for qualitative
      review of patients' records to improve the quality of documentation through the
      engagement of clinical staff in the review process. METHODS: The center developed
      a quality improvement system in which treatment team clinicians use a scored 30
      item protocol to measure the quality of record documentation by peers. Questions
      address whether the record documents the full range of the psychiatric treatment
      process, including assessment and diagnosis, treatment planning, and provision of
      clinical services. Other questions address specific contractual or regulatory
      requirements, such as whether procedure codes are correct, and evaluate the
      physician's record of medication management. Each treatment team at the mental
      health center's six clinics has a quality improvement work group, composed of the
      team psychiatrist and at least one other team clinician. Each month the work
      group meets to review two randomly selected medical records from another
      treatment team at the same clinic and arrive at a consensus score. An
      administrative oversight team meets regularly with clinician-reviewers to foster
      uniform scoring of the protocol throughout the center. RESULTS: An analysis of
      the trend in protocol scores over a 21-month period suggests that the procedure
      improves the quality of the documentation in patients' records. CONCLUSIONS: A
      team-based quality review process appears to have a positive impact on the
      quality of medical record documentation. Improved documentation may improve
      continuity of care and improve the accuracy of record information used for other
      quality measurement systems.

PMID- 10655009
TI  - Risk behaviors for sexually transmitted infections among men with mental
      disorders.
AB  - OBJECTIVE: Risk behaviors for sexually transmitted infections among men with
      mental disorders who were using outpatient psychiatric services and among men who
      had never been treated for a mental disorder were compared. METHODS: Ninety-two
      men with major mental disorders, including schizophrenia, bipolar disorder, and
      mood disorders, were individually matched for age and ethnicity with 92 men who
      had never been treated for mental illness. All subjects completed a
      semistructured interview about specific risk behaviors for sexually transmitted
      infections that they may have engaged in during the preceding year. RESULTS: The
      49 patients with mental disorders who had been sexually active in the preceding
      year were significantly more likely than the 78 sexually active comparison
      subjects to have known their sexual partner for less than one day and to report
      having been pressured into unwanted sexual intercourse. A strong but not
      significant trend was found for sexually active patients to have had sex with a
      male partner and sex with a drug user. Overall, the patients with mental
      disorders answered ten questions measuring AIDS knowledge questions significantly
      less well than the comparison subjects. CONCLUSIONS: The results underscore the
      priority for developing programs for preventing risk behaviors for sexually
      transmitted infections among men with mental disorders.

PMID- 10655011
TI  - A content analysis of state hospital policies on sex between inpatients.
AB  - Eighty-one state psychiatric hospitals in 16 states were surveyed about whether
      they had policies on sex between inpatients. Thirty-one hospitals responded by
      sending a copy of their policies, which were analyzed for explicit definitions
      and distinctions between various sexual behaviors; for the presence and content
      of statements about patients' rights and personal autonomy, duty to protect,
      competency to consent, and staff guidance and education; and for instructions on
      the management of sexual incidents. Fourteen of the 31 policies explicitly
      forbade inpatient sex; 12 stressed patient autonomy. Only five specified that
      staff should receive special training. The results indicate that hospitals vary
      widely in their attention and management approach to inpatients' sexual behavior.

PMID- 10655012
TI  - Length and number of hospitalizations in two cohorts of veterans with chronic
      schizophrenia.
AB  - Two cohorts of male veteran patients with schizophrenia were compared on several
      clinical and demographic measures. The first cohort, hospitalized in one of two
      Veterans Affairs hospitals between 1965 and 1975, consisted largely of Korean-era
      veterans. The second cohort, hospitalized between 1991 and 1994, were largely
      Vietnam-era veterans. Although treatment and management of patients with
      schizophrenia differed during the two eras and the second cohort had a
      significantly higher mean number of hospitalizations than the first, the two
      cohorts did not differ in total time hospitalized. The finding suggests the need
      to improve methods for relapse prevention.

PMID- 10655013
TI  - Relationship between service effectiveness and satisfaction among persons
      receiving Medicaid mental health services.
AB  - Relationships between service satisfaction, life satisfaction, and self-reported
      mental health status were examined for Iowa Medicaid mental health service
      recipients. Of the 16,579 persons who received services in 1993, a mail-out
      survey was sent to 2,520 persons and returned by 815 (32.3 percent). Persons with
      schizophrenia reported greater service satisfaction and life satisfaction than
      persons with other diagnoses, and their ratings of their mental health were
      higher. A relationship between service satisfaction and current life satisfaction
      was observed for persons with schizophrenia, affective disorder and adjustment
      disorder, but not for persons with anxiety disorder.

PMID- 10655014
TI  - Effect of clozapine on polypharmacy.
AB  - Prescribing patterns for a group of outpatients with schizophrenia were surveyed
      for changes after the initiation of clozapine. Data were drawn from computerized
      pharmacy records, direct case record reviews, and interviews with the attending
      psychiatrists. The number of patients with two or more psychotropic drugs
      decreased by 31 percent after the initiation of clozapine, and a trend toward the
      use of clozapine without additional neuroleptics was detected. Decreases occurred
      in the use of anticholinergic agents, carbamazepine, and benzodiazepines, but
      selective serotonin reuptake inhibitors and sodium valproate were more likely to
      be prescribed concomitantly with clozapine.

PMID- 10655015
TI  - Small-town psychiatry.

PMID- 10655016
TI  - Public leadership in child psychiatry.

PMID- 10655017
TI  - A case of delayed NMS induced by risperidone.

PMID- 10655018
TI  - Epiglottitis in a psychotic, non-English-speaking adult.

PMID- 10655020
TI  - Economic impact of digestive, nutritional and oral diseases in Canada.

PMID- 10655021
TI  - Change comes to the journal

PMID- 10655022
TI  - Thank you Dr alan thompson and Dr noel williams!

PMID- 10655023
TI  - Inflammatory bowel diseases in Indo-Canadians with and without antineutrophil
      cytoplasmic autoantibodies.
AB  - A sequentially evaluated cohort of Indo-Canadians with either ulcerative colitis
      or Crohn's disease were prospectively examined for antineutrophil cytoplasmic
      autoantibodies (ANCA). Of 84 patients, 62 had ulcerative colitis and 22 had
      Crohn's disease. About one-third were born in Canada, and two-thirds were
      migrants from India or other countries, particularly East African nations. There
      was a disease-based and geographically based male predominance. The mean age of
      Canadian-born patients was significantly less than that of those born in other
      countries. Moreover, for migrants, the mean duration of residence in Canada
      before developing disease was 8.9 years for Crohn's disease patients and 13.5
      years for ulcerative colitis patients. Moderate to severe disease was present;
      virtually all those with Crohn's disease had colonic involvement, and most of
      those with ulcerative colitis had extensive colonic disease. Overall, 40 of 84
      (48%) were seropositive for ANCA, including a majority of those with ulcerative
      colitis but not Crohn's disease. In addition, eight had cytoplasmic ANCA, a
      reported seromarker for extensive colitis. Seropositive and seronegative patients
      were similar in age, sex, birth or duration of residence in Canada, site and
      severity of disease, familial history and complications, including pouchitis.
      This study supports the view that these diseases arise in individuals with a
      genetic predisposition following exposure to some, as yet unknown, environmental
      factor.

PMID- 10655024
TI  - Omeprazole once or twice daily with clarithromycin and metronidazole for
      Helicobacter pylori.
AB  - BACKGROUND: Triple therapy for one week with omeprazole, clarithromycin and
      metronidazole (OCM) is accepted worldwide as a first line therapy for
      Helicobacter pylori eradication. It is unclear whether omeprazole needs to be
      given once or twice daily. OBJECTIVES: To assess the efficacy and safety of these
      regimens in a single-centre, Canadian practice. METHODS: Histologically proven H
      pylori-positive patients were treated for seven days with clarithromycin 250 mg
      bid and metronidazole 500 mg bid, and randomly allocated to omeprazole 20 mg
      either once or twice daily in this open, cohort study. Endoscopy with histology
      (two antrum and two body biopsies, Giemsa stain) was done four weeks or longer
      after the pills were completed to assess H pylori eradication. RESULTS: Whether
      omeprazole was given once or twice daily, eradication was high and the same in
      both arms. All-patients-treated eradication was 85% (39 of 46 in the omeprazole
      once daily group and 41 of 48 in the omeprazole twice daily group) and intent-to
      treat eradication was 80% (39 of 49 in the omeprazole once daily group and 41 of
      51 in the omeprazole twice daily group). Side effects were frequently seen,
      suffered by 65% to 69% of patients treated. However, these were mild and
      compliance was high, with 94% of patients taking all of their pills. Mild side
      effects included loose stools, taste disturbance, nausea, headache and upper or
      lower gastrointestinal gas. Only one patient (1%) from the omeprazole once daily
      arm stopped taking metronidazole due to excessive perspiring. CONCLUSIONS: In
      this community practice, OCM triple therapy was effective whether omeprazole was
      given once or twice daily. For those with financial constraint, omeprazole 20 mg
      once daily can be considered. The regimens were well tolerated without serious
      adverse events.

PMID- 10655025
TI  - Evolving concepts of the pathogenesis and treatment of the pruritus of
      cholestasis.
AB  - The site of the pathogenic events responsible for initiating the pruritus of
      cholestasis has been assumed to be the skin. This assumption cannot be excluded
      but is not supported by convincing data. Empirical therapies such as anion
      exchange resins and rifampicin often appear to be partially efficacious. Recent
      evidence suggests that altered neurotransmission in the brain may contribute to
      this form of pruritus. In particular, the hypothesis that increased central
      opioidergic tone is involved is supported by three observations: opiate agonists
      induce opioid receptor-mediated scratching activity of central origin, central
      opioidergic tone is increased in cholestasis and opiate antagonists reduce
      scratching activity in cholestatic patients. Apparent subjective ameliorations of
      pruritus following intravenous administration of ondansetron to cholestatic
      patients suggest that altered serotoninergic neurotransmission may also
      contribute to this form of pruritus.

PMID- 10655027
TI  - Pseudomembranous colitis: an update.
AB  - Clostridium difficile is the most common nosocomial infection of the
      gastrointestinal tract. Most cases are associated with antibiotic therapy that
      alters the fecal flora, allowing overgrowth of C difficile with production of its
      toxins. Diagnosis is made by detection of the organism or toxin in the stools. A
      variety of different tests can be used, but none is perfect. A stool culture can
      be positive in someone without diarrhea, ie, a carrier. While the cytotoxin is
      the gold standard, it is expensive, and there is a delay before results are
      available. Thus, many laboratories use the enzyme-linked immunoassay tests to
      detect toxin of C difficile because they are a more rapid screen. Depending on
      the specific test used, they can detect toxin A, toxin B or occasionally both.
      Sensitivity and specificity rates vary. First line therapy for C difficile
      disease should be metronidazole 250 mg qid for 10 days. Vancomycin should be
      reserved for severe cases where metronidazole has failed or where metronidazole
      cannot be tolerated or is contraindicated. Recurrent C difficile disease is a
      particularly vexing clinical problem. A variety of biotherapeutic approaches have
      been used. Retreatment with antibiotics is almost always necessary. In addition,
      the nonpathogenic yeast Saccharomyces boulardii has been showed to be of benefit
      as an adjunct in preventing further recurrences.

PMID- 10655026
TI  - Update on primary biliary cirrhosis.
AB  - The diagnosis of primary biliary cirrhosis (PBC) is most often made in the
      asymptomatic phase, sometimes before the development of abnormal liver
      biochemistry. The antimitochondrial antibody remains the predominant hallmark,
      although not all patients test positive, even when the most sensitive techniques
      are used. The etiology of PBC remains elusive; studies suggest that the
      interlobular bile duct destruction is immune based, and associated autoimmune
      diseases are common. There are no surrogate markers that predict outcome in
      asymptomatic patients, whose chance of survival is less than that of age- and sex
      matched populations but much better than the median survival of eight years in
      patients with symptomatic PBC. Symptoms common in this disease are fatigue,
      pruritus and xanthelasma, as well as complications of portal hypertension and
      osteoporosis. Treatment includes symptomatic and preventive measures, as well as
      specific therapeutic measures. Immunosuppressive therapy has yielded
      disappointing results in the long term management of PBC, and the only therapy
      shown to improve survival is the hydrophobic dihydroxy bile acid ursodeoxycholic
      acid. Treatment at a dose of 13 to 15 mg/kg/day is optimal, given in separate
      doses or as a single dose at least 4 h from giving the oral anion exchange resin
      cholestyramine, which may be used to control pruritus. However, liver
      transplantation remains the only cure for this disease, and the best
      postoperative survival is seen in patients whose serum bilirubin does not exceed
      180 micromol/L at the time of liver transplantation. Recurrence takes place but
      is rarely symptomatic and does not deter from the benefits of transplantation.

PMID- 10655028
TI  - Gene therapy applications in gastroenterology and hepatology.
AB  - Advantages and disadvantages of viral vectors and nonviral vectors for gene
      delivery to digestive organs are reviewed. Advances in systems for the
      introduction of new gene expression are described, including self-deleting
      retroviral transfer vectors, chimeric viruses and chimeric oligonucleotides.
      Systems for inhibition of gene expression are discussed, including antisense
      oligonucleotides, ribozymes and dominant-negative genes.

PMID- 10655029
TI  - Evolutionary genomics: reading the bands.
AB  - The human genome is not a uniform structure but, instead, is a mosaic of bands.
      Some of these bands can be seen by the eye. Stained with Giemsa and viewed under
      the microscope each human chromosome has a prototypical pattern of light and dark
      bands (G and R bands respectively). Other bands are not so easily viewed. The
      human genome is, for example, a mosaic of isochores, blocks of DNA within which
      the proportion of the bases G and C at silent sites (introns, third positions in
      codons, intergene spacer) is fairly uniform. Recent work by Matassi and
      colleagues(1) has revealed what might be a new and unexpected banding pattern.
      They have found that the genes which are close together on the chromosome have
      similar rates of evolution. BioEssays 22:105-107, 2000.

PMID- 10655031
TI  - Calcium signalling during zebrafish embryonic development.
AB  - Calcium signals appear throughout the first 24 hours of zebrafish development.
      These begin at egg activation, then continue to be generated throughout the
      subsequent zygote, cleavage, blastula, gastrula, and segmentation periods. They
      are thus associated with the major phases of pattern formation: cell
      proliferation, cell differentiation, axis determination, the generation of
      primary germ layers, the emergence of rudimentary organ systems, and therefore
      the establishment of the basic vertebrate body plan. When signals need to be
      transmitted across significant distances they take the form of waves, either
      intracellular waves when the cell size is large, or later in development when the
      cell size is reduced, intercellular waves. We will consider both types of calcium
      signals and their integration into signalling networks, and discuss their
      possible functions and developmental significance with regard to pattern
      formation. BioEssays 22:113-123, 2000.

PMID- 10655030
TI  - FGFs, heparan sulfate and FGFRs: complex interactions essential for development.
AB  - Fibroblast growth factors (FGFs) comprise a large family of developmental and
      physiological signaling molecules. All FGFs have a high affinity for the
      glycosaminoglycan heparin and for cell surface heparan sulfate proteoglycans. A
      large body of biochemical and cellular evidence points to a direct role for
      heparin/heparan sulfate in the formation of an active FGF/FGF receptor signaling
      complex. However, until recently there has been no direct demonstration that
      heparan is required for the biological activity of FGF in a developmental system
      in vivo. A recent paper by Lin et al.(1) has broken through this barrier to
      demonstrate that heparan sulfate is essential for FGF function during Drosophila
      development. The establishment of a role for heparan sulfate in FGFR activation
      in vivo suggests that tissue-specific differences in the structure of heparan may
      modulate the activity of FGF. BioEssays 22:108-112, 2000.

PMID- 10655032
TI  - Mammalian chromodomain proteins: their role in genome organisation and
      expression.
AB  - The chromodomain is a highly conserved sequence motif that has been identified in
      a variety of animal and plant species. In mammals, chromodomain proteins appear
      to be either structural components of large macromolecular chromatin complexes or
      proteins involved in remodelling chromatin structure. Recent work has suggested
      that apart from a role in regulating gene activity, chromodomain proteins may
      also play roles in genome organisation. This article reviews progress made in
      characterising mammalian chromodomain proteins and emphasises their emerging role
      in the regulation of gene expression and genome organisation. BioEssays 22:124
      137, 2000.

PMID- 10655033
TI  - All for one and one for all: condensations and the initiation of skeletal
      development.
AB  - Condensation is the pivotal stage in the development of skeletal and other
      mesenchymal tissues. It occurs when a previously dispersed population of cells
      gathers together to differentiate into a single cell/tissue type such as
      cartilage, bone, muscle, tendon, kidney, and lung and is the earliest stage
      during organ formation when tissue-specific genes are upregulated. We present a
      synopsis of our current understanding of how condensations are initiated and
      grown, how their boundaries and sizes are set, how condensation ceases, and how
      overt differentiation begins. Extracellular matrix molecules, cell surface
      receptors and cell adhesion molecules, such as fibronectin, tenascin, syndecan,
      and N-CAM, initiate condensation formation and set condensation boundaries. Hox
      genes (Hoxd-11-13) and other transcription factors (CFKH-1, MFH-1, osf-2),
      modulate the proliferation of cells within condensations. Cell adhesion is
      ensured indirectly through Hox genes (Hoxa-2, Hoxd-13), and directly via cell
      adhesion molecules (N-CAM and N-cadherin). Subsequent growth of condensations is
      regulated by BMPs, which activate Pax-2, Hoxa-2 and Hoxd-11 among other genes.
      Growth of a condensation ceases when Noggin inhibits BMP signalling, setting the
      stage for transition to the next stage of skeletal development, namely overt cell
      differentiation. BioEssays 22:138-147, 2000.

PMID- 10655034
TI  - SINE insertions: powerful tools for molecular systematics.
AB  - Short interspersed repetitive elements, or SINEs, are tRNA-derived retroposons
      that are dispersed throughout eukaryotic genomes and can be present in well over
      10(4) total copies. The enormous volume of SINE amplifications per organism makes
      them important evolutionary agents for shaping the diversity of genomes, and the
      irreversible, independent nature of their insertion allows them to be used for
      diagnosing common ancestry among host taxa with extreme confidence. As such, they
      represent a powerful new tool for systematic biology that can be strategically
      integrated with other conventional phylogenetic characters, most notably
      morphology and DNA sequences. This review covers the basic aspects of SINE
      evolution that are especially relevant to their use as systematic characters and
      describes the practical methods of characterizing SINEs for cladogram
      construction. It also discusses the limits of their systematic utility, clarifies
      some recently published misunderstandings, and illustrates the effective
      application of SINEs for vertebrate phylogenetics with results from selected case
      studies. BioEssays 22:148-160, 2000.

PMID- 10655035
TI  - Retroviruses and primate evolution.
AB  - Human endogenous retroviruses (HERVs), probably representing footprints of
      ancient germ-cell retroviral infections, occupy about 1% of the human genome.
      HERVs can influence genome regulation through expression of retroviral genes,
      either via genomic rearrangements following HERV integrations or through the
      involvement of HERV LTRs in the regulation of gene expression. Some HERVs emerged
      in the genome over 30 MYr ago, while others have appeared rather recently, at
      about the time of hominid and ape lineages divergence. HERVs might have conferred
      antiviral resistance on early human ancestors, thus helping them to survive.
      Furthermore, newly integrated HERVs could have changed the pattern of gene
      expression and therefore played a significant role in the evolution and
      divergence of Hominoidea superfamily. Comparative analysis of HERVs, HERV LTRs,
      neighboring genes, and their regulatory interplay in the human and ape genomes
      will help us to understand the possible impact of HERVs on evolution and genome
      regulation in the primates. BioEssays 22:161-171, 2000.

PMID- 10655036
TI  - Axon formation: a molecular model for the generation of neuronal polarity.
AB  - Neurons have unique structural and functional polarity. In general, information
      flows from the short dendrites to the long axon, and each neuron has multiple
      dendrites but only one axon. A detailed description of the cellular events
      leading to the establishment of axonal-dendritic polarity has been given from an
      in vitro hippocampal culture model system. Little is known, however, about the
      nature of the underlying molecular events. New data strongly suggest that actin
      depolymerization at a growth cone is crucial for axon fate determination. We
      hypothesize that an autocatalytic positive feedback loop at all growth cones
      locally regulates actin dynamics and other cellular events required for axon
      formation. Meanwhile, a negative feedback signal, produced by the positive
      feedback loop, propagates from all growth cones throughout the neuron and
      counteracts the positive feedback loops. Such feedback regulation provides a
      robust mechanism for spontaneous symmetry breaking and the formation of only one
      axon, even in a symmetric in vitro environment. Based on data from studies of
      cell migration, axon guidance, vesicle exocytosis, and the regulation of actin
      and microtubule polymerization, we propose a molecular scheme for the positive
      feedback loop and discuss possible negative feedback signals. BioEssays 22:172
      179, 2000.

PMID- 10655037
TI  - Fluorescent tags of protein function in living cells.
AB  - A cell's biochemistry is now known to be the biochemistry of molecular machines,
      that is, protein complexes that are assembled and dismantled in particular
      locations within the cell as needed. One important element in our understanding
      has been the ability to begin to see where proteins are in cells and what they
      are doing as they go about their business. Accordingly, there is now a strong
      impetus to discover new ways of looking at the workings of proteins in living
      cells. Although the use of fluorescent tags to track individual proteins in cells
      has a long history, the availability of laser-based confocal microscopes and the
      imaginative exploitation of the green fluorescent protein from jellyfish have
      provided new tools of great diversity and utility. It is now possible to watch a
      protein bind its substrate or its partners in real time and with submicron
      resolution within a single cell. The importance of processes of self-organisation
      represented by protein folding on the one hand and subcellular organelles on the
      other are well recognised. Self-organisation at the intermediate level of
      multimeric protein complexes is now open to inspection. BioEssays 22:180-187,
      2000.

PMID- 10655038
TI  - The cardiac muscle cell.
AB  - The cardiac myocyte is the most physically energetic cell in the body,
      contracting constantly, without tiring, 3 billion times or more in an average
      human lifespan. By coordinating its beating activity with that of its 3 billion
      neighbours in the main pump of the human heart, over 7,000 litres of blood are
      pumped per day, without conscious effort, along 100,000 miles of blood vessels. A
      detailed picture of the membrane organisation of the cardiac muscle cell
      underpins our understanding of how the electrical impulse, generated within the
      heart, stimulates coordinated contraction of the cardiac chambers. This article
      highlights, with the aid of modern cellular imaging methods, key components of
      the membrane machinery responsible for coupling electrical excitation and
      contraction in the cardiomyocyte, focusing on plasma membrane/sarcoplasmic
      reticulum and plasma membrane/plasma membrane junctions. BioEssays 22:188-199,
      2000.

PMID- 10655039
TI  - Hydra: an out-group moves toward the center.

PMID- 10655040
TI  - Craniofacial morphogenesis: a meeting in memory of Peter Thorogood.

PMID- 10655041
TI  - Popper's philosophy of science: a practical tool for the working biologist.

PMID- 10655043
TI  - Response to Jonathan Bard and Aubrey de Grey.

PMID- 10655042
TI  - Biologists abandon Popper at their peril.

PMID- 10655044
TI  - Census, race and science.

PMID- 10655045
TI  - Giving in to the blues.
AB  - The molecular players that direct the development of mammalian photoreceptors are
      slowly coming into focus. A study that elucidates the cause of enhanced S-cone
      syndrome, a disorder that may be caused by a distortion of retinal cell fate,
      reveals one such factor-although questions about its effects remain.

PMID- 10655046
TI  - A bird's eye view of global methylation.
AB  - Restriction landmark genomic scanning applied to a broad variety of cancer types
      can disclose tumour-specific and tumour-type-specific global methylation
      profiles. This and other genome-scanning approaches allows the rapid analysis of
      methylation profiles of thousands of genes in parallel-and promises to identify
      new genes critical to carcinogenesis and other biological processes.

PMID- 10655047
TI  - Pushing the envelope on lipodystrophy.
AB  - Autosomal dominant partial lipodystrophy (PLD), in which regional adipose loss is
      coupled with insulin resistance, is strongly associated with missense mutations
      in LMNA, encoding lamin A/C-a component of the nuclear envelope. This finding
      indicates that other proteins and functions of the nuclear envelope may have
      bearing on disorders of adipose tissue and insulin action.

PMID- 10655048
TI  - A take on the tectorial membrane.

PMID- 10655049
TI  - TOUCHINGbase

PMID- 10655050
TI  - The ethical challenges of in utero gene therapy.

PMID- 10655051
TI  - Nuclear transfer into mouse zygotes.

PMID- 10655052
TI  - Generation of mice from wild-type and targeted ES cells by nuclear cloning.

PMID- 10655053
TI  - Flu times two

PMID- 10655054
TI  - Gene-target recognition among members of the myc superfamily and implications for
      oncogenesis.
AB  - Myc and Mad family proteins regulate multiple biological processes through their
      capacity to influence gene expression directly. Here we show that the basic
      regions of Myc and Mad proteins are not functionally equivalent in oncogenesis,
      have separable E-box-binding activities and engage both common and distinct gene
      targets. Our data support the view that the opposing biological actions of Myc
      and Mxi1 extend beyond reciprocal regulation of common gene targets.
      Identification of differentially regulated gene targets provides a framework for
      understanding the mechanism through which the Myc superfamily governs the growth,
      proliferation and survival of normal and neoplastic cells.

PMID- 10655055
TI  - ARSACS, a spastic ataxia common in northeastern Quebec, is caused by mutations in
      a new gene encoding an 11.5-kb ORF.
AB  - Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS or SACS) is an
      early onset neurodegenerative disease with high prevalence (carrier frequency
      1/22) in the Charlevoix-Saguenay-Lac-Saint-Jean (CSLSJ) region of Quebec. We
      previously mapped the gene responsible for ARSACS to chromosome 13q11 and
      identified two ancestral haplotypes. Here we report the cloning of this gene,
      SACS, which encodes the protein sacsin. The ORF of SACS is 11,487 bp and is
      encoded by a single gigantic exon spanning 12,794 bp. This exon is the largest to
      be identified in any vertebrate organism. The ORF is conserved in human and
      mouse. The putative protein contains three large segments with sequence
      similarity to each other and to the predicted protein of an Arabidopsis thaliana
      ORF. The presence of heat-shock domains suggests a function for sacsin in
      chaperone-mediated protein folding. SACS is expressed in a variety of tissues,
      including the central nervous system. We identified two SACSmutations in ARSACS
      families that lead to protein truncation, consistent with haplotype analysis.

PMID- 10655056
TI  - Mutation of a nuclear receptor gene, NR2E3, causes enhanced S cone syndrome, a
      disorder of retinal cell fate.
AB  - Hereditary human retinal degenerative diseases usually affect the mature
      photoreceptor topography by reducing the number of cells through apoptosis,
      resulting in loss of visual function. Only one inherited retinal disease, the
      enhanced S-cone syndrome (ESCS), manifests a gain in function of photoreceptors.
      ESCS is an autosomal recessive retinopathy in which patients have an increased
      sensitivity to blue light; perception of blue light is mediated by what is
      normally the least populous cone photoreceptor subtype, the S (short wavelength,
      blue) cones. People with ESCS also suffer visual loss, with night blindness
      occurring from early in life, varying degrees of L (long, red)- and M (middle,
      green)-cone vision, and retinal degeneration. The altered ratio of S- to L/M-cone
      photoreceptor sensitivity in ESCS may be due to abnormal cone cell fate
      determination during retinal development. In 94% of a cohort of ESCS probands we
      found mutations in NR2E3 (also known as PNR), which encodes a retinal nuclear
      receptor recently discovered to be a ligand-dependent transcription factor.
      Expression of NR2E3 was limited to the outer nuclear layer of the human retina.
      Our results suggest that NR2E3 has a role in determining photoreceptor phenotype
      during human retinogenesis.

PMID- 10655057
TI  - Aberrant CpG-island methylation has non-random and tumour-type-specific patterns.
AB  - CpG islands frequently contain gene promoters or exons and are usually
      unmethylated in normal cells. Methylation of CpG islands is associated with
      delayed replication, condensed chromatin and inhibition of transcription
      initiation. The investigation of aberrant CpG-island methylation in human cancer
      has primarily taken a candidate gene approach, and has focused on less than 15 of
      the estimated 45,000 CpG islands in the genome. Here we report a global analysis
      of the methylation status of 1,184 unselected CpG islands in each of 98 primary
      human tumours using restriction landmark genomic scanning (RLGS). We estimate
      that an average of 600 CpG islands (range of 0 to 4,500) of the 45,000 in the
      genome were aberrantly methylated in the tumours, including early stage tumours.
      We identified patterns of CpG-island methylation that were shared within each
      tumour type, together with patterns and targets that displayed distinct tumour
      type specificity. The expression of many of these genes was reactivated by
      experimental demethylation in cultured tumour cells. Thus, the methylation of
      particular subsets of CpG islands may have consequences for specific tumour
      types.

PMID- 10655058
TI  - Targeted disruption of otog results in deafness and severe imbalance.
AB  - Genes specifically expressed in the inner ear are candidates to underlie
      hereditary nonsyndromic deafness. The gene Otog has been isolated from a mouse
      subtractive cDNA cochlear library. It encodes otogelin, an N-glycosylated protein
      that is present in the acellular membranes covering the six sensory epithelial
      patches of the inner ear: in the cochlea (the auditory sensory organ), the
      tectorial membrane (TM) over the organ of Corti; and in the vestibule (the
      balance sensory organ), the otoconial membranes over the utricular and saccular
      maculae as well as the cupulae over the cristae ampullares of the three semi
      circular canals. These membranes are involved in the mechanotransduction process.
      Their movement, which is induced by sound in the cochlea or acceleration in the
      vestibule, results in the deflection of the stereocilia bundle at the apex of the
      sensory hair cells, which in turn opens the mechanotransduction channels located
      at the tip of the stereo-cilia. We sought to elucidate the role of otogelin in
      the auditory and vestibular functions by generating mice with a targeted
      disruption of Otog. In Otog-/- mice, both the vestibular and the auditory
      functions were impaired. Histological analysis of these mutants demonstrated that
      in the vestibule, otogelin is required for the anchoring of the otoconial
      membranes and cupulae to the neuroepithelia. In the cochlea, ultrastructural
      analysis of the TM indicated that otogelin is involved in the organization of its
      fibrillar network. Otogelin is likely to have a role in the resistance of this
      membrane to sound stimulation. These results support OTOG as a possible candidate
      gene for a human nonsyndromic form of deafness.

PMID- 10655059
TI  - A genome-wide survey of RAS transformation targets.
AB  - An important aspect of multi-step tumorigenesis is the mutational activation of
      genes of the RAS family, particularly in sporadic cancers of the pancreas, colon,
      lung and myeloid system. RAS genes encode small GTP-binding proteins that affect
      gene expression in a global way by acting as major switches in signal
      transduction processes, coupling extracellular signals with transcription
      factors. Oncogenic forms of RAS are locked in their active state and transduce
      signals essential for transformation, angiogenesis, invasion and metastasis via
      downstream pathways involving the RAF/MEK/ERK cascade of cytoplasmic kinases, the
      small GTP-binding proteins RAC and RHO, phosphatidylinositol 3-kinase and others.
      We have used subtractive suppression hybridization (SSH), a PCR-based cDNA
      subtraction technique, to contrast differential gene expression profiles in
      immortalized, non-tumorigenic rat embryo fibroblasts and in HRAS- transformed
      cells. Sequence and expression analysis of more than 1,200 subtracted cDNA
      fragments revealed transcriptional stimulation or repression of 104 ESTs, 45
      novel sequences and 244 known genes in HRAS- transformed cells compared with
      normal cells. Furthermore, we identified common and distinct targets in cells
      transformed by mutant HRAS, KRAS and NRAS, as well as 61 putative target genes
      controlled by the RAF/MEK/ERK pathway in reverted cells treated with the MEK
      specific inhibitor PD 98059.

PMID- 10655060
TI  - LMNA, encoding lamin A/C, is mutated in partial lipodystrophy.
AB  - The lipodystrophies are a group of disorders characterized by the absence or
      reduction of subcutaneous adipose tissue. Partial lipodystrophy (PLD; MIM 151660)
      is an inherited condition in which a regional (trunk and limbs) loss of fat
      occurs during the peri-pubertal phase. Additionally, variable degrees of
      resistance to insulin action, together with a hyperlipidaemic state, may occur
      and simulate the metabolic features commonly associated with predisposition to
      atherosclerotic disease. The PLD locus has been mapped to chromosome 1q with no
      evidence of genetic heterogeneity. We, and others, have refined the location to a
      5.3-cM interval between markers D1S305 and D1S1600 (refs 5, 6). Through a
      positional cloning approach we have identified five different missense mutations
      in LMNA among ten kindreds and three individuals with PLD. The protein product of
      LMNA is lamin A/C, which is a component of the nuclear envelope. Heterozygous
      mutations in LMNA have recently been identified in kindreds with the variant form
      of muscular dystrophy (MD) known as autosomal dominant Emery-Dreifuss MD (EDMD
      AD; ref. 7) and dilated cardiomyopathy and conduction-system disease (CMD1A). As
      LMNA is ubiquitously expressed, the finding of site-specific amino acid
      substitutions in PLD, EDMD-AD and CMD1A reveals distinct functional domains of
      the lamin A/C protein required for the maintenance and integrity of different
      cell types.

PMID- 10655061
TI  - Kit/stem cell factor receptor-induced activation of phosphatidylinositol 3'
      kinase is essential for male fertility.
AB  - The c-kit-encoded transmembrane tyrosine kinase receptor for stem cell factor
      (Kit/SCF-R) is required for normal haematopoiesis, melanogenesis and
      gametogenesis. However, the roles of individual Kit/SCF-R-induced signalling
      pathways in the control of developmental processes in the intact animal are
      completely unknown. To examine the function of SCF-induced phosphatidylinositol
      (PI) 3'-kinase activation in vivo, we employed the Cre-loxP system to mutate the
      codon for Tyr719, the PI 3'-kinase binding site in Kit/SCF-R, to Phe in the
      genome of mice by homologous recombination. Homozygous (Y719F/Y719F) mutant mice
      are viable. The mutation completely disrupted PI 3'-kinase binding to Kit/SCF-R
      and reduced SCF-induced PI 3'-kinase-dependent activation of Akt by 90%. The
      mutation induced a gender- and tissue-specific defect. Although there are no
      haematopoietic or pigmentation defects in homozygous mutant mice, males are
      sterile due to a block in spermatogenesis, with initially decreased proliferation
      and subsequent extensive apoptosis occurring at the spermatogonial stem-cell
      level. In contrast, female homozygotes are fully fertile. This is the first
      report so far demonstrating the role of an individual signalling pathway
      downstream of Kit/SCF-R in the intact animal. It provides the first in vivo model
      for male sterility caused by a discrete signalling pathway defect affecting early
      germ cells.

PMID- 10655062
TI  - Limb-girdle muscular dystrophy type 2G is caused by mutations in the gene
      encoding the sarcomeric protein telethonin.
AB  - Autosomal recessive limb-girdle muscular dystrophies (AR LGMDs) are a genetically
      heterogeneous group of disorders that affect mainly the proximal musculature.
      There are eight genetically distinct forms of AR LGMD, LGMD 2A-H (refs 2-10), and
      the genetic lesions underlying these forms, except for LGMD 2G and 2H, have been
      identified. LGMD 2A and LGMD 2B are caused by mutations in the genes encoding
      calpain 3 (ref. 11) and dysferlin, respectively, and are usually associated with
      a mild phenotype. Mutations in the genes encoding gamma-(ref. 14), alpha-(ref.
      5), beta-(refs 6,7) and delta (ref. 15)-sarcoglycans are responsible for LGMD 2C
      to 2F, respectively. Sarcoglycans, together with sarcospan, dystroglycans,
      syntrophins and dystrobrevin, constitute the dystrophin-glycoprotein complex
      (DGC). Patients with LGMD 2C-F predominantly have a severe clinical course. The
      LGMD 2G locus maps to a 3-cM interval in 17q11-12 in two Brazilian families with
      a relatively mild form of AR LGMD (ref. 9). To positionally clone the LGMD 2G
      gene, we constructed a physical map of the 17q11-12 region and refined its
      localization to an interval of 1.2 Mb. The gene encoding telethonin, a sarcomeric
      protein, lies within this candidate region. We have found that mutations in the
      telethonin gene cause LGMD 2G, identifying a new molecular mechanism for AR LGMD.

PMID- 10655064
TI  - A role for smad6 in development and homeostasis of the cardiovascular system.
AB  - Smad proteins are intracellular mediators of signalling initiated by Tgf
      betasuperfamily ligands (Tgf-betas, activins and bone morphogenetic proteins
      (Bmps)). Smads 1, 2, 3, 5 and 8 are activated upon phosphorylation by specific
      type I receptors, and associate with the common partner Smad4 to trigger
      transcriptional responses. The inhibitory Smads (6 and 7) are transcriptionally
      induced in cultured cells treated with Tgf-beta superfamily ligands, and
      downregulate signalling in in vitro assays. Gene disruption in mice has begun to
      reveal specific developmental and physiological functions of the signal
      transducing Smads. Here we explore the role of an inhibitory Smad in vivo by
      targeted mutation of Madh6 (which encodes the Smad6 protein). Targeted insertion
      of a LacZ reporter demonstrated that Smad6 expression is largely restricted to
      the heart and blood vessels, and that Madh6 mutants have multiple cardiovascular
      abnormalities. Hyperplasia of the cardiac valves and outflow tract septation
      defects indicate a function for Smad6 in the regulation of endocardial cushion
      transformation. The role of Smad6 in the homeostasis of the adult cardiovascular
      system is indicated by the development of aortic ossification and elevated blood
      pressure in viable mutants. These defects highlight the importance of Smad6 in
      the tissue-specific modulation of Tgf-beta superfamily signalling pathways in
      vivo.

PMID- 10655063
TI  - A new gene involved in X-linked mental retardation identified by analysis of an
      X;2 balanced translocation.
AB  - X-linked forms of mental retardation (MR) affect approximately 1 in 600 males and
      are likely to be highly heterogeneous. They can be categorized into syndromic
      (MRXS) and nonspecific (MRX) forms. In MRX forms, affected patients have no
      distinctive clinical or biochemical features. At least five MRX genes have been
      identified by positional cloning, but each accounts for only 0.5%-1.0% of MRX
      cases. Here we show that the gene TM4SF2 at Xp11.4 is inactivated by the X
      breakpoint of an X;2 balanced translocation in a patient with MR. Further
      investigation led to identification of TM4SF2 mutations in 2 of 33 other MRX
      families. RNA in situ hybridization showed that TM4SF2 is highly expressed in the
      central nervous system, including the cerebral cortex and hippocampus. TM4SF2
      encodes a member of the tetraspanin family of proteins, which are known to
      contribute in molecular complexes including beta-1 integrins. We speculate that
      through this interaction, TM4SF2 might have a role in the control of neurite
      outgrowth.

PMID- 10655065
TI  - Fus deficiency in mice results in defective B-lymphocyte development and
      activation, high levels of chromosomal instability and perinatal death.
AB  - The gene FUS (also known as TLS (for translocated in liposarcoma) and hnRNP P2)
      is translocated with the gene encoding the transcription factor ERG-1 in human
      myeloid leukaemias. Although the functions of wild-type FUS are unknown, the
      protein contains an RNA-recognition motif and is a component of nuclear
      riboprotein complexes. FUS resembles a transcription factor in that it binds DNA,
      contributes a transcriptional activation domain to the FUS-ERG oncoprotein and
      interacts with several transcription factors in vitro. To better understand FUS
      function in vivo, we examined the consequences of disrupting Fus in mice. Our
      results indicate that Fus is essential for viability of neonatal animals,
      influences lymphocyte development in a non-cell-intrinsic manner, has an
      intrinsic role in the proliferative responses of B cells to specific mitogenic
      stimuli and is required for the maintenance of genomic stability. The involvement
      of a nuclear riboprotein in these processes in vivo indicates that Fus is
      important in genome maintenance.

PMID- 10655066
TI  - Heritable and inducible genetic interference by double-stranded RNA encoded by
      transgenes.
AB  - Double-stranded RNA interference (RNAi) is an effective method for disrupting
      expression of specific genes in Caenorhabditis elegans and other organisms.
      Applications of this reverse-genetics tool, however, are somewhat restricted in
      nematodes because introduced dsRNA is not stably inherited. Another difficulty is
      that RNAi disruption of late-acting genes has been generally less consistent than
      that of embryonically expressed genes, perhaps because the concentration of dsRNA
      becomes lower as cellular division proceeds or as developmental time advances. In
      particular, some neuronally expressed genes appear refractory to dsRNA-mediated
      interference. We sought to extend the applicability of RNAi by in vivo expression
      of heritable inverted-repeat (IR) genes. We assayed the efficacy of in vivo
      driven RNAi in three situations for which heritable, inducible RNAi would be
      advantageous: (i) production of large numbers of animals deficient for gene
      activities required for viability or reproduction; (ii) generation of large
      populations of phenocopy mutants for biochemical analysis; and (iii) effective
      gene inactivation in the nervous system. We report that heritable IR genes confer
      potent and specific gene inactivation for each of these applications. We suggest
      that a similar strategy might be used to test for dsRNA interference effects in
      higher organisms in which it is feasible to construct transgenic animals, but
      impossible to directly or transiently introduce high concentrations of dsRNA.

PMID- 10655067
TI  - Fosl1 is a transcriptional target of c-Fos during osteoclast differentiation.
AB  - Osteoclasts are bone-resorbing cells derived from haematopoietic precursors of
      the monocyte-macrophage lineage. Mice lacking Fos (encoding c-Fos) develop
      osteopetrosis due to an early differentiation block in the osteoclast lineage. c
      Fos is a component of the dimeric transcription factor activator protein-1 (Ap
      1), which is composed mainly of Fos (c-Fos, FosB, Fra-1 and Fra-2) and Jun
      proteins (c-Jun, JunB and JunD). Unlike Fra-1 (encoded by Fosl1), c-Fos contains
      transactivation domains required for oncogenesis and cellular transformation. The
      mechanism by which c-Fos exerts its specific function in osteoclast
      differentiation is not understood. Here we show by retroviral-gene transfer that
      all four Fos proteins, but not the Jun proteins, rescue the differentiation block
      in vitro. Structure-function analysis demonstrated that the major carboxy
      terminal transactivation domains of c-Fos and FosB are dispensable and that Fra-1
      (which lacks transactivation domains) has the highest rescue activity. Moreover,
      a transgene expressing Fra-1 rescues the osteopetrosis of c-Fos-mutant mice in
      vivo. The osteoclast differentiation factor Rankl (also known as TRANCE, ODF and
      OPGL; refs 8-11) induces transcription of Fosl1 in a c-Fos-dependent manner,
      thereby establishing a link between Rank signalling and the expression of Ap-1
      proteins in osteoclast differentiation.

PMID- 10655068
TI  - Mutations in the gene encoding peroxisomal alpha-methylacyl-CoA racemase cause
      adult-onset sensory motor neuropathy.
AB  - Sensory motor neuropathy is associated with various inherited disorders including
      Charcot-Marie-Tooth disease, X-linked adrenoleukodystrophy/adrenomyeloneuropathy
      and Refsum disease. In the latter two, the neuropathy is thought to result from
      the accumulation of specific fatty acids. We describe here three patients with
      elevated plasma concentrations of pristanic acid (a branched-chain fatty acid)
      and C27-bile-acid intermediates. Two of the patients suffered from adult-onset
      sensory motor neuropathy. One patient also had pigmentary retinopathy, suggesting
      Refsum disease, whereas the other patient had upper motor neuron signs in the
      legs, suggesting adrenomyeloneuropathy. The third patient was a child without
      neuropathy. In all three patients we discovered a deficiency of alpha-methylacyl
      CoA racemase (AMACR). This enzyme is responsible for the conversion of pristanoyl
      CoA and C27-bile acyl-CoAs to their (S)-stereoisomers, which are the only
      stereoisomers that can be degraded via peroxisomal beta-oxidation. Sequence
      analysis of AMACR cDNA from the patients identified two different mutations that
      are likely to cause disease, based on analysis in Escherichia coli. Our findings
      have implications for the diagnosis of adult-onset neuropathies of unknown
      aetiology.

PMID- 10655069
TI  - Transport of lipids from golgi to plasma membrane is defective in tangier disease
      patients and Abc1-deficient mice.
AB  - Mutations in the gene encoding ATP-binding cassette transporter 1 ( ABC1) have
      been reported in Tangier disease (TD), an autosomal recessive disorder that is
      characterized by almost complete absence of plasma high-density lipoprotein
      (HDL), deposition of cholesteryl esters in the reticulo-endothelial system (RES)
      and aberrant cellular lipid trafficking. We demonstrate here that mice with a
      targeted inactivation of Abc1 display morphologic abnormalities and perturbations
      in their lipoprotein metabolism concordant with TD. ABC1 is expressed on the
      plasma membrane and the Golgi complex, mediates apo-AI associated export of
      cholesterol and phospholipids from the cell, and is regulated by cholesterol
      flux. Structural and functional abnormalities in caveolar processing and the
      trans-Golgi secretory pathway of cells lacking functional ABC1 indicate that
      lipid export processes involving vesicular budding between the Golgi and the
      plasma membrane are severely disturbed.

PMID- 10655071
TI  - The changing face of biomedical research?

PMID- 10655070
TI  - Localization to Xq27 of a susceptibility gene for testicular germ-cell tumours.
AB  - Testicular germ-cell tumours (TGCT) affect 1 in 500 men and are the most common
      cancer in males aged 15-40 in Western European populations. The incidence of TGCT
      has risen dramatically over the last century. Known risk factors for TGCT include
      a history of undescended testis (UDT), testicular dysgenesis, infertility,
      previously diagnosed TGCT (ref. 7) and a family history of the disease. Brothers
      of men with TGCT have an 8-10-fold risk of developing TGCT (refs 8,9), whereas
      the relative risk to fathers and sons is fourfold (ref. 9). This familial
      relative risk is much higher than that for most other types of cancer. We have
      collected samples from 134 families with two or more cases of TGCT, 87 of which
      are affected sibpairs. A genome-wide linkage search yielded a heterogeneity lod
      (hlod) score of 2.01 on chromosome Xq27 using all families compatible with X
      inheritance. We obtained a hlod score of 4.7 from families with at least one
      bilateral case, corresponding to a genome-wide significance level of P=0.034. The
      proportion of families with UDT linked to this locus was 73% compared with 26% of
      families without UDT (P=0.03). Our results provide evidence for a TGCT
      susceptibility gene on chromosome Xq27 that may also predispose to UDT.

PMID- 10655072
TI  - Thromboembolic complications after treatment with monoclonal antibody against
      CD40 ligand.

PMID- 10655073
TI  - Thromboembolic complications after treatment with monoclonal antibody against
      CD40 ligand

PMID- 10655074
TI  - Failure of combined costimulatory blockade in animal transplant model.

PMID- 10655075
TI  - Reply to failure of combined costimulatory blockade in animal transplant model

PMID- 10655076
TI  - Celera: financial optimism, scientific skepticism.

PMID- 10655077
TI  - Rod photoreceptor rescue or degeneration.

PMID- 10655078
TI  - Reply to rod photoreceptor rescue or degeneration

PMID- 10655079
TI  - UN acknowledges HIV/AIDS as a threat to world peace.

PMID- 10655080
TI  - Biotechnology industry responds to gene therapy death.

PMID- 10655081
TI  - Activists threaten academic research funding.

PMID- 10655083
TI  - Australian universities told to commercialize

PMID- 10655082
TI  - Sanctions programs expand despite failure to increase vaccination.

PMID- 10655084
TI  - University of Arizona misconduct investigation ruled improper.

PMID- 10655085
TI  - From biotech to bank robbery

PMID- 10655086
TI  - Business group presses for broader release of scientific data.

PMID- 10655087
TI  - Insurers agree to cover cancer trial costs voluntarily.

PMID- 10655088
TI  - Vaccines and the induction of functional antibodies: time to look beyond the
      molecules of natural infection?
AB  - Infection with some pathogens induces weak functional antibody responses that are
      non-protective, and there has been some skepticism about a role for antibodies in
      vaccine design. However, newer data show that antibodies can protect against
      infection with these pathogens, and new methods to elicit production of
      functional antibodies should be sought.

PMID- 10655089
TI  - A new interpretation of the new england witch trials

PMID- 10655090
TI  - IgG surfaces as an important component in mucosal protection.

PMID- 10655091
TI  - Gut reaction

PMID- 10655092
TI  - Leaky vessels? Call Ang1!

PMID- 10655093
TI  - Does Alzheimer disease tilt the scales of amyloid degradation versus
      accumulation?

PMID- 10655094
TI  - New feelings about the role of sensory nerves in inflammation.

PMID- 10655095
TI  - The envelope, please: nuclear lamins and disease.

PMID- 10655096
TI  - Cyclopentenone prostaglandins-new allies in the war on inflammation.

PMID- 10655097
TI  - The first steps on the gene therapy pathway to anti-sickling success.

PMID- 10655099
TI  - Oral examination

PMID- 10655098
TI  - MIF mediation of sepsis.

PMID- 10655100
TI  - Research news

PMID- 10655101
TI  - Identification of the major Abeta1-42-degrading catabolic pathway in brain
      parenchyma: suppression leads to biochemical and pathological deposition.
AB  - Alzheimer amyloid beta-peptide (Abeta) is a physiological peptide constantly
      anabolized and catabolized under normal conditions. We investigated the mechanism
      of catabolism by tracing multiple-radiolabeled synthetic peptide injected into
      rat hippocampus. The Abeta1-42 peptide underwent full degradation through limited
      proteolysis conducted by neutral endopeptidase (NEP) similar or identical to
      neprilysin as biochemically analyzed. Consistently, NEP inhibitor infusion
      resulted in both biochemical and pathological deposition of endogenous Abeta42 in
      brain. This NEP-catalyzed proteolysis therefore limits the rate of Abeta42
      catabolism, up-regulation of which could reduce the risk of developing
      Alzheimer's disease by preventing Abeta accumulation.

PMID- 10655102
TI  - Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic
      mechanism.
AB  - Trypsin and mast cell tryptase cleave proteinase-activated receptor 2 and, by
      unknown mechanisms, induce widespread inflammation. We found that a large
      proportion of primary spinal afferent neurons, which express proteinase-activated
      receptor 2, also contain the proinflammatory neuropeptides calcitonin gene
      related peptide and substance P. Trypsin and tryptase directly signal to neurons
      to stimulate release of these neuropeptides, which mediate inflammatory edema
      induced by agonists of proteinase-activated receptor 2. This new mechanism of
      protease-induced neurogenic inflammation may contribute to the proinflammatory
      effects of mast cells in human disease. Thus, tryptase inhibitors and antagonists
      of proteinase-activated receptor 2 may be useful anti-inflammatory agents.

PMID- 10655103
TI  - Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication
      and ischemic stroke.
AB  - Cerebral edema contributes significantly to morbidity and death associated with
      many common neurological disorders. However, current treatment options are
      limited to hyperosmolar agents and surgical decompression, therapies introduced
      more than 70 years ago. Here we show that mice deficient in aquaporin-4 (AQP4), a
      glial membrane water channel, have much better survival than wild-type mice in a
      model of brain edema caused by acute water intoxication. Brain tissue water
      content and swelling of pericapillary astrocytic foot processes in AQP4-deficient
      mice were significantly reduced. In another model of brain edema, focal ischemic
      stroke produced by middle cerebral artery occlusion, AQP4-deficient mice had
      improved neurological outcome. Cerebral edema, as measured by percentage of
      hemispheric enlargement at 24 h, was decreased by 35% in AQP4-deficient mice.
      These results implicate a key role for AQP4 in modulating brain water transport,
      and suggest that AQP4 inhibition may provide a new therapeutic option for
      reducing brain edema in a wide variety of cerebral disorders.

PMID- 10655104
TI  - Protection from septic shock by neutralization of macrophage migration inhibitory
      factor.
AB  - Identification of new therapeutic targets for the management of septic shock
      remains imperative as all investigational therapies, including anti-tumor
      necrosis factor (TNF) and anti-interleukin (IL)-1 agents, have uniformly failed
      to lower the mortality of critically ill patients with severe sepsis. We report
      here that macrophage migration inhibitory factor (MIF) is a critical mediator of
      septic shock. High concentrations of MIF were detected in the peritoneal exudate
      fluid and in the systemic circulation of mice with bacterial peritonitis.
      Experiments performed in TNFalpha knockout mice allowed a direct evaluation of
      the part played by MIF in sepsis in the absence of this pivotal cytokine of
      inflammation. Anti-MIF antibody protected TNFalpha knockout from lethal
      peritonitis induced by cecal ligation and puncture (CLP), providing evidence of
      an intrinsic contribution of MIF to the pathogenesis of sepsis. Anti-MIF antibody
      also protected normal mice from lethal peritonitis induced by both CLP and
      Escherichia coli, even when treatment was started up to 8 hours after CLP.
      Conversely, co-injection of recombinant MIF and E. coli markedly increased the
      lethality of peritonitis. Finally, high concentrations of MIF were detected in
      the plasma of patients with severe sepsis or septic shock. These studies define a
      critical part for MIF in the pathogenesis of septic shock and identify a new
      target for therapeutic intervention.

PMID- 10655105
TI  - The cell cycle inhibitor p21 controls T-cell proliferation and sex-linked lupus
      development.
AB  - Here we show that the cell-cycle regulator p21 is involved in immune system
      function. T lymphocytes from p21-/- mice exhibit significant proliferative
      advantage over wild-type cells following prolonged stimulation, but not after
      primary activation. Consistent with this, p21-deficient mice accumulate abnormal
      amounts of CD4+ memory cells, and develop loss of tolerance towards nuclear
      antigens. Similar to human lupus, female p21-deficient mice develop antibodies
      against dsDNA, lymphadenopathy, and glomerulonephritis, leading to decreased
      viability. These data demonstrate a specialized role for p21 in the control of T
      cell proliferation, tolerance to nuclear antigens, and female-prone lupus. These
      findings could be the basis for new therapeutic approaches to lupus.

PMID- 10655106
TI  - Genetic correction of sickle cell disease: insights using transgenic mouse
      models.
AB  - Sickle cell disease is a hereditary disorder characterized by erythrocyte
      deformity due to hemoglobin polymerization. We assessed in vivo the potential
      curative threshold of fetal hemoglobin in the SAD transgenic mouse model of
      sickle cell disease using mating with mice expressing the human fetal Agamma
      globin gene. With increasing levels of HbF, AgammaSAD mice showed considerable
      improvement in all hematologic parameters, morphopathologic features and life
      span/survival. We established the direct therapeutic effect of fetal hemoglobin
      on sickle cell disease and demonstrated correction by increasing fetal hemoglobin
      to about 9-16% in this mouse model. This in vivo study emphasizes the potential
      of the SAD mouse models for quantitative analysis of gene therapy approaches.

PMID- 10655107
TI  - Myosin light chain kinase mediates sarcomere organization during cardiac
      hypertrophy in vitro.
AB  - During the development of hypertrophy, cardiac myocytes increase organization of
      the sarcomere, a highly ordered contractile unit in striated muscle cells.
      Several hypertrophic agonists, such as angiotensin II, phenylephrine, and
      endothelin-1, have been shown to promote the sarcomere organization. However, the
      signaling pathway, which links extracellular stimuli to sarcomere organization,
      has not been clearly demonstrated. Here, we demonstrate that myosin light chain
      kinase specifically mediates agonist-induced sarcomere organization during early
      hypertrophic response. Acute administration of a hypertrophic agonist,
      phenylephrine, or angiotensin II, causes phosphorylation of myosin light chain 2v
      both in cultured cardiac myocytes and in the adult heart in vivo. We also show
      that both sarcomere organization and myosin light chain 2v phosphorylation are
      dependent on the activation of Ca2+/calmodulin pathway, a known activator of
      myosin light chain kinase. These results define a new and specific role of myosin
      light chain kinase in cardiac myocytes, which may provide a rapid adaptive
      mechanism in response to hypertrophic stimuli.

PMID- 10655108
TI  - The ets protein PEA3 suppresses HER-2/neu overexpression and inhibits
      tumorigenesis.
AB  - Because HER-2/neu overexpression is important in cancer development, we looked
      for a method of suppressing the cell transformation mediated by HER-2/neu
      overexpression. We have identified that the DNA-binding protein PEA3, which is
      encoded by a previously isolated gene of the ets family, specifically targeted a
      DNA sequence on the HER-2/neu promoter and downregulated the promoter activity.
      Expression of PEA3 resulted in preferential inhibition of cell growth and tumor
      development of HER-2/neu-overexpressing cancer cells. This is a new approach to
      targeting HER-2/neu overexpression and also provides a rationale to the design
      for repressors of diseases caused by overexpression of pathogenic genes.

PMID- 10655109
TI  - Maspin is an angiogenesis inhibitor.
AB  - Maspin, a unique member of the serpin family, is a secreted protein encoded by a
      class II tumor suppressor gene whose downregulation is associated with the
      development of breast and prostate cancers. Overexpression of maspin in breast
      tumor cells limits their growth and metastases in vivo. In this report we
      demonstrate that maspin is an effective inhibitor of angiogenesis. In vitro, it
      acted directly on cultured endothelial cells to stop their migration towards
      basic fibroblast growth factor and vascular endothelial growth factor and to
      limit mitogenesis and tube formation. In vivo, it blocked neovascularization in
      the rat cornea pocket model. Maspin derivatives mutated in the serpin reactive
      site lost their ability to inhibit the migration of fibroblasts, keratinocytes,
      and breast cancer cells but were still able to block angiogenesis in vitro and in
      vivo. When maspin was delivered locally to human prostate tumor cells in a
      xenograft mouse model, it blocked tumor growth and dramatically reduced the
      density of tumor-associated microvessels. These data suggest that the tumor
      suppressor activity of maspin may depend in large part on its ability to inhibit
      angiogenesis and raise the possibility that maspin and similar serpins may be
      excellent leads for the development of drugs that modulate angiogenesis.

PMID- 10655111
TI  - Protection of macaques against vaginal transmission of a pathogenic HIV-1/SIV
      chimeric virus by passive infusion of neutralizing antibodies.
AB  - The development of the human immunodeficiency virus-1 (HIV-1)/simian
      immunodeficiency virus (SIV) chimeric virus macaque model (SHIV) permits the in
      vivo evaluation of anti-HIV-1 envelope glycoprotein immune responses. Using this
      model, others, and we have shown that passively infused antibody can protect
      against an intravenous challenge. However, HIV-1 is most often transmitted across
      mucosal surfaces and the intravenous challenge model may not accurately predict
      the role of antibody in protection against mucosal exposure. After controlling
      the macaque estrous cycle with progesterone, anti-HIV-1 neutralizing monoclonal
      antibodies 2F5 and 2G12, and HIV immune globulin were tested. Whereas all five
      control monkeys displayed high plasma viremia and rapid CD4 cell decline, 14
      antibody-treated macaques were either completely protected against infection or
      against pathogenic manifestations of SHIV-infection. Infusion of all three
      antibodies together provided the greatest amount of protection, but a single
      monoclonal antibody, with modest virus neutralizing activity, was also
      protective. Compared with our previous intravenous challenge study with the same
      virus and antibodies, the data indicated that greater protection was achieved
      after vaginal challenge. This study demonstrates that antibodies can affect
      transmission and subsequent disease course after vaginal SHIV-challenge; the data
      begin to define the type of antibody response that could play a role in
      protection against mucosal transmission of HIV-1.

PMID- 10655110
TI  - Human neutralizing monoclonal antibodies of the IgG1 subtype protect against
      mucosal simian-human immunodeficiency virus infection.
AB  - Although maternal human immunodeficiency virus type 1 (HIV-1) transmission occurs
      during gestation, intrapartum and postpartum (by breast-feeding), 50-70% of all
      infected children seem to acquire HIV-1 shortly before or during delivery.
      Epidemiological evidence indicates that mucosal exposure is an important aspect
      of intrapartum HIV transmission. A simian immunodeficiency virus (SIV) macaque
      model has been developed that mimics the mucosal exposure that can occur during
      intrapartum HIV-1 transmission. To develop immunoprophylaxis against intrapartum
      HIV-1 transmission, we used SHIV-vpu+ (refs. 5,6), a chimeric simian-human virus
      that encodes the env gene of HIV-IIIB. Several combinations of human monoclonal
      antibodies against HIV-1 have been identified that neutralize SHIV-vpu+
      completely in vitro through synergistic interaction. Here, we treated four
      pregnant macaques with a triple combination of the human IgG1 monoclonal
      antibodies F105, 2G12 and 2F5. All four macaques were protected against
      intravenous SHIV-vpu+ challenge after delivery. The infants received monoclonal
      antibodies after birth and were challenged orally with SHIV-vpu+ shortly
      thereafter. We found no evidence of infection in any infant during 6 months of
      follow-up. This demonstrates that IgG1 monoclonal antibodies protect against
      mucosal lentivirus challenge in neonates. We conclude that epitopes recognized by
      the three monoclonal antibodies are important determinants for achieving
      substantial protection, thus providing a rational basis for AIDS vaccine
      development.

PMID- 10655112
TI  - Paradoxical inhibition of T-cell function in response to CTLA-4 blockade;
      heterogeneity within the human T-cell population.
AB  - T-cell co-stimulation delivered by the molecules B7-1 or B7-2 through CD28 has a
      positive effect on T-cell activation, whereas engagement of cytotoxic T
      lymphocyte antigen 4 (CTLA-4) by these molecules inhibits activation. In vivo
      administration to mice of blocking monoclonal antibodies or Fab fragments against
      CTLA-4 can augment antigen-specific T-cell responses and, thus, therapy with
      monoclonal antibody against CTLA-4 has potential applications for tumor therapy
      and enhancement of vaccine immunization. The effects of B7-1 and B7-2 co
      stimulation through CD28 depend on the strength of the signal delivered through
      the T-cell receptor (TCR) and the activation state of T cells during activation.
      Thus, we sought to determine whether these factors similarly influence the effect
      of B7-mediated signals delivered through CTLA-4 during T-cell activation. Using
      freshly isolated human T cells and Fab fragments of a monoclonal antibody against
      CTLA-4, we demonstrate here that CTLA-4 blockade can enhance or inhibit the
      clonal expansion of different T cells that respond to the same antigen, depending
      on both the T-cell activation state and the strength of the T-cell receptor
      signal delivered during T-cell stimulation. Thus, for whole T-cell populations,
      blocking a negative signal may paradoxically inhibit immune responses. These
      results provide a theoretical framework for clinical trials in which co
      stimulatory signals are manipulated in an attempt to modulate the immune response
      in human disease.

PMID- 10655114
TI  - Directed vascular expression of the thromboxane A2 receptor results in
      intrauterine growth retardation.
AB  - Thromboxane (Tx) A2 is a platelet agonist, smooth muscle cell constrictor, and
      mitogen. Urinary Tx metabolite (Tx-M) excretion is increased in syndromes of
      platelet activation and early in both normal pregnancies and in pregnancy-induced
      hypertension. A further increment occurs in patients presenting with severe
      preeclampsia, in whom Tx-M correlates with other indices of disease severity.
      TxA2 exerts its effects through a membrane receptor (TP), of which two isoforms
      (alpha and beta; refs. 5,6) have been cloned. Overexpression of TP in the
      vasculature under the control of the pre-proendothelin-1 promoter results in a
      murine model of intrauterine growth retardation (IUGR), which is rescued by timed
      suppression of Tx synthesis with indomethacin. IUGR is commonly associated with
      maternal diabetes or cigarette smoking, both conditions associated with increased
      TxA2 biosynthesis.

PMID- 10655113
TI  - Molecular mimicry mediated by MHC class Ib molecules after infection with gram
      negative pathogens.
AB  - The development of many autoimmune diseases has been etiologically linked to
      exposure to infectious agents. For example, a subset of patients with a history
      of Salmonella infection develop reactive arthritis. The persistence of bacterial
      antigen in arthritic tissue and the isolation of Salmonella or Yersinia reactive
      CD8+ T cells from the joints of patients with reactive arthritis support the
      etiological link between Gram-negative bacterial infection and autoimmune
      disease. Models proposed to account for the link between infection and
      autoimmunity include inflammation-induced presentation of cryptic self-epitopes,
      antigen persistence and molecular mimicry. Several studies support molecular
      mimicry as a mechanism for the involvement of class II epitopes in infectious
      disease-induced self-reactivity. Here, we have identified an immunodominant
      epitope derived from the S. typhimurium GroEL molecule. This epitope is presented
      by the mouse H2-T23-encoded class Ib molecule Qa-1 and was recognized by CD8+
      cytotoxic T lymphocytes induced after natural infection. S. typhimurium
      stimulated cytotoxic T lymphocytes recognizing the GroEL epitope cross-reacted
      with a peptide derived from mouse heat shock protein 60 and recognized stressed
      macrophages. Our results indicate involvement of MHC class Ib molecules in
      infection-induced autoimmune recognition and indicate a mechanism for the
      etiological link between Gram-negative bacterial infection and autoimmunity.

PMID- 10655116
TI  - On the market

PMID- 10655115
TI  - Recombinant lipid-tagged antibody fragments as functional cell-surface receptors.

PMID- 10655118
TI  - Flocculation Kinetics and Cluster Morphology in Illite/NaCl Suspensions.
AB  - Using static and dynamic light-scattering techniques, we investigated the
      flocculation of geologic specimen illite and soil illite colloids suspended in
      NaCl solution at pH 8. Our results show that the two universality classes
      proposed by Lin and co-workers to characterize the diffusion and reaction-limited
      regimes of cluster-cluster flocculation do not apply to illite colloids, which
      have nonspherical morphology. Static light-scattering measurements yielded mass
      fractal dimensions for the soil illite clusters that were significantly above
      those required by universality. Those for specimen illite were influenced by the
      initial colloid concentration, suggesting that cluster restructuring had occurred
      during flocculation. Dynamic light-scattering measurements revealed a significant
      departure from linear growth of the mean cluster size with time, as required by
      universality in the diffusion-limited regime, and, for specimen illite, an
      oscillatory dependence of the mean cluster radius on time was observed in the
      transition from diffusion-limited to reaction-limited flocculation. Overall, the
      morphology, interactions, and restructuring of primary particles are believed to
      be responsible for the departure from universality in the flocculation behavior
      of the illite colloids. Copyright 2000 Academic Press.

PMID- 10655119
TI  - Adsorption and Interactions of Methyl Green with Montmorillonite and Sepiolite.
AB  - The divalent organic cation, methyl green (MG), undergoes a slow transformation
      (6 h) to a monovalent cation, carbinol (MGOH(+)) upon dilution of its solution
      (10 mM), or in a buffer at neutral pH. Adsorption isotherms of MG on
      montmorillonite were determined by two procedures, both of which yield a final pH
      of suspensions between 7 to 7.4. When the amounts of MG in suspension were lower
      than the cation-exchange capacity (CEC) of the clay (0.8 mol(c)/kg clay), no
      measurable amount of MG remained in solution. The maximal amounts of MGOH(+)
      adsorbed were larger than those of MG(2+), being 1.15 and 0.75 mol MG/kg clay,
      respectively, corresponding to 140% of the CEC in the first case. On a charge
      basis the adsorption of added MG(2+) amounts to 185% of the CEC, which raises the
      possibility that a certain fraction of MG(2+) transformed into the monovalent
      form during the incubation period, since other divalent organic cations
      previously studied only adsorbed up to the CEC (paraquat), or slightly above it
      (diquat). Adsorption of MG on sepiolite (CEC=0.15 mol(c)/kg) further emphasizes
      the two patterns of its adsorption. The maximal adsorbed amounts of MG(2+) and
      MGOH(+) were 0.09 and 0.30 mol/kg clay, respectively. X-ray diffraction
      measurements gave lower values for the basal spacings for montmorillonite-MG(+)
      than for MGOH(+), suggesting that MG(2+) binds two clay platelets together, as in
      the case of other divalent cations. A competition for adsorption between MG and
      the monovalent organic cation, acriflavin (AF), gave lower adsorbed amounts of AF
      when competing with MG(+), which is interpreted to be due to the smaller basal
      spacing in this case, which partially inhibits the entry of AF molecules into the
      interlammelar space. Spectra of montmorillonite-MG particles in the visible range
      exhibited significant differences between clay-MG and clay-carbinol. Copyright
      2000 Academic Press.

PMID- 10655120
TI  - Sol-Gel and Ultrafine Particle Formation via Dielectric Tuning of Inorganic Salt
      Alcohol-Water Solutions.
AB  - Under some conditions, inorganic salts can be as good precursors for sol-gel-type
      processing as those obtained from expensive metalloorganic precursors such as
      alkoxides. In this work, the formation of monodispersed hydrous zirconia
      microsphere particles (particularly nanosized) and gels was achieved in solutions
      of zirconyl chloride dissolved in alcohol-water mixed solvents. The dielectric
      property of the mixed alcohol-water solvent directly affects the nucleation and
      growth of zirconia clusters/particles in homogeneous solutions. A lower
      dielectric constant of mixed solvent corresponds to a lower solubility of
      inorganic solute and, thus, a shorter induction period for nucleation as well as
      higher solid particle growth kinetics. Dynamic light scattering (DLS) was used to
      monitor the homogeneous nucleation and growth processes, while final particles
      and gels were studied by scanning electron microscopy (SEM) and high-temperature
      X-ray diffraction (HTXRD). The sol-gel processes in the mixed solvent system can
      be adjusted using the processing parameters, including the initial inorganic salt
      concentration (C), alcohol/aqueous medium volume ratio of the mixed solution
      (RH), incubation temperature (T), incubation time (t), concentration of
      hydroxypropyl cellulose (HPC), and ammonia neutralization. Monodispersed
      submicron and nanoscale (<100 nm) zirconia microspheres/powders were successfully
      synthesized under conditions of high RH (5) and using HPC (molecular weight of
      100,000, 2.0x10(-3) g/cm(3)) and ammonia neutralization. Initial salt
      concentration affects the particle size significantly. Gel materials were
      obtained under conditions of low RH (1.0). Microstructure and transparency of
      gels changed significantly from low (0.05 M) to high (0.2 M) concentration of the
      metal salt. We have also demonstrated that monodispersed particle production can
      be achieved not only at low temperatures (<100 degrees C) but also at room
      temperature using an inorganic salt precursor. Copyright 2000 Academic Press.

PMID- 10655121
TI  - Preparation and Characterization of Stearate-Capped Titanium Dioxide
      Nanoparticles.
AB  - The preparation of titanium dioxide nanoparticles capped with stearate by sol-gel
      methods is presented in this paper. The nanoparticles are characterized by
      Fourier transform infrared spectroscopy and by X-ray photoelectron spectroscopy.
      Existence of the organic layer can be confirmed by the results of
      characterizations, which also indicate that the inorganic nuclei and organic
      surface layer are linked with chemical bonds. The nanoparticles are poorly
      crystallized based on the X-ray diffraction pattern. The mechanism of formation
      of the organo-capped nanoparticles is proposed to be competitive reactions
      between water and stearic acid, which is similar to a polymerization and
      inhibition processes. A structural model for organo-capped nanoparticles is also
      proposed. Copyright 2000 Academic Press.

PMID- 10655122
TI  - Capillary Rise in Granitic Rocks: Interpretation of Kinetics on the Basis of Pore
      Structure.
AB  - The capillary transport of water into granitic rocks has been interpreted on the
      basis of the structure of its porous network. An effective pore radius has been
      calculated from a three-sized single-pore model proposed by F. A. L. Dullien, El
      Sayed, and V. K. Batra (J. Colloid Interface Sci. 60, 497, 1977) Considering the
      porous network of granites as consisting of fissures grouped in two size types,
      macro- and microfissures, an effective radius was found from the characteristic
      radii for each type and the average of these two values. Good agreement between
      the effective radius calculated and the radius estimated using a capillary rate
      value measured experimentally provides a suitable basis for identifying
      interrelationships between the pore structure and moisture capillary rise. In
      fact, it is possible to predict the process rate from only two characteristic
      pore sizes, corresponding to the radii of macrofissures and microfissures. The
      abnormally low rate of capillary rise observed in one of the granites studied
      could be easily interpreted as due to the involvement exclusively of the
      macrofissures of its porous network in capillary transport. Copyright 2000
      Academic Press.

PMID- 10655123
TI  - Lack of Syneresis during Gelation of Dense Colloidal Suspensions.
AB  - This study reports experimental results about the shrinkage of particle networks
      produced by pH-induced destabilization of dense colloidal suspensions. The
      resulting solid networks exhibit no syneresis effects, at least prior to aging of
      the gel. From this lack of syneresis it is concluded that the solidification in
      wet particle systems either is not purely determined by energy (but is also
      influenced by entropic effects) or cannot be explained within the framework of
      (static) equilibrium thermodynamics at all. Copyright 2000 Academic Press.

PMID- 10655124
TI  - Surface Tension and Dynamic Contact Angle of Water in Thin Quartz Capillaries.
AB  - The surface tension of water has been measured in quartz capillaries with radii
      from 200 down to 40 nm. It appears that the surface tension does not differ from
      the known (bulk) values in the temperature range from 8 to 70 degrees C, within
      1% experimental error. The dynamic contact angle, theta(d), vanishes when the
      capillary surface is covered with a wetting film left behind the receding
      meniscus. In the case of a dry surface, theta(d) depends on the velocity of the
      meniscus motion. The results obtained do not agree with presently available
      theoretical predictions from hydrodynamic theories of dynamic contact angles.
      Rather the kinetics of water vapor adsorption ahead of the moving meniscus seems
      to be the major controlling agent of the dynamic contact angle. Copyright 2000
      Academic Press.

PMID- 10655125
TI  - Surface Energetics Evolution during Processing of Epoxy Resins.
AB  - The surface energetics evolution throughout the entire curing process of two
      epoxy resins is predicted using a previously developed semiempirical relationship
      between surface tension and the solubility parameter. Evolution of the
      temperature and time of both the solubility parameter and density is investigated
      and used for this prediction, as is the concept of molar volume or mass of the
      interacting element. The theoretical prediction is compared with measured surface
      tensions. Experimental data are determined at different times during an
      isothermal curing process by the Wilhelmy wetting force method for surface
      tension with viscous drag corrections. Once corrections for viscous effects on
      measured surface tensions are made, very good agreement is found for the surface
      energetics evolution. Moreover, the total surface energies of solid cured epoxy
      resins, which cannot be directly measured, can be estimated with this prediction.
      Finally, this study provides a tool for further understanding the final adhesive
      properties of polymeric material considering the time evolution of surface
      energetics during processing. Copyright 2000 Academic Press.

PMID- 10655126
TI  - Analysis of Contact Interactions between a Rough Deformable Colloid and a Smooth
      Substrate.
AB  - A model was developed for the effect of van der Waals interactions between a
      rough, deformable, spherical colloid and a flat, smooth, hard surface in contact.
      The model demonstrates the significant effect of colloid roughness on removal
      force. Small changes in colloid roughness produce large changes in the predicted
      removal force. Several authors attribute discrepancies in the observed
      interaction force between particles and surfaces to colloid roughness, and our
      model supports their hypotheses. Experimental data documenting the force required
      to remove colloids of polystyrene latex from silica substrates in aqueous
      solution were collected during AFM studies of this system. When colloid roughness
      exists, as is the case in this work, our model bounds the observed removal force.
      The predicted range of removal forces is in better quantitative agreement with
      our removal force data than are forces predicted by classical DLVO theory.
      Copyright 2000 Academic Press.

PMID- 10655127
TI  - Microgel Particles as a Matrix for Polymerization: A Study of Poly(N
      isopropylacrylamide)-Poly(N-methylpyrrole) Dispersions.
AB  - Poly(N-isopropylacrylamide) (PNIPAM) microgel particles dispersed in water have
      been used as a matrix for the polymerization of a hydrophobic monomer, N
      methylpyrrole (MPy). The presence of poly(MPy) (PMPy) within the dried composite
      particles has been confirmed using electron paramagnetic resonance (EPR)
      measurements which show a characteristic free-radical signal at g=2.007. Electron
      microscopy data (TEM) show that the composite PNIPAM-xPMPy particles have a
      "raspberry-like" morphology. (The value for x represents the volume percent of
      MPy added during synthesis with respect to the total microgel volume.) PCS data
      indicate that PMPy occupies the majority of the collapsed composite particle
      volume. The maximum value of x consistent with colloid stability for PNIPAM-xPMPy
      dispersions is 4.5%. Higher values of x result in coagulation due to
      interparticle bridging by PMPy. Variable temperature PCS measurements of the
      PNIPAM-xPMPy dispersions have been used to study the thermally induced collapse
      of the composite particles. The extent of collapse becomes less with increasing
      values for x. The embedded PMPy particles restrict the extent of PNIPAM network
      contraction. The stability of the PNIPAM-4.5PMPy dispersions was investigated by
      means of turbidity measurements using aqueous 0.1 M NaCl solution. The upper
      critical flocculation temperatures (UCFT) for PNIPAM and PNIPAM-4.5PMPy
      dispersions were identical (38-39 degrees C). The flocculation observed was found
      to be fully reversible. The composite dispersion stability in the absence of salt
      was attributed to electrosteric stabilization afforded by the PNIPAM matrix.
      These results indicate that PNIPAM microgel particles may have application as a
      matrix for the polymerization of hydrophobic monomers in water. Copyright 2000
      Academic Press.

PMID- 10655128
TI  - Structure of Hydrous Ferric Oxide Aggregates.
AB  - The small angle light scattering behavior of hydrous ferric oxide flocs is
      examined here and found to provide useful insights into the nature of the
      aggregates formed despite the large size of these aggregates at later times. The
      flocs appear to exhibit fractal properties over a significant size range though
      the aggregates appear to be easily disrupted through mixing effects resulting in
      breakup and/or restructuring to denser assemblages. Background electrolyte
      concentrations also have some impact on floc structure but mixing effects and
      apparent destabilization by ferric ions limit the effect of added electrolytes on
      the stability and structure of ferric oxyhydroxides. Similar estimates of fractal
      dimensions of these hydrous ferric oxide flocs are obtained both by static light
      scattering analysis and by a cluster mass scaling approach. The choice of density
      distribution cutoff function has some impact on derived size and structure
      parameters and further refinement in this area is needed. Copyright 2000 Academic
      Press.

PMID- 10655129
TI  - Metastable Equilibrium Solubility Behavior of Carbonated Apatites in the Presence
      of Solution Fluoride.
AB  - The aims of the present investigation were to assess the applicability of the
      metastable equilibrium solubility (MES) concept for the carbonated apatites
      (CAPs) over a range of pH and a wide range of solution fluoride concentrations
      and to examine the hypothesis that, in the presence of solution fluoride, a
      surface complex with the stoichiometry of fluorapatite (FAP) governs the MES
      behavior. Two CAP samples were prepared by precipitation from reaction media
      containing calcium nitrate (Ca(NO(3))(2).4H(2)O) and sodium phosphate
      (NaH(2)PO(4).H(2)O) at two different levels of sodium bicarbonate. The MES
      distributions of the two CAP preparations were determined by equilibrating
      approximately 10 mg of CAP powder in 2 L of 0.1 M acetate buffers (ionic
      strength=0.50 M) at pH 4.5 and 5.5 and at various levels of calcium, phosphate,
      and fluoride. The fluoride concentrations ranged from 0.03 to 12 ppm. From the
      compositions of the equilibrating buffer solutions, ion activity products based
      upon the stoichiometries of hydroxyapatite (HAP) and FAP were calculated in an
      attempt to determine the correct function governing the dissolution of the CAP
      preparations. The results of this study demonstrated that both CAP preparations
      exhibit the MES distribution phenomenon in solution media of varying pH and
      fluoride concentrations. Furthermore, the experimental MES data obtained with
      both CAP preparations at the lower pH (4.5) and at higher solution fluoride
      levels (>/=0.1 ppm) were essentially superimposable when plotted against the ion
      activity product based upon the stoichiometry of FAP, suggesting that in the
      presence of solution fluoride the MES governing surface complex may be an entity
      possessing a stoichiometry approximated by that of FAP. When the HAP
      stoichiometry was assumed to represent the surface complex, good superposition of
      the data was not possible. Copyright 2000 Academic Press.

PMID- 10655130
TI  - Dielectric Relaxation Around a Charged Colloidal Cylinder in an Electrolyte.
AB  - The polarizability and corresponding dielectric relaxation of the Debye-Huckel
      (DH) atmosphere surrounding a charged rod-like polyelectrolyte immersed in an
      ionic solution of a symmetrical electrolyte is determined following the method
      developed by J. A. Fornes [Phys. Rev. E 57, 2110 (1998)]. Several formulas are
      given to estimate the DH atmosphere parameters, namely, the polarizability at
      zero frequency, alpha(0), the relaxation time, tau, the cloud capacitance, C, the
      average displacement of the ionic cloud, delta, the square root dipole moment
      quadratic fluctuation, <p(2)>(1/2), and the thermal fluctuating field,
      <E(2)>(1/2). The Poisson-Boltzmann equation is solved numerically to apply the
      theory to a highly charged polyelectrolyte such as DNA in solution, although
      formulas valid for the DH approximation are also given. A dispersion in the
      polarizability and correspondingly in the dielectric constant of these solutions
      in the microwave region is predicted. For instance, considering a DNA length of
      1000 A, with its reduced linear charge density xi(0)=4.25 and ionization factor
      gamma=0.5, immersed in a NaCl solution (40 mM), we predict a polarizability of
      the DH atmosphere at zero frequency alpha(0) of 1x10(-33) Fm(2) ( approximately
      6.1x10(6)) times greater than the mean value of the polarizability of water) and
      the corresponding fluctuating dipole moment p of 2.1x10(-27) Cm ( approximately
      600 times greater than the permanent dipole moment of water molecule). The
      relaxation time and the average displacement of the ionic cloud are tau=1.6 ns
      and delta=14. A, respectively. This displacement is produced by the thermal
      fluctuating field, which, in this case, at room temperature is <E(2)>(1/2)=2
      x10(6) V/m. Copyright 2000 Academic Press.

PMID- 10655131
TI  - Electroviscous Effect in Dilute Suspensions of Alumina.
AB  - A study on the electroviscous effect of alumina suspensions has been made. At the
      low volume fraction of the particles studied here only a first-order effect was
      detected. Ubbelohde-type capillary viscometers have been used. A simple method to
      determine the hydrodynamic constant k(1) has been proposed. The experimental
      primary electroviscous coefficients corresponding to different electrolyte
      concentrations have been compared with two different theoretical approachs (I. G.
      Watterson, and L. R. White, J. Chem. Soc. Faraday Trans. 2 77, 1115 (1981); F. J.
      Rubio-Hernandez, E. Ruiz-Reina, and A. I. Gomez-Merino, J. Colloid Interface Sci.
      206, 334 (1998)) and the results suggest that the presence of a dynamic Stern
      layer plays a certain role in this effect. Copyright 2000 Academic Press.

PMID- 10655132
TI  - Stability of the Shape of a Viscous Drop under Buoyancy-Driven Translation in a
      Hele-Shaw Cell.
AB  - It has been shown (N. R. Gupta, A. Nadim, H. Haj-Hariri, and A. Borhan, J.
      Colloid Interface Sci. 218, 338 1999) that a circular drop translating in a Hele
      Shaw cell under the action of gravity is linearly stable for nonzero interfacial
      tension. In this paper, we use the boundary integral method to examine the
      nonlinear evolution of the shape of initially noncircular drops translating in a
      Hele-Shaw cell. For prolate initial deformations, it is found that the drop
      reverts to a circular shape for all finite Bond numbers considered. Initially
      oblate drops, on the other hand, are found to become unstable and break up if the
      initial shape perturbation is of sufficiently large magnitude. The critical
      conditions for the onset of drop breakup are examined in terms of the magnitude
      of the initial deformation as a function of Bond number. Two branches of marginal
      stability are identified and the effects of viscosity ratio and asymmetric
      initial perturbations on the stability diagram are discussed. Copyright 2000
      Academic Press.

PMID- 10655133
TI  - Electrophoretic Deposition: A Quantitative Model for Particle Deposition and
      Binder Formation from Alcohol-Based Suspensions.
AB  - We investigated electrophoretic deposition from a suspension containing
      positively charged particles, isopropanol, water, and Mg(NO(3))(2), with the aim
      of describing the deposition rates of the particles and Mg(OH)(2), which is
      formed due to chemical reactions at the electrode, in terms of quantitative
      models. LaB(6) particles were used as a model system. The particle layer is
      consolidated by simultaneous precipitation of Mg(OH)(2) which acts as a binder to
      hold the particles together. The Mg(OH)(2) content was determined solely by the
      amount of charge passed through the cell. Quantitative precipitation of all OH(-)
      formed at the electrode was observed, except at very low current. The occurrence
      of a minimum current was ascribed to a threshold for Mg(OH)(2) deposition. The
      same minimum current was observed for particle deposition. In combination with
      results using NaNO(3), where no adherent layer was formed, this illustrates that
      Mg(OH)(2) binder is necessary for consolidation. Once the minimum current was
      exceeded, it was found that all particles that migrate to the electrode under the
      influence of the electric field contribute to the formation of the layer, i.e.,
      the "sticking coefficient" for the particles equals 1.0. The applicability of the
      particle and Mg(OH)(2) deposition models was tested by variation of the
      Mg(NO(3))(2) concentration, pH, and water content. Copyright 2000 Academic Press.

PMID- 10655134
TI  - Adsorption Mechanism and Structure of the Montmorillonite Complexes with
      (CH(3))(2)XO (X=C, and S), (CH(3)O)(3)PO, and CH(3)-CN Molecules.
AB  - The formation of complexes with different ligands in the interlayer space of
      montmorillonite saturated in Na(+), Mg(2+), Ca(2+), Co(2+), Cu(2+), Ni(2+),
      Fe(3+), and Cr(3+) was studied. Acetone, acetonitrile, dimethyl sulfoxide, and
      trimethylphosphate were used as ligands. The nature of the complexes was studied
      by means of X-ray diffraction, infrared spectroscopy, thermogravimetric analysis,
      microcalorimetry, and ab initio quantum mechanical methods. In all cases, the
      organic ligands penetrate into the interlayer space at room temperature, forming
      complexes stable in vacuum with the interlayer cations. The ligand-cation ratio
      depends on the valence of the saturating cation. The cation-ligand interaction in
      these complexes has an ion-dipole electrostatic nature. The complexes are formed
      by the direct interaction of the oxygen or nitrogen atom of ligand and the
      interlayer cation. Using the quantum mechanical approach, allow us to determine
      the disposition of the ligand in these complexes. In all cases, only one layer of
      ligands is present in the stable complexes. Copyright 2000 Academic Press.

PMID- 10655135
TI  - Electrokinetic Properties of Fuzzy Colloidal Particles.
AB  - The presence of a thin polymer layer on the surface of a colloidal particle can
      have a profound effect on its electrophoretic mobility. The model developed here
      treats the hydrodynamics of the polymer layer as a distribution of Stokes
      resistance centers within a thin diffuse layer; fixed charge may reside on the
      surface of the particle core or throughout the layer. The theory is
      semianalytical in that asymptotic methods are used to simplify the equations but
      several integrals must be evaluated numerically. Special attention is paid to the
      effects of polarization and relaxation. It is shown that distributing immobile
      charge throughout the layer produces a response where the particle's mobility
      exceeds that found when the same amount of charge is spread uniformly over the
      surface of the rigid core. Increasing the drag due to the fuzzy layer always
      diminishes the mobility. In either case, the hydrodynamic permeability of the
      layer has a strong influence on particle movement. Results are also given for the
      dipole coefficient in the expression for the conductivity of a dilute suspension.
      Copyright 2000 Academic Press.

PMID- 10655136
TI  - Adsorption Kinetics of Some Polyethylene Glycol Octylphenyl Ethers Studied by the
      Fast Formed Drop Technique.
AB  - The adsorption kinetics of Triton X-100 and Triton X-405 at solution/air and
      solution/hexane interfaces is studied by the recently developed fast formed drop
      technique. The dynamic interfacial tension of Triton X-100 and Triton X-405
      solutions against hexane has been measured without preequilibration of the water
      and oil phases. It is found that the dynamic interfacial tension of Triton X-100
      solutions passes through a minimum. This strange behavior is attributed to
      partial solubility of the surfactant in hexane. Such minima of the dynamic
      interfacial tension of Triton X-405 solutions have not been observed, which
      correlates well with the solubilities of both surfactants in hexane reported in
      the literature. The dynamic surface tension of solutions of both surfactants and
      the dynamic interfacial tension of Triton X-405 solutions are interpreted by the
      Ward and Tordai model for diffusion controlled adsorption. It is shown that
      proper interpretation of the experimental data depends on the type of isotherm
      used. More consistent results are obtained when the Temkin isotherm is used
      instead of the Langmuir isotherm. The results obtained with Triton X-100 at the
      solution/air interface confirm that the adsorption of this surfactant occurs
      under diffusion control. The adsorption of Triton X-405 at solution/air and at
      solution/hexane interfaces seems to occur under diffusion control at short
      periods of time, but under mixed (diffusion-kinetic) control at long periods of
      time. A hypothesis is drawn to explain this phenomenon by changes in the shape of
      the large hydrophilic heads of Triton X-405 molecules. Copyright 2000 Academic
      Press.

PMID- 10655137
TI  - Correlation of the Pit Depth in Crystal Etching by Dissolution.
AB  - A theoretically rigorous formulation relating the pit depth to dissolution time
      for crystal etching is presented and verified. The data of K. Dunn, E. Daniel, P.
      J. Shuler, H. J. Chen, Y. Tang, and T. F. Yen [J. Colloid Interface Sci. 214, 427
      (1999)] for surface dissolution of barite are analyzed and correlated accurately.
      It is shown that the empirically determined power law pit growth function of F.
      Hunkeler and H. Bohni [Corrosion, 37(11), 645 (1981)] conforms to a special
      solution of the present formulation and their empirically determined power law
      exponent of 1/2 is theoretically justified. In addition, the present study
      provides some insight into the mechanism of the crystal dissolution rate process
      and the variation of pit depth during dissolution-induced etching. Copyright 2000
      Academic Press.

PMID- 10655138
TI  - Intrascleral concentration vs depth profile of mitomycin-C after episcleral
      application: impact of irrigation.
AB  - Mitomycin-C has been reported to cause toxic effects on the ciliary body after
      episcleral application during glaucoma surgery. We investigated the intrascleral
      diffusion of mitomycin-C in an experimental model. The episcleral sides of
      scleral quadrants of 14 human donor eyes were exposed for 5 min to sponges
      (corneal light shield, Merocel corp., Mystic, CT, U.S.A.) soaked with 200 microg
      ml(-1)mitomycin-C. After the exposure one of four quadrants was not irrigated and
      the episcleral sides of three quadrants were irrigated with 40, 100 and 200 ml
      saline. A 9 mm scleral disk was punched out with a trephine and frozen on a
      kryotome plate 2 min after the end of mitomycin-C exposure. An 8 mm diameter
      scleral disk was then cut with a trephine, again frozen on a kryotome plate and
      then horizontally dissected with a kryotome. For analysis purposes seven cuts of
      20 microm thickness were combined to one layer of 140 microm. Six layers could be
      reproduced and were analysed. The mitomycin-C concentrations of these layers were
      analysed by high-performance liquid chromatography. A concentration vs depth
      profile was calculated for each group, and the half-width of concentration was
      calculated by log-linear regression. The mitomycin-C concentration of layer 1 was
      24.51 microg g(-1)(+/-7.52) without irrigation, 13.15 microg g(-1)(+/-4.38) after
      40 ml irrigation, 10.29 (+/-3.53) after 100 ml irrigation and 8.4 microg g(-1)(+/
      1.62) after 200 ml irrigation. In layers 1-3 the concentration of mitomycin-C was
      significantly reduced by irrigation (ANOVA). In the deeper intrascleral layers
      irrigation had no effect on the mitomycin-C concentrations. Between layers 2 and
      6 the half-width of the mitomycin-C concentration was 101 microm (no-irrigation
      group), 141 microm (40 ml irrigation group), 153 microm (100 ml irrigation
      group), and 164 microm (200 ml irrigation group). Irrigation reduced the
      mitomycin-C concentration only down to half of the scleral thickness, leaving the
      deep intrascleral concentrations unchanged.

PMID- 10655139
TI  - Cellular photoablation to control postoperative fibrosis in filtration surgery:
      in vitro studies.
AB  - The purpose of this study was to evaluate the feasibility of cellular
      photoablation using fluorescence-generated photoreaction products as a method to
      control postoperative fibrosis in filtration surgery. The fluorescent probe, 2',
      7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein, acetoxymethyl ester (BCECF
      AM) is a cell membrane permeable compound rendered membrane-impermeable and
      fluorescent upon cleavage by intracellular esterases. Human scleral and Tenon's
      capsule fibroblasts were cultured and used as the target cells. Uptake and
      retention of the probe were determined with a fluorescence multi-well plate
      reader. Fibroblasts with or without intracellular probe were irradiated under
      conditions of fluorescence microscopy with diffuse blue light (450-490 nm,
      1.68x10(2)mW m(2-1)). The viability of cells was examined by trypan blue
      exclusion and crystal violet test. To better mimic a wound healing process the
      effect of cellular photoablation was verified in artificial lesions produced in
      cultured monolayers loaded with different concentrations of the probe. Uptake and
      retention of BCECF-AM is dependent on ambient concentration. When incorporated
      the probe is lethal to those cells exposed to the appropriate photo-irradiation.
      Cells exposed to BCECF-AM (for 45 min) at a concentration of approximately 10
      microm and irradiated for 1 min resulted in 100% cell death. Cellular
      photoablation in contrast to chemotherapeutic agents acts only on the targeted
      cells. This method shall be pursued as an alternative therapy to control
      postoperative fibrosis in filtration surgery.

PMID- 10655140
TI  - Up-regulation of crystallin mRNAs in form-deprived chick eyes.
AB  - Form-deprivation of chicks during early postnatal development results in ocular
      enlargement and great myopic refractive error (form-deprivation myopia). Previous
      studies have indicated that the retina, RPE and choroid play important roles in
      ocular enlargement in form-deprivation myopia. We aimed to isolate genes up
      regulated in the retina-RPE-choroid of form-deprived chick eyes. A suppression
      subtractive hybridization method was used to compare mRNA expression in the
      retina-RPE-choroid of form-deprived and control eyes. One up-regulated cDNA was
      isolated and identified as part of chick delta1-crystallin cDNA. Northern blot
      and RT-PCR analyses demonstrated that delta1-crystallin mRNA was up-regulated in
      the retina-RPE at day 7 after form-deprivation treatment. Semi-quantitative RT
      PCE analysis of the expression of several transcription factors indicated that
      Sox1 and Sox3 were upregulated in parallel with delta1-crystallin mRNA in form
      deprived eyes. Northern blot analysis demonstrated that alphaA-, betaA3/A1-,
      betaB1-, and betaB2-crystallin mRNAs were also up-regulated in form-deprived
      eyes. Although the detailed mechanisms and functions of the crystallin family
      genes in the retina-RPE-choroid of form-deprived eyes remain unclear, results of
      our study suggests that form-deprivation affects the expression of these genes in
      chick eyes.

PMID- 10655141
TI  - A novel lens epithelium gene, LEP503, is highly conserved in different vertebrate
      species and is developmentally regulated in postnatal rat lens.
AB  - The development of the lens is dependent on the proliferation of lens epithelial
      cells and their differentiation into fiber cells near the lens bow/equator.
      Identification of genes specifically expressed in the lens epithelial cells and
      their functions may provide insight into molecular events that regulate the
      processes of lens epithelial cell differentiation. In this study, a novel lens
      epithelium gene product, LEP503, identified from rat by a subtractive cDNA
      cloning strategy was investigated in the genome organization, mRNA expression and
      protein localization. The genomic sequences for LEP503 isolated from rat, mouse
      and human span 1754 bp, 1694 bp and 1895 bp regions encompassing the 5'-flanking
      region, two exons, one intron and 3'-flanking region. All exon-intron junction
      sequences conform to the GT/AG rule. Both mouse and human LEP503 genes show very
      high identity (93% for mouse and 79% for human) to rat LEP503 gene in the exon 1
      that contains an open reading frame coding for a protein of 61 amino acid
      residues with a leucine-rich domain. The deduced protein sequences also show high
      identity (91% between mouse and rat and 77% between human and rat). Western blot
      shows that LEP503 is present as a specific approximately 6.9 kDa band in the
      water-insoluble-urea-soluble fraction of lens cortex where lens epithelium is
      included. Immuno-staining shows that LEP503 is localized in the epithelial cells
      along the entire anterior surface of rat lens. Developmentally, LEP503 is
      expressed at a low level at newborn, and then the expression level increases by
      about ten-fold around postnatal day 14 and remains at this high level for about
      25 days before it drops back to the low level by postnatal day 84. These data
      suggest that the LEP503 may be an important lens epithelial cell gene involving
      the processes of epithelial cell differentiation.

PMID- 10655142
TI  - Differential gene expression in male and female rat lenses undergoing cataract
      induction by transforming growth factor-beta (TGF-beta).
AB  - Epidemiologic studies in humans as well as immunohistologic studies in animals
      have demonstrated significant sex differences in the propensity to develop
      cataract. Several studies suggest that estrogen may play a protective role
      against cataractogenesis. Indeed, male and ovariectomized female rat lenses have
      a greater susceptibility to cataract induced by transforming growth factor-beta
      (TGF-beta) than do normal female lenses. However, in spite of the current
      evidence that estrogen may play a pivotal role in cataractogenesis, the molecular
      mechanisms behind this phenomenon are largely undetermined. Our study utilized
      the differential display procedure to examine gene up- and down-regulation in
      male, normal female and ovariectomized female rat lenses exposed to TGF-beta.
      Male and normal female rat lenses were cultured with or without 0.15 ng ml(-1)TGF
      beta. Lenses were then harvested, and total RNA was isolated for analysis by
      reverse-transcriptase differential display. Differentially expressed mRNAs were
      subcloned, sequenced and identified through GenBank database searches. The
      original experiment was repeated with the addition of ovariectomized female TGF
      beta(+/-) conditions, and all differential patterns of gene expression were
      verified using Northern blot and RT-PCR analysis. Screening of approximately 12%
      of the mRNA population led to the identification of 27 differentially expressed
      cDNAs. Notably, strong gender differences were found in expression levels of
      gammaB-crystallin. In addition, proteasome Z subunit was up-regulated in TGF-beta
      treated male and ovariectomized female lenses, but was down-regulated in TGF-beta
      treated normal female lenses. This pattern of expression is consistent with the
      increased susceptibility of male and ovariectomized lenses to TGF-beta-induced
      cataract. We conclude that differential display is a useful and expedient method
      for analysing changes in gene expression in the lens. Structural and functional
      studies of the genes identified in this study may further elucidate mechanisms
      underlying the TGF-beta-induced cataract formation and differential rates of
      cataractogenesis in males vs females. In particular, our data suggest that the
      role of proteasome Z subunit in TGF-beta-induced anterior subcapsular cataract
      warrants further investigation.

PMID- 10655143
TI  - Creatine kinase in human retinal pigment epithelium.
AB  - Retinal pigment epithelial ion transport activity, and consequent ATP consumption
      vary significantly as a function of photoreceptor activity. In a variety of cell
      types, ATP levels are maintained during high-energy usage by phosphocreatine
      hydrolysis, catalysed by the enzyme creatine kinase. The present work was
      designed to assess the importance of creatine kinase in retinal pigment
      epithelial cell metabolism. To this end, activity measurements, non-denaturing
      gel electrophoresis, Western blot analysis and immunohistochemistry were used to
      characterize creatine kinase in retinal pigment epithelium. Total creatine kinase
      activity in the retinal pigment epithelium is approximately 0.05 micromol ATP mg
      protein(-1) min(-1). The bulk of this activity was mediated by the B-CK isoform.
      However, by immunoblotting, non-denaturing gel electrophoresis and
      immunohistochemistry, the presence of the M-CK isoform of creatine kinase was
      also detected. The M-CK isoform was plasma membrane associated and predominately
      localized to the apical surface. Creatine kinase in the retinal pigment
      epithelium could function in a spatial energy shuttle that helps to sustain
      apical plasma membrane ion transport activity.

PMID- 10655144
TI  - Comparison of rat retinal fixation techniques: chemical fixation and microwave
      irradiation.
AB  - In histological studies using retinas, eyes are commonly fixed with aldehyde
      derivatives administered by immersion or perfusion. However, the histology of rat
      retinas chemically fixed as a whole eye is typically inferior to the histology of
      retinas that are immediately fixed after acute dissection from the rest of the
      eye. Chemical fixation without dissection often results in neuronal swelling
      resembling excitotoxic damage induced by ischemia because the retina is protected
      by the sclera and is thus poorly accessible to immersion or perfusion fixation
      techniques. In order for the acute dissection technique to work properly, it must
      be completed in a timely manner, which may be difficult under some circumstances.
      Microwave irradiation is an alternative method for fixing tissues that are
      inaccessable to chemicals. We examined the effectiveness of microwave irradiation
      of the whole eye as a substitute for acute retinal dissection. To study the
      feasibility of microwave methods, we compared retinal morphology using microwave
      irradiation to morphology using conventional immersion fixation methods. Eyes
      were removed from rats, placed in a container with 2 or 20 ml artificial
      cerebrospinal fluid (aCSF) and irradiated with a household microwave oven. For
      morphological comparison, control eyes were immersed in a chemical fixative
      containing 1% paraformaldehyde and 1.5% glutaraldehyde. All eyes were embedded in
      araldite for evaluation by light microscopy. Retinal segments acutely isolated
      before immersion fixation revealed intact histology whereas retinal segments
      exposed to 60 min of simulated ischemia showed severe neuronal degeneration.
      Using an immersion technique, the retinas of chemically fixed whole eyes showed
      neuronal swelling similar to excitotoxic ischemic damage, suggesting that
      conventional immersion methods provide poor whole eye fixation. The neuronal
      degeneration observed with conventional immersion fixation was not found in
      retinas of whole eyes fixed with 20 sec of microwave irradiation. During
      microwave irradiation the temperature in the bathing aCSF rose to 55-72 degrees
      C. In some eyes, overcooking produced chromatin clumping and a small loss of
      contrast in staining. Although nuclear clumping and diminished staining
      occasionally result from overcooking, ischemic damage is well controlled with
      microwave fixation of enucleated eyes. When the optimal conditions are defined,
      microwave fixation may be preferable for retinal histology if chemical fixation
      following acute dissection is not feasible.

PMID- 10655145
TI  - Characterization of insulin-like growth factor-1 receptors in rabbit corneal
      epithelial cells.
AB  - Substance P (SP) and insulin-like growth factor-1 (IGF-1) synergistically
      facilitate corneal epithelial wound healing in vitro and in vivo. This synergism
      is mediated through the NK-1 receptors for SP, and IGF-1 does not modulate the
      binding affinity of NK-1 receptors. To clarify the effect of SP on the binding
      characteristics of IGF-1 receptors, the binding affinity and number of binding
      sites for IGF-1 in rabbit corneal epithelial cells were studied using a binding
      assay for(125)I-IGF-1. The binding affinity and number of binding sites for IGF-1
      were determined by Scatchard plot analysis. Cultured rabbit corneal epithelial
      cells bound specifically to IGF-1. For IGF-1 in corneal epithelial cells, the
      binding affinity was 4 n m and the number of binding sites was 1x10(5)binding
      sites cell(-1). Although IGF-2 and insulin also bind to IGF-1 receptors, their
      affinities were, respectively, eight- and 300-fold lower than that of IGF-1. IGF
      1 and IGF-2 stimulated corneal epithelial migration in the presence of SP, but
      insulin did not. Pretreatment of the corneal epithelial cells with SP (2x10(-5)m)
      failed to change the binding affinity or number of binding sites for IGF-1. These
      results demonstrated that corneal epithelial cells possess specific receptors for
      IGF-1. The synergistic effect of SP and IGF-1 on corneal epithelial wound healing
      does not result from regulation at the receptor level.

PMID- 10655146
TI  - Optical properties of rainbow trout lenses after in vitro exposure to polycyclic
      aromatic hydrocarbons in the presence or absence of ultraviolet radiation.
AB  - The optical properties of rainbow trout lenses were investigated after in vitro
      exposure to polycyclic aromatic hydrocarbons (PAHs) and ultraviolet (UV)
      irradiation, both because PAHs frequently contaminate aquatic environments and
      because UV exposure has generally increased with the decline of the ozone layer.
      Lenses were exposed to UV irradiation for 12 hr while immersed in culture medium.
      UV irradiation, with or without the presence of PAHs, was accomplished with one
      UVA and one UVB photoreactor lamp to yield a photon fluence rate of 9.27 micromol
      m(-2)s(-1)UVA (UVA:UVB 10.8, radiant exposure of 13.4 Jcm(-1)). Individual PAHs
      studied were fluorene, fluoranthene and benzo(a)pyrene. In addition, lenses were
      exposed to a solution of creosote, a wood preservative used in the aquatic
      environment that contains many PAHs. All PAH exposures, including creosote, were
      carried out either in the dark or concurrently with UV irradiation. A scanning
      laser monitor system was used to evaluate the optical properties of lenses for up
      to 236 hr after the UV/PAH treatments. Mean focal length variability (FLV)
      increased with time after concurrent exposure to UV irradiation and high
      concentrations of either fluoranthene (4900 n m), benzo(a)pyrene (265 n m) or
      creosote (70 microg ml(-1)), with FLV values ranging from, 0.21-0.41, 0.21-0.64
      and 0.15-0.22 mm, respectively, 72 hr after termination of the UV/PAH treatment.
      UV irradiation alone or exposure to PAHs in the dark brought about no changes in
      the optical properties of lenses. Also, fluorene in the presence or absence of UV
      had no effect, even at concentrations as high as 128 microm. Lenses were also
      unchanged by 12 hr exposures in the dark to solutions of either fluorene,
      fluoranthene, benzo(a)pyrene or creosote that had been previously UV irradiated
      for 12 hr. This meant that photomodified products of the individual PAHs or
      creosote were not cataractogenic and emphasized that simultaneous exposure to UV
      and PAHs or creosote was necessary for the increased FLV. The results point for
      the first time to an interaction between UV irradiation and PAHs as a potential
      contributing factor to cataract formation in fish.

PMID- 10655147
TI  - Imbalance in corneal redox state during herpes simplex virus 1-induced keratitis
      in rabbits. Effectiveness of exogenous glutathione supply.
AB  - A significant decrease in the antioxidant glutathione (GSH) was found in the
      corneal tissue of rabbits with Herpes Simplex 1 (HSV-1)-induced keratitis. Such a
      decrease was due to a loss of the reduced species, since no increase in its
      oxidized form was observed. Topical administration of purified GSH was able to
      reduce the virus titre in corneal tissue and, at the same time, was effective in
      reducing the severity and progression of keratitis and conjunctivitis. This
      effect was paralleled by a partial recovery in the corneal GSH content. In vitro
      experiments performed on HSV-1 infected corneal-derived rabbit cells showed that
      exogenous GSH reduced virus titre in the supernatant of infected cells. These
      results are in agreement with our previous findings that an oxidative
      environment, due to GSH depletion, is necessary for virus replication and suggest
      that topical GSH treatment could be considered as complementary therapy in HSV-1
      induced keratitis.

PMID- 10655148
TI  - CXC chemokine GRO is essential for neutrophil infiltration in LPS-induced uveitis
      in rabbits.
AB  - The purpose of this study was to investigate the role and regulation of the CXC
      chemokine GRO and the interaction between GRO and IL-8 in LPS-induced uveitis in
      rabbits. Uveitis was induced by intravitreal injection of 100 ng of LPS in
      rabbits. After the LPS injection, GRO was produced in aqueous humor and peaked at
      24 hr. Immunohistochemistry showed that ciliary epithelial cells were responsible
      for production of GRO. Blocking the activity of GRO by anti-GRO serum reduced LPS
      induced aqueous neutrophil counts by 80%, but did not reduce the mononuclear cell
      counts or protein levels or IL-8 levels. Regulation of GRO production by
      TNFalpha, IL-1 and IL-8 was studied. Anti-TNFalphamAb alone did not inhibit the
      24 hr LPS induced GRO levels, whereas rrIL-1Ra inhibited the GRO production by
      58%. The combination of anti-TNFalpha mAb and rrIL-1Ra inhibited 93% of GRO
      production. Although treatment with anti-IL-8 IgG inhibited the neutrophil
      infiltration by 66%, treatment with this antibody did not inhibit GRO production.
      Taken together, our results suggest that GRO is an essential mediator for
      neutrophil infiltration in LPS-induced uveitis in rabbits. Most of GRO production
      is mediated by TNFalpha and IL-1. GRO and IL-8 act in concert to mediate
      neutrophil infiltration.

PMID- 10655149
TI  - Human interphotoreceptor matrix contains serum albumin and retinol-binding
      protein.
AB  - It is usually assumed that IRBP (interphotoreceptor retinoid-binding protein) is
      the only protein present in the interphotoreceptor matrix (IPM) capable of
      shuttling visual-cycle retinoids between photoreceptors and the retinal pigment
      epithelium. However, this laboratory previously presented qualitative evidence
      (Western blots) that serum albumin is present in human IPM. Furthermore, Ong and
      coworkers (1994) found that cultured RPE cells synthesize serum retinol-binding
      protein (RBP) and secrete it, mainly into the apical culture medium, which would
      correspond to the IPM in intact eyes. As both of these proteins can bind all-
      trans -retinol and 11- cis -retinal, it was of interest to quantify the amounts
      of albumin and RBP in human IPM. We used radial immunodiffusion to accomplish
      this. The average molar ratio of serum albumin to IRBP in these samples was 1.9;
      that of RBP to IRBP was 0.015. The presence of a high concentration of serum
      albumin in the IPM in situ was confirmed by the intense immunohistochemical
      staining seen in sections of fresh human eyes. The human case is not unique;
      various concentrations of albumin were found in the IPM of all vertebrate species
      examined (by gel electrophoresis). These results indicate that both serum
      albumin, because of its very high concentration in the IPM, and RBP, because of
      its comparatively tight binding to retinoids, need to be considered, along with
      IRBP, as proteins that may participate in visual-cycle transport. The
      accompanying paper addresses this concern.

PMID- 10655150
TI  - IRBP enhances removal of 11- cis -retinaldehyde from isolated RPE membranes.
AB  - Interphotoreceptor retinoid-binding protein (IRBP) greatly enhances the
      conversion of all- trans -retinol to 11- cis -retinal by the retinal pigment
      epithelium (RPE) and facilitates 11- cis -retinal release from the RPE. However,
      the mechanisms by which IRBP exerts these effects are not clear. Using a model
      system of purified bovine IRBP and isolated bovine RPE membranes, we investigated
      the possibility that IRBP may favor the delivery of all- trans -retinol to, or
      the release of 11- cis -retinal from, RPE membranes. As the interphotoreceptor
      space contains serum retinol-binding protein (RBP) and serum albumin in addition
      to IRBP, we similarly examined the exchange of retinoids between RPE membranes
      and human RBP or bovine serum albumin (BSA). Isolated RPE membranes were loaded
      with radioactive 11- cis -retinal and incubated with solutions of IRBP, RBP, BSA
      or with buffer alone. Membranes (pellet) and retinoid-binding protein or buffer
      (supernatant) were separated by centrifugation and analysed for radioactive 11-
      cis -retinal. Membranes incubated with buffer alone released only 4-5% of their
      11- cis -retinal, while 25 microm IRBP removed 18-35%. More retinal was released
      as the membrane concentration was reduced. In contrast, RBP and BSA removed
      little retinal, even though both proteins are capable of binding this retinoid.
      Similar results were obtained with bovine liver membranes, consistent with the
      idea that the effects of IRBP do not depend on an RPE surface receptor for IRBP.
      IRBP was also markedly superior to RBP and BSA in removing all- trans -retinol
      from RPE membranes. In addition, IRBP efficiently delivered bound all- trans 
      retinol to membranes; however, in contrast to their differential removal of
      retinoids, all three binding proteins delivered comparable amounts of retinol to
      membranes. (This result supports the practice of using BSA as a retinoid carrier
      in in vitro experimental systems). We conclude that, whereas IRBP shares with
      other retinoid-binding proteins the ability to deliver retinol to membranes, IRBP
      is unique in its capacity to remove 11- cis -retinal from membranes. This may be
      the feature of IRBP that drives the vitamin A cycle to efficiently produce 11-
      cis -retinal.

PMID- 10655151
TI  - Optical coherence tomography (OCT) abnormalities in rhodopsin mutant transgenic
      swine with retinal degeneration.

PMID- 10655152
TI  - Molecular genetics and mechanism of autosomal dominant polycystic kidney disease.
AB  - Considerable progress toward understanding pathogenesis of autosomal dominant
      polycystic disease (ADPKD) has been made during the past 15 years. ADPKD is a
      heterogeneous human disease resulting from mutations in either of two genes, PKD1
      and PKD2. The similarity in the clinical presentation and evidence of direct
      interaction between the COOH termini of polycystin-1 and polycystin-2, the
      respective gene products, suggest that both proteins act in the same molecular
      pathway. The fact that most mutations from ADPKD patients result in truncated
      polycystins as well as evidence of a loss of heterozygosity mechanism in
      individual PKD cysts indicate that the loss of the function of either PKD1 or
      PKD2 is the most likely pathogenic mechanism for ADPKD. A novel mouse model,
      WS25, has been generated with a targeted mutation at Pkd2 locus in which a mutant
      exon 1 created by inserting a neo(r) cassette exists in tandem with the wild-type
      exon 1. This causes an unstable allele that undergoes secondary recombination to
      produce a true null allele at Pkd2 locus. Therefore, the model Pkd2(WS25/-),
      which carries the WS25 unstable allele and a true null allele, produces somatic
      second hits during mouse development or adult life and establishes an extremely
      faithful model of human ADPKD.

PMID- 10655153
TI  - Genotype-phenotype correlation in two frequent mutations and mutation update in
      type III glycogen storage disease.
AB  - Deficiency of glycogen debranching enzyme (AGL) activity causes glycogen storage
      disease type III (GSD-III). Generalized loss of AGL activity results in GSD-IIIa,
      and muscle-specific retention of AGL activity results in GSD-IIIb. To date, no
      common mutation has been described among GSD-III patients, except for three
      alleles; two linked specifically with GSD-IIIb, and the third found only in North
      African Jews with GSD-IIIa. Here we report two frequent mutations, each of which
      was found in the homozygous state in multiple patients, and each of which was
      associated with a subset of clinical phenotype in those patients with that
      mutation. A novel point mutation of a single T deletion at cDNA position 3964
      (3964delT) was first detected in an African American patient, who has a severe
      phenotype and early onset of clinical symptoms. The second mutation was an A to G
      transition at position -12 upstream of the 3' splice site of intron 32 (IVS32-12A
      > G). This lesion, previously implicated as a IIIb mutation in a Japanese
      patient, was identified in a confirmed GSD-IIIa Caucasian patient presenting with
      mild clinical symptoms. These two mutations together account for more than 12% of
      the molecular defects in the GSD-III patients tested. Our molecular and clinical
      data suggest a genotype-phenotype correlation for each of these mutations.
      Furthermore, this current study, coupled with our previous reports, describes the
      molecular tools necessary for the development of a DNA-based diagnostic test for
      GSD-III.

PMID- 10655154
TI  - Recombinant canine alpha-l-fucosidase: expression, purification, and
      characterization.
AB  - Canine fucosidosis has proven to be an excellent large animal model both for the
      equivalent human disorder and, in more general terms, for the central nervous
      system pathology found in many of the lysosomal storage disorders. Most
      importantly studies in this animal model were among the first to convincingly
      show that bone marrow transplantation could successfully modify the course of
      clinical central nervous system disease and to define some of the important
      parameters for successful treatment. In order to evaluate other, more generally
      applicable routes to treatment of central nervous system disease in the lysosomal
      storage disorders we have expressed recombinant canine alpha-l-fucosidase (rcFUC)
      in Chinese hamster ovary and Madin-Darby canine kidney cells to levels of between
      2 and 13 mg/liter of culture medium and purified the enzyme to apparent
      homogeneity by affinity chromatography on fucosylamine-linked agarose. rcFUC is
      composed of subunits of M(r) 50 kDa and the native enzyme is a homotrimer of M(r)
      156 kDa. Kinetic properties of rcFUC were similar to those of FUC isolated from
      both human and dog liver. rcFUC was shown to be effective in correcting the
      storage phenotype of human fucosidosis cells after endocytosis via the mannose-6
      phosphate-receptor-mediated pathway. It was also shown to degrade fucosylated
      storage products isolated from affected dog brain. The availability of large
      amounts of rcFUC will allow us to explore ways of extending the proven efficacy
      of enzyme replacement therapy to the treatment of central nervous system
      pathology using the fucosidosis dog as a model system.

PMID- 10655155
TI  - Methylenetetrahydrofolate reductase 677 C --> T polymorphism, plasma folate,
      vitamin B(12) concentrations, and risk of preeclampsia among black African women
      from Zimbabwe.
AB  - We conducted a case control study at Harare Maternity Hospital, Zimbabwe. We
      genotyped a total of 171 cases with preeclampsia or eclampsia and 185
      normotensive control subjects for the methylenetetrahydrofolate reductase (MTHFR)
      677 C --> T genotype. The wild-type allele frequency among cases and controls was
      91.2 and 91.3%, respectively. Only one subject (0.3%) was homozygous for the 677
      C --> T MTHFR genotype and this subject had preeclampsia. After adjustment for
      confounding factors, there was statistically no significant association between
      maternal MTHFR genotype and risk of preeclampsia (adjusted odds ratio = 1.0; 95%
      CI, 0.5-1.9). In addition, plasma homocyst(e)ine, vitamin B(12), and folate
      concentrations were not statistically different between normotensive control
      subjects with wild-type genotype as compared with normotensive subjects who were
      heterozygous for the mutant allele. Conversely, there was a strong graded
      association between maternal plasma folate concentration and risk of
      preeclampsia. Women with plasma folate concentrations less than 5.7 nmol/L
      experienced a 10. 4-fold increase in risk of preeclampsia. There was no clear
      pattern of preeclampsia risk and vitamin B(12) concentrations.

PMID- 10655156
TI  - Local anesthetics induce a decrease in the levels of glucose 1, 6-bisphosphate,
      fructose 1,6-bisphosphate, and ATP, and in the viability of melanoma cells.
AB  - Glycolysis is known to be the primary energy source in cancer cells. We
      investigated here the effect of local anesthetics, lidocaine and bupivacaine, on
      the levels of glucose 1,6-bisphosphate and fructose 1,6-bisphosphate, the two
      stimulatory signal molecules of glycolysis, and on ATP levels and cell viability
      in B16 melanoma cells. We found that both drugs induced a significant, dose
      dependent reduction in the levels of glucose 1,6-bisphosphate, fructose 1, 6
      bisphosphate, ATP, and cell viability. Bupivacaine was more potent than
      lidocaine. The decrease in glucose 1,6-bisphosphate and fructose 1,6
      bisphosphate, induced by the local anesthetics, preceded the reduction in the
      viability of melanoma cells, indicating that these are early changes and not a
      result of cell death. Cell viability was reduced in a close correlation with the
      fall in ATP. These findings suggest that the fall in the levels of the two signal
      allosteric regulators of glycolysis, induced by the local anesthetics, is one of
      the mechanisms that causes a reduction in glycolysis and ATP levels, which
      eventually leads to melanoma cell death. These experiments suggest that local
      anesthetics, and especially bupivacaine, are most promising agents in the
      treatment of melanoma.

PMID- 10655157
TI  - Platelet activating factor acetylhydrolase activity in lamb lungs is up-regulated
      in the immediate newborn period.
AB  - We recently showed that platelet activating factor (PAF) is an important
      modulator of pulmonary vasomotor tone in the fetus, with a significant decrease
      in circulating PAF levels in the immediate newborn period. In this study, we have
      determined PAF catabolism by PAF acetylhydrolase (PAF-Ah) in lungs of near-term
      fetal and newborn 2- to 16-h (<1 day) and 6- to 12-day-old lambs. The rate of PAF
      catabolism by lung homogenate protein from the three groups of lamb lungs was
      studied at 37 degrees C in 30 mM Tris buffer, pH 7.5, containing 0.01% BSA. Each
      lung homogenate protein was incubated for 10 min with 50 microM [(3)H]acetyl-PAF
      at pO(2) <50 Torr (hypoxia) and approximately 100 Torr (normoxia). PAF-Ah
      activity was quantified as amount of lyso-PAF produced. PAF-Ah activity (means +/
      SEM, nmol lyso-PAF/min/mg protein) in fetal lung homogenate was 1.19 +/- 0.14
      and 2.46 +/- 0.05 during hypoxia and normoxia, respectively. The corresponding
      values for the newborns were newborn <1 day, 1.65 +/- 0.26 and 2.95 +/- 0.07 and
      newborn 6-12 days, 1.25 +/- 0.10 and 2.84 +/- 0.05. In all groups, PAF-Ah
      activity was higher in normoxia than in hypoxia. During normoxia, PAF-Ah activity
      in newborn <1 day was significantly higher than the activity in fetus, but
      similar to the activity in newborn 6- to 12-day-old lamb lungs. These data show a
      significant up-regulation of PAF-Ah activity in lungs in the immediate newborn
      period. PAF-Ah gene expression measured by RT-PCR showed a significant up
      regulation of the PAF-Ah gene in lungs of lambs <1 day old, suggesting a
      transcriptional regulation of the PAF-Ah gene in the immediate newborn period.
      These results suggest that up-regulation of PAF-Ah activity after birth with
      oxygenation will result in a decrease in circulating PAF levels, thereby
      facilitating the fall in pulmonary vascular resistance in the immediate newborn
      period.

PMID- 10655158
TI  - Examination of the signal peptide region of human biotinidase using a baculovirus
      expression system.
AB  - Biotinidase deficiency is an autosomal recessive disorder of biotin recycling.
      Biotinidase cleaves the biotin from biocytin or short biotinyl-peptides to
      replenish the free biotin pool, or it can transfer the vitamin to specific
      proteins. The cDNA for human serum biotinidase has two in-frame start codons,
      potentially allowing for the synthesis of an enzyme with a signal peptide (SP)
      consisting of either 21 or 41 amino acids. In order to examine the requirements
      of the signal peptide region for the production and secretion of biotinidase,
      three different forms of the normal human serum biotinidase gene were constructed
      that encode either the 21-amino-acid SP (SP21-NL) or the 41-amino-acid SP (SP41
      NL) or without a SP (NoSP-NL). These constructs were expressed in insect cells
      via a baculovirus expression system. Biotinidase from cells with SP41-NL and SP21
      NL had immunoreactive and biotinyl-hydrolase-active enzyme in lysates and
      expression media. Cells with NoSP-NL had about 3% of the immunoreactive material
      and no enzyme activity in lysates and no immunoreactive protein or enzymatic
      activity in the expression medium. Lack of biotinidase from cells with NoSP-NL
      may be due to translation inefficiency or increased susceptibility of this
      species to protease degradation than the secreted forms. We have demonstrated
      that the 21-amino-acid signal peptide is sufficient to result in glycosylated,
      secreted biotinidase, but we cannot determine if the glycosylated biotinidase in
      the lysates or secreted in the medium of cells with SP41-NL use the first,
      second, or both ATGs in the SP region. Because this particular expression system
      has no mechanism for timing the movement of newly translated biotinidase protein,
      we cannot draw conclusions about the relative efficiency of SP41-NL versus SP21
      NL, but it is possible that either is used in vivo depending on particular
      cellular conditions.

PMID- 10655159
TI  - Kearns-Sayre syndrome presenting as 2-oxoadipic aciduria.
AB  - A patient with 2-oxoadipic aciduria and 2-aminoadipic aciduria presented at 2
      years of age with manifestations typical of organic acidemia, episodes of ketosis
      and acidosis, progressive to coma. This resolved and the key metabolites
      disappeared from the urine and blood. At 9 years of age she developed typical
      Kearns-Sayre syndrome with complete heart block, retinopathy, and
      ophthalmoplegia. Southern blot revealed a deletion in the mitochondrial genome.

PMID- 10655160
TI  - Evidence for a short-chain carnitine-acylcarnitine translocase in mitochondria
      specifically related to the metabolism of branched-chain amino acids.
AB  - Carnitine-acylcarnitine translocase (CATR) deficiency is a severe defect in fatty
      acid oxidation which presents early in life most frequently with hypoglycemia,
      hyperammonemia, and severe cardiac abnormalities. CATR exchanges acylcarnitines
      of various chain lengths for free carnitine across the mitochondrial membrane. In
      vitro studies in intact fibroblasts from patients with documented deficiency of
      CATR were probed with stable-isotope-labeled precursors and the resulting
      acylcarnitines were analyzed by tandem mass spectrometry. After a 72-h incubation
      with l-[(2)H(3)]carnitine the translocase-deficient cells produced acylcarnitines
      in which the deuterium was incorporated into short-chain acylcarnitines, C2-C5.
      Experiments with simultaneous incubation of l-[(2)H(3)]carnitine and l
      [(13)C(6)]isoleucine produced [(13)C(5)]2-methylbutyryl-[(2)H(3)]carnitine and
      [(13)C(3)]propionyl-[(2)H(3)]carnitine indicating exchange of labeled
      acylcarnitine from inside the mitochondrial matrix with labeled free carnitine.
      These studies support the possible existence of a "branched-chain" carnitine
      acylcarnitine translocator in mitochondria.

PMID- 10655163
TI  - Young Red Spheroidal Galaxies in the Hubble Deep Fields: Evidence for a Truncated
      Initial Mass Function at approximately 2 M middle dot in circle and a Constant
      Space Density to z approximately 2.
AB  - The optical-IR images of the northern and southern Hubble Deep Fields are used to
      measure the spectral and density evolution of early-type galaxies. The mean
      spectral energy distribution is found to evolve passively toward a mid-F star
      dominated spectrum by z approximately 2, becoming more sharply peaked around the
      4000 A break. We demonstrate with realistic simulations that hotter elliptical
      galaxies would be readily visible if evolution progressed blueward and brightward
      at z>2, following a standard initial mass function (IMF). The color distributions
      are best fitted by a "red" IMF, deficient above approximately 2 M middle dot in
      circle and with a spread of formation in the range 1.5<zf<2.5. Traditional age
      dating is spurious in this context; a distant elliptical can be young but appear
      red, with an apparent age greater than 3 Gyr independent of its formation
      redshift. Regarding density evolution, we demonstrate that the sharp decline in
      numbers claimed at z>1 results from a selection bias against distant red galaxies
      in the optical, where the flux is too weak for morphological classification, but
      is remedied with relatively modest IR exposures that reveal a roughly constant
      space density to z approximately 2, with 32 and 16 elliptical galaxies detected
      above and below z=1, respectively. We point out that the lack of high-mass star
      formation inferred here and the requirement of metals implicates cooling flows of
      preenriched gas in the creation of the stellar content of spheroidal galaxies.
      Deep-field X-ray images will be very helpful in examining this possibility.

PMID- 10655161
TI  - Gene-gene interaction in the RAS system in the predisposition to myocardial
      infarction in elder population of St. Petersburg (Russia).
AB  - The aim of this study was to estimate the frequencies of some DNA polymorphisms
      of two genes of the renin-angiotensin system (RAS), M235T angiotensinogen gene
      and insertion-deletion polymorphism in angiotensin-converting enzyme gene, in
      older (>55 years old) myocardial infarction survival and control groups. For this
      purpose 198 myocardial infarction (MI) patients and 152 randomly selected healthy
      persons have been analyzed. We have not found any differences in allele and
      genotype distribution in the above-mentioned genes for either group. However,
      statistical research showed a significant increase of double homozygotes IITT in
      the group of MI patients as compared with those in the control group. In this
      respect we suggested that gene-gene interaction in the RAS system may be
      considered to be a predisposing factor for MI development.

PMID- 10655164
TI  - Primordial Lithium and Big Bang Nucleosynthesis.
AB  - Recent determinations of the abundance of the light-element Li in very metal-poor
      stars show that its intrinsic dispersion is essentially zero and that the random
      error in the estimated mean Li abundance is negligible. However, a decreasing
      trend in the Li abundance toward lower metallicity indicates that the primordial
      abundance of Li can be inferred only after allowing for nucleosynthesis processes
      that must have been in operation in the early history of the Galaxy. We show that
      the observed Li versus Fe trend provides a strong discriminant between
      alternative models for Galactic chemical evolution of the light elements at early
      epochs. We critically assess current systematic uncertainties and determine the
      primordial Li abundance within new, much tighter limits:
      &parl0;Li&solm0;H&parr0;p=1.23+0.68-0.32x10-10. We show that the Li constraint on
      OmegaB is now limited as much by uncertainties in the nuclear cross sections used
      in big bang nucleosynthesis (BBN) calculations as by the observed abundance
      itself. A clearer understanding of systematics allows us to sharpen the
      comparison with 4He and deuterium and the resulting test of BBN.

PMID- 10655165
TI  - The Space Density of Primordial Gas Clouds near Galaxies and Groups and their
      Relation to Galactic High-Velocity Clouds.
AB  - The Arecibo H i Strip Survey probed the halos of approximately 300 cataloged
      galaxies and the environments of approximately 14 groups with sensitivity to
      neutral hydrogen masses >/=107 M middle dot in circle. The survey detected no
      objects with properties resembling the high-velocity clouds (HVCs) associated
      with the Milky Way or Local Group. If the HVCs were typically MHi=107.5 M middle
      dot in circle objects distributed throughout groups and galaxy halos at distances
      of approximately 1 Mpc, the survey should have made approximately 70 HVC
      detections in groups and approximately 250 detections around galaxies. The null
      detection implies that HVCs are deployed at typical distances of </=200 kpc from
      the galaxies or group barycenters. If the clouds are in virial equilibrium, their
      average dark matter fraction must be 98% or higher.

PMID- 10655162
TI  - The feasibility of PCR-based diagnosis of Prader-Willi and Angelman syndromes
      using restriction analysis after bisulfite modification of genomic DNA.
AB  - We have developed a novel PCR-based method for studying DNA methylation in the
      proximal region of 15q, using restriction analysis after bisulfite treatment of
      genomic DNA. This protocol can be used for the diagnosis of Prader-Willi and
      Angelman syndromes. Unlike the recently reported methylation-specific PCR
      protocol, our method avoids the use of multiplex amplification, thus overcoming
      the need to adjust relative primer amounts and the risk of obtaining false
      negative results.

PMID- 10655167
TI  - Conversion of Neutron Stars to Strange Stars as the Central Engine of Gamma-Ray
      Bursts.
AB  - We study the conversion of a neutron star to a strange star as a possible energy
      source for gamma-ray bursts. We use different recent models for the equation of
      state of neutron star matter and strange quark matter. We show that the total
      amount of energy liberated in the conversion is in the range of &parl0;1
      4&parr0;x1053 ergs (1 order of magnitude larger than previous estimates) and is
      in agreement with the energy required to power gamma-ray burst sources at
      cosmological distances.

PMID- 10655166
TI  - Broad Emission Line Regions in Active Galactic Nuclei: The Link with the
      Accretion Power.
AB  - We present a model that relates the width of the broad emission lines of active
      galactic nuclei (AGNs) to the Keplerian velocity of an accretion disk at a
      critical distance from the central black hole. This critical distance falls in a
      region bounded on the inward side by the transition radius between the radiation
      pressure- and the gas pressure-dominated region of the accretion disk and on the
      outward side by the maximum radius below which a stabilizing, radially accreting
      and vertically outflowing corona exists. We show that in the framework of this
      picture, the observed range of Hbeta FWHMs from broad-line to narrow-line type 1
      AGNs is well reproduced as a function of the accretion rate. This interval of
      velocities is the only permitted range and goes from approximately 20,000 km s-1
      for sub-Eddington accretion rates to approximately 1000 km s-1 for Eddington
      accretion rates.

PMID- 10655168
TI  - Comparing the Evolution of the Galaxy Disk Sizes with Cold Dark Matter Models:
      The Hubble Deep Field.
AB  - The intrinsic sizes of the field galaxies with I</=26 in the Hubble and ESO New
      Technology Telescope (NTT) Deep Fields are shown as a function of their redshifts
      and absolute magnitudes using photometric redshifts derived from the multicolor
      catalogs and are compared with the cold dark matter (CDM) predictions. Extending
      to the lower luminosities and to the higher z that our previous analysis
      performed on the NTT field alone, we find the distribution of the galaxy disk
      sizes at different cosmic epochs is within the range predicted by typical CDM
      models. However, the observed size distribution of faint (MB>-19) galaxies is
      skewed with respect to the CDM predictions, and an excess of small-size disks
      (Rd<2 kpc) is already present at z approximately 0.5. The excess persists up to z
      approximately 3 and involves brighter galaxies. Such an excess may be reduced if
      luminosity-dependent effects, like starburst activity in interacting galaxies,
      are included in the physical mechanisms governing the star formation history in
      CDM models.

PMID- 10655169
TI  - The X-Ray Emission of the Centaurus A Jet.
AB  - The extended nonthermal X-ray emission of extragalactic jets like Centaurus A can
      only be explained by in situ particle acceleration. The only energy source in the
      entire jet region is the magnetic field. Magnetic reconnection can convert the
      free energy stored in the helical configuration to particle kinetic energy. In
      the collisionless magnetized jet plasma, the inertia-driven reconnection is
      operating in a highly filamentary magnetic flux rope, and this results in a
      continuously charged particle acceleration. The synchrotron radiation of these
      particles can cause the observed X-ray emission in Centaurus A.

PMID- 10655170
TI  - Chandra X-Ray Detection of the Radio Hot Spots of 3C 295.
AB  - An observation of the radio galaxy 3C 295 during the calibration phase of the
      Chandra X-Ray Observatory reveals X-ray emission from the core of the galaxy,
      from each of the two prominent radio hot spots, and from the previously known
      cluster gas. We discuss the possible emission processes for the hot spots and
      argue that a synchrotron self-Compton (SSC) model is preferred for most or all of
      the observed X-ray emission. SSC models with near-equipartition fields thus
      explain the X-ray emission from the hot spots in the two highest surface
      brightness FR II radio galaxies, Cygnus A and 3C 295. This lends weight to the
      assumption of equipartition and suggests that relativistic protons do not
      dominate the particle energy density.

PMID- 10655172
TI  - Emission Lines in the Spectrum of the 3He Star 3 Centauri A.
AB  - Emission in the 4d-->4f transitions of Mn ii (multiplet 13, lambdalambda6122
      6132), in the 4f-->6g transitions of P ii, and in lambda6149.5 of Hg ii has been
      detected in the spectrum of the helium-weak star 3 Centauri A (B5 III-IVp).
      Weaker emission from the same Mn ii multiplet is also seen in the hot, mild HgMn
      star 46 Aquilae (B9 III). It is suggested that the emission is of photospheric
      origin and may be evidence for the stratification of manganese, phosphorus, and
      mercury in the photosphere of 3 Cen A and of manganese in 46 Aql.

PMID- 10655171
TI  - The Elusive Old Population of the Dwarf Spheroidal Galaxy Leo I.
AB  - We report the discovery of a significant old population in the dwarf spheroidal
      (dSph) galaxy Leo I as a result of a wide-area search with the ESO New Technology
      Telescope. Studies of the stellar content of Local Group dwarf galaxies have
      shown the presence of an old stellar population in almost all of the dwarf
      spheroidal galaxies. The only exception was Leo I, which alone appeared to have
      delayed its initial star formation episode until just a few gigayears ago. The
      color-magnitude diagram of Leo I now reveals an extended horizontal branch,
      unambiguously indicating the presence of an old, metal-poor population in the
      outer regions of this galaxy. Yet we find little evidence for a stellar
      population gradient, at least outside R>2' (0.16 kpc), since the old horizontal
      branch stars of Leo I are radially distributed as their more numerous
      intermediate-age helium-burning counterparts. The discovery of a definitely old
      population in the predominantly young dwarf spheroidal galaxy Leo I points to a
      sharply defined first epoch of star formation common to all of the Local Group
      dSph galaxies as well as to the halo of the Milky Way.

PMID- 10655173
TI  - Formation of Millisecond Pulsars with Heavy White Dwarf Companions: Extreme Mass
      Transfer on Subthermal Timescales.
AB  - We have performed detailed numerical calculations of the nonconservative
      evolution of close X-ray binary systems with intermediate-mass (2.0-6.0 M middle
      dot in circle) donor stars and a 1.3 M middle dot in circle accreting neutron
      star. We calculated the thermal response of the donor star to mass loss in order
      to determine its stability and follow the evolution of the mass transfer. Under
      the assumption of the "isotropic reemission model," we demonstrate that in many
      cases it is possible for the binary to prevent a spiral-in and survive a highly
      super-Eddington mass transfer phase (1<<M&d2;&solm0;M&d2;Edd<105) on a subthermal
      timescale if the convective envelope of the donor star is not too deep. These
      systems thus provide a new formation channel for binary millisecond pulsars with
      heavy CO white dwarfs and relatively short orbital periods (3-50 days). However,
      we conclude that to produce a binary pulsar with a O-Ne-Mg white dwarf or Porb
      approximately 1 day (e.g., PSR B0655+64) the above scenario does not work, and a
      spiral-in phase is still considered the most plausible scenario for the formation
      of such a system.

PMID- 10655174
TI  - A Second Luminous Blue Variable in the Quintuplet Cluster.
AB  - H- and K-band moderate-resolution and 4 um high-resolution spectra have been
      obtained for FMM 362, a bright star in the Quintuplet Cluster near the Galactic
      center. The spectral features in these bands closely match those of the Pistol
      Star, a luminous blue variable and one of the most luminous stars known. The new
      spectra and previously obtained photometry imply a very high luminosity for FMM
      362, L>/=106 L middle dot in circle, and a temperature of 10,000-13,000 K. Based
      on its luminosity, temperature, photometric variability, and similarities to the
      Pistol Star, we conclude that FMM 362 is a luminous blue variable.

PMID- 10655175
TI  - Does Turbulence in the Iron Convection Zone Cause the Massive Outbursts of eta
      Carinae?
AB  - Taken at face value, the observed properties of the central object in eta Carinae
      suggest a very massive, hot main-sequence star, only slightly evolved. If this is
      so, the star's extraordinarily high steady rate of mass loss must dynamically
      perturb its outer envelope down to the iron convection zone, in which the kinetic
      energy associated with turbulent convection can be directly fed into mass
      ejection. Runaway mass loss, triggered by either internal (pulsational,
      rotational) or external (tidal) forcing, would produce a secular oscillation of
      the outer envelope. In either case, the oscillation is potentially able to
      account for the observed approximately 5 yr cycles of visual outbursts in eta
      Car, including the giant eruption of 1843.

PMID- 10655176
TI  - eta Carinae: Testing a Binary Orbit Model with the Hubble Space Telescope/Space
      Telescope Imaging Spectrograph.
AB  - Ground-based spectroscopy of eta Car shows periodic changes in some emission-line
      wavelengths. These variations have been cited as strong evidence that this object
      is a 5.5 yr binary system and have been used to produce specific orbit models.
      High spatial resolution data obtained with the Hubble Space Telescope/Space
      Telescope Imaging Spectrograph, however, do not confirm the predicted velocity
      behavior; therefore, the published orbit models are almost certainly invalid.
      Wavelength fluctuations seen at ground-based spatial resolution most likely
      result from other effects, which we describe. If this object is a binary system
      (which has not been proven), then the parameters of the secondary star and of the
      orbit remain largely unknown.

PMID- 10655177
TI  - First Light Measurements of Capella with the Low-Energy Transmission Grating
      Spectrometer aboard the Chandra X-Ray Observatory.
AB  - We present the first X-ray spectrum obtained by the Low-Energy Transmission
      Grating Spectrometer (LETGS) aboard the Chandra X-Ray Observatory. The spectrum
      is of Capella and covers a wavelength range of 5-175 A (2.5-0.07 keV). The
      measured wavelength resolution, which is in good agreement with ground
      calibration, is Deltalambda approximately 0.06 A (FWHM). Although in-flight
      calibration of the LETGS is in progress, the high spectral resolution and unique
      wavelength coverage of the LETGS are well demonstrated by the results from
      Capella, a coronal source rich in spectral emission lines. While the primary
      purpose of this Letter is to demonstrate the spectroscopic potential of the
      LETGS, we also briefly present some preliminary astrophysical results. We discuss
      plasma parameters derived from line ratios in narrow spectral bands, such as the
      electron density diagnostics of the He-like triplets of carbon, nitrogen, and
      oxygen, as well as resonance scattering of the strong Fe xvii line at 15.014 A.

PMID- 10655178
TI  - Submillimeter Polarimetry of the Protostellar Outflow Sources in Serpens with the
      Submillimeter Common-User Bolometer Array.
AB  - Submillimeter polarimetric measurements of the 850 um dust continuum emission
      associated with the class 0/I protostars in the Serpens dark cloud core are
      presented. The data are used to infer the magnetic field morphology in the
      region. Dust grain alignment in accretion flows and/or outflows is also briefly
      considered. The polarization vectors around the SMM-NW cluster of sources are
      more ordered than those observed near the SMM-SE cluster. Toward SMM-NW, the
      vectors are generally orientated north-south; between the intensity peaks in the
      SMM-SE region, the vectors are approximately east-west. In both regions, we
      suggest that the polarization pattern may be dictated by a large-scale magnetic
      field. We consider whether the rough northwest-southeast ridge of submillimeter
      sources was formed via cloud collapse along field lines that run perpendicular to
      this ridge. However, our data offer only very tentative support for this
      hypothesis. We further note that, although overall the polarization pattern in
      Serpens does not appear to be affected by the many outflows in the region, toward
      the most luminous source, SMM 1, the source of the Serpens radio jet, the vectors
      deviate considerably from the general pattern, instead being roughly
      perpendicular to the flow axis, as one would expect from a B-field oriented
      parallel with the flow.

PMID- 10655179
TI  - Growth of an Initial Mass Function Cluster in a Turbulent Dense Core.
AB  - A simple model of condensation growth and collapse in a turbulent dense core
      yields a distribution of stellar masses that matches the main features of the
      stellar initial mass function (IMF). In this model, stars in the "flat" and
      "power-law" parts of the IMF come from condensations with negligible and
      substantial growth, respectively. The mass accretion rate of a condensation is
      proportional to its mass, and the probability of stopping accretion is equal in
      every time interval, so the growth is exponential and its duration follows a
      Poisson distribution. For mass growth e-folding time taugrow and mean duration
      taustop, the stellar mass m has a probability density per logarithmic mass
      interval of approximately m-x, where x identical withtaugrow&solm0;taustop. This
      power-law relation matches the IMF when taugrow approximately taustop, as is
      expected if each of these times is set by the same properties of the surrounding
      core gas. We specify exponential growth arising from Bondi accretion onto a
      stationary Bonnor-Ebert sphere, in a core heated and stirred by associated stars.
      This growth is exponential, unlike the Bondi accretion onto a star, but "slow,"
      with taugrow greater than the free-fall time of the condensation by a factor of
      approximately 4. We specify random stopping as due to sudden turbulent
      compression, which causes the condensation to collapse and stop accreting. For
      these mechanisms, a core with a density of 104 cm-3 grows a cluster of
      approximately 100 IMF-following stars with a mass range of 1-25 M middle dot in
      circle in 1.4 Myr, in accord with the masses and ages of embedded clusters.

PMID- 10655180
TI  - Extended Far-Infrared CO Emission in the OMC-1 Core of Orion.
AB  - We report on sensitive far-infrared observations of 12CO pure rotational
      transitions in the OMC-1 core of Orion. The lines were observed with the long
      wavelength spectrometer in the grating mode on board the Infrared Space
      Observatory, covering the 43-197 um wavelength range. The transitions from Jup=14
      up to Jup=19 have been identified across the whole OMC-1 core, and lines up to
      Jup=43 have been detected toward the central region, KL/IRc2. In addition, we
      have taken high-quality spectra in the Fabry-Perot mode of some of the CO lines.
      In KL/IRc2, the lines are satisfactorily accounted for by a three-temperature
      model describing the plateau and ridge emission. The fluxes detected in the high
      J transitions (Jup>34) reveal the presence of a very hot and dense gas component
      [T=1500-2500 K; N&parl0;CO&parr0;=2x1017 cm-2], probably originating from some of
      the embedded sources previously observed in the H2 near-infrared lines. At all
      other positions in the OMC-1 core, we estimate kinetic temperatures >/=80 K and
      as high as 150 K at some positions around IRc2, from a simple large-velocity
      gradient model.

PMID- 10655181
TI  - O-bearing Molecules in Carbon-rich Proto-Planetary Objects.
AB  - We present Infrared Space Observatory long-wavelength spectrometer observations
      of the proto-planetary nebula CRL 618, a star evolving very fast toward the
      planetary nebula stage. In addition to the lines of 12CO, 13CO, HCN, and HNC, we
      report on the detection of H2O and OH emission together with the fine-structure
      lines of [O i] at 63 and 145 um. The abundance of the latter three species
      relative to 12CO are 4x10-2, 8x10-4, and 4.5 (approximate value) in the regions
      where they are produced. We suggest that O-bearing species other than CO are
      produced in the innermost region of the circumstellar envelope. The UV photons
      from the central star photodissociate most of the molecular species produced in
      the asymptotic giant branch (AGB) phase and allow a chemistry dominated by
      standard ion-neutral reactions. They not only allow these reactions for the
      formation of O-bearing species but also modify the abundances of C-rich molecules
      like HCN and HNC for which we found an abundance ratio of approximately 1, which
      is much lower than in AGB stars. The molecular abundances in the different
      regions of the circumstellar envelope have been derived from radiative transfer
      models and from our knowledge of its physical structure.

PMID- 10655182
TI  - Rings in the Planetesimal Disk of beta Pictoris.
AB  - The nearby main-sequence star beta Pictoris is surrounded by an edge-on disk of
      dust produced by the collisional erosion of larger planetesimals. Here we report
      the discovery of substructure within the northeast extension of the disk midplane
      that may represent an asymmetric ring system around beta Pic. We present a
      dynamical model showing that a close stellar flyby with a quiescent disk of
      planetesimals can create such rings, along with previously unexplained disk
      asymmetries. Thus we infer that beta Pic's planetesimal disk was highly disrupted
      by a stellar encounter in the last hundred thousand years.

PMID- 10655183
TI  - Numerical Simulations of Oscillation Modes of the Solar Convection Zone.
AB  - We use the three-dimensional hydrodynamic code of Stein & Nordlund to
      realistically simulate the upper layers of the solar convection zone in order to
      study physical characteristics of solar oscillations. Our first result is that
      the properties of oscillation modes in the simulation closely match the observed
      properties. Recent observations from the Solar and Heliospheric Observatory
      (SOHO)/Michelson Doppler Imager (MDI) and Global Oscillations Network Group have
      confirmed the asymmetry of solar oscillation line profiles, initially discovered
      by Duvall et al. In this Letter, we compare the line profiles in the power
      spectra of the Doppler velocity and continuum intensity oscillations from the
      SOHO/MDI observations with the simulation. We also compare the phase differences
      between the velocity and intensity data. We have found that the simulated line
      profiles are asymmetric and have the same asymmetry reversal between velocity and
      intensity as observed. The phase difference between the velocity and intensity
      signals is negative at low frequencies, and phase jumps in the vicinity of modes
      are also observed. Thus, our numerical model reproduces the basic observed
      properties of solar oscillations and allows us to study the physical properties
      which are not observed.

PMID- 10655184
TI  - Screening for retinopathy of prematurity: no ophthalmologist required?

PMID- 10655185
TI  - Non-ophthalmologist screening for retinopathy of prematurity.
AB  - AIM: To determine if a non-ophthalmologist can accurately screen for retinopathy
      of prematurity (ROP) by evaluating the posterior pole blood vessels of the
      retina. ROP is a common ocular disorder of premature infants and may require
      multiple screening examinations by an ophthalmologist to allow for timely
      intervention. Since there is a strong correlation between posterior pole vascular
      abnormalities and vision threatening ROP, screening examinations performed by non
      ophthalmologist may yield useful clinical information in high risk infants.
      METHODS: Infants born at the Medical University of South Carolina who met
      screening criteria (n = 142) were examined by a single non-ophthalmologist using
      a direct ophthalmoscope to evaluate the posterior pole blood vessels for
      abnormalities of the venules and/or arterioles. To determine the accuracy of the
      non-ophthalmologist's clinical observations, infants were also examined by an
      ophthalmologist, using an indirect ophthalmoscope, who graded the posterior pole
      vessels as normal, dilated venules, or dilated and tortuous venules and
      arterioles (including "plus disease"). RESULTS: There was significant correlation
      (p <0.001) between the non-ophthalmologist's and ophthalmologist's diagnoses of
      posterior pole vascular abnormalities. 47 infants had normal posterior pole blood
      vessels by the non-ophthalmologist examination. Of these, 31 (66%) were
      considered to have normal vessels and 16 (34%) to have dilated venules by the
      ophthalmologist. The non-ophthalmologist correctly identified abnormal posterior
      pole vessels in all 21 infants diagnosed with abnormal arterioles and venules by
      the ophthalmologist. No infants with clinically important ROP ("prethreshold" or
      worse) would have failed detection by this screening method. CONCLUSION: Using a
      direct ophthalmoscope, a non-ophthalmologist can screen premature infants at risk
      for ROP by evaluating the posterior pole blood vessels of the retina. While not
      necessarily recommended for routine clinical practice, this technique may
      nevertheless be of value to those situations where ophthalmological consultation
      is unavailable or difficult to obtain.

PMID- 10655186
TI  - Analgesic effect of topical sodium diclofenac 0.1% drops during retinal laser
      photocoagulation.
AB  - AIMS: To evaluate the analgesic effect of topical sodium diclofenac 0.1% during
      retinal laser photocoagulation. METHODS: 87 patients, 45 with proliferative
      diabetic retinopathy treated with two sessions of panretinal photocoagulation
      (group A), and 42 patients with non-proliferative diabetic retinopathy who
      underwent grid treatment of the posterior pole (19 bilaterally) (group B). Sodium
      diclofenac 0.1% or sodium chloride 0.9% drops were topically applied 30-135
      minutes before laser treatment in a masked fashion. Patients who had two sessions
      were given the alternate drug in the second one. Pain level was evaluated
      immediately after laser treatment with the visual analogue scale (VAS). The
      results were statistically analysed. RESULTS: Patients in group A reported pain
      in 85/90 sessions (94%). The average pain level was 44.2% with sodium diclofenac
      0.1% drops and 53.1% with sodium chloride 0.9% drops (p = 0.011 by paired t
      test). Patients in group B reported pain in only 16/60 sessions (26. 7%), and the
      pain level ranged from 10% to 60% regardless of the kind of drops used. There was
      no correlation in either group between level of pain and time interval from
      application of the drops to laser treatment (30-135 minutes) or average energy
      level used (100-500 mW). CONCLUSION: Sodium diclofenac 0.1% is useful for pain
      reduction and should be applied before panretinal photocoagulation.

PMID- 10655187
TI  - Long term refractive outcome in eyes of preterm infants with and without
      retinopathy of prematurity: comparison of keratometric value, axial length,
      anterior chamber depth, and lens thickness.
AB  - BACKGROUND/AIMS: A longitudinal study of premature infants was conducted to
      examine changes in refractive status and their relation with age and factors
      influencing the occurrence and degree of myopia. Identification of which of the
      various refractive factors play important parts in relation to myopia in
      premature infants was attempted. METHODS: Under observation were 125 eyes in 65
      patients who were found to demonstrate no signs of retinopathy of prematurity
      (ROP) or who had grade I or II ROP without or after cryotherapy. Cycloplegic
      refractions were conducted at 6 months, 3 years, and 6 years of age; at 6 years
      of age keratometric values, lens thicknesses, and axial lengths were recorded,
      and anterior chamber depths also were measured. RESULTS: Myopia begins to appear
      at 6 months of age and its severity increases between the ages of 6 months and 3
      years. The condition showed no further progress in subjects older than 3 years.
      Of the 104 eyes with ROP, those eyes with cicatricial retinopathy tended towards
      myopia and high myopia while there was no difference in the degree of myopia
      related to whether or not cryotherapy was conducted. At 6 years of age, the
      premature infants exhibited shallower anterior chambers, thicker lenses, and
      higher axial lengths when the degree of the myopia was higher. The keratometric
      values, however, appeared to bear no relation to the degree of the myopia.
      CONCLUSION: These results suggest that the occurrence of myopia is related more
      strongly to whether or not there is cicatricial retinopathy than whether or not
      there is cryotherapy. Also, the degree of the myopia was found to be related to
      the depth of the anterior chamber, the thickness of the lens, and the change in
      axial length but not to keratometric value.

PMID- 10655188
TI  - A systematic review of drug induced ocular reactions in diabetes.
AB  - AIMS: To conduct a systematic review of drug induced adverse ocular effects in
      diabetes to determine if this approach identified any previously unrecognised
      adverse drug effects; to make a preliminary assessment of the feasibility of this
      approach in identifying adverse drug reactions; and to assess the current
      accessibility of this information to prescribing physicians. METHODS: Literature
      search of online biomedical databases. The search strategy linked eye disorders
      with adverse drug reactions and diabetes. Source journals were classified as
      medical, pharmaceutical, diabetes related, or ophthalmological. It was determined
      whether the reactions identified were recorded in drug datasheets and the British
      National Formulary. RESULTS: 63 references fulfilled the selection criteria, of
      which 45 were considered to be relevant to the study. The majority of these were
      case reports but cross sectional surveys, case-control and cohort studies, and
      review articles were also identified. 61% of the reactions were not recorded in
      the British National Formulary and 41% were not recorded in the datasheets. 55%
      appeared in specialist ophthalmology journals. CONCLUSIONS: This is a feasible
      approach to the identification of adverse drug reactions. Adverse reactions not
      listed in the most commonly used reference sources were found. The majority were
      published in specialist ophthalmology journals which might not be seen by
      prescribing physicians.

PMID- 10655189
TI  - Visual and anatomical results of surgery for long standing macular holes.
AB  - AIMS: To determine the visual and anatomical outcome of surgery for long standing
      idiopathic macular holes. METHODS: A retrospective review of 24 eyes of all 22
      patients who underwent surgery for idiopathic full thickness macular holes (FTMH)
      symptomatic for between 1 and 3 years. Postoperative follow up was for 6 months.
      Preoperative and postoperative visual acuities were recorded as well as the
      presence of anatomical closure of the hole. RESULTS: The mean duration of
      symptoms was 18.21 (SD 5.42) months). Anatomical closure of the FTMH was achieved
      in 17 (70.8%) of the eyes at 6 months. The logMAR acuity of the group where
      closure was achieved improved by a mean of 0.31, equivalent to a change of
      Snellen acuity from 6/60 to 6/29. Where the hole remained open the acuity
      deteriorated by a mean logMAR of 0.11 lines, equivalent to a change of Snellen
      acuity from 6/60 to 5/60. Anatomical closure of the hole was associated with a
      significantly improved acuity over non-closure (p<0.001). The degree of visual
      improvement was independent of the preoperative visual acuity (Spearman
      correlation coefficient 0.03, p=0.888), though preoperative acuity was related to
      the final acuity (Spearman correlation coefficient 0.701, p<0.001). Over the
      study period, six patients required cataract surgery, one patient developed
      secondary glaucoma, and one a retinal detachment. CONCLUSIONS: Vitrectomy with
      intraocular gas tamponade and postoperative posturing is a well tolerated and
      effective intervention for long standing macular holes. Anatomical closure of the
      macular hole is associated with a significant improvement in visual acuity.

PMID- 10655190
TI  - Raised plasma homocysteine as a risk factor for retinal vascular occlusive
      disease.
AB  - BACKGROUND/AIMS: A moderately elevated plasma concentration of the sulphur amino
      acid homocysteine is an independent risk factor for atherosclerotic vascular
      disease. Many of the risk factors associated with coronary, cerebral, and
      peripheral atherosclerotic vascular disease are common to retinal vascular
      occlusive disease but it is unclear whether elevated plasma concentrations of
      homocysteine are also associated with such disease. This study assessed the
      relation between retinal vascular occlusive disease and elevated levels of plasma
      total homocysteine (tHcy). METHODS: A retrospective case-control study involving
      hospital based controls and cases with retinal artery, central retinal vein
      (including hemiretinal vein), and branch retinal vein occlusions was performed.
      The relation between elevated tHcy, defined as a level greater than or equal to
      12 micromol/l and risk of retinal vascular occlusive disease was examined.
      RESULTS: 87 cases of retinal vascular occlusive disease including 26 cases of
      retinal artery occlusion, 40 cases with central retinal vein occlusion, and 21
      cases of branch retinal vein occlusion were compared with 87 age matched
      controls. Mean tHcy levels were higher in all disease groups and this difference
      was significant in patients with retinal artery occlusions (p= 0.032) and
      patients with central retinal vein occlusion (p=0.0001). When adjusted for known
      cardiovascular risk factors, tHcy was an independent risk factor for retinal
      vascular occlusive disease (OR 2.85 (95% CI 1.43-5.68)). CONCLUSIONS: Elevated
      tHcy is an independent risk factor for retinal vascular occlusive disease.
      Assessment of tHcy may be important in the investigation and management of
      patients with retinal vascular occlusive disease.

PMID- 10655192
TI  - Visual acuity measurements in a national sample of British elderly people.
AB  - BACKGROUND: Despite the fact that visual function has an important role in the
      quality of life in later years, very few studies have measured visual acuity in
      population based nationwide samples of British elderly people. Such measurements
      were carried out in the context of the national diet and nutrition survey of
      people aged 65 years or over (NDNS). METHODS: NDNS participants, who were living
      in 80 different randomly selected postcode areas of mainland Britain, were
      visited at their home by a nurse who measured visual acuity at 3 metres, using
      the Glasgow acuity card (GAC) method. In addition, a brief questionnaire related
      to ocular health was administered. RESULTS: Visual acuity was measured in 1362
      NDNS participants who were not classified as mentally impaired. Visual impairment
      (using the WHO low vision criteria) was measured in 195 (14.3%) subjects.
      Prevalence of visual impairment increased significantly with age (65-74 years
      3.1%; 75-84 years 11.6%; 85+ years 35.5%, p<0.001 for trend). Impaired vision was
      more common in subjects living in a nursing home (odds ratio adjusted for age
      2.59 (95% CI 2.23 to 2. 96)) and in women (odds ratio adjusted for age 1.55 (95%
      CI 1.21 to 1.89)). 132 (9.7%) subjects had previously undergone cataract surgery
      and another 157 (11.5%) had been told that they currently had cataract. Vision
      improved 0.2 log units or more (at least one Snellen line) with the aid of a
      pinhole occluder in 289 subjects (21. 2%). CONCLUSION: Results of this
      nationwide, community based study confirm that problems with poor distance visual
      acuity exist in a substantial part of the elderly community, particularly in
      women and people living in nursing homes.

PMID- 10655191
TI  - Coffee and doughnut maculopathy: a cause of acute central ring scotomas.
AB  - AIMS: To report the clinical features of five patients with non-progressive
      central ring scotomas of acute onset associated with excellent retained visual
      acuity. METHODS: Complete neuro-ophthalmological examinations were performed.
      Visual fields were performed by tangent screen, Goldmann, or Humphrey perimetry.
      In some cases further testing was carried out including fundus photography,
      fluorescein angiography, ERG, VEP, and neuroimaging. RESULTS: The patients were
      three women and two men whose ages ranged from 25 to 57 years. Four patients were
      heavy caffeine consumers while the fifth patient experienced an episode of
      hypotension. Vision loss was acute in all cases. The onset of vision loss was
      bilateral/simultaneous in three cases, bilateral/sequential in one case, and
      unilateral in one case. All affected eyes retained visual acuities of 20/25 or
      better. Colour vision was subnormal in three of four cases. Visual field defects
      were characterised by a central ring scotoma having an outer diameter less than
      10 degrees. Fundus examination demonstrated temporal optic nerve pallor in three
      patients (five of 10 affected eyes) and reddish, petaloid macular lesions in one
      patient. Good visual acuity was maintained for the duration of follow up in all
      five patients. CONCLUSION: Central ring scotomas with excellent retained visual
      acuity may present as an acute, bilateral syndrome in patients who are heavy
      caffeine consumers. The configuration of visual field loss and its location,
      combined with the presence of temporal pallor in five eyes, suggest that the
      defect localises to the inner layers of the macula. While these cases could be
      considered an expansion of the clinical spectrum of acute macular
      neuroretinopathy, some may represent a distinct entity.

PMID- 10655193
TI  - Pain relief with intracameral mepivacaine during phacoemulsification.
AB  - AIM: To assess the efficacy and safety of an intraoperative intracameral
      injection of mepivacaine, administered when patients experienced pain during the
      course of cataract surgery under topical anaesthesia. METHODS: This is a
      prospective placebo controlled double masked randomised clinical trial. 50 eyes
      were included; 25 receiving the active compound and 25 receiving placebo.
      Mepivacaine (2%, 0.4 ml) or placebo was administered intraoperatively under the
      iris of the patients who experienced pain during the course of
      phacoemulsification in spite of previous topical anaesthesia. Efficacy was
      evaluated by the patients themselves using a five point subjective pain rating
      scale, the Keele verbal pain chart. Safety was measured by assessing intraocular
      inflammation (clinical evaluation and laser flare meter), intraocular pressure,
      and endothelial cell count. RESULTS: The pain rating score significantly
      diminished after intracameral injection in the mepivacaine group (mean 3.0 (95%
      CI 2.6-3.4) v 0.8 (0.3-1.3), p<10(-4))) while remaining unchanged in the placebo
      group (2.9 (2.6-3.2) v 2.9 (2.5-3. 3)), the mean reduction in pain score being
      significantly different between the two groups (p<10(-4)). There was no
      indication of increased postoperative ocular inflammation, intraocular pressure
      change, or endothelial cell loss. CONCLUSIONS: These results suggest that it may
      not be necessary to systematically add intracameral anaesthesia with topical
      anaesthesia for cataract surgery. An intraoperative intracameral injection,
      performed only in patients who happen to suffer during surgery, is safe and
      effective.

PMID- 10655194
TI  - Vertical or asymmetric nystagmus need not imply neurological disease.
AB  - AIM: To indicate that congenital idiopathic nystagmus (CIN) and sensory defect
      nystagmus (SDN) can be vertical or asymmetric in some children. METHODS: Of 276
      children presenting with nystagmus for electrophysiological testing, 14 were
      identified as having CIN or SDN, yet had a nystagmus which was either vertical
      (n=11) or horizontal asymmetric (n=3). Flash electroretinograms and flash and
      pattern visual evoked potentials (VEPs) were recorded in all patients. Eye
      movement assessment, including horizontal optokinetic nystagmus (OKN) testing,
      was carried out in 11/14 patients. RESULTS: Eight patients (seven with vertical,
      one with asymmetric horizontal nystagmus) had congenital cone dysfunction. One
      patient with vertical and another with asymmetric nystagmus had cone-rod
      dystrophy. One patient with vertical upbeat had congenital stationary night
      blindness. Two patients (one downbeat, one upbeat nystagmus) had normal
      electrophysiological, clinical, and brain magnetic resonance imaging findings and
      were classified as having CIN. One patient with asymmetric nystagmus showed
      electrophysiological and clinical findings associated with albinism. Horizontal
      OKN was present in 80% of patients tested, including the three cases with
      horizontal asymmetric nystagmus. This is atypical in both CIN and SDN, where the
      OKN is usually absent. CONCLUSIONS: Vertical and asymmetric nystagmus are most
      commonly associated with serious intracranial pathology and its presence is an
      indication for neuroimaging studies. However, such nystagmus can occur in
      children with retinal disease, albinism, and in cases with CIN. These findings
      stress the importance of non-invasive VEP/ERG testing in all cases of typical and
      also atypical nystagmus.

PMID- 10655195
TI  - Comparison of the intraocular pressure lowering effect of latanoprost and a fixed
      combination of timolol-pilocarpine eye drops in patients insufficiently
      controlled with beta adrenergic antagonists. French Latanoprost Study Group, and
      the Swedish Latanoprost Study Group.
AB  - AIMS: To compare the effect on intraocular pressure (IOP) of latanoprost
      monotherapy and timolol-pilocarpine in patients with glaucoma or ocular
      hypertension with inadequately controlled IOP on topical beta adrenergic
      antagonists. METHODS: This was a multicentre, randomised, observer masked, 6 week
      study performed in France and Sweden. 23 centres enrolled 237 patients with
      glaucoma or ocular hypertension and an IOP of at least 22 mm Hg on treatment with
      topical beta adrenergic antagonists, alone or in combination. After a 21 day run
      in period on timolol 0.5% twice daily, patients were randomised either to
      latanoprost 0.005% once daily or to a fixed combination of timolol-pilocarpine
      twice daily. Changes in mean diurnal IOP from the baseline to the 6 week visit
      were determined with an analysis of covariance. RESULTS: Mean diurnal IOP was
      statistically significantly decreased from baseline in both groups (p<0.001).
      Switching to latanoprost treatment reduced mean diurnal IOP by 5.4 (SEM 0.3) mm
      Hg (ANCOVA -22%) and switching to timolol-pilocarpine treatment reduced mean
      diurnal IOP by 4.9 (0.4) mm Hg (-20%). Blurred vision, decreased visual acuity,
      decreased twilight vision, and headache were statistically significantly more
      frequent in the timolol-pilocarpine group. CONCLUSIONS: Latanoprost monotherapy
      was at least as effective as fixed combination timolol-pilocarpine twice daily
      treatment in reducing mean diurnal IOP in patients not adequately controlled on
      topical beta adrenergic antagonists. Latanoprost was better tolerated than
      timolol-pilocarpine regarding side effects. These results indicate that a switch
      to latanoprost monotherapy can be attempted before combination therapy is
      initiated.

PMID- 10655196
TI  - Detection of gonioscopically occludable angles and primary angle closure glaucoma
      by estimation of limbal chamber depth in Asians: modified grading scheme.
AB  - AIM: To evaluate the performance of limbal chamber depth estimation as a means of
      detecting occludable drainage angles and primary angle closure, with or without
      glaucoma, in an east Asian population, and determine whether an augmented grading
      scheme would enhance test performance. METHOD: A two phase, cross sectional,
      community based study was conducted on rural and urban areas of Hovsgol and
      Omnogobi provinces, Mongolia. 1800 subjects aged 40 to 93 years were selected and
      1717 (95%) of these were examined. Depth of the anterior chamber at the temporal
      limbus was graded as a percentage fraction of peripheral corneal thickness. An
      "occludable" angle was one in which the trabecular meshwork was seen in less than
      90 degrees of the angle circumference by gonioscopy. Primary angle closure (PAC)
      was diagnosed in subjects with an occludable angle and either raised pressure or
      peripheral anterior synechiae. PAC with glaucoma (PACG) was diagnosed in cases
      with an occludable angle combined with glaucomatous optic neuropathy and
      consistent visual morbidity. RESULTS: Occludable angles were identified in 140
      subjects, 28 of these had PACG. The 15% grade (equivalent to the traditional
      "grade 1") yielded sensitivity and specificity of 84% and 86% respectively for
      the detection of occludable angles. The 5% grade gave sensitivity of 91% and
      specificity of 93% for the detection of PACG. The interobserver agreement for
      this augmented grading scheme was good (weighted kappa 0.76). CONCLUSIONS: The
      traditional limbal chamber depth grading scheme offers good performance for
      detecting occludable drainage angles in this population. The augmented scheme
      gives enhanced performance in detection of established PACG. The augmented scheme
      has potential for good interobserver agreement.

PMID- 10655197
TI  - Variable R1 region in varicella zoster virus in fulminant type of acute retinal
      necrosis syndrome.
AB  - BACKGROUND/AIMS: Varicella zoster virus (VZV) is a causative agent in acute
      retinal necrosis (ARN) syndrome. However, in spite of aggressive antiviral
      therapy, clinical characteristics among patients have varied. Different viral
      strains were examined to determine their respective role in producing clinical
      characteristics. The viral strains were also compared with those of previously
      reported ones. METHODS: To differentiate VZV strains R1 and R5, variable regions
      of VZV were amplified by nested polymerase chain reaction (PCR) in 11 eyes of 10
      patients. Sequence analysis was also performed. RESULTS: Four cases had strains
      diverted only at the tip of the 3' end of the R1 variable region, similar to that
      of the H-N3 strain, which was previously reported. Conversely, other cases were
      diverted to other regions. Interestingly, some of the latter cases showed
      multiple PCR products in the R1 region that were generated by the truncation of
      either the 5' or 3' R1 region. Final visual acuities of these patients were less
      than 0.2. The former cases showed final visual acuities more than 0.4. Only two
      variants were from the R5 region. No patient had the same viral strain as the
      European Dumas type. CONCLUSION: These results showed that variable VZV strains
      participated in ARN. Using PCR of the R1 variable region, it was estimated that
      patients with a more fulminant type of ARN may have diverse viruses with
      extensive replication in the affected eyes.

PMID- 10655198
TI  - Fluid transport by cultured corneal epithelial cell layers.
AB  - BACKGROUND/AIMS: Fluid transport across the in vitro corneal epithelium is short
      lived, hence difficult to detect and characterise. Since stable rates of fluid
      transport across several cultured epithelial cell layers have been demonstrated,
      the behaviour of confluent SV40 transformed rabbit corneal epithelial cells
      (tRCEC) grown on permeable supports was examined. METHODS: Fluid transport was
      determined with a nanoinjector volume clamp; the specific electrical resistance
      of the layers was 184 (SEM 9) Omega cm(2). tRCEC layers transported fluid (from
      basal to apical) against a pressure head of 3 cm H(2)O for 2-3 hours. RESULTS: In
      the first hour, the rate of fluid transport was 5.2 (0.5) microl/h/cm(-2) (n=23),
      which is comparable with that found in other epithelia. Fluid transport was
      completely inhibited in 15-30 minutes by either 100 microM ouabain (n=6), 50
      microM bumetanide (n=6), or 1 microM endothelin-1 (ET-1; n=6). Preincubation with
      10 microM BQ123 (an ET(A) receptor antagonist) obviated inhibition by ET-1 (n=6).
      ET-1 also caused a 22% decrease in specific resistance. CONCLUSIONS: Fluid
      transport appears to depend on transepithelial Cl(- )transport since (1) their
      directions are the same (stroma-->tear), and (2) both bumetanide and ouabain
      inhibit it with similar time course. tRCEC appear useful to investigate aspects
      of the physiology and pharmacology of fluid transport across this layer,
      including receptor mediated control of this process.

PMID- 10655199
TI  - Apoptosis is a prominent feature of acute anterior uveitis in the Fischer 344
      rat.
AB  - AIMS: To examine the hypothesis that apoptosis of infiltrating cells contributes
      to spontaneous resolution of uveitis in clinically relevant rodent models.
      METHODS: Experimental melanin induced uveitis (EMIU) was induced in Fischer 344
      rats by immunisation with 250 microg bovine ocular melanin. Endotoxin induced
      uveitis (EIU) was induced by injection of 200 microg Escherichia coli
      lipopolysaccharide. Formalin fixed, paraffin embedded ocular cross sections were
      stained by terminal deoxynucleotidyl transferase mediated deoxyuridine
      triphosphate biotin nick end labelling (TUNEL) to identify apoptotic cells.
      Indirect immunoperoxidase staining of paraformaldehyde lysine periodate fixed
      tissue cross sections was used to demonstrate expression of inducible nitric
      oxide synthase (iNOS). RESULTS: TUNEL positive mononuclear cells were observed in
      the anterior uvea during both EMIU and EIU at all selected time points. However,
      whereas the majority of mononuclear cells appeared apoptotic from the outset of
      disease, neutrophils were notably TUNEL negative at all time points examined.
      Many infiltrating neutrophils expressed iNOS. CONCLUSION: Apoptosis occurs early
      in the course of rat EMIU and EIU, and may contribute to resolution of these
      diseases. In general, infiltrating mononuclear cells die rapidly, while
      neutrophils survive, producing inducible nitric oxide synthase which may
      contribute to disease pathogenesis.

PMID- 10655200
TI  - Apoptosis and apoptosis related gene expression in normal conjunctiva and
      pterygium.
AB  - BACKGROUND: Pterygium is a relatively common eye disease in the tropics whose
      aetiology and pathogenesis remain uncertain. As such, interest has focused on
      understanding the underlying mechanism of pterygia development. METHODS: 15
      specimens of pterygia from 15 eyes were examined, together with normal
      conjunctival tissue from the same eyes for the pattern of gene expression of
      genes associated with the induction or repression of apoptosis (p53, bcl-2, and
      bax). In addition, the samples directly for apoptotic cells were examined by the
      terminal deoxynucleotide transferase (TdT) mediated nick end labelling (TUNEL)
      methodology. RESULTS: In pterygia specimens apoptotic cells were found mainly
      confined to the basal layer of cells of the epithelial layer, situated
      immediately adjacent to the fibrovascular support layer. These cells were shown
      to express significant levels of p53 and bax, as well as the apoptosis inhibiting
      protein bcl-2. In contrast, normal conjunctival specimens displayed no bcl-2
      expression and apoptotic cells were seen throughout the entire width of the
      epithelial layer, coupled with high levels of bax expression. CONCLUSION: These
      results support a model whereby pterygia development is a result of disruption of
      the normal process of apoptosis occurring in the conjunctiva.

PMID- 10655202
TI  - Is ocular toxoplasmosis caused by prenatal or postnatal infection?

PMID- 10655201
TI  - Telomerase expression in uveal melanoma.
AB  - BACKGROUND/AIMS: Accumulating evidence indicates that telomerase activity is
      repressed in normal human somatic cells but reactivated in cancers and immortal
      cells, suggesting that activation of telomerase activity has a role in
      carcinogenesis and immortalisation. To date, telomerase in uveal melanoma and,
      whether, it may have a role in the development or progression of these tumours
      has not been described. The expression patterns and the activity of telomerase
      were investigated in 14 uveal melanoma and these results were correlated with
      histological and immunohistological features of these tumours. METHODS: A
      modified PCR based telomeric repeat amplification protocol (TRAP) assay was used
      to demonstrate telomerase activity in 14 uveal melanomas. In addition, in situ
      hybridisation was used to demonstrate the expression pattern of the telomerase
      RNA component (hTR) at the single cell level in eight of these globes. RESULTS:
      The TRAP assay revealed moderate telomerase activity in all uveal melanomas
      examined. In situ hybridisation visualised a moderate to high upregulation of hTR
      in the melanoma cells but not in the admixed reactive cells. There was no
      correlation among tumour location, cell type, or growth fraction and the amount
      of telomerase activity. In addition, the cells of the germinative zone of the
      lens demonstrated a strong hTR expression. CONCLUSION: Telomerase activity is
      upregulated in uveal melanomas. The expression of hTR was located to the tumour
      cells and not the reactive tumour infiltrating cells. Strong telomerase
      expression was also demonstrated in cells of the germinative zone of the lens.

PMID- 10655203
TI  - Diagnosis of external ocular infections: microbiological processing and
      interpretation.

PMID- 10655204
TI  - Laser pointers can cause permanent retinal injury if used inappropriately.

PMID- 10655205
TI  - Guido Pontecorvo ("Ponte"), 1907-1999.

PMID- 10655206
TI  - Antagonism of ultraviolet-light mutagenesis by the methyl-directed mismatch
      repair system of Escherichia coli.
AB  - Previous studies have demonstrated that the Escherichia coli MutHLS mismatch
      repair system can process UV-irradiated DNA in vivo and that the human MSH2.MSH6
      mismatch-repair protein binds more strongly in vitro to photoproduct/base
      mismatches than to "matched" photoproducts in DNA. We tested the hypothesis that
      mismatch repair directed against incorrect bases opposite photoproducts might
      reduce UV mutagenesis, using two alleles at E. coli lacZ codon 461, which revert,
      respectively, via CCC --> CTC and CTT --> CTC transitions. F' lacZ targets were
      mated from mut(+) donors into mutH, mutL, or mutS recipients, once cells were at
      substantial densities, to minimize spontaneous mutation prior to irradiation. In
      umu(+) mut(+) recipients, a range of UV fluences induced lac(+) revertant
      frequencies of 4-25 x 10(-8); these frequencies were consistently 2-fold higher
      in mutH, mutL, or mutS recipients. Since this effect on mutation frequency was
      unaltered by an Mfd(-) defect, it appears not to involve transcription-coupled
      excision repair. In mut(+) umuC122::Tn5 bacteria, UV mutagenesis (at 60 J/m(2))
      was very low, but mutH or mutL or mutS mutations increased reversion of both lacZ
      alleles roughly 25-fold, to 5-10 x 10(-8). Thus, at UV doses too low to induce
      SOS functions, such as Umu(2)'D, most incorrect bases opposite occasional
      photoproducts may be removed by mismatch repair, whereas in heavily irradiated
      (SOS-induced) cells, mismatch repair may only correct some photoproduct/base
      mismatches, so UV mutagenesis remains substantial.

PMID- 10655207
TI  - Palindromes as substrates for multiple pathways of recombination in Escherichia
      coli.
AB  - A 246-bp imperfect palindrome has the potential to form hairpin structures in
      single-stranded DNA during replication. Genetic evidence suggests that these
      structures are converted to double-strand breaks by the SbcCD nuclease and that
      the double-strand breaks are repaired by recombination. We investigated the role
      of a range of recombination mutations on the viability of cells containing this
      palindrome. The palindrome was introduced into the Escherichia coli chromosome by
      phage lambda lysogenization. This was done in both wt and sbcC backgrounds.
      Repair of the SbcCD-induced double-strand breaks requires a large number of
      proteins, including the components of both the RecB and RecF pathways. Repair
      does not involve PriA-dependent replication fork restart, which suggests that the
      double-strand break occurs after the replication fork has passed the palindrome.
      In the absence of SbcCD, recombination still occurs, probably using a gap
      substrate. This process is also PriA independent, suggesting that there is no
      collapse of the replication fork. In the absence of RecA, the RecQ helicase is
      required for palindrome viability in a sbcC mutant, suggesting that a helicase
      dependent pathway exists to allow replicative bypass of secondary structures.

PMID- 10655208
TI  - A homologue of the recombination-dependent growth gene, rdgC, is involved in
      gonococcal pilin antigenic variation.
AB  - Neisseria gonorrhoeae pilin undergoes high-frequency changes in primary amino
      acid sequence that aid in the avoidance of the host immune response and alter
      pilus expression. The pilin amino acid changes reflect nucleotide changes in the
      expressed gene, pilE, which result from nonreciprocal recombination reactions
      with numerous silent loci, pilS. A series of mini-transposon insertions affecting
      pilin antigenic variation were localized to three genes in one region of the Gc
      chromosome. Mutational analysis with complementation showed that a Gc gene with
      sequence similarity to the Escherichia coli rdgC gene is involved in pilus
      dependent colony phase variation and in pilin antigenic variation. Furthermore,
      we show that the Gc rdgC homologue is transcriptionally linked in an operon with
      a gene encoding a predicted GTPase. The inability to disrupt expression of this
      gene suggests it is an essential gene (engA, essential neisserial GTPase). While
      some of the transposon mutations in rdgC and insertions in the 5'-untranslated
      portion of engA showed a growth defect, all transposon insertions investigated
      conferred an aberrant cellular morphology. Complementation analysis showed that
      the growth deficiencies are due to the interruption of RdgC expression and not
      that of EngA. The requirement of RdgC for efficient pilin variation suggests a
      role for this protein in specialized DNA recombination reactions.

PMID- 10655209
TI  - Mechanisms of dinucleotide repeat instability in Escherichia coli.
AB  - The high level of polymorphism of microsatellites has been used for a variety of
      purposes such as positional cloning of genes associated with diseases, forensic
      medicine, and phylogenetic studies. The discovery that microsatellites are
      associated with human diseases, not only as markers of risk but also directly in
      disease pathogenesis, has triggered a renewed interest in understanding the
      mechanism of their instability. In this work we have investigated the role of DNA
      replication, long patch mismatch repair, and transcription on the genetic
      instability of all possible combinations of dinucleotide repeats in Escherichia
      coli. We show that the (GpC) and (ApT) self-complementary sequence repeats are
      the most unstable and that the mode of replication plays an important role in
      their instability. We also found that long patch mismatch repair is involved in
      avoiding both short deletion and expansion events and also in instabilities
      resulting from the processing of bulges of 6 to 8 bp for the (GpT/ApC)- and
      (ApG/CpT)- containing repeats. For each dinucleotide sequence repeat, we propose
      models for instability that involve the possible participation of unusual
      secondary structures.

PMID- 10655210
TI  - The Saccharomyces cerevisiae DNA recombination and repair functions of the RAD52
      epistasis group inhibit Ty1 transposition.
AB  - RNA transcribed from the Saccharomyces cerevisiae retrotransposon Ty1 accumulates
      to a high level in mitotically growing haploid cells, yet transposition occurs at
      very low frequencies. The product of reverse transcription is a linear double
      stranded DNA molecule that reenters the genome by either Ty1-integrase-mediated
      insertion or homologous recombination with one of the preexisting genomic Ty1 (or
      delta) elements. Here we examine the role of the cellular homologous
      recombination functions on Ty1 transposition. We find that transposition is
      elevated in cells mutated for genes in the RAD52 recombinational repair pathway,
      such as RAD50, RAD51, RAD52, RAD54, or RAD57, or in the DNA ligase I gene CDC9,
      but is not elevated in cells mutated in the DNA repair functions encoded by the
      RAD1, RAD2, or MSH2 genes. The increase in Ty1 transposition observed when genes
      in the RAD52 recombinational pathway are mutated is not associated with a
      significant increase in Ty1 RNA or proteins. However, unincorporated Ty1 cDNA
      levels are markedly elevated. These results suggest that members of the RAD52
      recombinational repair pathway inhibit Ty1 post-translationally by influencing
      the fate of Ty1 cDNA.

PMID- 10655211
TI  - A yeast heterogeneous nuclear ribonucleoprotein complex associated with RNA
      polymerase II.
AB  - Recent evidence suggests a role for the carboxyl-terminal domain (CTD) of the
      largest subunit of RNA polymerase II (pol II) in pre-mRNA processing. The yeast
      NRD1 gene encodes an essential RNA-binding protein that shares homology with
      mammalian CTD-binding proteins and is thought to regulate mRNA abundance by
      binding to a specific cis-acting element. The present work demonstrates genetic
      and physical interactions among Nrd1p, the pol II CTD, Nab3p, and the CTD kinase
      CTDK-I. Previous studies have shown that Nrd1p associates with the CTD of pol II
      in yeast two-hybrid assays via its CTD-interaction domain (CID). We show that
      nrd1 temperature-sensitive alleles are synthetically lethal with truncation of
      the CTD to 9 or 10 repeats. Nab3p, a yeast hnRNP, is a high-copy suppressor of
      some nrd1 temperature-sensitive alleles, interacts with Nrd1p in a yeast two
      hybrid assay, and coimmunoprecipitates with Nrd1p. Temperature-sensitive alleles
      of NAB3 are suppressed by deletion of CTK1, a kinase that has been shown to
      phosphorylate the CTD and increase elongation efficiency in vitro. This set of
      genetic and physical interactions suggests a role for yeast RNA-binding proteins
      in transcriptional regulation.

PMID- 10655212
TI  - Roles for the Saccharomyces cerevisiae SDS3, CBK1 and HYM1 genes in
      transcriptional repression by SIN3.
AB  - The Saccharomyces cerevisiae Sin3 transcriptional repressor is part of a large
      multiprotein complex that includes the Rpd3 histone deacetylase. A LexA-Sin3
      fusion protein represses transcription of promoters with LexA binding sites. To
      identify genes involved in repression by Sin3, we conducted a screen for
      mutations that reduce repression by LexA-Sin3. One of the mutations identified
      that reduces LexA-Sin3 repression is in the RPD3 gene, consistent with the known
      roles of Rpd3 in transcriptional repression. Mutations in CBK1 and HYM1 reduce
      repression by LexA-Sin3 and also cause defects in cell separation and altered
      colony morphology. cbk1 and hym1 mutations affect some but not all genes
      regulated by SIN3 and RPD3, but the effect on transcription is much weaker.
      Genetic analysis suggests that CBK1 and HYM1 function in the same pathway, but
      this genetic pathway is separable from that of SIN3 and RPD3. The remaining gene
      from this screen described in this report is SDS3, previously identified in a
      screen for mutations that increase silencing at HML, HMR, and telomere-linked
      genes, a phenotype also seen in sin3 and rpd3 mutants. Genetic analysis
      demonstrates that SDS3 functions in the same genetic pathway as SIN3 and RPD3,
      and coimmunoprecipitation experiments show that Sds3 is physically present in the
      Sin3 complex.

PMID- 10655213
TI  - Telomere structure regulates the heritability of repressed subtelomeric chromatin
      in Saccharomyces cerevisiae.
AB  - Telomeres, the protein-DNA structures present at the termini of linear
      chromosomes, are capable of conferring a reversible repression of Pol II- and Pol
      III-transcribed genes positioned in adjacent subtelomeric regions. This
      phenomenon, termed telomeric silencing, is likely to be the consequence of a more
      global telomere position effect at the level of chromatin structure. To
      understand the role of telomere structure in this position effect, we have
      developed an assay to distinguish between the heritability of transcriptionally
      repressed and derepressed states in yeast. We have previously demonstrated that
      an elongated telomeric tract leads to hyperrepression of telomere-adjacent genes.
      We show here that the predominant effect of elongated telomeres is to increase
      the inheritance of the repressed state in cis. Interestingly, the presence of
      elongated telomeres overcomes the partial requirement of yCAF-1 in silencing. We
      propose that the formation of a specific telomeric structure is necessary for the
      heritability of repressed subtelomeric chromatin.

PMID- 10655214
TI  - Functions of fission yeast orp2 in DNA replication and checkpoint control.
AB  - orp2 is an essential gene of the fission yeast Schizosaccharomyces pombe with 22%
      identity to budding yeast ORC2. We isolated temperature-sensitive alleles of orp2
      using a novel plasmid shuffle based on selection against thymidine kinase. Cells
      bearing the temperature-sensitive allele orp2-2 fail to complete DNA replication
      at a restrictive temperature and undergo cell cycle arrest. Cell cycle arrest
      depends on the checkpoint genes rad1 and rad3. Even when checkpoint functions are
      wild type, the orp2-2 mutation causes high rates of chromosome and plasmid loss.
      These phenotypes support the idea that Orp2 is a replication initiation factor.
      Selective spore germination allowed analysis of orp2 deletion mutants. These
      experiments showed that in the absence of orp2 function, cells proceed into
      mitosis despite a lack of DNA replication. This suggests either that the Orp2
      protein is a part of the checkpoint machinery or more likely that DNA replication
      initiation is required to induce the replication checkpoint signal.

PMID- 10655216
TI  - Suppressed recombination and a pairing anomaly on the mating-type chromosome of
      Neurospora tetrasperma.
AB  - Neurospora crassa and related heterothallic ascomycetes produce eight
      homokaryotic self-sterile ascospores per ascus. In contrast, asci of N.
      tetrasperma contain four self-fertile ascospores each with nuclei of both mating
      types (matA and mata). The self-fertile ascospores of N. tetrasperma result from
      first-division segregation of mating type and nuclear spindle overlap at the
      second meiotic division and at a subsequent mitotic division. Recently, Merino et
      al. presented population-genetic evidence that crossing over is suppressed on the
      mating-type chromosome of N. tetrasperma, thereby preventing second-division
      segregation of mating type and the formation of self-sterile ascospores. The
      present study experimentally confirmed suppressed crossing over for a large
      segment of the mating-type chromosome by examining segregation of markers in
      crosses of wild strains. Surprisingly, our study also revealed a region on the
      far left arm where recombination is obligatory. In cytological studies, we
      demonstrated that suppressed recombination correlates with an extensive unpaired
      region at pachytene. Taken together, these results suggest an unpaired region
      adjacent to one or more paired regions, analogous to the nonpairing and
      pseudoautosomal regions of animal sex chromosomes. The observed pairing and
      obligate crossover likely reflect mechanisms to ensure chromosome disjunction.

PMID- 10655215
TI  - The G protein-coupled receptor gpr1 is a nutrient sensor that regulates
      pseudohyphal differentiation in Saccharomyces cerevisiae.
AB  - Pseudohyphal differentiation in the budding yeast Saccharomyces cerevisiae is
      induced in diploid cells in response to nitrogen starvation and abundant
      fermentable carbon source. Filamentous growth requires at least two signaling
      pathways: the pheromone responsive MAP kinase cascade and the Gpa2p-cAMP-PKA
      signaling pathway. Recent studies have established a physical and functional link
      between the Galpha protein Gpa2 and the G protein-coupled receptor homolog Gpr1.
      We report here that the Gpr1 receptor is required for filamentous and haploid
      invasive growth and regulates expression of the cell surface flocculin Flo11.
      Epistasis analysis supports a model in which the Gpr1 receptor regulates
      pseudohyphal growth via the Gpa2p-cAMP-PKA pathway and independently of both the
      MAP kinase cascade and the PKA related kinase Sch9. Genetic and physiological
      studies indicate that the Gpr1 receptor is activated by glucose and other
      structurally related sugars. Because expression of the GPR1 gene is known to be
      induced by nitrogen starvation, the Gpr1 receptor may serve as a dual sensor of
      abundant carbon source (sugar ligand) and nitrogen starvation. In summary, our
      studies reveal a novel G protein-coupled receptor senses nutrients and regulates
      the dimorphic transition to filamentous growth via a Galpha protein-cAMP-PKA
      signal transduction cascade.

PMID- 10655217
TI  - EAT-20, a novel transmembrane protein with EGF motifs, is required for efficient
      feeding in Caenorhabditis elegans.
AB  - The pharynx of Caenorhabditis elegans is a neuromuscular organ responsible for
      feeding, concentrating food by its pumping movement. A class of mutants, the eat
      mutants, are defective in this behavior. We have identified a novel eat gene, eat
      20, encoding a unique transmembrane protein with three EGF motifs. Staining with
      a specific polyclonal antibody reveals that EAT-20 is expressed predominantly in
      the pharyngeal muscles and a subset of neurons. Some hypodermal cells also
      express EAT-20. eat-20 mutant animals are starved, have smaller brood sizes, and
      have prolonged egg-laying periods. The starvation apparently results from
      pharyngeal pumping defects, including a reduced pumping rate and "slippery
      pumping," in which the contents of the pharynx sometimes move rostrally. However,
      electrical activity of eat-20 mutants appears normal by electropharyngeogram.

PMID- 10655218
TI  - Self-inflicted wounds, template-directed gap repair and a recombination hotspot.
      Effects of the mariner transposase.
AB  - Aberrant repair products of mariner transposition occur at a frequency of
      approximately 1/500 per target element per generation. Among 100 such mutations
      in the nonautonomous element peach, most had aberrations in the 5' end of peach
      (40 alleles), in the 3' end of peach (11 alleles), or a deletion of peach with or
      without deletion of flanking genomic DNA (29 alleles). Most mariner mutations can
      be explained by exonuclease "nibble" and host-mediated repair of the double
      stranded gap created by the transposase, in contrast to analogous mutations in
      the P element. In mariner, mutations in the 5' inverted repeat are smaller and
      more frequent than those in the 3' inverted repeat, but secondary mutations in
      target elements with a 5' lesion usually had 3' lesions resembling those normally
      found at the 5' end. We suggest that the mariner transposase distinguishes
      between the 5' and 3' ends of the element, and that the 5' end is relatively more
      protected after strand scission. We also find: (1) that homolog-dependent gap
      repair is a frequent accompaniment to mariner excision, estimated as 30% of all
      excision events; and (2) that mariner is a hotspot of recombination in Drosophila
      females, but only in the presence of functional transposase.

PMID- 10655219
TI  - Mutational analysis of a histone deacetylase in Drosophila melanogaster: missense
      mutations suppress gene silencing associated with position effect variegation.
AB  - For many years it has been noted that there is a correlation between acetylation
      of histones and an increase in transcriptional activity. One prediction, based on
      this correlation, is that hypomorphic or null mutations in histone deacetylase
      genes should lead to increased levels of histone acetylation and result in
      increased levels of transcription. It was therefore surprising when it was
      reported, in both yeast and fruit flies, that mutations that reduced or
      eliminated a histone deacetylase resulted in transcriptional silencing of genes
      subject to telomeric and heterochromatic position effect variegation (PEV). Here
      we report the first mutational analysis of a histone deacetylase in a
      multicellular eukaryote by examining six new mutations in HDAC1 of Drosophila
      melanogaster. We observed a suite of phenotypes accompanying the mutations
      consistent with the notion that HDAC1 acts as a global transcriptional regulator.
      However, in contrast to recent findings, here we report that specific missense
      mutations in the structural gene of HDAC1 suppress the silencing of genes subject
      to PEV. We propose that the missense mutations reported here are acting as
      antimorphic mutations that "poison" the deacetylase complex and propose a model
      that accounts for the various phenotypes associated with lesions in the
      deacetylase locus.

PMID- 10655220
TI  - Diverse domains of THREAD/DIAP1 are required to inhibit apoptosis induced by
      REAPER and HID in Drosophila.
AB  - Significant amounts of apoptosis take place during Drosophila development. The
      proapoptotic genes reaper (rpr), grim, and head involution defective (hid) are
      required for virtually all embryonic apoptosis. The proteins encoded by these
      genes share a short region of homology at their amino termini. The Drosophila IAP
      homolog THREAD/DIAP1 (TH/DIAP1), encoded by the thread (th) gene, negatively
      regulates apoptosis during development. It has been proposed that RPR, GRIM, and
      HID induce apoptosis by binding and inactivating TH/DIAP1. The region of homology
      between the three proapoptotic proteins has been proposed to bind to the
      conserved BIR2 domain of TH/DIAP1. Here, we present an analysis of loss-of
      function and gain-of-function alleles of th, which indicates that additional
      domains of TH/DIAP1 are necessary for its ability to inhibit death induced by
      RPR, GRIM, and HID. In addition, that analysis of loss-of-function mutations
      demonstrates that th is necessary to block apoptosis very early in embryonic
      development. This may reflect a requirement to block maternally provided RPR and
      HID, or it may indicate another function of the TH/DIAP1 protein.

PMID- 10655221
TI  - The genetic structure of the Raleigh natural population of Drosophila
      melanogaster revisited.
AB  - The Raleigh natural population of Drosophila melanogaster was reanalyzed with
      special attention to possible dysgenic effects during the extraction of
      chromosomes. About 600 second chromosomes were extracted from the Raleigh natural
      population, half in the cytoplasm of wild-caught females (native genetic
      background) and half in the cytoplasm of the laboratory line, C160(In(2LR)SM1,
      Cy/In(2LR)bw(V1)) (foreign genetic background). We could not find significant
      differences between the two extraction schemes in the frequency of lethal second
      chromosomes (Q = 0.252 for the lines with the negative genetic background vs.
      0.231 for the lines with the foreign genetic background) or in the homozygous
      detrimental (D) and lethal (L) loads (D = 0.210 vs. 0.251; L = 0.287 vs. 0.264).
      The effective size of the population was estimated to be approximately 19,000,
      based on the allelism rate of lethal-bearing chromosomes. The homozygous load
      markedly decreased in the 15 years since a previous study of the same population.

PMID- 10655222
TI  - Non-Mendelian segregation of sex chromosomes in heterospecific Drosophila males.
AB  - Interspecific hybrids and backcrossed organisms generally suffer from reduced
      viability and/or fertility. To identify and genetically map these defects, we
      introgressed regions of the Drosophila sechellia genome into the D. simulans
      genome. A female-biased sex ratio was observed in 24 of the 221 recombinant
      inbred lines, and subsequent tests attributed the skew to failure of Y-bearing
      sperm to fertilize the eggs. Apparently these introgressed lines fail to suppress
      a normally silent meiotic drive system. Using molecular markers we mapped two
      regions of the Drosophila genome that appear to exhibit differences between D.
      simulans and D. sechellia in their regulation of sex chromosome segregation
      distortion. The data indicate that the sex ratio phenotype results from an
      epistatic interaction between at least two factors. We discuss whether this
      observation is relevant to the meiotic drive theory of hybrid male sterility.

PMID- 10655223
TI  - A genetic screen for novel components of the Ras/Mitogen-activated protein kinase
      signaling pathway that interact with the yan gene of Drosophila identifies split
      ends, a new RNA recognition motif-containing protein.
AB  - The receptor tyrosine kinase (RTK) signaling pathway is used reiteratively during
      the development of all multicellular organisms. While the core RTK/Ras/MAPK
      signaling cassette has been studied extensively, little is known about the nature
      of the downstream targets of the pathway or how these effectors regulate the
      specificity of cellular responses. Drosophila yan is one of a few downstream
      components identified to date, functioning as an antagonist of the RTK/Ras/MAPK
      pathway. Previously, we have shown that ectopic expression of a constitutively
      active protein (yan(ACT)) inhibits the differentiation of multiple cell types. In
      an effort to identify new genes functioning downstream in the Ras/MAPK/yan
      pathway, we have performed a genetic screen to isolate dominant modifiers of the
      rough eye phenotype associated with eye-specific expression of yan(ACT).
      Approximately 190,000 mutagenized flies were screened, and 260 enhancers and 90
      suppressors were obtained. Among the previously known genes we recovered are four
      RTK pathway components, rolled (MAPK), son-of-sevenless, Star, and pointed, and
      two genes, eyes absent and string, that have not been implicated previously in
      RTK signaling events. We also isolated mutations in five previously
      uncharacterized genes, one of which, split ends, we have characterized
      molecularly and have shown to encode a member of the RRM family of RNA-binding
      proteins.

PMID- 10655224
TI  - Functional domains of the Drosophila bicaudal-D protein.
AB  - The localization of oocyte-specific determinants in the form of mRNAs to the pro
      oocyte is essential for the establishment of oocyte identity. Localization of the
      Bicaudal-D (Bic-D) protein to the presumptive oocyte is required for the
      accumulation of Bic-D and other mRNAs to the pro-oocyte. The Bic-D protein
      contains four well-defined heptad repeat domains characteristic of intermediate
      filament proteins, and several of the mutations in Bic-D map to these conserved
      domains. We have undertaken a structure-function analysis of Bic-D by testing the
      function of mutant Bic-D transgenes (Bic-D(H)) deleted for each of the heptad
      repeat domains in a Bic-D null background. Our transgenic studies indicate that
      only the C-terminal heptad repeat deletion results in a protein that has lost
      zygotic and ovarian functions. The three other deletions result in proteins with
      full zygotic function, but with affected ovarian function. The functional
      importance of each domain is well correlated with its conservation in evolution.
      The analysis of females heterozygous for Bic-D(H) and the existing alleles Bic
      D(PA66) or Bic-D(R26) reveals that Bic-D(R26) as well as some of Bic-D(H)
      transgenes have antimorphic effects. The yeast two-hybrid interaction assay shows
      that Bic-D forms homodimers. Furthermore, we found that Bic-D exists as a
      multimeric protein complex consisting of Egl and at least two Bic-D monomers.

PMID- 10655225
TI  - Aberrant splicing and altered spatial expression patterns in fruitless mutants of
      Drosophila melanogaster.
AB  - The fruitless (fru) gene functions in Drosophila males to establish the potential
      for male sexual behaviors. fru encodes a complex set of sex-specific and sex
      nonspecific mRNAs through the use of multiple promoters and alternative pre-mRNA
      processing. The male-specific transcripts produced from the distal (P1) fru
      promoter are believed to be responsible for its role in specifying sexual
      behavior and are only expressed in a small fraction of central nervous system
      (CNS) cells. To understand the molecular etiology of fruitless mutant phenotypes,
      we compared wild-type and mutant transcription patterns. These experiments
      revealed that the fru(2), fru(3), fru(4), and fru(sat) mutations, which are due
      to P-element inserts, alter the pattern of sex-specific and sex-nonspecific fru
      RNAs. These changes arise in part from the P-element insertions containing splice
      acceptor sites that create alternative processing pathways. In situ hybridization
      revealed no alterations in the locations of cells expressing the P1-fru-promoter
      derived transcripts in fru(2), fru(3), fru(4), and fru(sat) pharate adults. For
      the fru(1) mutant (which is due to an inversion breakpoint near the P1 promoter),
      Northern analyses revealed no significant changes in fru transcript patterns.
      However, in situ hybridization revealed anomalies in the level and distribution
      of P1-derived transcripts: in fru(1) males, fewer P1-expressing neurons are found
      in regions of the dorsal lateral protocerebrum and abdominal ganglion compared to
      wild-type males. In other regions of the CNS, expression of these transcripts
      appears normal in fru(1) males. The loss of fruitless expression in these regions
      likely accounts for the striking courtship abnormalities exhibited by fru(1)
      males. Thus, we suggest that the mutant phenotypes in fru(2), fru(3), fru(4), and
      fru(sat) animals are due to a failure to appropriately splice P1 transcripts,
      whereas the mutant phenotype of fru(1) animals is due to the reduction or absence
      of P1 transcripts within specific regions of the CNS.

PMID- 10655226
TI  - The clock gene period of the housefly, Musca domestica, rescues behavioral
      rhythmicity in Drosophila melanogaster. Evidence for intermolecular coevolution?
AB  - In Drosophila, the clock gene period (per), is an integral component of the
      circadian clock and acts via a negative autoregulatory feedback loop. Comparative
      analyses of per genes in insects and mammals have revealed that they may function
      in similar ways. However in the giant silkmoth, Antheraea pernyi, per expression
      and that of the partner gene, tim, is not consistent with the negative feedback
      role. As an initial step in developing an alternative dipteran model to
      Drosophila, we have identified the per orthologue in the housefly, Musca
      domestica. The Musca per sequence highlights a pattern of conservation and
      divergence similar to other insect per genes. The PAS dimerization domain shows
      an unexpected phylogenetic relationship in comparison with the corresponding
      region of other Drosophila species, and this appears to correlate with a
      functional assay of the Musca per transgene in Drosophila melanogaster per-mutant
      hosts. A simple hypothesis based on the coevolution of the PERIOD and TIMELESS
      proteins with respect to the PER PAS domain can explain the behavioral data
      gathered from transformants.

PMID- 10655227
TI  - Mega-introns in the dynein gene DhDhc7(Y) on the heterochromatic Y chromosome
      give rise to the giant threads loops in primary spermatocytes of Drosophila
      hydei.
AB  - The heterochromatic Y chromosomes of several Drosophila species harbor a small
      number of male fertility genes (fertility factors) with several unusual features.
      Expression of their megabase-sized loci is restricted to primary spermatocytes
      and correlates with the unfolding of species-specific lampbrush loop-like
      structures resulting from huge transcripts mainly derived from clusters of loop
      specific Y chromosomal satellites. Otherwise, there is evidence from genetic
      mapping and biochemical experiments that at least two of these loops, Threads in
      Drosophila hydei and kl-5 in D. melanogaster, colocalize with the genes for the
      axonemal dynein beta heavy chain proteins DhDhc7(Y) and Dhc-Yh3, respectively.
      Here, we make use of particular Threads mutants with megabase-sized deletions for
      direct mapping of DhDhc7(Y)-specific exons among the large clusters of satellite
      DNA within the 5.1-Mb Threads transcription unit. PCR experiments with exon
      specific primer pairs, in combination with hybridization experiments with exon-
      and satellite-specific probes on filters with large PFGE-generated DNA fragments,
      offer a simple solution for the long-lasting paradox between megabase-sized loops
      and protein-encoding transcription units; the lampbrush loops Threads and the
      DhDhc7(Y) gene are one and the same transcription unit, and the giant size of the
      DhDhc7(Y) gene as well as its appearance as a giant lampbrush loop are merely the
      result of transcription of huge clusters of satellite DNA within some of its 20
      introns.

PMID- 10655228
TI  - A genetic test of the mechanism of Wolbachia-induced cytoplasmic incompatibility
      in Drosophila.
AB  - Cytoplasmic bacteria of the genus Wolbachia are best known as the cause of
      cytoplasmic incompatibility (CI): many uninfected eggs fertilized by Wolbachia
      modified sperm from infected males die as embryos. In contrast, eggs of infected
      females rescue modified sperm and develop normally. Although Wolbachia cause CI
      in at least five insect orders, the mechanism of CI remains poorly understood.
      Here I test whether the target of Wolbachia-induced sperm modification is the
      male pronucleus (e.g., DNA or pronuclear proteins) or some extranuclear factor
      from the sperm required for embryonic development (e.g., the paternal
      centrosome). I distinguish between these hypotheses by crossing gynogenetic
      Drosophila melanogaster females to infected males. Gynogenetic females produce
      diploid eggs whose normal development requires no male pronucleus but still
      depends on extranuclear paternal factors. I show that when gynogenetic females
      are crossed to infected males, uniparental progeny with maternally derived
      chromosomes result. This finding shows that Wolbachia impair the male pronucleus
      but no extranuclear component of the sperm.

PMID- 10655229
TI  - Nested cladistic analysis indicates population fragmentation shapes genetic
      diversity in a freshwater mussel.
AB  - Recently developed phylogeographic analyses that incorporate genealogical
      relationships of alleles offer the exciting prospect of disentangling historical
      from contemporary events. However, the relative advantages and shortfalls of this
      approach remain to be studied. We compared the nested cladistic method to the
      more traditional analysis of variance approach in a study of intraspecific
      genetic variation in the freshwater mussel, Lampsilis hydiana. We surveyed 257
      specimens for nucleotide sequence level variation in a fragment of the
      mitochondrial 16S rRNA gene. When compared side by side, nested cladistic
      analysis and analysis of molecular variance (AMOVA) identified fragmentation of
      Arkansas river populations from remaining populations to the southwest. Nested
      cladistic analysis identified a second, more recent separation of Ouachita and
      Upper Saline river populations that was not detected by AMOVA. Differences among
      analytical methods probably arise from treatment of spatial hierarchical
      information: hierarchical groups emerge via a parsimony criterion in nested
      cladistic analysis but must be specified a priori in AMOVA. Both methods
      identified significant genetic structure among localities within hierarchical
      groups. Results from AMOVA suggested little gene flow among local populations
      with an island model. However, inferences about process that gave rise to
      patterns at this level were not possible in nested cladistic analysis, because an
      ancestral (interior) haplotype was not observed for a key one-step clade in the
      parsimony network. Our results suggest that, under some circumstances, nested
      cladistic analysis has lower power than more traditional analysis of variance to
      infer processes at the local population level.

PMID- 10655231
TI  - BALB/c alleles at modifier loci increase the severity of the maternal effect of
      the "DDK syndrome".
AB  - The Om locus was first described in the DDK inbred mouse strain: DDK mice carry a
      mutation at Om resulting in a parental effect lethality of F(1) embryos. When DDK
      females are mated with males of other (non-DDK) inbred strains, e.g., BALB/c,
      they exhibit a low fertility, whereas the reciprocal cross, non-DDK females x DDK
      males, is fertile (as is the DDK intrastrain cross). The low fertility is due to
      the death of (DDK x non-DDK)F(1) embryos at the late-morula to blastocyst stage,
      which is referred to as the "DDK syndrome." The death of these F(1) embryos is
      caused by an incompatibility between a DDK maternal factor and the non-DDK
      paternal pronucleus. Previous genetic studies showed that F(1) mice have an
      intermediate phenotype compared to parental strains: crosses between F(1) females
      and non-DDK males are semisterile, as are crosses between DDK females and F(1)
      males. In the present studies, we have examined the properties of mice
      heterozygous for BALB/c and DDK Om alleles on an essentially BALB/c genetic
      background. Surprisingly, we found that the females are quasi-sterile when mated
      with BALB/c males and, thus, present a phenotype similar to DDK females. These
      results indicate that BALB/c alleles at modifier loci increase the severity of
      the DDK syndrome.

PMID- 10655230
TI  - A mammalian homologue of GCN2 protein kinase important for translational control
      by phosphorylation of eukaryotic initiation factor-2alpha.
AB  - A family of protein kinases regulates translation in response to different
      cellular stresses by phosphorylation of the alpha subunit of eukaryotic
      initiation factor-2 (eIF-2alpha). In yeast, an eIF-2alpha kinase, GCN2, functions
      in translational control in response to amino acid starvation. It is thought that
      uncharged tRNA that accumulates during amino acid limitation binds to sequences
      in GCN2 homologous to histidyl-tRNA synthetase (HisRS) enzymes, leading to
      enhanced kinase catalytic activity. Given that starvation for amino acids also
      stimulates phosphorylation of eIF-2alpha in mammalian cells, we searched for and
      identified a GCN2 homologue in mice. We cloned three different cDNAs encoding
      mouse GCN2 isoforms, derived from a single gene, that vary in their amino
      terminal sequences. Like their yeast counterpart, the mouse GCN2 isoforms contain
      HisRS-related sequences juxtaposed to the kinase catalytic domain. While GCN2
      mRNA was found in all mouse tissues examined, the isoforms appear to be
      differentially expressed. Mouse GCN2 expressed in yeast was found to inhibit
      growth by hyperphosphorylation of eIF-2alpha, requiring both the kinase catalytic
      domain and the HisRS-related sequences. Additionally, lysates prepared from yeast
      expressing mGCN2 were found to phosphorylate recombinant eIF-2alpha substrate.
      Mouse GCN2 activity in both the in vivo and in vitro assays required the presence
      of serine-51, the known regulatory phosphorylation site in eIF-2alpha. Together,
      our studies identify a new mammalian eIF-2alpha kinase, GCN2, that can mediate
      translational control.

PMID- 10655232
TI  - Fixation of advantageous alleles in partially self-fertilizing populations. The
      effect of different selection modes.
AB  - The expected fixation probability of an advantageous allele was examined in a
      partially self-fertilizing hermaphroditic plant species using the diffusion
      approximation. The selective advantage of the advantageous allele was assumed to
      be increased viability, increased fecundity, or an increase in male fitness. The
      mode of selection, as well as the selfing rate, the population size, and the
      dominance of the advantageous allele, affect the fixation probability of the
      allele. In general it was found that increases in selfing rate decrease the
      fixation probability under male sexual selection, increase fixation probability
      under fecundity selection, and increase when recessive and decrease when dominant
      under viability selection. In some cases the highest fixation probability of
      advantageous alleles under fecundity or under male sexual selection occurred at
      an intermediary selfing rate. The expected mean fixation times of the
      advantageous allele were also examined using the diffusion approximation.

PMID- 10655233
TI  - Saturation mapping of a gene-rich recombination hot spot region in wheat.
AB  - Physical mapping of wheat chromosomes has revealed small chromosome segments of
      high gene density and frequent recombination interspersed with relatively large
      regions of low gene density and infrequent recombination. We constructed a
      detailed genetic and physical map of one highly recombinant region on the long
      arm of chromosome 5B. This distally located region accounts for 4% of the
      physical size of the long arm and at least 30% of the recombination along the
      entire chromosome. Multiple crossovers occurred within this region, and the
      degree of recombination is at least 11-fold greater than the genomic average.
      Characteristics of the region such as gene order and frequency of recombination
      appear to be conserved throughout the evolution of the Triticeae. The region is
      more prone to chromosome breakage by gametocidal gene action than gene-poor
      regions, and evidence for genomic instability was implied by loss of gene
      collinearity for six loci among the homeologous regions. These data suggest that
      a unique level of chromatin organization exists within gene-rich recombination
      hot spots. The many agronomically important genes in this region should be
      accessible by positional cloning.

PMID- 10655234
TI  - Quantitative trait loci and candidate gene mapping of bud set and bud flush in
      populus.
AB  - The genetic control of bud phenology in hybrid poplar was studied by mapping
      quantitative trait loci (QTL) affecting the timing of autumn bud set and spring
      bud flush. The founders of the mapping pedigree were collected from widely
      separated latitudes to maximize segregating variation for dormancy-related traits
      in the F(2) generation-the female Populus trichocarpa parent is from Washington
      State (48 degrees N) and the male P. deltoides parent is from Texas (31 degrees
      N). Bud set and bud flush timing were measured on the F(2) generation in a
      replicated clonal field trial. Using a linkage map constructed of AFLP and
      microsatellite markers, three QTL controlling bud set and six QTL controlling bud
      flush were detected. Additionally, five candidate genes believed to be involved
      in perception of photoperiod (PHYB1, PHYB2) or transduction of abscisic acid
      response signals (ABI1B, ABI1D, and ABI3) were placed on the QTL map. PHYB2 and
      ABI1B were found to be coincident with QTL affecting bud set and bud flush.

PMID- 10655235
TI  - Identification of ascorbic acid-deficient Arabidopsis thaliana mutants.
AB  - Vitamin C (l-ascorbic acid) is a potent antioxidant and cellular reductant
      present at millimolar concentrations in plants. This small molecule has roles in
      the reduction of prosthetic metal ions, cell wall expansion, cell division, and
      in the detoxification of reactive oxygen generated by photosynthesis and adverse
      environmental conditions. However, unlike in animals, the biosynthesis of
      ascorbic acid (AsA) in plants is only beginning to be unraveled. The previously
      described AsA-deficient Arabidopsis mutant vtc1 (vitamin c-1) was recently shown
      to have a defect in GDP-mannose pyrophosphorylase, providing strong evidence for
      the recently proposed role of GDP-mannose in AsA biosynthesis. To genetically
      define other AsA biosynthetic loci, we have used a novel AsA assay to isolate
      four vtc mutants that define three additional VTC loci. We have also isolated a
      second mutant allele of VTC1. The four loci represented by the vtc mutant
      collection have been genetically characterized and mapped onto the Arabidopsis
      genome. The vtc mutants have differing ozone sensitivities. In addition, two of
      the mutants, vtc2-1 and vtc2-2, have unusually low levels of AsA in the leaf
      tissue of mature plants.

PMID- 10655236
TI  - A genetic map of tomato based on BC(1) Lycopersicon esculentum x Solanum
      lycopersicoides reveals overall synteny but suppressed recombination between
      these homeologous genomes.
AB  - F(1) hybrids between the cultivated tomato (Lycopersicon esculentum) and the wild
      nightshade Solanum lycopersicoides are male sterile and unilaterally
      incompatible, breeding barriers that impede further crosses to tomato. Meiosis is
      disrupted in 2x hybrids, with reduced chiasma formation and frequent univalents,
      but is normal in allotetraploid hybrids, indicating the genomes are homeologous.
      In this study, a partially male-fertile F(1) was backcrossed to tomato, producing
      the first BC(1) population suitable for genetic mapping from this cross. BC(1)
      plants were genotyped at marker loci to study the transmission of wild alleles
      and to measure rates of homeologous recombination. The pattern of segregation
      distortion, in favor of homozygotes on chromosomes 2 and 5 and heterozygotes on
      chromosomes 6 and 9, suggested linkage to a small number of loci under selection
      on each chromosome. Genome ratios nonetheless fit Mendelian expectations.
      Resulting genetic maps were essentially colinear with existing tomato maps but
      showed an overall reduction in recombination of approximately 27%. Recombination
      suppression was observed for all chromosomes except 9 and 12, affected both
      proximal and distal regions, and was most severe on chromosome 10 (70%
      reduction). Recombination between markers on the long arm of this chromosome was
      completely eliminated, suggesting a lack of colinearity between S.
      lycopersicoides and L. esculentum homeologues in this region. Results are
      discussed with respect to phylogenetic relationships between the species and
      their potential use for studies of homeologous pairing and recombination in a
      diploid plant genome.

PMID- 10655237
TI  - De novo evolution of satellite DNA on the rye B chromosome.
AB  - The most distinctive region of the rye B chromosome is a subtelomeric domain that
      contains an exceptional concentration of B-chromosome-specific sequences. At
      metaphase this domain appears to be the physical counterpart of the subtelomeric
      heterochromatic regions present on standard rye chromosomes, but its conformation
      at interphase is less condensed. In this report we show that the two sequence
      families that have been previously found to make up the bulk of the domain have
      been assembled from fragments of a variety of sequence elements, giving rise to
      their ostensibly foreign origin. A single mechanism, probably based on synthesis
      dependent strand annealing (SDSA), is responsible for their assembly. We provide
      evidence for sequential evolution of one family on the B chromosome itself. The
      extent of these rearrangements and the complexity of the higher-order
      organization of the B-chromosome-specific families indicate that instability is a
      property of the domain itself, rather than of any single sequence. Indirect
      evidence suggests that particular fragments may have been selected to confer
      different properties on the domain and that rearrangements are frequently
      selected for their effect on DNA structure. The current organization appears to
      represent a transient stage in the evolution of a conventional heterochromatic
      region from complex sequences.

PMID- 10655238
TI  - Identification of heading date quantitative trait locus Hd6 and characterization
      of its epistatic interactions with Hd2 in rice using advanced backcross progeny.
AB  - A backcrossed population (BC(4)F(2)) derived from a cross between a japonica rice
      variety, Nipponbare, as the recurrent parent and an indica rice variety,
      Kasalath, as the donor parent showed a long-range variation in days to heading.
      Quantitative trait loci (QTL) analysis revealed that two QTL, one on chromosome
      3, designated Hd6, and another on chromosome 2, designated Hd7, were involved in
      this variation; and Hd6 was precisely mapped as a single Mendelian factor by
      using progeny testing (BC(4)F(3)). The nearly isogenic line with QTL (QTL-NIL)
      that carries the chromosomal segment from Kasalath for the Hd6 region in
      Nipponbare's genetic background was developed by marker-assisted selection. In a
      day-length treatment test, the QTL-NIL for Hd6 prominently increased days to
      heading under a 13.5-hr day length compared with the recurrent parent,
      Nipponbare, suggesting that Hd6 controls photoperiod sensitivity. QTL analysis of
      the F(2) population derived from a cross between the QTL-NILs revealed existence
      of an epistatic interaction between Hd2, which is one of the photoperiod
      sensitivity genes detected in a previous analysis, and Hd6. The day-length
      treatment tests of these QTL-NILs, including the line introgressing both Hd2 and
      Hd6, also indicated an epistatic interaction for photoperiod sensitivity between
      them.

PMID- 10655239
TI  - Single gene control of postzygotic self-incompatibility in poke milkweed,
      Asclepias exaltata L.
AB  - Most individuals of Asclepias exaltata are self-sterile, but all plants lack
      prezygotic barriers to self-fertilization. To determine whether postzygotic
      rejection of self-fertilized ovules is due to late-acting self-incompatibility or
      to extreme, early acting inbreeding depression, we performed three diallel
      crosses among self-sterile plants related as full-sibs. The full-sibs segregated
      into four compatibility classes, suggesting that late acting self-incompatibility
      is controlled by a single gene (S-locus). Crosses between plants sharing one or
      both alleles at the S-locus are incompatible. An additional diallel cross was
      done among full-sib progeny from a cross of a self-sterile and a self-fertile
      plant. These progeny grouped into two compatibility classes, and plants within
      classes displayed varying levels of self-fertility. This suggests that the
      occasional self-fertility documented in natural pollinations is caused by pseudo
      self-fertility alleles that alter the functioning of the S-locus.

PMID- 10655240
TI  - Comparative sequence analysis and patterns of covariation in RNA secondary
      structures.
AB  - A novel method of RNA secondary structure prediction based on a comparison of
      nucleotide sequences is described. This method correctly predicts nearly all
      evolutionarily conserved secondary structures of five different RNAs: tRNA, 5S
      rRNA, bacterial ribonuclease P (RNase P) RNA, eukaryotic small subunit rRNA, and
      the 3' untranslated region (UTR) of the Drosophila bicoid (bcd) mRNA.
      Furthermore, covariations occurring in the helices of these conserved RNA
      structures are analyzed. Two physical parameters are found to be important
      determinants of the evolution of compensatory mutations: the length of a helix
      and the distance between base-pairing nucleotides. For the helices of bcd 3' UTR
      mRNA and RNase P RNA, a positive correlation between the rate of compensatory
      evolution and helix length is found. The analysis of Drosophila bcd 3' UTR mRNA
      further revealed that the rate of compensatory evolution decreases with the
      physical distance between base-pairing residues. This result is in qualitative
      agreement with Kimura's model of compensatory fitness interactions, which assumes
      that mutations occurring in RNA helices are individually deleterious but become
      neutral in appropriate combinations.

PMID- 10655241
TI  - Linkage disequilibrium, gene trees and selfing: an ancestral recombination graph
      with partial self-fertilization.
AB  - It is shown that partial self-fertilization can be introduced into neutral
      population genetic models with recombination as a simple change in the scaling of
      the parameters. This means that statistical and computational methods that have
      been developed under the assumption of random mating can be used without
      modification, provided the appropriate parameter changes are made. An important
      prediction is that all forms of linkage disequilibrium will be more extensive in
      selfing species. The implications of this are discussed.

PMID- 10655242
TI  - Estimation of population parameters and recombination rates from single
      nucleotide polymorphisms.
AB  - Some general likelihood and Bayesian methods for analyzing single nucleotide
      polymorphisms (SNPs) are presented. First, an efficient method for estimating
      demographic parameters from SNPs in linkage equilibrium is derived. The method is
      applied in the estimation of growth rates of a human population based on 37 SNP
      loci. It is demonstrated how ascertainment biases, due to biased sampling of
      loci, can be avoided, at least in some cases, by appropriate conditioning when
      calculating the likelihood function. Second, a Markov chain Monte Carlo (MCMC)
      method for analyzing linked SNPs is developed. This method can be used for
      Bayesian and likelihood inference on linked SNPs. The utility of the method is
      illustrated by estimating recombination rates in a human data set containing 17
      SNPs and 60 individuals. Both methods are based on assumptions of low mutation
      rates.

PMID- 10655243
TI  - Comparative genomics, marker density and statistical analysis of chromosome
      rearrangements.
AB  - Estimates of the number of chromosomal breakpoints that have arisen (e.g., by
      translocation and inversion) in the evolutionary past between two species and
      their common ancestor can be made by comparing map positions of marker loci.
      Statistical methods for doing so are based on a random-breakage model of
      chromosomal rearrangement. The model treats all modes of chromosome rearrangement
      alike, and it assumes that chromosome boundaries and breakpoints are distributed
      randomly along a single genomic interval. Here we use simulation and numerical
      analysis to test the validity of these model assumptions. Mean estimates of
      numbers of breakpoints are close to those expected under the random-breakage
      model when marker density is high relative to the amount of chromosomal
      rearrangement and when rearrangements occur by translocation alone. But when
      marker density is low relative to the number of chromosomes, and when
      rearrangements occur by both translocation and inversion, the number of
      breakpoints is underestimated. The underestimate arises because rearranged
      segments may contain markers, yet the rearranged segments may, nevertheless, be
      undetected. Variances of the estimate of numbers of breakpoints decrease rapidly
      as markers are added to the comparative maps, but are less influenced by the
      number or type of chromosomal rearrangement separating the species. Variances
      obtained with simulated genomes comprised of chromosomes of equal length are
      substantially lower than those obtained when chromosome size is unconstrained.
      Statistical power for detecting heterogeneity in the rate of chromosomal
      rearrangement is also investigated. Results are interpreted with respect to the
      amount of marker information required to make accurate inferences about
      chromosomal evolution.

PMID- 10655244
TI  - Oxygen: modulator of metabolic zonation and disease of the liver.

PMID- 10655245
TI  - Microstructural evolution of lipid aggregates in nucleating model and human biles
      visualized by cryogenic transmission electron microscopy.
AB  - Obtaining reliable information on the physical state and ultrastructure of bile
      is difficult because of its mixed aqueous-lipid composition and thermodynamic
      metastability. We have used time-lapse cryogenic transmission electron microscopy
      (cryo-TEM) combined with video-enhanced light microscopy (VELM) to study
      microstructural evolution in nucleating bile. A well-characterized model bile and
      gallbladder biles from cholesterol and pigment gallstone patients were studied
      sequentially during cholesterol nucleation and precipitation. In model bile,
      cholesterol crystallization was preceded by the appearance of the following
      distinct microstructures: spheroidal micelles (3-5 nm), discoidal membrane
      patches (50-150 nm) often in multiple layers (2-10), discs (50-100 nm), and
      unilamellar (50-200 nm) and larger multilamellar vesicles (MLVs). The membrane
      patches and discs appeared to be short-lived intermediates in a micelle-to
      vesicle transition. Vesicular structures formed by growth and closure of patches
      as well as by budding off from vesicles with fewer bilayers. MLVs became more
      abundant, uniform, and concentric as a function of time. In native bile, all the
      above microstructures, except discoidal membrane patches, were observed. However,
      native MLVs were more uniform and concentric from the beginning. When cholesterol
      crystals appeared by light microscopy, MLVs were always detected by cryo-TEM.
      Edges of early cholesterol crystals were lined up with micelles and MLVs in a way
      suggesting an active role in feeding crystal growth from these microstructures.
      These findings, for the first time documented by cryo-TEM in human bile, provide
      a microstructural framework that can serve as a basis for investigation of
      specific factors that influence biliary cholesterol nucleation and crystal
      formation.

PMID- 10655246
TI  - The isolated artery: an intrahepatic arterial pathway that can bypass the lobular
      parenchyma in mammalian livers.
AB  - Controversy persists concerning the distribution of intrahepatic arterial
      termination. Apart from nourishing structures in the portal tract, several
      authors have suggested arterial supply to some isolated vascular beds that bypass
      the parenchyma, but this was not verified morphologically. In the present study,
      the existence of an isolated hepatic artery unaccompanied by a portal vein or a
      bile duct was shown in livers of pigs and other mammals including the dog, seal,
      ox, horse, and man. After colored media injection, liver blocks were sampled near
      the hepatic capsule and hepatic vein and subject to histologic assessment. The
      hepatic artery dissociated from superficial portal tract, ramified, and
      anastomosed extensively, forming a capsular plexus that drained at places into
      peripheral sinusoids in which resistive structural elaborations were observed.
      The artery also dissociated and fed an intramural plexus (vasa vasorum) of
      hepatic veins. This was collected into a vessel that penetrated the intima into
      the vein's lumen. In smaller sublobular veins, the plexus emptied into adjacent
      sinusoids; in central veins, the plexus was poorly developed. In canine and
      phocine livers, which have a special throttling musculature in sublobular veins,
      the isolated arterioles were numerous; in bovine and equine livers, which have a
      thick fibrous investment, the capsular plexus was well-developed. Occurrence of
      the isolated artery also was confirmed in the human but not in the rodent liver.
      In conclusion, the isolated artery is responsible for isolated vascular beds, in
      which the transintimal pathway can bypass the lobular sinusoids.

PMID- 10655247
TI  - Progressive development of a Th1-type hepatic cytokine profile in rats with
      experimental cholangitis.
AB  - Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are
      presumed autoimmune chronic cholestatic liver diseases characterized by
      cholangitis and progressive loss of bile ducts. Cytokines have been postulated to
      be involved in the progression of these diseases, but their role is poorly
      defined. Our objectives were to characterize a rat model of cholangitis and to
      determine Type 1/Type 2 (Th1/Th2) cytokine profile shifts in this model.
      Cholangitis was induced in Sprague-Dawley rats (200 to 225 g) by low-dose oral
      administration of the biliary toxin alpha-naphthylisothiocyanate (ANIT) (1 g/kg
      powdered rat chow ad libitum) for 4, 7, and 14 days. Cholestasis was observed in
      ANIT-treated animals. Liver histology of ANIT-treated rats showed hepatic
      inflammation centered on damaged bile ducts, significant bile duct proliferation,
      and progressive fibrosis. Immunohistochemistry showed enhanced staining of
      hepatic major histocompatibility complex (MHC) II, CD4, and CD8 in portal areas
      of ANIT-treated animals. In addition, the hepatic cytokine profile became
      increasingly Th1 in nature with progressive ANIT treatment. In summary,
      experimental cholangitis biochemically and histologically mimics human chronic
      cholangitis and furthermore, is associated with a progressive shift to a more Th1
      dominant hepatic cytokine profile. Therefore, this model may be useful for
      examining the role of cytokines in the progression of chronic cholangitic
      diseases.

PMID- 10655248
TI  - Photodynamic therapy for advanced bile duct cancer: evidence for improved
      palliation and extended survival.
AB  - Median survival time of nonresectable hilar bile duct cancer is only 4 to 6
      months owing to tumor spread in the biliary tree, refractory cholestasis, and
      sepsis or liver failure. We explored whether local photodynamic therapy of
      nonresectable bile duct cancer could improve survival. A sample size of 23
      patients is required to detect an increase in 6-month survival rate from less
      than 50% to greater than 70% in a single-arm phase-II trial with a statistical
      power of 80% (Fleming's single step procedure; alpha = 0.05). Twenty-three
      consecutive patients (8 women, 15 men; 67 +/- 14 years) with nonresectable bile
      duct cancer (Bismuth type III n = 2, type IV n = 21) were treated with
      photodynamic therapy and biliary endoprosthesis. Photofrin (QLT Pharmaceuticals,
      Vancouver, Canada) (2 mg/kg body weight intravenously) was photoactivated after 1
      to 4 days with laser light (630 nm; 242 J/cm(2)) via endoscopic retrograde
      access. The 6-month survival rate was 91% after diagnosis and 74% after start of
      photodynamic therapy (30-day mortality rate was 4%) at a median follow-up time of
      10.3 months after diagnosis. Causes of death were tumor progression (n = 9) and
      bacterial infections (n = 4). The median rate of local tumor response was 74%,
      54%, 29%, and 67% after the first, second, third, fourth, and fifth photodynamic
      therapy. Time to progression ranged from 3 to 8 months. All patients, except 1
      with diffuse liver metastases, improved in cholestasis, performance, and quality
      of life. Photodynamic therapy can prevent tumor occlusion of hilar bile ducts.
      The apparent benefit in survival time should be confirmed in a controlled trial
      versus palliation by endoprosthesis only.

PMID- 10655249
TI  - Association of diabetes, serum insulin, and C-peptide with gallbladder disease.
AB  - An inconsistent association has been found between gallbladder disease and
      diabetes mellitus. We hypothesized that insulin resistance rather than diabetes
      status may be a primary factor involved in gallstone formation. A total of 5,653
      adult participants in the third United States National Health and Nutrition
      Examination Survey without known diabetes underwent gallbladder ultrasonography
      and phlebotomy after an overnight fast for measurement of serum insulin, C
      peptide, and glucose. Gallbladder disease was defined as ultrasound-documented
      gallstones or evidence of cholecystectomy. Subjects were characterized as having
      normal fasting glucose (<110 mg/dL), impaired fasting glucose (110 to <126
      mg/dL), or undiagnosed diabetes (>/=126 mg/dL). After controlling for other known
      gallbladder disease risk factors, among women, undiagnosed diabetes was
      associated with increased risk of gallbladder disease (prevalence ratio [PR] =
      1.91, 95% confidence interval [CI] = 1.29-2. 83); whereas impaired fasting
      glucose was unassociated. Gallbladder disease risk in women increased with levels
      of fasting insulin (PR = 1.63, 95% CI = 1.11-2.40) and C-peptide (PR = 2.07, 95%
      CI = 1.32-3. 25) comparing highest to lowest quintiles. However, the association
      of gallbladder disease with undiagnosed diabetes was not diminished when the
      model included fasting insulin (PR = 1.85, 95% CI = 1.24-2. 77). In men, there
      was a statistically nonsignificant association with undiagnosed diabetes (PR =
      2.11, 95% CI = 0.76-5.85), but no association of gallbladder disease with insulin
      or C-peptide. Among women higher fasting serum insulin levels increased the risk
      of gallbladder disease, but did not account for the increased risk in persons
      with diabetes.

PMID- 10655250
TI  - Increased activity of guanosine 3'-5'-cyclic monophosphate phosphodiesterase in
      the renal tissue of cirrhotic rats with ascites.
AB  - A possible defect of guanosine 3'-5'-cyclic monophosphate (cGMP) content in the
      renal tissue caused by an increased activity of cGMP phosphodiesterase (PDE) has,
      so far, not been evaluated in the pathogenesis of renal resistance to endogenous
      natriuretic peptides (ENP) in cirrhosis with ascites. To test this hypothesis the
      activity of cGMP-PDE and the concentration of cGMP were evaluated in vitro in the
      renal tissue of 10 control rats and 10 cirrhotic rats with ascites before and
      after the intravenous (IV) administration of Zaprinast (Sigma, St. Louis, MO), a
      specific cGMP-PDE inhibitor (30 microgram/kg/min). Moreover, the effects of the
      intravenous administration of Zaprinast (15 microgram/kg/min and 30
      microgram/kg/min) on renal plasma flow (RPF), glomerular filtration rate (GFR),
      and urinary sodium excretion (U(Na)V) were evaluated in 10 conscious control rats
      and 10 conscious cirrhotic rats with ascites. The effects of Zaprinast on plasma
      renin activity (PRA) was also evaluated in 10 control rats and in 10 cirrhotic
      rats with ascites. Finally, the effect of Zaprinast on RPF, GFR, and U(Na)V were
      evaluated in 10 cirrhotic rats after the IV administration of the ENP-receptor
      antagonist, HS-142-1. The renal content of cGMP was reduced in cirrhotic rats
      because of increased activity of cGMP-PDE. Zaprinast inhibited cGMP-PDE activity
      and increased the renal content of cGMP in these animals. The inhibition of cGMP
      PDE was associated with an increase in RPF, GFR, and U(Na)V and a reduction in
      PRA. HS-142-1 prevented any renal effect of Zaprinast in cirrhotic rats. In
      conclusion, an increased activity of the cGMP-PDE in renal tissue contributes to
      the renal resistance to ENP in cirrhosis with ascites.

PMID- 10655251
TI  - Cost-effectiveness of different strategies of cytomegalovirus prophylaxis in
      orthotopic liver transplant recipients.
AB  - Cytomegalovirus (CMV) is an important cause of morbidity and mortality in liver
      transplant recipients and several different strategies of CMV chemoprophylaxis
      are in practice. A cost-effective analysis was performed to compare these
      strategies. A hypothetical cohort of liver transplant recipients was followed up
      for a year posttransplantation in a Markov model, as they made possible
      transitions to different states of health with respect to CMV infection and
      disease. Different strategies of chemoprophylaxis were compared. Cost per
      patient, yield in terms of gain in quality-adjusted stages, amount of time spent
      in the state of CMV disease, and CMV-related mortality were the outcome measures
      compared. Oral ganciclovir administered universally to all transplant recipients
      was the most favored strategy. Restricting prophylaxis to defined high-risk
      groups or extending the duration of prophylaxis beyond 3 months did not improve
      cost-effectiveness. The strategy of short-term, oral ganciclovir-based
      chemoprophylaxis for CMV in liver transplant recipients is cost-effective by
      current standards of healthcare interventions.

PMID- 10655252
TI  - Oral budesonide in the treatment of patients with primary biliary cirrhosis with
      a suboptimal response to ursodeoxycholic acid.
AB  - Ursodeoxycholic acid (UDCA) is a safe and effective medical therapy for most
      patients with primary biliary cirrhosis (PBC). However, some patients show an
      incomplete response to UDCA therapy. Treatment with corticosteroids may be of
      benefit although at the expense of systemic side effects. Budesonide, a
      corticosteroid with an extensive first-pass hepatic metabolism appeared promising
      for the treatment of PBC. The aim of this study was to evaluate the safety and
      estimate the efficacy of budesonide in patients with PBC, who have shown a
      suboptimal response to UDCA. Twenty-two patients with PBC, 16 women, median age
      of 50 who had been on UDCA (13-15 mg/kg/d) for a mean of 46 months (range 6-108
      months) and had shown a persistent elevation of alkaline phosphatase activity at
      least 2 times the upper limit of normal were enrolled. Oral budesonide, 9 mg
      daily was administered for 1 year and patients continued on the same dosage of
      UDCA. There was a significant, but transitory improvement in serum levels of
      total bilirubin (P =.001) and a significant, but marginal improvement in serum
      alkaline phsophatase (P =.001) with combination therapy. The Mayo risk score
      increased significantly (P =.02) and there was a significant loss of bone mass (P
      <.001) of the lumbar spine. Budesonide-induced hyperglycemia and cosmetic adverse
      effects were noted in 2 patients. In conclusion, oral budesonide appears to add
      minimal, if any, additional benefit to UDCA, and it is associated with a
      significant worsening of osteoporosis in patients with PBC.

PMID- 10655253
TI  - Long-term results of a clinical trial of nadolol with or without isosorbide
      mononitrate for primary prophylaxis of variceal bleeding in cirrhosis.
AB  - It is clearly established that beta-blockers decrease the risk of a first
      variceal bleeding in cirrhosis. We have recently shown that the addition of
      isosorbide mononitrate to nadolol decreases the rate of variceal bleeding in
      patients with cirrhosis and varices, compared with nadolol alone, after a median
      follow-up of 30 months. It is not established if the long-term treatment with the
      combination continues to be beneficial. Therefore, we assessed the long-term
      effect of this combination on first variceal bleeding, complications, and death.
      One hundred forty-six cirrhotic patients with esophageal varices included in a
      previously published multicenter, randomized study comparing nadolol (40-160
      mg/d) with the combination nadolol plus isosorbide mononitrate (10-20 mg 3 times
      per day) were followed up for up to 7 years (median follow-up, 55 months). The
      primary end-point was variceal bleeding of any severity. Twenty-four patients (16
      in the nadolol group, and 8 in the combination group) experienced variceal
      bleeding (log rank test, P =.02). Cumulative risk of bleeding was 29% and 12%,
      respectively (95% CI for the difference, 1%-23%). Two and 4 patients,
      respectively, had bleeding from portal hypertensive gastropathy (log rank test, P
      =.20). Thirty and 25 patients, respectively, died during follow-up (log rank
      test, P =.13). Twelve and 10 patients, respectively, had de novo occurrence of
      ascites during follow-up (log rank test, P =.29). In conclusion, nadolol plus
      isosorbide mononitrate is significantly more effective than nadolol alone in the
      long-term use. Side effects are few, and no deleterious effects on ascites
      occurrence or on survival occur after long-term use of this combination.

PMID- 10655254
TI  - Early detection of hepatocellular carcinoma increases the chance of treatment:
      Hong Kong experience.
AB  - The prognosis for patients with hepatocellular carcinoma (HCC) is poor because of
      the low chance of curative treatment. To increase the chance of intervention and
      to improve survival, early detection of subclinical HCC (SCHCC) by alpha
      fetoprotein (AFP) and/or ultrasonography (USG) screening is implemented in many
      countries. Three hundred six Chinese patients with HCC diagnosed between January
      1995 and December 1997 were recruited. They were categorized into two groups: 142
      patients (group 1) had SCHCC diagnosed by screening (AFP and/or USG), and 164
      patients (group 2) presented with symptomatic HCC. The tumor size was
      significantly smaller in group 1 compared with that of group 2 (3.5 cm vs. 8.1
      cm; P <.0001). A significantly higher proportion of patients had bilobar
      involvement, multifocal HCC, diffuse-type HCC, portal vein infiltration, and
      distant metastasis in group 2 when compared with group 1. Operability and
      feasibility of treatment by transcatheter intra-arterial chemoembolization (TACE)
      in group 1 patients (26.8% and 45.1%, respectively) were significantly better
      than in group 2 patients (7.9% and 32.3%, P <.0001 and P =.03, respectively). The
      cumulative survival rate was significantly higher in group 1 than in group 2 (P
      <.0001). For those who had surgical resection and those who had TACE, group 1
      patients had a higher cumulative survival rate compared with that of group 2
      patients (P =.04 and P =.0003, respectively). Screening for HCC by AFP and/or USG
      can identify tumors at an early stage, resulting in a higher chance of receiving
      treatment. Whether it can improve survival requires a further prospective,
      randomized study.

PMID- 10655255
TI  - Effects of the histamine H(1) receptor blocker, pyrilamine, on spontaneous
      locomotor activity of rats with long-term portacaval anastomosis.
AB  - To find out whether the changes in the brain histaminergic system are involved in
      the pathophysiology of portal-systemic encephalopathy, we examined the effects of
      histamine H(1) receptor blockade on spontaneous locomotor activity, feeding, and
      circadian rhythmicity in rats with portacaval anastomosis (PCA). Pyrilamine, an
      H(1) receptor blocker (15 mg/kg/day), was delivered with osmotic minipumps.
      Spontaneous locomotor activity was recorded for 72 hours in the open-field with
      an electromagnetic detector. Food intake was monitored twice daily at the end of
      the light (7 PM) and the dark (7 AM) phases for 3 days. Histamine H(1) receptor
      density in the suprachiasmatic nucleus (SCN) was examined with receptor
      autoradiography, employing [(3)H]pyrilamine. PCA surgery led to decreased
      movement time and velocity and flattened amplitude of the circadian rhythms of
      locomotion and feeding. In sham-operated rats, pyrilamine significantly decreased
      the movement time and velocity, as well as the total food consumption and
      completely abolished the circadian rhythmicity of locomotion. In contrast,
      pyrilamine increased the movement time and velocity in PCA-operated rats,
      particularly in the dark phase, and improved the precision of the circadian
      rhythms of locomotion and feeding. Histamine H(1) receptor density was not
      altered by PCA surgery, whereas pyrilamine treatment led to the complete blockade
      of H(1) receptors in both sham- and PCA-operated rats. We suggest that
      histaminergic imbalance has contributed to the generation and maintenance of the
      decreased spontaneous locomotor activity and altered circadian rhythmicity
      following PCA surgery in the rat, probably via an H(1) receptor-mediated
      mechanism.

PMID- 10655256
TI  - Inherited coagulation disorders in cirrhotic patients with portal vein
      thrombosis.
AB  - The prevalence and pathogenesis of portal vein thrombosis (PVT) in patients with
      cirrhosis without hepatocellular carcinoma are not clearly defined. The role of
      thrombophilic genetic factors is well established in other venous thrombotic
      diseases, as well as in noncirrhotic portal thrombosis. Recently, new, inherited
      thrombophilic disorders (factor V Leiden [FVL], mutation G20210A of prothrombin
      [PTHR A(20210)], and mutation TT677 of methylenetetrahydrofolate reductase [MTHFR
      C677-->T]) have been identified and associated with increased risk of venous
      thrombosis. The aim of our study was to investigate the role of these
      thrombophilic disorders in the pathogenesis of PVT in cirrhotic patients. Twenty
      three cirrhotic patients with PVT and 40 cirrhotics without PVT were included. A
      group of 184 patients with deep vein thrombosis (DVT) and 431 healthy persons
      served as controls. The FVL, PTHR A(20210), and MTHFR C(677)-->T genotypes were
      identified by a polymerase chain reaction and restriction analysis. The
      frequencies of FVL, PTHR A(20210) mutation, and homozygous MTHFR C(677)-->T were
      13%, 34.8%, and 43.5% in cirrhotic patients with PVT and 7.5%, 2.5%, and 5% in
      cirrhotic patients without PVT, respectively. Five patients in the former group
      had associated defects. A thrombophilic genotype was detected in 69.5% of the
      patients with PVT. Identification of this high-risk group may have implications
      in patients who are candidates for major surgery or liver transplantation, and
      may influence the duration of oral anticoagulation.

PMID- 10655257
TI  - Diurnal changes of fibrinolysis in patients with liver cirrhosis and esophageal
      varices.
AB  - Variceal bleeding, whose triggering mechanisms are largely unknown, occurs with a
      circadian rhythmicity, with 2 peaks, one greater, in the evening, and one
      smaller, in the early morning. We assessed some clotting and hemodynamic
      parameters, possibly involved in variceal hemorrhage, over a 24-hour period, at 4
      hour intervals, in 16 patients with cirrhosis and esophageal varices and in 9
      controls. At each time interval, tissue plasminogen activator (tPA) and tPA
      inhibitor-1 (PAI-1) antigens and activities and total euglobulin fibrinolytic
      activity were determined and portal-vein flow velocity, volume, and congestion
      index were measured by duplex-Doppler. Significant circadian rhythms were
      searched for by least-squares and cosinor methods. tPA activity showed a
      circadian rhythm in cirrhosis, with a peak of 2.85 times the trough value,
      calculated at 18:42, and remained over 2.5-fold until shortly after 22:00. Total
      fibrinolytic activity showed a similar pattern, which was statistically
      significant also in controls. tPA and PAI antigens also showed significant
      circadian rhythm both in controls and cirrhotics, with higher values in the
      morning. Among the portal hemodynamic parameters only the congestion index showed
      significant rhythmic changes and only in cirrhosis, with the highest values in
      the late evening, but with limited diurnal excursion (+/- 5.5%). In conclusion,
      we showed the existence of a circadian rhythm of fibrinolysis in cirrhosis, whose
      temporal distribution might suggest a role of fibrinolysis in variceal hemorrhage
      on the basis of the comparison to the known chronorisk of variceal bleeding.

PMID- 10655258
TI  - Cost-effectiveness analysis of transjugular intrahepatic portosystemic shunt
      (TIPS) versus endoscopic therapy for the prevention of recurrent esophageal
      variceal bleeding.
AB  - For the prevention of recurrent esophageal variceal bleeding, studies show that
      patients treated with transjugular intrahepatic portosystemic shunt (TIPS) have
      lower rebleeding rates compared with endoscopic therapy. However, TIPS is
      associated with higher rates of portosystemic encephalopathy and possibly higher
      costs. The aim of this study was to conduct a cost-effectiveness analysis
      comparing TIPS with endoscopic sclerotherapy and endoscopic ligation for the
      prevention of recurrent esophageal variceal bleeding. Data for rates of
      rebleeding, death, complications, and crossover from endoscopy to TIPS were
      obtained from the literature. Costs for procedures and hospitalizations were
      obtained from two medical centers. Sensitivity analyses were performed varying
      probabilities of key variables. The patient population consisted of a
      hypothetical cohort of cirrhotic patients successfully treated for esophageal
      variceal bleeding with endoscopic sclerotherapy who received prophylactic
      sclerotherapy, ligation, or TIPS over 1 year. Endoscopic patients would receive
      propranolol. Mortality was similar for the three groups. The number of bleeds per
      patient for sclerotherapy, ligation, and TIPS would be 0.39, 0.32, and 0.07,
      respectively. The total annual costs per patient for sclerotherapy, ligation, and
      TIPS were $23,459, $23,111, and $26,275, respectively. The incremental cost per
      bleed prevented for TIPS compared with sclerotherapy and ligation was $8,803 and
      $12, 660, respectively. The incremental cost per bleed prevented for TIPS
      compared with sclerotherapy or ligation was sensitive to the cost of TIPS and the
      TIPS stenosis rate. Ligation had lower costs and lower recurrent bleeding rates
      than sclerotherapy. Compared with endoscopic therapy, TIPS leads to lower
      recurrent variceal bleeding rates and it is more cost effective in the short term
      for the prevention of recurrent esophageal variceal bleeding.

PMID- 10655259
TI  - Treatment of Wilson's disease with zinc. XVII: treatment during pregnancy.
AB  - Therapy of Wilson's disease continues to evolve. In 1997, zinc acetate was added
      to the list of drugs approved by the Food and Drug Administration, which includes
      penicillamine and trientine. The mechanism of zinc's anticopper action is unique.
      It induces intestinal cell metallothionein, which binds copper and prevents its
      transfer into blood. As intestinal cells die and slough, the contained copper is
      eliminated in the stool. Thus, zinc prevents the intestinal absorption of copper.
      It is universally agreed that pregnant Wilson's disease patients should remain on
      anticopper therapy during pregnancy. There are numerous reports of such patients
      stopping penicillamine therapy to protect their fetus from teratogenicity, only
      to undergo serious deterioration and even death from renewed copper toxicity.
      Penicillamine and trientine have teratogenic effects in animals, and
      penicillamine has known teratogenic effects in humans. In this report we discuss
      the results of 26 pregnancies in 19 women who were on zinc therapy throughout
      their pregnancy. The evidence is good that zinc protects the health of the mother
      during pregnancy. Fetal outcomes were generally quite good, although one baby had
      a surgically correctable heart defect and one had microcephaly.

PMID- 10655260
TI  - Annexin 1 expression and phosphorylation are upregulated during liver
      regeneration and transformation in antithrombin III SV40 T large antigen
      transgenic mice.
AB  - We have used a transgenic animal model, which constitutively develops
      hepatocarcinoma (Antithrombin III SV40 T large Antigen: ASV), to study the
      involvement of Annexin 1 (ANX1) in liver regeneration and malignant
      transformation. Primary hepatocytes isolated from normal mice did not express
      ANX1. In contrast, ANX1 was strongly expressed in hepatocytes of transgenic mice
      during constitutive development of hepatocarcinoma. In ASV transgenic mice, an
      elevated ANX1 level preceded the appearance of the tumor, indicating that it
      could be a good marker in the diagnosis of cancer. One-third hepatectomy in
      normal mice resulted in stimulation of ANX1 synthesis and phosphorylation. This
      upregulation correlated with increased synthesis of EGF and consequently with
      increased phosphorylation of the EGF receptor (EGF-R). Stable transfection of a
      hepatocyte cell line derived from ASV transgenic mice (mhAT2) with antisense
      complementary DNA for ANX1 reduced the proliferation rate as well as cytosolic
      phospholipase A(2) (cPLA(2)) activity. Thus, ANX1 expression and phosphorylation
      could be a factor implicated in liver regeneration and tumorigenesis, either
      through modulation of cPLA(2) activity or EGF-R function.

PMID- 10655261
TI  - Repeated concanavalin A challenge in mice induces an interleukin 10-producing
      phenotype and liver fibrosis.
AB  - Weekly injections of Concanavalin A (Con A) were performed in BALB/c mice to
      evaluate the pattern of cytokine production and liver injury. High serum levels
      of tumor necrosis factor alpha (TNF-alpha), interleukin 2 (IL-2), IL-4, and
      interferon gamma (IFN-gamma) were found in the serum after the first 2 injections
      of Con A but rapidly decreased from the third injection. Conversely, IL-10 serum
      levels after repeated Con A challenge increased by 7 times from week 1 to 20. In
      vivo depletion studies indicated that CD4(+) T cells are essential in IL-10
      production. Hepatocyte necrosis was only observed after the first injections of
      Con A whereas centrilobular inflammatory infiltrates persisted up to 20 weeks.
      Perisinusoidal liver fibrosis was also increasingly detected in BALB/c mice,
      whereas no fibrous change was observed in nude mice after 6 weeks of Con A
      challenge. The number of stellate cells, detected by immunostaining, increased
      after 20 weeks of Con A injections. Liver cytokine messenger RNA (mRNA)
      expression after 20 weeks showed expression of transforming growth factor beta1
      (TGF-beta1), IL-10, and IL-4 whereas IL-2 was no more expressed. The present
      study shows that mice repeatedly injected with Con A develop liver fibrosis. The
      cytokine-release pattern observed after 1 injection of Con A is rapidly shifted
      towards an immunomodulatory phenotype characterized by the systemic production of
      large amounts of IL-10.

PMID- 10655262
TI  - The glutathione precursor L-2-oxothiazolidine-4-carboxylic acid protects against
      liver injury due to chronic enteral ethanol exposure in the rat.
AB  - L-2-oxothiazolidine-4-carboxylic acid (OTC) is a cysteine prodrug that maintains
      glutathione in tissues. Here, its effect on alcohol-induced liver injury in an
      enteral alcohol feeding model was investigated. Male Wistar rats were given
      control high-fat or ethanol containing diets enterally for 4 weeks. Treated rats
      received 500 mg/kg/d of dietary OTC. Ethanol delivery, weight gain, and the
      cyclic pattern of ethanol in the urine were not different between the OTC-ethanol
      and ethanol groups. After 4 weeks, serum aspartate transaminase (AST), necrosis
      and inflammation were elevated significantly by ethanol compared with appropriate
      high-fat controls, effects blocked by OTC. Moreover, ethanol elevated hepatic
      tumor necrosis factor alpha (TNF-alpha) messenger RNA (mRNA) and the nuclear
      transcription factor nuclear factor kappaB (NFkappaB) 2-3 fold. NFkappaB in
      isolated Kupffer cells was also increased by ethanol. These effects were all
      blocked by OTC treatment. Additionally, superoxide production was higher in
      Kupffer cells isolated from ethanol-treated rats, an effect blunted by OTC. OTC
      also increased circulating glutathione (GSH) levels about 2-fold; however, GSH
      levels were not affected by ethanol or OTC in livers from the groups studied.
      Surprisingly, GSH was elevated by ethanol and OTC treatment in isolated Kupffer
      cells about 2-fold. Moreover, GSH (Ki-10 micromol/L) and cysteinyl-glycine, but
      not oxidized glutathione (GSSG) or OTC, blunted the LPS-induced increase in
      calcium in isolated Kupffer cells, possibly by activating a glycine-gated
      chloride channel due to their structural similarity with glycine. Collectively,
      it is concluded that GSH is protective, in part, by increasing circulating GSH,
      which blunts activation of Kupffer cells via the glycine-gated chloride channel.

PMID- 10655263
TI  - Galectin-1 exerts immunomodulatory and protective effects on concanavalin A
      induced hepatitis in mice.
AB  - Galectin-1, an endogenous lectin with immunomodulatory activities, induces
      selective, Fas-independent apoptosis of activated T cells. The aim of the present
      study was to evaluate the effect galectin-1 exerts on concanavalin A (Con A)
      induced hepatitis, a T-cell-dependent model of liver injury. Con A administration
      resulted in liver injury, as shown by the increased transaminase plasma levels
      and liver DNA fragmentation, and caused spleen T-cell activation, which was
      associated with a strong increment in liver infiltrating T helper cells.
      Moreover, Con A injection leads to a marked increase in plasma tumor necrosis
      factor alpha (TNF-alpha) and interferon gamma (IFN-gamma) levels. Galectin-1
      pretreatment dose-dependently prevented both liver injury and T-helper cell liver
      infiltration induced by Con A. In vivo and in vitro experiments indicated that
      the protective effects of galectin-1 depend on the selective elimination of Con A
      activated T cells. In addition, galectin-1 almost completely prevented the Con A
      induced increase in plasma TNF-alpha and IFN-gamma, an effect that was, at least
      in part, independent on the elimination of activated T helper cells, because
      galectin-1 prevented lipopolysaccharide (LPS)-induced release of TNF-alpha and
      IFN-gamma also from macrophages in vitro, without affecting their viability. The
      present study suggests that galectin-1 is potentially useful in the treatment of
      T-cell-mediated human liver disorders.

PMID- 10655264
TI  - Impact of hyperthermic preconditioning on postischemic hepatic microcirculatory
      disturbances in an isolated perfusion model of the rat liver.
AB  - Sublethal hyperthermia and the following recovery from this heat exposure,
      referred to as hyperthermic preconditioning, elicits a transient state of
      tolerance to oxidative insults through an intracellular protective response:
      stress response. The impact of hyperthermic preconditioning on hepatic
      microcirculatory disturbance, which is one of the determinants of
      ischemia/reperfusion-induced injury of the liver, was investigated by using
      intravital fluorescence microscopy. Thirty minutes of ischemia and a subsequent
      120 minutes of reperfusion was induced in an in situ isolated perfusion model of
      Sprague-Dawley rats. Heat stress was given by whole-body hyperthermia, and a
      subsequent recovery was allowed for 18 or 48 hours, respectively. Postischemic
      decrease in sinusoidal perfusion rate and sinusoidal diameter, leukocyte
      stagnation in sinusoids, and leukocyte adhesion in postsinusoidal venules were
      significantly attenuated in both hyperthermia-pretreated groups. A recovery of
      bile production, a reduction of liver enzyme release, and an attenuation of
      tissue edema and histological damage were also observed. A marked expression of
      heat shock protein (HSP) 70 and heme oxygenase (HO-1)/HSP32 was correlatively
      observed in the liver tissue coincident with the induction of these protective
      effects. Hyperthermic preconditioning provides a continuous long-term and
      constant inhibitory effect (up to 48 hours after heat exposure) on postischemic
      injury of the liver through the attenuation of microcirculatory disturbances.
      These beneficial effects might be associated with a concomitant increase in HSP70
      and HO-1/HSP32 expression.

PMID- 10655265
TI  - Doxorubicin preconditioning: a protection against rat hepatic ischemia
      reperfusion injury.
AB  - Doxorubicin produces clinically useful responses in a variety of human cancers.
      However, the toxicity of doxorubicin has limited its usefulness. This side effect
      is mainly due to the doxorubicin-mediated free radical formation. Administration
      of doxorubicin (10 mg/kg body weight) to rats intravenously induces heme
      oxygenase-1 (HO-1) in the liver. The levels of HO-1 protein were first detected
      at 6 hours and peaked at about 18 to 24 hours after the injection. It is known
      that HO-1 plays a protective role against the oxidative injury. Therefore, we
      have examined the protective effect of doxorubicin preconditioning against the
      hepatic ischemia-reperfusion injury. Partial hepatic ischemia was produced in the
      left and medium lobes for 45 minutes followed by 120 minutes reperfusion. When
      low doses of doxorubicin (1 mg/kg body weight) was intravenously administered to
      rats 2 days before the ischemia, the serum alanine transaminase (ALT) levels in
      the preconditioning rat were clearly improved compared with those in the rat
      without preconditioning. Under this situation, zinc-protoporphyrin IX, a specific
      inhibitor of HO-1, was injected subcutaneously to rats at 3 and 16 hours before
      the ischemia, the ALT levels were not improved by doxorubicin preconditioning.
      Histopathologic examination also supported these results. Although the HO-1
      protein level was fairly low 2 days after the doxorubicin administration,
      significant amounts of HO-1 protein were detected. Our results indicated that the
      induction of HO-1 played a protective role against hepatic ischemia-reperfusion
      injury and that doxorubicin preconditioning is more clinically useful than other
      preconditioning methods.

PMID- 10655267
TI  - Support of sinusoidal endothelial cell glutathione prevents hepatic veno
      occlusive disease in the rat.
AB  - Depletion of sinusoidal endothelial cell glutathione (GSH) has been proposed as a
      common mechanism leading to hepatic veno-occlusive disease (HVOD). This study
      examines whether intraportal infusion of GSH can prevent HVOD in the
      monocrotaline rat model. HVOD was induced in rats with monocrotaline 160 mg/kg
      i.g. on day 0. GSH was infused intraportally by mini-osmotic pump. Monocrotaline
      decreased GSH in sinusoidal endothelial cells, but not in liver homogenate.
      Infusion of GSH, 2 micromol/hr starting day - 1, prevented the decrease in
      sinusoidal endothelial cell GSH and protected against histological and clinical
      evidence of HVOD. Protection by GSH was dose-dependent (0.5-2 micromol/hr). In
      rats receiving continuous GSH infusion, treatment with buthionine sulfoximine
      starting day - 2 decreased sinusoidal endothelial cell GSH and attenuated the
      protective effect of GSH against monocrotaline. GSH infusion starting 24 hours
      after monocrotaline ("glutathione rescue") offered substantial protection to most
      rats. N-acetyl-L-cysteine conferred protection, but N-acetyl-D-cysteine (an
      antioxidant that is not a precursor for GSH) had little or no protective effect,
      and 4-hydroxy TEMPO, a free radical scavenger, was not protective.
      Discontinuation of the GSH infusion 5 days after monocrotaline administration led
      to severe hepatic veno-occlusive disease on day 6. In conclusion, monocrotaline
      selectively depletes sinusoidal endothelial cell GSH. Intraportal infusion of GSH
      protects against monocrotaline toxicity, at least partially by maintaining
      sinusoidal endothelial cell GSH levels. Glutathione infusion started after
      monocrotaline is partially protective. Monocrotaline induces prolonged changes in
      the liver that remain suppressed as long as GSH is infused.

PMID- 10655266
TI  - The role of protein kinase B and mitogen-activated protein kinase in epidermal
      growth factor and tumor necrosis factor alpha-mediated rat hepatocyte survival
      and apoptosis.
AB  - Perturbation of hepatocyte growth regulation is associated with a number of liver
      diseases such as fibrosis and cancer. These diseases are mediated by a network of
      growth factors and cytokines that regulate the induction of hepatocyte
      proliferation and apoptosis. In this study, we have investigated the role of
      signaling pathways activated by tumor necrosis factor alpha (TNF-alpha) and
      epidermal growth factor (EGF) in the regulation of apoptosis induced by
      transforming growth factor beta(1) (TGF-beta(1)), because this physiological
      factor is believed to regulate spontaneous apoptosis in the liver. We show that
      pretreatment with (10 ng/mL) EGF or (25 ng/mL) TNF-alpha can suppress TGF-beta(1)
      induced apoptosis by 73% and 50%, respectively, in isolated rat hepatocytes.
      However, suppression of TGF-beta(1)-induced apoptosis by EGF and TNF-alpha occurs
      via different protein kinase signaling pathways. Using specific inhibitors, we
      show that suppression of apoptosis by EGF is dependent on activation of
      phosphoinositide 3-kinase (PI 3-kinase) and the extracellular signal regulated
      kinase (ERK) mitogen-activated protein (MAP) kinase pathways, but not p38 MAP
      kinase. In contrast, suppression of TGF-beta(1)-induced apoptosis by TNF-alpha
      does not require PI 3-kinase and protein kinase B (PKB or Akt)-mediated pathways,
      but is dependent on ERK and p38 MAP kinase activity. These data contribute to our
      understanding of the intracellular survival signals that play a role in normal
      liver homeostasis and in diverse pathological conditions.

PMID- 10655268
TI  - The ratio of ELR+ to ELR- CXC chemokines affects the lung and liver injury
      following hepatic ischemia/ reperfusion in the rat.
AB  - Hepatic ischemia/reperfusion (I/R) results in a neutrophil-dependent lung and
      liver injury. The process of neutrophil recruitment and activation in this injury
      is at least partially dependent on the presence of the ELR+ CXC chemokines. Other
      investigations have shown that ELR- CXC chemokines can block ELR+ CXC chemokine
      neutrophil recruitment and activation in vitro. To begin to investigate the role
      of the balance between these 2 types of molecules in vivo in neutrophil
      recruitment and activation following hepatic I/R, we used our rat model of lobar
      hepatic I/R and pretreated animals with pharmacologic doses of gamma-interferon
      (gamma-IFN). gamma-IFN is known to upregulate some of the ELR- CXC chemokines,
      including gamma-IFN-inducible protein (IP-10) and monokine-induced by gamma-IFN
      (MIG), as well as down-regulate ELR+ CXC chemokine production. Following hepatic
      I/R or sham laparotomy, hepatic and pulmonary levels of the ELR- chemokines, IP
      10 and MIG, and the ELR+ chemokines, rat cytokine-induced neutrophil
      chemoattractant (KC), macrophage inflammatory protein-2 (MIP-2), and epithelial
      neutrophil activating protein (ENA-78) were determined by ELISA, and lung and
      liver injury were assessed. In response to gamma-IFN, hepatic and pulmonary
      levels of the ELR- chemokines were increased and the levels of the ELR+
      chemokines were decreased. Immunohistochemical staining confirmed the hepatocyte
      as the source of these molecules, as well as the changes in chemokine levels in
      response to gamma-IFN. There was an associated significant decrease in liver and
      lung injury, although there was no significant decrease in neutrophil influx in
      either tissue. This suggests that the alteration in the balance of ELR+ to ELR-
      CXC chemokines results in a decrease in tissue injury through a mechanism other
      than through an alteration in tissue neutrophil levels.

PMID- 10655269
TI  - Endotoxin induces structure-function alterations of rat liver peroxisomes:
      Kupffer cells released factors as possible modulators.
AB  - We report that endotoxin treatment results in decreased amounts of peroxisomes as
      well as changes in structure and function of peroxisomal membranes. Peroxisomes
      isolated from the liver of control and treated animals showed a marked decrease
      in total protein, but no significant alteration in the sodium dodecyl sulfate
      polyacrylamide gel electrophoresis (SDS-PAGE) protein profile. However, the
      Western blot study of the peroxisomal beta-oxidation enzymes and catalase showed
      an increase in those enzymes in the peroxisomal peak of normal density in
      endotoxin-treated rats. Disintegration of peroxisomal membranes by carbonate
      treatment from endotoxin-treated liver and change in the fluidity of peroxisomal
      membranes suggests alterations in peroxisomal membrane structure. No such
      alterations were found in mitochondrial or microsomal membranes of endotoxin
      treated livers. The lipid analysis of these organelles showed that the only
      organelle affected was the peroxisome, with a significant decrease in the
      phospholipid and cholesterol concentrations. To understand the mechanism of
      endotoxin-mediated alterations in peroxisomes, we studied the possible role of
      Kupffer cell secreted soluble factors (tumor necrosis factor alpha [TNF-alpha])
      on the peroxisomal structure/function. Inactivation/elimination of Kupffer cells
      by gadolinium chloride before endotoxin treatment did not normalize the overall
      peroxisomal protein amount and the lipid composition of isolated peroxisomes.
      However, the levels of individual protein amount in remaining peroxisomes were
      normalized. Endotoxin also decreased peroxisomal beta-oxidation, and this was
      partially restored with gadolinium treatment. These results clearly show that
      peroxisomes are severely affected by endotoxin treatment and suggest that the
      damage to this organelle may contribute, at least in part, to endotoxin-induced
      hepatic cytotoxicity.

PMID- 10655270
TI  - Iron overload in cirrhosis-HFE genotypes and outcome after liver transplantation.
AB  - Previously, we found appreciable hepatic iron deposition in one third of our
      patients undergoing liver transplantation (LTx) with approximately 10% of cases
      having quantifiable iron in the range of that seen in hereditary hemochromatosis
      (HHC). The aim of this study was to compare clinical outcome in liver transplant
      patients with and without iron overload. We also sought to determine the
      prevalence of HFE mutations in liver transplant patients with iron overload. Of
      456 consecutive liver transplants, 41 explants had an hepatic iron index (HII)
      greater than 1.9, and these cases were compared to 41 matched liver transplant
      recipients without increased hepatic iron. Posttransplantation complications,
      along with patient and graft survival were monitored. HFE gene testing was
      performed using DNA-based techniques. Kaplan-Meier 5-year patient survival after
      LTx was significantly lower in cases with hepatic iron overload compared to
      matched controls without iron excess (48% vs. 77%; P =.045). Fatal infections
      (especially fungal) were more common in patients with iron overload (24% vs. 7%;
      P =.03). Of the 41 patients with a liver explant HII greater than 1.9, only 4
      were C282Y homozygotes. Patients with severe hepatic explant iron overload
      undergoing LTx have a reduced survival compared to liver transplant recipients
      without explant iron excess. The reduced survival was attributable mainly to
      fatal bacterial and fungal infections. Despite the iron overload, HFE gene
      mutations were uncommon in patients with hepatic explant hemosiderosis.

PMID- 10655271
TI  - Phosphatidylinositol 3-kinase and protein kinase C contribute to the inhibition
      by interleukin 6 of phosphoenolpyruvate carboxykinase gene expression in cultured
      rat hepatocytes.
AB  - The participation of phosphatidylinositol 3-kinase (PI3-kinase), protein kinase
      C, and mitogen-activated protein kinase (MAP-kinase) in the inhibition by
      interleukin 6 (IL-6) and insulin of phosphoenolpyruvate carboxykinase (PCK) gene
      expression was investigated in cultured rat hepatocytes. IL-6 or insulin
      inhibited the glucagon-stimulated increase in PCK messenger RNA (mRNA) by about
      70%. In the presence of either the PI3-kinase inhibitor, wortmannin, or the
      protein kinase C inhibitor, GF109203x, the inhibition by IL-6 was only about 40%,
      although it was abolished with both inhibitors in combination. Wortmannin alone
      but not GF109203x prevented the inhibition by insulin of glucagon-stimulated PCK
      gene expression. The MAP-kinase pathway inhibitor, PD98059, did not affect IL-6
      or insulin inhibition of PCK mRNA increase. When chlorophenylthio-cyclic 3',5'
      adenosine monophosphate (CPT-cAMP) was used instead of glucagon, IL-6 or insulin
      inhibited the increase in PCK mRNA by 75% and 85%, respectively. The inhibition
      by IL-6 was only about 50% in the presence of either wortmannin or GF109203x
      alone but was abolished with the combination of both inhibitors. The inhibition
      by insulin was only about 50% in the presence of GF109203x and was abolished by
      wortmannin. The inhibitors did not affect the inhibition by IL-6 or insulin of
      the glucagon-stimulated increase in cAMP. It is concluded that the inhibition by
      IL-6 of PCK gene expression involved both PI3-kinase and protein kinase C,
      whereas the inhibition by insulin required only PI3-kinase. The inhibition
      occurred downstream from cAMP formation. Hence, IL-6 and insulin may share, in
      part, common signal transduction pathways in the inhibition of PCK gene
      expression.

PMID- 10655272
TI  - The cost of hepatitis A infections in American adolescents and adults in 1997.
AB  - The incidence of hepatitis A has declined in the United States for several
      decades, leading to an increased number of susceptible adolescents and adults.
      Because clinical severity increases with age, hepatitis A infections in older
      individuals cause greater morbidity, mortality, and treatment costs. Because the
      economic burden of hepatitis A has not been well described, we estimated its
      costs, from the societal perspective, for patients infected at distinct ages. A
      case-series study described treatment patterns, work loss, and symptom duration.
      Disease outcomes were estimated by an expert panel. Economic losses were
      calculated by applying normative data reflecting treatment charges, employee
      compensation, and the value of housekeeping services. In the case-series study,
      mean treatment charges were $740 for nonhospitalized patients versus $6,914 for
      hospitalized patients (P <.001). Symptom duration (67.8 vs. 34.4 days, P <.001)
      and work loss (33.2 vs. 15.5 days, P <.01) were also greater for those
      hospitalized. Nationally, we estimate 63,363 symptomatic hepatitis A infections
      occurred among adolescents and adults during 1997, resulting in 8,403 hospital
      admissions and 255 deaths. Nearly 2.5 million days of symptomatic illness and
      829,000 work-loss days resulted, and 7,466 years of life were lost. Under base
      case assumptions, annual hepatitis A costs were estimated at $488.8 million. In
      sensitivity analyses, this estimate varied from $332.4 to $579.9 million. These
      costs may be reduced by regionally targeted vaccination of children, as
      recommended by the Advisory Committee on Immunization Practices, although the
      cost effectiveness of this policy has not yet been established.

PMID- 10655273
TI  - T(14;18) translocation in chronic hepatitis C virus infection.
AB  - Pathogenic mechanisms of B-cell lymphoproliferative disorders in chronic
      hepatitis C virus (HCV) infection are unclear. We studied t(14;18) translocation
      by polymerase chain reaction in peripheral blood mononuclear cells from 50
      patients with HCV-related liver disease (group A), 7 with mixed cryoglobulinemia
      syndrome (group B), 55 with HCV-negative liver disease (group C), and 30 with HCV
      negative chronic rheumatic disorders or chronic infection by nonhepatotropic
      agents (group D). T(14;18) was significantly more frequent in group A (13/50
      patients = 26 %) and group B (5/7 = 71.4%) patients than in group C (1/55 = 3.6%)
      and group D (1/30 = 3.3%) ones. Immunoblot analysis showed bcl-2 over-expression
      in all t(14;18)-positive samples. In group A, 10/13 (77%) patients with t(14;18)
      and 13/37 (35%) without t(14;18) had serum cryoglobulins in the absence of mixed
      cryoglobulinemia symptoms (P <.05). These data indicate that t(14;18) and bcl-2
      over-expression in lymphoid cells are frequent in chronic HCV infection and
      suggest that this event may contribute to the pathogenesis of HCV-related
      lymphoproliferative disorders.

PMID- 10655274
TI  - Reduced hepatitis B virus surface antigen-specific Th1 helper cell frequency of
      chronic HBV carriers is associated with a failure to produce antigen-specific
      antibodies in the trimera mouse.
AB  - In chronic hepatitis B virus (HBV) infection weak antiviral immune responses are
      associated with viral persistence. We studied possible immune deficits underlying
      the lack of serum antibodies of such patients against the HBV surface antigen
      (HBsAg) in a novel human/mouse chimeric model. A hepatitis B surface antigen
      (HBs) vaccination of Balb/c mice engrafted with peripheral blood mononuclear
      cells (PBMC) of naturally HBV-immunized donors induced high frequencies of human
      HBsAg-specific B and T helper 1 (Th1) cells. These responses were associated with
      high serum anti-HBs antibody levels of the subclasses immunoglobulin G1 (IgG1)
      and IgG2 that are driven by interleukin-2 (IL-2) and interferon-gamma (IFN
      gamma). In contrast, PBMC of chronic HBV carriers transplanted into the chimera
      failed to produce anti-HBs antibodies after vaccination with HBsAg and exhibited
      a deficit of antigen-specific Th1 cells. A possible influence of HBsAg or viremia
      was excluded by the lack of viral replication in such chimera. The observed T
      cell defect was specific for HBsAg, as the B- and T-cell responses to tetanus
      toxoid (TT) were fully retained. Thus, our study shows that viral persistence in
      chronic HBV carriers is associated with an HBsAg-specific Th1 cell defect, which
      likely is responsible for the insufficient neutralizing anti-HBs-antibody
      response and is not reversed by HBs vaccination. Alternative approaches to induce
      HBs-specific Th1 cell responses might represent a future therapeutic option.

PMID- 10655275
TI  - Latent hepatitis B virus infection in healthy individuals with antibodies to
      hepatitis B core antigen.
AB  - Several recent reports have shown that hepatitis B virus (HBV) could be
      frequently transmitted to the recipients from donors who have antibodies to
      hepatitis B core antigen (anti-HBc) through liver transplantation. We provide
      here the molecular evidence of latent HBV infection accompanied with ongoing
      viral replication in the liver tissue of anti-HBc-positive healthy individuals.
      HBV DNA was detectable in 13 of 14 healthy donors who were positive for both anti
      HBc and antibodies to hepatitis B surface antigen (anti-HBs), but in none of 3
      who were positive for anti-HBs alone. The detected HBV genomes from these
      subjects included covalently closed circular DNA and pregenomic RNA, the
      replication intermediate of HBV. Notably, 5 of 7 cases tested were predominantly
      infected with wild type HBV strains without any mutations in the precore and core
      promoter regions under the presence of circulating antibody to hepatitis B e
      antigen. Interestingly, a predominant clone detected in one donor showed a 63
      nucleotide deletion in the precore region including an encapsidation signal
      sequence. Our findings indicate that the majority of healthy individuals positive
      for anti-HBc, which had been assumed to denote a past history of transient HBV
      infection, were latently infected with the episomal form of HBV accompanied by
      ongoing viral replication and few nucleotide mutations in the precore and core
      regions.

PMID- 10655276
TI  - Hepatitis B immunoglobulin discontinuation followed by hepatitis B virus
      vaccination: A new strategy in the prophylaxis of hepatitis B virus recurrence
      after liver transplantation.
AB  - It is widely agreed that hepatitis B virus immunoglobulin (HBIG) should be
      administered for at least 12 months to patients transplanted for hepatitis B
      virus (HBV)-related diseases to prevent HBV recurrence. No data are available,
      however, on how long this treatment should be used, and most centers currently
      administer HBIG on a life-long basis. Herein, we report the results of a new
      prophylactic strategy aiming at the discontinuation of HBIG treatment and
      consisting of the administration of double dose recombinant HBV vaccine (0, 1-,
      and 6-month schedule) to liver transplant recipients fulfilling the following
      criteria: (1) liver transplantation for conditions related to nonreplicative HBV
      infection (hepatitis B surface antigen [HBsAg] positive, hepatitis B e antigen
      [HBeAg] negative, and HBV DNA negative); (2) at least 18 months of HBIG
      administration; and (3) no HBV infection recurrence, normal or slightly altered
      liver graft function, and low-grade immunosuppression at the time of vaccination.
      Seventeen patients received HBV vaccination and 14 of them (82%) developed
      protective serum titers of anti-HBs (>10 IU/L). Six patients seroconverted after
      a first course of vaccination, whereas 8 patients required a second course (3
      additional doses of vaccine). Responding patients were followed for a median of
      14 months (range, 3-50) after seroconversion. During this period no HBV
      recurrence occurred and in only 2 patients a decrease of anti-HBs titers below 10
      UI/L was observed. Our data suggest that in selected liver transplant recipients,
      posttransplantation HBV vaccination may be a useful and cost-effective strategy
      in the prophylaxis of HBV recurrence, allowing the discontinuation of life-long
      HBIG treatment.

PMID- 10655277
TI  - Pilot study of combination therapy with ribavirin and interferon alfa for the
      retreatment of chronic hepatitis B e antibody-positive patients.
AB  - Twenty-four patients with chronic hepatitis B virus (HBV), antibody to hepatitis
      B e antigen (anti-HBe), HBV DNA positivity, and alanine transaminase (ALT)
      elevation who failed previous interferon alfa (IFN-alpha) therapy were included
      in a pilot study of combination therapy with ribavirin and IFN-alpha. The
      patients received daily oral ribavirin (1,000-1,200 mg according to body weight)
      plus 5 million units (MU) IFN-alpha2b three times a week for 12 months and were
      followed-up for 12 months. The median viremia level decreased significantly at
      the end of treatment (1.2 x 10(3) copies/mL) and follow-up (4.0 x 10(2)
      copies/mL) compared with the baseline (3.0 x 10(6) copies/mL; P <.05). After 12
      months, 8 of 24 (33%) patients had cleared HBV DNA and 12 (50%) had normal ALT
      levels. At the end of the study virological and biochemical response was 50% and
      21%, respectively. Thus, virological and biochemical response sustained in 5 of
      24 (21%) patients retreated with ribavirin and IFN-alpha; none of them lost
      hepatitis B surface antigen (HBsAg). Liver histology improved in 2 of 4 sustained
      responders but in none of the 12 nonresponders with paired biopsies (P =.05). The
      response was independent of dose and duration of previous treatment, viral load,
      or the distribution of HBV precore wild-type/mutant variants. However, sustained
      responders had significantly higher necroinflammation (P =.036) and fibrosis (P
      =.007) scores. IFN-alpha-related side effects were mild and reversible on
      discontinuation. In 4 (17%) patients who suffered nausea and diarrhea the
      ribavirin dosage was reduced by 50% after 1 month of therapy and finally
      discontinued in all of them. No patient had liver disease decompensation. In
      summary, combination therapy with ribavirin and IFN-alpha may be efficacious to
      treat viremic anti-HBe-positive patients with chronic hepatitis B who have failed
      previous IFN therapy.

PMID- 10655278
TI  - Quantification of intrahepatic hepatitis B virus (HBV) DNA in patients with
      chronic HBV infection.
AB  - No data are available about the amount of hepatitis B virus (HBV) genomes in
      liver of patients with chronic HBV infection. The aim of this study was to
      quantify the intrahepatic HBV DNA in hepatitis B surface antigen (HBsAg)-positive
      patients with either active or suppressed viral replication and in HBsAg-negative
      subjects with occult HBV infection. We optimized the Roche "Amplicor HBV Monitor"
      kit for quantifying liver HBV DNA and analyzed hepatic DNA extracts and serum
      samples from 19 HBs-Ag-positive and 43 HBsAg-negative individuals. Eight of the
      HBsAg carriers had active HBV replication, and for 3 of them we analyzed samples
      obtained before and at the end of 1 year of lamivudine treatment. Five hepatitis
      Delta virus (HDV) coinfected patients and 6 healthy HBsAg carriers had inhibited
      HBV activity. Among the HBsAg-negative subjects 21 had occult HBV infection and
      22 had no evidence of HBV infection. The median of HBV genomes per microgram of
      liver DNA milliliter of serum was 34,500 to 2,620,000 in patients with active
      viral replication, 20,000 to 3,900, 000 before and 10,000 to 2,800 at the end of
      therapy in lamivudine-treated individuals, 9,800 to 600 in HDV-infected
      individuals, and 7,450 to 17,400 in healthy HBsAg carriers. These data indicate
      that cases with suppressed HBV activity, despite the very low levels of viremia,
      maintain a relatively high amount of intrahepatic viral genomes. This virus
      reservoir is likely involved in HBV reactivation, which is usually observed after
      stopping lamivudine treatment. Finally, the analysis of cases with occult HBV
      infection showed that the assay we used was able to specifically detect and
      quantify as few as 100 copies of viral genomes per microgram of liver DNA.

PMID- 10655279
TI  - Which patients with hepatitis C develop liver complications?
AB  - To identify variables that are independent predictors of adverse outcomes in
      chronic hepatitis C, we analyzed a cohort of 455 patients followed for a median
      of 4.7 years. Associations were sought between demographic and behavioral
      factors, hepatitis C virus (HCV) genotype, liver histology and liver tests at
      entry, and development of liver complications, hepatocellular carcinoma (HCC),
      hepatic transplantation and liver-related death. Independent predictors were
      identified by multivariate analysis. The following were associated with a
      significantly higher rate of liver complications: age; birth in Asia, Europe,
      Mediterranean region, or Egypt; transmission by blood transfusion or sporadic
      cases; HCV genotypes 1b and 4 (compared with 1/1a); fibrosis stage 3 or 4
      (cirrhosis); serum albumin; bilirubin; prothrombin time; and alpha-fetoprotein.
      However, the only independent predictors of liver-related complications were
      sporadic transmission (P <.001), advanced fibrosis (P =.004), and low albumin (P
      <.001). The corresponding independent risk factors for HCC were male gender (P =.
      07), sporadic transmission (P <.001), and albumin (P <.001); bilirubin (P =.02)
      was an additional predictor of transplantation or liver-related death. It is
      concluded that only patients with advanced hepatic fibrosis or cirrhosis, are at
      risk of developing hepatic complications of chronic hepatitis C during 5-year
      follow-up. Among such patients, abnormalities in serum albumin, bilirubin, or
      prothrombin time indicate a high probability of complications. Patients without
      definite risk factors for HCV (sporadic cases) are at higher risk of
      complications, possibly because of interaction between older age, duration of
      infection, country of birth, and HCV genotypes 1b and 4.

PMID- 10655280
TI  - Cellular and humoral immune responses induced by intradermal or intramuscular
      vaccination with the major hepatitis B surface antigen.
AB  - The vaccination route may influence the success of immunization against
      pathogens. The conventional intramuscular (i.m.) application of a vaccine
      containing the hepatitis B virus (HBV) surface antigen (HBsAg) led to protective
      anti-HBs antibody levels in the majority of vaccine recipients. In this study, we
      vaccinated healthy volunteers and a group of i.m. vaccine nonresponders via the
      intradermal (i.d.) route and analyzed the HBV-specific B-cell response as well as
      class-II- and class-I-restricted T-cell responses by (3)H-thymidine uptake,
      enzyme-linked immunosorbent assay (ELISA) and enzyme-linked immunospot assay
      (ELISPOT). The results were then compared with i.m. vaccinated controls. I.d.
      vaccinations were well tolerated and induced neutralizing anti-HBs antibodies in
      all naive vaccine recipients and, importantly, all but one former i.m.
      nonresponder developed protective anti-HBs serum antibody levels after 2 or 3
      i.d. immunizations. On the cellular level, i.d. vaccine recipients showed
      significantly higher anti-HBs producing B-cell frequencies and more vigorous
      class-II-restricted T-helper (Th) cell responses than i.m. controls. However,
      although the HBsAg-specific T cells were characterized by their cytokine release
      as Th1-like cells in both groups, human leukocyte antigen (HLA)-A2+ individuals
      who received the soluble HBsAg via the i.d. route developed higher peptide
      specific cytotoxic CD8+ T cell precursor (CTLp) frequencies. In conclusion, i.d.
      HBsAg vaccination is more effective even in former i.m. vaccine nonresponders
      with respect to antibody induction and specific B- and T-cell responses. The
      induction of virus-specific CTLp may provide the rationale to study the i.d.
      HBsAg vaccine in the treatment of chronic hepatitis B.

PMID- 10655281
TI  - Cholelithiasis and the insulin resistance syndrome.

PMID- 10655282
TI  - Wilson's disease and pregnancy.

PMID- 10655283
TI  - A cytotoxic drug against reperfusion injury?

PMID- 10655284
TI  - "Silent killer" or benign disease? The dilemma of hepatitis C virus outcomes.

PMID- 10655285
TI  - The Tangier disease gene encodes yet another pathophysiologically relevant atp
      binding cassette protein.

PMID- 10655286
TI  - Iron beware: a common HFE gene polymorphism may prevent the accurate molecular
      diagnosis of homozygous hemochromatosis in low-risk, but not high-risk groups.

PMID- 10655287
TI  - Antisperm antibodies: use of the mixed agglutination reaction (MAR) test using
      latex beads.

PMID- 10655288
TI  - Antisperm antibodies: comment on the use of the MAR test using latex beads

PMID- 10655289
TI  - What effect does hydrosalpinx have on assisted reproduction? The role of
      salpingectomy remains controversial.

PMID- 10655290
TI  - Reclassification of azoospermia: the time has come?

PMID- 10655291
TI  - Recombinant follicle stimulating hormone in in-vitro fertilization treatment
      clinical experience with follitropin alpha and follitropin beta.
AB  - The objective of this prospective study was to compare the outcome of ovarian
      hyperstimulation for in-vitro fertilization (IVF) using two different
      preparations of recombinant follicle stimulating hormone (FSH). The study was
      based on 296 consecutive IVF cycles in 1997, 199 performed using follitropin
      alpha (Gonal-F) and 97 performed using follitropin beta (Puregon). Outcome was
      compared regarding pregnancy rate, oestradiol and progesterone response,
      endometrial thickness, follicle number, number of retrieved oocytes, fertilized
      oocytes, sperm count and sperm motility. There was no significant difference in
      outcome of stimulation. Clinical pregnancy rate was similar, 29.1% for Gonal-F
      and 28.1% for Puregon. There was no difference in endometrial response,
      oestradiol response, number of smaller (12-15 mm) or larger (>15 mm) follicles,
      number of oocytes retrieved, fertilized, divided and replaced, in sperm counts or
      in sperm progressive motility. There was a lower follicle number in the Puregon
      group, but not statistically significant. The serum progesterone concentrations
      on the day of oocyte retrieval, however, were significantly lower in the Puregon
      group. In conclusion, it was not possible to find significant differences in the
      IVF programme with regard to stimulation outcome between Gonal-F and Puregon. The
      results of this study indicate that Gonal-F and Puregon may be equally suitable
      for use in ovarian stimulation for IVF.

PMID- 10655293
TI  - High serum oestradiol concentrations in fresh IVF cycles do not impair
      implantation and pregnancy rates in subsequent frozen-thawed embryo transfer
      cycles.
AB  - High oestradiol concentrations may be detrimental to the success of in-vitro
      fertilization (IVF) treatment. A total of 1122 women aged <40 years who were
      undergoing their first IVF cycle were evaluated retrospectively. Serum oestradiol
      concentrations on the day of human chorionic gonadotrophin (HCG) administration
      were categorized into three groups: group A <10 000 pmol/l; group B 10 000-20 000
      pmol/l and group C >20 000 pmol/l. In fresh cycles, group A had significantly
      lower pregnancy rates per transfer (16.2 versus 23.7% respectively, P = 0.005,
      chi(2)) and implantation rates (8.7 versus 11.7% respectively, P = 0.037,
      chi(2)), when compared with group B. The pregnancy rate per transfer in group C
      was significantly lower than that in group B (12.1 versus 23.7%, P = 0.049,
      chi(2)) and group C had the lowest implantation rate (6.4%). In frozen-thawed
      embryo transfer cycles, implantation rates in groups A, B and C were similar
      (7.5, 8.1 and 9.6% respectively) and the pregnancy rates were also comparable in
      all groups. In conclusion, high serum oestradiol concentrations in fresh IVF
      cycles may adversely affect implantation and pregnancy rates. Embryo quality
      seemed unaffected as excess embryos from different groups had similar
      implantation and pregnancy rates in frozen-thawed embryo transfer cycles. The
      reduced implantation was probably due to an adverse endometrial environment
      resulting from high serum oestradiol concentrations.

PMID- 10655292
TI  - Local tolerance, pharmacokinetics, and dynamics of ganirelix (Orgalutran)
      administration by Medi-Jector compared to conventional needle injections.
AB  - The feasibility of administering a relatively high dose of the gonadotrophin
      releasing hormone (GnRH) antagonist ganirelix by means of a needle-free injection
      device, which could be useful in the long-term treatment of sex-steroid-dependent
      disorders, was evaluated in a randomized, crossover study in 16 healthy females.
      Local tolerance and pharmacokinetics of ganirelix administered by MediJector
      versus conventional needle injections were compared. Additionally, the
      pharmacodynamic effect was evaluated. Two milligrams of ganirelix was
      administered s.c. once daily for 7 days by Medi-Jector or conventional needle in
      a randomized sequence, without a washout period. No apparent differences in local
      tolerance were observed. Most injections (87.5%) gave either no or only a mild
      reaction. Of the moderate reactions, swelling and redness were reported most
      frequently (overall 4.9 and 8.5% per injection, respectively). Administration by
      Medi-Jector was bioequivalent to conventional needle injection with respect to
      the peak concentration and area under the curve. A profound suppression of
      luteinizing hormone and follicle stimulating hormone was observed. Serum
      oestradiol and progesterone concentrations were relatively low prior to treatment
      and remained low during the entire study period. In conclusion, administration of
      a relatively high dose of ganirelix by Medi-Jector might be useful for long-term
      treatment of sex-steroid dependent disorders.

PMID- 10655294
TI  - Highly degenerated distal centrioles in rhesus and human spermatozoa.
AB  - In humans and other mammals except rodents, the spermatozoa contribute the
      proximal centriole during fertilization. The inheritance of the distal centriole
      is not yet fully clear. In the present work, the distal centrioles of rhesus and
      human spermatozoa have been studied by transmission electron microscopy. The
      round and elongating rhesus spermatids possess both proximal and distal
      centrioles. The distal centriole extends posteriorly as an axoneme while the
      proximal centriole produces a microtubular adjunct. Ejaculated rhesus and human
      spermatozoa have intact proximal centrioles, but the distal centrioles have
      degenerated. The central pair of microtubules of the axoneme extends continuously
      into the distal centriolar region up to the sperm head. Serial transverse and
      longitudinal sections of the sperm neck region reveal few scattered microtubule
      duplexes or triplets in the distal centriolar region. The loss of the centriolar
      microtubules is more extensive on the ventral side of the neck region, the side
      where the proximal centriole resides. The distal centriole degenerates caudally
      from the rostral area. Immunogold electron microscopy with anti-beta-tubulin
      antibody showed that the distal centriolar regions possess 50% fewer gold
      particles than the proximal centrioles, indicating a significant loss of
      centriolar microtubules in the distal centriolar region. The A-tubules of the
      remaining triplets are filled with a dense material, as observed in the axoneme.
      Thus, rhesus and human spermatozoa introduce only proximal centrioles intact,
      whereas the distal centrioles are mostly disorganized in the mature spermatozoa.

PMID- 10655295
TI  - Evidence for the involvement of blood flow-related mechanisms in the ovulatory
      process of the rat.
AB  - To elucidate whether any relationship exists between ovarian blood flow and
      ovulation rate, the effects on these parameters were examined in equine chorionic
      gonadotrophin/human chorionic gonadotrophin (eCG/HCG) (15I U/15I U) primed rats
      after bilateral ligation and severance of either the ovarian branch of the
      uterine artery and vein (UL), the ovarian artery and vein (OL) or both sites
      (UL+OL) in comparison to sham operations. Laser Doppler flowmetry demonstrated
      the presence of microcirculatory vasomotion and a reduction of blood flow after
      UL, OL and UL+OL performed during the intervals 0-3 h (78, 66 and 19% of
      pretreatment values respectively) and 6-9 h (68, 57 and 20%) after HCG.
      Experiments utilizing radioactive microspheres also indicated decreased ovarian
      blood flow by UL and OL. Ovulation rate was assessed 20 h after HCG in animals
      where ligations had been performed at 0, 3, 6 and 9 h after HCG. No ovulations
      were seen after UL+OL and significantly decreased ovulation rates ( approximately
      50% of sham operated animals) were seen after UL at 0 and 3 h and after OL at 0,
      6 and 9 h. Progesterone concentrations in blood 20 h after HCG were reduced by OL
      but not UL and ovarian weights were unaffected by ligation. It is concluded that
      acute blood flow reduction during the ovulatory interval reduces ovulation rate
      in the rat.

PMID- 10655296
TI  - Pre-ovulatory graafian follicles are cooler than neighbouring stroma in pig
      ovaries.
AB  - Using an infra-red camera, domestic pig ovaries were thermo-imaged almost
      instantaneously at laparotomy or within a closed abdomen by endoscopy. Rectal and
      jugular vein temperatures were recorded using thermo-probes. Graafian follicles
      (7-10 mm diameter) were cooler than ovarian stroma in all experimental models
      examined, and both compartments were cooler than rectal and jugular temperatures.
      The mean difference between follicles and stroma in 73 observations was 1.3 +/-
      0.1 degrees C. When thermo-imaged under the fimbriated extremity of the Fallopian
      tube, follicles and stroma could still be distinguished. Follicles cooled
      slightly more rapidly than adjoining stroma during the first 10 s of a 60 s
      recording interval, after which curves for the two tissues remained parallel.
      Arresting ovarian blood supply for 5 min had a negligible influence on the
      temperature differentials. Endoscopy in three models recorded mean differentials
      between follicles and stroma of 0.6 +/- 0.1 degrees C to 1.1 +/- 0.1 degrees C.
      It is concluded that temperature gradients do exist in the ovarian tissues of
      mature animals, and that these are generated at least in part as a consequence of
      endothermic reactions within Graafian follicles.

PMID- 10655297
TI  - Spatially regulated differentiation of endometrial vascular smooth muscle cells.
AB  - Angiogenesis within the human endometrium involves the development of arterioles
      and elaboration of a capillary network. It was postulated that maturation of
      these arterioles involves a spatially regulated process of vascular smooth muscle
      cell (VSMC) differentiation. The endometrial vascular tree was therefore examined
      immunohistochemically for evidence of longitudinal and radial gradients of VSMC
      phenotype. Twenty-three hysterectomy specimens and 15 first trimester decidual
      tissues were studied. Five cytoskeletal markers (alpha and gamma-smooth muscle
      (sm) actin, sm myosin, desmin, vimentin), three endothelial markers (CD31, CD34,
      factor VIII related antigen) and two steroid receptors (oestrogen and
      progesterone) were detected immunohistochemically. alpha-sm actin was present
      throughout the wall of basal arterial segments and extended longitudinally
      towards the endometrial surface. Sm myosin expression was more restricted
      longitudinally and radially within in the vascular tree. The expression of gamma
      sm actin was even more restricted than myosin. In first trimester decidua,
      however, gamma-sm actin was widely distributed within the wall of spiral arteries
      that were not invaded by trophoblast. Oestrogen and progesterone receptors were
      present in peri-vascular stromal cells but absent from vascular smooth muscle and
      endothelium. Endometrial VSMC differentiation involves a progressive increase in
      cytoskeletal complexity and occurs in a spatially regulated fashion.

PMID- 10655298
TI  - Isolation, characterization and long-term culture of human myometrial
      microvascular endothelial cells.
AB  - Angiogenesis, defined as the growth of new vessels from pre-existing vessels,
      involves microvascular rather than large vessel endothelial cells. Accordingly,
      microvascular endothelial cell (MEC) proliferation assays are an appropriate in
      vitro model of angiogenesis. We have developed a method for the isolation and
      long-term culture of large numbers of MEC from the human myometrium, tissue
      readily available from hysterectomy specimens. Human myometrial MEC were
      positively selected from tissue dissociated sequentially with collagenase and
      trypsin using Ulex europeaus antigen-1 (UEA)-coated dynabeads. Cultured
      myometrial MEC displayed characteristic endothelial phenotype and function for up
      to 14 passages: cobblestone morphology, formed capillary-like tubes on Matrigel,
      expressed CD31, Factor VIII-related antigen, bound UEA lectin, incorporated 1,1'
      dioctadecyl-1,3,3,3', 3'-tetramethylindocarbocyanine perchlorate-labelled
      acetylated low density lipoprotein, migrated and proliferated in response to
      basic fibroblast growth factor (bFGF) and vascular endothelial growth factor
      (VEGF), but not epidermal growth factor. Optimal growth of human myometrial MEC
      occurred in a simple medium comprising M199, 5 ng/ml bFGF, 15% human serum, 5%
      fetal calf serum (FCS) and heparin. Human serum was essential for growth,
      although there was a synergistic effect when FCS was included. Almost identical
      dose-response curves were obtained for bFGF- and VEGF-induced myometrial MEC
      proliferation in early and late passage cells. Therefore myometrial MEC are a
      good model for in-vitro studies of uterine angiogenesis, since they have a stable
      phenotype and proliferative responsiveness to VEGF and bFGF for up to 14
      passages.

PMID- 10655299
TI  - Distribution and epidermal growth factor receptor expression of primordial
      follicles in human ovarian tissue before and after cryopreservation.
AB  - The freezing of ovarian tissue and the growth of immature oocytes from primordial
      follicles is an interesting concept in ovarian tissue transplantation and in
      vitro fertilization. In this study, the morphology and distribution of primordial
      follicles were studied in ovarian tissue from 24 women before and after
      cryopreservation. Cryopreservation did not significantly change either the
      morphology or number per unit volume of morphologically normal follicles in
      frozen ovarian tissue. Primordial follicles were predominant, accounting for
      78.6% and 82.6% of total follicles in fresh and frozen ovarian tissues
      respectively. The distribution of follicles was extremely uneven in ovarian
      tissue. A large variation in follicle numbers was observed in ovarian tissue
      samples from patient to patient, and even in the same patient, indicating that
      the number of follicles counted in one sample of ovarian tissue may not represent
      the number of follicles in other tissue samples. Ovarian tissue could be frozen
      in the form of strips instead of fragments for fast processing and better
      viability of ovarian tissue in cryopreservation. The number of follicles in
      ovarian tissue declined with the increasing age of the patients. An
      immunohistochemical study showed that immunoreactivity for the epidermal growth
      factor (EGF) receptor was detected in primordial follicles of adult ovarian
      tissue. EGF receptor staining was most intense in the oocytes of primordial
      follicles. Weak staining for EGF receptor was observed in some surrounding
      pregranulosa cells. Immunohistochemical staining for EGF receptor was also
      present in the stromal cells of ovarian tissue, but to a much lesser degree.
      There was no significant difference in the immunohistochemical staining for EGF
      receptor in ovarian tissue before and after cryopreservation.

PMID- 10655300
TI  - Successful treatment of recurrent pelvic desmoid tumour with tamoxifen: case
      report.
AB  - The case report of a young woman with recurrent pelvic desmoid tumour
      successfully treated with tamoxifen is described. The desmoid tumour recurred
      within 6 months after the initial exploratory laparotomy. Tamoxifen therapy led
      to complete relief of ascites within 2 months and complete tumour regression by
      the end of the fourth month, and the patient has remained stable for 6 years.
      Without sacrificing pelvic organs or major vessels and preserving reproductive
      ability, tamoxifen should be considered as the first drug of choice in such a
      recurrent condition.

PMID- 10655301
TI  - In-vitro fertilization in a spontaneous cycle: easy, cheap and realistic.
AB  - The results of in-vitro fertilization in natural cycles (NIVF) in women with
      tubal infertility at our department are presented. The study had a prospective
      design. We needed 75 cycles in 50 patients to obtain one oocyte from each
      patient. Successful oocyte recovery rate was 67% per started cycle and 82% per
      oocyte retrieval. Thirty-five embryos were transferred and resulted in four
      ongoing pregnancies (5.3% per cycle, 6.5% per oocyte retrieval, 11.4% per embryo
      transfer and 11.4% per embryo). Six patients who participated in the study made a
      second attempt at NIVF. Five of them conceived of which four were ongoing.
      Cumulative ongoing pregnancy rates are 9. 8% per cycle, 11.9% per oocyte
      retrieval, 19.5% per embryo transfer and 19.5% per embryo. We conclude that NIVF
      is an easy, cheap and realistic method to obtain a pregnancy for patients with
      tubal infertility.

PMID- 10655302
TI  - Experience with the elective transfer of two embryos under the conditions of the
      german embryo protection law: results of a retrospective data analysis of 2573
      transfer cycles.
AB  - The German embryo protection law (Embryonenschutzgesetz, ESchG) does not allow
      embryo selection. Therefore, only as many oocytes at the pronuclear stage (PN),
      as are planned to be transferred, are allowed to be cultured. It is not known
      whether, under these conditions, it is possible to reduce the number of embryos
      for transfer without a corresponding reduction of the overall pregnancy rate
      (PR). We retrospectively analysed 2573 consecutive transfer cycles following
      either in-vitro fertilization (IVF) or IVF/intracytoplasmic sperm injection. Out
      of these cycles, 234, 329 and 792 were performed with one, two, and three embryos
      respectively, because only that number was available (non-elective transfer).
      Another 123 and 1095 transfer cycles were performed with two and three embryos,
      respectively, which were selected from a higher number of PN oocytes (elective
      transfer). The clinical ongoing PR were 3.9, 9.1 and 17.7% respectively for the
      groups with non-elective transfer of 1, 2 and 3 embryos, and 22.0 and 22.5% for
      the groups with elective transfers with two and three embryos, respectively.
      There was no statistically significant difference in PR between the two elective
      embryo transfer groups up to the age of 40 years. The multiple pregnancy rate was
      reduced by 7.9%. The reduction of the number of embryos transferred from three to
      two can be performed even under the conditions of the ESchG without an effect on
      the overall PR.

PMID- 10655303
TI  - Clinical use of a pronuclear stage score following intracytoplasmic sperm
      injection: impact on pregnancy rates under the conditions of the German embryo
      protection law.
AB  - The German embryo protection law does not allow embryo selection, but only
      selection of pronuclear stage (PN) oocytes. Only as many PN oocytes are allowed
      to be selected as are planned to be transferred. Therefore, a clinically
      applicable score to assess the quality of PN oocytes would be helpful. A recently
      published score was used under the conditions of the German embryo protection law
      in 74 non-selected, consecutive intracytoplasmic sperm injection cycles. Only
      criteria which could be evaluated at the PN stage were included, i.e. not
      criteria which could only be assessed after pronuclear membrane breakdown or the
      first cleavage division. Supernumerary PN oocytes were cryopreserved after
      selection. A mean PN score of <13 (sum of scores of all selected PN
      oocytes/number of selected PN oocytes) led to a pregnancy rate of 4%, a mean PN
      score of > or =13 to a pregnancy rate of 22%. Embryo morphology and cumulative PN
      were correlated (r = 0.52, P < 0.05). The negative predictive value was 92% at a
      threshold of 13 for the mean PN score. The use of this and perhaps additional
      scoring systems of PN stage oocytes might help to offer patients in Germany the
      transfer of two selected PN oocytes, which would reduce the multiple pregnancy
      rate.

PMID- 10655304
TI  - Public perception on infertility and its treatment: an international survey. The
      Bertarelli Foundation Scientific Board.
AB  - The first large survey on the public perception of infertility and its treatment
      was conducted in six European countries, the USA and Australia. A representative
      sample of 8194 adults was polled, using standard validated methodology. The
      results obtained highlighted the following major aspects: (i) infertility is
      perceived as a disease by less than half of the people surveyed (38%), in
      contrast to the accepted medical opinion; (ii) awareness about the definition and
      incidence of infertility is relatively low, despite the fact that half of the
      people polled claimed to know someone affected by infertility; (iii) close to 90%
      of the adults surveyed knew about in-vitro fertilization (IVF), but less than one
      quarter of them knew about the chances of success of this assisted reproductive
      technology; and (iv) when confronted with the knowledge that the cost of three
      IVF cycles is roughly equivalent to the cost of a hip replacement (a commonly
      reimbursed procedure), a large majority (70%) of the individuals interviewed
      agreed that IVF should be reimbursable.

PMID- 10655305
TI  - Cryoprotective agent and temperature effects on human sperm membrane
      permeabilities: convergence of theoretical and empirical approaches for optimal
      cryopreservation methods.
AB  - Previous reports have left unresolved discrepancies between human sperm
      cryopreservation methods developed using theoretical optimization approaches and
      those developed empirically. This study was designed to investigate possible
      reasons for the discrepancies. Human spermatozoa were exposed to 1 mol/l
      glycerol, 1 mol/l dimethyl sulphoxide (DMSO), 1 mol/l propylene glycol (PG) or 2
      mol/l ethylene glycol (EG) at 22, 11 and 0 degrees C, then returned to isosmotic
      media while changes in cell volume were monitored. Activation energies (E(a)) of
      the hydraulic conductivity (L(p)) in the presence of cryoprotective agents (CPA)
      (L(p)(CPA)) were 22.2 (DMSO), 11.9 (glycerol), 15.8 (PG), and 7.8 (EG) kcal/mol.
      The E(a) values of the membrane permeability to CPA (P(CPA)) were 12.1 (DMSO),
      10.4 (glycerol), 8.6 (PG) and 8.0 (EG) kcal/mol. These data indicated that even
      at low temperatures, EG permeates fastest. The high L(p)(CPA) in the presence of
      EG and low associated E(a) would allow spermatozoa to remain closer to
      equilibrium with the extracellular solution during slow cooling in the presence
      of ice. Collectively, these data suggest that the increase of the E(a) of L(p) in
      the presence of CPA at low temperature is the likely reason for the observed
      discrepancy between theoretical predictions of spermatozoa freezing response and
      empirical data.

PMID- 10655306
TI  - The relationship between fertility potential measurements on cryobanked semen and
      fecundity of sperm donors.
AB  - Sperm penetration assay (SPA) scores obtained from cryobanked semen were
      correlated with therapeutic insemination (TI) fecundity in a group of established
      sperm donors, thereby evaluating the efficacy of the SPA in screening donors for
      sperm banking. While the SPA has been used to separate fertile from infertile
      males, we altered assay conditions to use frozen semen and to distinguish
      performance among fertile donors. Three frozen ejaculates from 11 pregnancy
      proven donors were analysed. Of 905 TI cycles, 275 recipients achieved 95
      pregnancies. There were no significant relationships between fecundity and donor
      semen, washed sperm parameters, sperm recoveries or recipient age. A significant
      relationship was revealed between mean SPA scores (range 8.7-66.6
      penetrations/ovum) and donor fecundity (range 0.04-0.16, P < 0.03). Sperm
      concentration was varied in an effort to establish the most sensitive test
      condition. Using 0.25x10(6) motile spermatozoa/ml, a highly significant
      relationship was observed (P < 0.002). The four donors with the lowest SPA scores
      achieved the four lowest fecundities. It is concluded that a modified SPA can be
      used on frozen donor semen to estimate donor fertility potential. If applied
      routinely in donor semen banking, poor quality applicants could be excluded,
      thereby increasing pregnancy rates while decreasing donor screening costs.

PMID- 10655307
TI  - Correlation between semen parameters and sperm aneuploidy rates investigated by
      fluorescence in-situ hybridization in infertile men.
AB  - Spermatozoa from 32 infertile patients and 13 controls with normal semen
      parameters were analysed using dual and triple colour fluorescence in-situ
      hybridization (FISH) techniques, in order to investigate the rates of aneuploidy
      for chromosomes 13, 18, 21, X and Y. The patients were divided into three groups
      according to their karyotypes or the karyotypes of their offspring: 15 were
      infertile men with abnormal semen parameters and normal karyotypes (group 1), 13
      were infertile men with abnormal karyotypes and normal or abnormal semen (group
      2) and four were infertile men with abnormal semen and normal karyotypes but
      whose wives conceived a child (or a fetus) with a numerical chromosomal
      abnormality through an intracytoplasmic sperm injection cycle (group 3). Patients
      with abnormal semen parameters showed a significantly higher aneuploidy rate for
      the investigated chromosomes in their spermatozoa compared to controls (P <
      0.005). Our data suggest the presence of a correlation between poor semen
      parameters and an increase in aneuploidy rate of chromosomes 13, 18, 21, X and Y
      in spermatozoa (r = -0.81071, P < 0.002); therefore the risk of a chromosomal
      aneuploidy in spermatozoa seems to be inversely correlated to sperm concentration
      and total progressive motility. Patients with abnormal karyotypes showed a higher
      incidence of diploidy and chromosomal aneuploidies compared to controls (P <
      0.002). This strongly suggests the presence of an interchromosomal effect of the
      cytogenetic rearrangement. Men who fathered a child with an abnormal karyotype
      through intracytoplasmic sperm injection did not present a higher aneuploidy rate
      for the investigated chromosomes in spermatozoa compared to patients with
      infertility due to a similar male factor but showed higher incidence of
      chromosomal aneuploidy compared to normal controls.

PMID- 10655308
TI  - High frequency of sub-optimal semen quality in an unselected population of young
      men.
AB  - Male reproductive function seems to have deteriorated considerably during the
      past 4-5 decades. However, studies of the reproductive function in unselected
      populations have not previously been reported. As the large majority of young men
      in Denmark are subjected to a compulsory medical examination for military
      service, this provided a unique opportunity to study the reproductive function in
      an unbiased population. Altogether 891 young men delivered a blood sample in
      which reproductive hormones were measured. From 708 of these men data were also
      obtained on semen quality and testis size. The median sperm concentration was 41
      x 10(6)/ml (mean 57.4 x 10(6)/ml). Men with ejaculation abstinence above 48 h had
      slightly higher sperm concentrations (median 45 x10(6)/ml, mean 63.2 x 10(6)/ml),
      but even in this subgroup, 21 and 43% respectively had sperm counts below 20 x
      10(6)/ml and 40 x 10(6)/ml. Among men with no history of reproductive diseases
      and a period of abstinence above 48 h, as many as 18 and 40% respectively had
      concentrations below 20 and 40 x 10(6)/ml. Sperm counts were positively
      correlated with testis size, percentage normal spermatozoa and inhibin B, and
      negatively correlated with percentage immotile spermatozoa and follicle
      stimulating hormone. Possible causes for this high frequency of young men with
      suboptimal semen quality are obscure and need to be explored. Whether these
      findings apply for young male populations of comparable countries remains to be
      seen.

PMID- 10655309
TI  - Zona pellucida damage to human embryos after cryopreservation and the
      consequences for their blastomere survival and in-vitro viability.
AB  - The study objective was to quantify zona pellucida (ZP) damage in cryopreserved
      human embryos. The influence of two different freezing containers was
      investigated, and the influence of freezing damage on the survival and viability
      of the embryos evaluated. ZP damage did not differ according to whether embryos
      originated from in-vitro fertilization (IVF) cycles or from IVF cycles in
      association with intracytoplasmic sperm injection (ICSI). The freezing container,
      however, significantly influenced the occurrence of ZP damage after
      cryopreservation. More damage was observed when the embryos were frozen-thawed
      using plastic cryovials than using plastic mini-straws (16.6% versus 2.3%; P <
      0.0001). A clear association was found between blastomere survival and ZP
      intactness. Consequently, the percentage of embryos with 100% blastomere survival
      was higher when embryos were frozen-thawed using plastic mini-straws. The further
      cleavage of frozen-thawed embryos suitable for transfer was not different whether
      there was ZP damage or not; however, it was higher when there was 100% blastomere
      survival as compared with when some blastomeres were damaged (79.0% versus 43.7%;
      P < 0.0001). Consequently, more embryos suitable for transfer cleaved further
      when they were frozen-thawed using plastic mini-straws. In conclusion, the aim of
      a cryopreservation programme should be to have as many fully intact embryos as
      possible after thawing. Increased ZP damage might indicate a suboptimal
      cryopreservation procedure.

PMID- 10655310
TI  - Regulation of human and mouse oocyte maturation in vitro with 6
      dimethylaminopurine.
AB  - It has been postulated that premature shortening of the oocyte growth phase due
      to the recovery of oocytes from small diameter follicles may be responsible for
      the developmental anomalies associated with in-vitro maturation. 6
      Dimethylaminopurine (DMAP) was used to artificially lengthen the pre-maturation
      period of oocyte growth, in vitro, by inhibiting germinal vesicle breakdown in
      mouse and human oocytes. DMAP inhibited the meiotic maturation of mouse and human
      oocytes and the inhibition was fully reversible. The timing of polar body
      extrusion was accelerated in mouse oocytes following the withdrawal of DMAP;
      however, the kinetics of nuclear maturation in human oocytes was unaffected by
      exposure to DMAP. All mouse and human DMAP-treated oocytes that matured to
      metaphase II expressed histone H1 kinase activity. Fertilization rates in both
      DMAP-treated and control mouse and human oocytes were comparable, and human
      embryonic development was similar in control and DMAP-treated oocytes. However,
      blastocyst development was significantly reduced in DMAP-treated mouse oocytes (P
      < 0.05). It is concluded that lengthening the prematuration growth phase, by
      temporarily inhibiting kinase activity with DMAP, does not directly improve
      oocyte developmental competence but provides a useful tool for further
      investigating meiotic and developmentally related events in vitro by manipulating
      meiotic resumption.

PMID- 10655311
TI  - Cryopreservation reduces the ability of hamster 2-cell embryos to regulate
      intracellular pH.
AB  - Vitrification of hamster 2-cell embryos impairs the activity of both the
      Na(+)/H(+) antiporter and HCO(3)(-)/Cl(-) exchanger; the two transport proteins
      responsible for the regulation of intracellular pH (pHi). The activities of both
      the Na(+)/H(+) antiporter and HCO(3)(-)/Cl(-) exchanger were significantly
      reduced at 4 h following warming compared to freshly collected embryos. Normal
      levels of activity of both transporters were not restored until 6 h after
      warming. Thus, cryopreservation of cleavage stage hamster embryos has a
      detrimental effect on their ability to maintain intracellular ionic homeostasis.
      Impairment of these pHi regulatory proteins resulted in the pHi of embryos being
      significantly elevated from the control values of 1.2 to 7.35 for approximately 4
      h after warming. In addition, an elevated pHi value significantly impaired
      oxidative metabolism. Therefore, the loss in developmental competence of embryos
      following cryopreservation may in part be explained by a reduced ability to
      regulate intracellular pH that results in perturbations in metabolism and
      disruption of energy production.

PMID- 10655312
TI  - A single medium supports development of bovine embryos throughout maturation,
      fertilization and culture.
AB  - Oocytes and embryos are typically exposed sequentially to varying culture media
      in standard in-vitro protocols. Expenditures of energy may be required following
      each medium change to adjust to the changing environment. Therefore, a single
      base medium was evaluated for its ability to support in-vitro maturation,
      fertilization and pre-implantation development (IVM/F/C) of bovine oocytes and
      embryos. Four treatments were examined: a standard maturation [tissue culture
      medium (TCM) 199 with bovine calf serum (BCS)], fertilization (modified Tyrode's
      medium with albumin, lactate and pyruvate) and culture (hamster embryo culture
      medium/TCM with BCS) system (control) and three synthetic oviductal fluid (SOF)
      treatments; maturation in SOF with bovine serum albumin (SOFBSA), SOF with bovine
      calf serum (SOFBCS) or the control maturation medium (TCM199 with BCS; SOF199),
      followed by fertilization and culture in SOF medium. The percentage of total
      inseminated oocytes successfully developing to the morula and blastocyst stage
      did not differ (P > 0. 05) between treatments (control, 30.5 +/- 3.5; SOFBSA,
      24.6 +/- 3.2; SOFBCS, 22.4 +/- 4.7; SOF199, 27.3 +/- 3.2). Embryos cultured in
      SOFBCS (92.1 +/- 6.4) had significantly higher cell numbers (P < 0. 05) than
      those cultured in control (74.8 +/- 4.8) and SOFBSA (71.6 +/- 6.6) but not SOF199
      (81.2 +/- 6.8). In conclusion, a single medium can be used successfully
      throughout maturation, fertilization and pre-implantation embryo development.
      Moreover, inclusion of serum during maturation in the single medium system
      resulted in significantly greater cell numbers, possibly reflecting increased
      quality of the embryos produced.

PMID- 10655313
TI  - Comparison of in-vitro development of embryos originating from either
      conventional in-vitro fertilization or intracytoplasmic sperm injection.
AB  - In this retrospective study on 1628 consecutive cycles performed during a period
      of 4 years, development in vitro is compared of embryos obtained after either
      conventional in-vitro fertilization (IVF) or intracytoplasmic sperm injection
      (ICSI). At 39-42 h after insemination or injection, embryos obtained after ICSI
      were significantly (P < 0.01) further developed (mean cell number 3.48 +/- 0.03)
      as compared with those obtained after IVF (3.22 +/- 0.03), whereas after 63-66 h
      of in-vitro development this difference was no longer present (mean cell number
      6.11 +/- 0.15 versus 6.09 +/- 0.13 respectively). Culture of surplus embryos
      obtained after IVF resulted in a significantly higher (P < 0.001) mean incidence
      of blastocyst formation per cycle as compared with the ICSI group (31.8 +/- 1.9
      versus 23.0 +/- 1.4 respectively). Blastocysts from both groups consisted of
      comparable numbers of cells. Blastocyst formation was also significantly higher
      when embryos were cultured in groups (31.2 +/- 1.8) compared to single culture
      (23.1 +/- 1.5; P < 0.01), in human tubal fluid (HTF) medium (29.2 +/- 1.7)
      compared with IVF-50(TM) medium (24.2 +/- 1.6; P < 0.01), and when they were
      cultured under 5% O(2) (30.3 +/- 1.5) compared with 20% O(2) (21.7 +/- 1.7; P <
      0.01). In all culture conditions used, the mean incidence of blastocyst formation
      per cycle showed comparable differences in favour of the IVF group as compared
      with the ICSI group.

PMID- 10655314
TI  - Assessment of growth factor effects on post-thaw development of cryopreserved
      mouse morulae to the blastocyst stage.
AB  - The objective of this study was to assess the influence of specific factors on
      post-thaw development of mouse cryopreserved morulae. Thawed morulae (n = 206)
      were randomly distributed between 10 treatment groups: medium alone control (CT),
      Vero (VR) cells, leukaemia inhibitory factor (1 ng/ml), interleukin-6 (1 ng/ml),
      transforming growth factor (TGF) alpha (2 ng/ml), epidermal growth factor (EGF)
      (4 ng/ml), platelet-derived growth factor (1 ng/ml), insulin-like growth factor
      (IGF)-I (30 ng/ml), IGF-II (1 ng/ml) and TGFbeta (2 ng/ml). At 4, 8, 20, 30 and
      48 h, a digitized image of each thawed embryo was captured and stored for later
      analysis. The following parameters were examined: blastocoel formation,
      blastocyst expansion, zona thickness and hatching. At termination of the
      experiment, cell number per embryo was determined by bisbenzimide staining. When
      contrasted to the medium alone control, co-culture consistently accelerated the
      development of frozen-thawed morulae to the hatched blastocyst stage, allowing
      embryos to recover rapidly from any damage sustained during the cryopreservation
      process. While no single growth factor/cytokine was able to completely mimic the
      results achieved with co-culture, all of the growth factors impacted positively
      on at least one of the morphological parameters studied. Cell proliferation was
      significantly stimulated by just 48 h exposure to growth factors, either through
      co-culture or by direct media supplementation. Co-culture again yielded the best
      results with a mean cell count of 217 +/- 76 cells per blastocyst as compared
      with 131 +/- 36 in control medium alone. Amongst the factors tested, IGF-I, IGF
      II and EGF had the greatest impact, with mean cell counts of 172 +/- 50, 168 +/-
      50 and 179 +/- 55 respectively. Whereas only 5% of CT embryos developed to
      blastocysts with > 200 cells, 51% of thawed embryos placed on co-culture
      monolayers and 25-32% of embryos cultured with IGF-I, IGF-II or EGF had > 200
      cells. This study for the first time systematically describes the effect of
      culture regimen and growth factor additives on the post-thaw development of
      cryopreserved embryos.

PMID- 10655315
TI  - Glycine transport by single human and mouse embryos.
AB  - Mouse zygotes and early cleavage-stage embryos have previously been shown to
      utilize glycine as an organic osmolyte, accumulating it to oppose any decrease in
      cell volume. Such glycine uptake in early cleavage-stage mouse embryos is via the
      glycine-specific Gly transporter. Mouse embryos also possess swelling-activated
      channels which function to release osmotically active glycine and other osmolytes
      when cell volume becomes too large. In this study it was found that human
      cleavage-stage embryos also transported glycine via a similarly saturable,
      sarcosine-inhibitable transporter, implying that the Gly transporter also
      mediates glycine transport in human embryos. Mouse zygotes have previously been
      shown to accumulate more intracellular glycine when cultured at increased
      osmolarities for 24 h. It was found in the current study that this ability was
      lost as preimplantation mouse embryo development proceeded, and that early
      cleavage-stage human embryos may also be capable of such osmosensitive
      accumulation of glycine. Finally, using spare human eggs which had failed to
      fertilize or cleave, the presence of swelling-activated currents resembling those
      in mouse zygotes was demonstrated. These data indicate that osmoregulation in
      early human embryos occurs via similar mechanisms as in the mouse.

PMID- 10655316
TI  - Prognostic value of first polar body morphology on fertilization rate and embryo
      quality in intracytoplasmic sperm injection.
AB  - The association between oocyte morphology and subsequent fertilization rate and
      embryo quality in intracytoplasmic sperm injection (ICSI) is subject to
      considerable controversy. This retrospective study was carried out to investigate
      a possible prognostic value of first polar body morphology with regard to
      fertilization rate and embryo quality. A total of 70 consecutive ICSI cases was
      included in this study. The results showed that classification based on first
      polar body morphology revealed a significant correlation with fertilization rate
      (P < 0.025) and embryo quality (P < 0.001). Cytoplasmic criteria showed no
      correlation in this respect. Present data indicate that ICSI of oocytes with
      intact well-shaped first polar bodies yields higher fertilization rates and
      higher quality embryos.

PMID- 10655317
TI  - Congenital bilateral absence of the vas deferens, cystic fibrosis mutation
      analysis and intracytoplasmic sperm injection.
AB  - The aim of this study was to assess the outcome of intracytoplasmic sperm
      injection (ICSI) with fresh and frozen-thawed surgically retrieved spermatozoa
      from men diagnosed with congenital bilateral absence of the vas deferens (CBAVD).
      Twenty-seven azoospermic men with their partners were treated [25 with CBAVD and
      two with clinical cystic fibrosis (CF)]. CF gene mutation analysis and genetic
      counselling was provided. Spermatozoa were aspirated by microsurgical epididymal
      sperm aspiration (MESA), percutaneous epididymal sperm aspiration (PESA) or open
      testis biopsy. Of the men with CBAVD, 60% carried a single mutation, 20% were
      compound heterozygotes, and 20% had no CF mutation identified. Of the 28 sperm
      aspiration procedures, 86% had supplementary spermatozoa for cryopreservation
      with 83% of those samples assessed as satisfactory when thawed. Of 29 cycles with
      fresh spermatozoa a fertilization rate of 76% of oocytes injected and 17% embryo
      implantation rate occurred. Twenty-four cycles in which cryopreserved spermatozoa
      were used resulted in an oocyte fertilization rate of 69% and embryo implantation
      rate of 20%. Eighteen clinical pregnancies occurred with 14 live births without
      congenital anomaly. Two pregnancies were achieved following pre-implantation
      genetic diagnosis. It is concluded that the presence of CF mutations in the male
      partner does not compromise in-vitro fertilization treatment outcomes or the
      opportunity for healthy live births.

PMID- 10655318
TI  - Cystic fibrosis gene mutations and infertile men with primary testicular failure.
AB  - It has been proposed that the gene responsible for cystic fibrosis, called the
      cystic fibrosis transmembrane conductance regulator (CFTR) gene, may play an
      important role in the process of spermatogenesis. A group of azoospermic men with
      primary testicular failure underwent CFTR mutation analysis, including assessment
      of the intron 8 polythymidine tract (IVS8-T tract). An association was not found
      between CFTR mutations or the 5T variant of the IVS8-T tract and the primary
      testicular failure phenotype. This finding suggests that CFTR does not play a
      significant role in the aetiopathogenesis of primary spermatogenic dysfunction.
      Therefore, the abnormal testicular histological findings in some post-pubertal
      men with cystic fibrosis may be a result of nutritional deficiency or testicular
      obstruction rather than a primary defect in spermatogenesis. In addition, the
      decreased sperm count in oligozoospermic men with CFTR mutations may be secondary
      to partial reproductive tract obstruction and not abnormal spermatogenesis.
      Lastly, routine screening of men with primary testicular failure for CFTR gene
      mutations is not warranted.

PMID- 10655319
TI  - Fluorescence in-situ hybridization of sex chromosomes in spermatozoa and spare
      preimplantation embryos of a Klinefelter 46,XY/47,XXY male.
AB  - It has been suggested recently that 47,XXY germ cells are able to progress
      through meiosis to produce hyperhaploid spermatozoa. We report on a 46,XY/47,XXY
      Klinefelter patient whose spermatozoa were recovered from the ejaculate and used
      for intracytoplasmic sperm injection (ICSI). Fluorescence in-situ hybridization
      (FISH) analysis of the patient's spermatozoa and of spare preimplantation embryos
      with DNA probes specific for chromosomes X, Y and 18 revealed sex chromosome
      hyperploidy in 3.9% of the sperm nuclei analysed (2.23% XY18, 1.12% XX18, 0.56%
      YY18), while only three out of 10 spare embryos analysed were normal for
      chromosomes tested. The abnormalities included two diploid mosaic embryos with
      the majority of the blastomeres normal for the chromosomes tested, and five
      embryos with mostly abnormal blastomeres and chaotic chromosome X, Y and 18
      patterns. None of the embryos analysed showed a XXY1818 or XXX1818 chromosome
      complement. The frequency of sex chromosome hyperploidy in the spermatozoa of the
      mosaic Klinefelter patient was higher than the mean reported for karyotypically
      normal males, supporting the hypothesis that 47,XXY germ cells are able to
      complete meiosis and produce aneuploid spermatozoa. However, most of the
      spermatozoa analysed were normal for sex chromosomes, and ICSI of the patient's
      spermatozoa did not result in a spare embryo with a uniform 47,XXY or 47,XXX
      chromosome complement. Instead, fertilization produced a high percentage of
      mosaic embryos with chaotic chromosome arrangements.

PMID- 10655320
TI  - Decreased sperm function of patients with myotonic muscular dystrophy.
AB  - Myotonic muscular dystrophy (MMD) is a genetic disease caused by a defective
      enzyme, myotoninkinase. Male patients with MMD are reported to have reduced
      fertility. The purpose of this work was to study sperm capacitation and acrosome
      reaction in the ejaculates of sterile males with MMD and of healthy males
      (control group). The expression of the specific D-mannose receptors was explored
      by microscopic examination and by flow cytometry analysis. In addition, the
      binding patterns of Pisum sativum (PSA) lectin to acrosome content and outer
      acrosomal membrane in the spermatozoa of each group were analysed. Both the
      capacitation and the acrosome reaction in the spermatozoa of the MMD group were
      deficient and these findings strongly suggest that these anomalies may account
      for the sterility of these patients.

PMID- 10655321
TI  - Compound genetic factors as a cause of male infertility: case report.
AB  - A 40 year old healthy Chinese male with primary infertility was seen in a
      university male infertility and genetic counselling clinic. He presented with
      congenital bilateral absence of the vas deferens (CBAVD) and the finding of
      testis atrophy. Fine needle aspiration mapping of the testis identified and
      localized sperm production within the testicles for in-vitro fertilization (IVF)
      and intracytoplasmic sperm injection (ICSI). Careful evaluation of testicular
      cytology revealed late maturation arrest of spermatogenesis. Cystic fibrosis gene
      mutation analysis revealed heterozygosity for the 5T variant within the
      polypyrimidine tract of intron 8. Cytogenetic analysis revealed a pericentric
      inversion of chromosome 6 with break points at p12 and q21
      [46,XY,inv(6)(p12q21)]. This case illustrates that spermatogenesis is not
      necessarily normal with congenital bilateral absence of the vas deferens.
      Compound genetic defects may coexist and underlie male infertility.

PMID- 10655322
TI  - Maternal constraint on fetal growth patterns in the rhesus monkey (Macaca
      mulatta): the intergenerational link between mothers and daughters.
AB  - The gestational experience of a mother can influence the intrauterine environment
      she provides her own offspring, allowing prenatal events to affect pregnancy
      outcomes across several generations. Using a multigenerational database, we
      determined the reproductive consequences for rhesus monkeys descended from small
      for-date and large-for-date birth weight matrilines. Both the maternal half
      brothers and -sisters of large-for-date infants exhibited enhanced fetal growth,
      but for small-for-date probands, only the maternal half-sisters experienced
      significant intrauterine growth constraint. In addition, the growth-restricted
      females were at higher risk of poor reproductive outcomes in adulthood, and they
      perpetuated the matrilineal birth weight pattern by selectively constraining the
      fetal development of their daughters. Collectively, these findings suggest a
      mechanism for the intergenerational persistence of suboptimal pregnancy outcomes.

PMID- 10655324
TI  - Relationship between preterm delivery and maternal height in teenage pregnancies.
AB  - A retrospective study was performed in 613 singleton pregnancies born to mothers
      aged < or =19 years over a 4-year period to determine the relationship between
      maternal height and preterm delivery (<37 weeks). The pregnancies were grouped
      according to maternal height quartiles for comparison of maternal and infant
      characteristics, obstetric complications and pregnancy outcome. The incidences of
      preterm delivery and labour decreased from 17.5% and 15.6% respectively in the
      lowest quartile, to 8.5% and 7.1% respectively in the highest quartile, without
      any difference in the risk factors or major complications. In the pregnancies
      without major complications, which included 73.3% of the cases of preterm labour,
      the rate of preterm labour was significantly and inversely correlated with the
      height quartiles. In the newborns, gestational age, birthweight and crown-heel
      length increased with the higher quartiles, but the ratio between infant crown
      heel length and maternal height (height ratio) decreased with the higher
      quartiles. Unlike birthweight and crown-heel length, the height ratio was not
      correlated with gestational age. Our findings suggested that the inherent risk of
      preterm delivery in teenagers was related to their immature physical development
      at the time of pregnancy, as reflected by the maternal height.

PMID- 10655323
TI  - Factor V leiden and prothrombin G20210A mutations, but not
      methylenetetrahydrofolate reductase C677T, are associated with recurrent
      miscarriages.
AB  - The aim of this study was to investigate the relationship between recurrent
      miscarriages and factor V Leiden, prothrombin G20210A and C677T
      methylenetetrahydrofolate reductase (MTHFR) mutations. In this case-control study
      the prevalence of factor V Leiden, prothrombin G20210A and C677T
      methylenetetrahydrofolate reductase mutations was determined in a consecutive
      series of 80 recurrent miscarriage patients and 100 controls. Fifteen of 80
      recurrent miscarriage patients and four out of 100 controls carried the factor V
      Leiden mutation (19 versus 4%, P = 0.003, odds ratio 5.5, 95% confidence interval
      (CI): 1.7-17). Seven of 80 recurrent miscarriage patients and two of 100 controls
      were carriers of the prothrombin G20210A mutation (9 versus 2%, P = 0.038, odds
      ratio 4.6, 95% CI: 0.9-23.2). Six of 80 recurrent miscarriage women and 15 of 100
      controls were homozygotes for the C677T MTHFR mutation (8 versus 15%, P = 0.134,
      odds ratio: 0.4, 95% CI: 0.1-1.2). Our results suggest that the presence of
      factor V Leiden and prothrombin G20210A polymorphism, but not MTHFR C677T
      homozygosity, could be additional risk factors for recurrent miscarriages.
      Furthermore, it was suggested that the prevalence of factor V Leiden and
      prothrombin G20210A mutations is more prominent in second trimester, primary
      fetal losses and it is independent of the existence of additional pathology
      predisposing to recurrent fetal losses.

PMID- 10655325
TI  - Predictive value of plasma human chorionic gonadotrophin following assisted
      conception treatment.
AB  - A total of 429 pregnancies after assisted conception treatment was analysed,
      using receiver operator characteristic curves. The best balance between
      sensitivity and specificity for predicting viable (single and multiple births)
      and non-viable (fetal heart positive abortions, ectopic and biochemical
      pregnancies) outcomes was human chorionic gonadotrophin (HCG) 50 IU/l on day 14
      and 200 IU/l on day 21 after treatment. Utilizing these indices all pregnancies
      could be classified into one of four groups. In group A (day 14 HCG <50 IU/l and
      day 21 <200 IU/l), the probability of a birth was 0%, pregnancy loss 72% and
      ectopic pregnancy 28%. Conversely for group D (day 14 HCG >50 IU/l and day 21
      >1000 IU/l), the likelihood of a birth was 90%, pregnancy loss 8% and ectopic
      pregnancy only 1%. Between groups A and D there was, as expected, a gradually
      shifting balance in favour of a reduction in ectopic (28, 13, 3, 1%) and
      biochemical pregnancies (70, 36, 33, 2%) and an increase in fetal heart positive
      pregnancy losses (2, 6, 13, 7%) and births (0, 44, 50, 90%). The majority of
      multiple pregnancies (98%) occurred in group D. Two accurately linked HCG
      measurements allowed a greater predictive accuracy of pregnancy outcome than
      could be obtained using either alone.

PMID- 10655326
TI  - Acardiac twin pregnancy: associated with trisomy 2: case report.
AB  - Acardiac anomaly is a rare complication of multiple pregnancies. Arterial-to
      arterial vascular anastomoses between twins, in the presence of a fused placenta,
      develop in the first trimester. Consequently the pump twin provides the acardius
      with blood. The second case of acardiac twin pregnancy with cytogenetic analysis
      of the acardiac showing the karyotype 47,XX,+2 is presented. Literature of
      acardiac twin pregnancies with different cytogenetic results and cases with
      trisomy 2 are reviewed, and a hypothesis of genesis is put forward.

PMID- 10655327
TI  - Counselling couples and donors for oocyte donation: the decision to use either
      known or anonymous oocytes.
AB  - In order to avoid a long waiting period, the Centre for Reproductive Medicine of
      the Free University of Brussels suggests that couples in need of donor oocytes
      search for a donor among family and friends. Recipient couples can choose between
      two types of donation: known donation, i.e. treatment with the oocytes of the
      donor recruited by the couple, or anonymous donation, i.e. an exchange of the
      donor recruited by the couple with a donor recruited by another couple in order
      to ensure anonymity between donor and recipients. In total, 144 couples were
      counselled by a psychologist in the decision-making process with regard to the
      kind of donation to be used. Some 68.8% of the recipient couples preferred known
      donation. This choice was mainly motivated by reasons related to fears associated
      with anonymity, such as fear of the unknown origin of genetic material and the
      trust that couples had in 'their' donor. Almost one-third of the couples opted to
      use anonymous oocytes. The desire to establish explicit boundaries between the
      two families involved was the major motivation for this choice. Approximately 44%
      of the couples were willing to tell the child about the oocyte donation.

PMID- 10655328
TI  - Screening before and during the use of oral contraceptives and hormone
      replacement therapy. The ESHRE Capri Workshop Group.
AB  - Most users of oral contraceptives (OC), and many users of hormone replacement
      therapy (HRT) are apparently healthy, using a preparation for preventative
      purposes. It is understandable, therefore, that many clinicians feel that they
      should screen women using these preparations for hidden disease. Sometimes this
      has resulted in women being subjected to a variety of procedures. This
      medicalization of the provision of care can inhibit women from availing
      themselves of these services. All screening programmes must have evidence that:
      early detection will affect the natural history of the disease; the performance
      characteristics of the test must be known; the test should be cost-effective,
      acceptable to users and providers, should influence clinical decisions, and
      treatment should exist for abnormal results. The tests time to time suggested
      before and during the use of OC and HRT do not fulfill these needs. Whether any
      of the contraindications for OC use are present can be determined simply by
      taking a history and performing a physical examination including measurement of
      blood pressure. The same policy applies to the women who will start HRT. If
      facilities are available for screening mammography this test should be performed
      prior to starting HRT as the oestrogen can promote the growth of an existing
      subclinical breast cancer. It is not cost effective to perform an endometrial
      biopsy in women without abnormal genital bleeding prior to starting HRT. Routine
      measurement of bone density is also not cost effective or necessary since no
      current available agent reduces the risk of fractures in women with osteoporosis
      more than HRT.

PMID- 10655329
TI  - Luteal support with vaginal or oral micronized progesterone.

PMID- 10655330
TI  - A comparison of three GnRH analogues in an IVF programme.

PMID- 10655331
TI  - Simplified hepatitis C virus genotyping by heteroduplex mobility analysis.
AB  - Heteroduplex mobility analysis (HMA) was used to genotype hepatitis C viruses
      (HCV) with PCR fragments derived from the 5' untranslated region (5'-UTR) or the
      NS5b region. HCV 5'-UTR fragments were amplified from 296 serum samples by use of
      a combined reverse transcription-PCR assay, and the genotypes of isolates were
      determined by sequencing. HCV genotype distributions in Australia were 39% for
      genotype 1a, 15% for 1b, 3% for 1a/b, <1% for 2a/c, 5% for 2b, 34% for 3a, <1%
      for 3b, and 1% for 4, and 1% of patients were infected with more than one
      genotype. Pairwise HMA of subtypes 1a, 1b, 2a/c, 2b, 3a, 3b, 4a, and 6a
      demonstrated that five distinct heteroduplex patterns were formed between the
      eight subtypes. A reference panel that contained a representative of each pattern
      (1a, 2b, 3a, 4a, and 6a) was used for genotyping. The pattern of heteroduplexes
      formed when a test isolate was mixed with the five reference isolates was
      correlated with the genotype, as determined by sequencing. Genotypes determined
      by HMA correlated exactly with sequencing results within the groups 1, 2, 3a,
      3b/4, and 6. HMA was also used to simplify the identification of mixed infection
      with two HCV genotypes. In further studies, with amplicons from the NS5b region,
      HMA classified isolates into their respective subtypes, and the heteroduplex
      mobility ratio correlated closely with nucleotide sequence variation at the
      isolate, subtype, and genotype levels. HMA provides an adaptable, inexpensive,
      and rapid method of genotyping HCV that requires fewer resources than DNA
      sequencing.

PMID- 10655332
TI  - Sequence analysis and clinical significance of the iceA gene from Helicobacter
      pylori strains in Japan.
AB  - The Helicobacter pylori iceA gene was recently identified as a genetic marker for
      the development of peptic ulcer in a Western population. To assess the
      significance of iceA subtypes of H. pylori in relation to peptic ulcer, 140
      Japanese clinical isolates (88 from Fukui and 52 from Okinawa) were
      characterized. Sequence analysis of the iceA1 gene from 25 representative
      Japanese strains was also carried out to identify the differences in iceA between
      the ulcer group and the gastritis group. The iceA1 genotype was not correlated
      with the presence of peptic ulceration in either area. In addition, sequence
      analysis led to identification of five deletions and five point mutations (a
      nonsense mutation or a 1-bp insertion) within the iceA1 open reading frame
      corresponding to previously published sequences. These mutations were identified
      in both clinical groups (ulcer and gastritis groups) in each area. Local DNA
      sequence analysis revealed that the endpoints of all five deletions coincided
      with direct repeats. We also found four strains that carried longer iceA1 open
      reading frames compared with that for strain 60190. In conclusion, carriage of an
      iceA1 strain does not seem to be a risk factor for peptic ulcer in Japanese
      subjects. The critical mutations in the iceA1 gene in some isolates from patients
      with peptic ulcers suggested that IceA does not participate in the pathogenesis
      of peptic ulcer in Japan. We also found deletion hot spots that were associated
      with direct repeats in iceA1 and that favored a small-deletion model of slipped
      mispairing events during replication. We showed that iceA1 sequence variations
      may be useful tools for analysis of the population genetics of H. pylori.

PMID- 10655333
TI  - Fluorometric assessment of In vitro antidermatophytic activities of antimycotics
      based on their keratin-penetrating power.
AB  - Keratin particles impregnated with amorolfine or clotrimazole in serial doubling
      dilutions (64 to 0.125 microg/ml) were used to evaluate the activities of these
      agents against 20 isolates each of Trichophyton mentagrophytes and Trichophyton
      rubrum in a yeast carbon broth medium incorporating Alamar Blue dye. The proposed
      MIC with keratin impregnation (MIC(K)) is defined as the lowest concentration of
      an agent used to impregnate keratin particles that effects a fluorescence-based
      fungal growth quotient of 0.05 or less. The conventional colorimetric and visual
      MICs of amorolfine for the dermatophytes, </=0.03 microg/ml for T. mentagrophytes
      and </=0.063 microg/ml for T. rubrum, were approximately half of those of
      clotrimazole for the same isolates. The superiority of the MIC(K)s of amorolfine
      for isolates of T. mentagrophytes (2.0 microg/ml; range, 0.5 to 8.0 microg/ml)
      and T. rubrum (4.0 microg/ml; range, 2. 0 to 8.0 microg/ml) over those of
      clotrimazole (32 microg/ml [range, 8.0 to >64 microg/ml] and 64 microg/ml [range,
      16 to >64 microg], respectively) may indicate the strong in vivo
      antidermatophytic activity of amorolfine as a topical agent. The new
      antidermatophytic susceptibility testing procedure has potential clinical utility
      for the in vitro screening of agents for use in the topical treatment of
      superficial mycoses.

PMID- 10655334
TI  - Genetic heterogeneities and phenotypic characteristics of strains of the genus
      Abiotrophia and proposal of Abiotrophia para-adiacens sp. nov.
AB  - The genus Abiotrophia represents a heterogeneous group of fastidious cocci that
      show a dependence on pyridoxal hydrochloride analogs for growth. The genetic
      heterogeneity in the genus Abiotrophia was examined by DNA-DNA hybridization, PCR
      assay of genomic DNA sequences, and restriction fragment length polymorphism and
      sequence homology analyses of the PCR-amplified 16S rRNA gene. Nine type or
      reference strains of Abiotrophia defectiva, Abiotrophia adiacens, and Abiotrophia
      elegans and 36 oral Abiotrophia isolates including the ones presumptively
      identified as Gemella morbillorum by the rapid ID32 STREP system were divided
      into four groups: A. defectiva (genotype 1), A. adiacens (genotype 2), A. elegans
      (genotype 4), and a fourth species (genotype 3) which we propose be named
      Abiotrophia para-adiacens sp. nov. A PCR assay specific for detection and
      identification of the novel Abiotrophia species was developed. A. para-adiacens
      generally produced beta-glucosidase but did not produce alpha- or beta
      galactosidase or arginine dihydrolase, did not ferment, trehalose, pullulan, or
      tagatose, and was serotype IV, V, or VI. Thus, it was distinguished
      phenotypically from A. adiacens, A. elegans, and A. defectiva as well as,
      apparently, from the recently described species Abiotrophia balaenopterae sp.
      nov., which produces arginine dihydrolase and which ferments pullulan but not
      sucrose (P. A. Lawson et al., Int. J. Syst. Bacteriol. 49:503-506, 1999). Strain
      ATCC 27527, currently listed as G. morbillorum, was a member of the species A.
      para-adiacens.

PMID- 10655335
TI  - Evaluation of the oxyrase OxyPlate anaerobe incubation system.
AB  - The Oxyrase OxyPlate anaerobe incubation system was evaluated for its ability to
      support the growth of clinically significant anaerobic bacteria previously
      identified by the Anaerobe Reference Laboratory at the Centers for Disease
      Control and Prevention. The results were compared with those obtained with
      conventional anaerobe blood agar plates incubated in an anaerobe chamber. We
      tested 251 anaerobic bacterial strains. Plates were read at 24, 48, and 72 h;
      growth was scored by a numerical coding system that combines the degree of growth
      and the colony size. Organisms (number of strains tested) used in this study were
      Actinomyces (32), Anaerobiospirillum (8), Bacteroides (39), Campylobacter (8),
      Clostridium (96), Fusobacterium (12), Leptotrichia (8), Mobiluncus (8),
      Peptostreptococcus (16), and Propionibacterium (24). At 24 h, 101 (40.2%) of the
      251 strains tested showed better growth with the anaerobe chamber than with the
      OxyPlate system, 10 (4.1%) showed better growth with the OxyPlate system, and the
      remaining 140 (55. 8%) showed equal growth with both systems. At 48 h, 173
      (68.9%) showed equal growth with both systems, while 78 (31.1%) showed better
      growth with the anaerobe chamber. At 72 h, 176 (70.1%) showed equal growth with
      both systems, while 75 (29.9%) showed better growth with the anaerobe chamber.
      The OxyPlate system performed well for the most commonly isolated anaerobes but
      was inadequate for some strains. These results indicate that the Oxyrase OxyPlate
      system was effective in creating an anaerobic atmosphere and supporting the
      growth of anaerobic bacteria within 72 h. OxyPlates would be a useful addition to
      the clinical microbiology laboratory lacking resources for traditional anaerobic
      culturing techniques.

PMID- 10655336
TI  - Species identification of Mycobacterium avium complex isolates by a variety of
      molecular techniques.
AB  - Organisms in the Mycobacterium avium complex (MAC; M. avium, M. intracellulare,
      and "nonspecific or X" MAC) are emerging pathogens among individual organisms of
      which significant genetic variability is displayed. The objective of the present
      study was to evaluate various molecular methods for the rapid and definitive
      identification of MAC species. Isolates were obtained from both human
      immunodeficiency virus (HIV)-positive patients and HIV-negative patients with and
      without known predisposing conditions. The isolates were initially hybridized
      with nucleic acid probes complementary to the rRNA of the respective
      mycobacterial species (AccuProbe Culture Confirmation kits for M. avium, M.
      intracellulare, and MAC species; Gen-Probe). Isolates were also examined by PCR
      and in some cases by Southern blot hybridization for the insertion element
      IS1245. Two other techniques included a PCR assay that amplifies the mig gene, a
      putative virulence factor for MAC, and hsp65 gene amplification and sequencing.
      This study led to the following observations. Eighty-five percent of the isolates
      from HIV-positive patients were M. avium and 86% of the isolates from HIV
      negative patients were M. intracellulare. Fifteen of the M. avium isolates did
      not contain IS1245 and 7% of the M. intracellulare isolates were found to carry
      IS1245. All of the M. avium strains were mig positive, and all of the M.
      intracellulare strains were mig negative.

PMID- 10655337
TI  - Rapid identification of bacteria from positive blood cultures by fluorescence
      based PCR-single-strand conformation polymorphism analysis of the 16S rRNA gene.
AB  - Bacteremia continues to result in significant morbidity and mortality,
      particularly in patients who are immunocompromised. Currently, patients with
      suspected bacteremia are empirically administered broad-spectrum antibiotics, as
      definitive diagnosis relies upon the use of blood cultures, which impose
      significant delays in and limitations to pathogen identification. To address the
      limitations of growth-based identification, the sequence variability of the 16S
      rRNA gene of bacteria was targeted for rapid identification of bacterial
      pathogens isolated directly from blood cultures using a fluorescence-based PCR
      single-strand conformation polymorphism (SSCP) protocol. Species-specific SSCP
      patterns were determined for 25 of the most common bacterial species isolated
      from blood cultures; these isolates subsequently served as a reference collection
      for bacterial identification for new cases of bacteremia. A total of 272 blood
      culture-positive patient specimens containing bacteria were tested. A previously
      determined SSCP pattern was observed for 251 (92%) specimens, with 21 (8%)
      specimens demonstrating SSCP patterns distinct from those in the reference
      collection. Time to identification from blood culture positivity ranged from 1 to
      8 days with biochemical testing, whereas identification by fluorescence-based
      capillary electrophoresis was obtained as early as 7 h at a calculated cost of
      $10 (U.S. currency) per specimen when tested in batches of 10. Limitations
      encountered included the inability to consistently detect mixed cultures as well
      as some species demonstrating identical SSCP patterns. This method can be applied
      directly to blood cultures or whole-blood specimens, where early pathogen
      identification would result in a timely diagnosis with possible implications for
      patient management costs and the mortality and morbidity of infections.

PMID- 10655338
TI  - Antimicrobial resistance of Neisseria gonorrhoeae and high prevalence of
      ciprofloxacin-resistant isolates in Japan, 1993 to 1998.
AB  - To assess the antimicrobial resistance of Neisseria gonorrhoeae isolated from
      1993 through 1998 in Japan, susceptibility testing was conducted on 502 isolates.
      Selected isolates were characterized by auxotype and analysis for mutations
      within the quinolone resistance-determining region (QRDR) in the gyrA and parC
      genes, which confer fluoroquinolone resistance on the organism. Plasmid-mediated
      penicillin resistance (penicillinase-producing N. gonorrhoeae) decreased
      significantly from 1993-1994 (7.9%) to 1997-1998 (2.0%). Chromosomally mediated
      penicillin resistance decreased from 1993-1994 (12.6%) to 1995-1996 (1.9%) and
      then increased in 1997-1998 (10.7%). Chromosomally mediated tetracycline
      resistance decreased from 1993-1994 (3.3%) to 1997-1998 (2.0%), and no plasmid
      mediated high-level tetracycline resistance was found. Isolates with
      ciprofloxacin resistance (MIC >/= 1 microg/ml) increased significantly from 1993
      1994 (6.6%) to 1997-1998 (24.4%). The proline-requiring isolates were less
      susceptible to ciprofloxacin than the prototrophic or arginine-requiring
      isolates. Ciprofloxacin-resistant isolates contained three or four amino acid
      substitutions within the QRDR in the GyrA and ParC proteins.

PMID- 10655340
TI  - Molecular detection and epidemiology of Sapporo-like viruses.
AB  - Sapporo-like viruses (SLVs) are associated with acute gastroenteritis in humans.
      Due to a limited supply of available reagents for diagnosis, little is known
      about the incidence and pathogenicity of these viruses. We have developed a first
      generation generic reverse transcriptase (RT) PCR assay based on a single primer
      pair targeting the RNA polymerase gene. With this assay, 55 (93%) of the 59 stool
      specimens collected in a 10-year period of time (1988 to 1998) and containing
      typical caliciviruses by electron microscopy tested positive and could be
      confirmed by Southern hybridization. By phylogenetic analysis, most SLV strains
      could be classified into one of the three recently described genotypes. However,
      three samples clustered separately, forming a potential new genotype. We
      sequenced the complete capsid gene of one of the strains in this cluster:
      Hu/SLV/Stockholm/97/SE. Alignment of the capsid sequences showed 40 to 74% amino
      acid identity among strains of the different clusters. Phylogenetic analysis of
      the aligned sequences confirmed the placing of Hu/SLV/Stockholm/97/SE into a new
      distinct genetic cluster. This is the first report on the development of a
      broadly reactive RT-PCR assay for the detection of SLVs.

PMID- 10655339
TI  - Detection of carbapenemase-producing Acinetobacter baumannii in a hospital.
AB  - Acinetobacter baumannii strains resistant to both imipenem (IPM) and ceftazidime
      (CAZ) were isolated from 1994 through 1996 at Gunma University Hospital. Nine
      isolates from different inpatients were examined for carbapenem-hydrolyzing
      activity and for the carbapemase gene bla(IMP) by the PCR method. All nine
      isolates were carbapenemase-producing strains that hydrolyzed IPM and that
      harbored bla(IMP). The bla(IMP) gene was transmissible by conjugation to an IPM
      susceptible recipient strain of A. baumannii and conferred resistance to IPM,
      CAZ, cefotaxime (CTX), ampicillin (AMP), and piperacillin (PIP). Either
      intermediate or high-level resistance to amikacin (AMK) was transferred from two
      and five strains, respectively, concomitantly with bla(IMP), and gentamicin (GEN)
      resistance was also transferred in one instance of high-level AMK resistance.
      Comparative examination of clinical isolates for resistance patterns to nine
      drugs, IPM, CAZ, CTX, aztreonam, AMP, PIP, AMK, GEN, and norfloxacin, in addition
      to pulsed-field gel electrophoresis patterns with NotI-digested genomic DNA,
      confirmed nosocomial transmission of infections involving carbapenemase-producing
      A. baumannii strains.

PMID- 10655341
TI  - Preliminary evaluation of a semisolid agar antifungal susceptibility test for
      yeasts and molds.
AB  - This report presents a semisolid agar antifungal susceptibility (SAAS) method for
      the rapid susceptibility screening of yeasts and molds. The reproducibility and
      accuracy of the SAAS method were assessed by comparing the MICs of amphotericin B
      and fluconazole obtained for 10 candidate quality control (QC) American Type
      Culture Collection yeast strains in >/=15 replicates with those found by six
      independent laboratories using the National Committee for Clinical Laboratory
      Standards (NCCLS) M27-P broth macrodilution method (M. A. Pfaller et al., J.
      Clin. Microbiol. 33:1104-1107, 1995). Overall, 96% of MICs for both drugs fell
      within 1 log(2) dilution of the modal MIC for each strain. The MICs for
      amphotericin B showed 99% agreement with the NCCLS proposed QC ranges within 1
      log(2) dilution. Likewise, the MICs for fluconazole at >/=75% growth reduction
      showed 99% agreement for seven strains. Three strains, Candida albicans ATCC
      24333 and ATCC 76615 and Candida tropicalis ATCC 750, showed a less sharp
      fluconazole endpoint at >/=75% growth reduction, but at >50% growth reduction,
      the agreement was 98% within 1 log(2) dilution of the proposed range. The MIC
      agreement within the proposed range for the suggested QC strains Candida
      parapsilosis ATCC 22019 and Candida krusei ATCC 6258 was 100% for fluconazole and
      100% within 1 log(2) dilution of the proposed range for amphotericin B. The SAAS
      method demonstrated the susceptibility or resistance of 25 clinical isolates of
      filamentous fungi such as Aspergillus fumigatus to amphotericin B, itraconazole,
      and fluconazole, usually within 48 h. Although the results are preliminary, this
      SAAS method is promising as a rapid and cost-effective screen and is worthy of
      concerted investigation.

PMID- 10655342
TI  - Detection of extended-spectrum beta-lactamases in clinical isolates of
      Enterobacter cloacae and Enterobacter aerogenes.
AB  - The aim of the present study was to investigate the frequency of extended
      spectrum beta-lactamases (ESBLs) in a consecutive collection of clinical isolates
      of Enterobacter spp. The abilities of various screening methods to detect ESBLs
      in enterobacters were simultaneously tested. Among the 68 consecutive isolates
      (56 Enterobacter cloacae and 12 Enterobacter aerogenes isolates) that were
      analyzed for beta-lactamase content, 21 (25 and 58%, respectively) possessed
      transferable ESBLs with pIs of 8.2 and phenotypic characteristics of SHV-type
      enzymes, 8 (14.3%) of the E. cloacae isolates produced a previously nondescribed,
      clavulanate-susceptible ESBL that exhibited a pI of 6.9 and that conferred a
      ceftazidime resistance phenotype on Escherichia coli transconjugants, and 2 E.
      cloacae isolates produced both of these enzymes. Among the total of 31 isolates
      that were considered ESBL producers, the Vitek ESBL detection test was positive
      for 2 (6.5%) strains, and the conventional double-disk synergy test (DDST) with
      amoxicillin-clavulanate and with expanded-spectrum cephalosporins and aztreonam
      was positive for 5 (16%) strains. Modifications of the DDST consisting of closer
      application of the disks (at 20 instead of 30 mm), the use of cefepime, and the
      use of both modifications increased the sensitivity of this test to 71, 61, and
      90%, respectively. Of the 37 isolates for which isoelectric focusing failed to
      determine ESBLs, the Vitek test was false positive for 1 isolate and the various
      forms of DDSTs were false-positive for 3 isolates.

PMID- 10655343
TI  - Comparison of sorbitol MacConkey agar and a two-step method which utilizes enzyme
      linked immunosorbent assay toxin testing and a chromogenic agar to detect and
      isolate enterohemorrhagic Escherichia coli.
AB  - Enterohemorrhagic Escherichia coli (EHEC) and specifically serotype O157:H7 are a
      significant cause of hemorrhagic gastrointestinal disease and the hemolytic
      uremic syndrome. Methods currently used in clinical microbiology labs, such as
      sorbitol-MacConkey (SMAC) agar, reliably detect only O157:H7. We have evaluated a
      two-step method that has the potential to identify and isolate all EHEC
      serotypes, including serotype O157:H7. This method utilizes a chromogenic
      selective-differential medium for the isolation of E. coli together with an
      enzyme-linked immunosorbent assay (ELISA) that detects the Shiga-like toxins Stx1
      and Stx2. Both are commercially available and usable in a wide range of clinical
      microbiology laboratories. Compared to a Vero cell cytotoxic assay, SMAC had
      sensitivities of 23.5% for the identification of all EHEC serotypes and of 50.0%
      for the identification of O157:H7 alone. The two-step method had sensitivities of
      76.5 and 100%, respectively. The ELISA alone had a sensitivity of 82.4% in the
      detection of Stx1 and Stx2. The specificity was 100% in all cases. Overall, 14
      EHEC isolates were obtained: 8 (58%) O157:H7, 2 (14%) O26, 2 (14%) O111:NM, 1
      (7%) O103:H2, and 1 (7%) O121:H19. All but one were isolated during the months of
      May to September. The two-step method was found to be considerably more expensive
      than SMAC for both positive and negative samples.

PMID- 10655344
TI  - Genomic variations in echovirus 30 persistent isolates recovered from a
      chronically infected immunodeficient child and comparison with the reference
      strain.
AB  - Seven sequential isolates of echovirus type 30 (EV30) were recovered over 22
      months from a child with severe combined immune deficiency syndrome. The
      nucleotide sequences of the 5' halves of the genomes (4,400 nucleotides) of the
      first (S1) and last (S7) isolates were determined and compared with that of the
      EV30 Bastianni reference strain, also determined in this study. In genome regions
      P1 and P2, 101 variations were identified between the two isolates. Synonymous
      differences far outnumbered nonsynonymous differences. Amino acid changes
      affected both capsid and nonstructural polypeptides (particularly 2B). The VP1
      nucleotide sequences of the seven isolates were determined to analyze genome
      evolution during the chronic infection. In the phylogenetic tree, the seven
      isolates were directly related to the prototype strain in an individual
      monophyletic group, strongly suggesting that the chronic infection in the child
      arose from a single persistent EV30 isolate. Four lineages were observed in the
      persistent isolates. Isolates S2, S4, S5, and S6 were close relatives of one
      another, whereas isolates S1 and S3 formed individual lineages. Isolate S7,
      distantly related to all other isolates, formed the fourth lineage. These
      findings suggest the quasispecies nature of the genomes of the seven sequential
      EV30 isolates. Grouping of persistent isolates on the basis of replicative
      capacities was consistent with phylogenetic relationships. Overall, the results
      indicate that genetically related EV30 variants with different replicative
      capacities coexisted in a carrier state, probably in the gastrointestinal tract,
      during the infection of the child.

PMID- 10655345
TI  - Production and characterization of recombinant Aspergillus fumigatus Cu,Zn
      superoxide dismutase and its recognition by immune human sera.
AB  - The Cu,Zn superoxide dismutase (SOD) of Aspergillus fumigatus has previously been
      purified and shown to be immunoreactive to the sera of patients with
      aspergillosis; however, the purification of large quantities of the enzyme for
      expanded immunological analysis is both difficult and time-consuming.
      Accordingly, a lambdaEMBL3 A. fumigatus genomic library was screened with
      degenerate oligonucleotides based on N-terminal amino acid sequence data; from
      this initial screen a 1,400-bp fragment was identified, labelled, and used to
      screen an A. fumigatus lambdagt11 cDNA library. A full-length cDNA encoding Cu,Zn
      SOD was subsequently identified and cloned. The cDNA encodes a protein of 154
      amino acids, which does not have a signal peptide. The A. fumigatus Cu,Zn SOD
      possesses the typical metal binding ligands of fungal Cu,Zn SODs (six histidines
      and one aspartic acid) and has significant overall homology with Cu, Zn SODs in
      general. A recombinant A. fumigatus Cu,Zn SOD has been expressed in Pichia
      pastoris, is enzymatically active, and has biochemical and biophysical properties
      that are similar to those of the native enzyme. A sheep polyclonal antibody
      raised against purified native A. fumigatus Cu,Zn SOD was reactive to the
      recombinant enzyme by immunoenzyme development of Western blots. Sixty percent of
      serum samples from patients with A. fumigatus infections were reactive against
      the recombinant Cu,Zn SOD via immunoenzyme development of Western blots,
      indicating that the recombinant protein may be useful in the serodiagnostic
      identification of A. fumigatus infections.

PMID- 10655347
TI  - Ability of the VITEK 2 advanced expert system To identify beta-lactam phenotypes
      in isolates of Enterobacteriaceae and Pseudomonas aeruginosa.
AB  - The Advanced Expert System (AES) was used in conjunction with the VITEK 2
      automated antimicrobial susceptibility test system to ascertain the beta-lactam
      phenotypes of 196 isolates of the family Enterobacteriaceae and the species
      Pseudomonas aeruginosa. These isolates represented a panel of strains that had
      been collected from laboratories worldwide and whose beta-lactam phenotypes had
      been characterized by biochemical and molecular techniques. The antimicrobial
      susceptibility of each isolate was determined with the VITEK 2 instrument, and
      the results were analyzed with the AES to ascertain the beta-lactam phenotype.
      The results were then compared to the beta-lactam resistance mechanism determined
      by biochemical and molecular techniques. Overall, the AES was able to ascertain a
      beta-lactam phenotype for 183 of the 196 (93.4%) isolates tested. For 111 of
      these 183 (60.7%) isolates, the correct beta-lactam phenotype was identified
      definitively in a single choice by the AES, while for an additional 46 isolates
      (25.1%), the AES identified the correct beta-lactam phenotype provisionally
      within two or more choices. For the remaining 26 isolates (14.2%), the beta
      lactam phenotype identified by the AES was incorrect. However, for a number of
      these isolates, the error was due to remediable problems. These results suggest
      that the AES is capable of accurate identification of the beta-lactam phenotypes
      of gram-negative isolates and that certain modifications can improve its
      performance even further.

PMID- 10655346
TI  - Value of different assays for detection of human cytomegalovirus (HCMV) in
      predicting the development of HCMV disease in human immunodeficiency virus
      infected patients.
AB  - In the present prospective study, five blood tests for detection of human
      cytomegalovirus (HCMV), nucleic acid sequence-based amplification (NASBA) for
      detection of early (immediate-early antigen) and late (pp67) mRNA, PCR for
      detection of HCMV DNA (DNA PCR), culture, and pp65 antigenemia assay, and culture
      and DNA PCR of urine and throat swab specimens were compared for their abilities
      to predict the development of disease caused by HCMV (HCMV disease). Of 101 human
      immunodeficiency virus (HIV)-infected patients with </=100 CD4(+) lymphocytes per
      mm(3), 25 patients developed HCMV disease. The pp65 antigenemia assay
      (sensitivity, 50%; specificity, 89%) and DNA PCR of blood (sensitivity, 69%;
      specificity, 75%) were most accurate in predicting the development of HCMV
      disease within the next 12 months. Both blood culture and late pp67 mRNA NASBA
      had high specificities (91 and 90%, respectively) but low sensitivities (25 and
      13%, respectively). The sensitivities of urine culture, DNA PCR, throat swab
      specimen culture, DNA PCR, and NASBA of blood for detection of the immediate
      early antigen were 73, 87, 53, 67, and 63%, respectively, and the specificities
      were 58, 46, 76, 60, and 72%, respectively. The positive predictive values of all
      tests however, were low and did not exceed 50%. In conclusion, virological
      screening by these qualitative assays for detection of HCMV is of limited value
      for prediction of the development of HCMV disease in HIV-infected patients.

PMID- 10655348
TI  - Screening for hepatitis C virus in human immunodeficiency virus-infected
      individuals.
AB  - Immunosuppression from human immunodeficiency virus (HIV) may impair antibody
      formation, and false-negative hepatitis C virus antibody (anti-HCV) tests have
      been reported in individuals coinfected with HIV and HCV. It is unknown if the
      frequency of false-negative tests is sufficiently high to change screening
      recommendations in this setting. Thus, the prevalence of false-negative results
      for anti-HCV by third-generation tests was determined with samples from HIV
      infected individuals. Sera from 559 HIV-infected and 944 HIV-negative
      prospectively followed injection drug users were tested for anti-HCV by a third
      generation enzyme immunoassay and for HCV RNA by using a branched DNA assay and
      the HCV COBAS AMPLICOR system. Of 559 HIV-infected participants, 547 (97.8%) were
      anti-HCV positive. One of the remaining 12 anti-HCV-negative participants was HCV
      RNA positive, and she later developed detectable anti-HCV. Of the 944 HIV
      negative participants, 825 (87.4%) were anti-HCV positive. One of the remaining
      119 anti-HCV-negative participants was HCV RNA positive, and she also developed
      detectable anti-HCV at a later visit. These data indicate that HIV infection does
      not alter the approach to hepatitis C virus screening, which should be performed
      with third-generation assays for anti-HCV unless acute infection is suspected.

PMID- 10655349
TI  - Pandemic spread of an O3:K6 clone of Vibrio parahaemolyticus and emergence of
      related strains evidenced by arbitrarily primed PCR and toxRS sequence analyses.
AB  - Vibrio parahaemolyticus O3:K6 strains responsible for the increase in the number
      of cases of diarrhea in Calcutta, India, beginning in February 1996 and those
      isolated from Southeast Asian travelers beginning in 1995 were shown to belong to
      a unique clone characterized by possession of the tdh gene but not the trh gene
      and by unique arbitrarily primed PCR (AP-PCR) profiles (J. Okuda, M. Ishibashi,
      E. Hayakawa, T. Nishino, Y. Takeda, A. K. Mukhopadhyay, S. Garg, S. K.
      Bhattacharya, G. B. Nair, and M. Nishibuchi, J. Clin. Microbiol. 35:3150-3155,
      1997). Evidence supporting a hypothesis that this clone emerged only recently and
      is spreading to many countries was obtained in this study. Of 227 strains
      isolated in a hospital in Bangladesh between 1977 and 1998, only 22 strains
      isolated between 1996 and 1998 belonged to the new O3:K6 clone (defined by the
      serovar, the tdh and trh typing, and AP-PCR profiles). The O3:K6 strains isolated
      from clinical sources in Taiwan, Laos, Japan, Thailand, Korea, and the United
      States between 1997 and 1998 were also shown to belong to the new O3:K6 clone.
      The clonality of the new O3:K6 strains was also confirmed by analysis of the
      toxRS sequence, which has been shown to be useful for phylogenetic analysis of
      the members of the genus Vibrio. The toxRS sequences of the representative
      strains of the new O3:K6 clone differed from those of the O3:K6 strains isolated
      before 1995 at least at 7 base positions within a 1,346-bp region. A new PCR
      method targeted to 2 of the base positions unique to the new O3:K6 clone was
      developed. This PCR method could clearly differentiate all 172 strains belonging
      to the new O3:K6 clone from other O3:K6 strains isolated earlier. One hundred
      sixty-six strains belonging to 28 serovars other than O3:K6 were also examined by
      the new PCR method. The tdh-positive and trh-lacking strains that belonged to the
      O4:K68 and O1:K untypeable serovars and were isolated in three countries and from
      international travelers beginning in 1997 gave positive results. The AP-PCR
      profiles of these strains were nearly identical to those of the new O3:K6 clone,
      and their toxRS sequences were 100% identical to that of the new O3:K6 clone. The
      results suggest that these strains may have diverged from the new O3:K6 clone by
      alteration of the O:K antigens. In conclusion, this study presents strong
      evidence for the first pandemicity in the history of V. parahaemolyticus and
      reports a novel toxRS-targeted PCR method that will be useful in epidemiological
      investigation of the cases associated with the current pandemic spread.

PMID- 10655350
TI  - Quantification of fungal DNA by using fluorescence resonance energy transfer and
      the light cycler system.
AB  - The Light Cycler technique combines rapid in vitro amplification of DNA in glass
      capillaries with real-time species determination and quantification of DNA load.
      We have established a quantitative PCR protocol for two clinically important
      pathogens, Candida albicans and Aspergillus fumigatus. The sensitivity of the
      assay was comparable to those of previously described PCR protocols (5 CFU/ml).
      Specific detection of C. albicans and A. fumigatus could be achieved. The assay
      showed a high reproducibility of 96 to 99%. The assay was linear in a range
      between 10(1) and 10(4) Aspergillus conidia. As capillaries do not have to be
      reopened for post-PCR analysis, the risk of carryover contaminations could be
      minimized. The Light Cycler allowed quantification of the fungal loads in a
      limited number of clinical specimens from patients with hematological
      malignancies and histologically proven invasive fungal infections. Five of nine
      positive samples had fungal loads between 5 and 10 CFU/ml of blood, two of nine
      positive samples had fungal loads between 10 and 100 CFU/ml of blood, and two of
      nine samples had fungal loads of more than 100 CFU/ml of blood. All samples were
      also found to be PCR positive by PCR-enzyme-linked immunosorbent assay analysis.

PMID- 10655351
TI  - Pig and goat blood as substitutes for sheep blood in blood-supplemented agar
      media.
AB  - In many developing countries sheep and horse blood, the recommended blood
      supplements in bacteriological media, are not readily available, whereas pig and
      goat blood are. Therefore, this study examined the use of pig and goat blood as
      potential substitutes for sheep blood in blood-supplemented bacteriologic media
      commonly used in clinical microbiology laboratories. In general, the growth
      characteristics and colony morphologies of a wide range of aerobic and anaerobic
      bacteria and Candida albicans were similar on media containing pig, goat, and
      sheep blood, although differences were found. Enterococcus sp. uniformly produced
      alpha-hemolysis when incubated in CO(2), but in anaerobic conditions the
      hemolysis varied. In contrast, beta-hemolytic streptococci produced identical
      hemolytic reactions on all three media. Synergistic hemolysis was not observed on
      pig blood agar in the CAMP test nor on goat blood agar in the reverse CAMP test.
      The preparation of chocolate agar (heated) with pig blood required heating to a
      higher temperature than with sheep or goat blood to yield suitable growth of
      Haemophilus species. In general, we conclude that pig and goat blood are suitable
      alternatives to sheep blood for use in bacteriological media in settings where
      sheep and horse blood are not readily available.

PMID- 10655352
TI  - Evaluation of a specific nested PCR targeting domain III of the 23S rRNA gene of
      "Tropheryma whippelii" and proposal of a classification system for its molecular
      variants.
AB  - "Tropheryma whippelii"-associated infections are usually confirmed
      histopathologically by using light microscopy. PCR assays targeting the 16S rRNA
      gene (16S rDNA) of "T. whippelii" are increasingly being applied for this
      purpose. Compared to microscopic analysis, PCR seems to be more sensitive, as
      indicated by the fact that several cases of Whipple's disease with negative
      histopathological findings but positive PCR results have been reported.
      Considering the lack of pathognomonic clinical features for this disease and the
      fact that "T. whippelii" DNA has repeatedly been found in patients without
      clinical Whipple's disease, such PCR results should be confirmed by additional
      tests. We have, therefore, evaluated a "T. whippelii"-specific nested PCR
      targeting domain III of the 23S rDNA with 41 clinical specimens known to contain
      "T. whippelii" 16S rDNA. All of these specimens were also positive for "T.
      whippelii" 23S rDNA. The specificity of the test was shown by sequencing of the
      amplicons and by the absence of amplicons in 38 negative controls. We consider
      this PCR test to be a suitable tool for confirming the presence of "T. whippelii"
      DNA in specimens with inconclusive histopathological findings. The information
      derived from sequencing of the partial "T. whippelii" 23S rDNA was then combined
      with our recent data of the 16S-23S rDNA spacer region of this organism. Overall,
      four different rDNA types are recognized in our proposed classification system
      for molecular variants of "T. whippelii." This preliminary scheme may provide a
      basis for further epidemiological and clinical studies with "T. whippelii" and
      associated diseases.

PMID- 10655353
TI  - Evaluation of the COBAS AMPLICOR CMV MONITOR test for detection of viral DNA in
      specimens taken from patients after liver transplantation.
AB  - Detection of cytomegalovirus (CMV) DNA in blood by PCR is a sensitive method for
      the detection of infection in patients posttransplantation. The test, however,
      has low specificity for the identification of overt CMV disease. Quantitative CMV
      PCR has been shown to overcome this shortcoming. The COBAS AMPLICOR CMV MONITOR
      test was evaluated by using consecutive serum and peripheral blood mononuclear
      cell (PBMN) samples from liver transplant patients. Twenty-five patients had CMV
      viremia (by shell vial cell culture assay) and/or tissue-invasive disease (by
      biopsy); 20 had no active infection. A total of 262 serum and 62 PBMN specimens
      were tested. Of 159 serum specimens from patients with overt CMV infection, the
      COBAS assay detected CMV DNA in 21 patients (sensitivity, 84%). Only 1 of 103
      samples from patients with no evidence of active infection had detectable CMV DNA
      (341 copies/ml). By comparison of 62 matching serum and PBMN samples by the same
      assay, 12 PBMN samples were exclusively positive, whereas only 2 serum samples
      were exclusively positive (P < 0.05). At the time of clinical CMV infection,
      viral copy numbers were higher in PBMNs than serum from four of five patients.
      The COBAS AMPLICOR CMV MONITOR test is a sensitive and specific test for the
      quantitative detection of CMV DNA in blood. Clinical applications of the assay
      will require further validation with samples from a larger population of
      transplant patients.

PMID- 10655354
TI  - The alleles of the bft gene are distributed differently among enterotoxigenic
      Bacteroides fragilis strains from human sources and can be present in double
      copies.
AB  - Enterotoxigenic Bacteroides fragilis (ETBF) strains are associated with diarrheal
      disease in children. These strains produce a zinc metalloprotease enterotoxin, or
      fragilysin, that can be detected by a cytotoxicity assay with HT-29 cells.
      Recently, three different isoforms or variants of the enterotoxin gene,
      designated bft-1, bft-2, and bft-3, have been identified and sequenced. We used
      restriction fragment length polymorphism analysis of the PCR-amplified
      enterotoxin gene to detect the isoforms bft-1 and bft-2 or bft-3 borne by ETBF.
      By sequencing the portion of the bft gene corresponding to the mature toxin in
      some strains and applying allele-specific PCR for strains categorized as bft-2 or
      bft-3, we found in our collection two strains harboring bft-3, a variant that had
      been described for isolates from East Asia. Analysis of 66 ETBF strains from
      different sources showed that bft-1 is the most frequent allele, being present in
      65% of isolates; it is largely predominant in isolates from feces of adults,
      while bft-2 is present in isolates from feces of children. This association is
      statistically significant (P, 0.0064). Sixteen strains were examined by Southern
      hybridization using, as probes, the bft and second metalloprotease genes, both
      included in a pathogenicity islet. Five strains were found to harbor double
      copies of both genes, suggesting that the whole islet was duplicated. Four of
      these strains, harboring bft-1 (three strains) or bft-2 (one strain), were found
      to produce a large amount of biologically active toxin, as determined by a
      cytotoxicity assay with HT-29 cells. The strains harboring bft-3, either in a
      single copy or in double copies, produced the smallest amount of toxin in our
      collection.

PMID- 10655355
TI  - High levels of Epstein-Barr virus DNA in blood of solid-organ transplant
      recipients and their value in predicting posttransplant lymphoproliferative
      disorders.
AB  - Epstein-Barr virus (EBV) DNA was quantitated in peripheral blood mononuclear
      cells (PBMC) from 25 healthy subjects, 105 asymptomatic solid-organ transplant
      (SOT) recipients, and 15 SOT recipients with symptomatic EBV infections by using
      a newly developed quantitative-PCR technique. Patients with symptomatic EBV
      infections had significantly higher (P < 0.001) median EBV DNA levels than
      asymptomatic SOT recipients and immunocompetent individuals. In SOT recipients,
      the positive predictive value of EBV DNA levels of >1, 000 genome equivalents
      (GE)/0.5 microg of total PBMC DNA was 64.7% for symptomatic EBV infection, while
      the negative predictive value was 96.1%. In 19 of 32 (59.3%) asymptomatic SOT
      recipients, EBV DNA levels were consistently below 1,000 GE for as long as 18
      months, while 10 of 32 (31.2%) patients had 1,000 to 5,000 EBV GE at least once
      during follow-up. In a minority of patients (3 of 32; 9.3%), >/=5,000 GE could be
      detected at least once during follow-up. Reduction of immunosuppressive treatment
      decreased EBV DNA levels by >/=1 log(10) unit in patients with symptomatic EBV
      infections. Quantification of EBV DNA is valuable for the diagnosis and
      monitoring of symptomatic EBV infections in SOT recipients.

PMID- 10655356
TI  - Prevalence of vancomycin-resistant enterococci in fecal samples from hospitalized
      patients and nonhospitalized controls in a cattle-rearing area of France.
AB  - Vancomycin-resistant enterococci (VRE) have emerged as nosocomial pathogens over
      the last decade, but little is known about their epidemiology. We report on the
      prevalence of VRE fecal colonization on the basis of a prospective study among
      patients hospitalized in a hematology intensive care unit and among
      nonhospitalized subjects living in the local community. A total of 243 rectal
      swabs from hematology patients and 169 stool samples from the control group were
      inoculated onto bile-esculin agar plates with and without 6 mg of vancomycin per
      liter and into an enrichment bile-esculin broth supplemented with 4 mg of
      vancomycin per liter. A total of 37% of the hospitalized patients and 11.8% of
      the subjects from the community were found to be VRE carriers. A total of 65 VRE
      strains were isolated: 12 (18.5%) E. faecium, 46 (70.7%) E. gallinarum, and 7
      (10.8%) E. casseliflavus strains. No E. faecalis strains were detected. All the
      E. faecium strains were of the vanA genotype. Molecular typing by pulsed-field
      gel electrophoresis revealed a different pattern for each vanA VRE strain that
      originated from an individual subject. To our knowledge, this is the first study
      to be carried out in a cattle-rearing region of France. It reports a higher VRE
      prevalence than that reported in previous European or U.S. studies. A partial
      explanation is the use of an enrichment broth step which enabled detection of
      strains which would otherwise have been missed, but the fact that subjects and
      patients were recruited from a predominantly agricultural area where vancomycin
      related antibiotics have recently been used in animal husbandry could also
      contribute to the high levels of VRE in patients and subjects alike.

PMID- 10655357
TI  - Pulsed-field gel electrophoresis analysis of nasopharyngeal flora in children
      attending a day care center.
AB  - To investigate how bacterial pathogens spread from child to child in a day care
      center, we monitored six children, two boys and four girls, born between August
      1995 and November 1997, attending a day care center and analyzed nasopharyngeal
      samples from them using pulsed-field gel electrophoresis (PFGE). We obtained
      nasopharyngeal cultures from all of the affected children and almost all of the
      unaffected children between September 1998 and March 1999 after some children
      presented simultaneously with purulent rhinorrhea. Moreover, when a child was
      found to have acute otitis media, nasopharyngeal secretions from the child were
      independently cultured during treatment. During this period, 28 isolates of
      Moraxella catarrhalis, 13 of Streptococcus pneumoniae, and 4 of Haemophilus
      influenzae were recovered. PFGE gave 8 patterns for M. catarrhalis, 10 for S.
      pneumoniae, and 1 for H. influenzae. PFGE patterns demonstrated spread of M.
      catarrhalis between children. However, each occurrence of clusters of infection
      with M. catarrhalis lasted 2 to 6 weeks, with a change in PFGE pattern between
      occurrences of clusters. The M. catarrhalis strain infecting each child also
      changed. Similarly, the S. pneumoniae strain in each child also changed. In
      contrast, infection with H. influenzae persisted for about 3 months in an
      affected child.

PMID- 10655358
TI  - PCR-Based assay to quantify human immunodeficiency virus type 1 DNA in peripheral
      blood mononuclear cells.
AB  - An assay that quantifies the amount of human immunodeficiency virus type 1 (HIV
      1) DNA in peripheral blood mononuclear cells has been developed. PCR
      amplification of the HIV-1 DNA is performed in the presence of an internal
      quantitation standard, and colorimetric detection of the amplified product is
      performed with microwell plates. The copies of HIV-1 DNA are normalized to total
      genomic DNA input. The assay has an analytical sensitivity of 10 input copies per
      amplification reaction and a three-log detection range. In an analysis of
      sequential samples from patients on combination therapy, HIV-1 DNA was
      quantifiable for all individuals tested, including those with undetectable plasma
      HIV-1 RNA. In a separate study, a comparison of HIV-1 DNA levels was made with a
      group of long-term survivors and progressors. The mean HIV-1 DNA levels were
      lower in the long-term survivors than in the progressors (P, 0.04). The mean HIV
      1 RNA levels were also lower, but the difference was not statistically
      significant (P, 0.164). A quantitative DNA assay will provide an additional tool
      to gain insight into the natural history of infection and the continued efficacy
      of potent antiretroviral therapies.

PMID- 10655359
TI  - Serology of culture-confirmed cases of human granulocytic ehrlichiosis.
AB  - We evaluated the antibody responses in the sera of 24 patients with culture
      confirmed human granulocytic ehrlichiosis (HGE). Antibody titers were measured by
      an indirect immunofluorescent-antibody assay (IFA) by using a local human isolate
      as the source of antigen. All patients received appropriate antimicrobial
      treatment. One hundred five serum specimens collected at baseline and at periodic
      intervals for up to 14 months were included in the study. Seroconversion was
      observed in 21 of 23 patients (91.3%) from whom convalescent-phase sera were
      obtained. Antibodies were first detected at an average of 11.5 days after onset
      of symptoms. Peak titers (>/=2,560 for 71.4% of patients and >/=640 for 95.2% of
      patients) were obtained an average of 14.7 days after onset of symptoms. Eleven
      of 13 patients (84.6%) from whom sera were collected between 6 and 10 months
      after onset of symptoms were still seropositive, and sera from 5 of 10 (50%)
      patients tested positive between 11 and 14 months after onset of symptoms. For a
      subset of 71 serum specimens from 17 patients with culture-confirmed HGE also
      tested by IFA by using either a human isolate from Wisconsin or an Ehrlichia equi
      isolate from a horse, there was qualitative agreement for 62 serum specimens (87.
      3%). Peak titers were higher, however, with the local human HGE isolate, but the
      difference was not statistically significant. In summary, most patients with
      culture-confirmed HGE develop antibodies within 2 weeks of onset of symptoms.
      Antibodies reach high titers during the first month and remain detectable in
      about one-half of patients at 1 year after onset of symptoms.

PMID- 10655360
TI  - Serologic testing for Trypanosoma cruzi: comparison of radioimmunoprecipitation
      assay with commercially available indirect immunofluorescence assay, indirect
      hemagglutination assay, and enzyme-linked immunosorbent assay kits.
AB  - The radioimmunoprecipitation assay (RIPA) has been used as a confirmatory test in
      several ongoing and published studies of Trypanosoma cruzi in blood donors in the
      United States. Despite its use as a confirmatory test, few studies are available
      comparing RIPA to commercially available serologic test methods. Thus, we
      compared RIPA with two indirect hemagglutination assays (Biolab Diagnostica SA,
      Sao Paulo, Brazil; Hemagen Diagnostics, Inc., Waltham, Mass.) and four different
      enzyme-linked immunosorbent assays (Abbott Laboratories, Abbott Park, Ill.;
      Embrabio, Sao Paulo, Brazil; Organon Teknika, Sao Paulo, Brazil; and Gull
      Laboratories, Salt Lake City, Utah) using a panel of 220 serum specimens from
      Brazilian blood donors with a range of T. cruzi antibody titers as determined by
      indirect immunofluorescence assay (IFA). A titer of 1:20 was used as the baseline
      for seropositivity. All IFA-negative serum specimens (n = 19) were nonreactive on
      all tests. At a titer of 1:20 (n = 9), reactivity rates varied considerably among
      the tests, with only the RIPA and the Organon and Gull assays identifying
      reactive specimens. For specimens at a 1:40 titer (n = 35), most assays
      identified at least 32 of 35 (91%) specimens as reactive, but the Biolab assay
      only identified 24 (69%). At higher titers (1:80, n = 56; 1:160, n = 101) the
      assays were comparable, with the exception of the Biolab assay, demonstrating
      rates of agreement with IFA of >/=98%. Overall, when compared with several other
      test formats, RIPA demonstrated equivalent or superior rates of agreement with
      IFA-positive specimens across all titers examined. In particular, at titers of
      >1:40, the RIPA compared favorably with other test methods currently in use,
      supporting its application as a confirmatory test, particularly in a research
      setting.

PMID- 10655361
TI  - A new alkaline pH-adjusted medium enhances detection of beta-hemolytic
      streptococci by minimizing bacterial interference due to Streptococcus
      salivarius.
AB  - A new selective medium (CNA-P) that reduces or eliminates the inhibitory activity
      of bacteriocin-producing Streptococcus salivarius against beta-hemolytic
      streptococci has been developed and compared with sheep blood agar (SBA) for the
      sensitive detection of small numbers of beta-hemolytic streptococci in clinical
      specimens. CNA-P has as its basis a commercial medium (Difco Columbia CNA agar)
      supplemented with 5% (vol/vol) sheep blood, and the CNA is further modified by
      addition of 100 mM PIPES buffer [piperazine-N,N'-bis(2-ethanesulfonic acid)] (pH
      7.5) to maintain cultures at an alkaline pH during incubation. CNA-P was shown to
      inhibit the production and/or release of four different types of S. salivarius
      bacteriocins or bacteriocin-like inhibitory molecules. The efficacies of CNA-P
      and SBA for detection of beta-hemolytic streptococci in 1,352 pharyngeal samples
      from 376 children were compared. The beta-hemolytic streptococcal isolates
      recovered from the samples included 314 group A (S. pyogenes), 61 group G, 33
      group B, and 5 group C streptococci. Of 314 samples that yielded S. pyogenes, 300
      were positive on CNA-P (96%) and 264 (86%) were positive on SBA. A significantly
      greater number of S. pyogenes isolates from these samples were recovered only on
      CNA-P (50 of 314) compared with the number of isolates recovered only on SBA (14
      of 314). In addition, the degree of positivity, a measure of the total numbers of
      S. pyogenes isolates on the plate, was significantly higher on CNA-P than on SBA
      (2.40 versus 2.07; P < 0.001). Interestingly, CNA-P was also found to enhance the
      hemolytic activity of streptolysin O, allowing detection of streptolysin S
      deficient S. pyogenes strains which might otherwise go undetected on SBA and
      other isolation media.

PMID- 10655362
TI  - Comparison of human papillomavirus detection and typing by cycle sequencing, line
      blotting, and hybrid capture.
AB  - We compared the results of human papillomavirus (HPV) detection and typing from
      781 cervical samples assayed by three methods: L1 consensus PCR followed by cycle
      sequencing, L1 consensus PCR with biotinylated primers followed by hybridization
      to a line blot, and Hybrid Capture assay. Both PCR assays used L1 consensus PCR
      with primers MY09 and MY11. We evaluated the amplification efficiencies of both
      PCR assays and also compared the specific HPV types detected by each method. The
      samples positive by the Hybrid Capture assay were compared to the specific types
      detected by the PCR-based assays. The concordance between the two PCR assays in
      producing an HPV amplicon visible by gel electrophoresis or in detecting any HPV
      type was moderate: kappa values were 0.61 (95% confidence interval [CI] = 0.56 to
      0.67) and 0.51 (95% CI = 0.46 to 0.58), respectively. The McNemar test for
      correlated proportions indicated that biotinylated PCR was less likely to produce
      a band (P = 0.001) and to detect an HPV type (P = 0.001) than the other PCR
      assay. In comparing the Hybrid Capture assay results with the HPV types detected
      by the PCR-based assays, we found that positivity by the Hybrid Capture assay for
      a number of samples may be due to cross-hybridization with HPV types not included
      in the Hybrid Capture assay probe cocktails.

PMID- 10655363
TI  - Multisite reproducibility of Etest for susceptibility testing of Mycobacterium
      abscessus, Mycobacterium chelonae, and Mycobacterium fortuitum.
AB  - A multicenter study was conducted to assess the inter- and intralaboratory
      reproducibility of the Etest for susceptibility testing of the rapidly growing
      mycobacteria. The accuracy also was evaluated by comparing Etest results to those
      obtained by broth microdilution. Ten isolates (four of the Mycobacterium
      fortuitum group, three of Mycobacterium abscessus, and three of Mycobacterium
      chelonae) were tested against amikacin, cefoxitin, ciprofloxacin, clarithromycin,
      doxycycline, imipenem, and trimethoprim-sulfamethoxazole in each of four
      laboratories. At each site, isolates were tested three times on each of three
      separate days (nine testing events per isolate) using common lots of media and
      Etest strips. Interlaboratory agreement among MICs (i.e., mode +/- 1 twofold
      dilution) varied for the different drug-isolate combinations and overall was best
      for trimethoprim-sulfamethoxazole (75% for one isolate and 100% for all others),
      followed by doxycycline and ciprofloxacin. Interlaboratory agreement based on
      interpretive category also varied and overall was best for doxycycline (100% for
      all isolates), followed by trimethoprim-sulfamethoxazole and ciprofloxacin.
      Interlaboratory reproducibility among MICs was most variable for imipenem, and
      agreement by interpretive category was lowest for imipenem and amikacin. Modal
      Etest MICs agreed with those by broth microdilution only for doxycycline and the
      sulfonamides. For all other drugs, the modal MICs by the two methods differed by
      more than +/- 1 twofold dilution for one or more isolates. In all cases, the
      Etest MIC was higher and would have caused reports of false resistance. In
      summary, the Etest in this evaluation did not perform as well as broth
      microdilution for susceptibility testing of the rapidly growing mycobacteria. It
      was problematic for most species and drugs, primarily because of a trailing
      endpoint and/or high MICs compared to broth. Its use will necessitate further
      investigation, including determination of the optimal medium and incubation
      conditions and clarification of endpoint interpretation.

PMID- 10655364
TI  - Prevalence of GB virus C/Hepatitis G virus infection among various populations in
      Surabaya, Indonesia, and identification of novel groups of sequence variants.
AB  - A molecular epidemiological study was performed to investigate the prevalence of
      GB virus C/hepatitis G virus (GBV-C/HGV) infection among various populations in
      Surabaya, Indonesia. The prevalence of GBV-C/HGV RNA, determined by reverse
      transcription-PCR for a portion of the NS3 region of the viral genome, was 2.7%
      (4 of 150) among randomly collected blood donor sera, which were all negative for
      both hepatitis B virus surface antigen and antibodies against hepatitis C virus
      (HCV). On the other hand, the prevalence among anti-HCV-positive blood donors was
      17.8% (13 of 73), with the ratio being significantly higher than that observed
      with the anti-HCV-negative blood donors (P < 0.001). A high prevalence of GBV
      C/HGV infection was also observed among patients with chronic liver disease, such
      as chronic hepatitis (5.7%), liver cirrhosis (11. 5%), and hepatocellular
      carcinoma (7.0%), and patients on maintenance hemodialysis (29.0%). No
      correlation was observed between GBV-C/HGV viremia and serum alanine
      aminotransferase levels in the populations tested, suggesting the possibility
      that GBV-C/HGV does not cause apparent liver injury. Phylogenetic analysis of
      sequences of a portion of the 5' untranslated region and the E1 region of the
      viral genome identified, in addition to a previously reported then novel group of
      GBV-C/HGV variants (group 4), another novel group of variants (group 5). This
      result suggests that GBV-C/HGV can be classified into at least five genetic
      groups. GBV-C/HGV isolates of group 4 and group 5 were each shown to comprise
      approximately 40% of the total Indonesian isolates.

PMID- 10655365
TI  - Characterization of Mycobacterium tuberculosis isolates from patients in Houston,
      Texas, by spoligotyping.
AB  - Mycobacterium tuberculosis isolates (n = 1,429) from 1,283 patients collected as
      part of an ongoing population-based tuberculosis epidemiology study in Houston,
      Texas, were analyzed by spoligotyping and IS6110 profiling. The isolates were
      also assigned to one of three major genetic groups on the basis of nucleotide
      polymorphisms located at codons 463 and 95 in the genes (katG and gyrA) encoding
      catalase-peroxidase and the A subunit of DNA gyrase, respectively. A total of 225
      spoligotypes were identified in the 1,429 isolates. There were 54 spoligotypes
      identified among 713 isolates (n = 623 patients) assigned to 73 IS6110 clusters.
      In addition, among 716 isolates (n = 660 patients) with unique IS6110 profiles,
      200 spoligotypes were identified. No changes were observed either in the IS6110
      profile or in the spoligotype for the 281 isolates collected sequentially from
      133 patients. Five instances in which isolates with slightly different
      spoligotypes had the same IS6110 profile were identified, suggesting that in rare
      cases isolates with different spoligotypes can be clonally related. Spoligotypes
      correlated extremely well with major genetic group designations. Only three very
      similar spoligotypes were shared by isolates from genetic groups 2 and 3, and
      none was shared by group 1 and group 2 organisms or by group 1 and group 3
      organisms. All organisms belonging to genetic groups 2 and 3 failed to hybridize
      with spacer probes 33 to 36. Taken together, the results support the existence of
      three distinct genetic groups of M. tuberculosis organisms and provide new
      information about the relationship between IS6110 profiles, spoligotypes, and
      major genetic groups of M. tuberculosis.

PMID- 10655366
TI  - Problems related to determination of MICs of oximino-type expanded-spectrum
      cephems for Proteus vulgaris.
AB  - During in vitro susceptibility testing of clinical isolates of Proteus vulgaris,
      we noted that the MICs of several expanded-spectrum cephems were much higher in
      the broth microdilution method than in the agar dilution method (termed the MIC
      gap phenomenon). Here we investigated the mechanism of the MIC gap phenomenon.
      Cephems with the MIC gap phenomenon were of the oximino type, such as cefotaxime,
      cefteram, and cefpodoxime, which serve as good substrates for inducible class A
      beta-lactamase (CumA) enzymes produced by P. vulgaris; this finding suggests a
      relationship between the MIC gap phenomenon and CumA. Since peptidoglycan
      recycling shares a system common to that inducing CumA, we analyzed the mechanism
      of the MIC gap phenomenon using P. vulgaris B317 and isogenic mutants with
      mutations in the peptidoglycan recycling and beta-lactamase induction systems.
      The MIC gap phenomenon was observed in the parent strain B317 but not in B317G
      (cumG-defective mutant; defective peptidoglycan recycling) and B317R (cumR
      defective mutant; defective CumA transcriptional regulator). No beta-lactamase
      activity was detected in B317G and B317R. beta-Lactamase activity and the MIC gap
      phenomenon were restored in B317G/pMD301 (strain transcomplemented by a cloned
      cumG gene) and B317R/pMD501 (strain transcomplemented by a cloned cumR gene).
      MICs determined by the agar dilution method increased when lower agar
      concentrations were used. Our results indicated that the mechanism of the MIC gap
      phenomenon is related to peptidoglycan recycling and CumA induction systems.
      However, it remains unclear how beta-lactamase induction of P. vulgaris is
      suppressed on agar plates.

PMID- 10655368
TI  - A novel and rapid PCR-based method for genotyping human papillomaviruses in
      clinical samples.
AB  - Many human papillomavirus (HPV) genotypes are associated with cervical carcinoma.
      We demonstrate the utility of an innovative technique for genotyping of HPV in
      cervical tissue samples. This method provides an accurate means of identification
      of the specific HPV genotypes present in clinical specimens. By using the MY09
      MY11 and the GP5(+)-GP6(+) consensus primer pairs, HPV sequences were amplified
      by nested PCR from DNA isolated from cervical smear samples. This led to the
      production of an approximately 140-bp PCR product from the L1 (major capsid) gene
      of any of the HPVs present in the sample. PCR was performed with a
      deoxynucleoside triphosphate mixture which resulted in the incorporation of
      deoxyuridine into the amplified DNA product at positions where deoxythymidine
      would normally be incorporated at a frequency of about once or twice per strand.
      Following the PCR, the product was treated with an enzyme mix that contains
      uracil N-glycosylase (UNG) and endonuclease IV. UNG removes the uracil base from
      the nucleotide, and endonuclease IV cleaves the phosphodiester bond at this newly
      formed abasic site, producing fragments of various sizes. By having end labeled
      one of the amplification primers, a DNA ladder which is analogous to a "T
      sequencing ladder" was produced upon electrophoresis of the products. By
      comparing this T-sequencing ladder to the known sequences of HPVs, the genotypes
      of unknown HPV isolates in samples were assigned. Data showing the utility of
      this technique for the rapid analysis of clinical samples are presented.

PMID- 10655367
TI  - Sequence variation in the ftsZ gene of Bartonella henselae isolates and clinical
      samples.
AB  - In a search for methods for subtyping of Bartonella henselae in clinical samples,
      we amplified and sequenced a 701-bp region in the 3' end of the ftsZ gene in 15
      B. henselae isolates derived from cats and humans in the United States and
      Europe. The ftsZ sequence variants that were discovered were designated variants
      Bh ftsZ 1, 2, and 3 and were compared with 16S rRNA genotypes I and II of the
      same isolates. There was no ftsZ gene variation in the strains of 16S rRNA type
      I, all of which were Bh ftsZ 1. The type II strains constituted two groups, with
      nucleotide sequence variation in the ftsZ gene resulting in amino acid
      substitutions at three positions, one of which was shared by the two groups. One
      16S rRNA type II isolate had an ftsZ gene sequence identical to those of the type
      I strains. Variants Bh ftsZ 1 and 2 were detected in tissue specimens from seven
      Swedish patients with diagnoses such as chronic multifocal osteomyelitis,
      cardiomyopathy, and lymphadenopathy. Patients with similar clinical entities
      displayed either Bh ftsZ variant. The etiological role of B. henselae in these
      patients was supported by positive Bartonella antibody titers and/or
      amplification and sequencing of a part of the B. henselae gltA gene. B. henselae
      ftsZ gene sequence variation may be useful in providing knowledge about the
      epidemiology of various B. henselae strains in clinical samples, especially when
      isolation attempts have failed. This report also describes manifestations of
      atypical Bartonella infections in Sweden.

PMID- 10655369
TI  - Use of epidemiologically well-defined subjects and existing immunofluorescence
      assays to calibrate a new enzyme immunoassay for human herpesvirus 8 antibodies.
AB  - Agreement between assays for the detection of human herpesvirus 8 (HHV-8)
      antibodies has been limited. In part, this disagreement has been because assay
      calibration (i.e., differentiating positive from negative results) has not been
      done in a standardized fashion with reference to a wide spectrum of HHV-8
      infected (true-positive) and HHV-8-uninfected (true-negative) persons. To
      describe the performance of an assay for HHV-8 antibodies more accurately, we
      used epidemiologically well-characterized subjects in conjunction with testing on
      two existing immunofluorescence assays for HHV-8 antibodies to define two groups:
      a group of 135 HHV-8-infected individuals (true positives), including Kaposi's
      sarcoma patients and those asymptomatically infected, and a group of 234
      individuals with a high likelihood of being HHV-8 uninfected (true negatives). A
      new enzyme immunoassay (EIA), using lysed HHV-8 virion as the antigen target, was
      then developed. With the above true positives and true negatives as references,
      the sensitivity and specificity of the EIA associated with different cutoff
      values were determined. At the cutoff that maximized both sensitivity and
      specificity, sensitivity was 94% and specificity was 93%. When the EIA was used
      to test a separate validation group, a distribution of seropositivity that
      matched that predicted for the agent of Kaposi's sarcoma was observed: 55% of
      homosexual men were seropositive, versus 6% seropositivity in a group of
      children, women, and heterosexual men. It is proposed that the EIA has utility
      for large-scale use in a number of settings and that the calibration method
      described can be used for other assays, both to more accurately describe the
      performance of these assays and to permit more-valid interassay comparison.

PMID- 10655370
TI  - Line probe assay for monitoring drug resistance in hepatitis B virus-infected
      patients during antiviral therapy.
AB  - Since the introduction of antiviral compounds such as lamivudine and famciclovir
      in the treatment schedules of patients with chronic hepatitis B virus (HBV)
      infection, the accumulation of a variety of mutations in the HBV polymerase gene
      has been observed. The selection of these mutations is generally considered the
      cause of viral nonresponsiveness and treatment failure. Therefore, the detection
      of these mutations is of clinical importance. Previously genotyped HBV strains
      isolated from treated and untreated patients were amplified with primers specific
      for the HBV polymerase region from amino acids 465 to 562. Amplified products
      were cloned into plasmid vectors. The clones were used as reference strains. A
      set of 38 highly specific oligonucleotide probes covering three different codon
      positions, L528M, M552V/I, and V/L/M555I, were selected. These probes were
      applied as 19 different lines on a membrane strip. The strips were then
      hybridized with PCR fragments from the reference panel, revealing the amino acids
      at the three codon positions simultaneously for each clone. PCR products
      generated from two patients infected with HBV genotypes A and C, respectively,
      and treated with nucleoside analogs were analyzed on these strips. A gradual
      increase in genetic HBV polymerase complexity was observed in follow-up samples
      compared to that in pretreatment samples. Additional analysis of HBV polymerase
      DNA fragments in recombinant plasmid clones demonstrated the existence of (i)
      clones with double mutations, (ii) clones with single mutations at either codon
      528, 552, or 555, and (iii) the simultaneous occurrence of two or more viral
      populations within one sample. This line probe assay detected the complex
      quasispecies nature of HBV and provided some insight into the dynamics of
      resistance mutations.

PMID- 10655371
TI  - SimulFluor respiratory screen for rapid detection of multiple respiratory viruses
      in clinical specimens by immunofluorescence staining.
AB  - A new rapid direct immunofluorescence assay (DFA) respiratory screen reagent for
      detection of seven common respiratory viruses (respiratory syncytial virus [RSV],
      influenza A and B viruses, parainfluenza virus types 1 to 3, and adenovirus) was
      compared with standard single or dual DFA reagents and culture. In total, 1,531
      respiratory samples were adequate for testing with both SimulFluor Respiratory
      Screen (RS) reagent (Chemicon International, Temecula, Calif.) and single or dual
      DFA reagents. The RS DFA reagent detected 367 (98.4%) and single or dual DFA
      reagents detected 368 (98.7%) of 373 DFA-positive samples. In addition, the RS
      DFA reagent was equivalent to or better than culture for detection of all viruses
      except adenovirus. Only 15 of 799 (1.9%) RS-negative samples inoculated into cell
      cultures yielded respiratory virus isolates (one RSV, five influenza A virus, two
      influenza B virus, one parainfluenza virus, and six adenovirus). Sixty-six other
      virus isolates (13 rhinovirus, 24 cytomegalovirus, 28 herpes simplex virus type
      1, and 1 enterovirus) were also recovered in culture. With cytospin preparation
      of slides, only 7.5% of samples submitted were deemed inadequate for DFA. The
      availability of a rapid DFA screening reagent for detection of multiple common
      respiratory viruses within 1 to 2 h of sample collection should be of great
      benefit in terms of patient management and infection control.

PMID- 10655372
TI  - Development of a real-time quantitative assay for detection of Epstein-Barr
      virus.
AB  - With the use of real-time PCR, we developed and evaluated a rapid, sensitive,
      specific, and reproducible method for the detection of Epstein-Barr virus (EBV)
      DNA in plasma samples. This method allowed us to screen plasma and serum samples
      over a range between 100 and 10(7) copies of DNA per ml using two sample
      preparation methods based on absorption. A precision study yielded an average
      coefficient of variation for both methods of less than 12%, with a coefficient of
      regression for the standard curve of a minimum of 0. 98. We detected EBV DNA in
      19.2% of plasma samples from immunosuppressed solid-organ transplant patients
      without symptoms of EBV infections with a mean load of 440 copies per ml. EBV DNA
      could be detected in all transplant patients diagnosed with posttransplant
      lymphoproliferative disorder, with a mean load of 544,570 copies per ml. No EBV
      DNA could be detected in healthy individuals in nonimmunosuppressed control
      groups and a mean of 6,400 copies per ml could be detected in patients with
      infectious mononucleosis. Further studies revealed that the inhibitory effect of
      heparinized plasma could be efficiently removed by use of an extraction method
      with Celite as the absorbent.

PMID- 10655373
TI  - Performance of a multiplex qualitative PCR LCx assay for detection of human
      immunodeficiency virus type 1 (HIV-1) group M subtypes, group O, and HIV-2.
AB  - Early detection of human immunodeficiency virus (HIV) in blood and blood products
      can be achieved by a sensitive nucleic acid amplification-based assay. We report
      on the performance of a PCR-based qualitative assay that detects both HIV type 1
      (HIV-1) and HIV-2 with a sensitivity of 20 to 50 copies/ml. The assay has a
      specificity of 99.6% and an inhibition rate of 1.7%. One milliliter of sample is
      processed with a manifold system and Qiagen columns, and one-third of the
      extracted sample is used for PCR amplification. An internal control sequence,
      which is processed and amplified with each sample, monitors for amplification
      inhibition. Samples are reverse transcribed and are then amplified by reverse
      transcription-coupled PCR, after which HIV-1- and HIV-2-specific probes are
      hybridized to the amplified products. Following hybridization, samples are
      detected in the LCx instrument by microparticle enzyme immunoassay techniques.
      The detection system has an automated inactivation step that controls for PCR
      contamination. The HIV-1/2 qualitative RNA assay detects HIV-1 group M subtypes
      A, B, C, D, E, F, and G and group O. Testing of several HIV-1 seroconversion
      panels has demonstrated that the HIV-1/2 qualitative RNA assay detects HIV
      infection on the average of 6 days before p24 antigen can be detected and 11 days
      before antibodies can be detected.

PMID- 10655374
TI  - Survival of enterococci and staphylococci on hospital fabrics and plastic.
AB  - The transfer of gram-positive bacteria, particularly multiresistant
      Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE), among
      patients is a growing concern. One critical aspect of bacterial transfer is the
      ability of the microorganism to survive on various common hospital surfaces. The
      purpose of this study was to determine the survival of 22 gram-positive bacteria
      (vancomycin-sensitive and -resistant enterococci and methicillin-sensitive and 
      resistant staphylococci) on five common hospital materials: smooth 100% cotton
      (clothing), 100% cotton terry (towels), 60% cotton-40% polyester blend (scrub
      suits and lab coats), 100% polyester (privacy drapes), and 100% polypropylene
      plastic (splash aprons). Swatches were inoculated with 10(4) to 10(5) CFU of a
      microorganism, assayed daily by placing the swatches in nutritive media, and
      examining for growth after 48 h. All isolates survived for at least 1 day, and
      some survived for more than 90 days on the various materials. Smaller inocula
      (10(2)) survived for shorter times but still generally for days. Antibiotic
      sensitivity had no consistent effect on survival. The long survival of these
      bacteria, including MRSA and VRE, on commonly used hospital fabrics, such as
      scrub suits, lab coats, and hospital privacy drapes, underscores the need for
      meticulous contact control procedures and careful disinfection to limit the
      spread of these bacteria.

PMID- 10655375
TI  - Comparison of three assays for cytomegalovirus detection in AIDS patients at risk
      for retinitis.
AB  - The purpose of this study was to determine the sensitivity and specificity of
      three different methods of cytomegalovirus (CMV) detection for AIDS patients at
      risk for CMV retinitis. Patients with CD4(+) counts of <100/microl and negative
      baseline screening eye examinations were tested for CMV infection by (i) pp65
      antigenemia expression in leukocytes, (ii) the Digene Hybrid Capture CMV DNA
      System, and (iii) the Roche Amplicor Qualitative PCR Test. The incidence of CMV
      retinitis in our study of 296 patients at the Medical Center of Louisiana-New
      Orleans HIV Outpatient Clinic was 7. 2 per 100 person-years (a total of 20
      episodes in 18 patients from April 1997 to February 1999). Receiver operating
      characteristic curves were calculated for each assay to determine optimal cutoff
      points which maximized the sensitivity and specificity of each assay. The
      sensitivities of the assays compared to the eye examinations were 80% for the
      pp65 antigenemia assay (cutoff, >0 cell per 1.5 x 10(5) leukocytes), 85% for the
      Digene assay (cutoff, 1,400 genome copies/ml of whole blood), and 60% for the
      Amplicor assay. The specificities of the assays were 84, 84, and 87%,
      respectively. The Digene assay with a cutoff of >/=1,400 genome copies/ml gave
      optimal sensitivity and specificity and was found to have predictive values equal
      to those of the more technically cumbersome antigenemia assay.

PMID- 10655376
TI  - Comparison of effects of medium composition and atmospheric conditions on
      detection of Bilophila wadsworthia beta-lactamase by cefinase and cefinase plus
      methods.
AB  - The influence of growth medium and incubation conditions on the detection of
      Bilophila wadsworthia beta-lactamase was tested with Cefinase and Cefinase Plus
      disks. The tests involved aerobic and anaerobic incubation with conventional disk
      and quantitative tube assays. The production of beta-lactamase was correlated
      with penicillin G, ampicillin, and ampicillin-sulbactam MICs and inhibition zones
      on penicillin (2-U) disks. The strains were grown on (i) brucella agar
      (brucella), (ii) brucella agar supplemented with 1% pyruvate (brucella-pyruvate),
      and (iii) brucella agar supplemented with 1% taurine (brucella-taurine). With the
      aerobic disk assay, 100, 100, and 7% of strains were positive after 30 min from
      growth on brucella-pyruvate, brucella, and brucella-taurine plates, respectively;
      of strains grown on brucella-taurine, 54% remained negative by the Cefinase
      assay, and 23% remained negative by the Cefinase Plus assay at 2 h. In
      quantitative assays, the strains became positive after 30 min from brucella
      pyruvate plates and after 1 h from brucella plates. The intensities of the
      reactions were strongest with brucella-pyruvate plates under anaerobic test
      conditions. Anaerobic incubation enhanced beta-lactamase detection of growth on
      brucella-taurine: at 3 h, 85% of strains were positive in comparison to 38% with
      aerobic incubation. All beta-lactamase-negative strains were susceptible to
      penicillin G and ampicillin; all beta-lactamase-positive strains were resistant
      to ampicillin and, with the exception of two strains, penicillin G. In
      conclusion, beta-lactamase production correlated with susceptibility to
      penicillin G and ampicillin. Brucella agar supplemented with 1% pyruvate was the
      most reliable medium for testing B. wadsworthia beta-lactamase, and anaerobic
      incubation expedited positive results. Brucella agar supplemented with taurine
      was unsuitable for B. wadsworthia beta-lactamase testing. Cefinase and Cefinase
      Plus results were in agreement, but Cefinase Plus yielded faster reactions.

PMID- 10655377
TI  - Differential diagnosis of Taenia saginata and Taenia solium infection by PCR.
AB  - We have designed species-specific oligonucleotides which permit the differential
      detection of two species of cestodes, Taenia saginata and Taenia solium. The
      oligonucleotides contain sequences established for two previously reported,
      noncoding DNA fragments cloned from a genomic library of T. saginata. The first,
      which is T. saginata specific (fragment HDP1), is a repetitive sequence with a 53
      bp monomeric unit repeated 24 times in direct tandem along the 1, 272-bp
      fragment. From this sequence the two oligonucleotides that were selected
      (oligonucleotides PTs4F1 and PTs4R1) specifically amplified genomic DNA (gDNA)
      from T. saginata but not T. solium or other related cestodes and had a
      sensitivity down to 10 pg of T. saginata gDNA. The second DNA fragment (fragment
      HDP2; 3,954 bp) hybridized to both T. saginata and T. solium DNAs and was not a
      repetitive sequence. Three oligonucleotides (oligonucleotides PTs7S35F1,
      PTs7S35F2, and PTs7S35R1) designed from the sequence of HDP2 allowed the
      differential amplification of gDNAs from T. saginata, T. solium, and Echinococcus
      granulosus in a multiplex PCR, which exhibits a sensitivity of 10 pg.

PMID- 10655378
TI  - Detection of TT virus DNA and GB virus type C/Hepatitis G virus RNA in serum and
      breast milk: determination of mother-to-child transmission.
AB  - To investigate the vertical transmission of the newly described TT virus (TTV),
      serum and breast milk samples from 46 women as well as sera from their 47
      newborns were examined for the presence of TTV DNA by PCR. TTV DNA was detected
      in 47.8% (n = 22) of the women. All but one child born to these women were also
      viremic for TTV from the first sample onward. TTV DNA was found in 73.9% (n = 17)
      of the breast milk samples derived from TTV viremic mothers. The one TTV-negative
      child born to a viremic mother remained negative during follow-up, although it
      was breast-fed. Our data show that TTV is highly effectively transmitted from
      mothers to their children during pregnancy. Although the majority of breast milk
      samples from viremic mothers are positive by TTV PCR, there is no need to
      discourage women from breast-feeding, because most children are TTV viremic even
      before breast-feeding begins.

PMID- 10655379
TI  - Use of PCR to detect Leishmania (Viannia) spp. in dog blood and bone marrow.
AB  - A PCR-based protocol for the detection of Leishmania (Viannia) parasites in
      canine blood, buffy coat, and bone marrow was developed and was then tested with
      field samples taken from a random sample of 545 dogs from villages in Peru where
      Leishmania (Viannia) braziliensis and Leishmania (Viannia) peruviana are endemic.
      Comparative tests with cultured parasites mixed with dog blood showed that the
      PCR assay's sensitivity was significantly dependent on the DNA extraction
      protocol and the PCR primers used. Mass screening of field samples by the
      preferred PCR protocol detected American cutaneous leishmaniasis (ACL) in 44 of
      545 (8.1%) dogs; 31 of 402 (7.7%), 20 of 223 (9.0%), and 8 of 46 (17.4%) were PCR
      positive when whole blood, buffy coat, and bone marrow aspirates, respectively,
      were tested. The high prevalence of Leishmania in both asymptomatic (7.6%) and
      symptomatic (18.0%) dogs provides further circumstantial evidence for their
      suspected role as reservoir hosts of ACL and indicates that hematogenous
      dissemination of parasites may be a more common pathological phenomenon than has
      previously been acknowledged. However, unlike for zoonotic visceral
      leishmaniasis, the comparatively low prevalence of Leishmania (Viannia) in the
      blood of symptomatic dogs indicates that PCR with blood cannot be the "gold
      standard" for the (mass) screening of samples in epidemiological studies.

PMID- 10655380
TI  - Correlation of oxacillin MIC with mecA gene carriage in coagulase-negative
      staphylococci.
AB  - The National Committee for Clinical Laboratory Standards has recently changed the
      oxacillin breakpoint from >/=4 mg/liter to >/=0. 5 mg/liter to detect methicillin
      resistant coagulase-negative staphylococci (CoNS) because the previous breakpoint
      lacked sensitivity. To determine the correlation between the new oxacillin
      breakpoint and the presence of the mecA gene, 493 CoNS of 11 species were tested.
      The presence of the mecA gene was determined by PCR, and oxacillin susceptibility
      was determined by the agar dilution method with Mueller-Hinton agar containing 2%
      NaCl and oxacillin (0. 125 to 4.0 mg/liter). The new breakpoint correctly
      classified all CoNS strains with mecA as methicillin resistant and strains of
      Staphylococcus epidermidis, S. haemolyticus, and S. hominis without mecA as
      methicillin susceptible. The breakpoint of >/=0.5 mg/liter was not specific for
      S. cohnii, S. lugdunensis, S. saprophyticus, S. warneri, and S. xylosus, in that
      it categorized 70 of 74 strains of these species without mecA (94.6%) as
      methicillin resistant. The results of this study indicate that the new oxacillin
      breakpoint accurately identifies strains of CoNS with mecA but is not specific
      for strains of certain species of CoNS without mecA.

PMID- 10655381
TI  - Molecular epidemiology of rabies virus isolates from Israel and other middle- and
      Near-Eastern countries.
AB  - A total of 226 isolates of rabies virus from different areas of Israel, including
      three human isolates and one sample from South Lebanon were identified between
      1993 and 1998 by direct immunofluorescence using monoclonal antibodies to the
      viral nucleoprotein (N). An epidemiological survey based on nucleotide sequence
      analysis of 328 bp from the C terminus of the N coding region and the noncoding
      region between the nucleoprotein and the phosphoprotein (NS gene) was performed.
      Phylogenetic analysis of the isolates from Israel showed that they were related
      geographically, but not according to host species. Five variants, related groups
      distributed among four geographical regions, were identified. In each region,
      rabies virus was isolated from more than one animal species. A comparison of the
      sequence analysis of rabies virus samples from the rest of world revealed a 2
      nucleotide change that distinguished the Middle East variants from the rest.

PMID- 10655382
TI  - Resistance of Trichomonas vaginalis to metronidazole: report of the first three
      cases from Finland and optimization of in vitro susceptibility testing under
      various oxygen concentrations.
AB  - Trichomonas vaginalis is a globally common sexually transmitted human parasite.
      Many strains of T. vaginalis from around the world have been described to be
      resistant to the current drug of choice, metronidazole. However, only a few cases
      of metronidazole resistance have been reported from Europe. The resistant strains
      cause prolonged infections which are difficult to treat. T. vaginalis infection
      also increases the risk for human immunodeficiency virus transmission. We present
      a practical method for determining the resistance of T. vaginalis to 5
      nitroimidazoles. The suggested method was developed by determining the MICs and
      minimal lethal concentrations (MLCs) of metronidazole and ornidazole for T.
      vaginalis under various aerobic and anaerobic conditions. Using this assay we
      have found the first three metronidazole-resistant strains from Finland, although
      the origin of at least one of the strains seems to be Russia. Analysis of the
      patient-derived and previously characterized isolates showed that metronidazole
      resistant strains were also resistant to ornidazole, and MLCs for all strains
      tested correlated well with the MICs. The suggested MICs of metronidazole for
      differentiation of sensitive and resistant isolates are >75 microg/ml in an
      aerobic 24-h assay and >15 microg/ml in an anaerobic 48-h assay.

PMID- 10655383
TI  - Comparison of PCR, antigenemia assay, and rapid blood culture for detection and
      prevention of cytomegalovirus disease after lung transplantation.
AB  - The goal of this study was to evaluate serial cytomegalovirus (CMV) blood
      culture, antigenemia testing, and qualitative and quantitative plasma CMV PCR for
      their ability to predict CMV disease and thus to direct preemptive therapy after
      lung transplantation. Forty-one patients provided 414 samples for blood culture,
      290 samples for antigenemia testing, and 432 samples for PCR. Seven patients
      developed 11 episodes of CMV disease. CMV PCR had sensitivity, specificity, and
      positive predictive and negative predictive values of 79, 99, 84, and 99%,
      respectively, compared with 48, 99, 85, and 98%, respectively, for antigenemia
      testing, and 8, 100, 100, and 97%, respectively, for culture. Only quantitative
      CMV PCR correlated with disease stage: asymptomatic patients had a mean of 1,500
      CMV DNA copies/ml, whereas patients who developed CMV disease had 5,087 copies/ml
      12 to 4 weeks before symptoms and 32,000 copies/ml at diagnosis. Furthermore, CMV
      PCR-measured DNA increased 5- to 10-fold immediately preceding symptoms. PCR and
      antigenemia test values decreased with anti-CMV therapy. CMV DNA (as detected by
      PCR), but not antigenemia, persisted in patients who later developed recurrent
      CMV disease. The data indicate that lung transplant recipients will benefit from
      monitoring of CMV disease by plasma CMV PCR.

PMID- 10655384
TI  - Analysis of genetic variability within the immunodominant epitopes of envelope
      gp41 from human immunodeficiency virus type 1 (HIV-1) group M and its impact on
      HIV-1 antibody detection.
AB  - The serodiagnosis of human immunodeficiency virus type 1 (HIV-1) infection
      primarily relies on the detection of antibodies, most of which are directed
      against the immunodominant regions (IDR) of HIV-1 structural proteins. Among
      these, the N-terminal region of gp41 contains cluster I (amino acids [aa] 580 to
      623), comprising the cytotoxic T-lymphocyte epitope (AVERYLKDQQLL) and the
      cysteine loop (CSGKLIC), and cluster II (aa 646 to 682), comprising an ectodomain
      region (ELDKWA). To delineate the epitope diversity within clusters I and II and
      to determine whether the diversity affects serologic detection by U.S. Food and
      Drug Administration (FDA)-licensed enzyme immunoassay (EIA) kits, gp41 Env
      sequences from 247 seropositive persons infected with HIV-1 group M, subtypes A
      (n = 42), B (n = 62), B' (n = 13), C (n = 38), D (n = 41), E (n = 18), F (n =
      27), and G (n = 6), and 6 HIV-1-infected but persistently seronegative (HIPS)
      persons were analyzed. While all IDR were highly conserved among both
      seropositive and HIPS persons, minor amino acid substitutions (<20% for any one
      residue, mostly conservative) were observed for all subtypes, except for B', in
      comparison with the consensus sequence for each subtype. Most importantly, none
      of the observed substitutions among the group M plasma specimens affected
      antibody detection, since all specimens (n = 152) tested positive with all five
      FDA-licensed EIA kits. Furthermore, all specimens reacted with a group M
      consensus gp41 peptide (WGIKQLQARVLAVERYLKDQQLLGIWGCSGKLICTTAVPWNASW), and high
      degrees of cross-reactivity (>80%) were observed with an HIV-1 group N peptide,
      an HIV-1 group O peptide, and a peptide derived from the homologous region of
      gp41 from simian immunodeficiency virus from chimpanzee (SIVcpz). Taken together,
      these data indicate that the minor substitutions observed within the IDR of gp41
      of HIV-1 group M subtypes do not affect antibody recognition and that all HIV-1
      seropositive specimens containing the observed substitutions react with the FDA
      licensed EIA kits regardless of viral genotype and geographic origin.

PMID- 10655385
TI  - Rapid diagnosis of bacteremia by universal amplification of 23S ribosomal DNA
      followed by hybridization to an oligonucleotide array.
AB  - The rapid identification of bacteria in blood cultures and other clinical
      specimens is important for patient management and antimicrobial therapy. We
      describe a rapid (<4 h) detection and identification system that uses universal
      PCR primers to amplify a variable region of bacterial 23S ribosomal DNA, followed
      by reverse hybridization of the products to a panel of oligonucleotides. This
      procedure was successful in discriminating a range of bacteria in pure cultures.
      When this procedure was applied directly to 158 unselected positive blood culture
      broths on the day when growth was detected, 125 (79.7%) were correctly
      identified, including 4 with mixed cultures. Nine (7.2%) yielded bacteria for
      which no oligonucleotide targets were present in the oligonucleotide panel, and
      16 culture-positive broths (10.3%) produced no PCR product. In seven of the
      remaining eight broths, streptococci were identified but not subsequently grown,
      and one isolate of Staphylococcus aureus was misidentified as a coagulase
      negative staphylococcus. The accuracy, range, and discriminatory power of the
      assay can be continually extended by adding further oligonucleotides to the panel
      without significantly increasing complexity or cost.

PMID- 10655386
TI  - Application of 16S rRNA gene sequencing to identify Bordetella hinzii as the
      causative agent of fatal septicemia.
AB  - We report on the first case of fatal septicemia caused by Bordetella hinzii. The
      causative organism exhibited a biochemical profile identical to that of
      Bordetella avium with three commercial identification systems (API 20E, API 20
      NE, and Vitek GNI+ card). However, its cellular fatty acid profile was not
      typical for either B. avium or previously reported strains of B. hinzii.
      Presumptive identification of the patient's isolate was accomplished by
      traditional biochemical testing, and definitive identification was achieved by
      16S rRNA gene sequence analysis. Phenotypic features useful in distinguishing B.
      hinzii from B. avium were production of alkali from malonate and resistance to
      several antimicrobial agents.

PMID- 10655387
TI  - Diagnosis of herpes simplex virus infections in the clinical laboratory by
      LightCycler PCR.
AB  - Herpes simplex virus (HSV) causes several clinical manifestations in both normal
      and immunocompromised hosts; this agent is the most frequently detected virus in
      diagnostic laboratories. Recovery of the virus in cell culture is considered the
      "gold standard" for detection of this virus from sources other than cerebrospinal
      fluid. LightCycler is a newly developed, commercially available system designed
      to rapidly perform PCR, with real-time detection of PCR products by a
      fluorescence resonance energy transfer assay. We compared the detection of HSV
      for 200 specimens (number of genital specimens, 160; number of dermal specimens,
      38; number of ocular specimens, 2) by shell vial cell cultures (MRC-5) and by
      LightCycler PCR. Of a total of 88 (44%) HSV strains detected, 69 (78%) were
      detected by both shell vial cell cultures and LightCycler PCR (DNA polymerase
      target). A total of 19 (22%) specimens were detected exclusively by LightCycler
      PCR. No specimens were positive by the shell vial assay only. All 19 discrepant
      samples had HSV DNA detected by an independent PCR directed to the thymidine
      kinase gene of the virus. The melting curve analysis feature of the LightCycler
      instrument identified identical genotype results for HSV type 1 (HSV-1) and HSV-2
      from 84 of 88 (96%) positive samples. Specimens can be extracted, target HSV DNA
      can be amplified, and HSV PCR products can be identified by genotype within 2 h
      after receipt of specimen into the laboratory. The increased level of accurate
      identification (all 88 positive samples) compared with that of shell vial cell
      culture (69 of 88 samples identified as positive) and the agreement of
      LightCycler PCR results with all shell vial positive results indicate the
      potential for routine implementation of this technology for laboratory diagnosis
      of HSV infections.

PMID- 10655388
TI  - Specificity and sensitivity of high levels of immunoglobulin G antibodies against
      pertussis toxin in a single serum sample for diagnosis of infection with
      Bordetella pertussis.
AB  - Laboratory confirmation of pertussis by culture, PCR, or detection of antibody
      increase in paired sera is hampered by low sensitivity in the later stages of the
      disease. Therefore, we investigated whether, and at which level, concentrations
      of immunoglobulin G (IgG) antibodies against pertussis toxin (PT), IgG-PT, in a
      single serum sample are indicative of active or recent pertussis. IgG-PT,
      measured by enzyme-linked immunosorbent assay in units per milliliter, was
      analyzed in 7,756 sera collected in a population-based study in The Netherlands,
      in the sera of 3,491 patients with at least a fourfold increase of IgG-PT, in
      paired sera of 89 patients with positive cultures and/or PCR results, and in the
      sera of 57 patients with clinically documented pertussis with a median follow-up
      of 1.4 years. We conclude that, independently of age, IgG-PT levels of at least
      100 U/ml are diagnostic of recent or active infection with Bordetella pertussis.
      Such levels are present in less than 1% of the population and are reached in most
      pertussis patients within 4 weeks after disease onset and persist only
      temporarily.

PMID- 10655389
TI  - Pathogenic clones versus environmentally driven population increase: analysis of
      an epidemic of the human fungal pathogen Coccidioides immitis.
AB  - For many pathogenic microbes that utilize mainly asexual modes of reproduction,
      it is unknown whether epidemics are due to either the emergence of pathogenic
      clones or environmentally determined increases in the population size of the
      organism. Descriptions of the genetic structures of epidemic populations, in
      conjunction with analyses of key environmental variables, are able to distinguish
      between these competing hypotheses. A major epidemic of coccidioidomycosis
      (etiologic agent, Coccidioides immitis) occurred between 1991 and 1994 in central
      California, representing an 11-fold increase above the mean number of cases
      reported from 1955 to 1990. Molecular analyses showed extensive genetic
      diversity, a lack of linkage disequilibria, and little phylogenetic structure,
      demonstrating that a newly pathogenic strain was not responsible for the observed
      epidemic. Epidemiological analyses showed that morbidity caused by C. immitis was
      best explained by the interaction between two variables, the lengths of droughts
      preceding epidemics and the amounts of rainfall. This shows that the principal
      factors governing this epidemic of C. immitis are environmental and not genetic.
      An important implication of this result is that the periodicity of cyclical
      environmental factors regulates the population size of C. immitis and is
      instrumental in determining the size of epidemics. This knowledge provides an
      important tool for predicting outbreaks of this pathogen, as well as a general
      framework that may be applied to determine the causes of epidemics of other
      fungal diseases.

PMID- 10655390
TI  - Rapid identification of bacteria in blood cultures by using fluorescently labeled
      oligonucleotide probes.
AB  - The applicability of whole-cell hybridization for the identification of
      pathogenic bacteria in blood from septic patients was examined. Oligonucleotide
      probes, fluorescently labeled with fluorescein isothiocyanate, directed against
      the variable regions of the 16S rRNAs of the following bacterial species and/or
      genera were used: Streptococcus spp., Enterococcus faecalis, Staphylococcus
      aureus, coagulase-negative staphylococci (CoNS), Escherichia coli, Pseudomonas
      aeruginosa, and the Enterobacteriaceae family. A probe specific for the rRNAs of
      almost all bacteria and its complementary, reversed counterpart was used as
      positive and negative control, respectively. The probes were used in conjunction
      with a fast and simple-to-use protocol for whole-cell hybridization. This
      protocol yields an identification after 25 to 45 min, depending on whether the
      bacterium is gram positive or gram negative. A total of 182 blood samples which
      tested positive in a blood culture machine were investigated. All probes except
      for the ones for S. aureus and the CoNS showed sensitivities and specificities of
      1.000. It was concluded that whole-cell hybridization is well suited for the fast
      screening of septic blood containing streptococci and/or enterococci or gram
      negative rods.

PMID- 10655391
TI  - Specific and rapid detection by fluorescent in situ hybridization of bacteria in
      clinical samples obtained from cystic fibrosis patients.
AB  - We report on the rapid and specific detection of bacteria commonly isolated from
      clinical specimens from cystic fibrosis (CF) patients by fluorescent in situ
      hybridization (FISH). On the basis of comparative sequence analysis, we designed
      oligonucleotide probes complementary to species-specific 16S rRNA regions of
      these microorganisms and demonstrated the specificities of the probes by
      hybridization of different remotely related as well as closely related reference
      strains. Furthermore, in a pilot project we investigated 75 sputum samples and 10
      throat swab specimens from CF patients by FISH and detected Pseudomonas
      aeruginosa, Burkholderia cepacia, Stenotrophomonas maltophilia, Haemophilus
      influenzae, and Staphylococcus aureus within these specimens. The specificity of
      FISH was 100% in comparison to the results of conventional microbial culture. In
      contrast, the sensitivity of standard laboratory cultivation was moderately
      higher, since the limit for microscopic detection of bacteria within sputum
      samples by FISH was approximately 4 x 10(5) CFU/ml of sputum (resulting in a 90%
      sensitivity for FISH). Moreover, we demonstrated that FISH will be useful for the
      rapid detection of bacteria that cause acute pulmonary exacerbations in CF
      patients, as demonstrated in patients with H. influenzae, S. aureus, and P.
      aeruginosa exacerbations. Therefore, FISH is a valuable additional method for the
      rapid and specific detection of bacteria in clinical samples from CF patients, in
      particular, patients with pulmonary exacerbations.

PMID- 10655392
TI  - Unusual case of Acanthamoeba polyphaga and Pseudomonas aeruginosa keratitis in a
      contact lens wearer from Gauteng, South Africa.
AB  - Acanthamoeba species can cause a chronic, progressive ulcerative keratitis of the
      eye which is not responsive to the usual antimicrobial therapy and is frequently
      mistaken for stromal herpes keratitis. An unusual case of coinfection with
      Acanthamoeba polyphaga and Pseudomonas aeruginosa as causes of corneal keratitis
      in a contact lens wearer from Gauteng, South Africa, is reported. These two
      pathogens have previously been assumed to be selectively exclusive. Cysts of the
      isolated acanthameba tolerated an incubation temperature of 40 degrees C,
      indicating a pathogenic species. This case highlights the importance of culture
      methods in the diagnosis of corneal infection and the choice of treatment
      regimen. The patient's history of careless contact lens-disinfecting habits
      emphasizes the need to adhere strictly to recommended methods of contact lens
      care.

PMID- 10655393
TI  - Fluorescent In situ hybridization allows rapid identification of microorganisms
      in blood cultures.
AB  - Using fluorescent in situ hybridization (FISH) with rRNA-targeted fluorescently
      labelled oligonucleotide probes, pathogens were rapidly detected and identified
      in positive blood culture bottles without cultivation and biotyping. In this
      study, 115 blood cultures with a positive growth index as determined by a
      continuous-reading automated blood culture system were examined by both
      conventional laboratory methods and FISH. For this purpose, oligonucleotide
      probes that allowed identification of approximately 95% of those pathogens
      typically associated with bacteremia were produced. The sensitivity and
      specificity of these probes were 100%. From all 115 blood cultures,
      microorganisms were grown after 1 day and identification to the family, genus, or
      species level was achieved after 1 to 3 days while 111 samples (96.5%) were
      similarly identified by FISH within 2.5 h. Staphylococci were identified in 62 of
      62 samples, streptococci and enterococci were identified in 19 of 20 samples,
      gram-negative rods were identified in 28 of 30 samples, and fungi were identified
      in two of two samples. Thus, FISH is an appropriate method for identification of
      pathogens grown in blood cultures from septicemic patients.

PMID- 10655394
TI  - Genotypic stability of cold-adapted influenza virus vaccine in an efficacy
      clinical trial.
AB  - An investigational live influenza virus vaccine, FluMist, contains three cold
      adapted H1N1, H3N2, and B influenza viruses. The vaccine viruses are 6/2
      reassortants, in which the hemagglutinin (HA) and neuraminidase (NA) genes are
      derived from the circulating wild-type viruses and the remaining six genes are
      derived from the cold-adapted master donor strains. The six genes from the cold
      adapted master donor strains ensure the attenuation, and the HA and NA genes from
      the wild-type viruses confer the ability to induce protective immunity against
      contemporary influenza strains. The genotypic stability of this vaccine was
      studied by employing clinical samples collected during an efficacy trial. Viruses
      present in the nasal and throat swab specimens and in supernatants after
      culturing the specimens were detected and subtyped by multiplex reverse
      transcriptase (RT)-PCR. Complete genotypes of these detected viruses were
      determined by a combination of RT-PCR and restriction fragment length
      polymorphism, multiplex RT-PCR and fluorescent single-strand conformation
      polymorphism, and nucleic acid sequencing analysis. The FluMist vaccine appeared
      to be genotypically stable after replication in the human host. All viruses
      detected during the 2-week postvaccination period were shed vaccine viruses and
      had maintained the 6/2 genotype.

PMID- 10655395
TI  - Capsule expression by bovine isolates of Staphylococcus aureus from Argentina:
      genetic and epidemiologic analyses.
AB  - Staphylococcus aureus is an important cause of bovine mastitis worldwide, and
      effective preventive or therapeutic modalities are lacking. Although most human
      S. aureus isolates produce capsular polysaccharides (CPs), few reports have
      described the prevalence of capsules on bovine isolates. This information is
      important for the rational design of a vaccine for the prevention of
      staphylococcal mastitis. We serotyped 195 S. aureus strains isolated between 1989
      and 1997 from the milk of mastitic cows in Argentina. Only 14 (7.1%) of the
      strains were serotype 5, and all were recovered between 1989 and 1992. Thirteen
      serotype 8 strains were identified, and 12 of these were isolated between 1991
      and 1994. The remaining 168 isolates were nonreactive (NR) with CP serotype 5
      (CP5)- or CP8-specific antibodies. Hybridization studies performed with genomic
      DNA from eight NR strains revealed that only three of them carried the capsule
      genes. Pulsed-field gel electrophoresis (PFGE) performed with 127 of the 195 S.
      aureus isolates revealed that most (86%) strains belonged to one of four major
      PFGE groups. Although 8 of 14 CP5 isolates showed a common PFGE pattern
      (arbitrarily defined as A1), 31 other A1 isolates from the same time period (1989
      to 1992) were not CP5 positive. In contrast, only nine PFGE type B3 isolates were
      recovered between 1990 and 1994, and eight of these were positive for CP8 (P <
      0.0003). The results of this study underscore the variability in capsule
      expression by S. aureus strains isolated from different geographical regions and
      cast doubt on the roles of CP5 and CP8 in the pathogenesis and immunoprophylaxis
      of bovine mastitis in Argentina.

PMID- 10655396
TI  - Serological confirmation of Chagas' disease by a recombinant and peptide antigen
      line immunoassay: INNO-LIA chagas.
AB  - Although screening for Trypanosoma cruzi antibodies is mandatory in most South
      American countries, current tests are insensitive and have poor specificity. A
      recently optimized line immunoassay (the INNO-LIA Chagas assay) for the
      serological confirmation of Chagas' disease was evaluated at a large blood bank
      in Sao Paulo, Brazil. Sera from blood donors who reacted in at least one of three
      serological screening assays (n = 1,604) and who returned for a follow-up were
      retested, and the donors were interviewed to assess their epidemiological risk.
      The results obtained by the confirmatory assay evaluated in this study were
      compared to those obtained by the three different screening assays. Upon
      consideration of the consensus results obtained by the three different screening
      assays as a "gold standard," the INNO-LIA Chagas assay showed a sensitivity of
      99.4% (95% confidence interval [CI], 98.3 to 99.9) and a specificity of 98.1%
      (95% CI, 96.6 to 99.0) for positive (n = 503) and negative (n = 577) sera. The
      INNO-LIA Chagas assay confirmed the results for significantly larger numbers of
      positive samples of at-risk individuals independent of the number of positive
      screening tests (P = 0.017, Mantel-Haenszel test). In conclusion, the INNO-LIA
      Chagas assay reliably confirmed the presence of antibodies to T. cruzi and can be
      implemented as a confirmatory assay for Chagas' disease serology.

PMID- 10655397
TI  - Simultaneous approach for nonculture PCR-based identification and serogroup
      prediction of Neisseria meningitidis.
AB  - A nonculture PCR-based method to characterize Neisseria meningitidis was used to
      test 225 clinical specimens. PCR correctly identified and predicted the
      serogroups of N. meningitidis of culture-proven meningococcal diseases and
      confirmed this diagnosis in 35% of suspected samples. This approach could be
      useful when culture fails to isolate N. meningitidis.

PMID- 10655398
TI  - Comparison of blood collected in acid-citrate-dextrose and EDTA for use in human
      immunodeficiency virus peripheral blood mononuclear cell cultures.
AB  - Paired blood samples collected in acid-citrate-dextrose and EDTA were compared
      for human immunodeficiency virus (HIV) infectivity on the day of collection or
      after 1 day of storage at room temperature. No significant differences between
      the anticoagulants were observed. Culture positivity was significantly associated
      with HIV RNA viral loads for both anticoagulants.

PMID- 10655399
TI  - Effect of a Mycoplasma hominis-like Mycoplasma on the infection of HEp-2 cells by
      the TW-183 strain of Chlamydia pneumoniae.
AB  - We isolated a Mycoplasma hominis-like mycoplasma from a stock culture of
      Chlamydia pneumoniae TW-183 obtained from the American Type Culture Collection
      and eradicated the contaminant by treating the stock suspension with a nonionic
      detergent, Igepal CA-630. The M. hominis-like mycoplasma neither inhibits nor
      enhances the infectivity of C. pneumoniae for HEp-2 cells.

PMID- 10655400
TI  - Clinical evaluation of the BDProbeTec ET system for rapid detection of
      Mycobacterium tuberculosis.
AB  - The performance of the BDProbeTec ET system (BD Biosciences, Sparks, Md.) for
      direct detection of Mycobacterium tuberculosis complex (MTBC) in respiratory
      specimens was evaluated by comparing results to those of conventional
      mycobacterial culture performed with the BACTEC 460 TB system and Middlebrook
      7H11 biplates. Patients known to have been on antituberculous therapy were
      excluded from the analysis. Of 600 evaluable specimens (4 specimens were excluded
      from the analysis due to failure of the internal amplification control [IAC])
      from 332 patients, 57 grew mycobacteria; 16 were MTBC (from 12 patients), and 41
      were nontuberculous mycobacteria. Of the 16 MTBC culture-positive specimens, 12
      were smear positive and 4 were smear negative. BDProbeTec ET detected 14 of the
      16 MTBC culture-positive specimens, resulting in initial overall sensitivity,
      specificity, and positive and negative predictive values of 87.5, 99.0, 70.0, and
      99.7%, respectively. After resolution of discrepancies by review of medical
      records and retesting of samples yielding discordant MTBC culture and BDProbeTec
      ET results, the revised overall sensitivity, specificity, and positive and
      negative predictive values of the BDProbeTec ET were respectively 93.8, 99.8,
      93.8, and 99.8% by specimen and 91.7, 99.7, 91.7, and 99.7% by patient. The
      BDProbeTec ET System offers the distinct advantage of including an IAC in the
      specimen well. These data suggest that the test performance is very good,
      especially for smear-positive samples. However, the number of patients with
      tuberculosis in our study, especially those with smear-negative disease, was
      small; therefore, additional studies are needed.

PMID- 10655401
TI  - Heterogeneous vancomycin resistance in methicillin-resistant Staphylococcus
      aureus strains isolated in a large Italian hospital.
AB  - Of 179 methicillin-resistant Staphylococcus aureus strains isolated from 1997 to
      1998, two strains (1.1%) gave subclones for which the vancomycin MICs were 8
      mg/liter. Pulsed-field gel electrophoresis showed identical restriction patterns
      for both isolates, suggesting transfer of a single clone between two different
      patients.

PMID- 10655402
TI  - Trends in antifungal susceptibility among Candida sp. Urinary isolates from 1994
      and 1998.
AB  - Antifungal susceptibilities were determined from 80 urinary isolates of Candida
      species collected in 1994 and 1998. Our findings demonstrate increasing geometric
      means of fluconazole MICs and fluconazole resistance in Candida albicans and
      Candida tropicalis (those for Candida glabrata were unchanged) within the 4-year
      span. Amphotericin B and voriconazole MICs remained constant.

PMID- 10655403
TI  - Reliability of the MB/BacT system for testing susceptibility of Mycobacterium
      tuberculosis complex isolates to antituberculous drugs.
AB  - The susceptibility of 115 Mycobacterium tuberculosis complex clinical isolates to
      isoniazid, streptomycin, ethambutol, and rifampin was assessed by the MB/BacT and
      BACTEC 460TB systems. The correlation between the two tests was 98.3% for
      isoniazid, 100% for streptomycin and rifampin, and 95.8% for ethambutol.
      Turnaround times for antimicrobial susceptibility testing ranged from 5 to 11
      days (median, 8.5 days) for MB/BacT and from 4 to 8 days (median, 6 days) for
      BACTEC 460TB.

PMID- 10655404
TI  - Genetic characterization of Campylobacter jejuni O:41 isolates in relation with
      Guillain-Barre syndrome.
AB  - Campylobacter jejuni O:41 strains are found in association with Guillain-Barre
      syndrome in South Africa. Strains of this serotype collected over 17 years were
      characterized by amplified fragment length polymorphism and flagellin typing to
      determine their clonal nature. Despite minor variation in GM1 expression, all of
      the strains were genetically indistinguishable, indicating that they are
      representative of a genetically stable clone.

PMID- 10655405
TI  - PCR-Based assay for discrimination between invasive and contaminating
      Staphylococcus epidermidis strains.
AB  - The discrimination between Staphylococcus epidermidis strains that contaminate
      and infect blood cultures is a daily challenge for clinical laboratories. The
      results of PCR detection of putative virulence genes were compared for
      contaminating strains, sepsis-related strains, catheter strains, and saprophytic
      strains. Multiplex PCR was used to explore the atlE gene, which is involved in
      initial adherence, the intercellular adhesion gene cluster (ica), which mediates
      the formation of the biofilm, and the agrA, sarA, and mecA genes, which might
      contribute to the pathogenicity of S. epidermidis. Whereas the atlE, agrA, and
      sarA genes were almost ubiquitously amplified, the ica and mecA genes were
      detected significantly more in infecting strains than in contaminating strains (P
      </= 0.02) and thus appeared to be related to the potential virulence of S.
      epidermidis.

PMID- 10655406
TI  - Failure to detect Chlamydia pneumoniae in brain sections of Alzheimer's disease
      patients.
AB  - A recent North American study detected Chlamydia pneumoniae in 17 of 19 brains of
      Alzheimer's patients and supposed a C. pneumoniae infection to be a risk factor
      for Alzheimer's disease (AD). In this study, we analyzed paraffin-embedded tissue
      samples of 20 AD patients by nested PCR and immunocytochemistry with a panel of
      antichlamydial antibodies and could detect neither C. pneumoniae-specific DNA nor
      chlamydial antigens. From our data, the presence of C. pneumoniae in the brains
      of Alzheimer's patients is not a common phenomenon; an association remains
      questionable.

PMID- 10655407
TI  - Presence of type III secretion genes in Burkholderia pseudomallei correlates with
      Ara(-) phenotypes.
AB  - Dot blot hybridization and PCR amplification of 14 Ara(+) and 8 Ara(-)
      Burkholderia pseudomallei strains showed that type III secretion (TTS) genes were
      present in all the Ara(-) strains but absent from all but one of the Ara(+)
      strains. The link between TTS genes and an Ara(-) phenotype suggests a role for
      TTS in virulence.

PMID- 10655408
TI  - Thyrotoxicosis induced by thyroid involvement of disseminated Aspergillus
      fumigatus infection.
AB  - Aspergillus fumigatus is increasingly recognized as an important nosocomial
      pathogen in severely immunocompromised patients. Infection is difficult to
      diagnose antemortem and typically has a fatal outcome. Here we report the case of
      a cardiac transplant recipient with disseminated A. fumigatus infection which
      clinically presented as thyrotoxicosis due to massive involvement of the thyroid
      gland.

PMID- 10655409
TI  - Hepatitis C virus quantitation: optimization of strategies for detecting low
      level viremia.
AB  - A long-term assessment of quantitative hepatitis C virus (HCV) testing was
      performed at the University of Pittsburgh Medical Center. The Quantiplex HCV RNA
      2.0 branched-chain DNA (bDNA) assay (Bayer Diagnostics) for hepatitis C viral
      load determination was used to test 3,471 specimens. bDNA-negative samples were
      also tested by an in-house qualitative reverse transcriptase (RT)-PCR assay with
      a measured sensitivity of fewer than 100 HCV genome equivalents per milliliter.
      Of 1,239 bDNA-negative specimens, 74.1% were negative and 25.9% were positive by
      RT-PCR, indicating the presence of viremia in a significant proportion of bDNA
      negative samples. We discuss the medical and economic implications of these
      results and propose two alternatives for clinical laboratories to consider in
      approaching quantitative HCV testing. For laboratories able to perform a
      sensitive RT-PCR assay for </=40% of the bDNA test cost, prescreening bDNA
      requests by RT-PCR may be the most cost-effective approach.

PMID- 10655410
TI  - Survival of aerobic and anaerobic bacteria in purulent clinical specimens
      maintained in the Copan Venturi Transystem and Becton Dickinson Port-a-Cul
      transport systems.
AB  - Recovery of aerobic and anaerobic bacteria from clinical specimens maintained in
      the Copan Venturi Transystem and the Becton Dickinson Port-a-Cul transport was
      assessed. Of 54 anaerobes, 53 were recovered after 4 h, and 52 were recovered
      after 24 h, from both systems. After 48 h, 45 and 50 were recovered from the two
      systems, respectively.

PMID- 10655411
TI  - Epidemic typhoid in vietnam: molecular typing of multiple-antibiotic-resistant
      Salmonella enterica serotype typhi from four outbreaks.
AB  - Multidrug-resistant Salmonella enterica serotype Typhi isolates from four
      outbreaks of typhoid fever in southern Vietnam between 1993 and 1997 were
      compared. Pulsed-field gel electrophoresis, bacteriophage and plasmid typing, and
      antibiotic susceptibilities showed that independent outbreaks of multidrug
      resistant typhoid fever in southern Vietnam are caused by single bacterial
      strains. However, different outbreaks do not derive from the clonal expansion of
      a single multidrug-resistant serotype Typhi strain.

PMID- 10655412
TI  - Diversity within the VP4 gene of rotavirus P[8] strains: implications for reverse
      transcription-PCR genotyping.
AB  - A degenerate version (1T1-D) of the rotavirus P[8]-specific primer (1T-1) allowed
      strains previously untypeable due to the accumulation of point mutations at the
      primer binding site to be P typed by reverse transcription-PCR. Sequencing of the
      cDNA followed by sequence alignment and phylogenetic analysis identified lineages
      and sublineages within the rotavirus P[8] types, while the use of 1T-1 or 1T-1D
      primers did not yield viral clusters in any particular lineage.

PMID- 10655413
TI  - Growth competition between Candida dubliniensis and Candida albicans under broth
      and biofilm growing conditions.
AB  - Seven isolates each of Candida albicans and Candida dubliniensis were paired (11
      pairs) and examined for competitive interaction. Equal numbers of CFU of each
      competitor were inoculated into Sabouraud dextrose broth and incubated at 37
      degrees C with vigorous shaking under conditions favorable to either broth or
      biofilm growth. Surviving proportions of each competitor were calculated from the
      broth culture at 24 and 96 h and the biofilm culture at 96 h, with species
      differentiation done on CHROMagar Candida medium. C. albicans had a competitive
      advantage over C. dubliniensis in broth culture and under biofilm growing
      conditions; however, with the presence of a supporting structure for biofilm
      formation, C. dubliniensis was able to better withstand the competitive pressures
      from C. albicans.

PMID- 10655414
TI  - Epidemiology of glycopeptide-resistant enterococci colonizing high-risk patients
      in hospitals in Johannesburg, Republic of South Africa.
AB  - Recent cases of infections caused by glycopeptide-resistant enterococci (GRE)
      have highlighted the emergence of these organisms in the Republic of South
      Africa. During May 1998 we conducted a prevalence study in four hospitals in
      Johannesburg and obtained 184 rectal swabs from patients identified as being at
      high risk for GRE colonization. Twenty enterococcal isolates showing various
      glycopeptide resistance genotypes were recovered: 3 Enterococcus faecium vanA
      isolates, 10 E. faecium vanB isolates, 6 E. gallinarum vanC1 isolates, and 1 E.
      avium vanA isolate. Macrorestriction analysis was used to demonstrate the clonal
      spread of GRE strains within hospitals. Evidence also demonstrated the likely
      persistence of the original E. faecium vanA isolate associated with the first
      confirmed death contributed to by GRE infection in South Africa in March 1997.

PMID- 10655415
TI  - Diagnostically and experimentally useful panel of strains from the Burkholderia
      cepacia complex.
AB  - Two new species, Burkholderia multivorans and Burkholderia vietnamiensis, and
      three genomovars (genomovars I, III, and IV) currently constitute the
      Burkholderia cepacia complex. A panel of 30 well-characterized strains
      representative of each genomovar and new species was assembled to assist with
      identification, epidemiological analysis, and virulence studies on this important
      group of opportunistic pathogens.

PMID- 10655416
TI  - Comparative evaluation of two branched-DNA human immunodeficiency virus type 1
      RNA quantification assays with lower detection limits of 50 and 500 copies per
      milliliter.
AB  - We have comparatively evaluated Quantiplex version 3.0 and version 2. 0 on 133
      plasma samples and a repetitive dilution series. Version 3. 0 yielded higher
      human immunodeficiency virus RNA values, and the ratio of version 3.0 results to
      version 2.0 results decreased from 3. 47 below 1,000 copies/ml to 1.97 above
      50,000 copies/ml [linear regression, log (version 3.0) = 0.915 + 0.871 x log
      (version 2.0); r(2) = 0.952].

PMID- 10655417
TI  - Epidemiology and microbiology of surgical wound infections.
AB  - This study included 676 surgery patients with signs and symptoms indicative of
      wound infections, who presented over the course of 6 years. Bacterial pathogens
      were isolated from 614 individuals. A single etiologic agent was identified in
      271 patients, multiple agents were found in 343, and no agent was identified in
      62. A high preponderance of aerobic bacteria was observed. Among the common
      pathogens were Staphylococcus aureus (191 patients, 28.2%), Pseudomonas
      aeruginosa (170 patients, 25.2%), Escherichia coli (53 patients, 7.8%),
      Staphylococcus epidermidis (48 patients, 7.1%), and Enterococcus faecalis (38
      patients, 5.6%).

PMID- 10655419
TI  - Temperature-sensitive strain of Cryptococcus neoformans producing hyphal elements
      in a feline nasal granuloma.
AB  - We report the isolation of a temperature-sensitive, serotype A, mating type alpha
      strain of Cryptococcus neoformans from a case of nasal cryptococcosis in a cat.
      The strain grew extremely slowly at 35 degrees C and failed to grow at 37 degrees
      C in vitro. Histopathological sections of the infected tissue revealed yeast
      cells producing hyphae up to several hundred micrometers in length, in addition
      to numerous encapsulated yeast cells typical of C. neoformans. The cultures grown
      on yeast extract-peptone-glucose agar at 35 degrees C also produced some yeast
      cells with germ tube-like hyphal elements up to 100 microm in length.

PMID- 10655418
TI  - PCR using 3'-mismatched primers to detect A2142C mutation in 23S rRNA conferring
      resistance to clarithromycin in Helicobacter pylori clinical isolates.
AB  - Twenty-five clarithromycin-resistant Helicobacter pylori strains (selected by
      agar dilution) were studied to detect A2142G and A2143G mutations in the 23S rRNA
      gene by a PCR-restriction fragment length polymorphism method and an A2142C
      mutation by PCR using a 3'-mismatched specific primer. A 700-bp amplified
      fragment was obtained by the mismatched PCR only in strains without an A2142G or
      A2143G mutation, indicating that those strains had the A2142C mutation.

PMID- 10655420
TI  - Infection of a hip prosthesis by Actinomyces naeslundii.
AB  - We present the case of a 77-year-old woman who developed an Actinomyces
      naeslundii infection of a hip prosthesis. The isolate grew well aerobically with
      5% CO(2). Possible diagnostic problems may arise in the microbiological
      laboratory because aerobic growth is not sufficiently accounted for in some of
      the traditional identification schemes and commercial test kits. Therefore,
      besides presenting an unusual pathogen in this setting, this report focuses on
      possible diagnostic problems in the microbiological laboratory.

PMID- 10655422
TI  - Is Mycoplasma pneumoniae associated with vascular disease?

PMID- 10655421
TI  - Bacteremia caused by a strain of Desulfovibrio related to the provisionally named
      Desulfovibrio fairfieldensis.
AB  - Eight isolates of Desulfovibrio spp. have been obtained over 5 years from
      abdominal or brain abscesses or blood. Seven isolates were part of a mixed flora
      [corrected]. One strain was isolated in pure culture from the blood of a patient
      with peritonitis of appendicular origin. According to the 16S rRNA gene
      sequences, this strain was close to Desulfovibrio fairfieldensis. The present
      report describes the fourth isolate of this recently described species to be
      isolated in pure culture or as a predominant part of the flora and to be
      associated with infectious processes. Thus, D. fairfieldensis may possess a
      higher pathogenic potential than other Desulfovibrio species.

PMID- 10655424
TI  - MEMORANDUM FOR: science writers and editors on the journal press list: phone call
      reminder increases likelihood of mammography

PMID- 10655423
TI  - MEMORANDUM FOR: science writers and editors on the journal press list: No
      advantage found for high-dose chemotherapy in high-risk breast cancer

PMID- 10655425
TI  - Will there be resistance to the RECIST (Response Evaluation Criteria in Solid
      Tumors)?

PMID- 10655426
TI  - Tubulin/microtubules: still a promising target for new chemotherapeutic agents.

PMID- 10655427
TI  - Gene patent race speeds ahead amid controversy, concern.

PMID- 10655428
TI  - Canada faces shortage of radiation therapists.

PMID- 10655429
TI  - Varied U.S. therapist training programs may prompt legislative action.

PMID- 10655430
TI  - Gene therapy in Europe: new initiatives seek streamlined debate.

PMID- 10655431
TI  - Clarification

PMID- 10655432
TI  - Bone marrow experts are still debating the value of purging.

PMID- 10655433
TI  - Diabetes and cancer: scientists search for a possible link.

PMID- 10655435
TI  - Workshop shapes communication plan on radiation fallout

PMID- 10655434
TI  - Stat bite: U.S. Incidence rates for childhood cancer by race/ethnicity.

PMID- 10655436
TI  - Outcomes research in oncology: history, conceptual framework, and trends in the
      literature.
AB  - "Outcomes research" is a commonly used term, but what does it really mean? In
      this review article, we 1) briefly review the historic background of outcomes
      research, paying particular attention to the social and political movements that
      helped shape the field; 2) present a conceptual framework to help classify the
      major areas of research and provide a working definition of outcomes research;
      and 3) review the oncology literature in the English language from 1966 through
      1998 to examine temporal trends and characterize the body of work being presented
      to the practicing oncology community. We conclude that outcomes research is a
      broad concept, which, in its current usage, describes an array of distinct types
      of research. However, common themes are apparent when outcomes research is viewed
      in the context of its historic origins and is contrasted with other established
      disciplines, especially clinical trials. Our literature review shows that
      outcomes studies are increasing in absolute numbers, in relative proportion of
      the oncology literature, and in quality. We suggest that as different branches of
      investigation develop their own literature and methodology-in effect, outgrowing
      the generic label of outcomes research-they become identified by separate, more
      precise terms.

PMID- 10655437
TI  - New guidelines to evaluate the response to treatment in solid tumors. European
      Organization for Research and Treatment of Cancer, National Cancer Institute of
      the United States, National Cancer Institute of Canada.
AB  - Anticancer cytotoxic agents go through a process by which their antitumor
      activity-on the basis of the amount of tumor shrinkage they could generate-has
      been investigated. In the late 1970s, the International Union Against Cancer and
      the World Health Organization introduced specific criteria for the codification
      of tumor response evaluation. In 1994, several organizations involved in clinical
      research combined forces to tackle the review of these criteria on the basis of
      the experience and knowledge acquired since then. After several years of
      intensive discussions, a new set of guidelines is ready that will supersede the
      former criteria. In parallel to this initiative, one of the participating groups
      developed a model by which response rates could be derived from unidimensional
      measurement of tumor lesions instead of the usual bidimensional approach. This
      new concept has been largely validated by the Response Evaluation Criteria in
      Solid Tumors Group and integrated into the present guidelines. This special
      article also provides some philosophic background to clarify the various purposes
      of response evaluation. It proposes a model by which a combined assessment of all
      existing lesions, characterized by target lesions (to be measured) and nontarget
      lesions, is used to extrapolate an overall response to treatment. Methods of
      assessing tumor lesions are better codified, briefly within the guidelines and in
      more detail in Appendix I. All other aspects of response evaluation have been
      discussed, reviewed, and amended whenever appropriate.

PMID- 10655438
TI  - Indanocine, a microtubule-binding indanone and a selective inducer of apoptosis
      in multidrug-resistant cancer cells.
AB  - BACKGROUND: Certain antimitotic drugs have antitumor activities that apparently
      result from interactions with nontubulin components involved in cell growth
      and/or apoptotic cell death. Indanocine is a synthetic indanone that has been
      identified by the National Cancer Institute's Developmental Therapeutics Program
      as having antiproliferative activity. In this study, we characterized the
      activity of this new antimitotic drug toward malignant cells. METHODS: We tested
      antiproliferative activity with an MTT [i.e., 3-(4,5-dimethylthiazol-2-yl)-2,5
      diphenyl tetrazolium bromide] assay, mitochondrial damage and cell cycle
      perturbations with flow cytometry, caspase-3 activation with fluorometry,
      alterations of the cytoskeletal components with immunofluorescence, and
      antimicrotubule activity with a tubulin polymerization assay.
      RESULTS/CONCLUSIONS: Indanocine is a cytostatic and cytotoxic indanone that
      blocks tubulin polymerization but, unlike other antimitotic agents, induces
      apoptotic cell death in stationary-phase multidrug-resistant cancer cells at
      concentrations that do not impair the viability of normal nonproliferating cells.
      Of the seven multidrug-resistant cell lines tested, three (i.e., MCF-7/ADR, MES
      SA/DX5, and HL-60/ADR) were more sensitive to growth inhibition by indanocine
      than were their corresponding parental cells. Confluent multidrug-resistant cells
      (MCF-7/ADR), but not drug-sensitive cancer cells (MCF-7) or normal peripheral
      blood lymphocytes, underwent apoptotic cell death 8-24 hours after exposure to
      indanocine, as measured by sequential changes in mitochondrial membrane
      potential, caspase activity, and DNA fragmentation. Indanocine interacts with
      tubulin at the colchicine-binding site, potently inhibits tubulin polymerization
      in vitro, and disrupts the mitotic apparatus in dividing cells. IMPLICATIONS: The
      sensitivity of stationary multidrug-resistant cancer cells to indanocine suggests
      that indanocine and related indanones be considered as lead compounds for the
      development of chemotherapeutic strategies for drug-resistant malignancies.

PMID- 10655439
TI  - Randomized trial of high-dose chemotherapy and blood cell autografts for high
      risk primary breast carcinoma.
AB  - BACKGROUND: Uncontrolled studies have reported encouraging outcomes for patients
      with high-risk primary breast cancer treated with high-dose chemotherapy and
      autologous hematopoietic stem cell support. We conducted a prospective randomized
      trial to compare standard-dose chemotherapy with the same therapy followed by
      high-dose chemotherapy. PATIENTS AND METHODS: Patients with 10 or more positive
      axillary lymph nodes after primary breast surgery or patients with four or more
      positive lymph nodes after four cycles of primary (neoadjuvant) chemotherapy were
      eligible. All patients were to receive eight cycles of 5-fluorouracil,
      doxorubicin (Adriamycin), and cyclophosphamide (FAC). Patients were stratified by
      stage and randomly assigned to receive two cycles of high-dose cyclophosphamide,
      etoposide, and cisplatin with autologous hematopoietic stem cell support or no
      additional chemotherapy. Tamoxifen was planned for postmenopausal patients with
      estrogen receptor-positive tumors and chest wall radiotherapy was planned for
      all. All P values are from two-sided tests. RESULTS: Seventy-eight patients (48
      after primary surgery and 30 after primary chemotherapy) were registered. Thirty
      nine patients were randomly assigned to FAC and 39 to FAC followed by high-dose
      chemotherapy. After a median follow-up of 6.5 years, there have been 41 relapses.
      In intention-to-treat analyses, estimated 3-year relapse-free survival rates were
      62% and 48% for FAC and FAC/high-dose chemotherapy, respectively (P =.35), and 3
      year survival rates were 77% and 58%, respectively (P =.23). Overall, there was
      greater and more frequent morbidity associated with high-dose chemotherapy than
      with FAC; there was one septic death associated with high-dose chemotherapy.
      CONCLUSIONS: No relapse-free or overall survival advantage was associated with
      the use of high-dose chemotherapy, and morbidity was increased with its use.
      Thus, high-dose chemotherapy is not indicated outside a clinical trial.

PMID- 10655440
TI  - Testing reminder and motivational telephone calls to increase screening
      mammography: a randomized study.
AB  - BACKGROUND: Prospective randomized trials have demonstrated that motivational
      telephone calls increase adherence to screening mammography. To better understand
      the effects of motivational calls and to maximize adherence, we conducted a
      randomized trial among women aged 50-79 years. METHODS: We created a stratified
      random sample of 5062 women due for mammograms within the Group Health
      Cooperative of Puget Sound, including 4099 women with prior mammography and 963
      without it. We recruited and surveyed 3743 (74%) of the women before mailing a
      recommendation. After 2 months, 1765 (47%) of the 3743 women had not scheduled a
      mammogram and were randomly assigned to one of three intervention groups: a
      reminder post-card group (n = 590), a reminder telephone call group (n = 585),
      and a motivational telephone call addressing barriers group (n = 590). The
      telephone callers could schedule mammography. We used Cox proportional hazards
      models to estimate the hazard ratio (HR) and 95% confidence interval (CI) for
      documented mammography use by 1 year. RESULTS: Women who received reminder calls
      were more likely to get mammograms (HR = 1.9; 95% CI = 1.6-2.4) than women who
      were mailed postcards. The motivational and reminder calls (average length, 8.5
      and 3.1 minutes, respectively) had equivalent effects (HR = 0.97; 95% CI = 0.8
      1.2). After we controlled for the intervention effect, women with prior
      mammography (n = 1277) were much more likely to get a mammogram (HR = 3.4; 95% CI
      = 2.7-4.3) than women without prior use (n = 488). Higher income, but not race or
      more education, was associated with higher adherence. CONCLUSIONS: Reminding
      women to schedule an appointment was as efficacious as addressing barriers.
      Simple intervention groups should be included as comparison groups in randomized
      trials so that we better understand more complex intervention effects.

PMID- 10655442
TI  - Prospective study of talc use and ovarian cancer.
AB  - BACKGROUND: Perineal talc use has been associated with an increased risk of
      ovarian cancer in a number of case-control studies; however, this association
      remains controversial because of limited supporting biologic evidence and the
      potential for recall bias or selection bias in case-control studies. In this
      study, we conducted a prospective analysis of perineal talc use and the risk of
      ovarian cancer. METHODS: The Nurses' Health Study is a prospective study of 121
      700 female registered nurses in the United States who were aged 30-55 years at
      enrollment in 1976. Talc use was ascertained in 1982 by use of a self
      administered questionnaire: after exclusions, 78 630 women formed the cohort for
      analysis. Three hundred seven epithelial ovarian cancers subsequently diagnosed
      in this cohort through June 1, 1996, were confirmed by medical record review and
      met inclusion criteria. Proportional hazards models by use of pooled logistic
      regression were used to derive relative risks (RRs) and 95% confidence intervals
      (CIs). RESULTS: In 1982, 40.4% (n = 31 789) of the cohort reported ever using
      talc, and 14.5% (n = 11 411) reported ever using talc daily. We observed no
      overall association with ever talc use and epithelial ovarian cancer
      (multivariate RR = 1.09; 95% CI = 0.86-1.37) and no increase in risk of ovarian
      cancer with increasing frequency of use. There was a modest elevation in risk for
      ever talc use and invasive serous ovarian cancer (multivariate RR = 1.40; 95% CI
      = 1.02-1.91). The risk of epithelial ovarian cancer for talc users was not
      greater among women who had never had a tubal ligation (multivariate RR = 0.97;
      95% CI = 0.71-1.32). CONCLUSION: Our results provide little support for any
      substantial association between perineal talc use and ovarian cancer risk
      overall; however, perineal talc use may modestly increase the risk of invasive
      serous ovarian cancer.

PMID- 10655441
TI  - Novobiocin and related coumarins and depletion of heat shock protein 90-dependent
      signaling proteins.
AB  - BACKGROUND: Heat shock protein 90 (Hsp90) interacts with and stabilizes several
      oncogenic protein kinases (e.g., p185(erbB2), p60(v-src), and Raf-1) and is
      required for the stability and dominant-negative function of mutated p53 protein.
      Two unrelated antibiotics, geldanamycin and radicicol, bind specifically to an
      atypical nucleotide-binding pocket of Hsp90, a site that shares homology with the
      adenosine triphosphate (ATP)-binding domain of bacterial DNA gyrase B. This
      interaction leads to destabilization of proteins that interact with Hsp90. Since
      the nucleotide-binding site of gyrase B is targeted by coumarin antibiotics
      (e.g., novobiocin), we investigated whether these drugs can also interact with
      Hsp90 and affect its activity. METHODS: We used immobilized novobiocin,
      geldanamycin, or radicicol to isolate either endogenous Hsp90 from cell lysates
      or Hsp90 deletion fragments translated in vitro. Effects of the coumarin
      antibiotics novobiocin, chlorobiocin, and coumermycin A1 on several proteins
      interacting with Hsp90 were assessed in vitro and in vivo. RESULTS: Hsp90 binding
      to immobilized novobiocin was competed by soluble coumarins and ATP but not by
      geldanamycin or radicicol. A carboxy-terminal Hsp90 fragment bound immobilized
      novobiocin but not immobilized geldanamycin, while a geldanamycin-binding amino
      terminal fragment did not bind novobiocin. All three coumarins markedly reduced
      cellular levels of p185(erbB2), p60(v-src), Raf-1, and mutated p53. Furthermore,
      novobiocin reduced Raf-1 levels in the spleens of mice treated with the drug.
      CONCLUSIONS: These coumarin antibiotics, particularly novobiocin, represent a
      first-generation alternative to other Hsp90-targeting drugs that are not as well
      tolerated. Novobiocin's unique interaction with Hsp90 identifies an additional
      site on this protein amenable to pharmacologic interference with small molecules.

PMID- 10655443
TI  - Delivery of c-myb antisense oligodeoxynucleotides to human neuroblastoma cells
      via disialoganglioside GD(2)-targeted immunoliposomes: antitumor effects.
AB  - BACKGROUND: Advanced-stage neuroblastoma resists conventional treatment; hence,
      novel therapeutic approaches are required. We evaluated the use of c-myb
      antisense oligodeoxynucleotides (asODNs) delivered to cells via targeted
      immunoliposomes to inhibit c-Myb protein expression and neuroblastoma cell
      proliferation in vitro. METHODS: Phosphorothioate asODNs and control sequences
      were encapsulated in cationic lipid, and the resulting particles were coated with
      neutral lipids to produce coated cationic liposomes (CCLs). Monoclonal antibodies
      directed against the disialoganglioside GD(2) were covalently coupled to the
      CCLs. (3)H-labeled liposomes were used to measure cellular binding, and cellular
      uptake of asODNs was evaluated by dot-blot analysis. Growth inhibition was
      quantified by counting trypan blue dye-stained cells. Expression of c-Myb protein
      was examined by western blot analysis. RESULTS: Our methods produced GD(2)
      targeted liposomes that stably entrapped 80%-90% of added c-myb asODNs. These
      liposomes showed concentration-dependent binding to GD(2)-positive neuroblastoma
      cells that could be blocked by soluble anti-GD(2) monoclonal antibodies. GD(2)
      targeted liposomes increased the uptake of asODNs by neuroblastoma cells by a
      factor of fourfold to 10-fold over that obtained with free asODNs. Neuroblastoma
      cell proliferation was inhibited to a greater extent by GD(2)-targeted liposomes
      containing c-myb asODNs than by nontargeted liposomes or free asODNs. GD(2)
      targeted liposomes containing c-myb asODNs specifically reduced expression of c
      Myb protein by neuroblastoma cells. Enhanced liposome binding and asODN uptake,
      as well as the antiproliferative effect, were not evident in GD(2)-negative
      cells. CONCLUSIONS: Encapsulation of asODNs into immunoliposomes appears to
      enhance their toxicity toward targeted cells while shielding nontargeted cells
      from antisense effects and may be efficacious for the delivery of drugs with
      broad therapeutic applications to tumor cells.

PMID- 10655444
TI  - Twinship and risk of postmenopausal breast cancer.
AB  - BACKGROUND: Intrauterine exposure to high levels of endogenous estrogens has been
      hypothesized to increase the risk of breast cancer. Because estrogens and other
      pregnancy hormones are substantially elevated in twin pregnancies, and possibly
      more so in dizygotic twin pregnancies, we evaluated the association between
      aspects of twin membership (i.e., belonging to a twin pair) and the risk of
      breast cancer. METHODS: In a cohort of 29 197 postmenopausal Iowa women with no
      prior diagnosis of cancer (except for nonmelanoma skin cancer), breast cancer
      risk factors were determined by use of a mailed questionnaire in 1986 (baseline);
      twin membership, sex of the twin, and zygosity were determined by use of a follow
      up questionnaire in 1992. RESULTS: Within the cohort, 1.8% (n = 538) of the women
      reported being a twin; of these, 24% (n = 130) were monozygotic twins, 63% (n =
      337) were dizygotic twins, and 13% (n = 71) did not know their zygosity. From
      1986 through 1996, 1230 breast cancers in the cohort were ascertained by linkage
      to the Iowa Cancer Registry. Compared with singletons, women who belonged to a
      twin pair were at elevated risk of breast cancer (multivariate-adjusted risk
      ratio [RR] = 1.72; 95% confidence interval [CI] = 1.22-2.42), with adjustment for
      educational level, family history of breast cancer, height, body mass index, body
      fat distribution, age at menarche, age at first live birth, use of hormone
      replacement therapy, and alcohol use. Multivariate-adjusted risk was elevated (in
      comparison with singletons) if the sex of the other twin was female (RR = 1.82;
      95% CI = 1.20-2.75); however, this risk was limited to female dizygotic twins (RR
      = 2.14; 95% CI = 1. 21-3.79), since no excess risk was evident for monozygotic
      twins (RR = 1.04; 95% CI = 0.43-2.50). The risk to women with a male twin was
      also elevated (RR = 1.49; 95% CI = 0.80-2.78) in comparison with singletons, but
      this estimate was not statistically significant. CONCLUSIONS: This cohort study
      lends further support to the theory that there are important intrauterine
      influences on carcinogenesis of the breast.

PMID- 10655445
TI  - Dietary folate consumption and breast cancer risk.

PMID- 10655446
TI  - Travel distance to radiation therapy and receipt of radiotherapy following breast
      conserving surgery.

PMID- 10655447
TI  - Re: Vitamin A analogue for breast cancer prevention: a grade of F or incomplete?

PMID- 10655449
TI  - RESPONSE: re: vitamin A analogue for breast cancer prevention: a grade of F or
      incomplete?

PMID- 10655448
TI  - Re: Vitamin A analogue for breast cancer prevention: a grade of F or incomplete?

PMID- 10655450
TI  - EDITOR'S NOTE: re: vitamin A analogue for breast cancer prevention: a grade of F
      or incomplete?

PMID- 10655451
TI  - Non-invasive exclusion of fetal aneuploidy in an at-risk couple with a balanced
      translocation.
AB  - A pregnant woman who was a carrier for a balanced chromosome translocation
      [46,XX, t(1;6) (p31;q14)] and who had had six miscarriages, declined invasive
      testing but agreed to non-invasive prenatal diagnosis by analysis of fetal cells
      in maternal blood. Monoclonal antibody (Mab) against the zeta (z) and gamma
      (gamma) chains of embryonic and fetal haemoglobin were used to identify fetal
      nucleated erythrocytes (FNRBC). There were no FNRBC detected at 7 weeks, one anti
      z-positive FNRBC was detected at 11 weeks, and 12 anti-gamma-positive FNRBC were
      detected at 20 weeks. Fluorescent in-situ hybridization was performed using
      probes for chromosomes X, Y, 1 and 6 to identify fetal gender and the presence of
      an unbalanced chromosomal translocation. A tentative prenatal diagnosis was made
      of a female fetus disomic for chromosomes 1 and 6. A female infant with a 46,XX
      karyotype was born at term. This is the first attempt of exclusion of a
      chromosome translocation using fetal cells isolated from maternal blood. There is
      an advantage of using fetal cells isolated from maternal blood for non-invasive
      prenatal diagnosis in couples who have a history of multiple miscarriages due to
      a parental translocation, and who decline invasive testing in a pregnancy that
      continues to the second trimester.

PMID- 10655452
TI  - Assessment of sex chromosome aneuploidy in sperm nuclei from 47,XXY and
      46,XY/47,XXY males: comparison with fertile and infertile males with normal
      karyotype.
AB  - Sex chromosome aneuploidy was assessed in spermatozoa from a 47,XXY male and a
      46,XY/47,XXY male using three colour fluorescence in-situ hybridization (FISH)
      and compared with two control groups. The first group included subjects of proven
      fertility and the second infertile males with normal constitutional karyotype.
      The frequencies of XX and YY disomic, XY hyperhaploid and diploid spermatozoa
      were significantly increased in the 47,XXY male compared to subjects from the two
      control groups (P < 0.0001). For the 46,XY/47,XXY sample, the same results were
      observed, except that the incidence of YY disomic spermatozoa did not differ
      significantly from the rate obtained in infertile patients. The frequency of sex
      chromosome aneuploidy did not differ significantly between the 47,XXY and the
      46,XY/47,XXY males, except for XX disomic sperm nuclei which was higher in the
      47,XXY patient. The frequency of chromosome 12 disomy was also increased in the
      two XXY individuals (0.42 and 0.49% respectively; P < 0.0001). The meiotic
      abnormalities observed in the two XXY patients arose through segregation errors
      in XY germ cells. The increased number of meiotic non-disjunctions observed in
      the germ cells of infertile males may be a common feature of the deficient oligo-
      or azoospermic testis. Patients with Klinefelter's syndrome with oligozoospermia
      have an increased risk of both sex chromosome and autosome aneuploidy in their
      progeny.

PMID- 10655453
TI  - Human placental gonadotrophin-releasing hormone-like factors: an artefact of
      human placental peptidases?
AB  - Non-denatured human placental cytosol fractions displaced tracer binding in
      parallel with gonadotrophin-releasing hormone (GnRH) isoform and agonist peptides
      in GnRH-specific radioimmunoassays and radioreceptor assays. However, placental
      immuno- and receptor binding-GnRH-like activity was highly correlated with
      inactivation of GnRH tracers, suggesting that placental GnRH-like factors may be
      an artefact of ligand degradation during assay. The properties and inhibitor
      sensitivities of the major (125)I-labelled GnRH-degrading enzymes of term
      placental cytosol were studied using a dextran-coated charcoal (DCC) adsorption
      assay as a rapid screen for GnRH tracer inactivation. Three different activities
      were demonstrable: (i) a cathepsin D-like enzyme (M(r) 55 kDa), active against
      all radiolabelled GnRH isoforms and agonists tested, optimal at acid pH, and
      inhibited specifically by pepstatin; (ii) a metallo-thiol endopeptidase activity
      (M(r) 70 kDa) optimal at alkaline pH (7-9) which degraded GnRH isoforms to a
      greater extent than GnRH analogues, inhibited dose-dependently by low
      concentrations of thiol reagents (N-ethylmaleimide, thimerosal), chelating agents
      (o-phenanthroline, EDTA), and by tosyl-phenylalanyl-chloromethyl ketone but not
      by other serine protease inhibitors; and (iii) a bacitracin-sensitive enzyme
      optimal at physiological pH. These observations permitted the development of a
      robust radioreceptor assay which minimized GnRH tracer degradation. Under these
      assay conditions, the GnRH-like radioreceptor assay activity of human placental
      cytosol fractions was markedly reduced.

PMID- 10655454
TI  - L-type voltage-dependent calcium channel alpha-1C subunit mRNA is present in
      ejaculated human spermatozoa.
AB  - The current study adds to the growing body of evidence that RNA is present in
      mature ejaculated human spermatozoa. We report that a sodium dodecyl sulphate
      (SDS)/citric acid extraction method is superior to guanidinium isothiocyanate in
      terms of reproducibility of RNA recovery from motile sperm populations from
      individual ejaculates. Using the SDS/citric acid method, RNA was recovered from
      both fresh and frozen-thawed motile spermatozoa. Sperm RNA were used as templates
      in reverse transcription-polymerase chain reaction (RT-PCR), in an attempt to
      identify partial RNA transcripts of a highly conserved region within the alpha-1C
      (pore-forming) subunit of L-type voltage-dependent calcium channels from 11
      individual donors. Control reactions employed primers derived from the human
      glyceraldehyde-3-phosphate dehydrogenase (GAPDH) sequence. In nine of the 11
      specimens, gene-specific PCR products were obtained with both the GAPDH and alpha
      1C primer pairs. DNA sequencing analysis confirmed that the respective spliced
      transcripts were amplified. The two cases in which no amplification was obtained
      were attributed to reduced RNA yield. These data are consistent with results from
      in-situ RT-PCR of rat testis sections indicating that the testis-specific calcium
      channel of that species was expressed uniformly in all stages of the germinal
      epithelium, including mature spermatozoa.

PMID- 10655455
TI  - Expression of receptors for insulin-like growth factor-I and transforming growth
      factor-beta in human follicles.
AB  - The in-vitro growth of immature oocytes in early follicles from cryopreserved
      human ovarian tissues is a new concept in in-vitro fertilization programmes for
      the treatment of infertile and cancer patients. To better understand the
      regulatory mechanism of follicular development, immunohistochemistry was used to
      study the expression of insulin-like growth factor (IGF) type I receptor (IGF-IR)
      and transforming growth factor-beta (TGFbeta) type I (TbetaR-I) and type II
      (TbetaR-II) receptors in fresh and frozen ovarian tissues from 14 women.
      Immunoreactivities for IGF-IR and TbetaR-I were present simultaneously in the
      oocytes of primordial, pre-antral and antral follicles. Staining for both IGF-IR
      and TbetaR-I was also observed in granulosa cells of primordial, pre-antral and
      antral follicles. IGF-IR and TbetaR-I also stained in thecal cells of pre-antral
      and antral follicles. Stromal cells in surrounding ovarian tissue expressed IGF
      IR and TbetaR-I at various follicular stages. Unlike TbetaR-I, TbetaR-II was
      expressed only in the oocytes of primordial and primary follicles, and with weak
      staining intensity in thecal cells. No significant staining for TbetaR-II was
      found in oocytes and granulosa cells of antral follicles. There was no difference
      in staining patterns for IGF-IR, TbetaR-I and TbetaR-II between fresh and frozen
      ovarian tissues, indicating that cryopreservation might not significantly alter
      the immunoreactivities of these receptors in frozen ovarian tissue. The results
      suggest that IGF-I and TGFbeta may participate in the regulation of follicular
      growth by binding to their receptors through an autocrine or paracrine mechanism.
      IGF-I and TGFbeta may be useful in regulating the in-vitro or in-vivo maturation
      of oocytes not only in later follicles but also very early follicles, from
      cryopreserved ovarian tissues for clinical use in the future.

PMID- 10655456
TI  - Characterization of an immortalized human granulosa cell line (COV434).
AB  - We have investigated the biological characteristics of an immortalized granulosa
      cell line (COV434), which may be used to study follicular and oocyte maturation
      in vitro. Granulosa cell function was defined as consisting of three distinct
      properties: (i) production of 17beta-oestradiol in response to follicle
      stimulating hormone (FSH); (ii) presence of specific molecular markers of
      apoptosis enabling the induction of follicular atresia; and (iii) capacity to
      form intercellular connections with cells surrounding an oocyte. The addition of
      FSH to the culture medium supplemented with 10% fetal calf serum and 4-androstene
      3,17-dione resulted in proliferation of the COV434 granulosa cells and in an
      increased synthesis of 17beta-oestradiol, indicating the presence of the FSH
      receptor and cytochrome P450 aromatase in these cells. The receptor for
      luteinizing hormone (LH) was undetectable. Similar expression of various
      apoptosis-associated genes was found in COV434 granulosa cells and in granulosa
      cells of patients stimulated with gonadotrophins for in-vitro fertilization, thus
      indicating that the immortalized COV434 granulosa cells were able to sustain
      apoptosis. Multiple intercellular connections were formed during co-culture of
      COV434 granulosa cells with cumulus cells containing an immature oocyte but not
      with cumulus cells devoid of an oocyte. Detailed morphological analysis of the
      intercellular connections with scanning electron microscopy and confocal light
      microscopy demonstrated the presence of long slender structures. It is concluded
      that the immortalized human granulosa cell line COV434 may be useful for
      experimental studies on follicular development.

PMID- 10655457
TI  - Diethylstilbestrol (DES)-induced cell cycle delay and meiotic spindle disruption
      in mouse oocytes during in-vitro maturation.
AB  - Due to the growing amount of data related to the deleterious effects of the
      synthetic oestrogenic compound, diethylstilbestrol (DES), on the female
      reproductive system, we tested the potential effects of this compound on mouse
      oocytes. Controlled time- and dose-dependent in-vitro experiments were carried
      out on isolated cumulus-oocyte-complexes (COCs) to examine the meiotic spindle
      assembly and chromosome distribution. alpha-tubulin, chromosomes and F-actin were
      labelled and detected by confocal laser scanning microscope. COCs were exposed to
      varying doses of DES (5-30 micromol/l) from the germinal vesicle (GV) stage to
      the end of metaphase II (MII) when meiosis I and meiosis II is normally
      completed. Exposure to DES during meiosis I caused a dose-dependent inhibition of
      cell cycle progression. In comparison with controls, fewer oocytes reached
      metaphase I (MI) at low doses (5 micromol/l) of DES, while none of the oocytes
      reached MI in high doses (30 micromol/l). When COCs were exposed to high doses of
      DES during meiosis II, fragmentation of first meiotic spindle was detected,
      whereas lower doses caused loosening of the first and the second meiotic
      spindles. No microtubular abnormalities were detected either in GV-stage oocytes
      or in cumulus cells. The above data demonstrate that one mode of action of DES on
      mouse oocytes is a severe yet reversible deterioration of meiotic spindle
      microtubule organization during maturation.

PMID- 10655458
TI  - Expression of cadherin adhesion molecules on human gametes.
AB  - The presence of cadherins, Ca(2+)-dependent cell-cell adhesion molecules which
      may be involved in gamete interaction, was investigated in human gametes.
      Expression of cadherin molecules was demonstrated using an anti-pan-cadherin
      antibody and specific antibodies against the three classical cadherins: E-
      (epithelial), P- (placental) and N- (neural) cadherins. Samples of 48 h old
      unfertilized oocytes and spermatozoa from in-vitro fertilizing semen samples were
      lysed and separated by electrophoresis. Localization of cadherins was determined
      on intact, fixed, permeabilized spermatozoa and oocytes by immunocytochemisty
      assessed by confocal microscopy. Immunoblotting with the pan-cadherin antibody
      revealed a single band of approximately 120 kDa in spermatozoa (whether 'fresh',
      capacitated, or frozen-thawed) and oocyte extracts. Oocytes presented all three
      classical cadherins with the appropriate molecular weights of 120-130 kDa. In
      sperm lysate we demonstrated the presence of E-cadherin but not N-cadherin. The
      anti-P antibody detected a 90 kDa peptide as the only immunoreactive antigen.
      Following immunocytochemistry of human oocytes all cadherin molecules were
      allocated predominantly to the plasma membrane with only traces in the cytoplasm.
      In spermatozoa, several staining patterns were observed with each of the pan
      cadherin, N-cadherin and E-cadherin antibodies mostly confined to different head
      regions. We conclude that cadherin molecules are present on plasma membranes of
      both human spermatozoa and oocytes and may play a role in the intricate
      recognition process preceding gamete fusion.

PMID- 10655459
TI  - Adhesion of menstrual endometrium to extracellular matrix: the possible role of
      integrin alpha(6)beta(1) and laminin interaction.
AB  - Previous in-vitro studies have shown that the endometrium preferentially adheres
      to the extracellular matrix (ECM) of the amnion and peritoneum. This interaction
      probably involves adhesion molecules, e.g. integrins. We evaluated the expression
      of integrins in naturally shed menstrual endometrium and the adhesion pattern of
      this tissue to different components of the ECM. To identify integrins and matrix
      components involved, blocking studies were performed. Most of the 15 menstrual
      tissue samples showed positive staining for each of the integrins investigated,
      except alpha(4)beta(1). Compared with binding to collagen IV, which was set at
      100%, adhesion to collagen I was 93% (not significant), to fibronectin 87% (P <
      0.05), and to laminin 74% (P < 0.05). Scanning electron micoscopy showed that
      endometrium adhered to laminin but hardly spread, whereas spreading was observed
      when layered on the other coatings. Compared with the control (which was set at
      100%), incubation with 4B4, a monoclonal antibody against the integrin beta(1)
      subunit, showed a significant reduction of adhesion (to approximately 50%; P <
      0.05) when layered on laminin and a smaller reduction (to 82-86%; P < 0.05) when
      layered on the other three coatings. Incubation with antibody GOH3 against
      integrin alpha(6)beta(1) resulted in a similar reduction in adhesion to laminin.
      Incubation with an RGD peptide significantly reduced adhesion (to 84%; P < 0.05)
      when plated on fibronectin. In conclusion, antegradely shed menstrual endometrium
      expresses various integrins. It shows preferential attachment to collagen IV and
      collagen I, when compared with fibronectin and laminin. Blockage of the integrin
      beta(1) subunit resulted in greatest disruption to adhesion when layered on
      laminin, implying that the interaction was mediated by the alpha(6)beta(1)
      integrin. Since this adhesion was not completely blocked, other mechanisms are
      likely to be involved.

PMID- 10655460
TI  - Induction of superoxide dismutase by decidualization in human endometrial stromal
      cells.
AB  - The present study was undertaken to investigate the effect of decidualization on
      superoxide dismutase (SOD) expression in human endometrial stromal cells (ESC).
      To induce decidualization, isolated ESC were incubated with medroxyprogesterone
      acetate (MPA, 10(-6) mol/l) and oestradiol (10(-8) mol/l) for 23 days. Insulin
      like growth factor-binding protein-1 (IGFBP-1) was used as a marker of
      decidualization. SOD mRNA in ESC was significantly increased on day 12 of the
      hormone treatment (P < 0.01), which was concomitant with the onset of IGFBP-1
      mRNA expression, and further increased until day 23 of the treatment in a manner
      similar to the change in IGFBP-1 expression. To examine the synergistic effect of
      human chorionic gonadotrophin (HCG) with MPA and oestradiol on SOD and IGFBP-1
      expression, ESC were incubated with HCG in the presence or absence of MPA and
      oestradiol. HCG had no synergistic effect on SOD and IGFBP-1 expression. SOD
      activities in the decidualized endometrial tissue obtained from patients given
      oestradiol and progesterone for 7-10 days were significantly higher than those in
      the non-decidualized endometrial tissue from patients without the hormone
      treatment (P < 0.01). In conclusion, SOD expression in ESC was induced by MPA and
      oestradiol accompanied by decidualization, suggesting that SOD may play important
      roles in decidualization of ESC.

PMID- 10655461
TI  - Endothelial nitric oxide synthase is differently expressed in human endometrial
      vessels during the menstrual cycle.
AB  - Endogenous nitric oxide (NO) can be synthesized by endothelial cells and can act
      as a potent vasodilator. We investigated endothelial nitric oxide synthase
      (eNOS), one of the three different enzymes responsible for the synthesis of NO by
      immunohistochemical methods throughout the menstrual cycle on 34 endometrial
      samples and compared its detection with the von Willebrand Factor (vWF) as a
      reliable marker molecule of the endothelium on serial sections. Immunoreactivity
      for eNOS was clearly localized in various types of arterial and venous
      endothelial cells as well as in capillaries. In addition, in some samples there
      was a positive staining in endometrial glandular epithelium. There was no
      staining in endometrial fibroblasts or in myometrial smooth muscle cells. Whereas
      the endothelium was constantly stained by the monoclonal antibody against vWF,
      eNOS was not always expressed in the endothelial lining of the vessels during the
      menstrual cycle. The number of vessels positively stained for eNOS increased
      gradually during the proliferation phase and most of the vessels were positive in
      the early secretory phase. These results suggest that its markedly increased
      expression during the early secretory phase of the menstrual cycle indicates a
      physiological significance.

PMID- 10655463
TI  - Hypothesis testing by X chromosome inactivation patterns may be more informative
      with lineage-specific cells.

PMID- 10655462
TI  - Presence of secretory leukocyte protease inhibitor in human endometrium and first
      trimester decidua suggests an antibacterial protective role.
AB  - Secretory leukocyte protease inhibitor (SLPI) is a neutrophil elastase inhibitor
      which also has antibacterial and anti-inflammatory properties. It is found
      associated with mucosal membranes. Although SLPI has been reported in the cervix
      it has not thus far been reported in human endometrium. This study investigates
      the presence of SLPI in endometrium, first trimester decidua and trophoblast.
      Cultured first trimester decidua was found to produce 4. 7 +/- 2.0 ng/mg/24 h of
      SLPI. Endometrium and trophoblast were both found to secrete significantly lower
      amounts of SLPI (P < 0.01) although endometrial expression was menstrual cycle
      dependent with increased secretion in the secretory phase. Although relatively
      low concentrations of SLPI were released from the endometrium during culture,
      most of the SLPI remained associated with the tissue and could be recovered with
      mild acid extraction. This is in agreement with the high isoelectric point (pI)
      for SLPI, associated with high solubility at low pH. The main site of SLPI
      synthesis in endometrium and decidua was found to be the glandular epithelium. An
      antibiotic role for SLPI in the endometrium and decidua during implantation and
      pregnancy would be consistent with the expression profile and localization of
      SLPI.

PMID- 10655464
TI  - Making back issues of PNAS online free.

PMID- 10655465
TI  - How close are we to implementing gene targeting in animals other than the mouse?

PMID- 10655466
TI  - Novel antimicrobial targets from combined pathogen and host genetics.

PMID- 10655467
TI  - A groovy new structure.

PMID- 10655468
TI  - Brown dwarfs: at last filling the gap between stars and planets.
AB  - Until the mid-1990s a person could not point to any celestial object and say with
      assurance that "here is a brown dwarf." Now dozens are known, and the study of
      brown dwarfs has come of age, touching upon major issues in astrophysics,
      including the nature of dark matter, the properties of substellar objects, and
      the origin of binary stars and planetary systems.

PMID- 10655469
TI  - Effective dimensional reduction algorithm for eigenvalue problems for thin
      elastic structures: a paradigm in three dimensions.
AB  - We present a methodology for the efficient numerical solution of eigenvalue
      problems of full three-dimensional elasticity for thin elastic structures, such
      as shells, plates and rods of arbitrary geometry, discretized by the finite
      element method. Such problems are solved by iterative methods, which, however,
      are known to suffer from slow convergence or even convergence failure, when the
      thickness is small. In this paper we show an effective way of resolving this
      difficulty by invoking a special preconditioning technique associated with the
      effective dimensional reduction algorithm (EDRA). As an example, we present an
      algorithm for computing the minimal eigenvalue of a thin elastic plate and we
      show both theoretically and numerically that it is robust with respect to both
      the thickness and discretization parameters, i.e. the convergence does not
      deteriorate with diminishing thickness or mesh refinement. This robustness is
      sine qua non for the efficient computation of large-scale eigenvalue problems for
      thin elastic structures.

PMID- 10655470
TI  - A relation between the principal axes of inertia and ligand binding.
AB  - The principal axes of inertia are eigenvectors that can be calculated for any
      rigid body. We report studies of the position of the principal axes in
      crystallographically solved protein molecules. We find with high frequency that
      at least one principal axis penetrates the surface of the respective protein in a
      region used for ligand binding. In antibody variable regions, an axis goes
      through the third hypervariable loop of the heavy chain. In major
      histocompatibility complex proteins, an axis goes through the peptide-binding
      groove. In protein-protein heterodimers, a principal axis of one subunit will
      often penetrate the interface formed with the other subunit. In many of these
      protein-protein complexes, the axis specifically intersects residues known to be
      critical for molecular recognition.

PMID- 10655471
TI  - Using lateral capillary forces to compute by self-assembly.
AB  - Investigations of DNA computing have highlighted a fundamental connection between
      self-assembly (SA) and computation: in principle, any computation can be
      performed by a suitable self-assembling system. In practice, exploration of this
      connection is limited by our ability to control the geometry and specificity of
      binding interactions. Recently, a system has been developed that uses surface
      tension to assemble plastic tiles according to shape complementarity and likeness
      of wetting [Bowden, N., Terfort, A., Carbeck, J. & Whitesides, G. M. (1997)
      Science 276, 233-235]. Here the capacity of this system to compute by SA is
      explored. Tiles were prepared to test the system's ability to generate three
      structures of increasing complexity: a periodic checkerboard tiling, an aperiodic
      Penrose tiling, and a computational tiling that simulates a one-dimensional
      cellular automaton. Matching rules for these tilings were enforced by coating
      tiles with patterns of hydrophobic and hydrophilic patches or wetting codes.
      Energetic, kinetic, and mechanistic details of SA explain differences between
      experimental structures and mathematically ideal ones. In particular, the growth
      mechanism observed appears incompatible with computations that make use of a
      chosen input.

PMID- 10655472
TI  - Six cloned calves produced from adult fibroblast cells after long-term culture.
AB  - Cloning whole animals with somatic cells as parents offers the possibility of
      targeted genetic manipulations in vitro such as "gene knock-out" by homologous
      recombination. However, such manipulation requires prolonged culture of nuclear
      donor cells. Previous successes in cloning have been limited to the use of cells
      collected either fresh or after short-term culture. Therefore, demonstration of
      genetic totipotency of cells after prolonged culture is pivotal to combining site
      specific genetic manipulations and cloning. Here we report birth of six clones of
      an aged (17-year-old) Japanese Black Beef bull using ear skin fibroblast cells as
      nuclear donor cells after up to 3 months of in vitro culture (10-15 passages). We
      observed higher developmental rates for embryos derived from later passages (10
      and 15) as compared with those embryos from an early passage (passage 5). The
      four surviving clones are now 10-12 months of age and appear normal, similar to
      their naturally reproduced peers. These data show that fibroblasts of aged
      animals remain competent for cloning, and prolonged culture does not affect the
      cloning competence of adult somatic donor cells.

PMID- 10655473
TI  - Single-target molecule detection with nonbleaching multicolor optical
      immunolabels.
AB  - We introduce and demonstrate the use of colloidal silver plasmon-resonant
      particles (PRPs) as optical reporters in typical biological assays. PRPs are
      ultrabright, nanosized optical scatterers, which scatter light elastically and
      can be prepared with a scattering peak at any color in the visible spectrum. PRPs
      are readily observed individually with a microscope configured for dark-field
      microscopy, with white-light illumination of typical power. Here we illustrate
      the use of PRPs, surface coated with standard ligands, as target-specific labels
      in an in situ hybridization and an immunocytology assay. We propose that PRPs can
      replace or complement established labels, such as those based on radioactivity,
      fluorescence, chemiluminescence, or enzymatic/colorimetric detection that are
      used routinely in biochemistry, cell biology, and medical diagnostic
      applications. Moreover, because PRP labels are nonbleaching and bright enough to
      be rapidly identified and counted, an ultrasensitive assay format based on single
      target molecule detection is now practical. We also present the results of a
      model sandwich immunoassay for goat anti-biotin antibody, in which the number of
      PRP labels counted in an image constitutes the measured signal.

PMID- 10655474
TI  - Optimization of the helper-dependent adenovirus system for production and potency
      in vivo.
AB  - Helper-dependent (HD) adenoviral vectors devoid of all viral coding sequences
      provide for safe and highly efficient gene transfer with long-lasting transgene
      expression. High titer stocks of HD vectors can be generated by using the cre
      recombinase system. However, we have encountered difficulties with this system,
      including rearranged HD vectors and variable efficiency of HD vector rescue.
      These problems represent a major hindrance, particularly with regard to large
      scale production. To overcome these limitations, we have modified the system in
      two ways: We constructed a new helper virus with a modified packaging signal and
      enhanced growth characteristics. We also redesigned the vector backbones by
      including noncoding adenovirus sequences adjacent to the right inverted terminal
      repeat and by incorporated a number of different segments of noncoding DNA of
      human origin as "stuffer." Comparison of these vectors showed that the nature of
      the stuffer sequence affects replication of the HD vector. Optimization of the
      system resulted in a more robust and consistent production of HD vectors with low
      helper contamination and high in vivo potency.

PMID- 10655475
TI  - Rational discovery of novel nuclear hormone receptor antagonists.
AB  - Nuclear hormone receptors (NRs) are potential targets for therapeutic approaches
      to many clinical conditions, including cancer, diabetes, and neurological
      diseases. The crystal structure of the ligand binding domain of agonist-bound NRs
      enables the design of compounds with agonist activity. However, with the
      exception of the human estrogen receptor-alpha, the lack of antagonist-bound
      "inactive" receptor structures hinders the rational design of receptor
      antagonists. In this study, we present a strategy for designing such antagonists.
      We constructed a model of the inactive conformation of human retinoic acid
      receptor-alpha by using information derived from antagonist-bound estrogen
      receptor-alpha and applied a computer-based virtual screening algorithm to
      identify retinoic acid receptor antagonists. Thus, the currently available
      crystal structures of NRs may be used for the rational design of antagonists,
      which could lead to the development of novel drugs for a variety of diseases.

PMID- 10655476
TI  - A nuclear export signal in the N-terminal regulatory domain of IkappaBalpha
      controls cytoplasmic localization of inactive NF-kappaB/IkappaBalpha complexes.
AB  - Appropriate subcellular localization is crucial for regulation of NF-kappaB
      function. Herein, we show that latent NF-kappaB complexes can enter and exit the
      nucleus in preinduction states. The nuclear export inhibitor leptomycin B (LMB)
      sequestered NF-kappaB/IkappaBalpha complexes in the nucleus. Using deletion and
      site-directed mutagenesis, we identified a previously uncharacterized nuclear
      export sequence in residues 45-54 of IkappaBalpha that was required for
      cytoplasmic localization of inactive complexes. This nuclear export sequence also
      caused nuclear exclusion of heterologous proteins in a LMB-sensitive manner.
      Importantly, a LMB-insensitive CRM1 mutant (Crm1-K1) abolished LMB-induced
      nuclear accumulation of the inactive complexes. Moreover, a cell-permeable p50 NF
      kappaB nuclear localization signal peptide also blocked these LMB effects. These
      results suggest that NF-kappaB/IkappaBalpha complexes shuttle between the
      cytoplasm and nucleus by a nuclear localization signal-dependent nuclear import
      and a CRM1-dependent nuclear export. The LMB-induced nuclear complexes could not
      bind DNA and were inaccessible to signaling events, because LMB inhibited NF
      kappaB activation without affecting the subcellular localization of upstream
      kinases IKKbeta and NIK. Our findings indicate that the dominant nuclear export
      over nuclear import contributes to the largely cytoplasmic localization of the
      inactive complexes to achieve efficient NF-kappaB activation by extracellular
      signals.

PMID- 10655477
TI  - CBP/p300 interact with and function as transcriptional coactivators of BRCA1.
AB  - BRCA1 is a breast and ovarian cancer-specific tumor suppressor, with properties
      of a transcription factor involved in DNA repair. We previously have shown the
      transactivation of heterologous promoters by the carboxyl terminus of BRCA1. We
      now describe that BRCA1-mediated transactivation is enhanced by p300/CBP (CREB
      binding protein) and that this effect was suppressed by the adenovirus E1A
      oncoprotein. We show a physical association of BRCA1 with the transcriptional
      coactivators/acetyltransferases p300 and CBP. Endogenous as well as overexpressed
      BRCA1 and p300 were found to associate in a phosphorylation-independent manner.
      BRCA1 interacts with the cAMP response element binding protein (CREB) domain of
      p300/CBP via both its amino and carboxyl termini. Finally, full-length BRCA1 is
      shown to transcriptionally activate the Rous sarcoma virus-long terminal repeat
      promoter, which was further stimulated by p300. Immunocolocalization analyses
      suggest that BRCA1 and p300 associate in a cell cycle-dependent manner. Our
      results support a role for BRCA1 in transcription.

PMID- 10655478
TI  - Enhanced association of mutant triosephosphate isomerase to red cell membranes
      and to brain microtubules.
AB  - In a Hungarian family with triosephosphate isomerase (TPI; D-glyceraldehyde-3
      phosphate keto-isomerase, EC 5.3.1.1) deficiency, two germ-line identical, but
      phenotypically differing compound heterozygote brothers (one of them with
      neurological disorder) have been identified with the same very low (<5%) TPI
      activity and 20- or 40-fold higher erythrocyte dihydroxyacetone phosphate levels
      as compared with normal controls. Our present studies with purified TPI and
      hemolysates revealed the binding of TPI, and the binding of human wild-type and
      mutant TPIs in hemolysate, to the red cell membrane, and the interference of
      binding with other hemolysate proteins. The binding of the mutant TPI is enhanced
      as compared with the wild-type enzyme. The increased binding is influenced by
      both the altered structure of the mutant and the changes in the red cell
      membrane. Compared with binding of glyceraldehyde-3-phosphate dehydrogenase, the
      isomerase binding is much less sensitive to ionic strength or blocking of the N
      terminal tail of the band-3 transmembrane protein. The binding of TPIs to the
      membrane decreases the isomerase activity, resulting in extremely high
      dihydroxyacetone phosphate levels in deficient cells. In cell-free brain extract,
      tubulin copolymerizes with TPI and with other cytosolic proteins forming highly
      decorated microtubules as shown by immunoblot analysis with anti-TPI antibody and
      by electron microscopic images. The efficacy order of TPI binding to microtubules
      is propositus > brother without neurological disorder > normal control. This
      distinct microcompartmentation of mutant proteins may be relevant in the
      development of the neurodegenerative process in TPI deficiency and in other, more
      common neurological diseases.

PMID- 10655479
TI  - Phosphorylation of human progesterone receptors at serine-294 by mitogen
      activated protein kinase signals their degradation by the 26S proteasome.
AB  - Ligand-dependent down-regulation that leads to rapid and extensive loss of
      protein is characteristic of several nuclear steroid receptors, including human
      progesterone receptors (PRs). In breast cancer cells, >95% of PRs are degraded 6
      h after the start of progestin treatment. The mechanism for down-regulation is
      unknown. We examined the role of PR phosphorylation by mitogen-activated protein
      kinases (MAPKs) in this process. Lactacystin and calpain inhibitor I, specific
      inhibitors of the 26S proteasome, blocked progestin-induced down-regulation, and
      ubiquitinated conjugates of PR accumulated in cells. Ligand-dependent PR
      degradation was also blocked by specific inhibition of p42 and p44 MAPKs. To
      define the targets of phosphorylation by this kinase, two serine/proline MAPK
      consensus sites on PR were mutated. We demonstrate that mutation of PR serine-294
      to alanine (S294A) specifically and completely prevents ligand-dependent receptor
      down-regulation. We also find that rapid, ligand-independent degradation of
      immature PR intermediates occurs by a proteasome-mediated pathway. These results
      demonstrate that PR destruction, by either of two alternate routes, is mediated
      by the 26S proteasome. Specifically, down-regulation of mature PRs occurs by a
      mechanism in which ligand binding activates PR phosphorylation by MAPKs at a
      unique serine residue, which then targets the receptors for degradation.

PMID- 10655480
TI  - A family of chromatin remodeling factors related to Williams syndrome
      transcription factor.
AB  - Chromatin remodeling complexes have been implicated in the disruption or
      reformation of nucleosomal arrays resulting in modulation of transcription, DNA
      replication, and DNA repair. Here we report the isolation of WCRF, a new
      chromatin-remodeling complex from HeLa cells. WCRF is composed of two subunits,
      WCRF135, the human homolog of Drosophila ISWI, and WCRF180, a protein related to
      the Williams syndrome transcription factor. WCRF180 is a member of a family of
      proteins sharing a putative heterochromatin localization domain, a PHD finger,
      and a bromodomain, prevalent in factors involved in regulation of chromatin
      structure.

PMID- 10655481
TI  - Permeation and gating residues in serotonin transporter.
AB  - The third transmembrane domain (TM3) of serotonin transporter (SERT) contains two
      isoleucine residues previously proposed to be involved in binding and transport
      of serotonin. When Ile-172 was replaced with cysteine, SERT became sensitive to
      inactivation by externally added [2-(trimethylammonium)ethyl]methanethio
      sulfonate (MTSET). The disulfide product of this inactivation was not sensitive
      to reduction by externally added sulfhydryl compounds, but apparently reacted
      with intracellular reducing agents to spontaneously regenerate active SERT. The
      apparent accessibility of this residue to both external and cytoplasmic reagents
      is consistent with its localization near a serotonin binding site that is
      alternately exposed to both internal and external media. In another SERT mutant,
      I179C, transport also was inactivated by MTSET but substrate binding was
      resistant. External substrate bound to the inactivated I179C and enhanced its
      reactivation by free thiols. In norepinephrine transporter (NET), cysteine
      replacement of Ile-155 (corresponding to SERT Ile-179) also rendered the
      transporter sensitive to MTSET inactivation. In NET I155C, cocaine enhanced this
      inactivation, and the substrate, dopamine, apparently protected against
      inactivation. The characteristics of this protection suggest that dopamine was
      transported, converting NET to a form in which Ile-155 was occluded. The results
      support the proposal that TM3 of SERT and NET constitute part of the substrate
      permeation pathway, and that Ile-172 in SERT resides close to the substrate
      binding site. They also suggest that Ile-179 in SERT (and Ile-155 in NET) is in a
      conformationally sensitive part of TM3, which may act as part of an external
      gate.

PMID- 10655482
TI  - A mitochondrial ferredoxin is essential for biogenesis of cellular iron-sulfur
      proteins.
AB  - Iron-sulfur (Fe/S) cluster-containing proteins catalyze a number of electron
      transfer and metabolic reactions. The components and molecular mechanisms
      involved in the assembly of the Fe/S clusters have been identified only
      partially. In eukaryotes, mitochondria have been proposed to execute a crucial
      task in the generation of intramitochondrial and extramitochondrial Fe/S
      proteins. Herein, we identify the essential ferredoxin Yah1p of Saccharomyces
      cerevisiae mitochondria as a central component of the Fe/S protein biosynthesis
      machinery. Depletion of Yah1p by regulated gene expression resulted in a 30-fold
      accumulation of iron within mitochondria, similar to what has been reported for
      other components involved in Fe/S protein biogenesis. Yah1p was shown to be
      required for the assembly of Fe/S proteins both inside mitochondria and in the
      cytosol. Apparently, at least one of the steps of Fe/S cluster biogenesis within
      mitochondria requires reduction by ferredoxin. Our findings lend support to the
      idea of a primary function of mitochondria in the biosynthesis of Fe/S proteins
      outside the organelle. To our knowledge, Yah1p is the first member of the
      ferredoxin family for which a function in Fe/S cluster formation has been
      established. A similar role may be predicted for the bacterial homologs that are
      encoded within iron-sulfur cluster assembly (isc) operons of prokaryotes.

PMID- 10655483
TI  - Identification of a transcriptional repressor related to the noncatalytic domain
      of histone deacetylases 4 and 5.
AB  - Histone deacetylases (HDACs) are involved in regulating transcription by
      modifying the core histones of the nucleosome. To date, six HDACs have been
      identified in mammalian cells: the yeast RPD3 homologs HDAC1, 2, and 3 and the
      yeast HDA1 homologs HDAC4, 5, and 6. HDAC4 and HDAC5 contain a noncatalytic N
      terminal domain. Herein, we report the identification of a protein HDRP (HDAC
      related protein) that shares 50% identity in deduced amino acid sequence to the
      noncatalytic N-terminal domain of HDAC4 and 5. The steady-state levels of HDRP
      mRNA are high in human brain, heart, and skeletal muscle and low in the several
      other tissues. HDRP has an apparent molecular mass of approximately 75 kDa. HDRP
      does not possess intrinsic HDAC activity but forms complexes with both HDAC1 and
      HDAC3. HDRP represses both basal and activated transcription in transient
      transfection assays when tethered to DNA as a Gal4-fusion protein. HDAC
      inhibitors do not reverse transcriptional repression mediated by Gal4-HDRP. Thus,
      HDRP is a transcriptional repressor and can repress transcription in the presence
      of HDAC inhibitors.

PMID- 10655485
TI  - Charge conductivity in peptides: dynamic simulations of a bifunctional model
      supporting experimental data.
AB  - Our previous finding and the given mechanism of charge and electron transfer in
      polypeptides are here integrated in a bifunctional model involving electronic
      charge transfer coupled to special internal rotations. Present molecular dynamics
      simulations that describe these motions in the chain result in the mean first
      passage times for the hopping process of an individual step. This "rest and fire"
      mechanism is formulated in detail-i.e., individual amino acids are weakly coupled
      and must first undergo alignment to reach the special strong coupling. This
      bifunctional model contains the essential features demanded by our prior
      experiments. The molecular dynamics results yield a mean first passage time
      distribution peaked at about 140 fs, in close agreement with our direct
      femtosecond measurements. In logic gate language this is a strongly conducting ON
      state resulting from small firing energies, the system otherwise being a
      quiescent OFF state. The observed time scale of about 200 fs provides
      confirmation of our simulations of transport, a model of extreme transduction
      efficiency. It explains the high efficiency of charge transport observed in
      polypeptides. We contend that the moderate speed of weak coupling is required in
      our model by the bifunctionality of peptides. This bifunctional mechanism agrees
      with our data and contains valuable features for a general model of long-range
      conductivity, final reactivity, and binding at a long distance.

PMID- 10655484
TI  - Biosynthesis of terpenoids: YchB protein of Escherichia coli phosphorylates the 2
      hydroxy group of 4-diphosphocytidyl-2C-methyl-D-erythritol.
AB  - A comparative analysis of all published complete genomes indicated that the
      putative orthologs of the unannotated ychB gene of Escherichia coli follow the
      distribution of the dxs, dxr, and ygbP genes, which have been shown to specify
      enzymes of the deoxyxylulose phosphate pathway of terpenoid biosynthesis, thus
      suggesting that the hypothetical YchB protein also is involved in that pathway.
      To test this hypothesis, the E. coli ychB gene was expressed in a homologous
      host. The recombinant protein was purified to homogeneity and was shown to
      phosphorylate 4-diphosphocytidyl-2C-methyl-D-erythritol in an ATP-dependent
      reaction. The reaction product was identified as 4-diphosphocytidyl-2C-methyl-D
      erythritol 2-phosphate by NMR experiments with various (13)C-labeled substrate
      samples. A (14)C-labeled specimen of this compound was converted efficiently into
      carotenoids by isolated chromoplasts of Capsicum annuum. The sequence of E. coli
      YchB protein is similar to that of the protein predicted by the tomato cDNA
      pTOM41 (30% identity), which had been implicated in the conversion of
      chloroplasts to chromoplasts.

PMID- 10655486
TI  - Electric field effect on cholesterol-phospholipid complexes.
AB  - Monolayer mixtures of dihydrocholesterol and phospholipids at the air-water
      interface are used to model membranes containing cholesterol and phospholipids.
      Specific, stoichiometric interactions between cholesterol and some but not all
      phospholipids have been proposed to lead to the formation of condensed complexes.
      It is reported here that an externally applied electric field of the appropriate
      sign can destabilize these complexes, resulting in their dissociation. This is
      demonstrated through the application of an electric field gradient that leads to
      phase separations in otherwise homogeneous monolayers. This is observed only when
      the monolayer composition is close to the stoichiometry of the complex. The
      electric field effect is analyzed with the same mean field thermodynamic model as
      that used previously to account for pairs of upper miscibility critical points in
      these mixtures. The concentrations of dihydrocholesterol, phospholipid, and
      complex vary strongly and sometimes discontinuously in the monolayer membrane in
      the field gradient. The model is an approximation to a two-dimensional liquid in
      which molecules freely exchange between free and complexed form so that the
      chemical potentials are constant throughout the membrane. The calculations are
      illustrated for a complex of about 15 molecules, composed of 5 cholesterol
      molecules and 10 phospholipid molecules.

PMID- 10655487
TI  - Rapid nanopore discrimination between single polynucleotide molecules.
AB  - A variety of different DNA polymers were electrophoretically driven through the
      nanopore of an alpha-hemolysin channel in a lipid bilayer. Single-channel
      recording of the translocation duration and current flow during traversal of
      individual polynucleotides yielded a unique pattern of events for each of the
      several polymers tested. Statistical data derived from this pattern of events
      demonstrate that in several cases a nanopore can distinguish between
      polynucleotides of similar length and composition that differ only in sequence.
      Studies of temperature effects on the translocation process show that
      translocation duration scales as approximately T(-2). A strong correlation exists
      between the temperature dependence of the event characteristics and the tendency
      of some polymers to form secondary structure. Because nanopores can rapidly
      discriminate and characterize unlabeled DNA molecules at low copy number,
      refinements of the experimental approach demonstrated here could eventually
      provide a low-cost high-throughput method of analyzing DNA polynucleotides.

PMID- 10655488
TI  - Localization of a peripheral membrane protein: Gbetagamma targets Galpha(Z).
AB  - To explore the relative roles of protein-binding partners vs. lipid modifications
      in controlling membrane targeting of a typical peripheral membrane protein,
      Galpha(z), we directed its binding partner, betagamma, to mislocalize on
      mitochondria. Mislocalized betagamma directed wild-type Galpha(z) and a palmitate
      lacking Galpha(z) mutant to mitochondria but did not alter localization of a
      Galpha(z) mutant lacking both myristate and palmitate. Thus, in this paradigm, a
      protein-protein interaction controls targeting of a peripheral membrane protein
      to the proper compartment, whereas lipid modifications stabilize interactions of
      proteins with membranes and with other proteins.

PMID- 10655489
TI  - Actin coating of secretory granules during regulated exocytosis correlates with
      the release of rab3D.
AB  - The present study describes a novel phenomenon in pancreatic acinar cells
      undergoing regulated exocytosis. When acinar cell preparations were challenged
      with the secretagogue carbamylcholine, a subpopulation of zymogen granules became
      coated with filamentous actin. These zymogen granules were always in proximity of
      the acinar cell apical membrane (the site of exocytosis) but did not appear to
      have fused yet. They were distinct from regular zymogen granules not only because
      of their association with filamentous actin, but also because the majority of
      them lacked the zymogen granule marker rab3D, a small GTPase implicated in
      regulated exocytosis. The apparent loss of rab3D, presumed to result from the
      release of rab3D from the granule membranes, could be prevented by agents that
      modulate the actomyosin system as well as by GTP[gammaS]. These data suggest that
      zymogen granules engaging in exocytosis become coated with actin before fusion
      and that this actin coating is tightly coupled to the release of rab3D. We
      propose that rab3D is involved in the regulation of actin polymerization around
      secretory granules and that actin coating might facilitate the movement of
      granules across the subapical actin network and toward their fusion site.

PMID- 10655491
TI  - Mouse VAP33 is associated with the endoplasmic reticulum and microtubules.
AB  - VAMP/synaptobrevin is a synaptic vesicle protein that is essential for
      neurotransmitter release. Intracellular injection of antisera against the Aplysia
      californica VAMP/synaptobrevin-binding protein ApVAP33 inhibited evoked
      excitatory postsynaptic potentials (EPSPs) in cultured cells, suggesting that
      this association may regulate the function of VAMP/synaptobrevin. We have
      identified and characterized a mouse homologue of ApVAP33, mVAP33. The overall
      domain structure of the proteins is conserved, and they have similar biochemical
      properties. mVAP33 mRNA is detectable in all mouse tissues examined, in contrast
      to the more restricted expression seen in A. californica. We analyzed the
      cellular distribution of mVAP33 protein in brain slices and cultured cortical
      cells by light and electron microscopy. Although present at higher levels in
      neurons, immunoreactivity was detected throughout both neurons and glia in a
      reticular pattern similar to that of endoplasmic reticulum-resident proteins.
      mVAP33 does not colocalize with VAMP/synaptobrevin at synaptic structures, but
      expression overlaps with lower levels of VAMP/synaptobrevin in the soma.
      Ultrastructural analysis revealed mVAP33 associated with microtubules and
      intracellular vesicles of heterogeneous size. In primary neuronal cultures, large
      aggregates of mVAP33 are also detected in short filamentous structures, which are
      occasionally associated with intracellular membranes. There is no evidence for
      accumulation of mVAP33 on synaptic vesicles or at the plasma membrane. These data
      suggest that mVAP33 is an endoplasmic-reticulum-resident protein that associates
      with components of the cytoskeleton. Any functional interaction between mVAP33
      and VAMP/synaptobrevin, therefore, most likely involves the delivery of
      components to synaptic terminals rather than a direct participation in synaptic
      vesicle exocytosis.

PMID- 10655492
TI  - Pho86p, an endoplasmic reticulum (ER) resident protein in Saccharomyces
      cerevisiae, is required for ER exit of the high-affinity phosphate transporter
      Pho84p.
AB  - In the budding yeast Saccharomyces cerevisiae, PHO84 and PHO86 are among the
      genes that are most highly induced in response to phosphate starvation. They are
      essential for growth when phosphate is limiting, and they function in the high
      affinity phosphate uptake system. PHO84 encodes a high-affinity phosphate
      transporter, and mutations in PHO86 cause many of the same phenotypes as
      mutations in PHO84, including a phosphate uptake defect and constitutive
      expression of the secreted acid phosphatase, Pho5p. Here, we show that the
      subcellular localization of Pho84p is regulated in response to extracellular
      phosphate levels; it is localized to the plasma membrane in low-phosphate medium
      but quickly endocytosed and transported to the vacuole upon addition of phosphate
      to the medium. Moreover, Pho84p is localized to the endoplasmic reticulum (ER)
      and fails to be targeted to the plasma membrane in the absence of Pho86p.
      Utilizing an in vitro vesicle budding assay, we demonstrate that Pho86p is
      required for packaging of Pho84p into COPII vesicles. Pho86p is an ER resident
      protein, which itself is not transported out of the ER. Interestingly, the
      requirement of Pho86p for ER exit is specific to Pho84p, because other members of
      the hexose transporter family to which Pho84 belongs are not mislocalized in the
      absence of Pho86p.

PMID- 10655490
TI  - Peptide-in-groove interactions link target proteins to the beta-propeller of
      clathrin.
AB  - The "WD40" domain is a widespread recognition module for linking partner proteins
      in intracellular networks of signaling and sorting. The clathrin amino-terminal
      domain, which directs incorporation of cargo into coated pits, is a beta
      propeller closely related in structure to WD40 modules. The crystallographically
      determined structures of complexes of the clathrin-terminal domain with peptides
      derived from two different cargo adaptors, beta-arrestin 2 and the beta-subunit
      of the AP-3 complex, reveal strikingly similar peptide-in-groove interactions.
      The two peptides in our structures contain related, five-residue motifs, which
      form the core of their contact with clathrin. A number of other proteins involved
      in endocytosis have similar "clathrin-box" motifs, and it therefore is likely
      that they all bind the terminal domain in the same way. We propose that a peptide
      in-groove interaction is an important general mode by which beta-propellers
      recognize specific target proteins.

PMID- 10655493
TI  - Up-regulation of the chondrogenic Sox9 gene by fibroblast growth factors is
      mediated by the mitogen-activated protein kinase pathway.
AB  - Recent experiments have established that Sox9 is required for chondrocyte
      differentiation. Here, we show that fibroblast growth factors (FGFs) markedly
      enhance Sox9 expression in mouse primary chondrocytes as well as in C3H10T1/2
      cells that express low levels of Sox9. FGFs also strongly increase the activity
      of a Sox9-dependent chondrocyte-specific enhancer in the gene for collagen type
      II. Transient transfection experiments using constructs encoding FGF receptors
      strongly suggested that all FGF receptors, FGFR1-R4, can transduce signals that
      lead to the increase in Sox9 expression. The increase in Sox9 levels induced by
      FGF2 was inhibited by a specific mitogen-activated protein kinase kinase
      (MAPKK)/mitogen-activated protein kinase/ERK kinase (MEK) inhibitor U0126 in
      primary chondrocytes. In addition, coexpression of a dual-specificity
      phosphatase, CL100/MKP-1, that is able to dephosphorylate and inactivate mitogen
      activated protein kinases (MAPKs) inhibited the FGF2-induced increase in activity
      of the Sox9-dependent enhancer. Furthermore, coexpression of a constitutively
      active mutant of MEK1 increased the activity of the Sox9-dependent enhancer in
      primary chondrocytes and C3H10T1/2 cells, mimicking the effects of FGFs. These
      results indicate that expression of the gene for the master chondrogenic factor
      Sox9 is stimulated by FGFs in chondrocytes as well as in undifferentiated
      mesenchymal cells and strongly suggest that this regulation is mediated by the
      MAPK pathway. Because Sox9 is essential for chondrocyte differentiation, we
      propose that FGFs and the MAPK pathway play an important role in chondrogenesis.

PMID- 10655494
TI  - Multiple endocytic pathways of G protein-coupled receptors delineated by GIT1
      sensitivity.
AB  - Recently, we identified a GTPase-activating protein for the ADP ribosylation
      factor family of small GTP-binding proteins that we call GIT1. This protein
      initially was identified as an interacting partner for the G protein-coupled
      receptor kinases, and its overexpression was found to affect signaling and
      internalization of the prototypical beta(2)-adrenergic receptor. Here, we report
      that GIT1 overexpression regulates internalization of numerous, but not all, G
      protein-coupled receptors. The specificity of the GIT1 effect is not related to
      the type of G protein to which a receptor couples, but rather to the endocytic
      route it uses. GIT1 only affects the function of G protein-coupled receptors that
      are internalized through the clathrin-coated pit pathway in a beta-arrestin- and
      dynamin-sensitive manner. Furthermore, the GIT1 effect is not limited to G
      protein-coupled receptors because overexpression of this protein also affects
      internalization of the epidermal growth factor receptor. However, constitutive
      agonist-independent internalization is not regulated by GIT1, because transferrin
      uptake is not affected by GIT1 overexpression. Thus, GIT1 is a protein involved
      in regulating the function of signaling receptors internalized through the
      clathrin pathway and can be used as a diagnostic tool for defining the endocytic
      pathway of a receptor.

PMID- 10655496
TI  - Expression of guanylin in "pars tuberalis-specific cells" and gonadotrophs of rat
      adenohypophysis.
AB  - The intestinal peptide guanylin regulates the electrolyte/water transport in the
      gastrointestinal epithelium by paracrine/luminocrine mechanisms. Because guanylin
      also circulates in the blood, we investigated the rat hypothalamo-pituitary
      region for expression and cellular localization of this peptide. Reverse
      transcriptase-PCR analyses with guanylin-specific primers revealed expression of
      the peptide in the pars tuberalis and pars distalis of the pituitary. Western
      blotting analyses in hypophyseal tissue extracts identified the expected 12.5-kDa
      immunoreactive peptide by using two different region-specific guanylin antisera.
      Light and electron microscopic immunocytochemistry with the same antisera
      localized guanylin in "pars tuberalis-specific cells" in the juxtaneural pars
      tuberalis adjacent to nerve endings and blood vessels of the hypothalamo
      pituitary portal system and in gonadotrophic cells within the distal pars
      tuberalis and ventrolateral part of the pars distalis. The presence and cell
      specific localization of guanylin within the hypothalamo-hypophyseal system
      indicate that this peptide may be specifically involved in paracrine and
      endocrine regulatory mechanisms.

PMID- 10655495
TI  - The sentrin-conjugating enzyme mUbc9 interacts with GLUT4 and GLUT1 glucose
      transporters and regulates transporter levels in skeletal muscle cells.
AB  - Glucose transport in insulin-regulated tissues is mediated by the GLUT4 and GLUT1
      transporters. Using the yeast two-hybrid system, we have cloned the sentrin
      conjugating enzyme mUbc9 as a protein that interacts with the GLUT4 COOH-terminal
      intracellular domain. The mUbc9 enzyme was found to bind directly to GLUT4 and
      GLUT1 through an 11-aa sequence common to the two transporters and to modify both
      transporters covalently by conjugation with the mUbc9 substrate, sentrin.
      Overexpression of mUbc9 in L6 skeletal muscle cells decreased GLUT1 transporter
      abundance 65%, resulting in decreased basal glucose transport. By contrast, mUbc9
      overexpression increased GLUT4 abundance 8-fold, leading to enhanced transport
      stimulation by insulin. A dominant-negative mUbc9 mutant lacking catalytic
      activity had effects opposite to those of wild-type mUbc9. The regulation of
      GLUT4 and GLUT1 was specific, as evidenced by an absence of mUbc9 interaction
      with or regulation of the GLUT3 transporter isoform in L6 skeletal muscle cells.
      The mUbc9 sentrin-conjugating enzyme represents a novel regulator of GLUT1 and
      GLUT4 protein levels with potential importance as a determinant of basal and
      insulin-stimulated glucose uptake in normal and pathophysiological states.

PMID- 10655497
TI  - Genomic interval engineering of mice identifies a novel modulator of triglyceride
      production.
AB  - To accelerate the biological annotation of novel genes discovered in sequenced
      regions of mammalian genomes, we are creating large deletions in the mouse genome
      targeted to include clusters of such genes. Here we describe the targeted
      deletion of a 450-kb region on mouse chromosome 11, which, based on computational
      analysis of the deleted murine sequences and human 5q orthologous sequences,
      codes for nine putative genes. Mice homozygous for the deletion had a variety of
      abnormalities, including severe hypertriglyceridemia, hepatic and cardiac
      enlargement, growth retardation, and premature mortality. Analysis of
      triglyceride metabolism in these animals demonstrated a several-fold increase in
      hepatic very-low density lipoprotein triglyceride secretion, the most prevalent
      mechanism responsible for hypertriglyceridemia in humans. A series of mouse BAC
      and human YAC transgenes covering different intervals of the 450-kb deleted
      region were assessed for their ability to complement the deletion induced
      abnormalities. These studies revealed that OCTN2, a gene recently shown to play a
      role in carnitine transport, was able to correct the triglyceride abnormalities.
      The discovery of this previously unappreciated relationship between OCTN2,
      carnitine, and hepatic triglyceride production is of particular importance
      because of the clinical consequence of hypertriglyceridemia and the paucity of
      genes known to modulate triglyceride secretion.

PMID- 10655498
TI  - Toward a protein-protein interaction map of the budding yeast: A comprehensive
      system to examine two-hybrid interactions in all possible combinations between
      the yeast proteins.
AB  - Protein-protein interactions play pivotal roles in various aspects of the
      structural and functional organization of the cell, and their complete
      description is indispensable to thorough understanding of the cell. As an
      approach toward this goal, here we report a comprehensive system to examine two
      hybrid interactions in all of the possible combinations between proteins of
      Saccharomyces cerevisiae. We cloned all of the yeast ORFs individually as a DNA
      binding domain fusion ("bait") in a MATa strain and as an activation domain
      fusion ("prey") in a MATalpha strain, and subsequently divided them into pools,
      each containing 96 clones. These bait and prey clone pools were systematically
      mated with each other, and the transformants were subjected to strict selection
      for the activation of three reporter genes followed by sequence tagging. Our
      initial examination of approximately 4 x 10(6) different combinations,
      constituting approximately 10% of the total to be tested, has revealed 183
      independent two-hybrid interactions, more than half of which are entirely novel.
      Notably, the obtained binary data allow us to extract more complex interaction
      networks, including the one that may explain a currently unsolved mechanism for
      the connection between distinct steps of vesicular transport. The approach
      described here thus will provide many leads for integration of various cellular
      functions and serve as a major driving force in the completion of the protein
      protein interaction map.

PMID- 10655499
TI  - Early disruption of centromeric chromatin organization in centromere protein A
      (Cenpa) null mice.
AB  - Centromere protein A (Cenpa for mouse, CENP-A for other species) is a histone H3
      like protein that is thought to be involved in the nucleosomal packaging of
      centromeric DNA. Using gene targeting, we have disrupted the mouse Cenpa gene and
      demonstrated that the gene is essential. Heterozygous mice are healthy and
      fertile whereas null mutants fail to survive beyond 6.5 days postconception.
      Affected embryos show severe mitotic problems, including micronuclei and
      macronuclei formation, nuclear bridging and blebbing, and chromatin fragmentation
      and hypercondensation. Immunofluorescence analysis of interphase cells at day 5.5
      reveals complete Cenpa depletion, diffuse Cenpb foci, absence of discrete Cenpc
      signal on centromeres, and dispersion of Cenpb and Cenpc throughout the nucleus.
      These results suggest that Cenpa is essential for kinetochore targeting of Cenpc
      and plays an early role in organizing centromeric chromatin at interphase. The
      evidence is consistent with the proposal of a critical epigenetic function for
      CENP-A in marking a chromosomal region for centromere formation.

PMID- 10655500
TI  - TAF250 is required for multiple developmental events in Drosophila.
AB  - The TFIID transcription initiation complex is composed of TBP and multiple TAFs.
      Studies in unicellular systems indicate that TAF250 is required for progression
      through G(1)/S of the cell cycle and repression of apoptosis. Here we extend
      these in vivo studies by determining the developmental requirements for TAF250 in
      a multicellular organism, Drosophila. TAF250 mutants were isolated in a genetic
      screen that also yielded TAF60 and TAF110 mutants, indicating that TAFs function
      coordinately to regulate transcription. Null alleles of TAF250 are recessive
      larval lethal. However, combinations of weak loss-of-function TAF250 alleles
      survive to adulthood and reveal requirements for TAF250 during ovary, eye,
      ocelli, wing, bristle, and terminalia development as well as overall growth of
      the fly. These phenotypes suggest roles for TAF250 in regulating the cell cycle,
      cell differentiation, cell proliferation, and cell survival. Finally, molecular
      analysis of TAF250 mutants reveals that the observed phenotypes are caused by
      mutations in a central region of TAF250 that is conserved among metazoan
      organisms. This region is contained within the TAF250 histone acetyltransferase
      domain, but the mutations do not alter the histone acetyltransferase activity of
      TAF250 in vitro, indicating that some other aspect of TAF250 function is
      affected. Because this region is not conserved in the yeast TAF250 homologue,
      TAF145, it may define an activity for TAF250 that is unique to higher eukaryotes.

PMID- 10655501
TI  - Recent, extensive, and preferential insertion of members of the miniature
      inverted-repeat transposable element family Heartbreaker into genic regions of
      maize.
AB  - A 314-bp DNA element called Heartbreaker-hm1 (Hbr-hm1) was previously identified
      in the 3' untranslated region of a mutant allele of the maize disease resistance
      gene HM1. This element has structural features of miniature inverted-repeat
      transposable elements (MITEs) and is a member of a large family of approximately
      4,000 copies in the maize genome. Unlike previously described MITEs, most members
      of the Hbr family display over 90% sequence identity. This, coupled with the
      insertion of an Hbr element into an allele of the HM1 gene, suggested that this
      family might have spread recently throughout the genome. Consistent with this
      view is the finding that Hbr insertion sites are remarkably polymorphic. Ten of
      ten loci containing Hbr elements were found to be polymorphic for the presence or
      absence of Hbr among a collection of maize inbred lines and teosinte strains.
      Despite the fact that over 80% of the maize genome contain moderate to highly
      repetitive DNA, we find that randomly chosen Hbr elements are predominantly in
      single or low copy regions. Furthermore, when used to query both the public and
      private databases of plant genes, over 50% of the sequences flanking these Hbr
      elements resulted in significant "hits." Taken together, these data indicate that
      the presence or absence of Hbr elements is a significant contributory factor to
      the high level of polymorphism associated with maize genic regions.

PMID- 10655502
TI  - Mice reconstituted with DNA polymerase beta-deficient fetal liver cells are able
      to mount a T cell-dependent immune response and mutate their Ig genes normally.
AB  - The ubiquitously expressed, error-prone DNA polymerase beta (polbeta) plays a
      role in base excision repair, and the involvement of this molecule in the
      nonhomologous end joining (NHEJ) process of DNA repair has recently been
      demonstrated in yeast. Polbeta-deficient mice are not viable, and studies on
      conditional mutants revealed a competitive disadvantage of polbeta(-/-) vs. wild
      type cells. We show here that polbeta-deficient mice survive up to day 18.5
      postcoitum, but die perinatally; a circumstance that allowed the investigation of
      a potential role of polbeta in lymphocyte development by transfer of fetal liver
      cells (FLC) derived from polbeta(-/-) embryos into lethally irradiated hosts. FLC
      transfers using mutant cells lead to an almost normal reconstitution of the
      lymphocyte compartment, indicating that polbeta-deficiency does not prevent V(D)J
      recombination, which is known to employ factors of the NHEJ pathway. Mice
      reconstituted with polbeta(-/-) FLC mount a normal T cell-dependent immune
      response against the hapten (4-hydroxy-3-nitrophenyl) acetyl (NP). Moreover,
      germinal center B cells from NP-immunized reconstituted mice show normal levels
      and patterns of somatic point mutations in their rearranged antibody genes,
      demonstrating that polbeta is not critically involved in somatic hypermutation.

PMID- 10655503
TI  - Comparative genomic sequence analysis of the human and mouse cystic fibrosis
      transmembrane conductance regulator genes.
AB  - The identification of the cystic fibrosis transmembrane conductance regulator
      gene (CFTR) in 1989 represents a landmark accomplishment in human genetics. Since
      that time, there have been numerous advances in elucidating the function of the
      encoded protein and the physiological basis of cystic fibrosis. However, numerous
      areas of cystic fibrosis biology require additional investigation, some of which
      would be facilitated by information about the long-range sequence context of the
      CFTR gene. For example, the latter might provide clues about the sequence
      elements responsible for the temporal and spatial regulation of CFTR expression.
      We thus sought to establish the sequence of the chromosomal segments encompassing
      the human CFTR and mouse Cftr genes, with the hope of identifying conserved
      regions of biologic interest by sequence comparison. Bacterial clone-based
      physical maps of the relevant human and mouse genomic regions were constructed,
      and minimally overlapping sets of clones were selected and sequenced, eventually
      yielding approximately 1.6 Mb and approximately 358 kb of contiguous human and
      mouse sequence, respectively. These efforts have produced the complete sequence
      of the approximately 189-kb and approximately 152-kb segments containing the
      human CFTR and mouse Cftr genes, respectively, as well as significant amounts of
      flanking DNA. Analyses of the resulting data provide insights about the
      organization of the CFTR/Cftr genes and potential sequence elements regulating
      their expression. Furthermore, the generated sequence reveals the precise
      architecture of genes residing near CFTR/Cftr, including one known gene
      (WNT2/Wnt2) and two previously unknown genes that immediately flank CFTR/Cftr.

PMID- 10655504
TI  - HIV-1 envelope induces activation of caspase-3 and cleavage of focal adhesion
      kinase in primary human CD4(+) T cells.
AB  - Binding of HIV type 1 (HIV-1) envelope glycoproteins to the surface of a CD4(+) T
      cell transduces intracellular signals through the primary envelope receptor, CD4,
      and a coreceptor, either CCR5 or CXCR4. Furthermore, envelope-CD4(+) cell
      interactions increase rates of apoptosis in peripheral blood mononuclear cells
      (PBMCs). We demonstrate that in primary T lymphocytes, recombinant HIV-1 envelope
      proteins induce the activation of caspase-3 and caspase-6, which belong to a
      family of cysteine proteases that, upon activation, promote programmed cell
      death. Envelope-mediated activation of caspase-3 and caspase-6 depended on
      envelope-CD4 receptor interactions; CCR5-utilizing as well as CXCR4-utilizing
      envelopes elicited this response. Focal adhesion kinase (FAK) is a substrate of
      both caspase-3 and caspase-6, and inactivation of FAK by these caspases promotes
      apoptosis. En-velope treatment of lymphocytes led to the cleavage of FAK in a
      manner consistent with caspase-mediated cleavage.

PMID- 10655505
TI  - Accelerated development of IgG autoantibodies and autoimmune disease in the
      absence of secreted IgM.
AB  - Individuals with systemic lupus erythematosus and rheumatoid arthritis are
      characterized by the presence of high levels of circulating IgM and IgG
      autoantibodies. Although IgG autoantibodies often are pathogenic, the role of IgM
      autoantibodies in autoimmune disease is not clear. Using mice that are unable to
      secrete IgM but are able to express surface IgM and IgD and to secrete other
      classes of immunoglobulins, we examined the effect of the absence of secreted IgM
      in the development of IgG autoantibodies and autoimmune disease in lupus-prone
      lymphoproliferative (lpr) mice. Compared with regular lpr mice, lpr mice that
      lack secreted IgM developed elevated levels of IgG autoantibodies to double
      stranded DNA and histones and had more abundant deposits of immune complexes in
      the glomeruli; they also suffered more severe glomerulonephritis and succumbed to
      the disease at an earlier age. Similarly, the absence of secreted IgM also
      resulted in an accelerated development of IgG autoantibodies in normal mice.
      These findings suggest that secreted IgM, including IgM autoantibodies produced
      naturally or as part of an autoimmune response, may lessen the severity of
      autoimmune pathology associated with IgG autoantibodies.

PMID- 10655506
TI  - Structural requirements of six naturally occurring isoforms of the IL-18 binding
      protein to inhibit IL-18.
AB  - A novel, constitutively expressed and secreted IL-18 binding protein (IL-18BP)
      neutralizes IL-18 and thereby suppresses the production of IFN-gamma, resulting
      in reduced T-helper type 1 immune responses. In the present study, four human and
      two mouse isoforms, resulting from mRNA splicing and found in various cDNA
      libraries, were expressed, purified, and assessed for binding and neutralization
      of IL-18 biological activities. Human IL-18BP isoform a (IL-18BPa) exhibited the
      greatest affinity for IL-18 with a rapid on-rate, a slow off-rate, and a
      dissociation constant (K(d)) of 399 pM. IL-18BPc shares the Ig domain of IL-18BPa
      except for the 29 C-terminal amino acids; the K(d) of IL-18BPc is 10-fold less
      (2.94 nM). Nevertheless, IL-18BPa and IL-18BPc neutralize IL-18 >95% at a molar
      excess of two. IL-18BPb and IL-18BPd isoforms lack a complete Ig domain and lack
      the ability to bind or neutralize IL-18. Murine IL-18BPc and IL-18BPd isoforms,
      possessing the identical Ig domain, also neutralize >95% murine IL-18 at a molar
      excess of two. However, murine IL-18BPd, which shares a common C-terminal motif
      with human IL-18BPa, also neutralizes human IL-18. Molecular modeling identified
      a large mixed electrostatic and hydrophobic binding site in the Ig domain of IL
      18BP, which could account for its high affinity binding to the ligand. It is
      likely that preferential secretion of functional and nonfunctional isoforms of IL
      18BP affect the immune response.

PMID- 10655507
TI  - Targeted inhibition of calcineurin prevents agonist-induced cardiomyocyte
      hypertrophy.
AB  - Cardiac hypertrophy is a major predictor of future morbidity and mortality.
      Recent investigation has centered around identifying the molecular signaling
      pathways that regulate cardiac myocyte reactivity with the goal of modulating
      pathologic hypertrophic programs. One potential regulator of cardiomyocyte
      hypertrophy is the calcium-sensitive phosphatase calcineurin. We show here that
      calcineurin enzymatic activity, mRNA, and protein levels are increased in
      cultured neonatal rat cardiomyocytes by hypertrophic agonists such as angiotensin
      II, phenylephrine, and 1% fetal bovine serum. This induction of calcineurin
      activity was associated with an increase in calcineurin Abeta (CnAbeta) mRNA and
      protein, but not in CnAalpha or CnAgamma. Agonist-dependent increases in
      calcineurin enzymatic activity were specifically inhibited with an adenovirus
      expressing a noncompetitive peptide inhibitor of calcineurin known as cain [Lai,
      M. M., Burnett, P. E., Wolosker, H., Blackshaw, S. & Snyder, S. H. (1998) J.
      Biol. Chem. 273, 18325-18331]. Targeted inhibition of calcineurin with cain or an
      adenovirus expressing only the calcineurin inhibitory domain of AKAP79 attenuated
      cardiomyocyte hypertrophy and atrial natriuretic factor expression in response to
      angiotensin II, phenylephrine, and 1% fetal bovine serum. These data demonstrate
      that calcineurin is an important regulator of cardiomyocyte hypertrophy in
      response to certain agonists and suggest that cyclosporin A and FK506 function to
      attenuate cardiac hypertrophy by specifically inhibiting calcineurin.

PMID- 10655508
TI  - Testosterone reduces neuronal secretion of Alzheimer's beta-amyloid peptides.
AB  - Alzheimer's disease (AD) is characterized by the age-related deposition of beta
      amyloid (Abeta) 40/42 peptide aggregates in vulnerable brain regions. Multiple
      levels of evidence implicate a central role for Abeta in the pathophysiology of
      AD. Abeta peptides are generated by the regulated cleavage of an approximately
      700-aa Abeta precursor protein (betaAPP). Full-length betaAPP can undergo
      proteolytic cleavage either within the Abeta domain to generate secreted
      sbetaAPPalpha or at the N- and C-terminal domain(s) of Abeta to generate
      amyloidogenic Abeta peptides. Several epidemiological studies have reported that
      estrogen replacement therapy protects against the development of AD in
      postmenopausal women. We previously reported that treating cultured neurons with
      17beta-estradiol reduced the secretion of Abeta40/42 peptides, suggesting that
      estrogen replacement therapy may protect women against the development of AD by
      regulating betaAPP metabolism. Increasing evidence indicates that testosterone,
      especially bioavailable testosterone, decreases with age in older men and in
      postmenopausal women. We report here that treatment with testosterone increases
      the secretion of the nonamyloidogenic APP fragment, sbetaAPPalpha, and decreases
      the secretion of Abeta peptides from N2a cells and rat primary cerebrocortical
      neurons. These results raise the possibility that testosterone supplementation in
      elderly men may be protective in the treatment of AD.

PMID- 10655509
TI  - Whole-body optical imaging of green fluorescent protein-expressing tumors and
      metastases.
AB  - We have imaged, in real time, fluorescent tumors growing and metastasizing in
      live mice. The whole-body optical imaging system is external and noninvasive. It
      affords unprecedented continuous visual monitoring of malignant growth and spread
      within intact animals. We have established new human and rodent tumors that
      stably express very high levels of the Aequorea victoria green fluorescent
      protein (GFP) and transplanted these to appropriate animals. B16F0-GFP mouse
      melanoma cells were injected into the tail vein or portal vein of 6-week-old
      C57BL/6 and nude mice. Whole-body optical images showed metastatic lesions in the
      brain, liver, and bone of B16F0-GFP that were used for real time, quantitative
      measurement of tumor growth in each of these organs. The AC3488-GFP human colon
      cancer was surgically implanted orthotopically into nude mice. Whole-body optical
      images showed, in real time, growth of the primary colon tumor and its metastatic
      lesions in the liver and skeleton. Imaging was with either a trans-illuminated
      epifluorescence microscope or a fluorescence light box and thermoelectrically
      cooled color charge-coupled device camera. The depth to which metastasis and
      micrometastasis could be imaged depended on their size. A 60-microm diameter
      tumor was detectable at a depth of 0.5 mm whereas a 1, 800-microm tumor could be
      visualized at 2.2-mm depth. The simple, noninvasive, and highly selective imaging
      of growing tumors, made possible by strong GFP fluorescence, enables the detailed
      imaging of tumor growth and metastasis formation. This should facilitate studies
      of modulators of cancer growth including inhibition by potential chemotherapeutic
      agents.

PMID- 10655510
TI  - A mutation in the alpha 3 chain of type IX collagen causes autosomal dominant
      multiple epiphyseal dysplasia with mild myopathy.
AB  - Multiple epiphyseal dysplasia (MED) is a degenerative cartilage condition shown
      in some cases to be caused by mutations in genes encoding cartilage oligomeric
      matrix protein or type IX collagen. We studied a family with autosomal dominant
      MED affecting predominantly the knee joints and a mild proximal myopathy. Genetic
      linkage to the COL9A3 locus on chromosome 20q13.3 was established with a peak
      log(10) odds ratio for linkage score of 3.87 for markers D20S93 and D20S164.
      Reverse transcription-PCR performed on the muscle biopsy revealed aberrant mRNA
      lacking exon 3, which predicted a protein lacking 12 amino acids from the COL3
      domain of alpha3(IX) collagen. Direct sequencing of genomic DNA confirmed the
      presence of a splice acceptor mutation in intron 2 of the COL9A3 gene
      (intervening sequence 2, G-A, -1) only in affected family members. By electron
      microscopy, chondrocytes from epiphyseal cartilage exhibited dilated rough
      endoplasmic reticulum containing linear lamellae of alternating electron-dense
      and electron-lucent material, reflecting abnormal processing of mutant protein.
      Type IX collagen chains appeared normal in size and quantity but showed defective
      cross-linking by Western blotting. The novel phenotype of MED and mild myopathy
      is likely caused by a dominant-negative effect of the exon 3-skipping mutation in
      the COL9A3 gene. Patients with MED and a waddling gait but minimal radiographic
      hip involvement should be evaluated for a primary myopathy and a mutation in type
      IX collagen.

PMID- 10655511
TI  - Antagonistic actions of analogs related to growth hormone-releasing hormone
      (GHRH) on receptors for GHRH and vasoactive intestinal peptide on rat pituitary
      and pineal cells in vitro.
AB  - Peptide analogs of growth hormone-releasing hormone (GHRH) can potentially
      interact with vasoactive intestinal peptide (VIP) receptors (VPAC(1)-R and
      VPAC(2)-R) because of the structural similarities of these two hormones and their
      receptors. We synthesized four new analogs related to GHRH (JV-1-50, JV-1-51, JV
      1-52, and JV-1-53) with decreased GHRH antagonistic activity and increased VIP
      antagonistic potency. To characterize various peptide analogs for their
      antagonistic activity on receptors for GHRH and VIP, we developed assay systems
      based on superfusion of rat pituitary and pineal cells. Receptor-binding
      affinities of peptides to the membranes of these cells were also evaluated by
      radioligand competition assays. Previously reported GHRH antagonists JV-1-36, JV
      1-38, and JV-1-42 proved to be selective for GHRH receptors, because they did not
      influence VIP-stimulated VPAC(2) receptor-dependent prolactin release from
      pituitary cells or VPAC(1) receptor-dependent cAMP efflux from pinealocytes but
      strongly inhibited GHRH-stimulated growth hormone (GH) release. Analogs JV-1-50,
      JV-1-51, and JV-1-52 showed various degrees of VPAC(1)-R and VPAC(2)-R
      antagonistic potency, although also preserving a substantial GHRH antagonistic
      effect. Analog JV-1-53 proved to be a highly potent VPAC(1) and VPAC(2) receptor
      antagonist, devoid of inhibitory effects on GHRH-evoked GH release. The
      antagonistic activity of these peptide analogs on processes mediated by receptors
      for GHRH and VIP was consistent with the binding affinity. The analogs with
      antagonistic effects on different types of receptors expressed on tumor cells
      could be utilized for the development of new approaches to treatment of various
      human cancers.

PMID- 10655512
TI  - Correction of ornithine accumulation prevents retinal degeneration in a mouse
      model of gyrate atrophy of the choroid and retina.
AB  - Deficiency of ornithine-delta-aminotransferase (OAT) in humans results in gyrate
      atrophy of the choroid and retina (GA), an autosomal recessive disorder
      characterized by ornithine accumulation and a progressive chorioretinal
      degeneration of unknown pathogenesis. To determine whether chronic, systemic
      reduction of ornithine can prevent this form of retinal degeneration, we used an
      arginine-restricted diet to maintain long term reduction of ornithine in a mouse
      model of OAT-deficiency (Oat(-/-)) produced by gene targeting. We evaluated the
      mice over a 12-month period by measurement of plasma amino acids,
      electroretinograms, and retinal histologic and ultrastructural studies. We found
      that an arginine-restricted diet substantially reduces plasma ornithine levels
      and completely prevents retinal degeneration in Oat(-/-). This result indicates
      that ornithine accumulation is a necessary factor in the pathophysiology of the
      retinal degeneration in GA and that restoration of OAT activity in retina is not
      required for effective treatment of GA.

PMID- 10655513
TI  - Overexpression of M68/DcR3 in human gastrointestinal tract tumors independent of
      gene amplification and its location in a four-gene cluster.
AB  - Fas-mediated apoptosis is an important regulator of cell survival, and
      abnormalities in this system have been shown to result in a number of human
      pathological conditions. A secreted member of the tumor necrosis factor receptor
      superfamily, DcR3, was recently reported to be amplified in human lung and colon
      cancers as a negative regulator of Fas-mediated apoptosis. We identified this
      gene, which we call M68. M68 genomic DNA, mRNA, and protein levels were examined
      in a series of human gastrointestinal tract tumors. Using M68
      immunohistochemistry and a scoring system similar to that used for HER-2/neu, we
      found that M68 protein was overexpressed in 30 of 68 (44%) human adenocarcinomas
      of the esophagus, stomach, colon, and rectum. Tumors examined by Northern blot
      revealed M68 mRNA highly elevated in a similar fraction of primary tumors from
      the same gastrointestinal tract regions, as well as in the colon adenocarcinoma
      cell lines SW480 and SW1116. Further, we found M68 protein to be overexpressed in
      a substantial number of tumors in which gene amplification could not be detected
      by fluorescence in situ hybridization or quantitative genomic PCR, suggesting
      that overexpression of M68 may precede amplification in tumors. Finally, we find
      that M68 lies within a four-gene cluster that includes a novel helicase-like gene
      (NHL) related to RAD3/ERCC2, a plasma membrane Ras-related GTPase and a member of
      the stathmin family, amplification or overexpression of which may also contribute
      to cell growth and tumor progression.

PMID- 10655514
TI  - Genetic reconstruction of individual colorectal tumor histories.
AB  - It is difficult to observe human tumor progression as precursor lesions are
      systematically removed. Alternatives to direct observations, commonly used to
      reveal the hidden past of species and populations, are sequence comparisons or
      molecular clocks. Noncoding microsatellite (MS) loci were employed as molecular
      tumor clocks in 13 human mutator phenotype (MSI(+)) colorectal tumors.
      Quantitative analysis revealed that specific patterns of somatic MS mutations
      accumulate with division after loss of mismatch repair (MMR). Tumors had unique
      patterns of MS mutation, and, therefore, based on this model, each tumor had its
      own unique history. Loss of MMR occurred very early relative to terminal clonal
      expansion, with an estimated average of 2,300 divisions since loss of MMR and 280
      divisions since expansion. Contrary to the classical adenoma-cancer sequence,
      MSI(+) adenomas were nearly as old as cancers (2,000 versus 2,400 divisions since
      loss of MMR). Negative clinical examinations preceded six tumors, independently
      documenting an absence of visible precursors during early MSI(+) adenoma or
      cancer progression. These findings further extend a window beyond visible
      progression since loss of MMR appears to start a genetic phase involving clone
      sizes or phenotypes below a threshold of clinical detection. This previously
      occult prologue before visible neoplasia is longer and therefore likely more
      important than generally appreciated.

PMID- 10655515
TI  - The kidney is an important site for in vivo phenylalanine-to-tyrosine conversion
      in adult humans: A metabolic role of the kidney.
AB  - Synthesis of Tyr in the human body occurs by hydroxylation of the indispensable
      amino acid Phe. Until now, it was believed that in humans, this process was
      restricted to the liver, but we provide compelling evidence of production of Tyr
      from Phe in the kidney. To determine whether the human kidney produces Tyr, we
      measured Tyr balance, the Tyr appearance rate, and the Phe-to-Tyr conversion in
      12 healthy human subjects by using [(15)N]Phe and [(2)H(4)]Tyr as tracers. Renal
      plasma flow was measured by using paraaminohippurate, and sampling from the
      femoral artery and renal veins was performed. The results were compared with
      those obtained in 12 control subjects undergoing hepatic vein catheterization and
      infusion of identical tracers. In all 12 subjects, there was a net uptake of Phe
      by the kidney (2.2 +/- 1.2 micromol/min), whereas Tyr was released (5.3 +/- 1.5
      micromol/min). In contrast, there was a net uptake of both Phe (9.5 +/- 1.2
      micromol/min) and Tyr (14.3 +/- 1.3 micromol/min) by the splanchnic bed. Phe
      conversion to Tyr occurred at a rate of 5.2 +/- 1.2 micromol/min in kidney and
      3.0 +/- 0.7 micromol/min in the splanchnic bed. The kidney contributed a
      substantial amount of Tyr to the systemic circulation where the splanchnic bed
      was a net remover of Tyr. Our results demonstrate that the kidney is the major
      donor of Tyr to the systemic circulation by its conversion of Phe to Tyr. This
      observation may have important clinical implications for patients with both renal
      and hepatic disease, who may be at risk of Phe overloading and Tyr deficiency,
      and it should be considered when parenteral or enteral nutrients are administered
      rich in Phe and low in Tyr.

PMID- 10655516
TI  - A habitat for psychrophiles in deep Antarctic ice.
AB  - Microbes, some of which may be viable, have been found in ice cores drilled at
      Vostok Station at depths down to approximately 3,600 m, close to the surface of
      the huge subglacial Lake Vostok. Two types of ice have been found. The upper
      3,500 m comprises glacial ice containing traces of nutrients of aeolian origin
      including sulfuric acid, nitric acid, methanosulfonic acid (MSA), formic acid,
      sea salts, and mineral grains. Ice below approximately 3,500 m comprises refrozen
      water from Lake Vostok, accreted to the bottom of the glacial ice. Nutrients in
      the accretion ice include salts and dissolved organic carbon. There is great
      interest in searching for living microbes and especially for new species in
      deepest Antarctic ice. I propose a habitat consisting of interconnected liquid
      veins along three-grain boundaries in ice in which psychrophilic bacteria can
      move and obtain energy and carbon from ions in solution. In the accretion ice,
      with an age of a few 10(4) years and a temperature a few degrees below freezing,
      the carbon and energy sources in the veins can maintain significant numbers of
      cells per cubic centimeter that are metabolizing but not multiplying. In the 4 x
      10(5)-year-old colder glacial ice, at least 1 cell per cm(3) in acid veins can be
      maintained. With fluorescence microscopy tuned to detect NADH in live organisms,
      motile bacteria could be detected by direct scanning of the veins in ice samples.

PMID- 10655517
TI  - The salicylate-derived mycobactin siderophores of Mycobacterium tuberculosis are
      essential for growth in macrophages.
AB  - Mycobacterium tuberculosis is an important pathogen of mammals that relies on 2
      hydroxyphenyloxazoline-containing siderophore molecules called mycobactins for
      the acquisition of iron in the restrictive environment of the mammalian
      macrophage. These compounds have been proposed to be biosynthesized through the
      action of a cluster of genes that include both nonribosomal peptide synthase and
      polyketide synthase components. One of these genes encodes a protein, MbtB, that
      putatively couples activated salicylic acid with serine or threonine and then
      cyclizes this precursor to the phenyloxazoline ring system. We have used gene
      replacement through homologous recombination to delete the mbtB gene and replace
      this with a hygromycin-resistance cassette in the virulent strain of M.
      tuberculosis H37Rv. The resulting mutant is restricted for growth in iron-limited
      media but grows normally in iron-replete media. Analysis of siderophore
      production by this organism revealed that the biosynthesis of all salicylate
      derived siderophores was interrupted. The mutant was found to be impaired for
      growth in macrophage-like THP-1 cells, suggesting that siderophore production is
      required for virulence of M. tuberculosis. These results provide conclusive
      evidence linking this genetic locus to siderophore production.

PMID- 10655518
TI  - A role for Salmonella fimbriae in intraperitoneal infections.
AB  - Enteric bacteria possess multiple fimbriae, many of which play critical roles in
      attachment to epithelial cell surfaces. SEF14 fimbriae are only found in
      Salmonella enterica serovar Enteritidis (S. enteritidis) and closely related
      serovars, suggesting that SEF14 fimbriae may affect serovar-specific virulence
      traits. Despite evidence that SEF14 fimbriae are expressed by S. enteritidis in
      vivo, previous studies showed that SEF14 fimbriae do not mediate adhesion to the
      intestinal epithelium. Therefore, we tested whether SEF14 fimbriae are required
      for virulence at a stage in infection after the bacteria have passed the
      intestinal barrier. Polar mutations that disrupt the entire sef operon decreased
      virulence in mice more than 1,000-fold. Nonpolar mutations that disrupted sefA
      (encoding the major structural subunit) did not affect virulence, but mutations
      that disrupted sefD (encoding the putative adhesion subunit) resulted in a severe
      virulence defect. The results indicate that the putative SEF14 adhesion subunit
      is specifically required for a stage of the infection subsequent to transit
      across the intestinal barrier. Therefore, we tested whether SefD is required for
      uptake or survival in macrophages. The majority of wild-type bacteria were
      detected inside macrophages soon after i.p. infection, but the sefD mutants were
      not readily internalized by peritoneal macrophages. These results indicate that
      the potential SEF14 adhesion subunit is essential for efficient uptake or
      survival of S. enteritidis in macrophages. This report describes a role of
      fimbriae in intracellular infection, and indicates that fimbriae may be required
      for systemic infections at stages beyond the initial colonization of host
      epithelial surfaces.

PMID- 10655519
TI  - Tyrosine phosphorylation of the Helicobacter pylori CagA antigen after cag-driven
      host cell translocation.
AB  - Helicobacter pylori strains associated with severe tissue damage and inflammation
      possess a unique genetic locus, cag, containing 31 genes originating from a
      distant event of horizontal transfer and retained as a pathogenicity island. The
      cag system is an Helicobacter-specific type IV secretion engine involved in
      cellular responses like induction of pedestals, secretion of IL-8, and
      phosphorylation of proteic targets. It has previously been reported that
      cocultivation of epithelial cells with Helicobacter pylori triggers signal
      transduction and tyrosine phosphorylation of a 145-kDa putative host cell
      protein. Herein, we demonstrate that this protein is not derived from the host
      but rather is the bacterial immunodominant antigen CagA, a virulence factor
      commonly expressed in peptic ulcer disease and thought to be an orphan of a
      specific biological function. Thus, CagA is delivered into the epithelial cells
      by the cag type IV secretion system where it is phosphorylated on tyrosine
      residues by an as yet unidentified host cell kinase and wired to eukaryotic
      signal transduction pathways and cytoskeletal plasticity.

PMID- 10655520
TI  - In vivo HIV-1 infection of CD45RA(+)CD4(+) T cells is established primarily by
      syncytium-inducing variants and correlates with the rate of CD4(+) T cell
      decline.
AB  - Switch from non-syncytium-inducing (NSI) to syncytium-inducing (SI) HIV type 1
      (HIV-1) is associated with accelerated CD4(+) T cell depletion, which might
      partially be explained by higher virulence of SI variants compared with NSI
      variants. Because NSI and SI variants use different coreceptors for entry of
      target cells, altered tropism might offer an explanation for increased
      pathogenesis associated with SI HIV-1 infection. To investigate whether SI and
      NSI HIV-1 variants infect different CD4(+) T cell subsets in vivo, the
      distribution of SI and NSI variants over CD4(+) memory (CD45RA(-)RO(+)) and naive
      (CD45RA(+)RO(-)) cells was studied by using limiting dilution cultures. In
      contrast to NSI variants that were mainly present in CD45RO(+) cells, SI variants
      were equally distributed over CD45RO(+) and CD45RA(+) cells. Infection of memory
      cells by both NSI and SI HIV-1 and infection of naive cells primarily by SI HIV-1
      corresponded closely with the differential cell surface expression of CXCR4 and
      CCR5. The frequency of SI-infected CD45RA(+) CD4(+) T cells, but not the
      frequency of NSI- or SI-infected CD45RO(+) CD4(+) T cells, correlated with the
      rate of CD4(+) T cell depletion. Infection of naive cells by SI HIV-1 may
      interfere with CD4(+) T cell production and thus account for rapid CD4(+) T cell
      depletion.

PMID- 10655521
TI  - A hippocampal interneuron associated with the mossy fiber system.
AB  - Network properties of the hippocampus emerge from the interaction of principal
      cells and a heterogeneous population of interneurons expressing gamma
      aminobutyric acid (GABA). To understand these interactions, the synaptic
      connections of different types of interneurons need to be elucidated. Here we
      describe a type of inhibitory interneuron of the hippocampal CA3 region that has
      an axon coaligned with the mossy fibers. Whole-cell patch-clamp recordings, in
      combination with intracellular biocytin filling, were made from nonpyramidal
      cells of the stratum lucidum under visual control. Mossy fiber-associated (MFA)
      interneurons generated brief action potentials followed by a prominent after
      hyperpolarization. Subsequent visualization revealed an extensive axonal arbor
      which was preferentially located in the stratum lucidum of CA3 and often invaded
      the hilus. The dendrites of MFA interneurons were mainly located in the strata
      radiatum and oriens, suggesting that these cells are primarily activated by
      associational and commissural fibers. Electron microscopic analysis showed that
      axon terminals of MFA interneurons established symmetric synaptic contacts
      predominantly on proximal apical dendritic shafts, and to a lesser degree, on
      somata of pyramidal cells. Synaptic contacts were also found on GABAergic
      interneurons of the CA3 region and putative mossy cells of the hilus. Inhibitory
      postsynaptic currents (IPSCs) elicited by MFA interneurons in simultaneously
      recorded pyramidal cells had fast kinetics (half duration, 3.6 ms) and were
      blocked by the GABA(A) receptor antagonist bicuculline. Thus, MFA interneurons
      are GABAergic cells in a position to selectively suppress the mossy fiber input,
      an important requirement for the recall of memory traces from the CA3 network.

PMID- 10655522
TI  - Expression of reelin in adult mammalian blood, liver, pituitary pars intermedia,
      and adrenal chromaffin cells.
AB  - Reelin regulates telencephalic and cerebellar lamination during mammalian
      development and is expressed in several structures of the adult brain; however,
      only traces of reelin were believed to be in peripheral tissues. Because reelin
      structurally resembles extracellular matrix proteins, and because many of these
      proteins are expressed in blood, we hypothesized that reelin also might be
      detectable in the circulation. Reelin (420 kDa) and two reelin-like
      immunoreactive bands (310 and 160 kDa) are expressed in serum and platelet-poor
      plasma of rats, mice, and humans, but these three bands were not detectable in
      serum of homozygous reeler (rl/rl) mice. Reelin plasma levels in heterozygous
      (rl/+) mice were half of those in wild-type littermates. Western blotting and
      immunocytochemistry using antireelin mAbs indicated that reelin-like
      immunoreactivity was expressed in a subset of chromaffin cells within the rat
      adrenal medulla and in a subset of cells coexpressing alpha-melanocyte
      stimulating hormone within the pituitary pars intermedia. However, surgical
      removal of adrenal or pituitary failed to decrease the amount of reelin (420-kDa
      band) expressed in serum. Adult liver expressed one-third of the reelin mRNA
      concentration expressed in adult mouse cerebral cortex. Full-length reelin
      protein was detectable in liver extracts in situ; acutely isolated liver cells
      also secreted full-length reelin in vitro. Liver appears to be a prime candidate
      to produce and maintain the circulating reelin pool. It now becomes relevant to
      ask whether circulating reelin has a physiologic role on one or more peripheral
      target tissues.

PMID- 10655523
TI  - Type 2 iodothyronine deiodinase expression in the cochlea before the onset of
      hearing.
AB  - Thyroid hormone signaling during a postnatal period in the mouse is essential for
      cochlear development and the subsequent onset of hearing. To study the control of
      this temporal dependency, we investigated the role of iodothyronine deiodinases,
      which in target tissues convert the prohormone thyroxine into triiodothyronine
      (T3), the active ligand for the thyroid hormone receptor (TR). Type 2 5'
      deiodinase (D2) activity rose dramatically in the mouse cochlea to peak around
      postnatal day 7 (P7), after which activity declined by P10. This activity peak a
      few days before the onset of hearing suggests a role for D2 in amplifying local
      T3 levels at a critical stage of cochlear development. A mouse cochlear D2 cDNA
      was isolated and demonstrated near identity to rat D2. In situ hybridization
      localized D2 mRNA in periosteal connective tissue in the modiolus, the cochlear
      outer capsule and the septal divisions between the turns of the cochlea.
      Surprisingly, D2 expression in these regions that give rise to the bony labyrinth
      was complementary to TR expression in the sensory epithelium. Thus, the
      connective tissue may control deiodination of thyroxine and release of T3 to
      confer a paracrine-like control of TR activation. These results suggest that
      temporal and spatial control of ligand availability conferred by D2 provides an
      unexpectedly important level of regulation of the TR pathways required for
      cochlear maturation.

PMID- 10655524
TI  - Two populations of kainate receptors with separate signaling mechanisms in
      hippocampal interneurons.
AB  - Consistent with the epileptogenic and deleterious effects of the potent
      neurotoxin kainate, the activation of kainate receptors reduces the synaptic
      inhibition induced by the amino acid gamma-aminobutyric acid (GABA).
      Extrapolating from these data led to the conclusion that kainate receptors are
      located presynaptically. However, kainate directly depolarizes the inhibitory
      interneurons, causing them to fire repeatedly. This effect might indirectly
      decrease the size of inhibitory postsynaptic currents recorded from pyramidal
      cells and places in doubt the presynaptic location for kainate receptors. Here we
      show that both effects, membrane depolarization and the reduction of inhibitory
      potentials, can be dissociated by several means, particularly by the natural
      agonist of kainate receptors, glutamate. Indeed, when applied at low
      concentrations, glutamate inhibited GABA release without affecting the firing
      rate of GABA interneurons. These results indicate that CA1 interneurons contain
      two populations of kainate receptors, each with different agonist sensitivity and
      coupled to distinct signaling pathways.

PMID- 10655525
TI  - Aberrant development of motor axons and neuromuscular synapses in erbB2-deficient
      mice.
AB  - Receptor tyrosine kinase erbB2, which is activated by neuregulin, is expressed in
      Schwann and muscle cells in the developing neuromuscular junction (NMJ). In vitro
      studies have shown that neuregulin promotes the survival and migration of Schwann
      cells and stimulates acetylcholine receptor gene transcription in cultured muscle
      cells. These findings suggest an important role for erbB2 in the development of
      the NMJ. Here we examine erbB2-deficient mice to determine whether erbB2 is
      required for NMJ development in vivo. Our analysis shows that there are pre- and
      postsynaptic defects of developing NMJ in erbB2-deficient embryos. The
      presynaptic defects include defasciculation and degeneration of the motor nerves,
      and an absence of Schwann cells. The postsynaptic defect features an impairment
      of junctional folds at the neuromuscular synapse in the mutants. These results
      demonstrate that erbB2 is essential for in vivo development of the NMJ.

PMID- 10655526
TI  - Adaptive responses and apoptosis in endothelial cells exposed to carbon monoxide.
AB  - Prior studies have shown that exposure to carbon monoxide (CO) will elevate the
      steady-state concentration of nitric oxide ((.)NO) in several cell types and body
      organs and that some toxic effects of CO are directed toward endothelial cells.
      Studies reported in this paper were conducted with bovine pulmonary artery
      endothelial cells exposed to 10 to 100 ppm CO to achieve concentrations between
      11 and 110 nM in air-saturated buffer. Exposure to 11 nM CO increased synthesis
      of manganous superoxide dismutase and conferred resistance against the lethal
      effects of 110 nM CO. At concentrations of 88 nM CO or more, exposures for 1 h or
      longer caused cell death that became apparent 18 h after the exposure ceased.
      Caspase-1 was activated in response to CO, and cell death was inhibited by a
      caspase-1 inhibitor. Alteration of proteolytic pathways by CO was indicated by
      the presence of ubiquitin-containing intracellular inclusion bodies.
      Morphological changes and caspase activation indicated that cell death was an
      apoptotic process. Cells exposed to 110 nM CO had higher concentrations of
      manganous superoxide dismutase and heme oxygenase-1 but no changes in glutathione
      peroxidase, glucose-6-phosphate dehydrogenase, thiols, or catalase. Elevated
      levels of antioxidant enzymes and apoptosis were inhibited by the nitric oxide
      synthase inhibitor, S-isopropylisothiourea, and the peroxynitrite scavenger,
      selenomethionine. These results show that biochemical effects of CO occur at
      environmentally relevant concentrations, that apoptotic cell death follows
      exposure to relatively high concentrations of CO, and that these actions of CO
      are mediated by nitric oxide.

PMID- 10655527
TI  - FIDDLEHEAD, a gene required to suppress epidermal cell interactions in
      Arabidopsis, encodes a putative lipid biosynthetic enzyme.
AB  - In plants, the outer epidermal cell wall and cuticle presents a semipermeable
      barrier that maintains the external integrity of the plant and regulates the
      passage of various classes of molecules into and out of the organism. During
      vegetative development, the epidermal cells remain relatively inert, failing to
      respond to wounding or grafting. During reproductive development and
      fertilization, however, the epidermis is developmentally more labile and
      participates in two types of contact-mediated cell interactions: organ fusion and
      pollen hydration. Here we describe the isolation and characterization of one gene
      whose product normally functions in blocking both types of epidermal cell
      interactions during vegetative development: the FIDDLEHEAD gene. As suggested by
      previous biochemical analyses, the gene encodes a protein that is probably
      involved in the synthesis of long-chain lipids found in the cuticle and shows
      similarity to a large class of genes encoding proteins related to beta-ketoacyl
      CoA synthases and chalcone synthases. In situ hybridization reveals an epidermal
      pattern of expression consistent with a role for this protein in the synthesis of
      lipid components that are thought to localize extracellularly and probably modify
      the properties of the cuticle.

PMID- 10655528
TI  - A novel subtype of type 1 diabetes mellitus characterized by a rapid onset and an
      absence of diabetes-related antibodies. Osaka IDDM Study Group.
AB  - BACKGROUND AND METHODS: Type 1 diabetes mellitus is now classified as autoimmune
      (type 1A) or idiopathic (type 1B), but little is known about the latter. We
      classified 56 consecutive Japanese adults with type 1 diabetes according to the
      presence or absence of glutamic acid decarboxylase antibodies (their presence is
      a marker of autoimmunity) and compared their clinical, serologic, and
      pathological characteristics. RESULTS: We divided the patients into three groups:
      36 patients with positive tests for serum glutamic acid decarboxylase
      autoantibodies, 9 with negative tests for serum glutamic acid decarboxylase
      antibodies and glycosylated hemoglobin values higher than 11.5 percent, and 11
      with negative tests for serum glutamic acid decarboxylase antibodies and
      glycosylated hemoglobin values lower than 8.5 percent. In comparison with the
      first two groups, the third group had a shorter mean duration of symptoms of
      hyperglycemia (4.0 days), a higher mean plasma glucose concentration (773 mg per
      deciliter [43 mmol per liter]) in spite of lower glycosylated hemoglobin values,
      diminished urinary excretion of C peptide, a more severe metabolic disorder (with
      ketoacidosis), higher serum pancreatic enzyme concentrations, and an absence of
      islet-cell, IA-2, and insulin antibodies. Immunohistologic studies of pancreatic
      biopsy specimens from three patients with negative tests for glutamic acid
      decarboxylase autoantibodies and low glycosylated hemoglobin values revealed T
      lymphocyte-predominant infiltrates in the exocrine pancreas but no insulitis and
      no evidence of acute or chronic pancreatitis. CONCLUSIONS: Some patients with
      idiopathic type 1 diabetes have a nonautoimmune, fulminant disorder characterized
      by the absence of insulitis and of diabetes-related antibodies, a remarkably
      abrupt onset, and high serum pancreatic enzyme concentrations.

PMID- 10655529
TI  - Amylase-resistant starch plus oral rehydration solution for cholera.
AB  - BACKGROUND: Although standard glucose-based oral rehydration therapy corrects the
      dehydration caused by cholera, it does not reduce the diarrhea. Short-chain fatty
      acids, which are produced in the colon from nonabsorbed carbohydrates, enhance
      sodium absorption. We conducted a study to determine the effects of an orally
      administered, nonabsorbed starch (i.e., one resistant to digestion by amylase) on
      fecal fluid loss and the duration of diarrhea in patients with cholera. METHODS:
      We randomly assigned 48 adolescents and adults with cholera to treatment with
      standard oral rehydration therapy (16 patients), standard therapy and 50 g of
      rice flour per liter of oral rehydration solution (16 patients), or standard
      therapy and 50 g of high-amylose maize starch, an amylase-resistant starch, per
      liter of oral rehydration solution (16 patients). The primary end points were
      fecal weight (for every 12-hour period during the first 48 hours after
      enrollment) and the length of time to the first formed stool. RESULTS: The mean
      (+/-SD) fecal weights in the periods 12 to 24 hours, 24 to 36 hours, and 36 to 48
      hours after enrollment were significantly lower in the resistant-starch group
      (2206+/-1158 g, 1810+/-1018 g, and 985+/-668 g) than in the standard-therapy
      group (3251+/-766 g, 2621+/-1149 g, and 2498+/-1080 g; P=0.01, P= 0.04, and
      P=0.001, respectively). From 36 to 48 hours after enrollment, fecal weight was
      also significantly lower with the resistant-starch therapy than with the rice
      flour therapy (985+/-668 g vs. 1790+/-866 g, P=0.01). The mean duration of
      diarrhea was significantly shorter with the resistant-starch therapy (56.7+/-18.6
      hours) than with standard therapy alone (90.9+/-29.8 hours, P=0.001) or the rice
      flour therapy (70.8+/-20.2 hours, P=0.05). Fecal excretion of starch was higher
      with the resistant-starch therapy (32.6+/-30.4) than with the standard therapy
      (11.7+/-4.1 g, P=0.002) or the rice-flour therapy (15.1+/-8.4 g, P=0.01).
      CONCLUSIONS: The addition of a resistant starch to oral rehydration solution
      reduces fecal fluid loss and shortens the duration of diarrhea in adolescents and
      adults with cholera.

PMID- 10655530
TI  - Correction of the hyper-IgM syndrome after liver and bone marrow transplantation.

PMID- 10655531
TI  - Images in clinical medicine. Gingival hyperplasia induced by phenytoin.

PMID- 10655532
TI  - Symptoms and suffering at the end of life in children with cancer.
AB  - BACKGROUND: Cancer is the second leading cause of death in children, after
      accidents. Little is known, however, about the symptoms and suffering at the end
      of life in children with cancer. METHODS: In 1997 and 1998, we interviewed the
      parents of children who had died of cancer between 1990 and 1997 and who were
      cared for at Children's Hospital, the Dana-Farber Cancer Institute, or both.
      Additional data were obtained by reviewing medical records. RESULTS: Of 165
      eligible parents, we interviewed 103 (62 percent), 98 by telephone and 5 in
      person. The interviews were conducted a mean (+/-SD) of 3.1+/-1.6 years after the
      death of the child. Almost 80 percent died of progressive disease, and the rest
      died of treatment-related complications. Forty-nine percent of the children died
      in the hospital; nearly half of these deaths occurred in the intensive care unit.
      According to the parents, 89 percent of the children suffered "a lot" or "a great
      deal" from at least one symptom in their last month of life, most commonly pain,
      fatigue, or dyspnea. Of the children who were treated for specific symptoms,
      treatment was successful in 27 percent of those with pain and 16 percent of those
      with dyspnea. On the basis of a review of the medical records, parents were
      significantly more likely than physicians to report that their child had fatigue,
      poor appetite, constipation, and diarrhea. Suffering from pain was more likely in
      children whose parents reported that the physician was not actively involved in
      providing end-of-life care (odds ratio, 2.6; 95 percent confidence interval, 1.0
      to 6.7). CONCLUSIONS: Children who die of cancer receive aggressive treatment at
      the end of life. Many have substantial suffering in the last month of life, and
      attempts to control their symptoms are often unsuccessful. Greater attention must
      be paid to palliative care for children who are dying of cancer.

PMID- 10655533
TI  - Congenital heart disease in adults. Second of two parts.

PMID- 10655534
TI  - Rapid-onset type 1 diabetes with pancreatic exocrine dysfunction.

PMID- 10655535
TI  - The search for a better oral rehydration solution for cholera.

PMID- 10655536
TI  - Care of children who are dying of cancer.

PMID- 10655538
TI  - Correction: Antitumor Activity of Thalidomide in Refractory Multiple Myeloma.

PMID- 10655537
TI  - Pigment-epithelium-derived factor--a key coordinator of retinal neuronal and
      vascular functions.

PMID- 10655539
TI  - Correction: Disorders of Iron Metabolism.

PMID- 10655540
TI  - Genetic variability in the regulatory region of presenilin 1 associated with risk
      for Alzheimer's disease and variable expression.
AB  - Mutations in the presenilin 1 ( PSEN1 ) gene have been implicated in 18-50% of
      autosomal dominant cases with early-onset Alzheimer's disease (EOAD). Also, PSEN1
      has been suggested as a potential risk gene in late-onset AD cases. We recently
      showed genetic association in a population-based study of EOAD, pointing to the
      5' regulatory region of PSEN1. In this study we systematically screened 3.5 kb of
      the PSEN1 upstream region and found four novel polymorphisms. Genetic analysis
      confirmed association of two polymorphisms with increased risk for EOAD. In
      addition, we detected two different mutations in EOAD cases at-280 and-2818
      relative to the transcription initiation site in exon 1A of PSEN1. Analysis of
      the mutant and wild-type-280 variants using luciferase reporter gene expression
      in transiently transfected neuroblastoma cells showed a 30% decrease in
      transcriptional activity for the mutant-280G PSEN1 promoter variant compared with
      the wild-type variant-280C. Our data suggest that the increased risk for EOAD
      associated with PSEN1 may result from genetic variations in the regulatory region
      leading to altered expression levels of the PSEN1 protein.

PMID- 10655541
TI  - The human centromeric survival motor neuron gene (SMN2) rescues embryonic
      lethality in Smn(-/-) mice and results in a mouse with spinal muscular atrophy.
AB  - Proximal spinal muscular atrophy (SMA) is a common motor neuron disease in humans
      and in its most severe form causes death by the age of 2 years. It is caused by
      defects in the telomeric survival motor neuron gene ( SMN1 ), but patients retain
      at least one copy of a highly homologous gene, centromeric SMN ( SMN2 ). Mice
      possess only one survival motor neuron gene ( Smn ) whose loss is embryonic
      lethal. Therefore, to obtain a mouse model of SMA we created transgenic mice that
      express human SMN2 and mated these onto the null Smn (-/-)background. We show
      that Smn (-/-); SMN2 mice carrying one or two copies of the transgene have normal
      numbers of motor neurons at birth, but vastly reduced numbers by postnatal day 5,
      and subsequently die. This closely resembles a severe type I SMA phenotype in
      humans and is the first report of an animal model of the disease. Eight copies of
      the transgene rescues this phenotype in the mice indicating that phenotypic
      severity can be modulated by SMN2 copy number. These results show that SMA is
      caused by insufficient SMN production by the SMN2 gene and that increased
      expression of the SMN2 gene may provide a strategy for treating SMA patients.

PMID- 10655543
TI  - Microsatellite instability in tumors as a model to study the process of
      microsatellite mutations.
AB  - We screened 42 sporadic gastric tumors and found that seven of them had
      significant microsatellite instability. These were then studied at 26
      microsatellite loci, comprising di-, tri- and tetranucleotide repeats. The
      instability level of individual microsatellites in the tumors was found to be
      positively correlated with the population average heterozygosity and variance of
      repeat number of the microsatellite loci, as predicted by the stepwise mutation
      model. Moreover, as is known to occur in human populations, instability was
      strongly correlated with the number of repeats at each microsatellite locus and
      with the perfection of the reiterated sequence. These results demonstrate that
      microsatellite mutations in unstable tumors show similarities to germline
      mutations and suggest that their study may be useful in understanding the
      mechanisms that generate microsatellite variability in human populations. We used
      this model to test the claims that the microsatellite mutation process is biased
      towards increased size and heterozygosity with wide differences in allele sizes.
      These assertions were not confirmed.

PMID- 10655542
TI  - Reduced survival motor neuron (Smn) gene dose in mice leads to motor neuron
      degeneration: an animal model for spinal muscular atrophy type III.
AB  - Spinal muscular atrophy (SMA) is caused by deletion or specific mutations of the
      telomeric survival motor neuron ( SMN ) gene on human chromosome 5. The human SMN
      gene, in contrast to the Smn gene in mouse, is duplicated and the centromeric
      copy on chromosome 5 codes for transcripts which preferentially lead to C
      terminally truncated SMN protein. Here we show that a 46% reduction of Smn
      protein levels in the spinal cord of Smn heterozygous mice leads to a marked loss
      of the cytoplasmic Smn pool and motor neuron degeneration resembling spinal
      muscular atrophy type 3. Smn heterozygous mice described here thus represent a
      model for the human disease. These mice could allow screening for SMA therapies
      and help in gaining further understanding of the pathophysiological events
      leading to motor neuron degeneration in SMA.

PMID- 10655544
TI  - Altered cholesterol metabolism in human apolipoprotein E4 knock-in mice.
AB  - Thevarepsilon4 allele of apolipoprotein E (apoE) is associated with an increased
      risk of developing Alzheimer's disease (AD). To accurately determine the isoform
      specific effects of human apoE on brain functions under physiological and
      pathological situations, we created mice expressing human apoE4 isoform in place
      of mouse apoE by utilizing the gene-targeting technique on the embryonic stem
      cells (knock-in). The homozygousvarepsilon4 (4/4) mice correctly expressed human
      apoE4 in the serum and the brain. The human apoE in the brain was found primarily
      in the astrocytes as was the mouse apoE in the wild-type (+/+) mice. In the 4/4
      mice, the serum cholesterol level was 2.5-fold that of the +/+ littermate
      controls on a regular diet. This marked elevation was accounted for by an
      accumulation of very low and low density lipo-proteins. In the brains of the 4/4
      mice, however, the amounts of total cholesterol and phospholipids were
      significantly decreased compared with the +/+ littermates. These findings
      indicate that cholesterol and lipid metabolism is markedly altered in the 4/4
      mice. Our human apoE4 knock-in mice will be useful in clarifying the role of apoE
      in the etiologies of AD and cardiovascular diseases in relation to cholesterol
      and lipid metabolism.

PMID- 10655545
TI  - Mutations of a human homologue of the Drosophila eyes absent gene (EYA1) detected
      in patients with congenital cataracts and ocular anterior segment anomalies.
AB  - The Drosophila eyes absent gene ( eya ) is involved in the formation of compound
      eyes. Flies with loss-of-function mutations of this gene develop no eyes and form
      the ectopic eye in the antennae and the ventral zone of the head on target
      expression. A highly conserved homo-logous gene in various invertebrates and
      vertebrates has been shown to function in the formation of the eye. In contrast,
      a human homologue, EYA1, has been identified by positional cloning as a candidate
      gene for branchio-oto-renal (BOR) syndrome, in which phenotypic manifestations
      are restricted to the areas of branchial arch, ear and kidney, with usually no
      anomalies in the eye. We have examined genomic DNA isolated from patients with
      various types of developmental eye anomaly for EYA1 mutations by the use of
      polymerase chain reaction-single-strand conformation polymorphism and sequencing.
      We identified three novel missense mutations in patients who had con-genital
      cataracts and ocular anterior segment anomalies. One of the patients had clinical
      features of BOR syndrome as well. This result implies that the human EYA1 gene is
      also involved in eye morphogenesis, and that a wide variety of clinical
      manifestations may be caused by EYA1 mutations.

PMID- 10655546
TI  - Multiple CYP1B1 mutations and incomplete penetrance in an inbred population
      segregating primary congenital glaucoma suggest frequent de novo events and a
      dominant modifier locus.
AB  - Primary congenital glaucoma (PCG) is an autosomal recessive disorder associated
      with unknown developmental defect(s) in the anterior chamber. Recently, we
      reported three distinct mutations in CYP1B1, the gene for cytochrome P4501B1, in
      25 Saudi families segregating PCG. For this report, we analyzed 37 additional
      families and confirmed the initial finding of decreased penetrance. Mutations and
      intragenic single-nucleotide polymorphisms (SNPs) were also analyzed from direct
      sequencing of all CYP1B1 coding exons. Eight distinct mutations were identified:
      G61E, R469W and D374N, the most common Saudi mutations, account for 72, 12 and
      7%, respectively, of all the PCG chromosomes. Five additional homozygous
      mutations (two deletions and three missense mutations) were detected, each in a
      single family. Affected individuals from five families had no CYP1B1 coding
      mutations, and each family had a unique SNP profile. The identification of eight
      distinct mutations in a single gene, on four distinct haplotypes, suggests a
      relatively recent occurrence of multiple mutations in CYP1B1 in Saudi Arabia.
      These data demonstrate decreased penetrance of the PCG phenotype in the Saudi
      population, because 40 apparently unaffected individuals in 22 families have
      mutations and haplotypes identical to their affected siblings. Two individuals
      were subsequently diagnosed with glaucoma and two others had abnormal ocular
      findings that are consistent with milder forms of glaucoma. Analysis of these 22
      kindreds suggests the presence of a dominant modifier locus that is not linked
      genetically to CYP1B1. Linkage and Southern analyses excluded three candidate
      modifier loci.

PMID- 10655547
TI  - The Hermansky-Pudlak syndrome (HPS) protein is part of a high molecular weight
      complex involved in biogenesis of early melanosomes.
AB  - Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder in which
      oculocutaneous albinism, bleeding tendency and a ceroid-lipofuscin lysosomal
      storage disease result from defects of multiple cytoplasmic organelles:
      melanosomes, platelet dense granules and lysosomes. The HPS polypeptide, a 700
      amino acid protein which is unrelated to any known proteins, is likely to be
      involved in the biogenesis of these different organelles. Here, we show that HPS
      is a non-glycosylated, non-membrane protein which is a component of two distinct
      high molecular weight complexes. In non-melanotic cells the HPS protein is
      contained almost entirely in an approximately 200 kDa complex that is widely
      distributed throughout the cytosol. In melanotic cells the HPS protein is
      partitioned between this cytosolic complex and a >500 kDa complex that appears to
      consist of the approximately 200 kDa complex in association with membranous
      components. Subcellular fractionation, immunofluorescence and immunoelectron
      microscopy studies indicate that the membrane-associated HPS complex of melanotic
      cells is associated with tubulovesicular structures, small non-coated vesicles,
      and nascent and early-stage melanosomes. These findings suggest that the HPS
      complex is involved in the biogenesis of early melanosomes.

PMID- 10655548
TI  - Huntingtin is required for normal hematopoiesis.
AB  - Huntington's disease (HD) is a neurodegenerative disease associated with
      polyglutamine expansion in huntingtin, a widely expressed protein. The function
      of huntingtin is unknown although huntingtin plays a fundamental role in
      development since gene targeted HD (-) (/-)mouse embryos die shortly after
      gastrulation. Expression of huntingtin is detected in spleen and thymus but its
      role in hematopoiesis has not been examined. To determine the function of
      huntingtin and to provide insight into potential pathologic mechanisms in HD, we
      analyzed the role of huntingtin in hematopoietic development. Expression of
      huntingtin was analyzed in a variety of hematopoietic cell types, and in vitro
      hematopoiesis was assessed using an HD ( +/-)and several HD( -) (/-)embryonic
      stem (ES) cell lines. Although wild-type, HD ( +/-)and HD( -) (/-)ES cell lines
      formed primary embryoid bodies (EBs) with similar efficiency, the numbers of
      hematopoietic progenitors detected at various stages of the in vitro
      differentiation were reduced in HD ( +/-)and HD( -/-)() ()ES cell lines examined.
      Expression analyses of hematopoietic markers within the EBs revealed that
      primitive and definitive hematopoiesis occurs in the absence of huntingtin.
      However, further analysis using a suspension culture in the presence of
      hematopoietic cytokines demonstrated a highly significant gene dosage-dependent
      decrease in proliferation and/or survival of HD ( +/-)and HD( -) (/-)cells.
      Enrichment for the CD34(+)cells within the EB confirmed that the impairment is
      intrinsic to the hematopoietic cells. These obser- vations suggest that
      huntingtin expression is required for the generation and expansion of
      hematopoietic cells and provides an alternative system in which to assess the
      function of huntingtin.

PMID- 10655549
TI  - Differentially regulated and evolved genes in the fully sequenced Xq/Yq
      pseudoautosomal region.
AB  - Human sex chromosomes, which are morphologically and genetically different, share
      few regions of homology. Among them, only pseudoautosomal regions (PARs) pair and
      recombine during meiosis. To better address the complex biology of these regions,
      we sequenced the telomeric 400 kb of the long arm of the human X chromosome,
      including 330 kb of the human Xq/YqPAR and the telomere. Sequencing reveals
      subregions with distinctive regulatory and evolutionary features. The proximal
      295 kb contains two genes inactivated on both the inactive X and Y chromosomes [
      SYBL1 and a novel homologue ( HSPRY3 ) of Drosophila sprouty ]. The GC-rich
      distal 35 kb, added in stages and much later in evolution, contains the X/Y
      expressed gene IL9R and a novel gene, CXYorf1, only 5 kb from the Xq telomere.
      These properties make Xq/YqPAR a model for studies of region-specific gene
      inactivation, telomere evolution, and involvement in sex-limited conditions.

PMID- 10655550
TI  - The establishment of telomerase-immortalized cell lines representing human
      chromosome instability syndromes.
AB  - The limited life span of normal human cells represents a substantial obstacle for
      biochemical analysis, genetic manipulation and genetic screens. To overcome this
      technical barrier, immortal human cell lines are often derived from tumors or
      produced by transformation with viral oncogenes such as SV40 large T antigen.
      Cell lines produced by these approaches are invariably transformed, genomically
      unstable and display cellular properties that differ from their normal
      counterpart. It was recently shown that the ectopic expression of hTERT, encoding
      the catalytic subunit of human telomerase, can extend the life span of normal
      human cells without causing cellular transformation and genomic instability. In
      the present study, we have used hTERT to extend the life span of normal human
      skin fibroblasts derived from patients afflicted with syndromes of genomic
      instability and/or premature aging. Our results show that hTERT efficiently
      extends the life span without altering the characteristic phenotypic properties
      of the cells. Thus, the ectopic expression of telomerase represents a major
      improvement over the use of viral oncogenes for the establishment of human cell
      lines.

PMID- 10655551
TI  - Mice deficient in the candidate tumor suppressor gene Hic1 exhibit developmental
      defects of structures affected in the Miller-Dieker syndrome.
AB  - HIC1 is a candidate tumor suppressor gene which is frequently hypermethylated in
      human tumors, and its location within the Miller-Dieker syndrome's critical
      deletion region at chromosome 17p13.3 makes it a candidate gene for involvement
      in this gene deletion syndrome. To study the function of murine Hic1 in
      development, we have created Hic1 -deficient mice. These animals die perinatally
      and exhibit varying combinations of gross developmental defects throughout the
      second half of development, including acrania, exencephaly, cleft palate, limb
      abnormalities and omphalocele. These findings demonstrate a role for Hic1 in the
      development of structures affected in the Miller-Dieker syndrome, and provide
      functional evidence to strengthen its candidacy as a gene involved in this
      disorder.

PMID- 10655552
TI  - A polymorphic L1 retroposon insertion in the centromere of the human Y
      chromosome.
AB  - We have identified a novel polymorphic L1 retroposon insertion, designated LY1,
      in the centromeric alphoid array of the human Y chromosome. The element belongs
      to the transpositionally active Ta subset and its presence is compatible with
      normal centromere function. It was found at highest frequency in China, where it
      accounts for 23% of the Han sample, and was present at low frequencies in the
      surrounding areas, but was not found at all outside Asia. Chromosomes carrying
      LY1 show considerable microsatellite diversity, suggesting an ancient origin for
      the lineage at approximately 10 000 years ago (with wide confidence limits), but
      only limited subsequent migration.

PMID- 10655553
TI  - Functional analysis of novel mutations in y(+)LAT-1 amino acid transporter gene
      causing lysinuric protein intolerance (LPI).
AB  - Lysinuric protein intolerance (LPI; MIM 222700) is an autosomal recessive
      disorder characterized by defective transport of the cationic amino acids lysine,
      arginine and ornithine at the basolateral membrane of the polar epithelial cells
      in the intestine and renal tubules, and by hyperammonemia after high-protein
      meals. LPI is caused by mutations in the SLC7A7 (solute carrier family 7, member
      7) gene encoding y(+)LAT-1 (y(+)L amino acid transporter-1), which co-induces
      together with 4F2 heavy chain (4F2hc) system y(+)L in Xenopus oocytes. All
      Finnish LPI patients share the same founder mutation 1181-2A-->T (LPI(Fin)) not
      found in LPI patients elsewhere. Mutation screening of 20 non-Finnish LPI
      patients revealed 10 novel mutations: four deletions, two missense mutations, two
      nonsense mutations, a splice site mutation and a tandem duplication. Five LPI
      mutations (L334R, G54V, 1291delCTTT, 1548delC and LPI(Fin)) were studied
      functionally. All mutant proteins failed to co-induce amino acid transport
      activity when expressed with 4F2hc in Xenopus oocytes. Immunostaining experiments
      revealed that frameshift mutants 1291delCTTT, 1548delC and LPI(Fin)remained
      intracellular on expression with 4F2hc. In contrast, the missense mutants L334R
      and G54V reached the oocyte plasma membrane when co-expressed with 4F2hc,
      demonstrating that they are transport-inactivating mutations. This finding,
      together with the strong degree of conservation among all members of this family
      of amino acid transporters, indicates that residues L334 and G54 play a crucial
      role in the function of the y(+)LAT-1 transporter.

PMID- 10655554
TI  - Dramatic, expansion-biased, age-dependent, tissue-specific somatic mosaicism in a
      transgenic mouse model of triplet repeat instability.
AB  - Myotonic dystrophy type 1 (DM1) is one of a growing number of inherited human
      diseases whose molecular basis has been implicated as the expansion of a
      trinucleotide DNA repeat. Expanded disease-associated alleles of >50 CTG repeats
      are unstable in both the germline and soma. Expansion of the unstable alleles
      over time and variation of the level of mutation between the somatic tissues of
      an individual are thought to account at least partially for the tissue
      specificity and progressive nature of the symptoms. We previously generated a
      number of transgenic mouse lines containing a large expanded CTG repeat tract
      that replicated a number of the features of unstable DNA in humans, including
      frequent sex-specific changes in allele length during intergenerational
      transmission. Small length change mutations were apparent in the somatic tissues
      of young mice in all of the lines generated, but the gross instability observed
      in human DM1 patients was not replicated. We now show that in one of the lines,
      Dmt -D, spectacular, expansion-biased, tissue-specific instability is observed in
      older mice. The highest levels of instability were detected in kidney with gains
      of >500 repeats, representing a tripling of allele length, in some cells.
      Mosaicism accumulated in an age-dependent manner, but the tissue specificity did
      not obviously correlate with cell turnover. Such gross somatic mosaicism was not
      observed in three other lines examined, further emphasizing a role for flanking
      DNA in modulating repeat stability.

PMID- 10655555
TI  - Genetic evidence for a trans-heterozygous model for cystogenesis in autosomal
      dominant polycystic kidney disease.
AB  - Polycystic kidney disease (ADPKD) is a condition with an autosomal dominant mode
      of inheritance and adult onset. Two forms of the disease, ADPKD1 and ADPKD2,
      caused by mutations in PKD1 and PKD2, respectively, are very similar, except that
      ADPKD1 patients run a more severe course. At the cellular level, ADPKD1 was first
      shown to be recessive, since somatic second hits are perhaps necessary for cyst
      formation. The near identical phenotype had suggested that ADPKD1 and ADPKD2
      might have a similar pathogenesis and that the two gene products, poly- cystins 1
      and 2, are part of a common developmental pathway. Work in transgenic mice showed
      that somatic loss of Pkd2 expression is necessary for renal cyst formation, and
      recently we showed that somatic mutations inactivating the inherited healthy
      allele were present in 9 of 23 cysts from a human ADPKD2 kidney, supporting a two
      hit loss-of-function model for ADPKD2 cystogenesis. Here, we provide the first
      direct genetic evidence that polycystins 1 and 2 do interact, perhaps as part of
      a larger complex. In cystic DNA from a kidney of an ADPKD1 patient, we showed
      somatic mutations not only in the PKD1 gene of certain cysts, but also in the
      PKD2 gene of others, generating a trans -heterozygous state with mutations in
      both genes. One mutation in PKD1 is of germinal nature and the mutation in the
      PKD2 gene is of somatic nature. The implications of such a situation are
      enormous, not only for ADPKD, but also for many other conditions with phenotypic
      heterogeneity and age-dependent penetrance.

PMID- 10655556
TI  - The cell cycle control gene ZAC/PLAGL1 is imprinted--a strong candidate gene for
      transient neonatal diabetes.
AB  - We describe a screen for new imprinted human genes, and the identification in
      this way of ZAC (zinc finger protein which regulates apoptosis and cell cycle
      arrest)/ PLAGL1 (pleomorphicadenoma of the salivary gland gene like 1) as a
      strong candidate gene for transient neonatal diabetes mellitus (TNDM). To screen
      for imprinted genes, we compared parthenogenetic DNA from the chimeric patient FD
      and androgenetic DNA from hydatidiform mole, using restriction landmark genome
      scanning for methylation. This resulted in identification of two novel imprinted
      loci, one of which (NV149) we mapped to the TNDM region of 6q24. From analysis of
      the corresponding genomic region, it was determined that NV149 lies approximately
      60 kb upstream of the ZAC / PLAGL1 gene. RT-PCR analysis was used to confirm that
      this ZAC / PLAGL1 is expressed only from the paternal allele in a variety of
      tissues. TNDM is known to result from upregulation of a paternally expressed gene
      on chromosome 6q24. The paternal expression, map position and known biological
      properties of ZAC / PLAGL1 make it highly likely that it is the TNDM gene. In
      particular, ZAC / PLAGL1 is a transcriptional regulator of the type 1 receptor
      for pituitary adenylate cyclase-activating polypeptide, which is the most potent
      known insulin secretagog and an important mediator of autocrine control of
      insulin secretion in the pancreatic islet.

PMID- 10655557
TI  - Robust autofocusing in microscopy.
AB  - BACKGROUND: A critical step in automatic microscopy is focusing. This report
      describes a robust and fast autofocus approach useful for a wide range of
      microscopic modalities and preparations. METHODS: The focus curve is measured
      over the complete focal range, reducing the chance that the best focus position
      is determined by dust or optical artifacts. Convolution with the derivative of a
      Gaussian smoothing function reduces the effect of noise on the focus curve. The
      influence of mechanical tolerance is accounted for. RESULTS: The method is shown
      to be robust in fluorescence, bright-field and phase contrast microscopy, in
      fixed and living cells, as well as in fixed tissue. The algorithm was able to
      focus accurately within 2 or 3 s, even under extremely noisy and low contrast
      imaging conditions. CONCLUSIONS: The proposed method is generally applicable in
      light microscopy, whenever the image information content is sufficient. The
      reliability of the autofocus method allows for unattended operation on a large
      scale.

PMID- 10655558
TI  - Laser scanning cytometry for comet assay analysis.
AB  - BACKGROUND: The comet assay (single-cell gel electrophoresis) is a sensitive
      method for evaluating nuclear DNA damage. Previously used evaluation methods for
      the comet assay are time consuming and have an inherent risk of biased selection
      of comets due to manual selection and categorization of comet images. Laser
      scanning cytometry (LSC), the principle of which is equivalent to flow cytometry,
      enables quantification of fluorescence emitted from the cells on a microscope
      slide. In the present study, we explored whether LSC could be used to determine
      the degree of DNA damage demonstrated by the comet assay. METHODS: DNA damage was
      induced by ultraviolet A irradiation of keratinocytes and visualized by the comet
      assay. The evaluation included (a) LSC determination of DNA-specific fluorescence
      in 1,000 comet heads (undamaged DNA), (b) image acquisition of comets by
      rescanning of the microscope slide, and (c) digital image analysis and
      computation of tail moment and DNA content in the comet tails. RESULTS: Cells
      with damaged DNA were observed in a sub-G(1) area because the comet head loses
      DNA to the tail. We found a strong inverse correlation between tail moment and
      DNA content per nucleus. CONCLUSIONS: LSC enables an automated method for cell
      recognition and evaluation of the comets, thus providing quantitative information
      about nuclear DNA damage without subjective selection of analyzed comets.

PMID- 10655559
TI  - Determination of intracellular organelles implicated in daunorubicin cytoplasmic
      sequestration in multidrug-resistant MCF-7 cells using fluorescence microscopy
      image analysis.
AB  - BACKGROUND: Anthracycline resistance is known to be mediated by P-glycoprotein (P
      gp) or multidrug-resistance related protein (MRP) as well as intracellular
      sequestration of drugs. METHODS: The resistance phenotype of doxorubicin-selected
      MCF-7(DXR) human breast adenocarcinoma cell line was characterized by cellular
      and nuclear daunorubicin efflux, P-gp and MRP expression and apoptosis induction.
      Daunorubicin sequestration was investigated through organelle markers (lysosomes,
      endoplasmic reticulum and Golgi apparatus) and daunorubicin co-localization by
      dual-color image analysis fluorescence microscopy using high numerical aperture
      objective lenses to achieve the smallest field depth and the best lateral
      resolution. Signal to noise and specificity ratios were optimized for
      daunorubicin and organelle fluorescent probes labeling. RESULTS: An original
      image analysis procedure was developed to investigate daunorubicin and organelles
      co-localization. The reliability of the image analysis was controlled through
      chromatic shift and intensity linearity measurement using calibrated microbeads.
      The main contribution (65%) of Golgi vesicles in daunorubicin sequestration was
      demonstrated. Although no rational relationship could be established between
      daunorubicin sequestration and apoptosis induction, no apoptosis was observed in
      MCF-7(DXR) cells. CONCLUSIONS: In addition to P-glycoprotein mediated drug efflux
      and without MRP overexpression, MCF-7(DXR) daunorubicin resistance phenotype
      involves drug sequestration within intracellular vesicles identified as Golgi
      vesicles and resistance to apoptosis induction.

PMID- 10655561
TI  - Analysis of enzyme kinetics in individual living cells utilizing fluorescence
      intensity and polarization measurements.
AB  - BACKGROUND: The Cellscan mark-S (CS-S) scanning cytometer was used for tracing
      enzymatic reactions in the same individual cells under various physiological
      conditions over periods of minutes. On-line reagent addition and changes in the
      experimental conditions (buffers, ions, substrates and inhibitors) were
      performed. METHODS: Kinetic events were monitored by fluorescence intensity (FI)
      and fluorescence polarization (FP) measurements of fluorescein diacetate (FDA)
      and chloromethyl fluorescein diacetate (CMFDA) intracellular hydrolysis. FP
      measurements have been used to assess the intracellular marker's mobility
      restrictions. RESULTS: Kinetic measurement along 1000 s of FDA labeled individual
      Jurkat T cells, indicated variation of 65% for FI(t) and approximately 10% for
      FP(t). While FI increased linearly with time, FP(t) decreased nonlinearly and
      asymptotically, reaching a constant value. The FP(t) of CMFDA-labeled cells was
      different from that of FDA-labeled cells. Average cellular Km of 3.9 microM was
      calculated from individual cell FDA hydrolysis curves. CONCLUSIONS: (1) Analysis
      of the reaction kinetics of intracellular enzymes can be refined by using FP
      measurements of the products of fluorogenic substrates in addition to the FI
      measurements. (2) Subpopulations or individual cells could be classified
      according to their reaction rates. (3) A specific dependence of FP(t) on type of
      enzyme substrate is suggested.

PMID- 10655560
TI  - Rapid detection of efflux pumps and their relation with drug resistance in yeast
      cells.
AB  - BACKGROUND: Cell drug resistance can be due to the presence of active efflux
      pumps (AEP). Identification of yeast cells with a resistance phenotype is
      important either from a clinical, agricultural or biotechnological point of view.
      Rapid and reliable methods to detect AEP can be therefore very useful. METHODS:
      Some yeast cells change their staining by calcein-AM, BCECF-AM, rhodamine 123 and
      DiOC(5), when pretreated with verapamil, CCCP or ATP depletion, or when
      pretreated with specific antimicrobial agents. This fact may be interpreted as an
      indication of the presence/absence of AEP. Six yeast species were tested with a
      flow cytometric method (FCM) and an epifluorescence microscopic method (EFM), and
      ten other species were evaluated only by EFM. The minimum inhibitory
      concentration (MIC) of penconazol, benomyl and cycloheximide for Saccharomyces
      cerevisiae and Kluyveromyces marxianus, were determined by growth inhibition on
      solid medium and were compared to the staining changes detected by FCM. RESULTS:
      The FCM and the EFM allowed the detection of AEP in all the yeast species tested.
      High MIC values for a drug were related with the presence of at least one AEP
      indicated by the cytometric data. CONCLUSIONS: The FCM revealed to be a robust
      assay whereas the EFM can be used as a preliminary test. It is possible to
      identify resistance/sensitivity patterns in yeast cells through cytometric
      detection methods of different efflux pumping systems.

PMID- 10655562
TI  - Flow cytometric, phase-resolved fluorescence measurement of propidium iodide
      uptake in macrophages containing phagocytized fluorescent microspheres.
AB  - BACKGROUND: Spectral interference (overlap) from phagocytosed green-yellow (GY)
      microspheres in the flow cytometric, red fluorescence emission measurement
      channel causes errors in quantifying damaged/dead alveolar macrophages by uptake
      of propidium iodide. METHODS: Particle burdens of uniform GY fluorescent
      microspheres phagocytosed by rat alveolar macrophages and the discrimination of
      damaged/dead cells as indexed by propidium iodide uptake were assessed with
      conventional and phase-sensitive flow cytometry. RESULTS: The fluorescence
      spectral emission from phagocytosed microspheres partly overlapped the propidium
      iodide red fluorescence emission and interfered with the measurement of
      damaged/dead cells when using conventional flow cytometry without subtractive
      compensation. This caused errors when estimating the percentage of nonviable,
      propidium iodide-positive, phagocytic macrophages. The interference was
      eliminated by employing phase-sensitive detection in the red fluorescence
      measurement channel based on differences in fluorescence lifetimes between the
      fluorescent microspheres and propidium iodide. Intrinsic cellular
      autofluorescence, whose fluorescence lifetime is approximately the same as that
      of the phagocytosed microspheres, also was eliminated in the phase-sensitive
      detection process. Because there was no detectable spectral interference of
      propidium iodide in the green fluorescence (phagocytosis) measurement channel,
      conventional fluorescence detection was employed. CONCLUSIONS: Phase-resolved,
      red fluorescence emission measurement eliminates spectral overlap errors caused
      by autofluorescent phagocytes that contain fluorescent microspheres in the
      analyses of propidium iodide uptake. Cytometry 39:45-55, 2000. Published 2000
      Wiley-Liss, Inc.

PMID- 10655563
TI  - A new method for the simultaneous analysis of growth and death of
      immunophenotypically defined cells in culture.
AB  - BACKGROUND: Internal standards have been used in flow cytometry methods to
      enumerate lymphoid subsets and hemopoietic progenitor cells ex vivo. However, the
      currently available methods cannot be readily applied to the analysis of cultured
      cells because of the frequent occurrence of cell death during in vitro assays.
      METHODS: This paper reports a new method for the enumeration of both viable and
      nonviable cells in culture. Cells were counted with the aid of an internal
      reference standard of microbeads, and live versus dead cell discrimination was
      performed using 7-amino-actinomycin D which allows the double staining of surface
      antigens. RESULTS: The method is more precise, accurate and sensitive than either
      conventional light microscopy-based or automated cell counting. Additionally, it
      may be used to accurately measure the number of apoptotic cells in a culture.
      RESULTS: Through the enumeration of surviving cells it is demonstrated that, when
      applied to the study of mitogen-activated T lymphocytes, current flow cytometry
      techniques (which do not use internal standards) for the study of the viability
      and apoptosis overestimate the fraction of viable cells and underestimate both
      the fraction of dead and apoptotic cells. CONCLUSIONS: The new method overcomes
      these limitations and is of use in the in vitro study of cell growth and
      apoptosis.

PMID- 10655564
TI  - High-throughput pretreatment system in automated urinary sediment analyzer.
AB  - BACKGROUND: Urine contains microscopically observable particles that can indicate
      certain types of disease in the urinary tract system. Determining these various
      types of sediments by manual operation is a cumbersome and time-consuming task.
      To eliminate this labor, we developed an automated urinary sediment analyzer with
      high-throughput pretreatment system. METHODS: The pretreatment system mainly
      consists of four reaction vessels for dying samples (urine), a sheath flow
      chamber, and an unique sample carrier mechanism from the reaction vessel to the
      flow chamber, which enables overlapped processing, and rapid transfer of samples
      with small dispersion and a short buildup time. RESULTS: The buildup time was
      experimentally found to be 1.8 s, and the extra-sample volume beside that for
      measurement was only 4.9 microl (1/20 of the total sample volume). CONCLUSIONS:
      Short buildup time results in high throughput of 120 samples per hour, and
      relatively small extra-volume contributes to reduce carryover.

PMID- 10655565
TI  - Flow cytometric visualisation of cytokine production by CD3-CD56+ NK cells and
      CD3+CD56+ NK-T cells in whole blood.
AB  - BACKGROUND: Natural killer (NK) cells produce multiple cytokines with potential
      immune regulatory roles. We standardised a whole-blood flow cytometry method to
      visualise intracellular cytokine production by NK cells for the study of NK cell
      biology and for clinical monitoring. METHODS: With a three-colour fluorescent
      labelling technique, specific cytokine production by NK or T cells was visualised
      directly in whole blood in the same sample after stimulation by phorbol 12
      myristate 13-acetate (PMA) and ionomycin and by electronically gating on the CD3
      ve/CD56+ve NK population or on the CD3+/CD56+ NK-T-cell population. RESULTS:
      Detectable levels of tumour necrosis factor-alpha (TNF-alpha) and interferon
      gamma (IFN-gamma) but not of interleukin-2 (IL-2) or IL-4 were easily observed in
      NK cells. The visualisation of the cytokine production by NK cells was dependent
      on the addition of a Golgi transport inhibitor, Brefeldin A. Other known stimuli
      for NK cells (IL-2 and CD16 monoclonal antibody and incubation with K562, the NK
      sensitive cell line) promoted IFN-gamma and TNF-alpha production in NK cells to a
      lesser extent than did PMA and ionomycin stimulation. CONCLUSIONS: This whole
      blood flow cytometric assay appears to be an useful and easy method to examine
      cytokine production by NK cells and/or by CD3+CD56+ NK-T lymphocytes in patients
      with relevant diseases.

PMID- 10655567
TI  - Cytometry 2000

PMID- 10655566
TI  - Molecular quantification of cell cycle-related gene expression at the protein
      level.
AB  - BACKGROUND: Immunofluorescence cytometry of antigen and DNA content provides
      relative measurements of the cell cycle phase distribution of a specific epitope.
      Measurement of correlated expression of epitopes on signaling and regulatory
      proteins will be useful in the study of the complex pathways involved in cell
      cycle regulation and carcinogenesis. However, to formulate regulatory pathway
      models, measurements of molecules per cell would be more useful than relative
      measurements of intensity. Here, we report on a system in which the relationship
      between molecules and fluorescence is determined for a reference set of cell
      lines that are then used to directly calculate the number of molecules for
      unknowns. To demonstrate the process, we calculated the cell cycle phase
      distribution of SV40 large T antigen (Tag) in the reference cells. METHODS: A set
      of cell line clones expressing different levels of Tag were isolated.
      Quantitative Western blots of these cells and purified, recombinant Tag were
      performed. Cells from the same sample were stained and analyzed by flow cytometry
      for Tag and DNA. The relationship between molecules and fluorescence was
      established and calculations were performed for the phase distributions of Tag.
      RESULTS: The five cell lines had 0.11, 0.27, 1.06, 2.44, and 2.63 x 10(6)
      molecules of Tag per cell, determined by Western blot. The average coefficient of
      variation was 10.6%. The relationship of molecules to fluorescence fit a linear
      equation (r(2) = 0.96) over the range, 0.11 - 2.63 x 10(6) molecules, however,
      the same equation did not fit the relationship between 0 molecules, defined by
      isotype staining controls, and the lowest expressing cell line. To calculate the
      phase distributions of molecules in the lowest cell line, a second linear
      equation from 0 to 110,000 molecules was used. CONCLUSIONS: This work describes a
      system where fixed cells expressing various levels of a target antigen quantified
      by Western blots can be used to standardize flow cytometric measurements of gene
      expression in absolute terms.

PMID- 10655568
TI  - Can Reed-Sternberg cells of classic Hodgkin's disease be considered B-cells?
AB  - During the last twenty years, the issue of the nature of Reed-Sternberg (RS)
      cells of Hodgkin's disease (HD) has been addressed by multiple methodological
      approaches. In recent times, a major insight into HD has been obtained through
      molecular studies of isolated cells which have proven the clonal nature of HD. In
      parallel to molecular investigations some novel biologic markers specifically
      associated with the different stages of mature B-cells have helped to define the
      cellular origin of HD. This review deals with histological features of HD and
      summarizes recent results from molecular and immunohistochemical studies focusing
      on the origin and the stage of differentiation of RS cells.

PMID- 10655569
TI  - Castleman's disease.
AB  - Castleman's disease (CD) is a rare atypical lymphoproliferative disorder whose
      morphology, soon after the original presentation of Castleman et al., has been
      definitely subdivided in a hyaline vascular (HV) and plasma cell (PC)
      histopathological pattern, with intermediate variants. The former occurs much
      more frequently than the latter and is usually localized to the mediastinum or
      pulmonary hilum. The latter involves lymph nodes separately or in aggregations
      and often displays multicentricity with systemic symptoms including autoimmune
      phenomena and aggressive course. Infections are the most frequent causes of
      patient demise in these cases, followed by malignancies such as Kaposi's sarcoma,
      malignant lymphoma or epithelial neoplasia. Increase of follicular dendritic
      reticulum cells (FDRC), often dysplastic, in the germinal center (GC) and
      marginal zone (MZ), broad MZ expansion with prominence of immunophenotypically
      aberrant B cells (Ki B3-negative, CD5-positive), possible predominance of
      paracortical plasma cells often with clusters of clonal l-light chain restricted
      plasma cells, increase of paracortical plasmacytoid monocytes, represent common
      hallmarks of CD. However, small hyalinized and hypervascular GCs with
      hypervascular interfollicular stroma and sinus effacement are common features of
      the HV variant, whereas hyperplastic GCs with plasma cell aggregates in lymph
      node paracortex and partially spared sinuses are characteristic features of the
      PC variant. The frequent concomitance of the HV and PC types at separate sites,
      together with transient morphological patterns from one type to the other and
      from the localized to multicentric form during the course of the disease, along
      with B and T cell impaired functions, with frequent development of
      autoantibodies, have suggested that CD is a single disorder related to immune
      dysregulation. A key event in the pathogenesis of CD has been recently suggested
      to be an abnormal production of a B cell growth factor, such as IL-6, leading to
      lymphoproliferation and plasma cell differentiation and being involved in the
      oncogenesis of plasmacytoma. In this event, Kaposi's sarcoma associated virus
      (HHV-8), which has been found in many cases of CD, especially in the multicentric
      form, could play a crucial role both in producing IL-6 and releasing angiogenic
      factors. A possible differentiation block may lead to the development of a
      malignant lymphoma. Kaposi's sarcoma or other malignant neoplasias can be
      supposed to be consequences of the immunodeficiency typical of CD.

PMID- 10655570
TI  - Changes in DNA content of myocardial cells after cardiac explantation.
AB  - To evaluate the changes in DNA content of myocardial cells, image cytometric
      measurement was performed on a series of specimens obtained from 7 explanted
      hearts with respect to different fixation times after cardiac explantation. Prior
      to fixation, the tissue samples were stored at 4 degrees C or at room
      temperature. When the tissue samples were stored at room temperature, the
      integrated optical density decreased after 48 hours from cardiac explantation.
      Meanwhile, the coefficient of variation of integrated optical density and the sum
      of intermediate ploidies of myocyte nuclei increased. However, no significant
      changes were found when tissue samples were kept at 4 degrees C. This study
      indicates that no significant changes in DNA content are found within two days
      from cardiac explantation.

PMID- 10655571
TI  - Sudden and unexpected infant death due to an hemangioendothelioma located in the
      medulla oblongata.
AB  - Herein, we report the case of a 4-month-old male infant dying suddenly and
      unexpectedly. Post mortem examination was requested with clinical diagnosis of
      Sudden Infant Death Syndrome (SIDS). Histological examination showed instead the
      presence of an hemangioendothelioma located in the medulla oblongata. Sudden
      unexpected death is the commonest form of death among babies between 1 month and
      1 year of age. Although the vast majority of these fatalities are related to
      SIDS, a very small percentage is due to primary neoplasm. Necroscopy studies of
      sudden infant death should always include an accurate histological examination of
      the medulla oblongata on serial sections but seldom do.

PMID- 10655572
TI  - Bursting metastasis in thymic carcinoma.
AB  - Thymic carcinomas (primitive malignant epithelial neoplasms of the thymus) are
      rare tumors which generally remain silent for long periods and rarely metastatize
      outside the chest. The authors present a case of a 49 year-old patient, with
      mediastinal mass complicated by pericardial effusion and rapidly extensive liver
      metastasis. Data in the literature indicate that completeness of the excision at
      initial operation is the most important prognostic factor, but the presence of
      necrosis, high number of mitosis and endolymphatic emboli in the specimens could
      indicate a poor prognosis, suggesting a tempestive treatment and a close follow
      up.

PMID- 10655573
TI  - Secretory meningioma, a rare meningioma subtype with characteristic glandular
      differentation: an histological and immunohistochemical study of 9 cases.
AB  - AIM: We studied the immunophenotype of 9 cases of secretory meningioma (SM), a
      rarely reported meningioma variant, characterized by small gland-like lumina
      filled with a PAS-positive, diastase-resistant substance. METHODS: Three samples
      of arachnoid tissue and 9 SMs were studied with a panel of monoclonal antibodies
      (MoAbs) against cytokeratins (Ck) 7,8, 20, vimentin, EMA, CEA and the mucin
      epitopes sialyl-Tn, Tn, CA19.9, CA125, against the BerEP4 and CD15; 3 colonic
      adenocarcinomas metastatic to the brain and a case of meningioma with metastasis
      from a gastric signet-ring cell carcinoma were also studied with the same panel
      of MoAbs for comparison. RESULTS: The 3 samples of arachnoid cap cells were
      positive only for EMA and vimentin in the supportive stroma. All 9 SMs resulted
      Ck7+, Ck8+, Ck20-, EMA+, CEA and mucin epitopes+, confirming at an
      immunohistochemical level the glandular differentiation. Notable exceptions were
      the negativity for BerEP4 and CD15 antigens. Conversely, the 3 metastatic colonic
      adenocarcinomas to the brain were Ck7-, Ck8+, Ck20+, CEA and mucin epitopes+,
      BerEP4 and CD15+; the gastric signet-ring cell carcinoma metastatic to a
      meningioma showed the same immunophenotype as the other metastatic
      adenocarcinomas with the exception of BerEP4 negativity. CONCLUSION: The
      different pattern of cytokeratin expression (Ck7+/Ck20- for SMs, and Ck7-/ Ck20+
      for adenocarcinomas) and the negativity for BerEP4 and CD15 epitopes of SMs,
      could be relevant for the distinction between SMs and metastatic adenocarcinomas.

PMID- 10655574
TI  - Pure yolk sac tumors in genital and extragenital sites: study on three pedriatic
      cases, with cytological findings on two.
AB  - Cytopathological findings on three pedriatic gonadic-extragonadic pure yolk sac
      tumor are reported: the highly variable histological patterns (reticular, solid,
      festooning or pseudopapillary, polyvesicular vitelline), reflecting
      differentiation towards extraembryonic yolk sac structures, are not appreciated
      in cytologic samples. Since the tumor's cytologic spectrum is very broad, the
      most diagnostic differential difficulty with yolk sac tumor is adenocarcinoma.
      The presence of intracellular and extracellular hyaline globules, that are
      periodic acid-Schiff stain (PAS) positive and diastase resistant and correspond
      to alpha-fetoprotein production, alpha-fetoprotein positivity of the neoplastic
      cells; showing nuclear pleomorphism and vacuolated "bubbly" cytoplasm are the
      most consistent cytologic hallmarks of this neoplasm, which diagnosis would be
      confirmed by histologic, immunocytochemical and clinical findings.

PMID- 10655576
TI  - Proceedings of the 14th international meeting of the adriatic society of
      pathology

PMID- 10655575
TI  - Sweat gland carcinoma with multiple local recurrences: a case report.
AB  - We report a case of primary, high grade sweat gland carcinoma, a rare tumor,
      occurring in the skin of the left axilla. The patient, a 54-year-old man, was
      treated with wide surgical excision and lymph node dissection; he had developed
      metastatic deposits in one regional lymph node. The neoplasm relapsed locally
      thrice in a period of 10 years; however, distant metastases were not found. The
      differential diagnosis of sweat gland tumors is discussed in the present article.

PMID- 10655583
TI  - Chromaffin-cell stimulation triggers fast millimolar mitochondrial Ca2+
      transients that modulate secretion.
AB  - Activation of calcium-ion (Ca2+) channels on the plasma membrane and on
      intracellular Ca2+ stores, such as the endoplasmic reticulum, generates local
      transient increases in the cytosolic Ca2+ concentration that induce Ca2+ uptake
      by neighbouring mitochondria. Here, by using mitochondrially targeted aequorin
      proteins with different Ca2+ affinities, we show that half of the chromaffin-cell
      mitochondria exhibit surprisingly rapid millimolar Ca2+ transients upon
      stimulation of cells with acetylcholine, caffeine or high concentrations of
      potassium ions. Our results show a tight functional coupling of voltage-dependent
      Ca2+ channels on the plasma membrane, ryanodine receptors on the endoplasmic
      reticulum, and mitochondria. Cell stimulation generates localized Ca2+
      transients, with Ca2+ concentrations above 20-40 microM, at these functional
      units. Protonophores abolish mitochondrial Ca2+ uptake and increase stimulated
      secretion of catecholamines by three- to fivefold. These results indicate that
      mitochondria modulate secretion by controlling the availability of Ca2+ for
      exocytosis.

PMID- 10655584
TI  - Activation of EphA2 kinase suppresses integrin function and causes focal-adhesion
      kinase dephosphorylation.
AB  - Interactions between receptor tyrosine kinases of the Eph family and their
      ligands, ephrins, are implicated in establishment of organ boundaries and
      repulsive guidance of cell migration during development, but the mechanisms by
      which this is achieved are unclear. Here we show that activation of endogenous
      EphA2 kinase induces an inactive conformation of integrins and inhibits cell
      spreading, migration and integrin-mediated adhesion. Moreover, EphA2 is
      constitutively associated with focal-adhesion kinase (FAK) in resting cells.
      Within one minute after stimulation of EphA2 with its ligand, ephrin-A1, the
      protein tyrosine phosphatase SHP2 is recruited to EphA2; this is followed by
      dephosphorylation of FAK and paxillin, and dissociation of the FAK-EphA2 complex.
      We conclude that Eph kinases mediate some of their functions by negatively
      regulating integrins and FAK.

PMID- 10655585
TI  - Specific interference with gene function by double-stranded RNA in early mouse
      development.
AB  - The use of double-stranded (ds) RNA is a powerful way of interfering with gene
      expression in a range of organisms, but doubts have been raised about whether it
      could be successful in mammals. Here, we show that dsRNA is effective as a
      specific inhibitor of the function of three genes in the mouse, namely maternally
      expressed c-mos in the oocyte and zygotically expressed E-cadherin or a GFP
      transgene in the preimplantation embryo. The phenotypes observed are the same as
      those reported for null mutants of the endogenous genes. These findings offer the
      opportunity to study development and gene regulation in normal and diseased
      cells.

PMID- 10655586
TI  - The transcription factor snail controls epithelial-mesenchymal transitions by
      repressing E-cadherin expression.
AB  - The Snail family of transcription factors has previously been implicated in the
      differentiation of epithelial cells into mesenchymal cells (epithelial
      mesenchymal transitions) during embryonic development. Epithelial-mesenchymal
      transitions are also determinants of the progression of carcinomas, occurring
      concomitantly with the cellular acquisition of migratory properties following
      downregulation of expression of the adhesion protein E-cadherin. Here we show
      that mouse Snail is a strong repressor of transcription of the E-cadherin gene.
      Epithelial cells that ectopically express Snail adopt a fibroblastoid phenotype
      and acquire tumorigenic and invasive properties. Endogenous Snail protein is
      present in invasive mouse and human carcinoma cell lines and tumours in which E
      cadherin expression has been lost. Therefore, the same molecules are used to
      trigger epithelial-mesenchymal transitions during embryonic development and in
      tumour progression. Snail may thus be considered as a marker for malignancy,
      opening up new avenues for the design of specific anti-invasive drugs.

PMID- 10655587
TI  - The transcription factor snail is a repressor of E-cadherin gene expression in
      epithelial tumour cells.
AB  - The adhesion protein E-cadherin plays a central part in the process of epithelial
      morphogenesis. Expression of this protein is downregulated during the acquisition
      of metastatic potential at late stages of epithelial tumour progression. There is
      evidence for a transcriptional blockage of E-cadherin gene expression in this
      process. Here we show that the transcription factor Snail, which is expressed by
      fibroblasts and some E-cadherin-negative epithelial tumour cell lines, binds to
      three E-boxes present in the human E-cadherin promoter and represses
      transcription of E-cadherin. Inhibition of Snail function in epithelial cancer
      cell lines lacking E-cadherin protein restores the expression of the E-cadherin
      gene.

PMID- 10655589
TI  - Plasticity in mouse neural crest cells reveals a new patterning role for cranial
      mesoderm.
AB  - The anteroposterior identity of cranial neural crest cells is thought to be
      preprogrammed before these cells emigrate from the neural tube. Here we test this
      assumption by developing techniques for transposing cells in the hindbrain of
      mouse embryos, using small numbers of cells in combination with genetic and
      lineage markers. This technique has uncovered a surprising degree of plasticity
      with respect to the expression of Hox genes, which can be used as markers of
      different hindbrain segments and cells, in both hindbrain tissue and cranial
      neural crest cells. Our analysis shows that the patterning of cranial neural
      crest cells relies on a balance between permissive and instructive signals, and
      underscores the importance of cell-community effects. These results reveal a new
      role for the cranial mesoderm in patterning facial tissues. Furthermore, our
      findings argue against a permanently fixed prepatterning of the cranial neural
      crest that is maintained by passive transfer of positional information from the
      hindbrain to the periphery.

PMID- 10655588
TI  - DNA-replication/DNA-damage-dependent centrosome inactivation in Drosophila
      embryos.
AB  - During early embryogenesis of Drosophila melanogaster, mutations in the DNA
      replication checkpoint lead to chromosome-segregation failures. Here we show that
      these segregation failures are associated with the assembly of an anastral
      microtubule spindle, a mitosis-specific loss of centrosome function, and
      dissociation of several components of the gamma-tubulin ring complex from a core
      centrosomal structure. The DNA-replication inhibitor aphidicolin and DNA-damaging
      agents trigger identical mitotic defects in wild-type embryos, indicating that
      centrosome inactivation is a checkpoint-independent and mitosis-specific response
      to damaged or incompletely replicated DNA. We propose that centrosome
      inactivation is part of a damage-control system that blocks chromosome
      segregation when replication/damage checkpoint control fails.

PMID- 10655590
TI  - Defects in pathfinding by cranial neural crest cells in mice lacking the
      neuregulin receptor ErbB4.
AB  - Mouse embryos with a loss-of-function mutation in the gene encoding the receptor
      tyrosine kinase ErbB4 exhibit misprojections of cranial sensory ganglion afferent
      axons. Here we analyse ErbB4-deficient mice, and find that morphological
      differences between wild-type and mutant cranial ganglia correlate with aberrant
      migration of a subpopulation of hindbrain-derived cranial neural crest cells
      within the paraxial mesenchyme environment. In transplantation experiments using
      new grafting techniques in cultured mouse embryos, we determine that this
      phenotype is non-cell-autonomous: wild-type and mutant neural crest cells both
      migrate in a pattern consistent with the host environment, deviating from their
      normal pathway only when transplanted into mutant embryos. ErbB4 signalling
      events within the hindbrain therefore provide patterning information to cranial
      paraxial mesenchyme that is essential for the proper migration of neural crest
      cells.

PMID- 10655591
TI  - A conserved docking motif in MAP kinases common to substrates, activators and
      regulators.
AB  - Mitogen-activated protein kinases (MAPKs) are specifically phosphorylated and
      activated by the MAPK kinases, phosphorylate various targets such as MAPK
      activated protein kinases and transcription factors, and are inactivated by
      specific phosphatases. Recently, docking interactions via the non-catalytic
      regions of MAPKs have been suggested to be important in regulating these
      reactions. Here we identify docking sites in MAPKs and in MAPK-interacting
      enzymes. A docking domain in extracellular-signal-regulated kinase (ERK), a MAPK,
      serves as a common site for binding to the MAPK kinase MEK1, the MAPK-activated
      protein kinase MNK1 and the MAPK phosphatase MKP3. Two aspartic acids in this
      domain are essential for docking, one of which is mutated in the sevenmaker
      mutant of Drosophila ERK/Rolled. A corresponding domain in the MAPKs p38 and
      JNK/SAPK also serves as a common docking site for their MEKs, MAPK-activated
      protein kinases and MKPs. These docking interactions increase the efficiency of
      the enzymatic reactions. These findings reveal a hitherto unidentified docking
      motif in MAPKs that is used in common for recognition of their activators,
      substrates and regulators.

PMID- 10655592
TI  - Nuclear sequestration of the exchange factor Cdc24 by Far1 regulates cell
      polarity during yeast mating.
AB  - Cytoskeletal rearrangements during the cell cycle and in response to signals are
      regulated by small Rho-type GTPases, but it is not known how these GTPases are
      activated in a spatial and temporal manner. Here we show that Cdc24, the guanine
      nucleotide exchange factor for the yeast GTPase Cdc42, is sequestered in the cell
      nucleus by Far1. Export of Cdc24 to a site of cell polarization is mediated by
      two mechanisms. At bud emergence, activation of the G1 cyclin-dependent kinase
      Cdc28-Cln triggers degradation of Far1 and, as a result, relocation of Cdc24 to
      the cytoplasm. Cells overexpressing a non-degradable Far1 were unable to polarize
      their actin cytoskeleton because they failed to relocate Cdc24 to the incipient
      bud site. In contrast, in response to mating pheromones, the Far1-Cdc24 complex
      is exported from the nucleus by Msn5. This mechanism ensures that Cdc24 is
      targeted to the site of receptor-associated heterotrimeric G-protein activation
      at the plasma membrane, thereby allowing polarization of the actin cytoskeleton
      along the morphogenetic gradient of pheromone. Either degradation of Far1 or its
      nuclear export by Msn5 was sufficient for cell growth, suggesting that the two
      mechanisms are redundant for cell viability. Taken together, our results indicate
      that Far1 functions as a nuclear anchor for Cdc24. This sequestration regulates
      cell polarity in response to pheromones by restricting activation of Cdc42 to the
      site of pheromone receptor activation.

PMID- 10655593
TI  - Kinesin and dynamin are required for post-Golgi transport of a plasma-membrane
      protein.

PMID- 10655594
TI  - Rapid initiation of Arabidopsis pollination requires the oleosin-domain protein
      GRP17.

PMID- 10655595
TI  - Science funding: how to sell biology.

PMID- 10655596
TI  - Presenilin mutants subvert chaperone function.
AB  - Mutant presenilin proteins, known to promote the development of Alzheimer's
      disease through increased generation of Abeta42 peptides, appear to compound this
      insult by downregulating the signalling pathway that adjusts levels of molecular
      chaperones in the endoplasmic reticulum in response to stress.

PMID- 10655597
TI  - CD95: more than just a death factor?
AB  - The CD95 protein delivers crucial signals for lymphocyte death, and may also
      negatively regulate T-lymphocyte activation by preventing the influx of calcium
      ions from the cell's exterior. The block in calcium-ion influx occurs through the
      activation of acidic sphingomyelinase and the release of ceramide, a metabolite
      that can also induce cell death.

PMID- 10655598
TI  - High tide of calcium in mitochondria.
AB  - Mitochondria in intact cells can transiently accumulate calcium during cell
      stimulation. The heterogeneity of the response, the extremely high calcium
      concentrations reached in the mitochondrial matrix, and the ensuing modulation of
      secretion add further complexity to the spatiotemporal aspects of signalling
      through calcium ions.

PMID- 10655599
TI  - Hush, hush: the origin of telomeric silence.

PMID- 10655600
TI  - DNA defects target the centrosome.
AB  - When cells enter mitosis with DNA that is unfit to be segregated, the
      consequences appear to be loss of centrosome function, abnormal spindles and a
      failure to segregate chromosomes. These defects may result from the workings of a
      surveillance mechanism that acts to cull irreparable nuclei.

PMID- 10655601
TI  - RNA interference: genetic wand and genetic watchdog.
AB  - In many species, introduction of double-stranded RNA (dsRNA) induces potent and
      specific gene silencing, a phenomenon called RNA interference or RNAi. The
      apparently widespread nature of RNAi in eukaryotes, ranging from trypanosome to
      mouse, has sparked great interest from both applied and fundamental standpoints.
      Here we review the technical improvements being made to increase the experimental
      potential of this technique. We also discuss recent advances in uncovering the
      proteins that act during the RNAi process, discoveries that have revealed
      enticing links between transposition, transgene silencing and RNAi.

PMID- 10655602
TI  - Taming tuberculosis--again.

PMID- 10655603
TI  - Restriction endonucleases: one of these things is not like the others.
AB  - The crystal structure of the restriction endonuclease BglII in complex with its
      DNA target site has been determined. The DNA binding mode and chemistry of
      catalysis are observed to differ from BamHI which cleaves a similar target site.
      These observations indicate that more divergence has occurred within this family
      of proteins than originally thought.

PMID- 10655604
TI  - Understanding membrane protein structure by design.
AB  - In contrast to soluble proteins, the primary interactions that specify and
      stabilize membrane protein structures are still largely a matter of speculation.
      Although van der Waals interactions have been gaining increasing favor as the
      dominant player, new results demonstrate the strength of hydrogen bonding in a
      membrane environment.

PMID- 10655605
TI  - Another brick in the wall.
AB  - The X-ray crystal structure of Mycobacterium tuberculosis antigen 85C elucidates
      the structural basis of fibronectin binding and catalysis of mycolic acid
      transfer by this potential drug target.

PMID- 10655606
TI  - Are DEAD-box proteins becoming respectable helicases?
AB  - The vaccinia NPH-II RNA helicase, a member of the DEAD/DExH-box protein family,
      has been shown to be a processive, unidirectional RNA helicase with a step size
      of about one half turn of a helix. This finding demonstrates that RNA helicases
      can function as molecular motors.

PMID- 10655607
TI  - History. The servant with the scissors.

PMID- 10655608
TI  - Picture story. Picking pathways.

PMID- 10655609
TI  - Structure and assembly of large lipid-containing dsDNA viruses.

PMID- 10655610
TI  - Conformational switch in the decoding region of 16S rRNA during aminoacyl-tRNA
      selection on the ribosome.
AB  - Binding of aminoglycoside antibiotics to 16S ribosomal RNA induces a particular
      structure of the decoding center and increases the misincorporation of near
      cognate amino acids. By kinetic analysis we show that this is due to
      stabilization of the near-cognate codon recognition complex and the acceleration
      of two rearrangements that limit the rate of amino acid incorporation. The same
      rearrangement steps are accelerated in the cognate coding situation. We suggest
      that cognate codon recognition, or near-cognate codon recognition augmented by
      aminoglycoside binding, promote the transition of 16S rRNA from a 'binding' to a
      'productive' conformation that determines the fidelity of decoding.

PMID- 10655611
TI  - Crystal structures of Escherichia coli phytase and its complex with phytate.
AB  - Phytases catalyze the hydrolysis of phytate and are able to improve the
      nutritional quality of phytate-rich diets. Escherichia coli phytase, a member of
      the histidine acid phosphatase family has the highest specific activity of all
      phytases characterized. The crystal structure of E. coli phytase has been
      determined by a two-wavelength anomalous diffraction method using the
      exceptionally strong anomalous scattering of tungsten. Despite a lack of sequence
      similarity, the structure closely resembles the overall fold of other histidine
      acid phosphatases. The structure of E. coli phytase in complex with phytate, the
      preferred substrate, reveals the binding mode and substrate recognition. The
      binding is also accompanied by conformational changes which suggest that
      substrate binding enhances catalysis by increasing the acidity of the general
      acid.

PMID- 10655612
TI  - The aspartic proteinase from Saccharomyces cerevisiae folds its own inhibitor
      into a helix.
AB  - Aspartic proteinase A from yeast is specifically and potently inhibited by a
      small protein called IA3 from Saccharomyces cerevisiae. Although this inhibitor
      consists of 68 residues, we show that the inhibitory activity resides within the
      N-terminal half of the molecule. Structures solved at 2.2 and 1.8 A,
      respectively, for complexes of proteinase A with full-length IA3 and with a
      truncated form consisting only of residues 2-34, reveal an unprecedented mode of
      inhibitor-enzyme interactions. Neither form of the free inhibitor has detectable
      intrinsic secondary structure in solution. However, upon contact with the enzyme,
      residues 2-32 become ordered and adopt a near-perfect alpha-helical conformation.
      Thus, the proteinase acts as a folding template, stabilizing the helical
      conformation in the inhibitor, which results in the potent and specific blockage
      of the proteolytic activity.

PMID- 10655613
TI  - Structure of a photoactive rhodium complex intercalated into DNA.
AB  - Intercalating complexes of rhodium(III) are strong photo-oxidants that promote
      DNA strand cleavage or electron transfer through the double helix. The 1.2 A
      resolution crystal structure of a sequence-specific rhodium intercalator bound to
      a DNA helix provides a rationale for the sequence specificity of rhodium
      intercalators. It also explains how intercalation in the center of an
      oligonucleotide modifies DNA conformation. The rhodium complex intercalates via
      the major groove where specific contacts are formed with the edges of the bases
      at the target site. The phi ligand is deeply inserted into the DNA base pair
      stack. The primary conformational change of the DNA is a doubling of the rise per
      residue, with no change in sugar pucker from B-form DNA. Based upon the five
      crystallographically independent views of an intercalated DNA helix observed in
      this structure, the intercalator may be considered as an additional base pair
      with specific functional groups positioned in the major groove.

PMID- 10655614
TI  - The Rac-RhoGDI complex and the structural basis for the regulation of Rho
      proteins by RhoGDI.
AB  - Rho family-specific guanine nucleotide dissociation inhibitors (RhoGDIs) decrease
      the rate of nucleotide dissociation and release Rho proteins such as RhoA, Rac
      and Cdc42 from membranes, forming tight complexes that shuttle between cytosol
      and membrane compartments. We have solved the crystal structure of a complex
      between the RhoGDI homolog LyGDI and GDP-bound Rac2, which are abundant in
      leukocytes, representing the cytosolic, resting pool of Rho species to be
      activated by extracellular signals. The N-terminal domain of LyGDI (LyN), which
      has been reported to be flexible in isolated RhoGDIs, becomes ordered upon
      complex formation and contributes more than 60% to the interface area. The
      structure is consistent with the C-terminus of Rac2 binding to a hydrophobic
      cavity previously proposed as isoprenyl binding site. An inner segment of LyN
      forms a helical hairpin that contacts mainly the switch regions of Rac2. The
      architecture of the complex interface suggests a mechanism for the inhibition of
      guanine nucleotide dissociation that is based on the stabilization of the
      magnesium (Mg2+) ion in the nucleotide binding pocket.

PMID- 10655615
TI  - Structural origins of the selectivity of the trifunctional oxygenase clavaminic
      acid synthase.
AB  - Clavaminate synthase (CAS), a remarkable Fe(II)/2-oxoglutarate oxygenase,
      catalyzes three separate oxidative reactions in the biosynthesis of clavulanic
      acid, a clinically used inhibitor of serine beta-lactamases. The first CAS
      catalyzed step (hydroxylation) is separated from the latter two (oxidative
      cyclization/desaturation) by the action of an amidinohydrolase. Here, we describe
      crystal structures of CAS in complex with Fe(II), 2-oxoglutarate (2OG) and
      substrates (N-alpha-acetyl-L-arginine and proclavaminic acid). They reveal how
      CAS catalyzes formation of the clavam nucleus, via a process unprecedented in
      synthetic organic chemistry, and suggest how it discriminates between substrates
      and controls reaction of its highly reactive ferryl intermediate. The presence of
      an unpredicted jelly roll beta-barrel core in CAS implies divergent evolution
      within the family of 2OG and related oxygenases. Comparison with other non-heme
      oxidases/oxygenases reveals flexibility in the position which dioxygen ligates to
      the iron, in contrast to the analogous heme-using enzymes.

PMID- 10655616
TI  - Understanding the immutability of restriction enzymes: crystal structure of BglII
      and its DNA substrate at 1.5 A resolution.
AB  - Restriction endonucleases are remarkably resilient to alterations in their DNA
      binding specificity. To understand the basis of this immutability, we have
      determined the crystal structure of endonuclease BglII bound to its recognition
      sequence (AGATCT), at 1. 5 A resolution. We compare the structure of BglII to
      endonuclease BamHI, which recognizes a closely related DNA site (GGATCC). We show
      that both enzymes share a similar alpha/beta core, but in BglII, the core is
      augmented by a beta-sandwich domain that encircles the DNA to provide extra
      specificity. Remarkably, the DNA is contorted differently in the two structures,
      leading to different protein-DNA contacts for even the common base pairs.
      Furthermore, the BglII active site contains a glutamine in place of the glutamate
      at the general base position in BamHI, and only a single metal is found
      coordinated to the putative nucleophilic water and the phosphate oxygens. This
      surprising diversity in structures shows that different strategies can be
      successful in achieving site-specific recognition and catalysis in restriction
      endonucleases.

PMID- 10655617
TI  - Crystal structure of the secreted form of antigen 85C reveals potential targets
      for mycobacterial drugs and vaccines.
AB  - The antigen 85 (ag85) complex, composed of three proteins (ag85A, B and C), is a
      major protein component of the Mycobacterium tuberculosis cell wall. Each protein
      possesses a mycolyltransferase activity required for the biogenesis of trehalose
      dimycolate (cord factor), a dominant structure necessary for maintaining cell
      wall integrity. The crystal structure of recombinant ag85C from M. tuberculosis,
      refined to a resolution of 1.5 A, reveals an alpha/beta-hydrolase polypeptide
      fold, and a catalytic triad formed by Ser 124, Glu 228 and His 260. ag85C
      complexed with a covalent inhibitor implicates residues Leu 40 and Met 125 as
      components of the oxyanion hole. A hydrophobic pocket and tunnel extending 21 A
      into the core of the protein indicates the location of a probable trehalose
      monomycolate binding site. Also, a large region of conserved surface residues
      among ag85A, B and C is a probable site for the interaction of ag85 proteins with
      human fibronectin.

PMID- 10655618
TI  - Crystal structures of a novel, thermostable phytase in partially and fully
      calcium-loaded states.
AB  - Phytases hydrolyze phytic acid to less phosphorylated myo-inositol derivatives
      and inorganic phosphate. A thermostable phytase is of great value in applications
      for improving phosphate and metal ion availability in animal feed, and thereby
      reducing phosphate pollution to the environment. Here, we report a new folding
      architecture of a six-bladed propeller for phosphatase activity revealed by the
      2.1 A crystal structures of a novel, thermostable phytase determined in both the
      partially and fully Ca2+-loaded states. Binding of two calcium ions to high
      affinity calcium binding sites results in a dramatic increase in thermostability
      (by as much as approximately 30 degrees C in melting temperature) by joining loop
      segments remote in the amino acid sequence. Binding of three additional calcium
      ions to low-affinity calcium binding sites at the top of the molecule turns on
      the catalytic activity of the enzyme by converting the highly negatively charged
      cleft into a favorable environment for the binding of phytate.

PMID- 10655619
TI  - Interhelical hydrogen bonding drives strong interactions in membrane proteins.
AB  - Polar residues in transmembrane alpha-helices may strongly influence the folding
      or association of integral membrane proteins. To test whether a motif that
      promotes helix association in a soluble protein could do the same within a
      membrane, we designed a model transmembrane helix based on the GCN4 leucine
      zipper. We found in both detergent micelles and biological membranes that helix
      association is driven strongly by asparagine, independent of the rest of the
      hydrophobic leucine and/or valine sequence. Hydrogen bonding between membrane
      helices gives stronger associations than the packing of surfaces in glycophorin A
      helices, creating an opportunity to stabilize structures, but also implying a
      danger that non-specific interactions might occur. Thus, membrane proteins may
      fold to avoid exposure of strongly hydrogen bonding groups at their lipid exposed
      surfaces.

PMID- 10655621
TI  - Modulated and pulsed photoacoustics in trace gas analysis.

PMID- 10655620
TI  - Asparagine-mediated self-association of a model transmembrane helix.
AB  - In membrane proteins, the extent to which polarity, hydrogen bonding, and van der
      Waals packing interactions of the buried, internal residues direct protein
      folding and association of transmembrane segments is poorly understood. The
      energetics associated with these various interactions should differ substantially
      between membrane versus water-soluble proteins. To help evaluate these
      energetics, we have altered a water-soluble, two-stranded coiled-coil peptide to
      render its sequence soluble in membranes. The membrane-soluble peptide associates
      in a monomer-dimer-trimer equilibrium, in which the trimer predominates at the
      highest peptide/detergent ratios. The oligomers are stabilized by a buried Asn
      side chain. Mutation of this Asn to Val essentially eliminates oligomerization of
      the membrane-soluble peptide. Thus, within a membrane-like environment,
      interactions involving a polar Asn side chain provide a strong thermodynamic
      driving force for membrane helix association.

PMID- 10655622
TI  - The new interfacial ubiquity of surface-enhanced Raman spectroscopy.

PMID- 10655623
TI  - Detecting proteins separated by 2-D gel electrophoresis.

PMID- 10655625
TI  - Seek and you shall find.

PMID- 10655624
TI  - Implementing LIMS: a "how-to" guide.

PMID- 10655626
TI  - Detection of nanocolloids with flow-field flow fractionation and laser-induced
      breakdown detection.
AB  - A new nanosize colloid detection method comprised of flow-field flow
      fractionation (FFFF) with laser-induced breakdown detection (LIBD) is presented,
      which is capable of characterizing the colloid size distribution as well as
      determining the number density of each size fraction in very low concentrations.
      The method facilitates the detection of aquatic colloids particularly in the
      lower range of nanometer size (< 50 nm) with the sensitivity much higher than a
      laser light-scattering method (LLS), i.e., the lower ppb range. The method is
      tested with a mixture of polystyrene colloids in three different nominal sizes,
      19, 50, and 102 nm, and the results are compared with those of the LLS method.
      For colloids of 19-nm diameter, the present method demonstrates the detection
      sensitivity over 3 orders of magnitude better than that of the LLS method. The
      limitation of the detection sensitivity arises from the surface bleeding of a
      ceramic frit overlying the separation channel of the used FFFF instrument.

PMID- 10655627
TI  - An SPR-based screening method for agonist selectivity for insulin signaling
      pathways based on the binding of phosphotyrosine to its specific binding protein.
AB  - A new screening method was developed that evaluates physiologically relevant
      chemical selectivity of agonists for insulin-signaling pathways. Phosphorylation
      (pY939) by an insulin-activated insulin receptor of a target peptide (Y939)
      derived from an insulin receptor substrate-1 (IRS-1) and its subsequent binding
      to another downstream target, the SH2 domain of PI-3 kinase (SH2N), were detected
      by surface plasmon resonance (SPR) spectrometry. This method is based on
      competitive binding of SH2N to pY939 either in a solution or on the gold surface
      of the SPR sensor chip. With increasing the concentration of pY939 in solution by
      the insulin-induced kinase reaction of insulin receptor, SH2N bound to pY939 in
      solution increases and the one on the sensor chip decreases, thereby causing a
      decrease in the SPR signal. The amount of thus-detected complex pY939-SH2N was
      found to depend on added insulin concentrations, confirming that the method
      utilized part of the sequential transduction mechanism of the insulin-signaling
      pathways. The kinase activity of insulin receptor-agonist complexes increased in
      the order of IGF-II < IGF-I < insulin, and neither vanadium ions nor thiazolidine
      type medicines for NIDDM, troglitazone and pioglitazone, directly acted on both
      the kinase reaction of insulin receptor or the binding of pY939 to SH2N. The
      present approach will thus become a general method for screening agonists for one
      specific pathway in tyrosine phosphorylation of IRS-1 in insulin signaling, which
      is regulated by specific protein-protein interaction between a phosphorylated
      tyrosine in IRS-1 and its corresponding SH2 domain-containing protein such as PI
      3 kinase, Grb2-Sos, or SHP2.

PMID- 10655628
TI  - Raman spectroscopic method for identification of clinically relevant
      microorganisms growing on solid culture medium.
AB  - Routine clinical microbiological identification of pathogenic microorganisms is
      largely based on nutritional and biochemical tests. In the case of severely ill
      patients, the unavoidable time delay associated with such identification
      procedures can be fatal. We present a novel identification method based on
      confocal Raman microspectroscopy. With this approach it is possible to obtain
      Raman spectra directly from microbial microcolonies on the solid culture medium,
      which have developed after only 6 h of culturing for the most commonly
      encountered organisms. Due to the limited thickness of microcolonies, some of the
      underlying culture medium is sampled together with the bacteria. Spectra measured
      at different depths in a microcolony contain different amounts of the medium
      signal. A mathematical routine, involving vector algebra, is described for the
      nonsubjective correction of spectra for variable signal contributions of the
      medium. To illustrate the possibilities of our approach for the identification of
      microorganisms, Raman spectra were collected from 6-h microcolonies of five
      bacterial strains on solid culture medium. The classification results show that
      confocal Raman microspectroscopy has great potential as a powerful new tool in
      clinical diagnostic microbiology.

PMID- 10655629
TI  - Development of multi-ESI-sprayer, multi-atmospheric-pressure-inlet mass
      spectrometry and its application to accurate mass measurement using time-of
      flight mass spectrometry.
AB  - The atmospheric pressure sampling nozzle (orifice, heated capillary, or inlet) of
      a high mass accuracy time-of-flight mass spectrometer (TOF-MS) was modified by
      replacing its single nozzle with multiple atmospheric pressure nozzles. This
      allowed multiple streams of liquids to be introduced into the MS in parallel (an
      electrosprayer for each nozzle), with minimum analyte interactions between the
      streams. The chemical contents of all liquid streams were analyzed concurrently
      using a single mass spectrometer. To obtain a higher mass accuracy by providing
      internal reference on each scan (acquisition) and to evaluate the suitability of
      TOF-MS for molecular-formula confirmation, a dual-ESI-sprayer, dual-nozzle
      version of this design was used. The accurate masses of tens of organic compounds
      in the mass range of 200-3000 Da were measured, and the results were compared
      with those obtained using dual-sprayer, single-nozzle TOF-MS. A significant
      improvement in mass accuracy was observed when the former technique was used.
      Comparison between the mass accuracy using dual-ESI-sprayer, dual-nozzle TOF-MS
      and that obtained using a double-focusing mass spectrometer operating under
      chemical ionization (CI) and fast atom bombardment (FAB) shows the suitability of
      the technique for elemental-composition confirmation. Approximately 85% of
      samples analyzed had mass errors of less than 5 ppm, and the other 15% had mass
      errors less than 8 ppm. Using a high-performance liquid chromatography (HPLC) as
      a device for introduction of one liquid stream (sample) and a syringe pump as a
      device for introduction of the second liquid stream (reference standard), the
      accurate mass of a tryptic digest of cytochrome c was measured. The range of mass
      errors was from -6.1 ppm to +3.6 ppm, a significant improvement over our
      previously reported mass accuracy for this digest using single-nozzle TOF-MS. The
      interactions between analytes in the liquid streams also were investigated using
      a variety of sample-introduction and nozzle-design combinations, including single
      ESI-sprayer, single-nozzle; dual-ESI-sprayer, single-nozzle; dual-ESI-sprayer, Y
      shaped inlet; and dual-ESI-sprayer, dual-inlet. The results demonstrated that the
      dual-ESI-sprayer, dual-inlet design provides reference peaks on every acquisition
      with minimum analyte-reference interaction and, therefore, higher consistent mass
      accuracy.

PMID- 10655630
TI  - Determination of perchlorate at trace levels in drinking water by ion-pair
      extraction with electrospray ionization mass spectrometry.
AB  - Perchlorate has been added to the U.S. Environmental Protection Agency's Drinking
      Water Contaminant Candidate List (CCL). The present work describes the analysis
      of perchlorate in water by liquid-liquid extraction followed by flow injection
      electrospray mass spectrometry (ESI/MS). Cationic surfactants, mostly
      alkyltrimethyl-ammonium salts, are used to ion-pair aqueous perchlorate, forming
      extractable ion pairs. The cationic surfactant associates with the perchlorate
      ion to form a complex detectable by ESI/MS. The selectivity of the extraction and
      the mass spectrometric detection increases confidence in the identification of
      perchlorate. The method detection limit for perchlorate based on 3.14 sigma n-1
      of seven replicate injections was 100 ng L-1 (parts per trillion). Standard
      addition was used to quantitate perchlorate in a drinking water sample from a
      contaminated source, and the concentration determined agreed within experimental
      error with the concentration determined by ion chromatography.

PMID- 10655631
TI  - Heterogeneity within MALDI samples as revealed by mass spectrometric imaging.
AB  - While matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS)
      has revolutionized the manner by which many large molecules are characterized,
      the highly variable appearance of MALDI mass spectra remains a concern. We have
      developed MALDI-based imaging as a diagnostic tool for examining the
      relationships between preparation strategy, sample morphology, and spectral
      quality. The imaging protocol involves the automated acquisition of mass spectra
      at 400-1600 positions within a single sample, followed by off-line processing and
      image display. Several sample types have been characterized, including a simple
      peptide mixture prepared in dried droplets of 2,5-dihydroxybenzoic acid and in
      thin films of alpha-cyano-4-hydroxycinnamic acid as well as a complex biological
      sample consisting of intact peptidergic neurons from the marine mollusk Aplysia
      californica. Imaging experiments provide a wealth of unbiased information
      concerning sample defects, spectral reproducibility, mass accuracy, differential
      analyte distributions, and the validity of internal standards.

PMID- 10655632
TI  - High-throughput flow cytometric DNA fragment sizing.
AB  - The rate of detection and sizing of individual fluorescently labeled DNA
      fragments in conventional single-molecule flow cytometry (SMFC) is limited by
      optical saturation, photon-counting statistics, and fragment overlap to
      approximately 100 fragments/s. We have increased the detection rate for DNA
      fragment sizing in SMFC to approximately 2000 fragments/s by parallel imaging of
      the fluorescence from individual DNA molecules, stained with a fluorescent
      intercalating dye, as they passed through a planar sheet of excitation laser
      light, resulting in order of magnitude improvements in the measurement speed and
      the sample throughput compared to conventional SMFC. Fluorescence bursts were
      measured from a fM solution of DNA fragments ranging in size from 7 to 154
      kilobase pairs. A data acquisition time of only a few seconds was sufficient to
      determine the DNA fragment size distribution. A linear relationship between the
      number of detected photons per burst and the DNA fragment size was confirmed.
      Application of this parallel fluorescence imaging method will lead to
      improvements in the speed, throughput, and sensitivity of other types of flow
      based analyses involving the study of single molecules, chromosomes, cells, etc.

PMID- 10655633
TI  - Producing "self-plasticizing" ion-selective membranes.
AB  - Polymer membranes have been explored for the analysis of ions that do not require
      plasticizers and with photocurable properties. This work was focused on
      investigating the viability of the methacrylic-acrylic copolymers as new self
      plasticizing membrane matrixes for ion-selective electrodes or other ion-sensor
      applications. Copolymers with glass transition temperatures ranging from -20 to 
      44 degrees C could be prepared without added plasticizer and were found to be
      functional as ion-selective membranes. Both free-radical solution polymerization
      and photopolymerization could be used, and "self-plasticizing" behavior of
      copolymers was observed with a high alkylacrylate (R = C4) content. This was
      found to be compatible with most commercially available ionophores, and sensors
      for potassium, sodium, calcium and pH were fabricated entirely by photocure
      procedures; single-step procedures for the immobilization of benzo-15-crown-5
      ionophore on these self-plasticizing copolymer matrixes were also developed. Even
      though the ionophore was immobilized, potentiometric studies revealed that the
      ionophore remained functional, and thus, these copolymers have the advantage of
      suffering neither leaching of ionophore nor plasticizers. All these sensors
      exhibited a Nernstian or near Nernstian response with selectivity comparable to
      plasticized PVC membranes or other plasticized and photocurable polymer
      membranes. The long-term response of the potassium sensor with immobilized
      ionophore and the sodium sensor showed little deterioration for as long as one
      month and three months, respectively, under continuous use.

PMID- 10655634
TI  - Charge reduction electrospray mass spectrometry.
AB  - A new mass spectrometric technique, charge reduction electrospray mass
      spectrometry (CREMS), allowing the analysis of complex mixtures of biological
      molecules is described. The charge state of ions produced by electrospray
      ionization may be reduced in a controlled manner to yield predominantly singly
      charged ions through reactions with bipolar (i.e., both positively and negatively
      charged) ions generated using a 210Po alpha particle source. The electrospray
      generated multiply charged ions undergo charge reduction in a "neutralization
      chamber" positioned before the entrance nozzle to the mass spectrometer. The ions
      are detected using a commercial orthogonal electrospray time-of-flight mass
      spectrometer, although the neutralization chamber can be adapted to virtually any
      mass analyzer. The CREMS results obtained exhibit a signal intensity drop-off
      with increasing oligonucleotide size similar to that observed with matrix
      assisted laser desorption/ionization mass spectrometry. Proton-transfer reactions
      were found to be responsible for reducing charge on proteins and oligonucleotides
      in both positive and negative ion mode.

PMID- 10655635
TI  - Direct plasma sample injection in multiple-component LC-MS-MS assays for high
      throughput pharmacokinetic screening.
AB  - The simultaneous dosing of numerous compounds followed by multiple-component
      analysis using LC-MS-MS (the N-in-1 approach) has significantly improved the
      throughput of the drug-screening process. However, plasma samples still need to
      be extracted before LC-MS-MS analysis, which frequently limits the throughput of
      the assay. In this work, a high-throughput on-line extraction technique has been
      developed for multiple-component LC-MS-MS assays using a high-flow column
      switching technique. In N-in-1 LC-MS-MS assays, high sensitivity is required
      since the dose level is generally reduced to minimize drug-drug interactions. In
      addition, good chromatographic separation is essential to minimize interference
      and suppression effects. The direct plasma sample injection method developed in
      this work has successfully met the two requirements for multiple-component LC-MS
      MS assays in high-throughput pharmacokinetic screening. Plasma samples containing
      a large number of potential drug candidates were directly injected onto an
      extraction column operated under a flow rate sufficiently high to exhibit a
      turbulent-flow profile. The extracted analytes were then eluted onto an
      analytical column via column switching for LC-MS-MS analysis. The use of
      turbulent flow resulted in a faster and more rugged extraction with reduced
      carryover compared with results obtained under laminar-flow conditions.
      Meanwhile, the use of a column-switching method maintained the chromatographic
      resolving power and high sensitivity of the LC-MS-MS assay. Separation
      efficiency, dynamic range, accuracy, and precision comparable with those of solid
      phase extraction have been achieved with the turbulent-flow column-switching
      technique. As a result, this technique has been successfully and routinely used
      for high-throughput pharmacokinetic screening.

PMID- 10655636
TI  - Direct TLC-MALDI coupling using a hybrid plate.
AB  - A new TLC-MALDI direct coupling method which recovers approximately 100% of the
      analyte is presented. The method makes use of a hybrid TLC-MALDI plate in which a
      silica layer and a MALDI layer are configured adjacently on a common backing.
      After TLC separation, the plate is rotated 90 degrees and the separated analyte
      spots are eluted from the silica layer to the MALDI layer via capillary action of
      the MALDI layer. Signal-to-noise ratios are significantly improved over
      previously reported coupling methods. Low-femtomole detection limits have been
      demonstrated for small cyclic peptides, which are comparable to detection limits
      for standard MALDI measurements.

PMID- 10655637
TI  - Capillary electrokinetic chromatography with charged linear polymers as a
      nonmicellar pseudostationary phase: determination of capacity factors and
      characterization by solvation parameters.
AB  - A permanent polycation, polydiallyldimethylammonium (PDADMA), is applied as a
      linear, polymeric, replaceable, and nonmicellar pseudostationary phase for the
      separation of neutral analytes by capillary electrokinetic chromatography. It is
      shown that this polymer used in the background electrolyte is able to separate
      the analytes even if it does not form micelles under the given conditions. The
      most favorable aspect for practical use lays in the simple replacement of the
      separation media after each run, thus generating highly reproducible conditions.
      To determine the capacity factors of the analytes, a new method, based on an
      isotachophoretic regime, has been introduced for the measurement of the
      electrophoretic mobility of the polymeric pseudo-stationary phase. The capacity
      factors in the separation system, derived from the mobilities of the polymer, the
      electroosmotic flow, and the mobilities of 15 individual aromatic analytes, range
      between 0.3 and 1.2 for the given separation media (aqueous solution of acetate
      buffer, pH 5.2, with 4% w/w PDADMA). The type of interaction in the
      pseudochromatographic system was clarified from solvation parameters based on the
      linear free energy relationship model. It was found that pi and n electron
      interactions and hydrogen-bond basicity of the polymer, as compared with the
      aqueous bulk phase, are the main cause of retention of the analytes.

PMID- 10655638
TI  - Electroosmosis- and pressure-driven chromatography in chips using continuous
      beds.
AB  - The application range of microchips can be extended to any mode of chromatography
      by filling the narrow channels with continuous polymer beds, exemplified by
      electrochromatography and ion-exchange chromatography. "Wall effects" are
      eliminated by anchoring the bed to the wall of the channel, an arrangement which
      has the additional advantage that no frits to support the bed are required. The
      design of the equipment is based on a quartz chip with all auxiliary pieces (for
      example, electrode vessels and fluid transfer fittings) placed in a rack, which
      permits a flexibility of great importance for automation. The same resolution and
      van Deemter plots were obtained in experiments performed in fused-silica
      capillaries and in chips for both low-molecular-weight (alkyl phenones,
      antidepressants) and high-molecular-weight substances (proteins). A sample of
      uracil, phenol, and benzyl alcohol was separated by electrochromatography in less
      than 20 s.

PMID- 10655639
TI  - Selectivity in capillary electrochromatography using native and single isomer
      anionic cyclodextrin reagents.
AB  - Separations of naphthalene compounds that differ in position of substitution and
      type of substituent were accomplished using cyclodextrin distribution capillary
      electrochromatography. Separation systems composed of running buffers containing
      mixtures of native neutral and single isomer anionic cyclodextrins (CDs) were
      employed yielding efficiencies of approximately 200,000 plates/meter. Solute
      migration rates and relative orders can be readily modified by changing CD types
      and concentrations. Experiments were performed to determine distribution
      coefficients between each of the CDs used in these studies and an aqueous running
      buffer. For this work, naphthalene-CD cavity inclusion is assumed to be the
      principal mode of interaction. The distribution coefficients for carboxymethyl
      beta-cyclodextrin (CM-beta-CD), degree of substitution 1, were 10-70% larger than
      those for native beta-CD and 75-1800% large than those for gamma-CD. The CM-beta
      CD was singly charged and yielded a narrow elution window. Nevertheless, baseline
      resolution was achieved for several substituted naphthalene compounds using CM
      beta-CD in conjunction with beta-CD or gamma-CD. Under certain conditions, the
      gamma-CD system yielded an elution order that differed from that of the beta-CD
      system. Heptakis-(2,3-dimethyl-6-sulfato)-beta-CD with its -7 charge produced a
      much larger elution window. The extensive substitution with sulfonic groups at
      the truncated bottom of the CD seemed to inhibit inclusion as the distribution
      coefficients for the naphthalene compounds were generally more than an order of
      magnitude smaller than those for CM-beta-CD. Moreover, there was evidence that
      this sulfato-CD interacted with both the capillary wall and neutral beta-CD. This
      work differs from prior uses of CDs in that relatively complicated mixtures of
      neutral, achiral compounds are separated using combinations of recently developed
      single-isomer CDs as running-buffer additives. The single-isomer CDs, as opposed
      to most highly complex derivatized CD products, facilitate predictions of
      separation performance for multicomponent samples. In this manner, the ability to
      use knowledge of distribution coefficients to predict elution characteristics for
      a ternary CD system is demonstrated.

PMID- 10655640
TI  - Ion chromatographic determination of acidity.
AB  - The practice of determining acid concentrations by titrations has remained
      unchanged for more than a century. We introduce a new approach to the
      determination of acid concentrations based on cation exchange chromatography. We
      demonstrate the ability of sulfonated styrene-divinylbenzene based stationary
      phases to separate the hydrogen ion from other monovalent cations. The eluent is
      a dilute solution of a neutral salt, sometimes containing a small concentration
      of the corresponding acid, e.g., sodium ethanesulfonate, pH adjusted with
      ethanesulfonic acid. The high equivalent conductance (approximately 350
      S.cm2/equiv) of H+ and relatively low eluent concentration allows sensitive
      conductometric detection of H+, down to the 50 microM level under favorable
      conditions. The conductometric response to H+ can be linear over a wide range of
      H+ concentrations, from sub-millimolar to several molar concentrations. The
      system allows the rapid quantitation of strong acids; weak acids can also be
      determined depending on pKa and injected concentration. The determinations of
      several strong and weak acids are presented along with factors that govern their
      chromatographic analysis.

PMID- 10655641
TI  - QSPR correlation and predictions of GC retention indexes for methyl-branched
      hydrocarbons produced by insects.
AB  - A successful interpretation of the complex manner by which the GC retention
      indexes of methylalkanes produced by insects are related to chemical structure
      was achieved using the quantitative structure-property relationship (QSPR)
      method. A general QSPR model including mainly topological descriptors was
      obtained for 178 data points. The error of the model is similar to the
      experimental error. The model was supported by (i) leave-one-out cross validation
      and (ii) division into three sets and prediction of each set from the other two.
      As a further test of the utility of the model, retention indexes were
      successfully predicted for an external set of 30 methyl-branched hydrocarbons not
      involved in the deduction of the correction equation from the main data set.
      General trends of the structural variation of compounds in any given range of
      retention index are discussed. The average error was 4.6 overall and 4.3 for the
      165 compounds remaining after leaving out small monomethyl alkanes.

PMID- 10655642
TI  - Adjusting selectivity in liquid chromatography by use of the thermally tuned
      tandem column concept.
AB  - In this study, we propose the novel "thermally tuned tandem column (T3C)" concept
      for the optimization of selectivity in LC by continuous adjustment of the
      stationary phase. Two columns with distinctly different chromatographic
      selectivities (e.g., polybutadiene- and carbon-coated zirconia) are serially
      coupled and independently temperature-controlled. Selectivity is "tuned" by
      adjusting the individual temperatures of the two columns. The effect of changing
      column temperature is quite analogous to changing the relative column lengths,
      thereby altering the relative and absolute contribution each column makes to the
      overall retention time in T3C. The distinct selectivity differences between
      polybutadiene- and carbon-coated zirconia as well as the extraordinary thermal
      stability of zirconia-based phases (thermally stable to 200 degrees C) allow us
      to tune the overall chromatographic selectivity over a very substantial range. We
      have developed a simplified useful model, which characterizes retention and
      selectivity for the T3C system as a function of the two column temperatures. The
      model is in good agreement with the experimental results. We also describe a
      simple computer-assisted optimization strategy based on the window diagram
      method, which facilitates the optimization of the T3C system with only four or
      five initial runs.

PMID- 10655643
TI  - Detection of the dipicolinic acid biomarker in Bacillus spores using Curie-point
      pyrolysis mass spectrometry and Fourier transform infrared spectroscopy.
AB  - Thirty-six strains of aerobic endospore-forming bacteria confirmed by polyphasic
      taxonomic methods to belong to Bacillus amyloliquefaciens, Bacillus cereus,
      Bacillus licheniformis, Bacillus megaterium, Bacillus subtilis (including
      Bacillus niger and Bacillus globigii), Bacillus sphaericus, and Brevi
      laterosporus were grown axenically on nutrient agar, and vegetative and
      sporulated biomasses were analyzed by Curie-point pyrolysis mass spectrometry
      (PyMS) and diffuse reflectance-absorbance Fourier-transform infrared spectroscopy
      (FT-IR). Chemometric methods based on rule induction and genetic programming were
      used to determine the physiological state (vegetative cells or spores) correctly,
      and these methods produced mathematical rules which could be simply interpreted
      in biochemical terms. For PyMS it was found that m/z 105 was characteristic and
      is a pyridine ketonium ion (C6H3ON+) obtained from the pyrolysis of dipicolinic
      acid (pyridine-2,6-dicarboxylic acid; DPA), a substance found in spores but not
      in vegetative cells; this was confirmed using pyrolysis-gas chromatography/mass
      spectrometry. In addition, a pyridine ring vibration at 1447-1439 cm-1 from DPA
      was found to be highly characteristic of spores in FT-IR analysis. Thus, although
      the original data sets recorded hundreds of spectral variables from whole cells
      simultaneously, a simple biomarker can be used for the rapid and unequivocal
      detection of spores of these organisms.

PMID- 10655644
TI  - Pentafluorinated probes for the X-ray photoelectron spectroscopic study of
      immobilized bifunctional silanes.
AB  - Bifunctional silanes constitute valuable linking agents for attachment of
      biomolecules at high levels of surface population density through the formation
      of thioether or disulfide bonds. Three such compounds, 1-((trifluoroacetyl)-thio)
      11-(trichlorosilyl)undecane, 1-bromo-11-(trichlorosilyl)undecane, and 1
      ((bromoacetyl)oxy)-11-(trichlorosilyl)undecane, are discussed in terms of their
      surface chemistry on silicon wafers. To examine the electrophilic and
      nucleophilic generation of sulfur-containing linkages, three new probes, N'
      (pentafluorophenyl)iodoacetohydrazide, N'-(pentafluorophenyl)-3-(2
      pyridylthio)propriono-hydrazide, and N'
      (pentafluorophenyl)mercaptoacetohydrazide, are introduced with respect to their
      reactions with silanized surfaces (studied by X-ray photoelectron spectroscopy).
      Thiol-functionalized surfaces obtained by silanization act as nucleophiles toward
      the probes. In air, low yields of conjugation are exhibited which are attributed
      to the unavailability of thiol groups because of intramolecular disulfide group
      formation instigated by oxygen or by disulfide exchange with the proprionyl
      probe. The behavior of electrophilic silanized surfaces toward the mercaptoacetyl
      containing probe is governed by the nature of the leaving group and by steric
      factors.

PMID- 10655645
TI  - A transparent tool for seemingly difficult calibrations: the parallel calibration
      method.
AB  - A new easy-to-understand calibration method for the analysis of spectral data is
      developed. The "parallel calibration" method is logically simple and intuitive
      yet often provides an improvement over more complex standard calibration methods.
      A description of the algorithm with a technical justification for the parallel
      algorithm is presented, underscoring the simplicity of the approach. In addition,
      performance as compared to that of the standard methods of classical least
      squares (CLS) and partial least-squares (PLS) regression is studied. Calibrations
      are carried out on a computer-generated simulation data set as well as two
      scientific data sets. The results show that the parallel method gives results
      comparable to or better than those of CLS and PLS methods in terms of mean
      squared error.

PMID- 10655646
TI  - Equivalent-circuit model for the thickness-shear mode resonator with a
      viscoelastic film near film resonance.
AB  - We derive a lumped-element, equivalent-circuit model for the thickness-shear mode
      (TSM) resonator with a viscoelastic film. This modified Butterworth-Van Dyke
      model includes in the motional branch a series LCR resonator, representing the
      quartz resonance, and a parallel LCR resonator, representing the film resonance.
      This model is valid in the vicinity of film resonance, which occurs when the
      acoustic phase shift across the film is an odd multiple of pi/2 rad. For low-loss
      films, this model accurately predicts the frequency changes and damping that
      arise at resonance and is a reasonable approximation away from resonance.
      Elements of the parallel LCR resonator are explicitly related to film properties
      and can be interpreted in terms of elastic energy storage and viscous power
      dissipation. The model leads to a simple graphical interpretation of the coupling
      between the quartz and film resonances and facilitates understanding of the
      resulting responses. These responses are compared with predictions from the
      transmission-line and Sauerbrey models.

PMID- 10655647
TI  - Protein redox potential measurements based on kinetic analysis with mediated
      continuous-flow column electrolytic spectroelectrochemical technique. Application
      to TTQ-containing methylamine dehydrogenase.
AB  - Kinetic determination of protein redox potentials with a mediated continuous-flow
      column electrolytic spectroelectrochemical technique (CFCESET) is described. In
      this method, the redox state of the mediator is completely regulated by the
      continuous-flow column electrolysis, and the homogeneous redox reaction between
      the mediator and a protein sample in the column is monitored spectroscopically at
      the downstream of the column. The protein/mediator reaction is in the pseudo
      first-order kinetics, and then the rate equation is analytically solved. The
      kinetic analysis provides the protein redox potential as well as the homogeneous
      rate constant. In the kinetic measurements, equilibration of the system within
      the column is not required, which allows the use of increased kinds of mediators.
      This method was successfully applied to quinoprotein methylamine dehydrogenase
      containing tryptophan tryptophylquinone (TTQ) as a prosthetic group. The kinetic
      aspect is also valuable for the thermodynamic analysis with the mediated CFCESET.
      The half-life time of the kinetics can be utilized to optimize the system for the
      attainment of the equilibrated state within the column and can provide the
      assurance that the system is in equilibrium.

PMID- 10655648
TI  - Polymeric membrane electrodes for monohydrogen phosphate and sulfate.
AB  - A zwitterionic bis(guanidinium) ionophore bearing an anionic closo-borane cluster
      (1) and a dihydrochloride analogue (2) are investigated in polymeric membrane ion
      selective electrodes (ISEs). Both compounds have been previously shown to complex
      and selectively extract oxoanions. By systematic variation of the kind and
      concentration of the ion-exchanger sites in the membrane, the optimal performance
      with the so far best sulfate selectivity is found for ISE membranes based on the
      dihydrochloride, whereas those with the zwitterion analogue are shown to possess
      a reasonably good selectivity for monohydrogen phosphate.

PMID- 10655649
TI  - Simultaneous determination and speciation of zinc, cadmium, lead, and copper in
      natural water with minimum handling and artifacts, by voltammetry on a gel
      integrated microelectrode array.
AB  - The paper reports a new approach based on a gel-integrated Hg-plated-Ir-based
      microelectrode array (GIME), for measuring Cu, Pb, Cd, and Zn speciation in
      natural waters. This paper focuses on the quantitative discrimination between
      mobile and colloidal metal species (size limit of a few nanometers), for which
      most classical separation techniques present severe drawbacks. Previous papers
      have shown qualitatively that GIME combined with square wave anodic stripping
      voltammetry (SWASV) has the basic characteristics required to discriminate
      between these two fractions directly on the unperturbed sample. In addition,
      because of the large sensitivity provided by GIME, complexation parameters
      (equilibrium constants and site concentrations) can be determined in little
      perturbed samples, particularly without metal addition or with small addition
      compared with natural concentrations. The advantages of this procedure are
      exemplified and the possible artifacts occurring when titrating the sample with
      metals, in particular intermetallic compound formation and other problems, are
      discussed in detail. The present paper shows that the characteristics of GIME
      make it a unique tool to get quantitative information on metal speciation at
      nanomolar or even subnanomolar levels, with only minor sample handling.

PMID- 10655650
TI  - Conditions for accurate Karl Fischer coulometry using diaphragm-free cells.
AB  - Factors influencing the extent of formation of oxidizable reduction products in
      coulometric cells used for Karl Fischer (KF) determination of water were
      investigated. For methanolic KF reagents buffered with imidazole (Im) or
      diethanolamine (DEA) (separately or in combination), three parameters were found
      to be of outmost importance: the cathodic current density, the pH, and the
      concentration of protonated base (ImH+ or DEAH+). For reagents buffered with only
      Im, the relative formation of oxidizable reduction products varied in the range 2
      40%; i.e., 51-70 micrograms of water was found for a 50 micrograms water sample,
      depending on the above-mentioned parameters. The lowest values were observed for
      reagents having a pH around 10 in combination with cathodic current densities in
      the range 2000-5000 mA cm-2. For all the Imbuffered reagents investigated, the
      addition of modifiers such as chloroform, hexanol, and carbon tetrachloride was
      found to decrease the formation of oxidizable reduction products significantly.
      For example, a reagent buffered at pH 10 containing 1 M hexanol gave less than
      0.3% formation in the current density interval from 200 to 4000 mA cm-2. The best
      reagents based on the above-mentioned modifiers were tested in the continuous
      coulometric mode with errors typically in the interval 0-0.5% using optimum
      conditions. One prerequisite for obtaining such small errors with diaphragm-free
      continuous coulometry is to use a cathode area no larger than 0.002 cm2. For some
      of the reagents based on both Im and DEA, the formation of oxidizable reduction
      products was close to zero at certain current densities, although the analytical
      performance was not as good as for the reagents buffered solely by Im due to
      longer conditioning and titration times.

PMID- 10655651
TI  - Flow injection monitoring and analysis of mixtures of hydrazine compounds using
      filter-supported bilayer lipid membranes with incorporated DNA.
AB  - This work describes a technique for the rapid and sensitive electrochemical flow
      injection monitoring and analysis of mixtures of hydrazine compounds using
      stabilized systems of filter-supported bilayer lipid membranes (BLMs) composed of
      egg phosphatidylcholine (egg PC) with incorporated DNA. Injections of hydrazines
      were made into flowing streams of a carrier electrolyte solution, and a transient
      current signal with a duration of seconds reproducibly appeared in less than one
      min after exposure of the DNA-modified lipid membranes to the hydrazines. The
      magnitude of this signal was linearly related to the concentration of hydrazines,
      which could be determined at sub-micromolar levels. Repetitive cycles of
      injection of hydrazines have shown no signal degradation during each cycle (30
      sequential injections). The time of appearance of the transient response was
      different for each hydrazine and increased in the order of hydrazine,
      methylhydrazine or dimethylhydrazine, and phenylhydrazine. The difference in time
      of response has allowed selective detection and analysis of these hydrazines in
      mixtures.

PMID- 10655652
TI  - Ceramic-based multisite microelectrodes for electrochemical recordings.
AB  - This paper describes the development and characterization of ceramic-based
      multisite arrays for electrochemical recordings in biological systems. These
      electrodes represent a parallel technology to the design of microelectrodes using
      silicon substrates. The ceramic substrates are stronger than silicon and are
      nonconducting, which makes them better suited for in vivo electrochemical
      measurements. The current designs are based on formation of four-site (50 x 50
      microns with 200 microns spacing) electrodes on ceramic wafers using
      photolithography. The recording sites and connecting lines are made of Pt with a
      polyimide coating to insulate the connecting lines. The resulting electrodes are
      cut from the wafers producing a 1 cm length microelectrode that tapers to a
      approximately 2-5 microns tip. Electrochemical measures of dopamine and hydrogen
      peroxide support that the sensitivity, selectivity, and response characteristics
      of the electrodes exceed those of previously published silicon substrate-based
      microelectrodes. This is the first demonstration of microarrays formed from
      ceramic substrates, and the data presented support the hypothesis that these
      microelectrodes may be useful for a variety of neurochemical and
      electrophysiological applications. Preliminary in vivo electrochemical recordings
      are presented.

PMID- 10655653
TI  - A microwave-induced plasma based on microstrip technology and its use for the
      atomic emission spectrometric determination of mercury with the aid of the cold
      vapor technique.
AB  - A new low-power, small-scale 2.45 GHz microwave plasma source at atmospheric
      pressure for atomic emission spectrometry based on microstrip technology is
      described. The MicroStrip Plasma (MSP) source was produced in microstrip
      technology on a fused-silica wafer and designed as an element-selective detector
      for miniaturized analytical applications. The electrodeless microwave-induced
      plasma (MIP) operates at microwave input power of 10-40 W and gas flows of 50
      1000 mL.min-1 of Ar. Rotational (OH) and excitation (Fe) temperatures were found
      to be 650 and 8000 K, respectively. Spatially resolved measurements of the Hg I
      253.7-nm atomic emission line with an electronic slitless spectrograph (ESS)
      showed that a cylindrically symmetric plasma with a diameter of about 1 mm is
      obtained. With the MSP, Hg could be determined by applying the flow injection
      cold vapor (FI-CV) technique with a detection limit of 50 pg.ml-1. In terms of
      the relative standard deviation, a time stability of < 1.4% for 45 replicates
      within 80 min can be realized at a concentration level of 10 ng.ml-1 of Hg. Hg
      could be determined in the leachate of a certified standard reference soil (STSD
      4) obtained by treatment with aqua regia at the 930 +/- 76 ng.g-1 level. Results
      obtained by calibration with aqueous solutions of Hg and with standard addition
      were found to be in good agreement with those of cold-vapor atomic absorption
      spectrometry.

PMID- 10655654
TI  - Quenching and enhancement of aroyl luminescence in excited nitrogen.
AB  - This study investigates both decreases and increases of aromatic carbonyl
      phosphorescence in excited nitrogen, i.e., in a gas-chromatographic device called
      the aroyl luminescence detector (ALD). The ALD responds, with nigh specificity,
      to subpicogram amounts of strongly phosphorescing aroyls. Aroyl response may,
      however, be quenched by coeluting peaks or gaseous impurities. This deleterious
      effect has been investigated with O2, H2, CH4, and C3H8 as model quenchers. Aroyl
      phosphorescence is more severely quenched than the nitrogen background, i.e., the
      so-called second-positive system, N2 (C 3 pi u)-->N2 (B 3 pi g). Oxygen, while
      being the strongest among the tested quenchers of aroyl phosphorescence, is the
      weakest quencher of nitrogen emission. The efficiency of various quenchers is
      similar for aroyl compounds of similar structure. It differs, however--though not
      by more than a factor of 2--among aroyls of different chemical types. In contrast
      to these intensity-reducing effects, aroyl phosphorescence is significantly
      enhanced by the addition of argon to (the carrier and excitation gas) nitrogen.
      It is proposed that the reaction sequence Ar*(3P0,2) + N2-->N2(C)*-->N2(B)* + hv-
      >N2(A)* + hv results in an increased yield of the metastable N2(A 3 sigma u+)
      state (this state being considered responsible for the n-->pi* excitation of
      aroyl compounds via an efficient triplet-triplet energy-transfer process).

PMID- 10655655
TI  - Precision trace gas analysis by FT-IR spectroscopy. 1. Simultaneous analysis of
      CO2, CH4, N2O, and CO in air.
AB  - We report the development of a method of trace gas analysis based on 1-cm-1
      resolution Fourier transform infrared (FT-IR) spectroscopy, deployable in both
      laboratory and field applications. Carbon dioxide, methane, nitrous oxide, and
      carbon monoxide may be analyzed simultaneously in a single air sample using this
      method. We have demonstrated that the method can provide analytical precision of
      the order of +/- 0.15 mumol mol-1 for CO2, +/- 0.9 nmol mol-1 for CH4, +/- 0.3
      nmol mol-1 for N2O, and +/- 0.3 nmol mol-1 for CO, expressed as mole fractions in
      dry air. The analytical precision is in all cases competitive with or superior to
      that of the more usual methods of analysis for these trace gases, namely,
      nondispersive infrared spectroscopy for CO2 and gas chromatography-based
      techniques for CH4, N2O, and CO. The novel FT-IR method relies on calibration
      using synthetically calculated absorbance spectra and a chemometric multivariate
      calibration algorithm, classical least squares.

PMID- 10655656
TI  - Precision trace gas analysis by FT-IR spectroscopy. 2. The 13C/12C isotope ratio
      of CO2.
AB  - We report the development of a method of carbon stable isotope ratio analysis
      based on 1-cm-1 resolution Fourier transform infrared (FT-IR) spectroscopy,
      deployable in both laboratory and field applications. We demonstrate the
      determination of the 13C/12C ratio of CO2 (i.e., delta 13CO2) in air with an
      analytical precision of the order of +/- 0.1/1000 (i.e., +/- 0.01%). The FT-IR
      method relies on calibration using synthetically calculated absorbance spectra
      and a multivariate calibration algorithm. The method requires no sample
      preparation other than optional drying of the sample and may be applied directly
      to ambient air samples containing approximately 350 mumol mol-1 CO2 (molar mixing
      ratio). It may also be applied to samples more concentrated in CO2, such as human
      breath, approximately 5% CO2. We demonstrate the utility of the technique to the
      analysis of delta 13CO2 in air during an experimental field campaign and to the
      laboratory-based analysis of human breath. A similar method could also be used to
      determine the H/D ratio in atmospheric water vapor.

PMID- 10655658
TI  - Effects of ethanol volume percent on fluorescein-labeled spinach apo- and
      holocalmodulin.
AB  - We report the effects of EtOH volume percent (0-70%) on spinach apo- and
      holocalmodulin that have been site-selectively labeled with fluorescein (F). In
      these experiments, calmodulin (CaM) has one F reporter group attached to Cys-26,
      and this site is located immediately adjacent to one of the four primary Ca(2+)
      binding sites (EF hands). The optimum analytical CaM-F sensitivity to Ca2+ occurs
      between approximately 10 and 30% EtOH. Our results also show that added EtOH
      causes changes in CaM and these changes are surprisingly different for apo- and
      holo-CaM. Apo-CaM-F appears to lose one of its two waters of hydration at
      approximately 20% EtOH and retains one water of hydration between approximately
      20 and 70% EtOH. In apo-CaM-F, the semiangle that describes the range over which
      the fluorescein reporter group can precess remains essentially constant (42 +/- 2
      degrees) between 0 and 70% EtOH. This shows that the fluorescein reporter group
      precessional freedom in apo-CaM-F is not affected significantly by EtOH. Holo-CaM
      F also appears to lose one water of hydration at approximately 20-30% EtOH but
      then appears to denature as the EtOH volume percent increases. The fluorescein
      reporter group semiangle within holo-CaM-F decreases from 43 +/- 1 degrees in
      neat aqueous buffer to 36 +/- 1 degrees at 70% EtOH. This shows that holo-CaM-F
      is less nativelike and the EF hand "closes down" about the fluorescein reporter
      group in holo-CaM-F as the EtOH volume percent increases.

PMID- 10655657
TI  - High-resolution multiwavelength surface plasmon resonance spectroscopy for
      probing conformational and electronic changes in redox proteins.
AB  - To date, surface plasmon resonance (SPR) spectroscopy identifies molecules via
      specific bindings with their ligands immobilized on a surface. We demonstrate
      here that a high-resolution multiwavelength SPR technique can measure the
      electronic states of the molecules and thus allow direct identification of the
      molecules. Using this new capability, we have studied the electronic and
      conformational differences between the oxidized and reduced states of cytochrome
      c immobilized on a modified gold electrode. When the wavelength of the incident
      light is far away from the optical absorption bands of the protein, a
      approximately 0.008 degree decrease in the resonance angle, due to a
      conformational change, occurs as the protein is switched from the oxidized to
      reduced states. When the wavelength is tuned to the absorption bands, the
      resonance angle oscillates at the wavelengths of the absorption peaks, which
      provides electronic signatures of the protein.

PMID- 10655659
TI  - Identification of dyes on ancient Chinese paper samples using the subtracted
      shifted Raman spectroscopy method.
AB  - The Stein Collection in the British Library contains the Diamond Sutra, the
      world's oldest, dated, printed document. The paper of the Diamond Sutra and other
      documents from the Stein collection is believed to be dyed yellow by a natural
      extract, called huangbo, from the bark of Phellodendron amurense, which contains
      three major yellow chromophores: berberine, palmatine, and jatrorrhizine.
      Conservation of these documents requires definite information on the chemical
      composition of the dyes but no suitable, completely noninvasive analytical method
      is known. Here we report resonance Raman studies of a series of pure dyes, of
      plant materials and extracts, and of dyed ancient and modern paper samples.
      Resonance Raman spectroscopy is used to enhance the spectra of the dyes over the
      signals from the paper matrixes in which they are held. The samples all give
      resonance Raman spectra which are dominated by intense fluorescence, but by using
      SSRS (subtracted shifted Raman spectroscopy) we have obtained reliable spectra of
      the pure dyes, native bark from the Phellodendron amurense, modern paper dyed
      with huangbo extracted from this bark, and ancient paper samples. For both
      ancient paper samples whose pigment bands were detected, the relative intensities
      of the bands due to berberine and palmatine suggest that the ancient paper is
      richer in berberine than its modern counterpart. This is the first nondestructive
      in situ method for detection of these pigments in manuscripts, and as such has
      considerable potential benefit for the treatment of irreplaceable documents that
      are believed to be dyed with huangbo but documents on which conservation work
      cannot proceed without definite identification of the chemical compounds that
      they contain.

PMID- 10655660
TI  - Beam injection flame furnace atomic absorption spectrometry: a new flame method.
AB  - A new flame method of atomic absorption spectrometry is described. The liquid
      sample to be analyzed is transported as a high-speed liquid jet into a heated
      tube which is positioned in an air/acetylene flame. The jet is generated by means
      of an HPLC pump which feeds a smooth jet nozzle having a diameter of 50 microns
      or smaller. After traveling a distance of 10 cm, the liquid jet enters a small
      sample introduction hole, impacts onto the opposite inner wall of the tube
      furnace, and immediately vaporizes (jet impact vaporization, JIV). Both the
      complete introduction of the entire sample and the extended residence time inside
      the absorption volume result in an improvement in power of detection from 6- to
      202-fold for 17 elements (Ag, As, Au, Bi, Cd, Cu, Hg, In, K, Pb, Pd, Rb, Sb, Se,
      Te, Tl, Zn). A standard deviation of 1.7-4.0% (n = 12, 50 microL) was achieved.
      Sample volumes between 10 microL and 1 mL have been investigated. For 50 microL
      sample volumes, the sampling frequency is 4/min. The new method can also be
      considered a simple, effective interface between HPLC and flame AAS.

PMID- 10655661
TI  - Detection of sodium and potassium in single human red blood cells by 193-nm laser
      ablative sampling: a feasibility demonstration.
AB  - The feasibility of quantifying sodium and potassium in single human erythrocytes
      was demonstrated by spectrochemical analysis of emissions from plasmas produced
      by 193-nm laser ablation of blood cells confined in a sheath flow. In one scheme,
      single blood cells that happened to be in the ablation volume were sampled. In
      another scheme, individual blood cells were first sighted and then synchronously
      ablated downstream. Plasma emission spectra of single ablated cells were
      captured, and the ratios of the analyte line intensity to the root-mean-square
      fluctuation of the continuum background were measured to be about 18 for sodium
      and 30 for potassium.

PMID- 10655662
TI  - A rotating ball inlet for on-line MALDI mass spectrometry.
AB  - The rotating ball inlet (ROBIN) is presented in a new design for on-line matrix
      assisted laser desorption/ionization (MALDI) mass spectrometry (MS). This method
      uses a capillary to deliver a matrix and analyte solution to the surface of a
      rotating ball upon which MALDI is carried out. The ball is in contact with a
      polymer gasket surrounding the capillary. Sample adhering to the surface of the
      ball is dragged past the gasket into the vacuum of the mass spectrometer where it
      is irradiated by a pulsed UV laser, and the resulting ions are mass-separated in
      a linear time-of-flight mass spectrometer. The mechanical sample introduction
      prevents clogging of the vacuum interface by matrix crystals or frozen solvent.
      Preliminary results from flow injection analysis (FIA) suggest that the new
      interface does not introduce a significant peak-tailing or memory effect. The
      system is capable of 20-30 h of continuous operation with a flow rate of 2
      microL/min before cleaning of the ball is needed. With the prototype inlet,
      concentration detection limits are at the low micromolar level.

PMID- 10655663
TI  - Determination of the compositional distribution of copolymers by frontal analysis
      continuous capillary electrophoresis.
AB  - Frontal analysis continuous capillary electrophoresis (FACCE) was carried out for
      a series of random copolymers of an ionic monomer, sodium 2-(acrylamido)-2
      methylpropanesulfonate (AMPS), and a nonionic monomer, acrylamide (AAM). The
      electropherograms appeared in order of anionic content and were generally
      sigmoidal, in contrast to that of hyaluronic acid (HA), which was abrupt and
      discontinuous. This difference could be related to the compositional
      heterogeneity of the copolymers, completely absent in the biopolymer. Through the
      range of copolymer composition (10-100% AMPS) the relationship between average
      mobility and nominal AMPS content could be described by a calibration curve,
      making it possible to deduce the compositional distribution of copolymer samples.

PMID- 10655664
TI  - [Physiological function of peroxisome proliferator-activated receptor].

PMID- 10655665
TI  - Incidence of histamine release after the administration of midazolam-ketamine in
      allergic patients.
AB  - OBJECTIVE: We examined the effects of midazolam-ketamine which was used during
      the induction of anesthesia against histamine release, skin reactions and
      hemodynamic changes in patients with a history of allergy. SUBJECTS: Forty
      allergic patients and 40 non-allergic patients undergoing oral surgery were
      examined. METHODS: Midazolam ketamine was used for the induction of anesthesia in
      40 patients with a history of allergy (M-K group) and thiamylal was used for the
      induction of anesthesia in 40 patients without any history of allergy (BARB
      group). Venous blood samples were obtained before induction as a control and 0.5,
      1, 3, 5 minutes after the administration of each drug in order to measure the
      plasma histamine level. In addition, any observed hemodynamic changes were
      simultaneously recorded. The plasma histamine level was measured using the HPLC
      (high performance liquid chromatography) post-label system. RESULTS: The
      incidence of histamine release, skin reactions and hemodynamic changes were
      37.5%, 10.0% and 7.5%, in the M-K group, and 40.0%, 12.5% and 12.5%, in the BARB
      group, respectively. Although the mean basal plasma histamine level in the M-K
      group (0.46 +/- 0.23 ng/ml) who had a history of allergy was much higher than
      that in the BARB group (0.28 +/- 0.17 ng/ml) (p < 0.001), the incidence of
      histamine release and clinical symptoms were similar between the two groups.
      CONCLUSIONS: The induction of anesthesia with midazolam-ketamine was thus found
      to be a valuable method for allergic patients, because the incidence of histamine
      release, skin reactions and hemodynamic changes in allergic patients were similar
      to those in non-allergic patients induced by thiamylal and no significant changes
      were observed in the plasma histamine level after the administration of midazolam
      ketamine in spite of the high level of basal plasma histamine.

PMID- 10655666
TI  - The basal plasma histamine level and eosinophil count in allergic and non
      allergic patients.
AB  - OBJECTIVE: The basal plasma histamine level and eosinophil count in the
      peripheral blood in patients with a history of allergy (allergic patients) were
      examined and compared with those in patients without any history of allergy (non
      allergic patients). SUBJECTS: We preoperatively examined 70 allergic patients and
      70 non-allergic patients who were all scheduled to undergo oral surgery. METHODS:
      The basal plasma histamine level and eosinophil count in the peripheral blood
      were measured preoperatively. The high performance liquid chromatography (HPLC)
      post label system was used to measure the plasma histamine level. RESULTS: The
      mean basal plasma histamine level in non-allergic patients and allergic patients
      were 0.31 +/- 0.27 ng/ml and 0.47 +/- 0.30 ng/ml, respectively (p < 0.01). The
      mean eosinophil counts in non-allergic patients and allergic patients were 3.3 +/
      3.0% and 5.3 +/- 3.4%, respectively (p < 0.01). The patients who had asthma,
      atopic dermatitis or a food-induced allergy showed a high level of basal plasma
      histamine compared to that in non-allergic patients. The patients with asthma,
      allergic rhinitis or atopic dermatitis all demonstrated a higher eosinophil count
      than non-allergic patients. In addition, the correlation between the plasma
      histamine level and the eosinophil count was statistically significant (p <
      0.05). CONCLUSIONS: The allergic patients had both higher basal plasma histamine
      levels and eosinophil counts than non-allergic patients (p < 0.01).

PMID- 10655667
TI  - Long-term treatment of portosystemic encephalopathy with oral branched-chain
      amino acids--a case report.
AB  - We treated a 68-year-old male patient of hepatic encephalopathy with oral
      branched chain amino acids-enriched formula (Aminoleban EN) in addition to
      lactulose. His encephalopathy was successfully controlled with this therapy for
      more than a year despite the high blood ammonia levels. Repeated amino acids
      analyses demonstrated that the deranged branched chain to aromatic amino acids
      ratio was attenuated with long-term Aminoleban EN administration both in plasma
      and in cerebrospinal fluid. Oral branched-chain amino acid supplement was very
      useful in improving the chronic portosystemic or hepatic encephalopathy in this
      patient.

PMID- 10655668
TI  - The specialty of neuroimaging in neurology: a counter revolution in Europe?

PMID- 10655669
TI  - [What is your diagnosis? Cholesterol granuloma or cholesterol cyst].

PMID- 10655670
TI  - [What is your diagnosis? Idiopathic hypertrophic pachymeningitis].

PMID- 10655671
TI  - Atlas of brain proton magnetic resonance spectra. Part III: Viral infections.

PMID- 10655672
TI  - Rathke's cleft cysts: surgical-MRI correlation in 16 symptomatic cases.
AB  - Rathke's cleft cysts (RCCs) are non neoplastic epithelial lesions of the sellar
      region that have been rarely reported as a clinical entity. We retrospectively
      reviewed the magnetic resonance imaging (MRI), intraoperative, and pathological
      findings of a series of 16 cases of RCCs operated at our institution since 1992.
      Concurrently, we discussed the different hypotheses about their embryological
      origin. The patients included 12 females and 4 males, 11 to 73 years of age.
      Endocrine disturbance was the most common presentation, followed by headaches and
      visual impairment. The location of the cyst was intrasellar in 7 cases,
      intrasellar and suprasellar in 6 cases, and suprasellar in 3 cases. The size of
      the cyst ranged from 8 to 26 mm (mean 12 mm). MRI signal intensity was quite
      variable on T1-weighted images. The cyst appeared hyperintense in 6 cases,
      hypointense in 6 cases, isointence in 3 cases, and heterogeneous in one case. On
      T2-weighted images (available in 13 cases), the signal intensity was more
      constant and appeared hyperintense in 11 cases and hypointense in 2 cases. After
      Gd-DTPA, we did not observe enhancement either of the cyst contents or of the
      cyst wall, but only of the pituitary gland in all patient. Most often, the
      pituitary gland was displaced inferiorly by the cyst located above showing a
      typical image of "an egg in a cup". Fifteen patients were operated upon via the
      transsphenoidal approach and one upon a frontal craniotomy. Intraoperatively, the
      cyst contents were gelatinous or thick, and dark colored. In 2 cases, it was
      cerebrospinal fluid-like corresponding to the signal observed on MRI. The
      position of the pituitary gland confirmed by surgery in 15 cases coincided with
      enhancement seen and MR imaging. In 13 cases where biopsy of the cyst wall was
      performed, it confirmed focally ciliated columnar or cuboid epithelium. A
      coexistent adenoma was found in one case. In conclusion, we consider that RCCs
      have varied MRI characteristics so that no pathognomonic sign may be observed.
      Except in few cases, there were no correlation between MRI and intraoperative
      findings. Therefore, even with MRI studies, differential diagnoses with others
      cystic lesions of the sellar region remains extremely difficult. The most
      interesting findings on MRI studies of RCCs were to locate the pituitary gland to
      help the surgeon to preserve pituitary tissue during surgery.

PMID- 10655673
TI  - [Tuberculosis of the central nervous system. MRI features and clinical course in
      12 cases].
AB  - OBJECTIVE: The aim of this study was to characterize the MR findings of various
      intracranial lesions in the central nervous system (CNS) tuberculosis. MATERIALS
      AND METHODS: The MRI findings (T1, T2 and T1 sequence after contrast) of 12
      proved cases (10 males, 2 females, 24 to 64 years old, average: 35) of CNS
      tuberculosis were reviewed; 4 patients were seropositive for HIV. RESULTS:
      Several types of lesions were identified: tuberculomas called miliary lesions if
      they were smaller than 2 mm in diameter (7 cases), in 1 case the tuberculoma was
      revealed by two large lesions and bi-hemispheric localisations, leptomeningitis
      (5 cases), infarction (4 cases), abscesses (3 cases with solitary lesions in 2/3
      cases), hydrocephalus (3 cases), pachymeningitis (2 cases). A tuberculomas
      leptomeningitis association was found in 4 patients. The pachymeningitis form had
      an unusual aspect in one case. Patients with leptomeningitis showed thick
      meningeal contrast enhancement involving all basal cisterns, expanding to the
      sylvian fissures level, and causing narrowing of the sylvian arteries. Massive
      infarctions resulted from arterial englobement or embols. In three out of five
      patients, leptomeningitis was the initial presentation. In seropositive patients,
      tuberculosis was severe with high mortality (3/4 patients), and associated with
      other multiple lesions. CONCLUSION: Central nervous system tuberculosis has
      different appearances, mostly tuberculomas and leptomeningitis. MR with contrast
      is necessary for follow-up during treatment.

PMID- 10655674
TI  - CT and MRI findings in primitive pituitary abscess: a case report and review of
      literature.
AB  - Pituitary abscess is not rare. Clinical and radiological features in a primitive
      pituitary abscess are reported. Transphenoidal surgery revealed an abscess.
      Preoperative diagnosis of pituitary abscess remains difficult. Sellar round
      cystic mass isointense to grey matter on T1, high intensity signal on T2, with a
      peripheral rim enhancement following gadolinium injection associated with
      thickened stalk and diabetes insipidus may be suggestive of pituitary abscess.

PMID- 10655675
TI  - [Ischemic vascular accidents in the acute phase].

PMID- 10655676
TI  - [Chlamydia pneumoniae infection and Mycoplasma pneumoniae infection in pediatric
      patients].
AB  - We evaluated a total of 1104 pediatric patients with acute lower respiratory
      tract infection for C. pneumoniae infection and M. pneumoniae infection by
      serology during July 1995 to December 1998. A microimmunofluorescence test was
      used for diagnosis of C. pneumoniae infection and a high density particle
      agglutination test for that of M. pneumoniae infection. Acute C. pneumoniae
      infection was found in 149 patients (13.5%), acute M. pneumoniae infection in 118
      patients (10.7%), and dual infection in 27 patients (2.4%). Among 305 patients
      with pneumonia, M. pneumoniae infection (83 patients, 27.2%) was more common than
      C. pneumoniae infection (47 patients, 15.4%). However among 799 patients with
      bronchitis. C. pneumoniae infection (102 patients, 12.8%) was more common than M.
      pneumoniae infection (35 patients, 4.4%). Patients with C. pneumoniae infection
      were more younger and more frequently wheezing than patients with M. pneumoniae
      infection. These findings demonstrate that C. pneumoniae infection in very common
      pathogen of pediatric lower respiratory tract infection as M. pneumoniae
      infection in Japan.

PMID- 10655677
TI  - [Kinetic analysis of anti-HIV titer in early stage of HIV infection--a new
      testing strategy to differentiate early HIV infection individuals from false
      positive cases].
AB  - We analyzed the anti-HIV antibody titer by particle agglutination (PA) on 11 HIV
      seroconversion panels. PA titer increased very rapidly and the titer went up to
      1,000 or more within 18.2 days after seroconversion. The results suggest that one
      to two weeks of duration will be enough to differentiate persons at the early
      stage of HIV infection from individuals with HIV screening test initially
      reactive but false positive. In Japan, HIV prevalence is very low and the
      majority of the HIV screening test-positive (reactive) cases turned out to be
      false positive. This HIV testing strategy (one to two weeks interval bleeding)
      will be very practical and useful to differentiate early stage of HIV infection
      cases from the majority of false positive cases.

PMID- 10655678
TI  - [Resistance against oral antibiotics to Streptococcus pneumoniae isolated from
      adult respiratory tract infections].
AB  - The resistance against oral antibiotics to Streptococcus pneumoniae (S.
      pneumoniae) isolated from adult patients with respiratory tract infections in the
      Kurume area in 1998 was studied. The frequency of resistant strains, which were
      isolated penicillin-intermediate S. pneumoniae and resistant S. pneumoniae (PISP,
      PRSP) were both 41.2%. We examined the minimal inhibitory concentrations (MIC) of
      oral antibiotics and the susceptibility ratio of the strains for the drugs based
      on the breakpoint MIC. The breakpoint MIC of pneumonia against oral beta-lactam
      antibiotics to PISP, PRSP, which were determined by Japan Society of
      Chemotherapy, were high in the order of FRPM > CDTR, CFPN > CFTM > CFDN, CPDX. In
      the case of the new oral quinolones, DU6859a > SPFX > LVFX > CPFX showed good
      results, in this order, DU6859a showed the most significant inhibitory effect to
      PISP, PRSP (MIC90 0.06 microgram/ml). By serotyping the percentage of 19, 6, 23
      was 42.9%, 21.4% and 14.3%.

PMID- 10655679
TI  - [Analysis of prevalent Orientia tsutsugamushi in Aichi Prefecture].
AB  - Orientia tsutsugamushi was isolated from one of 8 patients' sera in Aichi
      Prefecture, and was identified to have the same antigenicity with the KN-2 strain
      (KN-2 like) based on the reactivity with 13 types of strain-specific or cross
      reactive monoclonal antibodies to Karp, Gilliam, and Kato strains. Four isolates
      from 4 unfed larvae and adult of Leptotrombidium pallidum were also classified as
      the KN-3 like strains. Using indirect immunofluorescence, sera from 20 patients
      with tsutsugamushi disease were tested for reactivity with KN-1, KN-2, KN-3, and
      GJ-1 strains, isolated from patients in Gifu Prefecture. Fifteen sera showed the
      highest titer against KN-2 strain in Immunogloburin M (IgM). Of the other 5,
      three were higher for KN-3 strain in IgM, and two were KN-1 or GJ-1,
      respectively. These results suggested that KN-2 like strains were prevalent in
      the region where the number of patients has been ranked the highest in Aichi
      Prefecture. KN-1, KN-3, and GJ-1 like strains were also existed in this area. KN
      3 like strain was likely to be distributed in another area. Aichi Prefecture.

PMID- 10655680
TI  - [Evaluation of an optical immunoassay test for rapid detection of influenza A and
      B viral antigen].
AB  - An optical immunoassay test, FLU OIA (BIOSTAR, USA), was evaluated for the
      diagnosis of influenza viral infection. The reactivity of the FLU OIA test was
      evaluated using 42 influenza strains (25 human influenza A, 12 human influenza B,
      2 swine influenza A and 3 avian influenza A strains). The FLU OIA test showed
      positive results for all influenza strains. There was no evidence that cross
      reactivity occurred with non-influenza viruses. The detection limit of the FLU
      OIA test was found to be 3.0-6.5 x 10(4) pfu/assay for human influenza A and B
      strains. The sensitivity and specificity of the FLU OIA test compared to
      isolation in cell culture was 89.7% and 76.0% for testing of 54 nasopharyngeal
      aspirate specimens. The FLU OIA test is rapid and easy for the detection of
      influenza A and B viral antigen and provide a valuable tool for the rapid
      diagnosis of influenza viral infection.

PMID- 10655681
TI  - [Steroid pulse therapy and vital prognosis among pediatric cancer patients with
      sepsis].
AB  - The usefulness of glucocorticosteroid therapy in patients with sepsis has been
      controversial. We investigated the effect of steroid pulse therapy on the vital
      prognosis of pediatric patients with sepsis and followed the vital status up to
      one month after the use of pulse therapy. We reviewed the medical records of 89
      pediatric cancer patients with sepsis treated at our hospital between 1988 and
      1996. The risks of potential predictors were estimated by calculating crude and
      adjusted relative risk (RR). The total cumulative death was 33/89 (25%). All
      patients treated with steroid pulse therapy died (12/12). Patients with either
      interstitial pneumonia (IP), infection-associated hemophagocytic syndrome (IAHS)
      and graft-versus-host disease (GVHD) showed a significantly higher cumulative
      death (57% (12/21) vs 31% (21/68), p = 0.03). Increased risk of cumulative death
      was suggested for the older age group, inappropriate antimicrobial therapy, and
      the conditions requiring steroid pulse therapy (IP, IAHS, and GVHD), (crude RR
      were 1.6, 1.6, and 1.9, respectively). However, when adjusted for pulse therapy,
      these three factors no longer indicated risk elevation, (adjusted RR = 1.2, 1.2,
      and 0.3, respectively). On the other hand, steroid pulse therapy per se was
      independently associated with increased risk of cumulative death (crude RR = 3.6,
      adjusted RR = 10). Thus, the risk of the conditions requiring steroid pulse
      therapy (IP, IAHS, and GVHD) firstly observed could be regarded as an apparent
      association due to steroid pulse therapy.

PMID- 10655682
TI  - [Incidence of Salmonella serovar Hadar from sporadic cases in Tokyo, and drug
      resistance of isolates].
AB  - A total of 780 Salmonella serovar Hadar (S. Hadar) strains consisting of 601
      domestic strains and 179 imported strains isolated in Tokyo, 1980-1998, were
      examined regarding their incidence and drug-resistance. Domestic strains
      accounted for 7.2% of all Salmonella (8,359 strains) isolated from domestic
      cases, and imported strains accounted for 4.4% of all Salmonella (4,083 strains)
      isolated from imported cases. A drug-resistance test using 9 drugs (CP, TC, SM,
      KM, ABPC, ST, NA, FOR, and NFLX) showed that 586 strains (97.6%) of the domestic
      strains and 175 strains (97.8%) of the imported strains were resistant to some of
      the drugs, excluding NFLX. Drugs with a high resistance rate were TC and SM for
      both groups. Drug-resistance patterns of the resistant strains varied among the
      24 types. Among those, prevalent patterns recognized were TC.SM.KM (231 strains),
      TC.SM (205 strains), and TC.SM.KM.ABPC (65 strains) in the domestic strains, and
      TC.SM (135 strains) and TC (13 strains) in the imported strains.

PMID- 10655683
TI  - [Relationship between epidemiological data of adenovirus type 7 in Kawasaki City
      and restriction enzyme assay pattern of the virus].
AB  - Since April 1995 increased number of type 7 were isolated in Japan and also in
      Kawasaki city. From May 1996 to March 1999, Adenovirus type 7 (Ad7) were isolated
      from 49 patients with high body temperature, and longer febrile period were
      observed in infants and younger children. Lower respiratory tract infection
      occurred and a young child developed fatal pneumonia. Ad7 were isolated not only
      in summer but in winter. They were prevalent all season. We analyzed 27 strains
      of Ad7 genetically using restriction enzyme and compared the results with
      epidemiological and clinical data. Consequently we can not found any difference
      in genetic pattern between these Ad7 regardless of age or symptom. The pattern
      was all the same as Ad7d that of already issued in Japan.

PMID- 10655684
TI  - [A clinical evaluation of the new laboratory method that diagnoses bacterial
      infection, using silkworm larvae plasma].
AB  - Based upon the phenomenon that the peptidoglycan, a common component of Gram
      positive and negative bacteria, reacts specifically with silkworm larvae plasma
      (SLP), a new laboratory method named "SLP test" was developed to measure the
      reaction products in plasma quantitatively as SLP. This SLP test seems to be able
      to diagnose both Gram positive and negative bacterial infection. So we evaluated
      its usefulness in diagnosing clinical infectious diseases. This study included 14
      patients with result to positive bacterial blood culture, 22 patients with
      bacterial local infection, 7 patients without any evidence of bacterial
      infection, and 19 healthy volunteers. It seemed that the cut-off value of this
      SLP test should be set at 0.6 ng/ml. The sensitivity and specificity of this SLP
      test were 57.1%, 100%, respectively. A significant difference was not detected
      statistically between SLP values of patients with Gram positive and Gram negative
      bacterial infectious diseases. So the SLP test did not appeared specific to
      either Gram positive or Gram negative bacteria. This test may become a new method
      diagnosing bacterial infectious disease.

PMID- 10655685
TI  - [A case of acquired immunodeficiency syndrome (AIDS) with histoplasmosis].
AB  - Fungal infection is a major opportunistic infection in AIDS. Histoplasmosis is
      often seen in American AIDS, but only one case has been reported in Japan. We
      report a AIDS case of with histoplasmosis in Japan. The patient was a forty year
      old male living in the U.S from 1987 to 1990. He was diagnosed as candidial
      esophagitis in July, 1994, and human immunodeficiency virus type 1 (HIV) antibody
      positive led to a diagnosis of AIDS. He was admitted to our hospital with fever
      and lymphadenopathy (neck, abdomen) in August. The therapy for candidial
      esophagitis was successful and he was recovering, but he was newly diagnosed as
      atypical mycobacteriosis and Kaposi's sarcoma. Though the fever was slight, it
      persisted. He was discharged from our hospital in October. He was readmitted for
      a high fever and dehydration in December, but died after a week from disseminated
      intravascular coagulation (DIC). Histoplasma capsulatum was found by blood and
      ascites cultures on second admission. Many yeast like histoplasma cells in
      granuloma of the liver were found at autopsy. For moderate or severe
      histoplasmosis, amphotericin B is generally used as the first induction therapy.
      Fluconazole (FLCZ) is used as a maintenance therapy. We did not use amphotericin
      B, but used FLCZ because we did not diagnose histoplasmosis before death, and his
      general condition became worse. The effect of FLCZ therapy was unclear in our
      case because he had other infections. We expect that AIDS with histoplasimosis
      will increase in Japan through HIV infected patients infected in the U.S.A.

PMID- 10655686
TI  - [Fatal lactic acidosis in a patient with acquired immunodeficiency syndrome
      treated with stavudine, lamivudine and indinavir].
AB  - Recently, several class-related adverse events have been recognized with
      antiretroviral drugs. For nucleoside analogue reverse transcriptase inhibitors.
      (NRTI), lactic acidosis with hepatomegaly and hepatic steatosis have been
      reported. These appear to occur at a low frequency, but with a high fatality
      rate. We report a case of fatal lactic acidosis in a patient with acquired
      immunodeficiency syndrome (AIDS) treated with stavudine (d4T), lamivudine (3TC)
      and indinavir (IDV). A 48-year-old male AIDS patient was admitted with complaints
      of general fatigue and dyspnea. His medications at presentation included d4T, 3TC
      and IDV. Physical examination demonstrated icteric sclerae and abdominal
      tenderness with hepatomegaly. Laboratory data demonstrated a severe metabolic
      acidosis with an anion gap due to lactate accumulation. Despite intensive
      treatment, cardiorespiratory arrest occurred and this could not be resuscitated.

PMID- 10655687
TI  - Two patients with acute Q fever.

PMID- 10655688
TI  - Seroprevalence of Bartonella henselae among HIV-1 infected patients in Japan.

PMID- 10655689
TI  - [Change on chest CT findings of "primary infection of pulmonary Mycobacterium
      avium complex"].
AB  - We reviewed the chest CT findings of 15 patients with "primary infection of
      Mycobacterium avium complex". All of them were female and the average age of them
      was 64.9 years old. They received no or only insufficient therapy. Comparing the
      chest CT findings followed up for the average of 60.9 months interval, only three
      patients showed clear progression. All of the cases with less than three lobes
      involved at the onset unchanged or improved. On the radiographic features at the
      onset, small nodulousor infiltrative shadows were seen in all patients, and
      bronchiectasis in three patients. Cavity was not seen. The lesions of 12 patients
      were located in the right upper lobe, 13 patients in the right middle lobe and 14
      patients in the left lingula. Mild and limited cases may have potential with no
      or very slow progression, and case by case selective treatment should be
      considered.

PMID- 10655690
TI  - [An outbreak of Mycobacterium tuberculosis infection among young adults in close
      contact].
AB  - We experienced an outbreak of tuberculosis among young adults in close contact.
      The index case (case 1) was 22-year-old builder and was symptomatic for 9 months
      before diagnosis as pulmonary tuberculosis (PTB). His sputum smear was positive
      for tubercle bacilli. On immediate family contacts examination carried out at our
      hospital, his brother and sister (case 3, case 4) were detected as having PTB.
      His mother (case 5) and father (case 6) were later detected as having PTB by
      their symptomatic visits after some months, as tuberculin test as not done at
      first examination. Case 7 was 19-year-old-man, and was undiagnosed for 5 months.
      His sputum smear was positive. Immediately, contacts examination for case 7 as
      carried out at our hospital, and his colleague (case 8) was detected as having
      PTB. By interview with the case 7, it was found that the case 1 and the case 7
      were close friends and spent long time together. Case 10 was 30-year-old builder,
      and he was accidentally referred to our hospital and was diagnosed as PTB. By the
      interview with the case 10, it was found that the case 1 and case 10 were members
      of builders group. This fact was informed to the F health center, and contacts
      examination for other members of the group were carried out by the F health
      center, and two young men were detected as having PTB. Analysis of restriction
      fragment length polymorphism (RFLP) showed that the case 1, the case 5, the case
      7, and the case 10 were caused by the same strain of M. tuberculosis. Based on
      these findings, it is highly suspected that this outbreak was origined from the
      case 1, and 13 developed tuberculosis and 13 were primarily infected among
      contacts. The characteristics of this outbreak was that the family and contacts
      examination were enforced and most of the cases were detected at our hospital. If
      the outbreak of tuberculosis highly suspected, physicians should actively
      cooperate with health centers for contacts examination.

PMID- 10655691
TI  - [An epidemiologic study on the incidence rate of tuberculosis in Tochigi
      Prefecture].
AB  - The purpose of the study is to clarify chronological changes and the regional
      difference of the incidence of tuberculosis in Tochigi Prefecture. The difference
      between the first period (1980-1984) and the second period (1990-1994) was
      analyzed. The results are as follows; 1. The decrease of incidence in the age
      groups of 20-29 years and over 70 years slowed down in all types of tuberculosis
      and infectious pulmonary tuberculosis. 2. The incidence of tuberculosis in the
      southern part of Tochigi Prefecture was higher than in the other parts, and this
      could be explained by the fact that the people in the southern part were exposed
      heavier to tuberculosis infection in the past than the people in other parts. 3.
      In the public health center areas where the incidence rate of tuberculosis was
      high, the slow decline or even increase of the incidence rate among age groups
      less than 30 years and over 70 years of age was observed and this seemed to
      affect the higher incidence in these areas.

PMID- 10655692
TI  - [Outbreak of tuberculosis among middle aged employees in an office].
AB  - We experienced an outbreak of tuberculosis in a salesmen's office during the
      period from 1993 to 1997. The outbreak was detected retrospectively. In July,
      1997, a 47-year-old man was diagnosed as pulmonary tuberculosis. As he worked
      with a 42-year-old man who was already registered in our health center, we
      suspected an outbreak and started a survey. Contact examinations were carried out
      for 9 employees of his office and 3 members of his friends. As the result of
      these examinations, one employee showed strongly positive tuberculin skin test,
      and was indicated isoniazid chemoprophylaxis. Furthermore, some contacts told us
      that seven cases of active tuberculosis and three cases of primary infection
      indicated chemoprophylaxis had occurred among employees and their family members.
      The index case was a 41-year-old man who was diagnosed as tuberculosis in
      January, 1993. The second case among employees had previous history of pulmonary
      tuberculosis. Almost the patients among the employees had a hard life suffering
      from debts, and had heavy alcohol use. These facts may partly explain the spread
      of tuberculosis in this office. As each case was registered at different health
      centers, we hadn't noticed the outbreak for 4 years. But it is true that
      insufficient approach of health centers to contacts caused a serious delay of
      detecting the outbreak. A thorough investigation for contacts and complete
      contact examinations are needed.

PMID- 10655693
TI  - [Effects of INH (Isoniazid) inhalation in patients with endobronchial
      tuberculosis (EBTB)].
AB  - The effects of INH (Isoniazid) inhalation on clinical findings were studied
      retrospectively in 39 patients with endobronchial tuberculosis (EBTB). The
      diagnosis of EBTB and the assessment of bronchial stenosis were based on
      bronchoscopic examination. We divided the patients in two groups: 13 patients had
      been treated with only systemic chemotherapy of lung tuberculosis, and 26
      patients had been treated with systemic chemotherapy and INH inhalation (INH 200
      mg/day). As a result, there were no significant differences between both groups
      for duration of sputum culture positive and until ESR normalization. However, a
      significant improvement in bronchial stenosis and reduction of respiratory
      symptoms were seen in patients treated with systemic chemotherapy and INH
      inhalation. In conclusion, INH inhalation in addition to standard chemotherapy of
      lung tuberculosis is useful to prevent bronchial stenosis for the patients with
      EBTB.

PMID- 10655694
TI  - [Aerosolized therapy with streptomycin and steroids in treatment of bronchial
      stenosis due to endobronchial tuberculosis].
AB  - We had reported that aerosolized therapy with streptomycin and steroids is useful
      for ulcerative EBTB. However, the effectiveness of this therapy for bronchial
      stenosis has yet to be clarified. This study was undertaken to determine the
      effectiveness of aerosolized streptomycin and steroids in the treatment of
      bronchial stenosis due to EBTB. We performed flexible bronchoscopy in 64 patients
      with active erosive or ulcerative EBTB. Flexible bronchoscopy was performed at
      least twice in 54 patients, 27 patients treated with conventional therapy and 27
      patients treated with aerosol therapy. In those, we estimated the degree of
      bronchial stenosis between the first and last bronchoscopic examinations. We
      compared conventional therapy with aerosol therapy to clarify the usefulness of
      aerosol therapy for bronchial stenosis. We graded bronchial stenosis as minimal,
      mild, moderate, severe, or obstructive. We assessed the follow-up of bronchial
      stenosis as aggravation, no change, or improvement, using the first and last
      endoscopic findings. "Improvement" was defined as the last endoscopic findings
      improving by at least two grades. "Aggravation" was defined as the last
      endoscopic findings worsening by at least two grades. Other cases were defined as
      "no change". Conventional therapies led to aggravation in 13 patients, no change
      in 13 patients, and improvement in 1 patient. Aerosol therapy led to no change in
      24 patients, improvement in 3 patients. No patients developed aggravation. The
      differences between the therapeutic groups were significant. We concluded that
      aerosol therapy with streptomycin and steroids helps to treat bronchial stenosis
      due to ulcerative EBTB.

PMID- 10655696
TI  - [Surgical treatment for tuberculous tracheobronchial stenosis].
AB  - Thirty-nine patients with bronchial tuberculosis underwent bronchoplastic
      surgery. The modes of procedures were left upper sleeve lobectomy in 13 patients,
      sleeve resection of the left main bronchus in 11 patients, sleeve resection of
      the left main bronchus with concomitant left upper lobectomy in 2 patients, right
      upper sleeve lobectomy in 6 patients, sleeve resection of the right intermediate
      bronchus in 2 patients, right sleeve superior segmentectomy of the lower lobe in
      one patient, sleeve resection of the trachea with concomitant left pneumonectomy
      in one patient, left lower sleeve lobectomy in one patient, carinal resection
      with right upper sleeve lobectomy and middle lobectomy in one patient, and
      dilatation of the left main bronchus with a free skin graft reinforced with a
      steel wire in one patient. There were one operation death and one operation
      related death in 1950's. FEV 1.0% of 12 patients whose records of pulmonary
      function tests performed before and after surgery were available, were increased
      significantly from 67 +/- 10% to 82 +/- 8% in average. Three patients of
      laryngotracheal stenosis due to tuberculosis were treated with silicon T-tube. In
      2 patients their stenotic lesions were repaired by stenting only, for 36 and 56
      months. In one patient, T-tube could not be removed due to laryngeal malacia for
      more than 12 years.

PMID- 10655695
TI  - [Medical treatment for bronchial stenosis due to endobronchial tuberculosis].
AB  - It is needless to say that early diagnosis and appropriate treatment for
      endobronchial tuberculosis are most important, and bronchoscopic examination is
      necessary for early diagnosis. Although endobronchial tuberculosis frequently
      causes bronchial stenosis, there are no specific therapies to prevent the
      complication. To determine the effectiveness of corticosteroids in the prevention
      of complication of endobronchial tuberculosis, this study was undertaken. 18
      patients with endobronchial tuberculosis whose bronchoscopic findings showing
      ulcer formation or endobronchial polyp, out of 35 patients with endobronchial
      tuberculosis who were treated in Nihon University hospital from 1996 to 1998,
      were evaluated to determine the effectiveness of corticosteroids in the
      prevention of bronchial stenosis. We divided the patients into 2 groups: 11 who
      received systemic chemotherapy for tuberculosis only, and 7 who received systemic
      chemotherapy combined with oral corticosteroid. No significant differences
      distinguished the groups with respect to duration of positive sputum culture or
      reduction of respiratory symptoms. However, a significant alleviation of
      bronchial stenosis was observed in the patients who received systemic
      chemotherapy combined with oral corticosteroid. This study suggested that
      corticosteroid therapy in addition to standard chemotherapy for tuberculosis was
      effective for prevention of complication of endobronchial tuberculosis, such as
      bronchostenosis.

PMID- 10655697
TI  - [Surgical treatment and endobronchial stentplacement for tuberculous
      tracheobronchial strictures].
AB  - MATERIALS AND RESULTS: We have seventeen cases of operation for the tuberculous
      tracheobronchial cicatric strictures. Ten of them were tracheobronchial
      reconstructions to the strictures, and other seven cases were resections of the
      peripheral destroyed or infected pulmonary tissues (lobectomy 1, pneumonectomy
      6). In the reconstructions seven cases were of sleeve lobectomy (left 6, right
      1), three were of segmental resection of left main bronchus and trachea. The
      results were good in 6 sleeve lobectomies and 2 segmental resections of left main
      bronchus. All these 8 cases had no marked tracheal strictures, and their
      postoperative troubles were mild. Two cases with tracheal stricture (left sleeve
      lobectomy and tracheal segmental resection with left pneumonectomy) suffered from
      postoperative major complications. In the former the tracheal stentplacement was
      needed for a long time, in the latter its tracheal anastomosis was disrupted and
      the patient died six months later. Peripheral pulmonary resections could get the
      good results to disappear their longstanding various symptoms and signs. We tried
      to do the endoscopic dilatation or stenting to three tracheal strictures. One
      case was treated by the endoscopic electrocauteries and baloon dilatations
      totally in 15 times, but its late prognosis was poor and the patient died of the
      ventilatory disturbance 53 months later. Another one was the case of left upper
      sleeve lobectomy with tracheal stricture, and already mentioned its tracheal
      stent. In the third case the tracheal wall was damaged so deeply and extensively
      that the tracheomalacia might cause to suffocate. Then the tracheal stricture had
      been dilated with several sized stents step by step, finally a silicon long T
      tube was inserted into the trachea successfully. But 10 days later a hard mucous
      plug impacted inside the tube and the patient died. In recent Japanese
      literatures and meeting reports, there were sixty cases of endoscopic surgeries
      and stentplacement for tuberculous tracheobronchial strictures. In these cases
      about half ones were for the left main bronchus, one third for the trachea. In
      the former the rupture of bronchial wall happened in 6%, the dislocations of
      stent in 22% and restrictures came out in 26%. In the latter the complication
      death occurred in 14%, stent dislocations in 30% and restrictures in 46%, so it
      was only 30% to become to be free from tracheal stents. CONCLUSIONS: For the
      treatment of tuberculous cicatric tracheobronchial strictures, the reconstruction
      of main bronchus in cases without marked tracheal stenosis is a good indication
      to regain the lost pulmonary function. The resection of peripheral lung is also a
      good indication to reduce many symptoms and signs from them. However various
      endoscopic treatments involving stentplacement has not been established yet
      enough, especially in a point of late prognosis, so we have to be careful to do
      such procedures. The new apparatus with more durable and easily handled will be
      expected to develop in near future.

PMID- 10655698
TI  - [Roles of cerebral cortex in control of masticatory movements].

PMID- 10655699
TI  - [Research strategy of cognitive neurobiology challenging brain mechanisms of the
      human intelligence--viewing primate tool-use as an evolutionary precursor of the
      language].

PMID- 10655701
TI  - [A clinical study on treatment results of apicoectomy].
AB  - In this study, the treatment results of apicoectomy with orthograde filling were
      compared with those of apicoectomy with retrograde gutta-percha filling and
      retrograde sponge gold filling. The long-term follow-up results of the teeth
      treated by apicoectomy are presented, and the possible prognostic factors are
      discussed. The healing process of the apical bone cavity was analyzed with
      standard X-ray techniques and image analysis system. One hundred nineteen teeth
      were apicoectomized with orthograde filling, 196 teeth with retrograde gutta
      percha root filling and 42 teeth with sponge gold filling. There was no
      significant correlation between the treatment results and the sex or age of the
      patients, kinds of teeth, preoperative radiolucent areas, the number of
      operations or histopathological diagnosis of apical lesion. The success rate of
      apicoectomy with orthograde filling or apicoectomy with retrograde gutta-percha
      root filling was significantly higher than that with retrograde sponge gold
      filling. The filling materials and the operation method were considered to be the
      most important factors for a successful outcome. Bone reconstruction was found to
      start from the periphery of the bone cavity and the bone defect became gradually
      reduced in a star-like pattern. At 4 months after operation, in the successful
      cases, the area of bone cavity decreased 46-64% compared with before operation,
      but in the unsuccessful cases, the area did not change or increased 75-120%. Thus
      at 4 months after operation, it is possible to determine whether or not
      apicoectomy is successful.

PMID- 10655700
TI  - [Dental treatment and oral health care on Tokashiki Island, Okinawa].
AB  - Okinawa Prefecture has been promoting dental treatment and oral health care in
      places where there are no dentists. The Ministry of Health and Welfare has been
      cooperating with eight dental colleges, including Tokyo Medical and Dental
      University, for promotion thereof since 1961. The 155th promotion was held on
      Tokashiki Island. The caries prevalence rate of the students on Tokashiki Island
      was relatively high compared with the average caries prevalence rate of the same
      age group throughout Japan, and most of the caries were thought to be due to too
      many soft drinks. Resin filling was the most popular treatment during this
      promotion. Severe periodontal disease was observed in middle-aged persons, but we
      could only perform initial periodontal treatment because of the limited treatment
      period. Complete or partial dentures were made or repaired for many elderly. The
      questionnaire study showed most of the denture wearers on Tokashiki Island were
      satisfied with their dentures, although many dentures did not fit, and the
      prescription was improved. The period of this promotion was too short to perform
      complete dental treatment and to prevent caries and periodontal disease, and
      primary prevention and higher dental hygiene education should be strengthened in
      no dentist areas like Tokashiki Island.

PMID- 10655702
TI  - [Evaluation of masticatory comminute function using multiple variables--Part. I:
      Observation of mastication using inter-jaw positional EMG].
AB  - When masticatory efficiency is measured in the normal manner, it is necessary to
      collect samples. The purpose of this study was to devise a possible method of
      measuring masticatory efficiency, obviating the necessity for collection of the
      sample. Peanuts mastication by subjects whose degree of comminution was already
      known was observed by using an "Inter-jaw positional EMG" in which an element of
      the jaw positions is combined with EMG. Observation of the Inter-jaw positional
      EMG enables understanding the appearances of each 1-cycle chewing comminution.
      Moreover, changes in muscle activity and jaw movement caused by the progress of
      mastication can be observed by arranging the Inter-jaw positional EMG to record
      the chewing cycle, several times. In addition, three phases in peanut mastication
      was observed, and it was found that analysis of the first two phases when the
      changes appear is very effective because the changes move similarly with the
      changes of particle size. In addition, the Inter-jaw positional EMG and
      distribution of particle size were analyzed, and both changes caused by the
      progress of the cycle were similar. Thus, it is possible to estimate of the
      masticatory efficiency using the Inter-jaw positional EMG.

PMID- 10655703
TI  - [Effects of wearing complete dentures on swallowing in the elderly].
AB  - The purpose of this study was to evaluate effects of wearing complete dentures on
      swallowing in the elderly. Sixteen nondysphagic edentulous volunteers (mean age:
      75.0 yrs) were studied in terms of surface electromyography of the anterior belly
      of digastrics and masseter muscles, tongue pressure toward the hard palate, and
      the laryngeal movement. The subjects swallowed 2 ml water under four conditions,
      with upper and lower dentures, without lower denture, without upper denture, and
      without upper and lower dentures. Dipper-type of swallowing was prescribed. A
      repeated-measures ANOVA was used for statistical analysis. Total swallowing
      duration and the latent period until laryngeal elevation were significantly
      prolonged without upper or lower denture, and without both dentures (p < 0.05).
      They were significantly shorter without lower denture than those without upper
      denture, and without both dentures (p < 0.05). Duration of the preparatory stage
      was significantly prolonged without upper denture, and without both dentures
      comparing with the others (p < 0.05). Duration of the oral stage was
      significantly prolonged without upper denture, and without both dentures
      comparing with the duration with both dentures (p < 0.05). There were no changes
      in the pharyngeal stage with or without dentures. The prolongation of total
      swallowing duration was due to the prolongation of the preparatory and oral
      stages. The prolongation of swallowing would affect the oral-pharyngeal
      coordination of swallowing, and exacerbate the depression of swallowing functions
      with aging. These results suggested that wearing complete dentures contributes to
      maintain physiological procedure of swallowing in the elderly.

PMID- 10655704
TI  - [Observations of interproximal contact relationship during function].
AB  - Previous studies have shown that molar teeth pulsate at rest and displace linguo
      apically during clenching at the intercuspal position. These results suggested
      that teeth do not contact adjacent teeth and the distance between all adjacent
      teeth decreases during clenching. This study was conducted to investigate the
      interproximal contact relationship during clenching by a CCD microscope. Two
      subjects (Males: Aged 28 years) with normal dentition and occlusion were selected
      for in vivo observation. The observed contact points had optimum tightness which
      was defined by the insertion of a 50 microns thick stainless steel strip with
      some resistance, but not by that of a 110 microns strip. A space existed between
      the teeth at rest and the CCD microscope positioned on the buccal side could
      detect light from the lingual side. For dynamic observation, a lingual plate with
      a light source was fitted to each subject. When the subjects clenched, the light
      band was divided. Furthermore, a digital tension gauge was used to measure the
      interproximal force for pulling thin Titanium strips. The interproximal force
      significantly increased during clenching. In vitro, to estimate the relation
      between the width of the light band and the interproximal distance, two extracted
      teeth were used. Light bands were analyzed by computer. The distance between
      adjacent teeth at rest was 3-21 microns, and interproximal spaces disappeared
      during clenching. These results suggested that teeth do not contact adjacent
      teeth at rest but they do during clenching.

PMID- 10655705
TI  - [A clinical evaluation of masticatory function in maxillary bilateral free-end
      saddle removable partial denture in changes of mucosal support area].
AB  - The purpose of this study was to elucidate optimal relations between functional
      load distribution of periodontal supports and mucosal supports from denture
      bearing area in maxillary bilateral free-end-saddle RPD. Therefore, specially
      designed, palatal plate changeable RPDs were designed without changing occlusal
      relation and all other elements. The denture bearing area were measured by the
      thin foil method, standardized by Cubscraniophor. After wearing RPD, clinically
      physiological observation in occlusal contacts and loads were carried out by
      Prescale with an exclusive computer analyzing system. Masticatory muscular EMG
      and occlusal contacts were recorded with Prescale at i.p. clenching. Five
      maxillary bilateral shortened archcases were used for this prosthodontic research
      and studied in periodically at pre- and post-RPD treatments. These data were
      analyzed and compared with those of the control group. The outlines of these
      results were as follows: 1. The relation with mucosal denture supporting area and
      musculature activities were shown as y = -0.19x2 + 5.3x + 93.8, the maximal
      value: 13.48 cm2. 2. The direct proportion was observed in relation with
      anteroposterial location of masticatory center in dental arch and denture bearing
      area. 3. The optimal denture bearing area was observed in each shortened arch
      case.

PMID- 10655706
TI  - [Modification of noxious spinal stimulation on trigemino-trigeminal reflex-
      analysis in an in vitro brainstem-spinal cord preparation from newborn rats].
AB  - Whether reflex responses of the trigeminal motoneurons induced by the stimulation
      of the trigeminal sensory root (Vs) are inhibited by heterotopic noxious
      conditioning stimulation applied to the tail was investigated, using a novel in
      vitro brainstem-spinal cord preparation isolated together with the hindlimbs and
      tail of newborn rats. The neural activity evoked by electrical stimulation of Vs
      with a suction electrode was monitored from the trigeminal motor root (Vm) with a
      suction electrode in a recording chamber. The tail was pinched with forceps as
      the heterotopic noxious conditioning stimulation (tail pinch). In some
      experiments, a plastic septum sealed with Vaseline was used to partition the pool
      for the brainstem from that for the other part of the preparation. The results
      were as follows: (1) electrical stimulation of Vs induced a long lasting
      (duration: over 300 ms) positive potential with a peak-latency of about 80 ms in
      Vm; (2) the response was suppressed in amplitude by the tail pinch; (3) the
      suppressive effect of the tail pinch was blocked by bath application of naloxone
      (50 microM) to the brainstem chamber; and (4) removal of the mesencephalon from
      the preparation did not affect the suppressive effects of the tail pinch. It was
      concluded that the trigeminal reflex response is suppressed by noxious
      conditioning stimulation on the remote region, and that in this suppression
      opioid receptors located in the lower brainstem are involved. This in vitro
      preparation will be useful for investigations of the neural mechanisms underlying
      nociceptive modification of neural activity.

PMID- 10655707
TI  - [Influence of firing times and temperature on color stability of low-fusing
      porcelains for high-functional gold alloys].
AB  - The purpose of this study was to investigate the effect of firing conditions on
      color stability. Three commercially available porcelains for high functional gold
      alloys, Carrara (CA), Deguceram Gold (DE) and Duceragold (DU) were used. In this
      study color stability was investigated under fire treatment of 1st, 3rd, 5th
      times and firing temperatures of 0, 20, and 40 degrees C higher than the
      manufactures standard temperature (CA: 845 degrees C, DE: 780 degrees C, DU: 780
      degrees C). L* was degreased in CA 5 times, DE 3 times, DU by repeated firing. No
      difference was observed among L* of firing temperatures DE and DU, but L* was
      degreased in CA with firing temperatures of 40 degrees C higher. a* was degreased
      in CA, DU, DE with repeated firing, a* was degreased 5 times at firing
      temperatures of higher. b* was degreased in DU, but b* was increased in CA and DE
      with 5 firings. b* was increased with 5 findings at firing temperatures of 40
      degrees C higher.

PMID- 10655708
TI  - [Role of irradiation in breast conservation therapy for breast cancer].
AB  - Despite a worldwide consensus on the indication for breast conservation therapy
      (BCT), the proportion of patients treated with BCT in Japan was only 29.2% in
      1997. Indications of BCT and opinions against increasing the number of BCT in
      Japan are discussed along with the concept of evidence-based medicine (EBM). It
      is evident that in Japan as well, 70% to 90% of patients with breast cancer can
      be treated with BCT. The main aim of irradiation in BCT is to reduce inbreast
      recurrences (IBR), and randomized controlled trials have confirmed that
      irradiation to the breast reduces IBR. Currently, much concern is being directed
      to the issue of surgical margins in partial mastectomy, i.e., the definition of
      positivity of margins and how to treat margin-positive cases. The role of boost
      irradiation to the tumor bed and irradiation to lymph node areas are also
      discussed.

PMID- 10655709
TI  - [Recent trends in radiation therapy for pediatric cancer].
AB  - A recent strategy in the treatment of pediatric cancer is the "total cell kill",
      in which the main part of therapy depends on intensive, aggressive chemotherapy
      with or without bone marrow transplantation. Radiotherapy, like surgery, plays a
      role in local treatment. Recent progress in therapy has permitted cures even of
      patients with advanced cancer. Disease-free patients should have the same quality
      of life as that of healthy children of the same sex and age. Therefore, both
      saving the patient's life and providing him or her with a good quality of life
      are important in treatment policy. To obtain these goals, radiation therapy has
      been included in combined multi-modality therapy for the management of pediatric
      cancer. Other important concerns are to reduce the radiation dose and determine
      the timing of radiation therapy.

PMID- 10655710
TI  - [Experimental study of intraarterial injection of polidocanol as an embolic
      agent].
AB  - The treatment of hemangiomas and vascular malformations in the soft tissue
      presents several difficult problems. Transarterial embolization and/or
      percutaneous sclerosing therapy are useful for such lesions, but the
      effectiveness of these therapies is often partial, and serious problems like
      ulceration and tissue necrosis may occur. Therefore, we examined the efficacy of
      intraarterial injection of polidocanol solution as an embolic agent for
      hemangiomas and vascular malformations using the rabbit kidney. Three embolic
      agents were compared with polidocanol solution (polidocanol 3%, n = 5; absolute
      ethanol, n = 5; n-butyl-2 cyanoacrylate: NBCA, n = 5; polyvinyl alcohol: PVA, n =
      5). All embolizations were followed by angiography and resection after a week.
      Results showed that absolute ethanol (n = 5), NBCA (n = 4) and PVA (n = 1)
      embolized completely. In the specimens, this led to cell necrosis throughout the
      kidney. In contrast, polidocanol (n = 5) obstructed neither the main trunk of the
      renal artery nor the peripheral capillary arteries following angiography. In the
      specimens, the inner medulla of the kidney suffered necrosis. However, residual
      tissue with massive fibrotic change was seen. These results suggest the efficacy
      of "embolosclerosing" treatment for capillary vascular lesions and the
      possibility of alleviating complications from such therapy.

PMID- 10655712
TI  - [Comparative study of the physical properties of microcatheters frequently used
      for abdominal IVR].
AB  - The purpose of this study was to determine the physical properties of
      commercially available microcatheters through basic experiments. The materials
      included eleven different types of widely used microcatheters, ten of which were
      135 cm in length and the remaining one 113 cm. Five samples of each catheter were
      examined. For each catheter, we measured the flow rate, flexibility of the tip,
      rigidity of the proximal part, smoothness of the outer and inner surfaces, kink
      resistance of the tip, and pressure resistance of the whole catheter. In
      conclusion, an ideal microcatheter should satisfy the following criteria: 1) the
      internal lumen must be large enough to allow high flow volume, and the wall must
      be enforced by braiding to withstand higher injection pressure; 2) the tip of the
      catheter must be soft, but must increase in hardness as it approaches the
      proximal end; 3) it must have a hydrophilic coating on the surface for an
      appropriate length.

PMID- 10655711
TI  - [Power Doppler US in breast masses: correlation of spectral analysis findings
      with pathological features].
AB  - The purpose of this study was to clarify the usefulness of power Doppler imaging
      for the diagnosis of breast masses. Materials were histologically confirmed
      breast masses: 24 benign lesions, 4 non-invasive carcinomas, and 54 invasive
      carcinomas. In invasive breast carcinoma, pathological examination was used to
      classify the degree of intratumor fibrous stroma (IFS) into three groups. The
      relationships between IFS and Doppler spectral parameters (Vmax, Vmin, PI, RI)
      were evaluated retrospectively. High PI and low Vmin values were well correlated
      with IFS grade. Carcinomas with low IFS grades had higher Vmax values than benign
      lesions.

PMID- 10655714
TI  - Treatment outcome of definitive endoesophageal brachytherapy for epithelial or
      intramucosal esophageal cancer.

PMID- 10655713
TI  - [Prognosis and organ preservation in oropharyngeal cancer treated with
      radiotherapy].
AB  - The records of 102 patients with squamous cell carcinoma of the oropharynx
      treated at National Sapporo Hospital with external and/or interstitial
      radiotherapy between 1978 and 1996 were reviewed to evaluate the treatment
      results, focusing on primary control and functional preservation. Ninety-five
      patients had been primarily treated with curative intent initially. Of these 95
      patients, 4% were in stage I, 19% in stage II, 42% in stage III and 34% in stage
      IV. Twenty-one patients (22%) had been treated with multidisciplinary
      chemotherapy, and 19 patients (20%) had been boosted with brachytherapy mainly
      using Au-198 grains. The cause-specific survival rates at 5 and 10 years were 63%
      and 52%, respectively. The local control rates at 5 and 10 years were 70% and
      51%, respectively. The most important factors affecting local control were the
      subsite of the primary tumor and N stage. Based on these findings, it is
      considered that radiotherapy combined with/without chemotherapy except for N3 and
      the posterior wall type is an effective method of achieving tumor control and
      preserving organ function, compared with other methods including surgical
      procedures.

PMID- 10655715
TI  - [Three-phase gadolinium infusion in moving-table three-dimensional MR
      angiography].
AB  - Moving-table three-dimensional (3D) MR angiography provides images of long
      segments of arteries. However, deep veins are sometimes superimposed on the
      arteries below the knee, and peripheral arteries sometimes fail to be visualized.
      We have developed an imaging method with three-phase gadolinium infusion
      according to the mean blood flow velocity of the leg. Nineteen patients with
      various blood flow velocities were studied. Eighteen of the patients had no
      venous superimposition. All 19 patients showed good configuration of peripheral
      arteries with 16-18 ml of gadolinium. This method is useful for better
      visualization of peripheral arteries without venous superimposition.

PMID- 10655717
TI  - [Development and evaluation of a photo-rhinometer for clinical use].
AB  - We developed a photo-rhinometer (PRM) which is a modification of the Glatzel
      nasal mirror, and which can promptly evaluate nasal patency under natural
      respiration without any facial apparatus. We also investigated the clinical
      applications of the PRM. In PRM operation, moisture deposits resulting from
      expiratory nasal flow onto a glass plate are visualized for the right and left
      nostrils separately with an image analyzing computer at a television scan rate of
      1/30 of a second. These visualized moisture deposits are averaged over the
      initial 1 second and differentiated for the initial 90 milliseconds to obtain an
      average moisture deposit area (AMDA) and the velocity of the moisture deposit
      (VMD), respectively. The resulting PRM chart, a graphic presentation of the
      moisture deposit area versus time was expected to be useful for the visual
      evaluation of nasal patency. PRM measurements were performed on 100 adult
      volunteers who were selected without knowing whether they had any nasal symptoms
      or disorders. Results showed that statistical distributions of both AMDA and VMD
      were equivalent to the normal distribution. A significant correlation was
      observed between nasal conductance as determined by a rhinomanometer and AMDA as
      determined by the PRM, and also between the nasal conductance and the VMD, which
      is r = 0.66 and r = 0.78 respectively. In addition to the 100 cases, five cases
      of chronic sinusitis and ten cases of acute sinusitis, which had been
      conservatively treated, were investigated by using the PRM. In some of these
      cases where improvements in the nasal conditions and reduction of subjective
      nasal obstruction were recognized, increases in the AMDA and VMD showed a good
      correlation with improvements in the nasal disorder.

PMID- 10655716
TI  - [Analysis of outcome of free jejunal-autograft for head and neck reconstruction-
      postoperative complications and functional results of swallowing in 49 cases].
AB  - We evaluated postoperative results in 49 patients (39 men, 10 women) who
      underwent pharyngoesophageal reconstruction with free-jejunal autograft following
      total pharyngolaryngoesophagectomy in the Department of Otolaryngology, Hokkaido
      University School of Medicine from 1989 to 1997. Evaluation was performed
      regarding the following points: 1) postoperative complications, 2) factors that
      determine the functional results of swallowing, 3) relation between forms of
      jejunal anastomosis and swallowing. The primary malignancy site was hypopharynx
      (39), cervical esophagus (4), larynx (3), thyroid (2) and trachea (1),
      Reconstructions were made with free jejunal autograft alone in 45 cases and with
      free jejunum in combination with gastric pull-up in 4. In patients who underwent
      reconstruction with jejunum alone, the anastomosis of the jejunum to the pharynx
      was performed in side-to-end fashion in 22, end-to-end in 18 and rho-shaped in 4.
      In the 1 remaining case, we used jejunal-patch graft. Postoperative complications
      including minor or nongraft related, occurred in 24 of 49 (49.0%) patients. Among
      these, graft-related complications were graft failure in 1 (2.0%), fistula
      formation in 3 (6.1%) and graft stricture in 2 (4.0%). Re-operations were
      required in one case of graft failure and 2 of fistula formation. Consequently,
      the overall graft-survival rate was 98.0% (48/49). Therefore, we considered the
      method of reconstruction to be a reliable procedure with a high-success rate. The
      swallowing function after reconstructive surgery was studied in 35 patients who
      underwent side-to-end (18) and end-to-end (17) anastomosis of the jejunum to the
      pharynx. We indicated that appropriate tension in the jejunum was the most
      important factor for adequate swallowing function. The end-to-end group had a
      higher rate of taking normal diet compared with the side-to-end group. The rate
      of swallowing dysfunction was only 5.9% (1/17) in the end-to-end group. On the
      other hand, 4 of 18 (22.2%) cases in the side-to-end group were regarded as
      having poor swallowing function. As a result we considered the end-to-end
      proximal jejunal anastomosis to be the more desirable form.

PMID- 10655718
TI  - [A clinical study of inoperable head and neck cancers].
AB  - Thirty two patients with inoperable head and neck cancer seen at Jichi Medical
      School Hospital during the period 1978 to 1995 were analyzed. Distribution of the
      affected site was as follows: 15 cases of oropharynx, 12 of hypopharynx, and 3 of
      larynx. In order to study a better performance status, prognosis and side effects
      were compared between radiotherapy alone (17 patients) and combined
      radiochemotherapy (15 patients). Patients who received the combined therapy
      survived longer than those patients who received radiotherapy alone. Moreover,
      high QOL was obtained longer in the combined therapy. Therefore, we conclude that
      radiotherapy should be combined with chemotherapy for cases with inoperable head
      and neck cancer.

PMID- 10655719
TI  - [Cochlear implantation in children with inner ear malformation and postoperative
      performance].
AB  - Cochlear implantation in children with cochlear malformation is on the rise.
      However, only one case has been reported in Japan. The objective of this paper is
      to report the authors' experiences with cochlear implants in children with
      cochlear malformations and, to investigate the morphological classification of
      cochlear malformation, surgical procedure, complications, and speech perceptions
      after implantation. Five children (6 ears, including 1 Usher's syndrome and 1
      CHARGE association) with congenital inner ear malformations were implanted with
      multichannel cochlear implants (Nucleus Mini 22 device) between 1994 and 1998.
      Malformations included common cavity deformity 2, and incomplete partition 4. On
      the other hand, 4 cases with incomplete partition deformity underwent cochlear
      implantation by the transmastoid facial recess approach, 2 patients with common
      cavity deformity received implantation by the transmastoid labyrinthotomy
      approach. Complications such as facial twitching, cerebrospinal fluid (CSF)
      gusger, and flap-related problems were encountered. Facial twitching occurred in
      1 of 2 patients with common cavity where the electrode array extended into the
      internal auditory canal. CSF gusher was encountered in 1 of 4 patients with
      incomplete partition, and revision surgery was performed one week later. One
      patient had delayed cochlear implant infection and a split pericranial flap was
      used to cover the defect in the skin flap. Within 6 months, however, the revised
      pedestal site broke down because of recurrent flap infection. Finally, the
      cochlear implant was explanted, and the patient underwent a new cochlear
      implantation in the contralateral ear. All the patients had satisfactory speech
      reception and word acquisition, but still poor phonetic expression.

PMID- 10655720
TI  - [The positivity rate of specific IgE antibody to Japanese cedar pollen in
      Wakayama Prefecture].
AB  - The incidence of Japanese cedar pollinosis has been increasing each year in
      Japan. Japanese cedar pollinosis is a state of allergic response, mediated by
      IgE. So, it is important to know the state of sensitization against Japanese
      cedar pollen. The subjects were 1321 nonselective cases who were more than 16
      years of age and who live in Wakayama Prefecture. Specific IgE antibodies to
      Japanese cedar pollen were measured by Lumiward immunoassay system. The results
      showed that positivity for sera class 2 or higher was 30.9%. Furthermore, the
      positivity in 1995 was higher than the positivity in either 1985 (13.9%) or 1990
      (18.3%). The incidence of specific IgE antibody positivity was higher in males.
      Also the age distribution of the positivity was highest in the 20-29 years old
      group, and the positivity was decreased with age. We examined the kinds of
      factors influencing the positivity of specific IgE antibodies. However, the
      relation between the positivity of specific IgE antibodies and the various
      environmental factors was unclear.

PMID- 10655722
TI  - [Long-term outcome of coronary events in hemodialysis patients younger and older
      than 65 years of age].
AB  - BACKGROUND AND AIM: It has been reported that a coronary event is the leading
      cause of mortality in HD patients. The aim of this study was to examine and
      compare prospectively the effect of aging in relation to the in-hospital and the
      long-term outcome in HD patients with or without revascularization therapy who
      had experienced a coronary event. STUDY PATIENTS AND METHODS: Seventy consecutive
      HD patients with coronary events (9 AMI, 48 AP, and 13 CHF) were registered in
      this study and 69 patients underwent CAG. Patients were classified into elderly
      (> or = 65, n = 33) and younger (< 65, n = 37) groups based on their ages at the
      time of the events. Forty-six patients (21 vs 25) underwent initial coronary
      revascularization therapy. We followed 70 HD patients with coronary events for a
      mean period of 31 +/- 21 months (range: 1 day to 77 months). RESULTS: A level of
      64% of the elderly group and 41% of the younger group experienced coronary events
      within the first year of HD. The diseased vessels (2.2 vs 1.9 per patient) and
      stenotic lesions (2.8 vs 2.5 pre patients) were not significantly different
      between the two groups. The 70-month survival rate was significantly lower (21%
      vs 65%, p = 0.0423) in the elderly group than in the younger group. The
      complicated rate of stroke after a major event was significantly higher (14 vs 4,
      p = 0.0025) in the elderly group than in the younger group. Moreover 21 elderly
      patients (11 cardiac death, 5 stroke, 4 cancer) and 9 younger patients (8 cardiac
      death, 1 stroke) died during the 70-month follow-up period. CONCLUSIONS: Coronary
      events were most frequent in the first year of HD. Long-term survival rate was
      significantly lower in elderly patients than in younger patients. Cardiac death
      was the most common cause of death in both groups regardless of performing
      coronary revascularization. Death due to stroke and cancer was also more common
      in elderly patients.

PMID- 10655721
TI  - [Exhaled and nasal nitric oxide in patients with Japanese cedar pollinosis and
      effects of nasal steroids].
AB  - INTRODUCTION: Nitric oxide (NO) is produced by the action of NO synthase (NOS)
      using L-arginine as a substrate in various cells and found in air exhaled by
      humans. Previous studies suggest that almost all exhaled NO is derived from the
      upper airways and increases in patients with untreated asthma and allergic
      rhinitis. Exhaled NO is inhibited by treatment with inhalation of steroids that
      may be caused by inhibition of inducible nitric oxide synthase (iNOS). The
      purpose of this study is to determine whether exhaled and nasal NO increases in
      patients with Japanese cedar pollinosis compared with nonallergic healthy
      subjects, and whether it is affected by treatment with nasal steroids.
      Furthermore, we investigated its relation to nasal function and allergic
      rhinitis. SUBJECTS AND METHODS: 10 patients with Japanese cedar pollinosis and 5
      healthy normal subjects were tested. All subjects had no history of respiratory
      infection for at least 2 weeks and did not smoke. Exhaled NO was collected in a
      sampling bag from oral and nasal breathing, and nasal NO was sampled directly
      from the nasal cavity. Both were measured by a chemiluminescence NO analyzer,
      ML9841, at a detection limit of 1 part per billion (ppb). Subjects used nasal
      steroids for 2 weeks and were measured similarly afterwards. RESULTS: NO
      concentrations in nasal air and air exhaled from the nose in patients with
      Japanese cedar pollinosis (277.9 +/- 59.5 ppb, 34.4 +/- 3.9 ppb, n = 10) were
      higher than the normal subjects (153.3 +/- 30.6 ppb, 19.9 +/- 3.4 ppb, n = 5) (p
      < 0.05). NO exhaled from the mouth was not significantly different between
      patients (20.5 +/- 4.9 ppb) and normal subjects (23.7 +/- 2.6 ppb). In patients
      with Japanese cedar pollinosis, the concentration of nasal NO and nasal exhaled
      NO were significantly decreased after treatment with nasal steroids (144.0 +/-
      21.0 ppb, 26.1 +/- 3.0 ppb) (p < 0.01, p < 0.05), but there was no change in oral
      exhaled NO (17.2 +/- 3.3 ppb). In normal subjects, oral (22.5 +/- 5.3 ppb), nasal
      exhaled NO (19.1 +/- 2.3 ppb), and nasal NO (151.2 +/- 24.8 ppb) were not
      changed. CONCLUSION: In patients with Japanese cedar pollinosis, nasal NO was
      increased and decreased by nasal steroids. These results suggest that increased
      nasal NO in patients with allergic rhinitis is produced by induction of iNOS and
      that nasal NO produces the symptoms of nasal obstruction and rhinorrhea.

PMID- 10655723
TI  - [Paradoxical effect of L-arginine on nitric oxide (NO) synthesis and
      histopathological changes in 5/6 nephrectomized SD rats].
AB  - Whether L-Arginine (L-ARG) ameliorates or aggravates renal function and
      histopathological changes in several models of renal disease remains
      controversial as L-ARG is the substrate for nitric oxide (NO) synthase as well as
      the precursor of proline and polyamines which cause renal fibrosis. These
      ambiguous results might be attributed to differences in the dose and period of L
      ARG administration and the animal model used in each observation. Therefore, we
      tested the dose-dependent effect of L-ARG on mean blood pressure (MBP), 24-hour
      urinary excretion of protein (UP), NO metabolites (NO2(-) + NO3-) and cyclic GMP
      (cGMP), plasma asymmetrical dimethylarginine (ADMA), glomerular sclerosis index
      (SI) and % interstitial fibrosis area (%INT) in 5/6 nephrectomized SD rats. These
      5/6 nephrectomized SD rats were divided into 4 groups: 1. L-ARG 0.2 g/kg/day (0.2
      g ARG), 2. L-ARG 1 g/kg/day (1 g ARG), 3. L-ARG 2 g/kg/day (2 g ARG), 4. No
      administration of L-ARG(ARG(-)). Compared with ARG(-)MBP, UP and ADMA were
      significantly decreased and NO2(-) + NO3-, cGMP were significantly increased in
      the 0.2 g ARG. SI group and %INT were significantly increased in the 2 g ARG
      group and decreased in the 0.2 g ARG group. A small dose of L-ARG ameliorated
      glomerulosclerosis and interstitial fibrosis while a larger dose did not. SI,
      %INT and ADMA were inversely correlated with NO2(-) + NO3-. These data suggested
      that renal NO synthesis might attenuate glomerulosclerosis and interstitial
      fibrosis and the rise in ADMA and L-ARG might cause the decrease in NO.

PMID- 10655724
TI  - [Morphometric analysis of normal glomerular epithelial cells in rat and human].
AB  - It has been postulated that morphological changes of podocytes might be related
      to glomerular sclerotic lesions in experimental models and patients with
      glomerular diseases. To estimate the absolute number of podocytes in mammalian
      normal glomerulus, we analyzed normal glomeruli in four rats and six humans. In
      PAS stained light microscopic sections, at least 25 midsections of open glomeruli
      were photographed. Stereologic estimation was performed to obtain the following
      values: absolute values of glomerular volume (V), glomerular surface area (S),
      podocyte and intraglomerular cell number per glomerulus (P and IGC), glomerular
      surface area covered by one podocyte (S/P) and glomerular volume occupied by one
      intraglomerular cell (V/IGC). The glomerular volume, glomerular surface area and
      podocyte and intraglomerular cell numbers per glomerulus of human were
      significantly increased compared with those of the rat (V: 2.70 +/- 0.86 > 0.89
      +/- 0.19, S: 4.84 +/- 1.26 > 1.88 +/- 0.26, P: 407.7 +/- 88.2 > 153.8 +/- 84.0, p
      < 0.01 vs rat). On the other hand, there were no significant differences in
      glomerular surface area covered by one podocyte and glomerular volume occupied by
      one intraglomerular cell between the humans and rats (S/P: 1.25 +/- 0.20, 1.29 +/
      0.05, V/IGC: 2,471 +/- 487, 2,227 +/- 201, p < 0.01 vs rat). These data were
      almost the same as previously reported values. It appears that these values can
      be considered as standards for rats and humans in morphometric analysis of the
      glomerulus.

PMID- 10655725
TI  - [Clinical evaluation of kampo medication, mainly with wen-pi-tang, on the
      progression of chronic renal failure].
AB  - Previous studies have shown that Kampo (traditional Chinese) prescriptions,
      mainly Wen-Pi-Tang (Onpi-to, [symbol see: text]), have a useful effect in
      patients with chronic renal failure (CRF). We aimed to examine the long-term
      effect of Kampo prescriptions on serum creatinine (Cr) among patients with CRF.
      Patients with serum Cr levels of 2 mg/dl more were enrolled if they had at least
      4 recordings of serum Cr in the previous 6 months or more, and were followed-up
      until the start of dialysis. Eight patients aged 24-59 years with serum Cr 4.5
      mg/dl were enrolled in the study for 40 to 402 weeks (mean; 228.1 +/- 118.8
      weeks). The cause of CRF was chronic glomerulonephritis in 7 patients and
      systemic lupus erythematosus in 1 patient. The end points of the study were the
      slope of the reciprocal of the serum Cr concentration plot against time using
      Mitch's method, and the predicted period of pre-dialysis. The predicted pre
      dialysis period was defined as an increase in serum Cr by 10 mg/dl. As a result,
      the individual slopes were improved in 6 of 8 cases, in particular, in 4 of 5 Wen
      Pi Tang-treated cases. The average slope was improved significantly (p < 0.01) in
      Wen-Pi-Tang-treated cases, although it showed only a tendency to improve in all 8
      cases. The predicted pre-dialysis period was prolonged from 79.2 +/- 74.8 weeks
      to 389.5 +/- 355.4 weeks and 55.6 +/- 37.0 weeks to 262.4 +/- 145.8 weeks in all
      8 cases and Wen-Pi-Tang-treated cases, respectively. The observed pre-dialysis
      period was 228.1 +/- 118.8 weeks, which showed that Kampo prescriptions prolonged
      the predicted period for 186 additional weeks. In conclusion, this study
      demonstrated that the Kampo prescriptions, consisting mainly of Wen-Pi-Tang,
      retarded the progression of CRF.

PMID- 10655726
TI  - [Hyperhomocysteinemia in CAPD patients: peritoneal transport of total
      homocysteine at peritoneal equilibration test and daily elimination of total
      homocysteine].
AB  - Peritoneal equilibration tests (PET) were performed in patients on continuous
      ambulatory and automated peritoneal dialysis (CAPD, APD) to evaluate the
      peritoneal transport capabilities for total homocysteine (tHcy) and other amino
      acids. Forty-five patients (24 males, 21 females, 50.6 +/- 12.8 years old)
      maintained on PD for 43.4 +/- 30.3 months participated in the study. PET revealed
      a markedly lower dialysate to plasma (D/P) ratio of tHcy at 4 hours (0.148 +/-
      0.047) than those of other amino acids. A significant positive correlation
      between the D/P ratio of tHcy and the D/P ratio of creatinine was found, as well
      as between the D/P ratio of tHcy and the D/P ratio of albumin. The most
      significant positive correlation was found between dialysate and plasma levels of
      tHcy at 4 hours. There was no difference in the D/P ratio of tHcy between
      patients with D/P ratios of creatinine higher than the sample median of 0.68 and
      with D/P ratios of creatinine below 0.68, while the D/P ratios of other amino
      acids except threonine in the former patients tended to be higher than those of
      the latter patients. The D/P ratio of tHcy in patients with serum levels of
      albumin higher than 4.0 g/dl was significantly higher than that in patients with
      a ratio less than the sample median of 3.9 g/dl, whereas there were no
      significant differences in the D/P ratios of other amino acids. These
      observations suggest that the dialysate level of tHcy is primarily affected by
      the plasma level of tHcy, and that protein-bound Hcy mainly regulates the D/P
      ratio of tHcy. Daily peritoneal elimination of tHcy in 20 PD patients was 40.6 +/
      28.4 micromol. A significant positive correlation between the elimination of
      tHcy and plasma level of tHcy was also found. Daily elimination of tHcy in 7
      patients with APD tended to be lower than that in 13 patients with CAPD. These
      findings indicate that the daily peritoneal elimination of tHcy does not
      compensate for the daily amount of tHcy metabolized in normal kidney, and that
      other therapies, such as folic acid administration, are required to improve
      hyperhomocysteinemia in patients on PD.

PMID- 10655727
TI  - [Diagnostic significance of urinary immunoglobulin G in diabetic nephropathy].
AB  - An early manifestation of diabetic nephropathy, increased excretion of albumin,
      is now generally believed to be sufficiently specific, particularly in subjects
      with diabetes mellitus, to predict the subsequent development of clinically overt
      diabetic nephropathy. However, certain other proteins besides albumin may also be
      excreted in abnormal amounts during this early phase of diabetic nephropathy. We
      evaluated the diagnostic utility of urinary immunoglobulin G (IgG) in patients
      with diabetic nephropathy by comparing the findings with the clinical stage and
      renal biopsy specimen. Using 24-hour urine samples, IgG was measured by an enzyme
      linked immunosorbent assay. In addition, urine samples were assayed for albumin,
      transferrin, beta 2-microglobulin and N-acetyl-beta-D-glucosaminidase. Serum IgG
      concentration and HbA1c were also evaluated. A total of 197 patients with non
      insulin-dependent diabetes mellitus were enrolled in this study. Subjects were
      grouped according to the rate of urinary albumin excretion (clinical stage).
      Fifty of these cases were also divided into four groups according to the severity
      of diffuse glomerular lesions using Gellman's criteria. The urinary excretion of
      IgG was significantly increased in diabetic patients as compared with the healthy
      controls. Among diabetic patients, IgG level showed a significant increase with
      respect to the clinical stage of nephropathy and the progress of glomerular
      diffuse lesions. In the stage of normoalbuminuria, the urinary excretion of IgG
      showed a significant increase in parallel with the progress of glomerular diffuse
      lesions, whereas there was no relationship between the urinary excretion of
      albumin and the progress of glomerular diffuse lesions. While the excretion of
      IgG correlated with that of albumin and transferrin, there was no correlation
      between the excretion of IgG and the other laboratory indices evaluated. These
      findings indicate that measurement of urinary IgG may be more useful than
      albuminuria in detecting the early stage of diabetic nephropathy.

PMID- 10655729
TI  - [Marked hypernatremia in suprasellar germinoma lacking a sense of thirst].
AB  - We here report a 17-year-old high school boy having suprasellar germinoma who
      presented marked hypernatremia probably due to damages of both the osmoregulation
      and thirst centers. He was in good health until July, 1996, when he noticed
      slight general malaise and complained of dryness of the mouth, but without
      polyuria. He was found to have hypernatremia of mild degree (serum Na 151 mEq/l),
      but dropped out from the follow-up. In April, 1997, he was admitted to our
      hospital with complaints of general malaise and weakness of the upper and lower
      extremities. Serum Na was high at 202 mEq/l with a plasma osmolality of 390
      mOsm/kg H2O. He completely lacked a sense of thirst and polydipsia/polyuria.
      Computed tomography and magnetic resonance imaging indicated a suprasellar tumor,
      possibly a germinoma. Hypernatremia was first treated with intravenous infusion
      of a half-normal saline solution, followed by immediate polyuria of 3 to 6 l/day.
      Subsequently, nasal administration of desamino-D-arginine vasopressin (DDAVP)
      induced stabilization of serum Na to a range between 140 and 160 mEq/l. The tumor
      disappeared following steroid pulse therapy and irradiation of 50 Gy to the
      brain. At the time of discharge, he and his family were instructed to record the
      urine volume, amount of water intake, body weight and amount of DDAVP used. The
      patient was instructed to drink water corresponding to the urine volume while
      maintaining the dose of DDAVP. One year after treatment, the water balance
      reverted to a positive direction, leading to a normal range of serum Na probably
      because of partial recovery of the osmoreceptors and/or trained drinking habit.
      This case illustrates the so-called adipsic hypernatremia which is attributed to
      partial osmoreceptor destruction by a suprasellar germinoma.

PMID- 10655728
TI  - [Usefulness of serum cystatin-C as a marker of the renal function: a comparative
      evaluation with beta 2-microglobulin, alpha 1-microglobulin and creatinine].
AB  - We evaluated the usefulness of cystatin-C as a marker of renal function. Serum
      cystatin-C level was measured using latex agglutination tests in 885 patients
      with various forms of renal disease and 200 healthy subjects. In addition to
      cystatin-C, serum beta 2-microglobulin, alpha 1-microglobulin and serum
      creatinine (Scr) were measured concomitantly in the same sample. The serum
      cystatin-C level inversely correlated more closely with creatinine clearance
      (Ccr) (r = -0.90) than serum beta 2-microglobulin (r = -0.85), alpha 1
      microglobulin (r = -0.74) and Scr (r = -0.78). In patients with mildly impaired
      renal function (defined as Ccr 71-90 ml/min), a significant increase in cystatin
      C level was observed in 24% of patients, whereas elevated beta 2-microglobulin
      and Scr were seen in 8% and elevated alpha 1-microglobulin was seen in 17%. In
      patients with normal renal function (defined as Ccr > or = 100 ml/min), increased
      cystatin-C level was observed in 7% of patients, whereas beta 2-microglobulin was
      seen in 2%, Scr in 2% and alpha 1-microglobulin in 11%. These data suggest that
      cystatin-C is a better marker of glomerular filtration than beta 2-microglobulin,
      alpha 1-microglobulin and Scr. Moreover cystatin-C measurement offers improved
      clinical sensitivity as a screening test for early renal damage.

PMID- 10655730
TI  - [A case of significant natriuresis and improvement of proteinuria by Temocapril,
      an ACE inhibitor with biliary excretion, in loop diuretics resistant edema in
      membranous nephropathy].
AB  - A 50-year-old man with WPW syndrome and chronic atrial fibrillation controlled by
      digoxin exhibited nephrotic syndrome due to membranous nephropathy in 1994. For
      massive edema resistant to loop diuretics, administration of 2 mg/day of
      Temocapril, an ACE inhibitor with biliary excretion, was started. It provided
      marked natriuresis and rapid improvement of massive anasarca. Moreover, 6 months
      later at the time of writing this report, nephrotic proteinuria has decreased and
      abnormally depressed Ccr level has elevated. For massive edema resistant to loop
      diuretics in nephrotic syndrome, Temocapril might bring about a beneficial effect
      possibly through the induction of natriuresis, which has been suppressed by the
      over-expression of angiotensin II in tubulointerstitium.

PMID- 10655731
TI  - [A case of malignant hypertension in whom steroid improved renal function].
AB  - We report a case whose renal failure was due to malignant hypertension and in
      whom steroid facilitated the recovery of renal function. The patient, a 41-year
      old man, was admitted to our hospital because of malaise and macrohematuria. On
      admission, his blood pressure was 270/160 mmHg. The plasma renin activity (PRA)
      and aldosterone were markedly elevated. Chest X-ray, echo cardiography and
      electrocardiogram revealed marked hypertrophy. Hypertensive retinopathy and
      arteriosclerotic change were noted on ophthalmoscopy. Because of renal
      dysfunction (blood urea nitrogen 45.6 mg/dl, serum creatinine 4.9 mg/dl with
      massive proteinuria and increased FENa, renal biopsy was performed on the 8th
      clinical day. The specimens showed slight proliferation of mesangial cells with
      mesangiolysis and interstitial cell infiltration, in addition to marked
      arteriosclerosis and partial collapse of the glomerular tuft. After the
      administration of a Ca antagonist and angiotensin converting enzyme inhibitor
      (ACE-I), his mean blood pressure decreased to 100-130 mmHg, and urinary protein
      decreased as well. Nevertheless, renal dysfunction remained unchanged during the
      following 3 weeks. Thus, prednisolone (PSL, 30 mg/day) was administered on the
      22nd clinical day and renal function improved thereafter without a significant
      change in blood pressure. The improved renal function was maintained after PSL
      tapered off on the 184th clinical day. It is suggested that PSL might be the
      therapy of choice in malignant hypertension, when the renal function has not been
      improved by anti-hypertensive treatment alone.

PMID- 10655732
TI  - [Pain managements in the elderly].

PMID- 10655733
TI  - [The mechanism of intracellular signaling].

PMID- 10655735
TI  - [The deterioration of regimen comprehension in self-attending elderly patients
      and the effect of tutorials by pharmacists].
AB  - The purpose of this study was to assess whether regimen comprehension
      deteriorates in the elderly without obvious mental disability. Eligible patients
      were elderly who could visit hospitals by themselves. We recruited 138 patients
      (age: 43-89, 75 males and 63 females, underlying diseases: hypertension,
      hyperlipidemia, arrhythmia etc.) from our outpatient clinic. The participants
      were tested with a regimen comprehension scale (RCS: Jpn J Geriat 1997; 34:209
      214). The differences in scores among individuals increased with age. Scores of 5
      or less were recorded in 10 of 69 patients aged 65 or more, but in non of 69
      patients aged less than 65 (p < 0.01). The 60 patients who could not get full
      marks were classified into 2 groups: the tutored group (T) who were tutored by
      pharmacists about taking drugs, and the non-tutored group (N). Both group were
      tested again with RCS to evaluate the effect of tutorial. In T-group (n = 28),
      the second scores increased significantly (from 7.2 +/- 0.9 to 8.6 +/- 2.0 (m +/-
      SD); p < 0.01). Although the second scores showed a tendency to increase in N
      group (n = 29), there was no statistical significance. In 7 patients who obtained
      less than a score of 5 on the RCS and age- and gender-matched controls who
      received full marks on the RCS, the HDS-R test failed to show any differences
      between the two groups. Thus, we concluded that even in the self-attending
      elderly patients, the regimen comprehension deteriorated with age, and tutorials
      were considered to be effective.

PMID- 10655734
TI  - [The role of protein kinases and phosphatases in erythroid colony formation of
      elderly].
AB  - Using H-7, HA1001, FK506, cyclosporin A (CsA) and okadaic acid (OA), which are
      protein kinase and phosphatase inhibitors, we examined qualitative changes in
      hematopoietic precursor cells due to aging from the viewpoint of the role of
      protein kinases and phosphatases. Though H-7 and OA suppressed erythroid colony
      formation both in the elderly (age: 72-92, median: 86) and the young (age: 22-39,
      median: 29), no change due to aging was noted. HA1001 did not affect erythroid
      colony formation either in the elderly or the young. Erythroid colony formation
      was enhanced by FK506 and CsA in the young, however, erythroid colony formation
      was suppressed in the elderly. Similar examinations using cell fractions of non
      T, non-macrophage, non-T + T, and CD34 positive cells were performed in both
      groups. Enhancement of erythroid colony formation in the young and suppression in
      the elderly by FK506 using unseparated MNC disappeared after removal of T cells.
      Enhancement of colony formation in the young and suppression of colony formation
      in the elderly were recovered when T cells were added again. The effects of FK506
      and CsA on erythroid colony formation were thought to be the results of T cell
      inactivation, and the different sensitivity to FK506 and CsA in the elderly and
      young seemed to be the result of changes in the control mechanisms of
      hematopoiesis, such as the regulation of cytokine production by T cells, caused
      by aging.

PMID- 10655736
TI  - [Autonomic nerve function expressed by the baroreflex sensitivity (BRS) in
      elderly adults].
AB  - We examined 24 hour heart rate variability (HRV) components and baroreflex
      sensitivity (BRS) in elderly adults. Forty-eight subjects, aged 65-69 years old
      (24 men, 24 women) were examined in this study. BRS was measured in the morning
      (8:00-9:00) using noninvasive cross spectral analysis. There were significant
      correlations between BRS and low-frequency (LF) power (r = 0.593, p < 0.001) of
      HRV, and between BRS and high-frequency (HF) power (r = 0.402, p < 0.005). BRS
      values were lower in women compared with men (p < 0.01), and LF/HF was
      significantly lower in women than in men (p < 0.05).

PMID- 10655737
TI  - [Effects of aging and hyperlipidemia on plasma osteopontin level].
AB  - In order to elucidate a possible mechanism for accelerated atherogenesis as well
      as enhanced vascular calcification observed during the normal aging process, we
      measured plasma osteopontin (OPN) levels and examined their relation to aging and
      certain disease parameters. In all cases examined, no significant relation was
      found between the plasma OPN level and age, body mass index, blood pressure,
      plasma levels of glucose and insulin, serum levels of creatinine, triglyceride,
      and high density lipoprotein cholesterol. On the other hand, a significant
      negative correlation was found between the plasma OPN level and serum total
      cholesterol concentration (n = 78, r = -0.355, p = 0.0014). The serum level of
      low density lipoprotein (LDL) cholesterol, calculated by the formula of
      Friedewald, also showed a significant negative correlation to the plasma OPN
      level (n = 78, r = -0.301, p = 0.0075). In cases without diabetes mellitus and
      hypertension, a significant positive correlation was found between the plasma OPN
      level and age (n = 22, r = 0.445, p = 0.0378). It is postulated that OPN plays a
      negative regulatory role in the development of vascular calcification. Therefore,
      the observed negative relationship between the plasma OPN level and the serum
      levels of total cholesterol and LDL cholesterol, suggests a possibility that
      hypercholesterolemia facilitates vascular calcification by suppressing OPN
      synthesis. On the other hand, in non-diabetic and normotensive cases, the
      positive relationship between the plasma OPN level and age may reflect a defense
      mechanism against age-related increase of vascular calcification.

PMID- 10655738
TI  - [Brain computerized tomographic and ultrasonographic findings in patients with
      asymptomatic carotid bruits].
AB  - This study was conducted to clarify brain and carotid lesions in patients with
      asymptomatic carotid bruits and their characteristics. We studied 37 patients
      with carotid bruits, who had various diseases other than stroke and were all
      neurologically normal, using by brain computerized tomography (CT) and
      ultrasonography (US). On CT, localized low density areas (LDAs) and their
      distribution were assessed, as well as the grade of periventricular lucency
      (PVL). Carotid lesions on US were classified into 3 categories: plaque (locally
      thickened intima-media complex of 2.1 mm or more in thickness), stenosis
      (narrowed lumen between 50% and 90% of the linearly measured diameter), and
      occlusion (severely narrowed lumen more than 90%). Ankle pressure index (API)
      less than 0.9 was defined as low. Mean age was 73.2 years-old and 28 of them were
      men. Bruits were heard bilaterally in 15 patients. CT findings showed LDA in 13
      patients (35%) and severe PVL in 12 patients (32%). Twenty-three LDAs (13 in the
      left hemisphere and 10 in the right hemisphere) were seen and all were considered
      to be infarctions. Nineteen LDAs, 13 of them seen in the basal ganglia, were
      lacunae. Another 3 LDAs were seen in the watershed zone between the middle and
      posterior cerebral arteries, whereas the remaining one was a small cortical
      infarction in the left premotor area in the middle cerebral artery territory.
      Ultrasonography showed carotid lesions in 65 of 74 carotid arteries (plaque in
      28, stenosis in 26, and occlusion in 11) and low API in 18 of 37 patients.
      Compared with patients with normal CT finding, the frequency of hypertension (92%
      vs 50%) and ischemic heart disease (69% vs 29%) was significantly high in 13
      patients with silent infarction, although there was no difference in US findings.
      In the hemisphere ipsilateral to the carotid with bruits, which was frequently
      stenotic, the frequency of infarction was similar to that in the hemisphere
      ipsilateral to the carotid with no bruit. Regression analysis revealed that
      hypertension significantly correlated with the presence of cerebral infarction.
      These findings indicated that incidence of infarction in the elderly patients
      with asymptomatic carotid bruits was high and was associated with hypertension
      and advanced atherosclerosis in many organs, including the carotid and peripheral
      arteries. The reason for the lack of symptoms was considered to be that most of
      the infarctions were lacunae and located in the basal ganglia, although
      infarction did not significantly correlate with bruits or carotid lesions.

PMID- 10655739
TI  - [Clinical course of acute deep infarcts in carotid system--pathogenesis of
      progressing stroke].
AB  - We attempted to clarify the temporal profile and the predisposing factors for
      progressing neurological disorders in the patients with acute cerebral infarction
      in the territory of the deep perforators of the carotid system. The subjects were
      19 patients with mild hemiparesis admitted to our hospital within 24 hours of
      stoke onset, and their mean age was 59.9 +/- 9.1. Six of those patients (about
      32%) had gradual neurological deterioration after admission (progressive cases),
      and they had poor outcome compared with non-progressing patients. The mean
      progressing period was 3.7 +/- 1.0 days. Our examination suggest that both the
      changes in systemic hemodynamics and the risk factors for cerebrovascular disease
      (hypertension, diabetes mellitus, hyperlipidemia) do not always provide a
      correlation with the development of progressing stroke. However, we speculate
      that the impairment of the microcirculation plays a major role in progressing
      stroke in the territory of penetrating arteries because of the result that the
      mean infarct size of progressive patients had a tendency to be larger than that
      of non-progressive patients in the chronic stage.

PMID- 10655740
TI  - [A case of pituitary apoplexy approving as severe headache and nausea].
AB  - The causes of pituitary apoplexy are unclear. We report a case of pituitary
      apoplexy presenting with headache and nausea. On June 17th, 1997 a 74-year-old
      woman had complained of retro-orbital headache, fever and vomiting. A cold was
      diagnosed for which she recurred medication. In addition to the previous symptoms
      she was getting to lose appetite. She was admitted to our hospital for further
      examination and treatment on June 21. On admission neurological examination
      showed left pupil mydriasis, the left eye had no light reflex and the right eye
      had only a slight response to the light. She could hardly move both eyeballs up.
      Laboratory data showed a normal white blood cell count and the CRP was 16.2
      mg/dl. Lumbar puncture showed 97 mg/dl total protein and 82 cells per microliter,
      most of which were lymphocytes. We diagnosed viral infection based on the
      evidence of clinical symptoms and lumbar puncture data. The patient was treated
      with gamma-globulin and improved. From the 16th day of sickness we recognized
      symptoms of oculomotor paralysis and the syndrome of inappropriate antidiuretic
      hormone. On the 23rd day of sickness we strongly suspected pituitary apoplexy
      based on transaxial MR images. After absorption of intra-tumor hemorrhage, the
      oculomotor symptoms recurred. We finally reached a diagnosis of pituitary
      apoplexy based on pathological material, MR images, symptoms and laboratory data.
      We must think of pituitary apoplexy when we see an aged out-patient with severe
      headache, nausea, vomiting and oculomotor paralysis. It was difficult to diagnose
      this disease in the early time course of the disease.

PMID- 10655741
TI  - [A patient complaining of right hypochondralgia with back pain. Aortic dissection
      or cholelithiasis?].
AB  - A 70-year-old woman with a past history of cholecystolithiasis was admitted to a
      local clinic because of right hypochondralgia with back pain. Since physical
      examination revealed Murphy's sign, this patient was diagnosed as acute
      cholecystitis. The ultrasonographic examination of the gallbladder showed a stone
      of the cystic duct with no definitive wall thickening. CT scan revealed
      dissection of the abdominal aorta. She was then referred to our hospital for
      further examinations. She was observed in the cardiac care unit to determine
      whether the aneurysm and cholecystitis were in an acute or chronic state. Blood
      examinations and enhanced CT scan showed that her clinical symptoms originated
      not from cholelithiasis but from acute closing aortic dissection, Stanford
      classification type B. Close cooperation with a highly developed medical facility
      is essential when diagnosing elderly patients with symptoms open to a variety of
      interpretation.

PMID- 10655742
TI  - [Five cases of purple urine bag syndrome in a geriatric ward].
AB  - We report five cases of purple urine bag syndrome (PUBS). All the patients were
      women and they had been bed-ridden for a long period due to cerebrovascular
      diseases. They tended to be constipated as a result of habitual use of laxatives.
      Indicanuria was proven in the all urinary samples from the patients. The four
      assessable urinary cultures showed Proteus mirabilis contamination. Total days
      without evacuation per month in patients with PUBS and control subjects (5
      catheterized subjects without PUBS) were 16.5 +/- 3.7 and 6.8 +/- 4.8,
      respectively (mean +/- SD), showing a significant difference (p < 0.05). In each
      case, this syndrome was not considered to have affected their clinical course. We
      concluded that it is unnecessary to treat patients with PUBS aggressively.
      Control of evacuation and urological sanitation are important in these patients.

PMID- 10655743
TI  - [Child health care of the twenty first century for handicapped children in
      Japan].

PMID- 10655744
TI  - [Child neurology--future prospect. Interview by Toshiaki Abe].

PMID- 10655745
TI  - [Relapse of seizure after withdrawal of antiepileptic drug treatment in childhood
      epilepsy: age-dependent factors].
AB  - In 556 epileptic children, clinical and encephalographic factors concerning the
      discontinuation of antiepileptic drugs (AED) were studied, with emphasis on age
      related factors. Seizures relapsed in 80 patients (14.4%), the incidence being
      high in idiopathic generalized epilepsy with onsets in adolescence or adulthood
      (juvenile absence epilepsy, juvenile myoclonic epilepsy, grand mal on awakening),
      symptomatic partial epilepsy and symptomatic generalized epilepsy. The age
      distribution at the relapse showed two peaks; 9 to 11 and 17 to 19 years. The
      first peak represented patients with school-age onset epilepsies, and the second
      those with the adolescent or adult onset epilepsies. The age at discontinuation
      of AED depended on each epileptic syndrome, and the relapse rate was
      significantly higher when the AED was discontinued after adolescence. In 56
      patients, seizure relapsed during the withdrawal phase or less than 1 year after
      the discontinuation. The type of the relapsing seizure was the same as the
      previous ones. On the other hand, in 16 out of 24 patients whose relapse occurred
      1 year or more after the discontinuation, the seizure type was different from the
      previous ones. These results suggest the relevance of age-dependent factors to
      the discontinuation of therapy.

PMID- 10655746
TI  - [Apparently unprovoked seizures precipitated by prefebrile condition].
AB  - We investigated the clinical features of the patients whose body temperature
      exceeded 38 degrees C, in 0.5-6 hours after an afebrile seizure (prefebrile
      seizure). Patients with meningoencephalitis and epilepsy were excluded from this
      study. From May 1995 to April 1997, seven cases of prefebrile seizures admitted
      to PL hospital. Three of the 7 had a status and one had a cluster of seizures.
      Five patients had had several febrile seizures prior to the onset of prefebrile
      seizures. One developed epilepsy during the follow-up period. We speculate that
      prefebrile seizures have several factors of complex febrile seizures and require
      a careful follow-up.

PMID- 10655747
TI  - [Distribution in normal subjects of performance in Token test: a basic study for
      the diagnosis of learning disabilities].
AB  - For the diagnosis of specific reading disorder (SRD) we studied the distribution
      in 187 elementary school children of the scores of Token test. Token test was
      performed under two conditions: listening and reading by presenting the same
      sentences. The diagnosis required a normal score under the listening condition,
      an abnormally low score under the reading condition and significantly large
      discrepancy between them. This test is valid and convenient for the diagnosis of
      SRD.

PMID- 10655748
TI  - [Clinical applications and the effect of mexiletine on refractory epilepsies].
AB  - Twenty-four patients with refractory epilepsy were treated with mexiletine as an
      additional antiepileptic drug. As the initial responses, seizures were decreased
      by 50% or more in 7 (46.7%) of 15 patients with symptomatic partial epilepsy
      (SPE), in none of 7 with symptomatic generalized epilepsy (SGE), and in 1 of 2
      with undetermined epilepsy. Seizures increased in 3 patients (20.0%) with SPE,
      and in 3 (42.9%) with SGE. Concerning seizure types, mexiletine had significant
      effects on 1 of 2 patients with simple partial seizures, on 7 of 13 with complex
      partial seizures, on 1 of 5 with secondarily generalized seizures, and on 1 of 8
      with tonic seizures. No patients with a myoclonic seizure or atypical absence
      improved. Exacerbation of the seizures was observed in 2 of 13 patients with
      complex partial seizures, in 1 of 5 with secondarily generalized seizures, in 3
      of 8 with tonic seizures, and in 2 of 3 with myoclonic seizures. Partial seizures
      were controlled well, whereas generalized seizures sometimes worsened. EEG
      improved in 3 patients with SPE; decrease of focal spikes in 2 patients and
      disappearance of secondary generalization in 1. Follow-up for more than 3 months
      showed seizures to be lessened in 2 patients. Mexiletine is useful for the
      treatment of refractory epilepsies, especially SPE.

PMID- 10655749
TI  - [Cerebral palsy in twins in Okinawa].
AB  - Twin pregnancy is an important risk factor associated with cerebral palsy (CP).
      We investigated the prevalence and clinical features of CP in twins born from
      1988 to 1994 in Okinawa prefecture. The prevalence of CP in twins was 10.1 per
      1000 multiple births, and it was 6 times that in singletons (1.6 per 1000 live
      births). Twins weighing more than 2500 g had a higher prevalence of CP than
      singletons, but those weighing less than 2500 g had no significant difference.
      Our results indicate that the higher rate of CP in twins reflect their tendency
      to be low-birth weight. There may be specific events affecting twins weighing
      2500 g or more.

PMID- 10655750
TI  - [A case of Down syndrome with moyamoya syndrome presenting extensive multiple
      cerebral infarction during measles infection].
AB  - We report a case of a 2-year-old boy with Down syndrome complicated by Moyamoya
      syndrome who developed extensive multiple cerebral infarction after status
      epilepticus on the third day of a measles infection. MR angiography revealed the
      occlusion of the terminal portion of the bilateral internal carotid artery and
      the basilar artery. Fever, dehydration, activation of coagulation associated with
      the infection, relatively decreased cerebral blood flow during status
      epilepticus, and central nervous invasion of the measles virus may have played a
      role in the development of the infarction. Moyamoya like cerebrovascular lesions
      occur more often and is more aggressive in children with Down syndrome than in
      the general pediatric population, and their clinical presentation is always the
      infarction type. In patients with Down syndrome complicated by Moyamoya syndrome,
      an early diagnosis and prevention of infarction are important.

PMID- 10655751
TI  - [Event-related potential (P300) in two epileptic cases with continuous spike
      waves during slow wave sleep].
AB  - We studied the P300 of two epileptic cases with almost continuous diffuse spike
      wave discharges on sleep EEG: one with epilepsy with continuous spike-waves
      during slow wave sleep, and another with atypical benign partial epilepsy. These
      cases showed a marked prolongation of P300 latencies during nonconvulsive status
      epilepticus with continuous spike-waves during slow wave sleep. As they improved
      clinically and electroencephalographically, the latencies became normal. These
      findings indicate that P300 is a useful method to elucidate the pathophysiology
      of nonconvulsive status epilepticus with continuous spike-waves during slow wave
      sleep.

PMID- 10655752
TI  - [A nevoid basal cell carcinoma syndrome with chromosomal aberration].
AB  - We reported a boy with nevoid basal cell carcinoma syndrome (NBCCS) with
      chromosomal aberration. He showed multiple jaw cysts, basal cell carcinomas,
      hypertelorism, macrocephaly and mental retardation. Cranial CT revealed
      calcification of the falx cerebri and tentorium cerebelli, and dilatation of the
      lateral ventricles. MRI showed a thin corpus callosum. A chromosomal study
      revealed a deletion of 9q21.31-q22.31. He had generalized tonic-clonic seizures,
      which were well controlled. Since the gene for NBCCS was recently mapped to
      chromosome 9q22.3, we suspected that the deletion site in this patient was
      responsible for his symptoms of NBCCS.

PMID- 10655753
TI  - [A case of epilepsy with agammaglobulinemia improved by intravenous
      immunoglobulin therapy].
AB  - We report a 13-year-old boy having epilepsy with agammaglobulinemia. He developed
      without neurological deficits until the age of 4 years, when he had convulsive
      generalized status epilepticus. He suffered from recurrent infections, and the
      diagnosis of agammaglobulinemia was made at 5 years. At 8 years, he had complex
      partial seizures following an aura of epigastric discomfort. EEG recording showed
      right anteriotemporal spikes. He was diagnosed as having epilepsy and treated by
      antiepileptic drugs without success. At 10 years, intravenous immunoglobulin
      therapy was begun to treat recurrent infections. This therapy not only prevented
      infections, but also resulted in marked improvement of his epilepsy, both
      clinically and electroencephalographically.

PMID- 10655754
TI  - [Efficacy of methylprednisolone pulse and mild hypothermia therapies in patients
      with acute encephalopathy].
AB  - Five patients with acute encephalopathy underwent methylprednisolone pulse (mPSL
      P), hypothermia and their combination therapies (3 cases, 1 case and 1 case,
      respectively), with excellent outcome. Two cases with severe brain edema
      survived. One had severe brain damage as a sequelae. The remaining one recovered
      well after the combination therapy with mPSL-p and mild hypothermia, despite
      complete obstruction of the fourth ventricle on the first CT scan; the sequelae,
      hemiplegia and intelligent disturbance, was only mild. Four patients who received
      mPSL-P therapy within 6 hours after the onset of CNS symptoms recovered well
      though one was left with epilepsy. These results indicate that mPSL-P and/or
      hypothermia therapy will be chosen as the treatment of acute encephalopathy.

PMID- 10655755
TI  - [Three cases with acute encephalopathy related with adenovirus type 7 infection].
AB  - We studied the clinical and CT findings of 3 children with acute encephalopathy
      associated with adenovirus type 7 (AD-7) infection. Seizures in all the patients
      developed from 8 to 10 days after the onset of pyrexia. The values of serum AST,
      LDH and CRP elevated and those of WBC and serum protein decreased at the onset of
      encephalopathy. None of the patients had CSF leukocytosis. CT showed mild brain
      atrophy in all patients. A steroid pulse therapy was effective in one patient.
      The pathogenesis of encephalopathy is unknown. However, its onset and the success
      of the steroid pulse therapy suggested that it is a post infectious encephalitis.
      These findings, as well as the data of blood examination and of previous reports,
      implicated adverse effects of cytokines in the pathogenesis of this
      encephalopathy.

PMID- 10655756
TI  - [Effectiveness of continuous midazolam infusion for status epilepticus in
      children].

PMID- 10655757
TI  - [Three cases of hypoactivity and poor appetite with zonisamide-induced metabolic
      acidosis].

PMID- 10655758
TI  - [The significance of color duplex ultrasonography for the diagnosis of temporal
      arteritis].
AB  - We examined the usefulness of color duplex ultrasonography in patients suspected
      of having temporal arteritis. Five patients, who were all aged 70 or older,
      developed a new onset of localized headache with temporal artery abnormalities,
      and had an elevated erythrocyte sedimentation rate of > 100 mm/hour. The final
      diagnoses were temporal arteritis in three patients, polymyalgia rheumatica in
      one, and probable healed temporal arteritis in one. Color duplex ultrasonography
      showed stenoses, which were confirmed histologically as well, in the superficial
      temporal artery of all patients. The characteristic findings of active temporal
      arteritis were, however, demonstrated in only three biopsy specimens, and in the
      remaining two the stenoses were thought to be related to previous arteritis. The
      hypoechoic halo, which has been reported to be a characteristic finding of color
      duplex ultrasonography in active temporal arteritis, was detected in only one
      patient with active temporal arteritis and another one with probable healed
      temporal arteritis. No stenoses were demonstrated in the superficial temporal
      arteries of 30 control subjects (20 with at least one risk factor of
      atherosclerosis and 10 without it). Color duplex ultrasonography can therefore be
      considered a powerful method for detecting stenoses in the superficial temporal
      artery. Its ability to identify their etiology is, however, unsatisfactory, so
      that temporal artery biopsy remains undoubtedly the most reliable test for
      etiological evaluation. We thus recommend color duplex ultrasonography as a
      supplementary method for the diagnosis of temporal arteritis, because it can
      provide useful information concerning the appropriate site of temporal artery
      biopsy.

PMID- 10655759
TI  - [Abnormal respiratory regulation in myotonic dystrophy].
AB  - The abnormal respiratory regulation as well as respiratory muscle degeneration
      are thought to be involved in the pathogenesis of alveolar hypoventilation in
      myotonic dystrophy (MD). In the present study we recorded changes in oxygen
      saturation resulting from exercise and hyperventilation in MD, Duchenne muscular
      dystrophy (DMD) patients and healthy volunteers by pulse oxymetry. Following are
      the results obtained in this study. (1) In DMD individuals showing preexisting
      mild desaturation around 90-95%, mild muscle exercise such as drawing a picture
      always caused further desaturation, which is presumably due to an increase in
      oxygen demand. On the other hand the MD patients with the same level of
      desaturation often showed paradoxical improvement in oxygen saturation up to 95
      97% after a similar mild exercise, however, they showed obvious desaturation by a
      harder exercise such as propelling wheelchair. (2) There was a fluctuation of
      oxygen saturation at rest in MD, while this was not apparent in DMD patients and
      normal volunteers. (3) In MD and normal individuals, a strenuous hyperventilation
      is always followed by an oxygen desaturation through ventilatory suppression
      probably caused by hypocapnea resulting from the hyperventilation. This
      desaturation phase is much more prolonged in MD patients than in normal control
      subjects. The above data indicate further evidence of abnormal ventilatory
      regulation in MD.

PMID- 10655760
TI  - [Relationship between weight loss and dysphagia in patients with Parkinson's
      disease].
AB  - The purpose of this study was to investigate the relationship between weight loss
      and dysphagia in Parkinson's disease. We compared the height, body weight and the
      data of self-administered questionnaires concerning food intake and deglutition
      feelings in patients suffering from Parkinson's disease with normal controls. A
      structured interview was performed by nutritionists and nutrient intakes were
      calculated from the reported food intake over 5 days. Biochemical parameters were
      chosen from the chart. The subjects were 105 patients with Parkinson's disease,
      34 males with a mean age of 67.7 +/- 8.6 years and 71 females with a mean age of
      69.1 +/- 10.0 years (Hoehn-Yahr stage I6, II25, III51, IV20, V3). In addition, 47
      family members were used as control subjects: 26 males, 70.6 +/- 7.6 years and 21
      females, 64.9 +/- 7.7 years. Body mass index (BMI) in females with Parkinson's
      disease (20.2 +/- 3.5 kg/m2) was significantly lower (p < 0.005) than that in
      control females (23.0 +/- 3.0 kg/m2). There was no significant difference in BMI
      in males. The BMI was 21.9 +/- 3.0 kg/m2 in male patients with Parkinson's
      disease and 22.6 +/- 3.1 kg/m2 in controls. The occurrences of symptoms such as
      choking, cough, sputum, food in sputum, wet voice and pharyngeal discomfort
      following food intake in patients with Parkinson's disease vs. those in controls
      were 22% vs. 6%, 16% vs. 2%, 7% vs. 4%, 2% vs. 0%, 5% vs. 2% and 11% vs. 0%,
      respectively. Concerning symptoms such as choking, cough and pharyngeal
      discomfort, the occurrence was significantly more frequent in patients with
      Parkinson's disease than in controls (p < 0.05, p < 0.05, p < 0.05). We defined
      the dysphagic Parkinson patients as those who have at least one symptom of
      dysphagia such as choking, cough, sputum, food in sputum, wet voice and
      pharyngeal discomfort following food intake. The dysphagic subjects were present
      in 31% of Parkinson patients and in 7% of control subjects (p < 0.005), although
      half of the dysphagic Parkinson patients did not recognize it. No relationship
      between the occurrence of dysphagic symptoms and the Hoehn-Yahr stage was found.
      In patients with Parkinson's disease. BMI in the dysphagic group (19.1 +/- 3.6
      kg/m2) was significantly lower than that in the non-dysphagic group (21.6 +/- 3.0
      kg/m2) (p < 0.005). There was no relationship between BMI and the dose of
      levodopa. Patients in the dysphagic group showed significantly lower carbohydrate
      intake (186 +/- 49 g) than those in the non-dysphagic group (215 +/- 52 g) (p <
      0.05). Biochemical nutritional parameters were lower in the dysphagic group than
      those in the non-dysphagic group; 6.6 +/- 0.7 g/dl vs. 6.9 +/- 0.4 g/dl (p <
      0.005) in serum total protein, 3.8 +/- 0.5 g/dl vs. 4.1 +/- 0.4 g/dl (p < 0.01)
      in albumin and 173.4 +/- 33.0 mg/dl vs. 199.7 +/- 40.7 mg/dl (p < 0.05) in total
      cholesterol. These findings suggest that dysphagia, especially unrecognized
      dysphagia, plays a role in weight loss in Parkinson's disease.

PMID- 10655761
TI  - [Cerebral ischemia in patients with orthostatic syncope--the significance of
      orthostatic hypotension and large vessel disease in the cervical and intracranial
      region].
AB  - We performed 90 degrees head-up tilting test for 10 minutes in 100 patients (66
      men and 34 women) aged 50 years or more suffering from transient orthostatic
      syncope and measured their systolic blood pressure. Orthostatic hypotension (OH)
      was found in 51 patients, predominantly in men (38 cases). OH was complicated by
      large vessel disease (LV) as shown by MR angiography or carotid artery
      ultrasonography in 19 cases (37.3%). Progressive cerebral ischemia was found more
      frequently in patients with both OH and LV than in those with OH alone. Within
      the patients with OH alone, the drop in orthostatic blood pressure was greater in
      cases where progressive cerebral ischemia was present. In patients with both OH
      and LV, the minimum orthostatic systolic blood pressure was lower in those with
      progressive cerebral ischemia. These facts show that the marked drop in
      orthostatic blood pressure may be related to cerebral ischemic lesions and that
      the combination of OH and LV may develop cerebral ischemia in older patients with
      transient orthostatic syncope.

PMID- 10655762
TI  - [A case of typical Melkersson-Rosenthal syndrome with possible autosomal dominant
      inheritance].
AB  - Here we presented a case of 40-year-old woman who suffered from bilateral facial
      palsy and headache. She had allegedly had an episode of facial palsy, and facial
      edema at her age of 14 years. Physical examination revealed swelling of the lips,
      upward disturbance of the left eye, hypogeusia, the fissured tongue, and
      bilateral facial palsy. Oral administration of prednisolone 20 mg/day yielded
      gradual but complete improvement of the facial palsy and hypogeusia within two
      weeks. Careful analysis of family history disclosed that four members had oro
      facio-cervical edema and three had the fissured tongue. A diagnosis of Melkersson
      Rosenthal syndrome with possible autosomal dominant inheritance was made based on
      the clinical findings and familial aggregation of the incomplete form of this
      syndrome.

PMID- 10655763
TI  - [A case of stiff-man syndrome with head retraction like reflex myoclonus and
      jerky myoclonus of bilateral lower extremities which responded well to removal of
      mediastinal carcinoma].
AB  - A 58-year-old male presented with reflex myoclonus and stiffness of the left
      facial, tongue, shoulder, and lower limbs muscles. Muscle stiffness and gait
      progressively worsened, leading to frequent falls. Acoustic and cutaneous stimuli
      of head precipitated reflex myoclonus like head retraction. Cutaneous of lower
      extremities precipitated jerky myoclonus of bilateral lower extremities. CSF
      analysis were unremarkable. No anti GAD antibody or anti amphiphysin antibody was
      detected in the serum and CSF. On surface EMG the spasms initiated with 4-5 short
      burst discharges at intervals between 59 and 84 ms, followed by a tonic
      decrescendo activity up to 3 s. After diazepam treatment, stiffness and reflex
      myoclonus of lower extremities were disappeared and head retraction like reflex
      myoclonus was improved but remained. CT of the chest revealed a mediastinal
      tumor. Biopsy of the tumor revealed undifferential carcinoma. The patient further
      improved after the resection of the tumor. These findings suggest that this stiff
      man syndrome may occur as an autoimmune paraneoplastic syndrome of CNS.

PMID- 10655764
TI  - [A peculiar MRI findings in a case with slowly progressive cerebral ischemia
      caused by internal carotid artery stenosis possibly due to fibromuscular
      dysplasia].
AB  - A 47-year-old man developed progressive muscular weakness in the left arm. MR
      images revealed low intensity signal lesions with ring enhancement by Gd-DTPA in
      right fronto-parietal lobes. At that time cerebral angiography was not performed
      because he refused. A tuberculin skin test showed strongly positive reaction and
      then administration of anti-tuberculous drugs was started. His symptom had
      remained stable for one year, but left facial palsy and dysarthria added about
      two years later. MR images revealed expansion of the lesions in right parietal
      lobe, adding cortical high intensity signal lesions with Gd-DTPA enhancement on
      T1-weighted images. Angiography disclosed tubular stenosis of right internal
      carotid artery at the portion of cervical to petrous segment and the local
      stenosis at right renal artery. These lesions were considered to be caused by
      fibromuscular dysplasia, but not atherosclerosis, because we could not find any
      atherosclerotic lesions in other arteries including right carotid bifurcation.
      His manifesting symptoms were ascribed to slowly progressive cerebral ischemia.
      And peculiar MRI findings in his early stage resembled those of inflammatory
      granulomatous diseases.

PMID- 10655765
TI  - [A case of simultaneous medullary hemorrhage and hematomyelia].
AB  - We reported a case of simultaneous medullary hemorrhage and hematomyelia. A 93
      year-old woman, who had hypertension, was admitted to our hospital because of
      headache, numbness and weakness of the left extremities, and somnolence. On
      admission, weakness and disturbance of tactile sensations were observed in the
      left extremities. Magnetic resonance imaging showed medullary hemorrhage and
      hematomyelia and these two lesions were separated. Medullary hemorrhage was at
      the left dorsal paramedian area within mid-lower medulla oblongata, and
      hematomyelia was at the left side of the gray matter from medullo-cervical
      junction to upper cervical cord. Five days later from admission, weakness
      occurred in the right lower extremity and also in the upper extremity. This
      process suggested that the main lesion of tetraparesis was medullo-cervical
      junction. Review of 16 cases of medullary hemorrhage demonstrated that frequent
      neurological signs were palatal weakness, nystagmus, and disturbance of pain and
      temperature sense. But our case showed only disturbance of tactile sensations.
      Review of 19 cases of hematomyelia demonstrated that frequent neurological signs
      were sensory disturbance, paralysis and localized pain. Our case showed only
      paralysis. The cause of simultaneous hemorrhage was considered arteriovenous
      malformation or simultaneous multiple hypertensive hemorrhages.

PMID- 10655766
TI  - [A case of relapsing polychondritis with oculobulbar symptoms and successful
      treatment of respiratory failure with BiPAP].
AB  - A 66-year-old man developed diplopia, ptosis, dysphagia, and acute respiratory
      failure. The initial diagnosis was myasthenia gravis and prednisolone had been
      administrated for three years. Because of recurrent upper respiratory infections,
      prednisolone was tapered off. Two months later, auricular chondritis, arthritis,
      and conjunctivitis appeared. He was diagnosed as having relapsing polychondritis
      on the basis of histological findings of the ear lobe biopsy. Reinstituted
      prednisolone had the effect on the auricular chondritis, arthritis, and
      conjunctivitis, but no effect on dysphagia, hoarseness, and respiratory failure
      caused by the deformity of the pharynx and airway. Tracheal collapse usually
      causes rapid death, so early tracheostomy and the use of endotracheal prostheses
      have been recommended in patients with airway obstruction from relapsing
      polychondritis, but such surgical management can only partially open up the large
      airways and has no effect on smaller airways. In this case tracheostomy and
      endoluminal stent placement have helped improve the patient's respiratory
      failure, but have had little effect on its aggravation at night in the supine
      position. The use of BiPAP after surgical management can be an effective
      treatment for airway involvement in relapsing polychondritis probably because it
      keeps the narrowed airways from collapsing, especially at night.

PMID- 10655767
TI  - [A case of Bickerstaff's brainstem encephalitis during pregnancy].
AB  - Here we present a case of 23-year-old woman with Bickerstaff's brainstem
      encephalitis (BBE) during 13 weeks of pregnancy. After symptoms of the upper
      respiratory tract infection, she developed somnolence, marked disturbance of
      extraocular eye movements, cerebellar ataxia, hyperreflexia and spasticity of the
      lower limbs. An electroencephalogram revealed slow waves and brainstem auditory
      evoked potential disclosed prolongation of III-V interpeak intervals. Serum IgG
      anti-GQ1b antibody was detected. Plasma exchanges (PE) were performed four times.
      Although no patient with BBE during pregnancy has ever been reported, in the
      literatures the pregnant patients with Guillain-Barre syndrome had four sessions
      of plasmapheresis with safe. Neurological symptoms gradually improved after the
      PE. No serious adverse effects were noted. Although no definite therapy for BBE
      has been established, PE may be one of the selections even if the patients is
      pregnant.

PMID- 10655768
TI  - [Liver transplantation in type II citrullinemia].
AB  - We reported a case of adult-onset citrullinemia associated with
      hypertrigliceridemia and diabetes mellitus. A 24-year-old female was healthy
      until recently. She first felt intermittent headaches and nausea. Then she
      noticed memory loss and tiredness. Abnormal behavior such as getting lost on the
      way from her company sometimes occurred. She came to our hospital because these
      symptoms had been getting worse. Neurologically she had a very mild disturbed
      consciousness. An EEG recording showed diffuse slow wave with high amplitude. MR
      image of the brain showed hyper-intensity in globus pallidus with T1-weighted
      image. Plasma citrullin level was very high. Plasma ammonia and triglyceride
      showed a moderately high level. Using biopsied liver tissues, the enzymes of the
      urea cycle were analyzed. Argininosuccinate synthetase activity was extremely
      low. Because of clinical course and the result of liver biopsy, the patient was
      diagnosed as type 2 citrullinemia. A low protein diet was started, but
      intermittent nausea and consciousness disturbance did not improve. A partial
      liver transplantation was performed. The living donor was her father, a 50-year
      old male, who had normal liver function. After the liver transplantation, all
      neurological signs soon disappeared. Plasma citrulline, ammonia and triglyceride
      normalized rapidly. An EEG recording became normal, and the hyper-intensity in
      globus pallidus with T1-weighted MR image disappeared two months after surgery.
      Liver transplantation should be planned as soon as possible in a type 2
      citrullinemia patient.

PMID- 10655769
TI  - [A case of Miller Fisher syndrome with gadolinium-enhancing lesions in the
      cranial nerves and the cauda equina on magnetic resonance imaging].
AB  - MRI findings for a patient with Miller Fisher syndrome (MFS) are reported. A 25
      year-old woman presented with blephaloptosis, double vision, and gait disturbance
      after antecedent upper respiratory infection. Neurologic examination on admission
      revealed bilateral blephaloptosis and restriction of extraocular movement. She
      was unable to maintain an upright posture, nor able to walk because of severe
      truncal ataxia. Mild limb ataxia was also seen. The tendon reflexes were
      generally absent and she had hypesthesia in her shoulder and upper limbs. On the
      next day, her eyes became fixed in the central position. Based on these
      characteristic symptoms, she was diagnosed as having MFS and underwent
      plasmapheresis therapy six times. Although ataxia gradually reduced,
      ophthalmoplegia did not improve and severe symmetric facial nerve palsy appeared.
      Antiganglioside IgG antibodies (anti-GQ1b and GD1b) were detected in the sera on
      admission. Spinal fluid examination on day 18 revealed 5 cells/microliter and
      protein 171 mg/dl. T1-weighted images with Gd-DTPA on day 15 demonstrated
      enhancement of the posterior nerve roots of the cauda equina. MRI on day 32
      revealed swelling and enhancement of the bilateral oculomotor nerves, as well as
      the facial nerves and the abducens nerves. Marked improvement of ophthalmoplegia
      followed high dose intravenous immunoglobulin therapy. Gd-enhanced MRI after
      recovery showed no enhancement of the cauda equina, nor the cranial nerves. These
      findings well correlated with her clinical features. Although abnormal Gd
      enhancement of the cranial nerves or cauda equina in several neurological
      disorders has been documented, similar findings have been rarely reported in MFS.
      In our patient, IgG anti-GQ1b and GD1b antibodies were detected and the
      distribution of Gd-enhanced lesions was compatible with the distribution of the
      involved gangliosides. We suggest that contrast enhanced MRI is useful for
      identifying affected cranial nerves and cauda equina nerve roots. In addition,
      MRI may play a significant role in disclosing the pathophysiology of this
      disease.

PMID- 10655770
TI  - [Medial medullary infarction: report of three patients presented with central
      vestibular dysfunction without limb and lingual weakness].
AB  - The purpose of this article is to draw attention to atypical presentation of
      medial medullary infarction (MMI). With advanced imaging techniques, small
      infarctions occurring in the medulla are more easily identified. It is difficult,
      however, to make a clinical diagnosis of MMI if both hypoglossal nerve palsy and
      limb weakness are absent, because motor weakness is considered a cardinal
      manifestation of MMI. We describe here three patients who developed central
      vestibular dysfunction due to MMI without limb and lingual weakness. Case 1: A 44
      year-old, diabetic woman developed vomiting and numbness on her left upper limb.
      Examination revealed unidirectional horizontal and rotatory nystagmus beating
      toward the right side. There were no Horner syndrome and hypoglossal nerve palsy.
      Barre arm and leg signs and limb ataxia were absent. Romberg sign was negative.
      Hypesthesia was present on her left forearm, hand, and fingers. Thumb-localizing
      test was normal. Cranial MRI demonstrated an infarction in the right paramedian
      region of the upper medulla. MR angiography demonstrated irregularity of the
      basilar and the left vertebral arteries. Case 2: A 69-year-old woman suffered
      from dizziness and nausea. She showed unidirectional, left-beating horizontal
      nystagmus. There were no Horner syndrome and hypoglossal nerve palsy, Barre arm
      and leg signs, and limb ataxia. MRI disclosed an infarction in the left upper
      medial medulla. Case 3: A 47-year-old man developed vertigo when turning over in
      bed. He showed left-beating nystagmus without latency, when lying down. Horner
      syndrome and hypoglossal nerve palsy were absent MRI showed bilateral MMI, with
      the right lesion being larger than the left. MR angiography demonstrated a
      stenosis in the distal portion of the left internal carotid artery but not in the
      vertebral and basilar arteries and their branches. This case represents central
      positional vertigo. Vestibular syndrome seen in cases 1 and 2 was incomplete and
      incongruent, suggesting dysfunction of the central vestibular system. There have
      been only nine cases of MMI with horizontal nystagmus in primary position,
      including unidirectional horizontorotatory nystagmus. In these cases, horizontal
      nystagmus beats toward the side of the lesion. In sharp contrast, horizontal
      nystagmus typically beats away from the lesion side in cases of Wallenberg
      syndrome, suggesting different underlying mechanism. Unidirectional horizontal
      and rotatory nystagmus is generally associated with peripheral vestibular
      dysfunction. There has been no reported case of MMI presenting with vestibular
      dysfunction preserving motor power. Thus, this "benign" form of MMI might have
      been misdiagnosed as peripheral vestibular dysfunction before the era of MRI.

PMID- 10655771
TI  - [A case of myotonic dystrophy with intestinal pseudo-obstruction syndrome].
AB  - We experienced a patient of myotonic dystrophy presenting with intestinal pseudo
      obstruction syndrome (IPOS). He was admitted to our hospital because of
      repetitive vomiting lasting for 24 hours. Abdominal CT revealed dilated stomach,
      duodenum and jejunum with extensive fluid residues. This patient was successfully
      treated with conservative therapy by using intravenous administration of
      metoclopramide. The etiology of IPOS in myotonic dystrophy is not well
      understood. In addition to normal findings of autonomic function tests such as R
      R interval, Schellong test and sympathetic skin response, the efficacy of
      metoclopramide in treating IPOS suggests that acetylcholine (ACh) release is
      relatively preserved from the intestinal nerve plexus. Denervation
      hypersensitivity at the ACh receptors from long-standing dysfunction of autonomic
      system may be related to the cause of IPOS in myotonic dystrophy.

PMID- 10655772
TI  - [The clinical usefulness of MRI diffusion weighted images in herpes simplex
      encephalitis-like cases].
AB  - We examined the serial MRI diffusion weighted images (DWIs) in two patients with
      acute viral encephalitis similar to herpes simplex encephalitis (HSE). Patient 1.
      A 27-year-old woman was admitted to the psychiatry ward for her confusional state
      and convulsions. Because of abnormal CSF findings she was transferred to the
      neurology ward, and the infusion of acyclovir was started. On disease day 5. MRI
      demonstrated high signal intensity in the left lateral lobe both on T2 weighted
      images (T2WIs) and DWIs. On day 18, MRI showed progression of the lesions, so
      acyclovir was changed to ara-A. On day 26, no improvement was seen clinically or
      radiologically. Then, combination therapy with acyclovir, ara-A and gamma
      globulin was began. On day 36, she recovered completely, and abnormal intensity
      in MRI disappeared both on T2WIs and DWIs. Therefore, antiviral agent therapy was
      discontinued. Patient 2. A 31-year-old man was admitted for headache, fever and
      aphasia. On the next day, acyclovir was started and both DWIs and T2WIs of MRI
      demonstrated a high signal intensity in the left temporal lobe. Ten days later,
      he became perfectly well, and the increased signal intensity disappeared on DWIs,
      but not on T2WIs. Treatment was therefore discontinued. No relapse was in either
      patient. We concluded that serial MRI DWIs may be useful to determine when to
      discontinue the treatment in encephalitis.

PMID- 10655773
TI  - [Cauda equina syndrome due to recurrent malignant lymphoma of the spinal cord. A
      case report].
AB  - A 50-year-old man noticed a mass in the right cervical region and presented to
      our hospital. He underwent biopsy of a cervical lymph node, which revealed non
      Hodgkin's lymphoma (diffuse large B cell, lymphoblastic type) histologically. He
      was treated with chemotherapy (CHOP) and radiation, and achieved complete
      remission. Two months later, he was admitted because of distal pain and extensive
      numbness of the lower limb as well as weakness of the left leg. Lumbar MRI showed
      an area of abnormal intensity in the cauda equina. Cytological examination of
      cerebrospinal fluid showed class V (lymphoma cells), so he was diagnosed as
      having recurrent malignant lymphoma of the spinal cord. He was treated with
      intrathecal chemotherapy and irradiation. After the treatment the mass in the
      cauda equina disappeared and the neurological symptoms in his legs resolved. It
      is rare for malignant lymphoma to recur in the spinal cord, particularly the
      cauda equina. It is well known that cauda equina syndrome can be caused by
      vertebral lesions and primary spinal cord tumors, but it is also necessary to
      keep malignant lymphoma of the cauda equina in mind.

PMID- 10655774
TI  - [A case report of valproate encephalopathy].
AB  - A 24-years-old woman with epilepsy treated with valproic acid developed
      disorientation, acalculia, perseveration, slow responsiveness and loss of memory.
      The drug withdrawal induced a quick improvement of mental function. In this case,
      hyperammonemia, hypocarnitinemia, increased protein in cerebrospinal fluid were
      found. When the drug was discontinued, she had a dramatic improvement. Valproic
      acid caused encephalopathy because of metabolic abnormality in mitochondria in
      this case. In the cases of encephalopathy caused by valproic acid, the drug
      administration should be withdrawn, and appropriate measures had to be taken. In
      addition, elevation of ammonia in the blood, lactic acid and pyruic acid in the
      serum and cerebrospinal fluid, and decreased carnitine level in the serum will be
      useful to make a diagnosis of valproate-induced encephalopathy.

PMID- 10655775
TI  - [Report of the first congress of the "European Society for Emerging Infections".
      (Budapest, 13-16 September 1998)].
AB  - The first congress of the recently founded European Society for Emerging
      Infections was held in Budapest from 13 to 16 September 1998. About 200
      physicians, veterinarians, biologists and microbiologists attended this meeting.
      The euphoria of the 1970's with respect to infectious diseases is now gone.
      During the last twenty years about thirty new infections agents have been
      identified and re-emergence of old diseases which had disappeared to a large
      extent, has been reported in many countries. Most newly emerging diseases in man
      are of zoonotic origin or are closely related to disease in animal (wild or
      domestic) showing a parallel pathology. The nature of the etiologic agents varies
      widely: prions, viruses, chlamydia, rickettsiae, bacteria, protozoa etc. Several
      factors play a role in the emergence: mutations of the agents themselves;
      changing habits of man as the host: travel, sexual habits, etc.; modifications of
      the climate or environment can influence the expansion of vectors. The subjects
      discussed at the congress covered a wide field of diseases and agents: plague,
      retroviruses, antibiotic-resistant bacteria, influenza, lyme borreliosis, tick
      borne encephalitis, hantaviruses, rickettsioses and ehrlichiose, transmissible
      spongiform encephalopathies, Borna, lyssaviruses, E. coli, protozoa, chlamydia,
      etc.

PMID- 10655776
TI  - Infections with flaviviridae.
AB  - The family of the Flaviviridae contains 3 genera: (i) the hepaciviruses, to which
      belongs Hepatitis C virus (HCV), (ii) the flaviviruses and (iii) the
      pestiviruses. Over 140 million people, more than four times the number of HIV
      positive individuals, are chronically infected with the HCV. Hepatitis G virus
      (HGV) has not yet been assigned to a genus. The impact of this recently
      discovered virus is yet to be established. Infections with flaviviruses such as
      Yellow Fever virus (YFV), Dengue Fever virus (DENV), Japanese Encephalitis virus
      (JEV) and Tick-borne Encephalitis virus (TBEV) are emerging world-wide. The
      Pestiviruses, Bovine Viral Diarrhea virus (BVDV), Classical Swine Fever virus
      (CSFV) and Border Disease virus (BDV) have a serious impact on life-stock. At
      present, only treatment with interferon, alone or combined with ribavirin, has
      been approved for the treatment of HCV infections. No specific antivirals are
      available for the treatment of infections with Hepaci-, Flavi- or Pestiviruses.
      Possible targets for inhibition of the replication of Flaviviridae are the
      binding to, and the uptake of the virus in the cell; the internal ribosomal entry
      site (IRES) of Hepaci- and Pestiviruses; viral proteases; the viral RNA-dependent
      RNA polymerase and the viral helicase. The search for specific inhibitors of HCV
      replication is hindered by the absence of an efficient cell culture system for
      propagation of this virus. In addition, small laboratory animals, including mice,
      are not susceptible to HCV infection. Flaviviruses may cause infection in mice,
      but do so mainly following direct intracerebral inoculation. We have established
      a small animal model for flavivirus infections in SCID mice inoculated
      peripherally with the murine flavivirus Modoc.

PMID- 10655777
TI  - [Hantavirus infections in Belgium].
AB  - Hantavirus disease is a recently recognised zoonosis. The main vectors are
      infected but healthy wild rodents or laboratory rats. Transmission to man occurs
      via contact with, or inhalation of aerosolised excretions. The target organs in
      man are the kidney (Old World) or the lung (New World), probably via a local
      hyperproduction of pro-inflammatory cytokines. To date, more than 33 different
      hantaviruses have been characterised, at least 14 of them being of clinical
      importance. Each serotype has its own rodent vector and its own geographical
      spread. In Europe, the red bank vole (Clethrionomys glareolus) is the main rodent
      vector, carrying the Puumala (PUU) serotype, which is the etiologic agent of a
      viral affection known as Nephropathia epidemica (NE). PUU infection has been
      recognised for the first time in Belgium in 1983. From this date on,
      approximately 500 cases have been diagnosed. In our regions, a diagnosis of
      hantavirus disease is mandatory when a febrile patient presents with lumbaches,
      headache, and an acute renal failure with proteinuria, and particularly with
      thrombocytopenia.

PMID- 10655778
TI  - [Basic studies on the utility of ursodeoxycholic acid derivatives for clinical
      medicine].
AB  - The aim of this study was to determine whether the derivatives of ursodeoxycholic
      acid (UDCA) are useful compounds for clinical medicine. 1-1) A conjugate (5-ASA
      UDCA monophosphate) of UDCA monophosphate with 5-aminosalicylic acid (5-ASA) was
      newly synthesized, and basic studies on this compound were carried out. This
      compound was efficiently deconjugated by cholylglycine hydrolase (CGH) to release
      5-ASA, whereas it was completely resistant to deconjugation by pancreatic and
      intestinal mucosal enzymes. In animal experiments, the urinary excretion of N
      acetyl-5-ASA (Ac-5ASA) was measured for 24 h following the oral administration of
      20 mg of 5-ASA-UDCA monophosphate. Control rats excreted 276.3 +/- 89.0
      micrograms (mean +/- S.E.) of Ac-5ASA whereas rats with intestinal bacterial
      overgrowth excreted more (1224.1 +/- 231.5 micrograms; p < 0.01). These basic
      studies indicate that this compound is likely to offer a simple method for the
      evaluation of intestinal microorganisms without the use of radioisotopes or
      expensive, special apparatus. 1-2) The disulphate ester of ursodeoxycholyl-p
      aminobenzoic acid (PABA-UDCA) was synthesized and compared with PABA-UDCA for its
      use in the detection of intestinal bacteria. This compound, PABA-UDCA disulphate,
      had characters in common with PABA-UDCA in that it was deconjugated by CGH to
      release free PABA. Further, in rat experiments the urinary excretion of PABA was
      measured for 6 h after oral administration of 15 mg PABA-UDCA disulphate. Ten
      control rats excreted 188.2 +/- 13.6 micrograms (mean +/- S.E.) of PABA; 10 rats
      with an intestinal stagnantloop excreted more (530.1 +/- 30.1 micrograms; p <
      0.001): whereas 10 rats in each of three groups pretreated with oral
      administration of various antibiotics excreted less. PABA-UDCA disulphate is a
      single pass type substance in the gut and its oral administration test reflects
      the sum of the activities of bacteria in the small intestine and colon. From the
      results the obtained PABA-UDCA disulphate was considered a good material to
      detect intestinal bacteria. 2) A conjugate (Lys-UDCA) of UDCA with L-lysine was
      newly synthesized. In the incubation experiments with plasma, homogenates of the
      liver and small intestine, various pancreatic enzymes and CGH, Lys-UDCA was
      deconjugated by carboxypeptidases B and CGH. In the experiment using rodent
      everted gut sac, Lys-UDCA was actively absorbed from the terminal ileum. Lys-UDCA
      was recovered well in the bile after intravenous or intraileal administration of
      Lys-UDCA in biliary fistula rat. These data suggest that Lys-UDCA is a good
      prodrug of UDCA for intravenous administration. 3) A novel calcium-chelating
      agent, N"-ursodeoxycholyl-diethylenetriamine-N,N,N'-triacetic acid (UDCA-DTTA),
      was synthesized to study its ability to dissolve calcified gallstones. In the
      presence of the agent, sliced human gallstone with a composition of more than 50%
      calcium bilirubinate was thoroughly dissolved, indicating that calcium
      bilirubinate was dissolved from the gallstone. The ability to dissolve calcium
      was comparable to that of EDTA. However, the laminar structure of the sliced
      gallstone did not disappear in the presence of EDTA, whereas the structure
      disappeared in the presence of UDCA-DTTA. These results indicate that UDCA-DTTA
      is an interesting compound as a parent substance for developing a prodrug for an
      oral or intravenous agent to dissolve calcium-containing gallstones.

PMID- 10655779
TI  - [Bioenergetics of marine bacteria--respiration-coupled Na+ pump].
AB  - Marine bacteria are unique in the requirement for Na+ for optimal growth. Using a
      marine bacterium Vibrio alginolyticus, it was confirmed that Na+ is essential for
      the active uptake of all amino acids. Furthermore, the respiratory chain of V.
      alginolyticus was found to require Na+ for the maximum activity. The site of
      Na(+)-dependent activation is localized in the NADH-quinone reductase segment,
      where Na+ is extruded from the cells as a direct result of redox reaction. Thus,
      marine bacteria are able to directly generate sodium-motive force by respiratory
      chain activity. The sodium-motive force is directly coupled to the active uptake
      of nutrients and to the rotation of polar flagella. In addition to the energy
      coupling by proton circulation, marine bacteria are unique in utilizing Na+
      circulation for the energy coupling. The latter mode of energy coupling is
      superior to proton circulation especially at alkaline and Na(+)-rich conditions.
      The respiration-coupled Na+ pump is widely distributed among Gram-negative marine
      and moderately halophilic bacteria. Recently, it was found that the same type of
      Na+ pump is distributed in the Gram-negative pathogenic bacteria. Since the
      presence of Na+ pump widens the adaptability of bacteria to grow at harsh
      environments, Na+ pump is likely to be helpful for the growth of pathogenic
      bacteria in the host cells to manifest their pathogenicity.

PMID- 10655780
TI  - [Development of highly stereoselective reactions utilizing heteroatoms-
      asymmetric synthesis of alpha-substituted serines].
AB  - This article reviews the efficient methods for diastereoselective and
      enantioselective syntheses of alpha-substituted serines. A newly designed
      bislactim ether, ethyl (5S)- or (5R)-3,6-diethoxy-2,5-dihydro-5-isopropyl-2
      pyrazinecarboxylate, was treated with base or Lewis acid-tertiary amine to
      generate an enolate or enaminate (imine anion, metalloenamine). Alkylation or
      aldol-type reaction with the resultant enolate or enaminate proceeded in a highly
      diastereoselective manner to give the corresponding alkylated or aldol products,
      respectively. Reduction of these products with diisobutylaluminum hydride (DIBAL)
      followed by hydrolysis with hydrochloric acid afforded the desirable alpha
      substituted serines. The enantioselective aldol-type reaction of an achiral
      bislactim ether, ethyl 3,6-diethoxy-2,5-dihydro-2-pyrazinecarboxylate, was also
      investigated by employing Sn(OSO2CF3)2-triethylamine in the presence of an
      external chiral ligand, (--)-sparteine. Not only a stoichiometric amount, but
      also a catalytic amount of (--)-sparteine promoted the highly enantioselective
      aldol-type reactions. Interestingly, the stereoselective outcome of the Sn(II)
      mediated reaction differed from that of the Mg(II)-mediated one in the aldol-type
      reaction of the bislactim ethers with aliphatic aldehydes. On the other hand,
      chemoenzymatic synthesis of enantiomerically pure alpha-substituted serines must
      also be a convenient and useful procedure. Porcine liver esterase (PLE) or rabbit
      liver esterase (RLE) catalyzed hydrolysis of the pro-S ester group of diethyl
      alpha-alkyl-alpha-(benzyloxycarbonylamino)malonates to afford (R)-ethyl alpha
      alkyl-alpha-(benzyloxycarbonylamino)malonates each in excellent enantiomeric
      excess. Enantiodivergent reductions of these acid esters readily proceeded to
      furnish both the corresponding enantiomeric alpha-substituted serines. Finally,
      the application of these methodologies mentioned above to a total synthesis of
      ISP-I (a potent immunosuppressive principle in the Isaria sinclairii metabolite)
      is described. Asymmetric total synthesis of ISP-I has been achieved in a highly
      stereoselective manner by utilizing the Mg(II)-promoted aldol-type reaction with
      ethyl (5R)-3,6-diethoxy-2,5-dihydro-5-isopropyl-2-pyrazinecarboxylate and
      Schlosser modification of the Wittig reaction.

PMID- 10655781
TI  - [Synthesis of carbohydrate related compounds by using aldolase catalyzed
      reaction].
AB  - Enzymes proceed the reaction with high regio- and stereoselectivity under mild
      conditions, i.e. in an aqueous medium at room temperature. However, enzymatic
      reactions that catalyze carbon-carbon bond formation have not been utilized in
      organic synthesis until recently. We had an interest in an aldolase-catalyzed
      reaction which proceed carbon-carbon bond formation referred to aldol
      condensation, by which many bioactive compounds have been rationally synthesized.
      On the other hand, recent biological studies on cell recognition (cell adhesion)
      have disclosed the important roles of oligosaccharides on cell surfaces,
      especially which include glucuronic acid, 3-deoxy-D-manno-oct-2-ulosonic acid
      (KDO), and sialic acid in the structures e.g., sialyl Lewis X and endotoxins, in
      differentiation, induction, viral and bacterial infections, and immune response.
      As well as acidic oligosaccharides, basic ones have been utilized as practical
      medicines in the clinical level, like acarbose that acts as an amylase inhibitor.
      Based on these background, we embarked the synthesis of carbohydrate related
      compounds which can control the interaction between carbohydrates and
      carbohydrate recognition protein by the use of several aldolases. Azasugars,
      potent inhibitors toward glycosidases, were synthesized using fructose-1,6
      diphosphate (FDP)-aldolase and other dihdroxyacetonephosphate (DHAP)-dependent
      aldolases in the key step. Sialyl Lewis X mimetic, peptidic mimetic of RNA having
      anti-Vero toxin activity, mycestericin D, and aza-idulonic acid were prepared by
      taking advantage of L-threonine aldolase catalyzed reaction, which afford beta
      hydroxy-alpha-L-amino acids. A precursor of KDO, featured acidic sugar of
      endotoxins was provided by the reaction catalyzed with kynureninase, which
      generates beta-anion of L-alanine in its active site during the metabolic
      reaction from kynurenine to anthranilic acid.

PMID- 10655782
TI  - [Development of new deprotecting methodologies for peptides and application to
      studies on signaling mechanism].
AB  - This review summarizes the development of deprotecting methodologies for peptides
      and their practical application to the synthesis of disulfide bond- or
      phosphoamino acid-containing peptides. Acidic deprotecting systems utilizing
      Bronsted acid (HF, trifluoromethanesulfonic acid (TFMSA) and HBr etc.) have been
      used for the removal of protecting groups in peptide chemistry; however, these
      reagents are not always applicable to all of the peptides including cystine- or
      phosphoamino acid-containing peptides. Our attempt to utilize Lewis acid for the
      deprotective reaction resulted in the development of efficient and practical
      reagent systems (1 M trimethylsilyl trifluoromethanesulfonate (TMSOTf)-sulfide in
      trifluoroacetic acid (TFA) and 1 M trimethylsilyl bromide (TMSBr)-sulfide in TFA)
      suitable for peptide synthesis. A new disulfide bond-forming reaction using
      Tl(OCOCF3)3 was developed for the synthesis of cystine peptides. The use of
      TMSOTf or TMSBr-mediated deprotecting system in conjunction with the disulfide
      bond-forming reaction utilizing Tl (III) provides a procedure for the practical
      synthesis of cystine peptides. A two-step deprotection method consisting of high
      acidic (1 M TMSOTf-thioanisole in TFA, m-cresol, ethanedithiol) and low acidic
      (high acidic system + dimethyl sulfide--TMSOTf) treatments was successfully
      applied to the deprotection of protected phosphopeptide with dimethyl-protected
      phosphoamino acids. Furthermore, we synthesized phosphatase-resistant
      phosphoamino acid isosters bearing the substitution of a phosphate oxygen with a
      difluoromethylene. The syntheses of peptides possessing these nonhydrolyzable
      phosphoamino acids were achieved utilizing two-step deprotecting methodologies.
      Additionally, we demonstrated the usefulness of phosphatase-resistant
      phosphopeptides as biochemical tools for understanding signal transduction.

PMID- 10655783
TI  - [Synthesis and application of novel biaryl compounds with axial chirality as
      catalysts in enantioselective reactions].
AB  - A highly efficient process of aerobic oxidative coupling of 2-naphthol
      derivatives catalyzed by Cu(OH)Cl.TMEDA has been developed. Enantioselective
      oxidative coupling of 2-naphthol derivatives was achieved by the use of a chiral
      catalyst prepared from proline-derived diamine and cuprous chloride, affording
      the corresponding BINOL derivatives in good enantioselectivities of up to 78% ee.
      A new catalytic, enantioselective allylation of aldehydes with
      allyltrichlorosilanes exploiting (S)-3,3'-dimethyl-2,2'-biquinoline N,N'-dioxide
      as a catalyst affords homoallylic alcohols in virtually complete
      diastereoselectivities and high enantioselectivities of up to 92% ee, wherein the
      use of diisopropylethylamine as an additive has proven to be crucial for the
      acceleration of the catalytic cycle. It is also noteworthy that the above finding
      represents the first successful example of asymmetric reactions utilizing amine N
      oxide as a chiral catalyst.

PMID- 10655784
TI  - [Phorbols: chemical synthesis and chemical biology].
AB  - The phorbol esters, such as phorbol 12- myristate 13-acetate (PMA), are known to
      be powerful tumor promoters and activators of protein kinase C (PKC). First
      discovered by Nishizuka et al., PKC is a phospholipid- and calcium-dependent
      serine/threonine kinase, phisiologically activated by 1,2-diacyl-sn-glycerol
      (DAG). PKC is also known to be an important target for other structurally diverse
      tumor promoters such as ingenols, teleocidins, and aplysiatoxins. Structure
      activity analyses of a variety of analogs of DAG and these tumor promoters have
      been carried out. Although many pharmacophore models have been proposed from
      molecular modeling, no information about specific amino acid residues that
      interact with these ligands is available. Moreover it has been shown that the
      biological activity of 11-demethyl-13-deoxyphorbol esters 1, which were
      synthesized by our group, was not fully consistent with the pharmacophore models
      so far. Thus, we are now interested in determining the importance of the 13
      acetoxy group in phorbol ester-PKC complexes. This has led us to design new
      photoaffinity probes 66 and 67 and to carry out previously unprecedented
      photoaffinity labeling of PKC. Photoaffinity labeling of protein kinase C
      isozymes by both the probes resulted in specific cross-linking. Although the
      cross-linking yield is not very high, we suppose that determination of the cross
      linking site can be realized by taking advantage of subpicomole order analysis by
      mass spectrometry and other methodologies to clarify the role of individual
      cysteine rich domein (CRD) in native PKC. We have also designed a new phorbol
      ester-phosphatidylserine hybrid molecule 69. Because phosphatidylserines in
      phospholipid membranes are known to have specific interactions with phorbol ester
      PKC complexes, such a hybrid molecule can be expected to act as a specific
      inhibitor of PKC by preventing PKC from interacting with phospholipid membranes.
      The hybrid molecule was synthesized and preliminary biological activities were
      examined to inhibit PKC. A catalytic asymmetric synthesis of phorbol PMA is also
      currently under investigation. Progress is discussed.

PMID- 10655785
TI  - [Structure-protection mechanism of dipalmitoylphosphatidylcholine liposomes by
      adsorption of sucrose molecules in the liposome surface].
AB  - Molecular mechanism of structure-protection of dipalmitoylphosphatidylcholine
      (DPPC) liposomes by sucrose adsorption on/in the liposome surface was studied by
      performing fluorescence decay, quartz-crystal microbalance (QCM), and infrared
      reflection-absorption (IRRA) spectroscopic measurements. Thermally hydrated DPPC
      monolayers were newly introduced in place of the conventional DPPC liposomes,
      since the hydrated monolayers were expected to have similar surface property to
      that of liposomes. Studies of the fluidity and permeability of membrane in the
      monolayers and liposomes suggested that the thermally hydrated DPPC monolayers
      could be used as a model membrane in place of DPPC liposomes. With the hydrated
      DPPC monolayers, the adsorption rate of sucrose molecules in the DPPC monolayer
      was investigated by a combined technique of QCM and IRRA by the use of Langmuir
      Blodgett (LB) technique. It was found that the incorporation rate of sucrose into
      the monolayer in the liquid-expanded state was proportional to the bulk
      concentration of sucrose in the Langmuir trough. The linear relationship depicts
      the incorporation mechanism that sucrose molecules were deeply incorporated in
      the DPPC molecules, and the layer is formed as a single mingled layer. This
      molecular scheme readily supports the conventional hypotheses based upon water
      replacement and vitrification mechanisms. The IRRA spectra were further studied
      using newly found property of principal component analysis (PCA). PCA was found
      to have great potential to detect minute bands hidden in dominantly large bands,
      after theoretical speculation and simulations. The new analytical technique was
      employed to search for an unknown minute spectrum in the collection of raw
      spectra. The calculated abstract spectra yielded by PCA strongly suggested that
      there remained minute quantity of water in the dried LB films. The water
      molecules were also found to bind to PO2 group in the head group moiety of DPPC.
      The mass change of adsorbed and incorporated sucrose molecules in the DPPC
      monolayer were readily distinguished by PCA without any probe molecule, and they
      were followed semi-quantitatively by calculation of scores.

PMID- 10655786
TI  - [Chemical control of cell differentiation of human myeloleukemia K562 cell line].
AB  - Human myeloid leukemia K562 cells can be induced to differentiate to mature cells
      bidirectionary, i.e., hemin induces erythroid differentiation, while 12-O
      tetradecanoylphorbol 13-acetate (TPA) induces differentiation to monocytes. The
      differentiation-inducing activity of various hemin-related compounds suggested
      certain structural requirements for the activity: 1) the iron moiety of hemin is
      not essential, and 2) the propionic acid side chains of hemin play an important
      role in the differentiation and induction. In addition, we have examined the
      influence of some bioresponse-modifying factors on hemin/protoporphyrin IX
      induced differentiation of K562 cell line. Retinoids and tubulin-disruptors,
      themselves did not induce differentiation, enhanced hemin/protoporphyrin IX
      induced differentiation of K562 cells. We also examined the possible involvement
      of peripheral-type benzodiazepine receptor (PBR) in hemin/protoporphyrin IX
      induced differentiation on K562 cell lines. The PBR specific ligands modified
      hemin-induced differentiation. These results suggest a requirement for retinoids
      (or retinoids-like cofactors) for hemin/protoporphyrin IX-induced differentiation
      of K562 cells and the involvement of PBR in erythroid differentiation of K562
      cell line. Further we showed that TPA suppresses hemin-induced erythroid
      differentiation of K562 cells, while retinoids augment it. TPA is a potent
      inducer of heme oxygenase (HO), which catabolizes heme to biliverdin. An HO
      inhibitor, tin protoporphyrin (SnPP), suppresses TPA-induced K562 cell
      differentiation to monocytes. It was also found that cotreatment of K562 cells
      with SnPP and TPA induces erythroid differentiation of K562 cells, though SnPP
      alone or TPA alone does not induce erythroid differentiation, suggesting a role
      of HO in the directional switch of differentiation.

PMID- 10655787
TI  - [Effect of mixing of fine carrier particles on dry powder inhalation property of
      salbutamol sulfate (SS)].
AB  - The most commonly used formulations for dry powder inhalations are binary ordered
      mixes composed of micronized drugs and coarse carriers. An optimal dry powder
      aerosol formulation should possess an optimal inhalation property and a good flow
      property. These characteristics are especially important for a multidose dry
      powder inheler (DPI). In the present study, model powder blend were prepared
      consisting of synthesized sugar (different particle sized isomalt; IM-PF, IM-FS,
      IM-F) as a carrier and micronized salbutamol sulfate (SS). These ordered mixtures
      were aerosolized by the multidose JAGO DPI (SkyePharma AG) and in vitro
      deposition properties (fine particle fraction, FPF) were evaluated by a twin
      impinger (TI) at a flow rate of 60 l/min. The separation property between SS and
      carrier particles was investigated by the centrifuge method and air jet sieve
      (AJS) method. It was found that FPF decreased with increasing carrier particle
      size. However, a large carrier particle possesses a good flow property.
      Therefore, the effect of mixing of fine carrier particles (IM-PF) into the large
      carrier particles (IM-FS) on dry powder inhalation property was investigated.
      When the proportion of IM-PF (fine carrier) increase from 0% to 25% of the total
      carrier powder blend, the FPF also increases from 16.7% to 38.9%. It is concluded
      that the effect of mixing of fine carrier particles might be a suitable method
      for improving the dry powder inhalation properties.

PMID- 10655788
TI  - [Estimation of adverse drug reactions by the evaluation scores of subjective
      symptoms (complaints) and background of patients. II. Drug-induced extrapyramidal
      symptoms].
AB  - OBJECTIVES: The purpose of this study was to develop, implement, and assess an
      estimation procedure for preventing adverse drug reaction by subjective symptoms
      (complaints) of patients. This time, we focused and studied on drug-induced
      extrapyramidal symptoms. METHODS: We have built a database for CARPIS (Case
      Reports of Adverse Drug Reaction and Poisoning Information Systems) since 1987,
      and the case reports of adverse drug reaction accumulated in the CARPIS database
      to be total about 16,000. We studied for 180 cases of drug-induced extrapyramidal
      symptoms cumulated in CARPIS database. The evaluation scores were created based
      on the subjective symptoms and backgrounds of the patients. We estimated 180
      cases using these evaluation scores. RESULTS: We could estimate 178 cases (98.9%)
      in 180 cases to be drug-induced extrapyramidal symptoms using these evaluation
      scores. The validity of these evaluation scores were sensitivity = 98.9%,
      specificity = 98.0% and predictive value of positive test = 98.9%. The positive
      likelihood ratio was 49.5 and the negative likelihood ratio was 0.01.
      CONCLUSIONS: This study confirmed the validity of our evaluation scores. We
      reported the evaluation scores about drug-induced liver diseases before.
      Therefore, to apply these evaluation scores onto the clinical practice, we
      prepared an evaluation form for subjective symptoms and backgrounds of the
      patients with adverse drug reactions.

PMID- 10655789
TI  - [Molecular cloning of cDNAs coding Sarcophaga diptericin family].
AB  - We purified an antibacterial protein named sarcotoxin III from the hemolymph of
      injured larvae of Sarcophaga peregrina (Baba K., et al., J. Biochem., 102, 69-74
      (1987)). In this report we determined the partial amino acid sequence of
      sarcotoxin III and tried to conduct the cloning of sarcotoxin III cDNA. As a
      result we obtained two clones coding a protein similar to sarcotoxin III in
      sequence. Their primary structures are highly homologous to N-terminal sequences
      of an antibacterial protein from Phormia, diptericin, and another 8 kD
      antibacterial protein purified from Sarcophaga peregrina. These results suggested
      that sarcotoxin III is one of the proteins forming a diptericin family in
      Sarcophaga peregrina as well as newly obtained clone-coded products and 8 kD
      protein.

PMID- 10655790
TI  - Disease management: its place in wound care.

PMID- 10655791
TI  - Wound prevalence, types, and treatments in home care.
AB  - OBJECTIVE: To ascertain the number of home care patients with wounds, determine
      the types of wounds being treated in the community, and identify wound care
      treatments used at home. DESIGN: Descriptive, multisite, collaborative project.
      SETTING: 13 home care agencies located throughout lower Michigan that had
      voluntarily formed a research consortium. The location of patients visited was
      43% urban, 39% suburban, 16% rural, and 2% unaccounted. PATIENTS: Systematic
      sampling was used to select nurses in each agency to collect data. Nurses (n =
      281) recorded information about adult patients visited during the 1 week of the
      study. Data were recorded about 2847 patients, M age = 72.5 years. They included
      1793 women and 1040 men (gender was not recorded for 14 patients); most patients
      in the sample (72%) were white. MAIN PLANNED OUTCOMES: A significant number of
      home visits would include wound care and that wound care would be primarily done
      with tap water and gauze. RESULTS: Wounds were present in 36.3% of patients. Of
      the patients with wounds, 58.3% had 1 wound and 41.7% had multiple wounds. Wound
      types included surgical (62.4%), pressure ulcers (24.9%), and vascular leg ulcers
      (22.2%). Tap water and gauze were the most-used wound care treatments. Patients
      with wounds had significantly longer home care visits than patients without
      wounds. CONCLUSIONS: Patients with wounds are commonly found in home care. There
      is a low utilization of specialty dressings and commercial irrigation solutions
      across all wound types. Nurses who follow patients with wounds may need
      additional time to provide the care.

PMID- 10655792
TI  - Risk of pressure ulcer development in surgical patients: a review of the
      literature.
AB  - OBJECTIVE: The purpose of this paper is to review the scientific knowledge about
      risk factors for pressure ulcer development in the surgical population. DATA
      SOURCE: A literature review was conducted from 1960 to present using MEDLINE and
      the key words pressure ulcer, decubitus ulcer, surgery, surgical patient,
      research, clinical research, and human. All sources were English. STUDY
      SELECTION: Included were articles that specifically addressed the risk of
      pressure ulcers in the surgical population and had ulcer formation as an outcome
      measure. DATA EXTRACTION: All data were reviewed and extracted by the author.
      DATA SYNTHESIS: The development of pressure ulcers has been explored in only a
      small proportion of surgical patients. Few groups of surgical patients have been
      addressed. Major surgical populations potentially at risk because of their
      immobility, debility, and therapy have not been studied. A portion of the
      literature is quite old and one issue is whether the older studies are relevant,
      considering the rate of change in treatment. Pressure relief, seen as the single
      most important factor in pressure ulcer prevention, is underrepresented in the
      analysis of factors leading to pressure ulcer development. CONCLUSION: There is
      limited information about pressure ulcer risk in the preoperative,
      intraoperative, and postoperative periods. Because the surgical period is defined
      temporally, and more so than pressure ulcers in the chronically ill, this
      paradigm must be examined using a time-based evaluation. The Agency for Health
      Care Policy and Research guideline for pressure ulcer prevention needs to be
      tested in surgical patients.

PMID- 10655793
TI  - The role of zinc in wound healing.
AB  - Zinc deficiency has been associated with delayed wound healing. Because zinc
      deficiency may be common in the United States, foods rich in zinc, as well as all
      other essential nutrients, should be promoted in the diet of patients who are
      malnourished or at risk for malnutrition.

PMID- 10655794
TI  - Epidemiology of the diabetic foot: ulcerations and amputations.

PMID- 10655795
TI  - A wound care equation for the new millennium.

PMID- 10655796
TI  - Resources in wound care: 1999 directory.

PMID- 10655797
TI  - Research partnerships: academia, industry, patients, and clinicians.

PMID- 10655798
TI  - Core body temperature, skin temperature, and interface pressure. Relationship to
      skin integrity in nursing home residents.
AB  - OBJECTIVE: To ascertain the effects of 1-, 1 1/2-, and 2-hour turning intervals
      on nursing home residents' skin over the sacrum and trochanters. HYPOTHESES: (1)
      the higher the core body temperature, the higher the skin surface temperature;
      (2) the 2-hour turning interval would have significantly higher skin surface
      temperature; (3) there would be no relationship between skin surface temperature
      and interface pressure; and (4) the sacrum would have the lowest skin surface
      temperature. DESIGN: Modified Latin-square. SETTING: For-profit nursing home.
      PARTICIPANTS: Convenience sample of 26 residents who scored < 3 on the Short
      Portable Mini-Mental Status Questionnaire and did not have (1) open wounds; (2)
      albumin levels < 3.3 mg/dL; (3) severe arthritis; (4) cortisone, anticoagulation,
      insulin therapy or 3 medications for hypertension; and/or (5) were totally
      bedridden. MAIN OUTCOME MEASURE(S): First Temp measured core temperature; a
      disposable thermistor temperature probe, skin temperature; and a digital
      interface pressure evaluator, the interface pressure. RESULTS: Negative
      correlation (r = -.33, P = .003) occurred between core body temperature and skin
      surface temperature. Skin surface temperature rose at the end of the 2-hour
      turning interval but was not significant (F = (2.68) = .73, P = .49). Weak
      negative relationship (r = -12, P = .29) occurred between skin surface
      temperature and interface pressure, and sacral skin surface temperature was
      significantly lower for the left trochanter only (F = (8.68) = 7.05, P = .002).
      CONCLUSION: Although hypotheses were not supported, more research is needed to
      understand how time in position and multiple chronic illnesses interact to affect
      skin pressure tolerance.

PMID- 10655799
TI  - Identification and treatment of herpes lesions.
AB  - Infections caused by the herpes family of viruses are on the rise. Mucocutaneous
      herpes infections are caused by herpes simplex viruses 1 and 2 and varicella
      zoster virus. Herpes simplex virus commonly causes oral-labial or genital
      infection, and varicella-zoster virus causes chicken pox and shingles. Clinical
      features frequently are atypical, particularly in compromised patients.
      Therefore, a high index of suspicion must be maintained for early diagnosis.
      Availability of easy-to-perform rapid diagnostic tests and several potent
      antiherpetic agents have vastly improved the management of herpes infections.

PMID- 10655800
TI  - Use of telerehabilitation to manage pressure ulcers in persons with spinal cord
      injuries.
AB  - Pressure ulcers are a common and serious secondary complication of spinal cord
      injury. In addition to being costly and difficult to treat, pressure ulcers may
      interfere with many aspects of patient and family life, including the ability to
      meet educational, vocational, and social goals. Treatment of pressure ulcers
      includes weekly assessment by a clinician, a requirement that often is impossible
      for clients to meet. In an effort to improve outcomes in wound care treatment, a
      rehabilitation center undertook an exploratory project to determine whether wound
      care via telerehabilitation was a viable alternative to clinic visits.
      Telerehabilitation is the use of telecommunication technology to deliver
      rehabilitation services at a distance. Eight patients being followed in the
      outpatient clinic participated in the project. The Picasso Still-Image Videophone
      was used to capture and send images from the patients' homes to the clinic.
      Findings from the exploratory study demonstrated that pressure ulcers can be
      successfully managed via telerehabilitation.

PMID- 10655801
TI  - Off-loading techniques for neuropathic plantar wounds.

PMID- 10655802
TI  - There are several reasons why our information about maternal deaths is so
      sketchy.

PMID- 10655803
TI  - Interviews with the Alivio midwives: Mary Sommers, midwife; Carrie Hanson, CNM;
      Basia Klincewicz, CPM; Ceal Bacom, CNM. Interview by Ina May Gaskin.

PMID- 10655804
TI  - Epidural update.

PMID- 10655805
TI  - "Breastfeeding statistics up nationwide!" The truth behind the headline.

PMID- 10655806
TI  - From my birth to my baby's birth: generations of formula marketing tactics.

PMID- 10655807
TI  - What is "morning sickness" and what can I do to feel better? What massage
      techniques are helpful during labor?

PMID- 10655809
TI  - Anecdotes of a working breastfeeding mother.

PMID- 10655808
TI  - The healing power of birth.

PMID- 10655810
TI  - CoMadres Institute is born.

PMID- 10655811
TI  - Coyote woman's birth timeline.

PMID- 10655812
TI  - Nulliparas' preferences for epidural analgesia: their effects on actual use in
      labor.
AB  - BACKGROUND: Few studies have directly examined the reasons for choices of pain
      relief during labor. The purpose of this study was to investigate if women's
      preferences for epidural analgesia in labor have an impact on the use of
      intrapartum epidural analgesia. METHODS: Nulliparous women attending childbirth
      classes completed questionnaires about their antenatal preferences for the use of
      intrapartum epidural analgesia. Data on actual use of analgesia was obtained by
      chart review. The analysis included 303 women with either spontaneous or induced
      labor at term. RESULTS: The 185 women who planned to receive epidural analgesia
      had a markedly higher rate of epidural use (91%) than the 110 women who hoped to
      avoid it (57%) (p = 0.001). Of 237 epidurals administered, 169 (71%) were planned
      during the antenatal period. Among women receiving epidural analgesia, those
      planning to receive it tended to have more frequent early administration (< or =
      3 cm cervical dilation) than women who unsuccessfully tried to avoid epidural use
      (54% vs. 24%, p = 0.003). CONCLUSION: In our population of nulliparas, a woman's
      antenatal plan to receive epidural analgesia is strongly associated with her
      likelihood of receiving it. Women who plan to receive epidural analgesia have
      earlier administration.

PMID- 10655813
TI  - Changes in cesarean delivery in an Italian university hospital, 1982-1996: a
      comparison with the national trend.
AB  - BACKGROUND: The cesarean delivery rate in Italy rose dramatically from the mid
      1970s to 1996, accounting for 22.4 percent of all deliveries in the last national
      survey. The aim of this study was to analyze the results of the clinical practice
      of a new staff in the Department of Obstetrics and Gynecology of a university
      hospital, with particular focus on the application of common protocols. The rates
      of cesarean sections and perinatal mortality were chosen as parameters for good
      clinical practice and were compared with national data. METHODS: A new staff
      assumed the obstetric management at the hospital in 1982. Standardized protocols
      were implemented for all major indications for cesarean delivery (repeat cesarean
      section, dystocia, breech presentation, fetal distress). RESULTS: The rate of
      cesarean deliveries decreased from 26.4 to 12 percent and remained stable during
      the past decade. Other operative modalities were used for approximately 1.5
      percent of deliveries. The perinatal mortality decreased to 0.5 percent in 1994.
      To confirm whether or not staff followed common protocols, a review of three
      years (1994-1996) showed a fairly stable frequency of cesarean sections on
      different days and nights during the week, confirming the homogeneity of
      obstetric management. CONCLUSIONS: Our data showed that, irrespective of the
      local situation and of the risks of litigation, a significant reduction of
      cesarean sections can be achieved in a tertiary care center without detrimental
      effects on newborns, especially in a teaching hospital where residents are
      trained. Despite national trends suggesting the contrary, some women may choose
      to deliver in an obstetrics department with better care and fewer operative
      procedures than in hospitals with higher cesarean delivery rates.

PMID- 10655814
TI  - Does parental breastfeeding knowledge increase breastfeeding rates?
AB  - OBJECTIVE: Although improving mothers' knowledge about breastfeeding can increase
      rates and duration of breastfeeding, little is known about the influence of
      fathers' knowledge. The purpose of this study was to assess the knowledge of
      mothers and fathers about breastfeeding before and after receiving postpartum
      advice and its relationship to the frequency of breastfeeding. METHODS: A
      clinical trial was performed with mothers and fathers of normal children born at
      the Hospital de Clinicas de Porto Alegre, Brazil, between July 1994 and March
      1995. The study intervention consisted of postpartum advice supplied by means of
      a video film discussing basic topics of breastfeeding, an explanatory leaflet,
      and open discussion after viewing the video. The first 208 couples comprised the
      control group, the next 197 comprised experimental group 1, and the remaining 196
      comprised experimental group 2. Immediately after delivery, mothers and fathers
      in the three groups answered a test on breastfeeding knowledge; they completed
      the same test at the end of the first month. All families received home visits at
      the end of the first, second, fourth, and sixth months, or until breastfeeding
      ceased. Logistic regression was used to evaluate the association between the
      mothers' and fathers' knowledge and frequency of breastfeeding. RESULTS:
      Postpartum advice increased the breastfeeding knowledge of mothers and fathers.
      The mothers with the highest level of knowledge had a 6.5 times higher chance of
      exclusively breastfeeding at the end of the third month, and 1.97 times higher
      chance of continuing breastfeeding to the end of the sixth month compared with
      other mothers. The fathers' knowledge also significantly influenced breastfeeding
      rates. The children whose fathers knew more had a 1.76 higher chance of being
      exclusively breastfed at the end of the first month, and 1.91 higher chance of
      receiving maternal milk at the end of the third month. CONCLUSION: A simple,
      inexpensive strategy can increase the level of breastfeeding knowledge of mothers
      and fathers and, consequently, have a positive impact on the frequency of
      breastfeeding.

PMID- 10655815
TI  - Depressive symptoms in the late postpartum among low socioeconomic status women.
AB  - BACKGROUND: Postpartum depression has been the focus of much research in the past
      15 years, but little is known about factors associated with depression of longer
      duration or later onset. The purpose of this longitudinal study was to analyze
      the relationship between stressful life conditions and postnatal depression in a
      group of women of low socioeconomic status from the third week to the sixth month
      postpartum. METHODS: Nulliparas who met criteria for low socioeconomic status
      were recruited from the prenatal care clinics of four Montreal hospitals.
      Questionnaires were verbally administered in the home at 30 weeks' gestation, at
      3 and 9 weeks postpartum, and at 6 months postpartum. Blockwise multiple linear
      regression analyses were performed by entering predictor variables that included
      sociodemographic characteristics, chronic stressors, life events, and social
      support network. RESULTS: Sixty-eight women participated in the study. At 6
      months postpartum, 38.2 percent of the mothers had a Beck Depression Inventory
      score of 10 or more. After accounting for previous depression, analyses indicated
      that chronic stressors (maternal health problems, infant difficulty, lack of
      money for basic needs, frequent conflicts with network members) and poor social
      support (informational and emotional) were associated with postnatal depressive
      symptoms. CONCLUSIONS: Health practitioners should recognize that high depressive
      symptomatology frequently occurs among low socioeconomic status first-time
      mothers at six months postpartum. Chronic stressors and inadequate social support
      are the most important factors associated with this problem.

PMID- 10655816
TI  - The experience of stress incontinence after childbirth.
AB  - BACKGROUND: Epidemiological studies have reported prevalence of stress
      incontinence ranging from 23 to 67 percent during pregnancy and 6 to 29 percent
      after childbirth, but little is known about how the condition affects women at
      this time. The purpose of this study was to examine the effects of stress
      incontinence on women in their childbearing years. METHODS: Interviews were
      conducted with 42 women who experienced stress incontinence at 8 weeks postpartum
      and 15 women who reported symptoms one year after delivery. Analysis of the
      qualitative data involved exploring themes and patterns, relationships and
      connections, contradictions and contrasts, and the language used within
      individual accounts and across the spectrum of narratives. RESULTS: The results
      are presented within a framework that the women themselves adopted: day-to-day
      activities, putting the condition in some form of perspective, and feelings and
      emotions. For some women, stress incontinence had a great impact on their lives
      in terms of both their daily routine and psychologically, but others described it
      as a minor inconvenience that rarely disturbed their routine. Major concerns
      comprised the restrictions placed on the women, the worry or continual awareness
      stemming from the condition, and feelings of embarrassment associated with it.
      Twelve months after childbirth the effects appeared to have lessened, but a few
      women were still significantly affected, both physically and psychologically.
      CONCLUSIONS: Although many women experience physical and psychological symptoms
      of stress incontinence after delivery, this study demonstrated that few sought
      professional care or advice for their symptoms. Health professionals should be
      aware of the prevalence, and women's responses to, stress incontinence so that
      they can initiate appropriate support and care. Further research on stress
      incontinence on childbearing women is necessary.

PMID- 10655817
TI  - Are women carrying "basketballs" really having boys? Testing pregnancy folklore.
AB  - BACKGROUND: Antenatal ascertainment of fetal sex is a common feature of modern
      pregnancies. Women who opt not to learn fetal sex typically employ a variety of
      methods to forecast it. This study investigated the validity of prevalent
      folklore used to identify fetal sex before birth. METHOD: One hundred four
      pregnant women, who did not know the sex of the fetus, were administered a
      questionnaire to explore their perceptions of fetal sex and the basis for these
      predictions. RESULTS: Fetal sex was not systematically related to the shape of
      the woman's abdomen, prevalence of morning sickness, or comparisons with previous
      pregnancies. However, women who had more than twelve years of education correctly
      predicted fetal sex greater than chance (71% correct), in contrast to less
      educated women (43% correct). Contrary to expectations, women whose forecasts
      were based on psychological criteria (i.e., dreams or feelings) were more likely
      to be correct than those employing prevalent folklore criteria (i.e., the way a
      woman was carrying the pregnancy). CONCLUSIONS: In general, women were not good
      predictors of fetal sex. The mechanisms that promote maternal accuracy in
      predicting fetal sex for highly educated women are unknown. It is reasonable to
      expect that maternal perceptions of fetal sex contribute to the process of fetal
      attachment.

PMID- 10655818
TI  - Differences in the valuation of birth outcomes among pregnant women, mothers, and
      obstetricians.
AB  - BACKGROUND: Decisions are usually based on the perceived merits of alternative
      approaches. This process can be quantified by combining the probabilities of
      expected outcomes with their desirability. We studied differences in the
      valuation of birth outcomes among pregnant women, mothers, and obstetricians, and
      assessed how these would affect a particular obstetric decision. METHODS: In a
      study conducted at Leiden Hospital, Leiden, The Netherlands, 12 obstetricians, 15
      pregnant women, and 15 mothers participated in a standard reference gamble to
      determine the value of 12 different outcomes: 3 types of birth combined with 4
      states of infant outcome. These were then applied to an obstetric decision tree
      based on the Dublin trial of intermittent auscultation versus electronic
      intrapartum fetal heart rate monitoring. RESULTS: Contrary to obstetricians,
      women valued permanent neurologic handicap significantly higher than neonatal
      death (p < 0.01). Women expressed no overriding preferences for the type of
      birth, whereas obstetricians were clearly antipathetic to cesarean section.
      Within-group consistency was significantly higher for pregnant women and mothers
      than for obstetricians (p < 0.0001). However, application of the measured values
      to the obstetric decision tree merely led to marginal changes in overall expected
      value of the decision alternatives. CONCLUSIONS: Values attached to birth
      processes and outcomes differ significantly between (expectant) mothers and
      doctors. These differences should be recognized and respected in obstetric
      decision making.

PMID- 10655819
TI  - Low-birthweight prevention programs: the enigma of failure.
AB  - BACKGROUND: Low birthweight is the primary cause of neonatal morbidity and
      mortality in the United States. The purpose of our study was to identify factors
      associated with the effectiveness and apparent ineffectiveness of comprehensive,
      multicomponent, prenatal care programs for preventing low birthweight. METHODS:
      We reviewed obstetric, pediatric, and public health program evaluations, research
      reports, and commentaries, published in the English language literature, over the
      last four decades that pertained to the efficacy of prenatal care for preventing
      low birthweight. RESULTS: The heterogeneous nature of the services delivered and
      the lack of consistency in the definition of variables made it impossible to use
      rigorous, quantitative techniques to summarize this evaluation of the literature.
      Two general limitations of research design that emerged from our reviews were the
      focus on clusters of commonly associated risk factors, which has blurred the
      causal pathways linking specific risk factors to low birthweight, and the failure
      to examine process variables. These two methodologic problems have led
      investigators to erroneous conclusions that overstate the significance of
      negative intervention outcomes. The success and failure of low-birthweight
      prevention programs has rarely been examined in relation to evidence that the
      intervention actually modified the targeted risk factors. CONCLUSIONS: Few
      rigorous evaluations of well-designed programs have been conducted. Without an
      improvement in intervention designs and evaluation studies, recommendations to
      support or curtail the funding of comprehensive, multicomponent prenatal care
      services are inappropriate. Rigorously obtained evidence of the costs and
      benefits of approaches to the prevention of low birthweight are sorely needed.

PMID- 10655820
TI  - Early discharge after childbirth: too late for a randomized trial?

PMID- 10655821
TI  - Epidurals and cesareans: the jury is still out.

PMID- 10655822
TI  - Sheila Kitzinger's letter from Europe: midwives on trial.

PMID- 10655823
TI  - Bed rest in hospital for multiple pregnancy.

PMID- 10655824
TI  - Maternal attitudes to amniotomy and labor duration: a survey in early pregnancy.
AB  - BACKGROUND: Although maternal choice increasingly influences intrapartum care,
      little is known about maternal attitudes about many outcomes and interventions,
      particularly the length of labor. Early amniotomy decreases the length of labor
      and particularly the frequency of prolonged (> 12 hr) labor but is often avoided
      by health professionals. The objective of this survey was to assess the attitudes
      of women in a major Dublin teaching hospital about the length of labor,
      amniotomy, and epidural analgesia. METHODS: An anonymous, structured, self
      completed questionnaire was given to 438 women at their booking visit to the
      hospital antenatal clinic in February 1998. Participants could ring "agree,"
      "disagree," "don't know," or "don't care" to seven different statements. RESULTS:
      The questionnaire was returned by 398 (92%) women; demographic details were
      similar to those for the overall hospital population. Of these, 73.5 percent of
      women wanted a quick labor; 82 percent wanted it to last less than 12 hours.
      Nearly one-half specifically wanted epidural analgesia. Only 13 percent wished to
      avoid amniotomy; significantly more multiparas disagreed with "avoiding
      amniotomy." CONCLUSIONS: Many women want a quick and painless labor, and do not
      object to the interventions that help achieve this.

PMID- 10655825
TI  - Commentary: studying maternal experiences of childbirth.

PMID- 10655826
TI  - Mastitis in the first year postpartum.
AB  - BACKGROUND: Limited information is available about the frequency and risk factors
      for lactation mastitis. The purpose of this study was to investigate frequency,
      risk factors, and outcome for lactation mastitis. METHODS: We analyzed data from
      a cohort study of 350 mothers with healthy term infants, who were followed up for
      one year postpartum. RESULTS: Eighty-three women (23.7% of the sample) reported
      one or more episodes of mastitis symptoms, and 61 (17.4%) women reported symptoms
      including fever. Fifty-six women (16%) received one or more courses of
      antibiotics for mastitis. Thirty women (8.5%) of the total cohort had recurrent
      episodes of mastitis symptoms. A total of 123 episodes of mastitis symptoms were
      reported. No cases of abscess were reported. Using multiple logistic regression,
      the adjusted risk ratio for mastitis symptoms associated with sore nipples in the
      first month was 2.07 (95% CI = 1.17, 3.66). A reduced risk of mastitis was
      associated with maternal smoking during pregnancy, with supplementation with
      water in the first month, and with the use of a pacifier on a daily basis within
      the first month. A history of mastitis symptoms was associated with a longer
      overall duration of breastfeeding. CONCLUSIONS: Our results suggest that mastitis
      may be a marker for an ample milk supply. Mothers presenting with mastitis can be
      reassured that the outlook for continued successful lactation is good. Further
      research is needed to investigate the reasons for recurrence of mastitis and the
      etiology of episodes occurring late in lactation.

PMID- 10655827
TI  - Factors predicting cesarean delivery for American Indian women in New Mexico.
AB  - BACKGROUND: American Indian women have one of the lowest cesarean delivery rates
      among all ethnic groups evaluated in the United States. Our objective was to
      identify risk factors for cesarean delivery among American Indian women in New
      Mexico. METHODS: Live birth certificate data (1994) from the New Mexico Bureau of
      Vital Records and Health statistics were used to compare American Indian women
      who had a cesarean delivery with those who had a vaginal delivery. We examined
      demographic, prenatal, and intrapartum factors to determine risk factors for
      cesarean delivery. RESULTS: In 1994 American Indian women in New Mexico had a
      cesarean delivery rate of 12 percent. Risk factors for cesarean delivery included
      age equal to or over 35 years (OR = 1.8, 1.3-2.5) and nulliparity (OR = 1.9, 1.5
      2.5). Obstetric risk factors included prematurity (OR = 2.3, 1.5-3.6), low
      birthweight (OR = 2.6, 1.7-4.2), diabetes (OR = 1.7, 1.1-2.5), pregnancy-induced
      hypertension (OR = 2.6, 1.8-3.8), and labor and delivery complications (OR = 9.5,
      7.5-12.1). Age less than 20 years was negatively associated with cesarean
      delivery (OR = 0.5, 0.3-0.7). CONCLUSION: American Indian women have risk factors
      for cesarean delivery that are similar to those reported in other populations.
      Future prospective research evaluating intrapartum management may help identify
      reasons for the low cesarean birth rate.

PMID- 10655828
TI  - Commentary: low cesarean birth rates for American Indians.

PMID- 10655829
TI  - Breastfeeding experience and milk weight in lactating mothers pumping for preterm
      infants.
AB  - BACKGROUND: Research about parity or breastfeeding experience and its
      relationship with milk production in humans is limited. The purpose of this study
      was to determine if any difference in milk volume occurred among mothers with and
      without breastfeeding experience who used either a single or double breast
      pumping regimen the first 5 weeks postpartum. METHODS: A convenience sample of 39
      mothers of nonnursing preterm infants participated from two tertiary care centers
      in the midwestern United States. The sequential single pumping group consisted of
      20 mothers, 7 of whom had previous breastfeeding experience; the simultaneous
      double pumping group consisted of 19 mothers, 2 of whom had previous
      breastfeeding experience. Income and pumping group regimen were used as blocking
      variables, and average frequency of kangaroo care per week and average frequency
      of breast pumping per week were covariants in the repeated measures analysis of
      variance. RESULTS: Mothers with previous breastfeeding experience had greater
      milk weights over time, but weights were not significantly different when
      compared with those mothers with no previous breastfeeding experience. Additional
      analysis with the covariants of pumping frequency and kangaroo care, and with the
      independent variables of group, breastfeeding experience, and income resulted in
      statistically significantly greater milk yield in the women with previous
      breastfeeding experience. CONCLUSIONS: The findings of the two repeated analyses
      indicated the complexity of the milk production response, and the importance of
      considerations of environmental as well as physiologic factors.

PMID- 10655830
TI  - Adherence to the ten steps of the Baby-Friendly Hospital Initiative in Minnesota
      hospitals.
AB  - BACKGROUND: A worldwide campaign has been initiated to improve the in-hospital
      care of mothers and babies through increased breastfeeding. The four objectives
      of the current investigation were to determine the in-hospital breastfeeding rate
      for Minnesota hospitals, to analyze the relationship between the in-hospital
      breastfeeding rates and selected hospital demographic characteristics, to
      determine the rate of adherence to each of the Baby-Friendly Hospital Initiative
      (BFHI) Ten Steps, and to analyze the relationship between the adherence rates for
      each of the Ten Steps and selected demographic characteristics. METHODS: A
      descriptive survey was conducted and analyzed for the year of 1994 from 79 (83%)
      Minnesota hospitals. Respondents were directors of nursing, nursing managers, or
      other staff familiar with their hospital's breastfeeding policies and practices.
      RESULTS: The average breastfeeding initiation rate was 59 percent. Four of the
      Ten Steps were implemented with a low adherence rate (0-49%), five were
      implemented with a moderate rate (50-89%), and none was implemented with a high
      rate (90-100%). Breastfeeding initiation rates and adherence to the Ten Steps
      varied with the size of the city and the number of births per year. CONCLUSIONS:
      Improvements in breastfeeding policies, practices, and staff education are needed
      if Minnesota hospitals are to provide care consistent with the Ten Steps of the
      BFHI. The results provide baseline information to guide institutional change that
      could promote successful breastfeeding experiences for postpartum families. This
      survey instrument could be used easily by researchers in other sites to assess
      nine of the Ten Steps.

PMID- 10655831
TI  - Medical hypnosis for hyperemesis gravidarum.
AB  - Hyperemesis gravidarum in pregnancy is a serious condition that is often
      resistant to conservative treatments. Medical hypnosis is a well-documented
      alternative treatment. This article reviews the empirical studies of medical
      hypnosis for treating hyperemesis gravidarum, explains basic concepts, and
      details the treatment mechanisms. The importance of a thorough differential
      diagnosis and appropriate referrals is stressed. The article presents three case
      studies to illustrate the efficacy of this treatment approach. It is suggested
      that medical hypnosis should be considered as an adjunctive treatment option for
      those women with hyperemesis gravidarum. It is also stressed that medical
      hypnosis can be used to treat common morning sickness that is experienced by up
      to 80 percent of pregnant women. Its use could allow a more comfortable pregnancy
      and healthier fetal development, and could prevent cases that might otherwise
      proceed to full-blown hyperemesis gravidarum.

PMID- 10655832
TI  - Postpartum care of the mother and newborn: a practical guide. Technical Working
      Group, World Health Organization.
AB  - This paper defines the needs of women and their newborns, and classifies a number
      of practices common in postpartum care. It is a summary of the report, Postpartum
      Care of the Mother and Newborn: A Practical Guide, which was developed by a
      Technical Working Group of the World Health Organization and published in 1998.
      The report takes a comprehensive view of maternal and newborn needs during the
      postpartum period, examining major maternal and neonatal health challenges,
      nutrition and breastfeeding, birth spacing, immunization, HIV/AIDS, and the
      essential elements of care and service provision. The document lists
      recommendations, and classifies common practices in the postpartum period,
      dividing them into four categories: those which are useful, those which are
      harmful, those for which insufficient evidence exists, and those which are
      frequently used inappropriately.

PMID- 10655833
TI  - Cesarean delivery: improving on nature?

PMID- 10655834
TI  - Episiotomy for vaginal birth.

PMID- 10655835
TI  - Vaginal misoprostol for cervical ripening and labour induction in late pregnancy.

PMID- 10655836
TI  - Epidurals and breastfeeding.

PMID- 10655837
TI  - Breastfeeding: are boys missing out?

PMID- 10655838
TI  - 40,000 pounds 'gimmick'.

PMID- 10655839
TI  - Sick and tired of working.

PMID- 10655840
TI  - Fertility treatment.

PMID- 10655841
TI  - From cadet to dean. Interview by Dina Leifer.

PMID- 10655842
TI  - Before her time.

PMID- 10655843
TI  - Equal footing.

PMID- 10655844
TI  - Are you a manager or a leader?

PMID- 10655845
TI  - Breaking down the barriers.

PMID- 10655846
TI  - RCN R&D Co-ordinating Centre.

PMID- 10655847
TI  - What price research? Good preparation contributes to good performance.
AB  - Marie Cerinus uses a study into the value of clinical supervision to illustrate
      some of the resource issues involved in the conduct of action research. She
      describes the range and level of financial and personal commitment required if
      the research is to be successful.

PMID- 10655848
TI  - Power and representation in nursing: a literature review.
AB  - The concepts of power and representation hold a particular significance for the
      nursing profession. Joanna Du Plat-Jones examines their effects for both nurses
      and clients.

PMID- 10655849
TI  - A new national framework for mental health.
AB  - Last year's review of mental health care heralded innovative changes to services
      for people with mental health problems. But Steve Wood argues that the
      opportunity to provide adequate care for people with long-term problems has again
      been missed.

PMID- 10655850
TI  - Developing leadership skills in clinical practice and management.
AB  - Throughout the UK, increasing responsibility is being placed on clinical nurses
      to play a leadership role within healthcare settings. Recognising the challenges,
      Nursing Standard is once again collaborating with the Royal College of Nursing
      and its corporate partner, Smith and Nephew, in launching the fifth Clinical
      Practice and Management Awards. Editor in Chief Linda Thomas explains the awards
      and the benefits nurses can gain from taking part.

PMID- 10655852
TI  - Seeing the person with dementia.

PMID- 10655851
TI  - Understanding perioperative nursing.
AB  - Perioperative nursing is a complex arena that involves various roles and
      procedures. The authors here argue that the key to success is good
      multidisciplinary communication.

PMID- 10655853
TI  - SVQs and NVQs explained.

PMID- 10655854
TI  - Continuing care.

PMID- 10655855
TI  - Oh, the places we've been and the places we'll go!

PMID- 10655856
TI  - The importance of words and other things.

PMID- 10655857
TI  - The ethics of compassion.
AB  - The Georgetown Mantra of Bioethics, which includes the principles of beneficence,
      non-maleficence, autonomy, and justice, has largely been regarded as the mainstay
      of ethical principles in the healthcare setting. Moral or ethical decisions have
      been discussed using this framework. The purpose of this article is to argue that
      the ethics of compassion is a critical principle in making clinical decisions,
      especially in the case of the chronically ill patient. This suggests that the
      ethics of compassion may serve as an important adjunct to the Georgetown Mantra.

PMID- 10655858
TI  - ADA holds consensus conference on diabetic foot wound care.

PMID- 10655860
TI  - A multidisciplinary, therapy-based, team approach for efficient and effective
      wound healing: a retrospective study.
AB  - This paper presents a 4-year retrospective study (1994 to 1998) of therapy-based
      treatment outcomes for chronic wounds of all stages and most common etiologies.
      Treatment in this study consists of outpatient wound treatments given by trained
      therapists and nurses who were supervised by the podiatrist or internist. Many
      patients were referred to the clinic for last-resort treatment (i.e., electrical
      stimulation, topical hyperbaric therapy, etc.) before major lower extremity
      amputations: hip disarticulation, above knee amputation (AKA), below-knee
      amputation (BKA). This study does not consider age, sex, chronicity, or ethnicity
      because the authors want to demonstrate the effectiveness of this treatment
      approach for healing chronic wounds notwithstanding these variables. Wound
      healing was achieved in 100% of patients who completed their treatment program
      (233 patients with 242 wounds). This study shows the total average healing time
      for wounds is 7 weeks for Stage II wounds, 10 weeks for Stage III wounds, and 19
      weeks for Stage IV wounds. The average healing time for diabetic wounds is 14
      weeks (wounds of neuropathic origin heal in 12 weeks and wounds of ischemic
      origin heal in 16 weeks). The average healing time for venous stasis wounds is 8
      weeks. The study includes patients with ischemia who are not candidates for
      revascularization. The authors assert that the most effective treatment for wound
      healing is a therapy-based, multidisciplinary team approach. This retrospective
      study shows that the goal of complete healing is attainable.

PMID- 10655859
TI  - A comparison of an opaque foam dressing versus a transparent film dressing in the
      management of skin tears in institutionalized subjects.
AB  - Epidemiological studies suggest that at least 1.5 million skin tears occur each
      year in institutionalized adults. Despite this incidence, very little is known
      about the management of skin tears in elderly persons. Studies related to wound
      dressings and healing rates for these skin tears have rarely been reported in the
      medical literature. A randomized, prospective trial of 37 subjects compared the
      treatment of skin tears using either an opaque foam dressing or a transparent
      film dressing. Subjects had either a modified Payne-Martin Category II (25%-75%
      epidermal loss) or Category III (100% epidermal loss) skin tear. Category I skin
      tears (linear with no tissue loss) and skin tears greater than 48 hours old were
      excluded. Mean subject age was 85.1 +/- 9.7 years. Subjects were followed weekly
      until healed or for up to 21 days. Subjects in the comparison groups did not
      differ at baseline in age, sex, wound severity score, presence of diabetes,
      nutrition score, ambulation and mobility score, or mental status score. Complete
      healing occurred in 94% (16/17) of subjects treated with the foam dressing as
      opposed to 65% (11/17) of subjects treated with the film dressing (P < 0.05).
      Complete healing correlated only with dressing type (P < 0.05) and age (P <
      0.01). No other factor was associated with the healing outcome. The number of
      dressing changes was similar in each group, 3.1 +/- 1.2 versus 3.4 +/- 1.1. Based
      on the results of this study, we conclude that this opaque foam dressing is a
      superior wound dressing for skin tears.

PMID- 10655861
TI  - A randomized clinical study comparing a hydrocellular dressing to a hydrocolloid
      dressing in the management of pressure ulcers.
AB  - This study compared an adhesive hydrocellular dressing with a leading
      hydrocolloid dressing in the management of pressure ulcers. Forty adult patients
      of both sexes who had Stage II or III pressure ulcers (according to the Agency
      for Health Care Policy and Research system) were enrolled in the study and were
      randomized to either the hydrocellular or hydrocolloid dressing. Dressing changes
      were done as required, and each ulcer was assessed on a weekly basis. Patients
      were followed for 8 weeks, until ulcer closure was achieved, or until the patient
      was withdrawn from the study, whichever occurred first. The hydrocellular
      dressing was found to compare favorably with the hydrocolloid dressing. In terms
      of ease of use, the hydrocellular dressing was found to be significantly easier
      to remove (P < 0.001) and quicker to change (P < 0.001) than the hydrocolloid
      dressing. No differences were detected between the two dressing groups regarding
      mean wound pain, odor, and changes in ulcer appearance and ulcer area.

PMID- 10655862
TI  - Spinal cord injury, pressure ulcers, and support surfaces.

PMID- 10655863
TI  - The new bottom line.

PMID- 10655864
TI  - The historical context of business ethics: implications for choices and
      challenges in wound care.
AB  - Wound care clinicians are regularly asked to make decisions of an ethical nature
      within their work settings. Business and business practices are influenced by a
      number of factors, such as history, culture, and individual choices. This article
      describes business practices and ultimately business ethics from an historical
      context, the meaning of business culture within the dominant culture, and the
      debate over business ethics as it relates to choices and challenges for wound
      care clinicians.

PMID- 10655865
TI  - International Wound Care Ambassadorship. Robert J. Snyder, DPM.

PMID- 10655867
TI  - Choosing an adjunctive therapy for the treatment of chronic wounds.
AB  - Adjunctive therapies such as ultrasound, laser, ultraviolet light, superficial
      heating, pulsed electromagnetic fields, and electrical stimulation have all been
      indicated in the treatment of chronic wounds. The purpose of this article is to
      outline the issues a healthcare professional must consider when choosing the best
      adjunctive therapy for a chronic wound. It summarizes the effects of therapeutic
      modalities on the wound healing process, analyzes the clinical research evidence,
      discusses practical considerations, and reviews indications, contraindications,
      precautions, and safety considerations. Finally, an algorithm is presented to
      help guide the clinician in selecting a modality. In summary, research evidence
      exists in the literature that suggests these adjunctive therapies can directly
      stimulate new tissue growth, augment wound tissue strength, improve local
      circulation and oxygenation, reduce edema, and/or inhibit bacterial growth.
      Electrical stimulation and ultrasound are the only therapeutic modalities that
      currently have sufficient clinical research evidence to support their use in the
      treatment of chronic wounds. Practical issues such as cost, time and training
      required, and patient and therapist safety concerns, will ultimately influence
      the selection of these modalities.

PMID- 10655866
TI  - Infection in chronic wounds: controversies in diagnosis and treatment.
AB  - Chronic wounds all have bacterial contamination, which will not impair healing.
      Wound contamination must be distinguished from wound colonization and infection.
      Bacterial infection in wounds depends on the number of organisms present, their
      virulence, and host resistance. The most important indicators of infection are
      both local and systemic host characteristics and a holistic assessment of the
      patient. Several specimen collection and culture techniques are available to
      measure bacterial burden in the chronic wound. Advantages and disadvantages of
      each one discussed along with a rational approach to systemic antibiotic therapy.
      The presence of foreign material such as skin grafts or skin substitutes may
      lower the bacterial burden that may impair healing from 1.0 x 10(6) colony
      forming units to 1.0 x 10(5) or less. The benefits of wound debridement, wound
      irrigation, and local nonantibiotic modes of treatment have been proven but the
      use of topical antibiotics and antiseptics requires further assessment. More
      widespread use of multiple nonantibiotic modalities of treatment for infected
      chronic wounds and rational antibiotic prescribing should reduce the risk of
      future antimicrobial resistance such as MRSA.

PMID- 10655868
TI  - Growth factors in wound healing: the next great innovation?
AB  - Wound healing is a complex process that, in the vast majority of cases, normally
      leads to complete healing. It can be likened to the construction of a building,
      having many of the same requirements. As long as these requirements are
      satisfied, the healing of the acute wound proceeds uneventfully. Unfortunately,
      significant impediments to healing occasionally exist and the acute wound stops
      healing, becoming chronic. If these impediments can be controlled, most of these
      chronic wounds will eventually heal, albeit slowly. For example, the venous leg
      ulcer will heal once one applies proper compression therapy that provides the
      necessary support counteracting the underlying venous hypertension and provides
      appropriate wound care. Similarly, diabetic neuropathic foot ulcers will not heal
      until the disordered glucose metabolism is controlled and causative pressure on
      the foot is offloaded. Thus, successful healing of chronic wounds involves the
      treatment of underlying causes. Sometimes, however, proper management of these
      underlying diseases does not result in healing. Conventional therapy,
      unfortunately, does not have an answer for this dilemma. Growth factors provide a
      means by which cells are able to communicate with each other. They have profound
      effects on cell proliferation, migration, and extracellular matrix synthesis and
      release. Considering applying topically active growth factors directly to the
      wound surface in order to stimulate some aspect of the healing process has always
      been attractive. To date, Platelet-Derived Growth Factor (PDGF) has been the most
      researched of all the growth factors. Originally studied in the management of
      pressure ulcers, PDGF was eventually approved in North America for the treatment
      of diabetic lower extremity ulcers. The clinical data surrounding these
      indications will be reviewed. The future in growth factor research may require a
      greater understanding of how these substances interact with each other. Wound
      dressings of the future may include several growth factors, each with a specific
      function. In this way, the application of topically active growth factors to
      chronic ulcers just might be the next great innovation in wound healing.

PMID- 10655869
TI  - Publish or perish.

PMID- 10655870
TI  - What Medicare's looming insolvency hath wrought.

PMID- 10655871
TI  - Rethinking access in an information age.
AB  - Medical information is part of the growing global resource that constitutes the
      World Wide Web. Researching health information is one of the most common reasons
      for using the Internet. In 1997, nearly half of U.S. users spent time looking for
      health information or support on the Internet. More recently, the Internet allows
      medically naive users to question physicians and other clinicians about health
      related topics by e-mail and other digital communication methods. In the face of
      this growing technology, the term "access" now encompasses the availability of
      specialized information to the general public. This article reviews the meaning
      of access in terms of the growing information Movement, looks at opportunities
      this presents to clinicians, and analyzes barriers to widespread and appropriate
      information access.

PMID- 10655872
TI  - Nonhealing foot ulcer.

PMID- 10655873
TI  - International Wound Care Ambassadorship. Diane Merkle, RN, CETN.

PMID- 10655874
TI  - Wound management: a global perspective.

PMID- 10655875
TI  - Making clinical practice guidelines work: the experience of one home healthcare
      agency.
AB  - Almost 20 years have passed since clinical practice guidelines were introduced
      into the healthcare system and they have permeated into every area of clinical
      practice. Originally clinical practice guidelines were regarded, by healthcare
      chief executive officers, as "the answer" to the need to reduce inappropriate or
      unnecessary variation in clinical practice. Between 1990 and 1996, the U.S.
      Agency for Health Care Policy and Research introduced 19 practice guidelines in
      an effort to support evidence-based methods to assess medical treatments and to
      set high standards for the development of guidelines. This article will explore
      the development and/or adoption and clinical application of guidelines into
      practice.

PMID- 10655877
TI  - Smile.

PMID- 10655876
TI  - The treatment of ambulatory venous ulcer patients with warming therapy.
AB  - The standard treatment for ambulatory patients with venous ulcers is compression
      therapy. The aim of the present study was to develop a warming regimen to treat
      venous ulcers, which could be easily used by patients in their home or work
      environment. Five patients with a mean age of 66 years (51-80) who had venous
      ulcers for an average of 8 months (3-13) were treated with zip-up compression
      stockings (gradient compression 40 mmHg at the ankle) and a warming dressing. The
      latter was controlled by the patient to warm the ulcer to 38 degrees C for 1 hour
      three times daily. Warming therapy was carried out for 2 weeks and patients'
      ulcers were monitored for healing for 12 weeks. In all but one of the patients
      following warming therapy, there was marked increase in granulation tissue as
      well as a decrease in pain. Four of the five patients completely healed during
      the 12-week period. In conclusion, this study has demonstrated that warming
      therapy can be used by ambulatory patients with venous ulcers in conjunction with
      compression therapy. A randomized prospective study is in progress.

PMID- 10655878
TI  - Doing the right thing: computers and ethics.

PMID- 10655879
TI  - Iatrogenic injuries. Cardiac tamponade.

PMID- 10655880
TI  - When the flu killed millions.

PMID- 10655881
TI  - Another benefit of getting a BSN.

PMID- 10655882
TI  - Parents in the OR? You bet!

PMID- 10655883
TI  - Emergency contraceptive options.

PMID- 10655884
TI  - Pacemakers: keeping the beat today.

PMID- 10655885
TI  - Electronic infusion pumps.

PMID- 10655886
TI  - SAMe: a dietary remedy for mind and body?

PMID- 10655887
TI  - Reduce your risk when you draw blood.

PMID- 10655888
TI  - Design and implementation of a training programme for general practitioners in
      emergency surgery and obstetrics in precarious situations in Ethiopia.
AB  - Medecins Sans Frontieres (MSF) has been implementing medical assistance programs
      in Ethiopia since 1994, including the rehabilitation of health structures and the
      supply of drugs and medical equipment. In 1995, the serious shortage of surgeons
      in Ethiopia prompted MSF to add a programme to train general practitioners to
      perform surgery in the Woldya region. The results of the relevant feasibility
      study were encouraging. The programme's design is based on recent educational
      data and MSF's experience with introducing transcultural training in countries
      where unstable conditions prevail. The training programme is currently being
      studied by the Ethiopian Health Ministry for use as a model for training general
      practitioners in surgery throughout the country.

PMID- 10655889
TI  - Nutritional consequences of radiotherapy in early laryngeal carcinoma.
AB  - In treating patients with malignant head and neck disease, radiotherapy may
      compromise their oral intake and, thus, their nutritional status. This study
      aimed to assess a subgroup of patients who received small field radiotherapy,
      where their early primary tumour itself would not be expected to affect
      swallowing and where significant nutritional problems are not traditionally
      identified. A retrospective analysis of hospital records was undertaken on 61
      patients, treated for T1 and T2 N0 laryngeal squamous cell carcinoma with primary
      radical radiotherapy over a three year period (1993-1995 inclusive). At
      presentation, 97% had their weight and height recorded, enabling calculation of
      their body mass index (BMI); 13% presented with a BMI < 20 kg/m2 and the 26% of
      patients who complained of weight loss at presentation had a mean percentage
      weight loss of 5.35%. During treatment, 79% of patients had their weight recorded
      and 49% had a documented mean percentage weight loss of 6.4%. The mean BMI at the
      end of treatment was significantly lower than at presentation (P = 0.03). These
      effects occurred despite 80% of patients having at least one dietetic
      consultation (mean 3.5 consults), and 75% having received high protein/high
      calorie supplementation. The percentage weight loss during treatment correlated
      significantly with the gamma-glutamyl transpeptidase (gamma-GT) level at
      presentation. The biochemical markers, haemoglobin and albumin, were normal in
      the great majority at presentation and fell non-specifically during treatment in
      82% and 56% of patients, respectively. We conclude that significant numbers of
      patients with early laryngeal malignancy are undernourished at presentation and,
      despite dietetic support, endure considerable nutritional problems during
      radiotherapy. Attention to nutritional issues is mandatory even in this group of
      patients previously considered to be less at risk because of the site and early
      stage of their disease.

PMID- 10655890
TI  - Palliation in oesophageal neoplasia.
AB  - Oesophageal cancer is an increasingly common disease in the UK. Sadly, the
      overall results of treatment remain poor with overall 5 year survival of
      approximately 10%. More than 50% of patients receive purely palliative care from
      the outset. Of those having potentially curative treatment, 40% will not survive
      the first year and 70% will not survive 5 years. Good quality palliation is,
      therefore, required for the majority of patients.

PMID- 10655891
TI  - Video-assisted thoracoscopic surgery for spontaneous pneumothorax--a 7-year
      learning experience.
AB  - OBJECTIVES: To determine the effect of increasing experience of video-assisted
      thoracoscopic surgery (VATS) in the treatment of spontaneous pneumothorax (SP) on
      clinical efficacy and surgical practice. PATIENTS AND METHODS: A prospective
      study of 180 consecutive operations in 173 patients who underwent VATS for SP by
      a single surgeon during a 7 year period. RESULTS: 118 patients, mean age 32.1
      years (range 13-63 years), were treated for primary spontaneous pneumothorax
      (PSP) while 55 patients, mean age 65.9 years (range 28-92 years), were treated
      for secondary spontaneous pneumothorax (SSP). All patients had VAT parietal
      pleurectomy combined in 162 (90%) patients with stapled bullectomy. At a current
      median experience of 2.0 years (range 0.4-6.8 years), 12 (6.6%) patients required
      reoperation for treatment failures within 12 months of surgery--9 patients within
      30 days of VATS and 3 for late recurrent pneumothorax. Two patients (both with
      SSP) died within 30 days of surgery. When compared with PSP, VATS in SSP is
      characterized by an elderly, male predominance, a longer postoperative stay, a
      higher mortality rate and a lower rate of late recurrence. With increasing
      experience of the technique, there has been a significant decrease in treatment
      failures. In the treatment of PSP, both operating time and postoperative stay
      have decreased significantly with experience whilst the use of staple cartridges
      per patient has increased significantly with experience in both PSP and SSP.
      CONCLUSION: There is a demonstrable 'learning curve' effect on the clinical
      efficacy and surgical practice of video assisted thoracoscopic surgery for
      spontaneous pneumothorax.

PMID- 10655892
TI  - Setting up a breast cancer family history clinic.
AB  - Breast cancer causes around 21,000 deaths per year in the UK, the vast majority
      of these occurring in women aged over 50 years with no genetic predisposition to
      the disease. Screening and symptomatic services for these women, although by no
      means perfect or homogeneous, have gradually improved over the last 10 years and,
      perhaps as a result of this, together with increased use of adjuvant systemic
      therapy, mortality in this group has fallen. Despite this reassuring state of
      affairs, media interest in the disease and patients' perception of their risk of
      developing breast cancer have risen. Part of this is undoubtedly due to the new
      scientific developments in cancer genetics and, in particular, identification of
      the BRCA1 gene in 1994 and BRCA2 gene shortly afterwards. These genes are
      dominantly inherited with up to 80% penetrance; thus, women (and occasionally
      men) inherit these genes and have a high lifetime risk of developing breast
      cancer, usually at a younger age than average and possibly of a more aggressive
      phenotype. Unaffected family members can now be screened and, if they prove
      carriers, screening for early detection and prevention strategies such as
      bilateral prophylactic mastectomy can be offered. Because of the high risk of
      ovarian cancer in BRCA1 carriers, screening or prophylactic ovariectomy may also
      be considered.

PMID- 10655893
TI  - Rapid on-table colonic lavage with minimal mess.

PMID- 10655894
TI  - The use of a proforma improves colorectal cancer pathology reporting.
AB  - The detail and accuracy of pathological reporting for colorectal cancer is
      becoming increasingly recognised as important in the overall management of the
      patient. However, there is criticism of the variable standards of reporting. We
      assessed how the use of a proforma affected the completeness of reporting within
      one hospital. Data on all colorectal cancer patients attending one teaching
      hospital has been collected prospectively over a 15 month period from 1997 to
      1998. The Royal College of Surgeons/Association of Coloproctology proforma lists
      all items considered to be essential for a complete pathological report of
      colorectal cancer. Its introduction in September 1997 allowed us to compare
      reporting before the proforma to that after. Of 54 patients, 46 (85%) had one or
      more items missing from their report before introduction of the proforma compared
      with only 8/44 (18%) patients after the proforma (P < 0.001). Circumferential
      resection margins and apical node status were the items most often absent, being
      significantly more frequently reported after the proforma (P < 0.05 and P <
      0.001, respectively). There was no difference in the median number of lymph nodes
      harvested after proforma introduction. The introduction of the proforma has not
      only resulted in improvements in reporting, but has increased the dialogue
      between surgical oncologists and pathologists. These features should result in
      improved overall management of the colorectal cancer patient.

PMID- 10655895
TI  - The retroperitoneal approach to unusual abdominal aortic aneurysms.
AB  - A retroperitoneal approach was used to repair an infrarenal abdominal aortic
      aneurysm in three patients. The technique was used because of unusual pathology
      obscuring the aneurysm neck. We discuss the technique of retroperitoneal exposure
      and suggest advantages over conventional transperitoneal repair in patients with
      uncomplicated infrarenal abdominal aortic aneurysm.

PMID- 10655897
TI  - Effective securing of a drain.
AB  - The importance of effective anchoring of drains cannot be over emphasized. In
      this paper, we describe a safe and effective method of drain fixation used in 118
      cases between January 1998-99 in our department. This useful technique has the
      advantage of minimizing inadvertent drain displacement with its consequent
      complications.

PMID- 10655896
TI  - A survey of the current management of varicose veins by members of the Vascular
      Surgical Society.
AB  - The assessment and treatment of varicose veins by members of the Vascular
      Surgical Society of Great Britain and Ireland has been assessed by postal
      questionnaire. The response rate was 65%, of which 77% were general surgeons with
      a vascular interest, 21% were vascular surgeons only and 2% were non-vascular.
      Approximately four new patients with varicose veins are seen per surgeon per week
      in clinics with a median waiting time to be seen of 12 weeks. A median of three
      varicose vein operations per surgeon per week are undertaken with 10-15% of
      surgery being performed for recurrent disease. The commonest indications for
      surgery are symptomatic (97%) and complicated (98%) varicose veins, although 55%
      of surgeons also perform surgery for cosmesis. 65% surgeons routinely use hand
      held Doppler in the assessment of varicose veins; of the other methods available,
      Duplex scanning was used as the first line investigation by 83%. Although over
      60% of surgeons use sclerotherapy surgery is the preferred option for primary
      treatment for varicose veins associated with long or short saphenous reflux. 62%
      surgeons use deep venous thrombosis prophylaxis in patients undergoing varicose
      veins surgery selectively, and 27% use it routinely.

PMID- 10655898
TI  - The history and evolution of surgical instruments. X clamps, haemostats and
      related pivot-controlled forceps.

PMID- 10655899
TI  - Hernia repair. Clinical indicators.

PMID- 10655900
TI  - Conventional or laparoscopic inguinal hernia repair? The surgeon's choice.

PMID- 10655901
TI  - An audit of emergency abdominal aortic aneurysm repair to establish the necessity
      for an emergency vascular surgical rota.

PMID- 10655902
TI  - Posterior sternoclavicular dislocations--a diagnosis easily missed.

PMID- 10655904
TI  - Realizing visions.

PMID- 10655903
TI  - Adenocarcinoma within a rectal duplication.

PMID- 10655905
TI  - Effects of dexmedetomidine on isoflurane requirements in healthy volunteers. 1:
      Pharmacodynamic and pharmacokinetic interactions.
AB  - Dexmedetomidine is a highly selective alpha 2-adrenoceptor agonist with
      anaesthetic-sparing effects. We have determined the pharmacodynamic and
      pharmacokinetic interactions between dexmedetomidine and isoflurane in
      volunteers. Nine male subjects were allocated randomly to receive isoflurane
      anaesthesia preceded by infusion of dexmedetomidine on three separate occasions,
      2 weeks apart. Dexmedetomidine target plasma concentrations were 0.0 (placebo),
      0.3 ng ml-1 (low-dex) and 0.6 ng ml-1 (high-dex). End-tidal isoflurane
      concentrations at which gross purposeful movement and response to verbal commands
      occurred were identified. In the recovery period, sedation scores and digit
      symbol substitution tests were recorded. Venous blood samples were obtained
      before, during and after anaesthesia at predetermined intervals for measurement
      of plasma concentrations of dexmedetomidine and calculation of standard
      pharmacokinetic indices (AUC, Cl, Vss, T1/2 alpha, T1/2 beta). The end-tidal
      isoflurane concentration at which 50% of subjects first responded to the tetanic
      stimulus was 1.05% in the placebo group, 0.72% in the low-dex group and 0.52% in
      the high-dex group. We conclude that dexmedetomidine decreased isoflurane
      requirements in a dose-dependent manner and reduced heart rate, systolic and
      diastolic arterial pressures. Sedation and slight impairment of cognitive
      function persisted for several hours after anaesthesia and the end of infusion of
      dexmedetomidine. Isoflurane did not appear to influence the pharmacokinetics of
      dexmedetomidine.

PMID- 10655906
TI  - Effects of dexmedetomidine on isoflurane requirements in healthy volunteers. 2:
      Auditory and somatosensory evoked responses.
AB  - The anaesthetic-sparing activity of dexmedetomidine during isoflurane anaesthesia
      was examined, using the end-point of lack of response to tetanic nerve
      stimulation. Nine subjects were given two doses of dexmedetomidine (target plasma
      concentrations of 0.3 ng ml-1 and 0.6 ng ml-1, respectively) and saline on
      separate occasions. We measured auditory (AER) and somatosensory (SER) evoked
      responses at end-tidal isoflurane concentrations of 0.2-1.4%. Pa and P25-N35
      amplitudes increased as isoflurane concentration was reduced (P < 0.001).
      Dexmedetomidine had no significant effect on this relationship. In contrast, P15
      N20 (SER) amplitude increased (P < 0.001) as isoflurane concentration was
      reduced. The dose of dexmedetomidine had a significant interaction with this
      trend (P < 0.002). Decreasing the concentration of isoflurane at the high dose of
      dexmedetomidine had less impact on P15-N20 amplitude than decreasing isoflurane
      at the low dose or with saline. The mechanism by which dexmedetomidine spares
      isoflurane is discussed in the light of these evoked response changes.

PMID- 10655907
TI  - A prospective, randomized comparison of preoperative and continuous balanced
      epidural or paravertebral bupivacaine on post-thoracotomy pain, pulmonary
      function and stress responses.
AB  - Both epidural and paravertebral blocks are effective in controlling post
      thoracotomy pain, but comparison of preoperative and balanced techniques,
      measuring pulmonary function and stress responses, has not been undertaken
      previously. We studied 100 adult patients, premedicated with morphine and
      diclofenac, allocated randomly to receive thoracic epidural bupivacaine or
      thoracic paravertebral bupivacaine as preoperative bolus doses followed by
      continuous infusions. All patients also received diclofenac and patient
      controlled morphine. Significantly lower visual analogue pain scores at rest and
      on coughing were found in the paravertebral group and patient-controlled morphine
      requirements were less. Pulmonary function was significantly better preserved in
      the paravertebral group who had higher oxygen saturations and less postoperative
      respiratory morbidity. There was a significant increase in plasma concentrations
      of cortisol from baseline in both the epidural and paravertebral groups and in
      plasma glucose concentrations in the epidural group, but no significant change
      from baseline in plasma glucose in the paravertebral group. Areas under the
      plasma concentration vs time curves for cortisol and glucose were significantly
      lower in the paravertebral groups. Side effects, especially nausea, vomiting and
      hypotension, were troublesome only in the epidural group. We conclude that with
      these regimens, paravertebral block was superior to epidural bupivacaine.

PMID- 10655908
TI  - Postoperative analgesia with i.v. patient-controlled morphine: effect of adding
      ketamine.
AB  - We have studied the effect of adding ketamine to i.v. morphine patient-controlled
      analgesia (PCA) for the treatment of pain after laparotomy. Thirty patients were
      allocated randomly to receive PCA with saline or ketamine in a double-blind,
      randomized study. Analgesia was started in the recovery room when visual analogue
      scale (VAS) scores were > 4. A bolus dose of morphine 3 mg was given to all the
      patients followed by i.v. PCA. Simultaneously, an infusion of ketamine 2.5
      micrograms kg-1 min-1 or saline was started. Pain scores, morphine consumption
      and side effects were noted for up to 48 h after the start of PCA. VAS scores
      decreased significantly with time (P = 0.0001) and were similar (P = 0.3083) in
      both groups. Cumulative morphine consumption at 48 h was significantly lower in
      the ketamine group (28 mg) than in the control group (54 mg) (P = 0.0003). Nausea
      was less frequent in the ketamine group (P = 0.03).

PMID- 10655909
TI  - A potential mechanism of propofol-induced pain on injection based on studies
      using nafamostat mesilate.
AB  - To elucidate the mechanism of propofol-induced pain on injection, we performed
      several studies using nafamostat mesilate, a kallikrein inhibitor, or lidocaine.
      As both pretreatment and low-dose mixing with nafamostat produced the same
      effects on pain reduction, we used the latter method in the following
      experiments. Low-dose mixing had the same effect on injection pain as mixing with
      lidocaine. The extent of pain was assessed by measuring bradykinin concentrations
      by mixing with blood. Propofol and its lipid solvent mixed with blood produced
      approximately two-fold generation of bradykinin compared with the saline control,
      and this was inhibited completely by nafamostat and lidocaine. Injection of the
      lipid solvent before propofol significantly aggravated pain compared with prior
      injection of saline, although the lipid solvent injected twice caused no change
      in pain. These results suggest that the lipid solvent for propofol activates the
      plasma kallikrein-kinin system and produces bradykinin which modifies the
      injected local vein. This modification of the peripheral vein may increase the
      contact between the aqueous phase propofol and the free nerve endings of the
      vessel, resulting in aggravation of propofol-induced pain.

PMID- 10655910
TI  - Acoustic monitoring of intraoperative neuromuscular block.
AB  - Standard methods for accurate intraoperative measurement of neuromuscular block
      are either expensive or inconvenient and are not used widely. We have evaluated a
      new method of monitoring neuromuscular block using a low-frequency microphone.
      The method is based on the phenomenon of low-frequency sound emission by
      contracting skeletal muscle. Acoustic monitoring (MIC) with an air-coupled
      microphone was used to evaluate intraoperative neuromuscular block in 25
      anaesthetized patients. The MIC recorded the response of the adductor pollicis
      muscle to supramaximal electrical stimulation of the ulnar nerve with train-of
      four stimuli. The ratios of the first response (TI) to control (TC) were used for
      evaluation. Data obtained from the MIC were compared with simultaneous
      recordings, from the same hand, of mechanomyography (FDT), electromyography (EMG)
      and accelerography (ACC). Throughout the operative procedure, TI/TC ratios of the
      acoustic method correlated with the three reference devices: FDT, 12 patients,
      262 data sets, r = 0.86, bias (%MIC-%FDT) = mean -5.3 (SD 19.6)%; EMG, 18
      patients, 490 data sets, r = 0.85, bias (%MIC-%EMG) = -0.39 (20.29)%; and ACC, 13
      patients, 328 data sets, r = 0.91, bias (%MIC-%ACC) = -3.0 (15.6)%. We conclude
      that monitoring intraoperative neuromuscular block by a microphone which
      transduces low-frequency muscle sounds is clinically feasible.

PMID- 10655911
TI  - Double-blind comparison of sevofluran vs propofol and succinylcholine for
      tracheal intubation in children.
AB  - We have studied intubating conditions in 64 healthy children, aged 3-10 yr,
      undergoing adenotonsillectomy, in a double-blind, randomized study. Intubation
      was performed 150 s after induction using either 8% sevoflurane in nitrous oxide
      and oxygen or propofol 3-4 mg kg-1 with succinylcholine 2 mg kg-1. An
      anaesthetist blinded to the technique performed intubation and scored intubating
      conditions using Krieg and Copenhagen Consensus Conference (CCC) scores. The
      trachea was intubated successfully at the first attempt in all patients under
      clinically acceptable conditions, although scores were significantly better with
      propofol and succinylcholine. The sevoflurane technique cost 3.62 +/- 0.55 Pounds
      to completion of tracheal intubation, significantly more (P < 0.001) than the
      cost of propofol-succinylcholine and isoflurane (2.04 +/- 0.54 Pounds) when based
      on actual amount of drug used. This cost increased to 4.38 +/- 0.05 Pounds when
      based on whole ampoules, which is significantly more than the cost of sevoflurane
      (P < 0.001).

PMID- 10655912
TI  - Desflurane and isoflurane improve neurological outcome after incomplete cerebral
      ischaemia in rats.
AB  - We have investigated the effects of isoflurane and desflurane on neurological
      outcome in a rat model of incomplete cerebral ischaemia. We studied 40 non-fasted
      male Sprague-Dawley rats, anaesthetized, intubated and ventilated mechanically
      with isoflurane and nitrous oxide in oxygen (FlO2 0.3). Arterial and venous
      catheters were inserted for measurement of arterial pressure, drug administration
      and blood sampling. A biparietal electroencephalogram (EEG) was recorded
      continuously using subdermal platinum electrodes. At completion of surgery,
      administration of isoflurane was discontinued (with the exception of those
      animals receiving isoflurane as treatment) and rats were allowed an equilibration
      period of 30 min according to the following procedure: group 1 (n = 10), 66%
      nitrous oxide in oxygen and fentanyl (bolus 10 micrograms kg-1 i.v. followed by
      infusion at a rate of 25 micrograms kg-1 h-1); group 2 (n = 10), 1.0 MAC of
      isoflurane in oxygen (FlO2 0.3) and air; groups 3 and 4 (n = 10 per group), 1.0
      MAC or 1.5 MAC of desflurane in oxygen (FlO2 0.3) and air, respectively.
      Ischaemia was produced by combined unilateral common carotid artery ligation and
      haemorrhagic hypotension to 35 mm Hg for 30 min. Functional neurological deficit
      was evaluated for 3 days after cerebral ischaemia. At baseline, brain electrical
      activity was higher with fentanyl-nitrous oxide, 1.0 MAC of isoflurane and 1.0
      MAC of desflurane (groups 1-3) compared with 1.5 MAC of desflurane (group 4).
      Neurological outcome was improved in isoflurane and desflurane anaesthetized
      animals (groups 2-4), regardless of the concentration used compared with fentanyl
      nitrous oxide anaesthesia (group 1). The increase in plasma epinephrine and
      norepinephrine concentrations during ischaemia was significantly higher in
      fentanyl-nitrous oxide anaesthetized animals (group 1) compared with animals who
      received volatile anaesthetics (groups 2-4). These data suggest that cerebral
      protection produced by isoflurane and desflurane appears to be related to
      reduction in sympathetic activity rather than suppression of cerebral metabolic
      rate.

PMID- 10655913
TI  - Relaxation by sevoflurane, desflurane and halothane in the isolated guinea-pig
      trachea via inhibition of cholinergic neurotransmission.
AB  - We have studied relaxation of airway smooth muscle by sevoflurane, desflurane and
      halothane in the isolated guinea-pig trachea. Ring preparations were mounted in
      tissue baths filled with physiological salt solution (PSS), aerated continuously
      with 5% carbon dioxide in oxygen. Electrical field stimulation (EFS) elicited
      cholinergic contractions that were abolished by tetrodotoxin, indicating nerve
      mediated responses. Anaesthetics were added to the gas aerating the tissue baths.
      Halothane, sevoflurane and desflurane at 0.5-1.0 MAC markedly attenuated
      cholinergic contractions to EFS. Initiation of contractile responses to
      acetylcholine (ACh) were not affected by volatile anaesthetics, suggesting
      prejunctional inhibition (i.e. inhibition of acetylcholine release). When added
      to a maintained submaximal contraction to ACh, volatile anaesthetics induced
      relaxation, indicating postjunctional inhibition. We conclude that sevoflurane,
      desflurane and halothane inhibited postganglionic cholinergic neuroeffector
      transmission in the trachea. The effect was probably exerted via pre- and
      postjunctional mechanisms (i.e. inhibition of acetylcholine release and direct
      muscle actions). Sevoflurane and desflurane were more potent than halothane both
      pre- and postjunctionally.

PMID- 10655914
TI  - Role of inhaled nitric oxide in ischaemia-reperfusion injury in the perfused
      rabbit lung.
AB  - We have tested if inhaled nitric oxide (NO) is beneficial in ischaemia
      reperfusion (IR) lung injury using an isolated perfused rabbit lung model.
      Ischaemia for 60 min was followed by reperfusion and ventilation with nitric
      oxide 40 ppm (n = 6) or without nitric oxide ventilation (n = 6) for 60 min. In
      the control group (n = 6), the lungs were perfused continuously for 120 min.
      Permeability coefficient (Kfc) and vascular resistance (PVR) were measured
      serially for 60 min after reperfusion. We also determined the left lung W/D ratio
      and measured nitric oxide metabolites (NOx) and cGMP concentrations in
      bronchoalveolar lavage (BAL) fluid from the right lung. IR increased Kfc, PVR and
      W/D followed by decreased cGMP. Ventilation with nitric oxide restored these
      changes by preventing the decrease in cGMP. Differences in NOx concentrations in
      BAL fluid between the control and IR groups were not statistically significant.
      Our results indicate that IR impaired pulmonary vascular function and resulted in
      microvascular constriction and leakage. Ventilation with nitric oxide from the
      beginning of the reperfusion period improved pulmonary dysfunction such as
      vasoconstriction and capillary leak by restoring cGMP concentrations.

PMID- 10655916
TI  - Inflammation of the rat urinary bladder is associated with a referred thermal
      hyperalgesia which is nerve growth factor dependent.
AB  - We have assessed whether a referred somatic hyperalgesia to thermal stimulation
      of the hind limb of rats occurs after inflammation of the urinary bladder.
      Furthermore, we evaluated whether any such viscero-somatic hyperalgesia (VSH) is
      dependent on the neurotrophin nerve growth factor (NGF). Limb withdrawal
      thresholds from thermal stimulation of both fore and hind limbs were assessed
      simultaneously at baseline and at fixed times for 24 h after various
      interventions. After plotting curves for the difference in withdrawal time of
      fore and hind limbs against time, the area under the curve (AUC) was calculated
      to provide a single measure over the 24-h period. A negative value indicated
      relative hyperalgesia of the hind limb. With simple catheterization, although
      there was a trend towards hind limb hyperalgesia, there was no significant
      difference in this AUC (mean -100.5) compared with naive control animals (mean
      AUC +53.6). However, inflammation with 50% turpentine oil was associated with a
      significant change in AUC (mean -676.8), indicative of relative hyperalgesia of
      the hind limb. This hyperalgesia was mimicked by intra-vesical instillation of
      NGF (in place of turpentine) (mean AUC -1418.3 while mean AUC in naive animals
      was +439.4). Furthermore, prior administration of an NGF sequestering molecule,
      trkA-IgG, attenuated turpentine-induced VSH. These findings increase our
      knowledge of the nature of visceral and referred pain and further implicate NGF
      in the hyperalgesic response to inflammation of the urinary bladder.

PMID- 10655915
TI  - Thermal and mechanical antinociceptive action of spinal vs peripherally
      administered clonidine in the rat inflamed knee joint model.
AB  - It has been demonstrated recently that in addition to its spinal analgesic
      actions, the alpha 2 adrenoreceptor agonist clonidine also has peripheral
      analgesic activity. Few data are available regarding the antinociceptive effects
      of spinal vs peripherally delivered clonidine in inflammatory pain. Thus we have
      studied spinal (intrathecal = i.t.) and peripheral (intra-articular = i.a.)
      administration of clonidine in the rat inflamed knee joint model. Thermal and
      mechanical antinociception was assessed in rats over 28 h using a modified
      Hargreaves box and von Frey hairs after induction of tonic persistent
      inflammatory pain by injection of a kaolin-carrageenan mixture into the right
      knee joint. Thirty minutes after injection of kaolin-carrageenan, clonidine was
      administered via an i.t. catheter or by i.a. injection into the right inflamed
      knee joint or by subcutaneous injection (s.c.) (highest effective intra-articular
      dose). The specific site of action was assessed using the alpha 2 antagonist
      yohimbine i.t., i.a. or s.c. Clonidine i.t. resulted in thermal and mechanical
      antinociception during ongoing inflammation, which was not enhanced by
      inflammation. In contrast, i.a. delivery of clonidine, which also produced a dose
      dependent thermal and mechanical antinociceptive effect, revealed a leftward
      shift in the antinociceptive activity produced by ongoing inflammation. Yohimbine
      inhibited the antinociceptive action of clonidine at the site of delivery. We
      suggest that clonidine produces potent thermal and mechanical antinociception
      regardless of the route of administration. However, chronic inflammatory
      processing appears to enhance the antinociceptive efficacy of the peripheral
      alpha 2 agonist.

PMID- 10655917
TI  - Analgesic effect of intrathecal desipramine on carrageenan-induced thermal
      hyperalgesia in the rat.
AB  - We examined if intrathecal desipramine, a selective norepinephrine reuptake
      inhibitor, would modulate peripheral inflammation-induced hyperalgesia. Rats were
      chronically implanted with a lumbar intrathecal catheter and paw withdrawal
      latency (PWL) to noxious heat stimuli was assessed. Unilateral hindpaw
      inflammation was induced by intraplantar carrageenan injection. Carrageenan
      injection significantly (P < 0.05) reduced PWL of the injected paw (from mean
      11.4 (SEM 0.6) s to 3.5 (0.2) s, 3 h after carrageenan), but not of the
      contralateral side (from 11.6 (0.2) s to 11.2 (0.5) s). Intrathecal desipramine
      10, 30, 60 and 100 micrograms, which did not produce analgesic effects in
      untreated rats, dose-dependently reversed the shortened PWL on the ipsilateral
      side (3.3 (0.2), 5.3 (0.4), 6.2 (0.3) and 9.6 (0.2) s, respectively) without
      affecting the contralateral side. Pretreatment with intrathecal yohimbine 10
      micrograms did not antagonize the anti-hyperalgesic effects of desipramine (from
      9.6 (0.2) to 9.8 (0.3) s). Our results suggest that the mechanism underlying the
      analgesic effect of desipramine on inflammation-induced hyperalgesia is unlikely
      to be inhibition of norepinephrine reuptake within the spinal cord.

PMID- 10655918
TI  - Pulmonary aspiration of gastric contents in anaesthesia.

PMID- 10655919
TI  - Etomidate and the osteocalcin response to gynaecological surgery.
AB  - Circulating osteocalcin is a good marker of osteoblastic activity and decreases
      significantly after stressful physiological states such as major surgery.
      Glucocorticoids are known to inhibit osteoblastic activity and result in a
      decline in circulating osteocalcin. We used etomidate to inhibit the cortisol
      response to routine gynaecological surgery to determine if this would prevent the
      postoperative decline in osteocalcin. Twenty-four patients were allocated
      randomly to receive either thiopental or etomidate for induction of anaesthesia;
      all other aspects of anaesthesia and perioperative management were standardized.
      In the thiopental group, circulating cortisol increased significantly at 2 and 6
      h after the start of surgery and plasma osteocalcin concentrations decreased
      significantly to almost 50% of baseline values at 48 h. Etomidate abolished the
      cortisol response to surgery, and circulating osteocalcin concentrations did not
      change after operation. There was a significant difference in osteocalcin
      concentration between the groups at 48 h. We conclude that the cortisol response
      to surgery is associated with a postoperative decrease in circulating
      osteocalcin.

PMID- 10655920
TI  - Solvent for etomidate may cause pain and adverse effects.
AB  - We tested the hypothesis that the solvent for etomidate was a factor in the
      incidence of pain and other side effects after injection, and that these were
      associated with histamine release. Nine of 10 volunteers who received etomidate
      in a propylene glycol formulation reported moderate to severe pain on injection;
      only one of 10 subjects who received a lipid emulsion formulation reported mild
      pain (P < 0.05). The incidence of venous sequelae in the injected vein over the
      next 8 days was 50% in the propylene glycol group and 0% in the lipid emulsion
      group (P < 0.05). In one volunteer in the propylene group, there was a 13-fold
      increase in histamine concentrations and in one subject a four-fold increase. In
      the lipid emulsion group, no volunteer had an increase in histamine
      concentrations > 1 ng ml-1. We conclude that etomidate formulated in propylene
      glycol may cause direct injury to vascular endothelium resulting in pain and
      venous sequelae, whereas etomidate in lipid emulsion does not. There was no
      relationship between pain or venous sequelae and histamine release.

PMID- 10655921
TI  - Effects of propofol on extracellular acidification rates in primary cortical cell
      cultures: application of silicon microphysiometry to anaesthesia.
AB  - Propofol depresses both cerebral oxygen consumption and glucose utilization. We
      tested the hypothesis that these well described effects on brain metabolism are
      manifest by a reduction in neuronal acid production in vitro. The rate of
      extracellular acidification in primary cell cultures of rat cortical neurones was
      measured using a novel instrument (silicon microphysiometer) after stimulation
      with propofol 0.3, 3 and 30 micrograms ml-1. Intralipid 10% served as a control.
      Propofol 3 micrograms ml-1 caused a mean decrease of 1.51 (SEM 0.71)% in baseline
      acidification rate, which was significantly greater than that produced by 0.3
      microgram ml-1 or Intralipid alone (P < 0.05). The reduction after stimulation
      with propofol 30 micrograms ml-1 was 4.68 (0.35)% of baseline rates and this in
      turn was significantly greater than that elicited by propofol 3 or 0.3 microgram
      ml-1, or Intralipid (P < 0.001). We have confirmed the depressant effect of
      propofol on cerebral metabolism and established that propofol inhibits neuronal
      acid excretion in vitro.

PMID- 10655922
TI  - Neither nociceptin nor its receptor are present in human synovial fluid or
      tissue.
AB  - Our aim was to identify the nociceptin receptor and its endogenous ligand,
      nociceptin, in human peripheral tissue. Synovial tissue was obtained from 11
      patients (ASA I-III, 66-84 yr) undergoing elective total knee replacement.
      Synovial fluid was obtained from another 10 patients (ASA I-III, 57-81 yr). Fluid
      was mixed with trifluoroacetic acid and the tissue with isopentone before
      freezing at -70 degrees C. Nociceptin receptor identification was performed using
      a [3H]nociceptin binding assay and nociceptin detection by radioimmunoassay.
      There was no specific [3H]nociceptin binding to knee synovial tissue and
      radioimmunoassay did not detect nociceptin. Neither the nociceptin receptor nor
      nociceptin was found in human synovial tissue or fluid.

PMID- 10655923
TI  - Pre-ischaemic administration of procaine suppresses ischaemic glutamate release
      and reduces neuronal damage in the gerbil hippocampus.
AB  - The effects of intracerebroventricular administration of procaine 2 mumol on
      ischaemic release of neurotransmitter amino acids in the gerbil hippocampal CAI
      region were investigated using a microdialysis-high-performance liquid
      chromatography procedure. Histological outcome was examined by comparing delayed
      neuronal death between animals treated with procaine before ischaemia and animals
      treated after ischaemia. Transient forebrain ischaemia for 3 min produced
      increases in dialysate amino acid concentrations. Aspartate, glutamate and
      glycine reached 331%, 394% and 233% of pre-ischaemic values. Basal concentrations
      were restored immediately by reperfusion. Pre-ischaemic administration of
      procaine suppressed peak release and improved histological outcome. However, post
      ischaemic administration did not protect against ischaemic neuronal death.
      Improvement in ischaemic neuronal damage by pre-ischaemic administration of
      procaine may be related to suppression of excitatory amino acid release.

PMID- 10655925
TI  - Re-evaluation of appropriate size of the laryngeal mask airway.
AB  - We have assessed 32 males and 31 females in a randomized, crossover study to see
      if there was any difference in the correct positioning of the laryngeal mask,
      optimal ventilation (defined as no gas leak around the mask at an airway pressure
      of 18 cm H2O) and cuff visibility between sizes 4 and 5 masks in males and sizes
      3 and 4 in females. The position of the mask in relation to the glottis was
      assessed using a fibreoptic bronchoscope. There was no significant difference in
      correct positioning between the two sizes in either sex. Gas leak was
      significantly less frequent for a larger than a smaller mask (P < 0.01 for both
      sexes), whereas the cuff was more often seen in the mouth with larger masks (P <
      0.02 for males and P < 0.01 for females). Therefore, larger masks (size 4 in
      females and size 5 in males) provided a better seal than smaller sizes without
      worsening the relative position of the mask to the glottis; however, the larger
      mask came up within the mouth more often, which could interfere with
      tonsillectomy and could increase the risk of sore throat or lingual nerve damage.

PMID- 10655924
TI  - Comparison of pentastarch and Hartmann's solution for volume preloading in spinal
      anaesthesia for elective caesarean section.
AB  - We studied 160 patients undergoing elective Caesarean section under spinal
      anaesthesia who received a preloading volume of 15 ml kg-1 of 10% pentastarch in
      0.9% saline, or Hartmann's solution, in a prospective, randomized, double-blind
      study. We compared the incidence of spinal-induced hypotension in each group.
      Hypotension was defined as a decrease in systolic arterial pressure to less than
      70% of baseline values or < or = 90 mm Hg, whichever was the greater. The groups
      were comparable in physical characteristics and there was no serious morbidity.
      Fetal outcome was similar in both groups. Significantly more patients in the
      Hartmann's group (n = 38, 47.5%) developed hypotension than in the pentastarch
      group (n = 10, 12.5%) (P < 0.0001). Linear regression analysis showed that the
      only significant variable was type of fluid used. Blood glucose concentrations
      were not related to the presence of hypotension. We conclude that starches may be
      suitable for preloading in Caesarean section under spinal anaesthesia and provide
      an alternative to the aggressive use of vasoconstrictors.

PMID- 10655926
TI  - Influence of neuromuscular block, mode of ventilation and respiratory cycle on
      pharyngeal mucosal pressures with the laryngeal mask airway.
AB  - We tested the hypothesis that the pressure exerted by the laryngeal mask airway
      (LMA) against the pharyngeal mucosa varied with neuromuscular block, mode of
      ventilation and the respiratory cycle. We studied 20 anaesthetized adult
      patients. Microchip sensors were attached to a size 5 LMA at locations
      approximately corresponding to the base of the tongue, hypopharynx, lateral
      pharynx, oropharynx, posterior pharynx and piriform fossa. Mucosal pressures were
      measured with an intracuff pressure of 60 cm H2O under four conditions during
      anaesthesia using 2.0 MAC of sevoflurane: (1) apnoeic, non-paralysed; (2)
      spontaneously breathing, non-paralysed; (3) ventilated, paralysed and (4) non
      ventilated, paralysed. In conditions (2) and (3), mucosal pressures were measured
      at the end of inspiration and expiration. Mean mucosal pressure was less than 10
      cm H2O at all locations. There were no significant changes in mucosal pressure at
      any location between the four conditions. There was no variation between
      inspiration and expiration. With an intracuff pressure of 60 cm H2O in these
      circumstances, mucosal pressures were much less than considered safe for
      prolonged tracheal intubation.

PMID- 10655927
TI  - Cisatracurium neuromuscular block at the adductor pollicis and the laryngeal
      adductor muscles in humans.
AB  - We have compared the dose-response relationship (n = 30) and time course of
      neuromuscular block (n = 20) of cisatracurium at the laryngeal adductor and the
      adductor pollicis muscles. ED95 values for cisatracurium were 66.8 (95%
      confidence interval 61.3-72.3) micrograms kg-1 at the larynx and 45.2 (42.1-48.3)
      micrograms kg-1 at the adductor pollicis muscle (P < 0.0001). After
      administration of cisatracurium 0.1 mg kg-1, onset time was 2.7 (2.2-3.2) min at
      the larynx and 3.9 (3.0-4.8) min at the adductor pollicis (P < 0.0001). Time to
      95% recovery of the first twitch of the TOF was 26.9 (20.1-33.7) min and 45.6
      (39.7-51.5) min, respectively (P < 0.0001). We found that the laryngeal adductors
      were more resistant to the action of cisatracurium than the adductor pollicis
      muscle, but onset and recovery were faster at the larynx.

PMID- 10655928
TI  - Augmentation of vecuronium-induced neuromuscular block during sevoflurane
      anaesthesia: comparison with balanced anaesthesia using propofol or midazolam.
AB  - We have quantified the potentiating effects of 1.7% sevoflurane (n = 12) on
      vecuronium-induced neuromuscular block and compared the results with those
      obtained during balanced anaesthesia with propofol (n = 12) or midazolam (n = 12)
      in 36 patients. Neuromuscular function was monitored using an accelerograph and
      the train-of-four responses of the adductor pollicis muscle to ulnar nerve
      stimulation. Vecuronium 0.1 mg kg-1 was administered as an intubating dose, and
      maintenance doses of 0.02 mg kg-1 were administered on three occasions when T1/T0
      had recovered to 25%. Thereafter, spontaneous recovery was monitored until
      complete. Times to 25% recovery of T1/T0 (DUR25) after an intubating dose of
      vecuronium did not differ between groups (mean 44.2 (SD 18.7) min for
      sevoflurane, 38.3 (7.5) min for propofol and 35.5 (9.5) min for midazolam). DUR25
      values after each maintenance dose were 29.8 (9.5) min, 30.3 (10.4) min and 31.6
      (10.7) min during sevoflurane anaesthesia, and were significantly longer than
      values for propofol (21.7 (6.0) min, 21.5 (5.8) min and 21.9 (5.8) min) and
      midazolam (20.0 (5.9) min, 19.3 (7.7) min and 19.8 (8.0) min) (P < 0.05) in each
      case). Recovery index25-75% and interval from T1/T0 = 25% to T4/T1 = 0.7 after
      the final dose of vecuronium were significantly prolonged by sevoflurane (28.3
      (13.2) min and 42.7 (16.4) min) compared with propofol (17.6 (6.1) min and 26.6
      (9.8) min) or midazolam (16.3 (9.4) min and 26.0 (10.2) min) (P < 0.05 in each
      case).

PMID- 10655929
TI  - Living related donor liver transplantation in a patient with severe aortic
      stenosis.
AB  - We report the successful anaesthetic management of a young girl with Alagille's
      syndrome and severe aortic stenosis (resting pressure gradient 88 mm Hg)
      undergoing living related donor liver transplantation (LRDLT). The patient had
      end-stage liver disease and LRDLT was performed before replacement of the aortic
      valve. Anaesthesia was conducted uneventfully with the aid of a pulmonary artery
      catheter. Intra-aortic balloon pumping was used in the perioperative period for
      protection against myocardial ischaemia. Total clamping of the inferior vena cava
      was avoided during surgery and volume administration was guided by the pulmonary
      artery pressure. A stable circulation was maintained in the reperfusion period.
      The patient was discharged from hospital on day 54 after operation with normal
      liver function. Two years later her aortic valve was replaced successfully.

PMID- 10655930
TI  - Autotransfusion performed on a patient with cis AB blood group.
AB  - Cis AB blood group is a rare variant of the AB blood group resulting from
      inheritance of both A and B genes on one chromosome. It may lead to
      misclassification in ABO grouping and clinical misdiagnosis as a result of its
      divergence from the laws of Landsteiner and Mendel. We encountered a case of cis
      AB blood group, and we found that autotransfusion was useful during surgery in
      this patient with a rare blood group.

PMID- 10655931
TI  - Cardiovascular collapse associated with extreme iatrogenic PEEPi in patients with
      obstructive airways disease.
AB  - Chronic obstructive pulmonary disease (COPD) is commonly associated with positive
      alveolar pressure at end-expiration (intrinsic PEEP or PEEPi) caused by a
      prolonged expiratory time constant. Positive pressure ventilation (PPV) with
      large tidal volumes and high ventilatory frequencies may cause pulmonary
      hyperinflation, with increases in intrathoracic pressure and cardiopulmonary
      effects. We report two cases, one of fatal pulseless electrical activity, the
      other of life-threatening hypotension, both during vigorous manual PPV, in
      patients with severe COPD. This phenomenon has been well-recognized by
      intensivists but is reported poorly more widely.

PMID- 10655932
TI  - Unusual consequences of heroin overdose: rhabdomyolysis, acute renal failure,
      paraplegia and hypercalcaemia.
AB  - A 29-yr-old man, known to be a heroin addict, was found at home totally
      unrousable, bent on his hips in the lotus position. On admission, he required
      frequent ventricular defibrillation, external pacing and infusion of calcium. A
      diagnosis of rhabdomyolysis caused by heroin and cocaine overdose was made. He
      developed paraplegia below T12, acute renal failure, acute compartment syndrome
      in one leg and a coagulation defect. Despite a fasciotomy, a through-knee
      amputation of the leg was required. Haemodialysis was required for 26 days, and
      this period was complicated by increased serum calcium concentrations, which was
      treated with disodium pamindrate. Calcium deposits were palpable in the muscles
      and could be seen in vessels on limb x-rays. After 34 days, he was eventually
      discharged to a general surgical ward and subsequently into the community.

PMID- 10655933
TI  - Response to vecuronium in a patient with facioscapulohumeral muscular dystrophy.
AB  - Increased sensitivity to vecuronium has been noted in patients with Duchenne
      muscular dystrophy. We report the response to vecuronium in a patient with
      facioscapulohumeral muscular dystrophy (FSHD), an autosomal dominant disorder
      with an incidence of 10-20 cases per million. In this patient, sensitivity to an
      initial dose of vecuronium (0.02 + 0.08 mg kg-1) was normal, but recovery was
      faster and the effect of incremental doses of vecuronium (0.02 mg kg-1) was less
      than expected. Onset time and 25% recovery of T1/T0 after the intubating dose of
      vecuronium were 240 s and 22 min, respectively. Recovery index (spontaneous
      recovery of T1/T0 from 25% to 75%) was 9 min.

PMID- 10655934
TI  - Fatal nefopam overdose.
AB  - Nefopam is a non-opioid analgesic agent with a central mode of action involving
      activation of descending pain-modulating pathways and inhibition of synaptosomal
      uptake of hydroxytryptamine, norepinephrine and dopamine. Adverse effects during
      therapeutic use and after overdose of nefopam are known to involve the central
      nervous system (confusion and convulsions), the cardiovascular system
      (tachycardia and palpitations) and the kidneys (oliguria and renal failure). We
      report a death after nefopam overdose in a young woman who exhibited many of
      these features. It is only the second case of death after nefopam overdose in the
      literature.

PMID- 10655935
TI  - In vitro and in vivo assessment of the Ventrak 1550/Capnogard 1265 for single
      breath carbon dioxide analysis in neonates.
AB  - The Ventrak 1550/Capnogard 1265 (V&C) enables deadspace (VD) measurements to be
      made in neonates. The aim of our studies was to validate the V&C device for VD
      measurement in vitro (lung model) and in vivo (adult rabbits). Methods of
      measurement of VD using the V&C (automatic computation, interactive carbon
      dioxide-volume plot analysis, Bohr equation) were tested by comparing known added
      deadspace volumes (VDadd) with calculated VDadd. After producing a change in
      alveolar (VDalv) and physiological (VDphys) deadspace by in vivo broncho-alveolar
      lavage, VDalv and VDphys computed automatically were compared with values
      calculated by the Bohr-Enghoff equations. VDadd was slightly underestimated
      (absolute error in mean: automatically -0.61 ml; interactively -0.55 ml; Bohr 
      0.54 ml). The higher the VDadd, the lower the absolute errors and coefficients of
      variation (cv). The highest cv occurred for automatic analysis (approximately
      11%) compared with < 6% for interactive analysis or the Bohr equation. Average
      differences between results calculated automatically and by the Bohr-Enghoff
      equation were -0.79 ml for VDalv (95% confidence interval -2.02 to 0.44 ml) and 
      0.23 ml for VDphys (-0.6 to 0.14 ml). We conclude that the V&C can be used in
      newborn infants undergoing mechanical ventilation, if changes in VD are < 5 ml,
      interactive analysis or the Bohr equation should be used.

PMID- 10655938
TI  - Hidden hazards of scavenging.

PMID- 10655939
TI  - Analgesic efficacy of paracetamol and diclofenac in children receiving PCA
      morphine.

PMID- 10655940
TI  - Central nerve block and thromboprophylaxis.

PMID- 10655941
TI  - Central nerve block and thromboprophylaxis.

PMID- 10655942
TI  - Acute normovolaemic haemodilution vs controlled hypotension for blood
      conservation.

PMID- 10655943
TI  - Glycopyrrolate reduces nausea but is dry mouth acceptable?

PMID- 10655944
TI  - A new laryngoscope with flexible adjustable rigid blade.

PMID- 10655945
TI  - Gelatin may not be the cause of hypercoagulability.

PMID- 10655946
TI  - Metformin and perioperative risk.

PMID- 10655947
TI  - Acupressure and prevention of nausea and vomiting.

PMID- 10655948
TI  - Acupressure and prevention of nausea and vomiting.

PMID- 10655949
TI  - The hypolipidaemic effect of inulin: when animal studies help to approach the
      human problem.

PMID- 10655950
TI  - Mediterranean diet, fats and cardiovascular disease risk: what news?

PMID- 10655951
TI  - Micronutrients: highlights and research challenges from the 1994-5 National Diet
      and Nutrition Survey of people aged 65 years and over.
AB  - The aims of the National Diet and Nutrition Survey series are summarized, and the
      new National Diet and Nutrition Survey of people aged 65 years and over is
      explored, with particular emphasis on micronutrient intakes and status indices.
      Mean nutrient intakes were generally satisfactory for most micronutrients, but
      intakes of vitamin D, Mg, K and Cu were low. Intakes of vitamin D were far below
      the reference nutrient intake for people aged 65 years and over, and there was
      also biochemical evidence of vitamin D deficiency, for 8% of free-living and 37%
      of institution participants, attributed partly to limited exposure to sunlight. A
      substantial proportion of people living in institutions had inadequate
      biochemical status indices, notably for vitamin C, Fe and folate. Relationships
      between intake and status were close for vitamins. Mineral intakes did not
      correlate well with currently used status indices. Some intakes and indices,
      especially those of vitamin C, carotenoids, Na and K, were strongly correlated
      with socio-economic status and with north-south gradients in Britain. Future
      research challenges should address the functional and health significance of low
      intakes and sub-optimal biochemical indices for certain micronutrients,
      especially for people living in institutions; the shortcomings of mineral status
      indices especially as indicators of mineral intake; the social and geographical
      inequalities of micronutrient intakes and status, and why micronutrient status
      deteriorates with increasing age. The answers to these questions will help to
      define the characteristics of nutritional risk for older people in Britain, and
      to clarify future needs for education and intervention.

PMID- 10655952
TI  - Wholewheat flour ensures higher mineral absorption and bioavailability than white
      wheat flour in rats.
AB  - Consumption of unrefined whole flour is thought to affect mineral bioavailability
      because it contains high levels of fibre and phytic acid. The present experiment
      was designed to study the absorption of minerals from diets based on wholewheat
      flour and white wheat flour in rats. Two groups of male Wistar rats were fed on
      the diets for 3 weeks and absorption and tissue retention of minerals were
      studied. The rats fed on the wholewheat flour diet had significantly greater food
      intake, weight gain, faecal excretion and intestinal fermentation than those fed
      on the white flour diet. Mineral intakes, except for Ca, were significantly
      greater in rats fed on the wholewheat flour diet (4-fold for Mg, 2-fold for Fe
      and Zn). A significant rise in the apparent absorption of Fe (%) and a
      significant decrease in the apparent absorption of Zn (%) were observed. The
      amounts of minerals absorbed (mg/d) were significantly enhanced (excepted for Ca)
      with the wholewheat flour diet. Moreover, plasma and tibia levels of Mg and
      plasma, liver and tibia levels of Fe were significantly increased in rats fed on
      the wholewheat flour diet compared with those fed on the white flour diet. In
      conclusion, wholewheat flour, rich in phytic acid and minerals, did not have a
      negative effect on mineral absorption, but rather improved the bioavailability of
      some minerals. Human studies are needed to confirm these rat results before
      extrapolation to human nutrition.

PMID- 10655953
TI  - The effect of the daily intake of inulin on fasting lipid, insulin and glucose
      concentrations in middle-aged men and women.
AB  - The present study was carried out to examine the effect of the daily intake of 10
      g inulin on fasting blood lipid, glucose and insulin levels in healthy middle
      aged men and women with moderately raised total plasma cholesterol (TC) and
      triacylglycerol (TAG) levels. This study was a double-blind randomized placebo
      controlled parallel study in which fifty-four middle-aged subjects received
      either inulin or placebo for a period of 8 weeks. Fasting blood samples were
      collected before the supplementation period (baseline samples 1 and 2, separated
      by 1 week) and at weeks 4 and 8, with a follow-up at week 12. Compared with
      baseline values, insulin concentrations were significantly lower at 4 weeks (P <
      0.01) in the inulin group. There was a trend for TAG values, compared with
      baseline, to be lower in the inulin group at 8 weeks (P < 0.08) returning to
      baseline concentrations at week 12. On comparison of the inulin and placebo
      groups, the fasting TAG responses over the 8-week test period were shown to be
      significantly different (P < 0.05, repeated measures ANOVA), which was largely
      due to lower plasma TAG levels in the inulin group at week 8. The percentage
      change in TAG levels in the inulin group during the 8-week study was shown to
      correlate with the initial TAG level of the subjects (rs -0.499, P = 0.004). We
      therefore conclude that the daily addition of 10 g inulin to the diet
      significantly reduced fasting insulin concentrations during the 8-week test
      period and resulted in lower plasma TAG levels, particularly in subjects in whom
      fasting TAG levels were greater than 1.5 mmol/l. These data support findings from
      animal studies that fructans influence the formation and/or degradation of TAG
      rich lipoprotein particles, and the insulin data are also consistent with recent
      studies showing attenuation of insulin levels in fructan-treated rats.

PMID- 10655954
TI  - Olive oil- and fish oil-enriched diets modify plasma lipids and susceptibility of
      LDL to oxidative modification in free-living male patients with peripheral
      vascular disease: the Spanish Nutrition Study.
AB  - The present study describes a clinical trial in which Spanish patients suffering
      from peripheral vascular disease (Fontaine stage II) were given specific lipid
      supplements. Designed as a longitudinal intervention study, patients were
      provided with olive oil for 3 months, followed by a 3 month wash-out period, then
      supplemented with a combination of fish oil and olive oil for the final 3 months.
      Changes in plasma and lipoprotein fatty acid composition and susceptibility of
      LDL to in vitro oxidation were examined. Furthermore, lipid-supplement-induced
      changes in LDL properties were measured as relative electrophoretic mobility and
      macrophage uptake. In addition, thirteen patients not provided with olive oil and
      fish oil were included as a control group and twenty healthy age-matched
      individuals were used as a reference group. A complete clinical study and a
      nutritional survey concerning food habits and lifestyle were performed every 3
      months. Yao indices and claudicometry did not change significantly with dietary
      intervention although changes in plasma lipid composition suggested an
      improvement in the condition of the patients. The intake of the fish-oil
      supplement resulted in significantly increased plasma levels of eicosapentaenoic
      acid (20:5n-3) and docosahexaenoic acid (22:6n-3) in comparison with baseline
      concentrations, olive-oil and control groups. Fish-oil consumption significantly
      decreased plasma triacylglycerol levels compared with the olive-oil period,
      control and reference groups. The susceptibility of LDL to Cu-mediated oxidation
      was lower in the patients consuming olive oil and the fish-oil supplement than in
      the control group, and the uptake of LDL by macrophages was significantly lower
      in the group supplemented with fish oil. In conclusion, consumption of olive oil
      together with a dietary supplement of fish oil may be useful in the nutritional
      management of patients suffering from peripheral vascular disease in terms of
      increasing plasma n-3 long-chain polyunsaturated fatty acids and decreasing
      susceptibility of LDL to oxidation.

PMID- 10655955
TI  - Patterns of energy intake in patients with cirrhosis and healthy volunteers.
AB  - Fuel utilization and N economy are optimized in patients with cirrhosis by
      provision of several small meals throughout the day and a late-night snack of
      complex carbohydrate. Currently, however, only limited information is available
      on the patterns of energy intake in patients with chronic liver disease. The aims
      of the present study were to determine the number of days required to undertake
      such an investigation and to observe the daily distribution of energy intake in
      this patient population. Eight patients with cirrhosis and eight matched healthy
      volunteers kept weighed dietary intake records for fifteen separate days over a 6
      month period. The records were analysed for energy intake per hour and the number
      and size of energy intake episodes per 24 h calculated. Intake was verified
      against resting energy expenditure. Fourteen separate observational days were
      required to investigate the pattern of energy intake in the cirrhotic patients
      while 20 d were required for healthy volunteers. Considerable inter- and
      intrasubject variations in the number and size of energy intake episodes were
      observed in both the patients and healthy volunteers. However, no significant
      differences were observed between the mean total number of daily energy intake
      episodes (6.3 (SD 1.6) v. 7.0 (SD 1.4)) or in the distribution of daily energy
      intake between the two groups. Most patients and volunteers tended to eat
      frequent small meals, often including a late-night snack, rather than two or
      three large meals daily. It should, therefore, be possible to establish optimum
      patterns of energy intake in these patients in line with recent guidelines.

PMID- 10655956
TI  - Relation of BMI to a dual-energy X-ray absorptiometry measure of fatness.
AB  - Dual-energy X-ray absorptiometry (DXA) is a valid technique for measuring the
      fat, bone and lean (muscle, organs and water) masses of the body. We evaluated
      relationships of BMI (kg/m2) with independent measurements of fat and lean masses
      using DXA in 226 adult volunteers. The evaluation was an application of a general
      approach to compositional data which has not previously been used for describing
      body composition. Using traditional regression analyses, when lean mass was held
      constant, BMI varied with fat mass (men r 0.75, P < 0.05; women r 0.85, P <
      0.05); when fat mass was held constant, BMI varied with lean mass (men r 0.63, P
      < 0.05; women r 0.47, P < 0.05). In contrast, a regression model for
      compositional data revealed that BMI was: (a) strongly associated with log fat
      mass in both sexes (b1 4.86, P < 0.001 for all women and b1 5.96, P < 0.001 for
      all men); (b) not associated with bone mass, except in older men; (c) related to
      lean mass in women but not in men (b3 -4.04, P < 0.001 for all women and b1 
      2.59, P < 0.15 for all men). Women with higher BMI tended to have more fat mass
      and more lean mass than women with lower BMI. Men with higher BMI had more fat
      mass but similar lean mass to men with lower BMI. Investigators need to be alert
      to the inaccuracy of BMI to assign a fatness risk factor to individuals,
      especially among women.

PMID- 10655957
TI  - Are the advantages of the Mediterranean diet transferable to other populations? A
      cohort study in Melbourne, Australia.
AB  - A prospective cohort study, involving 141 Anglo-Celts and 189 Greek-Australians
      of both sexes aged 70 years or more, was undertaken in Melbourne, Australia. The
      objective was to evaluate whether adherence to the principles of the
      Mediterranean diet affects survival of elderly people in developed non
      Mediterranean countries. Diet was assessed using an extensive validated
      questionnaire on food intake. A one unit increase in a diet score, devised a
      priori on the basis of eight key features of the traditional common diet in the
      Mediterranean region, was associated with a 17% reduction in overall mortality
      (two-tailed P value 0.07). Mortality reduction with increasing diet score was at
      least as evident among Anglo-Celts as among Greek-Australians. We conclude that a
      diet that adheres to the principles of the traditional Mediterranean diet is
      associated with longer survival among Australians of either Greek or Anglo-Celtic
      origin.

PMID- 10655958
TI  - The effect of moderately and severely restricted dietary magnesium intakes on
      bone composition and bone metabolism in the rat.
AB  - Forty 3-week-old male rats, Wistar strain, average weight 59 g, were randomized
      by weight into five groups of eight rats each. Three groups were fed ad libitum
      on a semi-purified diet containing (per kg) 400 (adequate), 200 (moderately Mg
      restricted) or 20 (severely Mg-restricted) mg Mg for 3 weeks while two groups
      were pair-fed with the Mg-adequate diet in the same quantities as those consumed
      by the two Mg-restricted groups respectively. While weight gains and food
      conversion efficiency values for the Mg-restricted groups were similar to those
      of the corresponding pair-fed control groups, serum and kidney Mg, and femoral
      dry weight were reduced by 70, 7 and 9% respectively in the severely Mg
      restricted group and were unaffected in the moderately Mg-restricted group.
      Significant reductions were observed in urinary pyridinoline (Pyr) (by 44 and
      34%) and deoxypyridinoline (Dpyr) levels (by 40 and 33%) (markers of bone
      resorption), serum osteocalcin levels (by 46 and 28%) (marker of bone formation),
      femoral Mg levels (by 52 and 14%) and osteocalcin mRNA levels (by 46 and 22%)
      compared with the corresponding pair-fed controls, in the severely and moderately
      Mg-restricted groups respectively, and these reductions, except for those in
      urinary Pyr and Dpyr, were more marked in the severely Mg-restricted group.
      Femoral Ca and P concentrations were unaffected by dietary Mg restriction. These
      results show that not only severe but also moderate dietary restriction of Mg
      over 21 d results in qualitative changes in bone (i.e. reduced Mg concentration)
      as well as in aberrant bone turnover in young growing rats (i.e. severely
      depressed rates of bone formation and bone resorption), which may impair bone
      development and bone strength.

PMID- 10655959
TI  - Efficacy studies of probiotics: a call for guidelines.

PMID- 10655960
TI  - Functional food properties of non-digestable oligosaccharides.

PMID- 10655961
TI  - Vitamin A: not for vision only.

PMID- 10655962
TI  - Modelling human infant requirements for long-chain polyunsaturated fatty acids.

PMID- 10655963
TI  - Anthropometric measurement error and the assessment of nutritional status.
AB  - Anthropometry involves the external measurement of morphological traits of human
      beings. It has a widespread and important place in nutritional assessment, and
      while the literature on anthropometric measurement and its interpretation is
      enormous, the extent to which measurement error can influence both measurement
      and interpretation of nutritional status is little considered. In this article,
      different types of anthropometric measurement error are reviewed, ways of
      estimating measurement error are critically evaluated, guidelines for acceptable
      error presented, and ways in which measures of error can be used to improve the
      interpretation of anthropometric nutritional status discussed. Possible errors
      are of two sorts; those that are associated with: (1) repeated measures giving
      the same value (unreliability, imprecision, undependability); and (2)
      measurements departing from true values (inaccuracy, bias). Imprecision is due
      largely to observer error, and is the most commonly used measure of
      anthropometric measurement error. This can be estimated by carrying out repeated
      anthropometric measures on the same subjects and calculating one or more of the
      following: technical error of measurement (TEM); percentage TEM, coefficient of
      reliability (R), and intraclass correlation coefficient. The first three of these
      measures are mathematically interrelated. Targets for training in anthropometry
      are at present far from perfect, and further work is needed in developing
      appropriate protocols for nutritional anthropometry training. Acceptable levels
      of measurement error are difficult to ascertain because TEM is age dependent, and
      the value is also related to the anthropometric characteristics of the group of
      population under investigation. R > 0.95 should be sought where possible, and
      reference values of maximum acceptable TEM at set levels of R using published
      data from the combined National Health and Nutrition Examination Surveys I and II
      (Frisancho, 1990) are given. There is a clear hierarchy in the precision of
      different nutritional anthropometric measures, with weight and height being most
      precise. Waist and hip circumference show strong between-observer differences,
      and should, where possible, be carried out by one observer. Skinfolds can be
      associated with such large measurement error that interpretation is problematic.
      Ways are described in which measurement error can be used to assess the
      probability that differences in anthropometric measures across time within
      individuals are due to factors other than imprecision. Anthropometry is an
      important tool for nutritional assessment, and the techniques reported here
      should allow increased precision of measurement, and improved interpretation of
      anthropometric data.

PMID- 10655964
TI  - Retinyl palmitate supplementation by inhalation of an aerosol improves vitamin A
      status of preschool children in Gondar (Ethiopia).
AB  - We report successful vitamin A supplementation by inhalation of retinyl palmitate
      in a placebo-controlled pilot study in twenty-five preschool children (2-5 years
      of age) in the rural district of Gondar, Ethiopia. Preschool children (n 161)
      were randomly selected from 220 households. Out of this cohort, twenty-five
      children were randomly assigned to each of two treatment groups: one receiving
      retinyl palmitate by inhalation of two puffs of an aerosol containing 1 mg (3000
      IU) per delivery to give a total of 2 mg (6000 IU); and the other receiving an
      aerosol without retinyl palmitate. Both treatments were administered every 2
      weeks for 3 months. Serum retinol and retinol-binding protein concentrations in
      the vitamin A-treated group were 0.68 (SD 0.31) mumol/l and 59.4 (SD 24.2) mg/l
      before and 1.43 (SD 0.46) mumol/l (P < 0.01) and 97.3 (SD 31.2) mg/l (P < 0.05) 3
      months after supplementation with retinyl palmitate, suggesting that this novel
      method of delivery of retinyl palmitate by inhalation is effective in improving
      vitamin A status.

PMID- 10655965
TI  - Effects of dietary n-3 polyunsaturated fatty acids from plant and marine origin
      on platelet aggregation in healthy elderly subjects.
AB  - In the present intervention study we compared the effects of alpha-linolenic acid
      with those of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on
      platelet aggregation in vitro and ex vivo in healthy non-institutionalized
      elderly subjects. We also compared the effects of alpha-linolenic acid on
      platelet aggregation in elderly subjects with those in younger volunteers. During
      a run-in period of 3 weeks all subjects (thirty-eight elderly (> 60 years) and
      twelve younger volunteers (< 35 years)) received a diet rich in oleic acid. For
      the next 6 weeks the elderly subjects received a diet rich in oleic acid (n 11),
      alpha-linolenic acid (n 14) (6.8 g/d) or EPA/DHA (n 13) (1.05 g EPA plus 0.55 g
      DHA). The younger subjects were given a diet rich in alpha-linolenic acid. The
      diets did not affect ADP- or collagen-induced platelet aggregation in vitro in
      either platelet-rich plasma or whole blood. The ex vivo platelet aggregation as
      measured with filtragometry was significantly decreased in the elderly group that
      received EPA/DHA compared with the alpha-linolenic acid (P = 0.006) and the oleic
      acid (P = 0.005) diet groups. Effects of alpha-linolenic acid were not age
      dependent. Our results suggest that alpha-linolenic acid and EPA/DHA do not
      change in vitro platelet aggregation. Compared with oleic acid, EPA/DHA, but not
      alpha-linolenic acid, favourably affects ex vivo platelet aggregation in healthy
      elderly subjects.

PMID- 10655966
TI  - Blood cholesterol and apolipoprotein B levels in relation to intakes of animal
      and plant proteins in US adults.
AB  - Few studies have examined the association between specific sources of protein and
      blood lipids in a national sample of adults. We examined this relationship in a
      sample of adults 20 years and older who participated in phase 1 (1988-91) of the
      Third National Health and Nutrition Examination Survey, a representative sample
      of the United States non-institutionalized population. After excluding those
      participants who reported having been told they had high blood cholesterol
      concentrations, the final sample size was 6228. Mean intakes of different sources
      of proteins, as a percentage of total protein, were compared in quartiles of
      blood lipids. Intakes were adjusted for age, sex and race. Additional adjustments
      were made for other dietary variables, recall day, BMI, smoking, and income. We
      observed a lower percentage meat, fish and poultry (MFP) protein intake,
      including a lower percentage of beef and pork protein, among persons in the
      lowest quartile of serum total cholesterol and apolipoprotein B (ApoB)
      concentrations than among persons in the higher quartiles. The percentage of
      plant protein intake was higher in the lowest quartile than in the highest
      quartile of serum cholesterol. We also observed a higher percentage of fruit
      protein intake with lower serum cholesterol and ApoB concentrations. We conclude
      that in this cross-sectional sample, consumption of MFP proteins was consistently
      higher among persons with higher cholesterol concentrations while consumption of
      plant proteins was consistently higher among persons with lower cholesterol
      concentrations. Our findings support the importance of assessing intake of
      specific protein sources, especially in studies that address dietary intake in
      relation to blood lipids.

PMID- 10655967
TI  - Influence of feeding different vegetables on plasma levels of carotenoids, folate
      and vitamin C. Effect of disruption of the vegetable matrix.
AB  - Carotenoids, folate and vitamin C may contribute to the observed beneficial
      effects of increased vegetable intake. Currently, knowledge on the
      bioavailability of these compounds from vegetables is limited. We compared the
      efficacy of different vegetables, at the same level of intake (i.e. 300 g/d), in
      increasing plasma levels of carotenoids, folate and vitamin C and we investigated
      if disruption of the vegetable matrix would enhance the bioavailability of these
      micronutrients. In an incomplete block design, sixty-nine volunteers consumed a
      control meal without vegetables and three out of four vegetable meals (i.e.
      broccoli, green peas, whole leaf spinach, chopped spinach; containing between 1.7
      and 24.6 mg beta-carotene, 3.8 and 26 mg lutein, 0.22 and 0.60 mg folate and 26
      and 93 mg vitamin C) or a meal supplemented with synthetic beta-carotene (33.3
      mg). Meals were consumed for 4 d and fasting blood samples were taken at the end
      of each period. Consumption of the spinach-supplemented meal did not affect
      plasma levels of beta-carotene, although the beta-carotene content was 10-fold
      those of broccoli and green peas, which induced significant increases in plasma
      beta-carotene levels (28 (95% CI 6.4, 55)% and 26 (95% CI 2.6, 54)%
      respectively). The beta-carotene-supplemented meal increased plasma
      concentrations of beta-carotene effectively (517 (95% CI 409, 648)%). All
      vegetable meals increased the plasma concentrations of lutein and vitamin C
      significantly. Broccoli and green peas were, when expressed per mg carotenoid
      consumed, also more effective sources of lutein than spinach. A significant
      increase in plasma folate concentration was found only after consumption of the
      spinach-supplemented meal, which provided the highest level of folate. Disruption
      of the spinach matrix increased the plasma responses to both lutein (14 (95% CI
      3.7, 25)%) and folate (10 (95% CI 2.2, 18)%), whereas it did not affect the
      response to beta-carotene. We conclude that the bioavailabilities of beta
      carotene and lutein vary substantially among different vegetables and that the
      bioavailabilities of lutein and folate from spinach can be improved by disruption
      of the vegetable matrix.

PMID- 10655968
TI  - Relationships between fatty acid status of sow plasma and that of umbilical cord,
      plasma and tissues of newborn piglets when sows were fed on diets containing tuna
      oil or soyabean oil in late pregnancy.
AB  - To investigate the relationships between maternal, umbilical cord and piglet
      fatty acid status, multiparous sows (six per diet) were fed on diets containing
      supplements (30 g/kg) of either soyabean oil or tuna oil for the last 21 d of
      pregnancy. The proportions of most fatty acids differed between diets: in
      particular, the tuna-oil-containing diet supplied more 22:6n-3 and less 18:2n-6
      fatty acids than the soyabean-oil-containing diet. Maternal plasma fatty acid
      concentrations (mg/l) were greater than those in umbilical plasma and 20:4n-6 and
      22:6n-3 fatty acids were present in higher proportions (g/100 g fatty acids) in
      umbilical than maternal plasma. Feeding tuna oil increased the proportionate
      amounts (g/100 g fatty acids) of total n-3 fatty acids (particularly 22:6n-3) in
      umbilical cord, plasma and piglet tissues compared with feeding soyabean oil: in
      contrast, the proportion of 20:4n-6 was decreased by feeding tuna oil. Changes in
      piglet fatty acid proportions as a result of oil feeding were not influenced by
      piglet weight. While proportions of the long-chain n-3 and n-6 polyunsaturated
      fatty acids in piglet liver, spleen and reproductive tract (ovaries plus uterus
      of the female, testes of the male) correlated well with those of umbilical
      plasma, those in brain and retina were poorly correlated. Therefore umbilical
      plasma cannot be used to predict the fatty acid status of piglet brain.

PMID- 10655969
TI  - Effect of diet composition and ration size on key enzyme activities of glycolysis
      gluconeogenesis, the pentose phosphate pathway and amino acid metabolism in liver
      of gilthead sea bream (Sparus aurata).
AB  - The effects of diet composition and ration size on the activities of key enzymes
      involved in intermediary metabolism were studied in the liver of gilthead sea
      bream (Sparus aurata). High-carbohydrate, low-protein diets stimulated 6
      phosphofructo 1-kinase (EC 2.7.1.11), pyruvate kinase (EC 2.7.1.40), glucose-6
      phosphate dehydrogenase (EC 1.1.1.49) and 6-phosphogluconate dehydrogenase (EC
      1.1.1.44) enzyme activities, while they decreased alanine aminotransferase (EC
      2.6.1.2) activity. A high degree of correlation was found between food ration
      size and the activity of the enzymes 6-phosphofructo 1-kinase, pyruvate kinase,
      glucose-6-phosphate dehydrogenase (positive correlations) and fructose-1,6
      bisphosphatase (EC 3.1.3.11) (negative correlation). These correlations matched
      well with the high correlation also found between ration size and growth rate in
      starved fish refed for 22 d. Limited feeding (5 g/kg body weight) for 22 d
      decreased the activities of the key enzymes for glycolysis and lipogenesis, and
      alanine aminotransferase activity. The findings presented here indicate a high
      level of metabolic adaptation to both diet type and ration size. In particular,
      adaptation of enzyme activities to the consumption of a diet with a high
      carbohydrate level suggests that a carnivorous fish like Sparus aurata can
      tolerate partial replacement of protein by carbohydrate in the commercial diets
      supplied in culture. The relationship between enzyme activities, ration size and
      fish growth indicates that the enzymes quickly respond to dietary manipulations
      of cultured fish.

PMID- 10655970
TI  - Effects of dietary fats (fish, olive and high-oleic-acid sunflower oils) on lipid
      composition and antioxidant enzymes in rat liver.
AB  - The effects of two oleic-acid-rich diets (containing olive oil, OO, and high
      oleic-acid sunflower oil, HOSO) on plasma and liver lipid composition
      detoxification enzyme activities, were compared with those of a fish-oil (FO)
      diet and a control diet. Compared with the control diet, plasma and hepatic total
      triacylglycerol concentrations were increased in the animals fed on the HOSO and
      OO diets and decreased in those fed on the FO diet. The animals fed on FO showed
      the highest level of cholesterol in the liver and had lower plasma cholesterol
      concentrations when compared with those fed on the two oleic-acid-rich diets. In
      comparison with the animals fed on the diets enriched in oleic acid, the FO group
      showed higher hepatic levels of polyunsaturated fatty acids of the n-3 series and
      lower levels of fatty acids of the n-6 series. Livers of FO-fed rats, compared
      with those of OO- and HOSO-fed rats showed: (1) significantly higher activities
      of catalase (EC 1.11.1.6) glutathione peroxidase (EC 1.11.1.9) and Cu/Zn
      superoxide dismutase (EC 1.15.1.1); (2) no differences in the NADPH-cytochrome c
      reductase (EC 1.6.99.3) activity. The HOSO diet had a similar effect on liver
      antioxidant enzyme activities as the OO diet. In conclusion, it appears that
      changes in the liver fatty acid composition due mainly to n-3 lipids may enhance
      the efficiency of the antioxidant defence system. The two monounsaturated fatty
      acids oils studied (OO and HOSO), with the same high content of oleic acid but
      different contents of natural antioxidants, had similar effects on the
      antioxidant enzyme activities measured.

PMID- 10655971
TI  - Time-course of the change in blood pressure level in magnesium-deficient Wistar
      rats.
AB  - The aim of the present study was to determine whether a severely Mg-deficient
      diet can modify blood pressure in rats and whether these alterations in blood
      pressure are associated with a change in in vivo cardiovascular reactivity,
      alteration in plasma lipids and modification of the production of hormones
      involved in blood pressure regulation. Weanling male Wistar rats were pair-fed
      for 40 weeks with control (960 mg Mg/kg) and Mg-deficient (80 mg Mg/kg) diets. At
      2 weeks, blood pressure was lower in Mg-deficient rats, while heart rate was
      greater than in controls. Mg-deficiency-induced hypotension was transitory and
      the administration of antihistamine agents inhibited the appearance of this
      hypotensive phase, suggesting that histamine may play a role in lowering blood
      pressure. Until 15 weeks, blood pressures were similar for control and Mg
      deficient rats. Thereafter, blood pressure rose gradually until the end of the
      experiment in Mg-deficient rats. Heart rate remained higher in hypertensive Mg
      deficient rats. After 21 weeks, in vivo cardiovascular reactivity to
      noradrenaline was lower and reactivity to angiotensin II was unchanged in
      hypertensive Mg-deficient rats. At 2 and 21 weeks, hypomagnesaemia was
      accompanied by higher plasma levels of Ca, triacylglycerols and cholesterol.
      Plasma renin activity was higher at week 2, whereas levels of plasma angiotensin
      converting enzyme were lower at 2 and 21 weeks in Mg-deficient rats. The plasma
      aldosterone level was higher at 2 and 21 weeks while the vasopressin level did
      not change. Plasma corticosterone levels were lower at 2 weeks and higher at 21
      weeks. It is concluded that Mg deficiency induced a transitory hypotension
      followed by a sustained hypertension in rats. The release of vasodilator
      inflammatory agents may contribute to the early hypotension. The hypertensive
      phase may be explained by the increased sympathetic nervous activity induced by
      Mg deficiency even though the contribution of several hormonal systems implicated
      in blood pressure regulation remains to be elucidated.

PMID- 10655972
TI  - Fatty acid profiles of maternal adipose tissue in relation to infant development.

PMID- 10655973
TI  - Functional foods: cholesterol-lowering benefits of plant sterols.

PMID- 10655974
TI  - Dietary restriction of energy and sugar results in a reduction in human
      cytochrome P450 2E1 activity.
AB  - Dietary habits are often considered as a pathogenic factor for fatty liver. The
      impact of dietary intake and steatosis on drug metabolism remains poorly
      investigated. Our aim was to assess the effect of dietary intake on in vivo
      cytochrome P450 (CYP) activities in eleven patients with abnormal liver function
      tests potentially due to fatty liver and associated with a high-sugar diet. Liver
      function tests, liver volume, aminopyrine breath test (ABT) and chlorzoxazone
      (CZ) pharmacokinetics (area under the curve, AUC) which are known to reflect
      CYP2E1 activity were evaluated before and after 2 months restriction of dietary
      sugar intake. Features at inclusion were an increased BMI (30.3 (SD 3.2) kg/m2),
      high hepatic volume (1.96 (SD 0.48) litres), hyperechogenic liver parenchyma,
      elevated liver enzyme activities (alanine aminotransferase (EC 2.6.1.2) 58.6 (SD
      17.4) IU/1 with alanine aminotransferase: aspartate aminotransferase (EC 2.6.1.1)
      ratio > 1), together with a normal ABT value (0.68 (SD 0.21)% specific activity
      of administered dose of [14C]aminopyrine in breath after 1 h) and a high CYP2E1
      activity (CZ AUC 20.3 (SD 7.1) micrograms/ml per h). A dietary sugar restriction
      was prescribed. On the basis of repeated interviews by the same dietitian,
      unaware of any clinical and biochemical data, six patients remained complaint to
      the diet and exhibited reductions in BMI (P < 0.001), serum alanine
      aminotransferase (P = 0.008), liver volume (P = 0.002) and CYP2E1 activity (P =
      0.007), a significant increase in ABT (P < 0.001) together with the disappearance
      of liver hyperechogenicity at ultrasound. In contrast, the five non-compliant
      patients did not show any significant change in any of these variables. In
      conclusion, CYP2E1 activity is induced in patients with perturbations of liver
      function tests potentially due to fatty liver. In these patients, effective
      dietary sugar restriction is associated with a reduction in liver volume, a
      reduction in CYP2E1 activity and an increased aminopyrine metabolism rate.

PMID- 10655975
TI  - Fatty acid composition of white adipose tissue and breast milk of Mauritian and
      French mothers and erythrocyte phospholipids of their full-term breast-fed
      infants.
AB  - The fatty acid compositions of white adipose tissue, colostrum and mature milk
      triacylglycerols from Mauritian (n 13) and French (n 15) women were analysed and
      compared in order to highlight cultural differences in dietary intakes and their
      influence on milk fatty acid composition. Erythrocyte phosphatidylethanolamine
      and phosphatidylcholine fatty acid compositions were also investigated in their
      term infants, breast-fed over a period of 6 weeks. Fatty acid composition (g/100
      g) of all samples was determined by GLC and anthropometric measurements were
      assessed in the two populations at birth and on day 42. Comparisons of white
      adipose tissue fatty acid compositions demonstrated lower levels of saturated
      (23.64 (SE 1.54) v. 29.75 (SE 0.67), P < 0.01) and monounsaturated (39.44 (SE
      1.27) v. 54.84 (SE 0.75), P < 0.001) fatty acids and higher levels of
      polyunsaturated fatty acids (n-6 series: 32.47 (SE 1.31) v. 14.32 (SE 0.47), P <
      0.001 and n-3 series: 2.87 (SE 0.49) v. 0.80 (SE 0.07), P < 0.01) in Mauritian
      than in French samples respectively. Accordingly, milk fat of the Mauritian women
      contained higher levels of parent essential fatty acids and their longer-chain
      derivatives than did milk fat from French women. Higher levels of parent
      essential fatty acids but lower levels of long-chain polyunsaturated fatty acids
      were found in erythrocyte phospholipids of Mauritian infants compared with French
      infants. Infants' erythrocyte arachidonate and docosahexaenoate contents did not
      correlate with any anthropometric variables at birth or at day 42, neither did
      they correlate with anthropometric variation over the study period. Our results
      suggest the lack of a simple relationship between the amount of long-chain
      polyunsaturated fatty acids in human milk and their accretion in the erythrocyte
      phospholipids of breast-fed infants when provided concomitantly with high levels
      of both linoleic and alpha-linolenic acids in ratios which fall within
      recommended ranges.

PMID- 10655976
TI  - Spreads enriched with plant sterols, either esterified 4,4-dimethylsterols or
      free 4-desmethylsterols, and plasma total- and LDL-cholesterol concentrations.
AB  - In a 9-week study seventy-six healthy adult volunteers with an average age of 44
      (SD 11) years, with baseline plasma total cholesterol levels below 8 mmol/l,
      received in a balanced, double-blind, crossover design, a total of three
      different table spreads for personal use. Two spreads were fortified either with
      free (non-esterified) vegetable-oil sterols, mainly from soyabean oil (31 g
      sterol equivalents/kg; 0.8 g/d) or sheanut-oil sterols (133 g sterol
      equivalents/kg; 3.3 g/d). One spread was not fortified (control). Average intake
      of spread was 25 g/d for 3 weeks. None of the spreads induced changes in blood
      clinical chemistry or haematology. Plasma total- and LDL-cholesterol
      concentrations were statistically significantly reduced by 3.8% and 6% (both 0.19
      mmol/l) respectively, for the spread enriched with free soyabean-oil sterols
      compared with the control spread. The spread enriched with sheanut-oil sterols
      did not lower plasma total- and LDL-cholesterol levels. None of the plant-sterol
      enriched spreads affected plasma HDL-cholesterol concentrations. Plasma-lipid
      standardized concentrations of alpha- plus beta-carotene were not statistically
      significantly affected by the soyabean-oil sterol spread in contrast to lipid
      standardized plasma lycopene levels which showed a statistically significant
      decrease (9.5%). These findings indicate that a daily intake of free soyabean-oil
      sterols as low as 0.8 g added to a spread is effective in lowering blood total-
      and LDL-cholesterol levels with limited effects on blood carotenoid levels. The
      lowering in total- and LDL-cholesterol blood levels due to consumption of the
      vegetable-oil-sterol-enriched spread may be helpful in reducing the risk of CHD
      for the population.

PMID- 10655977
TI  - No effect of copper supplementation on biochemical markers of bone metabolism in
      healthy adults.
AB  - The influence of Cu supplementation of the usual diet for 6 weeks on biochemical
      markers of bone turnover and on putative indices of Cu status was investigated in
      healthy adults (twelve male and twelve female) aged 22-46 years, who participated
      in a double-blind placebo-controlled repeated crossover study. The study
      consisted of three 6-week supplementation regimens of 3 mg CuSO4, 3 mg Cu-glycine
      chelate (CuGC), and 6 mg CuGC, each separated by placebo periods of equal length.
      During baseline and on the last day of each dietary period, fasting morning first
      void urine and fasting blood serum, plasma and erythrocytes were collected. The
      habitual dietary Cu intakes in males and females were approximately 1.4 and 1.1
      mg/d respectively. Females had significantly higher (50%) plasma caeruloplasmin
      (Cp) protein concentrations than males at baseline. Cu supplementation had no
      effect on erythrocyte superoxide dismutase (SOD, EC 1.15.1.1) activity or plasma
      Cp protein (putative indices of Cu status) in the total group. Similarly, serum
      osteocalcin (a marker of bone formation), urinary creatinine (Cr) concentration,
      urinary pyridinoline: Cr or deoxypyridinoline: Cr excretion (markers of bone
      resorption) were unaffected in either the total group or in males and females
      separately, by any Cu supplementation regimen. It is concluded that Cu
      supplementation of the usual diet in healthy adult males and females had no
      effect on biochemical markers of bone formation or bone resorption over 6-week
      periods.

PMID- 10655978
TI  - Quantitative significance of measuring trimethylselenonium in urine for assessing
      chronically high intakes of selenium in human subjects.
AB  - The purpose of the present study was to investigate the effects of Se restriction
      on the excretion of Se in men who had consumed high levels of this element during
      their entire lives. With the use of stable isotopes of Se as selenite, the
      excretion of methylated Se in urine was investigated in Chinese men (n 10) who
      had habitual chronic high intakes of this element. The relationship between
      either urine Se or trimethylselenonium (TMSe) to the estimated long-term Se
      intake was not linear over the entire range of intake, which was also true for
      the infusion of labelled selenite. A non-linear relationship was also found
      between urine TMSe and urine Se both for TMSe arising from catabolism of
      endogenous body Se and that from infused selenite. The data suggest a close
      precursor-product relationship of urine Se and its TMSe component based on the
      nearly identical specific activities for these two selenocompounds. Although
      dimethylselenide in breath was not measured in the present study, combining
      urinary TMSe with this breath test may be more useful in the assessment of long
      term Se status.

PMID- 10655979
TI  - Effects of dietary coconut oil on fatty acid oxidation capacity of the liver, the
      heart and skeletal muscles in the preruminant calf.
AB  - The oxidative capacity of the liver, the heart and skeletal muscles for fatty
      acids were investigated in preruminant calves fed for 19 d on a milk-replacer
      containing either coconut oil (CO, rich in 12:0) or tallow (rich in 16:0 and
      18:1). Weights of the total body and tissues did not differ significantly between
      the two groups of animals but plasma glucose and insulin concentrations were
      lower in the CO group. Feeding on the CO diet induced an 18-fold increase in the
      hepatic concentration of triacylglycerols. Rates of total and peroxisomal
      oxidation of [1-14C]laurate, [1-14C]palmitate and [1-14C]oleate were measured in
      fresh tissue homogenates. Higher rates of total oxidation in liver homogenate and
      of peroxisomal oxidation in liver, heart and rectus abdominis muscle homogenates
      were observed with laurate used as substrate. Furthermore, the relative
      contribution of peroxisomes to total oxidation was 1.9-fold higher in the liver
      and in the heart with laurate than with oleate or palmitate. Finally, the
      peroxisomal oxidation rate of oleate was 1.5-fold higher in the hearts of calves
      fed on the CO diet. Whatever the tissue, citrate synthase (CS, EC 4.1.3.7) and
      cytochrome c oxidase (COX, EC 1.9.3.1) activities were similar between the two
      groups of calves but the COX: CS activity ratio was lower in the liver of the CO
      group. In conclusion, laurate is better catabolized by peroxisomes than long
      chain fatty acids, especially in the liver. Elongation of lauric acid after
      partial oxidation might explain the hepatic triacylglycerol accumulation in
      calves fed on the CO diet.

PMID- 10655980
TI  - Effects of conjugated linoleic acid (CLA) isomers on lipid levels and peroxisome
      proliferation in the hamster.
AB  - Effects of the conjugated linoleic acid (CLA) isomers cis-9, trans-11 (c9,t11
      CLA) and trans-10, cis-12 (t10,c12 CLA) on lipid metabolism and markers of
      peroxisome proliferation were investigated in hamsters fed on purified diets
      containing 30% energy as fat and 0.1 g cholesterol/kg for 8 weeks. Four groups (n
      32 each) received diets without CLA (control), with a mixture of equal amounts of
      c9,t11 and t10,c12 CLA (CLA mix), with c9,t11 CLA, and with t10,c12 CLA. The
      total amount of CLA isomers was 1.5% energy of 6.6g/ kg diet. CLA was
      incorporated into glycerides and exchanged for linoleic acid in the diet.
      Compared with the control, the CLA mix and t10,c12 CLA decreased fasting values
      of LDL- (21 and 18% respectively) and HDL-cholesterol (8 and 11%), increased VLDL
      triacylglycerol (80 and 61%, and decreased epididymal fat pad weights (9 and
      16%), whereas c9,t11 CLA had no significant effects. All CLA preparations
      increased liver weight, but not liver lipids. However, the increase in liver
      weight was much less in the c9,t11 CLA group (8%) than in the other two groups
      (25%) and might have been caused by the small amount of t10,c12 CLA present in
      the c9,t11 CLA preparation. Liver histology revealed that increased weight was
      due to hypertrophy. Markers of peroxisome proliferation, such as cyanide
      insensitive palmitoyl CoA oxidase (EC 1.3.3.6) and carnitine acetyl transferase
      (EC 2.3.1.7) activities, were not increased by CLA. Both c9,t11 CLA and t10,c12
      CLA were incorporated into phospholipids and triacylglycerols, but t10,c12 CLA
      only about half as much as c9,t11 CLA. In addition, linoleic acid and linolenic
      acid concentrations were lower in lipids of the t10,c12 CLA group compared with
      the c9,t11 CLA group. These data suggest that t10,c12 CLA stimulated the
      oxidation of all C18 polyunsaturated fatty acids. The results indicate that the
      t10,c12 CLA isomer, and not the so-called natural CLA isomer (c9,t11), is the
      active isomer affecting lipid levels in hamsters.

PMID- 10655981
TI  - Modifications induced by dietary lipid source in adipose tissue phospholipid
      fatty acids and their consequences in lipid mobilization.
AB  - The aim of the present work was to assess the influence of dietary lipid source
      on fatty acid phospholipid profiles and on lipid mobilization. Forty male Wistar
      rats were divided into four groups and fed on high-fat diets which provided olive
      oil, sunflower oil, palm oil or beef tallow. All rats received the same amount of
      energy to avoid hyperphagia and differences in energy intake among groups.
      Phospholipid fatty acids were determined by GC. Lipolysis was stimulated in
      subcutaneous and perirenal isolated adipocytes by several lipolytic agents, and
      assessed by the determination of released glycerol. After 4 weeks of feeding,
      differences in body and adipose tissue weights were not observed. Dietary
      regimens caused great changes in adipose tissue phospholipid composition: rats
      fed on palm oil and beef tallow had higher concentrations of saturated fatty
      acids and animals fed on olive oil or sunflower oil had greater amounts of oleic
      and linoleic acids, respectively. These modifications did not lead to important
      changes in adipocyte lipolysis. Significant differences were only observed
      between palm-oil- and beef-tallow-fed groups when lipolysis was stimulated by
      isoproterenol in subcutaneous adipocytes. The fact that our feeding protocol did
      not induce differences in fat accumulation among groups avoids misinterpretations
      due to adiposity changes. The differences observed between both saturated-fat-fed
      groups, therefore, should only be attributable to dietary lipids. Despite this
      effect, the data from this work indicate that some diet-induced changes in
      adipose tissue fatty acid composition may have little effect on overall function.

PMID- 10655982
TI  - Functional food properties of non-digestible oligosaccharides.

PMID- 10655983
TI  - The use of the dried blood spot sample in epidemiological studies.

PMID- 10655984
TI  - Acp. Best practice no 155. Pathological investigation of deaths following
      surgery, anaesthesia, and medical procedures.
AB  - The pathological investigation of deaths following surgery, anaesthesia, and
      medical procedures is discussed. The definition of "postoperative death" is
      examined and the classification of deaths following procedures detailed. The
      review of individual cases is described and the overall approach to necropsy and
      interpretation considered. There are specific sections dealing with the
      cardiovascular system (including air embolism, perioperative myocardial
      infarction, cardiac pacemakers, central venous catheters, cardiac surgery, heart
      valve replacement, angioplasty, and vascular surgery); respiratory system
      (postoperative pneumonia, pulmonary embolism, pneumothorax); central nervous
      system (dissection of cervical spinal cord), hepatobiliary and gastrointestinal
      system; musculoskeletal system; and head and neck region. Deaths associated with
      anaesthesia are classified and the specific problems of epidural anaesthesia and
      malignant hyperthermia discussed. The article concludes with a section on the
      recording of necropsy findings and their communication to clinicians and
      medicolegal authorities.

PMID- 10655985
TI  - Modulation of Helicobacter pylori induced interleukin-8 synthesis in gastric
      epithelial cells mediated by cag PAI encoded VirD4 homologue.
AB  - BACKGROUND: Strains of Helicobacter pylori carrying the virulence associated cag
      pathogenicity island (PAI) induce gastric epithelial synthesis of the chemokine
      interleukin-8 (IL-8), a neutrophil chemoattractant, and thereby a strong
      inflammatory response during chronic infection of the human gastric mucosa.
      Previous mutational analyses have shown that many genes in the cag PAI are needed
      to elicit IL-8 synthesis in gastric epithelial cells, and also that some genes
      are not involved. AIM: To test the possibility that certain genes in the cag PAI
      also downregulate (modulate) the inflammatory response elicited by cag+ H pylori
      infection. METHODS: Cells of L5F11, a derivative of the Kato-3 gastric epithelial
      cell line that carries an engineered IL-8 promoter-luciferase reporter gene
      fusion, were cocultured with H pylori strain 26695 or with an isogenic mutant in
      which most of the cag PAI ORF 10 gene, an Agrobacterium virD4 homologue, was
      deleted. Luciferase activity was measured to assess IL-8 gene transcription and
      secreted IL-8 was measured by enzyme linked immunosorbent assay to assess
      synthesis and release of IL-8 protein from gastric epithelial cells. RESULTS:
      Inactivation of ORF10 led to a 2.8-fold increase in IL-8 gene transcription and a
      3.6-fold increase in IL-8 synthesis and secretion. CONCLUSIONS: The results
      suggest that this VirD4 homologue participates in the control of inflammation
      that H pylori infection elicits by downregulating (modulating) the strong
      induction of IL-8 synthesis mediated by other cag encoded proteins.

PMID- 10655986
TI  - Increased expression of IL-10 and IL-12 (p40) mRNA in Helicobacter pylori
      infected gastric mucosa: relation to bacterial cag status and peptic ulceration.
AB  - AIMS: To investigate interleukin (IL)-12 (p40) and IL-10 mRNA expression levels
      in the gastric mucosa in relation to H pylori cag status, peptic ulceration, and
      histopathology. METHODS: In 81 dyspeptic patients, antral and corpus biopsies
      were taken for reverse transcriptase polymerase chain reaction (RT-PCR) and
      histology. G3PDH (control) and IL-10 and IL-12 were coamplified in a duplex PCR
      and the ratios of cytokines to G3PDH were determined. Bacterial ureA and cagA
      status was determined by RT-PCR. RESULTS: IL-10 mRNA expression in both the
      antral and corpus mucosa was greater (p < 0.01) in cagA positive infection than
      in H pylori negative patients with histologically normal mucosa. No increase in
      IL-10 mRNA expression was observed in cagA negative infection. Both in the antral
      and corpus mucosa, IL-12 mRNA expression was greater (p < 0.05) in cagA positive
      than in cagA negative infection and uninfected patients with normal gastric
      mucosa. In cagA positive infection, there was a correlation between IL-10 and IL
      12 mRNA expression in both the antral mucosa (r = 0.515, p < 0.01) and the corpus
      mucosa (r = 0.6, p < 0.005). IL-12 mRNA expression in the antral mucosa was
      significantly more frequent in H pylori positive patients with duodenal ulcer
      than in those with gastric ulcer or nonulcer dyspepsia. No difference was
      observed in IL-10 mRNA expression in relation to endoscopic diagnosis.
      CONCLUSIONS: CagA positive H pylori infection is associated with increased IL-10
      and IL-12 mRNA expression. The increased expression of IL-12 mRNA in the majority
      of patients with duodenal ulcer suggests that Th1 responses may predominate and
      play a role in the pathogenesis of duodenal ulceration.

PMID- 10655987
TI  - Cell proliferation in the post-surgical stomach, dietary salt, and the effect of
      H pylori eradication.
AB  - AIMS: To study the epithelial kinetics of the post-surgical stomach with
      reference to dietary salt intake and H pylori. METHODS: Endoscopic biopsies of
      the antrum/anastomosis and corpus were taken for histology and MIB-1
      immunostaining. The labelling index (LI%) was determined in the three zones of
      the gastric glands (zone 1 = surface + gastric pit; zone 2 = isthmus; zone 3 =
      gland base) in patients with vagotomy and pyloroplasty (n = 12),
      gastroenterostomy + vagotomy (n = 4), partial gastrectomy (n = 3), and Billroth I
      operation (n = 3). Dietary salt was determined by urinary sodium/creatinine
      ratio. Twelve patients were H pylori positive (10 vagotomy and pyloroplasty; 2
      partial gastrectomy) and had a repeat biopsy three months after antihelicobacter
      treatment (10 were H pylori negative after treatment). RESULTS: There was no
      correlation between salt intake and antrum/anastomosis (r = -0.34; p = 0.2) or
      corpus (r = -0.16; p = 0.2) labelling indices. Gastric mucosal proliferation is
      increased in the antrum/ anastomosis compared to the corpus in H pylori positive
      (p = 0.014) but not H pylori negative subjects (p = 0.084). This may reflect the
      different types of post-surgical stomach in each group. Gastric mucosal
      proliferation is reduced in antrum/anastomosis (p = 0.002) and corpus (p = 0.016)
      following H pylori eradication. CONCLUSIONS: Dietary salt does not influence
      gastric mucosal proliferation in the post-surgical stomach but H pylori may have
      a role in gastric stump carcinogenesis.

PMID- 10655988
TI  - ELISA is the superior method for detecting antineutrophil cytoplasmic antibodies
      in the diagnosis of systemic necrotising vasculitis.
AB  - BACKGROUND: Antineutrophil cytoplasmic antibodies (ANCA) have been used as a
      diagnostic marker for systemic necrotising vasculitis, a disease classification
      which includes Wegener granulomatosis, microscopic and classic polyarteritis
      nodosa, and Churg Strauss disease. OBJECTIVE: To compare the diagnostic value of
      the two methods for detecting these antibodies--immunofluorescence and enzyme
      linked immunosorbent assay (ELISA)--with respect to biopsy proven active systemic
      necrotising vasculitis in a clinically relevant population. METHODS: A
      prospective study to ascertain the patient's diagnosis at the time of each of the
      466 requests for ANCA received at one laboratory over a nine month period, and
      allocate each to one of five diagnostic groups: active and inactive biopsy proven
      systemic necrotising vasculitis, suspected systemic necrotising vasculitis, low
      probability systemic necrotising vasculitis, and not systemic necrotising
      vasculitis. RESULTS: ELISA was superior to immunofluorescence in the diagnosis of
      systemic necrotising vasculitis because it was less likely to detect other
      diseases. This was reflected in its specificity of 97% and positive predictive
      value of 73%, compared with 90% and only 50% for immunofluorescence (p = 0.0006
      and p = 0.013, respectively). ELISA had a negative predictive value of 98% which
      was not significantly different to immunofluorescence. ELISA was technically
      superior. CONCLUSIONS: ELISA is the superior method of ANCA detection in the
      diagnosis of systemic necrotising vasculitis and should be used in conjunction
      with a compatible clinical picture and histological evidence.

PMID- 10655989
TI  - A prospective audit of pacemaker function, implant lifetime, and cause of death
      in the patient.
AB  - AIM: To audit prospectively the reasons for pacemaker implantation, the duration
      of the pacemaker use, the cause of death, and pacemaker function after removal
      from the patient. METHODS: Pacemakers were removed at necropsy, or from the
      bodies of patients awaiting cremation, in three hospitals over a three year
      period. The cause of death was taken from the results of the necropsy or from the
      certified cause of death. Demographic data, including the time of implant and
      reasons for implantation, were checked. The pacemakers were analysed in terms of
      battery status, program, and output under a standard 470 ohm load. RESULTS: 69
      patients were studied. Average age at death was 78 and 80 years for men and
      women, respectively. The average duration since pacemaker implantation was 46
      months. Eleven patients had necropsies, showing that three died from ischaemic
      heart disease, six from cardiomyopathy, one from an aortic aneurysm, and one from
      disseminated neoplasia. From the necropsy results and death certificates, the
      distribution of causes of death in the group as a whole were ischaemic heart
      disease (21), cardiomyopathy (8), cerebrovascular disease (11), neoplasia (11),
      chest infection/chronic obstructive airways disease (8), and other causes (10).
      In all cases the pacemaker box function was within normal limits. CONCLUSIONS:
      Neither primary nor secondary pacemaker dysfunction was found. The study
      highlights the impact of arrhythmias in cardiomyopathy, and raises questions
      about the true role of ischaemic heart disease in these pacemaker requiring
      patients. The relatively short gap between pacemaker implantation and death
      requires further study.

PMID- 10655990
TI  - The reliability of sampling three to six nodes for staging breast cancer.
AB  - AIMS: To test the hypothesis that a correct qualitative assessment of axillary
      nodal status can be established by examining only a limited number of lymph
      nodes. METHODS: Slides from 499 pN1 or pN0 axillary dissection specimens relating
      to symptomatic breast cancer cases operated on at our institution between 1991
      and 1996 were reviewed. Nodes were ranked in descending order on the basis of
      their estimated size and lymphoid or metastatic tissue content. After ranking,
      all nodes were studied microscopically; 265 axillary clearance specimens were
      positive. RESULTS: Assessment of the 3-6 largest/firmest nodes can lead to the
      detection of 93-98% of node positive patients and can give a correct qualitative
      assessment of axillary node status in 96-99%. CONCLUSIONS: Sampling the 4-6
      largest/firmest nodes seems to be a reliable alternative for the staging of
      symptomatic breast cancer. These results suggest a reconsideration of the
      generally held view that a minimum of 10 nodes is required for adequate
      identification of the pN0 category.

PMID- 10655991
TI  - Routine immunofluorescence detection of Ro/SS-A autoantibody using HEp-2 cells
      transfected with human 60 kDa Ro/SS-A.
AB  - BACKGROUND: Ro/SS-A autoantibodies associated with systemic lupus erythematosus
      (SLE) and Sjogren syndrome may be missed during routine screening for antinuclear
      autoantibodies (ANA) by immunofluorescence using HEp-2 cells. AIMS: To
      investigate the use of HEp-2 cells transfected with human 60 kDa Ro/SS-A for
      routine detection of these antibodies. METHODS: 10,500 sera were screened at a
      dilution of 1:200 for Ro/SS-A antibodies, identified by intense
      immunofluorescence staining in 10-15% of hyperexpressing cells of either the
      nucleus and nucleolus combined or the nucleus alone. RESULTS: Ro/SS-A antibodies
      were identified in 160/2100 ANA positive sera (8%), of which seven were ANA
      negative (titre < 200) and 33 had weak ANA titres (200) in 85-90% of non
      hyperexpressing "background" cells. Enzyme linked immunosorbent assay (ELISA)
      confirmed the presence of Ro/SS-A antibodies in 110 newly diagnosed Ro/SS-A
      positive sera. Of these, 50 reacted with Ro/SS-A, 51 with Ro/SS-A and La/SS-B,
      and nine with Ro/SS-A and other extractable nuclear antigen (ENA) specificities.
      Fifteen sera which did not show Ro/SS-A antibodies by immunofluorescence tested
      positive for Ro/SS-A by immunodiffusion, counter-immunoelectrophesis, or ELISA;
      of these, 14 had ANA titres > 200. Clinical data from 95 Ro/SS-A positive
      patients showed that 52% had SLE, 24% Sjogren syndrome, 8% rheumatoid arthritis,
      and 16% other diseases. CONCLUSIONS: (1) HEp-2 cells transfected with human 60
      kDa Ro/SSA are useful for routine immunofluorescence detection for Ro/SS-A
      antibodies with a positive predictive value of 100%; (2) sera positive for Ro/SS
      A antibodies by immunofluorescence should be tested for ENA by other methods
      because > 50% of these sera will have another ENA reactivity in addition to Ro/SS
      A; (3) detection of Ro/SS-A by immunofluorescence may be missed in the presence
      of high titre ANAs; (4) with a detection sensitivity of 91%, a negative
      immunofluorescence results for Ro/SS-A does not exclude the presence of this
      autoantibody.

PMID- 10655992
TI  - Immunophenotyping of acute lymphoblastic leukaemia in routinely processed bone
      marrow biopsy specimens.
AB  - AIMS: To assess the value of immunophenotyping of acute lymphoblastic leukaemia
      (ALL) in routinely processed bone marrow trephine biopsy specimens and to
      establish a minimum panel of antibodies to assess lymphoid lineage and enable
      differentiation from acute myeloid leukaemia. METHODS: 45 routinely processed
      bone marrow biopsy specimens (formalin fixed, paraffin embedded and mildly
      decalcified in EDTA) reported to contain leukaemic infiltrates on the basis of
      cytomorphological and enzyme-cytochemical analysis of bone marrow smears (22 c
      ALL, 11 T-ALL, 2 B-ALL, 10 u-ALL (unclassified)) were immunostained by the ABC
      method with a broad panel of 26 antibodies against various haemopoietic antigens.
      RESULTS: Staining with antibodies directed against myeloperoxidase and lysozyme
      showed that seven cases were either biphenotypic or mixed leukaemias (2), or of
      myelogenous origin (acute myeloid leukaemia (AML)-M1 (2); AML-M4 (2); AML-M5a
      (1)). Five of these seven cases had been diagnosed initially as u-ALL. Three
      further cases with no compact leukaemic infiltrates were excluded. ALL was
      confirmed in the remaining 35 cases. Because of revised diagnoses, the total
      numbers of ALL subtypes changed (23 c-ALL, 8 T-ALL, 2 B-ALL, 2 u-ALL).
      Immunostaining of more than 10% of blast cells in at least one case was found
      with 19 of the 26 antibodies. The most sensitive lineage specific antibodies for
      diagnosis were found to be anti-CD10 for c-ALL (22/23) and beta F1 for T-ALL
      (6/8). Expression of aberrant antigens was fairly common--for example, 7/23 cases
      of c-ALL stained with antibodies against T cell associated antigens. CONCLUSIONS:
      Immunohistochemical investigation of routinely processed bone marrow biopsy
      specimens enables reliable detection of ALL subtypes c-ALL and T-ALL. A minimum
      panel of antibodies, against TdT, CD34, myeloperoxidase, lysozyme, CD10, CD79a,
      and CD20, and the antibody beta F1, is proposed for the immunophenotyping of
      acute leukaemia.

PMID- 10655993
TI  - Modified Genta triple stain for identifying Helicobacter pylori.
AB  - AIM: To evaluate whether lead nitrate could replace uranyl nitrate in the Genta
      stain for H pylori without sacrificing the advantages of the triple stain
      (Steiner silver impregnation combined with Alcian blue and haematoxylin/eosin
      (H&E)). METHODS: A comparison was made in 16 specimens between the original
      triple stain and the revised version. One pathologist evaluated all sections.
      RESULTS: Direct substitution of lead nitrate for uranium nitrate produced well
      stained organisms without interfering with H&E or Alcian blue staining. No
      difference was found in the ability to identify bacteria in 11 cases with H
      pylori density of 1 or 2 (on a scale of 0 to 5). CONCLUSIONS: The potential
      chemical and radiological hazards associated with uranium nitrate can be
      eliminated by using lead nitrate without sacrificing the advantages obtained by
      using the triple stain.

PMID- 10655994
TI  - A novel case of a sporadic desmoid tumour with mutation of the beta catenin gene.
AB  - A 42 year old man without familial adenomatous polyposis had recurrent desmoid
      tumours in the left subclavicular site. Histological examination showed a typical
      desmoid tumour. Molecular analysis was performed in genomic DNA from this tumour,
      using polymerase chain reaction-single strand conformation polymorphism (PCR
      SSCP) and direct sequencing methods. No mutation could be detected in the entire
      coding sequence of the APC gene, nor in H-ras, K-ras, N-ras, or p53 genes. On
      seeking a mutation of the beta catenin gene (CTNNB1), an activating mutation from
      ACC (Thr) to GCC (Ala) at codon 41 was found. Immunohistochemical staining showed
      that accumulated beta catenin protein was predominantly localised in the nuclei
      of desmoid cells. This is the first example of a sporadic desmoid tumour in which
      a mutation of the beta catenin gene was revealed.

PMID- 10655995
TI  - An analysis of relative costs and potential benefits of different policies for
      antenatal screening for beta thalassaemia trait and variant haemoglobins.
AB  - AIMS: To investigate the costs and potential benefits of different policies for
      antenatal screening for haemoglobinopathies in two multiethnic London
      communities. METHODS: 1000 consecutive antenatal patient samples referred to each
      of two London teaching hospital laboratories for haemoglobinopathy testing were
      investigated using the standard procedures of the laboratory in question. When
      the standard procedures did not include high performance liquid chromatography
      (HPLC), this technique was added, in order to assess its diagnostic value and
      cost-effectiveness. A comparison was made between the costs and potential
      benefits of universal testing for variant haemoglobins and beta thalassaemia
      trait using HPLC and the costs and potential benefits of universal testing for
      variant haemoglobins and selective testing for beta thalassaemia trait using the
      mean cell haemoglobin (MCH) as a screening test and less automated techniques
      than HPLC for definitive diagnosis. RESULTS: The costs of the two policies were
      found to be comparable, as the higher reagent/instrument costs of HPLC were
      offset by the lower labour costs. Universal testing of 2000 consecutive samples
      did not disclose any extra cases of beta thalassaemia trait which would not have
      been detected by universal screening and selective testing. However, six patients
      were found to have a haemoglobin A2 variant which can interfere with the
      diagnosis of beta thalassaemia trait. CONCLUSIONS: The introduction of universal
      testing by HPLC into British laboratories could be cost neutral and has potential
      benefits. If a higher cost is accepted then the greater degree of automation
      could be used to release skilled staff for other tasks within the laboratory.

PMID- 10655996
TI  - Expression of the 17-1A antigen in gastric and gastro-oesophageal junction
      adenocarcinomas: a potential immunotherapeutic target?
AB  - BACKGROUND: A murine monoclonal antibody against the 17-1A epithelial antigen has
      been shown to be a useful adjuvant therapy in colorectal cancer. Its clinical use
      could be extended to patients with upper gastrointestinal adenocarcinoma. AIM: To
      determine the distribution of the antigen in gastric and oesophageal
      adenocarcinoma. METHODS: The activity of two monoclonal antibodies active against
      17-1A epithelial antigen was studied in gastric and gastro-oesophageal junction
      adenocarcinomas: fresh frozen tissue from both the carcinoma and adjacent mucosa
      was stained using immunocytochemistry with a murine monoclonal antibody (17-1A
      edrecolomab, Glaxo Wellcome); paraffin embedded tissue was stained using the
      humanised monoclonal antibody 3622W94 (Glaxo Wellcome). RESULTS: 29 of 33 cancers
      (88%) stained with the murine antibody and 39 of 40 (98%) with the humanised
      antibody. The degree of staining was greater in well differentiated and
      moderately differentiated tumours. There was no staining of the normal background
      gastric or oesophageal mucosa, but areas of intestinal metaplasia stained
      intensely. The humanised monoclonal 3622W94 antibody produced more intense
      staining than the murine antibody. CONCLUSIONS: The high incidence of expression
      of the 17-1A antigen in patients with gastric and gastro-oesophageal junction
      adenocarcinomas suggests a potential role for these antibodies as an adjuvant
      treatment for these common cancers.

PMID- 10655997
TI  - Granulocytic sarcoma preceding AML M0 and the diagnostic value of CD34.
AB  - Granulocytic sarcoma with no demonstrable abnormalities in the peripheral blood
      or bone marrow is a rare but recognised initial manifestation of acute myeloid
      leukaemia and has led to diagnostic difficulties in some cases. A lymph node
      excisional biopsy from a patient presenting with cervical lymphadenopathy, a
      mediastinal mass, and a normal peripheral blood picture was reported to have
      features suggesting a T cell non-Hodgkin lymphoma, for which she was subsequently
      treated. However, 10 months later the patient developed acute myeloid leukaemia,
      FAB classification M0. The initial lymph node biopsy was reviewed and further
      immunohistochemical studies using antibodies against CD34 led to a revised
      diagnosis of primary granulocytic sarcoma.

PMID- 10655998
TI  - Misconceptions of the pathology of intracranial arterial aneurysms.

PMID- 10655999
TI  - Tissue banks in NHS histopathology laboratories and the Consensus Statement.

PMID- 10656000
TI  - Increasing rates of ciprofloxacin resistant campylobacter.

PMID- 10656001
TI  - More than merely academic: the new Academy of Medical Sciences.

PMID- 10656002
TI  - Forensic medical evidence in rape and child sexual abuse: controversies and a
      possible solution.

PMID- 10656004
TI  - Jet-lag and shift work: (1). Circadian rhythms.

PMID- 10656003
TI  - Cocaine: history, use, abuse.

PMID- 10656006
TI  - Unilateral pulsatile tinnitus relieved by contralateral carotid endarterectomy.

PMID- 10656005
TI  - Jet-lag and shift work: (2). Therapeutic use of melatonin.

PMID- 10656007
TI  - Communicating hydrocephalus after hypernatraemic dehydration.

PMID- 10656008
TI  - Fibrolipoma of the median nerve.

PMID- 10656009
TI  - Malignant eccrine poroma of the hand.

PMID- 10656010
TI  - Posterior interosseous nerve palsy after intravenous cannulation of forearm.

PMID- 10656011
TI  - Life-threatening puerperal infection with group A streptococcus.

PMID- 10656012
TI  - Ectopic pregnancies in two consecutive menstrual cycles.

PMID- 10656013
TI  - Selective embolization of bleeding renal angiomyolipoma in pregnancy.

PMID- 10656014
TI  - The modern doctor's dilemma: rationing and ethics in healthcare.

PMID- 10656015
TI  - Obligations of general practitioners to substance misusers.

PMID- 10656016
TI  - A Harley Street address.

PMID- 10656017
TI  - 'A fake of the most dangerous kind': the case of Brunson versus Fishbein.

PMID- 10656018
TI  - Bereavement in children.

PMID- 10656019
TI  - Bereavement in children.

PMID- 10656020
TI  - Bereavement in children.

PMID- 10656021
TI  - Senile squalor syndrome.

PMID- 10656022
TI  - Attention deficit hyperactivity disorder (ADHD).

PMID- 10656023
TI  - GDC's guidance on anaesthesia.

PMID- 10656024
TI  - Manuka honey against Helicobacter pylori.

PMID- 10656025
TI  - Traumatic facial palsy.

PMID- 10656026
TI  - Aortoenteric fistula.

PMID- 10656027
TI  - Aortoenteric fistula.

PMID- 10656028
TI  - Employer-sponsored health insurance and mandated benefit laws.
AB  - Regulations for the content of private health plans, called mandated benefit
      laws, are widespread and growing in the United States, at both state and federal
      levels. Three aspects of these laws are examined: their current scope; some
      economic reasons for their existence; and the theory and empirical evidence for
      their effects in health insurance markets. A growing body of literature suggests
      that society is paying a high price for enhanced coverage via mandated benefits.
      These laws increase insurance premiums, cause declines in wages and other fringe
      benefits, and lead some employers and their workers to forgo health benefits
      altogether. The cost of mandated benefit laws falls disproportionately on workers
      in small firms.

PMID- 10656029
TI  - Applying disease management strategies to Medicare.
AB  - Medicare coverage begins for many when they have already developed one or more
      chronic diseases, and it often pays for the latest and costliest phases.
      Population-based disease modeling, patient screening, and monitoring would be
      appropriate interventions for chronic renal disease. Patients who have not yet
      advanced to end-stage renal disease would benefit from management of diabetes and
      hypertension, avoidance of nephrotoxic substances, and better preparation for
      dialysis. Administrative support could take the form of clinical guidelines,
      physician-led multidisciplinary teams, integrated delivery systems, provider and
      patient education, and new information technologies. Medicare reflects the long
      term public perspective, and thus should further this new direction by supporting
      education, reimbursing for prevention efforts and allied health services,
      encouraging efficiency, and monitoring cost and quality outcomes.

PMID- 10656031
TI  - Infected physicians and invasive procedures: national policy and legal reality.
AB  - Recent reports of the transmission of hepatitis B, hepatitis C, and HIV from
      physicians to patients during invasive procedures have again raised the question
      of whether physicians infected with bloodborne pathogens should perform invasive
      procedures that place patients at risk, and if so, under what conditions.
      Attempts to formulate a national policy on this subject must consider the
      competing interests of the patient's welfare versus the physician's livelihood. A
      review of the legal aspects of this topic is provided to assist policy makers and
      to serve as a foundation for the recommended establishment of a multidisciplinary
      committee to develop a uniform national policy. Both legal and medical realities
      call for the formulation of a clear policy to guide those who must make the
      decisions on this issue.

PMID- 10656030
TI  - The changing landscape of health care financing and delivery: how are rural
      communities and providers responding?
AB  - Rural communities have not kept pace with the recent dramatic changes in health
      care financing and organization. However, the Medicare provisions in the Balanced
      Budget Act of 1997 will require rural providers to participate in the new
      systems. Case studies revealed the degree of readiness for change in six rural
      communities and charted their progress along a continuum, as reflected in three
      sets of activities: the development of networking; the creation of new strategies
      for managing patient care; and the adoption of new methods for contracting with
      health insurers. Some communities had constructed highly integrated systems,
      whereas others were just beginning to change their billing practices; a few were
      signing contracts for capitated care, in contrast to those that were resisting
      discounts in current fee structures. These six rural areas still have
      considerable ground to cover before their health care organization and financing
      reach the levels achieved by urban communities.

PMID- 10656032
TI  - Maternal substance abuse and infant health: policy options across the life
      course.
AB  - Maternal substance abuse is a significant contributor to infant morbidity and
      mortality. The setting of prenatal care has long been the focus of interventions
      and policies to prevent these adverse outcomes. However, substance abuse programs
      and policies that are designed for women who are not yet pregnant can have a
      significant impact upon this problem. Thus it is essential to view the female
      life course from a broader perspective in order to consider the full range of
      policy options for reducing the infant mortality and morbidity caused by maternal
      substance abuse. This framework also allows comparisons across and between
      substances and offers new directions for policy development.

PMID- 10656033
TI  - A political history of the Indian Health Service.
AB  - One of the few bright spots to emerge from the history of relations between
      American Indians and the federal government is the remarkable record of the
      Indian Health Service (IHS). The IHS has raised the health status of Indians to
      approximate that of most other Americans, a striking achievement in the light of
      the poverty and stark living conditions experienced by this population. The gains
      occurred in spite of chronically low funding and can be attributed to the
      combination of vision, stubbornness, and political savvy of the agency's
      physician directors and the support of a handful of tribal leaders and powerful
      allies in the Congress and the White House. Despite the agency's imperfections
      and the sizeable health problems that still exist among American Indians and
      Alaskan Natives, the IHS is an example of one federal program that has worked.

PMID- 10656034
TI  - The chemotherapy of rodent malaria. LVI. Studies on the development of resistance
      to natural and synthetic endoperoxides.
AB  - Chloroquine-sensitive Plasmodium berghei N and chloroquine-resistant P. yoelii
      ssp. NS were exposed to selection pressure, in the '2% relapse technique', from
      artemisinin, artesunate, a bicyclic, synthetic endoperoxide Ro 41-3823 (an
      analogue of arteflene) or Fenozan B07, a synthetic 1,2,4-trioxane endoperoxide.
      Whereas resistance against artemisinin did develop to a moderate level in both
      parasites, only a low level of resistance or none developed to the other
      compounds, and resistant parasites readily lost resistance once drug-selection
      pressure was withdrawn. The relevance of these observations and the experience of
      other investigators are discussed in relation to the possible risk that
      resistance may be developed in nature once endoperoxides are deployed widely
      against multidrug-resistant P. falciparum.

PMID- 10656035
TI  - Ganglioside treatment of acute Trypanosoma cruzi infection in mice promotes long
      term survival and parasitological cure.
AB  - Ganglioside treatment of mice during their acute infection with Trypanosoma cruzi
      promoted long-term survival and clearance of parasites from the bloodstream and
      organs. Additionally, such treatment completely prevented the clinical
      manifestations of the infection, and progression into the chronic stages of the
      disease, for at least 18 months post-infection. Trypanosoma cruzi must invade
      nucleated cells to survive and reproduce within the mammalian host, and it has
      been suggested that ganglioside treatment inhibits the parasite's phospholipase
      A2 enzymes (PLA2), which are involved in membrane destabilization. However, since
      total brain gangliosides were not toxic to the parasite, either in xenic or
      axenic cultures, it seems unlikely that their action in vivo relates to their
      inhibition of PLA2. Other possible mechanisms of action are discussed.

PMID- 10656036
TI  - Lectins and toxins in the plant diet of Phlebotomus papatasi (Diptera:
      Psychodidae) can kill Leishmania major promastigotes in the sandfly and in
      culture.
AB  - Leishmania major promastigotes are agglutinated and die in their vector,
      Phlebotomus papatasi, after the sandflies feed on some plants that are found in
      their natural habitat. In in-vitro assays, extracts of Ricinus communis
      (Euphorbiaceae), Capparis spinosa (Capparaceae), Prosopis farcta (Mimosaceae) and
      Tamarix nilotica (Tamaricaceae) agglutinated and killed the parasites. This
      activity could be inhibited by specific carbohydrates, indicating that it was the
      result of various lectins in the extracts. An extract of Solanum luteum
      (Solanaceae) lysed the promastigotes under similar conditions and this
      cytotoxicity was not abated by the sugars tested. High mortality of promastigotes
      occurred in infected flies after they ingested an extract of R. communis, even
      when the extract fed to the flies had been pre-mixed with glucose, a carbohydrate
      that inhibited the agglutination caused by such an extract in vitro. The results
      indicate that the lectins and toxins found in the vegetation in L. major foci may
      decrease the transmission of the parasite.

PMID- 10656037
TI  - Effect of mebendazole on human cystic echinococcosis: the role of dosage and
      treatment duration.
AB  - Fifty-three patients with single, multiple and/or multi-organ hydatid cysts were
      treated with mebendazole, in varying dosages (30-70 mg/kg.day) and over varying
      periods (6-24 months). Treatment failure was recorded if the mebendazole had no
      apparent effect on cyst morphology (monitored by radiology, ultrasonography and
      computed tomography) or only a parasitostatic effect (characterized by mixed and
      transitory, hypo- and hyper-echoic changes in the lesions). Cure was indicated by
      a parasitocidal effect (characterized by a totally echogenic picture, increased
      density of the cyst contents, reduction in the size or complete disappearance of
      the cysts, complete detachment of the endocysts and/or calcification of the cyst
      wall). Treatment failure was seen in about 40% of the patients and cure in about
      38%; the other 23% had an intermediate result considered as an improvement. Cure
      rates increased both with dosage and duration, daily dosages of 60-70, 50 and 30
      40 mg/kg curing 48%, 33% and 25%, respectively. The pre-treatment condition of
      any cysts should be taken into consideration when determining dosage and
      treatment duration.

PMID- 10656038
TI  - A double-blind, placebo-controlled study of the efficacy of oral penicillin,
      diethylcarbamazine or local treatment of the affected limb in preventing acute
      adenolymphangitis in lymphoedema caused by brugian filariasis.
AB  - Acute attacks of adenolymphangitis (ADL) contribute significantly to the
      morbidity seen in cases of filarial lymphoedema. Such cases are now being treated
      with multiple courses of the antifilarial drug diethylcarbamazine (DEC), either
      alone or in combination with antibiotics or anti-inflammatory drugs, based on
      anecdotal experience. In this, the first double-blind, placebo-controlled study,
      150 patients with lymphoedema caused by brugian filariasis, each of whom recalled
      two or more ADL attacks in the previous year, were enrolled on a comprehensive
      foot-care programme. Each was also randomly allocated to one of the following
      five daily regimens (30 patients/regimen) for 1 year: 800 mg oral penicillin; 1
      mg DEC/kg; 800 mg oral penicillin plus 1 mg DEC/kg; local antibiotics; or
      placebo. Each patient was followed up for another year. For each regimen group
      (including the placebo group), the number of ADL attacks in the treatment year
      was significantly less than that in the year prior to treatment (P < 0.001).
      Although, in all but the placebo group, there was a slight increase in the number
      of episodes in the follow-up year compared with the treatment year, the increase
      was only significant in the two groups given penicillin. Of all the treatments
      tested therefore, foot care seems to play the most important role in the
      prevention of ADL attacks. Additional benefit may accrue from local or systemic
      antibiotic use in those with high grades of oedema, but antifilarials have no
      place in the prevention of ADL attacks in an individual patient. These
      observations should help in the rational management and prevention of ADL attacks
      in filarial lymphoedema, so that the progression of the disease may be halted and
      morbidity reduced.

PMID- 10656040
TI  - The genital atrium as a good taxonomic character to distinguish between species
      of phlebotomine sandflies (Diptera: Psychodidae) from Venezuela.
AB  - The shape and size of the genital atria of 17 phlebotomine sandflies from
      Venezuela were examined. The atria were found to express constant characters
      among individuals of the same species and to be sufficiently different between
      species to allow taxonomic separation. The spines on the genital armature are
      described and the characters that can be used to classify individual specimens to
      species level identified. It is suggested that these characters can be of use on
      specimens where the spermathecae have been lost or where cryptic species are
      concerned. Dissection procedures to display the atrium are given.

PMID- 10656039
TI  - Bancroftian filariasis in the Varanasi region of north India: an epidemiological
      study.
AB  - The age- and sex-specific distributions of human infections with Wuchereria
      bancrofti were investigated at two sites in the Varanasi region of north India:
      one a rural, agricultural area (Chiraigaon) and the other an urban-slum area
      (Sunderpur). A random clinical and parasitological survey revealed that the
      prevalence of microfilaraemia and elephantiasis in the urban area (14% and 7.3%,
      respectively) were both higher than in the rural area (9% and 3.1%,
      respectively). In both areas, prevalence of microfilaraemia generally increased
      with age, to a maximum in those aged 20-29 years, and then declined. Within most
      age-groups, the prevalences of microfilaraemia and elephantiasis were higher in
      males than females. However, the prevalence of microfilaraemia in females from
      Chiraigaon who were aged > 30 years was higher than in their male counterparts.
      Though individual microfilarial intensities varied greatly, the geometric mean
      microfilarial intensity was higher in Sunderpur than in Chiraigaon (214 v. 196
      microfilariae/ml). All 83 subjects with elephantiasis, except one in Sunderpur,
      were amicrofilaraemic. The present results indicate that bancroftian filariasis
      is one of the major public-health problems in the study area.

PMID- 10656041
TI  - Prognostic factors for amputation in the case of envenoming by snakes of the
      Bothrops genus (Viperidae).
AB  - The prognostic factors for amputation following envenoming by snakes of the
      Bothrops genus were identified from the medical records of 3139 patients. Each of
      these patients had been bitten by Bothrops sp. and treated in the Hospital Vital
      Brazil, in Sao Paulo, Brazil, between 1981 and 1990. The 21 (0.67%) of the
      patients who had undergone amputation were compared with the 3118 who had not,
      with respect to the characteristics of the accident, the snake, the victim, the
      local and systemic manifestations of the envenoming and the treatment. There was
      an association between amputation and the month of the accident, the time of day
      when the accident happened, the length of the attacking snake, the anatomical
      region bitten, systemic bleeding and renal failure. Patients bitten in the
      fingers, during the cooler months, between 00.00 and 12.00 hours and/or by snakes
      > 60 cm in length, who developed blisters and abscesses at the site of the bite,
      systemic bleeding and/or renal failure underwent amputation more frequently than
      the others (P < 0.05 for each).

PMID- 10656042
TI  - Multi-system failure in Plasmodium vivax malaria: report of a case.

PMID- 10656043
TI  - Ptyalism as a side effect in the treatment of falciparum malaria with
      artemisinin.

PMID- 10656044
TI  - Plasmodium berghei in the white rat: severe malaria of pregnancy does not occur
      in the progeny of mothers infected during gestation.

PMID- 10656045
TI  - Inhibition of the development of the hepatic stages of Plasmodium yoelii
      nigeriensis by antihistaminic agents.

PMID- 10656046
TI  - 'Getting really desirable things done': how the citizens of Liverpool came to be
      major players in the fight against tropical diseases.

PMID- 10656047
TI  - Effects of the glycocalyx on the electrophoretic mobility of red cells and on
      streaming potentials in blood vessels: predictions of a structurally-based model.
AB  - The polyelectrolyte layer coating mammalian cells, known as the glycocalyx, may
      be important in communicating flow information to the cell. In this paper, the
      layer is modelled as a semi-infinite, doubly periodic array of parallel charged
      cylinders. The electric potential and ion distributions surrounding such an array
      are found using the linearized Poisson-Boltzmann equation and an iterative domain
      decomposition technique. Similar methods are used to calculate Strokes flows,
      driven either by a shear at infinity or by an electric field, parallel or
      transverse to the cylinders. The resulting electric streaming currents due to
      flow over endothelial cells, and the electrophoretic mobilities of red blood
      cells are deduced as functions of polymer concentration and electrolyte molarity.
      It is shown that only the top portion of the layer is important in these effects.

PMID- 10656048
TI  - The osmotic pressure of chondroitin sulphate solutions: experimental measurements
      and theoretical analysis.
AB  - We used equilibrium dialysis to measure the osmotic pressure of chondroitin
      sulphate (CS) solutions as a function of their concentration and fixed charge
      density (FCD) and the ionic strength and composition of the solution. Osmotic
      pressure varied nonlinearly with the concentration of chondroitin sulphate and in
      0.15 M NaCl at FCDs typical of uncompressed cartilage (approximately 0.4 mmol/g
      extrafibrillar H2O) was approximately 3 atmospheres. Osmotic pressure fell by 60%
      as solution ionic strength increased up to about 1 M, but remained relatively
      constant at higher ionic strengths. The ratio of Ca2+ to Na+ in the medium was a
      minor determinant of osmotic pressure. The data are compared with a theoretical
      model of the electrostatic contribution to osmotic pressure calculated from the
      Poisson-Boltzmann equation using a rod-in-cell model for CS. The effective radius
      of the polyelectrolyte rod is taken as a free parameter. The model qualitatively
      reproduces the non-linear concentration dependence, but underestimates the
      osmotic pressure by an amount that is independent of ionic strength. This
      difference, presumably arising from oncotic and entropic effects, is
      approximately 1/3 of the total osmotic pressure at physiological polymer
      concentrations and ionic strength.

PMID- 10656049
TI  - Thermomechanical analysis of collagen crosslinking in the developing ovine
      thoracic aorta.
AB  - We have used hydrothermal isometric tension (HIT) techniques in a sheep model to
      assess collagen crosslink stability and its contribution to the mechanical
      properties of the ovine thoracic aorta during perinatal and postnatal
      development. Aortic tissue was studied from fetal sheep, lambs, and adult sheep.
      Strips of tissue were loaded under isometric tension and heated to a 90 degrees C
      isotherm which was sustained for 3 hours. The decrease in load at this
      temperature is associated with collagen peptide bond hydrolysis and chain
      slippage, and the rate of this decrease is an inverse indicator of collagen
      crosslinking. The half-time of load decay (t1/2) was computed before and after
      tissue was treated with NaBH4 which stabilizes immature, reducible crosslinks. We
      observed a two-fold increase in t1/2 of untreated tissue from the lamb to the
      adult, indicating that aortic collagen crosslinking increased during postnatal
      development. Furthermore, the t1/2 of NaBH4-stabilized lamb tissue was similar to
      that of the untreated adult tissue, suggesting that much of the immature
      crosslinking in the lamb is stabilized during postnatal development. These
      observations suggest (a) increased crosslinking occurs during postnatal
      development and (b) that this increase is largely due to a conversion of immature
      crosslinks into their mature heat stable form.

PMID- 10656050
TI  - Computational study of the effect of geometric and flow parameters on the steady
      flow field at the rabbit aorto-celiac bifurcation.
AB  - Arterial hemodynamic forces may play a role in the localization of early
      atherosclerotic lesions. We have been developing numerical techniques based on
      overset or "Chimera" type formulations to solve the Navier-Stokes equations in
      complex geometries simulating arterial bifurcations. This paper presents three
      dimensional steady flow computations in a model of the rabbit aorto-celiac
      bifurcation. The computational methods were validated by comparing the numerical
      results to previously-obtained flow visualization data. Once validated, the
      numerical algorithms were used to investigate the sensitivity of the computed
      flow field and resulting wall shear stress distribution to various geometric and
      hemodynamic parameters. The results demonstrated that a decrease in the extent of
      aortic taper downstream of the celiac artery induced looping fluid motion along
      the lateral walls of the aorta and shifted the peak wall shear stress from
      downstream of the celiac artery to upstream. Increasing the flow Reynolds number
      led to a sharp increase in spatial gradients of wall shear stress. The flow field
      was highly sensitive to the flow division ratio, i.e., the fraction of total flow
      rate that enters the celiac artery, with larger values of this ratio leading to
      the occurrence of flow separation along the dorsal wall of the aorta. Finally,
      skewness of the inlet velocity profile had a profound impact on the wall shear
      stress distribution near the celiac artery. While not physiological due to the
      assumption of steady flow, these results provide valuable insight into the fluid
      physics at geometries simulating arterial bifurcations.

PMID- 10656051
TI  - A mechanism for erythrocyte-mediated elevation of apparent viscosity by
      leukocytes in vivo without adhesion to the endothelium.
AB  - In spite of the relatively small number of leukocytes in the circulation, they
      have a significant influence on the perfusion of such organs as skeletal muscle
      or kidney. However, the underlying mechanisms are incompletely understood. In the
      current study a combined in vivo and computational approach is presented in which
      the interaction of individual freely flowing leukocytes with erythrocytes and its
      effect on apparent blood viscosity are explored. The skeletal muscle
      microcirculation was perfused with different cell suspensions with and without
      leukocytes or erythrocytes. We examined a three-dimensional numerical model of
      low Reynolds number flow in a capillary with a train of erythrocytes (small
      spheres) in off-axis positions and single larger leukocytes in axisymmetric
      positions. The results indicate that in order to match the slower axial velocity
      of leukocytes in capillaries, erythrocytes need to position themselves into an
      off-axis position in the capillary. In such off-axis positions at constant mean
      capillary velocity, erythrocyte axial velocity matches on average the axial
      velocity of the leukocytes, but the apparent viscosity is elevated, in agreement
      with the whole organ perfusion observations. Thus, leukocytes influence the whole
      organ resistance in skeletal muscle to a significant degree only in the presence
      of erythrocytes.

PMID- 10656052
TI  - Evaluation and application of a simple and rapid method for the analysis of
      aflatoxins in commercial foods from Malaysia and the Philippines.
AB  - For application to the analysis of aflatoxins (AF) in commercial peanut and corn
      products, the ISOLUTE multimode column (IMC, solid phase multifunctional column)
      method was validated by comparing with the modified Florisil column (MFC) method.
      Twenty-two peanut and eight corn products from Malaysia and the Philippines were
      analysed for AFB1, AFB2, AFG1 and AFG2 firstly by the MFC method and then by the
      IMC method. For peanut products, 14 out of 22 samples were positive by the two
      methods in the range of 1-378 micrograms/kg of AF, and correlation coefficients
      (r) for AFB1 and AFB2 were 0.987 and 0.997, respectively. For corn and corn
      products, all the samples were positive in the range of 1-130 micrograms/kg, and
      r values were 0.992 and 0.805 for AFB1 and AFB2 respectively. Thus, the results
      were significantly (p < 0.01) in close agreement, particularly for lower range of
      1-50 micrograms/kg of AF concentrations in all the samples. For the occurrence of
      AF, 11 (65%) of peanut products from Malaysia were contaminated with AF at a mean
      level of 50 micrograms/kg (maximum 180 micrograms/kg) and two (40% products from
      the Philippines were contaminated with as high as 375 micrograms/kg and 177
      micrograms/kg of AF, respectively. All the corn products from the Philippines
      were contaminated with AF at a mean level of 44 micrograms/kg (maximum 130
      micrograms/kg). Contamination of commercial foods with high levels of AF is a
      very important issue to both the countries since these foods are very popular
      among children.

PMID- 10656053
TI  - Surveillance of stored grain from the 1997 harvest in the United Kingdom for
      ochratoxin A.
AB  - This survey examined 306 samples of farm-stored wheat, barley and oats as
      received at, or tested by, central grain depots in the UK. Samples were taken
      from lorries or from stored grain using the existing in-house procedures used for
      quality checking and examined for ochratoxin A using a fully validated analytical
      HPLC method with a detection limit of 0.1 microgram/kg. Ochratoxin A was detected
      in 21% of the samples examined, with barley more frequently contaminated than
      wheat. Mean concentrations of ochratoxin A found for all samples were 0.69
      microgram/kg in barley, 0.29 microgram/kg in wheat and 0.15 microgram/kg in oats.
      The highest concentration found was 17.8 micrograms/kg in a barley feed although
      concentrations of 81 and 30 micrograms/kg were found in 'reject-grade' wheat
      samples whose results were excluded from the main survey. In summary, 2.7 and
      0.3% of samples exceeded concentrations of 5 and 10 micrograms/kg respectively.
      There appeared to be significant relationships between ochratoxin A
      concentrations and moisture content, storage time and geographical area. Although
      conditions at harvest in 1997 were quite variable countrywide and often wet,
      results were similar to those found in earlier surveys carried out in the UK.

PMID- 10656054
TI  - Nitrate and nitrite in vegetables on the Danish market: content and intake.
AB  - The contents of nitrate and nitrite in lettuce, leek, potato, beetroot, Chinese
      cabbage and white cabbage on the Danish market were determined for 3 years in the
      period 1993-1997 as part of the Danish food monitoring programme. These
      vegetables are supposed to provide the major contribution to the intake of
      nitrate from the diet. Results for nitrate and nitrite in fresh and frozen
      spinach are also shown. The highest content of nitrate was found in lettuce
      followed by beetroot, Chinese cabbage, fresh spinach, leek, frozen spinach, white
      cabbage and potatoes. For all the products a great variation in the content of
      nitrate was found. For lettuce a characteristic variation throughout the year is
      clearly seen with the highest content in the winter period the lowest content in
      the summer period. Generally, the content of nitrite was low but in spinach high
      contents were found, probably due to improper storage conditions during
      transportation. The intake of nitrate and nitrite from these vegetables is
      calculated on the basis of two different consumption surveys. For both surveys
      the average intake of nitrate from the vegetables included in the monitoring
      programme is estimated to be approximately 40 mg day-1, whereas for nitrite the
      average intake is approximately 0.09 mg day-1. The total intake of nitrate and
      nitrite is estimated to be respectively 61 mg day-1 and 0.5 mg day-1.

PMID- 10656055
TI  - Monitoring for nitrate in UK-grown lettuce and spinach.
AB  - To comply with European Commission requirements, the UK is carrying out a
      monitoring programme on nitrate concentrations in lettuce and spinach. This paper
      reports the results obtained between June 1996 and April 1998. A total of 182
      samples of protected lettuce, 131 samples of outdoor-grown lettuce and 34 samples
      of fresh spinach were taken from the main growing areas of the UK. Nitrate
      concentrations in protected lettuce were influenced by the season with summer
      grown crops (mean of 2382 mg/kg) having lower levels than those grown in the
      winter (mean of 3124 mg/kg). Weather conditions also affected concentrations in
      protected lettuces with long hours of sunshine and low rainfall associated with
      low nitrate levels. Nitrate concentrations in outdoor-grown lettuces were lower
      (mean of 1085 mg/kg) than those in protected lettuces but there were insufficient
      data to determine if they were affected by the weather conditions or season.
      Similarly there were insufficient data to determine if weather conditions or
      season influenced nitrate concentrations in spinach (mean of 1900 mg/kg) but
      regional differences were observed.

PMID- 10656056
TI  - Relationship of dietary intake to DDE residues in breast milk of nursing mothers
      in Beirut.
AB  - Milk samples were collected from 32 nursing mothers living in the Beirut area,
      Lebanon. Dietary intakes of participating mothers were obtained from data of
      their diet histories, 24 h dietary recalls and food frequency questionnaires.
      Milk samples were screened for the presence of organochlorine pesticide residues
      and DDE levels were estimated using gas chromatographic techniques. The
      relationship between consumption of various food groups and DDE content of milk
      was investigated. A positive correlation was found between the consumption of
      either/or high fat meat, tuna fish and DDE levels in milk. Consumption of poultry
      products showed a weak correlation with DDE content of milk, whereas consumption
      of vegetable oils showed a negative correlation.

PMID- 10656057
TI  - Gastrointestinal tolerance of gamma-cyclodextrin in humans.
AB  - The gastrointestinal tolerance of gamma-cyclodextrin (gamma-CD) was examined in
      24 healthy human volunteers. In a double-blind, placebo-controlled, randomized
      cross-over study, single acute doses of 8 g maltodextrin (placebo) or 8 g gamma
      CD (test) were consumed as a mid-morning snack after addition to 100 g yogurt.
      Gastrointestinal symptoms as well as frequency and consistency of stools were
      recorded before and after lunch at between 3-4 and 7-8 h after intake
      respectively. The perception of the symptoms was rated on a subjective scale
      ranging from 1 ('more than normal') to 3 ('exceptionally more than normal').
      Following consumption of maltodextrin, five subjects reported a total of 12
      symptoms of which seven, two and three were rated as having grade 1, 2 and 3,
      respectively. Following consumption of gamma-CD, five subjects reported six
      symptoms all of which were graded as 1. Two subjects reported flatulence, which
      is a frequent consequence of the consumption of malabsorbed carbohydrates, after
      placebo and test treatment. The incidence of individual and combined side-effects
      as well as the number and consistency of faeces passed was not significantly
      different between placebo and test treatment. It is concluded that single doses
      of 8 g gamma-CD and maltodextrin are tolerated equally well. This is in keeping
      with a good digestibility of gamma-CD by salivary and pancreatic amylase.

PMID- 10656058
TI  - Uncommon presentations of non-Hodgkin's lymphoma.

PMID- 10656059
TI  - Prostate disease: an overview.

PMID- 10656060
TI  - Management of carcinoma of the prostate.
AB  - Every year in the UK nearly 10,000 men die from advanced prostate cancer. On
      average these individuals lose 9 years of their anticipated lifespan. The
      cumulative loss of expected life years therefore amounts to around 90,000 per
      annum, and many hundreds of thousands more retirement years are blighted or lost
      worldwide as a consequence of this very prevalent neoplasm.

PMID- 10656061
TI  - Clinical features and management of benign prostatic hyperplasia.
AB  - Benign prostatic hyperplasia represents the most common benign neoplastic
      condition afflicting men and has a major impact on the health of the population.
      It refers to a regional and nodular growth of stromal proliferation which,
      because of its proximity to the urethra, causes varying degrees of bladder
      outflow obstruction.

PMID- 10656062
TI  - Prostatitis.
AB  - Prostatitis, especially chronic prostatitis, is sometimes regarded as an obscure,
      ill-defined condition, perhaps because the anatomical location of the gland and
      ill-defined symptoms make diagnosis difficult. Treatment may appear time
      consuming and tiresome for doctor and patient, but by following established
      principles, diagnosis is often simple and management straightforward.

PMID- 10656063
TI  - Lanreotide and beyond: extending the therapeutic horizons.
AB  - Thirty years after the growth hormone inhibiting effects of somatostatin were
      first described, greater understanding of its activities is opening the door to
      potential treatments for diabetes, cancer and other disorders. Recent
      identification of five somatostatin receptor subtypes is allowing treatment to be
      carefully targeted in order to maximize efficacy, and minimize unwanted effects.

PMID- 10656064
TI  - Extending prescribing: nurse prescribing and the Crown Review.
AB  - This article discusses the implications of the Crown Review of the Prescribing,
      Supply and Administration of Medicines on the medical profession and its
      relationship with other health-care professions. To appreciate the far-reaching
      implications of the review, it is necessary to reflect on its origins. This
      article will summarize the history of nurse prescribing, and the current context
      in which health care is delivered.

PMID- 10656065
TI  - The influenza virus.
AB  - Influenza is a severe cause of morbidity and mortality throughout the world,
      resulting in annual outbreaks in all age ranges of the population. With an
      extensive animal reservoir the threat of emergence of a novel influenza virus,
      capable of causing a pandemic, has spurred research into novel therapies with
      which to fight the virus.

PMID- 10656066
TI  - Rivastigmine: a review.
AB  - The acetylcholinesterase inhibitors are the first useful and useable drugs for
      palliative treatment of dementia of the Alzheimer type. This article reviews the
      second-generation carbamate cholinesterase inhibitor, rivastigmine (EXELON,
      Novartis, Basel) whose distinctive pharmacology is not only of immediate clinical
      relevance but also the key to some tantalizing therapeutic possibilities.

PMID- 10656067
TI  - Dornase alpha and survival of patients with cystic fibrosis.
AB  - Dornase alpha can offer substantial clinical benefits to cystic fibrosis
      patients, but its long-term impact is as yet unknown. This article attempts to
      model the impact of continuous dornase alpha use on patient survival and its cost
      implications for the health-care provider.

PMID- 10656068
TI  - Catatonia. 1: History and clinical features.
AB  - Catatonia is commonly encountered in psychiatric and medical practice but is
      under-recognized. It occurs in association with a wide range of disorders and
      drugs. Psychiatric education and textbooks mistakenly only consider catatonia as
      a subtype of schizophrenia. This article, the first of two, reviews the
      development of the concept of catatonia, its epidemiology, clinical features and
      pathophysiology.

PMID- 10656069
TI  - Introducing clinical governance in an acute trust.
AB  - The introduction of clinical governance is a major imperative for the NHS. This
      paper describes the initial actions taken in a large acute trust to prepare for
      the clinical governance process. While this description is particular to one
      trust, it is hoped that it offers some generalizable lessons.

PMID- 10656070
TI  - Developing effective clinical audit.
AB  - Clinical audit received a mixed press when it was formalized as part of the
      health-care reforms in the early 1990's, and has continued to mixed reviews ever
      since. However, the latest governmental stipulations on clinical governance
      envisage a revitalized role for clinical audit. This paper advises on avoiding
      some of the pitfalls that await the unwary in developing effective clinical audit
      projects.

PMID- 10656071
TI  - Specialty choice, stress and personality: their relationships over time.
AB  - A longitudinal questionnaire study of 314 medical students followed up as
      preregistration house officers (PRHOs) and again 7 years later showed laboratory
      based doctors were the least happy with their choice of career and were the most
      stressed now, while surgeons were the most happy with their choice and the least
      stressed. These differences were apparent 10 years earlier. The study also
      describes perceived influences on specialty choice and explores how earlier
      factors, such as personality as students and stress in the PRHO year, may also
      have influenced specialty choice.

PMID- 10656072
TI  - The role of the autopsy in medical education.
AB  - The autopsy can make an important contribution to medical education. The decline
      in the hospital autopsy rate threatens this role. This article examines the
      educational opportunities that the post-mortem still provides.

PMID- 10656073
TI  - Primary adrenal B cell lymphoma.

PMID- 10656074
TI  - A case of mistaken identity: primary cutaneous lymphoma presenting as venous
      ulceration.

PMID- 10656075
TI  - High intensity training and the heart.

PMID- 10656076
TI  - Origin of the word 'stent'.

PMID- 10656077
TI  - The needle phobic obstetric patient.

PMID- 10656078
TI  - Dioxins in Belgian feed and food: chickens and eggs.

PMID- 10656079
TI  - Dioxin in feed and food: is public health running behind?

PMID- 10656080
TI  - Finding identity in a virtual world.

PMID- 10656081
TI  - Health inequality and public policy: one year on from the Acheson report.

PMID- 10656082
TI  - Being a woman is hard work: the policy implications of poor health among lone
      mothers.

PMID- 10656083
TI  - Lone mothers in Sweden: trends in health and socioeconomic circumstances, 1979
      1995.
AB  - STUDY OBJECTIVE: To study trends in the health and socioeconomic circumstances of
      lone mothers in Sweden over the years 1979-1995, and to make comparisons with
      couple mothers over the same period. DESIGN: Analysis of data from the annual
      Survey of Living Conditions (ULF), conducted by Statistics Sweden from 1979-1995.
      Comparison of demographic, socioeconomic and health status of lone and couple
      mothers and how these have varied over the 17 years of the study. Main outcome
      measures include prevalence of self perceived general health and limiting
      longstanding illness. PARTICIPANTS AND SETTING: All lone mothers (n = 2776) and
      couple mothers (n = 16,935) aged 16 to 64 years in a random sample of the Swedish
      population in a series of cross sectional surveys carried out each year between
      1979 and 1995. MAIN RESULTS: The socioeconomic conditions of lone mothers
      deteriorated during the period 1979-1995, with increasing unemployment and
      poverty rates. Lone mothers had worse health status than couple mothers
      throughout the period. In comparison with the first two periods, the prevalence
      of less than good health increased among both lone and couple mothers from the
      late 1980s onwards. For lone and couple mothers who were poor, their rates of
      less than good health were similar in the early 1980s, but in 1992-95 poor lone
      mothers were significantly more likely to report less than good health than poor
      couple mothers. Unemployed lone mothers had particularly high rates of ill health
      throughout the study period. CONCLUSIONS: As in other European countries, lone
      mothers are emerging as a vulnerable group in society in Sweden, especially in
      the economic climate of the 1990's. While they had very low rates of poverty and
      high employment rates in the 1980s, their situation has deteriorated with the
      economic recession of the 1990's. The health status of lone mothers, particularly
      those who are unemployed or poor, appears worse than that of couple mothers and
      in some circumstances may be deteriorating. Further study is needed to elucidate
      the mechanisms mediating their health disadvantage compared with couple mothers.

PMID- 10656084
TI  - When does cardiovascular risk start? Past and present socioeconomic circumstances
      and risk factors in adulthood.
AB  - STUDY OBJECTIVES: To compare associations of childhood and adult socioeconomic
      position with cardiovascular risk factors measured in adulthood. To estimate the
      effects of adult socioeconomic position after adjustment for childhood
      circumstances. DESIGN: Cross sectional survey, using the relative index of
      inequality method to compare socioeconomic differences at different life stages.
      SETTING: The Whitehall II longitudinal study of men and women employed in London
      offices of the Civil Service at study baseline in 1985-88. PARTICIPANTS: 4774 men
      and 2206 women born in the period 1930-53 who were administered questions on
      early socioeconomic circumstances. MAIN RESULTS: Adult occupational position
      (employment grade) was inversely associated (high status-low risk) with current
      smoking and leisure time physical inactivity, with waist/height, and with
      metabolic risk factors HDL cholesterol, triglycerides, post-load glucose and
      fibrinogen. Associations of these variables with childhood socioeconomic position
      (father's Registrar General Social Class) were weaker or absent, with the
      exception of smoking in women. Childhood social position was associated with
      adult weight in both sexes and with current smoking, waist/height, HDL
      cholesterol and fibrinogen in women. Height, a measure of health capital or
      constitution, was weakly linked with father's social class and more strongly
      linked with own employment grade. The combination of childhood disadvantage (low
      father's class) together with a low status clerical occupation in men was
      particularly associated with higher body mass index as an adult (interaction test
      p < 0.001). Adjustment for earlier socioeconomic position--using father's class
      and own education level simultaneously--did not weaken the effects of adult
      socioeconomic position, except in the case of smoking in women, when the grade
      effect was reduced by 59 per cent. CONCLUSIONS: Cardiovascular risk factors in
      adulthood were in general more strongly related to adult than to childhood
      socioeconomic position. Among women but not men there was a strong but
      unexplained link between father's class and adult smoking habit. In both sexes
      degree of obesity was associated with both childhood and adulthood social
      position. These findings suggest that the socially patterned accumulation of
      health capital and cardiovascular risk begins in childhood and continues,
      according to socioeconomic position, during adulthood.

PMID- 10656085
TI  - Socioeconomic and demographic predictors of mortality and institutional residence
      among middle aged and older people: results from the Longitudinal Study.
AB  - STUDY OBJECTIVES: To identify socioeconomic and demographic predictors of long
      term mortality and institutional residence in old age, taking into account
      changes in socioeconomic and demographic circumstances between the 1971 and 1981
      censuses. DESIGN: Multivariate logistic regression modelling of outcomes for 10
      year age cohorts of each gender. The outcomes were death by 31 December 1992;
      being in an institution in 1991. SETTING: Members of the Longitudinal Study (a 1%
      sample of the British Census): 43,092 men and 50,839 women aged 55-74 in 1971.
      MAIN RESULTS: Being in rented accommodation and in a household without access to
      a car carried 35-45% higher mortality rate over 21 years and similar excess risk
      of being in an institution in 1991. Marital status and living arrangements were
      weaker predictors of death but being single was a major predictor of moving to an
      institution for men. Losing household access to a car was a strong factor for
      mortality for men and for institutionalisation for men aged 55-64 in 1971. The
      effects were weaker for women. Moving into rented accommodation was a predictor
      of both outcomes for women and of death for the younger cohort of men. People who
      started to live alone in the inter-census period were at reduced risk of dying.
      CONCLUSIONS: These results demonstrate persistence of inequalities in health
      related outcomes throughout old age, both in those with unfavourable
      circumstances in mid-life and in those who, in later life, have lost earlier
      advantages.

PMID- 10656086
TI  - Variation in the provision of chemotherapy for colorectal cancer.
AB  - OBJECTIVE: To quantify the impact of patient, area and hospital characteristics
      on variations in the provision of chemotherapy for colorectal cancer. SUBJECTS:
      Incident cases of colorectal cancer (ICD 153-154), aged under 75 years and
      resident in Scotland, derived from linked hospital discharge records and death
      records for the period January 1990 to June 1994. The final analysis was carried
      out on 7852 patients resident in 823 areas and first admitted to one of 59
      hospitals. MAIN OUTCOME MEASURE: Whether a patient received chemotherapy (OPCS4
      procedure code X35.2) during any hospital episode in the six months after their
      first admission. METHODS: Multilevel logistic regression to separate effects of
      patients, areas and hospitals. RESULTS: During the study period, 8% (n = 626) of
      the study population received chemotherapy within six months of their first
      admission. Adjusting for comorbidities and emergency admissions, both age and
      deprivation were significantly associated with the treatment. The odds ratios
      (OR) of chemotherapy relative to patients aged 65-74 were 2.13 and 4.50 for
      patients aged 55-64 and under 55 respectively. Relative to patients resident in
      the most affluent areas, the OR of chemotherapy for patients resident in the most
      deprived areas was 0.73. Area level availability of the treatment was not
      significantly associated with a patient's odds of receiving the treatment while
      on site provision of chemotherapy at the hospital of first admission was (OR =
      4.32). There was significant unexplained variation between hospitals of first
      admission but not between areas of residence; between hospital variation
      decreased by 22% during the study period. CONCLUSION: Differences according to
      age may reflect both clinical and patient decisions regarding the benefits of the
      treatment relative to its toxicity. Lower treatment rates in deprived areas may
      indicate inequitable access to services. Hospital differences may reflect
      consultant effects and it would be expected that these should decrease now that
      the efficacy of the treatment has been recognised and guidelines have been
      issued.

PMID- 10656087
TI  - East Ireland 1980-1994: epidemiology of neural tube defects.
AB  - STUDY OBJECTIVE: The objective of the study was to describe the epidemiology of
      neural tube defects (NTD) in the eastern region of Ireland using the EUROCAT
      register of congenital malformations. DESIGN, SETTING AND PATIENTS: EUROCAT
      registries monitor the prevalence of congenital anomalies in defined populations
      using multiple sources for case ascertainment. All cases of NTD on the Dublin
      EUROCAT register born between 1980 and 1994 were extracted and analysed. The
      crude birth prevalence rate for all NTD, spina bifida, anencephaly and
      encephalocoele were calculated for each year. Parameters measured were: sex
      ratio, stillbirth rate, proportion of low birth-weight babies (< 2500 g) and the
      proportion who were premature (< 37 weeks gestation). MAIN RESULTS: Of 821 NTD
      cases, 419 (51.0%) had spina bifida, 322 (39.2%) had anencephaly, 69 (8.4%) had
      encephalocoele and 11 (1.3%) were iniencephalic. The crude birth prevalence of
      NTD decreased fourfold from 46.9/10,000 births in 1980 to 11.6/10,000 in 1994.
      The downward trend ceased during the early 1990's. Younger mothers had
      significantly higher rates of NTD affected births. Twenty two per cent of NTD
      cases had additional non-central nervous system anomalies. In 40 cases, there was
      a previous family history of NTD in siblings. Seasonal effects in birth
      prevalence were observed. Birth notification was the most frequent mechanism of
      ascertainment. CONCLUSION: There was a marked fall in the birth prevalence of NTD
      during the 15 year period. This change was real and not accounted for by pre
      natal screening and diagnostic practises with termination of pregnancy, which is
      not legally permissible in Ireland. Dietary factors may have had an influence.
      Rates of NTD in this region are still higher than many other parts of Europe.
      Primary prevention strategies through increased folic acid intake are necessary
      to further reduce NTD affected births.

PMID- 10656088
TI  - Similarities in the epidemiology of neural tube defects and coronary heart
      disease: is homocysteine the missing link?
AB  - It is hypothesised that a single aetiological pathway could explain both the
      strong ecological association between the birth prevalence of neural tube defects
      (NTD) and coronary heart disease (CHD) mortality and the potential efficacy of
      dietary measures, especially increased folic acid intake, in their prevention.
      The epidemiological similarities between NTD and CHD are strong and consistent
      suggesting that the relation is real rather than artefactual. It is suggested
      that this epidemiological association reflects a shared aetiology arising from
      the role of disturbed homocysteine metabolism in the pathogenesis of both
      conditions. Current public health measures designed to increase the intake of
      periconceptional folic acid in women, reinforced by a broadening of this policy
      to target both sexes throughout life, will (if successful) result in a reduction
      in both the birth prevalence of NTD and the incidence of CHD, although not
      necessarily contemporaneously. If disordered homocysteine metabolism is the cause
      of both NTD and CHD, this has implications for future research and preventive
      strategies for these serious and often lethal diseases.

PMID- 10656089
TI  - Duncan Memorial Lecture: Part 1. Dr Duncan's legacy in a remote New Guinea
      valley.

PMID- 10656090
TI  - Duncan Memorial Lecture: Part 2. Dr Duncan's legacy in Liverpool today.

PMID- 10656091
TI  - Deprivation and excess winter mortality.

PMID- 10656092
TI  - Sticky webs, hungry spiders, buzzing flies, and fractal metaphors: on the
      misleading juxtaposition of "risk factor" versus "social" epidemiology.

PMID- 10656093
TI  - The new GATT round: whose development? Whose health?

PMID- 10656094
TI  - Practice makes perfect: developing public health practice.

PMID- 10656095
TI  - ras Mutations and a cup of coffee: cause, confounder, effect modifier, or what
      else?

PMID- 10656096
TI  - Every step counts: towards a smoke free society.

PMID- 10656097
TI  - Inequality in health: socioeconomic differentials in mortality in Rome, 1990-95.
AB  - STUDY OBJECTIVE: Population groups with a lower socioeconomic status (SES) have a
      greater risk of disease and mortality. The aim of this study was to investigate
      the relation between SES and mortality in the metropolitan area of Rome during
      the six year period 1990-1995, and to examine variations in mortality
      differentials between 1990-92 and 1993-95. DESIGN: Rome has a population of
      approximately 2,800,000, with 6100 census tracts (CTs). During the study period,
      149,002 deaths occurred among residents. The cause-specific mortality rates were
      compared among four socioeconomic categories defined by a socioeconomic index,
      derived from characteristics of the CT of residence. MAIN RESULTS: Among men,
      total mortality and mortality for the major causes of death showed an inverse
      association with SES. Among 15-44 year old men, the strong positive association
      between total mortality and low SES was attributable to AIDS and overdose
      mortality. Among women, a positive association with lower SES was observed for
      stomach cancer, uterus cancer and cardiovascular disease, whereas mortality for
      lung and breast cancers was higher in the groups with higher SES. Comparing the
      periods 1990-92 and 1993-95, differences in total mortality between socioeconomic
      groups widened in both sexes. Increasing differences were observed for
      tuberculosis and lung cancer among men, and for uterus cancer, traffic accidents,
      and overdose mortality among women. CONCLUSIONS: The use of an area-based
      indicator of SES limits the interpretations of the findings. However, despite the
      possible limitations, these results suggest that social class differences in
      mortality in Rome are increasing. Time changes in lifestyle and in the prevalence
      of risk behaviours may produce differences in disease incidence. Moreover,
      inequalities in the access to medical care and in the quality of care may
      contribute to an increasing differentials in mortality.

PMID- 10656098
TI  - Suicide and unemployment in Italy, 1982-1994.
AB  - OBJECTIVE: To investigate whether either the condition of being unemployed, or
      changes in unemployment rates are associated with suicide risk. DESIGN:
      Administrative data for suicide according to occupational status have been
      analysed considering three employment categories: employed, seeking new job
      (unemployed), seeking first job (never employed). Comparison of suicide rates by
      economic position and correlation between suicide and unemployment rates have
      been made. SUBJECTS AND SETTINGS: 20,457 deaths by suicide registered in Italy
      among economically active people from 1982 to 1994. MAIN OUTCOME MEASURES: Change
      over time in suicide rates by economic position; coefficient of aggravation
      according to occupational status. RESULTS: Suicide rates among the unemployed are
      clearly and constantly higher than those among the employed: up to three times
      higher among men, and twice as high among women. Among the unemployed a clear and
      significant rise in suicide rates in both sexes took place over the study period;
      suicide rates among the employed showed a less marked increase. The rise in
      suicide rates was accompanied by a concurrent rise in unemployment rate
      percentage. Men seem to be affected most by this change in unemployment rate
      percentage; women are subject to less evident influences and variations.
      CONCLUSION: Different suicidal behaviour trends among unemployed compared with
      employed people indicate that unemployment (and above all the prospect of not
      having access to a working role) acts as a contributing factor for suicide.
      Unemployment, even if symptomatic of a mental disorder, should therefore always
      be taken into consideration as a risk factor for suicide: the potentially lethal
      consequences of its negative influence on both self esteem and the ability to use
      supportive networks in a efficient way is an element to which great attention
      should be paid.

PMID- 10656100
TI  - Short-term impact of a university based smoke free campaign.
AB  - STUDY OBJECTIVE: The aim of this study was to evaluate the impact of a smoke free
      programme implemented at the University of Geneva, Switzerland, in 1996. This
      programme included a prohibition to smoke in university buildings everywhere
      except in limited areas, and a smoking cessation counselling service. METHODS:
      Surveys were conducted before and four months after the programme was
      implemented, in representative samples of programme participants (n = 833) and
      university members not exposed to the programme (n = 1023). RESULTS: In
      retrospective assessments, participants reported being less bothered by
      environmental tobacco smoke after programme implementation, but no between group
      difference was detected in prospective assessments. Relationships between smokers
      and non-smokers improved moderately in the intervention group and remained
      unchanged in the comparison group (between group p = 0.001). Proportions of
      smokers who attempted to quit smoking in the past four months increased from 2.0%
      to 3.8% in the intervention group and remained unchanged at 3.5% in the
      comparison group (between group difference: p = 0.048). No impact on smoking
      prevalence (25%) was detected. The programme was appreciated by university
      members, although some of its modalities were criticised. CONCLUSION: A
      regulation prohibiting smoking everywhere but in limited areas of university
      buildings was acceptable and reduced the perception of bother by environmental
      tobacco smoke. It did not, however, influence smoking habits or attitudes toward
      smoking.

PMID- 10656099
TI  - Association between coffee drinking and K-ras mutations in exocrine pancreatic
      cancer. PANKRAS II Study Group.
AB  - STUDY OBJECTIVE: To analyse the relation between coffee consumption and mutations
      in the K-ras gene in exocrine pancreatic cancer. DESIGN: Case-case study.
      Consumption of coffee among cases with the activating mutation in the K-ras gene
      was compared with that of cases without the mutation. SETTING AND PATIENTS: All
      cases of pancreatic cancer newly diagnosed at five hospitals in Spain during
      three years were included in the PANKRAS II Study (n = 185, of whom 121 whose
      tissue was available for molecular analysis are the object of the present
      report). Over 88% were personally interviewed in hospital. DNA was amplified from
      paraffin wax embedded tissues, and mutations in codon 12 of K-ras were detected
      by the artificial RFLP technique. MAIN RESULTS: Mutations were found in tumours
      from 94 of 121 patients (77.7%). Mutations were more common among regular coffee
      drinkers than among non-regular coffee drinkers (82.0% v 55.6%, p = 0.018, n =
      107). The odds ratio adjusted by age, sex, smoking and alcohol drinking was 5.41
      (95% CI 1.64, 17.78). The weekly intake of coffee was significantly higher among
      patients with a mutated tumour (mean of 14.5 cups/week v 8.8 among patients with
      a wild type tumour, p < 0.05). With respect to non-regular coffee drinkers, the
      odds ratio of a mutated tumour adjusted by age, sex, smoking and alcohol drinking
      was 3.26 for drinkers of 2-7 cups/week, 5.77 for drinkers of 8-14 cups/week and
      9.99 for drinkers of > or = 15 cups/week (p < 0.01, test for trend). CONCLUSIONS:
      Pancreatic cancer cases without activating mutations in the K-ras gene had drank
      significantly less coffee than cases with a mutation, with a significant dose
      response relation: the less they drank, the less likely their tumours were to
      harbour a mutation. In exocrine pancreatic cancer the K-ras gene may be activated
      less often among non-regular coffee drinkers than among regular drinkers.
      Caffeine, other coffee compounds or other factors with which coffee drinking is
      associated may modulate K-ras activation.

PMID- 10656101
TI  - Perceived sensitivity of mammographic screening: women's views on test accuracy
      and financial compensation for missed cancers.
AB  - OBJECTIVES: To estimate women's expectations of the accuracy of screening
      mammography and to explore attitudes towards compensation for missed cancers.
      DESIGN: Cross sectional survey (by telephone). SETTING: Australia; population
      based survey conducted in April 1996. PARTICIPANTS: Random sample of women aged
      30-69 years. A total of 2935 women completed the Breast Health Survey (adjusted
      response rate 65%). A random sample of 115 completed this sub-survey on perceived
      sensitivity of mammographic screening and compensation for missed cancers.
      RESULTS: About one third of women (32.2%, 95% CI 23.7, 40.7) had an
      unrealistically high expectation of the sensitivity of screening mammography,
      reporting it to be 95% or higher. Approximately 40% of the women (43.5%, 95% CI
      34.4, 52.6) thought that screening mammography should pick up all cancers (should
      have a sensitivity of 100%). Just under half the women (45.2%, 95% CI 36.1, 54.3)
      said financial compensation should be awarded for a cancer missed by screening
      mammography even if the cancer was missed as a consequence of the small failure
      rate of the test. Younger women living in metropolitan areas and women who had
      realistic expectations of the accuracy of the tests were more likely to favour
      financial compensation. CONCLUSION: Unrealistically high expectations of the
      sensitivity of screening mammography were common in this group of women. Many
      women favoured financial compensation for missed cancers even if the cancer was
      missed solely because of the failure rate of the test. Public education is
      required to inform women of the limited sensitivity of breast cancer tests but
      this may not reduce claims for financial compensation when cancers are missed.

PMID- 10656102
TI  - Beer, wine, spirits and subjective health.
AB  - STUDY OBJECTIVE: To examine the association between intake of different types of
      alcoholic beverages and self reported subjective health. DESIGN: Cross sectional
      health survey with assessment of intake of beer, wine and spirits (at last non
      weekend day), smoking habits, social networks, physical activity, body mass
      index, educational level, presence of chronic disease, and self reported health.
      SETTING: WHO Copenhagen Healthy City Survey, Denmark. PARTICIPANTS: 4113 men and
      7926 women aged 18 to 100 years. MAIN RESULTS: Of the 12,039 subjects, 8680
      reported their health as optimal, and 3359 reported a suboptimal health. After
      controlling for the covariates, the relation between total alcohol intake and the
      proportion reporting suboptimal health was J shaped. Heavy drinkers of any of the
      three types of alcoholic beverages had a higher prevalence of suboptimal health
      than non-drinkers. However, only light (1-2 glasses of wine yesterday) and
      moderate (3-5) wine drinkers had significantly lower odds ratios for suboptimal
      health--0.72 (95% confidence limits; 0.56 to 0.92) and 0.65 (0.49 to 0.87),
      respectively--when compared with non-wine drinkers. Moderate beer or spirits
      drinkers did not differ significantly from non-drinkers of these beverages with
      regard to prevalence of suboptimal health. Consistently, beer preference drinkers
      had an odds ratio of 1.50 (1.25 to 1.80) for suboptimal health compared with wine
      preference drinkers. CONCLUSIONS: A light to moderate wine intake is related to
      good self perceived health, whereas this is not the case for beer and spirits.
      The causal relations creating this association are unknown and should be
      considered when interpreting the relation between different types of alcoholic
      beverages and subsequent morbidity and mortality.

PMID- 10656103
TI  - Randomised studies of income supplementation: a lost opportunity to assess health
      outcomes.
AB  - BACKGROUND: Despite the wealth of evidence linking low income to ill health,
      there is little information from randomised studies on how much and how quickly
      these risks can be reversed by improvements in income. OBJECTIVE: To conduct a
      systematic review of randomised studies of income supplementation, with
      particular reference to health outcomes. DESIGN: Extensive searches of electronic
      databases and contact with previous authors. As well as searching for trials that
      were specifically designed to assess the effects of increased income, studies of
      winners and losers of lotteries were also sought: if winning is purely chance,
      such studies are, in effect, randomised trials of increased income. RESULTS: Ten
      relevant studies were identified, all conducted in North America, mostly in the
      late 1960s and 1970s. Five trials were designed to assess the effects of income
      supplementation on workforce participation and randomised a total of 10,000
      families to 3-5 years of various combinations of minimum income guarantees and
      reduced tax rates. Two trials were designed to assess re-offending rates in
      recently released prisoners and randomised a total of 2400 people to 3-6 months
      of benefits. One trial was designed to assess housing allowances and randomised
      3500 families to three years of income supplements. One trial assessed the health
      effects of 12 months of income supplementation in 54 people with severe mental
      illness. Finally, one study compared three groups of people who won different
      amounts of money in a state lottery. In all these studies the interventions
      resulted in increases in income of at least one fifth. However, no reliable
      analyses of health outcome data are available. CONCLUSIONS: Extensive
      opportunities to reliably assess the effects of increases in income on health
      outcomes have been missed. Such evidence might have increased the consideration
      of potential health effects during deliberations about policies that have major
      implications for income, such as taxation rates, benefit policies, and minimum
      wage levels. Randomised evidence could still be obtained with innovative new
      studies, such as trials of full benefit uptake or prospective studies of lottery
      winners in which different sized winnings are paid in monthly installments over
      many years.

PMID- 10656104
TI  - Determinants of self rated health for Canadians with chronic disease and
      disability.
AB  - OBJECTIVE: To identify the factors associated with self rated health of people
      with and without chronic health conditions or long term disability. SETTING:
      Canadian household population. DESIGN: Analysis of 1994/95 National Population
      Health Survey interview data with 13,995 respondents aged 20 years and older.
      Determinants of poor and good compared with excellent health were examined using
      multivariate nominal logistic regression. Factors included in the analyses were
      illness related (chronic disease, long and short-term disability, and pain)
      demographic, lifestyle (smoking, physical activity, drinking), and social
      psychological resources (mastery, chronic stress, distress, self esteem, and
      social support). RESULTS: Illness related variables were associated with poor
      health, with smaller but significant contributions from demographic and lifestyle
      factors. Psychological resources, especially high mastery and self esteem, are
      associated with better health in those with chronic conditions or disability.
      CONCLUSION: The determinants of self rated health for people with chronic illness
      and disability make the greatest contribution to the findings for the overall
      population.

PMID- 10656105
TI  - Is the frequency of having an eye test associated with socioeconomic factors? A
      national cross sectional study in British elderly.

PMID- 10656107
TI  - Adjusted impact factors for comparisons between disciplines.

PMID- 10656106
TI  - Limited access to antiretroviral therapy for intravenous drug users in Europe.

PMID- 10656108
TI  - Nonallelism for the audiogenic seizure prone (Asp1) and the aryl hydrocarbon
      receptor (Ahr) loci in mice.
AB  - Previous studies showed an association between the Ahr locus on Chr 12 and a
      major gene, Asp1, that influences susceptibility to audiogenic seizures (AGS) in
      mice. Although the association was thought to involve close linkage, a
      pleiotropic effect of the Ahr locus on AGS susceptibility was not excluded. Two
      congenic strains, D2.B6N-Asp1b and the D2N.B6N-Ahrb1, were used to evaluate
      further the association between the Ahr and Asp1 loci. Both strains are
      genetically identical to the AGS susceptible DBA/2 (D2) strain except for a small
      amount of C57BL/6N (B6N) genome surrounding the Ahr locus and encompassing the
      Asp1 locus. The AGS susceptibility of both congenic strains is similar and
      significantly lower than that of the D2 strain. We found that the Ahr/Asp1
      critical region encompasses 5.5-7.0 cM from the proximal microsatellite marker
      D12Mit153 to the distal marker D12Mitl12. The D2N.B6N-Ahrb1 expresses B6 alleles
      for all markers within the critical region, whereas the D2.B6N-Asp1b expresses
      the B6 allele only at the Asp1 locus. Furthermore, we determined that the D2.B6N
      Asp1b mouse expresses both the D2 phenotype and genotype at the Ahr locus, i.e.,
      zoxazolamine paralysis and T to C and G to A transition mutations in the Ahr cDNA
      at bp sites 3330 and 3336, respectively. We therefore conclude that the Ahr and
      Asp1 loci are nonallelic and that the Ahr gene is excluded as a candidate for
      Asp1.

PMID- 10656109
TI  - Courtship behavior of brain mosaics in Drosophila.
AB  - Sites in the brain that show functional, sexual dimorphism in courtship behavior
      have been mapped at high resolution in male/female mosaics of Drosophila
      melanogaster. The sex mosaics were produced by enhancer-trap expression of GAL4
      driving the female-spliced form of the transformer gene (tra), revealing sites in
      the dorsal brain, lateral protocerebrum, suboesophageal, thoracic and abdominal
      ganglia, and suggesting the importance of cross-talk between these regions in the
      implementation of the courtship sequence.

PMID- 10656110
TI  - RNA editing in the Drosophila DMCA1A calcium-channel alpha 1 subunit transcript.
AB  - Messenger RNA editing of transcripts encoding voltage-sensitive ion channels has
      not been extensively analyzed--least of all in Drosophila, for which several
      channel-encoding genes are known. Previous sequence studies of D. melanogaster's
      cacophony gene, which encodes an alpha 1 calcium-channel subunit called Dmca1A,
      suggested that several nucleotides within the ORF of the primary transcript are
      edited such that "A-to-G" substitutions occur (these two nucleotides being the
      adenine that is found at the relevant sites in the sense strand of genomic DNA or
      the primary transcript, compared to the substitution of guanine that is detected
      at the level of cDNA analysis). Such A-to-G changes are the same kind of post
      transcriptional variations originally discovered--in a neurobiological context-
      for a ligand-sensitive channel in vertebrates. Here, we extracted RNA from adult
      flies and revealed, by RT-PCR and restriction-enzyme analyses, that transcript
      heterogeneity exists in vivo for three distinct edited sites within the cac
      encoded RNA. Each such nucleotide would lead to channel variability at the level
      of the Dmca1A polypeptide. Owing to cacophony being originally identified as a
      "behavioral gene," the possible significance of Dmca1A RNA editing for
      influencing the relevant neuro-functional phenotypes is discussed.

PMID- 10656111
TI  - The visually-induced jump response of Drosophila melanogaster is sensitive to
      volatile anesthetics.
AB  - Fruit flies jump when startled by a sudden decrease in light intensity. We show
      that this visually-induced jump response in Drosophila melanogaster is sensitive
      to three general anesthetic agents: halothane, enflurane, and methoxyflurane. The
      concentration of anesthetic required to inhibit this response is similar to that
      needed for the inhibition of other assays in flies and other organisms. We
      believe the simplicity of this assay coupled with the insight gained from the
      more complex electrophysiological monitoring of the same neural pathway will be
      of value in the genetic identification of the molecular target of volatile
      anesthetics.

PMID- 10656112
TI  - Vaccine protocols to optimise the protective efficacy of BCG.
AB  - SETTING: A deer model has been developed to study protection produced with BCG
      vaccination, against infection and the development of pathology, following
      experimental intratonsilar infection with virulent Mycobacterium bovis.
      OBJECTIVE: To determine how the dose of vaccine, the route of vaccination, the
      viability of the vaccine and exposure to glucocorticoids at the time of
      vaccination, may affect the protective efficacy of BCG vaccines. DESIGN: Deer
      were vaccinated with BCG and later challenged with virulent M. bovis via the
      tonsilar route. Protection against infection and development of disease was
      evaluated at necropsy six months after challenge with M. bovis, by histological
      examination and microbial culture. RESULTS: Significant protection against
      infection and disease were obtained following boosting with two low doses (5 x
      10(4) cfu) or moderate doses (5 x 10(7) cfu) of live (freshly cultured and
      lyophilized) BCG. Inferior levels of protection were obtained with high dose (5 x
      10(8) cfu) of live BCG. Similar levels of protection were found with vaccines
      given subcutaneously or via the tonsilar route. Killed vaccine in a mineral-oil
      adjuvant did not evoke protective immunity and treatment with dexamethasone prior
      to vaccination with live BCG ablated its efficacy. Protection against infection
      did not correlate with skin test delayed type hypersensitivity (DTH) or
      lymphocyte transformation to tuberculin. CONCLUSIONS: Two doses of live BCG gave
      significant protection against experimental infection and disease caused by
      virulent M. bovis. Single dose vaccine protected against disease but not
      infection. Vaccines administered at a dosage which did not evoke DTH, provided
      protection against tuberculosis infection and disease.

PMID- 10656113
TI  - Propelling novel vaccines directed against tuberculosis through the regulatory
      process.
AB  - The development of novel vaccines for use in the prevention and immunotherapy of
      tuberculosis is an area of intense interest for scientific researchers, public
      health agencies and pharmaceutical manufacturers. Development of effective anti
      tuberculosis vaccines for use in specific target populations will require close
      cooperation among several different international organizations including
      agencies responsible for evaluating the safety and effectiveness of new biologics
      for human use. In this review, the major issues that are addressed by regulatory
      agencies to ensure that vaccines are pure, potent, safe, and effective are
      discussed. It is hoped that the comments provided here will help accelerate the
      development of new effective vaccines for the prevention and treatment of
      tuberculosis.

PMID- 10656114
TI  - The capsule of Mycobacterium tuberculosis and its implications for pathogenicity.
AB  - Mycobacterium tuberculosis, one of the most prevalent causes of death worldwide,
      is a facultative intracellular parasite that invades and persists within the
      macrophages. Within host cells, the bacterium is surrounded by a capsule which is
      electron-transparent in EM sections, outside the bacterial wall and plasma
      membrane. Although conventional processing of samples for microscopy studies
      failed to demonstrate this structure around in vitro-grown bacilli, the
      application of new microscopy techniques to mycobacteria allows the visualization
      of a thick capsule in specimen from axenic cultures of mycobacteria. Gentle
      mechanical treatment and detergent extraction remove the outermost components of
      this capsule which consist primarily of polysaccharide and protein, with small
      amounts of lipid. Being at the interface between the bacterium and host cells,
      the capsule and its constituents would be expected to be involved in bacterial
      pathogenicity and past work supports this concept. Recent studies have identified
      several capsular substances potentially involved in the key steps of
      pathogenicity. In this respect, some of the capsular glycans have been shown to
      mediate the adhesion to and the penetration of bacilli into the host's cells; of
      related interest, secreted and/or surface-exposed enzymes and transporters
      probably involved in intracellular multiplication have been characterized in
      short-term culture filtrates of M. tuberculosis. In addition, the presence of
      inducible proteases and lipases has been shown. The capsule would also represent
      a passive barrier by impeding the diffusion of macromolecules towards the inner
      parts of the envelope; furthermore, secreted enzymes potentially involved in the
      detoxification of reactive oxygen intermediates have been identified, notably
      catalase/peroxidase and superoxide dismutase, which may participate to the active
      resistance of the bacterium to the host's microbicidal mechanisms. Finally, toxic
      lipids and contact-dependent lytic substances, as well as constituents that
      inhibit both macrophage-priming and lymphoproliferation, have been found in the
      capsule, thereby explaining part of the immunopathology of tuberculosis.

PMID- 10656115
TI  - Survival of mice infected with Mycobacterium smegmatis containing large DNA
      fragments from Mycobacterium tuberculosis.
AB  - Mycobacterium smegmatis is typically used as a bacterial host for cloning and
      expressing single genes or genomic libraries of the human pathogen Mycobacterium
      tuberculosis. To study virulence of M. tuberculosis, we set out to ask the
      question, whether a genomic library derived from M. tuberculosis H37Rv confers
      virulence to the non-virulent M. smegmatis. A representative library from the M.
      tuberculosis H37Rv genome was generated and transformed into wild-type M.
      smegmatis. Mice were challenged with recombinant clones by intravenous, aerogenic
      and intranasal infection. We were unable to detect either growth or persistence
      of recombinant clones in tissues of infected mice; instead, the infection was
      cleared. Since the concern that virulent traits might be transferred, bio-safety
      regulations often require the handling of these experiments at bio-safety Level
      3. However, we failed to find any evidence that the M. tuberculosis library
      confers virulence when expressed in M. smegmatis. We suggest that the results,
      presented here, should fundamentally alter the containment requirements for
      similar experiments in the future.

PMID- 10656116
TI  - Improved sensitivity for detection of tuberculosis cases by a modified Anda-TB
      ELISA test.
AB  - Tuberculosis is still a major health problem in most developing countries and its
      incidence is rising in many industrial countries. The diagnosis of tuberculosis
      depends primarily on identification of mycobacteria and on clinicoradiological
      evidence of the disease. Compared to other diagnostic methods, serological tests
      are faster and do not necessarily require samples that contain the tubercle
      bacilli. We have evaluated a modified version of a commercially available enzyme
      immunoassay test to detect the presence of circulating anti-mycobacterial IgG and
      IgM antibodies in tuberculosis patients. The sensitivity and the specificity of
      the test reaches 87% and 95% respectively. In conclusion, the modified Anda-TB
      enzyme immunoassay test offers a good and reliable test for diagnosis of
      tuberculosis in suspected cases of active pulmonary tuberculosis.

PMID- 10656117
TI  - Molecular analysis of rifampin and isoniazid resistance of Mycobacterium
      tuberculosis clinical isolates in Seville, Spain.
AB  - In this study we examined the mechanisms of resistance to rifampin (RMP) and
      isoniazid (INH) in 352 clinical isolates of Mycobacterium tuberculosis from
      Sevilla, Spain, using three different molecular methods: 1) PCR-single strand
      polymorphism analysis; 2) the commercial system Inno-LiPA RTB for RMP resistance;
      and 3) sequence analysis. Resistance to RMP was found in 21 strains, where the
      following mutations in the rpoB gene were detected: Ser531-->Leu (n = 14
      strains); His526-->Asp (n = 3), Asn518-->Ser (n = 1), Gln513-->Leu (n = 1) and a
      nine nucleotide deletion (n = 1). Resistance to INH occurred in 29 strains, with
      mutations observed in: a) katG gene: Ser315-->Thr (n = 12), Ile304-->Val (n = 1),
      and a partial deletion (n = 4); b) regulatory region of the inhA gene: nucleotide
      substitution C209T (n = 3). No mutation was found in the ahpC promoter.

PMID- 10656119
TI  - The use of space maintainers at a UK pediatric dentistry department.
AB  - Space maintainers have been in use in pediatric dentistry for many years. The use
      of these appliances, however, in terms of indications, contraindications, design,
      and construction, has gained little attention from researchers. It is clearly
      essential that when space maintainers are fitted, it is the result of careful
      planning and appropriate prescriptions.

PMID- 10656118
TI  - Cystic lymphangioma: its orofacial manifestations.
AB  - A patient age five years, nine months with cystic lymphangioma was studied to
      determine the causes of malocclusion and the optimum time for its treatment. The
      main findings were unilateral anterior and posterior crossbite and displacement
      of the mandibular midline due to maxillary deformity and mandibular rotation. The
      force of the cystic lymphangioma mass caused deformity of the maxilla and
      rotation of the mandible. The patient had no functional impairment of speech or
      mastication. A decision was made to defer treatment of malocclusion until
      complete surgical excision of the cystic lymphangioma can be undertaken, thereby
      minimizing the chance of malocclusion re-occurrence.

PMID- 10656120
TI  - In vitro study of 99m-technetium labeled pumice: penetration in fissures.

PMID- 10656121
TI  - Are we reaching very young children with needed dental services?
AB  - Recommendations by the Academy of Pediatric Dentistry urging a dental/oral
      examination of all infants before one year of age, have had limited impact on the
      profession and the general public. Significant numbers of pediatric dentistry
      specialists and general practitioners who provide care for children, disagree
      with the recommendations. Between the mid 1970s and 1990's, there has been no
      change in the percent of children less than six years of age who were reported to
      have visited a dentist in the past year. A review is provided of the dental
      disease needs and dental service patterns of very young children in the various
      demographic populations in an attempt to 1) increase practitioner awareness of
      the continuing needs for services and 2) develop a dialogue between the
      organizations of the profession and the dentists in practice, regarding
      directions to be taken in the future.

PMID- 10656123
TI  - And you thought the nation's economy was doing well: children remain in poverty.

PMID- 10656122
TI  - Assessment of early childhood caries and dietary habits in a population of
      migrant Hispanic children in Stockton, California.
AB  - OBJECTIVE: This study estimated the prevalence of early childhood caries (ECC)
      and related behavioral risk factors in a population of low-income, Mexican
      American children in Stockton, California. METHODS: We collected data for 220
      children ages six years or less using a parent-completed questionnaire and
      clinical dental examinations during the Su Salud Health and Education Fair in
      July 1995. We employed five case definitions of ECC: buccal or lingual caries on
      one or two primary maxillary incisors; caries on any surface of one or two
      primary maxillary incisors; and five decayed, missing (due to caries), or filled
      primary teeth. RESULTS: The prevalence of ECC ranged from 12.3 percent to 30.5
      percent, depending upon the case definition. More than 17 percent of children age
      two years had one primary maxillary incisor affected by caries on the buccal or
      lingual surface; 13.2 percent had two affected. Mean age at weaning from breast-
      or bottle-feeding and patterns of bottle use during sleep did not differ
      significantly between children with ECC and those without. There were no clear
      patterns of cariogenic food frequency and disease status. CONCLUSIONS: Our
      findings question whether feeding patterns with human breast milk, formula, or
      bovine milk are sufficient etiologic factors for this condition.

PMID- 10656124
TI  - Comparison of undergraduate pediatric dentistry clinical procedures from 1982-83
      through 1996-97.
AB  - Using the information obtained from the Collegiate Patient Management System a
      comparison of average numbers of procedures performed by third year dental
      students from 1983/84 to 1996/97 was made. The data were grouped in order to
      compare Group I (1983/1989) to Group II (1990/1997). Student's t-tests were
      performed to determine significant differences between the groups for the various
      procedures. The number of new patients in Group I was only 8.2 compared to Group
      II--7.9 and the total number of new and recall patients seen by students was
      Group I--33.5 compared to Group II--29.9. Students in Group I performed 19.3 one
      surface restorations compared to 11.8 (p = .0001) in the later group and 9.5 two
      surface restorations compared to 6.0 (p = .0003) for the 1990's group. Stainless
      steel crowns, pulpotomies, extractions and sealants were also compared. The total
      numbers of patients visits was 66.8 in GRP I compared to 49.6 (p;eq.0001) in GRP
      II. There has been a decrease in most student experiences in the undergraduate
      pediatric dental clinic in the past 15 years.

PMID- 10656125
TI  - Complications of apexification resulting from poor patient compliance: report of
      case.

PMID- 10656126
TI  - Augmentative communication in dental treatment of a nine-year-old boy with
      Asperger syndrome.
AB  - Dental treatment of a nine-year old boy with Asperger syndrome is described. A
      "social story" is used to explain and perform the treatment.

PMID- 10656127
TI  - The fusion of three primary incisors: report of case.
AB  - The occurrence of a fusion of three primary incisors is rare. A two-year-old
      Japanese girl was brought to the pediatric dental outpatient clinic, Tokyo Dental
      College, to receive a caries-prevention treatment. The fused tooth consisted of
      the maxillary primary central incisors and right maxillary lateral incisor.
      Primary left lateral incisor erupted normally and the other primary teeth were
      erupted. The radicular pulp chambers were fused into one for three fourths of the
      length from the apex, and only one root. The hair and skin of the patient
      appeared normal and no systemic abnormality or congenital disease was noted in
      the medical history of the patient and her family. The occurrence of a three
      tooth fusion, and no supernumerary tooth was confirmed.

PMID- 10656128
TI  - [Current approaches to the diagnosis and correction of atherogenic disorders in
      flight personnel].
AB  - The review demonstrates the importance of diagnosing early forms of
      atherosclerotic disorders in pilots. A particular attention has been given to
      hyperlipidemia as the leading risk factor accompanied by accumulation of
      atherogenic lipoproteins in blood. Underlying mechanisms have been analyzed,
      normal contents of main lipids in blood in various age groups were outlined.
      Discussed are various outlooks on the diagnostic significance of hyperlipidemias,
      and a principally new method of calculating the professional biological age. The
      relation between blood levels of lipids and other immunobiochemical indices has
      been traced. All round consideration is given to status of the immune system as
      well as changes preceding and attendant to atherosclerosis, and the role of lipid
      peroxidation in atherogenesis. The necessity to correct disorders in lipid
      metabolism with, specifically, dietary measures, pharmacological correction and
      non-medicinal therapy has been demonstrated. Application of of corrective
      measures depending on the severity of atherosclerosis is substantiated.

PMID- 10656129
TI  - [The inhibition of the thyroid and calcitonin-producing functions of the rat
      thyroid gland in weightlessness].
AB  - Histological, immunochemical and morphometric techniques were used to assess the
      functional activity of the thyroid parenchyma and calcitonin-producing C-cells of
      the thyroid gland (TG) in rats after 13 days on board Spacelab-2, in 5-6 hrs.,
      and 14 days following the return from space flight. For the first time the fact
      of inhibition of the thyroid parenchyma and C-cells functioning during space
      flight was ascertained. Similarity of changes in the TG activity in and shortly
      after the space flight suggests that the morphological criteria used in 5 hrs.
      post flight give quite good insight into the character of changes occurring
      during microgravity. Two weeks of readaptation to the Earth's gravity result in
      recovery of the calcitonin production whereas the thyroid parenchyma displays
      postflight hyperactivity even after 14 days of return.

PMID- 10656130
TI  - [The effect of long-term hypokinesia on the course of pathological processes in
      animals].
AB  - Reported are results of studying the development of pathology in rats and
      rabbits. Immobilization was found to markedly influence super-heating, local
      inflammation, and fever. In superheated animals, rise in the rectal temperature
      in the experiment and control proceeded at a similar speed; however, recovery of
      temperature in the control rats progressed significantly slower due to, probably,
      the hyper-compensatory reaction of animals to the thermal exposure. Life span of
      the control animals following heat exposure amounted to 160 +/- 13 min with a
      100% lethality, whereas in the experimental animals the lethality rate was
      essentially lower and they lived much longer before death. At all times symptoms
      of inflammation in the experimental animals were more distinct and complications
      on the background of immobilization were more frequent and severe; edema of
      tissues exceeded that in the control by 36.6-49.0%. Local hyperthermia also was
      greater by 1.1-1.4 degrees C compared with the control. Observed was higher
      frequency of secondary infections and complications. According to the
      pathomorphological examinations, immobilization enhanced the alterative
      processes, inhibited formation of the demarcation area, suppressed melting of
      necrotic masses and engendered other signs of more serious pathology. Analysis of
      the course of pyrogenous fever evidenced shortening of the T upward phase and
      extension of the post-peak fever as an effect of long-term immobilization.

PMID- 10656131
TI  - [An analysis of standards documents on the radiation safety problem in space
      flights and the proposals for their improvement].
AB  - The paper considers in retrospective the criteria of radiation hazard during
      space flight, and approaches to safeguarding the radiation safety to crew members
      adopted in a sequence of Russian and US standards defining the space radiation
      limits. Based on comparison of the magnitudes of radiation risk in space flight,
      total radiation risk over lifetime, the risk of fatal cancer, and risk relation
      to age, the most meaningful and age-independent criterion has been chosen to set
      limits and admissible total doses over cosmonaut's career. Justification is given
      to the range of these doses that still ensures socially acceptable levels of
      health and performance by the end of space career. Impliable dose limits for
      critical tissues (blood-forming organs, skin, lenticular epithelium) in
      consequence of a single acute or continuous exposure for a month, a year or
      career are discussed.

PMID- 10656132
TI  - [The effect of overloading from intensive maneuvering on the function of the
      peripheral chromatic field of vision].
AB  - Data on the peripheral chromatic field of vision (PCFV) in pilots after
      centrifugation and missions with intensive maneuvering associated with
      accelerations (+Gz) higher than 6 g are presented. Depression of the PCFV area
      due to hypergravity was most expressed in the shortwave section of the visible
      spectrum and closely linked with the state of cranial hemodynamics. Changes in
      PCFV persisted for quite long period, i.e. initial values did not regain
      following 40 min since exposure to accelerations. Correlation between the degree
      of PCFV changes and pilot's tolerance to accelerations was established. According
      to the factual data analysis, the PCFV technique can be used to evaluate the
      dynamics of G-tolerance during intensive maneuvering aircraft.

PMID- 10656133
TI  - [The characteristics of operator activity in a sensorially enriched environment].
AB  - The mechanism of Ukhtomskii's dominant was used to improve operator's performance
      activity. Recognition of visual images--obscured Arabic numerals--in a
      sensorially rich environment (classic or rock music records) turned to be more
      successful: time of the task was reduced and the probability of correct
      identification increased. A reverse U-shaped dependence between the intensity of
      music and identification was stated. Repetition of music fragments at a constant
      value marred the positive effect.

PMID- 10656134
TI  - [The vestibulo-cervico-ocular reflex in healthy persons].
AB  - The vestibular-cervical-ocular reflex (VCOR) results from interaction of the
      labyrinthine and cervical proprioceptive afferent flows. VCOR study was performed
      in 20 healthy test subjects. Analyzed were the coefficient of reactivity, VCOR
      phase shift, coefficient of COR involvement, and the coefficient of VOR-VCOR
      asymmetry. Functional dependence of cervical proprioceptive and vestibular
      afferentation in the healthy test subjects was demonstrated.

PMID- 10656135
TI  - [Changes in the NO-dependent regulation of the local cerebral blood flow in rats
      during adaptation to the conditions of simulated weightlessness].
AB  - The nitrogen oxide NO-dependent regulation of the cerebral blood flow was studied
      before and after 24-hr head-down immobilization (HDI) of intact and pre-trained
      rats. Training consisted in 2-hr tail-suspension each day of the 2-wk period.
      Blood flow was determined with the laser Doppler flowmetry following local
      injection of a NO synthesis blocker (L-NAME), and NO (sodium nitroprusside).
      Neither HDI nor pre-training per se influenced NO tonic production in the cortex
      of large hemispheres and cerebellum. However, in pre-trained animals HDI resulted
      in a significant blood flow response to the local blockade of NO synthesis in the
      cerebellum. None of the animals changed the reaction of the blood flow to the
      local injection of sodium nitroprusside. The conclusion was drawn that alteration
      in the NO-dependent regulation of the brain blood flow in pre-trained animals
      could manifest of adaptation to HDI in the course of 24-hr suspension.

PMID- 10656136
TI  - [Seasonal changes in the triiodothyronine level of the blood evoked by
      ultraviolet irradiation in vitro].
AB  - Ultraviolet irradiation (lambda = 254 nm) of the whole blood of juvenile bulls in
      vitro results in a plasmatic T3 increase dependent on the time of exposure.
      Dynamics of the growth of hormone content because of UV varies with season. No
      negative correlation between plasmatic T3 and T4 in irradiated and non-irradiated
      blood samples was stated. Hence, increased T3 levels in blood after UV
      irradiation in vitro is a consequence of the output of erythrocyte-deposited
      hormone rather than photoactivation of the T4 to T3 conversion.

PMID- 10656137
TI  - [Endogenous regulatory peptides, interferons and cytokines as adaptogens in
      exposure of the body to adverse environmental factors].
AB  - The authors summarize data on the efficacy of various prefabricated recombinant
      interferons against virus, bacterial, and chlamydial infections, and in
      unfavorable environments. The spaceflight factors were shown to have a negative
      influence on natural killers in the human body providing the immunological
      resistance and defence not only from foreign microorganisms but also the body
      cells transformed because of a virus infection or malignancy. Entalferon awakes a
      particular interest for its convenience in extreme conditions, space flight
      included. It is still an open issue whether the interferon sensitivity of natural
      killers is compromised by space flight. This trend of investigation seems to be
      of paramount importance and promise in the context of enhancing the antiviral,
      antimicrobic and antineoplastic immunity of cosmonauts.

PMID- 10656138
TI  - [Current approaches to the diagnosis and treatment of pilots with combined
      polyposis of the stomach and large intestine].
AB  - Findings of diagnostics and treatment of 198 pilots suffering from combined
      polyposis in the stomach and large intestine are presented. Different therapeutic
      tactics should be chosen for these patients. Annual dynamic evaluation should be
      made in case of a benign course and without an upward tendency, whereas diagnosed
      villus polyps, villus-tubular adenoma with the second or third phase of
      dysplasia, adenomatous polyps with regional 2nd or 3d phase dysplasia will
      require early polypectomy to be followed by yearly dynamic endoscopy. The
      proposed tactics is angled at early diagnostics of stomach and large intestine
      cancers. This tactics allows considerable prolongation of the flight career of
      pilots with the diagnosis of combined polypous lesions.

PMID- 10656139
TI  - [Myocardiodystrophy in flight personnel].
AB  - Presented are results of the review of 150 case records of pilots with myocardial
      dystrophies of various geneses. Analysis of the most informative clinical
      instrumental techniques for diagnosing myocardial dystrophy pointed out
      electrocardiography (the most typical ECG indications of this nosologic form are
      exemplified). The outgrowth of this analysis is an algorithm for diagnosing
      myocardial dystrophy in pilots.

PMID- 10656140
TI  - [Prophylactic food products for the nutrition of cosmonauts].
AB  - To supplement the daily cosmonauts' ration with biologically active substances
      able to increase adaptability and resistance to the adverse spaceflight factors,
      an assortment of prophylactic food products to be consumed at specific phases of
      mission has been developed. Principles of creating dietary compositions, i.e.
      selection of biologically adequate staples and appropriate use of alimentary
      supplements with anti-stress, adaptation assisting and antiradiation properties,
      and search for cooking technologies that will maximally preserve the original
      qualities of ingredients have been established. Some of these products were
      tested as components of the MIR rations in 1997-1998.

PMID- 10656141
TI  - [The influence of I. P. Pavlov and his school on the formation and development of
      ecological and extreme-situation physiology].

PMID- 10656142
TI  - [The participation of physicians in creating the first prototypes and improving
      diving equipment and the methodology for dives].

PMID- 10656143
TI  - [Explanation of enigmas of the Lynch syndrome thanks to a new carcinogenesis
      model characterized by an unorthodox initiation process].
AB  - The genotype-phenotype relationship of Lynch syndrome displays many enigmatic
      features which cannot be explained satisfactorily by the prevailing concepts of
      carcinogenesis and genetic predisposition to cancer. We propose here a new model
      of carcinogenesis divided into two and only two evolutive phases: a) a
      preliminary phase starting with the counter-selective loss of mismatch repair
      function, in which most clones with the RER mutator phenotype are eliminated
      through apoptosis or an accelerated ageing process; b) an explosive phase that is
      initiated only if mutations blocking apoptosis and senescence, rapidly acquired
      during the short life span of the non-transformed RER+ clones, eventually rescue
      one mismatch repair-deficient cell that gives rise to the malignant clone.
      Carcinogenesis is proposed here to progress irreversibly and very rapidly once
      initiated. We shall show how this model provides a meaningful etiologic and
      pathogenic interpretation of all the curious features of Lynch syndrome.

PMID- 10656144
TI  - [The presenilin mystery. The research winner-by-a knockout?].

PMID- 10656145
TI  - Identification of a gene linked to the Brassica S (self-incompatibility) locus by
      differential display.
AB  - Self-incompatibility in Brassica is controlled by a complex locus, the S locus,
      that includes several expressed genes. Two S locus genes, SLG and SRK, are
      expressed in the stigma and have been implicated in self-pollen recognition. The
      male component of this recognition system is also predicted to be encoded by a
      gene at the S locus but this gene has not been identified to date. In this study,
      we have used differential display to screen for polymorphic, S-locus-linked genes
      that are expressed in anthers. This approach has allowed the identification of a
      gene, named S5J, which was shown to segregate completely with the S locus. We
      discuss the possible role of this gene in the self-incompatibility response and
      evaluate the utility of differential display for the identification of genes at
      specific genetic loci.

PMID- 10656146
TI  - [LagoZ and LagZ, 2 genes depleted of CpG dinucleotides, derived from the LacZ
      gene for the study of epigenetic control].
AB  - The methylation of 5'CpG 3' dinucleotides within genes creates potential targets
      for protein complexes that bind to methylated DNA sequences and to histone
      deacetylases (MBD-HDAC). This can lead to transcriptional repression by
      modification of chromatic. To test the importance of this repression in vivo and
      to determine when during development these epigenetic controls are placed on
      genes, two novel genes have been engineered by directed mutagenesis of the CpG
      rich LacZ gene that are depleted of (LagZ) or completely lacking (LagoZ) CpG
      sequences. We report that the expression (transcriptional and translational) of
      the three genes is indistinguishable in transient assays in cleaving mouse
      embryos. Therefore, the complete absence of CpG sequences within three kilobases
      of coding sequence is compatible with its maintenance in the nucleus and with its
      expression. These molecules can now be used to study the ontogenesis of the CpG
      dependent repressive system in intact organisms.

PMID- 10656147
TI  - [Interactions of the Pseudomonas aeruginosa outer membrane proteins with plasma
      fibronectins. Bacterial adhesin investigation].
AB  - Pseudomonas aeruginosa adherence is a complex phenomenon largely mediated by pili
      involving specific receptor-ligand interactions. Anti-fibronectin antibodies as
      well as plasmatic fibronectin are able to inhibit P. aeruginosa adherence onto
      A549 cells showing that matricial fibronectin is an actual receptor for this
      bacterium. Experiments performed in vitro with human plasmatic fibronectin used
      as receptor and outer membrane proteins of P. aeruginosa as ligands show the
      presence of four fibronectin-binding proteins. These proteins with molecular mass
      of 70 +/- 2, 60 +/- 2, 48 +/- 2 and 36 +/- 1 kDa should be adhesins of P.
      aeruginosa on epithelial cell matrix in a non-pilus mediated adherence.

PMID- 10656148
TI  - Anatomy and histology of the babirusa (Babyrousa babyrussa) stomach.
AB  - Stomachs from six adult and one 12-month-old babirusa (Babyrousa babyrussa) were
      collected from zoological gardens. The babirusa stomach was larger than that of
      the domestic pig (Sus scrofa), and possessed a large diverticulum ventriculi. Its
      gastric glands were confined to a small, easily identifiable unit at the end of
      the corpus ventriculi, and the connections between the different stomach parts
      were wide and unrestricted, with the exception of the well-defined connection
      between the diverticulum ventriculi and the fundus ventriculi. Microscopically,
      the structure of the cardiac, gastric and pyloric glands was similar to that of
      Sus scrofa. However, the mucusproducing cardiac glands of babirusa occupied a
      larger area within the stomach (> 70% versus 33%). The pH in the lumen of the
      cardiac gland area lay between 5.3 and 6.4 and micro-organisms were found here.
      It was hypothesised that the babirusa is a nonruminant foregut-fermenting
      frugivore/concentrate selector.

PMID- 10656149
TI  - Biological control and invading freshwater snails. A case study.
AB  - Introductions of four species of freshwater snails occurred between 1972 and 1996
      onto Guadeloupe Island. Two of them, Melanoides tuberculata and Marisa
      cornuarietis, were subsequently used as biological control agents against
      Biomphalaria glabrata, the snail intermediate host of intestinal schistosomiasis.
      In 1996, a general survey was carried out in 134 sites which had already been
      investigated in 1972. The total number of mollusc species had increased from 19
      to 21. Site numbers housing B. glabrata and two other species had strongly
      declined. This decline may be mainly attributed to a competitive displacement by
      M. tuberculata and M. cornuarietis as illustrated by several biological control
      programmes. There were no changes in the remainder of the malacological fauna.

PMID- 10656150
TI  - Computed tomography fluoroscopy: techniques and applications.
AB  - Computed tomography fluoroscopy (CTF) was first introduced into clinical practice
      in Japan in 1993 and in the United States in 1995, yet it has been used
      predominantly at large academic hospitals. Early literature on CTF is composed
      primarily of abstracts that detail anecdotal experiences and that have been
      presented at major meetings. Scientific papers evaluating CTF in clinical
      practice have been introduced in scientific journals only recently. This article
      reviews the literature for CTF with specific emphasis on clinical techniques,
      applications, and results. It is the goal of the author to provide the reader
      with a basic working knowledge of how to perform CTF-guided procedures and how to
      integrate CTF into clinical practice.

PMID- 10656151
TI  - Magnetic resonance imaging of the elbow.

PMID- 10656152
TI  - The role of health professionals in the protection of the rights of women.

PMID- 10656153
TI  - Demands on obstetrical care in the urban environment: postpartal survey.
AB  - In recent years, obstetrical management reflecting the individual needs of
      parturient women and newborn children has acquired an increasing significance.
      Today, the majority of obstetrical departments provide alternatives to
      traditional methods of delivery. The purpose of this study was to analyze the
      current obstetric situation as perceived by the women concerned. During the lying
      in period spent in the care of the obstetrical department, 386 women were
      interviewed as to their birth experience. The questionnaire employed used a
      predominantly structured format. The present study examined a total of six of
      Vienna's municipal hospitals. The majority of women interviewed were satisfied
      with the standard of care provided by obstetricians and midwives. However,
      certain administrative and organizational aspects were subject to criticism, for
      example, shift changes among the medical staff as well as the presence of an
      excessive number of people during delivery were felt to detract from the intimate
      character of giving birth. In general, the standards of care provided by urban
      obstetrical departments as well as the experience of giving birth itself
      confirmed women's expectations. However, certain areas remain where improvements
      seem both desirable and feasible without requiring undue effort. Women who gave a
      positive assessment of their personal experience of delivery also tended to carry
      away a favorable impression of their stay in hospital as a whole.

PMID- 10656154
TI  - Cyclical mastalgia: premenstrual syndrome or recurrent pain disorder?
AB  - Approximately 8-10% of premenopausal women experience moderate to severe
      perimenstrual breast pain or cyclical mastalgia, monthly. This mastalgia can
      occur regularly for years until menopause, can interfere with usual activities,
      and is associated with elevated utilization of mammography among young women.
      Although mastalgia is a well documented symptom in premenstrual syndrome (PMS),
      it is unknown whether PMS is necessarily present in women with cyclical
      mastalgia. The present study prospectively examined mastalgia and its
      relationship to PMS. Thirty-two premenopausal women reporting recent mastalgia
      completed breast pain and menstrual symptom scales daily for 3-6 months. Eleven
      women (34.4%) met criteria for clinically significant cyclical mastalgia,
      reporting an average of 10.2 days of moderate-severe mastalgia monthly. Five
      women (15.6%) met criteria for PMS. Mastalgia was not significantly associated
      with PMS: 82% of women with clinical cyclical mastalgia did not have PMS.
      Cyclical mastalgia, although by definition associated with the menstrual cycle,
      is not simply premenstrual syndrome, and merits further investigation as a
      recurrent pain disorder whose presentation, etiology, and effective treatment are
      likely to differ from those of PMS.

PMID- 10656155
TI  - Lesbian couples as therapeutic donor insemination recipients: do they differ from
      other patients?
AB  - Reports were based on 23 lesbian couples seeking therapeutic donor insemination
      (TDI). Seventeen single women and 14 heterosexual couples with known infertility,
      due to vasectomy, were recipient controls. No group differences were found on
      self-esteem, psychiatric symptomatology or dyadic adjustment, except that
      lesbians reported greater dyadic cohesion than heterosexuals. Lesbians and single
      women were likely to disclose their use of TDI to others and had planned to
      disclose this to any child conceived; married couples were divided on this issue.
      Groups were alike in what they wanted to know about the donor (principally health
      variables and medical history), and in their concerns about the use of TDI
      (genetic and medical history). Groups differed in the reasons they elected to use
      TDI, with lesbian couples and single women choosing TDI affirmatively, and
      married couples accepting it as a last resort.

PMID- 10656156
TI  - Psychosomatic group treatment helps women with chronic pelvic pain.
AB  - This study evaluates group treatment for women suffering from chronic pelvic
      pain. The concept of group treatment was based on psychosomatic and physio
      therapeutical principles and on cognitive and operant behavioral therapy. Each
      group was composed of up to six women suffering from chronic pelvic pain, and two
      physiotherapists. Each group treatment session lasted 2.5 h per week for a period
      of 10 weeks. The women completed questionnaires and pain drawings four times
      during the treatment period from the beginning of the period till 15 months
      later. During 13 group treatment periods 53 women accomplished the treatment.
      Before the treatment the women had experienced pain for an average period of 5
      years and 9 months (ranging from 6 months to 22 years). The women's descriptions
      of the changes derived from group treatment were analyzed according to the
      Grounded Theory Method. A methodical triangulation of quantitative and
      qualitative data as well as analyzes of the drawings were applied. One year after
      the end of the treatment, 39% of the women were pain-free. The average level of
      pain measured according to the Visual Analog Scale was reduced from 2.8 to 0.9 (p
      < 0.01). The intake rate of analgesics was reduced from an average of 8.5 units
      to 0.9 units per week (p < 0.01). Furthermore a reduction in the use of the
      National Health Service and increases in gainful employment were registered. By
      means of the Grounded Theory Analysis a model of the development process was
      elaborated. The process begins with the development of self-knowledge, followed
      by the woman assuming self responsibility for her own life and performing self
      activeness. During the process the woman increases her feeling of self-control
      and personal mastery of her emotions. The women's pain drawings improved,
      resulting in more detailed drawings, the color intensity abating, the extent of
      pains declining, and the outlines blurring. In conclusion this kind of group
      treatment brings the women relief from their pain thus reducing the use of the
      National Health Service by women suffering from chronic pelvic pain. The women
      also experience a positive psychological development. This method of treatment,
      in which a synergetic combination of physical and psychological treatment
      mutually enhance the effect of the treatment, will probably have a beneficial
      impact on the treatment of other patients suffering from acute or chronic
      physical or psychological traumas or from chronic pains.

PMID- 10656157
TI  - The present state of family-centered obstetrics in Hungary: preparation for the
      delivery, open delivery-room, rooming-in.
AB  - This paper gives details of a survey carried out at hospitals in Hungary to
      examine how widespread family-centred obstetrics is, and to what extent
      obstetrics departments are able to meet the increasing demands exerted by
      society. Several aspects were focused on, including the characteristics of
      obstetrics departments, the preparation for delivery and maternity, open delivery
      rooms, delivery with the partner, early mother-baby contact, rooming-in and to
      what extent they operate. The study describes the findings on the basis of data
      sent back by 87 maternity departments, 81.3% of the institutions in the country.
      The data reveals that 96.6% of wards have preparatory courses for delivery and
      maternity, 98.8% of open delivery-rooms welcome the partner at the delivery,
      early mother-baby contact is possible in 97.7%, and 95.6% offer rooming-in. The
      study gives a comprehensive view of the present state of family-centred
      obstetrics, offering an opportunity for everyone to re-evaluate their practices
      and set up new objectives so that every mother and family can have easy access to
      family-centred obstetrics.

PMID- 10656158
TI  - In vitro tests of 1,3-dithia-2-thioxo-cyclopent-4-ene to evaluate the mechanisms
      of its hepatoprotective action.
AB  - Some in vitro tests were performed using 1,3-dithia-2-thioxo-cyclopent-4-ene
      (DT827A) to evaluate its mode of action on hepatoprotection. Experiments with
      leucine, uridine and thymidine uptakes using L-132 cells showed no increase in
      leucine uptake, but did show a tendency toward increases in both uridine and
      thymidine uptakes, which suggested a stimulating effect on RNA and DNA synthesis
      in vitro. DT827A did not influence GSH levels in the HepG2 cultured cell system,
      and did not show inhibition of cytochrome P450 2El in microsomes obtained from
      mouse liver. There may be no possibility for DT827A to protect a liver injury
      through its influence on liver GSH levels and inhibiting metabolic activation of
      CCl4 in this in vitro system. However, the inhibitory effect of DT827A on lipid
      peroxidation was observed in vitro, the same as the observation in vivo.
      Furthermore, when DT827A was incubated with Alamar Blue in the presence of a
      mixture of mouse liver S9 and mitochondrial fractions for 20 hr, DT827A showed
      more reducibility than it did in a case of non-incubation, and it was suggested
      that DT827A would be metabolized in the S9-mitochondrial fraction in vitro to
      show an increase of Alamar Blue reducibility. The protective effect of DT827A on
      a liver injury is due neither to its influence on liver GSH levels nor inhibition
      of the metabolic activation of CCl4, but a possible mechanism of action for the
      DT827 series of compounds to indicate an antioxidative effect would be brought
      about by the role of the compounds as a radical scavenger as well as its
      reductive effect.

PMID- 10656159
TI  - Novel action of quinolones on osteoclast-like cells.
AB  - Quinolones have a broad antibacterial spectrum against Gram-negative and Gram
      positive bacteria. The compounds, however, have a few adverse effects, such as
      convulsion and toxicity to articular cartilage. We observed that some quinolones
      such as Naldixic acid, Ofloxacin, and Norfloxacin have osteoclast-inducing
      effects. All quinolones we tested produced tumor necrosis factor-alpha and
      prostaglandin E2, and have potency as osteoclast inducers to cultured cells.
      These results suggest that some quinolones affect osteoclast induction or
      activation, and this may be related to the production of tumor necrosis factor
      alpha (TNF-alpha) and prostaglandin E2 (PGE2).

PMID- 10656160
TI  - Antitesticular effect of copper chloride in albino rats.
AB  - Copper chloride treatment adversely affects testicular activity in albino rats.
      To investigate its antitesticular effects mature (120 days) Wistar strain albino
      rats were treated intraperitoneally (i.p.) with copper chloride at doses of 1000,
      2000 and 3000 micrograms/kg body weight/day for 26 days. Significant reduction of
      testicular and accessory sex organs (seminal vesicle, ventral prostate) weight,
      along with inhibition of testicular delta 5-3 beta-hydroxysteroid dehydrogenase
      (delta 5-3 beta-HSD) and 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD)
      activity and reduction in plasma testosterone level, were observed at the doses
      of 2000 and 3000 micrograms/kg body weight/day. The degree of inhibition in all
      the parameters were increased with the increase of dosage. But no significant
      change was observed in the above parameters when the animals were treated with
      1000 micrograms/kg body weight/day dose. This suggests that copper produces a
      suppressive influence on male reproductive activity, mainly on testicular weight
      and steroidogenesis and accessory sex organ weight in a dose-dependent manner.

PMID- 10656161
TI  - Comparative toxicokinetic study of rubber antioxidants, 2-mercaptobenzimidazole
      and 2-mercaptomethylbenzimidazole, by single oral administration in rats.
AB  - Toxicokinetics of 2-mercaptobenzimidazole (MBI) and 2-mercaptomethylbenzimidazole
      (MMBI), rubber antioxidants with thioureylene structure, were compared after
      single oral administration in rats. Male Wistar rats received single oral
      administration of 2, 10, 50 and 250 mg/kg of MBI or MMBI. The serum and urine
      concentrations of MBI and MMBI were determined by HPLC. MBI and MMBI showed
      similar Cmax values, but the former disappeared slower in the serum than the
      latter and resulted in its larger AUC values. Analyses of MBI, MMBI and their
      desulfurated metabolites in urine suggested that these differences were due to
      their metabolic elimination rates. On the other hand, MBI and MMBI caused similar
      acute toxicities, such as loss of locomotive activity, ataxic gait, adoption of
      prone or side position and coma, being severer with higher serum concentrations
      at the moment. Similar acute toxicities between MBI and MMBI were explained by
      similar Cmax values at the same dose. It was suggested from these results that
      the slower disappearance and larger AUC values of MBI in the serum compared to
      MMBI might explain the strong thyroid toxicity which has been observed by
      repeated administration of MBI, but very weak thyroid toxicity by MMBI.

PMID- 10656162
TI  - Effects of alpha-chlorohydrin on rat sperm motions in relation to male
      reproductive functions.
AB  - alpha-chlorohydrin (ACH) is a known male reproductive toxicant and produces
      antifertility in rats. The present experiments were performed to determine the
      relationship between sperm motions and reproductive function, and to further
      examine the possible mechanism for antifertility. ACH was administered to male
      rats for 9 days at 1, 3 and 10 mg/kg/day. The males were mated with untreated
      females and their reproductive status was determined. All mated males failed to
      impregnate females at 10 mg/kg/day. Low pregnancy rate associated with a
      decreased implant number was seen at 3 mg/kg/day. When sperm motions were
      analyzed using the CellSoft computer-assisted sperm analyzer, percentage of
      motile sperm, curvilinear velocity (VCL) and amplitude of lateral head
      displacement (ALH) were reduced at 10 mg/kg/day. At 3 mg/kg/day, VCL and ALH were
      reduced but the percentage of motile sperm was comparable to that of controls. In
      order to examine a possible mechanism for the effect of ACH on fertility, the
      number of sperm reaching the oviducts of mated females and the number of
      fertilized eggs was evaluated. Half of the females mated with ACH-treated males
      at 3 mg/kg/day had very low sperm numbers in the oviducts. At 10 mg/kg/day, all
      the mated females had a very low sperm number. The percent of fertilized eggs in
      the oviducts of mated females was decreased in a dose-dependent manner. These
      findings suggest that the effect of ACH on fertility was directly related to
      decreased VCL and ALH as well as percentage of motile sperm, and by the mechanism
      in which the sperm number reaching the oviducts after mating was reduced, so the
      reduction resulted in only a rare chance to fertilize.

PMID- 10656163
TI  - Regulation of prostatic glutathione-peroxidase (GSH-PO) in rats treated with a
      combination of testosterone and 17 beta-estradiol.
AB  - In order to confirm the relationship between sex hormone administration and
      glutathione-peroxidase (GSH-PO) in the rat ventral prostate, the levels of GSH-PO
      mRNA, GSH-PO activity, and lipid peroxide (TBA) value in the ventral prostate
      were investigated. Male Crj:CD(SD)IGS rats were divided into six experimental
      groups. Group 1 consisted of intact controls. In group 2, rats were sacrificed
      two days after castration. In groups 3 and 4, rats were subcutaneously
      administered 1 mg/animal of testosterone daily for three or seven days after two
      days of castration, respectively. In groups 5 and 6, rats were subcutaneously
      administered 1 mg/animal of testosterone plus 0.01 mg/animal of 17 beta-estradiol
      (E2) daily for three or seven days after two days of castration, respectively.
      GSH-PO activity of the ventral prostate homogenate for testosterone or
      testosterone plus E2 administration to the castrated rat was increased and the
      TBA value was remarkably decreased. The prostatic GSH-PO mRNA level was
      diminished in the castrated rat ventral prostate, but was increased by
      testosterone or testosterone plus E2 administration. In particular, the GSH-PO
      mRNA level of testosterone plus E2-treated animals was higher than that of
      testosterone-treated animals. These findings strongly suggest that expression of
      GSH-PO in the rat ventral prostate is considered to be testosterone- or E2
      dependent. Furthermore, it is suggested that the transcription of prostatic GSH
      PO mRNA was regulated by testosterone or E2 and de novo synthesis of GSH-PO would
      thus be regulated at transcription level by testosterone or E2.

PMID- 10656164
TI  - Development of resistance to chloroform toxicity in male BDF1 mice exposed to a
      stepwise increase in chloroform concentration.
AB  - To investigate the development of resistance to chloroform toxicity, a 4-week
      inhalation study was conducted in which BDF1 male mice were exposed to a low
      level of chloroform for an initial two-week period, and thereafter the exposure
      concentration was increased for a second two-week period. The animals were
      exposed to inhalation of chloroform vapor 6 hr per day, 5 days per week, with
      clinical observation and measurement of body weight conducted. These results
      demonstrate that pre-exposure to chloroform at a low dose level induced
      resistance to a higher dose of chloroform in male mice. This resistance was
      dependent on the pre-exposure concentration.

PMID- 10656165
TI  - Effect of sodium arsenite on plasma levels of gonadotrophins and ovarian
      steroidogenesis in mature albino rats: duration-dependent response.
AB  - Effect of arsenic on ovarian steroidogenesis at the dose available in drinking
      water at wide areas of West Bengal is reported here. Weights of ovary, uterus and
      vagina along with biochemical activities of ovarian delta 5-3 beta-hydroxysteroid
      dehydrogenase (delta 5-3 beta-HSD) and 17 beta-hydroxysteroid dehydrogenase (17
      beta-HSD) and plasma levels of LH, FSH and estrogen were measured in mature rats
      of the Wistar strain at diestrous phase following subchronic treatment with
      sodium arsenite at a dose of 0.4 ppm/rat/day for 16 days (4 estrous cycles) and
      28 days (7 estrous cycles). A significant reduction in plasma levels of LH, FSH
      and estrogen along with significant diminution in the activities of ovarian delta
      5-3 beta-HSD and 17 beta-HSD were observed following sodium arsenite treatment
      for 28 days. This duration of treatment also resulted in a marked degree in
      diminution in the weights of ovary, uterus and vagina, but 16 days of treatment
      did not exhibit any significant effect on these above parameters. Arsenic-treated
      rats exhibited a prolonged diestrous phase in the estrous cycle in contrast to
      control rats having 4 days of a regular estrous cycle. Deposition of arsenic in
      ovary, uterus, vagina and plasma was also monitored in arsenic-treated rats. The
      results of our experiment suggest that duration of arsenic treatment is the
      critical factor for its adverse effect on ovarian activities at the dose within
      the range noted in drinking water at several areas of West Bengal in India.

PMID- 10656166
TI  - Suppressive effects of chlorogenic acid on N-methyl-N-nitrosourea-induced
      glandular stomach carcinogenesis in male F344 rats.
AB  - The modifying effects of chlorogenic acid (CA) on N-methyl-N-nitrosourea (MNU)
      induced glandular stomach carcinogenesis were investigated in five groups of male
      F344 rats. Rats in Groups 1 through 3 were given MNU in drinking water at a
      concentration of 400 ppm for 12 weeks. Animals of Group 1 were then kept on the
      basal diet alone, and those of Group 2 or 3 were fed a diet containing 500 or 250
      ppm CA for a subsequent 22 weeks. Group 4 was exposed to CA alone through the
      experimental period (36 weeks), and Group 5 was given the basal diet continuously
      and treated as a control. At the end of the experiment, the incidence of
      glandular stomach carcinoma of Group 3 was significantly smaller than that of
      Group 1 (p < 0.03). The incidence of adenomatous hyperplasia of Group 2 was also
      significantly lower than that of Group 1 (p < 0.02). In addition, the
      proliferating cell nuclear antigen (PCNA) labeling index of the epithelial cells
      from the non-neoplastic mucosa in rats of Group 2 or 3 was significantly smaller
      than that of Group 1 (p < 0.0001). These results suggest that CA has a
      chemopreventive effect on MNU-induced rat glandular stomach carcinogenesis by
      exposure during the post-initiation phase, and CA may be a promising agent for
      prevention of human stomach cancer.

PMID- 10656167
TI  - Pathomorphometrical characteristics of atherosclerosis in youth. A multinational
      investigation of WHO/World Heart Federation (1986-1996), using atherometric
      system.
AB  - BACKGROUND AND AIM: From 1986 to 1996, 1339 autopsies were performed on children
      and young adults, aged 5-34 years, in 18 countries of five continents in the
      course of the multinational investigation of the World Health
      Organization/International Society and Federation Cardiology (WHO/ISFC),
      "Pathobiological Determinants of Atherosclerosis in Youth" (PBDAY). A set of 966
      left-half thoracic and 947 left-half abdominal aortae and 958 right coronary
      arteries were processed in the Center of Investigations and References of
      Atherosclerosis of Havana (CIRAH), i.e., one of the Reference Centers of the
      PBDAY. Pathomorphological and morphometrical analyses were carried out by a well
      established method, the Atherometric System (AS). METHODS AND RESULTS: By
      qualitative analysis AS permitted the identification of each type of
      atherosclerotic lesions (AL). The quantitative analysis, using a digitizer (MYPAC
      Japan, a PC-Pentium 200 Mhz-32 MB RAM), and the software Atherosoft, allowed the
      measurement of the intima surface occupied by any kind of AL, and estimation of
      the volume occupied and thus the degree of obstruction and stenosis of the lumen.
      The autopsy data were divided into three age groups: a) 5 to 14 years; b) 15 to
      24 years and c) 25 to 34 and processed by age and sex. The commercial package
      NCSS was utilized for statistical analysis of the data. CONCLUSIONS: Of
      particular interest were the following findings: a) Atherosclerosis increases
      with age; b) Fatty streaks (FS) were always present already at 5 years of age,
      independent of the country, climate, state of nourishment, type and amount of
      foods and the habits and lifestyle of the population studied. FS progressed most
      rapidly from 15 to 24 years. The fibrous plaque began to appear slowly at the end
      of the second and rapidly progressed after the third decades. The severe plaque
      was rarely observed before 30 years of age; it appeared in the fourth decade and
      then progressed slowly, but steadily.

PMID- 10656168
TI  - World Health organization (WHO) and the World Heart Federation (WHF)
      pathobiological determinants of atherosclerosis in youth study (WHO/WHF PBDAY
      Study) 1986-1996. Histomorphometry and histochemistry of atherosclerotic lesions
      in coronary arteries and the aorta in a young population.
AB  - BACKGROUND AND AIM: The present work is a chapter in an investigation directed by
      the World Health Organization on the Pathobiological Determinants of
      Atherosclerosis In Youth (WHO-PBDAY). Our aim was to study the development of
      atherosclerotic lesions in a young population. METHODS AND RESULTS: Samples of
      left anterior descending coronary artery (LDC) and thoracic (TA) and abdominal
      aorta (AA) from five Collaborating Centres (Budapest/Hungary, Havana/Cuba,
      Heidelberg/Germany, Mexico City/Mexico, Peradeniya/Sri Lanka) of 214 subjects who
      died aged 15 and 34 were analysed at the Budapest Reference Centre. Slides
      stained with haematoxylin-eosin and with stains for extracellular matrix were
      quantitatively and qualitatively evaluated. Mean intima/media (I/M) ratio and the
      prevalence of type III-IV lesions (preatheroma; atheroma; calcified and fibrous
      atheroma) were determined and compared in different risk factor (high blood
      pressure, smoking) groups. High I/M ratio was found in the LDC and type III-IV
      lesions were frequently found both in the LDC and in the AA. I/M ratio and the
      occurrence of type III-IV lesions increased in all arteries by age.
      Atherosclerotic lesions in men were more severe, particularly in the LDC.
      Geographic origin had a limited effect on the histologic lesion parameters.
      Appearance of type III-IV lesions was associated with substantially different
      extracellular matrix changes. Myoelastic layer formation was found in each artery
      in both early and type III-IV lesions. Hypertension was associated with higher
      prevalence of type III-IV lesions in all arteries, in particular, in the TA;
      smoking showed a significant effect on the AA only. CONCLUSIONS: Atherosclerotic
      lesions were found in many of these young subjects. The effect of hypertension
      and smoking on their development suggests that control of risk factors, beginning
      in early adolescence, could help to prevent cardiovascular diseases.

PMID- 10656169
TI  - Low density lipoprotein cholesterol, lipoprotein(a), and apo(a) isoforms in the
      elderly: relationship to fasting insulin. Associazione Medica Sabin.
AB  - BACKGROUND AND AIM: Insulin resistance/hyperinsulinemia are often associated with
      aging and could play an important role in the development of glucose intolerance
      and dyslipidemia in the elderly. We investigated the relationship between plasma
      fasting insulin with total cholesterol (TC) and low density lipoprotein LDL
      cholesterol (LDL-C), triglycerides (TG), lipoprotein(a) [Lp(a)] levels
      apolipoprotein (a) [apo (a)] isoforms in 100 free-living "healthy" octo
      nonagenarians. METHODS AND RESULTS: Fasting insulin was positively correlated
      with TG, whereas a negative relation was found with TC and LDL-C (r = -0.29 and r
      = -0.28 respectively; p < 0.01), LDL-C/apo B, HDL-C and apo A-I levels. Fasting
      insulin was also inversely correlated with Lp(a) levels (r = -0.22; p < 0.03),
      whereas the latter were significantly related with TC and LDL-C (r = 0.30 and r =
      0.31; p < 0.005), TG (r = 0.21; p < 0.05) and apo B (r = 0.26; p < 0.02). There
      was a negative relation between Lp(a) levels and apo(a) isoforms: the greater the
      apo(a) molecular weight, the lower the Lp(a) level (p < 0.0001). Fasting insulin
      increased with apo(a) size, though the difference in insulin levels among apo(a)
      isoforms was not significant (p = 0.4). Multiple regression analysis showed that
      fasting insulin was the best predictor of LDL-C (R2 = 0.14; p = 0.002)
      irrespective of age, gender, BMI, waist circumference and TG, while apo(a)
      isoform size, BMI and waist circumference were related with Lp(a) irrespective of
      TC and LDL-C, TG and apo B (R2 = 0.35 to 0.37; p < 0.0001). CONCLUSIONS: These
      results suggest that fasting insulin levels significantly influence LDL-C
      metabolism in old age. Lp(a) levels seem to be very strongly related to genetic
      background, although an indirect relation with insulin through adiposity and/or
      other associated lipid abnormalities cannot be ruled out.

PMID- 10656170
TI  - Post-prandial effects of gemfibrozil vs simvastatin in hypercholesterolemic
      subjects with borderline hypertriglyceridemia.
AB  - BACKGROUND AND AIM: Impaired triglyceride-rich lipoprotein metabolism is most
      probably related to an enhanced cardiovascular risk, and may be associated with a
      pro-coagulant state. A double-blind, randomized study was undertaken to evaluate
      two widely utilized hypolipidemic drugs in the post-prandial phase and their
      impact on lipid, coagulation and fibrinolytic parameters. METHODS AND RESULTS:
      Thirty middle-aged men selected according to their low density lipoprotein
      cholesterol (LDL-C) > or = 160 and < or = 240 mg/dl and borderline
      hypertriglyceridemia (110-220 mg/dl) after at least one month of a lipid-lowering
      diet received gemfibrozil (600 mg bid) or simvastatin (20 mg qd) and the
      corresponding placebo. On enrollment and after 2 months of drug treatment, they
      were tested with a standard oral fat load (OFL) (35 g fat/m2 body surface). On
      both occasions plasma total-cholesterol, LDL-C, HDL-C, triglycerides,
      lipoprotein[a] (Lp[a]), tissue plasminogen activator (tPA), plasminogen activator
      inhibitor-1 (PAI-1), antithrombin-III (AT-III), plasminogen and fibrinogen were
      determined just before the meal (t0) and at times 2 hours, 4 h, 6 h, 8 h after it
      (t2-t8). A two-factor (time and visit) multivariate analysis for repeated
      measurements was performed to evaluate the data. Total cholesterol, and LDL-C
      were significantly diminished 2 months after both gemfibrozil and simvastatin,
      the latter being more active. Plasma triglycerides showed a marked reduction with
      gemfibrozil at all times, while simvastatin regimen yielded only minor
      modifications. HDL-C was only slightly increased by simvastatin; Lp[a] plasma
      levels were almost unaffected. Small fibrinogen (t0, t2, t6, t8), PAI-1 (t6) and
      AT III (t0-t8) increases were observed after gemfibrozil, while simvastatin did
      not significantly modify these parameters. CONCLUSIONS: In the post-prandial
      phase, gemfibrozil and simvastatin induce different metabolic effects that
      beneficially influence the lipid pattern, whereas fibrinolytic and coagulative
      parameters display minor variations of undetermined significance.

PMID- 10656172
TI  - Altered serum concentrations of TGF-beta 1 and Lp(a) lipoprotein and their
      correlation in patients with first acute myocardial infarction.
AB  - BACKGROUND AND AIM: The association between high plasma Lp(a) lipoprotein and
      coronary heart disease has been confirmed in numerous case/control and
      prospective studies. A high Lp(a) level has also been shown to be an independent
      genetic risk factor, while its inverse relationship with TGF-beta 1 has suggested
      that it may interfere with plasmin-mediated activation of TGF-beta 1 and result
      in increased endothelial activation, as well as migration and proliferation of
      vascular smooth muscle cells. The aim of this study was to evaluate Lp(a) and TGF
      beta 1 and their interactions in patients with first acute myocardial infarction
      (AMI). METHODS AND RESULTS: A total of 107 patients with first AMI and 103 age
      and sex-matched controls were studied. Very good agreement was found between QEI
      and RIA determinations of Lp(a) (p < 0.0001). Lp(a) levels were significantly
      elevated in cases (QEI: p < 0.031; RIA p < 0.002 respectively). Division by
      gender gave statistically significant differences in females only. Plasma levels
      of the active form of TGF-beta 1 were decreased in cases, though significantly (p
      < 0.029) in males only. CONCLUSIONS: Serum concentrations of Lp(a) and TGF-beta 1
      are significantly altered in AMI patients. The differences are gender-dependent:
      Lp(a) is higher in females, and TGF-beta 1 is lower in males. Increased Lp(a)
      levels are accompanied by decreased active TGF-beta 1 levels and this inverse
      correlation is statistically significant (p < 0.001).

PMID- 10656171
TI  - Elevated basal insulin secretion and normal dynamic insulin sensitivity in
      borderline hypertension.
AB  - BACKGROUND AND AIM: Borderline hypertension is often the initial stage of
      stabilized hypertension. This study aimed to provide insight on insulin behavior
      and its relationship with glucose metabolism by investigating insulin secretion
      and hepatic clearance in non-steady-state conditions in borderline hypertensive
      patients. METHODS AND RESULTS: We studied 15 patients (6 F, 9M, 44 +/- 2 yr, 78
      +/- 2 kg, systolic pressure 155 +/- 10 mmHg, diastolic 93 +/- 5) and 15
      comparable healthy controls. All underwent an intravenous glucose test, with
      minimal model analysis to measure insulin sensitivity S1, glucose effectiveness
      SG, insulin pre-hepatic release, hepatic extraction, and insulin appearance rate
      in the systemic circulation. Basal glucose (3.98 +/- 0.12 vs 3.94 +/- 0.11
      mmol/L, hypertensive vs control subjects respectively), i.v. glucose tolerance
      factor KG (2.0 +/- 0.2 vs 2.2 +/- 0.1% min-1), SG (0.035 +/- 0.004 vs 0.032 +/-
      0.007 min-1) and S1 [3.5 +/- 0.5 vs 3.8 +/- 0.3 10(4) min-1 (microU/mL)] were
      similar, both basal insulin and C-peptide exhibited a marked increase (87 +/- 8
      vs 46 +/- 6 pmol/L, p = 0.0003; 637 +/- 62 vs 381 +/- 76 pmol/L, p < 0.03)
      demonstrating insulin resistance in basal conditions. Insulin secretion per unit
      volume was greater in patients, both at basal (43 +/- 5 vs 24 +/- 5 pmol/L/min, p
      = 0.01) and after stimulation (total hormone released = 18 +/- 2 vs 11 +/- 2
      nmol/L in 4 h, p = 0.022). Post-hepatic insulin delivery was also elevated (basal
      = 11 +/- 1 vs 6 +/- 1 pmol/L/min, p < 0.002, total = 5 +/- 1 vs 3 +/- 0.3 nmol/L
      in 4 h, p = 0.02), while no difference was detected in hepatic extraction (66 +/-
      4% vs 66 +/- 3). CONCLUSION: Borderline hypertensive patients display normal
      glucose tolerance with basal insulin resistance and normal dynamic insulin
      sensitivity. Peripheral hyperinsulinemia derives from the combination of normal
      hepatic extraction with an overproduction of hormone, mostly due to the basal
      component. Because borderline hypertension often degenerates into overt disease,
      our results point to a progression that leads to the well-known insulin
      resistance proper to sustained hypertension.

PMID- 10656173
TI  - Dealing with hypertension in general practice. General implications of an Italian
      point of view. Several hundred Italian general practitioners who collaborated in
      the clinical and epidemiological projects.

PMID- 10656174
TI  - Control of biological activities of influenza virus hemagglutinin by its
      carbohydrate moiety.

PMID- 10656175
TI  - Chemically induced infection of CD4-negative HeLa cells with HIV-1.
AB  - Infection with human immunodeficiency virus type-1 (HIV-1) requires the presence
      of a CD4 molecule and chemokine receptors such as CXCR4 or CCR5 on the surface of
      target cells. However, it is still not clear how the virus enters the cells.
      Although CD4 was initially identified as the primary receptor for HIV-1, the
      expression of CD4 or one of the chemokine receptors alone is not sufficient to
      render susceptibility to infection with the virus. To ascertain whether or not
      adsorption of the virus needs charge-to-charge interaction between viral envelope
      and host cell membrane protein(s) and if binding alone promotes penetration of
      the virus into the cells, we have developed a chemically induced infection system
      targeting a CD4-negative and CXCR4-positive HeLa cell clone (N7 HeLa) which is
      usually not susceptible to infection with the LAI strain of HIV-1. Use of a poly
      L-lysine (PLL)-coated culture plate to enhance the attachment of the virus to the
      cells made N7 HeLa cells infectable with HIV-1 at very low efficiency. PLL alone
      cannot fully substitute for the function of the CD4 molecule. However, trypsin
      treated viruses, which have largely lost infectivity to CD4-positive MT-4 cells
      that are highly susceptible to HIV-1 infection, enhanced infectivity against N7
      HeLa cells when the PLL-coated plate was used. These results provide evidence
      that infection with HIV-1 requires both high binding affinity between viruses and
      cells, and then needs a modification of the viral envelope such as cleavage of
      gp120/160 to enhance the infection, probably resulting in exposure of the
      hydrophobic fusion domain of gp41. HIV-1 infection of N7 HeLa cells was also
      enhanced by treatment with low pH, 12-O-tetradecanoylphorbol-13-acetate (TPA) and
      some factor(s) from the MT-4 cell culture supernatant. Not only tight viral
      adsorption with cleavage of the viral envelope but also some activated status of
      the cells may be required for sufficient HIV-1 infection in this artificial
      condition.

PMID- 10656176
TI  - Role of interferon alpha (IFN-alpha) and interferon gamma (IFN-gamma) in the
      control of the infection of monocyte-like cells with human cytomegalovirus
      (HCMV).
AB  - The role of cytokines in the control of HCMV infection has been studied in THP-1
      cells, a macrophage-like cell model and in MRC-5 cells. HCMV replication was
      studied by immune detection of viral immediate-early antigens (IEA) and virus
      yield was evaluated in MRC-5 cells by immunoperoxidase staining. Pretreatment of
      MRC-5 and phorbol 12-myristate 13-acetate (PMA)-treated THP-1 cells with IFN
      alpha or IFN-gamma for 24 hr prior to the infection reduced the number of
      infected cells and virus yield. A synergistic anti-CMV activity in synthesis of
      early proteins was obtained with these cytokines in combination with TNF-alpha in
      differentiated THP-1 cells only. Treatment of HCMV-infected differentiated THP-1
      cells or MRC-5 cells with IFN-alpha or IFN-gamma alone had no inhibitory effect
      on virus replication, however the virus yield was reduced with ganciclovir. A
      synergistic anti-CMV activity in virus yield was obtained only when infected
      differentiated THP-1 cells were treated with ganciclovir in combination with IFN
      gamma. The current study shows that IFN-alpha and IFN-gamma can play a role in
      the reduction of HCMV replication in macrophage-like cells and in the efficiency
      of therapies with ganciclovir in this cell type and that the anti-CMV effect of
      cytokines may be different in fibroblasts and in macrophage-like cells.

PMID- 10656177
TI  - Genetic diversity and the absence of regional differences of Borrelia garinii as
      demonstrated by ospA and ospB gene sequence analysis.
AB  - Unfed adult Ixodes persulcatus ticks were collected from four locations of Nagano
      and Hokkaido in Japan. Infected Borrelia garinii were investigated by PCR-RFLP of
      the ospA and ospB gene sequences. The primer set amplified an approximately 1.6
      kb DNA fragment (0.7-kb in some strains), and BsrI, BstYI, or NlaIII digestion of
      the product resulted in six distinctively different PCR-RFLP groups and two
      independent borrelial strains. The representatives in each PCR-RFLP group and
      individuals from the borrelial strains were sequenced, and their deduced amino
      acid sequences were aligned. A neighbor-joining phylogenetic analysis showed that
      the B. garinii OspA or OspB sequences were each divided into three major clusters
      including isolates from both the Nagano and Hokkaido locations. There was no
      local difference in OspA/B sequences between Nagano and Hokkaido. The osp gene of
      Borrelia burgdorferi sensu lato is highly heterogeneous, and this was also
      confirmed by our sequence analysis. Some strains of the different PCR-RFLP groups
      had closely related OspA sequences, while the OspB sequences of these strains
      were quite different. These findings suggested intraspecies gene exchange and
      recombination events between the two genes in B. garinii.

PMID- 10656178
TI  - Complement receptor type 3 plays an important role in development of protective
      immunity to primary and secondary Corynebacterium pseudotuberculosis infection in
      mice.
AB  - The present study was performed to investigate the role of CR3, the type 3
      complement receptor, in host defense against primary and secondary
      Corynebacterium (C.) pseudotuberculosis infection in mice. Treatment of mice with
      5C6, an anti-CR3 monoclonal antibody (mAb), resulted in unrestricted
      multiplication of bacteria in the organs and dramatically increased mortalities
      of the infected mice. Histological examinations showed the inflammation,
      degeneration and necrosis of organs and revealed that the infection-enhancing
      effect of 5C6 mAb was associated with the failure of mice to focus mononuclear
      phagocytes at sites of bacterial multiplication. These results suggest that CR3
      plays an important role in host defense against primary as well as secondary C.
      pseudotuberculosis infection in mice.

PMID- 10656179
TI  - Profiling aging by gene arrays.

PMID- 10656180
TI  - Influence of age on hypoxia/reoxygenation-induced DNA fragmentation and bcl-2,
      bcl-xl, bax and fas in the rat heart and brain.
AB  - To test the hypothesis that the aging mammalian heart and brain might have
      increased vulnerability to acute stress, DNA fragmentation was studied after
      hypoxia-reoygenation in young adult (6 months) and old (22-24 months) F344 rats.
      Heart and brain tissue were examined at the following time points: 30, 60, or 90
      min of hypoxia (H, 5% O2, 95% N2) plus 2 h of reoxygenation (R, room air, 21%
      O2). With increasing duration of hypoxia preceding the reoxygenation, the extent
      of DNA fragmentation (in situ terminal dUTP nick end labeling, TUNEL, positive
      cells) was progressively higher in both age groups, greater in the old compared
      to that of the young adult rat. The levels of the anti-apoptotic proteins bcl-2
      and bcl-xL, were similar in young and old at baseline and tended to increase in
      both age groups after hypoxia/reoxygenation. The pro-apoptotic protein, bax, was
      higher at baseline in the old; it rose after hypoxia/reoxygenation in the young
      adult heart and brain, but was unchanged in the old heart and was decreased in
      the old brain. The ratios of bcl-2/bax and of bcl-xL/bax were higher in the old
      heart and brain compared to that in the young adult after hypoxia/reoxygenation.
      Thus, compared to that of the young adult, the heart and brain of the old rat
      have lower thresholds and are more vulnerable to injury induced by
      hypoxia/reoxygenation, despite rapid and heightened expression of the anti
      apoptotic proteins bcl-2 and bcl-xl. This could be due partly to the age
      associated increase in the basal expression of the pro-apoptotic protein bax, as
      well as possibly other factors.

PMID- 10656181
TI  - Effect of aluminium-induced Alzheimer like condition on oxidative energy
      metabolism in rat liver, brain and heart mitochondria.
AB  - Prolonged exposure of rats to aluminium (Al) can result in an Alzheimer-like
      condition. To get better insights into the biochemical defects underlying AD,
      senility and ageing we exposed rats for long durations (90-100 days) to soluble
      salt of aluminium (AlCl3) and checked its influence on mitochondrial respiratory
      activity in the liver, brain and heart. In the liver and brain mitochondria the
      ADP/O ratio was impaired with NAD+ linked substrates. State three respiration
      decreased with glutamate in the liver. For succinate, the ADP/O ratio decreased
      in the liver mitochondria while state three and four respiration decreased in the
      brain mitochondria. In both the tissues respiration rates decreased with
      ascorbate + TMPD as the substrate. In the heart mitochondria ADP/O ratios with
      NAD+ linked substrates decreased, while respiration rates increased with all the
      substrates except for ascorbate + TMPD. Temperature kinetics data showed
      different effects on ATPase in the mitochondria from the three tissues. Data on
      lipid/phospholipid profiles suggested that the observed changes in energy
      metabolism were not mediated via lipid changes. Long-term exposure to Al resulted
      in approximately 100% increase in Al content of liver and brain mitochondria but
      in the heart there was phenomenal 11-fold increase, indicating thereby that the
      effects of Al exposure were indirect rather than direct due to Al accumulation.

PMID- 10656182
TI  - Immune function did not decline with aging in apparently healthy, well-nourished
      women.
AB  - Nutrition plays a crucial role in immune function. Most studies on age-associated
      changes in immunocompetence in healthy adults did not examine the nutritional
      status of participants extensively. Inadequate nutritional status may confound
      the relationship of aging and immune response. The purpose of this study was to
      examine age-related changes in parameters of acquired and innate immunity in
      healthy and generally well-nourished older (62-88 years) versus younger (20-40
      years) women. Subjects were screened for participation using the health criteria
      of the SENIEUR protocol as well as a number of nutrition criteria related to
      undernutrition, and protein, iron, vitamin B12, and folate status. Young and old
      women did not differ in total T (CD3+), T-helper (CD4+), or T-cytotoxic (CD8+)
      cell number. However, older women tended to have lower T-cell proliferation
      response to concanavalin A (P < 0.10) and significantly reduced response to
      phytohemagglutinin (P < 0.05). No age-related changes were noted in natural
      killer cell number or cytotoxicity. Phagocytosis and subsequent oxidative burst
      activity also did not differ between young and old women. Most immune parameters
      were not compromised with aging in this cohort of apparently healthy, well
      nourished women. These findings highlight the importance of simultaneous
      examination of health and nutritional status in studies of immune function with
      aging.

PMID- 10656184
TI  - In vitro pituitary responsiveness to LHRH in young and old female rats. Influence
      of melatonin.
AB  - The effect of aging and melatonin on in vitro pituitary responsiveness to
      luteinizing hormone-releasing hormone (LHRH) was studied. Young cyclic (3-months
      old) control (cyclic-control, N = 15), and melatonin (MEL) treated for 2 months
      (150 microg/100 g BW) (cyclic-MEL, N = 15), old acyclic (23-months-old) control
      (acyclic-control, N = 13), and MEL-treated (acyclic-MEL, N = 18) rats were used.
      The hormones analyzed were luteinizing hormone (LH), follicle stimulating hormone
      (FSH) and prolactin (PRL). The results showed a different influence of the
      reproductive status as well as of melatonin on the basal secretion rate of both
      gonadotropins, i.e. LH and FSH. Only the basal FSH release was significantly
      reduced in cyclic-MEL and acyclic-controls compared to cyclic-controls. The
      hemipitutary FSH content raised to values similar to those observed for FSH
      secretion and only the cyclic-MEL group showed significantly higher FSH pituitary
      content than for release. LHRH addition to the incubation medium resulted in
      increased LH release for both cyclic and acyclic rats, but FSH release was only
      stimulated in acyclic rats. Melatonin treatment blunted this response in both
      cases. In addition, melatonin treatment inhibited prolactin release in acyclic
      MEL group after LHRH stimulation but not the basal levels. Pituitary LH and
      prolactin contents, were significantly higher than the pituitary LH and prolactin
      levels released from all groups studied, and were not affected by reproductive
      senescence nor by exogenous melatonin. These data indicate that aging influences
      more the secretory than the biosynthetic processes. Melatonin influences is
      endocrine status-dependent, being inhibitory when pituitary hormones reach their
      higher values.

PMID- 10656183
TI  - Age-related decline in activation of calcium/calmodulin-dependent phosphatase
      calcineurin and kinase CaMK-IV in rat T cells.
AB  - We have previously shown that the DNA binding activity of the transcription
      factor NFAT which plays a predominant role in IL-2 transcription decreases with
      age. Because the transactivation (dephosphorylation and nuclear translocation) of
      the NFAT-c (cytoplasmic component of the NFAT complex) is mediated by the
      calcium/calmodulin-dependent phosphatase, calcineurin (CaN), and because
      Ca2+/calmodulin-dependent kinases (CaMK-II and IV/Gr) have been shown to play a
      critical role in calcium signaling in T cells, it was of interest to determine
      what effect aging has on the activation and the levels of these calcium
      regulating enzymes. The induction of calcineurin phosphatase activity, and CaMK
      II and IV/Gr activities, were studied in splenic T cells isolated from Fischer
      344 rats at 6, 15, and 24 months of age. In addition, the changes in the protein
      levels of these enzymes were measured by Western blot. The calcineurin
      phosphatase activity and CaMK-II and IV kinase activities were at a maximum after
      the cells were incubated with anti-CD3 antibody for 5-10 minutes. The induction
      of calcineurin activity by anti-CD3 and by calcium ionophore (A23187) declined 65
      and 55%, respectively, between 6 and 24 months of age. The induction of CaMK-IV
      activity, but not CaMK-II activity by anti-CD3, was significantly less (by 54%)
      in T cells from old rats compared to T cells from young rats. The decline in the
      activation of these enzymes with age was not associated with changes in their
      corresponding protein levels. These results demonstrate that alterations in
      calcineurin phosphatase activity and CaMK-IV activity may contribute to the well
      documented age-related decline in T cell function.

PMID- 10656185
TI  - Accumulation of hemoglobin-associated acetaldehyde with habitual alcohol drinking
      in the atypical ALDH2 genotype.
AB  - BACKGROUND: Those with the atypical genotypes of low Km aldehyde dehydrogenase
      (ALDH2) have high blood concentrations of free acetaldehyde, an active metabolite
      of ethanol, after drinking alcohol. In the present study, we measured
      acetaldehyde reversibly bound to hemoglobin (HbAA) in Japanese male workers.
      METHODS: One hundred and sixty Japanese male workers in one plant participated
      with informed consent. The subjects were genotyped for the ALDH2 polymorphism by
      polymerase chain reaction method. HbAA levels were measured using a high
      performance liquid chromatography system with a fluorescence detector. For the
      study in which we examined accumulation of HbAA, eight Asian male volunteers
      participated with informed consent. RESULTS: Although HbAA levels were
      significantly correlated with recent alcohol consumption in both typical
      (ALDH2*1/*1) and atypical (ALDH2*1/*2) genotypes, the slope in ALDH2*1/*2 was
      significantly steeper than that in ALDH2*1/*1. Multiple regression analysis on
      relevant factors for HbAA revealed that not only recent but also daily alcohol
      consumption increased HbAA levels in those with the ALDH2*1/*2 genotype, which
      suggests that HbAA accumulates with habitual drinking. We measured HbAA levels
      before, during, and after alcohol consumption--one drink (0.4 ml/kg) per day--for
      7 consecutive days in male volunteers. During the drinking period, HbAA linearly
      increased in ALDH2*1/*2 (n = 4) but not in ALDH2*1/*1 (n = 4). After reaching
      peak levels (+76.1 nmol/g hemoglobin) following the seventh drink, HbAA levels
      gradually decreased but were significantly higher for 3 days after drinking was
      discontinued. CONCLUSIONS: We demonstrated that HbAA levels accumulate with
      habitual alcohol drinking in the atypical ALDH2 genotype. HbAA was shown to be a
      good biomarker for increased internal exposure levels to acetaldehyde.

PMID- 10656186
TI  - Alcohol deprivation effect is prolonged in the alcohol preferring (P) rat after
      repeated deprivations.
AB  - BACKGROUND: The alcohol deprivation effect (ADE) is a temporary increase in the
      ratio of ethanol/total fluid intake and the voluntary intake of ethanol solutions
      over baseline drinking conditions when ethanol access is reinstated after a
      period of alcohol deprivation. The ADE has been posited to be an animal model for
      alcohol craving. The current study examined the effects of initial deprivation
      length and number of deprivation exposures on the ADE in alcohol-preferring (P)
      rats. METHODS: Adult female P rats received 24-hr free-choice access to 10% (v/v)
      ethanol and water for 6 weeks. Rats were then randomly assigned to five groups
      deprived of ethanol for 0 (control), 2, 4, 6, or 8 weeks (W). All deprived groups
      were then given 24-hr access to ethanol for 2 weeks before being deprived of
      ethanol for another 2 weeks. RESULTS: After the initial ethanol deprivation
      period, the deprived groups displayed a similar 2-fold ADE (e.g., 4-W group; 4.6
      +/- 0.5 for baseline vs. 10.5 +/- 0.3 g/kg/day for the 1st reinstatement day)
      during the initial 24-hr period. Ethanol consumption began to return to control
      levels 48 (7.1 +/- 0.4 g/kg/day) and 72 (6.4 +/- 0.4 g/kg/day) hrs later. In
      addition, each deprived group showed increases in the ratio of ethanol/total
      fluid intake upon reinstatement, and there was a tendency for sustained higher
      ethanol intake ratios during the first 3 postexposure days for the 4-, 6-, and 8
      W groups, but only during the first 2 reinstatement days for the 2-W group. The
      second deprivation did not increase the magnitude of the ADE over that observed
      in the first deprivation during the initial 24-hr period of re-exposure, but it
      did prolong the duration of the ADE into the 2nd and 3rd reinstatement day for
      the 2-, 4-, and 6-W groups and into the 5th reinstatement day for the 8-W group.
      CONCLUSIONS: Equivalent robust ADEs can be seen in P rats with deprivation
      periods of 2-8 W, which suggests that the ADE has a rapid onset and is not
      affected by the durations of deprivation that were tested. The duration of the
      ADE was prolonged in P rats exposed to a second deprivation period, suggesting
      that factors associated with the ADE phenomenon could be strengthened by repeated
      deprivations.

PMID- 10656187
TI  - Quantitative trait loci affecting ethanol sensitivity in BXD recombinant inbred
      mice.
AB  - BACKGROUND: Genetic and environmental factors contribute to an individual's
      sensitivity to ethanol, although the exact genes underlying ethanol's effects are
      not known. Quantitative trait locus (QTL) mapping is one successful method for
      provisionally identifying genes participating in the mediation of a given
      behavior. QTL analyses seek to identify associations between a quantitative
      response and previously mapped marker genes across genetically diverse
      individuals. Many QTL analyses have been performed in BXD recombinant inbred (RI)
      strains of mice derived from a cross of C57BL/6J (B6) and DBA/2J (D2) progenitor
      strains. METHODS: We conducted a QTL analysis of ethanol-induced loss of righting
      reflex and ataxia using a panel of 25 BXD RI strains and the progenitors B6 and
      D2. We measured the duration of loss of righting reflex after injection and blood
      ethanol concentrations upon regaining of righting reflex. Ataxia was measured as
      the latency to fall from a vertical screen. RESULTS: Genome-wide QTL analyses
      correlating strain means with allelic status at >1500 markers identified several
      associations (p < or = 0.01). These provisional QTLs were on all chromosomes
      except 2, 5, 12, 13, and X, and several map near potential candidate genes.
      CONCLUSIONS: These results suggest that ethanol sensitivity is determined by the
      actions of multiple genes and further suggest their general chromosomal map
      locations. These provisional linkages will now be confirmed or rejected using
      additional genetically segregating populations.

PMID- 10656188
TI  - Dissociation of ethanol and saccharin preference in sP and sNP rats.
AB  - BACKGROUND: It has been proposed that ethanol intake and consumption of sweet
      tasting solutions are positively correlated in rodents. Experiment 1 of the
      present study investigated whether selectively bred ethanol-preferring (sP) and 
      nonpreferring (sNP) rats differed, consistently with the above hypothesis, as to
      saccharin intake and preference. Experiment 2 evaluated whether saccharin
      addition to the ethanol solution, likely resulting in a highly palatable fluid,
      would result in an increase in voluntary ethanol intake in sP rats. METHODS: The
      saccharin solution was offered, in free choice with water, at a fixed
      concentration of 1 g/liter for 6 consecutive days in Experiment 1A or at
      ascending concentrations (0.002 to 16.4 g/liter, doubling the concentration every
      day) in Experiment 1B. In Experiment 2, 1 g/liter saccharin was added to the
      standard 10% ethanol solution and offered to sP rats in free choice with water
      for 7 consecutive days. RESULTS: In both Experiments 1A and 1B, sP and sNP rats
      showed avidity for the saccharin solution with marginal line difference in
      saccharin intake and preference. In Experiment 2, daily ethanol intake remained
      stable at baseline levels (6-7 g/kg), irrespective of the saccharin addition to
      the ethanol solution. CONCLUSIONS: The results of Experiments 1A and 1B suggest
      that saccharin drinking behavior in sNP rats deviates from the hypothesis that
      saccharin and ethanol intakes may co-vary; thus, at least in sNP rats, saccharin
      and ethanol intakes do not appear to be influenced by the same genetic factors.
      The results of Experiment 2 provide further support to the existence of a central
      set-point mechanism that regulates daily ethanol intake in sP rats, likely based
      on the pharmacological effects of ethanol.

PMID- 10656189
TI  - Parental history of alcoholism and problem behaviors in Native-American children
      and adolescents.
AB  - BACKGROUND: A positive family history of alcoholism is one of the most consistent
      and powerful predictors of a person's risk for developing this disorder. This
      finding has stimulated much research on etiological vulnerability factors and
      mechanisms by which children of alcoholic parents are at high risk for developing
      alcohol-related problems. In primarily Euro-American samples, parental alcoholism
      has been associated with a variety of negative outcomes for children and
      adolescents, including problematic behavior. Native-American Indians, in addition
      to high rates of alcoholism and alcohol-related mortality, have the highest
      prevalence of a positive family history for alcoholism of all ethnic groups in
      the United States. METHODS: This study used the Achenbach Child Behavior
      Checklist (CBCL) to evaluate behavioral problems in 96 Mission Indian children
      and adolescents based on the presence or absence of parental alcohol dependence
      and sex of the offspring. RESULTS: Consistent with previous research, results
      indicated a high prevalence of a positive family history of alcoholism in these
      Native-American youths. Seventy-four percent of the offspring had either one or
      both parents with alcohol dependence (children of alcoholics). Only 7% had no
      first- or second-degree alcoholic relatives. Results indicated that sons of
      alcoholics scored significantly higher on the Total Behavior Problem scale, as
      well as the Internalizing and Externalizing scales, of the CBCL than sons of
      nonalcoholics, whereas there were no significant differences in CBCL scores
      between daughters of alcoholics and daughters of nonalcoholics. It is noteworthy
      that scores on the CBCL for Mission Indian children of alcoholics were comparable
      to scores in the published literature of children of alcoholics of other
      ethnicities. In addition, a relatively low percentage of youths were identified
      with significant levels of behavioral problems. CONCLUSIONS: These findings
      suggest that sons of alcoholics of Mission Indian heritage experience more
      problems than sons of nonalcoholics, but also suggest that Mission Indian
      children of alcoholics are not more vulnerable to behavioral problems than
      children of alcoholic parents of other ethnic backgrounds.

PMID- 10656190
TI  - Premorbid risk factors for alcohol dependence in antisocial personality disorder.
AB  - BACKGROUND: Many, but not all, types of antisocial personality disorders (ASP)
      are complicated by alcohol dependence. Therefore, some additional risk factors
      may exist for alcohol dependence co-occurring with ASP. We studied whether severe
      childhood conduct disorder and a family history of alcohol dependence are
      possible risk factors for the development of alcohol dependence in ASP. METHODS:
      The subjects were 81 male Japanese criminals diagnosed with DSM-III-R ASP.
      Relative risks of alcohol dependence for severe conduct disorder and for a
      positive family history were estimated by using a multiple logistic model.
      RESULTS: Forty-three subjects (53.0%) met criteria for DSM-III-R alcohol
      dependence. The relative risk of alcohol dependence for severe conduct disorder
      (n = 44), compared with mild conduct disorder, was 4.1; whereas the relative risk
      for a positive family history (n = 31), relative to a negative family history,
      was 1.9. Severe childhood conduct disorder was also associated with severe
      adulthood antisocial behavior and an earlier onset of alcohol dependence.
      CONCLUSIONS: The results suggest that severe childhood conduct disorder and a
      positive family history of alcohol dependence are independent premorbid risk
      factors for developing alcohol dependence among persons with ASP.

PMID- 10656191
TI  - Fetal associative learning mediated through maternal alcohol intoxication.
AB  - BACKGROUND: The aim of the present study was to analyze whether alcohol as an
      unconditioned stimulus is capable of supporting associative learning in near-term
      fetuses. METHODS: In experiment 1, we determined pharmacokinetic profiles of
      alcohol and of an aromatic substance (cineole) in amniotic fluid and maternal
      blood during late gestation. The results obtained through gas chromatographic
      analysis allowed a second experiment in which we explicitly paired peak levels of
      cineole with peak levels of alcohol in amniotic fluid and blood, by
      intragastrically administering cineole and ethanol to the dams during gestational
      days 17 through 20 (paired condition). Control groups were dams given cineole 4
      hr before commencement of an acute state of alcohol intoxication (long-delay
      group) or were only exposed to water administrations (water control group). The
      progeny were evaluated during postnatal day 16 in terms of behavioral
      responsiveness to intraorally infused solutions (cineole or alcohol presented in
      milk vehicle, or milk alone). RESULTS: Mouthing responsiveness to cineole was
      strongly affected by the nature of prenatal treatments. Pups in the paired
      prenatal condition mouthed significantly less than did long-delay and water
      controls. Physical and behavioral measures allowed us to reject the possibility
      that these effects were due to teratogenic effects of alcohol during late
      gestation. CONCLUSIONS: These results indicate that before birth, rat fetuses are
      capable of acquiring associative memories supported by the unconditioned
      properties of alcohol. This associative memory can be expressed during infancy
      through a significant reduction in mouth movements in the presence of the
      specific orosensory cue explicitly paired with alcohol interoceptive effects in
      utero.

PMID- 10656192
TI  - Comparison of cross-sectional and daily reports in studying the relationship
      between depression and use of alcohol in response to stress in college students.
AB  - BACKGROUND: Alcohol use in response to stress in college students may be affected
      by the presence of symptoms of depression. However, this is a challenging issue
      to study due to the various methodologies used as well as the possible effect of
      depressed mood on the accuracy of self-report. This study focused on
      methodological issues as possible sources of equivocal findings regarding the
      relationship between depressed mood and alcohol use in response to stress in a
      college student population. Findings may differ when these variables are examined
      cross-sectionally versus longitudinally. METHODS: Depressed mood and alcohol
      coping were assessed both cross-sectionally and repeatedly over time in 125
      college students. Participants were assessed at baseline using a diagnostic self
      report measure of depression as well as a measure of typical coping style. In
      addition, daily measures of stress, symptoms of depression, and coping were
      completed for 45 consecutive days. RESULTS: Different relationships between
      depressed mood and alcohol coping were found when depressed individuals were
      analyzed separately from those who were not depressed. Although a significant
      correlation between daily use of alcohol coping and daily depressed mood was
      found, there were no differences between depressed and nondepressed participants
      (as assessed at baseline) on daily alcohol coping. CONCLUSIONS: These findings
      have implications for research design as well as clinical assessment regarding
      the relationships between mood and use of alcohol for coping; the findings
      suggest that cross-sectional measures of mood and alcohol use may obscure
      differences as assessed repeatedly over time. In addition, these findings support
      the utility of frequent assessment of depressive symptoms when implementing or
      evaluating programs that target coping skills in college students.

PMID- 10656193
TI  - The value of CAGE, CUGE, and AUDIT in screening for alcohol abuse and dependence
      among college freshmen.
AB  - BACKGROUND: This study attempted to (1) determine the prevalence of alcohol
      problems in college freshmen, (2) assess the performance of both the CAGE and the
      Alcohol Use Disorders Identification Test (AUDIT) questionnaires in this
      population, and (3) assess the possibility of improving the CAGE and/or AUDIT.
      METHODS: A sample of 3564 consecutive college freshmen, with a mean age of 18
      years, at the Catholic University of Leuven, (Belgium) completed, during a cross
      sectional study, a questionnaire assessing drinking behavior and identifying
      students at risk as defined by DSM-IV criteria. The questionnaire also included
      the CAGE questionnaire and the AUDIT. Calculations of sensitivity, specificity,
      negative predictive value, positive predictive value, likelihood ratios, and
      receiver operating characteristic curves for different scores of the CAGE and the
      AUDIT were performed, using DSM-IV criteria as the reference standard. RESULTS:
      The area under the receiver operating characteristic curve of the CAGE and the
      AUDIT was 0.76 and 0.85, respectively. The cutoff score of 1 for the CAGE was
      associated with a sensitivity of 42%, a specificity of 87%, a positive predictive
      value of 36%, and a negative predictive value of 90%. A score of 6 or more for
      the AUDIT gave a sensitivity of 80%, a specificity of 78%, a positive predictive
      value of 37%, and a negative predictive value of 77%. These results were related
      with a prevalence of 14.1% of alcohol problems. Replacing one question of the
      CAGE by "often driving under the influence" resulted in the CUGE (acronym for
      "cut down, under influence, guilty feelings, and eye opener"), with an area under
      the curve of 0.96, a positive likelihood ratio of 8.7, and a negative likelihood
      ratio of 0.04. CONCLUSIONS: Prevalence of alcohol problems in college students is
      confirmed to be high. When screening for alcohol problems in a college freshmen
      population, one question seems extremely important. The newly constructed CUGE
      questionnaire may improve screening efforts in students, compared with existing
      questionnaires.

PMID- 10656194
TI  - Ability of baclofen in reducing alcohol intake and withdrawal severity: I-
      Preclinical evidence.
AB  - BACKGROUND: The similarities between the pharmacological effects of the gamma
      aminobutyric acid receptor agonist, baclofen, and the alcohol-substituting agent,
      gamma-hydroxybutyric acid, led us to investigate whether baclofen was capable of
      reducing (a) ethanol withdrawal syndrome in ethanol-dependent rats and (b)
      voluntary ethanol intake in ethanol-preferring rats. METHODS: In experiment 1,
      Wistar rats were rendered physically dependent on ethanol by the repeated
      administration of intoxicating doses of ethanol for 6 consecutive days. Baclofen
      was acutely administered intraperitoneally at doses of 10, 20, and 40 mg/kg. In
      experiment 2, baclofen (0, 2.5, 5, and 10 mg/kg, intraperitoneally) was
      administered once a day for 14 consecutive days to ethanol-preferring sP rats
      that had continuous access to ethanol (10%, v/v) and water under the two-bottle
      free choice regimen. RESULTS: In experiment 1, baclofen dose-dependently
      decreased the intensity of ethanol withdrawal signs; furthermore, 20 mg/kg of
      baclofen protected from audiogenic seizures in ethanol-withdrawn rats. In
      experiment 2, baclofen selectively and dose-dependently reduced voluntary ethanol
      intake; a compensatory increase in water intake left total fluid intake virtually
      unchanged. CONCLUSIONS: These results are in close agreement with those of a
      preliminary clinical study and suggest that baclofen may constitute a novel
      therapeutic agent for alcoholism.

PMID- 10656195
TI  - Ability of baclofen in reducing alcohol craving and intake: II--Preliminary
      clinical evidence.
AB  - BACKGROUND: Accumulating evidence shows the efficacy of the gamma-aminobutyric
      acid (GABA(B)) receptor agonist baclofen in reducing alcohol intake in rats, but
      no studies have been performed in alcoholics. In the present preliminary study we
      investigated the effect of short-term baclofen administration on craving for
      alcohol, ethanol intake, and abstinence from alcohol in alcoholic individuals.
      METHODS: Ten male current alcoholic individuals were admitted to the study.
      Baclofen was orally administered for 4 weeks, at a dose of 15 mg/day refracted in
      three times per day for the first 3 days, with the dose increased to 30 mg/day
      for the remaining 27 days. Each subject was checked as an outpatient every week
      for the 4 weeks; at each visit (T0-T4) craving level was evaluated by the Alcohol
      Craving Scale (ACS), and abstinence from alcohol was assessed based on the
      individual's self-evaluation, family member interview, and the main biological
      markers of alcohol abuse. A self-reported alcohol intake was recorded as the mean
      number of standard drinks consumed per day. RESULTS: Nine subjects completed the
      study; of these, two subjects continued to drink alcohol although they
      substantially reduced their daily drinks in the first week of treatment, whereas
      seven maintained abstinence throughout the experimental period. Craving was
      significantly reduced from the first week of the drug administration (p < 0.01)
      and remained so throughout the entire treatment period. Participants also
      reported that obsessional thinking about alcohol disappeared. Values of gamma
      glutamyltranspeptidase, alanine aminotransferase, and mean cellular volume
      significantly decreased by the end of the study. Tolerability was fair in all
      participants; headache, vertigo, nausea, constipation, diarrhea, abdominal pain,
      hypotension, increased sleepiness, and tiredness were present as side effects in
      the first stage of the treatment. No participants showed craving for the drug.
      CONCLUSIONS: With the limitations of the low number of individuals evaluated and
      the open design, this preliminary clinical study supports the preclinical
      evidence on the effect of baclofen in reducing alcohol intake. The anticraving
      properties of the drug suggest a possible role of baclofen in the treatment of
      individuals with alcohol problems.

PMID- 10656196
TI  - Alcohol consumption, alcohol dependence, and all-cause mortality.
AB  - BACKGROUND: This study examined the effects of alcohol consumption and DSM-IV
      alcohol dependence on the risk of mortality. METHODS: Data from the 1988 National
      Health Interview Survey Alcohol Supplement were matched to the National Death
      Index for the years 1988 to 1995 (baseline n = 37,682 U.S. adults age > or =25
      linked to 3,586 deaths). All mortality analyses were based on proportional
      hazards models that adjusted for age, sex, race/ethnicity, marital status,
      education, income, labor force status, body mass index, smoking status, and poor
      health indicators at baseline. RESULTS: When dependence was not considered and
      all past-year abstainers were used as the reference group, both light and
      moderate drinkers exhibited a reduced risk of mortality, with hazards ratios of
      0.76 (0.68-0.84) and 0.84 (0.74-0.96). Heavy drinkers had about the same risk of
      dying as did past-year abstainers, and very heavy drinkers had an increased risk
      that was not significant (OR = 1.17, CI = 0.93-1.47). When lifetime abstainers
      were used as the reference category, the protective effect of moderate drinking
      fell short of significance, and there were nearly significant increased risks
      among former drinkers and very heavy drinkers. When dependence was considered,
      light and moderate drinkers without dependence had a reduced mortality risk
      regardless of reference group, and there was no significant effect among heavy or
      very heavy drinkers without dependence. Among dependent drinkers, there was no
      protective effect of light or moderate drinking, and very heavy drinkers had a
      significantly increased risk (OR = 1.56 relative to past-year abstainers and 1.65
      relative to lifetime abstainers). CONCLUSIONS: Because alcohol dependence
      nullifies the protective effect of light and moderate drinking, it is important
      to understand its role as an independent risk factor for mortality. Differences
      between dependent and nondependent drinkers who drank comparable amounts suggest
      that this risk may result from longer and heavier drinking histories before
      baseline, more severe health problems at baseline, more heavy episodic drinking,
      and, possibly, differences in beverage preference.

PMID- 10656197
TI  - Ethanol increases the neurotoxic effect of tumor necrosis factor-alpha in
      cultured rat astrocytes.
AB  - BACKGROUND: The central nervous system is particularly sensitive to the cytotoxic
      effect of ethanol. In vivo and in vitro studies indicate that ethanol decreases
      cell proliferation in a number of cells types, including neurons and glial cells
      in the central nervous system. The cellular mechanisms involved in ethanol
      induced cell toxicity, however, are unclear. In this study, we examined the
      effect of ethanol on tumor necrosis factor-alpha (TNFalpha)-induced cell death in
      a homogeneous population of cultured rat astrocytes. METHODS: Flow cytometric and
      3-(4,5-dimethylthiazol-2-yl)-2,5-diphenytetrazolium bromide (MTT) dye reduction
      analyses were performed on cultured rat astrocytes to determine the effect of
      alcohol on TNFalpha-induced cell death. RESULTS: Flow cytometric analysis
      revealed that, in quiescent astrocytes, high concentrations of ethanol were
      required to increase DNA fragmentation and decrease cell viability. Preexposure
      of astrocytes to low concentrations of ethanol (10 to 50 mM), however, increased
      the sensitivity of astrocytes to TNFalpha with low TNFalpha concentrations (25 to
      50 ng/ml) resulting in increased DNA fragmentation. Furthermore, MTT dye
      reduction analysis revealed that exposure of astrocytes to 5 mM ethanol was
      sufficient to increase the susceptibility of astrocytes to the cytotoxic effect
      of ethanol. In a number of cell types, TNFalpha receptor binding results in the
      activation of specific signal transduction cascades, including the hydrolysis of
      sphingomyelin to ceramide. We show that preexposure of astrocytes to a low
      concentration of ethanol increased the sensitivity of astrocytes to
      sphingomyelinase, and C2-ceramide resulting in increased DNA fragmentation and
      decreased cell viability. More importantly, astrocytes prepared from rats exposed
      to ethanol prenatally showed increased susceptibility to TNFalpha-induced cell
      death. CONCLUSIONS: These studies suggest that ethanol increases the
      susceptibility of astrocytes to TNFalpha-induced cell death by shifting the
      balance of sphingolipid metabolism in favor of a pathway that increases the
      susceptibility of astrocytes to the cytotoxic effect of TNFalpha.

PMID- 10656198
TI  - Differential effects of ethanol on signal transduction.
AB  - BACKGROUND: PC12 pheochromocytoma cells were used as a model to study the effect
      of long-term ethanol exposure on signal transduction systems. In PC12 cells, the
      agonist bradykinin stimulates a phospholipase C specific for inositol-containing
      phospholipids and a phospholipase D specific for phosphatidylcholine. METHODS:
      PC12 cells were grown in monolayer and cultured in the presence and absence of 1%
      ethanol for 5 days. After this period, bradykinin-stimulated phospholipase C and
      D were measured. The effect of long-term ethanol on the bradykinin-mediated
      activation of mitogen-activated protein (MAP) kinase was also measured. RESULTS:
      In cells exposed to 1% ethanol for 5 days, bradykinin-stimulated phospholipase D
      was greatly attenuated, whereas bradykinin-stimulated phospholipase C was not
      altered. The tyrosine kinase inhibitor, genistein, blocked the bradykinin
      mediated activation of phospholipase D but did not affect the stimulation of
      phospholipase C. However, long-term ethanol treatment did not attenuate the
      ability of bradykinin to activate MAP kinase, which suggests that ethanol did not
      have a general effect on all tyrosine kinase pathways. CONCLUSIONS: Ethanol has a
      differential effect on signal transduction in PC12 cells. Activation of
      phospholipase D may be mediated by a kinase, whereas the activation of
      phospholipase C is probably mediated by the guanine nucleotide binding protein,
      Gq. Because of these differences in activation mechanism, the pathways may adapt
      differently to long-term exposure to ethanol.

PMID- 10656199
TI  - Genetic and developmental modulation of cardiac deficits in prenatal alcohol
      exposure.
AB  - BACKGROUND: Increasing evidence demonstrates that genetic background is an
      important modulator of alcohol's effects on the developing fetus. Such effects
      are separable from maternal ethanol metabolism. Here, we study ethanol's effects
      on cardiogenesis in an avian model that shows strong cell death within neuronal
      and neural crest precursors following ethanol exposure. METHODS: The study design
      tested the hypothesis that ethanol-induced losses of cardiac neural crest
      populations would disrupt outflow tract development and thus contribute to the
      valvuloseptal deficits observed in prenatal alcohol exposure. Three chick strains
      were exposed to alcohol at gestational windows between gastrulation and early
      heart septation (day 3 incubation), and then hearts were examined at the
      completion of morphogenesis (day 10 incubation). RESULTS: Ethanol's impact on
      cardiac development was influenced by fetal genetics. The B300 x Hampshire Red
      cross exhibited pronounced cell death within cardiac neural crest populations but
      had normal development of the heart and aortic arches. Neural crest migration and
      differentiation into the distal outflow tract were also normal in these embryos,
      which suggested a capacity to repair earlier losses. The DeKalb White x Hampshire
      Red cross also did not exhibit cardiac defects. Hearts of the B300 strain had a
      unique phenotype with respect to ethanol exposure and exhibited a thin
      ventricular compact layer, dilatation, and reduced myosin/deoxyribonucleic acid
      and myosin/protein content, a phenotype that indicates disrupted myocardial
      maturation and inductive cues. The deficit was only observed when ethanol
      exposure occurred at stages 15 or 18 and apparently was independent of neural
      crest cell death. Such ventricular thinning might go undetected in the absence of
      extensive screening. CONCLUSIONS: Results add to the increasing evidence that
      genetic background strongly modulates the effects of prenatal alcohol exposure.
      The results also suggest that embryos have a varying capacity to repair and
      recover from earlier neural crest losses.

PMID- 10656200
TI  - Prolonged exposure to intermittent alcohol vapors blunts hypothalamic
      responsiveness to immune and non-immune signals.
AB  - BACKGROUND: We have previously shown that long-term alcohol treatment blunts the
      ACTH response to alcohol itself, as well as to other stresses, and is accompanied
      by decreased pituitary responsiveness to vasopressin (VP), but not corticotropin
      releasing factor (CRF). The present work aims to determine the relevance of
      changes in CRF and VP receptors in the pituitary gland and/or peptide stores of
      CRF neurons in the paraventricular nucleus (PVN) of the hypothalamus, the areas
      that are most directly involved in ACTH release. METHODS: Intact male rats were
      exposed to alcohol using a new vapor delivery system which enables individual rat
      housing in boxes. Alcohol treatment was delivered for 6 hr once daily (0700
      1300), after which the rats were returned to their home cages where they had free
      access to food and water. Control rats were kept in similar boxes, but not
      exposed to alcohol. Total treatment time was 8 days. All animals were equipped
      with indwelling jugular cannulae that were used to monitor blood alcohol levels
      (BALs) as well as ACTH and corticosterone release throughout drug exposure. Due
      to the presence of a swivel, the animals' movements were not restricted or
      hindered by the presence of these cannulae. On the morning of day 9, the animals
      were decapitated under basal conditions or exposed to a neurogenic (mild
      electrofootshocks) or systemic [i.v. lipopolysaccharide (LPS)] stimulus. PVN
      neuronal responses, indicated by changes in mRNA concentrations of the immediate
      early genes (IEGs) c-fos and NGFI-B, and plasma ACTH levels were measured before
      and during endotoxemia or electrofootshocks. RESULTS: In the absence of alcohol,
      plasma ACTH and corticosterone remained at basal levels, indicating the absence
      of environment-induced stress. In rats exposed to alcohol, BALs were consistent
      and predictable, and we targeted peak values of about 200 mg%. At the end of the
      drug treatment period, there were no significant differences between CRF and VP
      receptor mRNA levels in the anterior pituitary of control and alcohol-treated
      rats. In contrast, alcohol treatment respectively decreased CRF and increased VP
      stores in the external zone of the median eminence. It also increased NGFI-B and
      c-fos transcripts in the magnocellular (m) portion of the PVN, but not the
      parvicellular (p) division of this nucleus under basal conditions (i.e., in the
      absence of shocks or LPS). After exposure to these stressors, on the other hand,
      all groups of rats showed significant increases in plasma ACTH levels as well as
      up-regulation of their PVN neuronal response, as indicated by changes in pPVN
      IEGs transcripts. However, these hormonal and neuronal responses were
      significantly blunted in animals pretreated with alcohol. CONCLUSIONS:
      Collectively, our results suggest that decreased PVN neuronal activation
      represents an important mechanism of the ability of long-term alcohol treatment
      to blunt the ACTH response to shocks or endotoxemia. In addition, the new system
      of alcohol delivery that we developed is practical and reliable, and has the
      significant advantage that it enables measurement of circulating hormone levels
      during drug exposure of the animals.

PMID- 10656201
TI  - Vegetable proteins: are they nutritionally equivalent to animal protein.
AB  - On the basis of the rate of animal growth, proteins have been traditionally
      classed as high quality, such as egg and milk protein, or low quality such as
      gluten. In general, vegetable proteins are of low quality but soy protein is an
      exception. The paper by Capristo et al. in this issue of the journal has shown
      that enteral formulations consisting of soy protein are as effective
      nutritionally as enteral formulations containing milk protein.

PMID- 10656202
TI  - Patients, doctors and knowledge.

PMID- 10656203
TI  - Effect of a vegetable-protein-rich polymeric diet treatment on body composition
      and energy metabolism in inactive Crohn's disease.
AB  - OBJECTIVE: Since malnutrition and lactose intolerance are frequently reported in
      Crohn's disease (CD), we evaluated the differences in terms of compliance-to
      treatment and nutritional status in inactive CD patients after two different
      treatments using either a standard polymeric diet or a vegetable-protein-rich and
      lactose-free diet. STUDY DESIGN: A case-control study. SUBJECTS: Forty CD
      patients with inactive disease were randomly divided into two groups. Group A (10
      men; aged 33.9+/-7.2 years; BMI, 21.8+/-1.7 kg/m2) received a conventional
      polymeric enteral diet, while group B (10 men; aged 35.6+/-6.8 years; BMI, 21.4+/
      1.8 kg/m2) was administered a soy-rich and lactose-free polymeric diet, over a 4
      week period. METHODS: All the patients had a clinical and laboratory examination.
      Body composition was assessed by isotopic dilution and resting metabolic rate
      (RMR), and substrate oxidation rates were measured by indirect calorimetry.
      RESULTS: Body weight significantly increased after treatment in both groups (A,
      P<0.05; and B, P<0.01), as well as fat-free mass (A, P<0.05; and B, P<0.05) and
      fat mass (A, P<0.05; and B, P<0.01). RMR slightly increased, although it did not
      reach statistical significance. Treatment did not influence substrate oxidation
      rates. Group B lactose-intolerant patients reported a greater compliance-to
      treatment than those in group A. CONCLUSIONS: This study showed that a polymeric
      enteral diet rich in vegetable protein and not containing milk protein, eaten at
      home, with no need for positioning a nasogastric tube, significantly improved
      body composition in inactive and lactose-intolerant CD patients, with no effect
      on energy metabolism, suggesting that it could be useful in improving nutritional
      status in these patients.

PMID- 10656204
TI  - IOIBD questionnaire on the clinical use of azathioprine, 6-mercaptopurine,
      cyclosporin A and methotrexate in the treatment of inflammatory bowel diseases.
AB  - OBJECTIVE: To obtain information on the clinical experience with azathioprine
      (AZA), 6-mercaptopurine (6-MP), cyclosporin A (CyA) and methotrexate (MTX) in the
      treatment of patients with inflammatory bowel disease (IBD) by
      gastroenterologists and internists in different countries. DESIGN: A
      questionnaire designed by the International Organization for the Study of
      Inflammatory Bowel Disease (IOIBD) was mailed to 300 gastroenterologists, living
      in North America (n = 76) and Europe (n = 224) (12 countries), to obtain
      information on clinical experience. PARTICIPANTS: More than half of the
      respondents (168/298; 56.4%) worked in university hospitals and 58/298 (19.5%) in
      general (non-university) hospitals. Two-thirds (65%) had more than 10 years'
      experience in gastroenterology. RESULTS: The respondents had personal experience
      with AZA (88.4%), 6-MP (33.3%), CyA (48.7%) and MTX (36.3%). AZA was prescribed
      more frequently in Europe (92.6%) than in North America (74.2%) (P = 0.0002), 6
      MP less frequently by the European than the North American respondents (23.8 and
      53.3% respectively, P = 0.0001). Two-thirds (69.7%) usually prescribed AZA
      together with steroids to Crohn's disease patients; 62.4% of the respondents
      prescribed AZA for periods longer than 24 months. For ulcerative colitis, 77.9%
      had experience with AZA (Europe > North America, P = 0.0001). AZA had been
      prescribed by 69 respondents to pregnant patients, without apparent toxicity.
      Acute pancreatitis had been observed after AZA by 56.7% respondents; 25
      malignancies were mentioned (six lymphoma, three leukaemia, three colon cancer,
      four renal carcinoma, nine others). CyA had been prescribed in acute ulcerative
      colitis by 140/291 respondents (North America 45.1%, Europe 49.1 %); of all
      respondents 63.9% treated < 5 patients with CyA, 36.1% 6-20 cases. CyA results
      were considered good in 29.5%, acceptable but with recurrences in 58.6%, and poor
      in 14.3%. MTX was prescribed in North America by 47.8% of the respondents, and by
      33.9% in Europe (not significant). Several significant differences were observed
      between the prescription behaviour of respondents working at university hospitals
      and non-university hospitals, in particular in relation to participation in
      clinical trials. CONCLUSIONS: Considerable experience exists in the use of
      immunosuppressive therapy in IBD; however, differential prescription behaviour
      exists in the choice of immunosuppressives between North America and Europe.
      These IOIBD study results may contribute to a better insight in the daily use of
      immunosuppressive agents in IBD by gastroenterologists and other specialists.

PMID- 10656206
TI  - Early determinants of inflammatory bowel disease: use of two national
      longitudinal birth cohorts.
AB  - OBJECTIVE: To examine previously cited early risk factors for inflammatory bowel
      disease. DESIGN: The 1946 National Survey of Health & Development (NSHD) and the
      1958 National Child Development Study (NCDS) are on-going, longitudinal birth
      cohort studies. A nested case-control design was used combining data from both
      cohorts; eight controls per case, matched for gender and social class, were
      selected randomly. METHODS: Data concerning maternal infection in pregnancy (NCDS
      only), childhood infection (measles, mumps and whooping cough), birth order,
      appendicectomy, breast-feeding and measures of poor housing conditions in
      childhood were analysed. In both cohorts, the member's hospital physician or
      medical records were used to confirm the diagnosis. RESULTS: Twenty-six cases of
      Crohn's disease and 29 cases of ulcerative colitis were identified. No
      significant association was found between the development of Crohn's disease or
      ulcerative colitis and any of the studied factors. There was a trend that those
      with Crohn's disease were more likely not to have been breast-fed (OR 0.4, 95% CI
      0.15-1.03) and not to have had an appendicectomy (OR < 1.00). The opposite was
      true of those with ulcerative colitis (OR 2.76, 95% CI 0.86-9.81 and OR 2.34, 95%
      CI 0.69-7.46, respectively). The prevalence of inflammatory bowel disease was
      5.12/1000 by the age of 43 years in NSHD and 2.02-2.54/1000 by the age of 33
      years in NCDS. CONCLUSIONS: The prevalence of inflammatory bowel disease in these
      cohorts is among the highest recorded in Europe. Childhood factors may be
      different for those with Crohn's disease and ulcerative colitis. These cohorts
      will be increasingly valuable data sources.

PMID- 10656205
TI  - Increase of bone mineral density with sodium fluoride in patients with Crohn's
      disease.
AB  - BACKGROUND AND AIMS: Low bone density with an increased risk of vertebral
      fractures is a frequent complication in inflammatory bowel disease. Since the
      aetiology of osteopathia in these patients is different compared to
      postmenopausal or steroid-induced osteoporosis, no treatment strategy is
      established. Supplementation of calcium and vitamin D has been shown to prevent
      further bone loss, but no data are available showing the anabolic effect of
      sodium fluoride in Crohn's disease. METHODS: We carried out a one-year
      prospective clinical trial in 33 patients with chronic active Crohn's disease who
      were randomly assigned to receive either calcium (500 mg b.i.d.) and 1000 IU
      vitamin D3 only, or retarded-release sodium fluoride (25 mg t.i.d.) additionally.
      The diagnosis of Crohn's disease had been made at least two years ago, and all
      patients had received systemic high-dose steroid therapy during the previous
      year. Eleven of 15 patients who received calcium/vitamin D and 15 of 18 patients
      who additionally received sodium fluoride completed the study. The primary
      endpoint of the study was the increase of bone mineral density, measured by dual
      energy X-ray absorptiometry (DXA) after one year of treatment. Bone-specific
      alkaline phosphatase and osteocalcin were used as markers for bone turnover.
      RESULTS: In the calcium/vitamin D only group, bone density was not significantly
      changed after one year of treatment, whereas in the calcium/vitamin D/fluoride
      group, bone density of the lumbar spine increased from -1.39+/-0.3 (Z-score, mean
      +/- SEM) to -0.65+/-0.3 (P<0.05) after one year of treatment. Increase of bone
      density was positively correlated to the osteoblastic markers bone-specific
      alkaline phosphatase (r = 0.53) and osteocalcin (r = 0.43). CONCLUSIONS: Sodium
      fluoride in combination with vitamin D and calcium is an effective, well
      tolerated and inexpensive treatment to increase lumbar bone density in patients
      with chronic active Crohn's disease and osteoporosis.

PMID- 10656207
TI  - Inflammatory bowel disease in Iceland, 1990-1994: a prospective, nationwide,
      epidemiological study.
AB  - BACKGROUND: Two separate nationwide, retrospective epidemiological studies of
      inflammatory bowel disease (IBD) in Iceland over a combined 40-year period, 1950
      1989, have shown a continually rising incidence. The main objective of this study
      was to investigate the incidence of IBD prospectively for the 5-year period 1990
      1994 to determine whether there still was an ongoing increase. METHODS: The
      retrieval of new cases of ulcerative colitis (UC) and Crohn's disease (CD) was
      based on a monthly review of all small and large intestinal tissue specimens with
      any type of inflammation submitted to all three departments of pathology in
      Iceland. All small intestinal X-ray records suggestive of CD were also reviewed.
      All possible new cases of IBD were then scrutinized by examination of the
      clinical records, using accepted criteria for confirmation or exclusion of IBD.
      RESULTS: A total of 215 cases of UC and 72 cases of CD were diagnosed, yielding a
      mean annual incidence for UC 16.5/100000 (95% confidence interval (CI) 14.4
      18.9), and for CD 5.5/100000 (95% CI 4.3-7.0). The highest combined age related
      incidence for UC was 28.7/100000 in the group aged 30-39 years, and for CD
      8.5/100000 in the groups aged 10-19 and 20-29 years. The most common extent in UC
      was proctosigmoid and the most frequent localization in CD was colonic only.
      CONCLUSIONS: This prospective study demonstrates a continuing and statistically
      significant increase in the incidence of both UC and CD in Iceland. The general
      changes identified for a few previously suggested environmental factors do not
      allow any firm conclusions as to their role in the observed increase in
      incidence. It is possible that there are some other causative factor(s).

PMID- 10656208
TI  - Patient knowledge and educational needs in irritable bowel syndrome.
AB  - OBJECTIVE: Educating patients with irritable bowel syndrome (IBS) about their
      disorder may promote a strong physician-patient interaction, is a recommended
      approach for treating mild IBS and may reduce healthcare use. Our aim was to
      identify the information needs, levels and associated factors in IBS, and to
      contrast this with patients with inflammatory bowel disease (IBD). DESIGN:
      Seventy adult IBS patients (Rome criteria) were prospectively recruited, together
      with 82 ulcerative colitis (UC) and 60 Crohn's disease (CD) patients. Demographic
      data, clinical data, and anxiety and depression scores (HAD scale) were recorded.
      Patients rated their perceived levels of disease knowledge and satisfaction with
      their knowledge level on visual analogue scales. Qualitative data on disease
      information needs were obtained by an open-ended question. SETTING:
      Gastroenterology out-patient clinic. RESULTS: The majority of IBS patients (77%;
      n = 54) and over half of IBD patients (56%; n = 79) required further information
      about their disease. The primary issues for IBS patients were bowel cancer risk
      and diet. Queries about medications ranked top for UC, while prognosis and cancer
      risk jointly ranked top for CD. In the IBS group, 27% rated their knowledge as <
      25 out of 100 compared to 10% of IBD patients. The perceived level of knowledge
      in IBS was significantly negatively associated with length of hospital consulting
      (r(s) = -0.32; P = 0.04). CONCLUSION: Most IBS patients feel insufficiently
      informed, particularly in relation to risk of serious disease and role of diet.
      Educating IBS patients about their disorder may play a role in reducing
      healthcare use.

PMID- 10656209
TI  - A novel method for detecting IgA endomysial antibodies by using human umbilical
      vein endothelial cells.
AB  - BACKGROUND: Although tissue transglutaminase was recently identified as the main
      autoantigen recognized by endomysial antibodies in coeliac patients, anti
      endomysium antibody detection still persists as the gold standard for coeliac
      disease screening and diagnosis. OBJECTIVES: (1) To evaluate human umbilical vein
      cells (HUVEC) as an alternative source of endomysial antigen and to assess their
      suitability in the diagnosis of coeliac disease. (2) To verify whether tissue
      transglutaminase is one target antigen eliciting the endomysial antibody fraction
      of coeliac serum IgA. SETTING: University teaching hospital. PATIENTS AND
      METHODS: Sera from 123 untreated adults with biopsy-proven coeliac disease and 84
      controls (40 healthy and 44 diseased) were assessed by indirect
      immunofluorescence, using HUVEC on glass slides prepared by cytocentrifugation
      and permeabilized by using Triton X (0.5%). Indirect immunofluorescence was
      performed: (1) using coeliac disease serum samples on HUVEC with or without prior
      incubation with tissue transglutaminase; and (2) incubating both HUVEC and monkey
      oesophagus with goat anti-guinea pig tissue transglutaminase antibody. RESULTS:
      All the coeliac patients, who were also positive on monkey oesophagus, showed the
      typical fluorescent homogeneous cytoplasmic stain on HUVEC. All control sera were
      negative both on HUVEC and on monkey oesophagus. IgA antibodies did not react
      with non-permeabilized cells, with intact membrane. Preincubation of coeliac sera
      with tissue transglutaminase abolished the typical fluorescent pattern. The
      incubation of anti-tissue transglutaminase antibody with monkey oesophagus and
      HUVEC resulted in an immunofluorescence staining pattern identical to that
      obtained with positive coeliac sera. CONCLUSIONS: (1) As a substrate for anti
      endomysial antibody, HUVEC may provide the same diagnostic accuracy as monkey
      oesophagus, thus bypassing economical and ethical problems. The HUVEC antigen
      reacting with IgA from coeliac disease sera is an intracellular rather than a
      cell-surface antigen, as IgA antibodies reacted only with permeabilized cells.
      (2) Pretreatment of untreated coeliac sera with tissue transglutaminase abolished
      almost completely the specific staining; incubation with anti-tissue
      transglutaminase antibody elicited the characteristic fluorescent pattern, thus
      confirming that tissue transglutaminase represents the prominent autoantigen in
      coeliac disease.

PMID- 10656210
TI  - Should relatives of coeliacs with mild clinical complaints undergo a small-bowel
      biopsy despite negative serology?
AB  - BACKGROUND AND OBJECTIVES: Small intestinal lesions in coeliac disease (CD) have
      a variable severity. Early diagnosis of CD is important because treatment allows
      a normal psycho-physical development, especially in children, and can avoid
      associated disorders. The aim of this study was to evaluate the predictive value
      of screening parameters for the detection and estimation of CD prevalence in
      first-degree relatives. METHODS: The screening was performed in 338 first-degree
      relatives of 134 coeliac families. Questionnaires and a physical examination
      followed by haematological analyses and serologyfor IgA anti-endomysium (EMA)/IgA
      antigliadin (AGA) antibodies were used in orderto selectthe candidates for small
      bowel biopsy. The small-bowel biopsy was indicated on the basis of clinical
      complaints, laboratory tests and serology performed in 96 (28%) of the study
      group. RESULTS: CD was diagnosed in 17/96 cases. Six of the 17 showed total
      villous atrophy (VA) (Marsh IIIc), five subtotal VA (Marsh IIIb) and six partial
      VA (Marsh IIIa). EMA and AGA were strongly positive in the six patients whose
      intestinal biopsy showed total VA. However, only one coeliac out of the six
      patients with partial VA had positive EMA and AGA. CONCLUSION: A significant
      proportion of coeliacs may be missed if cases are screened by serology only.
      Although endomysial antibody assay has been reported as a highly sensitive and
      specific test for detection of CD, we argue that using only EMA and AGA in
      screening is not enough for investigation of the true prevalence of CD. A
      combination of clinical parameters as described in this study and
      laboratory/serological tests is an important and practical contribution to
      improving the detection rate of CD.

PMID- 10656211
TI  - Endomysial antibody production is not related to histological damage after in
      vitro gluten challenge.
AB  - OBJECTIVE: To determine whether in vitro induction of endomysial antibodies is an
      in vitro marker of coeliac toxicity. DESIGN: To determine whether in vitro
      endomysial antibodies induced by gliadin incubation correlate with histological
      damage induced by in vitro gliadin challenge. METHODS: Small-bowel organ cultures
      from seven patients with treated coeliac disease were incubated in an organ
      culture system with gliadin; histological damage was morphometrically evaluated
      and endomysial antibodies were measured in the organ culture supernatant by
      indirect immunofluorescence. RESULTS: Although incubation with gliadin caused
      histological damage, there was no detectable production of endomysial antibody.
      CONCLUSIONS: In vitro, endomysial antibody induction cannot be used as a marker
      of coeliac toxicity. Endomysial antibodies are not necessary for generating the
      histological lesion of coeliac disease.

PMID- 10656212
TI  - Hepatocellular carcinoma in Belgium: clinical and virological characteristics of
      154 consecutive cirrhotic and non-cirrhotic patients.
AB  - OBJECTIVE: This study analyses the characteristics of patients with
      hepatocellular carcinoma (HCC) in a low endemic area with special emphasis on the
      differences between cirrhotic and non-cirrhotic patients. DESIGN AND SETTING: The
      files of 154 consecutive patients with HCC observed in a single tertiary care
      hospital have been investigated to determine epidemiological parameters and
      diagnostic procedures. RESULTS: Compared to non-cirrhotic cases, cirrhotic
      patients with HCC are older and have a more pronounced male predominance. Their
      disease is more advanced, they usually present with multi-focal tumours, rarely
      located in the left liver lobe. Antibodies to hepatitis C (anti-HCV) are present
      in 55%, 52% ever had contact with hepatitis B (HBV) and 31% were hepatitis B
      surface antigen (HBsAg)-positive. Six non-cirrhotic cases were anti-HCV-positive.
      alpha-Fetoprotein (AFP) elevation > 50 and > 400 microg/l was more frequently
      observed in cirrhotic patients with HCC (P = 0.016). A striking association was
      found between enhanced AFP levels and the presence of anti-HCV (P = 0.0006),
      while no such relation existed for AFP and HBV markers. The sensitivity of a
      'routine' ultrasound examination is disappointing for the early detection of HCC
      in cirrhotic patients. CONCLUSIONS: In our hospital, in a low endemic area for
      HCC, we have a surprisingly high proportion of non-cirrhotic patients with HCC
      (40%). In cirrhosis, usually the consequence of alcohol abuse or hepatitis B or
      C, small tumours can be missed by ultrasonography if not specifically looked for.
      AFP levels are particularly elevated in hepatitis C-induced HCC.

PMID- 10656213
TI  - Increased incidence of anti-cardiolipin antibodies in patients with hepatitis C
      is not associated with aetiopathogenetic link to anti-phospholipid syndrome.
AB  - OBJECTIVE: Chronic infection with hepatitis C virus (HCV) has been found to be
      associated with various diseases known as extra-hepatic manifestations of HCV.
      Recently, HCV has been implicated as a cause of the antiphospholipid syndrome
      (APLS). We conducted a study in a well-characterized area for epidemiological and
      prospective studies in the north-western part of Greece in order to address
      whether an aetiopathogenesis exists between HCV and APLS. DESIGN: Seventy-five
      patients with chronic hepatitis C were investigated for the presence of anti
      cardiolipin antibodies (anti-CL) and for a past medical history supportive to the
      diagnosis of APLS. In addition, 24 patients with well-defined APLS (primary or
      secondary) and 12 patients with systemic lupus erythematosus (SLE) were tested
      for the presence of markers of HCV infection (anti-HCV and HCV RNA). The SLE
      patients were anti-CL-positive but none of them had developed any of the known
      clinical features of APLS. In addition, 267 healthy subjects were investigated
      for the presence of anti-CL. METHODS: IgG and IgM anti-CL were determined by a
      quantitative isotype-specific solid phase enzyme-linked immunosorbent assay set
      up in our laboratory. Anti-HCV was determined using a third-generation enzyme
      immunoassay and a confirmatory third-generation recombinant immunoblot assay.
      Active virus replication was defined by the detection of HCV RNA using a
      combination assay based on a reverse transcriptase polymerase chain reaction and
      a DNA enzyme immunoassay. RESULTS: Of the HCV patients, 37.3% had IgG and/or IgM
      anti-CL (P<0.00005 compared to healthy controls (2.25%)). However, the mean
      titres of each specific isotype were significantly lower in HCV patients compared
      with those found in the APLS patients (P<0.05 for IgM and P<0.001 for IgG
      isotypes). The mean titres of IgG anti-CL were also significantly lower in HCV
      patients compared with those found in the SLE patients (P<0.01). All patients
      with APLS or SLE (n = 36) tested negative for HCV infection markers. In addition,
      neither thrombotic events nor thrombocytopenia were associated with a positive
      anti-CL test in HCV patients. CONCLUSIONS: A significant proportion of HCV
      patients (37.3%) had detectable anti-CL of low titre. However, this finding was
      not associated with the development of APLS. On the other hand, none of the APLS
      patients was positive for HCV. Taken together, our data rather failed to reveal
      an aetiopathogenetic link between HCV and APLS. For this reason, testing for HCV
      in patients with APLS or follow-up for the possibility of the development of APLS
      in HCV patients cannot be suggested, at least in Greek patients. More prospective
      studies of longer duration are required in order to address whether HCV is
      involved or not in the aetiopathogenesis of APLS.

PMID- 10656214
TI  - Cancer of the ampulla of Vater: results of a 20-year population-based study.
AB  - BACKGROUND: Relatively little attention has been given to the epidemiology and
      management of cancer of the ampulla of Vater. SETTING: A series of 111 patients
      with a cancer of the ampulla of Vater diagnosed over a 20-year period (1976-1995)
      in a well-defined French population was used to analyse its incidence, management
      and prognosis as well as to determine time trends. Prognosis was determined by
      using crude and relative survival rates. Factors predictive of survival were also
      identified using a relative survival model in a multivariate analysis. RESULTS:
      Age-standardized incidence rates were 3.8 per 1000000 inhabitants in men and 2.7
      per 1000000 inhabitants in women. Incidence increased over time in men from 1.9
      during the first period (1976-1980) to 5.9 during the last period (1991-1995). In
      women, incidence rates remained stable. A resection for cure was performed in 52
      cases (48.1%). Overall, 9.9% of these cancers were classified TNM stage I and
      54.1% stage IV. There was no significant variation in treatment modalities and in
      stage at diagnosis over the study period. The overall operative mortality rate
      was 7.5%. Relative survival rates were 58.9% at 1 year, 30.9% at 3 years and
      20.9% at 5 years. Five-year relative survival rates varied from 72.8% in TNM
      stage I cancers to 6.6% in TNM stage IV cancers. Age, treatment procedure and
      stage at diagnosis significantly influenced the prognosis of cancer of the
      ampulla of Vater. In a multivariate analysis, stage at diagnosis remained the
      major prognostic factor (P<0.01). CONCLUSIONS: Although its incidence is
      increasing in men, cancer of the ampulla of Vater remains a rare tumour in both
      sexes. No improvements in the management and care of patients have been achieved.
      Further studies are needed to enhance the understanding of this cancer.

PMID- 10656215
TI  - Protective effect of the nitric oxide donor molsidomine on indomethacin and
      aspirin-induced gastric injury in rats.
AB  - OBJECTIVE: To study the effect of the nitric oxide donor, molsidomine, on gastric
      and duodenal injury induced by indomethacin and aspirin. METHODS: Sprague-Dawley
      rats weighing 180-200 g were used after 24 h fasting. Indomethacin (5 mg/kg) was
      given subcutaneously as a single dose and followed by multiple injections of
      histamine. Molsidomine (0.05 mg/kg) or distilled water was given by gavage 30 min
      before indomethacin and repeated at 3 h intervals for two doses. Rats were killed
      2 h after the last dose of molsidomine. Aspirin (500 mg/kg) was given by gavage
      and repeated 2.5 h later. Molsidomine or distilled water was given 30 min before
      the initial aspirin dose and repeated after 2 h. Animals were killed 2.5 h after
      the second dose of aspirin. The severity of the gastric mucosal damage was graded
      from 0 to 3, and the duodenal bulb ulcer surface area calculated by two
      independent observers using a dissecting microscope. RESULTS: Indomethacin and
      aspirin resulted in significant gastric mucosal damage with median scores of 2
      (interquartile ranges 1.4-3, n = 16 and 2-3, n = 10, respectively). Molsidomine
      significantly ameliorated indomethacin- and aspirin-induced damage with median
      scores of 1 (interquartile ranges 0.5-1.5, n = 19 and 0.6-1.9, n = 10,
      respectively; P<0.008 and P<0.02, respectively (Mann-Whitney Utest)). Molsidomine
      had no effect on duodenal bulb ulcerations caused by indomethacin. CONCLUSION:
      Oral molsidomine has a protective effect on gastric mucosa against damage induced
      by ulcerogenic agents. This could have an important clinical benefit, especially
      in cardiac patients taking aspirin in addition to a nitric oxide donor such as
      molsidomine.

PMID- 10656217
TI  - The CLO test is unreliable in diagnosing H. pylori infection in post-surgical
      stomach; is there any role of H. pylori in peptic ulcer recurrence?
AB  - AIM: To evaluate the validity of the CLO test in detecting Helicobacter pylori in
      patients with gastric operation and to investigate the relationship of H. pylori
      with peptic ulcer recurrence in these patients. METHODS: In this prospective
      study, 110 consecutive patients, the majority of whom had undergone gastric
      operation for benign disease (n = 102), were included. Eighty patients (62
      males), aged 38-87 years, had had a gastrectomy (10 Billroth I, 70 Billroth II),
      and 30 patients (27 males), aged 36-73 years, had had a vagotomy (13 vagotomy
      plus gastroenterostomy, 17 vagotomy plus pyloroplasty). H. pylori was sought on
      multiple biopsy specimens, using CLO test and histology (modified Giemsa stain).
      The sensitivity, specificity, positive predictive value (PPV) and negative
      predictive value (NPV) of the CLO test were estimated using histology as 'gold
      standard'. RESULTS: Overall, 21 gastrectomy patients (26%) were H. pylori
      positive by CLO and 25 (31 %) were H. pylori-positive by histology. The estimated
      sensitivity, specificity, PPV and NPV of the CLO test, using histology as 'gold
      standard', were 68%, 91%, 77% and 86%, respectively. The CLO test was positive in
      67% of vagotomy patients (20 of 30), while 50% (15 of 30) were H. pylori-positive
      by histology. The estimated sensitivity, specificity, PPV and NPV of the CLO test
      were 87%, 53%, 65% and 80%, respectively. H. pylori prevalence by histology was
      50% in patients with vagotomy and 31% in those with gastrectomy (P = 0.0787).
      Recurrent ulcers were observed in 8/30 patients (27%) after vagotomy and in 10/72
      patients (14%) after gastrectomy. Recurrent ulcer was documented in 6/15 H.
      pylori-positive patients with vagotomy (40%), and in one of 25 H. pylori-positive
      patients with gastrectomy (4%). This difference was significant (Fisher's exact
      test, P = 0.007, relative risk 5.091, 95% CI 0.819-31.64). CONCLUSION: The CLO
      test seems to be unreliable in diagnosing H. pylori in post-surgical stomach. The
      H. pylori prevalence is higher, although not significantly, in vagotomized
      patients compared with gastrectomized patients, and in this group is closely
      related to the presence of recurrent ulcer. So, at least in this group of
      patients, it is strongly recommended to look for and eradicate H. pylori.

PMID- 10656216
TI  - 13C-octanoic acid breath test for gastric emptying measurement.
AB  - OBJECTIVES: The purpose of this multicentre study was to assess the accuracy and
      reproducibility of the 13C-octanoic acid breath test compared to scintigraphy for
      measurement of gastric emptying. METHODS: Sixty-nine healthy subjects (40 men, 29
      women; mean age 30 years, range 21-61) were studied at least once by using the
      13C-octanoic breath test. In 34 healthy subjects, gastric emptying was
      simultaneously measured by gastric scintigraphy, and the 13C-octanoic breath test
      was then repeated in 18 of these cases. Fifty-four patients (30 men, 24 women;
      mean age 46 years, range 13-74) with dyspeptic or reflux symptoms were studied
      according to the same procedure. RESULTS: The correlation between breath test and
      scintigraphic values was highly significant (r = 0.744, P<0.001). The concordance
      of results of scintigraphy and breath test (normal versus abnormal) and the
      reproducibility (Bland and Altman method) of the breath test were good (CVinter =
      24%, CVintra = 15%). As compared to scintigraphy, breath test detected an
      abnormal gastric emptying with 67% sensitivity and 80% specificity (ROC
      analysis). CONCLUSION: These results confirm the value of breath test as an
      accurate measurement of gastric emptying. Its excellent reproducibility makes it
      a method of choice for pharmacological studies. However, at least when
      scintigraphy is considered the gold standard, breath test sensitivity may be
      insufficient for the detection of gastroparesis in an individual patient.

PMID- 10656218
TI  - Seropositivity to Helicobacter pylori and CagA protein in schoolchildren of
      different ages living in urban and rural areas in southern Estonia.
AB  - OBJECTIVE: To evaluate Helicobacter pylori and CagA seropositivity in a non
      selected group of schoolchildren in southern Estonia, with reference to previous
      studies where high seroprevalence to H. pylori (87%) and anti-CagA positivity
      (63%) in an adult population from the same region were found. STUDY POPULATION: A
      total of 421 schoolchildren selected haphazardly from a random population (n =
      1018, ages 9, 12 or 15 years) and living in urban or rural areas. METHODS: H.
      pylori status was determined by evaluation of IgG antibodies against cell surface
      proteins of H. pylori, strain CCUG 17874, using standard ELISA. Anti-CagA IgGs
      were determined by ELISA using a recombinant fragment of CagA (CCUG 17874) as
      solid-phase antigen. Absorbance values > 0.3 (405 nm) were taken as a CagA
      positive result based on a study of 25 sera from H. pylori-negative children.
      RESULTS: Of the 421 subjects, 235 (56%) were H. pylori-ELISA positive, and 109
      out of the 235 (46%) were anti-CagA positive. Neither H. pylori nor CagA
      positivity were significantly different in girls and boys, or in children aged 9,
      12 or 15 years. The H. pylori prevalence rate (118/181, 65%) as well as CagA
      positivity (64/181, 35%) in rural areas were higher compared with those in towns
      (117/240, 49% and 54/240, 22%, respectively; P = 0.001 and P = 0.005).
      CONCLUSION: Of schoolchildren living in southern Estonia, 56% were seropositive
      to H. pylori. Half of them had anti-CagA antibodies. Schoolchildren living in
      rural areas were infected significantly more often with CagA-seropositive strains
      compared with those living in towns.

PMID- 10656220
TI  - Surveillance of Barrett's oesophagus: physicians' practices and review of current
      guidelines.
AB  - BACKGROUND: Endoscopic biopsy surveillance of Barrett's oesophagus is generally
      recommended. However, optimal patient selection and frequency of follow-up are
      subject to ongoing discussion. OBJECTIVE: To investigate current surveillance
      practices for Barrett's oesophagus in the Netherlands and to explore their
      concordance with the guidelines for Barrett's oesophagus surveillance as
      recommended by the International Society for Diseases of the Esophagus (ISDE).
      METHODS: An anonymous questionnaire was mailed to 269 specialist physicians
      working in the field of gastroenterology. RESULTS: The response rate was 88%
      (238/269). Most of the respondents (84%) performed regular endoscopic follow-up
      of Barrett's oesophagus. In 52%, endoscopic biopsy sampling corresponded to the
      ISDE guidelines (four-quadrant biopsies at 2 cm intervals). Agreement was 60%
      regarding the interval of surveillance for no dysplasia (every 2 years), 52%
      regarding the interval for low-grade dysplasia (every year) and 54% for
      management of high-grade dysplasia (oesophagectomy if diagnosis confirmed by a
      second pathologist or re-biopsy in the short term). When combining these three
      items, consistency with the ISDE guidelines decreased to 25%. Criteria to select
      patients for surveillance included age, presence of symptoms, length of Barrett's
      oesophagus and type of Barrett epithelium. CONCLUSIONS: The survey indicates
      widespread practice of cancer surveillance for patients with Barrett's oesophagus
      in the Netherlands. However, there is limited uniformity in the frequency and
      intensity of endoscopic histological follow-up. This variability in clinical
      practice may result from conflicting data and recommendations in the literature.
      Updated consensus is needed in this area.

PMID- 10656219
TI  - Quantitative DNA and morphometric analysis of gastroscopic brush smears by TV
      image analysis.
AB  - OBJECTIVES: To determine quantitative nuclear morpho-and densitometric
      classifiers and classification techniques for analysis of gastric, Feulgen
      stained brush smears. DESIGN: TV image analysis-based quantitative DNA and
      morphometric analysis of gastric brush smears in a prospective study. PATIENTS
      AND METHODS: Ninety-eight (11 normal, 77 gastritis (17 with intestinal
      metaplasia) and 10 adenocarcinoma) Feulgen-Schiff-stained gastric brush smears
      were analysed by TV image analysis. The classification of the smears was based on
      parallel histological examination. For standards, DNA content of lymphocyte cell
      cultures was determined by the image and by flow cytometry. From every nucleus,
      six morphometric (surface, layers, minimum diameter, maximum diameter, perimeter
      and form factor) and six densitometric (integrated optical density (IOD), average
      density, sigma density, minimum and maximum density and density range) parameters
      were simultaneously determined. The smear parameters (object cells CV, DNA index,
      2c deviation index, 5c exceeding rate, G1 -S-G2 ratio) were analysed together
      with the mean and SD values of the nuclear parameters by discriminant analysis
      and back-propagation neural networks. RESULT: The normal smears were all diploid
      and their S + G2 ratio was 15.24+/-7.75% (mean +/- SD). The gastritis smears were
      all diploid with a proliferation fraction of 20.89+/-6.75%. The tumours were
      aneuploid in eight of the ten cases with 5c exceeding rate > 6.23%, the S + G2
      fraction ratio was 34.72+/-10.12%. The mean nuclear surface area was 46+/-20,
      58+/-20 and 74+/-22 microm2 in normal, gastritis and malignant groups,
      respectively. Significant differences (P<0.05) were found in nuclear surface,
      minimum and maximum diameter, and perimeter parameters. Using linear discriminant
      analysis, 100% of the non-malignant cases and 70% of the tumour cases were
      correctly classified. Using 30 non-malignant and five malignant cases as a
      training set, the neural networks classified 95% of the remaining cases
      correctly. The DNA index increased significantly (P<0.05) in Helicobacter pylori
      positive cases compared to the negative ones. In gastritis with intestinal
      metaplasia, the proliferation ratio decreased significantly (P<0.05).
      CONCLUSIONS: The image analysis is a useful tool for quantitative gastric
      cytology. The combination of nuclear morphometric parameters and neural network
      classifiers with multivariate quantitative DNA analysis is suggested for gastric
      brush smear quantitative cytology analysis.

PMID- 10656221
TI  - Gliclazide-induced acute hepatitis.
AB  - There are few reports in the literature related to sulfonylurea-induced
      hepatotoxicity. We describe the case of acute hepatitis induced by gliclazide, a
      second generation sulfonylurea. A 60-year-old woman with diabetes mellitus (type
      2) developed an acute icteric hepatitis-like illness 6 weeks after the initiation
      of gliclazide therapy. Other causes of acute hepatocellular necrosis were
      excluded. Liver histology showed marked portal inflammation with lymphocytes,
      monocytes and eosinophils, associated with lobular inflammation (indicative of a
      histological pattern consistent with drug-induced hepatitis). The drug was
      immediately withdrawn and the patient was given glibenclamide. The patient
      recovered clinically and, in less than 4 weeks, her serum bilirubin and
      aminotransferases returned to normal levels. We believe that this is the first
      description of acute hepatitis caused by an idiosyncratic adverse reaction to
      gliclazide or to one of its metabolites. In conclusion, this case strongly
      suggests that gliclazide can induce acute icteric liver necro-inflammation which
      may be misdiagnosed clinically as acute viral hepatitis. In patients who show
      abnormal liver function tests, the immediate discontinuation of gliclazide is
      recommended.

PMID- 10656222
TI  - Aspergillus osteomyelitis after liver transplantation: conservative or surgical
      treatment?
AB  - We report on a liver transplant recipient who developed coxarthritis and lumbar
      spondylodiscitis due to Aspergillus flavus. He was treated with high-dose
      liposomal amphotericin B for 2 months followed by itraconazole. Because of
      intractable pain and severe, irreversible damage of the left hip, a Girdlestone
      resection was performed. The spondylodiscitis was treated successfully with anti
      fungal agents only, which indicates that, in the absence of neurological
      impairment, good clinical outcome can be achieved without surgery. This case
      demonstrates that surgical therapy, which is often proclaimed as unavoidable for
      the treatment of Aspergillus osteomyelitis, should be considered in particular in
      the case of intolerable pain due to irreversible joint damage or involvement of
      vital organs.

PMID- 10656223
TI  - Hereditary internal anal sphincter myopathy causing proctalgia fugax and
      constipation: further clinical and histological characterization in a patient.
AB  - Hereditary internal anal sphincter myopathy is a very rare condition, only three
      families have so far been described in the literature. In this case report
      further clinical and histological findings of one affected member of one of the
      above families are presented.

PMID- 10656224
TI  - French-Belgian Consensus Conference on Adult Gastro-oesophageal Reflux Disease
      'Diagnosis and Treatment': report of a meeting held in Paris, France, on 21-22
      January 1999. The Jury of the consensus conference.
AB  - This consensus conference followed the methodological rules developed by the
      French Agence Nationale d'Accreditation et d'Evaluation en Sante (ANAES).
      Briefly, this required an organizing committee, a working group whose task was to
      make a comprehensive critical review of the literature before the conference was
      held, a panel of experts and a jury. All the manuscripts were published in a
      special issue of Gastoenterologie Clinique et Biologique [1999; 23(suppl 1)]. The
      conference included (a) a public session with presentations by experts working in
      areas relevant to the consensus questions, (b) questions and statements from
      conference attendees, and (c) closed deliberations by the jury followed by the
      drafting of conclusions and recommendations. This paper describes those
      conclusions and recommendations.

PMID- 10656225
TI  - A paper which changed clinical practice (slowly). Jacob Holler on potassium
      deficiency in diabetic acidosis (1946).
AB  - It is often said that the introduction of insulin into clinical medicine made a
      'dramatic' difference to the mortality resulting from diabetic coma. This is true
      in the sense that before 1922 it was almost uniformly fatal, but until the 1950s
      the mortality in many large hospitals was as high as 30-50%. Often autopsy did
      not establish a cause of death. Many may have been a result of hypokalaemia, a
      complication which was not recognized until 1946; in that year in the Journal of
      the American Medical Association, Jacob Holler described a patient who developed
      respiratory paralysis 12h into treatment that, after several hours in an iron
      lung, was cured by potassium infusion. In the 5 years after Holler's paper there
      were many reports of deaths resulting from hypokalaemia, as well as several 'near
      misses', but clinicians were extremely cautious about early replacement probably,
      as an editorialist in The Lancet suggested, because 'the frightening effects of
      intravenous injections of potassium made clinicians reluctant to believe in a
      lack of potassium as a cause of trouble, except in very rare conditions such as
      familial periodic paralysis'. It had been known since 1923 that insulin lowered
      serum potassium, but this was not of great interest because the symptoms of
      hypokalaemia were not known. Also, potassium was not an electrolyte with which
      clinicians were familiar. Until the introduction of flame photometry in 1950, it
      was only measured in research studies as chemical methods took several hours to
      complete.

PMID- 10656226
TI  - Population-based genetic screening for the estimation of Type 1 diabetes mellitus
      risk in Finland: selective genotyping of markers in the HLA-DQB1, HLA-DQA1 and
      HLA-DRB1 loci.
AB  - AIMS: To improve sensitivity and specificity of the diabetes risk assessment of
      the population-based genetic screening used in the Finnish Diabetes Prediction
      and Prevention (DIPP) trial. METHODS: One thousand consecutive newborns enrolled
      in the DIPP were compared with 316 samples from children with Type 1 diabetes
      mellitus. A modification of the previously described technique based on
      hybridization of relevant PCR products with five lanthanide-labelled probes
      detected by time-resolved fluorometry (TRF) was used. A new probe was designed
      and allowed discrimination between DQB1*0602 and 0603 alleles, in addition to
      DQB1*02, *0301 or *0302, each of which required specific probes. A new, added
      screening strategy was developed for individuals carrying low-risk genotypes
      through specific typing of DQA1 *05 and *0201 alleles in DQB1*02 positive, and
      DRB1 typing for DR4 subtypes in DQB1*0302 positive subjects, with a new
      specifically designed high-resolution TRF-based DR4 subtyping technique. RESULTS:
      This two-step screening approach enhanced the sensitivity of the detection of
      genetic risk for Type 1 diabetes mellitus in this cohort up to 85.4%. In the
      general population cohort, 24.4% were identified for prospective follow-up, 2.6%
      of these are expected to develop Type 1 diabetes mellitus before the age of 15
      years. Exclusive typing for HLA-DQB1 locus as an alternative screening strategy
      had sensitivities of 26.3-77.2% with general population cohorts of 2.3-23.1%
      identified for follow-up. CONCLUSIONS: The described strategy for genetic
      prediction of Type 1 diabetes mellitus relies on the convenient genotyping
      procedure and could be applied in large scale screening projects such as DIPP.

PMID- 10656227
TI  - Endothelial dysfunction in Type 1 diabetes mellitus: relationship with LDL
      oxidation and the effects of vitamin E.
AB  - AIMS: To examine the hypothesis that increased susceptibility of low density
      lipoproteins (LDL) to oxidation predisposes to endothelial dysfunction in
      patients with Type 1 diabetes mellitus. METHODS: A cross-sectional study of 46
      non-nephropathic diabetic and 39 control subjects and in the diabetic patients, a
      3-month duration, randomized, placebo-controlled double-blind trial of vitamin E
      500 U/day. Flow-mediated vasodilatation (FMD) was measured in the forearm by high
      resolution ultrasound. LDL oxidation by Cu2+ was measured in vitro. RESULTS:
      Diabetic patients had greater basal and reactive forearm blood flow (geometric
      mean (SD%) flow (ml/min) 110.15 (19.19%) vs. 74.99 (23.17%); P=0.045, and 344.35
      (20.84%) vs. 205.17 (21.48%); P=0.007), compared with controls, but there was no
      difference in FMD (median (interquartile range) 0.00 (-0.01-0.02) vs. 0.02 (-0.01
      0.02) cm2; P=0.78). Diabetic LDL oxidation lag time correlated with
      postdilatation brachial artery area (r= 0.32; P=0.05) but not with FMD. Lag-times
      and total LDL oxidation by Cu2+, lipoprotein and vitamin E concentrations were
      similar in diabetic and control groups. Antibody titres to oxidized LDL (oxLDL)
      were higher in non-diabetic than diabetic subjects, and were unrelated to FMD. In
      diabetic patients, vitamin E increased mean (SD) plasma vitamin E levels (24.0
      (6.5) to 47.5 (7.5) gmol/l; P=0.0006) and resulted in increased FMD (delta 0.00 (
      0.02-0.01) vs. 0.01 (0.01-0.02)) cm2; P=0.0036), but no changes in LDL Cu2+
      oxidation profiles were observed. CONCLUSIONS: FMD is no different in Type 1
      diabetic and non-diabetic subjects and nor are indices of lipid peroxidation and
      in vitro LDL oxidation although levels of antibody to oxLDL are lower in
      diabetes. Vitamin E supplementation increases plasma vitamin E levels and may
      enhance FMD in diabetes but, in the absence of changes in LDL oxidation, this may
      not be mediated by reduced oxidation of LDL.

PMID- 10656228
TI  - Metformin inhibits catecholamine-stimulated lipolysis in obese, hyperinsulinemic,
      hypertensive subjects in subcutaneous adipose tissue: an in situ microdialysis
      study.
AB  - AIMS: Metformin has been reported to decrease the plasma concentrations of non
      esterified fatty acids in Type 2 diabetic subjects. This study investigated the
      effects of metformin on basal and catecholamine-stimulated lipolysis in abdominal
      subcutaneous adipose tissue of obese, hyperinsulinaemic, hypertensive subjects.
      METHODS: Fourteen subjects with severe obesity (12 female, twomale, age 35.4 +/-
      4 years, body mass index 48.2 +/- 2 kg/m2, body fat mass 63.3 +/- 5 kg) were
      recruited. Glycerol and lactate concentrations were determined in the presence of
      metformin and after administration of catecholamines using microdialysis.
      Simultaneously, blood flow was assessed with the ethanol escape method. RESULTS:
      Glycerol release was lowered by metformin during the 3-h experiment (P<0.01). The
      lipolytic activity of catecholamines was suppressed when adipose tissue was pre
      treated with metformin (P<0.001). Lactate concentration increased after
      application of metformin (P<0.01) and catecholamines (P<0.001). Blood flow was
      decreased in the presence of adrenaline (P < 0.01), but this effect was abolished
      by metformin. CONCLUSIONS: The present data demonstrate the effects of metformin
      on lipolysis in subcutaneous adipose tissue in vivo. In the large body fat mass
      of obese subjects, a reduction of lipolysis in adipose tissue may contribute to a
      decrease of VLDL synthesis in the liver resulting in a lowered plasma
      triglyceride concentration.

PMID- 10656229
TI  - Cross-sectional but not longitudinal associations between non-esterified fatty
      acid levels and glucose intolerance and other features of the metabolic syndrome.
AB  - AIMS: Cross-sectional studies have demonstrated an association between high non
      esterified fatty acid (NEFA) concentrations and glucose intolerance. However, the
      direction of causality in these studies is uncertain. The aim of this study was
      to examine whether NEFA levels predicted the development of glucose intolerance
      in a prospective population-based cohort study. METHOD: Four hundred and eighty
      one women and 345 men participated in a prospective cohort study in which NEFA
      concentrations and glucose tolerance were measured at baseline and then repeated
      at follow-up 4.5 years later. RESULTS: The data do not show longitudinal
      relationships between baseline NEFA levels and either glucose intolerance or
      other features of the metabolic syndrome at follow-up. In contrast, strong cross
      sectional associations were observed between NEFA measures and glucose
      intolerance (and other features of the metabolic syndrome) in both baseline and
      follow-up studies. At follow-up, fasting NEFA levels and two measures of NEFA
      suppression were markedly different in subjects with features of the metabolic
      syndrome, compared to subjects with normal glucose tolerance (NGT) (NGT vs.
      metabolic syndrome for each NEFA value, P< 0.001). CONCLUSIONS: These results
      support the hypothesis that plasma NEFA levels change as a consequence of the
      metabolic syndrome and do not support the notion that increased NEFA levels cause
      either the metabolic syndrome or diabetes.

PMID- 10656230
TI  - Poorly controlled elderly Type 2 diabetic patients: the effects of increasing
      sulphonylurea dosages or adding metformin.
AB  - AIMS: To assess the effects and safety of increasing sulphonylurea dosages or
      adding metformin in poorly controlled elderly Type 2 diabetic patients. METHODS:
      A 18-month multicentre clinical study was performed on sulphonylurea-treated
      diabetic patients over 70 years of age with well-preserved renal function, steady
      fasting blood glucose > or = 200 mg/dl and HbA1c > or = 9%. Patients were
      randomly assigned to sulphonylurea increased up to its maximum dosage (1st group)
      or to addition of metformin (2nd group). Glycaemic control, lipid pattern,
      haemostatic status and safety were monitored during run-in, at baseline and at
      scheduled intervals for 18 months. Results refer to 85 patients in the 1st group
      and 89 patients in the 2nd with complete data. RESULTS: Similar improvements in
      glycaemic levels were observed with both treatments within the first month and a
      similar decrease in HbA1c within the third month. No further changes occurred in
      glycaemic control. In the 1st group, fasting glucose (mmol/l, mean +/- SE)
      decreased from 14.21 +/- 0.49 to 9.88 +/- 0.21, average day-long glucose from
      14.87 +/- 0.27 to 10.69 +/- 0.19 and HbAt1c(%) from 10.32 +/- 0.13 to 8.66 +/-
      0.13. In the 2nd treatment group fasting glucose decreased from 14.59 +/- 0.61 to
      9.05 +/- 37.28, average day-long glucose from 15.09 +/- 0.29 to 10.32 +/- 0.21
      and HbA1c from 10.33 +/- 0.13 to 8.77+/-0.12 (for all P<0.0005). In this 2nd
      group, a decrease in LDL-cholesterol (P < 0.05) and an increase in HDL
      cholesterol levels (P < 0.02) were also observed. In the 1st group, anthrombin
      III activity increased significantly (P<0.01). In the 2nd group, significant
      reductions in markers of platelet function (FP4 and betaTG, P < 0.01), thrombin
      generation (FPA, F1 + 2 and D-D, P<0.01), and fibrinolysis inhibition (PAI-1
      activity, PAI-1 antigen, P< 0.001) were observed. Increases in some fibrinolytic
      activation markers (t-PA activity, and AT-III activity, P<0.01) occurred. Fasting
      lactate concentrations were unchanged in the metformin-treated group. No serious
      adverse effects were observed in either group. CONCLUSIONS: These results suggest
      that either high sulphonylurea dosages or a therapy combining lower sulphonylurea
      dosages with metformin are effective and safe in an aged but healthy population.
      Metformin provides additional benefits counteracting several cardiovascular risk
      factors but must be administered with caution, bearing in mind the general contra
      indications for the drug but not age alone.

PMID- 10656231
TI  - Childhood Type 1 diabetes mellitus and parental occupations involving social
      mixing and infectious contacts: two population-based case-control studies.
AB  - AIMS: To test the hypothesis that increased exposure to infections, through
      parental jobs involving high levels of social mixing, reduces the risk of
      childhood Type 1 diabetes mellitus. METHODS: Two population-based case-control
      studies of children diagnosed with Type 1 diabetes mellitus from Yorkshire (0-15
      years) and Northern Ireland (0-14 years) included 220 and 189 cases and 433 and
      465 controls, respectively. Parental occupations were coded using a standard
      occupational classification. Each job was allocated to high, medium or low levels
      of social mixing according to a predefined categorization. Odds ratios (OR) for
      the risk of childhood Type 1 diabetes were estimated for parental social mixing
      by age at diagnosis. RESULTS: Childhood Type 1 diabetes mellitus was not
      associated with high levels of parental occupational social mixing (Yorkshire -
      mothers: OR 1.07, 95% confidence interval (CI) 0.76-1.50; fathers: 1.15, 0.75
      1.76; Northern Ireland - heads of household, usually the father: 0.78, 0.49
      1.25). A larger proportion of mothers (39%) compared to fathers (18% Yorkshire,
      17% Northern Ireland) had jobs involving high levels of social mixing. Mothers
      with high social mixing jobs conferred a nonsignificant reduced risk of Type 1
      diabetes among children diagnosed under 5 years of age (0.58, 0.24-1.38) compared
      to those diagnosed at age 5 years and above (1.14, 0.77-1.69). CONCLUSIONS: No
      association between parental occupational social mixing and the risk of childhood
      Type 1 diabetes mellitus was detected for all ages combined. Mothers were more
      likely to have jobs involving high levels of social mixing than fathers. The
      possible protective effect of maternal high occupational social mixing on
      children diagnosed below 5 years of age merits further investigation.

PMID- 10656232
TI  - Incidence of childhood-onset Type 1 diabetes mellitus in Devon and Cornwall,
      England, 1975-1996.
AB  - AIMS: To determine the incidence of Type 1 diabetes mellitus (DM) in children
      aged 0-15 years in the far south-west of England between 1975 and 1996. METHODS:
      Patient information was collected to set up the Cornwall and Plymouth Children's
      Diabetes Register (CPCDR) through two main data sources; hospitals and the
      general practitioners in all surgeries in the study region. All children under 16
      years living within Cornwall and the Isles of Scilly, and the former Plymouth
      Health Authorities and diagnosed as having Type 1 DM during the study period were
      included. The case ascertainment was estimated by a capture-recapture method.
      Trends and differences in incidence of sex, age, time period and district of
      diagnosis were analysed by Poisson regression analysis. Roger's method was used
      to estimate the seasonal variations. RESULTS: A total of 522 subjects aged
      between 0 and 15 years were identified from 01/01/1975 to 31/12/1996, giving an
      overall crude incidence of 14.9/ 100 000 population/year. The case ascertainment
      was 94.4% (95% confidence interval (CI) 91.4- 97.6%) for the whole register.
      Poisson regression analysis showed that a significant increase of incidence
      (2.49% per year) was observed throughout the 22-year study period, which was
      mainly a result of the significant increase in the 0-4 year age-group (6.29% per
      year). The incidence significantly differed among the 22-years (P = 0.007), the
      three age groups (0-4, 5-9 and 10-14 years, P<0.001) and different sexes
      (P=0.049). The significant seasonal variations were detected with peak incidence
      appearing in autumn and winter. CONCLUSIONS: The first validated childhood-onset
      diabetes register has been set up in the far south-west of England. The incidence
      of childhood Type 1 DM in this region has increased significantly over the past
      two decades, especially in children under 5 years.

PMID- 10656233
TI  - The effect of long-term glycaemic control on serum lipoprotein(a) levels in
      patients with Type 2 diabetes mellitus.
AB  - AIMS: To examine whether long-term glycaemic control affects lipoprotein(a)
      (Lp(a)) levels in patients with Type 2 diabetes mellitus. METHODS: Eighty-nine
      Type 2 diabetic patients (38 men, 51 women) were recruited from the diabetes
      clinic. Based on HbA1c concentrations at baseline, patients were divided into two
      groups: those with HbA1c < 8.0% (n =45) and those with HbA1c > or = 8.0% (n=44).
      Comparisons of Lp(a) levels were made between both groups. The effect of long
      term glycaemic control on Lp(a) levels was investigated in a subgroup of 20
      patients, selected from those with baseline HbA1c > or = 8%. All these patients
      were treated with a goal of HbA1c <7%. RESULTS: Lp(a) levels were not
      significantly different between those with HbA1c< 8.0% and those with HbA1c, > or
      = 8.0%. No correlation between Lp(a) and HbA1c or fasting blood glucose levels
      was noted in diabetic patients as a whole. After 2 years of intensive glycaemic
      control, all patients exhibited remarkable improvement of therapy: their average
      HbA1c levels were 6.5 +/- 0.7%, being < 7% in 70% of patients. However, no change
      in Lp(a) levels were observed after 2 years (19.5 +/- 14.8-21.4 +/- 13.4 mg/dl, P
      = 0.390). CONCLUSION: These results indicate that improvement of glycaemic
      control does not affect serum Lp(a) levels in patients with Type 2 diabetes
      mellitus.

PMID- 10656234
TI  - Effects of 3-week oral treatment with the antioxidant thioctic acid (alpha-lipoic
      acid) in symptomatic diabetic polyneuropathy.
AB  - AIMS: To evaluate the efficacy and safety of short-term oral treatment with the
      antioxidant thioctic acid (TA) on neuropathic symptoms and deficits in patients
      with Type 2 diabetes mellitus with symptomatic polyneuropathy. METHODS: Patients
      were randomly assigned to oral treatment with 600 mg of TA t.i.d. (n = 12) or
      placebo (n = 12) for 3 weeks. Neuropathic symptoms (pain, burning, paraesthesiae,
      and numbness) in the feet were scored at weekly intervals and summarized as a
      Total Symptom Score (TSS). The Hamburg Pain Adjective List (HPAL) and the
      Neuropathy Disability Score (NDS) were assessed at baseline and day 19. RESULTS:
      At baseline the TSS, HPAL, and NDS were not significantly different between the
      groups. The TSS in the foot decreased from baseline to day 19 by -3.75 +/- 1.88
      points (-47%) in the TA group and by -1.94 +/- 1.50 points (-24%) in the placebo
      group (P= 0.021 for TA vs. placebo). The total HPAL score decreased from baseline
      to day 19 by -2.20 +/- 1.65 points (-60%) in the TA group and by -0.96 +/- 1.32
      points (-29%) in the placebo group (P = 0.072 for TA vs. placebo). The NDS
      decreased by -0.27 +/- 0.47 points in the TA group, whereas it slightly increased
      by +0.18 +/- 0.4 points in the placebo group (P = 0.025 for TA vs. placebo). No
      differences between the groups were noted regarding the rates of adverse events.
      CONCLUSIONS: These preliminary findings indicate that oral treatment with 600 mg
      of TA t.i.d. for 3 weeks may improve symptoms and deficits resulting from
      polyneuropathy in Type 2 diabetic patients, without causing significant adverse
      reactions.

PMID- 10656235
TI  - Length rather than a specific allele of dinucleotide repeat in the 5' upstream
      region of the aldose reductase gene is associated with diabetic retinopathy.
AB  - AIMS: To assess the possible contribution of a genetic factor to diabetic
      retinopathy. METHODS: (CA)n repeat length was investigated in the 5' upstream
      region of the gene coding for aldose reductase (AR), which is a key enzyme of the
      polyol pathway and plays a role in hyperglycaemia-induced tissue damage, in
      Japanese patients with Type 2 DM. RESULTS: The dinucleotide repeat length was
      significantly associated with proliferative diabetic retinopathy (PDR) (P= 0.029,
      Mann-Whitney U-test); i.e. shorter alleles were more prevalent in the PDR group
      than in the control group. CONCLUSIONS: (CA)n repeat length, rather than a
      specific allele, in the 5' upstream region of the AR gene is associated with
      diabetic retinopathy. These data suggest that the AR locus plays a role in
      genetic susceptibility to diabetic retinopathy and that dinucleotide repeats in
      genomic DNA may be related to disease predisposition.

PMID- 10656236
TI  - Higher post-absorptive C-peptide levels in Type 1 diabetic patients without renal
      complications.

PMID- 10656237
TI  - Effectiveness of treatment for impotence in diabetic men.

PMID- 10656238
TI  - The concept of sentinel node localization: how it started.
AB  - Intraoperative lymphatic mapping and sentinel lymphadenectomy (LM/SL) followed by
      selective complete lymphadenectomy (SCLND) has revolutionized the management of
      the regional lymph node basin in patients with solid tumors. Many investigators
      over the centuries have contributed to the understanding of the progression of
      tumor cells through the lymphatic system. This article discusses the conceptual
      background for the development of LM/SL in the original model of melanoma. The
      sentinel node hypothesis has been validated by a multicenter clinical trial
      showing that LM/SL in melanoma can be accurately performed in a uniform manner by
      multidisciplinary teams at cancer centers worldwide. Although the diagnostic and
      prognostic accuracy of LM/SL has been established, demonstration of the
      therapeutic use of this procedure awaits analysis of survival data from the
      multicenter randomized trial of wide excision alone versus wide excision plus
      LM/SL/SCLND.

PMID- 10656239
TI  - The pathologist's role in sentinel lymph node evaluation.
AB  - Patients with high-risk (thick, deeply invasive) primary melanoma were, in the
      past, managed by wide local excision and elective node dissection or wide local
      excision alone, with subsequent lymphadenectomy if the regional nodes developed
      clinically detectable metastases. We recently developed a more logical approach
      called selective lymph node dissection. To be effective, this requires close
      collaboration of surgeons, pathologists, and nuclear medicine physicians. The
      draining lymph node basin is identified preoperatively by lymphoscintigraphy.
      During surgery, a marker dye (isosulfan blue) and radioactive technetium labeled
      albumin are injected intradermally around the primary melanoma and the afferent
      lymphatics are followed up to the first lymph nodes of the ipsilateral regional
      nodal basin. The surgeon excises the blue-colored and maximally radioactive
      sentinel nodes and the pathologist critically evaluates these for the presence of
      a metastatic tumor. If the sentinel nodes are tumor free, no further nodal
      dissection is undertaken; if a tumor is present, a complete dissection of the
      nodal basin is performed. We have examined 1,119 sentinel lymph nodes from 669
      patients treated by selective lymph node dissection. We identified melanoma cells
      in sentinel nodes from 126 patients (17.8%). A single node contained tumors in
      67% of patients, 2 nodes were positive in 25%, and the remaining 12% of patients
      had three tumor-containing nodes. Melanoma cells were dispersed singly or in
      variably sized groups, usually in the peripheral nodal sinus. In around 40% of
      patients, immunohistochemistry is required to identify minute numbers of tumor
      cells. With experience, pathologists identify tumors in hematoxylin and eosin
      (H&E) preparations in an increasing proportion of lymph nodes. Tumor cells are
      more frequent in the sentinel nodes of patients with primary tumors of deeper
      Clark level and greater Breslow thickness. Tumor cells must be discriminated from
      capsular nevus cells, interdigitating dendritic leukocytes, macrophages, and
      intranodal neural tissues.

PMID- 10656240
TI  - Vital dyes in sentinel node localization.
AB  - Vital blue dyes were used to show the feasibility and accuracy of intraoperative
      lymphatic mapping of the sentinel node (SN) in patients with melanoma, breast
      cancer, and other solid tumors. Surgeons who have successfully completed an
      adequate number of cases of intraoperative mapping and sentinel lymph node
      dissection (SLND) can use blue dye alone to localize the SN. However,
      radiopharmaceutical agents can facilitate intraoperative mapping; preoperative
      lymphoscintigraphy can identify the location of the SN, and intraoperative
      mapping with the gamma probe can provide an auditory signal that complements the
      visual guide provided by the blue dye. Studies are required to establish more
      clearly the intralymphatic kinetics of the various radiopharmaceutical agents. An
      ongoing international Phase III trial in melanoma, the 2 upcoming trials in
      breast cancer, and similar trials for other solid tumors will further clarify the
      future role of SLND.

PMID- 10656241
TI  - Radiopharmaceuticals for lymphoscintigraphy: including dosimetry and radiation
      considerations.
AB  - The recognition of the importance of lymphoscintigraphy for identification of the
      sentinel lymph nodes in melanoma and breast cancer plays a significant role in
      the clinical management of these patients. The widespread clinical acceptance of
      this technique and the lack of an agreement on which radiopharmaceutical agent
      has the most ideal properties has resulted in a wide variety of agents being used
      clinically with other agents under investigation or development. This article
      reviews some of the physical properties that a radiopharmaceutical agent should
      possess and discusses in depth commonly used agents and lists some agents under
      development. This article also discusses the dosimetry and biological effects
      various radiopharmaceutical agents have for lymphoscintigraphy in melanoma and
      breast cancer patients. In view of the lack of a consensus agreement on which
      radiopharmaceutical agent will provide the optimal clinical information this
      article will provide an overview of potentially useful radiopharmaceutical agents
      and radiation dosimetry considerations.

PMID- 10656242
TI  - The intraoperative gamma probe: basic principles and choices available.
AB  - By taking advantage of the proximity to radioactive sentinel nodes and occult
      tumors achievable in an operative setting, intraoperative probes are becoming
      increasingly important in the surgical management of cancer. This article begins
      with a discussion of the statistical limitations of radiation detection and
      measurement and of the key performance parameters (sensitivity, energy
      resolution, and spatial resolution) that characterize detectors. The basic design
      and operating principle of radiation detectors used in intraoperative probes,
      scintillation and semiconductor detectors, are then reviewed. Scintillation
      detector-based intraoperative probes, generally using a NaI(T1) or a CsI(T1)
      crystal connected to a photomultiplier tube by a fiberoptic cable, have the
      advantages of reliability, relatively low cost, and high sensitivity, especially
      for medium- to high-energy photons. Disadvantages include poor energy resolution
      and scatter rejection, and bulkiness. Semiconductor (CdZn, CdZnTe, HgI2)-based
      probes are compact and have excellent energy resolution and scatter rejection,
      but with complex energy spectra reflecting charge-carrier trapping. Their main
      disadvantage is lower sensitivity. The performance parameters of various
      commercially available intraoperative probes are then compared. The article
      concludes with a discussion of the practical considerations in selecting and
      using intraoperative probes, including ergonomic and other design features, as
      well as performance parameters.

PMID- 10656243
TI  - Melanoma lymphoscintigraphy and lymphatic mapping.
AB  - Lymphoscintigraphy in melanoma has proven to be a reliable method to identify
      regional lymph nodes at risk for metastases. The first lymph node to drain a
      cutaneous lesion, the sentinel lymph node (SLN), is predictive of the metastatic
      status of the regional lymph node group. Lymphatic mapping allows for the
      identification of the SLN and for selective lymph node sampling. Selective lymph
      node sampling is less invasive and because only a small quantity of high-risk
      tissue is submitted for pathological examination, it allows for a more complete
      and comprehensive pathological examination, which identifies melanoma with up to
      100 times the sensitivity of conventional examinations.

PMID- 10656244
TI  - Sentinel node staging of early breast cancer using lymphoscintigraphy and the
      intraoperative gamma-detecting probe.
AB  - Sentinel node staging for breast cancer is increasingly used in place of axillary
      lymph node dissection but is not yet universally accepted. The problems of non
      standardized methodologies and lack of consensus on the optimum techniques to
      identify sentinel nodes are being addressed. Complementary use of radionuclide
      imaging before surgery, intraoperative probe detection, and blue dye have yielded
      the best reported sensitivities for finding a sentinel node (94%). The importance
      of imaging is summarized as identifying sentinel node(s), distinguishing sentinel
      from secondary nodes, guiding surgical incision planning, and facilitating lower
      doses. The learning curve phenomenon, which applies to the surgeon and the
      nuclear medicine physician, has been recognized; measures to minimize it are
      being implemented. Radiation exposure to operating room and pathology personnel
      is very low; estimates of exposure to the surgeon's hands are 0.2% of the annual
      whole body dose received by every human being from natural background and cosmic
      sources.

PMID- 10656245
TI  - Hepatic tissue in the left upper quadrant.

PMID- 10656246
TI  - Abnormal uptake in the sacrum on bone scan.

PMID- 10656247
TI  - Diffuse facial uptake on bone scintigraphy.

PMID- 10656248
TI  - Gallium-67 citrate accumulation in sinonasal regions.

PMID- 10656249
TI  - Luxury perfusion (hyperfixation) of cerebral flow imaging agent on brain SPECT.

PMID- 10656250
TI  - Identification of a novel aspartic protease (Asp 2) as beta-secretase.
AB  - The Alzheimer's disease beta-amyloid peptide (Abeta) is produced by excision from
      the type 1 integral membrane glycoprotein amyloid precursor protein (APP) by the
      sequential actions of beta- and then gamma-secretases. Here we report that Asp 2,
      a novel transmembrane aspartic protease, has the key activities expected of beta
      secretase. Transient expression of Asp 2 in cells expressing APP causes an
      increase in the secretion of the N-terminal fragment of APP and an increase in
      the cell-associated C-terminal beta-secretase APP fragment. Mutation of either of
      the putative catalytic aspartyl residues in Asp 2 abrogates the production of the
      fragments characteristic of cleavage at the beta-secretase site. The enzyme is
      present in normal and Alzheimer's disease (AD) brain and is also found in cell
      lines known to produce Abeta. Asp 2 localizes to the Golgi/endoplasmic reticulum
      in transfected cells and shows clear colocalization with APP in cells stably
      expressing the 751-amino-acid isoform of APP.

PMID- 10656251
TI  - Cloning and expression of VEMA: a novel ventral midline antigen in the rat CNS.
AB  - A variety of molecules expressed at the midline of the developing central nervous
      system (CNS) control multiple aspects of pattern formation and axon guidance. We
      recently identified monoclonal antibody (mAb) CARO 2 as a novel marker of the
      ventral midline in the developing rat CNS, and the corresponding antigen as a
      membrane-associated 28-kDa protein. We report here the isolation of cDNA clones
      encoding the mAb CARO 2 antigen, which we rename VEMA, for ventral midline
      antigen. The deduced amino acid sequence of VEMA contains a single transmembrane
      domain near its N-terminus and several tyrosine-based internalization motifs.
      These structural features are consistent with the association of VEMA to
      intracellular membranes. In situ hybridization analyses demonstrate that VEMA
      mRNA is predominantly expressed at the ventral midline. The restricted
      distribution of VEMA, as well as several characteristics of its primary
      structure, suggest a role for this protein in regulating axon guidance in the
      mammalian CNS.

PMID- 10656252
TI  - Regulation of phosphatidylcholine biosynthesis by mGluR1alpha expressed in human
      embryonic kidney 293 cells--A 31P-NMR study.
AB  - A recent report has demonstrated that inositol 1,4,5-trisphosphate (IP3)-induced
      Ca2+ release plays a crucial role in neurite growth. Here, using 31P-NMR, we
      examine whether activation of the metabotropic glutamate receptor 1 (mGluR1),
      which induces the production of IP3, could modulate phospholipid metabolism in
      human embryonic kidney 293 cells. mGluR1alpha- but not ionotropic glutamate
      receptor 1-expressing cells stimulated with glutamate exhibited a drastic
      reduction in the phosphorylcholine level, with corresponding increases in the
      level of phosphatidylcholine, a major phospholipid component. Quantitative
      analysis of cell growth revealed that mGluR1alpha-expressing cells cultured with
      100microM glutamate were statistically significantly longer than the
      nontransfected cells. The effect was no longer observed following coincubation
      with a metabotropic glutamate receptor antagonist, (RS)-alpha-methyl-4
      carboxyphenylglycine. These results suggest that mGluR1alpha activation triggers
      phosphatidylcholine biosynthesis and may contribute to neurite extension.

PMID- 10656253
TI  - Neuronal depolarization enhances the transcription of the neuronal serine
      protease inhibitor neuroserpin.
AB  - Neuroserpin is an axonally secreted neuronal serine protease inhibitor. Based on
      its inhibitory activity towards tissue plasminogen activator (tPA) and its
      predominant expression in the cerebral cortex, the hippocampus, and the amygdala,
      a role for neuroserpin in the regulation of neural plasticity has been suggested.
      We recently found that neuroserpin mRNA is increased in cultured hippocampal
      neurons upon depolarization with elevated extracellular KCl. Using luciferase
      reporter constructs containing segments of the promoter region of the neuroserpin
      gene, we identified a 200-bp segment near the transcription initiation site that
      is responsible for both the neuron-specific expression of the neuroserpin gene
      and the enhanced transcription resulting from depolarization. Nerve growth
      factor, which alone had no effect on the expression of neuroserpin mRNA in
      hippocampal neurons, had a marked potentiating effect when supplied in
      combination with elevated extracellular KCl. In contrast, the transcription
      factor zif/268 blocked neuroserpin transcription. These results implicate
      neuroserpin as an activity-regulated modulator of tPA activity at the synapse and
      provide further support for the occurrence of activity-regulated proteolytic
      processes at the synapse.

PMID- 10656254
TI  - A subset of fibroblast growth factors (Fgfs) promote survival, but Fgf-8b
      specifically promotes astroglial differentiation of rat cortical precursor cells.
AB  - Fibroblast growth factor-2 (Fgf-2 or basic Fgf) is known to promote the survival,
      proliferation, and differentiation of neural precursor cells. We have examined
      and compared the effects of Fgf-2 with those of Fgf-1, -4, -6, -7, -9, and -10,
      as well as three isoforms of Fgf-8 (-8a, -8b, and -8c), on the fate of cultured
      embryonic day 15 (E15) rat cortical cells. Clonal analysis, using retroviral
      tagging, shows that only Fgf-2, -4, and -8b can efficiently promote the survival
      of cortical precursor cells, the majority of which give rise to neurons.
      Surprisingly, and in contrast to other Fgfs, Fgf-8b also promotes astroglial
      differentiation of a subpopulation of these cells, which would otherwise appear
      to yield neurons. We also show that E15 cortical cells initially express the IIIc
      isoforms of Fgf-receptors (R-1,-2, and -3 but within 16 h of culturing they down
      regulate FgfR2-IIIc. These studies demonstrate that cortical precursor cells
      respond to Fgf stimulation in different ways depending on the ligand and by
      inference the Fgf receptors activated.

PMID- 10656255
TI  - Secretion from bovine chromaffin cells acutely expressing exogenous proteins
      using a recombinant Semliki Forest virus containing an EGFP reporter.
AB  - Acute expression of recombinant proteins throughout a population of postmitotic
      bovine chromaffin cells was achieved using the Semliki Forest virus expression
      system (P. Liljestrom and H. Garoff (1991) Biotechnology 9:1356-1361). The virus
      was modified to express a green fluorescent protein, which faithfully reported
      the expression of the recombinant proteins. Two types of reporting virus were
      constructed: the first included a second subgenomic element, and the second an
      internal ribosome entry site. Both were used to express the recombinant proteins
      beta-galactosidase, 5HT3 receptor, or tetanus toxin light chain. Beta
      galactosidase was used to quantify the rate of expression of recombinant protein
      in chromaffin cells, the 5HT3 receptor to trigger secretion, and the toxin to
      block secretion. The experiments clearly show that infection and expression of
      recombinant proteins throughout a population of chromaffin cells do not, per se,
      affect the rate and extent of triggered exocytosis, endocytosis, or membrane
      recycling pathways. The catecholamine content of the cell is unaltered, and the
      secretory mechanism can be accessed within a few hours after infection. This
      noncytopathic method of acutely expressing specific proteins at physiological
      levels in chromaffin cells offers a powerful new tool for dissecting the roles of
      many proteins implicated in exo- and endocytosis.

PMID- 10656256
TI  - Activin and bone morphogenetic proteins induce calcitonin gene-related peptide in
      embryonic sensory neurons in vitro.
AB  - The neuropeptide calcitonin gene-related peptide (CGRP) expressed by one-third of
      rat dorsal root ganglion (DRG) neurons mediates pain sensation and vasodilation.
      The developmental regulation of CGRP is poorly understood, but may involve target
      derived factors from skin or viscera. Few embryonic DRG neurons in defined
      culture express CGRP, indicating inductive signals are required. Follistatin
      blocked CGRP expression induced by serum or skin-conditioned medium, implicating
      transforming growth factor beta (TGFbeta) family members. Activin or bone
      morphogenetic proteins (BMPs) 2, 4, or 6 stimulated CGRP expression in 60% of DRG
      neurons. Brief BMP4 application supported maximal CGRP induction, suggesting that
      BMP4 is a "switch" rather than a continuous modulator of neuropeptide phenotype.
      DRG expressed corresponding receptor subunits and exhibited Smad1 transcription
      factor nuclear translocation following BMP stimulation. BMP mRNAs were present in
      embryonic targets innervated by CGRP-expressing neurons. Thus, specific TGFbeta
      family members are candidate regulators of CGRP expression in sensory neurons.

PMID- 10656257
TI  - Reciprocal Id expression and myelin gene regulation in Schwann cells.
AB  - Id proteins are thought to act as dominant negative antagonists of basic helix
      loop-helix (bHLH) transcription factors that direct differentiation in various
      cell types. We found that Schwann cells express all four Id-family genes and that
      their transcript levels were reciprocally regulated in pairs during nerve
      maturation in vivo and cAMP-mediated differentiation in vitro. The rapid
      induction as part of the early response to axonal membranes and cytokines
      suggested that Id3 is involved in myelin gene repression. An inverse relationship
      between Id1/3 and myelin P0 expression was consistent with a role for these two
      Id proteins as inhibitors of differentiation, and Id1/3 proteins strongly
      repressed myelin gene promoter activity. Nuclear factors isolated from Schwann
      cells and intact sciatic nerves were found to bind three different HLH
      recognition sequences (E boxes) in the proximal region of the P0 promoter, and
      production of these DNA binding complexes was altered during differentiation.
      These data support the concept that Id proteins regulate myelin gene expression
      by controlling the formation of specific bHLH DNA binding complexes with
      different E-box preferences.

PMID- 10656258
TI  - Cytokine and growth factor involvement in long-term potentiation.
AB  - Hippocampal long-term potentiation (LTP) is one of the best-studied models of
      learning and memory at the molecular level. While it has long been known that
      tetanic stimulation causes changes at the synapse within seconds to minutes,
      recent research has begun to focus on factors that may affect synaptic plasticity
      on a longer time scale. One group of factors with many of the characteristics
      predicted for both short- and long-term actions at the synapse is the cytokines
      and growth factors. In vitro, these proteins can alter neuronal morphology, gene
      expression, and proliferation, and many cytokines and their receptors are present
      in the adult CNS. Because brain-derived neurotrophic factor (BDNF) is the best
      studied synaptic modulator of this class, we begin by discussing the experimental
      evidence linking BDNF to LTP. Ten cytokines and growth factors that have been
      examined in the context of hippocampal LTP are then considered. We discuss the
      effects of LTP on the expression of the cytokines and explore the regulation of
      synaptic plasticity by exogenous application or antagonist perturbation of these
      proteins. The available evidence strongly supports a role for these factors in
      synaptic modulation and should prompt further exploration of their functions at
      the synapse.

PMID- 10656259
TI  - Turning a reference inside-out: commentary on an article by Stevens and Arkin
      entitled: "Are membrane proteins 'inside-out' proteins?" (Proteins 1999;36:135
      143)

PMID- 10656260
TI  - Correlation between changes in nuclear magnetic resonance order parameters and
      conformational entropy: molecular dynamics simulations of native and denatured
      staphylococcal nuclease.
AB  - Recent work has suggested that changes in NMR order parameters may quantitatively
      reflect changes in the conformational entropy of a protein ensemble. The extent
      of the mathematical relationship between local entropy changes as seen by NMR
      order parameters and the full protein entropy change is a complex issue. As a
      step towards a fuller understanding of this problem, molecular dynamics
      calculations of both native and denatured staphylococcal nuclease were performed.
      The N-H bond vector motion, in both explicit and implicit solvent, was analyzed
      to estimate local and global entropy changes. The calculated N-H bond vector
      order parameters from simulation agreed on average with experimental values for
      both native and denatured structures. However, the inverted-U profile of order
      parameters versus residue number observed experimentally for denatured nuclease
      was only partially reproduced by simulation of compact denatured structures.
      Comparisons made across the full set of simulations revealed a correlation
      between the N-H order parameter-based conformational entropy change and the total
      quasiharmonic-based conformational entropy change between the native and
      denatured structures. The calculations showed that about 25% of the total entropy
      change was reflected by changes in simulated S2 values. This result suggests that
      NMR-derived order parameters may be used to provide a reasonable estimate of the
      total conformational entropy change on protein folding.

PMID- 10656262
TI  - Optimized representations and maximal information in proteins.
AB  - In an effort to quantify loss of information in the processing of protein
      bioinformatic data, we examine how representations of amino acid sequence and
      backbone conformation affect the quantity of accessible structural information
      from local sequence. We propose a method to extract the maximum amount of peptide
      backbone structural information available in local sequence fragments, given a
      finite structural data set. Using methods of information theory, we develop an
      unbiased measure of local structural information that gauges changes in
      structural distributions when different representations of secondary structure
      and local sequence are used. We find that the manner in which backbone structure
      is represented affects the amount and quality of structural information that may
      be extracted from local sequence. Representations based on virtual bonds capture
      more structural information from local sequence than a three-state assignment
      scheme (helix/strand/loop). Furthermore, we find that amino acids show
      significant kinship with respect to the backbone structural information they
      carry, so that a collapse of the amino acid alphabet can be accomplished without
      severely affecting the amount of extractable information. This strategy is
      critical in optimizing the utility of a limited database of experimentally solved
      protein structures. Finally, we discuss the similarities within and differences
      between groups of amino acids in their roles in the local folding code and
      recognize specific amino acids critical in the formation of local structure.

PMID- 10656261
TI  - Can a pairwise contact potential stabilize native protein folds against decoys
      obtained by threading?
AB  - We present a method to derive contact energy parameters from large sets of
      proteins. The basic requirement on which our method is based is that for each
      protein in the database the native contact map has lower energy than all its
      decoy conformations that are obtained by threading. Only when this condition is
      satisfied one can use the proposed energy function for fold identification. Such
      a set of parameters can be found (by perceptron learning) if Mp, the number of
      proteins in the database, is not too large. Other aspects that influence the
      existence of such a solution are the exact definition of contact and the value of
      the critical distance Rc, below which two residues are considered to be in
      contact. Another important novel feature of our approach is its ability to
      determine whether an energy function of some suitable proposed form can or cannot
      be parameterized in a way that satisfies our basic requirement. As a
      demonstration of this, we determine the region in the (Rc, Mp) plane in which the
      problem is solvable, i.e., we can find a set of contact parameters that stabilize
      simultaneously all the native conformations. We show that for large enough
      databases the contact approximation to the energy cannot stabilize all the native
      folds even against the decoys obtained by gapless threading.

PMID- 10656263
TI  - How good is prediction of protein structural class by the component-coupled
      method?
AB  - Proteins of known structures are usually classified into four structural classes:
      all-alpha, all-beta, alpha+beta, and alpha/beta type of proteins. A number of
      methods to predicting the structural class of a protein based on its amino acid
      composition have been developed during the past few years. Recently, a component
      coupled method was developed for predicting protein structural class according to
      amino acid composition. This method is based on the least Mahalanobis distance
      principle, and yields much better predicted results in comparison with the
      previous methods. However, the success rates reported for structural class
      prediction by different investigators are contradictory. The highest reported
      accuracies by this method are near 100%, but the lowest one is only about 60%.
      The goal of this study is to resolve this paradox and to determine the possible
      upper limit of prediction rate for structural classes. In this paper, based on
      the normality assumption and the Bayes decision rule for minimum error, a new
      method is proposed for predicting the structural class of a protein according to
      its amino acid composition. The detailed theoretical analysis indicates that if
      the four protein folding classes are governed by the normal distributions, the
      present method will yield the optimum predictive result in a statistical sense. A
      non-redundant data set of 1,189 protein domains is used to evaluate the
      performance of the new method. Our results demonstrate that 60% correctness is
      the upper limit for a 4-type class prediction from amino acid composition alone
      for an unknown query protein. The apparent relatively high accuracy level (more
      than 90%) attained in the previous studies was due to the preselection of test
      sets, which may not be adequately representative of all unrelated proteins.

PMID- 10656264
TI  - Continuum electrostatic analysis of preferred solvation sites around proteins in
      solution.
AB  - To understand water-protein interactions in solution, the electrostatic field is
      calculated by solving the Poisson-Boltzmann equation, and the free energy surface
      of water is mapped by translating and rotating an explicit water molecule around
      the protein. The calculation is applied to T4 lysozyme with data available on the
      conservation of solvent binding sites in 18 crystallographically independent
      molecules. The free energy maps around the ordered water sites provide
      information on the relationship between water positions in crystal structure and
      in solution. Results show that almost all conserved sites and the majority of
      nonconserved sites are within 1.3 A of local free energy minima. This finding is
      in sharp contrast to the behavior of randomly placed water molecules in the
      boundary layer, which, on the average, must travel more than 3 A to the nearest
      free energy minimum. Thus, the solvation sites are at least partially determined
      by protein-water interactions rather than by crystal packing alone. The
      characteristic water residence times, obtained from the free energies at the
      local minima, are in good agreement with nuclear magnetic resonance experiments.
      Only about half of the potential sites show up as ordered water in the 1.7 A
      resolution X-ray structure. Crystal packing interactions can stabilize weak or
      mobile potential sites (in fact, some ordered water positions are not close to
      free energy minima) or can prevent water from occupying certain sites. Apart from
      a few buried water molecules that are strong binders, the free energies are not
      very different for conserved and nonconserved sites. We show that conservation of
      a water site between two crystals occurs if the positions of protein atoms,
      primarily contributing to the free energy at the local minimum, do not
      substantially change from one structure to the other. This requirement can be
      correlated with the nature of the side chain contacting the water molecule in the
      site.

PMID- 10656265
TI  - Solution structure of a peptide model of a region important for the folding of
      alpha-lactalbumin provides evidence for the formation of nonnative structure in
      the denatured state.
AB  - Elucidating the properties of the denatured state of proteins under conditions
      relevant for their folding is a key factor in understanding the folding process.
      We show that a peptide corresponding to residues 111-120 of human alpha
      lactalbumin has a pronounced propensity to adopt nonnative structure in aqueous
      solution. Two-dimensional NMR provides evidence for a structured, nonnative
      conformation in fast exchange with a random coil ensemble. A total of 78 Rotating
      Frame Overhauser Effects (ROEs) were used to calculate the conformation of the
      structured population. A nonnative cluster of hydrophobic residues involving the
      side chains of K114, W118, Ll119, and A120 is observed, which helps to stabilize
      a turn-like conformation in the vicinity of residues 115-118. The structure in
      30% (vol/vol) TFE was also calculated. Interestingly, the addition of TFE did not
      simply amplify the population of the structured conformer observed in H2O, but
      instead induced a new conformation. The implications for the folding of the
      intact protein are discussed. We also discuss the implications of this study for
      the relevance of the use of mixed TFE/H2O solvent systems to study isolated
      peptides.

PMID- 10656266
TI  - Stability analysis for the cavity-filling mutations of the Myb DNA-binding domain
      utilizing free-energy calculations.
AB  - We have analyzed the effect of cavity-filling mutations on protein stability by
      means of free-energy calculations based on molecular dynamics simulations to
      identify the factors contributing to stability changes caused by the mutations.
      We have studied the DNA-binding domain of Myb, which has a cavity in one of three
      homologous repeat units, and analyzed a series of mutations with nonnatural and
      natural amino acids at a single site, which change the size of the cavity. We
      found that the calculated free-energy changes caused by the mutations are in
      excellent agreement with experimental data (correlation coefficient 0.98). The
      free-energy changes in the native and denatured states were independently
      compared with the unfolding free-energy change (deltadeltaG) and cavity-volume
      changes (deltaV), and it was found that deltadeltaG and deltaV correlate with the
      native-state free-energy changes but not with the denatured-state free-energy
      changes. Further analyses in terms of enthalpy and entropy show that compensation
      between entropy and enthalpy occurs in the denatured state but not in the native
      state. The main contribution to the native-state free energy was found to be van
      der Waals interactions associated with the cavity. We estimate that the decrease
      in free energy per methylene group, which results from filling the cavity, is
      about 2 to 3 kcal/mol. These results suggest that the stabilization of a protein
      by cavity-filling mutations be determined primarily by the free energy associated
      with the cavity volume in the native state.

PMID- 10656267
TI  - Super-motifs and evolution of tandem leucine-rich repeats within the small
      proteoglycans--biglycan, decorin, lumican, fibromodulin, PRELP, keratocan,
      osteoadherin, epiphycan, and osteoglycin.
AB  - Leucine-rich repeats (LRRs) with 20-30 amino acids in unit length are present in
      many proteins from prokaryotes to eukaryotes. The LRR-containing proteins include
      a family of nine small proteoglycans, forming three distinct subfamilies: class I
      contains biglycan/PG-I and decorin/PG-II; class II: lumican, fibromodulin, PRELP,
      keratocan, and osteoadherin; and class III: epiphycan/PG-Lb and osteoglycin or
      osteoinductive factor. Comparative sequence analysis of the 34 available protein
      sequences reveals that these proteoglycans have two types of LRRs, which we call
      S and T. The type S LRR is 21 residues long and has the consensus sequence of
      xxaPzxLPxxLxxLxLxxNxI. The type T LRR has 26 residues; its consensus sequence is
      zzxxaxxxxFxxaxxLxxLxLxxNxL. In both "x" indicates variable residue; "z" is
      frequently a gap; "a" is Val, Leu, or Ile; and I is Ile or Leu. These type S and
      TLRRs are ordered into two super-motifs--STT with about 73 residues in classes I
      and II and ST with about 47 residues in class III. The 12 LRRs in the small
      proteoglycans of I and II are best represented as (STT)4; the seven LRRs of class
      III as (ST)T(ST)2. Our analyses indicate that classes I/II and III evolved along
      different paths after the establishment of the precursor ST, and classes I and II
      also diverged after the establishment of the precursor (STT)4.

PMID- 10656268
TI  - Role of hydrophobic interactions in yeast phosphoglycerate kinase stability.
AB  - Cold denaturation of yeast phosphoglycerate kinase (yPGK) was investigated by a
      combination of far UV circular dichroism (CD), steady-state and time-resolved
      fluorescence, and small angle X-ray scattering. It was shown that cold
      denaturation of yPGK cannot be accounted for by a simple two-state process and
      that an intermediate state can be stabilized under mild denaturing conditions.
      Comparison between far UV CD and fluorescence shows that in this state the
      protein displays a fluorescence signal corresponding mainly to exposed
      tryptophans, whereas its CD signal is only partially modified. Comparison with
      spectroscopic data obtained from a mutant missing the last 12 amino-acids (yPGK
      delta404) suggests that lowering the temperature mainly results in a
      destabilization of hydrophobic interactions between the two domains. Small angle
      X-ray scattering measurements give further information about this stabilized
      intermediate. At 4 degrees C and in the presence of 0.45 M Gdn-HCl, the main
      species corresponds to a protein as compact as native yPGK, whereas a significant
      proportion of ellipticity has been lost. Although various techniques have shown
      the existence of residual structures in denatured proteins, this is one example
      of a compact denatured state devoid of its main content in alpha helices.

PMID- 10656269
TI  - Monitoring of gene transfer for cancer therapy with radioactive isotopes.

PMID- 10656270
TI  - The search for consistency in the manufacture of PET radiopharmaceuticals.
AB  - Nuclear Medicine is the specialty of medical imaging, which utilizes a variety of
      radionuclides incorporated into specific compounds for diagnostic imaging and
      therapeutic applications. During recent years, research efforts in this
      discipline have concentrated on the decay characteristics of particular
      radionuclides and the design of unique radiolabeled tracers necessary to achieve
      time-dependent molecular images. Various oncology applications have utilized
      specific PET and SPECT radiopharmaceuticals, which have allowed an extension from
      functional process imaging in tissue to pathologic processes and nuclide directed
      treatments. One of the most widely recognized advantages of positron emission
      tomography (PET) is its use of the attractive, positron-emitting biologic
      radiotracers that mimic natural substrates. However, a major disadvantage is that
      these substances are relatively short-lived and unable to be transported great
      distances. At this time, economic considerations and regulatory guidelines
      associated with the creation of a PET facility, as well as the operational costs
      of maintaining both the facility and the necessary procedural documentation,
      continue to create interesting strategic dilemmas. This commentary will focus on
      the current approach and anticipated impact of pending regulations, which relate
      to the manufacture and formulation of a variety of PET radiopharmaceuticals used
      in clinical research and patient management at Memorial Hospital.

PMID- 10656271
TI  - Validity of 99mTc-DMSA renal uptake by planar posterior-view method in children.
AB  - Renal uptake of 99mTc-DMSA has been quantified by various methods. The aim of
      this study is to obtain a normal value for 99mTc-DMSA renal uptake calculated by
      the posterior view method and age variation, and to assess its clinical validity.
      Scintigrams of 238 children (0-12 years) with 99mTc-DMSA were reviewed. All the
      children had a clinical history of primary vesicoureteral reflux and/or
      neurogenic bladder, ureteral or urethral anomalies. Their kidneys were divided
      into two groups, "normal" and "abnormal" according to their scintigraphic
      findings and split renal functions. Percent renal uptake per injected dose (% RU)
      was quantitated from planar images at 2 hours after injection of an age-adjusted
      dose (26-95 MBq) of 99mTc-DMSA. Calculated total % RU, individual % RU of the
      right and left kidneys (mean +/- sd) in patients with normal kidneys were 40.7 +/
      5.0%, 20.2 +/- 3.0%, 20.4 +/- 2.7%, respectively. There was no significant
      correlation between % RU and age (r = 0.231). Longitudinal variation in the % RU
      in 9 patients ranged from 1.2% to 18%. Our conventional method for quantifyng %
      RU is simple, practical and feasible in routine clinical practice, especially for
      children under follow up.

PMID- 10656272
TI  - Comparison of Tc-99m MDP, Tc-99m HSA and Tc-99m HIG uptake in rheumatoid
      arthritis and its variants.
AB  - Tc-99m polyclonal immunoglobulin-G has been shown to be a successful agent in the
      depiction of active inflammation in rheumatoid arthritis (RA). The objective of
      this study was to compare the uptake behaviors of Tc-99m HIG and Tc-99m MDP in RA
      and variants of rheumatoid arthritis (VRA). Seventeen patients with RA and 8
      patients with VRA presenting with active inflammation were included in this
      study. Ten subjects with well-diagnosed degenerative joint disease constituted
      the control group. All joints in patients were also imaged with Tc-99m HSA to
      evaluate the vascularization status of the joints. Tc-99m HIG and HSA scans were
      obtained at 2, 4 and 24 hours after the injection of 555 MBq Tc-99m HIG and 296
      MBq Tc-99m HSA. Conventional bone scans were performed 4 hours after the
      injection of 740 MBq Tc-99m MDP. Target-to-background (T/B) ratios were obtained
      exclusively over the joint regions. Tc-99m HIG T/B ratios of the active joints in
      RA were significantly higher than those of the non-active joints and the control
      group (p < 0.05). Tc-99m HIG T/B ratios in active joints showed a progressive
      increase between 2 and 24 hour images (p < 0.05). In contrast, Tc-99m HSA T/B
      ratios decreased in all active joints significantly (p < 0.05) except the ankle
      joint region (p > 0.05). The T/B ratios in Tc-99m MDP bone scans were higher in
      all active joints than in non-active RA joints and joints of controls but
      significantly differences were only detected in wrist and elbow joints. All
      clinically active joints in VRA patients accumulated Tc-99m HIG and HSA, and
      showed increased Tc-99m MDP uptake. These joints had a very similar Tc-99m HIG
      retention pattern to the RA joints. The detection rate of active joint
      inflammation with Tc-99m HIG was much higher than that with Tc-99m MDP. The
      increasing Tc-99m HIG uptake ratio between 2 and 24 hours in contrast to Tc-99m
      HSA indicates the presence of other binding mechanisms besides increased
      vascularity in RA.

PMID- 10656273
TI  - Effect of edetate calcium disodium on yttrium-90 activity in bone of mice.
AB  - The kinetics of Yttrium-90 (Y-90) in bone of mice was investigated in combination
      with edetate calcium disodium (CaNa2EDTA). One group of mice were
      intraperitoneally administered 37.5 mg/kg CaNa2EDTA or 0.9% NaCl as a control at
      1, 22, 34, 46, 58, 70, 82, 94, 154 and 166 h after injection of Y-90 acetate
      (post-administration), and the biodistribution was studied at 3, 24, 72, 120 and
      168 h postinjection of Y-90 acetate. No difference between the post-CaNa2EDTA
      treated mice and the control was demonstrated in the radioactivity in the bone. A
      decrease in radioactivity in the liver and kidneys was accelerated, and the
      radioactivity was lower than the control at 120 h postinjection. The other group
      of mice were also given the same dose of chelator at 12 h and 1 h preinjection of
      Y-90 acetate and at 1, 22, 34, 46, 58, 70, 82, 94, 154 and 166 h after injection
      of Y-90 acetate (pre- and post-administration), the radioactivity in bone at 3 h
      postinjection was significantly lower than in the control (24.4 +/- 3.92% ID/g
      vs. 31.7 +/- 2.26% ID/g, p < 0.05), but the decrease was not sequential. A
      significant reduction in radioactivity in the blood, kidneys and liver was
      demonstrated at 3 h, 72 h and 72 h postinjection. In conclusion, the CaNa2EDTA
      with the administration schedule employed here cannot chelate the Y-90 from bone
      but the free Y-90 before deposition into bone.

PMID- 10656274
TI  - Reappraisal of Tc-99m DMSA scintigraphy for follow up in children with
      vesicoureteral reflux.
AB  - We reviewed Tc-99m DMSA scintigraphy in children with vesicoureteral reflux (VUR)
      in order to assess whether repeated Tc-99m DMSA scans are necessary for the
      follow up of these patients. Ninety-seven children who were followed up for more
      than one year (1-7.4 years, average 2.8 years) after the first DMSA scan were
      included in the study. Fifty-one patients had been diagnosed as primary VUR and
      46 as secondary VUR. Age at the first examination ranged from 0 to 14 years
      (average 5.1 years). Planar images were taken 2 hours after injection. The %
      renal uptake per injected dose (%RU) was calculated from posterior images.
      Kidneys in 11 patients (11.3%) changed morphologically during the follow up. Of
      these, new photon deficient areas (PD) were detected in only 4 patients (4.1%).
      All of these 4 patients had neurogenic bladder and were managed with self
      catheterization. Of the remaining 7 patients, cortical thinning progressed in 5
      patients (5.2%) and PDs resolved in 3 patients (3.1%). In one of these 7
      patients, PD resolved in one kidney and cortical thinning progressed in the
      contralateral kidney. Of 97 patients reviewed, % RU decreased more than 20%
      during the follow up in 6 patients (6.2%). All were diagnosed as secondary VUR
      due to neurogenic bladder. %RU decreased only in the contracted kidneys at the
      initial scan. Two of them underwent renal transplantation because of severe renal
      failure. In conclusion, new PD rarely developed and % RU decreased in only a few
      patients during the follow up of children with VUR. Repeated Tc-99m DMSA
      scintigraphy therefore seems to have little benefit in the follow up of children
      with VUR. It should be performed in selected patients with high risk of urinary
      tract infection or renal failure.

PMID- 10656275
TI  - Tumor scintigraphy by the method for subtracting the initial image with
      technetium-99m labeled antibody.
AB  - The method for subtracting the initial image from the localization image was
      evaluated for radioimmunoscintigraphy of tumors with technetium-99m (Tc-99m)
      labeled antibodies. Monoclonal antibodies were parental mouse and mouse-human
      chimeric antibodies to carcinoembryonic antigen (CEA), designated F11-39 and
      ChF11-39, respectively, both of which have been found to discriminate CEA in
      tumor tissues from the CEA-related antigens. After reduction of the intrinsic
      disulfide bonds, these antibodies were labeled with Tc-99m. In vivo studies were
      performed on athymic nude mice bearing the human CEA-producing gastric carcinoma
      xenografts. Though biodistribution results showed selective and progressive
      accumulation of Tc-99m labeled antibodies at the tumor site, high radioactivity
      in blood was inappropriate for scintigraphic visualization of the tumors within a
      few hours. We examined the subtraction of the initial Tc-99m image from the Tc
      99m localization image after a few hours. Subtracted images of the same count
      reflected the in vivo behavior of the Tc-99m radioactivity. The subtracted
      scintigrams revealed excellent tumor images with no significant extrarenal
      background. Visualization of the tumor site was dependent on antigen-specific
      binding and nonspecific exudation. These results demonstrate that a method of
      subtraction of the initial image may serve as a potentially useful diagnostic
      method for an abnormal site for agents with a low pharmacokinetic value.

PMID- 10656276
TI  - Landau-Kleffner syndrome: relation of clinical, EEG and Tc-99m-HMPAO brain SPECT
      findings and improvement in EEG after treatment.
AB  - Landau-Kleffner syndrome (LKS) is a rare childhood disorder characterized by
      acquired aphasia with seizures and electroencephalogram (EEG) abnormalities. Tc
      99m-HMPAO SPECT was performed in three right handed children with LKS. A relative
      decrease in perfusion was found in the left temporal cortex of all three patients
      and also in the left frontoparietal cortex of one patient with hyperkinetic
      behavior. Degree of regional cerebral perfusion impairment did not correlate with
      the severity of clinical and EEG abnormalities. Asymmetrical temporoparietal
      perfusion appears characteristic of LKS. SPECT findings in LKS were evaluated as
      useful in elucidating the pathogenic features of the disorder in the brain.

PMID- 10656277
TI  - Visualization of esophageal non-Hodgkin's lymphoma with Ga-67 scintigraphy.
AB  - Although non-Hodgkin's lymphoma of the gastrointestinal tract is common, primary
      esophageal lymphomas represent less than 1% of all gastrointestinal tumors. We
      report a case of primary non-Hodgkin's lymphoma of the esophagus. Ga-67
      scintigraphy showed characteristic intense accumulation in the esophageal wall.
      The histopathology belonged to the category of mucosa-associated lymphoid tissue
      lymphoma.

PMID- 10656278
TI  - Scintigraphic demonstration of renal cell carcinoma with I-131-6beta-iodomethyl
      19-norcholesterol: a case report.
AB  - Extraadrenal abnormal uptake on adrenocortical scintigraphy has been reported
      rarely in the normal gallbladder, lipid cell tumor of the ovary, or in clear cell
      type renal cell carcinoma. Clear cell type renal cell carcinoma contains glycogen
      and cholesterol like the adrenal gland, but the uptake of the radionuclide I-131
      cholesterol has been reported to be low and not sufficient to image it. Right
      renal and adrenal masses were incidentally discovered on abdominal CT scan in a
      patient with chronic renal failure resulting in bilateral acquired cystic kidney
      disease. Adrenocortical scintigraphy done to know the nature of the adrenal mass
      showed high uptake corresponding to the right renal mass and the right adrenal
      mass. Clear cell type renal cell carcinoma and adrenal adenoma with prominent
      clear cells were histologically confirmed on hematoxylin-eosin stain and in an
      immunohistochemical study with renal cell antibody. Not only low-density
      lipoprotein receptors mediated uptake but also overall replacement of the right
      non-tumorous renal parenchyma by acquired cysts may have played a role in imaging
      the renal cell carcinoma on adrenocortical scintigraphy.

PMID- 10656279
TI  - Two cases of focal nodular hyperplasia of the liver: value of scintigraphy with
      Tc-99m GSA and positron emission tomography with FDG.
AB  - Focal nodular hyperplasia (FNH) of the liver is relatively rare, and can be
      difficult to differentiate from other benign tumors arising in the liver. We
      describe a 23-year-old woman and a 25-year-old man with FNH. They were
      hospitalized for further evaluation of a space-occupying lesion in the liver.
      Scintigraphy with Tc-99m diethylenetriaminepentaacetic acid galactosyl human
      serum albumin (Tc-99m GSA) revealed increased radioactivity in the tumor in one
      patient and radioactivity similar to that in the normal part of liver in the
      other. F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) showed
      uptake similar to that of the normal liver in both patients. FNH was diagnosed on
      the basis of angiographic findings and histological findings in liver biopsy
      specimens. Our results show that scintigraphy with Tc-99m GSA and FDG-PET may
      provide information helpful in the diagnosis of FNH.

PMID- 10656281
TI  - MR and Tc-99m HMPAO SPECT images in a case of unusual widening of perivascular
      spaces (Virchow-Robin spaces).
AB  - We report a rare case of unusual widening of perivascular spaces (Virchow-Robin
      spaces). MR images showed multiple small round cystic areas along the perforating
      medullary arteries with signal intensity identical to the cerebrospinal fluid
      predominantly in the right cerebral white matter. Tc-99m HMPAO SPECT images
      showed no remarkable laterality and no definite ischemic lesion, and the
      neurological status of the patient was not remarkable. MR was a diagnostic
      examination and Tc-99m HMPAO SPECT was a useful supplementary examination in the
      evaluation of this case of unusual widening of Virchow-Robin spaces.

PMID- 10656280
TI  - Plummer's disease with spontaneous progression to hypothyroidism.
AB  - A case of Plummer's disease that spontaneously progressed to hypothyroidism is
      presented. A 49-year-old female visited our hospital because of a 3 kg decrease
      in body weight during the previous month and a painless nodule in the right
      anterior area of her neck. A diagnosis of Plummer's disease was made based on the
      results of thyroid function tests, thyroid scintigrams, and an ultrasonogram, but
      the patient's disease followed an usual clinical course. About two months later,
      she gradually developed manifestations of permanent hypothyroidism, and anti
      thyroid autoantibodies became positive. In spite of continuous administration of
      levothyroxine sodium, uptake of 99mTcO4- to the nodule was unchanged or rather
      increased according to the consecutive thyroid scintigraphies. These results
      suggested that this case represented an autonomously functioning nodule with
      underlying silent thyroiditis and Hashimoto's disease.

PMID- 10656282
TI  - Respiratory failure and pulmonary hypertension associated with Klippel-Feil
      syndrome.
AB  - A 28-year-old woman with a deformed thorax and kyphoscoliosis associated with
      Klippel-Feil syndrome developed respiratory failure with pulmonary hypertension.
      Pulmonary 133Xe ventilation and 99mTc-MAA perfusion scintigraphies showed
      maldistributions of lung ventilation and perfusion, and noticeably delayed 133Xe
      washout from the lungs. Dynamic breathing MR imaging showed poor and/or
      asynchronous respiratory movements of the chest wall and diaphragm. These
      findings indicate that the perfusion-ventilation imbalance, the decreased
      ventilatory turnover, and expiratory flow from the alveolar space partly derived
      from the impaired respiratory mechanics may be responsible for the respiratory
      complications in this patient.

PMID- 10656284
TI  - Breast parenchymal activity on scintimammography: comparison between bone-seeking
      agents and 99mTc-sestamibi.
AB  - The aim of this study was to evaluate breast parenchymal activity on
      scintimammography with bone-seeking agents and 99mTc-MIBI. Scintimammography was
      performed with bone-seeking agents in 61 patients and with 99mTc-MIBI in 33
      patients. Activity in the breast parenchyma contralateral to the suspected lesion
      was visually assessed by two independent observers. Increased breast parenchymal
      activity was shown in 19 of 61 patients examined with bone-seeking agents, while
      it was demonstrated in only two of 33 patients examined with 99mTc-MIBI. Breast
      parenchymal activity of bone-seeking agents was higher in patients aged 50 years
      or younger than in those older than 50. Increased parenchymal activity of bone
      seeking agents may disturb visualization of primary breast cancer especially in
      relatively young patients. Low parenchymal activity is suggested to be a
      favorable characteristic of 99mTc-MIBI as a scintimammographic agent.

PMID- 10656283
TI  - Iodine-123 iodobenzofuran (I-123 IBF) SPECT in patients with parkinsonism.
AB  - I-123 IBF is a dopaminergic antagonist which is suitable for SPECT imaging of D2
      receptors. The purpose of this study is to evaluate the potential usefulness of
      semi-quantitative parameters obtained from brain SPECT data of I-123 IBF for
      differential diagnosis in patients with parkinsonism (PN). Subjects were 10
      patients with PN: 2 patients with striato-nigral degeneration (SND), 5 patients
      with Parkinson's disease (PD), 2 patients with progressive supranuclear palsy
      (PSP) and one patient with olivo-ponto-cerebellar atrophy (OPCA). The data were
      acquired with a triple-head gamma camera at 2 hours after intravenous injection
      of 167 MBq of I-123 IBF. Transverse images were reconstructed by means of
      filtered backprojection, and attenuation correction was performed by Chang's
      method (mu = 0.08). The basal ganglia-to-frontal cortex ratio (GFR) and the basal
      ganglia-to-occipital cortex ratio(GOR) on slices of 5 different thicknesses were
      calculated. The GFR and GOR were lower in the SND group than in the other disease
      groups in all slices with different thicknesses (7.2 mm, 14.4 mm, 21.6 mm, 28.8
      mm and 43.2 mm). The semiquantitative parameters (GFR and GOR) obtained from
      brain SPECT data at 2 hours after intravenous injection of I-123 IBF may be
      useful for differential diagnosis in patients with PN.

PMID- 10656285
TI  - DNA damage in human leukocytes after ischemia/reperfusion injury.
AB  - Leukocytes have been shown to play an important role in the development of tissue
      injury after ischemia and reperfusion (I/R). In the present study, the effects of
      tourniquet-ischemia on induction of DNA damage in peripheral leukocytes and on
      respiratory burst of neutrophils in humans were examined. The DNA damage was
      measured as increased migration of DNA using the single-cell gel-electrophoresis
      technique (comet assay). Intracellular production of reactive oxygen species by
      neutrophils was measured flow-cytometrically using dihydrorhodamine 123 as
      indicator. Postischemic, significantly increased migration of DNA was found in
      leukocytes of 20 patients (tourniquet-ischemia of the lower limb for 65-130 min,
      anterior-cruciate-ligament-reconstruction) and in 10 experiments (1 volunteer,
      repeated tourniquet-ischemia of the upper limb for 60 min, no operation). DNA
      effects were most pronounced 5-30 min after tourniquet release, and then declined
      over a 2 h period, but did not return to preischemic baseline values. A similar
      time course showed the oxidative status of unstimulated granulocytes during
      reperfusion. Simultaneously, opposing changes were measured in formyl peptide (f
      MLP)- or phorbol ester (PMA)-stimulated granulocytes, which showed a
      significantly declined respiratory burst reaction after tourniquet-release
      indicating preactivation of neutrophils by IR. Our data suggest that IR induces
      genotoxic effects in human leukocytes presumably in response to oxidative stress
      during reperfusion.

PMID- 10656286
TI  - Levels of 8-hydroxydeoxyguanosine as a marker of DNA damage in human leukocytes.
AB  - We measured 8-hydroxy-2-deoxyguanosine (8-OHdG) levels in human leukocytes from
      healthy donors to evaluate oxidative DNA damage and its correlation with smoking,
      physical exercise, and alcohol consumption. A significant increase in oxidative
      DNA damage was induced by cigarette smoke, with the mean level of 8-OHdG being
      significantly higher in smokers (33.1 +/- 10.6 per 10(6) 2-deoxyguanosine (dG)
      [mean +/- SE], n = 16) compared with nonsmokers (15.3 +/- 1.8 per 10(6) dG, n =
      31) and former smokers (17.8 +/- 1.5 per 10(6) dG, n = 9). The highest values
      were observed after smoking more than 10 cigarettes per day (41.8 +/- 17.1 per
      10(6) dG, n = 9). A large interindividual variation in 8-OHdG levels was observed
      in all analyzed groups. We also observed a correlation between 8-OHdG levels and
      age in nonsmokers and former smokers. Neither frequency of physical exercise nor
      alcohol drinking significantly modified 8-OHdG levels in leukocytes.

PMID- 10656287
TI  - Oxidative stress involvement in chemically induced differentiation of K562 cells.
AB  - The erythroid differentiation of K562 cells could be achieved by exposure to
      several pharmacologic agents, including hemin, butyric acid (BA), and
      anthracycline antitumor drugs such as aclarubicin (ACLA) and doxorubicin (DOX).
      When used at subtoxic concentrations, these drugs induce the overexpression of
      erythroid genes, leading to hemoglobinization of cells. Because anthracyclines
      are known to generate oxidative damage, we intended to demonstrate the
      involvement of an oxidative stress in the chemically induced differentiation
      process. The addition of antioxidants to anthracycline- and BA-induced cells
      decreased their growth and dramatically reduced the percentage of differentiated
      cells at day 3. Northern blot analysis showed that antioxidants also decrease the
      expression of erythroid genes and related transcription factors in induced cells.
      Moreover, analyses of oxidative stress markers showed that treatment with BA,
      ACLA, and DOX lead to a decrease in reduced glutathione and antioxidant enzymes
      (glutathione peroxidase [GPx], glutathione reductase [GRase], CuZn superoxide
      dismutase [SOD], and catalase [CAT]). In addition, DOX increased thiobarbituric
      acid reactants (TBARs), and MnSOD activity was decreased by BA and DOX. Finally,
      the production of reactive oxygen species (ROS) by differentiating agents was
      demonstrated using the dihydroethidium probe in a microspectrofluorometric assay.
      Altogether, these results strongly suggest the involvement of an oxidative stress
      generated by BA or anthracyclines as the first step in the irreversible
      differentiation process. Additionally, these results underline the differences
      between BA, ACLA, and DOX molecular mechanisms.

PMID- 10656288
TI  - Hydrogen peroxide inhibits epidermal growth factor receptor internalization in
      human fibroblasts.
AB  - Several cellular signal transduction cascades are affected by oxidative stress.
      In this study, the effect of hydrogen peroxide (H2O2) on the endocytosis of the
      epidermal growth factor (EGF) receptor was investigated. Exposure of HER14 cells
      to H2O2 resulted in a concentration-dependent inhibition of EGF receptor
      internalization. Binding studies demonstrated that this H2O2-induced inhibition
      in internalization was not due to altered binding of EGF to its receptor.
      Addition of H2O2 at different time points during internalization showed that EGF
      receptor internalization was rapidly reduced, suggesting that one of the first
      steps in the internalization process is inhibited. In addition, H2O2 inhibited
      the internalization of a different receptor, the chicken hepatic lectin receptor,
      in a concentration-dependent manner as well. Treatment of cells with another
      inducer of oxidative stress, cumene hydroperoxide, also resulted in a decreased
      internalization. Finally, we showed that H2O2 inhibited EGF-induced mono
      ubiquitination of the EGF receptor pathway substrate clone 15, a process that
      normally occurs during EGF receptor endocytosis. These results clearly show that
      oxidative stress interferes with EGF signaling.

PMID- 10656289
TI  - Homocysteine exerts cell type-specific inhibition of AP-1 transcription factor.
AB  - Homocysteine (Hcy) exerts either promoting or suppressive effects on mitogenesis
      in a cell type-specific manner. Hcy elicits proliferation of vascular smooth
      muscle cells, but is rather inhibitory to growth of endothelial cells and NIH/3T3
      cells. In NIH/3T3 cells, we found that physiologically relevant concentrations
      (20-100 microM) of Hcy inhibit the activity of activating protein-1 (AP-1)
      transcription factor, although it is capable of eliciting immediate-early
      signaling events. Hcy induced p44/42 mitogen-activated protein kinase (MAPK)
      phosphorylation in control cells, but not in dominant negative p21ras transfected
      cells, indicating induction of the Ras-MAPK pathway. Hcy also induced the
      activity of serum response factor and expression of c-fos and c-jun genes.
      Despite the activation of these upstream events, Hcy potently inhibited AP-1
      activity. Oxidized forms of Hcy (Hcy thiolactone, homocystine) were less
      effective in affecting AP-1. Hcy-mediated inhibition of AP-1 activity was not
      observed in A7r5 vascular smooth muscle cells. These results demonstrate that Hcy
      exerts cell type- and redox-specific inhibition of AP-1 dependent biological
      events.

PMID- 10656290
TI  - Modulation of endoplasmic reticulum-bound cholesterol regulatory enzymes by
      iron/ascorbate-mediated lipid peroxidation.
AB  - Mammalian sterol regulatory enzymes are integral membrane proteins of the
      endoplasmic reticulum. They play a critical role in liver cholesterol homeostasis
      and the maintenance of overall cholesterol balance in different species. Because
      lipid peroxidation has been implicated in hepatic dysfunction and
      atherosclerosis, we hypothesized that its occurrence could alter the composition
      and properties of the bilayer lipid environment, and thereby affect the functions
      of these membrane proteins. Preincubation of rat liver microsomes with iron
      (Fe)/ascorbate (50 microM/200 microM), known to induce peroxidation, resulted in
      a significant inhibition of (i) the rate-limiting enzyme in cholesterol
      biosynthesis, HMG-CoA reductase (46%, p < .01), (ii) the crucial enzyme
      controlling the conversion of cholesterol in bile acids, cholesterol 7alpha
      hydroxylase (48%, p < .001), and (iii) the central enzyme for cholesterol
      esterification: Acyl-CoA:cholesterol acyltransferase (ACAT, 80%, p < .0001). The
      disturbances of these key enzymes took place concomitantly with the high
      production of malondialdehyde (350%, p < .007) and the loss of polyunsaturated
      fatty acids (36.19 +/- 1.06% vs. 44.24 +/- 0.41 in controls, p < .0008). While
      alpha-tocopherol simultaneously neutralized lipid peroxidation, preserved
      microsomal fatty acid status, and restored ACAT activity, it was not effective in
      preventing Fe/ascorbate-induced inactivation of both HMG-CoA reductase (44%, p <
      .01) and cholesterol 7alpha-hydroxylase (71%, p < .0001). These results indicate
      that Fe/ascorbate alters the activity of the rate-determining steps in liver
      cholesterol metabolism, either directly or via lipid peroxidation, capable of
      modifying their membrane environment. The present data also suggest that the
      three regulatory enzymes respond differently when exposed to Fe/ascorbate or
      antioxidants, which may be due to dissimilar mechanisms.

PMID- 10656292
TI  - Accumulation of single-strand breaks is the major cause of telomere shortening in
      human fibroblasts.
AB  - Telomere shortening triggers replicative senescence in human fibroblasts. The
      inability of DNA polymerases to replicate a linear DNA molecule completely (the
      end replication problem) is one cause of telomere shortening. Other possible
      causes are the formation of single-stranded overhangs at the end of telomeres and
      the preferential vulnerability of telomeres to oxidative stress. To elucidate the
      relative importance of these possibilities, amount and distribution of telomeric
      single-strand breaks, length of the G-rich overhang, and telomere shortening rate
      in human MRC-5 fibroblasts were measured. Treatment of nonproliferating cells
      with hydrogen peroxide increases the sensitivity to S1 nuclease in telomeres
      preferentially and accelerates their shortening by a corresponding amount as soon
      as the cells proliferate. A reduction of the activity of intracellular peroxides
      using the spin trap alpha-phenyl-t-butyl-nitrone reduces the telomere shortening
      rate and increases the replicative life span. The length of the telomeric single
      stranded overhang is independent of DNA damaging stresses, but single-strand
      breaks accumulate randomly all along the telomere after alkylation. The telomere
      shortening rate and the rate of replicative aging can be either accelerated or
      decelerated by a modification of the amount of oxidative stress. Quantitatively,
      stress-mediated telomere damage contributes most to telomere shortening under
      standard conditions.

PMID- 10656291
TI  - DNA damage in arsenite- and cadmium-treated bovine aortic endothelial cells.
AB  - Reactive oxygen species have been shown to be involved in the mutagenicity,
      clastogenicity, and apoptosis of mammalian cells treated with arsenic or cadmium.
      As these endpoints require several hours of cellular processing, it is not clear
      that reactive oxygen species damage DNA directly or interfere with DNA
      replication and repair. Using single-cell alkaline electrophoresis, we have
      detected DNA strand breaks (DSBs) in bovine aortic endothelial cells by a 4-h
      treatment with sodium arsenite (As) and cadmium chloride (Cd) in sublethal
      concentrations. As-induced DSBs could be decreased by nitric oxide (NO) synthase
      inhibitors, superoxide scavengers, and peroxynitrite scavengers and could be
      increased by superoxide generators and NO generators. Treatment with As also
      increased nitrite production. These results suggest that As-increased NO may
      react with O2*- to produce peroxynitrite and cause DNA damage. The results
      showing that Cd increased cellular H2O2 levels and that Cd-induced DSBs could be
      modulated by various oxidant modulators suggest that Cd may induce DSBs via O2*-,
      H2O2, and *OH. Nevertheless, the DSBs in both As- and Cd-treated cells seem to
      come from the excision of oxidized bases such as formamidopyrimidine and 8
      oxoguanine, as the Escherichia coli enzyme formamidopyrimidine-DNA glycosylase
      (Fpg) increased DSBs in cells treated with As, 3-morpholinosydnonimine (a
      peroxynitrite-generating agent), Cd, or H2O2.

PMID- 10656293
TI  - Fapyadenine is a moderately efficient chain terminator for prokaryotic DNA
      polymerases.
AB  - Hypoxanthine?xanthine oxidase?Fe3+?ethylenediaminetetraacetate (EDTA) was used to
      modify ss M13 mp18 phage DNA. The dominant base modifications found by GC/IDMS
      SIM were FapyGua, FapyAde, 8-hydroxyguanine, and thymine glycol. Analysis of in
      vitro DNA synthesis on oxidatively modified template by three DNA polymerases
      revealed that T7 DNA polymerase and Klenow fragment of polymerase I from
      Escherichia coli were blocked mainly by oxidized pyrimidines in the template
      whereas some purines that were easily bypassed by the prokaryotic polymerases
      constituted a block for DNA polymerase beta from calf thymus. DNA synthesis by T7
      polymerase on poly(dA) template, where FapyAde content increased 16-fold on
      oxidation, yielded a final product with a discrete ladder of premature
      termination bands. When DNA synthesis was performed on template from which
      FapyAde, FapyGua, and 8OHGua were excised by the Fpg protein new chain
      terminations at adenine and guanine sites appeared or existing ones were
      enhanced. This suggests that FapyAde, when present in DNA, is a moderately toxic
      lesion. Its ability to arrest DNA synthesis depends on the sequence context and
      DNA polymerase. FapyGua might possess similar properties.

PMID- 10656294
TI  - Effect of exhaustive exercise on membrane estradiol concentration, intracellular
      calcium, and oxidative damage in mouse thymic lymphocytes.
AB  - Early Ca2+ signaling events in cells of the immune system after exhaustive
      exercise challenge (8% slope, 32 m/min(-1) speed) of female C57BL/6 mice, and
      their effects on oxidative reactions in thymus were studied. Intracellular Ca2+
      and the oscillation of free extracellular Ca2+ were imaged with cell permeant
      cell and cell impermeant Fluo 3 calcium indicator in thymocytes. The role of
      estradiol was assessed by RIA for levels of membrane bound estradiol. Oxidative
      product release and membrane lipid peroxide were also evaluated. Intracellular
      Ca2+ levels were significantly higher in thymocytes of exercised compared with
      control mice (p < .001). There was a continuous flux of Ca2+ after exercise when
      cells were monitored in Ca2+ rich medium, with a significant influx between 160
      and 200 sec (p < .001). Membrane bound estradiol was elevated in thymocytes of
      exercised compared to control mice (p < .05). Immediately after exercise there
      was a greater release of oxidative products by thymocytes in exhaustively
      exercised compared with control animals. There was also significant generation of
      lipid peroxide in thymus of exercised mice (p < .001). The findings suggest that
      exhaustive exercise may stimulate estradiol uptake by receptors on thymocytes,
      with a possible opening up of estradiol-receptor operated channels for Ca2+ entry
      into cells. This may have damaging effects on thymic lymphocytes by the
      triggering of oxidative reactions as determined by higher oxidative product
      release and greater generation of lipid peroxide.

PMID- 10656295
TI  - Increased H2O2, vascular endothelial growth factor and receptors in the retina of
      the BBZ/Wor diabetic rat.
AB  - Hyperglycemia in diabetes induces increased levels of hydrogen peroxide (H2O2), a
      reactive oxygen species generated by reduced nicotinamide adenine dinucleotide
      (NADH) oxidase. Nontoxic levels of H2O2 increase endothelial cell permeability.
      Using a model of non-insulin-dependent diabetes, the BBZ/Wor rat, we investigated
      retinal levels of H2O2, vascular endothelial growth factor (VEGF) and its
      receptors, VEGF-R1 and VEGF-R2 by transmission electron microscopy at sites of
      the blood-retinal barrier (BRB). H2O2 localization was done by the cerium NADH
      oxidase method, and extravasation of endogenous serum albumin was used to
      document disruption of the BRB. Higher levels of H2O2 were detected in blood
      vessels of diabetic (78.7 +/- 4.84%) as compared with vessels from nondiabetic
      rats (39.0 +/- 4.47%). VEGF immunoreactivity was statistically higher in the
      inner BRB (24.67 +/- 0.33 colloidal gold particles/63 microm2 vs. 21.52 +/- 0.43
      colloidal gold particles/63 microm2, p = .0001) and outer BRB (42.56 +/- 0.45
      colloidal gold particles/63 microm2 vs. 15.51 +/- 0.51 colloidal gold
      particles/63 microm2, p = .0001) of diabetic rats as compared with age matched
      nondiabetic control rats. VEGF-R1 immunoreactivity was significantly higher in
      diabetic retinas in both the inner BRB (21.66 +/- 0.75 colloidal gold
      particles/63 microm2 vs. 12.69 +/- 0.61 colloidal gold particles/63 microm2, p =
      .0001) and outer BRB (22.76 +/- 2.36 colloidal gold particles/63 microm2 vs. 8.53
      +/- 2.67 colloidal gold particles/63 microm2, p = .0013). VEGF-R2 was
      statistically higher in the inner BRB (8.97 +/- 0.57 colloidal gold particles/63
      microm2 versus 7.03 +/- 0.65 colloidal gold particles/63 microm2, p = .0419) but
      not in the outer BRB (29.42 +/- 1.25 colloidal gold particles/63 microm2 vs.
      28.07 +/- 1.42 colloidal gold particles/63 microm2, p = .4889). H2O2 levels
      correlated with increased VEGF (correlation coefficient = 0.82, p = .001) in this
      model of nonproliferative diabetic retinopathy. These results support that
      hyperglycemia is one factor that induces retinal endothelial cells in vivo to
      increase H2O2 via NADH oxidase and stimulates increases in VEGF resulting in
      disruption of the BRB.

PMID- 10656297
TI  - Streptococcus mutans H2O2-forming NADH oxidase is an alkyl hydroperoxide
      reductase protein.
AB  - Nox-1 from Streptococcus mutans, the bacteria which cause dental caries, was
      previously identified as an H2O2-forming reduced nicotinamide adenine
      dinucleotide (NADH) oxidase. Nox-1 is homologous with the flavoprotein component,
      AhpF, of Salmonella typhimurium alkyl hydroperoxide reductase. A partial open
      reading frame upstream of nox1, homologous with the other (peroxidase) component,
      ahpC, from the S. typhimurium system, was also identified. We report here the
      complete sequence of S. mutans ahpC. Analyses of purified AhpC together with Nox
      1 have verified that these proteins act as a cysteine-based peroxidase system in
      S. mutans, catalyzing the NADH-dependent reduction of organic hydroperoxides or
      H2O2 to their respective alcohols and/or H2O. These proteins also catalyze the
      four-electron reduction of O2 to H2O2, clarifying the role of Nox-1 as a
      protective protein against oxygen toxicity. Major differences between Nox-1 and
      AhpF include: (i) the absolute specificity of Nox-1 for NADH; (ii) lower amounts
      of flavin semiquinone and a more prominent FADH2 to NAD+ charge transfer
      absorbance band stabilized by Nox-1; and (iii) even higher redox potentials of
      disulfide centers relative to flavin for Nox-1. Although Nox-1 and AhpC from S.
      mutans were shown to play a protective role against oxidative stress in vitro and
      in vivo in Escherichia coli, the lack of a significant effect on deletion of
      these genes from S. mutans suggests the presence of additional antioxidant
      proteins in these bacteria.

PMID- 10656296
TI  - Characterization of iodoacetate-mediated neurotoxicity in vitro using primary
      cultures of rat cerebellar granule cells.
AB  - The neuroprotective efficacy of antioxidant molecules against iodoacetate (IAA)
      neurotoxicity in rat cerebellar granule cell (CGC) cultures was investigated.
      Transient exposure to IAA caused a concentration-dependent decrease in cell
      viability (ED50 = 9.8 microM). Dizocilpine maleate (MK-801), and 1,2,3,4
      tetrahydro-6-nitro-2,3-dioxobenzo[f]quinoxaline-7-sulfonamide (NBQX), failed to
      prevent IAA toxicity. Certain antioxidant molecules were shown to be
      neuroprotective against IAA when combined with MK-801 but were ineffective when
      administered alone. (S)-(-)-Trolox, butylated hydroxytoluene (BHT), and U-83836E
      exhibited EC50 values of 78, 5.9, and 0.25 microM, respectively, in the presence
      of 10 microM MK-801. IAA also induced an increase in intracellular oxidative
      stress, which was quenched by the antioxidants (in the presence of MK-801) in
      cultures loaded with the oxidant sensitive dye 2'7'-dichlorodihydrofluorescein
      diacetate (DCFH-DA).

PMID- 10656298
TI  - A new approach for extracellular spin trapping of nitroglycerin-induced
      superoxide radicals both in vitro and in vivo.
AB  - Anti-ischemic therapy with nitrates is complicated by the induction of tolerance
      that potentially results from an unwanted coproduction of superoxide radicals.
      Therefore, we analyzed the localization of in vitro and in vivo, glyceryl
      trinitrate (GTN)-induced formation of superoxide radicals and the effect of the
      antioxidant vitamin C and of superoxide dismutase (SOD). Sterically hindered
      hydroxylamines 1-hydroxy-3-carboxy-2,2,5,5-tetramethylpyrrolidine (CP-H) and 1
      hydroxy-4-phosphonooxy-2,2,6,6-tetramethylpiperidin (PP-H) can be used for in
      vitro and in vivo quantification of superoxide radical formation. The
      penetration/incorporation of CP-H or PP-H and of their corresponding nitroxyl
      radicals was examined by fractionation of the blood and blood cells during a 1-h
      incubation. For monitoring in vivo, GTN-induced (130 microg/kg) O2*- formation CP
      H or PP-H were continuously infused (actual concentration, 800 microM) for 90 to
      120 min into rabbits. Formation of superoxide was determined by SOD- or vitamin C
      inhibited contents of nitroxide radicals in the blood from A. carotis. The
      incubation of whole blood with CP-H, PP-H, or corresponding nitroxyl radicals
      clearly shows that during a 1-h incubation, as much as 8.3% of CP-H but only 0.9%
      of PP-H is incorporated in cytoplasm. Acute GTN treatment of whole blood and in
      vivo bolus infusion significantly increased superoxide radical formation as much
      as 4-fold. Pretreatment with 20 mg/kg vitamin C or 15,000 U/kg superoxide
      dismutase prevented GTN-induced nitroxide formation. The decrease of trapped
      radicals after treatment with extracellularly added superoxide dismutase or
      vitamin C leads to the conclusion that GTN increases the amount of extracellular
      superoxide radicals both in vitro and in vivo.

PMID- 10656299
TI  - Differential oxidation of apolipoprotein E isoforms and interaction with
      phospholipids.
AB  - Accumulation of oxidized proteins has been demonstrated in the brain of patients
      suffering from Alzheimer's disease (AD). Among the proteins found in cerebral
      amyloid deposits, apolipoprotein (apo) E is a polymorphic protein which one
      specific isoform, apo E4, has been widely associated with AD. Apo E may be linked
      with AD by its isoform-specific interaction with lipids or other proteins in
      amyloid plaques. Using the myeloperoxidase oxidative system, we report that
      oxidation of the three recombinant apo E isoforms is differential (as estimated
      using immunoblot and high-performance liquid chromatography analysis), with apo
      E4 being more susceptible than apo E3, which in turn is much more susceptible
      than apo E2. In addition, susceptibility to thrombin proteolysis is reduced when
      apo E is oxidized, and oxidation of apo E decreases its incorporation into
      phospholipid discs by approximately 50%. Oxidation of apo E may contribute to
      inefficient lipid recycling in the brain, particularly regarding apo E4 and E3.
      Our results link and strengthen both the E4 allele linkage with AD and the role
      of protein oxidation in AD. The cerebral mechanisms underlying apo E oxidation
      and/or myeloperoxidase functions in vivo remain to be assessed.

PMID- 10656300
TI  - Vitamin E and heart disease: basic science to clinical intervention trials.
AB  - A review is presented of studies on the effects of vitamin E on heart disease,
      studies encompassing basic science, animal studies, epidemiological and
      observational studies, and four intervention trials. The in vitro, cellular, and
      animal studies, which are impressive both in quantity and quality, leave no doubt
      that vitamin E, the most important fat-soluble antioxidant, protects animals
      against a variety of types of oxidative stress. The hypothesis that links vitamin
      E to the prevention of cardiovascular disease (CVD) postulates that the oxidation
      of unsaturated lipids in the low-density lipoprotein (LDL) particle initiates a
      complex sequence of events that leads to the development of atherosclerotic
      plaque. This hypothesis is supported by numerous studies in vitro, in animals,
      and in humans. There is some evidence that the ex vivo oxidizability of a
      subject's LDL is predictive of future heart events. This background in basic
      science and observational studies, coupled with the safety of vitamin E, led to
      the initiation of clinical intervention trials. The three trials that have been
      reported in detail are, on balance, supportive of the proposal that supplemental
      vitamin E can reduce the risk for heart disease, and the fourth trial, which has
      just been reported, showed small, but not statistically significant, benefits.
      Subgroup analyses of cohorts from the older three trials, as well as evidence
      from smaller trials, indicate that vitamin E provides protection against a number
      of medical conditions, including some that are indicative of atherosclerosis
      (such as intermittent claudication). Vitamin E supplementation also produces an
      improvement in the immune system and protection against diseases other than
      cardiovascular disease (such as prostate cancer). Vitamin E at the supplemental
      levels being used in the current trials, 100 to 800 IU/d, is safe, and there is
      little likelihood that increased risk will be found for those taking supplements.
      About one half of American cardiologists take supplemental vitamin E, about the
      same number as take aspirin. In fact, one study suggests that aspirin plus
      vitamin E is more effective than aspirin alone. There are a substantial number of
      trials involving vitamin E that are in progress. However, it is possible, or even
      likely, that each condition for which vitamin E provides benefit will have a
      unique dose-effect curve. Furthermore, different antioxidants appear to act
      synergistically, so supplementation with vitamin E might be more effective if
      combined with other micronutrients. It will be extremely difficult to do trials
      that adequately probe the dose-effect curve for vitamin E for each condition that
      it might affect, or to do studies of all the possible combinations of other
      micronutrients that might act with vitamin E to improve its effectiveness.
      Therefore, the scientific community must recognize that there never will be a
      time when the science is "complete." At some point, the weight of the scientific
      evidence must be judged adequate; although some may regard it as early to that
      judgement now, clearly we are very close. In view of the very low risk of
      reasonable supplementation with vitamin E, and the difficulty in obtaining more
      than about 30 IU/day from a balanced diet, some supplementation appears prudent
      now.

PMID- 10656301
TI  - A look back and a glance ahead.

PMID- 10656302
TI  - Everett Kinsey lecture. The elusive causes of keratoconus: a working hypothesis.
AB  - PURPOSE: Keratoconus is a diseasethat has been recognized clinically for many
      years. However, it is only more recently that a better understanding has been
      achieved in the area of keratoconus pathogenesis. The purpose of this paper is to
      summarize the completed research, review ongoing studies, and present a
      hypothesis for keratoconus pathology. METHODS: We used immunochemistry and
      molecular techniques to characterize keratoconus corneas. RESULTS AND
      CONCLUSIONS: Our hypothesis attempts to incorporate many of the recognized
      biochemical and molecular abnormalities found in the keratoconus corneas. Our
      hypothesis states: 1) there is abnormal processing of the free radicals and
      superoxides within the keratoconus corneas; 2) there is a build-up of destructive
      aldehydes or peroxynitrites within the corneas; 3) the cells that are damaged
      irreversibly undergo the process of apoptosis; and 4) the cells that are damaged
      reversibly undergo wound healing or repair. As part of the wound healing process,
      various degradative enzymes and wound healing factors are upregulated, which
      leads to focal areas of corneal thinning and fibrosis. Future studies will be
      directed to testthis working hypothesis and determine if these theories are
      valid.

PMID- 10656303
TI  - Management of irregular astigmatism with rigid gas permeable contact lenses.
AB  - PURPOSE: The purpose of this study was to measure improvement in best corrected
      visual acuity with rigid gas permeable (RGP) contact lenses compared to best
      corrected spectacle visual acuity for patients with irregular astigmatism.
      METHODS: We compared best corrected visual acuity obtained with spectacle
      correction to best corrected visual acuity obtained with rigid gas permeable
      contact lenses for forty-eight eyes of 29 patients with irregular astigmatism.
      RESULTS: Patients with 20/20 spectacle visual acuity achieved, on average, no
      improvement in visual acuity with RGP contact lenses. Patients with 20/25-20/30
      spectacle visual acuity achieved a one line average improvement. Patients with
      20/40 spectacle visual acuity achieved a two line average improvement. Patients
      with 20/50-20/200 spectacle visual acuity achieved a four line average
      improvement and patients with spectacle visual acuity of 20/400, a six line
      average improvement. CONCLUSIONS: RGP contact lenses can provide a significant
      improvement in visual acuity compared to spectacle correction for patients with
      irregular astigmatism.

PMID- 10656304
TI  - Determination of protein deposits on RGP lenses by X-ray photoelectron
      spectroscopy.
AB  - PURPOSE: To establish a novel and objective screening method for evaluating the
      cleaning efficacy of contact lens care solutions for removal of protein deposits
      on single rigid gas permeable (RGP) lenses. METHODS: New and unworn RGP lenses
      containing no nitrogen atoms were incubated in a standard tear protein test
      solution. Protein deposition on lenses was determined by X-ray photoelectron
      spectroscopy (XPS) before and after standardized cleaning with commercially
      available care solutions (daily cleaners A, B) and a wetting/soaking solution or
      with 0.1w/v% sodium dodecyl sulfate (SDS) as a control. Cleaning efficacy was
      calculated based on the percentage of nitrogen atoms present in the total
      elements of the measured XPS scan spectrum. RESULTS: Nitrogen atoms originating
      from residual protein deposits on RGP lenses after cleaning were determined by
      XPS. The cleaning efficacy of the wetting/soaking solution was lower (74%) than
      that of daily cleaners A and B (95%) or SDS (96%) controls. CONCLUSIONS: XPS
      determination of residual protein deposits is a novel and direct evaluation
      method for determining the cleaning efficacy of RGP lens care solutions for
      single lenses.

PMID- 10656305
TI  - The prevalence and pattern of contact lens use in a Singapore community.
AB  - PURPOSE: We conducted a cross-sectional survey to determine the prevalence, socio
      demographic patterns, and characteristics of contact lens use in an electoral
      community in Singapore. METHODS: One thousand eight hundred fifteen persons aged
      between 12-55 years from 768 households were surveyed using a standardized pre
      tested questionnaire. RESULTS: The percentage of contact lens wearers in the
      survey populations was 9.0%. Forty-two percent of surveyed individuals were
      myopes, 21.8% of whom wore contact lenses. Contact lens wearers tended to be
      young Chinese females with higher level education and incomes. Most wore monthly
      disposable or daily wear soft contact lenses. Convenience and cosmesis were the
      main reasons cited for contact lens wear. Optometrists, who prescribed the bulk
      of contact lenses, were also the most influential in determining consumers'
      choice of lenses. CONCLUSION: Information gathered in this population-based
      survey may be used to facilitate national eye-care planning and provide a
      baseline for comparison with rates of lens wear found in other countries and in
      future surveys.

PMID- 10656306
TI  - Microbiological study of disposable soft contact lenses after photorefractive
      keratectomy.
AB  - PURPOSE: To evaluate the bacterial contamination of bandage disposable soft
      contact lenses used in patients following photorefractive keratectomy (PRK) and
      to correlate our findings with clinical data. METHODS: Forty-six patients (81
      eyes) underwent PRK. Immediately after each procedure, disposable soft contact
      lenses were positioned with sterile forceps. After 3 days, the lenses were
      removed in a sterile manner, placed in sterile Eppendorf pipettes containing 8 mL
      of enriched brain heart infusion broth, and analyzed for microbial contamination.
      RESULTS: Seven positive cultures were found: six gram positive cocci (7.4%) and
      one gram negative bacillus (1.2%). There was no clinical correlation with these
      findings. CONCLUSION: Isolated microorganisms were similar to those described in
      the literature as agents of bacterial keratitis and are components of the normal
      ocular flora. Klebsiela pneumoniae--considered an occasional or transient flora-
      was the exception. All isolated microorganisms but K. pneumoniae were sensitive
      to most of the antibiotics tested. Our findings suggest that the risk of
      infectious keratitis after PRK related to soft contact lens wear for 3 days seems
      to be low, which may be because lenses were not manipulated by the patient during
      the wearing period, and the postoperative antibiotic regimen was strictly
      followed by patients. However, care should be taken to instruct patients in
      proper lens care practices to reduce the risk of bacterial keratitis in contact
      lens wear following PRK.

PMID- 10656307
TI  - Effects of RGP lens extended wear on glucose-lactate metabolism and stromal
      swelling in the rabbit cornea.
AB  - PURPOSE: To assess the chronic effects of rigid gas-permeable (RGP) contact
      lenses on corneal swelling and glucose-lactate metabolism in the rabbit cornea
      during 1 month of continuous extended wear and to establish the relationship
      between these effects and the oxygen transmissibility (Dk/L) of the test lens
      polymer. METHODS: Four RGP lenses of varying Dk/L were tested in 8 rabbits per
      test group (left eyes served as controls). After 7 days and 1 month extended
      wear, the concentrations of lactate and glucose in the corneal epithelium, stroma
      and aqueous humor were determined by enzyme assay; and epithelial and stromal ATP
      concentrations were separately measured by bioluminescence techniques. Corneal
      thickness was measured at a standard morning time by ultrasonic pachymetry before
      and after 1, 7, 15 days and 1 month extended wear. RESULTS: After 7 days and 1
      month extended wear, generalized decreases were found in aqueous humor lactate
      levels for all test lenses, while concomitant increased aqueous glucose
      concentrations were observed. Total epithelial lactate levels correlated
      inversely with decreasing Dk/L levels for lower oxygen transmissible lenses (R =
      0.951, P = 0.0051); and remained unchanged after extended wear of the hyper
      oxygen transmissible Dk/L 125 test lens. By contrast, stromal lactate levels
      consistently decreased at all time points measured forextended wear of all test
      lenses. As expected, both epithelial and stromal ATP concentrations
      simultaneously decreased in extended wear. Overnight corneal swelling values
      after 24 hours wear of Dk/L = 27, 43, 70 and 125 test lenses were increased by
      9.8, 7.1, 5.5, and 5.2% while persistent (residual) stromal swelling after one
      month extended wear was 16.8, 10.1, 8.6, and 5.6% respectively, in excess of
      baseline values. CONCLUSIONS: Chronic RGP contact-lens induced hypoxia is
      associated with altered glucose-lactate metabolism in the cornea and aqueous
      humor with excess production of increased levels of lactate in the epithelium for
      lower Dk/L test lenses, but decreased lactate concentration in the stroma and
      aqueous humor. Extended wear of the hyper-oxygen transmissible test lens (Dk/L =
      125) however, produced no increase in epithelial lactate levels. Expected lens
      induced decreases in epithelial and stromal ATP were not dependent on lens-oxygen
      transmissibility. Despite the persistence of lower than normal stromal levels of
      lactate during 1 month of extended wear for all test lenses, residual corneal
      swelling values remained consistently elevated above baseline values. Taken
      together, these data establish that increased stromal lactate accumulation cannot
      account for persistent stromal edema in chronic extended wear of RGP lenses; and
      that this effect appears to be independent of lens-oxygen transmissibility and
      may thus represent the prolonged mechanical effect of lens wear itself.

PMID- 10656308
TI  - Large soft contact lenses in the management of leaking blebs.
AB  - PURPOSE: To investigate the efficacy of a new large permanent wear soft contact
      lens in the management of leaking blebs following trabeculectomy. METHODS: Twenty
      four patients with leakage from a trabeculectomy bleb, both fornix based and
      limbal based, with and without mitomycin adjuvant, were treated with a 78% water
      content soft contact lens of 17.5 mm diameter, fit according to each patient's
      keratometry readings. RESULTS: The leakage from a conjunctival trabeculectomy
      bleb was successfully treated in 22 out of 24 patients. CONCLUSIONS: The 17.5 mm
      78% water content permanent wear soft contact lens is a preferred method of
      management of leaking blebs when specifically tailored to the patient's corneal
      curvature.

PMID- 10656309
TI  - Infectious crystalline keratopathy.
AB  - PURPOSE: To review the diagnosis, microbial and pathological features,
      pathogenesis, and treatment of infectious crystalline keratopathy (ICK). METHODS:
      We reviewed the literature on infectious crystalline keratopathy. RESULTS AND
      CONCLUSIONS: ICK is an indolent corneal infection in which needle-like, branching
      crystalline opacities are seen within the corneal stroma, in the absence of
      appreciable corneal or anterior segment inflammation. In most cases it occurs as
      a complication of corneal surgery and keratitis, with an alpha-hemolytic
      Streptococcus being the cause of infection. Discontinuation of topical steroids
      with aggressive antibiotic therapy may suffice, but continued infection,
      vascularization, or scar formation may affect visual acuity and require
      penetrating keratoplasty.

PMID- 10656310
TI  - Denovo development of corneal guttae and Fuchs' dystrophy in corneal grafts.
AB  - PURPOSE: To describe two cases of de novo development of corneal guttae and
      Fuchs' dystrophy in donor tissue following penetrating keratoplasty (PK) for
      unrelated conditions. METHODS: Two patients underwent PK for keratoconus and a
      disciform scar secondary to herpes simplex virus. They were followed clinically
      for a period of 16 and 11 years, respectively. Specular microscopy was used in
      one patient. RESULTS: Corneal guttae were first noted 10 years and 4 years
      following transplantation in the first and second patient, respectively. In both
      cases, the corneal guttae gradually increased in number, involving the central
      and temporal portions of the corneal graft There were no corneal guttae present
      in the host corneal rim or contralateral cornea of either patient. CONCLUSIONS:
      These cases provide evidence to suggest that some corneas may be genetically
      predetermined to develop corneal guttae and Fuchs' dystrophy many years before
      any changes can be clinically detected.

PMID- 10656311
TI  - The diagnosis and management of Acanthamoeba keratitis.
AB  - PURPOSE: The purpose of this study was to evaluate the immunology, pathogenesis
      and therapy of Acanthamoeba keratitis. METHODS: The recent development of an
      animal model of Acanthamoeba keratitis and its impact on the medical treatment
      and immunology of Acanthamoeba keratitis was reviewed. RESULTS: After initial
      reports, Acanthamoeba infection of the cornea remained a rare disease until an
      association with contact lens wear was first recognized. Although the disease is
      closely associated with contact lens wear, it appeared that the contaminated
      solutions that were coming into contact with the lenses caused the disease. All
      types of contact lenses can be associated with development of Acanthamoeba
      keratitis. Therefore, the contact lens serves as a carrier of Acanthamoeba to the
      surface of the eye. The typical patient with Acanthamoeba keratitis is a young
      healthy individual who is either a contact lens wearer or has had significant
      exposure to water contaminated with Acanthamoeba. There are several risk factors
      such as corneal trauma, contaminated solution and contact lenses that have been
      reported to be associated with Acanthamoeba keratitis. In spite of significant
      improvement in the diagnosis of Acanthamoeba keratitis, progress in developing
      and utilizing effective antimicrobial agents for treating this disease have been
      disappointing. A growing body of evidence suggests that the mammalian immune
      system, if properly activated, is capable of preventing and controlling ocular
      infections. CONCLUSIONS: In order to develop effective immunotherapeutic
      modalities, and to better understand the immune effector mechanisms that protect
      the cornea against Acanthamoeba infection, it is necessary to fully characterize
      and evaluate the immunobiology of Acanthamoeba keratitis.

PMID- 10656312
TI  - Phototherapeutic keratectomy for anterior scarring in an epikeratophakia
      lenticule.
AB  - PURPOSE: To present a case of anterior scarring in an epikeratophakia lenticule
      and its partially successful treatment with the excimer laser. METHODS: Excimer
      laser phototherapeutic keratectomy (PTK) was used to reduce corneal scarring in
      an epikeratophakia lenticule. RESULTS: Visual acuity improved after two sessions
      of PTK. CONCLUSIONS: PTK is an alternative to epikeratophakia lenticule removal.

PMID- 10656313
TI  - Chemical modification of silk fibroin with 2-methacryloyloxyethyl
      phosphorylcholine. II. Graft-polymerization onto fabric through 2
      methacryloyloxyethyl isocyanate and interaction between fabric and platelets.
AB  - 2-Methacryloyloxyethyl phosphorylcholine (MPC) was grafted onto silk fabric in a
      two-step heterogeneous system through the vinyl bonds of 2-methacryloyloxyethyl
      isocyanate (MOI) modified on the fabric. First, habutae silk fabric was modified
      with the MOI monomer in anhydrous dimethyl sulfoxide using di-n-butyltin (IV)
      dilaurate and hydroquinone at 35 degrees C. The saturated weight gain of modified
      MOI monomer on the fabric was 7.3 wt% versus the original silk. Second, graft
      polymerization with MPC onto the MOI modified silk was conducted using 2,2'-azo
      bis[2-(2-imidazolin-2-yl)propane dihydrochloride] (VA-044) as an azo
      polymerization initiator. The weight of the grafted MPC eventually gained was
      about 26.0 wt%. The MOI-modified and MPC-grafted silk fabrics were analyzed by
      Fourier transform infrared (FT-IR) spectroscopy. To confirm the improved
      biocompatibility of the silk fabric, platelet adhesion was preliminarily tested
      measuring lactate dehydrogenase. The number of platelets adhering to polyMPC
      grafted silk fabric decreased by about one tenth compared to original and MOI
      modified silk after 60 min of contact with human platelet-rich plasma (1.0 x
      10(6) platelets cm(-2)).

PMID- 10656314
TI  - An in vitro investigation of the PEMA/THFMA polymer system as a biomaterial for
      cartilage repair.
AB  - A polymer system consisting of poly(ethyl methacrylate)/tetrahydrofurfuryl
      methacrylate (PEMA/THFMA) was investigated as a biomaterial for cartilage repair
      using chondrocyte culture. The PEMA/THFMA system and Thermanox control were shown
      to support chondrocytes seeded directly onto the surface for up to 28 days in
      culture. Differences were seen between the PEMA/THFMA system and Thermanox in DNA
      content, proliferation and glycosaminoglycon (GAG) synthesis. There was a
      significantly greater medium: cell GAG ratio for the PEMA/THFMA system compared
      to Thermanox. A greater number of chondrocytes isolated from the superficial zone
      of bovine cartilage attached to the PEMA/THFMA system compared to cells isolated
      from the deep zone, whereas the converse was seen for Thermanox. Matrix
      constituents including collagen type II were synthesised indicating that the
      differentiated phenotype was maintained for some of the chondrocytes, although
      the production of type I collagen indicated that dedifferentiation of some of the
      chondrocytes had occurred. In conclusion, this study has shown that the
      PEMA/THFMA system can support chondrocytes in vitro and together with further
      investigations could lead to the development of the polymer as an ideal candidate
      for articular cartilage repair.

PMID- 10656315
TI  - Chlorhexidine release from room temperature polymerising methacrylate systems.
AB  - A series of different methacrylate monomers (with either 1 or 2.5% dimethyl-p
      toluidine, DMPT) was gelled with poly(ethyl methacrylate) powder (containing
      benzoyl peroxide) thus forming a room temperature curing system. When doped with
      5.625% chlorhexidine diacetate the release from the tetrahydrofurfuryl
      methacrylate-based samples was considerably greater than that from other
      methacrylate monomers. This seems to be due to the formation of channels in the
      polymer. Nuclear magnetic resonance spectroscopy, of solutions that the samples
      were immersed in, showed chlorhexidine was indeed being released from the
      polymer. It also showed that doping the polymer with chlorhexidine hindered the
      polymerisation, resulting in a higher level of residual monomer and low molecular
      weight components being leached from the polymer. The DMPT also affected the
      polymerisation with greater leaching from the 2.5% DMPT sample.

PMID- 10656316
TI  - Formation of a bioactive graded surface structure on Ti-15Mo-5Zr-3Al alloy by
      chemical treatment.
AB  - Simple NaOH and heat treatments provided a Ti-15Mo-5Zr-3Al alloy with a bioactive
      graded surface structure of an amorphous sodium titanate, where the sodium
      titanate on the top surface gradually changed into the alloy substrate through
      titanium oxide. The sodium titanate was free of alloying species of Mo, Zr and
      Al, since almost all of them were released from the surface of alloy during the
      first NaOH treatment. The sodium titanate transformed into a hydrated titania via
      Na+ ion release to induce a bone-like apatite formation on the alloy substrate in
      a simulated body fluid (SBF). The alloying species neither were released into the
      SBF nor affected the apatite formation. In the process of apatite formation, the
      graded surface structure developed into one where the apatite on the top surface
      gradually changed into the alloy composition through hydrated titania and
      titanium oxide. It is expected that this graded structure will lead to a strong
      interfacial bonding strength between the apatite layer and the alloy substrate,
      thereby providing a tight integration of the alloy with living bone through the
      apatite layer.

PMID- 10656317
TI  - Improved cell adhesion by plasma-induced grafting of L-lactide onto polyurethane
      surface.
AB  - Lactide-grafted polyurethanes were prepared by exposing the polyurethane films to
      argon plasma discharge, followed by grafting L-lactide onto the plasma-treated
      surface. The modified surfaces were characterized by measuring the static contact
      angle and by electron spectroscopy for chemical analysis (ESCA). The water
      contact angle of polyurethanes was decreased by L-lactide grafting, indicating
      hydrophilicity of the modified surface. Grafting also increased the O/C atomic
      ratio and C(C=O)/Ctotal percentage on the surfaces as detected by ESCA. The
      grafted surfaces showed enhanced attachment and growth in both 3T3 fibroblast and
      human umbilical vein endothelial cell culture tests. Platelet adhesion to the
      modified surfaces was also reduced in vitro. L-Lactide monomers grafted onto
      polyurethane substrates could therefore be useful in facilitating endothelial
      cell seeding process in small vascular graft applications.

PMID- 10656318
TI  - Gamma irradiation of human bone allografts alters medullary lipids and releases
      toxic compounds for osteoblast-like cells.
AB  - The uncertainties about the transmission of prion proteins from xenogenic grafts
      prepared from bovine bone has led to the reconsideration of allogenic bone as a
      grafting material. Allografting is a complementary technique to autografting
      nowadays when large bone volumes are necessary. Several preparation techniques
      have been proposed. Fresh-frozen, freeze-dried and gamma irradiation are the most
      common. However, a large amount of lipids is present in the medullary spaces
      (near 70% in weight for a human femoral head). They are known to strongly
      influence the biocompatibility of the bone graft. The exact changes of lipids
      upon the sterilization and storage processes are poorly known. The aims of the
      present study were to appreciate the effects of gamma irradiation on medullary
      lipids and to identify the cytotoxicity of gamma-irradiated bank bone
      with/without lipid on cultures of osteoblast-like cells. Bone cores from 8
      femoral heads retrieved during prosthesis surgery for arthritis were prepared
      with a drilling trephine. Cores were either sterilized by gamma radiations (25000
      gray) or kept frozen until lipid extraction and lipofuschine-like dosage by
      Folch's method and fluorometric study. Peroxidated lipids appeared 2 to 3-fold
      higher in the gamma-irradiated cores than in frozen ones. Slices were prepared
      from bone cores and were transferred on confluent osteoblast-like cell layers
      (Saos-2). The raw slices (containing lipids) did not induce cell death. On the
      other hand, cell death was dramatically increased around the gamma-irradiated
      slices. Defatted slices which had been sterilized by gamma radiations or UV did
      not induce cell death. Defatting procedures should be added when preparing bone
      allografts in human bone banks.

PMID- 10656319
TI  - Effects of adding sodium and fluoride ions to glass ionomer on its interactions
      with sodium fluoride solution.
AB  - This investigates the effects of the addition of Na and F ions to a glass ionomer
      cement in which those ions are not inherently present on its interactions with
      dilute (0.2%) NaF solution. Both the effect of the solution on the cement's
      surface morphology and the effect of the cement on the solution in terms of take
      up of Na+ and F- and of change in pH are to be investigated. These results are to
      be compared to previous results obtained with glasses which contained both, one,
      or neither of the ions as components of their glasses. NaF (1.3% by weight in the
      mixed cement) was added to the powder components of a glass ionomer based on LG30
      glass (which contains Al, Si, Ca, P, and O only). Discs of cement were set in
      moulds at 37 degrees C for 1 h then stored in water at 37 degrees C for 3 days.
      Each test disc was then immersed in 10 ml 0.2% NaF solution whereas controls
      remained immersed in water (N = 3 for test and control). Test and control disc
      surfaces were assessed both qualitatively by electron microscopy and
      quantitatively by linear profilometry (Ra values). Potentiometry was used to
      measure solution pH and Na and F concentrations using a pH electrode and suitable
      ion selective electrodes both before and after cement immersion. The surface of
      test specimens was subject considerable disruption with the polysalt cement
      matrix being removed and residual glass particles being disclosed. The controls
      showed no such disruption. This effect was reflected in a significant difference
      of Ra. Such an effect was not shown by test and control surfaces of LG30 but a
      similar effect was to that shown by LG26 (which contains F as a glass component).
      Solution pH changed by 1 unit which was much more than the change shown by LG30
      or LG26 but is similar to that of AH2 and MP4 cements which both contain Na. The
      Na and F uptake was much lower than for LG30 whereas that of LG26 was higher than
      LG30. The Na:F ratio was 0.29:1 compared to 1.26:1 for LG30 (LG26 = 1.01:1, AH2 =
      1.02:1, MP4 = 1.04:1). Fluoride addition to a F-free glass ionomer renders it
      vulnerable to surface disruption by NaF solution showing that fluoride complexes
      produced in glass dissolution are not necessarily involved in this process.
      Sodium addition to a Na-free glass ionomer confirms the role of this cement in
      enhancing pH change in NaF solution. The level of uptake of F- from a NaF
      solution in much lower than that for the F-free glass ionomer which shows there
      is no direct relationship between F- uptake and surface disruption. The ratio of
      Na:F uptake is below 0.3:1, but the pH change is similar to cements where the
      ratio is close to unity which indicates that F-/OH- interchange is not a
      significant mechanism even when anion/cation uptake is not balanced.

PMID- 10656320
TI  - Effect of mechanical surface pretreatment on metal ion release.
AB  - The degree of metal ion dissolution from Ti-6Al-4V alloy hip replacement stems
      subjected to various mechanical and chemical surface pretreatments was analysed
      in vitro. High-dissolution rates were observed for nitric acid passivated samples
      that had been mechanically surface treated to increase the implant surface area.
      Significantly lower ion release levels were observed for mechanically treated
      samples which had been aged in de-ionised water. The application of an
      hydroxyapatite coating decreased the metal ion release from the nitric acid
      passivated samples (compared to the uncoated sample) and increased the metal ion
      dissolution from the aged samples. The dissolution behaviour of the samples is
      explained in terms of the diffusion processes occurring at the stem/solution
      interface and the morphological and chemical characteristics of the surface
      treated stems.

PMID- 10656321
TI  - Antibacterial silver-containing silica glass prepared by sol-gel method.
AB  - Recently, various inorganic antibacterial materials containing silver have been
      developed and some of them are in commercial use. Colorless and more chemically
      durable materials which slowly release the silver ion for a long period are,
      however, desirable to be developed for medical applications such as composite
      resin for dental restoration. In the present study, Si(OC2H5)4, Al(NO3)3 x 9H2O,
      AgNO3, HNO3, C2H5OH and H2O solutions with various Al/Ag atomic ratios under a
      constant Si/Ag atomic ratio of 1/0.023 were kept at 40 degrees C for gelation and
      drying. Thus obtained gels were pulverized into fine powders with average
      particle size of approximately 10 microm and then heat-treated at 900-1000
      degrees C for 2 h. For the composition Al/Ag = 0, a yellow-colored glass was
      formed, since the silver existed in the form of metallic colloids in the glass.
      However, for the compositions Al/Ag > or = 1, colorless glasses were successfully
      obtained, since the silver existed in the form of Ag+ ions in the glasses. For
      the composition Al/Ag = 0, the silver ions got released rapidly into the water,
      whereas, for the compositions Al/Ag > or = 1, they gradually got released into
      the water at a controlled rate. A composite of the obtained powders with Al/Ag
      atomic ratio of 1 with Bis-GMA/TEGDMA in 70:30 weight ratio showed excellent
      antibacterial property. The sol-gel derived silica glass powders containing
      silver with compositions Al/Ag > or = 1 are believed to be useful as an
      antibacterial material for medical applications such as filler of composite resin
      for dental restoration.

PMID- 10656322
TI  - Influence of glass composition on the properties of glass polyalkenoate cements.
      Part II: influence of phosphate content.
AB  - The influence of phosphate content of the glass on the formation of glass
      polyalkenoate cements was investigated. Glasses were synthesised based on (4.5 -
      2X)SiO2-3.0 Al2O3-(3.0 - X)CaO-(1.5 + X)P2O5-2.0 CaF2 and X was varied from -1.5
      to 0.8. The setting and working time of the cement pastes increased with the
      phosphate content of the glass (X). Increasing the phosphate content resulted in
      an initial increase in compressive strength followed by a sharp reduction in
      strength. Young's modulus and un-notched fracture strength exhibited a maximum at
      intermediate phosphate contents. Fracture toughness reduced at high phosphate
      contents, whilst toughness increased. Phosphate in the glass is thought to aid
      glass degradation by providing additional phosphorus-oxygen bonds for hydrolysis,
      but may also reduce the amount of aluminium released by reducing the
      susceptibility of aluminium-oxygen-silicon bonds to acid hydrolysis. The released
      phosphate may also compete with the carboxylate groups in the polysalt matrix
      cement for cations inhibiting the crosslinking reaction.

PMID- 10656323
TI  - High-molecular-weight kininogen preadsorbed to glass surface markedly reduces
      neutrophil adhesion.
AB  - Adsorbed proteins on biomaterial surfaces determine whether cells adhere, but
      rheological variables are also critical. Neutrophil adhesion under well-defined
      radial flow conditions was studied on glass preadsorbed with plasma proteins or
      plasma protein domain fragments. Fibrinogen, low-molecular-weight kininogen (LK),
      high-molecular-weight kininogen (HK), cleaved HK (HKa), and recombinant HK
      domains 3 and 5 (D3 and D5H) were used. The number of adherent cells on the HK
      and HKa surfaces was less than 10% that found on the fibrinogen absorbed surface.
      The degree of spreading was minimal and detachment of adherent neutrophils was
      observed. HK and HKa contain binding sites for both anionic surfaces and
      neutrophils in the same domain (D5H). When adsorbed to surfaces, HK and HKa did
      not have the neutrophil binding sites available and therefore exhibited an anti
      adhesive effect. Although D5H contains anionic surface binding sites, its small
      molecular size required a higher number of adsorbed molecules to cover the
      surface before a significant decrease in cell adhesion was observed. Since LK and
      D3 do not possess specific anionic surface binding sites, the adsorption of these
      proteins on glass was very low compared to HK and HKa. Thus, extensive cell
      adhesion and spreading were observed on the surfaces partially covered with
      preadsorbed LK and D3.

PMID- 10656324
TI  - Interaction of water-soluble collagen with poly(acrylic acid).
AB  - Interactions between poly(acrylic acid) labeled with pyrene (PAA-Py) and
      succinylated calfskin collagen (type I) (SCSC) were studied by fluorescence
      spectroscopy. PAA-Py exhibits a strong emission from pyrene monomer (intensity,
      I(M)) when it exists in an extended conformation. It exhibits another broad
      emission from pyrene excimer (intensity, I(E)) when it adopts a collapsed globule
      conformation. At pH 3, a value that is lower than the isoelectric point of SCSC,
      the ratio I(E)/I(M) value decreased cooperatively with increasing concentration
      of SCSC at constant PAA-Py concentration, under salt-free condition. On the other
      hand, this effect was not observed in the presence of 0.1 M NaCl. At pH 7, a
      value higher than the isoelectric point of SCSC, the ratio I(E)/I(M) was not
      affected by the presence of SCSC in the absence and presence of salt. From
      electrophoretic light scattering experiments, it was found that at pH 3 PAA-Py
      was negatively charged, while SCSC had a positive charge. Thus it is strongly
      suggested that the two polymers interact by electrostatic attraction at low pH
      where they are oppositely charged, and that PAA-Py adopts an extended
      conformation in the complex formed with SCSC. Similar interactions are believed
      to occur between dentinal collagen and the polycarboxylate component of glass
      ionomer cements.

PMID- 10656325
TI  - The machinability of cast titanium and Ti-6Al-4V.
AB  - This study investigated the machinability (ease of metal removal) of commercially
      pure (CP) titanium and Ti-6Al-4V alloy. Both CP Ti and Ti-6Al-4V were cast into
      magnesia molds. Two types of specimens (with alpha-case and without alpha-case)
      were made for CP Ti and Ti-6Al-4V. Machinability (n = 5) was evaluated as volume
      loss (mm3) by cutting/grinding the 3.0 mm surface using fissure burs and silicon
      carbide (SiC) under two machining conditions: (1) two machining forces (100 or
      300 gf) at two rotational speeds (15000 or 30000 rpm) for 1 min, and (2) constant
      machining force of 100 gf and rotational speed of 15000 rpm for 1, 2, 5, 10, and
      30 min. As controls, conventionally cast Co-Cr and Type IV gold alloys were
      evaluated in the same manner as the titanium. When fissure burs were used, there
      was a significant difference in the machinability between CP titanium with alpha
      case and without alpha-case. On the other hand, there was no appreciable
      difference in the amount of metal removed for each tested metal when using the
      SiC points.

PMID- 10656326
TI  - Endotoxin removal from protein solutions.
AB  - Endotoxins liberated by gram-negative bacteria are frequent contaminations of
      protein solutions derived from bioprocesses. Because of their high toxicity in
      vivo and in vitro, their removal is essential for a safe parenteral
      administration. A general method for the removal of endotoxins from protein
      solutions is not available. Methods used for decontamination of water, such as
      ultrafiltration, have little effect on endotoxin levels in protein solutions.
      Various techniques described in the patent literature are not broadly applicable,
      as they are tailored to meet specific product requirements. Besides ion
      exchangers and two-phase extraction, affinity techniques are applied with varying
      success. Also, taylor-made endotoxin-selective adsorber matrices for the
      prevention of endotoxin contamination and endotoxin removal are discussed for
      this purpose. After giving an overview of the properties of endotoxins and the
      significance of endotoxin contamination, this review intends to provide an
      overall picture of the various methods employed for their removal. Avenues are
      pointed out how to optimise a method with regard to the specific properties of
      endotoxins in aqueous solution.

PMID- 10656327
TI  - Biotechnological aspects of plum pox virus.
AB  - Plum pox potyvirus (PPV), the causal agent of a devastating disease that affects
      stone fruit trees, is becoming a target of intense studies intended both to fight
      against viral infection and to develop practical applications based on the
      current knowledge of potyvirus molecular biology. This review focuses on
      biotechnological aspects related to PPV, such as novel diagnostic techniques that
      facilitate detection and typing of virus isolates, strategies to implement
      pathogen-derived resistance through plant transformation, the potential use of
      genetic elements derived from the virus, and the recent development of PPV-based
      expression vectors.

PMID- 10656328
TI  - Biotransformation of protocatechuic aldehyde and caffeic acid to vanillin and
      capsaicin in freely suspended and immobilized cell cultures of Capsicum
      frutescens.
AB  - Freely suspended cells and immobilized cell cultures of Capsicum frutescens Mill.
      were treated with phenylpropanoid intermediates--protocatechuic aldehyde and
      caffeic acid to study their biotransformation ability. It was found that
      externally fed protocatechuic aldehyde and caffeic acids were biotransformed to
      vanillin and capsaicin. It was noted that this culture biotransformed externally
      fed protocatechuic aldehyde to vanillin more than its conversion to capsaicin,
      whereas, caffeic acid-treated cultures accumulated more capsaicin than vanillin.
      The maximum accumulation of vanillin (5.63 mg l(-1)) and capsaicin (3.83 mg l(
      1)) was recorded on the 6th and 15th day, respectively in immobilized C.
      frutescens cell cultures treated with protocatechuic aldehyde, which was 1.8 and
      1.4 times higher than in protocatechuic aldehyde-treated freely suspended cell
      cultures. Caffeic acid-treated immobilized C. frutescens cell cultures
      accumulated maximum vanillin and capsaicin at 2.68 and 3.03 mg l(-1) culture,
      respectively, on the 9th and 12th day, which was 1.65 and 1.33 times over freely
      suspended cultures treated with caffeic acid. The addition of S-adenosyl-L
      methionine, a methyl donor, to protocatechuic aldehyde-treated immobilized C.
      frutescens cell cultures, resulted in accumulation of vanillin (14.08 mg l(-1))
      on the 4th day, which was 2.5-fold higher than that in cultures treated with
      protocatechuic aldehyde alone, suggesting the influence of S-adenosyl-L
      methionine on O-methylation of protocatechuic aldehyde, resulting in more
      vanillin accumulation. The increase in vanillin accumulation was well correlated
      with an increase in specific activity of caffeic acid O-methyltransferase in
      protocatechuic aldehyde and S-adenosyl-L-methionine-treated immobilized C.
      frutescens cell cultures. This study also provides an example for an alternative
      route to formation of vanillin by C. frutescens cell cultures.

PMID- 10656329
TI  - Optimization of gibberellic acid production by immobilized Gibberella fujikuroi
      mycelium in fluidized bioreactors.
AB  - An orthogonal experimental design L9 (3(4)) was used to investigate effects of
      temperature, pH, C:N ratio (glucose-C, NH4Cl-N) and concentrations of rice flour
      on production of gibberellic acid by Gibberella fujikuroi in 3.5 l fluidized
      bioreactors. The gibberellic acid production in a fluidized bioreactor could
      reach 3.90 g l(-1), more than 3-times greater than previously reported for
      submerged and solid fermentations. pH, rice flour concentration and C:N ratio
      were the factors that most influenced the production of gibberellic acid; pH
      being the most important. The response surface of gibberellic acid production to
      changes in pH and C:N ratio or rice flour concentration indicated that greatest
      production was found with a C:N ratio of 36.8 and pH 5 while the optimum
      concentration for rice flour was 2 g l(-1) and production increased with
      increased pH. The effect of temperature on the production of gibberellic acid was
      also significant and greatest production was at 30 degrees C.

PMID- 10656330
TI  - Very high expression of an anti-carcinoembryonic antigen single chain Fv antibody
      fragment in the yeast Pichia pastoris.
AB  - In this paper we report the development of a recombinant strain of the yeast
      Pichia pastoris, which secretes an anti-carcinoembryonic antigen single chain Fv
      (scFv) antibody fragment to the culture supernatant as a biologically active
      protein, at levels of 1.2 g l(-1). The yeast scFv was purified by IMAC, with a
      final yield of approximately 0.440 g of 93% pure scFv per liter of culture
      supernatant. The specific activity in ELISA of the yeast scFv was almost three
      times higher than that of a bacterial periplasmic counterpart. These results
      reaffirm that the yeast P. pastoris is a suitable host for high level production
      of scFv antibody fragments with potential in vivo diagnostic and therapeutic
      applications.

PMID- 10656331
TI  - Propionic acid metabolism and poly-3-hydroxybutyrate-co-3-hydroxyvalerate (P3HB
      co-3HV) production by Burkholderia sp.
AB  - Mutants of Burkholderia sp. that are unable to grow on propionic acid (prp) but
      still accumulate P3HB-co-3HV from carbohydrate and propionic acid were studied.
      In shaken flask tests, yields of 3HV from propionic acid (Y(3HV/Prop)) increased
      from 0.10 g g(-1) in the wild type to c.a. 0.35 g g(-1) in mutants affected in
      alpha-oxidation pathway or to 0.80 g g(-1) in mutants not affected in that
      pathway. In bioreactor tests, mutant IPT 189 showed Y(3HV/Prop) = 1.20 g g(-1), a
      yield very close to the theoretical maximum of 1.35 g g(-1). Accumulation of 3HV
      units from unrelated carbon sources was undetectable in these mutants indicating
      that 3HV units are produced directly from propionic acid. Thus, the industrial
      use of those mutants to produce the copolymer from sucrose and propionic acid
      could significantly reduce the production costs. The results strongly suggest the
      existence of at least two pathways that are involved in the oxidation of
      propionic acid in Burkholderia sp. Their rates would be modulated by the
      availability of propionic acid.

PMID- 10656332
TI  - Effects of growth medium selection on plasmid DNA production and initial
      processing steps.
AB  - Cultures of recombinant Escherichia coli containing the plasmid pSVbeta were
      grown in three medium formulations to assess their effects on the characteristics
      of supercoiled plasmid DNA production for plasmid-based gene therapy. A semi
      defined medium containing casamino acids (SDCAS) was found to support higher cell
      densities and higher plasmid stability than a similar medium containing soya
      amino acids (SDSOY) or Luria-Bertani medium (LB). Differences were observed in
      the cell harvest characteristics, plasmid DNA primary recovery, plasmid DNA yield
      and quality between cells grown on LB and on SDCAS medium. Cells grown on SDCAS
      medium were more difficult to resuspend after harvest than those grown in LB
      medium and were less susceptible to alkaline lysis. The plasmid DNA content from
      SDCAS was predominantly supercoiled and was less contaminated by chromosomal DNA
      than plasmid DNA extracts derived from cells grown on LB medium. It was
      hypothesised that the different carbon:nitrogen ratio (C:N) of the medium may
      have been responsible for changing the cell wall polysaccharide composition
      resulting in the change in cell harvest and lysis characteristics. Results
      indicated that changing the C:N ratio of SDCAS medium between 1.21:1 and 12.08:1
      resulted in no alteration in cell wall polysaccharide composition or in cell
      susceptibility to chemical lysis or physical breakage. Plasmid DNA yields
      increased ten-fold with ten-fold increase in the C:N ratio of SDCAS medium.

PMID- 10656333
TI  - Effects of Pluronic F-68 on Tetrahymena cells: protection against chemical and
      physical stress and prolongation of survival under toxic conditions.
AB  - The effects of the non-ionic surfactant Pluronic F-68 (0.01% w/v) on Tetrahymena
      cells have been studied. A marked protection against chemical and physical stress
      was observed. The chemical stress effects were studied in cells suspended in
      buffer (starvation) or in buffers with added ingredients from a chemically
      defined medium (Ca2+, Mg2+, Na+, K+, trace metal ions). The physical stress was
      due to mechanical stress or hyperthermia. The data show that Pluronic: (a)
      prolongs the survival of low concentration cell suspensions during starvation;
      (b) prevents the cell death caused by low concentrations of Ca2+ (70 microM); (c)
      prolongs the survival of cells exposed to higher ion concentrations (10 mM Ca2+,
      or Na+ or K+); (d) postpones the death caused by trace metal ions like Zn2+, Fe3+
      and, Cu2+; (e) protects cells from the death caused by shearing forces; and (f)
      prolongs the survival of cells exposed to hyperthermia (43 degrees C). The
      cellular survival is increased at reduced temperatures (e.g. 4 degrees C instead
      of 36 degrees C) and at increased cellular concentrations (e.g. 100 cells ml(-1)
      instead of 25 or 10 cells ml(-1)). There is no effect of pre-incubation with
      Pluronic. The protective effect of Pluronic towards Tetrahymena is observed for
      concentrations in the range from 0.001 to 0.1% w/v.

PMID- 10656334
TI  - Removal of contaminant nucleic acids by nitrocellulose filtration during
      pharmaceutical-grade plasmid DNA processing.
AB  - Pharmaceutical-grade plasmid DNA for use in vaccines and gene therapy requires
      the development of reproducible and scaleable downstream processes. Shearing of
      chromosomal DNA at the commencement of the purification results in fragments that
      are difficult to separate from supercoiled plasmid DNA. Regulatory standards will
      probably require that the level of chromosomal DNA contamination is kept below
      0.01 mg mg(-1) plasmid DNA. This work reports the use of nitrocellulose membranes
      to decrease chromosomal DNA contamination in plasmid DNA preparations derived
      from a 450-l bioreactor. Clarified lysates, resuspended PEG precipitates and
      anion exchange chromatography elutes were filtered through nitrocellulose. In all
      the cases, chromosomal DNA was selectively retained by the membrane while most
      supercoiled plasmid DNA was recovered in the filtrate. Contamination levels
      dropped from over 27% to below 1% as measured by Southern analysis. Under ionic
      strength conditions equal to or above 1.5 M NaCl, a fraction of the contaminant
      RNA was also retained by the nitrocellulose membrane.

PMID- 10656335
TI  - Assembling of engineered IgG-binding protein on gold surface for highly oriented
      antibody immobilization.
AB  - The B-domain, which is one of IgG-binding domains of staphylococcal protein A,
      was repeated five times and a cysteine residue was introduced at its C-terminus
      by a genetic engineering technique. The resulting protein, designated B5C1,
      retained the same IgG-binding activity as native protein A. The B5C1 was
      assembled on a gold plate surface by utilizing a strong affinity between thiol of
      cysteine and a gold surface. IgG-binding activity of B5C1 on a gold surface was
      much higher than that of physically adsorbed B5, which lacks cysteine residue.
      Furthermore, antigen-binding activity of immobilized antibody molecules through
      the use of assembled B5C1 on a gold surface was about 4.3 times higher than that
      of physically adsorbed antibody molecules. Immobilization of highly oriented
      antibody molecules was realized with the engineered IgG-binding protein.

PMID- 10656336
TI  - Integrated bioprocess for production of human proinsulin C-peptide via heat
      release of an intracellular heptameric fusion protein.
AB  - An integrated bioprocess has been developed suitable for production of
      recombinant peptides using a gene multimerization strategy and site-specific
      cleavage of the resulting gene product. The process has been used for production
      in E. coli of the human proinsulin C-peptide via a fusion protein BB-C7
      containing seven copies of the 31-residues C-peptide monomer. The fusion protein
      BB-C7 was expressed at high level, 1.8 g l(-1), as a soluble gene product in the
      cytoplasm. A heat treatment procedure efficiently released the BB-C7 fusion
      protein into the culture medium. This step also served as an initial purification
      step by precipitating the majority of the host cell proteins, resulting in a 70%
      purity of the BB-C7 fusion protein. Following cationic polyelectrolyte
      precipitation of the nucleic acids and anion exchange chromatography, native C
      peptide monomers were obtained by enzymatic cleavage at flanking arginine
      residues. The released C-peptide material was further purified by reversed-phase
      chromatography and size exclusion chromatography. The overall yield of native C
      peptide at a purity exceeding 99% was 400 mg l(-1) culture, corresponding to an
      overall recovery of 56%. The suitability of this process also for the production
      of other recombinant proteins is discussed.

PMID- 10656337
TI  - Elicitor action via cell membrane of a cultured rice cell demonstrated by the
      single-cell transient assay.
AB  - In order to analyze intracellular signal transduction, we investigated the
      mechanism of chemical elicitor action by single-cell transient assay using green
      fluorescent protein (GFP) as a reporter gene. When the elicitor was applied from
      outside the cell into which the chitinase promoter and GFP reporter were
      introduced beforehand, fluorescence emission of GFP was observed. In contrast,
      when the elicitor was introduced in the cell to let the elicitor act from inside,
      no emission was observed. Addition of further elicitor from outside, however, did
      cause GFP emission. Therefore, it is clear that the elicitor does not act after
      entering the cell but that its signal is transduced into the cell via the cell
      membrane.

PMID- 10656338
TI  - Protein engineering of an IgG-binding domain allows milder elution conditions
      during affinity chromatography.
AB  - One of the problems in the recovery of antibodies by affinity chromatography is
      the low pH, which is normally essential to elute the bound material from the
      column. Here, we have addressed this problem by constructing destabilized mutants
      of a domain analogue (domain Z) from an IgG-binding bacterial receptor, protein
      A. In order to destabilize the IgG-binding domain, two protein engineered
      variants were constructed using site-directed mutagenesis of the second loop of
      this antiparallel three-helix bundle domain. In the first mutant (Z6G), the
      second loop was extended with six glycines in order to evaluate the significance
      of the loop length. In the second mutant (ZL4G), the original loop sequence was
      exchanged for glycines in order to evaluate the importance of the loop forming
      residues. Both mutated variants have a lower alpha-helical content, as well as a
      lower thermal and chemical stability compared to the parent Z-molecule. The
      affinity to IgG was slightly lowered in both cases, mainly due to higher
      dissociation rates. Interestingly, the elution studies showed that most of the
      bound IgG-molecules could be eluted at a pH as high as 4.5 from columns with the
      engineered ligands, while only 70% of the bound IgG could be eluted from the
      matrix with the parent Z as ligand.

PMID- 10656339
TI  - Expression of catalytic subunit of bovine enterokinase in the filamentous fungus
      Aspergillus niger.
AB  - The cDNA encoding for catalytic subunit of bovine enterokinase (EK(L)), to which
      the sequence for Kex2 protease cleavage site was inserted, was expressed in the
      protease deficient filamentous fungus Aspergillus niger AB1.13. Fungal
      transformants were obtained in which expression of the glucoamylase fusion gene
      resulted in secretion of the protein into growth medium. Fusion polypeptide was
      processed to mature EK(L) by endogenous Kex-2 like protease cleavage during
      secretory pathway. The highest quantity of EK(L), up to 5 mg l(-1), was obtained
      in soya milk medium. The secreted EK(L) was easily purified from other proteins
      found in A. niger culture supernatant, using ion exchange and affinity
      chromatography. The yield of the purified and highly active EK(L) was 1.9 mg l(
      1) of culture.

PMID- 10656340
TI  - An alpha-L-arabinofuranosidase from Penicillium purpurogenum: production,
      purification and properties.
AB  - Penicillium purpurogenum secretes arabinofuranosidase to the growth medium.
      Highest levels of enzyme (1.0 U ml(-1)) are obtained when L-arabitol is used as
      carbon source, while 0.85 and 0.7 U ml(-1) are produced with sugar beet pulp and
      oat spelts xylan, respectively. By means of a zymogram, three bands with
      arabinofuranosidase activity have been detected in the supernatant of a culture
      grown in oat spelts xylan. One of the enzymes was purified to homogeneity from
      this supernatant using gel filtration (BioGel P-100), cation exchange
      chromatography (CM-Sephadex C-50), hydrophobic interaction chromatography (phenyl
      agarose) and a second BioGel P-100 column. The enzyme is a monomer of 58 kDa with
      a pI of 6.5. Optimum pH is 4.0 and optimal temperature 50 degrees C. The
      arabinofuranosidase is highly specific for alpha-L-arabinofuranosides and
      liberates arabinose from arabinoxylan. The enzyme shows hyperbolic kinetics
      towards p-nitrophenyl-alpha-L-arabinofuranoside with a K(M) of 1.23 mM. A 36
      residue N-terminal sequence is over 70% identical to that of fungal
      arabinofuranosidases belonging to family 54 of the glycosyl hydrolases. Based on
      the sequence similarity and other biochemical properties it is proposed that the
      purified enzyme from P. purpurogenum belongs to family 54.

PMID- 10656341
TI  - Cerezyme--recombinant protein treatment for Gaucher's disease.

PMID- 10656342
TI  - An effective vaccine against Lyme disease.

PMID- 10656343
TI  - Compliance with hand washing.

PMID- 10656344
TI  - Cost of nosocomial infections in Wuhan No. 4 Hospital, China.

PMID- 10656345
TI  - Surgical-site complications associated with a morphine nerve paste used for
      postoperative pain control after laminectomy.

PMID- 10656346
TI  - Implementation of a practical antibiotic policy in the Czech Republic.

PMID- 10656347
TI  - Antibiotic cycling: is it ready for prime time?

PMID- 10656348
TI  - The influence of the composition of the nursing staff on primary bloodstream
      infection rates in a surgical intensive care unit.
AB  - OBJECTIVES: To determine the risk factors for acquisition of nosocomial primary
      bloodstream infections (BSIs), including the effect of nursing-staff levels, in
      surgical intensive care unit (SICU) patients. DESIGN: A nested case-control
      study. SETTING: A 20-bed SICU in a 1,000-bed inner-city public hospital.
      PATIENTS: 28 patients with BSI (case-patients) were compared to 99 randomly
      selected patients (controls) hospitalized > or =3 days in the same unit. RESULTS:
      Case- and control-patients were similar in age, severity of illness, and type of
      central venous catheter (CVC) used. Case-patients were significantly more likely
      than controls to be hospitalized during a 5-month period that had lower regular
      nurse-to-patient and higher pool-nurse-to-patient ratios than during an 8-month
      reference period; to be in the SICU for a longer period of time; to be
      mechanically ventilated longer; to receive more antimicrobials and total
      parenteral nutrition; to have more CVC days; or to die. Case-patients had
      significantly lower regular-nurse-to-patient and higher pool-nurse-to-patient
      ratios for the 3 days before BSI than controls. In multivariate analyses,
      admission during a period of higher pool-nurse-to-patient ratio (odds ratio
      [OR]=3.8), total parenteral nutrition (OR=1.3), and CVC days (OR=1.1) remained
      independent BSI risk factors. CONCLUSIONS: Our data suggest that, in addition to
      other factors, nurse staffing composition (ie, pool-nurse-to-patient ratio) may
      be related to primary BSI risk. Patterns in intensive care unit nurse staffing
      should be monitored to assess their impact on nosocomial infection rates. This
      may be particularly important in an era of cost containment and healthcare
      reform.

PMID- 10656349
TI  - Refinements of environmental assessment during an outbreak investigation of
      invasive aspergillosis in a leukemia and bone marrow transplant unit.
AB  - OBJECTIVES: To investigate an outbreak of aspergillosis in a leukemia and bone
      marrow transplant (BMT) unit and to improve environmental assessment strategies
      to detect Aspergillus. DESIGN: Epidemiological investigation and detailed
      environmental assessment. SETTING: A tertiary-care university hospital with a 37
      bed leukemia and BMT unit PARTICIPANTS: Leukemic or BMT patients with invasive
      aspergillosis identified through prospective surveillance and confirmed by chart
      review. INTERVENTIONS: We verified the diagnosis of invasive fungal infection by
      reviewing medical charts of at-risk patients, performing a case-control study to
      determine risk factors for infection, instituting wet mopping to clean all
      floors, providing N95 masks to protect patients outside high-efficiency
      particulate air (HEPA)-filtered areas, altering traffic patterns into the unit,
      and performing molecular typing of selected Aspergillus flavus isolates. To
      assess the environment, we verified pressure relationships between the rooms and
      hallway and between buildings, and we compared the ability of large-volume (1,200
      L) and small-volume (160 L) air samplers to detect Aspergillus spores. RESULTS:
      Of 29 potential invasive aspergillosis cases, 21 were confirmed by medical chart
      review. Risk factors for developing invasive aspergillosis included the length of
      time since malignancy was diagnosed (odds ratio [OR], 1.0; P=.05) and
      hospitalization in a patient room located near a stairwell door (OR, 3.7; P=.05).
      Two of five A. flavus patient isolates were identical to one of the environmental
      isolates. The pressure in most of the rooms was higher than in the corridors, but
      the pressure in the oncology unit was negative with respect to the physically
      adjacent hospital; consequently, the unit acted essentially as a vacuum that
      siphoned non-HEPA-filtered air from the main hospital. Of the 78 samples obtained
      with a small-volume air sampler, none grew an Aspergillus species, whereas 10 of
      40 cultures obtained with a large-volume air sampler did. CONCLUSIONS: During
      active construction, Aspergillus spores may have entered the oncology unit from
      the physically adjacent hospital because the air pressure differed. Guidelines
      that establish the minimum acceptable pressures and specify which pressure
      relationships to test in healthcare settings are needed. Our data show that large
      volume air samples are superior to small-volume samples to assess for Aspergillus
      in the healthcare environment.

PMID- 10656350
TI  - Evaluation of two retrospective active surveillance methods for the detection of
      nosocomial infection in surgical patients.
AB  - OBJECTIVE: To compare the sensitivity and specificity of two retrospective active
      surveillance methods based on review of the medical record and review of the
      discharge form in identfying nosocomial infection, taking the prospective
      surveillance method as the reference standard. DESIGN: Blind comparison of three
      active nosocomial infection surveillance methods. SETTING: Department of General
      Surgery of a tertiary-care hospital with a referral population of 266,000 people.
      METHODS: All operated patients admitted to the Department of Surgery for more
      than 24 hours and discharged from January 1, 1994, to December 31, 1994, were
      included. Prospective surveillance consisted of daily review of the patient's
      record during hospitalization. Retrospective surveillance consisted of review of
      the medical record and the discharge form. Sensitivity and specificity of both
      retrospective methods were calculated. RESULTS: Of the 1,514 patients included in
      the study, 1,476 (97.5%) were reviewed by means of the retrospective surveillance
      system. A total of 20, 8, and 4 hours per week was needed for the active
      prospective system, review of the medical record, and review of the hospital
      discharge form, respectively. The documented cumulative incidence of nosocomial
      infection was 21.8% for the prospective system, 19.6% for review of the medical
      record, and 12.6% for review of the discharge form. The overall sensitivity of
      review of the medical record was 88% and of the discharge form 56%, with a
      specificity of 99%. For review of the medical record, the highest sensitivity was
      93%, for urinary tract infections; for review of the discharge form, the highest
      was 57%, for surgical-wound infection. CONCLUSIONS: The retrospective method of
      review of the medical record was the most efficient active surveillance strategy
      in detecting nosocomial infection in surgical patients.

PMID- 10656351
TI  - Tuberculosis isolation: comparison of written procedures and actual practices in
      three California hospitals.
AB  - OBJECTIVE: To evaluate implementation of healthcare worker exposure control
      measures for tuberculosis (TB)-patient isolation, as specified by Centers for
      Disease Control and Prevention (CDC) guidelines and the hospital's TB-control
      policy. DESIGN: Prospective multihospital study comparing CDC guidelines and
      hospital policy for TB-patient isolation to once-weekly observations of TB
      patient isolation practices over 14 consecutive weeks at each hospital. SETTING:
      Three urban hospitals (two county, one private community) in counties in
      California with a high incidence rate of TB. MEASUREMENTS: Work practices for TB
      patient isolation were observed and ventilation performance of isolation rooms
      was assessed while patient rooms were in use for TB isolation. RESULTS: Of 170 TB
      patient rooms observed, 119 (70%) involved a patient in a designated TB isolation
      room, the room was under negative pressure, the door was closed, and a
      "respiratory precautions" sign was on the door; 32 patient-room units (19%) were
      not under negative pressure or not designated as negative-pressure rooms. Of 151
      patient-room units mechanically capable of negative pressure at a prior point in
      time, 16 (11%) were not under negative pressure at the time of use. Of 67 patient
      room units equipped with continuous monitoring devices, 8 (12%) involved devices
      that did not accurately reflect the direction of airflow. Of the 62 healthcare
      workers observed using a respirator for TB, 40 (65%) did not don the respirator
      properly. CONCLUSIONS: Implementing CDC guidelines for TB-patient isolation was
      feasible but imperfect in the three hospitals. Day-to-day work practices deviated
      from hospital policy. Prospectively quantifying the implementation of a hospital
      TB isolation policy while the room is in use may lead to improved estimates of
      risk and may help to identify and thereby prevent avoidable healthcare worker
      exposures to Mycobacterium tuberculosis aerosol. Auditing practices and verifying
      equipment performance is likely to identify unexpected problems in implementation
      of the TB control program.

PMID- 10656352
TI  - Antimicrobial activity of home disinfectants and natural products against
      potential human pathogens.
AB  - OBJECTIVE: To assess the efficacy of both natural products (vinegar, baking soda)
      and common commercial disinfectants (Vesphene IIse, TBQ, Clorox, Lysol
      Disinfectant Spray, Lysol Antibacterial Kitchen Cleaner, Mr. Clean Ultra,
      ethanol) designed for home or institutional use against potential human
      pathogens, including selected antibiotic-resistant bacteria. DESIGN: A
      quantitative suspension test was used to assess the efficacy of selected
      disinfectants following exposure times of 30 seconds and 5 minutes. Activity was
      assessed against Staphylococcus aureus, Salmonella choleraesuis, Escherichia coli
      O157:H7, and Pseudomonas aeruginosa. Selected disinfectants were also tested
      against poliovirus, vancomycin-susceptible and -resistant Enterococcus species,
      and methicillin-susceptible and -resistant S. aureus. RESULTS: The following
      compounds demonstrated excellent antimicrobial activity (>5.6-8.2 log10
      reduction) at both exposure times: TBQ, Vesphene, Clorox, ethanol, and Lysol
      Antibacterial Kitchen Cleaner. Mr. Clean eliminated 4 to >6 logs10 and Lysol
      Disinfectant approximately 4 logs10 of pathogenic microorganisms at both exposure
      times. Vinegar eliminated <3 logs10 of S. aureus and E. coli, and baking soda <3
      logs10 of all test pathogens. All tested chemical disinfectants completely
      inactivated both antibiotic-resistant and -susceptible bacteria at both exposure
      times. Only two disinfectants, Clorox and Lysol, demonstrated excellent activity
      (>3 log10 reduction) against poliovirus. CONCLUSIONS: A variety of commercial
      household disinfectants were highly effective against potential bacterial
      pathogens. The natural products were less effective than commercial household
      disinfectants. Only Clorox and Lysol disinfectant were effective against
      poliovirus.

PMID- 10656353
TI  - Prevalence of positive tuberculin skin reactions in a two-step testing program at
      a tertiary-care center in eastern North Carolina.
AB  - The results of performing two-step tuberculin skin testing of healthcare workers
      at a hospital in eastern North Carolina in 1997 and 1998 were reviewed. Of 1,248
      new employees, approximately 500 required two-step testing, which identified only
      5 new employees who might have been falsely labeled as converters during the
      subsequent year's surveillance testing.

PMID- 10656354
TI  - Microbiological evaluation of central venous catheter administration hubs.
AB  - We compared, in three intensive care units, colonization of hubs with hub
      protection boxes or hubs with needleless closed connectors; 137 central venous
      catheters and 451 hubs were randomized in two groups with similar
      characteristics. Catheter and hub colonization were not different between the two
      groups. Among 30 colonized catheters, the same isolate was found in only two
      hubs; hub contamination rarely is responsible for catheter colonization in short
      term catheters. Further studies are required to evaluate the benefit of protected
      hubs compared with unprotected hubs.

PMID- 10656355
TI  - Excessive use of vancomycin: a successful intervention strategy at an academic
      medical center.
AB  - The project goal was to decrease excessive vancomycin use. Interventions included
      an educational chart note the first day of therapy, followed by pharmacists
      discussing the need for continued therapy with patients' physicians. Empirical
      vancomycin use improved from 20% to 90% compliance with guidelines within 6
      months of the intervention.

PMID- 10656356
TI  - Practical guidelines for vancomycin usage, with prospective drug-utilization
      evaluation.
AB  - To strengthen guidelines for vancomycin use, practical guidelines were developed.
      A prospective survey was conducted of all patients receiving vancomycin during
      two 1-month periods, 1 year apart, during which significant improvements were
      noted. Practical guidelines may contribute to appropriateness of vancomycin use,
      serve as educational tools, and facilitate improved surveillance.

PMID- 10656357
TI  - Vancomycin use in pediatric hematology-oncology patients.
AB  - Across-sectional study was performed of pediatric hematology-oncology patients
      who received vancomycin; use was compared to the Centers for Disease Control and
      Prevention (CDC) recommendations for vancomycin use. Thirty-seven patients
      received 308 doses of vancomycin. AR patients initially received vancomycin as
      empirical therapy; 100% of this use was not consistent with the CDC
      recommendations.

PMID- 10656358
TI  - Nosocomial pseudo-outbreak of Fusarium verticillioides associated with sterile
      plastic containers.
AB  - Twenty-six patients were implicated in a nosocomial pseudo-outbreak of Fusarium
      verticillioides. Examination of clinical records and handling procedures revealed
      a fungal contamination of supposedly sterile containers used for biological
      materials. An accurate system of monitoring permitted us to determine the origin
      of the infection and the means of its spread.

PMID- 10656359
TI  - The threat of biological terrorism: a public health and infection control
      reality.
AB  - Bioterrorism is an emerging public health and infection control threat. Potential
      biological agents include smallpox, anthrax, plague, tularemia, botulinum toxin,
      brucellosis, Q fever, viral encephalitis, hemorrhagic fever, and staphylococcal
      enterotoxin B. An understanding of the epidemiology, clinical manifestations, and
      management of the more likely candidate agents is critical to limiting morbidity
      and mortality from a biological event. Effective response requires an increased
      index of suspicion for unusual diseases or syndromes, with prompt reporting to
      health authorities to facilitate recognition of an outbreak and subsequent
      intervention. Hospital epidemiology programs will play a crucial role in this
      effort.

PMID- 10656360
TI  - What's the score?
AB  - If you have calculated a confidence interval for an infection rate and found the
      interval extending into meaningless negative numbers, chances are the error is
      due to use of approximation formulae. Many of us unknowingly were taught to use
      the Wald approximation, which does not always approximate the exact binomial
      distribution accurately. Poor approximation can occur in infection surveillance
      at both small and large sample sizes.

PMID- 10656361
TI  - Control of influenza in the long-term-care facility: a review of established
      approaches and newer options.
AB  - Influenza infections pose a serious threat to residents of nursing homes and
      other long-term-care facilities. Annual vaccination of residents and staff with
      the currently licensed inactivated influenza vaccine continues to be the mainstay
      of prevention. Live attenuated influenza vaccine, which is expected to be
      licensed in the United States in the near future, may offer added protection for
      elderly persons when administered in conjunction with inactivated vaccine.
      Antiviral agents also can be useful as an adjunct to vaccination, especially for
      control of institutional outbreaks. Two new antiviral agents that appear to be
      less toxic than amantadine and rimantadine have recently been approved.

PMID- 10656362
TI  - OSHA announces enforcement of safety devices.

PMID- 10656363
TI  - A radiation biologist looks to the future.

PMID- 10656364
TI  - Future directions in 3-D treatment planning and delivery: a physicist's
      perspective.

PMID- 10656365
TI  - Submandibular salivary gland transfer prevents radiation-induced xerostomia.
AB  - BACKGROUND: Xerostomia is a significant morbidity of radiation therapy in the
      management of head and neck cancers. We hypothesized that the surgical transfer
      of one submandibular salivary gland to submental space, outside the proposed
      radiation field, prior to starting radiation treatment, would prevent xerostomia.
      METHODS: We are conducting a prospective clinical trial where the submandibular
      gland is transferred as part of the surgical intervention. The patients are
      followed clinically, with salivary flow studies and University of Washington
      quality of life questionnaire. RESULTS: We report early results of 16 patients
      who have undergone this procedure. Seven patients have finished and 2 patients
      are currently undergoing radiation treatment. In 2 patients, no postoperative
      radiation treatment was indicated. Two patients are waiting to start radiation
      treatment and 2 patients refused treatment after surgery. The surgical transfer
      was abandoned in 1 patient. All of the transferred salivary glands were
      positioned outside the proposed radiation fields and were functional. The
      patients did not complain of any xerostomia and developed only minimal oral
      mucositis. There were no surgical complications. CONCLUSIONS: Surgical transfer
      of a submandibular salivary gland to the submental space (outside the radiation
      field) preserves its function and prevents the development of radiation-induced
      xerostomia.

PMID- 10656366
TI  - Tumor radiosensitivity (SF2) is a prognostic factor for local control in head and
      neck cancers.
AB  - PURPOSE: To evaluate prospectively the prognostic value of SF2 for local control
      and survival in patients undergoing radiation therapy for head and neck cancers.
      METHODS AND MATERIALS: Following informed consent tumor specimens were obtained
      from 156 patients with primary carcinomas of the head and neck region. The
      specimens were assessed for the ability to grow in vitro (colony forming
      efficiency, CFE) and inherent radiosensitivity measured as the surviving fraction
      at 2 Gy (SF2) using a soft-agar clonogenic assay. Patients were treated mainly
      with neoadjuvant chemotherapy plus radiation therapy usually as a combination of
      accelerated external beam and interstitial radiotherapy. The probabilities of
      local control and survival were analyzed by univariate, bivariate and Cox
      multivariate analyses. RESULTS: Successful growth was achieved in 110/156
      specimens and SF2 values were obtained from 99/156. Eighty four out of these
      patients underwent radical treatment. The median SF2 value for the 84 tumors was
      0.40. At a mean follow-up time of 25 months (range 7-65) the median SF2 value of
      tumors from 14 patients who developed local recurrence was 0.53, which was
      significantly higher than the median of 0.38 for tumors from 70 patients without
      local recurrence (p = 0.015). Tumor SF2 was a significant prognostic factor for
      local control (p = 0.036), but not for overall survival (p = 0.20). Tumor SF2 was
      an independent prognostic factor for local control within bivariate and Cox
      multivariate analyses. CONCLUSIONS: This study has shown that tumor
      radiosensitivity measured as SF2 is a significant prognostic factor for local
      control in head and neck cancers.

PMID- 10656367
TI  - P53 overexpression is associated with bulky tumor and poor local control in T1
      glottic cancer.
AB  - PURPOSE: To study the role of two possible prognostic factors, p53 and tumor
      bulk, and their interaction with other tumor and treatment variables in early
      stage laryngeal cancer patients treated with curative radiotherapy. METHODS: One
      hundred two patients with T1N0M0 squamous cell carcinoma of the glottic larynx
      treated with definitive radiotherapy were analyzed. p53 status in pretreatment
      biopsy specimens was assessed by immunohistochemistry (IHC) using mouse
      monoclonal antibody DO-7. Tumors were classified as small surface lesions or
      bulky tumors. All tumor-related and treatment-related variables which might
      influence the outcome were analyzed. Local control after definitive radiotherapy
      was the end point of the study. RESULTS: The local control at 5 years for the
      entire group of patients was 78% (80/102) and 91% (93/102) after surgical
      salvage. p53 overexpression by IHC was seen in 37% (38/102) of patients. Tumors
      were classified as small volume in 69 (68%) and bulky in 33 (32%) patients. Five
      year local control was 48% for p53-positive patients as compared to 94% for p53
      negative patients (p = 0.0001). Tumor bulk was the other important prognostic
      factor, with 5-year local control of 91% for small tumors and 48% for bulky
      tumors (p = 0.0001). Patients who had both p53 positivity and bulky tumors did
      worse, with a 5-year local control of 23% as compared to 92% for all other groups
      combined (p = 0.0001). Among other variables, only the length of radiation time
      was of borderline significance. CONCLUSION: Both p53 overexpression and tumor
      bulk are independent prognostic factors for local control in early-stage glottic
      cancer treated with curative radiotherapy. The precise relationship between a
      genetic event, the p53 mutation, and an observable phenotype expression such as
      tumor bulk needs to be further defined.

PMID- 10656368
TI  - Early results of pulsed-dose-rate interstitial brachytherapy for head and neck
      malignancies after limited surgery.
AB  - PURPOSE: The aim of this study was to evaluate the relative incidence of toxicity
      and local control in patients with head and neck malignancies who underwent
      interstitial pulsed-dose-rate (PDR) brachytherapy (iBT). PATIENTS AND METHODS:
      From October 1997 to December 1998, 61 patients underwent interstitial PDR
      brachytherapy procedures in our department; 47 were patients with head and neck
      cancer. Forty patients received brachytherapy as part of their curative treatment
      regimen, and 7 patients were implanted for palliative purposes and excluded from
      the analysis of therapy efficacy. Twenty-four patients had interstitial
      brachytherapy procedures alone with D(REF) = 50 Gy; in 23 patients, iBT
      procedures were performed with D(REF) = 24 Gy in combination with external
      radiation. A dose per pulse (dp) of 0.5 Gy was prescribed for 38/47 patients, and
      a dp = 0.7 Gy for 9/47 patients. The pulses were delivered 24 h a day, with a
      time interval of 1 h between two pulses, resulting in an effective dose rate of
      0.5 Gy/h or 0.7 Gy/h. A follow-up of the patients was done to analyze acute and
      delayed toxicity, local control, and survival. The analysis was performed after
      median follow-up of 12 months (5-18 months). RESULTS: After a median follow-up of
      12 months, soft tissue necrosis was seen in one patient and bone necrosis in
      another. No other serious side effects were observed. Permanent locoregional
      tumor control was achieved in 37 of 40 patients. No distant metastases were
      observed. CONCLUSIONS: PDR interstitial brachytherapy with 0.5-0.7 Gy/h is a safe
      therapy. These preliminary results suggest that PDR interstitial brachytherapy of
      head and neck cancer is comparable with low-dose-rate (LDR) brachytherapy.

PMID- 10656369
TI  - The significance of extracapsular extension of axillary lymph node metastases in
      early-stage breast cancer.
AB  - PURPOSE: To investigate if extracapsular extension (ECE) of axillary lymph node
      metastases predicts for a decreased rate of disease-free survival or an increased
      rate of regional recurrence of breast carcinoma. METHODS: The study population
      consisted of 368 patients with T1 or T2 breast cancer and pathologically-positive
      lymph nodes treated with breast-conserving therapy between 1968 and 1986. The
      median number of sampled lymph nodes was 10. Median follow-up time for the
      surviving patients was 139 months (range 70-244). Twenty percent of the patients
      were treated with supraclavicular RT, and 64% received both axillary and
      supraclavicular RT, with a median dose to the nodes of 45 Gy. The following
      factors were evaluated: presence of ECE, number of sampled lymph nodes (LN),
      number of involved LN, size of primary tumor, histologic grade of tumor, presence
      of lymphatic vessel invasion (LVI), presence of an extensive intraductal
      component (EIC), radiation dose, use of adjuvant chemotherapy, and age of
      patient. Recurrences were reported as the 5-year crude sites of first failure,
      and were divided into breast recurrences (LR), regional nodal failure (RNF,
      defined as isolated axillary, supraclavicular, or internal mammary recurrence),
      and distant metastases (DM). RESULTS: One hundred twenty-two patients (33%) had
      ECE and 246 patients did not. The median number of LN with ECE was 1 (range 1-10)
      and 20% of patients had ECE in > or =4 LN. Patients with ECE tended to be older
      (median age 51 vs. 47, p = 0.01), and had a higher number of involved LN (median
      3 vs. 2, p = 0.005) than patients without ECE. Forty-three percent of patients
      with ECE had > or =4 involved LN compared to 15% of patients without ECE
      (p<0.0001). Models of ECE and the above factors revealed no significant
      correlation between ECE and either disease-free or overall survival. There was no
      statistically significant increase in local, regional nodal, or distant failures
      in patients with ECE as compared to patients without ECE. CONCLUSION: In this
      population of patients with nodal involvement, the presence of ECE correlates
      with the number of involved LN but does not appear to add predictive power to
      models of local, regional, or distant recurrence when the number of positive LN
      is included.

PMID- 10656370
TI  - Improving the dosimetric coverage of interstitial high-dose-rate breast implants.
AB  - PURPOSE/OBJECTIVE: We performed a retrospective computed tomography (CT)-based
      three-dimensional (3D) dose-volume analysis of high-dose-rate (HDR) interstitial
      breast implants to evaluate the adequacy of lumpectomy cavity coverage, and then
      designed a simple, reproducible algorithm for dwell-time adjustment to correct
      for underdosage of the lumpectomy cavity. METHODS AND MATERIALS: Since March
      1993, brachytherapy has been used as the sole radiation modality after lumpectomy
      in selected protocol patients with early-stage breast cancer treated with breast
      conserving therapy. In this protocol, all patients received 32 Gy in 8 fractions
      of 4 Gy over 4 days. Eleven patients treated with HDR brachytherapy who underwent
      CT scanning after implant placement were included in this analysis. For each
      patient, the postimplant CT dataset was transferred to a 3D treatment planning
      system, and the relevant tissue volumes were outlined on each axial slice. The
      implant dataset, including the dwell positions and dwell times, were imported
      into the 3D planning system and then registered to the visible implant template
      in the CT dataset. The calculated dose distribution was analyzed with respect to
      defined volumes via dose-volume histograms. Due to the variability of lumpectomy
      cavity coverage discovered in this 3D quality assurance analysis, dwell times at
      selected positions were adjusted in an attempt to improve dosimetric coverage of
      the lumpectomy cavity. Using implant data from 5 cases, a dwell-time adjustment
      algorithm was designed and was then tested on 11 cases. In this algorithm, a
      point P was identified using axial CT images, which was representative of the
      underdosed region within the cavity. The distance (d) from point P to the nearest
      dwell position was measured. A number of dwell positions (N) nearest to point P
      were selected for dwell time adjustment. The algorithm was tested by increasing
      the dwell times of a variable number of positions (N = 1, 3, 5, 7, 10, and 20) by
      a weighting factor (alpha), where alpha = f(d) and alpha > 1, and subsequently
      performing 3D dose-volume analysis to evaluate the improvement in lumpectomy
      cavity coverage. RESULTS: Before adjustment in the 11 implants, the median
      proportion of the lumpectomy cavity and target volume that received at least the
      prescription dose was 85% and 68%, respectively. After dwell-time adjustment,
      lumpectomy cavity coverage was significantly improved in all 11 cases. The median
      distance from point P to the nearest dwell position (d) was 1.4 cm (range 0.9
      1.9). The median volume of the lumpectomy cavity receiving 32 Gy increased from
      85.3% in the actual implant to 97.0% (range 74-100%) by increasing the dwell time
      of a single dwell position by a median factor (alpha) of 12.2 according to the
      above algorithm. With N = 3, the median proportion of the cavity volume receiving
      32 Gy was improved to 97.5% (range 77-100%), with a median alpha of 5.7. Further
      improvement in lumpectomy cavity coverage was relatively small by increasing
      additional dwell times. In addition, with N = 20, the median absolute volume of
      breast tissue receiving 150% of the prescription dose was 70.3 cm3 compared to
      26.3 cm3 in the actual implant; whereas with N = 1 or N = 3, this median volume
      was only 35.9 and 42.0 cm3, respectively. CONCLUSION: Lumpectomy cavity coverage
      sometimes appears suboptimal with interstitial HDR breast brachytherapy using our
      current technique. A simple dwell-time increase at only 1-3 dwell positions can
      compensate for some underdosage without creating significant regions of
      overdosage. Using simple methodology, a single reference point representing the
      underdosed region can be utilized for initial selection of the dwell positions to
      be increased.

PMID- 10656371
TI  - Fractionated stereotactic radiation therapy and single high-dose radiosurgery for
      acoustic neuroma: early results of a prospective clinical study.
AB  - PURPOSE: To prospectively assess the local control and toxicity rate in acoustic
      neuroma patients treated with linear accelerator-based radiosurgery and
      fractionated stereotactic radiation therapy. METHODS AND MATERIALS: We evaluated
      37 consecutive patients treated with stereotactic radiation therapy for acoustic
      neuroma. All patients had progressive tumors, progressive symptoms, or both. Mean
      tumor diameter was 2.3 cm (range 0.8-3.3) on magnetic resonance (MR) scan.
      Dentate patients were given a dose of 5x4 Gy or 5x5 Gy and edentate patients were
      given a dose of 1x10 Gy or 1x12.50 Gy prescribed to the 80% isodose. All patients
      were treated with a single isocenter. RESULTS: With a mean follow-up period of 25
      months (range 12-61), the actuarial local control rate at 5 years was 91% (only 1
      patient failed). The actuarial rate of hearing preservation at 5 years was 66% in
      previously-hearing patients. The actuarial rate of freedom from trigeminal nerve
      toxicity was 97% at 5 years. No patient developed facial nerve toxicity or other
      complications. CONCLUSION: In this unselected series, fractionated stereotactic
      radiation therapy and linear accelerator-based radiosurgery give excellent local
      control in acoustic neuroma. It combines a high rate of preservation of hearing
      with a very low rate of other toxicity, although follow-up is relatively short.

PMID- 10656372
TI  - Neurocognitive effects of therapeutic irradiation for base of skull tumors.
AB  - PURPOSE: To determine whether radiation therapy delivered to the paranasal
      sinuses causes any long-term impairment in neurocognitive function as a result of
      incidental brain irradiation. METHODS AND MATERIALS: Nineteen patients who
      received paranasal sinus irradiation at least 20 months and up to 20 years before
      assessment were given a battery of neuropsychologic tests of cognitive function.
      Radiation was delivered by a three-field (one anteroposterior and two lateral)
      technique. The median radiation dose was 60 Gy (range 50-68 Gy) in fractions of
      1.8 to 2 Gy. The volume of irradiated brain was calculated from planning computed
      tomography slices or simulation films. The results of the neuropsychologic tests
      were compared to normative control values. RESULTS: Memory impairment was found
      in 80% of the patients, and one-third manifested difficulty with visual-motor
      speed, frontal lobe executive functions, and fine motor coordination. Two of the
      patients had frank brain necrosis with resultant dementia and blindness, and
      three had evidence of brain atrophy. Three of the fourteen patients without
      documented cerebral atrophy or necrosis were disabled from their normal
      activities. Three patients also developed pituitary dysfunction. Neurocognitive
      symptoms were related to the total dose of radiation delivered but not to the
      volume of brain irradiated, side of radiation boost, or chemotherapy treatment.
      The pattern of test findings was consistent with radiation injury to subcortical
      white matter. CONCLUSIONS: Radiation therapy for paranasal sinus cancer may cause
      delayed neurocognitive side effects. Currently, however, the development of
      severe adverse effects appears to be decreasing because of improvements in the
      techniques used to deliver radiation. Lowering the total dose and improving dose
      distributions should further decrease the incidence of delayed brain injury due
      to radiation.

PMID- 10656373
TI  - Local control and overall survival in atypical meningioma: a retrospective study.
AB  - PURPOSE: To evaluate local control and overall survival after primary surgery for
      patients with atypical meningiomas. METHODS AND MATERIALS: From the Department of
      Pathology database, we identified 491 cases of meningioma treated at the
      Cleveland Clinic Foundation from 1979 through 1995. Thirty-three were diagnosed
      with atypical meningioma. Eleven of the excluded patients had incomplete records,
      were lost to follow-up, or received treatment elsewhere. Of the 22 evaluable
      patients, 15 underwent gross total resection (GTR), 4 had a subtotal resection
      (STR), and 3 had a resection of unknown extent. Eight patients received radiation
      therapy (2 after initial resection and 6 after at least one recurrence). The
      median radiation dose was 5,400 cGy (range 3,500-5,940). The median age at
      presentation was 55.5 years, the male:female ratio was 14:8, and 19/22 patients
      had a Karnofsky performance score (KPS) > or =80. The independent variables
      analyzed for overall survival and local control were gender, KPS (> or =80 vs. <
      80), extent of surgery (GTR vs. STR or unknown extent of surgery), and
      postoperative radiation therapy. RESULTS: Median survival was 10.6 years, with a
      median follow-up of 5.5 years (range 1.5-14.8). Eight of the 22 patients had
      local recurrence, including 2/15 with GTR, 3/4 with STR, and all 3 patients who
      underwent resection of unknown extent. At 10 years, patients with GTR had a
      higher local control rate than those who had either a STR or a resection of
      unknown extent (87% vs. 17%; p = 0.02). The 5- and 10-year overall survival rates
      for the entire group were 91% and 76%, respectively. Patients who had GTR had 5-
      and 10-year overall survival of 87% and 87%, respectively. Patients with STR or
      resection of unknown extent had 5- and 10-year overall survival rates of 100% and
      75%, respectively. CONCLUSION: In patients with atypical meningiomas, gross total
      resection is associated with a lower recurrence rate than in subtotal resection.

PMID- 10656374
TI  - Characteristics of 49 patients who survived for 5 years following radical
      radiation therapy for non-small cell lung cancer: the potential for cure.
AB  - PURPOSE: To investigate the long-term curative potential of radical radiation
      therapy (RT) for non-small cell lung cancer (NSCLC) by studying characteristics
      of patients from a large prospective database who survived >5 years after RT, and
      by analyzing survival beyond 5 years. METHODS AND MATERIALS: Five-year survivors
      were identified from a database containing information on 488 patients given
      radical RT following presentation to the Peter MacCallum Cancer Institute with
      NSCLC between 1984 and 1990. Additional data were obtained from case notes of
      survivors. RT was computed tomography (CT)-planned, conventionally-fractionated,
      and given without chemotherapy. RESULTS: Actuarial survival for 49 5-year
      survivors was 65% at 10 years. Five 5-year survivors had documented disease
      progression within the first 5 years and subsequently died. Of 44 patients free
      from-progression (FFP) at 5 years, an estimated 81% remained FFP in the second 5
      years. Age and histology were not significant prognostic factors, and only 22
      patients (4.5%) had weight loss >10%. For 277 patients who had not undergone
      thoracotomy, median RT dose was 60 Gy and survival at 5 and 10 years was 7% and
      3%, respectively. For 207 patients who received radical RT post-thoracotomy,
      median dose was 60 Gy and survival at 5 and 10 years was 24% and 18%,
      respectively. Five-year survivors of post-thoracotomy RT had been treated for
      gross residual disease (n = 10), positive-margin (n = 6), or probable microscopic
      residual disease (n = 17). Failure to regain ECOG performance status = 0 post
      thoracotomy was associated with reduced survival (p<0.0012). FFP in the second 5
      years was superior for patients who had postoperative radiotherapy (90%) compared
      to patients without thoracotomy (62%, p = 0.008). CONCLUSION: Most patients FFP
      >5 years after radical RT for NSCLC remained FFP in the following 5 years and
      were apparently cured. RT alone can cure small but significant numbers of
      patients. Long-term results of combined chemotherapy/RT protocols, which are
      associated with increased median survival, are awaited for comparison.

PMID- 10656375
TI  - High dose rate brachytherapy for superficial cancer of the esophagus.
AB  - PURPOSE: We analyzed our experience with external radiotherapy, combined modality
      treatment, or HDR brachytherapy alone to limited esophageal cancers. METHODS AND
      MATERIALS: From 1991 to 1996, 25 patients with limited superficial esophagus
      carcinomas were treated by high dose rate brachytherapy. The mean age was 63
      years (43-86 years). Five patients showed superficial local recurrence after
      external radiotherapy. Eleven patients without invasion of the basal membrane
      were staged as Tis. Fourteen patients with tumors involving the submucosa without
      spreading to the muscle were staged as T1. Treatment consisted of HDR
      brachytherapy alone in 13 patients, external radiotherapy and brachytherapy in 8
      cases, and concomitant chemo- and radiotherapy in 4 cases. External beam
      radiation was administered to a total dose of 50 Gy using 2 Gy daily fractions in
      5 weeks. In cases of HDR brachytherapy alone (13 patients), 6 applications were
      performed once a week. RESULTS: The mean follow-up is 31 months (range 24-96
      months). Twelve patients received 2 applications and 13 patients received 6
      applications. Twelve patients experienced a failure (48%), 11/12 located in the
      esophagus, all of them in the treated volume. One patient presented an isolated
      distant metastasis. In the patients treated for superficial recurrence, 4/5 were
      locally controlled (80%) by brachytherapy alone. After brachytherapy alone, 8/13
      patients were controlled (61%). The mean disease-free survival is 14 months (1-36
      months). Overall survival is 76% at 1 year, 37% at 2 years, and 14% at 3 years.
      Overall survival for Tis patients is 24% vs. 20% for T1 (p = 0.83). Overall
      survival for patients treated by HDR brachytherapy alone is 43%. One patient
      presented with a fistula with local failure after external radiotherapy and
      brachytherapy. Four stenosis were registered, two were diagnosed on barium
      swallowing without symptoms, and two required dilatations. CONCLUSION: High dose
      rate brachytherapy permits the treating of patients with superficial esophageal
      cancer with good tolerance. Early tumors, located in the mucosa, might be treated
      by HDR brachytherapy alone or by a combined modality treatment in which HDR
      brachytherapy can take place like a boost. This approach may cure localized
      recurrences.

PMID- 10656376
TI  - A preliminary analysis of health-related quality of life in the first year after
      permanent source interstitial brachytherapy (PIB) for clinically localized
      prostate cancer.
AB  - PURPOSE: To prospectively assess the health-related quality of life (HRQOL) and
      changes in HRQOL during the first year after permanent source interstitial
      brachytherapy (PIB). METHODS AND MATERIALS: Thirty-one men treated with PIB
      between September 1997 and March 1998 completed a quality of life (functional
      assessment of cancer therapy-prostate: FACT-P) and a urinary symptom
      questionnaire (international prostate symptom score: IPSS) prior to treatment
      (T0), 1 month (T1), 3 months (T3), 6 months (T6), and 12 months (T12) following
      PIB. All participants were treated with 125I alone. Repeated measures analyses of
      variance (ANOVA) were conducted on all quality of life and urinary outcome
      measures for all 31 patients at all time points. RESULTS: The median age of the
      study population was 66 (range 51-80). All men had clinical T1c-T2b prostate
      cancer. The Gleason score was < or =6 in 27/31 (87%). Median pretreatment PSA was
      7.8 ng/ml (range 1.1-20.6). The mean score (and standard deviation) at T0, T1,
      T3, T6, and T12 for the FACT-P questionnaire are as follows: 140.5 (13.5), 132.7
      (15.3), 137.2 (17.4), 140.1 (16.0), and 142.4 (15.3). For the global test across
      time, statistically significant differences were observed for the cumulative
      scores of FACT-P (p<0.0012). The decrease in HRQOL was most marked 1 month
      following PIB. Examination of the subscales within the FACT-P instrument
      demonstrated statistically significant changes over time for the following:
      physical well-being (PWB), functional well-being (FWB), and prostate cancer
      (PCS). By 3 months, all HRQOL measures had returned to near baseline. The mean
      score (and standard deviation) at T0, T1, T3, T6, and T12 for the IPSS
      questionnaire are as follows: 8.3 (5.5), 18.4 (8.0), 15.7 (7.4), 13.7 (7.4), and
      10.2 (5.7). For the global test across time, statistically significant
      differences were observed for the IPSS scores (p<0.0001). The maximum increase in
      IPSS occurred 1 month following PIB. CONCLUSION: The results of this preliminary
      analysis suggest that clinically meaningful decreases in HRQOL, as measured by
      the FACT-P instrument, are evident within weeks after PIB. By 3 months, however,
      FACT-P scores return to near baseline levels. A validated instrument designed to
      measure urinary symptoms (IPSS) demonstrates that moderate to severe urinary
      symptoms persist for at least 3-6 months following PIB. One year following PIB,
      the scores on the FACT-P and IPSS questionnaires had returned to baseline.

PMID- 10656377
TI  - Postimplant analysis of transperineal interstitial permanent prostate
      brachytherapy: evidence for a learning curve in the first year at a single
      institution.
AB  - PURPOSE: The utilization of transperineal interstitial permanent prostate
      brachytherapy (TIPPB) is increasing in the United States. Quality assessment of
      TIPPB is in its infancy, and to date, dosimetric analyses have only been reported
      from centers with a large experience in prostate brachytherapy. The purpose of
      this report is to critically analyze the dosimetric coverage achieved following
      TIPPB in the first 63 cases performed by a multidisciplinary group of
      investigators with no prior experience with TIPPB. METHODS AND MATERIALS: The
      information in this report concerns the first 63 men treated with TIPPB alone at
      our institution between September 1997 and September 1998. All men were treated
      similarly, adapting the methods described by Blasko and Grimm. All men were
      treated with 125I. The prescription dose was 144 Gy according to the TG43
      formalism. TIPPB was performed jointly by a radiation oncologist and a urologist.
      One month following TIPPB, all men underwent a computed tomography (CT) scan of
      the pelvis according to a protocol using 3-mm abutting slices. CT images were
      transferred by a local area network to a commercially available treatment
      planning system and dose-volume histograms were calculated with 0.5-mm pixel
      spacing. A variety of dosimetric endpoints were examined. A single measure of
      dose homogeneity, the dose-homogeneity index (DHI), is defined as the volume
      within the prostate that receives 100-150% of the prescription dose (144-216 Gy)
      divided by the volume within the prostate that receives 100% of the prescription
      dose (144 Gy). Three measures of target (prostate) dosimetric coverage are
      provided. C100 is defined as the percentage of the prostate volume defined on
      postimplant CT that receives at least 100% of the prescription dose. C90 and C80
      are similar but represent the percentage of the prostate volume that receive 90%
      and 80% of the prescription dose, respectively. Statistical analyses were
      performed using commercially available computer software. To investigate any
      changes with time the first 30 cases (group 1) are compared to cases 31-63 (group
      2). All p-values are two-sided. RESULTS: The mean C100, C90, and C80 for all 63
      patients were 80.7% (SD 10.1), 85.1% (SD 10.2), and 89.3% (SD 9.5). The
      quantifiers of implant adequacy were all improved in the most recent 33 patients
      compared to the first 30 patients, (group 1: C100, 75.8% [SD 12.2], C90 79.9% [SD
      11.4], C80 84.3% [SD 11.1]; group 2: C100, 85.2 [SD 7.0], C90 89.9% [SD 5.8], C80
      93.8% [SD 4.2]; p<0.001). The mean DHI was 0.538 SD (0.124). A multivariate model
      incorporating a number of variables (ultrasound volume, CT volume, total
      activity, activity/ seed, implant number) with C100 as the dependent variable
      found that the implant number was the only statistically significant predictor of
      C100 (p = 0.0001). Using C90 and C80 as the dependent variable produced similar
      results (C90, p = 0.0001; C80, p = 0.0001). CONCLUSION: In this single
      institution experience with the first 63 men receiving TIPPB by a
      multidisciplinary group of investigators, there is evidence for a learning curve.
      All quantifiers of implant adequacy improved as clinicians gained experience. In
      the most recent group of patients, quantifiers of implant adequacy are similar to
      those reported from other groups with significantly more experience with TIPPB.

PMID- 10656379
TI  - Interrelationship of proliferation and hypoxia in carcinoma of the cervix.
AB  - PURPOSE: In human cervix cancer treated with radiotherapy, we have previously
      shown from separate groups of patients that tumor hypoxia and proliferation rate
      as measured by bromodeoxyuridine (BrdU) labeling index (LI) are important
      determinants of clinical outcome. We now examine the relationship of these two
      pre-treatment predictive assays in 43 patients studied prospectively from 1994-98
      where both tests were performed for each patient. MATERIAL AND METHODS: Newly
      diagnosed patients with carcinoma of the cervix were examined under anesthesia
      for staging purposes. Patients were given BrdU (200 mg) by intravenous route
      prior to the procedure. Tumor oxygenation was measured with the Eppendorf pO2
      histograph. Biopsy of tumor was then performed and the BrdU LI was obtained by
      flow cytometry. The degree of tumor hypoxia for each tumor was expressed as
      median pO2 values, and as the percentage of pO2 readings <5 mm Hg (HP5). RESULTS:
      The median age was 53 years (range 23-79 years). There were 32 squamous, and 11
      non-squamous carcinomas. FIGO stages were: IB and IIA, 8; IIB, 17; IIIB, 18; with
      a median tumor size of 6 cm (range 2-10 cm). The patients received uniform
      treatment with radical radiation therapy. There were 22 diploid and 21 aneuploid
      tumors. The median LI, pO2, and HP5 were 8.0%, 5.4 mm Hg, and 46.8%,
      respectively. Tests for linear associations showed no significant correlation
      between median pO2 vs. LI (r = 0.078, p = 0.62), and HP5 vs. LI (r = -0.14, p =
      0.38). CONCLUSIONS: The clinical outcome in this group of patients is immature,
      but these results suggest that tumor hypoxia and proliferation measurements are
      independent and potentially complementary predictive assays in cervix carcinoma.
      Further investigations are required to examine the distribution of proliferating
      tumor cells and its relationship with hypoxic tumor cells in tissue sections with
      the use of immunohistological techniques and image analysis systems.

PMID- 10656378
TI  - Effects of urethrography on prostate position: considerations for radiotherapy
      treatment planning of prostate carcinoma.
AB  - PURPOSE: Retrograde urethrography is commonly used to define the prostate apex at
      simulation. This study evaluated the hypothesis that urethrography causes
      prostate displacement, resulting in an error in treatment planning. METHODS AND
      MATERIALS: Forty-five patients with carcinoma of the prostate were evaluated.
      Gold seeds were placed in the apex, posterior wall, and base of the gland. In the
      first 20 patients, the position of the seed-defined apex was compared at
      simulation (with urethrogram) and on day 1 of treatment (without urethrogram). In
      the second cohort of 25 patients, the effects of urethrography on prostate
      position were evaluated directly at simulation by comparing the position of apex
      pre- and post-urethrography. An analysis was performed to estimate the possible
      impact of urethrogram-induced prostate motion on target coverage. RESULTS: The
      mean superior displacement in the first and second cohort was 5.2 mm and 6.8 mm,
      respectively (combined mean shift 6.1 mm). With a 10-mm field margin below the
      tip of the urethrogram cone, 56% of patients in this study would have inadequate
      planning target volume (PTV) coverage. CONCLUSION: Retrograde urethrography
      causes a significant superior shift of the prostate. Strict reliance on
      urethrography in determining the inferior field margin could result in inadequate
      treatment.

PMID- 10656380
TI  - Primary carcinoma of the vagina: Tata Memorial Hospital experience.
AB  - PURPOSE: Carcinoma of the vagina is a rare gynecological malignancy comprising
      approximately 2% of all the gynecological malignancies. We have analyzed the
      treatment outcome of the patients treated at the Tata Memorial Hospital from
      January 1984 to December 1993. METHODS AND MATERIALS: In this 10-year period, 134
      patients of primary vaginal cancers were registered at our hospital. Of these, 75
      patients received complete treatment and are analyzed. RESULTS: Disease-free
      survival (DFS) for the whole group is 50%, and overall survival (OAS) is 60%.
      Most locoregional recurrences and distant failures are noted in the 2 years
      following treatment. DFS at 5 years is as follows: Stage I (5 patients), Stage
      IIA (37 patients), Stage IIB (15 patients), Stage III (14 patients), and Stage IV
      (4 patients); are 40%, 55%, 60%, 50%, and 25%, respectively. The DFS for patients
      with complete response (42 patients) to external radiation at 5 years is 68%,
      with partial response (25 patients) is 35%, and with poor or no response (6
      patients) is 18% (p = 0.0000). We observed that brachytherapy was an important
      part of the treatment, and patients who received brachytherapy (59 patients),
      either with a vaginal intracavitary applicator (30 patients) or interstitial
      implant (29 patients) had a DFS of 53% and 56%, respectively, while 15 patients
      who received external radiation alone had a DFS of 30%. Patients receiving
      brachytherapy within 4 weeks of external radiation had a DFS of 60% as compared
      to 30% when the interval was more than 4 weeks. CONCLUSION: The factors
      indicating prognosis are: site and extent of involvement, presence of lymph nodes
      at presentation, technique of brachytherapy, and interval between external
      radiation and brachytherapy.

PMID- 10656381
TI  - Results of irradiation or chemoirradiation for primary unresectable, locally
      recurrent, or grossly incomplete resection of gastric adenocarcinoma.
AB  - OBJECTIVE: To evaluate the results of irradiation +/- chemotherapy for patients
      with unresectable gastric carcinoma. MATERIALS AND METHODS: The records of 60
      patients with a gastric or gastroesophageal junction adenocarcinoma and a locally
      advanced unresectable primary (n = 28), a local or regional recurrence (n = 21),
      or gross residual disease following incomplete resection (n = 11) were
      retrospectively reviewed. Patients were treated with external beam irradiation
      (EBRT) alone or external beam plus intraoperative irradiation (IOERT), and 55 of
      the 60 (92%) patients received 5-FU based chemotherapy. RESULTS: The median
      survival for the entire cohort was 11.6 months. There was no significant
      difference in median survival between each of the three treatment groups. In
      examining the extent of disease there was a significant difference in survival
      based on the number of sites involved. Nine patients with disease limited to a
      single non-nodal site appeared to represent a favorable subgroup compared to the
      rest of the patients (median survival of 21.8 months vs. 10.2 months,p = 0.03).
      In the patients with recurrent disease, the number of sites involved (p = 0.05),
      and total dose adding external beam dose to IOERT dose (> 54 Gy vs. < or =54 Gy,
      p = 0.06) were of borderline significance in regard to survival. CONCLUSIONS: In
      patients with either primary unresectable, locally or regionally recurrent, or
      incompletely resected gastric carcinoma, the overall survival is similar, and
      related to the extent of disease based on the number of regional sites involved.
      The patients with a single non-nodal site of disease represent a favorable
      subgroup and patients with recurrent disease may benefit from total irradiation
      doses > 54 Gy.

PMID- 10656382
TI  - What is the best position of the arms in mantle field for Hodgkin's disease?
AB  - PURPOSE: To evaluate the best position of the arms in mantle field for Hodgkin's
      disease. METHODS AND MATERIALS: In 12 patients, with surgical clips placed at the
      time of an axillary dissection for breast cancer, the radiological projection of
      the clips according to three arm positions was prospectively evaluated: akimbo
      (A), extended (E), and up over the head (U). The surgical clips were arbitrarily
      separated into two groups: lower and upper. In each patient, the distance between
      the surgical clips and chest wall was measured, and the possibility of shielding
      the lungs and humeral heads was evaluated. RESULTS: The mean displacement of the
      lower clips away from the chest wall when the patients were in A, E, and U
      positions was 2.5, 3.0, and 4.6 cm, respectively. The upper group clips showed a
      lower difference in distance from chest wall. In the U position, there was always
      a clip of the lower group that projected over the humeral head, making it
      impossible to block this structure. CONCLUSION: In the A position, there is the
      possibility of blocking the humeral head, but it is necessary to irradiate more
      lung parenchyma. Type E treatment setup allows the shielding of both lung and
      humeral head, while maintaining adequate margins around the axillary nodes. In
      the U position, there is a greater possibility of shielding the lung parenchyma,
      but it is impossible to block the humeral heads.

PMID- 10656383
TI  - Biological dosimetry after total body irradiation (TBI) for hematologic
      malignancy patients.
AB  - PURPOSE: Biological dosimetry based on scoring chromosomal aberrations in
      peripheral lymphocytes was compared to physical dosimetry done for total body
      irradiation (TBI) before bone marrow transplantation (BMT) in patients with
      hematologic malignancies. PATIENTS AND METHODS: Fifteen patients undergoing TBI
      were included in the study. A total dose of 12 Gy in 2.5 days was fractionated
      into 2 or 3 daily doses of 1.8 Gy delivered by a 18 MV linear accelerator (dose
      rate: 15.8 cGy x min(-1)). Blood samples were obtained from patients before
      irradiation and after the first fraction of 1.8 Gy. A standard dose-effect curve
      was established by in vitro irradiation of healthy volunteer lymphocytes.
      Chromosomal aberrations were scored by the conventional cytogenetics (CCG) method
      for unstable anomalies and by fluorescent in situ hybridization (FISH) for stable
      anomalies. RESULTS: Healthy donor lymphocytes before irradiation yielded 0.1%
      dicentrics and 0.3% translocations of chromosome 4 (Chr. 4), that is 2.5% for the
      whole genome. Patients before irradiation had 2% of dicentrics and 1.1% of
      chromosome 4 translocations. The biologically estimated dose of the 15 patients
      after exposure to 1.8 Gy was 1.93 Gy (95% CI: 1.85-2.05) according to CCG, and
      2.06 Gy (95% CI: 1.75-2.15) by FISH. CONCLUSION: The dose estimated by biological
      dosimetry, in this case of homogeneously distributed radiation of TBI agrees well
      with the absorbed radiation dose calculated by physical dosimetry.

PMID- 10656384
TI  - Cataract incidence after total-body irradiation.
AB  - PURPOSE: The aim of this retrospective study was to evaluate cataract incidence
      in a homogeneously-treated group of patients after total-body irradiation (TBI)
      followed by autologous bone marrow transplantation or peripheral blood stem cell
      transplantation. METHODS AND MATERIALS: Between 1982 and 1994, a total of 260
      patients received either autologous bone marrow or blood stem cell
      transplantation for hematological malignancy at the University of Heidelberg. Two
      hundred nine of these patients received TBI in our hospital. Radiotherapy was
      applied as hyperfractionated TBI, with a median dose of 14.4 Gy in 12 fractions
      over 4 days. Minimum time between fractions was 4 h. Photons with an energy of 23
      MeV were used with a dose rate of 7-18 cGy/min. Ninety-six of the 209 irradiated
      patients were still alive in 1996; 86 of these patients (52 men, 33 women)
      answered a questionnaire and could be examined ophthalmologically. The median age
      at time of TBI was 38.5 years, with a range of 15-59 years. RESULTS: The median
      follow-up is now 5.8 years, with a range of 1.7-13 years. Cataract occurred in
      28/85 patients (32.9%) after a median of 47 months (1-104 months). In 6 of 28
      patients who developed a cataract, surgery of the cataract was performed. Whole
      brain irradiation prior to TBI had been performed more often in the group of
      patients developing cataract (14.3%) versus 10.7% in the group of patients
      without cataract. However, there was no statistical difference (Chi-square,
      p>0.05). CONCLUSION: Cataract is a common side effect of TBI. Cataract incidence
      found in our patients is comparable to results of other centers using a
      fractionated regimen for TBI. To assess the incidence of cataract after TBI, a
      long-term follow-up is required.

PMID- 10656385
TI  - Long-term results of fractionated strontium-90 radiation therapy for pterygia.
AB  - PURPOSE: The long-term safety and effectiveness of fractionated strontium-90
      radiation therapy (RT) for pterygium were reviewed retrospectively. METHODS AND
      MATERIALS: Between 1984 and 1996, 399 patients with 490 pterygia were treated
      with a strontium-90 eye applicator following surgical removal of the pterygium.
      The median follow-up period was 61 months (range 2-178). Of the 490 pterygia, 452
      were fresh, 17 were recurrences after surgical removal alone, and 21 were
      recurrences after surgical removal plus postoperative RT. Fractionated RT of 31
      42 Gy/4-5 fractions/22-29 days was given for 95.1% of the pterygia. RESULTS: In
      total, 58 (11.8%) local recurrences of pterygia were noted. The median time of
      local recurrences was 10 months, ranging from 2 to 93 months, and 16 recurrences
      (28%) were noted later than 24 months after treatment. The interval between
      surgery and the start of RT (1-3 days vs. >3 days) and recurrent pterygia were
      significant variables for local control in the multivariate analysis, while total
      RT dose (7-29 Gy vs. 31-50 Gy) was a marginally significant variable. Late
      toxicities that may be associated with strontium-90 RT were scleromalacia
      (scleral thinning) in 4 eyes, adhesion of eyelids in 3 eyes, and scleral ulcer in
      2 eyes. CONCLUSION: Fractionated strontium-90 RT of approximately 40 Gy/4-5
      fractions was safe and effective for preventing recurrence of pterygia, when RT
      was started within 3 days of surgery.

PMID- 10656386
TI  - Correlation between normal tissue complications and in vitro radiosensitivity of
      skin fibroblasts derived from radiotherapy patients treated for variety of
      tumors.
AB  - PURPOSE: To assess the relationship between fibroblast intrinsic radiosensitivity
      in vitro and late reactions of normal tissues in patients treated by definitive
      radiotherapy for variety of tumors. PATIENTS AND METHODS: Ten patients were
      selected for this study. They were treated by radical radiotherapy for variety of
      tumors, including non-Hodgkin's lymphoma, prostate, glottic larynx, anal canal,
      cervix, bladder, thyroid gland, and tonsil pillar. Five patients did not develop
      any significant late reactions (normally sensitive group, NS). The other five
      developed late complications in different normal tissues and organs that proved
      to be fatal in one patient (clinically hyper-sensitive group, HS). Fibroblast
      cultures were established from punch skin biopsy and radiosensitivity in vitro
      was measured. The survival fraction at 2 Gy (SF2) was calculated and compared
      between the two groups. RESULTS: SF2 ranged between 0.10 and 0.38 with a mean of
      0.24. The mean SF2 for each of the NS and the HS groups were 0.31 and 0.17,
      respectively. The non-parametric rank test of Mann-Whitney shows that the
      difference between the two groups is statistically significant (p = 0.01).
      CONCLUSION: This study indicates that the in vitro radiosensitivity of skin
      fibroblasts is correlated with late complications in different organs and normal
      tissues following radiotherapy for variety of tumors. It also lends support to
      the existence of a common genetic component determining the radiosensitivity of
      cells targeted by the late effects of ionizing radiation.

PMID- 10656387
TI  - The early supra-additive apoptotic response of R3327-G prostate tumors to
      androgen ablation and radiation is not sustained with multiple fractions.
AB  - PURPOSE: The treatment of R3327-G tumor-bearing rats with androgen ablation (AA)
      via castration results in a supra-additive increase in apoptosis when 2-8 Gy
      gamma-irradiation (RT) is given as a single dose 3-14 days afterwards. We report
      here the dose response and effect of multiple fractions on this supra-additive
      apoptotic response. MATERIALS AND METHODS: Dunning R3327-G tumors were grown in
      the flanks of Copenhagen rats and the experiments were initiated at a tumor
      volume of 1.0-1.5 cc. Androgen ablation was achieved by castration 3 days prior
      to gamma-irradiation. Apoptosis was measured with a terminal deoxynucleotidyl
      transferase dUTP-biotin nick end-labeling assay 6-h after RT, unless otherwise
      specified. RESULTS: The dose response of the supra-additive apoptotic response
      was assessed by irradiating castrated animals with single doses of 2, 4, 8, or 16
      Gy (n = 5 per group); tumor cell apoptosis at 6-h following irradiation was
      2.4%+/-0.7% (+/- SEM), 4.2%+/-0.8%, 6.5%+/-1.4%, and 1.6%+/-0.3%, respectively.
      The RT only and AA only controls had < 1% apoptosis. The effect of fractionated
      RT on apoptosis was investigated to determine if the supra-additive apoptotic
      response was sustained with repeated 2-8 Gy fractions. When tumor-bearing animals
      were treated with repeated daily 2-Gy fractions, there was a reduction in the
      level of the supra-additive apoptotic response. After five 2-Gy fractions at 24-h
      intervals, apoptosis in the combined treated tumors was at levels seen in the AA
      controls. This raised the possibility that more than 24 h are required for
      recovery of the high supra-additive apoptotic levels seen after one fraction.
      When the interfraction interval was extended to 96 h, there was no significant
      increase in apoptosis over the additive effect of AA and RT. Although there was a
      decline in supra-additive apoptosis with repeated fractions, a dose response for
      tumor growth delay was evident for RT alone using 2.5-Gy fractions. Moreover, the
      combination of AA + fractionated RT resulted in a supra-additive enhancement in
      tumor growth delay to 5 cc. CONCLUSION: The early supra-additive apoptotic
      response from AA and single fraction radiation is not seen at high single
      fraction doses and is not sustained with repeated fractions. Therefore, the
      classical apoptotic response that occurs within 24 h of irradiation is not likely
      to be the main mechanism responsible for any clinical benefit seen with this
      combination.

PMID- 10656388
TI  - In vitro efficacy of a novel chemoradiopotentiator--taxoltere metro.
AB  - PURPOSE: To evaluate the in vitro cytotoxic and radiopotentiating effects of a
      novel paclitaxel analog (taxoltere metro) on Chinese hamster ovary (CHO) cells
      and human colon cancer cells. METHODS AND MATERIALS: Three cell lines (CHO cells,
      HCT116 human colon carcinoma cells [paclitaxel-sensitive], and VM46 cells
      [paclitaxel-resistant subline of HCT116]) were employed in this study. Cell
      survival was determined using the standard colony-forming assay. The ID50 value
      (drug concentrations required to reduce colony formation to 50% of the control
      value) was determined as a cytotoxic index from each cell survival curve. The
      sensitizer enhancement ratio (SER) as a radiopotentiating endpoint was determined
      as the ratio of the D0 values (with or without drugs) under hypoxic or air
      conditions. RESULTS: Taxoltere metro was 5-15 times more effective in killing CHO
      cells than paclitaxel under both hypoxic and euoxic treatment conditions.
      Cytocidal effects of taxoltere metro on HCT116 cells and VM46 cells were 28 and
      70 times higher than those of paclitaxel (p<0.001), respectively. Taxoltere metro
      also produced significant radiopotentiating effects on euoxic CHO and HCT116
      cells, but not on hypoxic cells. The SER value of taxoltere metro for CHO cells
      was about 2.3 at a dose of 100 nM. With HCT116 cells, taxoltere metro yielded an
      SER of 1.2 at the low dose of 10 nM. In contrast, the parent compound paclitaxel
      yielded little or no radiosensitization with either CHO or HCT116 cells.
      CONCLUSION: The results demonstrate that taxoltere metro is significantly more
      potent than paclitaxel in chemoradiopotentiating CHO cells and HCT116 human colon
      carcinoma cells. The data strongly suggest that taxoltere metro could be a
      promising chemoradiopotentiating agent for treatment of cancer.

PMID- 10656389
TI  - Optimal radiotherapy for prostate cancer: predictions for conventional external
      beam, IMRT, and brachytherapy from radiobiologic models.
AB  - PURPOSE: To determine, on the basis of radiobiological models, optimal modalities
      of radiotherapy for localized prostate cancer, and to provide a rational basis
      for therapeutic decisions. METHODS AND MATERIALS: An algorithm based on
      extensions to the linear-quadratic (LQ) cell survival model is constructed for
      fractionated and protracted irradiation. These radiobiological models include
      prostate tumor cell line-derived LQ parameters, clonogen repopulation, repair of
      sublethal damage, hypoxia, and radioisotope decay. In addition, dose
      inhomogeneities for both IMRT and brachytherapy (125I and 103Pd) from patient
      derived Dose Volume Histograms (DVH), as well as dose escalation, are
      incorporated. Three risk groups are defined in terms of sets of biologic
      parameters tailored to correspond to clinical risk groups as follows: Favorable
      iPSA <10 and bGS < or =6 and stage T2; Intermediate-one parameter increased; and
      Unfavorable-two or more parameters increased. Tumor control probabilities (TCP)
      are predicted for conventional external beam radiotherapy (EBRT, including 3D
      CRT), intensity modulated radiotherapy (IMRT), and permanent brachytherapy.
      RESULTS: Brachytherapy is less susceptible to variations in alpha/beta than EBRT
      and more susceptible to variations in clonogen potential doubling time (Tp). Our
      models predict TCP consistent with the bNED results from recent dose escalation
      trials and long-term outcomes from brachytherapy. TCP from IMRT are
      systematically superior to those from conventional fractionated RT, and suggests
      its possible use in dose escalation without additional dose to surrounding normal
      tissues. For potentially rapidly dividing tumors (Tp < 30 days) 103Pd yields
      superior cell kill compared with 125I, but for very slowly proliferating tumors
      the converse is suggested. Brachytherapy predicts equivalent or superior TCP to
      dose escalated EBRT. For unfavorable risk tumors, combined 45 Gy
      EBRT+brachytherapy boost predicts superior TCP than with either modality alone.
      CONCLUSIONS: The radiobiological models presented suggest a rational basis for
      choosing among several radiotherapeutic modalities based on biologic risk
      factors. In addition, they suggest that IMRT may potentially be superior to 3D
      CRT in allowing dose escalation without increased morbidity, and that
      brachytherapy, as monotherapy or as boost, may achieve superior tumor control
      compared with dose escalation 3D-CRT. The latter conclusion is supported by
      clinical data.

PMID- 10656390
TI  - Regrowth delay analysis of irradiated tumors in the curative dose region.
AB  - PURPOSE: To develop a method to analyze regrowth delay times, including cured
      tumors. METHODS AND MATERIALS: Regrowth delay measured in the in vitro squamous
      cell carcinoma megacolony system following fractionated irradiation was analyzed
      using two different approaches. A conventional regrowth delay analysis based on
      means or medians of dose groups was contrasted with a one-step procedure using
      the inverse of individual regrowth delay times, where cured tumors are
      represented by an infinite delay time. Two data sets with different proportions
      of cured tumors were compared in this way. In addition, for both approaches,
      confidence limits were also generated by the bootstrap technique. RESULTS: The
      parameter estimated was the alpha/beta ratio. The inverse analysis yielded
      similar results as the conventional analysis, but with much smaller confidence
      limits. When the dataset was stripped by stepwise removal of lower dose groups
      with no cures, the estimates of the alpha/beta ratio remained definitely more
      robust in inverse analysis. Results of the bootstrap procedure confirmed the
      accuracy of the calculated confidence intervals. CONCLUSION: Regrowth delay
      analysis using reciprocal regrowth delay times is a useful tool, especially when
      the data shows large variations, or a substantial fraction of the dataset falls
      into the curative dose region.

PMID- 10656391
TI  - Temperature-dependent changes in physiologic parameters of spontaneous canine
      soft tissue sarcomas after combined radiotherapy and hyperthermia treatment.
AB  - PURPOSE: The objectives of this study were to evaluate effects of hyperthermia on
      tumor oxygenation, extracellular pH (pHe), and blood flow in 13 dogs with
      spontaneous soft tissue sarcomas prior to and after local hyperthermia. METHODS
      AND MATERIALS: Tumor pO2 was measured using an Eppendorf polarographic device,
      pHe using interstitial electrodes, and blood flow using contrast-enhanced
      magnetic resonance imaging (MRI). RESULTS: There was an overall improvement in
      tumor oxygenation observed as an increase in median pO2 and decrease in hypoxic
      fraction (% of pO2 measurements <5 mm Hg) at 24-h post hyperthermia. These
      changes were most pronounced when the median temperature (T50) during
      hyperthermia treatment was less than 44 degrees C. Tumors with T50 > 44 degrees C
      were characterized by a decrease in median PO2 and an increase in hypoxic
      fraction. Similar thermal dose-related changes were observed in tumor perfusion.
      Perfusion was significantly higher after hyperthermia. Increases in perfusion
      were most evident in tumors with T50 < 44 degrees C. With T50 > 44 degrees C,
      there was no change in perfusion after hyperthermia. On average, pHe values
      declined in all animals after hyperthermia, with the greatest reduction seen for
      larger T50 values. CONCLUSION: This study suggests that hyperthermia has biphasic
      effects on tumor physiologic parameters. Lower temperatures tend to favor
      improved perfusion and oxygenation, whereas higher temperatures are more likely
      to cause vascular damage, thus leading to greater hypoxia. While it has long been
      recognized that such effects occur in rodent tumors, this is the first report to
      tie such changes to temperatures achieved during hyperthermia in the clinical
      setting. Furthermore, it suggests that the thermal threshold for vascular damage
      is higher in spontaneous tumors than in more rapidly growing rodent tumors.

PMID- 10656392
TI  - Intensity modulation for breast treatment using static multi-leaf collimators.
AB  - PURPOSE: To achieve more uniform dose distributions in breast cancer treatment
      using multiple sets of multi-leaf collimator (MLC) defined fields. Dose
      uniformity for many breast cancer patients can be significantly improved by using
      two or more sets of portals and the "hot" regions of a traditional treatment can
      be significantly reduced. METHODS AND MATERIALS: Patients for breast cancer
      treatment are immobilized with alpha cradle in the traditional arm-up position
      and have a CT scan in the treatment position. The target volume is delineated on
      the 5-mm thick CT slices that are obtained from the lower neck to well below the
      breast target volume. Medial and lateral tangential fields at conventional gantry
      angles are designed with the aid of digitally reconstructed radiographs (DRRs).
      The MLC, without collimator rotation, is used to shape the field to spare as much
      lung as possible. The wedges and relative weights of the beams are optimized to
      provide the best dose uniformity. For the patients with large dose inhomogeneity,
      a second set of fields is designed. The weight of the original set of fields is
      reduced (usually to approximately 90%) so that the "original hot" regions receive
      the prescription dose; the second set of fields delivers a supplemental dose to
      the "cold" region, typically approximately 10% of the total dose. The second set
      of fields has the same beam parameters but "treat" only the part of breast tissue
      that is "cool." Presently, the design of the reduced field is an iterative
      process. The process can be extended to more than two sets of portals to obtain
      the desired dose uniformity. RESULTS: With 3D planning and multiple MLC fields,
      dose uniformity in the treatment of breast patients was improved from 7%-22% to
      approximately 7%-15%. The volume receiving these high doses decreased
      significantly and shifted from the lung to the target. By keeping the gantry
      angles and wedges the same for the multiple fields, treatments can be delivered
      quickly and reliably. The internal mammary nodes (IM) can also be treated without
      including significant amount of lung or heart in the field. CONCLUSION: Dose
      uniformity can be significantly improved by using this intensity modulation
      technique to treat certain breast patients. With these static MLC fields creating
      the intensity modulation, the dose uniformity to the breast can be significantly
      improved and the hot region in lung reduced. There is no increase in setup
      complexity. The small increase in treatment time is insignificant.

PMID- 10656393
TI  - The potential for sparing of parotids and escalation of biologically effective
      dose with intensity-modulated radiation treatments of head and neck cancers: a
      treatment design study.
AB  - PURPOSE: Conventional radiotherapy for cancers of the head and neck (HN) can
      yield acceptable locoregional tumor control rates, but toxicity of many normal
      tissues limits our ability to escalate dose. Xerostomia represents one of the
      most common complications. The purpose of this study is to investigate the
      potential of intensity-modulated radiotherapy (IMRT) to achieve adequate sparing
      of parotids and to escalate nominal and/or biologically-effective dose to achieve
      higher tumor control without exceeding normal tissue tolerances. METHODS AND
      MATERIALS: An IMRT optimization system, developed at our institution for research
      and clinical purposes, and coupled to a commercial radiation treatment planning
      system, has been applied to a number of cases of HN carcinomas. IMRT plans were
      designed using dose- and dose-volume-based criteria for 4 and 6 MV coplanar but
      non-collinear beams ranging in number from 5 to 15 placed at equi-angular steps.
      Detailed analysis of one of the cases is presented, while the results of the
      other cases are summarized. For the first case, the IMRT plans are compared with
      the standard 3D conformal radiation treatment (3DCRT) plan actually used to treat
      the patient, and with each other. The aim of the 3DCRT plan for this particular
      case was to deliver 73 Gy to the tumor volume in 5 fractions of 2 Gy and 28
      fractions of 2.25 Gy/fx; and 46 Gy to the nodes in 2 Gy/fx while maintaining
      critical normal tissues to below specified tolerances. The IMRT plans were
      designed to be delivered as a "simultaneous integrated boost" (SIB) using the
      "sweeping window" technique with a dynamic MLC. The simultaneous integrated boost
      strategy was chosen, partly for reasons of efficiency in planning and delivery of
      IMRT treatments, and partly with the assumption that dose distributions in such
      treatments are more conformal and spare normal tissues to a greater extent than
      those with sequential boost strategy. Biologically equivalent dose normalized to
      2 Gy/fx, termed here as normalized total dose (NTD), for this strategy was
      calculated using published head and neck fractionation data. RESULTS: IMRT plans
      were more conformal than the 3DCRT plans. For equivalent coverage of the tumor
      and the nodes, and for the dose to the spinal cord and the brainstem maintained
      within tolerance limits, the dose to parotids was greatly reduced. For the
      detailed example presented, it was shown that the tumor and the nodes in the
      3DCRT plan receive NTDs of 78 and 46 Gy, respectively. For the IMRT plan, a
      nominal dose of 70 Gy could be delivered to the tumor in 28 fractions of 2.5 Gy
      each, simultaneously with 50.4 Gy to nodes with 1.8 Gy/fx. The two are
      biologically equivalent to 82 and 46 Gy, respectively, if delivered in 2 Gy/fx.
      Similar computations were carried out for other cases as well. The quality of
      IMRT plans was found to improve with increasing number of beams, up to 9 beams.
      Dose-volume-based criteria led to a modest improvement in IMRT plans and required
      less trial and error. CONCLUSION: IMRT has the potential to significantly improve
      radiotherapy of HN cancers by reducing normal tissue dose and simultaneously
      allowing escalation of dose. SIB strategy is not only more efficient and yields
      better dose distributions, but may also be biologically more effective. Dose
      volume-based criteria is better than purely dose-based criteria. The quality of
      plans improves with number of beams, reaching a saturation level for a certain
      number of beams, which for the plans studied was found to be 9.

PMID- 10656394
TI  - A clinical method for real-time dosimetric guidance of transperineal 125I
      prostate implants using interventional magnetic resonance imaging.
AB  - PURPOSE: The clinical utility of an interventional magnetic resonance (IMR)
      guided implant technique with real-time dosimetric feedback is presented. METHODS
      AND MATERIALS: The work was carried out at a IMR unit at Brigham and Women's
      Hospital. Planning and dosimetric feedback were provided by a software system
      that provides an interface to the IMR images, anatomy demarcation, template
      registration, dose calculation engine for planning, and evaluating the implant.
      Planning during the procedure permits the incorporation of actual needle
      trajectories in the dose calculations. RESULTS: Fifteen patients were planned in
      the treatment position. During source placement, actual needle locations were
      incorporated into the dose calculations. After accounting for the observed needle
      trajectories of the planned needles, 14 of 15 patients (93%) required additional
      sources to achieve the desired coverage of the target volume. CONCLUSION: A
      brachytherapy implant procedure which provides clinically significant advances
      has been implemented. Specifically, the planning system allows dosimetric
      validation of the needle placement. This procedure is effective in delivering
      brachytherapy to the target volume and assuring that the implant is delivered in
      accordance with the preplan. The dosimetric feedback could be incorporated in
      ultrasound-guided implants.

PMID- 10656395
TI  - Seed fixity in the prostate/periprostatic region following brachytherapy.
AB  - PURPOSE: Although postoperative dosimetric analyses of prostate brachytherapy are
      commonly reported, the long-term persistence, or fixity, of seeds implanted in
      the prostate gland and periprostatic region remains unclear, with only a few
      reports regarding the loss or migration of the seeds in the implanted region and
      none which correlate lung embolization to pelvic seed loss. METHODS AND
      MATERIALS: The study population consisted of 175 consecutive patients implanted
      with either 125I (95 patients) or 103Pd (80 patients) using a mean of 136 seeds
      in a modified uniform loading approach to cover a planning volume that was 1.64
      times the ultrasound prostate volume. An average of 64% of 125I seeds were
      embedded in braided vicryl suture, and these seeds were used on the periphery and
      extra prostatic regions. Following CT-based dosimetric analysis on day 0, all
      patients had orthogonal plain films of the pelvis obtained from day 0 to day 502,
      with an average of 2.3 film pairs per patient. Routine diagnostic PA and lateral
      chest X rays were obtained for 156 patients over the same time period. RESULTS:
      The mean pelvic seed fixity was greater than 98% throughout the time covered by
      this study. The seed fixity rates for 125I and 103Pd, although nearly equal, were
      significantly different up to 60 days post implant. The median 125I seed loss per
      patient was only 1 seed through 180 days while for 103Pd, the median seed loss
      was 2 seeds at 28 and 60 days and 3 seeds at 180 days. The fraction of patients
      experiencing no seed loss decreased from 40% at 28 days to 20% at 180 days for
      125I and from 24% to 7% for 103Pd over the same time interval. Patient and
      treatment parameters closely correlated to local seed loss include the number of
      seeds implanted, the planning volume, and the number of loose seeds, and for
      125I, the fraction of seeds in suture. The fraction of seeds placed outside the
      gland was not correlated with seed loss. Of the seeds lost from the pelvis, about
      10% were found to embolize to the lungs. Among the 156 patients with post-implant
      chest X rays, the fraction of patients with pulmonary seed embolization was
      34/156 (21.8%). Of the 20 patients who had post-implant chest X rays obtained
      within 14 days of brachytherapy, none had seeds detected in the lungs, while of
      the 136 patients who had chest X rays obtained greater than 30 days following
      implantation, 25.0% (34 patients) were noted to have seeds visualized in the
      lungs. CONCLUSIONS: With a median follow-up of 9 months, 125I seeds embedded in a
      vicryl suture or 103Pd seeds can be safely implanted in the prostate and
      periprostatic tissue with a high probability of prostate bed seed fixity and a
      low incidence of radioactive seed embolization to the lungs.

PMID- 10656396
TI  - The American Brachytherapy Society recommendations for permanent prostate
      brachytherapy postimplant dosimetric analysis.
AB  - PURPOSE: The purpose of this report is to establish guidelines for postimplant
      dosimetric analysis of permanent prostate brachytherapy. METHODS: Members of the
      American Brachytherapy Society (ABS) with expertise in prostate dosimetry
      evaluation performed a literature review and supplemented with their clinical
      experience formulated guidelines for performing and analyzing postimplant
      dosimetry of permanent prostate brachytherapy. RESULTS: The ABS recommends that
      postimplant dosimetry should be performed on all patients undergoing permanent
      prostate brachytherapy for optimal patient care. At present, computed tomography
      (CT)-based dosimetry is recommended, based on availability cost and the ability
      to image the prostate as well as the seeds. Additional plane radiographs should
      be obtained to verify the seed count. Until the ideal postoperative interval for
      CT scanning has been determined, each center should perform dosimetric evaluation
      of prostate implants at a consistent postoperative interval. This interval should
      be reported. Isodose displays should be obtained at 50%, 80%, 90%, 100%, 150%,
      and 200% of the prescription dose and displayed on multiple cross-sectional
      images of the prostate. A dose-volume histogram (DVH) of the prostate should be
      performed and the D90 (dose to 90% of the prostate gland) reported by all
      centers. Additionally, the D80, D100, the fractional V80, V90, V100, V150 and
      V200 (i.e., the percentage of prostate volume receiving 80%, 90%, 100%, 150%, and
      200% of the prescribed dose, respectively), the rectal, and urethral doses should
      be reported and ultimately correlated with clinical outcome in the research
      environment. On-line real-time dosimetry, the effects of dose heterogeneity, and
      the effects of tissue heterogeneity need further investigation. CONCLUSION: It is
      essential that postimplant dosimetry should be performed on all patients
      undergoing permanent prostate brachytherapy. Guidelines were established for the
      performance and analysis of such dosimetry.

PMID- 10656397
TI  - Optimization of coplanar six-field techniques for conformal radiotherapy of the
      prostate.
AB  - PURPOSE: To determine the optimal coplanar treatment technique for six-field
      conformal radiotherapy of prostate only (PO) or prostate plus seminal vesicles
      (PSV). METHODS AND MATERIALS: A series of 6-MV six-field coplanar treatment plans
      were created for PO and PSV volumes in 10 patients prescribed to both 64 and 74
      Gy. All plans consisted of laterally-symmetric anterior oblique, lateral, and
      posterior oblique fields. The posterior oblique fields were varied through 20-45
      degrees relative to the lateral fields, and for each of these angles, the
      anterior oblique fields were varied through 25-65 degrees relative to lateral.
      The plans were compared by means of rectal volumes irradiated to 80% or more of
      the prescribed dose (V80); normal tissue complication probability (NTCP) for
      rectum, bladder, and femoral heads; and tumor control probability (TCP). Femoral
      head tolerance was designated as 52 Gy to no more than 10% volume. RESULTS: For
      the PO group, anterior oblique fields at 50 degrees from lateral and posterior
      oblique fields at 25 degrees from lateral produced the lowest V80, together with
      femoral head doses which were appropriate for most patients (V80 = 24.4+/-5.3% [1
      SD]). Compared to a commonly-used six-field (reference) plan with both anterior
      and posterior oblique fields at 35 degrees from lateral (V80 = 26.3+/-5.9%), this
      represented an improvement (p = 0.001). For the PSV group, the optimal anterior
      and posterior oblique fields were at 65 degrees and 30 degrees from lateral,
      respectively (V80 = 47.5+/-6.3%). Relative to the reference plan (V80 = 49.4+/
      5.6%), this was a marginal improvement (p = 0.07). CONCLUSION: The optimized six
      field plans provide increased rectal sparing at both standard and escalated
      doses. Moreover, the gain in TCP resulting from dose escalation can be achieved
      with a smaller increase in rectal NTCP using the optimized six-field plans.

PMID- 10656398
TI  - Treatable domain and optimal frequency for brain tumors during ultrasound
      hyperthermia.
AB  - PURPOSE: To examine the optimal ultrasound frequency and the treatable domain
      determined by the tumor size and tumor depth when an external ultrasound heating
      system is employed for the brain tumor hyperthermia. METHODS AND MATERIALS: This
      work employs a simplified model of a scanned ultrasound transducer power
      deposition (a cone with convergent/divergent shape) and a search algorithm to
      investigate the optimal frequency and the treatable domain. The distributions of
      temperature and SAR (specific absorption rate) ratio are used to determine the
      appropriateness of the acoustic window size and the input power level for a
      yielded set of tumor conditions. The factors considered are the acoustic window
      size, tumor size and depth, ultrasound frequency, and the acoustic absorption of
      the post-target bone behind the tumor. RESULTS: Simulation results demonstrate
      that the optimal frequency depends on the tumor depth and the acoustic absorption
      of the post-target bone. However, it is almost independent of the acoustic window
      size. The optimal frequency shifts to a higher level for a deeper tumor heating
      to reduce the effect of the high acoustic absorption of post-target bone.
      Moreover, the treatable domain is proportional to the acoustic window size and
      related to the ultrasound frequency. CONCLUSION: It may not be possible to
      deliver appropriate ultrasonic energy to heat a brain tumor without overheating
      the normal brain tissue and/or the post-target bone under the constraints of the
      available acoustic window size for the ultrasonic beam, ultrasonic attenuation of
      brain tissue, high absorption of post-target bone, and high blood perfusion rate.
      The results of this study can be a guideline for designing an optimal ultrasound
      heating system, arranging the transducers, and implementing further treatment
      planning for the brain tumor hyperthermia.

PMID- 10656399
TI  - Design and dosimetry of a novel 90Y beta source to prevent restenosis after
      angioplasty.
AB  - PURPOSE: Post-dilatation irradiation of the vessel wall is currently under
      investigation for prevention of restenosis after balloon dilatation. For the
      irradiation, special sources were designed for animal experiments which would
      give equivalent irradiation conditions and doses to the vessel wall that would
      later be employed for human application. METHODS AND MATERIALS: For the planned
      irradiations, a specially designed yttrium-wire of 0.45-mm diameter coated with a
      thin shrink tube to prevent contamination was deployed. Several leakage tests
      applied before and after application proved that the irradiation source was
      leakproof. Dosimetry was performed by using 0.1-mm-thick thermoluminescent
      dosimeters (TLD-100) calibrated against a primary standard. A shielding transport
      and application container was designed to facilitate the handling of the source
      during use, while reducing exposure of the medical personnel. RESULTS: The
      designed source proves to be flexible for the insertion into proximal coronary
      vessels, and positioning at the site of stenosis. It provides an optimum
      protection of the animal and requires little radiation protection efforts on
      behalf of the medical staff. Dosimetric calculations and measurements showed that
      a centering of the source inside the vessel could be achieved with a maximum
      deviation of 50% between maximum and average dose levels. CONCLUSION: A yttrium
      90 beta brachytherapy source was designed which provides high flexibility within
      proximal coronary arteries, ensures an adequate centering inside the artery, and
      provides irradiation conditions to the vessel wall of the experimental animal
      comparable to the application inside a human artery.

PMID- 10656400
TI  - Characterization and oxidative in vitro cross-linking of an extensin-like protein
      and a proline-rich protein purified from chickpea cell walls.
AB  - Two cell wall proteins from chickpea, known to be rapidly insolubilised by an
      elicitor-stimulated oxidative burst in-vivo, were purified from suspension cells.
      N-terminal protein sequencing revealed them as a proline-rich protein and an
      extensin-like protein. Oxidative cross-linking could be modelled in an in vitro
      system utilising horseradish peroxidase, H2O2 and the substrate proteins.

PMID- 10656401
TI  - Secologanin synthase which catalyzes the oxidative cleavage of loganin into
      secologanin is a cytochrome P450.
AB  - Secologanin synthase, an enzyme catalyzing the oxidative cleavage of the
      cyclopentane ring in loganin to form secologanin, was detected in microsomal
      preparations from cell suspension cultures of Lonicera japonica. The reaction
      required NADPH and molecular oxygen, and was blocked by carbon monoxide as well
      as by several other cytochrome P450 inhibitors, indicating that the reaction was
      mediated by cytochrome P450. Of the substrates examined, only specificity for
      loganin was demonstrated. A possible reaction mechanism is described.

PMID- 10656402
TI  - Lipoxygenase pathway in olive callus cultures (Olea europaea).
AB  - Stimulation of the lipoxygenase pathway in olive fruit initiates a cascade of
      reactions that begins with the regio- and stereospecific di-oxygenation of
      polyunsaturated fatty acids containing a cis, cis-1,4 pentadiene moiety. Later
      products of the pathway include volatiles that influence the organoleptic
      properties of harvested olive oil. In this study, we have investigated
      lipoxygenase activity in olive callus cultures, and found that there is evidence
      of several isoforms of the enzyme with different pH optima and substrate
      specificities. Endogenous lipoxygenase activity was detected throughout the
      growth cycle of olive callus, particularly during the log phase of growth,
      suggesting that olive lipoxygenases are intimately involved in growth. The most
      prominent lipoxygenase activity in tissue cultures was found to be soluble but
      significant activities were detected in the plastid fraction. In addition,
      hydroperoxide lyase (HPL) activity was measured in the calli; both 13- and 9-HPL
      activities were found which were particulate.

PMID- 10656403
TI  - CO2 as main carbon source for isoprenoid biosynthesis via the mevalonate
      independent methylerythritol 4-phosphate route in the marine diatoms
      Phaeodactylum tricornutum and Nitzschia ovalis.
AB  - Isoprenoid biosynthesis was investigated in the two diatoms Phaeodactylum
      tricornutum and Nitzschia ovalis by labeling experiments performed in mixotrophic
      growth conditions with sodium [1-(13)C]acetate, 13CO2, [1-(13)C]glucose, sodium
      [3-(13)C]pyruvate and 1-deoxy-D-[5,5-(2)H2]xylulose. A clear dichotomy was found.
      Acetate was the preferred carbon source for the formation of the sterols in the
      cytoplasm via the mevalonate pathway. Carbon dioxide was the main source for
      phytol biosynthesis in the chloroplasts via the mevalonate-independent
      methylerythritol 4-phosphate pathway. The two diatoms showed the same
      compartmentation for isoprenoid biosynthesis as that previously found in higher
      plants, the red alga Porphyridium cruentum and the Chrysophyte Ochromonas danica.

PMID- 10656404
TI  - Hexokinase activity alters sugar-nucleotide formation in maize root homogenates.
AB  - Two pools of hexokinase activities differing in sensitivity to ADP inhibition
      were characterised in maize roots. In order to evaluate how glucose utilisation
      could be affected by these hexokinases, glucose-6-P and NDP-5'-sugar levels were
      measured after a D-[U-14C]glucose pulse in root extracts in the presence of 0 or
      1 mM ADP. Analysis of radio-labelled activated sugars by paper chromatography
      revealed that: (1) without ADP, nearly 20% of the 14C appeared in NDP-5'-sugars;
      (2) 0.1 mM ADP inhibited 14C-NDP-5'-sugar formation by 85%; and (3) with 1 mM
      ADP, 14C-NDP-5'-sugars were undetectable, but substantial (14%) 14C accumulated
      as glucose-6-P. Mannoheptulose, a hexokinase inhibitor, blocked the NDP-5'-sugar
      formation, but did not modify the amount of 14C-glucose-6-P in root extracts
      either with or without ADP. The analysis of the hexokinase activities with 0.8 mM
      glucose in maize root extracts showed that: (1) mitochondrial hexokinase activity
      was totally inhibited by 30 mM mannoheptulose; and (2) the cytosolic hexokinase
      was inhibited by only 30%. These data suggest that NDP-5'-sugar synthesis is
      sensitive to ADP fluctuations and that mannoheptulose affects preferentially the
      mitochondrial-bound hexokinase, but the cytosolic form is less sensitive. We
      propose that the mitochondrial hexokinase is the main energy charge sensor in
      this pathway in maize.

PMID- 10656405
TI  - The diversity of chemical substances controlling the nyctinastic leaf-movement in
      plants.
AB  - Leaf-movement in nyctinastic plants has long been believed to be controlled by
      plant hormones that are common among all nyctinastic plants. We have identified
      several bioactive substances for nyctinasty, whose bioactivities were highly
      specific to the original plant, based on the bioassay using the original plant
      leaf, and have shown that nyctinastic leaf-movement is not regulated by plant
      hormones. Our present results are in accordance with Umrath et al.
      physiologically significant opinion.

PMID- 10656406
TI  - Sunflower sesquiterpene lactone models induce Orobanche cumana seed germination.
AB  - Six sunflower sesquiterpene lactone models which share structural features of the
      lactone rings of strigol and its synthetic analogues, the GR family, with
      different conformational flexibilities were tested as Orobanche cumana
      germination stimulants. Among them, parthenolide and 3,5-dihydroxydehydrocostus
      lactone significantly increased O. cumana germination, presenting higher activity
      than GR-24, used as a standard in the germination bioassay. The effect of these
      two compounds is species-specific, showing no germination stimulant activity on
      other Orobanche spp. tested (O. crenata, O. ramosa and O. aegyptiaca). Data
      presented are discussed in terms of a structure-activity relationship.

PMID- 10656407
TI  - Cenocladamide, a dihydropyridone alkaloid from Piper cenocladum.
AB  - A dihydropyridone alkaloid, cenocladamide, and a derivative of piplartine, 4'
      desmethylpiplartine were isolated along with piplartine from the leaves of Piper
      cenocladum. The structures of the new compounds were determined by spectroscopic
      methods and by comparison to piplartine. Concentrations of these amides in plants
      with and without ant mutualists, are compared.

PMID- 10656408
TI  - Antifungal nitro compounds from skunk cabbage (Lysichitum americanum) leaves
      treated with cupric chloride.
AB  - Two nitro compounds, 2-(4-methoxyphenyl)-1-nitroethane named as lysichitalexin
      and 2-(4-hydroxyphenyl)-1-nitroethane were isolated as stress metabolites from
      the leaves of Lysichitum americanum Hulten and St. John treated with cupric
      chloride. Their structures were determined by spectroscopic methods and chemical
      reactions. The former compound showed antifungal activities against Fusarium
      oxysporum and Cladosporium herbarum. Both compounds were isolated for the first
      time from this species and the former was isolated from natural sources for the
      first time. This is the first report on stress metabolites from a member of the
      Araceae.

PMID- 10656409
TI  - Biotransformation of the phytoalexin camalexin by the phytopathogen Rhizoctonia
      solani.
AB  - The unusual metabolism of the cruciferous phytoalexin camalexin by virulent and
      weakly virulent isolates of the root rot fungus Rhizoctonia solani Kuhn is
      reported. This biotransformation proceeded via 5-hydroxycamalexin, which was
      further biotransformed into more polar metabolites. Importantly, the metabolites
      resulting from transformation of camalexin were significantly less toxic to the
      pathogen than camalexin. Thus, it was concluded that R. solani can detoxify
      camalexin through oxidation of the indole ring. The chemistry involved in the
      structure determination of the intermediates of this pathway, their synthesis as
      well as antifungal activity is described.

PMID- 10656411
TI  - Brominated anisoles and cresols in the red alga Polysiphonia sphaerocarpa.
AB  - The red marine alga Polysiphonia sphaerocarpa was extracted by a simultaneous
      steam distillation-solvent extraction technique and several brominated compounds
      were identified by gas chromatography-mass spectrometry. The compounds detected
      were 2,4-dibromoanisole, 2,4,6-tribromoanisole, 3-bromocresol, 3,5-dibromocresol,
      3-bromo-4-hydroxybenzaldehyde, 3,5-dibromo-4-hydroxybenzaldehyde, 2-bromophenol,
      4-bromophenol, 2,4-dibromophenol, 2,6-dibromophenol and 2,4,6-tribromophenol.
      This is the first time brominated anisoles and cresols have been detected in
      marine algae.

PMID- 10656410
TI  - Infraspecific variability in the essential oil composition of Cistus
      monspeliensis leaves.
AB  - The leaf essential oils of Cistus monspeliensis plants growing wild on calcareous
      and siliceous soils in Provence (South of France) were analysed by GC and GC-MS.
      Qualitative and quantitative differences are noted in the essential oil
      composition between the Cistus populations from the two soil types. For
      chemotaxonomic purposes, a characterisation of the two types of oil is proposed.

PMID- 10656412
TI  - Carrageenans from chilean samples of Stenogramme interrupta (Phyllophoraceae):
      structural analysis and biological activity.
AB  - Carrageenans extracted from cystocarpic and tetrasporic Stenogramme interrupta
      were analysed by chemical and spectroscopic methods. The carrageenan from
      cystocarpic plants is composed predominantly of 0.5 M KCl-insoluble and 1 M KCl
      soluble fractions. The insoluble fraction contained iota-carrageenan as the major
      component with alpha-carrageenan and pyruvated carrageenan as minor components.
      The soluble fraction is highly heterogeneous and did not contain the precursors
      mu- and nu-carrageenans. The polysaccharide from tetrasporic plants is composed
      of zeta- and lambda-carrageenans, and low sulfated galactans. It is soluble in
      KCl and partly cyclized by alkaline treatment. The antiviral and anticoagulant
      properties of the insoluble polysaccharide fraction from cystocarpic S.
      interrupta and the polysaccharide from tetrasporic S. interrupta are reported the
      results of which suggest promising antiherpetic activity.

PMID- 10656413
TI  - Flavonol glycosides from Costus spicatus.
AB  - Two flavonol diglycosides, tamarixetin 3-O-neohesperidoside, kaempferide 3-O
      neohesperidoside and the known quercetin 3-O-neohesperidoside, together with six
      other known flavonoids were isolated from the leaves of Costus spicatus and their
      structures were elucidated by a combination of spectroscopic and chemical
      methods. The flavonol diglycosides were evaluated for inhibitory activity of
      nitric oxide production by activated macrophages (Fig. 1).

PMID- 10656414
TI  - An acylated phloroglucinol with antimicrobial properties from Helichrysum
      caespititium.
AB  - A new acylated form of a phloroglucinol with significant antimicrobial properties
      was isolated by bioactivity guided fractionation from Helichrysum caespititium
      (Asteraceae). The structure elucidation, and conformation of the new
      phloroglucinol, 2-methyl-4-[2',4',6'-trihydroxy-3'-(2-methylpropanoyl) phenyl]but
      2-enyl acetate, was established by high field NMR spectroscopic and MS data. The
      compound inhibited growth of Bacillus cereus, B. pumilus, B. subtilis and
      Micrococcus kristinae at the very low concentration of 0.5 microg/ml and
      Staphylococcus aureus at 5.0 microg/ml. Six fungi tested were similarly inhibited
      at low MICs, Aspergillus flavus and A. niger (1.0 microg/ml), Cladosporium
      chladosporioides (5 microg/ml), C. cucumerinum and C. sphaerospermum (0.5
      microg/ml) and Phylophthora capsici at 1.0 microg/ml.

PMID- 10656415
TI  - Oxygenated monoterpenoids from badea (Passiflora quadrangularis) fruit pulp.
AB  - The new monoterpenoids (2E)-2,6-dimethyl-2,5-heptadienoic acid, (2E)-2,6-dimethyl
      2,5-heptadienoic acid beta-D-glucopyranosyl ester, (5E)-2,6-dimethyl-5,7
      octadiene-2,3-diol, and (3E)-3,7-dimethyl-3-octene-1,2,6,7-tetrol were isolated
      from the fruit pulp of Passiflora quadrangularis along with the known 2,5
      dimethyl-4-hydroxy-3(2H)-furanone beta-D-glucopyranoside.

PMID- 10656416
TI  - Polystachynes A-E, five cis-neo-clerodane diterpenoids from Salvia polystachya.
AB  - From the aerial parts of Salvia polystachya five new neo-clerodane diterpenoids,
      polystachynes A-E, have been isolated. The structures were established by
      spectroscopic methods, including the X-ray analysis of polystachynes C and D. The
      known clerodanes salvifaricin, linearolactone and dehydrokerlin were also
      isolated.

PMID- 10656417
TI  - Xanthones and triterpenoids from the bark of Garcinia vilersiana.
AB  - The hexane extract of the bark of Garcinia vilersiana from Vietnam contained four
      triterpenoids (olean-12-ene-3beta,11alpha-diol, lupeol, beta-amyrin and oleanolic
      acid), and six xanthones (globuxanthone, subelliptenone H, subelliptenone B, 12b
      hydroxy-des-D-garcigerrin A, 1-O-methylglobuxanthone and symphoxanthone). The
      structure of 1-O-methylglobuxanthone, the only novel compound, was determined
      using 1D and 2D NMR techniques and by correlation with globuxanthone.

PMID- 10656418
TI  - Limonoid derivatives from Astrotrichilia voamatata.
AB  - The stem bark of Astrotrichilia voamatata (Meliaceae) has yielded the novel
      limonoids voamatins C and D. These compounds represent a new type of
      pentanortriterpenoid and are unique in containing a ring A cyclic ether.

PMID- 10656419
TI  - Bonaspectins and neobonaspectins, first sesquilignans and sesquineolignans from a
      convolvulaceous species.
AB  - Four new tetrahydrofuran-type sesquilignans, named bonaspectin A, bonaspectin B,
      bonaspectin C 4''-beta-glucoside and bonaspectin D 4''-beta-glucoside, as well as
      two new 8.O.4'-type sesquineolignans, named neobonaspectin A and B, were isolated
      from the aerial vegetative parts of Bonamia spectabilis (Convolvulaceae),
      together with the known compound rel-(7S,8S,7'R,8'R)-3,3',4,4',5,5'-hexamethoxy
      7.O.7',8.8'-lignan. Their structures were established on the basis of spectral
      data.

PMID- 10656420
TI  - 5-Lipoxygenase-derived oxylipins from the red alga Rhodymenia pertusa.
AB  - The lipid extract of the temperate red alga Rhodymenia pertusa has yielded four
      eicosanoid metabolites, three of which are new natural products. Using
      principally NMR and MS techniques, their structures were deduced as 5R,6S
      dihydroxy-7(E),9(E),11(Z),14(Z)-eicosatetraenoic acid (5R,6S-diHETE), 5R*,6S*
      dihydroxy-7(E),9(E),11(Z),14(Z),17(Z)-eicosapentaenoic acid (5R*,6S*-diHEPE), 5
      hydroxy-6(E),8(Z),11(Z),14(Z)-eicosatetraenoic acid (5-HETE), 5-hydroxy
      6(E),8(Z),11(Z),14(Z),17(Z)-eicosapentaenoic acid (5-HEPE). The co-occurrence of
      these metabolites strongly suggests that R. pertusa contains a unique 5R
      lipoxygenase system acting on both arachidonic and eicosapentaenoic acids.

PMID- 10656421
TI  - Sequence specific analysis of the heterogeneous glycan chain from peanut
      peroxidase by 1H-NMR spectroscopy.
AB  - The cationic peanut peroxidase is a complex enzyme consisting of a heme group,
      two calcium ions and three complex carbohydrate chains at positions Asn60, 144
      and 185. Details of the heme and calcium ligation, necessary for oxidation, have
      recently been revealed from the three-dimensional structure of the peroxidase.
      However, the three glycans that may be important for the stability of the enzyme
      as well as its activity were not resolved. In order to determine the
      configuration of one of these glycans, PNGase A was used to cleave the glycan
      from the enzyme at Asn-144. This glycan was studied by two dimensional 1H-NMR
      spectroscopy to identify the sugar linkages. The results indicated a glycan
      structure comprising a Man alpha1-6(Xyl beta1-2)Man beta1-4GlcNAc beta1-4(Fuc
      alpha1-3)GlcNAc beta core but with an additional Man alpha1-3 appendage linked to
      Man3. The glycan also appeared to be heterogeneous as was noted from a single
      terminating galactose being linked to approximately 20-25% glycan.

PMID- 10656422
TI  - A methylenedioxyflavonol from aerial parts of Blutaparon portulacoides.
AB  - The aerial parts from Blutaparon portulacoides yielded a flavonol whose structure
      was established as 3,5,3'-trihydroxy-4'-methoxy-6,7-methylenedioxyflavone. In
      addition, the aerial parts yielded the isoflavone irisone B and the steroids
      stigmasterol, sitosterol and campesterol. The roots of B. portucaloides furnished
      sitosteryl, stigmast-7-enyl and spinasteryl beta-D-glucopyranosides as well as
      vanillic acid.

PMID- 10656423
TI  - Phenolic constituents from Grevillea robusta.
AB  - Seven phenolic compounds were isolated from a MeOH extract of the leaves of
      Grevillea robusta. Their structures were determined by various spectral methods
      including 2D NMR spectroscopy.

PMID- 10656424
TI  - An isoflavone from Myristica malabarica.
AB  - Phytochemical investigation of the heartwood of Myristica malabarica has led to
      the isolation of the new 7,4'-dimethoxy-5-hydroxyisoflavone together with two
      other isoflavones, biochanin A and prunetin, and a 1,3-diarylpropanol and a rare
      alpha-hydroxydihydrochalcone.

PMID- 10656425
TI  - Treatment of metastatic cancer with tetrathiomolybdate, an anticopper,
      antiangiogenic agent: Phase I study.
AB  - Preclinical and in vitro studies have determined that copper is an important
      cofactor for angiogenesis. Tetrathiomolybdate (TM) was developed as an effective
      anticopper therapy for the initial treatment of Wilson's disease, an autosomal
      recessive disorder that leads to abnormal copper accumulation. Given the potency
      and uniqueness of the anticopper action of TM and its lack of toxicity, we
      hypothesized that TM would be a suitable agent to achieve and maintain mild
      copper deficiency to impair neovascularization in metastatic solid tumors.
      Following preclinical work that showed efficacy for this anticopper approach in
      mouse tumor models, we carried out a Phase I clinical trial in 18 patients with
      metastatic cancer who were enrolled at three dose levels of oral TM (90, 105, and
      120 mg/day) administered in six divided doses with and in-between meals. Serum
      ceruloplasmin (Cp) was used as a surrogate marker for total body copper. Because
      anemia is the first clinical sign of copper deficiency, the goal of the study was
      to reduce Cp to 20% of baseline value without reducing hematocrit below 80% of
      baseline. Cp is a reliable and sensitive measure of copper status, and TM was
      nontoxic when Cp was reduced to 15-20% of baseline. The level III dose of TM (120
      mg/ day) was effective in reaching the target Cp without added toxicity. TM
      induced mild copper deficiency achieved stable disease in five of six patients
      who were copper deficient at the target range for at least 90 days.

PMID- 10656426
TI  - Cyclin E expression, a potential prognostic marker for non-small cell lung
      cancers.
AB  - Cyclin E is a G1 cyclin that has been shown to be one of the key regulators of
      the G1-S transition and could consequently be a deregulated molecule in tumors.
      In the present study, we have characterized cyclin E expression by
      immunohistochemistry in 217 resected non-small cell lung cancers (NSCLCs) and
      found large variations in cyclin E expression among tumors. High-level cyclin E
      expression (a cyclin E-labeling index > or =30%), observed in 115 (53%) of 217
      NSCLCs, was more frequently found in tumors from smokers than from nonsmokers (P
      = 0.001), in squamous cell carcinomas than in nonsquamous cell carcinomas (P =
      0.0002), and in pT2-4 tumors than in pT1 tumors (P = 0.04) by the chi2 test.
      Multivariate logistic regression analysis for the correlation between cyclin E
      expression and various characteristics showed a significant association of high
      level cyclin E expression with squamous cell carcinomas (P = 0.005). Patients
      with tumors having high-level cyclin E expression survived a significantly
      shorter time than patients with tumors having low-level expression, both among
      the 151 patients with potentially curatively resected NSCLCs (5-year survival
      rates, 48 and 63%, respectively; P = 0.03) and the 103 patients with p stage I
      NSCLCs (5-year survival rates, 57 and 81%, respectively; P = 0.007). High-level
      cyclin E expression was also a significant and independent unfavorable prognostic
      factor in both patients with potentially curatively resected NSCLCs (P = 0.01)
      and in those with p stage I NSCLCs (P = 0.03) by Cox's proportional hazards model
      analysis. These findings indicate that cyclin E may play a pivotal role for the
      biological behavior of NSCLCs, and that a high level of cyclin E expression may
      be a new prognostic marker for NSCLCs.

PMID- 10656427
TI  - Effects of the polyamine analogues N1-ethyl-N11-((cyclopropyl)methyl)-4,8
      diazaundecane and N1-ethylN-11-((cycloheptyl)methyl)-4,8-diazaundecane in human
      prostate cancer cells.
AB  - The high levels of polyamines maintained in the prostate suggest that these
      compounds are important to prostate cell function and that disruption of
      polyamine metabolism may be an effective way to stop the growth of prostate
      cancer cells. The unsymmetrically alkylated polyamine analogues N1-ethyl-N11
      ((cyclopropyl)methyl)-4,8-diazaunde-cane (CPENSpm) and N1-ethyl-N11
      ((cycloheptyl)methyl)-4,8-diazaundecane (CHENSpm) have been shown previously to
      have cytotoxic effects in breast and non-small cell lung cancer cells. We have
      now investigated the responses of three human prostate cancer cell lines, LNCaP,
      PC3, and Du145, to these polyamine analogues and to the symmetrically alkylated
      analogue N1,N11-bis(ethyl)norspermine (BE 3-3-3). The Du145 cell line, in which
      IC50 values ranged from 0.65 to 0.8 microM, was the most sensitive to each of the
      polyamine analogues, although significant growth inhibition resulted in the other
      cell lines as well. CPENSpm and BE 3-3-3 but not CHENSpm caused significant
      decreases in the intracellular spermine and spermidine pools, although all three
      analogues accumulated to high levels in each of the cell lines.
      Spermidine/spermine N1-acetyltransferase activity was induced 23-250-fold in
      response to CPENSpm and BE 3-3-3, but it was not affected by CHENSpm. None of the
      analogues had significant effects on the activities of ornithine decarboxylase or
      S-adenosylmethionine decarboxylase. Quantitation of DNA fragmentation indicative
      of programmed cell death (PCD) showed that both CPENSpm and CHENSpm were
      effective inducers of PCD in all three prostate cell lines. In contrast, BE 3-3-3
      led to PCD only in LNCaP cells. The ability to induce PCD was the only parameter
      measured that correlated with cell line sensitivity to these polyamine analogues.

PMID- 10656428
TI  - Specific cytolytic T-cell responses to human CEA from patients immunized with
      recombinant avipox-CEA vaccine.
AB  - Avipox viruses are replication-defective members of the poxvirus family. Avipox
      derived vectors such as ALVAC (canarypox) and fowlpox have the ability to infect
      mammalian cells, including human cells, but do not replicate. The first clinical
      trial of an avipox recombinant vaccine for patients with advanced carcinomas has
      recently been conducted using the ALVAC vector and the human carcinoembryonic
      antigen (CEA) transgene (designated ALVAC-CEA; J. L. Marshall et al, J. Clin.
      Oncol., 17: 332-337, 1999). The T-cell responses elicited by patients before and
      after vaccination with the ALVAC-CEA recombinants are characterized in this
      report. Pre- and postvaccination peripheral blood mononuclear cells (PMBCs) of
      the eight patients positive for HLA-class I A2 allele, were incubated with the
      HLA-A2-CEA peptide CAP-1 and interleukin 2. In no cases using prevaccination
      PMBCs could cultures be established that had the ability to lyse C1R-A2 target
      cells pulsed with the CAP-1 peptide. However, T-cell cultures from seven of eight
      of these same patients, obtained from PBMCs after ALVAC-CEA vaccination, were
      shown to lyse C1R-A2 cells only when pulsed with CAP-1. Moreover, all seven of
      these T-cell cultures were shown to lyse allogeneic human carcinoma cell lines
      (SW1463 and SW480) that were both A2+ and expressed CEA; an allogeneic tumor cell
      line (LS174T) expressing CEA that was negative for A2 expression was not lysed.
      HLA-A2+ and CEA+ autologous tumor cells were also capable of being lysed by CEA
      specific T cells from this patient. Analysis of this CTL line also revealed the
      expression of several homing and adhesion-associated molecules. Fluorescence
      activated cell sorter analysis of the T-cell lines established from patients
      after ALVAC-CEA vaccination revealed that most were CD8+/CD4-, but many also had
      a CD8+/CD4+ component. Analyses of T-cell receptor Vbeta usage of several of the
      CEA-specific CTL lines showed a relatively diverse Vbeta pattern. These studies
      demonstrate for the first time the ability to vaccinate cancer patients with an
      avipox recombinant and derive T cells that are capable of lysing allogeneic and
      autologous tumor cells in a MHC-restricted manner. These studies thus form the
      rationale to use such replication-deficient recombinant vaccines in future cancer
      vaccine trials.

PMID- 10656429
TI  - Human autoantibodies to carcinoembryonic antigen (CEA) induced by a vaccinia-CEA
      vaccine.
AB  - Carcinoembryonic antigen (CEA) is a well-characterized oncofetal glycoprotein
      whose overexpression by human adenocarcinomas has been a target for cancer
      immunotherapy. Limited information is available regarding the ability of patients
      to mount an antibody response to this self-antigen following vaccination.
      Recombinant vaccinia viruses encoding full-length or internally deleted cDNAs for
      human CEA were used to vaccinate 32 patients with CEA-expressing adenocarcinomas,
      predominantly of colorectal origin. CEA-specific autoantibodies were induced by
      vaccination in 7 of 32 patients. None of the patients had CEA antibodies detected
      before vaccination. CEA specificity of the antibodies initially identified by
      ELISA was confirmed by competitive inhibition analysis as well as recognition of
      recombinant CEA produced in baculovirus-infected insect cell cultures and human
      cell cultures by Western blot. The CEA autoantibodies were predominantly IgG1,
      with a minority of patients also demonstrating IgM autoantibodies. CEA antibodies
      were of low titer and low avidity, based on competitive inhibition assays. These
      autoantibodies did not affect clinical serum CEA protein quantitation.
      Furthermore, elevated serum CEA levels commonly encountered in patients with
      advanced adenocarcinoma did not hinder detection of low avidity polyclonal CEA
      antibodies. CEA antibodies such as those induced in these pilot trials are
      projected to have modest antitumor activity. Thus, additional Phase I/II trials
      of recombinant vaccinia-CEA with alternative prime-boost approaches and/or
      augmentation strategies are warranted in an effort to enhance the frequency and
      avidity of CEA-specific autoantibodies and cytolytic T cells before Phase III
      trials.

PMID- 10656430
TI  - A phase I and pharmacokinetic study of the mitochondrial-specific rhodacyanine
      dye analog MKT 077.
AB  - This Phase I study was performed to evaluate the tolerability and pharmacokinetic
      behavior of MKT-077, a water soluble rhodacyanine dye analogue, which partitions
      into tumor cell mitochondria where it is thought to act as a metabolic poison,
      leading to G1 arrest and apoptosis. Thirteen patients with advanced solid
      malignancies were treated with MKT-077 administered as a 30-min i.v. infusion
      weekly for 4 weeks every 6 weeks at doses ranging from 42 to 126 mg/m2/week. The
      principal toxicity was renal magnesium wasting, which was dose-limiting (grade 3)
      in one patient at each of the 84- and 126-mg/m2 dose levels. The other three
      patients at the 126-mg/m2 dose level developed grade 2 hypomagnesemia, which was
      cumulative in nature, improved with i.v. magnesium supplementation, and was
      controlled in two patients by the administration of prophylactic magnesium before
      and after treatment with MKT-077. Given the requirement for extensive monitoring
      of serum magnesium levels, dose escalation >126 mg/m2 was not considered
      feasible. Thus, the recommended dose for disease-oriented studies with this
      schedule of MKT-077 is 126 mg/m2/week. Pharmacokinetic studies revealed a
      prolonged terminal half-life (37 +/- 17 h) and a large volume of distribution
      (685 +/- 430 liters/m2). Clearance averaged 39 +/- 13 liters/h/m2. Peak MKT-077
      plasma concentrations (1.2 +/-0.31 to 6.3 +/- 5.3 microg/ml) exceeded the IC50
      concentrations required for human CX-1 colon, MCF-breast, CRL-1420 pancreas, EJ
      bladder, and LOX melanoma tumor cell lines in vitro (0.15-0.5 microg/ml). These
      results indicate that at the recommended dose level of 126 mg/m2/week of MKT-077,
      the toxicity profile was consistent with the preferential accumulation of the
      agent within tumor cell mitochondria, and biologically relevant plasma
      concentrations were achieved.

PMID- 10656431
TI  - TP53 mutation and p53 overexpression for prediction of response to neoadjuvant
      treatment in breast cancer patients.
AB  - The value of p53 to predict the cytotoxic effect of two commonly used
      chemotherapy regimens was assessed in patients with advanced breast cancer.
      Response to a DNA-damaging combination therapy [fluorouracil, epirubicin,
      cyclophosphamide (FEC] considered to induce p53-dependent apoptosis was compared
      with a microtubule stabilizing therapy (paclitaxel) expected to be independent of
      p53 function. The p53 status of the patients' breast tumors was assessed using
      both immunohistochemistry (IHC) and direct sequencing of the entire p53 gene. p53
      findings were correlated with treatment response, and linkage between p53
      function and cellular response was assessed by terminal deoxynucleotidyl
      transferase-mediated nick end labeling assay. In a series of 67 breast tumors,
      19% had TP53 gene mutations, 40% had a positive p53 IHC, and 12% had both. In the
      FEC group, treatment failure was related to both the presence of TP53 gene
      mutations (P = 0.0029) and a positive IHC (P < 0.0001). Apoptosis was almost
      exclusively found in tumors having normal p53 in both parameters (P < 0.0001). In
      the paclitaxel group, treatment response was neither related to apoptosis nor to
      normal p53. Combination of sequencing and IHC results revealed a significant
      association between abnormal p53 and response to paclitaxel (P = 0.011). We found
      TP53 mutations, as well as p53 protein overexpression, to be associated with
      response to chemotherapy. Whereas clinical response to FEC was found to be
      dependent on normal p53, the cytotoxicity of paclitaxel was related to defective
      p53. The efficiency of paclitaxel during mitosis might be supported by lack of G1
      arrest due to p53 deficiency. Therefore, patients with p53-deficient tumors may
      benefit from paclitaxel.

PMID- 10656432
TI  - A phase I and pharmacokinetic study of melphalan using a 24-hour continuous
      infusion in patients with advanced malignancies.
AB  - The objectives of the present study were to determine the following: (a) the
      maximum tolerated dose (MTD) of melphalan using a 24-h continuous infusion; (b)
      the clinical toxicity; and (c) the pharmacokinetic characteristics of melphalan
      at each dose level. Twenty-one patients with refractory solid tumors were
      enrolled in the study. Melphalan, packaged in 3% sodium chloride, was
      administered i.v. over a 24-h period. Patients were assigned to one of three
      escalating dose levels of melphalan: (a) 20 mg/m2 (n = 5); (b) 30 mg/m2 (n = 7);
      and (c) 40 mg/m2 (n = 6). Each patient underwent pharmacokinetic evaluation
      during the first cycle of treatment. Melphalan concentrations in plasma were
      determined by high-performance liquid chromatography. Toxicity was evaluated
      after each course of chemotherapy. All of the patients were assessable for
      toxicity and pharmacokinetics, and 20 patients were assessable for response
      analysis. A total of 50 courses of melphalan was studied. The MTD was 30 mg/m2.
      The dose-limiting toxicity was neutropenia and thrombocytopenia. Hematotoxicity
      was reversible (nadir, 14-15 days; recovery, 3.5 and 12.5 days for 30 and 40
      mg/m2, respectively), cumulative, and related to the administered dose and to the
      history of previous therapy. There were six episodes of neutropenic sepsis.
      Individual pharmacokinetic parameters were estimated using a Bayesian approach
      and linear elimination kinetics. Data were compatible with a one-compartment
      model. Relationships have been found between the area under the plasma
      concentration-time curve and doses and between Css and doses. Moreover,
      clearance, t1/2 elimination, and volume of distribution did not change
      statistically with dose, which suggests linear kinetics. Two partial responses
      were observed in patients with ovarian carcinoma or adenocarcinoma of unknown
      primary origin, and another patient had stabilization disease. In conclusion,
      melphalan MTD was determined to be 30 mg/m2 when administered as a 24-h infusion.
      Hematological toxicity was the dose-limiting toxicity. The most important
      nonhematological toxicity encountered was nausea and vomiting. The recommended
      dose for Phase II studies was 30 mg/m2.

PMID- 10656433
TI  - A phase I and pharmacokinetic study of docetaxel administered in combination with
      continuous intravenous infusion of 5-fluorouracil in patients with advanced solid
      tumors.
AB  - Encouraged by preclinical synergism between docetaxel and 5-fluorouracil (5FU),
      we conducted a Phase I study of docetaxel in combination with continuous i.v.
      infusion of 5FU in patients with advanced solid tumors to determine the maximum
      tolerated dose, the recommended dose for Phase II studies, and the safety and
      pharmacokinetic profiles of this combination. Forty-two patients with advanced
      solid tumors, most of whom had been previously treated, received docetaxel on day
      1 as a 1-h i.v. infusion, immediately followed by a 5-day continuous i.v.
      infusion of 5FU, every 3 weeks without hematopoietic growth factor support. All
      patients were premedicated with methylprednisolone. Dose levels of docetaxel/SFU
      studied were (daily dose, in mg/m2) 60/300, 75/300, 75/500, 75/750, 85/750,
      85/1000, and 75/1000. Forty-one patients were assessable for toxicity. The
      maximum tolerated dose determined during the first cycle was 1000 mg/m2/day for 5
      days of 5FU with either 75 or 85 mg/m2 docetaxel. Dose-limiting toxicities at
      these dose levels were reversible secretory diarrhea (4 of 12 evaluable
      patients), stomatitis (2 patients), and febrile neutropenia (2 patients).
      Overall, grade 3/4 neutropenia and febrile neutropenia were seen in 63.4% and
      9.8% of the patients, respectively. Four patients experienced grade 3/4
      infection, which led to toxic death in one of them. There were five early deaths:
      (a) one was clearly treatment related; (b) two others were possibly treatment
      related or remotely treatment related; and (c) two deaths were not related to the
      study drugs. Partial responses were documented in 5 of 39 evaluable patients.
      Pharmacokinetic results of both drugs were consistent with those from single
      agent studies. The recommended dose of this combination, which showed acceptable
      toxicity and antitumoral activity at various dose levels, is 85 mg/m2 docetaxel
      given as a 1-h i.v. infusion on day 1 immediately followed by a 5-day continuous
      i.v. infusion of 5FU (750 mg/m2/day). This study has been extended by adding
      cisplatin on day 1 of the combination of docetaxel and 5FU.

PMID- 10656434
TI  - Cyclophosphamide and carboplatin and selective consolidation in advanced
      seminoma.
AB  - This prospective Phase II study assesses the clinical efficacy and complications
      of a treatment regimen of combination chemotherapy with cyclophosphamide and
      carboplatin and selective consolidation in advanced seminoma. Of 46 patients who
      entered the study between December 1992 and October 1998, 46 were evaluable.
      Thirty-two achieved a complete remission (70%; 95% confidence interval, 56-83%)
      after chemotherapy alone. Fourteen achieved a complete remission (30%; 95%
      confidence interval, 18-46%) after chemotherapy plus consolidation. Forty-three
      of the 46 patients (93%; 95% confidence interval, 82-97%) remained in remission
      after a median follow-up period of 27.4 months. No patient experienced
      nephrotoxic, neurotoxic, or ototoxic effects or hemorrhagic cystitis. No patient
      had neutropenic fever requiring hospitalization. Thirteen % required platelet
      transfusions, and 9% required transfusions of packed RBCs. For patients with
      advanced seminoma, treatment with cyclophosphamide and carboplatin and selective
      consolidation is safe and effective.

PMID- 10656435
TI  - Phase I trial of exisulind (sulindac sulfone, FGN-1) as a chemopreventive agent
      in patients with familial adenomatous polyposis.
AB  - Exisulind (sulindac sulfone; FGN-1), a metabolite of sulindac without known
      effects on prostaglandin synthesis, can promote apoptosis and inhibit
      tumorigenesis in preclinical systems. We performed a Phase I trial of this
      compound in patients with familial adenomatous polyposis (FAP) to examine the
      tolerability and safety of this drug in the cancer chemoprevention setting. Six
      patients each were treated with exisulind at doses of 200, 300, and 400 mg p.o.
      twice a day. Reversible hepatic dysfunction was noted in four of six patients
      treated at the 400-mg p.o., twice-a-day dose level, but in only one to two of six
      patients treated at each of the lower dose levels. The serum half-life of
      exisulind was 6-9 h; little drug accumulation was noted over time. A
      nonsignificant trend toward increased apoptosis in polyps was noted at the
      maximum tolerated dose, but no decrease in polyp numbers or significant effects
      on cellular proliferation was noted. After treatment, polyps tended to display a
      "halo" appearance grossly and mucinous differentiation histologically. The
      maximum safe dose of exisulind is 300 mg p.o. twice a day in patients with
      subtotal colectomies. Reversible hepatic dysfunction limits further dose
      escalation. A decrease in polyp numbers could not be demonstrated, but the trend
      toward increased apoptosis at the MTD and the observation of mucinous change
      histologically suggest that further investigation of drugs of this class might be
      warranted.

PMID- 10656436
TI  - Patients treated with antitumor drugs displaying neurological deficits are
      characterized by a low circulating level of nerve growth factor.
AB  - The aim of our study was to explore whether nerve growth factor (NGF) plays any
      role in the development of peripheral neuropathy induced by anticancer treatment.
      We measured the circulating NGF levels in 23 cancer patients before and after
      chemotherapy. We evaluated whether the development of peripheral neurotoxicity
      was associated with changes in basal NGF concentrations in patients studied with
      a comprehensive neurological and neurophysiological examination. The results of
      these studies showed that the circulating levels of NGF, which are about 20 pg/ml
      in plasma of controls, decrease during chemotherapy and in some cases completely
      disappeared after prolonged treatment with antitumor agents. The decrease in NGF
      levels seems to be correlated with the severity of neurotoxicity. These results
      clearly suggest that NGF might become a useful agent to prevent neuropathies
      induced by antineoplastic drugs and restore peripheral nerve dysfunction induced
      by these pharmacological compounds.

PMID- 10656437
TI  - Significance of integrin alpha5 gene expression as a prognostic factor in node
      negative non-small cell lung cancer.
AB  - The integrin family plays a major role in complex biological events such as
      differentiation, development, wound healing, and the altered adhesive and
      invasive properties of tumor cells. Integrin (alpha5beta1 is a classical
      fibronectin receptor, and it has been known as a tumor suppressor gene because
      tumor cells overexpressing alpha5beta1 are less tumorigenic than their parent
      cells. However, this finding conflicts with some recent data that suggests that
      the emergence of alpha5beta1 expression correlates with the tumor progression.
      We, therefore, investigated the expression of alpha5beta1 integrin in 20 lung
      cancer cell lines by flow cytometric analysis and in 88 node-negative non-small
      cell lung cancers (NSCLCs) by RT-PCR and immunohistochemical assays to determine
      the significance of this prognostic factor. In the 20 lung cancer cell lines, 8
      (40.0%) cell lines strongly expressed integrin alpha5, 3 (15.0%) cell lines had
      moderate or weak alpha5 expression, and the remaining 9 (45.0%) cell lines
      expressed no integrin alpha5. In the 88 node-negative NSCLC patients, 44 samples
      (50.0%) were evaluated as having integrin alpha5 overexpression, and the integrin
      alpha5 expression was significantly associated with the status of differentiation
      and the age of the patients (P = 0.0379 and 0.0312, respectively). In the node
      negative patients, the overall survival rate for patients with integrin alpha5
      overexpressed tumors was significantly worse than for those individuals whose
      tumors had normal integrin alpha5 expression (P = 0.016).

PMID- 10656438
TI  - Identification and localization of the cytokine SDF1 and its receptor, CXC
      chemokine receptor 4, to regions of necrosis and angiogenesis in human
      glioblastoma.
AB  - Glioblastoma multiforme (GBM) tumors display extensive histomorphological
      heterogeneity, with great variability in the extent of invasiveness,
      angiogenesis, and necrosis. The identification of genes associated with these
      phenotypes should further the molecular characterization, permitting better
      definition of glioma subsets that may ultimately lead to better treatment
      strategies. Therefore, we performed a differential mRNA display analysis
      comparing six GBM-derived primary cell cultures from patients having tumors with
      varied histomorphological features. We identified stromal cell-derived factor 1
      (SDF1) as a gene with varied expression. SDF1 (cytokine) and CXC chemokine
      receptor 4 (CXCR4) interactions are implicated in modulating cell migration. They
      are also implicated in modulating the immune response in AIDS patients by
      macrophage-mediated T-cell apoptosis. GBM patients also fail to mount an immune
      response, although their tumors are seemingly exposed to immune cells in regions
      of angiogenesis, where the blood-brain barrier is absent, or in areas of
      necrosis. To determine whether the expression and localization of SDF1 and CXCR4
      are consistent with such a role in these brain tumors, immunohistochemical
      analyses of these proteins were performed on normal brain and astrocytomas
      (grades II-IV). In normal brain tissue, low levels of SDF1 (0.5+) were observed
      in astrocytic processes, in neurons, and in the occasional phagocytic cells
      around vessels. CXCR4 expression was negative in brain tissue but was observed in
      phagocytic cells within the vessel lumen. In tumors, SDF1 and CXCR4 expression
      was colocalized when both were expressed, and SDF1 and CXCR4 expression increased
      with increasing tumor grade (from 0.5+ to 6+). Additionally, CXCR4 was expressed
      in neovessel endothelial cells. The proteins were expressed in regions of
      angiogenesis and degenerative, necrotic, and microcystic changes. Those tumors
      displaying greater amounts of these features had greater staining intensity of
      the proteins. The expression of SDF1 and CXCR4 did not colocalize with the
      proliferation marker MIB-1. Thus, our data suggest that SDF1 and CXCR4
      expressions: (a) increase with increasing grade; (b) colocalize to regions within
      these tumors where their interaction may contribute to angiogenesis and/or
      modulation of the immune response; and (c) may serve to characterize subsets of
      GBMs.

PMID- 10656439
TI  - Correlations among p53, Her-2/neu, and ras overexpression and aneuploidy by
      multiparameter flow cytometry in human breast cancer: evidence for a common
      phenotypic evolutionary pattern in infiltrating ductal carcinomas.
AB  - Human solid tumors develop multiple genetic abnormalities that accumulate
      progressively in individual cells during the course of tumor evolution. We sought
      to determine whether there are specific sequences of occurrence of these
      progressive evolutionary changes in human breast cancers by performing correlated
      cell-by-cell measurements of cell DNA content, p53 protein, Her-2/neu protein,
      and ras protein by multiparameter flow cytometry in 56 primary tumor samples
      obtained at surgery. In addition, p53 allelic loss and Her-2/neu gene
      amplification were determined by fluorescence in situ hybridization in cells from
      the same samples. We reasoned that if there is a specific order in which genetic
      changes occur, the same early changes would be found consistently in the cells
      with the fewest abnormalities. We reasoned further that late-developing
      abnormalities would not occur alone in individual cells but would almost always
      be found together with the early changes inherited by the same cells. By these
      criteria, abnormalities involving p53 generally occurred early in the course of
      development of invasive breast cancers, whereas ras protein overexpression was
      found to be a late-occurring phenomenon. Within individual tumors, cellular p53
      overexpression was often observed alone in individual cells, whereas ras protein
      overexpression was rarely observed in the absence of p53 overexpression and/or
      Her-2/neu overexpression in the same cells. Furthermore, the intracellular level
      of each abnormally expressed protein was found to increase progressively as new
      abnormalities were acquired. Infiltrating ductal carcinomas exhibited
      characteristic phenotypic patterns in which p53 allelic loss and/or p53 protein
      overexpression, Her-2/neu amplification and/or overexpression, aneuploidy, and
      ras overexpression accumulated within individual cells. However, this pattern was
      not a prominent feature of lobular breast cancers. All six lobular breast cancers
      studied were diploid. p53 allelic loss and/or early p53 overexpression, and late
      ras cooverexpression in the same cells were less common in lobular breast cancers
      than in infiltrating ductal carcinomas. Although Her-21neu overexpression was a
      common finding in lobular breast cancers, Her-2/neu amplification was not
      observed in these tumors.

PMID- 10656440
TI  - Expression of survivin and its relationship to loss of apoptosis in breast
      carcinomas.
AB  - Aberrant inhibition of programmed cell death (apoptosis) prevents normal
      homeostasis and promotes tissue tumorigenesis, but whether it also influences the
      outcome of common cancers has remained arguable. The expression of a novel IAP
      apoptosis inhibitor, survivin, in breast cancer and its association with tumor
      cell apoptosis and overall prognosis were examined in this study.
      Immunohistochemical analysis showed that survivin expression was positive in 118
      of 167 cases (70.7%) of breast carcinomas of histological stages I to IH. In
      contrast, no expression of survivin in adjacent normal tissue was detected.
      Although survivin expression was not correlated with p53 mutations, survivin
      positive cases were strongly associated with bcl-2 expression (78.0% versus
      47.5%; P = 0.0005) and reduced apoptotic index (0.62% +/- 0.51% versus 1.27% +/-
      1.37%; P < 0.0001). In addition, patients with low apoptotic index (<0.52%) had
      worse survival rates than the group with high apoptotic index (> or =0.52%; P =
      0.028), and multivariate Cox proportional hazard model analysis identified
      apoptotic index as an independent prognostic factor (P = 0.024). The results
      suggest that apoptosis inhibition by survivin, alone or in cooperation with bcl
      2, is a significant prognostic parameter of worse outcome in breast carcinoma.

PMID- 10656441
TI  - Cyclooxygenase-2 expression is related to prostaglandin biosynthesis and
      angiogenesis in human gastric cancer.
AB  - Although recent studies have demonstrated that cyclooxygenase (COX)-2 is
      overexpressed in various cancers including gastric cancer, the mechanisms
      underlying the contribution of COX-2 to tumorigenesis and tumor promotion still
      remain unclear. To determine the role of COX-2, we investigated the COX-2
      expression, the prostaglandin (PG) levels, and the microvessel density in 42
      patients with primary gastric adenocarcinoma. COX-2 protein was over-expressed in
      31 (74%) of 42 gastric cancers based on an immunoblot analysis. The intensity of
      COX-2 expression was found to significantly correlate with lymph node
      involvement. The COX-2 overexpressed cases showed significantly elevated levels
      of prostaglandin E2 (PGE2) in cancer tissues in comparison with the normal
      gastric mucosa by an immunoassay (201 +/- 90 versus 161 +/- 57 ng/mg protein; P <
      0.05). However, the COX-2 overexpression was not related to the levels of
      thromboxane B2 and 6-keto-prostaglandin F1alpha. The density of microvessel
      immunostained with CD34 was significantly higher in patients demonstrating COX-2
      overexpression than in those without such expression (63 +/-21 versus 45 +/-
      17/200 x; P < 0.01). Our data thus suggested COX-2 overexpression to be
      associated with increased PGE2 biosynthesis and angiogenesis in gastric cancer,
      which indicates that COX-2 may play a role in the development of gastric cancer.

PMID- 10656442
TI  - The prognostic value of angiogenesis by Chalkley counting in a confirmatory study
      design on 836 breast cancer patients.
AB  - This study addresses the prognostic value of estimating angiogenesis by Chalkley
      counting in breast cancer. A population-based group consisting of 836 patients
      with operated primary, unilateral invasive breast carcinomas was included from a
      predefined region and period of time. The median follow-up time was 11 years and
      4 months. The microvessels were immunohistochemically stained by antibodies
      against CD34. The Chalkley count was obtained by a 25-point grid within three,
      subjectively selected, vascular tumor areas of highest microvessel density. The
      Chalkley count was analyzed in three categories using predefined Chalkley cutoff
      points at five and seven. There were significant correlations between high
      Chalkley counts and axillary lymph node metastasis, large tumor size, high
      histological malignancy grade, and histological type. A high Chalkley count
      showed lower probabilities of recurrence-free survival (P < 0.0001) and overall
      survival (P < 0.0001). In the Cox multivariate analysis, the hazard ratio (and
      95% confidence interval) showed that the increased risk to die were: 1.55 (1.19
      2.03) with Chalkley counts between 5 and 7; 2.26 (1.72-2.98) with counts > or =7
      compared with counts < or =5; and 1.46 (1.14-1.87) with counts > or =7 compared
      with counts between 5-7. The study confirmed that estimation of angiogenesis by
      Chalkley counting had independent prognostic value in breast cancer patients. The
      Chalkley count could be useful to stratify node-negative patients for adjuvant
      treatment.

PMID- 10656443
TI  - Serum beta-2 microglobulin levels are a significant prognostic factor in
      Philadelphia chromosome-positive chronic myelogenous leukemia.
AB  - Our objective was to investigate the prognostic significance of serum beta-2
      microglobulin (B2M) levels among patients with chronic myelogenous leukemia
      (CML). All patients with Philadelphia chromosome-positive early chronic phase CML
      (i.e., within 1 year of diagnosis) treated with IFN alpha-based therapy at the M.
      D. Anderson Cancer Center between 1980 and 1997, in whom pretreatment B2M levels
      were available, were investigated. Two hundred one patients were evaluable. Their
      median B2M was 2.2 mg/dl (range, 1.1-20 mg/dl). Serum B2M levels were associated
      with other variables of prognostic significance, including age, spleen size, WBC
      count, percentage of peripheral and marrow blasts, and percentage of marrow
      basophils. Patients with B2M levels >2.9 mg/dl (ie., the upper quartile of the
      distribution) had a significantly lower rate of major cytogenetic response
      compared to those in the lower three quartiles (20 versus 52%; P < 0.01). They
      also had a shorter survival, with a 5-year survival rate of 48%, compared with
      75% for those in the lower quartiles (P = 0.01). High B2M levels (>2.9 mg/dl)
      could identify a group of patients with an adverse outcome within patients in
      stage I disease (P = 0.02). Results for patients in stages 2-4 were inconclusive
      because of the small number of patients in these groups. We conclude that serum
      B2M levels are an important, and probably independent, prognostic factor for
      patients with CML in early chronic phase treated with IFN-based therapy.

PMID- 10656444
TI  - Loss of nuclear p16 protein expression is not associated with promoter
      methylation but defines a subgroup of aggressive endometrial carcinomas with poor
      prognosis.
AB  - The p16INK4aa (CDKN2) tumor suppressor gene is altered in several tumor types,
      but the frequency and mechanism of inactivation are largely unknown for
      endometrial carcinomas. We therefore wanted to assess the pattern and prognostic
      impact of p16 protein expression and promoter region methylation in a population
      based series of 316 endometrial carcinoma patients with long-term and complete
      follow-up. Nuclear staining of p16 protein was related to clinicopathological
      variables, tumor markers, patient survival, and the presence of promoter region
      methylation. Absent/minimal nuclear staining for p16 protein was found in 14% of
      the tumors. Methylation of the p16 promoter region was found in only one tumor
      (0.7%) in a subset of 138 cases studied. This tumor lacked nuclear p16 protein
      expression as well. Loss of nuclear p16 staining was significantly associated
      with increased age, high FIGO (International Federation of Gynecology and
      Obstetrics) stage, serous papillary or clear cell histological types, high
      histological grade, aneuploidy, low estradiol and progesterone receptor
      concentrations, high expression of Ki-67, high intratumor microvessel density,
      and strong nuclear p53 protein expression. The 5-year survival was 47% for
      patients with absent/minimal nuclear p16 expression (n = 39) compared with 81%
      for patients with moderate/high nuclear p16 expression (n = 247; P < 0.0001). In
      Cox proportional hazards regression analysis, nuclear p16 expression showed an
      independent prognostic impact in addition to FIGO stage, age, Ki-67 expression,
      and microvessel density, with an adjusted hazard ratio of 2.9 (95% confidence
      interval, 1.3-6.5). The other variables lost their prognostic impact when nuclear
      p16 staining was added to the Cox model. In conclusion, loss of nuclear p16
      protein expression was associated with aggressive endometrial carcinomas and high
      proliferative activity (Ki-67) and was found to represent a strong and
      independent prognostic indicator. Methylation of the promoter region seems to be
      an uncommon mechanism of p16 inactivation in endometrial carcinoma.

PMID- 10656445
TI  - Prognostic significance of tissue prostate-specific antigen in endocrine-treated
      prostate carcinomas.
AB  - Fine-needle aspiration biopsy is a minimally invasive technique for obtaining
      sample material suitable not only for cytological grading but also for flow
      cytometry and for biochemical analyses. The prognostic value of tissue prostate
      specific antigen (T-PSA) from fine-needle aspiration biopsies was compared with
      serum total and free prostate-specific antigen, the ratio of free:total serum
      prostate-specific antigen, tumor stage, cytological grade, and DNA ploidy in 179
      patients with stage T2-T4 prostate cancer (CAP). The patients, who were free from
      bone metastases at the time of diagnosis, were treated by either orchidectomy or
      medical castration with GnRH analogues or high-dose parenteral depot estrogens.
      They were followed for at least for 71 months or until death, and the different
      variables were correlated to time to progression and time to death from CAP.
      Using Cox univariate analysis, T-PSA was shown to be the most important factor in
      predicting time to progression and time to death. When the patients were divided
      into three groups with respect to T-PSA, 56 of 60 (93%) of the patients with low
      T-PSA levels developed progressive disease, and 52 of 60 (87%) died of CAP. For
      patients with intermediate T-PSA levels, the corresponding figures were 9 of 60
      (15%) and 6 of 60 (10%). None of the 59 patients with high T-PSA values developed
      progressive disease. Similar but less pronounced relationships were found between
      tumor progress and CAP-specific death on the one hand and clinical stage,
      cytological grade, and DNA ploidy on the other. In a Cox multivariate stepwise
      analysis, T-PSA was the only important factor for time to progression and death.
      This was also true for the subgroup of patients with stages T2 and T3 disease
      only. The study shows that T-PSA is superior to other hitherto routinely used
      markers for the prediction of outcome of hormone-treated patients with newly
      diagnosed CAP.

PMID- 10656446
TI  - Platelet and coagulation activation with vascular endothelial growth factor
      generation in soft tissue sarcomas.
AB  - Angiogenesis and activated blood coagulation are involved in tumor growth and
      metastasis. Although some have suggested that activation of coagulation in tumors
      is not linked to activation of platelets, no data exist to either support or
      refute this concept. However, platelet turnover in cancer patients is often
      increased, and platelets are carriers of angiogenic growth factors. We
      hypothesized that platelets are involved in tumor-associated angiogenesis. To
      obtain evidence supporting this hypothesis, we have studied whether the
      angiogenic and coagulation pathways and platelets are concomitantly activated in
      cancer patients with soft tissue sarcomas (STSs) using a novel method to detect
      activated platelets in tumor specimens. Twelve patients with STS were selected on
      the basis of having intratumoral accumulation of fluid, which was aspirated.
      These accumulations demonstrated very high concentrations of vascular endothelial
      growth factor and coagulation factors (including thrombin-antithrombin-complex).
      Tumor specimens showed dense vascularization with intense vascular endothelial
      growth factor expression and the presence of activated platelets. Taken together,
      these results support the concept that angiogenesis, blood coagulation, and
      platelets are concomitantly activated in STS and support the hypothesis that
      platelets contribute to tumor-induced angiogenesis.

PMID- 10656447
TI  - Increased expression of S100A6 (Calcyclin), a calcium-binding protein of the S100
      family, in human colorectal adenocarcinomas.
AB  - The expression of S100A6 (also known as Calcyclin/2A9/ 5B10/PRA) in surgically
      resected human colorectal adenocarcinomas was examined to investigate whether
      S100A6 plays a role in the malignancy of human tumor cells. Western blot analysis
      using the lysates from colorectal adenocarcinomas and adjacent normal mucosa from
      10 patients revealed that the average S100A6 level of adenocarcinomas was
      significantly higher (about 2.4-fold) than that of normal mucosa.
      Immunohistochemical analysis using formalin-fixed paraffin-embedded surgical
      specimens and monoclonal anti-S100A6 antibody (mAbA6) demonstrated that 2(5%) of
      42 normal mucosa and 6 (46%) of 13 adenoma specimens were mAbA6-positive and
      showed granular staining localized at the supranuclear regions of epithelial
      cells, whereas 23 (55%) of 42 adenocarcinomas and 13 (100%) of 13 carcinoma cells
      that metastasized to the liver were mAbA6-positive and showed diffuse cytoplasmic
      staining. A significant correlation between S100A6 expression and Dukes' tumor
      stage or lymphatic permeation but not with other clinicopathological factors was
      shown. S100A6 was stained more intensely in peripheral portions than in central
      portions of adenocarcinomas, whereas Ki-67 (a growth marker) was stained equally
      in these two portions. These results suggest that S100A6 may be involved in the
      progression and invasive process of human colorectal adenocarcinomas.

PMID- 10656448
TI  - Prognostic significance of DNA ploidy, S-phase fraction, and tissue levels of
      aspartic, cysteine, and serine proteases in operable gastric carcinoma.
AB  - A consecutive series of 63 untreated patients undergoing surgical resection for
      stage I-IV gastric adenocarcinomas (GCs) has been prospectively studied. Our
      purpose was to analyze the predictive relevance of DNA ploidy, S-phase fraction
      (SPF), and tissue levels of lysosomal proteinases cathepsin D (CD), cathepsin B
      (CB), cathepsin L (CL), and urokinase-type plasminogen activator (uPA) and that
      of the intracellular cysteine proteinase inhibitor stefin A on clinical outcome.
      All of the patients taking part in this study were followed up for a median of 73
      months. DNA aneuploidy was present in 71% of the cases (45/63), whereas 9% of
      these (4/45) showed multiclonality. Both DNA ploidy and SPF were associated with
      tumor-node-metastasis (TNM) stage and node status, whereas only DNA ploidy was
      related to depth of invasion. CB, CL, uPA, but not CD, levels were significantly
      higher in GC as compared to paired normal mucosa, whereas stefin A levels were
      lower in tumor tissues. CB levels were significantly associated with TNM stage,
      nodal status, histological grade, and DNA ploidy. At univariate analysis, only
      node involvement, advanced TNM stage, DNA aneuploidy, and high SPF proved to be
      significantly related to quicker relapse and to shorter overall survival, whereas
      depth of invasion was related only to survival. With multivariate analysis, only
      high SPF (>15.2%) was related to risk of relapse (RR = 8.50), whereas high SPF
      and DNA aneuploidy were independently related to risk of death (RR = 1.88 and
      2.09, respectively). Our preliminary prospective study has identified SPF and DNA
      ploidy as important biological indicators for predicting the outcome of patients
      with GC.

PMID- 10656449
TI  - In vitro adenoviral vector p53-mediated transduction and killing correlates with
      expression of coxsackie-adenovirus receptor and alpha(nu)beta5 integrin in SUDHL
      1 cells derived from anaplastic large-cell lymphoma.
AB  - Adenoviral vector-mediated p53 expression induced apoptosis is a well established
      gene therapy approach that has been evaluated extensively in epithelial tumors
      but only recently in lymphoid malignancies mainly due to the known resistance of
      the lymphoid lineage to adenovirus infection. Recently, it was shown that this
      resistance is not absolute and that cell lines derived from anaplastic large cell
      lymphoma (ALCL) and some other lymphoid malignancies are efficiently transduced
      by adenoviral vectors. Normal circulating T lymphocytes do not express coxsackie
      adenovirus receptor (CAR) and alpha(nu)beta integrins and are relatively
      resistant to infection by adenovirus. These molecules serve as receptors for
      adenovirus entry into the cells. ALCL-derived SUDHL-1 cells were evaluated for
      transduction efficiency and expression of p53 after infection with an adenoviral
      vector containing wild-type p53 (AdWTp53). Cells derived from ALCL and
      circulating mononucleated cells (MNCs) were also evaluated for expression of CAR
      and alpha(nu)beta integrins. AdWTp53-mediated expression of p53 resulted in
      p21/WAF1 induction, G1 arrest, and apoptosis in SUDHL-1 cells. The expression of
      CAR and alpha(nu)beta5 integrin was high in SUDHL-1 cells and comparable to
      levels observed with epithelial tumor cells, but it was absent in MNCs. The
      susceptibility to adenoviral vector transduction of the tumor-derived cells
      implies an important biological difference between them and circulating MNCs,
      possibly underlying the malignant transformation that ALCL cells undergo. Further
      studies will be required to evaluate this initial observation in more cell lines
      and tissue derived from ALCL.

PMID- 10656450
TI  - EGF receptor and p21WAF1 expression are reciprocally altered as ME-180 cervical
      carcinoma cells progress from high to low cisplatin sensitivity.
AB  - Cell cycle regulators and signal transduction pathways can influence apoptotic
      sensitivity of tumor cells, and we previously described an association between
      EGFr overexpression, reduced DNA repair activity, and increased apoptotic
      sensitivity of ME-180 cervical carcinoma cells toward cis-diammedichloroplatinum
      (cDDP; K. Nishikawa, et al., Cancer Res., 52: 4758-4765, 1992). In the present
      study, the characteristics of ME-180 cells selected for high or low apoptotic
      sensitivity to cDDP (or camptothecin) were examined and compared to determine
      whether signal transduction components and cell cycle regulation were distinct in
      these isogenic drug response variant populations. As ME-180 cells progressed from
      high to low cDDP sensitivity [IC50 approximately 80 ng/ml in cDDP sensitive (PT
      S) to approximately 2000 ng/ml in cDDP-resistant (Pt-R) cells], there was a
      significant decrease in EGFr expression that paralleled the relative reduction in
      cDDP apoptotic responsiveness (approximately 30-fold). cDDP-resistant cells had
      the slowest rate of growth and more effectively reduced DNA adduct levels
      following cDDP exposure than parental cells. Cellular levels of the cell cycle
      inhibitor p21WAF1 inversely correlated with cDDP responsiveness with high levels
      of p21WAF1 expressed in drug-resistant Pt-R cells in the absence of elevated p53.
      cDDP stimulated a 2-fold increase in p53 levels in both drug-sensitive and drug
      resistant cells but caused a delayed reduction in p21WAF1 levels, suggesting p53
      independent regulation of p21WAF1 in ME-180 cells. Activation of EGFr in Pt-R
      cells stimulated cell cycle progression (2-fold), reduced p21WAF1 levels (>2
      fold), and increased sensitivity to cDDP (3-fold), suggesting that receptor
      signaling enhanced the efficacy of cDDP to induce cell death by relieving cell
      cycle restriction. These results demonstrate that the transition of ME-180 cells
      from a drug-sensitive to drug-resistant phenotype correlates with reciprocal
      changes in EGFr and p21WAF1 expression and provides additional evidence that the
      pathways controlled by these proteins may contribute to some forms of drug
      resistance.

PMID- 10656451
TI  - Drug-induced apoptosis in lung cnacer cells is not mediated by the Fas/FasL
      (CD95/APO1) signaling pathway.
AB  - Anticancer drugs exert at least part of their cytotoxic effect by triggering
      apoptosis. We previously identified chemotherapy-induced apoptosis in lung cancer
      cells and suggested a role for p53 alternative or complementary pathways in this
      process. Recently, a role for the Fas/FasL (CD95/Apo1) signaling system in
      chemotherapy-induced apoptosis was proposed in some cell types. In the present
      work, the involvement of the Fas/FasL system in drug-induced apoptosis in lung
      cancer cells was investigated upon exposure to four cytotoxic drugs (cisplatin,
      gemcitabine, topotecan, and paclitaxel). We assessed the expression of Fas and
      FasL and the function of the Fas pathway in six lung cancer cell lines (H460,
      H322, GLC4, GLC4/ADR, H187, and N417). All lung cancer cell lines expressed Fas
      and FasL at RNA and protein levels, and apoptosis could be induced in four of six
      cell lines upon exposure to the Fas agonistic monoclonal antibody (mAb) CLB
      CD95/15. Nevertheless, after drug exposure, no significant FasL up-regulation was
      observed, whereas the Fas expression was increased in the wild-type p53 cell line
      H460, but not in the other lines, proved to be mutant p53 by direct gene
      sequencing. Moreover, no correlation was observed in lung cancer cell lines
      between sensitivity to drugs and to a Fas agonistic mAb, and preincubation of
      cells with either the Fas-antagonistic mAb CLB-CD95/2 or a FasL-neutralizing mAb
      did not protect from drug-induced apoptosis. Taken together, these observations
      strongly argue against a role of the Fas/FasL signaling pathway in drug-induced
      apoptosis in lung cancer cells. Interestingly, caspase-8 activation was observed
      upon drug exposure, independently from Fas/FasL signaling.

PMID- 10656452
TI  - Induction of apoptosis in oral cancer cells by an anti-bcl-2 ribozyme delivered
      by an adenovirus vector.
AB  - Human oral cancer cells may have any of several genetic changes, but the role of
      the bcl-2 oncogene is relatively unexplored. To find out if this gene plays a
      significant role and whether it could act as a target for gene therapy of oral
      cancer, we have examined the effects of an anti-bcl-2 ribozyme on the phenotype
      of oral cancer cells. A hammer-head ribozyme was designed to cleave the bcl-2
      transcript after nucleotide 279 and was confirmed to be effective against a
      synthetic bcl-2 transcript. A gene encoding the ribozyme was cloned into an
      adenovirus vector and transferred to the human oral cancer cell lines 686LN,
      1483, and Tu183. Over a 6-day period, the growth of each cancer cell line was
      reduced, whereas growth of the fibroblast cell line FS7 was less inhibited.
      Inhibition of the oral cancer cells could be attributed to apoptosis, as
      indicated by the detection of histone-associated DNA fragments in an immunoassay.
      Northern blots showed no detectable reduction in the level of bcl-2 mRNA of Tu183
      cells, but Western blots showed a reduction of Bcl-2 protein at 24 h after
      infection with the ribozyme-expressing adenovirus vector. The results imply that
      (a) expression of the bcl-2 oncogene is necessary for the survival of oral cancer
      cells, (b) the bcl-2 gene transcript presents a target for gene therapy by
      ribozymes, and (c) an adenovirus vector is a suitable method for transfection of
      the ribozyme-expressing gene.

PMID- 10656453
TI  - Induction of apoptosis and inhibition of c-erbB-2 in breast cancer cells by
      flavopiridol.
AB  - Flavopiridol is a flavone that inhibits several cyclin-dependent kinases and
      exhibits potent growth-inhibitory activity against a number of human tumor cell
      lines, both in vitro and when grown as xenografts in mice. It is presently being
      investigated as a novel antineoplastic agent in the primary screen conducted by
      the Developmental Therapeutics Program, National Cancer Institute. Because breast
      cancer is the most common cancer and second leading cause of cancer-related
      deaths in women in the United States, we investigated whether flavopiridol could
      be an effective agent against a series of isogenic breast- cancer cell lines
      having different levels of erbB-2 expression and differential invasion and
      metastatic characteristics. Flavopiridol was found to inhibit the growth of MDA
      MB-435 (parental) and 435.eB (stable transfectants) cells that were established
      by transfecting c-erbB-2 cDNA into MDA-MB-435. Induction of apoptosis was also
      observed in these cell lines when treated with flavopiridol, as measured by DNA
      laddering, PARP, and CPP32 cleavages. We also found modest up-regulation of Bax
      and down-regulation of Bcl-2, but there was a significant down-regulation of c
      erbB-2 in flavopiridol-treated cells. Gelatin zymography showed that flavopiridol
      inhibits the secretion of matrix metalloproteinase (MMP; MMPs 2 and 9) in the
      breast cancer cells and that the inhibition of c-erbB-2 and MMPs may be
      responsible for the inhibition of cell invasion observed in flavopiridol-treated
      cells. Collectively, these molecular effects of flavopiridol, however, were found
      to be independent of c-erbB-2 overexpression, suggesting that flavopiridol may be
      effective in all breast cancer. From these results, we conclude that flavopiridol
      inhibits the growth of MDA-MB-435 breast cancer cells, induces apoptosis,
      regulates the expression of genes, and inhibits invasion and, thus, may inhibit
      metastasis of breast cancer cells. These findings suggest that flavopiridol may
      be an effective chemotherapeutic or preventive agent against breast cancer.

PMID- 10656454
TI  - The potential of soybean foods as a chemoprevention approach for human urinary
      tract cancer.
AB  - Isoflavones are excreted in human urine and can be modulated by soy-rich diets.
      Recently, isoflavones were suggested to have protective effects against bladder
      cancer cells. We sought to determine the efficacy of the antitumorigenic effects
      of isoflavones at concentrations found in the range of human urine excretion and
      compare normal urothelium and bladder cancer cells for differential cytotoxicity.
      A total of seven human bladder cancer cell lines and an immortalized
      uroepithelial cell line were used to examine the effects of genistein, daidzein,
      and biochanin-A, either individually or as an equal-proportion mixture regimen,
      on cell growth, DNA synthesis, alterations of cell cycle distribution, and
      induction of apoptosis. The role of cyclin B1 and cdc2 kinase in cell cycle
      arrest was analyzed. In addition, severe combined immunodeficient mice were used
      to confirm the anti-cancer effects of isoflavones in vivo. Cooperative action of
      isoflavones was more effective in growth inhibition and apoptosis induction than
      any single compound. Genistein tends to cause a dose-dependent induction of G2-M
      cell cycle arrest and an inhibition of cdc2 kinase activity. However, both
      daidzein and biochanin-A directly induced apoptosis without altering cell cycle
      distribution. The IC50 values in non-transformed cells were higher than those in
      most cancer cell lines, and the IC50 of the mixture regimen was within reach of
      the levels observed in urine after a soy challenge. Furthermore, both genistein
      and combined isoflavones exhibited a significant tumor suppressor effect in vivo
      (P < 0.05). The results justify the potential use of soybean foods as a practical
      chemoprevention approach for patients with urinary tract cancer.

PMID- 10656455
TI  - Effects of the bcr/abl kinase inhibitors AG957 and NSC 680410 on chronic
      myelogenous leukemia cells in vitro.
AB  - The tyrphostin AG957 (NSC 654705) inhibits p210bcr/abl, the transforming kinase
      responsible for most cases of chronic myelogenous leukemia (CML). The present
      studies were performed to determine the fate of AG957-treated cells and assess
      the selectivity of AG957 for CML myeloid progenitors. When K562 cells (derived
      from a patient with blast crisis CML) were treated with AG957, dose- and time
      dependent p210bc/abl down-regulation was followed by mitochondrial release of
      cytochrome c, activation of caspase-9 and caspase-3, and apoptotic morphological
      changes. These apoptotic changes were inhibited by transfection with cDNA
      encoding dominant negative caspase-9 but not dominant-negative FADD or blocking
      anti-Fas antibodies. In additional experiments, a 24-h AG957 exposure caused dose
      dependent inhibition of K562 colony formation in soft agar. To extend these
      studies to clinical samples of CML, peripheral blood mononuclear cells from 10
      chronic phase CML patients and normal controls were assayed for the growth of
      hematopoietic colonies in vitro in the presence of increasing concentrations of
      AG957. These assays demonstrated selectivity of AG957 for CML progenitors, with
      median IC50s (CML versus normal) of 7.3 versus >20 microM AG957 in granulocyte
      colony-forming cells (P < 0.001), 5.3 versus >20 microM in granulocyte/macrophage
      colony-forming cells (P < 0.05), and 15.5 versus > 20 microM in erythroid colony
      forming cells (P > 0.05). The adamantyl ester of AG957 (NSC 680410) down
      regulated p210bcr/abl in K562 cells and inhibited granulocyte colony formation in
      CML specimens at lower concentrations without enhanced toxicity in normal
      progenitors. These observations not only demonstrate that AG957-induced
      p210bcr/abl down-regulation is followed by activation of the cytochrome c/Apaf
      1/caspase-9 pathway but also indicate that this class of kinase inhibitor
      exhibits selectivity worthy of further evaluation.

PMID- 10656456
TI  - E1A-mediated paclitaxel sensitization in HER-2/neu-overexpressing ovarian cancer
      SKOV3.ip1 through apoptosis involving the caspase-3 pathway.
AB  - HER-2/neu-overexpressing breast cancer cells are more resistant to the
      chemotherapeutic agent paclitaxel (Taxol) than low-HER-2/neu-expressing breast
      cancer cells, and the adenoviral type 5 EIA can down-regulate HER-2/neu
      overexpression. Therefore, in this study, we asked (a) whether EIA might
      sensitize response to paclitaxel in human HER-2/neu-overexpressing ovarian cancer
      cells, and, if so, what is the mechanism responsible; and (b) whether this
      enhanced chemosensitivity would translate into a therapeutic effect in an ovarian
      cancer xenograft model. Consequently, we demonstrated that: (a) adenovirus type 5
      E1A could enhance the sensitivity of paclitaxel in paclitaxel-resistant HER-2/neu
      overexpressing human ovarian cancer cells in vitro by inducing apoptosis, (b)
      this induction was heavily dependent on activation of the caspase-3 pathway, and
      (c) nude mice bearing i.p. HER-2/neu-overexpressing human ovarian cancer cells
      and treated with both paclitaxel and E1A gene therapy survived significantly
      longer than did mice treated only with paclitaxel or E1A gene therapy. Thus, we
      concluded that the E1A gene enhanced both the in vitro and in vivo sensitivity of
      paclitaxel in paclitaxel-resistant HER-2/ neu-overexpressing ovarian cancer
      SKOV3.ipl cells. Because a Phase I clinical trial using E1A gene targeted to HER
      2/neu down-regulation has recently been completed, the current study also
      provided a scientific basis to further develop a novel therapy that combines
      paclitaxel and E1A gene therapy and its testing in a Phase II trial.

PMID- 10656457
TI  - Anti-HER2 antibody and heregulin suppress growth of HER2-overexpressing human
      breast cancer cells through different mechanisms.
AB  - Previous reports have shown that certain anti-HER2 antibodies and heregulin can
      inhibit clonogenic growth of breast and ovarian cancers that overexpress HER2.
      Anti-HER2 antibodies bind to HER2 directly, whereas heregulin does not bind to
      HER2 alone, but rather interacts with HER2 through the formation of heterodimers
      with HER3 or HER4. The purpose of the present study was to elucidate the
      mechanisms by which anti-HER2 antibody and heregulin inhibit tumor growth. The
      anti-HER2 monoclonal antibody (mAb) ID5 was found to block G1-S progression of
      the cell cycle, whereas heregulin inhibited passage through G2-M. Compatible with
      the effects on the cell cycle, treatment with mAb ID5 decreased levels of cyclin
      dependent kinase (CDK) 2, cyclin E, and CDK6 proteins and reduced cyclin E-CDK2
      associated kinase activity; mAb HD5-treated cells had increased p27Kip1
      expression and an increased association of p27Kip1 with CDK2. In contrast,
      treatment with heregulin increased protein levels of CDK2, CDK6, CDC2, and cyclin
      B1. More Retinoblastoma protein was found in the hypophosphorylated state in the
      cells treated with mAb ID5, whereas more retinoblastoma protein was in the
      hyperphosphorylated state in heregulin-treated cells. Heregulin was able to
      induce cell differentiation as assessed by Oil Red O staining and apoptosis as
      assessed by sub-G1 peak on flow cytometry and the presence of DNA fragmentation
      in ApopTag histochemistry staining. Neither differentiation nor apoptosis was
      observed in the cells treated with mAb ID5. We conclude that anti-HER-2 mAb ID5
      and heregulin exert growth inhibition through different mechanisms. In mammary
      cells overexpressing HER2, anti-HER2 mAb ID5 induces G1 arrest, whereas heregulin
      induces G2-M arrest, cell differentiation, and apoptosis.

PMID- 10656458
TI  - Cellular ATP depletion by LY309887 as a predictor of growth inhibition in human
      tumor cell lines.
AB  - The antifolate LY309887 is a specific glycinamide ribonucleotide
      formyltransferase inhibitor that blocks de novo purine synthesis and produces a
      depletion of purine nucleotides. The activity of LY309887 in six human tumor cell
      lines has been examined by growth inhibition and clonogenic assay after
      continuous exposure for three cell doubling times and by ATP depletion at 24 h.
      Three cell lines (CCRF-CEM, MCF7, and GC3) were sensitive to LY309887-induced
      growth inhibition (IC50: 5.6-8.1 nM), whereas the other cell lines (COR-L23, T
      47D, and A549) were comparatively resistant (IC50: 36-55 nM). Sensitivity to
      LY309887 cytotoxicity was consistent with sensitivity to growth inhibition in
      four of five cell lines tested (MCF7/GC3: 0.01% survival and COR-L23/T-47D: 1-5%
      survival at 100 nM LY309887). LY309887-induced ATP depletion was measured by
      luciferase-based ATP assay and confirmed by high performance liquid
      chromatography measurements. There was a linear relationship between ATP
      depletion and growth inhibition when data were analyzed for all six cell lines
      (r2 = 0.93; P < 0.0001). Depletion of 24-h cellular ATP concentrations to < 1 mM
      was associated with both cell growth inhibition and cytotoxicity in all cell
      lines studied. In conclusion, cellular ATP depletion induced by LY309887 can be
      used to predict growth inhibition and cytotoxicity in human tumor cells.

PMID- 10656459
TI  - Adenovirus-mediated expression of p53 or p21 in a papillary serous endometrial
      carcinoma cell line (SPEC-2) results in both growth inhibition and apoptotic cell
      death: potential application of gene therapy to endometrial cancer.
AB  - Papillary serous endometrial carcinoma is an aggressive tumor characterized by
      late-stage presentation, i.p. spread, and poor prognosis. It is histologically
      similar to serous papillary carcinoma of the ovary. Preclinical studies have
      shown that adenovirus-mediated expression of p53 in ovarian cancer cell lines
      causes growth inhibition and apoptosis in vitro and in vivo. Such studies provide
      the rationale for Phase I Adp53 gene therapy clinical trials in ovarian cancer.
      In the present study, we compared the efficacy of adenoviral vectors containing
      p53 (Adp53) or p21 (Adp21) in a papillary serous endometrial tumor cell line
      (SPEC-2) that contains mutated p53. Growth assays revealed that both Adp53 and
      Adp21 were efficacious in decreasing cell proliferation as assessed by anchorage
      dependent and anchorage-independent growth assays. However, as compared with
      Adp53, the effects of Adp21 tended to be more transient and less marked.
      Strikingly, Adp21, but not Adp53, induced a G1 arrest in SPEC-2 endometrial
      adenocarcinoma cells. In contrast, as assessed by induction of hypodiploid peaks,
      free DNA ends detected by a terminal deoxynucleotidyl transferase-based assay,
      and annexin V positivity, p53 was more effective than p21 in inducing cell death
      by apoptosis. Compatible with the more efficient induction of apoptosis, Adp53,
      but not Adp21, induced a marked increase in expression of the preapoptotic
      molecule BAX without a concomitant change in expression of the antiapoptotic
      mediator Bcl-2. The differential effects of Adp53 and Adp21 on cell cycle
      progression and apoptosis may be related to the reversibility of p21-induced cell
      cycle arrest and the irreversibility of p53-induced apoptosis. Thus, at least in
      the papillary serous endometrial carcinoma cell line SPEC-2, Adp53 may be more
      effective than Adp21 as a gene therapeutic. Nevertheless, these preclinical
      studies suggest that papillary serous endometrial carcinoma is a potential target
      for p53- or p21-mediated gene therapy.

PMID- 10656460
TI  - Balb/c mice as a preclinical model for raltitrexed-induced gastrointestinal
      toxicity.
AB  - Raltitrexed (RTX) is an antifolate thymidylate synthase (TS) inhibitor used for
      the treatment of advanced colorectal cancer. RTX induces proliferating tissue
      toxicities that are largely confined to the intestine, with diarrhea being a
      severe side effect in a small but significant minority of patients. Similarly,
      weight loss and diarrhea were observed in BALB/c mice, and a maximum tolerated
      dose (MTD) was determined as approximately 5-10 mg/kg/day x 5 days. At an
      equivalent dose of 10 mg/kg/day x 5 days (dl-5), DBA2 mice lost considerably less
      weight, leading to a higher MTD (>500 mg/kg/day x 5 days), and there was no
      evidence of diarrhea. Histopathological consequences of damage, such as changes
      in small intestinal crypt architecture and villus atrophy induced by the 10
      mg/kg/day dose, were greater and of longer duration in BALB/c mice. A higher dose
      of RTX (100 mg/kg/day x 5) induced weight loss and histopathological damage
      similar to that seen in BALB/c mice (10 mg/kg/ day x 5) but was of later onset,
      nadir, and recovery. Small changes to the colon were only observed in BALB/c
      mice. Pretreatment levels of plasma thymidine, deoxyuridine (approximately 1
      microM), and folate (approximately40 ng/ml) were similar in both mouse strains. A
      single injection of radiolabeled RTX (5 mg/kg/ day) did not lead to any marked
      difference 24 h later in the total drug concentration and distribution of
      polyglutamates (comprising 70-80% of drug extracted) in the liver, kidney, and
      intestinal epithelium (large and small intestine) between the two mouse strains.
      Further studies used a RIA to measure RTX polyglutamate formation in tissues at
      various times and drug doses. This led to the conclusion that, although there was
      a higher accumulation of RTX in BALB/c small intestinal epithelium (days 4-6), it
      may be an effect secondary to another undetermined cause of increased drug
      sensitivity. This model represents a vehicle by which the etiology and treatment
      of severe clinical toxicity induced by RTX may be evaluated.

PMID- 10656461
TI  - Histology and sensitivity to anticancer drugs of two human non-small cell lung
      carcinomas implanted in the pleural cavity of nude mice.
AB  - We have established two metastatic models of human non-small cell lung carcinoma
      (NSCLC)-the NCI-H460 large-cell carcinoma and the A549 adenocarcinoma-by
      inoculating tumor cells into the pleural space of nude mice. The objectives of
      this work were as follows: (a) to study the histological characteristics and
      growth and dissemination patterns of these tumors in nude mice; (b) to assess
      their sensitivity to drugs that have demonstrated significant clinical
      therapeutic effect in the treatment of NSCLC; and (c) to investigate the
      antitumor activity of S 16020-2, a new olivacine derivative, currently in Phase
      II clinical evaluation. In each of the two models, all animals developed lung
      tumors, resulting in 100% mortality. Histopathological study showed that these
      two tumors spread locally to contiguous structures, including the mediastinal
      pleura and diaphragm, with histological characteristics consistent with the human
      pathology. Anticancer drugs used for the treatment of NSCLC, such as cisplatin,
      doxorubicin, vinblastine, and etoposide, enhanced the life span of treated mice
      in the two models and were more active in the NCI-H460 than in the A549 model.
      The increases of survival time as compared to control groups were from 60 (P < or
      = 0.05) to 83% (P < or = 0.01) and from 21 to 40% for NCI-H460 and A549,
      respectively. Vinorelbine, paclitaxel, and irinotecan showed similar activities
      in the two models and increased the survival of treated mice by between 38 and
      79% (P < or = 0.001) and between 58 (P < or = 0.01) and 78% in the NCI-H460 and
      A549 models, respectively. However, none of these drugs was curative, reflecting
      the resistance of this disease to chemotherapy. S 16020-2 exhibited a remarkable
      antitumor activity, increasing the survival by 82% (P < or = 0.01) for NCI-H460
      and by 126% (P < or = 0.001) for A549. This drug was among the most active
      compounds in these models, thereby indicating its potential for the chemotherapy
      of this disease.

PMID- 10656462
TI  - Maternal exposure to tamoxifen during pregnancy increases carcinogen-induced
      mammary tumorigenesis among female rat offspring.
AB  - Tamoxifen is under investigation as a potential chemopreventive agent in women of
      child-bearing age who are at an increased risk to develop breast cancer. However,
      because tamoxifen may act as an estrogen in the fetus and high fetal estrogenic
      activity, in turn, may increase subsequent breast cancer risk, we wanted to
      determine the effects of a maternal exposure to tamoxifen during pregnancy on
      offspring's susceptibility to mammary tumorigenesis. Pregnant rats were injected
      s.c. with 20 microg of tamoxifen or oil vehicle daily during days 15 and 20 of
      gestation. In utero exposure to tamoxifen caused abnormalities in the development
      and function of the reproductive track, including a delayed puberty onset and
      changes in uterine wet weights. The tamoxifen-exposed offspring, treated with
      7,12-dimethylbenz[a]antracene (DMBA) at the age of 45 days, developed an
      increased incidence of mammary tumors. In week 18 after DMBA administration, 50%
      of the vehicle-controls had developed mammary tumors, whereas tumor incidence in
      the tamoxifen group was 95%. In addition, a significantly higher number of tumors
      in the tamoxifen-exposed group kept growing (rather than stopped growing or
      regressed) than in the control group. Furthermore, histopathological examination
      revealed that the mammary tumors in the tamoxifen offspring were less
      differentiated and exhibited a more aggressive phenotype, compared with the
      tumors growing in the controls. These results suggest that a maternal exposure to
      tamoxifen during pregnancy acts as an estrogen in the fetal mammary gland and
      increases the susceptibility to breast cancer among female offspring.

PMID- 10656463
TI  - Delayed administration of sodium thiosulfate in animal models reduces platinum
      ototoxicity without reduction of antitumor activity.
AB  - Platinum-based chemotherapeutic agents, such as carboplatin and cisplatin, are
      effective against many human tumors, but their use may be limited by a high
      incidence of ototoxicity. Delayed administration of the chemoprotective agent
      sodium thiosulfate (STS) reduces the ototoxicity of carboplatin in a guinea-pig
      model, when given up to 8 h after the chemotherapy, and also reduces hearing loss
      in patients given carboplatin with osmotic blood-brain barrier opening for
      treatment of brain tumors. We tested whether STS, given at times that achieved
      otoprotection, could impact the chemotherapeutic efficacy of carboplatin. The
      impact of STS was evaluated by measuring the onset of growth of LX-1 human small
      cell lung carcinoma s.c. xenografts in the nude rat. When STS was administered as
      two boluses, 2 and 6 h after treatment with carboplatin and etoposide, there was
      a decrease in the time to tumor progression. In contrast, when STS administration
      was delayed until 8 h after carboplatin/etoposide, there was no reduction in the
      antitumor cytotoxicity of the chemotherapy. STS infusion did not significantly
      affect ultrafilterable platinum pharmacokinetics in the guinea pig. To explore
      the potential wider applicability of STS, in a pilot study we tested its efficacy
      against cisplatin ototoxicity. Delayed administration of STS, 2 h after
      cisplatin, was protective against cisplatin-induced ototoxicity in the guinea pig
      model, as determined by electrophysiological measures. On the basis of these
      data, we suggest that delayed administration of STS may provide a mechanism to
      reduce the ototoxicity caused by administration of carboplatin or cisplatin for
      both central nervous system and systemic cancer chemotherapy.

PMID- 10656464
TI  - Correspondence re: T. Davis et al., therapy of B-cell lymphoma with anti-CD20
      antibodies can result in loss of CD20 antigen expression. Clin. Cancer Res., 5:
      611-615, 1999.

PMID- 10656465
TI  - Specifying the antecedents of breast-feeding duration in Peru through a
      structural equation model.
AB  - OBJECTIVE: To examine the effects of socioeconomic status and biocultural
      variables (planned pregnancy, prenatal care, timing of initiation of breast
      feeding and caesarean section delivery) on breast-feeding duration in Peru using
      structural equation models. DESIGN AND SETTING: Structural equation models were
      analysed with LISREL using data from the 1991-92 Peruvian Demographic and Health
      Survey. SUBJECTS: Models were tested among 6,020 women whose last child was born
      within 5 years of the survey and among 2,711 women whose last child was born 2-5
      years preceding the survey. RESULTS: Unplanned pregnancy and socioeconomic status
      had a negative influence on breast-feeding duration. Prenatal care was positively
      associated with the timing of breast-feeding initiation in both samples and with
      breast-feeding duration in the whole sample. The timing of breast-feeding
      initiation was inversely associated with breast-feeding duration only in the
      sample of older children. CONCLUSIONS: These results imply that an unplanned
      pregnancy, a delayed breast-feeding initiation, and higher socioeconomic status
      are risk factors for an earlier discontinuation of breast-feeding through complex
      mechanisms involving direct and indirect effects.

PMID- 10656466
TI  - Nutrient intake trends among African-Caribbeans in Britain: a migrant population
      and its second generation.
AB  - OBJECTIVE: To explore British African-Caribbean (AfC) nutrient intake by
      migration status (place of birth), diet (traditional Caribbean or more European)
      and age and relate this ecologically to coronary heart disease (CHD) mortality
      rates. DESIGN: Cross-sectional. SETTING: Inner-city Manchester, UK. SUBJECTS: Two
      hundred and fifty-five adults of AfC origin aged 25-79 years, randomly sampled
      from population registers. RESULTS: Caribbean-born people (mean age 56, and mean
      time in Britain 30 years) had significantly lower per cent energy from total and
      saturated fat than younger British-born AfC people (mean age 29 years) (31.3% vs.
      35%, difference in total fat 3.7%, 95%CI 2-5%; in saturated fat 10.9% vs. 12.6%,
      difference 1.7%, 95%CI 1-2.5%). The Caribbean-born group also ate more fruit
      (+84g/day-1, 95%CI 36-132g/day-1) and green vegetables (+26 g/day-1, 95%CI 3-49
      g/day-1). Men following a traditional diet (> or = 5 days week-1) similarly had a
      lower per cent energy from fat, at 30.4%, than less traditional eaters, at 33.1%
      (difference 2.7%, 95%CI 0.7-4.8%). African-Caribbean women, at relatively greater
      CHD risk than AfC men, had higher body mass indices (BMIs) than AfC men. Compared
      with national data, AfC subjects consumed some 7% and 5% less energy from total
      fat and saturated fat, respectively, with over 9% more from carbohydrate.
      However, there was marked convergence towards the national average in the
      youngest AfC groups aged 25-34 years, whatever their place of birth. CONCLUSIONS:
      Caribbean birthplace has an independent effect on total fat intake and percentage
      of energy from fat. Together with higher fruit and vegetable intake, these
      results are consistent with the dietary fat/antioxidant/CHD hypothesis.

PMID- 10656467
TI  - Dietary questions as determinants of mortality: the OXCHECK experience.
AB  - OBJECTIVE: To determine whether responses to simple dietary questions are
      associated with specific causes of death. DESIGN: Self-reported frequency intakes
      of various classes of foods and data on confounding factors were collected at the
      baseline survey. Death notifications up to 31 December 1997 were ascertained from
      the Office for National Statistics. Relative risk (RR) of death and 95%
      confidence intervals (CI) associated with baseline dietary factors were
      calculated by Cox regression. SETTING: Prospective follow-up study based on five
      UK general practices. SUBJECTS: Data were used from 11,090 men and women aged 35
      64 years (81% of the eligible patient population) who responded to a postal
      questionnaire in 1989. RESULTS: After 9 years of follow-up, 598 deaths were
      recorded, 514 of these among the 10,522 subjects with no previous history of
      angina. All-cause mortality was positively associated with age, smoking and low
      social class, as expected. Among the dietary variables, all-cause mortality was
      significantly reduced in participants who reported relatively high consumption of
      vegetables, puddings, cakes, biscuits and sweets, fresh or frozen red meat (but
      not processed meat), among those who reported using polyunsaturated spreads and
      among moderate alcohol drinkers. These associations were broadly similar for
      deaths from ischaemic heart disease (IHD), cancer and all other causes combined,
      and were not greatly attenuated by adjusting for potential confounding factors
      including social class. CONCLUSIONS: Responses to simple questions about
      nutrition were associated with mortality. These findings must be interpreted with
      caution since residual confounding by dietary and lifestyle factors may underlie
      the associations.

PMID- 10656468
TI  - Health potential of soy isoflavones for menopausal women.
AB  - OBJECTIVE: To review the current literature on the effects of soy isoflavones,
      one class of phyto-oestrogens, on cardiovascular diseases, osteoporosis, cancer
      and climacteric symptoms. DESIGN: Many study designs were employed in the reports
      reviewed here, including prospective human trials, observational human studies,
      animal experiments and in vitro cell studies that explored the protective or
      preventive effects of soy isoflavones (genistein, daidzein and glycitein alone or
      mixed). SETTING: Diverse settings were employed, depending on study design.
      SUBJECTS: Human subjects, mostly menopausal or postmenopausal, were included, as
      were animal models and specific cell types. RESULTS: The findings were: (i)
      isoflavones plus soy protein together were needed to obtain the highly
      significant beneficial results on blood lipids and arterial dimensions; (ii)
      isoflavone treatments alone at high doses (relative to above) consistently
      improved bone parameters in rodent ovariectomized models, but not in humans or
      primates; (iii) isoflavones were not consistent in exerting positive effects
      regarding the prevention or treatment of cancers of the mammary glands, uterus
      and colon; and (iv) the effects of isoflavones on climacteric symptoms were not
      clear-cut. CONCLUSIONS: The promise of soy isoflavones reducing chronic disease
      risk seems to be non-uniform, with the most conclusive benefits occurring in the
      prevention of cardiovascular diseases, but other organ systems, such as skeletal
      and reproductive tissues, may also benefit from the consumption of soy and soy
      derived products.

PMID- 10656469
TI  - Costs of a healthy diet: analysis from the UK Women's Cohort Study.
AB  - OBJECTIVE: To investigate the direct and indirect cost differences associated
      with eating a 'healthy' or 'unhealthy' diet. DESIGN: Analysis of data from a
      baseline postal questionnaire for the UK Women's Cohort Study, including a
      detailed food frequency questionnaire (FFQ), supplemented by a telephone
      interview on a sub-sample. SUBJECTS: The first 15,191 women who responded to the
      questionnaire, aged 35-69 years with similar numbers of meat eaters, fish eaters
      and vegetarians. RESULTS: A healthy diet indicator (hdi), with values from 0
      (lowest) to 8 (highest) was developed based on the WHO dietary recommendations.
      Direct monetary cost of the diet was calculated using prices from the 1995
      National Food Survey and the Tesco home shopping catalogue. Women in the healthy
      diet group were almost four times as likely to be vegetarian and have a higher
      educational level. For direct costs, the difference between the most extreme hdi
      groups was 1.48 day-1 (equivalent to 540 year-1), with fruit and vegetable
      expenditure being the main items making a healthy diet more expensive. Forty-nine
      per cent of the food budget was spent on fruit and vegetables in hdi group 8
      compared to 29% in hdi group 0. Interestingly, 52% of those questioned in both
      extreme hdi groups did not think that it was difficult to eat healthily.
      CONCLUSIONS: To achieve a particularly healthy diet independent predictive
      factors were spending more money, being a vegetarian, having a higher energy
      intake, having a lower body mass index (BMI) and being older.

PMID- 10656470
TI  - Taste and food preferences as predictors of dietary practices in young women.
AB  - OBJECTIVE: To investigate links between taste responses, self-reported food
      preferences and selected dietary outcomes in young women. METHODS: Subjects were
      159 women, with a mean age of 27.0 years. Taste responses were measured using
      aqueous solutions of 6-n-propylthiouracil (PROP) and sucrose. All subjects
      completed a 171-item food preference checklist, using nine-point category scales.
      Food preference data were reduced using principal components factor analyses,
      with the internal consistency of factor-based subscales established using
      Cronbach's alpha. Dietary intakes, available for a subset of 87 women, were based
      on 3 days of food records. Estimated intakes of carbohydrate, fibre and beta
      carotene were the key dietary outcome variables. RESULTS: Genetically-mediated
      sensitivity to the bitter taste of PROP was associated with reduced preferences
      for Brussels sprouts, cabbage, spinach and coffee beverages. Higher preferences
      for sucrose in water were associated with increased preferences for sweet
      desserts. Food preferences, in turn, were associated with measures of current
      diet. Reduced acceptability of vegetables and fruits was associated with lower
      estimated intakes of carbohydrate, fibre and beta-carotene. CONCLUSIONS: Taste
      responses to sucrose and PROP were predictive of some food preferences. Food
      preferences, in turn, were associated with food consumption patterns. Given that
      taste responsiveness to PROP is an inherited trait, there may be further links
      between genetic taste markers, eating habits and the selection of healthful
      diets.

PMID- 10656471
TI  - Iron intake and iron status of preschool children: associations with breakfast
      cereals, vitamin C and meat.
AB  - OBJECTIVE: To examine associations between breakfast cereal consumption and iron
      status and identify dietary patterns that might improve iron status in this
      vulnerable group. DESIGN: Analysis of data from the UK National Diet and
      Nutrition Survey (NDNS) of children aged 1.5-4.5 years, including dietary intakes
      calculated from 4-day weighed records. SUBJECTS: Data were used from 904 children
      with haematological measurements, excluding those taking iron supplements; 20%
      had low iron stores (ferritin < 10 microgl-1) while 8% were anaemic (Hb < 11 g dl
      1). RESULTS: High cereal consumers had significantly higher iron intakes than low
      cereal consumers (classified by tertiles) but the 10% difference in mean ferritin
      levels was not significant (P= 0.067). Lower intakes of vitamin C and meat among
      high consumers of cereal may have diluted the impact of cereal iron on iron
      status. When children were reclassified according to their intakes of vitamin C
      and iron from meat and breakfast cereals, the group with high (above median)
      intakes of two or more factors had a higher mean haemoglobin (Hb) level and a
      lower prevalence of anaemia compared with the group with low (below median)
      intakes of all three dietary constituents. CONCLUSIONS: Nutritional advice that
      aims to improve iron status should emphasize not only rich sources of iron but
      also factors that may enhance or inhibit absorption. Strategies to optimize iron
      status in this vulnerable age group include consuming an iron-fortified breakfast
      cereal, vitamin C-rich fruit or drink at breakfast, and avoiding tea with (or
      after) meals.

PMID- 10656472
TI  - An appraisal of vitamin B6 status indices and associated confounders, in young
      people aged 4-18 years and in people aged 65 years and over, in two national
      British surveys.
AB  - OBJECTIVE: To compare vitamin B6 status indices with each other and with
      potential confounding factors, in the datasets from two national British surveys
      and associated studies. DESIGN: Vitamin B6 status was measured by plasma
      pyridoxal phosphate (PLP) and plasma pyridoxic acid (PA) in both surveys, and
      also by erythrocyte aspartate aminotransferase activation coefficient (EAATAC) in
      one of the surveys. Plasma alpha1-antichymotrypsin was measured as an index of
      acute phase status; plasma creatinine was measured as an index of renal function;
      and plasma total alkaline phosphatase activity was measured as a proxy for PLP
      hydrolase activity. SETTING: The survey of people aged 65 years and over was
      carried out in 80 postcode sectors across mainland Britain during 1994-95 and the
      survey of young people was carried out in 132 postcode sectors across mainland
      Britain during 1997. SUBJECTS: Blood samples from c. 1,000 subjects of both sexes
      in each survey permitted measurements of plasma PLP and PA. There were also
      measurements of EAATAC in the young people's survey. RESULTS: According to
      published limits of normality, only 5% or less of the young people had
      unacceptable vitamin B6 status as measured by plasma PLP. About half had
      apparently unacceptable status by EAATAC, but this observation is difficult to
      interpret. The young people had considerably higher plasma concentrations of PLP
      and lower concentrations of PA than the older people. In both surveys, plasma PLP
      was strongly correlated with plasma PA and in the young persons' survey it was
      also correlated, although much less strongly, with the basal activity and
      activation coefficient of aspartate aminotransferase. Both plasma PLP and EAATAC
      (but not PA nor basal aspartate aminotransferase activity) were influenced by
      acute phase status in young people, as indicated by significant correlations with
      alpha1-antichymotrypsin. In people aged 65 years and over, PA (but not PLP) was
      correlated with renal function, as indicated by its relation with plasma
      creatinine; however PLP (but not PA) was correlated with plasma alkaline
      phosphatase activity. CONCLUSIONS: Several potential confounders - acute phase
      reaction, kidney malfunction and hydrolase activity - may influence vitamin B6
      status indices, although differently for different indices and different age
      groups. Since older people have relatively poor vitamin B6 status, which may have
      important health implications for them, more reliable vitamin B6 status indices
      are needed.

PMID- 10656473
TI  - Food and nutrient intake of a national sample of 4-year-old children in 1950:
      comparison with the 1990s.
AB  - OBJECTIVE: To evaluate the food and nutrient intake of members of a birth cohort
      study when young children in 1950 and investigate differences from present-day
      children's diets. DESIGN: One-day recall diet records from the MRC National
      Survey of Health and Development (NSHD) (1946 Birth Cohort) at age 4 years were
      analysed for energy and selected nutrients and compared to the published results
      for 4-year-olds in the 1992/93 National Diet and Nutrition Survey (NDNS).
      SETTING: England, Scotland and Wales in 1950 and 1992/93. SUBJECTS: 4,599
      children in 1950 and 493 children in 1992/93. RESULTS: Mean (SD) daily intakes in
      1950 were energy 1,445 (343) kcal, or 6.1 (1.4) MJ, protein 46 (11)g, fat 64
      (20)g, starch 117 (33)g, sugar 62 (24)g, unavailable carbohydrate 13 (4)g,
      calcium 736 (230) mg, iron 7.7 (2.1) mg, retinol 738 (1,273) microg, carotene
      1,049 (1,130) microg and vitamin C 40 (26) mg. Compared to 1992/93, the 1950 diet
      contained substantially more bread and vegetables and less sugar and soft drinks,
      giving it a higher starch and fibre content and making it more in line with
      current recommendations on healthy eating. However, fat provided 40% of energy in
      1950, compared to 35% in 1992/93. In 1950, red meat was an important source of
      iron, but by 1992 most iron came from fortified breakfast cereals. Vitamin C came
      mainly from vegetables in 1950, but from soft drinks in 1992. CONCLUSIONS: The
      relative austerity of post-war food supplies resulted in food and nutrient
      intakes in 1950 which in many respects may well have been beneficial to the
      health of young children, despite fat intake being higher than present-day
      recommendations.

PMID- 10656474
TI  - Evaluation of the Nutrition Education at Primary School (NEAPS) programme.
AB  - OBJECTIVE: To assess the impact and suitability of a pilot dietary educational
      programme for primary school pupils. The Nutrition Education at Primary School
      (NEAPS) programme aimed to build awareness of the benefits of healthy eating,
      induce positive behaviour change and increase the children's knowledge. DESIGN: A
      comparative quasi-experimental study with follow-up after 3 months. SETTING:
      Eight primary schools in the Eastern and North Western Health Boards and three
      control schools in the same board regions. SUBJECTS: Data were used from 821
      Irish school children aged 8-10 years old. METHODS: The education programme
      comprised 20 sessions over 10 weeks including circular worksheets, homework
      assignments and an aerobic exercise regime. At baseline and after 3 months pupils
      completed food diaries and a validated food pairing questionnaire on food
      behaviour, knowledge and preferences. RESULTS: Significant differences were found
      in the intervention children's behaviour and preference levels after the NEAPS
      programme (P < 0.01 in both sections). Knowledge levels were very high at
      baseline and though some individual items improved, average change overall was
      not significant. Rural children appeared to benefit more in behaviour and
      preferences from the programme (P <0.01). The NEAPS programme appeared to be less
      effective in pupils in disadvantaged areas (P < 0.01 for each of the sections:
      behaviour, preference and knowledge). One hundred and eighty-seven children
      completed food diaries. The intervention children's consumption of fruit and
      vegetables increased, and they consumed less salty snacks after the programme.
      Rural children were confirmed to have healthier diets at baseline. CONCLUSIONS:
      Following the NEAPS pilot programme positive changes were seen in the school
      children's eating behaviour and preferences for healthier foodstuffs. This
      suggests successful development of a culturally sensitive nutrition education
      programme for school children aged 8-10 years.

PMID- 10656475
TI  - Perceptions about body weight and weight reduction in Spain.
AB  - OBJECTIVE: To assess the more prevalent beliefs about body weight and the factors
      involved in weight changes in the Spanish adult population. DESIGN: A national
      survey was carried out according to an established protocol on Spanish subjects
      selected by a multistage procedure following a random route model, which was
      quota-controlled for several sociodemographic variables. This study was
      undertaken by the Spanish arm of a pan-European survey and was performed with a
      validated questionnaire. It contained questions to evaluate some aspects
      concerning the relationship between obesity, physical activity and health. We
      also estimated the proportion of self-reported overweight and obesity. SETTING:
      Spain. SUBJECTS: The sample included 1,000 subjects aged 15 years or older.
      RESULTS: Eleven per cent of the sample were obese (body mass index, BMI > 30 kg/m
      2) and an additional 32% were overweight (BMI > 25 and < 30 kg/m-2). Obesity
      prevalence was higher among older individuals, those with lower education and
      socioeconomic levels, and among housewives and retired or unemployed people. Most
      Spanish people believed that fat intake (51%) and the amount of food consumption
      (44%) were the major factors involved in weight gain, while physical activity was
      less mentioned (12%). The method most frequently used to lose weight was diet
      (9%). Individuals from central and southern regions payed more attention to
      genetics (20-27%) and physical activity (12-20%) as determinants of weight gain
      than people living in the north or northwest regions (15-17% and 8-9%,
      respectively). Normal weight people participated more often in some physical
      activity during their leisure time. CONCLUSIONS: The Spanish population is not
      familiar with factors influencing weight gain. Health promotion strategies should
      emphasize the role of physical activity, especially among older individuals,
      retired or unemployed subjects, those from lower educational or socioeconomic
      levels and among people living in the north or northwest of Spain.

PMID- 10656476
TI  - Does nutritionist review of a self-administered food frequency questionnaire
      improve data quality?
AB  - OBJECTIVE: This study sought to evaluate the benefit of utilizing a nutritionist
      review of a self-administered food frequency questionnaire (FFQ), to determine
      whether accuracy could be improved beyond that produced by the self-administered
      questionnaire alone. DESIGN: Participants randomized into a dietary intervention
      trial completed both a FFQ and a 4-day food record (FR) at baseline before entry
      into the intervention. The FFQ was self-administered, photocopied and then
      reviewed by a nutritionist who used additional probes to help complete the
      questionnaire. Both the versions before nutritionist review and after
      nutritionist review - were individually compared on specific nutrients to the FR
      by means, correlations and per cent agreement into quintiles. SETTINGS AND
      SUBJECTS: Three hundred and twenty-four people, a subset of participants from the
      Polyp Prevention Trial - a randomized controlled trial examining the effect of a
      low-fat, high-fibre, high fruit and vegetable dietary pattern on the recurrence
      of adenomatous polyps - were recruited from clinical centres at the University of
      Utah, University of Buffalo, Memorial Sloan Kettering Cancer Center in New York
      and Kaiser Permanente Medical Program in Oakland. RESULTS: Reviewing the FFQ
      increased correlations with the FR for every nutrient, and per cent agreement
      into quintiles for all nutrients except calcium. Energy was underestimated in
      both versions of the FFQ but to a lesser degree in the version with review.
      CONCLUSIONS: One must further evaluate whether the increases seen with
      nutritionist review of the FFQ will enhance our ability to predict diet-disease
      relationships and whether it is cost-effective when participant burden and money
      spent utilizing trained personnel are considered.

PMID- 10656477
TI  - Assessing the diet of adolescent girls in the UK.
AB  - OBJECTIVE: To assess the ability of a food frequency questionnaire (FFQ1) and a
      food checklist (FCL) to determine energy and macronutrient intakes of adolescent
      girls in the general population. DESIGN: Energy and macronutrient intakes
      determined by FFQ1 and the FCL were compared with those from a 7-day weighed
      dietary record (WDR). The reproducibility of FFQ1 was assessed by a comparison of
      intakes with those from a repeated questionnaire (FFQ2) completed a month later.
      SETTING: Southampton, UK. SUBJECTS: Forty-seven 15-year-old girls completed FFQ1
      and the WDR and FCL; and 61 girls completed FFQ1 and FFQ2. RESULTS: The broad
      dietary patterns described by the three methods of assessment were similar,
      although absolute intakes differed. Energy and macronutrient intakes determined
      by FFQ1 were higher than those recorded in the WDR (all P < 0.001), but intakes
      assessed by the FCL and WDR were similar. Only FFQ1-assessed energy intakes
      appeared consistent with predicted energy requirements. With the exception of
      protein intake, there was reasonable agreement between FFQ1 and the WDR in their
      estimation of energy and macronutrient intake (range of correlation coefficients
      0.28 for energy to 0.33 for carbohydrate). The poorer agreement between FFQ1 and
      the WDR in their estimates of protein intake arose principally from the
      misclassification of meat and fish intake, although there was no obvious
      explanation for this. Energy and macronutrient intakes were similar for FFQ1 and
      FFQ2. CONCLUSIONS: Adolescent girls give reproducible answers in response to a
      self-administered FFQ, which yield useful information about their broad dietary
      patterns. The FFQ may be a more suitable dietary assessment method than
      prospective records for use in general population studies of girls of this age.
      We discuss suggestions for its improved performance.

PMID- 10656478
TI  - Evaluation of a bar-code system for nutrient analysis in dietary surveys.
AB  - OBJECTIVE: A novel system for nutrient analysis has been developed and tested
      over 5 years. Its key features are a nutrient database of 600 commonly eaten
      foods (95% of foods eaten in 7-day surveys); a booklet identifying each food with
      a bar code, bar codes for gram weight and for portion sizes (small, medium,
      large) and a bar-code reader with dietary analysis software for PCs. In the
      present study the bar-code system has been evaluated by comparison with a
      commonly used manual entry nutrient analysis software for dietitians' use.
      DESIGN: Cross-sectional. SETTING: Glasgow city district. SUBJECTS: One hundred
      and sixty adults aged 18-65 years old. RESULTS: Comparing mean intakes for macro-
      and micronutrients, using the Bland and Altman method, the bias between the two
      methods was small, ranging from 0.93 to 1.03. The bar-code system took
      significantly less professional time in data entry and nutrient analysis than the
      widely used manual system (29min per 7-day diary vs. 47 min per 7-day diary, P <
      0.001). CONCLUSIONS: It is suggested that the bar-code system offers greater
      speed with a saving of professional time needed for nutrient analysis of dietary
      surveys. This system is commended for maintaining accuracy while promoting
      economy.

PMID- 10656479
TI  - A method to compensate for incomplete 24-hour urine collections in nutritional
      epidemiology studies.
AB  - OBJECTIVE: To develop a method to make use of incomplete 24-hour urinary samples
      in nutritional epidemiology, especially when validating the dietary intake of
      nitrogen (protein), sodium and potassium. DESIGN: Urinary data for men and women
      collected in three different studies were evaluated. The concentration of para
      aminobenzoic acid (PABA) in one 24-hour urine sample per person was compared with
      the concentrations of nitrogen, sodium, potassium and creatinine. SETTING: Men
      and women living in Cambridge, UK and women living in the town of Varberg,
      Sweden. SUBJECTS: In total, this study consists of data from 73 Swedish women (20
      50 years of age), 165 UK women (50-65 years) and 75 UK men (55-88 years).
      RESULTS: On average four out of 10 people in this study had a PABA recovery below
      85%. The linear regression equations for urinary excretion of nitrogen, sodium
      and potassium in relation to PABA recovery were y=2.3 + 0.088 x chi (r=0.99),
      y=45 + 0.82 x chi (r= 0.87) and y = 19 + 0.60 x chi (r= 0.93), respectively.
      CONCLUSIONS: The linear regression equations can be used for adjusting urinary
      nitrogen, sodium and potassium in urinary collections in cases where the PABA
      recovery is below 85%. Since it is common to obtain 24-hour urine collections
      with a PABA recovery below 85%, this method should increase the usefulness of
      biological markers of food intake in nutritional epidemiological studies and also
      increase the possibilities to study people that previously have been part of the
      drop-out group or the group with low motivation and cooperation. It is important
      to stress that we have not studied the relationship between PABA recovery and
      various urinary variables below the PABA recovery of 50%. Thus, in a case of PABA
      recovery below 50%, we do not recommend the use of this method to compensate for
      incomplete collections.

PMID- 10656480
TI  - Mutation Research Award 1997, Dr. Minako Nagao.

PMID- 10656481
TI  - A new approach to risk estimation of food-borne carcinogens--heterocyclic amines-
      based on molecular information.
AB  - Identification of causative agents for human cancers is the goal of our studies.
      We analyzed ordinary foods for mutagenicity, using the well-established
      Salmonella test. Heating fish and meat yielded mutagens that require metabolic
      activation for exhibition of mutagenicity. Structural determination revealed
      these mutagens to be heterocyclic amines (HCAs), their precursors in some cases
      being creatin(in)e, sugars and amino acids. Ten HCAs so far examined have all
      proved carcinogenic in mice and rats, inducing cancers in various organs such as
      in the mammary glands, prostate, lung, colon, skin, bladder and liver. Human
      exposure to HCAs is 0.1-12 microg/day, predominantly to 2-amino-1-methyl-6-phenyl
      imidazo[4,5-b]pyridine (PhIP) and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline
      (MeIQx). For these types of genotoxic carcinogens, DNA-adduct formation is
      crucially important and PhIP-DNA adducts have been detected in human tissues.
      However, the amounts of individual HCAs ingested by humans may not be sufficient
      to induce cancers by themselves and many environmental factors have also been
      implicated in neoplasia in man, with other considerable inter-individual
      variation in susceptibility, e.g., to colon carcinogenesis. This is in line with
      results obtained by feeding different strains of rats with HCA. Studies using
      lacI transgenic mice and rats have revealed that DNA adducts do not directly
      correlate with mutant frequencies at the organ level, or cancer incidence.
      However, sequencing of the Apc gene of rat colon tumors induced by PhIP revealed
      that it induces a signature mutation of G deletion from the GGGA sequence. This
      type of mutation is found in the p53 gene of 0.3% human cancers having p53
      somatic mutations, and it has been calculated that 3%-10% of the p53 mutations
      detected in human cancers could be ascribable to PhIP. Although there remains the
      possibility that other carcinogens involved in human carcinogenesis cause the
      same signature mutation, the available data point to an important role for PhIP.

PMID- 10656482
TI  - Interaction effects of 5-azacytidine with topoisomerase II inhibitors on CHO
      cells, as detected by cytogenetic analysis.
AB  - Different cell treatment protocols with the hypomethylating agent 5 azacytidine
      (5-aza C) were used in exponentially growing Chinese hamster ovary (CHO) cells in
      order to test its influence on the induction of chromosomal aberrations (CAs)
      induced by topoisomerase II inhibitors, ellipticine (EPC) and teniposide (VM-26).
      Cells pre-treated with 1 microg/ml 5-aza C for 1 h during the S-phase and post
      treated in the last 2 h of incubation with 0.6 microg/ml EPC or 0.04 microg/ml VM
      26 showed a reduction of 48% and 45%, respectively, in the frequencies of CAs as
      compared to the sum value of the frequencies obtained for each drug alone. 5-aza
      C added to the cultures for the last 2 h before cell fixation after a 30-min
      pulse treatment with EPC or VM-26 caused a 38% and 28% reduction, respectively.
      Simultaneous treatments with 5-aza C plus EPC, or 5-aza C plus VM-26 during the
      last 2 h of incubation (G2-phase), showed a significant effect of CA reduction
      (24%) only for the combination of 5-aza C + EPC. Preliminary assays with 5-aza C
      alone added to the cultures at different times demonstrated its effectiveness in
      inducing chromosome damage during the S-phase. Since S-phase-treated CHO cells
      showed a higher degree of reduction in the frequencies of CAs induced by EPC and
      VM-26, we suggest that 5-aza C incorporation into DNA may change the topo II
      cleavage sites, protecting the DNA from the induction of damage, or that the
      hypomethylation induced by incorporation of 5-aza C into DNA may change the
      chromatin structure facilitating the access to DNA repair enzymes. An alternative
      possibility is that 5-azaC can reactivate methylated genes involved in the repair
      of DNA double-strand breaks induced by topo II inhibitors.

PMID- 10656483
TI  - Adaptive response towards adriamycin in vitro: circumvention with verapamil.
AB  - In an attempt to identify mechanisms of adaptive response to adriamycin (ADR), we
      have earlier isolated ADR-resistant cell lines CHO/R and ME18/R by short-term
      pulse exposures of parent cell lines to this drug, followed by single-cell
      cloning. The results presented in this study have shown that the development of
      resistance to ADR was accompanied by cross-resistance to vinblastine and
      methotrexate. The resistance of tested cell lines towards ADR was substantially
      reversed by verapamil (VPL) at non-toxic concentrations. VPL abolished also the
      capability of these cell lines to express adaptive response after treatment of
      the cells with a conditioning dose of ADR. From the results of our study, we
      conclude that similar characteristics play a role in the mechanism of the
      phenomenon of adaptive response as in the mechanism of pleiotropic multidrug
      resistance.

PMID- 10656484
TI  - SOS chromotest and mutagenicity in Salmonella: evidence for mechanistic
      differences.
AB  - An examination of the relationship of the experimental results obtained with
      chemicals tested in the SOS chromotest and for mutagenicity in Salmonella
      indicates that the two assays respond to different genotoxic stimuli.
      Furthermore, the relationship between results obtained in these assays and in
      rodents carcinogenicity bioassays suggests that the short-term assays respond to
      a different spectrum of carcinogens. The same conclusions were reached based upon
      an analysis of the structural features associated with these three phenomena.
      With respect to using these short-term assays to predict carcinogens, the present
      results suggest that they are not equivalent, but complement one another.

PMID- 10656485
TI  - Evaluation of the database on mutant frequencies and DNA sequence alterations of
      vermilion mutations induced in germ cells of Drosophila shows the importance of a
      neutral mutation detection system.
AB  - The vermilion gene in Drosophila has extensively been used for the molecular
      analysis of mutations induced by chemicals in germ cells in vivo. The gene is
      located on the X-chromosome and is a useful target for the study of mutagenesis
      since all types of mutations are generated. We have critically evaluated this
      system with respect to sensitivity for mutation induction and selectivity for
      different types of mutations, using a database of more than 600 vermilion mutants
      induced in postmeiotic male germ cells by 18 mutagens. From most of these mutants
      the mutation has been analysed. These data showed 336 base substitutions, 96
      intra-locus DNA rearrangements and 78 multi-locus deletions (MLD). Mutants
      containing a MLD were either heterozygous sterile or homozygous and hemizygous
      lethal. The distribution of both basepair (bp) changes and intra-locus
      rearrangements over the coding region of the vermilion gene was uniform with no
      preferences concerning 5' or 3' regions, certain exons, splice sites, specific
      amino acid changes or nonsense mutations. Possible hotspots for base
      substitutions seem to be related to the type of DNA damage rather than to the
      vermilion system. Gene mutations other than bp changes were examined on sequence
      characteristics flanking the deletion breakpoints. Induction frequencies of
      vermilion mosaic mutants were, in general, higher than those of vermilion
      complete mutants, suggesting that persistent lesions are the main contributors to
      the molecular spectra. Comparison of induction frequencies of vermilion mutants
      and sex-linked recessive lethal (SLRL) mutants for the 18 mutagens showed that
      the sensitivity of the vermilion gene against a mutagenic insult is
      representative for genes located on the X-chromosome. The effect of nucleotide
      excision repair (NER) on the formation of SLRL mutants correlated with an
      increase of transversions in the vermilion spectra under NER deficient
      conditions. Furthermore, the clastogenic potency of the mutagens, i.e., the
      efficiency to induce chromosomal-losses vs. SLRL forward mutations, shows a
      positive correlation with the percentage of DNA deletions in the molecular
      spectra of vermilion mutants.

PMID- 10656486
TI  - Starvation-associated mutagenesis in yeast Saccharomyces cerevisiae is affected
      by Ras2/cAMP signaling pathway.
AB  - The number of revertants with restored ability to form colony increases in a time
      dependent manner during long-term selective starvation of dense mutant microbial
      cultures. This is due to starvation-associated (also called adaptive) mutations
      that arise in a replication independent manner. Here we report that in
      Saccharomyces cerevisiae the frequency of starvation-associated reversions of
      mutant genes whose products are necessary for amino acids biosynthesis are
      influenced by Ras2/cAMP signaling pathway. This signaling pathway is a yeast
      general regulatory pathway involved in nutritional sensing, UV response,
      sporulation control and life span control and its changes are manifested in both,
      cell cycle and life cycle. Inactivation of the RAS2 gene causes an increase in
      number of starvation-associated revertants in comparison to an isogenic wild type
      strain and a strain with constitutively activated Ras2/cAMP signaling pathway.
      Therefore, we suggest that starvation-associated mutagenesis is different from
      spontaneous mutagenesis and is related to the cellular capacity to adopt distinct
      physiological states in response to environmental signals.

PMID- 10656487
TI  - Influence of nucleotide excision repair and of dose on the types of vermilion
      mutations induced by diethyl sulfate in postmeiotic male germ cells of
      Drosophila.
AB  - The role of a defect for nucleotide excision repair (NER) in oocytes on the
      repair of DNA ethyl adducts induced by diethyl sulfate (DES) in male germ cells
      of Drosophila was analysed. Frequencies of mutations at multiple loci (recessive
      lethal mutations) and at the vermilion gene induced in NER+ conditions (cross
      NER+ x NER+) were compared with those fixed in a NER- background (NER- x NER+).
      The M(NER-)/M(NER+) mutability ratios for two DES concentrations, 10 mM and 15
      mM, were 2.21 and 1.49, respectively, indicating that NER repairs part of the DES
      induced damage. The majority of 28 fertile vermilion mutations produced by DES in
      NER- are transitions, both GC-AT (46.4%) and AT-GC (21.4%) transitions are found,
      the consequences of O6-ethylguanine and O4-ethylthymine, respectively.
      Transversions (21.5%), one +1 frameshift mutation (3.6%) and two deletions (7.1%)
      are most likely the result of N-alkylation damage. Furthermore, the DES-induced
      mutation spectra show interesting differences in relation to the exposure dose.
      All 10 mutants isolated in this and a previous [L.M. Sierra, A. Pastink, M.J.M.
      Nivard, E.W. Vogel, DNA base sequence changes induced by DES in postmeiotic male
      germ cells of Drosophila melanogaster, Mol. Gen. Genet. 237 (1993) 370-374] study
      from experiments with low DES-effectiveness are exclusively transitions,
      independent whether the females were of the NER+ or NER-genotype. This indicates
      that at lower DES effectiveness only O-alkylation damage is relevant, and that N
      alkylation damage is repaired. In experiments revealing high DES-effectiveness,
      vermilion mutations representing N-alkylation damage reached 43% (9/21) with NER-
      and 26% (7/27) with NER+ females, suggesting (i) that NER becomes involved at
      high adduct levels because then the base excision repair (BER) may be saturated,
      and (ii) that this involvement of NER causes the relative decrease from 43% to
      26% N-alkylation mediated sequence changes.

PMID- 10656488
TI  - Chemical carcinogenicity: can it be predicted from knowledge of mutagenicity and
      allergic contact dermatitis?
AB  - We investigated the suggestion [R.E. Albert, Environ. Health Perspect. 105 (1997)
      940-948.] that results of mutagenicity testing in Salmonella combined with
      allergic contact dermatitis (ACD) testing in humans would be predictive of
      carcinogenicity in rodents. Using the cancer bioassay results of the US National
      Toxicology Program (NTP), Salmonella mutagenicity tests and a highly predictive
      structure-activity relational model of ACD, we conclude that the combination is
      not more predictive than the results of the Salmonella mutagenicity assay alone.

PMID- 10656489
TI  - 5-methylcytosine at HpaII sites in p53 is not hypermutable after UVC irradiation.
AB  - Using a yeast based p53 functional assay we previously demonstrated that the UVC
      induced p53 mutation spectrum appears to be indistinguishable from the one
      observed in Non Melanoma Skin Cancer (NMSC). However, position 742 (codon 248,
      CpG site) represented the major hot spot in NMSC but was not found mutated in the
      yeast system. In order to determine whether UVC-induced mutagenic events may be
      facilitated at methylated cytosine (5mC), a yeast expression vector harbouring a
      human wild-type p53 cDNA (pLS76) was methylated in vitro by HpaII methylase.
      Methylation induced 98% protection to HpaII endonuclease. Unmethylated and
      methylated pLS76 vectors were then UVC irradiated (lambda(max): 254 nm) and
      transfected into a yeast strain containing the ADE2 gene regulated by a p53
      responsive promoter. The results revealed that: (i) 5mC at HpaII sites did not
      cause any difference in the UVC-induced survival and/or mutagenicity; (ii) none
      of the 20 mutants derived from methylated pLS76 showed p53 mutations targeted at
      HpaII sites; (iii) the UVC-induced p53 mutation spectra derived from methylated
      and unmethylated pLS76 were indistinguishable not only when classes of mutations
      and hot spots were concerned, but also when compared through a rigorous
      statistical test to estimate their relatedness (P = 0.85); (iv) the presence of
      5mC did not increase the formation of photo-lesions at codon 248, as determined
      by using a stop polymerase assay. Although based on a limited number of mutants,
      these results suggest that the mere presence of 5mC at position 742 does not
      cause a dramatic increase of its mutability after UVC irradiation. We propose
      that position 742 is a hot spot in NMSC either because of mutagenic events at 5mC
      caused by other UV components of solarlight and/or because not all the NMSC are
      directly correlated with UV mutagenesis but may have a "spontaneous" origin.

PMID- 10656490
TI  - Induction of multiple microtubule-organizing centers, multipolar spindles and
      multipolar division in cultured V79 cells exposed to diethylstilbestrol,
      estradiol-17beta and bisphenol A.
AB  - Inducibility of multipolar spindles and multipolar division by diethylstilbestrol
      (DES) and estradiol-17beta (E2) was investigated in terms of the mechanism of
      induction of aneuploidy by the estrogens. DES, E2 and bisphenol A (Bp-A), a
      structural analogue of DES, caused mitotic arrest and aberrant spindles, such as
      tripolar and multipolar spindles, in a concentration-dependent manner. Gamma
      tubulin, a well-characterized component of microtubule-organizing centers
      (MTOCs), was co-localized with the aberrant spindles induced by estrogens and Bp
      A. The number of gamma-tubulin signals in the mitotic cells coincided with that
      of the aberrant spindles and rose with an increasing concentration of the
      chemicals. The incidence and location of gamma-tubulin in interphase cells were
      not influenced by the chemicals. These results suggest that multiple MT
      nucleating sites were induced by the estrogens and Bp-A during the transition
      from interphase to the mitotic phase. DES, E2 and Bp-A induced multipolar
      division in a concentration-dependent process associated with the induction of
      aneuploidy.

PMID- 10656491
TI  - Cytogenetic damage and ras p21 oncoprotein levels from patients with chronic
      obstructive pulmonary disease (COPD), untreated lung cancer and healthy controls.
AB  - The purpose of the present communication was to determine in patients with
      chronic obstructive pulmonary disease (COPD), untreated lung cancer and healthy
      controls if there was a possible association between the disease state and
      biomarkers of cytogenetic damage and ras p21 oncoprotein levels, and if various
      exogenous confounding factors such as smoking habit and endogenous ones (sex,
      cancer in the immediate family) could affect these biomarkers. The individuals in
      all groups were as well-matched as possible for age to determine if this could be
      eliminated as a confounder. Peripheral blood and plasma were collected from 20
      COPD patients, 31 cancer patients and 20 healthy controls. Chromosomal
      aberrations (CA), sister chromatid exchanges (SCE) and high frequency SCE cells
      (HFC) were examined from the blood and ras p21 oncoproteins from the plasma.
      These parameters were used as biomarkers of genotoxic anomalies. All the
      biomarkers were examined for their relationship to the confounding factors.
      Results were analysed by a t-test, analysis of variance (ANOVA) and stepwise
      multivariate regression analysis. There was an increase in CA, although not
      statistically so, in COPD and cancer patients by comparison with healthy
      controls, but there was a statistically significant increase in SCE, HFC and ras
      p21 oncoproteins. There was also a statistically significant difference between
      respiratory volume parameters in COPD patients and controls. Respiratory
      parameters were not measured in cancer patients. Ras p21 oncoproteins were also
      statistically significantly increased in the COPD and cancer patients, suggesting
      that the disease state alone might be sufficient to increase the oncoproteins, or
      that some of the COPD patients were in the process of developing cancer or
      perhaps some would die from COPD before cancer developed. Smoking was shown to
      have a marked effect on all parameters investigated. Ex-smokers showed less
      effects. Since age was very well controlled, there was little effect due to age.
      There was an effect due to sex, but cancer in the immediate family had little
      effect on any of the parameters.

PMID- 10656492
TI  - Apoptosis and catastrophic cell death in benzo[a]pyrene-transformed human breast
      epithelial cells.
AB  - Apoptosis and mitotic death, bi- and multinucleation, giant cells and
      micronucleation were investigated in human breast epithelial cell lines
      transformed by benzo[a]pyrene (BP) (BP1, BP1-E and BP1-E1 cells) and in BP1 cells
      transfected with the c-Ha-ras oncogene (BP1-Tras cells). Since BP induces
      apoptosis and the abnormal expression of ras genes elicits catastrophic mitosis,
      both cell death phenomena were expected to occur in this system, especially in
      BP1-Tras cells. Regardless of the cell line considered, single-nucleate cells
      were found to be eliminated preferentially through apoptosis, while bi- and
      multinucleate cells were eliminated through catastrophic mitosis. Apoptosis and
      catastrophic mitosis were observed in all cell lines but were significantly more
      frequent in BP1-Tras cells. The abnormal expression of Ha-ras in the latter cells
      may enhance in this system the effects of the BP apoptosis path reported for BP
      transformed Hepa 1c1c7 hepatoma cells. Transfection with the ras oncogene also
      enhanced the mitotic disturbances, which produced multi- and micronucleation and
      mitotic death, possibly because of the genomic instability promoted by this
      oncogene in the BP-transformed cell line.

PMID- 10656493
TI  - A novel method for the parallel monitoring of mitotic recombination and
      clastogenicity in somatic cells in vivo.
AB  - Both homologous mitotic recombination (HMR), causing loss of heterozygosity (LOH)
      of the wild-type allele, and structural chromosome aberrations (CA) involve the
      formation of double-strand breaks in DNA. Whether the induction of CAs is always
      accompanied by HMR, or whether there exist DNA lesions specifically forming only
      one of the two end-points is unknown. Answering this fundamental question
      requires a system for the parallel detection of CAs and HMR, because only then is
      their analysis under strictly identical condition (dose, repair, genetic
      background) possible. We describe here a novel system for the parallel detection
      of HMR and loss of a whole chromosome as a measure of CA, utilizing somatic cells
      of Drosophila. In haploid germ cells of Drosophila, loss of a ring-shaped X
      chromosome (rX) constitutes a frequent event providing an efficient method for
      measuring clastogenicity. For somatic cells, however, it was unclear whether the
      development of such a system would be feasible. The generally accepted notion has
      been that in XX female genotypes, loss of an entire X-chromosome acts as a cell
      lethal when generated at or shortly after blastoderm stage. However, here we show
      that rX-loss, if induced in pre-ommatidia cells of 3rd instar larvae, generates
      viable clones visible as small white patches in the red compound eye. To set up
      optimal conditions for the detection and quantification of rX-loss compared to
      HMR, several protocols were developed and tested against model carcinogens
      (methyl methanesulfonate, cisplatin and 7,12-dimethylbenz[a]anthracene).
      Generally, we find striking differences in the efficiency of these carcinogens
      for recombination when compared with clastogenicity. The cross-linking agent
      cisplatin is 4- to 6-fold more clastogenic than recombinagenic. 7,12
      Dimethylbenz[a]-anthracene, on the contrary, produced less than a doubling effect
      for rX-loss but was highly active (20-times the background) for HMR. It appears
      therefore that both processes can be separated from each other. To the best of
      our knowledge, this is the first report suggesting, in terms of DNA adducts
      involved, qualitative differences between homologous recombination and
      clastogenic effects. Application of our system for studies on DNA repair may
      therefore provide new insight into the linkage of repair pathways in either of
      the two mechanisms.

PMID- 10656494
TI  - REV3 is required for spontaneous but not methylation damage-induced mutagenesis
      of Saccharomyces cerevisiae cells lacking O6-methylguanine DNA methyltransferase.
AB  - O6-methylguanine (O6-MeG) DNA methyltransferase (MTase) removes the methyl group
      from a DNA lesion and directly restores DNA structure. It has been shown
      previously that bacterial and yeast cells lacking such MTase activity are not
      only sensitive to killing and mutagenesis by DNA methylating agents, but also
      exhibit an increased spontaneous mutation rate. In order to understand molecular
      mechanisms of endogenous DNA alkylation damage and its effects on mutagenesis, we
      determined the spontaneous mutational spectra of the SUP4-o gene in various
      Saccharomyces cerevisiae strains. To our surprise, the mgt1 mutant deficient in
      DNA repair MTase activity exhibited a significant increase in G:C-->C:G
      transversions instead of the expected G:C-->A:T transition. Its mutational
      distribution strongly resembles that of the rad52 mutant defective in DNA
      recombinational repair. The rad52 mutational spectrum has been shown to be
      dependent on a mutagenesis pathway mediated by REV3. We demonstrate here that the
      mgt1 mutational spectrum is also REV3-dependent and that the rev3 deletion
      offsets the increase of the spontaneous mutation rate seen in the mgt1 strains.
      These results indicate that the eukaryotic mutagenesis pathway is directly
      involved in cellular processing of endogenous DNA alkylation damage possibly by
      the translesion bypass of lesions at the cost of G:C-->C:G transversion
      mutations. However, the rev3 deletion does not affect methylation damage-induced
      killing and mutagenesis of the mgt1 mutant, suggesting that endogenous alkyl
      lesions may be different from O6-MeG.

PMID- 10656495
TI  - Sequence specificity of Hprt lymphocyte mutation in rats fed the hepatocarcinogen
      2-acetylaminofluorene.
AB  - Rats fed the hepatocarcinogen 2-acetylaminofluorene (2-AAF) have a low, but
      significantly increased, frequency of lymphocyte Hprt mutants. In this study,
      mutants from 2-AAF-fed and control F344 rats were examined for mutations in the
      Hprt gene in order to determine if the 2-AAF treatment resulted in an agent
      specific mutation profile. The most common mutation from 2-AAF-treated rats was
      G:C-->T:A transversion (32% of all mutations) followed by 1-basepair (bp)
      deletion (19%); there were very few (5%) G:C-->A:T transitions. Among mutations
      from control rats, G:C-->A:T transition was the most common (43%), and there were
      very few G:C-->T:A transversions (5%) and no 1-bp deletions. The profile of
      mutations from 2-AAF-fed rats was significantly different from control rats (P =
      0.003) and was consistent with the types of mutations produced by 2-AAF in vitro.
      The results of this study indicate that even weak mutational responses in the
      lymphocyte Hprt assay are capable of producing mutation profiles that reflect the
      DNA damage inducing them.

PMID- 10656496
TI  - HRT and breast cancer risk: a clue for interpreting the available data.
AB  - Epidemiological and biological data on HRT and breast cancer risk are reviewed.
      Some aspects deserve consideration. (1) The majority of epidemiological data have
      been gathered from populations where high estrogen doses (> or = 1.25 mg daily of
      conjugated estrogens) were used as first line therapy. (2) HRT does not increase
      the risk in overweight women, even in the series in which a risk increase (in
      longterm users) is found. This could be as a result of the fact that oral
      estrogens, through their metabolic and hepatocellular effects, reverse some
      biological features of obesity (e.g. increased insulin-like growth factor I
      activity and decreased sex hormone binding globulin level) which potentially
      increase breast cancer risk, so balancing the estrogen stimulation. (3) The
      progestin addition seems to increase the risk when the 19 nor-testosterone
      derivatives are used. These androgenic compounds contrast the metabolic and
      hepatocellular effects of oral estrogens. To sum up, the possibility does exist
      that even the longterm use of oral estrogens at the right ('low') dose, with the
      addition of a non-androgenic progestin, will be shown to be associated with a
      very limited breast cancer risk increase.

PMID- 10656497
TI  - Postmenopausal hormone replacement in the woman with a reproductive risk factor
      for breast cancer.
AB  - OBJECTIVE: to assess the interaction between postmenopausal hormone replacement
      therapy (HRT) and various reproductive risk factors for breast cancer such as
      early menarche, late menopause, late first delivery and nulliparity. DESIGN:
      three cohort studies and fourteen case control studies, published between 1975
      and 1997, provided relative risks (RRs) of HRT use in women with, as well as in
      those without, a reproductive risk factor for breast cancer. METHODS: using an
      additive RR model reported before, we investigated whether the RR for breast
      cancer in women with a combination of HRT and a given reproductive risk factor
      result from a simple addition of RRs of HRT on the one hand, and of the pre
      existing reproductive risk factor on the other hand, or that synergism between
      both risk factors occurs. RESULTS: simple addition of RRs was shown in the case
      of early menarche and late menopause. Less increase of risk, suggesting
      antagonism, was found for both late first delivery and nulliparity in combination
      with HRT use. CONCLUSION: we could not observe any synergistic effect of the
      combined risks of any of the following reproductive risk factors for breast
      cancer: early menarche, late menopause, late first delivery or nulliparity on the
      one hand, with the risk resulting from HRT use on the other hand. Therefore, as
      far as the risk of breast cancer is concerned, the use of HRT appears not to be
      highly detrimental in women with a reproductive breast cancer risk factor, as it
      results in not more than a simple addition of risks at the most.

PMID- 10656498
TI  - Recommendations for estrogen and progestin replacement in the climacteric and
      postmenopause. European Progestin Club.
AB  - The diversity of function that sex steroids have proven to have in the female
      body, gives them a position of central importance in gynaecology. Scientific
      research demonstrates not only the well known genital functions of sexual
      steroids, furthermore, various extragenital organs are influenced and modulated
      by ovarian hormones. Therefore, the general benefit of HRT for the female
      organism becomes clearer and the clinical management of menopause is developing
      to a broad new discipline, the gender specific medicine. In clinical practise,
      phytosteroids are claimed by the patient and therefore, also of high interest for
      the scientific research. Also, tissue specificity of the endocrine treatment and
      the biological relevance of different steroid receptors of HRT are discussed,
      leading to the development of new HrT preparations. Individualisation, the
      tailoring of HRT, according to the patients needs, and low dose steroids
      management, will also become an important aspect in the recommendations for
      estrogen and progestin replacement therapy.

PMID- 10656499
TI  - Active lifestyle offsets HRT-induced suppression of T cell reactivity to
      mitogens.
AB  - OBJECTIVE: The purpose of the study was to investigate the combined impact of
      hormone replacement therapy (HRT) and active lifestyle on the phenotypic profile
      and in vitro activities of specific immune cells in postmenopausal women.
      METHODS: Healthy postmenopausal women aged 45-70 were assigned to one of four
      groups: (a) HRT/sedentary (n = 9); (b) HRT/active (n = 12); (c) no HRT/sedentary
      (n = 10); and (d) no HRT/active (n = 9). Blood samples were collected from each
      subject on 3 days within 1 week. The mean value of three samples was used to
      assess the in vitro response of T lymphocytes to the mitogens phytohemagglutinin
      and concanavalin A and natural killer cell activity. One of three blood samples
      was utilized for phenotypic analysis of circulating leukocytes. RESULTS: The
      mitogenic reactivity of T lymphocytes in whole blood cultures for the groups
      receiving HRT was lower than from the groups not receiving HRT. There also was a
      trend for T lymphocyte reactivity to be higher in the active women when compared
      to the sedentary women. In contrast, the phenotypic profile of leukocytes and
      natural killer cell activity were not significantly different for samples
      collected from the four groups. CONCLUSIONS: These data suggest that the
      suppressive effect of HRT on T cell function in postmenopausal women may be
      attenuated by a physically active lifestyle.

PMID- 10656500
TI  - Menopausal symptoms and symptom clustering in Chinese women.
AB  - OBJECTIVES: this paper aims to report the prevalence of symptoms in the Hong Kong
      Chinese perimenopausal women; to construct reported symptoms into symptom
      groupings; and to clarify whether the symptom groups are associated with
      menopausal status. METHODS: a random telephone survey of perimenopausal women
      aged 44-55 years was conducted in 1996. Eligible subjects were identified through
      telephone dialing of a random sample of the numbers listed in the residents'
      telephone directory. Standardized questionnaire, including a 22-item symptom
      check list, was administered over the telephone. The principal component analysis
      method followed by varimax rotation was used to examine the relations among the
      symptoms. RESULTS: differences in the prevalence of menstrual problems across the
      menopausal status were noted with perimenopausal women having the most
      complaints. Musculoskeletal conditions were the top complaints reported by the
      respondents, followed by headaches and psychological symptoms. About 10% of the
      women complained of hot flushes, and less than 5% of cold sweats. Five symptom
      clusters, namely psychological, musculoskeletal/gastrointestinal, non-specific
      somatic, respiratory, and vasomotor, have been identified. After adjustment for
      age, the analysis of variance showed that psychological, non-specific somatic and
      vasomotor symptoms were significantly associated with menopausal status, while
      musculoskeletal and respiratory were of borderline statistical significance.
      CONCLUSIONS: compared with pre- and post-menopausal women, perimenopausal women
      had the highest reports of symptom complaints. Musculoskeletal complaints were
      the most prevalent complaints, followed by psychological symptoms. While
      vasomotor symptoms were significantly associated with menopausal status, their
      prevalence was comparatively lower than that reported in Caucasian populations.

PMID- 10656501
TI  - Prevalence of postmenopausal symptoms in two age groups of elderly women in
      relation to oestrogen replacement therapy.
AB  - A cross-sectional study of the whole female population of ages 71 and 81 years in
      a defined part of Sweden was undertaken to investigate the prevalence of
      oestrogen treatment and postmenopausal symptoms. A questionnaire was mailed to
      2245 women, of whom 1084 (87%) aged 71 years and 611 (62%) aged 81 years left
      evaluable responses. Of the responding 71- and 81-year-old women 25 and 16%,
      respectively were receiving oestrogen, and 4 and 2% of all women of the
      respective age groups were on systemic treatment. Nearly half of all the women
      reported urinary incontinence, which was considerate for approximately half of
      these women. Five and 11% of the respective age groups had experienced more than
      two urinary tract infections (RUTI) in the last year. RUTI had occurred both in
      the oestrogen-treated group and in the non-treated group. Vegetative symptoms
      were still encountered among these elderly women. Previous fractures were
      frequent, being experienced after menopause by 29 and 39% of the 71- and 81-year
      old women respectively. Thirty-five and 39% of the women in respective age group
      had sought medical help for postmenopausal symptoms. Of the women with moderate,
      severe or unbearable urinary incontinence, 60 and 66% of the respective age
      groups had sought medical help. In only few of the totals of women on oestrogen
      had the treatment a complete effect. Only 2 and 1% of all women in respective age
      group had been offered and undergone surgery for their urinary incontinence.

PMID- 10656502
TI  - Effects of postmenopausal hypoestrogenism on skin collagen.
AB  - OBJECTIVE: The aim of our study was to evaluate the effect of aging and
      postmenopausal hypoestrogenism on skin collagen content. METHODS: Thirty-two
      women (mean age 48.78 +/- 9.86; year +/- S.D., range 28-68), 14 in premenopause
      and 18 in postmenopause, underwent skin biopsies performed during laparotomic
      operation. The amount of collagen type I, III and type III/type I ratio was
      evaluated by immunohistochemistry and computerised image analysis, and was
      related to age and years of postmenopause. RESULTS: In the postmenopausal
      patients, a significant (P < 0.01) decrease of percentage of skin collagen type
      I, type III and type III/type I ratio was observed in comparison to premenopausal
      women. The percentages of collagen type I, type III and type III/I ratio of all
      patients studied was significantly (P < 0.01) correlated with chronological age
      (r = 0.88, 0.89 and 0.61, respectively). Considering only postmenopausal
      subjects, the correlation with chronological age was significant (P < 0.01) for
      collagen type I and type III of postmenopausal women (r = 0.59, r = 0.64,
      respectively), but not for the type III/I ratio (r = 0.37, P = 0.131). The
      percentages of collagen type I, type III and type III/I ratio of postmenopausal
      women showed a significant (P < 0.01) inverse correlation with years of
      postmenopause (r = 0.76, 0.73 and 0.73, respectively). CONCLUSIONS: Our data
      suggest that the decrease of skin collagen is an estrogen-related phenomenon.

PMID- 10656503
TI  - Symptom reporting around the menopause in Beirut, Lebanon.
AB  - OBJECTIVES: to assess the extent to which women in Beirut suffer from symptoms in
      the course of the menopause transition, and to measure the medical management of
      menopause. METHODS: a survey was carried out on a representative sample of 298
      women; the questionnaire collected information on respondents' sociodemographic
      characteristics, life circumstances, general health, and reproductive health; it
      also included a symptom checklist, questions on the management of menopausal
      symptoms, and lifestyle questions. RESULTS: the article documents the frequencies
      of various symptoms associated with aging and menopause; the number of symptoms
      reported by respondents is negatively associated with employment, but other
      associations with sociodemographic variables are not significant; smoking is
      found to be high in the study population and is associated with the occurrence of
      hot flashes, but its association with other menopausal symptoms is not
      significant; over a third of the women seek help in dealing with the symptoms
      they experience, 15% use hormone replacement therapy, and 20% use calcium
      supplements.

PMID- 10656504
TI  - Effects of menopause and hormone replacement therapy on plasma lipids,
      lipoproteins and LDL-receptor activity.
AB  - A cross-sectional study of ninety six women was conducted to examine the effect
      of menopause and hormone replacement therapy (HRT) on plasma lipids, lipoproteins
      and oxidation of low density lipoproteins. The sample consisted of 26
      premenopausal women, 26 postmenopausal women taking no replacement hormones and
      43 postmenopausal women on hormone replacement therapy. Postmenopausal women not
      taking replacement hormones had significantly higher plasma cholesterol, low
      density lipoprotein (LDL) cholesterol and lipoprotein[a] (Lp[a]) levels compared
      to premenopausal women or postmenopausal women on HRT [6.00 +/- 0.15, 5.36 +/-
      0.17 (P < 0.01), 5.63 +/- 0.13 (P < 0.05) mmol/l, respectively for total
      cholesterol; 4.13 +/- 0.15, 3.64 +/- 0.15 (P < 0.05), 3.82 +/- 0.12 (P < 0.05)
      mmol/l, respectively for LDL-cholesterol; 48.19 +/- 9.90, 26.59 +/- 5.53 (P <
      0.03), 25.12 +/- 4.62 (P < 0.03) mg/dl, respectively for Lp[a]]. The differences
      in LDL cholesterol concentrations were inversely related to changes in LDL
      receptor activity (r = -0.27, P < 0.01). HRT use was found to be associated with
      a significantly smaller LDL particle size. Plasma triglyceride was significantly
      higher in women on HRT (1.16 +/- 0.07 mmol/l) than in the premenopausal group
      (0.96 +/- 0.07) or postmenopausal group not using HRT (0.87 +/- 0.06). There were
      no differences in LDL oxidation between the groups when LDL was oxidised in the
      presence of copper. Nor was there any difference in the uptake of copper-oxidised
      or macrophage-modified LDL into J774 macrophages. These results confirm the
      effect of menopause and exogenous hormones on plasma lipids and lipoproteins, and
      suggest that HRT modifies the activity of the LDL receptor. Hormone replacement
      did not appear to protect LDL from oxidation.

PMID- 10656505
TI  - Mismatch negativity (MMN) as a tool for investigating auditory discrimination and
      sensory memory in infants and children.
AB  - For decades behavioral methods, such as the head-turning or sucking paradigms,
      have been the primary methods to investigate auditory discrimination, learning
      and the function of sensory memory in infancy and early childhood. During recent
      years, however, a new method for investigating these issues in children has
      emerged. This method makes use of the mismatch negativity (MMN), the brain's
      automatic change-detection response, which has been used intensively in both
      basic and clinical studies in adults for twenty years. This review demonstrates
      that, unlike many other components of event-related potentials, the MMN is
      developmentally quite stable and can be obtained even from pre-term infants.
      Further, MMN amplitude is only slightly smaller in infants than is usually
      reported in school-age children and it does not seem to differ much from that
      obtained in adults. MMN latency has been reported to be slightly longer in
      infants than in adults but reaches adult values by the early school-age years.
      Child MMN does not seem to be analogous to adult MMN, however. For example,
      contrary to the results of adult studies, a prominent MMN can be obtained from in
      all waking- and sleep states in infants. Moreover, MMN scalp distribution seems
      to be broader and more central in children than in adults.

PMID- 10656506
TI  - Quantitative sensory testing: effect of site and skin temperature on thermal
      thresholds.
AB  - OBJECTIVE: To determine the effect of different sites and local skin temperature
      on thermal thresholds. METHODS: Cool and warm detection and cold and heat pain
      thresholds were compared in 46 normal volunteers at the thenar eminence (TE),
      dorsum of the hand (DH), volar surface of the wrist (VW) and dorsum of the foot
      (DF). RESULTS: The hand is more sensitive than the foot for cool and warm. TE is
      more sensitive for warm than DH and VW but the difference is clinically
      negligible. DH and VW are equally sensitive to warm. TE, DH, and VW are equally
      sensitive to cool. Inter-individual variance is smallest at TE. Warm and cool
      thresholds are independent of local skin temperature (range of 27-37 degrees C).
      TE is less sensitive for cold pain but otherwise the hand and the foot are
      equally sensitive to thermal pain. CONCLUSION: Testing of thermal thresholds in
      normal subjects can be adequately conducted at several sites at the hand,
      however, TE is preferred given the small inter-individual variability. TE may be
      preferred for evaluating hyperalgesia to cold given its higher threshold. Warming
      or cooling of the skin is unnecessary within the range normally encountered in
      routine clinical evaluation.

PMID- 10656507
TI  - Reproducibility of indices of axonal excitability in human subjects.
AB  - OBJECTIVES: Different indices of axonal excitability are now being measured in
      human subjects, both normal volunteers undergoing some test manoeuvre and
      patients with a variety of peripheral nerve disorders. The reproducibility of
      these indices has not previously been established, and was determined for
      cutaneous afferents in the median nerve of 12 healthy subjects, using threshold
      tracking techniques. METHODS: Refractoriness and supernormality were determined
      as the change in stimulus current required to produce a predetermined target
      potential when conditioned by a supramaximal stimulus at appropriate conditioning
      test intervals. Strength-duration time constant was calculated from the threshold
      currents using unconditioned test stimuli of 0.1 ms and 1.0 ms. The effects of
      changes in membrane potential on these indices was assessed by applying
      subthreshold DC currents (from 50% depolarizing to 50% hyperpolarizing), using
      the reciprocal of threshold (i.e., 'excitability') as an indicator of membrane
      potential. The intraindividual reproducibility was determined by repeating the
      study on each subject up to 10 times. RESULTS: Refractoriness and supernormality
      were variable between subjects (mean +/- SD of 31.5 +/- 9.5% and 13.2 +/- 3.8%,
      respectively) and within subjects (coefficient of variation 0.2104 and 0.21849,
      respectively). TauSD showed even greater interindividual variability (499.2 +/-
      115 micros) and intraindividual variability (coefficient of variation 0.2339).
      The slopes of relationships between each of the indices and axonal 'excitability'
      suggest that refractoriness is extremely sensitive to changes in excitability
      (0.9767 +/- 0.1907), tauSD less so (0.3766 +/- 0.1322), supernormality least
      (0.2223 +/- 0.1268). CONCLUSIONS: Under controlled conditions, refractoriness is
      the most sensitive and least variable of the indices of axonal excitability.
      However, small decreases in temperature greatly increase refractoriness but have
      little effect on tauSD. Given that 3 indices reflect different biophysical
      mechanisms, nodal and internodal, greater insight into the functional state of
      peripheral nerve axons will come when there are coherent changes in all 3
      indices.

PMID- 10656508
TI  - Predictive value of novel stimuli modifies visual event-related potentials and
      behavior.
AB  - OBJECTIVE: We examined how behavioral context influences novelty processing by
      varying the degree that a novel event predicted the occurrence of a subsequent
      target stimulus. METHODS: Visual event-related potentials (ERPs) and reaction
      times (RTs) were recorded in 3 detection experiments (23 subjects). The
      predictive value of a novel stimulus on the occurrence of a subsequent target was
      varied as was novel-target pairing intervals (200-900 ms). In Experiment 1, novel
      stimuli always preceded a target, in Experiment 2, 40% of novel stimuli were
      followed by a target, and in Experiment 3, novel stimuli occurred randomly.
      RESULTS: In Experiment 1, RTs following 100% predictive novels were shortened for
      targets at all spatial locations and novel-target pairing intervals. Novel
      stimuli predicting a target generated a central negativity peaking at 300 ms and
      reduced P3a and P3b ERPs. In Experiments 2 and 3, target RTs were prolonged only
      when novel and target stimuli were presented in the same spatial location at
      short ISIs (200 ms). The central novel N2 was smaller in amplitude in comparison
      to Experiment 1, and novelty P3a and target extrastriate N2 and posterior scalp
      P3b ERPs were enhanced. CONCLUSIONS: The enhanced N2 for 100% predictive novel
      stimuli appears to index an alerting system facilitating behavioral detection.
      The same novel stimuli with no predictive value distract attention and generate a
      different ERP pattern characterized by increased novelty P3a and target P3b
      responses. The results indicate that behavioral context determines how novel
      stimuli are processed and influence behavior.

PMID- 10656509
TI  - Latency shifts in the N2b component track phonological deviations in spoken
      words.
AB  - OBJECTIVE: We investigated event-related brain potentials (ERPs) elicited by a
      novel speech comprehension paradigm modelled after the neuropsychological Token
      Test. The objective of the study was to determine whether the ERPs were sensitive
      to differences in the initial phonemes of the speech stimuli. METHODS: Twenty
      seven healthy subjects identified incorrect spoken sentences on the computerised
      Token Test (CTT). The incorrect spoken sentences contained one word that did not
      match the previously studied animations. The initial phonemes of these words were
      either different than or similar to the initial phonemes of their correct
      counterparts. RESULTS: Different initial phonemes were associated with an early
      N2b, while words having similar initial phonemes resulted in a substantially
      delayed N2b. CONCLUSION: The delayed latency effect was due to whether the
      incorrect word's initial phoneme matched or mismatched that of the expected word.
      In both cases, this component reflected a mismatch with an existing cognitive
      template maintained in phonological working memory. The results indicate that
      this mismatching effect reflected primarily attentional detection rather than
      language processing.

PMID- 10656510
TI  - Stability of mismatch negativities in children.
AB  - OBJECTIVES AND METHODS: Mismatch negativities (MMN) to frequency and duration
      changes in a series of repetitive tones and to two different consonant-vowel
      syllables (ba and ga, standard da) were recorded in a test and retest session in
      15 children aged 7-11 years. Reliability within one session and stability between
      the sessions of MMN amplitudes and the ERP-components P1 and N1 were determined
      by correlation coefficients. RESULTS: Mean amplitudes of the grand averages
      showed a decrease of MMN during the second test session in a late latency window
      (400-500 ms) for the frequency MMN and of the MMN elicited by speech stimuli. The
      individual stability reached significance only for the duration deviant and one
      of the syllables. Compared to results found in adults with similar stimulus
      conditions the stability of the MMN in children seems to be somewhat lower. The
      components P1 and N1 to both stimulus types (tone and speech), however, showed a
      high reliability and individual stability. CONCLUSION: While MMN is a useful tool
      to study processing deficits in groups of children, as e.g. in language-impaired
      children, MMN as a individual diagnostic measure should be interpreted very
      cautiously.

PMID- 10656511
TI  - The correction of ocular artifacts: a topographic perspective.
AB  - OBJECTIVE: To evaluate the scalp topography of the potentials related to saccades
      and blinks. METHODS: The scalp topographies of the potentials associated with
      saccades and blinks were recorded in 60 subjects. The topographies were analyzed
      using both source components and attenuation factors, with each factor
      representing the fraction of the potential recorded in peri-ocular electrodes
      that contributes to the EEG recorded from a particular scalp location. RESULTS:
      Blinks and upward saccades generated potentials with very different topographies.
      Left and right saccades and up and down saccades generated equal but inverted
      fields except at peri-ocular locations where subtle inequalities occurred. The
      potentials associated with lateral saccades were consistently larger in female
      subjects than in male subjects. CONCLUSIONS: The differences in the scalp
      topographies between blinks and vertical saccades can be explained by the
      different ways in which they are generated. Blink potentials are caused by the
      eyelids sliding down over the positively charged cornea, whereas saccade
      potentials are caused by changes in the orientation of the corneoretinal dipole.
      Any compensation procedure for ocular artifacts must take into account the
      topographic differences between blinks and upward saccades.

PMID- 10656512
TI  - Visual contrast response functions in Parkinson's disease: evidence from
      electroretinograms, visually evoked potentials and psychophysics.
AB  - OBJECTIVES: Visual contrast detection thresholds and suprathreshold contrast
      discrimination thresholds were compared to luminance and flash/pattern
      electroretinograms (ERG) and visually evoked potentials (VEP) in patients with
      Parkinson's disease (n = 31), patients with multiple system atrophy (n = 6),
      patients with progressive supranuclear palsy (n = 6) and control patients without
      central nervous disease (n = 33). METHODS: The stimuli were luminance modulated
      full-field (flash) or horizontally oriented sinewave gratings (pattern), the
      latter having either a low (0.5 cycles/deg) or medium (4.0 cycles/deg) spatial
      frequency. Stimulus contrast ranged from 10 to 80% so that contrast response
      functions could be derived. RESULTS: Contrast thresholds were higher in the
      patients with Parkinson's disease than in the control patients. Contrast
      discrimination thresholds were also somewhat elevated in patients with
      Parkinson's disease. Pattern ERG amplitudes were significantly reduced in
      patients with Parkinson's disease for the medium spatial frequency stimulus, but
      less for the low spatial frequency and flash stimuli. CONCLUSIONS: Our results
      suggest that Parkinson's disease impairs contrast processing in the retina. VEP
      amplitudes did not significantly differ between the groups for the conditions
      tested. Patients with progressive supranuclear palsy also showed impaired
      contrast perception and reduced ERG amplitudes, whereas patients with multiple
      system atrophy were less impaired.

PMID- 10656513
TI  - Influence of pulse configuration and direction of coil current on excitatory
      effects of magnetic motor cortex and nerve stimulation.
AB  - This paper describes the influence of pulse configuration and current direction
      on the excitation of the hand-associated motor cortex and the median nerve by
      magnetic stimulation. Monophasic and biphasic current pulses with the same peak
      rise time of 80 micros and a maximum rate of current change (dI/dt) were
      discharged through an eight-shaped coil of the stimulator used (Dantec MagPro).
      Two current directions with opposite orientation in the coil axis were studied.
      FINDINGS: (1) for both, cortex and nerve stimulation, biphasic stimuli were more
      effective and elicited compound muscle action potentials (CMAPs) with lower
      thresholds and larger amplitudes. (2) Using biphasic pulses the direction of the
      currents in the first phase of the pulse did not influence the CMAP amplitude.
      (3) Using monophasic pulses induced currents oriented postero-anteriorly in the
      motor cortex or orthodromically along the nerve axis elicited larger CMAPs than
      currents in the opposite orientation. (4) Pulse configuration did not influence
      the CMAP-latencies and by this the stimulation site (cortex, nerve). CONCLUSION:
      Monophasic stimuli are useful to investigate excitation effects which are
      dependent on the current direction. The application of biphasic stimuli with
      their stronger excitation effects might be advantageous when patients with high
      cortical thresholds or deep lying nerves shall be investigated.

PMID- 10656514
TI  - High-resolution EEG mappings: a spherical harmonic spectra theory and simulation
      results.
AB  - Shown first is the equivalence between the multiple expansion (ME) of the brain
      electrical generator and the spherical harmonic spectra (SHS) of the potential
      generated by the electrical generator in an infinite volume conductor. Based on
      the equivalence, the SHS and the spatial filters which connect the SHS with the
      ME are deduced, in a concentric 3 sphere conductor and for the 5 EEG source
      mappings. They are cortical potential mapping (CPM), scalp Laplacian mapping
      (LM), pseudo-cortical potential mapping (PCPM), equivalent dipole layer mapping
      (EDM) and equivalent charge layer mapping (ECM). The theoretical simulation study
      of the spatial filters and mappings indicate that all 5 mappings provide higher
      resolution imaging maps of brain electrical activity than the scalp potential
      map. In the inverse problem, a spherical spline fit algorithm is provided to
      reconstruct the SHS of the scalp recording potential, and then the SHS and maps
      of the 5 mappings are reconstructed by utilizing the spatial filters and the SHS
      of the scalp potential. The results indicate that the correlativity order between
      a reconstructed map and the actual cortical potential map is CPM > or = EDM >
      PCPM > LM > ECM. An empirical VEP data study shows that any one of the 5 mappings
      also provides higher spatial resolution than the scalp potential map.

PMID- 10656515
TI  - P300 and blink instructions.
AB  - OBJECTIVES: The effects of instructions to refrain from blinking on the P300
      event-related brain potential (ERP) from auditory and visual stimuli were
      assessed. METHODS: An oddball paradigm was employed in which young adult subjects
      (n = 20) silently counted the infrequent target stimuli and were given either no
      instructions or told "do not blink" in different conditions, with auditory and
      visual stimulus tasks employed for all subjects. ERPs were recorded from the
      midline electrodes, with amplitude and latency of the P300 and other components
      obtained. RESULTS: P300 amplitude for both modalities and target/standard
      stimulus conditions was smaller and visual peak latency longer in the "do not
      blink" condition. Blink instructions did not directly affect the other
      components. CONCLUSIONS: Instructions to refrain from blinking can decrease P300
      amplitude and can increase peak latency.

PMID- 10656516
TI  - The impact of cyclic alternating pattern on heart rate variability during sleep
      in healthy young adults.
AB  - OBJECTIVE: Cyclic alternating pattern (CAP) consists of arousal-related phasic
      events while the complementary condition, non-CAP (NCAP), is characterized by a
      rhythmic background activity, reflecting a condition of stable arousal, during
      non-REM sleep. The arousal swings that accompany the appearance of CAP on the EEG
      are associated with transient variations of muscle tone and autonomic activities,
      including heart rate (HR). The aim of our study was to evaluate HR variability in
      relation to CAP during non-REM sleep in healthy adults. METHODS: Ten healthy
      subjects (mean age = 28.1 years) underwent 8 h polysomnography. HR variations
      were measured by power spectrum analysis. The ECG signals were segmented in
      correspondence of the different sleep stages and different CAP conditions.
      RESULTS: A significant difference between CAP and NCAP conditions was found in
      low frequency (LF) component (increased in CAP) and high frequency (HF) component
      (decreased in CAP). LF/HF ratio was increased in CAP. CONCLUSION: Physiological
      fluctuations of the EEG arousal level influence cardiac autonomic activity in
      normal subjects. The studies on nocturnal variation in sympathetic and vagal tone
      should take in account the microstructural sleep changes, other than the
      conventional polysomnographic parameters.

PMID- 10656517
TI  - Electroencephalogram of asymptomatic adult subjects.
AB  - OBJECTIVES: The objective of this study is to investigate the incidence of
      epileptiform activity, focal or generalized slowing, patterns of uncertain
      significance and the effects of hyperventilation, photic stimulation and sleep on
      the electroencephalogram of asymptomatic adult subjects. METHODS: The studied
      group consisted of 100 male subjects with a mean age of 34 years (range 18-45
      years). Each subject was screened closely for personal or family history of
      seizures, HIV, head trauma and drug abuse. Half of the subjects had a magnetic
      resonance imaging scan (MRI). RESULTS: In no subject resting or activated EEG
      showed any epileptiform activity or excessive slowing (focal or generalized). One
      subject demonstrated an H-response, one disclosed an alpha asymmetry of more than
      50% and one showed slow alpha variant. Fourteen and 6 positive burst (12%) and
      small sharp spikes (11%) were the two most common patterns of uncertain
      significance. CONCLUSION: In a carefully screened population of young and middle
      age adults, the incidence of epileptiform activity, photoparoxysmal response or
      excessive slowing is less than 1%.

PMID- 10656518
TI  - Load-dependence of fatigue related changes in tremor around 10 Hz.
AB  - OBJECTIVES: The aim of the study was to investigate the effects of different
      loads on tremor around 10 Hz during fatiguing contractions. METHODS: Eighteen
      healthy volunteers performed sustained isometric knee extensions at 30%, 50% and
      70% maximum voluntary contraction (MVC). During the fatiguing contractions,
      mechanical recordings were made with a high-resolution force sensor. Tremor-power
      was calculated for the 6-20 Hz frequency window as a function of time normalized
      to endurance time. RESULTS: Initial tremor power was different between the high
      and low load tasks. Changes of tremor with contraction time differed between the
      three tasks, in that tremor of the 30% MVC contraction showed the least decrease
      throughout the sustained contraction, whilst that of the 50% and 70% MVC showed
      progressively higher decreases. At failure, all 3 contractions merged to the same
      tremor level. CONCLUSION: Load-dependent, fatigue-related 6-20 Hz tremor changes
      during sustained submaximum voluntary contractions seem mainly the consequence of
      recruitment of new units and fatigue-related properties of the high threshold
      motor units of muscles.

PMID- 10656519
TI  - Hypoglycemic and hypoxic modulation of cortical micro-EEG activity in rat brain
      slices.
AB  - OBJECTIVE: Electroencephalogram (EEG) recordings exhibit stereotypic alterations
      during transient ischemia in mammals. One disadvantage of using in vitro models
      for ischemia studies is the lack of a sensitive electrophysiological measure for
      the degree of ischemic damage to a large population of neurons. The present study
      examined effects of hypoglycemia, hypoxia or both on an in vitro micro-EEG model,
      to determine whether this model provides a sensitive measure. METHODS: Theta
      frequency (4-8 Hz) micro-EEG oscillations were evoked in rat neocortical brain
      slices using the cholinergic agonist carbachol (100 microM) and the GABA(A)
      antagonist bicuculline (10 microM). Extracellular field micro-EEG signals and
      whole cell patch clamp recordings were used to monitor electrical activity.
      RESULTS: Upon removal of oxygen and/or glucose, theta oscillation amplitudes
      progressively declined to isoelectric levels. Low frequency delta oscillations
      (0.5-3.0 Hz) and burst suppression discharges were prominent during hypoglycemic
      episodes and upon recovery. Time to onset of isoelectric activity was faster in
      slices deprived of both glucose and oxygen (7.0 +/- 1.8 min) and oxygen alone
      (5.0 +/- 1.5 min) compared to hypoglycemia alone (25.6 +/- 3.8 min, P < 0.01,
      ANOVA). Hypoxia and hypoglycemia-induced isoelectric activity occurred prior to
      significant population spike depression from control levels (87.7 +/- 16.9%
      control amplitude, P > 0.35 (t test compared with control) for hypoglycemia; 93.6
      +/- 27.0%, P > 0.72 for hypoxia). Spreading depression (SD) was observed in 11/12
      (91.7%) slices deprived of both sugar and oxygen, but not in hypoxic (0/4) or
      hypoglycemic (0/5) slices. In all cases, SD occurred later than isoelectric
      activity. Theta oscillations recovered within 10 min in 12/13 (92.3%) slices that
      did not undergo SD, but slices that underwent SD failed to recover theta activity
      (0/4), though all (4/4) at least partially recovered the population spike (>40%).
      CONCLUSIONS: These results suggest that synchronized micro-EEG activity may be a
      useful and sensitive indicator of early-onset and possibly reversible ischemic
      damage.

PMID- 10656520
TI  - Magnetoencephalographic analysis of periodic lateralized epileptiform discharges
      (PLEDs).
AB  - OBJECTIVE: To clarify the spatial and temporal distribution of the
      electroencephalographic (EEG) pattern termed 'periodic lateralized epileptiform
      discharges' (PLEDs), we performed magnetoencephalography (MEG) to analyze PLEDs
      in a patient with a right parietal metastasis associated with meningeal
      carcinomatosis. METHODS: A 37-channel biomagnetometer was used to simultaneously
      record the EEG and MEG. Equivalent current dipole (ECD) source localization was
      calculated based on a single-dipole model and mapped onto a magnetic resonance
      image. Single-photon emission computed tomography with technetium-99-hexamethyl
      propyleneamine oxime (HMPAO-SPECT study) was also performed during both presence
      and absence of PLEDs according to an EEG monitor. RESULTS: By EEG the PLEDs,
      predominantly right-sided, consisted of a typical negative triphasic spike
      followed by a slow negative wave. By MEG the PLEDs had a sequence with 3 distinct
      components. ECDs in the 3 components were localized to the cortex around the
      lesion, although exact localization and dipole direction varied between
      components. HMPAO-SPECT demonstrated hypoperfusion of the lesion and adjacent
      cortex during both quiescence and appearance of PLEDs. CONCLUSION: Our results
      indicate that PLEDs originated from the hypoperfused cortex surrounding the
      lesion.

PMID- 10656521
TI  - Variability of epileptiform activity in long-term EEGs with short and long
      intervals in children with epilepsy.
AB  - OBJECTIVE: To evaluate the impact of the time factor on the amount of
      epileptiform activity in long-term EEG recordings in children with epilepsy.
      METHODS: Ten children with epilepsy of different types underwent three 24 h EEG
      examinations during two consecutive days and with a month's interval. The number
      of epileptiform discharges during selected corresponding periods of time was
      counted. RESULTS: The number of epileptiform discharges on three repeated
      examination days showed no significant difference (ANOVA P = 0.88) as
      intraindividual increases and decreases on different days counterbalanced each
      other within the group. However the standard deviations of the relative changes
      were larger between recordings with a month's interval compared to those for
      consecutive days (86% and 33%). The mean magnitude of change was 55% between days
      separated by a month compared to 24% on consecutive days. The difference was non
      significant but showed a trend towards larger changes with a longer interval (P =
      0.07). CONCLUSIONS: The variability of epileptiform activity was larger when the
      interval between recordings was 1 month compared to consecutive days. The
      magnitude of the relative changes between intervals of 1 and 30 days showed a
      trend towards a difference although not statistically significant. When
      evaluating repeated long-term EEGs in relation to therapy in children, these
      variations should be considered.

PMID- 10656523
TI  - Roles of calcium- and voltage-sensitive potassium currents in the generation of
      neuromagnetic signals and field potentials in a CA3 longitudinal slice of the
      guinea-pig.
AB  - OBJECTIVES: Roles of calcium- and voltage-sensitive potassium currents in
      generation of neuromagnetic signals and field potentials were evaluated using the
      longitudinal CA3 slice preparation of the guinea-pig. METHODS: Their roles were
      evaluated by using selective channel blockers (tetraethyl-ammonium (TEA) and 4
      aminopyridine (4AP)) and measuring their effects on the two types of signals and
      intracellular potentials. Fast gamma-aminobutyric acid type A inhibition was
      blocked with picrotoxin. RESULTS: Stimulation of the apical dendrites with an
      array of extracellular bipolar electrodes produced triphasic evoked magnetic
      fields with a spike and a slow wave typical of the slices. The evoked potentials
      in the apical and basal areas of the pyramidal cells closely resembled the
      magnetic field waveforms. Blockade of the potassium currents with TEA and 4AP had
      only subtle effects on the initial spike, but dramatically altered the slow wave.
      They also induced long-lasting spontaneous burst discharges synchronized across
      the slice. The results could be interpreted in terms of their known pre- and
      postsynaptic effects. Their post-synaptic effects were confirmed with
      intracellular recordings. CONCLUSION: Our results are consistent with a
      hypothesis that the calcium- and voltage-sensitive potassium currents, especially
      the A and C currents, play important roles in shaping the slow wave of the
      neuromagnetic and field potential signals produced by the mammalian hippocampus.

PMID- 10656522
TI  - The electroencephalogram through a software microscope: non-invasive localization
      and visualization of epileptic seizure activity from inside the brain.
AB  - OBJECTIVE: We developed a novel non-invasive analysis to localize the source and
      visualize the time course of electrical activity generated inside the brain but
      unclear from the scalp. This analysis applies to signals with unique waveform
      characteristics, such as seizures. METHODS: The method extracts activity from an
      EEG data matrix as a spatiotemporal component having waveforms uncorrelated to
      the other concurrent activities. The method also provides the location and
      orientation of the dipole generating this activity. We applied this method to ten
      scalp seizures in three patients with temporal lobe epilepsy and single-focus
      seizures confirmed by intracerebral recordings. A realistic head model based on
      MRI was used for computation of field distributions. RESULTS: When seizure
      activity was still not visually identifiable on the scalp, the method
      demonstrated in all scalp seizures a source in the temporal neocortex
      corresponding clearly to the region of seizure activity in intracerebral
      recordings. Frequency characteristics of the estimated activities also resembled
      those of the intracerebral seizures. CONCLUSIONS: This method enables estimation
      of focal brain activity when its effect on scalp EEG is unclear to visual
      examination. It works in situations where currently available source analyses
      methods, which require noiseless definite activity, are not applicable.

PMID- 10656524
TI  - Systematic approach to dipole localization of interictal EEG spikes in children
      with extratemporal lobe epilepsies.
AB  - OBJECTIVES: To assess the reliability of dipole localization based on residual
      variances (RV), using equivalent current dipole analysis of interictal EEG spikes
      in children with extratemporal lobe epilepsy. METHODS: Four pediatric patients
      with extratemporal lobe epilepsy were studied. Digital EEG was recorded from 19
      scalp electrodes. Computer programs for spike detection and clustering analysis
      were used to select spikes. Dipoles were calculated 5 times for each spike using
      different initial guesses by the moving dipole model. Standard deviation (SD) of
      the dipole positions was calculated at each time point in the 5 trials. RESULTS:
      We analyzed the dipoles at 1097 time points from 4 patients. Among 106 time
      points with RV < 2%, the SD was < 1 mm in 78 (74%), while in those with SD > 1 mm
      the dipole positions varied between 2.8 and 52.6 mm. Of dipoles with RV < 1%, 26
      of 27 (96%) had an SD < 1 mm; the one dipole with SD > 1 mm varied within 2.5 mm.
      The dipole localizations with RV < 2% corresponded to the epileptogenic zones
      identified on intracranial invasive video EEG and intraoperative ECoG.
      CONCLUSIONS: The systematic approach of equivalent current dipole analysis using
      spike detection, clustering analysis, and an RV < 2% as a standard is useful for
      identifying extratemporal epileptic regions.

PMID- 10656525
TI  - Corticomotoneuronal activity in ALS: changes in the peristimulus time histogram
      over time.
AB  - OBJECTIVE: The primary peak in the peristimulus time histogram (PSTH) reflects
      the initial rising phase of the excitatory post-synaptic potential (EPSP) evoked
      at the anterior horn cell. In ALS the primary peak is delayed in onset. increased
      in duration and desynchronized. abnormalities reflecting dysfunction of the
      corticomotoneurons. It is not known whether these abnormalities change over time
      in amyotrophic lateral sclerosis (ALS). METHODS: PSTHs were constructed from
      changes in the firing probability of single, voluntarily activated motor units
      subjected to subthreshold transcranial magnetic stimuli. We studied 58 motor
      units in 12 patients with ALS on two separate occasions (mean time interval of
      10.6 +/- 1.6 months). Results were compared with 49 motor units in 11 age matched
      controls. RESULTS: All the parameters except the amplitude differed significantly
      between normals and patients. In general the primary peak in ALS was complex,
      desynchronized and occasionally consisted of a double peak. The abnormalities
      persisted or were accentuated at tile follow up visit. This was reflected by an
      increase in the number of excess bins, longer duration and latency and decrease
      of synchrony. CONCLUSIONS: Increasing desynchronization of the primary peak over
      time in ALS reflects dysfunction of the monosynaptic corticomotoneuronal pathway
      and may also reflect activation of additional slow conducting and/or polysynaptic
      corticomotoneuronal connections.

PMID- 10656527
TI  - Approaches to anti-aging intervention: the promises and the uncertainties.
AB  - Humans have long sought the elixir to long life. Today, although advances in our
      understanding of the aging process have given gerontologists new insights in
      potential anti-aging interventions, public demand for these interventions is
      outpacing our current knowledge. My presentation begins with a brief historical
      background that outlines some of the past and present approaches to anti-aging
      interventions. Using the dietary restriction paradigm as a prototype, discussions
      center on a three-pathway model that provides the bases to design effective
      interventions: (1) retardation of biological aging, (2) suppression of age
      related disease, and (3) modulation of cross talk between (1) and (2). One other
      concept useful for discussion in relation to interventions is the enhancement of
      an organism's resistance to deter vulnerability to aging and disease. These
      models are best used to explain the efficacy of currently popular interventions
      such as antioxidant supplementation and hormone therapies. This presentation
      further highlights the promises that antioxidant supplements hold in warding off
      oxidative damage as well as their inherent problems and biological limitations.
      Also discussed here are the promises and uncertainties of anti-aging
      interventions by genetic manipulation, as seen in animal model studies, and
      prophylactic treatments targeted against disease, such as hormonal approaches
      using estrogen and DHEA, as well as other intervening measures.

PMID- 10656526
TI  - The human hand motor area is transiently suppressed by an unexpected auditory
      stimulus.
AB  - OBJECTIVE: To study the effect of a loud auditory stimulus on the excitability of
      the human motor cortex. METHODS: Ten normal volunteers participated in this
      study. The size of responses to transcranial magnetic or electrical cortical
      stimulation (TMS or TES) given at different times (ISIs) after a loud sound were
      compared with those to TMS or TES alone (control response). Different intensities
      and durations of sound were used at several intertrial intervals (ITIs). In
      addition, we examined how the presence of a preceding click modulated the effect
      of a loud sound (prepulse inhibition). The incidence of startle response evoked
      by various stimuli was also studied. RESULTS: A loud auditory stimulus suppressed
      EMG responses to TMS when it preceded the magnetic stimulus by 30-60 ms, whereas
      it did not affect responses to TES. This suggests that the suppression occurred
      at a cortical level. Significant suppression was evoked only when the sound was
      louder than 80 dB and longer than 50 ms in duration. Such stimuli frequently
      elicited a startle response when given alone. The effect was not evoked if the
      ITI was 5 s, but was evoked when it was longer than 20 s. A preceding click
      reduced the suppression elicited by loud sounds. CONCLUSIONS: Auditory stimuli
      that produced the greatest effect on responses to TMS had the same
      characteristics as those which yielded the most consistent auditory startle. We
      suggest that modulation of cortical excitability occurs in parallel with the
      auditory startle and both may arise from the same region of the brain-stem.

PMID- 10656528
TI  - Role of superoxide, NO and oxygen in the regulation of energy metabolism and
      suppression of senile diseases.
AB  - Although nitric oxide (NO) rapidly reacts with molecular oxygen under air
      atmospheric conditions, thereby losing its biological functions, the lifetime of
      this gaseous radical increases under physiologically low intracellular oxygen
      tensions. To understand the pathophysiological roles of NO and related molecules
      in aerobic life, we analyzed the effect of oxygen tensions on the NO-dependent
      processes in resistance arteries, isolated mitochondria, intact cells and enteric
      bacteria. Kinetic analysis revealed that NO enhanced the generation of cGMP and
      induced vasorelaxation of resistance arteries more potently under physiologically
      low oxygen tensions than under hyperbaric conditions. NO reversibly inhibited the
      respiration of isolated mitochondria, intact cells and Escherichia coli; the
      inhibitory effect was more marked under hypoxic conditions than under hyperbaric
      conditions. Kinetic analysis revealed that NO has pivotal action to increase
      arterial supply of molecular oxygen for the generation of ATP in peripheral
      tissues and to suppress energy production in mitochondria and cells in an oxygen
      dependent manner. These functions of NO are enhanced by decreasing oxygen tension
      in situ and suppressed by locally generated superoxide radicals. Thus, cross-talk
      of NO, superoxide and molecular oxygen constitutes a supersystem by which the
      energy metabolism in cells and tissues is beautifully regulated in a site
      specific manner depending on the relative concentrations of these three radical
      species.

PMID- 10656530
TI  - Structure and function of type I and II macrophage scavenger receptors.
AB  - Type I and II macrophage scavenger receptors are implicated in the pathologic
      deposition of cholesterol during the atherogenesis. There is a charged collagen
      structure of type I and II receptors identified as a ligand binding domain, which
      can recognize a wide range of negatively charged macromolecules including
      oxidized LDL as well as damaged or apoptotic cells and pathogenic micro
      organisms. After binding these ligands can be either internalized by endocytosis,
      phagocytosis, or remain at cell surface and mediate the adhesion. Under
      physiological condition, scavenger receptors serve to scavenge or clean up
      cellular debris and other related materials, as well as playing a role in the
      hosts defence. In pathological condition, they mediate the recruitment,
      activation and transformation of macrophages and other cells, which may be
      related to the development of atherosclerosis and to disorders caused by the
      accumulation of denatured materials, such as Alzheimer's disease.

PMID- 10656529
TI  - Dietary modulation of prostanoid synthesis in the aging process: role of
      cyclooxygenase-2.
AB  - To investigate the role of cyclooxygenase (COX) as a mediator for prostaglandin
      synthesis in relation to generation of reactive oxidant species (ROS), we
      quantitated the COX-derived ROS generation and the gene expression of COX-2, an
      inducible form of COX in aged kidney. In addition, the modulation by dietary
      restriction was investigated. COX-derived ROS generation increased with age in ad
      libitum (AL) rats, but dietary restriction (DR) suppressed the level. The amounts
      of COX-2 protein and mRNA increased with age in AL rats but maintained at low
      levels in DR group. It was found that the binding characteristics of a nuclear
      transcription factor, NF-kappaB were altered by aging. The binding activity of NF
      kappaB in aged kidney was significantly enhanced with the corresponding increase
      in mRNA and protein levels. These increases were closely in parallel to the
      increased ROS generation and gene expression of COX-2. The COX activity shown by
      NF-kappaB activation and the ROS generation by COX-mediated process were all
      modulated by DR. Our results suggest that the upregulation of COX-2 during aging
      may play an important role in many age-related diseases associated with aging
      process. And this upregulation was attenuated by DR. We propose that the
      modulation of the redox-sensitive transcription factor may well be a part of the
      mechanisms underpinning the anti-oxidative action of DR.

PMID- 10656531
TI  - Dietary antioxidants modulation of aging and immune-endothelial cell interaction.
AB  - Oxidative damage by free radicals, which is the basis for the free radical theory
      of aging, has been well investigated within the context of oxidant/antioxidant
      balance. Age-associated disorders are believed to be associated with the time
      dependent shift in the antioxidant/prooxidant balance in favor of oxidative
      stress. In this brief review, the importance of dietary antioxidant intervention
      on longevity and age-associated changes in bodily functions and diseases are
      discussed. Evidence has indicated that increasing the endogenous antioxidants
      defense system and modulation of free radical production by dietary restrictions
      contribute to increased longevity in animal models. Thus, increasing dietary
      intake of antioxidants is believed to increase longevity. Earlier studies have
      shown some increase in median life span in animal models. It was found that
      supplementing middle-aged (18 months) C57/BL mice with various antioxidants
      (vitamin E, glutathione, melatonin, and strawberry extract) had no effect on
      longevity as measured by the average age of death. Therefore, dietary antioxidant
      supplementation seems unlikely to increase longevity when begun in middle age;
      supplementation started in early life might be more effective. However, in middle
      aged mice, vitamin E was effective in reducing lung viral titer when animals were
      exposed to influenza virus. Vitamin E supplementation improves cell-mediated
      immunity in mice and in humans. In addition to modulating the oxidation of low
      density lipoproteins, vitamin E can modulate immune/endothelial cells
      interactions, thus reducing the risk of cardiovascular disease (CVD), a major
      cause of morbidity and mortality in elderly. Thus, antioxidants such as vitamin E
      from food sources or supplements appear to be promising for successful aging by
      improving immune function, and reducing the risk of several age-associated
      chronic diseases, such as CVD.

PMID- 10656532
TI  - Protective role of dietary polyphenols in oxidative stress.
AB  - The oxidative break down of the membrane polyunsaturated fatty acids is known to
      be accompanied by the formation of a complex mixture of lipidhydroperoxides and
      secondary products. These compounds are highly reactive and are capable of rapid
      reaction with cellular nucleophiles such as phospholipids and proteins, and it
      was found that these reaction products are candidates as impotant biomarkers to
      evaluate antioxidative activity of dietary antioxidants. The author has been
      involved in developing immunochemical detection methods for oxidative stress by
      application of polyclonal and monoclonal antibodies. From the hypothesis that
      endogenous antioxidants in plants must play an important role for antioxidative
      defense systems from oxidative stress, an intensive search for novel type of
      natural antioxidants has been carried out from numerous plant materials,
      including those used as foods, and we have isolated and identified a number of
      lipid-soluble and water-soluble dietary antioxidants from crop seeds, sesame
      seeds and some spices. In this paper, the recent progress of research on
      functions of dietary antioxidants is reviewed.

PMID- 10656533
TI  - Effects of aging on cerebellar noradrenergic function and motor learning:
      nutritional interventions.
AB  - Aging is associated with a decline in motor coordination and the ability to learn
      new motor learning skills. This loss of function is correlated with a decline in
      cerebellar beta-adrenergic receptor function. We have examined the role of
      oxidative stress on this system by exposing young rats to normobaric hyperoxia.
      This exogenous oxidative insult results in a decline in cerebellar beta
      adrenergic receptor function that resembles what is observed in normal aged rats.
      This effect of hyperoxia is blocked by antioxidants. We have also examined the
      effects of nutritional supplementation of aged rats with diets high in
      antioxidant capacity. Foods such as blueberries and spinach can prevent and/or
      reverse age-related declines in cerebellar noradrenergic receptor function.

PMID- 10656534
TI  - Efficacy of Choto-san on vascular dementia and the protective effect of the hooks
      and stems of Uncaria sinensis on glutamate-induced neuronal death.
AB  - Two different multicenter studies on the efficacy of Choto-san on patients with
      vascular dementia, one a well-controlled but non-double blind (60 patients), the
      other a double-blind controlled study (139 patients), were performed. In the well
      controlled study, Choto-san was superior in global improvement rating, utility
      rating and improvement of subjective symptoms, psychiatric symptoms and
      disturbance in daily living activities. In the double-blind study, with more
      objective criteria than the well-controlled study, Choto-san was also superior in
      global improvement rating, utility rating and improvement of subjective symptoms,
      psychiatric symptoms and disturbance in daily living activities. These results
      suggest that Choto-san is effective in the treatment of vascular dementia.
      Uncaria sinensis (OLIV.) HAVIL. (US) is the main medicinal plant composing Choto
      san. Glutamate-induced cell death of cultured cerebellar granule cells was
      protected by the application of water extract of US in a dose-dependent manner,
      and concentrations of 10(-5) to 10(-4) g/ml had a significant effect compared to
      exposure to glutamate only. Further, the increase of 45Ca2+ influx into cells by
      glutamate was also blocked by the water extract in a dose-dependent manner. These
      results suggest that US has a protective effect on glutamate-induced neuronal
      death in cultured cerebellar granule cells through the inhibition of Ca2+ influx.

PMID- 10656535
TI  - Cell death of dopamine neurons in aging and Parkinson's disease.
AB  - Dopamine neurons in the substantia nigra of human brain are selectively
      vulnerable and the number decline by aging at 5-10% per decade. Enzymatic and non
      enzymatic oxidation of dopamine generates reactive oxygen species, which induces
      apoptotic cell death in dopamine neurons. Parkinson's disease (PD) is also caused
      by selective cell death of dopamine neurons in this brain region. The
      pathogenesis of Parkinson's disease remains to be an enigma, but it was found
      that an endogenous MPTP-like neurotoxin, 1(R), 2(N)-dimethyl-6,7-dihydroxy
      1,2,3,4-tetrahydroisoquinoline [N-methyl(R)salsolinol, NM(R)Sal], may be one of
      the pathogenic agents of PD. NM(R)Sal increases in cerebrospinal fluid from
      untreated parkinsonian patients, and two enzymes, a (R)salsolinol synthase and a
      neutral N-methyltransferase, synthesize this neurotoxin in the nigro-striatum.
      The activity of a neutral N-methyltransferase is significantly higher in
      lymphocytes from parkinsonian patients than in control. The mechanism of cell
      death by this toxin was proved to be by the induction of apoptosis, by use of
      dopaminergic SH-SY5Y cells. The apoptosis was suppressed by anti-oxidants,
      suggesting that the generation of reactive oxygen species may initiate cellular
      death process. These results indicate that in aging and PD oxidative stress
      induces degeneration of dopamine neurons, and the antioxidant therapy may delay
      the decline of dopamine neurons in the brain.

PMID- 10656537
TI  - Symptomatic and neuroprotective properties of the aliphatic propargylamines.
AB  - This short review describes the development of several families of aliphatic
      propargylamine drugs. The parent family--the aliphatic N-methylpropargylamines
      are potent, specific, irreversible MAO-B inhibitors, like R-deprenyl; but devoid
      of R-deprenyl's toxicity and amphetaminergic effects. In addition the parent
      drugs are potent antiapoptoic agents. Their desmethyl and further oxidized
      metabolites whilst devoid of MAO-B inhibitory properties of R-2HMP (our chosen
      drug candidate) are described along with the suggestion that this drug be
      developed for the treatment of several human neurodegenerative conditions.

PMID- 10656536
TI  - Neuroprotection by (-)-deprenyl and related compounds.
AB  - There is an increasing number of data by in vitro and in vivo experiments,
      indicating that (-)-deprenyl is neuroprotective to dopamine neurons, even though
      detailed mechanism remains to be clarified. In this paper neuroprotection by (-)
      deprenyl and structurally related compounds was examined in concern with the
      suppression of apoptosis induced by a reactive oxygen species, peroxynitrite
      generated from SIN-1. The apoptotic DNA damage was quantitatively determined
      using dopaminergic SH-SYSY cells and by a single cell gel electrophoresis (comet)
      assay. DNA damage induced by peroxynitrite was proved to be apoptotic by
      prevention of the damage by cycloheximide or actinomycin-D. (-)-Deprenyl and
      other propargylamines protected the cells from apoptosis in a dose-dependent way.
      (-)-Deprenyl protected the cells even after it was washed out, suggesting that it
      may initiate the intracellular process to repress the apoptotic death program.
      The study on the structure-activity relationship of (-)-deprenyl analogues
      revealed that a N-propargyl residue with adequate size of hydrophobic structure
      is essentially required for the anti-apoptotic activity. These results suggest
      that (-)-deprenyl and related compounds may protect neurons from apoptosis and be
      applicable to delay the deterioration of neurons during advancing ageing and in
      neurodegenerative disorders.

PMID- 10656538
TI  - Pharmacological modifications of endogenous antioxidant enzymes with special
      reference to the effects of deprenyl: a possible antioxidant strategy.
AB  - Limited information is available on the upregulation of endogenous antioxidant
      enzymes by means of administering various pharmaceuticals and/or chemicals. It
      has been reported that ursodeoxycholic acid (UDCA), a bile acid originally
      identified from black bear bile (a Chinese medicine, Yutan) increased glutathione
      S-transferase (GST) activities in mouse livers, resulting in a decrease in
      systemic lethal toxicity of orally challenged 1-2-dichloro-4-nitrobenzene (DCNB).
      Also, ursolic acid found in herbal medicines (e.g. leaves of loquat) was reported
      to increase catalase (CAT) activities in mouse liver. Interestingly, the chemical
      structures of these two compounds are surprisingly similar to each other, despite
      the difference in their original sources. These results suggest that in the
      future, more and more compounds will be found to have effects on increasing
      endogenous antioxidant enzyme activities. Deprenyl is a monoamine oxidase B
      inhibitor but also possesses many other different pharmacological activities.
      Among these various pharmacological effects of deprenyl, a possible causal
      relationship between two effects of deprenyl, namely the prolongation of the
      survival of animals and upregulation of antioxidant enzymes in selective brain
      regions, has been postulated by the authors. In at least four different animal
      species (rats, mice, hamsters and dogs), a significant prolongation of survival
      by chronic administration of the drug has been reported by different groups
      including that of the authors. This group has reported that repeated
      administration of the drug for 2-3 weeks can significantly increase activities of
      both types of superoxide dismutase (SODs) (Cu, Zn-, and Mn-SODs) as well as of
      CAT selectively in brain dopaminergic regions. Both effects are dose dependent
      but excessive dosages become less effective and even cause an adverse effect
      (i.e. a decrease in enzyme activities and shortening of life span). The
      parallelism of the dose-effect relationship between the two phenomena suggests
      that modification of SOD and CAT levels is one possible mechanism for deprenyl's
      ability to prolong the life span of animals.

PMID- 10656539
TI  - Advances in the signal transduction of ceramide and related sphingolipids.
AB  - Recently, the sphingolipid metabolites ceramide, sphingosine, ceramide 1-P, and
      sphingosine 1-P have been implicated as second messengers involved in many
      different cellular functions. Publications on this topic are appearing at a
      rapidly increasing rate and new developments in this field are also appearing
      rapidly. It is thus important to summarize the results obtained from many
      different laboratories and from different fields of research to obtain a clearer
      picture of the importance of sphingolipid metabolites. This article reviews the
      studies from the last few years and includes the effects of a variety of
      extracellular agents on sphingolipid signal transduction pathways in different
      tissues and cells and on the mechanisms of regulation. Sphingomyelin exists in a
      number of functionally distinct pools and is composed of distinct molecular
      species. Sphingomyelin metabolites may be formed by many different pathways. For
      example, the generation of ceramide from sphingomyelin can be catalyzed by at
      least five different sphingomyelinases. A large variety of stimuli can induce the
      generation of ceramide, leading to activation or inhibition of various cellular
      events such as proliferation, differentiation, apoptosis, and inflammation. The
      effect of ceramide on these physiological processes is due to its many different
      downstream targets. It can activate ceramide-activated protein kinases and
      ceramide-activated protein phosphatases. It also activates or inhibits PKCs, PLD,
      PLA2, PC-PLC, nitric oxide synthase, and the ERK and SAPK/JNK signaling cascades.
      Ceramide activates or inhibits transcription factors, modulates calcium
      homeostasis and interacts with the retinoblastoma protein to regulate cell cycle
      progression. Most of the work in this field has involved the study of ceramide
      effects, but the roles of the other three sphingomyelin metabolites is now
      attracting much attention. The complex interactions between signaling components
      and ceramide and the controls regulating these interactions are now being
      identified and are presented in this review.

PMID- 10656540
TI  - Physiological roles of the leptin endocrine system: differences between mice and
      humans.
AB  - Leptin is a 16-kDa cytokine secreted in humans primarily but not exclusively by
      adipose tissues. Its concentration in blood is usually proportional to body fat
      mass, but is higher in women than in men not only because of a different
      distribution of and greater fat mass in women, but also because testosterone
      reduces its level in men. Leptin features in different ways during the life span.
      It is synthesized in the ovary, transported in the oocyte, and made by both fetus
      and placenta, particularly during the last month of gestation. It is made by the
      lactating mammary gland and ingested by the newborn infant in its milk. The prime
      importance of leptin is realized at puberty when it is necessary for progression
      to a normal adult reproductive status in females. Fasting and chronic
      undernutrition result in a lower level of leptin in the blood. Lack of leptin
      results in hunger, ensuring that the individual eat to survive, and also
      inhibition of reproduction, until such time as food and fat stores are adequate
      to supply energy for pregnancy and lactation. Thus, leptin is important for
      survival of the individual and survival of the species. Although an extremely
      rare genetic absence of leptin induces hyperphagia and obesity in humans, as it
      does in mice, there appears to be little role for leptin in humans in ensuring
      that fat stores are not in excess of adequate, that is, in preventing obesity.
      The mouse differs from humans in many respects, in particular in the far more
      drastic ways it conserves energy when it very rapidly adapts to lack of food.
      These include not only suppression of reproduction but also lowering of its body
      temperature (torpor), suppressing its thyroid function, suppressing its growth,
      and increasing secretion of stress hormones (from the adrenal). This review
      concentrates on roles of leptin in human physiology and pathophysiology but also
      discusses why some observations on actions of leptin in mice are not applicable
      to humans.

PMID- 10656541
TI  - Assessment of in vivo chromosomal aberrations--potency of zinc mercapto benzo
      thiazole.
AB  - Chromosomal aberrations are microscopically visible changes in the chromosome
      structure. The double-stranded breaks are the ultimate DNA lesions for
      chromosomal aberrations. The purpose of the present study was to evaluate the
      induction of chromosomal aberrations by the rubber accelerator zinc mercapto
      benzo thiazole (ZMBT). The experiment was designed with five groups, each
      composed of four Swiss albino mice. The first three groups received ZMBT at 1920,
      960, and 480 microg/20 g animal. The remaining two groups were the vehicle
      (cotton seed oil) and positive (methyl methane sulphonate) controls. Animals were
      given a single dose of test and control samples by IP injection. Colchicine (20
      microg/animal) was administered 90 minutes before sacrificing the animals. All
      the animals were sacrificed at the end of 36 h by cervical dislocation. Bone
      marrow preparations were made, stained with Giemsa stain, and examined for
      chromosomal abnormalities. The results indicated a lack of incidence of
      chromosomal abnormalities in the test and control groups. However, significant
      chromosomal abnormalities such as gaps, breaks, and translocations were observed
      in the positive control group. Hence, the study concluded that ZMBT at different
      concentrations fails to induce structural chromosomal aberrations in bone marrow
      cells.

PMID- 10656542
TI  - Fibrin scaffold as an effective vehicle for the delivery of acidic fibroblast
      growth factor (FGF-1).
AB  - The effect of wound healing by fibrin and acidic fibroblast growth factor (FGF-1)
      in an in vivo model was evaluated in this study. Four full-thickness wounds were
      made on the dorsum of each rabbit (n = 5). Each of these wounds had different
      treatment groups: control, topical FGF-1 (100 microg/9 cm2), fibrin (2.0 mL at 60
      mg/mL fibrinogen), and FGF-1 (100 microg/9 cm2)/fibrin. The animals were
      sacrificed at the end of 2 weeks. Histomorphometric analysis and mechanical
      testing were conducted to assess the healing response. FGF-1/fibrin treatment
      improved the mechanical properties of the healed tissue. Fibrin scaffold
      exhibited the desired tissue response, as demonstrated by the lack of
      inflammation, and was deemed an effective carrier for FGF-1.

PMID- 10656543
TI  - Exogenous surfactant therapy and mucus rheology in chronic obstructive airway
      diseases.
AB  - Exogenous surfactant is a specialized biomaterial used for substitution of the
      lipoprotein mixture normally present in the lungs-pulmonary surfactant.
      Respiratory Distress Syndrome is a disease of preterm infants mainly caused by
      pulmonary immaturity as evidenced by a deficiency of mature lung surfactant.
      Pulmonary surfactant is known to stabilize small alveoli and prevent them from
      collapsing during expiration. However, apart from alveoli, surfactant also lines
      the narrow conducting airways of the tracheobronchial tree. This paper reviews
      the role of this surfactant in the airways and its effect on mucus rheology and
      mucociliary clearance. Its potential role as a therapeutic biomaterial in chronic
      obstructive airway diseases, namely asthma, chronic bronchitis, and respiratory
      manifestations of cystic fibrosis, are discussed. This paper also attempts to
      elucidate the exact steps in the pathogenic pathway of these diseases which could
      be reversed by supplementation of exogenous surfactant formulations. It is shown
      that there is great potential for the use of present day surfactants (which are
      actually formulated for use in Respiratory Disease Syndrome) as therapy in the
      aforementioned diseases of altered mucus viscoelasticity and mucociliary
      clearance. However, for improved effectiveness, specific surfactant formulations
      satisfying certain specific criteria should be tailor-made for the clinical
      condition for which they are intended. The properties required to be fulfilled by
      the optimal exogenous surfactant in each of the above clinical conditions are
      enumerated in this paper.

PMID- 10656544
TI  - Effects of double cross-linking technique on the enzymatic degradation and
      calcification of bovine pericardia.
AB  - The strength, resorption rates, and biocompatibility of collagenous biomaterials
      are profoundly influenced by the method of cross-linking. The in vitro and in
      vivo calcification and enzymatic degradation of bovine pericardia (BP) after a
      series of surface modifications were studied as a function of exposure time.
      Collagenase degradations of modified BP were monitored by scanning electron
      microscopy and tensile strength measurements. Bovine pericardium was modified by
      a combination of different tissue fixatives such as glutaraldehyde (GA),
      carbodiimide (EDC), diisocyanate (HMDIC), and polyethylene glycol (PEG). GA-PEG
      EDC-PEG and GA-PEG-HMDIC-PEG combination treated BP retained maximum stability in
      collagenase digestion compared to GATBP. In vitro calcification studies and in
      vivo rat subcutaneous implantations of modified pericardium have shown
      substantial reduction in the calcification of double cross-linked BP with PEG
      modification. Further, the biocompatibility aspects of pericardial tissues were
      established by platelet adhesion and octane contact angle. It seems that cross
      links involving amino and carboxyl residues may provide new ways of controlling
      biodegradation and calcification.

PMID- 10656546
TI  - Burns and metabolism.

PMID- 10656545
TI  - Effect of resin matrix ratio, storage medium, and time upon the physical
      properties of a radiopaque dental composite.
AB  - Three light curing composite pastes with varying resin matrix ratios [bisphenol A
      glycidyl methacrylate (BIS-GMA)/urethane tetramethacrylate (UTMA) 25:75, BIS
      GMA/UTMA 50:50, and BIS-GMA/UTMA 75:25 w/w%] were prepared in combination with a
      radiopaque glass powder and camphorquinone photoinitiator. Cured samples were
      aged at 37 degrees C in three food simulating media such as citrate buffer (pH
      4.0), PBS buffer (pH 7.4), and 75% ethyl alcohol. Samples were withdrawn at
      specific intervals of 1, 15, 30, 45, and 60 days and tested for changes in
      mechanical properties, sorption, and solubility characteristics. Statistical
      calculations revealed significant changes in compressive strength (CS) for
      composites depending on the resin matrix ratio and type of medium used for aging.
      While diametral tensile strength (DTS) was affected adversely in citrate medium
      for composites with higher urethane content, samples stored in alcohol medium
      showed deterioration of transverse strength (TS) and microhardness (VMH) for all
      composites studied. Increase in BIS-GMA content in the resin matrix and storage
      in alcohol medium resulted in higher sorption and solubility values and lower
      microhardness.

PMID- 10656547
TI  - Cardiac surgery.

PMID- 10656548
TI  - Colon and rectal surgery.

PMID- 10656549
TI  - Endocrine surgery.

PMID- 10656550
TI  - Gastrointestinal conditions.

PMID- 10656551
TI  - General thoracic surgery.

PMID- 10656552
TI  - Neurological surgery.

PMID- 10656553
TI  - Obstetrics and gynecology.

PMID- 10656554
TI  - Ophthalmic surgery.

PMID- 10656555
TI  - Orthopaedic surgery.

PMID- 10656556
TI  - Otolaryngology.

PMID- 10656557
TI  - Pediatric surgery.

PMID- 10656558
TI  - Plastic and maxillofacial surgery.

PMID- 10656559
TI  - Surgical oncology.

PMID- 10656560
TI  - Transplantation.

PMID- 10656561
TI  - Trauma and critical care.

PMID- 10656562
TI  - Urology.

PMID- 10656564
TI  - Images for surgeons. Fatal opportunistic necrotizing colitis.

PMID- 10656563
TI  - Vascular surgery.

PMID- 10656565
TI  - Images for surgeons. Pylephlebitis secondary to intestinal ischemia.

PMID- 10656566
TI  - Biomolecular-chemical screening: a novel screening approach for the discovery of
      biologically active secondary metabolites. I. Screening strategy and validation.
AB  - Chemical screening using thin-layer chromatography and various staining reagents
      offers the opportunity to visualize an almost complete picture of a microbial
      secondary metabolite pattern (metabolic finger-print). A thorough application of
      this strategy resulted in a number of biologically active new secondary
      metabolites, although the screening strategy is per se not correlated to any
      biological activity. In the present paper we report on a novel approach called
      biomolecular-chemical screening which combines the chemical screening strategy
      with binding studies of biological relevance. Making use of thin-layer
      chromatography (TLC) and subsequent staining, biomolecular-chemical screening
      allows to examine binding properties of low molecular weight metabolites to
      certain bio-macromolecules. The screening strategy itself, as well as independent
      validation of the results using DNA as selected bio-macromolecule are presented.
      The biomolecular-chemical screening method is useful to screen binding behaviour
      towards DNA of both, pure metabolites by one-dimensional TLC, and crude extracts
      by two-dimensional TLC. Investigation of pure secondary metabolites as well as
      screening of crude microbial extracts and new secondary metabolites obtained with
      this screening strategy are presented in accompanying papers.

PMID- 10656567
TI  - Biomolecular-chemical screening: a novel screening approach for the discovery of
      biologically active secondary metabolites. II. Application studies with pure
      metabolites.
AB  - The novel screening strategy called "biomolecular-chemical screening" combines
      the advantages of the chemical screening approach--the analysis of the
      chromatographic and chemical behaviour of secondary metabolites on TLC plates-
      with binding studies of these molecules with bio-macromolecules like DNA. This
      approach was advantageously used to detect the interaction of pure compounds with
      DNA. In order to prove the reliability of the biomolecular-chemical screening and
      to examine DNA-binding properties, 470 pure secondary metabolites were analysed
      by this method. Besides the confirmation of already known binders with the TLC
      based method, for a number of natural products DNA-binding properties were
      discovered for the first time. In consequence, binding of pure compounds can be
      measured by 1D TLC in a reliable and easy manner, in which DNA is applied
      together with the test compound at the starting spot. Analysis is performed via
      differences in Rf-values in comparison to a reference chromatogram without DNA.

PMID- 10656568
TI  - Stresgenin B, an inhibitor of heat-induced heat shock protein gene expression,
      produced by Streptomyces sp. AS-9.
AB  - Stresgenin B was isolated as an inhibitor of heat-induced heat shock protein
      (HSP) gene expression from a culture broth of Streptomyces sp. AS-9 by silica gel
      chromatography and HPLC. The molecular formula of the novel compound was
      determined as C11H13NO5 by high resolution FAB-MS analysis, and the structure was
      determined by UV, 1H NMR, 13C NMR, HMQC, HMBC, and NOESY spectra. Stresgenin B
      inhibited heat-induced luciferase reporter-gene expression directed by the human
      hsp70B promoter in Chinese hamster ovary (CHO) cells at concentrations lower than
      the concentrations for inhibition of dexamethasone-induced luciferase reporter
      gene expression directed by the mouse mammary tumor virus (MMTV)-LTR promoter.
      The inhibition of heat-induced reporter gene expression was evident even when
      cells were exposed to stresgenin B only during heat stress treatment. Moreover,
      the compound inhibited heat-induced syntheses of hsp72/73, hsp90, and hsp110 and
      thereby suppressed the induction of thermotolerance. Stresgenin B showed moderate
      cytotoxic activities against several neoplastic cell lines and also showed
      antibacterial activities against Micrococcus luteus, Bacillus subtilis and
      Staphylococcus aureus strains.

PMID- 10656569
TI  - EM2487, a novel anti-HIV-1 antibiotic, produced by Streptomyces sp. Mer-2487:
      taxonomy, fermentation, biological properties, isolation and structure
      elucidation.
AB  - For the purpose of discovering novel agents that inhibit HIV-1 replication at the
      transcriptional level, we have established cell lines reflecting the HIV-1 long
      terminal repeat-driven gene expression. Using these cell lines, we have screened
      approximately 10,000 microorganism products and found that the culture
      supernatant of Streptomyces sp. Mer-2487 suppresses the HIV-1 Tat-induced gene
      expression without affecting the basal or tumor necrosis factor-alpha-induced
      transcription. The purified active component has a unique structure, as shown in
      Fig. 1. This compound has an inhibitory effect on HIV-1 replication in
      chronically infected cells as well as acutely infected cells, suggesting that the
      inhibition occurs at a postintegration step of HIV-1 proviral DNA in the HIV-1
      replication cycle.

PMID- 10656570
TI  - Agrochelin, a new cytotoxic antibiotic from a marine Agrobacterium. Taxonomy,
      fermentation, isolation, physico-chemical properties and biological activity.
AB  - Agrochelin, a new alkaloid cytotoxic substance, was produced by the fermentation
      of Agrobacterium sp. The compound was obtained from the bacterial cells by
      solvent extraction and purified by silica gel chromatography. Agrochelin (1) and
      its acetyl derivative (2) exhibited cytotoxic activity.

PMID- 10656571
TI  - Memnobotrins and memnoconols: novel metabolites from Memnoniella echinata.
AB  - Four novel metabolites have been isolated from a rice culture of Memnoniella
      echinata (JS6308) by solvent extraction and radial silica chromatography. The
      structures were elucidated by spectroscopic techniques, and the absolute
      stereochemistry of memnobotrin A determined by X-ray crystallography.

PMID- 10656572
TI  - Tylopeptins A and B, new antibiotic peptides from Tylopilus neofelleus.
AB  - Two new peptides, tylopeptins A and B, were isolated from the methanol extract of
      the fruiting body of the mushroom, Tylopilus neofelleus. These peptides were
      identified as peptaibols possessing an acetylated N-terminal residue, fourteen
      amino acids, and leucinol as the C-terminal amino alcohol. Sequential
      determination and complete 1H and 13C resonance assignments were based on
      positive ion FAB mass spectroscopy and two dimensional NMR techniques. These
      peptides were subsequently shown to be active against some gram-positive
      bacteria, but inactive against pathogenic fungi and gram-negative bacteria.

PMID- 10656573
TI  - In vitro microbiological characterization of novel cyclic homopentapeptides, CP
      101,680 and CP-163,234, for animal health use.
AB  - Two cyclic homopentapeptides, CP-101,680 and CP-163,234 [6a-(3',4'
      dichlorophenylamino) analogs of viomycin and capreomycin, respectively], were
      identified as novel antibacterial agents for the treatment of animal disease,
      especially for livestock respiratory disease. The in vitro microbiological
      characterization of both CP-101,680 and CP-163,234 was carried out using their
      parent compounds, viomycin and capreomycin, as controls. This characterization
      included antibacterial spectrum, influence of media, inoculum size, pH, EDTA,
      polymixin B nonapeptide (PMBN), serum, cell-free protein synthesis inhibition,
      and time-kill kinetics. Our results indicated that the capreomycin analog, CP
      163,234, showed slightly improved in vitro potency over the viomycin analog, CP
      101,680. Both analogs showed very potent cell-free protein synthesis inhibition
      activity and were bactericidal against Pasteurella haemolytica, P. multocida and
      Actinobacillus pleuropneumoniae at the level of 4 times and 8 times MICs. CP
      163,234 was bactericidal at the level of 4x and 8x MIC against E. coli, but re
      growth was observed after 24 hours incubation at both concentrations of CP
      101,680.

PMID- 10656574
TI  - Effective production of dehydro cyclic dipeptide albonoursin exhibiting
      pronuclear fusion inhibitory activity. I. Taxonomy and fermentation.
AB  - Strain KO-23, an actinomycete producing albonoursin as well as streptopyrone, was
      identified as Streptomyces albulus by morphological and biochemical studies.
      Fermentation conditions for albonoursin, a dehydro cyclic dipeptide exhibiting a
      pronounced inhibitory activity toward pronuclear fusion of sea urchin eggs, were
      optimized. Under the optimum conditions, the actinomycete produced 16 mg/liter of
      albonoursin, 30 times higher than that in the original culture. The cells
      cultivated under these conditions highly express biosynthetic enzymes for
      albonoursin, and thus are available for biosynthetic studies of dehydro cyclic
      peptides.

PMID- 10656575
TI  - Structures of flagranones A, B and C, cyclohexenoxide antibiotics from the
      nematode-trapping fungus Duddingtonia flagrans.
AB  - Spectroscopic data define the structures of the flagranones A (2), B (3) and C
      (4) from the nematode-trapping fungus Duddingtonia flagrans. These antibiotics
      are structurally related to the farnesylated cyclohexenoxides of the oligosporon
      group recently isolated from the nematode-trapping fungus Arthrobotrys
      oligospora, and show similar antimicrobial activity.

PMID- 10656576
TI  - Semisynthetic derivatives of madurahydroxylactone and their antibacterial
      activities.
AB  - Madurahydroxylactone is a secondary metabolite from Nonomuria rubra (former
      Actinomadura rubra) with in vitro activity against gram-positive bacteria and
      belongs to the family of benzo[a]naphthacenequinones. A series of derivatives of
      madurahydroxylactone were synthesized to investigate the effect on the
      antibacterial activity. Reaction with alcohols and amines gave cyclic acetals or
      aminals derived from the lactone form, whereas other amino reagents like
      hydroxylamines and acyl or sulfonyl hydrazides led to the corresponding imine
      derivatives of the aldehyde. Hydrazine, alkyl and aryl hydrazines react with
      madurahydroxylactone under cyclization to give compounds of the new heterocyclic
      basic structure naphthaceno[1,2-g]phthalazine. Some new compounds strongly
      inhibit gram-positive bacteria, in part stronger than the parent compound.

PMID- 10656577
TI  - Inhibition of cholesteryl ester transfer protein by fungal metabolites, L681,512.

PMID- 10656578
TI  - UCT1072s, new antitumor antibiotics with topoisomerase II mediated DNA cleavage
      activity, from Aspergillus sp.

PMID- 10656579
TI  - Structural modification of the lincomycin antibiotic.

PMID- 10656580
TI  - Resistance of tomato line Hawaii7996 to Ralstonia solanacearum Pss4 in Taiwan is
      controlled mainly by a major strain-specific locus.
AB  - Bacterial wilt caused by the soilborne bacterium Ralstonia solanacearum attacks
      hundreds of plant species, including many agriculturally important crops. Natural
      resistance to this disease has been found in some species and is usually
      inherited as a polygenic trait. In tomato, a model crop plant, genetic analysis
      previously revealed the involvement of several QTL (quantitative trait loci)
      controlling resistance and, in all of these studies with different strains of the
      pathogen, loci on chromosome 6 played the predominant role in controlling this
      trait. Using quantitative data collected from a greenhouse test F3 population, we
      identified a new locus on chromosome 12 that appears to be active specifically
      against a race 1 biovar 3 Pss4 bacterial strain endemic to Taiwan. Chromosome 6
      still contributes significantly to the control of the resistance, and weaker
      associations of the trait to other regions of the genome are observed. These
      results are discussed in the context of current molecular knowledge about the
      strain specificity of disease resistance genes.

PMID- 10656581
TI  - Carbon metabolism in developing soybean root nodules: the role of carbonic
      anhydrase.
AB  - A full-length cDNA clone encoding carbonic anhydrase (CA) was isolated from a
      soybean nodule cDNA library. In situ hybridization and immunolocalization were
      performed in order to assess the location of CA transcripts and protein in
      developing soybean nodules. CA transcripts and protein were present at high
      levels in all cell types of young nodules, whereas in mature nodules they were
      absent from the central tissue and were concentrated in cortical cells. The
      results suggested that, in the earlier stages of nodule development, CA might
      facilitate the recycling of CO2 while at later stages it may facilitate the
      diffusion of CO2 out of the nodule system. In parallel, sucrose metabolism was
      investigated by examination of the temporal and spatial transcript accumulation
      of sucrose synthase (SS) and phosphoenolpyruvate carboxylase (PEPC) genes, with
      in situ hybridization. In young nodules, high levels of SS gene transcripts were
      found in the central tissue as well as in the parenchymateous cells and the
      vascular bundles, while in mature nodules the levels of SS gene transcripts were
      much lower, with the majority of the transcripts located in the parenchyma and
      the pericycle cells of the vascular bundles. High levels of expression of PEPC
      gene transcripts were found in mature nodules, in almost all cell types, while in
      young nodules lower levels of transcripts were detected, with the majority of
      them located in parenchymateous cells as well as in the vascular bundles. These
      data suggest that breakdown of sucrose may take place in different sites during
      nodule development.

PMID- 10656582
TI  - Expression of a pathogen-induced gene can be mimicked by auxin insensitivity.
AB  - Following perception of a pathogenic attack, plants are able to develop a strong
      response with the corresponding activation of a plethora of defense-related
      genes. In this study we have characterized the mode of expression of the CEVI-1
      gene from tomato plants, which encodes an anionic peroxidase. CEVI-1 expression
      is induced during the course of compatible viral and subviral infections, like
      many other defense-related genes, but is induced neither in incompatible
      interactions nor by signal molecules such as salicylic acid, ethylene, or methyl
      jasmonate. Additionally, CEVI-1 is induced in detached leaf tissues following a
      pathway distinct from that related to the classical wound response. We also
      describe the characterization of the structural CEVI-1 gene and compare the mode
      of expression in different transgenic plant species harboring a CEVI-1::GUS
      construct. Furthermore, we have isolated mutants in Arabidopsis, called dth
      mutants, that are deregulated in the control of expression of this gene. From the
      initial analysis of some of these mutants it seems that activation of CEVI-1 gene
      expression correlates with a defect in the perception of auxins by the plant. All
      these results may suggest that, during systemic infections with viruses, auxin
      homeostasis is one of the components participating in the regulation of the
      overall defense response.

PMID- 10656583
TI  - Cyst germination proteins of the potato pathogen Phytophthora infestans share
      homology with human mucins.
AB  - We have cloned genes of Phytophthora infestans, the causal agent of potato late
      blight, that are activated shortly before the onset of invasion of the host
      tissue. The three genes isolated appear to be arranged in a genomic cluster and
      belong to a small polymorphic gene family. A conspicuous feature of the deduced
      proteins is an internal octapeptide repeat with the consensus sequence TTYAP TEE.
      Because of this structural motif, these novel P. infestans proteins were named
      Car (Cyst-germination-specific acidic repeat) proteins. One of the genes, car90,
      codes for 1,489 amino acids including 120 octapeptide tandem repeats. Car
      proteins are transiently expressed during germination of cysts and formation of
      appressoria and are localized at the surface of germlings. The structural motif
      of tandemly repeated oligopeptides also occurs in a prominent class of proteins,
      the mucins, from mammals. The P. infestans Car proteins share 51% sequence
      homology with the tandem repeat region of a subfamily of human mucins. According
      to the physiological functions ascribed to mucins, we suggest that Car proteins
      may serve as a mucous cover protecting the germling from desiccation, physical
      damage, and adverse effects of the plant defense response and may assist in
      adhesion to the leaf surface.

PMID- 10656584
TI  - Functional expression of the gene cu, encoding the phytotoxic hydrophobin cerato
      ulmin, enables Ophiostoma quercus, a nonpathogen on elm, to cause symptoms of
      Dutch elm disease.
AB  - We studied the involvement of the phytotoxic hydrophobin cerato-ulmin (CU) in
      pathogenesis and virulence of Dutch elm disease (DED) by expressing its encoding
      gene (cu) in Ophiostoma quercus, a nonpathogenic species on elm closely related
      to the DED pathogens O. ulmi and O. novo-ulmi. The production of the toxin was
      quantitatively determined in culture filtrates and in mycelial extracts of the
      transformants. Production of CU in vitro was associated with the ability to cause
      typical DED symptoms, consisting of foliar yellow and wilting and vascular tissue
      discoloration on a moderately resistant elm genotype. The presence of CU was
      monitored by enzyme-linked immunosorbent assay in symptomatic leaves of plants
      inoculated with O. quercus transformants expressing CU and found to be associated
      with wilt symptoms. In general, the virulence of the cu-expressing transformants,
      as measured in terms of vascular discoloration and percentage of defoliation, was
      lower than that of the mildly pathogenic isolate E2 of O. ulmi. However, one
      transformant (C39) displayed a virulence level intermediate between that of E2
      and 182, a highly virulent isolate of O. novo-ulmi. Our results indicate that CU
      production influences virulence in nonaggressive strains of Ophiostoma fungi.

PMID- 10656585
TI  - Specific binding sites for an antifungal plant defensin from Dahlia (Dahlia
      merckii) on fungal cells are required for antifungal activity.
AB  - Dm-AMP1, an antifungal plant defensin from seeds of dahlia (Dahlia merckii), was
      radioactively labeled with t-butoxycarbonyl-[35S]-L-methionine N-hydroxy
      succinimi-dylester. This procedure yielded a 35S-labeled peptide with unaltered
      antifungal activity. [35S]Dm-AMP1 was used to assess binding on living cells of
      the filamentous fungus Neurospora crassa and the unicellular fungus Saccharomyces
      cerevisiae. Binding of [35S]Dm-AMP1 to fungal cells was saturable and could be
      competed for by preincubation with excess, unlabeled Dm-AMP1 as well as with Ah
      AMP1 and Ct-AMP1, two plant defensins that are highly homologous to Dm-AMP1. In
      contrast, binding could not be competed for by more distantly related plant
      defensins or structurally unrelated antimicrobial peptides. Binding of [35S]Dm
      AMP1 to either N. crassa or S. cerevisiae cells was apparently irreversible. In
      addition, whole cells and microsomal membrane fractions from two independently
      obtained S. cerevisiae mutants selected for resistance to Dm-AMP1 exhibited
      severely reduced binding affinity for [35S]Dm-AMP1, compared with wild-type
      yeast. This finding suggests that binding of Dm-AMP1 to S. cerevisiae plasma
      membranes is required for antifungal activity of this protein.

PMID- 10656586
TI  - Analysis of Medicago truncatula nodule expressed sequence tags.
AB  - Systematic sequencing of expressed sequence tags (ESTs) can give a global picture
      of the assembly of genes involved in the development and function of organs.
      Indeterminate nodules representing different stages of the developmental program
      are especially suited to the study of organogenesis. With the vector
      lambdaHybriZAP, a cDNA library was constructed from emerging nodules of Medicago
      truncatula induced by Sinorhizobium meliloti. The 5' ends of 389 cDNA clones were
      sequenced, then these ESTs were analyzed both by sequence homology search and by
      studying their expression in roots and nodules. Two hundred fifty-six ESTs
      exhibited significant similarities to characterized data base entries and 40 of
      them represented 26 nodulin genes, while 133 had no similarity to sequences with
      known function. Only 60 out of the 389 cDNA clones corresponded to previously
      submitted M. truncatula EST sequences. For 117 cDNAs, reverse Northern (RNA)
      hybridization with root and nodule RNA probes revealed enhanced expression in the
      nodule, 48 clones are likely to code for novel nodulins, 33 cDNAs are clones of
      already known nodulin genes, and 36 clones exhibit similarity to other
      characterized genes. Thus, systematic analysis of the EST sequences and their
      expression patterns is a powerful way to identify nodule-specific and nodulation
      related genes.

PMID- 10656587
TI  - N-deacetylation of Sinorhizobium meliloti Nod factors increases their stability
      in the Medicago sativa rhizosphere and decreases their biological activity.
AB  - Nod factors excreted by rhizobia are signal molecules that consist of a chitin
      oligomer backbone linked with a fatty acid at the nonreducing end. Modifications
      of the Nod factor structures influence their stability in the rhizosphere and
      their biological activity. To test the function of N-acetyl groups in Nod
      factors, NodSm-IV(C16:2,S) from Sinorhizobium meliloti was enzymatically N
      deacetylated in vitro with purified chitin deacetylase from Colletotrichum
      lindemuthianum. A family of partially and completely deacetylated derivatives was
      produced and purified. The most abundant chemical structures identified by mass
      spectrometry were GlcN(C16:2)-GlcNAc-GlcNH2-GlcNAc(OH)(S), GlcN(C16,2)-GlcNAc
      GlcNH2-GlcNH2(OH)(S), and GlcN(C16:2)-GlcNH2-GlcNH2-GlcNH2(OH)(S). In contrast to
      NodSm-IV(C16:2,S), the purified N-deacetylated derivatives were stable in the
      rhizosphere of Medicago sativa, indicating that the N-acetyl groups make the
      carbohydrate moiety of Nod factors accessible for glycosyl hydrolases of the host
      plant. The N-deacetylated derivatives displayed only a low level of activity in
      inducing root hair deformation. Furthermore, the N-deacetylated molecules were
      not able to stimulate Nod factor degradation by M. sativa roots, a response
      elicited by active Nod factors. These data show that N-acetyl groups of Nod
      factors are required for biological activity.

PMID- 10656588
TI  - Reduced virulence caused by meiotic instability of the TOX2 chromosome of the
      maize pathogen Cochliobolus carbonum.
AB  - The mechanisms by which pathogenic fungi evolve are poorly understood. Production
      of the host-selective cyclic peptide HC-toxin is controlled by a complex locus,
      TOX2, in the plant pathogen Cochliobolus carbonum. Crosses between toxin
      producing (Tox2+) and toxin-nonproducing (Tox2-) isolates, as well as crosses
      between isolates in which the TOX2 genes were on chromosomes of different size,
      yielded progeny that had lost one or more copies of one or more of the TOX2
      genes. Of approximately 200 progeny analyzed, eight (4%) had lost at least one
      TOX2 gene. All of them still had at least one functional copy of all of the known
      genes required for HC-toxin production (HTS1, TOXA, TOXC, and TOXE). Most
      deletion strains could be explained by simple chromosome breaks resulting in the
      loss of major contiguous portions (0.8 to 1.4 Mb) of the 3.5-Mb TOX2 chromosome,
      whereas others had more complicated patterns. All deletion strains had normal
      growth and were fertile, indicating that the 1.4 Mb of DNA contained no essential
      housekeeping genes. Most strains were also still virulent (Tox2+), but two had a
      novel phenotype of reduced virulence (RV), characterized by smaller lesions that
      expanded at a reduced rate and an inability to colonize plants systemically.
      Although the RV strains made no detectable HC-toxin in culture, the RV phenotype
      was dependent on the presence of a functional copy of HTS1, which encodes the
      central enzyme in HC-toxin biosynthesis. We propose that the RV strains still
      make a low level of HC-toxin, at least in planta, and that this is due to the
      loss of one or more genes that contribute to, but are not absolutely required
      for, HC-toxin synthesis.

PMID- 10656589
TI  - Transmissible mitochondrial hypovirulence in a natural population of
      Cryphonectria parasitica.
AB  - A cytoplasmically transmissible hypovirulence syndrome has been identified in
      virus-free strains of the chestnut blight fungus Cryphonectria parasitica
      isolated from healing cankers on American chestnut trees in southwestern
      Michigan. The syndrome is associated with symptoms of fungal senescence,
      including a progressive decline in the growth potential and abundance of conidia,
      and elevated levels of respiration through the cyanide-insensitive alternative
      oxidase pathway. Conidia from senescing mycelia exhibited varying degrees of
      senescence ranging from normal growth to death soon after germination.
      Cytoplasmic transmission of hypovirulence between mycelia occurred by hyphal
      contact and coincided with the transfer of a specific restriction fragment length
      polymorphism from the mitochondrial DNA (mtDNA) of the donor strains into the
      mtDNA of virulent recipients. The transmission of the senescence phenotype was
      observed not only among vegetatively compatible strains but also among
      incompatible strains. Hypovirulence was present in isolates from the same
      location with different nuclear genotypes as identified by DNA fingerprinting.
      This study confirms that mitochondrial hypovirulence can occur spontaneously and
      spread within a natural population of a phytopathogenic fungus.

PMID- 10656590
TI  - Expression profiles of 22 novel molecular markers for organogenetic pathways
      acting in alfalfa nodule development.
AB  - During symbiotic nodule development, a variety of molecular signals of rhizobia
      and plant origin are likely to be involved in the control of the expression of
      specific genes in the legume Medicago sativa (alfalfa). Twenty-two new, nodule
      associated Expressed Sequence Tags (ESTs, MsNod clones) as well as 16 clones for
      previously reported alfalfa nodulins were identified by cold-plaque screening.
      Protein homologs were found for 10 of the 22 MsNod-encoded polypeptides,
      revealing putative novel functions associated with this symbiosis. Expression of
      these MsNod genes was investigated in spontaneous nodules (generated in the
      absence of bacteria), in nodules induced by a Sinorhizobium meliloti wild-type
      strain and Eps- and Bac- mutant derivatives, as well as in roots inoculated with
      a Nod- mutant strain. This analysis enabled us to correlate plant gene expression
      with the different stages of nodule ontogeny and invasion. The effect of
      phytohormones on MsNod gene expression was analyzed in cytokinin- and auxin
      treated alfalfa roots. Cytokinin induced the accumulation of seven MsNod
      transcripts, four of them were also regulated by the synthetic auxin 2,4-D (2,4
      dichlorophenoxyacetic acid). Comparison of MsNod expression profiles in wild-type
      and transgenic M. truncatula roots overexpressing the early nodulin Enod40
      suggested that one clone, the M. sativa L3 ribosomal protein homolog (MsNod377),
      is a putative component of an Enod40-dependent pathway acting during nodule
      development. These novel molecular markers may help in the investigation of gene
      networks and regulatory circuits controlling nodule organogenesis.

PMID- 10656591
TI  - Casuarina glauca prenodule cells display the same differentiation as the
      corresponding nodule cells.
AB  - Recent phylogenetic studies have implied that all plants able to enter root
      nodule symbioses with nitrogen-fixing bacteria go back to a common ancestor (D.E.
      Soltis, P.S. Soltis, D.R. Morgan, S.M. Swensen, B.C. Mullin, J.M. Dowd, and P.G.
      Martin, Proc. Natl. Acad. Sci. USA, 92:2647-2651, 1995). However, nodules formed
      by plants from different groups are distinct in nodule organogenesis and
      structure. In most groups, nodule organogenesis involves the induction of
      cortical cell divisions. In legumes these divisions lead to the formation of a
      nodule primordium, while in non-legumes they lead to the formation of a so-called
      prenodule consisting of infected and uninfected cells. Nodule primordium
      formation does not involve prenodule cells, and the function of prenodules is not
      known. Here, we examine the differentiation of actinorhizal prenodule cells in
      comparison to nodule cells with regard to both symbionts. Our findings indicate
      that prenodules represent primitive symbiotic organs whose cell types display the
      same characteristics as their nodule counterparts. The results are discussed in
      the context of the evolution of root nodule symbioses.

PMID- 10656592
TI  - Characterization of a Casuarina glauca nodule-specific subtilisin-like protease
      gene, a homolog of Alnus glutinosa ag12.
AB  - In search of plant genes expressed during early interactions between Casuarina
      glauca and Frankia, we have isolated and characterized a C. glauca gene that has
      strong homology to subtilisin-like protease gene families of several plants
      including the actinorhizal nodulin gene ag12 of another actinorhizal plant, Alnus
      glutinosa. Based on the expression pattern of cg12 in the course of nodule
      development, it represents an early actinorhizal nodulin gene. Our results
      suggest that subtilisin-like proteases may be a common element in the process of
      infection of plant cells by Frankia in both Betulaceae (Alnus glutinosa) and
      Casuarinaceae (Casuarina glauca) symbioses.

PMID- 10656593
TI  - Molecular cloning and characterization of a tobacco MAP kinase kinase that
      interacts with SIPK.
AB  - A tobacco MAP kinase termed SIPK (Salicylic acid-Induced Protein Kinase) is
      activated in response to a variety of stress signals, including pathogen attack
      and wounding (S. Zhang and D.F. Klessig, Proc. Natl. Acad. Sci. USA 95:7225-7230,
      1998; S. Zhang and D.F. Klessig, Proc. Natl. Acad. Sci. USA 95:7433-7438, 1998).
      Using the yeast two-hybrid system, we have identified a gene encoding a protein
      that interacts with SIPK but not the wounding induced protein kinase (WIPK),
      which is another tobacco MAP kinase. Sequence analysis indicated that this SIPK
      interacting protein is a member of the MAP kinase kinase family; thus, it was
      named SIPK kinase (SIPKK). Co-immunoprecipitation experiments demonstrated that
      SIPKK and SIPK interact in vitro. Consistent with its putative function as a
      kinase, SIPKK phosphorylated myelin basic protein in vitro. Interestingly, SIPKK
      was induced at the mRNA level after Tobacco mosaic virus (TMV) infection or
      wounding, albeit with kinetics that are too slow to account for the activation of
      SIPK following these stimuli.

PMID- 10656594
TI  - Potato mop-top virus RNA can move long distance in the absence of coat protein:
      evidence from resistant, transgenic plants.
AB  - Transgenic expression of a translatable version of the Potato mop-top virus
      (PMTV) coat protein (CP) gene (encoded by RNA 3) in Nicotiana benthamiana
      prevented production of symptoms and infective virus particles. RNAs 1 and 2
      accumulated in inoculated and systemic leaves but, apart from small amounts of CP
      transgene RNA transcript, no genomic-length RNA 3 was found. Crude leaf extracts
      from inoculated plants were not infective. However, when RNA extracts from such
      transgenic plants were inoculated to nontransgenic N. benthamiana and N.
      clevelandii, RNA 1 and RNA 2 replicated in systemic leaves of both species in the
      absence of RNA 3 and virus particles, but symptoms did not develop. We suggest
      that the triple-gene block proteins of PMTV (encoded by RNA 2) represent a class
      of long-distance RNA movement factors.

PMID- 10656595
TI  - MucR is necessary for galactoglucan production in Sinorhizobium meliloti EFB1.
AB  - Sinorhizobium meliloti can produce two types of acidic exopolysaccharides,
      succinoglycan and galactoglucan, that are interchangeable for infection of
      alfalfa nodules. Strain SU47 and derivatives produce only succinoglycan, unless
      it grows under phosphate limitation or carries a mutation in either of two
      regulatory loci, mucR or expR. It has been proposed that MucR acts as a
      transcriptional repressor that blocks the expression of the exp genes responsible
      for galactoglucan production. Strain EFB1 simultaneously produces both
      exopolysaccharides. Heterologous expression of lacZ transcriptional fusions of
      the expE promoters has shown that genetic background is more important that
      promoter sequence for exp gene expression, since expE promoters from both strains
      are expressed at high level in EFB1 and not in SU47. We have found that mucR is
      present in mucoid and nonmucoid strains, and in EFB1 differs from SU47 in only
      one conservative amino acid change. MucR proteins from both strains are
      interchangeable. An mucR mutant of EFB1 cannot produce galactoglucan and does not
      express mucS.

PMID- 10656596
TI  - Isolation, partial sequencing, and expression of pathogenesis-related cDNA genes
      from pepper leaves infected by Xanthomonas campestris pv. vesicatoria.
AB  - Specific cDNAs showing differential expression in bacteria-infected pepper leaves
      as opposed to healthy leaves were isolated from a pepper cDNA library from
      hypersensitive response (HR) lesions of leaves infected with an avirulent strain
      of Xanthomonas campestris pv. vesicatoria. Among a total of 282 cDNA clones
      tested, 36 individual cDNA genes (13%) hybridized strongly or differentially to
      the cDNA probes from bacteria-infected leaves. Ten Capsicum Annuum-Induced (CAI)
      genes encoding putative thionin, lipid transfer protein I and II, osmotin (PR-5),
      class I chitinase, beta-1,3-glucanase, SAR 8.2, stellacyanin, leucine-rich repeat
      protein, and auxin-repressed protein were identified. Two CAI genes showed little
      or no sequence homology to the previously sequenced plant genes. Transcripts of
      the CAI genes were strongly or preferentially induced in pepper tissues by
      infection with X. campestris pv. vesicatoria or Phytophthora capsici, and by
      abiotic elicitor treatment. In particular, most of the CAI genes were strongly
      induced in pepper tissues by ethephon and methyl jasmonate.

PMID- 10656597
TI  - A comparison of some clinical features of visual reinforcement audiometry and the
      distraction test.
AB  - The aim of this study was to compare aspects of visual reinforcement audiometry
      (VRA) and the distraction test (DT), the two most commonly used behavioural tests
      of hearing for young children. The number of assessments completed, time taken,
      parental opinion and levels of minimum responses were compared in a group of 20
      infants (mean age 17.7 months; SD 4.7 months; range 12-25 months) who had been
      selected from those referred from a local second-tier community audiology
      service. Each infant was assessed with each test following set protocols and a
      balanced design on two occasions separated by one week. Parental opinion was
      determined by application of two questionnaires, one after each session. There
      was no difference in the number of minimum response levels (MRLs) measured by the
      two tests. However, if a VRA protocol using three MRLs was assumed then the
      assessment was completed successfully in a significantly greater number of
      subjects with VRA. VRA took, on average, two minutes less than the DT to measure
      six MRLs. Most of the subject sample had normal hearing as defined by both tests.
      However, where MRLs were >30 dB HL for at least one of the tests, the DT elicited
      responses at significantly higher levels than VRA, suggesting that in these
      subjects the DT under-estimated hearing sensitivity. Seventy per cent of parents
      selected VRA when asked to choose between the tests.

PMID- 10656598
TI  - Monitoring noise susceptibility: sensitivity of otoacoustic emissions and
      subjective audiometry.
AB  - The capacity of different audiological methods to detect a high noise
      susceptibility was examined in 20 normally hearing and 26 especially noise
      susceptible subjects. The latter were selected from 422 soldiers in field
      studies: they had shown a temporary threshold shift (TTS) in pure tone audiometry
      (PTA) after regular training with firearms. In laboratory experiments, the TTS
      positive soldiers were re-examined using greatly reduced sound intensities, which
      caused no TTS in a control subject group. Before and after acoustic stimulation,
      different subjective (PTA, high frequency audiometry (HFA), upper limit of
      hearing (ULH)) and objective (transiently evoked otoacoustic emissions (TEOAE),
      distortion products (DPOAE)) audiological tests were performed. After exposure to
      low impact noise in the laboratory, in both PTA and HFA, a TTS was observed in
      11.5% (N = 3) of the noise-susceptible group (compared to 0% in the control
      group). In the TTS-positive group, deterioration of the ULH occurred in 28% (N =
      7) (compared to 15% (N = 3) in the control group). An ULH improvement occurred in
      only one subject (3.8%) (compared to 25% (N = 5) in the control group).
      Significant alterations of click-evoked OAE-amplitudes were found in 26.9% (N =
      7) of the selected groups, whereas stable emissions were observed in all but one
      subject (5%) of the control group. However, DPOAE alterations were seen in 19.2%
      (N = 5) of the TTS-positive soldiers but also in 25% (N = 5) of the control
      group. These results suggest that TEOAE provides a more sensitive and more
      objective method of detecting a subtle noise-induced disturbance of cochlear
      function than do PTA or DPOAE.

PMID- 10656599
TI  - Speech pattern audiometry in hearing impaired children.
AB  - The aim of this study was to investigate the use of speech pattern audiometry
      (SPA) in assessing speech perception abilities of a group of 25 children with
      sensorineural hearing loss, and to compare their aided performance on SPA tests
      of four different phoneme contrasts with scores achieved on recorded Manchester
      Junior Word Lists (MJWL) at their most comfortable listening level (MCLL). The
      listeners were 25 children, 19 with congenital and six with acquired hearing loss
      aged between eight and 14 years. They were classified into three groups according
      to the severity of the hearing loss in the better hearing ear (20-60 dB HL, 61-80
      dB HL and >81 dB HL). The SPA tests evaluated listeners' ability to identify word
      initial plosives differing in the phonetic features of voicing and place of
      articulation. The main outcome measures were the SPA gradient measures, the SPA
      labelling function configuration and MJWL scores. The group with the most severe
      hearing loss (>81 dB HL) showed significantly poorer performance on the SPA tests
      and MJWL tests than the groups with mild (20-60 dB HL) to moderate (61-80 dB HL)
      hearing losses. There was significantly better performance on the two plosive
      voicing contrast tests than the two plosive place contrasts. For the MJWL, the
      performance of the group with the more severe hearing loss was also significantly
      different from the mild and moderate hearing loss groups. A MJWL score of up to
      75% was associated with the random labelling configuration on all four SPA tests,
      emphasizing the different aspects of speech perception that were being examined
      with each type of test. This study suggests that there is a place for SPA as part
      of the test battery for speech perception testing in hearing-impaired children.

PMID- 10656600
TI  - Prevalence of hearing impairment and subjective hearing problems in a rural
      Danish population aged 31-50 years.
AB  - The objective of the present study was to describe the prevalence of subjective
      hearing problems and hearing impairment and to evaluate the relation between
      subjective hearing problems and audiometric thresholds, in a random sample of
      subjects aged 31-50 years. The study is cross-sectional and based on data from
      questionnaires (N = 1397) and pure tone audiometry (N = 905) in the Ebeltoft
      Health Promotion Project in Denmark. Hearing problems were significantly more
      prevalent in males than females. Males had significantly poorer average
      audiometric thresholds (0.5, 1, 2 and 4 kHz) in the better hearing ear (BE) and
      worse hearing ear (WE) than females. Average audiometric thesholds were poorer in
      the 41-50-year-old age group compared with the 31-40-year-old age group, the
      difference being most marked in males. Overall prevalence of hearing impairment
      (at least two threshold levels >25 dB HL) was 7.4% (95% confidence interval: 5.7
      9.1%) in BE and 15.9% (13.5-18.3%) in WE. Prevalence of impairment > or = 25, >
      or = 35 and > or = 45 dB HL (average across 0.5-4 kHz): (BE) 3.4% (2.2-4.6%),
      1.0% (0.3-1.6%) and 0.2% (0.0-0.5%); (WE) 11.6% (9.5-13.7%), 3.6% (2.4-4.9%) and
      1.7% (0.8-2.5%). An interesting sex difference was noted as females were aware of
      hearing problems at an earlier stage of impairment than males. In conclusion,
      hearing impairment is fairly prevalent in this young rural population, less
      prevalent, however, than in the British National Study of Hearing. It is proposed
      that general practitioners should take a more active part in primary prevention,
      early detection of hearing impairment and early referral for rehabilitation.

PMID- 10656601
TI  - Alternatives in screening at school entry: comparison of the childhood middle ear
      disease and hearing questionnaire (CMEDHQ) and the pure tone sweep test.
AB  - Some health authorities in the UK are discontinuing hearing screening at school
      entry, mainly because the pure tone sweep test is under-specific (i.e. fails too
      many children) and thus leads to unnecessary and costly, but unproductive, follow
      up assessment. A screening method with different properties such as a
      questionnaire could be a more cost-effective method of mass screening children.
      The MRC Institute of Hearing Research has developed and evaluated through several
      stages such a screening questionnaire (the Childhood Middle Ear Disease and
      Hearing Questionnaire (CMEDHQ), containing 11 scored questions under two broad
      headings: history and presentation of the disease, and consultation/treatment
      history. In a service-based evaluation, 2860 mainstream reception-year school
      children from two consecutive years, attending schools in south west Cumbria in
      the North-West Regional Health Authority received the sweep test and the CMEDHQ.
      (Although predominantly designed to detect middle ear problems, the questionnaire
      also has some potential to detect permanent hearing loss; thus providing a useful
      backstop for detection of permanent losses either missed or not present in
      earlier infancy.) The screening CMEDHQ obtained a very high response rate (90%).
      Follow-up included 235 control cases as well as all pure tone sweep test
      failures. Analysis, by use of a definition of cases conservative with respect to
      the sensitivity of the questionnaire, showed that the CMEDHQ has better
      specificity, but slightly lower sensitivity, than the pure tone sweep test for
      composite system decision (where 'case' = treated at ENT; 'non-case' = pass at
      whatever stage was reached before discharge). Follow-up indicated that the
      limited method available for assessing sensitivity might give an over-favourable
      view of the pure tone sweep test. Possible improvement of questionnaire
      sensitivity by further refinements is under examination. The findings show that
      it is worth conducting a fully parallel multi-district cost-effectiveness
      comparison of the pure tone sweep test versus the CMEDHQ.

PMID- 10656602
TI  - TEOAE-based estimation of the auditory threshold in the mid-octave frequencies.
AB  - The purpose of this study was to estimate the hearing levels, at the mid
      frequencies, of 233 ears with sensorineural hearing loss by classifying the
      corresponding transiently evoked otoacoustic emissions (TEOAE) recordings into
      three threshold groups. A classification algorithm was based upon a discriminant
      analysis of fast Fourier transform (FFT) data, evoked by non-linear click stimuli
      of 80 (+/-2) dB SPL per ear. To validate the efficiency of the proposed
      methodology TEOAE recordings were initially grouped by mean hearing level values
      of the 1 kHz and 2 kHz octaves into three threshold ranges according to two
      strategy schemes: in the first, TEOAE data were assigned into 10-19 dB HL, 20-39
      dB HL or > or = 40 dB HL groups. In the second, TEOAE data were assigned into 10
      29 > dB H >, 30-39 dB HL or > or = 40 dB HL groups. The most accurate prediction
      estimates were obtained from the second strategy scheme with a 90.9% accuracy in
      the 10-29 dB HL group, 82% in the 30-39 dB HL group and 71.4% in the > or = 40 dB
      HL group.

PMID- 10656603
TI  - Tumorigenicity of nitropolycyclic aromatic hydrocarbons in the neonatal B6C3F1
      mouse bioassay and characterization of ras mutations in liver tumors from treated
      mice.
AB  - The nitropolycyclic aromatic hydrocarbons (nitro-PAHs) 1-, 2-, and 3
      nitrobenzo[a]pyrene, 1- and 3-nitrobenzo[e]pyrene, 2- and 3-nitrofluoranthene, 9
      nitrodibenz[a,c]anthracene, and two of the parent PAHs fluoranthene and
      dibenz[a,c]anthracene were tested for tumorigenicity in the neonatal male B6C3F1
      mouse. 6-Nitrochrysene was used as a positive control. Mice were administered
      three intraperitoneal injections of test agent (400 nmol total) on 1, 8, and 15
      days after birth and evaluated for liver and lung tumors at 12 months of age. 2
      Nitrobenzo[a]pyrene and 6-nitrochrysene induced a high incidence of liver tumors
      (91-100%), while the remaining test compounds did not induce tumors at a rate
      significantly higher than the solvent control. 6-Nitrochrysene was the only test
      agent to produce a significant increase in the frequency of lung tumors. K- and H
      ras mutations were analyzed in liver tumors of treated mice and mainly occurred
      at the first base of K-ras codon 13, resulting in GGC --> CGC transversion. Since
      most of the tested nitro-PAHs are mutagens in vitro, the results of this study
      indicate that the in vitro mutagenicity of these compounds does not correlate
      with their tumorigenicity in the neonatal B6C3F1 mouse bioassay. Also, the
      results indicate that liver tumors from mice treated with nitro-PAHs possess ras
      mutations typical of PAHs and their derivatives.

PMID- 10656604
TI  - Laryngeal cancer and human papillomavirus: HPV is absent in the majority of
      laryngeal carcinomas.
AB  - Thirty laryngeal carcinomas from patients without pre-existing laryngeal
      papillomatosis were examined by PCR for the presence of HPV DNA. The utmost care
      was taken during sectioning of the tissue blocks and DNA-extraction in order to
      avoid false positive results. Three pairs of consensus primers were used:
      MY9/MY11, GP5+/GP6+ and CPI/CPII. HPV was detected in 1/30 carcinomas. The HPV
      type present could not be determined, but it was not type 6, 11, 13, 16, 18, 30,
      31, 33, 35 or 45. In other studies the reported frequency of HPV in laryngeal
      carcinomas, as estimated by PCR, varies between 3-85%. The reasons for this
      unacceptable variation in reported results are discussed. The present results
      indicate that HPV DNA does not have a major role in malignant tumours of the
      larynx in patients without pre-existing recurrent laryngeal papillomatosis.

PMID- 10656605
TI  - Antitumor effects of bis(ethyl)polyamine analogs on mammary tumor development in
      FVB/NTgN (MMTVneu) transgenic mice.
AB  - We studied the therapeutic potential of two polyamine analogs on breast cancer
      using FVB/NTgN (MMTVneu), a transgenic mouse model with neu/erb-B2 oncogene
      overexpression. Treatment was initiated at 31 weeks of age with
      bis(ethyl)norspermine (BE333) and its higher homolog, BE3333 as i.p. injections
      once weekly. There was a 40% reduction in the average number of tumors per mouse
      in both treatment groups, by 10 weeks of treatment. BE3333-treated mice had 70
      75% lower tumor volume than controls. Spermidine/spermine acetyl transferase
      activity was significantly higher in tumor tissues and kidneys of treated
      animals, whereas polyamine levels were lower than controls. Beneficial effects
      were also evident from the mortality rates in control and treatment groups. Our
      results suggest a potential use of selected bis(ethyl) polyamine analogs as
      antitumor agents in breast cancer.

PMID- 10656606
TI  - Highly activated matrix metalloproteinase-2 secreted from clones of metastatic
      lung nodules of nude mice injected with human fibrosarcoma HT1080.
AB  - The promoting effects of matrix metalloproteinase-2 (MMP-2) on lung metastasis of
      human fibrosarcoma cells (HT1080) were studied using nude mice. The fourth
      generation of HT1080 was established by consecutive clonal selection of
      metastatic lung nodules formed by intravenous transplantation. MMP-2 and MMP-9 in
      the culture supernatants of the first and fourth generation cells were analyzed
      by gelatin zymography and Western blotting, and quantified by scanning
      densitometry. In gelatin zymograms, mean ratios of values for the 59-kDa band
      (the active form of MMP-2) to those for the 72-kDa band (the inactive form of MMP
      2) for optical density; area, and volume measured by densitometry were 1.44 +/-
      0.12, 0.93 +/- 0.05, and 1.27 +/- 0.20, respectively, in the culture supernatant
      of fourth generation cells isolated from metastatic lung nodules. These values
      were significantly (P < 0.01) higher than those of first generation cells (0.70
      +/- 0.04, 0.48 +/- 0.01, and 0.57 +/- 0.42). Three weeks after intravenous
      transplantation of HT1080 cells into nude mice, the incidence of lung metastasis
      and mean number and diameter of metastatic nodules formed by injection of first
      generation cells were 20% (2 of 10 mice), 2.9 +/- 0.2 and 2.0 +/- 0.2 mm,
      respectively; while they were 100%, 99.8 +/- 7.2 and 4.3 +/- 0.3 mm following
      injection of fourth generation cells. These findings suggest that the active MMP
      2 produced by human fibrosarcoma cells is important for the cells to form lung
      metastatic lesions in nude mice.

PMID- 10656607
TI  - Uracil misincorporation, DNA strand breaks, and gene amplification are associated
      with tumorigenic cell transformation in folate deficient/repleted Chinese hamster
      ovary cells.
AB  - Clinical and experimental evidence has linked nutritional folic acid status to
      both anti- and procarcinogenic activity. Folate supplementation of normal cells
      appears to have a protective effect; however, folate supplementation of initiated
      cells may promote neoplastic progression. Given these considerations, the present
      series of experiments examines alterations in DNA metabolism and cumulative DNA
      lesions using an in vitro model of folate deprivation and repletion. DNA repair
      deficient CHO-UV5 cells were cultured in Ham's F-12 medium or in custom-prepared
      Ham's F-12 medium lacking in folic acid, thymidine and hypoxanthine for a period
      of 18 days without cell passage. The results indicated that progressive folate
      and nucleotide depletion leads to a significant increase in the ratio of
      dUTP/dTTP and to the misincorporation of uracil into DNA. These alterations were
      accompanied by growth inhibition, DNA strand breaks, abasic sites and phenotypic
      abnormalities. After 14 days in culture, there was significant increase in gene
      amplification potential in the chronically folate-deficient cells, but no
      significant increase in anchorage-independent growth or in neoplastic
      transformation. Acute folate repletion of the deficient cells was used as a
      proliferative stimulus under conditions of dNTP pool imbalance and multiple
      lesions in DNA. A further increase in gene amplification was accompanied by
      anchorage-independent growth and neoplastic cell transformation as evidenced by
      aggressive tumor growth in Balb/c nu/nu mice. Using a sensitive in vitro model
      system, these results emphasize the essentiality of folic acid for de novo
      nucleotide synthesis and the integrity of the DNA. However, the in vivo
      relevance, especially in terms of tumorigenic potential, is not clear.

PMID- 10656608
TI  - Mu3 opiate receptor expression in lung and lung carcinoma: ligand binding and
      coupling to nitric oxide release.
AB  - The mu3 opiate receptor subtype is expressed in human surgical specimens of both
      normal lung and non-small-cell lung carcinoma. Nitric oxide (NO) release is
      mediated through the mu3 receptor, and in lung carcinoma, morphine-stimulated NO
      release is significantly higher and prolonged than in normal lung. Using reverse
      transcriptase-polymerase chain reaction (RT-PCR) and Southern blot analysis we
      show that specific mu opioid receptor transcripts are present in lung carcinoma
      and other cells with the mu3 profile. Our findings identify a unique role for the
      mu3 opiate receptor in opiate-mediated NO release and suggest that endogenous
      opiates, through their release of NO, may play a role in cancer progression.

PMID- 10656609
TI  - Prostaglandin H synthase-medicated oxidation and binding to DNA of a detoxication
      metabolite of carcinogenic Sudan I, 1-(phenylazo)-2,6-dihydroxynaphthalene.
AB  - The metabolite of the carcinogenic azo dye Sudan I, 1-(phenylazo)-2,6
      dihydroxynaphthalene (6-OH-Sudan I), which is considered to be the detoxification
      product of this dye is metabolized by prostaglandin H synthase (PHS) in the
      presence of arachidonic acid or H2O2 in vitro. The apparent Michaelis constant
      value for 6-OH-Sudan I as a substrate is 98.9 microM. 1-(Phenylazo)-2,6
      naphthoquinone is a principal product of the 6-OH-Sudan I oxidation. This
      oxidation is inhibited by radical scavengers nitrosobenzene, ascorbate,
      glutathione and NADH. This indicates that PHS metabolizes 6-OH-Sudan I through a
      one-electron oxidation mechanism, giving rise to free radicals. During the PHS
      mediated reaction, 6-OH-Sudan I is activated to metabolites binding to protein
      and DNA. The 32P-postlabeling analysis of DNA modified by activated 6-OH-Sudan I
      provides evidence that covalent binding to DNA is the principal type of DNA
      modification. The PHS-mediated binding of 6-OH-Sudan I to DNA presumably proceeds
      through formation of 1-(phenylazo)-2,6-naphthoquinone. The results suggest
      strongly that the C-hydroxylated derivative of Sudan I (6-OH-Sudan I) should be
      evaluated as a proximate carcinogenic metabolite, which may participate in the
      initiation of Sudan I-carcinogenesis in the urinary bladder.

PMID- 10656610
TI  - Activation of blood coagulation and the activity of cancer procoagulant (EC
      3.4.22.26) in breast cancer patients.
AB  - The activity of cancer procoagulant (CP), prothrombin time (PT), activated
      partial thromboplastin time (APTT), the concentration of thrombin-antithrombin
      complexes (TAT) and the concentration of fibrinogen were analysed in blood of
      breast cancer patients scheduled for surgery. The serum level of CP activity was
      dependent on the stage of the disease. The CP activity was increased in 72% of
      patients with an early stage of cancer and in only 20% of patients with an
      advanced stage of the disease when compared to the baseline level for non-cancer
      controls. In all patients PT remained at normal levels (80-120%). There was no
      significant change in APTT (27-39 s) in early stage cancer patients. Only one
      patient with advanced cancer had APTT shortened to 23 s. Also one advanced stage
      patient had significantly elevated level of TAT (14.96 microg/l); in all other
      patients the concentration of TAT remained at normal levels (1-4.1 microg/l).
      Forty-four percent of early stage cancer patients and 22% of advanced cancer
      patients had an elevated level of fibrinogen (Fg) ( > 350 mg%). However, there
      was no correlation between the level of Fg and the CP activity (P > 0.05). The
      data suggest that: (1) serum CP activity increases at the early stage of breast
      cancer and decreases down to the normal level in the advanced stage of the
      disease; (2) there is no evidence of blood clotting activation in the early stage
      breast cancer patients; and (3) CP does not facilitate the activation of
      coagulation in the breast cancer patients or the level of such activation is
      below the sensitivity of assays used in the experiment.

PMID- 10656611
TI  - Concentration dependent promoting effects of sodium L-ascorbate with the same
      total dose in a rat two-stage urinary bladder carcinogenesis.
AB  - Sodium L-ascorbate (Na-AsA) has been demonstrated to be a strong promoter of rat
      urinary bladder tumor development initiated by N-butyl-N-(4
      hydroxybutyl)nitrosamine (BBN). In the present study, we investigated variation
      in its promoting activity when the same total dose was given with different
      concentrations and exposure times. After 4 weeks administration of 0.05% BBN,
      group 1 served as a control without any post-initiation treatment. The rats in
      groups 2-4 received 1.25% Na-AsA diet for 36 weeks, 2.5% Na-AsA for 18 weeks and
      5% Na-AsA for 8 weeks, respectively. Tumor number (papillomas and carcinomas) was
      greatest in group 3, and area in group 4 (P < 0.05). However, no enhancement was
      noted in group 2, although preneoplastic lesions were significantly increased.
      These results suggest that with the same total administration dose, high
      concentration of Na-AsA has the strongest promoting effects on tumor development
      in urinary bladder carcinogenesis.

PMID- 10656612
TI  - Effects of photodynamic therapy in combination with Adriamycin.
AB  - The combination of photodynamic therapy (PDT) and Adriamycin (ADM) was studied in
      the animal model system. Photohem (PH) was used as a photosensitizer. Mice
      bearing carcinoma epidermoides LL of the lung received PH once at a dose 10 mg/kg
      and after 24 h ADM was injected i.p. at a dose 3 mg/kg and tumors were
      illuminated with laser light after three different time intervals, 15 min, 3 and
      24 h. To evaluate the effect of PDT and PDT combined with ADM the intensity of
      lipid peroxidation in tumor tissue and in blood serum was determined using the
      thiobarbituric acid assay. PDT induces an increase of malondialdehyde (MDA)
      concentration in tumor tissue as well as in blood serum. When PDT is combined
      with ADM, the MDA level in tumor tissue is similar to the level of this product
      as in the PDT alone. No enhancement of the efficiency of the combined treatment
      was observed at these experimental conditions. This is also confirmed by the
      tumor growth dynamics, survival time of animals and flow cytometric DNA analysis
      of tumor cells. For the successful combination of PDT with chemotherapy it is
      suggested to apply the drugs at the regimen which will allow to avoid the
      interaction between two agents since the ground state interaction between PH and
      ADM is stated spectroscopically. It should lead to the conclusion that the
      sequence of the combination of two treatment modalities is an important factor
      for synergistic effect.

PMID- 10656613
TI  - The growth of an established murine non-Hodgkin lymphoma tumour is limited by
      switching to a phytohaemagglutinin-containing diet.
AB  - The growth of a non-Hodgkin lymphoma, developing subcutaneously as a solid tumour
      in NMRI mice, is markedly diminished by including phytohaemagglutinin (PHA), a
      lectin present in raw kidney bean (Phaseolus vulgaris), in the diet. In the
      experiment described in this communication the effect of first allowing tumours
      to develop for 5 days before switching the mice to a diet containing PHA at
      different concentrations was tested to establish whether or not feeding the
      lectin at late times also resulted in reducing tumour growth. This switch of diet
      indeed proved to be effective in slowing down growth of the lymphoma tumour. The
      reduced rate of growth occurs in a dose-dependent manner. We have suggested that
      a competition between the gut epithelium undergoing PHA-stimulated hyperplasia
      and the developing tumour may occur for polyamines and other nutrients from a
      common body pool and this could be an important contributory factor with regard
      to the observed low level of tumour growth following the feeding of PHA
      containing diet. Recent data which showed that the level of hyperplasia of the
      small bowel in response to feeding the PHA diets was higher in non-injected mice
      compared to those which had been injected with tumour cells substantiated the
      concept of competition between gut and tumour for nutrients and other
      requirements for growth.

PMID- 10656614
TI  - Family history of cancer, mutagen sensitivity, and increased risk of head and
      neck cancer.
AB  - To evaluate individual cancer susceptibility, 170 previously untreated patients
      with pathologically-confirmed squamous cell carcinoma of the oral cavity,
      pharynx, and larynx, and 175 age- and sex-matched health controls were
      investigated for the occurrence of cancer in first-degree relatives along with
      other established risk factors for head and neck cancer. More than 54% of these
      subjects were assayed for mutagen sensitivity by quantifying in-vitro bleomycin
      induced chromosomal breaks within peripheral blood lymphocytes. After adjusting
      for age, gender, education, family income, tobacco and alcohol consumption, the
      odds ratio associated with three or more first-degree relatives with cancer at
      any site was 3.79 (95% CI 0.9-15.9) with a linearly-increased trend in risk (P =
      0.040). Significantly elevated risk was found to be associated with a history of
      cancer within siblings (OR = 2.61, 1.2-5.6, P = 0.014). Patients with a family
      cancer history and mutagen sensitivity were at greatest risk (OR = 7.88, 2.5
      25.3, P = 0.005), indicating an additive interactive effect. The findings
      suggested that genetic familial influence is important in the causation of head
      and neck cancer.

PMID- 10656615
TI  - Strong intracellular and negative peripheral expression of fibronectin in tumor
      cells contribute to invasion and metastasis in papillary thyroid carcinoma.
AB  - The intracellular and stromal expression of fibronectin (FN) in invading and
      central parts of papillary thyroid carcinomas with/without lymph node (LN)
      metastasis (54 metastasizing cases, 52 non-metastasizing cases) were examined
      immunohistochemically. The intracellular expression of FN in tumor cells in
      invading parts was stronger than that in central parts in most cases (79/106
      cases, 74.5%). In invading parts, negative stromal FN was frequently found at the
      periphery of the tumor in cases with extracapsular soft tissue invasion (26/37
      cases). Tumor cells in invading parts in metastatic cases were significantly more
      likely to be negative for stromal FN at the periphery of the tumor than those in
      non-metastatic cases (P < 0.0001). The strong intracellular and negative stromal
      FN at the periphery of the tumor in invading parts were associated with invasion
      and metastasis in papillary thyroid carcinoma. These results suggest that these
      distinctive characteristics of FN may be useful for understanding invasion and
      metastasis in vivo.

PMID- 10656616
TI  - Reversal of resistance by GF120918 in cell lines expressing the ABC half
      transporter, MXR.
AB  - The emergence of several newly identified members of the ABC transporter family
      has necessitated the development of antagonists that are able to inhibit more
      than one transporter. We assessed the ability of the chemosensitizer GF120918 to
      function as a multispecific antagonist using cytotoxicity assays, rhodamine and
      calcein efflux assays, and confocal microscopy in cell lines expressing different
      multidrug resistance transporters. At a concentration of 1 microM in cytotoxicity
      assays, GF120918 was able to sensitize both S1-B1-20, a subline expressing P
      glycoprotein (Pgp), and S1-M1-80, a subline expressing a newly identified
      mitoxantrone transporter, MXR. GF120918 was ineffective in sensitizing MRP
      overexpressing MCF-7 VP-16 cells to etoposide as determined by cytotoxicity
      studies. In flow cytometry experiments, rhodamine 123 efflux in S1-B1-20 cells
      was decreased at GF120918 concentrations as low as 25-50 nM, with 250 nM giving
      complete inhibition of rhodamine efflux. Complete inhibition of rhodamine efflux
      in mitoxantrone-resistant S1-M1-80 cells required 10 microM. Examination of
      intracellular mitoxantrone accumulation by confocal microscopy confirmed higher
      levels of mitoxantrone in S1-B1-20 and S1-M1-80 cells when incubated in the
      presence of GF120918 than when incubated with mitoxantrone alone. Thus, GF120918
      appears to fit the paradigm of a multispecific blocker and is able to block
      rhodamine and mitoxantrone efflux by the newly identified mitoxantrone
      transporter. Further studies of this compound should be pursued to determine its
      feasibility for use in the clinic.

PMID- 10656617
TI  - Identification of benzo[a]pyrene metabolites in cervical mucus and DNA adducts in
      cervical tissues in humans by gas chromatography-mass spectrometry.
AB  - Epidemiological studies indicate that cigarette smoking increases the risk of
      cervical cancer. To address questions regarding possible mechanisms of tobacco
      related cervical carcinogenesis, in a pilot study, using supercritical fluid
      extraction and a gas chromatographic-mass spectrometric (GC-MS) technique, we
      detected and characterized benzo[a]pyrene and its metabolites, namely B[a]P
      dihydrodiols, phenols and tetraols in cervical mucus samples from eight smokers
      and non-smokers. Twenty-eight epithelial and stromal cervical tissue samples from
      seventeen patients undergoing surgery for non-malignant disease were
      quantitatively analyzed for BPDE-DNA adducts by a GC-MS technique. BPDE-DNA
      adducts were found in 25 samples. The mean level of BPDE-DNA adducts in
      epithelial cervical tissues of smokers was nearly two-fold greater than that in
      self-reported non-smokers; P = 0.02. The mean number of BPDE-adducts (+/- SD) in
      epithelial cervical tissues of smokers was 3.5 +/- 1.06 adducts/10(8) nucleotides
      while that in non-smokers was 1.8 +/- 0.96 adducts/10(8) nucleotides. The mean
      number of BPDE-DNA adducts in stromal cervical tissues of the same subjects was
      1.8 +/- 0.96 adducts/10(8) nucleotides in smokers and that in the stromal tissues
      of non-smokers was 1.4 +/- 1.1 adducts/10(8). These results suggest that
      polynuclear aromatic hydrocarbons (PAHs) from tobacco smoke and other
      environmental sources can be transported to the cervix where they are metabolized
      in the cervical epithelium to ultimate carcinogenic agents, although transport of
      ultimate carcinogenic metabolites from other organs to the cervix cannot be ruled
      out. Exposure of cervical epithelia to PAHs and their carcinogenic metabolites
      suggests a potential role of such carcinogens in the pathogenesis of cervical
      cancer in humans.

PMID- 10656618
TI  - Effects of methylselenocysteine on PKC activity, cdk2 phosphorylation and gadd
      gene expression in synchronized mouse mammary epithelial tumor cells.
AB  - Methylselenocysteine (MSC), an organic selenium compound is an effective
      chemopreventive agent against mammary cell growth both in vivo and in vitro but
      its mechanism of action is still not understood. We have previously demonstrated
      that MSC is able to inhibit growth in a synchronized TM6 mouse mammary epithelial
      tumor cell line at 16 h time point followed by apoptosis at 48 h. The decrease in
      cdk2 kinase activity was coincident with prolonged arrest of cells in S-phase.
      The present set of experiments showed that cdk2 phosphorylation was reduced by
      72% in the MSC-treated cells at 16 h time point. Expression for gadd34, 45 and
      153 was elevated 2.5 to 7 fold following MSC treatment only after 16 h time
      point. In order to investigate a possible upstream target for MSC, we analyzed
      protein kinase C (PKC) in this model. Total PKC activity was reduced in TM6 cells
      by MSC (50 microM) within 30 min of treatment, both in cytosolic (55.4 and 77.6%)
      and membrane (35.2 and 34.1%) fractions for calcium-dependent and independent
      PKCs, respectively. PMA significantly elevated the PKC activity in membrane
      fraction (P < 0.01) and MSC inhibited this activation by more than 57%. The
      effect of MSC was selenium specific as selenomethionine and sulfurmethyl-L
      cysteine (SMC) did not alter PKC activity either in cytosolic or membrane
      fraction. Immunoblot analysis showed that PKC-alpha was translocated to the
      membrane by PMA and MSC did not alter this translocation. PKC-delta was faintly
      detectable in membrane fractions of control and MSC-treated cells. MSC treatment
      slightly reduced levels of PKC-e (in cytosolic and membrane fractions) and PKC
      zeta (cytosolic fractions). The data presented herein suggest that PKC is a
      potential upstream target for MSC that may trigger one or all of the downstream
      effects; i.e. the decrease of cdk2 kinase activity, decreased DNA synthesis,
      elevation of gadd gene expression and finally apoptosis.

PMID- 10656619
TI  - Inhibition of initiation of simian virus 40 DNA replication in vitro by the
      ursodeoxycholic acid and its derivatives.
AB  - In this study, the effects of the ursodeoxycholic acid (UDCA), and its
      derivatives, on DNA replication were examined using simian virus (SV40) DNA
      replication in vitro. We found that UDCA and its derivatives inhibited SV40 DNA
      replication, and predominantly inhibited the initiation stage of DNA replication.
      UDCA and its derivatives inhibited the DNA cleavage by topoisomerase I (topo I).
      Among them, HS-1183 significantly reduced the activity of topo I. UDCA, at 100
      microM, significantly reduced polymerase alpha-primase (pol alpha-primase)
      activity, but HS-1030 and HS-1183 showed a weak inhibitory effect. The ssDNA
      binding activity of replication protein A (RPA) was little affected by UDCA and
      HS-1030, but was weakly inhibited by HS-1183. Based on their properties, we
      suggest that UDCA and its derivatives might inhibit some molecules that is
      required to establish replication forks during the initiation reaction and their
      cytotoxicity might be related to the inhibitory effect they have on this
      fundamental cellular process.

PMID- 10656620
TI  - Induction of somatic mutations but not methylated DNA adducts in lambdalacZ
      transgenic mice by dichlorvos.
AB  - In order to examine the in vivo genotoxic activity of dichlorvos, lambdalacZ
      transgenic mice (Muta Mouse) were treated i.p. with single (4.4 or 11 mg/kg) or
      multiple (5 x 11 mg/kg) doses of this agent and sacrificed 4 h or 14 days post
      treatment for DNA adduct measurement or mutant frequency analysis, respectively.
      Neither methylated DNA adducts nor an increase in mutant frequency were detected
      in the bone marrow, white blood cells, liver, spleen, lung, brain and sperm cells
      after the single doses. However, following multiple dosing a statistically
      significant 3-fold increase in mutant frequency was observed in the liver, while
      a non-statistically significant increase was observed in the bone marrow. In
      contrast, dimethylsulphate, a model methylating agent, gave rise to detectable
      DNA adducts but no increase in mutant frequency following i.p. administration of
      single (30 mg/kg) or multiple (10 x 6 mg/kg) doses.

PMID- 10656621
TI  - Expression of antioxidant proteins in human intestinal Caco-2 cells treated with
      dietary flavonoids.
AB  - Dietary flavonoids are known to scavenge free radicals but little information is
      available on their roles in antioxidant protein gene expression. The goal of this
      paper is to investigate the effect of flavonoid treatment on the antioxidant
      protein expression in human intestinal Caco-2 cells. The antioxidant proteins of
      interest were metallothionein (MT), catalase (CAT), and superoxide dismutase
      (SOD). Treatment of Caco-2 cells with 100 microM genistein, biochanin A, daidzein
      or kaempferol significantly increased MT mRNA up to 15 fold. On the contrary, CAT
      mRNA level was not affected by various flavonoids. We also developed gel activity
      assays to determine the specific activities of CAT and Cu/Zn SOD in flavonoid
      treated Caco-2 cells. Compared to the conventional spectrophotometric assays, the
      gel assays allow a separation of antioxidant activities of the enzymes from that
      of the flavonoids. CAT and Cu/Zn SOD were found not to be affected by 48-h
      treatment of 100 microM dietary flavonoids (genistein, biochanin A, daidzein,
      flavone, quercetin, or kaempferol). In conclusion, the effects of flavonoids on
      antioxidant protein expression are structure- and gene-specific. When evaluating
      antioxidant capacity of flavonoids, their ability to modulate antioxidant protein
      expression should also be taken into consideration.

PMID- 10656622
TI  - Circulating intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion
      molecule-1 (VCAM-1) and plasma thrombomodulin levels in glioblastoma patients.
AB  - Cellular adhesion molecules have been implicated in tumor progression and
      metastasis. Serum samples from 22 patients with glioblastoma (GBM), before
      surgery, and 19 sex and age matched healthy controls were analyzed for
      circulating levels of ICAM-1 and VCAM-1. At the same time also soluble plasma
      thrombomodulin, a marker of endothelial cell damage and activation, was detected.
      Soluble ICAM-1 and VCAM-1 levels were comparable in glioblastoma patients and
      healthy controls, while plasma thrombomodulin (TM) was significantly increased in
      cancer patients. There was no correlation between thrombomodulin levels and the
      presence of an intratumoral hemorrhage detected by CT scan, while entity of post
      contrast enhacemement at CT correlated with higher TM levels. Further study with
      serial sampling of GBM patients and correlation with enhancement at CT will allow
      to ascertain the value of serum TM as a marker of disease recurrence or
      angiogenesis in those tumors.

PMID- 10656624
TI  - Diagnostic accuracy of perforated compression grid approach for mammographically
      guided core needle biopsy of breast lesions.
AB  - The aim of this study was to evaluate the diagnostic accuracy of large core
      breast biopsy with the use of the perforated compression grid (PCG) in a series
      of 106 consecutive mammographically detected breast lesions. The PCG consists in
      a fenestrated paddle that replaces the usual mammographic compressor. Each hole
      in the grid is marked by letters and numbers in order to obtain the coordinates
      of the area to biopsy. By analysing the two orthogonal projections, the depth of
      the lesion in the breast is calculated. With the breast positioned in the PCG, a
      skin incision is made. After calculations about the depth of needle insertion,
      the tip of the needle is inserted proximally to the target area. In such a way,
      taking into consideration the total running of the needle (23 mm), a correct
      sampling is assured, and multiple needle passes are performed. Sensitivity was of
      90.62 and 90.90%, specificity was of 100 and 95.45% and positive predictive value
      was of 100 and 90.90% by excluding and including suspicious diagnoses,
      respectively, for each computation. In conclusion, the study indicated that image
      guided core biopsy performed by the approach of PCG is a cost-effective, simple
      and accurate technique for the diagnosis of breast lesions, and it could be
      proposed as a low-cost alternative where the stereotactic equipment is not
      available.

PMID- 10656623
TI  - Differential expression of nitric oxide synthase in human stomach cancer.
AB  - The level of expression and cellular localization of isoenzymes of nitric oxide
      synthase (NOS) was detected in human stomach tumor tissues. Tumor tissues showed
      70% higher activity of NOS than that of normal tissues (P < 0.01). Poorly
      differentiated adenocarcinoma tend to have higher activity (P < 0.05) than well
      differentiated and moderately differentiated tumor tissues. Aminoguanidine (AG),
      2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (AMT), NG-monomethyl-L-arginine (L
      NMMA), and Nomega-nitro-L-arginine (L-NNA) inhibited NOS activity in tumor
      tissues by 18, 14, 11 and 13%, respectively. The TNF-alpha mRNA expression was
      correlated with the inducible NOS (iNOS) level, which was high in adenocarcinomas
      and low in normal tissues. Tumor tissues showed higher expression of iNOS in
      gland epithelial cells but the level of eNOS was significantly decreased with an
      exception of concentrated localization in the proliferating capillary
      endothelium. These results revealed that isoforms of NOS might contribute
      differentially to growth and progression of human stomach tumor.

PMID- 10656625
TI  - Suramin blocks growth-stimulatory effects of platelet-derived growth factor on
      malignant fibrous histiocytomas in vitro.
AB  - The pattern of susceptibility of malignant cells to the cytostatic drug suramin
      is not fully clarified. Therefore, in the present paper we have assessed the
      effects of suramin on the growth of eight cell lines derived from human malignant
      fibrous histiocytomas, by measuring DNA synthesis. The effect of suramin (10-200
      microg/ml) on cells either unstimulated, or stimulated with platelet-derived
      growth factor (PDGF)-AA (10 ng/ml), PDGF-BB (10 ng/ml) or 10% fetal calf serum
      was studied. Four out of five cell lines unable to thrive without external growth
      factors showed growth inhibition by suramin. The two cell lines able to grow
      under serum-free conditions were unaffected by high-dose suramin. The exposure to
      suramin, at 200 microg/ml, abolished the growth stimulation caused by PDGF-AA and
      -BB. In contrast, a low dose of suramin (50 microg/ml), with or without PDGF,
      caused growth-stimulating effects in some cell lines. Our results indicate that
      high doses of suramin inhibit growth of malignant fibrous histiocytomas in vitro
      and that suramin exerts its growth-inhibitory effects on cells dependent on
      external growth factors. Low-dose treatment with suramin, however, may instead
      promote growth in both serum-dependent and -independent tumor cell lines.

PMID- 10656626
TI  - Amplification of the mdr1-gene is uncommon in recurrent ovarian carcinomas.
AB  - Ovarian carcinomas are known to rapidly develop drug resistance against
      chemotherapeutic agents. This phenomenon is often associated with the expression
      of pl70-glycoprotein. A high rate of transcription of the corresponding mdr1-gene
      in resistant tumors is reported. Amplification of the mdr1-gene has been observed
      in tumor cell lines exposed to cytotoxic drugs; however, significant information
      is lacking as to whether this holds true in clinical carcinomas. To fill this
      gap, we investigated the rate of gene amplification of the mdr1-gene in 63
      recurrent ovarian carcinomas and we determined the resistance pattern of these
      cells using an ex vivo assay. The tumors showed varying ex vivo resistance
      patterns which did not correlate to clinical parameters. Amplification of the
      mdr1-gene was not observed in any of the cancer specimens. Therefore, we conclude
      that mdr1-gene amplification is not a common pathway for the development of
      chemoresistance in clinical ovarian carcinomas.

PMID- 10656627
TI  - Increase of NAD glycohydrolase activity in uterine cervix cancers is caused by
      infiltration of lymphocytes.
AB  - CD38 is a type II transmembrane glycoprotein which is expressed by hematopoietic
      and nonhematopoietic cells in human. It has two functions of ADP-ribosyl cyclase
      and cyclic ADP-ribose hydrolase activities and the sum of these two enzyme
      activities is identical with NAD glycohydrolase (NADase) activity. The levels of
      NADase activity in human cervical carcinoma and normal cancer tissue were
      measured. With a total of 12 patients with cervical cancer and 11 women with
      normal cervix, cancer tissues were found to have significantly higher NADase and
      ADP-ribosyl cyclase activities than the control group. Moreover, immunoblot
      analysis showed an increase of immunoreactivity against CD38 in cervical cancer
      tissues compared with normal tissues. Immunohistochemical data indicated that the
      increase of CD38 expression was due to increased infiltration of lymphocytes.

PMID- 10656628
TI  - The effects of dietary iron overload on fumonisin B1-induced cancer promotion in
      the rat liver.
AB  - The present study was performed to determine whether excess hepatic iron
      modulates the cancer-initiating and promoting properties of FB1. Thirty-eight
      male F344 rats were divided into four dietary treatment groups: (i) control diet
      (AIN, n = 8); (ii) FB1 250 mg/kg diet (FB1, n = 10); (iii) 1-2% carbonyl iron
      (CI, n = 10); or (iv) FB1 plus iron loading (FB1/CI, n = 10) for 5 weeks (2 x 2
      factorial design). Hepatic iron concentrations in iron-loaded animals at 5 weeks
      were 444 +/- 56 (CI) and 479 +/- 80 micromol/g dry weight (FB1/CI) (mean +/-
      SEM). All the FB1-fed rats, in the presence or absence of CI, developed a toxic
      hepatitis with a 4-fold rise in serum alanine transaminase (ALT) levels. FB1
      appeared to augment iron-induced hepatic lipid peroxidation, as measured by the
      generation of thiobarbituric acid reacting substances (TBARS) in liver
      homogenates (P < 0.0001). Morphometric analysis showed that FB1 caused a
      significantly greater mean +/- SEM number of 'enzyme-altered' foci and nodules
      per cm2 (5.34 +/- 1.42 vs. 1.50 +/- 0.52, P < 0.05), as well as a greater area
      (%) of liver occupied by foci and nodules (0.33 +/- 0.12% vs. 0.05 +/- 0.03%, P <
      0.001), compared with FB1/CI. The addition of FB1 to dietary iron loading caused
      a shift in distribution of iron from hepatocytes to Kupffer cells, probably due
      to phagocytosis of necrotic iron-loaded hepatocytes. In conclusion, (i) FB1
      appears to cause toxicity in the liver independently from effects on lipid
      peroxidation; (ii) FB1 has a potentiating effect on iron-induced lipid
      peroxidation; and (iii) dietary iron loading appears to protect against the
      cancer promoting properties of FB1, possibly due to a stimulatory effect of iron
      on hepatocyte regeneration.

PMID- 10656629
TI  - Role of redox cycling and activation by DT-diaphorase in the cytotoxicity of 5
      (aziridin-1-yl)-2,4-dinitrobenzamide (CB-1954) and its analogs.
AB  - In tumor cell lines with high content of DT-diaphorase (EC 1.6.99.2), the
      cytotoxicity of 5-(aziridin-1-yl)-2,4-dinitrobenzamide (CB-1954) and its
      derivatives is exerted through DT-diaphorase-catalyzed formation of crosslinking
      species. However, little is known about other possible mechanisms of CB-1954
      action. We have examined the toxicity of CB-1954 and its derivatives to bovine
      leukemia virus-transformed lamb fibroblasts (line FLK), which possessed moderate
      DT-diaphorase activity, 260 units/mg protein. The action of these compounds was
      accompanied by lipid peroxidation, their toxicity was decreased by
      desferrioxamine and antioxidant N,N'-diphenyl-p-phenylene diamine (DPPD), but, in
      most cases, not by dicumarol, an inhibitor of DT-diaphorase. Using multiparameter
      regression analysis, we have found that the toxicity of CB-1954 derivatives as
      well as that of several non-alkylating nitroaromatics, increased upon the
      increase in their single-electron reduction potential (E(1)7) and octanol/water
      partition coefficient (P), and almost did not depend on their reactivity towards
      DT-diaphorase. It seems that in cell lines with a moderate amount of DT
      diaphorase, the toxicity of CB- 1954 and its analogs is exerted through their
      redox cycling.

PMID- 10656630
TI  - Disproportionate retrograde amnesia in a patient with herpes simplex
      encephalitis.
AB  - We describe a patient who developed a severe but temporally limited retrograde
      amnesia coupled with a relatively mild anterograde amnesia following herpes
      simplex encephalitis. The patient showed a profound retrograde amnesia for
      autobiographical events extending for about 10 years prior to the disease onset.
      Her knowledge about public events and famous persons was also impaired for this
      period. An MRI and SPECT demonstrated bilateral medial temporal pathology. This
      case represents a further instance of a relatively focal retrograde amnesia
      following brain damage. We review other reported cases with focal retrograde
      amnesia and consider theoretical and neuroanatomical accounts for the present
      case. Two factors may account for her amnesic patterns: a partial disruption of
      the store for premorbid binding codes (i.e., information that multimodal feature
      representations occurred synchronously); along with a relative preservation of
      the encoding process required to develop new synchronous codes.

PMID- 10656631
TI  - Arithmetic reasoning and implicit memory: a neuropsychological study on amnesia.
AB  - The present study investigates implicit memory and arithmetic reasoning in a
      group of severely amnesic patients. Priming effects have been observed in the
      retrieval of arithmetic facts in amnesic patients (Delazer, Ewen and Benke,
      1997), but no studies have so far investigated the effect of previous experience
      in a pure reasoning task. Findings indicate that answering to a first numerical
      series (e.g, 1 3 5 7, answer "9") facilitates answering to a second numerical
      series (2 4 6 8, answer "10") including different numbers but sharing the same
      underlying algorithm (+ 2). Within the model of Langdon and Warrington (1997)
      priming effects are attributed to the stage of abstract formula generation.

PMID- 10656632
TI  - Code-dependent pathways for number transcoding: evidence from a case of selective
      impairment in written verbal numeral to arabic transcoding.
AB  - This article presents a brain-damaged patient (RR) suffering from cognitive
      deficits following neurological insults, who showed a selective impairment in
      number transcoding. Except for written verbal numeral to arabic transcoding, his
      ability to transcode numerals, including writing arabic numerals to dictation, is
      largely preserved. Other number processing skills, including numeral recognition,
      numeral comprehension, and calculation, were unimpaired. Semantic and asemantic
      models of number processing cannot easily account for the patient's performance
      and it is suggested that the number transcoding system should include different
      code-dependent pathways for arabic transcoding from spoken verbal numerals and
      from written verbal numerals. Since the errors produced in the impaired
      transcoding rely upon the syntactical structure of numeral stimuli, it is also
      proposed that transcoding code-dependent pathways should reflect the structure of
      the verbal numeral system, especially the difference between sum and product
      relationships.

PMID- 10656634
TI  - Visual paralexias in a Spanish-speaking patient with acquired dyslexia: a
      consequence of visual and semantic impairments?
AB  - We report the case of a Spanish patient SC who misread 55 per cent of the single
      words shown to her. SC's reading accuracy was affected by word imageability and
      frequency. Nonword reading was very poor. The majority of SC's errors to real
      word targets bore a close visual similarity to the items that elicited them, but
      there was no indication of an effect of serial position on the probability that a
      letter from a target word would be incorporated into the error made to that word.
      SC made some visual errors in object naming and also showed evidence of a general
      semantic impairment. We consider the similarity between SC and patient AB
      reported by Lambon Ralph and Ellis (1997), and suggest that the very high levels
      of visual errors shown by these two patients may reflect a combination of visual
      and semantic impairments.

PMID- 10656633
TI  - Automatic versus strategic effects of phonology and orthography on auditory
      lexical access in brain-damaged patients as a function of inter-stimulus
      interval.
AB  - The influence of both phonological and orthographic information on auditory
      lexical access was examined in left- and right-hemisphere-damaged individuals
      using a lexical decision paradigm. Subjects were presented with prime-target
      pairs that were either phonologically related (tooth-youth), orthographically
      related (touch-couch), both phonologically and orthographically related (blood
      flood), or unrelated (bill-tent), at two inter-stimulus intervals (ISI)--100 ms
      and 750 ms--to tap more automatic versus more strategic processing. All groups
      demonstrated effects of orthography at both ISIs (facilitory at 100 ms ISI and
      inhibitory at 750 ms ISI), supporting the findings by Leonard and Baum (1997)
      that effects of orthography emerge independent of site of brain damage and
      suggesting that orthographic effects in auditory word recognition tend to be
      largely strategic. A facilitory effect of phonology was also found for all groups
      at both ISIs. The findings are discussed in relation to theories of lexical
      activation in brain-damaged individuals.

PMID- 10656635
TI  - The nature of the disorder underlying the inability to retrieve proper names.
AB  - Two patients with the syndrome of proper name anomia were investigated. Both
      patients were only able to produce around 50% of the names of contemporary
      celebrities, but performed significantly better on a task calling for naming of
      historical figures. The names of relatives and friends were spared in one
      patient, while the other retrieved names of people known since childhood much
      better than those of people familiar to him since the age of 25. Geographical
      names, names of monuments and masterpieces were preserved. The above
      dissociations are taken to imply that in moderately impaired patients, a temporal
      gradient effect concurs to modulate the severity of the naming block. A similar
      impairment was found in both patients when they attempted to retrieve or relearn
      familiar telephone numbers. This finding suggests that the core of the disorder
      resides in the inability to gain access to words used to identify a single
      entity, regardless of whether they belong to the class of proper or common names.

PMID- 10656636
TI  - Influence of response modality on awareness of contralesional tactile stimuli in
      right brain damaged patients.
AB  - Thirty right brain-damaged (RBD) patients with left tactile extinction (19 of
      whom also showed neglect) were given a sequence of 240 tactile stimuli--80 right,
      80 left, 80 bilateral--across 4 different response conditions: (a) verbal report
      of stimulated side/s, (b) motor report of stimulated side/s, (c) verbal report of
      unstimulated side/s, (d) motor report of unstimulated side/s. Earlier experiments
      based on similar tasks but involving RBD patients with visual extinction and/or
      neglect have shown that visual awareness of contralesional stimuli can be
      influenced by manipulation of response conditions. Since neglect and extinction
      can be double-dissociated both anatomically and behaviourally, the question
      arises of whether the underlying neuronal mechanisms are different. To answer
      this question the present work investigated the role of perceptual and premotor
      factors in generating tactile extinction in response to Double Simultaneous
      Stimulation (DSS). The hypothesis was that a directional response bias would
      result in an overall higher frequency of errors for verbal or motor responses
      indicating the ipsilesional side (right); a perceptual bias would instead result
      in errors distributed with similar frequency on the ipsilesional and the
      contralesional (left) side. Results showed that, in RBD patients, contralesional
      extinction was not influenced by response conditions (verbal/motor; report of
      stimulated/unstimulated side) and presence/absence of neglect. This suggests
      that: (1) among RBD patients, directional response biases are unlikely to play a
      role in extinction of tactile stimuli on DSS; (2) the mechanisms underlying
      extinction are, at least to some extent, different from those underlying
      unilateral neglect.

PMID- 10656637
TI  - Hypermnesia in unilateral neglect.
AB  - Thirteen right brain-damaged patients who were found to neglect pictures
      presented on the left of a display were presented the same stimuli, intermixed
      with foils, in a yes-no recognition test. Fifty per cent of patients claimed to
      have already seen one or more of the previously neglected pictures. This
      demonstrates that visual information that fails to access consciousness in
      neglect patients does retain the ability to surface as explicit memory at a later
      stage.

PMID- 10656638
TI  - "Developmental dysmnesia": a case report.
AB  - We report a 9-year-old girl who presented from an early age a severe and specific
      verbal memory disorder, in the absence of a definite etiology. The results of an
      extensive neuropsychological assessment showed a dissociation between normal
      visuo-spatial memory abilities and a marked short-term and long-term verbal
      memory impairment. We argue that our case is affected by "developmental
      dysmnesia", a condition so far described in two cases only (De Renzi and
      Lucchelli, 1990, and Temple, 1997). The disorder affected episodic as well as
      semantic verbal memory. The long term effects on learning and cognition of a
      memory deficit occurring early in childhood are discussed.

PMID- 10656639
TI  - Gender affects naming latencies for living and nonliving things: implications for
      familiarity.
AB  - Recent studies indicate the presence of a gender-by-category interaction in the
      naming abilities of both Alzheimer's patients and normal subjects (Laiacona,
      Barbarotto and Capitani, 1998; McKenna and Parry, 1994). In particular, males
      appear to be better than females at naming nonliving things and females better at
      naming living things. Similarly, in a recent study of semantic fluency, males
      retrieved more names of tools than females and females more names of fruit than
      males (Capitani, Laiacona and Barbarotto, 1999). Such findings have important
      implications for our understanding of category-specific disorders. The current
      study examined the naming latencies of normal subjects to pictures of living and
      nonliving things. We confirm a gender-by category interaction across both subject
      and item, with females being slower than males to name nonliving things and males
      slower to name living things. This finding could not be explained by differential
      difficulty of items or differences in gender-based familiarity ratings.

PMID- 10656640
TI  - SPECT in the management of patients with back pain and spondylolysis.
AB  - PURPOSE: Single photon emission computed tomography (SPECT) bone scans of the
      lumbar spine were evaluated in the management of patients with low back pain and
      suspected spondylolysis. MATERIALS AND METHODS: Thirty-three patients (mean age,
      30 years) with high clinical suspicion of pars interarticularis defects were
      included in the study. The results of lumbar radiographs and SPECT bone
      scintigraphy were compared and the influence of these results on patient
      management was evaluated. RESULTS: Twenty-six of the 33 patients had abnormal
      results of lumbar radiographs. Of the 21 patients with radiographs indicating
      spondylolysis, six had abnormal uptake in the pars regions on bone scintigraphy.
      One patient with normal results of lumbar radiographs had a SPECT bone scan
      showing uptake in the region of the pars interarticularis. CONCLUSIONS: SPECT
      bone scanning of the lumbar spine has a role in the treatment of patients with
      symptomatic spondylolysis.

PMID- 10656641
TI  - The long-term effects of force-transmission in an injured wrist, measured with
      dual-energy X-ray absorphometry: a case report.
AB  - PURPOSE: To investigate the feasibility of using a dual-energy X-ray
      absorphometry (DEXA) scan to predict long-term force-transmission patterns in
      wrists. MATERIAL AND METHODS: Both wrists of a man with morbid Kienbock stage
      IIIa disease of his left wrist (avascular necrosis of the lunate) were examined
      by a DEXA scan to determine the differences in bone density in the distal radius.
      RESULTS: In the distal radius of the injured wrist, a shift in bone density was
      seen toward the scaphoid fossa, which resembles the shift in force-transmission
      pattern described in force-transmission studies of the wrist. CONCLUSIONS: These
      differences can be interpreted as a result of an altered force-transmission
      pattern in the injured wrist.

PMID- 10656642
TI  - F-18 FDG uptake in breast infection and inflammation.
AB  - PURPOSE: Whole-body fluorine-18 fluorodeoxyglucose (F-18 FDG) positron emission
      tomography (PET) scanning has been useful in the management of breast cancer.
      However, F-18 FDG uptake sometimes has been associated with benign breast
      disease. Four cases are reported of F-18 FDG breast uptake caused by infectious
      or inflammatory mastitis that mimics malignant disease. METHODS AND RESULTS: Two
      women had F-18 FDG whole-body scans for the evaluation of a large breast mass
      after inconclusive results of ultrasonography. In both cases, intense focal F-18
      FDG breast uptake was noted that mimicked breast cancer. Histologic examination
      showed, in one patient, chronic granulomatous infiltration that likely
      represented tuberculous mastitis, because she showed a good clinical response to
      empirical anti-tuberculous treatment. The second patient had lactational changes
      associated with acute inflammation, and the culture grew Staphylococcus aureus.
      The breast mass completely disappeared 3 weeks after a course of antibiotic
      treatment. The other two patients had staging F-18 FDG PET scans 1 and 12 months
      after lumpectomy for breast carcinoma to detect residual, recurrent, or
      metastatic disease. Both scans showed a ring-like uptake in the involved breast,
      with superimposed intense focal uptake suggesting tumor necrosis centrally and
      malignant foci peripherally. In both cases, histologic examination revealed
      hemorrhagic inflammation secondary to postsurgical hematomas and no evidence of
      malignancy. CONCLUSION: Acute or chronic infectious mastitis and postsurgical
      hemorrhagic inflammatory mastitis should be considered in patients who have a
      breast mass, especially those with a history of tenderness or surgery.

PMID- 10656643
TI  - Chest wall recurrence of breast cancer detected by scintimammography.
AB  - A case of chest wall recurrence of breast cancer detected by scintimammography is
      presented. A 63-year-old woman who had a right mastectomy for breast carcinoma 24
      years earlier was evaluated for left axillary adenopathy. Although it was
      suspected that a second primary malignancy had developed in the left breast,
      results of mammography and magnetic resonance imaging of that breast were
      negative. Scintimammography performed with Tc-99m sestamibi confirmed a normal
      left breast but revealed a lesion in the right chest wall at the site of the
      previous mastectomy. This was surgically confirmed as recurrent breast carcinoma,
      which subsequently altered patient management.

PMID- 10656644
TI  - Unusual biliary scan appearance in a child with a transplanted liver with hepatic
      arterial thrombosis: a case report.
AB  - A 5-year-old girl with biliary atresia and a subsequent Kasai procedure is
      described. She had clinical symptoms suggestive of rejection after a recent
      orthotopic liver transplant A hepatobiliary scan showed partial hepatic
      infarction and a biloma in the infarcted area.

PMID- 10656645
TI  - Prediction of myocardial perfusion abnormalities by quantitative regional
      function using a radionuclide angiography database: a comparison with wall motion
      analysis.
AB  - PURPOSE: Myocardial perfusion and functional information during the same study is
      now feasible. A new assessment of regional ejection fraction at rest and peak
      exercise by first-pass radionuclide angiography using a "normal" database file
      has been developed. OBJECTIVE: This study was performed to assess the relation
      between this new method of quantitative regional ejection fraction and myocardial
      perfusion abnormalities and to compare this new technique with visual analysis of
      regional wall motion. METHODS: Consecutive patients (n = 126) with simultaneous
      first-pass radionuclide angiography and perfusion SPECT imaging were studied at
      rest and peak exercise using a same-day protocol. The area under the receiver
      operator characteristic curve (C index) was used to assess the concordance
      probability between perfusion and functional measurements, and logistic
      regression models were used to examine the ability of functional variables to
      predict perfusion results. RESULTS: A high concordance was found between the
      visual analysis of wall motion and perfusion abnormalities (C index = 0.796), and
      also between regional ejection fraction and perfusion defects (C index = 0.784).
      The maximal predictive power of functional variables was obtained by combining
      wall motion analysis and regional ejection fraction (C index = 0.859). Regional
      ejection fraction contributed, with 20% more information than provided by wall
      motion analysis alone (chi2 = 9.2, P = 0.0025). CONCLUSIONS: Quantitative
      regional ejection fraction using a normal database file has a strong relation to
      perfusion abnormalities and provides incremental information to regional wall
      motion analysis for predicting perfusion abnormalities. This new technique should
      be regarded as a potential adjunct to functional studies to evaluate patients
      with ischemic heart disease.

PMID- 10656646
TI  - Evaluation of pancreatic islet cell tumors by fluorine-18 fluorodeoxyglucose
      positron emission tomography: comparison with other modalities.
AB  - PURPOSE: Pancreatic islet cell tumors are potentially malignant tumors and are
      often difficult to detect with current imaging modalities. Positron emission
      tomography (PET) using fluorine-18-labeled fluorodeoxyglucose (FDG) is an imaging
      technique with high sensitivity for malignant tumors. The aim of this study was
      to assess the feasibility of FDG PET to detect pancreatic islet cell tumors.
      METHODS: Nineteen lesions of histologically proved islet cell tumors were
      evaluated in 12 patients (5 men, 7 women; ages 22 to 77 years). FDG uptake was
      analyzed semiquantitatively as a standardized uptake value. The diagnostic
      accuracy of PET was compared with that of US, CT, and MRI. RESULTS: Of 19
      lesions, 8 showed positive PET results (standardized uptake value > 2.3), and
      localization was indicated in 2 lesions. In nine tumors that were not detected by
      PET, seven were small tumors ranging from 1.5 to 8 mm in diameter and were not
      identified by other imaging methods. The sensitivity rate of PET was 53%, whereas
      those of US, CT, and MRI were 53%, 50%, and 53%, respectively. CONCLUSION: Our
      data suggest that FDG PET has a limitation in that it does not detect some small
      sized islet cell tumors, mainly depending on their size, but it has potential
      utility as a complementary modality for other imaging techniques.

PMID- 10656647
TI  - Current imaging and possible therapeutic management of glucagonoma tumors: a case
      report.
AB  - Glucagonomas, like other neuroendocrine tumors, express somatostatin receptors in
      more than 80% of cases. Unfortunately, because of the rarity of these tumors, the
      sensitivity and specificity of somatostatin analog (octreotide) imaging have not
      been established. Nonetheless, there have been limited reports in the literature
      supporting the use of indium In-111 DTPA N-terminal D-phenylalanine (D-PHE1)
      octreotide for glucagonoma imaging and may be most beneficial as an adjuvant to
      conventional imaging for tumor staging and therapeutic decision making. Current
      therapeutic applications of octreotide focus on stabilization of disease in
      tumors expressing somatostatin receptors, and tumor destruction, using beta
      emitting isotopes. In this report, imaging of a glucagonoma with In-111 DTPA-D
      PHE1 octreotide scintigraphy is described in a 51-year-old woman examined for a
      large palpable abdominal mass.

PMID- 10656648
TI  - Scintigraphic evaluation of colonic transit in two patients with idiopathic
      chronic constipation.
AB  - Bowel transit in two women with protracted constipation was evaluated after oral
      administration of In-111 DTPA in water. Serial abdominal images were obtained for
      as long as 96 hours to assess transit through the stomach, small bowel, and
      colon. In both patients, large bowel transit was delayed. A pattern of colonic
      inertia was observed in one patient, whereas retention in the distal colon was
      seen in the other patient. Both patients underwent total colectomy with marked
      symptomatic relief. Colonic transit studies of these patients are presented, and
      the literature is reviewed.

PMID- 10656649
TI  - Rhinoscintigraphy: a simple radioisotope technique to study the mucociliary
      system.
AB  - PURPOSE: This was a radioisotope study of nasal mucociliary clearance of total
      and subtotal nasal obstruction. METHODS: Rhinoscintigraphy was performed by
      insufflating 1.85 MBq (69 mCi) Tc-99m MAA in 20 patients. Six cases were regarded
      as the control group, because the presence of small spurs does not affect nasal
      patency. The remaining 14 patients had various rhinopathic conditions. Two
      regions of interest were selected, one in the nasal cavity and one in the
      pharynx. Mucociliary transport speed was calculated. RESULTS: This parameter
      appeared to be a sensitive index for the assessment of the degree of mucociliary
      alteration. It showed that polyposis impairs mucociliary transport most severely,
      thus confirming the results of other published studies. CONCLUSIONS:
      Rhinoscintigraphy proved to be a reliable, easily reproducible, and harmless
      method, so it may be used for follow-up examinations in patients who have had
      surgery of the nose and paranasal sinuses, and for drug therapy of rhinopathic
      conditions.

PMID- 10656650
TI  - Demonstration of infection of one cyst in a polycystic liver with Ga-67 citrate
      SPECT.

PMID- 10656651
TI  - Tc-99m sestamibi uptake in metastatic prostate carcinoma.

PMID- 10656652
TI  - Extraosseous uptake of Tc-99m HDP in muscular dystrophy.

PMID- 10656653
TI  - False-positive I-131 whole-body scan in follicular thyroid carcinoma caused by
      frontal sinus mucocele.

PMID- 10656654
TI  - Thoracic kidney detected on bone scan.

PMID- 10656655
TI  - Sternal fractures in motor vehicle accident victims restrained by lap-shoulder
      safety belts: can bone scintigraphy distinguish passenger from driver?

PMID- 10656656
TI  - Hiatal hernia depicted on Tc-99m sestamibi images: myocardial perfusion imaging.

PMID- 10656657
TI  - Detection of distant medullary thyroid carcinoma metastases by Tc-99m arcitumomab
      scintigraphy.

PMID- 10656658
TI  - Chronic tophaceous gout: scintigraphic findings on bone scan.

PMID- 10656659
TI  - I-123 MIBG and Tc-99m MDP scintigraphy in diagnosing paraganglioma extension.

PMID- 10656660
TI  - An unusual presentation of non-Hodgkin's lymphoma: a case report.

PMID- 10656661
TI  - Persistent binding of Tc-99m pertechnetate to erythrocytes in a patient receiving
      multiple pharmaceuticals.

PMID- 10656662
TI  - Pseudolymphoma of the lung: Benign pulmonary nodule with elevated
      fluorodeoxyglucose uptake.

PMID- 10656663
TI  - Cerebral perfusion impairment with normal magnetic resonance imaging findings in
      a patient with neuro-Behcet's disease.

PMID- 10656664
TI  - Current readings in nuclear medicine.

PMID- 10656665
TI  - Experimental evidence for the presence of a water network at the peptide-MHC
      interface.

PMID- 10656666
TI  - Reactivity and assay restriction profiles of monoclonal and polyclonal antibodies
      to acid phosphatases: a preliminary study.
AB  - The development of secure diagnostic immunoassays requires, among others,
      rigorous characterisation of potential antibody reagents. The reactivity profiles
      of seven antibodies (six monoclonal [MAb] and one polyclonal [PAb]) with putative
      specificity for tartrate-resistant acid phosphatase (TRAP) and/or osteoclasts
      were evaluated in enzyme-linked immunosorbent assay (ELISA) and/or
      immunocytochemistry. MAbs 2H1, 4E6 and 5Cl demonstrated assay restriction:
      exhibiting reactivity only in ELISA. The remaining three MAbs (G211D, G312G and
      V35B) and the PAb 8023 recognised recombinant TRAP (rTRAP) in ELISA and native
      acid phosphatases in selected tissues and cell lines. The latter were
      cytochemically assessed for both tartrate-sensitive acid phosphatase (TSAP) and
      TRAP. V35B showed reactivity against the monocytic leukaemia cell line U937 and
      guinea pig kidney tissue (both TSAP+ and TRAP+) and ECV304 (TSAP+) cells.
      Interestingly, the reactivity of MAb G211D co-localised with TRAP activity in the
      membrane of osteoclasts but also detected cytoplasmic components in U937 cells
      and human embryonic lung fibroblasts (TRAP+ and TRAP+). G211D exhibited
      immunoreactivity against placental trophoblasts (positive for total AP).
      Intriguingly, MAbs 2H1, 4E6, 5Cl and PAb 8023 cross-reacted with potato acid
      phosphatase in ELISA, suggesting reactivity to conformationally similar epitopes.
      Thus, some of these reagents could be used in the development of standardised
      diagnostic immunoassays or as drug-targeting agents for conditions in which the
      pathological process involves bone resorption, the MAbs G211D, 2H1, 4E6, 5Cl and
      PAb 8023 being useful in ELISA but not immunocytochemical detection of TRAP.

PMID- 10656667
TI  - Expression of an epitopic region of AspfI, an allergen/antigen/cytotoxin of
      Aspergillus fumigatus.
AB  - The gene for an 18 kD allergen/cytotoxin of Aspergillus fumigatus was cloned in
      pUC-19 vector and expressed in Escherichia coli JM109. Digestion of this gene
      with AluI resulted in four fragments of 216bp, 120bp, 39bp and 21bp. These
      fragments were cloned in the Sma-I site of pUC-19. The recombinants thus,
      generated after transformation in E. coli JM109, were screened using monoclonal
      antibodies raised against the AspfI. The fusion protein containing 120 bp AluI
      fragment was recognised by the MoAb indicating presence of epitope(s) in the 120
      bp region. The study indicates a viable strategy for identification and
      expression of an immunologically active domain of a major allergen/antigen of A.
      fumigatus for the first time.

PMID- 10656668
TI  - Upregulation of KIR expression on murine bone marrow cells by paraformaldehyde
      fixed tumor cells.
AB  - We have previously shown that the activation of mouse spleen NK cells by IL2 is
      markedly boosted if paraformaldehyde fixed tumor target cells are added during
      the activation phase. In the present study, we have shown that such a boosting
      effect is not seen if mouse bone marrow (BM) cells are used instead of spleen
      cells. Addition of fixed tumor cells (1:100 ratio of tumor cells to BM cells)
      however resulted in a marked increase in the expression of Ly49 molecules on BM
      cells. The enhancement of Ly49 expression was not seen if fixed allogeneic BM
      cells were added, suggesting that Ly49 upregulation was tumor specific.
      Expression of Ly49A as well as Ly49C isotypes were augmented by fixed tumor
      cells. Moreover, increased Ly49 expression was seen on cell populations
      expressing TCRbeta as well as NK1.1 markers. These results indicate that exposure
      to tumor cells may be an important factor regulating KIR expression on NK and T
      cells. Implications of these results are discussed.

PMID- 10656669
TI  - Green fluorescent protein-transgenic mice: immune functions and their application
      to studies of lymphocyte development.
AB  - Green fluorescent protein (GFP) transgenic (GFP+) mice express GFP in most
      tissues except erythrocytes and hair. Immune responses of GFP+ mouse and their
      application to studies of lymphocyte development were investigated. Flow
      cytometric analyses revealed that differentiation patterns of lymphocytes from
      GFP+ mice are equivalent to those from parental C57BL/6 mice. There was no
      difference in mature T-cell proliferative ability in response to allogeneic
      stimulator cells or anti-CD3epsilon stimulation between GFP+ and C57BL/6 mice.
      Furthermore, the anti-OVA antibody response of GFP+ mice was also the same as
      that of C57BL/6 mice. Taken together, these results show no immunological
      differences between GFP+ and C57BL/6 mice. Bone marrow transplantation and in
      vitro thymus reconstitution experiments were performed in an attempt to apply the
      GFP+ mice to the analysis of lymphocyte development. When bone marrow cells from
      GFP+ mice were transplanted. T and B lymphocytes containing GFP developed
      normally in scid recipients. Next we examined intrathymic T-cell development by
      hanging drop culture methods. GFP+ and CD4+8+ immature T-cells developed normally
      from bone marrow cells in the reconstituted thymus. The experimental system using
      hematopoietic cells from GFP+ mice is a powerful tool for visualizing lymphocyte
      development.

PMID- 10656670
TI  - Self-priming cell culture system for monitoring genetically-controlled
      spontaneous cytokine-producing ability in mice.
AB  - To monitor genetically-controlled cytokine-producing ability in mice in vitro, we
      developed a high-density cell culture system, which is preferable for inducing
      CD4+ T cell-dependent self-priming responses without any antigenic stimulation.
      When BALB/c spleen cells were cultured at high density (over 1.0 x 10(7)
      cells/well) in 12-well culture plate, they spontaneously produced cytokines
      including IFN-gamma, IL-2, IL-3, IL-5 and IL-6. The spontaneous cytokine
      production in this self-priming cell culture (SPCC) system was totally dependent
      on MHC class II-restricted CD4+ T cells. It was demonstrated that Th2-type BALB/c
      background mice exhibited higher levels of spontaneous cytokine production in
      SPCC culture compared with Th1-type C57BL/6 mice. Moreover, using BALB/c x
      C57BL/6 F1 mice and B10D2 congenic mice, it was demonstrated that highly
      spontaneous cytokine-producing ability in BALB/c background is genetically
      dominant and it is controlled by non-MHC genes. Unexpectedly, BALB/c mice
      spontaneously produced higher levels of IL-2 and IFN-gamma than C57BL/6 mice.
      However, BALB/c mice revealed lower levels of CTL and NK cell-generation in SPCC
      system compared with C57BL/6 mice. These results suggested that genetically
      controlled predisposition of BALB/c mice toward Th2 immunity appeared not to be
      derived from their poor IFN-gamma-producing ability but rather derived from their
      poor responsiveness to IFN-gamma.

PMID- 10656671
TI  - Apoptosis and the cell cycle in Xenopus laevis: PHA and PMA exposure of
      splenocytes.
AB  - T cell receptor (TCR) ligation and protein kinase C (PKC) activation stimulate
      proliferation and modulate apoptosis in both mammalian and amphibian lymphocytes.
      The potential relationship between apoptosis and the cell cycle in mature Xenopus
      laevis splenic lymphocytes is addressed by monitoring apoptosis and DNA synthesis
      over time, using incorporation of propidium iodide (PI) and flow cytometry.
      Aliquots of the same populations of cells are followed after exposure in vitro to
      phytohemagglutinin (PHA) or phorbol 12-myristate 13-acetate (PMA). Significant
      increases in apoptosis preceed those in DNA synthesis by 12 to 16 h following
      exposure to both reagents. Since apoptosis preceeds DNA synthesis, these dying
      cells clearly do not need to enter the S phase of the cell cycle before becoming
      apoptotic, in contrast to mammalian T cells. Another striking difference is that
      the reagent with weaker mitogenic properties in this species, PHA, is
      significantly a more potent apoptogen, than the strong mitogen, PMA. The two
      phenomena then appear to be inversely related in Xenopus cells. Data on DNA
      synthesis suggest independence of the two phenomena, as DNA synthesis is
      stimulated in direct proportion to the strength of each reagent as a mitogen.
      Mature mammalian T-cells undergo apoptosis only when previously activated. The
      Xenopus lymphocytes examined were not deliberately activated by exposure to
      antigen or lectin. PMA, a cancer promoter in mammals, usually 'rescues' mammalian
      cells from apoptosis, but stimulates apoptotic increases in Xenopus cells. Thus,
      mature Xenopus lymphocytes may be more readily stimulated to die by cancer
      inducing agents than mammalian lymphocytes. This could make them less susceptible
      to transformation into immortalized cancer cells. This characteristic may
      considerably contribute to the observed resistance to spontaneous and chemically
      induced neoplasia in wild type, non-isogeneic or non-inbred Xenopus.

PMID- 10656672
TI  - Treatment of H. pylori infected mice with antioxidant astaxanthin reduces gastric
      inflammation, bacterial load and modulates cytokine release by splenocytes.
AB  - Helicobacter pylori is a gram-negative bacterium affecting about half of the
      world population, causing chronic gastritis type B dominated by activated
      phagocytes. In some patients the disease evolves into gastric ulcer, duodenal
      ulcer, gastric cancer or MALT lymphoma. The pathogenesis is in part caused by the
      immunological response. In mouse models and in human disease, the mucosal immune
      response is characterized by activated phagocytes. Mucosal T-lymphocytes are
      producing IFN-gamma thus increasing mucosal inflammation and mucosal damage. A
      low dietary intake of antioxidants such as carotenoids and vitamin C may be an
      important factor for acquisition of H. pylori by humans. Dietary antioxidants may
      also affect both acquisition of the infection and the bacterial load of H. pylori
      infected mice. Antioxidants, including carotenoids, have anti-inflammatory
      effects. The aim of the present study was to investigate whether dietary
      antoxidant induced modulation of H. pylori in mice affected the cytokines
      produced by H. pylori specific T-cells. We found that treatment of H. pylori
      infected mice with an algal cell extract containing the antioxidant astaxanthin
      reduces bacterial load and gastric inflammation. These changes are associated
      with a shift of the T-lymphocyte response from a predominant Th1-response
      dominated by IFN-gamma to a Th1/Th2-response with IFN-gamma and IL-4. To our
      knowledge, a switch from a Th1-response to a mixed Th1/Th2-response during an
      ongoing infection has not been reported previously.

PMID- 10656673
TI  - Role of neutrophils in release of some cytokines and their soluble receptors.
AB  - Available data suggest that cytokines and soluble cytokine receptors, which are
      being produced by immunological cells, can modulate the immune response of the
      host. Although the production of mediators such as TNF-alpha and IL-6 as well as
      that of their soluble receptors has been extensively studied in tissue cells and
      mononuclear cells, it has not been fully investigated in neutrophils (PMN). In
      the present study we examined the ability of PMN to simultaneously release TNF
      alpha, IL-6 and their soluble receptors-sTNFRp55, sTNFRp75 and sIL-6R.
      Concentrations of soluble receptors were compared with expression of membrane
      bound TNF and IL-6 receptors. For comparative purposes, similar examinations with
      autologous peripheral blood mononuclear cells (PBMC) were performed. We found
      that PMN and PBMC have the same ability to release IL-6 and sTNFRp75. In
      contrast, there were significant differences in the release of TNF-alpha,
      sTNFRp55 and sIL-6R between these cells. Reduction in membrane TNF receptor
      expression, observed in this study, was associated with increase secretion of
      soluble TNF receptors by PMN and PBMC. The results suggest that PMN can play an
      essential role in modulating the inflammatory response by affecting the balance
      between pro-inflammatory mediators, such as TNF-alpha, and anti-inflammatory
      mediators, such as soluble TNF receptors.

PMID- 10656674
TI  - The P9 peptide sidechain specificity of I-Ad.
AB  - The murine MHC class II variant I-Ad confers susceptibility to herpes simplex
      virus (HSV)-induced keratitis and relative protection against type 1 diabetes
      mellitus. The association to these autoimmune diseases appears to be largely
      determined by the peptide sidechain specificity of the P9 pocket, which we
      therefore have analyzed in detail. Assessment of T-cell responses and I-Ad
      binding capacity of position 446-substituted analogs of an IgG2a allotype b
      (IgG2a(b)) heavy chain peptide demonstrates that engagement of the P9 pocket is
      crucial for effective peptide presentation. Sidechain size rather than charge
      decides the capacity to engage the P9 pocket. Thus, small, uncharged sidechains
      are accepted, whereas acidic and aromatic amino acids as well as lysine and
      arginine are disfavored. The specificity of the P9 pocket of I-Ad (serine beta57)
      is distinct from that of the diabetes-associated I-Ag7 (aspartic acid beta57),
      supporting the contention that the polymorphism at residue beta57 influences
      diabetes susceptibility via P9-specific effects on the repertoires of self
      peptides presented to T cells. Furthermore, the data rationalize the
      susceptibility to HSV-induced keratitis conferred by the a and the protection
      conferred by the b allotypes of the IgG2a heavy chain. Keratitogenic T cells,
      which cross-react with the viral UL6 protein and a corneal antigen, are silenced
      in IgG2a(b) mice because of antigenic mimicry with gamma2a(b) 435-451. Our
      finding that the lysine P9 residue of the corresponding gamma2a(a) allopeptide
      precludes high-affinity binding to I-Ad indicates that the susceptibility of
      IgG2a(a) mice reflects inefficient thymic presentation of autologous IgG2a and
      thus failure to purge the T-cell repertoire of the pathogenic clones.

PMID- 10656675
TI  - The humoral immune response to the kinetoplastid membrane protein-11 in patients
      with American leishmaniasis and Chagas disease: prevalence of IgG subclasses and
      mapping of epitopes.
AB  - The kinetoplastid membrane protein-11 (KMP-11) is a major target of the humoral
      immune response during Leishmania-infections. The majority of sera from visceral
      leishmaniasis, mucocutaneous leishmaniasis and even some cutaneous leishmaniasis
      patients contain detectable IgG antibodies against KMP-11. We also provide
      evidence that this protein may act as a potent antigen in T. cruzi infections,
      since most Chagas sera show immunological cross-reactivity. Therefore, KMP-11
      cannot be used as a specific diagnostical tool for the serodiagnosis of
      leishmaniasis in those regions where both, Leishmania and T. cruzi infections
      overlap geographically. When analyzing the subclass specificity of the antibody
      response to KMP-11 we observed the following order of reactivity: IgG1 > > IgG3 >
      IgG2 > IgG4, which is similiar to that seen in crude parasite extract. The
      mapping of antigenic determinants by using synthetic 20-mer peptides revealed the
      existence of predominantly conformational epitopes in leishmaniasis, while 50% of
      sera from Chagas patients reacted with a particular KMP-11 peptide. These results
      therefore suggest the presence of disease-specific B-cell epitopes.

PMID- 10656676
TI  - A procathepsin D specific monoclonal antibody that recognizes procathepsin D but
      not cathepsin D.

PMID- 10656677
TI  - A mutant streptokinase lacking the C-terminal 42 amino acids is less immunogenic.
AB  - Streptokinase (SK) is the most widely used compound for the treatment of
      myocardial infarction and the least expensive thrombolytic agent, but a drawback
      to its use is the widespread presence of anti-SK antibodies (Abs). Clinical
      failure of the activation of the fibrinolytic system by SK has been reported due
      to the presence of a high titer of anti-SK neutralizing Abs. Patients receiving
      SK therapy develop high anti-SK antibody titers, which might provoke severe
      allergic reactions. These Abs are sufficient to neutralize a standard dose of SK
      up to four years after initial SK administration. This is a clinical problem
      because of the increasing number of patients who have been treated once with SK
      for acute myocardial infarction (AMI) and are likely to require plasminogen
      activator treatment in the future. In previous in vitro studies, we have shown
      that a deletion mutant (mut-C42), lacking the 42 C-terminal residues, was
      significantly less antigenic when compared with the native molecule (SKC-2). In
      this study, 14 monkeys were subjected to treatment with SKC-2 and mut-C42 in
      order to compare their humoral response by determining SK neutralizing activity
      in monkey's sera. All monkeys developed anti-SKC-2 Ab titers, but in the case
      where treatment induced Abs directed against the C-terminus of SKC-2,
      neutralizing activity against the native protein was significantly higher than
      that developed against mutant SK mut-C42.

PMID- 10656678
TI  - Novel polymorphism in p21(waf1/cip1) cyclin dependent kinase inhibitor gene:
      association with human esophageal cancer.
AB  - p21(waf1/cip1), an important regulator of the cell cycle, binds to PCNA and acts
      as a mediator of the growth suppressing and apoptosis promoting functions of p53.
      We report a hitherto unobserved polymorphism in the carboxy terminal domain
      (codon 149) of p21(waf1/cip1) gene, the domain encoding the PCNA binding motif.
      The codon 149 polymorphism (GAT-->GGT) was observed in 42 of 50 (84%) esophageal
      squamous cell carcinomas (ESCCs) and eight of 50 (16%) normal individuals. The
      resultant amino acid substitution from aspartate to glycine may have vital
      implication in PCNA mediated cell cycle regulation by p21(waf1/cip1). The second
      polymorphism at codon 31, involving a C-->A transversion at nucleotide 168 (AGC-
      >AGA) changing the amino acid from serine to arginine, was observed in 2/50 (4%)
      ESCCs at a relatively lower frequency in the Indian population than that reported
      in the West. No significant association was observed between p21(wap1/cip1)
      polymorphism at codon 149 and p21(wap1/cip1) protein expression in ESCC in this
      cohort of patients. Interestingly, the frequency of p21(wap1/cip1) variants
      (codon 149) in ESCCs (18 of 19 cases) with wild-type p53 was significantly higher
      than in tumors with p53 mutations, suggesting that this polymorphism affects the
      p53 pathway and may play an important role in esophageal tumorigenesis. Analysis
      of p21(waf1/cip1) expression in relation to p53 gene and protein status revealed
      its induction by p53-dependent as well as independent pathways in esophageal
      tumorigenesis.

PMID- 10656679
TI  - Bcl-2 and Bax regulate the channel activity of the mitochondrial adenine
      nucleotide translocator.
AB  - Bcl-2 family protein including anti-apoptotic (Bcl-2) or pro-apoptotic (Bax)
      members can form ion channels when incorporated into synthetic lipid bilayers.
      This contrasts with the observation that Bcl-2 stabilizes the mitochondrial
      membrane barrier function and inhibits the permeability transition pore complex
      (PTPC). Here we provide experimental data which may explain this apparent
      paradox. Bax and adenine nucleotide translocator (ANT), the most abundant inner
      mitochondrial membrane protein, can interact in artificial lipid bilayers to
      yield an efficient composite channel whose electrophysiological properties differ
      quantitatively and qualitatively from the channels formed by Bax or ANT alone.
      The formation of this composite channel can be observed in conditions in which
      Bax protein alone has no detectable channel activity. Cooperative channel
      formation by Bax and ANT is stimulated by the ANT ligand atractyloside (Atr) but
      inhibited by ATP, indicating that it depends on the conformation of ANT. In
      contrast to the combination of Bax and ANT, ANT does not form active channels
      when incorporated into membranes with Bcl-2. Rather, ANT and Bcl-2 exhibit mutual
      inhibition of channel formation. Bcl-2 prevents channel formation by Atr-treated
      ANT and neutralizes the cooperation between Bax and ANT. Our data are compatible
      with a menage a trois model of mitochondrial apoptosis regulation in which ANT,
      the likely pore forming protein within the PTPC, interacts with Bax or Bcl-2
      which influence its pore forming potential in opposing manners.

PMID- 10656680
TI  - Tumour regression in a ligand inducible manner mediated by a chimeric tumour
      suppressor derived from p53.
AB  - The p53 tumour suppressor induces cell cycle arrest and apoptosis in response to
      cellular stresses. p53 is inactivated by various cellular and viral factors. We
      set out to generate regulatable p53 derivatives that are highly inducible by
      synthetic ligands, escape inactivation and efficiently induce apoptosis. We have
      generated Ligand Inducible Chimeric Tumour Suppressors (LI-CTS), that are
      inactive unless provided with artificial ligands. They are resistant to
      inactivation, due to the replacement of domains that mediate p53 inhibition by
      heterologous sequences. LI-CTS are activated by micromolar concentrations of
      ligand in a variety of cell lines. Following ligand addition, they translocate to
      the nucleus, activate p53 inducible genes and induce apoptosis. We have
      established human head and neck squamous cell carcinoma lines that stably express
      LI-CTS, which are inducible. These lines form tumours in nude mice in the absence
      of ligand. Addition of ligand inhibits tumour formation, and moreover, regresses
      established tumours by apoptosis. Although regulatable p53 expression has been
      achieved previously, our study provides the first demonstration of regulatable in
      vivo regression of tumours in a p53 based approach. Regulated inhibition and
      regression of tumours with a ligand inducible chimeric tumour suppressor could
      provide a novel approach to p53 based gene therapy.

PMID- 10656681
TI  - Self-association of the SET domains of human ALL-1 and of Drosophila TRITHORAX
      and ASH1 proteins.
AB  - The human ALL-1 gene is involved in acute leukemia through gene fusions, partial
      tandem duplications or a specific deletion. Several sequence motifs within the
      ALL-1 protein, such as the SET domain, PHD fingers and the region with homology
      to DNA methyl transferase are shared with other proteins involved in
      transcription regulation through chromatin alterations. However, the function of
      these motifs is still not clear. Studying ALL-1 presents an additional challenge
      because the gene is the human homologue of Drosophila trithorax. The latter is a
      member of the trithorax-Polycomb gene family which acts to determine the body
      pattern of Drosophila by maintaining expression or repression of the Antennapedia
      bithorax homeotic gene complex. Here we apply yeast two hybrid methodology, in
      vivo immunoprecipitation and in vitro 'pull down' techniques to show self
      association of the SET motifs of ALL-1, TRITHORAX and ASH1 proteins (Drosophila
      ASH1 is encoded by a trithorax-group gene). Point mutations in evolutionary
      conserved residues of TRITHORAX SET, abolish the interaction. SET-SET
      interactions might act in integrating the activity of ALL-1 (TRX and ASH1)
      protein molecules, simultaneously positioned at different maintenance elements
      and directing expression of the same or different target genes.

PMID- 10656682
TI  - Cooperative phosphorylation at multiple sites is required to activate p53 in
      response to UV radiation.
AB  - The activity of the tumor suppressor p53 is induced in response to DNA-damaging
      agents such as UV and gamma radiation. Phosphorylation is one of the key
      regulatory steps for activating p53 function. Recent reports have shown that p53
      is phosphorylated at both serines 15 and 392 in response to UV radiation.
      Phosphorylation at serine 15 prevents the binding of HDM2, a negative regulator
      of p53. Phosphorylation at serine 392 induces the DNA-binding function of p53. We
      examined the requirement for phosphorylation at both serines and show that both
      these modifications occur on the same molecule of p53. In vitro assays
      demonstrate that phosphorylation at either one of these sites is not sufficient
      to yield an active p53. Phosphorylation by DNA-PK, that modifies serines 15 and
      37, inhibits HDM2 binding to p53 but does not induce the DNA-binding activity of
      p53. Phosphorylation at serine 392, on the other hand, stimulates the DNA-binding
      ability of p53 but does not make it immune to binding and inhibition by HDM2.
      Thus, our results demonstrate that multiple sites need to be modified to yield a
      functional p53.

PMID- 10656683
TI  - The APC-hDLG complex negatively regulates cell cycle progression from the G0/G1
      to S phase.
AB  - The adenomatous polyposis coli (APC) gene is mutated in familial adenomatous
      polyposis and in many sporadic colorectal tumors. The carboxyl-terminal S/TXV
      motif of the APC gene product interacts with the PDZ domain of hDLG, the human
      homolog of the Drosophila lethal (1) discs larige-1 (dlg) tumor suppressor. In
      the present study, we found that overexpression of hDLG suppresses cell
      proliferation by blocking cell cycle progression from the G0/G1 to S phase. This
      inhibition of cell cycle progression was abolished when the PDZ, SH3 or guanylate
      kinase-like domain of hDLG was mutated. Moreover, overexpression of these mutant
      hDLGs partially interfered with the cell cycle blocking activity of APC.
      Consistent with this result, mutant APC lacking the S/TXV motif exhibited weaker
      cell cycle blocking activity than the intact APC. These results suggest that APC
      hDLG complex formation plays an important role in transducing the APC cell cycle
      blocking signal.

PMID- 10656684
TI  - Physical interaction between CDK9 and B-Myb results in suppression of B-Myb gene
      autoregulation.
AB  - B-Myb is a transcription factor belonging to the myb family, whose activity has
      been associated with augmented DNA synthesis and cell cycle progression. We
      showed recently that B-Myb autoregulates its own expression through promoter
      transactivation. We report in this study that CDK9, the cyclin T associated
      kinase, which phosphorylates and activates RNA-Polymerase II, suppresses B-Myb
      autoregulation through direct interaction with the carboxyl-terminus of the B-Myb
      protein. Down-regulation of the transactivating ability of B-Myb is independent
      of the kinase activity of CDK9, because a kinase deficient mutant (dn-CDK9) also
      represses B-myb gene autoregulation. Overexpression of CDK9 did not result in
      suppression of p53-dependent transactivation or inhibition of the basal activity
      of the promoters tested so far, demonstrating that CDK9 is a B-Myb-specific
      repressor. Rather, transfection of the dominant negative dn-CDK9 construct
      inhibited the basal activity of the reporter genes, confirming an essential role
      for CDK9 in gene transcription. In addition, Cyclin T1 restores B-Myb
      transactivating activity when co-transfected along with CDK9, suggesting that the
      down-regulatory effect observed on B-Myb is specifically due to CDK9 alone. Thus,
      our data suggest that CDK9 is involved in the negative regulation of activated
      transcription mediated by certain transcription factors, such as B-Myb. This may
      indicate the existence of a feedback loop, mediated by the different activities
      of CDK9, which links basal with activated transcription.

PMID- 10656685
TI  - The human non-muscle alpha-actinin protein encoded by the ACTN4 gene suppresses
      tumorigenicity of human neuroblastoma cells.
AB  - alpha-Actinins are actin-binding proteins important in organization of the
      cytoskeleton and in cell adhesion. We have cloned and characterized a cDNA from
      human neuroblastoma cell variants which encodes the second non-muscle alpha
      actinin isoform designated ACTN4 (actinin-4). mRNA encoded by the ACTN4 gene,
      mapped to chromosome 4, is abundant in non-tumorigenic, substrate-adherent human
      neuroblastoma cell variants but absent or only weakly expressed in malignant,
      poorly substrate-adherent neuroblasts. It is also present in many adherent tumor
      cell lines of diverse tissue origins. Cell lines typically co-express ACTN4 and
      ACTN1, a second non-muscle alpha-actinin gene. Expression is correlated with
      substrate adhesivity. Analysis of deduced amino acid sequences suggests that the
      two isoforms may differ in function and in regulation by calcium. Moreover, ACTN4
      exhibits tumor suppressor activity. Stable clones containing increased levels of
      alpha-actinin, isolated from highly malignant neuroblastoma stem cells [BE(2)-C]
      after transfection with a full-length ACTN4 cDNA, show decreased anchorage
      independent growth ability, loss of tumorigenicity in nude mice, and decreased
      expression of the N-myc proto-oncogene.

PMID- 10656686
TI  - p95(vav) associates with the type I interferon (IFN) receptor and contributes to
      the antiproliferative effect of IFN-alpha in megakaryocytic cell lines.
AB  - The vav proto-oncogene product is a 95 kDa protein predominantly expressed in
      hematopoietic cells. Vav presents a wide range of functional domains, including
      structural domains known to be involved in signal transduction. Triggering of
      various cytokine receptors among which type I interferon receptor induces a rapid
      and transient tyrosine phosphorylation of p95(vav). Nevertheless, the biological
      functions of p95(vav) are still unclear. This report is the first documentation
      on the physical association of p95(vav) with both alpha and beta type I
      interferon receptor chains, as demonstrated by co-immunoprecipitation and Western
      blot analysis in megakaryocytic cells (Dami and UT7). This interaction is
      increased by interferon-alpha/beta stimulation. Moreover, p95(vav) phosphorylated
      subsequently to type I interferon treatment, is translocated in the nucleus; a
      concomitant increase of its association with the regulatory subunit of the
      nuclear DNA-dependent protein kinase, KU-70 is observed in the nucleus. To
      determine whether p95(vav) participates in the biological response to type I
      interferons, we studied the effects of non modified Vav oligodeoxynucleotides on
      the antiproliferative effect of interferon-alpha on megakaryocytic cells. By this
      oligodeoxynucleotide strategy, we show that p95(vav) contributes greatly to the
      cell proliferation inhibition induced by type I IFN.

PMID- 10656687
TI  - Tyrosinase-related protein 2 as a mediator of melanoma specific resistance to cis
      diamminedichloroplatinum(II): therapeutic implications.
AB  - A major obstacle in the systemic treatment of advanced malignant melanoma is its
      intrinsic resistance to conventionally used chemotherapeutic agents. In order to
      investigate the mechanisms of this intrinsic resistance, we have previously
      utilized retroviral insertional mutagenesis on an early-stage, drug sensitive
      human melanoma cell line (WM35) to establish mutated cell lines that exhibited
      increased resistance to cis-diammi-nedichloroplatinum(II) (CDDP). Here, we
      demonstrate that this increased resistance to CDDP is mediated by the over
      expression of tyrosinase-related protein-2 (TYRP2), an enzyme that normally
      functions in the biosynthesis of the pigment, melanin. Northern and Western blot
      analyses revealed that the expression of TYRP2 in the virally-derived cell lines
      as well as in a panel of human melanoma cell lines positively correlated with
      their levels of resistance to CDDP. Furthermore, enforced expression of TYRP2 in
      WM35 cells by transfection elevated their resistance to CDDP. The increased CDDP
      resistance in the virally-derived clones and TYRP2 transfectants was accompanied
      by a reduction in CDDP-induced apoptosis. Interestingly, the virally-derived CDDP
      resistant clones also showed cross resistance to carboplatin and methotrexate,
      but not taxol, suggesting that TYRP2 over-expression may confer resistance
      specifically to DNA damaging agents. Overall, these results demonstrate a novel
      mechanism of drug resistance in human melanoma cells that is mediated by the over
      expression of TYRP2. Since TYRP2 is expressed only in cells of melanocytic
      lineage, this may represent the first report of a lineage-specific mechanism of
      drug resistance. In summary, these findings suggest a significant role for TYRP2
      in the intrinsic drug resistance phenotype of human melanoma cells and may have
      important implications in the development of chemosensitization strategies for
      the clinical management of this disease.

PMID- 10656688
TI  - Cell cycle regulated expression and phosphorylation of hpttg proto-oncogene
      product.
AB  - We recently isolated a cDNA for hpttg, the human homolog of rat pituitary tumor
      transforming gene. Now we have analysed the expression of hpttg as a function of
      cell proliferation. hPTTG protein level is up-regulated in rapidly proliferating
      cells, is down-regulated in response to serum starvation or cell confluence, and
      is regulated in a cell cycle-dependent manner, peaking in mitosis. In addition,
      we show that hPTTG is phosphorylated during mitosis. Immunodepletion and in vitro
      phosphorylation experiments, together with the use of a specific inhibitor,
      indicate that Cdc2 is the kinase that phosphorylates hPTTG. These results suggest
      that hpttg is induced by, and may have a role in, regulatory pathways involved in
      the control of cell proliferation.

PMID- 10656689
TI  - Expression of GPC3, an X-linked recessive overgrowth gene, is silenced in
      malignant mesothelioma.
AB  - Gene expression changes in rat asbestos-induced malignant mesothelioma (MM) cells
      were investigated by differential mRNA display. A mRNA transcript identified by
      this approach was abundant in normal rat mesothelial cells but not expressed in
      rat MM cell lines. Northern blot analysis confirmed that this transcript is
      uniformly silenced in rat MM cell lines and primary tumors. Nucleotide sequence
      analysis revealed that this transcript is encoded by the rat glypican 3 gene
      (GPC3), whose human homolog is mutated in the Simpson-Golabi-Behmel overgrowth
      syndrome. Allelic loss at the GPC3 locus was infrequent (6.9%) in MM cell lines,
      and no mutations were found. GPC3 transcript levels were markedly decreased in 16
      of 18 primary tumors and 17 of 22 human MM cell lines. Most of the cell lines
      were shown to have aberrant methylation of the GPC3 promoter region. In two of
      four human MM cell lines tested, GPC3 expression was restored after 2-deoxy 5
      azacytidine (DAC)-mediated demethylation of its promoter region. Ectopic
      expression of GPC3 inhibited in vitro colony formation of human MM cells.
      Collectively, these data suggest that down-regulation of GPC3 is a common
      occurrence in MM and that GPC3, an X-linked recessive overgrowth gene, may encode
      a negative regulator of mesothelial cell growth.

PMID- 10656690
TI  - Acidic substitution of the activation loop tyrosines in TrkA supports nerve
      growth factor-independent cell survival and neuronal differentiation.
AB  - TrkA is the receptor tyrosine kinase (RTK) for nerve growth factor (NGF) and
      stimulates NGF-dependent cell survival and differentiation in primary neurons.
      TrkA expression in neuronal tumors also supports NGF-dependent differentiation of
      neuroblastomas and apoptosis of medulloblastomas. Phosphorylation of the
      activation loop tyrosines in RTK's are essential to activation as well as
      allosteric changes that facilitate substrate interaction and phosphorylation.
      Acidic amino acid substitution of the activation loop tyrosines in TrkA,
      Tyr683Tyr684, was performed to mimic the negative charges normally induced by
      ligand activation and receptor phosphorylation. A total of eight independent
      mutants containing single or double substitutions were generated for comparison.
      Herein, we demonstrate that acidic substitution of the activation loop tyrosines
      is sufficient to induce allosteric changes required for constitutive TrkA kinase
      activity as well as phosphorylation of TrkA signaling proteins such as Shc,
      PLCgamma-1, FRS-2 and erk1/2. The strongest constitutively active TrkA mutants,
      GluAsp and AspGlu, support NGF-independent neuritogenesis and cell survival to
      levels approximately 65 and 80-100%, respectively, of NGF-activated wild type
      TrkA. Thus, constitutively active TrkA may provide a useful strategy in future
      therapeutic approaches to limit the development and progression of neuronal
      tumors.

PMID- 10656691
TI  - Ras protein is involved in the physiological regulation of phospholipase D by
      platelet derived growth factor.
AB  - Lipid-derived metabolites play an important role in the regulation of cell
      responses to external stimuli, including cell growth control, transformation and
      apoptosis. Phospholipase D (PLD) is one of the critical elements in the
      regulation of lipid metabolism and the generation of second messengers, some of
      them involved in cell growth control. Oncogenic Ras proteins affect the activity
      of PLD by two alternate mechanisms, involving a positive activation and a
      feedback negative loop. Here we investigate the involvement of the proto
      oncogenic Ras protein in the physiological activation of PLD induced by platelet
      derived growth factor (PDGF). Over-expression of the wild type Ras protein or
      some of its regulatory components, such as Shc or Grb2, induces an amplification
      of PLD activation by PDGF challenge. Furthermore, blocking the endogenous Ras by
      expression of the dominant negative mutant, H-Ras-Asn17 completely eliminated the
      activation of PLD by PDGF. Thus, PDGF requires a complex system for PLD
      regulation implying the existence of at least two positive regulatory pathways, a
      Ras-dependent and a PKC-dependent mechanism. These results imply that PLD is an
      important element in signaling by Ras proteins that is altered after ras-induced
      transformation.

PMID- 10656692
TI  - Preferential induction of RET/PTC1 rearrangement by X-ray irradiation.
AB  - Ionizing radiation is a well known risk factor of thyroid cancer development, but
      the mechanism of radiation induced carcinogenesis is not clear. The RET/PTC
      oncogene, an activated form of the RET proto-oncogene, is frequently observed in
      papillary thyroid carcinoma (PTC); RET/PTC1, -2 and -3 are known to be the three
      major forms. High frequencies of RET/PTC rearrangements have been observed in
      radiation-associated PTC, such as those appearing post-Chernobyl or post
      radiotherapy, but the rearrangement types differ between these two populations.
      We investigated whether a specific type of RET/PTC rearrangement was induced by X
      rays in vivo and in vitro. In human normal thyroid tissues transplanted in scid
      mice, the RET/PTC1 rearrangement was predominantly detected throughout the
      observation period (up to 60 days) after X-ray exposure of 50 Gy. On the other
      hand, RET/PTC3 was detected only 7 days after X-irradiation, and no transcript of
      RET/PTC2 was detected. These results are supported by the results of an in vitro
      study. The RET/PTC1 rearrangement was preferentially induced in a dose-dependent
      manner by X-rays within a high dose range (10, 50 and 100 Gy) in four cell lines.
      On the other hand, RET/PTC3 was induced at a much lower frequency, and no
      induction of RET/PTC2 was observed. These results suggest that the preferential
      induction of the RET/PTC1 rearrangement may play an important role in the early
      steps of thyroid carcinogenesis induced by acute X-irradiation.

PMID- 10656693
TI  - c-Myb acetylation at the carboxyl-terminal conserved domain by transcriptional co
      activator p300.
AB  - Transcription factor c-Myb plays important roles in cell survival and
      differentiation in immature hematopoietic cells. Here we demonstrate that c-Myb
      is acetylated at the carboxyl-terminal conserved domain by histone
      acetyltransferase p300 both in vitro and in vivo. The acetylation sites in vivo
      have been located at the lysine residues of the conserved domain (K471, K480,
      K485) by the use of the mutant Myb (Myb-KAmut), in which all three lysine
      residues are substituted into alanine. Electrophoretic mobility shift assay
      reveals that Myb-KAmut shows higher DNA binding activity than wild type c-Myb and
      that acetylation of c-Myb in vitro by p300 causes dramatic increase in DNA
      binding activity. Accordingly, transactivation activity of both mim-1 and CD34
      promoters by Myb-KAmut is higher than that driven by wild type c-Myb.
      Furthermore, the bromodomain of p300, in addition to the histone
      acetyltransferase (HAT) domain, is required for effective acetylation of c-Myb,
      and hGCN5 is revealed to be a factor acetyl-transferase for c-Myb in vitro. We
      present a new manner of post-translational modification of the c-Myb protein and
      the potential significance of the acetylation in c-Myb.

PMID- 10656694
TI  - Consequences of disruption of the interaction between p53 and the larger
      adenovirus early region 1B protein in adenovirus E1 transformed human cells.
AB  - The adenovirus early region 1B (Ad E1B) genes have no transforming capability of
      their own but markedly increase the transformation frequency of Ad E1A following
      co-transfection into mammalian cells. The larger E1B proteins of both Ad2/5 and
      Ad12 bind to p53 and inhibit its ability to transcriptionally activate other
      genes. We have previously demonstrated that synthetic peptides identical to the
      binding sites for p53 on both the Ad2 and Ad12 E1B proteins will disrupt the
      interaction in vivo and in vitro. In the work presented here we have examined the
      effects of complex dissociation on Ad E1-transformed human cells. It has been
      shown, using confocal microscopy, that when the peptide identical to the p53
      binding site was added to Ad5 E1-transformed cells it initally located in the
      cytoplasmic dense bodies where it caused disruption of the p53/E1B complex.
      Peptide and p53 then translocated to the nucleus. In Ad12 E1-transformed cells
      the peptide localized in the nucleus directly and there caused a reorganization
      of p53 staining from a highly organized, 'flecked' distribution to one in which
      nuclear staining was homogeneous and diffuse. Peptides added to either Ad5 E1 or
      Ad12 E1 transformed cells resulted in the release of transcriptionally active
      p53. Interestingly, the level of p53 then fell presumably as a result of
      proteasomal action - this was probably a reflection of the short half-life of
      'free' (i.e. dissociated) p53 compared to that of the bound protein. Free p53 did
      not cause apoptosis in target cells probably due to the presence of the smaller
      (19K) E1B proteins. However, addition of peptide leads to a significant reduction
      in cell growth rate. We have further demonstrated that a significant proportion
      of those cells which had taken up peptide had ceased DNA synthesis, probably due
      to a p53-induced cell cycle arrest. The role of the larger EIB protein during
      transformation is considered in view of these data.

PMID- 10656695
TI  - UV mutation signature in tumor suppressor genes involved in skin carcinogenesis
      in xeroderma pigmentosum patients.
AB  - Molecular analysis of p53 and patched (PTCH), two candidate tumor suppressor
      genes for non-melanocytic skin cancer, was performed in skin tumors from six
      patients affected by the cancer-prone disease xeroderma pigmentosum (XP). UV
      specific p53 mutations were detected at a frequency of 38-50% in all the tumor
      types analysed, including melanomas. Additional analysis of PTCH mutations in the
      subset of eight basal call carcinomas (BCC) revealed a very high mutation
      frequency of this gene (90%) which exceeded that detected in the p53 gene in the
      same tumors (38%). PTCH mutations were predominantly UV-specific C>T transitions.
      This mutation pattern is different from that reported in BCC from normal donors
      where PTCH mutation frequency is 27% and mutations are frequently deletions and
      insertions. These findings suggest that PTCH mutations represent an earlier event
      in BCC development than p53 alterations and that the inability of XP patients to
      repair UV-induced PTCH mutations might significantly contribute to the early and
      frequent appearance of BCC observed in these patients.

PMID- 10656696
TI  - Transcriptional repression of the human p53 gene by hepatitis B viral X protein.
AB  - Hepatitis B viral X protein (HBx) and the human p53 protein (p53) have been known
      as a transactivator and as a tumor suppressor, respectively. These two proteins
      have also been known to interact with each other to neutralize their authentic
      functions and the p53 represses the HBV enhancer/X promoter activity. Here we
      report that the promoter activity of the human p53 gene was strongly repressed by
      the HBx using the chloramphenicol acetyl transferase (CAT) assay. Analyses of
      serial deletion, site-directed mutagenesis and the heterologous promoter system
      showed that the site responsible for the repression was the E-box element in the
      promoter of the p53 gene. In addition, HBx as expected also repressed the
      activation of the p53 promoter by c-Myc through the E-box element. Northern blot
      analyses also showed that the expression of the p53 gene in the HepG2-K8 cell
      line, which expresses HBV genes including HBx, was much more repressed than that
      of the control cell HepG2. These results with previous data suggest that the
      shift of the reciprocal inhibitory activities at the levels of protein-protein
      interaction and transcription between HBx and p53 may play a decisive role in the
      HBV-related hepatocarcinogenesis.

PMID- 10656698
TI  - Ecology of mosquitoes (Diptera: culicidae) in areas of Serra do Mar State Park,
      State of Sao Paulo, Brazil. I - monthly frequency and climatic factors.
AB  - The ecology of mosquitoes were studied (Diptera: Culicidae) in areas of Serra do
      Mar State Park, State of Sao Paulo, Brazil. Systematized monthly human bait
      collections were made three times a day, for periods of 2 or 3 h each, in
      sylvatic and rural areas for 24 consecutive months (January 1991 to December
      1992). A total of 24, 943 specimens of adult mosquitoes belonging to 57 species
      were collected during 622 collective periods. Coquillettidia chrysonotum was the
      most frequent collected mosquito (45.8%) followed by Aedes serratus (6.8%), Cq.
      venezuelensis (6.5%), Psorophora ferox (5.2) and Ps. albipes (3.1%). The monthly
      averages of temperature and relative humidity were inserted in the ten-year
      average limits of maximum and minimum of the previous ten-years. Rainfall
      accompanied the curve of the ten-year averages. Those climatic factors were
      influential in the incidence of some species; temperature: Anopheles cruzii, An.
      mediopunctatus, Ae. scapularis, Ae. fulvus, Cq. chrysonotum, Cq. venezuelensis,
      Runchomyia reversa, Wyeomyia dyari, Wy. confusa, Wy. shannoni, Wy. theobaldi and
      Limatus flavisetosus; relative humidity: Ae. serratus, Ae. scapularis, Cq.
      venezuelensis and Ru. reversa; rainfall: An. cruzii, Ae. scapularis, Ae. fulvus,
      Cq. venezuelensis Ru. reversa, Wy. theobaldi and Li. flavisetosus.

PMID- 10656697
TI  - Cell line dependence of Bcl-2-induced alteration of glutathione handling.
AB  - Bcl-2 has been associated with both oxidative and antioxidative effects in vivo.
      Moreover, despite evidence that Bcl-2 is antiapoptotic by virtue of its effect on
      reactive oxygen species and their scavengers, Bcl-2 exerts its antiapoptotic
      effects even under anaerobic conditions. The reasons for the variable
      relationship between Bcl-2 and reactive oxygen species are not clear. The present
      studies demonstrate that the impact of Bcl-2 on glutathione (GSH) metabolism is
      cell line-dependent. Bcl-2 overproduction in PC12 cells is associated with
      increased functional thiol reserves, increased reductive activation of
      chemotherapeutic prodrugs, and GSH accumulation after treatment with N
      acetylcysteine. In contrast, Bcl-2-overproducing MCF-7 breast cancer cells
      demonstrate neither altered GSH handling nor potentiation of chemotherapeutic
      prodrug reduction. These findings indicate that the effects of Bcl-2 on GSH
      handling are millieu-dependent. This could account for the variable effects of
      Bcl-2 in in vivo systems. Furthermore, since our previous studies have
      demonstrated that reduction-dependent prodrugs may be useful chemotherapeutic
      agents against tumors that demonstrate altered GSH handling, screening in vitro
      for alteration of GSH handling may predict responsiveness of such tumors to these
      reduction-dependent agents.

PMID- 10656699
TI  - Ecology of mosquitoes (Diptera: Culicidae) in areas of Serra do Mar State Park,
      State of Sao Paulo, Brazil. II - habitat distribution.
AB  - The mosquito (Diptera: Culicidae) ecology was studied in areas of Serra do Mar
      State Park, State of Sao Paulo, Brazil. Systematized biweekly human bait
      collections were made three times a day, for periods of 2 or 3 h each, in
      sylvatic and rural areas for 24 consecutive months (January 1991 to December
      1992). A total of 24, 943 adult mosquitoes belonging to 57 species were collected
      during 622 collective periods. Aedes scapularis, Coquillettidia chrysonotum, Cq.
      venezuelensis, Wyeomyia dyari, Wy. longirostris, Wy. theobaldi and Wy. palmata
      were more frequently collected at swampy and at flooded areas. Anopheles
      mediopunctatus, Culex nigripalpus, Ae. serratus, Ae. fulvus, Psorophora ferox,
      Ps. albipes and the Sabethini in general, were captured almost exclusively in
      forested areas. An. cruzii, An. oswaldoi and An. fluminensis were captured more
      frequently in a residence area. However, Cx. quinquefasciatus was the only one
      truly eusynanthropic. An. cruzii and Ae. scapularis were captured feeding on
      blood inside and around the residence, indicating that both species, malaria and
      arbovirus vectors respectively, may be involved in the transmission of these such
      diseases in rural areas.

PMID- 10656700
TI  - Methicillin-resistant Staphylococcus aureus in human milk.
AB  - We collected and analyzed 500 samples of human milk, from five Brazilian cities
      (100 from each) to detect methicillin-resistant strains of Staphylococcus aureus
      (MRSA) producing enterotoxins. We found 57 strains of MRSA, and the mecA gene,
      responsible for resistance, was detected in all of them using a specific
      molecular probe. We examined 40 strains for the presence of four enterotoxins,
      after selecting a subset that included all strains from each region, except for
      the largest sample, from which 10 were randomly selected. Among these two
      presented enterotoxin B, and growth in human colostrum and trypicase soy broth.
      After 5 h of incubation at 37 degrees C, population sizes were already higher
      than 9.4 x 10(5) UFC/ml and enterotoxin was released into culture medium and
      colostrum. Our results stress the importance of hygiene, sanitary measures, and
      appropriate preservation conditions to avoid the proliferation of S. aureus in
      human milk.

PMID- 10656701
TI  - A new Culicoides from the Amazonian region, Brazil (Diptera: Ceratopogonidae).
AB  - A new Neotropical species of biting midge Culicoides (Haematomyidium), C. kampa
      Felippe-Bauer, Veras & Castellon, is described and illustrated based on female
      specimens from the Amazonian Region.

PMID- 10656702
TI  - A new nematode species (Seuratoidea, Cucullanidae) parasitizing Parauchenipterus
      striatulus (Steindachner, 1876) (Pisces, Auchenipteridae) in Brazil.
AB  - A new species of a cucullanid nematode is described, illustrated and compared
      with Cucullanus brevispiculus Moravec, Kohn & Fernandes, 1993 and C.
      rhamphichthydis Moravec, Kohn & Fernandes, 1997, two species previously reported
      as parasitizing freshwater fish in South America. The new species is
      characterized mainly by markedly short spicules, deirids and excretory pore
      situated posterior to the oesophago-intestinal junction, presence of strongly
      sclerotized plates in the oesophastome and oesophagus divided into two distinct
      portions.

PMID- 10656703
TI  - The fine structure of the endogenous stages of Isospora hemidactyli Carini, 1936
      in the Gecko Hemidactylus mabouia from North Brazil.
AB  - The ultrastructure is described of the meronts, microgamonts and young oocyst
      stages of Isospora hemidactyli of the gecko Hemidactylus mabouia from Belem, PA,
      north Brazil. The endogenous stages all develop in the nucleus of the gut
      epithelial cells. The nucleus remains intact up to the latest stages of the
      parasite's development, but degenerates by the time the oocyst appears. Merogonic
      division appears to be asynchronous, and some of the differentiated merozoites
      contained more than one nucleus. Microgamonts conform in structure with those of
      other eimeriids. Some of the type 2 wall-forming bodies disintegrate into smaller
      globules and ground substance of lower density.

PMID- 10656704
TI  - Cephalobellus lobulata n. sp. (Oxyurida:Thelastomatidae) A parasite of
      Neocurtilla claraziana Saussure (Orthoptera: gryllotalpidae) from Argentina.
AB  - Cephalobellus lobulata n. sp. (Oxyurida: Thelastomatidae) a parasite of the mole
      cricket Neocurtilla claraziana Saussure (Orthoptera: Gryllotalpidae) found in
      Argentina is described and illustrated. It is characterized by a short buccal
      cavity armed with three teeth, a striated cuticle with the first annule wide with
      four lobes and the second annule divided in twelve lobes. The male have three
      pairs of preanal papillae and two pairs of postanal papillae.

PMID- 10656705
TI  - Eimeria curvata n. sp.(Apicomplexa: Eimeriidae) in Columbina talpacoti and
      Scardafella squammata (Aves: Columbidae) from Brazil.
AB  - Eimeria curvata is a new coccidian described in the doves Columbina talpacoti and
      Scardafella squammata from western of the State of Sao Paulo, Brazil. The oocysts
      are ovoid to ellipsoid, 18.3 (17-19) microm x 15.5 (15-17) microm, with a shape
      index of 1.2 (1.1-1.3). The wall is colorless, smooth and double-layered. A polar
      granule is present, but there is no micropyle or oocyst residuum. The sporocysts
      are elongate, 12.3 (11.5-13) microm x 5.8 (5.5-6) microm with a curved anterior
      portion and a smooth, thin, single-layered wall. The Stieda body is protuberant
      and nipple-like; there is no substieda body. The sporozoites lie head-to-tail in
      the sporocyst and contain a large refractile body at the extremities. The
      sporocyst residuum contains small granules uniformly distributed in the middle of
      the sporocyst. The prevalence of E. curvata n. sp. was 17.4% and 12.8% in C.
      talpacoti and S. squammata, respectively.

PMID- 10656707
TI  - Inter-specific and developmental differences on the array of antennal
      chemoreceptors in four species of Triatominae (Hemiptera: reduviidae).
AB  - The aim of the work was to investigate the pattern of chemoreceptor sensilla in
      adults and fifth stage nymphs of Rhodnius prolixus, R. neglectus, Triatoma
      infestans and T. sordida in order to study differences and similarities between
      genera and species. Three types of sensilla were analyzed by light microscopy:
      thin-walled trichoidea, thick-walled trichoidea and basiconica. The number of
      sensilla of each three types were counted. The length of the antennal segments
      were also used as a variable for the analysis. The statistical analysis showed
      that the number of these antennal chemoreceptors had significant differences
      between species and between adults and nymphs of each species. Discriminant
      analysis separates incompletely the fifth stage nymphs of the four species and
      showed similarity between them. Discriminant analysis performed with 12 variables
      of the antennae, allowed a complete separation of the adults of the four species.

PMID- 10656706
TI  - Further studies on the molecular systematics of Biomphalaria snails from Brazil.
AB  - The polymerase chain reaction and restriction fragment length polymorphism (RFLP)
      of the internal transcribed spacer (ITS) region of the rRNA gene, using the
      enzyme DdeI were used for the molecular identification of ten species and one
      subspecies of Brazilian Biomphalaria. Emphasis is given to the analysis of B.
      oligoza, B. schrammi and B. amazonica. The RFLP profiles obtained using this
      enzyme were highly distinctive for the majority of the species and exhibited low
      levels of intraspecific polymorphism among specimens from different regions of
      Brazil. However, B. peregrina and B. oligoza presented very similar profiles that
      complicated their identification at the molecular level and suggested a very
      close genetic similarity between the two species. Others enzymes including
      HaeIII, HpaII, AluI and MnlI were tested for their ability to differentiate these
      species. For B. amazonica three variant profiles produced with DdeI were
      observed. The study demonstrated that the ITS contains useful genetic markers for
      the identification of these snails

PMID- 10656708
TI  - Palaearctic origin of Leishmania.
AB  - The hypothesis of a Palaearctic origin of Leishmania in the early Cenozoic,
      dispersal to the Nearctic in the late Eocene and to the Neotropical in the
      Pliocene is presented. It is further hypothesized that murid rodents and their
      immediate ancestors have been important mammalian reservoirs since the
      origination of Leishmania. Biochemical, molecular, biogeographical,
      entomological, mammalalogical and ecological support for these hypotheses are
      reviewed.

PMID- 10656709
TI  - First report of Temnocephala brevicornis Monticelli 1889 (Temnocephalidae:
      platyhelminthes) in Argentina.
AB  - Temnocephala brevicornis Monticelli 1889, ectosymbiont of Hydromedusa tectifera
      Cope 1869, is reported for the first time for Argentina. Numerous temnocephalans
      from Arroyo Villoldo in the locality of Magdalena, Buenos Aires, Argentina were
      stained in toto to be studied. This commensal species in turtles was originally
      cited in association with Hydromedusa maximiliani (Mikan) and Hydraspis radiolata
      Mikan in Brazil. Afterwards, it was found on other fresh water turtle species in
      Brazil and Uruguay.

PMID- 10656710
TI  - Immune response in cattle vaccinated against rabies.
AB  - In order to determine the best type of rabies vaccine to use as a booster, 78
      serological samples from singly vaccinated cattle were analyzed by
      counterimmunoelectrophoresis technique. The animals were divided into several
      groups, received the first vaccine dose with modified live virus vaccine (ERA
      strain) and were revaccinated with inactivated virus or modified live virus
      vaccines. Boosters were given at 2, 4, 8, 12 and 16 weeks following first
      vaccination. Results showed high titres in the cases of booster with inactivated
      vaccine. In all cases, however, detectable antibody titres declined quickly.

PMID- 10656711
TI  - Frequency of specific anti-Toxoplasma gondii IgM, IgA and IgE in colombian
      patients with acute and chronic ocular toxoplasmosis.
AB  - We studied the frequency of specific anti-Toxoplasma IgM, IgA and IgE antibodies
      in serum of 28 immunocompetent Colombian patients, selected by ophthalmologists
      and with lesions that were compatible with ocular toxoplasmosis. Patients were
      classified in three groups: (i) group 1 consisted of ten patients with a first
      episode; (ii) group 2, with seven patients with a recurrence and (iii) group 3,
      consisted of eleven patients with chronic chorioretinal lesion without uveitis.
      We found that 10/28 (35%) of Colombian patients with ocular toxoplasmosis
      possessed at least one serological marker for Toxoplasma infection different from
      IgG. In group 1 (first episode), we found simultaneous presence of specific IgM
      plus IgA plus IgE in 1/10 (10%). In group 2 (recurrences) in 1/7 (14%) we found
      IgM and IgA test positives and in 1/7 (14%) we found IgM and IgE tests positives.
      In group 3 (toxoplasmic chorioretinal scar) the IgA serological test was positive
      in 2/11 (18%). These results show that serum IgM or IgA or IgE can be present
      during recurrences.

PMID- 10656712
TI  - Cellulose acetate as solid phase in ELISA for plague.
AB  - Antigen from Yersinia pestis was adsorbed on cellulose acetate discs (0.5 cm of
      diameter) which were obtained from dialysis membrane by using a paper punch.
      ELISA for human plague diagnosis was carried out employing this matrix and was
      capable to detect amount of 1.3 microg of antigen, 3,200 times diluted positive
      serum using human anti-IgG conjugate diluted 1:4,000. No relevant antigen
      lixiviation from the cellulose acetate was observed even after washing the discs
      15 times. The discs were impregnated by the coloured products from the ELISA
      development allowing its use in dot-ELISA. Furthermore, cellulose acetate showed
      a better performance than the conventional PVC plates.

PMID- 10656713
TI  - Lipids shed into the culture medium by trypomastigotes of Trypanosoma cruzi.
AB  - Trypomastigote forms of Trypanosoma cruzi were metabolically labeled with [14C]
      ethanolamine and [3H]-palmitic acid. Lipids shed to the culture medium were
      analyzed and compared with the parasite components. Phosphatidylcholine and
      lysophosphatidylcholine accounted for 53% of the total incorporated precursor.
      Interestingly, phosphatidylethanolamine and its lyso derivative
      lysophosphatidylethanolamine, although present in significant amounts in the
      parasites, could not be detected in the shed material. Shed lipids were highly
      enriched in the desaturated fatty acids C16:1 and C18:1 when compared to the
      total fatty acid pool isolated from the parasites.

PMID- 10656714
TI  - Establishment and characterization of a new continuous cell line from Lutzomyia
      longipalpis (Diptera: psychodidae) and its susceptibility to infections with
      arboviruses and Leishmania chagasi.
AB  - Embryonic tissue explants of the sand fly Lutzomyia longipalpis (Lutz & Neiva
      1912) the main vector of Leishmania chagasi (Cunha and Chagas), were used to
      obtain a continuous cell line (Lulo). The tissues were seeded in MM/VP12 medium
      and these were incubated at 28 masculineC. The first subculture was obtained 45
      days after explanting and 96 passages have been made to date. Lulo is composed of
      epithelioid cells, showed a 0.04 generations/hour exponential growth rate and
      population doubling time at 24.7 h. The cell line isoenzymatic profiles were
      determined by using PGI, PGM, MPI and 6-PGDH systems, coinciding with patterns
      obtained from the same species and colony's pupae and adults. The species
      karyotype characteristics were recognized (2n = 8), in which pair 1 is
      subtelocentric and pairs 2, 3 and 4 are metacentric. Lulo was free from
      bacterial, fungal, mycoplasmic and viral infection. Susceptibility to five
      arbovirus was determined, the same as Lulo interaction with Leishmania
      promastigotes.

PMID- 10656716
TI  - Medicinal products: regulation of biosynthesis in space and time.
AB  - We live in a "Demon-Haunted World". Human health care requires the ever
      increasing resistance of pathogens to be confronted by a correspondingly fast
      rate of discovery of novel antibiotics. One of the possible strategies towards
      this objective involves the rational localization of bioactive phytochemicals.
      The conceptual basis of the method consists in the surprisingly little known
      gearings of natural products with morphology, ecology and evolution of their
      plant source, i. e. an introspection into the general mechanisms of nature.

PMID- 10656715
TI  - Colony polymerase chain reaction of stably transfected trypanosoma cruzi grown on
      solid medium.
AB  - Tools for the genetic manipulation of Trypanosoma cruzi are largely unavailable,
      although several vectors for transfection of epimastigotes and expression of
      foreign or recombinant genes have been developed. We have previously constructed
      several plasmid vectors in which recombinant genes are expressed in T. cruzi
      using the rRNA promoter. In this report, we demonstrate that one of these vectors
      can simultaneously mediate expression of neomycin phosphotransferase and green
      fluorescent protein when used to stably transfect cultured epimastigotes. These
      stably transfected epimastigotes can be selected and cloned as unique colonies on
      solid medium. We describe a simple colony PCR approach to the screening of these
      T. cruzi colonies for relevant genes. Thus, the methodologies outlined herein
      provide important new tools for the genetic dissection of this important
      parasite.

PMID- 10656717
TI  - Experimental toxoplasmosis in Balb/c mice. Prevention of vertical disease
      transmission by treatment and reproductive failure in chronic infection.
AB  - In a study of congenital transmission during acute infection of Toxoplasma
      gondii, 23 pregnant Balb/c mice were inoculated orally with two cysts each of the
      P strain. Eight mice were inoculated 6-11 days after becoming pregnant (Group 1).
      Eight mice inoculated on the 10th-15th day of pregnancy (Group 2) were treated
      with 100 mg/kg/day of minocycline 48 h after inoculation. Seven mice inoculated
      on the 10th-15th day of pregnancy were not treated and served as a control (Group
      3). Congenital transmission was evaluated through direct examination of the
      brains of the pups or by bioassay and serologic tests. Congenital transmission
      was observed in 20 (60.6%) of the 33 pups of Group 1, in one (3.6%) of the 28
      pups of Group 2, and in 13 (54.2%) of the 24 pups of Group 3. Forty-nine Balb/c
      mice were examined in the study of congenital transmission of T. gondii during
      chronic infection. The females showed reproductive problems during this phase of
      infection. It was observed accentuated hypertrophy of the endometrium and
      myometrium. Only two of the females gave birth. Our results demonstrate that
      Balb/c mice with acute toxoplasmosis can be used as a model for studies of
      congenital T. gondii infection. Our observations indicate the potential of this
      model for testing new chemotherapeutic agents against congenital toxoplasmosis.

PMID- 10656718
TI  - Standardization of broth microdilution method for Mycobacterium tuberculosis.
AB  - Indirect drug susceptibility tests of Mycobacterium tuberculosis was done to
      investigate the accuracy and feasibility of a broth microdilution method (BMM)
      for determining minimal inhibitory concentrations of conventional drugs against
      M. tuberculosis. Test drugs included isoniazid (H), rifampicin (R), ethambutol
      (E), streptomycin (S) and pyrazinamide (Z). Fifty isolates of M. tuberculosis
      from patients who had never received drug therapy, and H37Rv strain for control,
      were evaluated in the system. When comparing this method with the gold standard
      proportional method in Lowenstein-Jensen medium, sensitivity of 100% for all
      drugs and specifities of 91, 100, 96, 98 and 85% were observed respectively for
      H, R, E, S and Z. The BMM was read faster (14-20 days) than the proportional
      method (20-28 days). The microdilution method evaluated allows the testing of
      multiple drugs in multiple concentrations. It is easy to perform and does not
      require special equipment or expensive supplies. In contrast to radiometric
      method it does not use radioactive material.

PMID- 10656719
TI  - Haematophagy and cleptohaematophagy of clerada apicicornis (Hemiptera:
      lygaeidae), a potential biological control agent of rhodnius prolixus (Hemiptera:
      reduviidae).
AB  - Because of its ability to prey on Triatominae in rural houses, Clerada
      apicicornis has been suggested as a potential biological control agent of
      Rhodnius prolixus. It has also been suggested as a potential vector of mammalian
      trypanosomes such as Trypanosoma cruzi, because of its ability to take blood
      directly from mammals. To help resolve these conflicting ideas, we assessed the
      haematophagic behaviour of C. apicicornis by carrying out feeding trials on
      laboratory animals. Cleptohaematophagic behaviour was also assessed by allowing
      C. apicicornis to feed on R. prolixus previously engorged with avian blood. The
      low proportion of blood meals taken directly from laboratory animals indicates a
      facultative haematophagy in this species, whereas a greater proportion of nymphs
      and adults were able to obtain vertebrate blood by predation on engorged R.
      prolixus. The results suggest that C. apicicornis is unlikely to be effective as
      a biological control agent, but is also unlikely to have a significant role in
      the transmission of vertebrate pathogens.

PMID- 10656720
TI  - A checklist of arthropods associated with pig carrion and human corpses in
      southeastern brazil.
AB  - Necrophagous insects, mainly Diptera and Coleoptera, are attracted to specific
      stages of carcass decomposition, in a process of faunistic succession. They are
      very important in estimating the postmortem interval, the time interval between
      the death and the discovery of the body. In studies done with pig carcasses
      exposed to natural conditions in an urban forest (Santa Genebra Reservation),
      located in Campinas, State of Sao Paulo, southeastern Brazil, 4 out of 36
      families of insects collected - Calliphoridae, Sarcophagidae, Muscidae (Diptera)
      and Dermestidae (Coleoptera) - were considered of forensic importance, because
      several species were collected in large numbers both visiting and breeding in pig
      carcasses. Several species were also observed and collected on human corpses at
      the Institute of Legal Medicine. The species belonged to 17 different families, 6
      being of forensic importance because they were reared from human corpses or pig
      carcasses: Calliphoridae, Sarcophagidae, Muscidae, Piophilidae (Diptera),
      Dermestidae, Silphidae and Cleridae (Coleoptera). The most important species
      were: Diptera - Chrysomya albiceps, Chrysomya putoria, Hemilucilia segmentaria,
      Hemilucilia semidiaphana (Calliphoridae), Pattonella intermutans (Sarcophagidae),
      Ophyra chalcogaster (Muscidae), Piophila casei (Piophilidae); Coleoptera -
      Dermestes maculatus (Dermestidae), Oxyletrum disciolle (Silphidae) and Necrobia
      rufipes (Cleridae).

PMID- 10656721
TI  - Axillary sentinel lymph node examination in breast carcinoma.

PMID- 10656723
TI  - Assessing laboratory employee competence.

PMID- 10656724
TI  - Prosper Meniere.

PMID- 10656726
TI  - Employee competence and performance-based assessment: A college of American
      pathologists Q-probes study of larboratory personnel in 522 institutions.
AB  - OBJECTIVE: To survey employee competence assessment practices in departments of
      pathology and laboratory medicine and provide suggestions for improvement.
      DESIGN: A 3-part study consisting of a questionnaire about current competence
      assessment practices, an evaluation of compliance with stated competence
      assessment practices using personnel records of 30 employees, and a written
      appraisal of competence of 5 specimen-processing staff members per institution.
      SETTING: A total of 522 institutions participating in the College of American
      Pathologists 1996 Q-Probes program. MAIN OUTCOME MEASURES: Institutional
      competence assessment practices, compliance of each institution with their own
      practices, and determination of competence of specimen-processing personnel.
      RESULTS: Of the participating institutions, 89.8% had a written competence plan
      and 98.1% reported reviewing employee competence at least yearly. General
      competence was reviewed by direct observations (87.5%), review of test or quality
      control results (77.4%), review of instrument preventive maintenance (60.0%),
      written testing (52.2%), and/or other methods (20.8%). In 8.6% of institutions,
      employees who failed competence assessment were not allowed to continue their
      usual work. On review of records of 14 029 employees for adherence to the
      laboratory's general competence plan, adherence was 89.7% for direct
      observations, 85.8% for review of quality control and test results, 78.0% for
      review of instrument records, and 74.0% for written testing. Employee failure
      rate ranged from 0.9% to 6.4%, depending on the competence evaluated. Adherence
      to an institution's plan was 90.4% for new employees, 93.1% for computer skills,
      95.8% for laboratory safety, and 92.1% for continuing education. When a written
      competence assessment was given to 2853 specimen-processing staff members, 90.0%
      responded satisfactorily. CONCLUSIONS: Opportunities for improvement in employee
      competence assessment are numerous, and we provide several specific suggestions.

PMID- 10656727
TI  - Atypical epithelial cells and specimen adequacy: current laboratory practices of
      participants in the college of American pathologists interlaboratory comparison
      program in cervicovaginal cytology.
AB  - CONTEXT: The Bethesda System for reporting cervical/vaginal cytologic diagnoses
      introduced terminology for atypical squamous and glandular cells and categories
      for specimen adequacy. OBJECTIVES: To analyze current laboratory reporting
      practices and compare trends to previous surveys. DESIGN: Questionnaire surveys
      were mailed to 2000 laboratories in 1996 and 1997. PARTICIPANTS: Laboratories
      enrolled in the College of American Pathologists Interlaboratory Comparison
      Program in Cervicovaginal Cytology. MAIN OUTCOME MEASURES: Laboratory policies,
      criteria, and reporting rates for Bethesda System categories. RESULTS: The 1996
      specimen adequacy survey had 1166 respondents, and 768 laboratories returned the
      1997 questionnaire focusing on atypical squamous cells of undetermined
      significance (ASCUS) and glandular cells of undetermined significance (AGUS).
      Nearly all laboratories (92%) routinely reported specimen adequacy, an increase
      from the 66% rate in 1991. The median rate for unsatisfactory specimens was 0.5%
      (mean 0.95%), and the median rate for the satisfactory but limited category was
      5.8% (mean 9.3%). The Bethesda criteria for designating a specimen unsatisfactory
      were used by more than 90% of laboratories. Nearly all laboratories (97%) used
      the term ASCUS in 1997, and more than 80% of laboratories used the Bethesda
      criteria for this category. Median reporting rates for epithelial abnormalities
      were as follows: ASCUS, 4.5%; AGUS, 0.3%; low-grade squamous intraepithelial
      lesion (SIL), 1.6%; and high-grade SIL, 0.5%. The median ASCUS/SIL ratio was 2.0,
      with 80% of laboratories reporting ratios between 0.64 and 4.23. The median ASCUS
      rate and ASCUS/SIL ratio were higher than 1993 survey results. Nearly all
      laboratories attempted follow-up studies on patients with abnormal cytology
      results, and midsized laboratories achieved the highest rates of follow-up.
      Median rates of abnormalities following an ASCUS or AGUS diagnosis were 20% and
      15%, respectively. Laboratory respondents commonly used written recommendations
      in ASCUS/AGUS reports. CONCLUSIONS: Most laboratories that responded to the
      surveys had adopted Bethesda terminology and criteria for specimen adequacy and
      ASCUS/AGUS. Reporting rates for SIL and adequacy categories have remained stable,
      but median ASCUS rates and ASCUS/SIL ratios are higher than in 1993. The AGUS
      category is reported infrequently, but can be associated with significant
      pathology.

PMID- 10656728
TI  - Cd44: a marker of squamous differentiation in adenosquamous neoplasms.
AB  - OBJECTIVE: To test the hypothesis that CD44 standard (CD44[s]) and its other
      variants, CD44v6 and CD44v7-8, might be useful markers of squamous
      differentiation in epithelial tumors. DESIGN: We studied expression of CD44(s),
      CD44v6, and CD44v7-8 using immunohistochemistry in human tumors that had squamous
      differentiation, glandular differentiation, or both arising in the colon,
      stomach, esophagus, lung, pancreas, gallbladder, or uterus/cervix, as well as in
      adjacent nonneoplastic tissues. Formalin-fixed, paraffin-embedded archival tissue
      specimens of 33 adenosquamous tumors were used. All were stained with monoclonal
      antibodies against a conserved portion of CD44(s) and its variants, CD44v6 and
      CD44v7-8, using the avidin-biotin peroxidase method. RESULTS: CD44(s) and its
      variants consistently and strongly stained areas of tumors with well-developed
      squamous differentiation. These markers also consistently and strongly stained
      normal squamous mucosa. Reactivity for CD44 and its variants was lacking in
      normal glandular type epithelium and in adenocarcinomas composed entirely of well
      differentiated mucin-producing glands. Areas of well-differentiated carcinoma,
      both squamous and adenocarcinoma, were consistent with respect to both extent and
      intensity of staining. Staining in lymph nodes was similar to that in the primary
      tumors, with well-differentiated squamous foci being consistently positive, well
      differentiated mucin-producing adenocarcinoma foci consistently negative, and
      poorly differentiated foci showing variable staining. Although staining was less
      intense with the variants, it followed the same staining pattern as found for
      CD44(s). No differences in the extent or intensity of staining were identified in
      the metastatic versus primary tumor foci, nor was any difference identified
      between superficial and deeply invasive areas of primary tumors. CONCLUSIONS: Our
      study shows that CD44(s) and its variants are good markers of squamous epithelial
      differentiation in several types of normal epithelium and tumors, and that these
      markers can identify areas of well- to moderately differentiated elements in
      adenosquamous neoplasms. However, poorly differentiated tumors show an
      inconsistent staining pattern with CD44, such that it cannot be used as a
      reliable and practical marker of squamous differentiation in poorly
      differentiated neoplasms.

PMID- 10656729
TI  - Overexpression of cyclin A and cyclin B1 proteins in astrocytomas.
AB  - BACKGROUND: Cyclins are proteins that are expressed during the progression of a
      normal cell through the cell cycle. In a number of cancers, overexpression of
      cyclin A and cyclin B1 proteins has been reported, and in some instances the
      levels of expression correlated well with the grades of malignancy. The
      expression of cyclin A and cyclin B1 proteins in astrocytoma may be linked to the
      histologic grade or proliferative activities. OBJECTIVE: To study the expression
      of cyclin A and cyclin B1 proteins in astrocytomas and correlate the labeling
      indices (LIs) of cyclin A and cyclin B1 with histologic grade and Ki-67 LI.
      DESIGN: The surgical biopsy specimens from 65 adults with astrocytomas were
      reviewed and divided into grades based on the World Health Organization system.
      The paraffin sections were immunostained using primary antibodies against Ki-67,
      cyclin A, and cyclin B1. The LIs of these astrocytomas for the 3 different
      antibodies were determined by computerized image analysis. RESULTS: The cyclin A
      LI showed good correlation with astrocytoma grade and Ki-67 LI. Both the nuclear
      and cytoplasmic cyclin B LIs correlated well with the tumor grade but showed poor
      correlation with Ki-67 LI. CONCLUSIONS: This study suggests that although both
      cyclin A and B protein expression are related to the grade of malignancy in
      astrocytomas, cyclin A levels more generally reflect the proliferative state of
      these tumors. We also provide indirect evidence that cyclin B1 is associated with
      the aberrant progression through the G2-M phase checkpoint in astrocytomas.

PMID- 10656730
TI  - Uterine smooth muscle tumors: utility of classification by proliferation, ploidy,
      and prognostic markers versus traditional histopathology.
AB  - CONTEXT: Accurate categorization of uterine smooth muscle neoplasms by light
      microscopic examination is difficult. Multiple classification schemes have been
      proposed based on mitotic rate, nuclear atypia, and the presence or absence of
      necrosis. None of these classification systems has been entirely successful.
      Multiple ancillary techniques have been tested for their ability to predict
      behavior of uterine smooth muscle tumors. OBJECTIVE: We assayed 45 smooth muscle
      neoplasms for a variety of proliferation markers, oncogene protein products, and
      DNA ploidy level to determine if these markers supplied prognostically useful
      information over and above that obtained by routine light microscopic assessment.
      STUDY DESIGN: Forty-five uterine smooth muscle neoplasms were assessed for DNA
      ploidy; silver-staining nucleolar organizer regions (AgNORs); percent nuclear
      proliferating cell nuclear antigen (PCNA); expression of p53, Her-2/neu, and MDM
      2 protein; mitotic rate; and nuclear grade. These markers were correlated with
      histologic diagnosis and the occurrence of a clinically adverse event (death,
      metastasis, or recurrence). RESULTS: Diagnostic category (P <.001), nuclear grade
      (P <.002), mitotic activity (P <.001), mean AgNORs (P <.001), percent nuclear
      PCNA (P =.02), and expression of p53 (P =.02) all correlated with clinical
      outcome. No statistically significant correlation between clinical outcome and
      the categories MDM-2 expression, Her-2/neu expression, or DNA ploidy was seen.
      Nuclear grade, p53 expression, mitotic rate, AgNORs, and percent nuclear PCNA
      correlated with diagnosis. CONCLUSIONS: Diagnostic category, mitotic rate, AgNOR
      counts, PCNA, and p53 expression dichotomized uterine smooth muscle neoplasms
      into prognostically favorable and unfavorable groups. Although highly
      significant, the category AgNORs was no more successful than mitotic rate in
      dividing uterine smooth muscle neoplasms into prognostically favorable and
      unfavorable groups. Expression of p53 and percent nuclear PCNA dichotomized
      uterine smooth muscle neoplasms into prognostic groups, but neither technique
      reached the level of significance achieved by mitotic rate. Our data indicate
      that mitotic rate and the classification system of Kempson and Bari are at least
      as effective as the tested markers in separating uterine smooth muscle neoplasms
      into prognostic categories.

PMID- 10656731
TI  - Esophageal small cell carcinomas: clinicopathologic parameters, p53
      overexpression, proliferation marker, and their impact on pathogenesis.
AB  - OBJECTIVE: To evaluate the clinicopathologic features and the roles of p53 and
      MIB-1 in esophageal small cell carcinoma. METHOD: Twenty patients (14 men and 6
      women) with esophageal small cell carcinoma treated in our hospital from 1982
      through 1996 were studied. The clinicopathologic features, treatment received,
      and survival data of these patients were documented. Representative tissue was
      collected from each tumor, and immunohistochemical preparations for p53 protein
      and MIB-1 were made. RESULTS: Small cell carcinoma accounted for 1.3% of all
      esophageal malignant tumors. The median age of patients at presentation was 60
      years. On gross examination, the tumors were large ulcerative lesions (median
      length, 7.5 cm). In 17 patients in whom p53 immunohistochemical study was
      performed, p53 protein was detected in 65% (9 of 17). All stage IV tumors were
      negative for p53 expression. The median tumor cell MIB-1 score was high at 855
      (range, 810-964) positive cells per 1000. Overall median survival was 3.4 months.
      In patients who underwent chemotherapy, there was significant response.
      CONCLUSIONS: Esophageal small cell carcinoma is an aggressive tumor.
      Overexpression of p53 is associated with early stages of carcinogenesis. The high
      proliferative index, as defined by the MIB-1 immunohistochemical method, may be
      related to aggressive behavior and high sensitivity to chemotherapy and
      radiotherapy.

PMID- 10656732
TI  - p53, ErbB2, and TAG-72 expression in the spectrum of ductal carcinoma in situ of
      the breast classified by the Van Nuys system.
AB  - CONTEXT: The Van Nuys (VN) classification system for ductal carcinoma in situ
      (DCIS) of the breast is a simplified morphology-based system that uses the
      presence of nuclear pleomorphism and comedo-type necrosis to stratify DCIS
      lesions into 3 prognostic groups. OBJECTIVE: To determine if there is an
      underlying biological basis that correlates with the morphologic aspects of the
      VN classification system. DESIGN: We evaluated the expression of markers
      implicated in the development of breast cancer (p53, ErbB2, and TAG-72) in DCIS
      classified with the VN system. Forty-five cases of pure DCIS were classified as 8
      cases of VN1, 7 cases of VN2, and 30 cases of VN3. p53, ErbB2, and TAG-72 antigen
      expression was measured by immunohistologic means in each of the cases. RESULTS:
      Nuclear accumulation of p53 was only observed in VN3 (30%). ErbB2 overexpression
      was found only in VN2 (14%) and VN3 (43%). TAG-72 expression was observed in all
      categories of lesions but was more frequent in VN2 (71%) and VN3 (70%) compared
      with VN1 (25%). It appears that overexpression of ErbB2 and p53 are features
      associated with the high-grade lesions. CONCLUSION: The simplified VN
      classification system for DCIS has a clear underlying biological basis as
      evidenced by differential expression of tumor-associated antigens in each of the
      3 morphologic categories. These differences may contribute to the differential
      clinical behavior of the separate groups.

PMID- 10656733
TI  - Caspase inhibitor blocks human immunodeficiency virus 1-induced T-cell death
      without enhancement of HIV-1 replication and dimethyl sulfoxide increases HIV-1
      replication without influencing T-cell survival.
AB  - OBJECTIVES: To determine the relationship, if any, between reagents that modulate
      survival of T-cells and replication of human immunodeficiency virus 1 (HIV-1) and
      to determine the effects of the solvent dimethyl sulfoxide (DMSO) and drugs such
      as cyclosporin A and all-trans retinoic acid on HIV-1 replication. DESIGN: To
      first establish the direct effects of solvent alone (ie, DMSO) at various
      concentrations on HIV-1 replication, followed by the ability of various compounds
      such as the caspase inhibitor N-benzyloxycarbonyl-val-ala-asp-fluoromethylketone
      (z-VAD-fmk), cyclosporin A, and all-trans retinoic acid on HIV-1 replication.
      Next, to determine if HIV-1 induces T-cell apoptosis using TUNEL (TdT-mediated
      dUTP-biotin nick end-labeling) assays and DNA fragmentation and poly-(ADP-ribose)
      polymerase (PARP) cleavage, and then to examine how the various compounds
      influence T-cell survival after HIV-1 exposure. METHODS: The human T-cell line,
      CEM cells, were exposed to HIV(IIIB) and viral replication monitored using
      reverse transcription assays at 3, 6, and 9 days following infection. Cells were
      pretreated with various compounds dissolved in DMSO over a wide range of
      concentrations, and DMSO itself was also examined. T-cell death and apoptosis
      were assessed using TUNEL staining to detect 3'-OH DNA strand breaks and agarose
      gel electrophoresis to detect DNA fragmentation (laddering). Furthermore, PARP
      cleavage implicated in the apoptotic process was also examined. RESULTS: At very
      low levels, such as 0.002%, DMSO itself appears to enhance HIV-1 replication at 6
      and 9 days after infection. At low levels of cyclosporin A, such as 0.01
      microgram/mL, HIV-1 replication was further enhanced above the solvent effect,
      but at 1 microgram/mL, cyclosporin A strongly inhibited HIV-1 replication.
      Retinoic acid between 0.01 and 1 microgram/mL did not influence HIV-1
      replication. In addition, a discrepancy was noted in that HIV-1-infected T-cells
      were TUNEL positive, indicating DNA strand breaks; however, more complete DNA
      fragmentation was not detected nor was PARP cleavage identified. The induction of
      TUNEL positivity was blocked by the caspase inhibitor z-VAD-fmk but not by DMSO
      or cyclosporin A. Even though z-VAD-fmk blocked the appearance of TUNEL-positive
      T-cells, there was not a consistently observed increase in HIV-1 replication.
      CONCLUSION: Low levels of DMSO and cyclosporin A can enhance HIV-1 replication in
      CEM cells. At higher levels, cyclosporin A inhibits HIV-1 replication with no
      significant effects by all-trans retinoic acid. No evidence for classic apoptosis
      was detected in CEM cells after HIV-1 infection, although DNA strand breaks may
      be present as revealed by TUNEL positivity. There was no correlation between
      levels of HIV-1 replication and T-cell survival or death. The mechanism of T-cell
      death after HIV-1 infection requires further study, and investigators who add
      compounds dissolved in DMSO must include controls to carefully examine the direct
      effects of even trace levels of this solvent on HIV-1 replication.

PMID- 10656734
TI  - Detection of indinavir crystals in urine: dependence on method of analysis.
AB  - OBJECTIVES: To determine the frequency of crystalluria in patients treated with
      the human immunodeficiency virus protease inhibitor indinavir and to compare
      methods of detecting crystalluria. METHODS: A total of 308 freshly voided urine
      specimens from 168 patients treated with indinavir were evaluated by manual
      microscopy of sediment and microscopy with an automated workstation and by
      dipstick analysis. RESULTS: Crystals were detected in 22%, 31%, or 32% of
      specimens using, respectively, an automated workstation, manual microscopy, or
      both methods. Proteinuria or hemoglobinuria occurred significantly more often in
      specimens with (28%) than without (18%) crystals. Frequency of crystalluria was
      unrelated to specific gravity, but it increased at higher pH. Crystals were
      detected in 21% of specimens with pH less than 6 and 42% of specimens with pH of
      6 or higher. CONCLUSIONS: Crystalluria occurs in more than 30% of urine specimens
      from patients treated with indinavir, but detection rates vary substantially with
      method of analysis. Manual microscopy detected crystalluria 41% more often than
      did an automated workstation.

PMID- 10656735
TI  - Optic nerve damage in shaken baby syndrome: detection by beta-amyloid precursor
      protein immunohistochemistry.
AB  - BACKGROUND: Rapid acceleration-deceleration of an infant's head during
      intentional shaking should in theory exert stretch or shear forces upon the optic
      nerves sufficient to cause axonal injury. beta-Amyloid precursor protein (beta
      APP) immunohistochemistry recently has been shown to be a highly effective method
      for identifying diffuse axonal injury in the brains of infants with shaken baby
      syndrome. In this study, we investigated the utility of beta-APP in identifying
      optic nerve damage in infants who have sustained fatal whiplash shaking.
      MATERIALS AND METHODS: beta-Amyloid precursor protein immunohistochemistry was
      performed on formalin-fixed, paraffin-embedded sections of eyes (including optic
      disc and distal optic nerve) from infants less than 1 year of age with shaken
      baby syndrome (5 cases), combined shaken baby syndrome/blunt head trauma (3
      cases), and "pure" blunt head trauma (1 case). Nontraumatic control cases
      included infants who died of suffocation (1 case), sudden infant death syndrome
      (1 case), and positional asphyxia (1 case) and an enucleation from a child with a
      retinoblastoma (1 case). Matched hematoxylin-eosin-and neurofilament-stained
      sections were used for comparison. RESULTS: Three of the 5 shaken baby cases and
      all 3 combined shaken baby/blunt head trauma cases had optic nerve axonal injury
      identified by the presence of strongly beta-APP-immunoreactive beaded or swollen
      axonal segments. Axonal injury could not be detected in the corresponding
      hematoxylin-eosin-or neurofilament-stained sections. Optic nerve axonal injury
      was not seen in the case involving pure blunt head trauma or in the nontraumatic
      control cases. CONCLUSIONS: Optic nerve axonal injury is a prominent feature of
      intentional fatal whiplash head trauma in infants less than 1 year of age. beta
      Amyloid protein precursor immunohistochemistry appears to be the most effective
      method for demonstrating axonal damage in the optic nerve.

PMID- 10656736
TI  - Point-of-care glucose testing: effects of critical care variables, influence of
      reference instruments, and a modular glucose meter design.
AB  - OBJECTIVE: To assess the clinical performance of glucose meter systems when used
      with critically ill patients. DESIGN: Two glucose meter systems (SureStepPro and
      Precision G) and a modular adaptation (Immediate Response Mobile Analysis
      SureStepPro) were assessed clinically using arterial samples from critically ill
      patients. A biosensor-based analyzer (YSI 2700) and a hospital chemistry analyzer
      (Synchron CX-7) were the primary and secondary reference instruments,
      respectively. PATIENTS AND SETTING: Two hundred forty-seven critical care
      patients at the University of California, Davis, Medical Center participated in
      this study. OUTCOME MEASURES: Error tolerances of +/-15 mg/dL for glucose levels
      </=100 mg/dL and +/-15% for glucose levels >100 mg/dL were used to evaluate
      glucose meter performance; 95% of glucose meter measurements should fall within
      these tolerances. RESULTS: Compared to the primary reference method, 98% to 100%
      of SureStepPro and 91% to 95% of Precision G measurements fell within the error
      tolerances. Paired differences of glucose measurements versus critical care
      variables (Po(2), pH, Pco(2), and hematocrit) were analyzed to determine the
      effects of these variables on meter measurements. Po(2) and Pco(2) decreased
      Precision G and SureStepPro measurements, respectively, but not enough to be
      clinically significant based on the error tolerance criteria. Hematocrit levels
      affected glucose measurements on both meter systems. Modular adaptation did not
      affect test strip performance. CONCLUSIONS: Glucose meter measurements correlated
      best with primary reference instrument measurements. Overall, both glucose meter
      systems showed acceptable performance for point-of-care testing. However, the
      effects of some critical care variables, especially low and high hematocrit
      values, could cause overestimated or underestimated glucose measurements.

PMID- 10656737
TI  - Role for activation of matrix metalloproteinases in the pathogenesis of pulmonary
      lymphangioleiomyomatosis.
AB  - BACKGROUND: Matrix metalloproteinases (MMPs) have been shown to be involved in
      the pathogenesis of the destructive pulmonary lesions in patients with
      lymphangioleiomyomatosis (LAM); in the present report, the activation of these
      enzymes is examined. OBJECTIVE: To evaluate the role of MMPs and their activating
      enzymes, immunohistochemical and confocalmicroscopic techniques were used to
      localize alpha-smooth muscle actin (alpha-SMA), HMB-45, proliferating cell
      nuclear antigen (PCNA), MMP-2, membrane-type 1 MMP (MT1-MMP), MT2-MMP, and MT3
      MMP in lung tissues from 10 women with LAM. Tissue samples were obtained from 5
      patients before treatment and in 5 patients after hormone treatment (progesterone
      and/or tamoxifen citrate). RESULTS: Staining for alpha-SMA and MMP-2 was present
      in all the abnormal smooth muscle cells (LAM cells) in both groups. The
      percentages of PCNA-, MMP-2-, or MT1-MMP-positive LAM cells were much higher in
      the untreated group than in the treated group, whereas the percentages of HMB-45
      reactive LAM cells were similar in both groups. The reactions for MT1-MMP and
      PCNA were preferentially localized in small spindle-shaped LAM cells; the
      reaction for HMB-45 was found in large epithelioid LAM cells. Many of the PCNA
      positive cells were also positive for MT1-MMP. Staining for MT2-MMP and MT3-MMP
      was negative. CONCLUSIONS: This study demonstrates an association between
      cellular proliferation and the presence of MT1-MMP in LAM cells. The activation
      of MMP-2 by MT1-MMP may play an important role in the destruction of lung tissue
      in this disorder.

PMID- 10656739
TI  - Amyloid goiter with parathyroid involvement: a case report and review of the
      literature.
AB  - Although involvement of the thyroid gland by amyloid is a relatively common
      phenomenon, diffuse enlargement of the gland secondary to infiltration by amyloid
      is infrequent. We report the pathologic findings in a case of primary amyloid
      goiter with involvement of a parathyroid gland in an euthyroid patient who
      presented to his physician with an enlarged thyroid, upper airway obstructive
      symptoms, and dysphagia. The clinical features of amyloid goiter, including
      difficulties in preoperative diagnosis and management, are discussed.

PMID- 10656738
TI  - Fibromatosis of the breast: age-correlated morphofunctional features of 33 cases.
AB  - OBJECTIVE: To predict if antiestrogenic agents are useful in the treatment of
      breast fibromatoses, we undertook an immunohistochemical study of sex steroid
      hormone receptors (estrogen receptor, progesterone receptor, and androgen
      receptor) and protein pS2 in 33 cases. METHODS: The morphologic and
      immunohistochemical findings were correlated to patient menstrual status, which
      was categorized as childbearing age (n = 15), perimenopausal (n = 8), and
      postmenopausal (n = 10). RESULTS: Fibromatoses in women of childbearing age were
      more cellular, more mitotically active, and displayed a larger proportion of
      cells with mild atypia than those in perimenopausal and postmenopausal women. The
      hormonal status of these 3 groups does not explain the morphologic variations
      observed in these groups, inasmuch as no immunostaining for any of the hormone
      receptors was detected in the tumors. CONCLUSIONS: The absence of estrogen
      receptor and pS2 in breast fibromatoses suggests that antiestrogenic agents are
      unlikely to be beneficial in the management of these tumors. Assessment of the
      hormone receptor profile is a useful adjunct in the diagnosis of spindle cell
      lesions of the breast. Although most spindle cell carcinomas as well as
      fibromatoses of the breast do not express estrogen or progesterone receptors, the
      absence of androgen receptor reactivity would favor a diagnosis of fibromatosis
      over that of myofibroblastoma.

PMID- 10656740
TI  - Mixed ductal-endocrine carcinoma of the pancreas: a possible pathogenic mechanism
      for arrhythmogenic right ventricular cardiomyopathy.
AB  - We describe herein a case of a mixed ductal-endocrine pancreatic carcinoma. Rare
      cases of mixed pancreatic tumors have been described, with endocrine and exocrine
      components each making up a significant proportion of the neoplasm; to our
      knowledge, only one case has been reported with a mixed liver metastasis. In our
      case, ductal and endocrine cells were intimately admixed in the primary tumor and
      in a peripancreatic lymph node metastasis, diagnosed by standard light microscopy
      and double immunostaining for cytokeratin 19 and synaptophysin. The endocrine
      component was immunoreactive for somatostatin. Tumors with admixed endocrine and
      exocrine components support the hypothesis of a common endodermal histogenesis
      for the ductal and endocrine cells in the human pancreas.

PMID- 10656741
TI  - Myocyte transdifferentiation: a possible pathogenetic mechanism for
      arrhythmogenic right ventricular cardiomyopathy.
AB  - Adipose substitution of ventricular myocardium is characteristic of
      arrhythmogenic right ventricular cardiomyopathy, but is also found in other heart
      conditions. It is thought to be a consequence of myocyte loss due to myocarditis
      or other noxious stimuli. We describe a unique case of cardiomyopathy with a
      morphologic pattern suggestive of transdifferentiation from myocytes to mature
      adipocytes. Gross, histologic, and ultrastructural examination were performed on
      the heart of a female transplant patient with a clinical diagnosis of familial
      dilated cardiomyopathy. Gross examination showed fibroadipose substitution of the
      left ventricle and adipose replacement of the right. Histology,
      immunohistochemistry, and ultrastructure were highly suggestive of
      transdifferentiation from cardiac muscle to adipose tissue. Myocyte
      transdifferentiation could represent an alternative pathogenetic pathway to the
      myocyte-loss and adipose-replacement mechanism in arrhythmogenic right
      ventricular cardiomyopathy, or it could be the basis of a new type of familial
      cardiomyopathy.

PMID- 10656742
TI  - Intraductal papillary tumors of the major salivary glands: case reports of benign
      and malignant variants.
AB  - Intraductal papilloma is an extremely rare benign salivary gland tumor that
      occurs most commonly in the minor salivary glands. To our knowledge, a malignant
      counterpart of intraductal papilloma has not been described previously. We report
      one case each of benign and malignant intraductal papillary tumors. The benign
      tumor occurred in the sublingual gland and was a typical example of intraductal
      papilloma, with the exception that we found no previously published reports of
      this type of tumor in this location. The other patient had a left parotid gland
      tumor that was architecturally similar to the intraductal papilloma, with the
      addition of cytologic atypia, intraductal extension, microinvasion, and lymph
      node metastases. This tumor was diagnosed as intraductal papillary adenocarcinoma
      with an invasive component. Both patients were alive and well without evidence of
      recurrence 2 years and 6 months (case 1) and 6 years (case 2) after surgery.
      Immunohistochemical examination revealed that the tumor cells resembled duct
      luminal cells in both cases. The 2 tumors had different immunoreactivities for
      carcinoembryonic antigen, p53, and Ki-67. The malignant counterpart of
      intraductal papilloma should be considered in the differential diagnosis of
      salivary gland tumors with a predominantly papillary structure, even though this
      tumor is extremely rare.

PMID- 10656743
TI  - Primary neuroendocrine small cell carcinoma of the breast.
AB  - A 60-year-old Turkish woman presented with a left breast mass, which was
      considered for neoadjuvant chemotherapy. By the end of the treatment cycles, the
      tumor had decreased in size, and the patient underwent modified radical
      mastectomy with axillary lymph node dissection. Pathologic examination of the
      tumor revealed a small cell carcinoma with neuroendocrine features confirmed by
      immunohistochemical stains. Multiple axillary lymph nodes were involved by
      metastatic small cell carcinoma carrying the same morphologic characteristics
      noted in the primary breast tumor. We hereby present this case as a primary
      neuroendocrine small cell carcinoma of the breast. This entity occurs very rarely
      in the breast, and fewer than a dozen cases have been reported in the literature.
      Extrapulmonary small cell carcinoma of the breast is reportedly a very aggressive
      tumor for which no consensus for treatment has yet been drawn.

PMID- 10656744
TI  - Erythrocyte Fy antigen phenotyping helps differentiate so-called benign tertian
      malarias.
AB  - Isolated cases of malaria are increasing in frequency in nonendemic countries.
      Blood film examination remains a mainstay of diagnosis of these sporadic cases
      because immunologic and molecular methods are unavailable, expensive, and
      problematic. Two tertian malarial species, Plasmodium vivax and Plasmodium ovale,
      may appear to be similar morphologically. Plasmodium ovale infection is
      infrequent, and misdiagnosis of this species is common. Plasmodium vivax
      infection can be ruled out, however, if a patient's erythrocytes phenotype as
      Fy(a-b-), because these cells completely resist entry by the latter species.

PMID- 10656745
TI  - Leiomyoma of the male urethra: a case report and review of the literature.
AB  - We describe the case of a 48-year-old quadriplegic black man with history of C4
      C5 cervical spine and cord injury secondary to a fall, who presented to the
      University of Cincinnati Medical Center Urology Service with obstructive symptoms
      at urination. A bulbous urethral stricture was diagnosed and subsequently
      resected with primary urethral reanastomosis. On pathologic examination, the
      surgical specimen contained an epithelioid leiomyoma at the site of the urethral
      stricture. Although leiomyomas of the female urethra are relatively common, we
      identified only 2 previously reported cases of leiomyomas of the male urethra in
      the English-language medical literature. To the best of our knowledge, we
      describe the third case of leiomyoma of the male urethra, the first of the
      epithelioid type.

PMID- 10656746
TI  - Aggressive natural killer cell lymphoma presenting as an anterior mediastinal
      mass in a patient with acquired immunodeficiency syndrome.
AB  - We report a case of aggressive natural killer cell lymphoma presenting as an
      anterior mediastinal mass in an African-American man with acquired
      immunodeficiency syndrome. Histologically, the anterior mediastinal mass showed a
      diffuse dense infiltrate of atypical intermediate-sized and large lymphoid cells,
      as well as scattered immunoblasts with angiocentric and angiodestructive growth
      and extensive zonal necrosis. Similar lymphoid infiltrates were present in the
      patient's lungs, spleen, and bone marrow, accompanied by extensive
      lymphophagocytosis. Electron microscopic and cytologic examinations showed the
      presence of dense cytoplasmic granules. Immunophenotyping by flow cytometry and
      by immunohistochemistry yielded surface markers consistent with a natural killer
      cell lymphoma. The Epstein-Barr virus genome and monoclonality were detected by
      in situ hybridization and Southern blot analysis. Polymerase chain reaction
      confirmed the presence of type A Epstein-Barr virus. T-cell receptor gene
      rearrangement could not be identified by Southern blot analysis or polymerase
      chain reaction. To the best of our knowledge, this is the first reported case of
      designated natural killer cell lymphoma from the mediastinum, as well as the
      first reported case of natural killer cell lymphoma in a patient with acquired
      immunodeficiency syndrome. This tumor disseminated early and pursued a highly
      aggressive course. Epstein-Barr virus may play a role in the pathogenesis of this
      disease.

PMID- 10656747
TI  - Coccidioidomycosis meningitis with massive dural and cerebral venous thrombosis
      and tissue arthroconidia.
AB  - To our knowledge we report the first case of meningitis from Coccidioides immitis
      associated with massive dural and cerebral venous thrombosis and with mycelial
      forms of the organism in brain tissue. The patient was a 43-year-old man with
      late-stage acquired immunodeficiency syndrome (AIDS) whose premortem and
      postmortem cultures confirmed C immitis as the only central nervous system
      pathogenic organism. Death was attributable to multiple hemorrhagic venous
      infarctions with cerebral edema and herniation. Although phlebitis has been noted
      parenthetically to occur in C immitis meningitis in the past, it has been
      overshadowed by the arteritic complications of the disease. This patient's severe
      C immitis ventriculitis with adjacent venulitis appeared to be the cause of the
      widespread venous thrombosis. AIDS-related coagulation defects may have
      contributed to his thrombotic tendency.

PMID- 10656748
TI  - Acute myelomonocytic leukemia with histologic features resembling sarcomatoid
      carcinoma in bone marrow.
AB  - We report a case of primary acute myelomonocytic leukemia involving the bone
      marrow that resembled sarcomatoid carcinoma. The neoplastic cells in bone marrow
      biopsy specimens formed cohesive-appearing clusters and cords separated by an
      immature fibroblastic proliferation and myxoid stroma. Blasts in the bone marrow
      aspirate smears formed clusters and sheets, and a subset of blasts exhibited
      erythrophagocytosis. Dysgranulopoiesis was also present. Lineage was confirmed by
      immunohistochemical analysis of formalin-fixed, paraffin-embedded tissue. The
      tumor cells showed strong reactivity for lysozyme, myeloperoxidase, CD45, and
      CD68 and were negative for keratin, S100, CD20, and CD3. The serum lysozyme
      concentration (110 microgram/mL) was 13 times greater than the normal value (8
      microgram/mL). Cytogenetic studies performed on bone marrow aspirate material
      revealed a complex karyotype, including trisomy 8 and abnormalities of chromosome
      11q. We report this case of acute myelomonocytic leukemia because the neoplastic
      cells appeared cohesive and spindled, resembling sarcomatoid carcinoma, and
      therefore caused diagnostic difficulty. Other monocytic neoplasms with similar
      resemblance to carcinoma or sarcoma have been reported in the literature,
      suggesting that the tendency to appear cohesive may be an inherent characteristic
      of neoplastic cells with monocytic differentiation.

PMID- 10656749
TI  - Mediastinal atypical carcinoid and neurofibromatosis type 1.
AB  - We report a case of mediastinal atypical carcinoid in a 63-year-old woman with
      neurofibromatosis type 1 (NF-1), who presented with shortness of breath and a
      bulky mediastinal mass. Initial consideration was given to a neurogenic tumor.
      However, on thoracoscopic biopsy, the histologic appearance was consistent with
      an atypical carcinoid. Carcinoid tumors have been reported in association with NF
      1 previously, but commonly in such unusual sites as the ampulla of Vater and
      duodenum and not in the thorax. The bulky, extensive, and highly vascular nature
      of the lesion precluded resection or debulking surgery. To our knowledge, there
      are no previous reports of atypical carcinoid of the lung or mediastinum in a
      patient with neurofibromatosis. This case report, therefore extends the spectrum
      of solid neoplasia in general and carcinoid tumors in specific, as they occur in
      association with NF-1.

PMID- 10656750
TI  - Therapeutic monitoring of vancomycin.

PMID- 10656751
TI  - Pathologic quiz case: an unusual complication of systemic lupus erythematosus.

PMID- 10656752
TI  - Pathologic quiz case: infant girl with unilateral nephromegaly.

PMID- 10656753
TI  - Acute erythroleukemia, M6b.

PMID- 10656755
TI  - Most commons in pathology and laboratory medicine

PMID- 10656756
TI  - A new look at the origin, function, and "stem-cell" status of muscle satellite
      cells.
AB  - Muscle satellite cells have long been considered a distinct myogenic lineage
      responsible for postnatal growth, repair, and maintenance of skeletal muscle.
      Recent studies in mice, however, have revealed the potential for highly purified
      hematopoietic stem cells from bone marrow to participate in muscle regeneration.
      Perhaps more significantly, a population of putative stem cells isolated directly
      from skeletal muscle efficiently reconstitutes the hematopoietic compartment and
      participates in muscle regeneration following intravenous injection in mice. The
      plasticity of muscle stem cells has raised important questions regarding the
      relationship between the muscle-derived stem cells and the skeletal muscle
      satellite cells. Furthermore, the ability of hematopoietic cells to undergo
      myogenesis has prompted new investigations into the embryonic origin of satellite
      cells. Recent developmental studies suggest that a population of satellite cells
      is derived from progenitors in the embryonic vasculature. Taken together, these
      studies provide the first evidence that pluripotential stem cells are present
      within adult skeletal muscle. Tissue-specific stem cells, including satellite
      cells, may share a common embryonic origin and possess the capacity to activate
      diverse genetic programs in response to environmental stimuli. Manipulation of
      such tissue-specific stem cells may eventually revolutionize therapies for
      degenerative diseases, including muscular dystrophy.

PMID- 10656757
TI  - Plasticity of retrovirus-labelled myotubes in the newt limb regeneration
      blastema.
AB  - Two important indices of myogenic differentiation are the formation of syncytial
      myotubes and the postmitotic arrest from the cell cycle, both of which occur
      after fusion of mononucleate cells. We show here that these indices are reversed
      in the environment of the urodele limb regeneration blastema. In order to
      introduce an integrated (genetic) marker into newt myotubes, we infected
      mononucleate cells in culture with a pseudotyped retrovirus expressing human
      placental alkaline phosphatase (AP). After fusion the myotubes expressed AP and
      could be purified by sieving and micromanipulation so as to remove all
      mononucleate cells. When such purified retrovirus-labelled myotubes were
      implanted into a limb blastema they gave rise to mononucleate progeny with high
      efficiency. Purified myotubes labelled with fluorescent lipophilic cell tracker
      dye also gave rise to mononucleate cells; myotubes which were double labelled
      with the tracker dye and a nuclear stain gave rise to double-labelled
      mononucleate progeny. Nuclei within retrovirus-labelled myotubes entered S phase
      as evidenced by widespread labelling after injection of implanted newts with
      BrdU. The relation between the two aspects of plasticity is a critical further
      question.

PMID- 10656758
TI  - Ectopic CNS projections guide peripheral neuron axons along novel pathways in
      leech embryos.
AB  - Previous studies have indicated that the formation of stereotyped segmental
      nerves in leech embryos depends on the interactions between CNS projections and
      ingrowing afferents from peripheral neurons. Especially, CNS-ablation experiments
      have suggested that CNS-derived guidance cues are required for the correct
      navigation of several groups of peripheral sensory neurons. In order to directly
      test this hypothesis we have performed transplantations of CNS ganglia into
      ectopic sites in segments from which the resident ganglia have been removed. We
      find that the transplanted ganglia extend numerous axons distributed roughly
      equally in all directions. When these CNS projections reach and make contact with
      peripheral sensory axons they are used as guides for peripheral neurons to grow
      toward and into the ectopic ganglia even when this means following novel pathways
      that cross the midline and/or segmental boundaries. The peripheral sensory axons
      turn and grow toward the ectopic ganglia only when in physical contact with CNS
      axons, suggesting that diffusible chemoattractants are not a factor. These
      results demonstrate that the guidance cues provided by ectopic CNS projections
      are both necessary and sufficient to steer peripheral sensory neuron axons into
      the CNS.

PMID- 10656759
TI  - Hsp25 and the p38 MAPK pathway are involved in differentiation of cardiomyocytes.
AB  - The small heat-shock protein HSP25 is expressed in the heart early during
      development, and although multiple roles for HSP25 have been proposed, its
      specific role during development and differentiation is not known. P19 is an
      embryonal carcinoma cell line which can be induced to differentiate in vitro into
      either cardiomyocytes or neurons. We have used P19 to examine the role of HSP25
      in differentiation. We found that HSP25 expression is strongly increased in P19
      cardiomyocytes. Antisense HSP25 expression reduced the extent of cardiomyocyte
      differentiation and resulted in reduced expression of cardiac actin and the
      intermediate filament desmin and reduced level of cardiac mRNAs. Thus, HSP25 is
      necessary for differentiation of P19 into cardiomyocytes. In contrast, P19
      neurons did not express HSP25 and antisense HSP25 expression had no effect on
      neuronal differentiation. The phosphorylation of HSP25 by the p38/SAPK2 pathway
      is known to be important for certain of its functions. Inhibition of this pathway
      by the specific inhibitor SB203580 prevented cardiomyocyte differentiation of P19
      cells. In contrast, PD90589, which inhibits the ERK1/2 pathway, had no effect.
      Surprisingly, cardiogenesis was only sensitive to SB203580 during the first 2
      days of differentiation, before HSP25 expression increases. In contrast to the
      effect of antisense HSP25, SB203580 reduced the level of expression of the
      mesodermal marker Brachyury-T during differentiation. Therefore, we propose that
      the p38 pathway acts on an essential target during early cardiogenesis. Once this
      initial step is complete, HSP25 is necessary for the functional differentiation
      of P19 cardiomyocytes, but its phosphorylation by p38/SAPK2 is not required.

PMID- 10656760
TI  - Premeiotic aster as a device to anchor the germinal vesicle to the cell surface
      of the presumptive animal pole in starfish oocytes.
AB  - The germinal vesicle (GV) of starfish oocytes stays just beneath the oocyte
      cortex at the presumptive animal pole during the long period of oogenesis. We
      subjected oocytes to a centrifugal force field to detach the GV from the cortex.
      The association between the cortex and the GV persisted and withstood a small
      amount of centrifugal acceleration at 200 g. The GV was eventually separated from
      the cortex at 700 g. The amount of acceleration sufficient for the GV separation
      was lowered when the oocytes were pretreated with Nocodazole and was increased by
      Taxol pretreatment. Observation of microtubular structures with an anti-alpha
      tubulin antibody revealed the presence of a complex of spots and radiating arrays
      as was described by J. J. Otto and T. E. Schroeder (1984, Dev. Biol. 101, 274
      281) and called the premeiotic aster. Nocodazole shortened the astral arrays, and
      Taxol enhanced them. These observations indicate that the premeiotic aster works
      as a device to hold the GV in an eccentric position just beneath the oocyte
      cortex.

PMID- 10656761
TI  - mag-1, a homolog of Drosophila mago nashi, regulates hermaphrodite germ-line sex
      determination in Caenorhabditis elegans.
AB  - The Caenorhabditis elegans gene mag-1 can substitute functionally for its homolog
      mago nashi in Drosophila and is predicted to encode a protein that exhibits 80%
      identity and 88% similarity to Mago nashi (P. A. Newmark et al., 1997,
      Development 120, 3197-3207). We have used RNA-mediated interference (RNAi) to
      analyze the phenotypic consequences of impairing mag-1 function in C. elegans. We
      show here that mag-1(RNAi) causes masculinization of the germ line (Mog
      phenotype) in RNA-injected hermaphrodites, suggesting that mag-1 is involved in
      hermaphrodite germ-line sex determination. Epistasis analysis shows that ectopic
      sperm production caused by mag-1(RNAi) is prevented by loss-of-function (lf)
      mutations in fog-2, gld-1, fem-1, fem-2, fem-3, and fog-1, all of which cause
      germ-line feminization in XX hermaphrodites, but not by a her-1(lf) mutation
      which causes germ-line feminization only in XO males. These results suggest that
      mag-1 interacts with the fog, fem, and gld genes and acts independently of her-1.
      We propose that mag-1 normally allows oogenesis by inhibiting function of one or
      more of these masculinizing genes, which act during the fourth larval stage to
      promote transient sperm production in the hermaphrodite germ line. When the Mog
      phenotype is suppressed by a fog-2(lf) mutation, mag-1(RNAi) also causes
      lethality in the progeny embryos of RNA-injected, mated hermaphrodites,
      suggesting an essential role for mag-1 during embryogenesis. The defective
      embryos arrest during morphogenesis with an apparent elongation defect. The
      distribution pattern of a JAM-1::GFP reporter, which is localized to boundaries
      of hypodermal cells, shows that hypodermis is disorganized in these embryos. The
      temporal expression pattern of the mag-1 gene prior to and during morphogenesis
      appears to be consistent with an essential role of mag-1 in embryonic hypodermal
      organization and elongation.

PMID- 10656762
TI  - Cloning and expression of the Wnt antagonists Sfrp-2 and Frzb during chick
      development.
AB  - The Wnt genes are known to play fundamental roles during patterning and
      development of a number of embryonic structures. Receptors for Wnts are members
      of the Frizzled family of proteins containing a cysteine-rich domain (CRD) that
      binds the Wnt protein. Recently several secreted frizzled-related proteins
      (Sfrps) that also contain a CRD have been identified and some of these can both
      bind and antagonise Wnt proteins. In this paper we report the expression patterns
      of the chick homologues of Frzb, a known Wnt antagonist, and Sfrp-2. Both genes
      are expressed in areas where Wnts are known to play a role in development,
      including the neural tube, myotome, cartilage, and sites of epithelial
      mesenchymal interactions. Initially, Sfrp-2 and Frzb are expressed in overlapping
      areas in the neural plate and neural tube, whereas later, they have distinct
      patterns. In particular Sfrp-2 is associated with myogenesis while Frzb is
      associated with chondrogenesis, suggesting that they play different roles during
      development. Finally, we have used the early Xenopus embryo as an in vivo assay
      to show that Sfrp-2, like Frzb, is a Wnt antagonist. These results suggest that
      Sfrp-2 and Frzb may function in the developing embryo by modulating Wnt
      signalling.

PMID- 10656763
TI  - Vaccinia as a tool for functional analysis in regenerating limbs: ectopic
      expression of Shh.
AB  - Axolotls, with their extensive abilities to regenerate as adults, provide a
      useful model in which to study the mechanisms of regeneration in a vertebrate, in
      hopes of understanding why other vertebrates cannot regenerate. Although the
      expression of many genes has been described in regeneration, techniques for
      functional analysis have so far been limited. In this paper we demonstrate a new
      method for efficient overexpression of foreign genes in axolotls. Using vaccinia
      virus expressing beta-galactosidase microinjected into regenerating limbs, we
      show that vaccinia can infect both dividing and nondividing limb cells. The site
      of infection remains discrete and there is no secondary spread of infection to
      nearby cells. beta-Gal is expressed at high levels in blastema cells for about a
      week and in differentiated cells for longer. Blastemas that have been injected
      with vaccinia at different stages regenerate normally. As a test of the utility
      of vaccinia for functional analysis in regeneration, we constructed a virus
      expressing Shh and injected it into the anterior of regenerating limbs. Ectopic
      Shh expression caused extra digits, carpals, and tarsals in the hands and feet of
      regenerating limbs, suggesting that despite differences in the timing of
      expression and the eventual pattern, the function of Shh appears to be similar to
      that in the developing limbs of other vertebrates. Our results demonstrate that
      vaccinia virus is an excellent vector for ectopically expressing genes for
      secreted proteins and is a useful tool to study the function of signaling
      molecules during the process of regeneration in urodeles.

PMID- 10656764
TI  - Evidence that Src-type tyrosine kinase activity is necessary for initiation of
      calcium release at fertilization in sea urchin eggs.
AB  - The initiation of Ca(2+) release from internal stores in the egg is a hallmark of
      egg activation. In sea urchins, PLCgamma activity is necessary for the production
      of IP(3), which leads to the initial rise in Ca(2+). To examine the possible
      function of a tyrosine kinase in activating PLCgamma at fertilization, sea urchin
      eggs were treated with the specific Src kinase inhibitor PP1 or microinjected
      with recombinant Src-family SH2-domain proteins, which act as dominant
      interfering inhibitors of Src-family kinase function. Both modes of inhibiting
      Src-family kinases resulted in a specific and dose-dependent delay in the onset
      of Ca(2+) release from the endoplasmic reticulum at fertilization. The rise in
      cytoplasmic pH at fertilization also was inhibited by microinjection of Src
      family SH2-domain proteins. Further, an antibody directed against Src-type
      kinases recognized a protein of ca. M(r) 57K that was enriched in the membrane
      fraction of eggs. The kinase activity of this protein was stimulated rapidly and
      transiently at fertilization, as measured by autophosphorylation and by
      phosphorylation of an exogenous substrate. Together, these data indicate that a
      Src-type tyrosine kinase is necessary for the initiation of Ca(2+) release from
      the egg ER at fertilization and identify a Src-type p57 protein as a candidate in
      the signaling pathway leading to this Ca(2+) release.

PMID- 10656765
TI  - Positional regulation of Krox-20 and mafB/kr expression in the developing
      hindbrain: potentialities of prospective rhombomeres.
AB  - Krox-20 and mafB/kr encode transcription factors involved in the control of
      hindbrain development and are expressed in rhombomeres (r) 3 and 5 and 5 and 6,
      respectively. To analyse the regulation of the expression of these genes by
      positional cues, focusing on the stages just preceding the formation of
      rhombomeres, we have performed ectopic grafts involving single prospective
      rhombomeres (pr) or couples of pr on 4-6 somite avian embryos. Transplantation of
      pr6 in the pr5 position leads to Krox-20 activation and grafting of pr7 in the
      pr5 position results in mafB/kr activation. Furthermore, pr6 grafted in the pr5
      position develops an r5-like cytoarchitecture. These data establish that rostral
      transplantation can lead to anteriorization within the hindbrain. However,
      additional experiments indicate that the competence of the transplanted tissue
      for such anteriorization appears limited and that transformations corresponding
      to shifts of a single rhombomere are favoured. We also show that caudal
      transplantation of pr5 into the pr6 position can lead to a down-regulation of
      Krox-20 expression consistent with posteriorization, suggesting that caudalizing
      influences are present within the nonsomitic hindbrain after the 4- to 6-somite
      stage. Finally, combinations of extirpation and grafting experiments suggest that
      the regulation of mafB/kr expression in the r6-r7 region may involve
      anteriorizing influences in addition to previously identified posteriorizing
      signals from the somitic region.

PMID- 10656766
TI  - A conserved role for H15-related T-box transcription factors in zebrafish and
      Drosophila heart formation.
AB  - T-box transcription factors are critical regulators of early embryonic
      development. We have characterized a novel zebrafish T-box transcription factor,
      hrT (H15-related T box) that is a close relative of Drosophila H15 and a recently
      identified human gene. We show that Drosophila H15 and zebrafish hrT are both
      expressed early during heart formation, in strong support of previous work
      postulating that vertebrate and arthropod hearts are homologous structures with
      conserved regulatory mechanisms. The timing and regulation of zebrafish hrT
      expression in anterior lateral plate mesoderm suggest a very early role for hrT
      in the differentiation of the cardiac precursors. hrT is coexpressed with gata4
      and nkx2.5 not only in anterior lateral plate mesoderm but also in noncardiac
      mesoderm adjacent to the tail bud, suggesting that a conserved regulatory pathway
      links expression of these three genes in cardiac and noncardiac tissues. Finally,
      we analyzed hrT expression in pandora mutant embryos, since these have defects in
      many of the tissues that express hrT, including the heart. hrT expression is much
      reduced in the early heart fields of pandora mutants, whereas it is ectopically
      expressed subsequently. Using hrT expression as a marker, we describe a midline
      patterning defect in pandora affecting the anterior hindbrain and associated
      midline mesendodermal derivatives. We discuss the possibility that the cardiac
      ventricular defect previously described in pandora and the midline defects
      described here are related.

PMID- 10656767
TI  - Adult Apaf-1-deficient mice exhibit male infertility.
AB  - Release of cytochrome c from the mitochondria, and subsequent binding to
      apoptotic protease-activating factor-1 (Apaf-1), is a key trigger of apoptotic
      events. A complex composed of Apaf-1, dATP, and cytochrome c activates a series
      of cytoplasmic proteases called caspases, leading to apoptotic cell death. We
      have disrupted the Apaf-1 gene in the mouse. Like previous reports on this
      knockout model, we find that most Apaf-1 mutants die perinatally and frequently
      exhibit exencephaly and cranioschesis. We additionally find that the neural
      lesions that develop in the knockout are due to an excess of neural progenitor
      cells that manifests as early as embryonic day 9.5 in development. In contrast to
      previous reports on the Apaf-1 knockout mice, we find that 5% of the mutants
      successfully survive to adulthood. In these survivors, the brain develops
      normally, but in males, there is degeneration of spermatogonia resulting in the
      virtual absence of sperm. Thus, cytochrome c-mediated apoptosis is not absolutely
      required for normal neural development, but is essential for spermatogenesis.
      These findings strongly suggest that alternative apoptotic pathways work in
      conjunction with and parallel to Apaf-1 and can modify its effect on programmed
      cell death.

PMID- 10656768
TI  - Purification and analysis of in vivo-differentiated oligodendrocytes expressing
      the green fluorescent protein.
AB  - A complete understanding of the molecular mechanisms involved in the formation
      and repair of the central nervous system myelin sheath requires an unambiguous
      identification and isolation of in vivo-differentiated myelin-forming cells. In
      order to develop a novel tool for the analysis of in vivo-differentiated
      oligodendrocytes, we generated transgenic mice expressing a red-shifted variant
      of the green fluorescent protein under the control of the proteolipid protein
      promoter. We demonstrate here that green fluorescent protein-derived fluorescence
      in the central nervous system of 9-day- to 7-week-old mice is restricted to
      mature oligodendrocytes, as determined by its spatiotemporal appearance and by
      both immunocytochemical and electrophysiological criteria. Green fluorescent
      protein-positive oligodendrocytes could easily be visualized in live and fixed
      tissue. Furthermore, we show that this convenient and reliable identification now
      allows detailed physiological analyses of differentiated oligodendrocytes in
      situ. In addition, we developed a novel tissue culture system for in vivo
      differentiated oligodendrocytes. Initial data using this system indicate that,
      for oligodendrocytes isolated after differentiation in vivo, as yet unidentified
      factors secreted by astrocytes are necessary for survival and/or reappearance of
      a mature phenotype in culture.

PMID- 10656769
TI  - Developmental change in TATA-box utilization during preimplantation mouse
      development.
AB  - Activation of the embryonic genome during preimplantation mouse development is
      characterized by a marked reprogramming of gene expression that is essential for
      further development. Expression of the protein translation initiation factor eIF
      1A gene is driven by a proximal TATA-containing promoter and a distal TATA-less
      promoter. Using specific amplification of cDNA ends that resolves transcripts
      derived from the TATA-less and TATA-containing promoters, we find that 70% of the
      eIF-1A transcripts are derived from the TATA-containing promoter in the fully
      grown oocyte. Activation of the embryonic genome during the two-cell stage is
      accompanied by a change in promoter utilization such that only 25% of the
      transcripts are now derived from the TATA-containing promoter, i.e., 75% are
      derived from the TATA-less promoter. When one-cell embryos are cultured to the
      two-cell stage in the presence of alpha-amanitin, this change in transcript
      abundance is not observed, i.e., the distribution of transcripts is similar to
      that observed in the oocyte. By the blastocyst stage only 5% of the transcripts
      are generated from the TATA-containing promoter. If the change in TATA-box
      utilization for the eIF-1A reflects an underlying global change in TATA-box
      utilization, a dramatic change in promoter utilization may occur during
      preimplantation development such that TATA-less promoters are more efficiently
      utilized. Such a change in promoter utilization could contribute significantly to
      the reprogramming of gene expression that occurs during the maternal-to-zygotic
      transition.

PMID- 10656770
TI  - Subcellular trafficking of the nuclear receptor COUP-TF in the early embryonic
      cell cycle.
AB  - The nuclear receptor SpCOUP-TF is the highly conserved sea urchin homologue of
      the COUP family of transcription factors. Previous results from our laboratory
      demonstrated that SpCOUP-TF transcripts are localized in the egg and
      asymmetrically distributed in the early embryonic blastomeres (A. Vlahou et al.,
      1996, Development 122, 521-526). To examine the subcellular localization of
      SpCOUP-TF protein, polyclonal antibodies were separately raised against the
      divergent N-terminus as well as the conserved DNA-binding and ligand-binding
      domains. Immunohistochemical analyses suggest that SpCOUP-TF is a maternal
      protein residing in the cytoplasm of the unfertilized egg. After fertilization,
      and as soon as the two-cell-stage embryo, most of the receptor translocates from
      the cytoplasm to the cell nuclei. During the rapid embryonic cell division,
      SpCOUP-TF was found to shuttle from the interphase nuclear periphery to the
      condensed chromosomes in mitosis, in a cell-cycle-dependent manner. In an attempt
      to confirm these observations, the subcellular localization of myc-tagged human
      COUP-TF I introduced into the sea urchin embryo by RNA injection of fertilized
      eggs was examined. The pattern of human COUP-TF I subcellular localization,
      detected with a monoclonal myc antibody, recapitulated the essential features
      described for the endogenous SpCOUP-TF trafficking. Replacement of the N-terminus
      of the human receptor with the unique sea urchin N-terminus enhanced its
      localization to the nuclear rim during interphase. Deletion of the DNA-binding
      domain of human COUP-TF I resulted in loss of all aspects of nuclear periphery
      and chromosomal localization. Taken together these data suggest that SpCOUP-TF
      transcriptional activity is keyed on a cell-cycle-dependent mechanism that
      regulates chromosomal protein traffic.

PMID- 10656771
TI  - Spatiotemporal analysis of Ca(2+) waves in relation to the sperm entry site and
      animal-vegetal axis during Ca(2+) oscillations in fertilized mouse eggs.
AB  - Fertilized mouse eggs exhibit repetitive rises in intracellular Ca(2+)
      concentration ([Ca(2+)](i)) necessary for egg activation. Precise spatiotemporal
      dynamics of each [Ca(2+)](i) rise were investigated by high-speed Ca(2+) imaging
      during early development of monospermic eggs. Every [Ca(2+)](i) rise involved a
      Ca(2+) wave. In the first Ca(2+) transient, [Ca(2+)](i) increased in two steps
      separated by a "shoulder" point, suggesting two distinct Ca(2+) release
      mechanisms. The first step was a Ca(2+) wave that propagated from the sperm
      fusion site to its antipode in 4-5 s (velocity, approximately 20 microm/s in most
      eggs). The second step from the shoulder to the peak was a nearly uniform
      [Ca(2+)](i) rise of 12-15 s. A slight cytoplasmic movement followed the Ca(2+)
      wave in the same direction and recovered in 25-35 s. These characteristics
      changed as follows, as Ca(2+) oscillations progressed during the second meiosis
      up to their cessation at the stage of pronuclei formation ( approximately 3 h
      after fertilization). (1) The duration of Ca(2+) transients became shorter. (2)
      The shoulder point shifted to higher levels and the first step occupied most of
      the rising phase. (3) The rate of [Ca(2+)](i) rise became greater and wave speeds
      increased up to 80-100 microm/s or more. (4) The transient cytoplasmic movement
      always resulted from the Ca(2+) wave, although its displacement became smaller.
      (5) The Ca(2+) wave initiation site was freed from the sperm-fusion or -entry
      site and eventually localized in the cortex of the vegetal hemisphere. Since the
      shift of the wave initiation site to the vegetal cortex is observed in fertilized
      eggs of nemertean worms and ascidians, this might be an evolutionarily conserved
      feature.

PMID- 10656772
TI  - Membrane fusion proteins are required for oskar mRNA localization in the
      Drosophila egg chamber.
AB  - We used a genetic screen in Drosophila to identify mutations which disrupt the
      localization of oskar mRNA during oogenesis. Based on the hypothesis that some
      cytoskeletal components which are required during the mitotic divisions will also
      be required for oskar mRNA localization during oogenesis, we designed the
      following genetic screen. We screened for P-element insertions in genes which
      slow down the blastoderm mitotic divisions. A secondary genetic screen was to
      generate female germ-line clones of these potential cell division cycle genes and
      to identify those which cause the mislocalization of oskar mRNA. We identified
      mutations in ter94 which disrupt the localization of oskar mRNA to the posterior
      pole of the oocyte. Ter94 is a member of the CDC48p/VCP subfamily of AAA proteins
      which are involved in homotypic fusion of the endoplasmic reticulum during
      mitosis. Consistent with the function of the yeast ortholog, ter94-mutant egg
      chambers are defective in the assembly of the endoplasmic reticulum. We tested
      whether other membrane biosynthesis genes are required for localizing oskar mRNA
      during oogenesis. We found that ovaries that are mutant for syntaxin-1a, rop, and
      synaptotagmin are also defective in oskar mRNA localization during oogenesis. We
      suggest a pathway for the role of membrane assembly proteins on oskar mRNA
      localization.

PMID- 10656773
TI  - Subdivision of the cardiac Nkx2.5 expression domain into myogenic and nonmyogenic
      compartments.
AB  - Nkx2.5 is expressed in the cardiogenic mesoderm of avian, mouse, and amphibian
      embryos. To understand how various cardiac fates within this domain are
      apportioned, we fate mapped the mesodermal XNkx2.5 domain of neural tube stage
      Xenopus embryos. The lateral portions of the XNkx2.5 expression domain in the
      neural tube stage embryo (stage 22) form the dorsal mesocardium and roof of the
      pericardial cavity while the intervening ventral region closes to form the
      myocardial tube. XNkx2.5 expression is maintained throughout the period of heart
      tube morphogenesis and differentiation of myocardial, mesocardial, and
      pericardial tissues. A series of microsurgical experiments showed that myocardial
      differentiation in the lateral portion of the field is suppressed during normal
      development by signals from the prospective myocardium and by tissues located
      more dorsally in the embryo, in particular the neural tube. These signals combine
      to block myogenesis downstream of XNkx2.5 and at or above the level of
      contractile protein gene expression. We propose that the entire XNkx2.5/heart
      field is transiently specified as cardiomyogenic. Suppression of this program
      redirects lateral cells to adopt dorsal mesocardial and dorsal pericardial fates
      and subdivides the field into distinct myogenic and nonmyogenic compartments.

PMID- 10656774
TI  - Initiation of axillary and floral meristems in Arabidopsis.
AB  - Shoot development is reiterative: shoot apical meristems (SAMs) give rise to
      branches made of repeating leaf and stem units with new SAMs in turn formed in
      the axils of the leaves. Thus, new axes of growth are established on preexisting
      axes. Here we describe the formation of axillary meristems and floral meristems
      in Arabidopsis by monitoring the expression of the SHOOT MERISTEMLESS and
      AINTEGUMENTA genes. Expression of these genes is associated with SAMs and organ
      primordia, respectively. Four stages of axillary meristem development and
      previously undefined substages of floral meristem development are described. We
      find parallels between the development of axillary meristems and the development
      of floral meristems. Although Arabidopsis flowers develop in the apparent absence
      of a subtending leaf, the expression patterns of AINTEGUMENTA and SHOOT
      MERISTEMLESS RNAs during flower development suggest the presence of a highly
      reduced, "cryptic" leaf subtending the flower in Arabidopsis. We hypothesize that
      the STM-negative region that develops on the flanks of the inflorescence meristem
      is a bract primordium and that the floral meristem proper develops in the "axil"
      of this bract primordium. The bract primordium, although initially specified,
      becomes repressed in its growth.

PMID- 10656775
TI  - Characterization of a novel insertional mouse mutation, kkt: A closely linked
      modifier of Pax1.
AB  - We describe a novel transgene insertional mouse mutant with skeletal
      abnormalities characterized by a kinked tail and severe curvature of the spine.
      The disrupted locus is designated kkt for "kyphoscoliosis kinked tail." Malformed
      vertebrae including bilateral ossification centers and premature fusion of the
      vertebral body to the pedicles are observed along the vertebral column, and the
      lower thoracic and lumbar vertebrae are the most affected. Some of the homozygous
      kkt neonates displayed two backward-pointing transverse processes in the sixth
      lumbar vertebra (L6) that resembled the first sacral vertebra, and some displayed
      one forward- and one backward-pointing transverse process in L6. The fourth and
      fifth sternebrae were also fused, and the acromion process of the scapula was
      missing in kkt mice. The skeletal abnormalities are similar to those observed in
      the mouse mutant undulated (un). The transgene is integrated at the distal end of
      chromosome 2 close to the Pax1 gene, as revealed by FISH analysis. However,
      mutation of the Pax1 gene is responsible for the un phenotype, but the Pax1 gene
      in the kkt mice is not rearranged or deleted. Pax1 is expressed normally in kkt
      embryos and in the thymus of mature animals, and there is no mutation in its
      coding sequence. Thus, the skeletal abnormalities observed in the kkt mutant are
      not due to a lack of functional Pax1. Mouse genomic sequences flanking the
      transgene and PAC clones spanning the wild-type kkt locus have been isolated, and
      reverse Northern analysis showed that the PACs contain transcribed sequence.
      Compound heterozygotes between un and kkt (un(+/-)/kkt(+/-)) display skeletal
      abnormalities similar to those of un or kkt homozygotes, but they have multiple
      lumbar vertebrae with a split vertebral body that is more severe than in
      homozygous un or kkt neonates. Furthermore, the sternebrae are not fused and no
      backward-pointing transverse processes are detected in L6. It is therefore
      apparent that these two mutations do not fully complement each other, and we
      propose that a gene in the kkt locus possesses a unique role that functions in
      concert with Pax1 during skeletal development.

PMID- 10656776
TI  - Subpopulations of rat B2(+) neuroblasts exhibit differential neurotrophin
      responsiveness during sympathetic development.
AB  - Sympathetic neurons comprise a population of postmitotic, tyrosine hydroxylase
      expressing cells whose survival is dependent upon nerve growth factor (NGF) both
      in vivo and in vitro. However, during development precursors to rat sympathetic
      neurons in the thoracolumbar region are not responsive to NGF because they lack
      the signal transducing NGF receptor, trkA. We have previously shown that
      acquisition of trkA expression is sufficient to confer a functional response to
      NGF. Here we describe four subpopulations of thoracolumbar sympathetic
      neuroblasts which are mitotically active and unresponsive to NGF at E13.5 of rat
      gestation, but differ based upon their neurotrophic responsiveness in vitro. The
      survival in culture of the largest sympathetic subpopulation is mediated by
      neurotrophin-3 (NT-3) or glial-derived neurotrophic factor (GDNF), whereas the
      cell survival of two smaller subpopulations of neuroblasts are mediated by either
      solely GDNF or solely NT-3. Finally, we identify a subpopulation of sympathetic
      neuroblasts in the thoracolumbar region whose survival, exit from the cell cycle,
      induction of trkA expression, and consequent acquisition of NGF responsiveness in
      culture appear to be neurotrophin independent and cell autonomous. These
      subpopulations reflect the diversity of neurotrophic actions that occur in the
      proper development of sympathetic neurons.

PMID- 10656777
TI  - Molecular systematics of the old world monkey tribe papionini: analysis of the
      total available genetic sequences.
AB  - The phylogenetic relationships among the genera of the tribe Papionini are
      inferred using a taxonomic congruence approach in which gene trees derived for
      eight unlinked genetic sequence datasets are compared. Population genetics theory
      predicts that species relationships will be revealed with greater probability
      when the topology of gene trees from many unlinked loci are found to be
      congruent. The theory underlying this approach is described. Monophyly of the
      mangabeys is not supported by any of the gene trees; instead, they are
      polyphyletic with Cercocebus found to be the sister taxon to Mandrillus in five
      gene trees (with no conflicting trees), and Lophocebus found to be closely
      related to Papio and/or Theropithecus in all trees. Theropithecus and Papio are
      not strongly supported as sister taxa (present in one or two trees
      only);Lophocebus and Papio are supported as sister taxa in the majority of trees.
      A close relationship between Mandrillus and Papio is not supported in any of the
      trees.The relationships among Papio, Lophocebus, and Theropithecus cannot be
      resolved by congruence, probably due to the short time interval estimated between
      their divergences. The mtDNA COII sequences are used to estimate divergence dates
      within the papionins. The internode between the divergences of these species is
      estimated to be between 290 ka and 370 ka. Lastly, the evolution of morphological
      features such as long faces, suborbital facial fossae, and terrestrial skeletal
      adaptations is discussed.

PMID- 10656778
TI  - Micro-anatomy of the volar skin and interordinal relationships of primates.
AB  - Paleontological and molecular evidence have been employed to suggest that flying
      lemurs (Dermoptera) and primates form a monophyletic group, in sharp contrast
      with cranial and postcranial evidence indicating sister group relationships
      between flying lemurs and bats (Chiroptera). New evidence from the epidermis of
      the volar pads of primates, tree shrews, flying lemurs, bats, and other mammals
      was examined and mapped on to various hypotheses of archontan relationships. The
      micro-anatomy of the skin on the palm and sole of flying lemurs and bats differs
      fundamentally from that of tree shrews (Scandentia) and primates. The volar skin
      of flying lemurs and bats lacks the serial arrangement of papillary ridges and
      grooves ("fingerprints") found in primates, tree shrews, and many other mammals.
      Moreover, the junction between the epidermis and dermis in flying lemurs and bats
      is relatively flat and shows little or no development of the internal ridges that
      occur in primates and tree shrews. When mapped on to a set of cladograms of
      mammals currently allocated to the superorder Archonta, this new evidence does
      not support sister group relationships between flying lemurs and primates,
      regardless of the volar skin morphology that characterized the last common
      ancestor of Archonta. Micro-anatomical differences that distinguish the volar
      skin of flying lemurs and bats from that of primates and tree shrews reflect a
      profound dichotomy in the functional roles fulfilled by the extremities, which
      could be significant in a phylogenetic context.

PMID- 10656779
TI  - Body size, body shape, and long bone strength in modern humans.
AB  - To identify behaviorally significant differences in bone structure it is first
      necessary to control for the effects of body size and body shape. Here the
      scaling of cross-sectional geometric properties of long bone diaphyses with
      different "size" measures (bone length, body mass, and the product of bone length
      and body mass) are compared in two modern human populations with very different
      body proportions: Pecos Pueblo Amerindians and East Africans. All five major long
      bones (excluding the fibula) were examined. Mechanical predictions are that
      cortical area (axial strength) should scale with body mass, while section modulus
      (bending/torsional strength) should scale with the product of body mass and
      moment arm length. These predictions are borne out for section moduli, when
      moment arm length is taken to be proportional to bone length, except in the
      proximal femoral diaphysis, where moment arm length is proportional to
      mediolateral body breadth (as would be expected given the predominance of M-L
      bending loads in this region). Mechanical scaling of long bone bending/torsional
      strength is similar in the upper and lower limbs despite the fact that the upper
      limb is not weight-bearing. Results for cortical area are more variable, possibly
      due to a less direct dependence on mechanical factors. Use of unadjusted bone
      length alone as a "size" measure produces misleading results when body shape
      varies significantly, as is the case between many modern and fossil hominid
      samples. In such cases a correction factor for body shape should be incorporated
      into any "size" standardization.

PMID- 10656780
TI  - Basicranial influence on overall cranial shape.
AB  - This study examines the extent to which the major dimensions of the cranial base
      (maximum length, maximum breadth, and flexion) interact with brain volume to
      influence major proportions of the neurocranium and face. A model is presented
      for developmental interactions that occur during ontogeny between the brain and
      the cranial base and neurocranium, and between the neurobasicranial complex (NBC)
      and the face. The model is tested using exocranial and radiographic measurements
      of adult crania sampled from five geographically and craniometrically diverse
      populations. The results indicate that while variations in the breadth, length
      and flexion of the cranial base are mutually independent, only the maximum
      breadth of the cranial base (POB) has significant effects on overall cranial
      proportions, largely through its interactions with brain volume which influence
      NBC breadth. These interactions also have a slight influence on facial shape
      because NBC width constrains facial width, and because narrow-faced individuals
      tend to have antero-posteriorly longer faces relative to facial breadth than wide
      faced individuals. Finally, the model highlights how integration between the
      cranial base and the brain may help to account for the developmental basis of
      some morphological variations such as occipital bunning. Among modern humans, the
      degree of posterior projection of the occipital bone appears to be a consequence
      of having a large brain on a relatively narrow cranial base. Occipital buns in
      Neanderthals, who have wide cranial bases relative to endocranial volume, may not
      be entirely homologous with the morphology occasionally evident in Homo sapiens.

PMID- 10656781
TI  - The brain and its main anatomical subdivisions in living hominoids using magnetic
      resonance imaging.
AB  - Primary comparative data on the hominoid brain are scarce and major
      neuroanatomical differences between humans and apes have not yet been described
      satisfactorily, even at the gross level. Basic questions that involve the
      evolution of the human brain cannot be addressed adequately unless the brains of
      all extant hominoid species are analyzed. Contrary to the scarcity of original
      data, there is a rich literature on the topic of human brain evolution and
      several debates exist on the size of particular sectors of the brain, e.g., the
      frontal lobe. In this study we applied a non-invasive imaging technique (magnetic
      resonance) on living human, great ape and lesser ape subjects in order to
      investigate the overall size of the hominoid brain. The images were reconstructed
      in three dimensions and volumetric estimates were obtained for the brain and its
      main anatomical sectors, including the frontal and temporal lobes, the insula,
      the parieto-occipital sector and the cerebellum.A remarkable homogeneity is
      present in the relative size of many of the large sectors of the hominoid brain,
      but interspecific and intraspecific variation exists in certain parts of the
      brain. The human cerebellum is smaller than expected for an ape brain of human
      size. It is suggested that the cerebellum increased less than the cerebrum after
      the split of the human lineage from the African ancestral hominoid stock. In
      contrast, humans have a slightly larger temporal lobe and insula than expected,
      but differences are not statistically significant. Humans do not have a larger
      frontal lobe than expected for an ape brain of human size and gibbons have a
      relatively smaller frontal lobe than the rest of the hominoids. Given the fact
      that the frontal lobe in humans and great apes has similar relative size, it is
      parsimonious to suggest that the relative size of the whole of the frontal lobe
      has not changed significantly during hominid evolution in the Plio-Pleistocene.

PMID- 10656782
TI  - Fifth metatarsal morphology does not predict presence or absence of fibularis
      tertius muscle in hominids.
AB  - The leg muscle fibularis tertius (formerly peroneus tertius) is occasionally
      absent in humans, but it is rarely found in other primates. Phylogenetically and
      functionally it appears to be linked to efficient terrestrial bipedalism. An
      osseous indicator of the muscle would therefore be useful for interpreting the
      locomotor behavior of fossil hominids. To determine whether the presence of
      fibularis tertius can be detected osteologically, we isolated 58 human fifth
      metatarsals, noting which came from cadavers lacking the muscle. The bones were
      then ranked according to two characters that have been said to suggest presence
      of fibularis tertius in australopithecines: (1) sharpness of the dorsal shaft
      edge and (2) size and prominence of the dorsal tubercle. Presence of the muscle
      showed little association with the ranked characters, and the two criteria were
      uncorrelated. For example, one individual lacking a fibularis tertius exhibited
      nearly maximal expression of both features, whereas another possessing the muscle
      showed the weakest development of both. Only one of the 58 bones had a line
      comparable to that seen on SK 33380, a robust australopithecine fifth metatarsal
      from Member 3 of Swartkrans, South Africa. We conclude that fifth metatarsal
      morphology offers little reliable information about the presence of fibularis
      tertius or the timing of its appearance in the human career.

PMID- 10656783
TI  - The structure of the HIV-1 RRE high affinity rev binding site at 1.6 A
      resolution.
AB  - The crystal structure of a 28 nt RNA fragment containing the human
      immunodeficiency virus type 1 (HIV-1) Rev response element high affinity binding
      site for Rev protein has been solved at 1.6 A resolution. The overall structure
      of the RRE helix is greatly distorted from A-form geometry by the presence of two
      purine-purine base-pairs and two single nucleotide bulges. G48 and G71 form a
      Hoogsteen-type asymmetric base-pair with G71 adopting a syn conformation. The non
      canonical regions in the unliganded Rev response element molecule narrow the
      major groove width with respect to standard A-RNA. The Rev response element
      structure observed here represents a closed form of the Rev binding site and
      differs from conformations of the RNA observed previously by solution NMR
      studies.

PMID- 10656784
TI  - DNA-induced alpha-helix capping in conserved linker sequences is a determinant of
      binding affinity in Cys(2)-His(2) zinc fingers.
AB  - High-affinity, sequence-specific DNA binding by Cys(2)-His(2) zinc finger
      proteins is mediated by both specific protein-base interactions and non-specific
      contacts between charged side-chains and the phosphate backbone. In addition, in
      DNA complexes of multiple zinc fingers, protein-protein interactions between the
      finger units contribute to the binding affinity. We present NMR evidence for
      another contribution to high- affinity binding, a highly specific DNA-induced
      helix capping involving residues in the linker sequence between fingers. Capping
      at the C terminus of the alpha-helix in each zinc finger, incorporating a
      consensus TGEKP linker sequence that follows each finger, provides substantial
      binding energy to the DNA complexes of zinc fingers 1-3 of TFIIIA (zf1-3) and the
      four zinc fingers of the Wilms' tumor suppressor protein (wt1-4). The same alpha
      helix C-capping motif is observed in the X-ray structures of four other protein
      DNA complexes. The structures of each of the TGEKP linkers in these complexes can
      be superimposed on the linker sequences in the zf1-3 complex, revealing a
      remarkable similarity in both backbone and side-chain conformations. The
      canonical linker structures from the zinc-finger-DNA complexes have been compared
      to the NMR structure of the TGEKP linker connecting fingers 1 and 2 in zf1-3 in
      the absence of DNA. This comparison reveals that additional stabilization likely
      arises in the DNA complexes from hydrogen bonding between the backbone amide of
      E3 and the side-chain O(gamma) of T1 in the linker. We suggest that these DNA
      induced C-capping interactions provide a means whereby the multiple-finger
      complex, which must necessarily be domain-flexible in the unbound state as it
      searches for the correct DNA sequence, can be "snap-locked" in place once the
      correct DNA sequence is encountered. These observations provide a rationale for
      the high conservation of the TGEKP linker sequences in Cys(2)-His(2) zinc finger
      proteins.

PMID- 10656785
TI  - NMR solution structure of AlcR (1-60) provides insight in the unusual DNA binding
      properties of this zinc binuclear cluster protein.
AB  - The three-dimensional structure of the DNA-binding domain (residues 1-60) of the
      ethanol regulon transcription factor AlcR from Aspergillus nidulans has been
      solved by NMR. This domain belongs to the zinc binuclear cluster class. Although
      the core of the protein is similar to previously characterized structures,
      consisting of two helices organized around a Zn(2)Cys(6 )motif, the present
      structure presents important variations, among them the presence of two
      supplementary helices. This structure gives new insight into the understanding of
      the AlcR specificities in DNA binding such as longer consensus half-sites, in
      vitro monomeric binding but in vivo multiple repeat transcriptional activation,
      either in direct or inverse orientations. The presence of additional contacts of
      the protein with its DNA target can be predicted from a model proposed for the
      interaction with the consensus DNA target. The clustering of accessible negative
      charges on helix 2 delineates a possible interaction site for other determinants
      of the transcriptional machinery, responsible for the fine tuning of the
      selection of the AlcR cognate sites.

PMID- 10656786
TI  - Localized, stereochemically sensitive hydrophobic packing in an early folding
      intermediate of dihydrofolate reductase from Escherichia coli.
AB  - Mutational analysis was performed to probe the development of hydrophobic
      clusters during the early events in the folding of dihydrofolate reductase.
      Replacements were made in several hydrophobic subdomains to examine the roles of
      hydrophobicity and stereochemistry in the formation of kinetic intermediates.
      Amide protons in two of these clusters, including residues I91, I94, and I155,
      have been shown to be protected against solvent exchange within 13 ms of folding.
      Additional hydrophobic clusters were probed by substitutions at residues I2, I61,
      and L112; these residues are not protected from exchange until later in the
      folding reaction. Valine and leucine replacements at positions I91, I94, and I155
      significantly diminish the formation of the burst phase kinetic intermediate,
      relative to the wild-type protein. In contrast, I2 and I61 are insensitive to
      these substitutions in the first 5 ms of the folding reaction, as is the
      replacement of L112 with either isoleucine or valine. These results demonstrate
      that the tightly packed core of dihydrofolate reductase is acquired in a non
      uniform fashion, beginning in the submillisecond time frame. The progressive
      development of specific side-chain packing in localized hydrophobic clusters may
      be a common theme for complex protein folding reactions.

PMID- 10656787
TI  - Conformational changes in the bacterial SRP receptor FtsY upon binding of guanine
      nucleotides and SRP.
AB  - In cotranslational preprotein targeting in Escherichia coli, the signal
      recognition particle (SRP) binds to the signal peptide emerging from the ribosome
      and, subsequently, interacts with the signal recognition particle receptor, FtsY,
      at the plasma membrane. Both FtsY and the protein moiety of the signal
      recognition particle, Ffh, are GTPases, and GTP is required for the formation of
      the SRP-FtsY complex. We have studied the binding of GTP/GDP to FtsY as well as
      the SRP-FtsY complex formation by monitoring the fluorescence of tryptophan 343
      in the I box of mutant FtsY. Thermodynamic and kinetic parameters of the FtsY
      complexes with GDP, GTP, and signal recognition particle are reported. Upon SRP
      FtsY complex formation in the presence of GTP, the fluorescence of tryptophan 343
      increased by 50 % and was blue-shifted by 10 nm. We conclude that GTP-dependent
      SRP-FtsY complex formation leads to an extensive conformational change in the I
      box insertion in the effector region of FtsY.

PMID- 10656788
TI  - Selection of amino acid substitutions restoring activity of HIV-1 integrase
      mutated in its catalytic site using the yeast Saccharomyces cerevisiae.
AB  - The integration of proviral DNA into the genome of the host cell is an essential
      step in the replication of retroviruses. This reaction is catalyzed by a viral
      encoded enzyme, the integrase (IN). We have previously shown that human
      immunodeficiency virus type 1 (HIV-1) IN causes a lethal effect when expressed in
      yeast cells. This system, called yeast lethal assay, was used as a tool to study
      IN activity in a cellular context. The yeast lethal assay allowed the selection
      and characterization of mutations affecting both the lethal phenotype and the in
      vitro IN activities. IN mutants were produced by random PCR mutagenesis in an IN
      gene bearing the inactivating D116A mutation in the catalytic site. The
      corresponding D116A substituted IN does not lead to lethality in yeast.
      Subsequent selection of mutants able to restore the lethal effect of IN was
      carried out using the yeast lethal assay. We isolated three mutants presenting a
      restored phenotype. The mutated IN genes were sequenced and the corresponding
      proteins were purified to characterize their in vitro activities. The three
      mutants presented restoration of the in vitro strand transfer activity, while 3'
      processing was only partially restored.The three mutants differ from D116A IN by
      at least one amino acid substitution located in the N-terminal domain of the
      protein, outside of the active site. These new mutated HIV-1 INs may therefore
      allow a better understanding of the N-terminal domain function in the integration
      reaction. In addition, these results support our hypothesis that explains the
      lethal effect as a consequence of the nuclear damage caused by wild-type IN in
      yeast cells. These data also indicate that the yeast lethal assay can be used as
      a tool to study the retroviral integration mechanism in a cellular context and to
      select specific inhibitors.

PMID- 10656789
TI  - A DNA-binding domain swap converts the invertase gin into a resolvase.
AB  - DNA resolvases and invertases are closely related, yet catalyze recombination
      within two distinct nucleoprotein structures termed synaptosomes and
      invertasomes, respectively. Different protein-protein and protein-DNA
      interactions guide the assembly of each type of recombinogenic complex, as well
      as the subsequent activation of DNA strand exchange. Here we show that invertase
      Gin catalyzes factor for inversion stimulation dependent inversion on isolated
      copies of sites I from ISXc5 res, which is typically utilized by the
      corresponding resolvase. The concomitant binding of Gin to sites I and III in
      res, however, inhibits recombination. A chimeric recombinase, composed of the
      catalytic domain of Gin and the DNA-binding domain of ISXc5 resolvase, recombines
      two res with high efficiency. Gin must therefore contain residues proficient for
      both synaptosome formation and activation of strand exchange. Surprisingly, this
      chimera is unable to assemble a productive invertasome; a result which implies a
      role for the C-terminal domain in invertasome formation that goes beyond DNA
      binding.

PMID- 10656790
TI  - Probing a tRNA core that contributes to aminoacylation.
AB  - The contribution of the tRNA "core" to aminoacylation is beginning to be
      recognized. One example is the core region of Escherichia coli tRNA(Cys), which
      has been shown by biochemical studies to be important for aminoacylation. This
      core has several layers of unusual base-pairs, which are revealed by the recent
      crystal structure of the tRNA complexed with the elongation factor EF-Tu and an
      analog of GTP. One of these layers consists of a 9:[13:22] base-triple, rather
      than the 46:[13:22] or 45:[13:22] base-triple that is commonly observed in tRNA
      structure. Because 13:22 is an important element in aminoacylation of E. coli
      tRNA(Cys), a better understanding of its structure in the tRNA core will shed
      light on its role in aminoacylation. In this study, we used the phage T7
      transcript of the tRNA as a substrate. We probed the structure of 13:22 by
      dimethyl sulfate and tested its partner in a base-triple by generating mutations
      that could be assayed for aminoacylation. The results of this study in general
      are in a better agreement with a 46:[13:22] base-triple that we previously
      proposed. Although these results are not interpreted as direct proof for the
      46:[13:22] base-triple, they shed new light on features of the tRNA core that are
      important for aminoacylation.

PMID- 10656791
TI  - DNA polymerase switching: I. Replication factor C displaces DNA polymerase alpha
      prior to PCNA loading.
AB  - An important not yet fully understood event in DNA replication is the DNA
      polymerase (pol) switch from pol alpha to pol delta. Indirect evidence suggested
      that the clamp loader replication factor C (RF-C) plays an important role, since
      a replication competent protein complex containing pol alpha, pol delta and RF-C
      could perform pol switching in the presence of proliferating cell nuclear antigen
      (PCNA). By using purified pol alpha/primase, pol delta, RF-C, PCNA and RP-A we
      show that: (i) RF-C can inhibit pol alpha in the presence of ATP prior to PCNA
      loading, (ii) RF-C decreases the affinity of pol alpha for the 3'OH primer ends,
      (iii) the inhibition of pol alpha by RF-C is released upon PCNA loading, (iv) ATP
      hydrolysis is required for PCNA loading and subsequent release of inhibition of
      pol alpha, (v) under these conditions a switching from pol alpha/primase to pol
      delta is evident. Thus, RF-C appears to be critical for the pol alpha to pol
      delta switching. Based on these results, a model is proposed in which RF-C
      induces the pol switching by sequestering the 3'-OH end from pol alpha and
      subsequently recruiting PCNA to DNA.

PMID- 10656792
TI  - DNA polymerase switching: II. Replication factor C abrogates primer synthesis by
      DNA polymerase alpha at a critical length.
AB  - A crucial event in DNA replication is the polymerase switch from the synthesis of
      a short RNA/DNA primer by DNA polymerase alpha/primase to the pro?cessive
      elongation by DNA polymerase delta. In order to shed light on the role of
      replication factor C (RF-C) in this process, the effects of RF-C on DNA
      polymerase alpha were investigated. We show that RF-C stalls DNA polymerase alpha
      after synthesis of approximately 30 nucleotides, while not inhibiting the
      polymerase activity per se. This suggested that RF-C and the length of the primer
      may be two important factors contributing to the polymerase switch. Furthermore
      the DNA binding properties of RF-C were tested. Band shift experiments indicated
      that RF-C has a preference for 5' recessed ends and double-stranded DNA over 3'
      ends. Finally PCNA can be loaded onto a DNA template carrying a RNA primer,
      suggesting that a DNA moiety is not necessarily required for the loading of the
      clamp. Thus we propose a model where RF-C, upon binding to the RNA/DNA primer,
      influences primer synthesis and sets the conditions for a polymerase switch after
      recruiting PCNA to DNA.

PMID- 10656793
TI  - Mutations influencing the frr gene coding for ribosome recycling factor (RRF).
AB  - A total of 52 null, six reversion, and five silent mutations of frr (the gene
      encoding for ribosome recycling factor (RRF)) of Escherichia coli are discussed
      along with 12 temperature-sensitive (ts) mutations and 14 intergenic suppressor
      strains of ts RRF. The null mutations were classified into six different
      categories. A computer-based secondary structure analysis showed three domains;
      domain A which has the N-terminal helix, domain B which contains coil, alpha
      helix and beta-strand structure, and domain C which is a C-terminal helix. The ts
      mutations fell into domains A and C but not in domain B. More than a half of the
      null mutations fell into domain B while the silent mutations fell outside domain
      B. Substitution of Arg132 in domain C by other amino acids was observed among
      five independently isolated null mutants. It is suggested that domain B is
      important for maintaining the RRF structure, while the region including Arg132 is
      one of the active sites. A total of 14 intergenic suppressor strains of ts RRF
      were grouped into four categories, depending on which temperature-sensitive
      alleles were suppressed.

PMID- 10656794
TI  - Kinetic mechanism of the single-stranded DNA recognition by Escherichia coli
      replicative helicase DnaB protein. Application of the matrix projection operator
      technique to analyze stopped-flow kinetics.
AB  - Kinetics of the Escherichia coli primary replicative helicase DnaB protein
      binding to a single-stranded DNA, in the presence of the ATP non-hydrolyzable
      analog AMP-PNP, have been performed, using the fluorescence stopped-flow
      technique. This is the first direct determination of the mechanism of the ssDNA
      recognition by a hexameric helicase. Binding of the fluorescent etheno-derivative
      of a ssDNA to the enzyme is characterized by a strong increase of the nucleic
      acid fluorescence, which provides an excellent signal to quantitatively study the
      mechanism of ssDNA recognition by the helicase. The kinetic experiments have been
      performed with a ssDNA 20-mer, depsilonA(pepsilonA)(19), that encompasses the
      entire, total ssDNA-binding site of the helicase and with the 10-mer
      depsilonA(pepsilonA)(9), which binds exclusively to the ssDNA strong subsite
      within the total ssDNA-binding site. Association of the DnaB helicase with the 20
      mer is characterized by three relaxation times, which indicates that the binding
      occurs by the minimum three-step mechanism where the bimolecular binding step is
      followed by two isomerization steps. This mechanism is described by the equation:
      Helicase+ssDNAk1/(k1)<-->(k-1)(H-ssDNA)1(k2)<-->(k-2)(H-ssDNA)2 (k3)<-->(k-3)(H
      ssDNA)3. The value of the bimolecular rate constant, k(1), is four to six orders
      of magnitude lower than the value expected for the diffusion-controlled reaction.
      Moreover, quantitative amplitude analysis suggests that the major conformational
      change of the ssDNA takes place in the formation of the (H-ssDNA)(1). These
      results indicate that the determined first step includes formation of the
      collision and an additional transition of the protein-ssDNA complex, most
      probably the local opening of the protein hexamer. The data indicate that the
      binding mechanism reflects the interactions of the ssDNA predominantly through
      the strong ssDNA-binding subsite. The analysis of the stopped-flow kinetics has
      been performed using the matrix-projection operator technique, which provides a
      powerful method to address stopped-flow kinetics, particularly, the amplitudes.
      The method allowed us to determine the specific fluorescence changes accompanying
      the formation of all the intermediates. The sequential nature of the determined
      mechanism indicates the lack of the kinetically significant conformational
      equilibrium of the DnaB hexamer as well as a transient dissociation of the
      hexamer prior to the ssDNA binding. The significance of these results for the
      functioning of the DnaB helicase is discussed.

PMID- 10656795
TI  - Post-translational modification of p53 protein in response to ionizing radiation
      analyzed by mass spectrometry.
AB  - The p53 tumor suppressor protein promotes cell cycle arrest or apoptosis in
      response to DNA damage and other forms of stress. p53 protein functions as a
      transcription factor by binding to specific DNA sequences and regulating the
      transcription of target genes. This activity of p53 is reported to be regulated
      by phosphorylation and acetylation occuring at various sites on the molecule.
      Here, we have used a direct and non-radioactive approach involving mass
      spectrometric analysis of p53 protein to identify sites that are covalently
      modified in vivo, either constitutively or in response to ionizing radiation.
      Following partial purification by immuno-affinity chromatography and enzymatic in
      gel digestion, the resulting p53 peptides were analyzed by MALDI-TOF and
      nanoelectrospray mass spectrometry. Mass spectrometry analyses identified four
      sites at the N terminus that were phosphorylated in response to irradiation, a
      single constitutive phosphorylation site at serine 315 and several acetylation
      sites.

PMID- 10656796
TI  - CcpC, a novel regulator of the LysR family required for glucose repression of the
      citB gene in Bacillus subtilis.
AB  - Synergistic carbon catabolite repression of the Bacillus subtilis aconitase
      (citB) gene by glucose and a source of 2-ketoglutarate is dependent on DNA
      sequences located upstream of the gene. Mutations in a dyad symmetry element
      centered at position -66 and in a repeat of the downstream arm of the dyad
      symmetry at position -27 cause derepressed citB expression. In this work, a
      protein able to bind to a DNA fragment containing these elements was purified and
      identified. This protein, named CcpC (Catabolite control protein C), shares
      sequence similarity with members of the LysR family of transcriptional
      regulators. In addition to binding to the citB promoter, CcpC bound to the
      promoter of the citZ gene, which encodes the cell's major citrate synthase and is
      subject to carbon catabolite repression. In a ccpC null mutant, expression of
      both citB and citZ was derepressed in glucose-glutamine minimal medium,
      indicating that CcpC is a negative regulator of citB and citZ gene expression.
      DNase I footprinting experiments showed that CcpC binds to two sites within the
      citB promoter region, corresponding to the dyad symmetry and -27 elements. In the
      presence of citrate, a putative inducer, only the dyad symmetry element was fully
      protected by CcpC. When the dyad symmetry element was mutated, CcpC was no longer
      able to bind to either the dyad symmetry or -27 elements. Repression of citB and
      citZ gene expression during anaerobiosis also proved to be mediated by CcpC.

PMID- 10656797
TI  - Sequence signals for generation of antigenic peptides by the proteasome:
      implications for proteasomal cleavage mechanism.
AB  - Proteasomal cleavage of proteins is the first step in the processing of most
      antigenic peptides that are presented to cytotoxic T cells. Still, its
      specificity and mechanism are not fully understood. To identify preferred
      sequence signals that are used for generation of antigenic peptides by the
      proteasome, we performed a rigorous analysis of the residues at the termini and
      flanking regions of naturally processed peptides eluted from MHC class I
      molecules. Our results show that both the C terminus (position P1 of the cleavage
      site) and its immediate flanking position (P1') possess significant signals. The
      N termini of the peptides show these signals only weakly, consistent with
      previous findings that antigenic peptides may be cleaved by the proteasome with N
      terminal extensions. Nevertheless, we succeed to demonstrate indirectly that the
      N-terminal cleavage sites contain the same preferred signals at position P1'.
      This reinforces previous findings regarding the role of the P1' position of a
      cleavage site in determining the cleavage specificity, in addition to the well
      known contribution of position P1. Our results apply to the generation of
      antigenic peptides and bare direct implications for the mechanism of proteasomal
      cleavage. We propose a model for proteasomal cleavage mechanism by which both
      ends of cleaved fragments are determined by the same cleavage signals, involving
      preferred residues at both P1 and P1' positions of a cleavage site. The
      compatibility of this model with experimental data on protein degradation
      products and generation of antigenic peptides is demonstrated.

PMID- 10656798
TI  - Identification of collagen fibril fusion during vertebrate tendon morphogenesis.
      The process relies on unipolar fibrils and is regulated by collagen-proteoglycan
      interaction.
AB  - The synthesis of an extracellular matrix containing long (approximately mm in
      length) collagen fibrils is fundamental to the normal morphogenesis of animal
      tissues. In this study we have direct evidence that fibroblasts synthesise
      transient early fibril intermediates (approximately 1 micrometer in length) that
      interact by tip-to-tip fusion to generate long fibrils seen in older tissues.
      Examination of early collagen fibrils from tendon showed that two types of early
      fibrils occur: unipolar fibrils (with carboxyl (C) and amino (N) ends) and
      bipolar fibrils (with two N-ends). End-to-end fusion requires the C-end of a
      unipolar fibril. Proteoglycans coated the shafts of the fibrils but not the tips.
      In the absence of proteoglycans the fibrils aggregated by side-to-side
      interactions. Therefore, proteoglycans promote tip-to-tip fusion and inhibit side
      to-side fusion. This distribution of proteoglycan along the fibril required co
      assembly of collagen and proteoglycan prior to fibril assembly. The study showed
      that collagen fibrillogenesis is a hierarchical process that depends on the
      unique structure of unipolar fibrils and a novel function of proteoglycans.

PMID- 10656799
TI  - Human plasminogen catalytic domain undergoes an unusual conformational change
      upon activation.
AB  - Activation of the serine protease plasmin from its zymogen, plasminogen, is the
      key step in fibrinolysis leading to blood clot dissolution. It also plays
      critical roles in cell migration, such as in tumor metastasis. Here, we report
      the crystal structure of an inactive S741A mutant of human plasminogen catalytic
      domain at 2.0 A resolution. This structure permits a direct comparison with that
      of the plasmin catalytic unit. Unique conformational differences are present
      between these two structures that are not seen in other zymogen-enzyme pairs of
      the trypsin family. The functional significance of these differences and the
      structural basis of plasminogen activation is discussed in the light of this new
      structure.

PMID- 10656800
TI  - The 1.5 A crystal structure of a bleomycin resistance determinant from bleomycin
      producing Streptomyces verticillus.
AB  - Bleomycin (Bm)-binding protein, designated BLMA, which is a Bm resistance
      determinant from Bm-producing Streptomyces verticillus, was crystallized in a
      form suitable for X-ray diffraction analysis. The diffraction intensity data were
      collected up to a resolution of 1.5 A with a merging R-value of 0.054 at a
      completeness of 94 %. The BLMA structure, determined by the single isomorphous
      replacement method including the anomalous scattering effect (SIR-AS) at a
      resolution of 2.0 A, was refined at 1.5 A resolution. The final R-factor was 19.0
      % and R(free) was 22.1 % including 91 water molecules. The crystal packing showed
      a dimer form, which was generated by arm exchange. The 1.5 A high-resolution
      experiment allowed an analysis of the side-chain disorder of BLMA. The structural
      comparison of BLMA with a homologous protein from Streptoalloteichus hindustanus,
      designated Shble protein, showed that a Ser100-Gly103 loop was farther from the
      groove, which is a Bm-binding site, in BLMA than in the Shble protein.
      Furthermore the hydrophobicity of the groove in BLMA is much lower than that in
      the Shble protein. The structural differences between these proteins may be
      responsible for the observation that a half-saturating concentration (K(1/2)) of
      Bm is higher for BLMA than for the Shble protein.

PMID- 10656801
TI  - X-ray structure of yeast Hal2p, a major target of lithium and sodium toxicity,
      and identification of framework interactions determining cation sensitivity.
AB  - The product of the yeast HAL2 gene (Hal2p) is an in vivo target of sodium and
      lithium toxicity and its overexpression improves salt tolerance in yeast and
      plants. Hal2p is a metabolic phosphatase which catalyses the hydrolysis of 3'
      phosphoadenosine-5'-phosphate (PAP) to AMP. It is, the prototype of an
      evolutionarily conserved family of PAP phosphatases and the engineering of sodium
      insensitive enzymes of this group may contribute to the generation of salt
      tolerant crops. We have solved the crystal structure of Hal2p in complex with
      magnesium, lithium and the two products of PAP hydrolysis, AMP and Pi, at 1.6 A
      resolution. A functional screening of random mutations of the HAL2 gene in
      growing yeast generated forms of the enzyme with reduced cation sensitivity.
      Analysis of these mutants defined a salt bridge (Glu238 ellipsis Arg152) and a
      hydrophobic bond (Va170 ellipsis Trp293) as important framework interactions
      determining cation sensitivity. Hal2p belongs to a larger superfamily of lithium
      sensitive phosphatases which includes inositol monophosphatase. The hydrophobic
      interaction mutated in Hal2p is conserved in this superfamily and its disruption
      in human inositol monophosphatase also resulted in reduced cation sensitivity.

PMID- 10656802
TI  - Crystal structure of human procathepsin X: a cysteine protease with the proregion
      covalently linked to the active site cysteine.
AB  - Human cathepsin X is one of many proteins discovered in recent years through the
      mining of sequence databases. Its sequence shows clear homology to cysteine
      proteases from the papain family, containing the characteristic residue patterns,
      including the active site. However, the proregion of cathepsin X is only 38
      residues long, the shortest among papain-like enzymes, and the cathepsin X
      sequence has an atypical insertion in the regions proximal to the active site.
      This protein was recently expressed and partially characterized biochemically.
      Unlike most other cysteine proteases from the papain family, procathepsin X is
      incapable of autoprocessing in vitro but can be processed under reducing
      conditions by exogenous cathepsin L. Atypically, the mature enzyme is primarily a
      carboxypeptidase and has extremely poor endopeptidase activity. We have
      determined the three-dimensional structure of the procathepsin X at 1.7 A
      resolution. The overall structure of the mature enzyme is characteristic for
      enzymes of the papain superfamily, but contains several novel features. Most
      interestingly, the short proregion binds to the enzyme with the aid of a covalent
      bond between the cysteine residue in the proregion (Cys10p) and the active site
      cysteine residue (Cys31). This is the first example of a zymogen in which the
      inhibition of enzyme's proteolytic activity by the proregion is achieved through
      a reversible covalent modification of the active site nucleophile. Such mode of
      binding requires less contact area between the proregion and the enzyme than
      observed in other procathepsins, and no auxiliary binding site on the enzyme
      surface is used. A three-residue insertion in a highly conserved region, just
      prior to the active site cysteine residue, confers a significantly different
      shape on the S' subsites, compared to other proteases from papain family. The 3D
      structure provides an explanation for the rather unusual carboxypeptidase
      activity of this enzyme and confirms the predictions based on homology modeling.
      Another long insertion in the cathepsin X amino acid sequence forms a beta
      hairpin pointing away from the active site. This insertion, thought to be an
      equivalent of cathepsin B occluding loop, is located on the side of the protein,
      distant from the substrate binding site.

PMID- 10656803
TI  - X-ray structures of small ligand-FKBP complexes provide an estimate for
      hydrophobic interaction energies.
AB  - A new crystal form of native FK506 binding protein (FKBP) has been obtained which
      has proved useful in ligand binding studies. Three different small molecule
      ligand complexes and the native enzyme have been determined at higher resolution
      than 2.0 A. Dissociation constants of the related small molecule ligands vary
      from 20 mM for dimethylsulphoxide to 200 microM for tetrahydrothiophene 1-oxide.
      Comparison of the four available crystal structures shows that the protein
      structures are identical to within experimental error, but there are differences
      in the water structure in the active site. Analysis of the calculated buried
      surface areas of these related ligands provides an estimated van der Waals
      contribution to the binding energy of -0.5 kJ/A(2) for non-polar interactions
      between ligand and protein.

PMID- 10656804
TI  - Relationships between protein structure and dynamics from a database of NMR
      derived backbone order parameters.
AB  - The amplitude of protein backbone NH group motions on a time-scale faster than
      molecular tumbling may be determined by analysis of (15)N NMR relaxation data
      according to the Lipari-Szabo model free formalism. An internet-accessible
      database has been compiled containing 1855 order parameters from 20 independent
      NMR relaxation studies on proteins whose three-dimensional structures are known.
      A series of statistical analyses has been performed to identify relationships
      between the structural features and backbone dynamics of these proteins.
      Comparison of average order parameters for different amino acid types indicates
      that amino acids with small side-chains tend to have greater backbone flexibility
      than those with large side-chains. In addition, the motions of a given NH group
      are also related to the sizes of the neighboring amino acids in the primary
      sequence. The secondary structural environment appears to influence backbone
      dynamics relatively weakly, with only subtle differences between the order
      parameter distributions of loop structures and regular hydrogen bonded secondary
      structure elements. However, NH groups near helix termini are more mobile on
      average than those in the central regions of helices. Tertiary structure
      influences are also relatively weak but in the expected direction, with more
      exposed residues being more flexible on average than residues that are relatively
      inaccessible to solvent.

PMID- 10656805
TI  - Canonical structures for the hypervariable regions of T cell alphabeta receptors.
AB  - T cell alphabeta receptors have binding sites for peptide-MHC complexes formed by
      six hypervariable regions. Analysis of the six atomic structures known for Valpha
      and for Vbeta domains shows that their first and second hypervariable regions
      have one of three or four different main-chain conformations (canonical
      structures). Six of these canonical structures have the same conformation in
      complexes with peptide-MHC complexes, the free receptor and/or in an isolated V
      domain. Thus, for at least the first and second hypervariable regions in the
      currently known structures, the conformation of the canonical structures is well
      defined in the free state and is conserved on formation of complexes with peptide
      MHC. We identified the key residues that are mainly responsible for the
      conformation of each canonical structure. The first and second hypervariable
      regions of Valpha and Vbeta domains are encoded by the germline V segments.
      Humans have 37 functional Valpha segments and 47 Vbeta segments, and mice have 20
      Vbeta segments. Inspection of the size of their hypervariable regions, and of
      sites that contain key residues, indicates that close to 70 % of Valpha segments
      and 90 % of Vbeta segments have hypervariable regions with a conformation of one
      of the known canonical structures. The alpha and beta V gene segments in both
      humans and mice have only a few combinations of different canonical structure in
      their first and second hypervariable regions. In human Vbeta domains, the number
      of different sequences with these canonical structure combinations is larger than
      in mice, whilst for Valpha domains it is probably smaller.

PMID- 10656806
TI  - A synthetic peptide initiates Gerstmann-Straussler-Scheinker (GSS) disease in
      transgenic mice.
AB  - The molecular basis of the infectious, inherited and sporadic forms of prion
      diseases is best explained by a conformationally dimorphic protein that can exist
      in distinct normal and disease-causing isoforms. We identified a 55-residue
      peptide of a mutant prion protein that can be refolded into at least two distinct
      conformations. When inoculated intracerebrally into the appropriate transgenic
      mouse host, 20 of 20 mice receiving the beta-form of this peptide developed signs
      of central nervous system dysfunction at approximately 360 days, with
      neurohistologic changes that are pathognomonic of Gerstmann-Straussler-Scheinker
      disease. By contrast, eight of eight mice receiving a non-beta-form of the
      peptide failed to develop any neuropathologic changes more than 600 days after
      the peptide injections. We conclude that a chemically synthesized peptide
      refolded into the appropriate conformation can accelerate or possibly initiate
      prion disease.

PMID- 10656807
TI  - Analysis of JNK, Mdm2 and p14(ARF) contribution to the regulation of mutant p53
      stability.
AB  - Identification of Mdm2 and JNK as proteins that target degradation of wt p53
      prompted us to examine their effect on mutant p53, which exhibits a prolonged
      half-life. Of five mutant p53 forms studied for association with the targeting
      molecules, two no longer bound to Mdm2 and JNK. Three mutant forms, which exhibit
      high expression levels, showed lower affinity for association with Mdm2 and JNK
      in concordance with greater affinity to p14(ARF), which is among the stabilizing
      p53 molecules. Monitoring mutant p53 stability in vitro confirmed that, while
      certain forms of mutant p53 are no longer affected by either JNK or Mdm2, others
      are targeted for degradation by JNK/Mdm2, albeit at lower efficiency when
      compared with wt p53. Expression of wt p53 in tumor cells revealed a short half
      life, suggesting that the targeting molecules are functional. Forced expression
      of mutant p53 in p53 null cells confirmed pattern of association with JNK/Mdm2
      and prolonged half-life, as found in the tumor cells. Over-expression of Mdm2 in
      either tumor (which do express endogenous functional Mdm2) or in p53 null cells
      decreased the stability of mutant p53 suggesting that, despite its expression,
      Mdm2/JNK are insufficient (amount/affinity) for targeting mutant p53 degradation.
      Based on both in vitro and in vivo analyses, we conclude that the prolonged half
      life of mutant p53 depends on the nature of the mutation, which either alters
      association with targeting molecules, ratio between p53 and targeting/stabilizing
      molecules or targeting efficiency.

PMID- 10656808
TI  - Protein-protein interaction revealed by NMR T(2) relaxation experiments: the
      lipoyl domain and E1 component of the pyruvate dehydrogenase multienzyme complex
      of Bacillus stearothermophilus.
AB  - T(2) relaxation experiments in combination with chemical shift and site-directed
      mutagenesis data were used to identify sites involved in weak but specific
      protein-protein interactions in the pyruvate dehydrogenase multienzyme complex of
      Bacillus stearothermophilus. The pyruvate decarboxylase component, a
      heterotetramer E1(alpha(2)beta(2)), is responsible for the first committed and
      irreversible catalytic step. The accompanying reductive acetylation of the lipoyl
      group attached to the dihydrolipoyl acetyltransferase (E2) component involves
      weak, transient but specific interactions between E1 and the lipoyl domain of the
      E2 polypeptide chain. The interactions between the free lipoyl domain (9 kDa) and
      free E1alpha (41 kDa), E1beta (35 kDa) and intact E1alpha(2)beta(2) (152 kDa)
      components, all the products of genes or sub-genes over-expressed in Escherichia
      coli, were investigated using heteronuclear 2D NMR spectroscopy. The experiments
      were conducted with uniformly (15)N-labeled lipoyl domain and unlabeled E1
      components. Major contact points on the lipoyl domain were identified from
      changes in the backbone (15)N spin-spin relaxation time in the presence and
      absence of E1(alpha(2)beta(2)) or its individual E1alpha or E1beta components.
      Although the E1alpha subunit houses the sequence motif associated with the
      essential cofactor, thiamin diphosphate, recognition of the lipoyl domain was
      distributed over sites in both E1alpha and E1beta. A single point mutation (N40A)
      on the lipoyl domain significantly reduces its ability to be reductively
      acetylated by the cognate E1. None the less, the N40A mutant domain appears to
      interact with E1 similarly to the wild-type domain. This suggests that the lipoyl
      group of the N40A lipoyl domain is not being presented to E1 in the correct
      orientation, owing perhaps to slight perturbations in the lipoyl domain
      structure, especially in the lipoyl-lysine beta-turn region, as indicated by
      chemical shift data. Interaction with E1 and subsequent reductive acetylation are
      not necessarily coupled.

PMID- 10656809
TI  - Structural clues in the sequences of the aquaporins.
AB  - The large number of sequences available for the aquaporin family represents a
      valuable source of information to incorporate into three-dimensional structure
      determination. Phylogenetic analysis was used to define type sequences to avoid
      extreme over-representation of some subfamilies, and as a measure of the quality
      of multiple sequence alignment. Inspection of the sequence alignment suggested
      eight conserved segments that define the core architecture of six transmembrane
      helices and two functional loops, B and E, projecting into the plane of the
      membrane. The sum of the core segments and the minimum lengths of the
      interlinking loops constitute the 208 residues necessary to satisfy the aquaporin
      architecture. Analysis of hydrophobic and conservation periodicity and of
      correlated mutations across the alignment indicated the likely assignment and
      orientation of the helices in the bilayer. This assignment is examined with
      respect to the structure of the erythrocyte aquaporin 1 determined by electron
      crystallography. The aquaporin 1 tetramer is described as three rings of helices,
      each ring with a different exposure to the lipid environment. The sequence
      analysis clearly suggests that two helices are exposed along their whole lengths,
      two helices are exposed only at their N termini, and two helices are not exposed
      to lipid. It is further proposed that, besides loops B and E, the highly
      conserved motifs on helices 1 and 4, ExxxTxxF/L, could line the water channel.

PMID- 10656810
TI  - Identification of a penta- and hexapeptide of islet amyloid polypeptide (IAPP)
      with amyloidogenic and cytotoxic properties.
AB  - Pancreatic amyloid is found in more than 95 % of type II diabetes patients.
      Pancreatic amyloid is formed by the aggregation of islet amyloid polypeptide
      (hIAPP or amylin), which is a 37-residue peptide. Because pancreatic amyloid is
      cytotoxic, it is believed that its formation is directly associated with the
      development of the disease. We recently showed that hIAPP amyloid formation
      follows the nucleation-dependent polymerization mechanism and proceeds via a
      conformational transition of soluble hIAPP into aggregated beta-sheets. Here, we
      report that the penta- and hexapeptide sequences, hIAPP(23-27) (FGAIL) and
      hIAPP(22-27) (NFGAIL) of hIAPP are sufficient for the formation of beta-sheet
      containing amyloid fibrils. Although these two peptides differ by only one amino
      acid residue, they aggregate into completely different fibrillar assemblies.
      hIAPP(23-27) (FGAIL) fibrils self-assemble laterally into unusually broad
      ribbons, whereas hIAPP(22-27) (NFGAIL) fibrils coil around each other in a
      typical amyloid fibril morphology. hIAPP(20-27) (SNNFGAIL) also aggregates into
      beta-sheet-containing fibrils, whereas no amyloidogenicity is found for hIAPP(24
      27) (GAIL), indicating that hIAPP(23-27) (FGAIL) is the shortest fibrillogenic
      sequence of hIAPP. Insoluble amyloid formation by the partial hIAPP sequences
      followed kinetics that were consistent with a nucleation-dependent polymerization
      mechanism. hIAPP(22-27) (NFGAIL), hIAPP(20-27) (SNNFGAIL), and also the known
      fibrillogenic sequence, hIAPP(20-29) (SNNFGAILSS) exhibited significantly lower
      kinetic and thermodynamic solubilities than the pentapeptide hIAPP(23-27)
      (FGAIL). Fibrils formed by all short peptide sequences and also by hIAPP(20-29)
      were cytotoxic towards the pancreatic cell line RIN5fm, whereas no cytotoxicity
      was observed for the soluble form of the peptides, a notion that is consistent
      with hIAPP cytotoxicity. Our results suggest that a penta- and hexapeptide
      sequence of an appropriate amino acid composition can be sufficient for beta
      sheet and amyloid fibril formation and cytotoxicity and may assist in the
      rational design of inhibitors of pancreatic amyloid formation or other
      amyloidosis-related diseases.

PMID- 10656811
TI  - PYD2 encodes 5,6-dihydropyrimidine amidohydrolase, which participates in a novel
      fungal catabolic pathway.
AB  - Most fungi cannot use pyrimidines or their degradation products as the sole
      nitrogen source. Previously, we screened several yeasts for their ability to
      catabolise pyrimidines. One of them, Saccharomyces kluyveri, was able to degrade
      the majority of pyrimidines. Here, a series of molecular techniques have been
      modified to clone pyrimidine catabolic genes, study their expression and purify
      the corresponding enzymes from this yeast. The pyd2-1 mutant, which lacked the
      5,6-dihydropyrimidine amidohydrolase (DHPase) activity, was transformed with wild
      type S. kluyveri genomic library. The complementing plasmid contained the full
      sequence of the PYD2 gene, which exhibited a high level of homology with
      mammalian DHPases and bacterial hydantoinases. The organisation of PYD2 showed a
      couple of specific features. The 542-codons open reading frame was interrupted by
      a 63 bp intron, which does not contain the Saccharomyces cerevisiae branch-point
      sequence, and the transcripts contained a long 5' untranslated leader with five
      or six AUG codons. The derived amino acid sequence showed similarities with
      dihydroorotases, allantoinases and uricases from various organisms. Surprisingly,
      the URA4 gene from S. cerevisiae, which encodes dihydroorotase, shows greater
      similarity to PYD2 and other catabolic enzymes than to dihydroorotases from
      several other non-fungal organisms. The S. kluyveri DHPase was purified to
      homogeneity and sequencing of the N-terminal region revealed that the purified
      enzyme corresponds to the PYD2 gene product. The enzyme is a tetramer, likely
      consisting of similar if not identical subunits each with a molecular mass of 59
      kDa. The S. kluyveri DHPase was capable of catalysing both dihydrouracil and
      dihydrothymine degradation, presumably by the same reaction mechanism as that
      described for mammalian DHPase. On the other hand, the regulation of the yeast
      PYD2 gene and DHPase seem to be different from that in other organisms. DHPase
      activity and Northern analysis demonstrated that PYD2 expression is inducible by
      dihydrouracil, though not by uracil. Apparently, dihydrouracil and DHPase
      represent an important regulatory checkpoint of the pyrimidine catabolic pathway
      in S. kluyveri.

PMID- 10656812
TI  - DNA supercoiling during ATP-dependent DNA translocation by the type I restriction
      enzyme EcoAI.
AB  - Type I restriction enzymes cleave DNA at non-specific sites far from their
      recognition sequence as a consequence of ATP-dependent DNA translocation past the
      enzyme. During this reaction, the enzyme remains bound to the recognition
      sequence and translocates DNA towards itself simultaneously from both directions,
      generating DNA loops, which appear to be supercoiled when visualised by electron
      microscopy. To further investigate the mechanism of DNA translocation by type I
      restriction enzymes, we have probed the reaction intermediates with DNA
      topoisomerases. A DNA cleavage-deficient mutant of EcoAI, which has normal DNA
      translocation and ATPase activities, was used in these DNA supercoiling assays.
      In the presence of eubacterial DNA topoisomerase I, which specifically removes
      negative supercoils, the EcoAI mutant introduced positive supercoils into relaxed
      plasmid DNA substrate in a reaction dependent on ATP hydrolysis. The same DNA
      supercoiling activity followed by DNA cleavage was observed with the wild-type
      EcoAI endonuclease. Positive supercoils were not seen when eubacterial DNA
      topoisomerase I was replaced by eukaryotic DNA topoisomerase I, which removes
      both positive and negative supercoils. Furthermore, addition of eukaryotic DNA
      topoisomerase I to the product of the supercoiling reaction resulted in its rapid
      relaxation. These results are consistent with a model in which EcoAI
      translocation along the helical path of closed circular DNA duplex simultaneously
      generates positive supercoils ahead and negative supercoils behind the moving
      complex in the contracting and expanding DNA loops, respectively. In addition, we
      show that the highly positively supercoiled DNA generated by the EcoAI mutant is
      cleaved by EcoAI wild-type endonuclease much more slowly than relaxed DNA. This
      suggests that the topological changes in the DNA substrate associated with DNA
      translocation by type I restriction enzymes do not appear to be the trigger for
      DNA cleavage.

PMID- 10656813
TI  - Lead is unusually effective in sequence-specific folding of DNA.
AB  - DNA quadruplex structures based on the guanine quartet are typically stabilized
      by monovalent cations such as K(+), Na(+), or NH(+)(3). Certain divalent cations
      can also induce quadruplex formation, such as Sr(2+). Here we show that Pb(2+)
      binds with unusually high affinity to the thrombin binding aptamer,
      d(GGTTGGTGTGGTTGG), inducing a unimolecular folded structure. At micromolar
      concentrations the binding is stoichiometric, and a single lead cation suffices
      to fold the aptamer. The lead-induced changes in UV and CD spectra are
      characteristic of folded quadruplexes, although the long wavelength CD maximum
      occurs at 312 nm rather than the typical value of 293 nm. The one-dimensional
      exchangeable proton NMR spectrum shows resonances expected for imino protons
      involved in guanine quartet base-pairing. Furthermore, two-dimensional NMR
      experiments reveal NOE contacts typically seen in folded structures formed by
      guanine quartets, such as the K(+) form of the thrombin aptamer. Only sequences
      capable of forming guanine quartets appear to bind Pb(+2) tightly and change
      conformation. This sequence-specific, tight DNA binding may be relevant to
      possible genotoxic effects of lead in the environment.

PMID- 10656814
TI  - Domain III of Saccharomyces cerevisiae 25 S ribosomal RNA: its role in binding of
      ribosomal protein L25 and 60 S subunit formation.
AB  - Domain III of Saccharomyces cerevisiae 25 S rRNA contains the recognition site
      for the primary rRNA-binding ribosomal protein L25, which belongs to the
      functionally conserved EL23/L25 family of ribosomal proteins. The EL23/L25
      binding region is very complex, consisting of several irregular helices held
      together by long-distance secondary and tertiary interactions. Moreover, it
      contains the eukaryote-specific V9 (D7a) expansion segment. Functional
      characterisation of the structural elements of this site by a detailed in vitro
      and in vivo mutational analysis indicates the presence of two separate regions
      that are directly involved in L25 binding. In particular, mutation of either of
      two conserved nucleotides in the loop of helix 49 significantly reduces in vitro
      L25 binding, thus strongly supporting their role as attachment sites for the r
      protein. Two other helices appear to be primarily required for the correct
      folding of the binding site. Mutations that abolish in vitro binding of L25 block
      accumulation of 25 S rRNA in vivo because they stall pre-rRNA processing at the
      level of its immediate precursor, the 27 S(B) pre-rRNA. Surprisingly, several
      mutations that do not significantly affect L25 binding in vitro cause the same
      lethal defect in 27 S(B) pre-rRNA processing. Deletion of the V9 expansion
      segment also leads to under-accumulation of mature 25 S rRNA and a twofold
      reduction in growth rate. We conclude that an intact domain III, including the V9
      expansion segment, is essential for normal processing and assembly of 25 S rRNA.

PMID- 10656815
TI  - Mapping RNA-protein interactions in ribonuclease P from Escherichia coli using
      disulfide-linked EDTA-Fe.
AB  - The protein subunit of Escherichia coli ribonuclease P (which has a cysteine
      residue at position 113) and its single cysteine-substituted mutant derivatives
      (S16C/C113S, K54C/C113S and K66C/C113S) have been modified using a sulfhydryl
      specific iron complex of EDTA-2- aminoethyl 2-pyridyl disulfide (EPD-Fe). This
      reaction converts C5 protein, or its single cysteine-substituted mutant
      derivatives, into chemical nucleases which are capable of cleaving the cognate
      RNA ligand, M1 RNA, the catalytic RNA subunit of E. coli RNase P, in the presence
      of ascorbate and hydrogen peroxide. Cleavages in M1 RNA are expected to occur at
      positions proximal to the site of contact between the modified residue (in C5
      protein) and the ribose units in M1 RNA. When EPD-Fe was used to modify residue
      Cys16 in C5 protein, hydroxyl radical-mediated cleavages occurred predominantly
      in the P3 helix of M1 RNA present in the reconstituted holoenzyme. C5 Cys54-EDTA
      Fe produced cleavages on the 5' strand of the P4 pseudoknot of M1 RNA, while the
      cleavages promoted by C5 Cys66-EDTA-Fe were in the loop connecting helices P18
      and P2 (J18/2) and the loop (J2/4) preceding the 3' strand of the P4 pseudoknot.
      However, hydroxyl radical-mediated cleavages in M1 RNA were not evident with
      Cys113-EDTA-Fe, perhaps indicative of Cys113 being distal from the RNA-protein
      interface in the RNase P holoenzyme. Our directed hydroxyl radical-mediated
      footprinting experiments indicate that conserved residues in the RNA and protein
      subunit of the RNase-P holoenzyme are adjacent to each other and provide
      structural information essential for understanding the assembly of RNase P.

PMID- 10656816
TI  - Does a single metal ion bridge the A-9 and scissile phosphate groups in the
      catalytically active hammerhead ribozyme structure?
AB  - We have constructed a model structure that we believe represents the strongest
      possible physically and chemically reasonable representation of a hypothesized
      catalytically active hammerhead ribozyme structure in which a single divalent
      metal ion bridges the A9 and scissile phosphate groups. It has been proposed that
      such a structure arises from a conformational change in which the so-called
      ground-state structure (as observed by X-ray crystallography) rearranges in such
      a way that the pro-R oxygen atoms of both the A9 and scissile phosphate groups
      are directly coordinated by a single divalent metal ion in the transition-state
      of the hammerhead ribozyme cleavage reaction. We show that even the small subset
      of possible model structures that are consistent with these requirements, and
      that are stereochemically and sterically reasonable, are contradicted by
      experimental evidence. We also demonstrate that even a minimal subset of
      assumptions, i.e. that stems I and II are helical and that the two phosphate
      groups are coordinated by a divalent metal ion in the standard octahedral
      geometry, are sufficient to lead to this contradiction. We therefore conclude
      that such a mechanism of hammerhead ribozyme catalysis is untenable, at least in
      its present formulation.

PMID- 10656817
TI  - Nick recognition by DNA ligases.
AB  - Phage T7 DNA ligase seals nicked DNA substrates and is a representative member of
      the ATP-dependent class of DNA ligases. Although the catalytic mechanism of DNA
      ligases has been delineated, little is known about the nature of nick recognition
      by these enzymes. Here, we show that T7 ligase discriminates, at the nick-binding
      step, between nicks containing either a 5'-phosphate or a 5'-OH. T7 ligase binds
      preferentially to phosphorylated nicks and catalyses the sealing reaction. We
      also show using DNA footprinting studies, that T7 ligase binds asymmetrically to
      nicks as a monomer, with the protein interface covering between 12 and 14 bp of
      DNA. Based on molecular modelling studies we propose a structural model of the
      ligase-DNA complex consistent with these and other data. Using photo-crosslinking
      and site-directed mutagenesis we have identified two residues, K238 and K240,
      critical for the transadenylation and nick-sealing reactions. Sequence
      conservation and structural analysis supports the premise that these two lysine
      residues are critical for both nucleotide binding and DNA nick recognition. The
      implications of these results on the ligation mechanism are discussed.

PMID- 10656818
TI  - Fully synthetic human combinatorial antibody libraries (HuCAL) based on modular
      consensus frameworks and CDRs randomized with trinucleotides.
AB  - By analyzing the human antibody repertoire in terms of structure, amino acid
      sequence diversity and germline usage, we found that seven V(H) and seven V(L)
      (four Vkappa and three Vlambda) germline families cover more than 95 % of the
      human antibody diversity used. A consensus sequence was derived for each family
      and optimized for expression in Escherichia coli. In order to make all six
      complementarity determining regions (CDRs) accessible for diversification, the
      synthetic genes were designed to be modular and mutually compatible by
      introducing unique restriction endonuclease sites flanking the CDRs. Molecular
      modeling verified that all canonical classes were present. We could show that all
      master genes are expressed as soluble proteins in the periplasm of E. coli. A
      first set of antibody phage display libraries totalling 2x10(9) members was
      created after cloning the genes in all 49 combinations into a phagemid vector,
      itself devoid of the restriction sites in question. Diversity was created by
      replacing the V(H) and V(L) CDR3 regions of the master genes by CDR3 library
      cassettes, generated from mixed trinucleotides and biased towards natural human
      antibody CDR3 sequences. The sequencing of 257 members of the unselected
      libraries indicated that the frequency of correct and thus potentially functional
      sequences was 61 %. Selection experiments against many antigens yielded a diverse
      set of binders with high affinities. Due to the modular design of all master
      genes, either single binders or even pools of binders can now be rapidly
      optimized without knowledge of the particular sequence, using pre-built CDR
      cassette libraries. The small number of 49 master genes will allow future
      improvements to be incorporated quickly, and the separation of the frameworks may
      help in analyzing why nature has evolved these distinct subfamilies of antibody
      germline genes.

PMID- 10656819
TI  - Display of active subtilisin 309 on phage: analysis of parameters influencing the
      selection of subtilisin variants with changed substrate specificity from
      libraries using phosphonylating inhibitors.
AB  - Many attempts have been made to endow enzymes with new catalytic activities. One
      general strategy involves the creation of random combinatorial libraries of
      mutants associated with an efficient screening or selection scheme. Phage display
      has been shown to greatly facilitate the selection of polypeptides with desired
      properties by establishing a close link between the polypeptide and the gene that
      encodes it. Selection of phage displayed enzymes for new catalytic activities
      remains a challenge. The aim of this study was to display the serine protease
      subtilisin 309 (savinase) from Bacillus lentus on the surface of filamentous fd
      phage and to develop selection schemes that allow the extraction of subtilisin
      variants with a changed substrate specificity from libraries. Subtilisins are
      produced as secreted preproenzyme that mature in active enzyme autocatalytically.
      They have a broad substrate specificity but exhibit a significant preference for
      hydrophobic residues and very limited reactivity toward charged residues at the
      P4 site in the substrate. Here, we show that savinase can be functionally
      displayed on phage in the presence of the proteic inhibitor CI2. The free enzyme
      is released from its complex with CI2 upon addition of the anionic detergent LAS.
      The phage-enzyme can be panned on streptavidin beads after labelling by reaction
      with (biotin-N-epsilon-aminocaproyl-cystamine-N'-glutaryl)-l-Ala-l-Ala-l-P ro
      Phe(P)-diphenyl ester. Reactions of libraries, in which residues 104 and 107
      forming part of the S4 pocket have been randomised, with (biotin-N-epsilon
      aminocaproyl-cystamine-N'-glutaryl)-alpha-l-Lys-l-A la-l-Pro-Phe(P)-diphenylester
      allowed us to select enzymes with increased specific activity for a substrate
      containing a lysine in P4. Parameters influencing the selection as for instance
      the efficiency of maturation of mutant enzymes in libraries have been
      investigated.

PMID- 10656820
TI  - In vitro packaging of DNA of the Bacillus subtilis bacteriophage SPP1.
AB  - In vitro packaging of bacteriophage SPP1 DNA into procapsids is described and the
      requirements of this process were determined. Combination of proheads with an
      extract supplying terminase, DNA and phage tails yielded up to 10(7 )viable
      phages per milliliter of in vitro reaction under optimized conditions. The
      presence of neutral polymers and polyamines had a concentration and type
      dependent effect in the packaging reaction. The terminase donor extract lost
      rapidly activity at 30 degrees C in contrast to the stability of the prohead
      donor extract. Maturation to infective virions was observed using both procapsids
      assembled in SPP1 infected cells and procapsid-like structures assembled in
      Escherichia coli that overexpressed the SPP1 prohead gene clusters. Neither a
      majority of aberrant capsid-related structures present in the latter material nor
      procapsids lacking the portal protein inhibited DNA packaging. Addition of
      purified portal protein reduced DNA packaging activity in vitro only at
      concentrations 20-fold higher than those found in the SPP1 infected cell. The
      SPP1 DNA packaged in vitro originated exclusively from the terminase donor
      extract. This packaging selectivity was not observed in vivo during mixed
      infections. The data are compatible with a model for processive headful DNA
      packaging in which terminase and DNA co-produced in the same cell are tightly
      associated and can effectively discriminate the portal vertex of DNA packaging
      proficient proheads from aberrant structures, from portal-less procapsids, and
      from isolated portal protein.

PMID- 10656821
TI  - Shape and DNA packaging activity of bacteriophage SPP1 procapsid: protein
      components and interactions during assembly.
AB  - The procapsid of the Bacillus subtilis bacteriophage SPP1 is formed by the major
      capsid protein gp13, the scaffolding protein gp11, the portal protein gp6, and
      the accessory protein gp7. The protein stoichiometry suggests a T=7 symmetry for
      the SPP1 procapsid. Overexpression of SPP1 procapsid proteins in Escherichia coli
      leads to formation of biologically active procapsids, procapsid-like, and
      aberrant structures. Co-production of gp11, gp13 and gp6 is essential for
      assembly of procapsids competent for DNA packaging in vitro. Presence of gp7 in
      the procapsid increases the yield of viable phages assembled during the reaction
      in vitro five- to tenfold. Formation of closed procapsid-like structures requires
      uniquely the presence of the major head protein and the scaffolding protein. The
      two proteins interact only when co-produced but not when mixed in vitro after
      separate synthesis. Gp11 controls the polymerization of gp13 into normal (T=7)
      and small sized (T=4?) procapsids. Predominant formation of T=7 procapsids
      requires presence of the portal protein. This implies that the portal protein has
      to be integrated at an initial stage of the capsid assembly process. Its
      presence, however, does not have a detectable effect on the rate of procapsid
      assembly during SPP1 infection. A stable interaction between gp6 and the two
      major procapsid proteins was only detected when the three proteins are co
      produced. Efficient incorporation of a single portal protein in the procapsid
      appears to require a structural context created by gp11 and gp13 early during
      assembly, rather than strong interactions with any of those proteins. Gp7, which
      binds directly to gp6 both in vivo and in vitro, is not necessary for
      incorporation of the portal protein in the procapsid structure.

PMID- 10656822
TI  - Fast folding of a ribozyme by stabilizing core interactions: evidence for
      multiple folding pathways in RNA.
AB  - Folding of the Tetrahymena ribozyme under physiological conditions in vitro is
      limited by slow conversion of long-lived intermediates to the active structure.
      These intermediates arise because the most stable domain of the ribozyme folds 10
      50 times more rapidly than the core region containing helix P3. Native gel
      electrophoresis and time-resolved X-ray-dependent hydroxyl radical cleavage
      revealed that mutations that weaken peripheral interactions between domains
      accelerated folding fivefold, while a point mutation that stabilizes P3 enabled
      80 % of the mutant RNA to reach the native conformation within 30 seconds at 22
      degrees C. The P3 mutation increased the folding rate of the catalytic core as
      much as 50-fold, so that both domains of the ribozyme were formed at
      approximately the same rate. The results show that the ribozyme folds rapidly
      without significantly populating metastable intermediates when native
      interactions in the ribozyme core are stabilized relative to peripheral
      structural elements.

PMID- 10656823
TI  - Cu,Zn superoxide dismutase structure from a microbial pathogen establishes a
      class with a conserved dimer interface.
AB  - Macrophages and neutrophils protect animals from microbial infection in part by
      issuing a burst of toxic superoxide radicals when challenged. To counteract this
      onslaught, many Gram-negative bacterial pathogens possess periplasmic Cu,Zn
      superoxide dismutases (SODs), which act on superoxide to yield molecular oxygen
      and hydrogen peroxide. We have solved the X-ray crystal structure of the Cu,Zn
      SOD from Actinobacillus pleuropneumoniae, a major porcine pathogen, by molecular
      replacement at 1.9 A resolution. The structure reveals that the dimeric bacterial
      enzymes form a structurally homologous class defined by a water-mediated dimer
      interface, and share with all Cu,Zn SODs the Greek-key beta-barrel subunit fold
      with copper and zinc ions located at the base of a deep loop-enclosed active-site
      channel. Our structure-based sequence alignment of the bacterial enzymes explains
      the monomeric nature of at least two of these, and suggests that there may be at
      least one additional structural class for the bacterial SODs. Two metal-mediated
      crystal contacts yielded our C222(1) crystals, and the geometry of these sites
      could be engineered into proteins recalcitrant to crystallization in their native
      form. This work highlights structural differences between eukaryotic and
      prokaryotic Cu,Zn SODs, as well as similarities and differences among prokaryotic
      SODs, and lays the groundwork for development of antimicrobial drugs that
      specifically target periplasmic Cu,Zn SODs of bacterial pathogens.

PMID- 10656824
TI  - Crystal structure at 2.4 A resolution of E. coli serine hydroxymethyltransferase
      in complex with glycine substrate and 5-formyl tetrahydrofolate.
AB  - Serine hydroxymethyltransferase (EC 2.1.2.1), a member of the alpha-class of
      pyridoxal phosphate enzymes, catalyzes the reversible interconversion of serine
      and glycine, changing the chemical bonding at the C(alpha)-C(beta) bond of the
      serine side-chain mediated by the pyridoxal phosphate cofactor. Scission of the
      C(alpha)-C(beta) bond of serine substrate produces a glycine product and most
      likely formaldehyde, which reacts without dissociation with
      tetrahydropteroylglutamate cofactor. Crystal structures of the human and rabbit
      cytosolic serine hydroxymethyltransferases (SHMT) confirmed their close
      similarity in tertiary and dimeric subunit structure to each other and to
      aspartate aminotransferase, the archetypal alpha-class pyridoxal 5'-phosphate
      enzyme. We describe here the structure at 2.4 A resolution of Escherichia coli
      serine hydroxymethyltransferase in ternary complex with glycine and 5-formyl
      tetrahydropteroylglutamate, refined to an R-factor value of 17.4 % and R(free)
      value of 19.6 %. This structure reveals the interactions of both cofactors and
      glycine substrate with the enzyme. Comparison with the E. coli aspartate
      aminotransferase structure shows the distinctions in sequence and structure which
      define the folate cofactor binding site in serine hydroxymethyltransferase and
      the differences in orientation of the amino terminal arm, the evolution of which
      was necessary for elaboration of the folate binding site. Comparison with the
      unliganded rabbit cytosolic serine hydroxymethyltransferase structure identifies
      changes in the conformation of the enzyme, similar to those observed in aspartate
      aminotransferase, that probably accompany the binding of substrate. The
      tetrameric quaternary structure of liganded E. coli serine
      hydroxymethyltransferase also differs in symmetry and relative disposition of the
      functional tight dimers from that of the unliganded eukaryotic enzymes. SHMT
      tetramers have surface charge distributions which suggest distinctions in folate
      binding between eukaryotic and E. coli enzymes. The structure of the E. coli
      ternary complex provides the basis for a thorough investigation of its mechanism
      through characterization and structure determination of site mutants.

PMID- 10656825
TI  - The solution structure of ribosomal protein L36 from Thermus thermophilus reveals
      a zinc-ribbon-like fold.
AB  - We have determined the solution NMR structure of the ribosomal protein L36 from
      Thermus thermophilus. L36 is the smallest protein in the large subunit of the
      prokaryotic ribosome. The sequence contains three completely conserved cysteine
      residues and one conserved histidine residue in a C-X(2)-C-X(12)-C-X(4)-H motif.
      Extended X-ray absorption fine structure spectroscopy was used to confirm that a
      purified L36 sample contains an equimolar amount of zinc. The structure of L36
      was determined using simulated annealing based on NOE distance restraints,
      dihedral angle restraints and hydrogen bond distance restraints derived from NMR
      spectra of (15)N-labeled and non-labeled L36 samples at pH 7 and 12 degrees C,
      and by imposing tetrahedral zinc ion coordination geometry. The L36 fold is
      characterized by a triple-stranded antiparallel beta-sheet with the zinc-binding
      site at one end. The structure of the zinc site is well-determined and shows that
      the three cysteine sulphur atoms are supported by hydrogen bonds to backbone
      amide protons. The conserved histidine residue is located in a short 3(10)-helix
      and coordinates zinc by the N(delta1) atom. The electrostatic surface potential
      and location of conserved Arg, Lys and His side-chains suggest a large continuous
      L36-rRNA interaction interface. The folding topology as well as position and
      conformation of many conserved side-chains in L36 are very similar to those of
      zinc-ribbon domains found in the archaeal transcription factor TFIIB N terminus
      and the eukaryal transcription elongation factor hTFIIS C terminus. Given the
      relative antiquity of the ribosome it is possible that L36 reflects the parent of
      transcription-related zinc ribbons.

PMID- 10656826
TI  - Exploring local and non-local interactions for protein stability by structural
      motif engineering.
AB  - In order to probe the relative contribution of local and non-local interactions
      to the thermodynamic stability of proteins, we have devised an experimental
      approach based on a combination of motif engineering and sequence shuffling.
      Candidate chain segments in an immunoglobulin V(L) domain were identified whose
      conformation is proposed to be dominated by non-local interactions. Locally
      interacting structural motifs of a different conformation were then constructed
      as replacements, by introducing motif consensus sequences. We find that all nine
      replacements we constructed systematically reduce the folding cooperativity. By
      comparing this destabilising effect with the folding transitions of shuffled
      sequences for three of these motifs, we estimate the contribution of local,
      native interactions to the free energy of folding. Our results suggest that local
      and non-local interactions contribute to stability by an approximately equal
      amount, but that local interactions stabilise by increasing the resistance to
      denaturation while non-local interactions increase folding cooperativity. The
      systematic loss of stability by sequence shuffling in these host-guest
      experiments suggests that the designed interactions indeed are present in the
      native state, thus consensus sequence engineering may be a useful tool in
      structure design, but non-local interactions must be taken into account for
      global stability engineering. Statistical approaches are powerful tools for
      engineering protein structure and stability, but an analysis based on local
      sequence propensities alone does not adequately represent the balance of sequence
      and context in protein structures.

PMID- 10656827
TI  - Free energy landscapes of peptides by enhanced conformational sampling.
AB  - The free energy landscapes of peptide conformations in water have been observed
      by the enhanced conformational sampling method, applying the selectively enhanced
      multicanonical molecular dynamics simulations. The conformations of the peptide
      dimers, -Gly-Gly-, -Gly-Ala-, -Gly-Ser-, -Ala-Gly-, -Asn-Gly-, -Pro-Gly-, -Pro
      Ala-, and -Ala-Ala-, which were all blocked with N-terminal acetyl and C-terminal
      N-methyl groups, were individually sampled with the explicit TIP3P water
      molecules. From each simulation trajectory, we obtained the canonical ensemble at
      300 K, from which the individual three-dimensional landscape was drawn by the
      potential of mean force using the three reaction coordinates: the backbone
      dihedral angle, psi, of the first amino acid, the backbone dihedral angle, phi,
      of the second amino acid, and the distance between the carbonyl oxygen of the N
      terminal acetyl group and the C-terminal amide proton. The most stable state and
      several meta-stable states correspond to extended conformations and typical beta
      turn conformations, and their free energy values were accounted for from the
      potentials of mean force at the states. In addition, the contributions from the
      intra-molecular energies of peptides and those from the hydration effects were
      analyzed. Consequently, the stable beta-turn conformations in the free energy
      landscape were consistent with the empirically preferred beta-turn types for each
      amino acid sequence. The thermodynamic values for the hydration effect were
      decomposed and they correlated well with the empirical values estimated from the
      solvent accessible surface area of each molecular conformation during the
      trajectories. The origin of the architecture of protein local fragments was
      analyzed from the viewpoint of the free energy and its decomposed factors.

PMID- 10656828
TI  - Measuring denatured state energetics: deviations from random coil behavior and
      implications for the folding of iso-1-cytochrome c.
AB  - The changes in the free energy of the denatured state of a set of yeast iso-1
      cytochrome c variants with single surface histidine residues have been measured
      in 3 M guanidine hydrochloride. The thermodynamics of unfolding by guanidine
      hydrochloride is also reported. All variants have decreased stability relative to
      the wild-type protein. The free energy of the denatured state was determined in 3
      M guanidine hydrochloride by evaluating the strength of heme-histidine ligation
      through determination of the pK(a) for loss of histidine binding to the heme. The
      data are corrected for the presence of the N-terminal amino group which also
      ligates to the heme under similar solution conditions. Significant deviations
      from random coil behavior are observed. Relative to a variant with a single
      histidine at position 26, residual structure of the order of -1.0 to -2.5
      kcal/mol is seen for the other variants studied. The data explain the slower
      folding of yeast iso-1-cytochrome c relative to the horse protein. The greater
      number of histidines and the greater strength of ligation are expected to slow
      conversion of the histidine-misligated forms to the obligatory aquo-heme
      intermediate during the ligand exchange phase of folding. The particularly strong
      association of histidine residues at positions 54 and 89 may indicate regions of
      the protein with strong energetic propensities to collapse against the heme
      during early folding events, consistent with available data in the literature on
      early folding events for cytochrome c.

PMID- 10656829
TI  - Backbone dynamics and refined solution structure of the N-terminal domain of DNA
      polymerase beta. Correlation with DNA binding and dRP lyase activity.
AB  - Mammalian DNA polymerase beta functions in the base excision DNA repair pathway
      filling in short patches (1-5 nt) in damaged DNA and removing deoxyribose 5'
      phosphate from the 5'-side of damaged DNA. The backbone dynamics and the refined
      solution structure of the N-terminal domain of beta-Pol have been characterized
      in order to establish the potential contribution(s) of backbone motion to the DNA
      binding and deoxyribose 5'-phosphate lyase function of this domain. The N
      terminal domain is formed from four helices packed as two antiparallel pairs with
      a 60 degrees crossing between the pairs. The RMSD of the NMR conformers (residues
      13-80) is 0.37 A for the backbone heavy atoms and 0.78 A for all heavy atoms. NMR
      characterization of the binding site(s) for a ssDNA-5mer, ssDNA-8mer, ssDNA-9mer,
      and dsDNA-12mer shows a consensus surface for the binding of these various DNA
      oligomers, that surrounds and includes the deoxyribose 5'-phosphate lyase active
      site region. Connection segments between helices 1 and 2 and between helices 3
      and 4 each contribute to DNA binding. Helix-3-turn-helix-4 forms a helix-hairpin
      helix motif. The highly conserved hairpin sequence (LPGVG) displays a significant
      degree of picosecond time-scale motion within the backbone, that is possibly
      important for DNA binding at the phosphodiester backbone. An Omega-loop
      connecting helices 1 and 2 and helix-2 itself display significant exchange
      contributions (R(ex)) at the backbone amides due to apparent conformational type
      motion on a millisecond time-scale. This motion is likely important in allowing
      the Omega-loop and helix-2 to shift toward, and productively interact with,
      gapped DNA. The deoxyribose 5'-phosphate lyase catalytic residues that include
      K72 which forms the Schiff's base, Y39 which is postulated to promote proton
      transfer to the aldehyde, and K35 which assists in phosphate elimination, show
      highly restricted backbone motion. H34, which apparently participates in
      detection of the abasic site hole and assists in the opening of the hemiacetal,
      shows conformational exchange.

PMID- 10656830
TI  - beta-hairpin stability and folding: molecular dynamics studies of the first beta
      hairpin of tendamistat.
AB  - The stability and (un)folding of the 19-residue peptide, SCVTLYQSWRYSQADNGCA,
      corresponding to the first beta-hairpin (residues 10 to 28) of the alpha-amylase
      inhibitor tendamistat (PDB entry 3AIT) has been studied by molecular dynamics
      simulations in explicit water under periodic boundary conditions at several
      temperatures (300 K, 360 K and 400 K), starting from various conformations for
      simulation lengths, ranging from 10 to 30 ns. Comparison of trajectories of the
      reduced and oxidized native peptides reveals the importance of the disulphide
      bridge closing the beta-hairpin in maintaining a proper turn conformation,
      thereby insuring a proper side-chain arrangement of the conserved turn residues.
      This allows rationalization of the conservation of those cysteine residues among
      the family of alpha-amylase inhibitors. High temperature simulations starting
      from widely different initial configurations (native beta-hairpin, alpha and left
      handed helical and extended conformations) begin sampling similar regions of the
      conformational space within tens of nanoseconds, and both native and non-native
      beta-hairpin conformations are recovered. Transitions between conformational
      clusters are accompanied by an increase in energy fluctuations, which is
      consistent with the increase in heat capacity measured experimentally upon
      protein folding. The folding events observed in the various simulations support a
      model for beta-hairpin formation in which the turn is formed first, followed by
      hydrogen bond formation closing the hairpin, and subsequent stabilization by side
      chain hydrophobic interactions.

PMID- 10656831
TI  - Specificity and interactions of the protein OppA: partitioning solvent binding
      effects using mass spectrometry.
AB  - Mass spectrometry (MS) was used to characterise the binding of the 58 kDa protein
      OppA to 11 peptides with diverse properties. Peptides with two, three and five
      amino acid residues were added to OppA, and the mass spectra showed that the
      highest-affinity complexes are formed between OppA and tripeptide ligands. Lower
      affinity complexes were observed for OppA and dipeptide ligands, and no complex
      formation was detected with pentapeptides or a tripeptide in which the N-terminal
      amino group was acetylated. Tripeptides containing a single d amino acid residue
      were found not to bind to native OppA. Evidence from the peak width and the,
      charge in the spectra of the complexes suggests that the bound peptides are
      encapsulated by the protein in a solvent-filled cavity in the gas phase of the
      mass spectrometer. Analysis of the proportions of peptide-bound and free proteins
      under low-energy MS conditions shows a good correlation with solution-phase K(d)
      measurements where available. Increasing the internal energy of the gas-phase
      complex led to dissociation of the complex. The ease of dissociation is
      interpreted in terms of the intrinsic stability of the complex in the absence of
      the stabilising effects of bulk solvent. The results from this study demonstrate
      insensitivity to the hydrophobic and ionic properties, of the side-chains of the
      peptides, in contrast to the investigation of other protein ligand systems by MS.
      Moreover, these findings are in accord with the physiological role of this
      protein in allowing into the cell di- and tripeptides containing naturally
      occurring amino acids, regardless of their sequence, while barring access to
      potentially harmful peptide mimics.

PMID- 10656832
TI  - Statistical theory of combinatorial libraries of folding proteins: energetic
      discrimination of a target structure.
AB  - A self-consistent theory is presented that can be used to estimate the number and
      composition of sequences satisfying a predetermined set of constraints. The
      theory is formulated so as to examine the features of sequences having a
      particular value of Delta=E(f)-<E>(u), where E(f) is the energy of sequences when
      in a target structure and <E>(u) is an average energy of non-target structures.
      The theory yields the probabilities w(i)(alpha) that each position i in the
      sequence is occupied by a particular monomer type alpha. The theory is applied to
      a simple lattice model of proteins. Excellent agreement is observed between the
      theory and the results of exact enumerations. The theory provides a quantitative
      framework for the design and interpretation of combinatorial experiments
      involving proteins, where a library of amino acid sequences is searched for
      sequences that fold to a desired structure.

PMID- 10656833
TI  - Active and inhibited human catalase structures: ligand and NADPH binding and
      catalytic mechanism.
AB  - Human catalase is an heme-containing peroxisomal enzyme that breaks down hydrogen
      peroxide to water and oxygen; it is implicated in ethanol metabolism,
      inflammation, apoptosis, aging and cancer. The 1. 5 A resolution human enzyme
      structure, both with and without bound NADPH, establishes the conserved features
      of mammalian catalase fold and assembly, implicates Tyr370 as the tyrosine
      radical, suggests the structural basis for redox-sensitive binding of cognate
      mRNA via the catalase NADPH binding site, and identifies an unexpectedly
      substantial number of water-mediated domain contacts. A molecular ruler mechanism
      based on observed water positions in the 25 A-long channel resolves problems for
      selecting hydrogen peroxide. Control of water-mediated hydrogen bonds by this
      ruler selects for the longer hydrogen peroxide and explains the paradoxical
      effects of mutations that increase active site access but lower catalytic rate.
      The heme active site is tuned without compromising peroxide binding through a Tyr
      Arg-His-Asp charge relay, arginine residue to heme carboxylate group hydrogen
      bonding, and aromatic stacking. Structures of the non-specific cyanide and
      specific 3-amino-1,2, 4-triazole inhibitor complexes of human catalase identify
      their modes of inhibition and help reveal the catalytic mechanism of catalase.
      Taken together, these resting state and inhibited human catalase structures
      support specific, structure-based mechanisms for the catalase substrate
      recognition, reaction and inhibition and provide a molecular basis for
      understanding ethanol intoxication and the likely effects of human polymorphisms.

PMID- 10656834
TI  - Stator structure and subunit composition of the V(1)/V(0) Na(+)-ATPase of the
      thermophilic bacterium Caloramator fervidus.
AB  - The V-type Na(+)-ATPase of the thermophilic, anaerobic bacterium Caloramator
      fervidus was purified to homogeneity. The subunit compositions of the catalytic
      V(1) and membrane-embedded V(0) parts were determined and the structure of the
      enzyme complex was studied by electron microscopy. The V(1) headpiece consists of
      seven subunits present in one to three copies, and the V(0) part of two subunits
      in a ratio of 5:2. An analysis of over 7500 single particle images obtained by
      electron microscopy of the purified V(1)V(0) enzyme complex revealed that the
      stalk region, connecting the V(1) and V(0) parts, contains two peripheral stalks
      in addition to a central stalk. One of the two is connected to the V(0) part,
      while the other is connected to the first via a bar-like structure that is
      positioned just above V(0), parallel with the plane of the membrane. In
      projection, this bar seems to contact the central stalk. The data show that the
      stator structure that prevents rotation of the static part of V(0) relative to
      V(1) in the rotary catalysis mechanism of energy coupling in ATPases/ATPsynthases
      is more complex than previously thought.

PMID- 10656835
TI  - Social relationships and cardiovascular disease risk factors: findings from the
      third national health and nutrition examination survey.
AB  - Objective. Our aim was to study the associations between social relationships and
      several health behaviors in a national sample of the U.S. population. Methods.
      Using data from National Health and Nutrition Examination Survey III, which was
      conducted from 1988 to 1994, we examined the associations between the frequencies
      of organizational and individual relationships (derived from factor analysis) and
      cigarette smoking, not having had a blood pressure check during the preceding 12
      months, not having had a cholesterol check, not engaging in physical activity,
      and eating fruits and vegetables fewer than five times per day among men and
      women aged 18 years and older. Results. After adjusting for age, sex, race,
      educational attainment, marital status, and employment status, increases in
      organizational relationships were associated with decreases in all five
      behaviors: significant inverse linear trends were noted only for smoking and
      physical activity. For individual relationships, significant inverse linear
      trends were noted for not having a blood pressure check within the previous 12
      months, not having had a cholesterol check, and inadequate fruit and vegetable
      consumption. For physical inactivity, the shape of the relationship approximated
      a threshold response. For smoking, a significant positive linear trend was
      present. Conclusions. These results support findings from previous studies and
      indicate that social relationships have a beneficial effect on several behaviors
      that directly or indirectly affect the risk of cardiovascular disease.

PMID- 10656836
TI  - A message from preventive medicine and your physician

PMID- 10656837
TI  - Reduction of plasma catecholamines in humans during clinically controlled severe
      underfeeding.
AB  - BACKGROUND: Sympathetic hyperactivity is one factor for alterations encountered
      in the plurimetabolic syndrome, a cluster of metabolic abnormalities including
      obesity, hyperlipidemia, sometimes hyperglycaemia, and hypertonia. It was
      interesting to know if prolonged severe underfeeding (230 kcal/day) leads to
      decreases in catecholamines in those patients. METHODS: The plasma concentrations
      of catecholamines in patients (n = 16) suffering from plurimetabolic syndrome
      were studied before and during a 16-day period of medically controlled severe
      underfeeding (230 kcal/day) at rest and in response to exercise. RESULTS: During
      the period of underfeeding, mean norepinephrine concentrations decreased at rest
      from 1.45 to 0. 96 nmol/liter, and in response to exercise, from 6.1 to 3.2
      nmol/liter. Epinephrine concentrations decreased from 0.15 to 0.1 nmol/liter and
      from 0.26 to 0.17 nmol/liter, respectively. A significant decrease in
      catecholamine concentrations was observed only after 16 days of underfeeding.
      CONCLUSIONS: Clinically controlled underfeeding of patients with plurimetabolic
      syndrome may result in beneficial clinical and biochemical effects. The findings
      indicate that relatively long periods of underfeeding induce decreases in plasma
      catecholamine concentrations. Nevertheless, most of the fall in mean values in
      norepinephrine and also of the fall in blood pressure values occurred by Day 2.
      From those tendencies and from the significant changes in both parameters at Day
      16 of severe underfeeding one could conclude that altered sympathetic nervous
      system activity could contribute to the fall in blood pressure.

PMID- 10656838
TI  - Using language intensity to increase the success of a family intervention to
      protect children from ultraviolet radiation: predictions from language expectancy
      theory.
AB  - BACKGROUND: Even though people are informed about skin cancer prevention, they do
      not always comply with prevention advice. From Language Expectancy Theory, it was
      predicted that messages with high language intensity would improve compliance
      with sun safety recommendations and that this effect would be enhanced with
      deductive argument style. METHODS: Parents (N = 841) from a pediatric clinic and
      elementary schools received sun safety messages (newsletters, brochures, tip
      cards) by mail that varied in language intensity and logical style. Effects on
      attitudes and behavior were tested in a pretest-posttest factorial design.
      RESULTS: As hypothesized, parents receiving messages with high- as opposed to low
      intensity language complied more with sun safety advice. Messages with highly
      intense language were more persuasive when the arguments were formatted in a
      deductive style; low language intensity was more persuasive in inductively styled
      messages. CONCLUSIONS: By carefully adjusting messages features, health
      professionals can obtain further compliance beyond that produced by educating
      people about health risks and creating favorable attitudes and self-efficacy
      expectations. Highly intense language may be a good general strategy in
      prevention messages and works better when conclusions and recommendations are
      offered explicitly to recipients, especially when advice is aimed at reducing
      their personal risk.

PMID- 10656839
TI  - Predicting adolescent smoking: a prospective study of personality variables.
AB  - OBJECTIVE: We investigated how personality variables measured at 5th grade
      predict daily smoking in 12th grade. METHODS: A group of 3130 fifth graders was
      assessed for a propensity toward Rebelliousness, Risk Taking, Problem
      Helplessness, Affect Regulation, and Early Maturation and susceptibility to Peer
      Compliance and Peer Approval. Daily smoking status was determined for 94.7% of
      them 7 years later, in 12th grade. RESULTS: Rebelliousness and Risk Taking were
      the most significant predictors of smoking. There was no statistical evidence
      that the extent of prediction depended on gender or history of early smoking. No
      predictive evidence was seen for the other personality measures, including those
      describing susceptibility to peer influences. CONCLUSIONS: These results show
      that propensity toward rebelliousness and risk taking in childhood predicts
      adolescent smoking. They suggest that smoking prevention programs would do well
      to address the needs and expectations of rebellious and risk-taking youth.

PMID- 10656840
TI  - The role of health professionals in a community-based program to help women quit
      smoking.
AB  - BACKGROUND: Health professionals are credible sources of smoking cessation
      advice. This study describes changes in health professionals' reported provision
      of smoking cessation counseling activities for women during a community health
      education project that took place in two intervention counties (I) and compares
      these to reports from health professionals in two similar comparison counties
      (C). METHODS: Specific smoking cessation activities reported by physicians (I n =
      73, C n = 73), dentists (I n = 51, C n = 46), dental hygienists (I n = 38, C n =
      44), family planning and WIC (Special Supplemental Food Program for Women,
      Infants and Children) counselors (I n = 14 C n = 16), and community mental health
      counselors (I n = 57, C n = 23) were assessed by mailed surveys at baseline,
      after 4 years of countywide interventions, and 2 years later. RESULTS: Compared
      with health professionals in the comparison counties, significant increases in
      smoking cessation training (P < 0.01) and in reported referral of women to stop
      smoking groups, support groups, and one-to-one support were noted for physicians,
      family planning, and WIC counselors (P < 0.001); in training and referral to stop
      smoking groups and support groups by dentists and dental hygienists (P < 0.05);
      and in referral to support groups by community mental health counselors (P <
      0.05). Significant increases in setting quit dates (P < 0.05) and providing self
      help materials (P < 0.01) were also noted for family planning and WIC counselors.
      These effects were no longer demonstrable 2 years after external support for the
      countywide interventions was withdrawn. CONCLUSIONS: We suggest that an important
      aspect of facilitating consistent smoking cessation advice and counseling from
      health professionals in the future will be the provision of a broader range of
      regularly available smoking cessation support systems within communities than is
      generally available at this time in the United States.

PMID- 10656841
TI  - Changes in serum total cholesterol levels over 18 years in a cohort of men and
      women: The Nijmegen Cohort Study.
AB  - BACKGROUND: This study aimed to investigate to what extent cholesterol levels
      change in individuals in different age groups over an 18-year period. Factors
      that contribute to the changes, with respect to prevention of cardiovascular
      disease, were taken into account. METHODS: In 1977 serum cholesterol, systolic
      and diastolic blood pressures, body mass index, and smoking habits were measured
      in a cohort of 7,092 patients (men and women from 20 to 50 years of age) from six
      general practices in The Netherlands. In 1995, a sample of 2,600 of these same
      patients were invited to take part in a similar screening program; 2,335
      patients, consisting of 1,171 men and 1,164 women, agreed to participate.
      Patients were derived from both high-risk and low- to normal-risk category in
      1977. The differences in cholesterol between 1977 and 1995 were calculated and
      cholesterol levels were tracked over the study period by determining Pearson
      correlation coefficients. A multiple linear regression analysis was performed to
      investigate the determinants influencing the changes in cholesterol level.
      RESULTS: The mean cholesterol levels rose during the study period in all age
      groups. The highest mean increase in men was 1.23 mmol/L, or 20%, in the youngest
      age group (20-24 years), and in women the maximum mean increase was 1.12 mmol/L,
      or 17%, in the age group 40-44 years. Correlation coefficients between the 1977
      and 1995 readings varied from 0.63 in the youngest age group to 0.41 in the
      oldest. Body weight change during the study period, more than initial body
      weight, was found to have influenced the rise in serum cholesterol. At basic
      screening, 19.2% of the men and 12.4% of the women had cholesterol levels of 6. 5
      mmol/L or higher, as against 35.8 and 36.8%, respectively, in 1995. CONCLUSIONS:
      Over an 18-year period cholesterol level increased in most subjects, at a younger
      age in men than in women. The highest increase in women took place during the
      menopausal period. Weight gain, more than baseline weight, had a positive
      influence on the increase in cholesterol.

PMID- 10656842
TI  - A structural model of health behavior: a pragmatic approach to explain and
      influence health behaviors at the population level.
AB  - BACKGROUND: Behavior is influenced by individual-level attributes as well as by
      the conditions under which people live. Altering policies, practices, and the
      conditions of life can directly and indirectly influence individual behavior.
      This paper builds on existing ecological theories of health behavior by
      specifying structural mechanisms by which population-level factors effect change
      in individual health behaviors. METHODS: This paper moves ecological theory from
      model building to a pragmatic characterization of structural interventions. We
      examined social and environmental factors beyond individual control and
      mechanisms as to how they influence behavior. RESULTS: Four categories of
      structural factors are identified: (1) availability of protective or harmful
      consumer products, (2) physical structures (or physical characteristics of
      products), (3) social structures and policies, and (4) media and cultural
      messages. The first three can directly influence individuals through facilitating
      or constraining behavior. The fourth, media, operates by changing individual
      level attitudes, beliefs, and cognitions, as well as group norms. CONCLUSION:
      Interventions that target the four identified structural factors are a means to
      provide conditions that not only reduce high-risk behavior but also prevent the
      adoption of high-risk behaviors. Structural interventions are important and
      underutilized approaches for improving our nation's health.

PMID- 10656843
TI  - Likelihood of undergoing genetic testing for cancer risk: a population-based
      study.
AB  - BACKGROUND: Studies on public perceptions of genetic susceptibility testing for
      cancer risks are few and tend to focus on specific cancer risks of higher-risk
      populations, ignoring the general population and their perceived risk of getting
      any cancers. This study develops and tests a psychosocial model of the proximal
      and distal influences on likelihood of undergoing genetic susceptibility testing
      for cancer risk among a population-based sample. METHODS: The sample consisted of
      622 adults aged 18-75 interviewed by telephone. The survey instrument included
      measures derived from the Health Belief Model and adaptations of existing
      measures from the literature. Data were analyzed using structural equation
      modeling techniques. RESULTS: The model suggested independent main effects for
      perceived benefits, perceived barriers, perceived susceptibility, and pessimism
      while simultaneously accounting for the effects of age, socioeconomic status,
      family history of cancer, and awareness of the existence of genetic
      susceptibility testing for cancer risk. The model explained 34% of the variance
      in likelihood. CONCLUSIONS: While perceived benefits, perceived barriers,
      perceived susceptibility, and pessimism may directly impact likelihood, they may
      also mediate the effects of age, socioeconomic status, family history of cancer,
      and awareness of cancer genetic susceptibility testing, on likelihood.

PMID- 10656844
TI  - Cancers, mainly male, as population biomarkers for breast cancer mortality.
AB  - BACKGROUND: BCM correlates significantly with mor tality from other site-specific
      cancers and cardiovascular diseases for both sexes. These other mortalities could
      be used as independent biomarkers (predictors) of BCM allowing an evaluation of
      the importance of common etiological factors. METHODS: BCM (age-adjusted, 45-74
      years), obtained around 1992 from 37 countries worldwide, was estimated in
      multivariate regression to identify the best predictors. RESULTS: Male and female
      biomarkers predicted BCM with a R(2) of 0.80 and 0. 69, respectively. Strongest
      correlation was obtained with male colon, prostate, lung, and rectum cancer and
      female esophagus cancer (R(2) = 0.84, P < 0.0001). The estimated independent mean
      percentage contribution +/- SD to BCM was 40 +/- 7 from prostate cancer, 38 +/- 9
      from male colon, 13 +/- 6 from male lung and rectum cancer combined, and 9 +/- 3
      from female esophagus cancer. The regression equation (1992 data) predicted mean
      BCM in 28 available countries from 1967 to 1991 with a mean error of 5%. BCM in
      individual countries was also reliably predicted from 1967 to 1991, r = 0.86 to
      0.90 (P < 0.0001). In 1953, r was 0.74 (P < 0.0001). CONCLUSIONS: The evidence
      suggests a major influence of modifiable environmental factors common to BCM, its
      biomarkers, and both sexes: most likely nutrition, smoking, and alcohol intake.
      The results obtained with male data suggest a minor impact of sex-linked risk
      factors and, until recently, of treatment and early detection on BCM at the
      population level.

PMID- 10656845
TI  - Changing patterns of breast cancer stage at diagnosis in southern italy: hospital
      data as indicators of progressive changes.
AB  - BACKGROUND: In southern Italy diagnostic delay in breast cancer patients has been
      demonstrated to be related to the level of education and residency in rural
      areas. In order to verify whether late breast cancer diagnosis was actually in
      decline as a result of improving socioeconomic conditions and ongoing prevention
      programs, we evaluated clinical data from the tumor registry of the National
      Cancer Institute, Naples. METHODS: Four thousand two hundred forty consecutive
      breast cancer patients admitted to our institution from 1986 to 1997 were grouped
      into four 3-year periods according to their admission date. Using multiple
      logistic regression, chi(2) for trend and beta-coefficient were calculated in
      each pT and pN categories in order to discover the trend for the 1986-1997
      period. RESULTS: A progressive, statistically significant decrease in the number
      of patients with advanced cancer at the time of diagnosis was observed over the
      study period. In particular, chi(2) values for trend for each pT category, over
      the study period, were pT1 119.4 (P < 0.001) with positive chi-coefficient, pT2
      13.4 (P = 0.003) with negative beta, and pT3-pT4 152.2 (P < 0.001) with the
      strongest negative beta. CONCLUSIONS: Changing patterns of breast cancer stage at
      diagnosis have been demonstrated in women living in Southern Italy. They are
      consistent with an increasing orientation toward prevention. Data from hospital
      tumor registries are a useful source of information on diagnostic delay.

PMID- 10656846
TI  - Lines that connect: assessing the causality inference in the case of particulate
      pollution.
AB  - The question of when it would be appropriate to conclude that the associations
      between particulate pollution and various outcomes (including mortality) should
      be judged as causal in nature has been difficult and controversial. Although such
      a judgment must be subject to revision, the volume of new information and new
      experimental findings has been so great that such a reevaluation is required at
      frequent intervals. The useful summary by Gamble [PM(2. 5) and Mortality in Long
      Term Prospective Cohort Studies: Cause-Effect or Statistical Associations?
      Environ Health Perspect 106:535-554 (1998)] of the reasons why a causal inference
      was, in his opinion, not justified provides a basis for reevaluation in the light
      of new data. Such a reexamination indicates that the associative evidence is now
      stronger and that the biologic basis for a number of adverse effects has now been
      demonstrated. All of the useful guideline criteria customarily applied to such
      questions seem to have been met, although there is still much to be learned about
      interactive effects and the possibility of statistical thresholds.

PMID- 10656847
TI  - The role of epidemiology in the detection of harmful effects of radiation.
AB  - Data relating to acute injuries of atomic bomb survivors show that the life span
      study cohort is biased in favor of exceptionally low levels of radiosensitivity.
      These data also show that factors influencing the death rates of this cohort
      include irreversible damage to the immune system. These impressions are still
      awaiting confirmation. Meanwhile, the Oxford Survey of Childhood Cancers and
      surveys of nuclear workers show that at low dose levels the cancer risk is much
      greater than estimates based on atomic bomb survivors; the special association
      between leukemia and radiation is an exclusively high dose effect, and levels of
      radiosensitivity are much lower in the middle of the life span than at either
      extreme.

PMID- 10656848
TI  - Environmental estrogens induce transcriptionally active estrogen receptor dimers
      in yeast: activity potentiated by the coactivator RIP140.
AB  - We used three yeast genetic systems to investigate the estrogen-like activity of
      octylphenol (OP), bisphenol-A (BPA), o,p'-DDT, and o, p'-DDE to induce human
      estrogen receptor (hER) dimerization and transcriptional activation. We have
      demonstrated that OP, BPA, and o, p'-DDT can induce hER ligand-dependent
      dimerization using a yeast two-hybrid assay. All three xenoestrogens, plus
      estradiol, enhanced estrogen response element (ERE)-dependent transcriptional
      activation of hER. In the presence of receptor interacting protein 140 (RIP140),
      ERE-dependent activity was dramatically amplified by 100-fold for estradiol, OP,
      BPA, and o,p'-DDT. A yeast whole-cell [(3)H]estradiol binding assay was developed
      to determine the site of interaction on the hER. We determined nonspecific
      binding by parallel incubations run in the presence of 5 microM unlabelled
      estradiol in PCY2 yeast. At the concentrations tested, unlabeled estradiol, OP,
      and BPA displaced [(3)H]estradiol in this binding assay, whereas the
      concentrations of o,p'-DDT and o,p'-DDE tested were insufficient to inhibit
      binding. Incubating yeast in the presence of increasing concentrations of
      estradiol and OP (1 microM) or BPA (1 microM) neither blocked nor altered the
      effect of estradiol on hER activity. We observed no agonistic activity of o,p'
      DDE in any of the yeast models used. These results suggest that OP, BPA, and o,p'
      DDT exert their estrogen-like activity through the ER in a manner similar to that
      of estradiol, and the coactivator RIP140 markedly potentiates this activity.

PMID- 10656849
TI  - Plasma levels and redox status of ascorbic acid and levels of lipid peroxidation
      products in active and passive smokers.
AB  - Both active and passive smoking are regarded as risk factors for various
      diseases. To clarify the effects of active and passive smoking on plasma vitamin
      C levels and lipid peroxidation status, we examined the plasma levels of ascorbic
      acid (AA), its redox status [ratio of dehydroascorbate (DHAA) to total AA], the
      levels of thiobarbiturate reactive substance (TBARS), and the levels of lipid
      peroxides (LPO) in smokers, nonsmokers, and nonsmokers regularly exposed to
      environmental cigarette smoke (passive smokers). The study population consisted
      of 149 healthy males: 75 active smokers (consumption of > 15 cigarettes/day for
      more than 5 years), 36 passive smokers (more than 10 hr/week exposure to
      environmental cigarette smoke), and 38 nonsmokers (no cigarette smoke exposure).
      There were no significant differences in plasma TBARS and LPO levels among the
      three groups. Plasma levels of AA, the reduced form of vitamin C, were
      significantly lower in active smokers than in the combined nonsmoking groups (7.2
      +/- 3.5 and 8.4 +/- 3.4 microg/mL, respectively; p < 0.05). Although no
      significant differences were found in plasma DHAA levels among the three groups,
      the ratios of DHAA to total AA were significantly higher in active and passive
      smokers than nonexposed nonsmokers (11.2, 10.3, and 7.1%, respectively; p <
      0.05). These results indicate that passive smoking, as well as direct inhalation
      of cigarette smoke, affects the redox status of plasma AA. In passive smokers,
      the altered redox status of plasma AA suggests an oxidative stress.

PMID- 10656850
TI  - Estimating the mortality impacts of particulate matter: what can be learned from
      between-study variability?
AB  - Epidemiologic studies of the link between particulate matter (PM) concentrations
      and mortality rates have yielded a range of estimates, leading to disagreement
      about the magnitude of the relationship and the strength of the causal
      connection. Previous meta-analyses of this literature have provided pooled effect
      estimates, but have not addressed between-study variability that may be
      associated with analytical models, pollution patterns, and exposed populations.
      To determine whether study-specific factors can explain some of the variability
      in the time-series studies on mortality from particulate matter [less than/equal
      to] 10 microm in aerodynamic diameter (PM(10)), we applied an empirical Bayes
      meta-analysis. We estimate that mortality rates increase on average by 0.7% per
      10 microg/m(3) increase in PM(10) concentrations, with greater effects at sites
      with higher ratios of particulate matter [less than/equal to] 2.5 microm in
      aerodynamic diameter (PM(2.5))/PM(10). This finding did not change with the
      inclusion of a number of potential confounders and effect modifiers, although
      there is some evidence that PM effects are influenced by climate, housing
      characteristics, demographics, and the presence of sulfur dioxide and ozone.
      Although further analysis would be needed to determine which factors causally
      influence the relationship between PM(10) and mortality, these findings can help
      guide future epidemiologic investigations and policy decisions.

PMID- 10656851
TI  - Impact of climatic change on the northern latitude limit and population density
      of the disease-transmitting European tick Ixodes ricinus.
AB  - We examined whether a reported northward expansion of the geographic distribution
      limit of the disease-transmitting tick Ixodes ricinus and an increased tick
      density between the early 1980s and mid-1990s in Sweden was related to climatic
      changes. The annual number of days with minimum temperatures above vital
      bioclimatic thresholds for the tick's life-cycle dynamics were related to tick
      density in both the early 1980s and the mid-1990s in 20 districts in central and
      northern Sweden. The winters were markedly milder in all of the study areas in
      the 1990s as compared to the 1980s. Our results indicate that the reported
      northern shift in the distribution limit of ticks is related to fewer days during
      the winter seasons with low minimum temperatures, i.e., below -12 degrees C. At
      high latitudes, low winter temperatures had the clearest impact on tick
      distribution. Further south, a combination of mild winters (fewer days with
      minimum temperatures below -7 degrees C) and extended spring and autumn seasons
      (more days with minimum temperatures from 5 to 8 degrees C) was related to
      increases in tick density. We conclude that the relatively mild climate of the
      1990s in Sweden is probably one of the primary reasons for the observed increase
      of density and geographic range of I. ricinus ticks.

PMID- 10656852
TI  - A time-series analysis of acidic particulate matter and daily mortality and
      morbidity in the Buffalo, New York, region.
AB  - A component of particulate matter (PM) air pollution that may provide one
      biologically plausible pathway for the observed PM air pollution-health effect
      associations is aerosol acidity (H(+)). An increasing number of observational
      studies have demonstrated associations between H(+) and increased adverse health
      effects in the United States and abroad. Although studies have shown significant
      H(+) associations with increased morbidity in the United States, similar
      associations have yet to be shown with daily mortality. We considered a 2.5-year
      record of daily H(+) and sulfate measurements (May 1988-October 1990) collected
      in the Buffalo, New York, region in a time-series analysis of respiratory,
      circulatory, and total daily mortality and hospital admissions. Other
      copollutants considered included particulate matter [less than/equal to] 10
      microm in aerodynamic diameter, coefficient of haze, ozone, carbon monoxide,
      sulfur dioxide, and nitrogen dioxide. Various modeling techniques were applied to
      control for confounding of effect estimates due to seasonality, weather, and day
      of-week effects. We found multiple significant pollutant-health effect
      associations--most strongly between SO(4)(2-) and respiratory hospital admissions
      (as indicated by its t-statistic). Additionally, H(+) and SO(4)(2-) demonstrated
      the most coherent associations with both respiratory hospital admissions [H(+):
      relative risk (RR) = 1. 31; 95% confidence interval (CI), 1.14-1.51; and SO(4)(2
      ): RR = 1. 18, CI, 1.09-1.28] and respiratory mortality (H(+): RR = 1.55, CI, 1.
      09-2.20; and SO(4)(2-): RR = 1.24, CI, 1.01-1.52). Thus, acidic sulfate aerosols
      represent a component of PM air pollution that may contribute to the previously
      noted adverse effects of PM mass on human health, and the associations
      demonstrated in this study support the need for further investigations into the
      potential health effects of acidic aerosols.

PMID- 10656853
TI  - 50-Hertz magnetic field and calcium transients in Jurkat cells: results of a
      research and public information dissemination (RAPID) program study.
AB  - An effect on intracellular calcium continues to be proposed as a biochemical
      pathway for the mediation of biologic effects of electrical-power-frequency
      magnetic fields (MF). However, reproducible results among laboratories are
      difficult to attain and the characteristics of magnetic field effects on
      intracellular free calcium ([Ca(2+)](i)) are not well understood. We attempted to
      repeat the studies of Lindstrom et al. [Intracellular Calcium Oscillations in a T
      Cell Line by a Weak 50 Hz Magnetic Field. J Cell Physiol 156:395-398 (1993)] by
      investigating the effect of a 1.5-G 50-Hz MF on [Ca(2+)](i) in the Jurkat
      lymphocyte T-cell line. Changes in [Ca(2+)](i) were determined using microscopic
      imaging of fura-2 loaded Jurkat cells on poly-l-lysine-coated glass coverslips.
      The MF was generated by a single coil constructed with bifilar wire and located
      in the same plane as the cells. Cells were randomly exposed for 8 min to MF, sham
      field (SF), or no field (NF) conditions. The exposure condition remained coded
      until data analysis was complete. Each exposure period was preceded by an 8-min
      data collection to establish a baseline for [Ca(2+)](i). After each exposure
      condition, cells were exposed to anti-CD3 antibody that induced a rapid increase
      in [Ca(2+)](i) in responsive cells; this provided a positive control. [Ca(2+)](i)
      was analyzed for individual cells as spatially-averaged background-corrected
      340/380 nm ratios, and a [Ca(2+)](i) transient was considered significant for
      positive deviations from baseline of 3 [multiple] an estimate of noise in the
      baseline. Typically, 25-50 cells/field were viewed and approximately 50% had no
      [Ca(2+)](i) transients in the baseline period and also responded to positive
      control. Only cells responding to positive control and lacking changes in
      [Ca(2+)](i) during the baseline period were considered qualified for assessment
      during the exposure period. The incidences of [Ca(2+)](i) transients during the
      exposure period for two experiments (40 [multiple] objective) were 16.5, 14.6,
      and 14.2% for MF, SF, and NF, respectively, and were not statistically
      significantly different. Previous studies by Lindstrom et al. [Intracellular
      Calcium Oscillations in a T-Cell Line after Exposure to Extremely-Low-Frequency
      Magnetic Fields with Variable Frequencies and Flux Densities. Bioelectromagnetics
      16:41-47 (1995)] showed a high response rate (92%) for exposure to 1. 5-G 50-Hz
      MF when individual cells were preselected for investigation. We found no such
      effect when examining many cells simultaneously in a random and blind fashion.
      These results do not preclude an effect of MF on [Ca(2+)](i), but suggest that
      responsive cells, if they exist, were not identified using the approaches that we
      used in this study.

PMID- 10656854
TI  - Maternal drug abuse and human term placental xenobiotic and steroid metabolizing
      enzymes in vitro.
AB  - We evaluated the impact of maternal drug abuse at term on human placental
      cytochrome P450 (CYP)-mediated (Phase I) xenobiotic and steroid-metabolizing
      activities [aromatase, 7-ethoxyresorufin O-deethylase (EROD), 7-ethoxycoumarin O
      deethylase (ECOD), pyrene 1-hydroxylase (P1OH), and testosterone hydroxylase],
      and androstenedione-forming isomerase, NADPH quinone oxidoreductase (Phase II),
      UDP-glucuronosyltransferase (UGT), and glutathione S-transferase (GST) activities
      in vitro. Overall, the formation of androstenedione, P1OH, and testosterone
      hydroxylase was statistically significant between control and drug-abusing
      subjects; we observed no significant differences in any other of the phase I and
      II activities. In placentas from drug-abusing mothers, we found significant
      correlations between ECOD and P1OH activities (p < 0. 001), but not between ECOD
      and aromatase or P1OH and EROD activities; we also found significant correlations
      between blood cotinine and UGT activities (p < 0.01). In contrast, in controls
      (mothers who did not abuse drugs but did smoke cigarettes), the P1OH activity
      correlated with ECOD, EROD (p < 0.001), and testosterone hydroxylase (p < 0.001)
      activities. Our results (wider variation in ECOD activity among tissue from drug
      abusing mothers and the significant correlation between P1OH and ECOD activities,
      but not with aromatase or EROD activities) indicate that maternal drug abuse
      results in an additive effect in enhancing placental xenobiotic metabolizing
      enzymes when the mother also smokes cigarettes; this may be due to enhancing a
      "silent" CYP form, or a new placental CYP form may be activated. The change in
      the steroid metabolism profile in vitro suggests that maternal drug abuse may
      alter normal hormonal homeostasis during pregnancy.

PMID- 10656855
TI  - Determinants of polybrominated biphenyl serum decay among women in the Michigan
      PBB cohort.
AB  - Accidental contamination of the food chain in Michigan in 1973 with
      polybrominated biphenyls (PBBs) led to the establishment of a registry of exposed
      individuals in 1976. Serum was collected and analyzed for PBB at the time of
      enrollment and for targeted studies in the following years. We used the archived
      PBB data to study the elimination of PBB and to identify factors associated with
      elimination. A total of 380 women >= 16 years of age who had an initial PBB level
      of 2 ppb and at least two serum samples drawn when they were not pregnant were
      included in the analysis. The mean initial PBB level was 20.9 ppb (median 4) and
      mean time between the first and last measurement was 4.2 years (range 0.5-11.1).
      PBB was assumed to reach equilibrium in the body before substantial amounts were
      eliminated and before the first serum measurements were taken; therefore, the
      entire body was modeled as a single compartment for PBB with exponential decay.
      Subject-specific decay rate estimates were regressed on predictor variables
      including initial age, body mass index (BMI), smoking history, breast-feeding
      duration, and parity. In women with an initial PBB level < 10 ppb, the median
      half-life was 12.9 years; in those with > 10 ppb, the median half-life was 28.7
      years. Decay was significantly slower among women with an initial BMI at or above
      the median (BMI >= 23). The calculated half-life values are estimates of decay
      and can be used to estimate body burden of PBB at various points in time other
      than at the time of serum collection.

PMID- 10656856
TI  - Dielectric changes in membrane properties and cell interiors of human mesothelial
      cells in vitro after crocidolite asbestos exposure.
AB  - Asbestos induces cytogenetic and genotoxic effects in cultured cell lines in
      vitro. For further investigations of the fiber-induced cellular changes,
      electrorotation (ROT) measurements can be used to determine early changes of
      surface properties and dielectric cellular changes. In the present study, human
      mesothelial cells (HMC) were exposed to nontoxic concentrations of crocidolite
      asbestos (1 microg/cm(2)) for 12, 24, 30, 50, and 72 hr, and were investigated
      for changes in dielectric properties, morphologic and biochemical changes using
      ROT measurements, electron microscopy, and flow cytometry, respectively. The
      results of ROT measurements revealed slightly increased internal conductivity and
      decreased membrane conductance of HMC during the first 12 hr of exposure to
      crocidolite. This may be due to functional changes of ion channels of the
      cellular membrane. However, after exposures of >= 30 hr, reduced internal
      conductivity and increased membrane conductance of HMC occurred. These effects
      may be caused by permeabilization of the cell membrane and the leakage of ions
      into the surrounding medium. The membrane capacitance of HMC is always decreased
      during exposure of cells to crocidolite fibers. This decreased membrane
      capacitance may result from the observed reduction in the number of microvilli
      and from the shrinkage of cells as observed by electron microscopy and flow
      cytometry. Changes in composition of the plasma membrane were also observed after
      the labeling of phosphatidylserines (PS) on the cell surface. These observed
      changes can be related to apoptotic events. Whereas during the first 50 hr of
      exposure only a small number of HMC with increased exposure of PS on the cell
      surface was detected by flow cytometry, the dielectric properties of HMC showed
      marked changes during this time. Our results show that surface property changes
      of the cellular membrane of HMC as well as interior dielectric changes occur
      after the exposure of cells to crocidolite fibers. The observed changes are
      discussed in terms of complex combined cellular effects after amphibole asbestos
      exposure.

PMID- 10656857
TI  - Regression analysis of time trends in perinatal mortality in Germany 1980-1993.
AB  - Numerous investigations have been carried out on the possible impact of the
      Chernobyl accident on the prevalence of anomalies at birth and on perinatal
      mortality. In many cases the studies were aimed at the detection of differences
      of pregnancy outcome measurements between regions or time periods. Most authors
      conclude that there is no evidence of a detrimental physical effect on congenital
      anomalies or other outcomes of pregnancy following the accident. In this paper,
      we report on statistical analyses of time trends of perinatal mortality in
      Germany. Our main intention is to investigate whether perinatal mortality, as
      reflected in official records, was increased in 1987 as a possible effect of the
      Chernobyl accident. We show that, in Germany as a whole, there was a
      significantly elevated perinatal mortality proportion in 1987 as compared to the
      trend function. The increase is 4.8% (p = 0.0046) of the expected perinatal death
      proportion for 1987. Even more pronounced levels of 8.2% (p = 0. 0458) and 8.5%
      (p = 0.0702) may be found in the higher contaminated areas of the former German
      Democratic Republic (GDR), including West Berlin, and of Bavaria, respectively.
      To investigate the impact of statistical models on results, we applied three
      standard regression techniques. The observed significant increase in 1987 is
      independent of the statistical model used. Stillbirth proportions show
      essentially the same behavior as perinatal death proportions, but the results for
      all of Germany are nonsignificant due to the smaller numbers involved. Analysis
      of the association of stillbirth proportions with the (137)Cs deposition on a
      district level in Bavaria discloses a significant relationship. Our results are
      in contrast to those of many analyses of the health consequences of the Chernobyl
      accident and contradict the present radiobiologic knowledge. As we are dealing
      with highly aggregated data, other causes or artifacts may explain the observed
      effects. Hence, the findings should be interpreted with caution, and further
      independent evidence should be sought.

PMID- 10656858
TI  - PCB congener profile in the serum of humans consuming Great Lakes fish.
AB  - The State of Michigan has a long history of research into human exposure to
      environmental contaminants through consumption of recreationally caught fish. A
      large cohort of Lake Michigan residents who eat fish (fish-eaters) and those who
      do not eat fish (nonfish-eaters) established in 1980 served as the basis for the
      congener-specific polychlorinated biphenyl (PCB) exposure evaluation reported
      here. In this paper we present the serum PCB congener profile for a subset of
      this cohort who were over 50 years of age. Serum samples were collected in 1993
      1995 and were evaluated by a dual column capillary column gas chromatography
      procedure capable of detecting over 90 PCB congeners. This evaluation
      demonstrated significant PCB exposure in the fish-eaters (mean serum PCB of 14.26
      ppb; n = 101). This elevated exposure allowed the establishment of a detailed
      profile of the PCB congeners found in humans exposed by this route. Twenty-two
      congeners of varying concentrations were the most prevalent and constituted over
      95% of the total PCB present in most subjects. Four congeners, 138/163
      (2,2',3,4,4',5-PCB/2,3,3',4', 5,6-PCB), 180 (2,2',3,4,4',5,5'-PCB), and 153
      (2,2',4,4',5,5'-PCB), accounted for 55-64% of the total PCB load. Other
      congeners, some of toxicologic significance, were also detected by this
      analytical protocol. Nonfish-eaters had lower total serum PCB levels (mean = 4.
      56; n = 78), but the same general pattern of PCB congeners was present. It was
      demonstrated that careful selection of a subset of prevalent PCB congeners could
      provide a cost-effective assessment of exposure without losing critical
      scientific information.

PMID- 10656859
TI  - Outdoor air pollution, low birth weight, and prematurity.
AB  - This study tested the hypothesis, suggested by several recent reports, that air
      pollution may increase the risk of adverse birth outcomes. This study analyzed
      all singleton live births registered by the Czech national birth register in 1991
      in 67 districts where at least one pollutant was monitored in 1990-1991 (n =
      108,173). Maternal exposures to sulfur dioxide (SO(2)), total suspended particles
      (TSP), and nitrous oxides (NO(x)) in each trimester of pregnancy were estimated
      as the arithmetic means of all daily measurements taken by all monitors in the
      district of birth of each infant. Odds ratios of low birth weight (< 2,500 g),
      prematurity (< 37 weeks of gestation), and intrauterine growth retardation (IUGR;
      < 10th percentile of birth weight for gestational age and sex) were estimated by
      robust logistic regression. The median (and 25th and 75th percentile) trimester
      exposures were 32 (18, 56) microg/m(3) for SO(2); 72 (55, 87) microg/m(3) for
      TSP; and 38 (23, 59) microg/m(3) for NO(x). Low birth weight (prevalence 5.2%)
      and prematurity (prevalence 4.8%) were associated with SO(2) and somewhat less
      strongly with TSP. IUGR was not associated with any pollutant. The effects on low
      birth weight and prematurity were marginally stronger for exposures in the first
      trimester, and were not attenuated at all by adjustment for socioeconomic factors
      or the month of birth. Adjusted odds ratios of low birth weight were 1.20 [95%
      confidence interval (CI), 1.11-1.30] and 1.15 (CI, 1.07-1.24) for a 50
      microg/m(3) increase in SO(2) and TSP, respectively, in the first trimester;
      adjusted odds ratios of prematurity were 1.27 (CI, 1.16-1.39) and 1.18 (CI, 1.05
      1.31) for a 50 microg/m(3) increase in SO(2) and TSP, respectively, in the first
      trimester. Low gestational age accounted for the association between SO(2) and
      low birth weight. These findings provide further support for the hypothesis that
      air pollution can affect the outcome of pregnancy.

PMID- 10656860
TI  - Seasonal influences on childhood lead exposure.
AB  - We conducted a study to examine seasonal changes in residential dust lead content
      and its relationship to blood lead in preschool children. We collected blood and
      dust samples (floors, windowsills, and carpets) to assess lead exposure. The
      geometric mean blood lead concentrations are 10.77 and 7.66 microg/dL for the
      defined hot and cold periods, respectively (p < 0.05). Lead loading (milligrams
      per square meter) is the measure derived from floor and windowsill wipe samples
      that is most correlated with blood lead concentration, whereas lead concentration
      (micrograms per gram) is the best variable derived from carpet vacuum samples.
      The variation of dust lead levels for these three dust variables (floor lead
      loading, windowsill lead loading, and carpet lead concentration) are consistent
      with the variation of blood lead levels, showing the highest levels in the
      hottest months of the year, June, July, and August. The regression analysis,
      including the three representative dust variables in the equations to predict
      blood lead concentration, suggests that the seasonality of blood lead levels in
      children is related to the seasonal distributions of dust lead in the home. In
      addition, the outdoor activity patterns indicate that children are likely to
      contact high leaded street dust or soil during longer outdoor play periods in
      summer. Consequently, our results show that children appear to receive the
      highest dust lead exposure indoors and outdoors during the summer, when they have
      the highest blood lead levels. We conclude that at least some of the seasonal
      variation in blood lead levels in children is probably due to increased exposure
      to lead in dust and soil.

PMID- 10656861
TI  - Environmental medicine at a crossroad: health in the United States.

PMID- 10656862
TI  - Health effects of hexachlorobenzene and the TEF approach.

PMID- 10656864
TI  - Evaluating Floyd's effect on health in eastern North Carolina.
AB  - Since the now-famous storm of September 1999, the name "Floyd" has taken on new
      associations for many people in eastern North Carolina: devastation and
      environmental catastrophe. On 12 November 1999, representatives from state and
      federal agencies and local universities met on the NIEHS campus in Research
      Triangle Park, North Carolina, to discuss the environmental health implications
      of the floods following Hurricane Floyd. In addition to determining the potential
      long-term human health and ecological problems, participants hoped to develop
      strategies, collaborations, and partnerships to be used in the restoration of
      eastern North Carolina.

PMID- 10656863
TI  - NTP taps disinfection by-products for study.
AB  - The use of chlorination to purify water supplies is considered one of the most
      important public health advances of the twentieth century. Following the 1908
      introduction of widespread water chlorination, once-common diseases such as
      cholera, dysentery, and typhoid fever were practically eliminated. However, the
      chlorination cure-all proved to have a caveat: disinfection by-products (DBPs),
      which result from the reaction between the chlorine added during chlorination and
      organic material such as leaves and sediment in the source water. In the mid
      1970s, certain DBPs were found to cause adverse health effects including cancer
      in laboratory animals.

PMID- 10656865
TI  - Water world 2000.
AB  - Today, at least one-fifth of all people worldwide lack access to safe drinking
      water, a problem that will almost certainly worsen as the earth's population
      grows. Although the vast majority of industrial discharges into waterways are
      regulated and treated, and most cities and towns effectively monitor and treat
      their sewage for chemical contaminants, problems such as arsenic contamination
      and dangerous microorganisms still trouble public water supplies in wealthy
      nations. In developing countries, most cities discharge 80-90% of their untreated
      sewage directly into rivers and streams, which are used for drinking, bathing,
      and washing. This lack of sewage treatment has allowed dangerous microorganisms
      to spread, posing one of the greatest threats to human health in the developing
      world: waterborne diseases caused by deadly microbes in water. Contamination
      isn't the only problem: in many areas of the world, drinkable water is a scarce
      resource available to many only at high cost, when it is available at all.

PMID- 10656866
TI  - Lessons from the flood: will Floyd change livestock farming?
AB  - When Hurricane Floyd struck eastern North Carolina in September 1999, as many as
      50 waste lagoons, many of them several acres in size, were inundated by flood
      waters. Five lagoons breached, and waterborne animal waste produced nutrient
      pollution and raised the potential for exposure to pathogens and the risk of
      disease. As the state recovers, a common question being asked is whether state
      livestock regulations, particularly regarding facility siting and waste
      management methods, will be revised to accommodate future flood conditions.

PMID- 10656867
TI  - Saline solutions: the quest for fresh water.
AB  - Despite steady advances in the technology, desalination remains one of the most
      expensive ways to produce potable water. But as water scarcity forces communities
      to find new sources of drinking water, scientists are developing innovations that
      may soon make desalination a reasonable option for many more communities. The
      newest approach to desalination is membrane systems, which include reverse
      osmosis and electrodialysis systems. Current research seeks to make these systems
      more effective and less likely to produce environmentally hazardous by-products.
      Many facilities use traditional distillation to desalinate water, and efforts are
      being made to combine membranes and distillation for more efficient systems.

PMID- 10656869
TI  - Summertime blues

PMID- 10656868
TI  - This is your placenta on drugs

PMID- 10656870
TI  - Challenging the assumptions

PMID- 10656871
TI  - NIEHS leads research efforts addressing domestic health disparities
AB  - The NIEHS has emerged with a significant leadership role in the health
      disparities arena and has undertaken a number of activities to help eliminate
      health disparities influenced by the social and physical milieux. These
      activities include the announcement of the multiagency Request for Application
      (RFA) ES-00-004, "Health Disparities: Linking Biological and Behavioral
      Mechanisms with Social and Physical Environments," located online at
      http://grants. nih.gov/grants/guide/rfa-files/RFA-ES-00-004.html. Moreover, NIEHS
      director Kenneth Olden cochaired a director-level trans-NIH working group that
      has set research priorities directing the development of NIH initiatives on
      domestic health disparities beginning in FY 2001.

PMID- 10656873
TI  - beta-lapachone induces cell cycle arrest and apoptosis in human colon cancer
      cells.
AB  - BACKGROUND: Human colon cancers have a high frequency of p53 mutations, and
      cancer cells expressing mutant p53 tend to be resistant to current chemo- and
      radiation therapy. It is thus important to find therapeutic agents that can
      inhibit colon cancer cells with altered p53 status. beta-Lapachone, a novel
      topoisomerase inhibitor, has been shown to induce cell death in human
      promyelocytic leukemia and prostate cancer cells through a p53-independent
      pathway. Here we examined the effects of beta-lapachone on human colon cancer
      cells. MATERIALS AND METHODS: Several human colon cancer cell lines, SW480,
      SW620, and DLD1, with mutant or defective p53, were used. The antiproliferative
      effects of beta-lapachone were assessed by colony formation assays, cell cycle
      analysis, and apoptosis analysis, including annexin V staining and DNA laddering
      analysis. The effects on cell cycle and apoptosis regulatory proteins were
      examined by immunoblotting. RESULTS: All three cell lines, SW480, SW620, and
      DLD1, were sensitive to beta-lapachone, with an IC(50) of 2 to 3 microM in colony
      formation assays, a finding similar to that previously reported for prostate
      cancer cells. However, these cells were arrested in different stages of S phase.
      At 24 hr post-treatment, beta-lapachone induced S-, late S/G2-, and early S-phase
      arrest in SW480, SW620, and DLD1 cells, respectively. The cell cycle alterations
      induced by beta-lapachone were congruous with changes in cell cycle regulatory
      proteins such as cyclin A, cyclin B1, cdc2, and cyclin D1. Moreover, beta
      lapachone induced apoptosis, as demonstrated by annexin V staining, flow
      cytometric analysis of DNA content, and DNA laddering analysis. Furthermore, down
      regulation of mutant p53 and induction of p27 in SW480 cells, and induction of
      pro-apoptotic protein Bax in DLD1 cells may be pertinent to the anti
      proliferative and apoptotic effects of beta-lapachone on these cells.
      CONCLUSIONS: beta-Lapachone induced cell cycle arrest and apoptosis in human
      colon cancer cells through a p53-independent pathway. For human colon cancers,
      which often contain p53 mutations, beta-lapachone may prove to be a promising
      anticancer agent that can target cancer cells, especially those with mutant p53.

PMID- 10656874
TI  - Zinc finger transcription factors as molecular targets for nitric oxide-mediated
      immunosuppression: inhibition of IL-2 gene expression in murine lymphocytes.
AB  - BACKGROUND: Nitric oxide (NO) has frequently been shown to display
      immunosuppressive activities. We describe here a molecular mechanism contributing
      to this effect. MATERIALS AND METHODS: Murine T cell lymphoma EL4-6.1 cells were
      activated with the physiological stimulus interleukin (IL)-1beta to express IL-2
      mRNA in the presence or absence of subtoxic concentrations of the physiological
      spontaneous NO donor S-nitrosocysteine (SNOC). Subsequently, semiquantitative RT
      PCR and gel shift assays with nuclear extracts were performed to analyze the
      effects of NO on IL-2 mRNA expression and on the activity of the dominant
      regulating transcription factors Sp1, EGR-1, and NFATc. RESULTS: NO inhibits IL
      1beta-induced IL-2 mRNA expression in EL4-6.1 cells. The suppressive activity of
      NO was concentration dependent and found to be completely reversible.
      Importantly, NO at the concentrations used induced neither apoptosis nor
      necrosis. Dominant regulation of IL-2 gene expression is known to reside in the
      zinc finger transcription factors Sp1 or EGR-1 and in the non-zinc finger protein
      NFAT. NO abrogates the DNA binding activities of recombinant Sp1 and EGR-1. More
      importantly, gel shift assays also showed a lack of DNA binding of native Sp1
      derived from NO-treated nuclear extracts and that from NO-treated viable
      lymphocytes. This effect is selective, as the DNA binding activity of recombinant
      NFATc was not affected by NO. CONCLUSION: Inactivation of zinc finger
      transcription factors by NO appears to be a molecular mechanism in the
      immunosuppressive activity of NO in mammals, thus contributing to NO-mediated
      inhibition of IL-2 gene expression after physiological stimuli. The exact
      understanding of the molecular mechanism leading to NO-mediated, fully reversible
      suppression of immune reactions may lead to use of this naturally occurring tool
      as an aid in inflammatory diseases.

PMID- 10656875
TI  - Tyrosine phosphorylation of focal adhesion kinase and paxillin regulates the
      signaling mechanism of the rapid nongenomic action of dexamethasone on actin
      cytoskeleton.
AB  - We have previously shown that dexamethasone (DEX) stimulates rapid polymerization
      of actin and stabilization of microfilaments in human endometrial adenocarcinoma
      cells. As the content of total cellular actin and the concentration of the actin
      transcript did not change, we concluded that polymerization of actin by
      glucocorticoids involves nongenomic mechanisms. However, the signaling events by
      which the latter is achieved remain unknown. In the present study we evaluated
      whether tyrosine phosphorylation is required for the rapid, nongenomic DEX effect
      on actin assembly. In cells preincubated with the tyrosine kinase inhibitors,
      genistein or erbstatin analogue (EA), before adding DEX the G-/total actin ratio
      remained unchanged, whereas DEX in the absence of both inhibitors reduced the
      ratio by 25%. In addition, when cells were preincubated with the protein tyrosine
      phosphatase inhibitor pervanadate and subsequently incubated with DEX, the G
      /total actin ratio was dramatically reduced by 65%. Furthermore, DEX increased
      transiently the levels of tyrosine phosphorylation of focal adhesion kinase (FAK)
      and paxillin within 2 to 15 min, without a change in their expression levels.
      Pervanadate mimicked this effect of DEX and enhanced tyrosine phosphorylation of
      both proteins. In addition, when cells were exposed to the anticytoskeletal agent
      cytochalasin B, the basal levels of tyrosine phosphorylation of both proteins
      were reduced. This effect was reversed by DEX, indicating that actin cytoskeleton
      integrity is required for the effect of DEX on tyrosine phosphorylation of FAK
      and paxillin. Finally, we documented enhanced expression of the Ras-related GTP
      binding protein Rho-B after long-term (12- and 24-hr) treatment with DEX, whereas
      Rho-B levels remained unchanged after short-term (3- and 6-hr) treatment. Our
      observations demonstrate a novel mechanism through which the rapid nongenomic
      effect of DEX on actin assembly requires tyrosine phosphorylation of the
      cytoskeleton-associated proteins FAK and paxillin. We also propose that the DEX
      induced actin polymerization may constitute a mechanism for transduction of
      signals resulting in tyrosine phosphorylation of FAK and paxillin. Moreover, the
      enhanced Rho-B levels observed after long-term treatment with DEX imply a
      mechanism for the well-described, long-term effects of glucocorticoids on actin
      cytoskeleton.

PMID- 10656879
TI  - Frequencies of SCEs in peripheral blood lymphocytes of pesticide workers.

PMID- 10656876
TI  - Modulation of nucleoside [correction of nucleotide] triphosphate
      diphosphohydrolase-1 (NTPDase-1)cd39 in xenograft rejection.
AB  - BACKGROUND: There is increasing evidence showing that extracellular nucleosides
      [corrected] may be important mediators of vascular inflammation. Nucleoside
      [corrected] triphosphate diphosphohydrolase-1 (NTPDase-1, identical to CD39), the
      major vascular endothelial ectonucleotidase, is responsible for the hydrolysis of
      both extracellular ATP and ADP in the blood plasma to AMP. Studies were therefore
      conducted to evaluate the role of vascular NTPDase-1/cd39 in modulating platelet
      activation and vascular injury in cardiac xenografts. MATERIALS AND METHODS:
      Cardiac xenografts from both wild-type and cd39 knockout mice (C57BL/6 x 129 Svj)
      were transplanted into Lewis rats. Alterations in cd39 mRNA transcripts and
      NTPDase activity expression were evaluated in wild-type grafts in untreated rats
      and then following complement depletion and immunosuppression. Rejection
      responses were studied with both mutant and wild-type grafts in the following
      models: presensitization with or without complement depletion, complement
      depletion alone, and with chronic immunosuppression to induce long-term graft
      survival. RESULTS: NTPDase biochemical activity in wild-type xenografts rapidly
      decreased after transplantation but soon rebounded with graft survival. Elevated
      levels of cd39 mRNA with associated increases in NTPDase activity were observed
      in all long-term surviving wild-type grafts. Hyperacute xenograft rejection times
      were comparable in wild-type and mutant grafts but cd39-deficient grafts were
      subject to more rapid rejection and exhibited pronounced vascular injury in
      complement-depleted, presensitized rats. The cd39-deficient grafts in
      immunosuppressed recipients were subject to increased intravascular platelet
      sequestration and fibrin deposition; this resulted in focal myocardial infarction
      in long-term surviving mutant xenografts. CONCLUSIONS: Augmentation of NTPDase-1
      activity may be an important adaptive response for graft survival. Our results
      suggest that NTPDase-1/cd39 influences pathways of vascular injury in cardiac
      xenografts.

PMID- 10656877
TI  - Pharmacogenomics of the cystic fibrosis transmembrane conductance regulator
      (CFTR) and the cystic fibrosis drug CPX using genome microarray analysis.
AB  - BACKGROUND: Cystic fibrosis (CF) is the most common lethal recessive disease
      affecting children in the U.S. and Europe. For this reason, a number of ongoing
      attempts are being made to treat the disease either by gene therapy or
      pharmacotherapy. Several phase 1 gene therapy trials have been completed, and a
      phase 2 clinical trial with the xanthine drug CPX is in progress. The protein
      coded by the principal CFTR mutation, DeltaF508-CFTR, fails to traffic
      efficiently from the endoplasmic reticulum to the plasma membrane, and is the
      pathogenic basis for the missing cAMP-activated plasma membrane chloride channel.
      CPX acts by binding to the mutant DeltaF508-CFTR and correcting the trafficking
      deficit. CPX also activates mutant CFTR channels. The comparative genomics of
      wild-type and mutant CFTR has not previously been studied. However, we have
      hypothesized that the gene expression patterns of human cells expressing mutant
      or wild-type CFTR might differ, and that a drug such as CPX might convert the
      mutant gene expression pattern into one more characteristic of wild-type CFTR. To
      the extent that this is true, a pharmacogenomic profile for such corrective drugs
      might be deduced that could simplify the process of drug discovery for CF.
      MATERIALS AND METHODS: To test this hypothesis we used cDNA microarrays to study
      global gene expression in human cells permanently transfected with either wild
      type or mutant CFTR. We also tested the effects of CPX on global gene expression
      when incubated with cells expressing either mutant or wild-type CFTR. RESULTS:
      Wild-type and mutant DeltaF508-CFTR induce distinct and differential changes in
      cDNA microarrays, significantly affecting up to 5% of the total genes in the
      array. CPX also induces substantial mutation-dependent and -independent changes
      in gene expression. Some of these changes involve movement of gene expression in
      mutant cells in a direction resembling expression in wild-type cells.
      CONCLUSIONS: These data clearly demonstrate that cDNA array analysis of cystic
      fibrosis cells can yield useful pharmacogenomic information with significant
      relevance to both gene and pharmacological therapy. We suggest that this approach
      may provide a paradigm for genome-based surrogate endpoint testing of CF
      therapeutics prior to human administration.

PMID- 10656880
TI  - Spermatotoxic effects of nickel in mice.

PMID- 10656881
TI  - Clomazone residues in soil and runoff: measurement and mitigation.

PMID- 10656882
TI  - Persistent pollutants in sediments of the Yangtse River.

PMID- 10656883
TI  - Impaired health in flounder, Paralichthys spp. Inhabiting Coastal Chile.

PMID- 10656884
TI  - Effects of beta-naphthoflavone on the levels of glutathione S-transferase from
      liver of Pacu, Piaractus mesopotamicus.

PMID- 10656885
TI  - Toxicity of thiocyanate to fish, plankton, worm, and aquatic ecosystem.

PMID- 10656886
TI  - Acute toxicity of chlorine-produced oxidants (CPO) to the marine invertebrates
      Amphiporeia virginiana and Eohaustorius washingtonianus.

PMID- 10656887
TI  - Validation of the acute toxicity of inorganic chloramines to the fresh water
      invertebrate Daphnia magna.

PMID- 10656888
TI  - Bioavailability of apparent fulvic acid complexed copper to fish gills.

PMID- 10656889
TI  - Adsorption of metals in seawater to limpet (Patella vulgata) pedal mucus.

PMID- 10656890
TI  - Contamination of farm animals and fishes from Slovenia with heavy metals and
      sulfonamides.

PMID- 10656891
TI  - Heavy metals (Cd, Cu, Zn) in wood and wood-feeding insects and other
      invertebrates associated with decaying pine trees.

PMID- 10656892
TI  - Cadmium and lead contents in suburban and urban soils from two medium-sized
      cities of Spain: influence of traffic intensity.

PMID- 10656893
TI  - Effects of glyphosate and dalapon on total free amino acid profiles of
      Pseudosuccinea columella snails.

PMID- 10656894
TI  - Species- and age-related differences in susceptibility to pesticide exposure for
      two amphibians, Rana pipiens, and Bufo americanus.

PMID- 10656895
TI  - Effects of ammonium sulfate on growth of larval Northwestern salamanders, red
      legged and pacific treefrog tadpoles, and juvenile fathead minnows.

PMID- 10656896
TI  - Effects of calcium, magnesium, and sodium on alleviating cadmium toxicity to
      Hyalella azteca.

PMID- 10656897
TI  - Diazinon induced changes in the serum proteins of large mouth bass, Micropterus
      salmoides.

PMID- 10656898
TI  - Amelioration of fly-Ash by selected nitrogen fixing blue green algae.

PMID- 10656899
TI  - Reducing formaldehyde exposure in office environments using plants.

PMID- 10656900
TI  - Nonsurgical fluoroscopically guided dacryocystoplasty of common canalicular
      obstructions.
AB  - PURPOSE: To assess dacryocystoplasty in the treatment of epiphora due to
      obstructions of the common canaliculus. METHODS: Twenty patients with severe
      epiphora due to partial (n = 16) or complete (n = 4) obstruction of the common
      canaliculus underwent fluoroscopically guided dacryocystoplasty. In all cases of
      incomplete obstruction balloon dilation was performed. Stent implantation was
      attempted in cases with complete obstruction. Dacryocystography and clinical
      follow-up was performed at intervals of 1 week, and 3, 6, 12, and 18 months after
      the procedure. The mean follow-up was 6 months (range 3-18 months). RESULTS:
      Balloon dilation was technically successfully performed in all patients with
      incomplete obstructions (n = 16). In three of four patients with complete
      obstruction stent implantation was performed successfully. Subsequent to failure
      of stent implantation in one of these patients balloon dilation was performed
      instead. The long-term primary patency rate in patients with incomplete
      obstructions was 88% (n = 14/16). In three of four cases with complete
      obstruction long-term patency was achieved during follow-up. Severe
      complications, infections, or punctal splitting were not observed. CONCLUSION:
      Fluoroscopically guided balloon dacryocystoplasty is a feasible nonsurgical
      therapy in canalicular obstructions with good clinical results that may be used
      as an alternative to surgical procedures. In patients with complete obstructions
      stent placement is possible but further investigations are needed to assess the
      procedural and long-term results.

PMID- 10656901
TI  - PTA and stenting of benign venous stenoses in the pelvis: long-term results.
AB  - PURPOSE: To provide follow-up data on endovascular intervention for venous
      stenoses in the pelvis. METHODS: Between 1985 and 1995, 35 patients presented
      with 42 stenoses of the pelvic veins after operative thrombectomy and creation of
      an arteriovenous fistula, combined with intraoperative venous angioscopy. All
      patients underwent angioplasty and, if unsuccessful, percutaneous insertion of an
      endovascular stent (n = 7). RESULTS: Angioplasty with and without endovascular
      stenting was technically successful in 34 of 35 patients (97%). Average length of
      the stenoses was 20.6 mm (range 10-90 mm), average diameter before dilation 4.1
      mm (range 2-6 mm), and average diameter after dilation 10.1 mm (range 5-18 mm).
      Intraoperative angioscopy showed pathologic findings (intimal laceration or
      residual thrombotic material) in 14 patients. After an average follow-up period
      of 4.13 years, 24 (69%) patients had patent veins. The difference in the primary
      patency rate between patients with angioscopically abnormal veins (6 of 14
      patients, corresponding to a patency rate of 43%) and patients with
      angioscopically normal veins after thrombectomy (18 of 21 patients, corresponding
      to a patency rate of 86%) was statistically significant (p<0.01, log rank test).
      CONCLUSIONS: Percutaneous transluminal angioplasty and/or stenting are good
      treatment modalities for pelvic vein stenosis following surgical thrombectomy.
      Angioscopically abnormal veins have a poorer long-term patency, regardless of the
      type of intervention.

PMID- 10656902
TI  - Spiral CT quantification of aorto-renal calcification and its use in the
      detection of atheromatous renal artery stenosis: A study in 42 patients.
AB  - PURPOSE: To investigate whether a correlation exists between aortic and renal
      arterial calcifications detected with spiral CT and significant angiographic
      renal artery stenosis (RAS). METHODS: Forty-two patients (mean age 67 years,
      range 37-84 years), of whom 24 were hypertensive, prospectively underwent
      abdominal helical CT and aortic and renal arteriography. The 3-mm thickness CT
      scans (pitch = 1) were reconstructed each millimeter. A manual outline of the
      renal artery including its ostial portion was produced. Calcific hyperdensities
      were defined as areas of density more than 130 HU. CT data were compared with the
      presence or absence of RAS on angiography (24 cases); hypertension and age were
      taken into account (Mann-Whitney U-test). RESULTS: CT detection and
      quantification appeared to be reliable and reproducible. We did not find any
      correlation between aortic and renal arterial calcifications and RAS, even for
      the patients above 65 years, with or without hypertension. There was no
      correlation either between calcifications and hypertension in patients without
      RAS. CONCLUSION: In this population, aortic and renal arterial calcifications
      have no predictive value for RAS.

PMID- 10656903
TI  - Percutaneous implantation of a Port-Catheter System using the left subclavian
      artery.
AB  - PURPOSE: To evaluate the safety and feasibility of a percutaneous Port-Catheter
      System (PCS) implanted via the subclavian artery (SCA) for regional chemotherapy
      or chemoembolization of thoracic, abdominal, and pelvic malignant tumors.
      METHODS: Percutaneous puncture of the SCA was performed in 256 patients with
      thoracic, abdominal, or pelvic malignant tumors; then a catheter was inserted
      into the target artery. After the first transcatheter chemotherapy or
      chemoembolization with an emulsion of lipiodol and anticancer agents, an
      indwelling catheter was introduced with its tip placed in the target artery and
      its end subcutaneously connected to a port. RESULTS: The procedure was
      successfully completed in all 256 cases (100%). The indwelling catheter tip was
      satisfactorily placed in the target arteries in 242 cases (98%). Complications
      attributable to the procedure occurred in 20 (7.8%) cases, including pneumothorax
      (n = 10, 4%), hemothorax (n = 1, 0.4%), infections in the pocket (n = 4, 1.6%),
      and hematoma at the puncture site (n = 5, 2%). There were no severe sequelae or
      deaths. The duration of PCS usage was 1-36 months (median 9.5 months). During the
      course of treatment, occlusion of the target artery occurred in 20 cases (7.8%).
      Dislocation of the tip of the indwelling catheter occurred in 12 cases (4.7%); in
      10 of the 12, the tip of the indwelling catheter was repositioned into the target
      artery. In all 10 cases no large symptomatic hematomas developed after the PCS
      was removed. CONCLUSION: Percutaneous PCS implantation via the left SCA, a
      relatively new procedure, is a safe and less invasive treatment approach than
      surgical placement for malignancies.

PMID- 10656904
TI  - Intraarterial infusion chemotherapy with lipiodol-CDDP suspension for
      hepatocellular carcinoma.
AB  - PURPOSE: To quantitatively evaluate the usefulness of lipiodol-CDDP suspension
      (LCS) chemotherapy in hepatocellular carcinoma (HCC). METHODS: CDDP (cis
      diamminedichloroplatinum) powder was prepared by removing the water and NaCl from
      aqueous CDDP. Two quantities of prepared CDDP powder, 10 mg and 20 mg, were mixed
      with 1 ml each of iopamidol 300 mgI/ml (IP300) and lipiodol (LPD) using a high
      pressure pumping method, thus producing LCS. Thirty-two patients with HCC, who
      had good renal function [creatinine clearance (Ccr) 50 ml/min or more], received
      additional intraarterial infusion chemotherapy with LCS or LCS alone. RESULTS:
      The most frequently observed CDDP powder sizes were 5.95-10.90 microm (average:
      11.59 microm). The LCS obtained demonstrated a suspension of 2-12 microm (average
      3.69 microm) immediately after mixing, and no significant changes were observed
      in LCS particle sizes 3 hr after mixing. Moreover, the sustained release with LCS
      was observed for up to 3 hr. Meanwhile, the peripheral free platinum
      concentration between intraarterial infusion chemotherapy with LCS and
      intraarterial infusion with the aqueous solution of CDDP, with respect to
      variance residence time (VRT), showed a significant difference, with a p value of
      0.0382. The survival rate was 89.84% at 1 year, 73.78% at 2 years, and 68.51% at
      3 years. Furthermore, the platinum concentration in the tumor was 25-95 times the
      concentration in the surrounding liver parenchyma. CONCLUSION: Good clinical
      results can be expected by applying LCS to HCC.

PMID- 10656905
TI  - Early detection and treatment of hemodialysis access dysfunction.
AB  - PURPOSE: To assess the usefulness of a program for the early detection of
      hemodialysis graft dysfunction and the impact on graft survival of percutaneous
      transluminal angioplasty (PTA) and stent implantation to correct venous stenosis.
      METHODS: A program for the early detection of hemodialysis access graft
      dysfunction was carried out in 110 patients over a period of 80 months. Detection
      was based on physical examination, flow rate measurements, venous pressure, and
      analytical determinations performed at dialysis. The stenoses detected were
      treated by PTA or PTA plus stent deployment. Survival curves compared primary and
      assisted patency rates for the different graft types. RESULTS: The most important
      indicators of dysfunction were increased venous pressure and difficulty in
      cannulation of the graft. Significant stenoses were revealed by 227 (92.2%) of
      the 246 fistulography procedures performed. PTA results were satisfactory in 100%
      of the Thomas grafts, 74% of the Brescia-Cimino (BC) grafts, and 53% of the
      polytetrafluoroethylene (PTFE) grafts. Technical success rates for stent
      deployment were 92% for BC grafts and 100% for PTFE grafts, while functional
      success rates were 96% and 97%, respectively. The difference in the primary
      patency (P1) and assisted patency (AP) values was statistically significant for
      all three graft types. There was no significant difference in the patency rates
      for grafts treated by PTA alone or by PTA and stent deployment. CONCLUSION: A
      surveillance program helped prevent graft thrombosis, and intervention as
      required achieved excellent primary and assisted patency rates. Stent deployment
      salvaged a considerable number of accesses but did not significantly extend
      access survival time.

PMID- 10656906
TI  - Mechanical properties of metallic stents: how do these properties influence the
      choice of stent for specific lesions?
AB  - PURPOSE: To assess selected balloon-expandable and self-expanding stents for
      radial force, flexibility, radio-opacity, and trackability, and to relate these
      physical characteristics to potential indications for placement. METHODS: Force
      strain curves were plotted for each stent and the force required to produce 50%
      luminal narrowing was recorded. The ability of the stent to show elastic recoil
      following deformation was also noted. Flexibility was measured by bending the
      stents against a force transducer and recording the force required per degree of
      flexion. Radio-opacity was measured by comparing each stent against a standard
      aluminum step wedge. Trackability was measured by testing the ability of the
      stent on its delivery system to track over angles of 90 degrees and 60 degrees.
      RESULTS: The balloon-expandable stents showed greater radial strength and radio
      opacity but, apart from the AVE Iliac Bridge stent, showed poorer flexibility and
      trackability. The self-expanding stents showed less radial force but were able to
      re-expand following deformity. They were generally more flexible and had better
      trackability but lower radio-opacity. CONCLUSION: There is no stent which
      exhibits all the ideal properties required and therefore the interventionist will
      need to keep a range of stents available if all lesions are to be addressed.

PMID- 10656907
TI  - Fracture of Memotherm metallic stents in the biliary tract.
AB  - In a series of 66 patients who had palliation of malignant obstructive jaundice
      by percutaneous placement of Memotherm expanding metal stents, we report four
      cases of stent fracture. This has not been reported previously.

PMID- 10656908
TI  - Subclavian arteritis and pseudoaneurysm formation secondary to stent infection.
AB  - Technically uncomplicated percutaneous angioplasty and stent placement of a left
      subclavian artery stenosis was performed in a 56-year-old man for treatment of
      subclavian steal syndrome and vertebrobasilar insufficiency. Six days later the
      patient was readmitted with Staphylococcus aureus bacteremia and stigmata of
      septic emboli isolated to the ipsilateral hand. Nine days later he had computed
      tomography (CT) evidence of a contrast-enhancing phlegmon surrounding the stent.
      Despite clinical improvement and resolution of bacteremia on intravenous
      antibiotic therapy, the phlegmon progressed, and at day 21 a pseudoaneurysm was
      angiographically confirmed. The patient underwent surgical removal of the stented
      arterial segment and successful autogenous arterial reconstruction. The possible
      contributory factors leading to stent infection were prolonged right femoral
      artery access and an infected left arm venous access. Although the role of
      prophylactic antibiotics remains to be defined, it may be important in cases
      where the vascular access sheath remains in place for a prolonged period of time.

PMID- 10656909
TI  - Treatment of chronic type B aortic dissection with endovascular stent-graft
      placement.
AB  - A 74-year-old man with chronic aortic dissection was treated with an endovascular
      stent graft, fabricated from expanded polytetrafluoroethylene and a Z-stent. It
      was placed in the true lumen to close an entry tear. Closure was obtained
      immediately and thrombosis of the false lumen at the descending thoracic aorta
      was observed on computed tomography (CT) obtained 1 week later. No procedure
      related complications developed. The patient is doing well with no adverse events
      including aortic rupture or aortic branch ischemia.

PMID- 10656910
TI  - Isolation of the left innominate artery in an elderly patient without congenital
      heart disease.
AB  - We report a rare anomaly consisting of a right aortic arch with an isolated left
      innominate artery in an elderly man without congenital heart disease.

PMID- 10656911
TI  - Vascular complications in lumbar spinal surgery: percutaneous endovascular
      treatment.
AB  - Four patients underwent endovascular treatment of vascular injuries complicating
      lumbar spinal surgery. In two patients with massive retroperitoneal hemorrhage,
      the extravasating lumbar arteries were successfully embolized with microcoils.
      Two patients with large iliac arteriovenous fistula (AVF) were treated, one with
      embolization using a detachable balloon and coils, which failed, and the other
      with placement of a stent graft after embolization of distal runoff vessels,
      which occluded the fistula. We conclude that acute arterial laceration or delayed
      AVF complicating lumbar spinal surgery can be managed effectively with selective
      embolization or stent-graft placement, respectively.

PMID- 10656912
TI  - Migrated Hickman catheters: a simple repositioning method using a stiff
      hydrophilic guidewire.
AB  - We present a simple guidewire insertion technique and a new way of prepping for
      the procedure for readvancement of partially retracted Hickman catheters with the
      aid of a stiff hydrophilic guidewire.

PMID- 10656913
TI  - Interventional uroradiologic procedures performed using gadodiamide as an
      alternative to iodinated contrast material.
AB  - Three patients with either a history of severe allergic reactions to iodinated
      contrast or marked renal insufficiency underwent interventional uroradiologic
      procedures using full-strength gadodiamide (Gd) as a contrast agent in place of
      iodinated contrast material. The procedures were percutaneous access for
      nephrostolithotomy, antegrade pyelography with placement of a nephroureteral
      stent, and a diagnostic nephrostogram with exchange of a nephroureteral stent. Gd
      was visualized fluoroscopically and produced satisfactory digital radiographs
      without allergic reaction or worsening renal function. Gd can be useful in
      guiding interventional uroradiologic procedures when iodinated contrast material
      is contraindicated.

PMID- 10656914
TI  - Translumbar placement of paired hemodialysis catheters (Tesio catheters) and
      follow-up in 10 patients.
AB  - For lack of other suitable access, 10 consecutive patients received paired
      hemodialysis catheters for long-term hemodialysis using a translumbar approach to
      the inferior vena cava (IVC). All attempts were successful. Five paired catheters
      were placed using the single-puncture technique, and five using the dual-puncture
      technique. Catheters were in place for a total of 2252 catheter days. The average
      duration of catheter placement was 250 days (range 30-580 days). All catheters
      were functioning up to the time the study was completed or the patient died. The
      most common complication was partial dislodgment of the catheter in 3 of 23
      catheters (13%), all occurring in obese patients. One episode of retroperitoneal
      hemorrhage was noted in a patient having the single-access technique. There were
      no episodes of infection or IVC thrombosis.

PMID- 10656915
TI  - Re: filter placement in double inferior vena cava.

PMID- 10656916
TI  - Re: endovascular management of an inferior gluteal artery pseudoaneurysm
      secondary to tuberculous cold abscess.

PMID- 10656917
TI  - Long-term results of percutaneous transluminal angioplasty for hemodialysis shunt
      insufficiency
AB  - Purpose: The purpose of this study was to evaluate the long-term results of
      percutaneous transluminal angioplasty (PTA) for stenosis and/or occlusion of
      dialysis shunts. Methods: One hundred thirty-nine stenosed or thrombosed dialysis
      shunts (99 native fistulae, 37 grafts) in 122 patients were treated by PTA. In 39
      cases, additional PTA for restenosis was performed. In total, 230 PTAs were
      performed (1-10 PTA/shunt). Results: The initial success rate was 86% in cases
      without occlusion. In contrast, the success rate in cases with occlusion was 53%,
      significantly worse than in the cases without occlusion. In cases in which
      initial success was obtained, primary cumulative patency rates at 3, 6, and 12
      months were 87%, 60%, and 40%, respectively. With repeat PTA, secondary
      cumulative patency rates at 3, 6, 12, and 24 months were 96%, 83%, 63%, and 55%,
      respectively. Patency of native fistulae was better than patency of grafts. There
      was no significant relationship between the anatomical location of the stenoses
      and the patency rates. Conclusion: PTA is an effective treatment for shunt
      stenosis; although primary patency after PTA is not sufficient, repeated PTA
      increases patency.

PMID- 10656919
TI  - Announcements

PMID- 10656918
TI  - Analysis of hepatocellular carcinoma fed by internal thoracic artery
AB  - Purpose: The purpose of this study was to elucidate the clinical features of
      hepatocellular carcinoma (HCC) fed by the internal thoracic artery (ITA).
      Methods: In seven patients HCC fed by the ITA was confirmed by digital
      subtraction angiography. The number of previous transcatheter arterial
      embolization (TAE), the period from the first TAE to TAE of the ITA, tumor
      location, tumor size, and occlusion of the hepatic artery (HA) and other
      collateral vessels were explored in each case. Results: The HCCs were located in
      S4 of the liver (n = 5) and in S8 (n = 1) and were fed by the right ITA and one
      nodule in S2-3 was fed by the left ITA. Tumor size was 3-10 cm. The number of
      previous TAE of the HA ranged from 2 to 12. The period from the first TAE to TAE
      of the ITA was 3-53 months. Angiography of these patients showed occlusion of the
      HA in six cases, and of the extrahepatic collaterals including the inferior
      phrenic artery (IPA) in five cases, intercostal artery (ICA) in one case, and
      epicholedocal artery (EPA) in one case. Conclusion: The ITA often supplies HCC
      located in the anterior superior region of the liver under the diaphragm; there
      can be long-term survival with repeated TAE and occlusion of HA.

PMID- 10656920
TI  - Structure and mapping of the mouse matrilin-3 gene (Matn3), a member of a gene
      family containing a U12-type AT-AC intron.
AB  - The gene for murine matrilin-3, an extracellular matrix protein present in
      cartilage, was isolated and further characterized. The gene spans 23.4 kb and
      comprises 8 exons; with one exception, this reflects the modular structure of the
      protein. The major and a minor transcription start site were determined by RNase
      protection assays to positions approximately 72 nt and 87 nt upstream of the ATG
      codon, respectively. The promoter contains a TATA-like box 32 bp upstream of the
      main transcription start as well as several potential binding sites for
      eukaryotic transcription factors. As in all known matrilin genes, the last
      intron, separating the exons coding for the coiled-coil domain, does not follow
      the GT-AG rule and belongs to the subgroup of introns having AT-AC at the ends
      that are spliced by the U12-type spliceosome. The mouse matrilin-3 gene does not
      contain hidden exon sequences coding for the second vWFA-like domain present in
      all other matrilins. The intron that could possibly contain such sequences
      instead shows 75% repetitive sequences, indicating an evolutionary process that
      has led to the loss of sequences coding for vWFA2. Single-strand conformation
      polymorphism analysis was used to map the Matn3 gene to the proximal end of Chr
      12, linked to the genes Synd1, Apob, Dntb, and Kif3c.

PMID- 10656921
TI  - Mouse hexokinase II gene: structure, cDNA, promoter analysis, and expression
      pattern.
AB  - In mammalian tissues, the phosphorylation of intracellular glucose to glucose-6
      phosphate (Glu-6-P) is facilitated by four distinct hexokinase (HK) isoenzymes,
      designated as HKI-IV. Because of the role of HKII as a leading glycolytic enzyme
      in insulin-sensitive tissues such as skeletal muscle, heart, and adipose tissue,
      defects in HKII function could contribute to the development of insulin
      resistance and perhaps Type 2 diabetes. As a first step towards elucidation of
      the physiological role of HKII in insulin resistance and type 2 diabetes using
      mouse knock-out models, we determined the genomic structure, sequence of the cDNA
      and of 4.8 kb of the 5' regulatory region, and tissue-specific expression of the
      mouse HKII gene. The gene comprises 18 exons that span approximately 50 kb of
      DNA. Nucleotide sequence of the proximal promoter revealed a number of conserved
      putative transcription factor binding motifs. We also found numerous repeat
      elements throughout the mouse HKII gene. The mouse HKII cDNA is approximately 5.5
      kb in length and contains an open reading frome of 2751 bp encoding a protein of
      917 amino acids. The mouse HKII gene is predominantly expressed in skeletal
      muscle, heart, and adipose tissue. The transcription initiation and
      polyadenylation sites for the mouse HKII mRNA were similar to those of the rat
      and human genes.

PMID- 10656922
TI  - ETn insertion in the mouse Adcy1 gene: transcriptional and phylogenetic analyses.
AB  - Early retrotransposons (ETn) are murine transposable elements, bearing some
      structural similarity to integrated proviruses, and can be insertional mutagens.
      We have recently identified the causative mutation of the barrelless (Adcy1brl)
      phenotype as an integration of a 5.7-kb ETn in an intron of the adenylyl cyclase
      type I (Adcy1) gene. In the present study, Northern blot analysis shows that the
      ETn insertion results in loss of the normal Adcy1 transcript, a finding
      consistent with the loss-of-function Adcy1brl mutation, and generation of shorter
      transcripts. These aberrant transcripts are the products of abnormal RNA splicing
      and termination owing to the inserted sequence, and transcription initiation
      within the 3' long terminal repeat (LTR) of the ETn. The DNA sequences of the
      LTRs were compared in phylogenetic analyses with LTRs from 22 other ETn-related
      sequences. Three distinct families of ETn sequences can be identified on the
      basis of their LTRs. The ETn found in Adcy1brl is a member of a family that
      includes all classified ETn elements known to have recently transposed. Further,
      of the four known solitary (solo) LTRs, we have identified two that show evidence
      of recombination between LTRs from different ETn families.

PMID- 10656923
TI  - Coding sequence, chromosomal localization, and expression pattern of Nrf1: the
      mouse homolog of Drosophila erect wing.
AB  - In Drosophila, the erect wing (ewg) protein is required for proper development of
      the central nervous system and the indirect flight muscles. The fly ewg gene
      encodes a novel DNA-binding domain that is also found in four genes previously
      identified in sea urchin, chicken, zebrafish, and human. To identify mouse ewg
      homologs, we designed degenerate primers to the conserved DNA-binding domain. The
      RT-PCR product obtained from mRNA of the mouse muscle cell line C2C12 was used to
      screen cDNA libraries; a single gene was identified which encodes a predicted 503
      amino acid protein. The mouse ewg homolog, termed Nrf1, was mapped to proximal
      Chr 6. By RT-PCR and Northern analysis, Nrf1 was expressed in all tissues
      examined, and Northern analysis on adult tissues revealed a complex banding
      pattern suggesting extensive alternative splicing. Nrf1 hybridized to mRNA
      transcripts at approximately 2.2 kb, 4.0 kb, 4.4 kb, and 5.0 kb, with additional
      tissue-specific transcripts at 1.5 kb in testis, 1.9 kb in lung, and 3.7 kb in
      skeletal muscle. In situ hybridization on whole-mount E9-10.5 embryos showed a
      broad pattern of expression, with the highest levels of expression in the central
      nervous system, somites, first branchial arch, optic vesicle, and otic vesicle.

PMID- 10656924
TI  - Genetic mapping of the rat mutation creeping and evaluation of its positional
      candidate gene reelin.
AB  - We have previously described a rat autosomal recessive mutation, creeping (cre),
      causing severe ataxia and disarrangement of neuronal cells in the central nervous
      system. The mutant strain has recently been successfully inbred, named Komeda
      Zucker creeping (KZC) rat. In the present study, we have performed a genetic
      analysis of the creeping mutation, and mapped it to rat Chromosome (Chr) 4.
      Comparative mapping, together with the similarity of the phenotype, suggested
      that the creeping mutation is homologous to the mouse reeler mutation. In fact,
      reelin expression was markedly reduced in the homozygous mutant (cre/cre) animals
      compared with the normal littermates. Thus, the KZC rat should become a useful
      biological model with a novel mutation in the reelin gene.

PMID- 10656925
TI  - Gene structure and chromosomal mapping of the rat smooth muscle calponin gene.
AB  - Smooth muscle cells (SMC) express a battery of lineage-restricted genes whose
      encoded proteins impart the unique contractile phenotype that characterizes this
      muscle type. While the encoded function of many SMC-restricted genes has been
      extensively analyzed, less is known about their position within the genome and
      the regulatory factors governing their transcription. In this report, we define
      the gene structure, 5' promoter analysis, and chromosomal mapping of the rat
      smooth muscle calponin (CnnI) gene. The rat CnnI gene is comprised of seven exons
      spanning approximately 8 kb of genomic sequence. The intron-exon boundaries of
      the rat CnnI gene match precisely those in human and mouse. Primer extension and
      RNase protection assays indicate two major transcription start positions (tsp).
      Comparative sequence analysis of the 5' promoter region reveals several conserved
      cis regulatory elements, including a TA-rich element within 30 nt of the tsp that
      could be a recognition site for TATA-binding protein and two CCAAT boxes.
      Transient and stable transfection studies support the hypothesis that distal
      regulatory elements confer SMC-restricted expression of CnnI. Finally, using an
      F2 intercross, we have mapped the rat CnnI gene to the telomeric end of
      Chromosome (Chr) 8. These studies provide additional information relating to the
      control of CnnI gene expression and provide a platform to begin assessing the
      potential linkage of CnnI to spontaneous and experimental disease phenotypes in
      rats.

PMID- 10656926
TI  - An integrated linkage-radiation hybrid map of the canine genome.
AB  - Purebred dogs are a unique resource for dissecting the molecular basis of simple
      and complex genetic diseases and traits. As a result of strong selection for
      physical and behavioral characteristics among the 300 established breeds, modern
      dogs are characterized by high levels of interbreed variation, complemented by
      significant intrabreed homogeneity. A high-resolution map of the canine genome is
      necessary to exploit the mapping power of this unusual resource. We describe here
      the integration of an expanded canine radiation hybrid map, comprised of 600
      markers, with the latest linkage map of 341 markers, to generate a map of 724
      markers-the densest map of the canine genome described to date. Through the
      inclusion of 217 markers on both the linkage and RH maps, the 77 RH groups are
      reduced to 44 syntenic groups, thus providing comprehensive coverage of most of
      the canine genome.

PMID- 10656927
TI  - A missense variant of the porcine melanocortin-4 receptor (MC4R) gene is
      associated with fatness, growth, and feed intake traits.
AB  - Our knowledge of the genetic factors affecting obesity is increasing, but
      information about the individual gene effects remains limited in humans as well
      as in animal models. The melanocortin-4 receptor gene (MC4R) has been implicated
      in the regulation of feeding behavior and body weight in humans and mice. We have
      studied MC4R as a candidate gene for the control of economically important growth
      and performance traits in the pig. A missense mutation was identified in a region
      highly conserved among melanocortin receptor (MCR) genes. To determine whether
      there was an association of this MC4R polymorphism with phenotypic variation, we
      tested the mutation in a large number of individual animals from several
      different pig lines. Analyses of growth and performance test records showed
      significant associations of MC4R genotypes with backfat and growth rate in a
      number of lines as well as feed intake overall. It is probable that the variant
      amino acid residue of the MC4R mutation (or a closely linked mutation) causes a
      significant change of the MC4R function. These results support the functional
      significance of a pig MC4R missense mutation and suggest that comparative
      genomics based on model species may be equally important for application to farm
      animals as they are for human medicine.

PMID- 10656928
TI  - Mapping quantitative trait loci for bovine ovulation rate.
AB  - An elite, three-generation family from the USDA Meat Animal Research Center
      twinning population was examined for evidence of ovulation rate quantitative
      trait loci (QTL). This work was both a continuation of previously reported
      results suggesting evidence for ovulation rate QTL on bovine Chromosome (Chr) 7
      and an extension of a genome-wide search for QTL. Additional markers were typed
      on Chr 7 to facilitate interval mapping and testing of the hypothesis of one
      versus two QTL on that chromosome. In addition, 14 other informative markers were
      added to a selective genotyping genome screening of this family, and markers
      exhibiting nominal significance were used to identify chromosomal regions that
      were then subjected to more exhaustive analysis. For Chr 7, a total of 12 markers
      were typed over a region spanning the proximal two-thirds of the chromosome.
      Results from interval mapping analyses indicated evidence suggestive of the
      presence of QTL (nominal P<0.00077) within this region. Subsequent analysis with
      a model postulating two QTL provided evidence (P<0.05) for two rather than one
      QTL on this chromosome. Preliminary analysis with additional markers indicated
      nominal significance (P<0.05) for regions of Chrs 5, 10, and 19. Each of these
      regions was then typed with additional markers for the entire three-generation
      pedigree. Significant evidence (P<0.000026) of ovulation rate QTL was found for
      Chrs 5 and 19, while support on Chr 10 failed to exceed a suggestive linkage
      threshold (P>0.00077).

PMID- 10656929
TI  - Comparative gene mapping workshop: progress in agriculturally important animals.
AB  - Following the successful Comparative Mapping Workshop held at Fraser Island,
      Australia in 1995, HUGO organized a second workshop of 41 invited participants,
      held at Toulouse, France on May 3 and 4, 1999. The aim of the conference was to
      focus on recent developments in genome mapping in a variety of vertebrate
      species, with particular emphasis on progress in farm animals (cattle, pigs,
      chickens, sheep, horses, goats, and deer). In addition, representatives from
      important experimental mammalian and vertebrate organisms (e.g. mice, rats, dogs,
      fugu, and marsupials) also participated in the meeting. After a rapid overview of
      developments in the construction and comparison of genome maps in a wide variety
      of species, discussion focused on how comparative genomics will play a vital role
      in the genetic dissection of multigenic traits and the characterization of
      agriculturally important loci in agricultural species. Acceleration of gene
      discovery with heterologous ESTs (Expressed Sequence Tags) or collections of ESTs
      was discussed. Recent developments in the construction of cDNA libraries and the
      efficiency of tools such as whole genome radiation hybrids (RH) and large
      fragment clone libraries (YACs and in particular BACs) were discussed. Proposed
      criteria to improve the identification of homologous genes between species and
      recommendations for nomenclatures were identified. Particular emphasis was placed
      on how the integration of biological databases could help the scientific
      community.

PMID- 10656930
TI  - Strategies to optimize marker-assisted introgression of multiple unlinked QTL.
AB  - To optimize designs to implement marker-assisted introgression programs aiming to
      introgress three unlinked quantitative trait loci (QTL), the present paper
      studies different alternatives versus a traditional backcross or intercross
      phase. Four alternative backcross strategies appear to be more advantageous by
      having 50% less genotyping load than a traditional backcross strategy tracking
      all three QTL at a time through a single line. A multiplication phase following
      the selection of homozygous animals at the three QTL as an intercross alternative
      allows doubling of the number of homozygous animals in a mouse model compared
      with the first intercross generation. Within the same model, a second intercross
      alternative with individuals carrying all three QTL at the first intercross
      results in a 12-fold increase in the number of homozygous animals obtained in the
      first intercross generation. The same ranges of decrease are observed in the
      number of animals to be genotyped and the number of genotypings when targeting a
      fixed number of homozygous animals. An option, with two lines each carrying two
      QTL through the backcross phase and coupled with the second intercross
      alternative, appears to be the best introgression alternative. This option
      requires 76% fewer genotypings, 68% fewer animals to be genotyped, and costs 75%
      less than an option in which all three QTL are introgressed through a single
      line.

PMID- 10656931
TI  - Evolution of N-terminal sequences of the vertebrate HOXA13 protein.
AB  - While the the role of the homeodomain in HOX function has been evaluated
      extensively, little attention has been given to the non-homeodomain portions of
      the HOX proteins. To investigate the evolution of the HOXA13 protein and to
      identify conserved residues in the N-terminal region of the protein with
      potential functional significance, N-terminal Hoxa13 coding sequences were PCR
      amplified from fish, amphibian, reptile, chicken, and marsupial and eutherian
      mammal genomic DNA. Compared with fish HOXA13, the mammalian protein has
      increased in size by 35% primarily owing to the accumulation of alanine repeats
      and flanking segments rich in proline, glycine, or serine within the first 215
      amino acids. Certain residues and amino acid motifs were strongly conserved, and
      several HOXA13 N-terminal domains were also shared in the paralogous HOXB 13 and
      HOXD13 genes; however, other conserved regions appear to be unique to HOXA13. Two
      domains highly conserved in HOXA13 orthologs are shared with Drosophila AbdB and
      other vertebrate AbdB-like proteins. Marsupial and eutherian mammalian HOXA13
      proteins have three large homopolymeric alanine repeats of 14, 12, and 17-18
      residues that are absent in reptiles, birds, and fish. Thus, the repeats arose
      after the divergence of reptiles from the lineage that would give rise to the
      mammals. In contrast, other short homopolymeric alanine repeats in mammalian
      HOXA13 have remained virtually the same length, suggesting that forces driving or
      limiting repeat expansion are context dependent. Consecutive stretches of
      identical third-base usage in alanine codons within the large repeats were found,
      supporting replication slippage as a mechanism for their generation. However,
      numerous species-specific base substitutions affecting third-base alanine repeat
      codon positions were observed, particularly in the largest repeat. Therefore, if
      the large alanine repeats were present prior to eutherian mammal development as
      is suggested by the opossum data, then a dynamic process of recurring replication
      slippage and point mutation within alanine repeat codons must be considered to
      reconcile these observations. This model might also explain why the alanine
      repeats are flanked by proline, serine, and glycine-rich sequences, and it
      reveals a biological mechanism that promotes increases in protein size and,
      potentially, acquisition of new functions.

PMID- 10656932
TI  - Structure and organization of the mouse Atp2a2 gene encoding the
      sarco(endo)plasmic reticulum Ca2+-ATPase 2 (SERCA2) isoforms.

PMID- 10656933
TI  - The ubiquitin-activating enzyme E1 homologous genes on the mouse Y chromosome
      (Ube1y) represent one functional gene and six partial pseudogenes.

PMID- 10656934
TI  - Genomic locus and promoter region of rat Smad7, an important antagonist of
      TGFbeta signaling.
AB  - SMAD proteins are essential components of the intracellular signaling pathways
      utilized by members of the transforming growth factor beta (TGFbeta) superfamily
      of growth factors. Certain SMAD proteins (Smad1, 2, 3, and 5) can act as
      regulated transcriptional activators. This process involves phosphorylation of
      these proteins by activated TGFbeta receptors. Recently, Smad6 and Smad7 were
      identified; they antagonize TGFbeta signaling by preventing the activation of
      signal-transducing SMAD complexes. TGFbeta rapidly induces the expression of
      Smad7 mRNA, suggesting participation of Smad7 in a negative feedback loop to
      control TGFbeta responses. Similarly, epidermal growth factor (EGF) and
      interferon gamma (IFN-gamma) have been reported to induce Smad7 expression. In a
      rat model system of liver fibrosis, TGFbeta inducibility of Smad7 is abrogated
      during transformation of hepatic stellate cells (HSC), indicating an important
      switch in transcriptional regulation of the gene. With the detailed
      characterization of the rat Smad7 genomic organization including the promoter
      region, we present the first identified Smad7 gene so far. The gene is composed
      of four exons separated by three introns covering a DNA region of about 30
      kilobases (kb) in total. The major transcription start site is conserved between
      rat and mouse, and two polyadenylation signals were detected. In the promoter
      region, a potential CAGA box, a signal transducer and activator of transcription
      (STAT) factor-related recognition site, and different AP1 sites were identified,
      which could be the targets of TGFbeta, IFN-gamma, and EGF-dependent Smad7
      transcription initiation.

PMID- 10656935
TI  - B2 elements present in the human genome.

PMID- 10656936
TI  - Surgical outcomes. What are they and why should they be measured?

PMID- 10656937
TI  - Acute laparoscopic cholecystectomy. A case controlled study.
AB  - BACKGROUND: Acute laparoscopic cholecystectomy (ALC) has been performed
      successfully at a number of institutions. Interval laparoscopic cholecystectomy
      (ILC) is preferred by many surgeons because of its convenience and a perceived
      increased risk with acute surgery. METHODS: A case control study was undertaken.
      The case group was a consecutive series of patients who underwent ALC between
      October 1996 and October 1997. The control group underwent ILC between March 1996
      and March 1997 after at least one previous acute admission for gallstone disease.
      RESULTS: There were 81 patients in the case group and 100 in the control group.
      The groups were similar in terms of age, sex, and clinical diagnosis. Operative
      times (70 min vs 78 min, p = 0.60), major complications (4.9% vs 2%, p = 0.41),
      minor complications (4.9% vs 7%, p = 0.76), and conversion rates (7. 4% vs 7%)
      were similar in both groups. There were no bile duct injuries in either group.
      The median total hospital stay was 5 days in the case group and 8 days in the
      control group (p < 0.0001). CONCLUSIONS: Acute laparoscopic cholecystectomy can
      be performed safely at the first hospital admission, thus reducing hospital stay
      and minimizing inconvenience to patients.

PMID- 10656938
TI  - Laparoscopic esophagomyotomy for the treatment of achalasia in children. A
      preliminary report of eight cases.
AB  - BACKGROUND: Albeit rare in children, achalasia is a disorder with severe symptoms
      that causes growth impairment. The treatment of choice in children is the
      esophagomyotomy, although there are variations in the surgical approaches
      available and differences of opinion regarding the inclusion of an adjunctive
      antireflux procedure. The recent advent of the laparoscopic approach has had a
      profound impact on the treatment of achalasia in both adults and children.
      METHODS: In this report, we describe eight patients with severe achalasia who
      were treated by laparoscopic Heller's operation associated with a fundoplication
      according to either Dor's or Toupet's technique. The patients' ages ranged
      between 2 and 13 years. A five-port technique was used: a 10-mm port placed
      infraumbilically for the optics and four 5-mm ports. One was placed in the right
      abdominal quadrant for retraction of the left hepatic lobe, one in the left
      abdominal quadrant for the first operative instrument, one below the xyphoid
      appendix for the second operative instrument, and the last one to introduce a 5
      mm cannula laterally to the umbilicus to retract the stomach below. A 7-8-cm
      laparoscopic Heller esophagomyotomy was completed, followed by an anterior Dor
      fundoplication in six cases and a Toupet in two. The longitudinal division of the
      anterior esophageal musculature was performed with a scalpel or scissors. The
      myotomy was made along the stomach, extending for >/=2-3 cm. RESULTS: Mean
      operating time was 120 mins. Three complications were recorded. There were two
      perforations of the gastroesophageal mucosa; the first was sutured in laparoscopy
      and the second required a second operation. The third complication was a case of
      dysphagia resolved by dismounting a fundoplication that was too tight. At follow
      up, which lasted from 6 months to 5 years, the children were all free of
      symptoms. CONCLUSIONS: Laparoscopic Heller esophagomyotomy appears to be a
      complex and difficult operation, but it is as safe and effective as laparotomy in
      children with achalasia. However, complications can be numerous and severe at the
      beginning of a surgeon's experience.

PMID- 10656939
TI  - A new technique for laparoscopic exploration to find contralateral patent
      processus vaginalis.
AB  - BACKGROUND: Contralateral inguinal exploration in an infant with a symptomatic
      unilateral hernia is controversial. A patent processus vaginalis (PPV) may be
      found in up to 60% of term infants, and even in a greater number of preterm
      infants. However, only 10% to 30% of children will subsequently develop a
      contralateral hernia when only the symptomatic side is repaired. Standard
      contralateral laparoscopic inguinal exploration (CLIE) usually is performed
      through the ipsilateral groin with an angled scope or through the umbilicus with
      a 0 degrees scope. A significant number of children have a peritoneal veil
      shrouding the internal ring. To enhance the accuracy of contralateral groin
      exploration, we have used a laparoscopic technique of directly visualizing the
      internal ring through a lateral abdominal approach. METHODS: From January 1993
      through June 1997, we performed 141 CLIE on infants younger than 1 year of age
      with symptomatic unilateral inguinal hernia. After routine dissection on the
      symptomatic side, the sac was used to insufflate the abdominal cavity. A needle
      catheter was inserted on the contralateral abdominal wall and used to introduce a
      1.2-mm scope. If a PPV was identified, the potential hernia was repaired using
      standard techniques. RESULTS: Of the 141 CLIEs performed on patients younger than
      1 year of age, 39 (27.6%) were positive. There were no false-positives. In all,
      42 CLIEs (29.7%) were performed on infants born at less than 36 weeks gestation,
      and 14 of these infants (33.3%) had a positive exploration. The patients were
      followed for 3 to 57 months. No complications resulted from the technique. One
      patient had a recurrence on the repaired side. No patients who had a negative
      CLIE subsequently developed a contralateral hernia. CONCLUSIONS: The lateral
      abdominal approach for laparoscopic evaluation of the contralateral groin is safe
      and accurate, requiring no additional incisions. Longer follow-up is necessary to
      determine the true false-negative rate.

PMID- 10656940
TI  - A case controlled study of laparoscopic incisional hernia repair.
AB  - BACKGROUND: Although the feasibility of laparoscopic incisional herniorrhaphy has
      been demonstrated, its advantages over the open technique are still unproven.
      METHODS: Fourteen consecutive laparoscopic incisional hernia repairs were
      compared with 14 matched controls of the open repair done by the same surgeon at
      the same institution. The controls were selected by a medical record technician
      not connected with the study. The cases were selected to match diagnoses, ASA
      status, and body weight as closely as possible. The outcome data for operating
      time, blood loss, hospitalization, resumption of oral intake, and postoperative
      complications were analyzed for statistically significant differences. RESULTS:
      There was no statistical difference between the two groups in the parameters of
      blood loss, hospital days, or days to oral intake. The laparoscopic operation
      took 40% longer. Similar complications were seen in both groups. No mortality or
      early recurrences occurred in either group. CONCLUSION: Laparoscopic incisional
      hernia repair of at least moderate complexity had no demonstrable advantage over
      the open repair in the present study.

PMID- 10656941
TI  - Transesophageal echocardiographic assessment of hemodynamic function during
      laparoscopic cholecystectomy in healthy patients.
AB  - BACKGROUND: This study aimed by means of transesophageal echocardiography, to
      evaluate hemodynamic changes induced by pneumoperitoneum in patients with normal
      cardiac performance. METHODS: In this study, 11 ASA I-II patients (mean age, 39
      years) with normal cardiac performance undergoing laparoscopic cholecystectomy
      were evaluated. A 5-MHz transesophageal biplane phased-array transducer connected
      to an echocardiographer was inserted after induction of anesthesia. Data were
      collected at three different times: before insufflation (T1), 10 min after
      insufflation (T2), and 5 min after desufflation (T3). At these same times, heart
      rate, systolic blood pressure, diastolic blood pressure, end-tidal carbon dioxide
      (CO(2)), and peak airway pressure were recorded. Statistical analysis was
      performed using one-way and two-way analysis of variance (ANOVA). A p value less
      than 0.05 was considered significant. RESULTS: End-systolic and end-diastolic
      diameters of the left ventricle, contractility, and performance parameters did
      not change significantly. Conversely, at insufflation, color Doppler area of the
      mitral backflow increased significantly (p < 0.05) when already present or showed
      up abruptly (T1: 0.22 +/- 0.28 cm(2); T2: 1.28 +/- 1.02 cm(2); T3: 0.49 +/- 0.53
      cm(2)). CONCLUSIONS: Such an event is not interpreted as a mitral insufficiency.
      It is possibly the result of a "contrast effect" caused by the absorption of
      CO(2) microbubbles in the blood.

PMID- 10656942
TI  - Balloon-tipped cannulas for use in laparoscopic diagnosis and treatment of acute
      upper GI bleeding.
AB  - BACKGROUND: Percutaneous balloon-tipped laparoscopic cannulas designed for
      preperitoneal hernia repair can be readily used to treat gastric bleeding
      laparoscopically. METHODS: Between 1995 and 1997, we successfully used balloon
      tipped cannulas to visualize, biopsy, and suture acutely bleeding gastric lesions
      in five patients. These case histories are reviewed for this study. RESULTS:
      Patients received an average of six units of blood preoperatively (range, 0-15).
      Operative time averaged 207 min (range, 149-270). At surgery, gastrotomies were
      made for cannula placement under laparoscopic visualization. Operative findings
      included: lesser curve gastric ulcer, Mallory-Weiss tear, prepyloric ulcer,
      duodenal ulcer, and angiosarcoma. Three patients had successful percutaneous
      suture of bleeding gastric lesions. One patient was converted to open surgery.
      One patient had local resection of an angiosarcoma. CONCLUSION: The laparoscopic
      use of balloon-tipped cannulas allows the expeditious diagnosis and treatment of
      acute gastric hemorrhage.

PMID- 10656943
TI  - A new surgical strategy for cirrhotic patients with hepatocellular carcinoma and
      hypersplenism. Performing a hepatectomy after a laparoscopic splenectomy.
AB  - BACKGROUND: Hepatectomy for cirrhotic patients with hypersplenism is a high-risk
      operative procedure. We report herein a new strategy for high-risk patients with
      hepatocellular carcinoma (HCC). METHODS: Six cirrhotic patients with HCC and
      hypersplenism received a partial hepatectomy after first undergoing a
      laparoscopic splenectomy. We then compared the variables for these patients
      before splenectomy and before hepatectomy. RESULTS: The platelet count and the
      white blood cell count were found to be significantly elevated before
      hepatectomy. The ammonia value decreased significantly before hepatectomy. The
      albumin value tended to be elevated before hepatectomy. Furthermore, the Child's
      classification of all patients improved significantly before hepatectomy.
      However, other variables-such as the indocyanine green dye excretion test at 15
      min and the bilirubin value-did not change after splenectomy. For hepatectomy
      patients who first underwent a laparoscopic splenectomy, operation time ranged
      from 265 to 440 min (average time, 361 min), and blood loss ranged from 500 to
      2,200 ml (median volume, 1,300 ml). Four of six patients did not require any
      blood transfusion; furthermore, no patient needed a platelet-rich plasma
      transfusion. All but one patient, who suffered postoperatively from an
      intractable duodenal ulcer, had an uneventful postoperative course. CONCLUSION:
      Partial hepatectomy after an initial laparoscopic splenectomy is a new and
      effective choice of treatment for cirrhotic patients with HCC and hypersplenism.

PMID- 10656944
TI  - The efficacy of laparosonic coagulating shears for arterial division and
      hemostasis in porcine arteries.
AB  - BACKGROUND: Recently, the laparosonic coagulating shears (LCS) have been used
      widely in laparoscopic surgery. In the current study, the usefulness of LCS for
      arterial division and hemostasis was examined in porcine arteries. METHODS:
      Porcine arteries of several diameters (1, 3, and 5 mm) were removed and divided
      using LCS with different blade modes: shear, blunt, and flat. The division time
      and bursting pressure were registered. Additionally, divided sections stained by
      the Azan-Mallory method were observed microscopically. RESULTS: The division time
      was dependent on the blade modes used. With the flat mode, the bursting pressure
      of 5-mm arteries was significantly higher than the bursting pressure with shear
      and blunt modes. Histologically, cavitation and mild degeneration of the vessel
      walls occurred adjacent to the cutting edge. CONCLUSION: The LCS is a safe and
      useful device for arterial division and hemostasis for 5-mm arteries if an
      adequate blade mode is used.

PMID- 10656945
TI  - Repeat transthoracic endoscopic sympathectomy for palmar and axillary
      hyperhidrosis.
AB  - BACKGROUND: Patients undergoing an unsuccessful sympathectomy experience dryness
      on one hand and excessive sweating on the other. This is embarrassing for the
      patients, and resolution of both a previous failed sympathectomy and recurrent
      hyperhidrosis is important. METHODS: From September 1995 to January 1998, 24
      patients (11 men and 13 women; mean age, 28.2 years) underwent repeat
      transthoracic sympathectomy (TES). The repeat TES was performed with patients
      under general anesthesia using either a standard single-lumen endotracheal tube
      (12 patients) or a double-lumen endotracheal tube (12 patients). Ablation of T2
      and T3 ganglia and any Kuntz fiber was performed in treating patients with palmar
      hyperhidrosis, and a similar procedure was performed on T3 and T4 ganglia for
      patients with axillary hyperhidrosis. RESULTS: The reasons for failure of the
      previous TES were pleural adhesion (14/24), intact T2 ganglion (5/24), aberrant
      venous arch drainage to the superior vena cava (2/24), incomplete interruption of
      sympathetic nerve (2/24), and possible reinnervation (1/24). The mean operation
      time was 28 min (range, 18-72 min). In all, 23 patients had a satisfactory
      result, without recurrence of palmar or axillary hyperhidrosis. The mean follow
      up time was 22 months (range, 5-30 months). The average hospital stay was 1.8
      days. There was no surgical mortality. CONCLUSION: Repeat TES is a safe and
      effective method for treating both an unsuccessful sympathectomy and recurrent
      palmar or axillary hyperhidrosis.

PMID- 10656946
TI  - Effect of surgical stress on endogenous morphine and cytokine levels in the
      plasma after laparoscopoic or open cholecystectomy.
AB  - BACKGROUND: Endogenous morphine in the brain leads to various biological
      responses after surgery. The aim of this study was to determine whether morphine
      levels in the plasma would be enhanced by open laparotomy rather than by
      laparoscopic procedures. METHODS: We compared 19 patients who underwent
      laparoscopic cholecystectomy with five patients who underwent resection of the
      gallbladder by open laparotomy. Morphine levels in the plasma were measured by an
      electrochemical detection system. RESULTS: Postoperative endogenous morphine
      levels were higher with open laparotomy than with the laparoscopic technique
      (three h after surgery: open, 200 +/- 52.6 fmol/ml vs laparoscopy, 17.6 +/- 3.7,
      p < 0.01). This morphine elevation accounted for higher levels of cytokine,
      greater pain scores, and longer duration of fasting in open laparotomized
      patients than in laparoscopic cholecystectomy patients. Stress hormone levels in
      the plasma were also higher with open laparotomy than with laparoscopy.
      CONCLUSION: Morphine synthesis was enhanced by open laparotomy, resulting in
      greater biological response postoperatively than that seen with laparoscopic
      cholecystectomy.

PMID- 10656947
TI  - Laparoscopic cholecystectomy, Calot's triangle, and variations in cystic arterial
      supply.
AB  - BACKGROUND: The extrahepatic biliary tree with the exact anatomic features of the
      arterial supply observed by laparoscopic means has not been described heretofore.
      Iatrogenic injuries of the extrahepatic biliary tree and neighboring blood
      vessels are not rare. Accidents involving vessels or the common bile duct during
      laparoscopic cholecystectomy, with or without choledocotomy, can be avoided by
      careful dissection of Calot's triangle and the hepatoduodenal ligament. METHODS:
      We performed 244 laparoscopic cholecystectomies over a 2-year period between
      January 1, 1995 and January 1, 1997. RESULTS: In 187 of 244 consecutive cases
      (76.6%), we found a typical arterial supply anteromedial to the cystic duct, near
      the sentinel cystic lymph node. In the other cases, there was an atypical
      arterial supply, and 27 of these cases (11.1%) had no cystic artery in Calot's
      triangle. A typical blood supply and accessory arteries were observed in 18 cases
      (7.4%). CONCLUSION: Young surgeons who are not yet familiar with the handling of
      an anatomically abnormal cystic blood supply need to be more aware of the precise
      anatomy of the extrahepatic biliary tree.

PMID- 10656948
TI  - Time course of differences in lymphocyte proliferation rates after laparotomy vs
      CO(2) insufflation.
AB  - BACKGROUND: Our laboratory has previously demonstrated that cell-mediated immune
      function is significantly more suppressed after both laparotomy and laparoscopic
      assisted bowel resection than after peritoneal insufflation or open bowel
      resection, as assessed by delayed-type hypersensitivity (DTH) response. The
      purpose of this study was to further evaluate cell-mediated immunity by examining
      lymphocyte proliferation rates after laparotomy vs CO(2) insufflation. METHODS:
      Female Balb/C mice (n = 75) were randomly divided into the following three
      groups: (a) anesthesia control (A/C), (b) CO(2) insufflation (INS), and (c) sham
      laparotomy (OPEN). The A/C group mice underwent no procedure. The INS group
      underwent insufflation with CO(2) gas at 4-6 mmHg for 20 min. The OPEN group
      underwent a midline incision from xiphoid to pubic symphysis, which was clipped
      closed after 20 min. Splenocytes were obtained via splenic harvest and lymphocyte
      isolation on postoperative days (POD) 1, 2, 3, 4, and 8. Lymphocyte proliferation
      was determined by a nonradioactive colorimetric MTS/PMS assay 72 h after
      concanavalin A stimulation. RESULTS: The laparotomy group's lymphocyte
      proliferation rates were significantly lower than both the control and the
      insufflation groups on POD 2, POD 3, and POD 4. On POD 1 and POD 8, there were no
      significant differences in lymphocyte proliferation among the three groups. No
      differences were found between the control and insufflation groups at any point.
      CONCLUSIONS: After stimulation, lymphocytes proliferate at a lower rate after
      laparotomy than after CO(2) insufflation. Significant differences in lymphocyte
      proliferation rates between groups persist at least through POD 4. By POD 8, the
      mean lymphocyte proliferation rate in the laparotomy group was back to the
      baseline level. Our results suggest greater immunosuppression after sham
      laparotomy than after CO(2) insufflation.

PMID- 10656949
TI  - A simplified simulator for the training and evaluation of laparoscopic skills.
AB  - BACKGROUND: Laparoscopic skills can be measured objectively in a video
      laparoscopic cart simulator system. These scores have been shown to be
      sufficiently sensitive to distinguish differences in performance between
      residents at different levels of training. The purpose of this study was to
      compare a simplified mirrored-box simulator to the video-laparoscopic cart
      system. METHODS: A total of 22 surgical residents performed seven structured
      tasks in both simulators in random order. Scores reflected precision and speed.
      The tasks were transferring, cutting, clip + divide, looping, mesh placement +
      fixation, and suturing with intracorporeal and extracorporeal knots. RESULTS:
      There were no significant differences in mean raw scores between the simulators
      for six of the seven tasks. Resident total scores correlated well between
      simulators (r = 0.68, p = 0.001). Resident ranking also correlated well (r =
      0.69, p < 0. 001). CONCLUSIONS: A mirrored-box simulator was shown to provide a
      reasonable reflection of relative performance of laparoscopic skills. Practical,
      effective laparoscopic skills training and evaluation can be accomplished without
      the need for cumbersome equipment.

PMID- 10656951
TI  - Laparoscopic management of acute small bowel obstruction. Experience from a Saudi
      teaching hospital.
AB  - BACKGROUND: The use of laparoscopy has expanded to include the management of
      acute abdomen. This study describes the author's experience with laparoscopic
      management of acute small bowel obstruction. METHODS: From February 1994 through
      March 1998, 19 patients underwent laparoscopic intervention for acute small bowel
      obstruction. Their clinical data were analyzed to evaluate the outcome. RESULTS:
      A total of 19 patients underwent 20 exploratory laparoscopies. The cause of
      obstruction was diagnosed correctly in 17 of the patients (90%). Fifteen patients
      (79%) had adhesions, nine of which were postoperative. Of the 19 patients, 13
      (68%) had successful laparoscopic treatment. Laparotomy was required in six
      patients (32%) for various lesions including ileocecal tuberculosis. The average
      time for laparoscopy was 58 min. The mean postoperative hospital stay was 5 days.
      There was no morbidity or mortality in this series. CONCLUSIONS: Laparoscopy is a
      feasible and safe alternative to laparotomy for most patients with acute small
      bowel obstruction.

PMID- 10656950
TI  - Small bowel obstruction. Laparoscopic approach.
AB  - BACKGROUND: This is a retrospective review of our experience using a laparoscopic
      approach in the treatment of acute and chronic small bowel obstruction (SBO).
      MATERIALS AND METHODS: Of 136 patients hospitalized in our institutions for acute
      (94 cases: 69.1%) and chronic (42 cases: 30.8%) SBO, from January 1994 to March
      1998, 63 (46.3%) were approached laparoscopically. The etiology was accurately
      diagnosed in 58 cases (92%), and it was possible to treat it laparoscopically in
      82.5% (52 of 63 cases). In the remaining 11 cases (17.4%), a formal laparotomy
      was needed for bowel resection, due to an ischemic small bowel or for malignant
      disease. RESULTS: Overall, 82.5% of our cases were successfully treated
      laparoscopically. CONCLUSIONS: We conclude that, in experienced hands,
      laparoscopy is an excellent diagnostic and, in the majority of cases, a
      therapeutic surgical approach in selected patients with acute or chronic SBO.

PMID- 10656952
TI  - Laparoscopic ultrasonography during conservative ovarian surgery.
AB  - BACKGROUND: Most surgery for benign ovarian mass is now performed
      laparoscopically. Our purpose was to evaluate the usefulness of laparoscopic
      ultrasonography (LUS) in these operations. METHODS: Forty patients treated by
      laparoscopic extirpation of a benign ovarian tumor were examined perioperatively
      using an Aloka 7.5-MHz laparoscopic probe. Findings of preoperative vaginal and
      perioperative laparoscopic ultrasonography were compared with histologic
      diagnoses. The accuracy of LUS in localizing the tumor in the ovary and ensuring
      surgical radicalness was evaluated. RESULTS: LUS enabled correct diagnosis in
      34/40 and vaginal ultrasonography in 27/40 cases. Localization of the tumor was
      possible by LUS in all and visually in 21 ovaries. In 2 patients a radical tumor
      extirpation was not possible without laparoscopic ultrasonographic guidance.
      CONCLUSIONS: Diagnostic accuracy in LUS is better than in vaginal
      ultrasonography. LUS facilitates exact tumor localization and can be useful in
      confirming the radicalness of operation.

PMID- 10656953
TI  - 360 degrees laparoscopic fundoplication with tension-free hiatoplasty in the
      treatment of symptomatic gastroesophageal reflux disease.
AB  - BACKGROUND: Since laparoscopic Nissen fundoplication was first described by
      Cuschieri in 1989 and later by Dallemagne in 1991, this procedure has been widely
      employed for the treatment of symptomatic gastroesophageal reflux disease (GERD)
      and/or hiatal hernia. However, a relatively high incidence (7-11%) of
      intrathoracic Nissen valve migration/paraesophageal hernia following laparoscopic
      fundoplication has recently been reported. METHODS: Between November 1992 and
      August 1995, 65 consecutive patients with severe GERD and/or hiatal hernia
      underwent laparoscopic 360 degrees fundoplication. In nine of these 65 (13.8%)
      patients, an intrathoracic Nissen valve migration had occurred within 4 months.
      Six of these patients were symptomatic and were again submitted to the
      laparoscopic intervention. Videotapes of both the first and second operation were
      reviewed. In all cases, it was apparent that, at the first operation, closure by
      stitches of the hiatus was under tension, and at the second operation, the muscle
      fibers of the right crus were disrupted, probably due to the tension between the
      suture margins during the inspiratory movements of the diaphragm. These findings
      prompted us to perform an effective tension-free closure of the hiatus. A
      polypropylene mesh (3 x 4 cm) was placed on the hiatus behind the esophagus and
      fixed with eight metallic agraphes (2 + 2 on the superior edge and 2 + 2 on the
      lateral sides of the right and left cruses). RESULTS: Between August 1995 and
      February 1998, the technique, complete with 360 degrees fundoplication, was used
      for 67 patients with GERD. At mean follow-up of 22.5 months (range, 1-30), there
      was no evidence of postoperative paraesophageal hernia or complications related
      to the use of the mesh. CONCLUSIONS: This tension-free hiatoplasty seems to be an
      effective solution to prevent postoperative paraesophageal hernia in patients
      undergoing antireflux laparoscopic surgery. However, longer follow-up is still
      needed.

PMID- 10656955
TI  - Video-assisted thoracoscopic surgery in the management of loculated empyema.
AB  - BACKGROUND: Fibropurulent empyema (stage II of Light) does not respond to
      antibiotic therapy and simple drainage. If the condition is inadequately treated,
      restrictive pulmonary deficit develops, necessitating thoracotomy and
      decortication. We report our experience with the videoscopic management of stage
      II and limited stage III disease. METHODS: Ten consecutive patients underwent
      videoscopic debridement of fibropurulent empyema; three of them required removal
      of limited visceral and parietal rind. RESULTS: The mean operating time was 42 +/
      8.1 min. Postoperative pyrexia and leucocytosis settled within 4.2 +/- 2.1 days
      and 13.1 +/- 3.2 days, respectively. Intercostal chest tubes were removed by 4.5
      +/- 1.0 days. The mean fall in hematocrit following surgery was 4.9%. Parenteral
      analgesics were required for 1.0 +/- 0.5 days and oral analgesics for 3 +/- 1.6
      days. The mean postoperative stay was 11 +/- 8.1 days. No patient required any
      further intervention. CONCLUSIONS: Videoscopic debridement of empyema produces
      excellent results, with minimal patient morbidity and a short hospital stay. We
      recommend it as the preferred method for first-line management of fibropurulent
      (stage II) empyema.

PMID- 10656954
TI  - Videolaparoscopic cholecystectomy induces a hemostasis activation of lower grade
      than does open surgery.
AB  - BACKGROUND: Tissue injury after trauma and surgery may induce alterations in
      blood coagulation and fibrinolysis, and the hypercoagulable state observed after
      surgery can be associated with the risk of postoperative thromboembolic
      complications. Recently, videolaparoscopic (VLPS) cholecystectomy has been
      introduced, and its advantages over the open procedure seem related to the
      reduced surgical trauma. The aim of this study was to investigate hemostatic
      system alterations in patients who undergo open and VLPS cholecystectomy.
      METHODS: Fibrinogen, prothrombin fragment F1+2, D-dimer, and plasminogen
      activator inhibitor type-1 (PAI-1) activity was determined in 10 patients who
      underwent open (group A) and 10 patients who underwent VLPS cholecystectomy
      (group B), respectively. Blood samples were obtained the day of surgery in the
      morning (B1), after anesthesia (A1), 1 hour after the start of surgery (S1), then
      30 min (E.05) and 24 h (E.24) after the surgery. RESULTS: No significant
      differences were observed in baseline values between groups A and B for the
      parameters investigated. At 24 h after surgery, fibrinogen increased
      significantly (p < 0.05) in group A and also was significantly higher than in
      group B (p < 0.05). In group A, a marked increase in F1+2 levels (p < 0.01) was
      observed in all the samples, with the maximum values on the first day after
      surgery (3.7 nmol/l; 1.2-6.0 nmol/l), whereas in group B, a slight but
      significant increase in F1+2 levels (2.1 nmol/l; 1.1-3.9 nmol/l; p < 0.01) was
      observed only 30 min after the end of surgery. In both groups A and B, D-dimer
      markedly increased after surgery, without statistical significant differences
      between the two groups at any time. The PAI-1 activity plasma levels remained in
      the normal range during and after surgery in both groups. CONCLUSIONS: These
      results indicate that VLPS surgery induces an activation of the clotting system
      that, although of low degree and short duration, can lead to a transient
      prothrombotic state.

PMID- 10656956
TI  - Simultaneous laparoscopic biliary and retrocolic gastric bypass in patients with
      unresectable carcinoma of the pancreas.
AB  - BACKGROUND: A substantial number of patients with unresectable pancreatic cancer
      eventually develop biliary or gastric outlet obstruction. In some cases, they
      present initially with both complications. These conditions contribute markedly
      to their discomfort and certainly justify palliative intervention. The purpose of
      this study was to examine the feasibility and safety of simultaneous laparoscopic
      biliary and gastric bypass in patients with unresectable carcinoma of the
      pancreas. METHODS: Between August 1995 and July 1998, simultaneous laparoscopic
      biliary and retrocolic gastric bypass was performed successfully in 12
      consecutive patients with unresectable carcinoma of the pancreas. There were
      eight men and four women. Their median age was 72 years (range, 50-82). In all
      patients, the indications for gastrointestinal bypass were gastric outlet
      obstruction and obstructive jaundice. The following parameters were evaluated for
      each patient: procedure-related morbidity and mortality, operative time, length
      of hospital stay, overall survival, and ability to sustain oral nutrition during
      the survival period. RESULTS: All procedures were completed laparoscopically. The
      mean operative time was 89 +/- 29.56 min. There were no intraoperative
      complications. Postoperative morbidity consisted of wound infection in two
      patients and pneumonia in one patient. One patient died of multiorgan failure on
      postoperative day 2. The mean hospital stay was 6.4 +/- 1.5 days (range, 5-17).
      The mean survival time until death from underlying disease was 85 +/- 32. 46 days
      (range, 31-260). None of the patients had recurrent jaundice, and all of them
      were able to maintain oral nutrition. CONCLUSION: Simultaneous laparoscopic
      biliary and retrocolic gastric bypass is a safe and effective technique for the
      treatment of biliary and gastroduodenal obstruction in patients with unresectable
      pancreatic cancer.

PMID- 10656957
TI  - Perforating appendicitis. An indication for laparoscopy?
AB  - BACKGROUND: This pilot study was performed to reassess the widespread postulate
      that laparoscopic surgery is contraindicated in cases of perforating
      appendicitis. METHODS: A total of 75 children (appendiceal perforation: n = 67;
      perityphlic abscesses and peritonitis: n = 8) were analyzed in a prospective
      nonrandomized trial. Ten of them were treated by laparoscopic appendectomy.
      RESULTS: In the laparoscopy group, both pain and hospitalization were less time
      consuming (i.e., by 50% and 19%, respectively). Antibiotics use was down from 2.6
      over 6 days to 2.2. over 5.5 days, while the duration of surgery was up by 52%.
      Wound healing disturbances occurred in 10% (n = 1) and postoperative fever in 50%
      (n = 5) of patients, compared to 14% (n = 9) and 15% (n = 10) in the group
      treated by open surgery. All severe complications requiring reintervention (10%;
      massive subcutaneous abscess, n = 3; retrocolic abscess, n = 2; adhesion-related
      ileus, n = 3; appendicular stump, n = 1) were associated with open surgery.
      CONCLUSIONS: There was not a single major complication in the laparoscopy group.
      These unexpected results are in contrast to previous reports and have prompted us
      to initiate a prospective randomized trial.

PMID- 10656958
TI  - Ultrasound of colonic neoplasia. An intraoperative tool?
AB  - BACKGROUND: The accuracy of intraoperative ultrasound of the colon in the
      location and assessment of neoplastic lesions at the time of resection has not
      been reported. METHODS: An in vitro study was performed, with ultrasound imaging
      of colonic specimens resected for malignancy. The specimens were imaged empty,
      surrounded by saline, the lumen filled with saline. RESULTS: Excellent ultrasound
      images were produced, particularly when the colonic lumen was filled with saline.
      All lesions were located by this technique, and several impalpable synchronous
      polyps also were found. In two specimens, the remnants of a malignant polyp not
      visible with intraoperative colonoscopy were found by specimen ultrasound. The
      clarity of the image was such that the cancer stage often could be assessed.
      CONCLUSIONS: Direct ultrasound of the colon, using a high-frequency
      intraoperative probe, produced accurate images of neoplastic lesions in an in
      vitro setting. This technique may have a role in the intraoperative location and
      assessment of colorectal cancer.

PMID- 10656959
TI  - Port-site metastases after CO(2) laparoscopy. Is aerosolization of tumor cells a
      pivotal factor?
AB  - BACKGROUND: Animal experiments have shown that carbon dioxide (CO(2)) laparoscopy
      results in more port-site recurrences than gasless laparoscopy. Possible
      transport of aerosolized tumor cells by CO(2) was investigated in rats. METHODS:
      Abdominal cavities of 15 pairs of Wistar Agouti (WAG) rats were connected and 2 x
      10(6) or 16 x 10(6) CC 531 cells were injected in the first (donor) rat of each
      pair. Then 10 l of CO(2) were allowed to flow from the first (donor) to the
      second (recipient) rat. RESULTS: No tumor was found in the recipients after
      injection of 2 x 10(6) cells in the donors. Injection of 16 x 10(6) cells in the
      donors resulted in very limited tumor growth in the recipients. CONCLUSIONS:
      Aerosolization of tumor cells occurs, but the number of intraperitoneal tumor
      cells required for metastases to occur by this mechanism is extremely high.
      Therefore, aerosolization of tumor cells appears not to be of major relevance in
      the pathogenesis of port-site metastases.

PMID- 10656961
TI  - EndoScope: world literature reviews

PMID- 10656960
TI  - Influence of trocar placement and CO(2) pneumoperitoneum on port site metastasis
      following laparoscopic tumor surgery.
AB  - BACKGROUND: The mechanisms involved in the development of port site metastasis
      following laparoscopic tumor surgery remain controversial. Therefore, we decided
      to investigate the influence of trocar placement and CO(2) pneumoperitoneum on
      abdominal wound implantation in relation to intraperitoneal tumor growth in a
      rabbit model. METHODS: Rabbits received either CO(2) pneumoperitoneum with
      insertion of nine trocars (pneumoperitoneum group, n = 15), insertion of nine
      trocars alone (nonpneumoperitoneum group, n = 15), or nine abdominal incisions
      (control group, n = 13) 3 days after intraperitoneal inoculation of VX(2) cancer
      cells. RESULTS: The frequency of overall wound implantation on day 17 in the
      pneumoperitoneum group (24.4%) and nonpneumoperitoneum group (27.4%) tended to be
      higher than that in the control group (15.3%) (p = 0. 06). There was no
      significant difference among the three groups in the growth of cancer nodules on
      the omentum. CONCLUSIONS: The presence of a trocar may be a factor contributing
      to port site metastasis but CO(2) pneumoperitoneum appears not to be a factor.

PMID- 10656962
TI  - A needle-puncture that helped to change the world of surgery. Homage to Janos
      Veres.

PMID- 10656963
TI  - Ultrasound-assisted direct percutaneous endoscopic jejunostomy (DPEJ) tube
      placement.
AB  - Direct percutaneous endoscopic jejunostomy (DPEJ) is an effective method of
      enteral feeding. However, failure rates with this procedure remain high due to
      various technical problems. We describe a case where modifications in the
      technique and ultrasound guidance assisted in a difficult DPEJ placement. This
      technique has the potential to improve the success rate of this procedure in
      selected cases.

PMID- 10656965
TI  - The author replies

PMID- 10656964
TI  - A new technique for laparoscopic resection of a submucosal tumor on the posterior
      wall of the gastric fundus.

PMID- 10656966
TI  - Minilaparotomy vs the percutaneous approach for minimally invasive hepatic
      cryosurgery.

PMID- 10656968
TI  - News and notices

PMID- 10656967
TI  - The author replies

PMID- 10656969
TI  - Inhibition of phosphatidylinositol 4,5-bisphosphate-stimulated phospholipase D2
      activity by Ser/Thr phosphorylation.
AB  - Treatment of HeLa cells overexpressing PLD2 with the Ser/Thr-specific protein
      phosphatase inhibitor, okadaic acid, augmented spontaneous phosphorylation of
      PLD2 with concomitant inhibition of phosphatidylinositol 4,5-bisphosphate
      (PIP(2))-stimulated PLD2 activity. Dephosphorylation of the immunoprecipitated,
      spontaneously phosphorylated PLD2 in COS-7 cells by catalytic subunit of protein
      phosphatase 1gamma1 resulted in the stimulation of the PLD2 catalytic activity.
      These observations suggest that Ser/Thr phosphorylation regulates PLD2 activity.

PMID- 10656970
TI  - A calcium-inhibited Drosophila adenylyl cyclase.
AB  - Mammals possess a family of transmembrane, G-protein-responsive adenylyl cyclase
      isoforms (tmACs) encoded by distinct genes differing in their patterns of
      expression and modes of biochemical regulation. Our previous work confirmed that
      Drosophila melanogaster also possesses a family of tmAC isoforms defining the fly
      as a suitable genetic model for discerning mammalian tmAC function. We now
      describe a Drosophila tmAC, DAC39E, which employs a novel means for regulating
      its expression; differential exon utilization results in a developmental switch
      in DAC39E protein. DAC39E protein sequence is most closely related to mammalian
      type III AC, and it is predominantly expressed in the central nervous system
      (CNS) and olfactory organs, suggesting a role in processing sensory signaling
      inputs. DAC39E catalytic activity is inhibited by micromolar concentrations of
      calcium; therefore, DAC39E is oppositely regulated by calcium compared to the
      only other tmAC shown to be expressed in the Drosophila CNS, Rutabaga AC. The
      presence of both positively and negatively regulated tmACs suggests a complex
      mode of cross-talk between cAMP and calcium signal transduction pathways in the
      fly CNS.

PMID- 10656971
TI  - Reconstitution of Listeria motility: implications for the mechanism of force
      transduction.
AB  - Listeria monocytogenes and some other infectious bacteria polymerize their host
      cell's actin into tails that propel the bacteria through the cytoplasm. Here we
      show that reconstitution of this behavior in simpler media resolves two aspects
      of the mechanism of force transduction. First, since dilute reconstitution media
      have no cytoskeleton, we consider what keeps the tail from being pushed backward
      rather than the bacterium being propelled forward. The dependence of the
      partitioning of motion on the friction coefficient of the tail is derived.
      Consistent with experiments, we find that the resistance of the tail to motion is
      sensitive to its length. That even small tails are stationary in intact cells is
      attributed to anchoring to the cytoskeleton. Second, the comparatively low
      viscosity of some reconstitution media magnifies the effects of diffusion, such
      that a large gap will develop between the bacterium and its tail if they are
      unattached. At the viscosities of diluted platelet extracts, steady-state gaps of
      several bacterium lengths are predicted. Since such gaps are not observed, we
      conclude that Listeria must be attached to their tails. We consider what purposes
      such attachments might serve under physiological conditions. The implications for
      related pathogens and amoeboid locomotion are also discussed.

PMID- 10656972
TI  - Effects of hypoxia and glutathione depletion on hemoglobin- and myoglobin
      mediated oxidative stress toward endothelium.
AB  - We investigated the toxicity of hemoglobin/myoglobin on endothelial cells under
      oxidative stress conditions that include cellular hypoxia and reduced antioxidant
      capacity. Bovine aorta endothelial cells (BAECs), grown on microcarrier beads,
      were subjected to cycles of hypoxia and reoxygenation in a small volume of
      medium, and endothelial cell monolayers were depleted of their intracellular
      glutathione (GSH) by treatment with buthionine sulfoximine. Incubation of
      diaspirin cross-linked hemoglobin (DBBF-Hb) or horse skeletal myoglobin (Mb) with
      BAECs subjected to 3 h of hypoxia caused transient oxidation of the hemoproteins
      to the ferryl form (Fe(4+)). Formation of the ferryl intermediate was decreased
      in a concentration-dependent manner by the addition of L-arginine, a substrate of
      NO synthase, after 3 h of hypoxia. Optimal inhibition of ferryl formation,
      possibly due to the antioxidant action of NO, was achieved with 900 microM L
      arginine. Addition of hydrogen peroxide to GSH-depleted cells in the presence of
      DBBF-Hb or Mb significantly decreased cell viability. Ferryl Mb, but not ferryl
      DBBF-Hb, was observed in samples analyzed at the end of treatment, which may
      explain the greater toxicity observed with Mb as opposed to DBBF-Hb. This model
      may be utilized to identify causative agent(s) associated with hemoprotein
      cytotoxicity and in designing strategies to suppress or control heme-mediated
      injury under physiologically relevant conditions.

PMID- 10656973
TI  - Inhibition of hyaluronan synthesis by vesnarinone in cultured human
      myofibroblasts.
AB  - Hyaluronan (HA), which is a major component of the extracellular matrix (ECM), is
      regulated during myofibroproliferative responses to numerous forms of
      inflammatory stimuli. It is a key factor involved in cellular migration and
      adherence. The development of a potent and non-toxic inhibitor of HA synthesis
      would open up a new avenue for the treatment of fibrocontractive diseases such as
      pulmonary fibrosis and liver cirrhosis. In this study, the effects of vesnarinone
      (OPC-8212: 3,4-dihydro-6-[4-(3, 4-dimethoxybenzoyl)-1-piperazinyl]-2(1H)
      quinolinone) on the secretion of HA in human myofibroblast cell lines (MRC-5 and
      LI90 cells, referred to as pulmonary and hepatic myofibroblasts, respectively)
      were examined. Vesnarinone specifically and dose-dependently inhibited HA
      secretion by myofibroblasts up-regulated by fetal calf serum (FCS). The treatment
      of vesnarinone did not modify the phenotype of myofibroblast cells in culture.
      Vesnarinone also potently inhibited the HA secretion by the two myofibroblast
      cell lines up-regulated by transforming growth factor-beta1 (TGF-beta1) or tumor
      necrosis factor-alpha (TNF-alpha). The addition of vesnarinone to myofibroblasts
      resulted in a significant decrease of HA synthase (HAS) activity, with or without
      the addition of FCS or either cytokine. These findings suggest that vesnarinone
      inhibits the secretion of HA in myofibroblasts by specifically suppressing HAS
      activity, and may therefore prove useful for the treatment of chronic
      inflammation and tissue fibrosis.

PMID- 10656974
TI  - Biochemical interactions in the wnt pathway.
AB  - The wnt signal transduction pathway is involved in many differentiation events
      during embryonic development and can lead to tumor formation after aberrant
      activation of its components. The cytoplasmic component beta-catenin is central
      to the transmission of wnt signals to the nucleus: in the absence of wnts beta
      catenin is constitutively degraded in proteasomes, whereas in the presence of
      wnts beta-catenin is stabilized and associates with HMG box transcription factors
      of the LEF/TCF family. In tumors, beta-catenin degradation is blocked by
      mutations of the tumor suppressor gene APC (adenomatous polyposis coli), or of
      beta-catenin itself. As a consequence, constitutive TCF/beta-catenin complexes
      are formed and activate oncogenic target genes. This review discusses the
      mechanisms that silence the pathway in cells that do not receive a wnt signal and
      goes on to describe the regulatory steps involved in the activation of the
      pathway.

PMID- 10656975
TI  - H(2)O(2) activity on platelet adhesion to fibrinogen and protein tyrosine
      phosphorylation.
AB  - Platelets represent a target of reactive oxygen species produced under oxidative
      stress conditions. Controversial data on the effect of these species on platelet
      functions have been reported so far. In this study we evaluated the effect of a
      wide range of H(2)O(2) concentrations on platelet adhesion to immobilized
      fibrinogen and on pp72(syk) and pp125(FAK) tyrosine phosphorylation. Our results
      demonstrate that: (1) H(2)O(2) does not affect the adhesion of unstimulated or
      apyrase-treated platelets to immobilized fibrinogen; (2) H(2)O(2) does not affect
      pp72(syk) phosphorylation induced by platelet adhesion to fibrinogen-coated
      dishes; (3) H(2)O(2) reduces, in a dose-dependent fashion, pp125(FAK)
      phosphorylation of fibrinogen-adherent platelets; (4) concentrations of H(2)O(2)
      near to physiological values (10-12 microM) are able to strengthen the
      subthreshold activation of pp125(FAK) induced by epinephrine in apyrase-treated
      platelets; (5) H(2)O(2) doses higher than 0.1 mM inhibit ADP-induced platelet
      aggregation and dense granule secretion. The ability of H(2)O(2) to modulate
      pp125(FAK) phosphorylation suggests a role of this molecule in physiological
      hemostasis as well as in thrombus generation.

PMID- 10656976
TI  - Intra-articular knee joint effusion induces quadriceps avoidance gait patterns.
AB  - OBJECTIVES: (1) To identify adaptations caused by intra-articular knee joint
      effusion during walking and (2) to determine if knee joint effusion may be a
      causative factor in promoting quadriceps avoidance gait patterns. DESIGN: Gait
      testing of 14 healthy individuals who underwent incremental saline injections of
      the knee joint capsule.Background. Gait adaptations have been reported in the
      literature for knee injured and rehabilitating individuals. Knee joint capsular
      afferent activity can influence knee joint function. METHODS: Gait analysis was
      employed in a pre- and post-test, repeated measures design to determine lower
      extremity joint kinematics, kinetics, energetics and thigh EMG adaptations due to
      intra-articular knee joint effusion. RESULTS: Knee effusion caused an increase in
      hip and knee flexion through the stance phase. Knee extensor torque, impulse and
      negative and positive work were diminished with increased effusion levels.
      Quadriceps activity decreased and hamstring activity increased due to intra
      articular knee joint effusion. DISCUSSION: These adaptations cannot be attributed
      to an injury, surgery or rehabilitation. Thus, the results of this experiment
      suggest knee joint capsular distention, via knee joint effusion, may be
      responsible for many gait adaptations reported for knee injured individuals in
      previous investigations. CONCLUSIONS: Knee joint effusion and the subsequent
      capsular distention can cause major alterations in the normal gait cycle and can
      be considered a causative factor promoting the acquisition of quadriceps
      avoidance gait patterns. RELEVANCE: This study provides reference data on the
      effects of intra-articular knee joint effusion on gait parameters by which future
      studies of injured or rehabilitating individuals can be compared.

PMID- 10656977
TI  - Biomechanical considerations for rehabilitation of the knee.
AB  - Knowledge of the anatomy and biomechanics of the knee is critical for successful
      rehabilitation following knee injury and/or surgery. Biomechanics of both the
      tibiofemoral and patellofemoral joints must be considered. The purpose of this
      paper is to provide a framework for rehabilitation of the knee by reviewing the
      biomechanics of the tibiofemoral and patellofemoral joints. This will include
      discussion of the relevant arthrokinematics as well as the effects of open and
      closed chain exercises. The implications for rehabilitation of the knee will be
      highlighted.

PMID- 10656978
TI  - Biexponential recovery model of lumbar viscoelastic laxity and reflexive muscular
      activity after prolonged cyclic loading.
AB  - OBJECTIVES: To determine the rest duration required for full recovery of
      reflexive muscular activity and laxity/creep induced in the lumbar viscoelastic
      structures (e.g., ligaments, discs, etc.) after 50 min of cyclic loading, and to
      develop a model describing such recovery. BACKGROUND: It is well established that
      steady, cyclic or vibratory loading of the lumbar spine induces laxity/creep in
      its viscoelastic structures. It was also shown that such viscoelastic creep does
      not fully recover when subjected to rest equal in duration to the loading period.
      Rest periods of 24 h, however, were more than sufficient to allow full recovery.
      The exact period of time allowing full recovery of viscoelastic laxity/creep, and
      its pattern is not known. It is also not known what is the duration required for
      full recovery of reflexive muscular activity lost due to the laxity/creep induced
      in the spine during cyclic loading. METHODS: The lumbar spine of 'in vivo' feline
      preparations was subjected to 50 min of 0.25 Hz cyclic loading applied v ia the
      L4/5 supraspinal ligament. At the end of the loading period the spine was
      subjected to prolonged rest, interrupted by a single cycle loading applied hourly
      for measurement purposes until the laxity was fully recovered (>90%). Reflexive
      EMG activity was recorded with wire electrodes from the L-1-L-7 multifidus
      muscles. A biexponential model was fitted to the load and EMG recorded in the
      recovery period in order to represent viscous and elastic components of
      structures with different architecture (e.g., disc vs. ligament). RESULTS: Full
      recovery of the laxity induced by 50 min of cyclic loading at 0.25 Hz required 7
      h and was successfully fitted with a biexponential model. Similarly, EMG activity
      was fully recovered in 4 hours, and often exceeded its initial value during the
      following 3 h. CONCLUSIONS: Full recovery of laxity induced in the lumbar
      viscoelastic structures by a given period of cyclic loading requires rest
      periods, which are several folds longer than the loading duration. Similarly,
      reflexive muscular activity requires 4 h of rest in order to be restored.
      Meanwhile, significant laxity can be present in the joints, exposing the spine to
      potential injury and low back pain. Increased EMG activity at the end of the
      recovery period may indicate that pain was possibly induced in the spinal
      structures, inducing hyperexcitability of the muscles during passive loading.
      RELEVANCE: Although the data was derived from a feline model, and its
      extrapolation to the human model is not straightforward, the general pattern of
      decreasing reflexive muscular activity with cyclic loading is expected in both
      species. Therefore, workers who subject their spine to periods of cyclic loading
      may be exposed to prolonged periods of laxity beyond the neutral zone limits,
      without protection from the muscles and therefore the risk of possible injury and
      low back pain. Pain and muscle hyperexcitability could also be a factor
      associated with cyclic loading, being expressed several hours after work was
      completed.

PMID- 10656979
TI  - Cruciate ligament forces in the human knee during rehabilitation exercises.
AB  - OBJECTIVE: To determine the cruciate ligament forces occurring during typical
      rehabilitation exercises.Design. A combination of non-invasive measurements with
      mathematical modelling of the lower limb.Background. Direct measurement of
      ligament forces has not yet been successful in vivo in humans. A promising
      alternative is to calculate the forces mathematically. METHODS: Sixteen subjects
      performed isometric and isokinetic or squat exercises while the external forces
      and limb kinematics were measured. Internal forces were calculated using a
      geometrical model of the lower limb and the "dynamically determinate one-sided
      constraint" analysis procedure. RESULTS: During isokinetic/isometric extension,
      peak anterior cruciate ligament forces, occurring at knee angles of 35-40
      degrees, may reach 0.55x body-weight. Peak posterior cruciate ligament forces are
      lower and occur around 90 degrees. During isokinetic/isometric flexion, peak
      posterior cruciate forces, which occur around 90 degrees, may exceed 4x body
      weight; the anterior cruciate is not loaded. During squats, the anterior cruciate
      is lightly loaded at knee angles up to 50 degrees, after which the posterior
      cruciate is loaded. Peak posterior cruciate forces occur near the lowest point of
      the squat and may reach 3.5x body-weight. CONCLUSIONS: For anterior cruciate
      injuries, squats should be safer than isokinetic or isometric extension for
      quadriceps strengthening, though isokinetic or isometric flexion may safely be
      used for hamstrings strengthening. For posterior cruciate injuries, isokinetic
      extension at knee angles less than 70 degrees should be safe but isokinetic
      flexion and deep squats should be avoided until healing is well-advanced.
      RELEVANCE: Good rehabilitation is vital for a successful outcome to cruciate
      ligament injuries. Knowledge of ligament forces can aid the physician in the
      design of improved rehabilitation protocols.

PMID- 10656980
TI  - Interference screw fixation of doubled flexor tendon graft in anterior cruciate
      ligament reconstruction - biomechanical evaluation with cyclic elongation.
AB  - OBJECTIVE: To biomechanically evaluate interference screw fixation of the doubled
      flexor tendon graft in anterior cruciate ligament reconstruction using cyclic
      elongation. DESIGN: Biomechanical properties of the interference screw fixation
      of the flexor tendons were compared with those of three standard fixation
      techniques which had been commonly performed in anterior cruciate ligament
      reconstruction. BACKGROUND: The interference screw fixation of the flexor tendon
      graft has attracted notice because of various possible advantages. METHODS: Forty
      fresh frozen porcine hind limbs were divided into four groups of ten knees each.
      Anterior cruciate ligament reconstruction was carried out in each group using one
      of four different procedures. For each group, five femur-graft-tibia complexes
      underwent submaximal cyclic elongation of 5000 cycles after initial tension of 80
      N was applied. Then, tensile testing was performed in the same manner for the
      complex with a tensile tester. The remaining five complexes were examined in the
      same tensile test without applying any cyclic elongation. RESULTS: The initial
      tension was more rapidly relaxed by cyclic elongation in the flexor tendon graft
      fixed with interference screws than in the bone-patellar tendon-bone graft fixed
      with two standard techniques. After cyclic elongation, while the ultimate failure
      load of the former was significantly lower than the latter, the linear stiffness
      of the former was significantly higher than the flexor tendon graft fixed with
      sutures. CONCLUSION: The present study has clarified that the advantage of the
      interference fixation for the doubled flexor tendon graft is the high linear
      stiffness of the FGT complex, and the disadvantage of this screw is the low
      ultimate failure load of the FGT complex. RELEVANCE: The present study has
      suggested that vigorous activities should not be permitted for the patients in
      the early period after anterior cruciate ligament reconstruction using this
      fixation technique, because of its low ultimate failure load.

PMID- 10656981
TI  - A study of biomechanical parameters in gait analysis and sensitive cronaxie of
      diabetic neuropathic patients.
AB  - OBJECTIVE: The present investigation aims at studying the sensitive cronaxie in
      neuropathic and non-neuropathic diabetic patients as a measure of sensorial
      deficit. We seek to describe the gait using dynamic and temporal parameters. We
      have compared the results of the neuropathic patients to the results of a non
      diabetic group. We have looked for relationships between peak plantar pressure
      and sensitive cronaxie in selected plantar areas. DESIGN AND METHODS: The
      experimental procedures were divided in: (a) determination of the sensitive
      cronaxie in four selected plantar areas, (b) determination and description of
      peak plantar pressure, ground reaction force variables and single and double
      stance time. We analyzed and compared the results of the sensitive cronaxie and
      the biomechanical parameters obtained by three experimental groups: diabetic,
      neuropathic and non-diabetic subjects. RESULTS: The pathological response of the
      sensitive cronaxie worsened progressively for neuropathic and diabetic patients,
      respectively. Longer double and single stance times, lower minimum vertical force
      and lower growth rates were seen in the neuropathic patients when compared to
      diabetic and non-diabetic subjects. CONCLUSIONS: These results indicate an
      alteration in the neuropathic patient movement structure. We have speculated that
      compensatory musculoskeletal mechanisms have been developed by neuropathic
      patients to compensate for their sensorial deficit. Future research is necessary
      to verify the relationship between neurophysiological and dynamic variables,
      since this relationship seems to be a good parameter for the interpretation and
      comprehension of the peripheral neuropathy. RelevancePeripheral neuropathy is one
      of the most insidious chronic complications of diabetes. It has been observed
      that dynamic changes in gait are usually associated with the peripheral
      neuropathy somatosensory deficits. Biomechanical studies have highlighted that
      dynamic gait evaluation can identify functional alterations, besides the analysis
      of sensitive cronaxie as a measure of sensorial deficits. They are also useful as
      a complimentary routine in the clinic treatment of diabetes and its further long
      term complications.

PMID- 10656982
TI  - Contribution of the extrinsic and intrinsic hand muscles to the moments in finger
      joints.
AB  - OBJECTIVE: The purpose of this current work is to develop a method of estimating
      force produced by the extrinsic and intrinsic hand muscles, and to estimate the
      contribution of these muscles to the finger joint moments. DESIGN: Experimental
      methods and a biomechanical model were developed for the estimation of (a)
      moments produced at finger joints, and (b) contribution of the intrinsic and
      extrinsic muscles to the moments, (c) forces of the extrinsic and intrinsic
      muscles within individual fingers. BACKGROUND: Because of the differential
      insertions of the extrinsic flexors, it is possible to isolate their mechanical
      effect at finger joints. METHODS: During the experiment, the location of force
      application was varied in parallel along individual fingers. The points of force
      application were on the distal phalanx, at the distal interphalangeal joint, or
      at the proximal interphalangeal joint. RESULTS: When the point of force
      application was varied in the proximal direction from the distal phalanx to the
      proximal interphalangeal joint the moment at a given joint decreased. The
      intrinsic and extrinsic muscle forces were dependent on the experimental
      conditions. The extrinsic muscles were the major contributors in counterbalancing
      finger joint moments when the point of force application was distal beyond the
      proximal interphalangeal joint. CONCLUSION: This current work provides both an
      experimental protocol and a biomechanical model that allows estimation of the
      contribution of the intrinsic and extrinsic muscles to finger joint moments.
      RELEVANCE: This study suggests ways of identifying the source of functional
      deficiency in the hand.

PMID- 10656983
TI  - In vivo kinematic study of normal wrist motion: an ultrafast computed tomographic
      study.
AB  - OBJECTIVE: To quantify in vivo carpal kinematics of a normal wrist in a dynamic
      continuous model. DESIGN: The instantaneous changes in the radiocarpal and
      midcarpal joints during normal wrist motion were analyzed using ultrafast
      computed tomography (CT). BACKGROUND: Wrist injuries account for a considerable
      and growing proportion of work-related disorders and disability. However, little
      is known about normal wrist kinematics. METHODS: Ten uninjured subjects were
      studied using ultrafast CT to measure the continuous motion of the wrist from
      full flexion to full extension. Sagittal plane scanning was performed
      mediolaterally at six different locations as the wrists were moved slowly and
      repeatedly from full flexion to full extension. The data were printed to X-ray
      film and transferred to an independent work station with a video camera. The
      motion of the radiocarpal, midcarpal and wrist joints was determined by an image
      analyzing system. RESULTS: Wrist motion was expressed as a ratio of capitate
      lunate (C-L) (midcarpal) motion and radio-lunate (R-L) (radiocarpal) motion. In
      the volar flexion of normal wrists, the contribution of the radiocarpal joint and
      midcarpal joint were approximately equal; while dorsal flexion of the normal
      wrist occurred mainly at the midcarpal joint. CONCLUSIONS: In normal wrists, the
      radiocarpal joint and midcarpal joint contribute equally to volar flexion, while
      the midcarpal joint is more important in dorsal flexion. RELEVANCE: In this
      study, we demonstrated the suitability of using two-dimensional computed
      tomographic images in a quantitative study of flexion/extension kinematics of the
      normal wrist.

PMID- 10656984
TI  - Modeling the body/chair interaction - an integrative experimental-numerical
      approach.
AB  - OBJECTIVE: To develop a systematic methodology towards a realistic model, of the
      body/chair interaction as a tool to analyze sitting posture and the cushioning
      system influence on the pelvis/lower back stress development. BACKGROUND: The
      model concept comprises an integrative structure including both the pelvis girdle
      and the lower spine, as well as the surrounding soft tissues with their specific
      characteristic behavior during sitting. METHODS: In vivo measurements were
      performed, in order to obtain a set of contact moduli defining the behavior of
      the soft tissues under tension during the sitting down process. Additionally in
      vivo indentation of a metal ball into the same soft tissues during sitting were
      performed in order to obtain the characteristic moduli. A finite element model
      was also developed for the specific analyses. RESULTS: Validation of the model
      was achieved by comparing its results with in vivo measurements of contact
      stresses developed between the body and a stiff target seat area. Loading the
      model using two alternative cushioning materials lead to different sets of
      stresses within the model; as the stiffness of the seat decreased, the peak
      contact stresses, as well as the internal body stresses substantially decreased.
      RELEVANCE: Body/chair interaction model methodology may be a practical means to
      analyze and design structures and materials in order to achieve more comfort
      during work or leisure, as well as for geriatric or impaired subjects.

PMID- 10656985
TI  - The E2F transcription factors: key regulators of cell proliferation.
AB  - Ever since its discovery, the RB-1 gene and the corresponding protein, pRB, have
      been a focal point of cancer research. The isolation of E2F transcription factors
      provided the key to our current understanding of RB-1 function in the regulation
      of the cell cycle and in tumor suppression. It is becoming more and more evident
      that the regulatory circuits governing the cell cycle are very complex and highly
      interlinked. Certain aspects of RB-1 function, for instance its role in
      differentiation, cannot be easily explained by the current models of pRB-E2F
      interaction. One reason is that pRB has targets different from E2F, molecules
      like MyoD for instance. Another reason may be that we have not completely
      understood the full complexity of E2F function, itself. In this review, we will
      try to illuminate the role of E2F in pRB- and p53-mediated tumor suppression
      pathways with particular emphasis on the aspect of E2F-mediated transcriptional
      regulation. We conclude that E2F can mediate transcriptional activation as well
      as transcriptional repression of E2F target genes. The net effect of E2F on the
      transcriptional activity of a particular gene may be the result of as yet poorly
      understood protein-protein interactions of E2F with other components of the
      transcriptional machinery, as well as it may reflect the readout of the different
      ways of regulating E2F activity, itself. We will discuss the relevance of a
      thorough understanding of E2F function for cancer therapy.

PMID- 10656986
TI  - TGF-beta receptors and DNA repair genes, coupled targets in a pathway of human
      colon carcinogenesis.

PMID- 10656987
TI  - The PTEN tumor suppressor protein: an antagonist of phosphoinositide 3-kinase
      signaling.

PMID- 10656988
TI  - Heterochromatin function in complex genomes.

PMID- 10656990
TI  - Themes and variations: the first Salk Institute Cell Cycle Meeting, 18-22 June
      1999.

PMID- 10656989
TI  - Death in the snow: report on Keystone Conference on 'Apoptosis and Programmed
      Cell Death' at Breckenridge, CO, April 6-11th 1999.

PMID- 10656991
TI  - The Cold Spring Harbor Laboratory meeting on tyrosine phosphorylation and cell
      signaling. Cold Spring Harbor, NY, USA, May 12-16, 1999.

PMID- 10656992
TI  - Keystone Symposia on Molecular and Cellular Biology: 'The molecular basis of
      cancer'. Organizers: Carol L. Prives and George F. Vande Woude, Taos, NM, 15-21
      March 1999.
AB  - The Keystone Symposium on the Molecular Basis of Cancer was an excellent meeting,
      which stimulated the exchange of a great deal of information. This report was
      prepared to organize some of the results that provided new insights into the
      regulation of cell proliferation and apoptosis. We were unable to report on all
      of the talks and posters due mostly to our limited capacity to absorb and digest
      the large amount of results presented at the meeting. We apologize to those whose
      results were not covered in this report.

PMID- 10656993
TI  - Subtilase-like pro-protein convertases: from molecular specificity to therapeutic
      applications.
AB  - Limited proteolysis of most large protein precursors is carried out in vivo by
      the subtilisin-like pro-protein convertases. Many important biological processes
      such as peptide hormone synthesis, viral protein processing and receptor
      maturation involve proteolytic processing by these enzymes, making them potential
      targets for the development of novel therapeutic agents. However, the efficient
      development of such molecules requires a better understanding of the molecular
      mechanisms of proteolytic protein processing. Herein, we review the most recent
      findings on the molecular aspects of subtilisin-like convertase activity, such as
      the structural analysis of the proteases, the mechanisms of enzyme/substrate
      specificity, their interaction with other proteins such as 7B2, and the
      comparative tissue and cellular distribution of the enzymes and their substrates.
      These data are then used as a background for the review of the known biological
      functions of subtilisin-like pro-protein convertases, the reported clinical cases
      involving proteolytic processing defects and, finally, the ongoing development of
      new therapeutic inhibitor molecules based on this knowledge.

PMID- 10656994
TI  - Cloning and expression of a DAX1 homologue in the chicken embryo.
AB  - DAX1 is an unusual member of the orphan nuclear receptor family of transcription
      factors. Mutations in human DAX1 cause X-linked adrenal hypoplasia congenita,
      while abnormal duplication of the gene is responsible for male-to-female dosage
      sensitive sex reversal. Based on these and other observations, DAX1 is thought to
      play a role in adrenal and gonadal development in mammals. As DAX1 has not
      previously been described in any other vertebrate, a putative avian DAX1 clone
      was isolated from an embryonic chicken (Gallus domesticus) urogenital ridge cDNA
      library. The expression profile of this cDNA was then examined during
      gonadogenesis. The clone included the conserved 3' ligand-binding motif
      identified in humans and mice but the 5' region lacked the repeat motif thought
      to specify a DNA-binding domain in mammals. Southern blot analysis and
      fluorescence in situ hybridisation mapping showed that the gene is autosomal,
      located on chromosome 1q. Sequence comparisons showed that the putative chicken
      DAX1 protein has 63 and 60% identity with the human and mouse proteins
      respectively over the region of the conserved ligand-binding domain. However,
      stronger identity (74%) exists with a putative alligator DAX1 sequence over the
      same region. Northern blotting detected a single 1.4 kb transcript in late
      embryonic chicken gonads, while RNase protection assays revealed expression in
      the embryonic gonads of both sexes during the period of sexual differentiation.
      Expression increased in both sexes during gonadogenesis, but was higher in
      females than in males. This is the first description of a DAX1 homologue in a non
      mammalian vertebrate.

PMID- 10656996
TI  - Overlap of IGF- and heparin-binding sites in rat IGF-binding protein-5.
AB  - Using site-directed mutagenesis, we have undertaken a study of a potential IGF
      binding site in the C-terminal domain of rat IGFBP-5, lying close to or within a
      previously described heparin-binding domain (residues 201-218) in this protein.
      After analysis of binding activity using three different methods - ligand
      blotting, solution phase equilibrium binding and biosensor measurement of real
      time on- and off-rates - we report that the mutation of two highly conserved
      residues within this region (glycine 203 and glutamine 209) reduces the affinity
      of the binding protein for both IGF-I and IGF-II, while having no effect on
      heparin binding. In addition, we confirm that mutation of basic residues within
      the heparin-binding domain (R201L, K202E, K206Q and R214A) results in a protein
      that has attenuated heparin binding but shows only a small reduction in affinity
      for IGF-I and -II. Previous findings have described the reduction in affinity of
      IGFBP-5 for IGFs that occurs after complexation of the binding protein with
      heparin or other components of the extracellular matrix (ECM) and have postulated
      that such an interaction may result in conformational changes in protein
      structure, affecting subsequent IGF interaction. Our data suggesting potential
      overlap of heparin- and IGF-binding domains argue for a more direct effect of ECM
      modulation of the affinity of IGFBP-5 for ligand by partial occlusion of the IGF
      binding site after interaction with ECM.

PMID- 10656995
TI  - Human chorionic gonadotrophin-beta transcripts correlate with progesterone
      receptor values in breast carcinomas.
AB  - The pathophysiological role for the expression of human chorionic gonadotrophin
      (hCG) in malignant neoplasms is currently speculative. We investigated the
      overall expression of genes hCG-beta 5, 3, 8 and 7 in breast carcinoma (n=214),
      fibroadenoma (n=37) and macromastia (n=10) by quantitative reverse transcriptase
      PCR. Eighty (37.4%) of the breast cancer samples revealed positive hCG-beta mRNA
      expression and the mean value was 67. 9 copies per 200 ng total RNA (range: 0
      1743; 95% confidence interval (CI) for mean: 44-92). Fibroadenomas had more
      frequently detected (56.8%) and greater hCG-beta copy numbers (mean 86.9; range:
      0-845; 95% CI for mean: 35-138). Macromastia probes yielded no positive hCG-beta
      mRNA. The hCG-beta mRNA expression was significantly different in the three
      histological subgroups (P=0. 006). Among breast carcinomas, a positive
      correlation was detected between hCG-beta mRNA copy numbers and progesterone
      receptor (PgR) values (P<0.001). No significant differences were seen regarding
      disease-free (P=0.87) and overall survival (P=0.20) depending on hCG-beta mRNA
      status. Finally, our findings do not support a role for hCG-beta in malignant
      transformation of human breast cells and indicate a possible involvement of hCG
      beta in benign breast disease. The relationship with PgR expression may suggest
      that progestins regulate the expression of hCG in breast epithelial cells.

PMID- 10656997
TI  - Urocortin is the principal ligand for the corticotrophin-releasing factor binding
      protein in the ovine brain with no evidence for a sauvagine-like peptide.
AB  - To purify novel ligands for the corticotrophin-releasing factor binding protein
      (CRF-BP) from ovine brain, whole brain was homogenised in methanol and the
      supernatant extracted on Sep-pak C18 cartridges followed by a preliminary HPLC
      step. Three peaks of ovine CRF-BP ligand activity were detected in the HPLC
      fractions, the first two of which were also detected by a specific corticotrophin
      releasing factor two-site immunoradiometric assay, the third peak being detected
      by a human CRF-BP ligand assay, which will not detect ovine CRF. Human CRF-BP
      ligand-containing fractions were further purified by affinity chromatography on a
      human recombinant CRF-BP column with two additional HPLC steps. The human CRF-BP
      ligand was found to: (a) possess a molecular mass of 4707 Daltons, (b) have an N
      terminal amino acid sequence (5 residues) identical to rat urocortin, (c) be
      detected by a specific urocortin radioimmunoassay, (d) have high affinity for
      both the human and ovine CRF-BPs and (e) be present in many regions of the ovine
      brain. Additionally, a 300 bp cDNA fragment sharing 83% homology with the rat
      urocortin gene was cloned from ovine brain, the product of which was predicted to
      have an identical amino acid sequence to that of rat urocortin. These pieces of
      information confirmed the identity of the human CRF-BP ligand as an ovine
      urocortin. The specially developed CRF-BP ligand assays showed that the rank
      orders of affinity of the CRF family members for human CRF-BP were: carp
      urotensin-1>>human CRF=rat/ovine urocortin>human urocortin>>frog sauvagine>>ovine
      CRF, and those for the ovine CRF-BP were: carp urotensin-1> human CRF=rat/ovine
      urocortin>human urocortin> frog sauvagine>>ovine CRF. This study describes a
      successful technique for the purification and detection of peptide ligands for
      the CRF-BP. We conclude that urocortin is the principal ligand for the CRF-BP in
      ovine brain and we could find no evidence for a centrally located mammalian
      sauvagine-like peptide.

PMID- 10656998
TI  - FSH suppression of nitric oxide synthesis in porcine oocytes.
AB  - The present study was designed to evaluate the regulation of nitric oxide (NO)
      synthesis in porcine oocytes during follicular development. Cumulus-oocyte
      complexes were obtained by aspirating the small follicles of immature porcine
      ovaries and cultured at 39 degrees C for 24-72 h with FSH in a serum-free medium.
      The oocyte-surrounding cumulus cells markedly proliferated and expressed LH
      receptor mRNA in response to FSH. The endothelial type of NO synthase (eNOS) (130
      kDa) was detected in the oocyte, but not in the proliferated cumulus cells, by
      immunoblotting. The amount of oocyte eNOS did not significantly alter during
      culture, but measurement of nitrite and nitrate revealed FSH suppression of NO
      synthesis by approximately 50%. NO-releasing agents were added to the cultures to
      examine the effect of NO on the growth of cumulus cells. NO-releasing agents
      showed inhibitory effects on proliferation of the cumulus cells and expression of
      LH receptor mRNA. Thus, synthesis of eNOS-derived NO is suppressed in the porcine
      oocyte during development with no change in the enzyme amount, and it is
      suggested that it has an inhibitory function in the growth of cumulus cells.

PMID- 10656999
TI  - Phenotypic variability and origins of mutations in the gene encoding 3beta
      hydroxysteroid dehydrogenase type II.
AB  - Mutations in HSD3B2, the gene for 3beta-hydroxysteroid dehydrogenase type II
      (3beta-HSD II) have been detected and activities analysed through the in vitro
      expression of mutant cDNAs. Two full sibs with male pseudohermaphroditism were
      found to be double heterozygotes: N100S/266DeltaA. This genotype leads to the
      most profound loss of 3beta-HSD II enzyme activity (1.3% of normal) described to
      date in cases without severe salt-loss. One sib (N100S/266DeltaA) is the first
      reported male case of type II deficiency affected with premature adrenarche.
      Three apparently independent kindreds had propositi affected with the HSD3B2
      mutation A82T/A82T, which is associated with a non salt-losing phenotype with
      variable expressivity in females. These three families had the same extended
      HSD3B haplotype and are likely to have inherited the same ancestral mutation. The
      significance of this finding is discussed in the light of the presence of A82T
      mutation at a homologous position in pseudogene varphi5 that is present in the
      HSD3B cluster.

PMID- 10657000
TI  - Sodium butyrate/retinoic acid costimulation induces apoptosis-independent growth
      arrest and cell differentiation in normal and ras-transformed seminal vesicle
      epithelial cells unresponsive to retinoic acid.
AB  - Retinoic acid (RA) and sodium butyrate (NaB) are regulators of cell growth and
      differentiation. We studied their effect on normal (SVC1) or v-Ki-ras-transformed
      (Ki-SVC1) rat seminal vesicle (SV) epithelial cell lines. The treatment of these
      cells with 10(-((7( M RA did not produce significant changes in the morphological
      and biochemical parameters analyzed. When RA was used in combination with 2 mM
      NaB, the treatment induced substantial morphological changes, apoptosis
      independent growth arrest, up-regulation of tissue transglutaminase (tTGase), and
      down-regulation of beta and gamma RA receptor (RAR) mRNA expression. The same
      cells did not express RAR alpha either before or after NaB/RA treatment. A
      similar treatment did not change the amount of mRNA coding for the protein SV-IV
      (a typical differentiation marker of the SV epithelium) in normal or ras
      transformed cells nor the level of v-Ki-ras mRNA in Ki-SVC1 cells. These findings
      suggest that a defective RA/RARs signaling pathway is probably the biochemical
      condition that underlies the unresponsiveness to RA of our in vitro culture
      system, and indirectly points to the possibility that the NaB/RA-induced effects
      were brought about by a cooperation at the transcription level between the
      histone deacetylase inhibitory activity of NaB and the ability of RA/RAR to
      modulate the expression of various genes involved in the control of cell growth
      and differentiation.

PMID- 10657001
TI  - Identification of two new nonclassical members of the rat prolactin family.
AB  - The prolactin (PRL) family is comprised of a group of hormones/cytokines that are
      expressed in the anterior pituitary, uterus, and placenta. These proteins
      participate in the control of maternal and fetal adaptations to pregnancy. In
      this report, we have identified two new nonclassical members of the rat PRL
      family through a search of the National Center for Biotechnology Information
      dbEST database. The cDNAs were sequenced and their corresponding mRNAs
      characterized. Overall, the rat cDNAs showed considerable structural similarities
      with mouse proliferin-related protein (PLF-RP) and prolactin-like protein-F (PLP
      F), consistent with their classification as rat homologs for PLF-RP and PLP-F.
      The expression of both cytokines/hormones was restricted to the placenta. The
      intraplacental sites of PLF-RP and PLP-F synthesis differed in the rat and the
      mouse. In the mouse, PLF-RP was expressed in the trophoblast giant cell layer of
      the midgestation chorioallantoic and choriovitelline placentas and, during later
      gestation, in the trophoblast giant cell and spongiotrophoblast layers within the
      junctional zone of the mouse chorioallantoic placenta. In contrast, in the rat,
      PLF-RP was first expressed in the primordium of the chorioallantoic placenta
      (ectoplacental cone region) and, later, exclusively within the labyrinth zone of
      the chorioallantoic placenta. In the mouse, PLP-F is an exclusive product of the
      spongiotrophoblast layer, whereas in the rat, trophoblast giant cells were found
      to be the major source of PLP-F, with a lesser contribution from
      spongiotrophoblast cells late in gestation. In summary, we have established the
      presence of PLF-RP and PLP-F in the rat.

PMID- 10657002
TI  - Acute regulation of the bovine gene for the steroidogenic acute regulatory
      protein in ovarian theca and adrenocortical cells.
AB  - Upregulation of the steroidogenic acute regulatory protein (StAR) is implicated
      in the rapid synthesis and secretion of steroidogenic cells to produce steroids
      in response to stimulation by trophic hormones of the gonadal and stress axes. In
      the present study, we have assessed the kinetics of both StAR gene transcription
      and protein biosynthesis in primary cell cultures of bovine adrenocortical and
      ovarian theca cells, under conditions of acute stimulation by corticotrophin
      (ACTH) and luteinizing hormone (LH), respectively. In both cell systems,
      detectable upregulation of StAR gene transcription occurred within 1-2 h,
      reaching maxima at 4 h (theca cells) or 6 h (adrenocortical cells). mRNA levels
      returned rapidly to baseline, by 12 h or 24 h, respectively. Specific StAR
      protein levels were assessed by western blotting using a novel antibody raised
      against a bovine StAR peptide, and showed a similar fast upregulation, albeit
      delayed by 1-2 h compared with the mRNA. The response of the cultured theca cells
      was more acute than that of the adrenocortical cells, possibly reflecting the
      propensity of the LH receptor to desensitize rapidly, unlike the ACTH receptor.
      The primary bovine theca cell cultures were also used for fully homologous
      transfection studies using various deletion promoter-reporter constructs of the
      bovine StAR gene. Kinetic analysis of the results indicated that the acute
      transcriptional response resides within the proximal (-315 bp) promoter region,
      which includes two putative responsive elements for the steroidogenic factor-1.
      More distal promoter regions may be involved in modulating the specificity of
      expression by combining enhancer and inhibitory functions.

PMID- 10657003
TI  - Thyroid hormone deiodination in the domestic cat.
AB  - We have investigated thyroid hormone deiodination in the liver, kidney and
      thyroid of the domestic cat. Affinity labelling with (125)I-bromoacetyl reverse
      T(3) (125)(I-BrAc-rT(3) demonstrated that liver and kidney, but not the thyroid,
      express type I iodothyronine deiodinase (IDI), results that were confirmed by
      measuring the activity of the IDI using (125)I-rT(3) and T(4) as substrate.
      Feline hepatic and renal IDI metabolised rT(3) at approximately 0.2% of the rate
      of rat hepatic IDI under identical assay conditions. The K(m) of the feline
      enzyme was at least 500-fold greater than that of rat IDI. However, feline and
      rat hepatic IDI metabolised T(4) at a similar rate and had similar K(m) values
      (1.35 microM and 2.25 microM, respectively). This study demonstrates that cats
      and rats express IDI in the liver and kidney in similar concentrations; however,
      the feline enzyme appears unable to utilise rT(3) as a substrate under
      physiological conditions.

PMID- 10657004
TI  - The lipocalin sperm coating lizard epididymal secretory protein family: mRNA
      structural analysis and sequential expression during the annual cycle of the
      lizard, Lacerta vivipara.
AB  - The epididymal epithelial cells of the lizard (Lacerta vivipara) produce large
      amounts of specific proteins under androgenic control. Amongst them, a major
      protein family that binds to the head of spermatozoa, the lizard epididymal
      secretory protein (LESP) family, has been identified as a member of the lipocalin
      superfamily. LESPs are composed of 9 elements that present an identical molecular
      mass of 18 000 Da but have a large range of pHi (3.5 to 9). The structural
      analysis of this protein family was performed by the determination and comparison
      of both the aminoterminal sequence of each element and the complete sequence of
      three specific LESP cDNA clones. When not identical, LESP elements present
      randomly dispatched nucleotide and amino acid substitutions, indicating the
      existence of at least five LESP mRNA populations encoded by a multigenic family.
      We determined that these LESP genes are differentially expressed during the
      annual epididymal cycle.

PMID- 10657005
TI  - Differential expression of 17beta-hydroxysteroid dehydrogenases types 2 and 4 in
      human endometrial epithelial cell lines.
AB  - In the endometrium two enzymes are known to convert estradiol to its inactive
      metabolite estrone: microsomal 17beta-hydroxysteroid dehydrogenase type 2 (17beta
      HSD2) and peroxisomal 17beta-HSD4. In order to elucidate the particular function
      of each of these two different enzymes, the human endometrial epithelial cell
      lines HEC-1-A and RL95-2 were examined with respect to the expression of
      17betaHSD isozymes. They were compared with human endometrium in vivo. Non
      radioactive in situ hybridization revealed both enzymes in glandular epithelial
      cells of human endometrium. The two cell lines were screened for mRNA expression
      of 17beta-HSD 1-4 by RT-PCR and Northern blot. 17beta-HSD2 and 4 could be
      detected by either method, 17beta-HSD1 only by RT-PCR, 17beta-HSD3 not at all.
      Both cell lines were proven to have no receptor for progesterone which is known
      as a physiological inducer of several 17beta-HSD isozymes. To study the
      regulation of 17beta-HSD2 and 17betaHSD4, the concentration of fetal calf serum
      in the cell culture media was reduced stepwise to 0.3% by dilution with a defined
      serum replacement. This treatment led to an inhibition of 17beta-HSD2 mRNA
      expression and an increase in the mRNA expression of 17beta-HSD4. Concomitantly,
      distinct morphological changes were observed, such as a decrease in the number
      and length of microvilli and a decrease in the formation of domes on top of the
      monolayers. The endometrial epithelial cell lines HEC-1-A and RL95-2 represent a
      suitable in vitro model for further studies of the differential expression of the
      major endometrial HSD isozymes, independent of the effect of progesterone.

PMID- 10657006
TI  - Immunolocalisation of oestrogen receptor beta in human tissues.
AB  - Oestrogens exert their actions via specific nuclear protein receptors that are
      members of the steroid/thyroid receptor superfamily of transcription factors.
      Recently, a second oestrogen receptor (ERbeta) has been cloned, and using reverse
      transcription-PCR and immunohistochemistry it has been shown to have a wide
      tissue distribution in the rat that is distinct from the classical oestrogen
      receptor, ERalpha. Using commercial polyclonal antisera against peptides specific
      to human ERbeta, we have determined the sites of ERbeta expression in archival
      and formalin-fixed human tissue and compared its expression with that of ERalpha.
      ERbeta was localised to the cell nuclei of a wide range of normal adult human
      tissues including ovary, Fallopian tube, uterus, lung, kidney, brain, heart,
      prostate and testis. In the ovary, ERbeta was present in multiple cell types
      including granulosa cells in small, medium and large follicles, theca and corpora
      lutea, whereas ERalpha was weakly expressed in the nuclei of granulosa cells, but
      not in the theca nor in the copora lutea. In the endometrium, both ERalpha and
      ERbeta were observed in luminal epithelial cells and in the nuclei of stromal
      cells but, significantly, ERbeta was weak or absent from endometrial glandular
      epithelia. Epithelial cells in most male tissues including the prostate, the
      urothelium and muscle layers of the bladder, and Sertoli cells in the testis,
      were also immunopositive for ERbeta. Significant ERbeta immunoreactivity was
      detected in most areas of the brain, with the exception of the hippocampus - a
      tissue that stained positively for ERalpha. In conclusion, the almost ubiquitous
      immunohistochemical localisation of ERbeta indicates that ERbeta may play a major
      role in the mediation of oestrogen action. The differential expression of ERalpha
      and ERbeta in some of these tissues suggests a more complex control mechanism in
      oestrogenic potential than originally envisioned.

PMID- 10657007
TI  - Nitric oxide, iNOS, and inflammation in cystic fibrosis.
AB  - Nitric oxide (NO) is produced from three isoforms of nitric oxide synthase (NOS),
      neuronal (nNOS), endothelial (eNOS) and inducible (iNOS). Cystic fibrosis (CF)
      patients have an increased bacterial load in the airways which stimulates iNOS
      and therefore NO production. Upregulation of iNOS in normal epithelial cells
      protects the lung from damage, but in CF cells, iNOS is not upregulated and NO
      production is reduced. Reduced iNOS expression is associated with neutrophil
      sequestration in the lung, thus increasing the potential damage from neutrophil
      proteases and reactive oxygen species. In contrast, high concentrations of NO may
      augment the inflammatory process in acute lung injury from sepsis. Meng et al.
      have shown that cystic fibrosis epithelial cells, when stimulated by a cytokine
      mix and co-cultured with activated neutrophils, have reduced iNOS expression
      compared to normal epithelial cells. Although iNOS expression may not accurately
      reflect activity and NO production may arise from elsewhere, this study suggests
      that reduced iNOS expression may play a part in the pathophysiological processes
      in cystic fibrosis.

PMID- 10657008
TI  - Inflammatory mediators in acute pancreatitis.
AB  - Inflammatory mediators play a key role in acute pancreatitis and the resultant
      multiple organ dysfunction syndrome, which is the primary cause of death in this
      condition. Recent studies have confirmed the critical role played by inflammatory
      mediators such as TNF-alpha, IL-1beta, IL-6, IL-8, PAF, IL-10, C5a, ICAM-1, and
      substance P. The systemic effects of acute pancreatitis have many similarities to
      those of other conditions such as septicaemia, severe burns, and trauma. The
      delay between the onset of inflammation in the pancreas and the development of
      the systemic response makes acute pancreatitis an ideal experimental and clinical
      model with which to study the role of inflammatory mediators and to test novel
      therapies. Elucidation of the key mediators involved in the pathogenesis of acute
      pancreatitis will facilitate the development of clinically effective anti
      inflammatory therapy.

PMID- 10657009
TI  - Neutrophils enhance expression of inducible nitric oxide synthase in human normal
      but not cystic fibrosis bronchial epithelial cells.
AB  - The bronchial epithelium in cystic fibrosis (CF) expresses very low levels of the
      inducible form of nitric oxide synthase (iNOS). The product of iNOS, nitric oxide
      (NO), mediates anti-microbial effects and can reduce neutrophil sequestration in
      the lung. Heavy neutrophilic infiltration of the pulmonary epithelium is a major
      feature of the end-stage CF lung. This study hypothesized that the system whereby
      the pulmonary epithelium protects itself against exaggerated neutrophilic
      infiltration by producing NO is compromised in CF. Human neutrophils were
      activated by incubation with cytokines, added to monolayers of normal (16HBE14o-)
      and CF (CFBE41o-) bronchial epithelial cells and co-cultured for up to 72 h.
      Marked up-regulation of iNOS protein expression was seen in normal bronchial
      epithelial cells following neutrophil co-culture but the CF cells showed a
      significantly smaller increase (p<0.001). To determine whether the relative lack
      of protein was due to a defect in translation, RT-PCR of iNOS mRNA was carried
      out and a pattern of mRNA expression was seen paralleling that of the protein.
      The reduced production of NO by CF compared with normal epithelium was shown by
      the presence of significantly (p<0.001) less accumulated nitrites in medium after
      co-culture with neutrophils. In summary, this study shows that the normal
      production of NO by bronchial epithelium in response to contact with neutrophils
      is lacking in CF. As NO has been shown to oppose neutrophil sequestration, its
      relative lack in CF may underlie the heavy neutrophilic infiltration that
      characterizes the disease.

PMID- 10657010
TI  - Trefoil factor family domain peptides in the human respiratory tract.
AB  - Trefoil factor family domain peptides (TFF) are thought to be involved in mucosal
      epithelial restitution and wound healing of the gastrointestinal tract and are up
      regulated in ulceration and in a variety of solid tumours. It was hypothesized
      that TFFs are also expressed on mucosal surfaces of the human respiratory tract.
      Lung tissue, nasal polyps, and sputum samples from seven patients with cystic
      fibrosis (CF), two with chronic and acute bronchitis, and non-dysplastic material
      from two cases of bronchial adenocarcinoma were analysed for TFF expression by
      immunohistochemistry, immunofluorescence, western blot and RT-PCR. Expression of
      TFF1 and TFF3 was observed in material from all patients. TFFs were localized in
      goblet and ciliated cells, as well as in some submucosal cells of
      tracheobronchial tissues and nasal polyps from normal and CF individuals. In
      sputa of patients with CF and with chronic or acute bronchitis, TFF1 and TFF3
      were detected by western blotting. Freshly cultivated nasal epithelial cells
      transcribed and secreted TFFs and mucins, whereas nasal cells cultivated for 6
      weeks still expressed mucins, but not TFFs. Secreted TFFs and mucins also bound
      to the surface of Staphylococcus aureus in infected CF airways. In conclusion,
      TFF1 and TFF3 are expressed and secreted in normal and inflamed airways. The
      association of TFFs with bacteria may contribute to the anti-microbial
      mucociliary defence system.

PMID- 10657011
TI  - Quantitative immunohistochemical analysis of cytokine profiles in Epstein-Barr
      virus-positive and -negative cases of Hodgkin's disease.
AB  - Hodgkin's disease (HD) is a malignant lymphoproliferative disease characterized
      by the presence of Hodgkin-Reed-Sternberg cells surrounded by a reactive
      infiltrate. In Epstein-Barr virus (EBV)-associated cases (40-60%), at least two
      EBV-encoded proteins [latent membrane protein 1 (LMP1) and LMP2] are expressed,
      which are potential targets for cytotoxic T-lymphocytes (CTLs). Although in EBV
      positive cases significantly more activated (granzyme B-positive) CTLs and
      natural killer (NK) cells are present, the cytotoxic immune response is not
      sufficient for adequate killing of tumour cells. The production of
      immunomodulating cytokines within the tumour may be one of the mechanisms causing
      circumvention of the immune system. This study investigated by
      immunohistochemistry the presence of the immunosuppressive cytokine interleukin
      10 (IL-10) and other Th1/Th2-associated cytokines [IL-2, IL-4, interferon-gamma
      (IFN-gamma)] in the neoplastic cells and reactive lymphocytes of nine EBV
      positive and 18 EBV-negative cases of HD. The percentage of IL-10-expressing
      cells, both neoplastic and reactive, in EBV-positive cases was significantly
      higher (33.1% vs. 18.5% for the neoplastic cells and 21.6% and 12.2% for the
      reactive cells, p=0.003 and 0.04, respectively) than in EBV-negative cases. No
      difference in the percentage of IL-2-, IL-4- and IFN-gamma-expressing cells was
      observed. These results suggest that escape from local immune surveillance is not
      due to a shift from Th1 towards Th2, but may be caused by a direct effect of IL
      10 on the cytotoxic cells.

PMID- 10657012
TI  - Differential expression of matrix metalloproteinases and their inhibitors in non
      small cell lung cancer.
AB  - In a comprehensive immunohistochemical study of the expression of ten
      metalloproteinases (MMPs) and their four inhibitors (TIMPs) in 115 non-small cell
      lung carcinomas (NSCLCs), the findings have been correlated with the histological
      and clinical features of the tumours. All MMPs and TIMPs were expressed in
      tumours, with frequencies ranging from 41% for MMP-2 to 68% for MMP-13. Stromal
      immunoreactivity ranged from 6% for TIMP-4 to 87% for MMP-13. In some tumours, an
      overexpression of these proteins, as revealed by stronger staining in cancer
      cells than in adjacent normal bronchial epithelium, was also observed. The
      frequency ranged from 1% for MMP-3 to 28% for MMP-13. Compared with squamous cell
      carcinoma (SqCC), adenocarcinoma (AdC) more frequently overexpressed MMP-1, -11, 
      13, -14, and TIMP-2, and TIMP-1 and/or TIMP-2 overexpression positively
      correlated with more advanced stage disease. None of the MMP or TIMP expression
      correlated with the ras genotype of the tumours. The higher frequency of MMP
      overexpression in AdC than in SqCC may relate to the greater tendency of the
      former for systemic metastasis. The association of TIMP-1 overexpression with
      more advanced disease may suggest a role in prognosis.

PMID- 10657013
TI  - Immunohistochemical expression of nm23 in primary invasive malignant melanoma is
      predictive of survival outcome.
AB  - The objective of this study was to determine the utility of nm23 as an
      immunohistochemical indicator of prognosis in a large series (157 cases) of
      malignant melanoma and also in two subsets within this group: stage 1 tumours,
      whether in radial or vertical growth phase (140 cases); and stage 1 tumours in
      which a vertical growth phase component was positively identified (123 cases). A
      secondary objective was to explore the relationship between the
      immunohistochemical expression of nm23 and established clinical and histological
      indicators of prognosis in each of these three groups. In all groups it was found
      that strong immunoreactivity correlated positively with survival and inversely
      with indicators of poor prognosis, in keeping with transfection and mRNA studies
      and also with many immunohistochemical studies of other tumour types. That these
      findings are at variance with earlier reported immunohistochemical studies of
      melanoma highlights the importance of large case numbers of primary invasive
      tumours in studies which set out to explore the relationship between
      immunoreactivity and survival.

PMID- 10657014
TI  - Allelic changes at multiple regions of chromosome 5 are associated with
      progression of urinary bladder cancer.
AB  - This study has analysed 65 urothelial carcinomas for allelic imbalance at 22 loci
      of chromosome 5 and has determined three regions of interest. A commonly
      duplicated region was mapped to chromosome 5p between loci D5S1473 and D5S819,
      one region of deletion to chromosome 5q22-23 between loci D5S2055 and D5S659, and
      another to chromosome 5q33-34 between loci D5S1456 and D5S1465. An allelic
      imbalance was detected in 54% of the cases. Only 10% of grade 1 tumours showed
      allelic changes at chromosome 5, whereas 60% and 63% of grade 2 and grade 3
      cancers, respectively, had alterations of chromosome 5. The frequency of
      chromosome 5 changes increased from 24% in pTa tumours up to 72% in pT3-4
      tumours. Of particular interest, ten out of 12 urothelial carcinomas showing
      metastatic growth in regional lymph nodes at the time of cystectomy had
      alterations at chromosome 5. No specific region, but genetic changes in general
      were associated with the grading and staging of bladder cancers.

PMID- 10657015
TI  - Decreased HLA-A expression in prostate cancer is associated with normal allele
      dosage in the majority of cases.
AB  - A comparison has been made of the phenotypic expression of MHC class I antigens
      with the corresponding HLA-A genotype in 15 cases of benign prostatic hyperplasia
      (BPH) and 34 cases of primary locally invasive prostatic carcinoma. Expression of
      class 1 protein, detected by immunocytochemistry, was partially or completely
      lost in approximately 90% of the tumours examined. Comparative genomic analysis
      of the beta2 microglobulin (beta2m) gene and 15 individual HLA-A haplotypes using
      a polymerase chain reaction (PCR)-based method demonstrated abnormal gene dosage
      in the minority of cases: homozygous deletion of the beta2m locus was detected in
      one case and HLA-A allele in two cases (HLA-A1 and HLA-A2, respectively),
      representing approximately 8% of the population studied. This first comparative
      study of gene dosage and expression of class 1 protein reported for prostate
      cancer reveals that deletion is not the cause of the partial or complete loss
      seen in the majority of cases. This raises the possibility, in the future, for
      novel selective immunomodulatory therapeutic strategies which stimulate a
      clinically significant re-expression of class 1 protein and associated cytotoxic
      T-cell response.

PMID- 10657016
TI  - Computerized quantitative pathology for the grading of dysplasia in surveillance
      biopsies of Barrett's oesophagus.
AB  - Decision models for surveillance of Barrett's oesophagus (BO) are governed by the
      grade of dysplasia on endoscopic biopsy, but subjective grading is prone to
      observer variation. Computerized morphometry and immunoquantitation can
      objectively discriminate between different grades of dysplasia in oesophagectomy
      specimens with BO. The present study evaluated the feasibility of such
      quantitative analysis on surveillance biopsies of BO. Biopsy criteria for
      quantitative analysis were defined, excluding 101 (21%) of 472 archival BO
      surveillance biopsies. In the remaining haematoxylin and eosin (H&E) sections,
      105 areas that distinctively displayed no dysplasia (ND), low-grade dysplasia
      (LGD) or high-grade dysplasia (HGD) were demarcated. Agreement on double-blind
      examination by two experienced pathologists was reached in 66 areas (63%; kappa:
      0.44). For 21 ND/LGD and 11 LGD/HGD disagreement areas, corresponding sections
      for p53 and Ki67 immunohistochemistry were available. The best combination of two
      discriminating features was stratification index (SI) with p53 area % for ND
      versus LGD (89% correct classification), and SI with Ki67 area % for LGD versus
      HGD (91% correct classification). Fifteen of the 21 ND/LGD disagreement areas
      could be classified uniquely as either ND or LGD by SI and p53, and eight of the
      11 LGD/HGD disagreement areas as either LGD or HGD by SI and Ki67. Correlation
      coefficients for repeated measurements of SI, Ki67, and p53 by the same observer
      were 0.94, 0.92, and 0.86, and by two independent observers 0.86, 0.93, and 0.92,
      respectively. Computerized quantitative pathology on BO surveillance biopsies is
      feasible provided that well-defined biopsy criteria are used. Using a combination
      of features associated with cellular differentiation and proliferation, such as
      SI, p53, and Ki67, quantitative pathological analysis assists in reducing
      diagnostic variability in the grading of dysplasia during surveillance of BO.

PMID- 10657017
TI  - Differential levels of granzyme B, regulatory cytokines, and apoptosis in Crohn's
      disease and ulcerative colitis at first presentation.
AB  - The mechanisms of tissue damage in ulcerative colitis and Crohn's disease may
      reflect disordered humoral or cell-mediated effector mechanisms, respectively.
      Mucosal biopsies from untreated inflammatory bowel disease patients and normal
      controls were analysed for the expression of granzyme B, a cytotoxic effector
      molecule specifically associated with cell-mediated immunity, and for regulatory
      cytokines. Messenger RNA (mRNA) was analysed by reverse transcription-polymerase
      chain reaction and enzyme-linked oligonucleotide chemiluminescence assay. Mucosal
      biopsies were analysed by immunohistochemistry for granzyme B protein and
      lymphocyte markers and for the presence of apoptotic cells by terminal
      deoxynucleotidyl transferase end labelling. Granzyme B mRNA was elevated in
      Crohn's disease, but not in ulcerative colitis or control mucosal biopsies.
      Granzyme B mRNA levels correlated with interferon gamma mRNA levels in Crohn's
      disease. Granzyme B was expressed in CD3+, CD8+ T cells in the lamina propria of
      Crohn's disease mucosa and there were significantly more apoptotic cells in the
      lamina propria in Crohn's disease. In conclusion, granzyme B-expressing T
      lymphocytes are present in the focal mucosal lesions of Crohn's disease, together
      with spatially related apoptotic cell death. These results support the hypothesis
      that T-cell-mediated cytotoxic effector mechanisms may play a role in Crohn's
      disease.

PMID- 10657018
TI  - Expression and cellular localization of the urokinase-type plasminogen activator
      and its receptor in human hepatocellular carcinoma.
AB  - The urokinase-type plasminogen activator (uPA) and its receptor (uPAR) play an
      important role in tumour invasion. Previous studies have shown by RT-PCR that uPA
      and uPAR mRNAs are expressed in human hepatocellular carcinoma (HCC). Here, in
      situ hybridization, immunohistochemistry, and double immunofluorescence were used
      to identify the cells expressing uPA and uPAR in 26 HCCs. The results indicate
      that uPA and uPAR were expressed in every case, almost exclusively in stromal
      cells, mostly myofibroblasts and macrophages, except for rare tumoural
      hepatocytes expressing cytokeratin 7. These results show the important role of
      stromal cells of HCC in the pericellular proteolysis which facilitates cancer
      cell invasion.

PMID- 10657019
TI  - The relationship between inflammatory and serosal connective tissue changes in
      ileal Crohn's disease: evidence for a possible causative link.
AB  - The relationship between the gross connective tissue and inflammatory changes in
      ileal Crohn's disease remains unclear. This study investigated 20 patients
      undergoing ileal resection for Crohn's disease and 20 normal controls. The
      specimens were blocked in 1 cm serial sections and fully examined, including
      fresh morphometry and documentation of a range of pathological features.
      Pathological features of disease showed uniform distributions within affected
      segments, although specimens showed different patterns and severity of
      affliction. Serosal fat wrapping (FW) was present in all cases and was
      significantly greater than normals [mean 63.5% (SD 27. 8) vs. 21.0% (6.4),
      p<0.001], as was mesenteric thickening (MTh) [mean 18.0 mm (SD 11.1) vs. 5.9 mm
      (2.2), p<0.001]. The extent of FW correlated significantly with the degree of
      acute and chronic inflammation (r()=0.32 and 0.23 respectively, p<0.01),
      particularly the extent of transmural inflammation in the form of lymphoid
      aggregates (r()=0.35, p<0.01). MTh did not correlate with any features studied.
      These findings support the hypothesis that serosal connective tissue changes in
      Crohn's disease are related to the local effects of underlying chronic
      inflammatory infiltrates. Full thickness, radial samples from a grossly affected
      area are representative of the histopathological features present in a diseased
      segment as a whole.

PMID- 10657020
TI  - Integration and proliferation of transplanted cells in hepatic parenchyma
      following D-galactosamine-induced acute injury in F344 rats.
AB  - To determine whether liver repopulation with cell transplantation could be of
      therapeutic value in acute hepatic failure, it is necessary to establish the fate
      of transplanted hepatocytes. This study used dipeptidyl peptidase IV-deficient
      F344 rats as recipients to analyse the engraftment and proliferation of
      transplanted hepatocytes. Syngeneic hepatocytes were transplanted
      intrasplenically 24-30 h after induction of liver injury by D-galactosamine
      (GalN). Portosystemic shunting was analysed with 99m-Tc-labelled albumin
      microspheres. GalN-treated rats showed characteristic hepatic necrosis,
      inflammation, gamma-glutamyl transpeptidase activation, and regenerative
      activity, without increased portosystemic shunting (>99% 99m-Tc activity was in
      the liver in normal and GalN-treated rats). Transplanted cells entered hepatic
      sinusoids promptly and were observed in liver plates at 48 h. The number of
      transplanted cells increased in GalN-treated rats by approximately seven-fold
      (range two- to 12-fold), along with evidence for DNA synthesis between 3 and 14
      days after cell transplantation and greater prevalence of larger transplanted
      cell clusters. These findings indicate that the liver can be safely repopulated
      in animals with acute liver failure, although the time required for regenesis of
      plasma membrane structures and proliferation in transplanted hepatocytes will
      need to be considered in developing therapeutic strategies.

PMID- 10657021
TI  - Apoptosis in mycobacterium tuberculosis infection in mice exhibiting varied
      immunopathology.
AB  - This study examined mechanisms contributing to pulmonary immunopathology
      following acute Mycobacterium tuberculosis (MTB) infection in vivo in a murine
      model. A/J and C57BL/6 mice were intravenously infected with MTB (Erdman).
      Pathological differences were found between strains, unrelated to pulmonary load
      of bacilli. A/J mice developed progressive interstitial pneumonitis, while
      C57BL/6 mice maintained granuloma formation. The contribution of FAS and FAS
      ligand-mediated apoptosis was assessed via bioluminescent reverse transcription
      polymerase chain reaction (RT-PCR), immunohistochemical staining, and TUNEL
      assessment of DNA fragmentation. Cytokine messages for pulmonary tumour necrosis
      factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma), as well as for the
      lytic molecules perforin and granzyme B, were quantified. Immunohistochemical
      staining for CD3 receptor was performed to monitor lymphocytic lung infiltration.
      Soon after infection, A/J mice exhibited increased pulmonary IFN-gamma message,
      concurrent with the appearance of CD3+ lymphocytes distributed throughout the
      lung. C57BL/6 mice exhibited perivascular cuffing, with no accompanying increase
      in IFN-gamma message. A/J mice also had elevated levels of FAS and FAS ligand
      message and protein early after infection, while the C57BL/6 mice had no
      increased expression of these molecules. Both strains exhibited qualitatively
      similar numbers of TUNEL-positive cells throughout infection, with a marked
      increase on day 7. Apoptotic cells appeared to co-localize with acid fast
      bacilli. It is therefore proposed that apoptosis during initial granuloma
      formation following MTB infection may occur through a FAS/FAS ligand-independent
      pathway. Moreover, a failure of completion of the FAS/FAS ligand-mediated
      apoptosis pathway in the A/J mice may contribute to inefficient elimination of
      lymphocytes, thus further aggravating pulmonary pathology.

PMID- 10657022
TI  - Expression of apoptosis-regulatory genes in epithelial cells in pulmonary
      fibrosis in mice.
AB  - Up-regulation of Fas and Fas ligand and excessive apoptosis of bronchiolar and
      alveolar epithelial cells were identified in bleomycin-induced pulmonary fibrosis
      in mice. This study hypothesized that apoptosis-regulatory genes other than Fas
      Fas ligand, such as p53, p21 (Waf1/Cip1), bcl-2, bcl-x, and bax, may also
      participate in epithelial cell apoptosis in this model. The expression of these
      genes was assessed by reverse transcription polymerase chain reaction (RT-PCR),
      RT in situ PCR, or immunohistochemistry. The expression of p53 and p21 mRNA was
      concurrently up-regulated in the alveolar epithelial cells at 1 h to 7 days after
      intratracheal instillation of bleomycin. The expression of bcl-2 mRNA was weakly
      up-regulated at 1 h to 14 days, while the expression level of bcl-2 protein was
      not changed. The expression of bcl-x(L) and bax mRNA was strongly up-regulated at
      1 h to 7 days. The expression of bcl-x protein was up-regulated in lymphocytes
      and macrophages, whereas bax protein was up-regulated in both epithelial and
      inflammatory cells. It is concluded that epithelial cell apoptosis in this model
      may also be induced by the up-regulation of p53 and bax and by the imbalance
      between apoptosis-inducible and -inhibitory genes, in addition to the up
      regulation of the Fas-Fas ligand pathway.

PMID- 10657023
TI  - Prenatal cocaine exposure potentiates 5-HT(2a) receptor function in male and
      female rat offspring.
AB  - We have reported previously prenatal cocaine-induced functional deficits in
      serotonergic terminals, and gender-specific supersensitivity of postsynaptic 5
      HT(1A) receptor-mediated hormone responses in offspring. This study investigates
      the effects of prenatal exposure to cocaine on postsynaptic 5-HT(2A) receptor
      mediated responses in prepubescent male and female offspring. Pregnant rats were
      administered saline or (-)cocaine (15 mg/kg, s.c., b.i.d) from gestational day 13
      through 20. Changes in 5-HT(2A) receptor function in offspring were assessed by
      differences in the ability of DOI [4-iodo, 2,5-dimethoxyphenyl-isopropylamine; 2.
      0 mg/kg, s.c.] to elevate plasma levels of the hormones ACTH, corticosterone and
      renin. Basal hormone levels in male and female progeny were unaffected by
      prenatal cocaine exposure. However, prenatal exposure to cocaine significantly
      potentiated the magnitude of the ACTH response to DOI in both male (+19%) and
      female (+43%) progeny. Similarly, the DOI-induced elevation of plasma renin was
      markedly potentiated in male (+51%) and female (+83%) cocaine-exposed offspring.
      Although DOI significantly elevated corticosterone levels in both male and female
      offspring, the magnitude of corticosterone responses was not altered by prenatal
      exposure to cocaine. Densities of agonist ((125)I-DOI)-labeled receptors in
      hypothalamus and cortex were unaltered by prenatal exposure to cocaine. These
      data indicate prenatal cocaine-induced supersensitivity of postsynaptic 5-HT(2A)
      receptor function in male and female offspring without changes in receptor
      density. Synapse: 35:163-172, 2000.

PMID- 10657024
TI  - Acute administration of SCH23390 increases D(1) receptors on nonpyramidal neurons
      in rat mPFC.
AB  - Atypical antipsychotic drugs (APDs) such as clozapine and olanzapine antagonize
      both D(1) and D(2) receptors; however, little is known regarding their
      pharmacologic effect on specific neuronal elements within the local circuitry of
      corticolimbic regions, such as medial prefrontal cortex (mPFC). To characterize
      the effect of short-term antagonism of the D(1) receptor a high-resolution
      autoradiographic technique was used to assess the density (B(max)) and affinity
      (K(d)) of this receptor on pyramidal cells (i.e., large neurons (LNs, >/=100
      microm(2))), nonpyramidal cells (i.e., small neurons (SNs, <100 microm(2))) and
      in the surrounding neuropil (NPL) of layer VI in rat mPFC. Either normal saline
      or the selective D(1) antagonist SCH23390 (1.0 mg/kg/day) were administered for
      48 h via Alzet osmotic pumps. Frozen sections were incubated in [(3)H]SCH23390 (1
      8 nM) in the presence or absence of the competitive inhibitor SKF38393 (10
      microM). A microscopic adaptation to Scatchard analysis revealed a significant
      increase (82%) in B(max) for neuronal cell bodies (P < 0.05), but not for
      neuropil of drug-treated animals. Further analysis indicated that the increase in
      B(max) was present on SNs (94%, P < 0.05), but not LNs in SCH23390-treated rats.
      In contrast, K(d) values for LNs, SNs, and NPL were not significantly altered by
      drug treatment. Since the vast majority of SNs are nonpyramidal in nature, short
      term administration of a selective D(1) antagonist seems to be associated with a
      preferential upregulation of this receptor on interneurons. Overall, these
      results are consistent with the hypothesis that the mechanism of action of
      atypical antipsychotic medications involves changes in D(1) receptor activity
      associated with local circuit neurons in rat mPFC.

PMID- 10657025
TI  - Fenfluramine-induced increase in preproenkephalin mRNA levels in the striatum:
      interaction between the serotonergic, glutamatergic, and dopaminergic systems.
AB  - Fenfluramine (FE) is a halogenated amphetamine derivative that has been used in
      the treatment of obesity. It has been suggested that the effects of FE on the
      striatum are mediated by serotonergic mechanisms. However, several major afferent
      systems may be involved, and administration of FE may be useful to study
      interactions between these systems. In this work, the effects of FE on
      striatopallidal neurons and the possible involvement of the major striatal
      afferent systems were studied in rats by determination of FE-induced changes in
      striatal levels of preproenkephalin (PPE) mRNA using in situ hybridization.
      Injection of FE induced a significant increase (60%) in striatal levels of PPE
      mRNA. This increase was blocked by pretreatment with the D(1) dopamine receptor
      antagonist SCH-23390 or with the NMDA glutamate receptor antagonist MK-801, or by
      lesion of the serotonergic system with 5,7-dihydroxytryptamine or p
      chlorophenylalanine. In 6-hydroxydopamine lesioned rats, the lesion-induced
      increase in PPE mRNA levels was not affected by injection of FE, but was reduced
      by simultaneous serotonergic deafferentation. The results suggest that the
      serotonergic, glutamatergic, and dopaminergic system interact to increase
      striatal PPE mRNA levels after FE administration.

PMID- 10657026
TI  - In vivo characterization of p-[(18)F]MPPF, a fluoro analog of WAY-100635 for
      visualization of 5-HT(1a) receptors.
AB  - The in vivo and ex vivo distributions and the pharmacological profile of the
      fluorinated phenylpiperazine derivative p-[(18)F]MPPF (4-(2'-methoxyphenyl)-1-[2'
      (N-2"-pyridinyl)-p-fluorobenzamido]-et hyl piperazine) were evaluated in the cat
      brain as a potential selective antagonist for 5-HT(1A) receptors using PET. After
      intravenous injection of p-[(18)F]MPPF in cats, there was a rapid accumulation of
      radioactivity in the brain, with 4% of the total radioactivity injected present
      in the brain at 4 minutes postinjection. The highest uptakes of radioactivity
      were observed in the hippocampus and cingulate cortex, regions known to be rich
      in 5-HT(1A) receptors, whereas lower levels of radioactivity were observed in the
      cerebellum. The mean ratio of radioactivity in the hippocampus to the cerebellum
      was 4.29 (SD = 0.21; n = 5) from 40 to 90 minutes postinjection of p-[(18)F]MPPF.
      The corresponding ratio for the cingulate cortex was 3.01 (SD = 0.16; n = 5).
      Specific binding in the hippocampus and the cingulate cortex was markedly reduced
      following injection of unlabeled WAY-100635 and pindolol but was unaffected by
      treatment with alpha1, 5-HT(2), or reuptake inhibitor agents indicating
      reversibility and selectivity of p-[(18)F]MPPF binding to 5-HT(1A) receptors. Ex
      vivo autoradiographic study with p-[(18)F]MPPF in cat brain sections showed
      labeling of areas rich in 5-HT(1A) receptors with a regional brain distribution
      that closely matched that observed using PET. These results indicate that p
      [(18)F]MPPF may be a useful candidate for noninvasive PET imaging of 5-HT(1A)
      receptors in the living human brain.

PMID- 10657027
TI  - In situ examination of tyrosine hydroxylase activity in the rat locus coeruleus
      using (3',5')-[(3)H(2)]-alpha-fluoromethyl-tyrosine as substrate of the enzyme.
AB  - Tyrosine hydroxylase (TH) activity can be modified by changes in the specific
      activity of the enzyme (SA(TH)) or in the levels of active enzyme. We developed a
      methodology making it possible to measure with excellent anatomical resolution TH
      enzymatic activity and TH protein quantity by quantitative autoradiography and
      immunoautoradiography, respectively, from adjacent sections taken at serial
      intervals along the longitudinal extent of a same brain. SA(TH) was estimated by
      the slope of linear regressions established between TH activity and TH quantity
      measured at each anatomical plane. To evaluate TH activity, we used (3',5')
      [(3)H(2)]-(D, L)-alpha-fluoromethyl-tyrosine [(3)H(2)]-MFMT, which is transformed
      by TH to [(3)H]-MFM-dopa, a potent and irreversible substrate for aromatic amino
      acid decarboxylase. We found that the SA(TH) in the cell body area of the LC
      (PKA) was 48% lower than that evaluated in the surrounding pericoerulean neuropil
      (PCN). In the PCN, 22% only of TH level exhibited a level of enzymatic activity
      above threshold. We also examined how SA(TH) was distributed in the LC 15 min and
      3 days after RU 24722 treatment, a potent phasic and tonic activator of TH enzyme
      in noradrenergic neurons. Two distinct mechanisms have been observed: the short
      term effect was due to an increase in the SA(TH) in the PKA only, while the long
      term effect was mainly caused by an increase in the number of active TH proteins
      in the PCN. These results suggest that the fine regulation of TH activity which
      occurs in the different compartments of LC neurons may be critical in the
      functions involving the LC.

PMID- 10657028
TI  - Expression of NR1, NR2A-D, and NR3 subunits of the NMDA receptor in the cerebral
      cortex and olfactory bulb of adult rat.
AB  - Quantitative reverse transcriptase - polymerase chain reaction was used to
      analyze the relative expressions of NR1, NR2A, NR2B, NR2C, NR2D, and NR3 subunits
      of the NMDA receptor in the piriform, entorhinal, visual, and motor cortices as
      well as in the olfactory bulb of adult rat. The analysis detected clear
      differences in the relative proportions of the NMDA receptor subunits between the
      five forebrain regions examined. These differences were particularly striking
      when the piriform and motor cortices were compared. In the piriform cortex, NR1
      was the predominant transcript. The expression of NR2A was only slightly higher
      than half of that of NR1. NR2B was expressed even at lower levels ( approximately
      30% of NR1). NR2C and NR3 were expressed at levels which were approximately 15%
      of those of NR1. NR2D had the lowest levels of expression ( approximately 3% of
      NR1). In contrast, NR2B was the predominant transcript in the motor cortical
      region, where it was expressed at the levels close to 135% of those of NR1
      message. NR2A had the levels of expression of approximately 50% of those of NR1.
      The NR2C expression was close to 25% that of NR1, and the NR2D and NR3
      transcripts were totally absent from this cortical area. These findings suggest a
      significant regional variability of the NMDA receptors in the adult rat
      forebrain.

PMID- 10657029
TI  - Neurochemical neutralization of methamphetamine with high-affinity nonselective
      inhibitors of biogenic amine transporters: a pharmacological strategy for
      treating stimulant abuse.
AB  - The abuse of methamphetamine (METH) and other amphetamine-like stimulants is a
      growing problem in the United States. METH is a substrate for the 12
      transmembrane proteins which function as transporters for the biogenic amines
      dopamine (DA), serotonin (5-HT), and norepinephrine (NE). Increased release of
      CNS DA is thought to mediate the addictive effects of METH, whereas increased
      release of NE in both the peripheral and CNS is thought to mediate its
      cardiovascular effects. The neurotoxic effects of METH on both dopaminergic and
      serotonergic nerves requires the transport of METH into the nerve terminals.
      Thus, transport of METH into nerve terminals is the crucial first step in the
      production of METH-associated pharmacological and toxicological effects. A single
      molecular entity which would block the transport of METH at all three biogenic
      amine transporters might function to neurochemically neutralize METH. This agent
      would ideally be a high-affinity slowly dissociating agent at all three
      transporters, and also be amenable to formulation as a long-acting depot
      medication, such as has been accomplished with an analog of GBR12909. As a first
      step towards developing such an agent, we established an in vitro assay which
      selectively detects transporter substrates and used this assay to profile the
      ability of a lead compound, indatraline, to block the releasing effects of METH
      and MDMA at the DA, 5-HT, and NE transporters. The major finding reported here is
      that indatraline blocks the ability of METH and MDMA to release these
      neurotransmitters. Synapse 35:222-227, 2000. Published 2000 Wiley-Liss, Inc.

PMID- 10657030
TI  - Bcl-2 overexpression attenuates dopamine-induced apoptosis in an immortalized
      neural cell line by suppressing the production of reactive oxygen species.
AB  - Parkinson's disease is a neurodegenerative disease that is consequent to the loss
      of brain dopamine (DA) cells. These abnormalities are thought, in part, to be a
      manifestation of increased free radical production during the metabolism of
      catecholamines. The antiapoptic agent, bcl-2, has been shown to protect cells
      against the toxic effects of reactive oxygen species (ROS). Thus, we tested
      whether bcl-2 could attenuate the toxic effects of DA on immortalized neural
      cells. Our results show that DA caused dose-dependent cell death. The use of
      confocal microscopy and flow cytometry demonstrated that DA caused cell death
      through an apoptotic process. Moreover, DA caused a marked increase in ROS in
      these cells. Furthermore, overexpression of bcl-2 caused significant protection
      against DA-induced apoptosis. These results are discussed in terms of their
      support for a role of bcl-2 in the development of Parkinson's disease.

PMID- 10657031
TI  - Occupancy of brain nicotinic acetylcholine receptors by nicotine doses equivalent
      to those obtained when smoking a cigarette.

PMID- 10657032
TI  - Activation of accumbens cell firing by stimuli associated with cocaine delivery
      during self-administration.
AB  - Electrophysiological recording procedures were used in behaving rats (n = 11) to
      examine the responsiveness of nucleus accumbens (Acb) neurons to stimuli
      associated with intravenous cocaine delivery during self-administration sessions.
      Of 208 Acb neurons recorded during cocaine (0.33 mg/inf) self-administration
      sessions, 78 cells exhibited one of four types of patterned discharges (increases
      and/or decreases in firing rate) immediately before and/or following the cocaine
      reinforced response. All phasically active Acb cells were examined in test
      sessions consisting of "probe" trials (18-20 per session) during which either the
      drug only was delivered (0.33 mg/inf cocaine, 6 sec) or the stimulus only (tone
      houselight, 20 sec) was randomly presented by the computer, interspersed between
      reinforced lever press responses. Results show that Acb cells that exhibit
      postresponse changes in firing rate within seconds of the reinforced response
      appear to be controlled, at least in part, by the stimulus paired with cocaine
      delivery during the self-administration session and not via a direct
      pharmacological action of cocaine. In contrast, neurons displaying exclusively
      preresponse activity do not appear to be influenced by presentation of the drug
      associated stimulus or by a direct pharmacological action of the cocaine, but may
      be related to initiation of the operant response. These findings are discussed
      with respect to the role of the Acb in mediating conditioned responses associated
      with drug reinforcement.

PMID- 10657033
TI  - Long-term methamphetamine-induced decreases of [(11)C]WIN 35,428 binding in
      striatum are reduced by GDNF: PET studies in the vervet monkey.
AB  - The effects of glial cell line-derived neurotrophic factor (GDNF) pretreatment on
      methamphetamine (METH)-induced striatal dopamine system deficits in the vervet
      monkey were characterized with [(11)C]WIN 35,428 (WIN)-positron emission
      tomography (PET). WIN, a cocaine analog that binds to the dopamine transporter
      (DAT), was used to provide an index of striatal dopamine terminal integrity. In
      two subjects, GDNF (200 microg/40 microl) was injected into the caudate and
      putamen unilaterally vs. saline contralaterally. After 1-2 weeks, + and -GDNF
      striatal WIN-PET binding values were equivalent as calculated by multiple time
      graphic analysis, suggestive of an absence of unilateral DAT up-regulation. Three
      other subjects (n = 3) received GDNF injections into the caudate and putamen
      unilaterally and one week later, were administered METH HCl (2 x 2 mg/kg; i.m.,
      24 hours apart; a neurotoxic dosage for this species). At 1 week post-METH, WIN
      PET studies showed that mean WIN binding was decreased by 72% in the +GDNF and by
      92% in the -GDNF striatum relative to pre-drug assessment values. Thus, GDNF
      pretreatment reduced the extent of METH-induced decreases in WIN binding.
      Subsequent WIN-PET studies (1.5-9-month range) showed a protracted recovery of
      WIN binding in each striatum, indicative of long-term but partially reversible
      METH neurotoxicity. Further, at each time point, WIN binding remained relatively
      higher in the +GDNF vs. -GDNF striatum. These results provide further evidence
      that the adult non-human primate brain remains responsive to exogenously
      administered GDNF and that this pharmacotherapy approach can counteract aspects
      of neurotoxic actions associated with methamphetamine.

PMID- 10657034
TI  - Rapid and differential losses of in vivo dopamine transporter (DAT) and vesicular
      monoamine transporter (VMAT2) radioligand binding in MPTP-treated mice.
AB  - The dose- and time-dependent changes of in vivo radioligand binding to the
      neuronal membrane dopamine transporter (DAT) and vesicular monoamine transporter
      type 2 (VMAT2) were examined in mouse brain after MPTP (1-methyl-4-phenyl-1,2,3,6
      tetrahydropyridine) administrations. Regional brain distribution studies were
      done in male C57BL/6 mice using simultaneous injections of d-threo
      [(3)H]methylphenidate (DAT) and (+)-alpha-[(11)C]dihydrotetrabenazine (VMAT2).
      Single (55 mg/kg i.p. ) or multiple (4 x 10 mg/kg i.p., 1-hour intervals)
      administration of MPTP caused significant reductions in [(3)H]methylphenidate and
      [(11)C]dihydrotetrabenazine specific striatal binding, measured 14 days later.
      The single high dose of MPTP produced greater losses of
      [(11)C]dihydrotetrabenazine binding than did the multiple MPTP dosing regimen.
      Using the single high dose of MPTP, changes of in vivo binding of the two
      radioligands were determined at 1, 3, and 14 days after neurotoxin injection. At
      1 day, there are large losses of [(3)H]methylphenidate binding (DAT) but no
      changes in [(11)C]dihydrotetrabenazine binding to the VMAT2 site in the striatum.
      At 3 and 14 days, there were >50% losses of binding of both bot radioligands, but
      significantly (P < 0.001) greater losses of VMAT2 binding of
      [(11)C]dihydrotetrabenazine. These studies indicate that the losses of the
      neuronal membrane and vesicular transporters are not always equal, and do not
      occur in the same time frame, after administration of the neurotoxin MPTP.

PMID- 10657035
TI  - Anatomical distribution of sodium-dependent [(3)H]naloxone binding sites in rat
      brain.
AB  - The sulfhydryl alkylating reagent N-ethylmaleimide (NEM) blocks opioid receptor
      binding and receptor/G-protein coupling. Sodium partially restores [(3)H]naloxone
      binding after inhibition by NEM to reveal sodium-dependent [(3)H]naloxone sites,
      defined as binding in the presence of 50-100 mM NaCl after treatment of membranes
      or sections with 750 microM NEM. In the present study, receptor autoradiography
      of [(3)H]naloxone binding in control and NEM-treated tissue was used to examine
      the anatomical distribution of sodium-dependent [(3)H]naloxone sites in rat
      brain. In brain membranes, the pharmacology of sodium-dependent [(3)H]naloxone
      sites was consistent with that of mu opioid receptors. Relatively high IC(50)
      values for agonists and lack of effect of Gpp(NH)p on DAMGO displacement of
      [(3)H]naloxone binding in NEM-treated membranes indicated that the sodium
      dependent sites were low affinity sites, presumably uncoupled from G-proteins.
      Autoradiograms revealed that NEM treatment dramatically reduced [(3)H]naloxone
      binding in all brain regions. However, [(3)H]naloxone binding was increased in
      specific regions in NEM-treated sections in the presence of sodium, including bed
      nucleus of the stria terminalis, interpeduncular nucleus, periaqueductal gray,
      parabrachial nucleus, locus coeruleus, and commissural nucleus tractus
      solitarius. Sodium-dependent [(3)H]naloxone binding sites were not found in other
      areas that exhibited [(3)H]naloxone binding in control tissue, including the
      striatum and thalamus. These studies revealed the presence of a subpopulation of
      [(3)H]naloxone binding sites which are sodium-dependent and have a unique
      regional distribution in the rat brain.

PMID- 10657036
TI  - Maternal morphine alters parvalbumin immunoreactivity patterns in neonatal mouse
      brain.
AB  - The influence of chronic maternal morphine on the parvalbumin immunoreactive
      patterns in developing mouse brain was studied. Female Swiss mice were
      administered daily saline or morphine (30 or 60 mg/kg) for a period of 7 days
      before mating, gestation, and 21 days postpartum. Their pups were sacrificed on
      postnatal day 18 and the brains were examined histologically and
      immunohistochemically for parvalbumin-positive neurons. Histological observations
      revealed no significant changes in the cell number of the morphine-exposed
      neonatal forebrain, whereas the number of parvalbumin-positive neurons increased
      in layers II-IV of the parietal cortex I. Moreover, the number of parvalbumin
      positive dendrites increased remarkably in the cingulate and parietal I cortices
      of the morphine-exposed neonates, indicating the region-specific increase in the
      PV immunoreactive profiles. These results are consistent with the key roles
      played by the above brain regions in the altered behavioral patterns of the
      maternally addicted neonates, such as impaired somatosensory and cognitive
      performances. The mechanism of morphine action on parvalbumin expression in
      neonatal mouse brain is not evident, but alterations in the expression patterns
      of parvalbumin in specific regions of the developing brain might be one of the
      cellular mechanisms by which addictive drugs modify the functional aspects of the
      developing CNS.

PMID- 10657037
TI  - Role of high-affinity choline uptake on extracellular choline and acetylcholine
      evoked by NMDA.
AB  - Previous studies have shown that NMDA evokes a calcium-dependent and region
      specific increase in extracellular choline that is associated with a reduction of
      membrane phosphatidylcholine and precedes neuronal cell death. We investigated,
      using in vivo microdialysis, the contribution of high-affinity choline uptake on
      the increase in extracellular choline evoked by NMDA. Dialysis was performed in
      the presence of Neostigmine (0.5 microM), an acetylcholinesterase inhibitor, in
      prefrontal cortex or hippocampus of freely moving rats. Drugs were administered
      through the dialysis probe. In cholinergic denervation experiments, rats were
      subjected to sham or AMPA-induced lesion of cholinergic nuclei at least 2 weeks
      before microdialysis. Excitotoxic lesion of the medial septum / ventral diagonal
      band nuclei reduced hippocampal choline acetyltransferase activity by 74%,
      [(3)H]hemicholinium-3 binding by 32%, and completely abolished potassium-evoked
      acetylcholine release. Despite this reduction of presynaptic cholinergic
      function, perfusion of NMDA (300 microM) by retrodialysis produced an increase in
      hippocampal extracellular choline (249 +/- 22% of basal levels) that was similar
      to that observed in sham controls (301 +/- 35%). Inhibition of choline uptake
      with hemicholinium-3 in nonlesioned rats produced a sustained increase in
      dialysate choline (163 +/- 8%) and reduced acetylcholine to 33 +/- 2% of basal
      levels, consistent with a depletion of the acetylcholine pool due to precursor
      deficit. Simultaneous perfusion of hemicholinium-3 and NMDA produced a
      synergistic increase in dialysate choline (664 +/- 95% of basal levels),
      indicating that part of the choline released by NMDA is taken up. In contrast,
      NMDA antagonized the decrease of acetylcholine produced by hemicholinium-3. These
      results show that NMDA-evoked choline release is not mediated by inhibition of
      high-affinity choline uptake and indicate that choline released by NMDA can be
      used to sustain acetylcholine synthesis when there is a precursor deficit
      secondary to uptake inhibition.

PMID- 10657038
TI  - Dorsal raphe stimulation differentially modulates dopaminergic neurons in the
      ventral tegmental area and substantia nigra.
AB  - The serotoninergic (5-HT) input from the dorsal raphe nucleus (DRN) to midbrain
      dopamine (DA) neurons is one of the most prominent. In this study, using standard
      extracellular single cell recording techniques we investigated the effects of
      electrical stimulation of the DRN on the spontaneous activity of substantia nigra
      pars compacta (SNpc) and ventral tegmental area (VTA) DA neurons in anesthetized
      rats. Poststimulus time histograms (PSTH) revealed two different types of
      response in both SNpc and VTA. Some cells exhibited an inhibition-excitation
      response while in other DA neurons the initial response was an excitation
      followed by an inhibition. In SNpc, 56% of the DA cells recorded were initially
      inhibited and 31% of the DA cells were initially excited. In contrast, 63% of VTA
      DA cells were initially excited and 34% were initially inhibited. Depletion of
      endogenous 5-HT by the neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), and the 5
      HT synthesis inhibitor para-chlorophenylalanine (PCPA), almost completely
      eliminated the inhibition-excitation response in both SNpc and VTA DA cells,
      without changing the percentage of DA cells initially excited. Consequently, the
      proportion of DA neurons that were not affected by DR stimulation increased after
      5-HT depletion (from 13% to 60% in SNpc and from 6% to 31% in VTA). In several DA
      cells, DRN stimulation caused important changes in firing rate and firing
      pattern. These data strongly suggest that the 5-HT input from the DRN is mainly
      inhibitory. It also suggests that 5-HT afferences modulate SNpc and VTA DA
      neurons in an opposite manner. Our results also suggest that non-5-HT inputs from
      DR can also modulate mesencephalic DA neurons. A differential modulation of VTA
      and SNpc DA neurons by 5-HT afferences from the DRN could have important
      implications for the development of drugs to treat schizophrenia or other
      neurologic and psychiatric diseases in which DA neurons are involved.

PMID- 10657039
TI  - Differential effects of haloperidol on phencyclidine-induced reduction in
      substance P contents in rat brain regions.
AB  - We investigated the effects of a schizophrenomimetic drug, phencyclidine (PCP),
      on substance P (SP) contents in the discrete rat brain areas using an enzyme
      immunoassay for SP. The acute intraperitoneal (i.p.) administration of PCP (10
      mg/kg), which is a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA)
      type glutamate receptor and a dopamine uptake inhibitor, reduced the
      concentration of the peptide in the prefrontal cortex, limbic forebrain,
      striatum, and substantia nigra, but not in the ventral tegmental area, at 60 or
      120 min postinjection. A selective noncompetitive NMDA antagonist, dizocilpine
      hydrogen maleate ((+)-MK-801) (1 mg/kg, i.p.), also caused a decrease in the SP
      content in the prefrontal cortex and limbic forebrain but failed to alter the
      content in the other areas studied 30 min thereafter. Dopamine agonists,
      methamphetamine (4.8 mg/kg, i.p.) and apomorphine (4.4 mg/kg, i.p.), diminished
      the SP contents in the striatum and substantia nigra 60 min after their injection
      without effects in the prefrontal cortex, limbic forebrain, and ventral tegmental
      area. Furthermore, pretreatment with haloperidol (1 mg/kg, i.p.), a D2 preferable
      dopamine receptor antagonist and a typical antipsychotic, blocked the ability of
      PCP to decrease the SP concentrations in the substantia nigra but not in the
      prefrontal cortex. PCP, therefore, might diminish the SP levels by NMDA receptor
      mediated and dopamine-independent mechanisms in the prefrontal cortex and limbic
      forebrain, but by NMDA receptor-independent and dopamine-dependent mechanisms in
      the striatum and substantia nigra. The haloperidol-insensitive reduction of the
      frontal SP could be involved in certain neuroleptic-resistant symptoms of PCP
      treated animals, PCP psychosis, or schizophrenia.

PMID- 10657040
TI  - Presence of NMDA-type glutamate receptors in cingulate corticostriatal terminals
      and their postsynaptic targets.
AB  - The glutamatergic projection from the anterior cingulate cortex to the medial
      caudate-putamen nucleus (CPN) has been implicated in motor and cognitive
      functions, many of which are potently modulated by activation of N-methyl-D
      aspartate subtype of glutamate receptors (NMDARs). To determine the functional
      sites for NMDAR activation within this circuitry, we combined anterograde
      transport of biotinylated dextran amine (BDA) from deep layers of the rat
      anterior cingulate cortex with immunogold labeling of NMDAR subunit, NMDAR1, in
      the dorsomedial CPN. BDA-containing axons were seen in patch-like clusters in a
      neuropil that showed more uniform immunogold-silver labeling for NMDAR1. Electron
      microscopy of these regions showed that BDA-labeling was present exclusively in
      axons and terminals, 23% (98 of 421) of which also contained NMDAR1
      immunoreactivity (IR). BDA-labeled terminals often apposed NMDAR1-immunoreactive
      neuronal and glial profiles. These terminals also formed asymmetric excitatory
      type synapses with dendritic spines. Of 155 anterogradely labeled axon terminals
      forming asymmetric synapses, 34% were with NMDAR1-labeled, and 66% with unlabeled
      dendritic spines. These results provide ultrastructural evidence for the
      involvement of NMDARs in presynaptic regulation of glutamate transmission, and in
      postsynaptic modulation of the excitability of spiny neurons in patch-like
      compartments of the dorsomedial CPN. These dual NMDAR-mediated actions are likely
      to play a major role in the acquisition of new behaviors and reward-related
      processes that have been associated with cortical input to the striatal patch
      compartments.

PMID- 10657041
TI  - Sigma binding sites identified by [(3)H] DTG are elevated in aged Fischer-344 x
      Brown Norway (F1) rats.

PMID- 10657042
TI  - Initiation of a chromatin-based transcriptionally repressive state in the
      preimplantation mouse embryo: lack of a primary role for expression of somatic
      histone H1.
AB  - A chromatin-based transcriptionally repressive state develops during the two-cell
      stage in preimplantation mouse embryos. Correlated with the initial formation of
      this state is the expression of somatic histone H1, which could confer repression
      by promoting the formation of a transcriptionally repressive chromatin structure.
      To ascertain if the expression of histone H1 could play such a primary role in
      initiating the formation of this transcriptionally repressive state, the
      endogenous pool of somatic histone H1 in the two-cell embryo was greatly expanded
      by injection of 25 or 100 pg of histone H1 at the one-cell stage. The expression
      of the transcription-requiring complex, which is an accepted marker for genome
      activation, was then assessed during the two-cell stage. No significant
      inhibition was noted following the injection of 25 pg of histone H1. A transient
      inhibition was observed following injection of 100 pg, but this was likely due to
      a delay in cleavage to the two-cell stage. We conclude that it is unlikely that
      the expression of somatic histone H1 is a major factor in the initial
      establishment of the chromatin-based transcriptionally repressive state that
      accompanies genome activation.

PMID- 10657043
TI  - Failure of founder transgenic male mice to transmit an attenuated HSV thymidine
      kinase transgene results from mosaicism and sperm competition.
AB  - Previously we found that male mice carrying either of two attenuated herpes
      simplex virus thymidine kinase reporter transgenes displayed low level ectopic
      expression of the reporter gene in the testis and, although fertile, exhibited
      reduced fecundity. In contrast to males of later generations, many of the founder
      males failed to transmit the transgene to their progeny. This led to the
      suggestion that these fertile non-transmitting males are mosaic, with the sperm
      developing from the non-transgenic lineage outperforming those from the
      heterozygous transgenic lineage. Here we present the results of artificial
      insemination (AI) and in vitro fertilization (IVF) experiments designed to test
      this hypothesis. Albino CF(1) hybrid females were inseminated with mixtures of
      equal numbers of sperm from heterozygous transgenic (HT) males (equivalent to
      C57BL/6 x CBAF(2)) and CF(1) males. Similar mixed inseminations were carried out
      in parallel with sperm from non-transgenic (NT) siblings of the HT mice and 13
      day fetuses were scored by eye color to determine their paternity. The pooled
      data from five experiments gave ratios of CF(1) to HT and CF(1) to NT offspring
      of 8.13 and 0.22 respectively, implying a calculated HT to NT ratio of 0.027.
      This indicates that, in competition with each other, the NT sperm would be almost
      40 times more successful in fertilization than the HT sperm. Smaller differences
      were observed between HT and NT when AI was performed with unmixed sperm,
      consistent with the fertility of HT non-founder males. However, in five IVF
      experiments carried out with unmixed sperm, 142/212 oocytes exposed to NT sperm
      were activated and divided, while only 8/226 oocytes treated with HT sperm
      reached the two-cell stage. This confirms that HT sperm are defective and
      indicates that the IVF method employed amplified these deficiencies, which may
      have only a small effect upon natural reproduction when the HT sperm are not in
      competition with normal sperm.

PMID- 10657044
TI  - New method for culture of zona-included or zona-free embryos: the Well of the
      Well (WOW) system.
AB  - Culture of mammalian zygotes individually and in small groups results in lower
      developmental rates than culture of large groups. Zona-free zygotes also have
      impaired developmental potential in current culture systems. This paper describes
      a new approach to resolve the problems, the Well of the Well (WOW) system. Small
      wells (WOWs) were formed in four-well dishes by melting the bottom with heated
      steel rods. The WOWs were then rinsed, the wells were filled with medium, and the
      embryos were placed into the WOWs. To test the value of the WOW system a 3 x 3
      factorial experiment was performed. Bovine presumptive zygotes were cultured from
      day 1 to day 7 (day 0: day of insemination) using three modules (single embryos,
      embryo groups of five, or single zona-digested embryos) and three different
      culture systems (400 microl medium, 200 microl drops, or WOWs). An additional
      control group consisted of 40 to 50 embryos cultured in 400 microl medium. The
      WOW system resulted in higher blastocyst/oocyte rates for all three modules
      (single: 59%; group of five: 61%; single zona-digested: 53%) than the culture in
      drops or in wells (P < 0.05 for all). The developmental rate was independent of
      the number of WOWs per well. The cell number of blastocysts cultured in the WOW
      system did not differ from that of the controls. Apart from its theoretical value
      in revealing the role of different factors influencing embryo development in
      vitro, the WOW system may have immediate practical consequences in certain areas
      of mammalian embryo production.

PMID- 10657045
TI  - Uptake and incorporation of myo-inositol by bovine preimplantation embryos from
      two-cell to early blastocyst stages.
AB  - The uptake of myo-inositol and its incorporation into the phosphoinositides and
      inositol phosphates of the phosphatidylinositol (PtdIns) signal transduction
      system by in vivo preimplantation cattle embryos was investigated using [(3)H]
      myo-inositol. Uptake of inositol was examined in two-cell and four-cell embryos
      (day 2 after insemination), morulae (day 6) and early blastocysts (day 7). Uptake
      in all stages examined was largely sodium-dependent indicating the presence of a
      sodium-dependent inositol transporter. Uptake of inositol did not vary
      significantly from two-cell to early blastocyst stages when expressed either on a
      per embryo or a per microg of protein basis. Incorporation of inositol into the
      three phosphoinositides, PtdIns, PtdInsP, and PtdInsP(2), was detectable at all
      stages examined. In contrast, incorporation of inositol into inositol phosphates
      was not detected until blastocyst formation at day 7. The second messenger,
      Ins(1,4,5)P(3), was first detected in day 7 blastocysts.

PMID- 10657046
TI  - Multiparametric study of atresia in ewe antral follicles: histology, flow
      cytometry, internucleosomal DNA fragmentation, and lysosomal enzyme activities in
      granulosa cells and follicular fluid.
AB  - The differential quantitative participation of apoptosis and necrosis in ewe
      antral follicles of two different sizes, separated in four stages of atresia
      using macroscopic, histologic, and esteroid quantification methods was assessed.
      Annexin V binding and propidium iodide (PI) uptake was used to detect healthy
      live cells (Annexin V negative/PI negative), early apoptotic cells (Annexin V+/PI
      ), and necrotic or late apoptotic cells (PI+). Additionally we used
      internucleosomal DNA fragmentation as a quantitative estimate of apoptosis.
      Presence and distribution of lysosomal enzymes in follicular fluid and granulosa
      cells was used as a measure of necrotic cell death. DNA flow cytometry and gel
      electrophoresis were positively correlated with the progression of atresia, small
      atretic follicles tend to have higher percentages of internucleosomal cleaved DNA
      than follicles >6 mm. Annexin/PI binding also indicates that apoptosis and
      necrosis increase with atresia progression, generally apoptosis outweighs
      necrosis in small follicles. Acid phosphatase and glucosaminidase in follicular
      fluid of 3-6 mm follicles showed no significant modifications between healthy and
      initially atretic follicles, and only a small, but significant increase in
      activity in advancedly atretic follicles. On the contrary, lysosomal enzyme
      activity in follicles >6 mm showed positive correlation between atresia stages
      and the activities of acid phosphatase and glucosaminidase in follicular fluid. A
      similar size-differential behavior was found in free or membrane-bound lysosomal
      enzyme activity of granulosa cells. Necrosis, but principally apoptosis, were
      present during all stages of follicular maturation indicating that growth and
      maturation of ovarian follicles involves a continuous renewal of granulosa cells,
      regulated by apoptosis. Mechanisms regulating this equilibrium may participate in
      the final destiny, whether ovulation or atresia of ovarian follicles.

PMID- 10657047
TI  - Levels of antioxidant defenses are decreased in bovine spermatozoa after a cycle
      of freezing and thawing.
AB  - Growing evidence suggests that the generation of reactive oxygen species (ROS)
      and their detoxification by antioxidants plays a very important role in
      fertility. However, the relationship between the level of antioxidants in
      spermatozoa and the decreased fecundity following a freeze/thaw cycle remains
      poorly understood. We assessed the activities of antioxidant enzymes such as
      catalase, glutathione peroxidase (GPx), superoxide dismutase (SOD), and levels of
      reduced/oxidized glutathione (GSH/GSSG) in bovine semen. Sperm cells were
      isolated using a Percoll gradient to avoid contamination from seminal plasma,
      cellular debris, and other cell types. We found that bovine spermatozoa are
      poorly adapted to metabolize the toxic hydrogen peroxide (H(2)O(2)). Indeed, very
      low levels of GPx and an absence of catalase were observed. We also studied the
      effect of freezing and thawing bovine spermatozoa in a egg yolk-Tris-glycerol
      extender (EYTG). Cryopreservation significantly reduced sperm GSH levels by 78%
      and SOD activity by 50%. We also investigated whether the decrease in GSH level
      could be linked to oxidative metabolism and found that a greater reduction in
      intracellular GSH level occurred when fresh sperm cells were incubated in EYTG
      for 6 hr at 38.5 degrees C under aerobic conditions than when incubated under
      restricted oxygen availability. Our results strongly suggest the involvement of
      an oxidative stress during a freeze/thaw cycle and are consistent with the
      hypothesis that ROS generated during such a cycle are detrimental to sperm
      function.

PMID- 10657048
TI  - Detection of calcium ionophore induced membrane changes in dog sperm as a simple
      method to predict the cryopreservability of dog semen.
AB  - The sensitivity of dog sperm cells for extracellular Ca(2+)/Ca(2+)-ionophore
      challenge was compared to the detrimental effects of an optimized freeze/thawing
      protocol. Three sperm-rich fractions of ejaculates from 9 dogs were obtained, and
      one aliquot of each ejaculate was washed in a modified Tyrode's medium (HBT
      containing 0.1 mM Ca(2+)), without (control sample) and with 2.5 microM Ca(2+)
      ionophore (induced sample) and incubated for 60 min at 38 degrees C in humidified
      atmosphere. Another aliquot from the same semen fractions was diluted, washed in
      a Tris buffer, and packed into 0.5-ml straws with a Tris buffer containing 7.5
      vol % glycerol. The samples were stored for 1 week in liquid nitrogen after a
      computer-driven three-step freeze protocol and subsequently thawed for 50 sec in
      a 37 degrees C water bath and reconstituted into HBT. The acrosome integrity was
      determined using fluorescein-conjugated peanut agglutinin (PNA-FITC) as an
      acrosomal marker, while the vitality of the sperm cells was simultaneously
      assessed with the membrane impermeable DNA supravital stain ethidium homodimer 1
      (EthD-1) using fluorescence microscopy and flow cytometry. The motility of
      frozen/thawed sperm samples was evaluated by microscopic as well as computerized
      motility analyses. Remarkably, the percentage sperm cells that underwent acrosome
      reactions induced by Ca(2+)-ionophore correlated very positively (r = 0.93) with
      the amount of acrosome damage observed in cryopreserved sperm samples.
      Furthermore, the degree of cellular damage induced by Ca(2+)-ionophore treatment
      correlated very negatively (r = -0.99) with the relative amount of sperm cells
      that remained motile after cryopreservation. Such clear correlations between
      Ca(2+)-ionophore induced acrosome reaction and motility parameters for
      frozen/thawed dog sperm cells were not found, suggesting that the generation of
      acrosome leakage and sperm immotility are two independent detrimental processes
      occurring during cryopreservation. From these results it can be concluded that
      Ca(2+)-ionophore treatment followed by simultaneous determination PNA-FITC and
      EthD-1 staining can be used to predict the cryopreservability of ejaculates from
      individual dogs used as donors.

PMID- 10657049
TI  - Effects of aging on inositol 1,4,5-triphosphate-induced Ca(2+) release in
      unfertilized mouse oocytes.
AB  - We previously demonstrated in the mouse oocyte that in vivo postovulatory aging
      significantly suppresses activity of the endoplasmic reticulum (ER) Ca(2+)-ATPase
      (Igarashi et al. 1997. Mol Reprod Dev 48:383-390). We undertook the present study
      to further examine the effects of oocyte aging on Ca(2+) release from the
      inositol 1,4,5-triphosphate (InsP(3))-sensitive Ca(2+) channels of the ER
      membrane, because not only Ca(2+) reuptake, but also Ca(2+) release from the ER,
      substantially affect Ca(2+) oscillations in fertilized oocytes. A transient
      increase in cytosolic free Ca(2+) concentration ([Ca(2+)](i)) was induced by
      photolysis of caged InsP(3) microinjected into the cytoplasm in both fresh (14 hr
      post hCG) and aged (20 hr or 24 hr post hCG) oocytes, where the maximum rate of
      increase in [Ca(2+)](i) significantly decreased in the aged oocytes. Reduced ER
      Ca(2+) release in the aged oocyte may not be attributable to aging-related
      desensitization of the InsP(3)-sensitive Ca(2+) channels in the ER because
      concentrations of caged InsP(3) for half maximal [Ca(2+)](i) increase were
      identical for fresh and aged oocytes. The peak [Ca(2+)](i) response following
      administration of 5 microM thapsigargin, a specific ER Ca(2+)-ATPase inhibitor,
      was significantly reduced in the aged oocyte, suggesting reduction of the ER
      Ca(2+) stores. We conclude from these results that reduction of Ca(2+) release
      from the InsP(3)-sensitive Ca(2+) stores in the aged oocyte arises from depletion
      of the ER Ca(2+) stores with aging. These aging-related changes in Ca(2+) release
      and reuptake may account for alterations in Ca(2+) oscillations in aged
      fertilized oocytes.

PMID- 10657050
TI  - Genome organization in the human sperm nucleus studied by FISH and confocal
      microscopy.
AB  - The sperm nucleus has a unique chromatin structure where the DNA is highly
      condensed and associated with specific proteins, the protamines. It is a
      nondividing cell which is also transcriptionally inactive. After fusion with an
      oocyte, the sperm nucleus undergoes decondensation and, in the same time, starts
      replication and transcription. It has been suggested that somatic chromosomes
      during interphase are organized in territories which display a cell type and cell
      cycle specific distribution. The purpose of this work was to investigate whether
      chromosomes would also have a specific distribution in the sperm nucleus, which
      could be related to its inactive state, and have implications on the early stages
      of fertilization. In the present study, centromeric and telomeric sequences were
      detected by fluorescent techniques performed on human decondensed spermatozoa.
      Chromosome painting probes were used to detect the chromosome X and chromosome 13
      on interphase sperm nuclei. The fluorescent signals were captured in 3D with a
      confocal microscope. For each of these chromatin structures, the volume,
      position, and distribution of the signals were analyzed in samples of 30 nuclei
      with the help of image analysis software. The centromeres appeared grouped in
      several foci that were randomly distributed within the sperm nucleus. The
      telomeres gave an approximately haploid number of small signals, evenly
      distributed throughout the nucleus. The chromosomes X and 13 occupied 4.7% and 3.
      7% of the total nuclear volume, respectively. Interestingly, the X chromosome
      territory showed a preferential position in the anterior half of the volume of
      the nucleus, whereas chromosome 13 had a random position. This work shows a
      particular distribution of chromosome territories in the human sperm nucleus that
      could be related to mechanisms implicated in its specific functions. The analysis
      of more chromosomes and chromosomal structures, including the Y chromosome, would
      help to understand the structure of the human sperm chromatin, and its
      fundamental and clinical implications.

PMID- 10657051
TI  - Altered molecular dynamics and antioxidant status in the spermatozoa in
      testosterone-induced oligospermia in mouse.
AB  - Though supraphysiological doses testosterone (T) and its derivatives are known to
      suppress spermatogenesis in mammals by interfering with the hypothalamus
      pituitary axis leading to oligozoospermia, no study has been performed to
      evaluate the integrity of the sperm cells produced by such individuals. In T
      induced oligozoospermia in the mouse, the spermatozoa showed suppressed zona
      binding ability though the motility and viability remained unchanged. In order to
      assess whether this decreased zona-binding ability is due to perturbations in the
      mechanical properties of the sperm membranes, we attempted to examine the
      molecular dynamics employing a lipophilic spin label (16-doxyl stearate) and a
      protein-binding label (Mal-Net) in two sets of independent experiments. The
      results showed that the rotational freedom of lipophilic molecules reduced
      significantly within the first week of T-treatment. During weeks 1 through 4, the
      protein rotation was found to be retarded significantly. We observed a sharp
      increase in the ascorbyl radical associated with the cauda epididymal spermatozoa
      and epididymal fluid of testosterone-treated mice. Moreover, the glutathione
      (GSH) content in the spermatozoa and the epididymal fluid increased significantly
      after testosterone-treatment. Further, there was a elevation in the superoxide
      dismutase (SOD) activity and suppression in the superoxide anion radical
      generated by the cauda epididymal spermatozoa of testosterone-treated animals. A
      change in the mechanical properties of a bilayer could modify both the mechanical
      properties and the function of incorporated proteins. In many instances, a liquid
      crystalline bilayer is necessary for protein function. It is likely that the
      change in the physical properties of sperm membranes might cause the inhibition
      of enzymes associated with spermatozoa after T-treatment. The alterations in the
      sperm membrane structure and the antioxidant potentials of both the spermatozoa
      and the cauda epididymal fluid could also account for the decrease in the zona
      binding index of the spermatozoa in T-treated animals. Thus, this study
      demonstrates for the first time that supraphysiological doses of testosterone
      could modify the mechano-dynamic properties of sperm membranes and could perturb
      the redox status of both spermatozoa and the epididymal fluid.

PMID- 10657052
TI  - Variation of docosahexaenoic acid content in subsets of human spermatozoa at
      different stages of maturation: implications for sperm lipoperoxidative damage.
AB  - The oxidation of phospholipid-bound docosahexaenoic acid (DHA) has been shown to
      be one of the major factors that limit the motile life span of sperm in vitro.
      Sperm samples show high cell-to-cell variability in life span and, consequently,
      in susceptibility toward lipid peroxidation. Therefore, we postulated that there
      is also cell-to-cell variability in DHA concentration in human spermatozoa. In
      this study, the concentration of DHA in subsets of human spermatozoa isolated by
      a discontinuous Percoll density gradient was determined by gas chromatography.
      Four subsets of human spermatozoa were isolated using a discontinuous Percoll
      gradient: fraction 1 was enriched in immature germ cells and immature sperm,
      fractions 2 and 3 contained, mostly, immature sperm with cytoplasmic droplets,
      and fraction 4 contained, for the most part, morphologically normal sperm, as
      determined by histochemical analysis. The results indicated that there were
      significant differences in DHA content in sperm from all 4 fractions. DHA content
      in sperm from fraction 1 was 2.5-fold higher than that found in fraction 4. DHA
      content in mouse sperm obtained from the seminiferous tubules was 3-fold higher
      than that found in mouse sperm obtained from the epididymis, consistent with the
      findings observed in ejaculated human sperm. The results of this study indicate
      (i) there is cell-to-cell variability in the concentration of DHA in human sperm
      and (ii) that there is a net decrease in DHA content in sperm during the process
      of sperm maturation.

PMID- 10657053
TI  - Kinetics of onset of mouse sperm acrosome reaction induced by solubilized zona
      pellucida: fluorimetric determination of loss of pH gradient between acrosomal
      lumen and medium monitored by dapoxyl (2-aminoethyl) sulfonamide and of
      intracellular Ca(2+) changes monitored by fluo-3.
AB  - The onset of the zona pellucida-induced acrosome reaction in mouse sperm is
      marked by loss of the pH gradient existing in acrosome-intact sperm between the
      acidic acrosomal lumen and the suspending medium, due to pore formation between
      outer acrosomal and plasma membranes. In earlier work, it was shown that this pH
      gradient loss occurred in single sperm bound to structurally intact zonae
      pellucidae with a half-time of 2.1 min; the extended kinetics of this loss
      determined in a sperm population bound to intact zonae was due to a 180-min range
      of variable lag times. We hypothesized that this lag time range was due to steric
      constraints imposed by the three-dimensional structure of the structurally intact
      zona pellucida, and that this constraint should be removed in solubilized zonae.
      The fluorescent probe, Dapoxyl(TM) (2-aminoethyl)sulfonamide (DAES) allowed a
      test of this hypothesis in a population of sperm cells. It is a weak base that is
      non-fluorescent in aqueous solution, but which accumulates in the acidic
      acrosomal compartment due to the pH gradient with highly enhanced fluorescence;
      loss of the pH gradient leads to a decrease in fluorescence. The half-time for
      DAES fluorescence loss in a population of capacitated, acrosome-intact sperm in
      response to solubilized zona pellucida protein was 2.13 +/- 0.10 min (SEM, n =
      9). The agreement between single cell and cell population kinetics validates the
      hypothesis of steric constraint in the structurally intact zona pellucida. The
      change in intracellular Ca(2+) concentration in response to solubilized zona
      pellucida, as monitored with fluo-3, was a rapid increase, followed by a
      decrease, with a half-time of 0.85 +/- 0.09 min (SEM, n = 6) to a steady state
      level higher than the initial level, indicating this Ca(2+) transient as the
      precursor reaction to onset of the zona-induced acrosome reaction.

PMID- 10657054
TI  - An update on the physiology of two- and three-toed sloths.
AB  - Physiological and pharmacological research undertaken on sloths during the past
      30 years is comprehensively reviewed. This includes the numerous studies carried
      out upon the respiratory and cardiovascular systems, anesthesia, blood chemistry,
      neuromuscular responses, the brain and spinal cord, vision, sleeping and waking,
      water balance and kidney function and reproduction. Similarities and differences
      between the physiology of sloths and that of other mammals are discussed in
      detail.

PMID- 10657055
TI  - Characterization of the mucosal and systemic immune response induced by Cry1Ac
      protein from Bacillus thuringiensis HD 73 in mice.
AB  - The present paper describes important features of the immune response induced by
      the Cry1Ac protein from Bacillus thuringiensis in mice. The kinetics of induction
      of serum and mucosal antibodies showed an immediate production of anti-Cry1Ac IgM
      and IgG antibodies in serum after the first immunization with the protoxin by
      either the intraperitoneal or intragastric route. The antibody fraction in serum
      and intestinal fluids consisted mainly of IgG1. In addition, plasma cells
      producing anti-Cry1Ac IgG antibodies in Peyer's patches were observed using the
      solid-phase enzyme-linked immunospot (ELISPOT). Cry1Ac toxin administration
      induced a strong immune response in serum but in the small intestinal fluids only
      anti-Cry1Ac IgA antibodies were detected. The data obtained in the present study
      confirm that the Cry1Ac protoxin is a potent immunogen able to induce a specific
      immune response in the mucosal tissue, which has not been observed in response to
      most other proteins.

PMID- 10657056
TI  - Insect juvenile hormone: from "status quo" to high society.
AB  - Juvenile hormone (JH) exerts pleiotropic functions during insect life cycles. The
      regulation of JH biosynthesis by neuropeptides and biogenic amines, as well as
      the transport of JH by specific binding proteins is now well understood. In
      contrast, comprehending its mode of action on target organs is still hampered by
      the difficulties in isolating specific receptors. In concert with ecdysteroids,
      JH orchestrates molting and metamorphosis, and its modulatory function in molting
      processes has gained it the attribute "status quo" hormone. Whereas the
      metamorphic role of JH appears to have been widely conserved, its role in
      reproduction has been subject to many modifications. In many species, JH
      stimulates vitellogenin synthesis and uptake. In mosquitoes, however, this
      function has been transferred to ecdysteroids, and JH primes the ecdysteroid
      response of developing follicles. As reproduction includes a variety of specific
      behaviors, including migration and diapause, JH has come to function as a master
      regulator in insect reproduction. The peak of pleiotropy was definitely reached
      in insects exhibiting facultative polymorphisms. In wing-dimorphic crickets,
      differential activation of JH esterase determines wing length. The evolution of
      sociality in Isoptera and Hymenoptera has also extensively relied on JH. In
      primitively social wasps and bumble bees, JH integrates dominance position with
      reproductive status. In highly social insects, such as the honey bee, JH has lost
      its gonadotropic role and now regulates division of labor in the worker caste.
      Its metamorphic role has been extensively explored in the morphological
      differentiation of queens and workers, and in the generation of worker
      polymorphism, such as observed in ants.

PMID- 10657057
TI  - Efficacy, safety, quality control, marketing and regulatory guidelines for herbal
      medicines (phytotherapeutic agents).
AB  - This review highlights the current advances in knowledge about the safety,
      efficacy, quality control, marketing and regulatory aspects of botanical
      medicines. Phytotherapeutic agents are standardized herbal preparations
      consisting of complex mixtures of one or more plants which contain as active
      ingredients plant parts or plant material in the crude or processed state. A
      marked growth in the worldwide phytotherapeutic market has occurred over the last
      15 years. For the European and USA markets alone, this will reach about $7
      billion and $5 billion per annum, respectively, in 1999, and has thus attracted
      the interest of most large pharmaceutical companies. Insufficient data exist for
      most plants to guarantee their quality, efficacy and safety. The idea that herbal
      drugs are safe and free from side effects is false. Plants contain hundreds of
      constituents and some of them are very toxic, such as the most cytotoxic anti
      cancer plant-derived drugs, digitalis and the pyrrolizidine alkaloids, etc.
      However, the adverse effects of phytotherapeutic agents are less frequent
      compared with synthetic drugs, but well-controlled clinical trials have now
      confirmed that such effects really exist. Several regulatory models for herbal
      medicines are currently available including prescription drugs, over-the-counter
      substances, traditional medicines and dietary supplements. Harmonization and
      improvement in the processes of regulation is needed, and the general tendency is
      to perpetuate the German Commission E experience, which combines scientific
      studies and traditional knowledge (monographs). Finally, the trend in the
      domestication, production and biotechnological studies and genetic improvement of
      medicinal plants, instead of the use of plants harvested in the wild, will offer
      great advantages, since it will be possible to obtain uniform and high quality
      raw materials which are fundamental to the efficacy and safety of herbal drugs.

PMID- 10657058
TI  - Lima bean (Phaseolus lunatus) seed coat phaseolin is detrimental to the cowpea
      weevil (Callosobruchus maculatus).
AB  - The presence of phaseolin (a vicilin-like 7S storage globulin) peptides in the
      seed coat of the legume Phaseolus lunatus L. (lima bean) was demonstrated by N
      terminal amino acid sequencing. Utilizing an artificial seed system assay we
      showed that phaseolin, isolated from both cotyledon and testa tissues of P.
      lunatus, is detrimental to the nonhost bruchid Callosobruchus maculatus (F)
      (cowpea weevil) with ED50 of 1.7 and 3.5%, respectively. The level of phaseolin
      in the seed coat (16.7%) was found to be sufficient to deter larval development
      of this bruchid. The expression of a C. maculatus-detrimental protein in the
      testa of nonhost seeds suggests that the protein may have played a significant
      role in the evolutionary adaptation of bruchids to legume seeds.

PMID- 10657059
TI  - A simple HPLC-fluorescence method for the measurement of R,S-sotalol in the
      plasma of patients with life-threatening cardiac arrhythmias.
AB  - R,S-sotalol, a ss-blocker drug with class III antiarrhythmic properties, is
      prescribed to patients with ventricular, atrial and supraventricular arrhythmias.
      A simple and sensitive method based on HPLC-fluorescence is described for the
      quantification of R,S-sotalol racemate in 500 microl of plasma. R,S-sotalol and
      its internal standard (atenolol) were eluted after 5.9 and 8.5 min, respectively,
      from a 4-micron C18 reverse-phase column using a mobile phase consisting of 80 mM
      KH2PO4, pH 4.6, and acetonitrile (95:5, v/v) at a flow rate of 0.5 ml/min with
      detection at lambdaex = 235 nm and lambdaem = 310 nm, respectively. This method,
      validated on the basis of R,S-sotalol measurements in spiked blank plasma,
      presented 20 ng/ml sensitivity, 20-10,000 ng/ml linearity, and 2.9 and 4.8% intra
      and interassay precision, respectively. Plasma sotalol concentrations were
      determined by applying this method to investigate five high-risk patients with
      atrial fibrillation admitted to the Emergency Service of the Medical School
      Hospital, who received sotalol, 160 mg po, as loading dose. Blood samples were
      collected from a peripheral vein at zero, 0.5, 1.0, 1.5, 2.0, 3.0, 4. 0, 6.0,
      8.0, 12.0 and 24.0 h after drug administration. A two-compartment open model was
      applied. Data obtained, expressed as mean, were: C MAX = 1230 ng/ml, T MAX = 1.8
      h, AUC T = 10645 ng h-1 ml-1, Kab = 1.23 h-1, alpha = 0.95 h-1, ss = 0.09 h-1,
      t((1/2))ss = 7.8 h, ClT/F = 3.94 ml min-1 kg-1, and Vd/F = 2.53 l/kg. A good
      systemic availability and a fast absorption were obtained. Drug distribution was
      reduced to the same extent in terms of total body clearance when patients and
      healthy volunteers were compared, and consequently elimination half-life remained
      unchanged. Thus, the method described in the present study is useful for
      therapeutic drug monitoring purposes, pharmacokinetic investigation and
      pharmacokinetic-pharmacodynamic sotalol studies in patients with
      tachyarrhythmias.

PMID- 10657060
TI  - Study of urinary acidification in patients with idiopathic hypocitraturia.
AB  - Hypocitraturia (HCit) is one of the most remarkable features of renal tubular
      acidosis, but an acidification defect is not seen in the majority of
      hypocitraturic patients, whose disease is denoted idiopathic hypocitraturia. In
      order to assess the integrity of urinary acidification mechanisms in
      hypocitraturic idiopathic calcium stone formers, we studied two groups of
      patients, hypocitraturic (HCit, N = 21, 39.5 +/- 11.5 years, 11 females and 10
      males) and normocitraturic (NCit, N = 23, 40.2 +/- 11.7 years, 16 females and 7
      males) subjects, during a short ammonium chloride loading test lasting 8 h.
      During the baseline period HCit patients showed significantly higher levels of
      titratable acid (TA). After the administration of ammonium chloride, mean urinary
      pH (3rd to 8th hour) and TA and ammonium excretion did not differ significantly
      between groups. Conversely, during the first hour mean urinary pH was lower and
      TA and ammonium excretion was higher in HCit. The enhanced TA excretion by HCit
      during the baseline period and during the first hour suggests that the phosphate
      buffer mechanism is activated. The earlier response in ammonium excretion by HCit
      further supports other evidence that acidification mechanisms react promptly. The
      present results suggest that in the course of lithiasic disease, hypocitraturia
      coexists with subtle changes in the excretion of hydrogen ions in basal
      situations.

PMID- 10657061
TI  - Residual beta-cell function and microvascular complications in type 1 diabetic
      patients.
AB  - To determine the influence of residual beta-cell function on retinopathy and
      microalbuminuria we measured basal C-peptide in 50 type 1 diabetic outpatients
      aged 24.96 +/- 7.14 years, with a duration of diabetes of 9.1 +/- 6.2 years.
      Forty-three patients (86%) with low C-peptide (<0.74 ng/ml) had longer duration
      of diabetes than 7 patients (14%) with high C-peptide (> or =0.74 ng/ml) (9 (2
      34) vs 3 (1-10) years, P = 0.01) and a tendency to high glycated hemoglobin
      (HBA1) (8.8 (6-17.9) vs 7.7 (6.9-8.7)%, P = 0. 08). Nine patients (18%) had
      microalbuminuria (two out of three overnight urine samples with an albumin
      excretion rate (AER) > or =20 and <200 microg/min) and 13 (26%) had background
      retinopathy. No association was found between low C-peptide, microalbuminuria and
      retinopathy and no difference in basal C-peptide was observed between
      microalbuminuric and normoalbuminuric patients (0.4 +/- 0.5 vs 0.19 +/- 0.22
      ng/ml, P = 0.61) and between patients with or without retinopathy (0.4 +/- 0.6 vs
      0.2 +/- 0.3 ng/ml, P = 0.43). Multiple regression analysis showed that duration
      of diabetes (r = 0. 30, r2 = 0.09, P = 0.031) followed by HBA1 (r = 0.41, r2 =
      0.17, P = 0.01) influenced basal C-peptide, and this duration of diabetes was the
      only variable affecting AER (r = 0.40, r2 = 0.16, P = 0.004). In our sample of
      type 1 diabetic patients residual ss-cell function was not associated with
      microalbuminuria or retinopathy.

PMID- 10657062
TI  - Zinc accumulation in phosphate granules of Ucides cordatus hepatopancreas.
AB  - Amorphous phosphate granules are present in vertebrate and invertebrate
      organisms. The functions attributed to these structures depend on their mineral
      contents and organic matrix composition. In the present study we have determined
      zinc concentrations in the hepatopancreas of the crab Ucides cordatus from
      regions contaminated with zinc, and the elemental composition of hepatopancreal
      phosphate granules. Organisms were collected from the contaminated areas of
      Sepetiba Bay (SB) and Guanabara Bay (GB), and from a non-contaminated area,
      Ribeira Bay (RB). The first two sites are located near the metropolitan region of
      Rio de Janeiro city, Brazil. Atomic absorption spectroscopy (AAS) showed a
      significant difference (P<0.05) for zinc concentration in the hepatopancreas from
      organisms collected at the contaminated sites GB (210 +/- 20 microg/g dry weight)
      and SB (181 +/- 16 microg/g dry weight) compared to the non-contaminated site RB
      (76 +/- 14 microg/g dry weight). Phosphate granules isolated from
      hepatopancreatic tissue were studied by electron diffraction (ED), energy
      dispersive X-ray analysis (EDX) and electron spectroscopic imaging (ESI). ED of
      granules presented no diffraction spots, indicating that these structures are in
      an amorphous state, while EDX of granules isolated from a contaminated area
      contained P, Ca and Zn. Mg, Cl and Fe were also found in some of the spectra. ESI
      showed that O, P and Ca were colocalized in the mineralized layers of most
      granules observed. The correlation between the results obtained by AAS and those
      obtained by microanalytical techniques suggests that the hepatopancreatic
      granules of U. cordatus may be related to the phenomenon of heavy metal
      retention.

PMID- 10657063
TI  - Involvement of the caudal raphe nuclei in the feeding behavior of rats.
AB  - Involvement of the caudal raphe nuclei (raphe pallidus, RPa; raphe magnus, RMg,
      and raphe obscurus, ROb) in feeding behavior of adult rats was studied by
      measuring c-Fos protein expression, in animals submitted to the "meal-feeding"
      model of food restriction in which the rats were fed ad libitum only from 7:00 to
      9:00 h, for 15 days. The experimental groups submitted to chronic fasting, named
      'search for food' (SF), 'ingestion of food' (IF) and 'satiety of food' (SaF) were
      scheduled after a previous study in which the body weight and the general and
      feeding behaviors were evaluated by daily monitoring. Acute, 48-h fasting (AF)
      was used as control. In the chronic group, the animals presented a 16% reduction
      in body weight in the first week, followed by a continuous, slow rise in weight
      over the subsequent days. Entrainment of the sleep-wake cycle to the schedule of
      food presentation was also observed. The RPa was the most Fos immunopositive
      nucleus in the chronic fasting group, followed by the RMg. The ANOVA and Tukey
      test (P<0.05) confirmed these results. The IF group was significantly different
      from the other three groups, as also was the number of labeled cells in the RPa
      in SF and IF groups. Nevertheless, no significant difference was observed between
      RMg and RPa, or RMg and ROb in the SaF and AF. However, it is interesting to
      observe that the groups in which the animals were more active, searching for or
      ingesting food, presented a larger number of labeled cells. These results suggest
      a different involvement of the caudal raphe nuclei in the somatic and autonomic
      events of feeding behavior, corroborating the functions reported for them
      earlier.

PMID- 10657064
TI  - Effect of inhibitory avoidance training on [3H]-glutamate binding in the
      hippocampus and parietal cortex of rats.
AB  - Glutamate receptors have been implicated in memory formation. The aim of the
      present study was to determine the effect of inhibitory avoidance training on
      specific [3H]-glutamate binding to membranes obtained from the hippocampus or
      parietal cortex of rats. Adult male Wistar rats were trained (0.5-mA footshock)
      in a step-down inhibitory avoidance task and were sacrificed 0, 5, 15 or 60 min
      after training. Hippocampus and parietal cortex were dissected and membranes were
      prepared and incubated with 350 nM [3H]-glutamate (N = 4-6 per group). Inhibitory
      avoidance training induced a 29% increase in glutamate binding in hippocampal
      membranes obtained from rats sacrificed at 5 min (P<0.01), but not at 0, 15, or
      60 min after training, and did not affect glutamate binding in membranes obtained
      from the parietal cortex. These results are consistent with previous evidence for
      the involvement of glutamatergic synaptic modification in the hippocampus in the
      early steps of memory formation.

PMID- 10657065
TI  - Effects of emotional reactivity on inhibitory avoidance in the elevated T-maze.
AB  - The possibility of the presence of inter-individual emotional differences and the
      memory performance of rats was examined in the elevated T-maze. Two kinds of
      aversively motivated behaviors, inhibitory avoidance and escape learning, were
      measured. Based on the number of trials to achieve a learning criterion, rats
      were divided into two subgroups with either low or high avoidance reactivity (LAR
      or HAR, respectively). Retention test avoidance latencies showed that HAR animals
      had better avoidance memory (Mann-Whitney rank sum test, P = 0.0035). No such
      differences were found for the escape component of this test. These data suggest
      that individual emotional differences affect inhibitory avoidance performance,
      which may help to explain the dispersion of the data observed in other studies
      using this paradigm.

PMID- 10657066
TI  - Selective destruction of nigrostriatal dopaminergic neurons does not alter [3H]
      ryanodine binding in rat striatum.
AB  - Dopamine nigrostriatal neurons are important for motor control and may contain a
      particularly dense population of ryanodine receptors involved in the control of
      dopamine release. To test this hypothesis, we used a classical model of
      unilateral selective lesion of these neurons in rats based on 6-hydroxydopamine
      (6-OHDA) injection into the substantia nigra. Binding of [3H]-GBR 12935, used as
      a presynaptic marker since it labels specifically the dopamine uptake complex,
      was dramatically decreased by 83-100% in striatum homogenates after 6-OHDA
      lesion. On the contrary, no reduction of [3H]-ryanodine binding was observed. The
      present data indicate that [3H]-ryanodine binding sites present in rat striatum
      are not preferentially localized in dopaminergic terminals.

PMID- 10657068
TI  - Get wise to the web

PMID- 10657069
TI  - Gene therapy should welcome public scrutiny

PMID- 10657067
TI  - Alternative mitochondrial functions in cell physiopathology: beyond ATP
      production.
AB  - It is well known that mitochondria are the main site for ATP generation within
      most tissues. However, mitochondria also participate in a surprising number of
      alternative activities, including intracellular Ca2+ regulation, thermogenesis
      and the control of apoptosis. In addition, mitochondria are the main cellular
      generators of reactive oxygen species, and may trigger necrotic cell death under
      conditions of oxidative stress. This review concentrates on these alternative
      mitochondrial functions, and their role in cell physiopathology.

PMID- 10657070
TI  - The potential of BACE inhibitors for Alzheimer's therapy.

PMID- 10657072
TI  - Reply to "Genome canada update"

PMID- 10657071
TI  - Designer science and the "omic" revolution.

PMID- 10657073
TI  - Europe ratifies plant patents.

PMID- 10657075
TI  - Japan steps up GMO tests

PMID- 10657076
TI  - GM plants to be patented

PMID- 10657074
TI  - Genome Canada update.

PMID- 10657078
TI  - Finance boom in 4Q, 1999

PMID- 10657077
TI  - NIH tech transfer rules

PMID- 10657080
TI  - Initial public offerings, 4th quarter 1999

PMID- 10657079
TI  - GMO roundup

PMID- 10657082
TI  - Rapigene bargain buy for qiagen

PMID- 10657083
TI  - Amgen lists on easdaq

PMID- 10657081
TI  - Biopharmaceutical sector performance, 4th quarter 1999

PMID- 10657084
TI  - $100 million pesticide deal

PMID- 10657085
TI  - India joins rice project

PMID- 10657086
TI  - Human genome 90% done

PMID- 10657087
TI  - Gone, butt not begotten

PMID- 10657088
TI  - Research collaborations

PMID- 10657089
TI  - Biotech fundraising, 4Q 1999

PMID- 10657090
TI  - New rules for Bt corn

PMID- 10657092
TI  - Stem cell nuclear transfer

PMID- 10657091
TI  - Liver from bone

PMID- 10657093
TI  - Sugary synthetic genes

PMID- 10657094
TI  - Golden rice

PMID- 10657095
TI  - Monkey around with clones

PMID- 10657096
TI  - Comparative genomics in development

PMID- 10657097
TI  - Transformation turns to powder

PMID- 10657099
TI  - Mass spec and "quantum" mechanics

PMID- 10657100
TI  - Testing protease preferences

PMID- 10657098
TI  - Phytoremediation of organic mercury

PMID- 10657101
TI  - A new way to integrate

PMID- 10657102
TI  - Engineering better beans

PMID- 10657103
TI  - Technical reports

PMID- 10657105
TI  - A peptide mimetic of herceptin

PMID- 10657104
TI  - To bind or not to bind

PMID- 10657106
TI  - Sweet, but dry

PMID- 10657107
TI  - Moratorium hits Danish companies.

PMID- 10657108
TI  - Biotechnology becomes the new dot com.

PMID- 10657110
TI  - Japan banks on budget to boost biotechnology.

PMID- 10657109
TI  - Monsanto to merge with P&U.

PMID- 10657111
TI  - FDA, researchers consider first transgenic fish.

PMID- 10657112
TI  - Investigation of gene therapy begins.

PMID- 10657113
TI  - MAG's demise signals trouble for bioinformatics firms.

PMID- 10657114
TI  - Preservation of mammalian cells-learning nature's tricks.

PMID- 10657115
TI  - Taming the uncultured.

PMID- 10657116
TI  - So many genomes, so little time.

PMID- 10657118
TI  - Adenoviral vectors go retro.

PMID- 10657117
TI  - A taste test for proteases.

PMID- 10657119
TI  - Differentiating genomics companies.
AB  - As the value of raw sequence data diminishes, genomics companies are evolving new
      competencies as providers of information, therapeutic products, or novel
      technology.

PMID- 10657120
TI  - The pharmacological basis of anti-IgE therapy.
AB  - The treatment of asthma and allergic rhinitis using unique, humanized anti-IgE
      monoclonal antibodies with very particular binding specificities is now supported
      by the results of multiple phase II and III human clinical studies. The
      therapeutic efficacy of this approach is attributable to several pharmacological
      mechanisms. In addition to the expected effects of these monoclonal antibodies in
      neutralizing free IgE and inhibiting IgE production by B cells, several indirect
      biochemical and cellular effects have been uncovered during the course of the
      clinical trials. These include the accumulation of potentially beneficial IgE
      anti-IgE immune complexes and the downregulation of the high-affinity IgE Fc
      receptors (FcvarepsilonRI) on basophils and mast cells. This article analyzes the
      structural basis of the specificity of the anti-IgE antibodies and pertinent
      results from in vitro experiments, animal model studies, and human clinical
      trials in an attempt to provide a cogent pharmacological interpretation of the
      therapeutic effects of anti-IgE therapy in both the near- and long term. The
      development of anti-IgE therapy over the past 10 years provides an interesting
      example of the emergence of a conceptually new, biotechnology-produced
      pharmaceutical.

PMID- 10657121
TI  - Intracellular trehalose improves the survival of cryopreserved mammalian cells.
AB  - We report that the introduction of low concentrations of intracellular trehalose
      can greatly improve the survival of mammalian cells during cryopreservation.
      Using a genetically engineered mutant of Staphylococcus aureus alpha-hemolysin to
      create pores in the cellular membrane, we were able to load trehalose into cells.
      Low concentrations (0.2 M) of trehalose permitted long-term post-thaw survival of
      more than 80% of 3T3 fibroblasts and 70% of human keratinocytes. These results
      indicate that simplified and widely applicable freezing protocols may be possible
      using sugars as intracellular cryoprotective additives.

PMID- 10657122
TI  - Trehalose expression confers desiccation tolerance on human cells.
AB  - Many organisms that withstand desiccation express the disaccharide trehalose. We
      have now expressed the otsA and otsB genes of Escherichia coli, which encode
      trehalose biosynthetic enzymes, in human primary fibroblasts using a recombinant
      adenovirus vector. Infected cells produced increased amounts of trehalose with
      increasing multiplicity of infection (MOI). Human primary fibroblasts expressing
      trehalose could be maintained in the dry state for up to five days. Fourier
      transform infrared spectroscopy indicated that dry, but viable, human cells
      contained no detectable water. This study shows that mammalian cells can be
      engineered to retain viability in the absence of water.

PMID- 10657123
TI  - Measuring the peptides in individual organelles with mass spectrometry.
AB  - New sampling protocols combined with matrix-assisted laser desorption/ionization
      time-of-flight mass spectrometry (MALDI-TOF MS) allow the assay of single dense
      core vesicles. Understanding the packaging of vesicles is important as vesicles
      are the quanta of information for intercellular communication. Using vesicles
      from the exocrine atrial gland of Aplysia californica as the model, a wide range
      of bioactive peptides are detected within each vesicle. Although the expression
      of the egg-laying hormone gene family of type 1 atrial gland cells has been
      previously examined, chemical characterization of individual 1-2 microm diameter
      vesicles demonstrates that products from several genes are colocalized. The mass
      sensitivity of MALDI MS can be further improved to enable the analysis of even
      smaller subcellular organelles.

PMID- 10657124
TI  - Genomic integration and gene expression by a modified adenoviral vector.
AB  - A replication-deficient recombinant adenovirus encoding luciferase was
      constructed using 5' and 3' long terminal repeat (LTR) sequences of the Moloney
      murine leukemia virus. Gene expression was observed in cultured cells in vitro
      and in submandibular gland, cortex, and caudate nucleus for as long as three
      months in vivo. The vector integrated randomly into the genome of both dividing
      and nondividing cells as determined by fluorescence in situ hybridization (FISH)
      (10-15% of cells in vitro and 5% in rat spleen in vivo), gene walking, Southern
      hybridization, and polymerase chain reaction (PCR), in the absence of
      transcomplementing reverse transcriptase or integrase activity. The new vector
      combines the high titer and versatility of adenoviral vectors with the long-term
      gene expression and integration of retroviral vectors.

PMID- 10657125
TI  - Analysis of vertebrate SCL loci identifies conserved enhancers.
AB  - The SCL gene encodes a highly conserved bHLH transcription factor with a pivotal
      role in hemopoiesis and vasculogenesis. We have sequenced and analyzed 320 kb of
      genomic DNA composing the SCL loci from human, mouse, and chicken. Long-range
      sequence comparisons demonstrated multiple peaks of human/mouse homology, a
      subset of which corresponded precisely with known SCL enhancers. Comparisons
      between mammalian and chicken sequences identified some, but not all, SCL
      enhancers. Moreover, one peak of human/mouse homology (+23 region), which did not
      correspond to a known enhancer, showed significant homology to an analogous
      region of the chicken SCL locus. A transgenic Xenopus reporter assay was
      established and demonstrated that the +23 region contained a new neural enhancer.
      This combination of long-range comparative sequence analysis with a high
      throughput transgenic bioassay provides a powerful strategy for identifying and
      characterizing developmentally important enhancers.

PMID- 10657126
TI  - Synthesis of positional-scanning libraries of fluorogenic peptide substrates to
      define the extended substrate specificity of plasmin and thrombin.
AB  - We have developed a strategy for the synthesis of positional-scanning synthetic
      combinatorial libraries (PS-SCL) that does not depend on the identity of the P1
      substituent. To demonstrate the strategy, we synthesized a tetrapeptide
      positional library in which the P1 amino acid is held constant as a lysine and
      the P4-P3-P2 positions are positionally randomized. The 6,859 members of the
      library were synthesized on solid support with an alkane sulfonamide linker, and
      then displaced from the solid support by condensation with a fluorogenic 7-amino
      4-methylcoumarin-derivatized lysine. This library was used to determine the
      extended substrate specificities of two trypsin-like enzymes, plasmin and
      thrombin, which are involved in the blood coagulation pathway. The optimal P4 to
      P2 substrate specificity for plasmin was P4-Lys/Nle (norleucine)/Val/Ile/Phe, P3
      Xaa, and P2-Tyr/Phe/Trp. This cleavage sequence has recently been identified in
      some of plasmin's physiological substrates. The optimal P4 to P2 extended
      substrate sequence determined for thrombin was P4-Nle/Leu/Ile/Phe/Val, P3-Xaa,
      and P2-Pro, a sequence found in many of the physiological substrates of thrombin.
      Single-substrate kinetic analysis of plasmin and thrombin was used to validate
      the substrate preferences resulting from the PS-SCL. By three-dimensional
      structural modeling of the substrates into the active sites of plasmin and
      thrombin, we identified potential determinants of the defined substrate
      specificity. This method is amenable to the incorporation of diverse substituents
      at the P1 position for exploring molecular recognition elements in proteolytic
      enzymes.

PMID- 10657127
TI  - Rationally designed anti-HER2/neu peptide mimetic disables P185HER2/neu tyrosine
      kinases in vitro and in vivo.
AB  - Monoclonal antibodies specific for the p185HER2/neu growth factor receptor
      represent a significant advance in receptor-based therapy for p185HER2/neu
      expressing human cancers. We have used a structure-based approach to develop a
      small (1.5 kDa) exocyclic anti-HER2/neu peptide mimic (AHNP) functionally similar
      to an anti-p185HER2/neu monoclonal antibody, 4D5 (Herceptin). The AHNP mimetic
      specifically binds to p185HER2/neu with high affinity (KD=300 nM). This results
      in inhibition of proliferation of p185HER2/neu-overexpressing tumor cells, and
      inhibition of colony formation in vitro and growth of p185HER2/neu-expressing
      tumors in athymic mice. In addition, the mimetic sensitizes the tumor cells to
      apoptosis when used in conjunction with ionizing radiation or chemotherapeutic
      agents. A comparison of the molar quantities of the Herceptin antibody and the
      AHNP mimetic required for inhibiting cell growth and anchorage-independent growth
      showed generally similar activities. The structure-based derivation of the AHNP
      represents a novel strategy for the design of receptor-specific tumor therapies.

PMID- 10657128
TI  - Anchored multiplex amplification on a microelectronic chip array.
AB  - We have developed a method for anchored amplification on a microchip array that
      allows amplification and detection of multiple targets in an open format.
      Electronic anchoring of sets of amplification primers in distinct areas on the
      microchip permitted primer-primer interactions to be reduced and distinct zones
      of amplification created, thereby increasing the efficiency of the multiplex
      amplification reactions. We found strand displacement amplification (SDA) to be
      ideal for use in our microelectronic chip system because of the isothermal nature
      of the assay, which provides a rapid amplification system readily compatible with
      simple instrumentation. Anchored SDA supported multiplex DNA or RNA amplification
      without decreases in amplification efficiency. This microelectronic chip-based
      amplification system allows multiplexed amplification and detection to be
      performed on the same platform, streamlining development of any nucleic acid
      based assay.

PMID- 10657129
TI  - Stable transformation of erysiphe graminis an obligate biotrophic pathogen of
      barley.
AB  - Barley powdery mildew, Erysiphe graminis f.sp. hordei, is an obligate biotrophic
      pathogen and as such cannot complete its life cycle without a living host. The
      inability to transform this fungus and manipulate its genome has constrained
      research towards understanding its life cycle and pathogenicity. Here we describe
      an in planta transformation system based on delivery of DNA using a gold-particle
      gun and selection using benomyl or bialaphos. Using this method, we consistently
      obtained stable transformants with efficiencies comparable to other filamentous
      fungi. Stable expression of the beta-glucuronidase in E. graminis was
      demonstrated by co-transforming the uidA gene with the selectable markers.

PMID- 10657130
TI  - Identification and expression of isoflavone synthase, the key enzyme for
      biosynthesis of isoflavones in legumes.
AB  - Isoflavones have drawn much attention because of their benefits to human health.
      These compounds, which are produced almost exclusively in legumes, have natural
      roles in plant defense and root nodulation. Isoflavone synthase catalyzes the
      first committed step of isoflavone biosynthesis, a branch of the phenylpropanoid
      pathway. To identify the gene encoding this enzyme, we used a yeast expression
      assay to screen soybean ESTs encoding cytochrome P450 proteins. We identified two
      soybean genes encoding isoflavone synthase, and used them to isolate homologous
      genes from other leguminous species including red clover, white clover, hairy
      vetch, mung bean, alfalfa, lentil, snow pea, and lupine, as well as from the
      nonleguminous sugarbeet. We expressed soybean isoflavone synthase in Arabidopsis
      thaliana, which led to production of the isoflavone genistein in this nonlegume
      plant. Identification of the isoflavone synthase gene should allow manipulation
      of the phenylpropanoid pathway for agronomic and nutritional purposes.

PMID- 10657131
TI  - Phytodetoxification of hazardous organomercurials by genetically engineered
      plants.
AB  - Methylmercury is a highly toxic, organic derivative found in mercury-polluted
      wetlands and coastal sediments worldwide. Though commonly present at low
      concentrations in the substrate, methylmercury can biomagnify to concentrations
      that poison predatory animals and humans. In the interest of developing an in
      situ detoxification strategy, a model plant system was transformed with bacterial
      genes (merA for mercuric reductase and merB for organomercurial lyase) for an
      organic mercury detoxification pathway. Arabidopsis thaliana plants expressing
      both genes grow on 50-fold higher methylmercury concentrations than wild-type
      plants and up to 10-fold higher concentrations than plants that express merB
      alone. An in vivo assay demonstrated that both transgenes are required for plants
      to detoxify organic mercury by converting it to volatile and much less toxic
      elemental mercury.

PMID- 10657132
TI  - Epidermal growth factor receptor dimerization monitored in live cells.
AB  - We present a method for monitoring receptor dimerization at the membrane of live
      cells. Chimeric proteins containing the epidermal growth factor (EGF) receptor
      extracellular and transmembrane domains fused to weakly complementing beta
      galactosidase (beta-gal) deletion mutants were expressed in cells in culture.
      Treatment of the cells with EGF-like compounds for as little as 15 s resulted in
      chimeric receptor dimerization detectable as beta-gal enzymatic activity. The
      dose response of chimeric receptors was ligand specific. beta-galactosidase
      complementation was reversible upon removal of ligand and could be reinduced.
      Antibodies that block ligand binding inhibited receptor dimerization and beta-gal
      complementation. These results demonstrate that beta-gal complementation provides
      a rapid, simple, and sensitive assay for protein interactions and for detecting
      and monitoring the kinetics of receptor dimerization.

PMID- 10657133
TI  - A reliable, noninvasive technique for spindle imaging and enucleation of
      mammalian oocytes.
AB  - Factors affecting the efficiency of animal cloning remain to be elucidated.
      Enucleation of recipient oocytes is a critical step in cloning procedures and
      typically is performed by aspirating a portion of the cytoplasm underlying the
      first polar body. Enucleation is evaluated using epifluorescence after Hoechst
      staining for DNA, which may disrupt functions of the cytoplast, especially
      mitochondria. Mitochondrial DNA in Dolly and other cloned sheep has been shown to
      derive exclusively from recipient oocytes. Not only might evaluation of the
      aspirated karyoplast portion inadequately reflect the state of the cytoplast, it
      is also time consuming. Here we report a reliable, noninvasive technique for
      spindle imaging and enucleation of oocytes using a new microscope, the Pol-Scope.
      The efficiency of enucleation was 100%, and only 5.5% of the oocytes'
      mitochondria entered the karyoplast upon Pol-Scope-directed removal of the
      spindle. Moreover, Pol-Scope imaging of spindles and micromanipulation did not
      compromise the developmental competence of reconstituted oocytes and cytoplasts.

PMID- 10657134
TI  - A colorimetric assay for rapid screening of antimicrobial peptides.
AB  - The increased resistance of various bacteria toward available antibiotic drugs
      has initiated intensive research efforts into identifying new sources of
      antimicrobial substances. Short antibiotic peptides (10-30 residues) are
      prevalent in nature as part of the intrinsic defense mechanisms of most organisms
      and have been proposed as a blueprint for the design of novel antimicrobial
      agents. Antimicrobial peptides are generally believed to kill bacteria through
      membrane permeabilization and extensive pore-formation. Assays providing rapid
      and easy evaluation of interactions between antimicrobial membrane peptides and
      lipid bilayers could significantly improve screening for substances with
      effective antibacterial properties, as well as contribute to the elucidation of
      structural and functional properties of antimicrobial peptides. Here we describe
      a colorimetric sensor in which particles composed of phospholipids and
      polymerized polydiacetylene (PDA) lipids were shown to exhibit striking color
      changes upon interactions with antimicrobial membrane peptides. The color changes
      in the system occur because of the structural perturbation of the lipids
      following their interactions with antimicrobial peptides. The assay was also
      sensitive to the antibacterial properties of structurally and functionally
      related peptide analogs.

PMID- 10657136
TI  - Recent patents in obesity research

PMID- 10657135
TI  - Recent US patent legislation: what's new for biotech?
AB  - New reforms bring US law closer in line with those of other major countries.

PMID- 10657138
TI  - People

PMID- 10657137
TI  - An economic method for the fluorescent labeling of PCR fragments.
AB  - A poor man's approach to genotyping for research and high-throughput diagnostics.

PMID- 10657139
TI  - New products

PMID- 10657141
TI  - Merger terminated.

PMID- 10657140
TI  - Data mining in biotechnology.

PMID- 10657142
TI  - Electronic addressing for microchip arrays.

PMID- 10657143
TI  - Genetic identification of Candida species in HIV-positive patients using the
      polymerase chain reaction and restriction fragment length polymorphism analysis
      of its DNA.
AB  - The polymerase chain reaction was used to amplify a targeted region: an internal
      transcribed spacer region of the ribosomal DNA from 114 Candida isolates and 65
      reference strains. Unique product sizes were obtained for Candida glabrata, C.
      guillermondii and C. inconspicua. Isolates of C. albicans, C. tropicalis, C.
      dubliniensis and C. krusei could be identified following restriction digestion of
      the PCR products. The methods proved to be both simple and reproducible and may
      offer potential advantages over phenotyping methods.

PMID- 10657144
TI  - A novel, internally competitive polymerase chain reaction for quantification of
      human cytomegalovirus DNA in human leukocytes.
AB  - The rapid, low cost estimation of Human Cytomegalovirus (HCMV) viral load in the
      blood of immunosupressed individuals is crucial for the timely diagnosis of
      transplant recipients with clinically significant HCMV infections requiring
      treatment. To this end we have developed a novel polymerase chain reaction (PCR)
      assay with internal controls for competitive quantification of cytomegalovirus
      DNA in human leukocytes. The reaction simultaneously amplifies, under reduced
      stringency conditions, a 136 bp fragment of the HCMV LA gene together with a
      single anonymous 200 bp fragment of human DNA using a single-primer pair. The
      primers used are specific for the HCMV gene sequence but contain a single
      mismatch that permits the amplification of the competing human DNA fragment.
      Quantification is achieved by comparison of the amount of the two products. The
      assay quantifies between 10(3)and 10(6)HCMV genomes in 10(6)leukocytes, a range
      that permits low-level clinically unimportant HCMV infections to be distinguished
      from those likely to cause serious disease. The advantages of the method are that
      no external controls are needed, quantification is achieved from a single
      reaction and no separate measurement of host DNA concentration is required.

PMID- 10657145
TI  - Distribution and high frequency of novel alleles at NF1 polymorphic markers in
      the Italian population.
AB  - Segregation analysis of Neurofibromatosis type 1 (NF1) intragenic polymorphisms
      is a useful diagnostic tool for linkage analysis in familial cases and for the
      exclusion/detection of deletion in sporadic patients. We performed a segregation
      analysis of intragenic NF1 polymorphic markers in an Italian NF1 population
      consisting of 17 familial and 41 sporadic cases, for a total of 79 affected and
      105 unaffected individuals. The haplotype in linkage with the mutation could be
      identified in all of the familial cases. Furthermore, an intragenic deletion was
      found in one sporadic case and confirmed by means of FISH using an NF1 IVS27
      specific probe generated by a novel PCR procedure. In order to determine the
      allele frequencies at four NF1 polymorphisms in the Italian population, the
      unaffected family members and 25 unrelated Italian individuals were genotyped.
      Allele frequencies were found to be statistically different from those in the
      literature for markers IVS27AC28.4 and IVS38GT53.0. In addition four novel
      alleles were found in four unrelated subjects, and we observed a mutation during
      paternal gametogenesis in one case. These data suggest that NF1 polymorphic
      intragenic loci are unstable. It is unclear whether or not their marked
      instability may enhance the high mutation rate of the NF1 gene.

PMID- 10657146
TI  - Single-nucleotide polymorphisms may cause erroneous results in primer-introduced
      restriction enzyme analyses: a case of molecular misdiagnosis of homozygous vs
      heterozygous familial hypercholesterolemia.
AB  - PCR amplification followed by a primer introduced restriction analysis PCR (PIRA
      PCR) is a widely used method to detect point mutations. Usually the artificial
      RFLP is created by siting one nucleotide mismatch near the 3; end of the primer.
      This does not alter the hybrization of the primer to the target DNA sequence.
      Unfortunately, unexpected single nucleotide polymorphisms (SNPs) may lead to
      additional mismatches and result in no amplification of the allele having
      unexpected SNP. We describe a warning example in which heterozygous familial
      hypercholesterolemia patient had an unexpected SNP and this led to his
      misdiagnosis.

PMID- 10657147
TI  - Development of a PCR- and probe-based test for the sensitive and specific
      detection of the dog heartworm, Dirofilaria immitis, in its mosquito intermediate
      host.
AB  - The mosquito-borne filarial worm, Dirofilaria immitis, causes heartworm disease
      in dogs. Detection of this parasite in its mosquito intermediate host currently
      involves dissection and microscopic examination for larval stages. Although this
      method is used commonly as a screening tool for epidemiological surveys, it lacks
      both sensitivity and specificity. In this study, a more efficient PCR- and probe
      based diagnostic assay was developed. The target selected for this assay is a
      segment of the 16 S rRNA gene. The assay specifically detects as little as 10 pg
      of D. immitis genomic DNA, equivalent to DNA derived from one third stage larva
      (L(3)), but does not detect 100 ng (10 000-fold excess) of the purified DNA from
      several other filarial nematodes, including Dirofilaria striata, Dirofilaria
      tenuis, Dipetalonema reconditum, Wuchereria bancroftii, Brugia pahangi, B.
      malayi, Onchocerca volvulus or Loa loa. This assay also detects one L(3)of D.
      immitis, the minimal biological unit of infection, in a pool of 200 mosquito
      heads. This assay can serve as a highly specific and sensitive tool for
      efficiently screening the large numbers of mosquitoes to determine, with
      statistical validity the seasonal transmission pattern of D. immitis in a
      locality prior to designing a rational preventive medication program for that
      parasite.

PMID- 10657148
TI  - Mycobacteria distenct from Mycobacterium avium subsp. paratuberculosis isolated
      from the faeces of ruminants possess IS900-like sequences detectable IS900
      polymerase chain reaction: implications for diagnosis.
AB  - PCR targeting the 5' end of IS 900 has been considered specific for
      identification of Mycobacterium avium subsp. paratuberculosis and is frequently
      applied to confirm the presence of this organism in the diagnosis of Johne's
      disease. IS 900 PCR has also been applied to studies of the aetiology of Crohn's
      disease. Mycobacterium spp. isolated from the faeces of 3 clinically normal
      animals in 2 Australian states appeared not to be M. paratuberculosis but were
      positive by IS 900 PCR. The isolates were characterized using mycobactin
      dependency, biochemical tests, IS 900 and 16 S rRNA sequencing and restriction
      fragment length polymorphism (RFLP) using IS 900 as probe. DNA sequencing
      confirmed that the isolates had between 71% and 79% homology with M.
      paratuberculosis in the region of IS 900 amplified, were most closely related to
      Mycobacterium scrofulaceum, and confirmed the usefulness of restriction enzyme
      analysis of amplified product to identify the false positive results. RFLP
      analysis with Bst Ell detected three to five copies of the IS 900 -like element
      in the isolates. These were located in molecular weight fragments that were
      clearly different to IS 900 in previously characterized strains of M.
      paratuberculosis. It is likely that these isolates are environmental
      mycobacteria. Southern blotting with an internal probe is unlikely to provide
      differentiation of M. paratuberculosis from these organisms. We recommend the
      adoption of restriction endonuclease analysis of IS 900 PCR product as a routine
      precaution to prevent the reporting of false positive IS 900 PCR results.

PMID- 10657149
TI  - New mutations of the hydroxymethylbilane synthase gene in German patients with
      acute intermittent porphyria.
AB  - Acute intermittent porphyria (AIP) is a low-penetrant, autosomal dominant
      disorder caused by decreased activity of hydroxymethylbilane synthase (HMBS; MIM
      176 000), the third enzyme in the heme biosynthetic pathway. We report the first
      molecular analysis of HMBS gene mutations in classical AIP patients of German
      origin. The HMBS gene of 5 German AIP patients was analysed by DGGE-screening and
      direct sequencing of amplified genomic DNA. Five different mutations including
      four novel mutations were found. Three of them are single base substitutions that
      affected exon 3 (R16C), exon 10 (V202L), and intron 13 (T to A, IVS13+2) The two
      remaining mutations are frameshifts which produce a stop codon (del GA in exon 6
      and insA in exon 14). These mutations are likely to be responsible for the
      decrease in HMBS activity found in both erythrocytes and non-erythroid cell lines
      (lymphocytes). Our results demonstrate the allelic heterogeneity of HMBS
      mutations in AIP patients of German origin.

PMID- 10657150
TI  - Two frequent tetra-nucleotide repeat polymorphisms between VAPB and STX16 on
      chromosome 20q13.

PMID- 10657151
TI  - Identification of three polymorphisms in the dystrophin gene.
AB  - Three polymorphisms were identified in the dystrophin gene using the polymerase
      chain reaction (PCR) and single strand conformation analysis (SSCA). Two of them
      (in intron 3) were reported for the first time while the third (in intron 43) is
      of interest as it is found mostly in patients with a recombination event in the
      same region.

PMID- 10657152
TI  - Index

PMID- 10657153
TI  - Intra-cranial manifestations of the neurocutaneous syndromes.
AB  - The neurocutaneous syndromes or phakomatoses are a heterogeneous group of
      congenital disorders primarily involving structures derived from the
      embryological neuroectoderm. All of the syndromes involve the central nervous
      system (CNS). Peripheral nerves, skin and other organ systems may also be
      involved. Twenty to 30 disorders are now classified as neurocutaneous syndromes.
      This article reviews the intra-cranial imaging features of some of the commonest.

PMID- 10657154
TI  - Dynamic contrast enhanced MRI of prostate cancer: correlation with morphology and
      tumour stage, histological grade and PSA.
AB  - AIM: To quantify MRI enhancement characteristics of normal and abnormal prostatic
      tissues and to correlate these with tumour stage, histological grade and tumour
      markers. MATERIALS AND METHODS: Quantitative gradient recalled echo MR images
      were obtained following bolus injection of gadopentetate dimeglumine in 48
      patients with prostate cancer. Turbo spin-echo T2-weighted images at the same
      anatomical position were reviewed for the presence of tumours (45 regions),
      normal peripheral zone (33 regions), and normal appearing central gland (30
      regions). Time-signal intensity parameters (onset time, mean gradient and maximal
      amplitude of enhancement and wash-out score) and modelling parameters
      (permeability surface area product, lesion leakage space and maximum gadolinium
      concentration) were correlated with tumour stage, histological grade (Gleason
      score) and serum prostatic specific antigen (PSA) levels. RESULTS: Significant
      differences were noted between peripheral zone and tumour with respect to signal
      intensity and modelling parameters (P = 0.0001), except onset time. No
      differences between central gland and tumour enhancement values were seen. There
      was weak correlation between MRI tumour stage and tumour vascular permeability
      (r(2) = 12%; P = 0.02) and maximum tumour gadolinium concentration (r(2) = 14%; P
      = 0.015). However, no significant correlations were seen with Gleason score or
      PSA levels. CONCLUSION: Quantification of MR contrast enhancement characteristics
      allows tissue discrimination in prostate cancer consistent with known variations
      in microvessel density estimates.

PMID- 10657155
TI  - Longitudinal colour doppler study of superficial lymph nodes in non-Hodgkin's
      lymphoma patients on chemotherapy.
AB  - AIMS/METHODS: A longitudinal study of 22 malignant lymph nodes by colour Doppler
      (CD) and/or colour power (CP) ultrasonography was undertaken in 12 non-Hodgkin's
      lymphoma patients to delineate changes in vascularity, and correlate this
      response with clinical outcome. RESULTS: Reduced vascularity in response to
      chemotherapy was shown to be a positive prognostic sign. CONCLUSIONS: More
      persistent nodal vascularity may signify a less favourable prognosis.

PMID- 10657156
TI  - Clustering of breast microcalcifications: revisited.
AB  - AIM: To verify the diagnostic value of the traditional definition of 'clustering'
      of microcalcifications (more than five in the area of 1 cm(2)or 1 cm(3)) on
      mammography in the differential diagnosis of benign and malignant breast disease.
      METHODS AND MATERIALS: Three radiologists without knowledge of the final
      pathology retrospectively counted the number of microcalcifications per 0.25
      cm(2) (0.5 x 0.5 cm) unit area on mammography in 57 pathologically proven non
      palpable lesions including 26 cancers and 31 benign diseases. Pleomorphism of the
      microcalcifications, associated architectural distortion or mass or increased
      density and distribution of microcalcifications were also evaluated. RESULTS: The
      mean numbers of microcalcifications per 0.25 cm(2) were 16.4 in malignant and
      16.7 in benign diseases (no statistically significant difference between the two
      groups). Pleomorphism of the microcalcifications, associated architectural
      distortion or mass or increased density were, however, important determining
      parameters. Clustering was more frequently observed in benign diseases.
      CONCLUSION: In this study, the mean number of microcalcifications per unit area
      is much larger than the traditional definition of 'clustering' and clustering
      itself is not effective in the differential diagnosis of benign and malignant
      breast lesions. Imaging features other than numbers of calcification per unit
      area are more important in assessing the significance of mammographic clustered
      microcalcifications.

PMID- 10657157
TI  - Can we be sure about a radiological diagnosis of fat necrosis of the breast?
AB  - AIMS: We performed a review of the clinical, mammographic and sonographic
      findings of fat necrosis in a group of patients who presented with a lump in the
      breast. We aimed to show that, in the light of a non-specific combination of
      findings, an ultrasound-guided core-biopsy (CB) is a safe, quick and useful test
      to confirm the diagnosis. The procedure makes it possible to reassure the patient
      of the true identity of the lesion, thus avoiding the need for surgical excision
      or follow-up investigations. MATERIALS AND METHODS: We undertook a retrospective
      review of the clinical presentation, imaging findings and subsequent management
      of 23 histologically proven cases of fat necrosis. All patients had presented to
      a specialist breast clinic with a breast lump. RESULTS: Only 52% of patients had
      a definite history of trauma. Clinical examination intimated that the lump was
      possibly malignant in 22%, while 4.5% were probably malignant. Fifty-seven per
      cent of mammograms were completely normal, however ultrasound showed an
      abnormality in 100%. Of these 100%, 74% were interpreted as possibly malignant.
      The diagnosis of fat necrosis was histologically confirmed by ultrasound-guided
      needle core biopsy, performed at the time of initial presentation. All patients
      were subsequently discharged. The mean time interval from investigation and
      biopsy to final diagnosis and discharge of the patient was 5.9 days. CONCLUSION:
      We show that fat necrosis often has a confusing clinical presentation. Imaging by
      either mammography or ultrasound is often inconclusive and ultrasound-guided core
      biopsy will confirm the diagnosis sparing patients unnecessary radiological
      follow-up or surgical excision.

PMID- 10657158
TI  - Magnetic resonance appearance of normal inguinal nodes.
AB  - AIM: To identify adult inguinal lymph node anatomical subgroups using magnetic
      resonance imaging (MRI), to derive a normal range for nodal number and size and
      to describe their morphology. MATERIALS AND METHODS: Eighty-three oncology
      patients with low stage pelvic tumours had inguinal lymph node assessment by MRI.
      Nodes were divided into proximal superficial (PS), distal superficial (DS) and
      deep inguinal (DI) subgroups, their number counted in two planes, and their
      transaxial short axis diameter recorded. Consistency of the largest node was
      recorded for each anatomical subgroup and two vertical distances measured,
      between the skin surface and the ipsilateral pubis, and between the skin surface
      and the deepest node. RESULTS: Transaxial plane maximum nodal number at the three
      sites was: PS 5, DS 8, DI 3; and in the coronal plane: PS 7, DS 5, DI 3. Nodal
      size ranges were: PS 3-10 mm (mean 4 mm), DS 3-15 mm (mean 6 mm) and DI3-10 mm
      (mean 6 mm). There was no correlation between nodal size or number and age or
      gender. Nodes were usually uniformly solid (PS 44%; DS 37%, DI 45%), or fatty (PS
      39%; DS 33%; DI 25%). The range of distances between the skin and deepest lymph
      node was 2.5-16 cm depending on patient fatness. CONCLUSION: The mean number of
      nodes counted in the axial plane was six and in the coronal plane five. A maximum
      short axis diameter of 15 mm was recorded for inguinal lymph nodes.

PMID- 10657159
TI  - Technique for providing analgesia during percutaneous biliary interventional
      procedures.
AB  - AIMS: To evaluate the efficacy of interpleural analgesia during percutaneous
      transhepatic biliary procedures. METHOD: With the patient lying in the left
      lateral decubitus position a right sided interpleural catheter was sited at a
      chosen point between the 6th and 9th interspaces. Lignocaine was injected to
      provide a splanchnic and intercostal nerve block. The technique of interpleural
      block (IPB) is described. Assessment of the pulse, BP and O(2)saturation during
      the subsequent biliary procedure was made. The patient evaluated the maximum
      degree of pain felt during the biliary procedure according to a four-point pain
      scale (0-3). The nurse and radiologist also gave an objective assessment of the
      pain score. RESULTS: An IP catheter was successfully placed in 22 patients, one
      patient having the IPB on two occasions. Siting of the IP catheter failed in
      three patients. Good analgesia with no requirement for further analgesia or
      sedation was achieved in 11 patients on 12 occasions. Seven patients required
      additional small doses of analgesia for mild pain during the biliary procedure.
      IPB failed in four patients who required additional analgesia and sedation. No
      complication of the IPB technique occurred in our patient group. CONCLUSION: IPB
      is a safe and relatively effective method for analgesia during transhepatic
      percutaneous biliary procedures.

PMID- 10657160
TI  - Inflammatory abdominal aortic aneurysms: diagnosis with gadolinium enhanced T1
      weighted imaging.
AB  - AIM: Inflammatory abdominal aortic aneurysms (IAAA) are a variant of abdominal
      aortic aneurysms, which are associated with an increased morbidity. The diagnosis
      of IAAA has traditionally been established with a combination of clinical and
      laboratory findings together with contrast enhanced CT. There is a high incidence
      of renal impairment in this group, and therefore contrast enhanced CT may be
      harmful. PATIENTS AND METHODS: Five patients with IAAA underwent T1-weighted spin
      echo and gradient echo gadolinium enhanced abdominal MRI. A total of eight
      examinations were performed, including three patients who underwent repeat MRI
      following steroid therapy. RESULTS: The inflammatory cuff was clearly identified
      following gadolinium administration in all eight examinations. The cuff enhanced
      homogeneously in all patients with no alteration in appearance following steroid
      therapy. The intravenous administration of gadolinium DTPA enabled clearer
      definition of locally involved structures. CONCLUSION: Gadolinium enhanced MRI
      readily demonstrates features of IAAA. In view of potential renal impairment in
      this patient group, we recommend this technique in preference to contrast
      enhanced CT in the initial investigation of inflammatory abdominal aortic
      aneurysms.

PMID- 10657161
TI  - Scrub typhus: radiological and clinical findings.
AB  - OBJECTIVES: To describe the radiological and clinical findings of scrub typhus.
      We retrospectively analysed the radiographic, thin-section CT and clinical
      features of scrub typhus. METHODS: The study included 75 consecutive patients
      (median age = 47 years, range = 18-81 years) with scrub typhus. Plain chest
      radiographs were obtained in all 75 patients and 19 underwent thin-section CT
      within 6 days of initial radiography. The radiographic and thin-section CT
      findings were retrospectively analysed by three radiologists. RESULTS: Most
      common clinical symptoms were fever (73/75, 98%), myalgia (61/75, 81%) and
      headache (60/75%, 80%). Rash (59/75, 79%) and eschar (56/75, 75%) were the most
      common signs. Radiography showed abnormalities in 54/75 (72%) patients. The most
      frequent findings were parenchymal abnormalities (53/75, 71%) with lower lung
      predilection including bilateral reticulonodular opacities (30/75, 40%), ground
      glass opacity (19/75, 25%), consolidation (19/75, 25%), septal lines (27/75, 36%)
      and hilar lymph node enlargement (19/75, 25%). Thin-section CT (n = 19) showed
      ground-glass opacity (17/19, 89%) predominantly in the lower zones. Bronchial
      wall thickening (11/19, 58%), centrilobular nodules (9/19, 47%) and interlobular
      septal thickening (9/19, 47%) were less frequent findings. CONCLUSIONS: Scrub
      typhus is an acute febrile illness characterized by eschar, which usually has a
      limited course without serious complication. Diffuse bilateral reticulonodular
      opacities with lower lung predominance was the most frequent radiographic
      finding. Chest radiography and thin-section CT show pulmonary interstitial
      disease which may have a component of pulmonary oedema secondary to cardiac
      dysfunction.

PMID- 10657162
TI  - Correlation between the MRI changes in the lumbar multifidus muscles and leg
      pain.
AB  - AIM: In the assessment of the lumbar spine by magnetic resonance imaging (MRI),
      changes in the paraspinal muscles are frequently overlooked. In this study, our
      objective was to investigate the relationships between lumbar multifidus (MF)
      muscle atrophy and low back pain (LBP), leg pain and intevertebral disc
      degeneration. METHODS: A retrospective study of 78 patients (aged 17-72) with LBP
      presenting with back pain with or without associated leg pain was undertaken.
      Their MR images were visually analysed for signs of lumbar MF muscle atrophy,
      disc degeneration and nerve root compression. The clinical history in each case
      was obtained from their case notes and pain drawing charts. RESULTS: MF muscle
      atrophy was present in 80% of the patients with LBP. The correlation between MF
      muscle atrophy and leg pain was found to be significant (P < 0.01). However, the
      relationships between muscle atrophy and radiculopathy symptoms, nerve root
      compression, herniated nucleus pulposus and number of degenerated discs were
      statistically not significant. CONCLUSION: Examination of the paraspinal muscles
      looking for atrophy of MF muscle should be considered when assessing MR images of
      lumbar spine. This may explain the referred leg pain in the absence of other MR
      abnormalities.

PMID- 10657163
TI  - Case Report. Pre-natally diagnosed testicular torsion ultrasonographic features.

PMID- 10657164
TI  - Nephrostomy failure due to tumour lysis syndrome.

PMID- 10657165
TI  - CT-guided decompression of a foreign body obstructing the small bowel.

PMID- 10657166
TI  - High resolution computed tomography findings in a pathologically proven case of
      Gujjar lung.

PMID- 10657167
TI  - Malignant solitary fibrous tumour of the peritoneum.

PMID- 10657169
TI  - Reply to Dr frazer

PMID- 10657168
TI  - Ultrasound screening for hepatocellular carcinoma (HCC) in cirrhosis.

PMID- 10657172
TI  - What Does It Mean to Be a Naturalist at the End of the Twentieth Century?

PMID- 10657173
TI  - The Population Dynamics and Community Ecology of Root Hemiparasitic Plants.
AB  - Root hemiparasitic plants and their host plants interact directly, through
      parasitism, as well as indirectly, through scramble competition for resources. To
      understand the population dynamics and community ecology of root hemiparasitic
      plants and their hosts, models of resource-based competition have been extended
      to include resource parasitism. Parasitism provides a mechanism for parasitic
      plants to overcome deficits in their ability to compete for soil resources. The
      interaction ranges from competitive to exploiter-victim, depending on whether the
      benefits of parasitism overshadow the costs of competition. These models predict
      that as productivity in the system increases, parasitic plants should become more
      abundant. In diverse host communities, differences in the impact that parasites
      have on their hosts and the benefits that they receive from parasitizing
      different hosts may lead to nontransitive competitive relationships and a sort of
      apparent competition. The possible dynamics include paper-rock-scissors
      oscillations and indirect mutualisms between parasitic plants and their hosts
      that allow them to form coalitions that can exclude competitive dominants.

PMID- 10657174
TI  - Long-Term Experimental Evolution in Escherichia coli. VIII. Dynamics of a
      Balanced Polymorphism.
AB  - We describe the short- and long-term dynamics of a phenotypic polymorphism that
      arose in a population of Escherichia coli while it was serially propagated for
      almost 20,000 generations in a glucose-limited minimal medium. The two types,
      designated L and S, differ conspicuously in the size of the colonies they form on
      agar plates as well as the size of their individual cells, and these differences
      are heritable. The S type reached a detectable frequency (>1%) at generation
      6,000, and it remained above that frequency throughout the subsequent
      generations. In addition to morphological differences, L and S diverged in
      important ecological properties. With clones isolated at 18,000 generations, L
      has a maximal growth rate in fresh medium that is ~20% higher than that of S.
      However, experiments with conditioned media demonstrate that L and S secrete one
      or more metabolites that promote the growth of S but not of L. The death rate of
      L during stationary phase also increases when S is abundant, which suggests that
      S may either secrete a metabolite that is toxic to L or remove some factor that
      enables the survival of L. One-day competition experiments with the clones
      isolated at generation 18,000 show that their relative fitness is frequency
      dependent, with each type having an advantage when rare. When these two types are
      grown together for a period of several weeks, they converge on an equilibrium
      frequency that is consistent with the 1-d competition experiments. Over the
      entire 14,000-generation period of coexistence, however, the frequency of the S
      type fluctuated between approximately 10% and 85%. We offer several hypotheses
      that may explain the fluctuations in this balanced polymorphism, including the
      possibility of coevolution between the two types.

PMID- 10657175
TI  - A Reevaluation of Density-Dependent Population Cycles in Open Systems.
AB  - Studies motivated by consideration of barnacle populations have led to the
      prediction of two different dynamic states for space-limited open populations
      subject to density-dependent mortality. Population densities may cycle or
      fluctuate stochastically around a mean value. Despite the potential generality of
      the associated theory, there are few examples of population cycling in open
      systems that have been shown to be driven by density-dependent effects. This may
      be because settlement and growth processes are generally too slow or too variable
      to generate consistent cycles. An alternative explanation is examined in this
      article using spatially explicit simulations. Even under conditions of consistent
      settlement and growth, the cycles predicted in at least one previous study are
      shown to represent a special case. Clear population cycles are only observed when
      the density-dependent disturbances are constrained to reoccur in exactly the same
      location. In the more general case, where density-dependent disturbances respond
      to local variations in population density, the cycling predicted from simple
      models is difficult to detect. Hence, a failure to detect cycling in population
      density does not refute a role for density dependence. Density-dependent
      disturbances can create a characteristic spatial structure consisting of a mosaic
      of cohorts.

PMID- 10657176
TI  - Phylogenetic Analysis of Dioecy in Monocotyledons.
AB  - Surveys of plant breeding systems in angiosperm families have shown a significant
      association between monoecy and dioecy, and researchers have proposed that dioecy
      has tended to evolve from monoecy. We evaluated this hypothesis in the context of
      a phylogeny of 918 monocotyledons assembled from 19 published trees. Binary and
      multistate breeding system characters were mapped onto a set of composite trees,
      and alternative models of character change were compared using maximum
      likelihood. Over a range of tree topologies and optimizations, we found three to
      eight times as many changes from hermaphroditism to dioecy as we did from monoecy
      to dioecy. Also, the rate at which monoecy gave rise to dioecy was not
      significantly higher than the rate at which hermaphroditism gave rise to dioecy.
      Our analysis implies that the correlation of monoecy and dioecy in angiosperm
      families does not reflect a preponderance of changes from monoecy to dioecy.
      Instead, we postulate that the family-level correlation results from the
      clustering of breeding system changes in the underlying phylogeny. Our results
      suggest renewed attention to modeling the transition from hermaphroditism to
      dioecy, possibly involving transient intermediates such as gynodioecy.

PMID- 10657177
TI  - Patterns of Annual Seed Production by Northern Hemisphere Trees: A Global
      Perspective.
AB  - We tested whether annual seed production (masting or mast fruiting) in Northern
      Hemisphere trees is an evolved strategy or a consequence of resource tracking by
      comparing masting patterns with those of annual rainfall and mean summer
      temperatures, two environmental variables likely to correlate with available
      resources. There were generally significant negative autocorrelations between the
      seed crop in year x and year [Formula: see text] (year [Formula: see text] in
      species of Quercus requiring 2 yr to mature acorns), as expected if resources are
      depleted in mast years in part by switching resources from growth to
      reproduction. Spatial autocorrelation in annual seed production generally
      declined with distance but was statistically significant over large geographic
      areas. Variability in annual seed production was relatively high and inversely
      correlated with latitude and generally not bimodally distributed. Patterns of
      spatial autocorrelation in annual rainfall and summer temperatures are generally
      similar to those exhibited by annual seed production, and relative variability in
      annual rainfall is also inversely correlated with latitude. However, these
      environmental variables exhibit distinctly different patterns of temporal
      autocorrelation, are much less variable, and are more normally distributed than
      annual seed production. Combined with the inverse relationship between growth and
      reproduction previously documented, these results support the hypothesis that
      variability in annual seed production is an evolved strategy and that annual seed
      production is more or less normally distributed rather than an all-or-none
      phenomenon.

PMID- 10657178
TI  - Analysis of Clines with Variable Selection and Variable Migration.
AB  - We report a likelihood-based method that estimates both dispersal and natural
      selection using the rate of change of the shape of a cline when selection and
      migration are not constant through time. We have investigated the case of local
      adaptation of the mosquito Culex pipiens to organophosphate insecticides in the
      Montpellier area in France. We have analyzed the modification of the clinal
      patterns at two resistance loci during the period from breeding to overwintering.
      We show that mosquitoes migrate extensively from breeding to overwintering sites
      at a rate that is markedly different from previous estimates made during the
      breeding season only. This migration is also strongly asymmetrical, which can be
      explained by different geographical distributions of breeding and overwintering
      sites, by variation in mosquito density along the transect, or by behavioral
      biases. We found that the starting time of overwintering is likely to vary
      between northern and southern populations and that substantial fitness costs are
      associated with resistance alleles at the two loci during overwintering. These
      results illustrate how demography and adaptive microevolution can be studied
      using selected markers. The method provides a framework to use population
      genetics and statistical models to reveal ecological and evolutionary processes.

PMID- 10657179
TI  - Evolutionarily Stable Strategies for Consuming a Structured Resource.
AB  - A general consumer-resource model assuming discrete consumers and a continuously
      structured resource is examined. We study two foraging behaviors, which lead to
      fixed and flexible patch residence times, in conjunction with a simple consumer
      energetics model linking resource consumption, foraging behavior, and metabolic
      costs. Results indicate a single, evolutionarily stable foraging strategy for
      fixed and flexible foraging in a nonspatial environment, but flexible foraging in
      a spatial environment leads to consumer grouping, which affects the resource
      distribution such that no single foraging strategy can exclude all other
      strategies. This evolutionarily stable coexistence of multiple foraging
      strategies may help explain a dichotomous pattern observed in a wide variety of
      natural systems.

PMID- 10657180
TI  - Fluctuating Asymmetry as a Bioindicator of Stress: Comparing Efficacy of Analyses
      Involving Multiple Traits.
AB  - Researchers have suggested fluctuating asymmetry (FA) as an indicator of
      environmental stress and have usually tested this assertion by examining
      relations between FA of single traits and stress. Fluctuating asymmetry stress
      relations are real but are typically weak and difficult to detect. Researchers
      would like to maximize the probability of detecting FA-stress relations when they
      exist. We assert that analyses based on the FA of multiple traits may provide
      better methods for detecting stress. In this article, we used computer
      simulations to compare the ability of six analyses to detect differences in FA
      between stressed and unstressed populations. We show that the optimal analysis
      depends upon the underlying form of the FA distributions. We also show that two
      of the analyses had inflated Type I errors in some situations. Finally, we
      quantify the advantage of our preferred analysis over those of single-trait FA in
      detecting stress.

PMID- 10657181
TI  - Local Competition, Inbreeding, and the Evolution of Sex-Biased Dispersal.
AB  - Using game theory, we developed a kin-selection model to investigate the
      consequences of local competition and inbreeding depression on the evolution of
      natal dispersal. Mating systems have the potential to favor strong sex biases in
      dispersal because sex differences in potential reproductive success affect the
      balance between local resource competition and local mate competition. No bias is
      expected when local competition equally affects males and females, as happens in
      monogamous systems and also in polygynous or promiscuous ones as long as female
      fitness is limited by extrinsic factors (breeding resources). In contrast, a male
      biased dispersal is predicted when local mate competition exceeds local resource
      competition, as happens under polygyny/promiscuity when female fitness is limited
      by intrinsic factors (maximal rate of processing resources rather than resources
      themselves). This bias is reinforced by among-sex interactions: female philopatry
      enhances breeding opportunities for related males, while male dispersal decreases
      the chances that related females will inbreed. These results meet empirical
      patterns in mammals: polygynous/promiscuous species usually display a male-biased
      dispersal, while both sexes disperse in monogamous species. A parallel is drawn
      with sex-ratio theory, which also predicts biases toward the sex that suffers
      less from local competition. Optimal sex ratios and optimal sex-specific
      dispersal show mutual dependence, which argues for the development of coevolution
      models.

PMID- 10657182
TI  - Are Tolerance, Avoidance, and Antibiosis Evolutionarily and Ecologically
      Equivalent Responses of Plants to Herbivores?

PMID- 10657183
TI  - Control of epidemic diphtheria in the Newly Independent States of the Former
      Soviet Union, 1990-1998.

PMID- 10657184
TI  - The changing epidemiology of diphtheria in the vaccine era.
AB  - The epidemic of diphtheria in the Newly Independent States (NIS) of the former
      Soviet Union has drawn attention to our incomplete understanding of the
      epidemiology of diphtheria. Many unanswered questions remain concerning the
      reasons for a resurgence of diphtheria and for the shift in the age of patients
      and concerning the mechanisms for acquisition of immunity in adults through
      natural infection under unfavorable living conditions. Other unanswered questions
      relate to the precise role of socioeconomic factors and hygiene conditions in the
      initiation, buildup, and spread of the epidemic. Important characteristics of the
      NIS epidemic can be used to help predict the spread of future diphtheria
      epidemics. These characteristics include a high proportion of infected adults, a
      progressive spread of disease from urban centers to rural areas, and transition
      from initial amplification of disease in groups with high rates of close contacts
      in focalized, well-distinguished outbreaks to a more generalized epidemic.

PMID- 10657185
TI  - Successful control of epidemic diphtheria in the states of the Former Union of
      Soviet Socialist Republics: lessons learned.
AB  - Epidemic diphtheria reemerged in the Russian Federation in 1990 and spread to all
      Newly Independent States (NIS) and Baltic States by the end of 1994. Factors
      contributing to the epidemic included increased susceptibility of both children
      and adults, socioeconomic instability, population movement, deteriorating health
      infrastructure, initial shortages of vaccine, and delays in implementing control
      measures. In 1995, aggressive control strategies were implemented, and since
      then, all affected countries have reported decreases of diphtheria; however,
      continued efforts by national health authorities and international assistance are
      still needed. The legacy of this epidemic includes a reexamination of the global
      diphtheria control strategy, new laboratory techniques for diphtheria diagnosis
      and analysis, and a model for future public health emergencies in the successful
      collaboration of multiple international partners. The reemergence of diphtheria
      warns of an immediate threat of other epidemics in the NIS and Baltic States and
      a longer-term potential for the reemergence of vaccine-preventable diseases
      elsewhere. Continued investment in improved vaccines, control strategies,
      training, and laboratory techniques is needed.

PMID- 10657186
TI  - Diphtheria surveillance and control in the Former Soviet Union and the Newly
      Independent States.
AB  - The Newly Independent States (NIS) inherited a common approach to diphtheria
      control from the Soviet Union and maintained a centralized system of surveillance
      and control managed by Soviet-trained epidemiologists with a shared professional
      culture. This system had controlled a diphtheria resurgence in the 1980s. In
      response to the epidemic of the 1990s, NIS health authorities responded with a
      set of control measures based on the Soviet-era experience. These measures
      included intensified childhood vaccination, aggressive case investigation,
      widespread diphtheria screening in institutions, and vaccination of adults in
      high-risk occupation groups. These measures proved insufficient due to high
      levels of susceptibility among adults, excessive contraindications to childhood
      vaccination, and insufficient resources in many countries. After these initial
      delays in implementing effective measures in some countries, most of the NIS
      health authorities rapidly and successfully implemented mass immunization of the
      population against diphtheria once the strategy was adopted and sufficient
      vaccine was available.

PMID- 10657187
TI  - Diphtheria in the Russian Federation in the 1990s.
AB  - A resurgence of diphtheria spread throughout the Russian Federation in the early
      1990s; diphtheria had been well controlled, but circulation of toxigenic strains
      of Corynebacterium diphtheriae had persisted since the implementation of
      universal childhood vaccination in the late 1950s. More than 115,000 cases and
      3,000 deaths were reported from 1990 to 1997, and, in contrast to the situation
      in the prevaccine era, most of the cases and deaths occurred among adults.
      Contributing factors included the accumulation of susceptible individuals among
      both adults and children and probably the introduction of new strains of C.
      diphtheriae. Vaccine quality, vaccine supply, or access to vaccine providers did
      not significantly contribute to the epidemic. Mass vaccination of adults and
      improved childhood immunization controlled the epidemic. High levels of
      population immunity, especially among children, will be needed to prevent and
      control similar outbreaks in the future.

PMID- 10657188
TI  - Epidemic diphtheria in Ukraine, 1991-1997.
AB  - In 1991, Ukraine experienced a return of epidemic diphtheria after decades of
      control that had resulted in <40 sporadic cases reported every year. Increased
      incidence was first recorded in Kiev, Lviv, and Odessa. By 1993, the epidemic had
      spread to >50% of the oblasts (provinces) in the country, and by 1995, all
      regions were affected. In 1995, at the peak of the epidemic, >5,000 cases and
      >200 deaths were reported. As in Russia, >80% of these cases were diagnosed in
      persons 16-59 years old. In 1993, the government of Ukraine initiated a program
      of increased immunization among children and at-risk adults, and by 1995, a mass
      immunization strategy was adopted in an effort to arrest the epidemic, which was
      increasing exponentially. In 1996, the number of cases started to decrease, and
      data from 1998 indicate that the downward trend has continued. It is likely that
      the diphtheria epidemic in Ukraine started among children, who had been left
      vulnerable due to inadequate childhood immunizations, and then quickly spread to
      inadequately protected adults.

PMID- 10657189
TI  - Epidemic diphtheria in Belarus, 1992-1997.
AB  - In 1990, epidemic diphtheria reemerged in Russia and spread to Belarus in 1992,
      when 66 cases were reported. Diphtheria cases doubled each year in 1993 and 1994
      and peaked in 1995, when 322 cases were reported. Intensified routine
      immunization of young children and mass vaccination of older children and
      selected groups of adults were conducted in 1995 and were followed by mass
      vaccination campaigns targeting all adults in 1996. By the end of 1996, full
      immunization of >95% of children and coverage of>87% of adults with >/=1 dose
      resulted in a rapid decline in diphtheria cases. In 1998, only 36 cases of
      diphtheria were reported. More than 70% of the 965 cases and 26 fatalities
      reported during 1990-1998 occurred among persons >14 years of age. High levels of
      immunity among the entire population are needed for rapid control of diphtheria
      epidemics in the vaccine era.

PMID- 10657190
TI  - Epidemiology and control of diphtheria in the Republic of Moldova, 1946-1996.
AB  - In 1994-1996, the Republic of Moldova was stricken with an epidemic of diphtheria
      after >30 years of routine diphtheria immunization and the near absence of the
      disease for nearly 20 years. The intensity of the epidemic gradually grew,
      reaching a peak in 1994-1995. The epidemiology of diphtheria in Moldova during
      this period is described along with laboratory findings and control measures.
      Pharyngeal diphtheria was the predominant clinical form of the disease (97% of
      cases), and it most often developed in a localized form (70%), with 20% in the
      toxic form. The clinical diagnosis of diphtheria was bacteriologically confirmed
      in 91% of cases: Of the cases tested for biotype, 91.3% were gravis, 8.5% were
      mitis, and 0. 2% were intermedius. Of 494 toxigenic isolates from cases and
      carriers at the beginning of the epidemic, 47% were nonphagotypeable strains, and
      25.7% were phagotype VI strains. Aggressive population-based diphtheria control
      measures, a mass immunization campaign, rapid case identification, antibiotic
      prophylaxis and supplemental immunization of close contacts in clusters of
      infection, and high coverage with routine immunization rapidly controlled the
      epidemic within Moldova.

PMID- 10657191
TI  - Diphtheria in Lithuania, 1986-1996.
AB  - Diphtheria reappeared in Lithuania in 1986 and rose to epidemic levels by 1992.
      Between 1991 and 1996, 110 cases of diphtheria were registered, with an incidence
      of 0.03-1.15/100,000 population. Most cases (84%) and all 17 deaths occurred
      among persons >/=15 years, most of whom had never been vaccinated. Persons 40-49
      years old had the highest average annual age-specific morbidity (1.70/100,000)
      and mortality (0.53/100,000) rates. Low levels of immunity among individuals 40
      49 years old and migration to epidemic areas in Russia and Belarus contributed to
      the epidemic's occurrence. Between 1991 and 1995, toxigenic Corynebacterium
      diphtheriae strains were isolated from 84 of all registered patients (76%), and
      nontoxigenic strains were isolated from 13 (12%). By 1996, two mass vaccination
      campaigns, which provided one dose of vaccine to individuals 25-30 years old and
      three doses of vaccine to persons 31-60 years old, helped reduce the number of
      cases. The first campaign achieved 69% coverage; the second achieved 48%
      coverage.

PMID- 10657192
TI  - Diphtheria in Latvia, 1986-1996.
AB  - After nearly two decades without a diphtheria case in Latvia, the disease
      reappeared in 1986. From 1990 to 1996, case counts were highest among adults 40
      49 years of age, school-aged children, and adolescents. Nonetheless, the average
      annualized incidence of disease was highest among infants and preschoolers. In
      August 1995, mass vaccination efforts began to provide adults 25-60 years of age
      with at least one dose of vaccine. By the end of the year, a 77% coverage rate
      was achieved, resulting in a decrease of reported diphtheria cases by 1996. From
      February to September 1997, special outreach efforts were focused on hard-to
      reach populations; as a result, by June 1997, 55% of adults had received three
      doses of vaccine. While decreases in the incidence of and morbidity from
      diphtheria have occurred, additional efforts still need to be concentrated on
      improving vaccination coverage in adults and children <2 years of age and in
      reducing mortality from diphtheria.

PMID- 10657193
TI  - Diphtheria in Estonia, 1991-1996.
AB  - Clinical diphtheria reappeared in Estonia in 1991. Between 1991 and 1996, 61
      cases and 5 deaths occurred; 19 cases were among children 5-9 years of age, and
      11 were among persons 40-49 years of age. From 1993-1995, vaccine supplies
      donated by Finland were used in vaccination programs. In 1995, the International
      Federation of Red Cross and Red Crescent Societies and the Estonian Red Cross
      launched a mass vaccination campaign targeting the adult population. By the end
      of 1997, it was estimated that 46% of adults had received at least one dose of
      vaccine. Although the vaccination campaigns did not target the pediatric
      population, vaccination coverage in school-aged children remained high due to
      continuing routine vaccination programs. The reappearance and epidemic of
      clinical diphtheria cases and the mass vaccination campaign efforts demonstrated
      that preventive measures are important and must be maintained in order to keep
      diphtheria under control.

PMID- 10657194
TI  - Epidemic investigation of diphtheria in the Republic of Armenia, 1990-1996.
AB  - While incidence rates of diphtheria steadily declined in Armenia after World War
      II, reemergence of the disease in 1990 brought about changes in public health
      practices and identified resource needs. The Armenian Ministry of Health (MOH)
      routinely collected diphtheria case reports, as a reportable health outcome.
      Diphtheria incidence rates increased from 0.02/100,000 in 1993 to 1/100,000 (36
      cases) in 1994. The distribution of cases showed that the greatest number of
      illnesses and deaths occurred among persons 5-14 years old, yet incidence rates
      among persons 1-4 and 5-14 years old were similar (4. 4 cases/ and 4.3
      cases/100,000, respectively). During 1990-1996, 9 (75%) of 12 cases who died and
      18 (21%) of 84 cases who survived had not been vaccinated. The diphtheria
      epidemic in Armenia was an important, serious, and signal public health event.
      The Armenian MOH responded by revising immunization practices (1994), improving
      epidemic control measures (1995), and soliciting international resources (1992
      1996).

PMID- 10657195
TI  - Epidemic diphtheria in the 1990s: Azerbaijan.
AB  - The diphtheria epidemic in the former Soviet Union reached Azerbaijan in 1991,
      when 66 cases of diphtheria were reported, a number that compared with 4 cases in
      1990. From 1990-1996, 2182 cases of diphtheria and 286 diphtheria fatalities
      (case fatality rate: 13.1%) were reported in Azerbaijan, primarily among persons
      5-39 years of age. Almost 45% of cases and 61% of deaths occurred among children
      5-14 years of age. The high burden of severe disease among children and young
      adults suggested a different pattern of preexisting immunity against diphtheria
      in the Azerbaijani population than was observed in the concurrent diphtheria
      epidemic in Russia. Because resources were limited in Azerbaijan, mass
      immunization of the population was carried out in stages, focusing initially on
      school-aged children. Mass immunization campaigns targeting children were
      moderately successful in stabilizing the epidemic; mass immunization campaigns
      targeting both adults and children were eventually needed to fully stop the
      epidemic.

PMID- 10657196
TI  - Diphtheria epidemic in the Republic of Georgia, 1993-1997.
AB  - Epidemic diphtheria reemerged in the republic of Georgia in 1993. From 1993 to
      1997, 1405 cases were reported (28 in 1993, 312 in 1994, 429 in 1995, 348 in
      1996, and 288 in 1997), with a cumulative incidence of 25.8/100,000 and a case
      fatality ratio of 9.5%. During 1993-1997, 53% of the diphtheria cases occurred
      among persons >/=15 years of age. Unvaccinated patients were more likely to have
      toxic forms (relative risk=2.24; 95% confidence interval=1.69-2.96) or to die of
      diphtheria (relative risk=2.24; 95% confidence interval=1. 36-3.68) than those
      who had received at least one dose of diphtheria toxoid. Improvement in routine
      childhood vaccination coverage and implementation of mass adult vaccination
      campaigns have been critical to bringing the epidemic under control. By mid-1998,
      the overall diphtheria situation in Georgia appeared to have been controlled.
      Only 53 cases were reported from January to June 1998, representing a 64%
      decrease from the 148 cases during the corresponding period in 1997.

PMID- 10657197
TI  - Universal immunization: the diphtheria control strategy of choice in the Republic
      of Tajikistan, 1993-1997.
AB  - During the 1993-1997 diphtheria epidemic in Tajikistan, the incidence rate was
      the highest observed throughout the Newly Independent States of the former Soviet
      Union (76.2 cases/100,000 population in 1995). Factors that contributed to this
      situation included an increase in the number of persons who were not fully
      immunized, a breakdown of health care services and disease surveillance, civil
      war, an increase in migration, shortages of qualified medical personnel, and
      shortages of products, resources, and services. The Ministry of Health and
      numerous international organizations have worked to address the needs of the
      republic, and in the fourth quarter of 1995, the number of reported cases began
      to decrease. It is believed that this decrease was largely the result of routine
      immunization, implementation of national immunization days, and use of a World
      Health Organization-recommended system for working with patients and contacts,
      and it underscores the importance of universal diphtheria immunization with
      special booster doses in such an epidemic setting.

PMID- 10657198
TI  - Epidemic investigation of diphtheria, Republic of Kazakhstan, 1990-1996.
AB  - The diphtheria epidemic that began in Russia in 1990 reached Kazakhstan in 1992
      when 45 case-patients (a 50% increase over 1991) were reported. In 1993, 82 case
      patients were reported, and 489 were reported in 1994. The epidemic peaked in
      1995 when 1105 case-patients were reported (incidence rate=6.7/100,000
      population). In 1996, after public health practice modifications and several mass
      vaccinations, 455 case-patients were reported. From 1990 to 1996, children </=14
      years old represented 35% (2234) of the reported case-patients (and 33% of the
      population) but had a disproportionate share (49%) of the fatalities. Females
      represented 63% of the adult case-patients. In 1996, 297 (65%) of 455 case
      patients and 26 (84%) of 31 fatalities were unvaccinated. Kazakhstan controlled
      the diphtheria epidemic by using a multifaceted public health strategy of
      prevention and control, which included changing the routine immunization
      schedule, modifying the official list of contraindications to vaccination,
      conducting mass campaigns to vaccinate persons, and treating close contacts of
      case-patients with antibiotics.

PMID- 10657199
TI  - Epidemic diphtheria in the Kyrgyz Republic, 1994-1998.
AB  - The Kyrgyz Republic experienced a widespread diphtheria epidemic during 1994
      1998. National diphtheria surveillance and vaccination coverage information were
      used to describe the course of the epidemic. The epidemic began in August 1994,
      reached a peak in 1995 with 704 cases (incidence rate: 15.4/100,000 population)
      and 30 deaths, and declined to an incidence rate of 4.0/100,000 during the first
      8 months of 1998. Age-specific incidence was highest in 1995 among persons 15-19
      and 20-29 years old. Three rounds of mass vaccination with tetanus and diphtheria
      toxoids for adult use (Td) were conducted; reported coverage was 69% in 1995 and
      >95% in 1996 and 1997. Reported routine vaccination coverage with three doses of
      diphtheria toxoid by age 12 months increased from 62% in 1989 to 98% in 1997.
      Mass vaccination of the adult population with Td and improvements in childhood
      vaccination coverage played a major role in controlling the epidemic.

PMID- 10657200
TI  - Diphtheria epidemic in the Republic of Uzbekistan, 1993-1996.
AB  - The Republic of Uzbekistan, like the other Newly Independent States in the 1990s,
      experienced epidemic diphtheria during the 1990s. The outbreak in Uzbekistan
      began in 1993 in southern regions that bordered areas of Tajikistan that were
      experiencing a very intense diphtheria epidemic. However, the Uzbek epidemic
      rapidly spread and threatened to involve the entire country. From 1993-1996, 1169
      cases of diphtheria were reported, compared with 58 in 1990-1992. Unvaccinated or
      only partially vaccinated cases were more likely to have clinically severe forms
      of diphtheria than those who were fully vaccinated. Strong epidemiologic links
      with the Tajik diphtheria epidemic and the predominance of mitis biotype strains
      of Corynebacterium diphtheriae in Uzbekistan make it likely that the Uzbek
      outbreak arose independently of the predominantly biotype gravis epidemic that
      began in Russia. The epidemic appeared to be due to low population immunity and
      the large-scale reintroduction of toxigenic strains of C. diphtheriae. Several
      mass vaccination campaigns and general enhancement of routine immunization
      procedures led to control of the epidemic in 1996.

PMID- 10657201
TI  - Clinical characteristics and management of 676 hospitalized diphtheria cases,
      Kyrgyz Republic, 1995.
AB  - The Kyrgyz Republic experienced a widespread resurgence of diphtheria during 1994
      1998. To describe the clinical characteristics and management of diphtheria
      patients hospitalized in 1995, a retrospective chart review was conducted.
      Physician-diagnosed cases of diphtheria were classified according to the system
      recommended by the World Health Organization and UNICEF. Among 676 patients
      hospitalized with respiratory diphtheria, 163 (24%) were carriers, 186 (28%) had
      tonsillar forms, 78 (12%) had combined types or delayed diagnosis, and 201 (30%)
      had severe forms of diphtheria. The highest age-specific incidence rates occurred
      among persons 15-34 years old, and 70% of cases were among those >/=15 years of
      age. Myocarditis occurred among 151 patients (22%), and 19 patients died (case
      fatality ratio: 3%). Diphtheria antitoxin was administered to 507 patients (75%),
      and all patients received antibiotics (penicillin or erythromycin). Respiratory
      diphtheria remains a potentially fatal disease, commonly presenting with a
      typical membranous pharyngitis. Early diagnosis and treatment of cases with
      diphtheria antitoxin and antibiotics are the cornerstones of effective treatment.

PMID- 10657202
TI  - The pathology of diphtheria.
AB  - Diphtheria is an acute, communicable disease caused by Corynebacterium
      diphtheriae. The disease is generally characterized by local growth of the
      bacterium in the pharynx with pseudomembrane formation or, less commonly, in the
      stomach or lungs; systemic dissemination of toxin then invokes lesions in distant
      organs. Acute disease of the upper respiratory tract usually involves one or more
      of the following: tonsillar zones, larynx, soft palate, uvula, and nasal
      cavities. A recent epidemic in Russia emphasized the role of vaccination in
      reducing disease in children and adults.

PMID- 10657203
TI  - Risk factors for diphtheria: a prospective case-control study in the Republic of
      Georgia, 1995-1996.
AB  - The large-scale resurgence of diphtheria in the former Soviet Union offered a
      unique opportunity to evaluate risk factors for the transmission of respiratory
      diphtheria; therefore, a prospective case-control study was done in the republic
      of Georgia. In total, 218 diphtheria cases (hospitalized between October 1995 and
      March 1996) and 408 matched controls participated. One hundred cases (45%) were
      </=14 years of age, and 118 (55%) were >/=15 years of age (range: <1 to 75
      years). In the multivariate analyses, the following risk factors were found to be
      significant: lack of vaccination (matched odds ratio [mOR]=19.2), household
      exposure to diphtheria (mOR=7.4), exposure to skin lesions (mOR=5.8), history of
      eczema (mOR=3.4), fever with myalgia prior to illness (mOR=2.6), having tonsils
      (mOR=4.4), sharing a bed (mOR=1.9), sharing cups and glasses (mOR=2.7), and
      taking a bath less than once a week (mOR=2.6). These findings emphasize primary
      prevention through immunizations, secondary prevention following exposure to
      diphtheria (and to suspicious skin lesions), and adherence to strict standards of
      personal hygiene.

PMID- 10657204
TI  - Epidemic diphtheria in the Republic of Georgia, 1993-1996: risk factors for fatal
      outcome among hospitalized patients.
AB  - Epidemic diphtheria reemerged in the republic of Georgia in November 1993. To
      identify risk factors for fatal outcomes, clinical and epidemiologic data on all
      hospitalized diphtheria patients were examined. Medical charts of patients from
      1993-1995 were reviewed. A total of 659 cases and 68 deaths were identified (case
      fatality rate [CFR] = 10.3%). Fifty-two percent of all cases and 68% of deaths
      were in children </=14 years old. The highest CFR occurred among adults 40-49
      years of age (CFR=19%) and children 5-9 years of age (CFR=16%). Children who did
      not have the complete primary vaccination series with diphtheria toxoid and
      adults 40-49 years of age were the 2 groups at highest risk. Being a rural
      resident and having a long interval (>3 days) between onset of symptoms to
      antitoxin treatment were significantly associated with fatal outcomes.
      Immunization of children and 40- to 49-year-old adults was required to rapidly
      control the epidemic.

PMID- 10657205
TI  - Current approaches to the laboratory diagnosis of diphtheria.
AB  - Despite the success of mass immunization in many countries, diphtheria continues
      to play a major role as a potentially lethal resurgent infectious disease. Early,
      accurate diagnosis is imperative since delay in specific therapy may result in
      death. The microbiologic diagnosis of the disease, the identification of contacts
      and carriers, and the appropriate clinical management of these patients are
      therefore crucial. The epidemiology of diseases caused by Corynebacterium
      diphtheriae has changed dramatically over the decades, a situation that is
      highlighted by the resurgence of infections in the European region. These factors
      have strengthened the need for laboratories to screen for C. diphtheriae. Many
      modified and new methodologies are now used widely within laboratories for
      diphtheria diagnosis. Recent developments have focused upon methods for detection
      of the lethal and potent exotoxin produced by the causative organism, C.
      diphtheriae; this detection is the definitive test for the microbiologic
      diagnosis of diphtheria.

PMID- 10657206
TI  - The European Laboratory Working Group on Diphtheria: A global microbiologic
      network.
AB  - Increasing international travel, migration to and from epidemic areas, and the
      emergence of epidemic Corynebacterium diphtheriae strains globally have
      highlighted the need for better microbiologic surveillance and greater clinical
      and laboratory awareness. As part of the strategy developed by the World Health
      Organization, one major goal is particularly applicable to the microbiology and
      epidemiology of diphtheria: to improve surveillance for early detection of
      emerging and reemerging diseases by establishing a network of national and
      international laboratories. The European Laboratory Working Group on Diphtheria
      (ELWGD) was therefore formed in 1993 as a result of the epidemic situation in
      Eastern Europe. Currently, there is participation from 20 different countries
      from Western and Eastern Europe, the United States, Australia, and Southeast
      Asia. ELWGD is a prime example of a collaborative and coordinated approach to the
      microbiology of diphtheria and should serve as a potential model for other
      infectious diseases networks.

PMID- 10657207
TI  - Direct polymerase chain reaction for detection of toxigenic Corynebacterium
      diphtheriae strains from the Republic of Georgia after prolonged storage.
AB  - A total of 226 paired nose and throat swab specimens from 113 clinical diphtheria
      cases from the republic of Georgia were analyzed by direct polymerase chain
      reaction targeting both A and B subunits of the diphtheria toxin gene, tox. Even
      after prolonged transport and extensive storage (7-14 months) of the clinical
      specimens in silica gel packages, direct polymerase chain reaction detected the
      diphtheria tox gene in 54% of the specimens. Specimens obtained by throat swab
      were three times more likely than those obtained by nose swab to be positive for
      Corynebacterium diphtheriae.

PMID- 10657208
TI  - Biology and molecular epidemiology of diphtheria toxin and the tox gene.
AB  - Diphtheria toxin (DT) is an extracellular protein of Corynebacterium diphtheriae
      that inhibits protein synthesis and kills susceptible cells. The gene that
      encodes DT (tox) is present in some corynephages, and DT is only produced by C.
      diphtheriae isolates that harbor tox+ phages. The diphtheria toxin repressor
      (DtxR) is a global regulatory protein that uses Fe2+ as co-repressor. Holo-DtxR
      represses production of DT, corynebacterial siderophore, heme oxygenase, and
      several other proteins. Diagnostic tests for toxinogenicity of C. diphtheriae are
      based either on immunoassays or on bioassays for DT. Molecular analysis of tox
      and dtxR genes in recent clinical isolates of C. diphtheriae revealed several tox
      alleles that encode identical DT proteins and multiple dtxR alleles that encode
      five variants of DtxR protein. Therefore, recent clinical isolates of C.
      diphtheriae produce a single antigenic type of DT, and diphtheria toxoid
      continues to be an effective vaccine for immunization against diphtheria.

PMID- 10657209
TI  - Molecular epidemiology of diphtheria.
AB  - Molecular subtyping of Corynebacterium diphtheriae identified significant genetic
      diversity within the species and led to the identification of a unique clonal
      group that emerged in Russia in 1990 at the beginning of the current epidemic.
      Strains of this group belong to a distinct electrophoretic type complex and are
      of ribotypes D1 and D4. Identification of the group allowed for precise
      monitoring of the epidemic's progression and for rapid detection of cases
      imported to other countries. The evolution of this clonal group was monitored,
      and changes were identified. Molecular analysis revealed that no amino acid
      substitutions have occurred in the diphtheria toxin gene of the epidemic clone
      strains, reaffirming the use of the current vaccine as the single most effective
      preventive measure. Application of molecular subtyping methods and continuous
      monitoring of the spread of these clones has made it possible to distinguish
      rapidly between epidemic, endemic, and imported cases, allowing for
      implementation of timely and adequate preventive measures and providing
      reassurance that no secondary spread resulted from importations.

PMID- 10657210
TI  - Ukraine, 1992: first assessment of diphtheria vaccine effectiveness during the
      recent resurgence of diphtheria in the Former Soviet Union.
AB  - A case-control study in Ukraine provided the first data on the field
      effectiveness of Russian-produced vaccine during the 1990 diphtheria resurgence
      in the former Soviet Union. For each of 262 diphtheria cases <15 years of age who
      were reported from January through October 1992, 2 controls, matched by age and
      clinic, were selected. The effectiveness of three doses of diphtheria vaccine was
      98.2% (95% confidence interval: 90.3-99.9). Among controls, 84% had received
      three or more vaccinations by 2 years of age. These results suggest that the
      following five hypothesized causes of the outbreak appeared unlikely: appearance
      of a new "mutant" diphtheria strain, low potency of the Russian-produced
      diphtheria vaccine, inadequate cold chain, poor host immunogenicity due to
      radiation exposure from Chernobyl, and low routine childhood vaccination
      coverage. It is concluded that initial priority for scarce resources for
      controlling this outbreak should be placed on vaccination of persons susceptible
      to diphtheria (e.g., adults) rather than revaccination of children.

PMID- 10657211
TI  - Diphtheria toxoid vaccine effectiveness: A case-control study in Russia.
AB  - Prior to the completion of this and other studies, low effectiveness of
      diphtheria toxoid-containing vaccine was suspected to be a major contributing
      factor to the diphtheria epidemic that began in the Russian Federation in 1990. A
      vaccine effectiveness study was done in Moscow by enrolling physician-diagnosed
      cases and 10 control subjects per case. Controls were matched to cases by age (+/
      3 months) and clinic registration. Vaccination history was abstracted from a
      standardized form for case-patients and from clinic vaccination records for
      control subjects. Two hundred seventeen case-patients and 2169 matched controls
      were included in the study. Most controls (92%) had received three or more doses
      of a diphtheria toxoid vaccine, compared with 72% of case-patients. The vaccine
      effectiveness for three or more doses was 97% (95% confidence interval: 94.3
      98.4). Low vaccine effectiveness was not a contributing factor to the diphtheria
      epidemic in the Russian Federation. To control and prevent diphtheria epidemics,
      it is necessary to achieve and maintain high vaccination coverage with three or
      more doses of diphtheria toxoid among adults and children.

PMID- 10657212
TI  - Case-control evaluation of an adult diphtheria immunization program in Ukraine.
AB  - In response to concerns about diphtheria vaccine efficacy, a case-control study
      was undertaken in Ukraine in 1996 to determine whether those recently immunized
      were indeed protected from disease, whether multiple doses were more protective,
      whether contact with children was related to disease, and whether there were
      detectable differences in protective efficacy between Western and Russian
      vaccines. In each of the three sites (one rural and two urban), 60 adults with
      laboratory-confirmed cases of diphtheria were identified from health center
      records along with 2 adult controls, who were matched to the case by
      neighborhood. Demographic and vaccination data were gathered from health center
      records. Using conditional logistic regression to estimate odds ratios, it was
      determined that cases were more likely to have had no vaccine in the year prior
      to the index data (odds ratio, 5.0; 95% confidence interval, 2.8-9.0), for a
      vaccine efficacy of 80%. Two doses gave greater protection, living with children
      increased disease risk, and no difference was detectable between the Russian and
      Western vaccines.

PMID- 10657213
TI  - How many doses of diphtheria toxoid are required for protection in adults?
      Results of a case-control study among 40- to 49-year-old adults in the Russian
      Federation.
AB  - During the Russian diphtheria epidemic of the 1990s, adults had an unexpectedly
      high rate of disease. A retrospective, matched case-control study was done to
      measure the effectiveness of one, two, or three or more doses of diphtheria
      toxoid against diphtheria among 40- to 49-year-old Russians. Thirty-nine
      diphtheria case-patients and 117 controls were studied. Previous vaccinations
      were included if one dose was received within the previous 10 years. Five cases
      (13%) and 33 controls (28%) had received three or more doses of vaccine. The
      matched odds ratio was 0.3 (95% confidence interval, 0.1-0.9) for three or more
      doses compared with no doses, which was a vaccine effectiveness of 70% (95%
      confidence interval, 10-90). A trend existed toward milder disease with
      increasing doses (chi2 test for trend, P=.02). The results suggest that Russian
      adults, who were unlikely to have acquired immunity to diphtheria through
      immunization or natural infection, required at least three doses of diphtheria
      toxoid for reliable protection against disease.

PMID- 10657215
TI  - Evaluation of a single dose of diphtheria-tetanus toxoids among adults in Odessa,
      Ukraine, 1995: immunogenicity and adverse reactions.
AB  - Epidemic diphtheria spread to Ukraine in 1991, where it peaked in 1995 with
      >5,000 reported cases. To refine epidemic control strategies, immunogenicity of a
      tetanus-diphtheria toxoids vaccine (Td) containing 2 limits of flocculation (Lf)
      diphtheria toxoid was evaluated. During a mass vaccination campaign, adults at a
      clinic in Odessa received one dose of Td. At enrollment, 57.2% of 341 study
      participants had levels of diphtheria antitoxin (DAT) >/=0.1 IU/mL. Thirty and
      180 days after receiving one dose of Td, 91.5% and 84.5% of the participants,
      respectively, had DAT levels >/=0.1 IU/mL. However, among 40- to 49-year-old
      participants, only 78.8% and 73.8% had DAT levels >/=0.1 IU/mL at 30 and 180
      days, respectively. This study suggests that one dose of 2 Lf diphtheria toxoid
      is highly effective in raising DAT to protective levels in most adults; however,
      the study also shows that certain age groups, particularly persons 40-49 and, to
      a lesser degree, 30-39 years old may require additional doses or a complete three
      dose primary vaccination series for optimal protection against diphtheria.

PMID- 10657214
TI  - Immunogenicity of tetanus-diphtheria toxoids (Td) among Ukrainian adults:
      implications for diphtheria control in the Newly Independent States of the Former
      Soviet Union.
AB  - After 30 years of control, epidemic diphtheria returned to the Soviet Union in
      1990. To develop control strategies, the immunogenicity of the tetanus and
      diphtheria toxoids (Td) vaccine was assessed. Workers who were 18-67 years old
      received two Td immunizations separated by 30 days. A neutralization assay
      determined diphtheria antitoxin (DAT) on enrollment and on days 7, 30, 60, and
      425. On enrollment, 43.0% of 488 workers had DAT <0.1 IU/mL. After one dose,
      88.5% had DAT >/=0.1 IU/mL, after two doses, 92.2% had >/=0.1 IU/mL and >90% of
      participants <30 or >/=50 years of age attained >/=1.0 IU/mL; however, only 78.4%
      of those who were 30-39 years old and 51.8% of those who were 40-49 years old
      achieved >/=1.0 IU/mL after two doses. To control the epidemic in Ukraine, one Td
      dose should be administered to virtually the entire population (persons 30-49
      years old require three doses of Td for optimal individual protection and to
      maximize population immunity).

PMID- 10657216
TI  - Evaluation of a single dose of diphtheria toxoid among adults in the Republic of
      Georgia, 1995: immunogenicity and adverse reactions.
AB  - To determine the immunogenicity and safety of a single dose of diphtheria toxoid
      among adults, blood samples for detecting serum antitoxin levels were obtained
      from 18- to 59-year-old subjects (n=248) before and 30 days after immunization
      with Td (tetanus-diphtheria toxoids; manufactured by Serum Institute of India).
      By day 30, the seroprevalence of antitoxin levels >/=0.1 IU/mL increased from
      22.6% to 81.5%; median antitoxin levels increased from 0.01 to 4.0 IU/mL. These
      parameters were lowest among subjects who were 40-59 years old, especially among
      those 40-49 years old. Adverse reactions (local redness, swelling, induration,
      fever>39 degrees C) were reported by 5.3% of participants. Our findings suggest
      that, in general, one dose of the Indian-produced Td vaccine is efficacious and
      safe in inducing an adequate immune response against diphtheria in adults;
      however, in Georgia, persons 40-59 years old, especially those 40-49 years old,
      will require additional doses of toxoid to achieve protective levels of
      antitoxin.

PMID- 10657217
TI  - Immune response to diphtheria booster vaccine in the Baltic states.
AB  - A study was done to measure baseline levels of immunity to diphtheria and
      antibody responses to different doses of diphtheria vaccine in study participants
      in the three Baltic states. Diphtheria booster vaccines containing either 3
      (Estonia and Lithuania), 6 (Latvia), or 12 (Latvia) limit of flocculation units
      of diphtheria toxoid were administered to 2315 adults. Diphtheria antibody levels
      were tested before and 1-2 months after vaccination. Before vaccination, 40% of
      the participants in Estonia, 32% in Lithuania, and 38% in Latvia had antibody
      levels <0.01 IU/mL, the level for minimum protection. After vaccination, 79% of
      the participants in Estonia, 83% in Lithuania, and 81% in Latvia had antibody
      levels >0. 1 IU/mL, the minimum level for full protection. However, in each of
      the countries, about one-third of the 40- to 49-year-old participants would have
      benefited from additional doses of vaccine. There was not a significantly
      different antibody response among persons receiving the three different doses.
      Age and the level of prevaccination immunity had a modifying effect on the
      response to vaccination; however, sex did not.

PMID- 10657218
TI  - Role of health communications in Russia's diphtheria immunization program.
AB  - As part of a broader program in health communication assistance, project staff
      from Basic Support for Institutionalizing Child Survival worked with staff from
      Russia's oblast (regional) public health agencies to design and implement
      communication activities supporting local diphtheria immunization efforts.
      Because aggressive community outreach efforts and strong administrative sanctions
      had already achieved impressive adult coverage rates for first doses of
      diphtheria toxoid vaccine, communication interventions emphasized the need for
      second and third doses. Outcomes were assessed through vaccination coverage data
      and more qualitative measures. In one project site, the increase in adult
      coverage (two or more doses) was very modest. In a second site, with a stronger
      communications component, coverage increased significantly (from 20% to 80%).
      Although it is not possible to disentangle completely the effects of
      communications from other aspects of oblast immunization programs, these and
      other outcome data suggest that health communications can play an important role
      in Russia's ongoing mass immunization efforts.

PMID- 10657219
TI  - Contraindications to vaccination in the Russian Federation.
AB  - Failure to achieve high levels of immunity among children contributed to the
      epidemic of diphtheria that occurred in the Russian Federation during the 1990s.
      A major factor in this failure was the extensive list of contraindications to
      vaccination that was in use throughout the countries of the former Soviet Union.
      In 1980, the Ministry of Health (MOH) of the Soviet Union adopted an extensive
      list of contraindications for use of the diphtheria-tetanus toxoids-pertussis
      (DTP) vaccine. In 1994, the MOH of the Russian Federation revised the list of
      contraindications to vaccination to be largely in accord with World Health
      Organization recommendations. Since then, age-appropriate vaccination coverage
      has increased markedly: In 1996, DTP3 coverage among children 12 months of age
      had increased to 87% from 60% in 1990.

PMID- 10657220
TI  - Assessment of vaccination coverage among adults 30-49 years of age following a
      mass diphtheria vaccination campaign: Ukraine, April 1995.
AB  - Ukraine has been experiencing epidemic diphtheria since 1991. In efforts to
      control this epidemic, a mass vaccination campaign was held in April 1995.
      Persons not vaccinated in the previous 3 years were considered eligible for
      vaccination with tetanus-diphtheria toxoids (Td). Two cluster sample surveys were
      conducted to determine vaccination coverage achieved. In the urban and rural
      survey areas, respectively, 628 and 618 persons 30-49 years of age were
      interviewed. Fifty-nine percent of urban and 58% of rural participants were
      eligible for vaccination. During the vaccination campaign, 58% (95% confidence
      interval [95% CI], 47.1-69.2) of eligible persons received Td in the urban area,
      compared with 92% (95% CI, 89.2-95.3) in the rural area. Apparent barriers to
      vaccination included misconceptions about the safety, efficacy, and need for
      booster doses of Td. Future vaccination campaigns should include targeted
      information and education messages. Mass vaccination campaigns can be successful
      in vaccinating large numbers of adults; however, in urban areas, additional
      efforts may be required to achieve levels of coverage adequate to confer herd
      immunity and interrupt the diphtheria epidemic.

PMID- 10657221
TI  - Epidemic diphtheria in the Newly Independent States of the Former Soviet Union:
      implications for diphtheria control in the United States.
AB  - The re-emergence of diphtheria in the Newly Independent States of the former
      Soviet Union in the 1990s raised global awareness of the potential for resurgent
      disease in countries with long-standing immunization programs. In the United
      States, the large population of susceptible adults and the possibility of a
      reintroduction of toxigenic strains of diphtheria create a setting in which
      diphtheria could spread. In addition, at least one focus of continued circulation
      of endemic toxigenic Corynebacterium diphtheriae has been identified. Few
      physicians now have expertise in the diagnosis and treatment of persons with
      diphtheria, and laboratory capacity is lacking throughout the country. These
      concerns highlight the importance of maintaining high levels of age-appropriate
      diphtheria toxoid vaccination, surveillance, accessible and reliable laboratory
      testing, and training of health care providers. Although the risk of resurgence
      of diphtheria in the United States is low, public health authorities must ensure
      that the capacity to recognize, diagnose, and control diphtheria is maintained.

PMID- 10657222
TI  - Implications of the diphtheria epidemic in the Former Soviet Union for
      immunization programs.
AB  - The massive diphtheria epidemic in the former Soviet Union provides important
      lessons for all diphtheria immunization programs: It is important to achieve a
      high level of childhood immunization, maintain immunity against diphtheria in
      older age groups, and use anti-epidemic measures, including immunization, to
      control epidemics in the early phase. The immunization coverage among children
      should be at least 90%. Further studies are needed to elaborate the most
      effective strategy to maintain immunity against diphtheria in adults (periodic
      booster doses, immunization of selected age groups in health care settings, use
      of Td [tetanus-diphtheria toxoids with reduced diphtheria toxoid content] vaccine
      instead of monovalent tetanus toxoid whenever tetanus toxoid is indicated [e.g.,
      in treatment of wounds or in school-based immunization programs]). Efforts should
      be undertaken to monitor diphtheria immunity in different groups by conducting
      age-specific serologic studies.

PMID- 10657232
TI  - Thioredoxin reductase.
AB  - The mammalian thioredoxin reductases (TrxRs) are a family of selenium-containing
      pyridine nucleotide-disulphide oxidoreductases with mechanistic and sequence
      identity, including a conserved -Cys-Val-Asn-Val-Gly-Cys- redox catalytic site,
      to glutathione reductases. TrxRs catalyse the NADPH-dependent reduction of the
      redox protein thioredoxin (Trx), as well as of other endogenous and exogenous
      compounds. The broad substrate specificity of mammalian TrxRs is due to a second
      redox-active site, a C-terminal -Cys-SeCys- (where SeCys is selenocysteine), that
      is not found in glutathione reductase or Escherichia coli TrxR. There are
      currently two confirmed forms of mammalian TrxRs, TrxR1 and TrxR2, and it is
      possible that other forms will be identified. The availability of Se is a key
      factor determining TrxR activity both in cell culture and in vivo, and the
      mechanism(s) for the incorporation of Se into TrxRs, as well as the regulation of
      TrxR activity, have only recently begun to be investigated. The importance of Trx
      to many aspects of cell function make it likely that TrxRs also play a role in
      protection against oxidant injury, cell growth and transformation, and the
      recycling of ascorbate from its oxidized form. Since TrxRs are able to reduce a
      number of substrates other than Trx, it is likely that additional biological
      effects will be discovered for TrxR. Furthermore, inhibiting TrxR with drugs may
      lead to new treatments for human diseases such as cancer, AIDS and autoimmune
      diseases.

PMID- 10657233
TI  - Purification, characterization and gene cloning of two alpha-L
      arabinofuranosidases from streptomyces chartreusis GS901.
AB  - alpha-L-Arabinofuranosidases I and II were purified from the culture filtrate of
      Streptomyces chartreusis GS901 and were found to have molecular masses of 80 and
      37 kDa and pI values of 6.6 and 7.5 respectively. Both enzymes demonstrated
      slight reactivity towards arabinoxylan and arabinogalactan as substrates but did
      not hydrolyse gum arabic or arabinoxylo-oligosaccharides. alpha-L
      Arabinofuranosidase I hydrolysed all of the alpha-linkage types that normally
      occur between two alpha-L-arabinofuranosyl residues, with the following
      decreasing order of reactivity being observed for the respective disaccharide
      linkages: alpha-(1-->2) alpha-(1-->3) alpha-(1-->5). This enzyme cleaved the (1-
      >3) linkages of the arabinosyl side-chains of methyl 3, 5-di-O-alpha-L
      arabinofuranosyl-alpha-L-arabinofuranoside in preference to the (1-->5) linkages.
      alpha-L-Arabinofuranosidase I hydrolysed approx. 30% of the arabinan but
      hydrolysed hardly any linear arabinan. In contrast, alpha-L-Arabinofuranosidase
      II hydrolysed only (1-->5)-arabinofuranobioside among the regioisomeric methyl
      arabinobiosides and did not hydrolyse the arabinotrioside. Linear 1-->5-linked
      arabinan was a good substrate for this enzyme, but it hydrolysed hardly any of
      the arabinan. Synergism between the two enzymes was observed in the conversion of
      arabinan and debranched arabinan into arabinose. Complete amino acid sequencing
      of alpha-L-arabinofuranosidase I indicated that the enzyme consists of a central
      catalytic domain that belongs to family 51 of the glycoside hydrolases and
      additionally that unknown functional domains exist in the N-terminal and C
      terminal regions. The amino acid sequence of alpha-L-arabinofuranosidase II
      indicated that this enzyme belongs to family 43 of the glycoside hydrolase family
      and, as this is the first report of an exo-1, 5-alpha-L-arabinofuranosidase, it
      represents a novel type of enzyme.

PMID- 10657234
TI  - Quantitative analysis of gene amplification in insecticide-resistant Culex
      mosquitoes.
AB  - The amplification of carboxylesterase structural genes followed by their
      overexpression is the most common mechanism of resistance to organophosphorus
      insecticides in Culex mosquitoes. Most resistant Culex quinquefasciatus
      mosquitoes have co-amplified estalpha2(1) and estbeta2(1) genes. Recently,
      Southern, DNA dot-blot analysis and phosphorimaging technology were used to
      quantify the est gene copy number in aphids and mosquitoes. Although more
      accurate than autoradiography, this method relies on probe hybridization, which
      can be variable. We have directly measured gene and mRNA copy number by using
      real-time quantitative PCRs in mosquitoes. The acquisition of fluorescence from
      incorporation of the double-strand-specific dye SYBR GreenI into a PCR product
      once per cycle is used to provide an absolute quantification of the initial
      template copy number. Thus it has been possible to show that estalpha2(1) and
      estbeta2(1) are co-amplified approx. 80-fold in the genome of the resistant PelRR
      strain of C. quinquefasciatus. The two genes, although co-amplified in a 1:1
      ratio, are differentially transcribed: the estbeta2(1) gene from this amplicon
      has greater transcription than estalpha2(1) in all individual mosquito larvae
      tested, with an average ratio of 10:1. Purified esterases from mosquito
      homogenates were found in a ratio of 3:1, which, combined with the quantitative
      mRNA data, suggests the operation of both transcriptional and translational
      control mechanisms to regulate the expression of the amplified genes in C.
      quinquefasciatus insecticide-resistant mosquitoes.

PMID- 10657235
TI  - Rat liver nucleotide pyrophosphatase/phosphodiesterase is an efficient adenylyl
      transferase.
AB  - Rat liver nucleotide pyrophosphatase/phosphodiesterase I (NPP/PDE) catalysed
      efficiently the transfer of adenylate from ATP to alcohols (methanol, ethanol,
      propanol, ethylene glycol, glycerol, 2, 2-dichloroethanol and glycerol 2
      phosphate), which acted as adenylate acceptors competing with water with
      different efficiencies. NPP/PDE kinetics in alcohol/water mixtures were accounted
      for by rate equations for competitive substrates, modified to include alcohol
      negative co-operativity and, depending on the nature of the alcohol, enzyme
      denaturation by high alcohol concentrations or activation by low alcohol
      concentrations. The correlation of alcohol efficiencies with alcohol acidities,
      the comparison of rat liver with snake venom NPP/PDE, and the different effects
      of ionic additives on the efficiencies of glycerol 2-phosphate and glycerol
      provided evidence for interaction of the alcohols with a base catalyst, a non
      polar and a cationic subsite in the active centre of rat liver NPP/PDE. The
      enzyme thus appears to be well suited to act as transferase, and we propose that
      NPP/PDE could be an adenylylating agent in the membrane.

PMID- 10657236
TI  - A novel principle for conferring selectivity to poly(A)-binding proteins:
      interdependence of two ATP synthase beta-subunit mRNA-binding proteins.
AB  - Based on electrophoretic mobility-shift assays and UV cross-linking experiments,
      we present evidence in the present work for the existence of two mammalian
      cytosolic proteins that selectively interact with the 3'-untranslated region of
      the mRNA coding for the catalytic beta-subunit of mitochondrial ATP synthase
      (beta-mtATPase). One of the proteins, beta-mtATPase mRNA-binding protein (BARB)1,
      is a novel poly(A)-binding protein that specifically binds the poly(A) tail of
      the beta-mtATPase transcript. BARB1 achieves this mRNA selectivity through its
      interaction with a second protein, BARB2, that binds the beta-mtATPase mRNA
      through a 22-bp element with a uridylate core, located 75 bp upstream of the
      poly(A) tail. Conversely, in the absence of BARB1, BARB2 is still able to bind
      the beta-mtATPase mRNA, but does so with lower affinity. Thus the interaction
      between BARB1 and BARB2 and beta-mtATPase mRNA involves the formation of a
      complex between the two BARB proteins. We conclude that BARB1 and BARB2
      selectively bind the 3'-untranslated region of beta-mtATPase mRNA in a novel and
      interdependent manner. The complex between these two proteins may be involved in
      post-transcriptional regulation of gene expression.

PMID- 10657237
TI  - Dye-ligand chromatographic purification of intact multisubunit membrane protein
      complexes: application to the chloroplast H+-FoF1-ATP synthase.
AB  - n-Dodecyl-beta-D-maltoside was used as a detergent to solubilize the ammonium
      sulphate precipitate of chloroplast F(O)F(1)-ATP synthase, which was purified
      further by dye-ligand chromatography. Upon reconstitution of the purified protein
      complex into phosphatidylcholine/phosphatidic acid liposomes, ATP synthesis,
      driven by an artificial DeltapH/Deltapsi, was observed. The highest activity was
      achieved with ATP synthase solubilized in n-dodecyl-beta-D-maltoside followed by
      chromatography with Red 120 dye. The optimal dye for purification with CHAPS was
      Green 5. All known subunits were present in the monodisperse proton-translocating
      ATP synthase preparation obtained from chloroplasts.

PMID- 10657238
TI  - Genomic organization, chromosomal mapping and promoter analysis of the mouse
      selenocysteine tRNA gene transcription-activating factor (mStaf) gene.
AB  - mStaf is a zinc-finger protein that activates the transcription of the mouse
      selenocysteine tRNA gene. The mStaf gene is approx. 35 kb long and split into 16
      exons. All exon-intron junction sequences conform to the GT/AG rule. The
      transcription start site is located 83 bp upstream of the initiation codon.
      Chromosomal mapping localized the gene to mouse chromosome 7, region E3-F1.
      Sequence analysis of the proximal promoter region revealed several potential
      regulatory elements; these include the recognition elements of Sp1, Nkx, CP2,
      E2A, SIF (SIS-inducible factor), TFII-I and cAMP-responsive element (CRE), but no
      TATA sequences. Transfection experiments demonstrated that the 5'-flanking region
      (-1894 to +37) of the mStaf gene drives transcription in mouse NMuMG cells and
      that a construct containing a fragment from -387 to +37 showed the highest
      transcriptional activity. Deletion and mutation experiments suggested that four
      Sp1 sites played an important role for the basal promoter activity. Furthermore,
      electrophoretic mobility-shift assays demonstrated that Sp3 but not other Sp
      (specificity protein) family members binds to three of the Sp1 sites. Our present
      study suggests that Sp3 is involved in the basal transcriptional activation of
      the mStaf gene.

PMID- 10657239
TI  - A pyruvate-proton symport and an H+-ATPase regulate the intracellular pH of
      Trypanosoma brucei at different stages of its life cycle.
AB  - Regulation of intracellular pH (pH(i)) and H(+) efflux were investigated in
      Trypanosoma brucei bloodstream and procyclic trypomastigotes using the
      fluorescent dyes 2', 7'-bis-(2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF)
      acetoxymethyl ester and free BCECF respectively. pH(i) in bloodstream and
      procyclic trypomastigotes was 7.47+/-0.06 and 7. 53+/-0.07 respectively.
      Differences in the mechanisms for the regulation of pH(i) were noted between
      bloodstream and procyclic forms. Procyclic trypomastigotes maintained their pH(i)
      at neutral over a wide range of external pH values from 6 to 8, and in the
      absence of K(+) or Na(+). The H(+)-ATPase inhibitors N, N'-dicyclohexylcarbodi
      imide (DCCD), diethylstilboestrol and N-ethylmaleimide substantially decreased
      the steady-state pH(i) and inhibited its recovery from acidification. The rate of
      H(+) efflux in these forms was determined to be 62+/-6.5 nmol/min per mg of
      protein, and was substantially decreased by H(+)-ATPase inhibitors. The data
      support the presence of an H(+)-ATPase as the major regulator of pH(i) in
      procyclic trypomastigotes. In contrast, bloodstream trypomastigotes were unable
      to maintain a neutral pH under acidic conditions, and their steady-state pH(i)
      and recovery from acidification were unaffected by H(+)-ATPase inhibitors, except
      for DCCD (100 microM). Their steady-state pH(i) was markedly decreased in glucose
      free buffer or by >/=10 mM pyruvate, whereas procyclic trypomastigotes were
      unaffected by similar treatments. The rate of H(+) efflux in bloodstream
      trypomastigotes was 534+/-38 nmol/min per mg of protein, and was decreased in the
      absence of glucose and by the addition of pyruvate or DCCD. Pyruvate efflux in
      these forms was calculated to be 499+/-34 nmol/min per mg of protein, and was
      significantly inhibited by DCCD, 4, 4'-di-isothiocyanatodihydrostilbene-2,2'
      disulphonic acid and alpha-cyanohydroxycinnamic acid. The pyruvate analogues beta
      hydroxypyruvate, 3-bromopyruvate, 3-oxoglutarate, oxaloacetate, 3-oxoisovalerate
      and 3-oxoisohexanoate significantly decreased pH(i), as well as proton and
      pyruvate efflux, whereas lactate had only a small effect, and no effect was
      observed with citrate or fumarate. The inhibition by pyruvate analogues of
      pyruvate efflux, proton efflux and acidification of pH(i) supports the hypothesis
      that pyruvate efflux is accompanied by proton efflux and that this is the major
      pH(i) control mechanism in bloodstream forms. Inhibition by H(+)-ATPase
      inhibitors of residual H(+) efflux in the absence of glucose or in the presence
      of high extracellular pyruvate indicates a minor role for H(+)-ATPase(s) in
      control of pH(i) in bloodstream forms.

PMID- 10657241
TI  - Inactivation of cysteine proteases by peptidyl epoxides: characterization of the
      alkylation sites on the enzyme and the inactivator.
AB  - Erythro peptidyl epoxides are selective inactivators of cysteine proteases. The
      alkylation site, both on the enzyme papain and on the epoxide itself, was
      characterized. The inactivation of papain with the peptidyl epoxide erythro
      benzyloxycarbonyl-Phe-Ala-epoxide was followed by total hydrolysis by acid. Mass
      spectral analysis of the hydrolysate revealed, in addition to the expected amino
      acids, a unique signal of m/z 209 (MH(+)). Its high-resolution mass spectrum and
      daughter peak analysis correspond to the product of alkylation on cysteine and
      the expected fragmentation. A similar MS pattern was obtained for a synthetic
      model compound corresponding to the expected hydrolysis product. A (13)C NMR
      analysis of papain inactivated by a specifically (13)C-labelled peptidyl epoxide
      indicated that the alkylation of the enzyme's cysteine residue occurs on the
      primary carbon of the epoxide moiety.

PMID- 10657240
TI  - Activation of exocytosis by cross-linking of the IgE receptor is dependent on ADP
      ribosylation factor 1-regulated phospholipase D in RBL-2H3 mast cells: evidence
      that the mechanism of activation is via regulation of phosphatidylinositol 4,5
      bisphosphate synthesis.
AB  - The physiological stimulus to exocytosis in mast cells is the cross-linking of
      the high-affinity IgE receptor, FcepsilonR1, with antigen. We demonstrate a novel
      function for ADP-ribosylation factor 1 (ARF1) in the regulation of antigen
      stimulated secretion using cytosol-depleted RBL-2H3 mast cells for reconstitution
      of secretory responses. When antigen is used as the stimulus, ARF1 also
      reconstitutes phospholipase D activation. Using ethanol to divert the
      phosphatidic acid (the product of phospholipase D activity) to
      phosphatidylethanol causes inhibition of ARF1-reconstituted secretion. In
      addition. ARF1 causes an increase in phosphatidylinositol 4,5-bisphosphate
      (PIP(2)) levels at the expense of phosphatidylinositol 4-monophosphate. The
      requirement for PIP(2) in exocytosis was confirmed by using phosphatidylinositol
      transfer protein (PITPalpha) to increase PIP(2) levels. Exocytosis, restored by
      either ARF1 or PITPalpha, was inhibited when PIP(2) levels were depleted by
      phospholipase Cdelta1. We conclude that the function of ARF1 and PITPalpha is to
      increase the local synthesis of PIP(2), the function of which in exocytosis is
      likely to be linked to lipid-protein interactions, whereby recruitment of key
      components of the exocytotic machinery are targeted to the appropriate membrane
      compartment.

PMID- 10657242
TI  - Mutations of the serine phosphorylated in the protein phosphatase-1-binding motif
      in the skeletal muscle glycogen-targeting subunit.
AB  - Cellular functions of protein phosphatase-1 (PP1) are determined by regulatory
      subunits that contain the consensus PP1-binding motif, RVXF. This motif was first
      identified as the site of phosphorylation by cAMP-dependent protein kinase (PKA)
      in a skeletal muscle glycogen-targeting subunit (G(M)). We reported previously
      that a recombinant fusion protein of glutathione S-transferase (GST) and the N
      terminal domain of G(M) [GST-G(M)-(1-240)] bound PP1 in a pull down assay, and
      phosphorylation by PKA prevented PP1 binding. Here we report that substitution of
      either Ala or Val for Ser-67 in the RVS(67)F motif in GST-G(M)-(1-240)
      essentially eliminated PP1 binding. This was unexpected because other glycogen
      targeting subunits have a Val residue at the position corresponding to Ser-67. In
      contrast, a mutation of Ser-67 to Thr (S67T) in GST-G(M)(1-240) gave a protein
      that bound PP1 the same as wild type and was unaffected by PKA phosphorylation.
      Full length G(M) tagged with the epitope sequence DYKDDDDK (FLAG) expressed in
      COS7 cells bound PP1 that was recovered by co-immunoprecipitation, but this
      association was prevented by treatment of the cells with forskolin. By
      comparison, PP1 binding with FLAG-G(M)(S67T) was not disrupted by forskolin
      treatment. Neither FLAG-G(M)(S67A) nor FLAG-G(M)(S67V) formed stable complexes
      with PP1 in COS7 cells. These results emphasise the unique contribution of Ser-67
      in PP1 binding to G(M). The constitutive PP1-binding activity shown by G(M)(S67T)
      opens the way for studying the role of G(M) multisite phosphorylation in hormonal
      control of glycogen metabolism.

PMID- 10657243
TI  - Human N-benzoyl-L-tyrosyl-p-aminobenzoic acid hydrolase (human meprin): genomic
      structure of the alpha and beta subunits.
AB  - N-Benzoyl-L-tyrosyl-p-aminobenzoic acid hydrolase (PPH, human meprin), a zinc
      metalloendopeptidase of the astacin family, consists of two similar subunits. As
      well as in small-intestinal epithelial cells, the enzyme is found in lamina
      propria leucocytes, human cancer cells and colorectal cancer tissue, making it a
      potential candidate for a role in tumour formation and cancer progression. To
      elucidate the mechanisms that control PPH gene expression and to gain more
      insights into the evolutionary relationship of the two subunits, we analysed the
      complete exon-intron organization and searched for putative regulatory elements
      in 3 kb of the upstream region of both genes. The human gene for the alpha
      subunit is approx. 35 kb in size and contains 14 exons. The gene for the beta
      subunit is organized in 15 exons and spans approx. 27 kb. A comparison of both
      genes indicates strong structural similarities. The exons are almost identical in
      size, except exon 13 in PPHalpha, which codes for an additional I domain not
      present in PPHbeta. The locations of the respective exon-intron junctions and the
      intron phases are almost identical; five of them contain conserved split codons.
      The main variation is in the intron lengths. It can be concluded that PPHalpha
      and PPHbeta are derived from a common ancestor. Sequence analysis of the 5'
      flanking DNA with a computer search for promoter elements and different promoter
      constructs transfected into Caco-2 cells revealed a number of potential
      regulatory motifs and suggests that each of the two genes is regulated
      independently.

PMID- 10657244
TI  - Sp1 and chromatin environment are important contributors to the formation of
      repressive chromatin structures on the transfected human adenine nucleotide
      translocase-2 promoter.
AB  - The influence of chromatin on the human adenine nucleotide translocase isoform 2
      (ANT2) promoter was investigated in transfected cells treated with the
      deacetylase inhibitors butyrate and trichostatin A (TSA). Both inhibitors
      activated the expression of reporter plasmids transfected into HeLa cells,
      indicating that the promoter was suppressed by hypoacetylated chromatin and
      activated by hyperacetylation. Inhibitor-dependent activation was traced to the
      two Sp1-activation elements within the proximal promoter region, indicating that
      the Sp1 elements are repressed by chromatin structure. Repressive chromatin
      structures were also formed on the promoter integrated into a stable chromatin
      environment, as shown by the effects of TSA and butyrate on 14 single-cell
      derived NIH3T3 clones bearing the stable integrated ANT2 promoter. Both the basal
      expression of the luciferase reporter gene and the response to TSA and butyrate
      varied widely between clones. The range of basal expression (4000-fold) was due
      partially to variation in the formation of repressive chromatin, since clones
      with low basal expression were induced by TSA, but those with high basal
      expression were less effected. These data indicate that chromatin environment
      surrounding the integrated DNA exerts a strong influence on chromatin-dependent
      repression of the ANT2 promoter, and that the ability of Sp1 to activate ANT2
      expression is compromised in the repressed state.

PMID- 10657245
TI  - Histone synthesis in Leishmania infantum is tightly linked to DNA replication by
      a translational control.
AB  - We have analysed the regulation of histone synthesis in Leishmania infantum
      following inhibition of DNA replication. Run-on experiments indicated that
      transcription rates of the genes coding for the four core histones (H2A, H2B, H3
      and H4) were not affected by the inhibition with hydroxyurea of DNA synthesis.
      However, a dramatic decrease was observed in the newly synthesized histones after
      inhibition of DNA synthesis. Furthermore, the synthesis of both the histones and
      DNA resumed in promastigotes after removal of hydroxyurea, indicating that
      inhibition was reversible. Unlike most eukaryotes, in which the replication
      dependent histone transcripts decrease upon a replication blockade, the levels of
      L. infantum histone mRNAs do not change under similar conditions. Thus the
      present data indicate that histone synthesis in Leishmania is tightly coupled to
      DNA replication by a mechanism operating at the translational level.

PMID- 10657246
TI  - Export and transport of tRNA are coupled to a multi-protein complex.
AB  - Vigilin is a ubiquitous multi heterogeneous nuclear ribonucleoprotein (hnRNP) K
      homologous (KH)-domain protein. Here we demonstrate that purified recombinant
      human vigilin binds tRNA molecules with high affinity, although with limited
      specificity. Nuclear microinjection experiments revealed for the first time that
      the immuno-affinity-purified nuclear vigilin core complex (VCC(N)) as well as
      recombinant vigilin accelerate tRNA export from the nucleus in human cells. The
      nuclear tRNA receptor exportin-t is part of the VCC(N). Elongation factor (EF)
      1alpha is enriched in VCC(N) and its cytoplasmic counterpart VCC(C), whereas EF
      1beta, EF-1gamma and EF-1delta are basically confined to the VCC(C). Our results
      suggest further that vigilin and exportin-t might interact during tRNA export,
      provide evidence that the channeled tRNA cycle is already initiated in the
      nucleus, and illustrate that intracellular tRNA trafficking is associated with
      discrete changes in the composition of cellular cytoplasmic multi-protein
      complexes containing tRNA.

PMID- 10657247
TI  - A general kinetic approach to investigation of active-site availability in
      macromolecular catalysts.
AB  - A potentially general kinetic method for the investigation of active-site
      availability in preparations of macromolecular catalysts was developed. Three
      kinetic models were considered: (a) the conventional two-step model of enzyme
      catalysis, where the preparation contains only active catalyst (E(a)) and inert
      (i.e. non-binding, non-catalytic) material (E(i)); (b) an extension of the
      conventional model (a) involving only E(a) and E(i), but with non-productive
      binding to E(a) (in addition to productive binding); (c) a model in which the
      preparation contains also binding but non-catalytic material (E(b)), predicted to
      be present in polyclonal catalytic antibody preparations. The method involves
      comparing the parameters V(max) and K(m) obtained under catalytic conditions
      where substrate concentrations greatly exceed catalyst concentration with those
      (klim/obs, the limiting value of the first-order rate constant, k(obs), at
      saturating concentrations of catalyst; and Kapp/m) for single-turnover kinetics,
      in which the reverse situation obtains. The active-site contents of systems that
      adhere to model (a) or extensions that also lack E(b), such as the non-productive
      binding model (b), may be calculated using [E(a)](T)=V(max)/klim/obs. This was
      validated by showing that, for alpha-chymotrypsin, identical values of [E(a)](T)
      were obtained by the kinetic method using Suc-Ala-Ala-Pro-Phe-4-nitroanilide as
      substrate and the well-known 'all-or-none' spectroscopic assay using N-trans
      cinnamoylimidazole as titrant. For systems that contain E(b), such as polyclonal
      catalytic antibody preparations, V(max)/klim/obs is more complex, but provides an
      upper limit to [E(a)](T). Use of the kinetic method to investigate PCA 271-22, a
      polyclonal catalytic antibody preparation obtained from the antiserum of sheep
      271 in week 22 of the immunization protocol, established that [E(a)](T) is less
      than approx. 8% of [IgG], and probably less than approx. 1% of [IgG].

PMID- 10657248
TI  - Interactions between beta-enolase and creatine kinase in the cytosol of skeletal
      muscle cells.
AB  - We studied interactions in vivo between the cytosolic muscle isoform of creatine
      kinase (M-CK) and the muscle isoform of 2-phospho-D-glycerate hydrolyase (beta
      enolase) in muscle sarcoplasm by incubating glycerol-skinned fibres with FITC
      labelled beta-enolase in the presence or absence of free CK. A small amount of
      bound beta-enolase was observed in the presence of large concentrations of CK.
      The mobility of enolase was measured in cultured satellite cells by modulated
      fringe-pattern photobleaching. FITC-labelled beta-enolase was totally mobile in
      both the presence and the absence of CK but its diffusion coefficient was
      slightly lower in the presence of CK. This suggests a weak interaction in vivo
      between enolase and CK.

PMID- 10657249
TI  - Endoproteolytic processing of integrin pro-alpha subunits involves the redundant
      function of furin and proprotein convertase (PC) 5A, but not paired basic amino
      acid converting enzyme (PACE) 4, PC5B or PC7.
AB  - Several integrin alpha subunits undergo post-translational endoproteolytic
      processing at pairs of basic amino acids that is mediated by the proprotein
      convertase furin. Here we ask whether other convertase family members can
      participate in these processing events. We therefore examined the endoproteolysis
      rate of the integrin subunits pro-alpha5, alpha6 and alphav by recombinant furin,
      proprotein convertase (PC)5A, paired basic amino acid converting enzyme (PACE)4,
      PC1, PC2 and PC7 in vitro and/or ex vivo after overexpression in LoVo cells that
      were deficient in furin activity. We found that 60-fold more PC1 than furin was
      needed to produce 50% cleavage of pro-alpha subunit substrates in vitro; the
      defective pro-alpha chain endoproteolysis in LoVo cells was not rescued by
      overexpression of PC1 or PC2. No endoproteolysis occurred with PC7 either in
      vitro or ex vivo, although similar primary sequences of the cleavage site are
      found in integrins and in proteins efficiently processed by PC7, which suggests
      that a particular conformation of the cleavage site is required for optimal
      convertase-substrate interactions. In vitro, 50% cleavage of pro-alpha subunits
      was obtained with one-third of the amount of PC5A and PACE4 than of furin. In
      LoVo cells, PC5A remained more active than furin, PACE4 activity was quite low,
      and PC5B, which differs from PC5A by a C-terminal extension containing a
      transmembrane domain, was very inefficient in processing integrin alpha-subunit
      precursors. In conclusion, these results indicate that integrin alpha-subunit
      endoproteolytic processing involves the redundant function of furin and PC5A and
      to a smaller extent PACE4, but not of PC1, PC2, PC5B or PC7.

PMID- 10657250
TI  - Purification and inhibitory profile of phospholipase A2 inhibitors from
      Australian elapid sera.
AB  - Although the resistance of snakes to their own venom is well known, until now no
      investigators have examined the serum of Australian snakes. Here we describe the
      identification and purification of a range of phospholipase A(2) (PLA(2))
      inhibitors from the serum of Australian elapids. All PLA(2) inhibitors were
      composed of two protein chains, an alpha-chain and a beta-chain. The alpha-chains
      were approx. 22.5 kDa in size and variably glycosylated, whereas the beta-chains
      were approx. 19.8 kDa in size and not glycosylated. Identification of isoforms of
      the two subunit chains was significant because three of the six sera examined
      were from single snake specimens. In addition, the glycosylation patterns of the
      alpha-chains were thoroughly investigated in these unpooled sera. The functional
      and structural properties of the purified inhibitors were studied. Uniquely, a
      snake PLA(2) inhibitor was found to inhibit human type II PLA(2) enzyme, which
      has implications for the treatment of the many diseases in which PLA(2) enzymes
      have been implicated. Further, we demonstrate that the inhibitor forms a non
      covalent association with a purified PLA(2) enzyme. Finally, the purified PLA(2)
      inhibitor was shown to protect in vivo against the lethal affects of a homologous
      PLA(2) enzyme, suggesting a role for PLA(2) inhibitors in the treatment of snake
      bite victims.

PMID- 10657251
TI  - Expression and characterization of novel thrombospondin 1 type I repeat fusion
      proteins.
AB  - Thrombospondin (TSP)1 is a trimeric extracellular matrix protein that is held
      together by two cysteine residues. It is one of five TSP proteins that have been
      described to date with almost a universal heparin binding capability (TSP5 being
      the exception). The existence of two conformationally distinct structures in the
      TSP family (trimers and pentamers) prompted us to investigate the contribution of
      TSP1 trimeric structure to its inhibitory role in angiogenesis. We expressed full
      length recombinant human TSP1, its type I repeats, and murine TSP3 in a human
      embryonic kidney cell line and evaluated their effect on human dermal
      microvascular endothelial cell (HMVEC) proliferation and sprouting into tube-like
      structures in vitro. Additionally, two chimaeric molecules were constructed so
      that the type I repeats of TSP1 were expressed as either dimers (TSP1-Ig
      chimaera) or pentamers (TSP1-TSP3 chimaera). Dimeric and pentameric type I
      constructs are novel structures. We found that, similarly to full-length TSP1,
      intact trimeric type I repeats were inhibitory to HMVEC angiogenesis in vitro.
      However, dimeric and pentameric type I repeats of TSP1 only partially inhibited
      HMVEC proliferation and sprouting in vitro. TSP3, which is lacking type I
      repeats, had no inhibitory activity, confirming that type I repeats elicit the
      anti-angiogenic activity of TSP1.

PMID- 10657252
TI  - Subcellular localization of proteasomes and their regulatory complexes in
      mammalian cells.
AB  - Proteasomes can exist in several different molecular forms in mammalian cells.
      The core 20S proteasome, containing the proteolytic sites, binds regulatory
      complexes at the ends of its cylindrical structure. Together with two 19S ATPase
      regulatory complexes it forms the 26S proteasome, which is involved in ubiquitin
      dependent proteolysis. The 20S proteasome can also bind 11S regulatory complexes
      (REG, PA28) which play a role in antigen processing, as do the three variable
      gamma-interferon-inducible catalytic beta-subunits (e.g. LMP7). In the present
      study, we have investigated the subcellular distribution of the different forms
      of proteasomes using subunit specific antibodies. Both 20S proteasomes and their
      19S regulatory complexes are found in nuclear, cytosolic and microsomal
      preparations isolated from rat liver. LMP7 was enriched approximately two-fold
      compared with core alpha-type proteasome subunits in the microsomal preparations.
      20S proteasomes were more abundant than 26S proteasomes, both in liver and
      cultured cell lines. Interestingly, some significant differences were observed in
      the distribution of different subunits of the 19S regulatory complexes. S12, and
      to a lesser extent p45, were found to be relatively enriched in nuclear fractions
      from rat liver, and immunofluorescent labelling of cultured cells with anti-p45
      antibodies showed stronger labelling in the nucleus than in the cytoplasm. The
      REG was found to be localized predominantly in the cytoplasm. Three- to six-fold
      increases in the level of REG were observed following gamma-interferon treatment
      of cultured cells but gamma-interferon had no obvious effect on its subcellular
      distribution. These results demonstrate that different regulatory complexes and
      subpopulations of proteasomes have different distributions within mammalian cells
      and, therefore, that the distribution is more complex than has been reported for
      yeast proteasomes.

PMID- 10657253
TI  - Properties of Leishmania major dUTP nucleotidohydrolase, a distinct nucleotide
      hydrolysing enzyme in kinetoplastids.
AB  - We have previously reported the presence, in the parasitic protozoan Leishmania
      major, of an enzyme involved in controlling intracellular dUTP levels. The gene
      encoding this enzyme has now been overexpressed in Escherichia coli, and the
      recombinant enzyme was purified to homogeneity. Biochemical and enzymic analyses
      of the Leishmania enzyme show that it is a novel nucleotidohydrolase highly
      specific for deoxyuridine 5'-triphosphate. The enzyme has proved to be a dimer by
      gel filtration and is able to hydrolyse both dUTP and dUDP quite efficiently,
      acting as a dUTP nucleotidohydrolase (dUTPase)-dUDP nucleotidohydrolase but has a
      limited capacity to act upon other nucleoside di- or triphosphates. The reaction
      products are dUMP and PP(i) when dUTP is the substrate and dUMP and P(i) in the
      case of dUDP. The enzyme is sensitive to inhibition by the reaction product dUMP
      but not by PP(i). dUTPase activity is highly dependent on Mg(2+) concentrations
      and markedly sensitive to the phosphatase inhibitor, NaF. In summary, Leishmania
      dUTPase appears to be markedly different to other proteins characterized
      previously that accomplish the same function.

PMID- 10657254
TI  - Cloning and characterization of mouse extracellular-signal-regulated protein
      kinase 3 as a unique gene product of 100 kDa.
AB  - MAP (mitogen-activated protein) kinases are a family of serine/threonine kinases
      that have a pivotal role in signal transduction. Here we report the cloning and
      characterization of a mouse homologue of extracellular-signal-regulated protein
      kinase (ERK)3. The mouse Erk3 cDNA encodes a predicted protein of 720 residues,
      which displays 94% identity with human ERK3. Transcription and translation of
      this cDNA in vitro generates a 100 kDa protein similar to the human gene product
      ERK3. Immunoblot analysis with an antibody raised against a unique sequence of
      ERK3 also recognizes a 100 kDa protein in mouse tissues. A single transcript of
      Erk3 was detected in every adult mouse tissue examined, with the highest
      expression being found in the brain. Interestingly, expression of Erk3 mRNA is
      acutely regulated during mouse development, with a peak of expression observed at
      embryonic day 11. The mouse Erk3 gene was mapped to a single locus on central
      mouse chromosome 9, adjacent to the dilute mutation locus and in a region
      syntenic to human chromosome 15q21. Finally, we provide several lines of evidence
      to support the existence of a unique Erk3 gene product of 100 kDa in mammalian
      cells.

PMID- 10657255
TI  - Tetratricopeptide repeat domain of Yarrowia lipolytica Pex5p is essential for
      recognition of the type 1 peroxisomal targeting signal but does not confer full
      biological activity on Pex5p.
AB  - Peroxins are proteins required for peroxisome assembly and are encoded by the PEX
      genes. The Yarrowia lipolytica pex5-1 mutant fails to import a subset of
      peroxisomal matrix proteins, including those with a type 1 peroxisomal targeting
      signal (PTS1). Pex5p family members interact with a PTS1 through their
      characteristic tetratricopeptide repeat (TPR) domain. We used binding assays in
      vitro to investigate the nature of the association of Y. lipolytica Pex5p
      (YlPex5p) with the PTS1 signal. A purified recombinant YlPex5p fusion protein
      interacted specifically, directly and autonomously with a protein terminating in
      a PTS1. Wild-type YlPex5p translated in vitro recognized functional PTS1s
      specifically. This activity is abrogated by the substitution of an aspartic
      residue for a conserved glycine residue in the TPR domain (G455D) of YlPex5p
      encoded by the pex5-1 allele. Deletion analysis demonstrated that an intact TPR
      domain of YlPex5p is necessary but not sufficient for both interaction with a
      PTS1 and functional complementation of a strain lacking YlPex5p.

PMID- 10657256
TI  - Changes in gene expression in response to polyamine depletion indicates selective
      stabilization of mRNAs.
AB  - We used differential display analysis to identify mRNAs responsive to changes in
      polyamine synthesis. As an overproducing model we used the kidneys of transgenic
      hybrid mice overexpressing ornithine decarboxylase and S-adenosylmethionine
      decarboxylase, two key enzymes in polyamine biosynthesis. To identify mRNAs that
      respond to polyamine starvation, we treated Rat-2 cells with alpha
      difluoromethylornithine, a specific inhibitor of polyamine biosynthesis. We
      isolated 41 partial cDNA clones, representing 37 differentially expressed mRNAs.
      Of these, 15 have similarity with known genes, five appear to be similar to
      reported expressed sequence tags and seventeen clones were novel sequences. Of
      the 35 mRNAs expressed differentially after alpha-difluoromethylornithine
      treatment, 26 were up-regulated. The expression of only three mRNAs was altered
      in the transgenic animals and all three were down-regulated. Determination of
      mRNA half-life of three of the mRNAs up-regulated in response to polyamine
      depletion revealed that the accumulation results from stabilization of the
      messages. Because most of the transcripts identified from Rat-2 cells suffering
      polyamine starvation were accumulated, we conclude that polyamine depletion,
      while blocking cell growth, is stabilizing mRNAs. This may be due to the lack of
      spermidine for post-translational modification of the eukaryotic initiation
      factor 5A, which plays a major role in mRNA turnover. The coupling of mRNA
      stabilization with cell-growth arrest in response to polyamine starvation
      provides cells with an economical way to resume growth after recovery from
      polyamine deficiency.

PMID- 10657257
TI  - Adult and fetal haemoglobin J-Sardegna [alpha50(CE8)His-->Asp]: functional and
      molecular modelling studies.
AB  - Haemoglobin (Hb) J-Sardegna [alpha50(CE8)His-->Asp] is a haemoglobin variant
      characteristic of subjects from the island of Sardinia. Here we report a study of
      the functional properties of both fetal and adult Hb J-Sardegna. The results
      indicate that adult Hb J-Sardegna displays an oxygen affinity that is higher than
      that of adult Hb only in the presence of 2,3-diphosphoglycerate (2,3-DPG). On the
      contrary, at 20 degrees C, the oxygen affinity of fetal Hb J-Sardegna is
      identical to that of normal fetal haemoglobin, both in the presence and in the
      absence of 2,3-DPG. A significant difference between these two systems (i.e. a
      higher oxygen affinity of fetal Hb J-Sardegna) shows up very clearly only when
      temperature is increased to 37 degrees C. Hence in fetal Hb, the main effect of
      the amino acid substitution is a decrease in the overall enthalpy change of
      oxygenation. The results outline the role of the alpha(1)-beta(1) interface in
      assessing the thermodynamics of oxygen binding. The functional properties of both
      adult and fetal Hb J-Sardegna have been interpreted at the structural level in
      light of the results obtained by a computational modelling approach performed in
      comparison with HbA and Hb Aichi, a variant characterized by a different mutation
      [alpha50(CE8)His-->Arg] at the same position.

PMID- 10657258
TI  - Crystal structures of human pancreatic alpha-amylase in complex with carbohydrate
      and proteinaceous inhibitors.
AB  - Crystal structures of human pancreatic alpha-amylase (HPA) in complex with
      naturally occurring inhibitors have been solved. The tetrasaccharide acarbose and
      a pseudo-pentasaccharide of the trestatin family produced identical continuous
      electron densities corresponding to a pentasaccharide species, spanning the -3 to
      +2 subsites of the enzyme, presumably resulting from transglycosylation. Binding
      of the acarviosine core linked to a glucose residue at subsites -1 to +2 appears
      to be a critical part of the interaction process between alpha-amylases and
      trestatin-derived inhibitors. Two crystal forms, obtained at different values of
      pH, for the complex of HPA with the protein inhibitor from Phaseolus vulgaris
      (alpha-amylase inhibitor) have been solved. The flexible loop typical of the
      mammalian alpha-amylases was shown to exist in two different conformations,
      suggesting that loop closure is pH-sensitive. Structural information is provided
      for the important inhibitor residue, Arg-74, which has not been observed
      previously in structural analyses.

PMID- 10657259
TI  - Vascular endothelial growth factor stimulates dephosphorylation of the catenins
      p120 and p100 in endothelial cells.
AB  - Vascular endothelial growth factor (VEGF) is an endothelium-specific mitogen that
      induces angiogenesis and increases vascular permeability. These processes involve
      regulation of cell-cell adhesion, but molecular mechanisms have yet to be fully
      established. p120, also termed p120(ctn), and its variant p100 are catenins which
      associate with cadherins and localize to adherens junctions. VEGF was reported to
      stimulate tyrosine phosphorylation of catenins in endothelial cells. In contrast,
      we have found that VEGF potently stimulated a rapid and dose-dependent decrease
      in serine/threonine phosphorylation of p120 and p100. VEGF acted via VEGF
      receptor 2 to achieve this effect which was independent of activation of the
      extracellular-signal-regulated kinase pathway. Histamine and activators of
      protein kinase C had a very similar effect to that of VEGF on phosphorylation of
      p120 and p100, suggesting that these diverse stimuli may converge on a common
      signalling element regulating p120/p100 serine/threonine phosphorylation. These
      data raise the possibility that the dephosphorylation of p120 and p100 triggered
      by VEGF may contribute to mechanisms regulating permeability and/or motility
      through modulation of cadherin adhesiveness.

PMID- 10657260
TI  - Mechanisms of cGMP-dependent mesangial-cell relaxation: a role for myosin light
      chain phosphatase activation.
AB  - Although the cGMP-dependent relaxation of contractile cells seems to depend on
      the ability of the cyclic nucleotide to interfere with intracellular calcium,
      this does not appear to be the only mechanism involved. The present experiments
      were designed to analyse alternative mechanisms, trying to test the hypothesis
      that cGMP could relax rat mesangial cells by activating myosin light-chain
      phosphatase (MLC-PP), with the subsequent dephosphorylation of myosin light chain
      (MLC). The effect of a cGMP analogue, dibutyryl cGMP (dbcGMP), on angiotensin II
      (AII) and PMA-induced MLC phosphorylation (MLCP) was tested, in the presence of
      calyculin A (CA), an inhibitor of MLC-PP. MLCP was measured, after cell labelling
      with (32)P, by immunoprecipitation. dbcGMP prevented the increased MLCP induced
      by AII or PMA, and this inhibition was blocked by CA. dbcGMP also increased the
      MLC dephosphorylation observed in cells incubated with AII and in which MLC
      kinase and protein kinase C activities were blocked. The AII-elicited increased
      intracellular calcium concentration was only partially inhibited by dbcGMP. These
      results suggest that the cGMP-induced mesangial-cell relaxation could be due, at
      least partially, to the stimulation of MLC-PP.

PMID- 10657261
TI  - Structure-function studies of tryptophan mutants of equinatoxin II, a sea anemone
      pore-forming protein.
AB  - Equinatoxin II (EqtII) is a eukaryotic cytolytic toxin that avidly creates pores
      in natural and model lipid membranes. It contains five tryptophan residues in
      three different regions of the molecule. In order to study its interaction with
      the lipid membranes, three tryptophan mutants, EqtII Trp(45), EqtII Trp(116/117)
      and EqtII Trp(149), were prepared in an Escherichia coli expression system [here,
      the tryptophan mutants are classified according to the position of the remaining
      tryptophan residue(s) in each mutated protein]. They all possess a single
      intrinsic fluorescent centre. All mutants were less haemolytically active than
      the wild-type, although the mechanism of erythrocyte damage was the same. EqtII
      Trp(116/117) resembles the wild-type in terms of its secondary structure content,
      as determined from Fourier-transform infrared (FTIR) spectra and its fluorescent
      properties. Tryptophans at these two positions are buried within the hydrophobic
      interior of the protein, and are transferred to the lipid phase during the
      interaction with the lipid membrane. The secondary structure of the other two
      mutants, EqtII Trp(45) and EqtII Trp(149), was altered to a certain extent. EqtII
      Trp(149) was the most dissimilar from the wild-type, displaying a higher content
      of random-coil structure. It also retained the lowest number of nitrogen-bound
      protons after exchange with (2)H(2)O, which might indicate a reduced compactness
      of the molecule. Tryptophans in EqtII Trp(45) and EqtII Trp(149) were more
      exposed to water, and also remained as such in the membrane-bound form.

PMID- 10657262
TI  - Regulation of the juvenile hormone esterase gene by a composite core promoter.
AB  - Transcription from the core promoter of the juvenile hormone esterase gene (-61
      to +28) requires the presence of both an AT-rich motif (TATA box) and an
      initiator motif for any transcription to occur, when assayed by either
      transcription in vitro with lepidopteran Sf9 nuclear extracts or by transient
      transfection assay in Sf9 cells. Additional gel-shift experiments indicated that
      at least one additional binding site is essential for transcription to occur.
      Mutational analysis in the transcription-in vitro and cell-transfection assays
      demonstrated that a 14-bp region from +13 to +27 relative to the transcription
      start site is also essential for transcription to occur. Whereas the wild-type
      core promoter is highly transcriptionally active, inclusion of additional
      flanking sequences to position -212 reduces that activity approx. 100-fold, and
      inclusion of the 5' region out to position -500 reduces transcription by 200
      fold. The pattern of dependence on both the AT-rich motif and the initiator for
      detectable transcription, and the high innate activity being repressed by 5'
      binding factors, was recapitulated in mosquito C7-10 cells. This study
      demonstrates that the cellular juvenile hormone esterase gene is organized as a
      composite core promoter, dependent on both TATA-box and initiator-binding
      factors, an organization that has been more commonly reported for viral
      promoters. This highly active composite core promoter is made more complex by the
      absolute dependence on the presence of a third site shortly downstream from the
      initiator, which is distinct from the 'downstream promoter element' described
      from some TATA-less genes. The juvenile hormone esterase gene thus appears to be
      a model of a cellular composite core promoter with a multipartite, indispensible
      requirement for not just both the TATA box and initiator, but also for at least a
      third core element as well.

PMID- 10657264
TI  - Insulin resistance and hypertension: is impaired arterial baroreceptor
      sensitivity the missing link?

PMID- 10657265
TI  - Antenatal glucocorticoid therapy: a caveat to the applause.

PMID- 10657263
TI  - Ethanol, Zn2+ and insulin interact as progression factors to enhance DNA
      synthesis synergistically in the presence of Ca2+ and other cell cycle initiators
      in fibroblasts.
AB  - In serum-starved NIH 3T3 fibroblasts, ethanol (30-80 mM) promoted the effects of
      insulin and insulin-like growth factor I (IGF-I) on DNA synthesis in a Zn(2+)
      dependent manner. Ethanol and Zn(2+) were most effective when added shortly
      before or after insulin, indicating that all these agents facilitated cell cycle
      progression. The synergistic effects of ethanol, Zn(2+) and insulin (or IGF-I) on
      DNA synthesis required 1.1-2.3 mM Ca(2+), which seemed to act as the cell cycle
      initiator. When serum-starved cells were pretreated for 2 h with other cell cycle
      initiators such as 10% (v/v) serum, 50 ng/ml platelet-derived growth factor or 2
      ng/ml fibroblast growth factor, subsequent co-treatments with 60 mM ethanol,
      Zn(2+) and insulin for an 18 h period again synergistically increased DNA
      synthesis. Of the various signal transducing events examined, ethanol stimulated
      cellular uptake of (45)Ca and it enhanced the stimulatory effects of insulin on
      p70 S6 kinase activity in a Zn(2+)-dependent manner. In contrast, ethanol
      inhibited insulin-induced activating phosphorylation of p42/p44 mitogen-activated
      protein kinases; these inhibitory ethanol effects were prevented by Zn(2+). The
      results show that, in NIH 3T3 fibroblasts, ethanol can promote cell cycle
      progression in the presence of a cell cycle initiator as well as Zn(2+) and
      insulin (or IGF-I).

PMID- 10657266
TI  - Effects of insulin on the cardiac autonomic nervous system in insulin-resistant
      states.
AB  - The effects of insulin infusion on cardiac autonomic nervous system (ANS)
      activity were investigated in healthy subjects (n=15) and in patients with
      various types of insulin-resistance, such as obese subjects (n=20) and those with
      hypertension (n=15) or type II (non-insulin-dependent) diabetes (n=22). Healthy
      subjects and patients underwent euglycaemic hyperinsulinaemic glucose clamp, and
      cardiac ANS and haemodynamic changes were investigated by continuous recording of
      heart rate variability by the Holter technique and by venous occlusion
      plethysmography respectively. At baseline, healthy subjects had the highest
      values for total spectral power and the low-frequency (LF) component, and the
      lowest value for the high-frequency (HF) component. In the pooled data (n=72),
      the fasting plasma insulin concentration was correlated with baseline total
      spectral power (r=-0.37; P<0.001) and the LF/HF ratio (r=-0. 35; P<0.003). Such
      correlations were still significant (P<0.01 for both) after adjustment for body
      fat and mean arterial blood pressure. In a multivariate linear stepwise analysis
      (n=72), a model including body fat, waist/hip ratio, fasting plasma glucose
      concentration and insulin-mediated glucose uptake explained 47% of the
      variability of the change in the LF/HF ratio, with body fat (t=-3.11; P<0.01) and
      insulin-mediated glucose uptake (t=-3.48; P<0. 008) being significantly and
      independently associated with insulin-mediated changes in the LF/HF ratio.
      Insulin infusion reduced the total spectral power and increased the LF/HF ratio
      in healthy subjects, but not in insulin-resistant patients. In conclusion, our
      study demonstrates that insulin fails to stimulate cardiac ANS activity in
      insulin-resistant patients, independently of the causes of insulin resistance.

PMID- 10657267
TI  - Antenatal corticosteroid therapy and blood pressure at 14 years of age in preterm
      children.
AB  - Antenatal corticosteroid therapy substantially improves the survival rate of
      preterm infants, with few side effects. Higher blood pressure in adulthood has
      been described in several animal species after exposure to antenatal
      corticosteroids, but there are no similar reports in humans. The objective of the
      present study was to determine the relationship between exposure to antenatal
      corticosteroid therapy and blood pressure at 14 years of age. This was a cohort
      study of 210 preterm survivors with birthweights of <1501 g born in the Royal
      Women's Hospital, Melbourne, between 1 January 1977 and 31 March 1982. Blood
      pressure was measured in 177 subjects (84.3%) at 14 years of age with a standard
      mercury sphygmomanometer. Children exposed to antenatal corticosteroids (n=89)
      had higher systolic and diastolic blood pressures than those not exposed to
      corticosteroids (n=88) [mean difference (95% confidence interval) (mmHg):
      systolic, 4.1 (0.1-8.0); diastolic, 2.8 (0.05-5.6)]. However, few had blood
      pressure in the hypertensive range. It is concluded that antenatal corticosteroid
      therapy is associated with higher systolic and diastolic blood pressures in
      adolescence, and might lead to clinical hypertension in survivors well beyond
      birth.

PMID- 10657268
TI  - Enzyme load in pancreatic acinar cells is increased in the early stages of acute
      pancreatitis induced by duct obstruction in rats.
AB  - Trypsinogen and amylase content has been analysed by flow cytometry in individual
      pancreatic cells from rats with acute pancreatitis induced by pancreatic duct
      obstruction, from the earliest stages to 48 h after obstruction. Parallel
      morphological studies of the pancreas by electron microscopy and analysis of
      various parameters for the diagnosis of pancreatitis will allow research into the
      possible relationship between intracellular enzyme load and the severity of
      pancreatitis. Progressive increases in amylase activity in ascites and plasma,
      the volume of ascites, haematocrit, vacuolization, oedema and macrophage
      infiltration were observed between 1.5 h and 12 h after duct obstruction. A
      progressive increase in enzyme content was also observed in individual acinar
      cells at this stage. Interestingly, the larger increase was for trypsinogen, so
      that the trypsinogen/amylase ratio was significantly increased in all acinar
      cells by 12 h after duct obstruction. This represents a risk factor for the
      development of pancreatitis. Sections of pancreas taken from rats that had duct
      obstruction for 48 h showed massive dilatation and disorganization of the
      endoplasmic reticulum, focal apoptosis and necrosis. These severe alterations
      would affect enzyme synthesis, as reflected by the significant decrease in the
      intracellular enzyme load observed at this stage. However, not all acinar cells
      were affected equally by the damage induced by pancreatitis: R(1) cells appeared
      to be more sensitive than R(2) cells. In conclusion, intracellular accumulation
      of digestive enzymes occurs at early stages of pancreatitis, and this effect is
      proportionally greater for trypsinogen, a finding that could explain the degree
      of severity achieved in the course of pancreatitis.

PMID- 10657269
TI  - Calcium oxalate crystallization kinetics studied by oxalate-induced turbidity in
      fresh human urine and artificial urine.
AB  - We have studied the kinetics of oxalate-induced turbidity in fresh human urine
      and artificial urine. Assays are performed in 96-well plates, which allows many
      oxalate concentrations to be studied, repeatedly, in a short time. The metastable
      limit is defined in terms of the lowest oxalate concentration that gives a rate
      of change of attenuance significantly greater than the control. Interpretation of
      rates above this limit is based on ln/ln plots of initial rates against added
      oxalate concentration. This approach has a good theoretical basis, is well
      supported by our results and gives a turbidity rate index that is related to the
      product of the growth rate constant and a factor relating to the number and
      characteristics of the heteronuclei responsible for initiation of
      crystallization. This interpretation is posited upon the assumptions that second
      order crystallization kinetics occur in unseeded urine when supersaturation
      exceeds the metastable limit and that aggregation during the initial phase of
      crystallization does not significantly contribute to changes in turbidity.
      Metastable limits of urine from healthy volunteers corresponded to a calcium
      oxalate supersaturation ratio of approx. 10. The turbidity rate index was higher
      in human urine than in artificial urine. The metastable limit, based on either
      oxalate concentration or supersaturation, for induction of calcium oxalate
      crystallization in normal human urine is higher than is likely to be found in
      normal subjects in vivo. The shape of the relationship between the metastable
      limit (based on oxalate concentration) and calcium concentration emphasizes the
      benefit of achieving a low urine calcium concentration. Comparison of the
      turbidity rate indices for human and artificial urine suggests that the role of
      nucleation promoters is more dominant than that of growth inhibitors.

PMID- 10657270
TI  - Cerebral oxygenation at high altitude and the response to carbon dioxide,
      hyperventilation and oxygen. The Birmingham Medical Research Expeditionary
      Society.
AB  - Cerebral oxygenation is likely to be of critical importance in determining
      function at high altitude. The present study has used the technique of near-IR
      spectroscopy to monitor changes in cerebral regional oxygenation in response to
      inhaled carbon dioxide, hyperventilation and supplementary oxygen on ascent to
      4680 m over 3 days. At sea level, inhaled CO(2) resulted in a significant rise in
      cerebral regional oxygenation [from mean 69.6% (S.D. 2.4% to 71. 1+/-2.3%;
      means+/-S.D.; P<0.001). At 4680 m, CO(2) increased regional cerebral oxygenation
      (63.8+/-2.5% to 65.9+/-2.2%; P<0.001) and also increased peripheral oxygen
      saturation (75.1+/-6.1% to 83. 6+/-4.0%; P<0.001). Voluntary hyperventilation
      resulted in improved peripheral oxygen saturation at 2770 m, 3650 m and 4680 m,
      whereas cerebral regional oxygenation was reduced at sea level and at 2770 m,
      unchanged at 3650 m and increased at 4680 m. Supplementary oxygen (6 1itres/min)
      at 4680 m resulted in greater improvements in peripheral oxygen saturation
      (76.7+/-7.9% to 98.1+/-1.5%; P<0.001) and cerebral regional oxygenation (64.6+/
      3.3% to 70.6+/-2.9%; P<0. 001) than were found with CO(2) or hyperventilation. We
      conclude that attempts to increase CO(2) inhalation or ventilation at high
      altitude are likely to be beneficial for cerebral oxygenation in the short term.

PMID- 10657271
TI  - Oxygenation of the brain at altitude.

PMID- 10657272
TI  - Hepatic sugar phosphate levels reflect gluconeogenesis in lung cancer:
      simultaneous turnover measurements and 31P magnetic resonance spectroscopy in
      vivo.
AB  - Stable-isotope tracers were used to assess whether levels of phosphomonoesters
      (PME) and phosphodiesters (PDE) in the livers of lung cancer patients, as
      observed by (31)P magnetic resonance (MR) spectroscopy, reflect elevated whole
      body glucose turnover and gluconeogenesis from alanine. Patients with advanced
      non-small-cell lung cancer without liver metastases (n=24; weight loss 0-24%) and
      healthy control subjects (n=13) were studied after an overnight fast. (31)P MR
      spectra of the liver in vivo were obtained, and glucose turnover and
      gluconeogenesis from alanine were determined simultaneously using primed-constant
      infusions of [6, 6-(2)H(2)]glucose and [3-(13)C]alanine. Liver PME concentrations
      were 6% higher in lung cancer patients compared with controls (not significant);
      PME levels in patients with >/=5% weight loss were significantly higher than in
      patients with <5% weight loss (P<0.01). PDE levels did not differ between the
      groups. In lung cancer patients, whole-body glucose production was 19% higher
      (not significant) and gluconeogenesis from alanine was 42% higher (P<0. 05)
      compared with healthy subjects; turnover rates in lung cancer patients with >/=5%
      weight loss were significantly elevated compared with both patients with <5%
      weight loss and healthy subjects (P<0. 05). PME levels were significantly
      correlated with glucose turnover and gluconeogenesis from alanine in lung cancer
      patients (r=0.48 and r=0.48 respectively; P<0.05). In conclusion, elevated PME
      levels in lung cancer patients appear to reflect increased glucose flux and
      gluconeogenesis from alanine. These results are consistent with the hypothesis
      that elevated PME levels are due to contributions from gluconeogenic
      intermediates.

PMID- 10657273
TI  - Abnormal magnesium status in patients with cardiovascular diseases.
AB  - To investigate magnesium status in patients with cardiovascular diseases and in
      those presenting high factors for these diseases, we measured the concentrations
      of serum total Mg, serum ionized Mg and intra-erythrocyte Mg. Mg is an important
      cofactor for many enzymes, especially those involved in phosphate transfer
      reactions. Mg deficiency has been shown to be associated with fatal
      cardiovascular diseases, as well as with risk factors for these diseases. Only
      measurement of the serum concentration of total Mg is routinely available, but
      ionized Mg is the physiologically active component. Furthermore, most of the
      body's Mg is present in the intracellular space. Subjects included patients with
      ischaemic heart disease (n=80), cardiac arrhythmia (n=60), diabetes mellitus
      (n=36), essential hypertension (n=194) and hypercholesterolaemia (n=60). The same
      measurements were made in healthy controls (30 men and 26 women; mean age 58+/-11
      years). The serum ionized Mg concentration was measured with a selective ion
      electrode. The intra-erythrocyte Mg concentration was measured by atomic
      absorption. No gender difference was found for any Mg parameter, nor was age
      related to any Mg parameter. The serum albumin concentration was positively
      correlated only with the serum total Mg concentration. Although the serum total
      Mg concentration was similar in all groups, patients with diabetes mellitus and
      arrhythmia had lower serum levels of ionized Mg. Patients with essential
      hypertension exhibited higher intra-erythrocyte Mg concentrations than the
      healthy controls. Thus the measurement of serum total Mg concentration may
      obscure the presence of extracellular Mg deficiency in patients with arrhythmia
      and diabetes mellitus. Furthermore, the intracellular accumulation of Mg does not
      support the hypothesis of Mg deficiency in patients with essential hypertension.

PMID- 10657274
TI  - Chylomicron-remnant-induced foam cell formation and cytotoxicity: a possible
      mechanism of cell death in atherosclerosis.
AB  - The effects of chylomicron remnants on cytoplasmic lipid loading and cell
      viability were assessed in cultures of human monocyte-derived macrophages and
      rabbit arterial smooth muscle cells. At a cholesterol concentration of 150
      microg/ml, chylomicron remnants induced substantial cytoplasmic lipid loading of
      macrophages, but not of smooth muscle cells, within 6 h of exposure. Chylomicron
      remnants were found to be cytotoxic to macrophages and smooth muscle cells,
      although the latter were generally more resistant. Chylomicron remnants contained
      no detectable oxysterols (>1 ng) and contained less non-esterified ('free') fatty
      acids than non-lipolysed nascent chylomicrons. Chylomicron-remnant-induced
      cytotoxicity appeared to be time- and dose-dependent. Macrophage and smooth
      muscle cell viability were inversely related to the production of superoxide free
      radicals and were significantly improved in the combined presence of superoxide
      dismutase and catalase. Collectively, our data suggest that, in macrophages, cell
      viability is compromised as a consequence of superoxide free radical production
      following uptake of chylomicron remnants. We would suggest that, in arterial
      smooth muscle cells, chylomicron-remnant-induced cell death also occurs as a
      consequence of superoxide free radical production. Our observations in the
      present study suggest that macrophage foam cells in atherosclerotic plaques might
      be derived from the cellular uptake of chylomicron remnants. Furthermore,
      arterial accumulation of chylomicron remnants might contribute to plaque
      destabilization as a consequence of cell death following superoxide free radical
      production by macrophages and smooth muscle cells.

PMID- 10657275
TI  - Noradrenaline and nomega-monomethyl-L-arginine (L-NMMA): effects on haemodynamics
      and regional blood flow in healthy and septic sheep.
AB  - This prospective, non-randomized, controlled experimental study looks at the
      effects of N(omega)-monomethyl-L-arginine (L-NMMA) on haemodynamics, oxygen
      transport and regional blood flow in healthy and septic sheep, and compares these
      effects with those of noradrenaline (NA; norepinephrine). All sheep were
      chronically instrumented. Six sheep received L-NMMA (7 mg.kg(-1).h(-1)), six
      sheep received NA, and seven sheep received the carrier alone (0.9% NaCl). The NA
      dosage was continuously and individually adjusted to achieve the same increase in
      blood pressure as observed in matched sheep of the L-NMMA group (non-septic
      phase). Treatment was discontinued after 3 h. Sepsis was initiated and maintained
      by a continuous infusion of live Pseudomonas aeruginosa. After 24 h of sepsis,
      the sheep were again challenged over a treatment period of 3 h with their
      previously assigned drug (septic phase). During the non-septic phase of the
      experiment, NA and L-NMMA both caused an increase in mean arterial pressure (MAP)
      through vasoconstriction. Ater 24 h of sepsis, all sheep developed a hyperdynamic
      circulatory state. While L-NMMA caused an increase in MAP through intense
      vasoconstriction, NA caused MAP to increase through a further elevation of the
      cardiac index. The NA dosage needed was significantly higher in the septic phase
      compared with the non-septic phase, reflecting a reduced vascular responsiveness
      to catecholamines during sepsis. Renal blood flow remained unchanged during
      either treatment in both the non-septic and the septic phases. Nevertheless,
      urine output increased during NA treatment in both the non-septic and the septic
      phases, while L-NMMA caused urine output to increase only under septic
      conditions.

PMID- 10657276
TI  - Reproducible assessment of vaginal and rectal mucosal and skin blood flow: laser
      doppler fluximetry of the pelvic microcirculation.
AB  - Pelvic venous congestion is a common cause of chronic pelvic pain in women of
      reproductive age. Although this condition represents a functional disturbance of
      the pelvic circulation which is related to the menstrual cycle, its aetiology
      remains unknown. Indirect techniques demonstrate that the vasoconstrictive reflex
      response of the microcirculation of the foot to a rise in venous pressure is
      attenuated throughout the menstrual cycle. We wished to develop a simple and non
      invasive direct measure of pelvic blood flow to aid diagnosis of this condition.
      Laser doppler blood flux measurements of the skin of the big toe and of the
      vaginal and rectal mucosa in the follicular and luteal phases of the menstrual
      cycle in 12 healthy asymptomatic premenopausal women (mean age 30 years) with
      regular cycles and in four healthy asymptomatic postmenopausal women (mean age 59
      years) were carried out both in the supine position and in response to 40 degrees
      head-up tilt. The coefficient of variation of resting vaginal flux was lower for
      measurements in postmenopausal women (0.04) and in premenopausal women in the
      follicular phase (0. 07) compared with those in the luteal phase (0.16). At rest,
      vaginal blood flow was higher than rectal and skin flux in both premenopausal and
      postmenopausal women. In the follicular phase a decrease in flow was observed in
      response to head-up tilt in the skin (-32.0%), vagina (-34.3%) and rectum (
      9.4%). In the luteal phase this reflex was attenuated at these three sites (
      8.6%, +6.7% and +7.4% respectively). There were no significant reflex changes in
      postmenopausal women. Thus laser doppler fluximetry is a reproducible method for
      comparing the flux of blood in the microcirculation of the skin and of the
      vaginal and rectal mucosa. The skin is the least sensitive site for testing
      vascular reactivity in response to cyclical changes. The vaginal and rectal
      microcirculations are the most sensitive sites for testing visceral cyclical
      reactivity, and have the advantage of direct anatomical relevance. The follicular
      phase of the menstrual cycle is associated with greatest vascular reactivity and
      is the most appropriate phase during which to test for abnormal vascular
      responses.

PMID- 10657277
TI  - Forearm plethysmography: does the right arm know what the left is doing?

PMID- 10657278
TI  - Age-related changes in microvascular permeability: a significant factor in the
      susceptibility of children to shock?
AB  - During studies of the pathogenesis of dengue shock syndrome, a condition largely
      confined to childhood and characterized by a systemic increase in vascular
      permeability, we observed that healthy controls, age-matched to children with
      dengue shock syndrome, gave high values of filtration capacity (K(f)), a factor
      describing vascular permeability. We hypothesized that K(f) might be age
      dependent. Calf K(f) was studied in 89 healthy Vietnamese subjects aged 5 to 77
      years. The K(f) was highest in the youngest children [7. 53 (1.96-15.46) K(f)U;
      median (range); where the units of K(f), K(f)U=ml.min(-1).100 ml(-1).mmHg(-1)].
      Values were 3- to 4-fold lower towards the end of the second decade [4.69 (1.91
      7.06) K(f)U]. Young mammals are known to have a larger microvascular surface area
      per unit volume of skeletal muscle than adults. During development the proportion
      of developing vessels is greater. Moreover, the novel microvessels are known to
      be more permeable to water and plasma proteins than when mature. These factors
      may explain why children more readily develop hypovolaemic shock than adults in
      dengue haemorrhagic fever and other conditions characterized by increased
      microvascular permeability.

PMID- 10657279
TI  - Steroid hormone receptor expression and action in bone.
AB  - The skeleton is a complex tissue, and hormonal control of bone remodelling is
      elaborate. The important role that steroid hormones play in bone cell development
      and in the maintenance of normal bone architecture is well established, but it is
      only relatively recently that it has become possible to describe their precise
      mechanism of action. This review focuses not only on the steroid hormones
      (oestrogens, corticosteroids, androgens and progesterone), but also on related
      hormones (vitamin D, thyroid hormone and the retinoids), all of which act via
      structurally homologous nuclear receptors that form part of the steroid/thyroid
      receptor superfamily. By examining the actions of all of these hormones in vivo
      and in vitro, this review gives a general overview of the current understanding
      of steroid hormone action in bone. In addition, a comprehensive review of steroid
      hormone receptor expression in bone cells is included. Finally, the role that
      future developments, such as steroid hormone receptor knockout mice, will play in
      our understanding of steroid hormone action in bone is considered.

PMID- 10657280
TI  - Continuous assessment of intraocular pressure - telematic transmission, even
      under flight- or space mission conditions.
AB  - Fluid shift after entering into microgravity, but also under equivalent flight
      conditions leads to enormous increase of intraocular pressure. To assess this
      precisely position - and gravity independent, handsome, automatic tonometers have
      been developed (German-Spacelab D1-Mission, German-Spacelab D2-Mission, German
      Russian-MIR-Mission) telemetric transmission of measuring results of course would
      find scientific but also functional interest. The same is true for recently
      designed automatic intraocular pressure sensors, registering intraocular pressure
      continuously, day and night. Also recently designed new automatic
      ophthalmodynamometer, allowing directly to assess the intracranial pressure, but
      also perfusion pressure within the eye also could benefit from a direct
      telemetric transmission. New technical solutions allowing for the first time even
      telematic data transmission, are reported.

PMID- 10657281
TI  - Prevalence of cervical and lumbar disc disorders in pilots of the German armed
      forces.
AB  - On-duty and off-duty, military pilots of the Bundeswehr frequently complain of
      pains in the spine curtailing performance, reducing service hours and eventually
      leading even to unfitness for military flying duties. Such disorders may be
      caused by intervertebral disc alterations. In the period comprising August 1994
      and December 1998, 286 pilots (8.1% of all A/C pilots or weapon systems officers
      of the Bundeswehr) with disc-related disorders in the areas of the cervical and
      of the lumbar spine were examined at the German Air Force Institute of Aviation
      Medicine. Helicopter pilots had significantly higher rate of intervertebral disc
      disorders compared to the group of jet pilots and transport A/C pilots (9.9% :
      6.6%). The pilots had their first disorders at an average age of 39.2 yrs (jet
      p.: 37.6 yrs, helicopter p.: 40.4 yrs, transport A/C p.: 39.2 yrs). - Depending
      on the number of hours, namely after 2680 hours of flying on average, pilots had
      discopathies, (jet p.: 1830 h, helicopter p.: 3186 h, transport A/C p.: 2670 h). 
      Finally, the total group of pilots will be compared to a non-flying control
      group (consisting of air traffic control personnel of 11 army aviation regiments.

PMID- 10657282
TI  - Blood gas-analyses in patients with cystic fibrosis to estimate hypoxemia during
      exposure to high altitudes in a hypobaric-chamber.
AB  - OBJECTIVES: Patients with cystic fibrosis (CF) represent a special risk for
      commercial airlines. Even on ground conditions the oxygen partial pressure (paO
      subset2) of these patients is partially clearly reduced. The reduced air pressure
      on board of an airplane can cause a drop of the paO subset2 to a critical point
      (below 50 mmHg) during a flight. Therefore, medical assistance or at least oxygen
      supply over a longer time period could be necessary. Aim of this study was to
      investigate reaction and clinical outcome of patients with CF during a hypobaric
      chamber-flight at altitudes of 2. 000 and 3.000 m to appraise their risk for a
      flight-trip. METHODS: 10 CF-patients (age 19-35 years, mean age 30 y) were
      investigated in a hypobaric chamber prior to an already booked flight-trip to the
      Baleares (Spain). Lung-function, oxygen saturation (SO subset2) and paO subset2
      by pressure adjusted blood gas analysis were measured on ground level, at 2.000 m
      and 3.000 m pressure-altitude. RESULTS: Forced expiratory vital capacity (FVC)
      over the entire group was 2. 9 l (range 1.4 to 4.0 l), forced expiratory 1-second
      volume (FEV subset1) 2.08 l/sec (range: 1.22 to 3.61 l/sec). Values dropped
      slightly at 3.000 m chamber altitude (VC=2.7 l, FEV subset1=1.95 l/sec). SO
      subset2 decreased from 95 % on ground to 89% at 2.000 m and 86 % at 3.000 m
      chamber altitude. paO2 decreased from 79.5 mmHg at ground level to 60 mmHg at
      2000m and 45.5 mmHg at 3.000 m. Only one patient with a paO subset2 of 52 mmHg
      didn t fall below the critical flight limit of 50 mmHg. No patient felt below a
      paO subset2 of 40 mmHg. No patient experienced dyspnea during the chamber flight.
      Two patients without subjective symptoms before the chamber flight developed mild
      ear blocks during descent presumably due to swollen polyps. Complaints improved
      quickly by applying decongestant nose-spray. - CONCLUSION: The results of the
      chamber flights indicate that chronically adapted adult lung disease patients
      without accompanying heart disease and a paO subset2 of > 40 mmHg during flight
      can anticipate a safe flight trip. These results could be confirmed by the
      consecutive flight trip to Spain.

PMID- 10657283
TI  - NOAH--A mobile emergency care system.
AB  - Experiencing communication problems in our emergency services, we developed an
      innovative communication network and system the NOAH-system (NOAH, which stands
      for Notfall -, Organisations - und Arbeitshilfe or Emergency-Organisation Active
      Aide System). In contrast with the currently established emergency services
      communication in Germany by radio wave, data is transferred from the scene in the
      form of an electronic record on a mobile computer by means of the wireless data
      communication network Modacom (Mobile Data Communication), which is provided by
      German Telekom. It is received at the dispatch-centre in mentioned format and
      transferred to the admitting hospital without any loss of data. - In a
      prospective study, the technical and conceptual suitability of this system was
      investigated. It was shown that an admitting hospital was informed more than 20
      minutes in advance about the admittance of a patient. To assure the quality of
      transferred data, information was ranked by different criteria. This further
      demonstrated that much more precise information about a patient's condition was
      already available upon admittance in the hospital.

PMID- 10657285
TI  - Emergency medicine and air rescue in India: future perspectives.
AB  - 76.7% of Indian population lives in rural areas. About 160,000 primary health
      care centres and subcentres, established all over the country, are responsible
      for the emergency care in the countryside. A centre, manned by a qualified
      doctor, a nurse/midwife and paramedics, with basic equipment and facilities has
      to manage all types of medical emergencies in a population of 3000 - 5000. A
      patient who survives this emergency care has to be transferred to higher
      secondary / tertiary centre. In metropolitan areas there are larger hospitals
      some of them having well equipped casualty departments supervised by specialists,
      but the number of patients are so large that the management of emergency goes
      often haywire. Patient transport system is very inadequate. The ambulances are
      scarce and mostly not well equipped. Air rescue which is the most desired,
      because of the distances and road conditions, is only in a rudimentary state.
      Existing infrastructure more than 400 airports, airstrips and many helipads, well
      qualified flying personnel and well maintained small and large aircrafts is
      sufficient to have a well functioning Air Rescue system. But it is prohibitively
      expensive. Most individuals are neither able to afford Air Rescue on their own
      cost nor they are insured. With the growth of economy and ever increasing
      awareness of medical facilities, the demand of better standards of emergency
      medicine is going up. In next 20 years a different scenario is expected.
      Availability of information technology, privatization of insurance system and
      medical facilities and better transport system and roads in the coming years will
      facilitate a well functioning emergency medicine and air rescue in India.

PMID- 10657284
TI  - Telemetry as a new concept in long term monitoring of SIDS-risk infant.
AB  - Sudden Infant Death Syndrome (SIDS) is the most frequent cause of infant death
      within the period of 2 to 12 months in western countries. It has been found that
      a suit similar to that worn by the astronauts during the execution of experiments
      on the Spacelab Mission D-2 is a very simple and useful means to carry the
      sensors required to monitor vital signs of babies at risk. A small baby-suit has
      been developed with the same technology used for the Spacelab Mission. The baby s
      suit is equipped with similar sensors to record thoracic and abdominal
      respiratory movements as its big -space travel brother-. This is a typical
      example of a successful technology transfer from medical aerospace activities
      into fields of daily clinical routine. In addition to the above described
      sensors, ECG-electrodes were integrated, as well as sensors to record vascular
      oxygen saturation and the corresponding pulse curve, and the baby s movements.
      All these vital signs are registered by a medical monitor, and permanently stored
      and automatically analysed online. In case of a life-threatening situation the
      system alerts simultaneously the personal at hospital and the parents at home.
      The requisite software algorithms have been developed by DLR in Cooperation with
      the pediatricians of the Pediatric Hospital in Koln-Porz, Cologne. When the
      system registers an alteration of the parameters above described -as a signal of
      a change in the baby s health condition- all vital signs are transfered in real
      time to the supervising hospital via radio data transmission devices, mobile
      phone or a fixed network phone. The parents are also alerted by the device, and
      they can carry out the necessary reanimation procedures in case of an emergency.
      Parents will be trained in such actions when newborns must to be monitored. But
      nevertheless, they are guided and tele-assisted by an expert via telephone during
      the action. A clinical field trial, that will start in December 1999 at the
      Pediatric Hospital in Koln-Porz, Cologne, will evaluate the benefits of
      teleprotection by home monitoring of SIDS risk-babies.

PMID- 10657286
TI  - Interrater agreement for high grade carotid artery stenosis measurement and
      treatment decision.
AB  - OBJECTIVES: Randomized trials in North America (NASCET, ACAS) and Europe (ECST)
      have shown a beneficial effect of endarterectomy for patients with high grade
      carotid artery stenosis. The results of the NASCET and the ECST further suggest
      that the effect of endarterectomy differed by degree of stenosis, supporting the
      importance of stenosis measurement as a factor in the decision process regarding
      surgery. We investigated the interrater agreement for carotid artery stenosis
      measurements and treatment decision in a post hoc study on patients undergoing
      carotid surgery. METHODS: In a one-year series, 45 consecutive patients underwent
      preoperative conventional cerebral angiography followed by endarterectomy. Using
      a magnifying eyepiece and applying the two different measurement criteria of the
      randomized trials, angiograms were re-evaluated post hoc by three masked raters.
      Intra-class correlation coefficients (ICCs) with one-sided 95% confidence
      intervals (CIs) were calculated for the estimation of interrater agreement for
      degree of stenosis. Conger s kappa (k) statistics were used for the estimation of
      interrater agreement for a dichotomized stenosis evaluation, i.e. therapeutic
      decision on surgery (cut-off point for symptomatic stenosis: 70%, cut-off point
      for asymptomatic stenosis: 60%). RESULTS: ICCs were.74 (CI.63) for NASCET/ACAS
      criteria and.72 (CI. 59) for ECST criteria. k values were.55 (CI.42) for
      NASCET/ACAS criteria and.57 (CI.44) for ECST criteria. Disagreement for a
      therapeutic decision was seen in 6 of 23 symptomatic patients by NASCET criteria,
      in 2 of 23 symptomatic patients by ECST and in 4 of 22 asymptomatic patients by
      ACAS criteria. CONCLUSIONS: Overall, the interrater agreement for stenosis
      measurements was good. Agreement for therapeutic decisions on carotid surgery,
      however, was less strong. These findings suggest that accurate stenosis
      measurement may not suffice for reliable treatment decisions in patients with
      high grade carotid artery stenosis.

PMID- 10657287
TI  - Is the amount of trabecular bone-loss dependent on bone mineral Density? A study
      performed by three centres of osteoporosis using high resolution peripheral
      quantitative computed tomography.
AB  - For the risk getting osteoporosis as well as for diagnosis of osteoporosis 3
      facts are highly important: bone-mass, the amount of bone-loss and bone
      structures (microarchitecture of bone). All three parameters can be validated
      today with high precision but the amount of bone-loss seems to be the most
      important one, even for the decision of either antiresorptive or bone-stimulating
      therapy. But to calculate the amount of bone-loss until now at least two
      measurements of bone mineral density (BMD) are necessary which have to be
      performed within a certain period of time, depending on the reproducibility of
      the method to be used. If on the other hand the amount of bone-loss would be
      dependent on actual base-line bone-mass the right therapy could be started
      already after only one measurement of BMD. The aim of this study was therefore to
      investigate if there is any relation between the amount of bone-loss and base
      line volumetric BMD. For this we separately measured trabecular and cortical bone
      densities of 135 women in three independent centres of osteoporosis in Zurich and
      Munich using the method of high resolution quantitative computed tomography -
      pQCT - with the Densiscan 1000, Scanco Medical, Zurich. We did this at least
      twice and then compared absolute volumetric BMD in the first step before we
      calculated trabecular and cortical bone loss per year for each woman. We could
      not only confirm again that bone loss in trabecular bone was significantly higher
      than in cortical bone and that the non-weight-bearing trabecular bone as could be
      found in the distal radius seems to be the skeletal site of maximum bone-loss,
      but moreover - and this is the more important finding - we could show that the
      amount of relative bone-loss was the higher the lower trabecular base-line
      volumetric BMD was. According to this the rate of fast-loser (more than 3.5% per
      year) increased the lower trabecular base-line volumetric BMD was. These results
      may lead to a new screening-test for the assessment of the individual risk of
      osteoporosis and for the individual risk of fast bone-loss which now can be
      evaluated with only one single measurement of BMD, to treat the so classified
      patients not only earlier but even more rational, dependent if either
      antiresorptive therapy or stimulation of bone-formation seems to be more
      important.

PMID- 10657288
TI  - Carbamazepine to treat primary nocturnal enuresis: double-blind study.
AB  - Carbamazepine is chemically related to imipramine. It can reduce prostaglandin E2
      like activity in inflammation. It caused overflow urinary incontinence, increased
      bladder capacity, sensitized renal tubules to antidiuretic hormone and leading to
      antidiuresis. This encouraged to use carbamazepine to treat primary enuresis.
      Twenty-six patients of either sex with a history of enuresis from birth were
      included in study. Their age ranged between 7 and 15 years (mean 9.3 years). They
      were assessed by history, physical examination, blood glucose, renal function
      tests, intravenous urogram and videocystourethrography. 30 days drug-free
      observation was performed to establish baseline voiding pattern. This was
      followed by two, 30 day treatment periods of either placebo or carbamazepine (200
      mg) tablets, in a randomized, double-blind cross-over design. There was one week
      washout period between medications. The patients or their parents received
      calendar sheet to record wet and dry nights and offered subjective opinions
      concerning changes in sleep patterns, occurrence of nocturia and appearance of
      side-effects. A tablet was given to each patient before retiring. Those patients
      who showed no response to carbamazepine and placebo would be treated with 100 mg
      of indomethacin suppositories. The results show that of 26 patients 20 had 7 to
      30 of 30 dry nights with carbamazepine, while 6 had 0 to 5 of 30 dry nights. The
      latter 6 patients reacted in the same manner with placebo, 4 of them showed
      better response with use of indomethacin. Six patients had 10 to 15 of 30 dry
      nights during placebo therapy and 20 had 0 to 6 of 30 dry nights. The mean number
      of dry nights was 3.92 +/- 5.22 with placebo and was 18.8 +/- 8.82 with
      carbamazepine. The difference in response to placebo and carbamazepine was
      statistically significant (p < 0.001). All the patients who responded
      sufficiently to indomethacin slept until the morning. No side effect was noticed
      with either treatment and repeated serum electrolytes and other laboratory tests
      were normal after treatment. It might be concluded that carbamazepine is useful
      for treatment of primary nocturnal enuresis.

PMID- 10657289
TI  - Adaptive recognition by nucleic acid aptamers.
AB  - Nucleic acid molecules play crucial roles in diverse biological processes
      including the storage, transport, processing, and expression of the genetic
      information. Nucleic acid aptamers are selected in vitro from libraries
      containing random sequences of up to a few hundred nucleotides. Selection is
      based on the ability to bind ligand molecules with high affinity and specificity.
      Three-dimensional structures have been determined at high resolution for a number
      of aptamers in complex with their cognate ligands. Structures of aptamer
      complexes reveal the key molecular interactions conferring specificity to the
      aptamer-ligand association, including the precise stacking of flat moieties,
      specific hydrogen bonding, and molecular shape complementarity. These basic
      principles of discriminatory molecular interactions in aptamer complexes parallel
      recognition events central to many cellular processes involving nucleic acids.

PMID- 10657290
TI  - Regulation of protein secretion through controlled aggregation in the endoplasmic
      reticulum.
AB  - A system for direct pharmacologic control of protein secretion was developed to
      allow rapid and pulsatile delivery of therapeutic proteins. A protein was
      engineered so that it accumulated as aggregates in the endoplasmic reticulum.
      Secretion was then stimulated by a synthetic small-molecule drug that induces
      protein disaggregation. Rapid and transient secretion of growth hormone and
      insulin was achieved in vitro and in vivo. A regulated pulse of insulin secretion
      resulted in a transient correction of serum glucose concentrations in a mouse
      model of hyperglycemia. This approach may make gene therapy a viable method for
      delivery of polypeptides that require rapid and regulated delivery.

PMID- 10657291
TI  - Temporal trends in deep ocean Redfield ratios.
AB  - The Redfield ratio [carbon:nitrogen:phosphorus (C:N:P)] of particle flux to the
      deep ocean is a key factor in marine biogeochemical cycling. Changes in oceanic
      carbon sequestration have been linked to variations in the Redfield ratio on
      geological time scales, but this ratio generally is assumed to be constant with
      time in the modern ocean. However, deep-water Redfield ratios in the northern
      hemisphere show evidence for temporal trends over the past five decades. The
      North Atlantic Ocean exhibits a rising N:P ratio, which may be related to
      increased deposition of atmospheric nitrous oxides from anthropogenic N
      emissions. In the North Pacific Ocean, increasing C:N and C:P ratios are
      accompanied by rising remineralization rates, which suggests intensified export
      production. Stronger export of carbon in this region may be due to enhanced
      bioavailability of aeolian iron. These findings imply that the biological part of
      the marine carbon cycle currently is not in steady state.

PMID- 10657292
TI  - Dynamics of the pacific-north american plate boundary in the western united
      states
AB  - The vertically averaged deviatoric stress tensor field within the western United
      States was determined with topographic data, geoid data, recent global
      positioning system observations, and strain rate magnitudes and styles from
      Quaternary faults. Gravitational potential energy differences control the large
      fault-normal compression on the California coast. Deformation in the Basin and
      Range is driven, in part, by gravitational potential energy differences, but
      extension directions there are modified by plate interaction stresses. The
      California shear zone has relatively low vertically averaged viscosity of about
      10(21) pascal.seconds, whereas the Basin and Range has a higher vertically
      averaged viscosity of 10(22) pascal.seconds.

PMID- 10657293
TI  - High-speed electrically actuated elastomers with strain greater than 100%
AB  - Electrical actuators were made from films of dielectric elastomers (such as
      silicones) coated on both sides with compliant electrode material. When voltage
      was applied, the resulting electrostatic forces compressed the film in thickness
      and expanded it in area, producing strains up to 30 to 40%. It is now shown that
      prestraining the film further improves the performance of these devices. Actuated
      strains up to 117% were demonstrated with silicone elastomers, and up to 215%
      with acrylic elastomers using biaxially and uniaxially prestrained films. The
      strain, pressure, and response time of silicone exceeded those of natural muscle;
      specific energy densities greatly exceeded those of other field-actuated
      materials. Because the actuation mechanism is faster than in other high-strain
      electroactive polymers, this technology may be suitable for diverse applications.

PMID- 10657294
TI  - Two-dimensional electronic excitations in self-assembled conjugated polymer
      nanocrystals
AB  - Several spectroscopic methods were applied to study the characteristic properties
      of the electronic excitations in thin films of regioregular and regiorandom
      polythiophene polymers. In the regioregular polymers, which form two-dimensional
      lamellar structures, increased interchain coupling strongly influences the
      traditional one-dimensional electronic properties of the polymer chains. The
      photogenerated charge excitations (polarons) show two-dimensional delocalization
      that results in a relatively small polaronic energy, multiple absorption bands in
      the gap where the lowest energy band becomes dominant, and associated infrared
      active vibrations with reverse absorption bands caused by electron-vibration
      interferences. The relatively weak absorption bands of the delocalized polaron in
      the visible and near-infrared spectral ranges may help to achieve laser action in
      nanocrystalline polymer devices using current injection.

PMID- 10657295
TI  - Cool glacial temperatures and changes in moisture source recorded in oman
      groundwaters
AB  - Concentrations of atmospheric noble gases (neon, argon, krypton, and xenon)
      dissolved in groundwaters from northern Oman indicate that the average ground
      temperature during the Late Pleistocene (15,000 to 24,000 years before present)
      was 6.5 degrees +/- 0.6 degrees C lower than that of today. Stable oxygen and
      hydrogen isotopic groundwater data show that the origin of atmospheric water
      vapor changed from a primarily southern, Indian Ocean source during the Late
      Pleistocene to a dominantly northern, Mediterranean source today. The reduced
      northern water vapor source is consistent with a drier Last Glacial Maximum
      through much of northern Africa and Arabia.

PMID- 10657296
TI  - Cross-species interactions between malaria parasites in humans.
AB  - The dynamics of multiple Plasmodium infections in asymptomatic children living
      under intense malaria transmission pressure provide evidence for a density
      dependent regulation that transcends species as well as genotype. This
      regulation, in combination with species- and genotype-specific immune responses,
      results in nonindependent, sequential episodes of infection with each species.

PMID- 10657297
TI  - Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma.
AB  - Hereditary paraganglioma (PGL) is characterized by the development of benign,
      vascularized tumors in the head and neck. The most common tumor site is the
      carotid body (CB), a chemoreceptive organ that senses oxygen levels in the blood.
      Analysis of families carrying the PGL1 gene, described here, revealed germ line
      mutations in the SDHD gene on chromosome 11q23. SDHD encodes a mitochondrial
      respiratory chain protein-the small subunit of cytochrome b in succinate
      ubiquinone oxidoreductase (cybS). In contrast to expectations based on the
      inheritance pattern of PGL, the SDHD gene showed no evidence of imprinting. These
      findings indicate that mitochondria play an important role in the pathogenesis of
      certain tumors and that cybS plays a role in normal CB physiology.

PMID- 10657298
TI  - Honeybee navigation: nature and calibration of the "odometer".
AB  - There are two theories about how honeybees estimate the distance to food sources.
      One theory proposes that distance flown is estimated in terms of energy
      consumption. The other suggests that the cue is visual, and is derived from the
      extent to which the image of the world has moved on the eye during the trip. Here
      the two theories are tested by observing dances of bees that have flown through a
      short, narrow tunnel to collect a food reward. The results show that the
      honeybee's "odometer" is visually driven. They also provide a calibration of the
      dance and the odometer in visual terms.

PMID- 10657299
TI  - Population dynamical consequences of climate change for a small temperate
      songbird.
AB  - Predicting the effects of an expected climatic change requires estimates and
      modeling of stochastic factors as well as density-dependent effects in the
      population dynamics. In a population of a small songbird, the dipper (Cinclus
      cinclus), environmental stochasticity and density dependence both influenced the
      population growth rate. About half of the environmental variance was explained by
      variation in mean winter temperature. Including these results in a stochastic
      model shows that an expected change in climate will strongly affect the dynamics
      of the population, leading to a nonlinear increase in the carrying capacity and
      in the expected mean population size.

PMID- 10657300
TI  - Connectivity of marine populations: open or closed?
AB  - Most marine populations are thought to be well connected via long-distance
      dispersal of larval stages. Eulerian and Lagrangian flow models, coupled with
      linear mortality estimates, were used to examine this assumption. The findings
      show that when simple advection models are used, larval exchange rates may be
      overestimated; such simplistic models fail to account for a decrease of up to
      nine orders of magnitude in larval concentrations resulting from diffusion and
      mortality. The alternative process of larval retention near local populations is
      shown to exist and may be of great importance in the maintenance of marine
      population structure and management of coastal marine resources.

PMID- 10657302
TI  - Synaptic assembly of the brain in the absence of neurotransmitter secretion.
AB  - Brain function requires precisely orchestrated connectivity between neurons.
      Establishment of these connections is believed to require signals secreted from
      outgrowing axons, followed by synapse formation between selected neurons.
      Deletion of a single protein, Munc18-1, in mice leads to a complete loss of
      neurotransmitter secretion from synaptic vesicles throughout development.
      However, this does not prevent normal brain assembly, including formation of
      layered structures, fiber pathways, and morphologically defined synapses. After
      assembly is completed, neurons undergo apoptosis, leading to widespread
      neurodegeneration. Thus, synaptic connectivity does not depend on
      neurotransmitter secretion, but its maintenance does. Neurotransmitter secretion
      probably functions to validate already established synaptic connections.

PMID- 10657301
TI  - Eta-1 (osteopontin): an early component of type-1 (cell-mediated) immunity.
AB  - Cell-mediated (type-1) immunity is necessary for immune protection against most
      intracellular pathogens and, when excessive, can mediate organ-specific
      autoimmune destruction. Mice deficient in Eta-1 (also called osteopontin) gene
      expression have severely impaired type-1 immunity to viral infection [herpes
      simplex virus-type 1 (KOS strain)] and bacterial infection (Listeria
      monocytogenes) and do not develop sarcoid-type granulomas. Interleukin-12 (IL-12)
      and interferon-gamma production is diminished, and IL-10 production is increased.
      A phosphorylation-dependent interaction between the amino-terminal portion of Eta
      1 and its integrin receptor stimulated IL-12 expression, whereas a
      phosphorylation-independent interaction with CD44 inhibited IL-10 expression.
      These findings identify Eta-1 as a key cytokine that sets the stage for efficient
      type-1 immune responses through differential regulation of macrophage IL-12 and
      IL-10 cytokine expression.

PMID- 10657303
TI  - A subclass of Ras proteins that regulate the degradation of IkappaB.
AB  - Small guanosine triphosphatases, typified by the mammalian Ras proteins, play
      major roles in the regulation of numerous cellular pathways. A subclass of
      evolutionarily conserved Ras-like proteins was identified, members of which
      differ from other Ras proteins in containing amino acids at positions 12 and 61
      that are similar to those present in the oncogenic forms of Ras. These proteins,
      kappaB-Ras1 and kappaB-Ras2, interact with the PEST domains of IkappaBalpha and
      IkappaBbeta [inhibitors of the transcription factor nuclear factor kappa B (NF
      kappaB)] and decrease their rate of degradation. In cells, kappaB-Ras proteins
      are associated only with NF-kappaB:IkappaBbeta complexes and therefore may
      provide an explanation for the slower rate of degradation of IkappaBbeta compared
      with IkappaBalpha.

PMID- 10657304
TI  - Signaling and circuitry of multiple MAPK pathways revealed by a matrix of global
      gene expression profiles.
AB  - Genome-wide transcript profiling was used to monitor signal transduction during
      yeast pheromone response. Genetic manipulations allowed analysis of changes in
      gene expression underlying pheromone signaling, cell cycle control, and polarized
      morphogenesis. A two-dimensional hierarchical clustered matrix, covering 383 of
      the most highly regulated genes, was constructed from 46 diverse experimental
      conditions. Diagnostic subsets of coexpressed genes reflected signaling activity,
      cross talk, and overlap of multiple mitogen-activated protein kinase (MAPK)
      pathways. Analysis of the profiles specified by two different MAPKs-Fus3p and
      Kss1p-revealed functional overlap of the filamentous growth and mating responses.
      Global transcript analysis reflects biological responses associated with the
      activation and perturbation of signal transduction pathways.

PMID- 10657305
TI  - Antenatal corticosteroids to prevent neonatal respiratory distress syndrome. We
      do not know whether repeated doses are better than a single dose.

PMID- 10657306
TI  - The specialist of the discipline of general practice. Semantics and politics
      mustn't impede the progress of general practice.

PMID- 10657307
TI  - On target for health? Health targets may be valuable, but context is all
      important.

PMID- 10657308
TI  - Childhood obesity: time for action, not complacency. Definitions are unclear, but
      effective interventions exist.

PMID- 10657309
TI  - Doctor as murderer. Death certification needs tightening up, but it still might
      not have stopped Shipman.

PMID- 10657310
TI  - Tighter control on GPs to follow doctor's murder convictions.

PMID- 10657311
TI  - Earlier inquiry found no evidence of criminal activity.

PMID- 10657312
TI  - Surgeon amputated healthy legs.

PMID- 10657314
TI  - In brief

PMID- 10657313
TI  - College begins inquiry into removal of wrong kidney.

PMID- 10657315
TI  - French health staff strike over budget cuts.

PMID- 10657316
TI  - Women taking combination HRT are at greater risk of breast cancer

PMID- 10657317
TI  - PAR2 antagonists-the next generation of anti- inflammatories?

PMID- 10657318
TI  - UK lifts ban on frozen eggs.

PMID- 10657319
TI  - Drug company issues warning about flu drug.

PMID- 10657321
TI  - Advertisement breached code of practice

PMID- 10657322
TI  - Tube feeding bad for patients with dementia

PMID- 10657320
TI  - New advice issued on prevention of sudden infant death.

PMID- 10657323
TI  - Gene therapy experiments put on "clinical hold".

PMID- 10657324
TI  - Talks continue on UK juniors' pay.

PMID- 10657325
TI  - Patients, but not doctors, like mediation for settling claims.

PMID- 10657326
TI  - Informed choice in genetic screening for thalassaemia during pregnancy: audit
      from a national confidential inquiry.
AB  - OBJECTIVE: National audit of informed choice in antenatal screening for
      thalassaemia. DESIGN: Audit from the UK Confidential Enquiry into Counselling for
      Genetic Disorders. SETTING: Thalassaemia module of the UK Confidential Enquiry
      into Counselling for Genetic Disorders. SUBJECTS: 138 of 156 couples who had had
      a pregnancy affected by a major beta thalassaemia from 1990 to 1994. MAIN OUTCOME
      MEASURES: How and when genetic risk was identified for each couple, and whether
      and when prenatal diagnosis was offered. RESULTS: Risk was detected by screening
      before or during the first pregnancy in 49% (68/138) of couples and by diagnosis
      of an affected child in 28% (38/138) of couples. Prenatal diagnosis was offered
      in 69% (274/400) of pregnancies, ranging from 94% (122/130) for British Cypriots
      to 54% (80/149) for British Pakistanis and from 90% in the south east of England
      to 39% in the West Midlands. Uptake of prenatal diagnosis was 80% (216/274),
      ranging from 98% (117/120) among British Cypriots in either the first or second
      trimester to 73% (35/48) among British Pakistanis in the first trimester and 39%
      (11/28) in the second trimester. A demonstrable service failure occurred in 28%
      (110/400) of pregnancies, including 110 of 126 where prenatal diagnosis was not
      offered and 48 of 93 that ended with an affected liveborn infant. CONCLUSION:
      Although antenatal screening and counselling for haemoglobin disorders are
      standard practices in the United Kingdom, they are delivered inadequately and
      inequitably. An explicit national policy is needed, aiming to make prenatal
      diagnosis in the first trimester available to all couples and including ongoing
      national audit.

PMID- 10657327
TI  - Quality of life related to fear of falling and hip fracture in older women: a
      time trade off study.
AB  - OBJECTIVE: To estimate the utility (preference for health) associated with hip
      fracture and fear of falling among older women. DESIGN: Quality of life survey
      with the time trade off technique. The technique derives an estimate of
      preference for health states by finding the point at which respondents show no
      preference between a longer but lower quality of life and a shorter time in full
      health. SETTING: A randomised trial of external hip protectors for older women at
      risk of hip fracture. PARTICIPANTS: 194 women aged >/= 75 years enrolled in the
      randomised controlled trial or who were eligible for the trial but refused
      completed a quality of life interview face to face. OUTCOME MEASURES: Respondents
      were asked to rate their own health by using the Euroqol instrument and then rate
      three health states (fear of falling, a "good" hip fracture, and a "bad" hip
      fracture) by using time trade off technique. RESULTS: On an interval scale
      between 0 (death) and 1 (full health), a "bad" hip fracture (which results in
      admission to a nursing home) was valued at 0.05; a "good" hip fracture
      (maintaining independent living in the community) 0.31, and fear of falling 0.67.
      Of women surveyed, 80% would rather be dead (utility=0) than experience the loss
      of independence and quality of life that results from a bad hip fracture and
      subsequent admission to a nursing home. The differences in mean utility weights
      between the trial groups and the refusers were not significant. A test-retest
      study on 36 women found that the results were reliable with correlation
      coefficients within classes ranging from 0.61 to 0.88. CONCLUSIONS: Among older
      women who have exceeded average life expectancy, quality of life is profoundly
      threatened by falls and hip fractures. Older women place a very high marginal
      value on their health. Any loss of ability to live independently in the community
      has a considerable detrimental effect on their quality of life.

PMID- 10657328
TI  - Detection of Helicobacter pylori in stool specimens by non-invasive antigen
      enzyme immunoassay in children: multicentre Italian study.

PMID- 10657330
TI  - On ageing: contentment

PMID- 10657329
TI  - Effect of hormone replacement therapy on the pathological stage of breast cancer:
      population based, cross sectional study.

PMID- 10657331
TI  - Religion

PMID- 10657332
TI  - Primary care based randomised, double blind trial of amoxicillin versus placebo
      for acute otitis media in children aged under 2 years.
AB  - OBJECTIVE: To determine the effect of antibiotic treatment for acute otitis media
      in children between 6 months and 2 years of age. DESIGN: Practice based, double
      blind, randomised, placebo controlled trial. SETTING: 53 general practices in the
      Netherlands. SUBJECTS: 240 children aged 6 months to 2 years with the diagnosis
      of acute otitis media. INTERVENTION: Amoxicillin 40 mg/kg/day in three doses.
      MAIN OUTCOME MEASURES: Persistent symptoms at day four and duration of fever and
      pain or crying, or both. Otoscopy at days four and 11, tympanometry at six weeks,
      and use of analgesic. RESULTS: Persistent symptoms at day four were less common
      in the amoxicillin group (risk difference 13%; 95% confidence interval 1% to
      25%). The median duration of fever was two days in the amoxicillin group versus
      three in the placebo group (P=0.004). No significant difference was observed in
      duration of pain or crying, but analgesic consumption was higher in the placebo
      group during the first 10 days (4.1 v 2.3 doses, P=0.004). In addition, no
      otoscopic differences were observed at days four and 11, and tympanometric
      findings at six weeks were similar in both groups. CONCLUSIONS: Seven to eight
      children aged 6 to 24 months with acute otitis media needed to be treated with
      antibiotics to improve symptomatic outcome at day four in one child. This modest
      effect does not justify prescription of antibiotics at the first visit, provided
      close surveillance can be guaranteed.

PMID- 10657334
TI  - Modern english abusage

PMID- 10657333
TI  - General practice--time for a new definition.

PMID- 10657336
TI  - Lesson of the week: difficulties in diagnosing acute rheumatic fever-arthritis
      may be short lived and carditis silent.

PMID- 10657335
TI  - Recent advances: recent advances in intensive care.

PMID- 10657337
TI  - For want of a bag of blood

PMID- 10657338
TI  - ABC of heart failure. Non-drug management.

PMID- 10657339
TI  - Oral examinations-equal opportunities, ethnicity, and fairness in the MRCGP.

PMID- 10657340
TI  - New doctors

PMID- 10657342
TI  - A more helpful technique

PMID- 10657341
TI  - Should journals publish systematic reviews that find no evidence to guide
      practice? Examples from injury research.

PMID- 10657343
TI  - Zanamivir, influenza, and meningococcal disease. Zanamivir may help to fight
      potential flu epidemic.

PMID- 10657344
TI  - Very old people may not use excessive proportion of hospital budgets.

PMID- 10657345
TI  - Managing patients with lung cancer. Effective communication, palliative care, and
      guidelines are needed.

PMID- 10657346
TI  - Consumer involvement in research is essential.

PMID- 10657347
TI  - Morphine induced allodynia in child with brain tumour. Signs are more likely to
      have been due to underlying medical condition.

PMID- 10657348
TI  - Competing interests and controversy about third generation oral contraceptives.
      BMJ readers should know whose words they read.

PMID- 10657350
TI  - Immunisation does not rule out tetanus.

PMID- 10657349
TI  - Italian paediatric association has launched code on competing interests.

PMID- 10657351
TI  - Not such distant mirrors. Warm tap water by the bucketful may be useful in
      flushing body cavities and wounds.

PMID- 10657352
TI  - Obituaries

PMID- 10657353
TI  - BMA criticises benefits agency work

PMID- 10657355
TI  - Childfree and sterilised: Women's decision and medical responses

PMID- 10657354
TI  - Diagnosing cancer in primary care

PMID- 10657356
TI  - Driving mum crazy

PMID- 10657357
TI  - Specialists and generalists

PMID- 10657358
TI  - MMR, autism, and adam

PMID- 10657360
TI  - Language is the culprit

PMID- 10657359
TI  - Publish and be praised

PMID- 10657361
TI  - UK screening programme for haemoglobin disorders fails to reach many couples

PMID- 10657362
TI  - Hip fractures are profound threat to quality of life

PMID- 10657363
TI  - Immunoassay is promising non-invasive test for H pylori in children

PMID- 10657364
TI  - HRT makes no difference to the types of breast tumour found

PMID- 10657365
TI  - Even infants with otitis media do not need antibiotics

PMID- 10657366
TI  - New definition of general practice is needed to underpin education

PMID- 10657367
TI  - The potential use of glutathionyl hemoglobin as a clinical marker of oxidative
      stress.

PMID- 10657368
TI  - Homogeneous amplification and variant detection by fluorescent hybridization
      probes.

PMID- 10657369
TI  - Improved stable isotope dilution-gas chromatography-mass spectrometry method for
      serum or plasma free 3-hydroxy-fatty acids and its utility for the study of
      disorders of mitochondrial fatty acid beta-oxidation.
AB  - BACKGROUND: Disorders of fatty acid oxidation (FAO) are difficult to diagnose,
      primarily because in many of the FAO disorders measurable biochemical
      intermediates accumulate in body fluids only during acute illness. Increased
      concentrations of 3-hydroxy-fatty acids (3-OH-FAs) in the blood are indicative of
      FAO disorders of the long- and short-chain 3-hydroxy-acyl-CoA dehydrogenases,
      LCHAD and SCHAD. We describe a serum/plasma assay for the measurement of 3-OH-FAs
      with carbon chain lengths from C(6) to C(16). METHODS: We used stable isotope
      dilution gas chromatography-mass spectrometry (GC-MS) with electron impact
      ionization and selected ion monitoring. Natural and isotope-labeled compounds
      were synthesized for the assay. RESULTS: The assay was linear from 0.2 to 50
      micromol/L for all six 3-OH-FAs. CVs were 5-15% at concentrations near the upper
      limits seen in healthy subjects. In 43 subjects, the medians (and ranges) in
      micromol/L were as follows: 3-OH-C(6), 0.8 (0.3-2.2); 3-OH-C(8), 0.4 (0.2-1.0); 3
      OH-C(10), 0.3 (0.2-0.6); 3-OH-C(12), 0.3 (0.2-0.6); 3-OH-C(14), 0.2 (0.0-0.4);
      and 3-OH-C(16), 0.2 (0.0-0.5). 3-OH-FAs were increased in infants receiving
      formula containing medium chain triglycerides. Two patients diagnosed with LCHAD
      deficiency showed marked increases in 3-OH-C(14) and 3-OH-C(16) concentrations.
      Two patients diagnosed with SCHAD deficiency showed increased shorter chain 3-OH
      FAs but no increases in 3-OH-C(14) to 3-OH-C(16). CONCLUSION: Measuring blood
      concentrations of the 3-OH-FAs with this assay may be a valuable tool for helping
      to rapidly identify deficiencies in LCHAD and SCHAD and may also provide useful
      information about the status of the FAO pathway.

PMID- 10657370
TI  - Use of two reporter dyes without interference in a single-tube rapid-cycle PCR:
      alpha(1)-antitrypsin genotyping by multiplex real-time fluorescence PCR with the
      LightCycler.
AB  - BACKGROUND: alpha(1)-Antitrypsin is the major plasma serine protease inhibitor.
      Its deficiency is mainly associated with the alleles PI*S and PI*Z and can lead
      to obstructive lung disease in adults and to liver cirrhosis during childhood.
      METHODS: A multiplex PCR method has been established that uses two sets of
      primers to amplify the gene regions covering the PI*S or PI*Z mutations sites.
      Mutation detection was performed on the LightCycler by melting curve analysis of
      detection probes labeled with two different fluorescent dyes, LC-Red640 and LC
      Red705. RESULTS: Unequivocal genotyping results were obtained for all
      investigated samples in an assay time of approximately 30 min. The color
      compensation procedure greatly improved the readability of the resulting
      diagnostic melting curves. CONCLUSIONS: To our knowledge, this is the first
      report of simultaneous detection of two mutations in a single tube by PCR of
      genomic DNA and the use of two different reporter dyes with the LightCycler color
      compensation feature. This approach is a rapid, convenient, and economic
      alternative to other methods described to date for the detection of alpha(1)
      antitrypsin deficiency alleles.

PMID- 10657371
TI  - Compound heterozygous hemochromatosis genotype predicts increased iron and
      erythrocyte indices in women.
AB  - BACKGROUND: Women who inherit heterozygosity for the C282Y mutation of the HFE
      gene may have increased serum iron indices and hemoglobin and are less likely to
      develop iron deficiency compared with women with the wild-type genotype. METHODS:
      We performed a cross-sectional analysis of 497 women 20-44 years of age and 830
      women >51 years of age drawn from the Busselton (Australia) population study to
      assess the effects of the HFE genotype on serum iron and hematology indices.
      RESULTS: Heterozygosity for the C282Y mutation occurred in 13.8% of the study
      population, comprising 11.8% C282Y wild-type heterozygotes and 2.0% C282Y/H63D
      compound heterozygotes. In the younger age group, C282Y wild-type women did not
      have significantly increased serum iron, transferrin saturation, or hemoglobin
      values, and were not protected from developing iron deficiency, compared with
      women of the same age with the wild-type genotype. Young compound heterozygous
      women had higher means for serum iron (25.0 vs 16.9 micromol/L; P <0.001),
      transferrin saturation (42.0% vs 25.6%; P <0. 05), hemoglobin (139.4 vs 132.3
      g/L; P <0.05), and corpuscular volume (91.1 vs 87.7 fL; P <0.05), and a higher
      median ferritin (53 vs 44 microg/L; P <0.05) compared with the wild-type
      genotype. Similar results were observed for compound heterozygotes in the >51
      years age group. CONCLUSIONS: Women with the compound heterozygous HFE genotype
      C282Y/H63D, but not the C282Y wild-type genotype, had increased values for serum
      iron and transferrin saturation, and the younger age group also had increased
      hemoglobin values. We conclude that the compound heterozygous genotype may have a
      beneficial effect in protecting women from iron deficiency.

PMID- 10657372
TI  - Saposins A, B, C, and D in plasma of patients with lysosomal storage disorders.
AB  - BACKGROUND: Early diagnosis of lysosomal storage disorders (LSDs), before the
      onset of irreversible pathology, will be critical for maximum efficacy of many
      current and proposed therapies. To search for potential markers of LSDs, we
      measured saposins A, B, C, and D in patients with these disorders. METHODS: Four
      time-delayed fluorescence immunoquantification assays were used to measure each
      of the saposins in plasma from 111 unaffected individuals and 334 LSD-affected
      individuals, representing 28 different disorders. RESULTS: Saposin A was
      increased above the 95th centile of the control population in 59% of LSD
      patients; saposins B, C, and D were increased in 25%, 61%, and 57%, respectively.
      Saposins were increased in patients from several LSD groups that in previous
      studies did not show an increase of lysosome-associated membrane protein-1 (LAMP
      1). CONCLUSION: Saposins may be useful markers for LSDs when used in conjunction
      with LAMP-1.

PMID- 10657373
TI  - Automated assay for HER-2/neu in serum.
AB  - BACKGROUND: The extracellular domain of the HER-2/neu oncogene product is
      increased in sera of some patients with epithelial cancers. Our aim was to
      develop an automated serum assay for the extracellular domain of the HER-2/neu
      protein. METHODS: We used a monoclonal antibody labeled with fluorescein for
      capture and a monoclonal Fab' fragment labeled with alkaline phosphatase for
      detection. Separation of bound and free detection conjugate was performed with
      magnetizable particles coated with monoclonal antibody to fluorescein. Alkaline
      phosphatase activity was measured kinetically at 405 or 450 nm. RESULTS: The
      assay was linear from 0.1 to 250 microg/L. No hook effect was evident up to 10
      000 microg/L. Within-run imprecision (CV) was 0.8-1.2%, and total imprecision was
      1.1-1.7%. Cross-reactivity with human epidermal growth factor receptor, which has
      extensive homology with HER-2/neu extracellular domain, was <0.6%. Human anti
      mouse antibodies, heterophilic antibodies, and rheumatoid factor did not
      interfere, nor did the therapeutic monoclonal antibody Herceptin((R)). In 51
      healthy females, the mean value was 9.3 microg/L with a range of 6.4-14.0
      microg/L. No reagent lot-to-lot variability was detected over four lots of
      reagents tested. CONCLUSION: The Bayer Immuno 1(TM) assay for HER-2/neu was
      precise and resistant to interferences, characteristics that are essential for
      longitudinal monitoring of cancer patients.

PMID- 10657374
TI  - Expression of matrix metalloproteinase-2 and -9 and their inhibitors in
      peripheral blood cells of patients with chronic hepatitis C.
AB  - BACKGROUND: To clarify whether circulating matrix metalloproteinases (MMPs) and
      their tissue inhibitors (TIMPs) can be used as serum markers of
      fibroproliferation in chronic liver diseases, we studied the expression of MMP-2
      and MMP-9 in relation to TIMP-1 and TIMP-2 in peripheral blood mononuclear
      leukocytes (MNLs) and polymorphonuclear leukocytes (PMLs), and compared this
      expression to circulating concentrations and hepatic histology in patients with
      chronic active hepatitis C (CAH). METHODS: Quantitative reverse transcription
      PCR/ELISA assays were performed for MMP and TIMP RNA, and corresponding
      circulating protein concentrations were studied by ELISA in 20 healthy controls,
      40 patients with CAH, and 20 patients with hepatitis C-induced cirrhosis (Ci).
      RESULTS: MMP-2 mRNA was found almost exclusively in the liver, MMP-9 mRNA in
      leukocytes. TIMP RNA-equivalents were decreased in MNLs of CAH patients, but
      neither MMP-9 nor TIMP RNA expression showed any correlation to the extent of
      inflammation and fibrosis. MMP-2 and TIMP-1 protein concentrations were increased
      in Ci patients and showed a wide overlap in CAH patients and healthy controls.
      MMP-9 values were lower in CAH and Ci patients than in healthy controls. TIMP-2
      values showed a wide overlap in all three groups. The MMP-2/TIMP-1 and MMP-9/TIMP
      1 ratios were lower in Ci patients than in healthy controls; the MMP-2/TIMP-2 and
      MMP-9/TIMP-2 ratios were not different. Circulating TIMP-1 and the MMP-2/TIMP-1
      ratio correlated to the inflammatory activity in liver biopsies, but only the
      circulating MMP-2/TIMP-1 ratio also correlated with the degree of fibrosis.
      CONCLUSIONS: Peripheral blood cell expression of MMP-2, MMP-9, and TIMP revealed
      no correlation with the circulating concentrations of these proteins. Only the
      circulating MMP-2/TIMP-1 ratio correlated to the histological degree of fibrosis
      in hepatitis C and should be further evaluated as a progression marker in
      patients with chronic liver disease.

PMID- 10657375
TI  - Improved prediction of decreased creatinine clearance by serum cystatin C: use in
      cancer patients before and during chemotherapy.
AB  - BACKGROUND: Serum cystatin C, a cysteine protease inhibitor, has been suggested
      as a new marker of glomerular filtration rate (GFR). This study explored the
      possibility of replacing the creatinine clearance (CrCl) estimation of GFR with
      cystatin C in early detection of renal impairment in cancer patients on
      chemotherapy. METHODS: Serum creatinine and cystatin C concentrations as well as
      24-h CrCl were determined simultaneously in 72 cancer patients. Among them, 60
      were treated with combined chemotherapy with cisplatin (CDDP). Creatinine was
      determined enzymatically with a spectrophotometric method. Serum cystatin C was
      determined by a particle-enhanced turbidimetric immunoassay. RESULTS: Cystatin C
      and creatinine correlated significantly (P = 0.001) with CrCl. The correlation
      was significantly better for cystatin C than creatinine (r = 0.84 vs 0.74; P =
      0.01). Stepwise regression analysis identified no differences for the
      correlations between cystatin C and CrCl in patients with or without metastases
      (r = 0.82 and 0.84, respectively) as well as before treatment and before the
      fourth cycle of chemotherapy (r = 0.70 and 0.75, respectively). A cystatin C
      cutoff concentration of 1.33 mg/L had 87% sensitivity and 100% specificity for
      detecting CrCl <78 mL/min. ROC analysis indicated that cystatin C was superior to
      serum creatinine for predicting CrCl <78 mL/min (P <0.04). CONCLUSIONS: Serum
      cystatin C is superior to serum creatinine for detection of decreased CrCl and
      potentially for the estimation of GFR in cancer patients independent of the
      presence of metastases or chemotherapy.

PMID- 10657376
TI  - Sensitive and specific immunodetection of human glandular kallikrein 2 in serum.
AB  - BACKGROUND: Human glandular kallikrein 2 (hK2) is expressed in the prostate and
      is present in serum from men with prostate cancer. Specific detection in serum is
      difficult mainly because of low concentrations and immunological cross-reactivity
      with prostate-specific antigen (PSA). Our objectives were to design an assay with
      improved analytical detection and functional sensitivity and nonsignificant cross
      reactivity with PSA, and to characterize different immunoreactive forms of hK2.
      METHODS: In the assay, critical PSA epitopes were blocked with four monoclonal
      antibodies (MAbs) specific for PSA. Subsequently, hK2 was captured using a MAb
      against hK2 (5% cross-reactivity with PSA), and after washing, hK2 was detected
      by a europium-labeled MAb with identical affinity for hK2 and PSA. RESULTS: The
      analytical detection limit was <10 ng/L, and functional sensitivity was 30 ng/L.
      Cross-reaction with PSA was <0.01%. Between-assay imprecision was 3.1% for 1600
      ng/L hK2 and 4. 8% for 160 ng/L hK2; corresponding values for within-assay
      precision were 1.9% and 4.5%, respectively. Complexes of hK2-alpha(1)
      antichymotrypsin (ACT) were detected in vitro with -6% bias compared with the
      free form of hK2. Gel filtration of patient samples showed that hK2 correlated in
      size mainly with free hK2; only 4-19% corresponded to hK2 possibly complexed with
      ACT or protein C inhibitor. CONCLUSIONS: Our assay had extremely low cross
      reactivity with PSA, provided a very low detection limit, and allowed close to
      equimolar detection of the free and complexed forms of hK2. Moreover, we found
      that free hK2 is the predominant immunoreactive form of hK2 in serum.

PMID- 10657377
TI  - Very small apolipoprotein A-I-containing particles from human plasma: isolation
      and quantification by high-performance size-exclusion chromatography.
AB  - BACKGROUND: Very small apolipoprotein (apo) A-I-containing lipoprotein (Sm LpA-I)
      particles with pre-beta electrophoretic mobility may play key roles as "nascent"
      and/or "senescent" HDL; however, methods for their isolation are difficult and
      often semiquantitative. METHODS: We developed a preparative method for separating
      Sm LpA-I particles from human plasma by high-performance size-exclusion
      chromatography (HP-SEC), using two gel permeation columns (Superdex 200 and
      Superdex 75) in series and measuring apo A-I content in column fractions in 30
      subjects with HDL-cholesterol (HDL-C) concentrations of 0.4-3.83 mmol/L. RESULTS:
      Three major sizes of apo A-I-containing particles were detected: an approximately
      15-nm diameter ( approximately 700 kDa) species; a 7. 5-12 nm (100-450 kDa)
      species; and a 5.8-6.3 nm species (40-60 kDa, Sm LpA-I particles), containing 0.2
      3%, 80-96%, and 2-15% of plasma total apo A-I, respectively. Two subjects with
      severe HDL deficiency had increased relative apo A-I content in Sm LpA-I: 25% and
      37%, respectively. The percentage of apo A-I in Sm LpA-I correlated positively
      with fasting plasma triglyceride concentrations (r = 0. 581; P <0.0005) and
      inversely with total apo A-I (r = -0.551; P <0. 0013) and HDL-C concentrations (r
      = -0.532; P <0.0017), although the latter two relationships were largely
      attributable to extremely hypoalphalipoproteinemic subjects. The percentage of
      apo A-I in Sm LpA-I correlated with that in pre-beta-migrating species by crossed
      immunoelectrophoresis (r = 0.98; P <0.0001; n = 24) and with that in the d >1.21
      kg/L fraction by ultracentrifugation (r = 0.86; P <0. 001; n = 20). Sm LpA-I
      particles, on average, appear to contain two apo A-I and four phospholipid
      molecules but little or no apo A-II, triglyceride, or cholesterol. CONCLUSIONS:
      We present a new HP-SEC method for size separation of native HDL particles from
      plasma, including Sm Lp A-I, which may play important roles in the metabolism of
      HDL and in its contribution(s) to protection against atherosclerosis. This method
      provides a basis for further studies of the structure and function of Sm Lp A-I.

PMID- 10657378
TI  - Flow cytometric assessment of LDL ligand function for detection of heterozygous
      familial defective apolipoprotein B-100.
AB  - BACKGROUND: Familial defective apolipoprotein (apo) B-100 (FDB) is caused by a
      mutation in the apoB gene and characterized by decreased binding of LDL to LDL
      receptors because of reduced function of the apoB-100 ligand. FDB may be
      associated with severe hypercholesterolemia and cannot always be distinguished
      from familial hypercholesterolemia phenotypically. METHODS: We used a
      fluorescence flow cytometry assay with Epstein-Barr virus-transformed lymphocytes
      to detect reduced LDL ligand function by competitive binding with fluorescently
      conjugated LDL (DiI-LDL). The assay was tested and validated using LDL from
      patients heterozygous for the Arg(3500)-Gln mutation and their first-degree
      relatives. Knowing the actual apoB genotype of patients and relatives allowed us
      to assess the ability of the assay to predict the results of DNA analysis. The
      results were compared to measurements of LDL ligand function in unrelated healthy
      control subjects to characterize functionally the Arg(3500)-Gln mutation.
      RESULTS: Fluorescence was significantly increased in cells incubated with DiI-LDL
      in competition with unlabeled LDL from FDB(R3500Q) heterozygotes compared with
      cells incubated with DiI-LDL in competition with unlabeled LDL from relatives or
      unrelated healthy control subjects. Thus, patients heterozygous for the Arg(3500)
      Gln mutation had significantly reduced LDL ligand function. The binding affinity
      of LDL from FDB(R3500Q) heterozygotes was 32% of that in non-FDB relatives and
      healthy controls. The assay had a diagnostic sensitivity of 0.95 and diagnostic
      specificity of 0.89. CONCLUSIONS: The diagnostic accuracy of the assay was too
      low to allow reliable diagnosis of individual cases of heterozygous FDB(R3500Q).
      However, fluorescence flow cytometry may supplement genetic identification of FDB
      and functionally characterize gene mutations associated with major reductions in
      LDL ligand function.

PMID- 10657379
TI  - Sodium pump isoforms in xenotransplantation: importance of biochemical
      compatibility.
AB  - BACKGROUND: Xenotransplantation of pig hearts to humans could be hampered by the
      reportedly reduced affinity for digoxin of pig heart. We examined the hypothesis
      that expression of the individual alpha-subunit isoforms of the sodium pump
      [Na(+),K(+)-ATPase (NKA)], the receptor for the plant-derived cardiac glycosides,
      may be responsible for this difference. METHODS: We used a NKA-inhibition assay
      in combination with Western analysis, immunohistochemistry, and phosphorylation
      of the NKA alpha subunit to identify the distribution and expression of alpha
      isoforms in four chambers of porcine and human hearts. RESULTS: We confirmed that
      tissue from porcine heart is less sensitive to digitalis (IC(50) = 1740 nmol/L)
      when compared with human heart (IC(50) = 840 nmol/L), whereas porcine cerebral
      cortex-mix had an affinity comparable to that of human heart (IC(50) = 910
      nmol/L). Our data show that porcine cerebral cortex-mix and human heart contain
      all three alpha isoforms, whereas porcine heart expresses only the alpha1
      isoform. CONCLUSIONS: The different expressions of sodium pump isoforms in human
      vs porcine cardiac tissues suggests that porcine hearts may not be
      pharmacologically or endocrinologically compatible when used in humans. Studies
      of both pharmacologic and endocrinologic tissue compatibility are needed prior to
      selection of organs for xenotransplantation.

PMID- 10657380
TI  - Leukocyte counts in cerebrospinal fluid with the automated hematology analyzer
      CellDyn 3500 and the urine flow cytometer UF-100.
AB  - BACKGROUND: The counting of leukocytes and erythrocytes in cerebrospinal fluid
      (CSF) is still performed microscopically, e.g., using a chamber in most
      laboratories. This requires sufficient practical experience, is time-consuming,
      and may constitute a problem in emergency diagnostics. Specific automated systems
      for CSF cell counting are not available at present. METHODS: We tested the
      hematology analyzer CellDyn 3500 (CD) and the urine flow cytometer UF-100 (UF),
      which are not designed for CSF analysis. We studied >104 samples with both
      analyzers, and the counts obtained were compared with the reference method (Fuchs
      Rosenthal chamber). RESULTS: Good linearity in the medically relevant range of 15
      x 10(6) to 1000 x 10(6) leukocytes/L and a high degree of within-run accuracy
      were seen for both analyzers. Cell counting on the UF was excellent, especially
      when low cell counts were encountered (CV, 4. 9% compared with 28% observed for
      the CD). Method comparison showed that identical results could be detected for a
      majority of the count pairs. For a few samples, there was a discrepancy between
      the results from the analyzers and the counting chamber. In most cases, these
      were CSF samples containing a high proportion of lymphocytes. For these samples,
      the CD result led to a false-positive high leukocyte count, and on the UF these
      cells were not allocated to the leukocyte population, thus leading to false
      negative counts. CONCLUSIONS: Both analyzers should not be used for CSF cell
      counting in all cases at present. However, once the technical and software
      problems have been solved, routine use of the two analyzers for CSF analysis
      should be seriously contemplated.

PMID- 10657381
TI  - Strontium as a marker for intestinal calcium absorption: the stimulatory effect
      of calcitriol.
AB  - BACKGROUND: Intestinal strontium absorption is becoming accepted as a clinical
      and diagnostic tool for assessing intestinal calcium absorption in humans.
      However, little is known about whether intestinal strontium absorption, like that
      of calcium, is stimulated by calcitriol in healthy humans. METHODS: The effect of
      calcitriol on intestinal strontium absorption was measured in eight healthy men,
      ages 20-60 years. Before administration of calcitriol, two tests were performed
      with an interval of 10 days for calculating the within-subject variation (SE(R)).
      Before the third test, 0.5 microg of calcitriol was given twice daily for 3 days.
      In each test, the fractional strontium absorption (Fc(240)) and the area under
      the concentration-time curve (AUC(0-240)) 4 h after an oral strontium load of 2.5
      mmol were calculated. RESULTS: The within-subject SE(R) of Fc(240) and AUC(0-240)
      was 1.7 +/- 0.7 and 0.83 +/- 0.1, respectively. The stimulatory effect of
      calcitriol on Fc(240) and AUC(0-240) was 35% (21.8 +/- 2.0 to 28.8 +/- 2.4; P =
      0.003) and 61% (8.97 +/- 0.97 to 14.4 +/- 1.3 mmol. L(-1). min; P = 0.001),
      respectively. CONCLUSIONS: Although the reproducibility of AUC(0-240) and its
      sensitivity to calcitriol were better than those of Fc(240), the Fc(240) of
      strontium is preferred for a clinical test because of its simplicity, requiring
      only two instead of five blood samples.

PMID- 10657382
TI  - Evaluation of a bead-based enzyme immunoassay for the rapid detection of
      osteocalcin in human serum.
AB  - BACKGROUND: Circulating osteocalcin is a well-known marker for bone formation,
      but none of the commercial kits currently available can be used in automated
      systems. Here we present the first semiautomated assay for human serum
      osteocalcin. METHODS: Polystyrene beads were coated with antibodies against the
      COOH terminus of osteocalcin and used in the COBAS((R)) EIA System. Osteocalcin
      was detected with peroxidase-conjugated antibodies against the osteocalcin NH(2)
      terminus. RESULTS: The time required to analyze an unknown sample was 60 min,
      with a lower detection limit of 4.5 microg/L and a linear dose-response curve
      between 4.5 and 100 microg/L. The intraassay imprecision (CV) was 5-8% (n = 21);
      the interassay variation was 6-9% (n = 14). In samples from human volunteers and
      patients, data generated with the newly developed assay were comparable to those
      obtained with standard microtiter plate-based assays. CONCLUSIONS: The coated
      beads assay may be implemented on fully automated analyzers, which not only may
      further reduce imprecision but may also substantially increase the applicability
      of osteocalcin as a marker for bone metabolism in the routine clinical setting.

PMID- 10657383
TI  - Agreement among four homocysteine assays and results in patients with coronary
      atherosclerosis and controls.
AB  - BACKGROUND: Hyperhomocysteinemia has been associated with coronary
      atherosclerosis in many, but not all, prospective and retrospective studies. Some
      on these inconsistencies may be attributed to methodological variabilities.
      METHODS: In the present study, three newly commercially available assays and one
      in-house HPLC assay for total homocysteine (tHcy) were utilized in 99 subjects
      with angiographically documented atherosclerosis and in 91 community controls
      matched by age, gender, and smoking history. The in-house assay, a modified
      Fortin and Genest HPLC method, was compared with the Bio-Rad HPLC assay, the
      Abbott IMx((R)) fluorescence polarization immunoassay, and a Bio-Rad enzyme
      linked immunoassay (EIA) microtiter method. RESULTS: Correlation coefficient
      values between the in-house HPLC assay and the Bio-Rad HPLC, the Abbott IMx, and
      the Bio-Rad EIA assays were 0.95, 0.96 and 0.90, respectively. Although tHcy
      concentrations were higher in cases compared with controls by all four methods,
      the difference reached statistical significance only with the in-house HPLC
      procedure (median, 13.5 +/- 6.7 micromol/L in cases vs 10.9 +/- 4.8 micromol/L in
      controls; P <0. 01, adjusting for covariates), where it was an independent
      predictor of case or control status, along with hypertension, total cholesterol,
      and triglycerides. The tHcy distributions in cases and controls demonstrated
      significant overlap. The number of atherosclerotic major coronary vessels was
      associated with significantly higher tHcy (P <0.01 for trend) in all four
      methods. CONCLUSIONS: The three commercial assays for tHcy differed in analytical
      and clinical performance. Analytically, the Abbott IMx method showed the best
      comparability with the in-house assay, but clinically, the three commercial
      methods were similar and did not distinguish cases from controls.

PMID- 10657384
TI  - Measurement of plasma and intracellular S-adenosylmethionine and S
      adenosylhomocysteine utilizing coulometric electrochemical detection: alterations
      with plasma homocysteine and pyridoxal 5'-phosphate concentrations.
AB  - BACKGROUND: The relative changes in plasma and intracellular concentrations of S
      adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) may be important
      predictors of cellular methylation potential and metabolic alterations associated
      with specific genetic polymorphisms and/or nutritional deficiencies. Because
      these metabolites are present in nanomolar concentrations in plasma, methods of
      detection generally require time-consuming precolumn processing or metabolite
      derivatization. METHODS: We used HPLC with coulometric electrochemical detection
      for the simultaneous measurement of SAM and SAH in 200 microL of plasma, 10(6)
      lymphocytes, or 10 mg of tissue. Filtered trichloroacetic acid extracts were
      injected directly into the HPLC system without additional processing and were
      eluted isocratically. RESULTS: The limits of detection were 200 fmol/L for SAM
      and 40 fmol/L SAH. In plasma extracts, the interassay CV was 3.4-5.5% and the
      intraassay CV was 2.8-5.6%. The analytical recoveries were 96.8% and 97.3% for
      SAM and SAH, respectively. In a cohort of healthy adult women with mean total
      homocysteine concentrations of 7.3 micromol/L, the mean plasma value was 156
      nmol/L for SAM and 20 nmol/L for SAH. In women with increased homocysteine
      concentrations (mean, 12.1 micromol/L), plasma SAH, but not SAM, was increased (P
      <0.001), and plasma pyridoxal 5'-phosphate concentrations were reduced (P
      <0.001). Plasma SAM/SAH ratios were inversely correlated with homocysteine
      concentrations (r = 0.73; P <0.01), and the SAM/SAH ratio in plasma was directly
      correlated with the intracellular SAM/SAH ratio in lymphocytes (r = 0.70; P
      <0.01). CONCLUSIONS: Increased homocysteine in serum is associated with an
      increase in SAH and a decrease in the SAM/SAH ratio that could negatively affect
      cellular methylation potential. Accurate and sensitive detection of these
      essential metabolites in plasma and in specific tissues should provide new
      insights into the regulation of one-carbon metabolism under different nutritional
      and pathologic conditions.

PMID- 10657385
TI  - False positivity in a cyto-ELISA for anti-endothelial cell antibodies caused by
      heterophile antibodies to bovine serum proteins.
AB  - BACKGROUND: ELISAs with fixed endothelial cells or cell lines are widely used
      screening tests for anti-endothelial cell antibodies (AECAs), but spurious
      increases occur. We examined interferences by heteroantibodies and means to
      eliminate them. METHODS: AECAs were measured by ELISA on fixed layers of the
      human endothelial cell line, EA.hy 926, in a panel of 60 patient serum samples
      diluted in bovine serum albumin. Heteroantibodies against fetal calf serum (FCS)
      proteins were demonstrated and characterized in an ELISA-the interference assay
      that used FCS-coated plates and Tween 20-containing buffer as blocking agent and
      sample diluent, as well as by immunoblotting. RESULTS: In 12 of 60 patient serum
      samples, spurious increases of AECA titers were produced by endogenous antibodies
      reacting with FCS proteins from culture medium that were coated onto the solid
      phase at the time of cell plating. This mechanism of interference was supported
      experimentally by exposing extracellular matrix, varying cell density, and
      incubating wells with FCS alone. The heterophile antibodies were mainly IgG and
      IgA, and in inhibition experiments, they recognized serum proteins from goat,
      sheep, and horse. Washing cells free of FCS before plating, or adding FCS (100
      mL/L) to the patient sample diluent eliminated spurious signals from all 30
      tested sera, but the latter method had practical advantages. CONCLUSIONS:
      Antibodies against animal serum proteins are a frequent cause of erroneous
      results in cyto-ELISAs. The interference can be eliminated by simple antibody
      absorption in FCS-containing dilution buffer.

PMID- 10657386
TI  - Plasma troponin T and troponin I after minimally invasive coronary bypass
      surgery.

PMID- 10657387
TI  - Quantification of glycohemoglobin in blood by mass spectrometry applying multiple
      reaction monitoring.

PMID- 10657388
TI  - Evaluation of seven commercial ELISA kits compared with the C1q solid-phase
      binding RIA for detection of circulating immune complexes.

PMID- 10657389
TI  - Comparison of diagnostic performance of three new fast D-dimer assays in the
      exclusion of deep vein thrombosis.

PMID- 10657390
TI  - Point-of-care testing of triglycerides: evaluation of the Accutrend triglycerides
      system.

PMID- 10657391
TI  - Comparison of three methods for measuring LDL resistance against copper-induced
      oxidation.

PMID- 10657392
TI  - Simple sampling method and routine gas chromatography-mass spectrometry analysis
      in (13)C breath tests.

PMID- 10657393
TI  - Effect of oral creatine supplementation on random urine creatinine, pH, and
      specific gravity measurements.

PMID- 10657394
TI  - Artifactually low serum urea caused by antibodies to bacteria urease.

PMID- 10657395
TI  - Urinary glycosaminoglycan excretion in newly diagnosed essential hypertensive
      patients.

PMID- 10657396
TI  - Prenatal diagnosis of myotonic dystrophy using fetal DNA obtained from maternal
      plasma.

PMID- 10657397
TI  - Changes in academic productivity: implications for clinical laboratory research
      and development.

PMID- 10657398
TI  - PCR conditions for HFE C282Y: lack of effect of 5569G/A polymorphism with 55
      degrees C annealing.

PMID- 10657399
TI  - Hemolyzed specimens: a reason for rejection or a clinical challenge?

PMID- 10657400
TI  - Effect of rheumatoid factor on cardiac troponin I measurement using two
      commercial measurement systems.

PMID- 10657401
TI  - Correction for Stott et al.: simple multiplex PCR for the simultaneous detection
      of the C282Y and H63D hemochromatosis (HFE) gene mutations.

PMID- 10657402
TI  - Common DPYD mutation associated with 5-fluorouracil toxicity detected by PCR
      mediated site-directed mutagenesis.

PMID- 10657405
TI  - Placebo treatment in acute stroke trials : benefit or harm to patients?
AB  - BACKGROUND AND PURPOSE: Some stroke patients and their families express
      reservations about participating in trials of experimental therapies for acute
      stroke. Among many reasons given for this is the concern that by participating,
      patients may be deprived of some component of routine care. We sought to
      determine the effect on outcome of participating in a clinical stroke trial while
      being treated with placebo. METHODS: Prospective clinical information was
      collected for all patients admitted with acute ischemic stroke between July 1995
      and July 1996. A subgroup of these patients was enrolled in a clinical trial of
      acute stroke therapy and had been randomly assigned to the placebo group. The
      control group was selected from concurrent stroke patients who were not enrolled
      in any clinical trial. The National Institutes of Health Stroke Scale (NIHSS) was
      performed on admission and on day 7 after admission. The Glasgow Outcome Scale
      (GOS) was also performed at discharge. Stroke severity was classified as "severe"
      if NIHSS was >/=9 or GOS >/=3. Group comparisons were performed with chi(2)
      tests. RESULTS: One hundred twenty-six patients were evaluated. Forty-seven were
      placebo patients, and 79 were selected as control subjects. There were no
      significant differences between the groups with respect to age, sex, hematocrit,
      blood glucose level, history of hypertension, diabetes, smoking, or initial
      NIHSS. In addition, there was no difference between groups in terms of the
      frequency of baseline stroke subtype. Among our controls, 55 patients (70%) were
      on antithrombotic treatment during hospitalization, whereas none of our placebo
      patients were on any antithrombotic treatment. For the GOS at follow-up, a good
      outcome was attained by 76% of the control subjects and 72% of placebo patients
      (not significant). A severe NIHSS (>9) at follow-up, however, was documented in
      15% of controls and 59% of placebo patients (P<0.001). There was a trend toward a
      higher ("worse") mean follow-up NIHSS among placebo patients (mean NIHSS, 11)
      versus controls (mean NIHSS, 6) (P=0.09). CONCLUSIONS: Patients enrolled in the
      placebo arms of some acute clinical stroke trials have similar functional
      outcomes but more severe neurological deficits at 1 week than did a control
      group. These findings might be partially explained by the withholding of
      antithrombotic medication and the exclusion criteria inherent in most trials.
      Vigilance is required to ensure that all patients participating in stroke studies
      be guaranteed optimal known medical therapy.

PMID- 10657404
TI  - Selfotel in acute ischemic stroke : possible neurotoxic effects of an NMDA
      antagonist.
AB  - BACKGROUND AND PURPOSE: Based on neuroprotective efficacy in animal models, we
      evaluated the N-methyl D-aspartate antagonist Selfotel in patients with ischemic
      stroke, after doses up to 1.5 mg/kg were shown to be safe in phase 1 and phase 2a
      studies. METHODS: Two pivotal phase 3 ischemic stroke trials tested the
      hypothesis, by double-blind, randomized, placebo-controlled parallel design, that
      a single intravenous 1.5 mg/kg dose of Selfotel, administered within 6 hours of
      stroke onset, would improve functional outcome at 90 days, defined as the
      proportion of patients achieving a Barthel Index score of >/=60. The trials were
      performed in patients aged 40 to 85 years with acute ischemic hemispheric stroke
      and a motor deficit. RESULTS: The 2 trials were suspended on advice of the
      independent Data Safety Monitoring Board because of an imbalance in mortality
      after a total enrollment of 567 patients. The groups were well matched for
      initial stroke severity and time from stroke onset to therapy. There was no
      difference in the 90-day mortality rate, with 62 deaths (22%) in the Selfotel
      group and 49 (17%) in the placebo-treated group (RR=1.3; 95% CI 0.92 to 1.83;
      P=0.15). However, early mortality was higher in the Selfotel-treated patients
      (day 30: 54 of 280 versus 37 of 286; P=0.05). In patients with severe stroke,
      mortality imbalance was significant throughout the trial (P=0.05). CONCLUSIONS:
      Selfotel was not an effective treatment for acute ischemic stroke. Furthermore, a
      trend toward increased mortality, particularly within the first 30 days and in
      patients with severe stroke, suggests that the drug might have a neurotoxic
      effect in brain ischemia.

PMID- 10657406
TI  - Phase II studies of the glycine antagonist GV150526 in acute stroke : the North
      American experience. The North American Glycine Antagonist in Neuroprotection
      (GAIN) Investigators.
AB  - BACKGROUND AND PURPOSE: GV150526, a selective glycine site antagonist, reduces
      infarct volume in rats with focal cerebral ischemia. Safety and efficacy in
      humans with acute stroke are being investigated. We sought to further explore the
      safety, pharmacokinetics, and preliminary outcome of GV150526 treatment in
      patients with a clinical diagnosis of acute stroke. METHODS: Two trials were
      conducted in North America. The North American Glycine Antagonist in
      Neuroprotection trial (GAIN 1) (GLYA2001; United States only) was designed as a
      sequential dose escalation study. GAIN 2 (GLYA2005; United States and Canada) was
      designed to further assess the safety of the highest dose tolerated in GAIN 1.
      Both trials were randomized (2:1), double-blind, and placebo controlled.
      Treatment was started within 12 hours of symptom onset; patients with both
      ischemic stroke and primary intracerebral hemorrhage were included in both
      trials. RESULTS: The dose escalation study (GAIN 1) completed 3 dosing tiers.
      Enrollment was suspended before escalation to the fourth tier because of
      laboratory reports of transiently elevated bilirubin levels in a concurrent
      European study that employed the dose targeted for this tier. After review by an
      independent safety committee of the worldwide safety data, the second study (GAIN
      2) commenced. One hundred nine patients were randomized and dosed with study
      drug, either an 800-mg loading dose followed by 200 mg every 12 hours for 3 days
      of GV150526 or placebo. The incidence of serious adverse events was similar in
      the drug and placebo groups. Mild irritation at the infusion site and symptoms
      suggestive of mild and reversible altered mentation were reported more frequently
      in the GV150526 group than in the placebo group. Hyperbilirubinemia was reported
      in 6% of GV150526-treated patients compared with 3% of placebo-treated patients.
      Outcome at 4 weeks after stroke was better in GV150526-treated patients, but the
      studies were not powered to show statistical significance, and the baseline
      neurological deficits in the GV150526-treated patients were less severe.
      CONCLUSIONS: These preliminary studies suggest that GV150526 is well tolerated by
      patients with suspected acute stroke. Further pivotal studies testing the
      efficacy and safety of GV150526 in acute stroke are ongoing.

PMID- 10657407
TI  - Early [(11)C]Flumazenil/H(2)O positron emission tomography predicts irreversible
      ischemic cortical damage in stroke patients receiving acute thrombolytic therapy.
AB  - BACKGROUND AND PURPOSE: Central benzodiazepine receptor ligands, such as
      [(11)C]flumazenil (FMZ), are markers of neuronal integrity and therefore might be
      useful in the differentiation of functionally and morphologically damaged tissue
      early in ischemic stroke. We sought to assess the value of a benzodiazepine
      receptor ligand for the early identification of irreversible ischemic damage to
      cortical areas that cannot benefit from reperfusion. METHODS: Eleven patients (7
      male, 4 female, aged 52 to 75 years) with acute, hemispheric ischemic stroke were
      treated with alteplase (recombinant tissue plasminogen activator; 0.9 mg/kg
      according to National Institute of Neurological Disorders and Stroke protocol)
      within 3 hours of onset of symptoms. At the beginning of thrombolysis, cortical
      cerebral blood flow ([(15)O]H(2)O) and FMZ binding were assessed by positron
      emission tomography (PET). Those early PET findings were related to the change in
      neurological deficit (National Institutes of Health Stroke Scale) and to the
      extent of cortical damage on MRI or CT 3 weeks after the stroke. RESULTS:
      Hypoperfusion was observed in all cases, and in 8 patients the values were below
      critical thresholds estimated at 12 mL/100 g per minute, comprising 1 to 174
      cm(3) of cortical tissue. Substantial reperfusion was seen in most of these
      regions 24 hours after thrombolysis. In 4 cases, distinct areas of decreased FMZ
      binding were detected. Those patients suffered permanent lesions in cortical
      areas corresponding to their FMZ defects (112 versus 146, 3 versus 3, 2 versus 1,
      and 128 versus 136 cm(3)). In the other patients no morphological defects were
      detected on MRI or CT, although blood flow was critically decreased in areas
      ranging in size up to 78 cm(3) before thrombolysis. CONCLUSIONS: These findings
      suggest that imaging of benzodiazepine receptors by FMZ PET distinguishes between
      irreversibly damaged and viable penumbra tissue early after acute stroke.

PMID- 10657408
TI  - Intravenous tissue plasminogen activator for acute ischemic stroke in patients
      aged 80 years and older : the tPA stroke survey experience.
AB  - BACKGROUND AND PURPOSE: Intravenous tissue plasminogen activator (tPA)
      administered within 3 hours of symptom onset is the first available effective
      therapy for acute ischemic stroke (AIS). Few data exist, however, on its use in
      very elderly patients. We examined the characteristics, complications, and short
      term outcome of AIS patients aged >/=80 years treated with tPA. METHODS: Patients
      aged >/=80 years (n=30) were compared with counterparts aged <80 years (n=159)
      included in the tPA Stroke Survey, a US retrospective survey of 189 consecutive
      AIS patients treated with intravenous tPA at 13 hospitals. RESULTS: Risk of
      intracerebral hemorrhage (fatal, symptomatic, and total) was 3%, 3%, and 7% in
      the elderly age group and 2%, 6%, and 9%, respectively, in their younger
      counterparts (P=NS for all comparisons). Likelihood of favorable outcome, defined
      as modified Rankin score 0 to 1, National Institutes of Health Stroke Scale score
      </=5, or marked improvement by hospital discharge, was comparable between groups
      (37%, 54%, and 43% versus 30%, 54%, and 43%, respectively; P=NS for all
      comparisons). Elderly patients were more likely to be treated by stroke
      specialists (87% versus 60%; P=0.005) and less likely to have an identified
      protocol deviation (13% versus 33%; P=0.03). Elderly patients were discharged
      more often to nursing care facilities (17% versus 5%; P=0.003). In logistic
      regression models there were no differences in odds ratio for favorable or poor
      outcome, other than tendency for higher in-hospital mortality in elderly patients
      (odds ratio, 2.8; 95% CI, 0.81 to 9.62; P=0.10). CONCLUSIONS: Among AIS patients
      treated with intravenous tPA, age-related differences in characteristics and
      disposition were identified. No evidence for withholding tPA treatment for AIS in
      appropriately selected patients aged >/=80 years was identified.

PMID- 10657409
TI  - Identification of patients at risk for periprocedural neurological deficits
      associated with carotid angioplasty and stenting.
AB  - BACKGROUND AND PURPOSE: Transient or permanent neurological deficits can occur in
      the periprocedural period following carotid angioplasty and stenting (CAS),
      presumably due to distal embolization and/or hemodynamic compromise. We performed
      this study to identify predictors of neurological deficits associated with
      carotid angioplasty and stent placement. METHODS: We reviewed medical records and
      angiograms in a consecutive series of patients who underwent CAS for symptomatic
      or asymptomatic cervical internal carotid artery stenosis from June 1996 through
      December 1998. Using logistic regression analysis, we evaluated the effect of
      demographic, clinical, intraprocedural, and angiographic risk factors on
      subsequent development of periprocedural neurological deficits. Periprocedural
      neurological deficits were defined as new or worsening transient or permanent
      neurological deficits that occurred during or within 48 hours of the procedure.
      RESULTS: A total of 111 patients (mean age 68.2+/-9.1 years) who underwent CAS
      for asymptomatic (n=54) or symptomatic (n=57) stenoses were included in this
      study. A total of 14 periprocedural neurological deficits (13%) were observed
      either during (n=4) or after (n=10) the procedure. Three identified variables
      were independently associated with periprocedural neurological deficits:
      symptomatic lesion (OR 8.3, 95% CI 1.6 to 42.6), length of stenotic segment
      >/=11.2 mm (OR 5.2, 95% CI 1.2 to 22.5), and absence of hypercholesterolemia (OR
      5.4, 95% CI 1.4 to 20.9). Other variables, including age and degree of stenosis
      (defined by NASCET criteria), were not associated with periprocedural
      neurological deficits. CONCLUSIONS: A combination of clinical and angiographic
      variables can be used to identify patients at risk for periprocedural
      neurological deficits after CAS. Such identification may help in selection of
      patients who may benefit from novel pharmacological and mechanical preventive
      approaches.

PMID- 10657410
TI  - Effect of hypervolemic therapy on cerebral blood flow after subarachnoid
      hemorrhage : a randomized controlled trial.
AB  - BACKGROUND AND PURPOSE: Cerebral blood flow (CBF) is reduced after subarachnoid
      hemorrhage (SAH), and symptomatic vasospasm is a major cause of morbidity and
      mortality. Volume expansion has been reported to increase CBF after SAH, but CBF
      values in hypervolemic (HV) and normovolemic (NV) subjects have never been
      directly compared. METHODS: On the day after aneurysm clipping, we randomly
      assigned 82 patients to receive HV or NV fluid management until SAH day 14. In
      addition to 80 mL/h of isotonic crystalloid, 250 mL of 5% albumin solution was
      given every 2 hours to maintain normal (NV group, n=41) or elevated (HV group,
      n=41) cardiac filling pressures. CBF ((133)xenon clearance) was measured before
      randomization and approximately every 3 days thereafter (mean, 4.5 studies per
      patient). RESULTS: HV patients received significantly more fluid and had higher
      pulmonary artery diastolic and central venous pressures than NV patients, but
      there was no effect on net fluid balance or on blood volume measured on the third
      postoperative day. There was no difference in mean global CBF during the
      treatment period between HV and NV patients (P=0.55, random-effects model).
      Symptomatic vasospasm occurred in 20% of patients in each group and was
      associated with reduced minimum regional CBF values (P=0.04). However, there was
      also no difference in minimum regional CBF between the 2 treatment groups.
      CONCLUSIONS: HV therapy resulted in increased cardiac filling pressures and fluid
      intake but did not increase CBF or blood volume compared with NV therapy.
      Although careful fluid management to avoid hypovolemia may reduce the risk of
      delayed cerebral ischemia after SAH, prophylactic HV therapy is unlikely to
      confer an additional benefit.

PMID- 10657411
TI  - Risk factors for multiple intracranial aneurysms.
AB  - BACKGROUND AND PURPOSE: The presence of multiple intracranial aneurysms may be a
      sign of significant risk factors for aneurysm formation that differ from those
      factors that increase risk for aneurysm rupture. Only 2 studies concern
      independent risk factors for multiple aneurysms, and the results are in part
      controversial. This study was designed to identify independent risk factors for
      multiple intracranial aneurysms in patients with subarachnoid hemorrhage.
      METHODS: Of 266 patients with aneurysmal subarachnoid hemorrhage (139 men and 127
      women, aged 15 to 60 years), 80 (30%) had multiple intracranial aneurysms. The
      prevalence of several health-related habits, previous diseases, and medications
      of these patients were compared by multiple logistic regression between those
      with single and those with multiple aneurysms. RESULTS: On the basis of
      multivariate statistics, only regular cigarette smoking at any time was a
      significant risk factor for the presence of multiple aneurysms. The odds ratio
      (OR) of smoking for multiple aneurysms was 2.10 (95% CI, 1.06 to 4.13) after
      adjustment for age and sex. After additional adjustment for hypertension, the
      risk was 2.06 (95% CI, 1. 04 to 4.07). Of other variables, only age (OR, 1.02 per
      year; 95% CI, 1.00 to 1.05; P=0.09) and female sex (OR, 1.60; 95% CI, 0.90 to 2.
      85; P=0.11) showed a tendency to increase the risk for multiple aneurysms after
      adjustment for smoking. On the other hand, patients with hypertension had
      significantly (P=0.029) more aneurysms (1. 61+/-1.04) than did those without
      (1.37+/-0.68), although they did not more frequently have multiple aneurysms.
      CONCLUSIONS: Cigarette smoking and possibly also age and female sex seem to be
      risk factors for multiple intracranial aneurysms in patients of working age who
      have suffered a subarachnoid hemorrhage. Patients with hypertension seem to have
      more aneurysms than those without.

PMID- 10657412
TI  - Significant association of atrial vulnerability with atrial septal abnormalities
      in young patients with ischemic stroke of unknown cause.
AB  - BACKGROUND AND PURPOSE: Atrial septal abnormalities have been associated with
      cryptogenic ischemic stroke in young patients, but the causal link has not yet
      been established. Paradoxical embolism is considered the most likely mechanism
      but is rarely proven. It can be hypothesized that, in those patients, paroxysmal
      atrial arrhythmias, potentially favored by the anatomic abnormalities, can be
      another cause of thrombus formation and subsequent embolism to the brain. In this
      study we assessed the relationship between atrial vulnerability, reflecting
      arrhythmogenic properties of the atria, and atrial septal abnormalities in young
      patients with cryptogenic ischemic stroke. METHODS: We enrolled 62 consecutive
      patients aged <55 years who had ischemic stroke of unknown cause and
      transesophageal echocardiography to assess atrial septal aneurysm (ASA) or patent
      foramen ovale (PFO) (ie, atrial septal abnormalities). These patients underwent
      electrophysiological study to measure atrial refractoriness and conduction time
      defining a vulnerability index (ie, latent atrial vulnerability) and to assess
      the inducibility of sustained (lasting >60 seconds) atrial fibrillation with the
      use of programmed atrial stimulation. Actual atrial vulnerability was defined by
      the presence of both latent vulnerability and inducibility of sustained atrial
      fibrillation lasting >60 seconds. RESULTS: We found atrial vulnerability in 58%
      of patients with atrial septal abnormalities and in 25% of patients without (odds
      ratio=4.1 [95% CI, 1.3 to 12.7; P<0.02]). The difference between patients with
      and without PFO or between patients with both PFO and ASA and those without were
      also significant. Patients with inducible sustained atrial fibrillation had more
      frequent past history of palpitations and syncope than patients without (P<0.02).
      CONCLUSIONS: Atrial vulnerability is associated with atrial septal abnormalities
      in patients with cryptogenic stroke. This result raises the question of the
      potential role of transient atrial arrhythmias in thrombus formation in the
      presence of PFO or ASA.

PMID- 10657413
TI  - Influence of admission body temperature on stroke mortality.
AB  - BACKGROUND AND PURPOSE: The influence of body temperature on stroke outcome
      remains uncertain. The aim of this study was to investigate the prognostic role
      of admission body temperature on short-term and long-term mortality in a
      retrospective cohort study of patients with acute stroke. METHODS: A
      retrospective cohort of 509 patients with acute stroke, admitted to a tertiary
      hospital between July 1, 1995, and June 30, 1997, was studied. The relationship
      between admission body temperature and mortality both in-hospital and at 1-year
      mortality was evaluated. Body temperature on admission was classified as
      hypothermia (</=36.5 degrees C), normothermia (>36.5 degrees C and </=37.5
      degrees C), and hyperthermia (>37.5 degrees C). Logistic regression and
      proportional hazards function analysis were performed after adjustment for
      clinical predictors of stroke outcome. RESULTS: In ischemic stoke, mortality was
      lower among patients with hypothermia and higher among patients with
      hyperthermia. The odds ratio for in-hospital mortality in hypothermic versus
      normothermic patients was 0.1 (95% CI, 0.02 to 0.5). The relative risk for 1-year
      mortality of hyperthermic versus normothermic patients was 3.4 (95% CI, 1.6 to
      7.3). A similar but nonsignificant trend for in-hospital mortality was seen among
      patients with hemorrhagic stroke. CONCLUSIONS: An association between admission
      body temperature and stroke mortality was noted independent of clinical variables
      of stroke severity. Hyperthermia was associated with an increase in 1-year
      mortality. Hypothermia was associated with a reduction in in-hospital mortality.

PMID- 10657414
TI  - Effects of poststroke pyrexia on stroke outcome : a meta-analysis of studies in
      patients.
AB  - BACKGROUND AND PURPOSE: The effect of pyrexia on cerebral ischemia has been
      extensively studied in animals. In humans, however, such studies are small and
      the results conflicting. We undertook a meta-analysis using all such published
      studies on the effect of hyperthermia on stroke outcome. METHODS: Three databases
      were searched for all published studies that examined the relationship of raised
      temperature after stroke onset and eventual outcome. Combined probability values
      and odds ratios were obtained. A heterogeneity test was performed to ensure that
      the data were suitable for such an analysis. Morbidity and mortality were used as
      outcome measures. RESULTS: Nine studies were identified totaling 3790 patients,
      providing our study with 99% power to detect a 9% increase in morbidity and 84%
      power to detect a 1% increase in mortality for the pyrexial group. The combined
      odds ratio for mortality was 1.19 (95% CI, 0.99 to 1.43). A heterogeneity test
      was highly nonsignificant (P>0.05) for mortality, suggesting that the data were
      sufficiently similar to be meta-analyzed. Combined probability values were highly
      significant for both morbidity (P<0.0001) and mortality (P<0. 00000001).
      CONCLUSIONS: The results from this meta-analysis suggest that pyrexia after
      stroke onset is associated with a marked increase in morbidity and mortality.
      Measures should be taken to combat fever in the clinical setting to prevent
      stroke progression. The possible benefit of therapeutic hypothermia in the
      management of acute stroke should be further investigated.

PMID- 10657415
TI  - Blood pressure exceeding national guidelines among women after stroke.
AB  - BACKGROUND AND PURPOSE: After a transient ischemic attack or stroke, the risk for
      recurrence may be reduced by treatment of hypertension. The purpose of this study
      was to determine how commonly blood pressure exceeds national guidelines among
      patients who have had one of these events. METHODS: Subjects were 644 women
      participating in a randomized trial of estrogen for secondary stroke prevention.
      We measured blood pressure 1 month after the stroke or TIA while patients were
      under the care of their personal physicians. Among 536 patients, a second measure
      was made at an average of 2.9 years after the first. RESULTS: The mean age of
      participants was 71 years, and 73% reported a history of hypertension. At
      baseline, only 44% (280/644) of the women had blood pressure values within
      national guidelines (<140/90 mm Hg). With separate guidelines used for diabetics
      (<130/85 mm Hg) and nondiabetics (<140/90 mm Hg), the proportions of women within
      the guidelines were 27% and 44%, respectively. Overall, 39% of patients were
      within the diabetes-adjusted guidelines. Among patients whose blood pressure
      exceeded 140/90 mm Hg at first examination, 55% were still in excess at follow
      up. Features associated with severe hypertension at first examination (>160/100
      mm Hg) were history of hypertension, education less than college, and higher
      cognitive functioning. CONCLUSIONS: Blood pressure values in excess of national
      guidelines are common after stroke and TIA, especially among diabetic patients.
      Efforts to lower blood pressure control may enhance secondary prevention.

PMID- 10657417
TI  - Aortic atherosclerosis at middle age predicts cerebral white matter lesions in
      the elderly.
AB  - BACKGROUND AND PURPOSE: MRI scans of the brains of elderly people frequently show
      white matter lesions. Clinically, these lesions are associated with cognitive
      impairment and dementia. A relation between atherosclerosis and white matter
      lesions was found in some small cross-sectional studies. However, atherosclerosis
      is a gradual process that starts early in life. We investigated the longitudinal
      association between aortic atherosclerosis assessed during midlife and late life
      and cerebral white matter lesions. METHODS: We randomly sampled subjects between
      60 and 90 years old from 2 population-based follow-up studies in which subjects
      had their baseline examinations in 1975 to 1978 (midlife) and in 1990 to 1993
      (late life). In 1995 to 1996, subjects underwent 1.5-T MRI scanning; white matter
      lesions were rated in the deep subcortical and periventricular regions
      separately. Aortic atherosclerosis was assessed on abdominal radiographs that
      were obtained from 276 subjects in midlife and 531 subjects in late life.
      RESULTS: The presence of aortic atherosclerosis during midlife was significantly
      associated with the presence of periventricular white matter lesions
      approximately 20 years later (adjusted relative risk, 2.4; 95% CI, 1.2 to 5.0);
      the relative risks increased linearly with the severity of aortic
      atherosclerosis. No association was found between midlife aortic atherosclerosis
      and subcortical white matter lesions (adjusted relative risk, 1.1; 95% CI, 0.5 to
      2.3) or between late-life aortic atherosclerosis and white matter lesions.
      CONCLUSIONS: The pathogenetic process that leads to cerebral periventricular
      white matter lesions starts already in or before midlife. The critical period for
      intervention directed at prevention of white matter lesions and its cognitive
      consequences may be long before these lesions become clinically detectable.

PMID- 10657416
TI  - Control of blood pressure and risk of stroke among pharmacologically treated
      hypertensive patients.
AB  - BACKGROUND AND PURPOSE: Despite improved control of blood pressure during the
      last decades in the United States, a considerable proportion of treated
      hypertensives have not achieved target blood pressure levels. We estimated the
      proportion of strokes occurring among treated hypertensive patients that may be
      attributable to uncontrolled blood pressure. METHODS: A population-based case
      control study was conducted among treated hypertensive members of Group Health
      Cooperative of Puget Sound. Cases were treated hypertensive patients who
      sustained a first fatal or nonfatal, ischemic (n=460) or hemorrhagic (n=95)
      stroke during 1989-1996. Controls were a random sample of stroke-free, treated
      hypertensive Group Health Cooperative enrollees (n=2966), similar in age to the
      stroke cases. Multiple measurements of blood pressure and other cardiovascular
      risk factors were collected from medical records. Logistic regression was used to
      estimate the risk of ischemic stroke and hemorrhagic stroke associated with
      uncontrolled blood pressure, defined as diastolic blood pressure >90 mm Hg or
      systolic blood pressure >140 mm Hg. The fraction of strokes attributable to
      uncontrolled blood pressure among treated hypertensives was calculated. RESULTS:
      Blood pressure was uncontrolled in 78% of ischemic stroke cases, 85% of
      hemorrhagic stroke cases, and 65% of controls. After adjustment for potential
      confounders, uncontrolled blood pressure among treated hypertensive patients was
      moderately associated with ischemic stroke (risk ratio=1.5 [95% CI, 1.2 to 1. 9])
      and strongly related to hemorrhagic stroke (risk ratio=3.0 [95% CI, 1.7 to 5.4]).
      We estimated that 27% (95% CI, 11% to 39%) of the ischemic strokes and 57% (95%
      CI, 26% to 75%) of the hemorrhagic strokes among treated hypertensive patients
      were attributable to uncontrolled blood pressure. Overall, 32% (95% CI, 14% to
      45%) of all strokes were attributable to uncontrolled blood pressure.
      CONCLUSIONS: A considerable proportion of incident strokes among treated
      hypertensive patients may be prevented by achieving control of blood pressure.

PMID- 10657418
TI  - Recovery of ipsilateral dexterity after stroke.
AB  - BACKGROUND AND PURPOSE; Previous work indicated that patients within 1 month of
      parietal or posterior frontal damage are often abnormally slow or clumsy when
      using the ipsilateral hand for dexterity tasks. This article reports a 6-month
      follow-up study to assess recovery and the impact on functional outcome. METHODS:
      Twenty-four patients (80%) were available for follow-up. They used the
      ipsilateral hand on a dexterity test that simulated everyday hand function.
      Weakness and ideomotor apraxia were also assessed. Performance was compared with
      that of healthy age-matched control subjects using the same hand. Rating scales
      for self-care and dexterity in everyday life were completed by patients and
      carers. RESULTS: Significant recovery had occurred on all measures, but patients
      with left hemisphere damage remained impaired on the dexterity test, with 7
      patients (58%) scoring below the normal range. Five of these were apraxic.
      Reports of everyday functioning did not reflect this impairment, but there were
      inconsistencies in these reports, which raised doubts as to their accuracy.
      CONCLUSIONS: Ipsilateral dexterity shows recovery during the first 6 months, but
      there may be persistent impairment related to apraxia after left hemisphere
      stroke. It appears that the impact of this on functional outcome is typically
      small compared with the large effect of severity of contralateral paresis. It may
      be a significant factor in some cases, however, and direct observation of
      everyday functioning would be needed to clarify more subtle effects on outcome.

PMID- 10657419
TI  - Who benefits from treatment and rehabilitation in a stroke Unit? A community
      based study.
AB  - BACKGROUND AND PURPOSE: The beneficial effects of treatment and rehabilitation of
      patients with acute stroke in a dedicated stroke unit (SU) are well established.
      We wanted to examine if these effects are limited to certain groups of patients
      or if they apply to all patients independent of age, sex, comorbidity, and
      initial stroke severity. METHODS: This was a community-based study of outcome in
      1241 consecutive stroke patients from 2 communities in Copenhagen: In one
      (Frederiksberg), treatment and rehabilitation were given in general neurological
      and medical wards (GW), and in the other (Bispebjerg) in one single large SU.
      Outcome measures were initial, 1-year, and 5-year mortality rates, a poor outcome
      (initial death or discharge to a nursing home), and length of hospital stay
      (LOHS). Multivariate regression analyses were used to examine the independent
      effect of SU treatment on the various subgroups. RESULTS: The relative risks of
      initial death, poor outcome, and 1-year and 5-year mortality rates were reduced
      by 40% on average in patients treated in the SU compared with the GW. A
      beneficial effect of SU treatment was observed regardless of the patient's age,
      sex, comorbidity, and initial stroke severity. Those who benefited most appeared
      to be the patients with the most severe strokes (poor outcome: OR 0.17; 95% CI
      0.05 to 0.58). Those who benefited least were patients with mild or moderate
      strokes (poor outcome: OR 0.66; 95% CI 0.41 to 0.98) and patients <75 years of
      age (poor outcome: OR 0.66; 95% CI 0.36 to 1.19). LOHS was reduced by 2 to 3
      weeks in all who had their treatment in the SU except in patients with the most
      severe strokes. LOHS in these patients was similar to LOHS in the GW.
      CONCLUSIONS: A beneficial effect of treatment in a SU is achieved in completely
      unselected patients independent of their age, sex, comorbidity, and stroke
      severity. Those who had the most severe strokes appeared to benefit most. All
      patients with acute stroke should therefore have access to treatment and
      rehabilitation in a dedicated SU.

PMID- 10657420
TI  - Health-related quality of life among long-term survivors of stroke : results from
      the Auckland Stroke Study, 1991-1992.
AB  - BACKGROUND AND PURPOSE: The consequences of stroke are a major health concern.
      This study was conducted to compare the health-related quality of life among long
      term survivors of stroke with that of the general population. METHODS: Our data
      are taken from a population-based case-control study of all 6-year survivors of
      stroke with an age- and sex-matched control population. SF-36 mean scores for
      cases were compared with raw and standardized control and New Zealand norm mean
      scores. RESULTS: Of the original 1761 registered cases, 639 were still alive at 6
      year follow-up, and all of these participated in the study. Case patients were
      more likely than control subjects to be dependent in all basic activities of
      daily living. Crude mean scores were lower for women; as age increased; for those
      living in institutions; when the SF-36 was completed by proxy; and when help was
      required with the activities of daily living. Cases had statistically lower mean
      scores than both the control group and New Zealand norms for physical functioning
      and general health. After standardization for age and sex, no differences were
      found between cases and controls in mental health and bodily pain. CONCLUSIONS:
      Health-related quality of life appears to be relatively good for the majority of
      patients 6 years after stroke. Despite significant ongoing physical disability,
      survivors of stroke appear to adjust well psychologically to their illness.

PMID- 10657421
TI  - A predictive risk model for outcomes of ischemic stroke.
AB  - BACKGROUND AND PURPOSE: The great variability of outcome seen in stroke patients
      has led to an interest in identifying predictors of outcome. The combination of
      clinical and imaging variables as predictors of stroke outcome in a multivariable
      risk adjustment model may be more powerful than either alone. The purpose of this
      study was to determine the multivariable relationship between infarct volume, 6
      clinical variables, and 3-month outcomes in ischemic stroke patients. METHODS:
      Included in the study were 256 eligible patients from the Randomized Trial of
      Tirilazad Mesylate in Acute Stroke (RANTTAS). Six clinical variables and 1-week
      infarct volume were the prespecified predictor variables. The National Institutes
      of Health Stroke Scale, Barthel Index, and Glasgow Outcome Scale were the
      outcomes. Multivariable logistic regression techniques were used to develop the
      model equations, and bootstrap techniques were used for internal validation.
      Predictive performance of the models was assessed for discrimination with
      receiver operator characteristic (ROC) curves and for calibration with
      calibration curves. RESULTS: The predictive models had areas under the ROC curve
      of 0.79 to 0.88 and demonstrated nearly ideal calibration curves. The areas under
      the ROC curves were statistically greater (P<0.001) with both clinical and
      imaging information combined than with either alone for predicting excellent
      recovery and death or severe disability. CONCLUSIONS: Combined clinical and
      imaging variables are predictive of 3-month outcome in ischemic stroke patients.
      Demonstration of this relationship with acute clinical variables and 1-week
      infarct information supports future attempts to predict 3-month outcome with all
      acute variables.

PMID- 10657422
TI  - The stroke prognosis instrument II (SPI-II) : A clinical prediction instrument
      for patients with transient ischemia and nondisabling ischemic stroke.
AB  - BACKGROUND AND PURPOSE: In 1991 we developed the Stroke Prognosis Instrument (SPI
      I) to stratify patients with transient ischemic attack or ischemic stroke by
      prognosis for stroke or death in 2 years. In this article we validate and improve
      SPI-I (creating SPI-II). METHODS: To validate SPI-I, we applied it to 4 test
      cohorts and calculated pooled outcome rates. To create SPI-II, we incorporated
      new predictive variables identified in 1 of the test cohorts and validated it in
      the other 3 cohorts. RESULTS: For SPI-I, pooled rates (all 4 test cohorts) of
      stroke or death within 2 years in risk groups I, II, and III were 9%, 17%, and
      24%, respectively (P<0.01, log-rank test). SPI-II was created by adding
      congestive heart failure and prior stroke to SPI-I. Each patient's risk group was
      determined by the total score for 7 factors: congestive heart failure (3 points);
      diabetes (3 points); prior stroke (3 points); age >70 years (2 points); stroke
      for the index event (not transient ischemic attack) (2 points); hypertension (1
      point); and coronary artery disease (1 point). Risk groups I, II, and III
      comprised patients with 0 to 3, 4 to 7, and 8 to 15 points, respectively. For SPI
      I, pooled rates (3 cohorts excluding the SPI-II development cohort) of stroke or
      death within 2 years in risk groups I, II, and III were 9%, 17%, and 23%,
      respectively. For SPI-II, pooled rates were 10%, 19%, and 31%, respectively. In
      receiver operator characteristic analysis, the area under the curve was 0.59 (95%
      CI, 0.57 to 0.60) for SPI-I and 0.63 (95% CI, 0.62 to 0.65) for SPI-II,
      confirming the better performance of the latter. CONCLUSIONS: Compared with SPI
      I, SPI-II achieves greater discrimination in outcome rates among risk groups. SPI
      II is ready for use in research design and may have a role in patient counseling.

PMID- 10657423
TI  - Which parameters of beat-to-beat blood pressure and variability best predict
      early outcome after acute ischemic stroke?
AB  - BACKGROUND AND PURPOSE: In hypertensive populations, increasing blood pressure
      (BP) levels and BP variability (BPV) are associated with a greater incidence of
      target organ damage. After stroke, elevated 24-hour BP levels predict a poor
      outcome, although it is uncertain whether shorter-length BP recordings assessing
      mean BP levels and BPV have a similar predictive role. The objectives of this
      study were to compare the different measures of beat-to-beat BP and BPV on
      outcome after acute ischemic stroke and assess whether these parameters were
      affected by stroke subtype. METHODS: Ninety-two consecutive admissions with a CT
      confirmed diagnosis of acute ischemic stroke were recruited, of whom 54 had
      cortical infarction, 29 subcortical, and 9 posterior circulation infarction.
      Casual and two 5-minute recordings of beat-to-beat BP (Finapres, Ohmeda) were
      made under standardized conditions within 72 hours of ictus, with mean BP levels
      taken as the average of this 10-minute recording and BPV as the standard
      deviation. Outcome was assessed at 30 days as dead/dependent or independent
      (Rankin </=2). The effects of BP, BPV, and stroke subtype on outcome were studied
      with the use of logistic regression. Stroke subjects were subsequently divided by
      BP quartiles and within each quartile into low- and high-variability groups; the
      influence of high BPV on outcome was also assessed. RESULTS: The odds ratio for
      death/dependency was significantly higher in cortical strokes compared with
      subcortical and posterior circulation strokes even after controlling for
      differences in BP and BPV (OR 4.19, P=0.002). Beat-to-beat systolic BP (SBP),
      diastolic BP (DBP), and mean arterial pressure (MAP +/- SD) levels were higher in
      the dead/dependent group compared with the independent group (MAP 106+/-20.4 mm
      Hg vs 97+/-19.1 mm Hg, P<0.02), as was MAP variability: 6.1 (interquartile range
      4.5 to 7.4 mm Hg) versus 4.9 (3.8 to 6.4 mm Hg, P=0.02). The odds ratio for a
      poor outcome was 1. 38 (P=0.014) for every 10-mm Hg increase in MAP and 1.32
      (P=0.02) for every 1-mm Hg increase in MAP variability. Casual BP measurements
      had no prognostic significance. For the group as a whole when separated into BP
      quartiles, those with a high MAP and DBP but not SBP variability within each
      quartile had a worse prognosis compared with those with a low BPV. CONCLUSIONS: A
      poor outcome at 30 days after ischemic stroke was dependent on stroke subtype,
      beat-to-beat DBP, and MAP levels and variability. Important prognostic
      information can be readily obtained from a short period of noninvasive BP
      monitoring in the acute stroke patient. These findings have important
      implications, particularly regarding the use of hypotensive agents in the acute
      stroke period.

PMID- 10657424
TI  - Antithrombotic and antihypertensive management 3 months after ischemic stroke : a
      prospective study in an inner city population.
AB  - BACKGROUND AND PURPOSE: We sought to examine the frequency, predictors, and
      effects of nontreatment with antithrombotic and antihypertensive therapies 3
      months after ischemic stroke. METHODS: The population-based South London
      Community Stroke Register prospectively collected data on first-in-a-lifetime
      strokes between 1995 and 1997. Among patients registered with ischemic stroke,
      treatment status with antithrombotic and antihypertensive therapies was examined
      3 months after the event. RESULTS: In a cohort of 457 patients with ischemic
      stroke, 393 (86.0%) were considered appropriate for antiplatelet medication, 32
      (7.0%) for anticoagulant medication, and 254 (55.9%) for antihypertensive
      medication. The rates of nontreatment observed 3 months after the event were
      24.4% for antiplatelet, 59.4% for anticoagulant, and 29.5% for antihypertensive
      medication. Independent risk factors for nontreatment with antithrombotic
      therapies (antiplatelets and anticoagulants) were the subtype of stroke
      (nonlacunar infarct: OR=1. 60, 95% CI 1.07 to 2.54), stroke severity measured by
      the Glasgow Coma Scale (GCS) score (GCS </=13: OR 2.08, 95% CI 1.18 to 3.66) and
      the Barthel Index (BI) score 5 days after the event (BI </=10: OR 1. 85, 95% CI
      1.17 to 2.93). For antihypertensive therapies the stroke subtype (OR 2.46, 95% CI
      1.33 to 4.54), GCS score (OR 2.97, 95% CI 1. 35 to 6.53), BI score (OR 2.33, 95%
      CI 1.27 to 4.29), and ethnicity (Caucasian: OR 2.43, 95% CI 1.15 to 5.14) were
      independently associated with nontreatment. Cox regression modeling showed no
      significant association between the treatment status and recurrence-free 3-year
      survival rates after controlling for severity and subtype of stroke. CONCLUSIONS:
      Secondary prevention for a common disease such as stroke appears to be inadequate
      in the study area. Healthcare professionals need to consider antithrombotic and
      antihypertensive therapies for all stroke patients.

PMID- 10657425
TI  - Assessment of the thigh cuff technique for measurement of dynamic cerebral
      autoregulation.
AB  - BACKGROUND AND PURPOSE: Dynamic methods of measuring cerebral autoregulation have
      become an accepted alternative to static evaluation. This article aims to
      describe a set of data collected from healthy volunteers by a dynamic method, the
      purpose being to qualify and quantify expected results for those who may be
      designing a study using this technique. METHODS: Cerebral blood flow velocity
      (CBFV) (measured by transcranial Doppler) and arterial blood pressure (Finapres)
      were recorded in 16 normal subjects before, during, and after the induction of a
      blood pressure drop (release of bilateral thigh cuffs). This procedure was
      repeated 6 times for each subject. A mathematical model was applied to the data
      to generate an autoregulatory index (ARI) with values between 0 and 9. RESULTS:
      The ARI values for this sample population follow a normal distribution, with a
      mean+/-SD of 4.98+/-1.06 (n=15). Analysis of the cumulative mean ARI values of
      all subjects showed an exponential-type convergence of ARI toward the sample mean
      as the number of test iterations increased. The population average blood pressure
      drop on thigh cuff release was 26.4+/-7.1 mm Hg (n=16), occurring in 4.6+/-1. 7
      seconds. The corresponding population average drop for CBFV was 15. 6+/-5.8 cm/s,
      taking 2.5+/-1.0 seconds. No significant trend was noted in the measurements as
      the number of test iterations increased. The correlation between the predicted
      and actual CBFV, having a mean value of 0.76+/-0.19, showed evidence of a
      nonlinear relationship to ARI values. Significant correlation was also found
      between ARI and (1) arterial blood pressure before cuff release and (2) the
      magnitude of the drop in CBFV on cuff release. CONCLUSIONS: The distribution of
      ARI values is not significantly different from normal. At least 3 iterations of
      the test procedure should be performed and averaged to obtain the mean ARI for
      each subject. There is no significant evidence of physiological accommodation as
      the number of test iterations increases. The effects of mean blood pressure and
      the magnitude of the change in CBFV should be considered as possible covariates
      when ARI data are analyzed.

PMID- 10657426
TI  - Increased stroke incidence in Lund-Orup, Sweden, between 1983 to 1985 and 1993 to
      1995.
AB  - BACKGROUND AND PURPOSE: Some studies suggest that the incidence of stroke may
      continue to change. We examined recent temporal trends in a defined geographical
      area of southern Sweden. METHODS: Medical records at the University Hospital of
      Lund (hospital district population 224 126 in 1993) were retrospectively screened
      for possible first-ever strokes during 1993 to 1995. Included patients were
      classified into pathological subtypes (cerebral infarction, intracerebral
      hemorrhage, subarachnoid hemorrhage, and undetermined pathological type) and
      according to the Oxfordshire Community Stroke Project (OCSP) classification
      system. Stroke patients from a previous study from 1983 to 1985 in the same area
      were reevaluated with the same criteria. Epidemiological data for the 2 time
      periods were compared. RESULTS: There were 998 patients with first-ever stroke in
      1983 to 1985 and 1318 in 1993 to 1995. The total incidence rate per 100 000
      person-years (age-adjusted to the European population) increased from 134 (95%
      confidence limits [CL] 126 to 143) to 158 (95% CL 149 to 168). The incidence rate
      for patients <75 years of age increased from 94 (95% CL 85 to 103) in 1983 to
      1985 to 117 (95% CL 108 to 127) in 1993 to 1995, whereas the incidence rate for
      patients >/=75 years was stable. The age-adjusted incidence rates for the OCSP
      subtypes lacunar and posterior circulation syndromes increased significantly, by
      30% and 55%, respectively. CONCLUSIONS: A marked increase in the incidence of
      first-ever stroke was observed, surprisingly mainly confined to people <75 years
      of age. The underlying causes of this increase must be explored in future
      studies.

PMID- 10657428
TI  - Association between platelet glycoprotein Ibalpha genotype and ischemic
      cerebrovascular disease.
AB  - BACKGROUND AND PURPOSE: Platelets play pivotal roles in the development of
      ischemic cerebrovascular disease (CVD). The platelet glycoprotein (GP) Ib/IX/V
      complex is a receptor for von Willebrand factor, which plays a major role in the
      initial phase of platelet activation under high shear stress conditions. This
      study was designed to investigate the association between a genetic variation of
      this receptor and the prevalence of CVD. METHODS: Two hundred patients with
      ischemic CVD, as confirmed by brain CT and/or MRI, and 317 age- and sex-matched
      control subjects without clinical evidence of CVD or cardiovascular disease were
      analyzed for their genotype frequencies of the (145)Thr/Met dimorphism of the
      alpha-chain of GPIb (GPIbalpha). RESULTS: Genotypes with (145)Met (T/M and M/M)
      were more frequently found in the CVD patients (26.5%) than in control subjects
      (14.2%, P=0.0005). The genotype effect was more obvious in those <60 years of age
      or without acquired cardiovascular risk factors. The odds ratio for nonsmoking
      women <60 years of age was 10. 6 (95% confidence intervals, 2.2 to 51.7).
      Although the number of patients studied was small (n=24), transient ischemic
      attack showed the highest odds ratio (4.3, P=0.0004), followed by lacunar
      infarction (OR=2.2, P=0.0024) and atherothrombotic infarction (OR=1. 5,
      P=0.3143). Logistic regression analysis revealed that the presence of Met-allele
      was independently associated with CVD. CONCLUSIONS: Our study suggests that the
      platelet GPIbalpha genotype is a genetic risk factor for ischemic CVD.

PMID- 10657427
TI  - Genetic predisposition to stroke in relatives of hypertensives.
AB  - BACKGROUND AND PURPOSE: The genetic basis of stroke is poorly understood. We
      evaluated patterns of familial aggregation of hypertension and stroke to test the
      hypothesis that inherited susceptibility to these disorders may be determined by
      a common set of factors. METHODS: Genealogical and medical history information
      was obtained for a cohort of 354 hypertensive probands ascertained in a clinic
      based setting, their 1427 first-degree relatives, and 239 of their spouses. Risks
      of stroke and hypertension in biological and nonbiological relatives were
      compared with the logistic model of the generalized estimating equations adjusted
      for age and sex. RESULTS: The risk of hypertension was higher for the parents and
      siblings of the probands than for spouses (odds ratio [OR]=2.4; 95% CI, 1.8 to
      3.4; OR=2.2; 95% CI, 1.6 to 3.0, respectively). When the spouses were used as a
      reference group, the risk of stroke for parents of the hypertensive probands was
      7.3 times higher (OR=7.3; 95% CI, 3.6 to 14.8), while a nonsignificant but
      slightly increased risk for siblings (OR=1.6; 95% CI, 0.8 to 3.3) was observed.
      Controlling for hypertension, obesity, smoking, coronary heart disease, diabetes,
      and cholesterol resulted in decreased estimates of the risk of stroke for parents
      and siblings (OR(parents)=5.4; 95% CI, 2.6 to 11.2; OR(siblings)=1.2; 95% CI, 0.6
      to 2.5). The risk of stroke was significantly higher for hypertensive parents and
      siblings than for nonhypertensive parents (OR=5.2; 95% CI, 2.8 to 9. 7) and
      siblings (OR=5.8; 95% CI, 2.1 to 15.9). A history of hypertension was not
      associated with an increased risk for stroke in spouses (OR=0.7; 95% CI, 0.2 to
      3.1). The risk of stroke in hypertensive relatives of probands with stroke was
      higher than that of the normotensive relatives (OR=13.4). A less elevated risk
      ratio was observed in the relatives of probands who did not have a stroke
      (OR=4.0). CONCLUSIONS: Our data showing a higher occurrence of hypertension and
      stroke in parents of hypertensive probands compared with spouses suggest that
      some of the genetic factors predisposing to these conditions may be the same. The
      slightly increased risk to siblings compared with spouses was not significant,
      suggesting that elucidation of these factors through family studies of stroke may
      be difficult because of secular trends toward improved treatment for
      hypertension. Although a history of hypertension increases the risk of stroke
      among parents and siblings, multivariate analyses revealed a familial component
      to stroke independent of hypertension.

PMID- 10657429
TI  - Growth factors stimulate neointimal cells in vitro and increase the thickness of
      the neointima formed at the neck of porcine aneurysms treated by embolization.
AB  - BACKGROUND AND PURPOSE: Growth factors (GFs) may favor the healing of aneurysms
      treated with endovascular techniques by stimulating neointima formation. METHODS:
      Bilateral carotid aneurysms were constructed with venous pouches in 50 pigs and
      embolized intraoperatively with collagen sponges with and without GFs (platelet
      derived growth factor-BB [PDGF-BB] 0.15 or 1.5 microg or transforming growth
      factor-beta(1) [TGF-beta(1)] 60 or 600 ng) in each animal. DNA synthesis, cell
      proliferation, and collagen secretion assays were performed to assess the in
      vitro effects of GFs on neointimal cells harvested from the treated aneurysms.
      (125)I-PDGF-BB was used to study in vivo GF release from sponges. The thickness
      of the neointima at the surface of the sponges was measured 2 weeks after
      surgery. Since porcine aneurysms tend to heal after collagen sponge embolization,
      this experiment was repeated in dogs, which have shown a propensity for
      recurrence with the same technique, with 600 ng TGF-beta(1) or platelet extracts.
      RESULTS: PDGF-BB stimulated DNA synthesis and cell proliferation, while TGF
      beta(1) strongly increased collagen synthesis of neointimal cells in vitro.
      Clearance of (125)I-PDGF-BB from the sponges followed a biphasic curve, with 1.5%
      of exogenous PDGF-BB remaining at 1 week. The local delivery of PDGF-BB (0.15 or
      1.5 microg) and TGF-beta(1) (600 ng) significantly increased neointimal thickness
      at the neck of porcine aneurysms, while 60 ng of TGF-beta(1) had no demonstrable
      effect. TGF-beta(1) (600 ng) or platelet extracts had no influence on canine
      aneurysms. CONCLUSIONS: PDGF-BB and TGF-beta(1) can stimulate neointimal cells in
      vitro and neointima formation in vivo, but TGF-beta(1) and platelet extracts do
      not compensate for deficient thrombosis in canine aneurysms. Effects on the long
      term results of embolization remain speculative.

PMID- 10657430
TI  - Is the acetazolamide test valid for quantitative assessment of maximal cerebral
      autoregulatory vasodilation? An experimental study.
AB  - BACKGROUND AND PURPOSE: The cerebral vasodilating effect of acetazolamide (ACZ)
      injection has been used as an index of the autoregulatory vasodilation (or
      cerebral perfusion reserve). The question of whether the ACZ test assesses the
      maximal autoregulatory vasodilating capacity is not definitely resolved. The
      effects of ACZ injection on this reserve at a dose producing maximal vasodilation
      have never been evaluated and may help to resolve this problem. METHODS: The
      effect of ACZ injection on cerebral blood flow (CBF) autoregulation was tested in
      anesthetized rats. A pilot experiment evaluated the dose-effect relationship of
      injected ACZ, cumulative doses (n=4, group 1), and independent bolus doses (n=6,
      group 2). CBF was estimated by laser-Doppler flowmetry, and cerebrovascular
      resistance (CVR) was calculated from mean arterial blood pressure (MABP) and from
      CBF (expressed as a percentage of baseline CBF). A bolus of ACZ of 21 mg/kg
      produced the maximal cerebral vasodilation that could be obtained by ACZ
      administration. In the main experiment, MABP was lowered from 110 to 20 mm Hg by
      stepwise bleeding in 3 groups of 6 animals treated 10 minutes before bleeding by
      injection of saline (group 3), 7 mg/kg ACZ (group 4), or 21 mg/kg ACZ (group 5).
      RESULTS: The CVR-MABP relationship was linear in all groups, indicating that CBF
      autoregulation was still effective after ACZ administration. CONCLUSIONS: These
      results indicate that maximal ACZ-induced cerebral vasodilation is not
      quantitatively equivalent to maximal autoregulatory vasodilating capacity in
      anesthetized rats.

PMID- 10657431
TI  - Augmented vasoconstriction and thromboxane formation by 15-F(2t)-isoprostane (8
      iso-prostaglandin F(2alpha)) in immature pig periventricular brain microvessels.
AB  - BACKGROUND AND PURPOSE: Oxidant stress, especially in the premature, plays a
      major role in the pathogenesis of hypoxic-ischemic encephalopathies mostly
      manifested in the periventricular region. We studied the vasomotor mode of
      actions of the peroxidation product 15-F(2t)-isoprostane (15-F(2t)-IsoP) (8-iso
      prostaglandin F(2alpha)) on periventricular region during development. METHODS:
      Effects of 15-F(2t)-IsoP on periventricular microvessels of fetal, newborn, and
      juvenile pigs were studied by video imaging and digital analysis techniques.
      Thromboxane formation and intracellular Ca(2+) were measured by radioimmunoassay
      and by using the fluorescent indicator fura 2-AM. RESULTS: 15-F(2t)-IsoP-mediated
      constriction of periventricular microvessels decreased as a function of age such
      that in the fetus it was approximately 2.5-fold greater than in juvenile pigs. 15
      F(2t)-IsoP evoked more thromboxane formation in the fetus than in the newborn,
      which was greater than that in the juvenile periventricular region; this was
      associated with immunoreactive thromboxane A(2) (TXA(2)) synthase expression in
      the fetus that was greater than that in newborn pigs, which was greater than that
      in juvenile pigs. 15-F(2t)-IsoP-induced vasoconstriction was markedly inhibited
      by TXA(2) synthase and receptor blockers (CGS12970 and L670596). Vasoconstrictor
      effects of the TXA(2) mimetic U46619 on fetal, neonatal, and juvenile
      periventricular microvessels did not differ. 15-F(2t)-IsoP increased TXA(2)
      synthesis by activating Ca(2+) influx through non-voltage-gated channels in
      endothelial cells (SK&F96365 sensitive) and N-type voltage-gated channels (omega
      conotoxin sensitive) in astrocytes; smooth muscle cells were not responsive to 15
      F(2t)-IsoP but generated Ca(2+) transients to U46619 via L-type voltage-sensitive
      channels. CONCLUSIONS: 15-F(2t)-IsoP causes periventricular brain region
      vasoconstriction in the fetus that is greater than that in the newborn, which in
      turn is greater than that in the juvenile due to greater TXA(2) formation
      generated through distinct stimulatory pathways, including from endothelial and
      astroglial cells. The resulting hemodynamic compromise may contribute to the
      increased vulnerability of the periventricular brain areas to oxidant stress
      induced injury in immature subjects.

PMID- 10657432
TI  - Mechanism of endothelin-1-induced contraction in rabbit basilar artery.
AB  - BACKGROUND AND PURPOSE: Endothelin-1 (ET-1) is suggested to be a major cause of
      cerebral vasospasm after subarachnoid hemorrhage. However, the mechanism of ET-1
      induced contraction in cerebral arteries remains unclear. This study was
      undertaken to demonstrate the possible role of protein tyrosine kinase (PTK),
      mitogen-activated protein kinase (MAPK), and protein kinase C (PKC) in ET-1
      induced contraction. METHODS: PD-98059, damnacanthal, wortmannin, AG-490,
      genistein, calphostin C, and staurosporine were used to inhibit, or relax, the ET
      1-induced contraction of basilar artery, studied with an isometric tension
      system. Immunoprecipitation of MAPK in ET-1-stimultated rings of basilar artery
      without or with the above inhibitors was studied with Western blot. RESULTS: (1)
      ET-1 produced concentration-dependent contraction and MAPK immunoprecipitation in
      rabbit basilar artery by activation of ET(A) but not ET(B) receptors. (2) MAPK
      inhibitors PD-98059 and U-0126 produced dose-dependent inhibition of ET-1-induced
      contraction. (3) The Src tyrosine kinase inhibitor damnacanthal, the
      phosphatidylinositol-3 kinase inhibitor wortmannin, and the Janus tyrosine
      kinase(2) inhibitor AG-490 abolished ET-1-induced contraction. (4) The PKC
      inhibitor staurosporine but not calphostin C abolished ET-1-induced contraction,
      and the PTK inhibitor genistein partially reduced ET-1-induced contraction. (5)
      In arteries precontracted by ET-1, PD-98059, U-0126, wortmannin, AG-490,
      genistein, and staurosporine produced concentration-dependent relaxation. (6) ET
      1 induced a biphasic and time-dependent MAPK immunoprecipitation. (7) PD-98059, U
      0126, genistein, AG-490, and damnacanthal, but not staurosporine or wortmannin,
      abolished the effect of ET-1 on MAPK immunoreactivity. CONCLUSIONS: This study
      demonstrated that MAPK may be involved in ET-1-induced contraction in rabbit
      basilar artery. MAPK is downstream of PTK, Src, and Janus tyrosine kinase
      pathways but may not be downstream of phosphatidylinositol-3 kinase pathways. The
      possible involvement of PKC in ET-1-induced contraction requires further
      investigation. Inhibition of these pathways may offer alternative treatment for
      ET-1-induced contraction and cerebral vasospasm.

PMID- 10657433
TI  - Toxicity of Dutch (E22Q) and Flemish (A21G) mutant amyloid beta proteins to human
      cerebral microvessel and aortic smooth muscle cells.
AB  - BACKGROUND AND PURPOSE: Cerebral amyloid angiopathy (CAA) is characterized by the
      deposition of amyloid beta protein (Abeta) in cortical and leptomeningeal vessels
      of patients with Alzheimer's disease and hereditary cerebral hemorrhage with
      amyloidosis, Dutch type. Smooth muscle cells (SMC) from cerebral microvessels
      (MV) are of particular interest as a site of Abeta-related injury because CAA is
      much more pronounced in the tunica media of cortical arterioles than meningeal
      arteries. Patients carrying point mutations at residues 22 (E22Q) and 21 (A21G)
      of Abeta show severe CAA with various degrees of brain parenchymal Abeta
      deposition. The purpose of this study was to investigate the effects of 2 mutant
      E22Q- and A21G-Abeta peptides on MV and aortic SMC. MERHODS: SMC were isolated
      from human cerebral MV and aorta. Cell morphology, viability, and proliferation
      as parameters of Abeta toxicity were investigated after 3 days of peptide
      treatment by trypan blue exclusion and [(3)H]thymidine incorporation. RESULTS:
      E22Q-Abeta induced significant decreased cellular proliferation and viability, as
      well as obvious degeneration of both MV and aortic SMC. A21G-Abeta and wild-type
      Abeta did not cause significant toxicity, as judged by cell morphology,
      viability, or cell proliferation, on either type of SMC. CONCLUSIONS: E22Q-Abeta
      induced greater toxicity in all parameters than A21G-Abeta and wild-type Abeta
      with respect to both MV and aortic SMC. A21G-Abeta did not show a significant
      toxic effect on MV and aortic SMC. This differential effect may be linked to cell
      type-specific processing and metabolism of mutant forms of Abeta. Mutations in
      amyloid precursor protein may lead to CAA by different pathogenetic mechanisms or
      share an unknown property that distinguishes them from wild-type Abeta.

PMID- 10657434
TI  - Diffusion-weighted magnetic resonance imaging in brain death.
AB  - BACKGROUND; Traditionally the diagnosis of brain death is established on the
      basis of a combination of clinical signs and paraclinical methods. Diffusion
      weighted MRI is a new method sensitive to cerebral ischemia. Its value in brain
      death has not been demonstrated until now. CASE DESCRIPTION: A patient was
      referred to MRI with suspicion of a brain stem stroke. Echo-planar whole-brain,
      multislice, diffusion-weighted MRI was performed in addition to conventional
      sequences and MR angiography sequences. In addition to the extensive bilateral
      hyperintensities observed on T2-weighted images, diffusion-weighted MRI showed
      diffuse hyperintensities involving both hemispheres as well as a severe drop in
      the apparent diffusion coefficient in both affected hemispheres. There was also
      transtentorial herniation with compression of the brain stem as well as absence
      of flow voids on the T2-weighted images and absence of intracranial vessels on MR
      angiography. On the basis of the clinical and imaging findings, it was concluded
      that the patient was in a state of brain death. The patient died the same day.
      CONCLUSIONS: With the use of new fast techniques such as diffusion-weighted
      imaging, now MRI can not only display anatomic changes associated with severe
      brain suffering but can also demonstrate ultrastructural changes secondary to
      brain death and differentiate them from edematous changes seen on T2-weighted
      images.

PMID- 10657435
TI  - Asymptomatic embolization predicts stroke and TIA risk in patients with carotid
      artery stenosis.

PMID- 10657436
TI  - Carotid stenosis determines impairment of ipsilateral dexterity in stroke.

PMID- 10657437
TI  - Induced elevation of blood pressure in the acute phase of ischemic stroke in
      humans.

PMID- 10657438
TI  - Cerebral venous thrombosis and the G20210A mutation of factor II.

PMID- 10657439
TI  - Abstracts of literature

PMID- 10657440
TI  - The following is a list of major ongoing studies about stroke. Information about
      other multicenter studies that might be included in this list should be submitted
      to the stroke editorial office by the principal investigator. The list will
      appear in the february, june, and october issues of stroke

PMID- 10657441
TI  - Open tip rhinoplasty along with the repair of cleft lip in cleft lip and palate
      cases.
AB  - This paper is a report on a procedure to perform open tip rhinoplasty at the time
      of lip repair in unilateral and bilateral cleft lip and palate deformity. A total
      of 69 patients who had this operation between 1994 and 1997 have been reviewed.
      Conventionally there is hesitation to do radical nasal correction for the cleft
      lip patient because of the fear of possible growth retardation. The present
      technique, while it achieves excellent postoperative results constantly, does not
      entail any more trauma to the cartilage complex than any of the conventional
      closed rhinoplasty techniques. Early results obtained by this method appear to be
      superior to those by closed rhinoplasty techniques.

PMID- 10657442
TI  - A rural cleft project in Uganda.
AB  - Over an 8-month period a cleft project was organised across Uganda. The aim of
      the project was to travel to as many districts as possible in the available time
      and repair all the cleft patients who could be mobilised. Local surgeons were
      trained and the results of the project were assessed. This was a prospective
      study which assessed immediate patient outcome, feedback from participating
      hospitals and cost. The team visited 20 hospitals, many in remote rural areas.
      All equipment necessary for surgery was transported to the hospitals. 336 cleft
      lip repairs and 41 cleft palate repairs were performed on 343 patients. There was
      no anaesthetic morbidity or mortality and no immediate perioperative morbidity.
      Two cleft lip repairs developed partial wound dehiscence and there was one
      palatal fistula. Five local surgeons underwent cleft training. All centres
      participating in this project requested further visits. The total cost for each
      cleft repair was 27 pounds sterling. Visiting remote centres with a mobile team
      is an efficient, safe and cost-effective method to treat the large numbers of
      unrepaired clefts in developing countries.

PMID- 10657443
TI  - Free colon transfer for pharyngo-oesophageal reconstruction.
AB  - This report describes free transfer of transverse colon for reconstruction of the
      hypopharynx and cervical oesophagus. The transverse colon based on the middle
      colic vessels was used in three patients following laryngo-pharyngo
      oesophagectomy for hypopharyngeal squamous carcinoma. There were no flap failures
      or intra-abdominal complications. Solid diet was well tolerated. Transverse colon
      is easy to harvest, has a long vascular pedicle, wide diameter and good ischaemic
      tolerance. Contrast studies showed it to be a wide bore passive conduit. Compared
      with currently available options these features may allow better outcome in
      pharyngo-oesophageal reconstruction and warrant further evaluation.

PMID- 10657444
TI  - Preplanned correction of enophthalmos using diced cartilage grafts.
AB  - A simple technique for correcting post-traumatic enophthalmos is presented.
      Autogenous costal cartilage was chopped into small pieces and used to fill up the
      medial orbital wall defect in five patients. The measured degrees of enophthalmos
      ranged from 2 to 4 mm, and 3-5. 5 ml of filler material was introduced into the
      periorbital space. A conservative approach via upper and lower eyelid incisions
      was used. It was found that 1.37-1.5 ml of graft material results in 1 mm
      advancement of globe position. This correlation appears to be a useful treatment
      guideline for medial orbital wall blow-out fractures. Transient diplopia
      developed in three cases, but settled within 4 months. There were no other major
      sequelae after the operation. The follow-up period ranged from 8 months to 3
      years. The improved appearance and the stable results confirm the validity of
      this approach.

PMID- 10657445
TI  - Hydroxyapatite cement: an alternative for craniofacial skeletal contour
      refinements.
AB  - Hydroxyapatite cement is a calcium phosphate preparation composed of tetracalcium
      phosphate and dicalcium phosphate anhydrous powders. When mixed with water it
      isothermically forms a paste which can easily be shaped intraoperatively. This
      mixture sets in approximately 15-20 min and converts into water insoluble,
      nonceramic, microporous hydroxyapatite in 4 h. This biomaterial was used to
      correct either congenital or traumatic craniofacial contour irregularities or
      deficiencies in 20 patients. On follow-up there was only one patient who required
      repeat surgery for further correction, there were no other complications. The
      good cosmetic results, the ease of operation, the pliability of the cement paste
      allowing precise moulding during application, the short operation time and the
      avoidance of a donor site makes hydroxyapatite cement an attractive material for
      treating craniofacial contour defects. Careful long term follow-up is necessary
      to establish its safety and reliability.

PMID- 10657446
TI  - The versatile anterolateral thigh flap: a musculocutaneous flap in disguise in
      head and neck reconstruction.
AB  - In search of an alternative soft tissue free flap donor site to radial forearm
      flap and rectus abdominis flap in head and neck reconstruction, we used the
      anterolateral thigh flap for reconstruction of various defects in the head and
      neck in 59 patients. The aim was to demonstrate the versatility of this donor
      site and propose a new approach to achieve a safer flap dissection. With the
      exception of three cases, all defects resulted from excision of malignant
      tumours. The defects were categorised as full thickness defects of the mandible
      (33.9%), full thickness defects of the cheek (52.5%) and others (13.6%). During
      the flap dissection a direct septocutaneous pedicle was observed in 12% of the
      cases. In the remaining cases there were only musculocutaneous perforators and
      the flaps were raised either as a split vastus lateralis musculocutaneous flap
      (72%) or as a perforator flap (16%), depending on the required thickness. Total
      flap survival was 96.7% with one total and one partial failure and two re
      explorations (3.3%). The mean follow-up time was 7.1 months (range: 1-12 months).
      In conclusion, the anterolateral thigh flap is a versatile and dependable flap
      that can be adapted to any type of defect by modifying the flap design and
      composition. It should be considered to be a musculocutaneous flap of the vastus
      lateralis muscle that can also be raised as a perforator flap. When harvested and
      used in this context, the flap dissection becomes very safe and consistent,
      nullifying the only major disadvantage associated with this donor site.

PMID- 10657447
TI  - Breast reconstruction by tissue expansion. A retrospective technical review of
      197 two-stage delayed reconstructions following mastectomy for malignant breast
      disease in 189 patients.
AB  - Despite the advent of free tissue transfer, breast reconstruction by tissue
      expansion is an important technique in the armamentarium of the reconstructive
      breast surgeon. The concept is deceptively simple and yet in reality can produce
      difficult complications and poor results. A database was compiled of all the
      patients receiving tissue expanders and/or implants for cosmetic, congenital and
      reconstructive purposes between 1986 and 1998. 189 patients had 197 delayed two
      stage tissue expansion breast reconstructions following mastectomies for
      malignant breast disease between 1986 and 1997. 103 breasts (52%) had two
      uncomplicated stages. The remainder had one or more complications, revisional
      procedures for complications or alterations to the reconstruction for size,
      position or shape. Overall each breast reconstruction required 2.9 procedures
      (range 2-9). The complications and additional procedures are discussed. In
      particular, capsular contracture of the definitive implant (12%) was related to
      implant type and not to the speed of tissue expansion or the degree or duration
      of over-expansion. Although 17% of patients received radiotherapy, none of those
      who developed contracture around the definitive implant had this adjuvant
      therapy, P< 0.05. Twelve reconstructions (6%) totally failed due to complications
      of which six underwent secondary flap reconstruction. Twenty-one patients have
      subsequently developed metastatic disease of which 15 have died to date. Breast
      reconstruction by tissue expansion is still an important technique. It should be
      used carefully and thoughtfully by surgeons trained to deal with any
      complications. Patients need to be carefully selected and counselled prior to
      undertaking this process.

PMID- 10657448
TI  - Normal saline wound dressing--is it really normal?
AB  - Gauze swabs soaked in normal saline are frequently used as dressing on open
      wounds. Their exact mechanism of action is not known. This study was designed to
      assess the hypothesis that normal saline dressings act in part as an osmotic
      dressing. Ten patients had skin ulcers (n = 10) dressed with normal saline soaked
      sponges. Acting as controls (n = 10) identical sponges were placed upon intact
      skin. The sponge fluid osmolarity and electrolyte concentrations were serially
      assayed to test our hypothesis. In the control group, the osmolarity, sodium and
      chloride concentrations increased with time as a result of evaporation, altering
      it from an isotonic to a hypertonic dressing. However, in the ulcer group, the
      osmolarity, sodium and chloride concentrations in the sponge fluid remained
      relatively isotonic with time. This result is statistically significant (P<
      0.05). We postulate that, as a result of evaporation, the sponge dressing
      increases its tonicity. This draws fluid from the wound into the dressing so that
      a dynamic equilibrium occurs and the sponge dressing regains isotonicity. The
      dressing remains functional provided that the wound fluid is absorbed freely from
      the wound. This process is terminated when either the dressing completely absorbs
      the wound fluid or the dressing dries out. The latter often occurs prematurely in
      a contaminated wound or in a wound where exudate forms a non-permeable barrier
      which prevents osmosis and allows the remaining water in the dressing to
      evaporate completely. This correlates with the observation in clinical practice
      that for maximum efficacy the dressing should be changed regularly.

PMID- 10657449
TI  - An analysis of p16 tumour suppressor gene expression in acral lentiginous
      melanoma.
AB  - Acral lentiginous melanoma is a particularly aggressive melanocytic lesion but,
      due to its comparative rarity, biological investigations into the behaviour of
      this subtype of melanoma are lacking. The activity of the recently described p16
      tumour suppressor gene, thought to be the 'familial melanoma gene', was studied
      in 24 patients with subungual melanoma and 44 patients with plantar melanoma.
      Lower levels of p16 oncoprotein were demonstrated than that found in other
      histogenetic types of melanoma. Stratification of patients of all disease stages
      revealed a poorer survival in patients with low p16 expression (log rank test,
      chi(2)= 3.9, P = 0. 05). These data suggest that p16 inactivation may play an
      important role in the development and progression of acral lentiginous melanomas.
      However, the level of p16 expression was not prognostic since survival analysis
      on stratification of stage I patients according to p16 level did not reach
      statistical significance for both survival and disease free interval.

PMID- 10657450
TI  - Generation of an autologous tissue (matrix) flap by combining an arteriovenous
      shunt loop with artificial skin in rats: preliminary report.
AB  - The present experiment was designed to investigate the possibility of
      prefabricating a tissue flap in a rat by combining an arteriovenous (A-V) shunt
      loop with artificial skin dermis (AS). The A-V fistula loop was constructed
      between the right femoral artery and vein by the interposition of a vein graft
      and the loop was wrapped with a folded sheet of AS and buried beneath the
      inguinal skin. In the control group the folded sheet of AS was inserted without a
      vessel loop and embedded in the inguinal region as in the experimental group.
      There were three experiments. In experiment 1, the total volume of the generated
      tissue formed within the AS was calculated after 4 weeks in the experimental and
      control groups. In experiment 2, the AS in the experimental group was harvested
      at 2 (group 1) and 4 (group 2) weeks after insertion to assess the change in
      morphology over time. In experiment 3, full thickness skin grafts were placed
      over the generated tissue of the experimental groups to investigate the
      possibility of creating skin flaps. The total volume of tissue generated in the
      experimental group was significantly greater than in the control group (P< 0.01).
      Histological and carbon injection studies suggest that the new capillary bed is
      derived from the graft loop vessels and tissue generation and organisation of the
      AS were further advanced in group 2 than in group 1. The skin grafts placed over
      the tissues generated showed complete survival and could be raised as island
      flaps in both groups.

PMID- 10657451
TI  - The influence of helium-neon laser irradiation on the viability of skin flaps in
      the rat.
AB  - Low energy helium-neon (He-Ne) laser irradiation has been shown to induce various
      therapeutic effects. We investigated its effect on the viability of skin flaps in
      the rat. Thirty rats underwent skin flap elevation and were then divided into
      three equal groups. Group I (control) was not irradiated. Groups II and III were
      irradiated for 5 days postoperatively, Group II to the transition zone (between
      the live and expected necrotic areas) and Group III to the transitional and
      distal zones; total energy, 2.9 J/cm(2)for each rat. Ten days after the last
      treatment larger surviving areas were demonstrated macroscopically in Groups II
      and III (P< 0.01 and 0.001, respectively). Histological examination showed
      tremendous proliferation of capillaries (P</= 0.05) and fibroblasts in the
      responsive irradiated areas. In conclusion, postoperative low-energy (2.9
      J/cm(2)) He-Ne laser irradiation of the expected ischaemic zone of the rat flap
      can enlarge the surviving area. Irradiation of the whole expected ischaemic zone
      seems to be superior to irradiating the transition zone alone.

PMID- 10657452
TI  - A modified gag for cleft palate repair.
AB  - A number of modifications of the tongue blade of the Dott mouth gag for cleft
      palate surgery are described and illustrated. These modifications facilitate
      cleft palate surgery, especially on small infants and patients with micrognathia,
      as well as surgery under the microscope and also reduce the risk of compression
      of the endotracheal tube.

PMID- 10657453
TI  - Facio-genito-popliteal syndrome presenting with bilateral choanal atresia and
      maxillary hypoplasia.
AB  - The most classic characteristics of facio-genito-popliteal syndrome are cleft lip
      and/or palate, anomalies of the external genitalia and popliteal pterygium. A
      case of facio-genito-popliteal syndrome with bilateral choanal atresia and
      maxillary hypoplasia is presented. No previous report of such an association was
      found in the literature.

PMID- 10657454
TI  - Laurin-Sandrow syndrome--a surgical challenge.
AB  - We describe the sixth reported case of Laurin-Sandrow syndrome. This spectrum of
      congenital abnormalities includes complex syndactyly, often associated with ulnar
      duplication, mirror feet and columella deformities. We discuss Laurin-Sandrow
      syndrome and report on its surgical management.

PMID- 10657455
TI  - Application of dermal substitute (Integra) to donor site defect of forehead flap.
AB  - Although forehead flap has limited use, it may have a role as a 'third' line
      option. Its primary complication is the poor cosmetic defect on the forehead. A
      case is presented in which, after harvesting the flap for reconstruction of the
      oral cavity, a dermal substitute (Integra) together with split thickness skin
      graft was used for the management of this wound. The result was significantly
      improved over using split skin graft alone.

PMID- 10657456
TI  - A facial low-flow venous malformation treated with fibrin glue.
AB  - A young girl with recurrent swelling of a facial low-flow venous malformation was
      treated successfully by injection of fibrin glue.

PMID- 10657457
TI  - Successful partial ear replantation after prolonged ischaemia time.
AB  - We present the case of a 34-year-old male patient who had successful replantation
      of upper pole of pinna 33 h after amputation. As no vein was anastomosed,
      systemic heparinisation and subcutaneous injection of heparin to the replanted
      ear were used to encourage outflow. Complications included arterial spasm and
      bleeding. Management of similar cases as planned urgent cases rather than
      emergency cases is discussed.

PMID- 10657458
TI  - Free tissue transfer in patients with systemic lupus erythematosus.
AB  - Systemic lupus erythematosus is a non-organ specific, autoimmune disease
      characterised by antinuclear antibodies and vasculitis. This may manifest itself
      with areas of cutaneous necrosis which may require extensive excision and
      reconstruction. Major areas of skin and soft tissue loss may require coverage
      with either local or microvascular free tissue transfer. This presents potential
      difficulties in patients with generalised vasculitis. We present the case of a
      professional cellist with extensive soft tissue loss in her dominant hand,
      successfully reconstructed with a free latissimus dorsi muscle flap, treated with
      peri- and postoperative anticoagulation and corticosteroids.

PMID- 10657459
TI  - An unusual scalp swelling.

PMID- 10657460
TI  - The use of modified rhytidectomy for parotidectomy.

PMID- 10657461
TI  - Placement of sutures in tendon repair.

PMID- 10657462
TI  - Supernumerary muscle belly in ulnar artery forearm flap elevation.

PMID- 10657463
TI  - The use of 'retention dressings' on partial thickness wounds.

PMID- 10657464
TI  - Towards the quantification of disfigurement.

PMID- 10657465
TI  - Understanding corticotropin releasing factor neurobiology: contributions from
      mutant mice.
AB  - Mice with transgenic expression or deletion of the CRF peptide, transgenic
      expression of the CRF-BP or deletion of specific CRF receptor subtypes exist and
      will be valuable for examining candidate mediators in animal model systems
      recapitulating a variety of normal function. In particular, results described in
      this review implicate CRF in acute emotional responses studied in animal models
      of anxiety and drug abstinence. CRF also appears to play a role in behavioral and
      physiological plasticity judging by alterations in HPA reactivity to stress,
      information processing and energy balance regulation in CRF mutant models.
      Accordingly, the creation of genetically engineered mice now permits the
      evaluation of contributory roles for several CRF-related gene products in the
      pathophysiology of a variety of complex behavioral disorders. For example, the
      postulated causal linkage between overactivation of CRF systems and the hyper
      emotionality which characterizes human affective disorders can now be more
      thoroughly evaluated by examining the phenotype of CRF mutant mice in animal
      models of depression, dementia and substance abuse.

PMID- 10657466
TI  - Calcium-mediated endothelin signaling in C6 rat glioma cells.
AB  - Endothelin induced intracellular Ca(2+)signaling was studied in C6 rat glial
      cells. Endothelins 1 and 3 increased transiently intracellular
      Ca(2+)concentration, endothelin 3 being less potent inducer. Dibutyryl-cAMP
      treated cells responded with less sensitivity. While BQ123, a specific endothelin
      A receptor antagonist, inhibited both endothelins induced response in
      proliferating cells, it failed to inhibit in dibutyryl-cAMP treated ones.
      IRL1620, a specific endothelin B receptor agonist, was devoid of any significant
      effect. Although re-stimulation by both endothelins after endothelin-1 did not
      cause any Ca(2+)oscillation, both endothelins evoked new Ca(2+)transient after
      endothelin-3 stimulation. Our findings suggest that endothelin induced
      Ca(2+)signaling is mediated probably through the receptor A in proliferating C6
      cells. The lack of both BQ123 and IRL 1620 effect in dibutyryl-cAMP treated cells
      could be caused by an alteration of endothelin A receptor alone, by a change of
      receptor expression pattern, or by more complex postreceptor mechanism.

PMID- 10657467
TI  - Distributions of VIP, substance P, neurokinin A and neurotensin in rat heart: an
      immunocytochemical study.
AB  - Vasoactive intestinal peptide (VIP) is a peptide amide containing 28 amino acids
      which was first isolated from the intestine and is distributed over the entire
      body but primarily in the nervous system. It is released in response to the
      electrical stimulation of nerve fibres, stimulation of the vagus, prostaglandin
      E1, oxytocin, operation stress, corticosterone. In the cardiovascular system, VIP
      has a vasodilation, hypotension, positive chronotropic and inotropic effects.

PMID- 10657468
TI  - NK(2)-receptor mediated contraction in monkey, guinea-pig and human airway smooth
      muscle.
AB  - Neurokinins (NK) are implicated in airway pathology. Selective NK(2)-receptor
      antagonists may prove therapeutic in airway disease. We studied Neurokinin A
      (NKA) responses of isolated, cryopreserved cynomolgus monkey, fresh guinea pig,
      and fresh and cryopreserved human airways. NKA contracted monkey trachea (pD(2)=
      7.9), guinea-pig bronchus (pD(2)= 8.8) and human bronchus (pD(2)= 7.1). Potency
      rank order (pK(b)) of NK(2)-antagonists, SR 48968 and GR 159897, and a dual
      NK(1)/NK(2)-antagonist, MDL 103392, against NKA responses in monkey trachea,
      guinea pig and human bronchus, respectively, were SR 48968 (9.29 +/- 0.11, 9.15
      +/- 0.10 and 9.51 +/- 0.17) > GR 159897 (8.45 +/- 0.26, 8.19 +/- 0.13 and 8.57 +/
      0. 22) > MDL 103392 (6.55 +/- 0.13, 6.97 +/- 0.14 and 7.16 +/- 0.13). CP 99994
      (1 microM), a NK(1)-receptor antagonist, was inactive against NKA responses in
      all three species. The NK(3)-antagonist SR 142801 (1 microM) was inactive against
      NKA in monkey trachea and guinea-pig bronchus, but demonstrated weak antagonist
      activity (pK(b)= 6.97 +/- 0.03) in human bronchus. These findings demonstrate
      that NK(2)-receptors mediate tracheal smooth muscle contraction to NKA in
      cynomolgus monkey and that the pharmacological responsiveness of airway NK(2)
      receptors in the three species studied is similar. Furthermore, our results
      suggest that cryopreservation may extend the viability of human and non-human
      primate airway tissue for studies of neurokinin receptor pharmacology. Studies
      are needed to further determine the similarity in neurokinin pharmacology between
      fresh and cryopreserved airway tissue.

PMID- 10657469
TI  - Antisera to multiple antigenic peptides detect neuropeptide processing.
AB  - Peptides act as critical messengers of essential physiological function.
      Frequently, several peptides are encoded in the same precursor and, often, there
      is structure relatedness among the gene products. The complexity of protein
      precursors and presence of homologous peptides raises issues about regulation of
      gene expression and function of structurally-related peptides. We have determined
      the cellular location of DPKQDFMRFamide and SDNFMRFamide encoded in the
      Drosophila FMRFamide gene. We raised antisera that distinguish between the two
      peptides and conducted double label immunostaining utilizing antisera raised in
      the same host species. We found that DPKQDFMRFamide and SDNFMRFamide are present
      in distinct distribution patterns. We also established that the peptides are
      present in cells stained by FMRFamide antisera. Thus, our data are consistent
      with the conclusion that Drosophila contains cell-specific proteolytic processing
      enzymes capable of posttranslationally cleaving a polypeptide protein precursor
      to yield unique expression patterns of neuropeptides that may have diverse
      activities.

PMID- 10657470
TI  - Blockade of calcitonin gene-related peptide release after superior sagittal sinus
      stimulation in cat: a comparison of avitriptan and CP122,288.
AB  - The pathophysiological basis for the pain of migraine has been the subject of
      substantial attention and must include activation of elements of the trigeminal
      innervation of the cranial vessels, the trigeminovascular system. Recently,
      consideration of trigeminal-evoked neurogenic plasma protein extravasation (PPE)
      as a model for the pain has driven the search for compounds with specific anti
      extravasation properties. Calcitonin gene-related peptide (CGRP) is a marker for
      trigeminovascular activation and is released during the headache phase of
      migraine and cluster headache. CGRP may have a role in migraine through its
      potent cranial vasodilator effects or by an action on trigeminal nerve activity,
      both of which are targeted by 5HT(1B/1D)agonist drugs but does not itself produce
      PPE. It has been suggested that 5HT(1B/1D)agonists may have an anti-migraine
      effect via inhibition of PPE in the dura mater. Avitriptan and CP122,288 both
      have strong binding affinities for 5HT(1B/1D)receptors, but only CP122,288 is a
      potent inhibitor of PPE. In this study we sought to compare the effects of
      CP122,288 and avitriptan on jugular vein CGRP release after stimulation of the
      superior sagittal sinus (SSS) in the cat. In eleven anaesthetized cats external
      jugular vein blood samples were analyzed by radioimmunoassay for CGRP levels in
      three settings: a) control, b) 1 min after SSS stimulation and c) 1 min after SSS
      stimulation in presence of drug. Stimulation of the SSS resulted in release of
      CGRP from the external jugular vein (77+/-1 pmol/L). At a PPE-inhibitory dose in
      rat (100 ng/kg intravenously) CP122, 288 had no effect on CGRP release (77+/-6
      pmol/L) whereas at a clinically relevant dose (50 microgram/kg intravenously)
      avitriptan blocked CGRP release. This study demonstrates that the potent
      inhibitor of PPE, CP122, 288, which has been shown in clinical trials to be
      ineffective in treating acute migraine attacks, had no effect on CGRP release,
      whereas the effective anti-migraine drug and relatively impotent inhibitor of
      PPE, avitriptan, blocked CGRP release. These data emphasize the importance of
      CGRP release and its possible independence from PPE in migraine and more
      importantly suggest that other non-5HT-based pharmacological targets may account
      for PPE blockade in animal studies.

PMID- 10657471
TI  - Calcitonin gene-related peptide receptors in pig spleen and the involvement of
      the CGRP(1)receptor in the splenocyte function.
AB  - Calcitonin gene-related peptide (CGRP)-positive nerve fibers have been found in
      the trabecula and parenchyme area of pig spleen. Receptor studies have
      demonstrated that the CGRP binding site in pig spleen membranes has an average
      K(d)2.24 +/- 0.48 nM and B(max)78 +/- 4.09 fmol/mg of protein. In the K(d)range
      demonstrated in the binding studies, the dose-dependent suppressive effect of
      CGRP on spleen T lymphocyte proliferation was found with the maximal effect in
      10(-9)M concentration. The same effect, but in a different concentration, was
      found on peripheral blood T lymphocytes with the maximum in 10(-6)M
      concentration. Contrary to the results obtained through the simultaneous presence
      of CGRP and mitogen, preincubation with CGRP led to a stimulation of peripheral
      blood lymphocytes in response to ConA and had no effect on spleen T lymphocytes.
      These results illustrate the difference in CGRP effect between lymphocytes of
      different origins. Using CGRP(1)receptor antagonist CGRP(8-37), we established
      that the CGRP suppressive effect on spleen T lymphocyte proliferation is CGRP(1)
      receptor mediated.

PMID- 10657472
TI  - Effects of selective tachykinin-receptor antagonists on tachykinin-induced airway
      mucus secretion in the rat.
AB  - Tachykinins like substance P (SP), neurokinin A (NKA), neurokinin B (NKB)
      differentially stimulate airway mucus secretion with the following rank order of
      potency in rat trachea: SP>NKA>NKB. These differential actions are most likely
      due to different affinities to the tachykinin receptors, termed neurokinin
      (NK)(1), NK(2)and NK(3). In this study we characterized the receptor subtype
      responsible for the differential secretagogue effects in rat trachea by means of
      selective receptor antagonists and receptor agonists.SR 140333 [NK(1)-antagonist]
      completely inhibited SP action (283,29+/-21, 12%-->84,53+/-4, 09%; P<0,01) and
      significantly reduced the effects of NKA (179,08+/-17,34%-->118,86+/-6,7%;
      P<0,01) and NKB (171,89+/-5, 75%-->109,5+/-4,11%; P<0,01). SR 48968 [NK(2)
      antagonist] did not affect SP action, but reduced the effects of NKA and NKB. SR
      142801 [NK(3)-antagonist] did not change any effect of SP, NKA or NKB. [Sar(9)]SP
      (NK(1)-agonist) caused strong dose-dependent secretagogue effects similar to SP,
      [betaAla(8)]NKA (NK(2)-agonist) showed only slight and [Pro(7)]NKB (NK(3)
      agonist) no effects. The present data suggest that the secretagogue effects
      elicited by tachykinins in rat trachea are mediated via NK(1)receptors.

PMID- 10657473
TI  - BOC-CCK-4, CCK(B)receptor agonist, antagonizes anxiolytic-like action of morphine
      in elevated plus-maze.
AB  - This study investigated a role of cholecystokinin (CCK) in the anxiolytic-like
      action of morphine, an agonist of mu-opioid receptors, in the rat plus-maze model
      of anxiety. The acute administration of morphine (1 mg/kg) induced a significant
      increase of exploratory activity in the plus-maze, but did not affect the
      locomotor activity in the motility test. The higher dose of morphine (2.5 mg/kg)
      tended to decrease the locomotor activity and, therefore, did not cause the
      anxiolytic-like action in the plus-maze. The other drugs (naloxone, BOC-CCK-4, L
      365,260) and their combinations with morphine (0.5-1 mg/kg) did not affect the
      locomotor activity of rats. The opioid antagonist naloxone itself (0.5 mg/kg) did
      not change the exploratory activity in the plus-maze, but potently antagonized
      the anxiolytic-like action of morphine (1 mg/kg). An agonist of CCK(B)receptors
      BOC-CCK-4 (1-50 microgram/kg) induced a dose-dependent anxiogenic-like action in
      the plus-maze. Nevertheless, only one dose of BOC-CCK-4 (10 microgram/kg)
      completely reversed the action of morphine. Also, one dose of CCK(B)receptor
      antagonist L-365,260 (10 microgram/kg) was effective to modify the behaviour of
      rats in the elevated plus-maze. Namely, this dose of L-365,260 increased the
      ratio between open and total arm entries, a behavioural measure believed to
      reflect the anxiolytic-like action in the elevated plus-maze. The combination of
      L-365,260 (100 microgram/kg) with the sub-effective dose of morphine (0.5 mg/kg)
      caused the anxiolytic-like action in the plus-maze not seen if the drugs were
      given alone. In conclusion, morphine induces a potent anxiolytic-like action in
      the elevated plus-maze and CCK is acting as an endogenous antagonist of this
      effect of morphine.

PMID- 10657474
TI  - Overview on the sub-grouping of the crustacean hyperglycemic hormone family.
AB  - The Crustacean hyperglycemic hormones (CHHs) are an ever extending family of
      crustacean hormones mainly involved in carbohydrate metabolism, molt and
      reproduction. In this paper, we drew together 32 available CHH sequences, and
      applied the techniques of multiple sequence alignment, motif searching and amino
      acid conservation analysis to the characterization of the molecules independently
      of their biological function. The analysis clearly showed that the proteins
      clustered into two groups (CHH and VIH). Amino acid conservation analysis also
      subdivided the VIH group into sequences involved in reproduction (RIH) or in molt
      (MIH). Motif searching identified five motifs in each group of mature hormones.
      Motifs A2 and A3 were conserved in all sequences while motifs A1 and A1' were
      specific of the CHH and VIH groups respectively. This approach demonstrated the
      S. gregaria ion transport peptides as true members of the CHH group. The two main
      groups, CHH and VIH, are also discussed in terms of functional homogeneity.

PMID- 10657475
TI  - Characterization of potential regulatory elements within the rat arginine
      vasopressin proximal promoter.
AB  - In order to identify potential cis acting regulatory elements in the rat arginine
      vasopressin promoter, spanning nucleotides -374 to -36, we have carried out
      DNAase1 footprint analysis complemented by electrophoretic mobility shift
      analysis. This analysis has identified distinct transcription factor binding
      sites within this region. These are: 1) five E box motifs which are bound by
      members of the basic helix loop helix family of transcription factors; 2) two dGC
      rich elements which bind multiple complexes including Sp1; 3) a single AP1
      element which binds a complex containing c-Fos or Fos related antigens. The
      location of these elements and their relationship to one another suggests
      combinatorial interaction amongst these factors as a mechanism of transcriptional
      regulation of the rat arginine vasopressin proximal promoter.

PMID- 10657477
TI  - Meetings calendar

PMID- 10657476
TI  - Tachykinin NK(1)receptor-mediated inhibitory responses in the guinea-pig small
      intestine.
AB  - We used in vivo, in vitro studies and immunohistochemistry to elucidate the
      mechanisms activated by tachykinin NK(1)receptors in evoking inhibitory motor
      response in the guinea-pig small intestine. In vivo, the selective NK(1)receptor
      agonist GR 73,632 produced a dose-dependent suppression of the distension-induced
      duodenal contractions, and a decrease of basal tone. These effects were reduced
      by pretreatment with the NK(1)receptor antagonist SR 140,333. In L-Nomega-nitro-L
      arginine methylesther hydrochloride-pretreated animals, the suppressant effect of
      GR 73,632 on duodenal contractions was reduced, whereas the relaxation of the
      basal tone was unaffected. In vitro, GR 73,632 evoked a biphasic response
      consisting of a transient, tetrodotoxin-sensitive inhibitory effect followed by
      tetrodotoxin-resistant contractions. SR 140,333 blocked both inhibitory and
      excitatory motor responses induced by GR 73,632. NK(1)immunoreactivity was
      localized to myenteric and submucosal neurons and to interstitial cells of Cajal
      in the deep muscular plexus of the small intestine. NK(1)receptor-expressing
      neurons had Dogiel type I morphology and many of them were beta-nicotinamide
      adenine phosphate dinucleotide-diaphorase-positive, indicating they are
      inhibitory neurons. In conclusion, in the guinea-pig small intestine,
      NK(1)receptor stimulation evokes a myogenic excitatory motor response and a
      neurogenic inhibitory motor response that involves, at least in part, a
      nitrinergic pathway.

PMID- 10657478
TI  - Effects of ginsenosides injected intrathecally or intracerebroventricularly on
      antinociception induced by beta -endorphin administered intracerebroventricularly
      in the mouse.
AB  - The effect of total saponin fraction of ginseng injected intrathecally (i.t.) or
      intracerebroventricularly (i.c.v.) on the antinociception induced by beta
      endorphin administered i.c.v. was studied in ICR mice in the present study. The
      antinociception was assessed by the tail-flick test. Total saponin fraction at
      doses 0.1 to 1.0 microgram, which administered i.t. alone did not affect the
      latencies of tail-flick threshold, attenuated dose-dependently the inhibition of
      the tail-flick response induced by i.c.v. administered beta-endorphin (1
      microgram). However, total saponin fraction at doses 1 to 20 microgram, which
      administered i.c.v. alone did not affect the latencies of the tail-flick
      response, did not affect i.c.v. administered beta-endorphiun (1 microgram)
      induced antinociception. The duration of antagonistic action of total saponin
      fraction against beta-endorphin-induced antinociception lasted at least for 6 h.
      Various doses (from 0.1 to 1 microgram) of ginsenoside R(c), but not R(b2), R(d),
      Rg(1), R(b1)and R(e)injected i.t. dose-dependently attenuated antinociception
      induced by beta-endorphin administered i.c.v. Our results indicate that total
      saponin fraction injected spinally appears to have antagonistic action against
      the antinociception induced by supraspinally applied beta-endorphin. Ginsenoside
      R(c)appears to be responsible for blocking i.c.v. administered beta-endorphin
      induced antinociception. On the other hand, total ginseng fraction, at
      supraspinal sites, may not exert an antagonistic action against the
      antinociception induced by supraspinally administered beta-endorphin.

PMID- 10657479
TI  - Maxadilan interacts with receptors for pituitary adenylyl cyclase activating
      peptide in human SH-SY5Y and SK-N-MC neuroblastoma cells.
AB  - Receptors for pituitary adenylyl cyclase activating peptide (PACAP) have been
      identified in human SH-SY5Y neuroblastoma cells with PACAP being 1000-fold more
      potent than vasoactive intestinal peptide (VIP) in [(125)I]PACAP binding
      inhibition and stimulation of cAMP accumulation. Maxadilan, a vasodilator peptide
      from the salivary gland of the sand fly Lutzomyia longipalpis also specifically
      bound to SH-SY5Y cells, and was equipotent to PACAP in [(125)I]PACAP and
      [(125)I]maxadilan binding inhibition, and stimulation of cAMP accumulation.
      Maxadilan and PACAP also increased the cytosolic free calcium concentration. In
      human SK-N-MC neuroblastoma cells PACAP, VIP and maxadilan equipotently
      stimulated cAMP accumulation. The maximal effects of VIP and maxadilan were
      additive and reached those of PACAP alone. In human T47D breast carcinoma cells
      PACAP and VIP were also equipotent in the stimulation of cAMP accumulation, but
      maxadilan was inactive. The results are consistent with the interaction of
      maxadilan with PACAP specific PAC(1)receptors in SH-SY5Y cells, but not with VPAC
      receptors, not differentiating between VIP and PACAP in T47D cells. Moreover,
      maxadilan is a PAC(1)receptor specific agonist which allows discrimination of co
      expressed PAC(1)and VPAC receptors in SK-N-MC cells.

PMID- 10657480
TI  - The induction and potentiation of c-Jun and c-Fos expression in spinal neurons
      mediated by NK1 and NK2 receptors.
AB  - Specific antagonists were used to determine NK1 and NK2 receptor mediation of the
      expression of c-Jun and c-Fos inducible transcription factors. (ITFs) in dorsal
      horn neurons. The induction of c-Jun by C-fiber stimulation was strongly reduced
      in the superficial laminae by NK1 and NK2 antagonists, but only weakly in the
      deep laminae by NK2 antagonism. c-Fos induction was reduced in all laminae by
      both NK1 and NK2 antagonism but less than with c-Jun. The potentiation of c-Jun
      expression, caused by a preceding stimulus, was abolished in all laminae by NK1
      and NK2 antagonists, whereas that of c-Fos was reduced in all laminae but again
      less than that of c-Jun. Thus, the expressions of ITFs mediated by NK1 and NK2
      receptors are complex, depending upon the neurons and stimulus considered, and
      they are not a measure of the neurons' electrophysiological responsiveness.

PMID- 10657482
TI  - Effects of morphine and U-50,488H on neurochemical activity of the hypothalamic
      noradrenergic neurons and pituitary-adrenal response.
AB  - We examined the ability of morphine and U-50,488 H administered acutely to the
      rat to modify the hypothalamic noradrenaline (NA) content and turnover as well as
      corticosterone release. Hypothalamic NA and its metabolite 3-methoxy-4-hydroxy
      phenylethylen glycol (MHPG) were determined by high-performance liquid
      chromatography (HPLC). Plasma corticosterone was measured by radioimmunoassay
      (RIA). The administration of morphine (30 mg/kg i.p.) induced a decrease in the
      hypothalamic content of NA, with an enhancement in the MHPG and the MHPG/NA
      ratio. Similarly, the administration of U-50,488 H (15 mg/kg i.p.) produced an
      increase in the MHPG and MHPG/NA ratio without any changes in the NA content. The
      present results also show that corticosterone secretion was increased after acute
      morphine or U-50,488 H, in parallel with an enhanced NA turnover and strongly
      suggest that noradrenergic neurons have stimulatory effects on the HPA axis
      activity, reflecting an indirect action of opioid on the axis through
      hypothalamic catecholaminergic systems.

PMID- 10657481
TI  - Effects of histamine receptor antagonists injected intrathecally on
      antinociception induced by opioids administered intracerebroventricularly in the
      mouse.
AB  - The present study was designed to investigate the modulatory effects of blockade
      of spinal histamine receptors on antinociception induced by supraspinally
      administered mu-epsilon-, delta-, and kappa-opioid receptor agonists. The effects
      of intrathecal (i.t.) injections with cyproheptadine [a histamine-1 (H1) receptor
      antagonist], ranitidine (a H2 receptor antagonist), or thioperamide (a H3
      receptor antagonist) injected i.t., on the antinociception induced by morphine (a
      mu-receptor antagonist), beta-endorphin (an epsilon-receptor agonist), D-Pen(2,5)
      enkephalin (DPDPE, a delta-receptor agonist) or trans-3, 4-dichloro-N-methyl-N-[2
      (1-pyrrolidinyl) cyclohxyl] benzeocetamide (U50,488H, a kappa-receptor agonist)
      injected intracerebroventricularly (i.c.v.) were studied. The antinociception was
      assayed using the tail-flick test. The i.t. injection of cyproheptadine (from
      0.31 to 62 nmole), ranitidine (from 0.28 to 56 nmole), or thioperamide (from 0.24
      to 48 nmole) alone did not show any antinociceptive effect. The i.t. pretreatment
      with cyproheptadine or thioperamide dose-dependently attenuated the inhibition of
      the tail-flick response induced by i.c.v. administered morphine (0.6 nmole), b
      endorphin (0.03 nmole), DPDPE (1.5 nmole), and U50,488H (130 nmole). In addition,
      the i.t. pretreatment with ranitidine dose-dependently attenuated the inhibition
      of the tail-flick response induced by morphine, b-endorphin and U50,488H without
      affecting DPDPE-induced response. Our results suggest that spinal histamine H1
      and H3 receptors may involved in the production of antinociception induced by
      supraspinally applied morphine, b-endorphin, DPDPE and U50,488H. Spinal H2
      receptors appear to be involved in supraspinally administered morphine, b
      endorphin- and U50,488H-induced antinociception but not DPDPE-induced
      antinociception.

PMID- 10657483
TI  - Dynorphin A enhances mitogen-induced proliferative response and interleukin-2
      production of rat splenocytes.
AB  - It has been well known that immune function is modulated by endogenous opioid
      peptides: beta-endorphin and enkephalins. However, the effect of dynorphin A on
      the immune function has not been well documented. In this study, we investigated
      dynorphin A in the regulation of mitogen-induced proliferation and and
      interleukin-2 (IL-2) production of rat splenocytes. The results showed that
      dynorphin A 1-13 as well as dynorphin A 1-17 enhanced concanavalin A-stimulated
      [(3)H] thymidine uptake 46-112% and IL-2 production in a dose-dependent fashion.
      These effects were reversed by naloxone and norBNI, a selective kappa-receptor
      antagonist. Dynorphin A reduced cyclic AMP contents in spenocytes in naloxone and
      norBNI reversible fashion. The data suggest that dynorphin A enhanced mitogen
      stumulated lymphocyte proliferation and IL-2 production via kappa-opioid receptor
      and cAMP pathway.

PMID- 10657485
TI  - Lateralization of aminopeptidase A activity in substantia nigra, striatum and
      frontal cortex of rats.
AB  - Several brain aminopeptidase activities have been reported to be asymmetrical,
      but no direct correlation with lateralized functions has been proposed.
      Cholecystokinin (CCK) coexists with dopamine (DA) in the nigrostriatal system,
      which is involved in lateralized motor behaviors. Because aminopeptidase A
      activity is probably responsible for the hydrolysis of CCK, we studied the left
      right distribution of glutamate- (GluAP) and aspartate-aminopeptidase (AspAP)
      activities in their soluble (Sol) and membrane-bound (M-B) forms in the
      substantia nigra, striatum and cortex of rats. Although there was a highly
      significant predominance of the left side in the substantia nigra and striatum
      for Sol GluAP and M-B AspAP respectively, in the frontal cortex predominance was
      on the right side for M-B AspAP. These results suggest a relationship between
      aminopeptidase A activity and lateralized nigro-striato-cortical functions
      involving CCK.

PMID- 10657484
TI  - Calcitonin gene-related peptide causes long-term inhibition of contraction in rat
      thoracic aorta through a nitric oxide-dependent pathway.
AB  - Calcitonin gene-related peptide (CGRP) is released into the circulation during
      pathogenesis of endotoxin and septic shock and appears to partly mediate vascular
      problems of shock. To explore the function of CGRP during shock, we investigated
      long-term action of CGRP, alone or in combination with interleukin-1beta (IL
      1beta), another shock mediator, in isolated rings of rat thoracic aorta. CGRP or
      IL-1beta, by themselves, caused significant long-term (3 h) depression of
      contraction, while the combination of CGRP and IL-1beta had no synergistic
      effects. Dose-response curves to phenylephrine were significantly decreased and
      shifted to the right when aortic rings were incubated with 1 microM CGRP for 1 h
      followed by 2 h incubation without CGRP. Inducible nitric oxide synthase (iNOS)
      inhibitors, S-methylisothiourea sulfate (SMT) and N(G)-nitro-L-arginine (L-NNA),
      completely eliminated long-term depressant effect of CGRP. Our results suggest
      pathology of septic shock may involve long-term inhibition of vascular
      contraction mediated by CGRP via expression of iNOS.

PMID- 10657486
TI  - Expression of neuropeptides and other neuroendocrine markers in human
      phaeochromocytomas.
AB  - AIMS: Phaeochromocytomas may produce several neuropeptides as they are considered
      neuroendocrine tumours. Nevertheless, studies are scarce and no clear predictive
      biologic value has been stablished in the case of neuropeptides expression.
      METHODS: We have investigated immunohistochemically the neuropeptides expression
      of a serie of 36 phaeochromocytomas: 25 sporadic, seven familial type MEN
      (multiple endocrine neoplasm) and four familial phaeochromocytomas not associated
      with MEN syndrome. The reactivity for neuron-specific enolase (NSE),
      synaptophysin, vasoactive intestinal peptide (VIP), chromogranin A, calcitonin,
      ACTH, somatostatin and HMB-45 was tested according to the avidin-biotin complex
      (ABC) method using polyclonal antibodies. RESULTS: Phaeochromocytomas have a
      multiple synthetic activity as main neuroendocrine feature. Despite
      phaeochromocytoma tumour cells heterogeneity chromogranin and synaptophysin are
      the most common neuropeptides synthesised, as they are associated with the
      presence of neuroendocrine storage granules. We find a statistically significant
      higher synthesis of corticotrophin hormone in familial phaeochromocytomas than in
      sporadic forms, on the contrary the synthesis of VIP is statistically associated
      with sporadic forms of phaeochromocytomas. We also found a direct relation of
      ACTH and overexpression and malignant tumours and a positive relationship between
      NSE and benign forms of phaeochromocytomas.

PMID- 10657487
TI  - Regulatory peptides in the heart and major vessels of man and mammals.
AB  - Studies on the distribution of peptides in human tissues have been made either by
      measuring responses to localized stimuli or by subjecting extracts of different
      regions to radioimmunoassay (RIA). Attempts at isolating regulatory peptides from
      the mammalian tissues have resulted in the isolation of many bioactive fragments.
      Later, modification of initial isolation methods led to the identification of the
      native molecules in various tissues and body fluids. The present study examined
      atrial natriuretic peptide (ANP) and several other peptides in cardiac tissues of
      several species of laboratory mammal and human beings; using a sensitive and
      highly specific radioimmunoassays. In all the species studied, ANP-like
      immunoreactivity appeared to be highest in the heart tissue of rat. The peptide
      was highest in the right atrium (RA) of rat and lowest in the RA of guinea pig
      (P< 0.002). Neuropeptide Y (NPY) another abundant cardiac peptide was present in
      the cardiac tissues of all species but was more in the left atrium (LA) than the
      RA of all species (P<0.05). Calcitonin gene-related peptide (CGRP) was present
      throughout the cardiovascular system of the rat and guinea pig. Small but
      detectable amount of Neurotensin (NT) immunoreactivity was found in the rat but
      was consistently negative in the guinea pig cardiac tissues (P< 0.05). Substance
      P (SP) immunoreactivity was detected in the rat and higher quantities being in
      the Aorta but no trace of the peptide was detected in the left ventricle, aorta
      nor the pulmonary vein of post mortem human. Though the structure of most of the
      species studied has been elucidated, the primary structure of guinea pig ANP has
      not been fully generated. Thus the data obtained may suggest that in keeping with
      these mammalian peptides, the primary structures may be variant. With most of the
      peptides studied (e.g. ANP, Neuropepdide Y), immunoreactivity occurs
      predominantly in the atrial tissues, but is also present in vessels outside the
      heart, a finding which may be of functional significance.

PMID- 10657488
TI  - Age-related changes in the modulatory action of gastrin-releasing peptide,
      neuropeptide Y and sulfated cholecystokinin octapeptide in the proliferation of
      murine lymphocytes.
AB  - Several investigations have suggested that the interactions between the nervous
      and immune systems are modified with age. The aim of the present work was to
      study the effect in vitro of three neuropeptides: gastrin-releasing peptide
      (GRP), neuropeptide Y (NPY) and sulfated cholecystokinin octapeptide (CCK-8s) on
      the spontaneous, as well as on the response to mitogen (concanavalin A),
      proliferative activity of spleen, thymus and axillary node leukocytes from adult
      (24 +/- 2 weeks), mature (50 +/- 2 weeks) and old (72 +/- 2 weeks) BALB/c male
      mice. In control samples, in the absence of neuropeptide, we observed a decreased
      lymphoproliferation in mature and old mice with respect to the adults in response
      to mitogen in the three organs studied. As regards, the effect of the
      neuropeptides, they stimulate the spontaneous proliferation of leukocytes from
      all locations, in adult animals, an effect that is decreased with ageing (in both
      mature and old animals). The proliferation in response to mitogen was
      significantly decreased by the neuropeptides in adults, this effect being
      progressively reduced with age.

PMID- 10657490
TI  - Meetings calendar

PMID- 10657489
TI  - Tachykinin NK(3)receptor involvement in anxiety.
AB  - This study investigates the effects of intracerebroventricular injection of
      selective agonists and antagonists of tachykinin NK(3)receptor on performance of
      mice in the elevated plus-maze test. Mice were treated with either vehicle or 1,
      10, 100 or 500 pmol of neurokinin B or senktide ([succinil-Asp(6),
      MePhe(8)]substance P(6-11), a natural and synthetic selective NK(3)receptor
      agonists, respectively. Other mice received similar doses of [Trp(7)beta
      Ala(8)]NKA(4-10)or SR 142801 ((S)-N-(1-(3-(1-benzoyl-3-(3, 4-dichlorophenyl)
      piperidin-3-yl)propyl)-4-phenyl-piperidin- 4-yl)-N-m ethylacetamide) tachykinin
      NK(3)receptor selective peptide and non-peptide antagonists, respectively.
      Senktide significantly increased the frequency of entries and the time spent in
      the open arms, which is compatible with an anxiolytic action. Neurokinin B
      treatment did not alter the plus-maze parameters in a significant way.
      Conversely, the NK(3)peptide antagonist [Trp(7)beta-Ala(8)]NKA(4-10), but not
      SR142801 non-peptide antagonist, showed a reverse effect, i.e. an anxiogenic
      profile of action, reducing the frequency and the time spent in the open arms. Co
      injection of either senktide plus [Trp(7)beta-Ala(8)]NKA((4-10)), or senktide
      plus SR 142801, blocked the effects promoted by senktide, indicating that
      centrally-administered NK(3)receptor agonists and antagonists can modulate
      experimental anxiety.

PMID- 10657491
TI  - Further pharmacological characterization of the selective melanocortin 4 receptor
      antagonist HS014: comparison with SHU9119.
AB  - SHU9119 and HS014 are cyclic MSH analogues which are widely used to elucidate the
      physiology behind the various effects of the MSH peptides and their receptors. We
      carefully compared the potency of SHU9119 and HS014 in cells expressing the MC
      receptor clones. We found that both the peptides are partial agonists for the MC1
      and MC5 receptors while they are potent antagonists for the MC3 and MC4
      receptors. In agreement with earlier binding data, we found that SHU9119 has
      equal potency for the MC3 and MC4 receptor whereas HS014 has at least 10-fold
      higher potency for the MC4 receptor than the MC3 receptor in cAMP assay.
      Moreover, we synthesized analogues of HS014 where the C-terminal was truncated.
      We found that this C-terminal fragment of HS014, in particular the Lys(14), has a
      major influence on the affinity for the MC4 receptor without any particular
      influence on the affinity for the other MC receptors.

PMID- 10657492
TI  - Galanin inhibits acetylcholine release from rat cerebral cortex via a pertussis
      toxin-sensitive G(i)protein.
AB  - Galanin has been implicated in various physiological functions including memory,
      feeding and pain perception. Using rat cerebral cortical slices and synaptosome
      preparations incubated with [(3)H]choline in Kreb's-Ringer solution, galanin was
      shown to inhibit both spontaneous and K(+)-stimulated [(3)H]ACh release in a
      concentration-related manner [EC(50)= 35 nM]. The galanin-mediated inhibition on
      spontaneous and K(+)-stimulated [(3)H]ACh release was respectively regulated by
      pertussis toxin-sensitive G(alphai3)and G(alphai1). These suggest that galanin is
      a negative modulator of cortical cholinergic function and most probably acting on
      presynaptic cholinergic terminals. Although galantide blocked the galanin
      mediated inhibitory effect on [(3)H]ACh release, it mimicked galanin in blocking
      K(+)-stimulated [(3)H]ACh release, indicating that galantide may have a more
      complicated pharmacology than being a galanin receptor antagonist. In addition,
      we demonstrate that galanin and beta-amyloid peptide(1-42)synergistically
      attenuated K(+)-evoked [(3)H]ACh release from synaptosomes prepared from rat
      cerebral cortex. Since galanin is increased in Alzheimer's disease brain, our
      results suggest that galanin may be involved in cholinergic dysfunctions that
      occur in Alzheimer's disease.

PMID- 10657493
TI  - Olfactory bulbectomy increases prepro-enkephalin mRNA levels in the ventral
      striatum in rats.
AB  - The effects of bilateral olfactory bulbectomy (OBX) on prepro-enkephalin,
      thyrotropin-releasing hormone, and D-2 receptor mRNA levels in the ventral
      striatum were examined by in situ hybridization histochemistry. Pre- pro
      enkephalin mRNA levels were significantly increased in the olfactory tubercle
      (OT), but not in the nucleus accumbens, 14 days following bilateral OBX. Levels
      of D-2 receptor mRNA were also increased in the OT, though to a lesser degree.
      Prepro-thyrotropin-releasing hormone mRNA was unaffected by OBX. A separate
      experiment revealed no effect of OBX on enkephalin gene expression 7 days
      following surgery but a comparable elevation in pre- pro-enkephalin mRNA 14 and
      28 days post-surgery. The findings are consistent with previously-reported
      effects of dopamine lesions on striatal gene expression, suggesting that the
      observed effects may be mediated by deafferentation-induced alterations in
      dopaminergic transmission in the OT. Altered dopaminergic function in the OT may
      be particularly relevant to the 'anhedonia' that has been associated with the
      olfactory bulbectomized rat model of depression.

PMID- 10657494
TI  - Increased glucagon-like peptide-1 receptor expression in glia after mechanical
      lesion of the rat brain.
AB  - Glucagon-like peptide-1 (GLP-1)(7-36) amide, a member of the glucagon and related
      peptides family, and its receptor have an anatomically specific expression in the
      brain. Furthermore, the GLP-1 receptor is expressed in both neurons and glia.
      Because after a penetrating injury a large population of astrocytes become
      activated and augment their expression of numerous substances, we have used in
      situ hybridization to determine whether the expression of the GLP-1 receptor
      increases in response to a penetrating injury. We have found that GLP-1 receptor
      expression increases dramatically along the border of the injury. Furthermore,
      this expression can be colocalized to glial fibrillary acidic protein (GFAP) and
      non-GFAP mRNA containing cells, suggesting that at least part of this increase is
      due to an increase in GLP-1 receptor expression in glial cells.

PMID- 10657495
TI  - NPY/sympathetic and NPY/VIP innervation of the blood vessels supplying rat tooth
      related structures: effects of sympathectomy.
AB  - In order to better understand the regulation of blood flow to tooth-related
      structures, the patterns of VIP- and NPY-ergic innervations in the rat were
      examined. Nerve fibers showing NPY-like immunoreactivity (NPY-LI) frequently
      occurred in the walls of the large main arteries, as well as in association with
      the arterioles, to a high degree co-existing with tyrosine hydroxylase (TH),
      whereas VIP-LI was mainly restricted to the walls of the large arteries. After
      sympathectomy, no NPY/TH-LI nerve fibers were seen in blood vessel walls.
      However, a NPY-immunoreactive nerve population remained in the walls of the large
      arteries, NPY- and VIP-LI co-existing in this nerve population. Both
      immunoreactions were intense. The present study suggests that a NPY/sympathetic
      innervation as well as a VIP innervation (large arteries) are likely to have
      substantial roles in the balance and maintenance of vasoregulation in tooth
      related structures and that a NPY/VIP innervation becomes of particular
      importance when the NPY/sympathetic innervation is destroyed.

PMID- 10657496
TI  - Distribution of calcitonin-gene-related peptide, neuropeptide-Y, vasoactive
      intestinal polypeptide, cholecystokinin-8, substance P and islet peptides in the
      pancreas of normal and diabetic rats.
AB  - Neuropeptides and peptides are particularly important in the co-ordination of
      pancreatic exocrine and endocrine secretions. In diabetes mellitus, pancreatic
      endocrine secretion is particularly impaired. This study investigates whether
      there is a change in the pattern of distribution of neuropeptides including
      calcitonin-gene-related peptide (CGRP), neuropeptide-Y (NPY), vasoactive
      intestinal polypeptide (VIP), cholecystokinin-octapeptide (CCK-8), substance P
      (SP), and islet peptides including insulin (INS), glucagon (GLU), somatostatin
      (SOM) and pancreatic polypeptide (PP) in the pancreas of streptozotocin (STZ)
      diabetic rats. After the onset of diabetes, the pattern of distribution of INS,
      GLU, SOM and PP cells was deranged. CGRP was demonstrated in ganglion cells of
      both normal and diabetic pancreas. CGRP was also localized in nerve fibres
      innervating the blood vessels of both normal and diabetic pancreas. The pancreata
      of both normal and diabetic rats contained numerous NPY-immunopositive varicose
      nerve fibres in the wall of blood vessels. In normal pancreatic tissue, VIP
      immunopositive nerve fibres were observed in all areas of the pancreas. After the
      onset of diabetes, VIP-positive nerve fibres were still discernible in the
      interacinar regions of the pancreas. CCK-8 was identified in nerve fibres
      innervating both the normal and diabetic rat pancreata. These CCK-8
      immunopositive nerves were varicose in nature and distributed in the wall of
      blood vessels. SP was demonstrated in neurons located in the interlobular areas
      of normal tissue and in fine varicose nerve fibres of the interacinar region of
      STZ-induced diabetic pancreas. In conclusion, CGRP, NPY, VIP, CCK-8 and SP are
      well distributed in both normal and diabetic pancreas.

PMID- 10657497
TI  - Isolation and characterization of the mouse homolog of the preprodynorphin (Pdyn)
      gene.
AB  - We have isolated and sequenced the mouse preprodynorphin gene (Pdyn). The Pdyn
      gene can encode for six biologically active dynorphin peptides. The predicted
      mouse preprodynorphin has 90%, 67%, and 66% identity with the predicted rat,
      porcine, and human preprodynorphins, respectively. Using an RT-PCR technique, we
      show that the Pdyn gene starts being expressed at embryonic day 12.5, with a
      steep increase of expression by embryonic day 14.5; in the adult mouse it is
      expressed in the brain, but not in liver, heart, spleen, or kidney.

PMID- 10657498
TI  - Pharmacological characterization of mucin secretion from CHO-K1-hNK(1)R cells.
AB  - Numerous respiratory diseases increase mucin secretion from human airways.
      Several investigators hypothesize that mucin secretion from airway epithelium is
      NK(1)-receptor mediated. We have developed a mucin secretion assay using CHO-K1
      cells transfected with the human NK(1)receptor (CHO-K1-hNK(1)R) that respond to
      NK(1)-specific agonists. Cells were labeled with [(3)H]-glucosamine and
      stimulated with agonists including Ac-[Arg(6), Sar(9), Met(O(2))(11)] Substance
      P(6-11) (ASMSP; NK(1)-specific), [beta-Ala(8)]-Neurokinin A(4-10) (BANK; NK(2)
      specific), or human neutrophil elastase (HNE). Basal mucin secretion from CHO-K1
      hNK(1)R and non-transfected cells was similar. Stimulation of CHO-K1-hNK(1)R, but
      not CHO-K1, with ASMSP or BANK concentration-dependently increased mucin
      secretion (pD(2)value[Emax] = 8.9(1)+/-0.1(3)[175%] and 7.56+/-0.05[100%],
      respectively). SR140333 (NK(1)antagonist), but not SR48968 (NK(2)antagonist),
      decreased ASMSP- and BANK-induced mucin release from CHO-K1-hNK(1)R. In these
      cells, endothelin-1, angiotensin II, serotonin, phenylephrine, senktide, and
      methacholine showed negligible effects on mucin secretion. A similar lack of
      effect of these agonists was observed in non-transfected CHO-K1 cells. HNE
      increased mucin release four to five fold in both cell types. These studies
      demonstrate that stimulation of CHO- K1-hNK(1)R with ASMSP and BANK causes robust
      and NK(1)-selective mucin release.

PMID- 10657499
TI  - Sensory stimulation (acupuncture) increases the release of calcitonin gene
      related peptide in the saliva of xerostomia sufferers.
AB  - Over the last decade, several patients afflicted with xerostomia have been
      treated with acupuncture. Their salivary flow rates increased significantly and
      the improvement lasted during a long observation period. We also found that the
      release of several neuropeptides in the saliva of healthy subjects can be
      increased by acupuncture stimulation. The concentration of vasoactive intestinal
      polypeptide increased significantly in the saliva of xerostomic patients after
      acupuncture treatment. The release of the neuropeptide calcitonin gene-related
      peptide (CGRP) was investigated in the saliva of xerostomic patients in order to
      elucidate further the mechanisms of the effect of sensory stimulation
      (acupuncture) on the salivary secretion. CGRP-like immunoreactivity was measured
      with radioimmunoassay (RIA) before and after a double series of acupuncture
      treatment, in stimulated saliva of 14 patients who suffered from xerostomia. The
      results showed that the concentration of CGRP increased significantly (P<0.001)
      in the saliva of these patients after the end of acupuncture treatment as
      compared to base-line levels. Taking into consideration the influence of CGRP on
      the salivary flow, as well as its trophic effect, we concluded that the increased
      release of CGRP could be one of the factors that affect positively the salivary
      flow rates of xerostomic patients who were treated with acupuncture.

PMID- 10657500
TI  - Vascular neuropeptide Y Y1-receptors in the rat kidney: vasoconstrictor effects
      and expression of Y1-receptor mRNA.
AB  - Neuropeptide Y (NPY) -receptor subtypes were studied in the rat kidney in vivo by
      systemic administration of NPY, the two agonists [Leu(31), Pro(34)]NPY (Y1
      receptor agonist) and NPY (13-36) (Y2-receptor agonist), or the Y1-receptor
      antagonist BIBP 3226. Effects on mean arterial blood pressure (MAP) and renal
      arterial blood flow were recorded. The Y1-receptor agonist evoked a dose
      dependent increase in MAP concomitantly with a reduction in renal blood flow. At
      the largest dose administered (1.42 pmol/g), the Y1-agonist [Leu(31), Pro(34)]
      NPY increased MAP by 20 +/- 6 mmHg and reduced the renal vascular conductance by
      more than 50%. The same dose of the Y2-agonist NPY (13-36) did not evoke any
      clear-cut effects on the renal blood flow or MAP. Furthermore, administration of
      the Y1-receptor antagonist BIBP 3226 reduced the NPY-induced renal
      vasoconstriction, but did not affect the response to angiotensin II or
      phenylephrine. The effects evoked by 0.71 pmol/g NPY were almost abolished by 3
      mg/kg BIBP 3226. In situ hybridization histochemistry was used to study the
      expression of Y1-receptor mRNA in the developing rat kidney. The levels of Y1
      receptor mRNA expression in the vascular smooth muscle of the rat kidney varied
      at different ages, with low levels at postnatal day 10 and high levels at 20 days
      and again low levels at 40 days. In summary, the present study show a maturation
      specific expression pattern of NPY Y1-receptor mRNA as well as functional effects
      of vascular NPY receptors of the Y1-subtype in the rat kidney.

PMID- 10657501
TI  - Exercise and variations in neuropeptide concentrations in rheumatoid arthritis.
AB  - The aim of the present study was to investigate the influence of an exercise
      program on neuropeptide concentrations, disease activity, impairments and
      disabilities in rheumatoid arthritis (RA). Eleven females (median age 60 years,
      median disease duration 6.5 years, ARA functional classes I or II) exercised 30
      min daily for 4 weeks. The urine concentrations of calcitonin gene-related
      peptide-like immunoreactivity (CGRP-LI) and neuropeptide Y-like immunoreactivity
      (NPY-LI) were analyzed 1 week prior to exercise start, at exercise start, after 2
      and 4 weeks of exercise, and after a 4-week follow-up period. Measurements of
      disease activity, aerobic capacity, grip force, limb muscle function, and
      activities of daily living (ADL) were also undertaken. The results indicate a
      decrease (md 5.64 pM to md 3.48 pM, P</=0.05) of CGRP-LI concentrations after 4
      weeks' exercise. NPY-LI concentrations remained unchanged, as did disease
      activity and aerobic capacity. Muscle function and ADL capacity improved
      significantly (P</=0.05) after the exercise period. Only the improved grip force
      remained after the follow-up period. In conclusion the results indicate that
      decreased CGRP-LI concentration, probably reflecting a decreased sympathetic
      tone, follows physical exercise and suggest that regular physical activity might
      be important among individuals with RA to maintain a decreased sympathetic tone
      and less symptoms from their disease.

PMID- 10657502
TI  - Rat strain differences in response to galanin on the Morris water task.
AB  - Galanin acts as an inhibitory modulator of cholinergic transmission in the
      septohippocampal pathway of the rat. Centrally administered galanin induces
      performance deficits on rodent learning and memory tasks, including delayed non
      matching to position, T-maze delayed alternation, passive avoidance, starbust
      radial maze acquisition, and the Morris water task. The present study
      investigates differences in responsiveness to intraventricularly administered
      galanin across three strains of laboratory rat on acquisition of spatial learning
      in the Morris water task. Sprague-Dawley rats showed normal performance during
      training, but lack of selective quadrant search on the probe trial in response to
      galanin treatment. Long-Evans rats showed no effects of galanin on performance
      during training or probe trial. Wistar rats showed longer latencies to reach the
      hidden platform during training, and lack of selective quadrant search on the
      probe trial in response to galanin. Performance on the visible platform task and
      on locomotor activity in the open field was normal in rats treated with galanin.
      These results are consistent with an interpretation of strain differences in
      sensitivity to the inhibitory actions of galanin on learning and memory.

PMID- 10657503
TI  - Insulin-induced hypoglycemia activates a chemokinergic neuronal pathway in the
      hypothalamo-pituitary system.
AB  - Recently, we found the presence of cytokine-induced neutrophil chemoattractant
      (CINC) neuronal pathway in the hypothalamo-pituitary system. This observation
      prompted us to investigate the effect of insulin-induced hypoglycemia on CINC
      neuronal pathway in the hypothalamo-pituitary system. An insulin injection
      decreased the plasma glucose level, which followed a prompt rise in plasma ACTH
      level and an increase in serum CINC level. Before the insulin injection, the
      signal for CINCmRNA was undetectable in the paraventricular hypothalamic nucleus
      (PVN). The hypoglycemic challenge induced strong hybridization signals of CINC
      mRNA in the parvocellular and magnocellular subdivision of the PVN within 30 min,
      and reached the peak within 3 h. No change was observed in the supraoptic nucleus
      after the hypoglycemic challenge. These studies demonstrate the presence of a
      hypoglycemia-sensitive chemokinergic neuronal pathway in the hypothalamo
      neurohypophysial system and this newly described pathway will provide novel
      information for understanding pathophysiology of hypoglycemia.

PMID- 10657504
TI  - Altered biosynthesis and secretion of pro-opiomelanocortin in the intermediate
      and anterior pituitary of carboxypeptidase E-deficient, Cpe(fat)/ Cpe(fat)mice.
AB  - The biosynthesis and secretion of pro-opiomelanocortin (POMC) was examined in the
      pituitary of Cpe(fat)/ Cpe(fat)mice, which are deficient in carboxypeptidase E, a
      sorting receptor for the regulated secretory pathway (Cool D R, Normant E, Shen F
      S, et al. Cell 1997; 83: 73-83). Dopamine inhibited forskolin-stimulated
      accumulation of cAMP in the intermediate lobe of Cpe(fat)/ Cpe(fat)mice, showing
      that their dopamine receptors were fully functional. This result indicates that
      the elevated, dopamine-insensitive POMC secretion previously observed in the
      intermediate pituitary of Cpe(fat)/ Cpe(fat)mice was constitutive, rather than
      due to defective dopamine receptors. Concomitant with the increase in POMC
      secretion was a twofold increase in POMC mRNA levels and [(35)S]-methionine
      incorporation into POMC. In the anterior pituitary of Cpe(fat)/ Cpe(fat)mice, a
      1.6-fold increase in basal release of POMC was accompanied by a similar increase
      in [(35)S]-methionine incorporation into POMC, although POMC mRNA levels were
      unchanged. Thus, the intermediate and anterior pituitary of Cpe(fat)/
      Cpe(fat)mice compensate for the constitutive secretion of POMC by upregulating
      biosynthesis.

PMID- 10657505
TI  - Endomorphin-1 reduces carrageenan-induced fos expression in the rat spinal dorsal
      horn.
AB  - Intraplantar injection of carrageenan induced significant Fos expression in the
      superficial and deep spinal dorsal horn at the L(4)-L(5)segments and extensive
      peripheral edema of the ipsilateral foot in rats. Intraplantar injection of
      endomorphin-1, endogenous ligand for mu opioid receptor, in the same region
      produced dose-dependent reduction of carrageenan-induced Fos expression and
      peripheral edema, which were completely blocked by co-administration of
      intraplantar injection of naloxone (20 microgram). The systemic injection of the
      highest dose of endomorphin-1 (50 microgram) had no significant reductory effect
      on Fos expression and peripheral edema. These results further provided a strong
      evidence for involvement of mu opioid receptor in peripheral analgesia,
      particularly in inflammation pain.

PMID- 10657506
TI  - Chromogranin A in the central nervous system of the rat: pan-neuronal expression
      of its mRNA and selective expression of the protein.
AB  - Chromogranin A, a glycoprotein stored in secretory granules of neuroendocrine
      cells, displays a widespread distribution throughout the central nervous system
      of a variety of species. In situ hybridization histochemistry was employed to
      investigate the localization of chromogranin A mRNA in the central nervous system
      of the rat. The previously characterized monoclonal antibody, LK2H-10, was
      employed in an immunohistochemical study to compare the topographic localization
      of the chromogranin A protein with that of its mRNA. Although the latter, as
      revealed by in situ hybridization, displayed a ubiquitous, pan-neuronal
      localization throughout the rat brain, LK2H-10 immunoreactive cell bodies and
      axon terminals were disposed in a widespread, but highly regionally differential,
      distribution. This discrepancy suggests that chromogranin A is processed in a
      regionally differential fashion in the rat brain to yield one or multiple variant
      forms, one of which is specifically recognized by LK2H-10. Catecholaminergic cell
      groups consistently displayed LK2H-10 immunoreactivity. LK2H-10 immunopositive
      axon terminals were prominent in the circumventricular organs. In addition, LK2H
      10 immunoreactivity was also detected in a subset of astrocytes which
      demonstrated a widespread, but anatomically restricted, pattern of distribution.
      Consequently, the variant of chromogranin A labelled by LK2H-10 represents a
      novel neurochemical marker for regionally differential astrocytic diversity.

PMID- 10657508
TI  - Meetings calendar

PMID- 10657507
TI  - Luteinizing hormone-releasing hormone and function of the magnocellular
      vasopressinergic system.
AB  - Mechanisms by which luteinizing hormone-releasing hormone (LHRH) affects
      vasopressin secretion were investigated using the isolated rat hypothalamo
      neurohypophysial explants. LHRH in a concentration of 4 x 10(-7)M inhibited both
      the basal and K(+)-stimulated vasopressin release from explants isolated from
      euhydrated rats. When, however, the tissue was obtained from animals previously
      salt-loaded, the inhibitory effect of LHRH was completely abolished, thus
      implying a decrease in the sensitivity to LHRH. LHRH did not affect vasopressin
      secretion under conditions of generalized blockade of synaptic inputs by 15 mM
      MgSO(4), suggesting the indirect action of this neurohormone on the hypothalamic
      magnocellular system. It is concluded that LHRH may play the role of a
      neuromodulator of vasopressinergic neurones in the rat.

PMID- 10657509
TI  - Introduction to the reviews on peptides and the control of food intake and body
      weight.
AB  - The progress in the identification of peripheral and brain peptides that affect
      food intake and body weight is discussed in the accompanying 11 reviews. The
      reviews, succinct and critical, are useful guides to a dispersed literature that
      began in 1957. As reflected through the prism of these reviews, the field looks
      like a few small islands of scientific understanding surrounded by a vast sea of
      uncertain phenomena. This introduction discusses four themes that pervade the
      reviews. These are: (1) how to establish that an effect of a peptide is a
      physiological function of the endogenous peptide; (2) the importance of the
      interactions among peptides, amines and steroids for the central integration that
      underlies the control of food intake and body weight; (3) the need for simple and
      convenient generalizations to organize and interpret the apparently endless
      empirical reports; and (4) the persistent problems that remain untouched by
      current information, especially dietary-induced obesity and the role of peptides
      in the neural networks that control spontaneous eating.

PMID- 10657510
TI  - Role of hypothalamic neuropeptide Y in feeding and obesity.
AB  - The 36-amino-acid peptide, neuropeptide Y (NPY), is the most abundant peptide in
      the rat brain. When administered into the brain, NPY produces a variety of
      physiological actions including a pronounced stimulation of feeding in satiated
      rats. Elevations in hypothalamic NPY have been reported after food deprivation
      and in genetically obese rodents. NPY is believed to produce its actions through
      a portfolio of G-protein coupled receptors, Y1, Y2, Y4 and Y5. Studies using
      peptide analogs, receptor knockout animals and specific receptor antagonists
      suggest the Y1 and Y5 receptors are important in mediating the effects of NPY on
      food intake in rats. Development of specific receptor antagonists with improved
      pharmacokinetic properties will be required to determine the importance of NPY in
      human obesity and appetite disorders.

PMID- 10657511
TI  - Two important systems in energy homeostasis: melanocortins and melanin
      concentrating hormone.
AB  - Our understanding of the regulation of appetite and energy balance has advanced
      significantly over the past decade as several peptides, centrally or peripherally
      expressed, have been characterized and shown to profoundly influence food intake
      and energy expenditure. (1)The growing number of putative appetite-regulating
      neuropeptides includes peptides that are orexigenic (appetite-stimulating)
      signals and anorectic peptides. Neuropeptide Y (NPY), melanin concentrating
      hormone (MCH), orexins A and B, galanin, and agouti -related peptide (AgRP) all
      act to stimulate feeding while alpha-melanocyte stimulating hormone (alphaMSH),
      corticotropin releasing hormone (CRH), cholecystokinin (CCK), cocaine and
      amphetamine regulated transcript (CART), neurotensin, glucagon-like peptide 1
      (GLP 1), and bombesin have anorectic actions.(1) Leptin, expressed in the
      periphery in white adipose tissue, acts in the CNS to modulate the expression of
      several of these hypothalamic peptides.(1) This creates a functional link between
      the adipose tissue and the brain that translates the information on body fat
      provided by leptin to input into energy balance regulating processes. In the
      current review we examine the significant role of the melanocortin system
      (alphaMSH, agouti and AgRP peptides, and their receptors and mahogany protein)
      and melanin concentrating hormone in the regulation of energy balance.

PMID- 10657512
TI  - The role of corticotropin-releasing factor and urocortin in the modulation of
      ingestive behavior.
AB  - Participation of the hypothalamo-pituitary-adrenocortical axis, and its primary
      brain trigger, corticotropin-releasing factor (CRF) in the control of ingestive
      behavior can be inferred from data suggesting that CRF and its homologue
      urocortin act in brain to limit appetite following administration in rodents.
      Moreover, levels of endogenous CRF, CRF(1)and CRF(2)receptors and CRF-binding
      protein, which sequesters CRF and urocortin, are altered by changes in
      nutritional status brought about by food restriction/repletion. Mediation of the
      anorexic effects of CRF and urocortin appear not to privilege CRF(1)receptors,
      unlike the anxiogenic effects of CRF which are primarily a consequence of
      CRF(1)receptor activation. Such fear-like consequences of CRF system activation
      constitute a non-specific mechanism whereby the emergence of behaviors
      incompatible with food intake may appear to suppress appetite without affecting
      hunger per se. However, enhanced appetite following administration of CRF
      receptor antagonists and the involvement of CRF systems in sexual appetite and
      drug-seeking behavior all suggest a role for CRF in ingestive behavior. In
      particular, available evidence suggests that physiologically relevant suppression
      of appetite may accompany CRF system activation occurring as a consequence of
      stressor exposure induced by nutrient imbalance, for example, or under conditions
      of excessive intake or consumption of unfamiliar foodstuffs.

PMID- 10657513
TI  - Opioids and food intake: distributed functional neural pathways?
AB  - Agonists of the mu, delta, kappa and ORL(1)opioid receptors increase food intake
      while opioid receptor blockade decreases food intake. The majority of the
      collected data related to opioids and feeding has led to the speculation that
      opioids are involved in meal maintenance and orosensory reward; however, some
      data suggest that opioids may impact feeding associated with energy needs. Based
      on the wide distribution of CNS opioid receptors and the presence of other
      neuropeptides in the vicinity of opioidergic pathways, it seems likely that
      opioids affect multiple feeding systems. For example, opioids in the hindbrain
      might be involved in both sensory and metabolic aspects of food intake, those in
      the amygdala in processing of 'emotional' properties of foods, and those in the
      hypothalamus in energy needs. In this review we present data which support
      functional diversity of opioids in feeding behavior.

PMID- 10657514
TI  - The role of galanin in feeding behavior.
AB  - Galanin inhibits food consumption in satiated rats. Discovered relatively
      recently, galanin is a 29-amino-acid neuropeptide, not homologous with any other
      known peptide. Three G-protein-linked galanin receptor subtypes have been cloned.
      This review summarizes the mechanisms by which exogenously administered galanin
      may stimulate ingestion, discusses pharmacological and genetic investigations of
      the role of endogenous galanin on feeding and body weight, and speculates on the
      therapeutic potential of non-peptide galanin receptor antagonists for the
      treatment of appetite disorders.

PMID- 10657515
TI  - Role of bombesin-related peptides in the control of food intake.
AB  - In 1970, Erspamer et al.(1,14)isolated and characterized the tetradecapeptide
      bombesin (BN) from the skin of amphibian frog Bombina bombina. Subsequently,
      several BN-like peptides have been identified in mammals, consisting of various
      forms of gastrin-releasing peptide (GRP) and/or neuromedin B (NMB), together with
      their distinct receptor subtypes. It has been proposed that BN-related peptides
      may be released from the gastrointestinal (GI)-tract in response to ingested
      food, and that they bridge the gut and brain (through neurocrine means) to
      inhibit further food intake. Conversely, the suppression of release of BN-like
      peptides at relevant brain nuclei may signal the initiation of a feeding episode.
      The present review will describe recent pharmacological, molecular, behavioral
      and physiological experiments, supporting the contention that endogenous BN
      related peptides do indeed influence ingestive behaviors. Particular attention is
      focused on the relationship between these peptides in the peripheral compartment
      and their impact on central circuits using GRP and/or NMB as transmitters. In
      addition, however, we will point out various caveats and conundrums that preclude
      unequivocal conclusions about the precise role(s) of these peptides and their
      mechanism(s) of action. We conclude that BN-related peptides play an important
      role in the control of food intake, and may contribute to ingestive disruptions
      associated with anorexia (anorexia nervosa, AIDS and cancer anorexia), bulimia,
      obesity and depression. Hence, pharmacological targeting of these systems may be
      of therapeutic value.

PMID- 10657516
TI  - Cholecystokinin: proofs and prospects for involvement in control of food intake
      and body weight.
AB  - Evidence that CCK participates in the control of meal size is compelling, but the
      avenues by which CCK may affect daily food intake and body weight regulation are
      still uncertain. Although participation of brain CCK in control of food intake is
      acknowledged, our focus here is on participation of peripheral CCK in the control
      of food intake. Therefore, in this article we (1) review evidence for CCK's
      participation in control of meal size, (2) document involvement of CCK-A
      receptors located on vagal sensory neurons in control of food intake by exogenous
      and endogenous CCK, (3) point out apparent discrepancies in the experimental
      record, which auger for non-endocrine sources of CCK and non-vagal sites of CCK
      action, and (4) summarize recent observations, suggesting mechanisms by which CCK
      could participate in the control of daily food intake and body weight regulation.

PMID- 10657517
TI  - Effects of glucagon, insulin, amylin and CGRP on feeding.
AB  - The roles of the pancreatic peptides glucagon, insulin, and amylin in the
      inhibitory control of feeding are reviewed. Calcitonin gene-related peptide
      (CGRP) is also included because it is structurally and functionally related to
      amylin and because known amylin and CRRP receptors are activated by both
      peptides. Glucagon-like peptide 1, in contrast, is structurally distinct from
      pancreatic glucagon and does not cross-react with glucagon receptors, so it is
      not considered. Several detailed reviews of the feeding effects of these peptides
      have appeared recently; where appropriate, these are cited rather than the
      primary literature.

PMID- 10657518
TI  - Glucagon-like peptide-1 (7-36) amide: a central regulator of satiety and
      interoceptive stress.
AB  - Glucagon-like peptide-1 (7-36) amide (GLP-1) is processed from proglucagon in the
      distal ileum as well as in the CNS. In the periphery, GLP-1 acts as an incretin
      factor and profoundly inhibits upper gastrointestinal motility ('ileal brake'),
      the latter presumably involving the CNS. Within the CNS, GLP-1 has a satiating
      effect, since administration of GLP-1 into the third cerebral ventricle reduces
      short-term food intake (and meal size), while administration of GLP-1 antagonists
      have the opposite effect. In addition, activation of GLP-1 receptors in certain
      brain regions elicits strong taste aversions. Similarities between toxin- and GLP
      1-induced neuronal activity in the CNS (brain stem) suggest a role for central
      GLP-1 receptors in relaying interoceptive stress. Thus, regionally distinct GLP-1
      receptor populations in the CNS may be involved in satiety or malaise. It is
      argued that the satiating and aversive aspects of GLP-1 serve homeostatic and
      nonhomeostatic functions with respect to maintenance of nutrient balance.

PMID- 10657519
TI  - Interleukins and tumor necrosis factor as inhibitors of food intake.
AB  - Cytokines, such as interleukins and tumor necrosis factor-alpha (TNFalpha), are
      produced in response to immune stimulation and have systemic effects, mediated by
      the central nervous system (CNS). Interleukins, in particular interleukin [IL]
      1beta, and TNFalpha reduce food intake after peripheral and central
      administration, suggesting that they contribute to the anorexia during various
      infectious, neoplastic and autoimmune diseases. Because cytokines are mainly
      produced in the periphery during most of these diseases, IL-1beta and TNFalpha
      may inhibit feeding indirectly through neural and humoral pathways activated by
      their peripheral actions. Activation of afferent nerve fibers by locally produced
      cytokines in the periphery is involved in several cytokine effects, but is not
      crucial for the anorectic effect of systemic immune stimulation. Cytokines
      increase OB protein (leptin) expression in the adipose tissue, and leptin may
      contribute to, but is also not essential for, the anorectic effects of cytokines.
      Finally, circulating IL-1beta and TNFalpha may act directly on the brain or
      cytokine synthesis in the brain may contribute to the anorectic effect of
      systemic immune stimulation. Central mediators of the anorectic effects of
      cytokines appear to be neurochemicals involved in the normal control of feeding,
      such as serotonin, corticotropin releasing factor, histamine, alpha-melanocyte
      stimulating hormone, and neuropeptide Y. The well-documented cytokine production
      in the gut in relation to feeding and the expression of TNFalpha by adipocytes
      suggest that IL-1beta and TNFalpha may also play a role in the control of normal
      feeding and energy balance. All in all, reciprocal, synergistic and antagonistic
      interactions between various pleiotropic cytokines and between cytokines and
      neurochemicals form a complex network that mediates the effects of cytokines on
      feeding and energy balance.

PMID- 10657520
TI  - The role of enterostatin and apolipoprotein AIV on the control of food intake.
AB  - Procolipase is secreted as a protein consisting of 101 amino acids. In the
      intestinal lumen, procolipase is activated by trypsin and cleaves to form the
      active colipase and the pentapeptide from the amino terminus. This pentapeptide
      is called enterostatin. Pancreatic procolipase synthesis is stimulated by a high
      fat diet. A large body of evidence has been gathered in the past decade
      demonstrating the role of enterostatin in the inhibition of food intake; in
      particular, fat intake. This aspect of enterostatin will be discussed in this
      review. Other functions of enterostatin such as the inhibition of insulin
      secretion, will not. Apolipoprotein AIV is a protein synthesized by the human
      intestine. Similar to procolipase, the synthesis and secretion of apo AIV are
      also stimulated by fat absorption. In 1992, Fujimoto et al. first demonstrated
      that apo AIV is a satiety signal secreted by the small intestine following the
      ingestion of a lipid meal. Subsequently, this initial observation was followed by
      a number of studies supporting apo AIV's role in the inhibition of food intake.
      This review will discuss the role of apo AIV in inhibiting food intake.

PMID- 10657521
TI  - Meetings calendar

PMID- 10657522
TI  - Vasoactive intestinal polypeptide stimulates the proliferation of HaCaT cell via
      TGF-alpha.
AB  - It is well known that psoriasis, an immunogenetic cutaneous disorder whose major
      pathogenic findings are epidermal hyperplasia and T-cell infiltration, is
      aggravated by psychological stresses. Although the exact mechanism is not yet
      clarified, antidromic secretion of neuropeptides by cutaneous nerve fibers is
      thought to be involved. In this study, we examined the effect and mechanism of
      vasoactive intestinal polypeptide (VIP), one of the major neuropeptides, on the
      proliferation of HaCaT cell which is a spontaneous, immortalized, human
      keratinocyte cell line. Twenty-four and 48 h after its addition, 1 pM to 100 nM
      of VIP increased the number of cells cultured with/without serum. We indirectly
      verified VIP(1)R on the surface of HaCaT cell based on the proliferative ability
      of various VIP families such as VIP, PACAP and secretin, and increased PKA level
      30 min after stimulation. However, because H-89, a PKA inhibitor, did not inhibit
      the proliferative potential of VIP, its mitogenicity is not medicated through
      VIP(1)R. One nM VIP produced the TGF-alpha protein which is a strong mitogen of
      keratinocytes and increased in the psoriatic lesion 2.25 times more compared with
      the control. Genistein, a tyrosine kinase inhibitor, abrogated the mitogenic
      activity of VIP. Like VIP, VIP fragments, VIP(1-12) and VIP(10-28) also acted as
      a mitogen for HaCaT cells through the same mechanism. Collectively, our studies
      clearly show that VIP and its fragments stimulate keratinocyte growth, not
      through increased cAMP level, but through increased TGF-alpha protein production.

PMID- 10657523
TI  - Neuropeptides and capsaicin stimulate the release of inflammatory cytokines in a
      human bronchial epithelial cell line.
AB  - The role of neuropeptides in initiating and modulating airway inflammation was
      examined in a human bronchial epithelial cell line (i.e. BEAS-2B). At a range of
      concentrations, exposure of BEAS-2B cells to Substance P (SP) or calcitonin gene
      related protein resulted in immediate increases in intracellular calcium
      ([Ca(2+)](i)), the synthesis of the transcripts for the inflammatory cytokines,
      IL-6, IL-8 and TNFalpha after 2 h exposure, and the release of their proteins
      after 6 h exposure. Addition of thiorphan (100 nM), an inhibitor of neutral
      endopeptidase, enhanced the levels of SP-stimulated cytokine release. Stimulation
      of IL-6 by SP occurred in a conventional receptor-mediated manner as demonstrated
      by its differential release by fragments SP 4-11 and SP 1-4 and by the blockage
      of IL-6 release with the non-peptide, NK-1 receptor antagonist, CP-99 994. In
      addition to the direct stimulation of inflammatory cytokines, SP (0.5 microM), in
      combination with TNFalpha (25 units/ml), synergistically stimulated IL-6 release.
      BEAS-2B cells also responded to the botanical irritant, capsaicin (10 microM)
      with increases in [Ca(2+)](i) and IL-8 cytokine release after 4 h exposure. The
      IL-8 release was dependent on the presence of extracellular calcium. Capsaicin
      stimulated increases of [Ca(2+)](i) and cytokine release could be reduced to
      control levels by pre-exposure to capsazepine, an antagonist of capsaicin (i.e.
      vanilloid) receptor(s) or by deletion of extracellular calcium from the exposure
      media. The present data indicate that the BEAS-2B human epithelial cell line
      expresses neuropeptide and capsaicin-sensitive pathways, whose activation results
      in immediate increases of [Ca(2+)](i) stimulation of inflammatory cytokine
      transcripts and the release of their cytokine proteins.

PMID- 10657524
TI  - sst1 mRNA is the prominent somatostatin receptor mRNA in the rat gastrointestinal
      tract: reverse transcription polymerase chain reaction and in situ-hybridization
      study.
AB  - The inhibitory peptide hormone somatostatin and its receptors (sst1-sst5)
      regulate many physiological functions in the gastrointestinal tract. In an
      attempt to correlate the various effects of somatostatin in gastrointestinal
      physiology to individual sst subtypes sst1-sst5, mRNAs have been localized by
      semiquantitative reverse transcription polymerase chain reaction amplification
      and in situ hybridization of sst1 and sst3 in the rat alimentary tract. sst1-sst4
      mRNAs were found throughout the gastrointestinal tract, sst1 mRNA being more
      abundant than sst2 and much more abundant than sst3 and sst4 mRNAs. sst5
      transcripts were at the detection threshold. sst1 and sst3 mRNAs are present in
      enterocytes and enteric neurons suggesting a role of these subtypes in the
      somatostatin-mediated inhibition of acetylcholine release from myenteric neurons
      and of secretomotor neuron activity in the submucous plexus. The presence of sst3
      mRNA in smooth muscle cells points to an additional role of this receptor in
      regulating gut motility.

PMID- 10657525
TI  - Distribution of angiotensin II binding sites in the mouse thalamus: receptor
      binding study with fluorescent coupled peptides and their conversion to a light
      stable product.
AB  - Fluorescence-coupled peptides allow a non-radioactive receptor binding study
      whereby single cells can be examined under a fluorescence microscope. By the
      combination of such a method with immunohistochemistry, using an HRP-coupled anti
      fluorescein antibody, a permanent labeling can be achieved. By using this method
      the distribution of angiotensin II binding sites has been examined in the mouse
      thalamus. The results show that a moderate staining was obvious within the
      thalamus and that the distribution of binding sites in the thalamus is very
      homogeneous in the mouse brain. In detail, angiotensin II binding sites were
      found in the anterodorsal nucleus, in the laterodorsal and posterior nucleus of
      the thalamus, as well as in the lateral geniculate nucleus, the reticular
      thalamic nucleus and in the zona incerta.

PMID- 10657526
TI  - Neonatal handling in rats induces long-term effects on dynorphin peptides.
AB  - The effects of neonatal handling on the opioid dynorphin peptides in the brain
      and pituitary gland of Sprague-Dawley rats were investigated. Ten weeks after the
      neonatal handling, handled rats had higher tissue levels of dynorphin A and B in
      the hypothalamus, pituitary gland and striatum and slightly higher dynorphin B
      levels in the hippocampus, medulla oblongata and midbrain as compared with non
      handled controls. The results indicate a persistent upregulation of the dynorphin
      system in certain brain areas after neonatal handling, which could contribute to
      the behavioural changes in these rats observed later in life. Observation in the
      open field and the elevated plus-maze tests confirmed behavioural effects of
      neonatal handling, i.e. showing that handled rats exhibit attenuated fearfulness
      in novel environments as compared with non-handled rats.

PMID- 10657527
TI  - Successive occupancy by immediate early transcriptional factors of the tyrosine
      hydroxylase gene TRE and CRE sites in PACAP-stimulated PC12 pheochromocytoma
      cells.
AB  - We previously demonstrated that pituitary adenylate cyclase-activating
      polypeptide (PACAP) coordinately upregulates the expression of the tyrosine
      hydroxylase (TH) and dopamine beta-hydroxylase (DBH) genes by activating the
      cyclic AMP (cAMP) and protein kinase C (PKC) signaling pathways. In this study,
      we examined the effects of PACAP on the expression of fos and jun immediate early
      gene (IEG) families, expression of which can be up-regulated by both PKC and cAMP
      signaling pathways, in rat pheochromocytoma cell line PC12 cells. PACAP potently
      stimulated the expression of c-fos, fosB junB and junD, but not c-jun mRNAs, at
      doses of 0.1-10 nM, as revealed by Northern blot analysis. The effects of PACAP
      on the expression of these mRNAs in PC12 cells was rapid (30-60 min) and dose
      dependent. PACAP administration induced maximum expression of c-fos, fosB and
      junB mRNA after 60 min, and of junD mRNA after 8 h. Gel mobility shift assays
      using synthetic DNA oligonucleotides corresponding to the TH 5'-flanking region
      and nuclear extracts from PC12 cells demonstrated that PACAP enhanced formation
      of the specific protein complexes which bind to the TPA-responsive element (TRE)
      and cAMP-responsive element (CRE), respectively. Gel shift and supershift
      analyses showed that the TRE-binding factors and CRE-binding factors comprised
      fosB, c-fos, junB, and junD, and CRE-binding protein (CREB) and junD,
      respectively. JunB was dominant in the TRE-binding complexes at 4 h after
      addition of PACAP, whereas both JunD and JunB were dominant at 12 h. These
      results suggest that agonist occupancy of PACAP receptors activates
      transcriptional factors (Fos/Jun families and CREB) that interact with the TRE
      and CRE sites of the TH 5'-flanking region, contributing to transcriptional
      activation of TH gene.

PMID- 10657528
TI  - Suppression of conditioned fear by administration of CCKB receptor antagonist
      PD135158.
AB  - In order to examine the involvement of CCK in the formation of anxiety, we have
      investigated whether CCKB receptor antagonist PD135158 suppressed conditioned
      fear stress. Rats were individually subjected to 30 min of inescapable electric
      footshock in a chamber with a grid floor. First, the rats were individually
      subjected to 30 min of footshock. Twenty-four h after the footshock, the rats
      were again placed in the chamber and observed for 5 min without shocks. PD135158
      was administered 30 min before placing the rats in the chamber again. Secondly,
      PD135158 was administered 30 min before footshock. Thirdly, PD135158 was
      administered 5 min after footshock. Administration of PD135158 30 min before
      conditioned fear stress significantly reduced freezing behavior. Administration
      of PD135158 30 min before footshock also significantly reduced freezing behavior.
      But, administration of PD135158 5 min after footshock did not significantly
      reduce freezing behavior. PD135158 blocked not only the acquisition but also the
      expression of conditioned fear. These results suggest that the CCKB receptor
      might play an important role in conditioned fear stress and that it might be
      related to anxiety.

PMID- 10657529
TI  - Changes of environment and darkness enhance the NADPH-diaphorase staining in the
      rat paraventricular nucleus.
AB  - Nitric oxide (NO) plays an important role in the maintenance of autonomic
      homeostasis of the body. NO-producing neurons are activated in the brain during
      exposure to different levels of environmentally produced stimulations. These
      facts prompted the authors to investigate the levels of activation of NO
      producing neurons of the paraventricular nucleus of the hypothalamus (PVN)
      following change of environment and darkness. Cryostat sections were cut and
      processed for the histochemical detection of the NADPH-diaphorase (ND)-activity.
      Following change of the environment and darkness for 12 and 24 h, statistical
      analysis displayed a significant increase in the number of ND-neurons, especially
      in the posterior magnocellular and the lateral parvicellular subdivisions of the
      PVN. These data indicate that the ND-neurons of the PVN are influenced by changes
      of the environment and darkness.

PMID- 10657530
TI  - Pituitary adenylate cyclase-activating polypeptide (PACAP-27) enhances tyrosine
      hydroxylase activity in the nucleus accumbens of the rat.
AB  - Pituitary adenylate cyclase-activating polypeptide (PACAP-27) was incubated in a
      tyrosine hydroxylase (TyrOH) assay with a homogenate preparation of the nucleus
      accumbens of the rat. TyrOH activity was determined in vitro by measuring the
      production of L-dopa with HPLC-ECD. Only in the presence of adenosine nucleotides
      (ATP, App(NH)p) PACAP-27 increased TyrOH activity with a EC(50)of 100 nM. Since
      the PACAP-27 effect on TyrOH was abolished when homogenate or pellet of the
      nucleus accumbens were coincubated with CHAPS, the peptide effect appears to be
      receptor mediated. TyrOH activation produced by PACAP-27 increased in the
      presence of the phosphodiesterase inhibitor papaverine indicating the involvement
      of cAMP. The marked effect of the non-hydrolysable adenosine nucleotide App(NH)p
      also supports a cAMP-dependent TyrOH activation not related to ADP or an ADP
      dependent mechanism. This report's data suggest that PACAP-27 activates TyrOH in
      the rat nucleus accumbens through receptor-mediated cAMP formation. The exact
      receptor type present in the nucleus accumbens has yet not been specified.

PMID- 10657531
TI  - A radioiodinated 7alpha-O-iodoallyl diprenorphine for mapping opioid receptors.
AB  - The aim of the current research has been to validate an original radioiodinated
      diprenorphine (DPN) derivative suitable for imaging studies of opioid receptors.
      [(125)I]7alpha-O-iodoallyl diprenorphine (7alpha-O-IA-DPN) was prepared by
      radioiododestannylation and in vitro and in vivo opioid receptor binding assays
      were performed with CDF1 mouse brains. In vitro binding studies showed high
      affinity (K(i)= 0.4 +/- 0.2 nM) for mouse brain membranes. In vivo studies showed
      63% specific binding. Ex vivo autoradiography of brain sections confirmed high
      uptake and retention of [(125)I]7alpha-O-IA-DPN in regions rich in opioid
      receptors. This new radioiodinated DPN analogue appears to be a potential
      radioprobe for in vivo visualization of human cerebral opioid receptors with
      single photon emission computed tomography (SPECT).

PMID- 10657532
TI  - Possible involvement of central C-type natriuretic polypeptide receptor on water
      intake in spontaneously hypertensive rats, but not in normotensive Wistar-Kyoto
      rats.
AB  - The present study was designed to examine the possible role of brain C-type
      natriuretic polypeptide receptor (GC-B) in spontaneously hypertensive (SHR) and
      normotensive Wistar-Kyoto rats (WKY). The level of GC-B mRNA in various regions
      of the brain in both SHR and WKY was examined in the present study. The GC-B mRNA
      was unevenly distributed in rat brain, the transcript being expressed
      predominantly in the hypothalamus and cerebellum but comparatively at low level
      in the striatum and septum. However, the level in the septum was 3-fold higher in
      SHR than than in age-matched WKY, while no differences were observed in other
      regions of the brain. Intracerebroventricular administration of antisense
      oligonucleotide to GC-B mRNA inhibits the night-time water intake in SHR, but not
      in WKY. However, the daily food intake was not significantly altered by the
      injection of antisense oligonucleotide in both strains. These results demonstrate
      that the brain GC-B mRNA, particularly in septum, is increased in SHR and this
      increase may be closely related to the regulation of water-drinking behaviour in
      SHR.

PMID- 10657533
TI  - Fibrillar Alzheimer's amyloid peptide Abeta(1-42) stimulates low density
      lipoprotein binding and cell association, free radical production and cell
      cytotoxicity in PC12 cells.
AB  - Amyloid forming peptides are known to disturb vital cellular functions and induce
      cell death. However, the mechanisms by which fibrillogenic peptides induce
      cytotoxic effects in various cells has not been established. In this study the
      effects on low density lipoprotein binding and uptake of fibrils of the
      Alzheimer's amyloid beta-peptide (Abeta(1-42)), which is known to play a central
      role in the pathogenesis of Alzheimer's disease, were investigated in
      pheochromocytoma PC12 cells. Fibrillar Abeta(1-42) at micromol concentrations
      increased low-density lipoprotein (LDL) binding and cell association by 460% and
      200% respectively, and LDL degradation by about 62%. Approximately 49% and 34% of
      Abeta fibril stimulated LDL cell association and degradation was inhibited by
      anti-LDL receptor antibodies. The soluble form of Abeta had no effect on any of
      these measures of LDL metabolism. The observed increased glutathione reductase
      activity, DNA fragmentation (TUNEL assay) and decreased DNA synthesis ([(3)H]
      thymidine incorporation assay) in cells treated with Abeta(1-42) fibrils alone or
      together with LDL relative to controls, suggests that the interaction of fibrils
      with LDL receptors might be one possible pathway which contributes to fibril
      cytotoxicity.

PMID- 10657534
TI  - Low calcitonin gene-related, peptide-like immunoreactivity in cerebrospinal fluid
      from chronic pain patients.
AB  - Cerebrospinal fluid (CSF) levels of calcitonin gene-related peptide-like activity
      (CGRP-LI), were determined in 35 patients with painful orthopaedic disorders and
      the activity was compared to that of 12 healthy controls without pain. Fourteen
      patients had pain from osteoarthritis of the hip or the knee, 11 had rhizopathic
      pain due to a herniated lumbar disc and 10 had pain from a hip fracture. In all
      patients, decreased CGRP-LI was observed in CSF compared to the controls. The
      lowest values were found in the patients with osteoarthritis, while there was
      less, but still significant, reduction of CGRP-LI in the patients with herniated
      lumbar disc and those with a hip fracture. In most of the patients, CGRP-LI was
      also analysed at a second lumbar puncture after operative treatment, when pain
      had subsided or was reduced. However, the CGRP-LI remained low after treatment,
      which may suggest the influence of factors other than pain.

PMID- 10657535
TI  - Thyrotropin-releasing hormone-induced GH release after cocaine withdrawal in
      cocaine addicts.
AB  - During cocaine addiction the hypothalamus-pituitary axis is widely affected and a
      blunted response of thyroid stimulating hormone (TSH) to thyroid releasing
      hormone (TRH) consistent with a hyperthyroid state has been observed. Since the
      thyroid status can affect the release of growth hormone (GH) the authors
      evaluated TSH and GH responses to TRH in cocaine addicts at the time of drug
      withdrawal and 30 days after. Twenty-six male cocaine addicts and 11 healthy male
      control subjects agreed to participate in the study. TRH and placebo tests were
      performed at random at 5 day intervals at the time of drug withdrawal and after
      30 days. In drug addicts, at the time of the first test basal plasma levels of
      freeT3, freeT4 and TSH were normal, but the TSH response to TRH was impaired.
      After 30 days of cocaine abstinence basal freeT4 plasma levels were significantly
      lower, and TSH levels and the TSH response to TRH were higher than in the first
      test. At the first examination, basal GH concentrations were similar in cocaine
      addicts and in control subjects and GH did not respond to TRH. After 30 days of
      abstinence, basal GH plasma levels were unmodified, but the TRH became
      stimulatory of GH release in cocaine-deprived, but not in control subjects. In
      conclusion, in cocaine addicts, drug withdrawal is associated with a condition of
      subclinical hypothyroidism that makes the GH-releasing machinery sensitive to
      TRH.

PMID- 10657536
TI  - Structure-activity analysis of N-acetyl [Leu(28,31)] NPY 24-36: a potent
      neuropeptide Y Y(2) receptor agonist.
AB  - Neuropeptide Y (NPY) and a C-terminal analog of NPY, N acetyl [Leu(28,31)] NPY 24
      36, act at NPY Y(2) receptors to potently inhibit cardiac vagal activity. The C
      terminal analog is equipotent as NPY in inhibiting cardiac vagal activity but
      does not retain any pressor or Y(1) activity. This study investigates the
      importance of each amino acid in the 13 residue analog for functional activity by
      systematically substituting each residue with L-alanine. The inhibitory effect on
      cardiac vagal action decreased with substitution at residues 25,26,28,29 and 31.
      No decrease in activity was observed with alanine substitution at residues 24, 27
      or 30. Residues 32 and 34 retained activity only at high doses, while residues
      33, 35 and 36 were not active following alanine substitution. The difference in
      potency of the effective analogs suggests secondary structure of the peptide is
      as important for activity as retaining key amino acids.

PMID- 10657537
TI  - Differential modulation by baclofen on antinociception induced by morphine and
      beta-endorphin administered intracerebroventricularly in the formalin test.
AB  - Our previous studies have demonstrated that supraspinal GABAergic receptors are
      differentially involved in the antinociception induced by morphine and beta
      endorphin given intracerebroventricularly (i.c.v.) in the tail-flick and hot
      plate tests. These two models employed a phasic, thermal nociceptive stimulus.
      The present study was designed to examine the possible involvement of supraspinal
      GABAergic receptors in opioid-induced antinociception in the formalin test.
      Morphine (1 microg) and beta-endorphin (1 microg) given i.c.v. displayed the
      almost complete inhibitory effects against the hyperalgesic response in both
      phases. Muscimol (75-100 ng) and baclofen (5-10 ng) injected i.c.v. produced the
      hypoalgesic response in the both phases. The hypoalgesic response induced by
      muscimol and baclofen observed during the second phase was more pronounced than
      that observed during the second phase. Baclofen (2.5 ng), at the dose which did
      not affect the hyperalgesic response, resulted in a significant reversal of the
      i.c.v. administered beta-endorphin-induced hypoalgesic response observed during
      the second, but not the first, phase. However, the hypoalgesic response induced
      by i.c.v. administered morphine was not changed by the same dose of muscimol or
      baclofen injected i.c.v. Our results indicate that, at the supraspinal level,
      GABA(B)receptors appear to be involved in the modulation of antinociception
      induced by supraspinally administered beta-endorphin, but not morphine, in the
      formalin test model.

PMID- 10657538
TI  - Diazepam and buspirone alter neuropeptide Y-like immunoreactivity in rat brain.
AB  - Neuropeptide Y-like immunoreactivity (NPY-LI) was investigated in naIve Sprague
      Dawley rats subjected to acute, subchronic (7 days) or chronic (21 days)
      intraperitoneal treatment with diazepam (1 or 3 mg/kg once daily) or buspirone
      (1.5 or 5 mg/kg twice daily). NPY-LI was determined by radioimmunoassay in the
      amygdala, nucleus accumbens, hypothalamus and frontal cortex 24 h after the last
      dose of the drugs. Amygdala NPY-LI decreased after acute diazepam (3 mg/kg) or
      buspirone (1.5 mg/kg) and increased after subchronic treatment with both doses of
      diazepam and after chronic buspirone (1.5 mg/kg) treatment. Both diazepam and
      buspirone given in subchronic and chronic doses decreased NPY-LI levels in the
      nucleus accumbens. Hypothalamic NPY-LI changed only after chronic treatment: it
      decreased after diazepam and increased after buspirone (5 mg/kg). NPY-LI content
      in the frontal cortex decreased after subchronic diazepam (3 mg/kg) treatment and
      slightly increased after buspirone. The study has shown that both diazepam and
      buspirone affect NPY-LI levels in rats. These results suggest that the NPY system
      in the amygdala and nucleus accumbens is implicated in the anxiolytic effects of
      the drugs studied.

PMID- 10657540
TI  - Influence of age on nitric oxide modulatory action on Na(+), K(+)-ATPase activity
      through cyclic GMP pathway in proximal rat trachea.
AB  - Age-related changes in the modulatory action of nitric oxide (NO) on cyclic GMP
      levels and Na(+),K(+)-ATPase activity in the proximal rat trachea were
      investigated using sodium nitroprusside, 8-bromo-cyclic GMP and okadaic acid. At
      24 months, both control activities of Na(+), K(+)-ATPase and Mg(2+)-ATPase were
      decreased when compared to the segments from 4- and 12-month-old animals.
      However, cyclic GMP levels were similar among the three ages. Sodium
      nitroprusside (100 microM) induced stimulation of Na(+),K(+)-ATPase activity in
      segments from both 4- and 12-month-old animals, but not 24-month-old animals. The
      effect was specific for Na(+),K(+)-ATPase since Mg(2+)-ATPase activity was
      unaffected. Sodium nitroprusside induced an increase in nitrates/nitrites and
      cyclic GMP levels in proximal segments at 4, 12 and 24 months. The 8-bromo-cyclic
      GMP (100 microM) induced a similar specific stimulation of Na(+),K(+)-ATPase
      activity in segments from 4- and 12- but not 24-month-old animals. Okadaic acid
      (1 microM), a phosphatase-1 inhibitor, increased proximal Na(+), K(+)-ATPase but
      not Mg(2+)-ATPase activity in tissues from 4-, 12- and 24-month-old animals. Our
      results suggest that aging affects cyclic GMP pathway in proximal rat trachea by
      an action at the level of the cyclic GMP-dependent protein kinase.

PMID- 10657541
TI  - Affinity of cholecystokinin receptor antagonists for the gastrin-binding protein.
AB  - A 78 kDa gastrin-binding protein is a likely target for the anti-proliferative
      effects of the cholecystokinin (CCK) receptor antagonists D,L-4-benzamido-N,N
      dipropylglutaramic acid (proglumide) and N-4-chlorobenzoyl-L-tryptophan
      (benzotript) on colorectal carcinoma cell lines [Baldwin, G.S., 1994.
      Antiproliferative gastrin/cholecystokinin receptor antagonists target the 78-kDa
      gastrin-binding protein. Proc. Natl. Acad. Sci. USA 91, 7593-7597.]. Definition
      of the physiological role of the gastrin-binding protein has been hampered by the
      very low affinity of benzotript for the gastrin-binding protein. Benzotript
      analogues were therefore tested for their ability to inhibit the binding of
      iodinated gastrin to the gastrin-binding protein. The affinity of the most potent
      analogue (the D-isomer of benzotript, CR 665) was similar to the value reported
      previously for the L-isomer. In order to isolate more potent binding inhibitors,
      several selective CCK receptor antagonists were also tested as inhibitors of the
      binding of gastrin to the gastrin-binding protein. The affinity of the most
      potent binding inhibitor PD 149164 (benzenebutanoic acid, 4-fluoro-!b/-[[3-(1H
      indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo-[3.3 .1. 1(3,7)]dec-2
      yloxy)carbonyl]amino]propyl]amino]-, [R-(R*,S*)]-) was approximately 10-fold
      higher than the L-isomer of benzotript. PD 149164 may serve as the lead compound
      for the future development of more potent and selective gastrin-binding protein
      inhibitors.

PMID- 10657542
TI  - A novel effect of rebamipide: generation of [Ca(2+)](i) oscillations through
      activation of CCK(1) receptors in rat pancreatic acinar cells.
AB  - The protective effect of 2-(4-chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl]
      propionic acid (rebamipide) on gastric mucosa is well established. Here we
      demonstrate that rebamipide acts on pancreatic acinar cells to generate
      oscillations of intracellular Ca(2+) concentration ([Ca(2+)](i)) through the
      activation of cholecystokinin subtype 1 (CCK(1)) receptors. At concentrations
      higher than 5 microM, rebamipide induced [Ca(2+)](i) oscillations in individual
      fura-2-loaded pancreatic acinar cells. The frequency of oscillations increased
      with increasing concentrations of rebamipide, while the latency between
      stimulation of cells and initiation of [Ca(2+)](i) oscillations decreased with
      increasing concentration. The [Ca(2+)](i) oscillations evoked by rebamipide were
      inhibited by the CCK(1) receptor antagonist L-364,718 but not by atropine or the
      CCK(2) receptor antagonist L-365,260 indicating that rebamipide is a nonpeptide
      CCK(1) receptor agonist.

PMID- 10657543
TI  - Angiotensin II type 1 receptor-mediated increase in cytosolic Ca(2+) and
      proliferation in mesothelial cells.
AB  - We investigated the Ca(2+) signaling pathways of the response to angiotensin II
      in pleural mesothelial cells and the role of these Ca(2+) signaling pathways in
      mesothelial cell proliferation. Rat pleural mesothelial cells were maintained in
      vitro, and the Ca(2+) movement to angiotensin II was evaluated using the
      fluorescent Ca(2+) indicator fura 2. Furthermore, proliferation of mesothelial
      cells was assessed using a spectrophotometric 3-(4, 5-dimethylthazol-2-yl)-2,5
      diphenyl-2H-tetrasodium bromide (MTT) assay. Angiotensin II (1 pM-100 microM)
      induced in mesothelial cells a biphasic elevation of intracellular Ca(2+)
      concentration ([Ca(2+)](i)) that consisted of a transient initial component,
      followed by a sustained component. Neither removal of extracellular Ca(2+) nor
      inhibition of Ca(2+) influx by 1 microM nifedipine affected the angiotensin II
      induced initial transient elevation of [Ca(2+)](i) in mesothelial cells.
      Nifedipine did not block angiotensin II-induced sustained elevation of
      [Ca(2+)](i). Angiotensin II (1 pM-100 microM) had a proliferative effect on
      mesothelial cells in a dose-dependent manner. Angiotensin II type 1 (AT(1))
      receptor antagonist ([Sar(1), Ile(8)]angiotensin II) inhibited both angiotensin
      II-induced elevation of [Ca(2+)](i) and proliferation of mesothelial cells.
      Pertussis toxin did not affect angiotensin II-induced responses. These results
      suggest that angiotensin II-induced responses to mesothelial cells are extremely
      dependent on the angiotensin AT(1) receptor coupled with pertussis toxin
      insensitive G protein.

PMID- 10657544
TI  - ABT-627, an endothelin ET(A) receptor-selective antagonist, attenuates tactile
      allodynia in a diabetic rat model of neuropathic pain.
AB  - Tactile allodynia, the enhanced perception of pain in response to normally non
      painful stimulation, represents a common complication of diabetic neuropathy. The
      activation of endothelin ET(A) receptors has been implicated in diabetes-induced
      reductions in peripheral neurovascularization and concomitant endoneurial
      hypoxia. Endothelin receptor activation has also been shown to alter the
      peripheral and central processing of nociceptive information. The present study
      was conducted to evaluate the antinociceptive effects of the novel endothelin
      ET(A) receptor-selective antagonist, 2R-(4-methoxyphenyl)-4S-(1,3-benzodioxol-5
      yl)-1-(N, N-di(n-butyl)aminocarbonyl-methyl)-pyrrolidine-3R-carboxylic acid (ABT
      627), in the streptozotocin-induced diabetic rat model of neuropathic pain. Rats
      were injected with 75 mg/kg streptozotocin (i. p.), and drug effects were
      assessed 8-12 weeks following streptozotocin treatment to allow for stabilization
      of blood glucose levels (>/=240 mg/dl) and tactile allodynia thresholds (</=8.0
      g). Systemic (i.p.) administration of ABT-627 (1 and 10 mg/kg) was found to
      produce a dose-dependent increase in tactile allodynia thresholds. A significant
      antinociceptive effect (40-50% increase in tactile allodynia thresholds, P<0.05)
      was observed at the dose of 10 mg/kg, i.p., within 0.5-2-h post-dosing. The
      antinociceptive effects of ABT-627 (10 mg kg(-1) day(-1), p.o.) were maintained
      following chronic administration of the antagonist in drinking water for 7 days.
      In comparison, morphine administered acutely at a dose of 8 mg/kg, i.p., produced
      a significant 90% increase in streptozotocin-induced tactile allodynia
      thresholds. The endothelin ET(B) receptor-selective antagonist, 2R-(4
      propoxyphenyl)-4S-(1, 3-benzodioxol-5-yl)-1-(N-(2, 6-diethylphenyl)aminocarbonyl
      methyl)-pyrrolidine-3R-carboxy lic acid (A-192621; 20 mg/kg, i.p.), did not
      significantly alter tactile allodynia thresholds in streptozotocin-treated rats.
      Although combined i.p. administration of ABT-627 and A-192621 produced a
      significant, acute increase in tactile allodynia thresholds, this effect was
      significantly less than that produced by ABT-627 alone. These results indicate
      that the selective blockade of endothelin ET(A) receptors results in an
      attenuation of tactile allodynia in the streptozotocin-treated rat.

PMID- 10657545
TI  - Blockade of NMDA receptors in the nucleus accumbens elicits spontaneous tail
      flicks in rats.
AB  - The open channel blocker at N-methyl-D-aspartate (NMDA) receptors, dizocilpine,
      stereospecifically elicited spontaneous tail-flicks in rats - a reaction similar
      to those elicited by other drugs (tenocyclidine, phencyclidine and ketamine)
      acting as open channel blockers. Their relative potencies were strongly
      correlated with affinities at NMDA binding sites and labeled by [3H]dizocilpine
      in the frontal cortex (r=0.94) and, as determined previously [Millan, M. J.,
      Seguin, L., 1994. Chemically-diverse ligands at the glycine B site coupled to N
      methyl-D-aspartate (NMDA) receptors selectively block the late phase of formalin
      induced pain in mice, Neurosci. Lett., 178 (1994) 139-143], potency for eliciting
      antinociception (0. 93). The competitive antagonists at the NMDA receptor
      recognition site, (+/-)3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid
      (CPP), 4-phosphonomethyl-2-piperidine carboxylic acid (CGS19755), D, L-(E)-2
      amino-4-methylphosphono-3-pentanoic acid (CGP37849) and (3E)-1-ethyl ester-2
      amino-4-methyl-5-phosphono-3-pentenoic acid (CGP39551), likewise dose-dependently
      evoked spontaneous tail-flick. In contrast, antagonists/weak partial agonists at
      the coupled, glycine B site, 7-chloro-4-hydroxy-3-(3-phenoxy) phenyl-2(H)
      quinolinone (L701,324), (+)-1-hydroxy-3-aminopyrrolidine-2-one ((+)-HA966), (3R,
      4R)-3-amino-1-hydroxy-4-methyl-2-pyrrolidinone (L687,414), 6, 7-dichloro-1, 4
      dihydro-5-nitro, 2,3 quinoxalinedione (ACEA1021) and 2-carboxy-4,6-dichloro (1H)
      indole-3-propanoic acid (MDL29,951), were inactive. NMDA abolished induction of
      spontaneous tail-flick by CPP and CGS19755, but not by dizocilpine. Upon
      bilateral injection into the nucleus accumbens, dizocilpine immediately and dose
      dependently elicited spontaneous tail-flick, but it was ineffective in the
      ventrotegmental area and striatum. Similarly, injection of CPP into the nucleus
      accumbens elicited spontaneous tail-flick. Neither dizocilpine nor CPP elicited
      spontaneous tail-flick upon administration onto lumbar spinal cord. In
      conclusion, a pharmacologically specific spontaneous tail-flick-response is
      elicited by both open channel blockers and recognition site antagonists, but not
      glycine B site antagonists, at NMDA receptors. Their actions, mediated in the
      nucleus accumbens, may be differentiated by their respective resistance and
      sensitivity to NMDA.

PMID- 10657546
TI  - Changes in hypothalamic paraventricular nucleus catecholaminergic activity after
      acute and chronic morphine administration.
AB  - The participation of hypothalamic noradrenaline in the expression of
      neuroendocrine signs of morphine withdrawal has been proposed. The present study
      in rats examined: (1) the relationships between corticosterone secretion and the
      possible modifications in noradrenaline and dopamine content and turnover in the
      hypothalamic paraventricular nucleus after acute and chronic morphine
      administration; (2) the changes in cyclic adenosine monophosphate (cAMP) levels
      in the paraventricular nucleus after the same treatments. The results showed that
      acute morphine injection in control rats increased corticosterone release, 3
      methoxy-4-hydroxyphenylethylene glycol (MHPG) production, and noradrenaline
      turnover. Dopamine turnover in the paraventricular nucleus was decreased and the
      cAMP levels remained unchanged. In chronic morphine-treated rats, there was no
      elevation in noradrenaline turnover or in corticosterone secretion, indicating
      that tolerance developed to the acute effects of the opioid. Correspondingly, no
      alterations in dopamine turnover were observed when chronic morphine-treated rats
      were compared with control rats acutely injected with morphine. cAMP levels in
      the paraventricular nucleus were unchanged during the tolerant state. The results
      raise the possibility that noradrenergic afferents play a significant role in the
      alterations of paraventricular nucleus function and pituitary-adrenal axis
      activity in response to acute and chronic morphine and suggest that these
      modifications are not mediated through adenylate cyclase activation. The present
      data provide further support for the idea of adaptive changes in noradrenergic
      neurons projecting to the paraventricular nucleus during chronic morphine
      exposure.

PMID- 10657547
TI  - The effects of antipsychotics with 5-HT(2C) receptor affinity in behavioral
      assays selective for 5-HT(2C) receptor antagonist properties of compounds.
AB  - Many antipsychotics have marked antagonist effects at 5-hydroxytryptamine (5
      HT(2C)) receptors in vitro, which, however, have been difficult to show in
      behavioral assays. Here, we used two assays - hypolocomotion and hypophagia
      induced by the 5-HT(2C) receptor agonist 1-(3-chlorophenyl)piperazine (mCPP) - to
      try to characterize the 5-HT(2C) receptor antagonist properties of antipsychotics
      in vivo. Clozapine, olanzapine, pipamperone, and trans-5-chloro-2-methyl
      2,3,3a,12b-tetrahydro-1H-dibenz-[2,3:6, 7]oxepino[4,5-C] pyrrolidino maleate (ORG
      5222), modestly, but significantly, attenuated mCPP (10 mg/kg)-induced
      hypolocomotion. In contrast, risperidone and loxapine were inactive. The putative
      antipsychotic ORG 5222 significantly attenuated mCPP (5 mg/kg)-induced
      hypophagia, whereas the other antipsychotics were inactive. Selective antagonists
      at dopamine D(2)-like receptors, alpha(1)-adrenoceptors, alpha(2)-adrenoceptors,
      or muscarinic receptors were not able to antagonize the effects of mCPP in either
      assay. The results suggest that mCPP-induced hypolocomotion can be used to
      characterize the 5-HT(2C) receptor antagonist properties of antipsychotics,
      whereas mCPP-induced hypophagia appeared to be sensitive only to compounds highly
      selective for 5-HT(2C) receptors. Together, these assays may help to characterize
      functional, in vivo, 5-HT(2C) receptor antagonist properties of antipsychotics.

PMID- 10657548
TI  - Psychostimulant sensitization: differential changes in accumbal shell and core
      dopamine.
AB  - The nucleus accumbens has been subdivided into a shell and a core compartment on
      the basis of histochemical and connectional differences. Recently, we reported
      that behavioral sensitization to morphine is associated with an increased
      dopamine transmission in the caudate-putamen and in the nucleus accumbens core as
      well as a decreased response in the nucleus accumbens shell following acute
      morphine challenge. We have now performed a similar study in rats sensitized to
      amphetamine and to cocaine. Behavioral sensitization was induced by daily
      administration of a single dose of 1 mg/kg s.c. of amphetamine for 10 days or of
      10 mg/kg i.p. of cocaine twice a day for 14 days. Microdialysis was performed 10
      14 days after the last injection of amphetamine and 7-10 days after the last
      injection of cocaine. Both schedules resulted in robust behavioral sensitization
      in response to challenge with 0.25 and 0.5 mg/kg of amphetamine and to 5 and 10
      mg/kg of cocaine, respectively. Subjects pre-exposed to amphetamine showed a
      sensitization of dopamine transmission in the nucleus accumbens core but not in
      the nucleus accumbens shell. Subjects pre-exposed to cocaine showed sensitization
      of dopamine transmission in the core only to the lower dose of cocaine. In the
      shell no change was observed after the lower dose of cocaine while a significant
      reduction of the dopamine response was observed after the higher dose. These
      results suggest that behavioral sensitization might result from reciprocal
      changes in the response of nucleus accumbens dopamine in the shell and in the
      core to drug challenge.

PMID- 10657549
TI  - Participation of NMDA and kainate receptors of paraventricular nucleus in
      cardiovascular responses to glutamate receptor agonist.
AB  - The nuclei of the hypothalamus have been shown to be involved in central
      cardiovascular homeostasis. Recent studies suggest that glutamate-containing
      neurons have an important role in the regulation of central cardiovascular
      function. We report first on the effects of intracerebrally injected NMDA and non
      NMDA receptor ligands on blood pressure and heart rate in conscious Sprague
      Dawley rats. In the second part, we describe the effect of blockade of NMDA or
      kainate receptors in the paraventricular nucleus on glutamate receptor agonist
      induced blood pressure responses. Intracerebroventricular injections of L
      glutamic acid, NMDA and kainic acid produced increases in mean arterial pressure.
      Kainic acid produced significant decreases in heart rate. Microinjection of DL-2
      amino-5-phosphonopentanoic acid (APV; 25 and 50 nmol), a competitive NMDA
      receptor antagonist, into the paraventricular nucleus blunted the increases in
      the mean arterial pressure evoked by intracerebroventricular injections of NMDA
      (1 nmol), whereas microinjection of dinitroquinoxaline (DNQX; 20, 40 and 80
      pmol), which acts as an antagonist at kainate receptors, failed to antagonize the
      cardiovascular effects of intracerebroventricular kainic acid (10 pmol).
      Microinjections of NMDA (100 pmol) into the paraventricular nucleus produced
      pressor responses, but kainic acid (5 and 10 pmol) failed to affect either mean
      arterial pressure or heart rate. These results suggest participation of the
      glutamergic system in cardiovascular regulation via NMDA receptors located within
      the paraventricular nucleus of the hypothalamus in rats.

PMID- 10657550
TI  - Quinpirole treatment increases renal sympathetic nerve activity and baroreflex
      gain in conscious rabbits: a spectral study.
AB  - Intravenous administration of 0.3 mg/kg of quinpirole to conscious rabbits that
      had been pretreated with domperidone caused a marked increase in blood pressure
      and renal sympathetic nerve activity with a peak at 5-10 min after injection (25%
      and 3-fold increase, respectively). Spectral analysis of the blood pressure-renal
      sympathetic nerve activity relationship in the 0.2-0.4 Hz domain showed that
      baroreflex gain was markedly increased at 5-10 min (4-fold) and at 20-25 min
      after injection (3.7-fold). These results show that administration of the
      dopamine D(2)/D(3) receptor agonist quinpirole causes profound and long-lasting
      changes in the central integration of the sympathetic baroreceptor-vasomotor
      reflex.

PMID- 10657551
TI  - Rank-order inhibition by omega-conotoxins in human and animal autonomic nerve
      preparations.
AB  - The inhibitory effects of the omega-conotoxins GVIA, MVIIA and MVIIC on
      electrically-evoked, tetrodotoxin (10(-7) M)-sensitive, autonomic nerve activity
      were studied using human, rat or guinea-pig vas deferens and intestinal tissues.
      In each preparation from each species, nM concentrations of omega-conotoxins GVIA
      and MVIIA prevented the neuronally-mediated contractions, whereas omega-conotoxin
      MVIIC was either markedly less potent (IC(50)'s 1.4 or 2.9 log units more than
      for omega-conotoxin GVIA in guinea-pig ileum and rat vas deferens, respectively)
      or was without significant activity (human vas deferens, human Taenia coli) when
      tested at similar concentrations. In contrast the differences in potency between
      omega-conotoxins GVIA and MVIIC were considerably less when assayed directly on
      Ca(2+) channel currents evoked from rat superior cervical ganglion neurons in
      culture (approximately 0.1 log unit difference) and from a stable cell line
      expressing rat alpha(1B), alpha(2)delta, beta(1b) Ca(2+) channel subunits
      (approximately 0.9 log unit). These different rank-orders of inhibitory activity
      of the conotoxins support the suggestion that there are pharmacologically
      distinct N-type Ca(2+) channels in the peripheral nervous system, and that this
      tissue-dependent difference is seen in man.

PMID- 10657552
TI  - Differences in mediator of nonadrenergic, noncholinergic relaxation of the distal
      colon between Wistar-ST and Sprague-Dawley strains of rats.
AB  - Participation of nitric oxide and vasoactive intestinal peptide (VIP) in
      electrical field stimulation-induced nonadrenergic, noncholinergic (NANC)
      relaxation of longitudinal muscle and in balloon distension-induced descending
      NANC relaxation of circular muscle were studied in the distal colon of Wistar-ST
      and Sprague-Dawley rats. The extent of the nitric oxide-mediated component was
      approximately 50% in longitudinal and circular muscle of Sprague-Dawley rats,
      whereas this component was absent in both muscles of Wistar-ST rats. The extent
      of the VIP-mediated component was approximately 40% in longitudinal muscle of
      Wistar-ST rats and circular muscle of Sprague-Dawley rats, whereas this component
      was absent in circular muscle of Wistar-ST rats and longitudinal muscle of
      Sprague-Dawley rats. In circular muscle of Sprague-Dawley rats, in which
      participation of both nitric oxide and VIP in the relaxation was suggested,
      inhibition of descending relaxation by N(G)-nitro-L-arginine (L-NOARG) together
      with VIP-(10-28) was similar to that by either of the antagonists, and exogenous
      VIP-induced relaxation was not affected by L-NOARG, but exogenous nitric oxide
      induced relaxation was partly inhibited by VIP-(10-28). These results suggest a
      linkage of the pathways mediated by nitric oxide and VIP. In the
      immunohistochemical studies, nitric oxide synthase or VIP immunoreactive neurons
      were seen in the ganglia, primary internodal strands of the myenteric plexus and
      in the circular muscle layer. However, the overall appearance of immunoreactive
      cell bodies in the myenteric plexus and the numbers of immunoreactive fibers in
      the circular muscle layer appeared to be similar in Wistar-ST and Sprague-Dawley
      rats. These results suggest that mediators of NANC relaxation in the distal colon
      are different in different strains of rats, i.e., Wistar-ST and Sprague-Dawley,
      although no such difference was seen in immunohistochemical studies.

PMID- 10657553
TI  - Shortening velocity of skeletal muscle from humans with malignant hyperthermia
      susceptibility: effects of halothane.
AB  - The aim of this investigation was to assess the effect of halothane on the
      velocity of shortening and lengthening of muscle from normal subjects and from
      patients with malignant hyperthermia susceptibility. Strips were mounted
      horizontally at optimal length in normal Krebs-Ringer's solution and mechanical
      parameters were obtained before and after exposure to 3 vol.% halothane. The
      maximun shortening velocity at zero load (V(max)) was determined by using Hill's
      characteristic equation. The contraction and relaxation indices were measured
      under isotonic and isometric conditions: maximum shortening and lengthening
      velocities (maxV(c) and maxV(r), respectively); isometric peak twitch tension;
      peak of the positive (+dP/dt(max)) and negative (-dP/dt(max)) twitch tension
      derivative; ratio R1=maxV(c)/maxV(r) and ratio R2=(+dP/dt(max))/(-dP/dt(max)). In
      normal muscle, halothane markedly increased V(max), maxV(c) and peak twitch
      tension by 30+/-10%, 30+/-5% and 40+/-15%, respectively. The maxV(r) values
      increased concomitantly with the maxV(c) values, such that no change in the ratio
      R1 was observed. Both +dP/dt(max) and -dP/dt(max) increased such that the ratio
      R2 did not vary. In malignant hyperthermia susceptibility muscle, halothane
      induced a significant decrease in V(max) (-30+/-10%) and maxV(r) (-45+/-15%)
      without changing maxV(c). The decrease in maxV(r) was greater than that of
      maxV(c), such that the ratio R1 increased significantly. Peak twitch tension and
      +dP/dt(max) remained unchanged whereas -dP/dt(max) decreased significantly; the
      ratio R2 increased by 40+/-10%. These results suggest that halothane alters the
      contractile properties of malignant hyperthermia susceptibility muscle.

PMID- 10657554
TI  - Further evidence for the heterogeneity of functional muscarinic receptors in
      guinea pig gallbladder.
AB  - Previous studies have suggested the presence of multiple muscarinic receptor
      subtypes in guinea pig gallbladder smooth muscle, although the relative abundance
      and functional role of these subtypes remains an area of significant research
      efforts. The present study utilized both radioligand kinetic and functional
      experiments to further probe the nature of the muscarinic receptors in
      gallbladder smooth muscle and their mode of coupling to intra- and extra-cellular
      Ca(2+) sources. Dissociation kinetic studies using [3H]N-methylscopolamine
      ([3H]NMS) indicated that the binding profile in guinea pig gallbladder smooth
      muscle could not be reconciled with that expected for a single muscarinic
      receptor subtype, the latter determined in parallel experiments conducted on the
      cloned muscarinic M(1)-M(5) subtypes in Chinese hamster ovary (CHO) cells.
      Furthermore, comparison of the gallbladder data with the dissociation
      characteristics of [3H]NMS in guinea pig urinary bladder revealed a significantly
      different kinetic profile, with the urinary bladder, but not the gallbladder,
      demonstrating biphasic radioligand dissociation kinetics. In functional
      experiments, carbachol caused a concentration-dependent contraction of guinea pig
      gallbladder smooth muscle strips in Ca(2+)-free or 5 mM Sr(2+)-substituted
      physiological salt solutions (PSS) with amplitudes of the maximal contractions
      corresponding to 45.8+/-8.0% and 33.2+/-6.6% of control responses in normal PSS,
      respectively. Furthermore, the stimulus-response characteristics of carbachol
      mediated contraction appeared significantly altered in Ca(2+)-free PSS relative
      to normal or Sr(2+)-substituted PSS. The antagonist, methoctramine (1x10(-7)
      3x10(-5) M), exerted only a slight inhibition of carbachol (10(-5) M)-induced
      contractions in 5 mM Sr(2+)-substituted medium, whereas it was significantly more
      potent in antagonizing gallbladder contractions in response to 10(-5) M carbachol
      in the absence of extracellular Ca(2+). Both atropine and tripitramine were
      equipotent in antagonizing carbachol-induced contractions in Ca(2+)-free
      (pIC(50): 6.85+/-0.11 for atropine and 5.75+/-0.32 for tripitramine) and Sr(2+)
      substituted media (pIC(50): 6.88+/-0.25 for atropine and 5.70+/-0.16 for
      tripitramine), and pirenzepine was only slightly more potent in Ca(2+)-free PSS
      (pIC(50): 5.66+/-0.23) than in Sr(2+)-substituted PSS (pIC(50): 5.33+/-0.21).
      Taken together, our data indicate that carbachol contracts guinea pig gallbladder
      by stimulating two distinct muscarinic receptor subtypes linked to extracellular
      Ca(2+) influx and intracellular Ca(2+) release. These two subtypes may represent
      the muscarinic M(3) and M(4) receptors, although the presence of the muscarinic
      M(2) receptor subtype is also suggested from the binding data.

PMID- 10657555
TI  - Dopamine D(2) receptor ribozyme inhibits quinpirole-induced stereotypy in rats.
AB  - The injection of a dopamine D(2) receptor hammerhead ribozyme (20 microg) once
      daily for 5 days into the nucleus accumbens of rats resulted in an inhibition of
      stereotyped sniffing and locomotor activation produced by the selective dopamine
      D(2) receptor agonist, quinpirole (0.4 mg kg(-1) s.c.). The results suggest that
      ribozymes may be useful in the study of in vivo gene function in the brain.

PMID- 10657556
TI  - Inflammation, obesity, stress and coronary heart disease: is interleukin-6 the
      link?
AB  - There is mounting evidence that inflammation plays a role in the development of
      coronary heart disease (CHD). Observations have been made linking the presence of
      infections in the vessel wall with atherosclerosis, and epidemiological data also
      implicate infection in remote sites in the aetiology of CHD. In this article we
      propose a key role for the proinflammatory cytokine interleukin-6 (IL-6) in
      several mechanisms that contribute to the development of CHD. IL-6 is a powerful
      inducer of the hepatic acute phase response. Elevated concentrations of acute
      phase reactants, such as C-reactive protein (CRP), are found in patients with
      acute coronary syndromes, and predict future risk in apparently healthy subjects.
      The acute phase reaction is associated with elevated levels of fibrinogen, a
      strong risk factor for CHD, with autocrine and paracrine activation of monocytes
      by IL-6 in the vessel wall contributing to the deposition of fibrinogen. The
      acute phase response is associated with increased blood viscosity, platelet
      number and activity. Furthermore, raised serum amyloid A lowers HDL-cholesterol
      levels. IL-6 decreases lipoprotein lipase (LPL) activity and monomeric LPL levels
      in plasma, which increases macrophage uptake of lipids. In fatty streaks and in
      the atheromatous 'cap' and 'shoulder' regions, macrophage foam cells and smooth
      muscle cells (SMC) express IL-6, suggesting a role for this cytokine along with
      interleukin-1 (IL-1) and tumour necrosis factor-alpha (TNF-alpha), in the
      progression of atherosclerosis. Both these cytokines induce the release of IL-6
      from several cell types, including SMC. During vascular injury SMC are exposed to
      platelets or their products, and cytokine production by SMC further contributes
      to vascular damage. Furthermore, circulating IL-6 stimulates the hypothalamic
      pituitary-adrenal (HPA) axis, activation of which is associated with central
      obesity, hypertension and insulin resistance. Thus we propose a role for IL-6 in
      the pathogenesis of CHD through a combination of autocrine, paracrine and
      endocrine mechanisms. This hypothesis lends itself to testing using interventions
      to influence IL-6 secretion and actions.

PMID- 10657557
TI  - Governance of the concentration of plasma LDL: a reevaluation of the LDL receptor
      paradigm.

PMID- 10657558
TI  - Effect of dietary fat on the development of non-insulin dependent diabetes
      mellitus in obese Zucker diabetic fatty male and female rats.
AB  - The obese Zucker diabetic fatty male rat (ZDF/Gmi?trade mark omitted?-fa) has
      become a widely used animal model of NIDDM, in contrast to the obese ZDF females
      that rarely develop NIDDM. However, preliminary observations suggest that obese
      ZDF females may become diabetic on high-fat diets. Therefore, we studied the
      effect of dietary fat on development of NIDDM, dyslipidemia, and alterations in
      organ-specific serum panels in obese ZDF males and females. Results indicated
      different effects of dietary fat-content on development of diabetes in males and
      females. Males, even on low fat-content diets, developed diabetes but the process
      was accelerated as a function of dietary fat-content, whereas only the highest
      fat-content diet induced development of NIDDM in obese ZDF females. Additionally,
      triglyceride/apolipoprotein B ratios demonstrated gender-specific differences in
      the nature of circulating lipoprotein particles independent of diabetic state
      with values for females approximately twice those of males indicating more highly
      triglyceride-enriched lipoprotein particles in females. We conclude that the
      obese ZDF female rat has the potential to become an important animal model of
      NIDDM especially in women where few models currently exist.

PMID- 10657559
TI  - Large variations in human foam cell formation in individuals: a fully autologous
      in vitro assay based on the quantitative analysis of cellular neutral lipids.
AB  - The transformation of monocyte-derived macrophages into lipid-laden foam cells
      constitutes a characteristic and crucial event in the development of the earliest
      atherosclerotic lesions. We investigated whether the propensity to form foam
      cells varies among individuals. We developed a fully autologous foam cell assay
      based on a recently developed novel culture technique for human monocyte-derived
      macrophages (Wintergerst ES, Jelk J, Asmis, R. Differential expression of CD14,
      CD36 and the LDL receptor on human monocyte-derived macrophages. A novel cell
      culture system to study macrophage differentiation and heterogeneity, Histochem.
      Cell Biol. 1998;110:231-241). Thin layer chromatography and laser densitometry
      were used to determine cholesterol, triglyceride and cholesteryl ester levels in
      human macrophages. Aggregated LDL obtained by vortexing was found to be a
      reproducible stimulus of foam cell formation in human macrophages. In our hands,
      Cu(2+)-oxidized LDL also induced cholesteryl ester accumulation, but only when
      vortexed. We found that foam cell formation in an individual varied by less than
      25% over a 10-month period. In contrast, we observed a sevenfold difference in
      foam cell formation among eight male volunteers. The transfer of foam cells into
      culture medium with freshly thawed autologous serum resulted in a 75% regression
      within 1 week, independent of the amount of cellular cholesteryl esters
      accumulated. Foam cell formation correlated neither to serum nor to cellular
      cholesterol and triglyceride levels. The propensity to form foam cells could
      therefore represent a novel indicator of individual risk of atherogenesis.

PMID- 10657560
TI  - The distribution of oxidatively-modified lysine in the human vasculature.
AB  - Fifty-seven sections of human vessels, collected in the Pathobiological
      Determinants of Atherosclerosis in Youth study from individuals aged 25-34, were
      stained with two monoclonal antibodies to oxidatively-modified lysine. Intensity
      and extent of immunoreactivity were graded by three pathologists. Aorta from a
      Watanabe heritable hyperlipidemic (WHHL) rabbit was stained as a positive
      control. Intimal immunoreactivity in the rabbit was predominantly localized to
      lesions. Although immunoreactivity in humans was somewhat more intense in
      atherosclerotic plaques, substantial staining was present in intima with diffuse
      intimal thickening and coronary veins. Localization of oxidatively-modified
      lysine in humans did not correlate with localization or severity of
      atherosclerosis. Localization of immunoreactivity for oxidatively-modified lysine
      to intimal lesions in the WHHL rabbit may be due to absence of diffuse intimal
      thickening, which prevents retention of epitopes throughout the intima.

PMID- 10657561
TI  - Mercury accumulation and accelerated progression of carotid atherosclerosis: a
      population-based prospective 4-year follow-up study in men in eastern Finland.
AB  - Basic research and our previous studies have suggested that mercury exposure
      enhances lipid peroxidation and the risk of myocardial infarction, but there are
      no studies concerning the association between mercury accumulation and
      atherosclerosis. We therefore investigated whether high hair mercury content is
      associated with accelerated progression of carotid atherosclerosis, determined by
      ultrasonographic assessment of common carotid intima-media thickness (IMT), in a
      prospective study among 1014 men aged 42-60 years. In a linear regression model
      adjusting for other atherosclerotic risk factors, high hair mercury content was
      one of the strongest predictors of the 4-year increase in the mean IMT (P2.81
      microg/g (fifths) had an IMT increase of 0.105, 0.102, 0.113, 0.107 and 0.140
      mm/4 years, respectively (P=0.041 for heterogeneity between groups). The IMT
      increase was 0.034 mm/4 years (31.9%) greater in the highest fifth than in the
      other fifths (P<0.05 for the difference). These findings suggest that mercury
      accumulation in the human body is associated with accelerated progression of
      carotid atherosclerosis.

PMID- 10657562
TI  - Effect of coenzyme Q10 on experimental atherosclerosis and chemical composition
      and quality of atheroma in rabbits.
AB  - The effects of the administration of coenzyme Q10 (3 mg/kg per day) (group A,
      n=10) and placebo (aluminum hydroxide, 3 mg/kg per day) (group B, n=10) were
      compared over 24 weeks in a randomized, single-blind, controlled trial. There
      were two groups of rabbits receiving a trans fatty acid (TFA)-rich diet (5-8
      g/day) for 36 weeks. Oxidized rabbit chow with vitamin C plus ferric chloride was
      administered for 4 weeks in all rabbits. Intervention with coenzyme Q10 after
      feeding of TFA-rich diet was associated with a significant decline in
      thiobarbituric acid reactive substances (TBARS), diene conjugates and
      malondialdehyde, and an increase in plasma levels of vitamin E in the coenzyme Q
      group compared to placebo group. These changes, which were indicators of a
      decrease in oxidative damage, were independent of lipid lowering. The aortic and
      coronary artery plaque sizes, coronary atherosclerosis index, aortic and coronary
      atherosclerosis scores were significantly lower in the coenzyme Q group than
      placebo group. Aortic and coronary plaque frequencies, as well as frequencies of
      ulceration, thrombosis or hemorrhage, and cracks and fissures, were also
      significantly lower in the coenzyme Q group, indicating a better quality of
      atheroma compared to those in the control group. Aortic cholesterol,
      triglycerides and sudanophilia were significantly lower and vitamin E
      significantly higher in the coenzyme Q group in comparison to the placebo group
      indicating that coenzyme Q10 can have beneficial effect on the chemical
      composition of atheroma. The findings suggest that antioxidant therapy with
      coenzyme Q10 may be used as an adjunct to lipid lowering for additional
      beneficial effects related to chemical composition and quality of atheroma
      independent of hypolipidemic agents.

PMID- 10657563
TI  - Improved metabolic control reduces the number of postprandial apolipoprotein B-48
      containing particles in type 2 diabetes.
AB  - Postprandial lipoproteins are raised in diabetes and there is increasing evidence
      for the atherogenicity of the chylomicron remnant. Increased postprandial
      cholesteryl ester transfer has also been demonstrated in diabetes and may
      contribute to the atherogenic lipoprotein profile. The present study examined the
      effect of improving metabolic control on postprandial lipoproteins in 13 Type 2
      diabetic patients. Blood was taken fasting and at 2-h intervals following a high
      fat, 1100 kcal meal. Patients were brought into good control by intensified
      dietary advice and oral hyperglycaemic agents or insulin if blood glucose failed
      to respond. Fasting and postprandial cholesteryl ester transfer protein (CETP)
      and lecithin:cholesteryl acyltransferase (LCAT) were determined in six patients.
      Lipoproteins were isolated by sequential ultracentrifugation. Chylomicron and
      very low density lipoprotein (VLDL) apolipoprotein B-48 and apolipoprotein B-100
      were isolated by polyacrylamide gradient gel electrophoresis and quantified by
      densitometric scanning. CETP and LCAT were determined by an endogenous method
      which determined cholesterol esterification and transfer between the patients'
      lipoproteins. There was a significant reduction in postprandial chylomicron apo B
      48 (P<0.005), apo B-100 (P<0.0005) and chylomicron cholesterol (P<0.001)
      following improved diabetic control. The chylomicron lipid/apo B ratio increased
      with improved control (P<0.01). Postprandial CETP and LCAT were significantly
      reduced in good control (P<0.01 and P<0.05, respectively) and there were
      significant changes in HDL composition. The study shows that improvement in
      metabolic control in Type 2 diabetic patients leads to a reduction in
      postprandial chylomicron particles and less transfer of cholesterol to apo B
      containing lipoproteins.

PMID- 10657564
TI  - Are elevated levels of soluble ICAM-1 a marker of chronic graft disease in heart
      transplant recipients?
AB  - Positivity for circulating intercellular adhesion molecule-1 (ICAM-1) in heart
      transplant recipients has been claimed to predict the development of coronary
      artery disease and risk of graft failure. Soluble ICAM-1 were evaluated in 32
      heart transplant recipients. Five of these patients, who had undergone
      transplantation several years before, were positive for soluble ICAM-1 but did
      not present any clinical sign of graft rejection. Furthermore, although heart
      graft coronary disease was diagnosed in 15 of the 32 patients, they did not show
      significantly higher titres of soluble ICAM-1 compared to the remaining patients.
      These findings suggest that major caution is necessary when considering ICAM-1
      positivity as a marker of graft disease.

PMID- 10657565
TI  - Distribution of ultrasonographically-assessed dimensions of common carotid
      arteries in healthy adults of both sexes.
AB  - Our objective was to provide a description of 'normal' carotid artery dimensions
      which are increasingly used for detecting early atherosclerosis and predicting
      clinical complications. Far wall intima-media thickness (IMT), lumen diameter and
      cross-sectional area intima-media thickness (CSA-IMT) were measured on 1 cm
      distal common carotid artery segments on both sides by B-mode ultrasound, using
      an automated computerized edge-detection program, in 133 men and 216 women aged
      17-65 years and free from cardiovascular disease and traditional risk factors.
      IMT and CSA-IMT increased with age in both sexes and on both sides, while
      diameter did not, except on the right side in men. Women had lower diameter than
      men except on the left side at 30 years or below, while IMT did not differ
      between sexes except on the left side from 31 to 50 years where IMT was higher in
      men; as a result of their lower diameter, women had lower CSA-IMT than men except
      on the right side above 50 years. IMT was lower on the right side than on the
      left side in both sexes, except in 30-year old or younger men and 31- to 40-year
      old women, while diameter was higher on the right side than on the left side in
      men and women aged 31-40 years and in women aged 41-50 years; also CSA-IMT was
      lower on the right side than on the left side in both sexes above 40 years. These
      data provide reference values of carotid artery dimensions and show that age, sex
      and side of measurement should be taken into account in the interpretation of
      'normal' values of IMT and diameter in clinical practice and trials.

PMID- 10657566
TI  - Transdermal estrogens do not appear to modify the extent of lesional areas of
      aortic atherosclerosis in oophorectomized rabbits on a cholesterol-rich diet.
AB  - Cardiovascular disease (CVD) is the leading cause of death in older women in
      industrialised countries. It has been suggested that it is the cessation of
      estrogen production by the ovaries that puts postmenopausal women at increased
      risk of CVD. Estrogen therapy has demonstrated a protective effect against CVD
      and several reports suggest that diverse mechanisms may be involved. Oral
      estrogen appears to be associated with a better lipid profile than the use of
      transdermal estrogens; however, it is assumed that estrogens, oral and non-oral,
      have direct actions on the blood vessels that may exert an important role in
      cardiovascular disease prevention. To investigate the effect of transdermal
      estrogen therapy on aorta atherogenesis, we studied 20 cholesterol-fed New
      Zealand White rabbits for 4 months. The rabbits were oophorectomized and randomly
      assigned to two groups. Ten rabbits underwent bilateral ovariectomy followed by
      treatment with transdermal 17-beta-estradiol (group E) and the other 10 received
      placebo after sterilization (Group C). After diet total levels of cholesterol
      increase in group C from 50. 0+/-12.5 to 820.9+/-186.0 mg/dl, and in group E from
      52.6+/-9.4 to 811.4+/-213.0 mg/dl (no significant differences were observed
      between groups). Estrogen therapy increased twofold the total reactive
      antioxidant potential (TRAP group C: 22.5+/-16.7 mmol of Trolox/l vs. TRAP group
      E: 43.4+/-22.4 mmol of Trolox/l; P<0.04). At 4 months, the cholesterol-rich diet
      caused atherosclerotic lesions in both treated and untreated rabbits affecting
      18.7+/-14.5 and 21. 6+/-9.7% of the aortic surface respectively. In summary, the
      principal result from this study was that although treatment with transdermal 17
      beta-estradiol in cholesterol-fed ovariectomized rabbits increases the TRAP to
      pre-surgery values, it does not inhibit aortic cholesterol accumulation.

PMID- 10657567
TI  - Simvastatin enhanced sodium nitroprusside-induced apoptosis of smooth muscle
      cells. An involvement of geranylgeraniol.
AB  - A decrease in serum cholesterol is one of the most beneficial effects in anti
      atherogenesis. Nitric oxide is also an anti-atherogenic substance, inducing
      vasodilation and inhibits proliferation of smooth muscle cells (SMC). Therefore,
      we examined sodium nitroprusside (SNP)-induced apoptosis of vascular SMC with
      respect to cholesterol metabolism. Cultured vascular SMC from bovine carotid
      arteries and rat aorta were used. Apoptosis was determined by propidium iodide
      assay. Treatment of the SMC with SNP(100 micromol/l-1 mmol/l ) for 6 h induced a
      little nuclear fragmentation. SNP (1 mmol/l ) elicited apoptosis in 4.4+/-2.2% of
      cells. Pretreatment of SMC with simvastatin (1 microg/ml, 2 days), a
      hydroxymethylglutaryl Coenzyme A (HMG CoA) reductase inhibitor, synergistically
      enhanced SNP-induced apoptosis (% apoptosis =15. 9+/-3.3%). Either mevalonate
      (100 micromol/l) or geranylgeraniol (30 micromol/l) recovered the simvastatin (1
      microg/ml)-enhanced SMC apoptosis induced by SNP. Neither squalene (10 mmol/l)
      nor farnesol (30 micromol/l) had a recovery effect on the simvastatin-enhanced
      SMC apoptosis induced by SNP. Pretreatment with simvastatin (1 microg/ml) reduced
      total cholesterol content in SMC. Mevalonate (100 micromol/l) restored a decrease
      in total cholesterol content. However, incubation with LDL deficient serum did
      not enhance SNP-induced apoptosis of SMC, although treatment with LDL deficient
      serum decreased the total cholesterol content in SMC. These data suggested that
      decrease in HMG CoA reductase metabolites, especially geranylgeraniol might
      enhance the SNP-induced apoptosis of SMC, and that, apoptosis was not involved in
      a decrease in cholesterol of SMC.

PMID- 10657568
TI  - Metabolism of apolipoproteins AI and AII in subjects carrying similar apoAI
      mutations, apoAI Milano and apoAI Paris.
AB  - ApoAI Milano (AI(M)) and apoAI Paris (AI(P)) are mutant forms of apoAI in which
      cysteine is substituted for arginine at residues 173 and 151 respectively leading
      to the formation of homodimers and heterodimers with apoAII. Heterozygous
      subjects with these mutants are characterized by low levels of plasma HDL
      cholesterol and apoAI. The present study analyzed the metabolism of the different
      complexes of apoAI in three subjects, two AI(M) and one AI(P), using a primed
      constant infusion of trideuterated leucine. In AI(M) carriers, the mutant form
      was almost equally distributed in AI(M) dimer, AI(M):AII heterodimer and the
      monomer, whereas, in the AI(P) subject, the mutant apoAI was essentially in the
      apoAI(P):AII complex. Normal apoAI was low in the AI(M) subjects (20 and 16
      mg/dl) but very low in the AI(P) subject (0.3 mg/dl). In the AI(M) subjects, the
      low levels of apoAI were due to a rapid catabolism with a normal synthetic rate.
      However, the apoAI kinetics were heterogeneous with a rapid catabolism of the
      AI(M):AII complex (FCR of 0.430 and 0.401 day(-1)) and the AI(M) monomer (FCR of
      0.570 and 0.406 day(-1)) whereas the AI(M) dimer was catabolized slowly (FCR of
      0.114 and 0. 118 day(-1)). In contrast, AI(P) was catabolized relatively slowly
      with a FCR of 0.263, 0.182 and 0.258 day(-1) for AI(P) homodimer, apoAI(P):AII
      heterodimer and AI(P) monomer. In the three subjects, normal apoAI was
      catabolized quickly, with an FCR of 0.805 and 0.601 day(-1) in AI(M) carriers and
      0.526 day(-1) in the AI(P) carrier. Therefore, the low level of apoAI in the
      AI(P) carrier is caused by a low production rate of apoAI, particularly of normal
      apoAI. In conclusion, apoAI is kinetically heterogeneous in AI(M) and in AI(P)
      subjects. Moreover, the two mutations lead to significant differences in the
      kinetic behavior of mutant apoAI depending on its inclusion in its complexes.

PMID- 10657569
TI  - Association of apolipoprotein (Apo)E genotype with plasma apo E levels.
AB  - The purpose of this study was to investigate the effects of apolipoprotein (apo)
      E genotype on plasma apo E levels as well as serum total, low-density lipoprotein
      (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglyceride, and
      glucose values in 734 middle-aged and elderly, female and male subjects. Apo E
      allele frequencies were similar to those reported in other Caucasian populations.
      After adjustment for medications, alcohol use, smoking, age, and body mass index,
      apo E genotype was noted to have significant effects on apo E, total cholesterol,
      LDL cholesterol, and glucose levels in females, and on apo E, LDL cholesterol,
      and HDL cholesterol levels, as well as the total cholesterol (TC)/HDL cholesterol
      ratio in males. Female and male subjects with the apo E4 allele had significantly
      (P<0.05) lower plasma apo E (25 and 15%) and higher LDL cholesterol levels (5 and
      2%), while those with the apo E2 allele had significantly (P<0.05) higher apo E
      (32 and 27%) and lower LDL cholesterol levels (10 and 10%) than the apo E3/3
      group. Moreover, female apo E4 carriers had significantly (P<0.05) lower glucose
      values (11%) than the apo E3/3 group. These data are consistent with the concept
      that, in addition to the well known effects of apo E genotype on LDL-C values,
      this locus plays a very significant role in modulating plasma apo E levels.

PMID- 10657570
TI  - Absence of association between genetic variation in the promoter of the
      microsomal triglyceride transfer protein gene and plasma lipoproteins in the
      Framingham Offspring Study.
AB  - Microsomal triglyceride transfer protein (MTP) is a lipid transfer protein that
      is required for the assembly and secretion of very low density lipoproteins
      (VLDL) by the liver and chylomicrons by the intestine. The common G-493T
      polymorphism of the MTP promoter has been shown to be associated with decreased
      plasma LDL-cholesterol and ApoB content of VLDL. The purpose of the present study
      was, therefore, to investigate the association of this mutation with variations
      in lipid and apoprotein levels, lipoprotein subclass profiles and coronary heart
      disease (CHD) risk in a population-based sample of 1226 male and 1284 female
      Framingham Offspring participants. In men and women, no significant association
      was found between the G-493T MTP polymorphism and variations of plasma levels of
      total cholesterol, LDL-cholesterol, apoprotein B, HDL-cholesterol, apoprotein AI
      and triglycerides. In order to further investigate potential relationships with
      variations of lipoprotein phenotypes, lipoprotein subclass profiles were measured
      using automated nuclear magnetic resonance (NMR) spectroscopy. Each NMR profile
      yielded information on lipid mass of VLDL, LDL, and HDL subclasses. In both
      genders, there was no significant association between the G-493T polymorphism and
      variability of lipoprotein subclass distributions or lipoprotein particle size.
      Furthermore, no significant association was found between the polymorphism of the
      MTP promoter and prevalence or the age of onset of CHD. Thus, our results suggest
      that the G-493T mutation in the MTP promoter is unlikely to have significant
      implications for cardiovascular disease in men and women.

PMID- 10657571
TI  - Evaluation of the poly(ADP-ribose) polymerase gene in human stroke.
AB  - Nitric oxide (NO) and its reactant product, peroxynitrite, have been implied to
      mediate neuronal damage following cerebral ischemia. However, the cellular
      targets of these compounds remain unclear. Studies using poly(ADP-ribose)
      polymerase (PARP) inhibitors and PARP knock-out mice have recently demonstrated
      that excessive activation of this nuclear enzyme plays an important role in NO
      induced neurotoxicity. To evaluate the relevance of this plausible candidate gene
      to human stroke, we undertook a case-control study in Japanese. Participants
      comprised 213 cerebral infarction cases and 374 age- and sex-matched controls. As
      a primary investigation, we screened polymorphic sites of the PARP gene, and
      newly identified a total of four polymorphisms in 1230-bp 5'-flanking sequence.
      None of them were, however, located on the known promoter components of the gene.
      Two bi-allelic polymorphisms selected and a CA-repeat polymorphism were
      subsequently characterized in the case-control study, but none were significantly
      associated with cerebral infarction in the present study. Our data thus suggest
      that the tested PARP polymorphisms do not principally contribute to cerebral
      infarction, although extensive searches would be required to clarify whether the
      PARP gene plays an important role in the pathogenesis of human stroke.

PMID- 10657572
TI  - Sequence conservation in kringle IV-type 2 repeats of the LPA gene.
AB  - We have studied the homology of repeating kringle IV-type 2 (K IV-type 2)
      elements of the LPA gene. Two K IV-type 2 genomic polymerase chain reaction (PCR)
      fragment libraries were constructed, one from an individual with high and one
      from an individual with low Lp(a) lipoprotein level. Only minor K IV-type 2
      repeat length heterogeneity was observed. Sequence analysis data from the cloned
      K IV-type 2 repeats revealed a high degree of LPA sequence conservation in exons
      as well as in introns both within and between the two libraries. This sequence
      conservation of the IV-type 2 kringles is in agreement with our previously
      reported results of simultaneous 'batch' DNA sequence analyses of all the K IV
      type 2 repeats from single individuals. Sequence data from the clones, combined
      with genomic DNA sequencing, revealed that the K IV-type 2 reading frame of exons
      1 and 2 are extended into the conserved flanking introns by 519 base pairs (bp)
      and 312 bp, respectively. The theoretical coding capacity of the exon 1 extended
      open reading frame (ORF I) is three times larger (173 amino acids, aa) than the
      translated exon 1, and that of the extended open reading frame of exon 2 (ORF II)
      is about twice (104 aa) the length of exon 2. A central portion of the intron
      separating exons 1 and 2 also exhibited a high degree of sequence conservation,
      with the exception of a polymorphic CA repeat. Within the 61 K IV repeat clones
      analysed, 19 different CA repeat patterns with 12-18 CA dinucleotide repeats were
      observed. A comparison between the 37 clones from the individual with high Lp(a)
      lipoprotein level and the 24 clones from the individual with low Lp(a)
      lipoprotein level, revealed that seven of the CA repeat variants were present in
      both clone libraries. The observed high level of sequence conservation in K IV
      type 2 exons and introns matches relevant areas of the plasminogen gene, and our
      findings fit with recent K IV-type 2 duplications and evolutionary selection
      pressure theories, although gene conversion events could also explain the
      findings. DNA sequences within K IV-type 2 appeared to have no influence on Lp(a)
      lipoprotein level.

PMID- 10657573
TI  - Apoptosis of vascular smooth muscle cells induced by cholesterol and its oxides
      in vitro and in vivo.
AB  - The ability of cholesterol and its oxides to induce apoptosis in vascular smooth
      muscle cells in tissue culture and in a rabbit model of atherosclerosis was
      evaluated. Apoptosis was detected using DNA laddering and in situ end-labelling
      of fragmented DNA. Cholesterol oxides, but not cholesterol, were found to inhibit
      proliferation and induce apoptosis of vascular smooth muscle cells in tissue
      culture. 7-ketocholesterol was found to be the most potent inhibitor of
      proliferation, while 25-hydroxycholesterol was found to be the most potent
      inducer of apoptosis. These data suggest that the inhibition of proliferation and
      the induction of apoptosis by cholesterol oxides within vascular smooth muscle
      cells use different pathways, suggesting a differential role for these
      cholesterol oxides within the arterial wall. Cholesterol feeding after balloon
      injury in a rabbit model of atherosclerosis is known to result in the
      accumulation of cholesterol oxides. However, we found that cholesterol feeding
      had no effect on the level of apoptosis in the rabbit aortic wall after balloon
      injury, suggesting that the major factor determining apoptosis in our model was
      the balloon injury.

PMID- 10657574
TI  - Stromelysin-1 (MMP-3) expression driven by a macrophage-specific promoter results
      in reduced viability in transgenic mice.
AB  - Macrophage expression of matrix degrading metalloproteinases (MMPs) in human
      atheroma has been found to occur in rupture-prone areas of plaques. To
      investigate the effect of metalloproteinase activity on plaque stability, we
      attempted to generate mice that expressed a stromelysin-1 (MMP-3) transgene
      specifically in macrophages. Promoter sequences taken from a macrophage-tropic
      lentivirus (visna) were used to drive transgene expression. The transgene
      construct was expressed in macrophages in vitro and its autoactivation was
      established by casein zymography. Transgenic mice generated with this construct
      died at or before birth. No gross anatomical changes were observed in these mice.
      Embryos arising from a second round of oocyte injections with the transgene were
      examined at day 16 of gestation. Of the products of conception, approximately 40%
      resulted in vacant conceptuses. Only one animal of 38 examined carried the
      transgene and its expression of MMP-3 mRNA at E16 was faintly detected by RT-PCR.
      When a non-toxic reporter gene, luciferase, was substituted for the MMP-3 cDNA,
      healthy transgenic mice were produced that expressed the reporter gene in a wide
      variety of tissue macrophages, including those located in the brain, testis,
      lung, and thymus. These studies suggest that constitutive expression of MMP-3 in
      diverse populations of tissue macrophages leads to prenatal or neonatal death in
      the mouse. It appears likely that more sophisticated transcriptional control of
      MMP-3 expression will be required in order to generate stromelysin-1 transgenic
      mice that could be useful models for studying overexpression of this
      metalloproteinase's activity in the lesional macrophages of atherosclerotic
      plaques.

PMID- 10657575
TI  - Omacor in familial combined hyperlipidemia: effects on lipids and low density
      lipoprotein subclasses.
AB  - Elevations of plasma cholesterol and/or triglycerides, and the prevalence of
      small, dense LDL particles remarkably increase coronary risk in patients with
      familial combined hyperlipidemia (FCHL). A total of 14 FCHL patients were
      studied, to investigate the ability of Omacor, a drug containing the n-3 fatty
      acids eicosapentaenoic and docosahexaenoic acid (EPA and DHA), to favorably
      correct plasma lipid/lipoprotein levels and LDL particle distribution. The
      patients received four capsules daily of Omacor (providing 3.4 g EPA+DHA per day)
      or placebo for 8 weeks in a randomized, double-blind, cross-over study. Omacor
      significantly lowered plasma triglycerides and VLDL-cholesterol levels, by 27 and
      18%, respectively. Total cholesterol did not change but LDL-cholesterol and
      apolipoprotein B (apoB) concentrations increased by 21 and 6%. As expected, LDL
      particles were small (diameter=24.9+/-0.3 nm) and apoB-rich (LDL-cholesterol/apoB
      ratio=1.27+/-0.26) in the selected subjects. After Omacor treatment LDL became
      enriched in cholesterol (LDL-cholesterol/apoB ratio=1.40+/-0.17), mainly
      cholesteryl esters, indicating accumulation in plasma of more buoyant and core
      enriched LDL particles. Indeed, the separation of LDL subclasses by rate zonal
      ultracentrifugation showed an increase of the plasma concentration of IDL and of
      the more buoyant, fast floating LDL-1 and LDL-2 subclasses after Omacor, with a
      parallel decrease in the concentration of the denser, slow floating LDL-3
      subclass. However, the average LDL size did not change after Omacor (25.0+/-0.3
      nm). The resistance of the small LDL pattern to drug-induced modifications
      implies that a maximal lipid-lowering effect must be achieved to reduce coronary
      risk in FCHL patients.

PMID- 10657576
TI  - Effects of gemfibrozil on insulin sensitivity and on haemostatic variables in
      hypertriglyceridemic patients.
AB  - In order to assess the efficacy of gemfibrozil on lipid and haemostatic
      parameters in patients with plurimetabolic syndrome, a multicenter double-blind
      placebo controlled, parallel study was carried out in 56 patients with primary
      hypertriglyceridemia and glucose intolerance. These patients had elevated PAI
      activity and antigen and t-PA antigen levels at rest and after venous occlusion.
      Gemfibrozil reduced plasma triglyceride levels (P<0.001), whereas it increased
      free fatty acids (P<0.05) and high density lipoprotein cholesterol levels
      (P<0.05). In those patients reaching normalization of plasma triglyceride levels
      (triglyceride reduction > or =50%) (n=15), insulin levels (P<0.05) as well as the
      insulin resistance index were reduced by gemfibrozil treatment, suggesting an
      improvement of the insulin resistance index in this patient subgroup. Gemfibrozil
      treatment did not affect plasma fibrinolysis or fibrinogen levels, despite marked
      reduction of plasma triglycerides and improvement of the insulin sensitivity
      associated with triglyceride normalization.

PMID- 10657577
TI  - Lipoprotein (a) levels in normal pregnancy and in pregnancy complicated with pre
      eclampsia.
AB  - Lipoprotein (a) (Lp(a)) is recognised as a risk factor for arterial and venous
      thrombosis, a property which may relate to its structural similarity to
      plasminogen. Pregnancy is associated with a hypofibrinolytic state. Elevated
      Lp(a) may influence fibrinolysis and have an unfavourable role in pregnancy
      outcome. In this study alterations in plasma Lp(a) concentrations during normal
      pregnancy was examined, in a detailed longitudinal investigation, in ten women
      together with changes in other lipid parameters. In addition, Lp(a)
      concentrations were examined in subjects with pre-eclampsia (n=10) relative to
      matched controls (n=10), since it has recently been reported that a substantial
      increase in circulating Lp(a) occurs in this disorder. Lp(a) concentration
      increased steadily in normal pregnancy between 10 and 35 weeks with a doubling of
      the median value from 14.5 to 27.0 mg/dl (P=0.01). A significant increase in
      Lp(a) values was observed in all subjects with increasing gestation (median rise
      190%, range 117-340%). This increase was intermediate to those seen in plasma
      triglyceride and cholesterol. No significant difference in Lp(a) values was
      observed in subjects with pre-eclampsia, compared with matched normal pregnancy
      controls (median 14 mg/dl [IQR 4.7-69.0] in pre-eclampsia vs 20 mg/dl [9.0-56. 3]
      in controls; P=0.57), at a median gestation of 32 weeks. In conclusion, there is
      a 2-fold increase in Lp(a) during normal pregnancy, which may influence
      fibrinolysis. Circulating Lp(a) is not significantly elevated in women with pre
      eclampsia, and thus is unlikely to play a role in the pathophysiology of this
      disorder.

PMID- 10657578
TI  - Hyperlipoproteinemia affects cytokine production in whole blood samples ex vivo.
      The influence of lipid-lowering therapy.
AB  - Low-density lipoprotein (LDL)-receptor deficient mice, thus hypercholesterolemic,
      combine protection against infection with an ex vivo two- to threefold higher pro
      inflammatory cytokine production in macrophages. A pro-inflammatory cytokine
      profile ex-vivo is also associated with survival of gram-negative sepsis in man.
      We hypothesized that high lipoprotein levels would be associated with a pro
      inflammatory cytokine production and could explain the resistance to fatal
      infection. We treated 10 patients with familial hypercholesterolemia (FH) with
      HMG-CoA reductase inhibitors, and 13 patients with endogenous
      hypertriglyceridemia (HTG) with fibrates. Blood samples were stimulated ex vivo
      with lipopolysaccharide (LPS), to assess the cytokine production capacity. FH
      patients had significantly lower tumor necrosis factor-alpha (TNF-alpha)
      production, compared to normolipidemic controls (P=0. 001). Lipid lowering
      treatment in FH patients did not affect TNF-alpha production. HTG patients showed
      significantly higher TNF-alpha production at baseline than matched normolipidemic
      controls (P<0.001), while lowering of serum triglycerides in these patients
      resulted in a significant decrease in TNF-alpha production (P=0.019). The IL-10
      production was not affected. These data refute our hypothesis that high LDL
      cholesterol levels are associated with a pro-inflammatory cytokine production
      capacity. In contrast, the study suggests that very-low-density lipoprotein
      (VLDL) in hypertriglyceridemic patients augments TNF-alpha production.

PMID- 10657579
TI  - Postprandial lipaemia in familial hypercholesterolaemia: clinical and metabolic
      significance.

PMID- 10657580
TI  - Family heart association in UK.

PMID- 10657581
TI  - Familial hypercholesterolemia in Austria reflects the multi-ethnic origin of our
      country.

PMID- 10657582
TI  - Familial defective apolipoprotein B-100: a mutation emerged in the mesolithic
      ancestors of Celtic peoples?

PMID- 10657583
TI  - Arterial compliance: a tool in the evaluation of vascular disease in familial
      hypercholesterolemia.

PMID- 10657584
TI  - Comparison of the effects of bile acids on cell viability and DNA synthesis by
      rat hepatocytes in primary culture.
AB  - Bile acid-induced inhibition of DNA synthesis by the regenerating rat liver in
      the absence of other manifestation of impairment in liver cell viability has been
      reported. Because in experiments carried out on in vivo models bile acids are
      rapidly taken up and secreted into bile, it is difficult to establish steady
      concentrations to which the hepatocytes are exposed. Thus, in this work, a dose
      response study was carried out to investigate the in vitro cytotoxic effect of
      major unconjugated and tauro- (T) or glyco- (G) conjugated bile acids and to
      compare this as regards their ability to inhibit DNA synthesis. Viability of
      hepatocytes in primary culture was measured by Neutral red uptake and formazan
      formation after 6 h exposure of cells to bile acids. The rate of DNA synthesis
      was determined by radiolabeled thymidine incorporation into DNA. Incubation of
      hepatocytes with different bile acid species - cholic acid (CA), deoxycholic acid
      (DCA), chenodeoxycholic acid (CDCA) and ursodeoxycholic acid (UDCA), in the range
      of 10-1000 microM - revealed that toxicity was stronger for the unconjugated
      forms of CDCA and DCA than for CA and UDCA. Conjugation markedly reduced the
      effects of bile acids on cell viability. By contrast, the ability to inhibit
      radiolabeled thymidine incorporation into DNA was only slightly lower for
      taurodeoxycholic acid (TDCA) and glycodeoxycholic acid (GDCA) than for DCA. When
      the effect of these bile acids on DNA synthesis and cell viability was compared,
      a clear dissociation was observed. Radiolabeled thymidine incorporation into DNA
      was significantly decreased (-50%) at TDCA concentrations at which cell viability
      was not affected. Lack of a cause-effect relationship between both processes was
      further supported by the fact that well-known hepatoprotective compounds, such as
      tauroursodeoxycholic acid (TUDCA) and S-adenosylmethionine (SAMe) failed to
      prevent the effect of bile acids on DNA synthesis. In summary, our results
      indicate that bile acid-induced reduction of DNA synthesis does not require
      previous decreases in hepatocyte viability. This suggests the existence of a high
      sensitivity to bile acids of cellular mechanisms that may affect the rate of DNA
      repair and/or proliferation, which is of particular interest regarding the role
      of bile acids in the etiology of certain types of cancer.

PMID- 10657585
TI  - Fructose-mediated damage to lens alpha-crystallin: prevention by pyruvate.
AB  - Post-translational modifications in lens crystallins due to glycation and
      oxidation have been suggested to play a significant role in the development of
      cataracts associated with aging and diabetes. We have previously shown that alpha
      keto acids, like pyruvate, can protect the lens against oxidation. We hypothesize
      that they can also prevent the glycation of proteins competitively by forming a
      Schiff base between their free keto groups and the free -NH(2) groups of protein
      as well as subsequently inhibit the oxidative conversion of the initial glycation
      product to advanced glycation end products (AGE). The purpose of this study was
      to investigate these possibilities using purified crystallins. The crystallins
      isolated from bovine lenses were incubated with fructose in the absence and
      presence of pyruvate. The post-incubation mixtures were analyzed for fructose
      binding to the crystallins, AGE formation, and the generation of high molecular
      weight (HMW) proteins. In parallel experiments, the keto acid was replaced by
      catalase, superoxide dismutase (SOD), or diethylene triaminepentaacetic acid
      (DTPA). This was done to ascertain oxidative mode of pyruvate effects.
      Interestingly, the glycation and consequent formation of AGE from alpha
      crystallin was more pronounced than from beta-, and gamma-crystallins. The
      changes in the crystallins brought about by incubation with fructose were
      prevented by pyruvate. Catalase, SOD, and DTPA were also effective. The results
      suggest that pyruvate prevents against fructose-mediated changes by inhibiting
      the initial glycation reaction as well as the conversion of the initial glycated
      product to AGE. Hence it is effective in early as well as late phases of the
      reactions associated with the formation of HMW crystallin aggregates.

PMID- 10657586
TI  - Increased Na(+)/H(+) exchanger isoform 1 activity in spontaneously hypertensive
      rats: lack of mutations within the coding region of NHE1.
AB  - Enhanced Na(+)/H(+) exchange, measured as amiloride derivative-sensitive Na(+)
      and H(+) fluxes in cells with a preliminary acidified cytoplasm (Deltamu(H+)
      induced Na(+)/H(+) exchange), is one of the most prominent intermediate
      phenotypes of altered vascular smooth muscle cell (VSMC) function in
      spontaneously hypertensive rats (SHR). Analysis of Na(+)/H(+) exchange in F(2)
      hybrids of SHR and normotensive rats seems to be the most appropriate approach in
      the search for the genetic determinants of abnormal activity of this carrier.
      However, the measurement of Deltamu(H+)-induced Na(+)/H(+) exchange is hardly
      appropriate for precise analysis of the carrier's activity in VSMC derived from
      several hundred F(2) hybrids. To overcome this problem, we compared the rate of
      (22)Na influx under baseline conditions and in Na(+)-loaded (ouabain-treated)
      VSMC. The dose-dependency of the rate of Deltamu(H+)-induced H(+) efflux as well
      as of (22)Na influx in control and ouabain-treated cells on
      ethylisopropylamiloride (EIPA) concentration were not different (K(0.5)
      approximately 0.3 microM), suggesting that these ion transport pathways are
      mediated by the same carrier. EIPA-sensitive (22)Na influx in Na(+)-loaded cells
      was approximately 6-fold higher than in ouabain-untreated VSMC and was increased
      by 50-70% in two different substrains of SHR. About the same increment of EIPA
      sensitive (22)Na influx in Na(+)-loaded VSMC was observed in 5- to 6-week-old SHR
      (an age at which hypertension has not yet developed) as well as in stroke-prone
      SHR (SHRSP) with severe hypertension, indicating that the heightened activity of
      Na(+)/H(+) exchange is not a consequence of long-term blood pressure elevation.
      To examine whether or not the augmented activity of Na(+)/H(+) exchange in SHR is
      caused by mutation of NHE1, i.e. the only isoform of this carrier expressed in
      VSMC, we undertook single-stranded conformational polymorphism analysis of 23
      NHE1 cDNA fragments from SHR and SHRSP and sequencing of the 456-2421 NHE1 cDNA
      fragment. This study did not reveal any mutation in the entire coding region of
      NHE1. The lack of mutation in the coding region of NHE1 indicates that the
      augmented activity of the ubiquitous Na(+)/H(+) exchanger in primary hypertension
      is caused by altered regulation of carrier turnover number or/and its plasma
      membrane content.

PMID- 10657587
TI  - Evaluation of oxidative stress based on lipid hydroperoxide, vitamin C and
      vitamin E during apoptosis and necrosis caused by thioacetamide in rat liver.
AB  - After 12 h of thioacetamide (500 mg/kg body weight) administration to rats, the
      activity of caspase-3-like protease in the liver increased significantly compared
      to that in the control group. In plasma, the activity of caspase-3 was barely
      detectable in the control rat, but had increased significantly after 24 h of drug
      administration along with a dramatic increase in GOT. These results indicate that
      thioacetamide causes apoptosis in the liver by activating caspase-3, which is
      released to plasma by successive necrosis. At 24 h, the concentration of liver
      lipid hydroperoxides, a mediator of radical reaction, was 2.2 times as high as
      that of control rats. After 12 and 24 h of thioacetamide administration, the
      liver concentrations of vitamins C and E decreased significantly. The decrease of
      antioxidants and formation of lipid hydroperoxides 24 h after thioacetamide
      administration support the view that extensive radical reactions occur in the
      liver during the necrotic process.

PMID- 10657588
TI  - Low-frequency low-field magnetic susceptibility of ferritin and hemosiderin.
AB  - Low-frequency low-field magnetic susceptibility measurements were made on four
      samples of mammalian tissue iron oxide deposits. The samples comprised: (1) horse
      spleen ferritin; (2) dugong liver hemosiderin; (3) thalassemic human spleen
      ferritin; and (4) crude thalassemic human spleen hemosiderin. These samples were
      chosen because Mossbauer spectroscopic measurements on the samples indicated that
      they exemplified the variation in magnetic and mineral structure found in
      mammalian tissue iron oxide deposits. The AC-magnetic susceptometry yielded
      information on the magnetization kinetics of the four samples indicating samples
      1, 2, and 3 to be superparamagnetic with values of around 10(11) s(-1) for the
      pre-exponential frequency factor in the Neel-Arrhenius equation and values for
      characteristic magnetic anisotropy energy barriers in the range 250-400 K. Sample
      4 was indicated to be paramagnetic at all temperatures above 1.3 K. The AC
      magnetic susceptometry data also indicated a larger magnetic anisotropy energy
      distribution in the dugong liver sample compared with samples 1 and 3 in
      agreement with previous Mossbauer spectroscopic data on these samples. At
      temperatures below 200 K, samples 1-3 exhibited Curie-Weiss law behavior,
      indicating weak particle-particle interactions tending to favor antiparallel
      alignment of the particle magnetic moments. These interactions were strongest for
      the dugong liver hemosiderin, possibly reflecting the smaller separation between
      mineral particles in this sample. This is the first magnetic susceptometry study
      of hemosiderin iron deposits and demonstrates that the AC-magnetic susceptometry
      technique is a fast and informative method of studying such tissue iron oxide
      deposits.

PMID- 10657589
TI  - Kelley-Seegmiller syndrome due to a unique variant of hypoxanthine-guanine
      phosphoribosyltransferase: reduced affinity for 5-phosphoribosyl-1-pyrophosphate
      manifested only at low, physiological substrate concentrations.
AB  - A male child, who presented at the age of 3.5 years with acute renal failure, was
      diagnosed as having partial deficiency of hypoxanthine-guanine
      phosphoribosyltransferase (HPRT; EC 2.4.2.8). The underlying HPRT mutation was
      unique in that the specific activity of HPRT in erythrocyte and in fibroblast
      lysates was normal, but the rate of uptake of hypoxanthine into nucleotides of
      intact cultured fibroblasts was markedly reduced (23% of normal). The low
      functioning of HPRT in the intact fibroblasts was associated with decreased
      utilization of endogenously generated hypoxanthine and with decreased utilization
      of the cosubstrate 5-phosphoribosyl-1-pyrophosphate (PRPP). The non-utilized
      hypoxanthine was excreted into the incubation medium. The accumulation of PRPP
      was indicated by the 2.3-fold increase in the rate of uptake of adenine into
      intact cell nucleotides and by the 7. 5-fold enhancement of the rate of de novo
      purine synthesis. Kinetic studies of HPRT activity in fibroblast lysates revealed
      reduced affinity of the enzyme for PRPP (apparent K(m) 500 microM in comparison
      to 25 microM in control lysates), manifested in low activity at low
      (physiological), but not at high PRPP concentrations. The apparent K(m) for
      hypoxanthine was normal (23 microM in comparison to 14.2 microM in control
      lysates). With allopurinol treatment, our patient has had no problems since
      presentation, and is developing normally at 5 years of age.

PMID- 10657590
TI  - Attenuation of intestinal ischemia/reperfusion injury with sodium nitroprusside:
      studies on mitochondrial function and lipid changes.
AB  - Reactive oxygen species have been implicated in cellular injury during
      ischemia/reperfusion (I/R). Mitochondria are one of the main targets of oxygen
      free radicals and damage to this organelle leads to cell death. Reports suggest
      that nitric oxide (NO) may offer protection from damage during I/R. This study
      has looked at the functional changes and lipid alteration to mitochondria during
      intestinal I/R and the protection offered by NO. It was observed that I/R of the
      intestine is associated with functional alterations in the mitochondria as
      suggested by MTT reduction, respiratory control ratio and mitochondrial swelling.
      Mitochondrial lipid changes suggestive of activation of phospholipase A(2) and
      phospholipase D were also seen after (I/R) mediated injury. These changes were
      prevented by the simultaneous presence of a NO donor in the lumen of the
      intestine. These studies have suggested that structural and functional
      alterations of mitochondria are prominent features of I/R injury to the intestine
      which can be ameliorated by NO.

PMID- 10657591
TI  - Chinonin, a novel drug against cardiomyocyte apoptosis induced by hypoxia and
      reoxygenation.
AB  - The inhibitory effects of Chinonin, a natural antioxidant extracted from a
      Chinese medicine, on apoptotic and necrotic cell death of cardiomyocytes in
      hypoxia-reoxygenation process were observed in this study. The possible
      mechanisms of Chinonin on scavenging reactive oxygen species and regulating
      apoptotic related genes bcl-2 and p53 were also investigated. Neonatal rat
      cardiomyocytes were subjected to 24-h hypoxia and 4-h reoxygenation. Cell death
      was evaluated by DNA electrophoresis on agarose gel, cell death ELISA and annexin
      V-FLUOS/propidium iodide (PI) double staining cytometry. Hypoxia caused the
      increase of apoptotic rates and the release of lactate dehydrogenase (LDH), while
      reoxygenation not only further increased the apoptotic rates and leakage of LDH,
      but also induced necrosis of cardiomyocytes. In addition, hypoxia increased the
      levels of NO(2)(-)/NO(3)(-) and thiobarbituric acid reacted substances (TBARS),
      while reoxygenation decreased NO(2)(-)/NO(3)(-), but further increased TBARS in
      the cultured media. Moreover, hypoxia up-regulated the expression levels of bcl-2
      and p53 proteins, while reoxygenation down-regulated bcl-2 and further up
      regulated p53. Chinonin significantly decreased the rates of apoptotic and
      necrotic cardiomyocytes, and inhibited the leakage of LDH. It also diminished
      NO(2)(-)/NO(3)(-) and TBARS, down-regulated the expression level of p53 protein,
      and up-regulated bcl-2 protein, respectively. The results suggest that Chinonin
      has preventive effects against apoptotic and necrotic cell death and its
      protective mechanisms are related to the antioxidant properties of scavenging
      nitric oxide and oxygen free radicals, and the modulating effects on the
      expression levels of bcl-2 and p53 proteins.

PMID- 10657592
TI  - CXCR4 on human endothelial cells can serve as both a mediator of biological
      responses and as a receptor for HIV-2.
AB  - It has been shown that deletion of the chemokine receptor, CXCR4, causes
      disordered angiogenesis in mouse models. In the present studies, we examined the
      distribution and trafficking of CXCR4 in human endothelial cells, tested their
      responses to the CXCR4 ligand, SDF-1, and asked whether endothelial cell CXCR4
      can serve as a cell surface receptor for the binding of viruses. The results show
      that CXCR4 is present on endothelial cells from coronary arteries, iliac arteries
      and umbilical veins (HUVEC), but expression was heterogeneous, with some cells
      expressing CXCR4 on their surface, while others did not. Addition of SDF-1 caused
      a rapid decrease in CXCR4 surface expression. It also caused CXCR4-mediated
      activation of MAPK, release of PGI(2), endothelial migration, and the formation
      of capillary-like structures by endothelial cells in culture. Co-culture of HUVEC
      with lymphoid cells that were chronically infected with a CD4-independent/CXCR4
      tropic variant of HIV-2 resulted in the formation of multinucleated syncytia.
      Formation of the syncytia was inhibited by each of several different CXCR4
      antibodies. Thus, our findings indicate: (1) that CXCR4 is widely expressed on
      human endothelial cells; (2) the CXCR4 ligand, SDF-1, can evoke a wide variety of
      responses from human endothelial cells; and (3) CXCR4 on endothelial cells can
      serve as a receptor for isolates of HIV that can utilize chemokine receptors in
      the absence of CD4.

PMID- 10657593
TI  - Interleukin-1beta regulates CFTR expression in human intestinal T84 cells.
AB  - Cystic fibrosis is an autosomal recessive genetic disease, produced by a mutation
      in the CFTR gene that impairs its function as a chloride channel. In this work,
      we have examined the effects of interleukin-1beta (IL-1beta) on the expression of
      CFTR in human colonic T84 cells. Treatment of T84 cells with IL-1beta (0.25
      ng/ml) for 4 h resulted in an increased CFTR expression (mRNA and protein).
      However, higher doses of IL-1beta (1 ng/ml and over) produced inhibition of CFTR
      mRNA and protein expression. The protein kinase C (PKC) inhibitors H7 (50 microM)
      and GF109203X (1 microM) inhibited the stimulatory effect of IL-1beta. Similar
      effects were seen in the presence of the protein tyrosine kinase (PTK) inhibitors
      genistein (60 microM) and herbymicin A (2 microM). These results suggest that
      some PKC isoform(s) and at least a PTK might be involved in the CFTR up
      regulation induced by IL-1beta. The repression of CFTR up-regulation by
      cycloheximide (35.5 microM) suggests the participation of a de novo synthesized
      protein. Results obtained by using the RNA polymerase II inhibitor DRB (78
      microM), suggest that the increased mRNA levels seen after IL-1beta treatment are
      not due to an increased stability of the message. We conclude that the CFTR mRNA
      and protein levels are modulated by IL-1beta, this cytokine being the first
      extracellular protein known to up-regulate CFTR gene expression.

PMID- 10657594
TI  - Right ventricular upregulation of the Ca(2+) binding protein S100A1 in chronic
      pulmonary hypertension.
AB  - The Ca(2+) binding protein S100A1 increases the Ca(2+) release from the
      sarcoplasmatic reticulum by interacting with the ryanodine receptor. In order to
      understand whether this effect might be operative in the early course of
      hypertrophy, when myocardium is able to meet increased workload, we investigated
      the expression of S100A1 in a model of moderate right ventricular hypertrophy.
      The pulmonary arteries of nine pigs were embolised three times with Sephadex G
      50. After 70 days, all pigs showed a moderate pulmonary hypertension. Right
      ventricular tissue of embolised animals showed a significant increase of
      connective tissue and enlargement of myocyte diameters. In controls, we found a
      differential expression of S100A1 with significantly lower S100A1 protein levels
      in right ventricular compared to left ventricular tissue. In pulmonary
      hypertension, S100A1 expression increased significantly in hypertrophied right
      ventricles while it was unchanged in left ventricular tissue. No change was
      observed in the expression of SERCA2a and phospholamban. Our data show, for the
      first time, that moderate pressure overload results in an upregulation of S100A1.
      This may reflect an adaptive response of myocardial Ca(2+) homeostasis to a
      higher workload.

PMID- 10657595
TI  - Application of trocar technique in ultrasound-guided drainage of the gallbladder.
AB  - OBJECTIVE: The ultrasound-guided drainage of the gallbladder (USDGB) is mainly
      performed by Seldinger technique. We aim to evaluate the use of the easier
      performable trocar technique in draining critically ill patients with acute
      calculous or acalculous cholecystitis. PATIENTS AND METHODS: Critically ill
      patients with acute acalculous (AAC; n=29) or calculous cholecystitis (ACC; n=7)
      underwent trocar technique application of USD. Technical problems, complications
      and patients' further courses were recorded. RESULTS: In group 1 (AAC) 29/29
      patients could be drained without problems or complications. Three dislocations
      of the USDGB were seen. In group 2 (CAC) only four out of seven could be drained
      by this technique, in these four patients (a) major bleeding and (b)
      pericholecystic fluid collections were observed. In both groups no further
      complications during USDGB or its removal were seen. CONCLUSIONS: In acute
      acalculous cholecystitis the use of trocar technique in applying the USDGB is
      easy and bedside performable, in acute calculous cholecystitis the USD should be
      done by Seldinger technique.

PMID- 10657596
TI  - Microbubbles associated with mitral valve prostheses in pediatric patients.
AB  - OBJECTIVES: To assess whether microbubbles are associated with mitral valve
      prostheses in children and to investigate their relationship to exercise.
      BACKGROUND: Bright, highly mobile echoes are seen in left heart chambers of
      patients with mechanical mitral valve prostheses. The clinical importance of
      those microbubbles is not yet known but they survive long enough to reach the
      cerebral circulation. No such studies have been reported in children. METHODS:
      There were 20 male and 10 female patients with a mean age of 10.4 years (range 2
      16 years). Transthoracic echocardiography with calculation of cardiac output and
      ejection fraction was performed at baseline and after exercise following
      mechanical mitral valve replacement. Studies were evaluated for the presence of
      microbubbles. The mean time from operation to time of study was 18 months (range
      0.2-89 months). RESULTS: Of the 30 children evaluated, 28 (93%) had evidence of
      microbubbles. Exercise increased the number of microbubbles in 15 of the 26
      children. This was positively associated with an increase in cardiac output.
      CONCLUSIONS: (1) Microbubbles are commonly observed in children with mechanical
      mitral prostheses and are augmented by exercise. (2) This phenomenon is of a
      special concern in children due to their expected longevity with the prosthesis.

PMID- 10657597
TI  - Fetal and placental power Doppler imaging in normal and high-risk pregnancy.
AB  - OBJECTIVE: Computer analysis of organ power Doppler (PD) imaging has recently
      become available. The aim of the study was to evaluate gestational trends in
      placenta-, fetal lung-, liver- and kidney-blood flow in normal pregnancies and
      relate it to signals in high-risk pregnancies. METHODS: PD signals were recorded
      in normal singleton pregnancies between 26 and 42 weeks of gestation. Signals
      were also recorded in 63 high-risk pregnancies. Fixed preinstalled PD system
      installations for each organ were used during examinations. Images from PD scan
      were recorded on video tape and off-line analysed by computer. Mean flow signal
      intensity was calculated for each organ. Umbilical and uterine artery Doppler
      velocimetry were also recorded in high-risk pregnancies. RESULTS: PD signals from
      the four organs indicated increasing organ blood flow until approximately 34
      weeks of gestation, from where the organ signals seemed to decrease. High-risk
      pregnancies seemed to have lower PD signal intensity, which was more pronounced
      in cases with signs of placental vascular resistance. CONCLUSION: The results
      suggest that a decrease in fetal organ blood flow might indicate a centralisation
      of fetal circulation in normal pregnancy at term, as a physiological response to
      a decrease in placental perfusion. In the high-risk pregnancies the placental and
      fetal organ blood flow seem to be even further reduced, suggesting a more intense
      centralisation of circulation.

PMID- 10657598
TI  - Detection of vascular haemodynamics through a high-speed velocity profiler.
AB  - OBJECTIVE: This paper aims at demonstrating that ultrasound Doppler multigate
      spectral analysis performed with advanced equipment may provide detailed and
      significant haemodynamic information. METHODS: A novel multigate system was
      recently introduced and shown capable of performing real-time spectral analysis
      of Doppler data from 64 resolution cells located at different depths from the
      transducer. The system extends the typical capabilities of conventional Pulsed
      Wave (PW) equipment by displaying the full spectral content of Doppler signals
      over an ultrasound scan line rather than in a single resolution cell. In cases
      where it is appropriate to display the available information in a simpler form,
      parameters such as the maximum frequency can be extracted from each spectrum, by
      using conventional or advanced image processing methods. RESULTS: In-vitro
      experiments show that the multigate system can perform velocity measurements with
      good accuracy and precision. Examples of in vivo profiles detected from carotid,
      femoral and radial arteries are presented. In particular, the first results
      obtained from the aorta are shown. CONCLUSIONS: Blood flow behavior can be
      accurately investigated using a real-time multigate system which extends Doppler
      spectral analysis to a whole scan line.

PMID- 10657599
TI  - Volumetric analysis of the right and left ventricle in a porcine heart model:
      comparison of three-dimensional echocardiography, magnetic resonance imaging and
      angiocardiography.
AB  - Three-dimensional echocardiography and magnetic resonance imaging allow the
      volumetric analysis of ventricular volumes independent of geometric assumptions.
      The aim of the study was to compare these methods and the common
      angiocardiography in a cardiac model of known volume. METHODS/MATERIALS: Right
      and left ventricular (RV, LV-) volumes were measured in a specific animal model
      directly ('true volume') and with different imaging techniques. Three-dimensional
      echocardiography (3D-Echo) and magnetic resonance imaging (MRI), both of which
      permit a volume estimation without necessitating geometric assumptions, and
      angiocardiographic volumetry which is based on the Simpson rule were used in this
      study. RESULTS: The best results were achieved with MRI (RV: r(2)=0.99, mean
      difference: -1. 9+/-3.3%; LV: difference r(2)=0.99,: 2.9+/-5.0%). Likewise, 3D
      Echo showed a very good correlation with the true volumes (RV: r(2)=0.93,
      difference: 9.3+/-6.3%; LV r(2)=0.96, difference: 4.8+/-9.9%). The greatest
      deviations were observed during angiocardiographic volumetry (LV: r(2)=0.98;
      difference: 14.4+/-9.2%), particularly when measuring the right ventricle (RV:
      r(2)=0.82, difference: 57. 9+/-40.1%). Consequently, the direct comparison
      between 3D-Echo and the other methods yielded the best correspondence with MRI
      (RV: Bias: 3.7 ml, limits of agreement: 7.7 ml; LV: Bias: 3.7 ml, limits of
      agreement: 4.9 ml). In contrast, the differences between 3D-Echo and
      angiocardiography were marked (RV: Bias: 25.5 ml, limits of agreement: 11.1 ml;
      LV: Bias: 8.7 ml, limits of agreement: 13.2 ml). CONCLUSION: In a porcine cardiac
      model, 3D-Echo permits a relatively precise measurement of ventricular volumes
      with a slight under-estimation. MRI yielded the most precise volumetry, and the
      correlation between 3D-Echo and MRI was quite good. Particularly for the right
      ventricle, the angiocardiographic measurement was attached with the greatest
      error and thus appears ill-suited for the volumetry of geometrically more complex
      ventricles.

PMID- 10657600
TI  - An integrated system for the non-invasive assessment of vessel wall and
      hemodynamic properties of large arteries by means of ultrasound.
AB  - OBJECTIVES: To integrate methods for non-invasive assessment of vessel wall
      properties (diastolic diameter, distension waveform and intima-media thickness)
      and hemodynamic properties (blood flow velocity and shear rate distribution) of
      large arteries by means of dedicated ultrasound signal processing. METHODS: we
      have developed an arterial laboratory (ART-lab) system. ART-lab consists of
      software running on a standard personal computer, equipped with a data
      acquisition card for the acquisition of radio frequency (RF) ultrasound signals
      obtained with a conventional echo scanner. It operates either (1) off-line or (2)
      in real-time. Real-time operation is restricted to the assessment of vessel wall
      properties because of limitations in computational power. RESULTS: This paper
      provides an overview of ART-lab ultrasound radio frequency data acquisition and
      dedicated RF-signal processing methods. The capabilities of the system are
      illustrated with some typical applications. CONCLUSIONS: ART-lab in real-time
      mode is a useful tool for monitoring arterial vessel wall dynamics, while off
      line it can be employed to investigate the elastic vessel wall properties in
      combination with hemodynamics, such as blood flow velocity and shear rate
      distribution.

PMID- 10657601
TI  - Application of a new blood-mimicking fluid in a flow Doppler test object.
AB  - OBJECTIVE: To construct and apply a flow Doppler test object and its flow rig.
      METHODS: In this flow rig, particular attention was given to use of a long inlet
      length and to ensure the absence of disturbing particles. The latter was obtained
      by proper degassing, use of a filter and application of a fungicide. Two blood
      mimicking fluids were used, with a viscosity of 4 and 8 mPa s respectively.
      RESULTS: Predictable Poiseuille flow profiles were obtained. The velocity range
      could be extended by increasing the viscosity of the blood-mimicking fluid.
      Predictable axial velocities up to 2.5 m/s were obtained in an 8-mm tube and 5
      m/s in a 4-mm tube. CONCLUSION: Well-defined flow conditions that can be applied
      to investigate clinical ultrasound Doppler systems in a number of situations have
      been obtained.

PMID- 10657602
TI  - Acoustic cavitation and capillary bleeding. European Committee for Medical
      Ultrasound Safety (ECMUS).

PMID- 10657603
TI  - Thermal teratology. European Committee for Medical Ultrasound Safety (ECMUS).

PMID- 10657604
TI  - Cutting edge: IL-15 costimulates the generalized Shwartzman reaction and innate
      immune IFN-gamma production in vivo.
AB  - Sequential administration of LPS to SCID mice results in the generalized
      Shwartzman reaction, manifesting as rapid mortality via cytokine-induced shock.
      Here we demonstrate that in vivo neutralization of IL-15 before LPS priming
      significantly reduced lethality in this reaction (p = 0.0172). We hypothesize
      that LPS priming induces IL-12 and IL-15 that costimulate NK cell-derived IFN
      gamma. Such IFN-gamma may then in turn sensitize macrophages to elicit the
      Shwartzman reaction following a subsequent LPS challenge. Supporting this, IL-12
      and IL-15 synergized to induce murine NK cell IFN-gamma production in vitro. LPS
      stimulation of SCID mouse splenocytes resulted in measurable IFN-gamma
      production, which was reduced when IL-15 was neutralized or IL-2/15Rbeta was
      blocked. Pretreatment with either anti-IL-2/15Rbeta or anti-IL-15 Abs reduced
      serum IFN-gamma protein following LPS administration to SCID mice. Collectively,
      these data provide the first in vivo evidence that IL-15 participates in LPS
      induced innate immune IFN-gamma production and significantly contributes to the
      lethal Shwartzman reaction.

PMID- 10657605
TI  - Cutting edge: role of B lymphocytes in protective immunity against Salmonella
      typhimurium infection.
AB  - Infection of mice with Salmonella typhimurium gives rise to a disease similar to
      human typhoid fever caused by S. typhi. Since S. typhimurium is a facultative
      intracellular bacterium, the requirement of B cells in the immune response
      against S. typhimurium is a longstanding matter of debate. By infecting mice on a
      susceptible background and deficient in B cells (Igmu-/- mice) with different
      strains of S. typhimurium, we could for the first time formally clarify the role
      of B cells in the response against S. typhimurium. Compared with Igmu+/+ mice,
      LD50 values in Igmu-/- mice were reduced during primary, and particularly
      secondary, oral infection with virulent S. typhimurium. After systemic infection,
      Igmu-/- mice cleared attenuated aroA- S. typhimurium, but vaccine-induced
      protection against systemic infection with virulent S. typhimurium involved both
      B cell-dependent and -independent effector mechanisms. Thus, B cell-mediated
      immunity plays a distinct role in control of S. typhimurium in susceptible mice.

PMID- 10657606
TI  - Cutting edge: identification of GL50, a novel B7-like protein that functionally
      binds to ICOS receptor.
AB  - By the genetic selection of mouse cDNAs encoding secreted proteins, a B7-like
      cDNA clone termed mouse GL50 (mGL50) was isolated encoding a 322-aa polypeptide
      identical with B7h. Isolation of the human ortholog of this cDNA (hGL50) revealed
      a coding sequence of 309 aa residues with 42% sequence identity with mGL50.
      Northern analysis indicated GL50 to be present in many tissues including
      lymphoid, embryonic yolk sac, and fetal liver samples. Of the CD28, CTLA4, and
      ICOS fusion constructs tested, flow cytometric analysis demonstrated only mouse
      ICOS-IgG binding to mGL50 cell transfectants. Subsequent phenotyping demonstrated
      high levels of ICOS ligand staining on splenic CD19+ B cells and low levels on
      CD3+ T cells. These results indicate that GL50 is a specific ligand for the ICOS
      receptor and suggest that the GL50-ICOS interaction functions in lymphocyte
      costimulation.

PMID- 10657607
TI  - Cutting edge: B cells promote CD8+ T cell activation in MRL-Fas(lpr) mice
      independently of MHC class I antigen presentation.
AB  - Spontaneous CD8+ T cell activation in MRL-Faslpr mice is B cell dependent. It is
      unclear whether this B-dependent activation is mediated by direct Ag presentation
      via MHC class I proteins (i.e., cross-presentation) or whether activation occurs
      by an indirect mechanism, e.g., via effects on CD4+ cells. To determine how CD8+
      T cell activation is promoted by B cells, we created mixed bone marrow chimeras
      where direct MHC class I Ag presentation by B cells was abrogated while other
      leukocyte compartments could express MHC class I. Surprisingly, despite the
      absence of B cell class I-restricted Ag presentation, CD8+ T cell activation was
      intact in the chimeric mice. Therefore, the spontaneous B cell-dependent CD8+ T
      cell activation that occurs in systemic autoimmunity is not due to direct
      presentation by B cells to CD8+ T cells.

PMID- 10657608
TI  - Cutting edge: lipoxins rapidly stimulate nonphlogistic phagocytosis of apoptotic
      neutrophils by monocyte-derived macrophages.
AB  - Lipoxins (LX) are lipoxygenase-derived eicosanoids generated during inflammation.
      LX inhibit polymorphonuclear neutrophil (PMN) chemotaxis and adhesion and are
      putative braking signals for PMN-mediated tissue injury. In this study, we report
      that LXA4 promotes another important step in the resolution phase of
      inflammation, namely, phagocytosis of apoptotic PMN by monocyte-derived
      macrophages (Mphi). LXA4 triggered rapid, concentration-dependent uptake of
      apoptotic PMN. This bioactivity was shared by stable synthetic LXA4 analogues
      (picomolar concentrations) but not by other eicosanoids tested. LXA4-triggered
      phagocytosis did not provoke IL-8 or monocyte chemoattractant protein-1 release.
      LXA4-induced phagocytosis was attenuated by anti-CD36, alphavbeta3, and CD18
      mAbs. LXA4-triggered PMN uptake was inhibited by pertussis toxin and by 8-bromo
      cAMP and was mimicked by Rp-cAMP, a protein kinase A inhibitor. LXA4 attenuated
      PGE2-stimulated protein kinase A activation in Mphi. These results suggest that
      LXA4 is an endogenous stimulus for PMN clearance during inflammation and provide
      a novel rationale for using stable synthetic analogues as anti-inflammatory
      compounds in vivo.

PMID- 10657609
TI  - Recognition of a sequestered self peptide by influenza virus-specific CD8+
      cytolytic T lymphocytes.
AB  - The Ag receptors on CD8+ CTL recognize foreign antigenic peptides associated with
      cell surface MHC class I molecules. Peptides derived from self proteins are also
      normally presented by MHC class I molecules. Here we report that an H-2Kd
      restricted murine CD8+ CTL clone directed to an influenza hemagglutinin epitope
      can recognize a peptide derived from the murine mitochondrial aconitase enzyme in
      association with H-2Kd molecules. Surprisingly, this self peptide is not normally
      displayed on the cell surface associated with the restricting MHC class I
      molecule. Several lines of evidence suggest that this self peptide, although
      requiring association with the Kd molecule for CTL recognition, is not associated
      with this or other MHC class I allele under physiologic conditions in intact
      cells. Rather, it is sequestered in the cytoplasm associated with a carrier
      protein and is released only upon cell disruption. These results suggest a means
      of restricting the entry of self peptide into the class I pathway. In addition,
      this finding raises the possibility that self peptides sequestered within the
      cell can, after release from damaged cells, interact with MHC class I molecules
      on bystander cells and trigger autoimmune injury by virus-specific CTLs during
      viral infection.

PMID- 10657610
TI  - Transgenic expression of Fas ligand on thyroid follicular cells prevents
      autoimmune thyroiditis.
AB  - "Immune privilege" is defined as tissue resistance to aggression by specifically
      activated lymphocytes, and involves the interaction between Fas expressed on
      infiltrating cells and Fas ligand (FasL) constitutively expressed on the target
      tissue. To test whether ectopic expression of FasL on thyrocytes could prevent
      autoimmune aggression of the thyroid by activated lymphoid cells, three lines of
      transgenic mice expressing low, intermediate, and high levels of functional FasL
      on thyroid follicular cells were generated. Experimental autoimmune thyroiditis
      was induced by immunization with mouse thyroglobulin. In all of the experiments,
      the effects were dependent on the level of FasL expression. Low and intermediate
      expression had no or only weak preventive effects, respectively, whereas high
      FasL expression strongly inhibited lymphocytic infiltration of the thyroid. Anti
      mouse thyroglobulin-proliferative and cytotoxic T cell responses, as well as
      autoantibody production, were diminished in transgenic mice expressing high
      levels of FasL relative to controls. Furthermore, in these latter mice Th1
      responses to mouse thyroglobulin were profoundly down-regulated, uncovering a new
      potential role for FasL in peripheral tolerance to organ-specific Ags. In sum,
      the prevention of experimental autoimmune thyroiditis by FasL on thyrocytes is
      dependent on the level of FasL expression.

PMID- 10657611
TI  - TNF-alpha is the critical mediator of the cyclic AMP-induced apoptosis of CD8+4+
      double-positive thymocytes.
AB  - Apoptosis is one of the key regulatory mechanisms in tissue modeling and
      development. In the thymus, 95-98% of all thymocytes die by apoptosis because
      they failed to express a TCR with an optimal affinity for the selecting
      intrathymic peptide-MHC complexes. We studied the possible role of two prominent
      nerve growth factor (NGF-TNF) family member systems, Fas ligand (FasL)-Fas
      receptor (FasR) and TNF-alpha-TNFR, in apoptosis of murine CD8+4+ double-positive
      (DP) thymocytes induced via TCR-CD3- and cAMP-mediated signaling. TCR-CD3epsilon
      mediated apoptosis of DP thymocytes was found not to be dependent on either of
      the two systems. The FasL-FasR system was also found to be dispensable for the
      cAMP-mediated apoptosis. By contrast, cAMP agonists (dibutyryl-cAMP and
      forskolin) induced apoptosis via TNF-alpha, as evidenced by 1) the ability of
      anti-TNF-alpha mAbs to abrogate cAMP analogue-induced DP apoptosis in a dose
      dependent manner; and 2) increased resistance of DP thymocytes from TNF-alpha-/-
      and TNFR I-/-II-/- animals to cAMP agonist-mediated apoptosis. cAMP agonists
      induced DP thymocyte death by a combination of two mechanisms: first, they
      induced selective up-regulation of TNF-alpha production, and, second, they
      sensitized DP thymocytes to TNF-alpha. The latter effect may be due to the down
      regulation of TNFR-associated factor 2 protein. These results identify TNF-alpha
      as the critical mediator of cAMP-induced apoptosis in thymocytes and provide a
      molecular explanation for how the cAMP stimulators, including the sex steroids,
      may modulate T cell production output, as observed under physiological and
      pharmacological conditions.

PMID- 10657612
TI  - MHC polymorphism can enrich the T cell repertoire of the species by shifts in
      intrathymic selection.
AB  - The murine class I molecule H-2Kb and its natural gene conversion variant, H
      2Kbm8, which differs from H-2Kb solely at 4 aa at the bottom of the peptide
      binding B pocket, are expressed in coisogenic mouse strains C57BL/6 (B6) and B6.C
      H-2bm8 (bm8). These two strains provide an excellent opportunity to study the
      effects of Mhc class I polymorphism on the T cell repertoire. We recently
      discovered a gain in the antiviral CTL repertoire in bm8 mice as a consequence of
      the emergence of the Mhc class I allele H-2Kbm8. In this report we sought to
      determine the mechanism behind the generation of this increased CTL diversity.
      Our results demonstrate that repertoire diversification occurred by a gain in
      intrathymic positive selection. As previously shown, the emergence of the same
      Mhc allele also caused a loss in positive selection of T cell repertoire specific
      for another Ag, OVA-8. This indicates that a reciprocal loss-and-gain pattern of
      intrathymic selection exists between H-2Kb and H-2Kbm8. Therefore, in the thymus
      of an individual, a new Mhc allele can select new T cell specificities, while
      abandoning some T cell specificities selected by the wild-type allele. A
      byproduct of this repertoire shift is a net gain of T cell repertoire of the
      species, which is likely to improve its survival fitness.

PMID- 10657613
TI  - Adenoviral-mediated overexpression of monocyte chemoattractant protein-1
      differentially alters the development of Th1 and Th2 type responses in vivo.
AB  - The expression of chemokines during an immune response may participate in
      determining the intensity and type of the developing immune response. In the
      present study, we have examined the effect of overexpressing monocyte
      chemoattractant protein (MCP)-1 at the site of immunization during different
      stages of Th1- and Th2-type granulomatous responses. The overexpression of MCP-1
      by MCP-1 adenovirus during the sensitization phase of the purified protein
      derivative Th1-type model significantly reduced the elicitation of the
      granulomatous response. In contrast, the overexpression of MCP-1 during the
      sensitization phase of the schistosome egg Ag Th2 response led to an enhanced
      granulomatous reaction. When cytokines were examined upon restimulation of
      splenocytes ex vivo, an altered cytokine profile was observed, as compared with
      control mice. IFN-gamma and IL-12 were significantly reduced in the purified
      protein derivative Th1-type response, whereas IL-10 and IL-13 were up-regulated
      in the schistosome egg Ag Th2-type response. The regulation of the immune
      response was further examined by using the MCP-1 adenovirus at later time points
      during the elicitation phase. When MCP-1 was overexpressed during the elicitation
      phase of the responses, neither the Th1-type nor the Th2-type granuloma was
      altered. Likewise, the cytokine profiles after restimulation of splenocytes ex
      vivo were unchanged. Thus, the function of MCP-1 may depend on the stage and type
      of immune response.

PMID- 10657614
TI  - Functional maturation of adult mouse resting microglia into an APC is promoted by
      granulocyte-macrophage colony-stimulating factor and interaction with Th1 cells.
AB  - A precise knowledge of the early events inducing maturation of resting microglia
      into a competent APC may help to understand the involvement of this cell type in
      the development of CNS immunopathology. To elucidate whether signals from
      preactivated T cells are sufficient to induce APC features in resting microglia,
      microglia from the adult BALB/c mouse CNS were cocultured with Th1 and Th2 lines
      from DO11.10 TCR transgenic mice to examine modulation of APC-related molecules
      and Ag-presenting capacity. Upon Ag-specific interaction with Th1, but not Th2,
      cells, microglia strongly up-regulated the surface expression of MHC class II,
      CD40, and CD54 molecules. Induction of CD86 on mouse microglia did not require T
      cell-derived signals. Acutely isolated adult microglia stimulated Th1 cells to
      secrete IFN-gamma and, to a lesser extent, IL-2, but were inefficient stimulators
      of IL-4 secretion by Th2 cells. Microglia exposed in vitro to IFN-gamma showed
      enhanced expression of MHC class II, CD40, and CD54 molecules and became able to
      restimulate Th2 cells. In addition to IFN-gamma, GM-CSF increased the ability of
      microglia to activate Th1, but not Th2, cells without up-regulating MHC class II,
      CD40, or CD54 molecules. These results suggest that interaction with Th1 cells
      and/or Th1-secreted soluble factors induces the functional maturation of adult
      mouse microglia into an APC able to sustain CD4+ T cell activation. Moreover, GM
      CSF, a cytokine secreted by T cells as well as reactive astrocytes, could prime
      microglia for Th1-stimulating capacity, possibly by enhancing their
      responsiveness to Th1-derived signals.

PMID- 10657615
TI  - Disruption of T cell tolerance to self-immunoglobulin causes polyclonal B cell
      stimulation followed by inactivation of responding autoreactive T cells.
AB  - Scavenger receptor (SR)-specific delivery by maleylation of a ubiquitous self
      protein, Ig, to SR-bearing APCs results in self-limiting induction of autoimmune
      effects in vivo. Immunization with maleyl-Ig breaks T cell tolerance to self-Ig
      and causes hypergammaglobulinemia, with increases in spleen weight and
      cellularity. The majority of splenic B cells show an activated phenotype upon
      maleyl-Ig immunization, leading to large-scale conversion to a CD138+ phenotype
      and to significant increases in CD138-expressing splenic plasma cells. The
      polyclonal B cell activation, hypergammaglobulinemia, and autoreactive Ig
      specific T cell responses decline over a 2-mo period postimmunization. Following
      adoptive transfer, T cells from maleyl-Ig-immune mice taken at 2 wk
      postimmunization can induce hypergammaglobulinemia in the recipients, but those
      taken at 10 wk postimmunization cannot. Hypergammaglobulinemia in the adoptive
      transfer recipients is also transient and is followed by an inability to respond
      to fresh maleyl-Ig immunization, suggesting that the autoreactive Ig-specific T
      cells are inactivated peripherally following disruption of tolerance. Thus,
      although autoreactive T cell responses to a ubiquitous self-Ag, Ig, are induced
      by SR-mediated delivery to professional APCs in vivo resulting in autoimmune
      pathophysiological effects, they are effectively and rapidly turned off by
      inactivation of these activated Ig-specific T cells in vivo.

PMID- 10657616
TI  - Inhibition of IL-12 production in human monocyte-derived macrophages by TNF.
AB  - IL-12 is a pivotal cytokine that links the innate and adaptive immune responses.
      TNF-alpha also plays a key role in orchestrating inflammation and immunity. The
      reciprocal influence of these two inflammatory mediators on each other may have
      significant impact on the cytokine balance that shapes the type and extent of
      immune responses. To investigate the relationship between TNF-alpha and IL-12
      production, we analyzed the effects of exposure of human monocyte-derived
      macrophages to TNF-alpha on LPS- or Staphylococcus aureus-induced IL-12
      production in the presence or absence of IFN-gamma. TNF-alpha is a potent
      inhibitor of IL-12 p40 and p70 secretion from human macrophages induced by LPS or
      S. aureus. IL-10 is not responsible for the TNF-alpha-mediated inhibition of IL
      12. TNF-alpha selectively inhibits IL-12 p40 steady-state mRNA, but not those of
      IL-12 p35, IL-1alpha, IL-1beta, or IL-6. Nuclear run-on analysis identified this
      specific inhibitory effect at the transcriptional level for IL-12 p40 without
      down-regulation of the IL-12 p35 gene. The major transcriptional factors
      identified to be involved in the regulation of IL-12 p40 gene expression by LPS
      and IFN-gamma, i.e., c-Rel, NF-kappaB p50 and p65, IFN regulatory factor-1, and
      ets-2, were not affected by TNF-alpha when examined by nuclear translocation and
      DNA binding. These data demonstrate a selective negative regulation on IL-12 by
      TNF-alpha, identifying a direct negative feedback mechanism for inflammation
      induced suppression of IL-12 gene expression.

PMID- 10657617
TI  - Clonal characterization of a bipotent T cell and NK cell progenitor in the mouse
      fetal thymus.
AB  - We recently described a population of fetal thymocytes with a
      CD117+NK1.1+CD90lowCD25- phenotype, which were shown to contain committed T cell
      and NK cell progenitors. However, the characterization of a single cell with a
      restricted T and NK cell precursor potential was lacking. Here, using an in vitro
      model for T and NK cell differentiation, we provide conclusive evidence
      demonstrating the existence of a clonal lineage-restricted T and NK cell
      progenitor. These results establish that fetal thymocytes with a
      CD117+NK1.1+CD90lowCD25- phenotype represent bipotent T and NK cell progenitors.

PMID- 10657618
TI  - IL-4 suppression of in vivo T cell activation and antibody production.
AB  - Injection of mice with a foreign anti-IgD Ab stimulates B and T cell activation
      that results in large cytokine and Ab responses. Because most anti-IgD-activated
      B cells die before they can be stimulated by activated T cells, and because IL-4
      prolongs the survival of B cells cultured with anti-Ig, we hypothesized that
      treatment with IL-4 at the time of anti-IgD Ab injection would decrease B cell
      death and enhance anti-IgD-induced Ab responses. Instead, IL-4 treatment before
      or along with anti-IgD Ab suppressed IgE and IgG1 responses, whereas IL-4
      injected after anti-IgD enhanced IgE responses. The suppressive effect of early
      IL-4 treatment on the Ab response to anti-IgD was associated with a rapid, short
      lived increase in IFN-gamma gene expression but decreased CD4+ T cell activation
      and decreased or delayed T cell production of other cytokines. We examined the
      possibilities that IL-4 stimulation of IFN-gamma production, suppression of IL-1
      or IL-2 production, or induction of TNF-alpha or Fas-mediated apoptosis could
      account for IL-4's suppressive effect. The suppressive effect of IL-4 was not
      reversed by IL-1, IL-2, or anti-TNF-alpha or anti-IFN-gamma mAb treatment, or
      mimicked by treatment with anti-IL-2Ralpha (CD25) and anti-IL-2Rbeta (CD122)
      mAbs. Early IL-4 treatment failed to inhibit anti-IgD-induced Ab production in
      Fas-defective lpr mice; however, the poor responsiveness of lpr mice to anti-IgD
      made this result difficult to interpret. These observations indicate that
      exposure to IL-4, while T cells are first being activated by Ag presentation, can
      inhibit T cells activation or promote deletion of responding CD4+ T cells.

PMID- 10657619
TI  - CD27-mediated activation of murine NK cells.
AB  - CD27, a member of the TNF receptor superfamily, has been implicated in T cell
      activation, T cell development, and T cell-dependent Ab production by B cells. In
      the present study we examined the expression and function of CD27 on murine NK
      cells. Murine NK cells constitutively expressed CD27 on their surface.
      Stimulation with immobilized anti-CD27 mAb or murine CD27 ligand (CD70)
      transfectans solely could induce proliferation and IFN-gamma production of
      freshly isolated NK cells and enhanced the proliferation and IFN-gamma production
      of anti-NK1.1-sutimulated NK cells. Although NK cell cytotoxicity was not
      triggered by anti-CD27 mAb or against CD70 transfectants, prestimulation via CD27
      enhanced the cytotoxic activity of NK cells in an IFN-gamma-dependent manner.
      These results suggest that CD27-mediated activation may be involved in the NK
      cell-mediated innate immunity against virus-infected or transformed cells
      expressing CD70.

PMID- 10657620
TI  - TCR-independent activation of extrathymically developed, self antigen-specific T
      cells by IL-2/IL-15.
AB  - Naive intrathymically developed T cells, which express foreign Ag-specific TCR,
      do not express IL-2R. After antigenic stimulation, they express high affinity IL
      2R, which enables IL-2 to be used as an autocrine growth factor. On the contrary,
      extrathymically developed T cells, which express self Ag-specific TCR but are
      unresponsive to antigenic stimulation, spontaneously express low affinity IL-2R.
      In this study, we compared the responses of these two subsets of T cells to IL-2R
      stimulation and examined the influences of TCR-mediated signaling on the
      responses. IL-2 or IL-15 augmented the proliferative response of Ag-stimulated,
      intrathymically developed T cells. On the other hand, extrathymically developed T
      cells proliferated in response to IL-2 or IL-15, independently of Ag stimulation.
      Furthermore, both IL-2 and IL-15 induced IFN-gamma production of these T cells,
      which is strikingly augmented by the presence of IL-12. These results revealed
      functional differences between intrathymically developed, foreign Ag-specific T
      cells and extrathymically developed, self Ag-specific T cells. The latter can be
      activated by some inflammatory cytokines, in an Ag-independent manner, similar to
      NK cells.

PMID- 10657621
TI  - Measles virus induces abnormal differentiation of CD40 ligand-activated human
      dendritic cells.
AB  - Measles virus (MV) infection induces a profound immunosuppression responsible for
      a high rate of mortality in malnourished children. MV can encounter human
      dendritic cells (DCs) in the respiratory mucosa or in the secondary lymphoid
      organs. The purpose of this study was to investigate the consequences of DC
      infection by MV, particularly concerning their maturation and their ability to
      generate CD8+ T cell proliferation. We first show that MV-infected Langerhans
      cells or monocyte-derived DCs undergo a maturation process similarly to the one
      induced by TNF-alpha or LPS, respectively. CD40 ligand (CD40L) expressed on
      activated T cells is shown to induce terminal differentiation of DCs into mature
      effector DCs. In contrast, the CD40L-dependent maturation of DCs is inhibited by
      MV infection, as demonstrated by CD25, CD69, CD71, CD40, CD80, CD86, and CD83
      expression down-regulation. Moreover, the CD40L-induced cytokine pattern in DCs
      is modified by MV infection with inhibition of IL-12 and IL-1alpha/beta and
      induction of IL-10 mRNAs synthesis. Using peripheral blood lymphocytes from CD40L
      deficient patients, we demonstrate that MV infection of DCs prevents the CD40L
      dependent CD8+ T cell proliferation. In such DC-PBL cocultures, inhibition of
      CD80 and CD86 expression on DCs was shown to require both MV replication and CD40
      triggering. Finally, for the first time, MV was shown to inhibit tyrosine
      phosphorylation level induced by CD40 activation in DCs. Our data demonstrate
      that MV replication modifies CD40 signaling in DCs, thus leading to impaired
      maturation. This phenomenon could play a pivotal role in MV-induced
      immunosuppression.

PMID- 10657622
TI  - Signals from the IL-9 receptor are critical for the early stages of human
      intrathymic T cell development.
AB  - Highly purified human CD34+ hemopoietic precursor cells differentiate into mature
      T cells when seeded in vitro in isolated fetal thymic lobes of SCID mice followed
      by fetal thymus organ culture (FTOC). Here, this chimeric human-mouse FTOC was
      used to address the role of IL-9 and of the alpha-chain of the IL-9 receptor (IL
      9Ralpha) in early human T cell development. We report that addition of the mAb
      AH9R7, which recognizes and blocks selectively the human high affinity alpha
      chain of the IL-9R, results in a profound reduction of the number of human
      thymocytes. Analysis of lymphoid subpopulations indicates that a highly reduced
      number of cells undergo maturation from CD34+ precursor cells toward CD4+CD3-CD8
      CD1+ progenitor cells and subsequently toward CD4+CD8+ double positive (DP)
      thymocytes. Addition of IL-9 to the FTOC resulted in an increase in cell number,
      without disturbing the frequencies of the different subsets. These data suggest
      that IL-9Ralpha signaling is critical in early T lymphoid development.

PMID- 10657623
TI  - Inhibition of Th1 immune response by glucocorticoids: dexamethasone selectively
      inhibits IL-12-induced Stat4 phosphorylation in T lymphocytes.
AB  - Glucocorticoids are widely used in the therapy of inflammatory, autoimmune, and
      allergic diseases. As the end-effectors of the hypothalamic-pituitary-adrenal
      axis, endogenous glucocorticoids also play an important role in suppressing
      innate and cellular immune responses. Previous studies have indicated that
      glucocorticoids inhibit Th1 and enhance Th2 cytokine secretion. IL-12 promotes
      Th1 cell-mediated immunity, while IL-4 stimulates Th2 humoral-mediated immunity.
      Here, we examined the regulatory effect of glucocorticoids on key elements of IL
      12 and IL-4 signaling. We first investigated the effect of dexamethasone on IL-12
      inducible genes and showed that dexamethasone inhibited IL-12-induced IFN-gamma
      secretion and IFN regulatory factor-1 expression in both NK and T cells. This
      occurred even though the level of expression of IL-12 receptors and IL-12-induced
      Janus kinase phosphorylation remained unaltered. However, dexamethasone markedly
      inhibited IL-12-induced phosphorylation of Stat4 without altering its expression.
      This was specific, as IL-4-induced Stat6 phosphorylation was not affected, and
      mediated by the glucocorticoid receptor, as it was antagonized by the
      glucocorticoid receptor antagonist RU486. Moreover, transfection experiments
      showed that dexamethasone reduced responsiveness to IL-12 through the inhibition
      of Stat4-dependent IFN regulatory factor-1 promoter activity. We conclude that
      blocking IL-12-induced Stat4 phosphorylation, without altering IL-4-induced Stat6
      phosphorylation, appears to be a new suppressive action of glucocorticoids on the
      Th1 cellular immune response and may help explain the glucocorticoid-induced
      shift toward the Th2 humoral immune response.

PMID- 10657624
TI  - Processing and reactivity of T cell epitopes containing two cysteine residues
      from hen egg-white lysozyme (HEL74-90).
AB  - The Ag processing and structural requirements involved in the generation of a
      major T cell epitope from the hen egg-white lysozyme protein (HEL74-88),
      containing two cysteine residues at positions 76 and 80, were investigated.
      Several T cell hybridomas derived from both low responder (I-Ab) and high
      responder (I-Ak) mice recognize this region. These hybridomas are strongly
      responsive to native HEL, but unresponsive to the reduced and carboxymethylated
      protein. Air-oxidized HEL74-88 peptide was unable to bind I-Ak molecules and
      failed to stimulate T cells in the absence of intracellular Ag processing.
      Further functional competition assays showed that alkylation of cysteine residues
      with bulky methyl groups interferes with the contacts for the MHC class II
      molecules (I-Ak) of high responder mice and the I-Ab-restricted TCR of low
      responder mice. Serine substitutions of the cysteine residues of HEL74-88 either
      enhanced or abrogated T cell stimulation by the peptides without significant
      alterations in the class II binding. These results suggest that the cysteine
      residues of peptides must be free from disulfide bonding for efficient
      stimulation of T cells and yet frequently used modifications of cysteine residues
      may not be suitable for peptide-based vaccine development.

PMID- 10657625
TI  - Activation of macrophage CD8: pharmacological studies of TNF and IL-1 beta
      production.
AB  - Previously, we demonstrated that rat macrophages express CD8 and that Ab to CD8
      stimulates NO production. We confirm that CD8 is expressed by rat macrophages and
      extend understanding of its functional significance. Activation of CD8 alpha (OX8
      Ab) on alveolar macrophages stimulated mRNA expression for TNF and IL-1 beta and
      promoted TNF and IL-1 beta secretion. Similarly, OX8 Ab (CD8 alpha) stimulated
      NR8383 cells to secrete TNF, IL-1 beta, and NO. Activation of CD8 beta (Ab 341)
      on alveolar macrophages increased mRNA expression for TNF and IL-1 beta and
      stimulated secretion of TNF, but not IL-1 beta. Interestingly, anti-CD8 Abs did
      not stimulate IFN-gamma or PGE2 production, or phagocytosis by macrophages. OX8
      (CD8 alpha)-induced TNF and IL-1 beta production by macrophages was blocked by
      inhibitors of protein tyrosine kinase(s), PP1, and genistein, but not by
      phosphatidylinositol-3 kinase inhibitor, wortmannin. Moreover, OX8 stimulated
      protein tyrosine kinase activity in NR8383 cells. Further analysis of kinase
      dependence using antisense to Syk kinase demonstrated that TNF, but not IL-1
      beta, stimulation by CD8 alpha is Syk dependent. By contrast, protein kinase C
      inhibitor Ro 31-8220 had no effect on OX8-induced TNF production, whereas OX8
      induced IL-1 beta production was blocked by Ro 31-8220. Thus, there are distinct
      signaling mechanisms involved in CD8 alpha (OX8)-induced TNF and IL-1 beta
      production. In summary, macrophages express CD8 molecules that, when activated,
      stimulate TNF and IL-1 beta expression, probably through mechanisms that include
      activation of Src and Syk kinases and protein kinase C. These findings identify a
      previously unknown pathway of macrophage activation likely to be involved in host
      defense and inflammation.

PMID- 10657626
TI  - Ly49I NK cell receptor transgene inhibition of rejection of H2b mouse bone marrow
      transplants.
AB  - The Ly49 family of genes encode NK cell receptors that bind class I MHC Ags and
      transmit negative signals if the cytoplasmic domains have immunoregulatory
      tyrosine-based inhibitory motifs (ITIMs). 5E6 mAbs recognize Ly49C and Ly49I
      receptors and depletion of 5E6+ NK cells prevents rejection of allogeneic or
      parental-strain H2d bone marrow cell (BMC) grafts. To determine the function of
      the Ly49I gene in the rejection of BMC grafts, we transfected fertilized eggs of
      FVB mice with a vector containing DNA for B6 strain Ly49I (Ly49IB6). Ly49IB6 is
      ITIM+ and is recognized by 5E6 as well as Ly49I-specific 8H7 mAbs. Normal FVB H2q
      mice reject H2b but not H2d BMC allografts, and the rejection of H2b BMC was
      inhibited partially by anti-NK1.1 and completely by anti-asialo GM1, but not by
      anti-CD8, Abs. In FVB mice, NK1.1 is expressed on only 60% NK cells. FVB. Ly49IB6
      hosts failed to reject H2d or H2b BMC, but did reject class I-deficient TAP-1-/-
      BMC, indicating that NK cells were functional. Nondepleting doses of anti-Ly49I
      Abs reversed the acceptance of H2b BMC by FVB.Ly49IB6 mice. FVB.Ly49IB6+/- mice
      were crossed and back-crossed with 129 mice-H2b, 5E6-, poor responders to H2d BMC
      grafts. While transgene-negative H2b/q F1 or first-generation back-crossed mice
      rejected H2b marrow grafts (hybrid resistance), transgene-positive mice did not.
      Thus B6 strain Ly49I receptors transmit inhibitory signals from H2b MHC class I
      molecules. Moreover, Ly49IB6 has no positive influence on the rejection of H2d
      allografts.

PMID- 10657627
TI  - IFN-gamma activates the C3G/Rap1 signaling pathway.
AB  - IFN-gamma transduces signals by activating the IFN-gamma receptor-associated Jak
      1 and Jak-2 kinases and by inducing tyrosine phosphorylation and activation of
      the Stat-1 transcriptional activator. We report that IFN-gamma activates a
      distinct signaling cascade involving the c-cbl protooncogene product, CrkL
      adapter, and small G protein Rap1. During treatment of NB-4 human cells with IFN
      gamma, c-cbl protooncogene product is rapidly phosphorylated on tyrosine and
      provides a docking site for the src homology 2 domain of CrkL, which also
      undergoes IFN-gamma-dependent tyrosine phosphorylation. CrkL then regulates
      activation of the guanine exchange factor C3G, with which it interacts
      constitutively via its N terminus src homology 3 domain. This results in the IFN
      gamma-dependent activation of Rap1, a protein known to exhibit tumor suppressor
      activity and mediate growth inhibitory responses. In a similar manner, Rap1 is
      also activated in response to treatment of cells with type I IFNs (IFN-alpha, IFN
      beta), which also engage CrkL in their signaling pathways. On the other hand, IFN
      gamma does not induce formation of nuclear CrkL-Stat5 DNA-binding complexes,
      which are induced by IFN-alpha and IFN-beta, indicating that pathways downstream
      of CrkL are differentially regulated by different IFN subtypes. Taken altogether,
      our data demonstrate that, in addition to activating the Stat pathway, IFN-gamma
      activates a distinct signaling cascade that may play an important role in the
      generation of its growth inhibitory effects on target cells.

PMID- 10657629
TI  - Cloning and characterization of IL-10-related T cell-derived inducible factor (IL
      TIF), a novel cytokine structurally related to IL-10 and inducible by IL-9.
AB  - IL-9 is a Th2 cytokine active on various cell types such as T and B lymphocytes,
      mast cells, and eosinophils, and potentially involved in allergy and asthma. To
      understand better the molecular mechanisms underlying the activity of this
      cytokine, we used a cDNA subtraction method to identify genes specifically
      induced by IL-9 in mouse T cells. One of the IL-9-regulated genes isolated by
      this approach turned out to encode a 180-amino acid long protein, including a
      potential signal peptide, and showing 22% amino acid identity with IL-10. This
      protein, designated IL-10-related T cell-derived inducible factor (IL-TIF), is
      induced by IL-9 in thymic lymphomas, T cells, and mast cells, and by lectins in
      freshly isolated splenocytes. Experiments concerning the mechanism regulating IL
      TIF expression in T cells indicate that IL-9 induction is rapid (within 1 h),
      does not require protein synthesis, and depends on the activation of the Janus
      kinase (JAK)-STAT pathway. In vivo, constitutive expression of IL-TIF was
      detected by RT-PCR in thymus and brain, suggesting that the role of this new
      factor is not restricted to the immune system. Transfection of HEK293 cells with
      the IL-TIF cDNA resulted in the production of a glycosylated protein of about 25
      kDa that was found to induce STAT activation in mesangial and neuronal cell
      lines. Further studies will have to address the possibility that some of the IL-9
      activities may be mediated by IL-TIF.

PMID- 10657628
TI  - The balance of protein kinase C and calcium signaling directs T cell subset
      development.
AB  - Development of naive T cells into type 1 (Th1, Tc1) or type 2 (Th2, Tc2) effector
      cells is thought to be under the control of cytokines. In this study, we show
      that when both IL-12 and IL-4 are present, murine and human T cell
      differentiation is regulated by the balance of protein kinase C (PKC) and calcium
      signaling within T cells. Although both biochemical signals were required for T
      cell activation via the TCR, altering the balance between them redirected type 1
      cells to type 2 and vice versa. Stimulation of calcium signaling or inhibition of
      PKC favored type 1 differentiation, whereas stimulation of PKC or inhibition of
      calcineurin resulted in type 2 effectors. Altered peptide ligands induced
      distinct balances of PKC/calcium signaling and altered Tc1/Tc2 development in TCR
      transgenic CD8 T cells. The data suggest novel strategies for manipulation of the
      immune response in vivo.

PMID- 10657630
TI  - Analysis of the virus-specific and nonspecific B cell response to a persistent B
      lymphotropic gammaherpesvirus.
AB  - Respiratory challenge of mice with murine gammaherpesvirus 68 (gammaHV68) results
      in acute replication in respiratory epithelial cells and persistent, latent
      infection of B cells and macrophages. gammaHV68 elicits virus-specific Ab, and
      also nonspecifically activates B cells to Ab production through a CD4+ T cell
      dependent process. The current analysis characterizes virus-specific and
      nonspecific Ab production at the single cell level and investigates the
      requirements and nature of the nonspecific response. Virus-specific Ab-forming
      cell (AFC) numbers were dwarfed by the increase in total AFC in all sites
      examined, indicating substantial nonspecific Ab production. Clear increases and
      decreases in specific and total AFC numbers occurred in the lymph nodes draining
      the respiratory tract and the spleen, but AFC numbers in the bone marrow (BM)
      increased to a plateau and remained constant. The longevity of the BM response
      was reflected in a sustained increase in virus-specific and total serum Ab
      levels. Generally, the IgG2a and IgG2b isotypes predominated. Analysis of
      cytokine-deficient mice, CD40 ligand-deficient mice, and radiation BM chimeras
      lacking MHC class II expression specifically on B cells indicated that
      nonspecific Ab production is independent of IL-6 or IFN-gamma, and dependent on
      cognate CD4+ T cell help. Several observations were consistent with polyclonal B
      cell activation by gammaHV68, including the induction of durable serum levels of
      IgG reactive with mammalian dsDNA and murine type II collagen. Our findings
      indicate new directions for studies of this valuable model of gamma-herpesvirus
      pathogenesis.

PMID- 10657631
TI  - Regulator of G protein signaling 1 (RGS1) markedly impairs Gi alpha signaling
      responses of B lymphocytes.
AB  - Regulator of G protein signaling (RGS) proteins modulate signaling through
      pathways that use heterotrimeric G proteins as transducing elements. RGS1 is
      expressed at high levels in certain B cell lines and can be induced in normal B
      cells by treatment with TNF-alpha. To determine the signaling pathways that RGS1
      may regulate, we examined the specificity of RGS1 for various G alpha subunits
      and assessed its effect on chemokine signaling. G protein binding and GTPase
      assays revealed that RGS1 is a Gi alpha and Gq alpha GTPase-activating protein
      and a potential G12 alpha effector antagonist. Functional studies demonstrated
      that RGS1 impairs platelet activating factor-mediated increases in intracellular
      Ca+2, stromal-derived factor-1-induced cell migration, and the induction of
      downstream signaling by a constitutively active form of G12 alpha. Furthermore,
      germinal center B lymphocytes, which are refractory to stromal-derived factor-1
      triggered migration, express high levels of RGS1. These results indicate that RGS
      proteins can profoundly effect the directed migration of lymphoid cells.

PMID- 10657632
TI  - Membrane cofactor protein (MCP; CD46): isoform-specific tyrosine phosphorylation.
AB  - Membrane cofactor protein (MCP; CD46) is a widely expressed type 1 transmembrane
      glycoprotein that inhibits complement activation on host cells. It also is a
      receptor for several pathogens including measles virus, Streptococcus pyogenes,
      Neisseria gonorrhea, and Neisseria meningitidis. That MCP may have signaling
      capability was suggested by its microbial interactions. That is, binding of MCP
      on human monocytes by measles virus hemagglutinin or cross-linking by an anti-MCP
      Ab resulted in IL-12 down-regulation, while binding to MCP by Neisseria on
      epithelial cells produced a calcium flux. Through alternative splicing, MCP is
      expressed on most cells with two distinct cytoplasmic tails of 16 (CYT-1) or 23
      (CYT-2) amino acids. These play pivotal roles in intracellular precursor
      processing and basolateral localization. We investigated the putative signal
      transduction pathway mediated by MCP and demonstrate that CYT-2, but not CYT-1,
      is phosphorylated on tyrosine. We examined MCP tail peptides and performed Ab
      cross-linking experiments on several human cell lines and MCP isoform
      transfectants. We found an MCP peptide of CYT-2 was phosphorylated by a src
      kinase system. Western blots of the cells lines demonstrated that cells bearing
      CYT-2 were also phosphorylated on tyrosine. Additionally, we provide genetic and
      biochemical evidence that the src family of kinases is responsible for the latter
      phosphorylation events. In particular, the src kinase, Lck, is required for
      phosphorylation of MCP in the Jurkat T cell line. Taken together, these studies
      suggest a src family-dependent pathway for signaling through MCP.

PMID- 10657633
TI  - Human interdigitating dendritic cells induce isotype switching and IL-13
      dependent IgM production in CD40-activated naive B cells.
AB  - Interdigitating dendritic cells (IDC) represent a mature progeny of dendritic
      cells (DC) in vivo and are exhibiting a strong lymphocyte stimulatory potential.
      Because of the restricted localization to secondary lymphoid organs where
      decisive cellular interactions take place in the initial events of immunity, IDC
      regulatory function was addressed in relation to naive B cells. In this study, we
      demonstrate that human tonsillar IDC induce a dual response from CD40-activated
      IgD+/CD38- naive B lymphocytes. IDC direct naive B cells toward either isotype
      switching or an IL-13-dependent IgM secretion. IDC-dependent proliferation,
      isotype switching, and Ig production are all strictly mediated by soluble
      factors, suggesting that such skewing in B cell activation is the result of
      differential cytokine expression. Moreover, IDC-expressed IL-13 represents a
      novel source of a cytokine with recently established effects in Th2 induction as
      well as in immunological disorders resulting in allergic reactions.

PMID- 10657634
TI  - Transcription factor PU.1 is necessary for development of thymic and myeloid
      progenitor-derived dendritic cells.
AB  - Dendritic cells (DCs) are a heterogeneous population of cells that are
      specialized for Ag processing and presentation. These cells are believed to
      derive from both myeloid- and lymphoid-committed precursors. Normal human PBMC
      derived, human CD14+ cell (monocyte)-derived, and mouse hematopoietic progenitor
      derived DCs were shown to express the hematopoietic cell-restricted, ets family
      transcription factor PU.1. These populations represent myeloid progenitor-derived
      DCs. Hematopoietic progenitor cells from PU.1 gene-disrupted (null) mice were
      unable to generate MHC class IIhigh, CD11c+ myeloid-derived DCs in vitro. Mouse
      thymic DCs are proposed to be derived from a committed lymphoid progenitor cell
      that can give rise to T cells as well as DCs. Previously, we showed that CD4 and
      CD8 T cells developed in PU.1 null mice in a delayed manner and in reduced
      number. We examined the thymus of 10- to 12-day-old PU.1 null mice and found no
      evidence of DEC-205+, MIDC-8+ DCs in this tissue. Our findings indicate that PU.1
      regulates the development of both thymic and myeloid progenitor-derived
      populations of DCs, and expand its known role in hematopoietic development.

PMID- 10657635
TI  - Single-cytokine-producing CD4 memory cells predominate in type 1 and type 2
      immunity.
AB  - The patterns of Ag-induced cytokine coexpression in normal, in vivo-primed CD4
      memory T cells has remained controversial because the low frequency at which
      these cells occur has effectively prevented direct ex vivo measurements. We have
      overcome this limitation by using two-color cytokine enzyme-linked immunospot
      assays and computer-assisted image analysis. We found CD4 memory cells that
      simultaneously expressed IL-2, IL-3, IL-4, IL-5, and IFN-gamma to be rare (0
      10%). This cytokine segregation was seen in adjuvant-induced type 1, type 2, and
      mixed immunity to OVA, in Leishmania infection regardless of the Ag dose used or
      how long after immunization the assay was performed. The data suggest that type 1
      and type 2 immunity in vivo is not mediated by classic Th1 or Th2 cells but by
      single-cytokine-producing memory cells.

PMID- 10657637
TI  - Transgenic expression of cyclin D1 in thymic epithelial precursors promotes
      epithelial and T cell development.
AB  - We previously reported that precursors within the keratin (K) 8+5+ thymic
      epithelial cell (TEC) subset generate the major cortical K8+5- TEC population in
      a process dependent on T lineage commitment. This report demonstrates that
      expression of a cyclin D1 transgene in K8+5+ TECs expands this subset and
      promotes TEC and thymocyte development. Cyclin D1 transgene expression is not
      sufficient to induce TEC differentiation in the absence of T lineage-committed
      thymocytes because TECs from both hCD3epsilon transgenic and hCD3epsilon/cyclin
      D1 double transgenic mice remain blocked at the K8+5+ maturation stage. However,
      enforced cyclin D1 expression does expand the developmental window during which
      K8+5+ cells can differentiate in response to normal hemopoietic precursors. Thus,
      enhancement of thymic function may be achieved by manipulating the growth and/or
      survival of TEC precursors within the K8+5+ subset.

PMID- 10657636
TI  - Cancer immunotherapy targeting Wilms' tumor gene WT1 product.
AB  - The Wilms' tumor gene WT1 is expressed at high levels not only in acute
      myelocytic and lymphocytic leukemia and in chronic myelocytic leukemia but also
      in various types of solid tumors including lung cancers. To determine whether the
      WT1 protein can serve as a target Ag for tumor-specific immunity, three 9-mer WT1
      peptides (Db126, Db221, and Db235), which contain H-2Db-binding anchor motifs and
      have a comparatively higher binding affinity for H-2Db molecules, were tested in
      mice (C57BL/6, H-2Db) for in vivo induction of CTLs directed against these WT1
      peptides. Only one peptide, Db126, with the highest binding affinity for H-2Db
      molecules induced vigorous CTL responses. The CTLs specifically lysed not only
      Db126-pulsed target cells dependently upon Db126 concentrations but also WT1
      expressing tumor cells in an H-2Db-restricted manner. The sensitizing activity to
      the Db126-specific CTLs was recovered from the cell extract of WT1-expressing
      tumor cells targeted by the CTLs in the same retention time as that needed for
      the synthetic Db126 peptide in RP-HPLC, indicating that the Db126-specific CTLs
      recognize the Db126 peptide to kill WT1-expressing target cells. Furthermore,
      mice immunized with the Db126 peptide rejected challenges by WT1-expressing tumor
      cells and survived for a long time with no signs of autoaggression by the CTLs.
      Thus, the WT1 protein was identified as a novel tumor Ag. Immunotherapy targeting
      the WT1 protein should find clinical application for various types of human
      cancers.

PMID- 10657638
TI  - Cloning and characterization of the bovine MHC class I-like Fc receptor.
AB  - In the cow, maternal immunity is exclusively mediated by colostral Igs, but the
      receptor responsible for the IgG transport has not yet been identified. The role
      of an IgG-Fc receptor (FcRn) that resembles a class I MHC Ag in transporting IgGs
      through epithelial cells was recently shown in selected species. We now report
      the cloning and characterization of the bovine FcRn (bFcRn). The cDNA and deduced
      amino acid sequences show high similarity to the FcRn in other species, and it
      consists of three extracellular domains, a hydrophobic transmembrane region, and
      a cytoplasmic tail. Despite the high similarity of the extracellular domains with
      other species, the bovine cytoplasmic tail is the shortest thus far analyzed.
      Aligning the known FcRn sequences, we noted that the bovine protein shows a 3-aa
      deletion compared to the rat and mouse sequences in the alpha1 loop. Furthermore,
      we found a shorter transcript of the bFcRn reflecting an exon 6-deleted mRNA,
      which results from an inadequate splice acceptor site in intron 5 and produces a
      transmembrane-deficient molecule, as was previously demonstrated in the related
      MHC class I gene family in mouse and humans. The presence of bFcRn transcripts in
      multiple tissues, including the mammary gland, suggests their involvement both in
      IgG catabolism and transcytosis.

PMID- 10657639
TI  - Abrogation of CTL epitope processing by single amino acid substitution flanking
      the C-terminal proteasome cleavage site.
AB  - CTL directed against the Moloney murine leukemia virus (MuLV) epitope SSWDFITV
      recognize Moloney MuLV-induced tumor cells, but do not recognize cells
      transformed by the closely related Friend MuLV. The potential Friend MuLV epitope
      has strong sequence homology with Moloney MuLV and only differs in one amino acid
      within the CTL epitope and one amino acid just outside the epitope. We now show
      that failure to recognize Friend MuLV-transformed tumor cells is based on a
      defect in proteasome-mediated processing of the Friend epitope which is due to a
      single amino acid substitution (N-->D) immediately flanking the C-terminal anchor
      residue of the epitope. Proteasome-mediated digestion analysis of a synthetic 26
      mer peptide derived from the Friend sequence shows that cleavage takes place
      predominantly C-terminal of D, instead of V as is the case for the Moloney MuLV
      sequence. Therefore, the C terminus of the epitope is not properly generated.
      Epitope-containing peptide fragments extended with an additional C-terminal D are
      not efficiently translocated by TAP and do not show significant binding affinity
      to MHC class I-Kb molecules. Thus, a potential CTL epitope present in the Friend
      virus sequence is not properly processed and presented because of a natural
      flanking aspartic acid that obliterates the correct C-terminal cleavage site.
      This constitutes a novel way to subvert proteasome-mediated generation of proper
      antigenic peptide fragments.

PMID- 10657640
TI  - The murine liver-specific nonclassical MHC class I molecule Q10 binds a classical
      peptide repertoire.
AB  - The biological properties of the nonclassical class I MHC molecules secreted into
      blood and tissue fluids are not currently understood. To address this issue, we
      studied the murine Q10 molecule, one of the most abundant, soluble class Ib
      molecules. Mass spectrometry analyses of hybrid Q10 polypeptides revealed that
      alpha1alpha2 domains of Q10 associate with 8-9 long peptides similar to the
      classical class I MHC ligands. Several of the sequenced peptides matched
      intracellularly synthesized murine proteins. This finding and the observation
      that the Q10 hybrid assembly is TAP2-dependent supports the notion that Q10
      groove is loaded by the classical class I Ag presentation pathway. Peptides
      eluted from Q10 displayed a binding motif typical of H-2K, D, and L ligands. They
      carried conserved residues at P2 (Gly), P6 (Leu), and Pomega (Phe/Leu). The role
      of these residues as anchors/auxiliary anchors was confirmed by Ala substitution
      experiments. The Q10 peptide repertoire was heterogeneous, with 75% of the groove
      occupied by a multitude of diverse peptides; however, 25% of the molecules bound
      a single peptide identical to a region of a TCR V beta-chain. Since this peptide
      did not display enhanced binding affinity for Q10 nor does its origin and
      sequence suggest that it is functionally significant, we propose that the
      nonclassical class I groove of Q10 resembles H-2K, D, and L grooves more than the
      highly specialized clefts of nonclassical class I Ags such as Qa-1, HLA-E, and
      M3.

PMID- 10657641
TI  - Heavy chain diversity region segments of the channel catfish: structure,
      organization, expression and phylogenetic implications.
AB  - Circular DNA, derived from lymphocytes of juvenile channel catfish, was used to
      construct lambda libraries that were screened to identify the products of
      immunoglobulin DH-JH excision events. Clones were characterized that contained DH
      to JH recombination signal joints. The signal joints represented 23-bp
      recombination signal sequences (RSS) identical to germline JH segments that were
      adjacent to DH 12-bp RSS elements. DH flanking regions within the clones were
      used to probe a genomic library. Three germline DH gene segments containing 11-19
      bp coding regions flanked by 12-bp RSS elements with conserved heptamers and
      nonamers were identified. The DH locus is closely linked to the JH locus, and
      Southern blots indicate that the DH segments represent different single member
      gene families. Analysis of H chain cDNA shows that each germline DH segment was
      expressed in functional VDJ recombination events involving different JH segments
      and members of different VH families. Several aspects of CDR3 junctional
      diversity were evident, including deletion of coding region nucleotides, N- and P
      region nucleotide additions, alternate DH reading frame utilization, and point
      mutations. Coding region motifs of catfish DH segments are phylogenetically
      conserved in some DH segments of higher vertebrates. These studies indicate that
      the structure, genomic organization, and recombination patterns of DH segments
      typically associated with higher vertebrates evolved early in vertebrate
      phylogeny at the level of the bony fish.

PMID- 10657642
TI  - Elimination of Fc receptor-dependent effector functions of a modified IgG4
      monoclonal antibody to human CD4.
AB  - Several CD4 mAbs have entered the clinic for the treatment of autoimmune diseases
      or transplant rejection. Most of these mAbs caused CD4 cell depletion, and some
      were murine mAbs which were further hampered by human anti-mouse Ab responses. To
      obviate these concerns, a primatized CD4 mAb, clenoliximab, was generated by
      fusing the V domains of a cynomolgus macaque mAb to human constant regions. The
      heavy chain constant region is a modified IgG4 containing two single residue
      substitutions designed to ablate residual Fc receptor binding activity and to
      stabilize heavy chain dimer formation. This study compares and contrasts the in
      vitro properties of clenoliximab with its matched IgG1 derivative, keliximab,
      which shares the same variable regions. Both mAbs show potent inhibition of in
      vitro T cell responses, lack of binding to complement component C1q, and
      inability to mediate complement-dependent cytotoxicity. However, clenoliximab
      shows markedly reduced binding to Fc receptors and therefore does not mediate Ab
      dependent cell-mediated cytotoxicity or modulation/loss of CD4 from the surface
      of T cells, except in the presence of rheumatoid factor or activated monocytes.
      Thus, clenoliximab retains the key immunomodulatory attributes of keliximab
      without the liability of strong Fcgamma receptor binding. In initial clinical
      trials, these properties have translated to a reduced incidence of CD4+ T cell
      depletion.

PMID- 10657643
TI  - The tumor suppressor PTEN regulates T cell survival and antigen receptor
      signaling by acting as a phosphatidylinositol 3-phosphatase.
AB  - The tumor suppressor gene PTEN encodes a 55-kDa enzyme that hydrolyzes both
      protein phosphotyrosyl and 3-phosphorylated inositol phospholipids in vitro. We
      have found that the latter activity is physiologically relevant in intact T
      cells. Expression of active PTEN lead to a 50% loss of transfected cells due to
      increased apoptosis, which was completely prevented by coexpression of a
      constitutively active, membrane-bound form of protein kinase B. A mutant of PTEN
      selectively lacking lipid phosphatase activity, but retaining protein phosphatase
      activity, had no effects on cell number. Active (but not mutant) PTEN also
      decreased TCR-induced activation of the mitogen-activated protein kinase ERK2
      (extracellular signal-related kinase 2), as seen after inhibition of
      phosphatidylinositol 3-kinase. Our data indicate that PTEN is a
      phosphatidylinositol 3-phosphatase in T cells, and we suggest that PTEN may play
      a role in the regulation of T cell survival and TCR signaling by directly
      opposing phosphatidylinositol 3-kinase.

PMID- 10657644
TI  - A prominent role for Sp1 during lipopolysaccharide-mediated induction of the IL
      10 promoter in macrophages.
AB  - IL-10 is an antiinflammatory cytokine secreted by activated macrophages and Th2
      cells. IL-10 secretion promotes the down-regulation of proinflammatory cytokine
      synthesis and the development of Th2 responses. In macrophages, proinflammatory
      cytokines appear to be induced by similar mechanisms, but the IL-10 induction
      mechanisms have not been examined. We have analyzed the murine IL-10 promoter in
      the RAW264.7 macrophage line activated with LPS. A comprehensive mutant analysis
      revealed only one element upstream of the core promoter that was essential for
      promoter induction. A refined mutant analysis localized this element to
      nucleotides -89 to -78, and gel shift experiments revealed that it represents a
      nonconsensus binding site for Sp1. The functional relevance of Sp1 was supported
      by the high affinity of the interaction, the close correlation between the
      nucleotides required for Sp1 binding and promoter function, and the ability of an
      Sp1 consensus sequence to substitute for the -89/-78 promoter sequence. Evidence
      that Sp1 may be a target of signaling pathways involved in IL-10 induction was
      provided by the exclusive requirement for the Sp1 binding site, by the ability of
      the Sp1 site to confer induction to a heterologous promoter, and by the
      delineation of an Sp1 domain that can mediate induction. No relevant contribution
      from Rel, C/EBP (CCAAT/enhancer-binding protein), or AP-1 binding sites, which
      regulate most proinflammatory cytokine promoters, was observed. Together, these
      results demonstrate that IL-10 gene regulation is distinct from the regulation of
      proinflammatory cytokine genes, and suggest that Sp1 may be a central mediator of
      IL-10 induction.

PMID- 10657645
TI  - Polymeric IgA is superior to monomeric IgA and IgG carrying the same variable
      domain in preventing Clostridium difficile toxin A damaging of T84 monolayers.
AB  - The two exotoxins A and B produced by Clostridium difficile are responsible for
      antibiotic-associated enterocolitis in human and animals. When added apically to
      human colonic carcinoma-derived T84 cell monolayers, toxin A, but not toxin B,
      abolished the transepithelial electrical resistance and altered the morphological
      integrity. Apical addition of suboptimal concentration of toxin A made the cell
      monolayer sensitive to toxin B. Both toxins induced drastic and rapid epithelial
      alterations when applied basolaterally with a complete disorganization of tight
      junctions and vacuolization of the cells. Toxin A-specific IgG2a from hybridoma
      PCG-4 added apically with toxin A alone or in combination with toxin B abolished
      the toxin-induced epithelial alterations for up to 8 h. The Ab neutralized
      basolateral toxin A for 4 h, but not the mixture of the two toxins. Using an
      identical Ab:Ag ratio, we found that recombinant polymeric IgA (IgAd/p) with the
      same Fv fragments extended protection against toxin A for at least 24 h in both
      compartments. In contrast, the recombinant monomeric IgA counterpart behaved as
      the PCG-4 IgG2a Ab. The direct comparison between different Ig isotype and
      molecular forms, but of unique specificity, demonstrates that IgAd/p Ab is more
      efficient in neutralizing toxin A than monomeric IgG and IgA. We conclude that
      immune protection against C. difficile toxins requires toxin A-specific secretory
      Abs in the intestinal lumen and IgAd/p specific for both toxins in the lamina
      propria.

PMID- 10657646
TI  - Murine pro-B cells require IL-7 and its receptor complex to up-regulate IL-7R
      alpha, terminal deoxynucleotidyltransferase, and c mu expression.
AB  - Phenotypic analysis of bone marrow cells from IL-7 knockout (KO) mice revealed
      that B cell development is blocked precisely at the transition between pro-B
      cells and pre-B cells. In contrast, the generation of pre-pro-B cells and pro-B
      cells appeared to be normal, as judged by total cell numbers, proliferative
      indexes, D-JH and V-DJH gene rearrangements, and mRNA for recombinase-activating
      gene-1 (RAG-1), RAG-2, TdT, Ig mu, lambda 5, and VpreB. However, upon closer
      inspection, several abnormalities in pro-B cell development were identified that
      could be corrected by injection of rIL-7 in vivo. These included the absence of
      the subset of late pro-B cells that initiates cmu expression for pre-B cell Ag
      receptor (BCR) formation, and the failure of pro-B cells to up-regulate TdT and
      the IL-7R alpha (but not the common gamma-chain) chain. Similar defects were
      present in common gamma-chain and Jak3 KO mice, but not in lambda 5 or (excluding
      cytoplasmic Ig mu heavy chain (c mu)) RAG-1 KO mice, all of which also arrest at
      the late pro-B cell stage. Consequently, up-regulation of TdT and IL-7R alpha
      expression requires signaling through the high affinity IL-7R, but does not
      require cmu expression or a functional pre-BCR. Taken together, these results
      suggest that IL-7 and its receptor complex are essential for 1) up-regulating the
      expression of TdT and IL-7R alpha, 2) initiating the production of cmu and 3)
      promoting the formation of a functional pre-BCR in/on pro-B cells. These key
      events, in turn, appear to be prerequisite both for differentiation of pro-B
      cells to pre-B cells and for proliferation of these cell subsets upon continued
      stimulation with IL-7.

PMID- 10657647
TI  - The nucleotide-replacement spectrum under somatic hypermutation exhibits
      microsequence dependence that is strand-symmetric and distinct from that under
      germline mutation.
AB  - Somatic mutation is a fundamental component of acquired immunity. Although its
      molecular basis remains undetermined, the sequence specificity with which
      mutations are introduced has provided clues to the mechanism. We have analyzed
      data representing over 1700 unselected mutations in V gene introns and
      nonproductively rearranged V genes to identify the sequence specificity of the
      mutation spectrum-the distribution of resultant nucleotides. In other words, we
      sought to determine what effects the neighboring bases have on what a given base
      mutates "to." We find that both neighboring bases have a significant effect on
      the mutation spectrum. Their influences are complicated, but much of the effect
      can be characterized as enhancing homogeneity of the mutated DNA sequence. In
      contrast to what has been reported for the sequence specificity of the
      "targeting" mechanism, that of the spectrum is notably symmetric under
      complementation, indicating little if any strand bias. We compared the spectrum
      to that found previously for germline mutations as revealed by analyzing
      pseudogene sequences. We find that the influences of nearest neighbors are quite
      different in the two datasets. Altogether, our findings suggest that the
      mechanism of somatic hypermutation is complex, involving two or more stages:
      introduction of mis-pairs and their subsequent resolution, each with distinct
      sequence specificity and strand bias.

PMID- 10657648
TI  - Transfer of immune complexes from erythrocyte CR1 to mouse macrophages.
AB  - We are developing a potential therapeutic approach for removing pathogens from
      the circulation of primates in which the pathogen is bound to the complement
      receptor (CR1) on E using a bispecific mAb complex, a heteropolymer (HP). We have
      used mAb this approach to demonstrate that cleared prototype pathogens are
      localized to, phagocytosed in, and destroyed in the liver. Extension of this work
      to a clinical setting will require a detailed understanding of the mechanism by
      which the E-bound immune complex substrates are transferred to fixed tissue
      macrophages in the liver, the transfer reaction. Therefore, we examined an in
      vitro system to study this process using bacteriophage phiX174 as a model
      pathogen. E containing phiX174 (bound via an anti-CR1/anti-phiX174 HP) were
      incubated with P388D1 murine macrophages, and the two cell types were separated
      by centrifugation through Ficoll. Both E and macrophages were then probed and
      analyzed by RIA or flow cytometry. The results indicate that all three components
      of the E-bound IC (phiX174, HP, and CR1) were removed from the E and internalized
      by the macrophages. We found that transfer requires the Fc portion of IgG,
      because little transfer of phiX174 occurs when it is bound to E CR1 using a HP
      containing only Fab fragments. These findings, taken in the context of other
      studies, suggest a general mechanism for the transfer reaction in which Fc
      receptors facilitate close juxtaposition of the macrophage to the E-bound IC
      which then allows a macrophage-associated protease to cleave CR1. The released IC
      are then internalized and processed by the macrophages.

PMID- 10657649
TI  - Intestinal intraepithelial lymphocytes exert potent protective cytotoxic activity
      during an acute virus infection.
AB  - After systemic infection of mice with 104 PFU of lymphocytic choriomeningitis
      virus (LCMV), infected cells are detected simultaneously in various organs,
      including spleen and intestinal mucosa. Most notably, virus-infected cells are
      also present among CD11c+ dendritic cells in the subepithelial area of the small
      intestinal mucosa. Some of these virus-infected cells are in close spatial
      association with intestinal intraepithelial lymphocytes (IEL). Therefore, we
      compared virus-specific cytotoxic activity of CD8 splenocytes with that of IEL
      subsets. While ex vivo isolated TCRalphabeta+CD8alphaalpha+ IEL exert only
      minimal virus-specific cytotoxicity, maximum specific killing mediated by
      TCRalphabeta+CD8alphabeta+ IEL on day 8 postinfection exceeds maximum cytotoxic
      activity observed with CD8 splenocytes when assessed in vitro. Maximum cytotoxic
      activity of IEL is preceded by peak perforin and granzyme B mRNA expression in
      IEL around day 6 postinfection, suggesting a recent activation in situ. The
      antivirus cytotoxicity of in vivo primed IEL is further demonstrated by the
      protection from virus production in the spleen of mice infected with LCMV 10 h
      before adoptive cell transfer. These data indicate a potent priming of LCMV
      specific IEL in situ after systemic LCMV infection and suggest that cytotoxic IEL
      markedly contribute to the elimination of virus-infected cells in the intestinal
      mucosa.

PMID- 10657650
TI  - Role of tumor cell apoptosis in tumor antigen migration to the draining lymph
      nodes.
AB  - Establishment of an immune response against cancer may depend on the capacity of
      dendritic cells to transfer tumor Ags into T cell-rich areas. To check this
      possibility, we used a colon cancer cell variant that yields tumors undergoing
      complete T cell-dependent rejection when injected into syngeneic rats. We
      previously demonstrated that immunogenicity of these tumors depended on the early
      apoptosis of a part of these tumor cells. In this paper we show that fluorescent
      tumor cell proteins are released from FITC-labeled tumor cells and undergo
      engulfment by tumor-infiltrating monocytes without a phenotype of mature
      dendritic cells or macrophages. Fluorescence-labeled mononuclear cells with a
      phenotype of MHC class II+ dendritic cells are also found in the T cell areas of
      the draining lymph nodes. Interestingly, no fluorescent cell can be found in
      lymph nodes after a s.c. injection of Bcl2-transfected apoptosis-resistant tumor
      cells that yielded progressive tumors. Proliferation of tumor-immune T
      lymphocytes was induced by dendritic cells isolated from the draining lymph nodes
      recovered after a s.c. injection of apoptosis-sensitive, but not apoptosis
      resistant, tumor cells. These results show that tumor cell apoptosis releases
      proteins that are engulfed by inflammatory cells in the tumor, then transported
      to lymph node T cell areas where they can induce a specific immune response
      leading to tumor rejection.

PMID- 10657651
TI  - TGF-beta mediates CTLA-4 suppression of cellular immunity in murine kalaazar.
AB  - Recent studies indicate important roles for CTLA-4 engagement in T cells, and for
      TGF-beta production in the immunopathogenesis of murine kalaazar or visceral
      leishmaniasis, but a functional link between these two pathways in helping
      intracellular parasite growth is unknown. Here we report that Ag or anti-CD3
      activation of splenic CD4+ T cells from visceral leishmaniasis leads to intense
      CTLA-4-mediated TGF-beta1 production, as assessed either by CTLA-4 blockade or by
      direct CTLA-4 cross-linkage. Production of TGF-beta1 accounted for the reciprocal
      regulation of IFN-gamma production by CTLA-4 engagement. Following CD4+ T cell
      activation, intracellular growth of Leishmania chagasi in cocultured splenic
      macrophages required both CTLA-4 function and TGF-beta1 secretion. Cross-linkage
      of CTLA-4 markedly increased L. chagasi replication in cocultures of infected
      macrophages and activated CD4+ T cells, and parasite growth could be completely
      blocked with neutralizing anti-TGF-beta1 Ab. Exogenous addition of rTGF-beta1
      restored parasite growth in cultures protected from parasitism by CTLA-4
      blockade. These results indicate that the negative costimulatory receptor CTLA-4
      is critically involved in TGF-beta production and in intracellular parasite
      replication seen in murine kalaazar.

PMID- 10657652
TI  - NK markers are expressed on a high percentage of virus-specific CD8+ and CD4+ T
      cells.
AB  - NK cells have been phenotypically defined by the expression of specific markers
      such as NK1.1, DX5, and asialo-GM1 (ASGM1). In addition to NK cells, a small
      population of CD3+ T cells has been shown to express these markers, and a unique
      subpopulation of NK1. 1+CD3+ T cells that expresses an invariant TCR has been
      named "NKT cells." Here, we describe NK marker expression on a broad spectrum of
      MHC class I- and MHC class II-restricted T cells that are induced after acute
      viral infection. From 5 to >500 days post lymphocytic choriomeningitis virus
      (LCMV) infection, more than 90% of virus-specific CD8+ and CD4+ T cells coexpress
      one or more of these three prototypical NK markers. Furthermore, in vivo
      depletion of NK cells with anti-ASGM1 Ab resulted in the removal of 90% of virus
      specific CD8+ T cells and 50-80% of virus-specific CD4+ T cells. This indicates
      that studies using in vivo depletion to determine the role of NK cells in immune
      defense could potentially be misinterpreted because of the unintended depletion
      of Ag-specific T cells. These results demonstrate that NK Ags are widely
      expressed on the majority of virus-specific T cells and indicate that the NK and
      T cell lineages may not be as distinct as previously believed. Moreover, the
      current nomenclature defining NKT cells will require comprehensive modification
      to include Ag-specific CD8+ and CD4+ T cells that express prototypical NK Ags.

PMID- 10657653
TI  - Virulent Mycobacterium tuberculosis strains evade apoptosis of infected alveolar
      macrophages.
AB  - Human alveolar macrophages (AMphi) undergo apoptosis following infection with
      Mycobacterium tuberculosis in vitro. Apoptosis of cells infected with
      intracellular pathogens may benefit the host by eliminating a supportive
      environment for bacterial growth. The present study compared AMphi apoptosis
      following infection by M. tuberculosis complex strains of differing virulence and
      by Mycobacterium kansasii. Avirulent or attenuated bacilli (M. tuberculosis
      H37Ra, Mycobacterium bovis bacillus Calmette-Guerin, and M. kansasii) induced
      significantly more AMphi apoptosis than virulent strains (M. tuberculosis H37Rv,
      Erdman, M. tuberculosis clinical isolate BMC 96.1, and M. bovis wild type).
      Increased apoptosis was not due to greater intracellular bacterial replication
      because virulent strains grew more rapidly in AMphi than attenuated strains
      despite causing less apoptosis. These findings suggest the existence of
      mycobacterial virulence determinants that modulate the apoptotic response of
      AMphi to intracellular infection and support the hypothesis that macrophage
      apoptosis contributes to innate host defense in tuberculosis.

PMID- 10657654
TI  - CCR2 expression determines T1 versus T2 polarization during pulmonary
      Cryptococcus neoformans infection.
AB  - Pulmonary clearance of the encapsulated yeast Cryptococcus neoformans requires
      the development of T1-type immunity. The objective of this study was to determine
      the role of CCR2 in leukocyte recruitment and development of T1-type cell
      mediated immunity during pulmonary C. neoformans infection. Intratracheal
      inoculation of C. neoformans into CCR2 knockout (CCR2-/-) mice produced a
      prolonged pulmonary infection (5000-fold CFU at 6 wk compared with CCR2+/+ mice)
      and significant dissemination to the spleen and brain (160- and 800-fold
      greater). In addition, CCR2 deficiency resulted in significantly reduced
      recruitment of macrophages (weeks 1-3) and CD8+ T cells (weeks 1-2) into the
      lungs. The immune response in CCR2-/- mice was characterized by chronic pulmonary
      eosinophilia, crystal deposition in the lungs, pulmonary leukocyte production of
      IL-4 and IL-5 but not IFN-gamma, lack of anticryptococcal delayed-type
      hypersensitivity, and high levels of serum IgE. These results demonstrate that
      expression of CCR2 is required for the development of a T1-type response to C.
      neoformans infection and lack of CCR2 results in a switch to a T2-type response.
      Thus, CCR2 plays a critical role in promoting the development of T1- over T2-type
      immune responses in the lung following cryptococcus infection.

PMID- 10657655
TI  - Lipopolysaccharide induces actin reorganization and tyrosine phosphorylation of
      Pyk2 and paxillin in monocytes and macrophages.
AB  - The bacterial endotoxin LPS is a potent stimulator of monocyte and macrophage
      activation and induces adhesion of monocytes. Morphological changes in response
      to LPS have not been characterized in detail, however, nor have the signaling
      pathways mediating LPS-induced adhesion been elucidated. We have found that LPS
      rapidly induced adhesion and spreading of peripheral blood monocytes, and that
      this was inhibited by the Src family kinase inhibitor PP1 and the
      phosphatidylinositide 3-kinase inhibitor LY294002. LPS also stimulated actin
      reorganization, leading to the formation of filopodia, lamellipodia, and membrane
      ruffles in Bac1 mouse macrophages. Proline-rich tyrosine kinase 2 (Pyk2), a
      tyrosine kinase related to focal adhesion kinase, and paxillin, a cytoskeletal
      protein that interacts with Pyk2, were both tyrosine phosphorylated in response
      to LPS in monocytes and macrophages. Both tyrosine phosphorylation events were
      inhibited by PP1 and LY294002. Adhesion also stimulated tyrosine phosphorylation
      of Pyk2 and paxillin in monocytes, and this was further enhanced by LPS. Finally,
      Pyk2 and paxillin colocalized within membrane ruffles in LPS-stimulated cells.
      These results indicate that LPS stimulation of monocytes and macrophages results
      in rapid morphological changes and suggest that Pyk2 and/or paxillin play a role
      in this response.

PMID- 10657656
TI  - Selection of Babesia bovis-infected erythrocytes for adhesion to endothelial
      cells coselects for altered variant erythrocyte surface antigen isoforms.
AB  - Sequestration of Babesia bovis-infected erythrocytes (IRBCs) in the host
      microvasculature is thought to constitute an important mechanism of immune
      evasion. Since Ig is considered to be important for protection from disease, an
      in vitro assay of B. bovis sequestration was used to explore the ability of anti
      B. bovis Ig to interfere with IRBC cytoadhesion, and to identify IRBC surface Ags
      acting as endothelial cell receptors. Bovine infection sera reactive with the
      IRBC surface inhibited and even reversed the binding of IRBCs to bovine brain
      capillary endothelial cells (BBECs). This activity is at least partially
      attributable to serum IgG. IgG isolated from inhibitory serum captured the
      variant erythrocyte surface ag 1 (VESA1) in surface-specific immunoprecipitations
      of B. bovis-IRBCs. Selection for the cytoadhesive phenotype concurrently selected
      for antigenic and structural changes in the VESA1 Ag. In addition, the anti-VESA1
      mAb, 4D9.1G1, proved capable of effectively inhibiting and reversing binding of
      adhesive, mAb-reactive parasites to BBECs, and by immunoelectron microscopy
      localized VESA1 to the external tips of the IRBC membrane knobs. These data are
      consistent with a link between antigenic variation and cytoadherence in B. bovis
      and suggest that the VESA1 Ag acts as an endothelial cell ligand on the B. bovis
      IRBC.

PMID- 10657657
TI  - Stat6 signaling promotes protective immunity against Trichinella spiralis through
      a mast cell- and T cell-dependent mechanism.
AB  - Studies in mice infected with the gastrointestinal nematode parasite
      Nippostrongylus brasiliensis demonstrated that IL-4/IL-13 activation of Stat6
      suppresses development of intestinal mastocytosis and does not contribute to IL
      4/IL-13 production, but is still essential for parasite expulsion. Because
      expulsion of another gastrointestinal nematode, Trichinella spiralis, unlike N.
      brasiliensis expulsion, is mast cell dependent, these observations suggested that
      T. spiralis expulsion would be Stat6 independent. Instead, we find that Stat6
      activation by IL-4/IL-13 is required in T. spiralis-infected mice for the mast
      cell responses that induce worm expulsion and for the cytokine responses that
      induce intestinal mastocytosis. Furthermore, although IL-4 induces N.
      brasiliensis expulsion in the absence of B cells, T cells, and mast cells, mast
      cells and T cells are required for IL-4 induction of T. spiralis expulsion. Thus,
      Stat6 signaling is required for host protection against N. brasiliensis and T.
      spiralis but contributes to expulsion of these two worms by different mechanisms.
      The induction of multiple effector mechanisms by Stat6 signaling provides a way
      for a cytokine response induced by most gastrointestinal nematode parasites to
      protect against most of these parasites, even though different effector
      mechanisms are required for protection against different nematodes.

PMID- 10657658
TI  - Ras, protein kinase C zeta, and I kappa B kinases 1 and 2 are downstream
      effectors of CD44 during the activation of NF-kappa B by hyaluronic acid
      fragments in T-24 carcinoma cells.
AB  - We have investigated the ability of hyaluronic acid (HA) fragments to activate
      the transcription factor NF-kappa B. HA fragments activated NF-kappa B in the
      cell lines T-24, HeLa, MCF7, and J774. Further studies in T-24 cells demonstrated
      that HA fragments also induced I kappa B alpha phosphorylation and degradation,
      kappa B-linked reporter gene expression, and ICAM-1 promoter activity in an NF
      kappa B-dependent manner. The effect of HA was size dependent as neither
      disaccharide nor native HA were active. CD44, the principal cellular receptor for
      HA, was critical for the response because the anti-CD44 Ab IM7.8.1 blocked the
      effect on NF-kappa B. HA fragments activated the I kappa B kinase complex, and
      the effect on a kappa B-linked reporter gene was blocked in T-24 cells expressing
      dominant negative I kappa B kinases 1 or 2. Activation of protein kinase C (PKC)
      was required because calphostin C inhibited NF-kappa B activation and I kappa B
      alpha phosphorylation. In particular, PKC zeta was required because transfection
      of cells with dominant negative PKC zeta blocked the effect of HA fragments on
      kappa B-linked gene expression and HA fragments increased PKC zeta activity.
      Furthermore, damnacanthal and manumycin A, two mechanistically distinct
      inhibitors of Ras, blocked NF-kappa B activation. Transfection of T-24 cells with
      dominant negative Ras (RasN17) blocked HA fragment-induced kappa B-linked
      reporter gene expression, and HA fragments activated Ras activity within 5 min.
      Taken together, these studies establish a novel signal transduction cascade
      emanating from CD44 to Ras, PKC zeta, and I kappa B kinase 1 and 2.

PMID- 10657659
TI  - Human toll-like receptor 2 mediates monocyte activation by Listeria
      monocytogenes, but not by group B streptococci or lipopolysaccharide.
AB  - Human Toll like receptor (TLR) 2 has been implicated as a signaling receptor for
      LPS from Gram-negative bacteria and cell wall components from Gram-positive
      organisms. In this study, we investigated whether TLR2 can signal cell activation
      by the heat-killed group B streptococci type III (GBS) and Listeria monocytogenes
      (HKLM). HKLM, but not GBS, showed a time- and dose-dependent activation of
      Chinese hamster ovary cells transfected with human TLR2, as measured by
      translocation of NF-kappaB and induction of IL-6 production. A mAb recognizing a
      TLR2-associated epitope (TL2.1) was generated that inhibited IL-6 production from
      Chinese hamster ovary-TLR2 cells stimulated with HKLM or LPS. The TL2.1 mAb
      reduced HKLM-induced TNF production from human monocytes by 60%, whereas a CD14
      mAb (3C10) reduced the TNF production by 30%. However, coadministrating TL2.1 and
      3C10 inhibited the TNF response by 80%. In contrast to this, anti-CD14 blocked
      LPS-induced TNF production from monocytes, whereas anti-TLR2 showed no
      inhibition. Neither TL2.1 nor 3C10 affected GBS-induced TNF production. These
      results show that TLR2 can function as a signaling receptor for HKLM, possibly
      together with CD14, but that TLR2 is unlikely to be involved in cell activation
      by GBS. Furthermore, although LPS can activate transfected cell lines through
      TLR2, this receptor does not seem to be the main transducer of LPS activation of
      human monocytes. Thus, our data demonstrate the ability of TLR2 to distinguish
      between different pathogens.

PMID- 10657660
TI  - Selective inhibition of monocyte chemoattractant protein-1 gene expression in
      human embryonal kidney cells by specific triple helix-forming oligonucleotides.
AB  - Monocyte chemoattractant protein-1 (MCP-1) is a chemokine that is expressed by a
      variety of tissue cells in response to inflammatory stimuli, such as IL-1beta,
      TNF-alpha, and IFN-gamma. A major function of MCP-1 is the recruitment and
      activation of monocytes and T lymphocytes. Overexpression of MCP-1 has been
      implicated in a number of diseases, including glomerulonephritis and rheumatoid
      arthritis, indicating that the modulation of MCP-1 activity and/or expression is
      a desired therapeutic strategy. In the present study, our aim was to test whether
      the MCP-1 expression could be inhibited at the transcriptional level using triple
      helix-forming oligonucleotides (TFOs). We designed a TFO targeted to the SP-1
      binding site in the human MCP-1 gene promoter. Gel mobility shift assays
      demonstrated that the phosphodiester TFO formed a sequence-specific triplex with
      its dsDNA target with an EC50 of approximately 1.9 x 10(-7) M. The corresponding
      phosphorothioated oligonucleotide was also effective in this assay with an 8-fold
      higher EC50 value. Binding of the TFO to the target DNA prevented the binding of
      rSP-1 and of nuclear proteins in vitro. The TFO could also partially inhibit
      endogenous MCP-1 gene expression in cultured human embryonic kidney cells.
      Treatment of TNF-alpha-stimulated human embryonic kidney 293 cells with the TFO
      inhibited the secretion of MCP-1 in a dose-dependent manner (up to 45% at 5
      microM oligonucleotide). The inhibition of MCP secretion was caused at the level
      of gene transcription, because MCP-1 mRNA levels in oligonucleotide-treated cells
      were also decreased by approximately 40%.

PMID- 10657661
TI  - Induction of E-selectin expression by double-stranded RNA and TNF-alpha is
      attenuated in murine aortic endothelial cells derived from double-stranded RNA
      activated kinase (PKR)-null mice.
AB  - The adherence of leukocytes on the endothelium is mediated in part by the
      transient expression of the E-selectin adhesion molecule. Because we have
      previously shown that the dsRNA-activated kinase PKR mediates dsRNA induction of
      NF-kappaB, we used murine aortic endothelial (MuAE) cells isolated from wild-type
      and PKR-null mice to investigate the role of PKR in the induction of E-selectin
      expression by dsRNA (pIC) and TNF-alpha. E-selectin mRNA and protein expression
      was inducible by both pIC and TNF-alpha in wild-type MuAE cells, whereas
      induction of E-selectin expression by these agents was defective in PKR-null MuAE
      cells. Induction of E-selectin promoter activity and NF-kappaB DNA binding
      activity were substantially reduced in pIC- or TNF-alpha-treated PKR-null cells,
      indicating a role for PKR in both pIC and TNF-alpha induction of E-selectin via
      an NF-kappaB-dependent pathway. In PKR-null cells, pIC-mediated degradation of
      IkappaBbeta is deficient. Activation of this pathway requires the PKR-dependent
      degradation of the IkappaBbeta protein. Moreover, both phosphorylated and
      unphosphorylated activating transcription factor 2 DNA-binding activities were
      reduced in PKR-null aortic endothelial cells. These results indicate that the PKR
      is required for full activation of E-selectin expression by pIC and TNF-alpha in
      primary mouse aortic endothelial cells identifying activating transcription
      factor 2 as a new target for PKR-dependent regulation and suggest a role for PKR
      in leukocyte adhesion.

PMID- 10657662
TI  - Involvement of cytosolic phospholipase A2 and secretory phospholipase A2 in
      arachidonic acid release from human neutrophils.
AB  - The purpose of this study was to define the role of secretory phospholipase A2
      (sPLA2), calcium-independent PLA2, and cytosolic PLA2 (cPLA2) in arachidonic acid
      (AA) release from fMLP-stimulated human neutrophils. While fMLP induced the
      release of extracellular sPLA2 activity and AA, 70% of sPLA2 activity remained
      associated with the cell. Treatment with the cell-impermeable sPLA2 inhibitors
      DTT or LY311-727, or the anti-sPLA2 Ab 3F10 all inactivated extracellular sPLA2
      activity, but had minimal effect on neutrophil AA mass release. In contrast,
      coincubation of streptolysin-O toxin-permeabilized neutrophils with DTT, LY311
      727, or 3F10 all decreased [3H8]AA release from [3H8]AA-labeled, fMLP-stimulated
      cells. Exposure to fMLP resulted in a decrease in the electrophoretic mobility of
      cPLA2, a finding consistent with cPLA2 phosphorylation, and stimulated the
      translocation of cPLA2 from cytosolic to microsomal and nuclear compartments. The
      role of cPLA2 was further evaluated with the cPLA2 inhibitor methyl arachidonyl
      fluorophosphonate, which attenuated cPLA2 activity in vitro and decreased fMLP
      stimulated AA mass release by intact neutrophils, but had no effect on neutrophil
      sPLA2 activity. Inhibition of calcium-independent PLA2 with haloenol lactone
      suicide substrate had no effect on neutrophil cPLA2 activity or AA mass release.
      These results indicate a role for cPLA2 and an intracellular or cell-associated
      sPLA2 in the release of AA from fMLP-stimulated human neutrophils.

PMID- 10657663
TI  - Administration of IgG Fc fragments prevents glomerular injury in experimental
      immune complex nephritis.
AB  - Most human nephritis is due to glomerular deposition and/or formation of immune
      complexes (IC). In cultured mesangial cells, Fc receptor stimulation induces
      proliferation, matrix synthesis, and release of several mediators implicated in
      the initiation and progression of glomerular injury. Since Ig Fc fragments in
      vitro modified these phenomena, we studied the effects of systemic administration
      of IgG Fc fragments on the evolution of experimental IC nephritis. Fc fragment
      injection (1 mg/day i.p.) to rats with ongoing nephritis (proteinuria 20-50 mg/24
      h vs 9 +/- 0.2 mg/24 h in controls) markedly ameliorates proteinuria, renal
      function, and morphological renal lesions. This was accompanied by a reduction in
      the renal synthesis of chemokines (monocyte chemoattractant protein-1, IFN
      inducible protein-10, and cytokine-induced neutrophil chemoattractant-1), matrix
      proteins, and growth factors (platelet-derived growth factor, and TGF-beta), and
      in the activity of transcription factors. The treatment did not affect the
      glomerular deposition of IgG IC and complement C1q. In contrast, a decrease in
      the renal expression and production of C3 was observed without changes in serum
      complement levels. In vitro, very low complement consumption and no C3b covalent
      interaction were observed with Fc fragments, confirming that they did not modify
      systemic complement activity. These results indicate that the administration of
      Fc fragments prevents the development of glomerular damage in an aggressive model
      of proliferative glomerulonephritis through mechanisms involving a reduced local
      generation of complement, chemokines and growth factors. Modulation of IC
      mesangial cell interaction by Fc fragment administration could represent a new
      approach to the treatment of severe immune nephritis.

PMID- 10657665
TI  - Activated macrophages direct apoptosis and suppress mitosis of mesangial cells.
AB  - During inflammation in the glomerulus, the complement of resident myofibroblast
      like mesangial cells is regulated by mitosis and apoptosis, but the cellular
      mechanisms controlling the size of mesangial cell populations have remained
      obscure. Prompted by studies of development, we sought evidence that macrophages
      regulate mesangial cell number. Rat bone marrow-derived macrophages primed with
      IFN-gamma then further activated in coculture with LPS or TNF-alpha elicited a 10
      fold induction of rat mesangial cell apoptosis and complete suppression of
      mitosis, effects inhibitable by the NO synthase inhibitors L-monomethyl arginine
      and L-N(6)-(1-iminoethyl) lysine dihydrochloride. Complete dependence upon
      macrophage-derived NO was observed in comparable experiments employing activated
      bone marrow macrophages from wild-type and NO synthase 2(-/-) mice. Nevertheless,
      when mesangial cells were primed with IFN-gamma plus TNF-alpha, increased
      induction by activated macrophages of mesangial apoptosis exhibited a NO
      independent element. The use of gld/gld macrophages excluded a role for Fas
      ligand in this residual kill, despite increased expression of Fas and increased
      susceptibility to soluble Fas ligand exhibited by cytokine-primed mesangial
      cells. Finally, activated macrophages isolated from the glomeruli of rats with
      nephrotoxic nephritis also induced apoptosis and suppressed mitosis in mesangial
      cells by an L-monomethyl arginine-inhibitable mechanism. These data demonstrate
      that activated macrophages, via the release of NO and other mediators, regulate
      mesangial cell populations in vitro and may therefore control the mesangial cell
      complement at inflamed sites.

PMID- 10657664
TI  - Requirement of B7 costimulation for Th1-mediated inflammatory bone resorption in
      experimental periodontal disease.
AB  - The CD28 costimulation at TCR signaling plays a pivotal role in the regulation of
      the T cell response. To elucidate the role of T cells in periodontal disease, a
      system of cell transfer with TCR/CD28-dependent Th1 or Th2 clones was developed
      in rats. Gingival injection of specific Ag, Actinobacillus actinomycetemcomitans
      29-kDa outer membrane protein, and LPS could induce local bone resorption 10 days
      after the transfer of Ag-specific Th1 clone cells, but not after transfer of Th2
      clone cells. Interestingly, the presence of LPS was required not only for the
      induction of bone resorption but also for Ag-specific IgG2a production. LPS
      injection elicited the induction of expression of both B7-1 and B7-2 expression
      on gingival macrophages, which otherwise expressed only MHC class II when animals
      were injected with Ag alone. The expression of B7 molecules was observed for up
      to 3 days, which corresponded to the duration of retention of T clone cells in
      gingival tissues. Either local or systemic administration of CTLA4Ig, a
      functional antagonist of CD28 binding to B7, could abrogate the bone resorption
      induced by Th1 clone cells combined with gingival challenge with both Ag and LPS.
      These results suggest that local Ag-specific activation of Th1-type T cells by B7
      costimulation appeared to trigger inflammatory bone resorption, whereas
      inhibition of B7 expression by CTLA4Ig might be a therapeutic approach for
      intervention with inflammatory bone resorption.

PMID- 10657666
TI  - Experimental autoimmune encephalomyelitis on the SJL mouse: effect of gamma delta
      T cell depletion on chemokine and chemokine receptor expression in the central
      nervous system.
AB  - Experimental autoimmune encephalomyelitis (EAE) is a demyelinating disease of the
      central nervous system (CNS) that is a model for multiple sclerosis. Previously,
      we showed that depletion of gamma delta T cells significantly reduced clinical
      and pathological signs of disease, which was associated with reduced expression
      of IL-1 beta, IL-6, TNF-alpha, and lymphotoxin at disease onset and a more
      persistent reduction in IFN-gamma. In this study, we analyzed the effect of gamma
      delta T cell depletion on chemokine and chemokine receptor expression. In the CNS
      of control EAE mice, mRNAs for RANTES, eotaxin, macrophage-inflammatory protein
      (MIP)-1 alpha, MIP-1 beta, MIP-2, inducible protein-10, and monocyte
      chemoattractant protein-1 were detected at disease onset, increased as disease
      progressed, and fell as clinical signs improved. In gamma delta T cell-depleted
      animals, all of the chemokine mRNAs were reduced at disease onset; but at the
      height of disease, expression was variable and showed no differences from control
      animals. mRNA levels then fell in parallel with control EAE mice. ELISA data
      confirmed reduced expression of MIP-1 alpha and monocyte chemoattractant protein
      1 at disease onset in gamma delta T cell-depleted mice, and total T cell numbers
      were also reduced. In normal CNS mRNAs for CCR1, CCR3, and CCR5 were observed,
      and these were elevated in EAE animals. mRNAs for CCR2 were also detected in the
      CNS of affected mice. Depletion of gamma delta T cells reduced expression of CCR1
      and CCR5 at disease onset only. We conclude that gamma delta T cells contribute
      to the development of EAE by promoting an inflammatory environment that serves to
      accelerate the inflammatory process in the CNS.

PMID- 10657667
TI  - Viral IL-10 gene transfer decreases inflammation and cell adhesion molecule
      expression in a rat model of venous thrombosis.
AB  - Post-thrombotic inflammation probably contributes to chronic venous
      insufficiency, and little effective treatment exists. IL-10 is an anti
      inflammatory cytokine that previously has been shown to decrease perithrombotic
      inflammation and thrombosis. We investigated in a rat model whether local
      expression of viral IL-10 (vIL-10) in a segment of vein that undergoes thrombosis
      would confer an anti-inflammatory effect and how this effect might be mediated.
      Rats underwent inferior vena cava isolation, cannulation, and instillation of
      saline or adenovirus encoding either beta-galactosidase or vIL-10. Two days after
      transfection, thrombosis was induced, 2 days after this the rats underwent
      gadolinium (Gd)-enhanced magnetic resonance venography exam, and the vein
      segments were harvested. Tissue transfection was confirmed by either RT-PCR of
      vIL-10 or positive 5-bromo-4-chloro-3-indolyl beta-d-galactopyranoside (X-Gal)
      staining. vIL-10 significantly decreased both leukocyte vein wall extravasation
      and area of Gd enhancement compared with those in controls, suggesting decreased
      inflammation. Immunohistochemistry demonstrated decreased endothelial border
      staining of P- and E-selectin, while ELISA of vein tissue homogenates revealed
      significantly decreased P- and E-selectin and ICAM-1 levels in the vIL-10 group
      compared with those in controls. Importantly, native cellular IL-10 was not
      significantly different between the groups. However, neither clot weight nor
      coagulation indexes, including tissue factor activity, tissue factor Ag, or von
      Willebrand factor levels, were significantly affected by local vIL-10 expression.
      These data suggest that local transfection of vIL-10 decreases venous thrombosis
      associated inflammation and cell adhesion molecule expression, but does not
      directly affect local procoagulant activity.

PMID- 10657668
TI  - The effect of IL-5 and eotaxin expression in the lung on eosinophil trafficking
      and degranulation and the induction of bronchial hyperreactivity.
AB  - The mechanisms regulating the selective migration and degranulation of
      eosinophils in the asthmatic lung and the subsequent development of airways
      hyperreactivity (AHR) have not been fully delineated. In this investigation, we
      have employed a novel transgene model to facilitate the dissection of the
      contributions of IL-5 and/or eotaxin to eosinophil function in the absence of
      complex tissue signals derived from the allergic lung. Gene transfer of IL-5
      and/or eotaxin to the lungs of naive mice induced a pronounced and selective
      airways eosinophilia, but did not result in eosinophil degranulation or AHR.
      Airways eosinophilia occurred independently of the induction of a blood
      eosinophilia, but was markedly augmented by the coexpression of both cytokines
      and/or by the transient mobilization of eosinophils from the bone marrow by the
      administration of i.v. IL-5. However, for eosinophil degranulation and AHR to
      occur, the inhalation of Ag was required in association with IL-5 and eotaxin
      expression. Investigations in IL-5-deficient mice linked eosinophilia, and not
      solely IL-5 and eotaxin, with the induction of AHR. Furthermore, eosinophil
      degranulation and AHR were dependent on CD4+ T cells. Importantly, this
      investigation shows that IL-5 regulates eosinophilia within the lung as well as
      in the circulation and also amplifies eotaxin-induced chemotaxis in the airway
      compartment. Moreover, the interplay between these cytokines, CD4+ T cells, and
      factors generated by Ag inhalation provides fundamental signals for eosinophil
      degranulation and the induction of AHR.

PMID- 10657669
TI  - Role of p38 mitogen-activated protein kinase in a murine model of pulmonary
      inflammation.
AB  - Early inflammatory events include cytokine release, activation, and rapid
      accumulation of neutrophils, with subsequent recruitment of mononuclear cells.
      The p38 mitogen-activated protein kinase (MAPK) intracellular signaling pathway
      plays a central role in regulating a wide range of inflammatory responses in many
      different cells. A murine model of mild LPS-induced lung inflammation was
      developed to investigate the role of the p38 MAPK pathway in the initiation of
      pulmonary inflammation. A novel p38 MAPK inhibitor, M39, was used to determine
      the functional consequences of p38 MAPK activation. In vitro exposure to M39
      inhibited p38 MAPK activity in LPS-stimulated murine and human neutrophils and
      macrophages, blocked TNF-alpha and macrophage inflammatory protein-2 (MIP-2)
      release, and eliminated migration of murine neutrophils toward the chemokines MIP
      2 and KC. In contrast, alveolar macrophages required a 1000-fold greater
      concentration of M39 to block release of TNF-alpha and MIP-2. Systemic inhibition
      of p38 MAPK resulted in significant decreases in the release of TNF-alpha and
      neutrophil accumulation in the airspaces following intratracheal administration
      of LPS. Recovery of MIP-2 and KC from the airspaces was not affected by
      inhibition of p38 MAPK, and accumulation of mononuclear cells was not
      significantly reduced. When KC was instilled as a proinflammatory stimulus,
      neutrophil accumulation was significantly decreased by p38 MAPK inhibition
      independent of TNF-alpha or LPS. Together, these results demonstrate a much
      greater dependence on the p38 MAPK cascade in the neutrophil when compared with
      other leukocytes, and suggest a means of selectively studying and potentially
      modulating early inflammation in the lung.

PMID- 10657670
TI  - Engagement of the OX-40 receptor in vivo enhances antitumor immunity.
AB  - The OX-40 receptor (OX-40R), a member of the TNFR family, is primarily expressed
      on activated CD4+ T lymphocytes. Engagement of the OX-40R, with either OX-40
      ligand (OX-40L) or an Ab agonist, delivers a strong costimulatory signal to
      effector T cells. OX-40R+ T cells isolated from inflammatory lesions in the CNS
      of animals with experimental autoimmune encephalomyelitis are the cells that
      respond to autoantigen (myelin basic protein) in vivo. We identified OX-40R+ T
      cells within primary tumors and tumor-invaded lymph nodes of patients with cancer
      and hypothesized that they are the tumor-Ag-specific T cells. Therefore, we
      investigated whether engagement of the OX-40R in vivo during tumor priming would
      enhance a tumor-specific T cell response. Injection of OX-40L:Ig or anti-OX-40R
      in vivo during tumor priming resulted in a significant improvement in the
      percentage of tumor-free survivors (20-55%) in four different murine tumors
      derived from four separate tissues. This anti-OX-40R effect was dose dependent
      and accentuated tumor-specific T cell memory. The data suggest that engagement of
      the OX-40R in vivo augments tumor-specific priming by stimulating/expanding the
      natural repertoire of the host's tumor-specific CD4+ T cells. The identification
      of OX-40R+ T cells clustered around human tumor cells in vivo suggests that
      engagement of the OX-40R may be a practical approach for expanding tumor-reactive
      T cells and thereby a method to improve tumor immunotherapy in patients with
      cancer.

PMID- 10657671
TI  - Displacement of linker for activation of T cells from the plasma membrane due to
      redox balance alterations results in hyporesponsiveness of synovial fluid T
      lymphocytes in rheumatoid arthritis.
AB  - The T lymphocytes that reside in the synovium of the inflamed joints in patients
      with rheumatoid arthritis display severe hyporesponsiveness upon antigenic
      stimulation, which is probably due to their constant subjection to high levels of
      oxidative stress. Here we report that the synovial fluid T lymphocytes exert
      severely impaired phosphorylation of the adaptor protein linker for activation of
      T cells (LAT), a crucial component of the TCR-mediated signaling pathways. In
      healthy T lymphocytes, LAT is a membrane-bound protein and becomes phosphorylated
      by zeta-associated protein of 70 kDa (ZAP-70) upon TCR engagement. The molecular
      basis underlying the deficient phosphorylation of LAT and consequently the
      hyporesponsiveness of the synovial fluid T lymphocytes lies in the membrane
      displacement of LAT. We demonstrate that the subcellular localization of LAT is
      sensitive to changes in the intracellular levels of the antioxidant glutathione.
      The membrane anchorage of LAT, and consequently the phosphorylation of LAT and
      the cellular activation of the synovial fluid T lymphocytes upon TCR engagement,
      is restored in synovial fluid T lymphocytes after supplementation of the
      intracellular glutathione levels with N-acetyl-l -cysteine. These data suggest a
      role for the membrane displacement of LAT in the hyporesponsiveness of the
      synovial fluid T lymphocytes as a consequence of oxidative stress.

PMID- 10657672
TI  - Leukemia inhibitory factor, oncostatin M, IL-6, and stem cell factor mRNA
      expression in human thymus increases with age and is associated with thymic
      atrophy.
AB  - The roles that thymus cytokines might play in regulating thymic atrophy are not
      known. Reversing thymic atrophy is important for immune reconstitution in adults.
      We have studied cytokine mRNA steady-state levels in 45 normal human (aged 3 days
      to 78 years) and 34 myasthenia gravis thymuses (aged 4 to 75 years) during aging,
      and correlated cytokine mRNA levels with thymic signal joint (sj) TCR delta
      excision circle (TREC) levels, a molecular marker for active thymopoiesis. LIF,
      oncostatin M (OSM), IL-6, M-CSF, and stem cell factor (SCF) mRNA were elevated in
      normal and myasthenia gravis-aged thymuses, and correlated with decreased levels
      of thymopoiesis, as determined by either decreased keratin-positive thymic
      epithelial space or decreased thymic sjTRECs. IL-7 is a key cytokine required
      during the early stages of thymocyte development. Interestingly, IL-7 mRNA
      expression did not fall with aging in either normal or myasthenia gravis
      thymuses. In vivo administration of LIF, OSM, IL-6, or SCF, but not M-CSF, i.p.
      to mice over 3 days induced thymic atrophy with loss of CD4+, CD8+ cortical
      thymocytes. Taken together, these data suggest a role for thymic cytokines in the
      process of thymic atrophy.

PMID- 10657673
TI  - Variable expression of pathogenesis-related protein allergen in mountain cedar
      (Juniperus ashei) pollen.
AB  - Allergic diseases have been increasing in industrialized countries. The
      environment is thought to have both direct and indirect modulatory effects on
      disease pathogenesis, including alterating on the allergenicity of pollens.
      Certain plant proteins known as pathogenesis-related proteins appear to be up
      regulated by certain environmental conditions, including pollutants, and some
      have emerged as important allergens. Thus, the prospect of environmentally
      regulated expression of plant-derived allergens becomes yet another potential
      environmental influence on allergic disease. We have identified a novel
      pathogenesis-related protein allergen, Jun a 3, from mountain cedar (Juniperus
      ashei) pollen. The serum IgE from patients with hypersensitivity to either
      mountain cedar or Japanese cedar were shown to bind to native and recombinant Jun
      a 3 in Western blot analysis and ELISA. Jun a 3 is homologous to members of the
      thaumatin-like pathogenesis-related (PR-5) plant protein family. The amounts of
      Jun a 3 extracted from mountain cedar pollen varied up to 5-fold in lots of
      pollen collected from the same region in different years and between different
      regions during the same year. Thus, Jun a 3 may contribute not only to the
      overall allergenicity of mountain cedar pollen, but variable levels of Jun a 3
      may alter the allergenic potency of pollens produced under different
      environmental conditions.

PMID- 10657674
TI  - CD47 engagement inhibits cytokine production and maturation of human dendritic
      cells.
AB  - Upon encounter with bacterial products, immature dendritic cells (iDCs) release
      proinflammatory cytokines and develop into highly stimulatory mature DCs. In the
      present study, we show that human monocyte-derived DCs functionally express the
      CD47 Ag, a thrombospondin receptor. Intact or F(ab')2 of CD47 mAb suppress
      bacteria-induced production of IL-12, TNF-alpha, GM-CSF, and IL-6 by iDCs. 4N1K,
      a peptide derived from the CD47-binding site of thrombospondin, also inhibits
      cytokine release. The inhibition of IL-12 and TNF-alpha is IL-10-independent
      inasmuch as IL-10 production is down-modulated by CD47 mAb and blocking IL-10 mAb
      fails to restore cytokine levels. CD47 ligation counteracts the phenotypic and
      functional maturation of iDCs in that it prevents the up-regulation of
      costimulatory molecules, the loss of endocytic activity, and the acquisition of
      an increased capacity to stimulate T cell proliferation and IFN-gamma production.
      Interestingly, regardless of CD47 mAb treatment during DC maturation, mature DC
      restimulated by soluble CD40 ligand and IFN-gamma, to mimic DC/T interaction,
      produce less IL-12 and more IL-18 than iDCs. Finally, CD47 ligation on iDCs does
      not impair their capacity to phagocytose apoptotic cells. We conclude that
      following exposure to microorganisms, CD47 ligation may limit the intensity and
      duration of the inflammatory response by preventing inflammatory cytokine
      production by iDCs and favoring their maintenance in an immature state.

PMID- 10657675
TI  - Modulation of NF-kappa B activity and apoptosis in chronic lymphocytic leukemia B
      cells.
AB  - Chronic lymphocytic leukemia (CLL) is an indolent malignancy of CD5+ B
      lymphocytes. CLL cells express CD40, a key regulator of B cell proliferation,
      differentiation, and survival. In nonmalignant B cells, CD40 ligation results in
      nuclear translocation and activation of NF-kappaB proteins. Based on observations
      that in some CLL cases, the tumor cells express both CD40 and its ligand, CD154
      (CD40 ligand), we proposed a model for CLL pathogenesis due to CD40 ligation
      within the tumor. To evaluate this issue, we used freshly isolated CLL B cells to
      examine constitutive and inducible NF-kappaB activity by electrophoretic mobility
      shift assay. We consistently observed high levels of nuclear NF-kappaB-binding
      activity in unstimulated CLL B cells relative to that detected in nonmalignant
      human B cells. In each case examined, CD40 ligation further augmented NF-kappaB
      activity and prolonged CLL cell survival in vitro. The principle NF-kappaB
      proteins in stimulated CLL cells appear to be quite similar to those in
      nonmalignant human B cells and include p50, p65, and c-Rel. In a CD154-positive
      case, blocking CD154 engagement by mAb to CD154 resulted in inhibition of NF
      kappaB activity in the CLL cells. The addition of anti-CD154 mAb resulted in
      accelerated CLL cell death to a similar degree as was observed in cells exposed
      to dexamethasone. These data indicate that CD40 engagement has a profound
      influence on NF-kappaB activity and survival in CLL B cells, and are consistent
      with a role for CD154-expressing T and B cells in CLL pathogenesis. The data
      support the development of novel therapies based on blocking the CD154-CD40
      interaction in CLL.

PMID- 10657676
TI  - Mutational analysis of the superantigen staphylococcal exfoliative toxin A (ETA).
AB  - Exfoliative toxin A (ETA) is known to be a causative agent of staphylococcal
      scalded skin syndrome (SSSS). Although relatively little is known about exactly
      how the exfoliative toxins (ETs) cause SSSS, much has been discovered recently
      that may help elucidate the mechanism(s) by which ETA exhibits activities such as
      lymphocyte mitogenicity and epidermolytic activity. Here, we have shown that
      highly purified ETA does have T lymphocyte mitogenic activity in that wild-type
      ETA induced T cell proliferation whereas several single amino acid mutants lacked
      significant activity. Neither wild-type ETA nor any single amino acid mutants
      were proteolytic for a casein substrate, yet esterase activity was detected in
      wild-type ETA and several mutants, but eliminated in other mutants. A mutation in
      aa 164 (Asp to Ala) showed a 9-fold increase in esterase activity as well.
      Finally, we correlated esterase activity with epidermolytic activity. All mutants
      that lost esterase activity also lost epidermolytic activity. Conversely, mutants
      that retained esterase activity also retained exfoliative activity, implicating
      serine protease or serine protease-like activity in the causation of SSSS.
      Moreover, the mutants that displayed markedly reduced T cell superantigenic
      activity retained their epidermolytic activity (although some of these mutants
      required higher doses of toxin to cause disease), which suggests an ancillary
      role for this activity in SSSS causation.

PMID- 10657677
TI  - Resection of solid tumors reverses T cell defects and restores protective
      immunity.
AB  - We have previously reported that CTL were demonstrable early after inoculation of
      CMS5 fibrosarcoma cells, but that they disappeared within 3 wk. These mice were
      unable to reject a challenge with CMS5 tumor cells. Other studies demonstrated
      cell surface phenotype and signaling abnormalities of cells within the spleen.
      Since we assumed that such an environment would make it more difficult to elicit
      antitumor immune responses via immunotherapy, we asked whether resection of the
      tumor could reverse these abnormalities. Although early after tumor cell
      inoculation tumor resection leads to the development of immunity, the effect at
      late time points has not been studied critically. To test this, mice were
      inoculated s.c. with CMS5 cells and after 28 days the tumors were resected. We
      observed a gradual normalization of the cellular phenotype of the spleen. In
      particular, there was a decrease in the number of Mac1+/Gr1(high) cells and an
      increase in the number of CD3+ cells in the spleen within 24-48 h of tumor
      resection. By day 10, these values were normal. Levels of p56lck increased as
      well. The functional implications of these changes were illustrated by the
      reduced growth rate or the complete rejection of a challenge of tumor cells in
      the resected mice. Both CD4+ and CD8+ cells were involved in the restoration of
      tumor immunity. Our results suggested that tumor resection not only led to the
      reversal of immune suppression, but also unmasked a population of primed T cells
      able to mediate protective immunity.

PMID- 10657678
TI  - Production of IFN-gamma and IL-10 to Shigella invasins by mononuclear cells from
      volunteers orally inoculated with a Shiga toxin-deleted Shigella dysenteriae type
      1 strain.
AB  - Volunteers were orally administered invasive, non-Shiga toxin-producing Shigella
      dysenteriae 1 to establish a challenge model to assess vaccine efficacy. In
      stepwise fashion, four separate groups were given 3 x 10(2), 7 x 10(3), 5 x
      10(4), or 7 x 10(5) CFU. Using PBMC, proliferative responses and cytokine
      production were measured to S. dysenteriae whole-cell preparations and to
      purified recombinant invasion plasmid Ags (Ipa) C and IpaD. Anti-LPS and anti-Ipa
      Abs and Ab-secreting cells were also evaluated. Preinoculation PBMC produced
      considerable quantities of IL-10 and IFN-gamma, probably secreted by monocytes
      and NK cells, respectively, of the innate immune system. Following inoculation,
      PBMC from 95 and 87% of volunteers exhibited an increased production of IFN-gamma
      and IL-10, respectively, in response to Shigella Ags. These increases included
      responses to IpaC and IpaD among those volunteers receiving the lowest inoculum.
      No IL-4 or IL-5 responses were detected. Whereas there were no Ab or Ab-secreting
      cell responses in volunteers receiving the lowest inoculum, other dose groups had
      moderate to strong anti-LPS and anti-Ipa responses. These results suggest that in
      humans, type 1 responses play an important role in mucosal and systemic immunity
      to S. dysentariae 1.

PMID- 10657679
TI  - IL-1 beta protects human chondrocytes from CD95-induced apoptosis.
AB  - This study addresses the effects of IL-1 beta on apoptosis induced by agonistic
      anti-CD95 (Fas) Ab. IL-1 beta inhibited anti-CD95 Ab-induced apoptosis in all
      preparations of normal human articular chondrocytes tested. Inhibitors of nitric
      oxide synthase or cyclooxygenase did not influence the protective effect of IL-1
      beta, indicating that nitric oxide and PGs were not involved in the modulation of
      CD95-induced apoptosis. However, when the IL-1 beta-dependent induction of NF
      kappa B was inhibited, the antiapoptotic effect of IL-1 beta was partially
      reversed, suggesting that NF-kappa B-mediated gene activation is part of the
      protective mechanism. In addition, IL-1 beta significantly increased the
      expression of Bcl-2. The protein tyrosine kinase inhibitor herbimycin A
      completely eliminated the protective effect of IL-1 beta on CD95-induced
      apoptosis. These findings suggest that IL-1 beta modulates the CD95 death cascade
      in chondrocytes by mechanisms that involve tyrosine phosphorylation events and NF
      kappa B-dependent gene activation.

PMID- 10657680
TI  - Clonotype analysis of human alloreactive T cells: a novel approach to studying
      peripheral tolerance in a transplant recipient.
AB  - The recognition of allo-MHC and associated peptides on the surface of graft
      derived APC by host T cells (direct pathway allorecognition) plays an important
      role in acute rejection after organ transplantation. However, the status of the
      direct pathway T cells in stable long term transplants remains unclear. To detect
      alloreactive T cell clones in PBL and the allograft during the transplant
      tolerance, we utilized RT-PCR instead of functional assays, which tend to
      underestimate their in vivo frequencies. We established alloreactive CD4+ and
      CD8+ T cell clones from peripheral blood sampled during the stable tolerance
      phase of a patient whose graft maintained good function for 9 years, 7 without
      immunosuppression. We analyzed the sequence of TCR Vbeta and Valpha genes and
      made clonotype-specific probes that allowed us to detect each clone in peripheral
      blood or biopsy specimens obtained during a 1-year period before and after the
      rapid onset of chronic rejection. We found an unexpectedly high level of donor
      HLA-specific T cell clonotype mRNA in peripheral blood during the late tolerance
      phase. Strong signals for two CD4+ clonotypes were detected in association with
      focal T cell infiltrates in the biopsy. Chronic rejection was associated with a
      reduction in direct pathway T cell clonotype mRNA in peripheral blood and the
      graft. Our data are inconsistent with the hypothesis that direct pathway T cells
      are involved only in early acute rejection events and suggest the possibility
      that some such T cells may contribute to the maintenance of peripheral tolerance
      to an allograft.

PMID- 10657681
TI  - Successful TCR-based immunotherapy for autoimmune myocarditis with DNA vaccines
      after rapid identification of pathogenic TCR.
AB  - The identification of TCRs of autoimmune disease-inducing T cells within a short
      period of time is a key factor for designing TCR-based immunotherapy during the
      course of the disease. In this study, we show that experimental autoimmune
      carditis-associated TCRs, Vbeta8.2 and Vbeta10, were determined by
      complementarity-determining region 3 (CDR3)-spectratyping analysis and subsequent
      sequencing of the CDR3 region of spectratype-derived TCR clones. Immunotherapy
      targeting both Vbeta8.2 and Vbeta10 TCRs using mAbs and DNA vaccines
      significantly reduced the histological severity of experimental autoimmune
      carditis and completely suppressed the inflammation in some animals. Since
      depletion or suppression of one of two types of effector cells does not improve
      the severity of the disease significantly, combined TCR-based immunotherapy
      should be considered as a primary therapy for T cell-mediated autoimmune
      diseases. TCR-based immunotherapy after rapid identification of autoimmune
      disease-associated TCRs by CDR3 spectratyping can be applicable, not only to
      animal, but also to human autoimmune diseases whose pathomechanism is poorly
      understood.

PMID- 10657682
TI  - Can adverse neonatal experiences alter brain development and subsequent behavior?
AB  - Self-destructive behavior in current society promotes a search for
      psychobiological factors underlying this epidemic. Perinatal brain plasticity
      increases the vulnerability to early adverse experiences, thus leading to
      abnormal development and behavior. Although several epidemiological
      investigations have correlated perinatal and neonatal complications with abnormal
      adult behavior, our understanding of the underlying mechanisms remains
      rudimentary. Models of early experience, such as repetitive pain, sepsis, or
      maternal separation in rodents and other species have noted multiple alterations
      in the adult brain, correlated with specific behavioral phenotypes depending on
      the timing and nature of the insult. The mechanisms mediating such changes in the
      neonatal brain have remained largely unexplored. We propose that lack of N-methyl
      D-aspartate (NMDA) receptor activity from maternal separation and sensory
      isolation leads to increased apoptosis in multiple areas of the immature brain.
      On the other hand, exposure to repetitive pain may cause excessive
      NMDA/excitatory amino acid activation resulting in excitotoxic damage to
      developing neurons. These changes promote two distinct behavioral phenotypes
      characterized by increased anxiety, altered pain sensitivity, stress disorders,
      hyperactivity/attention deficit disorder, leading to impaired social skills and
      patterns of self-destructive behavior. The clinical important of these mechanisms
      lies in the prevention of early insults, effective treatment of neonatal pain and
      stress, and perhaps the discovery of novel therapeutic approaches that limit
      neuronal excitotoxicity or apoptosis.

PMID- 10657683
TI  - Prediction of respiratory distress syndrome by the level of pulmonary surfactant
      protein A in cord blood sera.
AB  - The purpose of this study was to determine the utility of measuring the level of
      pulmonary surfactant protein A (SP-A) in cord blood sera to predict for
      respiratory distress syndrome (RDS). SP-A levels in cord blood sera from 48
      infants born at gestational ages < 32 weeks were measured by a sandwich ELISA
      system. Mean value of SP-A in cord blood was 5.8 ng/ml in cases with RDS and 15.1
      ng/ml in those without RDS (p = 0.002). The best cut-off point of cord blood SP-A
      to predict RDS was determined as 10 ng/ml. The sensitivity and the specificity of
      the cut-off point for predicting RDS were 81 and 76%, respectively. Multivariate
      regression analysis showed that high SP-A level in cord blood, premature rupture
      of the membranes longer than 24 h and heavy birth weight were all significantly
      related to the non-RDS outcome.

PMID- 10657684
TI  - Missense mutations in norrie disease gene are not associated with advanced stages
      of retinopathy of prematurity in Kuwaiti arabs.
AB  - Retinopathy of prematurity (ROP) is a disease characterized by retinal
      neovascularization, possibly leading to retinal detachment and finally blindness.
      In a proportion of ROP cases, the disease progresses to advanced stages despite
      rigorous intervention. Missense mutations of the Norrie disease (ND) gene have
      been associated with progression of the disease in ROP cases from the USA. We
      have investigated the presence of ND gene mutations in 102 premature newborns of
      Kuwaiti Arab origin to replicate this finding in a different population/racial
      group. 56 (55%) of these newborns had normal eyes and served as controls. In 35
      (34%) cases, the ROP regressed spontaneously during stage 1-3. In 11 (11%) cases,
      ROP progressed to advanced stages. A PCR-RFLP method was used to detect the
      mutations in exon 3 of the ND gene and confirmed the DNA sequence by direct
      sequencing of the PCR product. The [R121W] mutation of the ND gene was not
      detected in the premature newborns screened from our Kuwaiti population/group.
      For the second mutation [L108P], a genotype (PP) was present in 98% of the
      premature newborns screened and only in 1 of 56 normal infants was the (LL)
      genotype detected. Our population is genetically homogenous in that genotype (PP)
      was detected at codon 108 in almost all controls and ROP cases. We did not find
      an association between the presence or absence of missense mutations of the ND
      gene and the risk of severe ROP.

PMID- 10657685
TI  - Effect of cisapride on acid gastro-oesophageal reflux during treatment with
      caffeine.
AB  - About 50% of preterm infants and neonates receiving methylxanthines for
      respiratory stimulation will develop a pathological gastro-oesophageal reflux
      (GOR) pattern. In the face of potential GOR-related complications the effect of a
      concomitant treatment with a prokinetic agent, such as cisapride, should be
      evaluated. In this study 32 formerly preterm infants were studied simultaneously
      by 24-hour oesophageal pH monitoring and cardio-respirogram before the presumed
      end of caffeine treatment. In 14 of these infants a reflux index (RI; percentage
      of recording time) of more than 4% could be detected (pH <4). Ten of them were
      treated orally with cisapride (0. 2 mg/kg t.i.d.). Data of pH monitoring, cardio
      respirogram and caffeine serum concentrations were obtained before and 5 days
      after introducing cisapride. The RI and the frequency of GOR decreased
      significantly with cisapride. The steady-state serum concentrations of caffeine
      were not influenced by cisapride and the extent of periodic breathing remained
      unchanged. In conclusion, cisapride has a positive influence on GOR parameters
      during caffeine treatment without impairing the oral bioavailability or
      therapeutic effect of caffeine.

PMID- 10657686
TI  - Essential fatty acids and their long-chain polyunsaturated metabolites in
      maternal and cord plasma triglycerides during late gestation.
AB  - The fatty acid composition of plasma lipids was determined in 41 pairs of mothers
      and their term infants at time of birth (38-42 postmenstrual weeks) by high
      resolution capillary gas-liquid chromatography. Linoleic and alpha-linolenic
      acids were found at smaller concentrations in cord than in maternal
      triglycerides, in contrast to strikingly higher proportions of their long-chain
      polyunsaturated metabolites (LC-PUFA), which indicates a preferential
      maternofetal transport for certain physiologically important LC-PUFA. While no
      significant gestational age-dependent changes occurred in maternal plasma
      triglycerides, the values for most of the fetal long-chain n-3 metabolites
      increased with the duration of gestation, possibly reflecting an increased
      transplacental fatty acid passage during late pregnancy or a maturation of
      desaturation in the fetal liver.

PMID- 10657687
TI  - Urinary nitrite excretion after prophylactic intravenous immunoglobulin in
      premature infants.
AB  - AIMS: To investigate the correlation between the prophylactic administration of
      intravenous immunoglobulin (IVIG) to preterm infants and urinary nitrite levels,
      which can be utilized as an index of endogenous nitric oxide (NO) formation, and
      to determine if NO formation plays a role in both therapeutic and adverse effects
      of IVIG. METHODS: 28 healthy preterm infants were included in this prospective
      study. They had a mean gestational age of 29.4 +/- 2.2 weeks and weight of 1,387
      +/- 371 g. Prophylactic IVIG infusion at a dose of 0.5 g/kg/day was administered
      when they were 3-10 days old. Urine samples of the neonates were obtained for
      analysis on days 1, 2 and 3 after IVIG administration as well as 1 day before.
      Urinary nitrite levels obtained in the subjects were normalized for urinary
      creatinine concentrations. RESULTS: The mean urinary nitrite levels were: 2.77 +/
      1.66 micromol/mmol creatinine before IVIG administration; 4.33 +/- 3.88
      micromol/mmol creatinine on the 1st day of IVIG; 3.77 +/- 2.73 micromol/mmol
      creatinine on the 2nd day, and 3.64 +/- 3.28 micromol/mmol creatinine on the 3rd
      day. There was a significant increase in urinary nitrite levels between before
      and after IVIG administration. There was no statistical difference in urinary
      nitrate levels between days 1, 2 and 3 after IVIG administration. CONCLUSION: We
      demonstrated that urinary nitrite excretion is significantly elevated in preterm
      infants after prophylactic IVIG administration and this result suggests that
      endogenous NO formation may play an important role in both the therapeutic and
      adverse effects of IVIG.

PMID- 10657688
TI  - Endothelin concentrations in preterm infants treated with human recombinant
      erythropoietin.
AB  - BACKGROUND: Increased endothelin-1 (ET-1) production following recombinant
      erythropoietin (Epo) administration is a presumed etiology for the hypertension
      reported in some adults. It is unknown whether Epo has similar effects in preterm
      infants. METHODS: Serum ET-1 and Epo concentrations were measured prior to study,
      and following the second and third doses in 20 preterm infants receiving
      intravenous (IV) or subcutaneous (SC) Epo. Blood pressures were monitored prior
      to Epo administration and during the first, second, and third dose. RESULTS:
      Infants (963 +/- 54 g birth weight, 27.4 +/- 0.6 weeks gestational age, 18 +/- 3
      days of life; mean +/- SEM) had baseline Epo concentrations of 5.5 +/- 1.3 mU/ml
      and ET-1 concentrations below the lower limits of detection (<1 pg/ml). Epo
      concentrations were 1,848 +/- 274 and 1,672 +/- 295 mU/ml following the second
      and third IV dose, respectively, while Epo concentrations were 420 +/- 92 and 290
      +/- 35 mU/ml after the second and third SC dose, respectively (p < 0.005, SC
      versus IV). ET-1 concentrations remained below the limits of detection in all but
      6 infants, whose concentrations were <3.3 pg/ml. Blood pressures did not increase
      above baseline in either group during the study period. CONCLUSION: Despite the
      wide range of Epo concentrations measured, no correlation was observed between
      Epo concentrations, ET-1 concentrations, and blood pressure during the 1-week
      study period. The long-term effects of Epo on ET-1 concentrations and blood
      pressure in preterm infants require further study.

PMID- 10657689
TI  - Effect of SOD-mimetic Fe-chlorine e6-Na on the level of brain lipid peroxide of
      rat fetal brains exposed to reactive oxygen species leading to intrauterine
      growth retardation.
AB  - The influence of oxidative stress in rat brain and liver on intrauterine growth
      retardation (IUGR) in rat fetuses was examined. Twenty pregnant Wistar rats were
      used. On the 15th day of pregnancy, uterine artery and vein were ligated
      bilaterally using a modified Wigglesworth method. On the 21st day of pregnancy,
      the fetuses were delivered by hysterotomy. Fetal blood was collected by cardiac
      puncture. Fetal brain and liver were removed for the analysis of lipid peroxide.
      Sham surgical operations were performed in the control rats. Within the ligated
      group, a superoxide dismutase mimicking substance, Fe-chlorine e6-Na (FeCNa), was
      injected intraperitoneally once a day from day 15 of gestation to day 20. Fetal
      blood, brain, and liver were stored at -70 degrees C until analysis. Control rats
      received an equivalent volume of saline. In growth-retarded fetuses, both
      superoxide released from erythrocytes and brain lipid peroxide showed
      significantly higher levels, but not superoxide dismutase in erythrocytes and
      liver lipid peroxide. These changes were alleviated by injection of superoxide
      dismutase-mimicking substance, FeCNa. Rat fetuses with intrauterine growth
      retardation suffered from a significant oxidative stress in utero. The increase
      in reactive oxygen species was alleviated by an injection of FeCNa.

PMID- 10657690
TI  - Effects of combined superoxide dismutase and catalase on somatosensory evoked
      potentials and neuropathologic changes in asphyxiated newborn lambs.
AB  - The lamb model of neonatal asphyxia has been used to describe changes in cerebral
      blood flow, oxygen metabolism and mitochondrial function following a standard
      asphyxial insult. In addition, abnormalities in cerebral hemodynamics and
      mitochondrial function after asphyxia have been associated with injury mediated
      by oxygen free radicals. The purpose of this investigation was to describe
      changes in brainstem auditory and somatosensory evoked potentials and pathologic
      changes after asphyxia in the newborn lamb. In addition, the hypothesis that
      treatment with the oxygen free radical scavenging enzymes superoxide dismutase
      and catalase would enhance postasphyxia recovery of evoked potentials and
      ameliorate pathologic injury was tested. Electrophysiologic and pathologic
      abnormalities after asphyxia were demonstrated, but treatment with oxygen radical
      scavengers had no effect on these abnormalities.

PMID- 10657691
TI  - Maturational changes in endothelium-derived nitric oxide-mediated relaxation of
      ovine pulmonary arteries.
AB  - Endothelium-derived nitric oxide (EDNO) modulates the responses of pulmonary
      vasculature. The present study was designed to determine EDNO-mediated responses
      of pulmonary arteries (PA) of term fetal, newborn, and adult sheep. Vessel rings
      were suspended in organ chambers and their isometric tension was recorded. In
      vessels preconstricted with endothelin-1, acetylcholine had no effect on fetal PA
      but caused a greater endothelium-dependent relaxation in adult PA than in newborn
      PA. In vessels without endothelium, nitric oxide and 8-bromo-cGMP caused greater
      relaxation in adult PA than in newborn PA while causing the least relaxation in
      fetal PA. Acetylcholine had no effect on cGMP content in fetal PA but caused a
      greater endothelium-dependent increase in cGMP content in adult PA than in
      newborn PA. In vessels without endothelium, nitric oxide caused a smaller
      increase in cGMP content of fetal PA than of newborn PA while causing the
      greatest increase in cGMP of adult PA. These results demonstrate an age-dependent
      increase in EDNO-mediated responses of ovine pulmonary arteries. A change in
      receptor and/or receptor coupling, in soluble guanylate cyclase activity, and in
      cGMP responsiveness of vascular smooth muscle may contribute to the phenomenon.

PMID- 10657692
TI  - Effect of fasting on hepatic lipase activity in the liver of developing rats.
AB  - The effect of fasting on hepatic lipase was studied during postnatal development
      in the rat. It was found that fasting produced a significant decrease in hepatic
      lipase only in neonatal (1-day-old) and adult (60-day-old) rats. We studied the
      effect of fasting on the distribution of hepatic lipase between extracellular
      (heparin-releasable) and intracellular (liver-retained or residual) compartments
      in perfused livers, and on the secretion of hepatic lipase by isolated
      hepatocytes. Fasting had similar effects in neonates and adults: it decreased
      both the heparin-releasing and the residual activities in perfused livers, and
      also decreased the rate of hepatic lipase secretion by isolated hepatocytes.
      Finally, the effect of fasting on hepatic lipase mRNA relative abundance in
      developing rat livers was determined. No difference was observed among the groups
      studied. It is concluded that the mechanisms involved in the effect of fasting on
      hepatic lipase appear to be similar in neonates and adult animals and may involve
      the post-translational processing of the enzyme.

PMID- 10657693
TI  - Mechanisms of progenitor maturation are conserved in the striatum and cortex.
AB  - We recently reported that developmental changes in the expression of epidermal
      growth factor receptors (EGFRs) by cortical progenitor cells regulate their fate
      and migration. Higher levels of EGFRs are expressed by later embryonic progenitor
      cells and are required for several responses to EGF family ligands, including
      astrocyte differentiation and migration. Progenitor cells in the ganglionic
      eminence (GE), the forerunner of the striatum, also exhibit a developmental
      increase in EGFR expression. The striatum differs from the cortex in several
      respects, including cytoarchitecture, the timing of changes in EGFRs, and the
      level of transforming growth factor-alpha (TGFalpha) expression. To determine
      whether signaling mediated by EGFRs in GE progenitors regulates their fate and
      migration as observed in cortex, we used a retrovirus to increase EGFR expression
      in embryonic GE progenitor cells prematurely. As in cortex, premature elevation
      of EGFRs promoted the departure of GE progenitors from the ventricular zone and
      their differentiation into astrocytes. Settling patterns of infected cells in the
      striatum, however, differed from the patterns observed in cortex. In addition,
      the extent of premature astrocyte differentiation reached similar levels in
      striatal cells, even in the presence of greater endogenous TGFalpha. These
      findings suggest that additional factors play an important role in modulating
      EGFR-mediated changes in cell fate. Together with previous studies in cortex,
      these observations in the striatum indicate that a conserved mechanism involving
      developmental changes in EGFR expression regulates cell fate and the timing of
      migration.

PMID- 10657694
TI  - Expression of the EGF receptor family members ErbB2, ErbB3, and ErbB4 in germinal
      zones of the developing brain and in neurosphere cultures containing CNS stem
      cells.
AB  - The epidermal growth factor receptor family consists of four related tyrosine
      kinases: the epidermal growth factor receptor (EGF-R or ErbB), ErbB2, ErbB3, and
      ErbB4. These receptors are capable of extensive cross-activation upon the binding
      of their ligands - the EGF family of peptides for EGF-R and the neuregulins for
      ErbB3 and ErbB4. Since EGF-R is expressed by proliferating cells in the central
      nervous system (CNS), including multipotent CNS stem cells, we examined the
      expression of ErbB2, ErbB3 and ErbB4 in the germinal epithelia of the developing
      rat brain using in situ hybridization. ErbB2 and ErbB4 mRNAs were widely
      distributed within the germinal zones as early as E12. However, as development
      proceeded, ErbB2 mRNA was mainly present within the layers of cells immediately
      adjacent to the ventricular surface - the ventricular zone, while ErbB4 mRNA was
      predominantly expressed by subventricular zone cells, in the regions where these
      specialized germinal epithelia were present. ErbB3 mRNA distribution within
      germinal epithelia was more restricted, primarily confined to the diencephalon
      and rostral midbrain. Cultured neurospheres, which contain CNS stem cells,
      expressed ErbB2, ErbB4 and, to a lesser extent, ErbB3 protein as demonstrated by
      Western blot analysis. This expression declined during following differentiation.
      Heregulin-beta1, a neuregulin, had no effect on the proliferative capacity of
      neurospheres. Overall, our results indicate that ErbB2, ErbB3 and ErbB4 may play
      important and distinct roles in the genesis of the CNS. However, our in vitro
      data do not support a role for neuregulins in proliferation, per se, of CNS stem
      cells.

PMID- 10657695
TI  - Calcium dynamics of neocortical ventricular zone cells.
AB  - Cell-cell signaling within the neocortical ventricular zone (VZ) has been shown
      to influence the proliferation of VZ precursor cells and the subsequent
      differentiation and fate of postmitotic neurons. Calcium (Ca(2+)), a ubiquitous
      second messenger implicated in the regulation of many aspects of development, may
      play a role in these signaling events. Accordingly, we have examined the
      spatiotemporal patterns of spontaneous intracellular free Ca(2+) ([Ca(2+)](i))
      fluctuations of cells within the intact neocortical VZ. Previous observations
      have demonstrated that similar patterns of spontaneous [Ca(2+)](i) increase occur
      in both proliferative and postmitotic cortical cells, suggesting that they may be
      mechanistically similar. Our results suggest that the changes in [Ca(2+)](i) in
      VZ cells and cortical plate neurons are likely triggered by different mechansims,
      and imply that similar changes in [Ca(2+)](i) may underlie different signaling
      events during distinct phases of neocortical development.

PMID- 10657696
TI  - Gap junction-mediated coupling in the postnatal anterior subventricular zone.
AB  - We have studied gap junctional communication in the anterior subventricular zone
      (SVZa) of postnatal rodents, revealed by intercellular diffusion of dyes in brain
      slices. Extensive intercellular dye spread was evident in the SVZa. Coupling was
      not uniform, being characteristically larger in the outer borders of this layer,
      overlapping the previously described peripheral zone of concentration of S-phase
      cells. Intercellular spread of the dye was unaffected by acidification, but
      totally blocked by high Ca(2+) concentrations. In addition, application of some
      known uncoupling agents as carbenoxolone and halothane led to a marked reduction
      of dye spread in the SVZa. Our results demonstrate the presence of dye coupling
      mediated by gap junctions in the SVZa. Furthermore, the spatial organization of
      dye coupling in these slices strongly suggests the existence of cell compartments
      in the postnatal SVZa.

PMID- 10657697
TI  - Exploiting the dynamics of S-phase tracers in developing brain: interkinetic
      nuclear migration for cells entering versus leaving the S-phase.
AB  - Two S-phase markers for in vivo studies of cell proliferation in the developing
      central nervous system, tritiated thymidine ((3)H-TdR) and bromodeoxyuridine
      (BUdR), were compared using double-labeling techniques in the developing mouse
      cortex at embryonic day 14 (E14). The labeling efficiencies and detectability of
      the two tracers were approximately equivalent, and there was no evidence of
      significant tracer interactions that depend on order of administration. For both
      tracers, the loading time needed to label an S-phase cell to detectability is
      estimated at <0.2 h shortly after the injection of the label, but, as the
      concentration of the label falls, it increases to approximately 0.65 h after
      about 30 min. Thereafter, cells that enter the S-phase continue to become
      detectably labeled for approximately 5-6 h. The approximate equivalence of these
      two tracers was exploited to observe directly the numbers and positions of nuclei
      entering (labeled with the second tracer only) and leaving (labeled with the
      first tracer only) the S-phase. As expected, the numbers of nuclei entering and
      leaving the S-phase both increased as the interval between the two injections
      lengthened. Also, nuclei leaving the S-phase rapidly move towards the ventricular
      surface during G2, but, unexpectedly, the distribution of the entering nuclei
      does not differ significantly from the distribution of the nuclei in the S-phase.
      This indicates that: (1) the extent and rate of abventricular nuclear movement
      during G1 is variable, such that not all nuclei traverse the entire width of the
      ventricular zone, and (2) interkinetic nuclear movements are minimal during S
      phase.

PMID- 10657698
TI  - Differential response of ventral midbrain and striatal progenitor cells to
      lesions of the nigrostriatal dopaminergic projection.
AB  - In response to injury, progenitor cells in the adult brain can proliferate and
      generate new neurons and/or glia, which may then participate in injury-induced
      compensatory processes. In this study, we explore the ability of young adult mice
      to generate new cells in response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
      (MPTP) lesions, which selectively kill nigrostriatal dopaminergic neurons. Using
      the thymidine analogue 5-bromo-2'-deoxyuridine (BrdU), we labeled dividing cells
      3, 10, and 15 days after MPTP lesion. A robust proliferative response was seen
      specifically in the substantia nigra (SN) and the dorsal striatum 3 days
      postlesion; the response persisted 10-14 days. To explore the fate of
      proliferative cells, we administered BrdU 3 days postlesion and examined the
      phenotype of BrdU(+) cells at various times thereafter, using double
      immunolabeling. In the striatum, nearly all newly-generated cells rapidly
      differentiated into GFAP(+) astrocytes that participated in the injury-induced
      glial reaction. In the SN, however, reactive astroglia were not BrdU(+). Some
      midbrain cells co-immunostained for BrdU and Mac-1, a microglial marker. However,
      most BrdU(+) cells in the SN failed to express markers for microglia, astroglia,
      oligodendroglia, or neurons, suggesting that they may remain as uncommitted
      progenitors. Thus, progenitors in the vicinity of the degenerating dopaminergic
      cell bodies respond differently to lesion than progenitors in the vicinity of the
      degenerating axon terminal. Although the putative midbrain progenitors appear
      uncommitted 22 days after their birth, it is possible that they may adopt neural
      or glial fates if allowed to survive longer, or if exposed to exogenous factors.

PMID- 10657699
TI  - Noggin is a negative regulator of neuronal differentiation in developing
      neocortex.
AB  - Bone morphogenetic proteins (BMPs) trigger neuronal differentiation of
      neocortical precursors within the ventricular zone (VZ) [Li et al. (1998): J
      Neurosci 18:8853-8862]. BMP-2/4 protein is concentrated at the VZ surface and
      BMPs rapidly promote the differentiation of neocortical precursors in both
      dissociated cell and explant cultures. Noggin binds to BMP-2/4 with high
      affinity, and prevents binding to cell surface receptors. In the present study,
      we used human recombinant noggin protein to determine whether endogenous BMP-2/4
      triggers neuronal differentiation in dissociated cell culture. We find that
      noggin inhibits the differentiation of neocortical neurons: noggin decreases the
      number of MAP-2- and TUJ1-positive cells after 24 h of treatment, yet has no
      effect on either proliferation or cell survival. Noggin also significantly
      decreases neurite growth of MAP-2-positive cells. In addition, using Western blot
      analysis we show that noggin protein is present in developing cortex at E15.
      These results are consistent with previous results showing that endogenous BMPs
      trigger neuronal differentiation in the neocortical VZ and also indicate that a
      balance of noggin and BMP may regulate the differentiation of neocortical neurons
      in vivo.

PMID- 10657700
TI  - Developmental changes in progenitor cell responsiveness to bone morphogenetic
      proteins differentially modulate progressive CNS lineage fate.
AB  - Although multipotent progenitor cells capable of generating neurons, astrocytes
      and oligodendrocytes are present within the germinal zones of the brain
      throughout embryonic, postnatal and adult life, the different neural cell types
      are generated within discrete temporospatial developmental windows. This might
      suggest that multipotent progenitor cells encounter different signals during each
      developmental stage, thus accounting for separate waves of lineage commitment and
      cellular differentiation. This study demonstrates, however, that progenitor cell
      responses to the same class of signals, the bone morphogenetic proteins (BMPs),
      change during ontogeny, and that these same signals may thus initiate progenitor
      cell elaboration of several different lineages. BMPs promote cell death and
      inhibit the proliferation of early (embryonic day 13, E13) ventricular zone
      progenitor cells. At later embryonic (E16) stages of cerebral cortical
      development, BMPs exhibit a concentration-dependent dissociation of cellular
      actions, with either enhancement of neuronal and astroglial elaboration (at 1-10
      ng/ml) or potentiation of cell death (at 100 ng/ml). Finally, during the period
      of perinatal cortical gliogenesis, BMPs enhance astroglial lineage elaboration.
      By contrast, oligodendroglial lineage elaboration is inhibited by the BMPs at all
      stages. Further, application of the BMP antagonist noggin to cultured progenitors
      promotes the generation of oligodendrocytes, indicating that endogenous BMP
      signaling can actively suppress oligodendrogliogenesis. These observations
      suggest that developmental changes in neural progenitor cell responsiveness to
      the BMPs may represent a novel mechanism for orchestrating context-specific
      cellular events such as lineage elaboration and cellular viability.

PMID- 10657701
TI  - Regulation of neuronal differentiation in human CNS stem cell progeny by leukemia
      inhibitory factor.
AB  - The generation of diverse types of neural cells during development occurs through
      the progressive restriction of the fate potential of neuroepithelial progenitor
      cells. This process is controlled by factors intrinsic and extrinsic to the cell.
      While the effect of extrinsic cues on multipotent stem cells of the murine
      central nervous system (CNS) is becoming clearer, little is known of neural stem
      cells of human origin. We sought to establish the roles played by two cytokines,
      leukemia inhibitory (LIF) and ciliary neurotrophic factor (CNTF), and by nerve
      growth factor (NGF) and platelet-derived growth factor (PDGF) in regulating
      neuronal and astroglial differentiation in cultured embryonic diencephalic human
      stem cells. While NGF did not influence either neuronal or glial formation, PDGF
      surprisingly decreased the percentage of stem cell-generated neurons, an effect
      opposite to that observed in murine progenitors. Furthermore, while we confirmed
      the known ability of LIF and CNTF to support astroglial differentiation, we also
      observed that, in contrast with their murine counterparts, the fraction of CNS
      stem cell-generated neurons in human cultures was enhanced twofold in the
      presence of both cytokines. These findings highlight important differences
      between humans and rodents in regard to the way epigenetic cues regulate the
      function of neural stem cells.

PMID- 10657702
TI  - Precursor cells in the subventricular zone of the adult mouse are actively
      inhibited from differentiating into neurons.
AB  - The adult mouse subventricular zone (SVZ) contains precursor cells capable of
      generating new neurons which populate the olfactory bulb. The SVZ precursors,
      however, appear to be restricted in their capacity to generate neurons in other
      regions of the brain indicating a tight regulation of their differentiation. We
      demonstrate in vitro that explants of SVZ are unable to generate neurons from
      dividing precursors, even though precursors are present and dividing within
      explant cultures. However, when plated as single cells in fibroblast growth
      factor-1 or with no growth factor, approximately 1% of harvested cells gave rise
      to clones containing neurons and astrocytes, indicating that bipotential
      precursors were present in the explants. Inhibitory effects of cell density were
      more directly shown by plating freshly isolated SVZ cells, or explant-derived SVZ
      cells, at increasing cell density. The frequency of neuron-containing wells was
      found to be greatly reduced at higher cell concentrations: >100 cells/well in the
      case of explant-derived cells and >500 cells in the case of freshly isolated
      cells. Thus, it appears that the precursor's ability to generate neurons is
      actively inhibited by paracrine mechanisms which may be mediated by either cell
      cell contact or by short-range factors.

PMID- 10657703
TI  - Selective apoptosis within the rat subependymal zone: a plausible mechanism for
      determining which lineages develop from neural stem cells.
AB  - During development, the output of the subventricular zone (SZ) becomes
      increasingly restricted, yet it still harbors multipotential progenitors. The
      output of the SZ could be gated by selectively eliminating inappropriately
      specified progenitors. Using in situ end-labeling (ISEL) to identify apoptotic
      cells, nearly 60% of the ISEL(+) cells in the juvenile forebrain were localized
      to the SZ. Of these dying cells, at least 9% could be identified as neurons, 4%
      as astrocytes, and 12% as oligodendrocytes. The remainder were negative for the
      stem cell marker nestin, as well as other markers evaluated. To test the
      hypothesis that committed progenitors were under selective pressures, neural
      stem/progenitor cells were allowed to differentiate in vitro in the presence or
      absence of the caspase 3 inhibitor z-DEVD-fmk. DEVD increased neuronal production
      10-fold over control cultures. By contrast, the development of astrocytes and
      oligodendrocytes was not affected. Altogether, these data support the hypothesis
      that selective forces within the postnatal rat forebrain control the types of
      precursors that emerge from the germinal matrix. Furthermore, they suggest that
      different mechanisms control neuronal versus glial cell numbers.

PMID- 10657704
TI  - Caspase regulation of neuronal progenitor cell apoptosis.
AB  - Programmed cell death (apoptosis) of both proliferating neuroblasts and
      postmitotic neurons is essential for normal nervous system development. To study
      the molecular regulation of apoptosis in neuronal progenitor cells, we developed
      a flow cytometric assay capable of distinguishing between viable, apoptotic, and
      necrotic cell populations. Incubation of freshly dissociated telencephalic cells
      from gestational day 12-13 mouse embryos with either cytosine arabinoside (AraC)
      or staurosporine caused a marked increase in the percentage of apoptotic cells.
      Both drugs induced caspase-3 activation, as determined by in vitro cleavage of a
      caspase-3 substrate and immunocytochemical detection of activated caspase-3.
      Treatment of telencephalic cells with the broad caspase inhibitor BAF, blocked
      caspase-3 activation and protected cells against both AraC and staurosporine
      induced apoptotic death. These results indicate that neuronal progenitors possess
      a caspase-dependent apoptotic pathway, the activation of which may regulate
      neuronal progenitor cell numbers in vivo.

PMID- 10657705
TI  - Independent controls for neocortical neuron production and histogenetic cell
      death.
AB  - We estimated the proportion of cells eliminated by histogenetic cell death during
      the first 2 postnatal weeks in areas 1, 3 and 40 of the mouse parietal neocortex.
      For each layer and for the subcortical white matter in each neocortical area, the
      number of dying cells per mm(2) was calculated and the proportionate cell death
      for each day of the 2-week interval was estimated. The data show that cell death
      proceeds essentially uniformly across the neocortical areas and layers and that
      it does not follow either the spatiotemporal gradient of cell cycle progression
      in the pseudostratified ventricular epithelium of the cerebral wall, the source
      of neocortical neurons, or the 'inside-out' neocortical neuronogenetic sequence.
      Therefore, we infer that the control mechanisms of neocortical histogenetic cell
      death are independent of mechanisms controlling neuronogenesis or neuronal
      migration but may be associated with the ingrowth, expansion and a system-wide
      matching of neuronal connectivity.

PMID- 10657706
TI  - Musashi1: an evolutionally conserved marker for CNS progenitor cells including
      neural stem cells.
AB  - In situ detection of neural progenitor cells including stem-like cells is
      essential for studying the basic mechanisms of the generation of cellular
      diversity in the CNS, upon which therapeutic treatments for CNS injuries,
      degenerative diseases, and brain tumors may be based. We have generated rat
      monoclonal antibodies (Mab 14H1 and 14B8) that recognize an RNA-binding protein
      Musashi1, but not a Musashi1-related protein, Musashi2. The amino acid sequences
      at the epitope sites of these anti-Musashi1 Mabs are remarkably conserved among
      the human, mouse, and Xenopus proteins. Spatiotemporal patterns of Musashi1
      immunoreactivity in the developing and/or adult CNS tissues of frogs, birds,
      rodents, and humans indicated that our anti-Musashi1 Mabs reacted with
      undifferentiated, proliferative cells in the CNS of all the vertebrates tested.
      Double or triple immunostaining of embryonic mouse brain cells in monolayer
      cultures demonstrated strong Musashi1 expression in Nestin(+)/RC2(+) cells. The
      relative number of Musashi1(+)/Nestin(+)/RC2(+) cells increased fivefold when
      embryonic forebrain cells were cultured to form 'neurospheres' in which stem-like
      cells are known to be enriched through their self-renewing mode of growth.
      Nestin(+)/RC2(-) cells, which included Talpha1-GFP(+) neuronal progenitor cells
      and GLAST(+) astroglial precursor cells, were also Musashi1(+), as were GFAP(+)
      astrocytes. Young neurons showed a trace of Musashi1 expression. Cells committed
      to the oligodendroglial lineage were Musashi(-). Musashi1 was localized to the
      perikarya of CNS stem-like cells and non-oligodendroglial progenitor cells
      without shifting to cell processes or endfeet, and is therefore advantageous for
      identifying each cell and counting cells in situ.

PMID- 10657708
TI  - Promoter-based isolation and fluorescence-activated sorting of mitotic neuronal
      progenitor cells from the adult mammalian ependymal/subependymal zone.
AB  - Neuronal precursor cells are widespread in the subependyma of the forebrain
      ventricular lining, and may provide a cellular substrate for brain repair. We
      have previously identified and isolated them from fetal brain, by sorting
      forebrain cells transfected with plasmid DNA encoding the gene for green
      fluorescent protein (hGFP), driven by the early neuronal promoter for Talpha1
      tubulin (P/Talpha1). Fetal neuronal precursors were thereby identified and
      harvested with both a high degree of enrichment, and a virtual abolition of glial
      contaminants. We have now extended this approach to include the isolation and
      purification of neuronal progenitors from the adult brain. Dissociates of the
      lateral ventricular wall, that included the combined ependymal/subependymal zone,
      were obtained from 3-month-old adult rats. These cells were cultured and
      transfected with P/Talpha1:hGFP plasmid DNA. Two days later, the cells were
      redissociated, sorted on the basis of Talpha1-driven GFP expression, and
      replated. The majority of these cells expressed the early neuronal proteins Hu
      and TuJ1/betaIII-tubulin upon FACS; within the week thereafter, most matured as
      morphologically-evident neurons, that coexpressed betaIII-tubulin and MAP-2.
      Fewer than 5% expressed astrocytic markers, compared to over half of the cells in
      matched samples that were either not sorted, or sorted after transfection with a
      plasmid bearing the nonfluorescent lacZ gene under the control of P/Talpha1
      tubulin. Thus, the use of a fluorescent transgene under the control of an early
      neuron-selective promoter permits the enrichment of neuronal progenitor cells
      from the adult rat brain, in a form that may allow their heterologous
      implantation.

PMID- 10657707
TI  - Characterization and distribution of a new cell surface marker of neuronal
      precursors.
AB  - In a screen for novel cell surface markers of neuronal progenitors, we recently
      identified mAb 2F7 that recognizes an epitope present on both progenitor cells
      and postmitotic neurons, in the developing CNS and PNS. In the embryonic rat
      telencephalon, the mAb 2F7 epitope is expressed by migratory and postmigratory
      neurons in the developing cerebral cortex, as well as by presumptive neuronal
      progenitor cells of the ventricular zone. In the neonatal forebrain mAb 2F7
      labels postmitotic neurons, including those of the developing cerebral cortex and
      olfactory bulb, as well as the axons of the corpus callosum. While mAb 2F7
      immunoreactivity is present on only a low density of the neuronal progenitor
      cells situated in the anterior part of the subventricular zone, a progressively
      higher proportion of cells forming the rostral migratory stream express this
      epitope. mAb 2F7 labels the surfaces of neurons and neuronal precursors, but not
      mature oligodendrocytes and astrocytes in primary cultures derived from the rat
      neural tube. In vivo, migrating neural crest cells, motor neurons, and axonal
      projections associated with the spinal cord express the mAb 2F7 epitope.
      Immunoblot analyses reveal that the mAb 2F7 epitope resides on several high
      molecular-weight, membrane-associated proteins, and is likely to be composed of N
      linked carbohydrate. These findings suggest that mAb 2F7 recognizes a novel
      epitope that is present on progenitor cells and postmitotic, differentiating
      neurons in the developing mammalian nervous system.

PMID- 10657709
TI  - Regulation of proximal tubule transport by endogenously produced angiotensin II.

PMID- 10657710
TI  - Alterations of arterial function in end-stage renal disease.
AB  - Cardiovascular disease is a major cause of morbidity and mortality in patients
      with end-stage renal disease (ESRD). Epidemiological and clinical studies have
      shown that this is most frequently related to damage of large conduit arteries.
      Macrovascular disease develops rapidly in uremic patients and is responsible for
      the high incidence of ischemic heart disease, sudden death, peripheral artery
      diseases, and congestive heart failure. The most frequent causes of these
      complications are occlusive lesions due to atherosclerosis. Nevertheless,
      atherosclerosis, a disease characterized by the presence of plaques, represents
      only one form of structural response to metabolic and hemodynamic alterations
      which interfere with the process of aging, i.e., arteriosclerosis, characterized
      by dilation/hypertrophy and stiffening of arteries. The vascular complications in
      ESRD are ascribed to two different but associated mechanisms, namely
      atherosclerosis and arteriosclerosis. Whereas the former principally affects the
      conduit function with ischemic lesions being the most characteristic consequence,
      the latter primarily disturbs the cushioning function of large arteries.
      Arteriosclerosis in ESRD patients is characterized by diffuse dilation and
      hypertrophy of large conduit arteries and stiffening of arterial walls and
      represents a clinical form of accelerated aging process. The main clinical
      characteristics of arterial stiffening concern changes in blood pressure with
      isolated increase in systolic pressure and normal or lower diastolic pressure.
      The consequences of these alterations are: (1) an increased left ventricular
      afterload with development of left ventricular hypertrophy and increased
      myocardial oxygen demand and (2) altered coronary perfusion and subendocardial
      blood flow distribution. Epidemiological studies have identified arterial
      remodeling and stiffening as independent predictors of overall and cardiac
      mortality in ESRD patients.

PMID- 10657712
TI  - Effects of postdialysis urea rebound on the quantification of pediatric
      hemodialysis.
AB  - Urea rebound (UR) causes single pool urea kinetic modeling (UKM), which is based
      on end-dialysis urea instead of its equilibrated value (Ceq), to erroneously
      quantify hemodialysis (HD) treatment. We estimated the impact of postdialysis UR
      on the results of formal variable volume single pool (VVSP) UKM [Kt/V, urea
      distribution volume (V), urea generation rate (G), normalized protein catabolic
      rate (nPCR), and urea reduction ratio (URR)] in children on chronic HD. Thirty
      eight standard pediatric HD sessions in 15 stable patients (9 female, 6 male)
      aged 14.5 +/- (SD) 3.28 years were investigated. The HD sessions lasted 3.75 +/-
      0.43 h. The single pool urea clearance was 4.84 +/- 1.25 ml/min/kg. All HD
      sessions were evaluated by VVSP and URR (%) with postdialysis urea taken at the
      end of HD and with Ceq taken 60 min after the end of HD, incorporating double
      pool effects and representing true double pool values. The anthropometric V was
      calculated by Cheek and Mellits formulae for children. VVSP significantly
      overestimated Kt/V by 0.26 +/- 0.18 U (1.68 +/- 0.36 vs. 1.42 +/- 0.30, p <
      0.0001), i.e., 19. 05 +/- 13.07%, G/V (0.20 +/- 0.04 vs. 0.18 +/- 0.04, p <
      0.0001), nPCR (1.26 +/- 0.23 vs. 1.18 +/- 0.22 g/kg/day, p < 0.0001), and URR
      (73.92 +/- 6.49 vs. 69.22 +/- 7.06, p < 0.0001). VVSP significantly
      underestimated kinetic V in comparison to anthropometric V (18.74 +/- 4.04 vs.
      20.76 +/- 4.43 liters or expressed as V/body weight: 58 +/- 8 vs. 65 +/- 9%, p <
      0.05), while double pool kinetic V was more accurate (21.45 +/- 4.34 liters,
      V/body weight: 64 +/- 6%, p > 0.05). We conclude that UR has a significant effect
      on all results of UKM even after standard pediatric HD, and the degree of this
      efffect is documented. We suggest an increase of the minimum required prescribed
      single pool Kt/V in children and reduction of any delivered single pool Kt/V by
      approxiamtely 0.26 Kt/V U. Overestimation of nPCR by approximately 0.08 g/kg/day
      and underestimation of V by 8.5% should be kept in mind.

PMID- 10657711
TI  - Selenium depletion in hemodialysis patients treated with polysulfone membranes.
AB  - BACKGROUND/AIMS: Epidemiological, animal and human studies have indicated that
      selenium deficiency is a risk factor for death from malignant diseases. The
      mechanisms that could modify selenium status may, therefore, be of particular
      interest in hemodialysis patients, considering their high cancer mortality rates.
      We aimed at evaluating the effect of hemodialysis with polysulfone membranes on
      selenium status. METHODS: Twenty- eight chronically dialyzed patients and 32 age
      matched healthy controls were enrolled in the study. Serum and dialysis fluid
      selenium concentrations, serum total protein, and hemoglobin concentrations and
      serum glutathione peroxidase activity were determined before and after the
      hemodialysis procedure. RESULTS: The (mean +/- SD) serum selenium and total
      protein concentrations and glutathione peroxidase activities were significantly
      (p < 0.05) higher in healthy controls (75.9 +/- 8.3 microg/l, 78 +/- 6 g/l, and
      23.8 +/- 4.8 mU/20 microl, respectively) than in the patients. There was no
      significant difference between serum selenium concentration before (63.6 +/- 11.
      6 microg/l) and after (64.4 +/- 11.4 microg/l) hemodialysis sessions, although
      hemoglobin and total serum protein concentrations and serum glutathione
      peroxidase activities increased (from 98.5 +/- 1.3 to 114.8 +/- 1.5 g/l, from 64
      +/- 8 to 71 +/- 9 g/l, and from 16.8 +/- 1.8 to 18.9 +/- 1.9 mU/20 microl,
      respectively) significantly (p < 0.05) during hemodialysis, indicating
      hemoconcentration. The selenium concentration doubled, and protein appeared in
      the dialysates during dialysis session. The correlation of the selenium
      concentrations with the protein concentrations in the dialysate is significant (p
      < 0.01) with a Spearman R value of 0.97. CONCLUSION: The results of the present
      study suggest that selenium is lost through the pores of polysulfone membranes
      during hemodialysis which is associated with their protein permeability.

PMID- 10657713
TI  - No association between deletion-type angiotensin-converting enzyme gene
      polymorphism and left-ventricular hypertrophy in hemodialysis patients.
AB  - Left-ventricular hypertrophy (LVH), a bad prognostic sign, is a common finding in
      hemodialysis patients. The aim of the study was to analyze factors, including
      angiotensin-converting enzyme (ACE) genotype that may have an effect on the
      development of LVH in hemodialysis patients. Seventy-nine hemodialysis patients
      (42 males, 37 females, mean age 37.7 +/- 13.1 years) and 82 age- and sex-matched
      normotensive healthy controls (40 males, 42 females, mean age 35.6 +/- 5.7 years)
      were included. Left-ventricular mass index (LVMI) was higher in the hemodialysis
      group compared to controls (170.1 +/- 69.3 versus 84.9 +/- 15.7 g/m(2), p <
      0.001). Fourty-three hypertensive patients in the hemodialysis group had an
      increased LVMI compared to 36 normotensive hemodialysis patients (194.2 +/- 75.5
      versus 141.2 +/- 48.0 g/m(2), p < 0.001). On univariate analysis, LVMI was found
      to be correlated with blood pressure (r = 0.38, p < 0.001), time spent on
      dialysis (r = 0.22, p = 0.02) and hemoglobin levels (r = -0.21, p = 0.03). No
      correlation was found between LVMI and age (r = 0.09, p = 0.22), predialytic
      creatinine (r = 0.09, p = 0.21) and albumin (r = -0.10, p = 0.18). On
      multivariate analysis for the predictors of LVMI, blood pressure, time spent on
      dialysis and hemoglobin levels were also found to be significant. LVMI in DD, ID
      and II genotypes were 155.0 +/- 71.2, 181.6 +/- 60.6, and 163.6 +/- 83.4 g/m(2),
      respectively (p > 0.05). No association between LVMI and DD genotype was found.
      ACE genotype distribution was similar in hemodialysis patients and healthy
      controls. It was concluded that LVH in hemodialysis patients was mainly related
      to hypertension, anemia and time spent on dialysis and the DD genotype had no
      effect on LVMI in hemodialysis patients.

PMID- 10657714
TI  - Renal complications of high-dose chemotherapy and peripheral blood stem cell
      transplantation.
AB  - Following bone marrow transplantation, acute renal failure and proteinuria are
      common complications with a high mortality, particularly in patients requiring
      hemodialysis. Incidence, potential predisposing factors, and outcome of acute
      renal complications in patients with hematological malignancies receiving
      autologous peripheral blood stem cell transplantation were prospectively studied
      in 53 patients. Eight patients developed acute renal failure. Three of them
      required hemodialysis. Of all patients with acute renal failure, only those
      requiring hemodialysis died, due to nonrenal causes. Only 1 of the 45 patients
      without renal failure died. Mild proteinuria of predominantly tubular origin
      occurred in 16 patients, in 3 with and in 13 without acute renal failure. As
      predisposing factors for acute renal failure were identified: renal hypoperfusion
      due to systemic inflammatory response syndrome, sepsis or septic shock, and
      combined administration of nephrotoxic drugs. Especially those patients receiving
      high numbers of nephrotoxic drugs in combination with renal hypoperfusion were
      likely to develop acute renal failure. These results suggest that patients
      receiving high-dose chemotherapy and autologous peripheral blood stem cell
      transplantation have a low risk of developing acute renal failure and
      proteinuria.

PMID- 10657715
TI  - Incidence of acquired renal cysts in biopsy specimens.
AB  - AIMS: This study investigated whether or not acquired renal cysts develop in
      patients with mild chronic renal failure. METHODS: A retrospective study was
      carried out using renal biopsy specimens from 720 patients. A renal cyst was
      defined as a tubule dilated >200 microm. RESULTS: Renal cysts were found in 21 of
      720 renal biopsy specimens. Serum creatinine of 21 patients with renal cysts was
      significantly higher than that of 699 patients without cysts (2.59 +/- 2.64 vs.
      1.09 +/- 0.79 mg/dl) (p < 0.0001). Poor renal function (serum creatinine >1.6
      mg/dl) reveals more cyst formation on biopsy specimens than good renal function
      (serum creatinine <1.5 mg/dl). Cysts were observed in 11 of 607 (1.8%) patients
      less than 50 years of age and in 10 of 113 (8.8%) patients over 51 years. To
      exclude simple cysts which are commonly observed in older subjects, 11 patients
      under 50 years of age were extensively examined. Mean serum creatinine was 2.98
      +/- 3.06 mg/dl (0.7-10.4 mg/dl). These 11 patients revealed low creatinine
      clearance of 47.5 +/- 25.6 ml/min (5-71 ml/min). Creatinine clearances in 7
      patients were 52-71 ml/min (serum creatinine 0.7-2.0 mg/ dl). One of 11 biopsy
      specimens with cysts was examined by immunohistochemistry on lectin. This
      specimen was positive for tetragonolobus lectin and negative for peanut lectin,
      suggesting that the epithelial cells lining the cyst were derived from proximal
      tubules, unlike those of simple cysts. CONCLUSION: These results suggest that low
      normal renal function such as creatinine clearances 52-71 ml/min due to nephron
      loss is sufficient to induce acquired cyst development in various renal diseases.

PMID- 10657716
TI  - Clinicopathologic study on prognostic markers in IgA nephropathy.
AB  - BACKGROUND/AIM: Few prognostic markers have found general acceptance in IgA
      nephropathy (IgAN). The aim of the present study was to search for significant
      predictor(s) at the time of biopsy. METHODS: Fifty-five patients with IgAN
      undergoing evaluation and treatment at our institution were examined regarding
      clinicopathologic features at the time of renal biopsy and, if possible, at
      follow-up. Factors predictive of outcome were evaluated. Renal histopathology was
      quantified using a glomerulosclerosis index (GSI), a tubulointerstitial index
      (TII), and a crescent index (CI). RESULTS: The serum creatinine concentration (S
      Cr) showed positive correlations with proteinuria and serum total cholesterol
      concentration, as well as with histopathologic findings. Heavy proteinuria (> or
      =3.0g/24 h) was associated with higher S-Cr and greater severity of pathologic
      abnormalities than with milder proteinuria. At follow-up, 6 patients progressed
      to chronic renal insufficiency, in whom the S-Cr increased by at least 50% to
      reach or exceed 1.5 mg/dl (132.6 micromol/l). By univariate analysis, elevated
      GSI, TII, and S-Cr, presence of nephrotic syndrome, elevated CI, and elevated
      total cholesterol were found to be negative predictors, in descending order of
      odds ratio. In multivariate analysis, however, only TII independently predicted
      unfavorable outcome. CONCLUSION: Renal biopsy in IgAN may be the most powerful
      predictor for renal outcome; an advanced tubulointerstitial lesion is
      unfavorable.

PMID- 10657717
TI  - Evaluation of IGF system component levels and mitogenic activity of uremic serum
      on normal human osteoblasts.
AB  - To test the hypothesis that impairment in bone formation in renal osteodystrophy
      in adults with chronic renal failure (CRF) might be mediated in part by
      alterations in circulating levels of the insulin-like growth factor (IGF) system
      components, we compared serum levels of IGF-I, IGF-II, IGF-binding protein
      (IGFBP)-3, IGFBP-4 and IGFBP-5 in adults with CRF (CRF patients with parathyroid
      hormone (PTH) < 100 pg/ml, PTH > 300 pg/ml and end-stage renal failure (ESRF)
      patients) versus age-matched controls. To evaluate the biological significance of
      alterations in circulating level of IGF system components, we compared the
      mitogenic activity of the sera on proliferation of normal human osteoblasts in
      vitro by using [(3)H]thymidine incorporation. We found severalfold increased
      serum levels of IGFBP-3 (2-fold), IGFBP-4 (5-fold) and slightly increased IGF-II
      levels in ESRF patients as well as a 2.6-fold increase in free IGF-I in CRF
      patients with PTH < 100 pg/ml. The mitogenic activity was found to be increased
      in serum of kidney failure patients compared to controls. This was most
      pronounced in CRF patients with PTH < 100 pg/ml showing also a significant
      increase in free IGF-I and the lowest levels of the IGF-inhibitory IGFBP-4. Our
      data support the hypothesis that alterations in serum levels of stimulating (i.e.
      free IGF-I) and inhibitory IGF system components (i.e. IGFBP-4) may influence
      osteoblastic cell proliferation in renal osteodystrophy.

PMID- 10657718
TI  - Cell adhesion molecule expression in murine lupus-like nephritis induced by
      lipopolysaccharide.
AB  - BACKGROUND: Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion
      molecule (VCAM) are thought to play important roles in leukocyte recruitment to
      the kidney. We therefore chose to study mesangial cell adhesion molecule
      expression in vitro, and the role of these molecules in experimental lupus-like
      nephritis. METHODS AND RESULTS: When cultured murine mesangial cells were
      stimulated with interferon-gamma (IFgamma) and tumor necrosis factor-alpha
      (TNFalpha), mRNA levels for ICAM-1 and VCAM markedly increased. These molecules
      were detected at the cell surface by flow cytometry. Since lipopolysaccharide
      (LPS) stimulates TNFalpha and IFgamma production in vivo, we treated mice with
      Streptococcus minnesota LPS in order to study renal adhesion molecule expression.
      LPS treatment induced mesangial proliferative glomerulonephritis characterized by
      leukocyte infiltration, and increases in total glomerular cellularity, volume and
      matrix area. mRNA levels for ICAM-1 and VCAM were increased in the kidneys of LPS
      treated versus control mice. ICAM-1 and VCAM molecules were constitutively
      expressed in renal vascular endothelium. At 3 and 5 weeks, this vascular staining
      intensified, and some ICAM-1 and VCAM expression was induced in the glomerular
      mesangium. ICAM-1 and VCAM induction occurred early and correlated in time with
      leukocyte infiltration. CONCLUSION: Interactions between cell adhesion molecules
      expressed by intrinsic glomerular cells and infiltrating leukocytes play a role
      in the initiation of LPS-induced lupus-like nephritis. These observations are
      potentially relevant to the understanding and treatment of certain types of human
      glomerulonephritis.

PMID- 10657719
TI  - IgA nephropathy and Reiter's syndrome. Report of two cases and review of the
      literature.
AB  - Immunoglobulin A (IgA) nephropathy is the commonest type of primary
      glomerulonephritis worldwide. It has previously been reported in association with
      the seronegative spondyloarthropathies (ankylosing spondylitis, Behcet's
      syndrome, psoriatic arthritis, Reiter's syndrome and the postenteritic
      arthritides). Since this condition was first described in 1968, 5 previous case
      reports of biopsy-proven IgA nephropathy associated with Reiter's syndrome have
      been published in the English-language literature. Here we report 2 more such
      cases, along with a review of the literature describing the association of IgA
      nephropathy and a number of other immune-complex-mediated glomerulonephritides
      with the seronegative spondyloarthropathies.

PMID- 10657720
TI  - Excessive number of skin cancers in an Italian renal transplant recipient.

PMID- 10657721
TI  - Cefuroxime-induced acute renal failure.

PMID- 10657722
TI  - Vitamin D receptor gene polymorphism and diabetes mellitus prevalence in
      hemodialysis patients.

PMID- 10657723
TI  - Procalcitonin in patients undergoing chronic hemodialysis.

PMID- 10657724
TI  - High grade lymphoma in a post-renal transplant patient. Description of a case and
      literature review.

PMID- 10657725
TI  - The captopril test: an aid to identify hypertensive children with renal scarring.

PMID- 10657726
TI  - Systemic proteolytic enzyme treatment diminishes urinary interleukin 6 in
      diabetic patients.

PMID- 10657727
TI  - Improved response to erythropoietin therapy with long-term continuous iron
      supplementation.

PMID- 10657728
TI  - Severe hypomagnesemia in a neonate with isolated renal magnesium loss.

PMID- 10657729
TI  - Endoscopic renal biopsy in pediatric patients: comparison of retroperitoneoscopy
      assisted and retroperitoneoscopic methods.

PMID- 10657730
TI  - Regulation of hypothalamic proopiomelanocortin by leptin in lean and obese rats.
AB  - The mechanisms by which leptin influences energy homeostasis are not entirely
      understood. Several observations indicate that proopiomelanocortin (POMC) is
      involved in the regulation of food intake and may be a mediator of leptin action.
      To further study this interaction, a sensitive solution hybridization assay was
      used to compare the levels of POMC mRNA in the medial basal hypothalamus (MBH) of
      lean (+/+, +/fa(f)) and obese leptin receptor-deficient (fa(f)/fa(f)) rats. POMC
      peptide products were also measured by RIA in the same animals. Cytoplasmic POMC
      RNA levels were significantly reduced by 53% in obese rats as compared with lean
      controls: 0.30 +/- 0.04 vs. 0.64 +/- 0.07 pg/microgram total RNA (p < 0.02).
      Significant reductions in mean concentrations of hypothalamic POMC-derived
      peptides from the same dissections were detected in the obese rats vs. lean
      controls: alpha-MSH 1.77 +/- 0.07 vs. 2.34 +/- 0.10; beta-EP 4.06 +/- 0.24 vs.
      5.86 +/- 0.36; gamma(3)-MSH 5.32 +/- 0. 20 vs. 6.52 +/- 0.12 ng/mg protein (p <
      0.001). To determine whether leptin stimulates POMC gene transcription, the acute
      effect of an intracerebroventricular (i.c.v.) injection of leptin (5 microgram)
      on POMC primary transcript was quantified in the MBH of lean rats after a 16-hour
      fast. There was a significant 167% increase in mean POMC hnRNA levels 3 h after
      i.c.v. leptin injection (1.15 +/- 0.22 pg/MBH; p < 0.02), but not after 1 h (0.76
      +/- 0.08 pg/MBH), compared to saline controls (0.69 +/- 0.08 pg/MBH). 4 h after
      the injection of leptin, POMC hnRNA was still increased, but to a lesser extent
      (140%), as compared with control animals (p = 0.006). These studies demonstrate
      for the first time in the leptin receptor-deficient rat that there is an
      associated decrease in POMC gene expression and peptide levels in the MBH.
      Furthermore, the acute increase in the levels of POMC primary transcript in non
      obese rats after a single i.c.v. injection of leptin supports a role for leptin
      in the regulation of POMC gene transcription. Taken together, these studies
      provide further evidence that POMC is an important mediator of the effects of
      leptin on food intake and energy expenditure.

PMID- 10657731
TI  - Sexually dimorphic ontogeny of GABAergic influences on periventricular
      somatostatin neurons.
AB  - The biosynthesis and secretion of somatostatin (SRIH) within the hypothalamic
      periventricular-median eminence (PeN-ME) pathway follows a sexually
      differentiated developmental pattern beginning in the early neonatal period. It
      is generally accepted that testosterone plays a role in these processes, but the
      mechanisms underlying the age and sex differences are poorly understood. The
      present study sought to investigate the hypothesis that gamma-aminobutyric acid
      (GABA) may play a role in determining sex differences in SRIH neuronal activity.
      Using an in vitro hypothalamic preparation where more than 97% of the
      immunoreactive SRIH is contained within the PeN-ME pathway, peptide release in
      response to the GABA(A) receptor antagonist, bicuculline, was followed through
      development. In the male a stimulatory response, indicative of an inhibitory
      GABAergic tone on SRIH secretion, was observed as early as postnatal day (P) 5.
      This persisted throughout juvenile development (P10, P17) and was present also in
      the adult male (P75), but in the peripubertal period the response to bicuculline
      was first lost (P25) and then reversed to an inhibition (P40), suggesting a
      transient switch to an apparent stimulatory GABAergic tone on SRIH release. By
      contrast, in the female, no bicuculline responsiveness was seen until P25 when it
      caused a decrease in SRIH release which persisted into adulthood. Using in situ
      hybridization studies we found no evidence to support the view that these age-
      and sex-dependent differences were due to changes in the expression of GABA(A)
      receptor alpha-subunits (alpha(1) and alpha(2)) which are colocalised in the PeN
      SRIH neurons. Following adult gonadectomy, the bicuculline response was abolished
      in the male, whereas, in the female it was reversed and identical in magnitude to
      the response in the intact male. These results demonstrate marked sex differences
      in GABA(A)-receptor-mediated influences on SRIH release which develop soon after
      birth and, in the adult, depend on gonadal factors. In the male these factors
      activate a primarily inhibitory influence, whereas in the female they facilitate
      an apparently stimulatory tone of GABA on SRIH secretion via the GABA(A)
      receptor. Our findings thus support the view that GABAergic transmission may play
      a key role in generating sex differences in the mode of SRIH secretion from the
      hypothalamus which has been shown to be a major factor in determining the
      sexually dimorphic patterns of growth hormone secretion.

PMID- 10657732
TI  - Isoform-specific exocytotic protein mRNA expression in hypothalamic magnocellular
      neurons: regulation after osmotic challenge.
AB  - Exocytosis is regulated by proteins which interact to promote docking and fusion
      of secretory granules with the plasma membrane. We have used in situ
      hybridization to study the mRNA expression for vesicle-associated membrane
      protein (VAMP) isoforms VAMP-1 and VAMP-2, synaptosomal-associated protein of 25
      kDa (SNAP-25) isoforms SNAP-25a and SNAP-25b, mammalian homologue of unc-18 (munc
      18) and Hrs-2 in neurosecretory neurons of the magnocellular paraventricular
      (PVN) and supraoptic (SON) nuclei of normal and osmotically challenged animals.
      In PVN and SON neurons of normal animals, strong labeling was demonstrated for
      VAMP-2 and SNAP-25a mRNA, whereas VAMP-1 or SNAP-25b mRNA could not be detected.
      Salt-loading (2% NaCl as drinking water), an animal model which increases the
      expression and secretion of hormones from hypothalamic magnocellular neurons,
      resulted in significantly increased mRNA levels for VAMP-2 (36%, 28%), munc-18
      (74%, 68%) and SNAP-25a (59%, 77%) in the PVN and SON, respectively. There was no
      significant increase in Hrs-2 mRNA levels in the PVN, whereas a significant
      increase (22%) was observed in the SON. In the posterior pituitary,
      immunohistochemistry showed a marked decrease in numbers and intensity of
      vasopressin-immunoreactive (-IR) nerve endings after salt-loading. There were no
      obvious changes in numbers or intensity of VAMP-2-, munc-18-, Hrs-2- or SNAP-25
      IR fibers. Large varicosities containing VAMP-2- and Hrs-2 immunocreactivity were
      seen in salt-loaded animals. The results show isoform-specific mRNA expression in
      neurosecretory neurons and an increased mRNA expression of proteins participating
      in the molecular regulation of exocytosis during an experimental situation
      characterized by increased secretion.

PMID- 10657733
TI  - Expression of vasoactive intestinal peptide/peptide histidine isoleucine in
      several hypothalamic areas during the turkey reproductive cycle: relationship to
      prolactin secretion.
AB  - The present study examined the changes in vasoactive intestinal peptide (VIP) and
      peptide histidine isoleucine (PHI) gene expression in the hypothalamus and
      compared their level of expression to prolactin (PRL) secretion throughout the
      turkey reproductive cycle. Both VIP and PHI expression were determined using in
      situ hybridization histochemistry and reverse transcription-polymerase chain
      reaction/Southern blot analysis. Plasma PRL levels were determined by
      radioimmunoassay. The changes in total hypothalamic VIP and PHI mRNA steady-state
      levels mirrored the changes seen in plasma PRL across the reproductive stages. In
      situ hybridization revealed that VIP mRNA was highly expressed throughout the
      hypothalamus and predominated within the ventromedial nucleus (VMN), inferior
      hypothalamus, and infundibular nuclear complex (INF). PHI mRNA was expressed in
      very low abundance within the same areas expressing VIP mRNA. VIP mRNA abundance
      within the VMN and INF was lowest in nonphotostimulated hens (VMN, 13.8 +/- 1.7;
      INF, 17.0 +/- 1.8 arbitrary densitometric units (ADU)), intermediate in laying
      hens (VMN, 29.6 +/- 3.3; INF, 35.4 +/- 4.3 ADU), and highest in incubating hens
      (VMN, 76.4 +/- 10.2; INF, 119.2 +/- 3.4 ADU). Levels decreased when birds shifted
      from incubation to photorefractoriness (VMN, 75%; INF, 82%). This relationship
      was not observed within other areas of the hypothalamus. The expression of PHI
      mRNA was also highest in the VMN and INF of incubating hens but no correlation
      between PHI mRNA and the other reproductive states was observed. This study
      provides additional evidence that VIP is the avian PRL-releasing factor, and
      suggests that the central site for avian PRL regulation lies within the INF of
      the hypothalamus.

PMID- 10657734
TI  - Regional serotonin metabolism under basal and restraint stress conditions in the
      brain of transgenic mice with impaired glucocorticoid receptor function.
AB  - Transgenic (TG) mice deficient in glucocorticoid receptors (GR) were used in
      order to study the effects of a reduced GR function on adrenocorticotropin
      hormone and corticosterone plasma levels and on serotonin metabolism in different
      brain areas under basal resting conditions, after a 30-min restraint stress and
      60 min after the end of the restraint stress. There was no difference in basal or
      stress-induced levels of either adrenocorticotropin hormone or corticosterone in
      control and TG mice, but the return of adrenocorticotropin hormone to basal
      values after the end of the stress was delayed in TG mice. Under basal
      conditions, the ratio 5-hydroxyindoleacetic acid/5-hydroxytryptamine was
      decreased only in the hippocampus of TG mice compared to controls. In the brain
      stem, the ratio 5-hydroxyindoleacetic acid/5-hydroxytryptamine increased compared
      to basal values after a 30-min restraint stress and values were still high 60 min
      after the end of the restraint stress in both control and TG mice. In the
      hippocampus, the ratio 5-hydroxyindoleacetic acid/5-hydroxytryptamine increased
      at the end of the stress and returned to basal levels 60 min later in control
      mice, whereas there was no change at the end of the stress but an increase 60 min
      later in TG mice. Finally there was no change in serotonin metabolism in the
      cortex, striatum or hypothalamus in either group or situation. Our results
      support the hypothesis of a tonic activation of serotonin turnover by
      corticosterone through GR in the mouse hippocampus. Moreover, stress-induced
      stimulation of serotonin metabolism in the brain stem and hippocampus appears to
      be delayed in TG mice compared to control mice. These results are particularly
      relevant for mood disorders such as depression where alterations of
      serotoninergic transmission might be secondary to an impairment of GR functions.

PMID- 10657735
TI  - Psychological and endocrine responses to psychosocial stress and
      dexamethasone/corticotropin-releasing hormone in healthy postmenopausal women and
      young controls: the impact of age and a two-week estradiol treatment.
AB  - In this placebo-controlled double-blind study, psychological and endocrine stress
      responses were investigated in healthy postmenopausal placebo-treated women (n =
      15; 60-75 years; placebo via transdermal patches), healthy postmenopausal
      estradiol-treated women (n = 13; 60-79 years; 0.1 mg 17beta-estradiol daily via
      transdermal patches) and young controls (n = 15; 20-31 years; untreated). The
      aged subjects received estradiol or placebo treatment for 14 days. All subjects
      were then exposed to the 'Trier Social Stress Test' (TSST) and the dexamethasone
      (Dex)-human corticotropin-releasing hormone (hCRH) test (100 microgram hCRH after
      premedication with 1.5 mg Dex). Psychological parameters including perceived
      stressfulness, mood and subjective well-being were measured by visual analog
      scales, a mood questionnaire and a mood diary, respectively. Results show that
      the TSST induced significant increases in adrenocorticotropin (ACTH), free
      salivary cortisol, total plasma cortisol and heart rates (all p < 0.0001).
      Regardless of age, comparable hormonal response patterns were observed in the
      TSST as indicated by similar peak levels and recovery phases. Visual analog
      scales confirmed that the same amount of stress was experienced by young and
      elderly subjects. In both age groups, hCRH injection after Dex premedication
      provoked significant increases in ACTH, free salivary cortisol and total plasma
      cortisol (all p < 0.0001). In contrast to the psychosocial stressor, elderly
      women were found to respond with a markedly enhanced cortisol response compared
      to young controls in the Dex-CRH test (p < 0.025). Additional investigation of
      morning cortisol profiles could not reveal any age-related differences in basal
      hypothalamus-pituitary-adrenal (HPA) axis activity. Following estradiol
      treatment, estradiol levels significantly increased only in substituted
      postmenopausal women (p < 0.001) reaching concentrations typically found in
      younger women during the follicular phase of the menstrual cycle. Corticosteroid
      binding globulin levels did not differ significantly between groups. When
      confronted with the TSST, no response differences emerged between the three
      groups. However, estradiol treatment appeared to blunt the total plasma cortisol
      response in the Dex-CRH test, resulting in smaller increases in untreated
      premenopausal women and estradiol-treated postmenopausal women compared to
      placebo-treated postmenopausal women (p < 0.02). In sum, no response differences
      were observed after confrontation with a psychosocial stress test in our sample
      of healthy elderly subjects. As shown with the Dex-CRH test, our data suggest
      that the negative feedback of the HPA axis in elderly women is altered. Moreover,
      the current data suggest that estradiol replacement may modulate HPA feedback
      sensitivity in humans.

PMID- 10657736
TI  - Dehydroepiandrosterone response to the adrenocorticotropin test and the combined
      dexamethasone and corticotropin-releasing hormone test in patients with multiple
      sclerosis.
AB  - Basic and clinical research suggest that disturbed neuroendocrine function may be
      involved in the pathogenesis and course of autoimmune diseases including multiple
      sclerosis (MS). Dehydroepiandrosterone (DHEA) in this connection is of particular
      interest as it appears to have effects on the immune system. Moreover, DHEA
      levels are decreased in chronic inflammatory diseases. To further investigate the
      role of DHEA in MS, we administered the adrenocorticotropin (ACTH) stimulation
      test and the combined dexamethasone and corticotropin-releasing hormone (DEX-CRH)
      test to 24 patients with active MS (13 women, 11 men; age 39 +/- 2 years, mean +/
      SEM; Expanded Disability Status Scale, EDSS score 4.4 +/- 0. 4, mean +/- SEM; 12
      with acute relapse, 12 with chronic progression) and to 18 healthy controls
      matched for age and sex (8 women, 10 men; age 37 +/- 3 years). There were no
      statistically significant differences in the plasma cortisol response to ACTH
      between any groups. In the DEX-CRH test, plasma cortisol concentrations showed
      higher values before (DEX-pretreated) and after CRH stimulation in the MS
      patients than in the controls (AUC(cortisol) 738.3 +/- 154.5 vs. 295.7 +/- 55.8;
      p < 0.05), this finding was more pronounced in chronic progressive patients. DHEA
      concentrations were decreased in MS patients (AUC (DHEA) 14.4 +/- 1.6 vs. 23 +/-
      2.4; p < 0.05) and cortisol/DHEA ratios were increased in the patients compared
      to the controls (p < 0.05). There was a positive correlation between the EDSS
      score and maximum cortisol/DHEA ratio (r = 0.45; p = 0.031). As with the
      hypothalamic-pituitary-adrenal axis system, our results suggest a dysfunction in
      the DHEA secretion in patients with MS.

PMID- 10657737
TI  - Generation of a recombinant herpes simplex virus type 1 expressing the rat
      corticotropin- releasing hormone precursor: endoproteolytic processing,
      intracellular targeting and biological activity.
AB  - We describe the generation of a recombinant herpes simplex virus type 1 (HSV1)
      vector, tsK/CRH10, derived from the temperature-sensitive mutant tsK, expressing
      rat pre-procorticotropin-releasing hormone (ppCRH). In hypothalamic neurons,
      within the paraventricular and supraoptic nuclei, this neuropeptide precursor is
      processed to mature CRH (1-41), the key modulator of the hypothalamic-pituitary
      adrenal stress response. We used the recombinant HSV1 tsK/CRH10 to study
      posttranslational processing, intracellular localization and biological activity
      of proCRH (pCRH) within neuronal, glial and epithelial cell lines. We showed that
      CRH-like immunoreactivity expressed in neuronal, glial and epithelial cells
      infected with tsK/CRH10 was biologically active, could be detected
      intracellularly and was also secreted. Our data also show that within Neuro2a and
      NG115 cells, the CRH precursor is cleaved to yield a CRH-like immunoreactive
      fragment of approximately 4.75 kD which could account for mature CRH (1-41). No
      endoproteolytic processing of the precursor takes place within the astrocytic
      1321 NI cell line. Using immunocytochemistry techniques we detected CRH-like
      immunoreactivity within the endoplasmic reticulum-Golgi region in all cells and
      within secretory vesicles of Neuro2a and NG115 cells, suggesting correct
      targeting to the regulated secretory pathway within these cells. Our results
      demonstrate that the HSV1 recombinant vector expressing the full-length CRH
      precursor molecule constitutes an excellent delivery system for both cell lines
      and postmitotic neurons in vitro, which has enabled the study of targeting,
      endoproteolytic processing and biological activity of this neuropeptide
      precursor. Furthermore, it can also be used to generate transient transgenesis of
      the CRH precursor in vivo, to study neuroendocrine-immune interactions within the
      mammalian central nervous system.

PMID- 10657738
TI  - The transcription of corticotropin-releasing hormone in human endometrial cells
      is regulated by cytokines.
AB  - Corticotropin-releasing hormone (CRH), a hypothalamic neuropeptide, is also
      produced in the human endometrium where it participates in local inflammatory
      phenomena associated with the decidualization of endometrial stroma and the
      implantation of the fertilized egg. The inflammatory cytokines interleukin 1 (IL
      1), IL-6 and leukemia inhibitory factor (LIF) appear to be the dominant local
      regulators of these intrauterine inflammatory processes. In the present study we
      have examined the direct interactions between cytokines and CRH in the
      endometrium. For this purpose we have measured the effects of IL-1, IL-6 and LIF
      on the activity of CRH promoter inserted in human endometrial cells in culture.
      Homologous transient transfection experiments were conducted employing a 0.9-kb
      fragment of the 5' flanking region of the human CRH gene coupled to the
      luciferase reporter gene, using Ishikawa human endometrial cells. We have found
      that IL-1beta increased the activity of CRH gene promoter, in a time- and dose
      dependent manner. This effect was antagonized by the IL-1 receptor antagonist IL
      1ra and blocked completely by the cyclo-oxygenase inhibitor indomethacin.
      Similarly, IL-6 increased the activity of CRH promoter in a dose-dependent
      fashion, an effect partially reversed by indomethacin. LIF did not have any
      apparent effect. In conclusion, our data suggest that IL-1 and IL-6 exert a
      strong stimulatory effect on the expression of endometrial CRH. This effect is
      most probably mediated via prostaglandins. Based on these data we hypothesize
      that in the human endometrium interleukins, prostaglandins and CRH form a local
      network regulating the inflammatory phenomena taking place within the uterine
      cavity.

PMID- 10657739
TI  - Chronic ventromedial hypothalamic infusion of norepinephrine and serotonin
      promotes insulin resistance and glucose intolerance.
AB  - The ventromedial hypothalamus (VMH) is involved in the regulation of peripheral
      metabolism. We and others have shown that activities, or extracellular
      metabolites of norepinephrine (NE) and serotonin (5-HT) are elevated in the VMH
      of both genetically and seasonally insulin-resistant and glucose-intolerant
      animals. This study examined whether chronic increases in VMH NE and 5-HT
      concentration of normal animals might lead to insulin-resistant and glucose
      intolerant conditions in hamsters. Euinsulinemic, glucose-tolerant hamsters were
      infused continuously for 5 weeks into the right VMH with either vehicle, NE (5 or
      25 nmol/h), 5-HT (2.5 nmol/h), or NE (5 or 25 nmol/h) plus 5-HT (2.5 nmol/h)
      through osmotic minipumps. Compared to vehicle, NE (25 nmol/h) significantly
      increased the glucose total area under the curve (TAUC) by 32% during glucose
      tolerance tests (GTT) conducted after 5 weeks' infusion. 5-HT alone significantly
      increased the GTT insulin TAUC (131%) and basal plasma insulin level (116%) but
      not glucose TAUC. NE (5 nmol/h) plus 5-HT infusion significantly increased
      insulin TAUC (129%) and basal plasma insulin (120%), whereas NE (25 nmol/h) plus
      5-HT infusion significantly increased both the GTT glucose and insulin TAUC (43
      and 113%, respectively), as well as basal plasma insulin level (158%), relative
      to vehicle infusion. Our findings demonstrate for the first time the differential
      and, more importantly, interactive effects of increased VMH NE and 5-HT in
      producing hyperinsulinemia, insulin resistance and glucose intolerance.

PMID- 10657740
TI  - Alpha-B-crystallin in neuropathology.
AB  - alphaB-Crystallin, which has homology with the small heat shock proteins, is the
      basic subunit of alpha-crystallin, a major component of the vertebrate eye lens.
      These crystallins have for a long time been thought to be absolutely lens
      specific. However, about a decade ago alphaB-crystallin has been detected
      extralenticularly in many tissues among which the central nervous system. Under
      pathological conditions the expression level of alphaB-crystallin frequently
      increases. For this reason it is considered to be a useful marker in a variety of
      neurodegenerative diseases. In this mini-review, a number of typical
      neurodegenerative disorders is dealt with in which alphaB-crystallin may play a
      role.

PMID- 10657741
TI  - Alpha-B-crystallin expression in tissues derived from different species in
      different age groups.
AB  - alphaB-Crystallin is constitutively expressed in a variety of tissues including
      the nervous system, the eye, heart and striated muscles and the kidney. The
      functional significance of the protein in the different cell populations is not
      yet known. Experimental data indicate that mechanical stress to the cells might
      play a role but that there is also a close correlation with markers of oxidative
      activity. Increased expression of alphaB-crystallin is seen in a number of age
      related degenerative diseases. Whether aging per se induces expression of the
      protein has not been investigated yet. In this study tissue samples of the
      anterior eye segment, optic nerve, heart muscle and thyroid gland from mouse,
      rat, pig, cow and human donors of different age groups were investigated with
      immunohistochemical methods. alphaB-Crystallin levels in heart muscle and optic
      nerve samples from different species and different age groups were investigated
      using protein immunoblotting (dot blot) and the mRNA levels using
      semiquantitative PCR methods. The results showed that neither in heart muscle
      known to show constitutively high amounts of the protein nor in nonlenticular eye
      tissues with variations in staining intensity of different cell populations or in
      glandular cells studied for the first time, there were significant age-related
      staining differences. Dot blot methods as a quantitative evaluation method gave
      similar results. There were, however, species differences. In the eye these
      differences could be due to functional differences related to the development of
      a fovea centralis and an accommodative system in primates. In addition, in all
      mouse tissues there was less protein expression than in the other species.
      Differences in the absolute life span might be a factor involved in alphaB
      crystallin expression. In summary the findings show that an increase in alphaB
      crystallin with age may occur but is not a general phenomenon in tissues
      constitutively expressing this protein.

PMID- 10657742
TI  - Vascular and glial changes in the retrolaminar optic nerve in glaucomatous monkey
      eyes.
AB  - Vascular and glial changes of the retrolaminar optic nerve were studied in monkey
      eyes with increased intraocular pressure (IOP) from 1 to 4 years and with
      different stages of optic nerve atrophy. In histological cross-sections of
      retrolaminar optic nerves of 11 rhesus and 6 cynomolgus monkeys the entire area,
      number of axons and vessels and area of pial septa were quantitated and three
      different kinds of nerve degeneration classified. Ultrathin sections of these
      different stages were performed and the number of open and occluded vessels was
      determined. In addition, in cynomolgus monkey optic nerves immunohistochemical
      staining for alphaB-crystallin, glial fibrillary acidic protein (GFAP) and
      vimentin was performed. Even in animals with the same duration of glaucoma and
      comparable mean IOP values the axon degeneration varied considerably.
      Independently of axon loss the number of capillaries in the rhesus monkeys
      remained constant, whereas there was a slight decrease in the cynomolgus monkeys.
      Some of the vessels, especially in the most severely damaged regions, were
      occluded. The density of glial cells increased whereas the total number remained
      nearly constant. In control sections all astrocytes stained for GFAP and alphaB
      crystallin. In the glaucomatous optic nerves the density of alphaB-crystallin-
      and GFAP-positive cells was significantly increased. The vascular reaction in the
      retrolaminar glaucomatous optic nerves differs from that described in the
      prelaminar region. We assume that in the postlaminar region in areas with
      diminished nutritional needs vessels occlude and finally degenerate.

PMID- 10657743
TI  - Regulation of trabecular meshwork contractility.
AB  - Ample evidence supports the theory that trabecular meshwork possesses smooth
      muscle-like properties. Trabecular meshwork cells express a large number of
      transporters, channels and receptors, many of which are known to regulate smooth
      muscle contractility. It has been shown that trabecular meshwork can be induced
      to contract and relax in response to pharmacological agents. In the model of the
      bovine eye, confirmed in some cases by experiments on primates, agents that
      contract trabecular meshwork reduce outflow. On the cellular level, this is
      coupled with depolarization and a rise in intracellular calcium. Relaxation of
      trabecular meshwork, on the other hand, appears to be coupled to a stimulation of
      the maxi-K channel, inducing hyperpolarization and a closure of L-type calcium
      channels. No significant differences between cells from a human and a bovine
      source emerged, either in classical measurements of membrane voltage, in
      measurements of intracellular calcium or patch-clamp experiments. Thus,
      pharmacological agents that relax trabecular meshwork seem promising candidates
      for further research - the ultimate goal being an improvement of glaucoma therapy
      in humans.

PMID- 10657745
TI  - Ultrastructure of retinal cells transplanted to the rabbit choroid.
AB  - PURPOSE: Allogenic rabbit-to-rabbit retinal cell transplants survive in the
      choroid, which is not as expected because it has not been shown that this is an
      immune-privileged site. We have therefore examined the ultrastructure of such
      transplants, looking for features that might explain the phenomenon. METHODS:
      Rabbit retinal tissue fragment transplants were produced with previously
      described methods. The donor age was 15 days and the transplants were examined by
      standard electron microscopy when the transplants were 1-2 months (3 transplants)
      or 3-4 months old, of postconception age (3 transplants). RESULTS: The
      transplants survived and developed as expected from previous observations.
      Rosettes were seen, but they were not as common as in transplants produced with
      the same technique in the subretinal space of rabbits. Photoreceptor outer
      segments were not seen in the transplants. At 1 month, there was an incomplete
      sheath of Muller cells around the transplants, and a complete one at 3-4 months.
      There was also a well-developed basement membrane around the transplant at 3-4
      months, but less so at 1 month. Blood vessels did not enter the transplant. The
      fenestrations in the choriocapillaris were not affected as long as the pigment
      epithelium was normal. CONCLUSIONS: The enclosure of the transplants by Muller
      cells might help to insulate them from the immune system of the host, but it is a
      late phenomenon and it is not likely to have much effect for the first few weeks
      after the transplantation. We suspect that either the rabbit choroid is an immune
      privileged site, even though there is no previous direct evidence for this, or
      that the retinal tissue itself is responsible for the prolonged survival at this
      site.

PMID- 10657744
TI  - Full-thickness retinal transplants: a review.
AB  - Embryonic full-thickness rabbit neuroretinal sheets were transplanted to the
      subretinal space of adult hosts. This was accomplished by using a new
      transplantation technique involving vitrectomy and retinotomy. The grafts were
      followed from 10 to 306 days after surgery and were then examined by different
      histological techniques. In the light microscope, the transplants were seen to
      develop the normal retinal lamination and fusion with the host retina, especially
      after long survival times. Ultrastructurally, normal photoreceptor outer
      segments, well integrated with the host retinal pigment epithelium, were found.
      Growth cones were present in the zone of fusion between graft and host retina.
      Immunohistochemical labeling revealed many of the normal retinal components not
      previously found in retinal transplants, and graft-host connections between
      neurons in the rod pathway were seen. The morphology of vibratome-sectioned
      neuroretinal sheets as well as adult full-thickness grafts was also examined.
      These transplantation types showed less of the normal morphology compared with
      embryonic full-thickness grafts. The immunogenicity of embryonic full-thickness
      and fragmented grafts was compared using major histocompatibility complex
      immunolabeling. Fragmented grafts elicited a response from the host immune system
      similar to a chronic transplant rejection. This reaction was absent in the full
      thickness grafts which is in accordance with their good long-term survival.

PMID- 10657746
TI  - Oxidative stress and age-related cataract.
AB  - The authors review the available evidence supporting the possible role of
      oxidative stress in cataract formation from an epidemiological and a clinical
      point of view. They discuss in more detail what is presently known about the
      molecular mechanisms of response of the mammalian lens to an oxidative insult and
      report unpublished data on gene modulation upon oxidative stress in a bovine lens
      model. Main research endeavors that seem to be a most promising source of new
      insights into the problem of age-related cataract formation are briefly
      discussed.

PMID- 10657747
TI  - The ageing lens.
AB  - The human lens grows by a process of epithelial cell division at its equator and
      the formation of generations of differentiated fibre cells. Despite the process
      of continuous remodelling necessary to achieve growth within a closed system, the
      lens can retain a high level of light transmission throughout the lifetime of the
      individual, with the ability to form sharp images on the retina. Continuous
      growth of the lens solves the problem imposed by terminal differentiation within
      a closed, avascular system, from which cells cannot be shed. The lens fibre tips
      arch over the equator to meet anteriorly and posteriorly and form branching
      sutures of increasing complexity. The stages of branching may create the optical
      zones of discontinuity seen on biomicroscopy. The lens is exposed to the
      cumulative effects of radiation, oxidation and postranslational modification.
      These later proteins and other lens molecules in such a way as to impair membrane
      functions and perturb protein (particularly crystallin) organisation, so that
      light transmission and image formation may be compromised. Damage is minimised by
      the presence of powerful scavenger and chaperone molecules. Progressive
      insolublisation of the crystallins of the lens nucleus in the first five decades
      of life, and the formation of higher molecular weight aggregates, may account for
      the decreased deformability of the lens nucleus which characterises presbyopia.
      Additional factors include: the progressive increase in lens mass with age,
      changes in the point of insertion of the lens zonules, and a shortening of the
      radius of curvature of the anterior surface of the lens. Also with age, there is
      a fall in light transmission by the lens, associated with increased light
      scatter, increased spectral absorption, particularly at the blue end of the
      spectrum, and increased lens fluorescence. A major factor responsible for the
      increased yellowing of the lens is the accumulation of a novel fluorogen,
      glutathione-3-hydroxy kynurenine glycoside, which makes a major contribution to
      the increasing fluorescence of the lens nucleus which occurs with age. Since this
      compound may also cross-link with the lens crystallins, it may contribute to the
      formation of high-molecular-weight aggregates and the increases in light
      scattering which occur with age. Focal changes of microscopic size are observed
      in apparently transparent, aged lenses and may be regarded as precursors of
      cortical cataract formation.

PMID- 10657748
TI  - Comparison of the effects of preserved and unpreserved formulations of timolol on
      the ocular surface of albino rabbits.
AB  - Thirty-six albino rabbits, randomly divided into six groups, were used to study
      their ocular tolerance to (a) 0.25 and 0.50% Timoptol preserved with 0.01%
      benzalkonium chloride, (b) 0.25 and 0.50% Timoptol-LP, a gel-forming solution
      preserved with 0. 012% benzododecinium bromide, and (c) 0.25 and 0.50% Timabak
      unpreserved in the ABAK eyedrops dispenser. All eyedrops were applied in the
      right eye for 60 days. A clinical follow-up with slitlamp examination and break
      up time evaluation was performed for 2 months. At the end of the experimentation,
      the animals were sacrificed and their eyes enucleated for histological analyses
      of the conjunctiva and cornea. There was no significant difference in the
      clinical examination between each group, except for the break-up time evaluation
      between Timoptol and Timabak at each concentration which was better with the
      unpreserved timolol. Histological results showed a significant difference in the
      corneal stroma edema between preserved and unpreserved timolol. This study
      confirms that using unpreserved timolol may be beneficial for the long-term
      treatment of glaucomatous patients as it increases tear film stability and
      decreases epithelial permeability and stromal aggression of the cornea.

PMID- 10657749
TI  - Immunolocalization of c-Fos and c-Jun in rat ocular surface epithelium.
AB  - We immunohistochemically located c-Fos and c-Jun, the major components of
      transcription factor activator protein 1 (AP1), in normal epithelia of rat cornea
      and conjunctiva to determine the expression of these genes in the ocular surface
      epithelia. Immunoreactivity for c-Fos was detected in the nuclei of basal cells
      of the limbal and conjunctival epithelia, while that for c-Jun was detected in
      the cytoplasm of the cells of these epithelia. The corneal epithelium lacked
      immunoreactivity for either protein. AP1 may have an important role in the
      maintenance of homeostasis of limbal and conjunctival epithelia.

PMID- 10657750
TI  - The effect of propolis extract in experimental chemical corneal injury.
AB  - PURPOSE: To investigate the effect of propolis, a natural resin produced by
      honeybees, in the treatment of alkali-injured rabbit eyes. METHOD: A corneal
      alkali burn was induced by applying filter paper immersed in 1 N NaOH on the
      central axis of the right corneas of 24 rabbits for 30 s. The animals were
      divided into three treatment groups: group 1 (control) was given 0.3% tobramycin
      and phosphate-buffered solution; group 2 was treated with antibiotic coverage and
      topical 1% ethanolic extract of propolis; group 3 received antibiotic coverage
      and topical 1% dexamethasone. The dexamethasone-treated group was maintained as
      the positive control. Drugs were instilled 4 times a day for 7 days. The corneal
      inflammation was evaluated by calculating the average inflammatory index obtained
      from clinical observation of the ciliary hyperemia, central and peripheral
      corneal edema at 24 h, 48 h, on day 5 and day 7, before sacrificing the animals.
      Then, the corneas underwent routine histological examination. RESULTS: The
      effects of dexamethasone and propolis on healing of injured corneas were similar
      (p>0.05) and significantly better than controls at 24 h (p<0.01, p< 0.05,
      respectively), and on day 7 (p<0.05) with respect to the inflammatory index. On
      histological observation, inflammatory cell infiltration was lower as compared to
      control in both the dexamethasone and propolis groups (p<0.001) and similar with
      each other (p>0.05). CONCLUSIONS: Our study shows that propolis has an anti
      inflammatory effect comparable to dexamethasone in chemical corneal injury.

PMID- 10657751
TI  - Experimental corneal neovascularization by basic fibroblast growth factor
      incorporated into gelatin hydrogel.
AB  - The study was designed to investigate the feasibility of using an acidic gelatin
      hydrogel as a biodegradable vehicle for basic fibroblast growth factor (bFGF).
      bFGF was incorporated by polyion complexation into a biodegradable hydrogel
      prepared by cross-linking acidic gelatin with the isoelectric point of 4.9. The
      dried hydrogel (sized to 2x1 mm) was hydrated with bFGF aqueous solution
      including different doses of bFGF (20, 50, 125, 250 and 500 ng) and implanted
      into a rabbit corneal pocket (2.5x2 mm). As a control group, the gelatin hydrogel
      without bFGF or bFGF alone (500 ng) was used. Corneal angiogenesis was evaluated
      by biomicroscopy, corneal fluorescein angiography and histology for 21 days.
      Photographs were taken and corneal angiogenesis was evaluated by image analysis.
      The hydrogel degraded with time after its implantation into the corneal pocket.
      Experimental eyes receiving the hydrogel containing more than 50 ng of bFGF
      demonstrated significant corneal angiogenesis. Control eyes and eyes receiving
      the hydrogel containing 20 ng of bFGF showed no corneal angiogenesis. Corneal
      angiogenesis, which occurred on the 3rd or 4th day after implantation, reached
      maximal growth on about day 7 and regressed from day 10 after implantation. The
      area of angiogenesis showed a dose-dependency on bFGF. The gelatin hydrogel
      itself induced neither angiogenesis nor inflammation. These results suggested
      that acidic gelatin hydrogel releases bioactive bFGF with its biodegradation,
      resulting in corneal neovascularization.

PMID- 10657752
TI  - Combined pharmacologic therapy in a rabbit model of proliferative
      vitreoretinopathy (PVR).
AB  - PURPOSE: This study was designed to evaluate the efficacy of a combined
      treatment, previously used to prevent fibrosis after glaucoma surgery, to inhibit
      an experimental model of proliferative vitreoretinopathy (PVR). METHODS: Two
      groups of albino rabbits were used. In the control group (group 1, n = 14),
      experimental PVR was induced using vitrectomy, retinotomies, cryotherapy and
      intraocular injection of platelet-rich plasma. In the experimental group (group
      2, n = 15), after PVR was induced, the following treatment was administered for 4
      weeks: systemic methylprednisolone, sodium diclofenac and colchicine combined
      with topical atropine 1%, adrenaline 10% and dexamethasone phosphate 0.1%. Follow
      up consisted of fundus examination for 4 weeks. Results were classified
      according to Fastenberg's classification. Only retinal detachments were
      considered to compare the two groups. Nonparametric test was used. RESULTS:
      Retinal detachments were observed in 85.7% of group 1 and 33.3% of group 2 at the
      end of the follow-up (p<0.01). No major systemic complications were observed.
      CONCLUSIONS: Combined therapy seems to be useful for treating experimental PVR.

PMID- 10657753
TI  - Ophthalmological effects of high altitude.
AB  - High altitude has various effects on human beings. Altitude-related illnesses are
      a frequent cause of morbidity and occasional mortality in travelers to high
      altitudes throughout the world. The mountaineers all around the world are
      familiar with this condition, which is called acute mountain sickness (AMS). The
      primary altitude illnesses are AMS, high-altitude pulmonary edema and high
      altitude cerebral edema. Altitude has potential undesired ophthalmological
      effects. The pathogenesis of these syndromes remains unclear despite considerable
      research in this field. Most of these problems are primarily preventable with an
      adequate level of information before and during travel. Further studies are
      needed to reveal the exact relationship between high altitude and
      ophthalmological findings. In this article, ophthalmological effects of high
      altitude, likely to be encountered by mountaineers as well as other enthusiasts
      of high altitude sports are reviewed. Emphasis on aviation and aerospace medicine
      is briefly given under related SUB_TITLEs.

PMID- 10657754
TI  - Steroid sensitivity and postoperative course of seven patients with Behcet's
      disease.
AB  - Systemic administration of steroids to patients with Behcet's disease in Japan is
      often followed by a worsening in ocular symptoms. The sensitivity of 7 patients
      with Behcet's disease to steroids which were administered during and after
      intraocular surgery was therefore measured, and their postoperative course was
      reviewed. Three of the 7 showed a low steroid sensitivity, and the frequency of
      postoperative inflammatory episodes and the intraocular pressure were both higher
      for this group than for the 4 who showed high steroid sensitivity.

PMID- 10657755
TI  - Drug transport in the mammalian central nervous system: multiple complex systems.
      A critical analysis and commentary.
AB  - The rate of entry into and distribution of drugs and endogenous substances within
      the mammalian central nervous system (CNS) depend on the peculiar anatomy of the
      blood-brain and blood-cerebrospinal fluid barriers, the physicochemical nature of
      the substance or drug, and in many cases, multiple, complex specialized carriers.
      This review summarizes a systemic methodological and integrative approach to
      understanding the pharmacokinetic behavior of many drugs in the CNS in the
      context of the CNS barrier systems, focusing on recent data, several broad
      principles and selected examples. Standards of proof for valid conclusions are
      emphasized.

PMID- 10657756
TI  - Ca2+ influx mediates apoptosis induced by 4-aminopyridine, a K+ channel blocker,
      in HepG2 human hepatoblastoma cells.
AB  - Apoptosis appears to be implicated in the pathogenesis and therapeutic
      applications of cancer. In this study we investigated the induction of apoptosis
      by 4-aminopyridine (4-AP), a K(+) channel blocker, and its mechanism in HepG2
      human hepatoblastoma cells. 4-AP reduced cell viability and induced DNA
      fragmentation, a hallmark of apoptosis, in a dose-dependent manner. In addition,
      4-AP induced a sustained increase in intracellular Ca(2+) concentration, which
      was completely inhibited by the extracellular Ca(2+) chelation with EGTA. 4-AP
      also induced Mn(2+) influx, indicating that the 4-AP-induced increased
      intracellular Ca(2+) levels were due to activation of Ca(2+) influx pathway. 4-AP
      also depolarized membrane potential that was measured by using di-O-C(5)(3), a
      voltage-sensitive fluorescent dye. 4-AP-induced Ca(2+) influx was significantly
      inhibited not by voltage-operative Ca(2+) channel blockers (nifedipine or
      verapamil), but by flufenamic acid (FA), a known nonselective cation channel
      blocker. Quantitative analysis of apoptosis by the flow cytometry revealed that
      treatment with either FA or BAPTA, an intracellular Ca(2+) chelator,
      significantly inhibited the 4-AP-induced apoptosis. Taken together, these results
      suggest that the observed 4-AP-induced apoptosis in the HepG2 cells may result
      from Ca(2+) influx through the activation of voltage-sensitive Ca(2+)-permeable
      non-selective cation channels. These results further suggest that membrane
      potential change by modulation of K(+) channel activity may be involved in the
      mechanism of apoptosis in human hepatoma cells.

PMID- 10657757
TI  - Choline is a full agonist in inducing activation of neuronal nitric oxide
      synthase via the muscarinic M1 receptor.
AB  - The present study was designed to characterize the interaction of choline with
      the M(1) subtype of the muscarinic acetylcholine receptor. Using Chinese hamster
      ovary cells transfected with neuronal nitric oxide synthase and the cloned human
      M(1) receptor (CHO hM(1)/nNOS cells), we investigated choline's effects on
      production of nitric oxide and elevation of intracellular [Ca(2+)]. Choline
      showed the properties of a full agonist in inducing the sustained plateau of
      increased intracellular [Ca(2+)], although it was only a partial agonist in
      inducing the larger, transient [Ca(2+)] peak. Choline was also found to act as a
      full agonist in stimulating the production of nitric oxide. These results have
      implications for efforts in the clinical treatment of dementia.

PMID- 10657758
TI  - Effect of antioxidants on pyrogallol-induced delay in gastric emptying in rats.
AB  - The effect of a free radical generator pyrogallol on gastric emptying was studied
      in rats. Pyrogallol at doses of 25, 50, 100 and 150 mg/kg (i.p.) produced dose
      dependent inhibition of gastric emptying. Pretreatment with vitamin C (100 and
      500 mg/kg, p.o.), and vitamin E (100 and 500 mg/kg, p.o.) significantly reversed
      the inhibition in gastric emptying caused by pyrogallol 100 mg/kg. However, the
      combination of vitamin C and vitamin E (100 mg/kg) produced synergistic effect.
      Glutathione (100 mg/kg i.v.) 5-min pretreatment also reversed the inhibition of
      gastric emptying caused by pyrogallol 100 mg/kg. Ondansetron (3 mg/kg, p.o.)
      significantly reversed the pyrogallol effect. The effect of pyrogallol on
      malondialdehyde (MDA) levels and 5-HT levels in the stomach tissue was also
      studied. Pyrogallol at a dose of 100 mg/kg, i.p., significantly increased MDA
      levels and 5-HT levels in the stomach. Pretreatment with a combination of vitamin
      C and vitamin E (100 mg/kg, p.o.) and glutathione (100 mg/kg, i.v.) significantly
      ameliorated the rise in stomach tissue MDA caused by pyrogallol but had no
      significant effect on the rise in 5-HT levels caused by pyrogallol. The effect of
      different doses of 5-HT on gastric emptying was also studied. 5-HT had a
      differential effect on gastric emptying. The low and high doses (0.1, 0.3 and 30
      mg/kg, i.p.) significantly inhibited the gastric emptying while doses ranging
      from 1 to 10 mg/kg, i.p., had no significant effect on the gastric emptying. The
      pretreatment with antioxidants, combination of vitamin C and vitamin E (100 mg/kg
      each, p.o.) and glutathione (100 mg/kg, i. v.) had no effect on the 5-HT (0.3
      mg/kg, i.p.)-induced delay in gastric emptying. The result indicate the role of
      free radicals gastric emptying, and antioxidants may be of potential therapeutic
      value in disease conditions where free radicals are known to be released and the
      gastrointestinal effects are observed as symptoms or side effects of drug
      therapy.

PMID- 10657759
TI  - Differential effect of antiallergic drugs on IgE-mediated cutaneous reaction in
      passively sensitized mice.
AB  - We investigated the effect of several antiallergic agents on murine IgE-mediated
      biphasic cutaneous reaction. Mice were passively sensitized by an intravenous
      injection of monoclonal anti-dinitrophenol (anti-DNP) IgE antibody. Skin reaction
      was elicited by an epicutaneous challenge of dinitrofluorobenzene (DNFB) and
      occurred biphasically with immediate-phase response (IPR) and late-phase response
      (LPR) at 1 and 24 h, respectively. Classical histamine H1 receptor antagonists
      and some chemical mediator-release inhibitors, such as diphenhydramine and
      terfenadine, inhibited IPR, but not LPR. In contrast, leukotriene B(4) (LTB(4))
      receptor antagonist (ONO-4057) inhibited LPR only. Antagonists for LTC(4), D(4),
      E(4) receptor (ONO-1078) and platelet-activating factor (PAF) receptor (Y-24180)
      significantly inhibited both IPR and LPR, similarly to prednisolone. We recently
      found that a third-phase inflammatory reaction with marked infiltration of
      eosinophils (named very-late-phase response; vLPR), which is supposed to be a
      more important reaction in allergic diseases, was induced, peaking at day 8
      following IPR and LPR in this model. The effect of these drugs on the triphasic
      skin reaction can be scored based on efficacy against IPR / LPR / vLPR; +/+/+
      (prednisolone, a PAF receptor antagonist Y-24180, cyclosporin A and FK-506), +/-/
      (diphenhydramine), +/+/- (azelastine and LT receptor antagonist ONO-1078), and 
      /+/+ (an LTB(4) receptor antagonist ONO-4057). Thus the inhibitory effect on vLPR
      as well as LPR may relate to the inhibition of eosinophil function mediated by
      LTB(4) and PAF and/or T cells. These findings may provide the basis for a
      treatment modality using various antiallergic agents in allergic disease.

PMID- 10657760
TI  - Altered relaxant responses to adenosine and adenosine 5'-triphosphate in the
      corpus cavernosum from men and rats with diabetes.
AB  - The present study was aimed at investigating the effects of diabetes on the
      cavernosal smooth muscle relaxations mediated by adenosine and adenosine
      triphosphate (ATP) in tissues obtained from men and rats. Adenosine- and ATP
      induced relaxant responses showed an enhanced sensitivity with an unaltered
      effectiveness in diabetic men. Adenosine-elicited relaxation in diabetic rat
      corporeal tissues exhibited enhanced effectiveness with unaltered sensitivity,
      whereas ATP-induced relaxations were decreased in diabetic animals when compared
      to control animals. Tetraethylammonium pretreatment, but not glibenclamide, L
      NAME and 8-phenyltheophylline, normalized enhanced apparent affinity to adenosine
      in tissue from diabetic men and effectiveness (E(max)) to adenosine in diabetic
      rats. These results suggest that adenosine-elicited relaxation in diabetes is
      controlled at the receptor level events including K(+) channels in men whereas in
      rats postreceptor-related events including K(+) channels control the adenosine
      induced relaxation. These relaxations to adenosine and ATP in men and rats with
      and without diabetes may be nitric oxide-independent mechanisms. Our results also
      suggest that ATP-induced relaxation did not involve K(ATP) channels and Ca
      activated K(+) channels.

PMID- 10657761
TI  - Lack of efficacy of topical capsaicin in serotonin-induced itch.
AB  - Capsaicin (CAP) has been demonstrated to be an effective topical inhibitor of
      cutaneous vasodilatation, pain and pruritus induced by a variety of chemical and
      physical stimuli. In a previous study, we showed a significantly inhibitory
      effect of topical CAP treatment on histamine-induced itch and cutaneous vascular
      reactions in healthy subjects compared to atopic eczema patients. As serotonin is
      proposed to play a pathophysiological role in some types of pruritus (e.g. uremic
      and hepatic pruritus) and CAP has been described to be successful in hemodialysis
      related pruritus, we investigated the antipruritic effect of topical CAP on
      serotonin-induced reactions in 10 healthy volunteers in comparison to untreated
      skin (UPS) and placebo substance (vehicle)-treated skin (VS). On the first day,
      serotonin iontophoresis was performed in untreated skin. One week later, the
      treatments started, using either CAP 0.05% liniment or a placebo liniment
      (vehicle) 3 times daily over a 5-day period. On day 6, serotonin was applied by
      iontophoresis within the pretreated skin. After another 1-week break, the
      treatments were performed vice versa on the corresponding infrascapular region.
      Weal and flare areas were planimetrically evaluated. Itch sensations were
      documentated by the volunteer on a scale over a 24-min follow-up period. The
      examination also comprised alloknesis, which stands for induction of perifocal
      sensations by usually non-itching stimuli. In CAP-treated skin, serotonin-induced
      wheals were significantly larger post-application compared to non-pretreated
      skin. Wheals were significantly larger in VS than in UPS. Comparison of serotonin
      induced flares in the different study arms did not reveal any significant
      differences. Itch sensations were not significantly reduced by topical CAP
      application. The areas of alloknesis were smaller in capsaicin-treated skin
      compared to VS and UPS, but did not reach significant value. In conclusion,
      topical CAP application is not effective in serotonin-induced itching in healthy
      volunteers. Serotonin is most unlikely to play a role in the mechanism of action
      of CAP.

PMID- 10657762
TI  - Kinetics of plasma and tissue distribution of 9-cis-retinoic acid in rat.
AB  - The biotransformation and tissue distribution of 9-cis-retinoic acid was
      investigated in hairless rats. Indeed, only limited information is available
      about the pharmacokinetics of 9-cis-retinoic acid. Assuming that the target site
      for retinoids is the skin, tissue distribution study is therefore particularly
      justified. Following single oral administration of 30 mg/kg of 9-cis-retinoic
      acid, the parent drug and five metabolites were detected in plasma. Additionally,
      concentrations of 9-cis-retinoic acid and metabolites were determined in the skin
      and seven other tissues. The distribution of 9-cis-retinoic acid was rapid in all
      of the organs studied (T(max) </=2 h). In skin, unchanged 9-cis-retinoic acid was
      still measurable up to 168 h after administration and was undetectable in other
      organs and plasma after 48 h.

PMID- 10657763
TI  - Transglutaminase reactivity of human involucrin.
AB  - Human involucrin (hINV) is assembled into cornified structures via formation of
      transglutaminase (TG)-dependent interprotein epsilon-(gamma-glutamyl)lysine
      bonds. The hINV sequence includes 150 glutamine residues that could function as
      potential sites of cross-link formation. The present studies were designed to
      evaluate the extent to which hINV can function as a TG substrate under optimal
      conditions and in the absence of other substrates. Incubation of hINV with TG
      results in formation of 4-5 isopeptide bonds per hINV molecule. When the small
      amine donor (14)C-putrescine is included in the reaction, 48 Q residues are
      labled. Isotope distribution and sequence analysis suggests that the (14)C
      putrescine-labeled sites are located throughout the protein. Our present results
      show that many hINV Q residues can be utilized for cross-link formation, and that
      hINV can be cross-linked at very high cross-link densities. These results suggest
      that, in vivo, factors other than hINV structure limit the number of residues
      used for cross-link formation.

PMID- 10657764
TI  - Induction of antiproliferative effects in HaCaT cells by a synthetic
      hydroperoxide.
AB  - The effects of decylhydroperoxide (DHP) on proliferation were assessed in HaCaT
      keratinocytes. DHP, a model compound of lipid peroxidation, reduced proliferation
      dose dependently. The analyses of cell number, DNA synthesis and cell cycle
      distribution suggest a delayed progression through S-phase of DHP-treated HaCaT
      cells. It has been proven that necrotic and apoptotic cell death were also causes
      for the DHP-induced decrease in proliferation. Moreover, in HaCaT cultures
      treated with the highest DHP concentration, apoptosis occurred to a much greater
      extent thus playing an overproportional role in the decline in living cell
      number. Results with the radical scavenger ascorbic acid and the iron chelator
      deferoxamine support the conclusion that an iron-catalyzed radical formation from
      DHP may induce the DHP-mediated reduction in proliferation.

PMID- 10657765
TI  - Predicting visual assessment of allergic patch test reactions by non-invasive
      measurements.
AB  - The quantification of allergic patch test reactions to several compounds was
      evaluated on patients using laser Doppler velocimetry (LDV), transepidermal water
      loss and colorimetry. The correlation between visual scores and instrumental
      measurements was investigated by the implementation of a modern statistical
      method: a classification tree. The LDV showed the highest correlation with the
      severity of the reaction. The best prediction model was obtained when the data of
      the three instruments were considered together. Using the classification tree
      methodology, a model of classification, independent of human observation, was
      developed. The technique can not only predict an allergic reaction for a new
      patient, but can also give a measure of how reliable its predictions are. This
      new method, when entirely standardised and approved, could help in the
      harmonisation of patch test reactions in different laboratories, thus allowing a
      more homogenous interpretation of these reactions.

PMID- 10657766
TI  - Comparative caustic and biological activity of trichloroacetic and glycolic acids
      on keratinocytes and fibroblasts in vitro.
AB  - OBJECTIVES: Beside their causticity, the biological mechanism by which
      trichloroacetic acid (TCA) and glycolic acid (GA), two agents extensively used
      for chemical peeling, might act remains unknown. The purpose of this study was to
      examine in vitro the effect of TCA and GA on human keratinocytes and the
      influence of the released epithelial mediators on collagen and matrix
      metalloproteinases (MMPs) production by human dermal fibroblasts. METHOD:
      Cultured keratinocytes were treated by TCA and GA at 10 mg/ml brought to pH 3, 5
      and 7, and the conditioned media neutralized to pH 7 were added to human normal
      skin fibroblasts. RESULTS: TCA was cytotoxic for keratinocytes at each tested pH.
      The conditioned medium depressed protein and collagen synthesis and the
      expression of MMPs when added to fibroblasts as did also TCA when added directly
      to fibroblasts. GA was not cytotoxic for keratinocytes at neutral pH and the
      conditioned medium obtained at each pH applied to fibroblasts did not alter
      protein, collagen nor MMPs production while causing an elevated secretion of IL
      6. CONCLUSION: TCA exerts a toxic effect on keratinocytes and fibroblasts while
      GA does not alter the metabolism of fibroblasts but induces the secretion of IL
      6.

PMID- 10657767
TI  - Broad spectrum herbal therapy against superficial fungal infections.
AB  - Skin disease associated with keratinized tissues in animal and human beings has
      been investigated. The essential oil of Eucalyptus pauciflora in vitro showed
      strong antifungal activity at 1.0 microl/ml against human pathogenic fungi, viz.
      Epidermophyton floccosum, Microsporum audouinii, M. canis, M. gypseum, M. nanum,
      Trichophyton mentagrophytes, T. rubrum, T. tonsurans and T. violaceum. The oil
      has heavy doses of inoculum potential at 1.0 microl/ml. Moreover, it did not
      exhibit any adverse effects on mammalian skin up to 5% concentrations. Further,
      we formulated the oil in the form of ointment 'BSHT' (broad spectrum herbal
      therapy) (1% v/v) and subjected it to topical testing on patients attending the
      outpatient department of M.L.N. Medical College, Allahabad. Fifty patients were
      selected on the basis of KOH-positive results and diagnosed as either tinea
      pedis, tinea corporis or tinea cruris. After the second week of treatment, all
      patients were KOH-negative. At the end of medication, 60% of patients recovered
      completely and 40% showed significant improvement from the disease. No KOH
      negative cases of relapse were observed when patients were re-examined after 2
      months following the end of treatment. Thus, the ointment can be exploited
      commercially after undergoing successful multicenter clinical trials, which are
      in progress.

PMID- 10657768
TI  - [Oral and dental health of a population of school children from the Zou region of
      Benin (1998)].
AB  - Dental caries is becoming increasingly common in developing countries but very
      few attempts have been made to assess its prevalence accurately. We therefore
      carried out an epidemiological survey in 1998 in the south of Benin, to estimate
      the prevalence of dental caries in 300 school children, both boys and girls, aged
      12 to 14 years. Each child underwent a dental examination and interview and the
      data obtained were recorded in a personal clinical record. We determined DMF
      index for various subgroups of children. We then analyzed DMF index and its
      correlation with sex, age, socioeconomic level, the urban or rural origin of the
      child, diet and daily dental hygiene practices. We found that mean DMF index at
      age 12 years was 0.83 (38.7% had dental caries and 4.4% had fillings), and thus,
      61. 3% of the children were free of dental caries. We also found that 80% of the
      children had an accumulation of tartar. More boys than girls had dental caries.
      Rural children were less likely to have dental caries than urban children. The
      prevalence of caries appears to be low despite poor dental hygiene and a lack of
      dental treatment. These results conflict with those of most other studies.
      However, they should be interpreted with caution because the population studied
      was very homogeneous (selection bias), the age of the children could be no more
      than approximate (some were probably younger than 12 and others older than 14,
      because the registry system is inaccurate), there had been health education
      classes in some schools before the survey and it was difficult to define
      socioeconomic level and a sugary diet. For example, the lower socioeconomic level
      (no TV, radio, electricity or tap water) was probably an accurate representation
      of children from the rural area, whereas urban children were proud of being well
      equipped and may have had a tendency to exaggerate. The prevalence of dental
      caries in this population is currently as low as that for most pre-industrial
      African countries. To avoid problems in the future, dental health services
      require reorganization and should stress measures for preventing dental caries:
      changes in dietary habits, the promotion of traditional tooth brushing practices,
      the systematic surveillance of dental caries at school and the removal of tartar.

PMID- 10657770
TI  - [A stromal tumor of the small intestine with schwann cell differentiation].

PMID- 10657769
TI  - [The costs of treating HIV-infected children in Abidjan, Ivory Coast, 1996-1997].
AB  - Little is known about the costs of treating HIV-infected children in Africa.
      However, this is one of the factors that must be taken into account when
      assessing the cost-effectiveness of strategies aimed at reducing the transmission
      of HIV from mother to child. The aim of this study was to estimate the direct
      costs of the treatment of African children born to HIV-infected mothers and the
      additional costs of treating those children who are themselves infected with the
      virus. We assessed the direct costs of care for a sample of children born in 1996
      to HIV-positive mothers participating in a clinical trial to evaluate the
      efficacy of administering a short course of zidovudine to the mother in the peri
      partum period, in Abidjan, Ivory Coast (DITRAME ANRS 049a). We systematically
      reviewed the medical records of these children and recorded drug prescriptions,
      clinical investigations, consultations with medical specialists, hospital
      admissions and transportation costs during their first year of life. This study
      included 78 children, 15 of whom were HIV-positive. The mean cost of treatment
      was 1,671 FF (254 Euros) per child-year for infected children, 709 FF (108 Euros)
      more than the mean cost of treatment for HIV-negative children born to HIV
      positive mothers. Thus, HIV infection resulted in a 74% increase in treatment
      costs. The mean cost of a drug prescription was 50 FF (7.6 Euros), and could have
      been halved if only generic drugs had been prescribed. This study was limited to
      the direct costs of pediatric HIV infection and did not take into account the
      cost of health service provision in Ivory Coast or the indirect costs for the
      family. These results were obtained in the context of a prospective clinical
      trial within a system providing free and unlimited access to health care. In a
      city where the mean salary of a civil servant is 900 FF (137 Euros) per month,
      the expenditure necessary to pay for the basic care of one HIV-infected child is
      high. Health-care services in sub-Saharan Africa should make more use of generic
      drugs and pediatric HIV infection provides a clear example of the benefits to be
      obtained by such a rational strategy for the use of scarce health resources.

PMID- 10657771
TI  - [Esophageal perforation, a complication of endoscopic sclerotherapy for
      esophageal varices].

PMID- 10657772
TI  - [Exotropia in black Cameroonians].
AB  - We carried out this study to increase our knowledge and understanding of
      exotropia (divergent strabismus) in general, but particularly in black people, in
      whom it occurs more frequently. We carried out a prospective study in the
      department of ophthalmology of Douala General Hospital from November 1991 to June
      1998. All patients underwent oculomotor examination and skiascopye. In a series
      of 225 consecutive strabismus cases, we identified 147 cases of exotropia
      (59.51%) in 67 male patients (45.58%) and 80 female patients (54.42%). In 59.86%
      of these cases, exotropia was evident before the age of one year and 59.19% had
      amblyopia. The mean age at first examination was 17.04 years (+/- 12.12 years).
      Hyperopia was the most common form of ametropia (59.86%) and 39 patients (26.53%)
      had parents, children or siblings who also had exotropia. We found that exotropia
      was the most common form of strabismus in black people in Cameroon and that it
      spontaneously progressed to amblyopia in a significant number of cases. We
      therefore recommend early, active treatment.

PMID- 10657773
TI  - [Prevention of wasting and opportunistic infections in HIV-infected patients in
      West Africa: a realistic and necessary strategy before antiretroviral treatment].
AB  - The medical inequalities between countries of the North and South
      (infrastructure, drug availability, medical techniques) are particularly marked
      in terms of the challenge posed by HIV infection. We propose a strategy for
      monitoring adult patients in West Africa that is appropriate to the situation in
      the field and to economic constraints. The aim of this strategy is to increase
      the quality of life and the life expectancy of HIV-infected adults and to prevent
      the overcrowding of hospital departments with patients in the terminal phase of
      AIDS. We analyzed the biological and clinical spectrum of HIV infection before
      the onset of the diseases that define AIDS (excluding pulmonary tuberculosis). We
      found that it was particularly important to diagnose B-stage diseases early,
      especially atypical chronic cutaneous and mucous diseases. Careful analysis of
      data from a routine hemogram (total lymphocyte count 2500/ml; paradoxical
      eosinopenia), even in the absence of a CD4 lymphocyte count, should also enable
      clinicians from a wide variety of health structures to identify the HIV-infected
      patients most likely to benefit from more detailed clinical follow up,
      prophylaxis of opportunistic infections using cotrimoxazole, nutritional checkups
      and prevention of wasting. Cachexia is the most common AIDS-associated disease in
      West African patients. It involves an overall decrease in calorific intake,
      diarrhea, immune system activation, an increase in TNFalpha production and
      greater energy expenditure when resting. Recent nutritional studies have shown
      that it is vital to optimize the calorific intake of HIV-infected patients
      presenting with chronic diarrhea, before the onset of severe immune deficiency,
      to prevent wasting. So, spontaneous calorific intake should de routinely
      determined in HIV-infected patients and an optimal diet provided. Specific
      training in nutrition is required for doctors and nurses, as is consideration of
      the logistic organization required to provide nutritional support to HIV-infected
      adults. Despite the large number of individuals infected and the lack of
      sophisticated paraclinical facilities, we feel that it is possible to establish
      rational management "a minima" of HIV infection in West Africa, whilst waiting
      for antiretroviral drugs to become more widely available. This strategy could be
      of direct benefit to patients without swallowing up the financial resources of
      the health system in expensive biological follow up. Such basic management is
      also required before the new antiretroviral drugs become widely available.
      Research should be carried out in parallel in several reference centers in West
      Africa to determine the most effective associations of antiretroviral drugs and
      the optimal timing of treatment during the course of infection and to assess the
      potential side effects of these drugs in HIV patients exposed to recurrent
      antigenic stimulation by a wide diversity of pathogens.

PMID- 10657774
TI  - Pernicious anemia: the African experience (3 cases reports).
AB  - We report three cases of pernicious anemia diagnosed in women in Africa. All
      three women had macrocytic anemia with megaloblasts evident on medullogram. The
      patients had neurological signs of combined sclerosis and the presence of
      megaloblasts confirmed the diagnosis of pernicious anemia. All were successfully
      treated parenterally with vitamins. This disease seems to be underdiagnosed in
      Africa given the number of cases reported in previous studies.

PMID- 10657775
TI  - [Support program for the implementation of the Bamako initiative: analysis of the
      creation of eight health districts, Gnagna province].
AB  - The implementation of the Bamako initiative is a central pillar of the health
      policy of Burkina Faso. The NGO, ASI, working with the health authorities, has
      set up a program involving the creation of eight health districts in the province
      of Gnagna. The program covers a population of 115,000 inhabitants in 134 villages
      and was progressively established between 1994 and 1997. The health districts
      were set up in phases (2 in the first year and 3 in each of the following two
      years). The method used to select the members of the village management
      committees is one of the key aspects of the program. It required a large amount
      of effort to increase the awareness of villages, and much activity because each
      committee is elected by the various villages of the district. The training of the
      managers of these committees and of the managers of the pharmaceutical warehouses
      in each district is also a key element. In our initial assessment, we noted
      balance in the accounting of the pharmaceutical warehouses of each district,
      adhesion of the population to the program, dynamics in the management committees
      and, above all, the autonomy of the committees. The first results in terms of
      health are very fragmentary and difficult to interpret because the program has
      been running for such a short time. We considered the long-term elements of the
      program, the necessity to set up a system for monitoring activities and the
      quality of care. An initial assessment showed a clear improvement in the
      availability of drugs in the 8 districts. Health promotion activities have not
      yet been developed in these districts. This type of program requires the follow
      up and support of the management committees, and will be the object of the second
      phase, begun in 1998.

PMID- 10657776
TI  - [Evaluation of the psychological consequences of environmental catastrophes: a
      feasibility study based on the 1992 floods in the Vaucluse].
AB  - Scientific studies of environmental disasters, whether human or natural in
      origin, have shown that the psychological impact of such events may be
      considerable and long-lasting. Several natural disasters have occurred in France,
      but their impact on public psychological health has not been assessed. In
      September 1992, there was a major flood in southeast France (Vaucluse), which
      caused 38 deaths. Four years later, we performed a pilot cross-sectional study to
      assess the feasibility of a larger epidemiological study to assess the
      psychological impact of this flood. Two affected towns were chosen for this
      study: Vaison-la-Romaine (VLR), where the flood was very sudden and 29 people
      were killed, and Bedarrides, where the water level rose more slowly. In
      Bedarrides, households were randomly selected from a list of victims (n = 100)
      and in Vaison-la-Romaine, households were randomly selected from the telephone
      directory (n = 140). Exposure to the flood was assessed by a series of questions,
      the answers to which were used to calculate an exposure score. The questionnaire
      also included psychometric scales for post-traumatic stress disorder (QE-PTSD),
      anxiety (Spielberger State-Trait Anxiety Inventory) and depression (Beck
      Depression Inventory). In Bedarrides, the participation rate was high: 69% of the
      selected households were successfully contacted and found to be eligible for
      inclusion and 74% agreed to a face-to-face interview. In Vaison-la-Romaine, 51%
      of the selected households were contacted and eligible and 50% agreed to the face
      to-face interview. Our survey showed that exposure was multidimensional and that
      it was possible to calculate an exposure score suitable for the analysis of
      exposure-effect relationships. The PTSD scale was completed well by the
      interviewees, several of whom did not fill in the depression and anxiety scales
      correctly. However, analysis of the responses obtained showed that these tools
      had a high level of internal consistency. Cross-correlations between the various
      psychological scales used in this study were highly significant (p < 10-4). There
      was some degree of association between some psychometric scales and exposure.
      This pilot study shows that a cross-sectional study of the long-term
      psychological consequences of an environmental disaster could be carried out
      several years after the event but that the feasibility of such a study depends
      ultimately on its acceptance by the public and the relevant authorities. It
      underlines the need to collect exposure data immediately after the event and
      enabled us to identify and to adapt the tools required for this kind of
      evaluation. It should encourage public health decision-makers to support such
      evaluation and to improve the psychological and social support available to
      people exposed to floods.

PMID- 10657778
TI  - [Problems with the approach to diagnosis and treatment of testicular cancer in a
      developing country: the case of an eight-year-old boy from Cameroon].
AB  - Testicular cancer is believed to be rare among members of the black sub-Saharan
      population and has therefore been little studied in Africa. This may account for
      the problems encountered in the treatment of this condition, which are perfectly
      illustrated by this clinical case. We present here a brief report of the optimal
      diagnostic methods and therapeutic indications for this malignant disease.

PMID- 10657777
TI  - [Cost of tetanus toxoid injection using a jet-injector (Imule) in collective
      immunization in Senegal: comparison with injection using a syringe and
      resterilizable needle].
AB  - Needle-less jet injectors were developed by the US army after World War II. Their
      principal use, however, has been in the administration of lyophilized vaccines
      from multidose vials to at-risk populations in developing countries. In 1983, a
      hepatitis B epidemic occurred among customers of a beauty clinic in California
      (USA) following the use of jet-injectors, demonstrating a clear risk of cross
      contamination associated with this technique. As a result, the WHO and Unicef
      stopped recommending jet-injectors for collective immunizations in developing
      countries. To eliminate the risk of contamination, Pasteur Merieux Serums et
      Vaccins (now Aventis Pasteur) developed, in 1990, jet-injectors for use with
      single-use vaccine cartridges. These injectors were tested for tetanus toxoid,
      DTP, influenza, hepatitis A and typhoid Vi vaccination. The immunogenic reaction
      was as strong and the injection as well tolerated as for injections using a
      standard needle and syringe. The additional cost of the Imule technique was
      evaluated in a district-wide (127,000 inhabitants) tetanus toxoid immunization
      program at Velingara, Senegal in 1993. The total cost was estimated to be 1.51 FF
      (76 F CSA, 0.32 US dollars) for one dose of tetanus vaccine given by needle and
      syringe and 2.41 FF (121 F CSA, 0.56 US dollars) for one dose given by Imule.
      Thus, the additional cost of injection by ImuleTM was 0.90 FF (45 F CSA, 0.21 US
      dollars). The cost of cross infection in sub-Saharan Africa has been estimated to
      be 2.37 FF (118 F CSA, 0.55 US dollars) per injection if injection practices are
      not supervised. Therefore, the Imule technique may be considered to be cost
      effective. However, the technique is still not completely reliable, as shown by
      the total breakdown of four jet injectors during this vaccination session.
      Lyophilized vaccines have also not been tested in the field. Vaccinators prefer
      Imule, training is easy and immunization can be carried out on a day-to-day basis
      with no vaccine wastage. Imule is not yet in mass production, which would reduce
      costs. In the face of the ever-increasing risk of cross-contamination during
      vaccination sessions in sub-Saharan Africa, the Imule technique deserves
      considerable attention.

PMID- 10657780
TI  - Listening to more voices

PMID- 10657779
TI  - [Frequency and susceptibility to antibiotics of Neisseria gonorrhoeae at Lome].
AB  - A cross-sectional study was carried out by the bacteriology laboratory of the
      Lome-Tokoin University Hospital, to determine the frequency of gonorrhea in
      patients providing vaginal or urethral samples, and to investigate the
      susceptibility of N. gonorrhoeae to antibiotics. The samples were treated
      according to classic bacteriological methods and the disk diffusion tests were
      used to investigate antibiotic susceptibility. The samples were taken from 420
      patients, 246 of whom were male (26.86% ?NdT: d'ou vient ce chiffre??, 58.33% si
      420 patients, 61.19% si 402 patients?) and 156 of whom were female (37.14% ?NdT:
      plutot 38.8% si 402 patients?) ?NdT: et le reste?? Il me semble que c'est plutot
      402 patients en total (= 246 + 156). Sinon il y a 18 patients qui ne sont ni male
      ni femelle?!?. N. gonorrhoeae was isolated from 88 patients, giving a prevalence
      of 20.95% ?NdT: ou 21.89% si 402 patients?. We isolated strains of the bacterium
      from 76 men (25.78% ?NdT: incorrect, 30. 89%? and 12 women (7.69%).
      Ciprofloxacin, ofloxacin and netilmicin were the most effective antibiotics. The
      cyclins, cotrimoxazole and penicillin were less effective.

PMID- 10657781
TI  - Join ENA in nashville!!

PMID- 10657782
TI  - Emergency nurses have a voice--will they use it in 2000?

PMID- 10657784
TI  - Lyme vaccine: some caveats

PMID- 10657783
TI  - Benchmarking ED staffing: ENA's new database helps.

PMID- 10657785
TI  - Nursing triage indispensable to ED care: "Zero waiting room time" has been proved
      a fad

PMID- 10657787
TI  - The most important scientific breakthrough of the last millennium

PMID- 10657786
TI  - Innovative plan for drug-seeking patients

PMID- 10657788
TI  - Acute MI: an atypical presentation.

PMID- 10657789
TI  - The use of ultrasound in blunt trauma.

PMID- 10657790
TI  - Ambulatory payment classifications.

PMID- 10657791
TI  - Inside washington

PMID- 10657792
TI  - Thrombolytic therapy for patients with acute stroke in the ED setting.

PMID- 10657793
TI  - As we celebrate: reflections on Anita Dorr and early ENA days.

PMID- 10657794
TI  - A conversation with ENA co-founder, Judy Kelleher, RN, MSN, CEN. Interview by
      Iris C Frank.

PMID- 10657795
TI  - CEN review questions

PMID- 10657796
TI  - Tips on avoiding lidocaine infiltration for simple wound repairs and using LET
      effectively in the emergency department: one pediatric ED nurse's experience.

PMID- 10657797
TI  - The ED rapid sequence intubation drug organizer.

PMID- 10657798
TI  - Clinical nurses forum

PMID- 10657799
TI  - A model for prehospital personnel continuing education.

PMID- 10657800
TI  - From the feds

PMID- 10657801
TI  - A duty to follow up on laboratory reports.

PMID- 10657802
TI  - Managers forum

PMID- 10657803
TI  - Media reviews

PMID- 10657804
TI  - The triage game.

PMID- 10657805
TI  - Coping with asthma: the National Institutes of Health Asthma Guidelines.

PMID- 10657806
TI  - What do we really KNOW about telephone triage?

PMID- 10657807
TI  - Is the SANE role within the scope of nursing practice? On "pelvics,"
      "colposcopy," and "dispensing of medications".
AB  - Clearly communicating with other professionals and with sexual assault survivors
      about the boundaries and imitations of the SANE medical-forensic examination is
      important. Although SANEs work cooperatively in an interdisciplinary sexual
      assault response team model to better meet the needs of sexual assault victims,
      they function as independent professional nurses in their role of collecting
      medical forensic evidence. Properly defined to focus on assessment,
      identification, and documentation of trauma, the SANE role is an independent
      professional role but is still within the scope of basic nursing practice. The
      answer to our question, "Is the SANE role advanced practice nursing or is it
      within the scope of basic nursing practice?" is thus "The SANE role is clearly
      within the scope of basic nursing practice."

PMID- 10657808
TI  - Quality management survival strategies for the trauma coordinator.

PMID- 10657810
TI  - Village

PMID- 10657809
TI  - An 8-day-old infant with poor perfusion and diaphoresis.

PMID- 10657811
TI  - Continuing education test

PMID- 10657812
TI  - Making an impact on pediatric bone health.

PMID- 10657813
TI  - As good as the real thing.

PMID- 10657814
TI  - Cytokine dysregulation in the hyperimmunoglobulinemia E syndrome.

PMID- 10657815
TI  - Can children follow a fat-modified diet and have adequate nutrient intakes
      essential for optimal growth and development?

PMID- 10657816
TI  - Universal newborn screening for hemoglobinopathies.

PMID- 10657817
TI  - Defects in energy metabolism: coming of age, slowly.

PMID- 10657818
TI  - Short stature and delayed puberty in gymnasts: influence of selection bias on leg
      length and the duration of training on trunk length.
AB  - BACKGROUND: Delays in bone age, the onset of puberty, and skeletal growth in
      gymnasts could be, in part, the reason for an interest in gymnastics, rather than
      being the result of vigorous exercise. We hypothesized that short stature and
      delayed bone age are present at the start of gymnastics, and training delays
      growth, producing short stature, even after retirement. METHODS: Sitting height
      and leg length were measured in 83 active female gymnasts, 42 retired gymnasts,
      and 154 healthy control subjects. Results were expressed as age-specific SD
      scores (mean +/- SEM). RESULTS: In the cross-sectional data, active gymnasts had
      delayed bone age (1.3 +/- 0.1 years), reduced height -1.32 +/- 0.08 SD, sitting
      height -1.24 +/- 0.09 SD, and leg length, -1.25 +/- 0.08 SD (all P <.001).
      However, in those training for less than 2 years, the deficit was confined to leg
      length (-0.8 +/- 0.2 SD). During 2 years of follow-up of 21 gymnasts, only the
      deficit in sitting height worsened (by 0.4 +/- 0.1 SD). In 13 gymnasts followed
      up in the immediate 12 months after retirement, sitting height accelerated,
      resulting in a lessening of the deficit in sitting height by 0.46 +/- 0.14 SD (P
      <.01). Adult gymnasts who had been retired for 8 years had no deficit in sitting
      height, leg length, or menstrual dysfunction. CONCLUSIONS: Short stature in
      active gymnasts is partly due to selection of individuals with reduced leg
      length. Reduced sitting height is likely to be acquired but is reversible with
      cessation of gymnastics. A history of gymnastic training does not appear to
      result in reduced stature or menstrual dysfunction in adulthood.

PMID- 10657819
TI  - Augmented trochanteric bone mineral density after modified physical education
      classes: a randomized school-based exercise intervention study in prepubescent
      and early pubescent children.
AB  - BACKGROUND: Of the few exercise intervention studies focusing on pediatric
      populations, none have confined the intervention to the scheduled physical
      education curriculum. OBJECTIVE: To examine the effect of an 8-month school-based
      jumping program on the change in areal bone mineral density (aBMD), in grams per
      square centimeter, of healthy third- and fourth-grade children. STUDY DESIGN: Ten
      elementary schools were randomized to exercise (n = 63) and control groups (n =
      81). Exercise groups did 10 tuck jumps 3 times weekly and incorporated jumping,
      hopping, and skipping into twice weekly physical education classes. Control
      groups did regular physical education classes. At baseline and after 8 months of
      intervention, we measured aBMD and lean and fat mass by dual-energy x-ray
      absorptiometry (Hologic QDR-4500). Calcium intake, physical activity, and
      maturity were estimated by questionnaire. RESULTS: The exercise group showed
      significantly greater change in femoral trochanteric aBMD (4.4% vs 3.2%; P <.05).
      There were no group differences at other sites. Results were similar after
      controlling for covariates (baseline aBMD change in height, change in lean,
      calcium, physical activity, sex, and ethnicity) in hierarchical regression.
      CONCLUSIONS: An easily implemented school-based jumping intervention augments
      aBMD at the trochanteric region in the prepubertal and early pubertal skeleton.

PMID- 10657820
TI  - Why is exercise capacity reduced in subjects with pectus excavatum?
AB  - BACKGROUND: Exercise capacity is often limited in subjects with pectus excavatum
      (PE), but the mechanism is unknown. OBJECTIVES: We attempted to quantify exercise
      capacity and to investigate whether limitation of venous return to the heart
      contributes to exercise intolerance in PE. METHODS: A total of 13 patients with
      PE (mean age, 19 +/- 6 years) and 20 control subjects (mean age, 25 +/- 11 years)
      underwent sitting and supine incremental cycling and exercise Doppler stroke
      volume (SV) measurements. RESULTS: Supine peak oxygen uptake (V'O(2)max) for the
      patients (1351 +/- 345 mL/min) and control subjects (1505 +/- 330 mL/min) was not
      different. In contrast, sitting V'O(2)max was lower in the patients than in the
      control subjects, 1480 +/- 462 and 1994 +/- 581 mL/min, respectively (P =.02).
      Supine exercise SV was not different between groups. Moreover, only in the
      patients with PE was supine exercise SV, 70 +/- 18 mL, higher than sitting
      exercise SV, 55 +/- 14 mL (P =.015). The corresponding values for the control
      subjects were 70 +/- 18 mL and 65 +/- 19 mL (P = NS). CONCLUSIONS: Patients with
      PE exercising in the sitting position have reduced V'O(2)max and SV, whereas
      during supine exercise they approached the control values. The supine advantage
      in PE suggests that upright exercise capacity in this disease is affected by
      reduced filling of the heart in the non-supine position.

PMID- 10657821
TI  - Efficacy of vaccination with live attenuated, cold-adapted, trivalent, intranasal
      influenza virus vaccine against a variant (A/Sydney) not contained in the
      vaccine.
AB  - OBJECTIVE: To determine the safety, immunogenicity, and efficacy of revaccination
      of children with live attenuated influenza vaccine. STUDY DESIGN: A 2-year
      multicenter, double-blind, placebo-controlled, efficacy field trial of live
      attenuated, cold-adapted trivalent influenza vaccine administered by nasal spray
      to children. This report summarizes year 2 results, a year in which the epidemic
      strain of influenza A/Sydney was not well matched to the vaccine strains. Each
      year, vaccine strains were antigenically equivalent to the contemporary
      inactivated influenza vaccine. In year 2, a single intranasal revaccination was
      administered. Active surveillance for influenza was conducted during the
      influenza season by means of viral cultures. Influenza cases were defined as
      illnesses with wild-type influenza virus isolated from respiratory secretions.
      RESULTS: In year 2, 1358 (85%) children, 26 to 85 months of age, returned for
      revaccination. The intranasal vaccine was easily accepted, well tolerated, and
      immunogenic. Revaccination resulted in 82% to 100% of the vaccinated children in
      a subset studied for immunogenicity being seropositive as compared with 26% to
      65% of placebo recipients, depending on the influenza strain tested. No serious
      adverse events were associated with the vaccine. In addition to the strains in
      the vaccine, antibody was induced to the variant strain A/Sydney/H3N2. In year 2,
      influenza A/Sydney/H3N2, a variant not contained in the vaccine, caused 66 of 70
      cases of influenza A; nonetheless, intranasal vaccine was 86% efficacious in
      preventing A/Sydney influenza. Eight cases of lower respiratory tract disease
      were associated with A/Sydney influenza; all cases were in the placebo group.
      CONCLUSIONS: This live attenuated, cold-adapted influenza vaccine was safe,
      immunogenic, and efficacious against influenza A/H3N2 (including a variant,
      A/Sydney, not contained in the vaccine) and influenza B. The characteristics of
      this vaccine make it suitable for routine use in children to prevent influenza.

PMID- 10657822
TI  - Defective interleukin-12/interferon-gamma pathway in patients with
      hyperimmunoglobulinemia E syndrome.
AB  - OBJECTIVE: Patients with the hyperimmunoglobulinemia E (hyper-IgE) syndrome are
      reported to have defective production of interferon gamma (IFN-gamma). Because
      IFN-gamma is a major activator of polymorphonuclear leukocytes (PMNs), this could
      result in defective PMN chemotaxis and markedly elevated IgE levels because of
      the unopposed action of interleukin (IL)-4. IL-12, an important enhancer of IFN
      gamma production, also suppresses IgE production. This study assessed the IL
      12/IFN-gamma pathway in patients with hyper-IgE syndrome. METHODS: Production of
      IL-12 and IFN-gamma by mononuclear cells from 10 patients with hyper-IgE syndrome
      in response to a number of stimuli was determined, as well as the effect of IL-12
      on IFN-gamma release and cell proliferation. RESULTS: IL-12 and IFN-gamma
      production by the patients' cells was similar to that of control subjects
      independent of the stimulus used, except for Staphylococcus aureus, with which
      cells of patients with hyper-IgE syndrome released markedly less IFN-gamma
      (19.8%; P <.002). The ability of recombinant IL-12 to enhance IFN-gamma release
      from patients' cells in response to all stimuli was, however, significantly lower
      than with control cells (12% to 51%; P <.03). CONCLUSION: The lymphocytes of
      patients with hyper-IgE syndrome have an impaired response to IL-12, resulting in
      decreased IFN-gamma production, which may be of key importance in the
      pathogenesis of the immune abnormalities of hyper-IgE syndrome.

PMID- 10657823
TI  - Nutrient intakes and dietary patterns of young children by dietary fat intakes.
AB  - OBJECTIVE: To determine whether low fat intake is associated with increased risk
      of nutritional inadequacy in children 2 to 8 years old and to identify eating
      patterns associated with differences in fat intake. STUDY DESIGN: Using 2 days of
      recall from the Continuing Survey of Food Intake by Individuals (CSFII), 1994 to
      1996, we classified 2802 children into quartiles of energy intake from fat (<29%,
      29% to 31.9% [defined as moderate fat], 32% to 34.9%, and > or =35%) and compared
      nutrient intakes, the proportion of children at risk for inadequate intakes, Food
      Pyramid servings, and fat content per serving across quartiles. RESULTS: More
      children in quartile 2 were at risk for inadequate intakes of vitamin E, calcium,
      and zinc than children in higher quartiles (P <.0001); more children in quartiles
      3 and 4 were at risk for inadequate intakes of vitamins A and C and folate (P
      <.001). Fruit intake decreased across quartiles (P <.0001); whereas vegetable,
      meat, and fat-based condiment intakes increased (P <.0001). Fat per serving of
      grain, vegetables, dairy, and meat increased across quartiles (P <.0001).
      CONCLUSIONS: Moderate-fat diets were not consistently associated with an
      increased proportion of children at risk for nutritional inadequacy, and higher
      fat diets were not consistently protective against inadequacy. Dietary fat could
      be reduced by judicious selection of lower-fat foods without compromising
      nutritional adequacy.

PMID- 10657824
TI  - Nutritional status of children with cystic fibrosis measured by total body
      potassium as a marker of body cell mass: lack of sensitivity of anthropometric
      measures.
AB  - OBJECTIVE: To investigate measures aimed at defining the nutritional status of
      cystic fibrosis (CF) populations, this study compared standard anthropometric
      measurements and total body potassium (TBK) as indicators of malnutrition.
      METHODS: Height, weight, and TBK measurements of 226 children with CF from Royal
      Children's Hospital, Brisbane, Australia, were analyzed. Z scores for height for
      age, weight for age, and weight for height were analyzed by means of the National
      Centre for Health Statistics reference. TBK was measured by means of whole body
      counting and compared with predicted TBK for age. Two criteria were evaluated
      with respect to malnutrition: (1) a z score < -2.0 and (2) a TBK for age <80% of
      predicted. RESULTS: Males and females with CF had lower mean height-for-age and
      weight-for-age z scores than the National Centre for Health Statistics reference
      (P <.01), but mean weight-for-height z score was not significantly different.
      There were no significant gender differences. According to anthropometry, only
      7.5% of this population were underweight and 7.6% were stunted. However, with TBK
      as an indicator of nutritional status, 29.9% of males and 22.0% of females were
      malnourished. CONCLUSION: There are large differences in the percentage of
      patients with CF identified as malnourished depending on whether anthropometry or
      body composition data are used as the nutritional indicator. At an individual
      level, weight-based indicators are not sensitive indicators of suboptimal
      nutritional status in CF, significantly underestimating the extent of
      malnutrition. Current recommendations in which anthropometry is used as the
      indicator of malnutrition in CF should be revised.

PMID- 10657825
TI  - Parent and child mealtime behavior in families of children with cystic fibrosis.
AB  - OBJECTIVES: We investigated the hypothesis that children with cystic fibrosis
      (CF) and their parents would show more maladaptive behaviors during dinner than
      children without CF and their parents. STUDY DESIGN: Children with CF (n = 32)
      and their parents were compared with 29 children without CF and their parents on
      the rate and frequency of parent-child behaviors during a typical dinner in the
      families' homes by using multivariate analyses of variance. RESULTS: When the
      rate of behavior, controlling for meal length, was examined, no differences were
      found between groups. However, parents of children with CF were found to differ
      from parents of control subjects in the frequency of direct and indirect commands
      (P <.05), coaxes (P <.01), physical prompts (P <.01), and feeding their child (P
      <.05). Children with CF were found to engage in more talk, spend more time away
      from the table, refuse food, and exhibit more noncompliance toward commands to
      eat than control children (P <.05 for all child variables). When behaviors were
      examined as a function of meal phase, parents of children with and without CF
      both showed an increase in commands (P <.01), coaxes (P <.05), feeds (P <.01),
      and physical prompts (P <.01) in the second half of the meal as compared with the
      first. Children with CF and the control children showed an increase in behaviors
      incompatible with eating during the second half of the meal compared with the
      first (P <.01). When faster eaters were compared with slower eaters, faster
      eaters consumed a higher percentage of the recommended daily allowance of energy
      (P <.01) than slower eaters and showed a trend to be at higher weight percentiles
      for age and sex (P =.08) regardless of group (CF or control). CONCLUSIONS:
      Children with CF and their parents do not differ from children without CF and
      their parents in the rate of behaviors exhibited or types of strategies used to
      encourage eating. However, children with CF and their parents engage in these
      behaviors more frequently. Our data do not support typical parenting behaviors as
      effective in meeting the CF dietary requirements. Additional support in the form
      of child behavior management training may be needed to assist parents in meeting
      their child's caloric requirements.

PMID- 10657826
TI  - Universal versus targeted screening of infants for sickle cell disease: a cost
      effectiveness analysis.
AB  - OBJECTIVE: To compare the health outcomes, costs, and incremental cost
      effectiveness of universal neonatal screening for sickle cell disease (SCD) with
      screening targeted to African Americans. STUDY DESIGN: A cost-effectiveness
      analysis was done by using a Markov simulation model that considered the costs
      and outcomes associated with the prevention and treatment of sepsis in those with
      sickle cell anemia and sickle beta(0)-thalassemia. Three strategies were
      compared: (1) no screening, (2) targeted screening of African Americans, and (3)
      universal screening for SCD. RESULTS: In the base case analysis, targeted
      screening of African Americans compared with no screening cost $6709 per
      additional year of life saved, and universal screening compared with targeted
      screening cost $30,760 per additional year of life saved. In a sensitivity
      analysis, the cost per additional year of life saved with universal screening
      compared with targeted screening was positively correlated with the delivery rate
      of targeted screening and was inversely related to the proportion of African
      Americans in the population. CONCLUSIONS: Targeted screening of African American
      newborns for SCD compared with no screening is always cost-effective. Universal
      screening compared with targeted screening always identifies more infants with
      disease, prevents more deaths, and is cost-effective given certain delivery rates
      for targeted screening and proportions of African Americans in the population.

PMID- 10657827
TI  - Cerebral white matter disease in children may be caused by mitochondrial
      respiratory chain deficiency.
AB  - Several mitochondrial diseases are known to occasionally involve the cerebral
      white matter, namely Leigh syndrome, Kearns-Sayre syndrome, and MELAS syndrome,
      but in these cases the major finding is alteration in the basal ganglia and
      brainstem. Here we report on severe diffuse white matter involvement and
      respiratory chain enzyme deficiency or mitochondrial DNA rearrangement in 5
      unrelated families. It is interesting that white matter lesions were the only
      abnormal neuroradiologic feature in 3 of the 5 families, and multiple small cyst
      like white matter lesions were found in 2 of 5 probands. Respiratory chain
      deficiency should be considered in the diagnosis of severe white matter
      involvement in childhood.

PMID- 10657828
TI  - Feasibility and safety of AS-3 red blood cells for neonatal transfusions.
AB  - OBJECTIVES: Most extremely low birth weight (<1 kg) infants receive red blood
      cell (RBC) transfusions. RBCs stored up to 42 days can be transfused safely in
      small volumes to preterm infants; however, because the formulation of RBC
      anticoagulant/preservative solutions differs, clinical studies are required to
      document the safety of each solution before widespread use. Our goal was to study
      the feasibility and safety of AS-3 anticoagulant/preservative solution to preterm
      infants. STUDY DESIGN: Two clinical studies were conducted in sequence: (1) a
      randomized trial to compare RBC transfusions given as stored (< or =42 days) AS-3
      RBCs (11 infants) versus fresh (< or = 7 days) citrate, phosphate, dextrose, and
      adenine RBCs (10 infants) and (2) a subsequent evaluation of the safety of stored
      AS-3 RBCs in 33 additional preterm infants given 120 AS-3 RBC transfusions.
      RESULTS: Results of both the randomized study and the subsequent evaluation
      documented that AS-3 RBCs stored < or =42 days and transfused in small volumes
      (15 mL/kg) were safe for RBC transfusions of preterm infants. Donor exposure was
      significantly reduced, clinical transfusion reactions were rare, and post
      transfusion blood hematocrit, pH, and plasma Na, K, Ca, lactate, and glucose
      measurements were similar when AS-3 and citrate, phosphate, dextrose, and adenine
      RBC transfusions were compared. CONCLUSIONS: AS-3 RBCs can be used safely for
      small-volume RBC transfusions for preterm infants.

PMID- 10657829
TI  - Changing practices of red blood cell transfusions in infants with birth weights
      less than 1000 g.
AB  - OBJECTIVE: Extremely low birth weight (ELBW) infants frequently undergo
      transfusion because they are critically ill, often need artificial ventilation,
      and have the highest blood sampling loss in relation to their weight. During the
      last decade our transfusion guidelines were changed 3 times to become more
      restrictive. We hypothesized that these modifications substantially decreased the
      number of transfusions in our ELBW infants. METHODS: We performed a single-center
      analysis of 256 infants with birth weights from 500 to 999 g who were admitted
      from 1989 to 1997 and included 3 study periods, each starting with newly modified
      transfusion guidelines in April 1989, September 1991, and January 1995. We
      evaluated prospectively recorded clinical data and retrospective chart analysis
      for transfusion-related information. RESULTS: The median number of transfusions
      per infant decreased from 7 in the first period to 2 in the third period, whereas
      donor exposure decreased from 5 to 1 and blood volume transfused decreased from
      131 to 37 mL/kg birth weight (P <.01). The median venous hematocrit measured
      before transfusion decreased from 43% to 35% in infants who underwent ventilation
      and from 41% to 31% in spontaneously breathing infants. The median birth weight
      decreased from 870 to 740 g and the median gestational age from 27 to 25
      completed weeks (P <.01). The overall survival rate was 75% and did not change.
      The incidences of retinopathy, intraventricular hemorrhage, and patent ductus
      arteriosus remained unchanged. CONCLUSION: Over this 9-year period with
      increasingly restrictive transfusion guidelines, the transfusion number decreased
      by 71% and the donor exposure by 80% in ELBW infants without adverse clinical
      effects.

PMID- 10657830
TI  - Oropharyngeal dysphagia and aspiration in patients with ataxia-telangiectasia.
AB  - OBJECTIVES: To determine whether patients with ataxia-telangiectasia exhibit
      oropharyngeal dysphagia with concomitant aspiration and to examine the
      relationships among swallowing function, age, and nutritional status. STUDY
      DESIGN: Seventy patients (mean age, 10.7 years; range, 1.8 to 30 years) had
      feeding/swallowing and nutritional evaluations. Fifty-one patients, in whom there
      were concerns about swallowing safety, were examined with a standardized
      videofluoroscopic swallow study. RESULTS: Fourteen of the 51 patients (27%) with
      histories suggestive of dysphagia demonstrated aspiration. Of these, silent
      aspiration (aspiration without a cough) occurred in 10 (71%) patients. Aspirators
      were significantly older than non-aspirators (mean age, 16.9 vs 10.8 years; P
      =.002). Advancing age was the strongest factor associated with aspiration during
      continuous drinking (P =.01). In patients with ataxia-telangiectasia, weight and
      weight/height were abnormally low at all ages and most compromised in older
      patients. Patients who aspirated had significantly lower mean weight (P <.002)
      and weight/height z scores (P <.001) than did patients who did not aspirate.
      CONCLUSIONS: Oropharyngeal dysphagia is common and appears to be progressive in
      patients with ataxia-telangiectasia. Older patients also have a higher incidence
      of poorer nutritional status. The relationship between dysphagia and nutritional
      status deserves further investigation.

PMID- 10657831
TI  - Dual sugar permeability testing in diarrheal disease.
AB  - OBJECTIVE: To assess the validity of the use of a blood specimen for the sugar
      permeability test because of the high failure rate of 5-hour urine collection in
      young children with diarrhea. STUDY DESIGN: Simultaneous 5-hour urine collections
      and timed blood tests were taken after ingestion of an isotonic solution of
      lactulose (L) and L-rhamnose (R) in 24 children with acute gastroenteritis and 25
      children without diarrhea in a control group. Sugars were measured with high
      performance liquid chromatography, and the percent of recovered sugars was
      expressed as an L-R ratio. RESULTS: With acute gastroenteritis the geometric mean
      L-R ratios (95% confidence intervals) were 12.4 (9.3 to 16.3) in urine and 9.4
      (6.7 to 13.1) in blood compared with 6.7 (5.0 to 8.8) and 5.9 (4.4 to 7.8),
      respectively, in the control group. The level of agreement (kappa) among normal,
      intermediate, and high ratios for blood and urine was 0.71 (0.51 to 0.92). The
      failure rate of L-R tests was significantly reduced with a blood specimen (urine
      37% vs blood 10%; P <.0001). CONCLUSIONS: Intestinal permeability testing on a
      blood specimen is a valid alternative to urine collection in young children and
      has a significantly lower test failure rate.

PMID- 10657832
TI  - Safety and utility of the routine surveillance biopsy in pediatric patients 2
      years after heart transplantation.
AB  - OBJECTIVES: The standard for diagnosing allograft rejection after heart
      transplantation is the endomyocardial biopsy, but the value of routine
      surveillance biopsies after 2 years after transplant is controversial. The
      objective of this study was to determine the necessity and safety of surveillance
      biopsies and to correlate rejection with signs and symptoms beyond the second
      post-transplant anniversary in pediatric patients. STUDY DESIGN: We reviewed the
      results of 899 biopsies and coincident clinical histories in 56 pediatric
      patients, comprising 314 patient-years of follow-up. Patients were classified as
      having symptoms or not based on a blinded review of their clinical status and
      echocardiograms. Biopsies were classified as negative or positive with
      established criteria. RESULTS: After biopsies performed less than 2 years after
      transplant or as a follow-up for a positive biopsy were excluded, 481 biopsies
      were available for analysis, of which 20 (4%) were positive. Positive biopsies
      were found in 15 (3%) of 456 biopsies in patients without symptoms compared with
      5 (20%) of 25 biopsies in patients with symptoms. Patients with symptoms were 6
      times more likely to have a positive biopsy compared with patients without
      symptoms. Of the positive rejection episodes, 75% occurred in patients without
      symptoms. CONCLUSION: Although rejection is uncommon in pediatric patients
      greater than 2 years after transplant, episodes of treatable allograft rejection
      can occur in the absence of clinical signs and symptoms. This study emphasizes
      the safety of and the need to continue to perform routine surveillance biopsies
      in patients without symptoms, even after the second post-transplant year.

PMID- 10657833
TI  - Intermittent intravenous cyclophosphamide arrests progression of the renal
      chronicity index in childhood systemic lupus erythematosus.
AB  - OBJECTIVE: To assess prospectively the safety and efficacy of a 36-month course
      of systematic bolus intravenous cyclophosphamide therapy (IVCY) for children with
      lupus nephritis. STUDY DESIGN: Sixteen children with lupus nephritis were treated
      with IVCY for 36 months. Renal biopsies performed before and after treatment were
      scored for activity and chronicity. SLEDAI scores, laboratory measures, and
      prednisone dosage were recorded at the time of each treatment. RESULTS: After 36
      months of IVCY therapy, the renal biopsy activity index decreased from 9 +/- 4 to
      1 +/- 1 (P <.001) without a change in chronicity. The mean creatinine clearance
      increased from 90 +/- 23 to 107 +/- 23 mL/min/1.73 mol/L(2) (P <.01), and the
      mean 24-hour urine protein excretion decreased from 2.0 +/- 2.4 g/24 h to 0.5 +/-
      0.7 g/24 h (P <.05). The mean SLEDAI score decreased from 19 +/- 5.2 to 2.9 +/-
      3.1 (P <.001). The mean prednisone dosage decreased from 35.5 +/- 20 mg/d to 14.0
      +/- 3 mg/d (P <.001). No significant complications occurred. CONCLUSIONS: Thirty
      six months of systematic IVCY therapy led to decreased renal biopsy activity
      without progression of chronicity, with excellent disease control and a greater
      than 50% reduction in mean corticosteroid dose.

PMID- 10657834
TI  - Sickle-cell disease not identified by newborn screening because of prior
      transfusion.
AB  - Erythrocyte transfusion can impair detection of sickle-cell disease,
      galactosemia, or biotinidase deficiency with newborn screening. We report on 4
      infants with SCD in whom delayed diagnosis was associated with neonatal
      transfusion. In 2 cases, the initial newborn screening showed no hemoglobin S. In
      no case was the recommended screening >/=120 days from the last transfusion
      obtained. Two children had significant SCD-related morbidity before diagnosis.

PMID- 10657836
TI  - Hypothyroidism in primary hyperoxaluria type 1.
AB  - We describe 4 patients, aged 3 months to 23 years, with end-stage renal disease
      and severe, symptomatic hypothyroidism. All 4 had primary hyperoxaluria type 1
      (PH1) with diffuse tissue (kidneys, skeleton, eyes, heart) calcium-oxalate
      deposition, a condition known as oxalosis. The hypothyroidism responded to
      thyroid hormone replacement therapy. Clinical hypothyroidism within the framework
      of PH1/oxalosis was probably caused by thyroid tissue damage from an abundance of
      calcium oxalate. We recommend that thyroid function be monitored in patients with
      PH1 and oxalosis.

PMID- 10657835
TI  - Mitochondrial respiratory chain complex I deficiency with clinical and
      biochemical features of long-chain 3-hydroxyacyl-coenzyme A dehydrogenase
      deficiency.
AB  - The mitochondrial respiratory chain and the fatty acid oxidation cycle are
      theoretically interdependent on each other for normal function. We describe a
      patient with complex I deficiency who had clinical and biochemical features of
      long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency including liver
      failure, cardiomyopathy, and consistent urine organic acid pattern. Patients with
      features of either a respiratory chain or fatty acid oxidation disorder should
      have the defect characterized biochemically because of the implications with
      respect to potential therapy and genetic counseling.

PMID- 10657837
TI  - Defective inactivation of leukotriene B4 in patients with Sjogren-Larsson
      syndrome.
AB  - In 6 patients with Sjogren-Larsson syndrome (SLS), the urinary excretion of
      leukotriene B(4) (LTB(4)) and omega-hydroxy-LTB(4) was found to be highly
      elevated, whereas omega-carboxy-LTB(4) was absent. This abnormal pattern of
      urinary excretion of LTB(4) and its metabolites appears to be unique to patients
      with SLS and offers a new approach to the diagnosis of this disorder. Moreover,
      defective inactivation of LTB(4) might be of pathophysiologic significance in the
      disease.

PMID- 10657838
TI  - Sjogren-Larsson syndrome.

PMID- 10657839
TI  - Chronic watery diarrhea in a 22-month-old girl.

PMID- 10657840
TI  - Neurodevelopmental disabilities in child neurology: the creation of a new sub
      board.

PMID- 10657841
TI  - Sudden death in Hunter syndrome caused by complete atrioventricular block.

PMID- 10657843
TI  - Reply

PMID- 10657842
TI  - Latex allergy in patients with spina bifida.

PMID- 10657844
TI  - Screening for microalbuminuria in type 1 diabetes.

PMID- 10657845
TI  - Reply

PMID- 10657846
TI  - Viral vectors for gene delivery and gene therapy within the endocrine system.
AB  - The transfer of genetic material into endocrine cells and tissues, both in vitro
      and in vivo, has been identified as critical for the study of endocrine
      mechanisms and the future treatment of endocrine disorders. Classical methods of
      gene transfer, such as transfection, are inefficient and limited mainly to
      delivery into actively proliferating cells in vitro. The development of viral
      vector gene delivery systems is beginning to circumvent these initial setbacks.
      Several kinds of viruses, including retrovirus, adenovirus, adeno-associated
      virus, and herpes simplex virus, have been manipulated for use in gene transfer
      and gene therapy applications. As different viral vector systems have their own
      unique advantages and disadvantages, they each have applications for which they
      are best suited. This review will discuss viral vector systems that have been
      used for gene transfer into the endocrine system, and recent developments in
      viral vector technology that may improve their use for endocrine applications -
      chimeric vectors, viral vector targeting and transcriptional regulation of
      transgene expression.

PMID- 10657847
TI  - Ceiling culture of mature human adipocytes: use in studies of adipocyte
      functions.
AB  - Adipocytes contain large lipid droplets in their cytoplasm. When cultured, they
      float on top of the medium, clump together, and do not gain equal and sufficient
      access to the medium. Morphological changes cannot be observed and the majority
      of adipocytes undergo cell lysis within 72 h of isolation. We have used a ceiling
      culture method for human mature adipocytes which uses their buoyant property to
      allow them to adhere to a floating glass surface, where they remain viable for
      several weeks. Using confocal immunofluorescence microscopy we showed the
      cellular expression and subcellular localization of leptin in ceiling-cultured
      adipocytes. The secretion of leptin was increased from ceiling cultures following
      tumour necrosis factor-alpha treatment. Proliferation of mature human adipocytes
      in serum-containing medium was demonstrated by incorporation of
      bromodeoxyuridine, 2% of adipocytes showing positive incorporation after 4 h
      labelling. Proliferation was also evident from the budding of daughter cells.
      Apoptosis in the ceiling cultures was increased by 48 h serum deprivation (30-35
      vs 10-15% in the control) and was assayed by propidium iodide staining and
      terminal deoxynucleotidyl transferase-mediated dUTP-fluorescein nick-end
      labelling. Lipolysis, analysed by liquid scintillation counting, was increased by
      forskolin (10 microM for 90 min) and lipogenesis, shown by autoradiography, was
      stimulated by insulin (10 and 100 nM for 4 h). These findings indicate that
      ceiling-cultured adipocytes maintain adipocyte-specific functions and that
      ceiling culture, which overcomes the shortcomings of adipocyte suspension
      culture, can be used to study adipocyte cell biology.

PMID- 10657848
TI  - Estrogen mediates the sex difference in post-burn immunosuppression.
AB  - Previous studies in our laboratory have demonstrated that cell-mediated immune
      function was suppressed in female, but not male, mice at 10 days after burn
      injury and was mediated, in part, by increased production of interleukin-6 (IL
      6). Because 17beta-estradiol (E(2)) influences immune function after trauma and
      the hormone is known to regulate IL-6 production, the effect of E(2) on immune
      function after thermal injury was examined. Increased circulating concentrations
      of E(2) corresponded with suppressed delayed-type hypersensitivity (DTH) and
      splenocyte-proliferative responses, and increased circulating concentrations of
      IL-6 in female mice after burn. Ovariectomy restored the suppressed DTH response
      and decreased IL-6 concentrations, and administration of exogenous E(2) to both
      ovariectomized females and intact male mice resulted in a suppressed DTH
      response. In addition, in vitro treatment with E(2) suppressed splenocyte
      proliferation in a macrophage-dependent manner and enhanced macrophage production
      of IL-6. These results strongly suggest that the sex difference in cell-mediated
      immunity 10 days after burn injury is mediated by altered concentrations of E(2),
      which in turn modulate key macrophage-derived immunoregulatory cytokines.

PMID- 10657849
TI  - Evidence for complement-dependent and -independent inhibition of insulin
      secretion from clonal beta-cells incubated in the presence of sera of newly
      diagnosed IDDM patients.
AB  - There are conflicting reports on the effect of serum from patients with insulin
      dependent diabetes mellitus (IDDM) or normal human serum on beta-cell function
      and insulin secretion. Here, we report that the sera of newly diagnosed IDDM
      patients potently suppresses insulin secretion from a clonal rat pancreatic beta
      cell line (BRIN-BD11), but do not alter cell viability. Indeed, the viability of
      the beta-cells was not significantly different between cells cultured in 10%
      (v/v) IDDM sera, normal human sera, or fetal calf serum after 24, 48 and 72 h.
      Alanine-stimulated insulin secretion from cells cultured for 24 h in (10% v/v)
      IDDM patient sera was reduced to 48% of that secreted from cells cultured in (10%
      v/v) normal human sera. After depletion of the complement components C1q and C3,
      the inhibition of insulin secretion induced by IDDM patient sera was
      significantly reversed (no significant difference was observed between cells
      cultured in complement-depleted IDDM patient sera and cells cultured in normal
      human sera or complement-depleted normal human sera). The concentration of
      glutamic acid decarboxylase (GAD) autoantibodies was markedly increased in the
      sera of six out of nine newly diagnosed IDDM patients in this study, whereas
      insulin auto-antibodies (IAA) were detected in the sera of three of the nine
      patients and islet-cell antibodies (ICA) in the sera of five of them. In
      addition, the concentration of soluble terminal complement complexes (SC5-9) was
      greater in some of the beta-cell culture media samples after 24 h incubation when
      the incubation medium was supplemented with IDDM patient sera than when
      supplementation was with normal human sera. We propose that the mechanism of sera
      induced inhibition of insulin secretion from clonal beta-cells may involve
      complement- and cytokine-stimulated intracellular events that attenuate the
      metabolite-induced secretory process.

PMID- 10657850
TI  - Discrete cell- and stage-specific localisation of fibroblast growth factors and
      receptor expression during testis development.
AB  - Fibroblast growth factors (FGFs) are a family of heparin binding proteins
      involved in many biological processes. These growth factors act through tyrosine
      kinase receptors (FGFRs); we have previously used immunohistochemistry to study
      FGFRs-1-4 in foetal, immature and adult rat testes, and found a discrete cell-
      and stage-specific localisation. Alternative mRNA splicing of FGFRs-1-3 leads to
      functional variants (IIIb and IIIc) with distinct ligand binding affinities,
      therefore we have identified the specific expression of functional FGFR variants
      and the expression and localisation of FGF ligands in testes from foetal,
      immature and adult rats. Using reverse transcriptase-polymerase chain reaction
      (RT-PCR), we found that mRNAs for FGFR-1 IIIb and IIIc, FGFR-2 IIIc, FGFR-3 IIIc
      and FGFR-4 were expressed in foetal, immature and adult testes. Ligands FGFs-1-5,
      and -8, which can signal through these receptors, were also expressed in testes
      at each age. Localisation of the ligands FGFs-1, -3 and -4 to rat testes by
      immunohistochemistry showed a discrete cell- and stage-specific localisation that
      altered during testis development. This study has shown that the ligands FGFs-1, 
      3 and -4 are expressed in the testis and have the capacity to signal through
      appropriate receptors that are also co-localised or expressed in adjacent cell
      types in the testis. Collectively, the expression profiles of the seven FGFR
      variants and FGFs-1-5 and -8 suggest a functional importance in testicular
      development and spermatogenesis. It is concluded that, future studies on the role
      of other FGF ligands, in particular FGFs-1-4, are warranted.

PMID- 10657851
TI  - Conversion of dehydroepiandrosterone to downstream steroid hormones in
      macrophages.
AB  - Dehydroepiandrosterone (DHEA) is a ubiquitous adrenal hormone with
      immunomodulatory effects such as inhibition of the production of monokines.
      Whether DHEA itself or the downstream steroids are the immunomodulatory effector
      hormones in target cells is not known. In this study, we investigated the
      conversion of DHEA to downstream steroid hormones in target macrophages. Within 1
      day of culture with radiolabeled DHEA, monocyte-derived macrophages converted
      DHEA to significant amounts of Delta5-derivatives such as 16OH-DHEA, 3beta,
      17beta-androstenediol (A'diol), and 3beta,16alpha, 17beta-androstenetriol
      (A'triol). However, the production of Delta4-steroids (androstenedione (A'dione),
      testosterone (T), and 16OH-T) and estrogens (estrone, estradiol, and estriol) was
      relatively low. Further cultivation of macrophages for 5 days with radiolabeled
      DHEA resulted in a significant (P<0.05) increase of the molar amounts of A'triol
      (P=0.012), 16OH-T (P=0.008), and estriol (P=0.003). In contrast to monocyte
      derived macrophages, monocytes did not express aromatase mRNA, which was
      demonstrated by RT-PCR (P<0.01). Furthermore, DHEA in macrophages significantly
      inhibited one of the downstream converting enzymes, the aromatase, which was not
      demonstrated in the presence of the typical macrophage activator,
      lipopolysaccharide (LPS) (P<0.01). In conclusion, conversion of DHEA to
      physiologically relevant amounts of Delta5- and Delta4-steroids and estrogens was
      demonstrated in monocyte-derived macrophages. The conversion depends on
      maturation of monocytes and local factors such as the presence of LPS. The
      conversion of DHEA leads to an increase of downstream effector hormones in target
      macrophages which may be an important factor for local immunomodulation.

PMID- 10657852
TI  - 8-bromo-cyclicAMP stimulates glucose transporter-1 expression in a human
      choriocarcinoma cell line.
AB  - Facilitative glucose transporter-1 (GLUT1) is abundant in trophoblast cells and
      is responsible for glucose transport in the placenta. However, the change in GLUT
      expression in human placenta upon trophoblast differentiation remains to be
      clarified. Therefore, we first examined the localization of GLUT1 and GLUT3 using
      human first-trimester chorionic villi. We found that GLUT1 and GLUT3 were mainly
      localized to syncytiotrophoblast and cytotrophoblast cells respectively. We
      analyzed whether placental GLUT1 and GLUT3 expression changes during
      differentiation using a human choriocarcinoma (BeWo) cell line which is known to
      show functional and morphological differentiation in response to cAMP in culture.
      Treatment of BeWo cells with 8-bromo-cyclicAMP (8-bromo-cAMP) increased the level
      of hCG secretion and induced cell fusion leading to the formation of large
      syncytia. Treatment of BeWo cells with 8-bromo-cAMP also resulted in a
      significant increase in glucose uptake on days 2-3 of culture. The stimulating
      effect of 8-bromo-cAMP on glucose uptake was concentration dependent. Northern
      and immunoblot analyses revealed that the levels of mRNA and protein of GLUT1,
      but not of GLUT3, were significantly increased by 8-bromo-cAMP. These findings
      suggest that 8-bromo-cAMP stimulates GLUT1 expression with differentiation in
      BeWo cells.

PMID- 10657853
TI  - Nitric oxide synthase activity and progesterone release by isolated corpora lutea
      of rabbits in the early and mid-luteal phases of pseudopregnancy are modulated
      differently by prostaglandin E-2 and prostaglandin F-2alpha via adenylate cyclase
      and phospholipase C.
AB  - By examining in vitro the effects of prostaglandin E-2 (PGE-2) and prostaglandin
      F-2alpha (PGF-2alpha) induced in the corpora lutea (CL) of pseudopregnant
      rabbits, we have demonstrated that these prostaglandins modulate luteal nitric
      oxide synthase (NOS) activity and progesterone production differently, depending
      on the age of the CL. On CL obtained on day 4 of pseudopregnancy (day-4), PGE-2
      was found to depress NOS total activity to 13% of control and to significantly
      increase basal progesterone secretion by 61%, while PGF-2alpha had no effect. On
      day-9 CL, PGE-2 was ineffective, but PGF-2alpha caused a 2.5-fold increase of NOS
      activity and a marked decrease in progesterone production. Using specific
      inhibitors, we found that the regulatory actions of PGE-2 in vitro are mediated
      via the adenyl cyclase/protein kinase A (PKA) second messenger system, while the
      PGF-2alpha-induced luteolytic effects on day-9 CL depend upon activation of the
      phospholipase C/protein kinase C (PKC) system. The different responsiveness of
      day-4 and day-9 CL to PGE-2 and PGF-2alpha could depend on receptor availability
      for these two prostaglandins, even if other cellular mechanisms cannot be
      excluded. The present study supports a functional role for NOS in regulating the
      steroidogenic capacity of rabbit CL, and reveals a novel interaction between a
      stimulatory G-protein-coupled receptor and PKC/PKA-mediated signal transduction
      modulating NOS activity.

PMID- 10657854
TI  - Stimulation of glucose transport by thyroid hormone in 3T3-L1 adipocytes:
      increased abundance of GLUT1 and GLUT4 glucose transporter proteins.
AB  - In 3T3-L1 adipocytes we have examined the effect of tri-iodothyronine (T(3)) on
      glucose transport, total protein content and subcellular distribution of GLUT1
      and GLUT4 glucose transporters. Cells incubated in T(3)-depleted serum were used
      as controls. Cells treated with T(3) (50 nM) for three days had a 3.6-fold
      increase in glucose uptake (P<0.05), and also presented a higher insulin
      sensitivity, without changes in insulin binding. The two glucose carriers, GLUT1
      and GLUT4, increased by 87% (P<0.05) and 90% (P<0. 05), respectively, in cells
      treated with T(3). Under non-insulin-stimulated conditions, plasma membrane
      fractions obtained from cells exposed to T(3) were enriched with both GLUT1 (3.
      29+/-0.69 vs 1.20+/-0.29 arbitrary units (A.U.)/5 microg protein, P<0.05) and
      GLUT4 (3.50+/-1.16 vs 0.82+/-0.28 A.U./5 microg protein, P<0.03). The incubation
      of cells with insulin produced the translocation of both glucose transporters to
      plasma membranes, and again cells treated with T(3) presented a higher amount of
      GLUT1 and GLUT4 in the plasma membrane fractions (P<0.05 and P<0.03
      respectively). These data indicate that T(3) has a direct stimulatory effect on
      glucose transport in 3T3-L1 adipocytes due to an increase in GLUT1 and GLUT4, and
      by favouring their partitioning to plasma membranes. The effect of T(3) on
      glucose uptake induced by insulin can also be explained by the high expression of
      both glucose transporters.

PMID- 10657855
TI  - Endogenous vasopressin contributes to hypothalamic-pituitary-adrenocortical
      alterations in aged rats.
AB  - The ageing process in animals and humans is thought to be accompanied by a
      gradual impairment of corticosteroid receptor function, which is reflected by
      increased pituitary-adrenocortical hormone secretion at baseline and a number of
      aberrant neuroendocrine function test results. The latter include the ACTH and
      corticosteroid responses to a combined dexamethasone (DEX)/corticotropin
      releasing hormone (CRH) challenge. The excessive hormonal response to this test
      among aged individuals has been taken as indirect evidence of enhanced endogenous
      arginine vasopressin (AVP) release, which - together with peripherally
      administered CRH - is capable of overriding DEX-induced ACTH suppression. The
      current study was designed to explore the role of endogenous AVP in mediating
      excessive hypothalamic-pituitary-adrenocortical (HPA) activity in ageing. The
      combined DEX/CRH test was administered to aged (22-24 months old) Wistar rats and
      the effect of the AVP type 1 (V1) receptor antagonist, d(CH(2))(5)Tyr(Me)AVP, on
      ACTH release was studied. Infusion of the V1 receptor antagonist after DEX
      pretreatment and before CRH administration prevented the CRH-induced rise in ACTH
      secretion in comparison with vehicle-treated aged rats (area under the
      concentration-time curve: 699+/-479 versus 2896+/-759; P<0.01). This difference
      was absent in young (3 months old) control rats. In situ hybridization showed an
      increased number of AVP mRNA-expressing neurons in the parvocellular but not the
      magnocellular, portion of the hypothalamic paraventricular nucleus in DEX
      pretreated aged rats. The number and synthetic activity of parvocellular neurons
      expressing CRH mRNA was also increased. We have concluded that the increased HPA
      activity in aged rats involves enhanced synthesis and release of AVP from
      parvocellular neurons, possibly secondary to impaired corticosteroid receptor
      function.

PMID- 10657856
TI  - The expression of renin and the formation of angiotensin II in bovine aortic
      endothelial cells.
AB  - One controversy in the field of vascular angiotensin generation has surrounded
      the nature and particularly the source of vascular renin. This study investigated
      the expression of renin protein and its mRNA in aortic endothelial cells using
      immunocytochemistry, Western blotting, in situ hybridization and reverse
      transcription PCR (RT-PCR). Using a monoclonal antibody against human renin,
      immunocytochemical analysis revealed positive immunoreactivity in the cytoplasm
      of cultured bovine aortic endothelial cells. Immunoblotting of solubilized
      proteins separated by SDS-PAGE from cultured aortic endothelial cells identified
      two immunoreactive species with molecular masses of approximately 37-40 kDa. In
      situ hybridization showed that renin mRNA was localized in the cytoplasm of these
      cells. Using RT-PCR of RNA extracted from bovine aortic endothelial cells with
      primers specific for human renin, a clear single band was detected, which had the
      predicted size of 142 bp for (pro)renin. Angiotensin II (Ang II) was assayed in
      conditioned medium (CM) from cultured bovine aortic endothelial cells, and in
      addition, the effects of Ang II and CM on the proliferation of aorta smooth
      muscle cells (ASMC) were also studied. The results showed that CM contained Ang
      II equivalent to 15.05+/-4.67 pg/10(6) cells. Assay of smooth muscle cell
      proliferation by cell number, and by tritiated thymidine uptake, showed that
      proliferative responses in the presence of Ang II at a concentration of 10(-6)M
      were evident within 1 day of subculture, and cell numbers were nearly twice those
      of controls after 2 days. Thymidine incorporation into ASMC was also increased by
      Ang II in a dose-dependent manner and by endothelial cell CM. In both cases,
      stimulated proliferation was inhibited by the Ang II type 1 (AT1) receptor
      selective antagonist, losartan. These findings suggest that these vascular
      endothelial cells are a source of locally synthesized renin that may thus be
      involved in vascular Ang II generation. They also suggest that Ang II produced by
      the endothelial cells may be secreted and stimulate ASMC proliferation via the
      AT1 receptor.

PMID- 10657857
TI  - Transforming growth factor-beta induces growth inhibition and IGF-binding protein
      3 production in prostatic stromal cells: abnormalities in cells cultured from
      benign prostatic hyperplasia tissues.
AB  - The IGF axis has been implicated in the pathogenesis of benign prostatic
      hyperplasia (BPH) via the paracrine action of IGFs and IGF-binding proteins
      (IGFBPs). In this study, we examined the regulation of cell growth and IGFBP-3
      secretion by transforming growth factor-beta (TGF-beta) in prostatic stromal cell
      (PC-S) cultures from histologically normal tissues and tissues from BPH. PC-S
      cultures were treated with varying doses of TGF-beta1. Forty-eight hour
      conditioned media (CM) from these cultures were subjected to Western
      immunoblotting and ligand blotting for detection and quantification of IGFBPs.
      IGFBPs-2, -3 and -4 were detected in the CM from normal PC-S cultures. In CM from
      BPH PC-S, IGFBP-3 levels were 2-fold lower at baseline than in the normal PC-S
      CM, in addition to the differences in IGFBPs-2 and -5 which we have previously
      reported. In response to TGF-beta1, a 15-fold increase in the levels of IGFBP-3
      was observed in normal PC-S CM, while a mere 2-fold increase was observed in BPH
      PC-S CM (P<0.001). These findings were confirmed by specific immunoblotting and
      immunocytochemistry. IGFBP-3 mRNA levels detected by Northern blotting of total
      RNA extracted from similar cultures showed the induction of IGFBP-3 expression by
      TGF-beta1 in normal PC-S and its lack of induction in BPH PC-S. Cell growth
      inhibition in response to TGF-beta1 correlated with the IGFBP-3 concentrations
      found in CM. Normal PC-S showed a 60% decrease in cell number after 10 days in
      media with 1 ng/ml TGF-beta1, compared with the untreated control. The decrease
      in proliferation observed in comparably treated BPH cells was only 20% (P<0.001).
      In conclusion, BPH PC-S had a reduced IGFBP-3 response to TGF-beta1 and
      demonstrated decreased TGF-beta1-induced growth inhibition relative to normal PC
      S. We hypothesize that in normal PC-S, TGF-beta exerts its anti-proliferative
      effects by stimulating the production of IGFBP-3, which acts as an inhibitory
      factor, either by inhibiting IGFs or directly by interacting with cells, and that
      this process is altered in BPH PC-S.

PMID- 10657858
TI  - Effect of chronic administration of an aromatase inhibitor to adult male rats on
      pituitary and testicular function and fertility.
AB  - The aim of the present study was to evaluate the effects of the administration of
      a potent non-steroidal aromatase inhibitor, anastrozole, on male reproductive
      function in adult rats. As anastrozole was to be administered via the drinking
      water, a preliminary study was undertaken in female rats and showed that this
      route of administration was effective in causing a major decrease in uterine
      weight (P<0.02). In an initial study in male adult rats, anastrozole (100 mg/l or
      400 mg/l) was administered via the drinking water for a period of 9 weeks.
      Treatment with either dose resulted in a significant increase ( approximately
      10%) in testis weight and increase in plasma FSH concentrations (P<0.01)
      throughout the 9 weeks. Mating was altered in both groups of anastrozole-treated
      rats, as they failed to produce copulatory plugs. Histological evaluation of the
      testes from anastrozole-treated rats revealed that spermatogenesis was grossly
      normal. In a more detailed study, adult rats were treated with 200 mg/l
      anastrozole via the drinking water for periods ranging from 2 weeks to 1 year.
      Plasma FSH and testosterone concentrations were increased significantly (P<0.001)
      during the first 19 weeks of treatment. However, LH concentrations were increased
      only at 19 weeks (P<0.001) in anastrozole-treated rats, and this coincided with a
      further increase in circulating and intratesticular testosterone concentrations
      (P<0.05). No consistent change in inhibin-B concentrations was observed during
      the study. Suppression of plasma oestradiol concentrations could not be
      demonstrated in anastrozole-treated animals, but oestradiol concentrations in
      testicular interstitial fluid were reduced by 18% (P<0.01). Mating was again
      inhibited by anastrozole treatment, but could be restored by s.c. injection of
      oestrogen, enabling demonstration that rats treated for 10 weeks or 9 months were
      still fertile. Testis weight was increased by 19% and 6% after treatment for 19
      weeks and 1 year, respectively. Body weight was significantly decreased (P<0.01)
      by 19 weeks of anastrozole treatment; after 1 year the animals appeared to have
      less fat as indicated by a 27% decrease in the weight of the gonadal fat pad. The
      majority of anastrozole-treated animals had testes with normal spermatogenesis
      but, occasionally, seminiferous tubules showed abnormal loss of germ cells or
      contained only Sertoli cells. Ten percent of anastrozole-treated animals had
      testes that appeared to contain only Sertoli cells, and one rat had 'giant'
      testes in which the tubule lumens were severely dilated. Morphometric analysis of
      the normal testes at 19 weeks showed no difference in the number of Sertoli cells
      or germ cells, or the percentage volumes of the seminiferous epithelium, tubule
      lumens and interstitium between control and anastrozole-treated rats. On the
      basis of the present findings, oestrogen appears to be involved in the regulation
      of FSH secretion and testosterone production, and is also essential for normal
      mating behaviour in male rats. Furthermore, these data suggest that the brain and
      the hypothalamo-pituitary axis are considerably more susceptible than is the
      testis to the effects of an aromatase inhibitor. Anastrozole treatment has
      resulted in a model of brain oestrogen insufficiency.

PMID- 10657859
TI  - High-resolution micro-computed tomography analyses of the abnormal trabecular
      bone structures in klotho gene mutant mice.
AB  - Inactivation mutation of the recently discovered klotho gene in mice causes a
      syndrome resembling aging. Manifestations include short life span,
      atherosclerosis, gonadal atropy, skin atropy, emphysema, ataxia and ectopic
      calcification. These mice also exhibit abnormally high bone density in the
      epiphyses of their tibiae based on X-ray and histological analyses. However,
      micro-structures of the trabecular bones in arbitrary two-dimensional planes or
      three-dimensional regions are difficult to analyze by these techniques.
      Therefore, we applied high resolution micro-computed tomography (microCT) to
      characterize the micro-structural abnormality in the trabecular bone in long
      bones as well as in vertebrae of four- to six-week-old klotho mutant mice. Two
      dimensional microCT analyses in the mid-sagittal plane as well as three
      dimensional microCT analyses indicated that the trabecular bone volume fraction
      measured in the proximal metaphyses of the tibiae was increased more than twofold
      in klotho mutant mice compared with the wild-type mice. Similarly, the trabecular
      bone area fraction in the mid-sagittal plane of the lumbar vertebral bodies was
      also increased by about 80% at the proximal and distal ends. No significant
      difference was observed with regard to the cortical thickness in the mid-shaft of
      femora between klotho mutant and wild-type mice. Three-dimensional microCT
      analyses also indicated that the trabecular number and thickness of the proximal
      metaphyses of the tibiae were increased by about 80% and 300% respectively in the
      klotho mutant mice, while trabecular separation was 60% less in klotho mutant
      mice compared with the wild-type mice. These quantitative microCT analyses
      indicate that the inactivation of klotho gene expression results in an increase
      in three-dimensional bone volume fraction, number and thickness of the trabecular
      bones in these mice.

PMID- 10657860
TI  - HIV protease inhibitors block human preadipocyte differentiation, but not via the
      PPARgamma/RXR heterodimer.
AB  - A recent prospective clinical study has shown that antiviral therapy with HIV
      protease inhibitors (PIs) is associated with a syndrome of peripheral fat wasting
      (lipodystrophy) and disordered glucose and lipid metabolism (Carr et al. 1999).
      We have studied the effects of indinavir and saquinavir, two HIV protease
      inhibitors, on cultured primary human preadipocytes and report that these
      compounds inhibit their differentiation. However, we find that these agents do
      not inhibit either transcriptional activation or adipocyte P2 gene induction by
      the PPARgamma/RXR nuclear receptor heterodimer. Together, our findings suggest
      that impaired adipogenesis is the basis of PI-associated lipodystrophy, but that
      this occurs via a PPARgamma/RXR-independent mechanism.

PMID- 10657861
TI  - Program summary of the sixty-ninth annual meeting of the american association of
      physical anthropologists to be held at the Adam's mark hotel, san antonio, texas,
      april 10-april 15, 2000

PMID- 10657862
TI  - The sixty-ninth annual meeting of the American Association of Physical
      Anthropologists.

PMID- 10657863
TI  - Program schedule

PMID- 10657865
TI  - Arthur edward jones, MD, FRCP, FRCS, FRCR, DMRT, HonFACR

PMID- 10657866
TI  - Oral ciprofloxacin vs. intravenous ceftriaxone administered in an outpatient
      setting for fever and neutropenia in low-risk pediatric oncology patients:
      randomized prospective trial.
AB  - BACKGROUND: Infections are one of the major complications in children undergoing
      chemotherapy. Monotherapy with either ciprofloxacin or ceftriaxone is safe and
      efficient in low-risk patients (solid tumors and stage I/II lymphomas). The same
      drugs may be used in an outpatient setting, decreasing costs and the risk of
      nosocomial infections. PROCEDURE: Low-risk patients (N = 70) with episodes of
      fever and neutropenia (N = 116) were randomized to receive either oral
      ciprofloxacin or intravenous ceftriaxone as outpatients. Only one patient had a
      central venous catheter. RESULTS: Episodes of fever and neutropenia were
      classified as fever of unknown origin (41% vs. 32%) or clinically documented
      infection (56% vs. 63%) in the ciprofloxacin and ceftriaxone groups,
      respectively. Most of these infections were of upper respiratory tract, skin, or
      gastrointestinal origin. The mean duration of neutropenia was 5 vs. 6 days. Fever
      persisted for 1-9 days (mean 2 vs. 3 days). Therapy was successful with no
      modifications in 83% vs. 75% of the episodes. Patients were admitted in 7% vs. 4%
      of the episodes. No bone or joint side effects were seen in either group. All
      patients survived. CONCLUSIONS: Outpatient therapy with either oral ciprofloxacin
      or intravenous ceftriaxone for fever and neutropenia is effective and safe in
      pediatric patients with solid tumors and stage I/II non-Hodgkin lymphoma (low
      risk patients).

PMID- 10657867
TI  - Cost analysis of filgrastim for the prevention of neutropenia in pediatric T-cell
      leukemia and advanced lymphoblastic lymphoma: a case for prospective economic
      analysis in cooperative group trials.
AB  - BACKGROUND: Growth factor use has been shown to ameliorate chemotherapy-induced
      neutropenia, leading to shorter hospital stays and lower use of parenteral
      antibiotics, two costly areas of cancer treatment. Prior reports on pediatric
      patients have shown evidence of cost savings in some studies, but no such
      evidence in others. In this study a retrospective analysis compared the costs of
      inpatient supportive care for pediatric patients with T-cell leukemia and
      advanced lymphoblastic lymphoma enrolled in a Pediatric Oncology Group trial.
      PROCEDURE: Patients 1-22 years of age were randomized to receive either
      granulocyte colony-stimulating factor (G-CSF; n = 45) or no G-CSF (n = 43)
      following induction and two cycles of maintenance therapy. There were no
      significant differences in neutropenia-related outcomes during the induction
      phase. During maintenance therapy, G-CSF patients had significantly fewer days to
      an ANC >500 cells/microl and a trend towards fewer days of hospitalization. Data
      on resource utilization were tabulated from case report forms. Costs were imputed
      from national data on hospitalization costs, average wholesale prices of
      pharmaceuticals, and patient billing information from a single institution.
      RESULTS: Total median costs of supportive care were $34,190 for patients
      receiving G-CSF and $28,653 for patients not receiving G-CSF (P > 0. 05 for the
      cost difference). Sensitivity analyses demonstrated that the total cost
      difference was not statistically significant, even in scenarios that included
      reasonable variations in estimates of the range of the length of stay, antibiotic
      regimen, and dosage and cost of G-CSF. CONCLUSIONS: In the setting of pediatric
      leukemia, the cost of growth factor may offset potential savings from shorter
      hospital stays or lower antibiotic use, a finding consistent with that from the
      Children's Cancer Study Group.

PMID- 10657868
TI  - Importance of local treatment in pediatric soft tissue sarcomas with microscopic
      residual after primary surgery: results of the Italian Cooperative Study RMS-88.
AB  - BACKGROUND: The goal of primary excision in soft tissue sarcomas is the complete
      removal of the tumor by a nonmutilating procedure. However, microscopic residuals
      may be left after a conservative procedure because of inadequate preoperative
      assessment or difficulties during the operation. The purpose of this report is to
      describe the treatment and the outcome in patients, enrolled in the Italian
      Cooperative Study RMS-88, with microscopic residuals after primary excision (IRS
      Group IIa). PROCEDURE: Microscopic residuals were evident at histology in 52 of
      90 patients who had a macroscopic complete primary excision: 25 rhabdomyosarcomas
      (RMS) and 27 nonrhabdo-soft tissue sarcomas (NRSTS). Eighteen patients were
      treated with primary reexcision (PRE) and chemotherapy (CT) using VA or IVA
      regimens; 27 patients received radiation therapy (RT; 40 Gy) and IVA; 7 children
      in whom PRE was not feasible and RT could not be administered for age <3 years
      were treated with CT (IVA) alone. RESULTS: Of the 18 patients who underwent a
      successful PRE + CT, the local relapses were 3 (16.6%); of 27 cases who had RT +
      CT there were 4 local relapses (14.8%); 3 local relapses occurred in those 7
      patients in whom CT alone was administered (43%). CONCLUSIONS: Microscopic
      residuals after primary surgery were difficult to manage because of the absence
      of a measurable target. PRE represented the treatment of choice for children <3
      years of age who cannot receive RT and for paratesticular sites. PRE and RT
      showed similar results in achieving local control in extremity and trunk sites,
      but they could not always avoid local recurrence. In particular PRE was not
      effective in tumors larger than 5 cm. If microscopic residuals could not be
      avoided and PRE was not possible, adequate RT was effective both for RMS and for
      NRSTS.

PMID- 10657869
TI  - Seroprevalence of hepatitis B, hepatitis C, and human immunodeficiency virus
      infections in children with cancer at diagnosis and following therapy in Turkey.
AB  - BACKGROUND: Children with cancer receiving intensive chemotherapy require
      multiple transfusions and are at increased risk for blood transmittable diseases
      such as hepatitis B virus (HBV), hepatitis C virus (HCV), and human
      immunodeficiency virus (HIV) infections. PROCEDURE: Sera from 50 children (24
      female, 26 male) admitted between January, 1994, and December, 1995, with solid
      tumors receiving intensive chemotherapy and multiple transfusions were
      investigated for HBsAg, anti-HBs, anti-HBc, anti-HCV, and anti-HIV by ELISA at
      diagnosis and at the end of therapy. RESULTS: HBsAg, HBV, HCV, and HIV
      seropositivities were 0%, 4%, 2% and 0% at diagnosis and 10%, 20%, 14% and 0% at
      the end of therapy, respectively. CONCLUSIONS: The high seroprevalence of HCV may
      be due to the lack of anti-HCV screening of blood products in the blood banks
      during the study period. Although the HBV seroprevalance of 20% found in this
      study is much lower than the value of 56% found in a previous study conducted
      during 1986-1989 in a similar patient population and a similar setting, it is
      still high. Children infected with HBV during immunosuppressive therapy are at
      greater risk of becoming chronic carriers and precautions must be taken for
      immunization of these children.

PMID- 10657871
TI  - Mild errors of morphogenesis in malignancy: macroscopic manifestation of genetic
      instability?

PMID- 10657870
TI  - Population-based study of the pattern of molecular markers of minimal residual
      disease in childhood and adult acute lymphoblastic leukemia: an assessment of the
      practical difficulty of representative sampling for trial purposes. Northern
      Region Haematology Group.
AB  - BACKGROUND: The prevalence, in unselected patients with acute lymphoblastic
      leukaemia (ALL), of clonal rearrangements suitable for minimal residual disease
      (MRD) studies has not been formally investigated. PROCEDURE: This was a
      prospective, demographic study of the frequency of molecular markers of MRD in
      all patients with ALL presenting over 5 years within the Northern Health Region
      of England (population 3.1 million). Presentation marrow samples were examined to
      detect informative markers. RESULTS: One hundred twenty-four children (age <15
      years) developed non-Burkitt ALL. No material was available for study in 21.
      Eighty-six had clonal gene rearrangements (BCR/ABL, immunoglobulin heavy chain
      (IGH) and/or T cell receptor (TCR) gene rearrangements). All entered remission;
      84 (68% of the original cohort) survived to become eligible for MRD studies. One
      hundred sixteen adults developed ALL, of whom 48 were not studied due to
      insufficient cellular material in the bone marrow aspirate or to logistical
      problems in central referral of samples from other hospitals. Material from
      elderly adults (age >55 years) was less likely to be sent for analysis, 36% vs.
      59% (P = 0.024). Thirty-eight had BCR/ABL and/or IGH/TCR gene rearrangements.
      Thirty-one (27% of the original cohort) entered remission and became eligible for
      MRD studies. Informative gene rearrangements were more common in children than
      adults (83% vs. 63%, P < 0.003). CONCLUSIONS: The results reveal substantial
      potential, unintentional, selection bias. Large-scale multicentre studies of MRD
      in children may well produce clinically relevant and representative data. Those
      who mount similar studies in adults should not assume they will be similarly
      representative or as successful in accrual of material.

PMID- 10657872
TI  - Comparative genomic hybridization analysis of clear cell sarcoma of the kidney.
AB  - BACKGROUND: Clear cell sarcoma of the kidney (CCSK) is a rare malignant pediatric
      tumor, distinguished from the Wilms tumor by its characteristic histologic
      features and a more aggressive clinical behavior with a tendency to metastasize
      to bone. Genetic studies on CCSK are limited and no consistent findings have been
      reported. PROCEDURE: We examined four cases of CCSK for presence of consistent
      genetic alterations using comparative genomic hybridization (CGH). This is the
      first report concerning CGH analysis of CCSK. RESULTS: Three of the tumors showed
      no chromosome gains or losses. One of the tumors had gains of 1 q and the
      terminal end of 11 q. CONCLUSIONS: These results are consistent with previous
      findings of limited chromosomal changes in CCSK karyotypes. Gain of 1 q in CCSK
      warrants further investigation. Copy number gains of 1 q have been repeatedly
      demonstrated in soft tissue and bone sarcomas, as well as other tumors, implying
      the presence of genes involved in tumor development and/or progression.

PMID- 10657873
TI  - Cellular expression of MDM2 and p53 in childhood leukemias with poor prognosis.
AB  - BACKGROUND: Previous studies have suggested that altered expression or
      dysfunction of the tumor suppressor gene p53 or the oncogene MDM2 could indicate
      disease progression in children with leukemia who would fail to achieve complete
      remission or who would relapse. While these studies mainly have described
      aberrations of MDM2 and p53 function at the DNA and mRNA-level, we have examined
      p53 and MDM2 expression at the protein level. Mutation of the p53 tumor
      suppressor gene may result in cellular accumulation of the p53 protein, due to
      prolonged half-life of the abnormal protein. The p53 protein can also be rendered
      nonfunctional by overexpression of proteins that bind to p53, such as MDM2. Both
      pathways have been proposed to disrupt cell cycle regulation in humans. Recent
      studies have shown that increased expressions of MDM2 as well as of p53 can be
      detected at the protein level in the absence of gene amplification. PROCEDURE:
      Forty-three bone marrow samples were analyzed immunohistochemically for p53 and
      MDM2. Twenty-nine bone marrow samples were obtained in children with active,
      prognostically unfavorable leukemia and MDS. Fourteen bone marrow samples were
      from children with non-malignant hematological disorders. RESULTS: p53 protein
      was expressed in 12 patients and MDM2 in 17 patients with leukemia. In the
      control group MDM2 expression was detected in one child, while p53 was not found
      in any of the samples. CONCLUSIONS: Our findings of p53 or MDM2 positive cells in
      a majority of children with unfavorable prognostic features suggests that
      dysfunction of the p53-dependent cell growth control have a role in the
      development of high risk leukemias.

PMID- 10657874
TI  - Hypofractionated moderate dose radiation, intrathecal chemotherapy, and
      repetitive reinduction/reconsolidation systemic therapy for central nervous
      system relapse of acute lymphoblastic leukemia in children.
AB  - BACKGROUND: We assessed efficacy and morbidity of chemotherapy and 1, 800 cGy of
      hypofractionated craniospinal irradiation (CSI) in children with central nervous
      system (CNS) relapse following first remisssion of acute lymphoblastic leukemia
      (ALL). PROCEDURE: Nineteen patients with isolated CNS relapse and 4 with combined
      CNS/marrow or CNS/testicular relapse received treatment according to Children's
      Hospital of Philadelphia (CHOP) protocols CHP-449 and CHP-497. CNS treatment
      included intrathecal methotrexate, cytarabine, and hydrocortisone and 1,800 cGy
      CSI in 16 fractions over 12 months. Systemic therapy consisted of reinductions
      with vincristine, prednisone, and daunorubicin and reconsolidations with
      cytarabine, etoposide, and L-asparaginase every 56 days for 2 years. Outcome
      measures were event-free survival (EFS), survival, growth, and neuropsychologic
      assessment or school performance. RESULTS: Follow-up of survivors from first
      relapse ranges from 52 to 133 months(median 91 months). Actuarial survival and
      EFSat 10 years are 58% (CI95 = 38-78%) and 54% (CI95 = 32-76%). Events include 2
      second CNS, 4 marrow, 1 testicular, and 2 testicular/marrow relapses and 1
      secondary leukemia. EFS is 100% (CI95 = 93-100%) in 9 patients with recurrence
      more than 26 months from diagnosis. Three patients have significant treatment
      related reduction in stature. Median full-scale IQs of 6 patients tested were 112
      pretreatment and 111 posttreatment among surviving patients. All 17 survivors
      attend regular school, but 2 receive supplementary special services. CONCLUSIONS:
      Lower dose, hypofractionated CSI, intrathecal chemotherapy, and moderately
      intensive systemic chemotherapy provide excellent disease control for patients
      with late isolated CNS or combined marrow and CNS relapse. Children with brief
      first remissions remain at substantial risk of subsequent relapse with this
      therapy, especially in the marrow and testes.

PMID- 10657875
TI  - Experience with aggressive therapy in three children with unresectable malignant
      liver tumors.
AB  - BACKGROUND: Children with malignant liver tumors often present with unresectable
      disease but need not be considered incurable. The advent of effective
      chemotherapy makes aggressive management feasible, as our experience with three
      such patients demonstrates. Procedure and Results One child with an unresectable
      undifferentiated sarcoma of the liver and two others with unresectable primary
      hepatoblastoma and lung metastases were treated with initial chemotherapy,
      followed by aggressive surgical management. Treatment with chemotherapy followed
      by hepatectomy and liver transplantation (cadaveric or live donor) in two
      children has resulted in disease-free survivals of 79 and 38 months. The third
      patient is alive and well 24 months following chemotherapy and aggressive
      resection of the primary and 12 metastatic lesions. CONCLUSIONS: Initial
      chemotherapy for unresectable liver tumors with or without metastases is
      supported by the review of the literature. Consideration of orthotopic liver
      transplantation (OLT) from cadaveric or living related donor is warranted when
      the malignancy is demonstrably chemosensitive, independent of initial staging.
      Aggressive resection of primary and metastatic disease may be called for in
      selected cases.

PMID- 10657876
TI  - Liver transplantation for malignant liver tumors in children.

PMID- 10657877
TI  - "International notes"

PMID- 10657878
TI  - The SIOP burkitt lymphoma pilot study in Malawi, Africa.

PMID- 10657879
TI  - High-dose intense chemotherapy in South African children with B-cell lymphoma:
      morbidity, supportive measures, and outcome.
AB  - BACKGROUND: Twenty-five percent of South African children aged 6-71 months are
      undernourished and have stunted growth. The tolerance and efficacy of short, high
      dose intense chemotherapy for B-cell lymphomas in such a population were unknown.
      PROCEDURE: Nineteen consecutive children diagnosed with B-cell lymphoma after
      1993 at Tygerberg Hospital (TBH) in the Republic of South Africa (RSA) were
      treated according to the LMB-89 protocol. RESULTS: Among the 19 children treated
      according to the LMB-89 protocol, there were 3 children in group A (completely
      resected St. Jude stage I and abdominal stage II), 14 in group B (nonresected
      stage I, nonabdominal stage II, all stage III, stage IV with bone marrow
      involvement but <70% Burkitt cells and without CNS involvement) and 2 in group C
      (patients with >70% Burkitt cells in bone marrow and/or CNS involvement). Overall
      survival for these children was 79% (median follow-up 53.5 months,range 20-70
      months) compared to 25% (median follow-up 131 months, range 71-173months) for 24
      children who had been treated with COM+/-P prior to 1993 (P = 0.002). Toxicity
      was noteworthy in the children treated with LMB-89. They had a mean of 2.6
      episodes of febrile neutropenia and 1.9 episodes of stomatitis per patient and
      required intensive support, but there were no toxic deaths. CONCLUSIONS: A major
      step forward was achieved for South African children with B-cell lymphoma.
      Despite a high prevalence of malnutrition and endemic infections in the RSA, the
      implementation of the LMB-89 protocol significantly improved survival with
      manageable morbidity. Our findings suggest that treatment centres that cannot
      measure methotrexate (MTX) serum levels should not exceed 3.0 g/m(2) of MTX. If
      supportive care facilities are limited, consideration should be given to reducing
      the doses of cyclophosphamide and of doxorubicin in the treatment schedules.

PMID- 10657880
TI  - Concomitant chemoradiotherapy for childhood poor-prognosis gliomas.

PMID- 10657881
TI  - Systemic near-fatal anaphylactic reaction after intrathecal methotrexate
      administration.

PMID- 10657882
TI  - Detection of minimal residual disease by mutant p53 immunocytochemistry in acute
      myelogenous leukemia.

PMID- 10657883
TI  - Anterior mediastinal mass in childhood non-Hodgkin lymphoma: dilemma of post
      therapy imaging.

PMID- 10657884
TI  - Adolescents and cancer.

PMID- 10657885
TI  - FLAG (fludarabine, high-dose cytarabine and G-CSF) for refractory and high-risk
      relapsed acute leukemia in children.

PMID- 10657886
TI  - Interpersonal psychotherapy for anorexia nervosa.
AB  - OBJECTIVE: This paper outlines the rationale for treating individuals with
      anorexia nervosa using interpersonal psychotherapy. METHOD: We review
      theoretical, empirical, and psychotherapy literature relating to interpersonal
      functioning in anorexia nervosa. RESULTS: Etiological theories emphasize
      interpersonal and family dysfunction in the development of anorexia nervosa.
      Research supports the notion that families of individuals with anorexia nervosa
      have dysfunctional patterns of communication. The history of treatment for
      anorexia nervosa emphasizes the need for resolution of interpersonal dysfunction,
      within the traditions of psychodynamic, family therapy, and multidimensional
      therapies. DISCUSSION: Interpersonal psychotherapy is a time-limited
      psychotherapy based on the notion that regardless of etiology, interpersonal
      relationships are intertwined with symptomatology. The goals of the therapy are
      to improve interpersonal functioning and thereby decrease symptomatology. Factors
      identified as important in the development of anorexia nervosa are readily
      conceptualized within the interpersonal psychotherapy problem areas of grief,
      interpersonal disputes, interpersonal deficits, and role transitions.

PMID- 10657887
TI  - Pregnancy: outcome and impact on symptomatology in a cohort of eating-disordered
      women.
AB  - OBJECTIVE: This study investigates both the impact of eating disorders (ED) on
      pregnancy outcome and the impact of pregnancy on cognitive and behavioral
      symptoms of EDs. METHOD: Data on pregnancy outcome (live birth [LB], therapeutic
      abortion [TAB], and spontaneous abortion [SAB]) and ED symptomatology were
      collected as part of a large, prospective longitudinal study of anorexia nervosa
      (AN) and bulimia nervosa (BN). Data were gathered using a semistructured
      interview administered every 6 months to 246 subjects. RESULTS: We identified 54
      women who reported 82 pregnancies (46 LB, 25 TAB, and 11 SAB). Pregnancy outcome
      was not significantly related to any of the clinical variables studied. Women
      with BN showed a significant decrease in the severity of their ED symptoms during
      pregnancy, and this decrease was sustained through 9 months postpartum. Women
      with AN also demonstrated a significant reduction in ED symptoms, however, these
      symptoms returned to prepregnancy levels by 6 months postpartum. CONCLUSIONS: Our
      prospective findings reveal an elevated TAB rate for ED women along with a
      general reduction in the severity of ED symptoms during pregnancy.

PMID- 10657888
TI  - A longitudinal study of the role of childhood temperament in the later
      development of eating concerns.
AB  - OBJECTIVE: This study examined the relationship between childhood temperament and
      the later development of eating and body concerns in early adolescent children.
      METHOD: The Australian Temperament Project has followed a cohort of children from
      birth, assessing temperament factors such as Negative Emotionality, Persistence,
      Approach/Withdrawal, and Activity. Using a longitudinal design, the study reports
      on the relationship between temperament measured from infancy onward and eating
      and body concerns at 12-13 years of age. Participants (597 girls, 631 boys)
      completed the Eating Disorders Inventory subscales Drive For Thinness, Body
      Dissatisfaction, and Bulimia, and an estimate of their current size. Parents
      described their child's temperament and body size. RESULTS: High Negative
      Emotionality and low Persistence were the factors most associated with risk
      status over time, particularly in girls. DISCUSSION: While it is unlikely that
      temperamental characteristics per se lead to disordered eating, it is argued that
      in combination with other risk factors, certain temperamental characteristics may
      increase vulnerability.

PMID- 10657889
TI  - Neuroanatomy of human appetitive function: A positron emission tomography
      investigation.
AB  - OBJECTIVE: The mediating neuroanatomy of human appetitive function is poorly
      understood. A state induction paradigm was employed, in conjunction with positron
      emission tomography, to test the hypothesis that limbic/paralimbic regions
      respond to the desirability of food stimuli. METHODS: Eight normal subjects were
      studied during each of three conditions, involving visual exposure to high
      caloric food, low-caloric food, and nonfood stimuli. Subjective indices of hunger
      were measured via analog scales. RESULTS: Planned contrasts demonstrated
      significant increases in desire to eat and decreases in left temporoinsular
      cortical blood flow during the high-caloric versus control conditions.
      DISCUSSION: Results implicate the temporo-insular cortex in normal appetitive
      function, suggesting that activity within this region is associated with the
      desirability or valence of food stimuli, prior to ingestion. These data will
      provide a broad foundation for future studies of patients with eating disorders.

PMID- 10657890
TI  - Eating pathology and obesity in women at risk for breast cancer recurrence.
AB  - OBJECTIVE: This cross-sectional study investigated the relationship among
      obesity, depressive symptoms, eating attitudes and behaviors, and dietary intake.
      It compared women at risk for recurrence of breast cancer and women who had not
      been diagnosed with breast cancer and were recruited from the same community and
      age group (middle-aged and older). METHOD: Body mass index (BMI), dietary intake,
      self-reported depressive symptoms, and eating disorder psychopathology (assessed
      with the Eating Disorder Examination - Questionnaire [EDE-Q]) were examined in
      women who had been diagnosed with breast cancer (n = 56) and the comparison group
      of women with no breast cancer history (n = 52). Multivariate regression analysis
      was used to identify factors independently associated with global and subscale
      EDE-Q scores and BMI. RESULTS: BMI and depressive symptoms were significantly and
      independently associated with global and subscale EDE-Q scores in women at risk
      for breast cancer recurrence and women with no breast cancer history. Dietary
      restriction was also significantly associated with EDE-Q scores in the group with
      no breast cancer history. CONCLUSIONS: An association among obesity, depressive
      symptomatology, and abnormal eating attitudes and behavior may affect response to
      standard nutritional interventions in women at risk for breast cancer recurrence.

PMID- 10657891
TI  - Comorbidity of bulimia nervosa and alcohol use disorders: results from the
      National Women's Study.
AB  - OBJECTIVE: The nature of the relationship between bulimia nervosa (BN) and
      alcohol abuse/alcohol dependence (AA/AD) and the extent to which women with BN+AA
      differ from women with BN-AA were examined in a national sample of women (N =
      3,006). METHOD: The sample of was generated by multistage geographic sampling and
      interviews were conducted by telephone. RESULTS: AA was higher in women with BN
      compared to women without BN or binge eating disorder, only when the influence of
      major depressive disorder (MDD) and posttraumatic stress disorder (PTSD) was
      controlled. Prevalence rates of AA and AD were similar in women with BN, MDD, and
      PTSD. Analyses indicated that the relationship between BN and AA/AD may be
      indirect and influenced by associations with MDD and PTSD. Women with BN+AA did
      not differ from those with BN-AA on most variables concerning victimization,
      family of origin, and disordered eating. DISCUSSION: Evaluation of MDD and PTSD
      in women presenting for treatment of BN and/or alcohol use disorders (AUDs) is
      recommended.

PMID- 10657892
TI  - Personality features differentiate late adolescent females and males with chronic
      bulimic symptoms.
AB  - OBJECTIVE: The authors examined gender differences in bulimia-related personality
      variables among late adolescents with chronic bulimic symptoms. METHOD: Ninety
      seven females and 14 males were included in the study. They participated in
      surveys in 1982, and again in 1992, and at each session reported elevated bulimic
      symptoms. Each respondent completed subscales of the Eating Disorders Inventory
      (Bulimia, Drive for Thinness, Perfectionism, and Interpersonal Distrust).
      RESULTS: Even compared to males with similar levels of chronic bulimic symptoms,
      females with chronic bulimic symptoms reported more drive for thinness; compared
      to females with chronic bulimic symptoms, males with chronic bulimic symptoms
      reported more perfectionism and interpersonal distrust. DISCUSSION: Late
      adolescent males and females with chronic bulimic symptoms can be distinguished
      on the basis of personality features. These findings have implications for
      theory, as well as for clinical assessment and therapeutics.

PMID- 10657893
TI  - Three studies on the factorial distinctiveness of binge eating and bulimic
      symptoms among nonclinical men and women.
AB  - OBJECTIVE: According to DSM-IV's proposed nosology, binge eating disorder is
      separable from bulimia nervosa. The basis for separation rests with compensatory
      behaviors (e.g., induced vomiting)-people with bulimia nervosa engage in
      compensatory behaviors, whereas those with binge eating disorder do not. We
      addressed the validity of this nosology. METHODS: In three studies on 2,015 young
      men and women, we used factor-analytic techniques to assess whether bulimic and
      binge eating symptoms are separable in men and women. Results and Discussion
      Results of the three studies converged: Although binge eating symptoms may be
      distinct from bulimic symptoms among young men, the two syndromes are factorially
      inseparable among young women. Nosologic and sociocultural implications are
      noted.

PMID- 10657894
TI  - Dissonance prevention program decreases thin-ideal internalization, body
      dissatisfaction, dieting, negative affect, and bulimic symptoms: A preliminary
      experiment.
AB  - OBJECTIVE: Because psychoeducational primary prevention programs for eating
      disorders have met with little success, this preliminary experiment tested a
      dissonance-based targeted preventive intervention. METHOD: Female undergraduates
      (N = 30) with elevated body image concerns were assigned to a three-session
      intervention, wherein they voluntarily argued against the thin ideal, or a
      delayed-intervention control condition. Participants completed a baseline,
      termination, and a 1-month follow-up survey. RESULTS: The intervention resulted
      in a subsequent decrease in thin-ideal internalization, body dissatisfaction,
      dieting, negative affect, and bulimic symptomatology, with most changes remaining
      at the 1-month follow-up. DISCUSSION: These preliminary results suggest that this
      dissonance-based targeted prevention intervention reduces bulimic pathology and
      known risk factors for eating disturbances, and provide experimental support for
      the claim that thin-ideal internalization contributes to body dissatisfaction,
      dieting, negative affect, and bulimic symptoms.

PMID- 10657895
TI  - Negative affect moderates the relation between dieting and binge eating.
AB  - OBJECTIVE: Although laboratory experiments suggest that negative affect
      inductions potentiate the relation between dieting and disinhibited eating,
      little research has tested whether this finding generalizes to binge eating in
      the natural environment. Thus, we assessed whether negative affect moderated the
      relation between dieting and binge eating in a passive-observational study.
      METHOD: This aim was addressed with longitudinal data from a community sample of
      adolescents (N = 631). RESULTS: For females, dieting and negative affect
      predicted binge eating in cross-sectional and prospective analyses, but negative
      affect potentiated the relation between dieting and binge eating only in the
      cross-sectional analyses. Similar, but attenuated results were found for males.
      DISCUSSION: Findings converge with those from laboratory studies in suggesting
      that negative affect moderates the relation between dieting and binge eating, but
      also imply that dieting and negative affect constitute independent risk factors
      for binge eating. The lack of prospective effects may suggest that the
      interactive relations have a short time lag or are difficult to detect
      prospectively.

PMID- 10657897
TI  - Binge eating disorder and bulimia nervosa: differences in the quality and
      quantity of binge eating episodes.
AB  - OBJECTIVE: This study sought to examine the differences in the quantity and
      quality of binges between binge eating disorder (BED) and bulimia nervosa.
      METHOD: Patients (N = 77) seeking treatment for eating disorders were assessed on
      binge content. RESULTS: Results suggest no differences in binge quantity with BED
      and bulimia, but there were differences in the binge quality. The binges of
      bulimics were higher in carbohydrates and sugar than those with BED. DISCUSSION:
      The higher levels of obesity of our BED individuals may account for the lack of
      differences between those with bulimia and BED. The importance of increasing our
      knowledge of the continuum of weight and binging is discussed.

PMID- 10657896
TI  - Utilization of empirically supported psychotherapy treatments for individuals
      with eating disorders: A survey of psychologists.
AB  - OBJECTIVE: The purpose of this study was to assess the primary methods used by
      psychotherapists in treating individuals with eating disorders and to determine
      the extent to which certain empirically supported psychotherapies (i.e.,
      cognitive behavioral therapy [CBT] and interpersonal psychotherapy [IPT]) are
      used in clinical settings. METHOD: Surveys developed for this study were sent to
      500 psychologists randomly selected from a list of all licensed doctoral-level
      psychologists in an upper midwestern state. RESULTS: Despite the findings that
      CBT techniques were reported to be frequently used, most respondents identified
      something other than CBT or IPT as their primary theoretical approach. In
      addition, the majority of respondents indicated not having received training in
      the use of manual-based, empirically supported treatment approaches for working
      with individuals with eating disorders, although most reported a desire to obtain
      such training. CONCLUSIONS: Although commonly referred to as the "treatments of
      choice" in research literature, manual-based, empirically supported approaches to
      working with individuals with eating disorders has not received adequate
      dissemination.

PMID- 10657898
TI  - BTG gene expression in the p53-dependent and -independent cellular response to
      DNA damage.
AB  - Exposure of mammalian cells to genotoxic agents evokes a complex cellular
      response. An ordered series of molecular events is necessary to sense DNA damage,
      transduce the signal, and ultimately delay the cell cycle or trigger apoptosis.
      Recently, we have shown that BTG2/TIS21 gene expression was induced in response
      to DNA damage through a p53-dependent pathway. This gene belongs to a newly
      identified family of structurally related genes whose other known human members
      are BTG1, BTG3, and Tob. To define the respective involvement of these four
      related genes in the cellular response to DNA damage, we studied their expression
      in human cell lines after a variety of genotoxic treatments. Our results
      demonstrated that were BTG1, BTG2/TIS21, and Tob genes the DNA damage--inducible
      genes. However, BTG2/TIS21 appeared to be the only p53-transcriptional target
      gene. We speculate that BTG proteins may play a coordinate role in a general
      transduction pathway that is induced in response to DNA damage. It has been
      previously described that recombinant BTG1 and BTG2/TIS21 can physically interact
      with PRMT1, an arginine methyl transferase, suggesting that BTG1 and BTG2/TIS21
      induction may lead to posttranslational modifications of cellular proteins. In
      support of this hypothesis, we showed that the endogenous induction of BTG1 and
      BTG2 after genotoxic treatment was correlated with a modulation of protein
      methylation.

PMID- 10657899
TI  - Inhibition of atypical PKC blocks ultraviolet-induced AP-1 activation by
      specifically inhibiting ERKs activation.
AB  - Since ultraviolet (UV) radiation is a major etiologic factor in the development
      of human skin cancers, investigating the signal transduction pathways initiated
      by UV radiation may help with the understanding of the molecular mechanisms of UV
      induced carcinogenesis. Our previous studies demonstrated that UV-induced
      activator protein-1 (AP-1) activation is blocked by dominant negative atypical
      PKCs (aPKCs). Here we investigated the role of aPKC in UV-induced activation of
      mitogen activated protein (MAP) kinase family members which are considered to be
      the mediators of AP-1 activation. We found that UV radiation led to translocation
      of protein kinase C (PKC) zeta and activation of MAP kinase family members as
      well as an increase of AP-1-dependent transcription activation at the same dose
      range. Pretreatment of cells or mouse skin with antisense oligonucleotides of
      PKCzeta impaired UV-induced activation of AP-1 in JB6 cells as well as in AP-1
      luciferase transgenic mice. It also inhibited UV-induced activation of ERKs but
      not of JNK and p38 kinases in JB6 cells. In contrast, no significant inhibition
      of AP-1 activation and MAP kinase activation were observed in cells treated with
      sense oligonucleotides of PKCzeta. Furthermore, overexpression of a dominant
      negative mutant of PKClambda/iota specifically inhibited activation of
      extracellular signal-regulated protein kinases (ERKs) but not of c-jun N-terminal
      kinases (JNKs) nor p38 kinases induced by UV radiation. These results
      demonstrated that inhibition of aPKC impairs UV-induced AP-1 activation via
      suppression of ERKs activation but not of JNKs or p38 kinase activation.

PMID- 10657900
TI  - Genomic imbalance in rat mammary gland carcinomas induced by 2-amino-1-methyl-6
      phenylimidazo(4,5-b)pyridine.
AB  - 2-Amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP), a compound found in
      cooked meat, is a mammary gland carcinogen in female Sprague-Dawley rats. PhIP
      induced rat mammary gland carcinomas were examined for mutations in several genes
      (exons) known to regulate cell growth and apoptosis, including p53 (4-8),
      p21(Waf1) (coding region), Apc (14, 15), B-catenin (3), E-cadherin (9,13,15), Bcl
      x (coding region), Bax (3), IGFIIR (28), and TGFBIIR (3). DNA from 30 carcinomas
      was examined by single-strand conformation polymorphism analysis, but no
      mutations were detected in these genes or gene regions. DNA from carcinomas and
      matching normal tissue were further screened for allelic imbalance by using a
      polymerase chain reaction-based approach with primers to known microsatellite
      regions located throughout the rat genome. Of 53 markers examined, 12 revealed
      allelic imbalance. Microsatellite instability (MSI) was detected at two markers,
      one on chromosome 4 and one on chromosome 6. Sixty-five percent and 96% of all
      carcinomas examined (N=23) showed MSI at these loci on chromosomes 4 and 6,
      respectively, supporting the notion that MSI plays a role in PhIP-induced mammary
      carcinogenesis. Loss of heterozygosity (LOH), an indication of a possible tumor
      suppressor gene, was observed at 10 markers distributed on chromosomes 3, 10, 11,
      14, and X. The frequency of LOH at these markers was 75-94%, supporting that the
      regions of allelic imbalance were largely similar for the PhIP-induced carcinomas
      examined in this study. When PhIP-induced carcinomas from rats placed on high-fat
      and low-fat diet were compared, no unique regions of allelic imbalance or
      statistical differences in the frequency of allelic imbalance were observed.
      Therefore, the high-fat diet, known to be a promoter of PhIP-induced rat mammary
      carcinogenesis, did not appear to influence allelic imbalance in the carcinomas.
      Interestingly, 7,12-dimethylbenz[a]-anthracene-induced mammary carcinomas did not
      show allelic imbalance at 11 of the 12 loci that showed allelic imbalance in PhIP
      induced carcinomas. These findings suggest that distinct chemical carcinogens
      induce different patterns of allelic imbalance during rat mammary carcinogenesis.
      Since several of the known genes involved in carcinogenesis did not harbor
      mutations in PhIP-induced carcinomas, further studies are needed to clarify the
      critical genes involved in PhIP-induced mammary carcinogenesis and to determine
      whether regions of LOH harbor potentially novel tumor suppressor genes involved
      in this disease.

PMID- 10657901
TI  - CAD, a c-Myc target gene, is not deregulated in Burkitt's lymphoma cell lines.
AB  - Although the Myc family of transcription factors is upregulated in many human
      tumors, it is unclear which genes are targets for the deregulated Myc. Previous
      studies suggest that hamster and rat carbamoyl phosphate synthase, aspartate
      transcarbamylase, dihydroorotase Cad genes are regulated by c-Myc. In fact, of
      all putative target genes thought to be activated by c-Myc, only the Cad gene
      showed loss of growth regulation in rat cells nullizygous for c-Myc. However, it
      was unknown whether upregulation of CAD, which performs the first three rate
      limiting steps of pyrimidine biosynthesis, contributes to c-Myc's role in human
      neoplasia. To explore this possibility, we cloned the human cad promoter. We
      found that c-Myc could bind to an E box in the human cad promoter in gel shift
      assays and that growth regulated transcription from the human cad promoter was
      dependent on this c-Myc binding site. However, the increased amount of c-Myc
      found in Burkitt's lymphoma cell lines did not lead to increased cad mRNA levels.
      Thus, we suggest that although c-Myc is clearly important for the normal
      transcriptional control of the cad promoter, it is unlikely that increased levels
      of CAD are important mediators of c-Myc-induced neoplasia. Therefore, an
      understanding of the mechanism by which overexpressed c-Myc contributes to the
      development of Burkitt's lymphoma requires the identification of additional c-Myc
      target genes.

PMID- 10657902
TI  - Tumor necrosis factor-alpha promotes human papillomavirus (HPV) E6/E7 RNA
      expression and cyclin-dependent kinase activity in HPV-immortalized keratinocytes
      by a ras-dependent pathway.
AB  - Tumor necrosis factor-alpha (TNF-alpha) inhibits growth of normal cervical
      keratinocytes but stimulates proliferation of human papillomavirus (HPV)
      immortalized and cervical carcinoma-derived cell lines when mitogens such as
      epidermal growth factor (EGF) or serum are depleted. Current work identifies the
      mechanism of growth stimulation. TNF-alpha promoted cell cycle progression by
      increasing expression of HPV-16 E6/E7 RNAs and enhancing activity of cyclin
      dependent kinase (cdk)2 and cdc2 after 3 d. Increased kinase activity was
      mediated by upregulation of cyclins A and B and decreases in cdk inhibitors
      p21(waf) and p27(kip). TNF-alpha stimulated these changes in part by increasing
      transcription and stabilization of RNA for amphiregulin, an EGF receptor ligand,
      and amphiregulin directly increased HPV-16 E6/E7 and cyclin A RNAs. To define
      which components of the EGF receptor signaling pathway were important, HPV
      immortalized cells were transfected with activated or dominant negative mutants
      of Ha-ras, raf, or MAPKK. Expression of activated Ha-ras maintained HPV-16 and
      cyclin gene expression and promoted rapid growth in the absence of EGF.
      Furthermore, ras activation was necessary for TNF-alpha mitogenesis as
      transfection with a dominant negative ras mutant (Asn-17) strongly inhibited
      growth. Thus, activation of ras promotes expression of HPV-16 E6/E7 RNAs, induces
      cyclins A and B, and mediates growth stimulation of immortal keratinocytes by TNF
      alpha. These studies define a pathway by which ras mutations, which occur in a
      subset of cervical cancers, may contribute to pathogenesis. Mol. Carcinog. 27:97
      109, 2000. Published by Wiley-Liss, Inc.

PMID- 10657903
TI  - Abnormal structure and expression of PTEN/MMAC1 gene in human uterine cancers.
AB  - The PTEN/MMAC1 gene, located on human chromosome 10q23, has recently been
      implicated as a candidate tumor suppressor gene in human cancers. In the present
      study, 12 uterine cancer cell lines and 87 uterine cancers of various grades and
      histological type were analyzed for PTEN/MMAC1 gene. Three of 44 endometrial
      carcinoma (7%) showed no PTEN/MMAC1 mRNA expression by RT-PCR analysis.
      Sequencing analysis of entire coding region of PTEN/MMAC1 gene revealed mutations
      in three of six endometrial cancer cell lines (50%) and 17 of 44 endometrial
      cancer tissues (39%). In contrast, for cervical cancers, only one of six cancer
      cell lines (2%) showed mutation, and one of 43 cancer tissues (2%) had an
      abnormality. Overall, 36% of the abnormal spots were located in exon 5, 24% were
      in exon 8, 16% were in exon 3, and 8% were in exon 6, and single cases of
      abnormality were found in exons 1, 4, and 7. Our results revealed that, in total,
      60% of abnormalities were clustered in exons 5 and 8. Exon 5 is a functional
      domain of the PEN/MMAC1 gene, and therefore, abnormalities in this region may be
      important for loss of PTEN/MMAC1 gene function. Finally, we found a high
      frequency of PTEN/MMAC1 gene abnormalities in endometrial carcinomas but a low
      frequency in cervical carcinomas. These findings suggest that disruption of
      PTEN/MMAC1 by mutation or absence of expression may contribute to the
      pathogenesis or neoplastic evolution in a large proportion of endometrial
      carcinomas but in a small proportion of cervical carcinomas.

PMID- 10657904
TI  - Photoreactivation does not alter ras and p53 mutation spectra in ultraviolet
      radiation-induced corneal sarcomas of Monodelphis domestica.
AB  - When chronically exposed to ultraviolet radiation (UV), opossums of the species
      Monodelphis domestica develop corneal sarcomas at high frequency. Post-UV
      exposure to photoreactivating light enhances repair of UV-induced pyrimidine
      dimers and suppresses, but does not abrogate, corneal tumor development. We
      compared mutation spectra in ras and p53 genes in 32 eye tumors from Monodelphis
      exposed to UV alone and in 25 tumors from Monodelphis exposed to UV followed by
      photoreactivation in order to identify the particular types of mutation
      suppressed by enhanced repair of pyrimidine dimers. Mutations were detected by
      polymerase chain reaction amplification followed by direct sequencing or by
      "cold" single-strand conformational polymorphism analysis. The overall frequency
      of mutations was low, and there was no statistically significant difference
      between the two groups of tumors in the frequency or type of mutation. All
      mutations occurred at dipyrimidine sites, and most were C to T or CC to TT
      mutations, the hallmark UV-induced mutations. Hotspots of p53 mutation identified
      in a previous study of invasive tumors were absent, and mutations identified in
      the present study included synonymous mutations not previously detected. The
      difference in stage of the tumors examined is believed to account for these
      differences. The preponderance of signature UV mutations in p53 and ras genes
      confirm that UV is the proximate carcinogen for these tumors. The low incidence
      of mutations suggest that neither ras activation nor p53 inactivation is
      essential for tumor formation. Mutations attributable specifically to pyrimidine
      dimer formation could not be identified.

PMID- 10657905
TI  - Profiles of cytokine mRNAs in the skin and lymph nodes of SENCAR mice treated
      epicutaneously with dibenzo[a,l]pyrene or dimethylbenz[a]anthracene reveal a
      direct correlation between carcinogen-induced contact hypersensitivity and
      epidermal hyperplasia.
AB  - The potent carcinogenicity of dibenzo[a,l]pyrene (DB[a,l]P) in mouse skin is
      associated with an inflammatory response and a striking epidermal hyperplasia.
      The mechanism of these tissue responses is not known. However, a recent study has
      shown DB[a,l]P to be a contact sensitizer. In view of the programmed expression
      of cytokines during induction of contact hypersensitivity (CHS) and elicitation
      of CHS reactions, we analyzed cytokine mRNAs in treated skin and draining lymph
      nodes of SENCAR mice, at selected times after a single, epicutaneous application
      of DB[a,l]P or dimethylbenz[a]anthracene (DMBA), a substantially weaker
      carcinogen and a weaker contact sensitizer than DB[a,l]P. Cytokine mRNAs were
      quantified by first-strand DNA synthesis with reverse transcriptase (RT) and DNA
      amplification by the polymerase chain reaction (PCR). Histopathology of treated
      skin was determined in the same experiments. Time-response profiles of interferon
      (IFN) gamma and interleukin (IL) 2 in the DLN and IL1beta, IL10, tumor necrosis
      factor (TNF) alpha, and IL4 mRNAs in the skin of mice treated with 200 nmol of
      DB[a,l]P were in remarkable agreement with established profiles in mice treated
      with conventional contact sensitizers, e.g., oxazolone or dinitrochlorobenzene.
      Strong upregulation of DLN IFNgamma mRNA coupled with little change in IL 2 mRNA
      suggested a CD8(+) T-cell response characteristic of CHS induction. Coordinate
      expression of epidermal IL1beta, TNFalpha, and IL10 mRNAs, 24 h after DB[a,l]P
      treatment, was also characteristic of CHS induction. IL1beta and IL10 are
      upregulated by allergens and not by chemical irritants. Time-response profiles of
      epidermal IL1beta, TNFalpha, IL10, and IL4 mRNAs, 3-14 d after DB[a,l]P
      treatment, corresponded with expression of these cytokines during elicitation of
      CHS reactions. Epidermal IL4 is specifically upregulated during CHS reactions.
      Cytokine mRNA responses were dose-dependent (50, 100, and 200 nmol of DB[a,l]P)
      and markedly weaker in animals treated with 400 nmol of DMBA. Significantly, the
      intensity of epidermal hyperplasia correlated with the strength of the cytokine
      mRNA signals in DLN and skin. In conclusion, our data support carcinogen-specific
      CHS as a mechanism by which the very potent carcinogen DB[a,l]P induces epidermal
      hyperplasia, a requirement for tumor promotion in mouse skin.

PMID- 10657907
TI  - Allele-specific losses of heterozygosity on chromosomes 1 and 17 revealed by
      whole genome scan of ethylnitrosourea-induced gliomas of BDIX x BDIV hybrid rats

PMID- 10657908
TI  - In press

PMID- 10657906
TI  - Overexpression of p21 protein in radiation-transformed mouse 10T(1/2) cell
      clones.
AB  - In order to investigate the hypothesis that aberrant expression of cell-cycle
      regulatory proteins may represent early events in the process of carcinogenesis,
      levels of expression of the negative regulators p21(waf1/cip1) (p21), p27(kip1)
      (p27), and p16(ink4a) (p16) and/or the positive regulators cyclin D(1) and cyclin
      E were examined by western blot analysis in cells transformed in vitro by
      ionizing radiation. The levels of these proteins in 12 independently derived
      mouse 10T(1/2) cell clones transformed by 1.5 Gy of alpha radiation were compared
      with those in nine similarly derived nontransformed control clones. Constitutive
      levels of p21 were very low in all control clones, whereas p21 expression was
      significantly elevated in nine of 12 transformed clones. Two of the three
      transformed clones displaying low levels of p21 expressed increased levels of
      p53. p21 regulation was also altered in response to radiation in transformed
      clones as compared with controls, only minimal induction was observed 4 h
      following gamma irradiation. Western blot analysis indicated a constant
      expression of p27 protein but slightly decreased levels of p16 in these
      transformed clones. Cyclin D(1) was overexpressed in 11 of 12 transformed clones;
      in only two of these were the levels of cyclin E elevated. Overall, the results
      suggest that alterations in the expression of cell cycle regulatory proteins may
      represent important events in radiation-induced oncogenic transformation in
      vitro. Although the specific alterations vary among different transformed clones,
      overexpression and aberrant regulation of p21 appear to be the most frequent
      ones.

PMID- 10657909
TI  - Lung cancer

PMID- 10657910
TI  - Molecular events in bronchogenic carcinoma and their implications for therapy.
AB  - Lung cancer patients suffer a 15% overall survival despite advances in
      chemotherapy, radiation therapy and surgery. This unacceptably low survival rate
      is due to the usual finding of advanced disease at diagnosis. Detecting
      preneoplastic lesions and determining which invasive lesions are prone to
      metastasize or recur can be formidable tasks. Understanding the molecular events
      that occur during the multistep process of bronchogenic carcinogenesis may make
      these tasks more surmountable. Approaches leading to identification of patients
      susceptible to cancer formation include detection of poor metabolizers of
      carcinogens, those unable to repair genetic alterations, those with activated
      oncogenes or inactivated tumor suppressor genes, and those at risk of poor
      outcomes. Detection may be achieved at the cellular, chromosomal, genetic, or
      protein level. Novel therapies can then be developed that prevent tumor
      initiation into and promotion through the multistep carcinogenesis pathway,
      conversion from preneoplastic into invasive malignancies, and progression into
      metastasis or recurrences. Therapeutic success of chemoprevention can be followed
      by changes in molecular marker levels. Blockade of activated tumor-promoting
      oncogenes or replacement of inactivated tumor-suppressing or apoptosis-promoting
      genes can be achieved by gene therapy. Development of these novel molecular
      diagnostic and therapeutic strategies could result in prevention of cancer
      formation or at least prolongation of disease-free survival.

PMID- 10657911
TI  - Lung cancer chemoprevention.
AB  - Lung cancer is the leading cause of cancer death in the United States. The
      persisting grim lung cancer incidence and mortality figures argue powerfully for
      new approaches such as chemoprevention for controlling this disease. Retinoids
      are among the most intensively studied cancer chemoprevention agents, including
      in the lung. Several randomized clinical or translational chemoprevention trials
      (e.g., of retinoids, beta-carotene, or combined folic acid and vitamin B(12))
      have been conducted in lung pre-malignancy. Retinoid studies have produced
      important data on molecular/cellular markers of lung carcinogenesis, e.g., loss
      of heterozygosity (LOH) at 3p and 9p and retinoic acid receptor-beta (RAR-beta).
      Two large randomized trials with a lung cancer endpoint, the Alpha-Tocopherol,
      Beta-Carotene (ATBC) Prevention Study and the Beta-Carotene and Retinol Efficacy
      Trial (CARET), found that beta-carotene (+/- retinol) was harmful (in smokers).
      Recently completed lung-second-primary-tumor-prevention trials include the
      retinoids retinyl palmitate and 13-cis-retinoic acid (13cRA) and N-acetylcysteine
      (NAC). Vitamin E and selenium show promise for lung cancer prevention, based on
      positive secondary/subset analyses of three large-scale, randomized National
      Cancer Institute (NCI) cancer prevention trials. Future directions of lung cancer
      chemoprevention include the study of molecular markers of risk and drug activity,
      molecular targeting study, improved imaging techniques (e.g., molecular imaging)
      and new drug delivery systems.

PMID- 10657912
TI  - The international system for staging lung cancer.
AB  - The International System for Staging Lung Cancer is a consistent, reproducible
      classification for the anatomic extent of disease in patients with lung cancer. A
      revision of the system in use since 1986 included modifications of the rules for
      stage grouping the TNM (T-primary tumor, N-regional lymph nodes, and M-distant
      metastasis) anatomic subsets. More specific stage categories and consistency for
      reporting the end results for Stage I, Stage II, and Stage IIIA disease are
      provided. Survival data support the revised categories and confirm the
      significant relationship between the extent of the disease and prognosis for
      patients with this disease.

PMID- 10657913
TI  - Noninvasive clinical staging modalities for lung cancer.
AB  - Clinical staging of lung cancer helps to determine the extent of disease and
      stratify patients into similar therapeutic and prognostic categories. A primary
      goal of clinical staging is to separate patients with potentially resectable
      disease from those that are unresectable. Initial assessment of the patient by
      history and physical examination combined with laboratory values can suggest
      metastatic spread of the disease. When abnormal, these clinical factors may have
      value in terms of predicting prognosis, but their use in early stage lung cancer
      is limited because of the low prevalence of symptoms, physical exam findings, and
      laboratory abnormalities in this group. For clinical staging, patients almost
      always undergo a postero-anterior and lateral chest radiograph and a computed
      tomography (CT) scan of the chest and upper abdomen to include the liver and
      adrenal glands. Although CT scanning provides exquisite anatomic information, it
      is less than optimal for determining lymph node status. Over the last several
      years, CT scanning combined with positron-emission tomography (PET) using
      fluorodeoxyglucose (FDG) has significantly improved the accuracy of clinical
      staging. The use of FDG-PET continues to be defined in the non-invasive
      evaluation of the primary tumor, nodal involvement, and metastatic disease.
      Despite the recent advancements in radiologic assessment of lung cancer, invasive
      sampling is still often performed for pathologic confirmation.

PMID- 10657914
TI  - Surgical management of early stage lung cancer.
AB  - For patients with lung cancer, the greatest hope for cure rests with patients
      with early stage disease. Surgery has been the standard of care for this group
      with the best 5-year survival of only 65% being achieved in patients with
      earliest pathologic Stage IA disease. Using strategies gained from the management
      of patients with advanced disease, clinicians are investigating the use of
      perioperative chemotherapy and radiotherapy to improve survival. In addition,
      biologic and molecular markers are being evaluated to assist in predicting
      prognosis and to identify those patients at increased risk for recurrent disease.
      Postoperative surveillance of patients using helical computed tomography (CT)
      scanning is being investigated to detect early recurrences and second primary
      lesions. With such treatment and management plans on the horizon, the prognosis
      of patients with early stage non-small cell lung cancer (NSCLC) may be improved.

PMID- 10657915
TI  - Surgery for advanced stage lung cancer.
AB  - Therapeutic strategy in advanced stage disease remains controversial.
      Theoretically resectable, Stage IIIa disease includes a high proportion of non
      resectable nodal diseases. Overall 5-year survival after surgery remains lower
      than 15%. Randomized trials comparing the results of surgery alone with induction
      chemotherapy followed by surgery showed a significant benefit to induction
      therapy. Currently, Stage IIIb diseases are considered unresectable;
      nevertheless, selected patients are able to undergo an extended resection after
      induction treatments. In highly selected cases, a surgical resection can be
      performed in T4 tumors. Surgical resection must be included in a combined
      multidisciplinary strategy of treatment, and is proposed only for responders.
      Resectability criteria have to be defined with clinical trials designed to
      increase the local control by surgery. Thus, so-called Stage IIIb tumors can be
      divided in two subcategories: potentially resectable and definitively non
      resectable. Some locally advanced, initially unresectable tumors (Stage IIIb) can
      become operable after induction chemoradiotherapy. The French staging system,
      based upon prognostic and therapeutic subcategories, splits N2 involvement into
      two subcategories: mN2 (minimal), found at the thoracotomy; and cN2 (clinical),
      histologically proven at the pre-treatment staging. T4 tumors are divided in
      potentially resectable T4(1) (invasion of superior vena cava, carina, lower
      trachea, left atrium), and definitively non-resectable T4(2) (malignant pleural
      or pericardial effusion, invasion of oesophagus, and vertebrae). Thus, Stage III
      can be separated into three subcategories, A, B, and C, instead of the two
      current substages. Stage IIIA includes T3 N1 M0 and T1-T3mN2M0 tumors. Stage IIIB
      includes T1-T3cN2M0 and T4(1)N0-N2MO tumors. Stage IIIC includes T4(2)N0-N3M0 and
      T1-T4(1)N3M0 tumors. In this way, the therapeutic options in non-small-cell lung
      cancer (NSCLC) will be clarified with 1) a "primary surgery" subgroup, including
      Stages I, II, and IIIA, 2) an "induction treatment" subgroup, including Stage
      IIIB, and 3) a "non-surgical" subgroup, including Stages IIIC and IV.

PMID- 10657916
TI  - Role of multimodality treatment for lung cancer.
AB  - Locally advanced non-small cell lung cancer (NSCLC) is, in fact, a systemic
      disease requiring a multimodality approach for optimal treatment. The role of
      preoperative chemotherapy has been established and is now an accepted treatment
      for resectable Stage IIIA NSCLC. Several studies have addressed the feasibility
      and efficacy of preoperative chemotherapy followed by surgery. All these
      induction chemotherapy trials have reported a high radiographic response rate,
      high respectability rate and improved survival in completely resected patients.
      The findings of three published randomized trials indicate that the survival rate
      of Stage IIIA patients is better with induction chemotherapy plus surgical
      resection than with resection alone. More recently, Phase II trials using
      concurrent chemoradiotherapy have been tested with encouraging results. Chemo
      therapy combined with thoracic radiotherapy has emerged as a primary treatment
      option for locally advanced, unresectable NSCLC. Randomized trials and subsequent
      meta-analyses have shown a clear survival benefit with platinum-based combination
      chemotherapy administered with thoracic radiation-as compared to radiation alone
      in treating inoperable Stage IIIA and IIIB lung cancer. Combined modality
      treatment in locally advanced NSCLC continues to evolve and is the subject of
      ongoing research. Despite clinical advances, many aspects of the management of
      these patients are yet to be fully clarified: Is surgical resection really
      necessary for Stage IIIA patients? What is the value of altered-fractionation
      radiotherapy and three-dimensional conformal radiation therapy? What is the
      optimal sequencing of radiotherapy and chemotherapy? In this regard, new
      chemotherapeutic agents may provide additional benefits in the multimodality
      approach, and it is for this reason that various studies are underway which have
      incorporated new agents in the front line setting. Finally, a better
      understanding of the biology of tumors could well help us to optimize treatments.
      In the future, molecular classification of NSCLC may provide a useful tool when
      making therapy-related decisions.

PMID- 10657917
TI  - The management of superior sulcus tumors.
AB  - Lung cancers arising from the extreme apex of the lung-superior sulcus tumors
      (SST)-have distinct symptoms and signs at presentation and a characteristic
      appearance on imaging. However, in their early stages, these tumors are often
      missed by traditional anterior/posterior chest X-rays. Recent advances in
      computed tomography (CT) and magnetic resonance imaging (MRI) have made selection
      of patients with potentially resectable of SST more accurate. If mediastinoscopy
      reveals no mediastinal lymph nodes involved, the patient can be treated with
      surgery followed by radiation therapy with or without chemotherapy. If
      mediastinoscopy reveals microscopic mediastinal lymph node involvement, the
      patient can be treated with induction radiation therapy and concurrent
      chemotherapy followed by surgery. If mediastinoscopy reveals gross mediastinal
      lymph node involvement (N2), or if CT reveals N3 or T4 lesions, the patient can
      be treated with concurrent chemotherapy and radiation therapy to relieve
      symptoms; the outcome of such treatment appears to be better than that of
      sequential chemotherapy followed by radiation therapy. Whenever possible, to
      enhance the patient's quality of life, surgery should be considered to improve
      function and relieve pain.

PMID- 10657918
TI  - Lung conservation techniques: bronchial sleeve resection and reconstruction of
      the pulmonary artery.
AB  - Bronchial and vascular reconstructive procedures are a technically feasible
      alternative to pneumonectomy and have the advantage of sparing functioning lung
      parenchyma. Between 1989 and 1999, we performed bronchovascular sleeve resection
      and reconstruction in 145 patients (109 men, 36 women; age range, 26 to 76 years,
      mean, 56 years) with non-small-cell lung cancer (NSCLCL). Forty-one patients had
      induction chemotherapy and 3 had pre-operative radiotherapy. Immediate and long
      term postoperative evaluation included bronchoscopy, spirometry,
      electrocardiogram, Doppler echocardiography, and perfusion lung scans, computed
      tomography and, only recently, angio-magnetic resonance (MR) imaging. Follow-up
      ranged between 3 months and 10 years (mean, 3.7 years) and is complete for all
      patients. We report the results of this series and conclude that morbidity,
      mortality, and functional data indicate that bronchovascular reconstructions are
      equal to standard lobectomy in terms of pulmonary function. Long-term survival is
      comparable with that reported for standard resection (lobectomy-pneumonectomy).
      These findings suggest that even complex lung-sparing operations can be proposed
      as adequate procedures in the treatment of lung cancer as long as a complete
      anatomical resection is obtained.

PMID- 10657919
TI  - Surgical palliation of airway obstruction resulting from lung cancer.
AB  - Bronchogenic carcinoma remains a relentless plague of modern society causing far
      more deaths than the well-popularized "AIDS epidemic" and secondary only to
      cardiovascular disease as a cause of death in America. Despite medical advances
      and treatment breakthroughs, only 40% of newly identified lung cancer patients
      are "potentially curable". Therefore, a large portion of this patient population
      will require palliative care and treatment. Surgical palliation is somewhat a
      misnomer in that most endobrachial lesions causing significant obstruction that
      result in dyspnea are not amenable to surgical intervention, i.e., operative
      resectional therapy. The palliative management options of airway obstruction
      resulting from advanced stage lung cancer will be reviewed, including the
      historical aspects, development and current use of laser resection, airway
      stenting, and endobrachial brachytherapy for management of unresectable airway
      tumors. These modalities frequently are used simultaneously in the same patient
      and may be used in conjunction with current chemotherapeutic and conventional
      external-beam radiation protocols.

PMID- 10657920
TI  - Pathogenesis and management of respiratory insufficiency following pulmonary
      resection.
AB  - The underlying principle of the surgical treatment of non-small-cell lung cancer
      (NSCLC) is complete removal of the local/regional disease within the thorax.
      Pulmonary resection should be as conservative as possible without compromising
      the adequacy of tumor removal. A multitude of factors influence the incidence and
      severity of complications following pulmonary resection including the pre
      operative physical and psychological status of the patient, the pathologic
      process requiring resection, the physiologic impact of the procedure, and the
      addition of pre-operative or postoperative adjuvant therapy. The insidious onset
      of interstitial changes on chest X-ray (CXR) 1 to 2 days after pulmonary
      resection forewarns of respiratory distress; however, the pathophysiology of
      adult respiratory distress syndrome (ARDS) with progression to respiratory
      failure requiring mechanical ventilation and advanced critical care often
      unfolds. Management of patients with severe respiratory failure remains primarily
      supportive. "Good critical care" is the mainstay of therapy: this includes gentle
      mechanical ventilation to avoid ventilator-induced barotrauma and over-extension
      of remaining functional alveoli, diuresis, infection identification and
      management, and nutritional support. New therapeutic strategies that may impact
      on outcomes in the adult population include pressure-limited ventilation
      (permissive hypercapnia), inverse ratio ventilation, high-frequency jet
      ventilation, high-frequency oscillatory ventilation, intratracheal pulmonary
      ventilation, and prone position ventilation. In addition, alternative therapies
      such as partial liquid ventilation, inhaled nitric oxide, and extracorporeal
      techniques including extracorporeal membrane oxygenation (ECMO), extracorporeal
      carbon dioxide removal (ECCO(2)R), intravascular oxygenation (IVOX), and
      arteriovenous carbon dioxide removal (AVCO(2)R), provide additional modalities. A
      component of some or all of these strategies is finding a role in clinical
      practice.

PMID- 10657921
TI  - Determination of heat loss from the feet and insulation of the footwear.
AB  - This study compared the methods of determining the footwear insulation on human
      participants and the thermal foot model. Another purpose was to find the minimal
      number of measurement points on the human foot that is needed for insulation
      calculation. Bare foot was tested at 3 ambient temperatures on 6 participants.
      Three types of footwear were tested on 2 participants. The mean insulation for a
      bare foot obtained on the participant and model were similar. The insulation of
      warm footwear measured by the 2 methods was also similar. For thin footwear the
      insulation values from the participants were higher than those from the thermal
      model. The differences could be related to undefined physiological factors. Two
      points on foot can be enough to measure the insulation of footwear on human
      participants (r =.98). However, due to the big individual differences of humans,
      and good repeatability and simplicity of the thermal foot method, the latter
      should be preferred for testing.

PMID- 10657922
TI  - A comparison of two methods of determining thermal properties of footwear.
AB  - The present European Standard for footwear testing (Standard No. EN 344:1992;
      European Committee for Standardization [CEN], 1992) classifies footwear thermally
      by a temperature drop inside the footwear during 30 min at defined conditions.
      Today, other methods for footwear thermal testing are also available. The aim of
      this study was to compare EN 344:1992 with a thermal foot method. Six boots were
      tested according to both methods. Additional tests with modified standard tests
      were also carried out. The methods ranked the footwear in a similar way. However,
      the test according to standard EN 344:1992 is a pass-or-fail test, whereas data
      that is gained from the thermal foot method gives more information and allows
      further use in research and product development. A change of the present standard
      method is suggested.

PMID- 10657923
TI  - Job satisfaction and importance of work aspects related to predominant values and
      reactivity.
AB  - The aim of the study is to answer whether 2 predominant values--achievement or
      social relations--and reactivity influence (a) the importance of work aspects,
      (b) satisfaction with them and overall job satisfaction, (c) connections between
      overall job satisfaction and satisfaction with work aspects. Bank employees were
      investigated with the Strelau Temperament Inventory-Revised by Strelau,
      Angleitner, Bantelman, and Ruch (1990, reactivity), Orientation to Work Values
      Inventory by Seifert and Bergmann (1983, values), and Work Description Inventory
      by Neuberger and Allerbeck (1978; importance and satisfaction with work aspects,
      overall job satisfaction). Predominant values, reactivity, and their interaction
      influence the importance of work aspects. The values affect overall job
      satisfaction and satisfaction with Conditions. Reactivity does not affect overall
      job satisfaction, but it strongly influences the structure of satisfaction with
      work aspects, and low-reactives compared to high-reactives are more satisfied
      with 4 out of the 7 considered aspects. Among the high-reactives, connections
      between overall job satisfaction and satisfaction with work aspects depend on
      their predominant values. It was concluded that reactivity can modify regulative
      functions of personal values towards overall job satisfaction: The values have a
      rather declarative character for low-reactives, but meeting aspirations connected
      with their values is very important for high-reactives' job satisfaction.

PMID- 10657924
TI  - The relevance of error analysis in graphical symbols evaluation.
AB  - In an increasing number of modern tools and devices, small graphical symbols
      appear simultaneously in sets as parts of the human-machine interfaces. The
      presence of each symbol can influence the other's recognizability and correct
      association to its intended referents. Thus, aside from correct associations, it
      is equally important to perform certain error analysis of the wrong answers,
      misses, confusions, and even lack of answers. This research aimed to show how
      such error analyses could be valuable in evaluating graphical symbols especially
      across potentially different user groups. The study tested 3 sets of icons
      representing 7 videophone functions. The methods involved parameters such as
      hits, confusions, missing values, and misses. The association tests showed
      similar hit rates of most symbols across the majority of the participant groups.
      However, exploring the error patterns helped detect differences in the graphical
      symbols' performances between participant groups, which otherwise seemed to have
      similar levels of recognition. These are very valuable not only in determining
      the symbols to be retained, replaced or re-designed, but also in formulating
      instructions and other aids in learning to use new products faster and more
      satisfactorily.

PMID- 10657925
TI  - Determination of alphacypermethrin in the air by capillary gas chromatography.
AB  - A new method for sampling and chemical analysis of alphacypermethrin in workplace
      air has been described. Air samples were taken using a glass tube filled with
      silica gel with chemically bounded octadecyl phase. Chromatographic
      determinations were conducted using an HP-5 capillary column (10 m x 0.53 mm) and
      an electron-capture detector. Alphacypermethrin recovery was 100.15%. The
      calculated detection limit for a 60-L air sample was 0.0001 mg/m(3).

PMID- 10657926
TI  - Certification of highly complex safety-related systems.
AB  - The BIA has now 15 years of experience with the certification of complex
      electronic systems for safety-related applications in the machinery sector. Using
      the example of machining centres this presentation will show the systematic
      procedure for verifying and validating control systems using Application Specific
      Integrated Circuits (ASICs) and microcomputers for safety functions. One section
      will describe the control structure of machining centres with control systems
      using "integrated safety." A diverse redundant architecture combined with
      crossmonitoring and forced dynamization is explained. In the main section the
      steps of the systematic certification procedure are explained showing some
      results of the certification of drilling machines. Specification reviews, design
      reviews with test case specification, statistical analysis, and walk-throughs are
      the analytical measures in the testing process. Systematic tests based on the
      test case specification, Electro Magnetic Interference (EMI), and environmental
      testing, and site acceptance tests on the machines are the testing measures for
      validation. A complex software driven system is always undergoing modification.
      Most of the changes are not safety-relevant but this has to be proven. A
      systematic procedure for certifying software modifications is presented in the
      last section of the paper.

PMID- 10657927
TI  - Luminance of the surround and visual fatigue of VDT operators.
AB  - Luminance distribution in the visual field is considered as one of causal factors
      with a significant influence on visual fatigue, especially for intensive and
      extended Video Display Terminal (VDT) work. The aim of the study was to define
      visual fatigue of VDT operators for different values of surrounding luminance.
      Experiments were carried out in laboratory conditions under 3 lighting
      conditions. Only 1 lighting parameter--the luminance of the wall behind the
      display (surrounding luminance)--changed. Visual fatigue was measured both by a
      subjective evaluation of different visual complaints (asthenopic symptoms) and by
      objective measurements of changes in the following visual functions:
      accommodation, convergence, habitual horizontal phoria, critical fusional
      frequency (CFF), and visual acuity. The same experiments were done for CRT
      (Cathode Ray Tube) and LCD TFT (Liquid Crystal Display with Thin Film Transistor)
      screens. The results of the study have shown that there was no significant
      influence of the value of surrounding luminance on the asthenopic symptoms for
      either type of screen. A general tendency towards bigger visual complaints for
      LCD TFT than for CRT participants was found. An objective evaluation of visual
      fatigue demonstrated a tendency towards bigger changes in visual functions with
      an increase of surrounding luminance for both screens. Statistical analysis of
      the results has shown that surrounding luminance influences significantly the
      reduction of the accommodation amplitude (significance level <.05).

PMID- 10657928
TI  - Occupational health care in small and medium-sized enterprises--introduction of
      services to craftsmen by using their professional networks.
AB  - In order to ensure equality of occupational health care among employees of small
      and medium-sized enterprises (SMEs) and of larger companies amendments in the
      regulations of the numerous German accident insurance funds had to be made to
      provide for full availability of services, as requested by German and European
      law. According to these amendments, sectors formerly exempted due to small size
      and due to lack of an adequate number of qualified personnel, had to be covered
      by occupational health care. In order to reach this target group new strategies
      of care delivery had to be developed, making use of pre-existing infrastructure
      and networks. In Germany, district trade association (Kreishandwerkerschaften)
      have proved to be very effective for introducing occupational safety and health
      care into SMEs by either hiring external multidisciplinary services or by
      establishing a common service to be used by all associated crafts establishments.
      In a study conducted by the Federal Office for Health and Safety at Work in 1996
      (Boldt, Gille, & Grahl, 1997), 7 district trade association were looked at in
      detail for their strategies. The results were discussed and supplemented in a 2
      day workshop.

PMID- 10657929
TI  - Occupational health care in small and medium sized enterprises--How many doctors
      do we need and how do we ensure good care?
AB  - The translation of the framework directive 89/391/EEC (Council Directive
      89/391/EEC) into national law aims at supplying occupational protection and
      health care to all employees of large, small, and medium-sized enterprises (SMEs)
      likewise, depending on assessed exposure. Prior incomplete protection of the
      German workforce with bias against the SMEs requires an assessment of
      quantitative and qualitative adequacy of present occupational health care
      practice and also of future needs. Therefore, the Federal Institute for
      Occupational Safety and Health of Germany initiated a study to evaluate the
      present state of occupational health care in 4 regions with different geographic
      and economic structure. Based on these data the future demand for adequately
      trained occupational physicians will be estimated by employing a statistical
      method that allows for including a large number of modifying variables (economic
      development, demographic change, etc.). Expected result of the applied technique
      are the estimated minimal and maximal number of occupational physicians that have
      to be trained to meet future demand. In the same study models of best practice
      will be identified and evaluated for general application. The project started in
      October 1997 and will be finished by January 2000.

PMID- 10657930
TI  - An analysis of work environments and operations in hot and humid areas.
AB  - Crews on tankers traveling and hauling cargo on the lower reaches of the
      Mississippi River during the hot and humid (H&H) summer season face various
      occupational safety and ergonomics problems. Evaluation of medical data reveals
      that a large number of the crewmembers experience job related injuries, diseases,
      disorders, and exhaustion as a result of adverse environmental conditions
      (National Institute for Occupational Safety and Health [NIOSH], 1993). The
      accidents and injuries that occurred were characterized and then analysis was
      used to recommend constructive remedies and solutions. The results were also used
      to design and develop better work environments on the tankers and in the general
      industry. In H&H conditions, the body's chemical reactions constantly change in
      order to maintain the best possible reaction to changing environments. This
      chemical reaction increases blood flow to the skin through sweating. Body
      metabolism stabilizes body temperature through muscular work and convection,
      evaporation and radiation remove heat.

PMID- 10657931
TI  - Increasing epithelial junction permeability enhances gene transfer to airway
      epithelia In vivo.
AB  - Gene transfer to airway epithelia is the most direct approach for treating the
      progressive lung disease associated with cystic fibrosis. However, the
      transduction efficiency is poor when viral vectors are applied to the mucosal
      surface. We reported previously that gene transfer via the apical surface of
      human airway epithelia in vitro was improved by formulating vectors with
      ethyleneglycol-bis-(2-aminoethyl ether)- N,N,N',N'-tetraacetic acid (EGTA) in a
      hypotonic buffer. First, we investigated the mechanism for this enhancement. When
      100-nm fluorescent beads were applied to the apical surface in the presence of
      EGTA, paracellular deposition of the particles was noted. Transmission electron
      microscopy verified that the epithelial junction complex was disrupted under
      these conditions. The Ca(2+) chelators EGTA, 1,2-bis (2-aminophenoxy)-ethane
      N,N,N',N'-tetraacetic acid (BAPTA), and ethylenediaminetetraacetic acid all
      caused a rapid, reversible drop in transepithelial resistance and facilitated
      gene transfer with retrovirus or adenovirus in vitro. When Ca(2+) chelators were
      applied to rabbit tracheal epithelia or human nasal epithelia in vivo, the
      transepithelial voltage decreased, and amiloride sensitivity was lost, suggesting
      that epithelial junctions opened. Importantly, this novel formulation enhanced
      both retroviral- and adenoviral-mediated gene transfer to rabbit tracheal
      epithelia in vivo. This technique may have applications for vector or drug
      delivery to airway epithelia and other polarized cells.

PMID- 10657932
TI  - Could the risk of asthma and atopy be reduced by a vaccine that induces a strong
      T-helper type 1 response?

PMID- 10657933
TI  - Could asthma be worsened by stimulating the T-helper type 1 immune response?

PMID- 10657934
TI  - Signal transduction pathways of apoptosis and inflammation induced by the tumor
      necrosis factor receptor family.

PMID- 10657935
TI  - Tumor necrosis factor-alpha-induced lung cell expression of antiapoptotic genes
      TRAF1 and cIAP2.
AB  - Tumor necrosis factor (TNF) receptor (TNFR)-associated factors 1 and 2 (TRAF1 and
      TRAF2) and inhibitor of apoptosis proteins cIAP1 (MIHB) and cIAP2 (MIHC) were
      recently identified as proteins that associate with the TNF-alpha receptors TNFRI
      (p55) and TNFRII (p75) and inhibit TNF-alpha-induced programmed cell death or
      apoptosis. In the original reports, TRAF1 expression, unlike the ubiquitous
      TRAF2, was restricted to specific tissues in the lung, spleen, and testis. TNF
      alpha is increased in the lung in many forms of pulmonary disease. In the current
      study, Western analysis, immunohistochemistry, and ribonuclease protection assays
      were used to determine whether TNF-alpha regulates the expression of these TNFR
      associated proteins in lung cells. We demonstrate for the first time TNF-alpha
      dose-dependent induction of TRAF1 protein and messenger RNA (mRNA) in human H441
      and A549 pulmonary adenocarcinoma cell lines, as well as in lung cells of
      C57BL/6J mice after intratracheal administration of TNF-alpha. In contrast to the
      epithelial cells, TRAF1 was not induced by TNF-alpha in U937 cells, a human
      monocytic cell line, suggesting cell type-specific regulation. Similarly, cIAP2
      mRNA was induced by TNF-alpha in both H441 and A549 pulmonary epithelial cells
      but not in U937 cells. TNF-alpha is a primary mediator of acute pulmonary
      inflammation and contributes to the pathophysiology of chronic lung diseases such
      as bronchopulmonary dysplasia (BPD), a fibrotic disease of prematurely born
      infants. Immunohistochemical staining of human neonatal lung tissue demonstrated
      increased TRAF1 in lungs of infants dying of pneumonia or BPD in comparison with
      those dying of congenital malformation. These studies support the hypothesis that
      the TRAF1 and cIAP2 genes are highly regulated in pulmonary cells and may play a
      role in human lung disease.

PMID- 10657936
TI  - Qualitative and quantitative analysis of embryonic pulmonary vessel formation.
AB  - Vessel formation in the lung has been described as occurring by two mechanisms:
      proximal, or branch, pulmonary arteries develop via angiogenesis; and distal,
      smaller vessels form by vasculogenesis. Connections between the proximal and
      distal vessels establish the final vascular network. The preponderance of vessel
      formation has been suspected to occur during the canalicular stage of lung
      development. To test these hypotheses, reporter gene expression under control of
      the regulatory domain of fetal liver kinase-1 (flk), an early endothelial cell
      specific marker, was used to evaluate mouse lungs from embryonic day 10.5 (E10.5)
      through 2 wk postnatal age. Morphologic assessment was performed after
      histochemical staining, and quantification of vessel development by a
      chemiluminescent assay was compared with overall embryonic lung growth. LacZ
      expression under flk promoter control allowed: (1) early identification of
      differentiating endothelial cells of the branch pulmonary arteries; (2)
      visualization of distal vessels forming in the lung mesenchyme (primary capillary
      network) with subsequent remodeling; (3) recognition of early continuity between
      proximal and distal vessels, occurring by E10.5; and (4) assessment of developing
      pulmonary veins and venous confluence. Quantitative analysis revealed increased
      flk regulated beta-galactosidase (beta-gal) activity of 12 ng beta-gal/lung at
      E12.5 to 3,215 ng beta-gal/lung at 2 wk, which corresponded to overall lung
      growth during this period as shown by an increase in total protein content per
      lung from 35 microg at E12.5 to 6,456 microg at 2 wk after birth. We identified
      endothelial cell precursors of the developing pulmonary vasculature before vessel
      lumen formation. Continuity between the proximal pulmonary artery and vessels
      forming in the distal mesenchyme was present even at the earliest stage
      evaluated, suggesting endothelial cell differentiation at the site of vessel
      formation (i.e., vasculogenesis) as occurs with development of the aorta.
      Finally, we demonstrated that lung vessel development was not accentuated during
      the canalicular stage, but occurred at all stages and directly corresponded to
      overall lung growth.

PMID- 10657937
TI  - Efficient gene transfer into human normal and cystic fibrosis tracheal gland
      serous cells with synthetic vectors.
AB  - Submucosal gland serous cells are believed to play a major role in the
      physiopathology of cystic fibrosis (CF) and may represent an important target for
      CF gene therapy. We have studied the efficiency of reporter gene transfer into
      immortalized normal (MM-39) and CF (CF-KM4) human airway epithelial gland serous
      cells using various synthetic vectors: glycosylated polylysines (glycofectins),
      polyethylenimine (PEI) (25 and 800 kD), lipofectin, and lipofectAMINE. In both
      cell lines, a high luciferase activity was achieved with various glycofectins,
      with PEI 25 kD, and with lipofectAMINE. After three transfections applied daily
      using alpha-glycosylated polylysine, 20% of the cells were transfected. At 24 h
      after CF transmembrane conductance regulator (CFTR) gene transfer into CF-KM4
      cells using alpha-glycosylated polylysine, the immunolocalization of CFTR was
      analyzed by laser scanning confocal microscopy and the transgenic CFTR was
      detected by an intense labeling of the plasma membrane. The presence of membrane
      lectins, i. e., cell surface receptors binding oligosaccharides, was also
      examined on MM-39 and CF-KM4 cells by assessing the binding and uptake of
      fluorescein-labeled neoglycoproteins and fluorescein-labeled glycoplexes
      (glycofectins complexed to plasmid DNA). Among all the neoglycoproteins and
      glycoplexes tested, those bearing alpha-mannosylated derivatives were most
      efficiently taken up by both normal and CF gland serous cells. However, alpha
      mannosylated polylysine was quite inefficient for gene transfer, indicating that
      the efficiency of gene transfer is determined both by the uptake of the complexes
      and also by their intracellular trafficking. Moreover, our results show that an
      efficient in vitro gene transfer was achieved in human airway gland serous cells
      with the same synthetic vectors described to efficiently transfect human airway
      surface epithelial cells.

PMID- 10657938
TI  - Regulation of T-helper type 2 cell and airway eosinophilia by transmucosal
      coadministration of antigen and oligodeoxynucleotides containing CpG motifs.
AB  - The characteristic features of bronchial asthma, including airway eosinophilia
      and elevated immunoglobulin (Ig)E levels, are known to be orchestrated by T
      helper (Th) 2 cells. Oligodeoxynucleotides containing CpG motifs (CpG) have
      recently been highlighted as an immunomodulator that biases toward a Th1-dominant
      phenotype. However, CpG may incur nonspecific Th1 activation and toxic effects.
      In this study we report a novel inhibition of Th2 cells by transmucosal
      inoculation of antigen and CpG. Intratracheal instillation of CpG inhibited
      airway eosinophilia and Th2 cytokine production in antigen-sensitized mice. The
      inhibition was observed when CpG was given at the same time or in advance of
      antigen challenge. Notably, concomitant administration of CpG and antigen (as
      opposed to either one alone) was essential for the inhibitory effects. The
      antigen dose could be minimized to avoid a harmful boost of eosinophilia. CpG had
      few effects on systemic anti-ovalbumin IgE responses. These results demonstrate
      that a synergism between transmucosally administered allergen and CpG inhibits
      Th2 cells in parallel with an improvement in airway eosinophilia and
      hyperresponsiveness without impeding systemic immune responses. Our data imply
      that inhalation of a minimal amount of allergen plus CpG could be a novel
      desensitization therapy for patients with bronchial asthma.

PMID- 10657939
TI  - Dipeptidyl peptidase I cleaves matrix-associated proteins and is expressed mainly
      by mast cells in normal dog airways.
AB  - Dipeptidyl peptidase I (DPPI) is a cysteine protease found in many tissues,
      including the lung. Major cell types expressing DPPI in vitro include
      myelomonocytic cells, cytotoxic T cells, and mast cells. After activation and
      degranulation, cytotoxic T cells and mast cells secrete DPPI. With a goal of
      clarifying possible roles for DPPI in lung diseases, we sought to identify cells
      expressing DPPI in lung tissue, hypothesizing that lung mast cells are major
      producers of DPPI and that secreted DPPI cleaves extracellular matrix proteins.
      To address these hypotheses, we used immunohistochemical techniques to localize
      DPPI in normal dog airways, lung, and cultured mast cells, and we used purified
      DPPI to examine cleavage of matrix-associated proteins in vitro. We found that
      mast cells are the major identifiable source of DPPI in airways and that
      macrophages are the major source in alveoli. Within mast cells, DPPI localizes to
      cytoplasmic granules. We also found that DPPI endoproteolytically cleaves the
      extracellular matrix proteins fibronectin and collagen types I, III, and IV. The
      finding of DPPI in airway mast cells and its cleavage of matrix proteins suggest
      the possibility that DPPI plays a role in mast cell-mediated turnover of matrix
      proteins and in airway remodeling of chronic airway diseases such as asthma.

PMID- 10657940
TI  - Three-dimensional mapping of ozone-induced acute cytotoxicity in tracheobronchial
      airways of isolated perfused rat lung.
AB  - Acute lung injury induced by reactive oxygen gases such as ozone (O(3)) is focal
      and site-selective. To define patterns of acute epithelial injury along
      intrapulmonary airways, we developed a new analytic approach incorporating
      labeling of permeable cells, airway microdissection, and laser scanning confocal
      microscopy, and applied it to isolated perfused rat lungs where ventilation and
      breathing pattern could be controlled. After exposure to O(3) (0, 0.25, 0.5, or
      1.0 ppm), lungs were lavaged to assess lactate dehydrogenase (LDH) and protein,
      or infused with the permeability marker ethidium homodimer-1 (EthD-1) via
      tracheal cannula, gently lavaged, and fixed by airway infusion. The airway tree
      of the right middle lobe was exposed by microdissection of the axial pathway down
      to the terminal bronchioles; the dissection was incubated with a second nuclear
      dye, YOPRO-1, to label all nuclei; and whole mounts were examined by confocal
      microscopy. Abundance of EthD-1-positive (injured) cells was estimated as the
      number per epithelial volume using stereology on Z-series of projected images.
      For ozone concentrations of 1.0 ppm, lavage fluid LDH and total protein did not
      increase over controls. Exposure produced a concentration- dependent but
      nonhomogeneous increase in the abundance of EthD-1-labeled cells in proximal and
      distal conducting airways both in the main pathway, including terminal
      bronchioles, and in side branches. Overall, the highest EthD-1 labeling occurred
      in the side branches of the most proximal part of the airway tree at 1 ppm with
      the adjacent axial pathway airway having approximately one-third the labeling
      density. Density of EthD-1-labeled cells was lowest in terminal bronchioles at
      all O(3) doses. For the model we used, identification of injured epithelial cells
      by differential permeability and laser confocal microscopy appeared to be highly
      sensitive and permitted mapping of acute cytotoxicity throughout the airway tree
      and quantitative comparisons of sites with different branching histories and
      potential dosimetry rates.

PMID- 10657941
TI  - Adhesion and pollution particle-induced oxidant generation is neither necessary
      nor sufficient for cytokine induction in human alveolar macrophages.
AB  - Adhesion of human monocytes (MOs) results in the rapid transcriptional activation
      of cytokine genes that are dependent on nuclear factor (NF)-kappaB. Several
      pathways leading to activation of NF-kappaB have been described, including those
      involving reactive oxygen intermediates (ROIs) and members of the mitogen
      activated protein (MAP) kinase superfamily. To investigate the involvement of
      tyrosine phosphorylation (TP) and oxidant generation in interleukin (IL)-8 and
      GRO messenger RNA induction, MOs and human alveolar macrophages (AMs) were
      adhered to plastic or exposed to a particulate pollutant, residual oil fly ash
      (ROFA). Both stimuli caused rapid TP and ROI production in MOs and AMs. However,
      neither NF-kappaB translocation nor IL-8 gene induction occurred in adhered or
      ROFA-exposed AMs. Analysis of MAP kinase activation found phosphorylation of Jun
      amino-terminal kinase (JNK) and p38 in the AMs, but not of extracellular
      regulated kinase/MAP kinase (ERK/MAPK). AMs stimulated with lipopolysaccharide
      activated ERK/MAPK, in addition to JNK and p38, and showed translocation of NF
      kappaB. In contrast to AMs, MO adhesion or exposure to ROFA particles in
      suspension rapidly activated p38, JNK, and ERK/MAPK, and activated NF-kappaB
      binding as well as IL-8 mRNA expression. Pretreatment with the tyrosine kinase
      inhibitors genistein or herbimycin A before adherence had no effect on
      transcriptional activation in MOs, whereas adherence and ROFA-induced oxidant
      generation was inhibited in both MOs and AMs. Taken together, these data indicate
      that NF-kappaB activation or generalized transcriptional activation of cytokine
      genes are independent of changes in oxidant stress imposed on phagocytes by
      adhesion. Furthermore, the data suggest that certain environmental responses in
      AMs may be uncoupled from activation of NF-kappaB.

PMID- 10657942
TI  - Cell type-specific regulation of fibrinogen expression in lung epithelial cells
      by dexamethasone and interleukin-1beta.
AB  - Our recent studies demonstrating the expression of fibrinogen (FBG) by an
      alveolar type II cell line stimulated with proinflammatory mediators and also in
      the inflamed pulmonary epithelium of animals with Pneumocystis carinii pneumonia
      suggest that extrahepatic FBG participates in the local acute phase response
      (APR) to infection and subsequent wound repair. However, the mechanisms that
      regulate extrahepatic FBG expression are poorly understood. This study compares
      the regulation of hepatic and pulmonary FBG expression by mediators of the APR,
      interleukin (IL)-6, IL-1beta, and dexamethasone (DEX), a synthetic
      glucocorticoid. Northern blotting and metabolic labeling studies revealed that IL
      6 with or without DEX upregulates gammaFBG messenger RNA and protein, whereas IL
      1beta inhibits gammaFBG expression in human lung (A549) and liver (HepG2)
      epithelial cells. In contrast, the addition of DEX relieved the IL-1beta-mediated
      inhibition of FBG expression in lung epithelial cells only; this response is
      termed "DEX rescue." Studies with cycloheximide indicate that only DEX rescue
      required de novo protein synthesis. Nuclear run-on analysis revealed no increase
      in gammaFBG transcription by DEX treatment. Although DEX treatment alone
      increased the stability of gammaFBG transcripts in lung cells, this effect was
      not observed in the presence of IL-1beta. Together, these results suggest that
      pre-existing transcription factors mediate the effects of IL-6 with or without
      DEX, DEX, and IL-1beta on gammaFBG gene expression in lung and liver cells. Also,
      the data suggest that DEX induces new protein synthesis of an inhibitor of IL
      1beta signal transduction to effectively "rescue" FBG production in lung but not
      liver epithelial cells. This cell type-specific stimulation of FBG production by
      glucocorticoids to overcome IL-1beta inhibition may promote pulmonary wound
      repair mechanisms.

PMID- 10657943
TI  - Proinflammatory roles of T-cell receptor (TCR)gammadelta and TCRalphabeta
      lymphocytes in a murine model of asthma.
AB  - The role of lymphocytes bearing alphabeta or gammadelta T-cell receptors (TCRs)
      was assessed during the acute allergic response in a mouse model of asthma. The
      inflammatory immune response to ovalbumin (OVA) was characterized in wild-type
      C57BL/6J mice and congenic TCRbeta(-/-) and TCRdelta(-/-) mice by evaluation of
      airway eosinophilia, histopathology, serum immunoglobulin (Ig)E levels, and in
      vivo airway responsiveness to methacholine. OVA-challenged wild-type mice
      demonstrated marked pulmonary inflammation, evidenced by airway eosinophilia (68
      +/- 7 x 10(4) cells), peribronchial lympho-plasmocytic infiltration, and elevated
      serum IgE (4.9 +/- 0.6 microg/ml). These responses were markedly attenuated in
      TCRdelta(-/-) animals (5.0 +/- 1.0 x 10(4) eosinophils and 1.6 +/- 0. 3 microg/ml
      IgE) and were completely absent in TCRbeta(-/-) mice (< 1 x 10(3) eosinophils and
      0.38 +/- 0.21 microg/ml IgE). Similar results were observed in mice treated with
      anti-TCRgammadelta or anti-TCRalphabeta monoclonal antibodies. Airway
      responsiveness to aerosolized methacholine was also reduced in challenged
      TCRdelta(-/-) animals relative to challenged wild-type mice. These results
      demonstrate that acute allergic airway responses are dependent upon intact
      TCRalphabeta and TCRgammadelta lymphocyte function and that TCRgammadelta cells
      promote acute airway sensitization.

PMID- 10657944
TI  - Regulation of human 12/15-lipoxygenase by Stat6-dependent transcription.
AB  - Human 12/15-lipoxygenase is a lipid-peroxidating enzyme implicated in the
      pathophysiology of atherosclerosis and airway inflammation. Interleukin (IL)-4
      specifically induces 12/15-lipoxygenase messenger RNA, protein, and enzymatic
      activity in primary cultures of human monocytes and airway epithelial cells. The
      induction of the human 12/15-lipoxygenase by IL-4 suggests that the signal
      transducer and activator of transcription (Stat)-6 protein is critical for its
      expression. Several putative Stat6 response elements are located in the proximal
      1.8 kb of 12/15-lipoxygenase 5'-flanking region. In this study we use BEAS-2B
      human airway epithelial cells as a model to demonstrate the dependence of 12/15
      lipoxygenase expression on the IL-4/Stat6 signal transduction pathway. Transient
      transfections of human 12/15-lipoxygenase promoter/luciferase reporter genes
      indicate that this induction occurs through direct transcriptional mechanisms
      mediated by a specific Stat6 response element located 952 base pairs upstream of
      the translational start codon. Using this Stat6 response element as a probe,
      electrophoretic mobility shift assays show an IL-4-dependent binding activity in
      nuclear extracts. Supershift assays confirm that Stat6 participates in this
      binding complex. These data indicate that the human 12/15-lipoxygenase gene is
      induced in airway epithelial cells through Stat6-dependent transcriptional
      mechanisms mediated by a specific Stat6 response element in the 5'-flanking
      region.

PMID- 10657945
TI  - Thrombin upregulates interleukin-8 in lung fibroblasts via cleavage of
      proteolytically activated receptor-I and protein kinase C-gamma activation.
AB  - Acute and chronic interstitial lung diseases are accompanied by evidence of
      inflammation and vascular injury. Thrombin activity in bronchoalveolar lavage
      fluid from such conditions is often increased, as well as interleukin (IL)-8. We
      observed that conditioned medium from lung fibroblasts exposed to thrombin has
      chemotactic activity for polymorphonuclear cells, and that this activity can be
      abolished by antibody to IL-8. We report that thrombin stimulates expression of
      IL-8 in human lung fibroblasts on both the messenger RNA and protein levels in a
      time- and dose-dependent manner. Stimulation of IL-8 expression by thrombin is
      inhibited by specific thrombin inhibitors. Synthetic thrombin receptor agonist
      peptide-14 mimics thrombin's stimulation of IL-8 expression in a dose-dependent
      manner consistent with the idea that upregulation of IL-8 by thrombin in human
      lung fibroblasts requires cleavage of proteolytically activated receptor-I. We
      demonstrate further that thrombin-induced IL-8 synthesis is regulated by protein
      kinase (PK) C. PKC-gamma may be involved in the upregulation of lung fibroblast
      IL-8 by thrombin because stimulation of lung fibroblasts with thrombin caused
      significant upregulation of PKC-gamma and because PKC-gamma antisense
      oligonucleotides inhibited the accumulation of PKC-gamma protein and IL-8
      protein. Our data suggest that the PKC-gamma isoform increase observed after
      thrombin stimulation is required for thrombin-induced IL-8 formation by human
      lung fibroblasts.

PMID- 10657946
TI  - Acute cigarette smoke-induced connective tissue breakdown is mediated by
      neutrophils and prevented by alpha1-antitrypsin.
AB  - Recent studies have suggested that macrophage-derived metalloproteases are the
      critical mediators of cigarette smoke-induced emphysema, in contrast to earlier
      hypotheses that this process was mediated by neutrophil elastase. To determine
      whether smoke can acutely induce connective tissue breakdown in the lung and to
      examine the mediators of this process, we exposed C57-BL/6 mice to whole
      cigarette smoke and used high-performance liquid chromatography to examine lavage
      fluid levels of desmosine (DES), a marker of elastin breakdown, and
      hydroxyproline (HP), a marker of collagen breakdown. Smoke produced a dose
      response increase in lavage neutrophils, DES, and HP, but not lavage macrophages
      (MACs). This effect was evident by 6 h after exposure to two cigarettes.
      Pretreatment with an antibody against polymorphonuclear leukocytes (PMNs) reduced
      lavage PMNs to undetectable levels after smoke exposure, did not affect MAC
      numbers, and prevented increases in lavage DES and HP. Intraperitoneal injection
      of a commercial human alpha1-antitrypsin (alpha1AT) 24 h before smoke exposure
      increased serum alpha1AT levels approximately 3-fold and completely abolished
      smoke-induced connective tissue breakdown as well as the increase in lavage PMNs,
      again without affecting MAC numbers. We conclude that in this model cigarette
      smoke can acutely induce connective tissue breakdown and that this effect is
      mediated by neutrophil-derived serine proteases, most likely neutrophil elastase.
      Exogenous alpha1AT is protective and appears to inhibit both matrix degradation
      and PMN influx, suggesting that alpha1AT has anti-inflammatory as well as
      antiproteolytic effects in this system.

PMID- 10657947
TI  - Leukocyte common-antigen-related tyrosine phosphatase receptor: altered
      expression of mRNA and protein in the New England Deaconess Hospital rat line
      exhibiting spontaneous pheochromocytoma.
AB  - Regulation of cell proliferation by protein tyrosine phosphatases (PTPs) suggests
      that PTPs are important tumor suppressor genes. The gene encoding the leukocyte
      common-antigen-related (LAR) PTP receptor maps to chromosome 1p32-33, a region in
      which loss of heterozygosity is associated with human pheochromocytoma and other
      neuroectodermal tumors. The rat pheochromocytoma PC12 cell line was originally
      derived from the transplantable P259 tumor originating from the New England
      Deaconess Hospital (NEDH) line of Wistar inbred rats. Compared with their Wistar
      counterparts, 1-2-year-old NEDH rats exhibit a high incidence of spontaneous
      pheochromocytomas. This study investigates whether levels of LAR transcripts and
      protein are altered in NEDH adrenal tissue prior to tumor onset. In addition,
      alternative splicing of an LAR extracellular domain [LAR alternatively spliced
      element-c (LASE-c)], regulating LAR interaction with extracellular matrix
      components, was examined. These changes in LAR expression and alternative
      splicing were hypothesized to be more pronounced in tumor tissue and PC12 cells.
      Northern blot analysis demonstrated the presence of the approximately 5 kb LAR
      transcript in all cell lines examined, except PC12. In adrenal medulla tissue
      harvested from 2-3-month-old rats, LAR approximately 8 and approximately 5 kb
      transcript expression was decreased in NEDH compared with Wistar samples. RT-PCR
      demonstrated increased splicing of the LASE-c 27 bp alternatively spliced insert
      in the LAR extracellular domain in NEDH adrenal medulla tissue. Even greater LASE
      c splicing was detected in adrenal medulla tumor tissue derived from 12-month-old
      NEDH rats and in PC12 cells. Western blot analysis demonstrated decreased levels
      of LAR protein and increased levels of LASE-c containing LAR protein isoforms in
      NEDH adrenal medulla tissue. These studies demonstrate that patterns of altered
      LAR expression present in PC12 cells and in pheochromocytoma tumor tissue are
      also present in adrenal tissue predisposed to a high incidence of spontaneous
      pheochromocytoma.

PMID- 10657948
TI  - Expression analysis of the group IIA secretory phospholipase A(2) in mice with
      differential susceptibility to azoxymethane-induced colon tumorigenesis.
AB  - The murine non-pancreatic secretory phospholipase A(2) (sPLA(2)) has been
      proposed as a tumor modifier of multiple intestinal neoplasia (Min). A genetic
      polymorphism in the mouse gene that causes a disruption in exon 3 results in loss
      of functional protein. Mouse strains with a disrupted sPLA(2) gene are
      susceptible to the Min phenotype and develop numerous intestinal polyps, whereas
      mice with normal sPLA(2) develop only a limited number of polyps. The following
      study was undertaken to test the hypothesis that sPLA(2) plays an equivalent role
      in murine susceptibility to the colon carcinogen azoxymethane (AOM). sPLA(2)
      status was confirmed by sequencing in mice that are highly susceptible (A/J),
      susceptible (SWR/J) and resistant (AKR/J) to AOM-induced tumorigenesis.
      Constitutive expression of sPLA(2) mRNA was compared in small intestine and colon
      of untreated mice using semi-quantitative RT-PCR. Whereas mRNA expression was
      nearly absent in A/J mice, AKR/J mice exhibited extensive expression throughout
      the intestine. Despite the wild-type sPLA(2) gene, colonic mRNA expression in
      SWR/J mice was significantly lower relative to AKR/J. Immunohistochemical
      analysis of sPLA(2) protein confirmed the mRNA data. The effect of AOM on colonic
      sPLA(2) expression was also examined. Twenty-four weeks after the last of six
      weekly injections of AOM (10 mg/kg i.p.), RT-PCR analysis of distal colons
      revealed a significant increase in mRNA in normal-appearing epithelium and tumor
      tissue from AOM-treated mice relative to controls. However, there was no
      corresponding increase in protein expression in A/J mice. The absence of sPLA(2)
      expression within control colons of tumor-susceptible A/J mice together with low
      expression in SWR/J colons is consistent with its potential role as an intestinal
      tumor modifier, but the carcinogen-induced increase in expression raises doubts
      as to the significance of sPLA(2) in inhibiting carcinogenesis.

PMID- 10657949
TI  - Cyclooxygenase-2 expression in human pancreatic adenocarcinomas.
AB  - Cyclooxygenase-2 (COX-2) expression is up-regulated in several types of human
      cancers and has also been directly linked to carcinogenesis. To investigate the
      role of COX-2 in pancreatic cancer, we evaluated COX-2 protein expression in
      primary human pancreatic adenocarcinomas (n = 23) and matched normal adjacent
      tissue (n = 11) by immunoblot analysis. COX-2 expression was found to be
      significantly elevated in the pancreatic tumor specimens compared with normal
      pancreatic tissue. To examine whether the elevated levels of COX-2 protein
      observed in pancreatic tumors correlated with the presence of oncogenic K-ras, we
      determined the K-ras mutation status in a subset of the tumors and corresponding
      normal tissues. The presence of oncogenic K-ras did not correlate with the level
      of COX-2 protein expressed in the pancreatic adenocarcinomas analyzed. These
      observations were also confirmed in a panel of human pancreatic tumor cell lines.
      Furthermore, in the pancreatic tumor cell line expressing the highest level of
      COX-2 (BxPC-3), COX-2 expression was demonstrated to be independent of Erk1/2
      activation. The lack of correlation between COX-2 and oncogenic K-ras expression
      suggests that Ras activation may not be sufficient to induce COX-2 expression in
      pancreatic tumor cells and that the aberrant activation of signaling pathways
      other than Ras may be required for up-regulating COX-2 expression. We also report
      that the COX inhibitors sulindac, indomethacin and NS-398 inhibit cell growth in
      both COX-2-positive (BxPC-3) and COX-2-negative (PaCa-2) pancreatic tumor cell
      lines. However, suppression of cell growth by indomethacin and NS-398 was
      significantly greater in the BxPC-3 cell line compared with the PaCa-2 cell line
      (P = 0.004 and P < 0.001, respectively). In addition, the three COX inhibitors
      reduce prostaglandin E(2) levels in the BxPC-3 cell line. Taken together, our
      data suggest that COX-2 may play an important role in pancreatic tumorigenesis
      and therefore be a promising chemotherapeutic target for the treatment of
      pancreatic cancer.

PMID- 10657950
TI  - Tumour-specific distribution of BRCA1 promoter region methylation supports a
      pathogenetic role in breast and ovarian cancer.
AB  - The role of BRCA1 in sporadic breast and ovarian cancers remains elusive. Direct
      involvement of BRCA1 in the development of breast and ovarian cancer is suggested
      by the finding that the BRCA1 promoter region CpG island is methylated in a
      proportion of breast and ovarian cancers. The aim of this study was to compare
      the incidence of BRCA1 promoter region methylation in tumours in which loss of
      BRCA1 has been shown to play a role in pathogenesis (breast and ovarian
      carcinomas) with the incidence in tumours in which BRCA1 is unlikely to play a
      role in pathogenesis. Promoter region hypermethylation was significantly more
      common (P < 0.008) in breast and ovarian cancer (6/38 tumours methylated) than in
      colon cancer (0/35 tumours methylated) or in leukaemias (0/19 samples
      methylated). The restriction of BRCA1 promoter region hypermethylation to breast
      and ovarian cancer is consistent with a pathogenetic role of BRCA1 promoter
      methylation in these tumours. We suggest that the rarity of observed BRCA1
      mutations in sporadic breast and ovarian cancer is due to the greater likelihood
      of BRCA1 inactivation by non-mutational mechanisms such as methylation.

PMID- 10657951
TI  - Expression of the p53 homologue p63alpha and deltaNp63alpha in normal and
      neoplastic cells.
AB  - A burgeoning family of p53-related genes have been described recently, including
      p73 and p63. Both these genes encode proteins with many similarities to p53 but
      also with the potential for forming a range of related species by alternative
      promoter usage and alternative splicing. In order to begin the characterization
      of p63, we generated a polyclonal serum (designated SC1) that recognizes the C
      terminus of p63alpha. We have shown that this reagent recognizes p63alpha but not
      p53 nor p73. By western blot analysis both p63alpha and the N-terminal truncated
      form of p63alpha (DeltaNp63alpha) were found in a range of cell lines. Similar
      immunoblot analysis of tissues reveals considerable complexity with at least four
      SC1-immunoreactive isoforms being identified. In immunohistological studies SC1
      immunoreactivity is widely detectable, being predominantly associated with
      proliferative compartments in epithelia. However, non-proliferative populations
      can also show SC1 immunostaining. No simple relationship between the isoforms
      identified by immunoblotting of tissue lysates and the tissue immunostaining
      characteristics was identified. A previously unrecognized species intermediate in
      mobility between p63alpha and DeltaNp63alpha was found in several tissues,
      including nerve and peripheral blood lymphocytes. Interestingly, there is
      suppression of p63alpha expression in HaCat cells in a time- and concentration
      dependent manner after UV and MMS treatment. Our data provide further information
      about the complexity of p63 and the SC1 serum will prove to be a useful tool in
      further studies of this p53 homologue.

PMID- 10657952
TI  - Suppression of apoptosis in C3H mouse liver tumors by activated Ha-ras oncogene.
AB  - Liver tumors were induced in male C3H mice by a single injection of N
      nitrosodiethylamine and characterized with respect to the presence of base
      substitutions in the hot-spot position at codon 61 of the Ha-ras proto-oncogene.
      An increase in Ha-ras mutation prevalence was found with time after induction of
      tumors, suggesting that the activated ras gene provides a selective growth
      advantage. However, no significant differences in 5-bromodeoxyuridine labeling
      indices were evident between ras mutated and ras wild-type tumors, demonstrating
      that cell division rates in the two tumor populations were very similar.
      Apoptotic indices were determined by counting eosinophilic apoptotic bodies. The
      frequency of occurrence of apoptotic bodies was found to be approximately five
      times lower in tumors with Ha-ras mutations when compared with tumors not showing
      the mutation. This demonstrates that the activated p21(Ras) protein has anti
      apoptotic activity in transformed mouse hepatocytes in vivo and suggests that the
      preferential outgrowth of Ha-ras-mutated hepatoma cells is mediated by
      suppression of apoptosis rather than by stimulation of cell division.

PMID- 10657953
TI  - The effect of hOGG1 and glutathione peroxidase I genotypes and 3p chromosomal
      loss on 8-hydroxydeoxyguanosine levels in lung cancer.
AB  - Polymorphic genes for the peroxide scavenger glutathione peroxidase I (GPX1) and
      8-hydroxydeoxyguanosine (8-OHdG) DNA glycosylase/apurinic (AP) lyase (hOGG1) map
      to loci on chromosome 3p which are subject to frequent loss of heterozygosity
      (LOH) in lung tumours. Levels of the pro-mutagenic, oxidative DNA lesion 8-OHdG,
      were measured in 37 paired normal and tumorous lung specimens using HPLC with
      electrochemical detection. Lung tumours were also analysed for 3p LOH by
      fluorescent PCR with Genescan analysis. No significant difference was observed
      between 8-OHdG levels in tumour [7.7 +/- 6.7 (mean +/- SE) 8-OHdG/10(6) 2'
      deoxyguanosine (dG)] and normal (8.1 +/- 8.8 8-OHdG/10(6) dG) lung tissue. Adduct
      levels in normal lung tissue DNA were not associated with constitutive hOGG1
      genotype although there was a trend towards lower 8-OHdG levels in individuals
      possessing the ALA6 GPX1 polymorphism. Lung tumours exhibiting 3p LOH (40%)
      contained higher levels of 8-OHdG adducts (10.9 +/- 2.6 8-OHdG/10(6) dG) (P =
      0.05) and lower GPX1 enzyme activity [45.5 nmol glutathione (GSH)/min/mg] (P =
      0.09) when compared with tumours without LOH at these sites (5.55 +/- 0.87 8
      OHdG/10(6) dG and 63.6 nmol GSH/min/mg, respectively). In conclusion, tumours
      with 3p LOH at loci associated with hOGG1 and GPX1 appear to have compromised
      oxidative defence mechanisms as measured by reduced GPX1 enzyme activity and
      elevated 8-OHdG levels and this may affect the prognosis of lung cancer patients.

PMID- 10657954
TI  - Chemopreventive effect of 24R,25-dihydroxyvitamin D(3) in N, N'-dimethylhydrazine
      induced rat colon carcinogenesis.
AB  - In this study we investigated the effects of 24R,25-dihydroxyvitamin D(3)
      [24R,25(OH)(2)D(3)] on N,N'-dimethylhydrazine (DMH)-induced rat colon
      carcinogenesis. For experiments 1 and 2, 50 F344 male, 6-week-old rats were
      divided into five groups in each experiment. Animals were given s.c. injections
      of DMH once a week for 4 weeks. Those in groups 1-5 were given 24R,25(OH)(2)D(3)
      in the diet (10, 5, 2.5, 1.25 or 0 p.p.m., respectively) during the post
      initiation stage in experiment 1 and during the initiation stage in experiment 2.
      At termination, the numbers of aberrant crypt foci (ACF) in the rat colonic
      mucosa were decreased dose-dependently in rats treated with 24R,25(OH)(2)D(3)
      during the post-initiation stage, but not in the initiation stage. For experiment
      3, 15 male, 9-week-old rats were divided into three groups and given
      24R,25(OH)(2)D(3) in the diet (10, 5 or 0 p.p.m.). Animals were injected with 5
      bromo-2'-deoxyuridine (BrdU) i.p. 1 h before death to examine DNA synthesis in
      the colon mucosa. BrdU labeling indices were decreased dose-dependently in
      colonic crypts of rats treated with 24R, 25(OH)(2)D(3). In experiment 4, using
      the multicarcinogenic protocol we could analyze our data with respect to not only
      one separate organ, but at the organism level. Sixty-eight male, 6-week-old rats
      were treated with DMH, N-methylnitrosourea, 2, 2'-dihydroxy-di-n
      propylnitrosamine, diethylnitrosamine and N-butyl-N-(4-hydroxybutyl)nitrosamine
      in weeks 1-4 and were then given 24R,25(OH)(2)D(3) in the diet (5, 1 or 0 p.p.m.)
      throughout weeks 5-30. Examination of the development of tumors and preneoplastic
      lesions in various organs revealed that 24R, 25(OH)(2)D(3) inhibited colonic
      tumor development significantly but exerted no effects on tumor induction in
      other organs. In conclusion, these results strongly indicate that
      24R,25(OH)(2)D(3) inhibits colon carcinogenesis specifically, without any
      enhancement of carcinogenesis in other organs, when administered in the post
      initiation phase.

PMID- 10657955
TI  - Chemoprevention of pulmonary carcinogenesis by brief exposures to aerosolized
      budesonide or beclomethasone dipropionate and by the combination of aerosolized
      budesonide and dietary myo-inositol.
AB  - This investigation is part of an effort to develop chemoprevention for
      carcinogenesis of the lung. It focuses on the efficacy of low doses of synthetic
      glucocorticoids administered either as single agents or in combination with a
      second compound, myo-inositol. Glucocorticoids are potent inhibitors of
      carcinogenesis. The use of low doses is important to avoid potential side
      effects. The synthetic glucocorticoid budesonide, administered by aerosol for 20
      s three times a week, was studied to determine its effects on benzo[a]pyrene
      induced pulmonary adenoma formation in female A/J mice. Two dose levels were
      employed, 10 and 25 microg/kg body wt. The lower dose produced a 34% reduction in
      lung tumor formation and the higher dose level a 60% reduction in lung tumors. In
      additional groups of mice, the effects of 0.3% myo-inositol added to the diet was
      found to reduce pulmonary tumor formation by 53%. The two agents given in
      combination resulted in a greater inhibition of lung tumor formation than either
      by itself. Budesonide at 10 microg/kg body wt plus 0.3% myo-inositol reduced the
      number of tumors by 60% and budesonide at 25 microg/kg body wt plus 0.3% myo
      inositol reduced lung tumor formation by 79%. To determine whether a
      glucocorticoid other than budesonide would have inhibitory effects in this
      experimental model, beclomethasone dipropionate administered by aerosol for 20 s
      three times a week was studied as a single agent and showed almost identical
      inhibitory properties to budesonide. The doses of the glucocorticoids calculated
      on a daily basis are within the range of those used widely for control of chronic
      allergic respiratory diseases in the human. The capacity of low doses of inhaled
      glucocorticoids to prevent pulmonary neoplasia and the enhancement of this
      preventive effect by myo-inositol, an essentially non-toxic compound, are
      findings that should encourage further work to evaluate the applicability of
      these agents to the prevention of neoplasia of the lung in the human.

PMID- 10657956
TI  - White blood cell DNA adducts and fruit and vegetable consumption in bladder
      cancer.
AB  - The 'Mediterranean diet', a diet rich in cereals, fruit and vegetables, has been
      associated with lowering the risk of a variety of cancers of the digestive tract
      and the bladder. In a previous study, we showed that the high phenolic content
      these dietary components produce in the urine could be associated with higher
      antimutagenic properties of the urine and lower arylamine-DNA adducts in
      exfoliated bladder cells. We have conducted a case-control study on 162 bladder
      cancer patients and 104 hospital controls. Total aromatic DNA adducts were
      measured in white blood cells (WBC) of all subjects by (32)P-post-labelling.
      Genetically based metabolic polymorphisms were analysed by PCR-RFLP (NAT2, GSTM1,
      GSTT1, GSTP1, COMT and NQO1). All subjects were interviewed about their tobacco
      use, dietary habits and other risk factors. The odds ratio (OR) for the risk of
      bladder cancer according to the presence/absence of WBC DNA adducts (detection
      limit 0.1 RALx10(8)) was 3.7 [95% confidence interval (CI) 2.2-6.3] and a dose
      response relationship with levels of adducts was apparent. The association
      between case/control status and the presence of WBC DNA adducts was significantly
      stronger in the subjects who consumed fewer portions of fruit or vegetables per
      day (OR 7.80, 95% CI 3.0-20.30 for 0-1 portions of vegetables) than in the heavy
      consumers (OR 4.98 for consumers of 2 portions daily, OR 1.97 for consumers of >
      or =3 portions; similar but lower estimates were found for the intake of fruit).
      No association was noticed between tobacco smoking and WBC DNA adducts. Only NAT
      2, among the several genotypes considered, was associated in a statistically
      significant way with the risk of bladder cancer (OR 1.72, 95% CI 1.03-2.87) and
      with the levels of WBC DNA adducts. Our report suggests that fruit and vegetables
      could protect against bladder cancer by inhibiting the formation of DNA adducts.

PMID- 10657957
TI  - Polymorphisms in the human aromatase cytochrome P450 gene (CYP19) and breast
      cancer risk.
AB  - The aromatase enzyme catalyses the conversion of androgens to oestrogens in the
      oestrogen biosynthesis pathway. Because increased exposure to oestrogens is
      considered to be a risk factor for breast cancer, the human aromatase gene
      (CYP19) is a plausible candidate for low penetrance breast cancer susceptibility.
      Preliminary reports have suggested that specific alleles of a TTTA repeat may be
      associated with differences in breast cancer risk. We have identified two new
      polymorphisms in the CYP19 gene: a TCT insertion/deletion in intron 4 and a G-->T
      substitution in intron 6, which have rare allele frequencies of 0.35 and 0.45,
      respectively, in the British population. Comparison was made between the
      frequencies of these alleles and those of the TTTA repeat in up to 599 breast
      cancer cases and 433 normal controls from the East Anglian, British population.
      We found strong linkage disequilibrium between the alleles of these three loci,
      but no significant association of any alleles with breast cancer risk. The
      maximum odds ratios observed were: 1.03 (95% CI 0.68-1.55) for the intron 4 TCT
      insertion/deletion polymorphism [del/del versus ins/ins]; 1.56 (95% CI 0.63-3.83)
      for the intron 4 [TTTA](10) allele; 1.29 (95% CI 0. 75-2.21) for the intron 6 G-
      >T polymorphism [TT versus GG]. We conclude that the CYP19 gene has no major role
      in common breast cancer incidence in the British population.

PMID- 10657958
TI  - Inhibitory effects of 1,3-diaminopropane, an ornithine decarboxylase inhibitor,
      on rat two-stage urinary bladder carcinogenesis initiated by N-butyl-N-(4
      hydroxybutyl)nitrosamine.
AB  - Overexpression of ornithine decarboxylase (ODC) has been shown to be
      characteristic of tumor development and progression in humans and experimental
      animals. Therefore, we have examined the effects of 1, 3-diaminopropane
      dihydrochloride (DAP), a potent inhibitor of ODC, on rat two-stage urinary
      bladder carcinogenesis initiated with N-butyl-N-(4-hydroxybutyl)nitrosamine
      (BBN). In experiment 1 (36 weeks), 6-week-old F344 male rats were administered
      0.05% BBN in drinking water for 4 weeks and then divided into four groups.
      Animals of groups 1 and 2 received basal diet and drinking water supplemented
      with or without DAP (2 g/l). Groups 3 and 4 were given diet containing 5% sodium
      L-ascorbate (NaAsA), a typical urinary bladder tumor promoter, and drinking water
      with or without DAP. Administration of DAP to group 1 significantly reduced tumor
      size, multiplicity and incidence, particularly of papillomas, when compared with
      group 2 values. DAP together with NaAsA (group 3) also decreased tumor size
      relative to the group 4 case. To determine the effects of DAP on the early stages
      of bladder carcinogenesis and its mechanisms, a similar protocol was conducted
      (experiment 2) with death after 20 weeks. DAP treatment caused complete
      inhibition (0% incidence) of papillary and/or nodular hyperplasia in group 1 but
      was without influence in group 3, as compared with the respective controls.
      Moreover, the ODC activity, bromodeoxyuridine labeling indices and mRNA
      expression levels of cyclin D1 in the urinary bladder mucosa, determined by
      northern blotting, were markedly lower in group 1 than in group 2, but values
      were comparable for both groups administered NaAsA. Assessment of mRNA expression
      levels of the angiogenic vascular endothelial growth factor suggested no
      involvement in the inhibitory effects of DAP on urinary bladder carcinogenesis.
      The results indicate that inhibition of ODC could reduce urinary bladder
      carcinogenesis in rats, particularly in the early stages, through
      antiproliferative mechanisms.

PMID- 10657959
TI  - Localization of tumor suppressor gene candidates by cytogenetic and short tandem
      repeat analyses in tumorigenic human bronchial epithelial cells.
AB  - Radon exposure is associated with increased risk for bronchogenic carcinoma.
      Mutagenesis analyses have revealed that radon induces mostly multi-locus
      chromosome deletions. Based on these findings, it was hypothesized that deletion
      analysis of multiple radon-induced malignant transformants would reveal common
      mutations in chromosomal regions containing tumor suppressor genes responsible
      for malignant transformation. This hypothesis was supported by a previous study
      in which tumorigenic derivatives of the human papillomavirus 18-immortalized
      human bronchial epithelial cell line BEP2D were established following irradiation
      with 30 cGy of high linear energy transfer radon-simulated alpha-particles.
      Herein, we describe the analyses of 10 additional tumorigenic derivative cell
      lines resulting from the irradiation of five additional independent BEP2D
      populations. The new transformants have common cytogenetic changes, including the
      loss of chromosome (ch)Y, one of three copies of ch8, one of two copies of
      ch11p15-pter and one of three copies of ch14. These changes are the same as those
      reported previously. Analysis of PCR-amplified short tandem repeats of
      informative loci confirmed the loss of heterozygosity (LOH) at 12 loci spanning
      the length of ch8 in cell lines from four of the total of eight irradiation
      treatments to date and the loss of chY in all cell lines (8 of 8). LOH analysis
      with a total of 17 informative loci confirmed loss on ch14 in transformants from
      seven of eight irradiation treatments and indicated a 0.5-1.7 cM region of common
      involvement centered around locus D14S306. No LOH was detected at any of the
      informative loci on ch11. The overall results support our stated hypothesis.
      Further studies are currently in progress to determine whether the ch8 and ch14
      regions contain genes with tumor suppressor function in bronchial epithelial
      cells.

PMID- 10657960
TI  - Redox-dependent toxicity of diepoxybutane and mitomycin C in sea urchin
      embryogenesis.
AB  - The effects and mechanisms of action of diepoxybutane (DEB) and mitomycin C (MMC)
      were investigated on sea urchin embryogenesis, (Sphaerechinus granularis and
      Paracentrotus lividus). DEB- and MMC-induced toxicity was evaluated by means of
      selected end-points, including developmental defects, cytogenetic abnormalities
      and alterations in the redox status [oxygen-dependent toxicity, Mn-superoxide
      dismutase (MnSOD) and catalase activities and glutathione (GSH) levels]. Both DEB
      and MMC exhibited developmental toxicity (at concentrations ranging from 3 x 10(
      5) to 3 x 10(-4) M and 3 x 10(-6) to 3 x 10(-5) M, respectively) expressed as
      larval abnormalities, developmental arrest and mortality. The developmental
      effects of both compounds were significantly affected by oxygen at levels ranging
      from 5 to 40%. These results confirmed previous evidence for oxygen-dependent MMC
      toxicity and are the first report of oxygen dependence for DEB toxicity. Both DEB
      and MMC exerted significant cytogenetic abnormalities, including mitotoxicity and
      mitotic aberrations, but with different trends between the two chemicals, at the
      same concentrations as exerted developmental toxicity. The formation of reactive
      oxygen species was evaluated using: (i) luminol-dependent chemiluminescence
      (LDCL); (ii) reactions of the main antioxidant systems, such as GSH content and
      MnSOD and catalase activities. The results point to clear-cut differences in the
      effects induced by DEB and MMC. Thus, DEB suppressed GSH content within the
      concentration range 10(-7)-3 x 10(-5) M. The activity of catalase was stimulated
      at lower DEB levels (10(-7)-10(-6) M) and then decreased at higher DEB
      concentrations (> or =10(-5) M). Increasing MMC concentrations induced LDCL and
      MnSOD activity (> or =10(-6) M) greatly and modulated catalase activity (10(-7) -
      10(-6) M). GSH levels were unaffected by MMC. The results suggest that oxidative
      stress contributes to the developmental and genotoxic effects of both toxins
      studied, although through different mechanisms.

PMID- 10657961
TI  - Effects of UV light and tumor promoters on endogenous vitamin E status in mouse
      skin.
AB  - Recent reports indicate that both orally administered and topically applied alpha
      tocopherol (vitamin E, TH) prevent UVB-induced skin carcinogenesis in mice.
      Because UVB exposure causes the formation of oxidants associated with tumor
      promotion, epidermal TH status may be an important determinant of susceptibility
      to photocarcinogenesis. To test this hypothesis, we studied the status of
      epidermal TH in C3H mice following exposure to single and repeated UVB exposures
      at doses typical of chronic photocarcinogenesis protocols. Exposure of mice to a
      single 13 kJ/m(2) dose over 60 min resulted in no acute depletion of epidermal TH
      and a modest increase in TH within 6-12 h. Daily exposure to 6.5 kJ/m(2) over 30
      min resulted in a gradual increase in epidermal TH, which reached 5-fold after
      five daily exposures. The increase in epidermal TH was accompanied by an increase
      in the TH oxidation products alpha-tocopherolquinone (TQ) and alpha
      tocopherolhydroquinone (THQ). We also studied the effect of the prooxidant
      chemical tumor promoter benzoyl peroxide and the prooxidant azo initiators
      azobis(amidinopropane HCl) and azobis(2, 4-dimethylvaleronitrile). Topical
      application of these prooxidant chemicals acutely oxidized epidermal TH to TQ and
      THQ. Topical treatments with the phorbol ester tumor promoter 12-O
      tetradecanoylphorbol-13-acetate (TPA) increased epidermal TH levels without
      producing a significant accumulation of TH oxidation products. The results
      indicate that UVB and tumor promoting chemicals all exert qualitatively different
      effects on epidermal TH status and that UVB and TPA trigger an adaptive response
      involving epidermal TH accumulation.

PMID- 10657962
TI  - Neoplastic transformation of mammary epithelial cells in rats is associated with
      decreased apoptotic cell death.
AB  - Previous studies have shown that terminal end buds (TEBs) in the murine mammary
      gland have high proliferative activity and demonstrate apoptotic cell death
      (ACD). Since TEBs are considered the place of origin of most chemically induced
      mammary carcinomas, we hypothesized that the development of hyperplastic and
      premalignant (carcinoma in situ, CIS) lesions in TEBs is associated with either a
      further increase in cell proliferation and/or with a decrease in ACD. To test
      this hypothesis we used the N-methyl-N-nitorosourea (MNU) carcinogenesis model in
      rats, where the occurrence of mammary tumors is preceded by hyperplastic and
      premalignant lesions arising mostly in TEBs, as well as in ducts and alveoli. The
      percentage of proliferating cells, as evaluated by 5-bromodeoxyuridine labeling
      (BrdU-LI), was similar in TEBs to those in terminal endbud hyperplasia (TEBH),
      CIS, and carcinomas (CA), whereas the percentage of apoptotic cells (apoptotic
      index, AI) was relatively high in TEBs and decreased in TEBH, CIS, and CA. This
      indicates that neoplastic transformation of mammary epithelial cells in TEBs is
      not associated with an increase in cell proliferation, but with a decrease in
      ACD. In addition to TEBH, hyperplastic lesions developed in ductal branching
      areas (ductal hyperplasia, DH) and alveolar structures (alveolar hyperplasia,
      AH). However, BrdU-LI in both DH and AH was lower than in TEBH, whereas the AI
      values were similar, suggesting that TEBH has a higher potential for progression
      and malignant transformation than DH and AH. In mammary tumors apoptotic cells
      were rare in the peripheral, proliferative areas, but frequent close to the
      necrotic areas, suggesting that intratumoral factors may significantly affect
      ACD. Thus, it appears that dissociation between cell proliferation and apoptosis
      occurs in the hyperplastic stages of mammary carcinogenesis and that neoplastic
      transformation of mammary epithelial cells is associated with decreased ACD but
      not with increased cell proliferation.

PMID- 10657963
TI  - Using polymerase arrest to detect DNA binding specificity of aristolochic acid in
      the mouse H-ras gene.
AB  - The distribution of DNA adducts formed by the two main components, aristolochic
      acid I (AAI) and aristolochic acid II (AAII), of the carcinogenic plant extract
      aristolochic acid (AA) was examined in a plasmid containing exon 2 of the mouse c
      H-ras gene by a polymerase arrest assay. AAI and AAII were reacted with plasmid
      DNA by reductive activation and the resulting DNA adducts were identified as the
      previously characterized adenine adducts (dA-AAI and dA-AAII) and guanine adducts
      (dG-AAI and dG-AAII) by the (32)P-post-labeling method. In addition, a
      structurally unknown adduct was detected in AAII-modified DNA and shown to be
      derived from reaction with cytosine (dC-AAII). Sites at which DNA polymerase
      progress along the template was blocked were assumed to be at the nucleotide 3'
      to the adduct. Polymerase arrest spectra showed a preference for reaction with
      purine bases in the mouse H-ras gene for both activated compounds, consistent
      with previous results that purine adducts are the principal reaction products of
      AAI and AAII with DNA. Despite the structural similarities among AAI-DNA and AAII
      DNA adducts, however, the polymerase arrest spectra produced by the AAs were
      different. According to the (32)P-post-labeling analyses reductively activated
      AAI showed a strong preference for reacting with guanine residues in plasmid DNA,
      however, the polymerase arrest assay revealed arrest sites preferentially at
      adenine residues. In contrast, activated AAII reacted preferentially with adenine
      rather than guanine residues and to a lesser extent with cytosine but DNA
      polymerase was arrested at guanine as well as adenine and cytosine residues with
      nearly the same average relative intensity. Thus, the polymerase arrest spectra
      obtained with the AA-adducted ras sequence do not reflect the DNA adduct
      distribution in plasmid DNA as determined by (32)P-post-labeling. Arrest sites of
      DNA polymerase associated with cytosine residues confirmed the presence of a
      cytosine adduct in DNA modified by AAII. For both compounds adduct distribution
      was not random; instead, regions with adduct hot spots and cold spots were
      observed. Results from nearest neighbor binding analysis indicated that flanking
      pyrimidines displayed the greatest effect on polymerase arrest and therefore on
      DNA binding by AA.

PMID- 10657964
TI  - Transgenic rats carrying human c-Ha-ras proto-oncogenes are highly susceptible to
      N-methyl-N-nitrosourea mammary carcinogenesis.
AB  - A rat line carrying three copies of the human c-Ha-ras proto-oncogene, including
      its own promoter region, was established and designated Hras128. Expression of
      the transgene was detected in all organs examined from Hras128 rats by northern
      blot analysis. To examine its influence on susceptibility to N-methyl-N
      nitrosourea (MNU)-induced mammary carcinogenesis, female rats were treated with
      50 mg/kg MNU i.v. at 50 days of age. All 22 Hras128 transgenic rats rapidly
      developed multiple and large mammary carcinomas within as little as 8 weeks after
      MNU treatment (14.1 tumors/rat, average diameter 16.4 mm). In contrast, 24 non
      transgenic littermates developed no or only small tumors (0.46 tumors/rat,
      average diameter 7.4 mm) within this period. PCR-restriction fragment length
      polymorphism (RFLP) analysis and direct sequencing for the transduced human c-Ha
      ras proto-oncogene indicated that 38 out of 44 tumors (86.4%) contained cells
      with mutations at codon 12 in exon 1. However, the signal densities of the
      mutated bands observed in the RFLP analyses revealed the presence of mixed
      populations of mutated and non-mutated cells in the tumors, the latter being in
      the majority. PCR-single strand conformation polymorphism analysis detected no
      mutations in codons 12 or 61 of the endogenous rat c-Ha-ras gene of Hras128 rat
      tumors. The results thus indicate that rats carrying the transduced human c-Ha
      ras proto-oncogene are highly susceptible to MNU-induced mammary carcinogenesis
      and that this is not primarily due to mutations of the transgene or endogenous c
      Ha-ras gene.

PMID- 10657965
TI  - Inhibitory effects of combined administration of antibiotics and anti
      inflammatory drugs on lung tumor development initiated by N-nitrosobis(2
      hydroxypropyl)amine in rats.
AB  - The effects of antibiotics and anti-inflammatory drugs on the promotion stage of
      lung carcinogenesis initiated with N-nitrosobis(2-hydroxypropyl)amine (BHP) in
      rats were investigated in two experiments with a similar protocol. In experiment
      1, rats received tap water containing 2000 p.p.m. BHP for 12 weeks followed by
      basal diet or basal diet containing 0.02% erythromycin (EM), 0. 04% ampicillin
      (ABPC), 1.5% sho-saiko-to, 0.02% EM plus 1.5% sho-saiko-to or 0.04% ABPC plus
      1.5% sho-saiko-to for 8 weeks after BHP administration. The development of
      adenocarcinomas (AC), squamous cell carcinomas (SqC) and adenosquamous carcinomas
      (ASqC) was completely inhibited in rats given ABPC plus sho-saiko-to and the
      numbers of lung lesions including alveolar hyperplasias, adenomas and carcinomas
      were decreased in rats given EM plus sho-saiko-to or ABPC plus sho-saiko-to.
      Neutrophil and macrophage infiltration into alveolar spaces of the lung were also
      markedly suppressed. In experiment 2, rats received BHP in the same manner as in
      experiment 1 and basal diet or basal diet containing 0.04% ABPC, 0.006%
      piroxicam, 0.04% ABPC plus 0.006% piroxicam and 0.04% ABPC plus 0.75% ougon for 8
      weeks. The incidence and number of carcinomas, including ACs, SqCs and ASqCs were
      decreased in rats given ABPC plus piroxicam or ABPC plus ougon. Bacteria, mainly
      Escherichia coli, were detected in broncho-alveolar lavage of rats receiving BHP.
      The results suggest that chronic inflammation might be involved in the
      progression of lung carcinogenesis by BHP in rats and its suppression may
      therefore be useful as a chemopreventive strategy in lung cancer clinics.

PMID- 10657966
TI  - Oxidative damage in an esophageal adenocarcinoma model with rats.
AB  - Oxidative damage has long been related to carcinogenesis in human cancers and
      animal cancer models. Recently a rat esophageal adenocarcinoma (EAC) model was
      established in our laboratory by using esophagoduodenal anastomosis (EDA) plus
      iron supplementation. Our previous study suggested that iron supplementation
      enhanced inflammation and the production of reactive nitrogen species in the
      esophageal epithelium, which could contribute to esophageal adenocarcinogenesis.
      Here we further characterized oxidative damage in this model. We were
      particularly interested in how excess iron was deposited in the esophagus, and
      which cells were targeted by oxidative damage. Male Sprague-Dawley rats received
      iron supplementation (50 mg Fe/kg/month, i.p.) starting 4 weeks after EDA. The
      animals were killed at 11, 30 or 35 weeks after surgery. EAC appeared as early as
      week 11 after surgery, and increased over time, up to 60% at 35 weeks after
      surgery. All EACs were well-differentiated mucinous adenocarcinoma at the
      squamocolumnar junction. Iron deposition was found at the squamocolumnar junction
      and in the area with esophagitis. Esophageal iron overload could result from
      transient increase of blood iron after i.p. injection, and the overexpression of
      transferrin receptor in the premalignant columnar-lined esophagus (CLE) cells.
      Oxidative damage to DNA (8-hydroxy-2'-deoxyguanosine), protein (carbonyl content)
      and lipid (thiobarbituric acid reactive substance) in the esophagus was
      significantly higher than that of the non-operated control. CLE cells were
      believed to be the target cells of oxidative damage because they overexpressed
      heme oxygenase 1 and metallothionein, both known to be responsive to oxidative
      damage. We propose that oxidative damage plays an important role in the formation
      of EAC in the EDA model, and a similar situation may occur in humans with
      gastroesophageal reflux and iron over-nutrition.

PMID- 10657967
TI  - DNA adduct formation and molecular analysis of in vivo lacI mutations in the
      mammary tissue of Big Blue rats treated with 7, 12-dimethylbenz[a]anthracene.
AB  - Recently we compared the lacI and Hprt mutant frequencies (MFs) and types of
      mutations in lymphocytes of Big Blue((R)) (BB) rats exposed to 7,12
      dimethylbenz[a]anthracene (DMBA) under conditions that result in mammary gland
      tumors. In this study, we have examined the target mammary tissue for DMBA
      induced DNA adducts, lacI MF and types of lacI mutations. Seven-week-old female
      BB rats were given single doses of 0, 20 or 130 mg/kg DMBA by gavage and the DNA
      adducts and lacI MFs in the mammary tissue were measured over a period of 14 days
      and 18 weeks, respectively, following treatment. The lacI MF in the mammary
      tissue increased for 10 weeks and then remained relatively constant; 130 mg/kg
      DMBA produced a 14-fold increase in the MF (255 +/- 50 x 10(-6) p.f.u.) over
      control MF (18. 3 +/- 4 x 10(-6) p.f.u.). (32)P-post-labeling analysis of DNA
      from mammary tissue and splenic lymphocytes of treated rats revealed two major
      adducts. Comparison of these adducts with DMBA standards indicated that the
      adducts formed by DMBA involved both G:C and A:T base pairs. DNA sequencing
      revealed that the majority of DMBA-induced lacI mutations were base pair
      substitutions and that A:T-->T:A (44% of the independent mutations) and G:C-->T:A
      (24% of the independent mutations) transversions were the predominant types.
      Furthermore, the mutational results revealed a 'hotspot' for a G-->T mutation in
      codon 95 (GTG-->TTG) of the lacI gene in mammary tissue. These results suggest
      that DMBA is highly mutagenic to lacI in mammary tissue and that adducts with
      both G:C and A:T base pairs participate in forming mutations in DMBA-treated BB
      rats.

PMID- 10657968
TI  - 32P-post-labelling of 7-(3-chloro-2-hydroxypropyl)guanine in white blood cells of
      workers occupationally exposed to epichlorohydrin.
AB  - Epichlorohydrin (ECH) is a simple 3-carbon epoxide of industrial importance. It
      has been shown to be genotoxic in several systems and carcinogenic in
      experimental animals. The aim of the present investigation was to study DNA
      adducts of ECH as a biomarker of occupational exposure to this chemical. 7-(3
      Chloro-2-hydroxypropyl)guanine (7-CHP-guanine) was analysed in DNA from white
      blood cells using an anion exchange-based adduct enrichment protocol of the (32)P
      post-labelling/HPLC-based assay. Blood samples were collected from seven workers
      handling ECH (exposed), nine workers not handling ECH but normally present in the
      premises where this chemical is used (potentially exposed) and 13 office and
      factory workers from locations in the plant where ECH is not handled (controls).
      7-CHP-guanine was detected in five of the seven workers exposed to ECH (1.6-7.1
      mol/10(9) mol nucleotides) and in two of the nine workers potentially exposed to
      ECH (0.8-1.5 mol/10(9) mol nucleotides). This adduct was not detected in any of
      the 13 controls. The difference in adduct levels between exposed workers and
      controls was statistically significant (Mann-Whitney test, P < 0.001), as was the
      difference between exposed workers and potentially exposed workers (P = 0.017).
      The recovery of 7-CHP-guanine in the (32)P-post-labelling assay was on average 48
      +/- 7%, which is considerably higher than previously reported for other 7
      alkylguanines. The method used had a limit of detection of approximately 0.4 mol
      adduct/10(9) mol nucleotides using 20 microg DNA. This study shows for the first
      time ECH-induced DNA adducts in humans and suggests that 7-CHP-guanine may be
      used as a biomarker of occupational exposure to ECH.

PMID- 10657969
TI  - Transition mutation in codon 248 of the p53 tumor suppressor gene induced by
      reactive oxygen species and a nitric oxide-releasing compound.
AB  - Exposing the human bronchial epithelial cell line BEAS-2B to the nitric oxide
      (NO) donor sodium 1-(N,N-diethylamino)diazen-1-ium-1, 2-diolate (DEA/NO) at an
      initial concentration of 0.6 mM while generating superoxide ion at the rate of 1
      microM/min with the hypoxanthine/xanthine oxidase (HX/XO) system induced C:G-
      >T:A transition mutations in codon 248 of the p53 gene. This pattern of
      mutagenicity was not seen by 'fish-restriction fragment length
      polymorphism/polymerase chain reaction' (fish-RFLP/PCR) on exposure to DEA/NO
      alone, however, exposure to HX/XO led to various mutations, suggesting that co
      generation of NO and superoxide was responsible for inducing the observed point
      mutation. DEA/NO potentiated the ability of HX/XO to induce lipid peroxidation as
      well as DNA single- and double-strand breaks under these conditions, while 0.6 mM
      DEA/NO in the absence of HX/XO had no significant effect on these parameters. The
      results show that a point mutation seen at high frequency in certain common human
      tumors can be induced by simultaneous exposure to reactive oxygen species and a
      NO source.

PMID- 10657970
TI  - Kinetics of DNA adduct formation and removal in mouse hepatocytes following in
      vivo exposure to 5,9-dimethyldibenzo[c,g]carbazole.
AB  - 5,9-Dimethyldibenzo[c,g]carbazole (DMDBC), a potent mouse hepatocarcinogen, has
      been shown to induce a non-linear increase in mutant frequency in the liver of
      the transgenic MutaMouse. To gain insight into the mechanisms underlying the
      mutagenicity of DMDBC in vivo, DNA damage formation and removal were monitored in
      mouse hepatocytes over 4-144 h after a single skin application of 10 or 90 mg/kg
      DMDBC. DNA adducts were measured by (32)P-post-labeling. DNA repair was assessed
      by: (i) the unscheduled DNA synthesis (UDS) assay, which measures [(3)H]thymidine
      incorporation into hepatocyte DNA undergoing excision repair; (ii) the Comet
      assay, which detects DNA strand breaks transiently produced between the incision
      and rejoining steps of the excision repair process. A plateau of approximately
      400 DNA adducts/10(8) nucleotides was reached 24 h after treatment with 10 mg/kg
      and remained unchanged until 144 h. UDS activity was significantly induced at 15
      and 24 h, while no DNA strand breaks were observed at any sampling time. These
      results suggest that DNA repair mechanisms were efficiently induced and the
      formation of a high degree of DNA damage was avoided at this dose level.
      Following exposure to 90 mg/kg DMDBC, the number of DNA adducts increased sharply
      to a maximum at 24 h ( approximately 8000/10(8) nucleotides) and then declined to
      approximately 500/10(8) nucleotides at 144 h. UDS activity was markedly induced
      from 15 to 72 h. Low levels of DNA strand breaks were observed at 24 and 48 h.
      The formation of large numbers of DNA adducts and the emergence of DNA strand
      breaks despite a strong initial induction of UDS activity suggested that DNA
      repair mechanisms were saturated at this dose level. This phenomenon could partly
      account for the non-linear induction of gene mutations previously reported in the
      liver of the transgenic MutaMouse.

PMID- 10657971
TI  - Human phenol sulfotransferases hP-PST and hM-PST activate propane 2-nitronate to
      a genotoxicant.
AB  - The industrial solvent 2-nitropropane (2-NP) is a genotoxic hepatocarcinogen in
      rats. The genotoxicity of the compound in rats has been attributed to
      sulfotransferase-mediated formation of DNA-reactive nitrenium ions from the
      anionic form of 2-NP, propane 2-nitronate (P2N). Whether human sulfotransferases
      are capable of activating P2N is unknown. In the present study we have addressed
      this question by investigating the genotoxicity of P2N in various V79-derived
      cell lines engineered for expression of individual forms of human
      sulfotransferases, the phenol-sulfating and the monoamine-sulfating phenol
      sulfotransferases (hP-PST and hM-PST) and the human hydroxysteroid
      sulfotransferase (hHST). Genotoxicity was assessed by measuring the induction of
      DNA repair synthesis and by analyzing the formation of DNA modifications. P2N
      induced repair synthesis in V79-hP-PST and V79-hM-PST cells, whereas induction of
      repair synthesis in V79-hHST cells was negligible. P2N also resulted in the
      formation of 8-aminodeoxyguanosine and increased the level of 8-oxodeoxyguanosine
      in V79-hP-PST cells, but not in the parental V79-MZ cells, which do not show any
      sulfotransferase activity. Acetone oxime, the tautomeric form of the first
      reduction product of 2-NP, 2-nitrosopropane, was inactive in all cell lines. The
      results show that the human phenol sulfotransferases P-PST and M-PST are capable
      of metabolically activating P2N (P-PST >> M-PST) and that the underlying
      mechanism is apparently identical to that resulting in the activation of P2N in
      rat liver, where 2-NP causes carcinomas. These results support the notion that 2
      NP should be regarded as a potential human carcinogen.

PMID- 10657972
TI  - A defect in a single allele of the Mlh1 gene causes dissociation of the killing
      and tumorigenic actions of an alkylating carcinogen in methyltransferase
      deficient mice.
AB  - Mice with mutations in both alleles of the Mgmt and the Mlh1 gene, the former
      encoding a DNA repair methyltransferase and the latter a protein functioning at
      an early step of mismatch repair, are as resistant to the killing action of
      alkylating agents as are wild-type mice. These mice yielded a large number of
      tumors when exposed to alkylating carcinogens, but this characteristic was
      subdued since they also showed a relatively high level of spontaneous
      tumorigenicity, as a consequence of the defect in mismatch repair. This
      complexity is now resolved by introducing the Mlh1(+/-) mutation, instead of
      Mlh1(-/-), in these methyltransferase-deficient mice. Mgmt(-/-) Mlh1(+/-) mice,
      with about half the amount of MLH1 protein as Mgmt(-/-) Mlh1(+/+) mice, were
      resistant to the killing action of N-methyl-N-nitrosourea (MNU), up to the level
      of 30 mg/kg body wt. Eight weeks after exposure to this dose of MNU, 40% of MNU
      treated Mgmt(-/-) Mlh1(+/-) mice had thymic lymphomas and there were no tumors in
      those mice not given the treatment. It seems that the cellular content of MLH1
      protein is a critical factor for determining if damaged cells enter into either
      one of the two pathways leading to mutation induction or to apototic cell death.
      Loss of Mlh1 expression was frequently observed in tumors of Mgmt(-/-) Mlh1(+/-)
      mice and this might be related to progression of the tumors.

PMID- 10657973
TI  - Animal products and K-ras codon 12 and 13 mutations in colon carcinomas.
AB  - K-ras gene mutations (codons 12 and 13) were determined by PCR-based mutant
      allele-specific amplification (MASA) in tumour tissue of 185 colon cancer
      patients: 36% harboured mutations, of which 82% were located in codon 12. High
      intakes of animal protein, calcium and poultry were differently associated with
      codon 12 and 13 mutations: odds ratios (OR) and 95% confidence intervals (95% CI)
      for codon 12 versus codon 13 were 9.0 (2.0-42), 4.1 (1.4-12) and 15 (1.4-160),
      respectively. In case-control comparisons, high intakes of animal protein and
      calcium were positively associated with colon tumours harbouring codon 12
      mutations [for animal protein per 17 g, OR (95% CI) = 1.5 (1.0-2.1); for calcium
      per 459 mg, 1.2 (0.9-1.6)], while inverse associations were observed for tumours
      with K-ras mutations in codon 13 [for animal protein 0.4 (0.2-1.0); for calcium
      0.6 (0. 3-1.2)]. Transition and transversion mutations were not differently
      associated with these dietary factors. These data suggest a different dietary
      aetiology of colon tumours harbouring K-ras codon 12 and 13 mutations.

PMID- 10657974
TI  - Correlation between growth control, neoplastic potential and endogenous
      connexin43 expression in HeLa cell lines: implications for tumor progression.
AB  - A HeLa cell line, obtained from the ATCC, was cloned and found to exhibit a
      spectrum of in vitro and in vivo growth characteristics as well as variable
      expression of endogenous connexin43 (Cx43), a widely expressed gap junction
      protein implicated in growth control. The majority of clones expressed functional
      Cx43, which contrasted with previous studies reporting that HeLa cells are
      completely negative for Cx43 mRNA/protein expression. This endogenous Cx43
      expression correlated with increased growth control: Cx43-positive clones
      exhibited a decreased saturation density and a diminished growth capacity when in
      co-culture with growth-controlled normal cells in constrast to Cx43-negative
      clones. Endogenous Cx43 expression was negatively correlated with neoplastic
      potential as evidenced by attenuated anchorage-independent growth and decreased
      tumorigenicity in immunodeficient mice. Treatment of Cx43-negative cells with 5
      aza-2'-deoxycytidine resulted in expression of Cx43, suggesting gene silencing
      via DNA methylation. These results support the concept of growth control via
      junctionally transmitted signals and suggest an epigenetic mechanism for tumor
      cells to circumvent this control during carcinogenesis. Moreover, the
      heterogeneous nature of this cell line and the ease of connexin43 gene induction
      suggest caution in the interpretation of results involving gene transfection
      using noninducible gene expression systems.

PMID- 10657975
TI  - No change in spontaneous mutation frequency or specificity in dietary restricted
      mice.
AB  - It is well known that dietary restricted rodents live longer and are generally
      healthier than their ad libitum fed counterparts, with fewer tumors.
      Additionally, while dietary restriction appears to reduce the frequency of
      chemically induced mutation in laboratory animals, relatively little is known
      regarding the effect of dietary restriction on spontaneous mutational events.
      Although spontaneous mutation rates are generally low compared with chemically
      induced events, spontaneous mutations accumulate in most tissues over the
      lifetime of the animal and are therefore expected to contribute significantly to
      spontaneous neoplasia. It is generally presumed that dietary restriction results
      in less oxidative damage and a lowering of the mutation frequency. Here we report
      the results of dietary restriction on mutation frequency and specificity in lacI
      transgenic mice aged 6 and 12 months. Unexpectedly, no changes were observed in
      either the frequency or specificity of mutation in dietary restricted mice,
      compared with ad libitum controls. We therefore conclude that dietary restriction
      appears to have no appreciable effect on spontaneous mutation, at least in
      chromosomal DNA.

PMID- 10657976
TI  - Oxidative DNA damage in human lymphocytes: correlations with plasma levels of
      alpha-tocopherol and carotenoids.
AB  - In order to investigate whether oxidative damage is associated with differences
      in antioxidant intake, we measured the levels of 8-oxo-7, 8-dihydro-2'
      deoxyguanosine (8-oxodGuo) in lymphocytes and alpha-tocopherol and several
      carotenoids in plasma of women with different dietary habits. We found that women
      from Granada (Spain), a region with a typically Mediterranean diet, had
      significantly higher levels of 8-oxodGuo compared with Malmo (Sweden), a region
      with a Northern European dietary intake pattern (2.30 +/- 0.78 versus 1.59 +/-
      1.01 8-oxodGuo/10(-6) deoxyguanosine). Levels of plasma alpha-tocopherol and
      carotenoids were higher in Granada and these values were significantly positively
      correlated with levels of 8-oxodGuo. Our results do not support the hypothesis
      that a Mediterranean diet rich in alpha-tocopherol and carotenoids protects cells
      against oxidative DNA damage. It is possible, however, that consumption of foods
      other than fruits and vegetables, including fats, are responsible for the higher
      levels of 8-oxodGuo in Granada. Further studies are warranted to better elucidate
      the role of antioxidants in the modulation of oxidative stress in vivo.

PMID- 10657977
TI  - Altered surface expression and increased turnover of the alpha6beta4 integrin in
      an undifferentiated carcinoma.
AB  - The integrin alpha6beta4, predominantly expressed on tissues of epithelial
      origin, is known to be variably expressed on carcinomas. The biochemical changes
      resulting in altered expression during tumor progression are unknown. We have
      analyzed the expression of alpha6beta4 in a multi-step mouse model of skin
      carcinogenesis representing normal keratinocyte, benign papilloma and malignant
      undifferentiated carcinoma. All cell lines expressed the alpha6 integrin
      exclusively as the alpha6beta4 integrin heterodimer. Analysis of this integrin by
      flow cytometry and immunoprecipitation of surface labeled proteins revealed that
      the undifferentiated carcinoma cells have an approximately 75% reduction in
      surface expression of the integrin as compared with the keratinocyte and
      papilloma cell lines. The alpha6beta4 integrin which remains expressed on the
      carcinoma cells is diffusely distributed in the membrane and has an approximately
      2.5-fold increased biological turnover as compared with normal keratinocytes. The
      decreased biological half-life and the loss of polarized expression of
      alpha6beta4 on the carcinoma cells suggests an altered functional role for the
      alpha6beta4 integrin on carcinoma cells during tumor progression. These factors
      may contribute to the known supression of hemidesmosome structures and the
      increased migration phenotype associated with some epithelial carcinomas.

PMID- 10657978
TI  - Curcumin-containing diet inhibits diethylnitrosamine-induced murine
      hepatocarcinogenesis.
AB  - Curcumin has been widely used as a spice and coloring agent in foods. Recently,
      curcumin was found to possess chemopreventive effects against skin cancer,
      forestomach cancer, colon cancer and oral cancer in mice. Clinical trials of
      curcumin for prevention of human cancers are currently ongoing. In this study, we
      examine the chemopreventive effect of curcumin on murine hepatocarcinogenesis.
      C3H/HeN mice were injected i.p. with N-diethylnitrosamine (DEN) at the age of 5
      weeks. The curcumin group started eating 0.2% curcumin-containing diet 4 days
      before DEN injection until death. The mice were then serially killed at the
      scheduled times to examine the development of hepatocellular carcinoma (HCC) and
      changes in intermediate biological markers. At the age of 42 weeks, the curcumin
      group, as compared with the control group (DEN alone), had an 81% reduction in
      multiplicity (0.5 versus 2.57) and a 62% reduction in incidence (38 versus 100%)
      of development of HCC. A series of intermediate biological markers were examined
      by western blot. While hepatic tissues obtained from the DEN-treated mice showed
      a remarkable increase in the levels of p21(ras), PCNA and CDC2 proteins, eating a
      curcumin-containing diet reversed the levels to normal values. These results
      indicate that curcumin effectively inhibits DEN-induced hepatocarcinogenesis in
      the mouse. The underlying mechanisms of the phenomenon and the feasibility of
      using curcumin in the chemoprevention of human HCC should be further explored.

PMID- 10657979
TI  - The physician-scientist: career issues and challenges at the year 2000.

PMID- 10657980
TI  - The importance of being proline: the interaction of proline-rich motifs in
      signaling proteins with their cognate domains.
AB  - Acommon focus among molecular and cellular biologists is the identification of
      proteins that interact with each other. Yeast two-hybrid, cDNA expression library
      screening, and coimmunoprecipitation experiments are powerful methods for
      identifying novel proteins that bind to one's favorite protein for the purpose of
      learning more regarding its cellular function. These same techniques, coupled
      with truncation and mutagenesis experiments, have been used to define the region
      of interaction between pairs of proteins. One conclusion from this work is that
      many interactions occur over short regions, often less than 10 amino acids in
      length within one protein. For example, mapping studies and 3-dimensional
      analyses of antigen-antibody interactions have revealed that epitopes are
      typically 4-7 residues long (1). Other examples include protein-interaction
      modules, such as Src homology (SH) 2 and 3 domains, phosphotyrosine binding
      domains (PTB), postsynaptic density/disc-large/ZO1 (PDZ) domains, WW domains,
      Eps15 homology (EH) domains, and 14-3-3 proteins that typically recognize linear
      regions of 3-9 amino acids. Each of these domains has been the subject of recent
      reviews published elsewhere (2 3 4 5 6 7). Among the primary structures of many
      ligands for protein-protein interactions, the amino acid proline is critical. In
      particular, SH3, WW, and several new protein-interaction domains prefer ligand
      sequences that are proline-rich. In addition, even though ligands for EH domains
      and 14-3-3 domains are not proline-rich, they do include a single proline
      residue. This review highlights the analysis of those protein-protein
      interactions that involve proline residues, the biochemistry of proline, and
      current drug discovery efforts based on proline peptidomimetics.-Kay, B. K.,
      Williamson, M. P., Sudol, M. The importance of being proline: the interaction of
      proline-rich motifs in signaling proteins with their cognate domains.

PMID- 10657981
TI  - The balance sheet for transcription: an analysis of nuclear RNA metabolism in
      mammalian cells.
AB  - The control of RNA synthesis from protein-coding genes is fundamental in
      determining the various cell types of higher eukaryotes. The activation of these
      genes is driven by promoter complexes, and RNA synthesis is performed by an
      enzyme mega-complex-the RNA polymerase II holoenzyme. These two complexes are the
      fundamental components required to initiate gene expression and generate the
      primary transcripts that, after processing, yield mRNAs that pass to the
      cytoplasm where protein synthesis occurs. But although this gene expression
      pathway has been studied intensively, aspects of RNA metabolism remain difficult
      to comprehend. In particular, it is unclear why >95% of RNA polymerized by
      polymerase II remains in the nucleus, where it is recycled. To explain this
      apparent paradox, this review presents a detailed description of nuclear RNA
      (nRNA) metabolism in mammalian cells. We evaluate the number of active
      transcription units, discuss the distribution of polymerases on active genes, and
      assess the efficiency with which the products mature and pass to the cytoplasm.
      Differences between the behavior of mRNAs on this productive pathway and primary
      transcripts that never leave the nucleus lead us to propose that these represent
      distinct populations. We discuss possible roles for nonproductive RNAs and
      present a model to describe the metabolism of these RNAs in the nuclei of
      mammalian cells.-Jackson, D. A., Pombo, A., Iborra, F. The balance sheet for
      transcription: an analysis of nuclear RNA metabolism in mammalian cells.

PMID- 10657982
TI  - Antisense oligonucleotides against cytochrome P450 2C8 attenuate EDHF-mediated
      Ca(2+) changes and dilation in isolated resistance arteries.
AB  - Using a novel vessel culture technique in combination with antisense
      oligonucleotide transfection, we tested whether the endothelium-derived
      hyperpolarizing factor (EDHF) is a cytochrome P450 (CYP)-related compound.
      Isolated resistance arteries from hamster gracilis muscle (n=19) were perfused
      and exposed to antisense (As), sense (S), or scrambled (Scr) oligonucleotides
      against the coding region of CYP2C8/9, an isoform expressed in endothelial cells.
      Thereafter, NO- and prostaglandin-independent, EDHF-mediated vascular responses
      associated with hyperpolarization [i.e., decrease in smooth muscle calcium (Fura
      2) and vasodilation] were studied after the application of acetylcholine (ACh).
      These EDHF-mediated responses were markedly attenuated (by 70%) by As- but not by
      S- or Scr-oligonucleotide treatment. However, the responses to norepinephrine
      (0.3 micromol/l), the NO donor sodium nitroprusside (1 micromol/l), and the K(Ca)
      channel activator NS1619 (100 micromol/l) were unaltered. As treatment, which
      specifically targeted the endothelial layer (as assessed by confocal microscopy),
      had no inhibitory effect on increases in endothelial calcium to ACh. It is
      concluded that a CYP2C8/9-related isoform functions as an EDHF synthase in
      hamster resistance arteries and that a product of this enzyme is an EDHF, or at
      least an integral part of the signaling cascade leading to EDHF-mediated
      responses.-Bolz, S.-S., Fisslthaler, B., Pieperhoff, S., de Wit, C., Fleming, I.,
      Busse, R., Pohl, U. Antisense oligonucleotides against cytochrome P450 2C8
      attenuate EDHF-mediated Ca(2+) changes and dilation in isolated resistance
      arteries.

PMID- 10657983
TI  - Endothelial dysfunction and peroxynitrite formation are early events in
      angiotensin-induced cardiovascular disorders.
AB  - Angiotensin II (ANG II) is a well-established participant in many cardiovascular
      disorders, but the mechanisms involved are not clear. Vascular cell experiments
      suggest that ANG II is a potent stimulator of free radicals such as superoxide
      anion, an agent known to inactivate nitric oxide and promote the formation of
      peroxynitrite. Here we hypothesized that ANG II reduces the efficacy of NO
      mediated vascular relaxation and promotes vascular peroxynitrite formation in
      vivo. ANG II was infused in rats at sub-pressor doses for 3 days. Systolic blood
      pressure and heart rate were unchanged on day 3 despite significant reductions in
      plasma renin activity. Thoracic aorta was isolated for functional and
      immunohistochemical evaluations. No difference in isolated vascular contractile
      responses to KCI (125 mM), phenylephrine, or ANG II was observed between groups.
      In contrast, relaxant response to acetylcholine (ACh) was decreased sixfold
      without a change in relaxant response to sodium nitroprusside. Extensive
      prevalence of 3-nitrotyrosine (3-NT, a stable biomarker of tissue peroxynitrite
      formation) immunoreactivity was observed in ANG II-treated vascular tissues and
      was specifically confined to the endothelium. Digital image analysis demonstrated
      a significant inverse correlation between ACh relaxant response and 3-NT
      immunoreactivity. These data demonstrate that ANG II selectively modifies
      vascular NO control at sub-pressor exposures in vivo. Thus, endothelial
      dysfunction apparently precedes other established ANG II-induced vascular
      pathologies, and this may be mediated by peroxynitrite formation in vivo.
      Wattanapitayakul, S., Weinstein, D. M., Holycross, B. J., Bauer, J. A.
      Endothelial dysfunction and peroxynitrite formation are early events in
      angiotensin-induced cardiovascular disorders.

PMID- 10657984
TI  - Mechanism of receptor-oriented intercellular calcium wave propagation in
      hepatocytes.
AB  - Intercellular calcium signals are propagated in multicellular hepatocyte systems
      as well as in the intact liver. The stimulation of connected hepatocytes by
      glycogenolytic agonists induces reproducible sequences of intracellular calcium
      concentration increases, resulting in unidirectional intercellular calcium waves.
      Hepatocytes are characterized by a gradient of vasopressin binding sites from the
      periportal to perivenous areas of the cell plate in hepatic lobules. Also,
      coordination of calcium signals between neighboring cells requires the presence
      of the agonist at each cell surface as well as gap junction permeability. We
      present a model based on the junctional coupling of several hepatocytes differing
      in sensitivity to the agonist and thus in the intrinsic period of calcium
      oscillations. In this model, each hepatocyte displays repetitive calcium spikes
      with a slight phase shift with respect to neighboring cells, giving rise to a
      phase wave. The orientation of the apparent calcium wave is imposed by the
      direction of the gradient of hormonal sensitivity. Calcium spikes are coordinated
      by the diffusion across junctions of small amounts of inositol 1,4, 5
      trisphosphate (InsP(3)). Theoretical predictions from this model are confirmed
      experimentally. Thus, major physiological insights may be gained from this model
      for coordination and spatial orientation of intercellular signals.-Dupont, G.,
      Tordjmann, T., Clair, C., Swillens, S., Claret, M., Combettes, L. Mechanism of
      receptor-oriented intercellular calcium wave propagation in hepatocytes.

PMID- 10657985
TI  - Spatial learning induced changes in expression of the ryanodine type II receptor
      in the rat hippocampus.
AB  - Calcium signaling critical to neural functions is mediated through Ca(2+)
      channels localized on both the plasma membrane and intracellular organelles such
      as endoplasmic reticulum. Whereas Ca(2+) influx occurs via the voltage- or/and
      ligand-sensitive Ca(2+) channels, Ca(2+) release from intracellular stores that
      amplifies further the Ca(2+) signal is thought to be involved in more profound
      and lasting changes in neurons. The ryanodine receptor, one of the two major
      intracellular Ca(2+) channels, has been an important target for studying Ca(2+)
      signaling in brain functions, including learning and memory, due to its
      characteristic Ca(2+)-induced Ca(2+) release. In this study, we report regional
      and cellular distributions of the type-2 ryanodine receptor (RyR2) mRNA in the
      rat brain, and effects of spatial learning on RyR2 gene expression at mRNA and
      protein levels in the rat hippocampus. Using in situ hybridization, reverse
      transcription polymerase chain reaction, and ribonuclease protection assays,
      significant increases in RyR2 mRNA were found in the hippocampus of rats trained
      in an intensive water maze task. With immunoprecipitation and immunoblotting,
      protein levels of RyR2 were also demonstrated to be increased in the microsomal
      fractions prepared from hippocampi of trained rats. These results suggest that
      RyR2, and hence the RyR2-mediated Ca(2+) signals, may be involved in memory
      processing after spatial learning. The increases in RyR2 mRNA and protein at 12
      and 24 h after training could contribute to more permanent changes such as
      structural modifications during long-term memory storage. Zhao, W., Meiri, N.,
      Xu, H., Cavallaro, S., Quattrone, A., Zhang, L., Alkon, D. A. Spatial learning
      induced changes in expression of the ryanodine type II receptor in the rat
      hippocampus.

PMID- 10657986
TI  - An oncolytic herpes simplex virus type 1 selectively destroys diffuse liver
      metastases from colon carcinoma.
AB  - Viruses used for gene therapy are usually genetically modified to deliver
      therapeutic transgenes and prevent viral replication. In contrast, replication
      competent viruses may be used for cancer therapy because replication of some
      viruses within cancer cells can result in their destruction (oncolysis). Viral
      ribonucleotide reductase expression is defective in the HSV1 mutant hrR3.
      Cellular ribonucleotide reductase, which is scarce in normal liver and abundant
      in liver metastases, can substitute for its viral counterpart to allow hrR3
      replication in infected cells. Two or three log orders more of hrR3 virions are
      produced from infection of colon carcinoma cells than from infection of normal
      hepatocytes in viral replication assays. This viral replication is oncolytic. A
      single intravascular administration of hrR3 into immune-competent mice bearing
      diffuse liver metastases dramatically reduces tumor burden. hrR3-mediated tumor
      inhibition is equivalent in immune-competent and immune-incompetent mice,
      suggesting that viral oncolysis and not the host immune response is the primary
      mechanism of tumor destruction. HSV1-mediated oncolysis of diffuse liver
      metastases is effective in mice preimmunized against HSV1. These results indicate
      that replication-competent HSV1 mutants hold significant promise as cancer
      therapeutic agents. Yoon, S. S., Nakamura, H., Carroll, N. M., Bode, B. P.,
      Chiocca, E. A., Tanabe, K. K. An oncolytic herpes simplex virus type 1
      selectively destroys diffuse liver metastases from colon carcinoma.

PMID- 10657987
TI  - Oxidative damage to mitochondrial DNA is inversely related to maximum life span
      in the heart and brain of mammals.
AB  - DNA damage is considered of paramount importance in aging. Among causes of this
      damage, free radical attack, particularly from mitochondrial origin, is receiving
      special attention. If oxidative damage to DNA is involved in aging, long-lived
      animals (which age slowly) should show lower levels of markers of this kind of
      damage than short-lived ones. However, this possibility has not heretofore been
      investigated. In this study, steady-state levels of 8-oxo-7, 8-dihydro-2'
      deoxyguanosine (8-oxodG) referred to deoxyguanosine (dG) were measured by high
      performance liquid chromatography (HPLC) in the mitochondrial (mtDNA) and nuclear
      (nDNA) DNA from the heart of eight and the brain of six mammalian species ranging
      in maximum life span (MLSP) from 3.5 to 46 years. Exactly the same digestion of
      DNA to deoxynucleosides and HPLC protocols was used for mtDNA and nDNA.
      Significantly higher (three- to ninefold) 8-oxodG/dG values were found in mtDNA
      than in nDNA in all the species studied in both tissues. 8-oxodG/dG in nDNA did
      not correlate with MLSP across species either in the heart (r=-0.68; P<0.06) or
      brain (r = 0.53; P<0.27). However, 8-oxodG/dG in mtDNA was inversely correlated
      with MLSP both in heart (r=-0.92; P<0.001) and brain (r=-0.88; P<0.016) tissues
      following the power function y = a(.)x(b), where y is 8-oxodG/dG and x is the
      MLSP. This agrees with the consistent observation that mitochondrial free radical
      generation is also lower in long-lived than in short-lived species. The results
      obtained agree with the notion that oxygen radicals of mitochondrial origin
      oxidatively damage mtDNA in a way related to the aging rate of each species.
      Barja, G., Herrero, A. Oxidative damage to mitochondrial DNA is inversely related
      to maximum life span in the heart and brain of mammals.

PMID- 10657988
TI  - Involvement of hepatocyte growth factor/scatter factor and met receptor signaling
      in hair follicle morphogenesis and cycling.
AB  - HGF/SF and its receptor (Met) are principal mediators of mesenchymal-epithelial
      interactions in several different systems and have recently been implicated in
      the control of hair follicle (HF) growth. We have studied their expression
      patterns during HF morphogenesis and cycling in C57BL/6 mice, whereas functional
      hair growth effects of HGF/SF were assessed in vivo by analysis of transgenic
      mice and in skin organ culture. In normal mouse skin, follicular expression of
      HGF/SF and Met was strikingly localized: HGF/SF was found only in the HF
      mesenchyme (dermal papilla fibroblasts) and Met in the neighboring hair bulb
      keratinocytes. Both HGF/SF and Met expression peaked during the initial phases of
      HF morphogenesis, the stage of active hair growth (early and mid anagen), and
      during the apoptosis-driven HF regression (catagen). Met+ cells in the regressing
      epithelial strand appeared to be protected from undergoing apoptosis. Compared to
      wild-type controls, transgenic mice overexpressing HGF/SF under the control of
      the MT-1 promoter had twice as many developing HF and displayed accelerated HF
      development on postnatal day 3. They also showed significant catagen retardation
      on P17. In organ culture and in vivo, HGF/SF i.c. resulted in a significant
      catagen retardation. These results demonstrate an important role of HGF/SF and
      Met in murine hair growth control and suggest that Met-mediated signaling might
      be exploited for therapeutic manipulation of human hair growth disorders.
      Lindner, G., Menrad, A., Gherardi, E., Merlino, G., Welker, P., Handjiski, B.,
      Roloff, B., Paus, R. Involvement of hepatocyte growth factor/scatter factor and
      Met receptor signaling in hair follicle morphogenesis and cycling.

PMID- 10657989
TI  - Uncoupling of cell proliferation and differentiation activities of basic
      fibroblast growth factor.
AB  - FGF-2 exerts its pleiotropic effects on cell growth and differentiation by
      interacting with specific cell surface receptors. In addition, exogenously added
      FGF-2 is translocated from outside the cell to the nucleus during G1-S
      transition. In this study, we show that a single point mutation in FGF-2
      (substitution of residue serine 117 by alanine) is sufficient to drastically
      reduce its mitogenic activity without affecting its differentiation properties.
      The FGF-2(S117A) mutant binds to and activates tyrosine kinase receptors and
      induces MAPK and p70S6K activation as strongly as the wild-type FGF-2. We
      demonstrate that this mutant enters NIH3T3 cells, is translocated to the nucleus,
      and is phosphorylated similar to the wild-type growth factor. This suggests that
      FGF-2 mitogenic activity may require, in addition to signaling through cell
      surface receptors and nuclear translocation, activation of nuclear targets. We
      have previously shown that, in vitro, FGF-2 directly stimulates the activity of
      the casein kinase 2 (CK2), a ubiquitous serine/threonine kinase involved in the
      control of cell proliferation. We report that, in vivo, FGF-2(WT) transiently
      interacts with CK2 and stimulates its activity in the nucleus during G1-S
      transition in NIH3T3 cells. In contrast, the FGF-2(S117A) mutant fails to
      interact with CK2. Thus, our results show that FGF-2 mitogenic and
      differentiation activities can be dissociated by a single point mutation and that
      CK2 may be a new nuclear effector involved in FGF-2 mitogenic activity.-Bailly,
      K., Soulet, F., Leroy, D., Amalric, F., Bouche, G. Uncoupling of cell
      proliferation and differentiation activities of basic fibroblast growth factor
      (FGF-2).

PMID- 10657990
TI  - Nuclear localization of PAPS synthetase 1: a sulfate activation pathway in the
      nucleus of eukaryotic cells.
AB  - Sulfation is a major modification of many molecules in eukaryotes that is
      dependent on the enzymatic synthesis of an activated sulfate donor, 3'
      phosphoadenosine 5'-phosphosulfate (PAPS). While sulfate activation has long been
      assumed to occur in the cytosol, we show in this study that human PAPS synthetase
      1 (PAPSS1), a bifunctional ATP sulfurylase/adenosine 5'-phosphosulfate (APS)
      kinase enzyme sufficient for PAPS synthesis, accumulates in the nucleus of
      mammalian cells. Nuclear targeting of the enzyme is mediated by its APS kinase
      domain and requires a catalytically dispensable 21 amino acid sequence at the
      amino terminus. Human PAPSS1 and Drosophila melanogaster PAPSS localize to the
      nucleus in yeast and relieve the methionine auxotrophy of ATP sulfurylase- or APS
      kinase-deficient strains, suggesting that PAPSS1 is fully functional in vivo when
      targeted to the nucleus. A second PAPS synthetase gene, designated PAPSS2, has
      recently been described, mutations of which are responsible for abnormal skeletal
      development in human spondyloepimetaphyseal dysplasia and murine brachymorphism.
      We found that PAPSS2, which localizes to the cytoplasm when ectopically expressed
      in mammalian cells, is relocated to the nucleus when coexpressed with PAPSS1.
      Taken together, these results indicate that a sulfation pathway might exist in
      the nucleus of eukaryotic cells. -Besset, S., Vincourt, J.-B., Amalric, F.,
      Girard, J.-P. Nuclear localization of PAPS synthetase 1: a sulfate activation
      pathway in the nucleus of eukaryotic cells.

PMID- 10657991
TI  - Mitochondrial endogenous oxidative damage has been overestimated.
AB  - The oxidatively induced DNA lesion 8-oxo-dG in mitochondrial DNA (mtDNA) is
      commonly used as a marker for oxidative damage to mitochondria, which in turn is
      thought to be a fundamental cause of aging. For years, mitochondrial levels of 8
      oxo-dG were believed to be approximately 10-fold higher in mtDNA than in nuclear
      DNA even in normal, young animals. However, studies in our own and other
      laboratories have shown that this lesion is efficiently repaired. Also,
      mutational consequences specific to 8-oxo-dG (G to T transversions) are rarely
      reported. In the present study, we showed that the levels of damage measured
      using high-pressure liquid chromatography/electrochemical detection and an
      enzymatic/Southern blot assay were comparable. The latter assay does not require
      isolation of mitochondria, and so this assay was then used to determine the level
      of in vivo damage present in rat liver mtDNA both with and without organelle
      isolation. Levels of 8-oxo-dG are approximately threefold higher when measured in
      mtDNA purified from isolated mitochondria than when measured without prior
      mitochondrial isolation. Furthermore, most genomes were free of endogenous enzyme
      sensitive sites (i.e., they did not contain 8-oxo-dG), and only after
      mitochondrial isolation were levels higher in mtDNA than in a nuclear sequence.
      Anson, R. M., Hudson, E., Bohr, V. A. Mitochondrial endogenous oxidative damage
      has been overestimated.

PMID- 10657992
TI  - Enzyme replacement therapy in a mouse model of aspartylglycosaminuria.
AB  - Aspartylglycosaminuria (AGU), the most common lysosomal disorder of glycoprotein
      degradation, is caused by deficient activity of glycosylasparaginase (AGA). AGA
      deficient mice share most of the clinical, biochemical and histopathologic
      characteristics of human AGU disease. In the current study, recombinant human AGA
      administered i.v. to adult AGU mice disappeared from the systemic circulation of
      the animals in two phases predominantly into non-neuronal tissues, which were
      rapidly cleared from storage compound aspartylglucosamine. Even a single AGA
      injection reduced the amount of aspartylglucosamine in the liver and spleen of
      AGU mice by 90% and 80%, respectively. Quantitative biochemical analyses along
      with histological and immunohistochemical studies demonstrated that the
      pathophysiologic characteristics of AGU were effectively corrected in non
      neuronal tissues of AGU mice during 2 wk of AGA therapy. At the same time, AGA
      activity increased to 10% of that in normal brain tissue and the accumulation of
      aspartylglucosamine was reduced by 20% in total brain of the treated animals.
      Immunohistochemical studies suggested that the corrective enzyme was widely
      distributed within the brain tissue. These findings suggest that AGU may be
      correctable by enzyme therapy.-Dunder, U., Kaartinen, V., Valtonen, P., Vaananen,
      E., Kosma, V.-M., Heisterkamp, N., Groffen, J., Mononen, I. Enzyme replacement
      therapy in a mouse model of aspartylglycosaminuria.

PMID- 10657993
TI  - Role of activating protein-1 and high mobility group-I(Y) protein in the
      induction of CD44 gene expression by interleukin-1beta in vascular smooth muscle
      cells.
AB  - CD44 is a multifunctional cell adhesion molecule that participates in
      pathological states such as inflammation and tumorigenesis. CD44 is induced on
      vascular smooth muscle cells after arterial wall injury and may mediate their
      proliferation and migration into the neointima during arteriosclerosis. We have
      demonstrated elsewhere that the proinflammatory cytokine interleukin (IL)-1beta
      up-regulates CD44 mRNA and protein expression in cultured rat aortic smooth
      muscle cells (RASMC) by increasing gene transcription. By transient transfection
      of 5'-deletion constructs into RASMC, we show in the present study that a
      conserved AP-1 site 110 base pairs from the transcription start site of the mouse
      CD44 promoter is important for basal activity. Mutation of the AP-1 site
      significantly reduced induction of promoter activity by IL-1beta, and
      electrophoretic mobility shift assays demonstrated that Fos and c-Jun were
      present in the CD44 AP-1 binding complex after IL-1beta stimulation. In addition,
      cotransfection of the architectural transcription factor high mobility group
      (HMG)-I(Y) protein with c-Fos and c-Jun markedly increased trans-activation of
      the CD44 promoter. Taken together, our studies demonstrate that AP-1 proteins are
      a central regulatory component used by IL-1beta to modulate expression of CD44
      during an inflammatory response in vascular smooth muscle cells and that
      transcription of CD44 by AP-1 proteins is enhanced by HMG-I(Y). -Foster, L. C.,
      Wiesel, P., Huggins, G. S, Panares, R., Chin, M. T., Pellacani, A., Perrella, M.
      A. Role of activating protein-1 and high mobility group-I(Y) protein in the
      induction of CD44 gene expression by interleukin-1beta in vascular smooth muscle
      cells.

PMID- 10657994
TI  - Coordinate modulation of Sp1, NF-kappa B, and p53 in confluent human malignant
      melanoma cells after ionizing radiation.
AB  - Regulation of transcriptional responses in growth-arrested human cells under
      conditions that promote potentially lethal damage repair after ionizing radiation
      (IR) is poorly understood. Sp1/retinoblastoma control protein (RCP) DNA binding
      increased within 30 min and peaked at 2-4 h after IR (450-600 cGy) in confluent
      radioresistant human malignant melanoma (U1-Mel) cells. Increased phosphorylation
      of Sp1 directly corresponded to Sp1/RCP binding and immediate-early gene
      induction, whereas pRb remained hypophosphorylated. Transfection of U1-Mel cells
      with the human papillomavirus E7 gene abrogated Sp1/RCP induction and G(0)/G(1)
      cell cycle checkpoint arrest responses, increased apoptosis and radiosensitivity,
      and augmented genetic instability (i.e., increased polyploidy cells) after IR.
      Increased NF-kappaB DNA binding in U1-Mel cells after IR treatment lasted much
      longer (i.e., >20 h). U1-Mel cells overexpressing dominant-negative IkappaBalpha
      S32/36A mutant protein were significantly more resistant to IR exposure and
      retained both G(2)/M and G(0)/G(1) cell cycle checkpoint responses without
      significant genetic instability (i.e., polyploid cell populations were not
      observed). Nuclear p53 protein levels and DNA binding activity increased only
      after high doses of IR (>1200 cGy). Disruption of p53 responses in U1-Mel cells
      by E6 transfection also abrogated G(0)/G(1) cell cycle checkpoint arrest
      responses and increased polyploidy after IR, but did not alter radiosensitivity.
      These data suggest that abrogation of individual components of this coordinate IR
      activated transcription factor response may lead to divergent alterations in cell
      cycle checkpoints, genomic instability, apoptosis, and survival. Such coordinate
      transcription factor activation in human cancer cells is reminiscent of
      prokaryotic SOS responses, and further elucidation of these events should shed
      light on the initial molecular events in the chromosome instability phenotype.
      Yang, C.-R., Wilson-Van Patten, C., Planchon, S. M., Wuerzberger-Davis, S. M.,
      Davis, T. W., Cuthill, C., Miyamoto, S., Boothman, D. A. Coordinate modulation of
      Sp1, NF-kappa B, and p53 in confluent human malignant melanoma cells after
      ionizing radiation.

PMID- 10657995
TI  - Cytosolic immunization allows the expression of preATF-saporin chimeric toxin in
      eukaryotic cells.
AB  - In this work, we have devised an intracellular immunization strategy for the
      expression in high amounts of ATF-saporin, a targeted chimeric toxin constituted
      by the ATF receptor binding domain of human urokinase and the plant ribosome
      inactivating protein saporin, which has been shown to be highly cytotoxic to
      target cells. This strategy may allow the production of highly toxic secretory
      proteins in eukaryotic cells, avoiding cell suicide caused by autointoxication.
      The procedure consists of equipping host cells with cytosolic neutralizing
      antibodies directed toward the toxic domain of the heterologous polypeptide. We
      show that this intracellular immunization is essential for the synthesis of
      correctly folded, biologically active ATF-SAP in the high amounts needed to
      investigate its in vivo anti-metastatic potential. Such a strategy should be
      generally useful for the production of toxic molecules of therapeutic value whose
      folding and maturation require transit through the eukaryotic secretory pathway.
      Fabbrini, M. S., Carpani, D., Soria, M. R., Ceriotti, A. Cytosolic immunization
      allows the expression of preATF-saporin chimeric toxin in eukaryotic cells.

PMID- 10657996
TI  - Different point mutations in the met oncogene elicit distinct biological
      properties.
AB  - The MET proto-oncogene, encoding the tyrosine kinase receptor for HGF, controls
      genetic programs leading to cell growth, invasiveness, and protection from
      apoptosis. Recently, MET mutations have been identified in hereditary and
      sporadic forms of papillary renal carcinoma (PRC). Introduction of different
      naturally occurring mutations into the MET cDNA results in the acquisition of
      distinct biochemical and biological properties of transfected cells. Some
      mutations result in a high increase in tyrosine kinase activity and confer
      transforming ability in focus forming assays. These mutants hyperactivate the Ras
      signaling pathway. Other mutations are devoid of transforming potential but are
      effective in inducing protection from apoptosis and sustaining anchorage
      independent growth. These Met(PRC) receptors interact more efficiently with the
      intracellular transducer Pi3Kinase. The reported results show that MET(PRC)
      mutations can be responsible for malignant transformation through different
      mechanisms, either by increasing the growth ability of cells or by protecting
      cells from apoptosis and allowing accumulation of other genetic lesions.
      Giordano, S., Maffe, A., Williams, T. A., Artigiani, S., Gual, P., Bardelli, A.,
      Basilico, C., Michieli, P., Comoglio, P. M. Different point mutations in the met
      oncogene elicit distinct biological properties.

PMID- 10657998
TI  - Inhibition of the Rac1 GTPase protects against nonlethal ischemia/reperfusion
      induced necrosis and apoptosis in vivo.
AB  - Reperfusion of ischemic tissue results in the generation of reactive oxygen
      species that contribute to tissue injury. The sources of reactive oxygen species
      in reperfused tissue are not fully characterized. We hypothesized that the small
      GTPase Rac1 mediates the oxidative burst in reperfused tissue and thereby
      contributes to reperfusion injury. In an in vivo model of mouse hepatic
      ischemia/reperfusion injury, recombinant adenoviral expression of a dominant
      negative Rac1 (Rac1N17) completely suppressed the ischemia/reperfusion-induced
      production of reactive oxygen species and lipid peroxides, activation of nuclear
      factor-kappa B, and resulted in a significant reduction of acute liver necrosis.
      Expression of Rac1N17 also suppressed ischemia/reperfusion-induced acute
      apoptosis. The protection offered by Rac1N17 was also evident in knockout mice
      deficient for the gp91phox component of the phagocyte NADPH oxidase. This work
      demonstrates the crucial role of a Rac1-regulated oxidase in mediating the
      production of injurious reactive oxygen species, which contribute to acute
      necrotic and apoptotic cell death induced by ischemia/reperfusion in vivo.
      Targeted inhibition of this oxidase, which is distinct from the phagocyte NADPH
      oxidase, should provide a new avenue for in vivo therapy aimed at protecting
      organs at risk from ischemia/reperfusion injury.-Ozaki, M., Deshpande, S. S.,
      Angkeow, P., Bellan, J., Lowenstein, C. J., Dinauer, M. C., Goldschmidt-Clermont,
      P. J., Irani, K. Inhibition of the Rac1 GTPase protects against nonlethal
      ischemia/reperfusion-induced necrosis and apoptosis in vivo.

PMID- 10657997
TI  - In situ detection of AP sites and DNA strand breaks bearing 3'-phosphate termini
      in ischemic mouse brain.
AB  - Our aims were to examine whether oxidative DNA damage was elevated in brain cells
      of male C57BL/6 mice after oxidative stress, and to determine whether neuronal
      nitric oxide synthase (nNOS) was involved in such damage. Oxidative stress was
      induced by occluding both common carotid arteries for 90 min, followed by
      reperfusion. Escherichia coli exonuclease III (Exo III) removes apyrimidinic or
      apurinic (AP) sites and 3'-phosphate termini in single-strand breaks, and
      converts these lesions to 3'OH termini. These ExoIII-sensitive sites (EXOSS) can
      then be postlabeled using digoxigenin-11-dUTP and Klenow DNA polymerase-I, and
      detected using fluorescein isothiocyanate-IgG against digoxigenin. Compared with
      the non-ischemia controls, the density of EXOSS-positive cells was elevated at
      least 20-fold (P < 0.01) at 15 min of reperfusion, and remained elevated for
      another 30 min. EXOSS mainly occurred in the cell nuclei of the astrocytes and
      neurons. Signs of cell death were detected at 24 h of reperfusion and occurred
      mostly in the neurons. Both DNA damage and cell death in the cerebral cortical
      neurons were abolished by treatment with 3-bromo-7-nitroindazole (30 mg/kg,
      intraperitoneal), which specifically inhibited nNOS. Our results suggest that
      nNOS, its activator (calcium), and peroxynitrite exacerbate oxidative DNA damage
      after brain ischemia.-Huang, D., Shenoy, A., Cui, J., Huang, W., Liu, P. In situ
      detection of AP sites and DNA strand breaks bearing 3'-phosphate termini in
      ischemic mouse brain.

PMID- 10657999
TI  - Hypoxic depression of circadian rhythms in adult rats.
AB  - Because the circadian rhythms of oxygen consumption (VO(2)) and body temperature
      (T(b)) could be contributed to by differences in thermogenesis and because
      hypoxia depresses thermogenesis in its various forms, we tested the hypothesis
      that hypoxia blunts the normal daily oscillations in VO(2) and T(b). Adult rats
      were instrumented for measurements of T(b) and activity by telemetry; VO(2) was
      measured by an open-flow method. Animals were exposed to normoxia (21% O(2)),
      hypoxia (10.5% O(2)), and normoxia again, each 1 wk in duration, in either a
      12:12-h light-dark cycle ("synchronized") or constant light ("free running"). In
      this latter case, the period of the cycle was approximately 25 h. In synchronized
      conditions, hypoxia almost eliminated the T(b) circadian oscillation, because of
      the blunting of the T(b) rise during the dark phase. On return to normoxia, T(b)
      rapidly increased toward the maximum normoxic values, and the normal cycle was
      then reestablished. In hypoxia, the amplitude of the activity and VO(2)
      oscillations averaged, respectively, 37 and 56% of normoxia. In free-running
      conditions, on return to normoxia the rhythm was reestablished at the expected
      phase of the cycle. Hence, the action of hypoxia was not on the clock itself but
      probably at the hypothalamic centers of thermoregulation. Hyperoxia (40% O(2)) or
      hypercapnia (3% CO(2)) had no significant effects on circadian oscillations,
      indicating that the effects of hypoxia did not reflect an undifferentiated
      response to changes in environmental gases. Modifications of the metabolism and
      T(b) rhythms during hypoxia could be at the origin of sleep disturbances in
      cardiorespiratory patients and at high altitude.

PMID- 10658000
TI  - Human calf microvascular compliance measured by near-infrared spectroscopy.
AB  - The purpose of this study is to develop a new method for the measurement in
      humans of the compliance of the microvascular superficial venous system of the
      lower limb by near-infrared spectroscopy (NIRS). This method is complementary to
      strain-gauge plethysmography, which does not allow compliance between deep and
      superficial venous or between venous and arterial compartments to be
      distinguished. In practice, hydrostatic pressure (P) changes were induced in a
      calf region of interest by head-up tilt of the subject from alpha = -10 to 75
      degrees. For P < or = 24 mmHg, the measured compliance [0.086 +/- 0.005 (SD) ml.
      l(-1). mmHg(-1)] based on NIRS data of total, deoxygenated, and oxygenated
      hemoglobin, reflects essentially that of the superficial venous system. For P >
      or = 24 mmHg, no distinction can be made between arterial and venous volumes
      changes. However, by following the changes in oxy- and deoxyhemoglobin in the P
      range -16 to 100 mmHg, it appears to be possible to assess the characteristics of
      the vasomotor response of the arteriolar system.

PMID- 10658001
TI  - Effects of primary resuscitation from shock on distribution of myocardial blood
      flow.
AB  - Hemorrhagic shock alters heterogeneity of regional myocardial perfusion (RMP) in
      the presence of critical coronary stenosis in pigs. Conventional resuscitation
      has failed to reverse these effects. We hypothesized that improvement of the
      resuscitation regime would lead to restoration of RMP heterogeneity. Diaspirin
      cross-linked hemoglobin (10 g/dl; DCLHb) and human serum albumin (8.0 g/dl; HSA)
      were used. After baseline, a branch of the left coronary artery was stenosed;
      thereafter, hemorrhagic shock was induced. Resuscitation was performed with
      either DCLHb or HSA. At baseline, the fractcal dimension (D) of subendocardial
      myocardium was 1.31 +/- 0.083 (HSA) and 1.35 +/- 0.106 (DCLHb) (mean +/- SD).
      Coronary stenosis increased subendocardial D slightly but consistently only in
      the DCLHb group (1.39 +/- 0.104; P < 0.05). Shock reduced subendocardial D: 1.21
      +/- 0.093 (HSA; P = 0.10), 1.25 +/- 0.092 (DCLHb; P < 0.05). Administration of
      DCLHb increased subendocardial D in 7 of 10 animals (1.31 +/- 0.097; P = 0.066).
      HSA was ineffective in this respect. DCLHb infusion restored arterial pressure
      and increased cardiac index (CI) to 80% of baseline values. Administration of HSA
      left animals hypotensive (69 mmHg) and increased CI to 122% of the average
      baseline value. Shock-induced disturbances of the distribution of RMP were
      improved by administration of DCLHb but not by HSA.

PMID- 10658002
TI  - An oral essential amino acid-carbohydrate supplement enhances muscle protein
      anabolism after resistance exercise.
AB  - This study was designed to determine the response of muscle protein to the bolus
      ingestion of a drink containing essential amino acids and carbohydrate after
      resistance exercise. Six subjects (3 men, 3 women) randomly consumed a treatment
      drink (6 g essential amino acids, 35 g sucrose) or a flavored placebo drink 1 h
      or 3 h after a bout of resistance exercise on two separate occasions. We used a
      three-compartment model for determination of leg muscle protein kinetics. The
      model involves the infusion of ring-(2)H(5)-phenylalanine, femoral arterial and
      venous blood sampling, and muscle biopsies. Phenylalanine net balance and muscle
      protein synthesis were significantly increased above the predrink and
      corresponding placebo value (P < 0.05) when the drink was taken 1 or 3 h after
      exercise but not when the placebo was ingested at 1 or 3 h. The response to the
      amino acid-carbohydrate drink produced similar anabolic responses at 1 and 3 h.
      Muscle protein breakdown did not change in response to the drink. We conclude
      that essential amino acids with carbohydrates stimulate muscle protein anabolism
      by increasing muscle protein synthesis when ingested 1 or 3 h after resistance
      exercise.

PMID- 10658003
TI  - Modulation of arterial baroreflex control of heart rate by skin cooling and
      heating in humans.
AB  - The purpose of this study was to examine the effects of skin cooling and heating
      on the heart rate (HR) control by the arterial baroreflex in humans. The subjects
      were 15 healthy men who underwent whole body thermal stress (esophageal
      temperatures, approximately 36.8 and approximately 37.0 degrees C; mean skin
      temperatures, approximately 26.4 and approximately 37.7 degrees C, in skin
      cooling and heating, respectively) produced by a cool or hot water-perfused suit
      during supine rest. The overall arterial baroreflex sensitivity in the HR control
      was calculated from spontaneous changes in beat-to-beat arterial pressure and HR
      during normothermic control and thermal stress periods. The carotid baroreflex
      sensitivity was evaluated from the maximum slope of the HR response to changes in
      carotid distending pressure, calculated as mean arterial pressure minus neck
      pressure. The overall arterial baroreflex sensitivity at existing arterial
      pressure increased during cooling (-1.32 +/- 0.25 vs. -2.13 +/- 0.20 beats. min(
      1). mmHg(-1) in the control and cooling periods, respectively, P < 0.05), whereas
      it did not change significantly during heating (-1.39 +/- 0. 23 vs. -1.40 +/-
      0.15 beats. min(-1). mmHg(-1) in the control and heating periods, respectively).
      Neither the cool nor heat loadings altered the carotid baroreflex sensitivity in
      the HR control. These results suggest that the sensitivity of HR control by the
      extracarotid (presumably aortic) baroreflex was augmented by whole body skin
      cooling, whereas the sensitivities of HR control by arterial baroreflex remain
      unchanged during mild whole body heating in humans.

PMID- 10658004
TI  - Effects of ventilation on the surfactant system in sepsis-induced lung injury.
AB  - The present study examined the effects of mechanical ventilation, with or without
      positive end-expiratory pressure (PEEP), on the alveolar surfactant system in an
      animal model of sepsis-induced lung injury. Septic animals ventilated without
      PEEP had a significant deterioration in oxygenation compared with preventilated
      values (arterial PO(2)/inspired O(2) fraction 316 +/- 16 vs. 151 +/- 14 Torr; P <
      0.05). This was associated with a significantly lower percentage of the
      functional large aggregates (59 +/- 3 vs. 72 +/- 4%) along with a significantly
      reduced function (minimum surface tension 17.7 +/- 1.8 vs. 11.8 +/- 3.8 mN/m)
      compared with nonventilated septic animals (P < 0.05). Sham animals similarly
      ventilated without PEEP maintained oxygenation, percent large aggregates and
      surfactant function. With the addition of PEEP, the deterioration in oxygenation
      was not observed in the septic animals and was associated with no alterations in
      the surfactant system. We conclude that animals with sepsis-induced lung injury
      are more susceptible to the harmful effects of mechanical ventilation,
      specifically lung collapse and reopening, and that alterations in alveolar
      surfactant may contribute to the development of lung dysfunction.

PMID- 10658005
TI  - Effects of an androgenic steroid on exercise-induced cardiac remodeling in rats.
AB  - Habitual exercise results in a rightward shift in left ventricular end diastolic
      (LVED) pressure-volume or internal dimension (P-D) relationships [left
      ventricular (LV) remodeling]. However, exercise-mediated LV hypertrophy (LVH)
      produces an increased LV relative wall thickness [ratio (h/r) of wall thickness
      (h) to internal radius (r)] and hence a decrement in diastolic wall stress
      despite LV remodeling. In this study, the effect of chronic administration of an
      androgenic steroid on exercise-induced LV remodeling and h/r was examined in
      rats. Habitual exercise on voluntary running wheels resulted in LVH and a
      rightward shift in the LVED P-D relationships. However, LVH was sufficient to
      increase LVED h/r. Androgenic steroid administration to exercised rats, without
      influencing the development of exercise-induced LVH, produced a further rightward
      shift in the LVED P-D relationship associated with an increased diameter
      intercept. As a consequence, LVED h/r was reduced to control values. The steroid
      mediated effects were not associated with alterations in either the quantity or
      quality of LV collagen. In conclusion, high-dose androgenic steroid
      administration alters exercise-induced LV remodeling and subsequently reduces the
      beneficial effect of physiological LVH on LV h/r.

PMID- 10658006
TI  - Dexamethasone and thyroid hormone pretreatment upregulate alveolar epithelial
      fluid clearance in adult rats.
AB  - The in vivo effect of 48-h glucocorticoid and thyroid hormone 3,3', 5-triiodine-L
      thyronine (T(3)) pretreatment on alveolar epithelial fluid transport was studied
      in adult rats. An isosmolar 5% albumin solution was instilled, and alveolar fluid
      clearance was studied for 1 h. Compared with controls, dexamethasone pretreatment
      increased alveolar fluid clearance by 80%. T(3) pretreatment stimulated alveolar
      fluid clearance by 65%, and dexamethasone and T(3) had additive effects (132%).
      Propranolol did not inhibit alveolar fluid clearance in either group, indicating
      that stimulation was not secondary to endogenous beta-adrenergic stimulation.
      With the use of bromodeoxyuridine in vivo labeling, there was no evidence of cell
      proliferation. Alveolar fluid clearance was partially inhibited by amiloride in
      all groups. Fractional amiloride inhibition was greater in dexamethasone- and
      dexamethasone-plus-T(3)-pretreated rats than in control animals, but less in T(3)
      pretreated rats. In summary, pretreatment with dexamethasone, T(3), or both in
      combination upregulate in vivo alveolar fluid clearance similarly to short-term
      beta-adrenergic stimulation. The effects are mediated partly by increased
      amiloride-sensitive Na(+) transport, because the stimulated alveolar fluid
      clearance was more amiloride sensitive than in control rats. These observations
      may have clinical relevance because glucocorticoid therapy is commonly used with
      acute lung injury.

PMID- 10658007
TI  - Bronchial vasodilation evoked by increased lower airway osmolarity in dogs.
AB  - Hyperosmotic saline solutions stimulate lower airway sensory nerves. To determine
      whether airway hyperosmolarity evokes neurally mediated changes in bronchial
      artery blood flow (Qbr), we measured the effect of injection of small volumes (1
      ml) of hyperosmotic saline into a right lobar bronchus on Qbr of anesthetized,
      artificially ventilated dogs. In 14 dogs, hyperosmotic saline (1,200 and 2,400
      mmol/l) increased Qbr by 58 +/- 12 (SE) and 118 +/- 12%, respectively, from a
      baseline of 8 +/- 2 ml/min. Qbr increased within 6-8 s of the injections, peaked
      at 20 s, and returned to control over 2-3 min. Isosmotic saline had minimal
      effects. In contrast, hyperosmotic saline decreased flow in an intercostal artery
      that did not supply the airways. The bronchial vasodilation was decreased by 72
      +/- 11% after combined blockade of alpha-adrenoceptors and muscarinic cholinergic
      receptors and by 66 +/- 6% when the cervical vagus nerves were cooled to 0
      degrees C. Blockade of H(1) and H(2) histamine receptors did not reduce the
      nonvagal response. We conclude that hyperosmolarity of the lower airways evokes
      bronchial vasodilation by both a centrally mediated reflex that includes
      cholinergic and adrenergic efferent pathways and by unidentified local
      mechanisms.

PMID- 10658008
TI  - Microvascular and myocardial contractile responses to ischemia: influence of
      exercise training.
AB  - We hypothesized that exercise training preserves endothelium-dependent
      relaxation, lessens receptor-mediated constriction of coronary resistance
      arteries, and reduces myocardial contractile dysfunction in response to ischemia.
      After 10 wk of treadmill running or cage confinement, regional and global indexes
      of left ventricular contractile function were not different between trained and
      sedentary animals in response to three 15-min periods of ischemia (long-term; n =
      17), one 5-min bout of ischemia (short-term; n = 18), or no ischemia (sham
      operated; n = 24). Subsequently, coronary resistance vessels ( approximately 106
      +/- 4 microm ID) were isolated and studied using wire myographs. Maximal ACh
      evoked relaxation was approximately 25, 40, and 60% of KCl-induced
      preconstriction after the long-term, short-term, and sham-operated protocols,
      respectively, and was similar between groups. Maximal sodium nitroprusside-evoked
      relaxation also was similar between groups among all protocols, and
      vasoconstrictor responses to endothelin-1 and U-46619 were not different in
      trained and sedentary rats after short-term ischemia or sham operation. We did
      observe that, after long-term ischemia, maximal tension development in response
      to endothelin-1 and U-46619 was blunted (P < 0.05) in trained animals by
      approximately 70 and approximately 160%, respectively. These results support our
      hypothesis that exercise training lessens receptor-mediated vasoconstriction of
      coronary resistance vessels after ischemia and reperfusion. However, training did
      not preserve endothelial function of coronary resistance vessels, or myocardial
      contractile function, after ischemia and reperfusion.

PMID- 10658009
TI  - Chronic exercise training improves ACh-induced vasorelaxation in pulmonary
      arteries of pigs.
AB  - We hypothesized that exercise training would lead to enhanced endothelium
      dependent vasodilation in porcine pulmonary arteries. Pulmonary artery rings (2-
      to 3-mm OD) were obtained from female Yucatan miniature swine with surgically
      induced coronary artery occlusion (ameroid occluder). Exercise training was
      performed for 16 wk, and vasomotor responses were studied by using standard
      isometric techniques. Contractile responses to 80 mM KCl, isosmotic KCl (10-100
      mM), and norepinephrine (10(-8) to 10(-4) M) did not differ between sedentary
      (Sed) and exercise-trained (Ex) pigs. Relaxation was assessed to endothelium
      dependent and endothelium-independent vasodilators after norepinephrine
      contraction. Pulmonary arteries of Ex pigs exhibited greater maximal relaxation
      to ACh (61.9 +/- 3.5%) than did those of Sed pigs (52.3 +/- 3.9%; P < 0.05).
      Endothelium-independent relaxation to sodium nitroprusside did not differ.
      Inhibition of nitric oxide synthase significantly decreased acetylcholine-induced
      relaxation, with greater inhibition in arteries from Ex pigs (P < 0.05).
      Inhibition of cyclooxygenase enhanced relaxation to acetylcholine in arteries
      from Sed pigs. We conclude that exercise training enhances endothelium-dependent
      (ACh-mediated) vasorelaxation in pulmonary arteries by mechanisms of increased
      reliance on nitric oxide and reduced production of a prostanoid constrictor.

PMID- 10658010
TI  - Measuring leg muscle and fat mass in humans: comparison of CT and dual-energy X
      ray absorptiometry.
AB  - Dual-energy X-ray absorptiometry (DEXA) is reported to be inferior to computed
      tomography (CT) to measure changes in appendicular soft tissue composition. We
      compared CT- and DEXA-measured thigh muscle and fat mass to evaluate the random
      and systematic discrepancies between these two methods. Thigh skeletal muscle
      area (single-slice CT) was suboptimally (r(2) = 0.74, P < 0.0001) related to DEXA
      measured thigh fat-free mass (FFM). In contrast, thigh muscle and adipose tissue
      volumes (multislice CT) were highly related to DEXA-measured thigh FFM and fat
      (both r(2) = 0.96, P < 0.0001). DEXA-measured leg fat was significantly less than
      multislice-CT-measured leg adipose tissue volume, whereas multislice-CT-measured
      leg muscle mass was less (P < 0.0001) than DEXA-measured leg FFM. The systematic
      discrepancies between the two approaches were consistent with the 10-15% nonfat
      components of adipose tissue. In conclusion, CT and DEXA measures of appendicular
      soft tissue are highly related. Systematic differences between DEXA and CT likely
      relate to the underlying principles of the techniques.

PMID- 10658011
TI  - Gender differences in glucoregulatory responses to intense exercise.
AB  - We compared glucoregulatory responses to intense exercise (14 min at 88% maximum
      O(2) uptake) between genders (16 men, 12 women). Analysis of covariance of
      maximum O(2) uptake showed no gender effect, with 82% of variance due to fat-free
      mass (FFM). Glycemia rose comparably during exercise but was higher in women
      during recovery (P = 0.02). Glucose production [rate of appearance (R(a)); in
      mg/min] increased markedly in both; stepwise multiple regression and analysis of
      covariance of R(a) (peak and incremental area under the curve) showed no effect
      of gender, body weight, or FFM. Glucose uptake [rate of disappearance (R(d))]
      increased less than R(a) and slower in women. R(d) area under the curve related
      to FFM (P = 0.01) but not gender or body weight. Norepinephrine and epinephrine
      responses (13-18x baseline) were the same and correlated significantly with R(a).
      Exercise insulin and glucagon changes were slight, but postexercise
      hyperinsulinemia was greater in women (P = 0.018), along with higher R(d).
      Therefore, intense exercise glucoregulation is qualitatively similar between
      genders, with a "feed-forward" regulation of R(a) (consistent with catecholamine
      mediation). However, women have a lesser R(d) response, related to FFM. This
      combination leads to greater recovery-period hyperglycemia and hyperinsulinemia.

PMID- 10658012
TI  - Effects of atropine and L-NAME on cutaneous blood flow during body heating in
      humans.
AB  - We sought to investigate further the roles of sweating, ACh spillover, and nitric
      oxide (NO) in the neurally mediated cutaneous vasodilation during body heating in
      humans. Six subjects were heated with a water-perfused suit while cutaneous blood
      flow was measured with a laser-Doppler flowmeter. After a rise in core
      temperature (1. 0 +/- 0.1 degrees C) and the establishment of cutaneous
      vasodilation, atropine and subsequently the NO synthase inhibitor N(G)-nitro-L
      arginine methyl ester (L-NAME) were given to the forearm via a brachial artery
      catheter. After atropine infusion, cutaneous vascular conductance (CVC) remained
      constant in five of six subjects, whereas L-NAME administration blunted the rise
      in CVC in three of six subjects. A subsequent set of studies using intradermal
      microdialysis probes to selectively deliver drugs into forearm skin confirmed
      that atropine did not affect CVC. However, perfusion of L-NAME resulted in a
      significant decrease in CVC (37 +/- 4%, P < 0.05). The results indicate that
      neither sweating nor NO release via muscarinic receptor activation is essential
      to sustain cutaneous dilation during heating in humans.

PMID- 10658013
TI  - Substrate profile in rat soleus muscle fibers after hindlimb unloading and
      fatigue.
AB  - Limb muscles from rats flown in space and after hindlimb unloading (HU) show an
      increased fatigability, and spaceflight has been shown to result in a reduced
      ability to oxidize fatty acids. The purpose of this investigation was to
      determine the effects of HU on the substrate content in fast- and slow-twitch
      fibers and to assess the substrate utilization patterns in single slow type I
      fibers isolated from control and HU animals. A second objective was to assess
      whether HU altered the ability of the heart or limb muscle to oxidize pyruvate or
      palmitate. After 2 wk of HU, single fibers were isolated from the freeze-dried
      soleus and gastrocnemius muscles. HU increased the glycogen content in all fiber
      types, and it increased lactate, ATP, and phosphocreatine in the slow type I
      fiber. After HU, the type I fiber substrate profile was shifted toward that
      observed in fast fibers. For example, fiber glycogen increased from 179 +/- 16 to
      285 +/- 25 mmol/kg dry wt, which approached the 308 +/- 23 mmol/kg dry wt content
      observed in the post-HU type IIa fiber. With contractile activity, the type I
      fiber from the HU animal showed a greater utilization of glycogen and
      accumulation of lactate compared with the control type I fiber. HU had no effect
      on the ability of crude homogenate or mitochondria fractions from the soleus or
      gastrocnemius to oxidize pyruvate or palmitate. The increased fatigability after
      HU may have resulted from an elevated glycolysis producing an increased cell
      lactate and a decreased pH.

PMID- 10658014
TI  - Myosin heavy chain composition of skeletal muscles in young rats growing under
      hypobaric hypoxia conditions.
AB  - This study investigated the effects of voluntary wheel running on the myosin
      heavy chain (MHC) composition of the soleus (Sol) and plantaris muscles (Pla) in
      rats developing under hypobaric choronic hypoxia (CH) conditions during 4 wk in
      comparison with those of control rats maintained under local barometric pressure
      conditions (C) or rats pair-fed an equivalent quantity of food to that consumed
      by CH animals (PF). Compared with C animals, sedentary rats subjected to CH
      conditions showed a significant decrease in type I MHC in Sol (-12%, P < 0.01).
      Although strongly decreased under hypoxia, spontaneous running activity increased
      the expression of type I MHC (P < 0.01) so that no difference in the MHC profile
      of Sol was shown between CH active and C active rats. The MHC distribution in Sol
      of PF rats was not significantly different from that found in C animals. CH
      resulted in a significant decrease in type I (P < 0.01) and type IIA (P < 0.005)
      MHC, concomitant with an increase in type IIB MHC in Pla (P < 0.001), compared
      with C and PF animals. In contrast to results in Sol muscle, this slow-to-fast
      shift in the MHC profile was unaffected by spontaneous running activity. These
      results suggest that running exercise suppresses the hypoxia-induced slow-to-fast
      transition in the MHC expression in Sol muscles only. The hypoxia-induced
      decrease in food intake has no major influence on MHC expression in developing
      rats.

PMID- 10658015
TI  - Effect of muscle mass and intensity of isometric contraction on heart rate.
AB  - The purpose of this study was to determine the effect of muscle mass and the
      level of force on the contraction-induced rise in heart rate. We conducted an
      experimental study in a sample of 28 healthy men between 20 and 30 yr of age
      (power: 95%, alpha: 5%). Smokers, obese subjects, and those who performed regular
      physical activity over a certain amount of energetic expenditure were excluded
      from the study. The participants exerted two types of isometric contractions:
      handgrip and turning a 40-cm-diameter wheel. Both were sustained to exhaustion at
      20 and 50% of maximal force. Twenty-five subjects finished the experiment. Heart
      rate increased a mean of 15.1 beats/min [95% confidence interval (CI): 5.5-24.6]
      from 20 to 50% handgrip contractions, and 20.7 beats/min (95% CI: 11.9-29.5) from
      20 to 50% wheel-turn contractions. Heart rate also increased a mean of 13.3
      beats/min (95% CI: 10.4-16.1) from handgrip to wheel-turn contractions at 20%
      maximal force, and 18.9 beats/min (95% CI: 9. 8-28.0) from handgrip to wheel-turn
      contractions at 50% maximal force. We conclude that the magnitude of the heart
      rate increase during isometric exercise is related to the intensity of the
      contraction and the mass of the contracted muscle.

PMID- 10658016
TI  - An investigation of pulmonary surfactant physicochemical behavior under airway
      reopening conditions.
AB  - Airway reopening mechanics depend on surfactant physicochemical properties.
      During reopening, the progression of a finger of air down an airway creates an
      interface that is continually expanding into the bulk fluid. Conventional
      surfactometers are not capable of evaluating physicochemical behavior under these
      conditions. To study these aspects, we investigated the pressure required to push
      a semi-infinite bubble of air down a fluid-filled cylindrical capillary of radius
      R. The ionic surfactant SDS and pulmonary surfactant analogs L-alpha
      dipalmitoylphosphatidylcholine and Infasurf were investigated. We found that the
      nonequilibrium adsorption of surfactant can create a large nonequilibrium normal
      stress and a surface shear stress (Marangoni stress) that increase the bubble
      pressure. The nonphysiological surfactant SDS is capable of eliminating the
      normal stress and partially reducing the Marangoni stress. The main component of
      pulmonary surfactant, L-alpha-dipalmitoylphosphatidylcholine, is not capable of
      reducing either stress, demonstrating slow adsorption properties. The clinically
      relevant surfactant Infasurf is shown to have intermediate adsorption properties,
      such that the nonequilibrium normal stress is reduced but the Marangoni stress
      remains large. Infasurf's behavior suggests that an optimal surfactant solution
      will have sorption properties that are fast enough to reduce the reopening
      pressure that may damage airway wall epithelial cells but slow enough to maintain
      the Marangoni stress that enhances airway stability.

PMID- 10658017
TI  - Vascular hyporesponsiveness in simulated microgravity: role of nitric oxide
      dependent mechanisms.
AB  - Simulated microgravity depresses the ability of arteries to constrict to
      norepinephrine (NE). In the present study the role of nitric oxide-dependent
      mechanisms on the vascular hyporesponsiveness to NE was investigated in
      peripheral arteries of the rat after 20 days of hindlimb unweighting (HU). Blood
      vessels from control rats and rats subjected to HU (HU rats) were cut into 3-mm
      rings and mounted in tissue baths for the measurement of isometric contraction.
      Mechanical removal of the endothelium from carotid artery rings, but not from
      aorta or femoral artery rings, of HU rats restored the contractile response to NE
      toward control. A 10-fold increase in sensitivity to ACh was observed in
      phenylephrine-precontracted carotid artery rings from HU rats. In the presence of
      the nitric oxide synthase (NOS) substrate L-arginine, the inducible NOS inhibitor
      aminoguanidine (AG) restored the contractile responses to NE to control levels in
      the femoral, but not carotid, artery rings from HU rats. In vivo blood pressure
      measurements revealed that the peak blood pressure increase to NE was
      significantly greater in the control than in the HU rats, but that to AG was less
      than one-half in control compared with HU rats. These results indicate that the
      endothelial vasodilator mechanisms may be upregulated in the carotid artery,
      whereas the inducible NOS expression/activity may be increased in the femoral
      artery from HU rats. These HU-mediated changes could produce a sustained
      elevation of vascular nitric oxide levels that, in turn, could contribute to the
      vascular hyporesponsiveness to NE.

PMID- 10658018
TI  - Apoptosis in microvascular endothelial cells of perfused rabbit lungs with acute
      hydrostatic edema.
AB  - We test the hypothesis that microvascular endothelial cells may undergo apoptosis
      in response to acute pulmonary venous hypertension. The isolated rabbit lungs
      were perfused in situ for 4 h with left atrial pressure of 0, 10, or 20 mmHg at a
      constant blood flow. Edema formation was monitored by lung weight gain. To assay
      for apoptosis, we performed agarose gel electrophoresis of DNA, in situ nick end
      labeling of DNA strand breaks, and electron microscopy. We also examined the
      levels of expression of Bcl-2, a suppressor of apoptosis, in microvascular
      endothelial cells using an immunohistochemical technique. In a vascular pressure
      dependent fashion, we found apoptosis in endothelial cells of alveolar septal
      capillaries, as well as expression of Bcl-2 in arteriolar and venular endothelial
      cells. We conclude that acute pulmonary venous hypertension induces apoptosis in
      capillary endothelial cells but not in arteriolar and venular endothelial cells,
      suggesting that microvascular endothelial cell apoptosis is dependent on the
      levels of Bcl-2 expression and influences the formation or resolution of acute
      hydrostatic lung edema.

PMID- 10658019
TI  - Airway narrowing and internal structural constraints.
AB  - A computer model has been developed to simulate the movement restriction in the
      lamina propria-submucosa (L-S) layer (sandwiched by the basement membrane and the
      muscle layer) in a cartilage-free airway due to constriction of the smooth muscle
      layer. It is assumed that the basement membrane is inextensible; therefore, in
      the two-dimensional simulation, the perimeter outlining the membrane is a
      constant whether the airway is constricted or dilated. The cross-sectional area
      of the L-S layer is also assumed to be constant during the simulated airway
      narrowing. Folding of the mucosal membrane in constricted airways is assumed to
      be a consequence of the L-S area conservation and also due to tethering between
      the basement membrane and the muscle layer. The number of tethers determines the
      number of folds. The simulation indicates that the pressure in the L-S layer
      resulting from movement restriction can be a major force opposing muscle
      contraction and that the maximum shortening of the muscle layer is inversely
      proportional to the number of tethers (or folds) and the L-S layer thickness.

PMID- 10658020
TI  - Enhanced inotropic response to dobutamine in strength-trained subjects with left
      ventricular hypertrophy.
AB  - To determine whether strength-trained individuals with physiological concentric
      left ventricular (LV) hypertrophy exhibit enhanced inotropic responses to
      catecholamines, we studied 11 bodybuilders, aged 33.0 +/- 2 (SE) yr old, and 10
      sedentary healthy subjects, aged 31.3 +/- 2.4 yr old, at baseline and during
      infusion of incremental doses of dobutamine after atropine. The bodybuilders had
      larger LV mass, posterior wall and septal wall thicknesses, and wall thickness-to
      radius ratio, assessed with two-dimensional echocardiography, than did the
      sedentary subjects. There was a significant correlation between LV mass and lean
      body mass irrespective of training status. Baseline LV fractional shortening was
      similar in the two groups. There was a greater inotropic response to dobutamine
      in the strength-trained individuals, as evidenced by a steeper slope of the
      fractional shortening-end-systolic wall stress relationship with a higher y-axis
      intercept and by a shallower end-systolic wall stress-end systolic diameter
      relationship without changes in end-diastolic diameter. The heart rate response
      to dobutamine was attenuated in the strength-trained athletes. There was a
      significant correlation (r = 0.604, P < 0.05) between the inotropic sensitivity
      to dobutamine and LV mass normalized for lean body mass in the bodybuilders. The
      data suggest that concentric LV physiological hypertrophy in the resistance
      trained individuals is associated with enhanced inotropic but not chronotropic
      responses to catecholamines.

PMID- 10658021
TI  - NaHCO(3) and KHCO(3) ingestion rapidly increases renal electrolyte excretion in
      humans.
AB  - This paper describes and quantifies acute responses of the kidneys in correcting
      plasma volume, acid-base, and ion disturbances resulting from NaHCO(3) and
      KHCO(3) ingestion. Renal excretion of ions and water was studied in five men
      after ingestion of 3.57 mmol/kg body mass of sodium bicarbonate (NaHCO(3)) and,
      in a separate trial, potassium bicarbonate (KHCO(3)). Subjects had a Foley
      catheter inserted into the bladder and indwelling catheters placed into an
      antecubital vein and a brachial artery. Blood and urine were sampled in the 30
      min period before, the 60-min period during, and the 210-min period after
      ingestion of the solutions. NaHCO(3) ingestion resulted in a rapid, transient
      diuresis and natriuresis. Cumulative urine output was 44 +/- 11% of ingested
      volume, resulting in a 555 +/- 119 ml increase in total body water at the end of
      the experiment. The cumulative increase (above basal levels) in renal Na(+)
      excretion accounted for 24 +/- 2% of ingested Na(+). In the KHCO(3) trial,
      arterial plasma K(+) concentration rapidly increased from 4.25 +/- 0.10 to a peak
      of 7.17 +/- 0.13 meq/l 140 min after the beginning of ingestion. This increase
      resulted in a pronounced, transient diuresis, with cumulative urine output at 270
      min similar to the volume ingested, natriuresis, and a pronounced kaliuresis that
      was maintained until the end of the experiment. Cumulative (above basal) renal
      K(+) excretion at 270 min accounted for 26 +/- 5% of ingested K(+). The kidneys
      were important in mediating rapid corrections of substantial portions of the
      fluid and electrolyte disturbances resulting from ingestion of KHCO(3) and
      NaHCO(3) solutions.

PMID- 10658022
TI  - Genomic scan for maximal oxygen uptake and its response to training in the
      HERITAGE Family Study.
AB  - This study aimed to identify human genomic regions that are linked to maximal
      oxygen uptake (VO(2 max)) in sedentary individuals or to the responsiveness of
      VO(2 max) to a standardized endurance training program. The results of a genomic
      scan based on 289 polymorphic markers covering all 22 pairs of autosomes
      performed on the Caucasian families of the HERITAGE Family Study are presented.
      The mean spacing of the markers was 11 cM, and a total of 99 families and 415
      pairs of siblings were available for the study. VO(2 max) in the sedentary state
      was adjusted for the effects of age, sex, body mass, fat mass, and fat-free mass,
      whereas the VO(2 max) response was adjusted for age and baseline level of the
      phenotype. Two analytic strategies were used: a single-point linkage procedure
      using all available pairs of siblings (SIBPAL) and a multipoint variance
      components approach using all the family data (SEGPATH). Results indicate that
      linkages at P values of 0.01 and better are observed with markers on 4q, 8q, 11p,
      and 14q for VO(2 max) before training and with markers on 1p, 2p, 4q, 6p, and 11p
      for the change in VO(2 max) in response to a 20-wk standardized endurance
      training program. These chromosomal regions harbor many genes that may qualify as
      candidate genes for these quantitative traits. They should be investigated in
      this and other cohorts.

PMID- 10658023
TI  - Structural basis of muscle O(2) diffusing capacity: evidence from muscle function
      in situ.
AB  - Although evidence for muscle O(2) diffusion limitation of maximal O(2) uptake has
      been found in the intact organism and isolated muscle, its relationship to
      diffusion distance has not been examined. Thus we studied six sets of three
      purpose-bred littermate dogs (aged 10-12 mo), with 1 dog per litter allocated to
      each of three groups: control (C), exercise trained for 8 wk (T), or left leg
      immobilized for 3 wk (I). The left gastrocnemius muscle from each animal was
      surgically isolated, pump-perfused, and electrically stimulated to peak O(2)
      uptake at three randomly applied levels of arterial oxygenation [normoxia,
      arterial PO(2) (Pa(O(2))) 77 +/- 2 (SE) Torr; moderate hypoxia, Pa(O(2)): 33 +/-
      1 Torr; and severe hypoxia, Pa(O(2)): 22 +/- 1 Torr]. O(2) delivery (ml. min(-1).
      100 g(-1)) was kept constant among groups for each level of oxygenation, with
      O(2) delivery decreasing with decreasing Pa(O(2)). O(2) extraction (%) was lower
      in I than T or C for each condition, but calculated muscle O(2) diffusing
      capacity (Dmus(O(2))) per 100 grams of muscle was not different among groups.
      After the experiment, the muscle was perfusion fixed in situ, and a sample from
      the midbelly was processed for microscopy. Immobilized muscle showed a 45%
      reduction of muscle fiber cross-sectional area (P < 0.05), and a resulting 59%
      increase in capillary density (P < 0.05) but minimal reduction in capillary-to
      fiber ratio (not significant). In contrast, capillarity was not significantly
      different in T vs. C muscle. The results show that a dramatically increased
      capillary density (and reduced diffusion distance) after short-term
      immobilization does not improve Dmus(O(2)) in heavily working skeletal muscle.

PMID- 10658024
TI  - Decreased thin filament density and length in human atrophic soleus muscle fibers
      after spaceflight.
AB  - Soleus muscle fibers were examined electron microscopically from pre- and
      postflight biopsies of four astronauts orbited for 17 days during the Life and
      Microgravity Sciences Spacelab Mission (June 1996). Myofilament density and
      spacing were normalized to a 2. 4-microm sarcomere length. Thick filament density
      ( approximately 1, 062 filaments/microm(2)) and spacing ( approximately 32.5 nm)
      were unchanged by spaceflight. Preflight thin filament density (2, 976/microm(2))
      decreased significantly (P < 0.01) to 2,215/microm(2) in the overlap A band
      region as a result of a 17% filament loss and a 9% increase in short filaments.
      Normal fibers had 13% short thin filaments. The 26% decrease in thin filaments is
      consistent with preliminary findings of a 14% increase in the myosin-to-actin
      ratio. Lower thin filament density was calculated to increase thick-to-thin
      filament spacing in vivo from 17 to 23 nm. Decreased density is postulated to
      promote earlier cross-bridge detachment and faster contraction velocity. Atrophic
      fibers may be more susceptible to sarcomere reloading damage, because force per
      thin filament is estimated to increase by 23%.

PMID- 10658025
TI  - Contractile and fatigue properties of the rat diaphragm musculature during the
      perinatal period.
AB  - The following two hypotheses regarding diaphragm contractile properties in the
      perinatal rat were tested. First, there is a major transformation of contractile
      and fatigue properties during the period between the inception of inspiratory
      drive transmission in utero and birth. Second, the diaphragm muscle properties
      develop to functionally match changes occurring in phrenic motoneuron
      electrophysiological properties. Muscle force recordings and intracellular
      recordings of end-plate potentials were measured by using phrenic nerve-diaphragm
      muscle in vitro preparations isolated from rats on embryonic day 18 and postnatal
      days 0-1. The following age-dependent changes occurred: 1) twitch contraction and
      half relaxation times decreased approximately two- and threefold, respectively;
      2) the tetanic force levels increased approximately fivefold; 3) the ratio of
      peak twitch force to maximum tetanic force decreased 2.3-fold; 4) the range of
      forces generated by the diaphragm in response to graded nerve stimulation
      increased approximately twofold; 5) the force-frequency curve was shifted to the
      right; and 6) the propensity for neuromuscular transmission failure decreased. In
      conclusion, the diaphragm contractile and phrenic motoneuron repetitive firing
      properties develop in concert so that the full range of potential diaphragm force
      recruitment can be utilized and problems associated with diaphragm fatigue are
      minimized.

PMID- 10658026
TI  - Exercise exacerbates acute mountain sickness at simulated high altitude.
AB  - We hypothesized that exercise would cause greater severity and incidence of acute
      mountain sickness (AMS) in the early hours of exposure to altitude. After passive
      ascent to simulated high altitude in a decompression chamber [barometric pressure
      = 429 Torr, approximately 4,800 m (J. B. West, J. Appl. Physiol. 81: 1850-1854,
      1996)], seven men exercised (Ex) at 50% of their altitude-specific maximal
      workload four times for 30 min in the first 6 h of a 10-h exposure. On another
      day they completed the same protocol but were sedentary (Sed). Measurements
      included an AMS symptom score, resting minute ventilation (VE), pulmonary
      function, arterial oxygen saturation (Sa(O(2))), fluid input, and urine volume.
      Symptoms of AMS were worse in Ex than Sed, with peak AMS scores of 4.4 +/- 1.0
      and 1.3 +/- 0.4 in Ex and Sed, respectively (P < 0.01); but resting VE and
      Sa(O(2)) were not different between trials. However, Sa(O(2)) during the exercise
      bouts in Ex was at 76.3 +/- 1.7%, lower than during either Sed or at rest in Ex
      (81.4 +/- 1.8 and 82.2 +/- 2.6%, respectively, P < 0.01). Fluid intake-urine
      volume shifted to slightly positive values in Ex at 3-6 h (P = 0.06). The
      mechanism(s) responsible for the rise in severity and incidence of AMS in Ex may
      be sought in the observed exercise-induced exaggeration of arterial hypoxemia, in
      the minor fluid shift, or in a combination of these factors.

PMID- 10658027
TI  - Catchlike property of rat diaphragm: subsequent train frequency effects in
      variable-train stimulation.
AB  - A high-frequency burst of pulses at the onset of a subtetanic train of
      stimulation allows skeletal muscle to hold force at a higher level than expected
      from the extra pulses alone because of the catchlike property of muscle. The
      present study tested the hypothesis that the presence and degree of force
      increase induced by a high-frequency burst are strongly modulated by the
      subsequent train frequency. Rat diaphragm muscle strips (studied in vitro at 37
      degrees C) underwent two-, three-, or four-pulse bursts [interpulse interval
      (IPI) of 5 or 10 ms] at the onset of 10- to 50-Hz subtetanic trains. Force was
      quantified during the train with respect to its peak value (F(peak)), mean value
      (F(mean)), and force-time integral (F(area)), and it was compared with that
      produced during subtetanic trains of an equal number of pulses without preceding
      pulse bursts (Diff-F(peak), Diff-F(mean), Diff-F(area)). F(peak) and F(mean)
      increased with two-, three-, and four-pulse bursts, and Diff-F(peak) and Diff
      F(mean) increased progressively with decreasing frequency of the subtetanic
      train. F(area), the best reflection of catchlike force augmentation, was
      increased mainly by the four-pulse bursts with an IPI of 10 ms, and Diff-F(area)
      was maximal at subsequent train frequencies of 15-25 Hz. The use of incorrect
      patterns of burst stimulation could also precipitate F(area) decreases, which
      were observed with the four-pulse, 5-ms IPI paradigm. The time required to reach
      80% of maximal force (T(80%)) became shorter for each of the pulse burst
      stimulation patterns, with maximal reduction of Diff-T(80%) occurring at a
      subsequent train frequency of 20 Hz in all cases. These data indicate that extra
      pulse burst stimulation paradigms need to incorporate the optimal combinations of
      extra-pulse number, IPI, and the frequency of the subsequent subtetanic train to
      take greatest advantage of the catchlike property of muscle.

PMID- 10658028
TI  - Diuretic effect of hypoxia, hypocapnia, and hyperpnea in humans: relation to
      hormones and O(2) chemosensitivity.
AB  - We studied the contributions of hypoxemia, hypocapnia, and hyperpnea to the acute
      hypoxic diuretic response (HDR) in humans and evaluated the role of peripheral
      O(2) chemosensitivity and renal hormones in HDR. Thirteen healthy male subjects
      (age 19-38 yr) were examined after sodium equilibration (intake: 120 mmol/day)
      during 90 min of normoxia (NO), poikilocapnic hypoxia (PH), and isocapnic hypoxia
      (IH) (days 1-3, random order, double blind), as well as normoxic voluntary
      hyperpnea (HP; day 4), matching ventilation during IH. O(2) saturation during PH
      and IH was kept equal to a mean level measured between 30 and 90 min of breathing
      12% O(2) in a pretest. Urine flow during PH and IH (1.81 +/- 0.92 and 1.94 +/-
      1.03 ml/min, respectively) but not during HP (1.64 +/- 0.96 ml/min) significantly
      exceeded that during NO (control, 1.38 +/- 0.71 ml/min). Urine flow increases vs.
      each test day's baseline were significant with PH, IH, and HP. Differences in
      glomerular filtration rate, fractional sodium clearance, urodilatin, systemic
      blood pressure, or leg venous compliance were excluded as factors of HDR.
      However, slight increases in plasma and urinary endothelin-1 and epinephrine with
      PH and IH could play a role. In conclusion, the early HDR in humans is mainly due
      to hypoxia and hypocapnia. It occurs without natriuresis and is unrelated to O(2)
      chemosensitivity (hypoxic ventilatory response).

PMID- 10658029
TI  - Reciprocal activation of hypopharyngeal muscles and their effect on upper airway
      area.
AB  - We examined in awake goats, 1) with intact upper airways (UAW), the effect of
      altering chemical drive on pharyngeal constrictors [thyropharyngeus (TP) and
      hypopharyngeus (HP)] and a dilator [stylopharyngeus (SP)], and 2) with an
      isolated UAW, the effect of activation of these muscles on supraglottic UAW
      (UAW(SG)) area. During eupnea in nine goats with intact UAW, the TP and HP were
      active during expiration, whereas the SP exhibited tonic expiratory and phasic
      inspiratory activity. After mechanically induced apneas (MIA), TP activity
      increased (263%, P < 0.02), HP activity exhibited a small, varied response, and
      SP activity greatly decreased (10%, P < 0.02). During resumption of respiratory
      effort, all goats exhibited absent/reduced airflow, and when diaphragm activity
      was 95% of control, TP activity remained elevated (135%) and SP activity was
      reduced (56%, P < 0.02). During hypercapnia, 1) TP activity decreased (P < 0.02),
      2) HP response varied, and 3) SP activity increased (P < 0.02). After MIA in six
      goats with isolated UAW, TP activity increased 198% (P < 0.02) and UAW(SG) area
      (endoscopically determined) decreased (to 15% of control, P < 0.02). During
      recovery from MIA, a correlation was found between UAW(SG) area and the ratio of
      SP to TP activity. We conclude that the reciprocal activation of mechanically
      opposing dilator and constrictor muscles in the hypopharynx is correlated to
      changes in the UAW(SG) area, and an imbalance in activity of these opposing
      muscles can lead to UAW(SG) narrowing.

PMID- 10658030
TI  - Progressive resistance training reduces myosin heavy chain coexpression in single
      muscle fibers from older men.
AB  - The purpose of this study was to examine myosin heavy chain (MHC) and myosin
      light chain (MLC) isoforms following 12 wk of progressive resistance training
      (PRT). A needle biopsy was taken from the vastus lateralis to determine fiber
      type expression [ATPase (pH 4.54) and MHC/MLC] in seven healthy men (age = 74.0
      +/- 1.8 yr). Subjects were also tested for 1-repetition maximum (1-RM), pre- and
      posttraining. The progressive knee extensor protocol consisted of three sets at
      80% of 1-RM 3 days/wk for 12 wk. Freeze-dried, single muscle fibers were
      dissected for MHC and MLC analysis and then subjected to SDS-PAGE and silver
      staining, pre- and posttraining. MHC expression increased in the I (10.4%; P <
      0.05) and decreased in I/IIa (9.0%; P < 0.05), I/IIa/x (0.9%; P < 0.05), and
      IIa/x (8.9%; P < 0.05) isoforms, with no change in the IIa and IIx isoforms, pre-
      vs. posttraining (total fibers = 3,059). The MLC(3f)-to-MLC(2) ratio did not
      change with the PRT in either the MHC I or MHC IIa isoforms (total fibers = 902),
      pre- to posttraining. ATPase fiber distribution did not significantly differ
      following training (I: 50. 4 +/- 6.7 vs. 51.9 +/- 7.9, IIa: 36.8 +/- 5.3 vs. 41.1
      +/- 7.0, IIb: 12.8 +/- 5.6 vs. 7.0 +/- 4.0%; pre- vs. posttraining,
      respectively). 1-RM increased (51.9%; P < 0.05) from pre- to posttraining. The
      PRT provide a stimulus for alterations in MHC isoforms, which demonstrated a
      decrease in all hybrid isoforms and an increase in MHC I expression (not found in
      the ATPase results), unlike the MLC ratio (3:2), which was not altered with
      training.

PMID- 10658031
TI  - Downregulation in muscle Na(+)-K(+)-ATPase following a 21-day expedition to 6,194
      m.
AB  - To investigate the hypothesis that acclimatization to altitude would result in a
      downregulation in muscle Na(+)-K(+)-ATPase pump concentration, tissue samples
      were obtained from the vastus lateralis muscle of six volunteers (5 males and 1
      female), ranging in age from 24 to 35 yr, both before and within 3 days after a
      21-day expedition to the summit of Mount Denali, Alaska (6,194 m). Na(+)-K(+)
      ATPase, measured by the [(3)H]ouabain-binding technique, decreased by 13.8% [348
      +/- 12 vs. 300 +/- 7.6 (SE) pmol/g wet wt; P < 0.05]. No changes were found in
      the maximal activities (mol. kg protein(-1). h(-1)) of the mitochondrial enzymes,
      succinic dehydrogenase (3.63 +/- 0.20 vs. 3.25 +/- 0.23), citrate synthase (4. 76
      +/- 0.44 vs. 4.94 +/- 0.44), and malate dehydrogenase (12.6 +/- 1. 8 vs. 12.7 +/-
      1.2). Similarly, the expedition had no effect on any of the histochemical
      properties examined, namely fiber-type distribution (types I, IIA, IIB, IC, IIC,
      IIAB), area, capillarization, and succinic dehydrogenase activity. Peak aerobic
      power (52.3 +/- 2.1 vs. 50.6 +/- 1.9 ml. kg(-1). min(-1)) and body mass (76.9 +/-
      3.7 vs. 75.5 +/- 2.9 kg) were also unaffected. We concluded that acclimatization
      to altitude results in a downregulation in muscle Na(+)-K(+)-ATPase pump
      concentration, which occurs without changes in oxidative potential and other
      fiber-type histochemical properties.

PMID- 10658032
TI  - Ventilatory and arousal responses of sleeping lambs to respiratory challenges:
      effect of prenatal maternal anemia.
AB  - We have examined the effects of exposure to chronic maternal anemia, throughout
      the final one-third of gestation, on postnatal ventilatory and arousal responses
      to hypoxia, hypercapnia, and combined hypoxia-hypercapnia in sleeping lambs.
      While resting quietly awake, lambs from anemic ewes had higher arterial PCO(2)
      levels than control animals during the first 2-3 postnatal wk, but pH, arterial
      PO(2), and arterial O(2) saturation were not different. During active and quiet
      sleep lambs from anemic ewes had higher end-tidal CO(2) levels than control
      animals when breathing room air and at the time of spontaneous arousal or when
      aroused by progressive hypercapnia or by combined hypoxia-hypercapnia.
      Ventilation and arterial O(2) saturation during uninterrupted sleep and
      ventilatory responsiveness to hypoxia (inspiratory O(2) fraction, 10%),
      progressive hypercapnia, and combined hypoxia/hypercapnia were not significantly
      affected by exposure to maternal anemia. Our findings show that maternal anemia
      results in elevated PCO(2) levels in the offspring. This effect may be due, at
      least in part, to altered pulmonary function.

PMID- 10658033
TI  - Effects of swimming training on three superoxide dismutase isoenzymes in mouse
      tissues.
AB  - The purpose of the present study was to investigate the effects of swimming
      training on the changes in three superoxide dismutase (SOD) isoenzymes in mice.
      The trained mice underwent a 6-wk swimming program (1 h/day, 5 days/wk) in water
      at 35-36 degrees C. Immunoreactive extracellular SOD (EC-SOD), copper- and zinc
      containing SOD (CuZn-SOD), and manganese-containing SOD (Mn-SOD) contents and
      their mRNA abundance were determined in serum, heart, lung, liver, kidney, and
      gastrocnemius muscle. EC-SOD content in liver and kidney was significantly
      increased with training. After training, CuZn-SOD content rose significantly only
      in kidney but decreased significantly in heart, lung, and liver. Mn-SOD content
      showed a significant increase in lung, kidney, and skeletal muscle but a
      significant decrease in liver. In most tissues, however, the changes in SOD
      isoenzyme contents were not concomitant with those in their mRNA levels. The
      results obtained thus suggest that, except for kidney, the responses in mouse
      tissues of three SOD isoenzymes (protein levels and mRNA abundance) to swimming
      training are different and that kidney may be one of the most sensitive organs to
      adapt to oxidative stress during physical training, although the mechanism
      remains vague.

PMID- 10658034
TI  - Effects of positive end-expiratory pressure ventilation on cerebral venous
      pressure with head elevation in dogs.
AB  - Mechanical ventilation with positive end-expiratory pressure (PEEP) may prevent
      venous air embolism in the sitting position because cerebral venous pressure
      (Pcev) could be increased by the PEEP-induced increase in right atrial pressure
      (Pra). Whereas it is clear that there is a linear transmission of the PEEP
      induced increase in Pra to Pcev while the dog is in the prone position, the
      mechanism of the transmission with the dog in the head-elevated position is
      unclear. We tested the hypothesis that a Starling resistor-type mechanism exists
      in the jugular veins when the head is elevated. In one group of dogs, increasing
      PEEP linearly increased Pcev with the dog in the prone position (head at heart
      level, slope = 0.851) but did not increase Pcev when the head was elevated. In
      another group of dogs, an external chest binder was used to produce a larger PEEP
      induced increase in Pra. Further increasing Pra increased Pcev only after Pra
      exceeded a pressure of 19 mmHg (break pressure). This sharp inflection in the
      upstream (Pcev)-downstream (Pra) relationship suggests that this may be caused by
      a Starling resistor-type mechanism. We conclude that jugular venous collapse
      serves as a significant resistance in the transmission of Pra to Pcev in the head
      elevated position.

PMID- 10658035
TI  - Skeletal muscle contractile and noncontractile components in young and older
      women and men.
AB  - To examine the influences of age, gender, and habitual physical activity level on
      human skeletal muscle composition, we developed a relatively simple magnetic
      resonance imaging method for the quantitation of leg anterior compartment
      contractile and noncontractile content. We studied 23 young (11 women and 12 men,
      26-44 yr old) and 21 older (10 women and 11 men, 65-83 yr old) healthy adults.
      Analysis was by two-factor (age, gender) ANOVA. Physical activity, quantitated by
      three-dimensional accelerometer worn about the waist for 1 wk, was not different
      between groups. Men had larger contractile and noncontractile cross-sectional
      areas (cm(2)) than women, with no gender effect on percent noncontractile area.
      Young subjects had larger contractile areas and smaller absolute (cm(2)) and
      relative (percent total) noncontractile areas than older subjects. There was a
      significant linear relationship between physical activity and percent
      noncontractile area in older (r = -0.68, P = 0.002) but not young subjects. These
      data demonstrate a more than twofold increase in the noncontractile content of
      locomotor muscles in older adults and provide novel support for physical activity
      as a modulator of this age-related change in muscle composition.

PMID- 10658036
TI  - Role of Ca(2+) fluctuations in L6 myotubes in the regulation of the hexokinase II
      gene.
AB  - Expression of the hexokinase (HK) II gene in skeletal muscle is upregulated by
      electrically stimulated muscle contraction and moderate-intensity exercise.
      However, the molecular mechanism by which this occurs is unknown. Alterations in
      intracellular Ca(2+) homeostasis accompany contraction and regulate gene
      expression in contracting skeletal muscle. Therefore, as a first step in
      understanding the exercise-induced increase in HK II, the ability of Ca(2+) to
      increase HK II mRNA was investigated in cultured skeletal muscle cells, namely L6
      myotubes. Exposure of cells to the ionophore A-23187 resulted in an approximately
      threefold increase in HK II mRNA. Treatment of cells with the extracellular
      Ca(2+) chelator EGTA did not alter HK II mRNA, nor was it able to prevent the A
      23187-induced increase. Treatment of cells with the intracellular Ca(2+) chelator
      1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetra(acetoxymethyl)
      ester (BAPTA-AM) also resulted in an approximately threefold increase in HK II
      mRNA in the absence of ionophore, which was similar to the increase in HK II mRNA
      induced by the combination of BAPTA-AM and A-23187. In summary, a rise in
      intracellular Ca(2+) is not necessary for the A-23187-induced increase in HK II
      mRNA, and increases in HK II mRNA occur in response to treatments that decrease
      intracellular Ca(2+) stores. Depletion of intracellular Ca(2+) stores may be one
      mechanism by which muscle contraction increases HK II mRNA.

PMID- 10658037
TI  - Effect of recombinant SP-C surfactant in a porcine lavage model of acute lung
      injury.
AB  - Synthetic surfactants allow examination of the effects of specific components of
      natural surfactant. To determine whether surfactant containing apoprotein C,
      dipalmitoyl-phosphatidylcholine, phosphatidylglycerol, and palmitic acid restores
      gas-exchanging function in acute lung injury (ALI), we administered such
      surfactant (in doses of 50 or 100 mg/kg and in volumes from 1 to 6 ml/kg) or
      phospholipid (PL) alone, by intratracheal instillation, to pigs with ALI induced
      by massive saline lavage. Animals ventilated with 100% O(2) and receiving 1, 2,
      4, or 6 ml/kg of 50 mg/kg recombinant surfactant apoprotein C (rSP-C) surfactant
      or 2 ml/kg of 50 mg/kg PL (control) had mean arterial PO(2) values, 4 h after
      treatment, of 230, 332, 130, 142, or 86 Torr, respectively. Animals receiving 1,
      2, or 4 ml/kg of 100 mg/kg rSP-C surfactant or 2 ml/kg of 100 mg/kg PL (control)
      had mean arterial PO(2) values of 197, 214, 148, or 88 Torr, respectively.
      Surfactant PL distribution was homogeneous. Hyaline membrane formation was
      reduced in treated animals. Thus, in this model of ALI, rSP-C with PL has the
      capacity to improve gas exchange and possibly modify lung injury.

PMID- 10658038
TI  - Role of denervation in modulating IIb MHC gene expression in response to T(3)
      plus unloading state.
AB  - Previously, we have reported that the combination of hindlimb suspension (HS) and
      thyroid hormone [triiodothyronine (T(3))] treatment induces the de novo
      expression of the fast IIb myosin heavy chain (MHC) gene in the soleus. Thus we
      tested the hypotheses that the induction of IIb MHC expression with HS + T(3) is
      prevented with denervation and that this IIb induction is regulated by
      transcriptional processes. Adult female rats were subjected to 2 wk of combined
      HS + T(3) in which one side of the lower leg was simultaneously denervated. HS +
      T(3) caused decreased expression of the slow type I MHC and concomitant increases
      in both the fast type IIx and IIb MHC isoforms in the intact soleus muscle.
      Denervation prevented the endogenous expression of the IIb MHC gene at both the
      protein and mRNA levels. Although HS + T(3) intervention was able to markedly
      increase the expression of the 2.6-kb IIb MHC promoter-reporter construct using
      direct gene transfer, this induction, however, was not inhibited by denervation.
      These findings collectively suggest that normal innervation is essential for
      inducing the unique expression of the IIb MHC in a slow muscle in response to HS
      + T(3); however, in the denervated muscle, there is a discordance between the
      regulation of the endogenous IIb MHC gene relative to the exogenous IIb MHC
      promoter-reporter construct.

PMID- 10658039
TI  - Effect of menstrual cycle phase on carbohydrate supplementation during prolonged
      exercise to fatigue.
AB  - The effects of menstrual cycle phase and carbohydrate (CHO) supplementation were
      investigated during prolonged exercise. Nine healthy, moderately trained women
      cycled at 70% peak O(2) consumption until exhaustion. Two trials were completed
      during the follicular (Fol) and luteal (Lut) phases of the menstrual cycle.
      Subjects consumed 0.6 g CHO. kg body wt(-1). h(-1) (5 ml/kg of a 6% CHO solution
      every 30 min beginning at min 30 of exercise) or a placebo drink (Pl) during
      exercise. Time to exhaustion during CHO increased from Pl values (P < 0.05) by
      14.4 +/- 8.5 (Fol) and 11.4 +/- 7.1% (Lut); no differences were observed between
      menstrual cycle phases. CHO attenuated (P < 0.05) the decrease in plasma glucose
      and insulin and the increase in plasma free fatty acids, tryptophan, epinephrine,
      and cortisol observed during Pl for both phases. Plasma alanine, glutamine,
      proline, and isoleucine were lower (P < 0.05) in Lut than in Fol phase. CHO
      resulted in lower (P < 0.05) plasma tyrosine, valine, leucine, isoleucine, and
      phenylalanine. These results indicate that the menstrual cycle phase does not
      alter the effects of CHO supplementation on performance and plasma levels of
      related substrates during prolonged exercise.

PMID- 10658040
TI  - Glycogen loading alters muscle glycogen resynthesis after exercise.
AB  - This study compared muscle glycogen recovery after depletion of approximately 50
      mmol/l (DeltaGly) from normal (Nor) resting levels (63.2 +/- 2.8 mmol/l) with
      recovery after depletion of approximately 50 mmol/l from a glycogen-loaded (GL)
      state (99.3 +/- 4.0 mmol/l) in 12 healthy, untrained subjects (5 men, 7 women).
      To glycogen load, a 7-day carbohydrate-loading protocol increased muscle glycogen
      1.6 +/- 0.2-fold (P < or = 0.01). GL subjects then performed plantar flexion
      (single-leg toe raises) at 50 +/- 3% of maximum voluntary contraction (MVC) to
      yield DeltaGly = 48.0 +/- 1.3 mmol/l. The Nor trial, performed on a separate
      occasion, yielded DeltaGly = 47.5 +/- 4.5 mmol/l. Interleaved natural abundance
      (13)C-(31)P-NMR spectra were acquired and quantified before exercise and during 5
      h of recovery immediately after exercise. During the initial 15 min after
      exercise, glycogen recovery in the GL trial was rapid (32.9 +/- 8.9 mmol. l(-1).
      h(-1)) compared with the Nor trial (15.9 +/- 6.9 mmol. l(-1). h(-1)). During the
      next 45 min, GL glycogen synthesis was not as rapid as in the Nor trial (0.9 +/-
      2.5 mmol. l(-1). h(-1) for GL; 14.7 +/- 3.0 mmol. l(-1). h(-1) for Nor; P < or =
      0.005) despite similar glucose 6-phosphate levels. During extended recovery (60
      300 min), reduced GL recovery rates continued (1.3 +/- 0.5 mmol. l(-1). h(-1) for
      GL; 3.9 +/- 0.3 mmol. l(-1). h(-1) for Nor; P < or = 0.001). We conclude that
      glycogen recovery from heavy exercise is controlled primarily by the remaining
      postexercise glycogen concentration, with only a transient synthesis period when
      glycogen levels are not severely reduced.

PMID- 10658041
TI  - Ventilation heterogeneity does not change following pulmonary microembolism.
AB  - By using the multiple-breath helium washout technique, ventilation heterogeneity
      (VH) after embolic injury in the lung can be quantitatively partitioned into the
      conductive and acinar components. Total VH, represented by the normalized slope
      of the phase III alveolar plateau, Sn(III (total)), was studied for 120 min in
      three groups of anesthetized and paralyzed mongrel dogs. Group 1 (n = 3) received
      only normal saline and served as controls. Group 2 (n = 4) received repeated
      infusions of polystyrene beads (250 microm) into the right atrium at 10, 40, 80,
      and 120 min. Group 3 (n = 3) was similarly treated, except that the embolic beads
      used were 1,000 microm in diameter. The data show that, despite repeated embolic
      injury by polystyrene beads of different diameters, there was no significant
      increase in total VH. The acinar component of Sn(III), which represents VH in the
      distal airways, accounts for over 90% of the total VH. The conductive component
      of Sn(III), which represents VH between larger conductive airways, remains
      relatively constant and a minor component. We conclude that pulmonary
      microembolism does not result in significant redistribution of ventilation.

PMID- 10658042
TI  - Carbonic anhydrase inhibition delays plasma lactate appearance with no effect on
      ventilatory threshold.
AB  - The effect of carbonic anhydrase (CA) inhibition with acetazolamide (Acz, 10
      mg/kg body wt iv) on exercise performance and the ventilatory (VET) and lactate
      (LaT) thresholds was studied in seven men during ramp exercise (25 W/min) to
      exhaustion. Breath-by-breath measurements of gas exchange were obtained.
      Arterialized venous blood was sampled from a dorsal hand vein and analyzed for
      plasma pH, PCO(2), and lactate concentration ([La(-)](pl)). VET [expressed as
      O(2) uptake (VO(2)), ml/min] was determined using the V-slope method. LaT
      (expressed as VO(2), ml/min) was determined from the work rate (WR) at which [La(
      )](pl) increased 1.0 mM above rest levels. Peak WR was higher in control (Con)
      than in Acz sutdies [339 +/- 14 vs. 315 +/- 14 (SE) W]. Submaximal exercise VO(2)
      was similar in Acz and Con; the lower VO(2) at exhaustion in Acz than in Con
      (3.824 +/- 0. 150 vs. 4.283 +/- 0.148 l/min) was appropriate for the lower WR.
      CO(2) output (VCO(2)) was lower in Acz than in Con at exercise intensities >/=125
      W and at exhaustion (4.375 +/- 0.158 vs. 5.235 +/- 0.148 l/min). [La(-)](pl) was
      lower in Acz than in Con during submaximal exercise >/=150 W and at exhaustion
      (7.5 +/- 1.1 vs. 11.5 +/- 1.1 mmol/l). VET was similar in Acz and Con (2.483 +/-
      0.086 and 2.362 +/- 0.110 l/min, respectively), whereas the LaT occurred at a
      higher VO(2) in Acz than in Con (2.738 +/- 0.223 vs. 2.190 +/- 0.235 l/min). CA
      inhibition with Acz is associated with impaired elimination of CO(2) during the
      non-steady-state condition of ramp exercise. The similarity in VET in Con and Acz
      suggests that La(-) production is similar between conditions but La(-) appearance
      in plasma is reduced and/or La(-) uptake by other tissues is enhanced after the
      Acz treatment.

PMID- 10658043
TI  - Muscle metabolism during heavy-intensity exercise after acute acetazolamide
      administration.
AB  - Carbonic anhydrase (CA) inhibition is associated with a lower plasma lactate
      concentration ([La(-)](pl)), but the mechanism for this association is not known.
      The effect of CA inhibition on muscle high-energy phosphates [ATP and
      phosphocreatine (PCr)], lactate ([La(-)](m)), and glycogen was examined in seven
      men [28 +/- 3 (SE) yr] during cycling exercise under control (Con) and acute CA
      inhibition with acetazolamide (Acz; 10 mg/kg body wt iv). Subjects performed 6
      min step transitions in work rate from 0 W to a work rate corresponding to
      approximately 50% of the difference between the O(2) uptake at the ventilatory
      threshold and peak O(2) uptake. Muscle biopsies were taken from the vastus
      lateralis at rest, at 30 min postinfusion, at end exercise (EE), and at 5 and 30
      min postexercise. Arterialized venous blood was sampled from a dorsal hand vein
      and analyzed for [La(-)](pl). ATP was unchanged from rest values; no difference
      between Con and Acz was observed. The fall in PCr from rest [72 +/- 3 and 73 +/-
      3.6 (SE) mmol/kg dry wt for Con and Acz, respectively] to EE (51 +/- 4 and 46 +/-
      5 mmol/kg dry wt for Con and Acz, respectively) was similar in Con and Acz. At
      EE, glycogen (mmol glucosyl units/kg dry wt) decreased to similar values in Con
      and Acz (307 +/- 16 and 300 +/- 19, respectively). At EE, no difference was
      observed in [La(-)](m) between conditions (46 +/- 6 and 43 +/- 5 mmol/kg dry wt
      for Con and Acz, respectively). EE [La(-)](pl) was higher during Con than during
      Acz (11.4 +/- 1.0 vs. 8.2 +/- 0.6 mmol/l). The similar [La(-)](m) but lower [La(
      )](pl) suggests that the uptake of La(-) by other tissues is enhanced after CA
      inhibition.

PMID- 10658045
TI  - Cutaneous blood flow during exercise is higher in endurance-trained humans.
AB  - This study determined whether cutaneous blood flow during exercise is different
      in endurance-trained (Tr) compared with untrained (Untr) subjects. Ten Tr and ten
      Untr men (62.4 +/- 1.7 and 44.2 +/- 1.8 ml. kg(-1). min(-1), respectively; P <
      0.05) underwent three 20-min cycling-exercise bouts at 50, 70, and 90% peak
      oxygen uptake in this order, with 30 min rest in between. The environmental
      conditions were neutral ( approximately 23-24 degrees C, 50% relative humidity,
      front and back fans at 2.5 m/s). Because of technical difficulties, only seven Tr
      and seven Untr subjects completed all forearm blood flow and laser-Doppler
      cutaneous blood flow (CBF) measurements. Albeit similar at rest, at the end of
      all three exercise bouts, forearm blood flow was approximately 40% higher in Tr
      compared with Untr subjects (50%: 4.64 +/- 0.50 vs. 3. 17 +/- 0.20, 70%: 6.17 +/-
      0.61 vs. 4.41 +/- 0.37, 90%: 6.77 +/- 0. 62 vs. 5.01 +/- 0.37 ml. 100 ml(-1).
      min(-1), respectively; n = 7; all P < 0.05). CBF was also higher in Tr compared
      with Untr subjects at all relative intensities (n = 7; all P < 0.05). However,
      esophageal temperature was not different in Tr compared with Untr subjects at the
      end of any of the aforementioned exercise bouts (50%: 37.8 +/- 0.1 vs. 37.9 +/-
      0.1 degrees C, 70%: 38.1 +/- 0.1 vs. 38.1 +/- 0.1 degrees C, and 90%: 38.8 +/-
      0.1 vs. 38.6 +/- 0.1 degrees C, respectively). We conclude that a higher CBF may
      allow Tr subjects to achieve an esophageal temperature similar to that of Untr,
      despite their higher metabolic rates and thus higher heat production rates,
      during exercise at 50-90% peak oxygen uptake.

PMID- 10658044
TI  - Water and carbohydrate ingestion during prolonged exercise increase maximal
      neuromuscular power.
AB  - This study investigated the individual and combined effects of water and
      carbohydrate ingestion during prolonged cycling on maximal neuromuscular power
      (P(max)), thermoregulation, cardiovascular function, and metabolism. Eight
      endurance-trained cyclists exercised for 122 min at 62% maximal oxygen uptake in
      a 35 degrees C environment (50% relative humidity, 2 m/s fan speed). P(max) was
      measured in triplicate during 6-min periods beginning at 26, 56, 86, and 116 min.
      On four different occasions, immediately before and during exercise, subjects
      ingested 1) 3.28 +/- 0.21 liters of water with no carbohydrate (W); 2) 3.39 +/-
      0.23 liters of a solution containing 204 +/- 14 g of carbohydrate (W+C); 3) 204
      +/- 14 g of carbohydrate in only 0.49 +/- 0.03 liter of solution (C); and 4) 0.
      37 +/- 0.02 liter of water with no carbohydrate (placebo; Pl). These treatments
      were randomized, disguised, and presented double blind. At 26 min of exercise,
      P(max) was similar in all trials. From 26 to 116 min, P(max) declined 15.2 +/-
      3.3 and 14.5 +/- 2.1% during C and Pl, respectively; 10.4 +/- 1.9% during W (W >
      C, W > Pl; P < 0.05); and 7.4 +/- 2.2% during W+C (W+C > W, W+C > C, and W+C >
      Pl; P < 0. 05). As an interesting secondary findings, we also observed that
      carbohydrate ingestion increased heat production, final core temperature, and
      whole body sweating rate. We conclude that, during prolonged moderate-intensity
      exercise in a warm environment, ingestion of W attenuates the decline in P(max).
      Furthermore, ingestion of W+C attenuates the decline in maximal power more than
      does W alone, and ingestion of C alone does not attenuate the decline in P(max)
      compared with Pl.

PMID- 10658046
TI  - Ca(2+)-dependent K(+) channels and Na(+)-K(+)-ATPase mediate H(2)O(2)- and
      superoxide-induced relaxations in canine trachealis.
AB  - We examined the ionic mechanisms underlying the responses of canine trachealis to
      superoxide (generated in vitro by using xanthine oxidase or added exogenously)
      and peroxide (generated spontaneously in vitro by the dismutation of superoxide
      or added exogenously). Although neither had any effect on resting tone, both
      triggered relaxations in carbachol-precontracted tissues. These relaxations were
      eliminated by catalase but were much less sensitive to the hydroxyl radical
      scavenger dimethylthiourea, indicating they were mediated primarily by peroxide.
      These relaxations were decreased in magnitude and/or slowed by nifedipine (10(-6)
      M), ouabain (10(-6) M), or tetraethylammonium (25 mM), but not by 4-aminopyridine
      (5 mM), and were small or absent in tissues precontracted with 30 mM KCl.
      Finally, peroxide triggered membrane hyperpolarization and elevated cytosolic
      concentration of Ca(2+) (primarily via release from the internal store). Thus
      peroxide-mediated relaxations seem to involve Ca(2+) release, opening of Ca(2+)
      dependent K(+) channels, hyperpolarization, closure of Ca(2+) channels, and
      relaxation. In addition, some other free radical (hydroxyl radical?) may activate
      the Na(+)-K(+) pump, also hyperpolarizing the membrane and causing relaxation.

PMID- 10658047
TI  - Hypoxemia-induced modification of troponin I and T in canine diaphragm.
AB  - Impaired muscle function (fatigue) may result, in part, from modification of
      contractile proteins due to inadequate O(2) delivery. We hypothesized that severe
      hypoxemia would modify skeletal troponin I (TnI) and T (TnT), two regulatory
      contractile proteins, in respiratory muscles. Severe isocapnic hypoxemia
      (arterial partial pressure of O(2) of approximately 25 Torr) in six pentobarbital
      sodium-anesthetized spontaneously breathing dogs increased respiratory frequency
      and electromyographic activity of the diaphragm and internal and external
      obliques, with death occurring after 131-285 min. Western blot analysis revealed
      proteolysis of TnI and TnT, 17.5- and 28-kDa fragments, respectively, and higher
      molecular mass covalent complexes, one of which (42 kDa) contained TnI (or some
      fragment of it) and probably TnT in the costal and crural diaphragms but not the
      intercostal or abdominal muscles. These modifications of myofibrillar proteins
      may provide a molecular basis for contractile dysfunction, including respiratory
      failure, under conditions of limited O(2) delivery.

PMID- 10658048
TI  - Enhanced endothelium-dependent vasodilation in older endurance-trained men.
AB  - We hypothesized that abnormal endothelium-dependent vasodilation (EDD) found in
      older otherwise healthy subjects can be attenuated with long-term endurance
      training. Ten endurance-trained men, 68.5 +/- 2.3 yr old, and 10 healthy
      sedentary men, 64.7 +/- 1.4 yr old, were studied. Aerobic exercise capacity (VO(2
      max)), fasting plasma cholesterol, insulin, and homocysteine concentrations were
      measured. Master athletes had higher VO(2 max) (42 +/- 2.3 vs. 27 +/- 1.4 ml. kg(
      1). min(-1), P < 0.001), slightly higher total cholesterol (226 +/- 8 vs. 199 +/-
      8 mg/dl, P = 0.05), similar insulin, and higher homocysteine (10.7 +/- 1.3 vs.
      9.2 +/- 1.4 micromol/ml, p = 0.02) concentrations. Brachial arterial diameter,
      determined with vascular ultrasound, during the hyperemic response was greater in
      the master athletes than in controls (P = 0.005). Peak vasodilatory response was
      109.1 +/- 2 vs. 103.6 +/- 2% (P < 0.05) in the athletes and controls,
      respectively. Endothelium-independent vasodilation in response to nitroglycerin
      was similar between the two groups. The increased arterial diameter during the
      hyperemic response correlated significantly with the VO(2 max) in the entire
      population (r = 0.66, P < 0.002). Our results suggest that long-term endurance
      exercise training in older men is associated with systemic enhanced EDD, which is
      even detectable in the conduit arteries of untrained muscle.

PMID- 10658049
TI  - Segregated signal averaging of sympathetic baroreflex responses in humans.
AB  - The goal of this study was to merge the methods currently used to assess beat-by
      beat changes in muscle sympathetic nerve activity with a signal-averaging
      approach and overcome the inherent subjectivity and time-consuming nature of
      manual analysis of baroreflex-mediated sympathetic responses in humans. This is a
      retrospective study using data obtained during two prior studies [J. R.
      Halliwill, J. A. Taylor, and D. L. Eckberg. J. Physiol. (Lond.) 495: 279-288,
      1996; C. T. Minson, J. R. Halliwill, T. Young, and M. J. Joyner. FASEB J. 13:
      A1044, 1999]. Beat-by-beat arterial pressure (Finapres device) and muscle
      sympathetic nerve activity (microneurography) were recorded in seven healthy,
      nonsmoking, normotensive subjects (2 men, 5 women) between the ages of 23 and 32
      yr during arterial pressure changes induced by bolus injections of nitroprusside
      and phenylephrine. The muscle sympathetic nerve activity-diastolic pressure
      relationship was analyzed by both the traditional manual detection method and a
      novel segregated signal-averaging method. The results show the two analysis
      approaches are highly correlated across subjects (r = 0.914, P < 0. 05) and are
      in close agreement [slope for manual detection -6.17 +/- 0.91 (SE) vs. slope for
      segregated signal averaging -5.98 +/- 0.83 total integrated activity. beat(-1).
      mmHg(-1); P = 0.60]. However, a considerable time savings is seen with the new
      method (min vs. h). Segregated signal averaging as developed here provides a
      valid alternative to "by-hand" analysis of beat-by-beat changes in muscle
      sympathetic nerve activity that occur during dynamic baroreflex-mediated changes
      in sympathetic outflow. This approach provides an objective, rapid method to
      analyze nerve recordings.

PMID- 10658050
TI  - Waging war on modern chronic diseases: primary prevention through exercise
      biology.
AB  - In this review, we develop a blueprint for exercise biology research in the new
      millennium. The first part of our plan provides statistics to support the
      contention that there has been an epidemic emergence of modern chronic diseases
      in the latter part of the 20th century. The health care costs of these conditions
      were almost two-thirds of a trillion dollars and affected 90 million Americans in
      1990. We estimate that these costs are now approaching $1 trillion and stand to
      further dramatically increase as the baby boom generation ages. We discuss the
      reaction of the biomedical establishment to this epidemic, which has primarily
      been to apply modern technologies to stabilize overt clinical problems (e.g.,
      secondary and tertiary prevention). Because this approach has been largely
      unsuccessful in reversing the epidemic, we argue that more emphasis must be
      placed on novel approaches such as primary prevention, which requires attacking
      the environmental roots of these conditions. In this respect, a strong
      association exists between the increase in physical inactivity and the emergence
      of modern chronic diseases in 20th century industrialized societies.
      Approximately 250,000 deaths per year in the United States are premature due to
      physical inactivity. Epidemiological data have established that physical
      inactivity increases the incidence of at least 17 unhealthy conditions, almost
      all of which are chronic diseases or considered risk factors for chronic
      diseases. Therefore, as part of this review, we present the concept that the
      human genome evolved within an environment of high physical activity.
      Accordingly, we propose that exercise biologists do not study "the effect of
      physical activity" but in reality study the effect of reintroducing exercise into
      an unhealthy sedentary population that is genetically programmed to expect
      physical activity. On the basis of healthy gene function, exercise research
      should thus be viewed from a nontraditional perspective in that the "control"
      group should actually be taken from a physically active population and not from a
      sedentary population with its predisposition to modern chronic diseases. We
      provide exciting examples of exercise biology research that is elucidating the
      underlying mechanisms by which physical inactivity may predispose individuals to
      chronic disease conditions, such as mechanisms contributing to insulin resistance
      and decreased skeletal muscle lipoprotein lipase activity. Some findings have
      been surprising and remarkable in that novel signaling mechanisms have been
      discovered that vary with the type and level of physical activity/inactivity at
      multiple levels of gene expression. Because this area of research is underfunded
      despite its high impact, the final part of our blueprint for the next millennium
      calls for the National Institutes of Health (NIH) to establish a major initiative
      devoted to the study of the biology of the primary prevention of modern chronic
      diseases. We justify this in several ways, including the following estimate: if
      the percentage of all US morbidity and mortality statistics attributed to the
      combination of physical inactivity and inappropriate diet were applied as a
      percentage of the NIH's total operating budget, the resulting funds would equal
      the budgets of two full institutes at the NIH! Furthermore, the fiscal support of
      studies elucidating the scientific foundation(s) targeted by primary prevention
      strategies in other public health efforts has resulted in an increased efficacy
      of the overall prevention effort. We estimate that physical inactivity impacts 80
      90% of the 24 integrated review group (IRG) topics proposed by the NIH's Panel on
      Scientific Boundaries for Review, which is currently directing a major
      restructuring of the NIH's scientific funding system. Unfortunately, the primary
      prevention of chronic disease and the investigation of physical
      activity/inactivity and/or exercise are not mentioned in the almost 200 total
      subtopics comprising t

PMID- 10658051
TI  - Genomics, genes, and environmental interaction: the role of exercise.
AB  - Regular exercise has been shown to improve control of lipid abnormalities,
      diabetes mellitus, hypertension, and obesity, with the greatest benefits realized
      by sedentary individuals who begin to exercise. Responses to exercise
      interventions are often highly variable among individuals, however, and research
      has indicated that response to exercise may be mediated in large part by
      variation in genes. As we strive to unravel the complex etiology of diseases like
      obesity, diabetes, and cardiovascular disease through the use of molecular and
      genetic tools now available, understanding the interaction and influence of
      environmental factors, such as exercise, on gene expression and function has
      taken on increasing importance. This review briefly summarizes strategies
      presently being used to elucidate genes and genetic effects that may be mediated
      or influenced by exercise and serves to illustrate the importance of considering
      the effect of exercise when investigating genes related to health or other
      physiological outcomes.

PMID- 10658052
TI  - Effects of exercise on GLUT-4 and glycogenin gene expression in human skeletal
      muscle.
AB  - To investigate the effect of exercise on GLUT-4, hexokinase, and glycogenin gene
      expression in human skeletal muscle, 10 untrained subjects (6 women and 4 men,
      21.4 +/- 1.2 yr, 66.3 +/- 5.0 kg, peak oxygen consumption = 2.30 +/- 0.19 l/min)
      exercised for 60 min on a cycle ergometer at a power output requiring 73 +/- 4%
      peak oxygen consumption. Muscle samples were obtained by needle biopsy before,
      immediately after, and 3 h after exercise. Gene expression was quantified,
      relative to 29S ribosomal protein cDNA, by RT-PCR. GLUT-4 gene expression was
      increased immediately after exercise (1.7 +/- 0.4 vs. 0.9 +/- 0.3 arbitrary
      units; P < 0.05) and remained significantly higher than baseline 3 h after the
      end of exercise (2. 2 +/- 0.4 vs. 0.9 +/- 0.3 arbitrary units; P < 0.05).
      Hexokinase II gene expression was significantly higher than the resting value 3 h
      after the end of exercise (2.9 +/- 0.4 vs. 1.3 +/- 0.3 arbitrary units; P <
      0.05). Exercise increased glycogenin mRNA more than twofold (2.8 +/- 0.6 vs. 1.2
      +/- 0.2 arbitrary units; P < 0.05) 3 h after the end of exercise. For the first
      time, we report that a single bout of exercise is sufficient to cause
      upregulation of GLUT-4 and glycogenin gene expression in human skeletal muscle.
      Whether these increases, together with the associated increase in hexokinase II
      gene expression, lead to increased expression of these key proteins in skeletal
      muscle and contribute to the enhanced skeletal muscle glucose uptake, glycogen
      synthesis, and insulin action observed following exercise remains to be
      determined.

PMID- 10658053
TI  - Regular exercise enhances insulin activation of IRS-1-associated PI3-kinase in
      human skeletal muscle.
AB  - Insulin action in skeletal muscle is enhanced by regular exercise. Whether
      insulin signaling in human skeletal muscle is affected by habitual exercise is
      not well understood. Phosphatidylinositol 3-kinase (PI3-kinase) activation is an
      important step in the insulin-signaling pathway and appears to regulate glucose
      metabolism via GLUT-4 translocation in skeletal muscle. To examine the effects of
      regular exercise on PI3-kinase activation, 2-h hyperinsulinemic (40 mU. m(-2).
      min(-1))-euglycemic (5.0 mM) clamps were performed on eight healthy exercise
      trained [24 +/- 1 yr, 71.8 +/- 2.0 kg, maximal O(2) uptake (VO(2 max)) of 56.1 +/
      2.5 ml. kg(-1). min(-1)] and eight healthy sedentary men and women (24 +/- 1 yr,
      64.7 +/- 4.4 kg, VO(2 max) of 44.4 +/- 2.7 ml. kg(-1). min(-1)). A [6, 6
      (2)H]glucose tracer was used to measure hepatic glucose output. A muscle biopsy
      was obtained from the vastus lateralis muscle at basal and at 2 h of
      hyperinsulinemia to measure insulin receptor substrate-1(IRS-1)-associated PI3
      kinase activation. Insulin concentrations during hyperinsulinemia were similar
      for both groups (293 +/- 22 and 311 +/- 22 pM for trained and sedentary,
      respectively). Insulin-mediated glucose disposal rates (GDR) were greater (P <
      0.05) in the exercise-trained compared with the sedentary control group (9.22 +/-
      0.95 vs. 6.36 +/- 0.57 mg. kg fat-free mass(-1). min(-1)). Insulin-stimulated PI3
      kinase activation was also greater (P < 0.004) in the trained compared with the
      sedentary group (3.8 +/- 0.5- vs. 1.8 +/- 0.2-fold increase from basal).
      Endurance capacity (VO(2 max)) was positively correlated with PI3-kinase
      activation (r = 0.53, P < 0.04). There was no correlation between PI3-kinase and
      muscle morphology. However, increases in GDR were positively related to PI3
      kinase activation (r = 0.60, P < 0.02). We conclude that regular exercise leads
      to greater insulin-stimulated IRS-1-associated PI3-kinase activation in human
      skeletal muscle, thus facilitating enhanced insulin-mediated glucose uptake.

PMID- 10658054
TI  - Intracellular mechanisms responsible for exercise-induced suppression of
      macrophage antigen presentation.
AB  - In a previous study, we demonstrated that exhaustive exercise suppressed
      peritoneal macrophage antigen presentation (AP). In this study, we explored the
      intracellular mechanism(s) responsible for this suppression. Pathogen-free male
      BALB/c mice (8 +/- 2 wk) were randomly assigned to either home cage control (HCC)
      or exhaustive exercise stress (Exh, 18-30 m/min for 3 h/day) treatment groups.
      The mice underwent treatments for a period of 4 days during induced peritoneal
      thioglycollate inflammation. Elicited macrophages were harvested, purified, and
      incubated with chicken ovalbumin (C-Ova, 2. 5 and 10 mg/ml) for 18 h. After
      macrophages were washed, they were cocultured with C-Ova-specific T cells for 48
      h at which time the supernates were harvested and analyzed via ELISA for
      interleukin (IL)-2 as an indication of macrophage AP. There was no significant (P
      > 0.05) difference in macrophage AP between cells fixed with paraformaldehyde vs.
      those that remained unfixed, suggesting that Exh did not affect production of
      soluble factors influencing macrophage AP (i.e., IL-1, IL-4, PGE(2)). The ability
      of macrophages to generate C-Ova immunogenic peptides was analyzed using FITC
      labeled C-Ova, which shows fluorescence only when degraded intracellularly. There
      was a significant ( approximately 20%, P < 0. 05) suppression in fluorescence in
      the Exh compared with HCC, indicating a possible defect in the ability of
      macrophages from Exh to degrade C-Ova into immunogenic peptides. Macrophages were
      also incubated with C-Ova immunogenic peptide in a manner identical to that for
      native C-Ova. We found a similar suppression ( approximately 22-38%, P < 0.05) in
      macrophage AP using a C-Ova peptide when compared with native C-Ova in the Exh
      group, indicating reduced major histocompatibility complex (MHC) II loading
      and/or C-Ova-MHC II complex cell surface expression. In conclusion, these data
      indicate an intracellular defect in the macrophage antigen processing pathway
      induced by Exh.

PMID- 10658055
TI  - Current status of and problems in the treatment of gastric and duodenal ulcer
      disease: introduction.

PMID- 10658056
TI  - Management of peptic ulcers: emerging issues.
AB  - Most peptic ulcers are caused by Helicobacter pylori infection. The infection is
      best diagnosed by a radiolabeled carbon urea breath test, which also can prove
      that eradication therapy was successful. Serologic testing is useful for
      establishing prior or present infection but not to determine if the infection has
      been eradicated. Endoscopic tests usually are not needed to establish a
      diagnosis. Modern ulcer treatment consists of H. pylori eradication in infected
      patients. A combination of a proton pump inhibitor plus clarithromycin and
      amoxicillin or a proton pump inhibitor plus bismuth, metronidazole, and
      tetracycline are the most effective regimens. Reinfection is less than 2% per
      year in developed countries. Evidence suggests that H. pylori eradication may
      foster the development of erosive esophagitis, but confirmatory studies are
      needed. Studies also suggest an interaction between H. pylori infection and
      peptic ulcers related to the use of nonsteroidal antiinflammatory drugs (NSAIDs).
      However, the studies are conflicting: One shows that H. pylori eradication
      protects against NSAID-related ulcers; another suggests protection afforded by
      the infection. Non-H. pylori peptic ulcers remain a challenge, especially in the
      United States, where one study showed that 42% of peptic ulcers were not due to
      the infection. Some non-H. pylori ulcers are refractory to usual doses of
      antisecretory drugs.

PMID- 10658057
TI  - Current status of indications for surgery in peptic ulcer disease.
AB  - The eradication of Helicobacter pylori in patients with peptic ulcer disease has
      greatly diminished the need for antiulcer surgery. However, in societies where
      such drug therapy is considered too expensive and because occasional patients
      remain refractory to optimal medical therapy, elective surgery for duodenal ulcer
      disease is still carried out. If the required expertise is available, it can be
      undertaken laparoscopically. The advent of endoscopic therapies such as heater
      probe therapy and injection sclerotherapy has also greatly diminished the need
      for emergency surgery in bleeding peptic ulcer disease. Once again, however, when
      such therapy fails surgery is still indicated. Even with perforated peptic ulcer
      disease the role of surgery has receded somewhat, but here not because of changes
      in drug therapy. Nonoperative management of perforation is indicated in fit
      patients if the diagnosis is in doubt, in any patient when surgical facilities
      are unavailable (e.g., remote geographic areas, on board ship), or when a patient
      is extremely ill either because of co-morbidity or late presentation of the
      disease. Operation should be considered in all patients when the perforation is
      established to be unsealed, particularly after

PMID- 10658058
TI  - Proximal gastric vagotomy: does it have a place in the future management of
      peptic ulcer?
AB  - Proximal gastric vagotomy (PGV) is a modification of truncal vagotomy, which was
      introduced by Dragstedt for the treatment of duodenal ulcer (DU) in 1943. It is a
      technically demanding operation; but when performed by an experienced surgeon, it
      is safe and gives a cure rate for DU of more than 90%, with minimal side effects.
      The operation permanently alters the natural history of the disease and may be
      used for gastric ulcer (GU), with ulcer excision; but it is not as effective.
      Further adaptations, such as posterior truncal vagotomy with anterior
      seromyotomy, were introduced to simplify and shorten the operation, but they did
      not receive wide acceptance. Recently, with the identification of Helicobacter,
      it was found that DU can also be cured by eliminating the infection. PGV is
      therefore used electively in patients with persistent DU that is not Helicobacter
      positive or in the few in whom Helicobacter cannot be eliminated. In patients
      with bleeding or perforated DUs, PGV may be used in conjunction with underrunning
      the vessel or patching the perforation. However, few surgeons doing emergency
      peptic ulcer surgery have experience with PGV, so simple suture followed by
      medical treatment is the safest option. Because elective PGV is now a rare
      procedure, patients should be referred to a center with special expertise. If
      Helicobacter becomes resistant to antibiotics in the future, surgery may be
      needed regularly again, but the technical nuances would have to be learned.

PMID- 10658059
TI  - Parietal cell vagotomy versus vagotomy-antrectomy: ulcer surgery in the modern
      era.
AB  - Patients with peptic ulcer occasionally develop complications that require
      surgical intervention, despite the advances in medical treatment and changes in
      the natural history of disease. The clinical surgeon must make a decision about
      performing "selective vagotomy antrectomy versus highly selective vagotomy,"
      based on the information discussed herein. The goals for operative treatment
      remain safe correction of the presenting problem, avoidance of perioperative
      morbidity and mortality, and freedom from disabling postoperative side effects.
      This paper addresses broad aspects of the details of surgical interventions;
      because most operative procedures are performed in urgent circumstances in
      patients who often have a variety of conditions, it is not surprising that there
      is no best operation suited to every complication of ulcer.

PMID- 10658060
TI  - New surgical strategy for gastroduodenal ulcer: laparoscopic approach.
AB  - Although peptic gastroduodenal ulcers are rarely treated surgically today, when
      surgery is required a laparoscopic approach is possible with its well known
      advantages. The most widely used technique is vagotomy by various modalities.
      Training in laparoscopy requires good instrumentation to avoid complications.
      Vagotomy can be truncal and bilateral via laparoscopy or thoracoscopy, which is
      the easiest and quickest procedure; moreover, the sequelae are less important and
      less frequent, as has been reported. It can also be highly selective or mixed,
      such as the Taylor procedure; and large series have been reported with good
      results. Gastric resection is rarely used for peptic ulcers, although it is
      feasible laparoscopically; it requires a large experience. Long-term results of
      laparoscopic vagotomy are now available and have indicated the same results as
      are attained with open surgery.

PMID- 10658061
TI  - Trends in perforated peptic ulcer: incidence, etiology, treatment, and prognosis.
AB  - After increasing steeply at the beginning of the twentieth century, ulcer
      perforation incidence during the last decades has declined in the young and in
      men, and it has risen among the elderly and in women. These changes can be
      attributed to a cohort phenomenon: Ulcer perforation risk is particularly common
      in the cohorts born after the turn of the twentieth century and is less common in
      previous and succeeding birth cohorts. A decline in total incidence is expected
      with the death of the high risk cohorts. Most ulcer perforations among subjects <
      75 years of age can be attributed to smoking. Subjects with a history of ulcer
      perforation therefore have poorer long-term survival than the general population,
      most pronounced for younger generations. About one of four ulcer perforations can
      be attributed to the use of nonsteroidal antiinflammatory drugs, a risk factor of
      particular importance in the elderly. Ulcer perforation was frequently treated by
      gastric resection in former days, whereas suture, being the first method
      introduced in 1887, is the method of choice today. The introduction of
      antibiotics improved the prognosis of ulcer perforation surgery greatly.
      Postoperative lethality decreased until 1950 but has remained stable since then.
      Lethality is higher in the elderly and is higher after gastric than after
      duodenal perforation. The delay before surgical treatment is a strong determinant
      for lethality, complication rates, and hospital costs. Treatment delay seems to
      have increased during the last

PMID- 10658062
TI  - Trends in peptic ulcer bleeding and surgical treatment.
AB  - An evidence-based approach is followed, with grading of evidence by study design,
      to evaluate surgical treatment of a bleeding peptic ulcer. In contrast to
      endoscopic treatment, reports of surgical treatment are rare, with only five
      randomized trials having been identified. Epidemiologic studies have demonstrated
      that the incidence of emergency surgery has not changed despite major
      improvements with endoscopic treatment. There are no proven alternatives to
      emergency operation for massive bleeding uncontrollable by endoscopic procedures.
      There is some debate about surgery for rebleeding, but no randomized trial has
      assessed whether a second endoscopic treatment alone is preferable to surgery
      with or without repeated endoscopic treatment. Concerning the type of operative
      procedure, the existing body of evidence, including two randomized studies,
      indicates that patients are best served by a relatively aggressive surgical
      approach. Today the value of these studies is limited owing to prevention of
      ulcer recurrence by eradication and technical improvements of local procedures
      (e.g., arterial ligation). Early elective surgery was tested in two randomized
      studies and several uncontrolled series, which demonstrated that it may be
      beneficial in high risk groups and harmful in others. Indications for early
      elective surgery should be refined taking into account updated prognostic
      information and more effective endoscopic treatment. Because of a new
      understanding of ulcer disease the role of surgery has changed markedly within
      the last years, no longer aiming to cure the disease but primarily to stop the
      hemorrhage. Evidence, however, is not derived from properly randomized controlled
      trials but is based on theoretic arguments and knowledge from studies not
      primarily dealing with operative treatment.

PMID- 10658063
TI  - Efficacy of endoscopic pure ethanol injection method for gastrointestinal ulcer
      bleeding.
AB  - We reviewed endoscopic hemostatic effects of the pure ethanol injection (PEI)
      method for reducing emergency operations and deaths due to gastroduodenal ulcer
      bleeding. During 17 years beginning in June 1979 in Tohoku University Hospital,
      331 patients underwent endoscopic hemostasis by the PEI method. Initial
      hemostasis was successfully obtained in all cases. Rebleeding occurred in about
      4% of the patients, and rehemostasis was obtained successfully in all of them.
      Complete hemostasis was obtained in 330 of 331 patients (99. 7%) using the PEI
      method; there were no deaths. Only one patient required emergency operation after
      hemostasis because of repeated neogenetic bleeding complicated with a perforation
      and another because of an unidentifiable neogenetic ulcer bleeding located just
      above the Vater papilla. None required other endoscopic hemostasis or
      interventional radiology. Moreover, after introduction of "second-look"
      endoscopy, the rebleeding rate decreased to about 1% with PEI hemostasis. Based
      on these excellent hemostatic effects of the PEI method, we believe that a
      comparative study with other hemostatic methods is not needed.

PMID- 10658064
TI  - Surgical treatment of complicated duodenal ulcers: controlled trials.
AB  - Indications for surgery of duodenal ulcer (DU) have changed radically because of
      the efficacy of H(2)-antagonists, endoscopic procedures, and eradication of
      Helicobacter pylorus. The aim of this study was to analyze the current literature
      to determine if definitive surgery is still relevant for complicated DU
      (bleeding, perforation, gastric outlet obstruction). Two studies have compared
      early to late surgery in terms of bleeding. One recommended early surgery
      (significant reduction in mortality) in the elderly, but no statistically
      significant difference was found when analyzed with "intention to treat." In the
      other, mortality with early surgery was five times higher than with expectant
      therapy (when it was possible). Two studies comparing different surgical
      techniques for bleeding favored the radical procedure. Of at least 15 studies
      comparing endoscopic treatments, however, none has compared endoscopic therapy to
      surgical intervention for bleeding DU. One trial, comparing nonoperative to
      surgical treatment for perforation, found similar rates of morbidity,
      intraabdominal abscess, and mortality; but the hospital stay was longer (p <
      0.001). Nonoperative treatment failed more often (p < 0.05) in patients over age
      70. In three trials, postoperative morbidity (excepting wound sepsis in one) was
      not significantly increased by definitive surgery, with less ulcer recurrence (p
      < 0.05) compared with simple closure. Laparoscopy (versus laparotomy) was shown
      to take longer (p < 0.001) but required less postoperative analgesics (p < 0.03);
      there were no statistically significant differences as concerns the duration of
      nasogastric aspiration, intravenous drips, hospital stay, time to resume normal
      diet, Visual Analogous Scale pain scores for the first 24 hours after surgery,
      morbidity, reoperation rate, or mortality. Of 48 laparoscopic patients, 11 (23%)
      underwent conversion to open surgery. Three surgical techniques [highly selective
      vagotomy (HSU) + gastrojejunostomy (group 1), HSV + Jaboulay gastroduodenostomy
      (group 2), or selective vagotomy (group 3) + antrectomy) for gastric outlet
      obstruction (GOO)] showed that although postoperative results were similar
      (except wound sepsis in one trial), long-term Visick scores were significantly (p
      < 0.01) better in group 1 than in group 2, but not in group 3. Further studies
      are needed to determine the exact prevalence of Helicobacter pylori in
      complicated DU and to compare (1) definitive to minimal surgery (stop the
      bleeding or close the perforation) combined with antisecretory drugs and
      eradication of H. pylori; (2) surgery to endoscopic treatment combined with
      eradication of H. pylori; and (3) for GOO, surgery to balloon dilatation combined
      with eradication of H. pylori.

PMID- 10658065
TI  - Long-term prognosis after partial gastrectomy for gastroduodenal ulcer.
AB  - The decline in duodenal ulcer disease and the established relation of peptic
      ulcer to Helicobacter pylori have virtually abolished the need for elective ulcer
      surgery. However, a substantial proportion of the population around retirement
      age has previously been subjected to partial gastric resection due to peptic
      ulcer, and the long-term outcome of these patients is of continuing relevance.
      Patients subjected to elective surgery could represent a selected group of
      healthy subjects with a lower overall morbidity, but reports indicate that
      patients operated on for peptic ulcer have more advanced disease associated with
      excess smoking and a different pattern of social behavior. The surgical procedure
      induces enterogastric reflux, leading to profound changes in the remnant mucosa
      and the formation of carcinogens in the gastric juice. In addition, metabolic
      abnormalities are common, especially fat malabsorption. Evaluation of the impact
      of these factors on morbidity and mortality is difficult. Increased mortality in
      gastrointestinal tumors (especially gastric stump carcinoma), respiratory
      diseases and other smoking-related malignancies, and suicide are found in the
      long-term follow-up after partial gastric resection due to peptic ulcer. However,
      these hazards to life are offset by a decreased mortality in cardiovascular
      disease. Preventive measures against suicide and especially tobacco smoking are
      recommended to improve th outcome for this cohort.

PMID- 10658066
TI  - Risk of stomach cancer in patients with peptic ulcer disease.
AB  - The relation between peptic ulcer and stomach cancer has long been disputed, but
      there is accumulating evidence that gastric ulcer disease is positively
      associated and duodenal ulcerations negatively associated with the risk of
      developing stomach cancer. As Helicobacter pylori infection is associated with
      both types of ulceration and stomach cancer, the varying outcomes of the
      infection indicate that factors other than the infection must be of importance.
      At present, there is no convincing evidence that pharmacologic inhibition of acid
      secretion for treatment of peptic ulcer increases the risk of stomach cancer.
      However, some recent studies indicate that prolonged treatment with proton pump
      inhibitors may accelerate the development of atrophic gastritis, a risk factor
      for stomach cancer, in individuals infected with H. pylori. It has repeatedly
      been shown that there is an at least twofold increased risk of stomach cancer 15
      years after gastric resection for peptic ulcer disease, and that the risk
      increases with the passage of time. Whether vagotomy has the same risk-increasing
      effect is still unclear.

PMID- 10658067
TI  - Effects of medical treatment on gastric mucosal abnormalities in gastroduodenal
      ulcer disease.
AB  - The development of carcinoma in cases of gastric ulcer disease during long-term
      H(2)-blocker treatment is slowly increasing, and ulcers that require such
      treatment exhibit the characteristics of intractable conditions, including linear
      ulcers, simultaneous gastric and duodenal ulcers, immature intestinal metaplasia
      of the gastric epithelium, and atrophic gastritis accompanied with multiple ulcer
      cicatrices. The incomplete form of intestinal metaplasia resembling Filipe's type
      III lesions and showing structural atypia developed in the background gastric
      mucosa in such cases, and the characteristics of this metaplasia included
      structural atypia, a residuum of gastric-type mucous cells, rapid proliferative
      activity, and in some areas abnormal expression of P53 protein. In addition, in
      rat studies it was demonstrated that prolonged administration of H(2)-blockers
      while gastric ulcers were present accelerated cell proliferation in the
      background gastric mucosa in the long term. Accordingly, it was considered
      possible that the development of the incomplete form of intestinal metaplasia,
      which was strongly suggested to have some relation to the sites where intestinal
      type gastric carcinoma appeared, was accelerated by mucosal injury due to chronic
      ulcers and by persistent elevation in intragastric pH. The results of the present
      study of gastric carcinoma as a complication of peptic ulcer disease indicated
      the possibility that Helicobacter pylori was a major contributory factor to the
      development of the incomplete form of intestinal metaplasia from damage to the
      background mucosa, but it was unclear whether H. pylori made any direct
      contribution to carcinogenesis.

PMID- 10658068
TI  - Pathologic evaluation of surgical margins and local recurrences after breast
      conserving surgery without irradiation.
AB  - This study was undertaken to evaluate the status of margins of the excised breast
      tissue using our own method. We also determined the indications for breast
      conserving surgery without irradiation by examining the characteristics of
      patients with local recurrence and comparing relapse-free survival (RFS) and
      overall survival (OS) of patients who underwent wide excision without irradiation
      with those of 267 patients who underwent total mastectomy. Eighty-two patients
      with a 3 cm diameter or less invasive carcinoma were treated with wide excision
      and axillary dissection between 1987 and 1996. Patients who histologically had
      four or more axillary lymph node metastases, positive pathologic margins, or a
      high degree of in situ ductal carcinoma around the main tumor in consecutive step
      sections were excluded from this study. During a median follow-up of 6 years
      (range 2-11 years), six patients (7.3%) had local recurrence and five (6.0%) had
      regional or distant recurrences as their site of first failure. At 11 years the
      life-table values for RFS and OS for the wide excision-treated group were 84.7%
      and 92.1%, respectively, compared with 85.0% and 90.0%, respectively, for
      patients treated by total mastectomy. RFS and OS were similar in the two
      treatment groups. Results in the present study indicate that if the patients
      treated by breast-conserving surgery are carefully selected and there are no foci
      in the pathologic margins, there is a low degree of in situ ductal carcinoma
      around the tumor, and no multicentricity, it might be unnecessary to administer

PMID- 10658069
TI  - Gelatinase A, membrane type 1 matrix metalloproteinase, and extracellular matrix
      metalloproteinase inducer mRNA expression: correlation with invasive growth of
      breast cancer.
AB  - Invasive breast cancer varies widely in biologic aggressiveness, from fairly
      indolent tumors to rapidly disseminating carcinomas. Matrix metalloproteinases
      have enzymatic activity and assist in tumor invasion by degrading basement
      membranes and extracellular matrix. The extracellular matrix metalloproteinase
      inducer EMMPRIN is thought to stimulate fibroblasts to produce the zymogen pro
      gelatinase A. The membrane type 1-matrix metalloproteinase (MT1-MMP) is thought
      to assist in tumor invasion and metastasis by activating pro-gelatinase A, which
      shows enhanced expression in various tumors. Overexpression of gelatinase A has
      shown to correlate with a malignant phenotype in many tumor forms. The aim of the
      study was to investigate the mRNA expression pattern of MT1-MMP, gelatinase A,
      and EMMPRIN in breast tumors. Formalin-fixed paraffin-embedded breast tissue
      samples from 18 patients operated on with breast-conserving surgery for invasive
      breast carcinoma <20 mm between 1977 and 1985 were analyzed using the mRNA in
      situ hybridization technique. Most of the patients were node-negative (15/18) and
      underwent postoperative irradiation to the breast (16/18). The median age at
      diagnosis was 52 years (21-83 years). At the time of the study 11 patients were
      alive, 4 without recurrence; 7 patients had been operated for ipsilateral breast
      tumor recurrences, and 2 had distant metastases. The median follow-up was 112
      months (102-193 months). Seven patients died of disseminated breast cancer; their
      median follow-up was 43 months (22-116 months). (35)S-labeled antisense and sense
      mRNA probes transcribed from linearized plasmids containing cDNA for the matrix
      metalloproteinases gelatinase A and MT1-MMP and the glycoprotein EMMPRIN were
      hybridized to 5 microm paraffin-embedded tissue sections. Several invasive
      carcinomas were surrounded by normal tissue and carcinoma in situ lesions.
      Gelatinase A, MT1-MMP, and EMMPRIN mRNA expression were detected in all of the
      carcinomas. The gelatinase A mRNA expression was mainly localized to stromal
      cells at moderate to high levels surrounding the invading carcinoma cells but was
      also seen in single cells at low levels in in situ lesions and in some normal
      glandular cells. MT1-MMP and EMMPRIN were expressed in all of the carcinomas and
      were mainly localized to tumor cells; but they were also seen to some extent in
      single cells at low levels in in situ lesions and in normal glandular cells. No
      differences in levels of expression for gelatinase A, MT1-MMP, or EMMPRIN were
      seen in patients who survived compared to patients who died from metastatic
      disease. The co-expression of gelatinase A, MT1-MMP, and EMMPRIN mRNA in invasive
      breast carcinoma supports the theory that these proteins interact and are
      important for the invasive phenotype in breast carcinoma. Hence EMMPRIN may be a
      central factor for stimulation of gelatinase A activation. Specific inhibition
      for individual MMP members could in the future be target-specific events in
      breast tumor progression. Inhibition of EMMPRIN could be such a target.

PMID- 10658070
TI  - Value of axillary sentinel nodal status in breast cancer.
AB  - Axillary clearance in node-negative breast cancer patients is performed only for
      staging and prognostic purposes. The sentinel node concept may provide an
      alternative conservative approach for these patients. This paper reports on the
      learning experience with lymphatic mapping involving the use of patent blue dye
      for the identification of sentinel lymph nodes (SLNs), followed by axillary
      dissection. The histopathology of the SLNs included serial sectioning and
      immunostaining for cytokeratin and epithelial membrane antigen, the remaining
      nodes being processed as usual. Of the 70 mapping procedures, 58 were successful;
      the surgical performance revealed a well defined learning period. The mean
      diameter of the successfully mapped tumors was 2.4 cm (ranging from in situ
      carcinoma to 4.8-cm invasive cancer). The mean numbers of SLNs and non-SLNs were
      1.3 (range 1-3) and 19 (range 7-42), respectively. There were 36 SLN-positive
      cases, 21 of which had metastases only to these nodes. There were 19 node
      negative cases, and 3 SLNs were falsely negative. Possible causes of the errors
      during lymphatic mapping are analyzed in the light of experiences published to
      date. SLN biopsy seems a good approach to enhancing the selectivity of axillary
      lymphadenectomy, but the limitations of the procedure must be evaluated and
      carefully considered.

PMID- 10658071
TI  - Five-year prospective audit of routine intravenous cholangiography and selective
      endoscopic retrograde cholangiography with or without intraoperative
      cholangiography in patients undergoing laparoscopic cholecystectomy.
AB  - Consensus has never been reached regarding the need or the imaging technique for
      evaluating the common bile duct (CBD) in patients considered for cholecystectomy.
      With the advent of laparoscopic cholecystectomy there has been a resurgence of
      interest in the role of preoperative intravenous cholangiography (IVC) as an
      alternative for evaluating the CBD. The purpose of this audit was to assess
      whether a diagnostic workup based on IVC, which permits selective use of
      intraoperative cholangiography (IOC) and endoscopic treatment of CBD stones
      before surgery, could be useful in patients undergoing laparoscopic
      cholecystectomy (LC). In patients without jaundice, gallstone pancreatitis, a
      prior diagnosis of CBD stones, a prior history of contrast allergy, or a risk of
      contrast-associated acute renal failure, IVC was performed routinely. Patients
      suspected to have CBD stones based on IVC results or with inconclusive IVC and
      patients with a strong clinical suspicion of CBD stones were referred for
      endoscopic retrograde cholangiography (ERC). IOC was carried out in patients who
      had a history of contrast allergy or risk of contrast-associated acute renal
      failure and whenever the surgeon was in doubt as to the biliary anatomy or CBD
      clearance. IVC was carried out in 1155 patients, ERC in 225, and IOC in 54. IVC
      was conclusive in 1132 patients, with a diagnostic accuracy of 99%. Our workup
      permitted the sequential endoscopic-laparoscopic treatment of
      cholecystocholedocholithiasis in 162 cases. During the follow-up period residual
      CBD stones were detected in four patients. Our diagnostic workup showed that
      routine IVC exposes the population to a large radiation burden, and the cost is
      high for the small number of patients who benefit. Moreover, it does not seem
      helpful in reducing the incidence of CBD injuries during LC.

PMID- 10658072
TI  - Radical resection of periampullary tumors in the elderly: evaluation of long-term
      results.
AB  - Increasingly, patients of advanced age are coming for evaluation of periampullary
      tumors. Although several studies have demonstrated the safety of resecting
      periampullary tumors in older patients, few long-term survival data have been
      reported. Between 1983 and 1992 various periampullary masses were resected in 70
      patients over age 65 (range 65-87 years). Total pancreatectomy was performed in
      11 patients, and 59 patients underwent pancreaticoduodenectomy. The mean duration
      of hospitalization was 17 +/- 15 days. Major complications occurred in 27
      patients (39%), and operative mortality rate was 8.5%. Overall median survival
      was 24 months; and 5-year survival was 25%. Perioperative outcome was compared in
      patients aged 65 to 74 years and in patients > or =75 years old. The older age
      group required longer periods in the surgical intensive care unit
      postoperatively, but the long-term survival was similar in the two age groups.
      Radical resection with the intent to cure periampullary tumors is safe in
      selected patients of advanced age, and long-term survival is in the range of
      expected survival for younger patients with the same tumors.

PMID- 10658073
TI  - Measurement of serum hyaluronate as a predictor of human liver failure after
      major hepatectomy.
AB  - Serum hyaluronate can be used as an index of hepatic sinusoidal endothelial cell
      function. This study was designed to evaluate its application as a predictor of
      liver failure after major hepatectomy. Thirty-six patients who underwent right
      liver lobectomy after percutaneous transhepatic right branch portal vein
      embolization were divided into two groups based on their postoperative clinical
      course (groups 1 and 2, with and without postoperative liver failure, n = 6 and n
      = 30, respectively). We serially measured serum hyaluronate levels using a
      sandwich binding protein assay system before and after hepatectomy and determined
      relations with progression of the underlying chronic liver disorder, portal
      venous pressure, and liver growth of the left lobe after portal embolization.
      Serum hyaluronate levels were significantly elevated, in line with the degree of
      severity of the underlying chronic liver disorder, and correlated well with the
      portal venous pressure and the hypertrophic ratio of the left lobe subsequent to
      portal embolization. Serum hyaluronate levels in group 1 were significantly
      higher than those in group 2 before surgery and increased steeply during the
      early period after hepatectomy. These results suggest that the serum hyaluronate
      reflects the hepatic functional reserve, and serial measurement of this parameter
      after hepatectomy can serve as a simple indicator for early detection of
      posthepatectomy liver failure.

PMID- 10658074
TI  - Postoperative hepatic catabolic stress response in patients with cirrhosis and
      chronic hepatitis.
AB  - Open (OC) or laparoscopic (LC) cholecystectomy is considered a relative
      contraindication in patients with liver cirrhosis. The effect of LC and OC on the
      hepatic catabolic stress response was studied in patients with postnecrotic liver
      cirrhosis and chronic hepatitis to define the most suitable procedure from a
      metabolic point of view. Altogether 14 patients with cirrhosis and 14 with
      chronic hepatitis were randomized to LC or OC (n = 7 in each group). The increase
      in the functional hepatic nitrogen clearance (FHNC) was quantified. Changes in
      glucose, insulin, glucagon, cortisol, epinephrine, norepinephrine, and
      prostaglandin E(2) (PGE(2)) were observed. There was no difference in FHNC
      between LC and OC in any of the patients. Among cirrhotic patients OC caused a
      132% increase in FHNC (p < 0.05) and among the hepatitis patients a 69% increase
      (p < 0.05). In contrast, there was no significant increase following LC in any of
      the patients. OC increased fasting glucose and insulin in the hepatitis patients
      (p < 0.01 and p < 0.001, respectively) and in the cirrhosis group (p < 0.01 and p
      < 0.05, respectively). Alanine stimulation increased glucose in hepatitis
      patients after OC (p < 0.05) and after LC (p < 0.01). Stimulated glucagon
      increased after OC in the hepatitis group (p < 0.05). During stimulation cortisol
      was higher following LC in hepatitis patients (p < 0.01) and cirrhotic patients
      (p < 0.05). Fasting PGE(2) was down-regulated after LC in hepatitis patients (p <
      0.05) and cirrhotic patients (p < 0.01) and after OC in the hepatitis group (p <
      0.001). FHNC is similar after LC and OC. Thus from a metabolic point of view, LC
      has no advantage over OC.

PMID- 10658075
TI  - Hepatic adenoma and focal nodular hyperplasia: differential diagnosis and
      treatment.
AB  - The diagnosis of benign hepatic tumors as hepatic adenoma (HA) and focal nodular
      hyperplasia (FNH) remains a challenge for clinicians and surgeons. The importance
      of differentiating between these lesions is based on the fact that HA must be
      surgically resected and FNH can be only observed. A series of 23 female patients
      with benign liver tumors (13 FNH, 10 HA) were evaluated, and a radiologic
      diagnostic algorithm was employed with the aim of establishing preoperative
      criteria for the differential diagnosis. All patients were submitted to surgical
      biopsy or hepatic resection to confirm the diagnosis. Based only on clinical and
      laboratory data, distinction was not possible. According to the investigative
      algorithm, the diagnosis was correct in 82.6% of the cases; but even with the
      development of imaging methods, which were used in combination, the
      differentiation was not possible in four patients. For FNH cases scintigraphy
      presented a sensitivity of 38.4% and specificity of 100%, whereas for HA the
      sensitivity reached 60% and specificity 85.7%. Magnetic resonance imaging,
      employed when scintigraphic findings were not typical, presented sensitivities of
      71.4% and 80% and specificities of 100% and 100% for FNH and HA, respectively.
      Preoperative diagnosis of FNH was possible in 10 of 13 (76.9%) patients and was
      confirmed by histology in all of them. In one case, FNH was misdiagnosed as HA.
      The diagnosis of HA was possible in 9 of 10 (90%) adenoma cases. Surgical biopsy
      remains the best method for the differential diagnosis between HA and FNH and
      must be performed in all doubtful cases. Surgical resection is the treatment of
      choice for all patients with adenoma and can be performed safely. With the
      evolution of imaging methods it seems that the preoperative diagnosis of FNH may
      be considered reliable, thereby avoiding unnecessary surgical resection.

PMID- 10658076
TI  - Hepatic vein reconstruction by external iliac vein graft using vascular clips.
AB  - The utility of hepatic vein reconstruction following resection of segments VII
      and VIII plus the right hepatic vein (RHV) is still controversial. The purpose of
      this study was to investigate the surgical benefits of hepatic vein
      reconstruction using stapled vascular clips and the draining area of hepatic vein
      using angiographic computed tomography (CT) to determine strict indications for
      hepatic vein reconstruction. Five patients underwent RHV reconstruction by
      external iliac vein graft using stapled vascular clips (VCS clips) following
      resection of segments VII and VIII, regardless of whether an inferior right
      hepatic vein (IRHV) was present. In eight other patients CT during arterial
      portography (CTAP) under temporary RHV occlusion using a balloon catheter was
      performed to determine the drainage area of the RHV. Operating times were 240 to
      400 minutes (mean 336 +/- 59 minutes), and the mean hepatic vein reconstruction
      time was 26 +/- 5 minutes. There were no complications related to the surgery.
      Follow-up examinations showed patency of the graft in all cases; three patients
      are still alive with long-term graft patency of 10 to 24 months. CTAP under RHV
      occlusion demonstrated that segment VI and part of segment V were almost
      hypoattenuated in cases of absent or small IRHV, although those segments were
      hyperattenuated in thick IRHV and RHV-IRHV communicating patients. In conclusion,
      this anastomotic technique using vascular clips resulted in sound patency of the
      graft, which was accomplished by a simple technique. Preoperative CT AP with the
      RHV occlusion method can be useful for determining whether hepatic vein
      reconstruction is necessary.

PMID- 10658077
TI  - Surgical results in patients with hepatitis B-related hepatocellular carcinoma
      and positive hepatitis B early antigen.
AB  - Hepatitis B virus (HBV) infection is the major risk factor in the pathogenesis of
      hepatocellular carcinoma (HCC). Patients who are positive for hepatitis B early
      antigen (HBeAg) have active liver disease. The present study aimed to evaluate
      the possible role of HBeAg in patients with resectable HCC. A series of 249 HCC
      patients with complete preoperative hepatitis marker who had undergone
      potentially curative resection were enrolled. Patients with hepatitis C virus
      infection were excluded. Of these patients, 27 were positive for hepatitis B
      surface antigen (HBsAg) and HBeAg (group I), 171 were positive for HBsAg and
      negative for HBeAg (group II), and 51 were negative for hepatitis B markers
      (group III). The clinicopathologic features and postoperative survivals were
      compared among the three groups. The prevalence of HBeAg was 10.8%. Group I
      patients were significantly younger and had worse liver function, smaller tumors,
      and a higher incidence of liver cirrhosis and chronic active hepatitis than those
      in groups II and III. No increase in tumor invasiveness was noted in group I
      patients. The operative morbidity, mortality, and postresection survival were
      comparable among the three groups. Our findings indicated that HBeAg positivity
      is not a negative factor for resection in HCC patients and has no significant
      influence on postresection survival.

PMID- 10658103
TI  - Outcome measurement of the treatment of maxillary fractures: a prospective
      analysis of 100 consecutive cases.
AB  - We performed a prospective study of 100 consecutive patients presenting to our
      unit with complex maxillary fractures. Fracture severity was assessed according
      to the alpha-numeric scoring system of Cooter and David and correlated with
      outcome. Regional maxillary and total fracture scores demonstrated a positive
      correlation with complication rates, with correlation coefficients of 0.89 and
      0.98 respectively. Ocular and orbital complications were most commonly seen with
      these complex injuries, but occlusal problems were much less common. Despite
      close consultant-led supervision in a specialised centre, these injuries
      frequently result in long term problems.

PMID- 10658104
TI  - 109 cases of blepharoptosis treated by forked frontalis muscle aponeurosis
      procedure with long term follow-up.
AB  - 109 cases of severe or recurrent blepharoptosis have been treated with the forked
      frontalis muscle aponeurosis (FFMA) technique since 1989. In comparison with
      other frontalis muscle flap (FMF) protocols, this technique has three advantages:
      (i) no skin incision in the lower rim of the eyebrow; (ii) no incision in the
      frontalis muscle; and (iii) no dissection under the frontalis muscle. The FFMA is
      formed at the junction of the frontalis and orbicularis muscles. The 9-year
      follow-up shows that this is a highly effective procedure. The postoperative
      function of the frontalis muscle is good and the lack of damage has been
      confirmed by EMG. There are a few complications such as the sluggishness of the
      upper eyelid on downward gaze and the possibility of asymmetrical brow height in
      unilateral blepharoptosis. However, this technique may serve as the best choice
      in the treatment of severe or recurrent blepharoptosis.

PMID- 10658105
TI  - Elevation of a constructed auricle using the anteriorly based mastoid fascial
      flap.
AB  - Two-stage methods for reconstruction of congenital microtia have been widely
      utilised. To obtain a desirable auriculocephalic angle and provide a nutrient
      support to the constructed auricle, elevation of reconstructed ears using a
      costal cartilage graft, the anteriorly based mastoid fascial flap transfer and a
      skin graft was performed as the second operation for nine microtia patients. In
      this procedure, the mastoid fascial flap was used instead of the temporoparietal
      fascial flap. Following the elevation of the reconstructed ear the anteriorly
      based mastoid fascial flap was harvested. A carved costal cartilage was grafted
      at the posterior wall of the concha and covered with the mastoid fascial flap,
      followed by a full-thickness skin graft from the inguinal region. The skin grafts
      took well and the appropriate auriculocephalic angle was preserved in all cases.
      This method was easy to perform and did not leave any scar in the temporal hair
      bearing area.

PMID- 10658106
TI  - Fascial flaps based on perforators for reconstruction of defects in the distal
      forearm.
AB  - Twenty fascial flaps were used in the reconstruction of defects in the distal
      forearm, wrist and hand in 18 patients over a 2-year period. In 16 patients the
      fascial flaps were based on a single fascial feeding vessel or 'perforator'
      arising from the anterior interosseous artery and/or ulnar artery when the radial
      artery had been used as the donor vessel in free flap reconstruction elsewhere in
      the body. There was no loss of any fascial flap in the study. The use of fascial
      flaps based on fascial feeders of the anterior interosseous and ulnar arteries
      extends the range of fascial flaps that can be raised in the forearm for
      reconstruction of defects in the distal forearm, wrist and hand.

PMID- 10658107
TI  - The lumbar artery perforator based island flap: anatomical study and case
      reports.
AB  - A lumbar artery island flap can be elevated based on a single lumbar artery. We
      studied the vascular anatomy using 21 specimens of lumbar arteries in 11
      cadavers, and investigated the skin territory of the artery using fluorescein
      injection. We observed lumbar perforators emerging through the lumbar fascia at
      the lateral border of the erector spinae muscle, situated 5-9 cm from the
      midline. The diameter of the vascular bundle at the site of perforation ranged
      from 1 to 5 mm. Perforators of the second and fourth lumbar arteries were much
      more developed than others. The cutaneous territory supplied by the second lumbar
      artery extended from the posterior midline to the lateral border of the rectus
      sheath, and at least 10 cm above the anterosuperior iliac spine. We transferred
      four clinical flaps for coverage of ulcers on the lower back. All flaps survived
      and their donor site defects were closed primarily. The cadaver dissection, the
      injection study and our clinical success have confirmed the feasibility of lumbar
      artery island flaps.

PMID- 10658108
TI  - Vaginal reconstruction with the femoral veno-neuroaccompanying artery
      fasciocutaneous flap.
AB  - The arterial anatomy of the anteromedial thigh was investigated in ten fresh
      cadavers that had been systemically injected with a lead oxide-gelatin mixture.
      The arteries accompanying the great saphenous vein and the anterior cutaneous
      branches of the femoral nerve were found to have branches not only to the
      cutaneous vein and nerve, but also to the skin. On the basis of the anatomy of
      these accompanying arteries, a pedicled fasciocutaneous flap containing them was
      developed consisting of an adipofascial pedicle and a skin island. This flap has
      been named the femoral veno-neuroaccompanying artery fasciocutaneous flap (the
      femoral V-NAF flap, the great saphenous-femoral V-NAF flap) and has been applied
      in three cases of vaginal reconstruction.

PMID- 10658109
TI  - Pulsed dye laser therapy for viral warts.
AB  - Twenty-eight patients with 103 recalcitrant and 20 simple viral warts were
      treated with the Cynosure PhotoGenica V pulsed dye laser at 585 nm, and fluencies
      of 6.0-9.0 J/cm(2). An eradication rate of 92% for recalcitrant warts after an
      average of 2.1 (range 1-7) treatments and 75% for simple warts after an average
      of 1.6 (range 1-2) treatments was achieved with a mean follow-up period of 7.2
      (range 3-15) months. Mild hypopigmentation was noted in one patient and
      superficial infection in another. Unlike ablative treatment modalities, with
      pulsed dye laser therapy, no wound was created thus avoiding prolonged
      postoperative pain, disability and scarring. Treatment was well tolerated by
      patients, most of whom returned to work or normal activities immediately
      postoperatively. Pulsed dye laser is an effective treatment for both recalcitrant
      and simple warts. It is the treatment of choice for these lesions in cosmetically
      sensitive areas.

PMID- 10658110
TI  - Experimental study of mechanical microvascular anastomosis with new biodegradable
      ring device.
AB  - The commercially available mechanical vascular anastomotic device with ring-pin
      technique employs polyethylene rings and stainless steel pins, but even after
      healing of the anastomotic site, the ring remains. To resolve this disadvantage,
      the ring material was replaced by biodegradable material, and a ring coupling
      device was fabricated. This new ring was used to anastomose the femoral vein of
      rabbits, and morphological observations were made macroscopically and by light
      and scanning electron microscopy. Of the 58 anastomosed veins, 54 were patent,
      giving a patency rate of 92.9%. The ring was largely absorbed 15 weeks after
      anastomosis and completely after 30 weeks. Histologically, re-endothelialisation
      was observed in 1 week. Infiltration of inflammatory cells was significant around
      the ring at 3 weeks, but inflammation subsided within 6 weeks. There were no
      findings indicating adverse effects of the stainless steel pins remaining outside
      the vascular wall.

PMID- 10658111
TI  - Haemodynamics and oxygen tension in the microcirculation of ischaemic skin flaps
      after neural blockade and haemodilution.
AB  - The aim of this study was to evaluate the effects of neural blockade and extended
      normovolaemic haemodilution on haemodynamics and oxygenation in the
      microcirculation of ischaemic skin flaps using a recently developed island flap
      on the back of Syrian golden hamsters. One part of the flap was made ischaemic by
      inducing a random perfusion pattern following interruption of the axial blood
      supply. The model permitted quantitative assessment of the microhaemodynamics and
      oxygen tension in all microvascular segments by the use of intravital microscopy.
      Oxygen tension was measured with the phosphorescence decay method. Neural
      blockade was induced by applying 2% lidocaine to the neurovascular flap pedicle.
      Haemodilution was achieved by isovolaemic exchange of 50% of the total blood
      volume with dextran 70. One hour after surgery (baseline), centreline velocity
      was significantly reduced to 20-44% in all the microvessels in the randomly as
      compared to the axially perfused part, whereas the diameters were slightly larger
      (ns). In the control group, blood flow declined by 20-75% (P< 0.01 vs. baseline)
      over time in the entire flap. Flow reduction was significantly attenuated by
      haemodilution in the entire flap, but more pronounced in the ischaemic part.
      Neural blockade caused marked vasodilatation and significantly improved blood
      flow in the axially but not in randomly perfused microvessels. After 8 h, oxygen
      tension ranged from 4.0 to 6.1 mmHg in the axial part (means, ns between groups),
      whereas in the ischaemic part, it was 0.8-1.0 mmHg (P< vs. axial) in the control
      and neural blockade groups, and 1.7 mmHg (ns vs. axial and between groups) after
      haemodilution. Our findings indicate that neural blockade does not improve
      microcirculation and oxygenation in randomly perfused flap tissue because the
      sympathetic regulation of its microcirculation is overruled by autoregulatory
      mechanisms. Normovolaemic haemodilution, even after a 50% exchange, augments
      oxygenation in ischaemic flap tissue due to increased blood flow particularly in
      the randomly perfused tissue.

PMID- 10658112
TI  - Cellular artificial skin substitute produced by short period simultaneous culture
      of fibroblasts and keratinocytes.
AB  - We developed a novel artificial skin substitute consisting of two collagen sponge
      layers with different pore sizes and cross-link densities. Fibroblasts suspended
      in 0.5 ml Dulbecco-modified Eagle's medium (DMEM) + 10% fetal bovine serum (FBS)
      were seeded on the lower dermal sponge layer, then epidermal collagen sponge and
      0.1 ml suspension of keratinocytes in KGM were layered in this order. After a few
      hours, the medium was changed to DMEM + 5% FBS. These processes were carried out
      in one day, and the composite layers were then cultured by the air-liquid
      interface culture method. Three to five days after seeding, keratinocytes had
      grown to about ten layers, and fibroblasts had grown three-dimensionally into the
      lower dermal sponge layer. This novel cellular artificial skin substitute was
      grafted onto nude mice and took in 4 weeks. This skin substitute has the
      advantage of a shorter culturing period than previously cultured skins, and may
      be clinically useful for grafting that is urgently required in patients with
      severe generalised burns.

PMID- 10658113
TI  - Differential responses of collagen and glycosaminoglycan syntheses and cell
      proliferation to exogenous transforming growth factor beta 1 in the developing
      mouse skin fibroblasts in culture.
AB  - Skin fibroblast cultures were established from mouse foetuses at days 14, 15, 16
      and 18 of gestation and from newborn mice. Modulations of mitotic and
      biosynthetic phenotypes of the fibroblasts by transforming growth factor beta1
      (TGFbeta1) were studied. Treatment of the fibroblasts with TGFbeta1 at doses of 1
      and 10 ng/ml for 48 h resulted in significant stimulation of cell proliferation
      in the 15-, 16- and 18-day foetal fibroblasts and a slight stimulation in the 14
      day foetal fibroblasts. Treatment with TGFbeta1 resulted in stimulation of
      collagen synthesis approximately 2-fold in the 18-day foetal and newborn
      fibroblasts, but failed to stimulate it in the 14-, 15- and 16-day foetal
      fibroblasts. TGFbeta1 stimulated glycosaminoglycan (GAG) synthesis throughout all
      developmental stages approximately 1.8-2.6 fold. Histological study demonstrated
      that skin wounds made at day 16 of gestation were replaced with normal-appearing
      dermis, but at day 18 the wounds left dermal fibrosis and lack of hair follicles.
      These results indicate that the modulations of fibroblast phenotypes
      (proliferation and syntheses of collagen and GAG) in response to TGFbeta1 occur
      at different stages of gestation. Ontogenic transitions of skin wound healing and
      collagen synthetic phenotype with TGFbeta1 treatment in cultured fibroblasts
      occurred between days 16 and 18 of gestation, suggesting that the
      unresponsiveness of collagen synthesis to exogenous TGFbeta1 in cell culture may
      be related to the phenomenon of scarless wounds in the foetus.

PMID- 10658114
TI  - Plastic surgery in the UK and the USA--comparisons and contrasts: some thoughts
      for the future in the UK.

PMID- 10658115
TI  - An audit of breast reduction without drains.
AB  - Fifty consecutive patients who underwent breast reduction have been audited to
      determine whether or not using drains adversely affected their outcome. The mean
      age of the patients was 32 years and the mean mass of breast tissue excised was
      750 g. There were two early complications (within 30 days postoperatively): one
      seroma and one minor wound dehiscence. Both were dealt with on an outpatient
      basis. There was one late complication of a breast abscess 6 weeks
      postoperatively.These results are comparable with previously published series of
      breast reduction surgery using wound drainage, suggesting that the absence of
      drains does not adversely affect postoperative recovery.

PMID- 10658116
TI  - Complications following correction of prominent ears: an audit review of 122
      cases.
AB  - Correction of prominent ears is a commonly performed operation, not without
      complications. We present a retrospective analysis of the results of 122
      operations for correction of prominent ears performed in the 12 months from April
      1995 to March 1996, and the results of a patient questionnaire. Complications
      were recorded and analysed. Anterior scoring appears to have a higher
      complication rate if supplemented by cartilage sutures. Complication rates appear
      to be highest for unsupervised SHOs. Head bandages are particularly likely to
      fall off in boys under 7 years of age.

PMID- 10658117
TI  - Juvenile xanthogranuloma variant: a clinicopathological case report and review of
      the literature.
AB  - Juvenile xanthogranuloma is a relatively rare cutaneous lesion. In order to make
      an early diagnosis and be alert to the possibility of visceral complications and
      associated medical conditions, plastic surgeons should be aware of the entity.
      The classic presentation is that of successive eruptions in the head, neck and
      upper trunk of initially red papules or nodules which later become yellow and
      finally brown flattened plaques or macules. This report is of an unusual variant
      with atypical histology including frequent mitoses and a lack of Touton giant
      cells.

PMID- 10658118
TI  - Palmar fasciectomy and keloid formation.
AB  - A 53-year-old Caucasian with keloid formation on the palmar surface of the hand
      following Dupuytren's contracture release is presented. Only two other cases of
      keloid formation on the hand have been found in English literature, both on black
      patients. This is the first known case with association of Dupuytren's disease to
      be reported. Surgical excision of the keloid with intraoperative injection of
      triamcinolone of the wound edges resulted in clinical cure.

PMID- 10658119
TI  - Plastic surgery and pseudoxanthoma elasticum.
AB  - Pseudoxanthoma elasticum is a cause of abnormal skin laxity. A case of lower face
      and neck skin laxity is presented with its treatment by cutaneous rhytidectomy.

PMID- 10658120
TI  - Obesity and breast reduction surgery.

PMID- 10658121
TI  - Problems associated with the use of internal mammary vessels as recipients for
      free flap breast reconstruction.

PMID- 10658122
TI  - Malignant melanoma disguised by a tattoo.

PMID- 10658123
TI  - Primary repair of incomplete unilateral cleft lip.

PMID- 10658124
TI  - Stitch tricks.

PMID- 10658126
TI  - Scalp cleaning following surgery.

PMID- 10658125
TI  - Superficial inferior epigastric vein (SIEV): 'lifeboat' for DIEP/TRAM flaps.

PMID- 10658127
TI  - Pre-Christmas traumas: the guillotine letter box.

PMID- 10658129
TI  - Notices

PMID- 10658128
TI  - A collective term for plastic surgeons.

PMID- 10658130
TI  - An investigation into the mechanism of orbital blowout fractures.
AB  - For over a century, since the first description of an orbital 'blowout' fracture,
      there has been debate and confusion regarding the mechanism of production of
      these fractures. An orbital blowout fracture throughout this paper refers to
      fractures exhibiting displacement of the orbital floor or walls without an
      associated fracture of the orbital rim. These are the so called 'pure' blowout
      fractures as described by Converse. Involvement of the orbit in a variety of
      facial fracture patterns is easily explained on anatomical grounds. The orbital
      blowout fracture and symptom complex are readily recognisable but explanation of
      the mechanisms involved is not easily apparent. Experimental and clinical studies
      have generally aimed to support one or other of two proposed mechanisms. The
      'buckling' theory contends that the fracture is produced as a result of
      transmission of force to the orbital floor from a blow to the orbital rim (Fig.
      1). The 'hydraulic' theory differs in suggesting the force is transmitted to the
      floor via a direct blow to the globe (Fig. 2). Review of the literature reveals
      that there are major flaws in the design and execution of previous experimental
      methods. Most studies have incorporated some or all of the following limitations:
      low numbers, unquantified forces, non human models, incomplete soft tissues, poor
      simulation of in vivo conditions and a failure to isolate the position of the
      striking force. No study has ever provided a direct comparison between the two
      mechanisms under identical conditions. We present the results of such a study
      undertaken on 47 fresh cadaver orbits using the same quantifiable force and under
      the same experimental conditions. The results demonstrate that the efforts to
      establish either mechanism as the primary aetiology have been misplaced. Both
      mechanisms produce orbital blowout fractures. The fractures produced, however,
      are fundamentally different in their size, position and likely clinical
      significance.

PMID- 10658131
TI  - Sphincter pharyngoplasty for the surgical management of speech dysfunction
      associated with velocardiofacial syndrome.
AB  - There are no reports in the literature that document the effectiveness of
      sphincter pharyngoplasty as a surgical alternative to pharyngeal flap for
      management of velopharyngeal dysfunction in patients with velocardiofacial
      syndrome. A retrospective review of patients with velocardiofacial syndrome was
      undertaken at our tertiary cleft care centre. All patients were managed between
      1984 and 1996 at the Cleft Palate and Craniofacial Deformities Institute, St
      Louis Children's Hospital. Subjects (n = 19) underwent velopharyngeal surgical
      management on the basis of perceptual speech evaluations and instrumental
      assessments of inadequate velopharyngeal closure. All patients had a molecular
      diagnosis of velocardiofacial syndrome based on fluorescent in situ hybridisation
      analysis of peripheral blood lymphocytes and independent evaluation by a medical
      geneticist. Surgical outcome was classified as successful if perceptual speech
      assessment indicated elimination of hypernasality, nasal emission and turbulence,
      and instrumental assessment indicated 100% velopharyngeal closure. Results showed
      that 18 of 19 patients were managed successfully with sphincter pharyngoplasty.
      Our data corroborate that sphincter pharyngoplasty is a reasonable alternative to
      pharyngeal flap in patients with velopharyngeal dysfunction secondary to
      velocardiofacial syndrome.

PMID- 10658132
TI  - Multiple cutaneous malignancies arising in limbs with signs of lymphatic
      insufficiency in transplant patients.
AB  - We report the cases of four renal transplant patients who developed multiple skin
      cancers located preferentially on lymphoedematous lower limbs. All skin tumours
      appeared post-transplant and the diagnosis was confirmed on histologic
      examination. In addition, one of the patients also underwent mastectomy with
      axillary dissection and radiotherapy for a left breast ductal carcinoma and
      subsequently developed multiple squamous carcinomas and intraepithelial
      carcinomas on the left upper limb.The aetiology of lymphoedema in these patients
      is multifactorial. In addition to immunosuppression, ultraviolet exposure,
      genetic factors and possibly infection with the human papilloma virus, which are
      thought to have a role in the aetiology of certain skin tumours, lymphoedema may
      have contributed to the predominant location of these skin malignancies on the
      lymphoedematous limbs.

PMID- 10658133
TI  - Circumferential torsoplasty.
AB  - Abdominoplasty procedures are often unsatisfactory in correcting body deformities
      remaining after massive weight loss. Lateral flanks, hip rolls and buttock ptosis
      need also to be addressed surgically. To achieve a more noticeable improvement in
      body contour, a circumferential torsoplasty procedure was performed in 30
      patients during the years 1993-1997. Twenty of them had had a gastroplasty
      procedure before with a mean weight loss of 49.5 kg. Mean operative time was 210
      min (range 150-420 min). The total resection weight ranged from 2 to 8.96 kg
      (mean 4.3 kg). Mean operative blood loss was 635 ml (range 300-1900 min). The
      mean hospital stay was 12 days. Minor complications occurred in four patients and
      major complications in one. Both patients and surgeons considered the outcome
      very satisfactory.

PMID- 10658134
TI  - New insights in the development of Dupuytren's contracture: a review.
AB  - Recent advances in the understanding of myofibroblast histology and function, the
      activity of fibrogenic cytokines, the role of the extracellular matrix and of
      free radicals are contributing to an understanding of the aetiology of
      Dupuytren's disease but not yet to its treatment. Surgical excision remains the
      best treatment.

PMID- 10658135
TI  - Ruby laser-assisted hair removal: an ultrastructural evaluation of cutaneous
      damage.
AB  - Ruby laser-assisted hair removal is thought to act via selective photothermolysis
      of melanin in the hair follicles. Although initial clinical trials of permanent
      hair removal using ruby lasers are promising, the exact mechanisms of hair
      destruction and the potential damage to other structures of skin are not known.
      The aim of this study was to evaluate the cutaneous ultrastructural changes
      following ruby laser hair removal. Nineteen healthy Caucasian patients with dark
      (brown/black) hair were treated with the ruby laser and biopsies taken after 0,
      2, 3, 5, 7, 14 and 21 days. Specimens were examined by light and electron
      microscopy. Laser-treated specimens showed widespread coagulation and charring of
      subcutaneous hair shafts. These obviously damaged follicles were randomly
      dispersed amongst intact follicles within the same treatment sites. Microscopic
      changes were also seen in the basal epidermis where melanin was concentrated,
      irrespective of any obvious macroscopic damage. A low level of inflammatory
      response seen up to 2 weeks after treatment always followed laser treatment.
      Suprabasal epidermal necrosis was only seen in patients with blister formation
      after treatment. Ruby laser irradiation results in selective damage to the hair
      follicles, with microscopic changes to the basal epidermis. The damage is
      probably compounded by the inflammatory response to the damaged hair. The normal
      appearance and distribution of collagen in the dermal layer supported the
      clinical evidence that laser-assisted hair removal, if performed correctly, does
      not lead to scar formation.

PMID- 10658136
TI  - In vivo analysis of the microcirculation of osteomyocutaneous flaps using
      fluorescence microscopy.
AB  - Previous studies have indicated that freely transferred osteomyocutaneous flaps
      may fail despite anastomotic patency. While microvascular dysfunction is thought
      to be one of the major causes for this type of flap failure, little is known of
      its underlying mechanisms, probably due to the lack of adequate experimental
      models allowing detailed intravital microcirculatory analysis. Herein we report
      quantitative analysis of the microcirculation of periosteum, muscle, subcutis and
      skin by intravital fluorescence microscopy using an osteomyocutaneous free flap
      model in the hindlimb of rats. The microcirculation of the different tissues was
      studied after microanastomotic transfer (free flap), and was compared to that
      after solely elevating the tissue, mimicking a pedicled osteomyocutaneous flap.
      Transferred flaps, which were exposed to 1 h of ischaemia during the anastomotic
      procedure, showed a slight but significant decrease (P< 0.05) of functional
      capillary density in muscle, subcutis and skin when compared with the
      microcirculation of pedicled flaps, while capillary diameters, red blood cell
      velocity and blood flow of perfused capillaries remained almost unaffected. The
      decrease of functional capillary density was associated by a significant (P<
      0.05) inflammatory response, as indicated by the increased number of leukocytes
      adherent to the endothelial lining of postcapillary venules. While the functional
      capillary density of periosteum was not affected by the free transfer procedure,
      the inflammatory response was found similar when compared with that observed in
      muscle and subcutis. Thus, our study indicates that even after a short 1-h
      ischaemic time period, capillary perfusion failure and leukocyte-endothelial cell
      interaction are the main events, characterising microvascular dysfunction after
      free transfer of osteomyocutaneous flaps. Using the model described herein,
      intravital microscopic analysis of the microcirculation proved an appropriate
      tool to study the individual microvascular response after free tissue transfer,
      and may thus be used to evaluate the effectiveness of novel therapeutic regimens
      which aim at counteracting microcirculatory dysfunction in free osteomyocutaneous
      flaps.

PMID- 10658137
TI  - A resorbable nerve conduit as an alternative to nerve autograft in nerve gap
      repair.
AB  - Poly-3-hydroxybutyrate (PHB) occurs within bacterial cytoplasm as granules and is
      available as bioabsorbable sheets. Previously, the advantage of PHB in primary
      repair has been investigated while in this study the same material has been used
      to bridge an irreducible gap. The aim was to assess the level of regeneration in
      PHB conduits compared to nerve autografts. The rat sciatic nerve was exposed, a
      10 mm nerve segment was resected and bridged with either an autologous nerve
      graft or a PHB conduit. The grafted segments were harvested up to 30 days.
      Immunohistochemical staining was performed and computerised quantification of
      penetration distance and volume of axonal regeneration was estimated by protein
      gene product (PGP) immunostaining and calcitonin gene-related peptide (CGRP)
      positive fibres. Penetration and proliferation density of Schwann cells into the
      conduit was measured by quantifying S-100 staining. The inflammatory response was
      quantified with ED-1 staining for macrophages. Antibodies to vWf provided an
      assessment of angiogenesis and capillary infiltration. Percentage immunostaining
      for PGP in autograft and PHB groups showed a progressive increase up to 30 days
      with a significant linear trend with time and an increase in the volume of axonal
      regeneration. A similar pattern of progressive increase with time was observed
      with CGRP immunostaining for both groups and with S-100 in the PHB group. Good
      angiogenesis was present at the nerve ends and through the walls of the conduit.
      The results demonstrate good nerve regeneration in PHB conduits in comparison
      with nerve grafts.

PMID- 10658138
TI  - A technique for repair of the 'unrepairable' cleft palate.
AB  - The 'unrepairable' cleft palate may be described as one in which the width of the
      cleft exceeds the sum of the widths of the palatal shelves. A report of such a
      case is presented, and the technique used to repair the cleft using bilateral
      buccinator musculomucosal flaps is described. It is offered as a suggested
      technique for the management of such cases in the future.

PMID- 10658139
TI  - The prepuce flap in the reconstruction of male anal stenosis.
AB  - Circumferential stenosis of the male anal canal was repaired using a subcutaneous
      prepuce flap. The stenosis was released to create a rhomboid defect. Then, to
      cover the defect a rectangular flap was designed on the hairless ventral side of
      the penis. The flap was raised over the Buck's fascia while preserving the
      subcutaneous vessels in the dartos fascia, which formed the pedicle of the flap.
      The flap was transposed to the defect by passing it through a tunnel in the
      perineum. The postoperative course was uneventful and the result was good. The
      flap had reliable vascularity, was very thin, and pliable so that it could adapt
      to the rhomboid defect in the anal canal.

PMID- 10658140
TI  - Ossification in the rectus sheath following free rectus flap.
AB  - Heterotopic ossification (HO) is a rare complication of laparotomy wounds. In
      this report, we describe an unusual presentation of ossification within the
      closed sheath following the harvest of a free rectus flap for lower limb
      reconstruction. Of specific interest to this case is that access to the rectus
      was gained through a lower transverse approach. Furthermore, the extremities of
      this incision were utilised for harvest of cancellous bone from the iliac crests.
      Given that one explanation for HO is intraoperative seeding it is of note that no
      problem was encountered in the wound intimately associated with the bony
      disruption.

PMID- 10658141
TI  - Multiple tumour presentation of trichilemmal carcinoma.
AB  - Trichilemmal carcinoma is a rare skin tumour occurring in the sun-exposed areas
      of the elderly. It originates from the external root sheath of the hair follicle
      and is the malignant form of the trichilemmoma. Clinically, it may be mistaken
      for a squamous cell carcinoma, basal cell carcinoma, nodular melanoma or
      keratoacanthoma. It is distinct from the proliferating trichilemmal tumour.
      Trichilemmal carcinoma is usually a solitary lesion and an extensive literature
      search revealed no previously reported cases of multiple tumour presentation. We
      describe a case of trichilemmal carcinoma arising from three distinct sites in
      the same patient and discuss the differential diagnoses, histological features
      and probable aetiology of this rare tumour.

PMID- 10658142
TI  - Lower abdominal wall reconstruction using the anterior thigh fasciocutaneous
      flap.
AB  - Full thickness defects of the lower abdominal wall are uncommon. They can occur
      in congenital abdominal wall defects, acute trauma and following resection of
      soft tissue tumours. In reconstruction of defects not amenable to primary
      closure, three problems need to be addressed: (i) the fascial layer needs to be
      reconstructed; (ii) stable and sensate skin coverage is needed as the lower
      abdominal waistline area is subject to pressure; (iii) it is desirable to restore
      the contour of the abdominal wall. We present a case with a large area of
      radiation dermatitis and recurrence of a malignant ovarian tumour in the lower
      abdominal wall. After en bloc resection the 25 x 6 cm lower abdominal defect was
      reconstructed with a sensate anterior thigh fasciocutaneous flap. The vascular
      supply was reliable and the outcome was good. The reasons for using this
      fasciocutaneous flap in preference to the other options are discussed.

PMID- 10658143
TI  - Dorsocommissural flap.
AB  - We present a case of dorsoradial skin loss over the middle phalanx of the middle
      finger with section of the central slip of the extensor tendon and loss of one
      lateral band following mechanical injury. Successful primary reconstruction of
      the central slip was performed by retrograde flap from the central slip of the
      extensor tendon tied with barb-wire over a padded button, splinted for 2 weeks
      with a K-wire, and skin cover with a dorsocommissural flap based on the second
      web space. Other reconstructive options are discussed.

PMID- 10658144
TI  - General body growth in children with cleft lip and palate in a developing
      country.

PMID- 10658145
TI  - Contour deformity at the internal mammary recipient site.

PMID- 10658146
TI  - A new tie-over dressing for hypospadias repair.

PMID- 10658147
TI  - Problems associated with the use of suction drains following free tissue transfer
      in reconstruction during head and neck surgery.

PMID- 10658149
TI  - Notices

PMID- 10658148
TI  - Breast implant infection following nipple piercing.

PMID- 10658151
TI  - Subject index

PMID- 10658152
TI  - Imaging of postnatal maturation of the skull base.
AB  - The skull begins to form when mesenchyme thickens and condenses around the
      developing brain. At the skull base, most of this mesenchyme derives from neural
      crest, and some arises from general head mesenchyme. This article reviews the
      patterns for maturation of the ossification, sutures, and synchondroses in the
      occipital, the sphenoid, and the orbitoseptal regions, and reports additional
      data derived from specific study of CT scans of the skull base in children and
      young adults.

PMID- 10658153
TI  - Imaging of the osseous, membranous, and perilymphatic labyrinths.
AB  - The inner ear is located within the petrous portion of the temporal bone and
      consists of the membranous, perilymphatic, and the outer osseous labyrinths.
      Together, these structures form the end organs for mediating hearing and balance.
      This article provides a detailed review of the neonatal anatomy and development
      of these structures, knowledge of which derives in great part from advances in CT
      and sophisticated MR imaging. Current research should soon enable clinicians to
      identify a wide variety of subtle lesions of the inner ear that heretofore have
      been inaccessible to imaging diagnosis.

PMID- 10658154
TI  - Imaging of congenital anomalies of the temporal bone.
AB  - This article briefly presents the embryology of the ear and discusses the
      external auditory canal and middle ear, including first branchial cleft
      anomalies, external auditory canal atresia and stenoses, congenital
      cholesteatoma, and congenital teratoma. Topics related to the labyrinths include
      aplasia, the common-chamber anomaly, the pseudo-Mondini and Mondini
      malformations, semicircular canal dysplasia, and the large vestibular aqueduct.
      Vascular malformations and variations also are presented, including the absent
      and aberrant internal carotid artery, the persistent stapedial artery, and high
      jugular bulb; cerebrospinal fluid and perilymph fistulas are the subjects of the
      final section.

PMID- 10658155
TI  - Embryology and anatomy of the neck.
AB  - As a prelude to understanding pathologic conditions of the pediatric neck, this
      article presents the embryologic development of the neck, fascial planes, and key
      anatomic structures. Detailed discussion includes the normal development of the
      neck and illustrates, using selected CT and MR images, the fascial spaces, larynx
      and trachea, thyroid, parathyroid, and vascular and lymphatic anatomy.

PMID- 10658156
TI  - Imaging of congenital anomalies of the branchial apparatus.
AB  - One of the most challenging topics for radiologists is congenital anomalies
      arising from abnormal embryogenesis of the branchial apparatus. Defects of the
      branchial apparatus result in a spectrum of anomalies that includes fistulas,
      sinuses, cysts, temporal bone anomalies, craniofacial malformations, and systemic
      disorders. A better understanding of the various radiologic abnormalities is
      aided by an understanding of their embryonic origins. This article reviews the
      spectrum of abnormalities that are secondary to anomalous embryogenesis of the
      branchial arches.

PMID- 10658157
TI  - Imaging of the pediatric orbit.
AB  - This article addresses the embryology of the eye, the imaging of common
      congenital malformations involving the globe, and imaging features of common
      retro-ocular masses. Clinical entities resulting in alterations in the size and
      contour, and those producing leukokoria, also are discussed.

PMID- 10658158
TI  - Imaging of congenital vascular and lymphatic anomalies of the head and neck.
AB  - Congenital lymphatic and vascular malformations and infantile hemangiomas can be
      combined under the heading of endothelial malformations. Based on their biologic
      behavior, endothelial malformations can be divided into two groups: infantile
      hemangiomas and vascular malformations. Vascular malformations can be subdivided
      into lymphatic, capillary, venous, and arteriovenous malformations. Often
      frightening for the patient and the patient's family, some endothelial
      malformations, however, will resolve; yet others can lead to long-term
      disfigurement and even can be fatal-due to airway obstruction, secondary
      infection, or exsanguination. When recognized early, however, the appropriate
      therapy, or watchful waiting, can be initiated, and the long-term physical and
      psychological consequences of these malformations can be minimized.

PMID- 10658160
TI  - The pediatric airway: a review of differential diagnosis by anatomy and
      pathology.
AB  - In children, lesions involving and affecting the airway are numerous and vary in
      origin. Categorizing these lesions by origin (traumatic, inflammatory, congenital
      or developmental, neoplastic, and vascular) or by anatomy (nasal airway and
      nasopharynx, oral airway and oropharynx, larynx, trachea, and extrinsic lesions)
      will aid in narrowing the differential diagnosis and may guide imaging.

PMID- 10658159
TI  - Pediatric sinonasal imaging: normal anatomy and inflammatory disease.
AB  - Pediatric sinonasal anatomy changes and develops from birth to adolescence. This
      article elucidates the normal anatomy and patterns of development in the
      pediatric population. Issues in pediaric sinusitis include indications for
      imaging, the nonspecificity of sinus opacification, and the importance of
      clinical information. Sinonasal physiology is briefly discussed to offer insight
      into the interpretation of radiographic findings. Cystic fibrosis, polyps, and
      choanal atresia, representing the spectrum of common pediatric sinonasal
      inflammatory disorders are illustrated, and the spectrum of orbital and
      intracranial complications of sinusitis is reviewed.

PMID- 10658161
TI  - Nodal and nonnodal inflammatory processes of the pediatric neck.
AB  - In the pediatric neck, inflammatory processes are common and usually are nodal in
      origin. Virtually every pediatric infection, including viral diseases, can result
      in dramatic cervical adenopathy. The differential diagnosis for a dominant
      pediatric node, however, is different from that in adults, with neoplastic
      disease occurring less frequently. When nonnodal cervical infections or abcesses
      occur, it is important to identify the source and involvement of major vessels,
      the airway, and the mediastinum. This article reviews common nodal processes and
      the complications of suppurative adenopathy. Nodal and nonnodal inflammatory
      processes are discussed, with emphasis on the clinical presentation and common
      imaging findings.

PMID- 10658162
TI  - Imaging extracranial masses of the pediatric head and neck.
AB  - This article focuses on the many benign and malignant extracranial head and neck
      neoplasms that occur in the pediatric patient. Discussion emphasizes the imaging
      characteristics of lesions by location: the orbit, the sinonasal cavity, the
      nasopharynx, the face and jaw, and the neck.

PMID- 10658163
TI  - Doppler sonography of head and neck masses in children.
AB  - This article presents a clinical approach to the investigation of a child with a
      mass of the head or neck. The anatomy of the head and neck region is reviewed,
      and the technique of Doppler sonography in children is outlined. The pathology
      and the sonographic appearance of common head and neck masses specific to
      children are described.

PMID- 10658164
TI  - Imaging of orofacial clefting disorders.
AB  - This article discusses the imaging and clinical features of patients with facial
      clefts. Patients with facial clefts are classified according to interocular
      distance. Typing of facial clefts is emphasized to determine which patients need
      to undergo not only imaging, but also imaging of the brain, to assess associated
      intracranial anomalies. The genetics, treatment, and implications that these
      clefting disorders have on the growth of the face are also discussed.

PMID- 10658165
TI  - Selected interventional procedures for pediatric head and neck vascular lesions.
AB  - Although vascular malformations are commonly seen in children, they are lesions
      managed best by an experienced multidisciplinary team. Recognizing,
      investigating, and diagnosing the type of vascular malformation is critical to
      determining treatment modality and pathway. Generic identification-despite
      Mulligan's excellent classification-or confusing vascular malformations with
      hemangiomas are both inappropriate because treatment is quite different for these
      separate groups of diseases. Additionally, an understanding of the recognition
      and classification of vascular malformations is essential for effective family
      counseling and management of these childhood lesions.

PMID- 10658166
TI  - Metabolic myopathies. A diagnostic evaluation.
AB  - This article briefly reviews the initial approach to the patient suspected of
      having metabolic myopathy. Diagnostic highlights include relevant points of
      history, physical examination, blood work-up, forearm ischemic exercise test,
      electrophysiologic testings and muscle biopsy. The diagnostic evaluation is
      discussed in detail in separate articles.

PMID- 10658167
TI  - Muscle responses to exercise in health and disease.
AB  - Exercise intolerance is a common presenting symptom. The physiology of exercise
      intolerance in illustrative neurologic diseases is reviewed. Roles for exercise
      testing are identified, particularly in the evaluation of metabolic myopathies.
      The potential benefits of low intensity aerobic exercise training are described.

PMID- 10658168
TI  - MR spectroscopy and imaging in metabolic myopathies.
AB  - Magnetic resonance spectroscopy and imaging of muscle and brain offers new
      possibilities for noninvasive diagnosis of metabolic myopathies. These functional
      techniques allow assessment of the pathophysiology of these disorders and also
      can be used for monitoring disease evolution and response to therapy. In this
      article, the authors review the magnetic resonance spectroscopy and imaging
      features of mitochondrial encephalomyopathies, glycolytic disorders, and
      hypothyroidism.

PMID- 10658169
TI  - The molecular diagnosis of metabolic myopathies.
AB  - The metabolic myopathies are distinguished by extensive clinical and genetic
      heterogeneity within and between individual disorders. There are a number of
      explanations for the variability observed that go beyond single gene mutations or
      degrees of heteroplasmy in the case of mitochondrial DNA mutations. Some of the
      contributing factors include protein subunit interactions, tissue-specificity,
      modifying genetic factors, and environmental triggers. Advances in the molecular
      analysis of metabolic myopathies during the last decade have not only improved
      the diagnosis of individual disorders but also helped to characterize the
      contributing factors that make these disorders so complex.

PMID- 10658170
TI  - Mitochondrial myopathy diagnosis.
AB  - Oxidative phosphorylation (OXPHOS) accounts for approximately 95% of the
      adenosine triphosphate (ATP) produced by the cell. The central nervous system,
      peripheral nervous system, cardiac muscle, skeletal muscle, and smooth muscle are
      highly susceptible to dysfunction of this complex enzyme system. Although most
      OXPHOS diseases are multisystem disorders, the neuromuscular manifestations are
      often prominent and play an important role in patient diagnosis. To assist the
      neurologist in evaluating these complex patients, this article focuses on
      selected samples of OXPHOS diseases with identifiable neuromuscular abnormalities
      and presents an evaluation algorithm to facilitate patient diagnosis.

PMID- 10658171
TI  - Glycogen storage myopathies.
AB  - The glycogen storage myopathies are caused by enzyme defects in the
      glycogenolytic or in the glycolytic pathway affecting skeletal muscle alone or in
      conjunction with other tissues. The authors review recent findings in this area,
      including a new entity, aldolase deficiency, and the wealth of molecular genetic
      data that are rapidly accumulating. Despite this progress, genotype-phenotyp3
      correlations are still murky in most glycogen storage myopathies.

PMID- 10658172
TI  - Acid maltase deficiency and related myopathies.
AB  - There are 11 glycogen diseases (GSD), nine of which are associated with myopathy.
      Most of these glycogen storage myopathies are associated with dynamic symptoms
      and signs in that the major neuromuscular complaints are exercise-induced muscle
      pain, cramps, and myoglobinura (e.g., GSD V or McArdle's disease associated with
      myophosphorylase deficiency). The other types of glycogen storage myopathies are
      considered static in that they are associated with fixed weakness rather than
      dynamic symptoms and signs. The static glycogen storage myopathies include: GSD I
      or Pompe's disease (acid maltase or (-glucosidase deficiency), GSD II or Cori
      Forbes disease (debranching enzyme deficiency), and GSD IV or Andersen's disease
      (branching enzyme deficiency). This article reviews the clinical, laboratory,
      electrophysiologic, histopathologic, and pathogenesis of these static GSD
      myopathies.

PMID- 10658173
TI  - Disorders of lipid metabolism in skeletal muscle.
AB  - Lipid storage myopathies are typically present with recurrent episodes of
      myoglobinuria and hypoglycemia, triggered by fasting or infection. Dilated
      cardiomyopathy can occur. This article will discuss an approach to lipid storage
      myopathies and describes various forms of disorders by fatty acid oxidation.

PMID- 10658174
TI  - Myoadenylate deaminase deficiency. A common inherited defect with heterogeneous
      clinical presentation.
AB  - Myoadenylate deaminase deficiency is a clinically heterogeneous metabolic
      disorder that is commonly diagnosed in a variety of neurologic settings. Although
      the molecular basis for this purine nucleotide catabolic derangement may
      typically be attributed to the inheritance of a single prevalent mutant allele,
      the clinical spectrum in the absence of other definable abnormalities can range
      from asymptomatic to mild exercise-induced myalgia. Moreover, myoadenylate
      deaminase deficiency is also found associated with other definable neuromuscular
      disorders. The myoadenylate deaminase deficiency in these latter cases may, in
      part, be precipitated by pathologic change or act synergistically in combination
      with another metabolic disease.

PMID- 10658175
TI  - Periodic paralyses.
AB  - The periodic paralyses are a group of muscle diseases with abnormalities of
      channels. These abnormalities result in paralysis or weakness with or without
      poor relaxation of muscle. Hypokalemic periodic paralyses, potassium-sensitive
      periodic paralyses, and paramyotonia congenita are reviewed. The clinical
      findings, pathophysiologic abnormalities, diagnostic evaluations, and possible
      treatments are included in this article.

PMID- 10658176
TI  - Endocrine myopathies.
AB  - This article provides a review of some of the muscular disorders that can arise
      from some of the commonly seen endocrinologic disturbances. Thyroid, parathyroid,
      and adrenal dysfunctions as they relate to neuromuscular symptoms are discussed.
      Common clinical presentations of the endocrine myopathies are highlighted, along
      with diagnostic evaluation and treatments.

PMID- 10658177
TI  - Myoglobinuria.
AB  - Myoglobinuria refers to an abnormal pathologic state in which an excessive amount
      of myoglobin is found in the urine, imparting a cola-like hue, usually in
      association with myonecrosis and a clinical picture of weakness, myalgias, and
      edema. Myoglobinuria is produced by multiple causes: any condition that
      accelerates the use or interferes with the availability of oxygen or energy
      substrates to muscle cells can result in myoglobinuria, as can events that
      produce direct muscle injury, either mechanical or chemical. Acute renal failure
      is the most serious complication, which can be prevented by prompt, aggressive
      treatment. In patients surviving acute attacks, recovery of muscle and renal
      function is usually complete.

PMID- 10658178
TI  - Tissue wasting in patients with chronic obstructive pulmonary disease.
AB  - Malnutrition is common among individuals suffering from hypoxemic chronic
      obstructive pulmonary disease (COPD), advanced HIV disease, and in patients with
      chronic, severe congestive heart failure. Although increased morbidity and
      mortality has been associated with weight loss in these conditions, the
      pathophysiology of malnutrition remains somewhat unclear for each. In COPD, the
      primary postulated mechanism is hypermetabolism resulting in elevated total
      caloric expenditure arising from increased airway resistance, increased O2 cost
      of ventilation, increased dietary induced thermogenesis, inefficient substrate
      use and perhaps, increased levels of proinflammatory cytokines. In AIDS,
      postulated mechanisms include hypermetabolism arising from increased activation
      of proinflammatory cytokines, along with futile cycling of fatty acids and de
      novo lipogenesis early in the course of HIV infection; intestinal malabsorption
      and anorexia also play a role in many inflicted individuals. In cardiac cachexia,
      dietary and metabolic factors, and levels and activity of cytokines, thyroid
      hormone, catecholamines and cortisol have been suggested as being responsible for
      causing weight loss in a most cases.

PMID- 10658180
TI  - The oligodendroglia cytoskeleton in health and disease.
AB  - Oligodendrocytes have a high rate of synthetic activity and produce vast amounts
      of myelin. The membrane production requires specific sorting and transport
      processes and structural support. In culture, oligodendrocytes extend flat
      membranous sheets containing an extensive cytoskeletal network of microtubules
      (MTs) and microfilaments (MFs). The microtubules participate in the elaboration
      and stabilization of the myelin-containing cellular processes and have an impact
      not only on the complex oligodendroglia architecture but also influence their
      functions. They participate in intracellular sorting processes and the
      translocation of myelin basic protein (MBP) mRNAs to the forming myelin sheath.
      The two major groups of neuronal microtubule-associated proteins (MAPs), MAP2 and
      tau are expressed in oligodendrocytes and might be involved in the regulation of
      MT stability and organization. Myelin-specific proteins, such as MBP and 2',3'
      cyclic nucleotide 3'-phosphohydrolase (CNP), interact with the cytoskeleton.
      Glial changes occur in a variety of neurodegenerative diseases, and glial
      fibrillary tangles and glial cytoplasmic inclusions (GCls), containing abnormal
      microtubular structures which stain positively for stress proteins and
      microtubule-associated proteins, are found in oligodendrocytes of the affected
      brains. The role of MTs and their associated proteins in oligodendrocytes during
      normal development and pathological situations is specifically emphasized in this
      review.

PMID- 10658179
TI  - High throughput analysis of gene expression in the human brain.
AB  - The human brain is thought to have the greatest complexity of gene expression of
      any region of the body, reflecting the diverse functions of neurons and glia.
      Studies of gene expression in the human brain may yield fundamental information
      about the phenotype of brain cells in different stages of development, in
      different brain regions, and in different physiological and pathological states.
      As the human genome project nears completion, several technological advances
      allow the analysis of thousands of expressed genes in a small brain sample. This
      review describes available sources of human brain material, and several high
      throughput techniques used to measure the expression of thousands of genes. These
      techniques include expressed sequence tag (EST) sequencing of cDNA libraries;
      differential display; subtractive hybridization; serial analysis of gene
      expression (SAGE); and the emerging technology of high density DNA microarrays.
      Measurement of gene expression with microarrays and other technologies has
      potential applications in the study of human brain diseases, including cognitive
      disorders for which animal models are typically not available. Gene expression
      measurements may be used to identify genes that are abnormally regulated as a
      secondary consequence of a disease state, or to identify the response of brain
      cells to pharmacological treatments.

PMID- 10658181
TI  - Localization and processing of CLN3, the protein associated to Batten disease:
      where is it and what does it do?
AB  - Although the CLN3 gene for Batten disease, the most common inherited
      neurovisceral storage disease of childhood, was identified in 1995, the function
      of the corresponding protein still remains elusive. A key to understanding the
      pathology of this devastating disease will be to elucidate the function of CLN3
      at the molecular level. CLN3 has proven difficult to study, as it is predicted to
      be a membrane protein, and is of apparently low abundance in cells. Different
      groups have reported differing subcellular localization of CLN3. The purpose of
      this review is to critically examine the various cell biological approaches
      undertaken to localize CLN3 and to piece together a potential function for CLN3
      in neuronal cells. The most likely conclusion of this is that CLN3 is a
      lysosomal/endosomal protein that is trafficked through the endoplasmic reticulum
      (ER) and Golgi. Furthermore, studies are required to confirm whether CLN3 has a
      potential role in the recycling of synaptic vesicles through the
      endosome/lysosome.

PMID- 10658182
TI  - Caspase-3 is required for apoptosis-associated DNA fragmentation but not for cell
      death in neurons deprived of potassium.
AB  - Caspases are crucial effectors of the cell death pathway activated by virtually
      all apoptosis-inducing stimuli within neurons and nonneuronal cells. Among the
      caspases, caspase-3 (CPP32) appears to play a pivotal role and has been found to
      be necessary for developmentally regulated cell death in the brain. We have used
      mice lacking caspase-3 (-/-CPP32) to examine its involvement in cultured
      cerebellar granule neurons induced to undergo apoptosis by potassium deprivation
      (K+). We find that, following K+ deprivation, neurons from -/-CPP32 mice die to
      the same extent as those from normal (+/+) mice. Although a small delay in the
      induction of cell death is observed in -/-CPP32 neurons, the rate of cell death
      is generally comparable to that of +/+ cultures. Though not critical for neuronal
      death, caspase-3 is required for DNA fragmentation and chromatin condensation as
      judged by the absence of these apoptotic features in -/-CPP32 neurons.
      Boc.Asp.fmk, a pan caspase inhibitor, partially protects +/+ neurons from low-K+
      mediated cell death and does so to the same extent in -/-CPP32 cultures,
      suggesting the involvement of a caspase other than caspase-3 in cell death.
      However, the protective effect of boc.Asp.fmk is not seen beyond 24 hr,
      suggesting that the effect of caspase inhibition is one of delaying rather than
      preventing apoptosis. The more selective caspase inhibitors DEVD.fmk, IETD.fmk,
      and VEID.fmk fail to affect cell death, indicating that members inhibited by
      these agents (such as caspases - 6 ,7, 8, 9 and 10) are also not involved in low
      K+-mediated apoptosis.

PMID- 10658183
TI  - In vitro depalmitoylation of neurospecific peptides: implication for infantile
      neuronal ceroid lipofuscinosis.
AB  - Palmitoyl protein thioesterase 1 (PPT1) removes palmitate from specific cysteine
      residues in peptides and proteins. We have previously shown that a palmitoylated
      myelin glycoprotein. Po octapeptide (IRYCWLRR) can be specifically
      depalmitoylated by PPT1 in vitro (Cho and Dawson [1998] J. Neurochem. 171 ;323
      329). To characterize further the substrate specificity of PPT1, we prepared
      various palmitoylated oligopeptides, based on palmitoylated sequences from
      different proteins. A truncated tetrapeptide from Po (RY[palmitoyl]-CW) was as
      good a substrate as the octapeptide Po, with optimal activity at pH 4.0. In
      contrast, other peptide substrates showed marked differences. Thus, the
      deacylation of GAP-43 (MLCCMRR), rhodopsin (VTTLCCGKN), and Galpha subunit
      (MGCLGNSK) peptides was more efficient at neutral pH (7.4) than at acidic pH
      (4.0), with the greatest efficiency toward the Galpha peptide (five- to sixfold
      higher than other substrates). Infantile neuronal ceroid lipofuscinosis (INCL) is
      caused by PPT1 deficiency, and the absence of enzymatic activity was confirmed
      with GAP-43 peptide as well as the Po peptide. LA-N-5 human neuroblastoma cells
      overexpressing PPT1 showed increased depalmitoylation of all the peptide
      substrates, indicating that these peptides are deacylated by PPT1. An amide
      derivative of a palmitoylated K-Ras peptide (AcG-palmitoyl diamino propionate
      VKIKK) acted as an enzyme pseudosubstrate and inhibited PPT1 enzyme activity in a
      dose-dependent manner. The peptide itself (AcGCVKIKK) did not affect PPT
      activity. In summary, PPT1 is able to hydrolyze a range of cysteinyl peptide
      sequences found in both neuron-specific and ubiquitous (e.g., Galpha) proteins.
      The inhibitor of PPT1 activity should facilitate the development of a model for
      INCL and help explain the neuronal death in this disease.

PMID- 10658184
TI  - Primary astrocytes retrovirally transduced with a tyrosine hydroxylase transgene
      driven by a glial-specific promoter elicit behavioral recovery in experimental
      parkinsonism.
AB  - We used a retroviral-mediated gene transfer system to transduce primary rat
      astrocytes with a transgene in which the activity of a tyrosine hydroxylase (TH)
      cDNA is under the transcriptional control of a human promoter of the glial
      fibrillary acidic protein (GFAP). The engineered cells were tested for their
      therapeutic efficacy in a rodent model of Parkinson's disease (PD). The method is
      based both on the properties of astrocytes, as well as on those of the promoter.
      Astrocytes are an integral part of the neural tissue, have a long life span, are
      more resistant to oxidative stress than neurons, and possess an efficient
      secretory system. The GFAP promoter is active throughout postnatal life, and its
      activity is up-regulated by many insults to the brain, including PD. Transduced
      astrocytes were implanted into the striata of rats lesioned with 6
      hydroxydopamine (6-OHDA), and the efficacy of grafted cells tested. Implanted
      astrocytes induced a significant reduction in the turning behavior that occurs in
      response to apomorphine for at least 4 weeks after grafting, and transgenic mRNA
      and protein could be detected in implanted brains. These results indicate that
      the gFa2-TH construct can be readily adapted to be used with a retroviral gene
      transfer system to obtain nontumorigenic cells that sustain a sufficient level of
      transgene activity to enable therapeutic effectiveness for prolonged periods.
      These results further endorse the use of astrocytes for gene therapy in the
      central nervous system.

PMID- 10658185
TI  - Myelin debris clearance during Wallerian degeneration in the goldfish visual
      system.
AB  - We have examined the clearance of myelin debris from the visual pathways of the
      goldfish during Wallerian degeneration. Both the rate and pattern of myelin
      disappearance from the optic nerve and tract were determined using
      immunohistochemistry on frozen sections, as well as plastic sections and electron
      microscopy. Animals with and without regenerating optic axons were examined in
      order to determine whether the axons play a role in myelin clearance. We found
      that myelin is cleared at different rates along the visual paths. Thus, virtually
      all myelin debris is gone in the optic tract and distal optic nerve stump by 4
      weeks after surgery, while in the cranial nerve segment, myelin clearance is
      still incomplete at 6 weeks postoperative. These temporal and spatial patterns of
      myelin clearance are the same in animals with and without regenerating axons,
      thus indicating that growing axons do not influence this process. Finally,
      ultrastructural observations revealed that both astrocytes and microglia
      participate in phagocytosing myelin debris in the optic nerve, while in the
      tract, the vast majority of debris is removed by microglia alone. These data are
      discussed with regard to possible mechanisms controlling the differential
      expression of myelin clearance.

PMID- 10658186
TI  - Chemokine antagonist infusion attenuates cellular infiltration following spinal
      cord contusion injury in rat.
AB  - Spinal cord injury is accompanied by an initial inflammatory reaction followed by
      secondary injury that is caused, in part, by apoptosis. Recruitment of leukocytes
      from the blood compartment to the site of inflammation in the injured spinal cord
      has been attributed to locally generated chemotactic agents (cytokines and
      chemokines). In addition to upregulation in the message levels of a number of
      chemokines, we have found up-regulation in the message levels of several
      chemokine receptors following spinal cord contusion injury. To reduce the
      inflammatory response after spinal cord injury, we have blocked the interaction
      of chemokine receptors with their ligands using the vMIPII chemokine antagonist.
      Using a rat model of spinal cord contusion injury, we show that continuous
      infusion of the antagonist for up to 7 days results in a decrease in infiltrating
      hematogenous cells at the site of injury. Histological evaluation ofthe tissue
      showed fewer activated macrophages at the site of injury. Concomitantly, reduced
      neuronal loss and gliosis were observed in the antagonist infused spinal cord. In
      addition, increased expression of Bcl-2 gene, an endogenous inhibitor of
      apoptosis, was seen in the antagonist infused spinal cord at 7 days post injury.
      Morphologically, staining with the bisbenzamide dye Hoechst 33342 showed
      significantly more apoptotic bodies in the vehicle compared to antagonist infused
      spinal cord. Our data suggest that chemokine antagonist infusion post-injury
      results in limiting the inflammatory response following spinal cord contusion
      injury, thereby attenuating neuronal loss, possibly due to decreased apoptosis.
      These findings support the contention that disrupting chemokine interactions with
      their receptors may be an effective approach in reducing the secondary damage
      after spinal cord injury.

PMID- 10658187
TI  - Perturbation of myelination by activation of distinct signaling pathways: an in
      vitro study in a myelinating culture derived from fetal rat brain.
AB  - An in vitro myelinating mouse-derived model system has been adapted and optimized
      for fetal rat brain. In these mixed brain cell (MBC) cultures, myelinogenesis was
      studied by examining the effect of signaling pathways that are involved in the
      timing of oligodendrocyte differentiation. When PMA, a protein kinase C (PKC)
      activator, was kept present during development, the early myelin protein, CNP,
      was expressed in oligodendrocytes as promptly as in control MBC cultures. In
      contrast, continuous activation of signaling pathways triggered by FGF-2 caused a
      delay in the expression of CNP. The expression of the late myelin proteins MBP
      and PLP in oligodendrocytes was impeded by both PMA- and FGF-2-treatment, and, as
      a consequence, also myelin formation. Surprisingly, the continuous presence of
      PDGF during development also prevented myelin formation, even though all myelin
      specific proteins were significantly expressed. Taken together, the data indicate
      that this in vitro myelinating culture system represents an excellent system to
      study signaling events necessary for the onset of myelination. Moreover, the
      present results demonstrate that oligodendrocyte differentiation in the presence
      of neurons and astrocytes can be manipulated both by extracellular and
      intracellular signaling factors. Importantly, differentiation per se is not
      necessarily culminating into myelination.

PMID- 10658188
TI  - Decrypting the spectrum of antigen-specific T-cell responses: the avidity
      repertoire of MBP-specific T-cells.
AB  - Myelin basic protein (MBP) is a well-characterized autoantigen potentially
      involved in the pathogenesis of the most common human demyelinating disease of
      the central nervous system (CNS), multiple sclerosis (MS). It is known that MBP
      specific T-cell responses differ widely among different individuals and also
      within a single donor in terms of fine specificity and functional characteristics
      including the avidity in antigen recognition. In this report, we demonstrate that
      the in vitro selection of MBP-reactive T-cell repertoire is strictly dependent
      upon the antigen dose used in the primary cultures. MBP-specific T-cell lines
      (TCLs) were generated from MS patients and healthy donors using different antigen
      concentration in cultures (0.1 to 50 microg/ml). In both MS patients and
      controls, the number of obtained T-cell lines was affected by the antigen
      concentration. In addition, low and high antigen concentrations selected in vitro
      different T-cell populations in terms of peptide specificity patterns and
      different functional avidities in antigen recognition. Low concentrations of MBP
      in the primary cultures yielded a small number of TCLs recognizing the specific
      antigen with higher avidity whereas high antigen concentrations allowed the in
      vitro expansion of a higher numbers of T-cells recognizing MBP with lower
      avidity. The use of different antigen concentrations in the primary cultures can
      be applied as a simple experimental system to investigate the overall avidity
      repertoire of antigen-specific T-cell response in humans.

PMID- 10658189
TI  - GAL4/UAS-WGA system as a powerful tool for tracing Drosophila transsynaptic
      neural pathways.
AB  - Visualization of specific transsynaptic neural pathways is an indispensable
      technique for understanding the relationship between structure and function in
      the nervous system. Here, we demonstrate the application of the wheat germ
      agglutinin (WGA) transgene technique for tracing transsynaptic neural pathways in
      Drosophila. The intracellular localization of WGA was examined by immunoelectron
      microscopy. WGA signals were detected in granule-like structures in both the
      outer photoreceptor cells expressing WGA and the second-order laminar neurons.
      Misexpression of tetanus toxin (TNT), which inactivates N-synaptobrevin, in the
      outer photoreceptor cells resulted in the elimination of on/off transients in
      electroretinogram (ERG) recordings and in a great reduction in WGA transfer into
      laminar neurons, suggesting that anterograde WGA transsynaptic transfer is
      dependent mainly on synaptic transmission. Retrograde WGA transfer was also
      detected upon its forced expression in muscle cells. WGA primarily expressed in
      muscle cells was taken up by motoneuron axons and transported to their cell
      bodies in the ventral nerve cord, suggesting that WGA can trace motoneuronal
      pathways in combination with the muscle-specific GAL4 driver. Thus, the GAL4/UAS
      WGA system should facilitate the dissection of the Drosophila neural circuit
      formation and/or synaptic activity in various regions and at various
      developmental stages.

PMID- 10658190
TI  - Influence of factors secreted by wobbler astrocytes on neuronal and motoneuronal
      survival.
AB  - During late postnatal development, mice with the autosomal recessive wobbler
      mutation (wr/wr) develop motoneuron degeneration associated with astrogliosis in
      the spinal cord. In vitro, primary wobbler astrocytes are also affected,
      exhibiting abnormal cell-cell contacts. To characterize further the wobbler
      disease, we investigated the in vitro effects of wobbler astrocytes on primary
      neuronal cultures from the spinal cords of 15-day-old wild-type mouse and rat
      embryos. Cocultures with the wobbler astrocytes, or direct addition of wobbler
      astrocyte-conditioned medium, led to a decrease in neuron number in primary mixed
      neuronal cultures, containing motoneurons and interneuron-like cells. In
      contrast, wobbler astrocyte-conditioned medium enhanced survival of highly
      purified motoneurons. These in vitro results suggest the possibility that wobbler
      astrocytes act not on motoneurons directly but, rather, through other spinal
      neurons to induce motoneuron degeneration in the wobbler disease.

PMID- 10658191
TI  - Estrogenic stimulation of neurite growth in midbrain dopaminergic neurons depends
      on cAMP/protein kinase A signalling.
AB  - Previous work from this laboratory indicates that the differentiation of mouse
      midbrain dopaminergic neurons is influenced by estrogen. These effects may be
      transmitted either through classical nuclear receptors or via "nongenomic"
      mechanisms, including the interaction with hypothetical membrane receptors
      coupled to distinct intracellular signalling pathways. The latter mechanism seems
      to be of particular interest for the observed interactions of estrogen with
      developing dopaminergic neurons, insofar as estrogen has been shown to increase
      intracellular calcium levels within seconds. This study focuses on signal
      transduction cascades that might be activated by estrogen during differentiation
      of dopaminergic cells. Treatment with 17beta-estradiol or a membrane-impermeable
      estrogen-BSA construct (E-BSA) increased neurite growth and arborization of
      dopaminergic neurons. This effect was inhibited by antagonists of cAMP/ protein
      kinase A (PKA) and calcium signalling pathways but not by the estrogen receptor
      antagonist ICI. In addition, estrogen exposure stimulated the phosphorylation of
      CREB in midbrain dopaminergic cells as studied by quantitative double-labelling
      immunocytochemistry and gel shift assay. Again, this effect was antagonized only
      by the simultaneous treatment with inhibitors of the cAMP/PKA or calcium pathways
      and not by ICI pretreatment. These data together with our previous findings
      demonstrate that estrogen can interact with membrane binding sites on
      dopaminergic neurons, thereby stimulating the cAMP/PKA/phosphorylated cAMP
      responsive element binding protein (CREB) signalling cascade, most likely through
      the activation of calcium-dependent kinases. In conclusion, rapid "nongenomic"
      estrogen signalling represents another mechanism, in addition to the activation
      of classical nuclear estrogen receptors, that is capable of influencing neuronal
      differentiation in the mammalian brain.

PMID- 10658193
TI  - Acute ultrastructural effects of MPTP on the nigrostriatal pathway of the C57BL/6
      adult mouse: evidence of compensatory plasticity in nigrostriatal neurons.
AB  - Acute doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) elicited
      degenerative and apparently compensatory changes in the nigrostriatum of injected
      animals within 1 day of treatment. In the substantia nigra pars compacta (SNc),
      low-dose (20 mg/kg) administration elicited early degeneration of mitochondria in
      the absence of other effects. In the striatum, a low MPTP dose resulted in myelin
      unwinding, demyelination, cytoplasmic shrinkage, and disturbance of synaptic
      communication, as evinced by a profound reduction in synaptic vesicle production.
      High-dose (40 mg/kg) administration generated more drastic axonal degeneration
      leading to cell elimination in the striatum. At neither dose was mitochondrial
      disturbance evident in the striatum. Evidence is presented that darkened synaptic
      boutons, visible at this level of MPTP administration, were part of healthy
      enlarged axons with an elevated number of synaptic contacts. These spared
      neuronal processes, therefore, were hypothesized to compensate for the MPTP
      induced death of dopaminergic neurons by adaptive structural modifications that
      would serve to enhance their functional capability.

PMID- 10658192
TI  - Novel biphasic effect of pyrrolidine dithiocarbamate on neuronal cell viability
      is mediated by the differential regulation of intracellular zinc and copper ion
      levels, NF-kappaB, and MAP kinases.
AB  - Nuclear factor kappaB (NF-kappaB) is a transcription factor involved in the
      expression of a wide range of genes, most of which code for proteins that play a
      role in immunity and inflammation. Pyrrolidine dithiocarbamate (PDTC) is a well
      known inhibitor of NF-kappaB. Although its mechanism of action is conferred by
      its antioxidant property, other mechanisms by which PDTC can act as a prooxidant,
      metal chelator, and free thiol group modulator have recently been suggested. Here
      we report that PDTC caused a dual effect on cell viability in neuronal rat
      pheochromocytoma (PC12) cells, depending on its concentration. Increase of
      intracellular zinc and copper ion levels selectively potentiated the cytotoxic
      PDTC effect in a dose-dependent manner, and thiol reagents, such as glutathione
      and N-acetylcysteine, as well as divalent metal-chelating reagents, such as EDTA
      and bathocuproline disulfonic acid, blocked its cell death effect. The
      differential effect of PDTC on cell viability correlates well with the inhibition
      of NF-kappaB activities. In addition, PDTC differentially activated microtubule
      associated protein (MAP) kinases, such as extracellular signal-regulated kinase
      (ERK), c-Jun N-terminal kinase (JNK), but not p38, depending on its dose, and the
      coaddition of glutathione (GSH), other antioxidants, and metal ions also
      modulated their activities. Furthermore, stable Bcl-2 expression blocked the PDTC
      induced cell death. These results suggest that the thiol groups and free zinc and
      copper ion levels are important for the novel biphasic PDTC effect on cell
      viability, which is associated with the differential activation of NF-kappaB and
      MAP kinases.

PMID- 10658194
TI  - Multiple polyphosphoinositide pathways regulate apoptotic signalling in a dorsal
      root ganglion derived cell line.
AB  - The polyphosphoinositides play important roles in transmembrane signalling but
      are also involved in anchoring cell surface proteins, organellar transport,
      cytoskeleton organization, and cell survival. The polyphosphoinositides
      synthesized by phosphatidylinositol-3 kinase (PI-3K), (Ptd(3,4)InsP2, and
      PtdIns(3,4,5)P3), appear to play a critical role in cell survival by membrane
      recruitment and activation of Akt kinase. Inhibitors of PI3K, wortmannin, and
      LY294002, induced a time-dependent activation of caspase-3 (CPP32), with a peak
      at 6 hr, leading to subsequent cell death by apoptosis in a dorsal root ganglion
      cell line (F-11). Lowering cyclic AMP (cAMP) levels enhanced both caspase-3
      activation and cell death induced by PI3K inhibitors, whereas a nonhydrolyzable
      cAMP analog (Bt2cAMP), lowered CPP32 and was protective. We stably transfected
      the F-11 cells with the constitutively active p110 catalytic subunit of PI-3
      kinase and observed resistance to both caspase-3 (CPP32) activation and
      subsequent apoptosis induced by either wortmannin or LY294002. Treatment of F-11
      cells with bradykinin (BK) stimulated the hydrolysis of a different
      polyphosphoinositide, PtdIns(4,5)P2, and enhanced both wortmannin-induced caspase
      3 (CPP32) activation and subsequent apoptosis. PtdIns(4,5)P2 is also a precursor
      of the anti-apoptotic PtdIns(3,4,5) P3 and lowering cAMP levels with opioid
      agonists for 30 min enhanced both the hydrolysis of PtdIns(4,5) P2 and cellular
      apoptosis. The enhancement was opioid dose-dependent and opioid antagonist
      (naloxone)-reversible and was also seen following 24-hr exposure to opioids such
      as U69,593 and Dala2, Dleu5 enkephalin (DADLE). However, unlike the bradykinin
      stimulation of PtdIns(4,5)P2 hydrolysis following activation of phospholipase C,
      the opioid-enhanced hydrolysis was independent of external Ca2+ and was blocked
      by pertussis toxin, suggesting a different mechanism involving GI, GO, or
      betagamma-subunits. In summary, both the receptor-mediated lowering of cAMP
      levels and the hydrolysis of 4,5-polyphosphoinositides have no direct effect on
      caspase-3 activity or apoptosis but do exacerbate the activation of caspase-3
      like activity and subsequent cell death by apoptosis induced by inhibitors of 3
      polyphosphoinositide synthesis. We suggest that multiple polyphosphoinositide
      pathways are involved in the regulation of apoptosis.

PMID- 10658195
TI  - Fine T cell receptor repertoire analysis of spinal cord T cells responding to the
      major and minor epitopes of myelin basic protein during rat autoimmune
      encephalomyelitis.
AB  - Experimental autoimmune encephalomyelitis is a disease induced by neuroantigen
      reactive T cells bearing particular types of T cell receptor (TCR). Although the
      nature of TCRs of encephalitogenic T cells has been partially delineated using
      encephalitogenic T cell clones established in vitro, the entire TCR repertoire
      formed in situ after immunization with neuroantigen remains unclear. In the
      present study, we immunized Lewis rats with myelin basic protein (MBP) and its
      fragment peptides and determined the TCR repertoire of spinal cord T cells formed
      after the immunization by CDR3 spectra-typing. It was revealed that the
      oligoclonal expansion of Vbeta2, Vbeta8.2, and Vbeta17 spectratypes was
      detectable after immunization with guinea pig MBP and its immunodominant epitope,
      the 68-88 sequence, whereas immunization with a peptide containing a minor
      epitope induced Vbeta10 expansion. Immunization with rat MBP induced much broader
      TCR Vbeta expansion (all of the above Vbetas plus Vbeta3). These findings suggest
      that TCRs activated by immunization with guinea pig MBP used as heteroclitic
      immunogen recognize autoantigen, rat MBP. Furthermore, the strategy used in this
      study gives insight into the pathogenesis of autoimmune disease and provides
      useful information for designing TCR-based immunotherapy.

PMID- 10658196
TI  - Stiffening the stingray skeleton - an investigation of durophagy in myliobatid
      stingrays (Chondrichthyes, batoidea, myliobatidae).
AB  - The stingray family Myliobatidae contains five durophagous (hard prey specialist)
      genera and two planktivorous genera. A suite of morphological features makes it
      possible for the hard prey specialists to crush mollusks and crustaceans in their
      cartilaginous jaws. These include: 1) flat, pavement-like tooth plates set in an
      elastic dental ligament; 2) multiple layers of calcified cartilage on the surface
      of the jaws; 3) calcified struts running through the jaws; and 4) a lever system
      that amplifies the force of the jaw adductors. Examination of a range of taxa
      reveals that the presence of multiple layers of calcified cartilage, previously
      described from just a few species, is a plesiomorphy of Chondrichthyes. Calcified
      struts within the jaw, called "trabecular cartilage," are found only in the
      myliobatid genera, including the planktivorous Manta birostris. In the
      durophagous taxa, the struts are concentrated under the area where prey is
      crushed, thereby preventing local buckling of the jaws. Trabecular cartilage
      develops early in ontogeny, and does not appear to develop as a direct result of
      the stresses associated with feeding on hard prey. A "nutcracker" model of jaw
      function is proposed. In this model, the restricted gape, fused mandibular and
      palatoquadrate symphyses, and asynchronous contraction of the jaw adductors
      function to amplify the closing force by 2-4 times.

PMID- 10658197
TI  - Paedogenesis in european newts (Triturus: salamandridae): cranial morphology
      during ontogeny.
AB  - A cross-sectional analysis using different ontogenetic stages (larvae, juveniles,
      paedotypic, and metamorphic adults) of the smooth newt, Triturus vulgaris, and
      the alpine newt, T.alpestris, revealed a broad spectrum of perennibranchiation
      influences on cranial ontogeny in European newts, more pronounced than previously
      thought. These influences included marked variation in ossification levels,
      pronounced morphometric variability of many cranial elements, and considerable
      skull shape changes in the transition from larvae to the adult stage. In
      comparison with metamorphosed individuals, paedotypic newts had a higher level of
      variability in both individual cranial traits and cranial shape changes. Sexual
      size difference of the skull traits was mostly negligible, especially in
      comparison to the influence of paedogenesis. The main changes in cranial shape of
      the European newts occurred during metamorphosis. Cranial morphological
      organization in the majority of examined paedotypes corresponds to cranial
      organization at late larval stages prior to metamorphosis or at the onset of
      metamorphosis.

PMID- 10658198
TI  - Regression of the lateral oviducts during the larval-adult transformation of the
      reproductive system of Melipona quadrifasciata and Frieseomelitta varia.
AB  - Toward the end of the larval phase (prepupa), the reproductive systems of
      Melipona quadrifasciata and Frieseomelitta varia workers are anatomically
      similar. Scanning electron microscopy showed that during this developmental phase
      the right and left ovaries are fused and form a heart-shaped structure located
      above the midgut. Each ovary is connected to the genital chamber by a long and
      slender lateral oviduct. During pupal development, the lateral oviducts of
      workers from both species become extremely reduced due to a drastic process of
      cell death, as shown by transmission electron microscopy. During the lateral
      oviduct shortening, their simple columnar epithelial cells show some signs of
      apoptosis in addition to necrosis. Cell death was characterized by cytoplasmic
      vesiculation, peculiar accumulation of glycogen, and dilation of cytoplasmic
      organelles such as mitochondria and rough endoplasmic reticulum. The nuclei, at
      first irregularly contoured, became swollen, with chromatin flocculation and
      various areas of condensed chromatin next to the nuclear envelope. At the end of
      the pupal phase, deep recesses marked the nuclei. At emergence, worker and queen
      reproductive systems showed marked differences, although reduction in the lateral
      oviducts was an event occurring in both castes. However, in queens the ovarioles
      increased in length and the spermatheca was larger than that of workers. At the
      external anatomical level, the reproductive system of workers and queens could be
      distinguished in the white- and pink-eyed pupal phase. The metamorphic function
      of the death of lateral oviduct cells, with consequent oviduct shortening, is
      discussed in terms of the anatomical reorganization of the reproductive system
      and of the ventrolateral positioning of adult worker bee ovaries.

PMID- 10658199
TI  - Uterine morphology during the annual cycle in Chalcides ocellatus tiligugu
      (Gmelin) (Squamata: scincidae).
AB  - The uterus of the viviparous skink Chalcides ocellatus tiligugu was studied by
      SEM and LM during the annual cycle. Three functional phases were identified:
      preovulatory (spring), gestatory (summer), and quiescent (autumn-winter),
      characterized by changes in the uterine wall (mainly the endometrial layer). In
      the preovulatory phase, the uterine wall increases in thickness; its luminal
      epithelium has ciliated cells and two types of unciliated secretory cells. The
      first type secretes sulfated glycosaminoglycans (GAGs), which form the amorphous
      inner layer of the eggshell membrane; the second type secretes acidic
      glycoproteins that form the intrafibrillar matrix of the outer layer of the
      eggshell membrane. The lamina propria contains simple alveolar glands that
      secrete the collagen fibers of the eggshell membrane. During the gestatory phase,
      the glycoproteins produced by secretory cells of the second type have
      histotrophic activity for the developing embryo. The uterus widens to form
      incubation chambers with two hemispheres, one embryonic and the other
      abembryonic. Both a chorioallantoic placenta and an omphaloplacenta with
      histotrophic activity are present in late gestation. The chorioallantoic
      placenta, with aspects of a Weekes (1935) Type III placenta, develops in the
      embryonic hemisphere. The omphaloplacenta forms at the vegetative pole of the egg
      and shows cellular hypertrophy of the bilaminar omphalopleure and uterus. During
      the quiescent phase, the uterus gradually decreases in thickness and activity;
      its luminal epithelium does not show secretory activity. The annual variations in
      the myometrial layer involved the inner circular and the outer longitudinal
      muscle layers.

PMID- 10658200
TI  - Fine structure of the oxynticopeptic cells in the gastric glands of the ruin
      lizard, Podarcis sicula campestris De Betta, 1857.
AB  - The results of an ultrastructural investigation of the gastric glands of the ruin
      lizard are reported. In this reptile the stomach can be divided into a larger
      fundus and a smaller pars pilorica. Fundic glands are characterized by three main
      kinds of cells: mucous, endocrine, and oxynticopeptic; the latter were not
      observed in the pyloric glands. The morphological features of the oxynticopeptic
      cells change from the proximal to the distal region of the fundic mucosa. In the
      proximal region, numerous electron-dense secretory granules, a well-developed
      granular endoplasmic reticulum, an evident Golgi complex, and a reduced system of
      smooth-surfaced vesicles and tubules in the apical cytoplasm characterize these
      cells. In the distal fundic region, oxynticopeptic cells possessed numerous
      mitochondria and a well-developed smooth-surfaced endoplasmic reticulum, but
      secretory granules were rare. These data suggest the existence of a gradient in
      the production of proteolytic enzymes, and perhaps also of hydrochloric acid,
      along the oral-aboral axis of the stomach. The results are discussed with regard
      to the evolution of the gastric glands and of the digestive mechanism in
      vertebrates.

PMID- 10658201
TI  - Locomotion in the quail (Coturnix japonica): the kinematics of walking and
      increasing speed.
AB  - Hindlimb segmental kinematics and stride characteristics are quantified in
      several quail locomoting on a treadmill over a six-fold increase in speed. These
      data are used to describe the kinematics of a walking stride and to identify
      which limb elements are used to change stride features as speed increases. In
      quail, the femur does not move during locomotion and the tarsometatarsus
      phalangeal joint is a major moving joint; thus, quail have lost the most proximal
      moving joint and added one distally. The tibiotarsus and tarsometatarsus act
      together as a fixed strut swinging from the knee during stance phase (the ankle
      angle remains constant at a given speed) and the tarsometatarsus-phalangeal joint
      appears to have a major role in increasing limb length during the propulsive
      phase of the stride. Speed is increased with greater knee extension and by
      lengthening the tibiotarsus/tarsometatarsus via increased ankle extension at
      greater speeds. Because the femur is not moved and three distal elements are,
      quail move the limb segments through a stride and increase speed in a way
      fundamentally different from other nonavian vertebrates. However, the three
      moving joints in quail (the knee, ankle, and tarsometatarsophangeal joint) have
      strikingly similar kinematics to the analogous moving joints (the hip, knee, and
      ankle) in other vertebrates. Comparisons to other vertebrates indicate that birds
      appear to have two modes of limb function (three- and four-segment modes) that
      vary with speed and locomotory habits.

PMID- 10658202
TI  - Ultrastructure of the developing fibrocartilage of the os penis of rat.
AB  - Development of the fibrocartilage of the os penis of rat was studied by
      transmission electron microscopy. Prepubertal (0-4 weeks of development) and
      pubertal (4-8 weeks of development) males were examined. Effects of castration on
      the development of the fibrocartilage were also examined. During the first 0-4
      weeks of development, cells in the primordium of the fibrocartilage became large
      and the cytoplasm had well-developed rough endoplasmic reticulum (rER) and many
      intermediate filaments. Collagen fibers increased markedly in amount in the
      extracellular matrix (ECM) during the period. For 4-6 weeks, when gonadal
      secretion of androgens increases, the cells developed into mature chondrocytes
      with lacunae. Collagenous bundles were pushed away from the lacunae, resulting in
      a characteristic appearance of this fibrocartilage. The cytoplasm of the mature
      chondrocytes of the fibrocartilage was characterized by many intermediate
      filaments, oil droplets, glycogen granules, and well-developed rER. At 6 weeks,
      calcification started on the cell membrane of the mature chondrocytes. At 8
      weeks, a large part of the cartilage matrix was calcified. Matrix vesicles that
      originate from degenerated chondrocytes were found in the ECM of decalcified
      samples. In castrated males, cells of the primordium of the fibrocartilage ceased
      further development after castration. Intermediate filaments were still abundant
      in the cytoplasm and collagen fibers increased even after castration, but mature
      chondrocytes never differentiated. There were no signs of matrix vesicle
      formation, calcification, or cell degeneration in the fibrocartilage primordium.
      The developmental process of the fibrocartilage can be subdivided into two
      phases: collagenous matrix formation during the prepubertal period (0-4 weeks),
      and maturation of chondrocytes and calcification after puberty (4-8 weeks).

PMID- 10658203
TI  - Homologies among different adductor mandibulae sections of teleostean fishes,
      with special regard to catfishes (Teleostei: siluriformes).
AB  - The adductor mandibulae complex has been a subject of discussion and
      uncertainties due to a wide range of differentiations and fusions that have
      occurred during teleost evolution. The adductor mandibulae of numerous catfishes
      was studied in detail and compared with that of several other teleosts described
      in the literature. Our observations and comparisons demonstrate that: 1) the
      adductors mandibulae Aomega, A2, and A3 of acanthopterygians correspond,
      respectively, to the Aomega, A2, and A3 of ostariophysines; 2) the antero-dorso
      lateral (A1) and the antero-ventro-lateral (A1-OST) sections of the adductor
      mandibulae present, respectively, in acanthopterygians and in basal
      ostariophysines are the result of two different patterns of differentiation of
      this muscle; 3) some derived ostariophysines present a lateral section of the
      adductor mandibulae attached to the upper jaw (A0) that is not homologous with
      any other section of this muscle present in any other ostariophysine or
      acanthopterygian fish; 4) the configuration of the adductor mandibulae present in
      Diplomystes seems to be the plesiomorphic condition for catfishes; and 5) the
      muscle retractor tentaculi, present in a large number of catfishes, is derived
      from the inner section of the adductor mandibulae (A3) and, thus, is not
      homologous with the lateral bundle of this muscle (A0) that inserts on the upper
      jaw in some derived ostariophysine fishes.

PMID- 10658204
TI  - Development of the caudal neurosecretory system of the nile tilapia Oreochromis
      niloticus: an immunohistochemical and electron microscopic study.
AB  - The development of the caudal neurosecretory system (CNSS) of the Nile tilapia,
      Oreochromis niloticus, has been investigated by means of UI/oCRF (urotensin
      I/ovine corticotropin-releasing factor) immunohistochemistry and transmission
      electron microscopy. UI-like immunoreactive perikarya and fibers are first
      detected in the caudal spinal cord of larval fish about 4 days after hatching
      (stage 21). In the region of the future urophysis two bundles of strongly
      immunoreactive neurosecretory fibers are observed. At this stage, neurosecretory
      axons terminate on the meninx sheath of the spinal cord with immature
      neurosecretory terminals. The histogenesis of the urophysis begins at stage 24.
      The future neurohemal organ consists of a small ventral swelling of the spinal
      cord, which is associated with dilated vessels. At this stage, neurosecretory
      axons terminate on the basal lamina of the ingrowing blood vessels. Further
      development occurs by means of progressive branching of vessels and the
      concomitant increase in the number of neurosecretory terminals. In the caudal
      spinal cord, immunoreactive neurons also increase in number and progressively
      differentiate morphologically. Typical features of the mature CNSS are
      recognizable in 4-month-old juveniles. Data suggest that in tilapia both the
      synthesis and the release of urophysial hormones begin before morphogenesis of
      the neurohemal organ takes place.

PMID- 10658205
TI  - Microtubule-actomyosin interactions in cortical flow and cytokinesis.

PMID- 10658206
TI  - Dynamic study of cell mechanical and structural responses to rapid changes of
      calcium level.
AB  - Cell shape control is complex since it may involve multiple cytoskeletal
      components and metabolic pathways. Here we present a kinetic study of the
      mechanical and structural responses of cells from the monocytic THP-1 line to a
      rapid increase of cytosolic calcium level. Cells were exposed to ionomycin in a
      medium of varying calcium concentration and they were probed at regular intervals
      for (1) cortical rigidity as determined with micropipette aspiration, and (2)
      content and distribution of polymerized actin, myosin or ABP-280, as determined
      with flow cytometry and/or confocal microscopy. An increase of free intracellular
      calcium level induced: (1) a biphasic deformability change with marked stiffening
      within a second, and significant softening a minute later; (2) a biphasic change
      of actin polymerization with initial decrease (within less than a second) and
      rapid recovery (within a few seconds); (3) a topographical redistribution of
      microfilaments with an oscillatory behavior of the cortical fraction, while no
      substantial redistribution of myosin or ABP-280 was detected. It is suggested
      that a regulation of cell rigidity might be achieved without any structural
      change by suitable modulation of the lifetime of bridges formed between
      microfilaments by actin binding proteins.

PMID- 10658207
TI  - Mammalian homolog of the yeast cyclase associated protein, CAP/Srv2p, regulates
      actin filament assembly.
AB  - Control of cell shape and motility requires rearrangements of the actin
      cytoskeleton. One cytoskeletal protein that may regulate actin dynamics is CAP
      (cyclase associated protein; CAP/Srv2p; ASP-56). CAP was first isolated from
      yeast as an adenylyl cyclase associated protein required for RAS regulation of
      cAMP signaling. In addition, CAP also regulates the actin cytoskeleton primarily
      through an actin monomer binding activity. CAP homologs are found in many
      eukaryotes, including mammals where they also bind actin, but little is known
      about their biological function. We, therefore, designed experiments to address
      CAP1 regulation of the actin cytoskeleton. CAP1 localized to membrane ruffles and
      actin stress fibers in fixed cells of various types. To address localization in
      living cells, we constructed GFP-CAP1 fusion proteins and found that fusion
      proteins lacking the actin-binding region localized like the wild type protein.
      We also performed microinjection studies with affinity-purified anti-CAP1
      antibodies in Swiss 3T3 fibroblasts and found that the antibodies attenuated
      serum stimulation of stress fibers. Finally, CAP1 purified from platelets through
      a monoclonal antibody affinity purification step stimulated the formation of
      stress fiber-like filaments when it was microinjected into serum-starved Swiss
      3T3 cells. Taken together, these data suggest that CAP1 promotes assembly of the
      actin cytoskeleton.

PMID- 10658208
TI  - Forced expression of a dominant-negative chimeric tropomyosin causes abnormal
      motile behavior during cell division.
AB  - Forced expression of the chimeric human fibroblast tropomyosin 5/3 (hTM5/3) in
      CHO cell was previously shown to affect cytokinesis [Warren et al., 1995: J. Cell
      Biol. 129:697-708]. To further investigate the phenotypic consequences of
      misexpression, we have compared mitotic spindle organization and dynamic 2D and
      3D shape changes during mitosis in normal cells and in a hTM5/3 misexpressing
      (mutant) cell line. Immunofluorescence microscopy of wild type and mutant cells
      stained with monoclonal anti-tubulin antibody revealed that the overall
      structures of mitotic spindles were not significantly different. However, the
      axis of the mitotic spindle in mutant cells was more frequently misaligned with
      the long axis of the cell than that of wild type cells. To assess behavioral
      differences during mitosis, wild type and mutant cells were reconstructed in 2D
      and 3D and motion analyzed with the computer-assisted 2D and 3D Dynamic Image
      Analysis Systems (2D-DIAS, 3D-DIAS). Mutant cells abnormally formed large numbers
      of blebs during the later stages of mitosis and took longer to proceed from the
      start of anaphase to the start of cytokinesis. Furthermore, each mutant cell
      undergoing mitosis exhibited greater shape complexity than wild type cells, and
      in every case lifted one of the two evolving daughter cells off the substratum
      and abnormally twisted. These results demonstrate that misexpression of hTM5/3 in
      CHO cells leads to morphological instability during mitosis. Misexpression of
      hTM5/3 interferes with normal tropomyosin function, suggesting in turn that
      tropomyosin plays a role through its interaction with actin microfilaments in the
      regulation of the contractile ring, in the localized suppression of blebbing, in
      the maintenance of polarity and spatial symmetry during cytokinesis, and in cell
      spreading after cytokinesis is complete.

PMID- 10658210
TI  - Characterization of muscle filamin isoforms suggests a possible role of gamma
      filamin/ABP-L in sarcomeric Z-disc formation.
AB  - Filamin, also called actin binding protein-280, is a dimeric protein that cross
      links actin filaments in the cortical cytoplasm. In addition to this ubiquitously
      expressed isoform (FLN1), a second isoform (ABP-L/gamma-filamin) was recently
      identified that is highly expressed in mammalian striated muscles. A monoclonal
      antibody was developed, that enabled us to identify filamin as a Z-disc protein
      in mammalian striated muscles by immunocytochemistry and immunoelectron
      microscopy. In addition, filamin was identified as a component of intercalated
      discs in mammalian cardiac muscle and of myotendinous junctions in skeletal
      muscle. Northern and Western blots showed that both, ABP-L/gamma-filamin mRNA and
      protein, are absent from proliferating cultured human skeletal muscle cells. This
      muscle specific filamin isoform is, however, up-regulated immediately after the
      induction of differentiation. In cultured myotubes, ABP-L/gamma-filamin localises
      in Z-discs already at the first stages of Z-disc formation, suggesting that ABP
      L/gamma-filamin might play a role in Z-disc assembly.

PMID- 10658209
TI  - Myotonic dystrophy protein kinase (DMPK) induces actin cytoskeletal
      reorganization and apoptotic-like blebbing in lens cells.
AB  - DMPK, the product of the DM locus, is a member of the same family of serine
      threonine protein kinases as the Rho-associated enzymes. In DM, membrane
      inclusions accumulate in lens fiber cells producing cataracts. Overexpression of
      DMPK in cultured lens epithelial cells led to apoptotic-like blebbing of the
      plasma membrane and reorganization of the actin cytoskeleton. Enzymatically
      active DMPK was necessary for both effects; inactive mutant DMPK protein did not
      produce either effect. Active RhoA but not constitutive GDP-state mutant protein
      produced similar effects as DMPK. The similar actions of DMPK and RhoA suggest
      that they may function in the same regulatory network. The observed effects of
      DMPK may be relevant to the removal of membrane organelles during normal lens
      differentiation and the retention of intracellular membranes in DM lenses.

PMID- 10658211
TI  - Localization of wild type and mutant class I myosin proteins in Aspergillus
      nidulans using GFP-fusion proteins.
AB  - We have examined the distribution of MYOA, the class I myosin protein of the
      filamentous fungus Aspergillus nidulans, as a GFP fusion protein. Wild type GFP
      MYOA expressed from the myoA promoter is able to rescue a conditional myoA null
      mutant. Growth of a strain expressing GFP-MYOA as the only class I myosin was
      approximately 50% that of a control strain, demonstrating that the fusion protein
      retains substantial myosin function. The distribution of the wild type GFP-MYOA
      fusion is enriched in growing hyphal tips and at sites of septum formation. In
      addition, we find that GFP-MYOA is also found in patches at the cell cortex. We
      have also investigated the effects of deletion or truncation mutations in the
      tail domain on MYOA localization. Mutant GFP-MYOA fusions that lacked either the
      C-terminal SH3 or a portion of the C-terminal proline-rich domain had subcellular
      distributions like wild type MYOA, consistent with their ability to complement a
      myoA null mutant. In contrast, mutants lacking all of the C-terminal proline-rich
      domain or the TH-1-like domain were mainly localized diffusely throughout the
      cytoplasm, but could less frequently be found in patches, and were unable to
      complement a myoA null mutant. The GFP-MYOA DeltaIQ mutant was localized into
      large bright fluorescent patches in the cytoplasm. This mutant protein was
      subsequently found to be insoluble.

PMID- 10658231
TI  - Factors influencing the detection rate of drug-related problems in community
      pharmacy.
AB  - This study analyzes relationships between the number of drug-related problems
      detected in community pharmacy practice and the educational level and other
      characteristics of pharmacy personnel and their work sites. Random samples of
      pharmacists, prescriptionists and pharmacy technicians were drawn nationwide in
      Sweden. One hundred and forty-four (63%) of those meeting the inclusion criteria
      agreed to take part. The participants documented medication-related problems,
      interventions and patient variables on a data collection form. The drug-related
      problems were weighted by the number of patients served by each professional. The
      regression analysis showed the educational level of the professional to have a
      statistically significant effect on the detection rate, with pharmacists finding
      on average 2.5 more drug-related problems per 100 patients than prescriptionists
      and about 3.6 more than technicians. Previous participation in a study or
      activity on drug-related problems and the size of the pharmacy also had
      statistically significant effects on the problem detection rate. The use of open
      ended questions to create a dialogue with the patient seemed to be a successful
      means to discover problems. The results of this study indicate the importance of
      education and training of pharmacy personnel in detection of drug-related
      problems. This findings speaks in favor of increasing the pharmacist to other
      personnel ratio, provided the higher costs will be offset by societal benefits.

PMID- 10658233
TI  - Compliance with prescribed drugs: challenges for the elderly population.
AB  - Compliance with prescribed drug regimens is particularly important among the
      elderly because of their increased vulnerability and greater burden of chronic
      disorders. This narrative review discusses the factors that are important to
      compliance, with particular reference to the elderly. These factors are the
      patient's perceptions of his disease and it's treatment, the physician's
      perceptions, the manner the physician assumes and the language he uses to
      communicate with the patient, the patient's living situation, regular medication
      review, and a continuity of health care provision. Since it is the patient who
      decides how to use the therapy, his or her involvement in the process of
      explaining and understanding it is the key to improved compliance.

PMID- 10658232
TI  - Abuse/misuse of non-prescription drugs.
AB  - AIM: To investigate the abuse of non-prescription (over-the-counter; OTC)
      products in Northern Ireland. METHOD: A structured questionnaire covering various
      aspects of OTC drug abuse was mailed to all 509 community pharmacies in Northern
      Ireland. RESULTS: 253 responses were received (response rate 49.7%) after two
      mailings. Pharmacists named 112 OTC products they perceived were being abused in
      Northern Ireland. These were classified into 8 groups, with opioids,
      antihistamines and laxatives the most frequently reported. The frequency of abuse
      of all product groups was perceived to be either increasing or static. The number
      of clients suspected of abuse over a three-month period ranged from 0 to 700
      (median = 10, mode = 6) with 55% being regular customers. Pharmacists employed
      several methods to limit patient access to products of abuse. The most common
      technique was to keep the product out of sight. Others included additional client
      questioning, providing advice and limiting the quantity of product sold. The
      majority of respondents agreed their role could be extended to include other
      methods of dealing with abusers, including participation in harm-reduction
      programmes to wean abusers off products. Geographical region and location of
      pharmacy were not significant factors in the abuse of OTC products. CONCLUSIONS:
      Pharmacists in Northern Ireland perceive abuse and misuse of OTC products to be
      occurring in practice. Current methods employed for dealing with it are
      inadequate. Research into methods of effectively dealing with OTC abuse/misuse is
      required and has commenced on the basis of these findings.

PMID- 10658234
TI  - Trends of generic substitution in community pharmacies.
AB  - The purpose of this study is to measure the rate of genetic drug substitution by
      pharmacists, and factors influencing generic substitution, such as the extent of
      drugs listed on the formulary as well as physicians' and patients' acceptance
      rate of generic substitutes. A total of 9,328 prescription orders were
      retrospectively reviewed from 94 pharmacies which were selected at random. The
      substitution rate by pharmacists, which is the rate using the number of
      prescriptions eligible for substitution as the denominator, has risen from 47% in
      1979 to 96% in 1997; double the rate over the past 20 years. The net substitution
      rate, which uses all prescriptions as the denominator, was 30% in 1997; over 4
      times greater than the rate in 1979. Physicians wrote most prescriptions (86%)
      using the brand name of the drug, which has been the trend for the past 20 years.
      Of the prescriptions ordered by brand name, 47% were substitutable according to
      the New Jersey formulary. Of these prescriptions, prescribers allowed generic
      substitution 77% of the time. Out of these prescriptions, 97% of patients agreed
      to use a generic substitute if the physician approved of substitution. Generic
      substitution rates have increased, probably due to greater acceptance of generics
      by physicians and pharmacists as well as encouragement from external sources such
      as third party payers. Health care professionals, third parties, and patients all
      have an important role to play in order to increase the use of generics, and
      therefore reduce drug expenditures.

PMID- 10658235
TI  - The use of eardrops in an ENT department.
AB  - A survey of the pattern of usage of ototopical preparations in out-patients of
      the ENT department of a Dutch University Hospital has been performed. Data on
      clinical presentation and previous treatment of the patient, otoscopic results,
      prescribed current treatment and, if available, results of microbiological
      examination were collected. One-hundred and twenty-one evaluable patients were
      prospectively included. For 20% of the patients it concerned a first
      manifestation of the symptoms, 35% had a recurrence after a period free of
      symptoms and in 37% it concerned patients with persisting symptoms despite
      treatment. Forty-five percent of the patients' ears concerned had an intact
      tympanic membrane, in 25% a perforation was present and in 12% middle ear
      ventilation tubes were in situ. Thirty-five percent had already received previous
      treatment with ear drops. The species most often isolated was Staphylococcus
      aureus, followed by Pseudomonas aeruginosa. A wide range of products were
      prescribed. While previous treatment occurred with combination preparations, for
      current prescriptions, ofloxacin was most often used. Most patients received 2 to
      3 drops 3 times a day for 7 to 10 days, which is in accordance with
      recommendations in the literature. Potentially ototoxic substances are regularly
      used in daily practice. Ofloxacin is widely used even thought it is not
      registered for this indication in the Netherlands and the development of
      resistance has to be taken into account. A new policy based on this survey is
      proposed, which will reduce the number of different preparations used and will
      eliminate ofloxacin from first the treatment.

PMID- 10658236
TI  - Impact of ASCO guidelines for the use of hematopoietic colony stimulating factors
      (CSFs): survey results of fifteen Paris university hospitals.
AB  - To assess whether physicians comply with American Society of Clinical Oncology
      (ASCO) guidelines for the use of CSFs, a prospective survey was performed in 15
      Paris university hospitals involved in cancer treatment in 1997. If 45% of the
      prescriptions complied with the guidelines, primary prophylactic administration,
      which represented 52% of cases, did not comply with ASCO guidelines. These
      results suggested that primary prophylactic administration was one major clinical
      situation in which physicians could benefit from guidance to use a CSFs and that
      criteria defined by ASCO to allow primary prophylactic administration were not
      applied in clinical practice.

PMID- 10658237
TI  - Stability of buprenorphine, haloperidol and glycopyrrolate mixture in a 0.9%
      sodium chloride solution.
AB  - Combinations of opioids and adjuvant drug solutions are often used in clinical
      practice while little information is available on their microbiological or
      chemical stability. Currently there are no commercially available, prepacked,
      ready-to-use epidural or subcutaneous mixtures. Thus, epidural and subcutaneous
      analgesic mixtures must be prepared in the pharmacy on an as-needed basis. Such
      mixtures are typically used for the treatment of severe pain in cancer patients.
      The aim of this study was to investigate the microbiological and chemical
      stability of a buprenorphine, haloperidol and glycopyrrolate mixture in a 0.9%
      sodium chloride solution. A high performance liquid chromatographic (HPLC) method
      and pH-meter were used to conduct the analyses. Antimicrobial activity of each
      component was studied by an agar dilution method. According to the results from
      the chemical and microbiological stability studies, this mixture can be stored in
      polypropylene (PP) syringes and polyvinyl chloride (PVC) medication cassettes for
      at least 30 days at either 21 degrees C or 4 degrees C, and for 16 days in PP
      syringes at 36 degrees C, and for 9 days in PVC medication cassettes at 36
      degrees C.

PMID- 10658238
TI  - Stability of dithranol in creams.
AB  - The stability of the anthrachinone derivative dithranol in creams was studied
      during storage at temperatures of 4 degrees C and 20 degrees C. Aluminum-coated
      tubes with 0.1, 0.3 and 0.5% dithranol were stored and samples were analysed
      immediately and after 3, 6 and 12 months of storage. The 0.3% dithranol cream was
      also stored in polypropylene tubes. Drug concentration was analysed by high
      performance liquid chromatography. All concentrations tested were stable for 12
      months of storage at 4 degrees C in aluminum-coated tubes. This means that these
      low concentrations are sufficiently stable to be prepared in advance for at least
      12 months if prepared as described and kept refrigerated. Polypropylene tubes
      should not be used.

PMID- 10658239
TI  - Economic evaluation of Viaflex with vial adapter in a unit-dose drug distribution
      system.
AB  - The cost of parenteral admixtures has an important impact on the hospital budget.
      Recently, a Viaflex with vial adapter (named 'minibag plus' in some countries)
      has been commercialized in order to facilitate parenteral admixture preparation.
      In the present study a preparation using Viaflex with a vial adapter has been
      economically compared with a preparation with a traditional Viaflex (without
      adapter) in a centralized unit or in nursing wards in a unit-dose drug
      distribution system. A cost-analysis was conducted from the hospital point of
      view. Direct costs were considered: these included supplies and human resources.
      Differences in the whole process between the two types of Viaflex were analysed.
      The process included: purchasing, reception, storage, medical order record,
      preparation in the Pharmacy Service (PS), delivery from the PS to the nursing
      unit, preparation by the nurse, return of unused material to the PS. Human
      resource costs were estimated by time counting and multiplying by the average
      salary. To estimate wasted material, drug and supplies delivered from the PS and
      returned to the PS were counted during 26 days. With the new Viaflex costs are
      reduced by 30% in comparison with drug dilution using the traditional Viaflex in
      a centralized unit of the PS, and by 13.4% in comparison with preparation with
      the traditional Viaflex in the nursing ward. In addition it can be estimated that
      contamination risk with the new Viaflex is lower than preparation in the nursing
      ward with the traditional Viaflex. Therefore, owing to its lower cost we
      recommend the use of Viaflex with vial adapter for drug dilution for those vials
      that are compatible with the system.

PMID- 10658240
TI  - Population review of 1998: England and Wales.
AB  - This article outlines the main features of the population of England and Wales in
      1998. Where 1998 figures have not yet been produced, data for the latest
      available year are given.

PMID- 10658241
TI  - Childbearing outside marriage in western Europe.
AB  - Across most European states in recent decades there have been significant
      increases in childbearing outside marriage. This article examines the extent to
      which women have their first child in one of four settings: prior to any
      partnership; in their first cohabiting partnership; in first marriage; and after
      a first partnership. Temporal changes in these behaviours and variation according
      to background characteristics of the women are also examined. For the women who
      had a child outside any partnership, we examine the extent to which they go on to
      form partnerships and how long after the birth this happens. For those who had
      their first child within a cohabiting union, we examine the extent to which they
      marry and how long after the birth this occurs. Finally, we investigate whether
      children born within cohabiting unions that do and do not convert into marriages
      are more or less likely than those born within marriage to see their parents
      separate.

PMID- 10658242
TI  - The new subnational population projections model: methodology and projection
      scenarios.
AB  - This article describes the most recent process of projecting population at the
      subnational level in England. It briefly explains the reasons why projecting
      population at the subnational level is important, describes the model and how it
      was used to produce the latest set of long-term subnational population
      projections in England published by the Office for National Statistics (ONS) in
      1998. The article then discusses how the model may be applied to answer various
      'what-if' questions about future population.

PMID- 10658243
TI  - Which authorities are alike?
AB  - This article describes the first results from the recent revision to The ONS
      classification of local and health authorities of Great Britain to allow for
      boundary changes. For each local and health authority of Great Britain as at
      April 1999 it presents 'most similar' authorities as measured by a selection of
      37 socioeconomic and demographic variables from the 1991 Census. These results
      will assist local and health authorities in identifying other appropriate
      authorities for comparative studies. A second article, to be published in
      Population Trends 99, will present the results of the analysis to identify groups
      of authorities in a hierarchy of new Clusters, Groups and Families for the
      revised classification.

PMID- 10658244
TI  - Demographic data for Europe--a review of sources.
AB  - Population Trends had provided an overview of European and world demographic
      issues since its inception in 1975. This article covers the abundant sources of
      demographic data on all European countries with information on their availability
      in printed and electronic formats.

PMID- 10658245
TI  - [Empirical treatment of urinary infections in urologic surgery].
AB  - Emergency prescription of empirical antibiotic therapy is justified in a context
      of febrile urinary tract infection, or to shorten the preoperative period in a
      hospitalised infected patient. The severity of the infection, its origin
      (community or nosocomial), morphological characteristics of the bacteria on
      direct examination, and urinary dip-stick data must be taken into account to
      select the most appropriate antibiotic while waiting for the antibiotic
      susceptibility test results.

PMID- 10658246
TI  - [Drug-induced urinary calculi in 1999].
AB  - Drug-induced urolithiasis are observed in 1.6% of the urinary calculi in France.
      Drugs crystals are identified in two thirds of these stones. Other drugs are
      responsible for stones which have an apparent metabolic origin (one third of the
      cases). Stone analysis using physical methods such as infrared spectroscopy is
      needed to unambiguously identify stones containing drugs. The inquiry is an
      important step to identify lithogenetic drugs which do not crystallize in the
      stones. The main substances which were identified in stones over the past decade
      were indinavir monohydrate (31.4%), triamterene (11.1%), sulphonamides (10.5%)
      and amorphous silica (4.5%). The main drugs involved in the nucleation and growth
      of metabolic stones were calcium and vitamin D supplementation (15%) and long
      term treatment with carbonic anhydrase inhibitors (8%). Stone prevention is based
      on drug withdrawal or change in dosage with additional measures including an
      increase of diuresis and, if necessary, changes in the urine pH.

PMID- 10658247
TI  - [Transperitoneal laparoscopic nephrectomy].
AB  - OBJECTIVES: To evaluate the feasibility and complications of transperitoneal
      laparoscopic nephrectomy. MATERIAL AND METHODS: 30 transperitoneal laparoscopic
      nephrectomies were performed between November 1992 and October 1998: 17 for
      malignant lesions (10 renal cell carcinomas, 7 urothelial tumours) and 13 for
      benign lesions. RESULTS: The operation was performed entirely by laparoscopy in
      25 cases, with 4 conversions: 3 for technical problems (difficulties of
      dissection: 1, haemorrhage: 2). One patient underwent laparotomy on the same day
      and three patients were transfused. The mean operating time was 116 minutes. No
      laparoscopy-specific complications were observed. CONCLUSION: A standard
      technique must be performed regardless of the disease: systematic open
      laparoscopy, wide colonic dissection, exposure of the vessels and resection in
      the plane of the radical nephrectomy. The risk of cancer dissemination with
      laparoscopy appears to be non-existent for renal cell carcinomas and
      controversial for urothelial tumours. Complications were always benign, although
      there is always a risk of bleeding, regardless of the operator's experience. The
      current technical conditions of laparoscopic surgery and its extension to all
      forms of visceral surgery should encourage the use of this technique by
      urologists, particularly for renal surgery.

PMID- 10658248
TI  - [Value of Fuhrman's nuclear grade: comparison with other prognostic factors of
      renal epithelial tumors].
AB  - OBJECTIVE: To assess the prognostic value of Fuhrman's nuclear grade and to
      compare it to various clinical and histological prognostic factors of renal
      carcinomas. PATIENTS AND METHOD: Single-centre retrospective study of 102
      patients operated for renal tumours between January 1985 and December 1990 (mean
      follow-up: 8.2 years). Prognostic assessment was studied from survival curves.
      RESULTS: The prognostic factors most closely correlated with survival were, in
      decreasing order, metastatic invasion, nuclear grade, stage of local extension
      and lymph node invasion. A significant (p < 0.01) survival difference was only
      observed between Fuhrman grade 2 and grade 3 tumours. This difference was
      accentuated (p < 0.001) when grade 1 and 2 tumours were compared to grade 3 and 4
      tumours. Fuhrman's nuclear grade is independent of the side affected, the tumour
      volume, its multifocal nature, microscopic venous invasion and metastatic
      invasion at the time of diagnosis. Fuhrman's nuclear grade is correlated with
      invasion of fat, the presence of a contingent of eosinophilic cells, stage of
      local extension, lymph node invasion and the subsequent development of
      metastases. CONCLUSION: This study confirms the importance of Fuhrman's nuclear
      grade among the various prognostic factors of renal carcinomas and quantifies its
      value with respect to other prognostic factors.

PMID- 10658249
TI  - [The Dornier Compact: one year experience with a new generation mobile unit
      lithotriptor for the treatment of renal and ureteral calculi].
AB  - OBJECTIVES: To evaluate the clinical results after one year's experience with a
      new generation lithotriptor, the Dornier Compact Delta. MATERIAL AND METHODS: The
      authors treated 278 patients between the ages of 7 and 88 years, presenting with
      ureteral stones in 49% of cases. The mean stone diameter was 10.5 (range: 3 to 50
      mm). The Compact Delta is equipped with a fixed or induced frequency
      electromagnetic shock wave generator. Stones are visualized by digital
      fluoroscopy and/or ultrasound scanning. Therapeutic centering is performed by
      isocentric displacement of the patient. Corrections can be easily made during
      treatment. An average of 3,202 (range: 500-5,800) shock waves were applied with a
      mean energy level of 4.5 (range: 1-6). Treatment was performed without
      premedication. RESULTS: A feeling of discomfort or even pain was reported in 75%
      of cases and treated with intravenous analgesic. Ninety-five per cent of patients
      were discharged with no residual stones or with residual fragments in the process
      of spontaneous evacuation. This result was obtained with one treatment session in
      66% of cases and two sessions in 25% of cases. Five per cent of patients required
      a postoperative complementary manipulation. CONCLUSION: The combination of
      digital fluoroscopic and ultrasound stone detection ensures rapid and reliable
      localization. The Compact Delta is efficient and does not induce any
      complications. The preliminary results with this new mobile system show an
      equivalent efficacy to that of the fixed system with greater flexibility and
      improved comfort of use.

PMID- 10658250
TI  - [Calcium oxalate lithiasis. Relationship between biochemical risk factors and
      crystalline phase of the stone].
AB  - OBJECTIVES: To identify biochemical risk factors specific to each crystalline
      phase of calcium oxalate (calcium oxalate monohydrate and calcium oxalate
      dihydrate) in order to allow more specific medical management of calcium oxalate
      stones and better prevention of recurrences. MATERIAL AND METHODS: The authors
      compared the urine biochemistry (morning and 24-hour) of 19 patients with stones
      containing more than 95% of calcium oxalate monohydrate with those of 16 patients
      with stones containing more than 60% of calcium oxalate dihydrate (calcium
      phosphate < 12%). RESULTS: Urinary calcium, expressed as excretion rate and as
      concentration, and the calcium/citrate ratio were significantly higher in the
      calcium oxalate dihydrate group than in the calcium oxalate monohydrate group:
      (9.2 +/- 3.8 mmol/24 h versus 4.4 +/- 1.7 mmol/24 h); (4.9 +/- 2.1 mmol/l versus
      2.4 +/- 1.1 mmol/l); (3.3 +/- 1.6 versus 1.6 +/- 0.7). The mean pH of the morning
      urine was lower in the calcium oxalate monohydrate group, just below the cut-off
      value of 5.5. CONCLUSION: There is a strong correlation between predominantly
      calcium oxalate dihydrate stones and hypercalciuria or calcium/citrate ratio > 3.
      The close relationship between urine biochemistry and crystalline phases of
      calcium oxalate confirms the clinical value of morphoconstitutional analysis of
      urinary stones. Identification of risk factors, based on stone analysis, allows
      more specific medical management of the stones and, in the longer term, better
      prevention of recurrences.

PMID- 10658251
TI  - [Outpatient treatment of pelvic ureteral calculi with extracorporeal lithotripsy.
      Report of a series of 200 patients consecutively treated].
AB  - OBJECTIVE: To demonstrate the feasibility of first-line outpatient treatment of
      symptomatic stones of the pelvic ureter (sometimes immediately following an
      episode of renal colic), without anaesthesia, by extracorporeal shock-wave
      lithotripsy using a latest generation apparatus (EDAP LT02) with concomitant dual
      guidance. PATIENTS AND METHODS: The mean age of the patients was 45 years. The
      mean stone diameter was 7 mm (range: 3 to 25 mm). Lithotripsy was performed under
      dual ultrasound and fluoroscopic guidance. All patients were reviewed at 3 months
      with follow-up and x-rays. RESULTS: Fragmentation was considered to be complete
      in 79% of cases, partial in 10.5% of cases and absent in 10.5% of cases. Overall,
      87% of stones were completely eliminated at 3 months. The only complication was
      fever of 38.5 degrees C requiring urinary tract drainage and subsequent
      ureteroscopy. Complementary treatment was necessary in 26 cases: ureteroscopy (n
      = 20), alkalinization (n = 1), Dornier ESWL (n = 5). CONCLUSION: ESWL by EDAP
      LT02 allows first-line outpatient treatment of stones of the pelvic ureter with a
      satisfactory success rate.

PMID- 10658252
TI  - [Studer's bladder: functional results and morbidity in 33 patients].
AB  - OBJECTIVE: Several types of enterocystoplasty can be performed after
      cystoprostatectomy for cancer. The objective of this study was to evaluate our 8
      year experience with Studer's technique. PATIENTS AND METHODS: The medical files
      of 33 patients were studied retrospectively. The median age was 60 years. Bladder
      replacement was performed when frozen section histological examination of
      urethral biopsies was negative. The median follow-up was 41 months. Continence
      was evaluated by means of a questionnaire. Patients not using any pads or only
      using pads as a precaution were considered to be diurnally continent, and those
      using no more than one pad per night were considered to be nocturnally continent.
      RESULTS: Postoperative surgical morbidity consisted of two pelvic abscesses, two
      cases of obstructive acute pyelonephritis, one occlusion, and three wound
      complications. Eight patients developed urethroneovesical stenosis and seven
      ureters were reimplanted because of stenosis (two right ureters and five left
      ureters). Diurnal and nocturnal continence rates were 67% and 74% at 12 months,
      and 80% and 94% at 24 months, respectively. Seven patients developed acute
      pyelonephritis, renal function deteriorated in one patient (preoperative renal
      failure) and one patient developed acidosis. CONCLUSION: Studer's technique is a
      simple technique providing satisfactory functional results while preserving the
      upper tract by means of a simple and original antireflux system (ileal ureter)
      with a median follow-up of 41 months, although it was associated with a
      considerable stenosis and pyelonephritis rate.

PMID- 10658253
TI  - [Intraurethral Macroplastic injections in the treatment of urinary incontinence
      after prostatic surgery].
AB  - OBJECTIVES: To evaluate the results and the place of a minimally invasive
      intraurethral injection technique designed to improve the efficacy of the
      urethral sphincter in urinary incontinence after prostatic surgery. MATERIALS AND
      METHODS: A prospective study of 26 Macroplastique injections performed in 15
      patients with a mean age of 66.4 years (range: 54 to 78 years) was conducted over
      an 18-month period. Eleven patients received 2 injections. Prostatic surgery
      consisted of retropubic radical prostatectomy (9 cases), transurethral resection
      (4 cases) or open prostatectomy (2 cases). Three patients received pelvic
      irradiation. Evaluation at 1, 3 and 12 months consisted of clinical questionnaire
      and urodynamic assessment. RESULTS: Rapid deterioration of the initial
      improvement was observed (40% success at 1 month; 71% at 3 months; 33% at 6
      months; 26% at 12 months). No significant influence was demonstrated for post
      prostatectomy radiotherapy, the patient's age, more proximal bladder dysfunction,
      severity of incontinence or preoperative status. However, better results were
      observed when the resting urethral closure pressure remained higher than 30 cm
      H2O. CONCLUSION: We believe that intraurethral injections still have a place in
      the therapeutic armamentarium for incontinence after prostatic surgery with
      satisfactory initial results, which unfortunately deteriorate after 3 months. Our
      study confirms the value of Macroplastique compared to other substances. It is
      difficult to define the predictive factors of failure, but a closure pressure
      greater than 30 cm H2O remains essential. Finally, an interval of at least 3
      months should be observed before repeating this procedure in the case of an
      insufficient result.

PMID- 10658254
TI  - [Urinary continence after retropubic radical prostatectomy: retrospective study
      with self-administered questionnaire].
AB  - OBJECTIVES: To precisely evaluate the incidence of urinary incontinence after
      radical prostatectomy and its impact on quality of life. MATERIAL AND METHODS: A
      self-administered questionnaire was sent to 116 patients operated between 1987
      and 1996. Preoperative and postoperative urinary continence, the time until
      urinary continence was achieved, the presence of urgent micturition, the degree
      of discomfort caused by urinary incontinence and associated voiding disorders
      were assessed. RESULTS: The questionnaire response rate was 96.6%. The urinary
      incontinence rate (continuous use of pads) was 13.4%. No predictive factor for
      postoperative urinary incontinence was identified. Urge incontinence was present
      in 31.3% of cases. 85% of patients claimed to be satisfied with the operation and
      95.4% declared that they would be willing to undergo radical prostatectomy again.
      CONCLUSION: The incidence of urinary incontinence after radical prostatectomy is
      acceptable and the morbidity that it generates is well tolerated and has little
      impact on quality of life.

PMID- 10658255
TI  - [Detection of circulating prostatic cells with RT-PCR PSA in prostatic cancer].
AB  - OBJECTIVES: The detection of circulating prostatic cells by molecular biology
      techniques (RT-PCR) can be useful in the staging of localized prostate cancer
      prior to radical prostatectomy in some institutions. After describing their
      technique, the authors report their results. PATIENTS: 80 RT-PCR were performed:
      32 in a control group (including 11 women free of any neoplastic disease, 11
      healthy men, and 10 men with benign prostatic hyperplasia before resection), and
      48 in patients with prostate cancer (43 with clinically localized cancer and 5
      with metastatic cancer). RESULTS: In the control group, none of 11 women had a
      positive RT-PCR, 1 of the healthy men was positive (orchidopexy) and 3 of the 11
      patients with benign prostatic hyperplasia were positive, but none of them had
      tumour on the resection chips. None of the 5 metastatic patients were positive.
      In the patients treated by radical prostatectomy, no correlation was observed
      between RT-PCR results, pathological stage, positive resection margin status and
      laboratory progression after radical prostatectomy. CONCLUSION: This PSA RT-PCR
      technique developed in this institution does not appear to be useful for the
      molecular staging of prostate cancer. This study demonstrates the difficulty of
      standardization of this technique which limits its routine use.

PMID- 10658256
TI  - [Comparative study of 230 women to determine the maximum closure pressure and
      functional length of the urethra at 0, 3, 6 and 9 o'clock].
AB  - OBJECTIVE: The maximum closure pressure (MCP) of the urethra, measured by the
      urethral profile, constitutes an index of urinary continence. The objective of
      this study, in a large population of women, was to evaluate the possible
      variations of MCP and functional length (FL) of the urethra, according to the
      position of a urodynamic probe designed to perform lateral sectorial
      measurements. MATERIAL AND METHODS: Measurements were performed between July and
      December 1998, in 230 patients with a mean age of 55 years, using a probe
      perfused with water and equipped with an urethral side orifice. We compared, by
      analysis of variance for repeated measures, MCP and mean FL at 0 o'clock (MCPm0,
      LFm0), 3 o'clock (MCPm3, LFm3), 6 o'clock (MCPm6, LFm6) and 9 o'clock (MCPm9,
      LFm9). RESULTS: The values for MCPm and LFm obtained according to the rotation of
      the probe were as follows: MCPm0 = 65.68 +/- 12.46 cmH20, MPCm3 = 55.44 +/- 16.97
      cmH20, MCPm6 = 58.07 +/- 15.85 cmH20, and MCPm9 = 53.85 +/- 16.89 cmH20, LFm0 =
      28.92 +/- 5.32 mm, LFm3 = 30.18 +/- 6.82 mm, LFm6 = 32.40 +/- 6.82 mm and LFm9 =
      30.83 +/- 6.07 mm. CONCLUSION: LCP may variable considerably in the same subject
      according to rotation of the probe. In our series, MCPm at 0 o'clock was
      significantly higher than MCPm at 3 o'clock, 6 o'clock and 9 o'clock. This
      difference appears to increase with age. The lowest values for MCPm were observed
      at 3 o'clock and 9 o'clock. The MCPm at 6 o'clock was intermediate and the
      closest value to the mean pressure calculated from MCPm in the four positions. On
      the other hand, FL varied only slightly according to the position of the probe.

PMID- 10658257
TI  - [Should plasma prolactin assay be routinely performed in the assessment of
      erectile dysfunction? Report of a series of 445 patients. Review of the
      literature].
AB  - OBJECTIVE: To define the value of plasma prolactin assay in the assessment of
      erectile insufficiency. MATERIAL AND METHODS: Plasma prolactin assay
      (radioimmunoassay) was performed in 445 patients presenting with erectile
      insufficiency (mean age 52.5 years). RESULTS: 9 patients (2%) presented plasma
      prolactin levels greater than 25 ng/ml and 4 (0.9%) of them had levels higher
      than 35 ng/ml. Eight of these 9 patients were taking hyperprolactinaemic drugs.
      The aetiology remained unclear in 1 patient, but the pituitary gland was normal
      on CT scan. REVIEW OF THE LITERATURE: In the population of men with erectile
      insufficiency, 2.7% of subjects have plasma prolactin levels greater than 20 or
      25 ng/ml. 1.3% have levels greater than 35 or 40 ng/ml and 0.6% present pituitary
      tumours. In the case of pituitary tumours responsible hyperprolactinaemia and
      erectile insufficiency: 1) plasma prolactin is greater than 30 ng/ml in 90% of
      cases and greater than 50 ng/ml in 83% of cases; 2) total plasma testosterone is
      less than 3 ng/ml in 88% of cases and less than 4 ng/ml in 96% of cases; 3)
      libido is decreased in 90% of cases. CONCLUSION: The prevalence of
      hyperprolactinemia and pituitary tumours in the population of men with erectile
      insufficiency is low. Moreover, certain criteria are suggestive of
      hyperprolactinemia, especially when it is secondary to a pituitary tumour.
      Consequently, routine plasma prolactin assay is not justified. This assay should
      only be performed when libido is impaired, total plasma testosterone is decreased
      or when the patient presents certain signs such as headache, gynaecomastia or
      visual disturbances.

PMID- 10658258
TI  - [Primary non-Hodgkin's malignant lymphoma of the adrenal gland. Case report and
      review of the literature].
AB  - Primary lymphoma of the adrenal gland is an exceptional site for non-Hodgkin's
      malignant lymphoma, as fewer than 50 cases have been reported in the
      international literature. To our knowledge, this is the first reported case of
      intraoperative discovery. The diagnosis of primary adrenal lymphoma can be
      suggested in the case of bilateral involvement and adrenal insufficiency, but
      there are no specific clinical or complementary criteria. The main differential
      diagnoses are adrenal metastases and adenomas. Management is often that of an
      incidentaloma. Primary NHML of the adrenal gland has a poor prognosis with a mean
      survival of 15 months. Only one case with a survival of 8 years has been reported
      in a patient treated with adjuvant radiotherapy, while basic treatment consists
      of combination chemotherapy. Our patient was treated by adrenalectomy followed by
      close surveillance.

PMID- 10658259
TI  - [IgA deficiency and multiple Staphylococcus aureus perirenal abscesses. A case
      report].
AB  - The authors report the case of a patient with IgA deficiency who presented with a
      low-grade renal abscess. Due to the atypical nature of the clinical features and
      imaging, the diagnosis was not established prior to surgery. Despite radical
      surgery, the abscess recurred several weeks later. In the light of this case, the
      authors discuss the various possible diagnoses that must be considered in the
      presence of these types of images and the therapeutic approach during initial
      management. They discuss the various immune deficiencies to be investigated in a
      particular infectious context.

PMID- 10658260
TI  - [Ureteral compression by mesenteric desmoid tumor. Report of 2 cases].
AB  - The authors report two cases of abdominal fibromatosis corresponding to Gardner's
      syndrome, causing hydronephrosis by extrinsic ureteric compression in young men
      in whom any form of surgical resection would have been in vain. These cases of
      ureteric compression were treated endoscopically by placement of a double J
      ureteric stent associated with treatment by tamoxifen in one case and sulindac in
      the other, with apparent stabilization of the disease. The two patients are
      regularly followed in the department with ureteric stent replacement two to three
      times a year.

PMID- 10658261
TI  - [Pseudotumor eosinophilic cystitis with very acute course. Report of a case].
AB  - The authors report a case of eosinophilic cystitis with a very acute course after
      partial cystectomy, requiring semi-urgent total cystoprostatectomy with ileal
      bladder replacement. The patient is completely asymptomatic ten years after the
      operation. This case can be classified with the pseudoneoplastic forms of
      interstitial cystitis occurring in patients with a history of urological surgery.
      The two-stage course of the disease suggests the combination of two
      pathophysiological mechanisms: repeated aggression to the urothelial wall
      responsible for an intense inflammatory reaction and allergy to suture material,
      accounting for the subsequent rapid development.

PMID- 10658262
TI  - [Chronic urine retention disclosing isolated spinal dermoid cyst].
AB  - Spinal dermoid cysts are congenital lesions. Neurological symptoms are related to
      the affected area of the vertebral canal. The commonest type involves the
      sacrococcygeal area. Lesions of the cauda equina are found which result in
      sciatic pain, paresis of the bladder and rectum, flaccid paresis of the legs,
      and/or sphincter disturbances. The histology is typical and benign. The images on
      CT and MR provide diagnosis. We report a case of spinal dermoid cyst revealed by
      chronic urinary retention.

PMID- 10658263
TI  - [Obstructive malformation of the verumontanum].
AB  - The authors report the case of a 23-year-old man presenting with obstructive
      polypoid hyperplasia of the verumontanum, 4 cm long, inducing dysuria with
      residual urine, demonstrated on urethroscopy and requiring endoscopic resection.
      The symptoms resolved completely after treatment.

PMID- 10658264
TI  - [Severe injury of the female urethra resulting from pelvic fracture. Report of a
      case].
AB  - The authors report the case of a woman presenting with urethrovesical rupture and
      vaginal fistula following pelvic trauma. This is a rare lesion, only 30 cases
      were reported in the literature [12]. The diagnosis may be initially missed, as
      it requires a meticulous emergency uro-gynaecological examination. Lesions
      involve the bladder and almost all of the urethra, injuring both the smooth and
      the striated sphincters. Treatment by reconstructive surgery after good exposure
      of the fistula achieved a good anatomical result and a moderate functional
      result.

PMID- 10658266
TI  - [Treatment of acute prostatitis].

PMID- 10658265
TI  - [Value of ultrasonography in the assessment of urinary incontinence in women].

PMID- 10658267
TI  - [Gynecomastia].
AB  - Gynaecomastia is the least rare manifestation of the male breast disease.
      Urologists must therefore be able to distinguish the various forms of
      gynaecomastia, eliminate a testicular tumour and identify the main causes by
      performing a simple but complete assessment. Medical treatment is fairly
      disappointing. Surgical treatment is required in patients presenting with
      complications or when persistent gynaecomastia is aesthetically bothersome.

PMID- 10658268
TI  - [Modified Dyplay technique in the treatment of anterior hypospadias. Immediate
      and long term results in 321 cases and review of the literature].
AB  - OBJECTIVES: Description of a surgical technique in the treatment of anterior
      hypospadias, a frequent malformation for which the treatment is not devoid of
      complications. Evaluation of the short-term as well as the long-term results.
      MATERIAL AND METHODS: Retrospective study of 321 patients treated according to
      this method. 58 patients were reviewed with a mean follow-up of 71 months.
      RESULTS: The immediate results were marked by the development of 16 fistulas
      (5%), 4 of which closed spontaneously. Five cases (1.6%) of meatal retraction and
      6 meatal stenoses (1.9%) were observed. The overall complication rate requiring
      specific treatment was 5.6%. The long-term results showed meatal retraction in
      20.7% of cases, meatal stenosis in 1.7% of cases and fistula in 3.5% of cases.
      This is the series with the longest mean follow-up. Comparison with the currently
      proposed technique suggests that this technique is indicated in the treatment of
      anterior hypospadias. Long-term analysis of the results strongly encourages
      regular and prolonged follow-up of children treated for hypospadias in the first
      2 years. CONCLUSION: The modified Duplay technique is reliable, can be easily
      performed, and gives perfectly satisfactory results, even in the long-term, for
      the treatment of anterior hypospadias.

PMID- 10658269
TI  - [History and geography of ritual circumcision].
AB  - Ritual circumcisions can be classified into types according to the circumstances
      in which they are performed. Spiritual circumstances which express a community
      identity, usually religious and surrounded by a complex significance related to
      numerous myths, especially biblical and African. Non-religious circumcisions,
      particularly well illustrated by the USA model, comprise, apart from
      controversial medical and scientific reasons, a real social dimension and also
      reflect a desire for community membership. Regardless of the circumstances,
      surgeons may sometimes be asked to perform circumcision and should be aware of
      the significance of this procedure.

PMID- 10658270
TI  - [Endocytosis of EGF-receptor complexes at various cell cycle stages].
AB  - Parameters of EGF-receptor complex endocytosis have been studied in the early and
      late G1 phase and in mitosis. As a model, mouse mammary epithelial cells HC11
      were used, whose growth depends on EGF presence in the medium. The Scatchard
      analysis has demonstrated that the surface receptors are represented by two
      receptor populations: 4800 high affinity (KD = 10(-11) M) receptors, and 73,000
      low affinity (KD = 4.10(-9) M) receptors. Incubation of cells with the growth
      factor (5 ng/ml) resulted in a decrease in 125I-EGF binding, with its level being
      low until entering the S-phase. Under these conditions, receptors disposed on the
      plasma membrane presented a homogeneous population (KD = 8.10(-11) M, 14,000
      receptors per cell). No reliable difference was revealed between the EGF-receptor
      complexes, internalized in early and late G1 phases, in respect to the
      internalization rate, level of recycling, degradation, and dynamics of
      compartmentalization. However, endocytosis of EGF-receptor complexes was found to
      be completely blocked in mitosis at the stage of internalization.

PMID- 10658271
TI  - [Karyological characteristics of Down's syndrome: clinical and theoretical
      aspects].
AB  - These data have been collected from St. Petersburg Down Syndrome Register that
      comprises information on 1778 liveborn children with the Down syndrome, including
      three twin sets, ascertained within 1970-1996. Karyotypes were obtained in 1223
      cases, of which 1119 (90.7%) displayed regular trisomy. Mosaicism was found in 44
      cases (3.6%), including 21 males and 24 females, and among these one familial
      case of mosaicism in a daughter and in a healthy mother. Of 70 cases of
      translocations, 41(5.7%) were Robertsonian D ones. 21 (17 inherited, 16 de novo
      and 8 of unknown origin), 28 translocations of isochromosomes 21q; 21q (1
      inherited translocation 21; 22, 22 de novo and 5 of unknown origin). One child
      received the anomaly from his 46XX/45XX, t(D;G) mother-carrier. In 6 cases, free
      trisomy 21 was associated with structural or numerical anomalies:
      46XY,t(13;14)mat + 21 in twins, 47XY,t(C;C) + 21, 47XY,t(10;15)pat + 21,
      47XY,inv(19)mat + 21, 47XX + 21/48XX + 21 + ring, 48XXX + 21. In 12 families
      parental mosaicism was shown or suspected. In 6 families one parent had
      chromosome anomaly, in three cases it was not inherited: t(15;22) and t(6;21) in
      mothers and an additional small marker in a father. In cases confirmed
      cytogenetically an increased sex ratio was shown (679 males and 551 females, SR =
      1.23), but it was not shown in patients not tested cytogenetically (264 males and
      275 females, SR = 0.96, different from the expected 297 males and 242 females, P
      < 0.01).

PMID- 10658272
TI  - Scanning for pleasure.

PMID- 10658273
TI  - Mapping the monochorionic equator--the new frontier.

PMID- 10658274
TI  - Doppler waveform analysis of the intertwin blood flow in acardiac pregnancy:
      implications for pathogenesis.
AB  - OBJECTIVE: To investigate interfetal hemodynamics in acardiac twins and the
      implications for pathogenesis. DESIGN: A retrospective study. SUBJECTS: All
      acardiac twins involved in this study were identified by B-mode ultrasound at a
      teaching hospital in Taiwan. METHODS: Color Doppler imaging and, in one case,
      color power angiography were used to assess umbilical blood flow between acardiac
      twins and their normal co-twins. Placental anastomoses were examined by
      pathologists after delivery. RESULTS: In total five sets of acardiac twins and
      their normal co-twins were enrolled. Autonomous cardiac activity in the form of a
      contractile pocket was detected in two cases. Analysis of the pattern of the
      Doppler waveforms in each case enabled us to classify the type of hemodynamics
      into one of three categories: 'collision-summation', typified by a pattern of
      cyclic alternations of bidirectional flow; 'twin-pulse', which described the
      simultaneous recordings of two opposite constant flows with different pulsating
      rates; and the 'pump in' pattern, which indicated pulsatile flow in the reversed
      direction towards the acardiac mass. In two cases we detected, we believe for the
      first time, an artery-to-vein placental anastomosis between the acardiac twin and
      its co-twin. The nature of the vascular connections were confirmed on
      pathological follow-up. CONCLUSIONS: Our observations suggest that acardiac twins
      may be not only the result of but also the cause of placental vascular
      anastomoses, which may involve either artery-to-artery or artery-to-vein
      anastomoses.

PMID- 10658275
TI  - Prognostic factors in severe twin-twin transfusion syndrome treated by endoscopic
      laser surgery.
AB  - OBJECTIVE: The aim of this study was to investigate clinical and sonographic
      parameters, in particular Doppler blood flow measurements, in severe second
      trimester twin-twin transfusion syndrome before and after endoscopic laser
      coagulation of the placental vascular anastomoses, to correlate these data with
      fetal outcome and to determine whether fetal blood flow measurements could help
      to estimate the probability of fetal survival. METHODS: In 121 cases of severe
      twin-twin transfusion syndrome examined between 17 and 26 weeks of gestation, the
      following investigations were performed: fetal biometry, placental location,
      deepest pool of amniotic fluid, echocardiography and Doppler sonography of the
      umbilical arteries and the ductus venosus of both twins before and after
      fetoscopic laser ablation of the placental anastomoses. RESULTS: The overall
      survival rate was 64% (156/242). Both fetuses survived in 48% (58/121) and one
      fetus survived in 33% (40/121), resulting in 81% (98/121) of pregnancies with at
      least one survivor. Gestational age at the time of the procedure and placental
      location had no significant influence on fetal survival. The amniotic fluid
      volume drained after laser coagulation correlated significantly (p = 0.038) with
      the risk of miscarriage or extremely premature delivery within 4 weeks of the
      procedure. Intertwin discrepancy in abdominal circumference showed a significant
      negative correlation (p = 0.004) with the probability for survival of donor
      fetuses. Before the procedure, 19% (23/121) of donor twins and 5% (6/121) of
      recipient twins showed absent or reversed end-diastolic flow in the umbilical
      artery (p = 0.001). This finding had no significant influence on the survival
      rate of donors. An increase of waveform indices in the umbilical artery 1 day
      after the procedure compared to immediately after the procedure correlated
      significantly with a lower probability for survival of donors (p = 0.042) and
      recipients (p = 0.018). Before the procedure, 37% (45/121) of recipient twins and
      9% (10/113) of donor twins showed absent or reversed flow during atrial
      contraction in the ductus venosus (p < 0.0001). This finding had a significant
      negative influence on the survival rate of recipient fetuses (p = 0.02).
      Furthermore, an increase of waveform indices in the ductus venosus 1 day after
      the procedure compared to immediately after the procedure correlated
      significantly with a lower probability of survival in recipients (p = 0.005).
      CONCLUSIONS: Fetoscopic laser coagulation of the placental vascular anastomoses
      in severe mid-trimester twin-twin transfusion is a potentially corrective and
      effective, minimally invasive procedure. Doppler investigation of the umbilical
      and fetal circulations provides important information on the fetal condition,
      prognosis and therapeutic effects of the intervention. Signs of congestive heart
      failure in the recipient may reduce the probability of survival, whereas
      increased placental resistance in the donor before the procedure is not
      necessarily associated with a reduction in the probability of survival after
      laser coagulation.

PMID- 10658276
TI  - Implementation of nuchal translucency image-scoring method during ongoing audit.
AB  - OBJECTIVE: The aim of this study was to evaluate the contribution of an ongoing
      audit, using the image-scoring method, to the quality of nuchal translucency
      images and to set the basic standards required from the examiners. DESIGN:
      Evaluation of nuchal translucency images, before, during and after the
      implementation of an ongoing audit, without knowledge of the time period or the
      examiner. SUBJECTS: A total of 315 nuchal translucency scans were performed by
      three examiners. METHODS: Each of the retrospective, intermediate and prospective
      time periods included blind scoring of 105 images. The effect of the ongoing
      audit was examined by comparing the distribution of the quality groups and the
      mean final score between the time periods, for all cases and for each examiner
      separately. Improvement of the criteria was assessed by comparing the rate of
      scans meeting the demands between the time periods. RESULTS: The quality of the
      images improved significantly as the mean final score changed from 4.62 +/- 0.21
      to 6.19 +/- 0.19 and to 6.91 +/- 0.16 (p < 0.0001) and the rate of obtaining
      acceptable scans rose from 72% to 88% and to 92% (p < 0.001), respective to the
      three time periods. Whereas the three major criteria improved significantly
      before and after implementation of the audit (mid-sagittal section from 48% to
      94%, caliper placement from 60% to 75% and skin line from 19% to 77%), the minor
      criteria remained unchanged (image size 90%, amnion demonstration 25% and head
      position 77%). The average scores of two examiners, for whom improvement was more
      pronounced, were used to determine the basic standards required from examiners
      subjected to the audit as follows: unacceptable, none; intermediate, 5%;
      reasonable, 65%; excellent, 30%; with a mean final score of 7.25. CONCLUSIONS:
      Implementation of an ongoing audit, using the image-scoring method, proved to be
      an efficient method for surveillance and improving the quality of nuchal
      translucency images. We recommended centers or individuals practicing first
      trimester ultrasound screening to consider its routine utilization, in an
      unbiased and strict manner.

PMID- 10658277
TI  - Evaluation of cerebral perfusion pressure changes in laboring women: effects of
      epidural anesthesia.
AB  - OBJECTIVE: To compare the effect of epidural anesthesia on cerebral perfusion
      pressure in laboring women. STUDY DESIGN: Maternal cerebral blood flow velocity
      was assessed in seven laboring patients with continuous epidural anesthesia and
      15 without, using transcranial Doppler. Maternal cerebral blood flow velocity was
      assessed during the first stage at the trough of a contraction, at the peak of a
      contraction and at the second stage during pushing over the course of four
      contractions. Calculated estimated cerebral perfusion pressure: eCPP =
      Vmean/(Vmean - Vdiastolic) x (mean BP - diastolic BP), where V is velocity and BP
      is blood pressure; modified from Aaslid and colleagues. An index of
      cerebrovascular resistance, the resistance area product, was calculated: RAP =
      mean BP/mean velocity. We calculated an index of cerebral blood flow (cerebral
      blood flow index): CBF index = eCPP/RAP. RESULTS: In non-epidural patients, the
      eCPP fell significantly at the peak of a contraction and during pushing.
      Cerebrovascular resistance, RAP, rose significantly during the peak of a
      contraction, although cerebral blood flow did not change. In patients undergoing
      epidural anesthesia, the stages of labor had no significant effect on eCPP or
      RAP; however, these values were lower than those in patients without epidural
      anesthesia. CONCLUSIONS: The epidural group had a lower eCPP and RAP and cerebral
      blood flow index compared to the non-epidural group. In the non-epidural group,
      the mean arterial pressure was higher in all stages of labor with a trend towards
      an increase in eCPP and cerebral blood flow index.

PMID- 10658278
TI  - Assessment of fetal heart rate variability and velocity variability by Doppler
      velocimetry of the descending aorta at 10-20 weeks of gestation.
AB  - OBJECTIVES: Determination of gestational age-related modulations in fetal heart
      rate and descending aorta blood flow velocity in the early human fetus and
      comparison of aortic variability data with data obtained from the umbilical
      artery. It is hypothesized that these modulations present in the umbilical artery
      also occur in the descending aorta. METHODS: Doppler studies of descending aorta
      velocity waveforms were performed at 10-20 weeks in 55 normal pregnant women. In
      24 of the 55 women, Doppler recordings from both the descending aorta and the
      umbilical artery were collected. Absolute values and variability of fetal heart
      rate, peak systolic and time-averaged velocities were determined from flow
      velocity waveforms of at least 18 s in duration. RESULTS: From 10 to 20 weeks of
      gestation, the descending aorta peak systolic and time-averaged velocities
      increased, whereas the fetal heart rate decreased. The descending aorta peak
      systolic variability also increased. However, the time-averaged velocity
      variability and fetal heart rate variability remained constant during the study
      period. In the subset of 24 women, the fetal heart rate variability and velocity
      variability data from the descending aorta and umbilical artery were not
      significantly different. CONCLUSIONS: Reproducible fetal heart rate and velocity
      variability data can be derived from the descending aorta and umbilical artery.
      The increase in heart rate variability observed in the umbilical artery was not
      seen in recordings obtained from the descending aorta. Different fetal activity
      states may be the underlying mechanism for these heart rate variability
      discrepancies.

PMID- 10658279
TI  - Early fetal megacystis between 11 and 15 weeks of gestation.
AB  - OBJECTIVE: The purpose of this study was to evaluate the prognostic criteria of
      early fetal megacystis. DESIGN: A prospective, transvaginal ultrasound, cross
      sectional study at 11-15 weeks of gestation at a tertiary referral fetal medicine
      unit. SUBJECTS AND METHODS: Sixteen pregnancies out of a total of 5240 were
      identified with early fetal megacystis. Fetal biometry, morphology, amniotic
      fluid, bladder size and volume were also evaluated. The karyotype was available
      in 15 cases. Vesicocentesis was performed in six fetuses and three had
      concomitant cystoscopies. RESULTS: In six fetuses, the megacystis was isolated.
      In the remaining ten, we detected associated hygroma (n = 5), nuchal translucency
      (n = 3), omphalocele (n = 1), mild pyelectasis (n = 1) and bilateral talipes (n =
      1). In three cases the fetuses demonstrated renal hyperechogenicity with cysts,
      and in two cases oligohydramnios was found; four cases (25%) had chromosomal
      abnormalities; 47, XY + 13 (two cases), 47, XY + 18 and 47, XY + 21. Only one
      fetus from this study survived. In the remaining 13 cases, termination was
      proposed after counselling of the patients on the poor prognosis. The mean
      gestational age at termination was 15.5 +/- 2.4 weeks (range 12-20). Three fetal
      transabdominal cystoscopies did not allow us to view the valves; one urethral
      atresia was suspected, and confirmed postnatally. CONCLUSIONS: We found a high
      rate of associated malformations, especially intestinal malformations. The
      systematic evaluation of the intestinal enzymes in the amniotic fluid and urine
      samples might be an important aid in the diagnosis of multiple malformations,
      such as cloacal dysgenesis.

PMID- 10658280
TI  - Fetal intracranial tumors detected by ultrasound: a report of two cases and
      review of the literature.
AB  - Two cases of fetal intracranial tumors detected prenatally by ultrasound,
      together with a review of the literature on this rare disease, are presented.
      Sonographic features, histopathological type and location of the tumors, sex
      distribution, associated anomalies and overall prognosis are described as well as
      obstetric and postnatal therapeutic management.

PMID- 10658281
TI  - Intrauterine sling: a complication of the stuck twin syndrome.
AB  - Stuck twin syndrome usually presents with polyhydramnios in the recipient sac and
      severe oligohydramnios in the donor sac. The donor is displaced against the
      uterine wall and remains adherent in that position. We present a case in which
      the diagnosis was more complicated, owing to the suspension of the stuck twin by
      a sling within the sac of the recipient. A monochorionic diamnionic twin
      gestation was complicated by twin-twin transfusion syndrome at 18 weeks of
      gestation. In our example, the stuck twin was suspended by a sling from the
      placenta. The sling band represented the intertwin membrane that was folded upon
      itself. Amniotic fluid from the recipient twin was present in three dimensions
      around the stuck twin, except for the sling band. The suspension of the stuck
      twin by a sling within the amniotic fluid of the recipient is an unusual
      manifestation of the stuck twin syndrome.

PMID- 10658282
TI  - Antenatal visualization of vascular anastomoses in monochorionic twins using
      color Doppler sonography: the protective function of these anastomoses and the
      phenomenon of interference beating.
AB  - This report concerns the antenatal visualization and velocimetry of an
      arterioarterial and a venovenous anastomosis in a monochorionic twin pregnancy
      using color Doppler sonography. The phenomenon of 'interference beating' occurs
      when two flow velocity waveforms are superimposed in one blood vessel. This
      characteristic image can be generated antenatally to confirm the existence of a
      vascular communication. We were able to reveal these anastomoses postnatally
      using the dye injection technique.

PMID- 10658283
TI  - Second-trimester molecular prenatal diagnosis of sporadic Apert syndrome
      following suspicious ultrasound findings.
AB  - Apert syndrome, an autosomal dominant disorder characterized by craniosynostosis,
      mid-facial malformations, symmetric bony syndactyly of hands and feet, and
      varying degrees of mental retardation, is most frequently caused by a de novo
      mutation. Two missense mutations in the fibroblast growth factor receptor 2
      (FGFR2) gene have been found to account for the disorder in approximately 98% of
      affected patients. Seven cases of prenatal ultrasound diagnosis have been
      reported. Although one earlier diagnosis has been made in a familial case,
      sporadic cases have not been definitively diagnosed until the third trimester
      when craniosynostosis is usually detected. We report a second-trimester molecular
      diagnosis of a sporadic case, based on the ultrasound observation of fetal
      'mitten hands' and craniosynostosis. We discuss the approach to such ultrasound
      features, given the current availability of molecular diagnosis for Apert
      syndrome.

PMID- 10658284
TI  - Uterine anomalies and failed surgical termination of pregnancy: the role of
      routine preoperative transvaginal sonography.
AB  - Although used extensively in the assessment of many gynecological conditions,
      transvaginal ultrasonography is not performed routinely prior to termination of
      pregnancy in the UK. We describe a case in which surgical evacuation of the
      uterus failed. Postoperatively, transvaginal ultrasonography demonstrated a
      bicornuate uterus with a viable pregnancy within the left horn. Subsequent
      medical termination of pregnancy was successful. This case shows the potential
      value of transvaginal ultrasonography prior to termination of pregnancy. A
      prospective trial is needed to assess whether its routine introduction into
      clinical practice will lead to a reduction in morbidity resulting from
      termination.

PMID- 10658285
TI  - First-trimester diagnosis of conjoined twins: a report of three cases.

PMID- 10658286
TI  - Deriving risks of Down's syndrome from nuchal translucency measurements.

PMID- 10658287
TI  - Omphalopagus conjoined twins.

PMID- 10658288
TI  - The role of ACE inhibitors.

PMID- 10658289
TI  - Beneficial effects of ACE inhibitors: insights from animal models.

PMID- 10658290
TI  - Improved survival after myocardial infarction.

PMID- 10658291
TI  - Improved outcome in heart failure.

PMID- 10658292
TI  - ACE inhibitors in heart failure: the question of dose.

PMID- 10658293
TI  - The ATLAS study: low-dose versus high-dose lisinopril in heart failure.

PMID- 10658294
TI  - Results of the ATLAS study.

PMID- 10658295
TI  - Causes of death in the ATLAS study: effects of high-dose ACE inhibitors.

PMID- 10658296
TI  - Implications of the ATLAS study for clinical practice.

PMID- 10658297
TI  - Assessment of Treatment with Lisinopril and Survival ATLAS study.

PMID- 10658298
TI  - Heart failure management in primary care: implications of the ATLAS study.

PMID- 10658299
TI  - Systems and the cost of failure.

PMID- 10658300
TI  - SWORD '98: surveillance of work-related and occupational respiratory disease in
      the UK.
AB  - The SWORD surveillance scheme, now 10 years old, uses systematic reporting from
      physicians to provide a picture of the incidence of occupational respiratory
      disease in the United Kingdom. An estimated total of 2966 incident cases was
      derived from reports by chest and occupational physicians during the 1998
      calendar year. Occupational asthma continues to be the most-reported respiratory
      condition, with an estimated 822 cases (27% of total cases). The proportion of
      cases of mesothelioma (23%), benign pleural disease (21%) pneumoconiosis (7%) and
      inhalation injuries (6%) remain similar to those estimated in past years,
      although fewer cases overall were reported. The most commonly identified agents
      causing asthma in 1998 were enzymes, isocyanates, laboratory animals and insects,
      colophony and fluxes, flour, latex, and glutaraldehyde. An increased incidence of
      respiratory diseases of short latency was seen in mining, whilst cases in
      chemical, mineral products and motor vehicle manufacture remained high; lower
      rates were noted in wood products and textile manufacture when compared with 1997
      figures. Inhalation accidents over the past 3 years were reviewed; gaseous agents
      and combustion products accounted for nearly half of cases. High rates for
      inhalation injuries were seen in coal miners, fuel production, motor vehicle
      manufacturing, water purification, and chemical manufacturing.

PMID- 10658301
TI  - Variations in self-reported health by occupational grade in the British Post
      Office: the Q-health project.
AB  - Between 1995 and 1998 a national sample of 58,501 (42,885 males, 15,616 females)
      Post Office employees (29%) completed and returned a postal questionnaire survey
      providing information on demographic characteristics, physical and psychological
      health, health and lifestyles and health screening behaviour. Response rates by
      occupational grade were as follows: manual (male 69.3%, females 43.6%); clerical
      (male = 11.8%, female, 42.3%); middle management (males 15.5%, females 10.7%) and
      senior management (males 3.4%, females 3.3%). A number of differences in health
      status occurred with occupational grade. Angina, high blood pressure, obesity,
      smoking, arthritis, disability, GP consultations and abnormal smears were all
      more prevalent in lower occupational grades. Height, job satisfaction, seat belt
      use and breast self-examination were also lower in lower status jobs. Some
      findings were unexpected: GHQ scores indicated better mental health in lower
      grades, whilst knowledge and frequency of testicular self-examination and
      attendance for mammograms were higher in lower grades. Self-reports for asthma,
      diabetes and family history of bowel cancer were also greater in higher grades.
      These findings are considered in terms of response bias, health selection, the
      psychosocial work environment, occupational health interventions and the nature,
      meaning and organization of social position within the Post Office.

PMID- 10658302
TI  - Respiratory abnormalities among male foundry workers in central Taiwan.
AB  - The objectives of this study were to determine the relationship between exposure
      levels and respiratory abnormalities, to measure FVC and FEV1(1) changes per year
      based on work duties and to investigate the prevalence of and factors related to
      pneumoconiosis. A total of 583 male workers from 50 iron foundries in central
      Taiwan were investigated. First, workers' respiratory symptoms were categorized
      using a modified American Thoracic Society (ATS) questionnaire and then were
      verified by physician's examination. Next, pulmonary function tests were
      performed including: forced vital capacity (FVC), forced expiratory volume in one
      second (FEV1) and forced expiratory flow rate. A chest radiograph was used to
      diagnose pneumoconiosis according to ILO criteria. Furnace workers were found to
      have the highest prevalence of chronic phlegm, thoracic disorders and chronic
      bronchitis. In general, smokers had a higher prevalence of respiratory symptoms
      as compared with non-smokers. Pulmonary function abnormalities and pneumoconiosis
      were closely linked to smoking and work duration. After adjusting for age, height
      and smoking there was a significant decrease based on work duration in FVC and
      FEV1 for furnace and moulding workers compared with after-processing and
      administrative workers. The overall prevalence of pneumoconiosis was 8.8%,
      highest among furnace (16.3%) and after-processing workers (11.4%) and lowest
      among administrative workers (2.5%). Using multiple logistic regression, the risk
      of developing pneumoconiosis (as compared with the administrative workers) for
      furnace workers was highest (8.98 times greater risk), followed by after
      processing workers (6.77 times greater risk) and moulding workers (5.41 times
      greater risk). Prolonged exposure to free silica, and smoking habits, can result
      in respiratory abnormalities among foundry workers.

PMID- 10658303
TI  - Indicators of cardiovascular risk among workers exposed to high intermittent
      levels of carbon disulphide.
AB  - The effects of exposure to carbon disulphide have been studied mostly among
      workers in the viscous rayon industry, where the usual exposure profile has been
      relatively steady exposure over work shifts. We investigated 13 workers in a
      small chemical company who were exposed to low levels, peaking intermittently to
      relatively high levels in the range of 100-200 ppm at the end of the work shift,
      a pattern that may change the risk profile. Our investigation was part of a
      compliance order that was fought by the company and our access and follow-up was
      limited. Two workers had burns on their bodies associated with exposure to
      caustic. Four had elevations in total serum cholesterol, one had elevated serum
      triglycerides and three had elevations in fasting blood glucose--two of them were
      known to be diabetics before employment and one had a history of unexplained
      peripheral neuropathy. No consistent pattern suggestive of a defined lipoprotein
      abnormality was obvious but several atherogenic profiles were observed. Five had
      abnormalities on electrocardiogram, four of whom appeared to be among the most
      heavily exposed. The presence of these changes taken together in this context may
      suggest accelerated atherosclerotic changes. Tests of liver and kidney function
      were within the normal range for all workers, as was a complete blood count. Four
      of the workers had evidence of a bilateral reduction in hearing threshold at
      4,000 Hz. A complete set of recommendations was forwarded to the employer,
      emphasizing further control of exposure to carbon disulphide, personal protection
      requirements and a cardiovascular risk reduction programme. Conditions improved
      in the plant following modifications introduced in response to a stop work order
      from the provincial government's occupational health and safety agency. However,
      a fire in 1998 put the company out of business and ended further follow-up or
      interventions. We conclude that these findings, while difficult to interpret
      because of the circumstances of the investigation, are compatible with an
      atherogenic effect of exposure to peaking levels of carbon disulphide. The
      observation should be tested in a larger population with fewer confounding
      factors and greater control over the investigation.

PMID- 10658304
TI  - Absenteeism and mortality of workers exposed to electromagnetic fields in the
      French Electricity Company.
AB  - The objective of this study was to describe the health status of electricity
      workers exposed to electromagnetic fields during their job. Two groups of exposed
      workers were studied from 1978 to 1993: the live line workers (n = 121) and the
      substation workers (n = 232.7) of the French Electricity Company (EDF). A control
      group was randomly selected from all the company non-management male employees;
      one control for each exposed subject was matched for the first year of
      employment. Absenteeism indices and mortality rates were computed and compared in
      the exposed and control groups. The absence rates were 1.98% in the substation
      workers and 2.5% in the control group (p < 0.001) and 2.7% in the live-line
      workers and 2.8% in the control group (NS). No effect of the length of exposure
      was found. However the medical causes of sickness absence were different: exposed
      employees had less psychiatric and respiratory diseases but more accidents at
      work than their control group. Relative risks of accidents at work were 1.2 95%
      confidence interval (CI) = 1.08-1.33[ for substation workers and 3.22 (CI = 1.78
      5.88) for live line workers. EDF electromagnetic field exposed workers seemed not
      to be affected by any specific health problems except for an excess of accidents
      at work.

PMID- 10658305
TI  - The management of occupational health by NHS Trusts in the north of England.
AB  - This paper reports the findings of an audit of the management of occupational
      health arrangements in 36 NHS Trusts in the Northern and Yorkshire region of
      England. A questionnaire was designed based on a national NHS occupational health
      standard to obtain data on eight categories of occupational health activity:
      health and safety; pre-employment assessments; Infection Control; health
      surveillance; sickness absence; ill-health retirement; health promotion and
      record storage. The management arrangements for occupational health were varied.
      Assessments of workplace hazards, prevention of HIV-positive workers from
      performing exposure-prone invasive procedures and the assessment of pregnant
      workers were identified as issues for further consideration. Provision of
      competent and effective occupational health services will assist in the
      management of sickness absence and in the protection and promotion of health of
      staff. It will also contribute to the health and safety of patients.

PMID- 10658306
TI  - A review of mental health morbidity associated with OFSTED inspections of schools
      in one metropolitan local authority.
AB  - Anecdotally there appeared to be a relationship between OFSTED inspections and
      mental health morbidity. This study was set up to examine this relationship in
      one metropolitan local authority. Inspected schools were matched with schools
      from the same local authority that were not inspected. The rate of sickness
      absence per 100 whole time equivalent staff in inspected schools was 5.4 as
      compared with 2.1 in matched schools. The relative risk of a spell of sickness
      absence due to mental ill-health in an inspected versus an uninspected school was
      2.52 (95% confidence interval = 1.19-5.31). The study indicates that there may be
      a relationship between the OFSTED inspection process and mental health morbidity.
      Some recommendations are made.

PMID- 10658307
TI  - Mortality due to asbestos-related causes among railway carriage construction and
      repair workers.
AB  - The objective of this study was to further clarify the cancer risk associated
      with asbestos exposure in railway carriage construction and repair. The cohort
      included 734 subjects employed between 1 January 1945 and 31 December 1969. Vital
      status was ascertained at 31 December 1997. Mortality was investigated in the
      time span 1970-97. Forty-two subjects (6%) were lost to follow-up and eight
      causes of death (4%) could not be ascertained. The overall mortality was not
      above the expected value. Among neoplastic diseases, excesses were observed for
      lung standardized mortality ratio (SMR) = 124; 90% confidence interval (CI) = 87
      172; 26 obs), pleura (SMR = 1,327; CI = 523-2,790; 5 obs), larynx (SMR = 240; CI
      = 95-505; 5 obs), liver (SMR = 241; CI = 126-420; 9 obs), pancreas (SMR = 224; CI
      = 98-443; 6 obs) and multiple myeloma (SMR = 429; CI = 117-1,109; 3 obs). The
      observed excess of lung and pleural neoplasms can be causally related to asbestos
      exposure in the manufacture of railway carriages. A causal role of asbestos
      exposure in the raised SMRs from laryngeal and pancreatic neoplasms and multiple
      myeloma cannot be conclusively proven.

PMID- 10658308
TI  - A systematic review of the effectiveness of health promotion interventions in the
      workplace.
AB  - The aim of this study was to identify and critically review evaluations of the
      effectiveness of health promotion programmes in the workplace. In line with
      guidelines for 'good practice' within the literature on workplace health
      promotion, this study aimed to assess the extent to which evaluated interventions
      considered employees' expressed needs or involved employee-employer partnerships.
      Overall, 110 outcome evaluations were located. Only a quarter of these reported
      that interventions were implemented in response to the explicit needs and/or
      views of the employees and very few involved partnerships. Most of the programmes
      targeted individual behaviour and supportive organizational change was limited.
      The majority of the outcome evaluations were not sufficiently rigorous to make a
      strong case for the effectiveness of workplace health promotion. However, some
      pointers to success were identified. It was concluded that there seems to be a
      wide disparity between what counts as 'good practice' within workplace health
      promotion and what is reported in the evaluation of effectiveness literature.
      This is not to say that 'good practice' does not exist, but that either such
      programmes are not rigorously evaluated for their effectiveness and/or that many
      of the evaluation findings remain outside the public domain.

PMID- 10658309
TI  - Effects of a low-intensity worksite-based nutrition intervention.
AB  - Male employees from four local worksites were recruited to participate in a short
      term and low-intensity nutrition intervention which focused on promoting low-fat
      dietary habits. The sites were randomized to control conditions or to the
      intervention programme that consisted of an individualized health risk appraisal,
      group sessions, mass media activities and environmental changes. Participants
      were seen before and three months after intervention to measure blood lipids,
      nutrition knowledge and dietary changes. Eighty-three per cent of all eligible
      subjects were screened (n = 770) and follow-up measures were obtained for 82%.
      The score for nutrition knowledge improved significantly in the intervention
      group. There was also a net reduction in the intake of total calories and in the
      percentage of energy from total fat. Reported intake of carbohydrates and
      proteins increased. For all employees assessed, there were no changes in mean
      total cholesterol level or fatty acid composition. Only among participants with
      hypercholesterolemia was a significant reduction in blood cholesterol observed.
      This low-intensity intervention programme achieved some self-reported dietary
      changes and was successful (at least in part because statistical regression needs
      to be considered) in obtaining a more short-term beneficial cholesterol level in
      employees at higher cardiovascular risk.

PMID- 10658310
TI  - Health surveys in the workplace: comparison of postal, email and World Wide Web
      methods.
AB  - Health surveys in the workplace are an important part of epidemiology, needs
      assessment and health promotion. Since the workplace is changing rapidly with the
      use of computer networks, we examined the feasibility, validity and cost of
      health surveys using e-mail and the World Wide Web (WWW). Five hundred
      systematically sampled university staff in a convenience sample of 10 English
      universities were surveyed using either e-mail alone, e-mail plus a WWW form or
      postal questionnaire. Response rates, speed of response, validity and costs were
      examined. The postal survey obtained the best response rate: 72% as compared with
      34% for e-mail alone and 19% for the WWW, but it was also the most expensive at
      92p per reply, with 35p for e-mail, and 41p for the WWW. Most of the electronic
      responses were made within five days. In 1997, the increased response rate
      justified the higher cost of postal questionnaires. e-mail and WWW surveys are
      easy, quick and inexpensive to administer, and despite low response rates may be
      useful for pilot studies. The rapid changes in the spread and use of information
      technology means we have to keep reassessing the methods we use for health
      surveys in the workplace.

PMID- 10658311
TI  - Reviewing car fleet performance after advanced driver training.
AB  - Following a review of car fleet performance information, the high cost of
      accidents in a small fleet was highlighted. Measures were introduced, including
      advanced driver training and fleet performance followed-up. Significant
      improvements in accident rates, with reduced costs were recorded. The savings
      achieved outweighed the expenditure on the measures introduced.

PMID- 10658312
TI  - How should we keep lead workers under surveillance?

PMID- 10658313
TI  - 'Sisters under the skin'--a view from Public Health Medicine.

PMID- 10658314
TI  - Auditing health and safety management systems--an insurer's view.

PMID- 10658315
TI  - Prevalence and cost of work-related skin disease.

PMID- 10658316
TI  - Respiratory symptoms, sensitization and dust exposure in small bakeries.

PMID- 10658317
TI  - Refining the computation of topic based impact factors--some suggestions.

PMID- 10658318
TI  - Automated high-throughput liquid-liquid extraction for initial purification of
      combinatorial libraries.
AB  - An automated high-throughput liquid-liquid extraction (LLE) methodology has been
      developed and utilized for the initial purification of the combinatorial library
      samples containing unreacted amines and other water-soluble byproducts or
      impurities. Various extraction solvents were evaluated along with different
      extraction devices. The LLE method was automated using 96-well-format plates and
      a robotic liquid-handling workstation. In the optimized LLE method, crude
      combinatorial library samples were dissolved in a water-immiscible organic
      solvent, butyl acetate, and added to each well in a 96-well-format plate packed
      with an inert support material coated with hydrochloric acid. Separation occurs
      based on the partitioning of the compounds between two liquid phases. Product
      recovery, purity, and amine removal efficiency were determined by HPLC with and
      without precolumn derivatization. The automated method was successfully applied
      to the cleanup of some representative combinatorial library samples with greater
      than 98% amine removal and an average product purity of 90%. The application of
      the automated high-throughput LLE method should greatly reduce the labor, time,
      and cost associated with the purification of combinatorial libraries.

PMID- 10658319
TI  - A generic strategy to analyze the spatial organization of multi-protein complexes
      by cross-linking and mass spectrometry.
AB  - Most cellular functions are performed by multi-protein complexes. The identity of
      the members of such complexes can now be determined by mass spectrometry. Here we
      show that mass spectrometry can also be used in order to define the spatial
      organization of these complexes. In this approach, components of a protein
      complex are purified via molecular interactions using an affinity tagged member
      and the purified complex is then partially cross-linked. The products are
      separated by gel electrophoresis and their constituent components identified by
      mass spectrometry yielding nearest-neighbor relationships. In this study, a
      member of the yeast nuclear pore complex (Nup85p) was tagged and a six-member sub
      complex of the pore was cross-linked and analyzed by 1D SDS-PAGE. Cross-linking
      reactions were optimized for yield and number of products. Analysis by MALDI mass
      spectrometry resulted in the identification of protein constituents in the cross
      linked bands even at a level of a few hundred femtomoles. Based on these results,
      a model of the spatial organization of the complex was derived that was later
      supported by biological experiments. This work demonstrates, that the use of mass
      spectrometry is the method of choice for analyzing cross-linking experiments
      aiming on nearest neighbor relationships.

PMID- 10658320
TI  - Combined scanning electrochemical-atomic force microscopy.
AB  - A combined scanning electrochemical microscope (SECM)-atomic force microscope
      (AFM) is described. The instrument permits the first simultaneous topographical
      and electrochemical measurements at surfaces, under fluid, with high spatial
      resolution. Simple probe tips suitable for SECM-AFM, have been fabricated by
      coating flattened and etched Pt microwires with insulating, electrophoretically
      deposited paint. The flattened portion of the probe provides a flexible
      cantilever (force sensor), while the coating insulates the probe such that only
      the tip end (electrode) is exposed to the solution. The SECM-AFM technique is
      illustrated with simultaneous electrochemical-probe deflection approach curves,
      simultaneous topographical and electrochemical imaging studies of track-etched
      polycarbonate ultrafiltration membranes, and etching studies of crystal surfaces.

PMID- 10658321
TI  - Integrated microanalytical technology enabling rapid and automated protein
      identification.
AB  - Protein identification through peptide mass mapping by matrix-assisted laser
      desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) has become
      a standard technique, used in many laboratories around the world. The traditional
      methodology often includes long incubations (6-24 h) and extensive manual steps.
      In an effort to address this, an integrated microanalytical platform has been
      developed for automated identification of proteins. The silicon micromachined
      analytical tools, i.e., the microchip immobilized enzyme reactor (mu-chip IMER),
      the piezoelectric microdispenser, and the high-density nanovial target plates,
      are the cornerstones in the system. The mu-chip IMER provides on-line enzymatic
      digestion of protein samples (1 microL) within 1-3 min, and the microdispenser
      enables subsequent on-line picoliter sample preparation in a high-density format.
      Interfaced to automated MALDI-TOF MS, these tools compose a highly efficient
      platform that can analyze 100 protein samples in 3.5 h. Kinetic studies on the
      microreactors are reported as well as the operation of this microanalytical
      platform for protein identification, wherein lysozyme, myoglobin, ribonuclease A,
      and cytochrome c have been identified with a high sequence coverage (50-100%).

PMID- 10658322
TI  - The effect of stationary-phase pore size on retention behavior in micellar liquid
      chromatography.
AB  - One of the limitations that has restricted the applicability of micellar liquid
      chromatography (MLC) is the weak eluting power of micellar mobile phases compared
      to conventional hydro-organic mobile phases used in reversed-phase liquid
      chromatography. This may be the result of Donnan or steric exclusion of the
      micelles from the pores of the stationary phase, within which nearly all (> or =
      99%) of the stationary phase resides and the analytes spend most of their time.
      To determine whether wide-pore stationary phases would overcome this limitation
      in MLC, several C8 and C18 stationary phases ranging from 100 to 4000 A were
      investigated using a diverse set of test solutes and micellar solutions of
      anionic, neutral, and cationic surfactants as mobile phases. With the larger pore
      size stationary phases, the eluting power of the MLC mobile phases was enhanced
      with all surfactant types, the greatest effect being with the neutral surfactant.
      Differences in retention behavior were observed between various solute types and
      between the C8 and C18 stationary phases. These differences appear to be related
      to the relative hydrophobicity of the solutes and to differences in the
      surfactant-modified stationary phases. Partitioning behavior of representative
      solutes on the large-pore C8 and C18 columns was shown to follow the three-phase
      partitioning model for MLC. Methylene group selectivity data showed only minor
      differences in the stationary-phase characteristics between the small- and large
      pore size C18 columns. The true eluting power of micellar mobile phases was
      revealed with wide-pore stationary phases and was demonstrated by the separation
      and elution of an extended series of alkylphenones on C18 columns.

PMID- 10658323
TI  - A comparative study of the chromatographic selectivity of polystyrene-coated
      zirconia and related reversed-phase materials.
AB  - The chromatographic selectivities of polystyrene-coated zirconia (PS-ZrO2) have
      been investigated in detail by means of homologue series retention studies and
      studies of a variety of nonpolar aromatic positional isomers. This material has
      been compared to polybutadiene-coated zirconia, octadecyl- and phenyl-bonded
      silica, and polymer-based reversed phases. In addition, the separations of a wide
      variety of compound classes on PS-ZrO2 were compared with those on other aromatic
      and aliphatic RPLC phases. The PS-ZrO2 material exhibits substantial differences
      in selectivity toward nonpolar and polar analytes as compared to other phases,
      especially with respect to polybutadiene-coated zirconia (PBD-ZrO2). On PS-ZrO2,
      polynuclear aromatic hydrocarbons (PAHs) are retained much more than are
      alkylbenzenes, whereas on PBD-ZrO2 the opposite is observed. In addition, PS-ZrO2
      has much greater selectivity than does PBD-ZrO2 for the separation of structural
      isomers which differ in the position of phenyl groups. In general, even though
      the carbon content of PS-ZrO2 is much lower than that of conventional reversed
      phase materials, such as octadecyl-bonded silica (C18-SiO2), polar analytes
      exhibit sufficient retention and differential selectivity on PS-ZrO2 that
      resolution comparable to that on C18-SiO2 can be obtained but with substantially
      improved analysis times.

PMID- 10658324
TI  - A family of single-isomer, sulfated gamma-cyclodextrin chiral resolving agents
      for capillary electrophoresis. 1. Octakis(2,3-diacetyl-6-sulfato)-gamma
      cyclodextrin.
AB  - The first member of the single-isomer, sulfated gamma-cyclodextrin family, the
      sodium salt of octakis(2,3-diacetyl-6-sulfato)-gamma-cyclodextrin (ODAS-gamma CD)
      has been synthesized, analytically characterized, and used to separate, by
      capillary electrophoresis, a variety of neutral, acidic, basic, and amphoteric
      enantiomers in low pH background electrolytes. The anionic effective mobilities
      of the neutral and anionic analytes were found to increase with the concentration
      of ODAS-gamma CD. For weakly binding cationic analytes, the effective mobilities
      went from cationic high values, through zero, to increasingly larger anionic
      values as the concentration of ODAS-gamma CD was increased. For the strongly
      complexing cationic analytes, the effective mobilities became anionic even at
      very low ODAS-gamma CD concentrations and became smaller as the ionic strength of
      the background electrolyte increased with the increasing ODAS-gamma CD
      concentration. Separation selectivity followed the predictions of the charged
      resolving agent migration model: for neutral analytes it decreased as the
      concentration of ODAS-gamma CD was increased. For cationic analytes,
      selectivities were found to increase as the cationic effective mobilities
      approached zero, then decreased as the concentration of ODAS-gamma CD was
      increased further. The extent of peak resolution that could be realized with ODAS
      gamma CD strongly depended on the magnitude of separation selectivity and the
      normalized electroosmotic flow mobility. ODAS-gamma CD proved to be a broadly
      applicable chiral resolving agent.

PMID- 10658325
TI  - One-dimensional protein analysis of an HT29 human colon adenocarcinoma cell.
AB  - A single HT29 human colon adenocarcinoma cell was introduced into a fused-silica
      capillary and lysed, and the protein content was fluorescently labeled with the
      fluorogenic reagent 3-(2-furoyl)quinoline-2-carboxaldehyde. The labeled proteins
      were separated by capillary electrophoresis in a submicellar buffer and detected
      by laser-induced fluorescence in a postcolumn sheath-flow cuvette. Several dozen
      components were resolved. A number of experiments were done to verify that these
      components were proteins. Most components of the single-cell electropherogram had
      the same mobility as components present in the 30-100 kDa fraction of a protein
      extract prepared from the cell culture. One component was identified as a
      approximately 100 kDa protein by co-injecting the sample with purified protein
      obtained from an SDS-PAGE gel. Protein expression varied significantly between
      cells, but the average expression was consistent with that observed from a
      protein extract prepared from 10(6) cells.

PMID- 10658326
TI  - On-column visualization of sample migration in liquid chromatography.
AB  - A quantitative on-column visualization technique for evaluating solute migration
      in liquid chromatography columns was described. This technique employed a matched
      refraction index phase system in high-pressure glass columns. In this case, the
      mobile phase was carbon tetrachloride and the stationary phase was a C18 silica.
      Because the refractive indexes of the two phases were the same, the column bed,
      otherwise opaque, was transparent to the eye. Zones of colored solutes could be
      injected (iodine for instance) and their migration studied along the column.
      Photographing the sample band during its migration allowed chromatographic
      information to be extracted using digital technology. As an example of
      applications for this technique, we show the sample entry through various inlet
      fittings. The results demonstrate that chromatographers should pay more attention
      to the selection of inlet frits. Importantly, the frit porosity should be matched
      to the particle size of the packing.

PMID- 10658328
TI  - A study on liquid-liquid distribution based on single picoliter droplets and in
      situ electrochemical measurements.
AB  - A microelectrode technique combined with the microcapillary
      injection/manipulation of a single organic droplet in water was developed. The
      technique was applied to the study of the distribution of a ferrocene derivative
      across a single-picoliter-nitrobenzene-droplet/water interface and to the
      simultaneous in situ electrochemical determination of the distributed solute in
      the picomole-femtomole range. The liquid-liquid distribution processes were
      discussed in terms of droplet size and solute concentration (in water)
      dependencies of the interfacial mass transfer rate.

PMID- 10658327
TI  - Spatially addressed deposition and imaging of biochemically active bead
      microstructures by scanning electrochemical microscopy.
AB  - A new procedure is described to deposit paramagnetic beads on surfaces to form
      microscopic agglomerates. By using surface-modified beads, microscopic structures
      with defined biochemical activity are formed. The shape and size of agglomerates
      were characterized by scanning electron microscopy (SEM), and the biochemical
      activity was mapped with scanning electrochemical microscopy (SECM). This
      approach is demonstrated using beads modified with anti-mouse antibodies (Ab).
      After allowing them to react with a conjugate of mouse IgG and alkaline
      phosphatase (ALP), the beads were deposited as agglomerates of well-defined size
      and shape. The biochemical activity was recorded in the generation-collection
      SECM mode by oxidizing 4-aminophenol formed in the ALP-catalyzed hydrolysis of 4
      aminophenyl phosphate at the surface of the beads. The signal height correlated
      with both the amount of beads present in one agglomerate and the proportion of Ab
      binding sites saturated with the ALP mouse IgG conjugate. The feedback mode of
      the SECM was used to image streptavidin-coated beads after reaction with
      biotinylated glucose oxidase.

PMID- 10658329
TI  - Membrane characterization of anion-selective CHEMFETs by impedance spectroscopy.
AB  - Impedance spectroscopy can be used to determine the influence of several membrane
      parameters on the membrane resistance of anion selective CHEMFETs. The
      concentration of the ammonium sites in the membrane, the anion-receptor complex
      stoichiometry, and the polarity of the membrane matrix are of particular
      importance. In general the resistance of polysiloxane membranes is higher than
      that of PVC membranes. However, in polysiloxane membranes the membrane polarity
      can be influenced by the type or concentration of polar substituents on the
      polysiloxane chain. Polysiloxane ion-exchange membranes with 25 mol% of polar
      sulfone substituents exhibit the same conductance as NPOE plasticized PVC
      membranes. Remarkably, the membrane resistance of cation-selective polysiloxane
      membranes is much lower and is much less dependent on the substituents.

PMID- 10658330
TI  - An instrument for simultaneous EQCM impedance and SECM measurements.
AB  - A novel combination of an electrochemical quartz crystal microbalance (EQCM) and
      a scanning electrochemical microscope (SECM) has been built. Unlike conventional
      EQCMs, the instrument described here allows rapid in situ measurement of the
      modulus of the quartz crystal's transfer function. Data analysis in the complex
      plane for the Butterworth-Van Dyke (BVD) equivalent circuit yields the real and
      the imaginary components R (damping resistance) and XL (reactive inductance) of
      the crystal's electroacoustic impedance around its resonant frequency of 10 MHz.
      The influence of different tip shapes of an approaching microelectrode on the
      electroacoustic impedance of the quartz crystal was studied and found to be
      minimal for certain geometries. The capability of the EQCM/SECM instrument was
      tested in cyclic voltammetric plating/stripping experiments using a copper(I)
      chloride solution of high concentration in 1 M HCl. Four parameters, XL, R, the
      substrate, and the tip current, can be recorded simultaneously. Depletion layer
      effects were observed and could be corrected for to yield accurate current
      efficiencies for potentiodynamic and potentiostatic copper plating. The
      amperometric response of the SECM tip positioned closely to the substrate
      reflects the concentration changes of electroactive ions in the diffusion layer
      of the substrate electrode.

PMID- 10658331
TI  - Identification of arsenosugars at the picogram level using nanoelectrospray
      quadrupole time-of-flight mass spectrometry.
AB  - State-of-the-art analytical methods for arsenic speciation rely typically on the
      availability of standards of defined structure, limiting the applicability of
      such methods to the determination of known compounds. Our previous high-energy
      tandem mass spectrometric studies demonstrated the strength of mass spectrometry
      for generating structurally diagnostic ions that allow for the identification of
      arsenic-containing ribofuranosides (arsenosugars) without the use of standards.
      We now report a more widely applicable and more sensitive approach, using
      negative-ion nano-electrospray low-energy tandem mass spectrometry for the
      generation of structurally useful product ions that allow for identification of
      arsenosugars at the picogram level. In the negative-ion mode, numerous product
      ions, suitable for characterizing naturally occurring dimethylated arsenosugars,
      were generated in high abundance. Application of the method to an algal extract
      unequivocally demonstrated the presence of a single dimethylated arsenosugar. In
      the positive-ion mode, characteristic tandem mass spectra were obtained for four
      trimethylarsonioribosides, allowing their identification without the need for
      standards. Overall it was demonstrated that nano-ES-MS/MS techniques can be used
      for characterizing arsenosugars on a routine basis, a necessary requirement for
      assessing potential health risks associated with consuming foods containing
      elevated levels of arsenosugars and for improving our understanding of arsenic
      biochemistry.

PMID- 10658332
TI  - A micromachined chip-based electrospray source for mass spectrometry.
AB  - A micromachining process is described for fabricating a mass spectrometry
      electrospray source on a silicon chip. The process utilizes polymer (parylene)
      layers to form a system of chambers, filters, channels, and hollow needle
      structures (electrospray emitters) that extend more than a millimeter beyond the
      edge of the silicon substrate. The use of photoresist as the sacrificial layer
      facilitates the creation of long channels. Access to the channel structures on
      the chip is through a port etched through the silicon substrate that also serves
      as a sample reservoir. A reusable chip holder consisting of two plastic plates
      and an elastomer gasket provides the means to mount the chip in front of the mass
      spectrometer inlet and make electrical and gas connections. The electrospray
      emitters have tapered tips with 5 microns x 10 microns rectangular openings. The
      shape of the tip can be varied depending on the shape of the mask used to protect
      the parylene structures during the final plasma etch. The parylene emitters are
      physically robust and require only a high electric field to achieve stable
      electrospray operation over a period of a few hours. Direct comparisons with
      conventional glass or fused silica emitters indicated very similar performance
      with respect to signal strength and stability, spectral quality, and endurance.
      The automated MS/MS analysis of a mixture of tryptic peptides was no more
      difficult and yielded nearly identical results as the analysis of the same sample
      using a conventional nanospray device. This work demonstrates that an efficient
      electrospray interface to mass spectrometry can be integrated with other on-chip
      structures and mass-produced using a batch process.

PMID- 10658333
TI  - Electrospray ionization tandem mass spectrometry for structural elucidation of
      protonated brevetoxins in red tide algae.
AB  - Brevetoxins, the toxic components of "red tide" algae, all share one of two
      robust polycyclic ether backbone structures, but they are distinguished by
      differing side-chain substituents. Electrospray ionization mass spectrometry
      analyses of brevetoxins have shown that the polyether structure invariably has a
      very high affinity for sodium cations that results in the production of abundant
      (M + Na)+ ions even when sodium cations are only present as impurities. Because
      the ionic charge tends to remain localized on the sodium atom and because at
      least two bonds must be broken in order to produce polycyclic backbone
      fragmentation, it is extremely difficult to obtain abundant product ions (other
      than Na+) from (M + Na)+ brevetoxin precursor ions in low-energy collision
      induced dissociation (CID) MS/MS experiments. This report establishes that acid
      additives (oxalic acid, trifluoroacetic acid, and particularly hydrochloric acid)
      in aqueous methanol solutions can promote high yields of protonated brevetoxin
      molecules (MH+ ions) for Btx-1, -2, and -9 brevetoxins. Most importantly, unlike
      their (M + Na)+ counterparts, MH+ precursor ions offer readily detectable product
      ions in CID MS/MS experiments, even under low-energy collisions. This direct
      structural characterization approach has provided decomposition information from
      brevetoxins that was previously inaccessible, including the identification of
      diagnostic product ions for "type A" brevetoxins (m/z 611) and "type B"
      brevetoxins (m/z 779, 473, 179) and characteristic ions for Btx-1 (m/z 221, 139),
      Btx-2 (m/z 153), and Btx-9 (m/z 157, 85). Precursor ion scans and constant
      neutral loss scans are proposed to enable screening of individual type A or type
      B brevetoxins present in naturally occurring mixtures.

PMID- 10658334
TI  - Effect of experimental parameters on the ESI FT-ICR mass spectrum of fulvic acid.
AB  - Fulvic acid (FA) is a heterogeneous mixture of organic macromolecules found in
      the waters, soils, and sediments of the earth's surface. The ability of
      electrospray ionization (ESI) to effectively transfer large ions from the
      solution phase to the gas phase and the coupling of ESI to the high-mass
      resolution capabilities of Fourier transform ion cyclotron resonance mass
      spectrometry (FT-ICR MS) provide a potential method for the mass spectrometric
      analysis of FA. Positive- and negative-ion ESI FT-ICR MS analyses of four
      reference International Humic Substances Society FAs were performed. The spray
      solution composition was found to have a dramatic effect on the ion
      distributions, with high-mass aggregates (m/z approximately 2000-4000) being
      formed in less polar spray solutions. Positive-ion spectra for each FA obtained
      under optimum conditions resulted in number-average molecular weights ranging
      from 1700 to 1900. The mass spectra were extremely complex, with ion
      distributions on the order of m/z approximately 500-3000. The presence of more
      than one ion at each nominal mass was routinely observed. Negative-ion ESI
      analysis of the FA samples resulted in the observation of multiply charged ions
      whose distributions could be affected by the acidification of the spray solution.
      Solution parameters which have been reported to affect molecular weight
      distributions of FA such as pH, ionic strength, and concentration of multivalent
      cations were found to have little or no effect on the observed m/z distributions.

PMID- 10658335
TI  - Separation of isomeric peptides using electrospray ionization/high-resolution ion
      mobility spectrometry.
AB  - In this paper, the first examples of baseline separation of isomeric
      macromolecules by electrospray ionization/ion mobility spectrometry (ESI/IMS) at
      atmospheric pressure are presented. The behavior of a number of different
      isomeric peptides in the IMS was investigated using nitrogen as a drift gas. The
      IMS was coupled to a quadrupole mass spectrometer, which was used for
      identification and selective detection of the electrosprayed ions. The mobility
      data were used to determine their average collision cross sections. The gas-phase
      ions of isomeric peptides were found to have different collision cross sections.
      In all cases, doubly charged ions exhibited significantly (8-20%) larger
      collision cross sections than the respective singly charged species. The analysis
      of mixtures of the isomeric peptides clearly demonstrated the capability of IMS
      to separate gas-phase peptide ions due to small differences in their
      conformational structures, which cannot be determined by mass spectrometry. An
      actual resolving power of 80 was achieved for two doubly charged reversed
      sequenced pentapeptides. Baseline separation was provided for ions differing by
      only 2.5% in their measured collision cross sections; partial separation was
      shown for isomeric ions exhibiting differences as small as 1.1%.

PMID- 10658336
TI  - Secondary electrospray ionization ion mobility spectrometry/mass spectrometry of
      illicit drugs.
AB  - A secondary electrospray ionization (SESI) method was developed as a
      nonradioactive ionization source for ion mobility spectrometry (IMS). This SESI
      method relied on the gas-phase interaction between charged particles created by
      electrospray ionization (ESI) and neutral gaseous sample molecules. Mass
      spectrometry (MS) was used as the detection method after ion mobility separation
      for ion identification. Preliminary investigations focussed on understanding the
      ionization process of SESI. The performance of ESI-IMS and SESI-IMS for illicit
      drug detection was evaluated by determining the analytical figures of merit. In
      general, SESI had a higher ionization efficiency for small volatile molecules
      compared with the electrospray method. The potential of developing a universal
      interface for both GC- and LC-MS with an addition stage of mobility separation
      was demonstrated.

PMID- 10658337
TI  - Ultrasensitive determination of phencyclidine in body fluids by surface
      ionization organic mass spectrometry.
AB  - Gas chromatography (GC)/surface ionization organic mass spectrometry (SIOMS) has
      been found to give much higher sensitivity for measurements of phencyclidine
      (PCP) than the conventional GC/electron impact (EI)-mass spectrometry (MS). Thus,
      we have established a detailed procedure for measurements of PCP in body fluids
      by both mass chromatography and selected-ion monitoring (SIM) of SIOMS using
      pethidine as an internal standard (IS). Good linearity was found in the range of
      0.25-10 ng/mL of whole blood or urine, when measured by mass chromatography, and
      in the range of 0.025-1.0 ng/mL of whole blood by SIM. The recoveries of PCP and
      IS spiked to whole blood were 106 +/- 17% at 1 ng/mL and 113 +/- 11% at 5 ng/mL;
      that of IS was 97.8 +/- 10.4% at 5 ng/mL. The detection limits (signal-to-noise
      ratio = 3) were estimated to be 0.05 ng/mL of whole blood or urine by mass
      chromatography and 0.01 ng/mL of whole blood by SIM. The coefficients of intraday
      and interday variations were not greater than 10.3%. We could detect PCP from rat
      whole blood 2 h after subcutaneous injection of PCP (1 mg/kg) by mass
      chromatography. The mean PCP concentration in rat blood was 47.7 +/- 6.2 ng/mL
      (mean +/- SD, n = 4).

PMID- 10658338
TI  - Modern mass spectrometric methodologies in monitoring milk quality.
AB  - Structural modifications induced by industrial treatments on milk proteins have
      been investigated using a new analytical protocol based on mass spectrometric
      procedures (electrospray and matrix assisted laser desorption ionization mass
      spectrometry) providing a direct correlation between the severity of the
      treatment and the damages observed. The application of this procedure to the
      analysis of whey proteins from milk samples submitted to different thermal
      processes confirmed that under these conditions protein modification is
      essentially due to the nonenzymatic glycation of amino groups by lactose
      (Maillard reaction). A detailed structural investigation of the modification
      sites, carried out by the mass mapping strategy, revealed the occurrence of
      preferentially lactosylated sites in both alpha-lactalbumin and beta
      lactoglobulin.

PMID- 10658339
TI  - Relative sensitivity factors for alkali metal and ammonium cations in single
      particle aerosol time-of-flight mass spectra.
AB  - A variety of factors have been investigated with regard to the quantitation of
      chemical species within individual ambient aerosol particles analyzed by laser
      desorption time-of-flight mass spectrometry. Spectrum to spectrum differences in
      the interaction of the particle with the ionization laser beam, which affect the
      absolute peak areas in the mass spectra, can be minimized by using relative peak
      areas instead of absolute peak areas in each spectrum. Whereas absolute peak
      areas vary by an average of 59% for a given ion peak in single particle mass
      spectra of a monodisperse aerosol of particles formed from the same solution,
      relative peak areas in the same mass spectra vary only by an average of 16%.
      Relative sensitivity factors (RSF) relating the mass spectral ion intensity of
      NH4+ and the alkali metal cations Li+, Na+, K+, Rb+, and Cs+ in single particle
      aerosol time-of-flight mass spectrometry to their bulk concentrations have been
      determined. The values for Li+/Na+, K+/Na+, Rb+/Na+, Cs+/Na+, and NH4+/Na+ are
      found to be 0.14, 5.1, 6.0, 7.9, and 0.014, respectively. The higher response for
      heavier cations of the alkali metals is consistent with the periodic trends of
      both ionization potential and lattice energies of the species of interest. The
      response factor for sodium and potassium cations has been used to accurately
      determine the relative amounts of Na+ and K+ in sea-salt particles, by analyzing
      a sample of approximately 360 ambient sea-salt particles. The relative amounts of
      Na+ and K+ are found to be 97 and 3% in particles, respectively, whereas in
      seawater they are, on average, 98 and 2%.

PMID- 10658340
TI  - Source identification of underground fuel spills by solid-phase
      microextraction/high-resolution gas chromatography/genetic algorithms.
AB  - Solid-phase microextraction (SPME), capillary column gas chromatography, and
      pattern recognition methods were used to develop a potential method for typing
      jet fuels so a spill sample in the environment can be traced to its source. The
      test data consisted of gas chromatograms from 180 neat jet fuel samples
      representing common aviation turbine fuels found in the United States (JP-4, Jet
      A, JP-7, JPTS, JP-5, JP-8). SPME sampling of the fuel's headspace afforded well
      resolved reproducible profiles, which were standardized using special peak
      matching software. The peak-matching procedure yielded 84 standardized retention
      time windows, though not all peaks were present in all gas chromatograms. A
      genetic algorithm (GA) was employed to identify features (in the standardized
      chromatograms of the neat jet fuels) suitable for pattern recognition analysis.
      The GA selected peaks, whose two largest principal components showed clustering
      of the chromatograms on the basis of fuel type. The principal component analysis
      routine in the fitness function of the GA acted as an information filter,
      significantly reducing the size of the search space, since it restricted the
      search to feature subsets whose variance is primarily about differences between
      the various fuel types in the training set. In addition, the GA focused on those
      classes and/or samples that were difficult to classify as it trained using a form
      of boosting. Samples that consistently classify correctly were not as heavily
      weighted as samples that were difficult to classify. Over time, the GA learned
      its optimal parameters in a manner similar to a perceptron. The pattern
      recognition GA integrated aspects of strong and weak learning to yield a "smart"
      one-pass procedure for feature selection.

PMID- 10658341
TI  - [The role of Czech physicians in the etiology, clinical aspects and epidemiology
      of exanthematous typhus].
AB  - Typhus fever was a lethal disease of mankind. Elucidation of its origin and
      spread was due to more or less unscientific approaches at the time. Only in the
      second half of the 19th and at the beginning of the 20th century the period of a
      scientific approach to knowledge of its etiology, clinical aspects and
      epidemiology started. A great contribution was made in this respect by Czech
      doctors. The latter included Professor Hlava who made a series of experiments
      which were among the first which investigated the etiology of this disease. He
      may be therefore quite rightly included among one of the discoverers of the
      origin of typhus fever.

PMID- 10658342
TI  - [Factors affecting the occurrence and development of invasive meningococcal
      disease and development of Neisseria meningitis carrier state--results of a
      nationwide prospective questionnaire survey of cases and controls].
AB  - The nationwide prospective questionnaire study of cases and controls was
      implemented during the period from October 1996 till May 1998. Thirty-nine
      districts participated (= 54.2% of district hygiene stations) and 107 invasive
      meningococcal diseases were included in the study (= 76.9% of diseases recorded
      during the given period in the Czech Republic by active surveillance). A total of
      390 subjects were included in the study-107 with invasive meningococcal diseases,
      211 healthy controls and 72 healthy carriers of Neisseria meningitidis. This is
      the first study in the Czech Republic which analyzes comprehensively
      socioeconomic, health and stress factors in relation to the genesis and
      development of invasive meningococcal disease or carriership of N. meningitidis.
      The relationship between these factors and meningococcal disease or carriership
      was evaluated by the chi square test: odds ratio (OR) and statistical
      significance (p for chi square-Yates correction or Fischer's exact test). For the
      development of invasive meningococcal disease in particular, risk factors are
      significant (p < 0.05) which at the time weaken the overall resistance of the
      organism: febrile diseases, respiratory diseases, other diseases, exertion,
      exposure to cold, mental stress, other stress, injury, staying in places outside
      the home on brigades, training courses, stay in crowded premises. As to long-term
      factors the development of the disease is influenced by a contaminated
      environment, passive smoking and lower education of the mother which indicates a
      different lifestyle. Conversely, factors negatively correlated with the
      development of the disease are active participation in sports and favourable
      economic conditions. For death: significant risk factors (p < 0.05) are also
      factors which weaken the resistance of the organism: exertion, mental stress,
      other stress (= alcohol consumption), staying outside the home on brigades,
      training courses etc. For carriership risk factors are significant (p < 0.05)
      when the mucosal membranes of the upper airways are impaired (staying in a dusty
      environment, in smoke-filled rooms, contaminated atmosphere, active smoking,
      passive smoking) and factors where contact with other people is frequent
      (overcrowded rooms, multi-generation housing, use of public transport, staying
      outside the home on brigades, training courses etc.). A risk factor is also lower
      education of parents which indicates a different lifestyle. Conversely, factors
      negatively correlated with carriership are favourable economic conditions,
      frequent outdoor stay and active participation in sports. By comparison of
      factors significantly associated with the development of invasive meningococcal
      disease or carriership data are assembled for the implementation of effective
      preventive measures.

PMID- 10658343
TI  - [Prevention of viral hepatitis B in exposure to carriers of HBsAG in Plzen in
      1998].
AB  - In 1998 in five Plzen laboratories 128 HBsAg carrierships were found. In 64.8%
      the patient was evaluated at the time of sampling as a "healthy carrier". Based
      on the assessed positivity family contacts of these subjects were offered
      examination of hepatic markers of free immunization. Most people responded
      because of personal contact with a HBsAg positive patient. Postinfection markers
      (HBsAg, anti-HBcAg) were detected in 20.6%, in the control group in 5.1% of the
      examined subjects. 64% sensitive subjects were immunized. Based on the financial
      costs of the study, it was calculated that examination and immunization of
      contacts of HBsAg positive subjects in the whole republic would require a sum of
      46 million crowns. If laboratory examinations of family contacts were left out
      the costs would be cca 75%.

PMID- 10658344
TI  - [Molecular biology and serologic analysis in an epidemic of viral hepatitis B in
      vaccinated patients on hemodialysis].
AB  - The authors analyzed an epidemic of viral hepatitis B during which 43% patients
      of the hemodialyzation centre in K were infected. Using the method of sequence
      analysis of the DNA of hepatitis B virus they identified the source of infection.
      They monitored serologically the course of infection in all infected subjects and
      the state of specific antibody immunity in patients and staff. 22% infections
      were manifested clinically and 75% infected HBsAg positive patients developed
      chronic hepatitis. Although 38 of 42 hemodialyzed patients were vaccinated
      against hepatitis B, 20 patients lacked anti-HBs antibodies before the epidemic.
      Only one of the patients without anti-HBs was not infected. In 10 immune patients
      the rise of antibody levels confirmed that they were also exposed to HBV. The
      effectiveness of vaccination against VHB in hemodialyzed patients is markedly
      lower. Vaccination of these patients is an important but only supplementary
      provision in VHB prevention. Sequence analysis of HBV DNA may be a useful tool of
      epidemiological analysis.

PMID- 10658345
TI  - [Single-step polymerase chain reaction in the detection of Borrelia burgdorferi
      and the genome species in the Ixodes ricinus tick].
AB  - The objective of the work to introduce screening PCR into the diagnosis of
      Borrelia burgdorferi sensu lato in the vector selection of the most suitable
      primer, derived from chromosomal DNA and detection of different genome species.
      The sensitivity of primers, described in the literature (LD, 16S, Wk, 5S-23S) was
      tested by different amounts of DNA strains of borrelias. The most sensitive
      primer--LD was used for detection of borrelias in the vector. Ticks were
      collected in municipal parks from 1995-1997. A total of 635 ticks were examined.
      The positivity of the group differs in individual years: 9.2% in 1995, 3.4% in
      1996, and 4.5% in 1997. Adult ticks were markedly more infected than nymphs.
      Borrelia garinii prevails at the site, Borrelia burgdorferi sensu stricto was not
      detected so far. Mixed infection with Borrelia garinii/Borrelia afzelii was found
      in 1997 in one sample (female ticks). PCR is a sensitive and specific method
      suitable for assessment of the herd immunity of ticks with borrelias. It makes it
      possible to differentiate with a relatively high sensitivity individual genome
      species of Borrelia burgdorferi in the vector. Before its use the sensitivity of
      the reaction must be tested in the presence of tick DNA.

PMID- 10658346
TI  - [Effect of needle and syringe exchange programs on the spread of viral hepatitis
      C].
AB  - The authors examined a total of 224 clients (147 men and 77 women) of the Contact
      centre for drug-dependent subjects "Drug out" in Usti nad Labem. The subjects,
      parenteral abusers of hard drugs. The majority of examined subjects were 20-24
      years old and accounted for 50.9% of the whole group. In all the history of abuse
      was assessed, the type of drug they took and are taking at present, how long they
      have been taking it, route of administration of the drug. Participation in the
      exchange programme was focused on the adherence to using their own injection
      tools. In addition the authors assessed whether the subjects had hepatitis. After
      they obtained informed consent, if possible, 4 ml venous blood samples were
      taken. The blood was examined for anti-HCV by the method of micro-enzyme
      immunoassay (MEIA) on an Axsym apparatus of Abbott Co. The positive response to
      anti-HCV was assessed in 83, i.e. 37.1%. Abusers who took drugs for longer
      periods were more frequently infected. So far it proved possible to obtain
      samples repeatedly from 38 clients who were originally negative. In the latter
      new positivity was found in 36.8%. The incidence of new positivity is
      35.7/100/year. Evaluation of the participation in the exchange programme of
      needles and syringes was made with the following conclusion the provisions
      resolve the position only partly, they reduce the rate of spread of infections
      but do not eliminate the risk. The spread of VHC in the population of drug
      abusers is due to the risky procedure during preparation of the drug dose and
      lack of adherence to the principle of using their own needles and syringes.
      During implementation of preventive programmes in the population a comprehensive
      approach is needed including information on the spread of viral hepatitis and HIV
      infection. VHC is a problem to which systematic attention must be paid on account
      of its impact on health and economics. These problems cumulate and develop after
      a certain time interval.

PMID- 10658347
TI  - LDL-receptor gene polymorphism in patients with early-onset coronary artery
      disease.
AB  - Simultaneous amplification of the promoter and 17 (out of 18) exons of the LDL-R
      gene (along with flanking intron sequences) was performed in 36 patients with
      hypercholesterolemia and early-onset coronary artery disease. The identification
      of the PCR-products on denaturing gradient gel electrophoresis (DGGE) revealed 34
      cases of heteroduplexes in 24 patients. The heteroduplexes in exons 12, 10, and 2
      (31%, 28% and 22%, respectively) probably reflect common polymorphism of LDL-R
      gene, while heteroduplexes in exons 6, 4 and 13 are less frequent (5.6%, 5.6%,
      and 2.8%, respectively). Significant association between the genetic variants, or
      polymorphism with clinical manifestations, could not be established.

PMID- 10658348
TI  - A case of Friedreich's ataxia confirmed by DNA-analysis.
AB  - The first case of DNA-confirmed Friedreich's ataxia in Bulgaria is presented. The
      results from the DNA studies of the index patient revealed two alleles with an
      expansion between 500 and 1500 repeats of the GAA trinucleotide in the first
      intron of the X25 gene. The parents had one normal allele with 7-22 repeats and
      one allele with a similar expansion to that of the patient in the first intron of
      the X25 gene. These results confirm the homozygous mode of transmission of the
      abnormal alleles (with an expansion of the GAA trinucleotide in the first intron
      of the X25 gene) from the two normal heterozygous parents to their affected
      offspring.

PMID- 10658349
TI  - Influence of stage of glaucoma, age and examination time on reliability
      parameters in computed perimetry with Dicon TKS 4000.
AB  - OBJECTIVE: To evaluate the influence of glaucoma stage, age, and examination time
      on reliability parameters in computed perimetry with DICON TKS 4000. METHODS: A
      total of 370 eyes of glaucoma patients were examined in random order with program
      9 (30 degrees Threshold grid). They were allocated to 5 groups according to the
      visual field changes: no changes (112 eyes); mild changes (132 eyes); moderate
      changes (62 eyes); severe changes (44 eyes); end stage changes (20 eyes). The
      reliability of each examination was assessed by the rate of false positive
      responses (FP), fixation losses (FL), and the number of presentations (PR).
      RESULTS: Fixation losses > or = 20% were observed in 60.8% of the examined eyes.
      Such a rate of FL occurred more frequently in the initial stages of glaucoma--75%
      in group 1 vs 10% in group 5. There was a moderate negative correlation between
      the rate of FL and the stage of glaucoma (r = -0.31, p < 0.001). There was a
      negative correlation between the examination time and the rate of FL (r = -0.35,
      p < 0.001). No correlation was found between the age of patients and FL. There
      was a slight correlation between the stage of glaucoma and FP (r = 0.14, p <
      0.01), as well as between examination time and FP (r = 0.28, p < 0.001). There
      was no correlation between age and FP. The mean examination time for the whole
      study sample was 9.0 +/- 2.5 min. It correlated positively with PR (r = 0.96) and
      the stage of disease (r = 0.80). CONCLUSION: FP, FL and PR are dependent on the
      stage of glaucoma and examination time. The lower frequency of FL in severe
      stages of glaucoma can be accounted for by the kinetic fixation and the procedure
      for testing FL (projecting a stimulus in the blind spot).

PMID- 10658350
TI  - Incidence of goiter among children in a village with nitrate contamination of
      drinking water.
AB  - An epidemiological survey was conducted on the incidence of goiter among children
      in the 6-14 years age group, permanently living in a village with an increased
      content of nitrate pollutants in drinking water. Their incidence of goiter was
      compared to that in a control group of children. The study comprised a total of
      359 children--181 from the experimental village and 178 from the control village.
      A high percentage (40.9%) of goiter is observed among the children in the village
      with nitrate contamination of drinking water. A statistically significant
      difference in goiter incidence in children between the experimental and control
      village is present.

PMID- 10658351
TI  - PCR studies on the presence of Chlamydia trachomatis in the upper urinary tract
      of patients with obstructive pyelonephritis.
AB  - Chlamydia trachomatis infections are among the most common sexually transmitted
      diseases in the world and it is only logical to hypothesize that it alone or in
      association with mycoplasmas can participate in the initiation and persistence of
      upper urinary tract infections. Having in mind the inconclusive evidence
      regarding the role of C. trachomatis in upper urinary tract infections we decided
      to study the presence of C. trachomatis in the upper urinary tract of patients
      with obstructive pyelonephritis using the polymerase chain reaction. We studied
      20 patients (12 female and 8 male, aged 20-60 years) with symptoms and signs of
      acute pyelonephritis in accordance with Kunin's criteria (1997). Samples were
      taken during surgery of the upper urinary tract by aspirating urine from the
      renal pelvis or the ureter above the level of the obstruction and analyzed for
      the presence of bacterial pathogens using routine microbiological techniques and
      employing the "AMPLICOR CT/NG" test (Roche Diagnostic Systems, Branchburg, NJ,
      USA) for the presence of C. trachomatis. Chlamydia trachomatis was found in the
      aspirated urine of 5 patients (25%). In 3 of the patients the microbiological
      tests of the aspirated urine did not establish any other microbial agent. In the
      other two Escherichia coli and Proteus mirabilis were cultured. The analysis of
      the clinical and laboratory findings in the patients with Chlamydia trachomatis
      infection alone and those with an associated bacterial pathogen failed to reach
      statistical significance. Following the operation all of the patients received
      treatment with Ofloxacin 200 mg bid for 7 days with a favorable clinical and
      laboratory outcome. In our opinion, the AMPLICOR CT/NG test is a sensitive and
      specific method for diagnosing low-number Chlamydia trachomatis infections of the
      upper urinary tract in patients with obstructive pyelonephritis. Chlamydia
      trachomatis should be considered as a possible etiologic agent in acute
      pyelonephritis and the therapeutic regimen in such patients should be targeted at
      its possible underlying presence.

PMID- 10658352
TI  - A study on the influence of basic nutrients on glucose and glycine transport in
      the small intestine.
AB  - INTRODUCTION: The present study addresses the questions of the onset of
      adaptation of the small intestine transport functions to different nutritional
      effects and of the extent to which the detected changes could be interpreted as
      adaptive. MATERIAL AND METHODS: Two independent experiments with male white rats
      as experimental animals were carried out. In the first experiment three groups of
      animals were subjected to a single administration of respectively unadulterated
      protein, carbohydrates and fatty food and were examined 4 hours after end of
      feeding. In the second experiment the same diets were applied in the course of 10
      days. In both experiments the glucose and glycine absorption was studied by means
      of the method of accumulating preparation from the mucosa of small intestine "in
      vitro". RESULTS: We found that rapid readjustment responses to the nutritional
      effects of basic nutrients could be detected as early as 4 hours after the food
      intake only in the carbohydrate transport systems. In the case of amino acids
      adequate changes in their transport systems were registered as late as 10 days
      after their reception. CONCLUSIONS: The mechanisms of the rapid adaptive
      responses are probably not associated with any quantitative changes in the enzyme
      and transport capacity of the small intestine but amount to its efficient
      readjustment in accordance with the specific nutritional effect.

PMID- 10658353
TI  - Arthrosonography in the evaluation of osteoarticular and soft-tissue structures
      in rheumatology.
AB  - BACKGROUND: Real-time ultrasonography is a widely available, reliable,
      diagnostically sensitive and specific noninvasive modality which allows measuring
      of the thickness of different anatomical landmarks which form joints, of the
      periarticular soft tissue and connective tissue structures, of their echogenicity
      and the amount of joint effusion. The present study was designed to assess the
      clinical and diagnostic applicability of high-frequency ultrasonography in
      rheumatology. METHODS: We used SONOACE 1500 (Medison Europe GmbH) with a 7.5 MHz
      transducer. RESULTS: We demonstrate the most characteristic ultrasonographic
      patterns which have diagnostic significance in the seven most common
      rheumatologic disorders. DISCUSSION: The pathological ultrasonographic patterns
      of the joints, periarticular and soft-tissue structures in rheumatologic
      disorders we present give an insight into the clinical applicability of
      arthrosonography and its inherent advantages over the conventional radiological
      examination--namely, ultrasonography is noninvasive, uses no radiation, which
      allows reproducibility and follow-up, widely available and relatively inexpensive
      and as such can be performed at bedside or on an outpatient basis.

PMID- 10658354
TI  - Dermatoglyphics in schizophrenia: qualitative aspects.
AB  - OBJECTIVE: The study was designed to analyse the value of specific dermatoglyphic
      characters in assessing prenatal injuries in schizophrenic patients. Analysis of
      pattern frequency in schizophrenics and normal controls, sex related differences
      in hand-print patterns in schizophrenic patients, and relationship between
      dermatoglyphic characters and age of onset of the disease was made. METHOD: Hand
      prints of 42 schizophrenic inpatients meeting the DSM-IV criteria for
      schizophrenia and 36 normal controls were obtained using the ink method. To avoid
      possible confounding, patients with diagnoses of the schizophrenic spectrum,
      i.e., schizophreniform and schizoaffective, schizotypal and schizoid personality
      disorder were excluded from the study. RESULTS: Statistically significant
      differences in the finger-print patterns were found between the schizophrenic
      patients and controls. In males this was largely attributed to the increase of
      whorls and in females--to the increase of arches. Patients with early age of
      onset showed higher frequency of Lr pattern in the hypothenar area. In terms of
      dermatoglyphic characters and season of birth the differences did not reach
      statistical significance. CONCLUSION: The results show an association between the
      frequency of certain dermatoglyphic characters and schizophrenia. The nature of
      association can be better evaluated by using the schizophrenia types in further
      analyses.

PMID- 10658355
TI  - Quantitative analysis of the expression of apoptosis-related genes.
AB  - BACKGROUND: The development and subsequent introduction of current molecular
      biology techniques allows the elucidation of some of the mechanisms of the
      programmed cell death (apoptosis). The overexpression of the genes directly (B
      cell leukemia/lymphoma-2, BCL-2) or indirectly (multidrug resistance gene-1,
      MDR1) involved in the suppression of apoptosis, as well as the low-level
      expression of their antagonists (BCL-2 associated X-protein, BAX) result in
      longer survival and the development of drug resistance in malignant cells. AIM:
      The objective of this study was to design our own appropriate primers and to
      synthesize internal RNA standards and this way to evaluate the rate of expression
      of the MDR1, BCL-2 and BAX genes using a competitive reverse transcription and
      polymerase chain reaction (cRT-PCR). MATERIAL AND METHODS: Peripheral blood or
      bone marrow aspirates from 5 patients and 3 healthy controls were used for RNA
      extraction. Competitive RT-PCR was employed utilizing the constructed specific
      primers and synthesized internal RNA standards. Following electrophoresis, the
      PCR products stained with ethidium bromide were evaluated on the "Gel Doc 1000TM"
      video image system. RESULTS: The constructed primers specific for each of the
      three genes and synthesized internal RNA standards with a suitable deletion allow
      receiving the yield of well-separated competitive amplicons. The measured band's
      intensity of light and the calculated standard/patient ratio were employed in the
      analysis of the MDR1, BCL-2 and BAX gene expression. CONCLUSIONS: Competitive RT
      PCR is a non-radioactive and comparatively rapid molecular biology method
      suitable for everyday laboratory practice. The possibility for simultaneous
      evaluation of the expression of several genes could help in the elucidation of
      some of the mechanisms underlying the prolonged survival of malignant cells.

PMID- 10658356
TI  - A panel of indices in newborns with birthweight more than 2500 grams treated with
      conventional ventilation during the neonatal period.
AB  - Intelligent application of the monitoring methods forms the mainstay of the
      diagnostic and treatment strategy in intensive care and is in harmony with the
      basic principle of minimal handling in neonatal intensive care. Thus, based on
      the monitoring data it is possible to derive a number of equipment, oxygen
      derivative, respiratory, hemodynamic, metabolic and other indices. The
      information provided by these indices is significantly greater and more important
      than that gained from the initial data (ventilatory parameters) and biologic
      variables). It is of foremost importance for the successful performance of both
      conventional and nonconventional ventilation techniques and the evaluation of the
      newborn status as well as for prognostic discussions and conclusions. In the
      present study we used the Neonatal Intensive Computer File developed by the
      author with graphic trends for visualization of the dynamics of indices over time
      in each and every one of the neonates in our groups of patients which are
      statistically analyzed using standard methods and computer models. A total of 30
      neonates (14 survived and 16 non-survived) who had been treated with conventional
      ventilation during the neonatal period were enrolled in the study. Our results
      show that: 1. The dynamics of indices between the survived and the non-survived
      shows significant differences in terms of values, dynamics and general tendency.
      2. Major relationships between the different indices are observed and their
      correct interpretation improves the information yield of each and every one of
      the above-mentioned indices. There are identical tendencies in the dynamics of
      MAP, OI and VI values in the survived whereas in the non-survived these indices
      are discordant. The improvement in a/A values coincides in time with that of
      AaDO2 reduction, or the improvement in oxygenation is accompanied by a reduction
      of the degree of shunting in the survived which is a favorable prognostic
      indication, whereas decrease in a/A values in the presence of practically
      unchanged AaDO2 values suggests an unfavorable outcome. The improvement in
      compliance is accompanied by improvement in the rate of oxygenation in the
      survivor group whereas in the non-survivors the deterioration in oxygenation is
      accompanied by a decrease in compliance and reflects the major underlying
      pathologic mechanism of gas exchange. 3. The panel of indices used by us
      specifies exactly the onset of the changes in gas exchange. 4. The application of
      the panel of indices contributes to more profound diagnostic reasoning and
      conclusions as well as the therapy and prognosis ad vitam.

PMID- 10658357
TI  - Endogenous serum interferon-alpha in patients with chronic hepatitis B virus
      infection.
AB  - Serum endogenous interferon-alpha was determined in 42 patients with chronic
      hepatitis B virus infection by radioimmunoassay using an Abbott kit (USA). The
      study sample included 26 males and 16 females, aged 3 to 59 years (mean, 30.1).
      Ten of these patients had a history of acute viral hepatitis B carrying HBsAg for
      more than 6 months. Thirty two patients were accidentally found to be virus
      carriers for 8 months to 15 years. Six of these were treated with interferon
      alpha and one with Ursofalk. Forty one patients (97.62% +/- 2.38) were anti
      HBcIgG positive which confirmed former hepatitis B virus infection. Only one
      patient who was anti-HBcIgG positive was found to be also anti-HBcIgG positive,
      anti-HBcIgM positive, HBeAg negative, and anti-HBe positive later biophysically
      verified as exacerbated chronic active hepatitis. Serum HBeAg was detected in 13
      of the whole sample (30.95% +/- 7.13); 8 patients (32% +/- 9.33) were HBV-DNA
      positive, i.e., a third of the cases presented with active replication of the
      hepatitis B virus. In all 42 patients with chronic hepatitis B virus infection
      (convalescence and health HBsAg carriers) serum interferon-alpha levels were nil
      or close to nil. Only in the patient with chronic active hepatitis the serum
      interferon level was 3.83 IU/ml. These data support the observations that
      interferon-alpha production is reduced in chronic hepatitis B virus infection and
      are consistent with the view that treatment with exogenous interferon-alpha
      stimulates the clearance of the virus.

PMID- 10658358
TI  - On the disturbances in carbohydrate metabolism in pre-dialysis patients with
      chronic renal failure.
AB  - We describe some of the aspects of impaired carbohydrate metabolism in
      predialysis uremic patients. METHODS: A total of seventy-five nondiabetic
      patients with chronic renal failure (CRF) were enrolled in the present study. The
      level of glycosylated hemoglobin was measured in 51 patients using kits from
      Merck and an oral glucose challenge test was performed in 20 according to a
      standard protocol. The levels of immunoreactive insulin and growth hormone (GH)
      were measured in all predialysis patients using original kits and an automatic
      minigamma counter (Abbott, USA). The results were compared with those from 30
      healthy controls. RESULTS: In patients with first degree CRF the level of
      glycosylated hemoglobin was 5.9 +/- 05%. In patients with second and third degree
      CRF there was a trend towards higher glycosylated hemoglobin levels--6.3 +/- 0.6%
      (P > 0.05; u = 1.1) as compared with the controls--5.5 +/- 0.4%. The analysis of
      the results from the oral glucose challenge test revealed impaired glucose
      tolerance in 12 predialysis patients with CRF with blood glucose levels of 9.1 +/
      1.6 mmol/l at the second hour following the ingestion of glucose. Nine of those
      had second or third degree CRF. The baseline levels of plasma immunoreactive
      insulin showed a tendency towards increase in the patients with uremia as
      compared with the controls (7.2 +/- 1.1 IU/ml versus 6.4 +/- 0.7 IU/ml) whereas
      no significant difference was found at the 1st, 2nd or 3rd hour following the
      ingestion of glucose as compared with the healthy controls. Five of our patients
      had significantly elevated basal insulin levels. With regard to GH levels, we
      found similar baseline values in our study patients and the controls. At the 1st
      hour following the glucose challenge the GH values showed a tendency towards
      increase in the uremic patients--6.1 +/- 1.1 ng/ml. In 4 of our study patients we
      found significantly elevated GH levels at the 1st hour following the ingestion of
      glucose (6.6 +/- 0.7 ng/ml). CONCLUSIONS: 1. No significant disturbances in
      carbohydrate metabolism were found in patients with mild (initial) CRF. 2. In
      patients with moderate and advanced CRF we found changes consistent with impaired
      carbohydrate metabolism and a tendency towards an increase in the basal
      immunoreactive insulin levels. 3. Growth hormone levels showed a different
      pattern of change in predialysis patients and those changes cannot be explained
      by the changes in carbohydrate metabolism.

PMID- 10658359
TI  - Evaluation of external breathing in children living in a region with industrial
      pollution.
AB  - BACKGROUND: The changes in respiratory functions are among the most sensitive
      indicators available for the evaluation of the influence of air pollution on
      health. OBJECTIVE: The objective of the present study was to evaluate the
      respiratory functions of children from three schools situated at a different
      distance from the major sources of air pollution--an asbestos-cement plant, a
      fertilizer plant and a steam-power plant which utilize brown coal as a main
      source of energy. METHODS: Comprehensive functional investigation of breathing
      (FIB) was performed on 97 children from the town of Dimitrovgrad--mean age 10.4
      +/- 0.1 years and height 145 +/- 0.6 cm (mean +/- Sx) in a special university
      medical center laboratory. The characterization of the degree of air pollution
      was based on the analysis of the mean yearly concentrations of particulate
      matter, sulfur dioxide, nitrogen dioxide, ammonia and hydrogen sulphide in the
      three zones of exposure in the town on the basis of the criteria outlined in the
      Uniform National System for Control of Air Pollution in Bulgaria. RESULTS: The
      mean yearly concentrations of particulate matter up to 0.19 mg/m3, of hydrogen
      sulphide--up to 0.07 mg/m3, of nitrogen dioxide--up to 0.025 mg/m3, of ammonia-
      up to 0.16 mg/m3, of hydrogen sulphide--up to 0.13 mg/m3 and lead aerosols--up to
      0.00012 mg/m3 recorded at the different stations reached statistical significance
      at some of them. No significant differences were found in the values of lung
      function parameters of the healthy children from all three zones. MEF50% (94 +/-
      2%) and the Single Breath Transfer Factor (TLCO = 93 +/- 1.5%) showed a tendency
      towards lower values. CONCLUSIONS: In the low-grade pollution that we found in
      the present study no significant differences were found in the lung function
      parameters of the children from the three regions.

PMID- 10658360
TI  - Effect of dacarbazine (DTIC) on cultures from malignant melanoma of the choroid:
      an immunohistochemical and electron microscopic study.
AB  - INTRODUCTION: Dacarbazine (DTIC) is a very effective chemotherapeutic agent used
      in the treatment of cutaneous melanoma; it also could have a potential
      therapeutic value as an antimetastatic agent in the treatment of choroidal
      melanoma. OBJECTIVE: To study the HMB-45 and S100 protein expression in choroidal
      melanoma cultures with and without DTIC, and compare the immunohistochemical and
      electron microscopic changes in both groups. METHODS: Five- and seven-day
      cultures of choroidal melanoma (n = 21) were cultivated in diffusion chambers.
      The cultures were divided in two groups: I group (control group)--the cells were
      grown in 199-medium; II group--the cells were in 199-medium supplemented with
      0.03 mg/ml of DTIC. Immunohistochemical studies were performed with paraffin
      embedded material of the cultures by the avidin-biotin-alkaline phosphatase
      technique. Araldit-embedded material was studied by electron microscopy. RESULTS:
      The expression of HMB-45 and S100 protein in the cultures with DTIC ranged from
      slightly positive to negative. The tumor cells were severely damaged. Electron
      microscopy in this group showed presence only of cellular fragments. In the DTIC
      free group the HMB-45 and S100 expressions were strongly positive. There were no
      electron microscopic evidence of cellular death. CONCLUSION: DTIC suppresses the
      growth of choroidal melanoma in vitro. These results indicate that further
      studies are warranted to elucidate the effect of DTIC in vivo.

PMID- 10658361
TI  - Expression of human blood group antigens A and B in stomach cells of C. carpio,
      C. auratus, R. ridibunda and H. sapiens.
AB  - Human blood group ABH antigens are found not only on red blood cell membranes,
      but in many other cell types as well. Their biological functions still remain
      unclear. The aim of the present study was to examine the cellular expression of
      these antigens in the stomach of representatives of different Vertebrates--Pisces
      and Amphibia and to compare it with their expression found in Man. The
      immunohistochemical technique applied was based on the biotinstreptavidin
      peroxidase complex. Monoclonal antibodies to human A and B antigens were used as
      primary antibodies in the system. Stomach paraffin sections from Cyprinus carpio,
      Carassius auratus, Rana ridibunda and Homo sapiens were examined. Blood group
      antigens were found mainly in tunica mucosa of C. carpio, C. auratus and R.
      ridibunda. Tunica muscularis and tunica serosa were always immunonegative. The
      antigens were localized in the apical part of the cytoplasm of epithelial cells
      in lamina epithelialis. Strong positive reaction was seen in secretory granules
      of the stomach of C. auratus, while in R. ridibunda the antigens were expressed
      by single epithelial cells in cardial stomach glands. A and B antigens were not
      found in human stomach sections most probably due to the negative secretor status
      of the individuals studied. Our results show that ABH human blood group antigens
      are evolutionary conserved structures similarly expressed by different
      Vertebrates. The phylogenetic stability in their cellular expression possibly
      results from the important biological role they have. Future large scale
      systematic investigations could elucidate the undefined and disputable
      physiological functions of human blood group antigens.

PMID- 10658362
TI  - Characteristics of tidal expiratory flow pattern in healthy people and patient
      with chronic obstructive pulmonary disease.
AB  - According to data reported in literature tidal breathing parameters and
      especially tidal expiratory flow pattern parameters can be useful in
      distinguishing airflow obstruction. The purpose of the present study was to
      investigate the parameters of the tidal breathing in healthy people and patients
      with chronic obstructive pulmonary disease. The study sample included 158
      patients with COPD in clinically stable condition and different degree of
      functional disturbances (FEV1% pred. = 42% +/- 15%; ATS dyspnea scale = 2.5 +/-
      0.9; mean +/- SD). The control group of healthy subjects consisted of 43 men and
      37 women. The obtained results show that TPTEF/TE (the time necessary to reach
      the peak expiratory flow in tidal breathing over the total expiratory time) and
      VPTEF/VE (the volume necessary to reach the peak expiratory flow in tidal
      breathing over the total expiratory volume) are an independent aspect of tidal
      breathing. In healthy people these parameters show weak negative correlation with
      age and high variability. In COPD they are statistically significantly lower than
      those of healthy people but, since they are highly variable, they cannot be used
      for an individual assessment. The increase of the mean inspiratory flow (TV/Tin)
      and the shortening of VPTEF/VE, TPTEF/TE and Tin/Ttot, are indicative of the lung
      mechanics changes which have a bearing on dyspnea, too. According to factor
      analysis the parameters of tidal breathing are four separate dimensions: 1.
      Breathing frequency and respiratory times; 2. Relationship between the
      respiratory times; 3. Minute ventilation, mean expiratory flow, mean inspiratory
      flow and tidal volume; 4. Parameters of the expiratory flow VPTEF/VE and
      TPTEF/TE. The parameters of forced expiration and those of tidal breathing are
      separate dimensions of the functional profile of patients with COPD.

PMID- 10658363
TI  - Immunoprecipitation against exogenous antigens in the zone of alpha-1, alpha-2
      and beta-globulins--a new immune phenomenon?
AB  - According to data by H. Zhabilov serum fractions in the zone of alpha 1, alpha 2
      and beta-globulins from healthy people form a characteristic precipitation curve
      in terms of structure and density with the TNP (thymus nuclear protein) and CNP
      (carcinoma nuclear protein) as antigens when tested in two-dimensional agarose
      gel electrophoresis. The observed immune phenomenon has not so far, to the best
      of our knowledge, been reported in the scientific literature and has profound
      implications for fundamental and applied immunology. The object of the present
      study was to confirm Zhabilov's data and study the ontogenetic aspect of the
      problem. We used 45 sera of children from different age groups, of healthy adult
      controls, HIV-infected and cancer patients. The sera were tested against the
      following exoantigens: TNP (thymus nuclear protein), CNP (carcinoma nuclear
      protein-Viral Genetics Inc, LA), as well as against ST (staphylococcal toxin), SL
      (streptolysin) and LPS (lipopolysaccharide) from Gram-negative bacteria (National
      Center for Parasitic and Infectious Diseases, Sofia, Bulgaria). Two-dimensional
      electrophoresis was used modified after the protocol of UCLA chemical labs. The
      results of our study show that immediately following birth the precipitation
      curve is barely discernible reaching the normal shape following 1 month-5 years
      of age. The precipitation curve from HIV-infected sera and those of cancer
      patients is similar to that of newborns. The results from our unpublished
      observations with sera from other biologic species tested against the same
      antigens show similar results: no curve was observed in fish whereas the reaction
      was positive with frogs, birds, rabbits and other mammals. This confirmation of
      the basic biologic law of ontogenesis being a repetition of phylogenesis gives us
      reason to consider those fractions as participating in the immune maturation of
      organisms for acquired immune response. There exists a possibility that they
      might be part of the already known immunomediators or a stage in the transition
      from non-specific to specific immunoglobulins which have not lost their
      importance in immunogenesis. The lack of previous studies in this respect and the
      observation and confirmation of this reaction in two different labs underscore
      the importance of this new immune phenomenon.

PMID- 10658364
TI  - A comparative analysis of the postoperative complications of thyroid cancer
      surgery related to surgical approach.
AB  - A retrospective study of the postoperative complications in 129 patients treated
      for thyroid cancer in the clinics of surgery of the Higher Medical Institute for
      a period of 9 years (1988-1996) was performed. The majority of the patients (90)
      were treated by total thyroidectomy. Subtotal thyroidectomy was performed in 21
      and thyroid lobectomy in 15 patients. Postoperative complications occurred in 56
      of the operated patients. Of these 5 had permanent and 51 transient
      complications. Most of the complications (80.35 +/- 3.56%) ensued from total
      thyroidectomy. The variety of the complications included permanent
      hypoparathyroidism in 3 patients, transient hypocalcemia in 37 patients, injury
      of the recurrent laryngeal nerves in 11 patients, esophageal damage in 1 patient,
      hematoma within the operation field in 1 patient and suppuration of the operative
      wound in 1 patient. Four of the patients with injury of the recurrent laryngeal
      nerve suffered from obstruction of the airways which required temporary
      tracheostoma to be performed. No lethal postoperative outcome was observed. The
      data of the study are discussed in relation with the literature data.

PMID- 10658365
TI  - Mucocutaneous infections in hematological malignancies.
AB  - INTRODUCTION: Mucocutaneous infections of diverse etiology are frequent
      complications in patients with hematological malignancies. OBJECTIVE: To study
      the incidence, predisposing factors, microbiology, and primary clinical
      manifestations of these complications in oncohematological patients. MATERIAL AND
      METHODS: The study included 862 patients (394 females and 468 males) with
      hematological malignancies, treated in the Clinic of Hematology of the Higher
      Medical Institute, Plovdiv from 1990 to 1998. The patients were divided into
      three groups according to the primary disorder: lymphoproliferative disorders
      (541 patients), myeloproliferative disorders (296 patients), and bone marrow
      insufficiency (25 patients). RESULTS AND DISCUSSION: The mucocutaneous infections
      studied included most often abscesses and pyodermias. The predominant isolate was
      Staphylococcus aureus. Viral infections were caused mainly by herpes simplex
      virus type I and, less frequently, varicella zoster virus with intercostal
      localization. Candida species was isolated predominantly in oropharyngeal and
      esophageal mycoses. CONCLUSION: Prolonged cytostatic-induced neutropenia and
      suppressed cellular immune response are the principal factors for the infectious
      complications in hematological malignancies. The early clinical diagnosis and
      prompt etiological treatment of the mucocutaneous infections are crucial for the
      prophylaxis of the systemic infectious complications.

PMID- 10658367
TI  - Retrosternal (intrathoracic) goitre--diagnosis and surgical treatment.
AB  - For a period of 12 years (1987-1998) 2033 patients underwent surgical treatment
      of the thyroids in the surgical clinics of the Higher Medical Institute in
      Plovdiv. Retrosternal or intrathoracic goitre was found in 29 patients (p +/- Sp
      = 1.43 +/- 0.26%). Of these, seven were males and 22 females all aged 32 to 76
      years. Twenty two of the patients were euthyroid and seven hyperthyroid (75.9 +/-
      7.9% and 24.1 +/- 7.8%, respectively). Compression of adjacent organs was
      detected in 19 of the patients (65.5 +/- 8.8%) (P < 0.05). X-ray,
      ultrasonography, scintigraphy (gamma-chamber), computed tomography, and in cases
      of voice disorders, direct laryngoscopy were used in making the diagnosis. All
      patients underwent surgical treatment. Cervical collar incision was suitable in
      27 patients and in one patient longitudinal sternotomy was used and in other, who
      had deep posterior mediastinal goitre, Hart's method of combined thoracotomy and
      cervicotomy was required. The weight of the resected glands varied from 50 to
      1500 g. The results obtained are discussed in terms of the incidence, type, and
      site of the retrosternal (intrathoracic) goitre, capabilities of the contemporary
      methods of diagnostics, surgical necessities, surgical approach and compared with
      literature data.

PMID- 10658366
TI  - A comparative study of the effect of halothane, isoflurane and propofol on
      partial arterial oxygen pressure during one-lung ventilation in thoracic surgery.
AB  - BACKGROUND: Conducting one lung ventilation (OLV) in thoracic surgery highlights
      the issue of the onset (prevention and treatment) of clinically significant
      arrhythmogenic hypoxemia. The halogenated volatile anaesthetics are the drugs of
      choice in thoracic surgery despite the numerous experimental data showing their
      inhibiting effect on the hypoxic pulmonary vasoconstriction (HPV). The
      intravenous anaesthetic agent propofol has not been shown to influence this
      reflex mechanism. The object of the present study was to compare in clinical
      conditions the arterial oxygenation in patients undergoing noncardiac thoracic
      procedures, requiring a period of one lung ventilation during general anaesthesia
      with volatile anaesthetics halothane, isoflurane and total intravenous
      anaesthesia (TIVA) with propofol/fentanyl. MATERIAL AND METHODS: The study
      included 45 patients divided in three groups consisting of 15 anaesthetized
      subjects each: group A--halothane; group B--isoflurane and group C-
      propofol/fentanyl. Arterial blood samples for blood-gas analysis were taken as
      follows: first probe (T1)--after two lung ventilation (TLV) was maintained for 15
      min., second probe (T2)--after 45 min. of stable OLV and the third probe (T3)-
      during wound closure. The changes in PaO2 were statistically analyzed using the
      methods of descriptive and dispersion analyses. RESULTS: A significant decrease
      in PaO2 during stable OLV compared with TLV (P < 0.05) was found in patients of
      all three groups. There was no significant difference in PaO2 between the
      subjects in the three groups during respective regimens of ventilation.
      CONCLUSION: TIVA with propofol/fentanyl can be successfully applied in thoracic
      surgery as an alternative of general anaesthesia with halogenated volatile
      anaesthetics.

PMID- 10658368
TI  - Relationship between absolute and relative hematocrit changes and bone marrow
      response in rats.
AB  - The object of the present study was to evaluate the physiologic mechanisms
      regulating erythropoiesis by monitoring the changes in reticulocyte count in the
      circulation and the formation of erythroblastic islands in the bone marrow
      following hypertransfusion and dehydration. Forty-eight male Wistar rats (110-130
      grams) were transfused with 70% isogenic suspension of washed and packed red
      cells at a dose of 2.5 ml/100 g body weight intravenously on two consecutive days
      (absolute erythrocytosis) or deprived of water for three days to produce relative
      erythrocytosis and then injected i.v. with saline at a dose of 2.5 ml/100 g body
      weight with water provided at libitum. Hematocrit was measured using the
      microhematocrit method. Reticulocytes were enumerated using the new methylene
      blue stain. Plasma EPO levels were measured radioimmunologically and a bone
      marrow suspension was prepared for morphological examination and absolute
      erythroblastic islands determination. We observed a marked suppression of
      erythropoiesis following the transfusion as evidenced by the elevation in
      hematocrit values up to 0.64 +/- 0.04, a decrease in reticulocyte count and
      plasma EPO reduction--13.5 +/- 3.4 mU/ml (P < 0.05) and a suppression of EO
      formation in the bone marrow (P < 0.01). The hematocrit of the dehydrated rats
      was elevated during the first 24 hours (P < 0.001). Reticulocytes, as well as EO,
      decreased on day 3 down do 53.6 x 10(9)/l +/- 9.8 x 10(9)/l (P < 0.001) and 153.6
      x 10(3) +/- 21.5 x 10(3)/femur (P < 0.001), respectively. The EPO level was
      measured simultaneously--16.3 +/- 4.2 mU/ml versus 24.6 +/- 5.3 mU/ml at day 1 (P
      < 0.001). Following rehydration, a fast increase in the hematocrit value with a
      concomitant increase in EO and the reticulocyte counts was observed. Our results
      show that the absolute and relative changes in hematocrit values are paramount in
      the feedback mechanism for erythroid homeostasis.

PMID- 10658369
TI  - A successful one-stage reconstruction of the esophagus in a newborn with a long
      gap esophageal atresia and tracheo-esophageal fistula.
AB  - A method of one-stage surgery of long gap esophageal atresia was applied in a
      newborn child. An anterior muco-muscular flap was moulded from the upper pouch
      and transposed to the lower pouch of the esophagus. The technique allowed the
      tension in the anastomosis between the two parts of the esophagus to be reduced.
      The child had no feeding abnormalities during the follow-up till the age of 5
      years.

PMID- 10658370
TI  - Comparative study of the polarization of dental caries in 7-, 12- and 14-year-old
      children from Plovdiv, Bulgaria.
AB  - INTRODUCTION: As a result of the anticaries prevention programs the percentage of
      persons with high level of DMFT decreases and the percentage of persons free of
      caries increases. This demands the formulation of a new approach in determining
      the strategies and priorities of the preventive programs and the amount of the
      needed dental services. MATERIAL AND METHODS: A clinico-statistical study of
      dental caries comprising 600 children of 7, 12 and 14 years of age (300 boys and
      300 girls) from Plovdiv was carried out in 1997. The diagnosis of dental caries
      was visual-tactile. In every age group the percentages of persons with different
      levels of DMFT were determined. The findings were compared with the results
      gathered in 1992. RESULTS: It was found that with age the percentage of persons
      free of caries decreased and the percentage of the persons with high level of
      DMFT increased. In 1992 15.07% of 12-year-old children were carriers of 59.26% of
      the total number of DMFT, while in 1997 10.00% were carriers of 25.75% of the
      total number DMFT. CONCLUSIONS: The most pronounced polarization of dental caries
      was found in the 7-year-old children group. In Plovdiv the polarization of dental
      caries in the 12-year-old children group was less pronounced in 1997 than in
      1992.

PMID- 10658371
TI  - Extradural meningioma in the left fronto-temporo-parietal region.
AB  - A case of a 47-year-old male patient who presented with a history of complaints
      of headache, vertigo and an expanding painful swelling on the left side of the
      head over the last year is reported. The lump was 15 x 15 cm and protruded 1-3
      centimeters. Neurological examination revealed the presence of a mild right
      hemiparesis with right central facial palsy. Plain skull X-ray film demonstrates
      a heterogeneous bone thickening in the left fronto-temporo-parietal region with a
      small osteolytic focus and spotted shadows. Computed tomography scan of the skull
      showed that a major part of the squamas of the frontal and temporal bones were
      transformed into spiculoform structures turned outwards and inwards. Thus the
      bone appeared thickened overall. There were no alterations in the cerebral
      structures. The tumour was completely removed. It was located extradurally and
      through the bones extended to the soft tissues under the skin. The histological
      findings showed a meningioma with hemorrhages and necroses and the presence of
      lipids containing xanthochromic cells. After a surgical extirpation of the tumour
      a reduction of the neurological symptomatology and subjective complaints was
      observed.

PMID- 10658372
TI  - Effects of low-intensity electromagnetic fields on behavioral activity of rats.
AB  - The present study aimed at comparative assessment of the changes in behavioral
      activity of rats after exposing them to low intensity electromagnetic fields
      (EMFs) in the meter, decimeter and centimeter ranges. The experiments were
      carried out on 24 Wistar rats divided into 4 groups (1 control and 3
      experimental), treated with different EMFs. The rats were irradiated on the head
      area at power density of 10 mW/cm2. Using a conventional shuttle box, the
      conditioned and non-conditioned responses and spontaneous motor activity of the
      rats were studied. The results suggest that exposure to EMFs in the three ranges
      can slow down the formation of conditioned responses--this was clearly marked in
      the rats exposed to meter EMFs, whereas the effects of centimeter EMFs were
      delayed in time. The behavioral effects were mild at athermal dosages and the
      animals adapted easily to exposure conditions. This study shows that
      determination of the effects of different EMFs should be done for each of the
      ranges separately; determination of the exact dosage of the electromagnetic
      fields can help to avoid their negative biological effects.

PMID- 10658373
TI  - Prostaglandin E2 in preinduction cervical ripening in postdate pregnancy.
AB  - Unripe cervix is a widely recognised factor contributing to the failure to induce
      labour. Its presence is associated with high frequency of operative delivery,
      adverse fetal outcome and high maternal morbidity. MATERIAL: We studied the
      efficacy of PGE2 application for preinduction cervical ripening in women with
      postdate pregnancy. Two PGE2-containing preparations were used--Prepidil-gel and
      Prostin E2 (Upjohn). They were administered to 42 women with postdate pregnancy,
      unripe cervices and indications for labour induction. The study sample was
      divided into two groups: group I (20 women) received Prepidil-gel, group II (22
      women)--Prostin E2. RESULTS: 85.7% of the women responded favourably to the
      ripening effect of PGE2. There was no difference in the efficacy, safety and
      outcome of pregnancy between the two groups. CONCLUSION: Prostaglandin PGE2 is
      effective for preinduction cervical ripening in women with postdated pregnancy.
      The authors give their preference to Prostin E2 because it is easier to apply.

PMID- 10658374
TI  - Surgical treatment for patients with lung cancer complicated by severe pulmonary
      emphysema.
AB  - Ten patients with lung cancer complicated by severe pulmonary emphysema,
      underwent lung reduction surgery between 1995 and 1997. Patients meeting the
      following criteria were defined as having severe pulmonary emphysema: (1) forced
      expiratory volume in 1 s (FEV1%) of < 55% and (2) characteristic, severe findings
      of emphysema in chest x-rays and chest computed tomography scans. 9 men and 1
      woman (mean age: 70.8; range: 59-78 years), were all smokers (smoking index: 500
      2450). Preoperative lung function showed an average percent vital capacity of
      87.8% (range: 67-108%) and an average FEV1% of 35.9% (range: 27-54%). The
      histological types of lung cancer were squamous cell carcinoma (4 patients),
      adenocarcinoma (5 patients), and large cell carcinoma (1 patient). Four patients
      were in clinical stage IA, 3 in stage IB, and 1 each was in stages IIA, IIIA, and
      IIIB. Lobectomy was conducted in 3 cases and partial resection in the remaining
      7. Five of the 10 patients underwent thoracoscopic resection. After surgery,
      patients died one at 2 months and the other at 17; 3 survived but 3 suffered
      cancer recurred; and 5 patients without recurrence. In complications, bronchial
      air leakage requiring postoperative treatment. Postoperative lung function showed
      an average percent vital capacity of 71.4% (range: 41-90%) and an average FEV1%
      of 41.3% (range: 28-61%). We found an important relationship between the location
      of the perfusion defect (target area) in pulmonary perfusion scintigram in
      relation to the lung cancer site and postoperative improvement of lung function.
      One patient with lung cancer associated with severe respiratory obstruction
      underwent lobectomy after confirmation of the perfusion defect by pulmonary
      perfusion scintigram. Postoperative FEV1% in this patient was restored to the
      preoperative level. In general, partial thoracoscopic resection was effective in
      patients with early-stage lung cancer.

PMID- 10658375
TI  - Are superficial bullae with broad bases suitable for ablation?
AB  - Superficial bullae with broad bases are not suitable for resection, because the
      residual lung is too deformed to re-expand adequately when we resect them.
      Therefore, we believe superficial bullae with broad bases are suitable for
      ablation. It is not clear, however, whether ablated superficial bullae with broad
      bases remain contracted after treatment or not. We examined the morphologic
      changes of ablated superficial bullae with broad bases on chest computed
      tomographs. Ten patients with superficial bullae with broad bases that could be
      identified on computed tomograph underwent ablation using an electrocoagulator.
      These bullae were examined by chest computed tomograph preoperatively and again
      one, three and 12 months after surgery. There were no intra-operative
      complications. Postoperatively, the only complication was prolonged air leak
      (more than 7 days) in 1 (10%) patient. Pneumothorax after the operation presented
      in 1 (10%) patient. Morphologically, a disappearance of air space associated with
      bulla-wall thickness was observed in 9 (90%) of the 10 heat-ablated lesions and
      air space decreased in 1 (10%) lesion. Heat ablation proved to be effective in
      patients with SBBs. Lesions remained contracted for at least one year after the
      operation.

PMID- 10658376
TI  - Superior biocompatibility of heparin-bonded circuits in pediatric cardiopulmonary
      bypass.
AB  - BACKGROUND: Heparin bonding of pediatric cardiopulmonary bypass circuits may
      decrease activation of blood compartments as inflammatory responses. We studied
      the biocompatibility of heparin-bonded circuits in infant cardiac surgery.
      METHODS: Twenty-four infants undergoing elective cardiac surgery were randomly
      assigned to either a nonheparin-bonded control circuit (n = 12) or a fully
      heparin-bonded circuit (n = 12) including membrane oxygenator, reservoir, and all
      tubing. Blood samples were used to identify differences in complement activation
      and cytokine release between groups during and after cardiopulmonary bypass. The
      postbypass oxygenation index was also compared. RESULTS: The C3 activation
      product in the heparin-bonded group was significantly lower during (p < 0.01) and
      just after (p < 0.05) cardiopulmonary bypass. No statistically significant
      difference in C4 activation products was observed. Lower interleukin-6 and tumor
      necrosis factor-alpha were found immediately after cardiopulmonary bypass (p <
      0.05) and a higher mean postbypass oxygenation index was also seen (p < 0.05) in
      the heparin-bonded group. CONCLUSION: We found that a heparin-bonded
      cardiopulmonary bypass circuit reduced inflammatory response and improved
      oxygenation in pediatric cardiac surgery. These results suggest that the superior
      biocompatibility of the bonded circuit may reduce pulmonary complications.

PMID- 10658377
TI  - Clinical role of blood heparin level monitoring during open heart surgery.
AB  - Protamine has been used for neutralizing heparin and its dosage is decided by the
      initial fixed dose of heparin. Adequate protamine neutralization is very
      important to reduce complications. To attenuate excess reactions, in particular,
      whole blood heparin concentration during and after cardiopulmonary bypass was
      measured using Hepcon, and the efficacy of optimal protamine dose in open heart
      surgery was evaluated. Twenty patients were randomly divided into two comparable
      groups, P and C. In the C group, heparin was neutralized with an initial fixed
      dose of protamine, 1.67 mg protamine per milligram total heparin (n = 8). In the
      P group, protamine dose was determined for residual heparin concentration (n =
      12). In the P group, blood heparin concentrations at 60 minutes after the
      establishment of cardiopulmonary bypass, just after cardiopulmonary bypass and
      first protamine administration were 2.35 +/- 0.14, 2.31 +/- 0.17 and 0.13 +/-
      0.08 U/ml, respectively. Concentrations reached zero with the second protamine
      administration. The requirement of transfusion (659 +/- 224 vs. 1559 +/- 323 ml,
      p = 0.0314), pulmonary vascular resistance index just after the protamine
      administration (190 +/- 22 vs. 286 +/- 18 dyne.s.cm-5.m2, p = 0.0137) and the IL
      8 levels (just after protamine: 26.9 +/- 5.1 vs. 43.5 +/- 5.9 pg/ml, p = 0.0499,
      12 hours after cardiopulmonary bypass: 37.1 +/- 12.1 vs. 86.8 +/- 20.0, p =
      0.0435) in the P group were significantly lower than those in the C group. These
      data suggested that heparin level monitoring in whole blood may be useful to
      determine the optimal dose of protamine resulting in the decrease of a
      requirement of blood components in open heart surgery and attenuating in
      transient pulmonary hypertension and excess protamine-induced inflammatory
      reactions.

PMID- 10658378
TI  - Analysis of the elephant trunk method in patients with extensive thoracic aortic
      aneurysm.
AB  - We assessed the appropriate length of an elephant trunk prosthesis based on our
      experience with 9 patients experiencing extensive thoracic aneurysms. There were
      3 patients with a true aneurysm, 5 patients with a dissecting aortic aneurysm,
      and 1 patient with a true plus dissecting aortic aneurysm. The subjects were 4
      men and 5 women and, at the time of operation, were from 38 to 74 years old. The
      second-stage operations were performed on 6 patients from 9 days to 6 months
      after the first-stage operation. In the first-stage operation, one patient died
      of pneumonia during the hospital stay and another died of multi-organ infarction
      after 15 months. In the second-stage operation, two patients died of brain
      hemorrhage in the chronic stage after the operation. The length of the elephant
      trunk prosthesis was 3 cm in the three early patients, and in one of them the
      elephant trunk could not be utilized due to its insufficient length. In the next
      three patients, the length was extended to 5 cm, but one of patient experienced
      an expansion of the aneurysm in the descending aorta due to a graft of
      insufficient length which could not decompress the aneurysmal wall. Therefore, in
      the last three patients, the length was further extended to 10 cm, and the second
      stage operation was performed uneventfully on the 64th, 9th and 45th day,
      respectively after the first-stage operation within a continuous hospital stay.
      Neither expansion of the aneurysm nor thromboembolism was found during the
      waiting period for any of the second-stage operations. Accordingly, we recommend
      using a 10 cm elephant trunk prosthesis.

PMID- 10658379
TI  - Combined resection of the aorta for an esophageal carcinoma invading the aorta
      through a right transthoracic approach.
AB  - The prognosis of esophageal carcinoma invading the thoracic aorta has been
      extremely poor, as it has been either not resected or only palliatively resected.
      In recent years a remarkable improvement in survival has been achieved in
      advanced esophageal carcinoma through an aggressive dissection of the upper
      mediastinal lymph nodes. This implied that resection only of the aorta without
      lymph node dissection in these patients was not adequate for curability. Although
      a resection of the aorta would seem to be performed more easily through a left
      thoracotomy than through a right thoracotomy, the upper mediastinal lymph node
      dissection was unsatisfactory through a left thoracotomy. Therefore, we performed
      combined resection of the aorta using a temporary aorta-aorta bypass together
      with upper mediastinal lymph node dissection through a right thoracotomy for four
      patients with the esophageal carcinoma invading the thoracic aorta. This
      operative procedure was performed safely, and had the advantage that full
      observation on the extent of the carcinoma was attained together with subsequent
      radical lymph node dissection in the same field through only the right thoracic
      approach. This operation may provide a possibility for cure to patients with an
      esophageal carcinoma invading the aorta, who would otherwise receive only
      palliative treatment.

PMID- 10658380
TI  - A lung metastasis from giant cell tumor of bone at eight years after primary
      resection.
AB  - We report a case of extensive pulmonary metastasis from a histologically benign
      giant cell tumor. A 34-year-old woman had undergone tumor resection, curettage
      and artificial bone grafting for giant cell tumor in the left tibia. At eight
      years after surgery, a chest radiograph revealed an extensive tumor shadow in the
      right thoracic cavity. Tumor resection with right upper and middle bilobectomy
      was performed. Its histological features were consistent with those of the
      primary tumor of the tibia. Distant metastases from a giant cell tumor of bone
      are rare, with only 50 reported cases. Metastasis has occurred mainly within 3
      years after the primary resection. However, in 20% of reported cases, metastasis
      occurred after 5 years or longer. Long-term follow-up and careful observation for
      distant metastasis are necessary for this histologically benign disease.

PMID- 10658381
TI  - A subclavian artery aneurysm associated with aortitis syndrome.
AB  - We performed surgery on a 61-year-old woman who had increasingly severe right
      shoulder pain and paresthesia in her right upper extremity as a result of a large
      right subclavian artery aneurysm. She had suffered from aortitis syndrome for 10
      years for which she was treated with steroids and had multiple arterial lesions,
      including bilateral subclavian artery aneurysms, abdominal aortic aneurysm and
      obstruction of bilateral superficial femoral arteries. The right subclavian
      artery aneurysm measured 4 cm in diameter and rupture appeared imminent,
      prompting surgical therapy. Via the supraclavicular incision approach and
      additional partial sternotomy, the aneurysm was excluded and the brachiocephalic
      to right axillar arterial bypass was set up using an extended
      polytetrafluoroethylene graft. The patient recovered without complications and a
      subclavian artery aneurysm demonstrated by computed tomography was thrombosed 1
      month after surgery. In conclusion, we recommend the exclusion technique to treat
      subclavian artery aneurysms in cases in which aneurysmectomy is likely to injure
      adjacent veins and nerves.

PMID- 10658382
TI  - Aortic dissection complicating cardiac surgery in a patient with calcified
      ascending aorta.
AB  - Aortic dissection is a rare but devastating complication of cardiac surgery.
      Adequate and early diagnosis of intraoperative aortic dissection and quick
      therapeutic decision making are the keys for saving patients in such cases. We
      describe the case of a 68-year-old man referred for CABG and mitral valve
      replacement with severe calcification of the ascending aorta. Intra-operative
      transesophageal echocardiography was useful for diagnosis of intra-operative
      aortic dissection and malperfusion of the true lumen. Immediate switching of the
      arterial perfusion site established flow in the true lumen with prompt subsidence
      of the expanded false lumen. CABG, mitral valve replacement and graft replacement
      of the ascending aorta could be simultaneously performed in this patient.

PMID- 10658383
TI  - Carcinosarcoma of the lung mis-diagnosed preoperatively as a mediastinal tumor.
AB  - Carcinosarcoma of the lung is an uncommon tumor and is rarely preoperatively
      correctly diagnosed. The prognosis of patients with carcinosarcoma is extremely
      poor, despite treatment. A 79-year-old man was mis-diagnosed preoperatively as
      having a malignant mediastinal tumor. Excision of the tumor with segmentectomy of
      the lung revealed it was composed of a variety of carcinomatous and sarcomatous
      elements, which is a clear manifestation of the histogenetic totipotentiality of
      carcinosarcoma. He was subsequently treated with adjuvant chemotherapy and
      irradiation. He remains well at sixteen months after the operation, to date. Here
      we report this rare true case of a carcinosarcoma, focusing on the difficulty of
      a correct preoperative diagnosis.

PMID- 10658384
TI  - Clindamycin or penicillin V?

PMID- 10658385
TI  - HIV/AIDS and infection control.

PMID- 10658386
TI  - The perception of caries prevention.

PMID- 10658387
TI  - Educational sites on the Internet.

PMID- 10658388
TI  - Moving toward evidence-based dentistry.

PMID- 10658389
TI  - Control of x-radiation in dentistry. Canadian Dental Association.

PMID- 10658390
TI  - Supernumerary teeth--an overview of classification, diagnosis and management.
AB  - Most supernumerary teeth are located in the anterior maxillary region. They are
      classified according to their form and location. Their presence may give rise to
      a variety of clinical problems. Detection of supernumerary teeth is best achieved
      by thorough clinical and radiographic examination. Their management should form
      part of a comprehensive treatment plan. This article presents an overview of the
      clinical problems associated with supernumerary teeth and includes a discussion
      of the classification, diagnosis and management of this difficult clinical
      entity.

PMID- 10658392
TI  - Trust is the key.

PMID- 10658393
TI  - Evidence-based dentistry: a general practitioner's perspective.

PMID- 10658394
TI  - Ethics in an aging society: challenges for oral health care.
AB  - Health and aging are deeply meaningful and complex realities. The demographic
      reality of the Canadian population in the 21st century requires an in-depth
      understanding of the health care goals of older people, an analysis of the
      attitudes toward older people that affect societal decision making and the
      educational and policy changes required to effect positive change. Viewing these
      issues through the lens of oral health care allows an analysis of health care
      goals for the older population. A look at representative cases where oral health
      needs were not met uncovers some of the attitudes and values about oral health,
      the goals of health care and the unique circumstances of older people that
      present barriers to appropriate care.

PMID- 10658395
TI  - ATSP '99. The business of telemedicine.

PMID- 10658396
TI  - Toward a virtual electronic patient record.

PMID- 10658397
TI  - The business of Cyberhealthcare.

PMID- 10658398
TI  - On the Rim: the making of HL7's Reference Information Model.

PMID- 10658399
TI  - Designing yourpractice.com: ten steps to an informative Website.

PMID- 10658400
TI  - Web conferencing at the USUHS medical school.

PMID- 10658401
TI  - Doing IT right at the University of Utah.

PMID- 10658402
TI  - The physician and the Internet: observer or participant?

PMID- 10658403
TI  - MEDNET '99. Cybermedicine enters the new millennium.

PMID- 10658404
TI  - HealthSec '99. Security and privacy in the health information age.

PMID- 10658406
TI  - Evolution of the user/computer interface: Part I, Data input.

PMID- 10658405
TI  - MIE '99. A bridge to knowledge: medical informatics in Europe.

PMID- 10658407
TI  - [Effect of non-depolarizing muscle relaxants on autonomic nervous system activity
      -assessment by heart rate variability analysis].
AB  - We investigated the effect of d-tubocurarine (d-Tc), pancuronium (PAN),
      vecuronium (VEC), and rocuronium (ROC) on the autonomic nervous system in cats by
      measuring changes in the invasive mean arterial pressure (MAP), heart rate (HR),
      and heart rate variability following four administrations of each drug at 2.ED95.
      Heart rate variability analysis was used to assess the effects of the drugs on
      sympathetic and parasympathetic nervous system function using low-frequency (0.04
      0.22 Hz) component (LF) and high-frequency (0.22-0.60 Hz) component (HF).
      Comparisons of the HR, MAP, LF, HF, and LF/HF ratio before and after drug
      administration were made for each drug. The administration of d-Tc caused a
      significant decrease in MAP and a significant increase in HR accompanied by
      increase in LF, HF, and LF/HF ratio. The increases in the LF, HF and LF/HF ratio
      appeared to be related to the mean abrupt enhancement of sympathetic and
      parasympathetic nervous system function caused by changes in circulatory
      dynamics. PAN caused a significant increase in HR, and a significant decrease in
      the HF, which we thought were related to suppression of cardiac parasympathetic
      function. Neither VEC nor ROC produced a significant change in any of the
      parameters and were considered to have no significant effect on the autonomic
      nervous system.

PMID- 10658409
TI  - [Extent and duration of isobaric 0.5% bupivacaine spinal anesthesia by using new
      open-end pencil point spinal needle].
AB  - Extent and duration of isobaric 0.5% bupivacaine spinal anesthesia by using two
      spinal needles; a new 25 gauge open-end pencil point spinal needle (needle tip is
      open as a hole after pulling out the stylet, Doctor Japan Co., Japan) and a 25
      gauge Quincke needle (TOP Co., Japan) were studied clinically in 24 patients for
      elective lower extremity surgery. Patients were randomly assigned into two groups
      of 12 patients each according to the spinal needle used. Lumbar puncture was
      performed between L3-4 with the patient in lateral decubitus position. After
      isobaric 0.5% bupivacaine 4.0 ml was injected in 20 seconds, the patient was
      placed in supine position, and the onset of anesthesia was assessed by loss of
      cold sensation (alcohol sponge), sensory block (pinprick) and motor block
      (modified Bromage's scale) in every 5 minutes until 30 minutes. Recovery of motor
      block and adverse effects were assessed by a blinded observer. Sensory block at
      30 minutes by Quincke needle was Th 8.4 +/- 1.0 and by new open-end pencil point
      needle it was Th 8.5 +/- 3.2 dermatomes. Two groups did not differ significantly
      in sensory block and also in motor block. No adverse effect was observed in both
      groups. These results indicate that this new open-end pencil point spinal needle
      is very useful for preventing adverse effects of spinal anesthesia.

PMID- 10658408
TI  - [Pre-incisional administration of ketamine reduced the postoperative pain].
AB  - This study was designed to examine the postoperative analgesic effect of pre
      /post-incisional administration of ketamine. Thirty-nine female patients
      scheduled for transabdominal hysterectomy were randomly allocated into 3 groups.
      Patients in group-K1 (n = 13) received intravenous ketamine 100 mg before
      surgical incision and patients in group-K2 (n = 13) received the same after
      laparotomy. Group-C (n = 13) did not receive any ketamine. All patients were
      anesthetized with combined spinal/epidural anesthesia supplemented with
      sevoflurane 0.5% and nitrous oxide in oxygen. Postoperative pain was controlled
      by epidural infusion of the mixture of fentanyl (25 mcg.ml-1) and bupivacaine
      (3.8 mg.ml-1) at 2.1 ml.hr-1. Analgesic effect was assessed by visual analogue
      scale (VAS) and verbal rating scale (VRS). VAS and VRS in group-K1 were
      significantly lower compared with those in group-C, while there was no difference
      between group-K2 and C. The incidence of side effects and additional use of
      analgesics were similar among the three groups. In conclusion, pre-incisional
      administration of ketamine reduced the postoperative pain, but post-incisional
      ketamine was not effective.

PMID- 10658410
TI  - [Effects of various lidocaine compounds on cuff pressure of a reinforced tracheal
      tube].
AB  - Effects of various lidocaine compounds on cuff pressure of a tracheal tube were
      studied. Thirty reinforced tracheal tubes (Mallinckrodt Medical, Ireland) were
      divided into five groups and the cuffs were treated with normal saline, 2%
      lidocaine jelly, plain lubricant jelly, 4% lidocaine solution or 8% lidocaine
      pump spray. The cuff pressures of each tube was measured with 5, 10, 15, and 20
      ml of air at the time of 0, 30, 60, 90, and 120 min after the treatment. The cuff
      pressures with 20 ml of air (P20) were compared among the groups. Thirty min
      after the treatment on the cuffs, P20 of the tubes with lidocaine spray
      significantly decreased than that of the control tubes with normal saline. In 2
      of 10 tubes on which lidocaine had been sprayed, the cuffs were damaged 90 min
      after the treatment. Any jelly or solution on the cuffs did not influence the
      cuff pressure-volume relationship. We conclude that lidocaine pump spray should
      not be used as a lubricant on the cuff of a reinforced tracheal tube.

PMID- 10658411
TI  - [Lidocaine metabolism associated with epidural anesthesia in patients for hepatic
      surgery].
AB  - We measured plasma concentrations of lidocaine and its principal metabolite,
      monoethylglycinexylidide (MEGX) associated with thoracic epidural anesthesia
      using continuous infusion of lidocaine in 10 patients for hepatectomy and other
      10 patients for elective abdominal surgery as a control. Plasma concentrations of
      lidocaine and MEGX were analysed by fluorescence polarization immunoassay and
      high performance liquid chromatography, respectively. Plasma lidocaine
      concentration increased gradually, and peaked to 5.1 +/- 2.3 micrograms.ml-1
      (mean +/- SD) at the end of surgery in the hepatectomy group, but not in the
      control group. No significant differences were observed in plasma MEGX
      concentration between these two groups. Our findings suggest that MEGX formation
      by the hepatic cytochrome P-450 system might be impaired associated with hepatic
      surgery. Hypoperfusion of the liver induced by surgical manipulation may have
      contributed to this impaired metabolism.

PMID- 10658412
TI  - [Intra-aortic balloon occlusion of the descending thoracic aorta for intra
      abdominal hemorrhage].
AB  - Intra-aortic balloon occlusion (IABO) of the descending aorta is beneficial to
      rescue patients in shock following traumatic intra-abdominal hemorrhage. The
      authors experienced four such patients who had received IABO of the descending
      thoracic aorta to maintain hemodynamics prior to operation. After hemostasis, the
      balloon was deflated gradually. Releasing the balloon in the operating room was,
      however, abandoned in two patients because of severe deoxygenation and life
      threatening arrhythmia. In the other two patients, the balloon was successfully
      deflated during the operations; one of them died a week later from multiple organ
      failure. We conclude that shortening the aortic occlusion time as well as the
      treatments for adverse effects of balloon release are important in the anesthetic
      management of patients receiving IABO.

PMID- 10658413
TI  - [Postoperative sore throat and intracuff pressure: comparison among endotracheal
      intubation, laryngeal mask airway and cuffed oropharyngeal airway].
AB  - We studied which device is most useful to reduce postoperative sore-throat. We
      investigated the relationship between intracuff pressure and postoperative sore
      throat in using endotracheal intubation (ET), the laryngeal mask airway (LMA) and
      the cuffed oropharyngeal airway (COPA) in adult patients. We classified sore
      throat into categories; pain at rest, hoarseness and dysphasia. We evaluated pain
      at rest by the score (0: no pain, 1: mild discomfort, 2: mild pain, 3: severe
      pain). Pain at rest (scores 1, 2, 3) was complained by 10 patients in ET group, 3
      in LMA group, 5 in COPA group on the day of operation, showing significantly
      lower incidence of pain at rest in LMA group than in ET group. Hoarseness was
      complained by 15 patients in ET group, 2 in LMA group and 4 in COPA group,
      showing significantly lower incidence of hoarseness in LMA and COPA groups than
      in ET group. Dysphasia was complained by 3 in ET group, 1 in LMA group and 2 in
      COPA group, showing no significant difference. These results suggest that LMA is
      most appropriate to reduce postoperative sore-throat.

PMID- 10658414
TI  - [Evaluation of mortality of patients admitted to ICU for the last 12 years].
AB  - We evaluated mortality of 2689 patients admitted to the Intensive Care Unit,
      Osaka University Hospital from January, 1987 to December, 1998. The patients were
      divided into 3 groups. Group A consisted of 1408 patients who underwent
      cardiovascular surgery, group B, 1082 patients who underwent other surgical
      procedures and group C, 199 patients who were transferred from the department of
      medicine. We studied mortality rate, causes of death, correlation between length
      of ICU stay and mortality rate, and mortality rate among age groups for 12 years.
      The main causes of death were cardiac failure and sepsis in group A, and
      respiratory failure and sepsis in group B and C. Mortality rate in each group
      showed no significant change for the last 12 years. Those who stayed more than 2
      weeks in ICU showed a significantly higher mortality rate (p < 0.0001). Thus,
      length of ICU stay and mortality rate showed a positive correlation (p < 0.0001).
      The youngest group (age 0-1) showed a significantly higher mortality rate than
      other age groups (p < 0.0001). As sepsis was the most important cause of death in
      all the groups, the prevention and treatment of infection are the most important
      issue in our ICU to reduce mortality rate.

PMID- 10658415
TI  - [Right phrenic nerve palsy in a patient with ventricular septal perforation after
      acute myocardial infarction].
AB  - A 77-year-old female had acute myocardial infarction and ventricular septal
      perforation (VSP). An operation was performed 14 days after VSP. During
      cardiopulmonary bypass, a patch was sutured in place on the left side of the
      defect under a mild hypothermia with topical cardiac cooling procedure. In the
      postoperative period, mechanical ventilation was continued with use of pulmonary
      monitor (CP-100, BICORE). When the patient was weaned of mechanical ventilation,
      work of breathing increased (WOBp: 1.67 J.l-1) without the change of SaO2, PaO2,
      PaCO2 and the respiratory state. After extubation, the chest X-ray showed
      elevated right diaphragmatic level and a diagnosis of unilateral diaphragmatic
      paralysis was made. Oral intake was started two days after extubation. SpO2
      decreased after oral intake, and it was significantly improved by taking a left
      lateral position. The symptoms disappeared 47 days after the operation. It should
      be noticed that the rise of endoceliac pressure in the patient who had a
      unilateral phrenic nerve palsy, affected the SpO2.

PMID- 10658416
TI  - [Complications of spinal anesthesia as the initial symptom in patients with
      spinal tumor--a report of two cases].
AB  - This report describes the onset of symptoms of spinal cord compression by tumor
      after spinal anesthesia. Two patients underwent caesarean section.
      Postoperatively, they complained of backache and heaviness in the legs. MRI
      demonstrated spinal tumor and laminectomy was performed in one case.
      Postoperatively symptoms improved rapidly. In another case, operation was not
      performed, but the patient recovered gradually. Onset of symptoms of spinal cord
      compression by tumor after lumbar puncture can be attributed to displacement of
      the mass or to vascular engorgement. If after the lumbar puncture, a patient
      complains numbness, loss of strength, and paresthesias in the legs, we should
      suspect the presence of the spinal tumor.

PMID- 10658417
TI  - [Epidural anesthesia and general anesthesia using the cuffed oropharyngeal airway
      for an obese patient with Duchenne's muscular dystrophy].
AB  - Duchenne's muscular dystrophy is a genetic disorder whose features include
      abnormal responses to muscular relaxants and possible respiratory dysfunction
      after general anesthesia. The purpose of this report is to describe one
      management strategy used successfully to anesthetize an obese man with this
      disorder for atypical mastectomy. The anesthetic management during surgery
      involves epidural anesthesia using 2% mepivacaine and general anesthesia using
      the cuffed oropharyngeal airway. Postoperatively 0.25% bupivacaine was infused
      for epidural analgesia. The patient was observed in the intensive care unit until
      the first postoperative day and showed an uncomplicated intra- and post-operative
      course.

PMID- 10658418
TI  - [Intraoperative indirect monitoring of electrocardiogram].
AB  - The electrocardiogram (ECG) is used as a standard monitoring method during
      anesthesia and operation. But during the operation of severely burnt patients,
      the electrodes for ECG cannot be placed on the ideal points for the standard limb
      leads. We tried the indirect monitoring of the ECG. We placed the electrodes on
      the sheet over the operating table, and connected the patient and the electrodes
      with water. By this way the ECG similar to the standard limb leads could be
      recorded. This method is useful for the patients, with such diseases as severe
      burn, severe atopic dermatitis and epidermolysis bullosa hereditaria.

PMID- 10658419
TI  - Ecoterrorism and nontraditional military threats.
AB  - The menace facing U.S. service personnel from ecoterrorism and other
      nontraditional threats may increase as military deployments in war and peace
      increase, the availability of devastating biological, chemical, and radioactive
      agents increases, and adversaries or terrorist groups become more inclined to use
      them. A vital concern for field medical commanders is the requirement to
      understand the environmental issues associated with military deployment. More
      important is the need to recognize potential ecological threats to deployed
      military troops. The Gulf War was replete with numerous documented acts of
      ecoterrorism. The current world crisis from terrorism dictates that we be
      knowledgeable of the medical consequences of weapons of mass destruction and
      skilled in the management of casualties. The processes of human health risk
      assessment of deployed soldiers and ecological risk assessment are discussed as
      strategies to effectively prevent or reduce the health and medical consequences
      of ecoterrorism.

PMID- 10658420
TI  - Human and behavioral factors contributing to spine-based neurological cockpit
      injuries in pilots of high-performance aircraft: recommendations for management
      and prevention.
AB  - In high-performance aircraft, the need for total environmental awareness coupled
      with high-g loading (often with abrupt onset) creates a predilection for cervical
      spine injury while the pilot is performing routine movements within the cockpit.
      In this study, the prevalence and severity of cervical spine injury are assessed
      via a modified cross-sectional survey of pilots of multiple aircraft types (T-38
      and F-14, F-16, and F/A-18 fighters). Ninety-five surveys were administered, with
      58 full responses. Fifty percent of all pilots reported in-flight or immediate
      post-flight spine-based pain, and 90% of fighter pilots reported at least one
      event, most commonly (> 90%) occurring during high-g (> 5 g) turns of the
      aircraft with the head deviated from the anatomical neutral position. Pre-flight
      stretching was not associated with a statistically significant reduction in neck
      pain episodes in this evaluation, whereas a regular weight training program in
      the F/A-18 group approached a significant reduction (mean = 2.492; p < 0.064).
      Different cockpit ergonomics may vary the predisposition to cervical injury from
      airframe to airframe. Several strategies for prevention are possible from both an
      aircraft design and a preventive medicine standpoint. Countermeasure strategies
      against spine injury in pilots of high-performance aircraft require additional
      research, so that future aircraft will not be limited by the human in control.

PMID- 10658422
TI  - War wounds to the foot.
AB  - Thirty-nine patients with foot injuries were admitted to the Clinic for
      Orthopedic Surgery in Lovran during the war against Croatia. All of them were
      soldiers wounded by antipersonnel mines. All of the patients were treated using
      the same protocol. Primary wound care included debridement, necrectomy, and three
      dimensional external fixation with or without Kirschner wires. External fixation
      facilitated postoperative wound care, prevented vicious contracture position, and
      made fracture healing possible with early weight bearing.

PMID- 10658421
TI  - Surgical wound morbidity in an austere surgical environment.
AB  - Surgical wound morbidity was analyzed for a U.S. military field hospital deployed
      to the Republic of Haiti in support of Operation New Horizons 1998. The purpose
      of the analysis was to determine if procedures performed in the field hospital
      had greater infectious risks as a result of the environment compared with
      historical reports for traditional hospital or clinic settings. Acceptable
      historical infection rates of 1.5% for clean surgical cases, 7.7% for clean
      contaminated cases, 15.2% for contaminated cases, and 40% for dirty cases have
      been noted. There were 827 operations performed during a 6-month period, with the
      majority of patients assigned American Society of Anesthesiologists Physical
      Status Classification class I or II. The distribution of these cases was: 72%
      clean cases, 5% clean contaminated cases, 4% contaminated cases, and 19% dirty
      cases. The overall wound complication rate was 3.6%, which included 5 wound
      infections, 11 wound hematomas, 8 superficial wound separations, and 6 seromas.
      The infectious morbidity for clean cases, the index for evaluation of infectious
      complications, was 0.8%, well within the accepted standards. There were two major
      complications that required a return to the operating room: a wound dehiscence
      with infection in an orchiectomy, and a postoperative hematoma with airway
      compromise in a subtotal thyroidectomy. There were no surgical mortalities. The
      infectious wound morbidity for operations performed in the field hospital
      environment was found to be equivalent to that described for the fixed hospital
      or clinic settings. No special precautions were necessary to ensure a low
      infection rate. The safety for patients undergoing elective surgical procedures
      has been established. Further training using these types of facilities should not
      be limited based on concerns for surgical wound morbidity.

PMID- 10658424
TI  - Ottowa ankle rules in a USA Army troop medical clinic in South Korea.

PMID- 10658423
TI  - Association of Helicobacter pylori infection with gastric cancer.
AB  - BACKGROUND: Helicobacter pylori has generated public health interest since its
      identification in 1983. Past studies have suggested that the bacterium plays a
      role in the pathogenesis of gastric cancer. More recent studies support the
      conclusion that the association of H. pylori with gastric cancer is causal. The
      purpose of this article is to review the available evidence supporting the
      association of H. pylori with gastric cancer. METHODS: We performed a critical
      review of the relevant literature published in the English language on H. pylori
      and gastric cancer using MEDLINE, Index Medicus for the years 1985 to 1997. The
      reference lists of selected articles also were reviewed to capture citations for
      further pertinent studies. RESULTS: H. pylori is thought to be the major cause of
      chronic atrophic gastritis. H. pylori gastritis is worldwide in distribution. H.
      pylori is now categorized by the International Agency for Cancer Research as a
      group 1 carcinogen, i.e., an agent that is carcinogenic to humans. Several
      reports from the United States have found the highest frequencies of gastric
      cancer in geographic areas and populations with the highest rates of acquisition
      of H. pylori infection. The high prevalence of H. pylori infection has been
      documented most notably in blacks and Hispanics, who also are at high risk for
      gastric cancer. CONCLUSIONS: New studies that focus on the epidemiology and
      pathology of H. pylori improve our understanding of its relationship with gastric
      cancer and advance the development of gastric cancer prevention and control
      strategies that are proposed.

PMID- 10658425
TI  - Canine visceral leishmaniasis in Sicily.
AB  - The Sicilian province of Catania is an active foci for human visceral
      leishmaniasis (VL) in the Mediterranean area. Approximately 10 to 15 cases of VL
      are diagnosed via hospital admissions each year in this community. Recently, an
      increase in VL case reporting by Sicilian physicians was noted, with 38 and 37 VL
      cases in 1996 and 1997, respectively. Before 1995, there were no reported VL
      cases among U.S. military personnel or their family members living in Sicily.
      However, since 1996, there have been four cases referred to Walter Reed Army
      Medical Center for diagnosis and treatment, all involving the children of
      personnel assigned to Naval Air Station Sigonella. Exposure histories for all
      infected individuals excluded exposure to Leishmania parasites outside of Sicily.
      All patients lived in areas where vectoring sandflies are present. All had dogs
      as family pets. To evaluate the level of infection among dogs owned by Navy
      personnel and their families, U.S. Navy Environmental and Preventive Medicine
      Unit 7, in a collaborative study with the U.S. Army Veterinary Clinic, Naval Air
      Station Sigonella, and the Walter Reed Army Institute of Research, performed
      clinical evaluation and serological testing of 50 dogs residing with U.S.
      personnel assigned to Naval Air Station Sigonella. The data indicate a high
      exposure rate to Leishmania (60% of the animals tested had elevated
      immunoglobulin M antibody levels) in the study population, suggesting that they
      were infected with Leishmania infantum. Distribution of seropositive dogs by sex
      was equal. Most of the dogs studied appeared to be in good health. However,
      inapparent infection of dogs, seen by Italian veterinarians, has been observed
      throughout all areas of Catania. Sandflies responsible for vectoring L. infantum
      were trapped in the same locations as the dogs sampled in this study. The level
      of subclinical infection was 75% among seropositive dogs. The overall level of
      canine infection observed was higher than expected. This study demonstrates an
      increased risk to military working dogs and companion dogs of U.S. personnel for
      infection with L. infantum during a 2- to 3-year tour in Sicily.

PMID- 10658426
TI  - The combat soldier.
AB  - The Gulf War illness problem is seen as a post-war syndrome related to veteran
      discontent rather than as a new phenomenon. It is here proposed that application
      of social psychiatric thinking and workmen's compensation experience can help in
      understanding the problem. Social psychiatry has been neglected in the training
      of so many psychiatrists that many of them fail to understand the Army as a
      community and to recognize that a community's parts may develop symptom neuroses.
      Most psychiatrists, however, do know that a symptom neurosis will not disappear
      until it no longer serves its purpose. The young soldier may know that he is
      being trained for combat duty but manages to distance himself from the terrible
      realities of military combat by creating a psychic reality that protects him.
      Social psychiatric emphasis is used to describe his response when brought face to
      face with himself as a combatant with overwhelming responsibilities and genuine
      lethal danger. The brilliance and relevance of social thinking is demonstrated by
      examples from the works of Gustave LeBon and Georg Simmel so that its application
      to present--and future--military problems may be brought into focus.

PMID- 10658427
TI  - Deployment and the probability of spousal aggression by U.S. Army soldiers.
AB  - OBJECTIVE: To determine the relationship between length of soldier deployment and
      self-reports of moderate and severe spousal violence. METHODS: The Conflict
      Tactics Scale was used to measure self-reports of behaviors exhibited in marital
      conflict. Surveys were administered to a 15% random sample of 26,835 deployed and
      nondeployed married active duty U.S. Army men and women in the 50 United States
      during the period 1990 to 1994. Multinomial logistic regression and ordered
      probit analysis were used to estimate the probabilities of moderate and severe
      violence by length of deployment. RESULTS: After controlling for demographic
      variables, the probability of severe aggression was significantly greater for
      soldiers who had deployed in the past year compared with soldiers who had not
      deployed. CONCLUSIONS: Deployment contributes a significant but small increase to
      the probability of self-reported spousal aggression during a 1-year period.
      Although deployment is a military operation, similar effects may be observed in
      certain civilian occupations.

PMID- 10658428
TI  - Focused obstetrical clinic for active duty junior enlisted service women: model
      for improved outcomes.
AB  - OBJECTIVE: To evaluate the utility of an interdisciplinary clinic in improving
      perinatal outcomes for all pregnant patients of junior enlisted rank (E4 and
      below) in response to previous reports that this group is at higher risk for
      adverse outcomes. METHODS: The study population included all junior enlisted
      active duty patients (E4 and below) delivering between January 1, 1993, and June
      30, 1996. Outcomes for patients receiving care in a focused active duty
      obstetrical clinic were compared with outcomes in similar cohorts of senior
      active duty patients (E5 and above) and non-active duty pregnant patients.
      Evaluation was based on perinatal outcomes, including chorioamnionitis,
      postpartum hemorrhage, intrauterine growth retardation, cesarean delivery,
      preterm delivery rates (< 37 weeks), postterm delivery rates (> 41 weeks),
      postpartum days, mean gestational age at delivery, mean delivery weights, Apgar
      scores at 1 and 5 minutes, preeclampsia, and premature labor. Variables with
      potential to confound perinatal outcomes were also studied. Confounding variables
      included tobacco use, gestational diabetes, chronic hypertension, thyroid
      disease, history of substance abuse, and alcohol use. Power analysis accomplished
      before initiation of the study showed adequate sample size (> 240 patients in
      each group) to demonstrate statistically different rates of preterm delivery.
      Statistical analysis was done using the chi 2 test for categorical variables and
      Student's t test for continuous variables. RESULTS: There were no statistical
      differences between junior active duty patients, senior active duty patients, and
      non-active duty patients in preterm delivery and other outcome variables.
      CONCLUSION: The focused obstetrical clinic, conducted for junior enlisted
      soldiers by a senior nurse practitioner, appears to provide an intervention that
      ensures perinatal outcomes equal to those of both the non-active duty and the
      senior active duty population.

PMID- 10658429
TI  - Demographic and psychosocial risk factors for preterm delivery in an active duty
      pregnant population.
AB  - The effects of work climate, pregnancy transitions stress, maternal medical
      conditions, health risk behaviors, psychological health, and demographic
      characteristics were examined among 269 pregnant military women. The study found
      that single and separated/divorced military women were at greater risk for
      preterm delivery than married women. Unmarried participants were more likely to
      belong to ethnic minorities, were lower ranking, less educated, and reported a
      greater number of medical conditions than married participants. Psychosocial
      variables distinguished the three marital status groups--married, single, and
      separated/divorced--but none of these variables was related to preterm delivery.
      In a logistic regression analysis, marital status was a more significant
      predictor of preterm delivery than were medical conditions.

PMID- 10658430
TI  - Gender-related personal attributes and psychological adjustment among U.S. Army
      soldiers.
AB  - Personality characteristics associated with successful adaptation to military
      life are often described in gender-related terms. However, valid, reliable
      measures of gender-related personality characteristics have not been established
      for military populations. The purpose of this study was to validate an instrument
      for measuring gender-related personality characteristics in an active duty
      population. The Extended Personal Attributes Questionnaire was administered to
      1,060 male soldiers and 305 female soldiers in U.S. Army support units. Results
      of a factor analysis indicated that there are three separate factors. The first
      denotes negatively valued aggressive traits (Negative Masculinity), the second
      denotes negatively valued passive traits (Negative Femininity), and the third
      combines positive instrumental and positive expressive traits, referred to as the
      Combined factor. Although positive instrumental traits (referred to as
      Masculinity) were related to fewer psychological symptoms, Negative Masculinity
      and Negative Femininity were associated with increased psychological symptoms.
      Positive expressive traits (referred to as Femininity) were unrelated to
      psychological symptoms.

PMID- 10658431
TI  - Demographic differences in body composition of Navy and Marine Corps personnel:
      findings from the perception of wellness and readiness assessment.
AB  - With the recent increase in women's representation in the military, baseline
      physical measurement data are needed to help set appropriate accession and
      retention standards and to design useful prevention and intervention programs in
      the areas of physical fitness and health. This study incorporated several body
      composition indices to obtain anthropometric data for a representative sample of
      1,292 active duty Navy and Marine Corps women and men. It also assessed the
      extent to which personnel met weight-for-height and body fat standards. The
      prevalence of overweight was considerably lower among Marine Corps women compared
      with Navy women and was slightly less for Marine Corps men compared with their
      Navy counterparts. Between one-fifth and one-third of military personnel exceeded
      Navy/Marine Corps weight-for-height standards. Navy women tended to meet weight
      standards more often than Navy men. Fewer Marine Corps women than men were
      overweight, but more exceeded their weight-for-height standards.

PMID- 10658432
TI  - Estimated cost of dental treatment for active duty and recruit U.S. military
      personnel.
AB  - This paper estimates the cost of restoring U.S. military personnel to optimal
      oral health. The data come from a 30-site oral health survey of Army, Navy,
      Marine Corps, and Air Force personnel conducted from February 1994 to January
      1995. A systematic random sample of 2,711 recruits was drawn. From a
      prestratified, random sample of 15,924 active duty personnel, 13,050 (82%
      response rate) participated in the survey. Applying their best clinical judgment,
      one dentist per site charted comprehensive dental treatment needs on each service
      member. Radiographs were used. After the samples were weighted to reflect the
      1994 population of recruits (202,144) and active duty personnel (1,699,662),
      treatment costs were calculated applying median fees reported by U.S. general
      dentists in 1995. Results show total estimated costs of $1.9 billion for active
      duty personnel and $203 million for recruits. Periodontal disease accounts for
      the greatest proportion (47%) of active duty treatment costs, and oral surgery
      accounts for the greatest proportion (32%) of recruit treatment costs. The cost
      of restoring U.S. service members to optimal oral health is substantial.

PMID- 10658434
TI  - Perceptions of quality: predictors of positive ratings in a military health care
      system.

PMID- 10658433
TI  - The influence of patient sociodemographic characteristics on patient
      satisfaction.
AB  - The patient satisfaction responses of active duty Army patients in military
      facilities were analyzed to determine (1) if patients differ along
      sociodemographic characteristics, (2) the predictors of satisfaction, and (3) the
      sociodemographic characteristics that moderate patients' satisfaction. Regression
      results suggest that access, communication, outcomes, and quality predict 42% of
      the variation in patients' satisfaction scores. Additionally, an analysis of
      variance suggests that patient satisfaction evaluations are significantly
      different along sociodemographic characteristics excepting marital status and
      duty location. Finally, patients' sociodemographic characteristics, with the
      exceptions of gender and marital status, moderate patients' satisfaction. These
      findings suggest that patients' satisfaction differs significantly along age,
      rank, gender, education, race, health status, and utilization individually, but
      this difference predicts only 5% of patients' satisfaction ratings. This study
      provides areas of consideration for improving active Army patients' satisfaction
      in military facilities and suggests theoretically and empirically supported ways
      to prioritize scarce resources and optimize efforts when faced with constraints.

PMID- 10658435
TI  - Uterine perforation resulting in bowel infarction: sharp traumatic bowel and
      mesenteric injury at the time of pregnancy termination.
AB  - BACKGROUND: By law, elective terminations of pregnancy are not performed in U.S.
      military institutions. However, in the civilian sector, more than a million
      abortions are performed each year, some of which are on military beneficiaries.
      Although complications are relatively rare, patients not uncommonly present for
      follow-up care to their military installation. We report the case of a patient
      who presented after a second-trimester elective abortion and was found to have
      suffered uterine perforation with mesenteric and bowel injury that required bowel
      resection. CASE: An 18-year-old gravida 1 para 0 female presented from an
      outlying facility 1 week after elective termination at 18 weeks of gestation with
      complaints of severe abdominal pain, nausea, and vomiting. Exploratory laparotomy
      for presumed bowel obstruction revealed uterine perforation and bowel
      devitalization and necrosis, which required small bowel resection. Fetal bones
      were discovered within the surgical specimen. CONCLUSION: Morbid, even
      potentially fatal, complications can occur as a result of pregnancy termination.
      With second-trimester procedures, perforation can result in injury to abdominal
      viscera from the perforating instruments or even from sharp fetal bony
      structures. Military gynecologic surgeons, who are not in abortion practice, must
      nevertheless be cognizant of the potential for perforation leading to serious
      visceral injury.

PMID- 10658436
TI  - Fatal cerebroembolism from nonbacterial thrombotic endocarditis in a trauma
      patient: case report and review.
AB  - Nonbacterial thrombotic endocarditis (NBTE) is a rare condition that may result
      in an unexpected and usually fatal cerebroembolism. It occurs in a variety of
      clinical situations, including malignancy, immune disorders, and sepsis, but it
      has rarely been reported after trauma. The formation of NBTE appears to require a
      hypercoagulable state and changes in valvular morphology, e.g., during a
      hyperdynamic state. Patients with disseminated intravascular coagulation have a
      21% incidence of NBTE. Although NBTE is usually found at autopsy, premorbid
      detection by echocardiography is currently possible and feasible. Untreated
      patients have a high incidence of embolic events, but anticoagulation with
      heparin may be life-saving. A lethal case of NBTE in a severely injured patient
      is reported here with the purpose of increasing awareness among medical personnel
      caring for trauma patients. Recommendations have been made for surveillance
      echocardiography in high-risk patients, e.g., critically ill patients with sepsis
      or disseminated intravascular coagulation.

PMID- 10658437
TI  - [The opinion of the vascular surgeon].

PMID- 10658438
TI  - Planning of clinical trials evaluating treatments in peripheral vascular disease
      due to atherosclerosis.

PMID- 10658439
TI  - [Analysis of costs and results of prostaglandin (PGE1 alpha-cyclodestrin) therapy
      of peripheral arterial diseases].
AB  - BACKGROUND: In this study patients with peripheral vascular disease were treated
      with PGE1 alpha-ciclodestrina. In the intermittent claudication group (walking
      distance at inclusion between 200-600 m) we included 55 patients treated with
      PGE1 alpha-ciclodestrina (15 diabetics) and 22 controls (not treated with PGE1
      alpha-ciclodestrina). In the critical ischemia group 46 patients were treated and
      47 patients followed up as controls (rest pain or necrotic lesions had been
      present for more than 2 weeks). METHODS: Patients with intermittent claudication
      were evaluated by a treadmill test (walking distance was the endpoint) and in
      those with critical ischemia the number of minor and major amputations in 12
      months were considered as endpoints. A dose of PGE1 alpha-ciclodestrina (60-80
      micrograms/day for 2 days) was repeated either every 6 or, in alternative, every
      10 weeks. In the control group only antiplatelet agents, support treatment
      (control of risk factors) and exercise were used. RESULTS: All subgroups of
      patients treated with PGE1 alpha-ciclodestrina with intermittent claudication
      increased their walking distance (including the subgroup of diabetics). In
      critical ischemia there were no major amputations (only 2 minor amputations) in
      the PGE1 alpha-ciclodestrina group vs 10.6% (of major amputations) in the control
      group. Also an evaluation of laser Doppler flow, volume flow and transcutaneous
      PO2 indicated in subgroups of patients an improvement of microcirculation and
      limb perfusion with PGE1 alpha-ciclodestrina. CONCLUSIONS: The cost analysis and
      the quality of life evaluation indicated a benefit of preserving limbs from
      amputation.

PMID- 10658440
TI  - [Intra-arterial infusion of PGE1 alpha cyclodextrin].
AB  - BACKGROUND: Intra-arterial infusion of PGE1 alpha-ciclodestrina was achieved by
      intrafemoral catheter in critical limb ischemia. METHODS: The acute infusion of
      10 micrograms in 20 minutes, in 50 ml of saline was followed by chronic infusion
      20 micrograms/die of PGE1 alpha-ciclodestrina for 5 days. Three male patients
      (age 65 +/- 12) with severe critical ischemia and rest pain with initial,
      localised (> 0.5 cm in diameter) necrosis were treated. There was no possibility
      of revascularisation in these patient. RESULTS: No side effects due to the intra
      arterial infusion were observed. After the acute infusion skin flux (measured
      with laser Doppler at the dorsum of the foot) was increased on average 15.2 times
      (P < 0.01). The increase in flux was still present 10 days after the initial
      intra-arterial infusion. Pain was greatly decreased or disappeared in the three
      following 3 weeks. CONCLUSION: In conclusion, even on the basis of limited
      clinical data, intra-arterial infusion acutely improves skin perfusion in
      critical limb ischemia. It could be considered a fast acting treatment in
      critical ischemia and also a rapid method to evaluate the possibility of
      improving distal perfusion with PGE1 alpha-ciclodestrina (i.e. patients not
      responding to intra-arterial infusion could be considered for amputation).

PMID- 10658441
TI  - [European trial of PGE1 alpha cyclodextrin. Short-term vs. long-term therapy in
      intermittent claudication].
AB  - BACKGROUND: The efficacy, safety and cost of prostaglandin E1 (PGE1 alpha
      ciclodestrina) in the treatment of severe intermittent claudication was studied
      comparing a long term treatment protocol (LTP) with a short term treatment
      protocol (STP) in a randomised, 20-week study. METHODS: The study has selected
      120 patients (109 were included and 99 completed the study). The average total
      walking distance at inclusion was 65.5 +/- 8 m (range 20-109). Phase 1 was a 2
      week run-in phase (no treatment) for both protocols. In LTP phase 2 was the main
      treatment phase. The treatment was performed with 2-hour infusions (60 micrograms
      PGE1 alpha-ciclodestrina, 5 days each week for 4 weeks. In phase 3 (4-week
      interval period) PGE1 alpha-ciclodestrina was administered twice a week (same
      dosage). In phase 4 (monitoring lasting 3 months, from week 9 to 20) no drugs
      were used. In STP phase 2 treatment was performed in two days with a 2-hour
      infusion (1st day: morning 20 micrograms, afternoon 40 micrograms; 2nd day 60
      micrograms, morning and afternoon). The reduced dosage was used only at the first
      cycle to evaluate reduced tolerability or side effects. Full dosage (60
      micrograms b.i.d.) was used for all other cycles. The same cycle was repeated at
      the beginning of weeks 4, 8, 12 (phase 3). The observation period was between
      weeks 12 and 20 (phase 4). For both protocols a treadmill test was performed at
      inclusion, at the beginning of each phase and at the end of 20th week. A similar
      progressive physical training plan (based on walking) and a reduction in risk
      factors plan was used in both groups. RESULTS: Intention-to-treat analysis
      indicated an increase in walking distance which improved at 4 weeks (101.5% in
      STP vs 78.3% in LTP), at 8 weeks (260.9% in STP vs 107.3% in LTP) and at 20 weeks
      (351% in STP vs 242% in LTP). Comparable increases in pain-free walking distance
      were observed in the two groups. No serious drug-related side effects were
      observed. Local, mild, adverse reactions were seen in 7% of the treated subjects
      in the LTP and 5% in the STP. The average cost of LTP was approximately 6.588
      ECU; for STP the average costs was approximately 1881 ECU. The cost to achieve an
      improvement in walking distance of 1 m was 35.6 ECU with the LTP and 9.45 ECU
      with the STP (26% of the LTP cost; P < 0.02). For an average 100% increase in
      walking distance LTP cost was 1937 ECU vs 550 ECU with STP (P < 0.02). The cost
      of PGE1 alpha-ciclodestrina (including infusion and operative costs) was 25% of
      the total cost for LTP (24.9% for STP). CONCLUSION: In summary between-group
      analysis favours STP considering walking distance and costs. Results indicate
      good efficacy and tolerability of PGE1 alpha-ciclodestrina treatment. With STP
      less time is spent in infusion and more can be spent in the exercise program. STP
      reduces costs, speeds up rehabilitation and may be used in a larger number of non
      specialised units available to follow the protocol.

PMID- 10658442
TI  - ["Responders and non-responders" to PGE1 and alpha-cyclodextrin].
AB  - BACKGROUND: In this study we evaluated a group of 76 patients (mean age 66 +/-
      12) treated with the short-term PGE1 alpha-ciclodestrina protocol (60
      micrograms/die for 2 days). Responders to PGE1 alpha-ciclodestrina treatment were
      considered patients with an increase in flow/perfusion and an associated
      improvement in signs/symptoms. Moderate responders were considered patients with
      only flow/perfusion increase or only sign/symptoms improvement. Non-responders
      were characterised by no increase in flow/perfusion and no clinical improvement.
      METHODS: Signs/symptoms variations were measured on an analogue scale line.
      Perfusion measurements (laser Doppler, transcutaneous PO2, arterial inflow with
      straingauge plethysmography) were recorded after the two days of the short term
      treatment. RESULTS: In the group of 38 patient with claudication (200-600 m) 54%
      were considered responders, 12% non responders and 34% moderate responders. In
      the more severe claudication group (distance < 200 m) including 18 patients, 66%
      were responders, 8% non responders and 26% were considered moderate responders.
      In the rest pain group (13 patients) there were 63% responders, 9% non-responders
      and 28% moderate responders. In the gangrene group (10 patients) 60% were
      considered responders, 10% non-responders and 3% moderate responders. The overall
      percentages were 61.25% of responders, 10% of non-responders and 28.75% moderate
      responders. CONCLUSIONS: The evaluation of the response to PGE1 alpha
      ciclodestrina treatment may indicate which group of patients will benefit from
      the treatment and which group will have no benefits or only limited benefits.
      This may induce changes in treatment (i.e. increasing doses, more prolonged
      treatment) or other solutions (revascularisation if possible, arterial infusion
      or amputation).

PMID- 10658443
TI  - [Increasing transcutaneous PO2 in arteriopathies during treatment with PGE1 alpha
      cyclodextrin].
AB  - BACKGROUND: Transcutaneous PO2 values (at the dorsum of the foot) were evaluated
      in a group of 8 patients (mean age 66 +/- 11) with critical ischemia including 4
      patients (mean age 65 +/- 10) with gangrene[. A group of 5 comparable normal
      controls was also studied. METHODS: Patients were treated with PGE1 alpha
      ciclodestrina (60 mu/die, in two infusions lasting 3 hours; one in the morning
      and one in the afternoon) for 6 days. RESULTS: Results indicated a maximum
      increase in PO2 between the second and third day which remains higher than values
      observed before treatment up to 4 weeks. In another group of patients (6
      claudicants with walking distance between 200 and 400 m, 4 with rest pain and 4
      with localised gangrene) PO2 foot/chest ratio was studied. The ratio was
      significantly increased after 6 days of PGE1 alpha-ciclodestrina treatment. The
      evaluation of PO2 with an exercise test on treadmill (including 6 claudicants, 4
      patients with rest pain and 5 normal controls) indicated a large decrease in PO2
      with exercise in limbs with critical ischemia; the PO2 decrease on effort was
      less visible in claudicants. Recovery time to pre-exercise values was also very
      long in subjects with critical ischemia. The exercise test may be useful to
      monitor the efficacy of PGE1 alpha-ciclodestrina treatment. However the test is
      not standardised and commonly used. CONCLUSIONS: In conclusion this study
      indicated that PO2 increases after PGE1 alpha-ciclodestrina treatment may last
      for at least 4 weeks and also that transcutaneous PO2 could be an effective
      method to follow up changes in perfusion. However tests based on PO2 measurements
      should be standardised to constitute a common evaluation method.

PMID- 10658444
TI  - [Circadian variations of cutaneous blood flow in normal subjects and in patients
      with peripheral arteriopathies. Effect of PGE1 and alpha-cyclodextrin].
AB  - BACKGROUND: In this study the circadian skin flux pattern was evaluated in 10
      normal reference subjects and in 35 patients (mean age 68 +/- 11) subdivided in
      groups (10 with intermittent claudication (200-400 m of walking distance), 10
      diabetics with claudication, 7 patients with rest pain and 8 with localised
      gangrene). METHODS: A laser Doppler flowmeter was used to monitor skin flux for
      24 hours. In patients with intermittent claudication the circadian pattern was
      comparable to normal subjects. In diabetics the daily curve showed several
      irregular peaks mostly dissociated from activity or rest. RESULTS: In patients
      with critical ischaemia severe alterations of the circadian pattern were observed
      (the daily curve was flattened and dissociated from activity or rest)
      particularly in gangrene. PGE1 alpha-ciclodestrina treatment (60 micrograms/day)
      partially restored the circadian pattern and increased the average values of the
      24-hour curve. In rest pain and gangrene the infusion of PGE1 alpha-ciclodestrina
      in the late evening increased the average night flux (which tended to fall to
      very low levels causing pain) and prevented or abolished night rest pain.

PMID- 10658445
TI  - [Reduction of cardiovascular morbidity/mortality in arteriopathies treated ith
      PGE1 alpha-cyclodextrin].
AB  - BACKGROUND: Cardiovascular morbidity and mortality were evaluated in two groups
      of vascular patients (one treated with PGE1 alpha-ciclodestrina according to the
      short term protocol and one reference group) with a follow up of at least 24
      month. METHODS: The former group included patients who had been treated with at
      least four PGE1 alpha-ciclodestrina, short-term treatment cycles per year while
      the latter was a historical reference group managed without prostaglandins. The
      two groups were comparable for sex and age distribution. RESULTS: In the PGE1
      alpha-ciclodestrina group 142 patients (mean age 64 +/- 17; M:F = 84:58) had been
      treated (47 for intermittent claudication and 95 for critical ischemia: 43 for
      rest pain, and 52 for localised gangrene). The historical reference group
      included 157 patients (mean age 65 +/- 18: M:F = 91:66); 53 with intermittent
      claudication and 104 with critical ischemia (49 rest pain, 55 gangrene). In
      claudicants yearly cardiovascular morbidity was reduced from the 15% observed in
      the reference group to 10% in patients treated with PGE1 alpha-ciclodestrina.
      Yearly mortality decreased from 11% in the reference group to 6% in the treated
      group. In rest pain patients morbidity decreased from 24% in the reference group
      to 19% in the treated group. Mortality also decreased (from 16% to 11%). In
      patients with gangrene the difference in morbidity between the reference group
      (35%) and the PGE1 alpha-ciclodestrina group (27%) was even more evident (P <
      0.025). In this group the mortality per year was reduced from 26% in the
      reference group to 17% in the PGE1 alpha-ciclodestrina treated group. CONCLUSION:
      It appears that cyclic treatment with PGE1 alpha-ciclodestrina produces not only
      an improvement in signs and symptoms related to vascular disease but also an
      important decrease in cardiovascular morbidity and mortality which has not been
      previously reported.

PMID- 10658446
TI  - [Cardiovascular morbidity/mortality modified by the use of FGE1 alpha
      cyclodextran and calcium heparin in patients with severe vascular diseases].
AB  - BACKGROUND: Morbidity and mortality were evaluated in three groups of vascular
      patients: one group was treated with PGE1 alpha-ciclodestrina according to the
      short term protocol; the second group was treated with PGE1 alpha-ciclodestrina
      and subcutaneous calcium heparin (SCH; 0.5 ml once daily, in the evening) while a
      third group was a historical reference group. METHODS: All included patients had
      a follow up of at least 12 months. The historical reference group had been
      managed without PGE1 alpha-ciclodestrina or SCH while in the two PGE1 alpha
      ciclodestrina groups included patients who had been treated with at least four
      PGE1 alpha-ciclodestrina short-term treatment cycles per year. The 3 groups were
      comparable for sex and age distribution. In the PGE1 alpha-ciclodestrina group
      142 patients (64 +/- 17; M:F = 84:58) had been treated (47 for intermittent
      claudication and 95 for critical ischemia). The historical reference group
      included 157 patients (65 +/- 18: M:F = 91:66); 53 with intermittent claudication
      and 104 with critical ischemia). The group treated with PGE1 alpha-ciclodestrina
      and SCH included 74 patients (27 with claudication and 47 with critical
      ischemia). RESULTS: In claudicants yearly cardiovascular morbidity was reduced
      from 15.5% in the reference group to 10.2% in patients treated with PGE1 alpha
      ciclodestrina and to 7.9% in those treated with PGE1 alpha-ciclodestrina and SCH.
      Mortality decreased from 11.3% in the reference group to 6% in the PGE1 alpha
      ciclodestrina group and to 5.1% in the PGE1 alpha-ciclodestrina + SCH group. In
      patients with critical limb ischemia morbidity decreased from 28.6% in the
      reference group to 23.2% in PGE1 alpha-ciclodestrina-group and to 19.4% in the
      PGE1 alpha-ciclodestrina + SCH group. Mortality also decreased from 16%
      (reference group) to 13% in the PGE1 alpha-ciclodestrinagroup, to 10.3% in the
      PGE1 alpha-ciclodestrina + SCH group. CONCLUSION: Cyclic treatment with PGE1
      alpha-ciclodestrina produces an important decrease in cardiovascular morbidity
      and mortality which could be further reduced by the chronic use of subcutaneous
      calcium heparin.

PMID- 10658447
TI  - [Intramuscular injections of PGE1 in patients with severe claudication].
AB  - BACKGROUND: In this pilot study we selected 12 patients with short range
      claudication and treated, after informed consent, 6 patients (mean age 63 +/- 5;
      range 55-65) with severe claudication (walking distance < 100 m). Selection
      criteria were patent common and deep femoral artery, occluded superficial femoral
      artery with patent popliteal artery, with posterior tibial Doppler pressure > 50
      mmHg and anterior tibial > 40 mmHg. METHODS: Patients were evaluated with a
      treadmill test performed to their walking limit. PGE1 was used by intramuscular
      injections (for a total of 80 micrograms, divided in 4 injections). The
      injections were about 2 cm deep in the posterior calf muscles. An exercise
      program was associated. Patients were required to walk 20 minutes just after the
      injections and to follow an exercise program (walking slowly at least 30 minutes,
      3 times daily, in the following 4 weeks). RESULTS: Both the PGE1 group and a
      comparable control group (12 patients mean age 62 +/- 4; range 56-65) were
      treated with ASA and pentoxyfillin (400 mg t.i.d.). In the PGE1 group the average
      total walking distance at inclusion was 25 +/- 16 (range 0-52); it increased to
      113 +/- 55 (range 50-289) (after 1 week) and to 117 +/- 27 (range 30-1020) at 4
      weeks. No important changes were observed in the control group (54 +/- 6 m at
      inclusion, 58 +/- 8 after one week and 63 +/- 7 after 4 weeks). There were no
      important side effects. One patient experienced important injection pain which
      disappeared in a few hours. No significant changes in tibial pressures were
      observed. CONCLUSIONS: Intramuscular injection of PGE1 may be an interesting
      treatment option in patients with severe intermittent claudication but these
      preliminary findings should be verified in larger randomised studies.

PMID- 10658448
TI  - [Global analysis of data from studies with PDE1 alpha-cyslodextrin].
AB  - BACKGROUND: A group of patients with severe peripheral vascular disease has been
      treated with PGE1 alpha-ciclodestrina (as reported in the previous 9 articles)
      including 595 patients (mean age 64.52 +/- 12; 307 with intermittent claudication
      and 237 with critical limb ischemia, rest pain and gangrene). Also 51 diabetics
      were studied and treated (25% with claudication and the remaining group with
      critical ischemia and/or neuropathy). The mean dosage administered in most
      patients (83% were treated with the short-term protocol) had been 20 + 40
      micrograms on the first day and 60 + 40 micrograms on the second day. METHODS:
      Subjects had been treated on average 2.6 times (cycles of short term treatment);
      37% of patients had received at least 3 cycles of short term treatment.
      Clinically relevant side effects have been observed in 30 patients (5% of the 595
      treated patients). Temporary suspension of treatment has reduced/abolished side
      effects in 18 out of 30 patients and only in 5 patients (0.8%) therapy had to be
      suspended. Clinical improvement was evaluated according to subjective
      improvement, objective improvement (as defined by the treating physician/surgeon)
      and one or more physiological parameters (flux, flow, treadmill test). Among
      patients with intermittent claudication (only considered endpoint was walking
      distance) 78% was significantly improved. In patients with critical ischemia
      (endpoints were pain control, decrease of ischemic areas and perfusion
      improvement, objectively measured) 66% of patients improved. In diabetics
      (including both claudicants and subjects with critical ischemia) 58% improved.
      CONCLUSIONS: Global analysis of the previous 9 studies indicates that PGE1 alpha
      ciclodestrina treatment is effective, there are few and controllable (in most
      patients) side effects and the treatment (particularly the short term protocol)
      is very cost effective.

PMID- 10658449
TI  - Image-guided epilepsy surgery.
AB  - Interactive image-guided techniques used in conjunction with three-dimensional
      images allow accurate planning and performance of a variety of neurosurgical
      procedures. The frameless stereotactic Viewing Wand System was used to provide
      real-time correlation of the operating field and computerized images in over 22
      neurosurgical operations carried out for intractable epilepsy. The overall
      results of the surgery demonstrated favorable results, with class 1 + class 2
      outcomes in 86.4% of the present series. Our experience shows that the Viewing
      Wand System is most helpful as an adjunctive navigational device in the
      microsurgical treatment of epilepsy.

PMID- 10658450
TI  - Permissible arterial occlusion time in aneurysm surgery: postoperative
      hyperperfusion caused by temporary clipping.
AB  - The relationship between hyperperfusion and temporary clipping was evaluated to
      determine the safe limit for the duration of temporary clipping in aneurysm
      surgery. Twenty-one patients surgically treated for a ruptured aneurysm were
      examined using xenon-enhanced computed tomography on postoperative days 4 to 13.
      Eight of the 16 patients undergoing temporary clipping had focal hyperperfusion;
      whereas the five patients without temporary clipping had no hyperperfusion. Mean
      total temporary clipping time in patients with hyperperfusion was significantly
      longer than that in patients without (31.9 vs. 13.9 minutes, p = 0.0157) and mean
      maximum single temporary clipping time in patients with hyperperfusion was also
      significantly longer than in patients without (18.4 vs. 8.6 minutes, p = 0.0313).
      Moreover, cerebral infarction was related to hyperperfusion (p = 0.0027). These
      results support the hypothesis that temporary clipping during aneurysm surgery
      causes postoperative hyperperfusion and cerebral infarction. Temporary clipping
      may be harmful when performed for more than 20 minutes of total duration, since
      postoperative hyperperfusion was seen under this condition.

PMID- 10658451
TI  - Histological changes in the rat common carotid artery following simultaneous
      topical application of cotton sheet and cyanoacrylate glue.
AB  - Histological changes in and around the arterial walls of rats were investigated
      following simultaneous topical application of cotton sheet and cyanoacrylate
      glue. The bilateral common carotid arteries were exposed using sterile
      techniques, and the test materials were applied to the right artery. The left
      artery served as a control. Changes in arterial histology were evaluated at 2
      weeks, 1 month, 2 months, and 3 months after surgery. Extensive inflammation
      consisting primarily of histiocytes and multinuclear giant cells was observed
      around the materials, but tended to decrease by 3 months. Necrosis in the media
      and fibrosis in the adventitia initially appeared around 2 weeks, and became
      advanced by 2-3 months. At 2-3 months, disruption of elastic fibers and marked
      fibrosis in the media were seen, and endothelial proliferation in the intima
      appeared. Intimal proliferation was observed at both the experimental and other
      sites of the vessels. The present results suggest that simultaneous use of the
      test materials can cause the arterial occlusive lesions observed following
      aneurysmal surgery.

PMID- 10658452
TI  - Diffusion-weighted echo planar imaging of acute brain infarction: a preliminary
      report.
AB  - The clinical usefulness of diffusion-weighted echo planar imaging (DW-EPI) was
      studied in 55 patients with acute brain ischemia. Ischemic lesions were
      identified on DW-EPI as hyperintense regions in all patients before changes were
      detected by conventional magnetic resonance imaging techniques in 12 cases
      studied earlier than 6 hours after onset. The earliest case was verified on DW
      EPI at 50 minutes after onset. The ultra-fast imaging technique took less than 2
      minutes to perform even for restless patients. Three patients had cardioembolic
      middle cerebral artery occlusion, and emergent percutaneous transluminal
      recanalization was carried out. Chronological changes in the signal of brain
      ischemia on DW-EPI depended on the site and size of the lesion, lacunar infarct
      of basal ganglia, and/or massive infarct due to major vessel occlusion, and were
      affected by associated hemorrhagic events. Coronal DW-EPI could more easily
      demarcate ischemia in the brainstem and/or cerebellum than axial scans when
      susceptibility artifacts were present. Coronal scans also demonstrated the site
      and direction of the pyramidal tract and its anatomical correlation with the
      lesions. DW-EPI has potential for the diagnostic and therapeutic planning of
      patients with acute brain ischemia.

PMID- 10658453
TI  - Morphometric comparison of the human optic nerve fiber with various other human
      nerve fibers.
AB  - The morphometric characteristics of nerve fibers of the human optic nerve in the
      chiasmatic region were measured with the combination of an image analyzer and a
      computer, using the Luxol fast blue-periodic acid-Schiff-hematoxylin
      discriminative staining method. The mean axonal transverse area of the human
      optic nerve fibers was 0.644 +/- 0.361 micron 2. Comparison of the size of the
      axon of the human optic nerve fiber with that of various other human nerves
      showed optic nerve fibers were definitely thinner than the other nerve fibers,
      and were surrounded by a thinner myelin sheath. Optic nerves may be more liable
      to mechanical damage at surgery that previously believed.

PMID- 10658454
TI  - Dural sinus thrombosis in a patient with protein S deficiency--case report.
AB  - A 23-year-old female presented with dural sinus thrombosis caused by protein S
      deficiency. She suffered superior sagittal sinus thrombosis 6 days after
      delivering her first child. Past history showed deep vein thrombosis at the age
      of 20. While conservative management was initiated because of the potential risk
      of increasing intracranial hemorrhage, several hours later she deteriorated
      rapidly because of severe brain swelling with massive hemorrhage. The patient
      died despite surgical decompression. Autopsy disclosed organized thrombus in the
      superior sagittal and transverse sinuses. Although the total concentration of
      protein S was normal, the free protein S concentration and protein S activity
      were decreased. Protein S deficiency is a rare cause of dural sinus thrombosis,
      but is associated with a high mortality rate, so accurate diagnosis and urgent
      intervention are required.

PMID- 10658455
TI  - Dual origin of the vertebral artery--case report.
AB  - A 27-year-old female presented with dual origin of the left vertebral artery.
      Twenty-six cases of this rare congenital vascular anomaly have been reported. In
      general, the medial leg of the dual origin of the vertebral artery enters a
      higher transverse foramen (usually the fifth or less frequently the fourth) than
      the lateral leg, which usually enters the sixth. Exceptions to this rule occur
      when the medial and lateral legs of the right vertebral artery enter the right
      seventh and sixth transverse foramina, respectively. This congenital vascular
      anomaly has diagnostic and therapeutic implications in any intervention involving
      the proximal vertebral artery.

PMID- 10658456
TI  - Magnetic resonance imaging artifact following acoustic neurofibroma surgery--case
      report.
AB  - Metallic artifacts in magnetic resonance (MR) imaging occur mostly in patients
      who have received an implant at surgery. Similar artifacts are now increasingly
      recognized in patients in whom high-speed drills have been used. A 15-year-old
      male with neurofibromatosis 2 had undergone excision of acoustic neurofibroma on
      the left 1.5 years prior to the present admission. MR imaging to evaluate the
      acoustic neurofibroma on the right showed a metallic artifact at the site of the
      previous surgery. Computed tomography did not show any evidence of metal debris.
      The artifact was probably caused by metallic dust or debris from a high-speed
      drill during the first surgery. We suggest that care should be taken to prevent
      deposition of such debris in the operative field to prevent this complication.

PMID- 10658457
TI  - Surgical management of symptomatic intrasellar arachnoid cysts--two case reports.
AB  - Two patients with symptomatic intrasellar arachnoid cyst were successfully
      treated. A 67-year-old female with a cyst 20 mm in diameter developed headache
      and visual disturbance. She was treated by transsphenoidal surgery. A 59-year-old
      male with a cyst measuring 35 x 30 x 50 mm causing headache, visual disturbance,
      and deterioration of consciousness was managed by wide resection of the cyst wall
      via craniotomy. Postoperative courses in both patients were uneventful.
      Transsphenoidal surgery may be suitable for small to medium-sized cysts, although
      tight packing of the sella is mandatory to prevent leakage of cerebrospinal
      fluid. However, craniotomy is recommended for large intra- and suprasellar
      arachnoid cysts to avoid this complication, and to achieve sufficient
      communication between the cyst and the subarachnoid cistern.

PMID- 10658458
TI  - Skull metastasis of Ewing's sarcoma--three case reports.
AB  - Three cases of skull metastasis of Ewing's sarcoma were treated. The metastatic
      lesion was located at the midline of the skull above the superior sagittal sinus
      in all cases. Surgery was performed in two patients with solitary skull lesions
      involving short segments of the superior sagittal sinus without remarkable
      systemic metastasis, resulting in good outcome. The third patient had extensive,
      multiple tumors involving the superior sagittal sinus which could not be excised,
      and died due to intracranial hypertension. The surgical indication for skull
      metastasis of Ewing's sarcoma depends on the location and length of the involved
      superior sagittal sinus, and general condition.

PMID- 10658459
TI  - Endoscopic aqueductal plasty via the fourth ventricle through the cerebellar
      hemisphere under navigating system guidance--technical note.
AB  - A 1-year 8-month-old boy presented with isolated fourth ventricle after
      ventriculoperitoneal shunting for hydrocephalus associated with ventricular and
      subarachnoid hemorrhage. The therapeutic endoscope was inserted through the thin
      left cerebellar hemisphere. Endoscopic aqueductal plasty was performed via the
      enlarged fourth ventricle under guidance from a navigating system. Endoscopic
      aqueductal plasty via the fourth ventricle under navigating system guidance is a
      useful procedure enabling less invasive surgery for isolated fourth ventricle
      associated with slit-like ventricle after shunt placement.

PMID- 10658460
TI  - [Electromyographic study of the striated urethral sphincter by using the
      bulbocavernosus reflex: study of the normal voluntary voiding and the involuntary
      sphincter relaxation].
AB  - PURPOSE: The aim of this study was to investigate the sacral reflex activity at
      the striated urethral sphincter relaxation by evoking the potential of the
      bulbocavernosus reflex (BCR). METHODS: 17 normal male subjects were investigated.
      BCR was elicited by electrical stimulation of dorsal nerve of the penis, and the
      evoked potential of the BCR (BCR-EP) was recorded by a concentric needle
      electrode at the periurethral striated muscle. In normal subjects BCR was
      performed at rest and during voluntary voiding. In 8 of the normal subjects
      electrical stimulation was increased gradually during voluntary voiding, and
      changes of BCR-EP were studied. 3 male patients with neurogenic bladder suffering
      from urinary incontinence caused by involuntary sphincter relaxation (IVSR) were
      also investigated. In these patients with neurogenic bladder, BCR was performed
      at rest and during voluntary voiding as well as during involuntary voiding.
      RESULTS: In the normal subjects stable BCR-EP was elicited at rest and
      disappeared during voluntary voiding. But a gradually increased larger
      stimulation clearly demonstrated BCR-EP during voluntary voiding. In 3 patients
      with neurogenic bladder, stable ECR-EP was elicited at rest. During involuntary
      voiding caused by IVSR obvious BCR-EP was also elicited, but its amplitude was
      slightly less than the amplitude of BCR-EP at rest. During voluntary voiding in 2
      of the 3 patients BCR-EP was recognized but the amplitude was much less, and in
      the third patient BCR-EP could not be recognized. CONCLUSION: BCR-EP was
      suppressed during voluntary voiding in normal subjects, but insufficiently
      suppressed in the patients with neurogenic bladder. In these patients BCR-EP
      during voluntary voiding was suppressed more distinctly than BCR-EP during
      involuntary voiding due to IVSR. In urodynamic study, the detrusor contraction
      and the sphincter relaxation were common phenomenon in both voluntary voiding and
      involuntary voiding, but the difference in the degree of the BCR suppression
      depended on whether micturition was voluntary or involuntary. It was suggested
      that the measurement of BCR-EP could distinguish involuntary voiding caused by
      pathological urethral sphincter relaxation from voluntary voiding.

PMID- 10658461
TI  - [Intravesical bacillus Calmette-Guerin instillation therapy for carcinoma in situ
      of the urinary bladder and prediction of effects by urinary cytologic
      examination].
AB  - PURPOSE: We investigated the effects of intravesical BCG instillations for
      carcinoma in situ (CIS) of the urinary bladder. And we have retrospectively
      analyzed the prediction of effects by fresh urinary cytologic examinations before
      instillation. MATERIAL AND METHODS: 33 patients were treated for bladder CIS
      (1991-1997) with a median follow-up of 30 months (range from 9 to 90 months). The
      patients (27 males and 6 females) ranged in age from 46 to 91 (average 71 years)
      and received 6 to 12 weekly BCG Tokyo 172 strain 80 mg instillations. They were
      divided into 3 groups based on tumor history: primary (9), secondary (15),
      concurrent (9). The prediction of effects were analyzed by scoring fresh urinary
      cytologic examinations before instillation. RESULTS: 22 cases (67%) were
      responded and they have remained free of disease for follow-up period. The
      statistic evaluation proved to show the significance between the effects of
      treatment and the sum of scoring (cellular appearance and existence of large
      nuclear cells). CONCLUSION: We confirmed the effects of this treatment. The
      prediction of effect of this treatment seemed to be indicative by fresh urinary
      cytologic examinations before instillation, especially cellular appearance and
      existence of large nuclear cells.

PMID- 10658462
TI  - [Laparoscopic radical nephrectomy for renal cell carcinoma--transperitoneal
      anterior approach].
AB  - PURPOSE: To evaluate the usefulness of transperitoneal anterior approach in
      laparoscopic radical nephrectomy for patients with renal cell carcinoma.
      MATERIAL: Ten patients (Eight males and two females) with small renal cell
      carcinoma less than 7 cm in diameter were treated with laparoscopic radical
      nephrectomy between June 1997 and May 1999. Clinical stage was T1aN0M0 in 6 cases
      and T1bN0M0 in 4 cases. METHOD: Of the 10 patients, the initial four received
      preoperative embolization of the renal artery. Under general anesthesia
      laparoscopic radical nephrectomy via transperitoneal anterior approach was
      performed in all patients. This procedure facilitates initiated early access to
      the renal vessels as does open radical nephrectomy. The kidney was dissected en
      bloc with Gerota's fascia and delivered from the small skin incision without
      morcellation. RESULT: Two patients needed conversion to open surgery. The mean
      operating time of eight patients except for conversion cases was 247 minutes and
      the mean blood loss was 258 ml. There was no major complication associated with
      laparoscopic procedure. CONCLUSION: Transperitoneal anterior approach in
      laparoscopic radical nephrectomy is a suitable and useful procedure for the
      treatment of small renal cell carcinoma because it enables us to avoid possible
      tumor manipulation by early access to the renal vessels as open radical
      nephrectomy.

PMID- 10658463
TI  - [Effect of aging and diseases on male sexual function assessed by the
      International Index of Erectile Function].
AB  - PURPOSE: Many epidemiological factors contribute to erectile dysfunction (ED).
      The objective of the present research was to investigate the risk factors of ED
      and the influence of aging on male sexual function, to obtain some insight into
      prevention of ED. METHODS: The study sample consisted of employees, aged from 22
      to 59 years old of ten companies in Japan, who responded to the International
      Index of Erectile Function (IIEF) questionnaire and a survey of health status and
      related variables. The IIEF sexual activity questionnaire includes 15 items
      related to male sexual activity organized into five domains (that is erectile
      function, orgasmic function, sexual desire, intercourse satisfaction, overall
      satisfaction) to which 967 of the 1,020 subjects (94.8%) provided complete
      responses. These 967 men constitute the present study sample. For statistical
      analysis, ANOVA with Scheffe's (post hoc) test was conducted, and statistical
      significance was set at p < 0.05. RESULTS: Presence of hypertension, heart
      disease, diabetes and hyperlipidemia was associated with a significantly
      decreased score for erectile function in subjects in their fifties (p < 0.05),
      however, it was not significant in the other age groups. In subjects, who were
      free from risk factors for sexual function, there was significant correlation
      between age and the scores for erectile function, orgasmic function, sexual
      desire and intercourse satisfaction. CONCLUSIONS: Aging and chronic disorders
      that have been considered to be putative risk factors for ED, therefore affect
      male sexual function in the elderly. The IIEF was suggested to be suited for use
      in studies assessing epidemiology of ED.

PMID- 10658465
TI  - [Endoscopic ureteroureterostomy for a complete obstructed ureter: a case report].
AB  - We report a case in which the completely obstructed ureter was successfully
      treated by endourological procedure. The patient was a 66-year-old male who had
      been admitted for panperitonitis caused by diverticulitis perforation of the
      sigmoid colon. About one month later, leakage of both stool and urine and left
      hydronephrosis were observed. Therefore, left percutaneous nephrostomy was
      performed and the artificial anus was created. Radiographic examination showed
      about 1 cm defect on the lower one-third of the left ureter. (1st Operation) A
      9.5 Fr. rigid ureteroscope was inserted into the left ureter transurethrally and
      a 7.5 Fr. flexible ureteroscope was inserted percutaneously. Antegrade puncture
      using a stiff end of a 0.038-inch guidewire into the obstructed segment was
      failed. Then, we bit off the obliterated tissue with a biopsy forceps
      transurethrally towards the light from the flexible scope, and a 12 Fr. double-J
      stent was indwell. (2nd Operation) Eight weeks after the first operation, a 12
      Fr. ureteroresectoscope was inserted transurethrally. Full-thickness cold-knife
      incision of the re-established ureter was failed, however. (3rd Operation) Two
      weeks after the second operation, a 12.5 Fr. ureteroscope was inserted
      transurethrally, and a full-thickness incision in the lateral position of the re
      established ureter was successfully made by KTP-laser. Then, a 12 Fr.
      endopyelotomy stent was placed. (Result) Six weeks after the third operation, the
      stent was removed and DIP revealed the improvement in hydronephrosis. The patient
      presented no recurrence at 2-year follow up.

PMID- 10658464
TI  - [A case of crossed fused kidney with simple ureterocele].
AB  - A 32-year-old man consulted Osaka National hospital with chief complaints of
      dysuria and macrohematuria. DIP and CT revealed that the right kidney deviated to
      the lower pole of the left kidney and they fused together. The right ureter
      crossed over the supine. The calcified shadow existed in the lower end of the
      left ureter with cobra head image. He had no external anomalies. Under diagnosing
      crossed fused kidney (inverted L shaped) complicated the left ureterocele with a
      stone, transurethral incision of ureterocele (TUI) was performed. We made
      transverse incision and extracted stone, 7 mm in size (calcium oxalate 96% and
      calcium phosphate 4%). Three months later after the operation, IVP, CG and VCG
      revealed the down-sized ureterocele and no VUR. Crossed renal ectopia complicated
      many anomalies about 50%. Among them anomalies of the urinary tract was most
      frequent about 30%. But crossed renal ectopia with ureterocele wasn't reported so
      far in Japanese literature.

PMID- 10658466
TI  - [A case of acquired hemophilia A discovered by right renal bleeding].
AB  - An 81-year-old man was referred to our hospital with a chief complaint of
      asymptomatic macrohematuria. Cystoscopy revealed bleeding from the right ureteral
      orifice. Various examinations, including ureteroscopy, failed to find any
      abnormalities. As gingival bleeding followed the macrochematuria, further
      examinations of blood coagulatory function were undertaken. Decreased factor VIII
      coagulant activity accompanied by the presence of factor VIII inhibitor was
      revealed, leading to a final diagnosis of acquired hemophilia A. Macrohematuria
      and gingival bleeding immediately disappeared with oral administration of
      prednisolone at 30 mg per day, and the titer of factor VIII inhibitor decreased
      to an undetectable level by the 45th day of treatment. We emphasized the
      importance of blood coagulation testing in the examination of patients with
      macrohematuria.

PMID- 10658467
TI  - [Birth cohort analysis of obesity in an occupational setting].
AB  - PURPOSE: The purpose of this study was to analyze the transition of body mass
      index (BMI) by birth cohort and to determine the relationship between BMI and
      high blood pressure, for the health management of workers in an industry.
      SUBJECTS AND METHODS: The eligible study subjects were 3,043 male workers at
      printing and papermaking plants who were 20 to 49 years of age in 1986 and whose
      annual health checkup information was available for both 1991 and 1996. First, we
      analyzed the transition of BMI by 5-year birth cohort. Second, we analyzed the
      relationship between BMI and high blood pressure (systolic blood pressure > = 140
      mmHg or diastolic blood pressure > = 90 mmHg) using multiple logistic regression
      models. In this analysis, we excluded 596 subjects who were diagnosed as having
      high blood pressure in 1986 and 17 subjects whose alcohol drinking habits were
      unknown. Consequently, we had 2,430 study subjects. RESULTS: (1) All the birth
      cohorts showed that the proportion of obese subjects (BMI > = 26.4) became higher
      as age advanced. The proportion was higher for younger cohort. (2) By multiple
      logistic regression models, age at the beginning of the study, BMI, change of BMI
      in 5 or 10 years, and alcohol drinking habits were related to the risk of having
      high blood pressure. CONCLUSION: In the health management of workers, it is
      necessary to evaluate the risk by birth cohort. Also, we consider that we need to
      initiate obesity counseling before the workers become 30 years of age.

PMID- 10658469
TI  - [Analysis of items missing in responses to a series of follow-up surveys in
      Japanese elderly].
AB  - PURPOSES: We examined whether the percentage of items missing and the factors
      related to item missing differ across follow-up surveys, Variables targeted to
      examine missing items included health indicators (activities of daily living,
      cognitive function, self-rated health, Center for Epidemiologic Studies-
      Depression, and PGC Morale Scale), health habits (cigarette smoking, alcohol
      consumption, physical exercise, and relative weight), and socioeconomic
      indicators (educational attainment, income, and social networks). METHODS:
      Longitudinal data were collected at intervals of three years since 1987 through a
      national survey of Japanese adults aged 60 and over, At the baseline survey, a
      total of 2,200 interviews were completed from the list of 3,288 names. At the
      following three follow-up surveys, 1,671, 1,369, and 1,068 persons were
      reinterviewed respectively. Possible factors related to appearance of a missing
      item consisted of five aspects; 1) demographic variables (age and sex), 2) social
      status (educational attainment, existence of a spouse, and job status), 3) health
      status (activities of daily living and cognitive function), 4) cooperative
      attitude toward a survey, and 5) whether an item had been missing at the previous
      survey (s). Those factors were analyzed for each variable respectively. If a
      group with scaled or collective items had one or more missing items, we
      classified that group as a missing item group. RESULTS: 1. The percentage of
      cases with items missing was 5 percent or more for four variables; CES-D, PGC
      Morale Scale, income, and health habits. Those percentages were almost constant
      over the four surveys. 2. Factors related to appearance of items missing differed
      by psychological variables such as, CES-D and PGC Morale Scale, income, or health
      habits. Those factors had constant impact on appearance of items missing over
      follow-up surveys. 3. Regarding CES-D, PGC Morale Scale, income, or health
      habits, persons with an item missing at a previous survey, or who did not have a
      cooperative attitude toward the survey had a significant impact on an increase in
      the percentage of missing items. CONCLUSION: Characteristics of persons with
      items missing differs among the variables, and those characteristics may
      contribute to the incidence of items missing in subsequent surveys.

PMID- 10658468
TI  - [Characteristics of each activity domain comprising ADL for partially dependent
      older adults].
AB  - The purpose of this study was to examine the characteristics of each activity
      domain which make up activities of daily living (ADL). We used the ADL index with
      a unidimensional scale for partially dependent older adults, and examined the
      distribution of the ADL score and self-evaluation of health and physical fitness.
      There were 466 subjects from age 60 to 98 (132 male, 81.7 +/- 8.22 years; 334
      female, 82.5 +/- 7.25 years). Seventeen items representing 7 domains (holding and
      changing the posture of the body, dressing, toilet usage, bathing, manual
      activity, walking, and locomotion and carrying) were selected as ADL items. Each
      item was measured on a dichotomous scale. A questionnaire consisting of 17 ADL
      items and two questions concerning self-evaluation of health and physical fitness
      were administered on subjects by institutional therapists (OT, PT, nurse, social
      worker). An examination of the cumulative relative frequency distribution curve
      of total score showed that ADL scores of all domains can be used to assess ADL
      achievement ability level with a wide range from low to high level. It is
      inferred that the total score will be low when the score is low for holding and
      changing body-posture, toilet usage and manual activity. On the other hand, it
      will be high when the score is high for dressing and walking. ADL abilities for
      all domains also tended to be higher in persons with higher perceptual levels of
      health and physical fitness.

PMID- 10658470
TI  - [Distributions of the numbers of monitoring stations in the surveillance of
      infectious diseases in Japan].
AB  - To describe the characteristics of monitoring stations for the infectious disease
      surveillance system in Japan, we compared the distributions of the number of
      monitoring stations in terms of population, region, size of medical institution,
      and medical specialty. The distributions of annual number of reported cases in
      terms of the type of diseases, the size of medical institution, and medical
      specialty were also compared. We conducted a nationwide survey of the pediatrics
      stations (16 diseases), ophthalmology stations (3 diseases) and the stations of
      sexually transmitted diseases (STD) (5 diseases) in Japan. In the survey, we
      collected the data of monitoring stations and the annual reported cases of
      diseases. We also collected the data on the population, served by the health
      center where the monitoring stations existed, from the census. First, we compared
      the difference between the present number of monitoring stations and the current
      standard established by the Ministry of Health and Welfare (MHW). Second, we
      compared the distribution of all medical institutions in Japan and the monitoring
      stations in terms of the size of the medical institution. Third, we compared the
      average number of annual reported cases of diseases in terms of the size of
      medical institution and the medical specialty. In most health centers, the number
      of monitoring stations achieved the current standard of MHW, while a few health
      centers had no monitoring station, although they had a large population. Most
      prefectures also achieved the current standard of MHW, but some prefectures were
      well below the standard. Among pediatric stations, the sampling proportion of
      large hospitals was higher than other categories. Among the ophthalmology
      stations, the sampling proportion of hospitals was higher than other categories.
      Among the STD stations, the sampling proportion of clinics of obstetrics and
      gynecology was lower than other categories. Except for some diseases, it made
      little difference in the average number of annual reported cases of diseases in
      terms of the type of medical institution. Among STD, there was a great difference
      in the average number of annual reported cases of diseases in terms of medical
      specialty.

PMID- 10658471
TI  - [Determination of the numbers of monitoring medical institutions necessary for
      estimating incidence rates in the surveillance of infectious diseases in Japan].
AB  - Our purpose was to determine the number of monitoring stations (medical
      institutions) necessary for estimating incidence rates in the surveillance system
      of infectious diseases in Japan. Infectious diseases were selected by the type of
      monitoring stations: 15 diseases in pediatrics stations, influenza in influenza
      stations, 3 diseases in ophthalmology stations and 5 diseases in the stations of
      sexually transmitted diseases (STD). For each type of monitoring station, 5 cases
      of the number of monitoring stations in each health center, including the number
      determined from presently established standards and the actual number in 1997,
      were given. It was assumed that monitoring stations were randomly selected among
      medical institutions in health centers. For each infectious disease, each case
      and each type of monitoring station, standard error rates of estimated numbers of
      incidence cases in the whole country were calculated in 1993-1997 using the data
      of the surveillance of infectious diseases. Among 5 cases of monitoring stations,
      the case satisfied the condition that those standard error rates were lower than
      the critical values, was selected. The critical values were 5% in pediatrics and
      influenza stations, and 10% in ophthalmology and STD stations. The numbers of
      monitoring stations in the selected cases were 3,000 in pediatrics stations,
      5,000 in influenza stations (including all pediatrics stations), 605 in
      ophthalmology stations and 900 in STD stations.

PMID- 10658472
TI  - [Effectiveness of portable toothbrush use on reducing cigarette consumption and
      improving oral health].
AB  - There have been many studies on the influence of smoking on health, and in recent
      years, there have also been studies examining the relationship between smoking
      and oral health, concluding that smoking has a considerable detrimental effect on
      oral health. We introduced in a number of companies the idea of "Non smoking
      through the use of a portable toothbrush" as a means of giving up smoking while
      at the same time promoting oral health. The results demonstrated that consumption
      of cigarettes was reduced in about 50 percent of cases, while some improvement in
      mouth freshness was seen in about 90 percent. The study also showed that the
      success rate in reducing cigarette consumption through the use of a portable
      toothbrush was higher in highly motivated subjects, leading us to conclude that
      motivation is a major factor in reducing cigarette consumption. The study
      impressed on us the importance of educating people on the effect of smoking on
      oral health and the possibility of using a portable toothbrush as a means of
      reducing smoking.

PMID- 10658473
TI  - [Incidence proportion estimation, prevalence and effective visiting nurse care of
      pressure ulcers].
AB  - PURPOSE: The purpose of this study are as follows: 1. To determine incidence
      proportion estimations and prevalence of pressure ulcers in home care settings.
      2. To clarify the effective nursing care for prevention and treatments of
      pressure ulcers at visiting nursing service stations. 3. To show whether
      demographic characteristics are factors in pressure ulcer development. METHODS:
      This research is a part of the series of studies on prevalence of pressure ulcers
      in 934 visiting nursing service stations on October 1995 in Japan. This was
      followed in November 1, 1996 to October 31, 1997, by another investigation for
      incidence proportion estimation and prevalence of pressure ulcers and their
      relationship to nursing care facilities, in which questionnaires were mailed to
      620 facilities that participated in the first research. Responses from 294
      (47.4%) facilities and 1,208 subjects were received. We analyzed the responses
      from 215 facilities (73.1%) and 864 subjects to the two types of questionnaires.
      RESULTS: Prevalence of pressure ulcers was found to be 8.0% (95% CI: 7.5-8.6) on
      July 1, 1997 and incidence proportion estimation was 3.7% (95% CI: 3.3-4.1) from
      November 1, 1996 to October 31, 1997 for the 10,750 clients in 215 facilities.
      The number of prescriptions for turning of client sleep position (p = 0.044), and
      having a standard care assessment procedure (p = 0.015) were significantly higher
      for no-present pressure ulcer than in facilities with under 5% having present
      pressure ulcers and facilities with over 5% having present pressure ulcers.
      Subtracting the prevalence point in 1997 from 1995, the utilization of a primary
      nursing care plan (p = 0.021), and the number of part-time nurses (p = 0.008)
      were significantly higher in the groups that had a decrease or no-change compared
      to the increased groups. 45.6% of the ulcers identified were situated on the
      sacrum/buttocks and 39.4% of the ulcers were grade 2. The mean total score on the
      Braden Scale was 12.7. A score of 18 may be considered as the cut-off point in
      home care settings. DISCUSSION: Prevalence of pressure ulcers was found to be
      8.0% and incidence proportion estimation was 3.7%. The present findings
      concerning incidence proportion estimation and prevalence of pressure ulcers and
      the practice of nursing care in visiting nursing service stations suggests
      possibility for improving outcomes for clients with pressure ulcers and for those
      at risk factors of developing them.

PMID- 10658474
TI  - [Midterm achievement and problems of all municipal health and welfare plans for
      the elderly in Yamagata Prefecture].
AB  - PURPOSE: This study was made for providing information in the preparation of
      Social Welfare Systems in municipalities. METHODS: Based on seven official
      reports by Yamagata Prefecture, quantitative data on health and welfare services
      were analyzed. We investigated the midterm achievement and problems of a
      Municipal Health and Welfare Plan for the Elderly in all 44 municipalities by
      mail survey (response rate 100%). The questionnaire included the progress
      situation of the plan, the existence of an assessment organization, and the
      characteristics of the plan. RESULTS: Both health service and welfare service
      achieved targets level to a degree. Concerning the progress situation, "The
      midterm achievement is not satisfactory" for 65.9% (29 municipalities). The main
      reasons were "budgets" (93.1%, 27 municipalities) and "lack of manpower" (75.9%,
      22 municipalities) all of which indicates "lack of home helpers". 58.6% of all 44
      municipalities were reconsidering the plan. In assessment organization existed in
      31.8% (14 municipalities) of all municipalities. CONCLUSION: It is necessary that
      analysis should consider not only use of quantitative data but also qualitative
      one. The major problems found are that community characteristics were not
      reflected and the opinion of inhabitants were not considered.

PMID- 10658475
TI  - [Red cell membrane disorders: historical perspectives from dawn to enlightenment
      (II)].

PMID- 10658476
TI  - [Phase II clinical study of SH L 573 (fludarabine phosphate) in patients with
      chronic lymphocytic leukemia].
AB  - We conducted a multicenter phase II clinical study of fludarabine phosphate, a
      new purine nucleotide analogue, in patients with chronic lymphocytic leukemia
      (CLL). Fludarabine phosphate was administered at a dose of 20 mg/m2/day
      intravenously for 5 days every 4 weeks as one course. Six courses as a maximum
      were repeated. The response rate was 38.5% (95% confidence intervals: 20.2% to
      59.4%), with 1 complete remission and 9 partial remissions out of 26 treated
      patients. Major drug-related adverse reactions were fever, nausea, weakness, and
      paresthesia of the fingers; as a grade-3 reaction, varicella was also reported.
      Neutropenia and thrombocytopenia were observed as manifestations of hematologic
      toxicity. Clinical laboratory test results revealed abnormalities in hepatic
      function, including increased GPT, but none of these was rated grade 3 or 4.

PMID- 10658477
TI  - [Pulmonary function after allogeneic hematopoietic stem cell transplantation].
AB  - This study was undertaken to identify the factors influencing pulmonary function
      in patients who underwent hematopoietic stem cell transplantation (HCT).
      Pulmonary function tests were evaluated before and after HCT in 51 adult patients
      who underwent HCT between 1993 and 1998. The patients with hematologic
      malignancies were given total body irradiation. Graft-versus-host disease (GVHD)
      prophylaxis consisted of cyclosporine A and short-term methotrexate. Six patients
      suffered from acute GVHD above grade II and 27 patients suffered from chronic
      GVHD. The post-transplant % diffusing capacity (%DLco) 100 days after HCT was
      significantly lower than pretransplant values (82 +/- 21% versus 71 +/- 15%, p <
      0.01). The %DLco at 100 days was significantly lower in patients with chronic
      GVHD than in patients without chronic GVHD (66 +/- 16% versus 77 +/- 9%, p <
      0.05). These findings suggested chronic GVHD is related to the decreased %DLco
      values observed 100 days after HCT.

PMID- 10658478
TI  - [CD30-positive anaplastic large cell lymphoma of bone treated with autologous
      peripheral blood stem cell transplantation].
AB  - A 30-year-old man was admitted to our hospital with the chief complaints of fever
      and pain in the right shoulder, axilla, and inguinocrural region. Computed
      tomography, magnetic resonance imaging, 67Ga-scintigraphy, and bone-scintigraphy
      revealed osteolytic lesions in the ribs and right ilium. Biopsy specimens from
      lesions in the right ilium confirmed the diagnosis of CD 30-positive anaplastic
      large cell lymphoma. The patient was treated with 6 courses of CHOP therapy
      followed by high-dose chemotherapy and autologous peripheral blood stem cell
      transplantation. He achieved and remained in remission with no evidence of
      relapse 14 months later.

PMID- 10658479
TI  - [Epstein-Barr virus-associated hemophagocytic syndrome during mid-term pregnancy
      successfully treated with combined methylprednisolone and intravenous
      immunoglobulin].
AB  - A 32-year-old woman in the 16th week of pregnancy was admitted to our hospital
      because of high fever. Laboratory findings disclosed pancytopenia and extremely
      elevated serum LDH and ferritin levels. Coagulation tests showed disseminated
      intravascular coagulation. Serum soluble interleukin-2 receptor, tumor necrosis
      factor-alpha, and interleukin-6 levels were high, but serum interferon-gamma was
      below the detectable limit. Reactive Epstein-Barr virus (EBV) infection was
      diagnosed on the basis of a high titer of IgG antibodies to the EBV capsid
      antigen and early antigen. EBV was demonstrated in the peripheral blood and bone
      marrow cells by polymerase chain reaction. Mature histiocytosis and
      hemophagocytosis were detected in the bone marrow. A diagnosis of EBV-associated
      hemophagocytic syndrome (EBV-AHS) was made. Neither prednisolone (PSL 30 mg/day,
      P.O.) nor methylprednisolone (m-PSL) pulse therapy (1,000 mg/day for 3 days)
      induced a response. Thereafter, treatment with m-PSL pulse therapy (1,000 mg/day
      for 3 days) and i.v. administrations of high-dose immunoglobulin (20 g/day for 3
      days) in combination with acyclovir (750 mg/day) and gabexate mesilate (2 g/day)
      induced remission of the disease. Maintenance therapy consisted of PSL (5 mg/day,
      P.O.) and camostat mesilate (600 mg/day, P.O.). The patient delivered a healthy
      male infant in the 35th week of pregnancy via natural birth. Reports of pregnant
      women with EBV-AHS are rare, and the choice of therapy has not yet been
      established. The present case study suggested the above combination treatment is
      useful and safe, and capable of changing the fulminant course of EBV-AHS during
      pregnancy without the use of anticancer drugs.

PMID- 10658481
TI  - [History, present and future of medicine].

PMID- 10658480
TI  - [Malignant lymphoma with c-myc gene rearrangement in a patient receiving long
      term treatment for multiple myeloma].
AB  - We encountered a 65-year-old woman with diffuse large B-cell lymphoma showing
      t(8;14)(q24;q32) and c-myc gene rearrangement that developed following 12 years
      of melphalan-based chemotherapy for multiple myeloma. Short-term remission was
      obtained by CHOP chemotherapy. However, shortly thereafter the patient died of an
      aggressive progression of lymphoma. It was suspected that the lymphoma was a
      secondary malignancy related to the treatment with cytotoxic agents and radiation
      for prolonged multiple myeloma. The chromosomal abnormality t(8;14)(q24;q32) is
      rare in secondary malignancies. Overexpression of c-myc by gene rearrangement may
      be associated with clinical courses manifested by the rapid progression of
      lymphoma.

PMID- 10658482
TI  - [Molecular biology].

PMID- 10658483
TI  - [Transplantation. Blood, bone marrow and solid organs].

PMID- 10658484
TI  - [Rheumatoid arthritis--an acute medical condition].

PMID- 10658485
TI  - [The malignant lymphoproliferative diseases. Therapeutic progress and laboratory
      findings].

PMID- 10658486
TI  - [Testicular cancer. Development of effective medical treatment for young cancer
      patients].

PMID- 10658487
TI  - [Insulin].

PMID- 10658488
TI  - [Obesity and type 2 diabetes. Therapeutic failures].

PMID- 10658490
TI  - [Eradication of smallpox. The first great progress of vaccination immunology].

PMID- 10658489
TI  - [Human reproduction. The 20th century has given us new possibilities to direct
      the human reproduction].

PMID- 10658491
TI  - [Stomach ulcer--a relapsing disease?].

PMID- 10658492
TI  - [Ischemic heart disease--focus on treatment and prevention, future visions].

PMID- 10658493
TI  - [Maler syndrome, epidemic poisonings and environmental medicine].

PMID- 10658494
TI  - [Tuberculosis, suicide and alcohol. Development of the society, health care and
      disease in Greenland during the 20th century].

PMID- 10658495
TI  - [Anesthesiologic principles used in the treatment of polio patients. A great
      progress in intensive care].

PMID- 10658496
TI  - [Dialysis--a life-saving therapeutic principle in acute and chronic renal
      failure. Survival and quality of life improved by new technological progresses
      and new biological findings during the last century].

PMID- 10658497
TI  - [Thorotrast. How an immediate success can become a failure in the long run].

PMID- 10658498
TI  - [Thalidomide--failure or success? A controversial drug during the last fifty
      years--the pendulum swings--a renaissance for thalidomide?].

PMID- 10658499
TI  - [Penicillin and antibiotics--an adventure with a sad end?].

PMID- 10658500
TI  - [Diagnostic imaging].

PMID- 10658501
TI  - [Function diagnosis].

PMID- 10658502
TI  - [Na+,K(+) pump's significance for physiology and clinical findings.
      Identification of the Na(+)-K(+) pump defined molecular targets for regulation
      and therapy].

PMID- 10658503
TI  - [Coronary bypass surgery].

PMID- 10658504
TI  - [Alloplasty. Development of well-functioning and durable joint implant--a
      biomechanical and biological challenge].

PMID- 10658505
TI  - [Cataract surgery over 4000 years].

PMID- 10658506
TI  - [Neuroleptics and dopamine. How the antipsychotic breakthrough resulted in
      improved knowledge about the biology of schizophrenia].

PMID- 10658507
TI  - [ECT and antidepressive agents].

PMID- 10658508
TI  - [Psychosurgery. Treatment of mental disease by destruction of seemingly normal
      brain tissue].

PMID- 10658509
TI  - [Epidemiology].

PMID- 10658510
TI  - [From textbook to Internet].

PMID- 10658511
TI  - Storage and processing in visuo-spatial working memory.
AB  - Visuo-spatial working memory has been used to account for performance in a wide
      range of visuo-spatial tasks, including perceptuo-motor tracking and immediate
      recall of visually presented patterns. However a developing body of evidence
      points to a fractionation of the concept into visuo-spatial processing that calls
      on general purpose executive resources, and a visual 'cache' memory for temporary
      storage in on-line cognition. Two related experiments are described which address
      whether processing and temporary memory draw on overlapping or on distinct
      resources in working memory. Experiment 1 demonstrates that participants can
      accurately respond to a series of targets appearing in random locations whether
      or not they have the additional load of retaining and subsequently recalling the
      appearance of each target. Memory for target appearance likewise is largely
      unaffected by the additional load of requiring a response to each target.
      Experiment 2 demonstrates similar findings when verbal labeling of the patterns
      is inhibited through the use of articulatory suppression. Results are interpreted
      as consistent with a multiple component working memory system.

PMID- 10658512
TI  - Swedish and English secondary school pupils' attitudes towards, and conceptions
      of, bullying: concurrent links with bully/victim involvement.
AB  - Thirteen and fifteen year old Swedish and English secondary school pupils (n =
      210) completed a questionnaire designed to measure attitudes towards, and
      conceptions of, bullying. The older participants also provided peer nominations
      of classmates thought to be bullies and victims. Significant differences between
      pupils from the two countries, between younger and older pupils, and between
      girls and boys emerged on a number of these variables. For example, a
      significantly larger percentage of English pupils than Swedish pupils indicated
      that name calling is bullying, whereas the reverse was true for leaving somebody
      out. These results suggest that findings concerning incidence of, and beliefs
      about, bullying may not generalise from one group of pupils to another. Overall,
      participants tended to express anti-bullying attitudes. The present results also
      add to the small but growing set of findings which suggest that pupils' attitudes
      concerning bullying and their actual involvement in bullying are associated
      concurrently. Attitudes were found to significantly predict involvement in
      bullying even after the variance shared with participants' sex had been
      controlled. Specifically, those pupils that expressed the weakest anti-bullying
      attitudes were found to be most often nominated by peers as a bully. The
      implications of these results for anti-bullying interventions were discussed.

PMID- 10658513
TI  - The dimensionality of the 12-item version of the Eating Attitudes Test.
      Confirmatory factor analyses.
AB  - The assumed three-dimensional structure of the 12-item version of the Eating
      Attitudes Test was examined by confirmatory factor analysis in a non-clinical
      sample of 224 female and 261 male adolescents in grade 8 aged 14-15 years.
      Alternative models were examined. Data did neither support a three-dimensional
      structure, nor a one-dimensional structure using twelve items. Three dimensions
      were supported when one and three items were omitted from the girls' and boys'
      analyses, respectively. A second order factor structure was supported in both
      genders. Conceptual and psychometric issues are discussed. A discussion of the
      measurement domain of the eating problem construct in non-clinicals is warranted.

PMID- 10658514
TI  - Attention-Deficit/Hyperactivity symptoms in Icelandic schoolchildren: assessment
      with the Attention Deficit/Hyperactivity Rating Scale-IV.
AB  - Four hundred and twenty-seven normal Icelandic children, six and eight years of
      age, were rated by their parents and three hundred and sixteen children by their
      teachers with the Teacher and Parent versions of the Attention
      Deficit/Hyperactivity Disorder Rating Scale-IV (AD/HDRS-IV). For two hundred and
      sixty-five of the children both parent and teacher ratings were obtained. The
      factor structures of the AD/HDRS-IV for parents and teachers were in line with
      theoretical expectations. A Hyperactivity-Impulsivity factor and an Inattention
      factor were thus well supported. The subscale reliabilities were high. Boys
      scored higher than girls on all measures and there was a decrease of symptoms
      with age for boys, as expected. There was evidence of convergent validity for all
      scales, but discriminant validity of the AD/HDRS-IV subscales is less certain.
      Generally the instruments seem promising for further research. Some differences
      are noted in comparison with earlier studies. Thus scores obtained in this study
      were somewhat lower than those found in American studies, especially for
      teachers. Also the prevalence of ADHD based on rating scales was lower than in
      comparable previous studies. The similarity in symptom structure between this and
      previous studies is emphasized, but the possible role of cultural homogeneity in
      explaining different results with regard to teachers' ratings of symptoms is
      suggested.

PMID- 10658515
TI  - The role of parents' self-esteem, mastery-orientation and social background in
      their parenting styles.
AB  - In order to examine the extent to which parents' levels of education, financial
      resources, self-esteem, and their mastery-orientation versus task-avoidance are
      associated with their parenting styles and parental stress, data from two studies
      were analyzed. In Study I, parents of 105 6 to 7-year old children were asked to
      fill in scales measuring their parenting styles and parental stress, mastery
      orientation, financial resources, and their level of education. In Study II, 235
      parents were asked to fill in the same scales. An identical pattern of results
      was found in the two studies. Parents' self-esteem and their use of mastery
      oriented strategy were found to be associated with authoritative parenting and
      low parental stress, whereas parents' low level of education was related to an
      authoritarian parenting style. The results further showed that the impact of
      parents' self-esteem on authoritative parenting and parental stress was partly
      mediated by their use of a mastery-oriented strategy.

PMID- 10658516
TI  - Interpreting the WPPSI subtests scores of language impaired children--a
      structural approach.
AB  - The problem of characterising more specifically the cognitive requirements
      involved in subtests from standardised measures of intelligence represents a main
      problem in the research on exceptional populations. Seventy-five specifically
      language impaired (SLI) preschool children and 49 normally developing children
      were administered the Wechsler Preschool and Primary Scale of Intelligence
      (WPPSI). The scaled scores on the WPPSI were categorised according to Bannatyne's
      suggested regrouping to determine whether the pattern Spatial > Conceptual >
      Sequential could be observed in the data. The predicted pattern was only
      partially confirmed for language impaired children. The scaled scores on the
      WPPSI were then recategorized according to their structural complexity. Since
      structurally complex tasks contain more categories than the structurally simpler
      tasks, the pattern structurally Simple > Moderate > Complex was predicted and
      confirmed for language impaired children. Furthermore, it was hypothesized that
      the structurally Complex categories would discriminate better between language
      impaired children and normally developing children than any other recoded
      categories. This hypothesis was confirmed. The low scores obtained by language
      impaired children on structurally Complex categories were interpreted as the
      result of capacity limitations in information processing rather than a deficit of
      any particular mental ability.

PMID- 10658517
TI  - Formula-based dosing for carboplatin.

PMID- 10658518
TI  - Rho-like GTPases: their role in epithelial cell-cell adhesion and invasion.
AB  - The family members of small Rho-like GTPases, RhoA, Rac1 and Cdc42Hs, are
      regulators of diverse cellular signalling pathways, including cytoskeletal
      organisation, transcription and cell-cycle progression. Recent research has given
      insight into the complex regulation of cell-cell adhesion and migratory responses
      of epithelial cells. The Rho-like GTPases RhoA, Rac1 and Cdc42Hs as major
      determinants of cytoskeletal organisation have been identified as key regulators
      of epithelial architecture, as well as of cell migration. These findings
      highlight the complex regulation and cross-talk of GTPase-dependent signalling
      pathways arising from cell-cell and cell-matrix interactions. The molecular
      mechanism of how Rho-like GTPases couple to molecules mediating either cell-cell
      adhesion or cell migration will be of particular interest to understand the
      invasive phenotype of epithelial tumours.

PMID- 10658519
TI  - Should chemotherapy alone be the initial treatment for glottic squamous cell
      carcinoma?

PMID- 10658520
TI  - A comparison of methods of calculation for estimating carboplatin AUC with a
      retrospective pharmacokinetic-pharmacodynamic analysis in patients with advanced
      non-small cell lung cancer. European Lung Cancer Working Party.
AB  - We retrospectively analysed the data obtained in a large randomised trial
      performed in 505 eligible patients with advanced non-small cell lung cancer. Its
      purpose had been to compare a combination of carboplatin (200 mg/m2) and
      cisplatin (60 mg/m2) with or without the addition of ifosfamide. The present
      retrospective analysis assessed two ways of dosing carboplatin: according to body
      surface area (mg/m2) or to the estimated targeted area under the concentration
      versus time curve (AUC). Two different methods were used in the latter
      calculation: the Calvert formula using the Cockroft approximation to evaluate the
      glomerular filtration rate and the Chatelut equation. There was an excellent
      linear correlation between them. With the Chatelut method, the calculated
      administered AUC were lower. Whichever method was used, carboplatin AUC was not
      significantly associated with antitumour response rate nor patient survival. A
      statistically significant increase in haematological toxicity, mainly
      thrombopenia, was observed with an increase in the AUC. This effect was observed
      whatever AUC variable was considered, i.e. total dosage at course one, total
      dosage during the first three chemotherapy courses or dose intensity during the
      first three courses. The effect remained highly significant after adjustment for
      treatment arm. We conclude that for a moderate carboplatin dose in non-small cell
      lung cancer, the therapeutic index could be improved if dosage is calculated
      according to the AUC.

PMID- 10658521
TI  - The dissection of internal mammary nodes does not improve the survival of breast
      cancer patients. 30-year results of a randomised trial.
AB  - The lymph nodes of the internal mammary chain represent a primary station
      draining the lymph from the breast and their removal or their irradiation has
      been considered an important step in breast cancer treatment. From January 1964
      to January 1968, 737 patients with breast cancer were randomised at the National
      Cancer Institute in Milan to undergo either Halsted mastectomy or extended
      mastectomy with internal mammary node dissection. Patients with non-disseminated
      carcinoma classified as T1, T2, T3, N0, N1 were eligible for the study. No
      patients received postoperative radiotherapy or systemic therapy. After 30 years
      of follow-up, the overall survival curves and the specific survival curves do not
      show any difference between the patients of the two groups. Among the 558
      patients who died in the 30 year interval period, 395 (71%) died from breast
      carcinoma (201 in the Halsted group and 194 in the extended mastectomy group) and
      163 from other causes. This study shows that the removal of internal mammary
      nodes does not improve the survival of patients treated for breast carcinoma.
      This finding supports the theory that treatment of regional nodes does not
      influence the survival of cancer patients. The prognostic value of internal
      mammary node status is, however, high and a biopsy on a selected lymph node
      should be considered for staging purposes.

PMID- 10658522
TI  - Lack of correlation between timing of surgery in relation to the menstrual cycle
      and prognosis of premenopausal patients with early breast cancer.
AB  - In a retrospective cohort of a randomised study of adjuvant endocrine,
      chemotherapy and chemoendocrine therapy, we investigated the correlation between
      timing of mastectomy and relapse-free survival (RFS) and overall survival (OS) in
      721 premenopausal patients with early breast cancer. The median follow-up was
      10.1 years (range: 6.1-19.1 years). We grouped the patients by three kinds of
      classification according to Badwe, Senie, and Hrushesky. The logrank test after
      the Kaplan-Meier curves showed that there were no significant differences between
      the categorised menstrual phase in cycle and RFS or OS, except for RFS using
      Badwe's classification, where the patients whose timing of operation was in the
      follicular phase had a better RFS compared with those in the luteal phase. These
      were confirmed by the Cox proportional hazard model. These results suggest that a
      positive result might be a chance finding, dependent upon the cut-off levels in
      the menstrual cycle.

PMID- 10658523
TI  - Cisplatin (P), vinblastine (V) and bleomycin (B) combination chemotherapy in
      recurrent or advanced granulosa(-theca) cell tumours of the ovary. An EORTC
      Gynaecological Cancer Cooperative Group study.
AB  - The aim of this study was to investigate the clinical activity and toxicity of a
      modified PVB regimen (cisplatin, vinblastine and bleomycin) in patients with
      advanced or recurrent, pure granulosa cell tumours (GCTs) or mixed granulosa
      theca cell tumours (GTCTs). The PVB regimen consisted of cisplatin (P) 20 mg/m2
      intravenous (i.v.) days 1-5, vinblastine (V) 0.15 mg/kg i.v. days 1-2 and
      bleomycin (B) 30 mg i.v. on day 2, and 15 mg on day 15, for 28 days. 38 eligible
      patients were entered in this trial. Prior to PVB all patients underwent surgery
      and 13 received postoperative radio- or other prior chemotherapy. The median
      number of PVB cycles was 4 in both groups. In the group of 25 patients who had
      received prior surgery only, 7 and 6 patients had complete and partial responses,
      respectively (response rate: 52%, 95% confidence limits: 31.3-72.2%). At a median
      follow-up of 39 months, 6 patients were alive with no evidence of disease, 6 were
      alive with disease, 12 died due to malignant disease and 1 died due to
      intercurrent disease. The median time to progression was 13.9 months. The median
      survival was 25.4 months. 3-year survival was 49% (95% confidence limits: 29
      69%). In the group of 13 patients who had previously received postoperative radio
      or chemotherapy, 5 complete and 5 partial responses were observed on PVB
      (response rate: 77%, 95% confidence limit: 46.2-95.0%). At a median follow-up of
      50 months, 6 patients were still alive, only 1 without evidence of disease, 6
      died due to malignant disease and 1 died due to intercurrent disease. The median
      time to progression was 19.3 months. The median duration of survival was 41.1
      months. Accompanying toxicity was distributed in a similar pattern for both
      groups. Severe toxicity was mainly documented as haematological toxicity,
      nausea/vomiting and alopecia. Furthermore cisplatin-related peripheral
      neurotoxicity and mild/moderate signs of bleomycin-related pulmonary toxicity
      were observed. The present data confirm the therapeutic activity of the PVB
      regimen in advanced/recurrent GCTs. The response rate was moderately high
      compared with previous studies, with a median duration of response of 20 months
      for both groups.

PMID- 10658524
TI  - Oxaliplatin added to the simplified bimonthly leucovorin and 5-fluorouracil
      regimen as second-line therapy for metastatic colorectal cancer (FOLFOX6).
      GERCOR.
AB  - For patients resistant to leucovorin (LV) and 5-fluorouracil (5-FU), the addition
      of oxaliplatin (85 or 100 mg/m2) to bimonthly LV-5-FU has given a response rate
      of 20-46%. The highest response rate has been observed with oxaliplatin 100 mg/m2
      (FOLFOX2). The present phase II study (FOLFOX6) infused oxaliplatin (100 mg/m2)
      with LV (400 mg/m2) as a 2-h infusion on day 1, followed by bolus 400 mg/m2 and a
      46-h infusion (2.4-3 g/m2) of 5-FU, every 2 weeks. Among the 60 patients treated,
      16 (27%) had partial responses (95% confidence interval: 15-38), 27 (45%) had
      stable disease, 15 (25%) experienced disease progression and 2 (3%) had non
      measurable disease. From the start of FOLFOX6, median progression-free survival
      was 5.3 months and median survival 10.8 months. From the 448 cycles analysed, NCI
      CTC grade 3-4 toxicities per patient were: peripheral neuropathy 16%, nausea 7%,
      diarrhoea 7%, mucositis 5%, neutropenia 24%, thrombocytopenia 2%. Overall 26
      (46%) patients experienced grade 3-4 toxicities. Because of toxicity, only 36% of
      the patients received > or = 90% of the scheduled oxaliplatin dose intensity.
      FOLFOX6 was active in pretreated patients resistant to LV-5-FU and is being
      investigated as first-line therapy. We are now investigating FOLFOX7, a regimen
      with a higher oxaliplatin dose intensity and a lower 5-FU dose.

PMID- 10658525
TI  - CPT-11 (irinotecan) addition to bimonthly, high-dose leucovorin and bolus and
      continuous-infusion 5-fluorouracil (FOLFIRI) for pretreated metastatic colorectal
      cancer. GERCOR.
AB  - CPT-11 (irinotecan) has shown activity in patients with advanced colorectal
      cancer resistant to leucovorin (LV) and 5-fluorouracil (5-FU). In this study, the
      simplified bimonthly LV-5-FU regimen was combined with CPT-11 (FOLFIRI) as third
      line therapy for patients with advanced colorectal cancer. Continuous infusion of
      5-FU was administered with disposable pumps as outpatient therapy. FOLFIRI
      consisted of CPT-11 180 mg/m2 as a 90-min infusion day 1; LV 400 mg/m2 as a 2-h
      infusion during CPT-11, immediately followed by 5-FU bolus 400 mg/m2 and 46-h
      continuous infusion of 2.4-3 g/m2 every 2 weeks. Among the 33 patients treated, 2
      had partial responses for an overall response rate of 6%; 20 patients were
      stabilised (61%) and 11 had disease progression (33%). From the start of FOLFIRI,
      median progression-free survival was 18 weeks and median survival was 43 weeks.
      For the 242 cycles analysed, NCI-CTC toxicities grade 3-4 per patient were nausea
      15%, diarrhoea 12% and neutropenia 15%. Overall, 10 patients (30%) experienced
      grade 3-4 toxicity. 7 patients (21%) had grade 2 alopecia. FOLFIRI generated
      activity and acceptable toxicity, in heavily pretreated patients, with limited
      diarrhoea, mostly asymptomatic neutropenia and manageable nausea and relatively
      uncommon alopecia. This regimen is suitable for studies in chemotherapy-naive
      patients.

PMID- 10658526
TI  - Toxicity, supportive care and costs of two chemotherapy protocols for treatment
      of childhood ALL in Russia: BFM 90m and MB 91.
AB  - Since the late 1980s, polychemotherapy protocols for the treatment of childhood
      acute lymphoblastic leukaemia (ALL) derived from Western European and American
      regimens have been introduced in Russian paediatric oncology centres. Whereas
      treatment results were significantly improved compared with the results of former
      non-standard treatment strategies, the substantial toxicity of these protocols
      required a high standard of supportive care, and the high costs of treatment
      became a major problem. In 1991, a new protocol was developed with the aim of
      reducing toxicity and costs without affecting efficacy of the treatment. Since
      1991, a single-centre study comparing the new Russian Protocol, Moscow-Berlin 91
      (MB), with a modified version of the protocol ALL BFM 90 (BFM) of the Berlin
      Frankfurt-Munster group was performed in Moscow to evaluate possible advantages
      of the new protocol under Russian conditions. The aim of the present analysis was
      to compare toxicity, need of supportive care and expense of both regimens (BFM,
      25 pts; MB, 32 pts). Hepatotoxicity (liver enzymes), nephrotoxicity (creatinine),
      duration of neutropenia, and platelet transfusions were similar in both
      protocols. The median erythrocyte transfusion level was greater in the BFM (1000
      ml/m2) than the MB patients (505 ml/m2, P < 0.01), as was the length of
      intravenous (i.v.) antibiotic therapy (22 days BFM versus 9 days MB, P < 0.01),
      treatment delays (39 days BFM versus 21 days MB, P < 0.001), and duration of in
      patient treatment (47 days BFM versus 18 days MB, P < 0.001). Side-effects of the
      MB protocol occurred mainly during induction therapy. Total costs (mean
      cost/person/m2 body surface) of treatment including supportive care were 1.73
      fold higher for the BFM protocol than MB, whereas costs of cytostatic drugs were
      comparable in both groups. In Russia both protocols were feasible. During
      consolidation therapy tolerance to treatment was better in MB 91 compared with
      BFM 90m, whereas toxicity during induction therapy was similar in both protocols.
      With respect to costs and side-effects, the MB 91 protocol appears to be an
      alternative to established protocols for countries with limited financial and
      clinical resources.

PMID- 10658527
TI  - Fetal rhabdomyomatous nephroblastoma: a tumour of good prognosis but resistant to
      chemotherapy.
AB  - Fetal rhabdomyomatous nephroblastoma (FRN) is a rare variant of Wilms' tumour.
      The tumour chiefly consists of fetal striated muscle with particularly distinct
      striations and central nuclei. To determine the effect of (preoperative)
      chemotherapy in the treatment of this subtype of nephroblastoma, a retrospective
      analysis was performed. By 1 November 1991, SIOP 9 had registered 852 patients
      (pts) from 55 centres. We report on 13 children diagnosed with FRN between 1988
      and 1992 with a median age of 2 years and 1 month (range 1 month-8 years 6
      months). There were 7 boys and 6 girls. 9 patients were classified as stage I, 2
      as stage II, 1 as stage III and 1 as stage V. 12 patients received preoperative
      chemotheraphy with actinomycin-D and vincristine for 2 weeks (1 pt), 4 weeks (5
      pts) and 8 weeks (6 pts) respectively. The average tumour volume at registration
      (determined by ultrasonography) in 12/13 patients was 965 cm3 (range 17.3-2520
      cm3). 3/7 of the FRN patients showed no tumour regression after 4 weeks
      preoperative CT and 4/8 after 8 weeks preoperative chemotheraphy (compared with
      only 28 and 34%, after 4 and 8 weeks CT, of all trial patients). Of 13 patients,
      10% are alive and free of disease with a mean follow up of 4 years. This variant
      of Wilms' tumour is a poor responder to preoperative chemotherapy and is
      associated with a generally favourable outcome in most of all unilateral cases
      when treated by surgery.

PMID- 10658528
TI  - Risk factors for breast cancer in women under 40 years.
AB  - The relation between hormonal and lifestyle factors and breast cancer risk in
      women younger than 40 years was investigated using data from two case-control
      studies conducted in Italy between 1983 and 1994. Cases were 579 women with
      histologically confirmed, incident breast cancer and controls were 668 women
      admitted to hospital for acute, non-neoplastic, non-hormone-related diseases.
      Breast cancer risk was inversely related to age at menarche with a multivariate
      odds ratio (OR) of 0.53 (95% confidence interval, CI, 0.31-0.89) for women
      reporting menarche at the age of > or = 15 years compared with < 12 years. Breast
      cancer risk was significantly higher in parae than in nulliparae (OR 1.58), and
      was directly associated with age at first birth (OR 5.31 among women aged > or =
      30 years at first birth compared with those aged < 20), and inversely with time
      since last birth (OR 3.80 for < 3 years compared with > or = 12). Compared with
      women reporting no abortion, the OR were 1.10 for any spontaneous, 0.87 for any
      induced and 0.90 for > or = 2 abortions. With reference to oral contraceptive
      use, the OR was 1.05 for ever users compared with never users, and no material
      association was evident with duration, time since first and last use. The OR was
      1.79 for more than 13 years of education compared with < 9, 1.85 for a family
      history of breast cancer and 1.85 for a history of benign breast disease. Breast
      cancer risk was inversely related to body mass index with an OR of 0.51 (95% CI
      0.26-0.97) for > or = 30 kg/m2 compared to < 20. Total energy and alcohol intake
      were directly related to the risk (OR 1.38 and 1.27 for the highest tertiles of
      intake compared with the lowest), although the estimates were not significant,
      whilst raw vegetable and beta-carotene consumption were inversely related to
      breast cancer risk (OR 0.57 and 0.67 for the highest tertile of intake compared
      with the lowest). Thus, most risk factors in this large dataset of women aged
      less than 40 years were similar to those described in breast cancer epidemiology
      at any age. Of interest are the inverse associations with body mass index, age at
      menarche and time since last birth, the direct ones with age at first and last
      birth, and the higher risk of parous women compared with nulliparae.

PMID- 10658529
TI  - Familial testicular cancer in a single-centre population.
AB  - Familial occurrence of testicular cancer suggests a genetic predisposition to the
      disease. A genetic susceptibility may also be reflected by the occurrence of
      bilateral testicular neoplasms and the high rates of urogenital developmental
      anomalies in families prone to testicular cancer. In this study, the proportion
      of familial testicular cancer cases was analyzed retrospectively in a single
      centre population of 693 testicular cancer patients treated between 1977 and 1997
      and the relative risk (RR) for first-degree relatives of patients was estimated.
      In addition, the existence of bilateral testicular neoplasms and urogenital
      developmental anomalies in familial testicular cancer patients was evaluated. 24
      of the 693 patients (3.5%) had a first-degree relative with testicular cancer.
      These 24 cases belonged to 17 families; in 7 of these 17 families both affected
      first-degree family members were part of the study population of 693 patients.
      Consequently, the 693 studied patients belonged to a total of 686 families. Thus,
      the actual proportion of familial testicular cancer was 2.5% (17 of 686
      families). The familial cases consisted of 11 brother pairs, including 2 pairs of
      identical twins and 1 pair which also had two affected cousins, and 6 father-son
      pairs (in total 36 cases, 12 treated elsewhere). Estimates of the RR to first
      degree relatives showed a 9- to 13-fold increased RR to brothers (P < 0.001) and
      a 2-fold increased RR to fathers (P = non-significant (n.s)) of testicular cancer
      patients. Among the 36 patients with familial testicular cancer, 2 (5.6%) had
      bilateral testicular cancer, 4 (11.1%) had undescended testis, 3 (8.3%) had
      inguinal hernia, and 1 (2.8%) showed renal hypoplasia. The present data on
      familial occurrence of testicular cancer may lend support to a role of genetic
      factors in the aetiology of testicular cancer.

PMID- 10658530
TI  - Role of Bcl-2 family proteins (Bax, Bcl-2 and Bcl-X) on cellular susceptibility
      to radiation in pancreatic cancer cells.
AB  - The aim of this study was to examine Bax, Bcl-2 and Bcl-XL proteins in human
      pancreatic cancer cell lines and to clarify the mechanism of radiation
      resistance. PANC-1 and AsPC-1 pancreatic cell lines were used, both having
      mutated p53. Radioresistant PANC-1/Rad cells and AsPC-1/Rad cells were obtained
      by repeated 5 Gy irradiation of PANC-1 cells and AsPC-1 cells, respectively.
      Radiation was found to inhibit the growth of PANC-1 cells and AsPC-1 cells. After
      exposure to radiation, detached cells were subjected to FITC-TUNEL staining to
      calcualte the ratio of apoptosis. TUNEL positive ratios increased dose
      dependently in both cell lines. Western blotting showed that the basal level of
      the Bax/Bcl-2 ratio reflected the radiosensitivity of these cell lines, and Bax
      expression was obviously upregulated after irradiation in the presence of mutated
      p53, but Bcl-2 expression remained almost constant. Both PANC-1/Rad and AsPC
      1/Rad cells had greater Bcl-XL expression than the parental cells, and the basal
      level of the Bax/Bcl-2 ratio was no longer predictive of radiosensitivity.
      Upregulated expression of Bax protein after irradiation was not related to
      induction of apoptosis in these cells, suggesting that overexpression of Bcl-XL
      and functional reconstruction of Bcl-2 family proteins are important factors in
      acquired radioresistance.

PMID- 10658531
TI  - Paracrine regulation of ovarian cancer by endothelin.
AB  - Previous studies have demonstrated that endothelin (ET) isoforms (ET-1, ET-2 and
      ET-3) can act in an autocrine manner in ovarian cancer while in breast cancer
      their role has been proposed to be that of a paracrine mitogen. To explore the
      possibility that endothelin isoforms might function not only as autocrine
      regulators but also as paracrine mitogens in ovarian cancers, we investigated
      their effects on the growth of ovarian fibroblasts derived from ovarian
      carcinomas, the interaction between ovarian carcinoma and fibroblast cells and
      the location of the isoform expression in primary ovarian tumours. ET-1, ET-2 and
      ET-3 stimulated the growth of three ovarian fibroblast cell lines at
      concentrations ranging from 10(-12) M to 10(-7) M. Inhibition of 125I-ET binding
      by the ETA receptor antagonist BQ123 and the ETB receptor antagonist BQ788
      suggested the presence of both types of ET receptors in fibroblast cells. In the
      absence of ET-1, neither BQ 123 nor BQ 788 inhibited growth. However, both
      antagonists inhibited ET-1 stimulated growth suggesting the involvement of both
      receptor types in ET-1 growth regulation. In contrast to carcinoma cells which
      secrete measurable levels of ET-1, fibroblast cell lines did not secrete
      detectable protein. Co-culture experiments (using porous membrane insert wells)
      of fibroblasts with carcinoma cells demonstrated that growth of both populations
      of cells was increased compared with either grown in isolation. In this system,
      growth of the fibroblast cell line was partially inhibited by both BQ123 and
      BQ788, whilst growth of the PE014 carcinoma cell line was inhibited by only
      BQ123. RT-PCR measurements detected the presence of the ETA receptor subtype in
      10/10 primary ovarian cancers but the presence of ETB receptor in only 6/10
      cancers. Using specific antibodies, ET-1 was found in 11/15, ET-2 in 5 of 7 and
      ET-3 in 5/7 primary ovarian cancers predominantly in the epithelial cells but
      with some stromal expression. These data indicate that the ET isoforms may
      stimulate growth of the fibroblast population within an ovarian cancer in
      addition to stimulating the epithelial cells and since the ETs are expressed in
      the majority of ovarian cancers, this paracrine effect may contribute to the
      overall growth of the tumour.

PMID- 10658532
TI  - Vitamin K3 induces cell cycle arrest and cell death by inhibiting Cdc25
      phosphatase.
AB  - Our early reports have indicated that vitamin K3 (VK3) exerts antitumour activity
      by inhibiting Cdk1 activity and overexpressing the c-myc gene to induce an
      apoptotic cell death. In the present study, we investigated the effect of VK3 on
      Cdc25 phosphatase, a Cdk1 activator and c-Myc-downstream protein. Increased
      protein level but decreased activity of Cdc25A phosphatase was found in cervical
      carcinoma SiHa cells treated with VK3 for 1 h and allowed to recover for 8, 24,
      30 or 45 h. The binding of VK3 to Cdc25 phosphatase was proven by incubating
      [methyl-3H]-VK3 with the 27 kDa-catalytic domain of Cdc25A phosphatase at 35
      degrees C for 2 h. We found that VK3 inhibited cyclin E expression at late G1
      phase and cyclin A at G1/S transition of the aphidicolin-synchronised SiHa cells,
      but had no effect on Cdk2 and Cdk4. The inhibition of cyclins E and A expression
      was associated with cell cycle progression delay in the S phase. These results
      indicate that binding of VK3 to the catalytic domain of Cdc25 phosphatase results
      in the formation of inactive, hyperphosphorylated Cdk1 that subsequently induces
      cell cycle arrest, leading to cell death. These findings suggest a possible
      therapeutic strategy, with VK3 serving as a potential antagonist to tumours
      expressing high levels of proteins containing cysteine such as oncogenic Cdc25A
      phosphatase.

PMID- 10658533
TI  - Effect of novel CAAX peptidomimetic farnesyltransferase inhibitor on angiogenesis
      in vitro and in vivo.
AB  - Ras oncogenes can contribute to tumour development by stimulating vascular
      endothelial growth factor (VEGF)-dependent angiogenesis. The effect of Ras on
      angiogenesis may be affected by farnesyltransferase inhibitors (FTI) since
      farnesylation of Ras is required for its biological activity. In this paper we
      evaluated the effect of A-170634, a novel and potent CAAX FTI on angiogenesis.
      Human umbilical vein endothelial cell (HUVEC) tube formation and VEGF secretion
      were used to assess the effect of A-170634 on angiogenesis in vitro. In vivo,
      nude mice were injected with the K-ras mutant colon carcinoma cell line HCT116
      and treated subcutaneously with A-170634 using osmotic minipump infusion for 10
      days. The effect of A-170634 on corneal angiogenesis in vivo was assessed using
      pellets containing hydron, VEGF, A-170634 or vehicle. In vitro, A-170634
      selectively inhibited farnesyltransferase activity over the closely related
      geranylgeranyltransferase I, inhibited Ras processing, blocked anchorage
      dependent and -independent growth of HCT116 K-ras mutated cells, decreased HUVEC
      capillary structure formation, decreased VEGF secretion from tumour cells and
      HUVEC growth stimulating activity in a dose-dependent manner. In vivo, tumour
      growth was decreased by 30% and vascularisation in and around the tumours was
      reduced by 41% following drug-treatment with no apparent toxicity to the animals.
      VEGF-induced corneal neovascularisation was reduced by 80% following A-170634
      treatment for 7 days. The data presented here demonstrated that A-170634 was a
      potent and selective peptidomimetic CAAX FTI with anti-angiogenic properties.
      These results implied that A-170634 may affect tumour growth in vivo by one or
      more antitumour pathways.

PMID- 10658534
TI  - Influence of the schedule of exposure on the cytotoxic effect of melphalan on
      human 8226 and A2780 cells.
AB  - Melphalan was investigated for antitumoral activity using two schedules of
      exposure (solid versus sequential exposure) in two human cancer cell lines (8226
      and A2780). Sequential exposure of melphalan was more effective than solid
      exposure at the same total dose. The IC50 values averaged 8.2 (solid exposure)
      and 0.16 microgram/ml (sequential exposure) for 8226 cells (myeloma), and 7.5
      (solid) and 0.53 microgram/ml (sequential) for A2780 cells (ovarian carcinoma).
      Intracellular melphalan accumulation, determined by high-performance liquid
      chromatography, showed that the area under the intracellular concentration of
      melphalan versus time curve (between 0 and 30 h) was significantly higher after
      sequential doses (9.4 micrograms/ml x h) than after solid dose (6.6 micrograms/ml
      x h). Moreover, intracellular/extracellular concentration ratios indicated that
      melphalan uptake followed a passive transport system. The increase of both
      duration of exposure (11 h after solid exposure versus 20 h after sequential
      doses) and intracellular concentrations 5-6 h after the beginning of the
      experiment (approximately 3 times higher after sequential doses) indicate
      sequential administration of melphalan could be more effective than solid
      exposure.

PMID- 10658535
TI  - Comments on: mutations in mitochondrial control region DNA in gastric tumours of
      Japanese patients, Tamura, et al. Eur J Cancer 1999, 35, 316-319.

PMID- 10658536
TI  - Acute effects of urban air pollution on respiratory health of children with and
      without chronic respiratory symptoms.
AB  - OBJECTIVES: To investigate to what extent different components of air pollution
      are associated with acute respiratory health effects in children with and without
      chronic respiratory symptoms. METHODS: During three consecutive winters starting
      in 1992-3, peak expiratory flow (PEF) and respiratory symptoms were registered
      daily in panels of children of 7-11 years old with and without symptoms, living
      in urban areas with high traffic intensity in The Netherlands. Simultaneously,
      panels of children living in non-urban areas were studied. Daily measurements of
      particles with aerodynamic diameter < 10 microns (PM10), black smoke (BS),
      sulphate, SO2, and NO2 were performed in both areas. RESULTS: The contrast in
      particle concentrations (PM10, BS, and sulphate) between urban and non-urban
      areas was small, but there was more contrast in the concentrations of SO2 and
      NO2. In children with symptoms from both areas, significant associations were
      found between PM10, BS, and sulphate concentrations and the prevalence of
      symptoms of the lower respiratory tract (LRS) and decrements in PEF. Particle
      concentrations were also associated with use of bronchodilators in the urban
      areas, but not in the non-urban areas. After stratification by use of medication,
      stronger associations were found in children who used medication than in children
      who did not use medication. The magnitude of the estimated effects was in the
      order of a twofold increase in the use of bronchodilators, a 50% increase in LRS,
      and an 80% increase in decrements in PEF for a 100 micrograms/m3 increase in the
      5 day mean PM10 concentration. In children without symptoms, significant
      associations were found between concentrations of PM10 and BS and decrements in
      PEF in both areas, but these associations were smaller than those for children
      with symptoms. No associations with respiratory symptoms were found. CONCLUSIONS:
      The results suggest that children with symptoms are more susceptible to the
      effects of particulate air pollution than children without symptoms, and that use
      of medication for asthma does not prevent the adverse effects of particulate air
      pollution in children with symptoms.

PMID- 10658537
TI  - Bioreactivity of carbon black and diesel exhaust particles to primary Clara and
      type II epithelial cell cultures.
AB  - OBJECTIVES: To begin to elucidate the mechanisms of particle toxicity to the
      lung, the bioreactivity of four carbon black (CB) and diesel exhaust particles
      ((DEPs), a surrogate for particulate matter of aerodynamic diameter < 10 microns
      (PM10), were examined with primary cultures of Clara and type II epithelial
      cells. METHODS: The particles were extensively characterised by surface
      chemistry, size, and aggregation properties. Toxicity of the particles was
      assessed by determining cell attachment to an extracellular matrix substratum.
      RESULTS: The spherulite size range for the particles ranged from 50, 40, 20, 20,
      and 30 nm for CB1-4 and DEPs. All particle samples had different surface chemical
      compositions. CB1 was the least toxic to Clara (170 micrograms) and type II cells
      (150 micrograms) and CB4 was the most toxic (55 micrograms and 23 micrograms
      respectively). DEPs stored for 2 weeks were equally toxic to both epithelial cell
      types (27-28 micrograms). DEPs became progressively less toxic to type II cells
      with time of storage. Both primary epithelial cell types internalised the
      particles in culture. CONCLUSIONS: Bioreactivity was found to be related to CB
      particle spherulite size and hence surface area: the smaller the particle and
      larger the surface area, the more toxic the particles. Also, CB particles with
      the most complicated surface chemistry were the most bioreactive. Freshly
      prepared DEPs were equally toxic to type II and Clara cells and they became
      progressively less toxic to the type II cells with time. With all CB and DEPs,
      the primary epithelial cells internalised the particles, although this was noted
      most in cells of low functional competence.

PMID- 10658538
TI  - Clinical lead poisoning in England: an analysis of routine sources of data.
AB  - OBJECTIVE: To examine the occurrence of clinical lead poisoning in England based
      on routine sources of data. METHODS: Three routine data sources were examined,
      over different periods according to availability of data: (a) mortality for
      England, 1981-96; (b) hospital episode statistics data for England, for the 3
      years 1 April 1992-31 March 1995; (c) statutory returns to the Health and Safety
      Executive under the reporting of injuries, diseases, and dangerous occurrences
      regulations (RIDDOR), also for the period 1 April 1992-31 March 1995. Also,
      analyses of blood lead concentrations carried out by the Medical Toxicology Unit,
      Guy's and St Thomas' Hospital Trust in London during the period 1 January 1991-31
      December 1997 were examined. The analyses were performed both for industrial
      screening purposes and in response to clinicians' requests where lead poisoning
      was suspected. This is one of several laboratories carrying out such analyses in
      the United Kingdom. RESULTS: One death, of a 2 year old girl, was coded to lead
      poisoning in England during 1981-96. Analysis of hospital episode statistics data
      identified 83 hospital cases (124 admissions) over 3 years with any mention of
      lead poisoning, excluding two with admissions dating from 1965 and 1969. For
      these 83 cases the median hospital stay per admission was 3 days (range 0-115
      days). Five were coded as having received intravenous treatment. Further clinical
      details of these cases beyond what is routinely recorded on the hospital episode
      statistics database were not available, except for blood lead concentrations in
      cases also identified on the Medical Toxicology Unit database. Eighteen cases
      (22%) were below 5 years of age of whom 10 (56%) came from the most deprived
      quintile of electoral wards. There was evidence to suggest spatial clustering of
      cases (p = 0.02). Six occupational cases were reported under RIDDOR in England
      during the period of study, two of whom were identified on the hospital episode
      statistics database. One further occupational case was identified on hospital
      episode statistics. Blood lead analyses for 4424 people carried out by the
      Medical Toxicology Unit (estimated at about 5% of such analyses in England over 7
      years) found that among 547 children aged 0-4, 45 (8.2%) had a blood lead
      concentration in excess of 25 micrograms/dl, the action level in the United
      Kingdom for investigation, or removal of environmental sources of lead. At all
      ages, there were 419 (9.5%) such people, including 106 adults with no mention of
      industrial exposure. CONCLUSIONS: Both mortality and hospital admission ascribed
      to lead poisoning in England are rare, but cases continue to occur and some, at
      least, seem to be associated with considerable morbidity. Lead poisoning was
      confirmed as a probable cause of clinical signs and symptoms in only a small
      proportion of those in whom a blood lead concentration was requested. Where
      indicated, appropriate remedial action for the safe removal of environmental
      sources of lead should be taken.

PMID- 10658539
TI  - Biological monitoring of occupational exposure to inorganic arsenic.
AB  - OBJECTIVES: This study was undertaken to assess reliable biological indicators
      for monitoring the occupational exposure to inorganic arsenic (iAs), taking into
      account the possible confounding role of arsenicals present in food and of the
      element present in drinking water. METHODS: 51 Glass workers exposed to As
      trioxide were monitored by measuring dust in the breathing zone, with personal
      air samplers. Urine samples at the end of work shift were analysed for biological
      monitoring. A control group of 39 subjects not exposed to As, and eight
      volunteers who drank water containing about 45 micrograms/l iAs for a week were
      also considered. Plasma mass spectrometry (ICP-MS) was used for the analysis of
      total As in air and urine samples, whereas the urinary As species (trivalent,
      As3; pentavalent, As5; monomethyl arsonic acid, MMA; dimethyl arsinic acid, DMA;
      arsenobetaine, AsB) were measured by liquid chromatography coupled with plasma
      mass spectrometry (HPLC-MS) RESULTS: Environmental concentrations of As in air
      varied widely (mean 84 micrograms/m3, SD 61, median 40) and also the sum of
      urinary iAs MMA and DMA, varied among the groups of exposed subjects (mean 106
      micrograms/l, SD 84, median 65). AsB was the most excreted species (34% of total
      As) followed by DMA (28%), MMA (26%), and As3 + As5 (12%). In the volunteers who
      drank As in the water the excretion of MMA and DMA increased (from a median of
      0.5 to 5 micrograms/day for MMA and from 4 to 13 micrograms/day for DMA). The
      best correlations between As in air and its urinary species were found for total
      iAs and As3 + As5. CONCLUSIONS: To avoid the effect of As from sources other than
      occupation on urinary species of the element, in particular on DMA, it is
      proposed that urinary As3 + As5 may an indicator for monitoring the exposure to
      iAs. For concentrations of 10 micrograms/m3 the current environmental limit for
      iAs, the limit for urinary As3 + As5 was calculated to be around 5 micrograms/l,
      even if the wide variation of values needs critical evaluation and application of
      data. The choice of this indicator might be relevant also from a toxicological
      point of view. Trivalent arsenic is in fact the most active species and its
      measure in urine could be the best indicator of some critical effects of the
      element, such as cancer.

PMID- 10658540
TI  - Prevalence and risk factors for latex allergy: a cross sectional study in a
      United Kingdom hospital.
AB  - OBJECTIVES: To determine the prevalence and risk factors for symptoms related to
      gloves, and the relation between symptoms and immunological evidence of type 1
      hypersensitivity to latex in a United Kingdom health care setting. METHODS: A
      cross sectional survey was carried out among 773 employees at a British hospital.
      A self administered questionnaire was used to collect information about symptoms
      related to gloves and associated risk factors in a sample of hospital staff who
      were likely to use gloves at work. All of those who reported symptoms suggestive
      of type 1 hypersensitivity were invited for skin prick testing and measurement of
      specific IgE to latex (RAST). RESULTS: Among the 372 responders, symptoms related
      to gloves were common, 49% reported redness or itching of the hands, 14% reported
      urticaria, and 6% reported chest tightness. However, the frequency of positive
      skin prick tests and RASTs was surprisingly low (only two subjects tested
      positive). CONCLUSIONS: These findings indicate the need for caution in the
      interpretation of symptoms related to gloves even when they seem to suggest type
      1 hypersensitivity.

PMID- 10658541
TI  - Clinically important FEV1 declines among coal miners: an exploration of
      previously unrecognised determinants.
AB  - OBJECTIVES: The relation between occupational exposure to dust and loss of
      ventilatory lung function is now well established. However, many exposures during
      work and other activities might also have important roles in determining
      clinically important losses of lung function. In this study, we attempted to
      explore additional plausible determinants of exposures and other potential risk
      factors for clinically important decline in forced expiratory volume in 1 second
      (FEV1) during work in dusty trades. METHODS: The study was performed in 264
      underground coal miners whose lung function had been followed up for an average
      of 11 years. With an extensive follow up questionnaire, miners were asked about
      their occupational and non-occupational exposures, smoking, personal and family
      medical history, and living conditions during childhood. RESULTS: Several
      variables of the mine environment (as well as previously recognised effects of
      mining work and region) were found to be associated with excess decline in FEV1,
      including work in roof bolting, exposure to explosive blasting, and to control
      dust spraying water that had been stored in holding tanks. Use of respiratory
      protection seemed to reduce the risk of decline in FEV1. Other factors that were
      found to be associated with declines in pulmonary function included smoking, body
      mass, weight gain, childhood pneumonia, and childhood exposure in the home to
      passive tobacco smoke and possibly smoke due to wood and coal fuels. Miners with
      excessive decline in FEV1 were less likely to be working in mining jobs at follow
      up. CONCLUSIONS: These findings suggest the existence of additional risk factors
      for decline in lung function in dusty trades, and may be useful in developing
      additional approaches to the prevention of chronic respiratory disease.

PMID- 10658542
TI  - Analysis of a petrol plume over England: 18-19 January 1997.
AB  - OBJECTIVES: About 7000 tonnes of unleaded petrol were discharged into the English
      Channel after a tanker collision off Ostend on Saturday 18 January 1997. The
      petrol evaporated and the vapour plume was carried across the central part of
      England to Wales, resulting in reports of unidentified odours, and irritation of
      the eyes, skin, and upper respiratory tract. This work uses this incident to show
      how marine and atmospheric dispersion modelling together with routine air quality
      monitoring can assist in identifying hazards to the population at risk from
      chemical incidents. METHODS: Public health surveillance and results from
      environmental sampling were compared with the behaviour of the plume as predicted
      by computer modelling. RESULTS: The predicted plume path and dispersion were
      shown to correlate well with the results from surveillance and environmental
      analysis. CONCLUSIONS: There is a need for public health professionals to
      interact with medical toxicologists, atmospheric and marine scientists and
      engineers, and other environmental experts in managing events of this nature.

PMID- 10658543
TI  - Reproductive endocrine effects of acute exposure to toluene in men and women.
AB  - OBJECTIVES: Despite observation of adverse reproductive effects of toluene,
      including alterations of serum gonadotropins (luteinising hormone (LH) and
      follicle stimulating hormone (FSH)) in humans, little is known of the mechanism
      of toxicity. The hypothesis was tested that toluene acutely suppresses pulsatile
      gonadotropin secretion by measuring LH and FSH at frequent intervals during
      controlled exposure to toluene. METHODS: Women in the follicular and luteal
      phases of the menstrual cycle and men were randomised to inhale filtered air with
      or without 50 ppm toluene through a mouthpiece for 3 hours (19% of the OSHA
      permissible exposure limit). Blood was sampled by intravenous catheter at 20
      minute intervals for 3 hours before, 3 hours during, and 3 hours after exposure.
      Plasma LH, FSH, and testosterone were measured. Pulse amplitude, pulse frequency,
      and mean concentrations of LH and FSH for each of the 3 hour periods before,
      during and after exposure to toluene versus sham exposure were calculated with
      the ULTRA pulse detection program and compared by analysis of variance (ANOVA)
      with repeated measures. RESULTS: In men mean concentrations of LH showed a
      significant interaction (p < 0.05) between exposure and sampling period, with a
      greater LH decline during exposure to toluene than sham exposure. However, there
      was no concomitant effect on testosterone concentrations. The LH pulse frequency
      of women in the luteal phase showed a trend towards a significant interaction
      between exposure and sampling period (p = 0.06), with a greater decline in pulse
      frequency during exposure to toluene than sham exposure. There were no other
      significant effects of exposure to toluene. CONCLUSIONS: Three hour exposure to
      50 ppm toluene did not result in abnormal episodic LH or FSH secretion profiles,
      however, subtle effects on LH secretion in men and women in the luteal phase were
      found. The clinical relevance of these effects is unclear, indicating the need
      for further study of reproductive function in exposed workers.

PMID- 10658544
TI  - Mortalities of workers at the Nitro plant with exposure to 2
      mercaptobenzothialzole.
AB  - OBJECTIVES: An update of a study of workers exposed to 2-mercaptobenzothiazole
      (MBT) at a rubber chemicals plant in Nitro, West Virginia is reported. The
      earlier study found high rates of lung cancer, prostate cancer, and bladder
      cancer in these workers who also had potential exposure to 4-aminobiphenyl (PAB),
      a potent bladder carcinogen. METHODS: This cohort mortality study examines the
      mortalities of 1059 full time white male production workers employed at the plant
      from 1955 to 1977. A detailed exposure assessment was done on the 600 workers
      with exposure to MBT. Nine years of additional follow up to the previous study
      are added. RESULTS: It was found that MBT workers have expected rates of lung
      (standardised mortality ratio (SMR) = 1.0 95% confidence interval (95% CI) 0.7 to
      1.5) and prostate (SMR = 0.9, 95% CI 0.2 to 2.3) cancer. There was an excess of
      bladder cancer among MBT workers who had definite exposure to PAB (SMR = 27.1,
      95% CI 11.7 to 53.4), and MBT workers with potential exposure to PAB (SMR = 4.3,
      95% CI 1.4 to 10.0). However, there were no deaths from bladder cancer among
      workers with no exposure to PAB (SMR = 0.0, 95% CI 0.0 to 24.7), although there
      were only 0.2 deaths expected. CONCLUSIONS: The potential confounding of exposure
      to an unknown portion of PAB in the MBT workers makes it impossible to evaluate
      risk of bladder cancer in this population at this time. However, exposure to MBT
      does not seem to increase the risk of most cancers including cancers of the lung
      and prostate.

PMID- 10658545
TI  - Cancer incidence in a cohort of Swedish sewage workers: extended follow up.
AB  - OBJECTIVES: To study the cancer incidence in a cohort of Swedish sewage workers.
      An increased incidence of cancer of the stomach, the kidney and the nervous
      system in this cohort was previously reported. This new analysis reports on 9
      more years of follow up. METHODS: The study is an analysis of a cohort of all 711
      employees at 17 Swedish sewage plants employed for at least for 1 year during the
      years 1965-86. Assessment of exposures was performed by classification of work
      tasks. Standardised incidence ratios (SIRs), and 95% confidence intervals (95%
      CIs) were calculated. RESULTS: The total cancer incidence was not significantly
      increased (SIR = 1.2, 95% CI 0.92 to 1.5) but the incidence of prostate cancer
      was (SIR = 1.6, 95% CI 1.0 to 2.5), and based on two cases only, there seemed to
      be a significant increase of cancer of the nose and the nasal sinuses (SIR = 12,
      95% CI 1.5 to 44). The incidence of stomach cancer was also increased (SIR = 2.3,
      95% CI 0.99 to 4.5). There was no relation between cancer incidence and level of
      sewage exposure. CONCLUSIONS: Sewage workers did not have an increased risk of
      cancer, and the increased risk estimates for some specific cancer sites were not
      conclusive.

PMID- 10658546
TI  - Correlation between urinary 2-methoxy acetic acid and exposure of 2-methoxy
      ethanol.
AB  - OBJECTIVES: To examine the correlation between airborne 2-methoxy ethanol (ME)
      exposures and the urinary 2-methoxy acetic acid (MAA) and to recommend a
      biological exposure index (BEI) for ME. METHODS: 8 Hour time weighted average
      (TWA) personal breathing zone samples and urine samples before and after the
      shift were collected from Monday to Saturday for 27 workers exposed to ME and on
      Friday for 30 control workers. RESULTS: No correlation was found between airborne
      exposure to ME and urinary MAA for nine special operation workers due to the use
      of personal protective equipment. For 18 regular operation workers, a significant
      correlation (r = 0.702, p = 0.001) was found between urinary MAA (mg/g
      creatinine) on Friday at the end of the shift and the weekly mean exposures of ME
      in a 5 day working week. The proposed BEI, which corresponds to exposure for 5
      days and 8 hours a day to 5 ppm, extrapolated from the regression equation is 40
      mg MAA/g creatinine. A significant correlation was also found between the weekly
      increase of urinary MAA (Friday after the shift minus Monday before the shift)
      and the weekly mean exposures of ME (r = 0.741). The recommended value of the
      weekly increase of urinary MAA for 5 days repeated exposures of 5 ppm ME is 20
      mg/g creatinine. No urinary MAA was detected in workers in the non-exposed
      control group. CONCLUSIONS: The Friday urinary MAA after the shift or the weekly
      increase of urinary MAA is a specific and a good biomarker of weekly exposure to
      ME.

PMID- 10658547
TI  - Air pollution and hospital admissions for respiratory and cardiovascular diseases
      in Hong Kong.
AB  - OBJECTIVE: To investigate short term effects of concentrations of pollutants in
      ambient air on hospital admissions for cardiovascular and respiratory diseases in
      Hong Kong. METHODS: Retrospective ecological study. A Poisson regression was
      performed of concentrations of daily air pollutant on daily counts of emergency
      hospital admissions in 12 major hospitals. The effects of time trend, season, and
      other cyclical factors, temperature, and humidity were accounted for.
      Autocorrelation and overdispersion were corrected. Daily concentrations of
      nitrogen dioxide (NO2), sulphur dioxide (SO2), ozone (O3), and particulate matter
      < 10 microns in aerodynamic diameter (PM10) were obtained from seven air
      monitoring stations in Hong Kong in 1994 and 1995. Relative risks (RR) of
      respiratory and cardiovascular disease admissions (for an increase of 10
      micrograms/m3 in concentration of air pollutant) were calculated. RESULTS:
      Significant associations were found between hospital admissions for all
      respiratory diseases, all cardiovascular diseases, chronic obstructive pulmonary
      diseases, and heart failure and the concentrations of all four pollutants.
      Admissions for asthma, pneumonia, and influenza were significantly associated
      with NO2, O3, and PM10. Relative risk (RR) for admissions for respiratory disease
      for the four pollutants ranged from 1.013 (for SO2) to 1.022 (for O3), and for
      admissions for cardiovascular disease, from 1.006 (for PM10) to 1.016 (for SO2).
      Those aged > or = 65 years were at higher risk. Significant positive interactions
      were detected between NO2, O3, and PM10, and between O3 and winter months.
      CONCLUSIONS: Adverse health effects are evident at current ambient concentrations
      of air pollutants. Further reduction in air pollution is necessary to protect the
      health of the community, especially that of the high risk group.

PMID- 10658548
TI  - Clearance of man made mineral fibres from the lungs of sheep.
AB  - OBJECTIVES: To compare the clearance rate, the related pathology, and the
      chemical and morphological changes of three man made mineral fibres (MMMFs) in
      the sheep model of pneumoconiosis. METHODS: Fibrous particles were extracted from
      lung parenchyma and analysed by transmission electron microscopy (TEM) and energy
      dispersive spectroscopy (EDS). RESULTS: The concentration of MMMF11, MMMF21,
      refractory ceramic fibre (RCF-1), and crocidolite asbestos fibres decreased with
      time according to a slow and a fast kinetic component. There was a statistical
      difference in the four regression lines as a function of time and the type of
      fibres (p < 0.001). The diameter of MMMFs decreased during the course of the
      time, whereas the crocidolite fibres did not seem to show any change. There was a
      statistical difference in the four regression lines as a function of time (p =
      0.037) and type of fibres (p < 0.001). Ferruginous bodies were counted in the 40
      sheep for which the latency period was 2 years. No typical ferruginous bodies
      were found in the groups exposed to MMMFs. The geometric mean concentration of
      asbestos bodies in the group exposed to crocidolite was 2421 bodies/g lung tissue
      (95% CI 385 to 15260). CONCLUSIONS: The number of initially retained fibres
      decreased with time according to a slow and a fast kinetic component. MMMF11 and
      MMMF21 have similar clearance, faster than RCF-1 and crocidolite. The geometric
      mean diameter and length of MMMF decreased with time, but crocidolite did not.
      After 2 years in the sheep tracheal lobe, ferruginous bodies were not found in
      all three MMMF groups but were substantial in the crocidolite group. Clearance is
      thought to proceed through dissolution and macrophage translocation.

PMID- 10658549
TI  - Preventing commercial fishing deaths in Alaska.
AB  - OBJECTIVES: To evaluate the effectiveness of the United States Commercial Fishing
      Industry Vessel Safety Act of 1988 in reducing the high occupational death rate
      (200/100,000/year in 1991-2) among Alaska's commercial fishermen. METHODS:
      Comprehensive surveillance of deaths in commercial fishing was established by our
      office during 1991 and 1992 for Alaska. Demographic data and data on risk factors
      and incidents were compiled and analysed for trend. RESULTS: During 1991-8, there
      was a significant (p < 0.001) decrease in deaths in Alaska related to commercial
      fishing. Although drownings from fishermen falling overboard and events related
      to crab fishing vessels (often conducted far offshore and in winter) have
      continued to occur, marked progress (significant downward trend, p < 0.001) has
      been made in saving the lives of people involved in vessels capsizing and
      sinking. CONCLUSIONS: Specific measures tailored to prevent drowning associated
      with vessels capsizing and sinking in Alaska's commercial fishing industry have
      been successful. However, these events continue to occur, and place fishermen and
      rescue personnel at substantial risk. Additional strategies must be identified to
      reduce the frequency of vessels capsizing and sinking, to enable parallel
      improvements in the mortality among crab fishermen, and to prevent fishermen
      falling overboard and drownings associated with them.

PMID- 10658550
TI  - Analysis by sex of low back pain among workers from small companies in the Paris
      area: severity and occupational consequences.
AB  - OBJECTIVES: To describe workers with low back symptoms, to identify risk factors
      and to assess the occupational consequences separately in men and women. METHODS:
      A descriptive study was conducted between 1 October 1996 and 31 December 1996 in
      a sample of workers selected at random from all types of small companies in the
      Paris area. A group of 202 occupational physicians interviewed 7129 workers with
      a standardised questionnaire including the Nordic questionnaire. Data analysis
      was performed by sex in the two groups: with low back pain and without low back
      pain over the previous 12 months. The group with low back pain was then divided
      into four subgroups: mild cases (without referred pain), moderate cases (with
      referred pain above the knee), serious cases (with referred pain below the knee),
      and low back pain with occupational consequences. RESULTS: 7010 questionnaires
      were able to be evaluated. The sample consisted of 54.8% of men (3842) and 45.2%
      of women (3168), with a mean age of 37.8 and 37.0 years, respectively (p < 0.05).
      The following risk factors occurred significantly more often in men: high weight,
      height, body mass index (BMI), smoking, number of children, increased driving
      time and work time, material handling tasks, uncomfortable working positions.
      Most women were clerks (53%). Non-conditional logistic regression applied to the
      whole sample identified female sex as a risk factor (odds ratio (OR) = 1.85, 95%
      confidence interval (95% CI) 1.58 to 2.13). The following risk factors were
      common to both sexes: lifting weights > 10 kg, in women (OR 1.69, 95% CI 1.27 to
      2.25) and in men (OR 1.27, 95% CI 1.06 to 1.53), uncomfortable working positions
      (OR 2.04, 95% CI 1.58 to 2.17 and OR 1.85, 95% CI 1.69 to 2.43), and absence of
      means to achieve good quality work (OR 1.39, 95% CI 1.19 to 1.63 and OR 1.38, 95%
      CI 1.15 to 1.65), respectively. Driving was a risk factor only in men and its
      importance increased with driving time (driving > 4 hours a day (OR 1.61, 95% CI
      1.24 to 2.09)). Severe low back pain was linked to female sex (10.2% of women v
      6.6% of men), high BMI, aging, and uncomfortable working positions. Low back pain
      with occupational consequences (n = 258) was not linked to sex, but only to aging
      and severity. CONCLUSIONS: The incidence and severity of low back pain were
      higher in women, although they seemed to be less exposed to known occupational
      risk factors. However, our results indicate a preponderance of these risk factors
      among female workers. Particular attention must therefore be paid to lifting of
      weights and uncomfortable working positions in female jobs (clerk, trading,
      health care staff).

PMID- 10658551
TI  - Analysis of sickness absence among employees of four NHS trusts.
AB  - OBJECTIVES: To determine the value of using routinely collected sickness absence
      data as part of a health needs assessment of healthcare workers. METHOD: Sickness
      absence records of almost 12900 NHS staff for one calendar year were analysed.
      Three measures of absence, the absence rate, the absence frequency rate, and the
      mean duration of absence, were assessed for the population and comparisons made
      between men and women, full and part time and different occupational groups of
      staff. Also, the main causes of sickness absence were found. RESULTS: Almost 60%
      of the study population had no spells of sickness absence in the year of study
      and almost 20% had only one spell of sickness absence. Female staff were more
      likely to have experienced sickness absence than male staff. Although absence due
      to conditions related to pregnancy were included in the analysis, the incidence
      of these was not sufficient to account for the higher rates of absence among
      female staff. In general, full time staff had greater rates of sickness absence
      than part time staff. 71% of all absences were of < 1 week duration. The main
      known causes of sickness absence were respiratory disorders, digestive disorders,
      and musculoskeletal disorders. CONCLUSIONS: The transition from units managed
      directly from the health board to trusts with individual responsibility for
      personnel issues at the time of data collection resulted in variations in the
      quality of data available for analysis. This together with the use of "dump"
      codes has influenced the quality of the analysis. However, such data should be
      available for analysis to tailor occupational health care to the needs of the
      population.

PMID- 10658552
TI  - Dutch occupational physicians and general practitioners wish to improve
      cooperation.
AB  - OBJECTIVES: To investigate cooperation between occupational physicians (OPs) and
      general practitioners (GPs). METHODS: Literature review; structured interviews;
      questionnaires sent to randomised samples of OPs (n = 232) and GPs (n = 243).
      RESULTS: Actual cooperation is poor. However, more than 80% of both groups
      responded that they want to improve their cooperation, aiming at better quality
      of care. Obstacles identified by OPs include insufficient knowledge among GPs
      about occupational health services (OHSs) (57%) and their patients' working
      conditions (52%). OPs also consider that GPs suspect them of serving employers
      more than employees (44%) and of verifying reasons of absence, with information
      from GPs (34%). Responses from GPs confirm these two suspicions (48%, response
      58%), adding obstacles like commercialisation of OHS, lack of financial
      incentives, etc. Both groups are unanimous about prerequisites for improvement,
      especially guaranteeing the professional autonomy of OPs (OPs 86%, GPs 76%).
      CONCLUSION: As a first step to overcome obstacles to cooperation, OPs must
      clarify their position to GP colleagues. Initiatives have been taken after
      presenting this study.

PMID- 10658553
TI  - Provision and staffing of NHS occupational health services in England and Wales.
AB  - OBJECTIVES: To establish the extent of Occupational Health (OH) service provision
      in the National Health Service (NHS). METHODS: Two postal questionnaires were
      used to obtain information from purchasers and providers in the NHS in England
      and Wales. RESULTS: 99.6% of trust and health authority employers claim to
      provide some form of OH service to their employees indicating widespread
      recognition of need, but virtually no service is provided to other staff such as
      general practitioners (GPs), general dental practitioners (GDPs), and their
      staff. There is a wide variability in the range and quality of OH services,
      suggested by the enormous differences in medical staffing levels, and the
      contractual restrictions where the OH service is provided by another NHS
      employer. Only about a third (highest estimate) to a quarter (lowest estimate) of
      NHS staff have access to a specialist occupational physician. CONCLUSIONS:
      Substantial inequality of access to OH services exists for the NHS workforce,
      despite previous guidance. There is no real evidence to suggest why the extent of
      provision of OH services varies so greatly between institutions.

PMID- 10658554
TI  - Effect of spirometer temperature on FEV1 in a longitudinal epidemiological study.
AB  - OBJECTIVES: To assess the magnitude of error in pulmonary function measurements
      introduced by variation in spirometer temperature under field conditions. In a
      large scale epidemiological study of school children, the influence was
      investigated of spirometer temperature on forced expiratory volume in 1 second
      (FEV1) measured with dry rolling seal volumetric spirometers and conventional
      body temperature, pressure, and saturation (BTPS) corrections. METHODS: Linear
      regression analyses were performed on data from 995 test-retest pairs on 851
      different children, with 1-110 days between test and retest, and spirometer
      temperature differences between -13 degrees C and +9 degrees C. RESULTS: After
      adjusting for effects of growth (test-retest intervals) and circadian variation
      (changes in times of testing), differences in standard BTPS corrected FEV1 showed
      significant (p < 0.05) dependence on differences in spirometer temperature
      between tests (-0.24%/degree C). CONCLUSIONS: When spirometer temperatures vary
      widely, standard BTPS correction does not fully adjust for gas contraction. To
      improve accuracy of volume measurements in epidemiological studies, additional
      correction for variation in spirometer temperature should be considered.

PMID- 10658555
TI  - Future impact of genetic screening in occupational and environmental medicine.
AB  - New genetic technologies open up the possibility of predictive screening, both
      for individual genetic risk factors for susceptibility to workplace hazards and
      for late onset (both single gene and multifactorial) hereditary disease. Although
      the initiative for testing may lie with employers and employees there are many
      potential stakeholders--from family members and workplace colleagues to insurers
      and society in general. The role of the occupational health professional will not
      only involve the contextual interpretation of genetic test results but also the
      myriad of associated ethical and moral questions. This paper considers a range of
      ethical issues with which the occupational health professional may be confronted
      as genetic technology advances.

PMID- 10658556
TI  - Applications of new technology in molecular epidemiology and their relevance to
      occupational medicine.
AB  - Technological advances in molecular biology over the past 2 decades have offered
      more complex techniques that can be used to study the role of specific exogenous
      agents and host variables that cause ill health. Increasingly, studies in human
      populations use this new technology, combined with epidemiological methods, to
      shed light on the understanding of the biological processes associated with
      development of disease. This approach has many potential applications in
      occupational and environmental medicine (OEM), and some aspects of the work in
      this growing field are reviewed. An understanding of biochemistry and genetics at
      the molecular level, specific knowledge on metabolism and mechanisms of action,
      and epidemiology have become increasingly important for the OEM practitioner.
      This is necessary to consider the major question of validation and relevance of
      these molecular biomarkers. As end users, OEM practitioners should also consider
      the impact of these advances on their practices. For example, the availability of
      genetic tests to identify susceptible workers raises issues of ethics, individual
      privacy, right to work, and the relevance of such tests. Several studies have
      presented data on the association of environmental measurements and various
      biomarkers for internal and biologically effective dose, genetic polymorphisms,
      and early response markers. Given the limitations of individual molecular
      biomarkers in assessing risk to health, and the multifactorial nature of
      environmental disease, it is likely that such an approach will increase our
      understanding of the complex issue of mechanisms of disease and further refine
      the process of risk assessment.

PMID- 10658557
TI  - Molecular methods of measurement of hepatitis B virus, hepatitis C virus, and
      human immunodeficiency virus infection: implications for occupational health
      practice.
AB  - Over the past decade, several molecular techniques for the detection of human
      immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus
      (HCV) have been developed that have implications for occupational health
      practice. This review describes the techniques used for qualitative and
      quantitative detection of the viral genome, and briefly explains nucleic acid
      sequencing and analysis of phylogenetic trees. The review also discusses the
      current and potential uses of these techniques in investigations of transmission
      of bloodborne viruses by patient to worker and worker to patient, in the
      management of occupational exposure to blood, in research, and in the development
      of guidance and policy on infected healthcare workers who perform procedures
      prone to exposure.

PMID- 10658558
TI  - Exposure assessment of high molecular weight sensitisers: contribution to
      occupational epidemiology and disease prevention.
AB  - An important group of sensitising agents are so called high molecular weight
      sensitisers--proteins or glycoproteins with molecular weights in the 5-70 kDa
      range that can provoke a specific IgE response in workers exposed to these
      agents. Exposure to high molecular weight sensitisers could only be evaluated
      indirectly in the recent past. Few measurement techniques existed that made it
      possible to measure the allergens directly. As a result, few studies focused on
      establishing exposure-response relations, and exposure standards have not been
      established for high molecular weight sensitisers, or those that have are of
      doubtful scientific basis. Recent use of immunoassays changed this perspective
      dramatically. Antibodies used in the assays can originate from human serum
      (sensitized workers), serum from sensitised animals (rabbits producing polyclonal
      antibodies), or animal derived cell cultures producing monoclonal antibodies.
      Although few comparative studies exist, the available evidence suggests that
      although the correlation of allergen concentrations obtained with different
      assays is good, large systematic differences occur. The use of conversion factors
      to make data from previously performed allergen measurements comparable or
      exchangeable is limited and thorough standardization of assays is preferred.
      Validation and comparison of different assays by comparisons between laboratories
      seem important issues that have not received the attention needed.
      Epidemiological studies in several industries that used immunoassay for the
      exposure characterisation have shown that risk of sensitisation increases with
      increasing exposure to allergens. Several studies have also shown that clear
      differences in potency seem to exist. Sensitisation to rat urinary allergens and
      fungal alpha-amylase occurred in the pg/m3 and ng/m3 range. The main research
      questions of the near future have to focus on the prevention of occupational
      sensitisation. Standard setting seems possible for some allergenson the basis of
      the available scientific evidence for the existence of exposure response
      relations. However, assays for characterising exposure to allergens have to be
      rigorously standardised before they can be used under field conditions.

PMID- 10658559
TI  - Flow cytometry in the exploration of the physiopathology of occupational lung
      disease.
AB  - Flow cytometry is a simple analytical technique used for the investigation of
      cells taken from various sources. Cells are identified by both their physical
      characteristics and the presence or absence of specific molecules on the cell
      surface. These molecules may be either phenotypic, or induced by a specific
      stimulus. Flow cytometry has been used to identify the nature and extent of the
      immune response in several occupational respiratory conditions including
      occupational asthma, irritant induced respiratory problems, and asbestos related
      lung disease. Also, it may be of value in monitoring workplace exposure to some
      hazardous materials. Although of limited diagnostic value at present, the
      technique has provided an insight into the modulation of immune cells, and their
      function, in people exposed to hazardous materials in the workplace. In this
      review, the principals of flow cytometry will be explored and the use of flow
      cytometry to investigate occupational respiratory disease will be discussed.

PMID- 10658560
TI  - Measurement of human exposure to biologically relevant fractions of inhaled
      aerosols.
AB  - Aerosol sampling has evolved with changes in technology and our understanding of
      the importance of assessing the biologically relevant fractions of the total
      aerosol. During the past decade there has been international agreement on the
      definitions for the inhalable, thoracic, and respirable fractions and instruments
      have been developed to collect samples according to these conventions. These
      measurement techniques are now well established in the workplace and are
      increasingly being applied to assessments of non-occupational exposure, as the
      practical difficulties in obtaining samples over 24 hours have been solved. It is
      argued that multiple aerosol size fractions should be measured for hazardous
      substances--such as inorganic lead--in which inhaled material may either be
      absorbed in the alveoli (respirable) or cleared from the ciliated airways in the
      lung to the gut and then absorbed (thoracic and extrathoracic). Such measurements
      should improve the evaluation of the risk for inhaled lead, particularly for non
      occupational exposure of children. Also, passive aerosol sampling techniques may
      enable measurements of non-occupational exposure to be made over several weeks
      and this would also help improve the reliability of the risk evaluation for
      aerosol toxicants with a long biological half life. However, further development
      of these techniques is required if they are to be practicable and biologically
      relevant.

PMID- 10658561
TI  - New technologies in the use of exhaled breath analysis for biological monitoring.
AB  - Breath analysis is an attractive non-invasive procedure for screening workers
      exposed to solvents. It has been used in numerous laboratory based studies and
      for field research. Despite the obvious advantages in routine biological
      monitoring it has failed to become widely accepted as a tool in occupational
      hygiene. Recent advances in breath sampling and analysis are such that it is
      likely to become more widely used in the future. In this paper, the past 5 years
      have been reviewed to try to assess what developments might now contribute to the
      increased use of breath analysis in biological monitoring; in particular, the
      development of a selected ion flow tube mass spectrometer for real time direct
      analysis of trace gases in breath and the more immediately available and less
      expensive indirect methods involving collection devices with adsorbent tubes is
      important. The introduction of guidance values for biological monitoring with
      clear advice on sampling times and the recognition of the importance of quality
      assurance programmes will help improve confidence in the technique.

PMID- 10658562
TI  - Development of an expert system for the interpretation of serial peak expiratory
      flow measurements in the diagnosis of occupational asthma. Midlands Thoracic
      Society Research Group.
AB  - If asthma is due to work exposures there must be a relation between these
      exposures and the asthma. Asthma causes airway hyperresponsiveness and
      obstruction; the obstruction can be measured with portable meters, which usually
      measure peak expiratory flow, or sometimes forced expiratory volume in 1 second
      (FEV1). These can be measured serially (for instance 2 hourly) over several weeks
      at and away from work. Once occupational asthma develops, the asthma will be
      induced by many non-specific triggers common to non-occupational asthma. The
      challenge is to identify changes in peak expiratory flow due to work among other
      non-occupational causes. Standard statistical tests have been found to be
      insensitive or non-specific, principally because of the variable period for
      deterioration to occur after exposure, and the sometimes prolonged time for
      recovery to occur, such that days away from work may initially have lower
      measurements than days at work. A computer assisted diagnostic aid (Oasys) has
      been developed to separate occupational from non-occupational causes of airflow
      obstruction. Oasys-2 is based on a discriminant analysis, and achieved a
      sensitivity of 75% and a specificity of at least 94%; therefore peak expiratory
      flow monitoring combined with Oasys-2 analysis is better to confirm than to
      exclude occupational asthma. A neural network version in development has improved
      on this. Both have been based on expert interpretation of peak flow measurements
      plotted as daily maximum, mean, and minimum, with the first reading at work taken
      as the first reading of the day. Oasys has been evaluated with independent
      criteria against measurements made in a wide range of occupational situations.
      Oasys is sufficiently developed to be the initial method for the confirmation,
      although less so for exclusion of occupational asthma.

PMID- 10658563
TI  - Conceptual model for assessment of dermal exposure.
AB  - Dermal exposure, primarily to pesticides, has been measured for almost half a
      century. Compared with exposure by inhalation, limited progress has been made
      towards standardisation of methods of measurement and development of biologically
      relevant exposure measures. It is suggested that the absence of a consistent
      terminology and a theoretical model has been an important cause of this lack of
      progress. Therefore, a consistent terminology based on a multicompartment model
      for assessment of dermal exposure is proposed that describes the transport of
      contaminant mass from the source of the hazardous substance to the surface of the
      skin. Six compartments and two barriers together with eight mass transport
      processes are described. With the model structure, examples are given of what
      some existing methods actually measure and where there are limited, or no,
      methods for measuring the relevant mass in a compartment or transport of mass.
      The importance of measuring the concentration of contaminant and not mass per
      area in the skin contaminant layer is stressed, as it is the concentration
      difference between the skin contamination layer and the perfused tissue that
      drives uptake. Methods for measuring uptake are currently not available.
      Measurement of mass, concentration, and the transport processes must be based on
      a theoretical model. Standardisation of methods of measurement of dermal exposure
      is strongly recommended.

PMID- 10658564
TI  - Analysis of incidence of childhood cancer in the West Midlands of the United
      Kingdom in relation to proximity to main roads and petrol stations.
AB  - OBJECTIVES: To investigate whether there is an excess of leukaemias in 0-15 year
      old children among those living in close proximity (within 100 m) of a main road
      or petrol station. METHODS: Data for 0-15 year old children diagnosed between
      1990 and 1994 in the United Kingdom West Midlands were used. Postcode addresses
      were used to locate the point of residence which was compared with proximity to
      main roads and petrol stations separately, and to both together. Odds ratios
      (ORs) were calculated with solid tumours as a control, and incidence ratios (IRs)
      with population density as a control. RESULTS: The method based on solid tumours
      as a control showed ORs of 1.61 (95% confidence interval (95% CI) 0.90 to 2.87)
      and 1.99 (95% CI 0.73 to 5.43), for those living within 100 m of a main road or
      petrol station respectively. When population was used as a control, the estimated
      IRs for leukaemia were 1.16 (95% CI 0.74 to 1.72) and 1.48 (95% CI 0.65 to 2.93)
      for residence within 100 m of a main road or petrol station respectively, but
      neither reached significance at the 95% level. Results for residence in close
      proximity to both a main road and petrol station were inconsistent, but there
      were few. The influence of socioeconomic factors as represented by the Townsend
      deprivation index on leukaemia incidence was not significant and the results were
      not explicable on the basis of impact of social class. CONCLUSIONS: The results
      are suggestive of a small increase in risk of childhood leukaemia, but not solid
      tumours, for those living in close proximity to a main road or petrol station.
      This increase in risk is not, however, significant and a larger study is
      warranted to establish the true risk and causes of any increase in risk.

PMID- 10658565
TI  - Risk of stomach cancer associated with 12 workplace hazards: analysis of death
      certificates from 24 states of the United States with the aid of job exposure
      matrices.
AB  - OBJECTIVE: To investigate the risk of gastric cancer associated with 12 workplace
      exposures suspected or discussed as aetiological agents in previous reports.
      METHODS: A case-control study was conducted based on the death certificates of
      several million deaths in 24 states of the United States in 1984-96. Overall, the
      data base included 41,957 deaths from stomach cancer among subjects aged > or =
      25 years. These were 20,878 white men, 14,125 white women, 4215 African American
      men, and 2739 African American women. Two controls for each case were selected
      from among subjects who died from non-malignant diseases, frequency matched to
      cases by geographic region, race, sex and 5 year age group. Each three digit
      occupation and industry code listed in the 1980 United States census was
      classified for probability and intensity of exposure to asbestos, inorganic dust,
      metals, lead, polycyclic aromatic hydrocarbons (PAHs), nitrogen oxides,
      nitrosamines, sulphuric acid, fertilisers, herbicides, other pesticides
      (including insecticides and fungicides), and wood dust. These job exposure
      matrices were subsequently applied to the occupation-industry combinations in the
      death certificates of study subjects, separately by sex and race. RESULTS: Risk
      of stomach cancer showed a modest association with occupational exposure to
      inorganic dust (odds ratio (OR) = 1.06; 95% confidence interval (95% CI) 1.03 to
      1.11) with significant increasing trends by probability and intensity of exposure
      overall and by cross classification of the two exposure matrices. Workplace
      exposure to nitrosamines also showed a modest association (OR = 1.06; 95% CI 1.01
      to 1.11), but the excess risk was even smaller after adjusting for inorganic dust
      exposure. Risk of gastric cancer was not associated with any of the other
      workplace exposures considered in this study. CONCLUSIONS: Non-differential
      misclassification of exposure may have caused negative findings in this study,
      and inorganic dust may be a partial surrogate for exposure to other unknown risk
      factors. Alternatively, our results suggest that occupational factors contribute
      little to the aetiology of gastric cancer. Inorganic dust might act through non
      specific mechanisms, similar to those proposed for salt, aspirin, and heat by
      other authors.

PMID- 10658566
TI  - Measurement of vitamin D3 metabolites in smelter workers exposed to lead and
      cadmium.

PMID- 10658567
TI  - Exposure-response relations of alpha-amylase sensitization in British bakeries
      and flour mills.

PMID- 10658568
TI  - Breathe easy: training programme.

PMID- 10658569
TI  - Health effects among workers in sewage treatment plants.

PMID- 10658570
TI  - New drugs-reports of new drugs recently approved by the FDA. Abacavir sulfate.

PMID- 10658571
TI  - Towards the development of novel antibiotics: synthesis and evaluation of a
      mechanism-based inhibitor of Kdo8P synthase.
AB  - The design and two synthetic pathways to aminophosphonate 4 which mimics the
      ionic and steric properties of putative oxocarbenium intermediate 3 in the Kdo8P
      synthase-catalyzed reaction are reported. It was found that 4 is a slow-binding,
      most potent inhibitor of the enzyme yet tested, with a Ki value of 0.4 microM.

PMID- 10658572
TI  - Molecular recognition by acetylcholinesterase at the peripheral anionic site:
      structure-activity relationships for inhibitions by aryl carbamates.
AB  - Substituted phenyl-N-butyl carbamates (1-9) are potent irreversible inhibitors of
      Electrophorus electricus acetylcholinesterase. Carbamates 1-9 act as the
      peripheral anionic site-directed irreversible inhibitors of acetylcholinesterase
      by the stop-time assay in the presence of a competitive inhibitor, edrophonium.
      Linear relationships between the logarithms of the dissociation constant of the
      enzyme inhibitor adduct (Ki), the inactivation constant of the enzyme-inhibitor
      adduct (k2), and the bimolecular inhibition constant (k(i)) for the inhibition of
      Electrophorus electricus acetylcholinesterase by carbamates 1-9 and the Hammett
      substituent constant (sigma), are observed, and the reaction constants (ps) are 
      1.36, 0.35 and -1.01, respectively. Therefore, the above reaction may form a
      positive charged enzyme-inhibitor intermediate at the peripheral anionic site of
      the enzyme and may follow the irreversible inactivation by a conformational
      change of the enzyme.

PMID- 10658573
TI  - Synthesis and biological activity of 4-alkoxy chalcones: potential hydrophobic
      modulators of P-glycoprotein-mediated multidrug resistance.
AB  - A series of 4-alkoxy-2',4',6'-trihydroxychalcones have been synthesized and
      evaluated for their ability to inhibit P-glycoprotein-mediated multidrug
      resistance (MDR) by direct binding to a purified protein domain containing an ATP
      binding site and a modulator-interacting region. The introduction of hydrophobic
      alkoxy groups at position 4 led to much more active compounds as compared to the
      parent chalcone. The binding affinity increased as a function of the chain
      length, up to the octyloxy derivative for which a K(D) of 20 nM was obtained.

PMID- 10658574
TI  - Synthesis of the nanomolar photoaffinity GABA(B) receptor ligand CGP 71872
      reveals diversity in the tissue distribution of GABA(B) receptor forms.
AB  - A radioiodinated probe, [125I]-CGP 71872, containing an azido group that can be
      photoactivated, was synthesized and used to characterize GABA(B) receptors.
      Photoaffinity labeling experiments using crude membranes prepared from rat brain
      revealed two predominant ligand binding species at approximately 130 and
      approximately 100 kDa believed to represent the long (GABA(B)R1a) and short
      (GABA(B)R1b) forms of the receptor. Indeed, these ligand binding proteins were
      immunoprecipitated using a GABA(B) receptor-specific antibody confirming the
      receptor specificity of the photoaffinity probe. Most convincingly, [125I]-CGP
      71872 binding was competitively inhibited in a dose-dependent manner by cold CGP
      71872, GABA, saclofen, (-)-baclofen, (+)-baclofen and (L)-glutamic acid with a
      rank order and stereospecificity characteristic of the GABA(B) receptor.
      Photoaffinity labeling experiments revealed that the recombinant GABA(B)R2
      receptor does not bind [125I]-CGP 71872, providing surprising and direct evidence
      that CGP 71872 is a GABA(B)R1 selective antagonist. Photoaffinity labeling
      experiments using rat tissues showed that both GABA(B)R1a and GABA(B)R1b are co
      expressed in the brain, spinal cord, stomach and testis, but only the short
      GABA(B)R1b receptor form was detected in kidney and liver whereas the long
      GABA(B)R1a form was selectively expressed in the adrenal gland, pituitary, spleen
      and prostate. We report herein the synthesis and biochemical characterization of
      the nanomolar affinity [125I]-CGP 71872 and CGP 71872 GABA(B)R1 ligands, and
      differential tissue expression of the long GABA(B)R1a and short GABA(B)R1b
      receptor forms in rat and dog.

PMID- 10658575
TI  - Synthesis and BZR affinity of pyrazolo[1,5-a]pyrimidine derivatives. Part 1:
      study of the structural features for BZR recognition.
AB  - Examination of the pharmacophoric points of the pyrazolo[1,5-a]pyrimidine
      derivatives, ligands for BZR, previously published led us to the design of a
      novel class of 3,6-diaryl-4,7-dihydro-pyrazolo[1,5-a]pyrimidin-7-ones and to
      determine the groups involved in the BZR recognition.

PMID- 10658576
TI  - Mitomycin C linked to DNA minor groove binding agents: synthesis, reductive
      activation, DNA binding and cross-linking properties and in vitro antitumor
      activity.
AB  - Mitomycin C (MC) is a natural cytotoxic agent used in clinical anticancer
      chemotherapy. Its antitumor target appears to be DNA. Upon bioreductive
      activation MC alkylates and cross-links DNA. MC derivatives were synthesized in
      which MC was linked to DNA minor groove binding agents, analogous to netropsin
      and distamycin. One, two and three N-methylpyrrole carboxamide units were
      conjugated with MC by a (CH2)5-tether to the 7-amino group of MC (11, 12 and 13,
      respectively). In contrast to MC 11, 12 and 13 displayed non-covalent affinity to
      DNA. Their bioreductive activation by NADPH-cytochrome c reductase proceeded as
      fast as that of MC. Metabolites arising from reductive and low-pH activation were
      characterized and found to be analogous to those of MC. DNA cross-linking
      activities were weak and decreased with an increasing number of N-methylpyrrole
      carboxamide units linked with the mitomycin molecule. No adducts were formed with
      calf thymus DNA in detectable amounts. In vitro antitumor activities of 11-13
      were determined using the NCI in vitro antitumor screen. The conjugates 11-13 are
      growth inhibitory; however, their activities are 1.5-2 orders of magnitude lower
      than that of MC. COMPARE analysis indicates that the mechanism of the action of
      11 and 12 correlates moderately with MC but negatively with distamycin. Conjugate
      13 correlates neither with MC nor with distamycin. The results suggest that the
      basic cause of the observed low activity of the MC-minor groove binder conjugates
      is the fast irreversible decay of the activated MC, competing effectively with
      the slow drug delivery to CpG sites, required for the alkylation.

PMID- 10658577
TI  - Pseudo-cyclic oligonucleotides: in vitro and in vivo properties.
AB  - We have designed and studied antisense oligodeoxynucleotides (oligonucleotides;
      oligos) which we call 'pseudo-cyclic oligonucleotides' (PCOs). PCOs contain two
      oligonucleotide segments attached through their 3'-3'- or 5'-5'-ends. One of the
      segments of the PCO is an antisense oligo complementary to a target mRNA, and the
      other is a short protective oligo that is 5-8 nucleotides long and complementary
      to the 3'- or 5'-end of the antisense oligo. As a result of complementarity
      between the antisense and protective oligo segments, PCOs form intramolecular
      pseudo-cyclic structures in the absence of the target RNA. The antisense oligo
      segment of PCOs used for the studies described here is complementary to an 18
      nucleotide-long site on the mRNA of the protein kinase A regulatory subunit
      RIalpha (PKA-RIalpha). Thermal melting studies of PCOs in the absence and
      presence of the complementary RNA suggest that the pseudo-cyclic structures
      formed in the absence of the target RNA dissociate, bind to the target RNA, and
      form heteroduplexes. The results of RNase H cleavage assays suggest that PCOs
      bind to complementary RNA and activate RNase H in a manner similar to that of an
      18-mer conventional antisense PS-oligo. In snake venom (a 3'-exonuclease) or
      spleen (a 5'-exonuclease) phosphodiesterase digestion studies, PCOs are more
      stable than conventional antisense oligos because of the presence of 3'-3'- or 5'
      5'-linkages and the formation of intramolecular pseudo-cyclic structures. PCOs
      with a phosphorothioate antisense oligo segment inhibited cell growth of MDA-MB
      468 and GEO cancer cell lines similar to that of the conventional antisense PS
      oligo, suggesting efficient cellular uptake and target binding. The nuclease
      stability studies in mice suggest that PCOs have higher in vivo stability than
      antisense PS-oligos. The studies in mice showed similar pharmacokinetic and
      tissue distribution profiles for PCOs to those of antisense PS-oligos in general,
      but rapid elimination from selected tissues.

PMID- 10658578
TI  - Molecular dynamics of NPY Y1 receptor activation.
AB  - A three-dimensional model of the human neuropeptide Y(NPY)Y1 receptor (hY1) was
      constructed, energy refined and used to simulate molecular receptor interactions
      of the peptide ligands NPY, [L31, P34]NPY, peptide YY (PYY) and pancreatic
      polypeptide (PP), and of the nonpeptide antagonist R-N2-(diphenylacetyl)-N-(4
      hydroxyphenyl)methyl-argininamide (BIBP3226) and its S-enantiomer BIBP3435. The
      best complementarity in charges between the receptor and the peptides, and the
      best structural accordance with experimental studies, was obtained with amino
      acid 1-4 of the peptides interacting with Asp194, Asp200, Gln201, Phe202 and
      Trp288 in the receptor. Arg33 and Arg35 of the peptides formed salt bridges with
      Asp104 and Asp287, respectively, while Tyr36 interacted in a binding pocket
      formed by Phe41, Thr42, Tyr100, Asn297, His298 and Phe302. Calculated
      electrostatic potentials around NPY and hY1 molecules indicated that ligand
      binding is initiated by electrostatic interactions between a highly positive
      region in the N- and C-terminal parts of the peptides, and a negative region in
      the extracellular receptor domains. Molecular dynamics simulations of NPY and
      BIBP3226 interactions with the receptor indicated rigid body motions of TMH5 and
      TMH6 upon NPY binding as mechanisms of receptor activation, and that BIBP3226 may
      act as an antagonist by constraining these motions.

PMID- 10658579
TI  - A new convenient transformation of erythromycin A into clarithromycin.
AB  - Erythromycin A was transformed into clarithromycin by the sequence of reactions:
      selective thexyldimethylsilylation of the 9-oxime, trimethylsilylation of the
      2',4''-hydroxy groups, methylation of the resulting 2',4''-[O
      bis(trimethylsilyl)]-9-[O-(dimethylthexylsilyl)oxime] and acidic regeneration of
      the protected functionalities.

PMID- 10658580
TI  - 1-[2-Hydroxy-3-octadecan-1'-oate]propyl-2'',2'',5'',5''-tetramethyl pyrolidine-N
      oxyl-3''-carboxylate as a potential spin probe for membrane structure studies.
AB  - The synthesis of a new minimum steric perturbing proxyl nitroxide, which is a
      derivative of glycerol and contains a stearic acid moiety, has been carried out.
      Its localization in model membrane L-alpha-dipalmitoyl phosphatidyl choline
      (DPPC) was ascertained with the help of ESR, DSC, 1H and 31P NMR techniques. The
      nitroxide was used for detecting the changes in the phase transition temperature
      of the model membranes in the presence and absence of drugs. The permeation of
      the vasodilating drug epinephrine has also been studied using this spin label.
      The results prove the potential applicability of the new spin probe in the spin
      labeling of biomembranes.

PMID- 10658581
TI  - Enantioselective synthesis and biological evaluation of 5-o-carboranyl pyrimidine
      nucleosides.
AB  - Base-modified carborane-containing nucleosides such as 5-o-carboranyl-2'
      deoxyuridine (CDU) when combined with neutrons have potential for the treatment
      of certain malignancies. Lack of toxicity in various cells, high accumulation in
      cancer cells and intracellular phosphorylation are desirable characteristics for
      modified nucleosides used in boron neutron capture therapy (BNCT) for brain
      tumors and other malignancies. The aim of this work was to synthesize the two
      beta-enantiomers of several 5-o-carboranyl-containing nucleosides. These
      derivatives may possess favorable properties such as high lipophilicity, high
      transportability, the ability to be phosphorylated, and resistance to catabolism.
      Beta-isomers of 2',3'-dihydroxynucleosides and analogues containing a heteroatom
      in the sugar moiety were also synthesized. Carboranyl pyrimidine nucleosides were
      prepared either from the parent beta-D-nucleoside, beta-L-nucleoside, or by a
      coupling reaction. The dioxolane derivative 7 was prepared by a coupling reaction
      between protected 5-o-carboranyluracil (8, CU) and the corresponding protected
      heterocycle. Specific catalysts were used during the N-glycosylation process to
      favor the formation of the beta-isomer. Biological evaluation of these new chiral
      5-o-carboranyl pyrimidine derivatives indicated that most of these compounds have
      low toxicity in a variety of normal and malignant cells and achieved high
      cellular levels in a lymphoblastoid cell line. Increasing the number of hydroxyl
      groups on the sugar moiety decreased the cellular accumulation and serum binding
      to different extents. Five compounds were identified for further biological
      evaluation as potential agents for BNCT.

PMID- 10658582
TI  - Model studies on a synthetically facile series of N-substituted phenyl-N'-pyridin
      3-yl ureas leading to 1-(3-pyridylcarbamoyl) indolines that are potent and
      selective 5-HT(2C/2B) receptor antagonists.
AB  - A model series of 5-HT2C antagonists have been prepared by rapid parallel
      synthesis. These N-substituted phenyl-N'-pyridin-3-yl ureas were found to have a
      range of 5-HT2C receptor affinities and selectivities over the closely related 5
      HT2A receptor. Extrapolation of simple SAR, derived from this set of compounds,
      to the more active but synthetically more complex 1-(3-pyridylcarbamoyl)indoline
      series allowed us to target optimal substitution patterns and identify potent and
      selective 5-HT(2C/2B) antagonists.

PMID- 10658583
TI  - Nonpeptidic HIV protease inhibitors possessing excellent antiviral activities and
      therapeutic indices. PD 178390: a lead HIV protease inhibitor.
AB  - With the insight generated by the availability of X-ray crystal structures of
      various 5,6-dihydropyran-2-ones bound to HIV PR, inhibitors possessing various
      alkyl groups at the 6-position of 5,6-dihydropyran-2-one ring were synthesized.
      The inhibitors possessing a 6-alkyl group exhibited superior antiviral activities
      when compared to 6-phenyl analogues. Antiviral efficacies were further improved
      upon introduction of a polar group (hydroxyl or amino) on the 4-position of the
      phenethyl moiety as well as the polar group (hydroxymethyl) on the 3-(tert-butyl
      5-methyl-phenylthio) moiety. The polar substitution is also advantageous for
      decreasing toxicity, providing inhibitors with higher therapeutic indices. The
      best inhibitor among this series, (S)-6-[2-(4-aminophenyl)-ethyl]-(3-(2-tert
      butyl-5-methyl-phenylsulfa nyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one
      (34S), exhibited an EC50 of 200 nM with a therapeutic index of > 1000. More
      importantly, these non-peptidic inhibitors, 16S and 34S, appear to offer little
      cross-resistance to the currently marketed peptidomimetic PR inhibitors. The
      selected inhibitors tested in vitro against mutant HIV PR showed a very small
      increase in binding affinities relative to wild-type HIV PR. Cmax and absolute
      bioavailability of 34S were higher and half-life and time above EC95 were longer
      compared to 16S. Thus 34S, also known as PD 178390, which displays good antiviral
      efficacy, promising pharmacokinetic characteristics and favorable activity
      against mutant enzymes and CYP3A4, has been chosen for further preclinical
      evaluation.

PMID- 10658584
TI  - Ring-substituted 11-oxo-11H-indeno[1,2-b]quinoline-6-carboxamides with similar
      patterns of cytotoxicity to the dual topo I/II inhibitor DACA.
AB  - A series of ring-substituted analogues of the topoisomerase inhibitor 11-oxo-11H
      indeno[1,2-b]quinoline-6-carboxamides was prepared and evaluated. The compounds
      were prepared by Pfitzinger reaction of the appropriate isatin-7-carboxylic acids
      and 1-indanones, followed by selective thermal decarboxylation of the resulting
      tetracyclic diacids, subsequent oxidation of the methylene group with alkaline
      permanganate under carefully controlled conditions, and 1,1'-carbonyldiimidazole
      induced amidation. The compounds were evaluated in a panel of cell lines in
      culture. The largest increases in cytotoxicity (five to tenfold) were shown by 4
      substituted analogues, with the 4-Cl derivative having an IC50 of 8 nM against
      the Lewis lung carcinoma.

PMID- 10658585
TI  - Synthesis and anti-HIV activity of 1,1,3-trioxo-2H,4H-thieno[3,4
      e][1,2,4]thiadiazines (TTDs): a new family of HIV-1 specific non-nucleoside
      reverse transcriptase inhibitors.
AB  - The anti-HIV activity of a novel series of 1,1,3-trioxo-2H,4H-thieno[3,4
      e][1,2,4]thiadiazines (TTDs) has been described. The compounds were synthesized
      via Curtius rearrangement of appropriate sulfamoylcarboxy azides which, in turn,
      were prepared from known starting materials. Several 4-substituted-2-benzyl
      derivatives were found to selectively inhibit human immunodeficiency virus type 1
      [HIV-1 (IIIB)] replication in MT-4 and CEM cells. These TTDs were also effective
      against other strains of HIV-1 (RF, HE, MN, NDK), including those that are
      resistant to AZT, but not against HIV-2 (ROD) or simian immunodeficiency virus
      [SIV(MAC251)] at subtoxic concentrations. Some of the test compounds exhibited
      antiviral activity against L100I RT mutant virus, but significantly lost
      antiviral activity against K103N, V106A, E138K, Y181C and Y188H RT mutant
      viruses. Compounds 6d, 6f and 6g were inhibitory to HIV-1 RT at concentrations
      that rank between 16.4 and 59.8 microM (nevirapine: IC50 = 4.5 microM against HIV
      1 RT). Inhibition of HIV-1 RT by compound 6g was purely non-competitive with
      respect to the natural substrate (dGTP), which is in agreement with the nature of
      inhibition shown by other NNRTIs such as nevirapine and delarvidine. A structure
      activity relationship was established for the anti-HIV activity of these
      heterocyclic compounds. TTDs represent a new chemical class of non-nucleoside HIV
      1 reverse transcriptase inhibitors (NNRTIs).

PMID- 10658586
TI  - Alpha-galactose based neoglycopeptides. Inhibition of verotoxin binding to
      globotriosylceramide.
AB  - Solution and solid phase strategies for the synthesis of alpha-galactose based
      neoglycopeptide derivatives 2-13 were developed. Neoglycopeptides generated were
      tested for the inhibition of verotoxin binding to globotriosylceramide (Gb3)
      using ELISA. Among all of the compounds tested, only the lipid derivatives of
      neoglycopeptides, 11, 12 and 13 were found to be inhibitors, IC50 = 2.0 mM (11b
      and 12c) and 0.2 mM (11c and 13c). All of the inhibitors (11b, 11c, 12c and 13c)
      have a similar branching of the two alpha-galactosyl units at the N-terminal
      glycine residue of a short peptide and a lipid moiety attached at the C-terminal
      site. Both of these factors seem to be crucial for the inhibition. It is
      interesting to note that the inhibitors have only a portion of the natural
      trisaccharide ligand. The secondary groups either may contribute in sub-site
      oriented interactions with the protein receptors or may mimic the internal sugar
      units of the cell-surface ligand, Gb3.

PMID- 10658587
TI  - Synthesis and monoamine oxidase B substrate properties of 1-methyl-4-heteroaryl
      1,2,3,6-tetrahydropyridines.
AB  - Six analogues of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine [MPTP, (1)] bearing
      various heteroaryl groups at C-4 were synthesized and examined for their
      monoamine oxidase B substrate properties. The C-4 substituents include the 1
      ethylpyrrol-2-yl, 1-propylpyrrol-2-yl, 1-isopropylpyrrol-2-yl, 1
      cyclopropylpyrrol-2-yl, 3-ethylfuran-2-yl and 3-ethylthien-2-yl groups. The
      results provide information concerning steric and polar interactions between the
      C-4 substituent and the active site of MAO-B that are transmitted to the position
      of oxidation at C-6 of the tetrahydropyridinyl moiety.

PMID- 10658588
TI  - Synthesis and antimalarial activity in vitro of potential metabolites of
      ferrochloroquine and related compounds.
AB  - In man, the two major metabolites of the antimalarial drug chloroquine (CQ) are
      monodesethylchloroquine (DECQ) and didesethylchloroquine (di-DECQ). By analogy
      with CQ, the synthesis and the in vitro tests of some amino derivatives of
      ferrochloroquine (FQ), a ferrocenic analogue of CQ which are presumed to be the
      oxidative metabolites of FQ, are reported. Desmethylferrochloroquine 1a and
      didesmethylferrochloroquine 2 would be more potent against schizontocides than CQ
      in vitro against two strains (HB3 and Dd2) of Plasmodium falciparum. Other
      secondary amino derivatives have been prepared and proved to be active as
      antimalarial agents in vitro, too.

PMID- 10658589
TI  - Helenanolide type sesquiterpene lactones. Part 5: the role of glutathione
      addition under physiological conditions.
AB  - Sesquiterpene lactones (STLs) are known to exert most of their numerous
      biological activities through inhibition of enzymes and other functional proteins
      by forming covalent bonds with free cysteine residues in these macromolecules.
      The question arises how these drugs can alkylate such vital target structures
      instead of being quickly deactivated by reaction with the cysteine group of
      glutathione (GSH) which is present in high concentrations in all cells. We have
      measured in this study the pH dependent kinetics of GSH addition to the
      cyclopentenone and alpha-methylene-gamma-lactone group of helenanolide type
      sesquiterpene lactones using UV-spectrophotometry. The reaction with GSH at
      physiological pH proceeds very quickly but is reversible so that a fraction of
      STL molecules will always be available for reaction with protein targets. In
      agreement with these chemical data, helenalin-mono- and -bis-glutathionyl adducts
      were demonstrated to inhibit the nuclear transcription factor NF-kappaB at
      concentrations similar to the free sesquiterpene lactone.

PMID- 10658590
TI  - The molecular structure of 2alpha-hydroxyneoanisatin and structure-activity
      relationships among convulsant sesquiterpenes of the seco-prezizaane and
      picrotoxane types.
AB  - The molecular structure of 2alpha-hydroxyneoanisatin, a positional isomer of the
      potent neurotoxin anisatin, was determined by X-ray crystallographic analysis.
      This compound and four further seco-prezizaane type sesquiterpene lactones
      previously isolated from Illicium floridanum, which represent different
      structural types with respect to the mode of cyclisation, did not induce
      anisatin/picrotoxinin-like convulsions in mice. Based on these results and
      literature data for other seco-prezizaanes, structural requirements for
      convulsant activity are discussed. Comparison of the three dimensional molecular
      shape and electrostatic properties of active and inactive seco-prezizaane type
      lactones with compounds of the picrotoxane type resulted in the identification of
      a common pharmacophore structure for these different skeletal classes of
      convulsant natural products.

PMID- 10658591
TI  - The neurokinin-1 and neurokinin-2 receptor binding sites of MDL103,392 differ.
AB  - Several small molecule non-peptide antagonists of the NK-1 and NK-2 receptors
      have been developed. Mutational analysis of the receptor protein sequence has led
      to the conclusion that the binding site for these non-peptide antagonists lies
      within the bundle created by transmembrane domains IV-VII of the receptor and
      differs from the binding sites of peptide agonists and antagonists. The current
      investigation uses site-directed mutagenesis of the NK-1 and NK-2 receptors to
      elucidate the amino acids that are important for binding and functional activity
      of the first potent dual NK-1/NK-2 antagonist MDL103,392. The amino acids found
      to be important for MDL103,392 binding to the NK-1 receptor are Gln-165, His-197,
      Leu-203, Ile-204, Phe-264, His-265 and Tyr-272. The amino acids found to be
      important for MDL103,392 binding to the NK-2 receptor are Gln-166, His-198, Tyr
      266 and Tyr-289. While residues in transmembrane (TM) domains IV and V are
      important in both receptors (Gln-165/166 and His-197/198), residues in TM V and
      VI are more important for the NK-1 receptor and residues in TM VII play a more
      important role in the NK-2 receptor. These data are the first report of the
      analysis of the binding site of a dual tachykinin receptor antagonist and
      indicate that a single compound (MDL103,392) binds to each receptor in a
      different manner despite there being a high degree of homology in the
      transmembrane bundles. In addition, this is the first report in which a model for
      the binding of a non-peptide antagonist to the NK-2 receptor is proposed.

PMID- 10658592
TI  - Synthesis and biological activity of 22-iodo- and (E)-20(22)-dehydro analogues of
      1alpha,25-dihydroxyvitamin D3.
AB  - Construction of 25-hydroxy-steroidal side chain substituted with iodine at C-22
      was elaborated on a model PTAD-protected steroidal 5,7-diene and applied to a
      synthesis of (22R)- and (22S)-22-iodo-1alpha,25-dihydroxyvitamin D3.
      Configuration at C-22 in the iodinated vitamins, obtained by nucleophilic
      substitution of the corresponding 22S-tosylates with sodium iodide, was
      determined by comparison of their iodine-displacement processes and cyclizations
      leading to isomeric five-membered (22,25)-epoxy-1alpha-hydroxyvitamin D3
      compounds. Also, 20(22)-dehydrosteroids have been obtained and their structures
      established by 1H NMR spectroscopy. When compared to the natural hormone, (E)
      20(22)-dehydro-1alpha,25-dihydroxyvitamin D3 was found 4 times less potent in
      binding to the porcine intestinal vitamin D receptor (VDR) and 2 times less
      effective in differentiation of HL-60 cells. 22-Iodinated vitamin D analogues
      showed somewhat lower in vitro activity, whereas (22,25)-epoxy analogues were
      inactive. Interestingly, it was established that (22S)-22-iodo-1alpha,25
      dihydroxyvitamin D3 was 3 times more potent than its (22R)-isomer in binding to
      VDR and four times more effective in HL-60 cell differentiation assay. The
      restricted mobility of the side chain of both 22-iodinated vitamin D compounds
      was analyzed by a systematic conformational search indicating different spatial
      regions occupied by their 25-oxygen atoms. Preliminary data on the in vivo
      calcemic activity of the synthesized vitamin D analogues indicate that (E)-20(22)
      dehydro-1alpha,25-dihydroxyvitamin D3 and 22-iodo-1alpha,25-dihydroxyvitamin D3
      isomers were ca. ten times less potent than the natural hormone 1alpha,25-(OH)2D3
      both in intestinal calcium transport and bone calcium mobilization.

PMID- 10658593
TI  - Synthesis and biological evaluation of a conformationally free seco-analogue of
      the immunosuppressant FR901483.
AB  - The synthesis of an azaspirocyclic analogue of FR901483, phosphate 2, is
      described based on the implementation of a key 5-endo aminocyclization promoted
      by iodine for direct functionalization of the 1-azaspiro[4.5]decane ring at the C
      3 atom. Compound 2 has no inhibitory activity in the cell proliferation assays
      reported.

PMID- 10658594
TI  - Synthesis and beta-lactamase inhibitory activity of new 6beta
      cysteinesulfonamidopenicillanic acids.
AB  - New 6beta-cysteinesulfonamidopenicillanic acids and their sulfoxides were
      synthesized by sulfonylation of 6beta-aminopenicillanic acid or its (S)-sulfoxide
      with (R)-N-benzyloxycarbonylcysteinesulfonyl chloride ethyl ester (2a, 1b) and
      (R)-N-benzyloxycarbonylcysteinesulfonyl chloride benzyl ester (2a, 2b). The
      corresponding 6beta-cysteinesulfonamidopenicillanic acids sulfones 1c and 2c were
      prepared by oxidation of the sulfoxides 1b and 2b with potassium permanganate in
      aqueous medium. When combined with ampicillin some of the compounds reduced the
      minimal inhibitory concentrations of ampicillin against beta-lactamase producing
      strains.

PMID- 10658595
TI  - 3-(1',1'-Dimethylbutyl)-1-deoxy-delta8-THC and related compounds: synthesis of
      selective ligands for the CB2 receptor.
AB  - The synthesis and pharmacology of 15 1-deoxy-delta8-THC analogues, several of
      which have high affinity for the CB2 receptor, are described. The deoxy
      cannabinoids include 1-deoxy-11-hydroxy-delta8-THC (5), 1-deoxy-delta8-THC (6), 1
      deoxy-3-butyl-delta8-THC (7), 1-deoxy-3-hexyl-delta8-THC (8) and a series of 3
      (1',1'-dimethylalkyl)-1-deoxy-delta8-THC analogues (2, n = 0-4, 6, 7, where n =
      the number of carbon atoms in the side chain-2). Three derivatives (17-19) of
      deoxynabilone (16) were also prepared. The affinities of each compound for the
      CB1 and CB2 receptors were determined employing previously described procedures.
      Five of the 3-(1',1'-dimethylalkyl)-1-deoxy-delta8-THC analogues (2, n = 1-5)
      have high affinity (Ki = < 20 nM) for the CB2 receptor. Four of them (2, n = 1-4)
      also have little affinity for the CB1 receptor (Ki = > 295 nM). 3-(1',1'
      Dimethylbutyl)-1-deoxy-delta8-THC (2, n = 2) has very high affinity for the CB2
      receptor (Ki = 3.4 +/- 1.0 nM) and little affinity for the CB1 receptor (Ki = 677
      +/- 132 nM).

PMID- 10658596
TI  - Carbonic anhydrase activators: amino acyl/dipeptidyl histamine derivatives bind
      with high affinity to isozymes I, II and IV and act as efficient activators.
AB  - Reaction of histamine (Hst) with tetrabromophthalic anhydride and protection of
      its imidazole moiety with tritylsulfenyl chloride, followed by hydrazinolysis,
      afforded N-1-tritylsulfenyl-histamine, a key intermediate which was further
      derivatized at its aminoethyl moiety. Reaction of the key intermediate with N-Boc
      amino acids/dipeptides (Boc-AA) in the presence of carbodiimides afforded, after
      deprotection of the imidazolic and amino moieties, a series of compounds with the
      general formula AA-Hst (AA = amino acyl; dipeptidyl). The new derivatives were
      assayed as activators of three carbonic anhydrase (CA) isozymes, hCA I, hCA II
      (cytosolic forms) and bCA IV (membrane-bound form). Efficient activation was
      observed against all three isozymes, but especially against hCA I and bCA IV,
      with affinities in the nanomolar range for the best compounds. hCA II was, on the
      other hand, activatable with affinities around 10-20 nM. This new class of CA
      activators might lead to the development of drugs/diagnostic agents for the CA
      deficiency syndrome, a genetic disease of bone, brain and kidneys.

PMID- 10658597
TI  - Biosynthesis of 20-hydroxyecdysone in Ajuga hairy roots: fate of 6alpha- and
      6beta-hydrogens of lathosterol.
AB  - The fate of 6alpha- and 6beta-hydrogens of lathosterol during the transformation
      into 20-hydroxyecdysone was chased by feeding [3alpha,6beta-2H2]- and
      [3alpha,6alpha-2H2]-lathosterols to hairy roots of Ajuga reptans var.
      atropurpurea. The behavior of 6beta-hydrogen, which mostly migrated to the C-5
      position of 20-hydroxyecdysone, was in agreement with that of C-6 hydrogen of
      cholesterol. The results strongly supported the view that cholesterol and
      lathosterol are first metabolized into 7-dehydrocholesterol, which is then
      converted into 20-hydroxyecdysone via 7-dehydrocholesterol 5alpha,6alpha-epoxide
      in the hairy roots.

PMID- 10658598
TI  - Substrate/inhibition studies of bacteriophage T7 RNA polymerase with the 5'
      triphosphate derivative of a ring-expanded ('fat') nucleoside possessing potent
      antiviral and anticancer activities.
AB  - As part of an effort to explore the mechanism of potent, broad spectrum antiviral
      and anticancer activities of a number of ring-expanded ('fat') nucleosides that
      we recently reported, a representative 'fat' nucleoside 4,6-diamino-8-imino-8H-1
      beta-D-ribofuranosylimidazo[4,5-e][1,3]di azepine (1) was converted to its 5'
      triphosphate derivative (2), and biochemically screened for possible inhibition
      of nucleic acid polymerase activity, employing synthetic DNA templates and the
      bacteriophage T7 RNA polymerase as a representative polymerase. Our results
      suggest that 2 is a moderate inhibitor of T7 RNA polymerase, and that the 5'
      triphosphate moiety of 2 appears to be essential for inhibition as nucleoside 1
      alone failed to inhibit the polymerase reaction.

PMID- 10658599
TI  - 2-Carboxymethylendothal analogues as affinity probes for stabilized protein
      phosphatase 2A.
AB  - Endothal (1diacid) and [3H]cantharidic acid ([3H]CA) bind with high affinity to
      the catalytic subunit of protein phosphatase 2A (PP2A). PP2A in liver cytosol was
      greatly stabilized with 30% glycerol as a preliminary step in the potential use
      of endothal-type derivatives for affinity chromatography. We report here the
      first introduction of a functionalizable group into endothal which allows
      retention of binding site affinity (assayed as [3H]CA binding in mouse liver
      cytosol). 2-Carboxymethylendothal anhydride (7) was prepared in two steps and 97%
      overall yield from cis-aconitic anhydride and furan. The potency of 7 was
      retained on conversion to two 2-carboxymethyl esters but not to two 2-(n
      alkylcarboxamidomethyl) analogues.

PMID- 10658600
TI  - Synthesis of beta-substituted naphth-1-yl ethylamido derivatives as new
      melatoninergic agonists.
AB  - Naphthalene melatoninergic ligands with alkyl groups (Me, Et, Pr, Bz) in the beta
      position of the ethylamido chain were synthesised. The affinity of the compounds
      for chicken brain melatonin receptors was evaluated using 2-[125I]-iodomelatonin
      as the radioligand. An increase in the affinity was observed with the beta-methyl
      derivatives and the greatest increase was seen with the (-) enantiomers. The
      introduction of a 2- or 7-MeO group on the naphthalene ring and the lengthening
      (Et, Pr) of the alkylamido chain gave potent compounds such as (-)1h (Ki = 24
      pM). The functional activity of these compounds was evaluated by the aggregation
      of melanophores in Xenopus laevis tadpoles. The potency to produce lightening of
      the skin of Xenopus laevis was related to the affinities values of the molecules
      at melatonin chicken brain receptors. The most potent ligands were found to be
      full agonists and compound 1h was 25 fold more potent than melatonin in this
      bioassay.

PMID- 10658601
TI  - Synthesis of peptide aldehydes via enzymatic acylation of amino aldehyde
      derivatives.
AB  - Two ways for semi-enzymatic preparation of the peptide aldehydes are proposed:
      (1) enzymatic acylation of amino alcohols with acyl peptide esters and subsequent
      chemical oxidation of the resulting peptide alcohols with DMSO/acetic anhydride
      mixture or (2) enzymatic acylation of the preliminarily obtained by a chemical
      route amino aldehyde semicarbazones. Subtilisin 72, serine proteinase with a
      broad specificity, distributed over macroporous silica, was used as a catalyst in
      both cases. Due to the practical absence of water in the reaction mixtures the
      yields of the products in both enzymatic reactions were nearly quantitative. The
      second way seems to be more attractive because all chemical stages were carried
      out with amino acid derivatives, far less valuable compounds than peptide ones. A
      series of peptide aldehydes of general formula Z-Ala-Ala-Xaa-al (where Xaa-al =
      leucinal, phenylalaninal, alaninal, valinal) was obtained. The inhibition
      parameters for these compounds, in the hydrolysis reactions of corresponding
      chromogenic substrates for subtilisin and alpha-chymotrypsin, were determined.

PMID- 10658602
TI  - D-ring substituted rhazinilam analogues: semisynthesis and evaluation of
      antitubulin activity.
AB  - Novel (-)- and (+)-rhazinilam derivatives substituted on the D-ring (compounds 3,
      4, 5 and 6) have been prepared from (+)-vincadifformine 7 and (-)-tabersonine and
      evaluated against the disassembly of microtubules into tubulin. Along with this
      study, a reproducible 'one pot' semisynthesis of (-)-rhazinilam 1 from (+)-1,2
      didehydroaspidospermidine 2 was performed allowing the easy preparation of these
      new compounds.

PMID- 10658603
TI  - A comparative molecular field analysis and molecular modelling studies on
      pyridylimidazole type of angiotensin II antagonists.
AB  - A large number of compounds known as "AII (Angiotensin II) antagonists" have been
      developed for the treatment of various heart diseases such as hypertension,
      congestive heart failure, and chronic renal failure. Most of the currently known
      AII receptor antagonists share a similar chemical structure, consisting of
      nitrogen atoms, a lipophilic alkyl side chain and an acidic group. As a new
      series, we have designed and synthesized various pyridylimidazole derivatives. In
      this report we would like to discuss the structure-activity relationship of these
      series of compounds using the comparative molecular field analysis (CoMFA)
      methods. We could come up with a good CoMFA model (cross-validated and
      conventional r2 values equal to 0.702 and 0.991, respectively) and the validity
      of the model was confirmed by synthesizing and measuring their biological
      activity of additional 6 compounds suggested by the model. This result provides
      additional information on the structural requirement for structurally diverse
      group of AII receptor antagonists.

PMID- 10658604
TI  - Synthesis of oligonucleotides containing a new azobenzene fragment with efficient
      photoisomerizability.
AB  - The azobenzene derivatives possessing substituents of ROCH2CH2O- and-CH2CH2OR' or
      -CONHCH2CH2OR' at p,p'-positions, where R and R' are 4,4'-dimethoxytrityl and 2
      cyanoethyl-N,N'-diisopropylphophoramidite, have been synthesized for linking two
      oligonucelotide segments. It has been found that the azobenzene linkers
      efficiently undergo trans-cis isomerization by exposing to UV light. The
      conversion efficiency showed slight dependence on structure or conformation of
      oligonucleotides attached to the azobenzene chromophore. The cis-form of the
      azobenzene in oligonucleotides was sufficiently stable at low temperature under
      dark. The present findings would open the way for light switch of nucleic acid
      structures.

PMID- 10658605
TI  - Synthesis of novel unnatural amino acid as a building block and its incorporation
      into an antimicrobial peptide.
AB  - Considering the biological mechanism and in vivo stability of antimicrobial
      peptides, we designed and synthesized novel unnatural amino acids with more
      positively charged and bulky side chain group than lysine residue. The unusual
      amino acids, which were synthesized by either solution phase or solid phase, were
      incorporated into an antimicrobial peptide. Its effect on the stability,
      activity, and the structure of the peptide was studied to evaluate the potential
      of these novel unnatural amino acids as a building block for antimicrobial
      peptides. The incorporation of this unusual amino acid increased the resistance
      of the peptide against serum protease more than three times without a decrease in
      the activity. Circular dichroism spectra of the peptides indicated that all novel
      unnatural amino acids must have lower alpha helical forming propensities than
      lysine. Our results indicated that the unnatural amino acids synthesized in this
      study could be used not only as a novel building block for combinatorial
      libraries of antimicrobial peptides, but also for structure-activity relationship
      studies about antimicrobial peptides.

PMID- 10658606
TI  - Synthesis and inotropic activity of hydroindene derivatives.
AB  - A synthetic approach to hydroindenic inotropic agents has been developed,
      starting from enantiopure Hajos-Parrish (1). Hajos-Wiechert (2), and related
      diketones. Their transformation into C-1 formyl derivatives and other subsequent
      synthetic targets is described. The results of the thermodynamic equilibration
      between both epimers of each formyl derivative are analysed. The inotropic
      activities of selected compounds on right and left atrial preparations are also
      evaluated and discussed.

PMID- 10658607
TI  - Synthesis and histamine H3 receptor activity of 4-(n-alkyl)-1H-imidazoles and 4
      (omega-phenylalkyl)-1H-imidazoles.
AB  - The influence of lipophilic moieties attached to a 4-1H-imidazole ring on the
      histamine H3 receptor activity was systematically investigated. Series of 4-(n
      alkyl)-1H-imidazoles and 4-(omega-phenylalkyl)-1H-imidazoles were prepared, with
      an alkyl chain varying from 2-9 methylene groups and from 1-9 methylene groups,
      respectively. The compounds were tested for their activity on the H3 receptor
      under in vitro conditions. For the 4-(n-alkyl)-1H-imidazoles the activity is
      proportional to chain length, ranging from a pA2 value of 6.3 +/- 0.2 for 4-(n
      propyl)-1H-imidazole to a pA2 value of 7.2 +/- 0.1 for 4-(n-decyl)-1H-imidazole.
      For the series 4-(omega-phenylalkyl)-4H-imidazoles an optimum in H3 activity was
      found for the pentylene spacer: 4-(omega-phenylpentyl)-1H-imidazole has a pA2
      value of 7.8 +/- 0.1.

PMID- 10658608
TI  - Probing the hydrophobic pocket of farnesyltransferase: aromatic substitution of
      CAAX peptidomimetics leads to highly potent inhibitors.
AB  - Cysteine farnesylation at the carboxylate terminal tetrapeptide CAAX of Ras
      protein is catalyzed by farnesyltransferase. This lipid modification is necessary
      for regulatory function of both normal and oncogenic Ras. The high frequency of
      Ras mutation in human cancers has prompted an intensive study on finding ways of
      controlling oncogenic Ras function. Inhibition of farnesyltransferase is among
      the most sought after targets for cancer chemotherapy. We report here the design,
      synthesis and biological characterization of a series of peptidomimetics as
      farnesyltransferase inhibitors. These compounds are extremely potent towards
      farnesyltransferase with IC50 values ranging from subnanomolar to low nanomolar
      concentrations. They have a high selectivity for farnesyltransferase over the
      closely related geranylgeranyltransferase-I. Structure-activity relationship
      studies demonstrated that a properly positioned hydrophobic group significantly
      enhanced inhibition potency, reflecting an improved complementarity to the large
      hydrophobic pocket in the CAAX binding site.

PMID- 10658609
TI  - Syntheses and studies of multiwarhead siderophore-5-fluorouridine conjugates.
AB  - Siderophores are microbial iron chelating agents that sequester physiologically
      essential iron for microbes. Conjugation of drugs to siderophores allows use of
      active iron transport for microbially directed drug delivery. Syntheses and
      biological studies are described of the first multidrug isocyanurate-based
      siderophore analogues separately containing one, two, and three 5-fluorouridine
      (5-FU) derivatives as the drug component. The results indicate that a single
      siderophore can be used to deliver multiple drugs to target pathogenic
      microorganisms.

PMID- 10658610
TI  - Magnocellular neurons of the rat supraoptic nucleus are endowed with functional
      nicotinic acetylcholine receptors.
AB  - Acetylcholine can stimulate the release of vasopressin. In organ-cultured
      hypothalamo-neurohypophyseal systems, acetylcholine enhanced vasopressin release
      by acting in or near the supraoptic nucleus Extracellular recordings suggested
      that acetylcholine can increase supraoptic neuron excitability. These effects
      could be mimicked, in part, by nicotine or blocked by nicotinic antagonists,
      suggesting that they might be mediated by nicotinic acetylcholine receptors.
      Autoradiography indicated that alpha-bungarotoxin binding sites are present in
      the supraoptic nucleus; however, neither acetylcholine nor nicotine binding sites
      could be detected. Thus, the existence, let alone the nature, of nicotinic
      receptors in the supraoptic nucleus has so far remained elusive. The present work
      attempts to determine: (i) whether functional nicotinic receptors are present in
      this nucleus; (ii) whether they are located on neurosecretory magnocellular cells
      or at presynaptic sites; (iii) what their pharmacological and biophysical
      properties are; (iv) whether they influence the activity of all or only part of
      supraoptic neurons. Whole-cell recordings were performed in hypothalamic slices
      or in acutely dissociated supraoptic neurons and the effect of nicotinic agonists
      was tested under voltage-clamp conditions. Autoradiography was done in coronal
      hypothalamic sections, using [3H]epibatidine and [125I]alpha-bungarotoxin as
      ligands. Our results indicate that supraoptic neurons possess functional
      nicotinic receptors containing the alpha7 subunit.

PMID- 10658611
TI  - Olfactory experience decreases responsiveness of the olfactory bulb in the adult
      rat.
AB  - We recently reported the existence of dramatic modifications of the olfactory
      bulb reactivity following a very simple manipulation of the olfactory input as an
      exposure to an odorant. The present study aimed at testing the possibility that
      such effects could depend on the nature of the exposure odour. For this purpose,
      rats were exposed 20 min per day during six consecutive days to cineole, methyl
      amyl ketone, isoamyl acetate or with no odour in the control group. On day 7,
      rats were anaesthetized and the spontaneous activity of mitral/tufted cells was
      recorded along with their responses to the familiar odour and to four novel
      odours. Results revealed that: (i) the firing frequencies were not significantly
      different in the four groups; (ii) the proportion of excitatory responses was
      considerably decreased in the exposed groups while the number of non-responses
      was significantly enhanced; (iii) excitatory responses were decreased not only to
      the familiar odour but also to four other novel odours; (iv) this lower
      responsiveness was long lasting at least for isoamyl acetate exposure; and (v)
      increasing concentration of test odours was not enough to allow mitral/tufted
      cells to recover control responsiveness. All of these effects have a differential
      importance according to the exposure odour. In particular, the more powerful an
      odour is in activating control cells, the more non-specific the decrease in
      mitral/tufted cell reactivity is. Hypotheses on the underlying mechanisms are
      advanced.

PMID- 10658612
TI  - The human forebrain has discrete estrogen receptor alpha messenger RNA
      expression: high levels in the amygdaloid complex.
AB  - Estrogen is considered to play an important role in neuropsychiatric disorders
      and the estrogen receptors mediate the action of the hormone. In the present
      study, the messenger RNA expression pattern of the estrogen receptor alpha
      subtype was identified in the post mortem human brain. High stringent in situ
      hybridization histochemistry was performed using a riboprobe specific for the
      estrogen receptor alpha subtype. The human brain was mainly characterized by
      abundant estrogen receptor alpha messenger RNA expression in the amygdala and
      hypothalamus, but labeling (lower) was also found in the extended sublenticular
      amygdala, cerebral cortex, and hippocampus. In the amygdala, the estrogen
      receptor alpha messenger RNA was preferentially expressed in medially-localized
      nuclei suggesting that estrogen regulates distinct human amygdala-mediated
      functions. The Cynomologous monkey brain was also examined in the present study
      and a similar distribution of the estrogen receptor alpha messenger RNA signal
      was observed in the human and monkey brain. However, the primate expression
      pattern differed in part from the known distribution in the rat. The current
      results show that estrogen receptor alpha messenger RNA is expressed in discrete
      areas of the human brain not only related to neuroendocrine function, but also
      emotion, memory, and cognition, which is consistent with the hypothesized
      involvement of estrogen in schizophrenia, affective disorders, and Alzheimers
      disease.

PMID- 10658614
TI  - Impaired recovery of noradrenaline levels in apolipoprotein E-deficient mice
      after N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine lesion.
AB  - We investigated the effect of the noradrenergic neurotoxin, N-(2-chloroethyl)-N
      ethyl-2-bromobenzylamine (DSP-4) (1 or 3 x 50 mg/kg, intraperitoneally), on
      hippocampal, cortical and cerebellar noradrenaline levels after recovery of one,
      five and 11 months in control and apolipoprotein E-deficient mice. Apolipoprotein
      E-deficient mice had lower hippocampal noradrenaline levels than control mice.
      DSP-4-lesioned control mice had a more extensive recovery of hippocampal and
      cortical noradrenaline levels than DSP-4-lesioned apoE-deficient mice after five
      months' survival. Furthermore, the hippocampal noradrenaline levels after five
      and 11 months and cortical noradrenaline levels after five months of recovery had
      slightly recovered in control but not in apolipoprotein E-deficient mice treated
      with a single dose of DSP-4 compared with mice treated with three doses of DSP-4.
      These results show that apolipoprotein E-deficient mice have impaired recovery
      capacity in their locus coeruleus neurons.

PMID- 10658613
TI  - Reciprocal modulation of glutamate and GABA release may underlie the
      anticonvulsant effect of phenytoin.
AB  - Although conventional wisdom suggests that the effectiveness of phenytoin as an
      anticonvulsant is due to blockade of Na+-channels this is unlikely to be it's
      sole mechanism of action. In the present paper we examined the effects of
      phenytoin on evoked and spontaneous transmission at excitatory (glutamate) and
      inhibitory (GABA) synapses, in the rat entorhinal cortex in vitro. Evoked
      excitatory postsynaptic potentials at glutamate synapses exhibited frequency
      dependent enhancement, and phenytoin reduced this enhancement without altering
      responses evoked at low frequency. In whole-cell patch-clamp recordings the
      frequency of excitatory postsynaptic currents resulting from the spontaneous
      release of glutamate was reduced by phenytoin, with no change in amplitude, rise
      time or decay time. Similar effects were seen on miniature excitatory
      postsynaptic currents, recorded in the presence of tetrodotoxin. Evoked
      inhibitory postsynaptic potentials at GABA synapses displayed a frequency
      dependent decrease in amplitude. Phenytoin caused a reduction in this decrement
      without affecting the responses evoked at low frequency. The frequency of
      spontaneous GABA-mediated inhibitory postsynaptic currents, recorded in whole
      cell patch mode, was increased by phenytoin, and this was accompanied by the
      appearance of much larger amplitude events. The effect of phenytoin on the
      frequency of inhibitory postsynaptic currents persisted in the presence of
      tetrodotoxin, but the change in amplitude distribution largely disappeared. These
      results demonstrate for the first time that phenytoin can cause a simultaneous
      reduction in synaptic excitation and an increase in inhibition in cortical
      networks. The shift in balance in favour of inhibition could be a major factor in
      the anticonvulsant action of phenytoin.

PMID- 10658615
TI  - Deficits in nerve growth factor release and tyrosine receptor kinase
      phosphorylation are associated with age-related impairment in long-term
      potentiation in the dentate gyrus.
AB  - Previous findings have indicated that nerve growth factor may play a role in the
      expression of long-term potentiation in perforant path-granule cell synapses and
      that nerve growth factor treatment restores the ability of aged rats to sustain
      long-term potentiation. In this study, we have attempted to analyse the changes
      which occur in nerve growth factor release and tyrosine receptor kinase
      phosphorylation following tetanization in tissue prepared from dentate gyrus of
      young rats, as well as aged rats which did or did not sustain long-term
      potentiation. We report that KCl-stimulated nerve growth factor release was
      significantly increased in slices of the dentate gyrus or whole hippocampus, but
      not in synaptosomes prepared from the dentate gyrus. KCl-induced nerve growth
      factor release was also significantly enhanced in slices prepared from tetanized,
      compared with untetanized, tissue obtained from young rats and aged rats which
      sustained long-term potentiation; this response was absent in tissue prepared
      from aged rats which failed to sustain long-term potentiation, perhaps due to the
      enhanced basal nerve growth factor release observed in this tissue. Tetanization
      increased tyrosine receptor kinase phosphorylation in the dentate gyrus of young
      rats and aged rats which sustained long-term potentiation. In parallel with the
      changes in nerve growth factor release, tyrosine receptor kinase phosphorylation
      was markedly increased in untetanized tissue, which may contribute to the lack of
      effect in tetanized tissue prepared from aged rats which failed to sustain long
      term potentiation. We observed that nerve growth factor concentration and
      tyrosine receptor kinase expression were decreased in aged, compared with young,
      rats. The data suggest that deficits in nerve growth factor release and
      subsequent signalling may contribute to age-related deficits in long-term
      potentiation.

PMID- 10658617
TI  - Autoradiographic study of striatal dopamine re-uptake sites and dopamine D1 and
      D2 receptors in a 6-hydroxydopamine and quinolinic acid double-lesion rat model
      of striatonigral degeneration (multiple system atrophy) and effects of embryonic
      ventral mesencephalic, striatal or co-grafts.
AB  - The influence of embryonic mesencephalic, striatal and mesencephalic/striatal co
      grafts on amphetamine- and apomorphine-induced rotation behaviour was assessed in
      a rat model of multiple system atrophy/striatonigral degeneration type using
      dopamine D1 ([3H]SCH23390) and D2 ([3H]spiperone) receptor and dopamine re-uptake
      ([3H]mazindol) autoradiography. Male Wistar rats subjected to a sequential
      unilateral 6-hydroxydopamine lesion of the medial forebrain bundle followed by a
      quinolinic acid lesion of the ipsilateral striatum were divided into four
      treatment groups, receiving either mesencephalic, striatal,
      mesencephalic/striatal co-grafts or sham grafts. Amphetamine- and apomorphine
      induced rotation behaviour was recorded prior to and up to 10 weeks following
      transplantation. 6-Hydroxydopamine-lesioned animals showed ipsiversive
      amphetamine-induced and contraversive apomorphine-induced rotation behaviour.
      Amphetamine-induced rotation rates persisted after the subsequent quinolinic acid
      lesion, whereas rotation induced by apomorphine was decreased. In 11 of 14
      animals receiving mesencephalic or mesencephalic/striatal co-grafts, amphetamine
      induced rotation scores were decreased by >50% at the 10-week post-grafting time
      point. In contrast, only one of 12 animals receiving non-mesencephalic (striatal
      or sham) grafts exhibited diminished rotation rates at this time-point.
      Apomorphine-induced rotation rates were significantly increased following
      transplantation of mesencephalic, striatal or sham grafts. The largest increase
      of apomorphine-induced rotation rates approaching post-6-hydroxydopamine levels
      were observed in animals with striatal grafts. In contrast, in the co-graft
      group, there was no significant increase of apomorphine-induced rotation compared
      to the post-quinolinic acid time-point. Morphometric analysis revealed a 63-74%
      reduction of striatal surface areas across the treatment groups. Striatal
      [3H]mazindol binding on the lesioned side (excluding the demarcated graft area)
      revealed a marked loss of dopamine re-uptake sites across all treatment groups,
      indicating missing graft-induced dopaminergic re-innervation of the host. In
      eight (73%) of the 11 animals with mesencephalic grafts and reduced amphetamine
      induced circling, discrete areas of [3H]mazindol binding ("hot spots") were
      observed, indicating graft survival. Dopamine D1 and D2 receptor binding was
      preserved in the remaining lesioned striatum irrespective of treatment
      assignment, except for a significant reduction of D2 receptor binding in animals
      receiving mesencephalic grafts. "Hot spots" of dopamine D1 and D2 receptor
      binding were observed in 10 (83%) and nine (75%) of 12 animals receiving striatal
      grafts or co-grafts, consistent with survival of embryonic primordial striatum
      grafted into a severely denervated and lesioned striatum. Our study confirms that
      functional improvement may be obtained from embryonic neuronal grafts in a double
      lesion rat model of multiple system atrophy/striatonigral degeneration type. Co
      grafts appear to be required for reversal of both amphetamine- and apomorphine
      induced rotation behaviour in this model. We propose that the partial reversal of
      amphetamine-induced rotation asymmetry in double-lesioned rats receiving
      mesencephalic or mesencephalic/striatal co-grafts reflects non-synaptic graft
      derived dopamine release. The changes of apomorphine-induced rotation following
      transplantation are likely to reflect a complex interaction of graft- and host
      derived striatal projection pathways and basal ganglia output nuclei. Further
      studies in a larger number of animals are required to determine whether
      morphological parameters and behavioural improvement in the neurotransplantation
      multiple system atrophy rat model correlate.

PMID- 10658616
TI  - Tachykinins increase [3H]acetylcholine release in mouse striatum through multiple
      receptor subtypes.
AB  - Tachykinins have been suggested to play a significant role in the mammalian
      striatum, at least in part by the control of acetylcholine release from
      cholinergic interneurons. In the present study, we have examined the ability of
      known tachykinin agonists and antagonists to modulate the activity of these
      interneurons in mouse striatal slices. Using whole-cell patch-clamp recordings,
      the selective neurokinin-1, neurokinin-2 and neurokinin-3 receptor agonists
      [sar9,Met(O2)11]substance P, [beta-ala8]neurokinin A(4-10) and senktide each
      produced a dose-dependent depolarization of visually identified cholinergic
      interneurons that was retained under conditions designed to interrupt synaptic
      transmission. The nature of these neurons and the expression of multiple
      tachykinin receptors was confirmed using single-cell reverse transcriptase
      polymerase chain reaction analysis. Using in vitro superfusion techniques, the
      selective neurokinin-1, neurokinin-2 and neurokinin-3 receptor agonists
      [sar9,Met(O2)11]substance P, [beta-ala8]neurokinin A(4-10) and senktide,
      respectively, each produced a dose-dependent increase in acetylcholine release,
      the selectivity of which was confirmed using the neurokinin-1, neurokinin-2 and
      neurokinin-3 receptor antagonists SR140333, GR94800 and SR142801 (100 nM). U73122
      (10 microM), a phospholipase C inhibitor, blocked [sar9,Met(O2)11]substance P-
      and senktide-induced acetylcholine release, but had no effect on [beta
      ala8]neurokinin A(4-10)-induced release. The protein kinase C inhibitors
      chelerythrine and Ro-31-8220 (both 1 microM) significantly inhibited responses
      induced by all three agonists. These findings indicate that tachykinins modulate
      the activity of mouse striatal cholinergic interneurons. Furthermore, neurokinin
      2 receptors are shown to perform a role in mouse that has not been identified
      previously in other species.

PMID- 10658618
TI  - Age-related dopamine deficiency in the mesostriatal dopamine system of zitter
      mutant rats: regional fiber vulnerability in the striatum and the olfactory
      tubercle.
AB  - Oxidant stress has been implicated in the pathogenesis of Parkinson's disease. To
      test the oxidant stress hypothesis of dopaminergic degeneration, age-related
      changes in the mesostriatal dopamine neuron system were compared between zitter
      mutant rats which have abnormal metabolism of oxygen species in the brain and
      Sprague-Dawley rat as a control using the neurochemistry and
      immunohistochemistry. Dopamine content in the caudate-putamen, nucleus accumbens
      and olfactory tubercle of zitter rats decreased significantly with age, and was
      lower than that found in corresponding age-matched controls. In the zitter rats,
      the reduction of dopamine was more prominent in the caudate-putamen than in the
      nucleus accumbens and olfactory tubercle. A characteristic decline of tyrosine
      hydroxylase-immunoreactive fibers in the caudate-putamen of the zitter rat was
      also observed. In the dorsolateral caudate-putamen, reduction of tyrosine
      hydroxylase-immunoreactive fibers was observed in the matrix-like area, whereas
      in the ventromedial caudate-putamen the reduction occurred in the patch-like
      areas. Degeneration of tyrosine hydroxylase-immunoreactive fibers which was
      characterized by swollen varicosities and clustered fibers was observed in the
      caudate-putamen and nucleus accumbens and preceded loss of normal tyrosine
      hydroxylase-immunoreactive fibers in the caudate-putamen. Thus, the depletion of
      dopamine in the terminal areas is related to axonal degeneration. However, there
      was no degenerative tyrosine hydroxylase-immunoreactive fibers in the olfactory
      tubercle at any examined age, but reductions of tyrosine hydroxylase
      immunoreactive fibers and dopamine contents were noted in the olfactory tubercle
      after four months-of-age. Since the zitter rats have an abnormal oxygen
      metabolism, the degeneration of tyrosine hydroxylase-immunoreactive fibers could
      result from an accumulation of superoxide species. The present results provide
      support for the oxidant stress hypothesis of dopaminergic neuronal degeneration
      and further indicate the region-specific vulnerability of the nigrostriatal
      dopamine system.

PMID- 10658619
TI  - Striatal dopaminergic correlates of stable parkinsonism and degree of recovery in
      old-world primates one year after MPTP treatment.
AB  - Despite widespread use of the primate 1-methyl-4-phenyl-1,2,3,6
      tetrahydropyridine (MPTP) model of Parkinson's disease, there is a paucity of
      data concerning the relationship between striatal dopaminergic function and
      behavior over time. This study examines the relationship between markers of
      dopamine neuron integrity and dopaminergic metabolic activity in striatal
      subregions with the degree of parkinsonian disability in 32 monkeys treated with
      MPTP one year earlier. Based on the parkinsonian summary score during the month
      following MPTP treatment, each monkey was assigned to one of four severity
      categories. We called these categories "Severe", "Moderate", "Mild" and
      "Asymptomatic". Monkeys in the Severe category were behaviorally stable, and loss
      of dopamine concentration was greater than 98% in all subregions of striatum one
      year after MPTP treatment. This value was not significantly different from the
      level of depletion, reported previously, at one to two months after MPTP in
      Severe monkeys, and apparently this loss of striatal dopamine is beyond the level
      from which effective compensations can occur. The parkinsonian disabilities in
      monkeys of other severity groups (Moderate, Mild, Asymptomatic) improved
      significantly over the year, despite having mean dopamine depletion of 75-99% in
      different subregions of striatum at one to two months after MPTP treatment. At
      one year after MPTP treatment, the mean dopamine depletions in different
      subregions of caudate nucleus and putamen had diminished in Asymptomatics (21
      81%), Milds (35-96%), and Moderates (86-97%). Dopamine loss in nucleus accumbens
      was relatively spared compared with most striatal subregions, yet in Severe
      monkeys the decrease in this region reached 96%. In addition, at one year after
      MPTP treatment, there was a significant linear relationship between parkinsonian
      behavioral severity category and dopamine concentration, and homovanillic acid
      concentration and homovanillic acid/dopamine ratio in the striatum. The re
      establishment of dopamine levels and homovanillic acid/dopamine ratios was most
      pronounced in putamen, ventromedial caudate nucleus and nucleus accumbens. Thus
      the small difference in striatal dopamine loss that distinguishes monkeys with
      widely different behavior at one to two months after MPTP increases over time. We
      suggest that the milder the initial loss, the greater capacity there is for
      regeneration or sprouting of dopamine terminals, which is reflected in marked
      increases in dopamine levels and modest elevations of metabolic activity
      (homovanillic acid/dopamine ratio). With greater initial losses, there is less
      capacity to increase terminal density, which is reflected later by smaller
      increases in striatal dopamine levels and more marked increases in metabolic
      activity. It appears that 5-10% of normal striatal dopamine levels is sufficient
      for overtly normal motor performance in non-human primates.

PMID- 10658621
TI  - Neurotensin attenuates the quinpirole-induced inhibition of the firing rate of
      dopamine neurons in the rat substantia nigra pars compacta and the ventral
      tegmental area.
AB  - In the present study we describe the excitatory effects of the bioactive peptide
      neurotensin on the electrical activity of dopamine neurons (simultaneously
      recorded) in the substantia nigra pars compacta and the ventral tegmental area.
      The neurotensin fragment (8-13) induced comparable increases in firing rate of
      the substantia nigra and ventral tegmental area dopamine neurons (EC50 values 30
      and 45 nM, respectively). The neurotensin receptor antagonist SR142948A
      antagonized the excitatory effects of neurotensin fragment (8-13) (pA2 values 8.4
      and 8.2, respectively). Furthermore, it was found that a low concentration of
      neurotensin fragment (8-13) (1 nM) attenuated the inhibition of the firing rate
      by the selective dopamine D2 receptor agonist quinpirole in both neuron types
      (e.g., the effect of 0.01 microM quinpirole was reduced by approximately 60% in
      the presence of 1 nM neurotensin fragment [8-13]). Antagonism of this neurotensin
      fragment (8-13) effect by SR142948A confirms that neurotensin receptors can
      reduce the effect of dopamine D2 receptors at the single-cell level. These
      results are discussed in the light of possible roles for neurotensin in
      neurological disorders such as Parkinson's disease and schizophrenia.

PMID- 10658620
TI  - Intrasubthalamic nucleus metabotropic glutamate receptor activation: a
      behavioral, Fos immunohistochemical and [14C]2-deoxyglucose autoradiographic
      study.
AB  - Metabotropic glutamate receptors are a major class of excitatory amino acid
      receptors. Eight metabotropic glutamate receptor subtypes have been cloned, and
      are classified into three groups (I, II and III) based on amino acid sequence
      identity, effector systems and pharmacological profile. Previous results have
      shown that unilateral stimulation of metabotropic glutamate receptors in the
      subthalamic nucleus with the non-subtype-selective metabotropic glutamate
      receptor agonist 1S,3R-1-amino-1,3-cyclopentane dicarboxylate results in
      contralateral rotation in rats and Fos expression in the subthalamic nucleus.
      This suggests that metabotropic glutamate receptor stimulation results in altered
      subthalamic nucleus activity with consequent altered basal ganglia activity on
      the injected side. We sought to determine the metabotropic glutamate receptor
      subtype(s) involved and the functional neuroanatomy underlying the rotational
      behavior. Unilateral intrasubthalamic nucleus injection of group II or group III
      metabotropic glutamate receptor agonists induced contralateral rotation. In
      addition to producing rotation, group II and group III metabotropic glutamate
      receptor agonists induce toxicity in the subthalamic nucleus and overlying
      thalamus. Following group II or group III subthalamic nucleus metabotropic
      glutamate receptor stimulation, there is Fos-like immunoreactivity in the globus
      pallidus, subthalamic nucleus, substantia nigra pars reticulata and
      entopeduncular nucleus, suggesting altered activity in subthalamic nucleus target
      regions. However, examination of [14C]2-deoxyglucose uptake suggests that the
      alterations in basal ganglia activity are different following group II versus
      group III metabotropic glutamate receptor stimulation, suggesting that rotation
      is occurring via different mechanisms. It appears that stimulation of subthalamic
      nucleus group II metabotropic glutamate receptors induces rotation by increasing
      subthalamic nucleus activity. These results suggest that group II metabotropic
      glutamate receptor antagonists may be useful for alleviating subthalamic nucleus
      overactivity in Parkinson's disease.

PMID- 10658622
TI  - The absence of reactive astrocytosis is indicative of a unique inflammatory
      process in Parkinson's disease.
AB  - Virtually any neurological disorder leads to activation of resident microglia and
      invasion of blood-borne macrophages, which are accompanied by an increase in
      number and change in phenotype of astrocytes, a phenomenon generally termed
      reactive astrocytosis. One of the functions attributed to activation of
      astrocytes is thought to involve restoration of tissue damage. Hitherto, the role
      of astrocytes in the inflammatory reaction occurring in Parkinson's disease has
      not received much attention. In the present study, we examined the inflammatory
      events in autopsies of the substantia nigra and putamen from Parkinson's disease
      patients using age-matched autopsies from normal patients as controls. In the
      substantia nigra, activation of microglia was consistently observed in all
      Parkinson's disease autopsies as verified from immunohistochemical detection of
      CR3/43 and ferritin. Activation of resident microglia was not observed in the
      putamen. No differences were observed between controls and Parkinson's disease
      autopsies from the substantia nigra and putamen, in terms of distribution,
      cellular density or cellular morphology of astrocytes stained for glial
      fibrillary acidic protein or metallothioneins I and II, the latter sharing high
      affinity for metal ions and known to be induced in reactive astrocytes, possibly
      to exert anti-oxidative effects. Together, these findings indicate that the
      inflammatory process in Parkinson's disease is characterized by activation of
      resident microglia without reactive astrocytosis, suggesting that the progressive
      loss of dopaminergic neurons in Parkinson's disease is an ongoing
      neurodegenerative process with a minimum of involvement of the surrounding
      nervous tissue. The absence of reactive astrocytosis in Parkinson's disease
      contrasts what follows in virtually any other neurological disorder and may
      indicate that the inflammatory process in Parkinson's disease is a unique
      phenomenon.

PMID- 10658623
TI  - Chronic morphine increases GABA tone on serotonergic neurons of the dorsal raphe
      nucleus: association with an up-regulation of the cyclic AMP pathway.
AB  - Major adaptations after chronic exposure to morphine include an up-regulation of
      the adenosine 3',5'-monophosphate pathway. Acute opioids, via mu-opioid
      receptors, disinhibit midbrain serotonergic neurons by suppressing inhibitory
      GABAergic transmission in the dorsal raphe nucleus and adjacent periaqueductal
      gray. This study examined whether chronic morphine induces a compensatory
      increase in GABA inputs to 5-hydroxytryptamine neurons and whether this was
      associated with an up-regulation of the adenosine 3',5'-monophosphate pathway.
      The firing rate of serotonergic neurons was reduced in brain slices from morphine
      dependent rats, an effect reversed by the GABA(A) antagonist bicuculline. The
      reduction in firing rate was accompanied by an increased frequency of spontaneous
      GABAergic inhibitory postsynaptic currents, indicating increased GABA tone in the
      slice. The increase in GABA tone in brain slices from dependent rats was
      associated with increased induction of inhibitory postsynaptic currents by the
      adenylyl cyclase activator forskolin, suggesting an up-regulation of the
      adenosine 3',5'-monophosphate pathway. Indeed, chronic morphine increased levels
      of adenylyl cyclase VIII (but not of adenylyl cyclase I, III or V)
      immunoreactivity in the dorsal raphe nucleus area. Two adenosine 3',5'
      monophosphate-mediated mechanisms for the increase in GABA tone were discerned.
      The first, which predominated when impulse-flow was blocked by tetrodotoxin,
      involves protein kinase A since it was sensitive to protein kinase A inhibitors.
      The second, seen when impulse-flow was intact (i.e. absence of tetrodotoxin), was
      insensitive to protein kinase A inhibitors but was suppressed by ZD7288, a
      blocker of hyperpolarizing-activated Ih channels which are directly activated by
      adenosine 3',5'-monophosphate. We conclude that chronic morphine induces an up
      regulation of the adenosine 3',5'-monophosphate pathway in GABAergic inputs to
      serotonergic cells, resulting in an increase in spontaneous and impulse-flow
      dependent GABA release. These changes would lead to an increase in GABA tone and
      subsequently to the reported decrease in serotonergic activity during opiate
      withdrawal.

PMID- 10658624
TI  - 5-Hydroxytryptophan, but not L-tryptophan, alters sleep and brain temperature in
      rats.
AB  - The precise role of serotonin (5-hydroxytryptamine) in the regulation of sleep is
      not fully understood. To further clarify this role for 5-hydroxytryptamine, the 5
      hydroxytryptamine precursors L-tryptophan (40 and 80 mg/kg) and L-5
      hydroxytryptophan (25-, 50-, 75-, 100 mg/kg) were injected intraperitoneally into
      freely behaving rats 15 min prior to dark onset, and subsequent effects on sleep
      wake activity and cortical brain temperature were determined. L-5
      hydroxytryptophan, but not L-tryptophan, induced dose-dependent changes in sleep
      wake activity. During the 12-h dark period, non-rapid eye movement sleep was
      inhibited in post-injection hours 1-2 by the two lowest L-5-hydroxytryptophan
      doses tested, while the two highest doses induced a delayed increase in non-rapid
      eye movement sleep in post-injection hours 3-12. These highest doses inhibited
      non-rapid eye movement sleep during the subsequent 12-h light period. The finding
      that L-5-hydroxytryptophan, but not L-tryptophan, induced a dose-dependent and
      long-lasting decrease in cortical brain temperature regardless of whether or not
      non-rapid eye movement sleep was suppressed or enhanced contributes to a growing
      list of conditions showing that sleep-wake activity and thermoregulation,
      although normally tightly coupled, may be dissociated. The initial non-rapid eye
      movement sleep inhibition observed following low doses of L-5-hydroxytryptophan
      may be attributable to increased serotonergic activity since 5-hydroxytryptamine
      may promote wakefulness per se, whereas the delayed non-rapid eye movement sleep
      enhancement after higher doses may be due to the induction by 5-hydroxytryptamine
      of sleep-inducing factor(s), as previously hypothesized. The period of non-rapid
      eye movement sleep inhibition beginning 12 h after administration of L-5
      hydroxytryptophan doses that increase non-rapid eye movement sleep is
      characteristic of physiological manipulations in which non-rapid eye movement
      sleep is enhanced. The results of the present study suggest that the complex
      effects of 5-HT on sleep depend on the degree and time course of activation of
      the serotonergic system such that 5-HT may directly inhibit sleep, yet induce a
      cascade of physiological processes that enhance subsequent sleep.

PMID- 10658625
TI  - c-fos expression, behavioural, endocrine and autonomic responses to acute social
      stress in male rats after chronic restraint: modulation by serotonin.
AB  - The effects in male rats of serotonin depletion (using the neurotoxin 5,7
      dihydroxytryptamine) on the cross-sensitization of an acute social stress (defeat
      by a larger resident male) by previous repeated restraint stress (10 days, 60 min
      per day) was studied. Previous restraint increased freezing responses during
      social defeat in sham-operated rats, but this was not observed in those with
      depleted serotonin (83% or more in different regions of the brain). In contrast,
      neither heart rate (tachycardia) nor core temperature responses (hyperthermia)
      were accentuated in previously restrained rats (i.e. neither showed heterotypical
      sensitization), and neither adapted to repeated restraint (there is a hypothermic
      core temperature response during restraint). Corticosterone levels, which did
      adapt, nevertheless did not show accentuated responses to social defeat in
      previously restrained rats, though samples could only be taken 60 min after
      defeat. c-fos expression in the central nucleus of the amygdala 60 min after
      social defeat was increased by previous restraint. No other areas examined in the
      hypothalamus (e.g., paraventricular nucleus) or brainstem (e.g., solitary
      nucleus) showed differences related to previous restraint. Serotonin depletion
      reduced the expression of c-fos in the frontal cortex, lateral preoptic area,
      medial amygdala, central gray, medial and dorsal raphe, and locus coeruleus after
      social stress, but this was not altered by previous restraint. These results show
      that serotonin depletion has selective effects on the cross-sensitization of
      responses in previously stressed rats to a heterotypical stressor.

PMID- 10658626
TI  - Expression of the 5-HT1B receptor by subtypes of rat trigeminal ganglion cells.
AB  - The type of trigeminal ganglion cells that express 5-HT1B receptors has not been
      well characterized, despite the fact that these receptors are important targets
      for anti-migraine drugs. We have therefore used combined in situ hybridization
      and immunofluorescence to examine the expression of 5-HT1B receptor messenger RNA
      in identified subpopulations of rat trigeminal ganglion cells. 5-HT1B-expressing
      cells accounted for 15% of all trigeminal ganglion cells, were medium sized, and
      showed immunoreactivity for either 200,000 mol. wt neurofilament, calcitonin gene
      related peptide, or nerve growth factor receptor (trkA). In contrast few 5-HT1B
      cells showed immunoreactivity for substance P or binding of the lectin Griffonia
      simplicifolia IB4. Our results are consistent with 5-HT1B receptors acting to
      control the release of calcitonin gene-related peptide from trigeminal neurons
      with finely myelinated axons. 5-HT1B receptor agonists may reduce neurogenic
      vasodilation by activating such receptors. However many nociceptive trigeminal
      neurons, including the substance P and IB4-binding populations, do not express
      the 5-HT1B receptor.

PMID- 10658627
TI  - Increased exocytotic capability of rat cerebellar granule neurons cultured under
      depolarizing conditions.
AB  - To obtain insights into the mechanisms underlying activity-dependent survival of
      neurons, we surveyed various indices of cellular activity in rat cerebellar
      granule neurons cultured under conditions advantageous and disadvantageous for
      survival. Previously, we reported that the turnover of Ca2+ (both influx and
      efflux) is activated in raised K+-cultures (survival condition), although the
      cytoplasmic Ca2+ concentration is not affected. We also reported that endocytotic
      activity was high in the high K+-cultures. In the present study, we used the
      release of FM1-43 dye [N-(3-triethylammoniumpropyl)-4-(4-dibutylamino)styryl)py
      ridium bromide] to determine the exocytotic capabilities of neurons cultured in
      normal K+ (death condition), high K+ (survival condition) and brain-derived
      neurotrophic factor-supplemented (survival condition) media. The FM1-43 releases
      triggered by K+-induced depolarization and glutamate exposure were significantly
      higher in the high K+-cultures than in normal K+-cultures. Interestingly, the
      neurons whose survival was supported by brain-derived neurotrophic factor did not
      show high exocytotic capability, indicating that the high exocytotic capability
      is not a mere result of viability. However, the number of synaptic sites per cell
      (as monitored by synaptophysin immunopositivity) was unaffected by culture
      conditions. The present results suggest that an enhanced exocytotic activity
      supported by a strengthened exocytotic capability may underlie the high viability
      of rat cerebellar granule neurons cultured under depolarizing conditions.

PMID- 10658628
TI  - Overexpression of alpha2C-adrenoceptors impairs water maze navigation.
AB  - We investigated the role of overexpression of alpha2C-adrenoceptors in water maze
      navigation in mice transgenically manipulated to have a threefold overexpression
      of the alpha2C-adrenoreceptors. Alpha2C-adrenoreceptors overexpressing mice swam
      more in the peripheral annulus of the pool and did not find the hidden escape
      platform as well as the wild type control mice. A subtype-nonselective alpha2
      adrenoreceptor antagonist, atipamezole (ATI, 1000 microg/kg, s.c.), fully
      reversed the deficit in platform finding and search strategy in overexpressing
      mice. Noradrenaline depletion (-95%) induced by N-(2-chloroethyl)-N-ethyl-2
      bromobenzylamine (DSP-4) did not impair platform finding of wild type or
      overexpressing mice. The DSP-4 lesion slightly increased swimming in the
      peripheral annulus in wild type mice, but not in overexpressing mice. The DSP-4
      lesion produced a dissociable effect on the action of atipamezole to improve
      platform finding and search strategy in overexpressing mice: atipamezole did not
      alleviate the platform finding deficit in DSP-4 lesioned overexpressing mice, but
      normalized their abnormal search strategy. These results suggest that the
      abnormal search pattern and deficit in the accuracy of platform finding are
      mediated by constitutive activity of overexpressed alpha2C-adrenoreceptors.

PMID- 10658629
TI  - Glycine receptor (gephyrin) immunoreactivity is present on cholinergic neurons in
      the dorsal vagal complex.
AB  - We previously demonstrated that microinjection of exogenous glycine into the
      nucleus tractus solitarii of anesthetized rats elicits responses that are
      qualitatively like those elicited by microinjection of acetylcholine at the same
      site. The responses to glycine, like those to acetylcholine, are blocked by
      administration of a muscarinic receptor antagonist and prolonged by
      administration of an acetylcholinesterase inhibitor. Furthermore, glycine leads
      to release of acetylcholine from the nucleus tractus solitarii and surrounding
      dorsal vagal complex. An anatomical framework for interactions between
      glycinergic and cholinergic neurons was established by studies that identified
      glycine terminals and receptors in the dorsal vagal complex. The current study
      investigated the relationship between glycine receptors and neuronal elements
      that were immunoreactive for choline acetyltransferase in the dorsal vagal
      complex. Neurons that were immunoreactive for choline acetyltransferase were
      located in the dorsal motor nucleus of the vagus, hypoglossal nucleus and nucleus
      ambiguus, and stained cells were also present in medial, intermediate, and
      ventrolateral subnuclei of the nucleus tractus solitarii. We found that glycine
      receptors, immunolabeled with an antibody to gephyrin, were present on
      cholinergic dendrites in the nucleus tractus solitarii. Gephyrin immunoreactivity
      was also present on dendrites that did not stain for choline acetyltransferase.
      These data further support the contribution of cholinergic neurons in mediating
      cardiovascular responses to glycine in the nucleus tractus solitarii.

PMID- 10658631
TI  - Localization and action of adenosine A2a receptors in regions of the brainstem
      important in cardiovascular control.
AB  - In vitro autoradiography and central microinjections of a P1 adenosine A2a
      receptor antagonist have been employed to investigate a possible role for
      centrally located adenosine A2a receptors in modulation of the baroreceptor
      reflex. In vitro autoradiography using [125I]4-(2-[7-amino-2-[2
      furyl][3,2,4]triazolol[2,3-a][1,3,5]tr iazin-5-yl-amino]ethyl)phenol
      ([125I]ZM241385), the high-affinity adenosine A2a receptor antagonist, revealed a
      heterogeneous distribution of adenosine A2a binding sites within the lower
      brainstem of the rat. Image analysis showed high levels of binding in rostral
      regions of both the nucleus tractus solitarius and the ventrolateral medulla.
      Intermediate levels of binding were observed in the commissural nucleus tractus
      solitarius and the dorsal vagal motor nucleus, with low levels of binding in
      caudal regions of the nucleus tractus solitarius and the ventrolateral medulla,
      and the hypoglossal nucleus. Unilateral microinjections of unlabelled ZM241385
      into the nucleus tractus solitarius had no effect on baseline levels of arterial
      pressure, heart rate and phrenic nerve activity recorded in anaesthetized,
      artificially ventilated rats. However, microinjections of ZM241385 reduced the
      bradycardia evoked by stimulation of the ipsilateral aortic nerve. In contrast,
      ZM241385 had no effect on the depressor response or the reduction in phrenic
      nerve activity evoked by aortic nerve stimulation. Our results indicate that
      adenosine A2a binding sites are located in a number of brainstem regions involved
      in autonomic function, consistent with the idea that adenosine acts as a
      neuromodulator of a variety of cardiorespiratory reflexes. Specifically, the data
      support the hypothesis that adenosine A2a receptors located within the nucleus
      tractus solitarius are activated during baroreceptor stimulation and have an
      important modulatory role in the pattern of cardiovascular changes associated
      with this reflex.

PMID- 10658630
TI  - Activation of brain neurons following central hypervolaemia and hypovolaemia:
      contribution of baroreceptor and non-baroreceptor inputs.
AB  - In the present study we have used the detection of Fos, the protein product of c
      fos, to determine the distribution of neurons in the medulla and hypothalamus
      that are activated by changes in central blood volume. Experiments were conducted
      in both barointact and barodenervated conscious rabbits, to determine the
      contribution of arterial baroreceptors to the pattern of Fos expression evoked by
      changes in central blood volume, induced either by intravenous infusion of an
      isotonic modified gelatin solution, or by partial occlusion of the vena cava.
      These procedures resulted in a significant increase and decrease, respectively,
      in right atrial pressure over a 60 min period. In control experiments, barointact
      and barodenervated rabbits were subjected to the identical procedures except that
      no changes in central blood volume were induced. In comparison with the control
      observations, central hypervolaemia produced a significant increase in the number
      of Fos-immunoreactive neurons in the nucleus tractus solitarius, area postrema,
      the caudal, intermediate and rostral parts of the ventrolateral medulla,
      supraoptic nucleus, paraventricular nucleus, arcuate nucleus, suprachiasmatic
      nucleus and median preoptic nucleus. The overall pattern of Fos expression
      induced by central hypervolaemia did not differ significantly between barointact
      and barodenervated animals. Similarly, the overall pattern of Fos expression
      induced by central hypovolaemia did not differ significantly between barointact
      and barodenervated animals, but did differ significantly from that produced by
      hypervolaemia. In particular, central hypovolaemia produced a significant
      increase in Fos expression in the same regions as above, but also in the
      subfornical organ and organum vasculosum lamina terminalis. In addition, compared
      with central hypervolaemia, hypovolaemia produced a significantly greater degree
      of Fos expression in the rostral ventrolateral medulla and supraoptic nucleus.
      Furthermore, double-labelling for tyrosine hydroxylase immunoreactivity
      demonstrated that neurons in the ventrolateral medulla that expressed Fos
      following hypovolaemia were predominantly catecholamine cells, whereas following
      hypervolaemia they were predominantly non-catecholamine cells. Finally, double
      labelling for vasopressin immunoreactivity demonstrated that the number of
      Fos/vasopressin immunoreactive cells in the supraoptic nucleus was approximately
      10 times greater following hypovolaemia compared with hypervolaemia, but there
      were very few such double-labelled neurons in the paraventricular nucleus in
      response to either stimulus. The results demonstrate that central hypervolaemia
      and hypovolaemia each induces reproducible and specific patterns of Fos
      expression in the medulla and hypothalamus. The degree and pattern of Fos
      expression was unaffected by arterial baroreceptor denervation, indicating that
      it is primarily a consequence of inputs from cardiac receptors, together with an
      increase in the level of circulating hormones such as atrial natriuretic peptide,
      angiotensin II or vasopressin. Furthermore, the pattern of Fos expression
      produced by central hypervolaemia and hypovolaemia is distinctly different from
      that evoked by hypertension and hypotension, respectively [Li and Dampney (1994)
      Neuroscience 61, 613-634], particularly in hypothalamic regions. These findings
      therefore indicate that the central pathways activated by changes in blood volume
      are, at least in part, separate from those activated by changes in arterial
      pressure.

PMID- 10658633
TI  - Expression and action of cyclic GMP-dependent protein kinase Ialpha in
      inflammatory hyperalgesia in rat spinal cord.
AB  - Several lines of evidence have shown a role for the nitric oxide/cyclic guanosine
      monophosphate signaling pathway in the development of spinal hyperalgesia.
      However, the roles of effectors for cyclic guanosine monophosphate are not fully
      understood in the processing of pain in the spinal cord. The present study showed
      that cyclic guanosine monophosphate-dependent protein kinase Ialpha but not Ibeta
      was localized in the neuronal bodies and processes, and was distributed primarily
      in the superficial laminae of the spinal cord. Intrathecal administration of a
      selective inhibitor of cyclic guanosine monophosphate-dependent protein kinase
      Ialpha, Rp-8-[(4-chlorophenyl)thio]-cGMPS triethylamine, produced a significant
      antinociception demonstrated by the decrease in the number of flinches and shakes
      in the formalin test. This was accompanied by a marked reduction in formalin
      induced c-fos expression in the spinal dorsal horn. Moreover, cyclic guanosine
      monophosphate-dependent protein kinase Ialpha protein expression was dramatically
      increased in the lumbar spinal cord 96 h after injection of formalin into a
      hindpaw, which occurred mainly in the superficial laminae on the ipsilateral side
      of a formalin-injected hindpaw. This up-regulation of cyclic guanosine
      monophosphate-dependent protein kinase Ialpha expression was completely blocked
      not only by a neuronal nitric oxide synthase inhibitor, 7-nitroindazole, and a
      soluble guanylate cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one,
      but also by an N-methyl-D-aspartate receptor antagonist, dizocilpine maleate (MK
      801). The present results indicate that noxious stimulation not only initially
      activates but also later up-regulates cyclic guanosine monophosphate-dependent
      protein kinase Ialpha expression in the superficial laminae via an N-methyl-D
      aspartate-nitric oxide-cyclic guanosine monophosphate signaling pathway,
      suggesting that cyclic guanosine monophosphate-dependent protein kinase Ialpha
      may play an important role in the central mechanism of formalin-induced
      inflammatory hyperalgesia in the spinal cord.

PMID- 10658632
TI  - Effect of streptozotocin-induced diabetes on the activity of calcium channels in
      rat dorsal horn neurons.
AB  - We have previously found that spinal dorsal horn neurons from streptozotocin
      diabetic rats, an animal model for diabetes mellitus, show the prominent changes
      in the mechanisms responsible for [Ca2+]i regulation. The present study aimed to
      further characterize the effects of streptozotocin-induced diabetes on neuronal
      calcium homeostasis. The cytoplasmic Ca2+ concentration ([Ca2+]i) was measured in
      Fura-2AM-loaded dorsal horn neurons from acutely isolated spinal cord slices
      using fluorescence technique. We studied Ca2+ entry through plasmalemmal Ca2+
      channels during potassium (50 mM KCl)-induced depolarization. The K+-induced
      [Ca2+]i elevation was inhibited to a different extent by nickel ions, nifedipine
      and omega-conotoxin suggesting the co-expression of different subtypes of
      plasmalemmal voltage-gated Ca2+ channels. The suppression of [Ca2+]i transients
      by Ni2+ (50 microM) was the same in control and diabetic neurons. On the other
      hand, inhibition of [Ca2+]i transients by nifedipine (50 microM) and omega
      conotoxin (1 microM) was much greater in diabetic neurons compared with normal
      animals. These data suggest that under diabetic conditions the activity of N- and
      L- but not T-type voltage-gated Ca2+ channels substantially increased in dorsal
      horn neurons.

PMID- 10658634
TI  - Capsaicin-sensitive afferents are involved in signalling transneuronal effects
      between cutaneous sensory nerves.
AB  - The aim of the present study was to investigate changes in contralateral nerves
      associated with peripheral nerve injuries. Transection and subsequent
      regeneration of the saphenous nerve on one side caused a suppression of the
      ability of the contralateral saphenous nerve to produce a neurogenic plasma
      extravasation response. This effect was transient, and was first evident two
      weeks after injury, reaching its maximum at four weeks, but was no longer
      detectable at eight weeks. This change was paralleled by a decrease in the
      content of substance P, a neuropeptide involved in neurogenic plasma
      extravasation, in the contralateral nerve. The neurotoxin capsaicin was used to
      deplete the nerve of a subclass of C-fibres, namely the polymodal nociceptor
      afferents. Pretreatment of the nerve to be lesioned with capsaicin was sufficient
      to significantly attenuate the changes in the plasma extravasation response and
      substance P content observed on the contralateral side. The effectiveness of the
      capsaicin treatment was confirmed by histological examination. These results
      strongly suggest that changes observed at a site distant from the location of the
      nerve injury are dependent on the integrity of capsaicin-sensitive C-fibre
      afferents within the injured nerve. Furthermore, given that the contralateral
      nerve has commonly been used as the control for an injury conducted on the
      homologous nerve or muscle on the opposite side of the body, the underlying
      assumption being that the contralateral nerve remained unchanged, the present
      findings emphasize the need for separate groups of control animals which have
      undergone no surgical procedures.

PMID- 10658635
TI  - Incipient cauda equina syndrome as a model of somatovisceral pain in dogs: spinal
      cord structures involved as revealed by the expression of c-fos and NADPH
      diaphorase activity.
AB  - Segmental and laminar distribution of Fos-like immunoreactive, reduced
      nicotinamide adenine dinucleotide phosphate diaphorase (NADPHd)-exhibiting and
      double-labeled (Fos-like immunoreactive and NADPHd-exhibiting) neurons was
      examined in lower lumbar and sacral segments of the dog spinal cord using the
      model of multiple cauda equina constrictions. NADPHd histochemistry was used as
      marker of nitric oxide synthase-containing neurons. The appearance and the time
      course of Fos-like immunoreactive, NADPHd and double-labeled neurons was studied
      at 2 h and 8 h postconstriction characterized as the incipient phase of cauda
      equina syndrome. The occurrence of Fos-like immunoreactive and NADPHd-exhibiting
      neurons in fully developed cauda equina syndrome was studied at five days
      postconstriction. An increase in Fos-like immunoreactivity in superficial laminae
      (I-II) and an enhanced NADPHd staining of lamina VIII neurons were found. A
      statistically significant increase in Fos-like immunoreactive neurons was found
      in laminae I-II and VIII-X 8 h postconstriction, and in contrast, a prominent
      decrease in Fos-like immunoreactive neurons was found in laminae I-II,
      accompanied by a statistically significant increase in Fos-like immunoreactive
      neurons in more ventrally located laminae VII-X at five days postconstriction.
      Quantitative analysis of laminar distribution of constriction-induced NADPHd
      exhibiting neurons revealed a considerable increase in these neurons in laminae
      VIII-IX 8 h postconstriction and a statistically highly significant increase in
      NADPHd-exhibiting neurons in laminae VII-X five days postconstriction.
      Concurrently, the number of NADPHd-exhibiting neurons in laminae I-II was greatly
      reduced. While a low number of double-labeled neurons was found throughout the
      gray matter of lower lumbar and sacral segments at 2 h postconstriction, a
      statistically significant number of double-labeled neurons was found in lamina X
      8 h and in laminae VII-X five days postconstriction. The course and distribution
      of anterograde degeneration resulting five days after multiple cauda equina
      constrictions are compared with segmental and laminar distribution of Fos-like
      immunoreactive and NADPHd-exhibiting neurons. Prominent involvement of the spinal
      cord neurons appearing in the lumbosacral segments at the early beginning and in
      fully developed cauda equina syndrome results in a Fos-like immunoreactivity and
      strongly enhanced NADPHd staining of some neuronal pools. Under such
      circumstances, an early cauda equina decompression surgery is advisable aimed at
      decreasing or preventing the derangement of the neural circuits in the
      lumbosacral segments.

PMID- 10658642
TI  - Casein kinase 2 as a potentially important enzyme in the nervous system.
AB  - Protein kinase CK2 is a ubiquitous and pleiotropic seryl/threonyl protein kinase
      which is highly conserved in evolution indicating a vital cellular role for this
      kinase. The holoenzyme is generally composed of two catalytic (alpha and/or
      alpha') and two regulatory (beta) subunits, but the free alpha/alpha' subunits
      are catalytically active by themselves and can be present in cells under some
      circumstances. Special attention has been devoted to phosphorylation status and
      structure of these enzymic molecules, however, their regulation and roles remain
      intriguing. Until recently, CK2 was believed to represent a kinase especially
      required for cell cycle progression in non-neural cells. At present, with respect
      to recent findings, four essential features suggest potentially important roles
      for this enzyme in specific neural functions: (1) CK2 is much more abundant in
      brain than in any other tissue; (2) there appear to be a myriad of substrates for
      CK2 in both synaptic and nuclear compartments that have clear implications in
      development, neuritogenesis, synaptic transmission, synaptic plasticity,
      information storage and survival; (3) CK2 seems to be associated with mechanisms
      underlying long-term potentiation in hippocampus; and (4) neurotrophins stimulate
      activity of CK2 in hippocampus. In addition, some data are suggestive that CK2
      might play a role in processes underlying progressive disorders due to
      Alzheimer's disease, ischemia, chronic alcohol exposure or immunodeficiency virus
      HIV. The present review focuses mainly on the latest data concerning the
      regulatory mechanisms and the possible neurophysiological functions of this
      enzyme.

PMID- 10658636
TI  - Role of gonadal hormones in formalin-induced pain responses of male rats:
      modulation by estradiol and naloxone administration.
AB  - The aim of this study was to assess the possible mediation of endogenous opioids
      in the effects of gonadal hormones on the responses to formalin pain. We studied
      the effects of intracerebroventricular injection of estradiol and/or naloxone on
      the magnitude and time-course of the formalin-evoked behavioural and hormonal
      responses of intact and gonadectomized male rats. Animals were gonadectomized or
      left intact; on days 20 and 21 after surgery, they were intracerebroventricularly
      injected with 17beta-estradiol (1 microg/5 microl) or saline. On day 22, the
      animals received naloxone (2.5 microg/5 microl) or saline
      intracerebroventricularly and then, 15 min later, were subcutaneously injected
      with formalin (50 microl, 5%) or only pricked with a syringe needle in the dorsal
      hindpaw. The rats were then introduced to a testing apparatus where the formalin
      induced licking, flexing and jerking of the injected limb and the other
      spontaneous behaviours were recorded for 60 min. At the end of the test, the
      animals were killed and blood was collected from the trunk. Gonadectomy and
      naloxone increased flexing duration independently of the other treatments. In
      gonadectomized rats, estrogen increased licking duration and decreased paw-jerk
      frequency during the first phase (0-15 min) of the formalin test. During the
      second phase (16-60 min), licking was increased by estrogen only in intact
      animals. Treatment with naloxone completely abolished all these modifications.
      The three measures of activity (rearing, inner and outer crossing) showed that
      while in sham-treated animals the gonadectomy-induced decrease in activity was
      completely counteracted by estrogen administration, in formalin-treated animals
      the gonadectomy-induced decrease was not affected by estrogen. In fact, estrogen
      appeared to further depress the motor activities in the formalin groups. Naloxone
      reversed these modifications only for outer crossing frequency, blocking the
      gonadectomy-induced decrease in sham-treated animals. Corticosterone plasma
      levels were increased by formalin only in estrogen-treated animals, independently
      of naloxone. In conclusion, these data indicate an important role of both male
      gonadal hormones and estrogen in formalin-pain responses, acting through opiate
      and non-opiate mechanisms.

PMID- 10658638
TI  - Studies of cerebrospinal fluid flow and penetration into brain following lateral
      ventricle and cisterna magna injections of the tracer [14C]inulin in rat.
AB  - Parasynaptic communication, also termed volume transmission, has been suggested
      as an important means to mediate information transfer within the central nervous
      system. The purpose of the present study was to visualize by autoradiography the
      available channels for fluid movement within the extracellular space following
      injection of the inert extracellular marker [14C]inulin into the lateral
      ventricle or cisterna magna. Bolus injections of 5 microl of 1 microCi of
      [14C]inulin were made in awake rats via chronically implanted cannulae. After
      survival times ranging from 5 min to 4 h, brains were processed for in vivo
      autoradiography. At 5 min the tracer distributed throughout the ventricles,
      subarachnoid spaces and cisterns "downstream" of the injection sites. Penetration
      into the brain from these sites was complex with preferential entry along the
      ventral side of the brain, especially into the hypothalamus and brainstem. By 4 h
      virtually the entire brain was labeled irrespective of the site of tracer
      application. Sustained tracer entry from subarachnoid spaces suggests that some
      areas act as depots to trap circulating material. This mechanism may contribute
      to the pattern of deep penetration at later time-points. The spatial and temporal
      characteristics of fluid movement throughout the brain are instructive in the
      interpretation of many experimental procedures involving injection of molecules
      into the cerebrospinal fluid.

PMID- 10658643
TI  - Neuronal Ca2+ -activated Cl- channels--homing in on an elusive channel species.
AB  - Ca2+ -activated Cl- channels control electrical excitability in various
      peripheral and central populations of neurons. Ca2+ influx through voltage-gated
      or ligand-operated channels, as well as Ca2+ release from intracellular stores,
      have been shown to induce substantial Cl- conductances that determine the
      response to synaptic input, spike rate, and the receptor current of various kinds
      of neurons. In some neurons, Ca2+ -activated Cl- channels are localized in the
      dendritic membrane, and their contribution to signal processing depends on the
      local Cl- equilibrium potential which may differ considerably from those at the
      membranes of somata and axons. In olfactory sensory neurons, the channels are
      expressed in ciliary processes of dendritic endings where they serve to amplify
      the odor-induced receptor current. Recent biophysical studies of signal
      transduction in olfactory sensory neurons have yielded some insight into the
      functional properties of Ca2+ -activated Cl- channels expressed in the
      chemosensory membrane of these cells. Ion selectivity, channel conductance, and
      Ca2+ sensitivity have been investigated, and the role of the channels in the
      generation of receptor currents is well understood. However, further
      investigation of neuronal Ca2+ -activated Cl- channels will require information
      about the molecular structure of the channel protein, the regulation of channel
      activity by cellular signaling pathways, as well as the distribution of channels
      in different compartments of the neuron. To understand the physiological role of
      these channels it is also important to know the Cl- equilibrium potential in
      cells or in distinct cell compartments that express Ca2+ -activated Cl- channels.
      The state of knowledge about most of these aspects is considerably more advanced
      in non-neuronal cells, in particular in epithelia and smooth muscle. This review,
      therefore, collects results both from neuronal and from non-neuronal cells with
      the intent of facilitating research into Ca2+ -activated Cl- channels and their
      physiological functions in neurons.

PMID- 10658641
TI  - Specific glutathione binding sites in pig cerebral cortical synaptic membranes.
AB  - Glutathione (gamma-glutamylcysteinylglycine) is a neuromodulator at glutamate
      receptors, but may also act as a neurotransmitter at sites of its own. The Na+
      independent binding of [3H]glutathione to pig cortical synaptic membranes was
      characterized here using glycine, cysteine analogs, dipeptides and glutathione
      derivatives, and ligands selective for known glutamate receptors. L-Glutamate,
      pyroglutamate, quinolinate, (S)-5-fluorowillardiine and 6-nitro-7
      sulfamoylbenzo[f]quinoxaline-2,3-dione were weak inhibitors at concentrations of
      0.5 or 1 mM. D-Glutamate, L- and D-aspartate, glutamine, quisqualate, kynurenate,
      other N-methyl-D-aspartate receptor ligands and non-N-methyl-D-aspartate receptor
      ligands failed to displace [3H]glutathione. Except for weak inhibition by D
      serine (0.5 mM), glycine and other ligands of the glycine co-activatory site in
      the N-methyl-D-aspartate receptors had no displacing effect. Similarly,
      metabotropic glutamate group I, II and III receptor agonists and antagonists and
      compounds acting at the glutamate uptake sites were generally inactive.
      Glutathione, oxidized glutathione, S-nitrosoglutathione, gamma-L
      glutamylcysteine, cysteinylglycine, cysteine, cysteamine and cystamine were the
      most potent displacers (IC50 values in the micromolar range), followed by
      dithiothreitol, glutathione sulfonate and the S-alkyl derivatives of glutathione
      (S-methyl-, -ethyl-, -propyl-, -butyl- and -pentylglutathione). L-Homocysteinate
      and aminomethanesulfonate exhibited a moderate efficacy. Thiokynurenate, a
      cysteine analog and an antagonist at the N-methyl-D-aspartate receptor glycine co
      activatory site, was a potent activator of glutathione binding. At 1 mM, some
      dipeptides also slightly activated the binding, gamma-L-glutamylleucine and gamma
      L-glutamyl-GABA being the most effective. The specific binding sites for
      glutathione in brain synaptic membranes are not identical to any known excitatory
      amino acid receptor. The cysteinyl moiety is crucial in the binding of
      glutathione. The oxidation or alkylation of the cysteine thiol group reduces the
      binding affinity. The strong activation by thiokynurenate may indicate that the
      glutathione receptor protein contains a modulatory site to which co-agonists may
      bind and allosterically activate glutathione binding. The novel population of
      specific binding sites of glutathione gives rise to the possibility that they may
      have profound effects on synaptic functions in the mammalian central nervous
      system. The glutathione binding sites may be an important, and for the most part
      unrecognized, component in signal transduction in the brain.

PMID- 10658645
TI  - Evaluation of Wzz/MPA1/MPA2 proteins based on the presence of coiled-coil
      regions.

PMID- 10658637
TI  - Brain oxytocin: differential inhibition of neuroendocrine stress responses and
      anxiety-related behaviour in virgin, pregnant and lactating rats.
AB  - The involvement of brain oxytocin in the attenuated responsiveness of the
      hypothalamo-pituitary-adrenal axis and the oxytocin systems to external stressors
      found in pregnant and lactating rats has been studied, including both
      neuroendocrine and behavioural aspects. Intracerebroventricular infusion of an
      oxytocin receptor antagonist (0.75 microg/5 microl), but not of vehicle, elevated
      basal corticotropin and corticosterone secretion into blood of virgin female, but
      not of late pregnant or lactating rats. Oxytocin antagonist treatment further
      elevated the stress-induced (exposure to the elevated plus-maze or forced
      swimming) secretion of both corticotropin and corticosterone, but only in virgin
      and not in pregnant or lactating rats. Thus, corticotropin and corticosterone
      plasma concentrations remained attenuated in antagonist-treated pregnant and
      lactating animals. In contrast, infusion of the oxytocin antagonist significantly
      elevated the stress-induced secretion of oxytocin into blood in pregnant and
      lactating, but not in virgin, animals, indicating an autoinhibitory influence of
      intracerebral oxytocin on neurohypophysial oxytocin secretion induced by non
      reproduction-related stimuli. Treatment with oxytocin antagonist 10 min prior to
      behavioural testing on the elevated plus-maze significantly reduced the anxiety
      related behaviour in both pregnant and lactating rats, without exerting similar
      effects in virgin female rats. The results demonstrate a tonic inhibitory effect
      of endogenous oxytocin on corticotropin and, consequently, corticosterone
      secretion in virgin female rats, an effect which is absent in the peripartum
      period. In contrast, an anxiolytic action of endogenous oxytocin was detectable
      exclusively in pregnant and lactating rats. Therefore, we conclude that the
      actions of intracerebral oxytocin include independent effects on the responses of
      the hypothalamo-pituitary-adrenal axis and oxytocin systems to stressors and the
      anxiety-related behaviour which are modulated by the reproductive state of the
      animals.

PMID- 10658644
TI  - Aging in peripheral nerves: regulation of myelin protein genes by steroid
      hormones.
AB  - The process of aging deeply influences morphological and functional parameters of
      the peripheral nerves. Interestingly, recent observations performed in our
      laboratory on the rat sciatic nerves have indicated that the deterioration of
      myelin occurring in the peripheral nerves during aging may be explained by the
      fall of the messenger levels of the major peripheral myelin proteins
      (glycoprotein Po, myelin basic protein and peripheral myelin protein 22). At
      least in the case of the Po, the low levels of its messengers and of the protein
      itself found in aged animals are increased by the treatment with a physiological
      progesterone derivative like dihydroprogesterone. It has also been found that in
      normal adult male rats the levels of the messengers for Po in the sciatic nerve
      are increased by progesterone, dihydroprogesterone and tetrahydroprogesterone;
      surprisingly, the gene expression of peripheral myelin protein 22 is stimulated
      only by tetrahydroprogesterone. These observations have been confirmed in
      parallel studies performed on Schwann cell cultures. Since tetrahydroprogesterone
      does not bind to the progesterone receptor but is a ligand for the GABAA
      receptor, the hypothesis has been put forward that part of the steroidal effects
      reported might occur not through the classical progesterone receptor, but rather
      via an interaction with the GABAA receptor. In other experiments it has been
      found that the gene expression of Po may be decreased by orchidectomy and
      restored by treatment with the androgen dihydrotestosterone. Altogether, these
      observations suggest the future use of physiological and/ or synthetic steroid
      hormones as a possible therapeutic approach for some pathological situations
      occurring in peripheral nerves during aging and demyelinating diseases.

PMID- 10658640
TI  - Differential neurite growth on astrocyte substrates: interspecies facilitation in
      green fluorescent protein-transfected rat and human neurons.
AB  - In the present study, we used co-culture of astrocytes from one species with
      neurons from a different species to examine neuritic outgrowth. We include a
      focus on human cells. Three types of neuron were used, including rat hippocampal
      dentate granule cells, rat hypothalamic neurons and human cortical neurons. To
      visualize neuronal processes, neurons were either immunostained with GABA
      antiserum or transfected with the jellyfish green fluorescent protein gene. The
      entire axonal and dendritic fields of single neurons could be quantitatively
      analysed based on their strong green fluorescent protein label. Astrocytes were
      obtained from rat hippocampus or hypothalamus, chicken cortex, normal human
      cortex, human cortex lesion, and from the sclerotic human hippocampus after
      surgery for intractable temporal lobe epilepsy. In the absence of astrocytes,
      isolated neurons died within three to four days. In contrast, neurons from both
      rat and human brains survived and extended dendrites and axons on rat, chicken
      and human astrocytes or in their conditioned medium. Astrocytes from interspecies
      cultures were not only capable of enhancing the survival of neuron co-cultures,
      but neuronal neurite extension in some cases was even greater on heterospecific
      astrocytes than on homospecific astrocytes. To support the hypothesis that
      synaptogenesis of rat hippocampal neurons was accelerated by a substrate of human
      astrocytes, we used a functional assay based on time-lapse confocal laser or
      digital imaging of calcium responses to transmitter release; synaptic responses
      were found earlier when rat neurons were grown on rat or human astrocytes than in
      the absence of these astrocytes. These data indicate that rodent glial cells
      enhance human neurite extension, and that rat neurite outgrowth can be used as a
      type of bioassay for the neurite promoting capacity of different derivations of
      human glia.

PMID- 10658646
TI  - Novel roles of sigmaN in small genomes.

PMID- 10658639
TI  - Alzheimer's disease presenilin-1 exon 9 deletion and L250S mutations sensitize SH
      SY5Y neuroblastoma cells to hyperosmotic stress-induced apoptosis.
AB  - Mutations in the presenilin-1 (PS1) and presenilin-2 (PS2) genes account for the
      majority of early-onset familial Alzheimer's disease cases. Recent studies
      suggest that presenilin gene mutations predispose cells to apoptosis by
      mechanisms involving altered calcium homeostasis and oxidative damage. In the
      present study, we determined whether PS1 mutations also sensitize cells to
      hyperosmotic stress-induced apoptosis. For this, we established SH-SY5Y
      neuroblastoma cell lines stably transfected with wild-type PS1 or either the PS1
      exon 9 deletion (deltaE9) or PS1 L250S mutants. Cultured cells were exposed to an
      overnight (17 h) serum deprivation, followed by a 30 min treatment with either 20
      mM glucose, 10 nM insulin-like growth factor-1 or 20 mM glucose + 10 nM insulin
      like growth factor-1. Cells were then cultured for a further 3, 6 or 24 h and
      stained for apoptotic condensed nuclei using propidium iodide. Confirmation that
      cells were undergoing an active apoptotic process was achieved by labelling of
      DNA strand breaks using the terminal dUTP nick end labelling (TUNEL) technique.
      We also determined cell viability using 3-(4,5-dimethyl-thiazol-2-yl)-2,5
      diphenyltetrazolium bromide (MTT) reduction. Propidium iodide staining revealed
      that all cell lines and controls showed an increased number of apoptotic cells
      appearing with condensed nuclei at 24 h compared with 6 h and 3 h. High glucose
      induced hyperosmotic stress resulted in significantly more apoptotic cells in the
      PS1 deltaE9 and PS1 L250S mutation cell lines at 24 h, compared with the wild
      type PS1 lines (P < 0.001, ANOVA for both comparisons). Mean values (+/-S.D.) for
      the percentage number of apoptotic cells at 24 h following high glucose treatment
      were 16.1 +/- 3.5%, 26.7 +/- 5.5% and 31.0 +/- 5.7% for the wild-type PS1, PS1
      deltaE9 and PS1 L250S lines, respectively. The pro-apoptotic effects of high
      glucose treatment were reversed by 10 nM insulin-like growth factor-1, although
      to a lesser extent in the mutation cell lines (5.8 +/- 2.4%, 15.2 +/- 7.3% and
      13.2 +/- 2.0% for the wild-type PS1, PS1 deltaE9 (P < 0.01 for comparison with
      wild-type PS1) and PS1 L250S (P < 0.01 for comparison with wild-type PS1)
      transfected lines, respectively. TUNEL labelling of cells at 24 h following
      treatment gave essentially the same results pattern as obtained using propidium
      iodide. The percentage number of apoptotic cells with DNA strand breaks (means +/
      S.D.) following high glucose treatment was 15.4 +/- 2.6% for the wild-type PS1,
      26.8 +/- 3.2% for the PS1 deltaE9 (P < 0.001 for comparison with wild-type PS1)
      and 29.7 +/- 6.1% for the PS1 L250S transfected lines (P < 0.001 for comparison
      with wild-type PS1). The PS1 deltaE9 and PS1 L250S transfected lines also showed
      a higher number of apoptotic cells with DNA strand breaks at 24 h following high
      glucose plus insulin-like growth factor-1 treatment (11.4 +/- 2.0% and 14.3 +/-
      2.8%, respectively), compared with values for the wild-type PS1 lines (8.5 +/-
      2.4%). These differences were significant (P < 0.01) for the comparison of wild
      type PS1 and PS1 L250S, but not PS1 deltaE9 lines. The mutation-related increases
      in number of apoptotic cells at 24 h following high glucose treatment were not
      accompanied by significant differences in cell viability at this time-point. Our
      results indicate that PS1 mutations predispose to hyperosmotic stress-induced
      apoptosis and that the anti-apoptotic effects of insulin-like growth factor-1 are
      compromised by these mutations. Perturbations of insulin-like growth factor-1
      signalling may be involved in PS1 mutation-related apoptotic neuronal cell death
      in Alzheimer's disease.

PMID- 10658647
TI  - Use of green fluorescent protein (GFP) to study the invasion pathways of
      Edwardsiella tarda in in vivo and in vitro fish models.
AB  - Edwardsiella tarda is a fish pathogen that causes systemic infections in many
      food and ornamental fish. E. tarda PPD130/91 and PPD125/87 were selected as
      representatives of the virulent and avirulent groups, respectively, from eight
      fish isolates, and transformed with plasmids encoding either green fluorescent
      protein (pGFPuv) or blue fluorescent protein (pBFP2). Two host models were used
      to study the invasion pathway of E. tarda in vitro and in vivo. Epithelioma
      papillosum of carp (EPC) was used as the first model. Virulent and avirulent E.
      tarda strains were found to adhere to and invade EPC cells. Interactions between
      E. tarda and host cells examined under confocal microscopy and intracellular
      growth were followed at different time points. Bacterial internalization of
      PPD130/91 and PPD125/87 involved microfilaments and protein tyrosine kinase since
      cytochalasin D (an inhibitor of microfilament polymerization) and genistein (an
      inhibitor of protein tyrosine kinase) prevented internalization. Confocal studies
      revealed co-localization of polymerized actin with bacteria. Staurosporine, a
      protein kinase C inhibitor, accelerated internalization of PPD125/87, whereas
      PD098059, a mitogen-activated protein kinase (MAPK) kinase inhibitor prevented
      internalization of PPD130/91. In the second model, blue gourami were infected
      with E. tarda intramuscularly. Mortalities were observed in PPD130/91(pGFPuv)
      infected fish with high bacterial numbers detectable in all organs.
      PPD125/87(pBFP2)-infected fish did not die and the bacterial population decreased
      over time. Mixed infections comprised of both PPD130/91(pGFPuv) and
      PPD125/87(pBFP2), where inoculum size was similar to the single infections,
      caused mortalities in fish. High bacterial populations were noted only in the
      fish body muscle. The PPD125/87(pBFP2) population in the fish decreased after 5
      d. The number of PPD130/91(pGFPuv) also decreased in the fish organs, except for
      continued high growth in the body muscle. Histology revealed necrosis of the
      tissue (body muscle and liver) and fluorescent bacteria in fish that were
      infected with PPD130/91(pGFPuv) but not with PPD125/87(pBFP2). This study showed
      that fluorescent proteins are a useful tool for investigating bacterial host cell
      infection, and information elucidated here sheds new light on the interactions
      between E. tarda and its hosts.

PMID- 10658648
TI  - Invasion of fish epithelial cells by Photobacterium damselae subsp. piscicida:
      evidence for receptor specificity, and effect of capsule and serum.
AB  - Photobacterium damselae subsp. piscicida is a fish pathogen which causes serious
      disease in commercial warmwater fish species. Because information on the initial
      stages of the infection is scarce, an investigation of the invasion ability of
      this pathogen was undertaken utilizing a fish epithelial cell line (epithelioma
      papillosum carpio, EPC), a virulent capsulated strain of P. damselae (MT1415), an
      avirulent non-capsulated strain of P. damselae (EPOY-8803-ii) and Escherichia
      coli HB101 as a non-invasive control. P. damselae was found to be able to adhere
      to and invade fish epithelial cells and remain inside them for 6-9 h. There were
      no significant differences in invasiveness between the capsulated and non
      capsulated strains. A kinetics study demonstrated that P. damselae invasiveness
      was more efficient at low m.o.i., reaching saturation at higher m.o.i.,
      suggesting internalization may be receptor-mediated. Invasion efficiency (IE) was
      significantly higher than in the control E. coli HB101. Engulfment of bacteria
      was possibly by an endocytic process and was unaffected by killing the bacteria
      with UV light. However, heat-killed bacteria had significantly reduced invasion
      capability. Ultrastructural studies showed that inside the epithelial cells, the
      bacteria remained within large vacuoles for a few hours and no evidence of
      intracellular replication was found, by either fluorescence or electron
      microscopic studies. Normal sea bass serum slightly reduced the invasion
      capability of the MT1415 strain, but heat-inactivated normal serum had no effect.
      On the other hand, heat-inactivated fish antiserum raised against the same strain
      reduced the percentage of invaded epithelial cells by 50%. As for other
      pathogens, an intracellular phase of P. damselae may be a mechanism to delay or
      avoid phagocytosis and host immune responses, favouring the spread of infection.

PMID- 10658649
TI  - Identification of a novel glycoprotein-binding activity in Streptococcus pyogenes
      regulated by the mga gene.
AB  - The interaction between Streptococcus pyogenes and the host cell surface is not
      completely understood. Characterization of the adhesion mechanisms of the
      bacterium to the host cell surface is needed in order to develop new vaccines and
      anti-adhesion drugs. The presence of glycoprotein-binding activities among
      streptococcal strains was investigated. An activity binding to thyroglobulin,
      fetuin, asialofetuin and mucin but not non-glycosylated proteins was found to be
      present in the majority of the S. pyogenes strains studied. Cross-inhibition
      experiments suggested that the glycoproteins share a common structure recognized
      by the bacteria. The glycoprotein-binding activity was found to be proteinaceous,
      tightly attached to the bacterial surface and it also mediated the adherence of
      bacteria to solid surfaces coated with glycoproteins. The activity was found by
      transposon mutagenesis and complementation to be regulated by the multiple-gene
      regulator Mga, which has been implicated as a regulator of S. pyogenes virulence
      factors.

PMID- 10658650
TI  - Adhesion of Candida albicans to oral streptococci is promoted by selective
      adsorption of salivary proteins to the streptococcal cell surface.
AB  - Adhesion of Candida albicans to saliva-coated surfaces is an important early step
      in the colonization of the oral cavity. C. albicans cells also adhere to several
      species of oral streptococci including Streptococcus gordonii, Streptococcus
      oralis and Streptococcus sanguinis in what are believed to be multi-modal
      interactions. It is now demonstrated that incubation of streptococcal cells of
      these species with human parotid saliva further promotes the adhesion of C.
      albicans cells by up to 2-3-fold. Various species of streptococci were shown to
      adsorb different protein components of parotid saliva to their cell surfaces. The
      basic proline-rich proteins (bPRPs), to which C. albicans cells bind on
      nitrocellulose blot overlay, were strongly adsorbed to the surface of S. gordonii
      cells but not to S. oralis cells. Parotid saliva that was pre-adsorbed with S.
      gordonii cells and then applied to hydroxylapatite beads was <50% effective at
      supporting adhesion of C. albicans compared with control (non-adsorbed) saliva,
      demonstrating that bPRPs are major pellicle receptors. C. albicans cells did not
      adsorb bPRPs from fluid-phase parotid saliva. Following size-exclusion
      chromatography of parotid saliva samples, pooled fractions enriched in bPRPs
      promoted maximal adhesion of C. albicans to S. gordonii cells. The results
      demonstrate that C. albicans cells recognize only surface-bound forms of bPRPs
      and suggest that these proteins adsorbed to enamel or to streptococcal surfaces
      promote C. albicans adhesion and oral colonization.

PMID- 10658651
TI  - Effects of hydration on molecular mobility in phase-bright Bacillus subtilis
      spores.
AB  - The molecular mobility of 31P and 13C in dormant Bacillus subtilis spore samples
      with different water concentrations was investigated by high-resolution solid
      state NMR. Lowest molecular mobility was observed in freeze-dried preparations.
      Rehydration to a 10% weight increase resulted in increases in molecular motions
      and addition of excess water furthered this effect. A spore slurry which had been
      freeze-dried displayed after addition of excess water similar NMR spectra to
      native wet preparations. Dipicolinic acid (DPA), which is mainly located in the
      core, was detected at all hydration levels in 13C cross-polarization magic angle
      spinning (CPMAS) but not in single-pulse magic angle spinning (SPMAS) spectra,
      indicating that hydration had no effect on its mobility. The molecular mobility
      of 31P, present mainly in core-specific components, was strongly dependent on
      hydration. This result suggests reversible water migration between inner spore
      compartments and the environment, whereas 13C spectra of DPA indicate that it is
      immobilized in a water-insoluble network in the core. Scanning transmission
      electron microscopy revealed that freeze-dried spores were significantly longer
      and narrower than fully hydrated spores and had a 3% smaller volume.

PMID- 10658652
TI  - Complete spore-cortex hydrolysis during germination of Bacillus subtilis 168
      requires SleB and YpeB.
AB  - The role of the sleB gene of Bacillus subtilis, which encodes a putative spore
      cortex-lytic enzyme, and the downstream ypeB gene were investigated. Both SleB
      and YpeB were required for normal germination to occur. The corresponding mutants
      formed phase-bright, heat-resistant spores with no apparent defects in dormancy.
      However, mutant spore suspensions lost optical density slower than the wild-type
      and spores were phase-grey even 12 h after the triggering of germination. Since
      the loss of heat resistance and release of dipicolinic acid was similar to the
      wild-type, these mutants were blocked in the later stages of germination. The
      mutants were nevertheless capable of outgrowth on rich agar to form colonies,
      indicating that other spore components can compensate for their function
      sufficiently to allow outgrowth. The expression and regulation of the operon was
      examined using a lacZ transcriptional fusion. Expression of the operon began 2 h
      after the onset of sporulation and was under the control of RNA polymerase
      containing the forespore-specific sigma factor, sigmaG. The application of
      reverse phase HPLC revealed that the mutants do not have any structural defect in
      the dormant spore cortex and therefore these genes are not required for normal
      spore-cortex synthesis. The analysis of peptidoglycan dynamics during germination
      showed, however, that the cortex was only partially hydrolysed in both mutants.
      This analysis also revealed that the likely hydrolytic bond specificity of SleB
      is likely to be that of a lytic transglycosylase.

PMID- 10658653
TI  - Proteome analysis of Bacillus subtilis extracellular proteins: a two-dimensional
      protein electrophoretic study.
AB  - To analyse the proteome of Bacillus subtilis extracellular proteins,
      extracellular protein samples were prepared from culture media (minimal medium
      containing 0.4% glucose) of parental B. subtilis 168, a secA-temperature
      sensitive mutant and an ffh conditional mutant, and examined by two-dimensional
      gel electrophoresis. Approximately 100 to 110 spots were visualized in a gel of
      B. subtilis 168 extracellular proteins. Over 90% and 80% of these disappeared in
      the absence of SecA and Ffh, respectively. Thirty-eight obvious spots on the gel
      of the B. subtilis 168 preparation were selected and compared with spots obtained
      under SecA- or Ffh-deficient conditions. The appearance of 36 of these 38 spots
      depended on SecA and Ffh. Nineteen additional extracellular proteins were
      detected in cultures maintained in cellobiose, maltose and soluble starch. Among
      23 proteins of which the N-terminal amino acid sequences were determined, 17 were
      extracellular proteins having signal peptides in their precursor form. Two
      membrane proteins, Yfnl and YflE, were cleaved behind 226Ala-Tyr-Ala228 and
      213Ala-Leu-Ala215, respectively, and of which products seemed to be liberated
      into the culture medium. The production of Yfnl and YflE were also dependent on
      SecA and Ffh. These results indicate that most extracellular proteins target to
      and translocate across the cytoplasmic membrane by co-operation between the
      signal-recognition particle and Sec protein-secretion pathways. In contrast, a
      spot for Hag appeared independent from SecA and Ffh. Intracellular proteins Gap,
      SodA and KatA were identified in the extracellular protein samples. On the basis
      of these results and computer searches, it was predicted that B. subtilis
      produces 150 to 180 proteins extracellularly.

PMID- 10658654
TI  - Chaperone-like activities of the CsaA protein of Bacillus subtilis.
AB  - The growth and protein export defects of Escherichia coli secA51(Ts) strains can
      be suppressed by the CsaA protein of Bacillus subtilis. The present studies
      indicate that this effect can be attributed to chaperone-like activities of CsaA.
      First, CsaA stimulated protein export in secB, groES and dnaJ mutant strains of
      E. coli. Second, CsaA suppressed the growth defects of dnaK, dnaJ and grpE
      mutants of E. coli. Third, and most importantly, CsaA exhibited chaperone-like
      properties by stimulating the reactivation of heat-denatured firefly luciferase
      in groEL, groES, dnaK and grpE mutant strains of E. coli, and by preventing the
      aggregation of heat-denatured luciferase in vitro. Thus, it seems that CsaA
      suppresses the growth and secretion defects of E. coli secA(Ts) strains either by
      improving the translocation competence of exported pre-proteins, thereby making
      them better substrates for mutant SecA proteins, or by stimulating the
      translocation activity of mutant SecA proteins.

PMID- 10658655
TI  - An unusual pectate lyase from a Bacillus sp. with high activity on pectin:
      cloning and characterization.
AB  - The gene pelA encoding a pectate lyase from the strain Bacillus sp. BP-23 was
      cloned and expressed in Escherichia coli. The nucleotide sequence of a 1214 bp
      DNA fragment containing pelA gene was determined, revealing an ORF of 666
      nucleotides that encoded a protein of 23233 Da. The deduced amino acid sequence
      of the encoded enzyme showed homology to pectate lyases A, B, C and D from
      Fusarium solani, Pel-3 and PelB from Erwinia carotovora and Pell from Erwinia
      chrysanthemi. Homology was also found to the protein deduced from the Bacillus
      subtilis yvpA gene, the function of which is unknown. The heterologous expressed
      enzyme depolymerized polygalacturonate and pectins of methyl esterification
      degree from 22 to 89%, and exhibited similar activity on polygalacturonate and on
      89% esterified citrus pectin. Optimum temperature and pH for enzymic activity
      were 50 degrees C and pH 10, respectively. Ca2+ was required for activity on
      pectic substrates, while the enzyme was strongly inhibited by Ba2+.

PMID- 10658656
TI  - Changes in protein synthesis during the adaptation of Bacillus subtilis to
      anaerobic growth conditions.
AB  - After a shift of Bacillus subtilis from aerobic to anaerobic growth conditions,
      nitrate ammonification and various fermentative processes replace oxygen
      dependent respiration. Cell-free extracts prepared from wild-type B. subtilis and
      from mutants of the regulatory loci fnr and resDE grown under aerobic and various
      anaerobic conditions were compared by two-dimensional gel electrophoresis.
      Proteins involved in the adaptation process were identified by their N-terminal
      sequence. Induction of cytoplasmic lactate dehydrogenase (LctE) synthesis under
      anaerobic fermentative conditions was dependent on fnr and resDE. Anaerobic
      nitrate repression of LctE formation required fnr-mediated expression of narGHJI,
      encoding respiratory nitrate reductase. Anaerobic induction of the
      flavohaemoglobin Hmp required resDE and nitrite. The general anaerobic induction
      of ywfl, encoding a protein of unknown function, was modulated by resDE and fnr.
      The ywfl gene shares its upstream region with the pta gene, encoding the
      fermentative enzyme acetyl-CoA:orthophosphate acetyltransferase. Anaerobic
      repression of the synthesis of a potential membrane-associated NADH dehydrogenase
      (YjlD, Ndh), and anaerobic induction of fructose-1,6-bisphosphate aldolase (FbaA)
      and dehydrolipoamide dehydrogenase (PhdD, Lpd) formation, did not require fnr or
      resDE participation. Synthesis of glycerol kinase (GlpK) was decreased under
      anaerobic conditions. Finally, the effect of anaerobic stress induced by the
      immediate shift from aerobic to strictly anaerobic conditions was analysed. The
      induction of various systems for the utilization of alternative carbon sources
      such as inositol (IoIA, IoIG, IoIH, IoII), melibiose (MeIA) and 6-phospho-alpha
      glucosides (GIvA) indicated a catabolite-response-like stress reaction.

PMID- 10658657
TI  - Multiple stress responses in Streptococcus mutans and the induction of general
      and stress-specific proteins.
AB  - The authors have previously demonstrated that Streptococcus mutans shows an
      exponential-phase acid-tolerance response following an acid shock from pH 7.5 to
      5.5 that enhances survival at pH 3.0. In this study the response of S. mutans H7
      to acid shock was compared with the responses generated by salt, heat, oxidation
      and starvation. Prior induction of the acid-tolerance response did not cross
      protect the cells from a subsequent challenge by the other stresses; however,
      prior adaptation to the other stresses, except heat (42 degrees C), protected the
      cells during a subsequent acid challenge at pH 3.5. Starvation by fivefold
      dilution of the basal medium (BM) plus fivefold reduction of its glucose content
      increased the numbers of survivors 12-fold, whereas elimination of glucose from
      fivefold-diluted BM led to a sevenfold enhancement compared to the control cells;
      this indicated a relationship between the acid and starvation responses. The
      stress responses were further characterized by comparing the 2D electrophoretic
      protein profiles of exponential-phase cells subjected to the various stress
      conditions. Cells were grown to exponential phase at pH 7.5 (37 degrees C) and
      then incubated for 30 min under the various stress conditions in the presence of
      14C-labelled amino acids followed by cell extraction, protein separation by 2D
      gel electrophoresis and image analysis of the resulting autoradiograms. Using
      consistent twofold or greater changes in IOD % as a measure, oxidative stress
      resulted in the upregulation of 69 proteins, 15 of which were oxidation-specific,
      and in the downregulation of 24 proteins, when compared to the control cells. An
      acid shock from pH 7.5 to 5.5 enhanced synthesis of 64 proteins, 25 of them acid
      specific, while 49 proteins exhibited diminished synthesis. The dilution of BM
      resulted in the increased formation of 58 proteins, with 11 starvation-specific
      proteins and 20 showing decreased synthesis. Some 52 and 40 proteins were
      enhanced by salt and heat stress, with 10 and 6 of these proteins, respectively,
      specific to the stress. The synthesis of a significant number of proteins was
      increased by more than one, but not all stress conditions; six proteins were
      enhanced by all five stress conditions and could be classified as general stress
      proteins. Clearly, the response of S. mutans to adverse environmental conditions
      results in complex and diverse alterations in protein synthesis to further cell
      survival.

PMID- 10658658
TI  - Serum-starvation-induced changes in protein synthesis and morphology of Borrelia
      burgdorferi.
AB  - It has been demonstrated previously that motile Borrelia burgdorferi cells
      transform into non-motile cyst-forms when incubated for several weeks in BSKII (a
      complex medium) lacking rabbit serum. B. burgdorferi cells cannot synthesize
      fatty acids de novo and serum is thought to provide a source of fatty acids and
      lipids. When B. burgdorferi cells were serum-starved in defined RPMI medium, -90%
      of the cells formed spherical cysts within 48 h. Cyst formation was inhibited by
      tetracycline. Cyst opening and recovery of vegetative cells was rapidly induced
      by the addition of either BSKII or rabbit serum. The percentage of viable cells
      recovered from cysts ranged from 2.9% to 52-5%. Viability was inversely
      proportional to cyst age. Protein synthesis by B. burgdorferi during serum
      starvation was examined by labelling cells with Tran35S-Label and analysing the
      labelled proteins by two-dimensional gel electrophoresis and fluorography. The
      synthesis of over 20 proteins was induced during serum starvation. Western blots
      of proteins from vegetative cells and cysts probed with sera from either B.
      burgdorferi-infected humans or monkeys revealed that several cyst proteins were
      antigenic. These data suggest that cells of B. burgdorferi, although possessing a
      small genome and extremely limited biosynthetic capabilities, rapidly respond to
      conditions of serum starvation by inducing changes in protein synthesis and cell
      morphology. This study may help explain how cells of B. burgdorferi can survive
      periods of nutrient deprivation in different hosts and host tissues.

PMID- 10658659
TI  - Identification and overexpression of ltnl, a novel gene which confers immunity to
      the two-component lantibiotic lacticin 3147.
AB  - Production and immunity of the two-component lantibiotic lacticin 3147 is encoded
      by the 60-2 kb lactococcal plasmid pMRC01. A 12.6 kb region of this plasmid,
      containing ten genes in two divergently arranged gene clusters, has been
      subcloned in Lactococcus lactis subsp. cremoris MG1363 and has been shown to
      confer both lacticin 3147 production and immunity. Further subcloning revealed
      that the smaller of the two clusters (ItnRIFE) confers immunity. Although the
      ItnF and E genes are homologous to ABC transporters which confer immunity to
      other lantibiotics, deletion analysis indicates that they do not play a role in
      the immunity exhibited by this subclone in L. lactis subsp. cremoris MG1363.
      Also, a deletion in ItnR (which resembles a family of transcriptional repressors)
      had no effect on immunity. The remaining gene, Itnl, encodes a 116 amino acid
      protein with a predicted membrane location which bears no homology to other
      bacteriocin immunity proteins. Confirmation of its role in immunity was obtained
      when it was observed that disruption of Itnl resulted in a complete loss of
      immunity. When Itnl was cloned into the expression vector pMG36e, the resulting
      construct conferred levels of immunity comparable to pMRC01. This confirmed that
      under the control of a strong promoter, the Itnl gene product alone is sufficient
      to confer lacticin immunity. In addition, heterologous expression of Itnl was
      observed in Enterococcus faecalis OG1X. On cloning Itnl behind a nisin-inducible
      promoter, it was observed that the level of immunity was dependent on nisin
      concentration. Using this construct, the authors have demonstrated a potential
      role for Itnl as food-grade selectable marker. Thus, Ltnl appears to represent a
      new class of lantibiotic immunity proteins.

PMID- 10658660
TI  - The mycarose-biosynthetic genes of Streptomyces fradiae, producer of tylosin.
AB  - The tylCK region of the Streptomyces fradiae genome was sequenced, revealing an
      incomplete set of five tylC genes encoding all-but-one of the enzymes involved in
      the biosynthesis of mycarose. The latter is a 6-deoxyhexose sugar required during
      production of the macrolide antibiotic, tylosin. The missing mycarose
      biosynthetic gene, tylCVI, was found about 50 kb distant from its functional
      partners, on the other side of the tylG (polyketide synthase) gene complex.
      Mutational analysis, involving targeted gene transplacement, was employed to
      confirm the functions of specific genes, including tylCVI. Particularly
      interesting was the similarity between the tylosin-biosynthetic
      mycarosyltransferase enzyme, TylCV, and proteins of the macrolide
      glycosyltransferase (MGT) family that inactivate macrolides via glycosylation of
      attached sugar residues and are involved in resistance and/or antibiotic efflux.
      The arrangement of genes within the 'mycarose cluster' would allow their
      expression as two short operons with divergent, and perhaps co-regulated,
      promoters. Whether displacement of tylCVI relative to the other tylC genes
      provides additional regulatory opportunities remains to be established.

PMID- 10658661
TI  - Two new tailoring enzymes, a glycosyltransferase and an oxygenase, involved in
      biosynthesis of the angucycline antibiotic urdamycin A in Streptomyces fradiae
      Tu2717.
AB  - Urdamycin A, the principal product of Streptomyces fradiae Tu2717, is an
      angucycline-type antibiotic and anticancer agent containing C-glycosidically
      linked D-olivose. To extend knowledge of the biosynthesis of urdamycin A the
      authors have cloned further parts of the urdamycin biosynthetic gene cluster.
      Three new ORFs (urdK, urdJ and urdO) were identified on a 3.35 kb fragment, and
      seven new ORFs (urdL, urdM, urdJ2, urdZl, urdGT2, urdG and urdH) on an 8.05 kb
      fragment. The deduced products of these genes show similarities to transporters
      (urdJ and urdJ2), regulatory genes (urdK), reductases (urdO), cyclases (urdL) and
      deoxysugar biosynthetic genes (urdG, urdH and urdZ1). The product of urdM shows
      striking sequence similarity to oxygenases (N-terminal sequence) as well as
      reductases (C-terminal sequence), and the deduced amino acid sequence of urdGT2
      resembles those of glycosyltransferases. To determine the function of urdM and
      urdGT2, targeted gene inactivation experiments were performed. The resulting urdM
      deletion mutant strains accumulated predominantly rabelomycin, indicating that
      UrdM is involved in oxygenation at position 12b of urdamycin A. A mutant in which
      urdGT2 had been deleted produced urdamycin I, urdamycin J and urdamycin K instead
      of urdamycin A. Urdamycins I, J and K are tetracyclic angucyclinones lacking a C
      C connected deoxysugar moiety. Therefore UrdGT2 must catalyse the earliest
      glycosyltransfer step in the urdamycin biosynthetic pathway, the C
      glycosyltransfer of one NDP-D-olivose.

PMID- 10658662
TI  - Elucidation of anthracyclinone biosynthesis by stepwise cloning of genes for
      anthracyclines from three different Streptomyces spp.
AB  - The anthracycline skeleton is biosynthesized by aromatic (type II) polyketide
      synthases. Furthermore, three post-polyketide steps are needed to form the basic
      aglycone of anthracyclines. Auramycinone was produced in Streptomyces lividans by
      introducing nine structural genes from three different anthracycline-producing
      Streptomyces species. The genes used to construct the auramycinone biosynthesis
      cluster were derived from nogalamycin-, daunomycin- and aclacinomycin-producing
      Streptomyces strains. The biosynthetic stages were divided into polyketide and
      post-polyketide steps on the assumption that the first stable intermediate would
      be nogalonic acid, named analogously to aklanonic acid, the precursor of several
      anthracyclines. Single genes were cloned in the expression construct in the order
      determined by the proposed biosynthetic pathway. This facilitated investigation
      of the products formed in the heterologous host after addition of each separate
      gene to the construct. The results thus elucidate the biosynthesis steps,
      products and the genes responsible for the reactions needed to build up an
      anthracyclinone.

PMID- 10658663
TI  - cDNA-AFLP analysis of differential gene expression in the prokaryotic plant
      pathogen Erwinia carotovora.
AB  - For studies of differential gene expression in prokaryotes, methods for
      synthesizing representative cDNA populations are required. Here, a technique is
      described for the synthesis of cDNA from the potato pathogens Erwinia carotovora
      subsp. atroseptica (Eca) and Erwinia carotovora subsp. carotovora (Ecc) using a
      combination of short oligonucleotide (11-mer) primers that were known to anneal
      to conserved sequences in the 3' regions of enterobacterial genes. Specific PCR
      amplifications with primers designed to anneal to 14 known genes from either Eca
      or Ecc revealed the presence of the corresponding transcripts in cDNA, suggesting
      that the cDNA represented a broad genomic coverage. cDNA-amplified fragment
      length polymorphism (cDNA-AFLP) was used to identify differentially expressed
      genes in Eca, including one that shows significant similarity, at the protein
      level, to an avirulence gene from Xanthomonas campestris pv. raphani. Northern
      analysis was used to confirm that differentially amplified cDNA fragments were
      derived from differentially expressed genes. This is the first report of the use
      of cDNA-AFLP to study differential gene expression in prokaryotes.

PMID- 10658664
TI  - Critical nucleotides in the interaction of CatR with the pheBA promoter:
      conservation of the CatR-mediated regulation mechanisms between the pheBA and
      catBCA operons.
AB  - The promoter of the plasmid-borne pheBA genes encoding enzymes for phenol
      degradation resembles the catBCA promoter and is activated by CatR, the regulator
      of the chromosomally encoded catechol-degradative catBCA genes in Pseudomonas
      putida. In this study, site-directed mutagenesis of the pheBA promoter region was
      performed. The interrupted inverted repeat sequence of the CatR recognition
      binding site (RBS) of the pheBA promoter is highly homologous to that of the
      catBCA promoter. However, the RBS was shown not to be the sole important feature
      for high-affinity binding of CatR to this site. Mutagenesis of the activation
      binding site (ABS) of CatR, which overlaps the -35 hexamer sequence TTGGAT of the
      promoter, revealed that the two G nucleotides in this sequence are important for
      promoter activity but not for CatR binding. All other substitutions made in the
      ABS negatively affected both the promoter activity and CatR binding. The spacer
      sequence of the pheBA and catBCA promoters between the -10 and -35 hexamers is 19
      bp, which is longer than optimal. However, reducing the spacer region of the
      pheBA promoter was not sufficient for CatR-independent promoter activation. An
      internal binding site (IBS) for CatR is located downstream of the transcriptional
      start site of the catBCA genes and it negatively regulates the operon. A similar
      IBS was identified in the case of the pheBA operon and tested for its
      functionality. The results indicate a conservation of CatR-mediated regulation
      mechanisms between the pheBA promoter and the catBCA promoter. This universal
      mechanism of CatR-mediated transcriptional activation could be of great
      importance in enabling catechol-degrading bacteria to expand their substrate
      range via horizontal transfer of the phenol degradative genes.

PMID- 10658665
TI  - Genetics and regulation of two distinct haem-uptake systems, phu and has, in
      Pseudomonas aeruginosa.
AB  - A gene cluster similar to haem iron uptake loci of bacterial pathogens was
      identified in Pseudomonas aeruginosa. This phu locus ('Pseudomonas haem uptake')
      consisted of the phuR receptor gene and the phuSTUVW operon encoding a typical
      ABC transporter. Expression of phuR and phuSTUVW from mapped transcriptional
      start sites occurred under iron-restricted growth conditions and was directly
      controlled by the Fur protein. Binding of Fur was demonstrated by DNase
      footprinting of two adjacent 'Fur boxes' that overlapped both the phuR and
      phuSTUVW promoters. Two tandem repeats of 154 bp were identified downstream of
      the phuSTUVW operon, each of which contained a strong Fur-dependent promoter
      driving expression of iron-regulated RNAs antisense to phuSTUVW. Mutant strains
      with deletions in phuR and phuSTUV showed greatly reduced growth with either haem
      or haemoglobin as the only iron source: the defects were complemented by plasmids
      harbouring the phuR or the phuSTUV genes, respectively. Deletions of phuW or of
      the tandem repeats had only minor effects on haem utilization. The remaining haem
      and haemoglobin uptake still observed in the deltaphuR or deltaphuSTUV deletion
      mutants was due to a second haem-acquisition system, has, which was also under
      the direct control of Fur. This second haem-receptor gene, hasR, was identified
      upstream of and in an operon with hasA, encoding a haem-binding extracellular
      protein. A deltahasR mutant also exhibited decreased utilization of haem and
      haemoglobin, and a deltaphuR deltahasR double mutant was virtually unable to take
      up either compound. Both the PhuR and HasR proteins were detected in the outer
      membrane fraction of P. aeruginosa grown in low-iron media. Taken together, the
      evidence suggests that the phu and has loci encode two distinct systems required
      for the acquisition of haem and haemoglobin in P. aeruginosa.

PMID- 10658666
TI  - Three pathways for trehalose biosynthesis in mycobacteria.
AB  - Trehalose is present as a free disaccharide in the cytoplasm of mycobacteria and
      as a component of cell-wall glycolipids implicated in tissue damage associated
      with mycobacterial infection. To obtain an overview of trehalose metabolism, we
      analysed data from the Mycobacterium tuberculosis genome project and identified
      ORFs with homology to genes encoding enzymes from three trehalose biosynthesis
      pathways previously characterized in other bacteria. Functional assays using
      mycobacterial extracts and recombinant enzymes derived from these ORFs
      demonstrated that mycobacteria can produce trehalose from glucose 6-phosphate and
      UDP-glucose (the OtsA-OtsB pathway) from glycogen-like alpha(1-->4)-linked
      glucose polymers (the TreY-TreZ pathway) and from maltose (the TreS pathway).
      Each of the pathways was found to be active in both rapid-growing Mycobacterium
      smegmatis and slow-growing Mycobacterium bovis BCG. The presence of a disrupted
      treZ gene in Mycobacterium leprae suggests that this pathway is not functional in
      this organism. The presence of multiple biosynthetic pathways indicates that
      trehalose plays an important role in mycobacterial physiology.

PMID- 10658667
TI  - Phylogenetic relationships of Pleurotus species according to the sequence and
      secondary structure of the mitochondrial small-subunit rRNA V4, V6 and V9
      domains.
AB  - A comparative study of the V4, V6 and V9 domains of the mitochondrial small
      subunit (SSU) rRNA was conducted to evaluate the use of these sequences to
      investigate phylogenetic relatedness within the genus Pleurotus. The PCR products
      encompassing these regions from 48 isolates belonging to 16 Pleurotus species
      were sequenced and compared. From this comparison, the length and sequence of the
      three domains were found to be constant within a species. Significant inter
      species variations due to insertion/deletion events were found, in most cases
      occurring in regions not directly involved in the maintainance of the standard
      SSU rRNA secondary structure. Phylogenetic analysis based upon these
      mitochondrial sequences was in agreement with relationships previously
      established by morphological descriptions and with previous studies based upon
      the nuclear genome or isozymes; moreover such analysis resolved some ambiguities
      in earlier analyses. It was confirmed that P. ostreatus and P. florida represent
      a single species, as well as P. pulmonarius and P. sajor-caju. The phylogenetic
      analysis also made it possible to assess the relative positions of P.
      rattenburyi, P. lampas, P. sapidus, P. colombinus and P. eryngii. The results
      clearly showed that sequences of the V4, V6 and V9 domains of the mitochondrial
      SSU rRNA could provide good markers for use in the taxonomy and phylogeny of
      species of Basidiomycota. Because of their nucleotide conservation, the major
      advantage of these species-specific markers was the possibility to study only one
      isolate from each species to determine phylogenetic relatedness.

PMID- 10658668
TI  - Monitoring the kinetics of glycoprotein synthesis and secretion in the
      filamentous fungus Trichoderma reesei: cellobiohydrolase I (CBHI) as a model
      protein.
AB  - The authors have developed methodology to study the kinetics of protein synthesis
      and secretion in filamentous fungi. Production of cellobiohydrolase I (CBHI) by
      Trichoderma reesei was studied by metabolic labelling of the proteins in vivo
      with [35S]methionine or [14C]mannose, and subsequent analysis of the labelled
      proteins using two-dimensional gel electrophoresis. Analysis of the different pl
      forms of the nascent proteins allowed monitoring of the maturation of CBHI during
      the transport along the biosynthetic pathway. The maturation of the pi pattern of
      CBHI as well as secretion into culture medium was prevented by treatment with the
      reducing agent DTT. The pl forms of CBHI detectable in the presence of DTT
      corresponded to the early endoplasmic reticulum forms of the protein. Removal of
      N-glycans by enzymic treatment (endoglycosidase H or peptide-N-glycosidase F), or
      chemical removal of both N- and O-glycans, changed the pl pattern of CBHI,
      showing that glycan structures are involved in formation of the different pl
      forms of the protein. By quantifying the labelled proteins during a time course,
      parameters describing protein synthesis and secretion were deduced. The mean
      synthesis time for CBHI under the conditions used was 4 min and the minimum
      secretion time was 11 min. The methodology developed in this study provides tools
      to reveal the rate-limiting factors in protein production and to obtain
      information on the intracellular events involved in the secretion process.

PMID- 10658669
TI  - Analysis of two formaldehyde oxidation pathways in Methylobacillus flagellatus
      KT, a ribulose monophosphate cycle methylotroph.
AB  - The roles of cyclic formaldehyde oxidation via 6-phosphogluconate dehydrogenase
      and linear oxidation via the tetrahydromethanopterin (H4MPT)-linked pathway were
      assessed in an obligate methylotroph, Methylobacillus flagellatus KT, by cloning,
      sequencing and mutating two chromosomal regions containing genes encoding enzymes
      specifically involved in these pathways: 6-phosphogluconate dehydrogenase,
      glucose-6-phosphate dehydrogenase and methenyl H4MPT cyclohydrolase (gndA, zwf
      and mch). No null mutants were obtained in gndA or zwf, implying that the cyclic
      oxidation of formaldehyde is required for C1 metabolism in this obligate
      methylotroph, probably as the main energy-generating pathway. In contrast, null
      mutants were generated in mch, indicating that the H4MPT-linked pathway is
      dispensable. These mutants showed enhanced sensitivity to formaldehyde,
      suggesting that this pathway plays a secondary physiological role in this
      methylotroph. This function is in contrast to Methylobacterium extorquens AM1, in
      which the H4MPT-linked pathway is essential.

PMID- 10658670
TI  - Pathways for glutamate biosynthesis in the yeast Kluyveromyces lactis.
AB  - Purified glutamate synthase (GOGAT) from Kluyveromyces lactis was characterized
      as a high-molecular-mass polypeptide, a distinction shared with previously
      described GOGATs from other eukaryotic micro-organisms. Using degenerate
      deoxyoligonucleotides, designed from conserved regions of the alfalfa, maize and
      Escherichia coli GOGAT genes, a 300 bp PCR fragment from the K. lactis GOGAT gene
      KIGLT1 was obtained. This fragment was used to construct null GOGAT mutants of K.
      lactis by gene replacement. These mutants showed no growth defect phenotype and
      were able to grow on ammonium as sole nitrogen source. Double mutants obtained
      from a cross between a previously described KIGDH1 mutant and the K. lactis null
      GOGAT strain were full glutamate auxotrophs. These results indicate that
      glutamate biosynthesis in K. lactis is afforded through the combined action of
      KIGDH1 and KIGLT1 products.

PMID- 10658671
TI  - Communicative skills--a matter of negligence?

PMID- 10658672
TI  - Polyploidy: occurrence in nature, mechanisms, and significance for the
      megakaryocyte-platelet system.
AB  - OBJECTIVE: Polyploidy, the state of having greater than the diploid content of
      DNA, has been recognized in a variety cells. Among these cell types, the
      megakaryocytes are classified as obligate polyploid cells, developing a polyploid
      DNA content regularly during the normal life cycle of the organism, while other
      cells may become polyploid only in response to certain stimuli. The objective of
      this review is to briefly describe the different cell cycle alterations that may
      lead to high ploidy, while focusing on the megakaryocyte and the importance of
      high ploidy to platelet level and function. MATERIALS AND METHODS: Relevant
      articles appearing in scientific journals and books published in the United
      States and in Europe during the years 1910-1999 were used as resources for this
      review. We selected fundamental studies related to cell cycle regulation as well
      as studies relevant to the regulation of the endomitotic cell cycle in
      megakaryocytes. Also surveyed were publications describing the relevance of high
      ploidy to high platelet count and to platelet reactivity, in normal situations
      and in a disease state. RESULTS: Different cells may achieve polyploidy through
      different alterations in the cell cycle machinery. CONCLUSIONS: While
      upregulation of cyclin D3 further augments ploidy in polyploidizing
      megakaryocytes in vivo, future investigation should aim to explore how normal
      megakaryocytes may initiate the processes of skipping late anaphase and
      cytokinesis associated with high ploidy. In humans, under normal conditions,
      megakaryocyte ploidy correlates with platelet volume, and large platelets are
      highly reactive. This may not apply, however, to the disease state.

PMID- 10658673
TI  - In utero transfer and expression of exogenous genes in sheep.
AB  - OBJECTIVE: We have previously reported that directly injecting low-titer
      retroviral vector supernatant into pre-immune sheep fetuses resulted in the
      transfer and long-term expression of the bacterial NeoR gene within the
      hematopoietic system of these animals for over 5 years. In the present studies,
      we investigated whether using a higher titer vector would enable more efficient
      transduction and expression of the transgenes within the hematopoetic cells in
      sheep injected in utero. MATERIALS AND METHODS: Sixteen pre-immune sheep fetuses
      were injected intraperitoneally with the G1nBgSvNa8.1 helper-free retroviral
      vector supernatant encoding the bacterial NeoR and LacZ genes (titer: 1x10(7)
      cfu/mL). RESULTS: Over the 2-year time course of these studies, the presence and
      expression of the NeoR and LacZ genes were demonstrated in 12 of the 14 animals
      evaluated by several immunological and biochemical methods. Seven of the 12 sheep
      examined by flow cytometric analysis contained > or =6% transduced peripheral
      blood lymphocytes. Vector distribution was widespread without any detectable
      pathology. Importantly, PCR analyses and breeding experiments demonstrated that
      the germ line was not altered. CONCLUSIONS: These studies confirmed that direct
      injection of an engineered retrovirus is a feasible means of safely delivering
      foreign genes into a developing fetus and thus achieving long-term expression of
      the transgenes within the recipient's hematopoietic cells. Furthermore,
      expression of the NeoR gene from these studies was higher than that reported in
      our previous study in which a lower titer vector was used.

PMID- 10658674
TI  - Cultivated H-RS cells are resistant to CD95L-mediated apoptosis despite
      expression of wild-type CD95.
AB  - OBJECTIVE: In most cases of classic Hodgkin's disease (HD), Hodgkin and Reed
      Sternberg (H-RS) cells clonally derive from germinal-center B cells. Within their
      rearranged immunoglobulin genes, somatic mutations rendering potentially
      functional immunoglobulin gene rearrangements nonfunctional were detected,
      indicating that H-RS cells do not express a B-cell receptor. Under physiologic
      conditions, these cells would undergo apoptosis within the germinal center.
      However, H-RS cells clonally expand, disseminate, and lead to clonal relapse of
      HD, indicating their resistance to induced programmed cell death. The underlying
      mechanism remains to be elucidated. MATERIALS AND METHODS: [corrected] Analysis
      of receptor-ligand interactions in primary H-RS cells is difficult to perform due
      to their scarcity in vivo and their low proliferation rate in vitro. Therefore,
      two [corrected] B-cellular H-RS cell lines (L1236 and L428) were used to test for
      the expression of CD95 by flow cytometry and for the induction of apoptosis after
      incubation with CD95L obtained from retrovirally transduced murine myoblasts.
      Sequence analysis of CD95 cDNA obtained from these H-RS cell lines was performed.
      RESULTS: Expression of CD95 on the cell surface was detected in both cell lines.
      However, after incubation with CD95L, the cells did not undergo apoptosis. To
      test whether mutations within the CD95 cDNA sequence caused resistance to
      apoptosis in H-RS cells, sequence analysis of CD95 cDNA obtained from L1236 and
      L428 was performed. In both cell lines, CD95 was not affected by somatic
      mutations. CONCLUSIONS: Our results indicate that the two H-RS cell lines L1236
      and L428 are resistant to CD95-mediated apoptosis induced via CD95L, although
      wild-type CD95 is expressed. For further characterization of the mechanisms
      leading to prevention of apoptotic cell death in H-RS cells, it is necessary to
      determine impairments within the signaling cascade following CD95 activation.

PMID- 10658675
TI  - Leukemic cells from murine myeloid leukemia display an intrinsic ability for
      autonomous proliferation.
AB  - OBJECTIVE: Human acute myeloid leukemia (AML) cells can proliferate in vitro in
      the absence of added growth factors when cultured at high cell density. Autocrine
      growth factor production is a postulated mechanism of autonomous growth. We
      sought to examine this using murine AML cells. MATERIALS AND METHODS: We have
      utilized a Moloney murine leukemia virus (M-MuLV) model of AML to investigate the
      nature of autonomous in vitro growth of myeloid leukemic cells. RESULTS: Like
      human AML, M-MuLV-induced myeloid leukemic cells displayed autonomous growth in
      unstimulated high cell density cultures. However, replating of individual,
      primary, growth factor autonomous colonies of leukemic cells demonstrated the
      presence of clonogenic cells capable of autonomous growth when cultured at low
      cell density. In addition, there was heterogeneity in the progeny of these cells:
      both factor-dependent leukemic cells and cells autonomous of exogenous factor
      were observed. CONCLUSION: We propose that clonogenic cells capable of autonomous
      growth at low cell density represent leukemic progenitors while the majority of
      leukemic cells derived from these "autonomous" leukemic cells are factor
      dependent.

PMID- 10658676
TI  - Presence of primitive lymphoid progenitors with NK or B potential in ex vivo
      expanded bone marrow cell cultures.
AB  - OBJECTIVE: In previous work, we showed that CD34+ bone marrow cells can be
      successfully expanded along the myeloid pathway in stroma- and serum-free
      conditions in the presence of SCF+IL-3+IL-6+Flt3-l+G-CSF+MGDF. Due to the lack of
      phenotypically detectable lymphoid cells, it was necessary to address the
      question of the lymphoid potential of the expanded populations under these
      conditions. MATERIALS AND METHODS: The present report describes a long-term
      culture system that supports human B- and NK-cell differentiation from the day 14
      fraction without further selection of the more primitive cells. In NK
      proliferation assays, the cells were maintained over stroma cells in the presence
      of IL-2 for 4-5 weeks. NK initiating cells (NK-IC) were determined by a limiting
      dilution assay. In B-cell cultures, the expanded cells were maintained over MS5
      in the presence of Flt3-l for 4-8 weeks. RESULTS: NK cells rose from 0.2%+/-0.04%
      at culture initiation to 71%+/-6% at week 5. These cells displayed cytolytic
      activity. NK-IC evaluation showed a mean 18-fold expansion in the day 14 expanded
      fraction as compared to the initial day 0 fraction. Similarly, CD19+ cells rose
      from 0.1% at culture initiation to 30%+/-1% at week 6. Cells produced under these
      B-LTC conditions were CD34-CD19+CD10+. We also demonstrated that the CD34+/Lin-
      sorted cells from the day 14 fraction gave rise to NK and B cells. CONCLUSION:
      This culture system permits the revelation of a population that, although poorly
      represented in terms of phenotypically detectable cells, nevertheless retains
      high levels of lymphoid NK and B potential after 14 days expansion. Such data
      suggest the persistence, or expansion, of lymphoid progenitors and, hence, the
      multipotentiality of the expanded progenitor/stem cells.

PMID- 10658677
TI  - Characteristic expression of Hck in human B-cell precursors.
AB  - OBJECTIVE: To identify molecules involved in signaling for early B-cell
      development, we investigated the expression of signal transduction-related
      proteins in B-cell progenitors. MATERIALS AND METHODS: [corrected] Normal as well
      as leukemic B-cell progenitors were examined by immunoblotting and
      immunofluorescence study. RESULTS: [corrected] In a survey of the expression of a
      broad range of signal transduction molecules, the Src-family protein tyrosine
      kinases were found to be differentially expressed in early B-cell
      differentiation. [corrected] Analysis of freshly prepared precursor-B acute
      lymphoblastic leukemia cells and B-lineage cell lines showed Hck and Lyn are
      major Src-family protein tyrosine kinases expressed in this type of leukemic
      blasts. [corrected] However, heterogeneity of Hck and Lyn expression was found in
      these cells, and precursor-B acute lymphoblastic leukemia cells subsequently were
      classified according to the expression pattern of Hck and Lyn as Hck/Lyn dual
      negative, Hck-predominant, Hck/Lyn dual-positive, and Lyn-predominant. Further
      studies on normal B-lineage cells indicated that the Src-family protein tyrosine
      kinases are expressed sequentially in a differentiation-dependent fashion during
      B-cell ontogeny and that the predominant expression of Hck is a common feature in
      B-cell progenitors, whereas Lyn expression is more significant in mature B cells.
      CONCLUSIONS: Although the biologic significance remains unknown, sequential
      expression of Src-family protein tyrosine kinases should play a role in
      regulation of early B-cell differentiation.

PMID- 10658678
TI  - Differential expression of multiple unexpected genes during U937 cell and
      macrophage differentiation detected by suppressive subtractive hybridization.
AB  - OBJECTIVE: The objective of this study was to identify new markers of
      myelomonocytic differentiation using a sensitive technique that permits detection
      of rare differential gene expression. MATERIALS AND METHODS: [corrected]
      Suppressive subtractive hybridization (SSH) was performed between the human
      myelomonocytic U937 cell line and 1 alpha, 25-dihydroxyvitamin D3 and
      transforming growth factor beta 1 differentiated U937 cells. cDNA clones with
      significant increased expression in differentiated U937 cells over
      nondifferentiated U937 cells were characterized by sequencing. [corrected] The
      pattern of differential gene expression obtained by SSH was confirmed by cDNA
      Southern and Northern blots on the undifferentiated vs. differentiated U937
      cells, and by reverse transcriptase polymerase chain reaction on undifferentiated
      human CD34(+) stem cells isolated from bone marrow vs. peripheral blood CD14(+)
      mature monocytes. RESULTS: Seven cDNAs never associated with in vitro U937 cell
      myelomonocytic differentiation (prolactin, 11-beta hydroxysteroid dehydrogenase
      [11 beta-HSD)] haptoglobin alpha (2FS)-beta precursor, GLIPR, RTVP, the RNA
      helicase P68, and spermidine-spermine N1-acetyltransferase) were identified. The
      first five of these genes previously were associated with immune function and the
      last two are important for intermediary metabolism. Differential expression was
      confirmed in CD34(+)/CD14(+) monocyte differentiation for all genes but 11 beta
      HSD. CONCLUSIONS: We identified six new markers of U937 cell differentiation,
      which also are differentially expressed during normal human myelomonocytic
      differentiation.

PMID- 10658679
TI  - Abl kinase but not PI3-kinase links to the cytoskeletal defects in Bcr-Abl
      transformed cells.
AB  - OBJECTIVE: The purpose of this study was to investigate the contribution of Abl
      kinase and phosphatidylinositol 3-kinase (PI3-kinase) to the altered adhesive
      properties and cytoskeletal defects in a Bcr-Abl transformed fibroblast cell
      model. MATERIALS ANID METHODS: Two fibroblast cell lines stably transfected with
      Bcr-Abl were compared to their parental counterparts for alterations in their
      adhesive properties in an attachment assay and for abnormalities in their
      cytoskeletal architecture by immunofluorescence microscopy. Cells then were
      treated with specific inhibitors of either the Abl kinase CGP57148 or the PI3
      kinase LY294002 to determine whether these treatments would restore normal
      cytoarchitecture and adhesion. RESULTS: [corrected] Significant defects in
      cytoskeletal architecture were observed using this fibroblast model of Bcr-Abl
      expression. Specific changes include loss of stress fibers and focal adhesions,
      which correlated with an adhesive defect. [corrected] Treatment of Bcr-Abl
      expressing cells with CGP57148, but not LY294002, resulted in reversion of cells
      to a near-normal phenotype, as assessed by immunofluorescence and attachment of
      Bcr-Abl transformed fibroblasts. CONCLUSIONS: Our studies demonstrate that Bcr
      Abl tyrosine kinase but not PI3- kinase activity is required for maintenance of
      cytoskeletal rearrangements resulting from Bcr-AbI expression. Further,
      inhibition of Abl kinase restored normal adhesive properties to the Bcr-Abl
      expressing cells, demonstrating the contribution of Bcr-Abl kinase activity to
      abnormal cytoskeletal function.

PMID- 10658680
TI  - Residual damage of lymphohematopoietic repopulating cells after irradiation of
      mice at different stages of development.
AB  - OBJECTIVE: The purpose of this study was to evaluate the repopulating properties
      of bone marrow (BM) from mice irradiated during embryonic and adult stages of
      development. MATERIALS AND METHODS: Four-day-old embryos, 17-day-old fetuses, and
      12-week-old mice were irradiated with of 1 or 3 Gy of x-rays. At 3 and 9 months
      postirradiation, the effects generated within the different compartments of
      repopulating cells (RCs) were evaluated by determining, in a BM competition
      assay, the contribution of the irradiated precursors to the lymphohematopoiesis
      of recipients at different times posttransplantation (3, 9, and 15 months).
      RESULTS: The irradiation of 4-day-old embryos with either 1 or 3 Gy did not
      produce residual repopulation or differentiation effects within the different RCs
      assayed. However, significant impairments in RC functionality were observed in
      mice irradiated on the 17th day postconception or at the 12th week of age.
      Whereas irradiation of these animals with 1 Gy did not impair the long-term
      functionality of the very primitive 15-month-old RCs, irradiation with 3 Gy
      generated sustained impairment in all tested types of hematopoietic progenitors
      and RCs. Moreover, repopulation data derived from the analysis of recipient BM
      and thymus strongly suggested that the observed effects were produced within the
      multipotent pool of lymphohematopoietic RCs. CONCLUSIONS: Our data show the
      generation of long-term effects in the multipotent RCs of mice irradiated at
      fetal and adult stages of growth and reveals the normal functionality of the RCs
      from animals irradiated during the early stages of embryonic development.

PMID- 10658681
TI  - Enhancement of the anti-tumor activity of a peripheral blood progenitor cell
      graft by mobilization with interleukin 2 plus granulocyte colony-stimulating
      factor in patients with advanced breast cancer.
AB  - OBJECTIVE: Autologous interleukin 2 (IL-2)-activated natural killer (NK) cells
      kill a broad spectrum of tumor targets, including breast cancer. We hypothesized
      that mobilization with IL-2 and granulocyte colony-stimulating factor (G-CSF) for
      collection of peripheral blood progenitor cells (PBPC) may enhance the anti-tumor
      activity of the graft in autograft recipients. We determined the dose-limiting
      toxicity and maximum tolerated dose of subcutaneous IL-2 given with G-CSF for
      PBPC mobilization, the ability of IL-2 + G-CSF mobilized stem cells to
      reconstitute hematopoiesis, and the in vitro immunologic function of the graft in
      patients with advanced breast cancer. MATERIALS AID METHODS: Forty-three women
      with stage IIIA/B or metastatic breast cancer underwent mobilization of PBPC with
      IL-2 administered subcutaneously for 14 days along with G-CSF for the latter 7
      days. IL-2 was given in a dose-escalated manner, with the maximum tolerated dose
      determined to be 1.75 x 10(6) IU/m(2)/day. Fifteen women with stage IIIA/B or
      metastatic breast cancer underwent G-CSF mobilization alone and served as a
      control group. RESULTS: [corrected] Fifty-two percent of the patients mobilized
      with 1L-2 at the maximum tolerated dose reached the target number of CD34(+)
      cells for transplantation with three aphereses compared to 93% of control
      patients who were mobilized with G-CSF alone. [corrected] There was no
      significant impact on time to engraftment of neutrophils or platelets using
      either mobilization regimen. The addition of subcutaneous IL-2 to mobilization
      increased the cytotoxicity of IL-2-activated mononuclear cells from the PBPC
      product against the breast cancer cell target, MCF-7, and increased the
      percentage of NK cells and activated T cells in the PBPC product. The enhanced NK
      cell number was sustained in the early posttransplant period. CONCLUSIONS:
      [corrected] IL-2 + G-CSF mobilization is safe, may lead to a more immunologically
      functional graft without impairing hematologic recovery, and thus merits further
      exploration to evaluate the clinical anti-tumor efficacy of these immunocompetent
      grafts. [corrected] Limitations of this combined approach to stem cell
      mobilization include a decrease in the number of CD34(+) cells mobilized with the
      combined cytokines and the short duration of the increased number of anti-tumor
      effector cells after transplant.

PMID- 10658682
TI  - Cytogenetic response to autografting in chronic myelogenous leukemia correlates
      with the amount of BCR-ABL positive cells in the graft.
AB  - OBJECTIVE: An important step in successful autografting of patients with chronic
      myelogenous leukemia is the delivery of a leukemia-free graft. We conducted this
      study to determine whether the cytogenetic response after autografting was
      correlated with the number of BCR ABL-positive cells present within the stem cell
      grafts. MATERIALS AND METHODS: By BCR-ABL mRNA quantification, we studied the
      serial pheresis products from 40 Philadelphia (Ph)-positive patients who received
      ICE/mini-ICE mobilization therapy and underwent autologous stem cell
      transplantation. We correlated the residual disease within the graft reinfused
      with the cytogenetic response following transplantation, taking into
      consideration those responses that lasted 12 months or more. RESULTS: Thirty-two
      patients received a graft with 0-35% Ph-metaphases and 19 received a graft with
      BCR-ABL/ABL ratio < or =0.01. After a median of 27 months (range, 12-50) from
      transplant, 18 patients achieved complete or major cytogenetic response lasting
      at least 12 months, and 14 of them (78%) received a graft with BCR-ABL/ABL ratio
      < or =0.01 (range, 0.0003-0.01). Twenty-two patients experienced short-lived
      responses or had >35% Ph-positive cells in the marrow after transplant, but only
      5 of them (23%) had a graft with BCR-ABL/ABL ratio < or =0.01 (range, 0.001
      0.01). Therefore, we found a strong association between a BCR-ABL/ABL ratio less
      than or =0.01 and the achievement of complete or major cytogenetic remission
      after autografting (chi(2) test, p = 0.0001). Patients reinfused with grafts
      contaminated at low levels with leukemic cells also showed a longer duration of
      the response (log-rank test, p = 0.0009). Eleven patients were reinfused with the
      lowest level of contaminated stem cell collections, according to the BCR-ABL/ABL
      ratio. None of these patients experienced prolonged neutropenia or
      thrombocytopenia following stem cell reinfusion and nine of them had long-lasting
      complete or major cytogenetic responses after transplant. CONCLUSION: This study
      demonstrates that the number of BCR-ABL positive cells present in a stem cell
      graft is an important predictive factor for the achievement and the duration of
      cytogenetic response after autografting. [corrected]

PMID- 10658683
TI  - On the spatial pattern of casualties in earthquakes.

PMID- 10658684
TI  - GIS mapping of earthquake-related deaths and hospital admissions from the 1994
      Northridge, California, Earthquake.
AB  - PURPOSE: Earthquakes pose a persistent but unpredictable health threat. Although
      knowledge of geologic earthquake hazards for buildings has increased, spatial
      relations between injuries and seismic activity have not been explained. METHODS:
      Fatal and hospital-admitted earthquake injuries due to the 1994 Northridge
      Earthquake were identified. Geographical Information Systems software was used to
      map all injury locations. Injuries were analyzed with regard to distance from the
      earthquake epicenter, the Modified Mercalli Intensity Index, peak ground
      acceleration, and proportion of damaged residential buildings. RESULTS: Injury
      severity was inversely related to distance from the epicenter and increased with
      increasing ground motion and building damage. However, injury incidence and
      severity were not completely predicted by seismic hazard and building damage, and
      injuries of all severities occurred in a large geographic area. Average distance
      to the epicenter was smallest for injuries related to falling building parts and
      largest for cutting/piercing injuries and falls. CONCLUSIONS: The injuries from
      the Northridge Earthquake extended beyond the areas of highest environmental
      activity. Factors such as age and activity during the earthquake may be equally
      important in predicting injury from earthquakes as seismic features.

PMID- 10658685
TI  - The epidemiology of ovarian cancer: a population-based study in Olmsted County,
      Minnesota, 1935-1991.
AB  - PURPOSE: To determine trends in incidence and survival between 1935 and 1991 and
      to evaluate risk factors for ovarian cancer among Olmsted County, Minnesota
      women. METHODS: All newly diagnosed cases of ovarian cancer among Olmsted County
      women in 1975-1991 were identified using the medical records linkage system of
      the Rochester Epidemiology Project. In order to assess trends, incidence rates in
      the subset of Rochester women were compared with Rochester rates for 1935-1974.
      Survival was evaluated by the Kaplan-Meier product-limit method. A case-control
      analysis of risk factors compared Olmsted County women with invasive epithelial
      ovarian cancer and an age-matched group of women from the community by logistic
      regression. RESULTS: Altogether, 129 Olmsted County women were newly diagnosed
      with ovarian cancer in 1975-1991. The age-adjusted (to 1970 United States whites)
      incidence rate was 22.5 per 100,000 person-years. Median survival from initial
      diagnosis was 3.7 years. Compared to an equal number of controls, the 103 women
      with invasive epithelial disease were more likely to be nulliparous (odds ratio
      [OR] 1.9; 95% CI 0.95-3.9) but less likely to have a history of thyroid disease
      (OR 0.4; 95% CI 0.2-0.8), hypertension (OR 0.4; 95% CI 0.1-0.9) or nonsteroidal
      estrogen use (OR 0.5; 95% CI 0.2-0.9). Prior hysterectomy (OR 0.5; 95% CI 0.2
      0.9) and unilateral oophorectomy (OR 0.2; 95% CI 0.04-0.7) were also associated
      with reduced risk. CONCLUSION: The incidence of ovarian cancer in this community
      in 1975-1991 was little changed from rates 20 years earlier. There has been some
      improvement in survival from ovarian cancer in this population compared to 1935
      1974, but still less than 50% survive for 5 years. Prior hysterectomy and
      unilateral oophorectomy appear protective for ovarian cancer.

PMID- 10658686
TI  - Primary malignancies of the thyroid: epidemiologic analysis of the Florida Cancer
      Data System registry.
AB  - PURPOSE: Descriptive epidemiology of thyroid cancer in Florida. METHODS: The
      Florida Cancer Data System (FCDS) registry was used to identify patients with the
      different histologic subtypes of thyroid cancer occurring in Florida from 1981
      through 1993. RESULTS: The FCDS recorded 5746 primary malignancies of the
      thyroid. The average annual incidence of all types of thyroid cancer was 37.0
      cases/1,000,000 population. One type of thyroid cancer (papillary carcinoma)
      accounted for the overall increase during the 13 years of this study. There was
      no difference in incidence based on Hispanic ethnicity, but the incidence in
      Blacks was half that of Whites, and Blacks showed less advanced disease at the
      time of diagnosis. CONCLUSIONS: The increase in incidence of only one histologic
      type of thyroid cancer suggests that the increasing rate is not an artifact
      related to the utilization of new diagnostic technologies. The lower incidence
      and tendency to have less advanced thyroid cancer in Blacks would indicate that
      racial differences in thyroid cancer are not likely explained by socioeconomic
      factors such as access to medical care. A substantial amount of the difference in
      incidence between Whites and Blacks is explained by differences in age
      distribution.

PMID- 10658687
TI  - Breast cancer and electromagnetic fields--a review.
AB  - PURPOSE: Several statements have been issued to the effect that no consistent,
      significant link has been demonstrated between cancer and electromagnetic fields
      (EMF). However, there continues to be much interest in a possible association
      with breast cancer, in part because breast cancer risk is substantially higher in
      industrialized countries than in other areas, and electric power generation and
      consumption is one of the hallmarks of industrialized societies. In 1987, Stevens
      proposed a biological mechanism whereby two products of electric power
      generation, EMF and light at night, might contribute to mammary carcinogenesis
      through inhibition of melatonin. METHODS: We conducted a comprehensive review of
      the epidemiologic literature and hypothesized mechanisms pertaining to EMF
      exposure and the risk of breast cancer, in order to assess whether or not there
      was evidence to suggest a link between EMF and breast cancer. RESULTS: Some
      occupational epidemiological studies have demonstrated an increased incidence of
      breast cancer among mainly male electrical workers. It has been difficult to
      study women, as few are employed in these types of occupations. In all, there
      have been eleven occupational studies related to breast cancer in women, and
      statistically significant risk ratios have been observed: 1.98 for pre-menopausal
      women in occupations with high EMF exposure in one study, 2.17 in all women who
      worked as telephone installers, repairers, and line workers in another study, and
      1.65 for system analysts/ programmers, 1.40 for telegraph and radio operators,
      and 1.27 for telephone operators in a third study. However, six of the studies
      did not find any significant effects and two found effects only in subgroups. The
      results of the eight studies of residential exposure and four electric blanket
      studies have been inconsistent, with most not demonstrating any significant
      association. However, this might be attributed, at least to some extent, to
      difficulties in assessing residential exposure in these studies, as well as other
      methodological considerations. CONCLUSIONS: The biologic plausibility of an
      association between EMF and breast cancer, coupled with suggestive data from
      occupational studies and unexplained high incidence rates of breast cancer,
      suggests that further investigation of this possible association is warranted.

PMID- 10658688
TI  - Stress management intervention for primary prevention of hypertension: detailed
      results from Phase I of Trials of Hypertension Prevention (TOHP-I).
AB  - PURPOSE: Stress Management Intervention (SMI) was one of seven nonpharmacologic
      approaches evaluated in Phase I Trials of Hypertension Prevention (TOHP-I) for
      efficacy in lowering diastolic blood pressure (BP) in healthy men and women aged
      30 to 54 years with diastolic BP 80-89 mm Hg. METHODS: A total of 242 and 320
      participants were randomized to SMI or an "assessment only" SMI Control,
      respectively, at four clinical centers. The SMI consisted of 37 contact hours in
      21 group and two individual meetings over 18 months and included: training in
      four relaxation methods, techniques to reduce stress reactions, cognitive
      approaches, communication skills, time management, and anger management within a
      general problem-solving format. Standardized protocols detailed methods and
      timing for collecting BP, psychosocial measures, and urinary samples from both
      SMI and SMI Control participants. RESULTS: In intention-to-treat analyses,
      although significant baseline to termination BP reductions were observed in both
      groups, net differences between the SMI and SMI Control groups' BP changes (mean
      (95% CI)) were not significant: -0.82 (-1.86, 0.22) for diastolic BP, and -0.47 (
      1.96, 1.01) for systolic BP. Extensive adherence sub-group analyses found one
      effect: a significant 1.36 mm Hg (p = 0.01) reduction in diastolic BP relative to
      SMI Controls at the end of the trial for SMI participants who completed 61% or
      more of intervention sessions. CONCLUSIONS: While the TOHP-I SMI was acceptable
      to participants as evident from high levels of session completion, the absence of
      demonstrated BP lowering efficacy in intention-to-treat analyses suggests that
      the TOHP-I SMI is an unlikely candidate for primary prevention of hypertension in
      a general population sample similar to study participants. The isolated finding
      of significant diastolic BP lowering in SMI participants with higher adherence
      provides very weak evidence of SMI BP lowering efficacy and may be a chance
      finding. Whether similar or other stress management interventions can produce
      significant BP lowering in populations selected for higher levels of BP, stress,
      or intervention adherence remains to be demonstrated.

PMID- 10658689
TI  - Alternative strategies for selecting population controls: comparison of random
      digit dialing and targeted telephone calls.
AB  - PURPOSE: This project was carried out to identify a valid framework for selecting
      controls to be used in a population-based case-control study of breast cancer,
      and to compare participation rates and characteristics between women contacted
      using a standard random digit dialing (RDD) strategy and those who were sent a
      letter of presentation prior to telephone contact (targeted telephone calls,
      TTC). METHODS: Twelve hundred women, ages 20-74, were sampled from the Department
      of Motor Vehicles (DMV) and Health Care Financing Administration (HCFA) records.
      Women for whom telephone numbers were obtained (N = 771) were randomly assigned
      to RDD or TTC. The respondents participated in a brief telephone interview. Odd
      ratios (OR) and their 95% confidence intervals (CI) were used to estimate
      differences in characteristics of the respondents between the two contact
      strategies. RESULTS: Telephone numbers were obtained for 79% of women aged > or =
      55 years and for only 38% of women aged < 55 years. Interviews were obtained for
      48% of women for whom we obtained telephone numbers, and for 77% of women for
      whom eligibility was confirmed via telephone contact. Participation of target
      women appeared to be higher for the TTC than the RDD group (42% vs. 35%, p =
      0.054). Among respondents who were > or = 55 years old, those in the TTC group
      were 80% more likely (OR = 1.8, 95% CI: 0.9-3.4) to report a serious medical
      condition than women in the RDD group, 60% less likely (OR = 0.4, 95% CI: 0.2
      1.0) to report having used oral contraceptives, and 80% less likely (OR = 0.2,
      95% CI: 0.1-0.5) to report having had breast surgery. CONCLUSIONS:
      Characteristics of respondents differed according to method of contact. These
      differences, along with the sampling frame used, should be considered when
      interpreting findings of case-control studies.

PMID- 10658690
TI  - The new population standard for age-adjusting death rates.

PMID- 10658691
TI  - Hot stuff: thermal ablation.

PMID- 10658692
TI  - Centennial dissertation. Honoring Arthur W. Goodspeed, MD and James B. Bullitt,
      MD. CT and MR imaging and nontraumatic neurologic emergencies.
AB  - This review has highlighted some of the disease processes that produce diagnostic
      difficulty in the emergency neuroradiology setting. Because radiologists are
      often the first individuals to consider these entities, they must be familiar
      with the clinical features that suggest the diagnosis. Furthermore, acquaintance
      with the various imaging findings of these diseases will allow early diagnosis
      and will help limit the severe complications that follow these neurologic
      emergency conditions if left untreated.

PMID- 10658693
TI  - Centennial sounding board. In my view: a centennial essay.

PMID- 10658694
TI  - The disabled patient.

PMID- 10658695
TI  - American College of Radiology standards, accreditation programs, and
      appropriateness criteria.

PMID- 10658696
TI  - Liver and bone window settings for soft-copy interpretation of chest and
      abdominal CT.
AB  - OBJECTIVE: We evaluated whether the use of multiple window and level settings on
      a soft-copy workstation improves diagnostic accuracy on chest and abdominal CT.
      We hypothesized that routinely using window and level settings during soft-copy
      interpretation would beneficially affect the final diagnosis without compromising
      efficiency. MATERIALS AND METHODS: Two hundred three randomly selected abdominal
      and chest CT scans were interpreted by three radiologists using a four-monitor
      soft-copy workstation (images per screen, nine; resolution, 2K). After the
      initial interpretations, all scans were reevaluated by the same radiologists
      using additional liver and bone window and level settings. Differences in
      conspicuity and characterization of abnormalities were graded on a three-point
      scale. RESULTS: Conspicuity and characterization of abnormalities were improved
      in 67% of abnormal findings (81/121; p = 0.01). Improvement (a finding that
      substantially affected the final diagnosis) was present in 18% of abnormal
      findings (22/121; p = 0.04). On average, the evaluation of images at multiple
      window and level settings required an additional 40 sec per case. CONCLUSION: The
      use of multiple window and level settings during soft-copy interpretation
      resulted in improved lesion detectability and characterization with greater
      diagnostic efficacy. Using soft-copy workstations, radiologists can evaluate
      images using multiple settings without compromising efficiency.

PMID- 10658697
TI  - A new device to limit extravasation during contrast-enhanced CT.
AB  - OBJECTIVE: The extravasation detection accessory (EDA) is designed for use during
      contrast-enhanced CT studies performed with a power injector. The EDA detects the
      changes in soft-tissue impedance that occur with enhanced extravasation and halts
      the further infusion of contrast material via a feedback circuit to the injector.
      We tested the sensitivity of this device in a model of contrast extravasation.
      MATERIALS AND METHODS: Study subjects had an extravasation of 5% dextrose in
      water (nonionic contrast equivalent) in one arm and 0.9% sodium chloride solution
      (ionic contrast equivalent) in the other. An EDA was placed over the site of
      infusion and connected to a power injector. Injections were performed at 0.25
      ml/sec (n = 40), 2.5 ml/sec (n = 62), or 5 ml/sec (n = 20). RESULTS: At infusion
      rates of 2.5 and 5 ml/sec, the device halted the injector in every subject after
      an average volume of 12.5 +/- 1.6 ml was delivered. At 0.25 ml/sec, the device
      failed to halt the injector in 11 of 20 events. After reprogramming the
      algorithm, 10 more subjects were tested at the lowest injection rate. The device
      halted 18 of 20 extravasation events with an average volume of 3.7 +/- 0.5 ml.
      CONCLUSION: In our model of contrast extravasation, the EDA halted a power
      injector with reliability and reproducibility before a large volume of contrast
      material was delivered. The sensitivity of the device approached, but did not
      reach, 100%. This device may serve to diminish the morbidity of extravasation
      events.

PMID- 10658698
TI  - Near real-time CT fluoroscopy using computer automated scan technology in
      nonvascular interventional procedures.

PMID- 10658699
TI  - Thermal ablation therapy for focal malignancy: a unified approach to underlying
      principles, techniques, and diagnostic imaging guidance.

PMID- 10658700
TI  - Percutaneous ethanol injection for treatment of adrenal metastasis from
      hepatocellular carcinoma.
AB  - OBJECTIVE: With the improved prognosis of patients with hepatocellular carcinoma,
      the likelihood of diagnosing adrenal metastasis has increased. We performed
      percutaneous ethanol injection for adrenal metastasis in seven patients and
      evaluated its efficacy. CONCLUSION: Percutaneous ethanol injection was
      successfully performed in nine nodules in seven patients. During follow-up, six
      nodules in five patients showed no increase in size. Four patients were alive 6
      28 months after injection, one patient died of hepatic failure, one of brain
      metastasis, and one of multiple metastases. Percutaneous ethanol injection can be
      an alternative treatment for adrenal metastasis of hepatocellular carcinoma.

PMID- 10658701
TI  - Power Doppler sonography: evaluation of hepatocellular carcinoma after treatment
      with transarterial embolization or percutaneous ethanol injection therapy.
AB  - OBJECTIVE: The aim of this study was to compare tumor detectability by assessing
      the vascularity on power and color Doppler sonography and CT after transarterial
      embolization or percutaneous ethanol injection therapy or both in hepatocellular
      carcinoma. SUBJECTS AND METHODS: Forty-seven nodules of hepatocellular carcinoma
      (size, 28 +/- 7 mm [mean +/- standard deviation]; range, 20-40 mm) in 38 patients
      were treated with transarterial embolization (n = 6), percutaneous ethanol
      injection therapy (n = 23), and transarterial embolization plus percutaneous
      ethanol injection therapy (n = 9). Power Doppler sonography, color Doppler
      sonography, and CT were performed before and 2 weeks, 3 months, and 6 months
      after the treatments. The existence of hepatocellular carcinoma was confirmed by
      positive findings for color signals on both Doppler sonography techniques and for
      tumor stains on CT. All the tumors were determined to be malignant by microscopic
      examination of biopsy specimens. RESULTS: Before the treatments, power Doppler
      sonography (100%) and CT (100%) were significantly more effective than color
      Doppler sonography (61.7%) (p < 0.001, for both). Six months after the
      treatments, the sensitivity of power Doppler sonography (87.5%) was significantly
      better than that of color Doppler sonography (12.5%) but was not significant in
      comparison with CT (66.6%). However, power Doppler sonography detected color
      signals in two of three tumors in which iodized oil was accumulated and no tumor
      stain appeared on CT, and the two lesions detected with power Doppler sonography
      were carcinomas. CONCLUSION: Power Doppler sonography can be considered the most
      sensitive technique in assessing the viability of hepatocellular carcinoma
      treated with transarterial embolization or percutaneous ethanol injection therapy
      or both.

PMID- 10658702
TI  - Determining risk of traumatic aortic injury: how to optimize imaging strategy.
AB  - OBJECTIVE: Our objective was to develop and validate a clinical prediction rule
      that determines patient probability of traumatic aortic injury to guide selection
      of optimal screening imaging strategy. MATERIALS AND METHODS: A 2-year, single
      institution retrospective case-control study was conducted of 31 cases of
      traumatic aortic injury and 171 random major trauma control subjects. The
      presence of potential injury predictors was determined from chart review.
      Logistic regression was used to determine injury predictors, and clinically
      similar predictors were combined into composite predictors. The composite
      predictors were used to develop a seven-point injury index clinical prediction
      rule using multivariate logistic regression. Injury probabilities were determined
      through Bayes' theorem. Bootstrap validation was performed. RESULTS: Predictors
      of aortic injury included head injury (odds ratio, 18.3; 95% confidence interval
      [CI], 7.3-46), pelvic fracture (odds ratio, 27.3; 95% CI, 8.8-85), pneumothorax
      (odds ratio, 27.3; 95% CI, 8.8-85), and lack of seat belt use (odds ratio, 6.8;
      95% CI, 2.6-17). The seven composite predictors of age, unrestrained vehicle
      occupant, hypotension, thoracic injury, abdominopelvic injury, extremity
      fracture, and head injury, were combined into the seven-point injury index. In
      the injury index, each composite predictor had an adjusted odds ratio of 7.1 (95%
      CI, 3.7-13.5), and the odds ratios were additive. The injury index prediction
      rule had an area under the receiver operating characteristic curve of 0.97. All
      injured patients had at least one composite predictor. CONCLUSION: The
      probability of traumatic aortic injury can be estimated from the injury index
      prediction rule. Because cost-effectiveness of various imaging strategies depends
      on probability of injury, the prediction rule can guide imaging selection.

PMID- 10658703
TI  - 1999 ARRS Executive Council Award. Creation of saccular aneurysms in the rabbit:
      a model suitable for testing endovascular devices. American Roentgen Ray Society.
AB  - OBJECTIVE: This study developed an animal model of intracranial aneurysms
      suitable for evaluating emerging endovascular devices for aneurysmal therapy. We
      characterized the short-, medium-, and long-term attributes of this endovascular
      technique for saccular aneurysmal creation in the rabbit. MATERIALS AND METHODS:
      The right common carotid artery was surgically exposed in nine New Zealand white
      rabbits. Using endovascular techniques, we occluded the origin of the right
      common carotid artery with a pliable balloon. Elastase was incubated
      endoluminally in the proximal common carotid artery above the balloon. The common
      carotid artery was ligated distally. Animals were studied angiographically and
      sacrificed at 2 weeks (n = 3), 10 weeks (n = 3), and 24 weeks (n = 3) after
      aneurysm creation. Histology was obtained. RESULTS: Saccular aneurysms formed in
      eight of the nine rabbits. The aneurysm projected from the apex of an
      approximately 90 degree curve of the parent vessel, the brachiocephalic artery.
      Mean aneurysm diameter was 4.5 mm (SD, 1.2 mm), and mean height was 7.5 mm (SD,
      1.6 mm). All samples showed thinned elastic lamina and no evidence of
      inflammation. In four of eight aneurysms, unorganized thrombus was present in the
      dome of the aneurysm. CONCLUSION: Arterial aneurysms with intact endothelium and
      deficient elastic lamina were reliably created in an area of high shear stress in
      New Zealand white rabbits. Three of these aneurysms remained patent for at least
      6 months. We found a simple procedure that can be readily applied to the testing
      of new endovascular devices for a reliable creation of aneurysms in rabbits.

PMID- 10658704
TI  - CT angiography of complications in pediatric patients treated with intravascular
      stents.
AB  - OBJECTIVE: Our goal was to determine whether CT angiography can reveal
      complications in pediatric patients and young adults treated with intravascular
      stents for obstructive vascular lesions. CONCLUSION: CT angiography can reveal
      complications in pediatric patients treated with intravascular stents for
      obstructive lesions. Potentially, CT angiography could replace the more invasive
      conventional angiography currently used for intravascular stent placement and
      follow-up examinations.

PMID- 10658705
TI  - Placement of hemodialysis catheters through dilated external jugular and
      collateral veins in patients with internal jugular vein occlusions.

PMID- 10658706
TI  - Internal jugular and upper extremity central venous access in interventional
      radiology: is a postprocedure chest radiograph necessary?
AB  - OBJECTIVE: The necessity of obtaining a postprocedure chest radiograph after
      central venous access using the upper extremity or internal jugular veins and
      interventional radiologic techniques was evaluated. SUBJECTS AND METHODS: A
      prospective study of 937 consecutive central venous access procedures in
      interventional radiology using the internal jugular veins or upper extremities
      was performed from June 1995 through September 1997. Established interventional
      radiologic techniques were used to place various ports (n = 34) and tunneled (n =
      670) and nontunneled (n = 233) catheters. All catheters were positioned using
      fluoroscopy and readjusted if necessary before termination of the procedure.
      Afterward, a chest radiograph was obtained with the patient upright to evaluate
      catheter position and possible procedural complications. Procedural complications
      and manipulations or interventions that resulted from the radiographic findings
      were noted. In addition, nursing time for acquisition of the chest radiograph was
      recorded. RESULTS: We found seven procedural complications (four air emboli, two
      pneumothoraces, one innominate vein laceration) significant enough to alter the
      patient's treatment. These complications were apparent during the examination.
      Postprocedure chest radiography failed to reveal any unknown complications and
      revealed only one catheter sufficiently malpositioned to require manipulation.
      The amount of nursing time to acquire postprocedure chest radiographs ranged from
      8 to 40 min (mean, 23 min) per patient. CONCLUSION: When imaging guidance and
      interventional radiologic techniques are used for upper extremity and internal
      jugular central venous access, performing postprocedure chest radiography yields
      little benefit.

PMID- 10658707
TI  - Detection of clinically silent intracranial emboli ipsilateral to internal
      carotid occlusions during cerebral angiography.
AB  - OBJECTIVE: Embolic ischemic events have long been suspected to occur in the
      cerebral arteries distal to an ipsilateral occluded internal carotid artery
      (ICA). Documentation of microemboli by transcranial Doppler sonography during
      catheter angiography in patients with ICA occlusions provides objective evidence
      of such distal emboli. SUBJECTS AND METHODS: Seven patients undergoing carotid
      angiography were evaluated with transcranial Doppler sonography. Patients were
      also screened for ICA occlusions using carotid duplex sonography. In the seven
      patients, we saw five right ICA occlusions and two left ICA occlusions. Real-time
      visual and auditory confirmations of emboli were obtained by recognizing their
      specific spectral signatures and harmonic qualities. Routes of collateral flow
      were determined from angiography. Specific phases of the examination were
      correlated with embolic occurrences. RESULTS: Overall, emboli were seen during
      all phases of arteriography. In the individual patients, emboli were identified
      in one to four of the eight angiographic phases we defined. Most emboli occurred
      during catheter flushing and contrast injection rather than during wire and
      catheter manipulation. The emboli were detected in the middle cerebral artery
      distribution ipsilateral to the occluded ICA in all seven patients. Collateral
      flow patterns included, in four patients, external carotid artery-to-ICA
      collateral flow; in all seven patients, patent anterior communicating arteries;
      and in three patients, patent posterior communicating arteries. CONCLUSION:
      Emboli seen in middle cerebral arteries ipsilateral to occluded ICAs during
      cerebral angiography strongly indicate that emboli can occur distal to an
      occlusion. Our findings support the thought that emboli arising from sources
      proximal to an occluded ICA may reach the hemisphere distal to the occlusion,
      resulting in parenchymal ischemia or infarction.

PMID- 10658708
TI  - Software-triggered contrast-enhanced three-dimensional MR angiography of the
      intracranial arteries.
AB  - OBJECTIVE: We investigated the effectiveness of software-triggered contrast
      enhanced three-dimensional (3D) MR angiography in evaluating intracranial
      arteries. SUBJECTS AND METHODS: We studied 38 patients with suspected brain
      lesions. Imaging was performed using a 1.5-T superconducting MR system with a
      commercially available head coil. To monitor signal intensity changes we used
      software to place a tracker volume at the basilar artery or the internal carotid
      artery. A 20-ml bolus of gadodiamide hydrate was administered through the
      antecubital vein at a rate of 2-4 ml/sec, followed by a saline flush. Three
      dimensional MR angiography using a spoiled gradient-echo sequence with centric K
      space ordering was triggered by the arrival of the contrast bolus in the tracker
      volume. Imaging times ranged from 12 to 20 sec. We used MR images to assess the
      effectiveness of contrast-enhanced 3D MR angiography in revealing intracranial
      arteries with minimal venous overlap. RESULTS: The software triggered imaging on
      the arrival of the contrast bolus in 81.6% of examinations. In 77.6% of
      examinations, the resulting MR angiograms revealed intracranial arteries with
      minimal venous overlap. CONCLUSION: Software-triggered contrast-enhanced 3D MR
      angiography with centric K-space ordering is a promising technique for viewing
      intracranial arteries.

PMID- 10658709
TI  - MR imaging of spinal hemangioblastoma.

PMID- 10658710
TI  - Endovascular stenting of atherosclerotic stenosis in a basilar artery after
      unsuccessful angioplasty.

PMID- 10658711
TI  - Helical CT findings in patients who have undergone stapes surgery for
      otosclerosis.

PMID- 10658712
TI  - MR imaging of the distribution and location of acute hamstring injuries in
      athletes.
AB  - OBJECTIVE: Although hamstring injuries are common in athletes, the distribution
      and location of such injuries have not been well defined. We used MR imaging to
      determine the frequency of injury by muscle, involvement of one or more muscles,
      and location of injuries within the musculotendinous unit. SUBJECTS AND METHODS:
      We performed MR imaging on 15 consecutive college athletes with clinically
      diagnosed acute hamstring injuries. A hamstring injury was diagnosed and located
      on MR imaging by identifying high signal intensity within the muscle on T2
      weighted images. RESULTS: We found that 10 athletes had injuries of a single
      muscle with six injuries of the biceps femoris, three of the semitendinosus, and
      one of the semimembranosus. In an additional five athletes, we found primary
      injuries of the biceps femoris and secondary injuries of the semitendinosus. The
      injuries occurred in diverse locations within the muscles including five injuries
      at the proximal musculotendinous junction, two at the distal musculotendinous
      junction, four within the proximal half of the muscle belly, and four in the
      distal half. All eight intramuscular injuries were located at the
      musculotendinous junction within the muscle. CONCLUSION: The biceps femoris is
      the most commonly injured hamstring muscle and the semitendinosus is the second
      most commonly injured. Although hamstring injuries often involve one muscle
      injured proximally, multiple muscles were involved in 33% of athletes (5/15) and
      the injuries were distal in 40% of athletes (6/15). All intramuscular injuries
      occurred at the musculotendinous junction, either at the ends of the muscle or
      within the muscle belly.

PMID- 10658713
TI  - CT appearance of shotgun wadding.

PMID- 10658714
TI  - Helical CT of skeletal muscle metastases from primary carcinomas.
AB  - OBJECTIVE: To determine the clinical and helical CT findings in patients with
      skeletal muscle metastases from carcinoma, we reviewed the cases of 15
      consecutive patients who had muscle metastases diagnosed by contrast-enhanced
      helical CT. MATERIALS AND METHODS: Between February 1992 and August 1997, 15
      patients (30 lesions) had metastatic disease to muscle from primary carcinoma
      diagnosed by helical CT in our institution. Patient data and imaging findings
      were retrospectively reviewed. RESULTS: Ten of 15 patients (67%) were known to
      have a malignancy at the time of CT. Patients complained of pain at the site of
      skeletal muscle metastases in five (17%) of 30 lesions, and in 11 (37%) of 30
      lesions a mass was palpable. Lesion size averaged 3.2 cm (range, 0.7-7.8 cm).
      Thirteen of 15 patients had metastatic disease elsewhere at the time of skeletal
      muscle metastasis diagnosis. Muscles and other structures most commonly involved
      by metastatic disease included erector spinae (n = 9), psoas (n = 4), rotator
      cuff (n = 4), gluteal (n = 3), and abdominal (n = 3). The most common appearance
      of metastatic disease to muscle on contrast-enhanced helical CT was that of a rim
      enhancing mass with central hypoattenuation in 25 (83%) of 30 lesions.
      CONCLUSION: Metastatic disease to skeletal muscle tends to be found in people
      with advanced-stage neoplasms. It may be an incidental finding on CT because pain
      is an uncommon feature; a minority of lesions were palpable in our series. The
      most common appearance on contrast-enhanced helical CT is a rim-enhancing
      intramuscular lesion with central hypoattenuation.

PMID- 10658715
TI  - In vitro MR imaging of hyaline cartilage: correlation with scanning electron
      microscopy.
AB  - OBJECTIVE: Our goal was to determine how the three-dimensional structure of
      hyaline cartilage affects its MR appearance and to correlate this appearance with
      detailed structural analysis using scanning electron microscopy and freeze
      fracture sectioning techniques. MATERIALS AND METHODS: In vitro 7-T spin-echo MR
      images of hyaline cartilage specimens from four patients undergoing above-knee
      amputations were obtained parallel and perpendicular to the main magnetic field.
      Specimens were imaged with low- and high-power scanning electron microscopy after
      freeze fracturing. The corresponding images from both techniques were analyzed
      with specific attention to the three-dimensional structure of the cartilage,
      collagen fibril orientation, and respective changes in the MR appearance.
      RESULTS: Freeze fracturing of cartilage reveals a curved fracture plane. Expected
      changes in signal intensity predicted by the magic angle effect correlated with
      observed changes in signal intensity across the thickness of the sample. Changes
      in individual collagen fibril orientation did not correspond to MR layering.
      CONCLUSION: The three-dimensional organization of collagen in cartilage has a
      strong influence on the MR appearance of cartilage. This influence is caused by
      the restriction of water mobility and the resulting magic angle effect caused by
      curvature of the collagen network, possibly because of the influence on
      proteoglycan orientation.

PMID- 10658716
TI  - Paraspinal synovial sarcoma.

PMID- 10658717
TI  - Sonographic assessment of osteochondritis dissecans of the humeral capitellum.
AB  - OBJECTIVE: The purpose of this study was to determine the efficacy of sonography
      for revealing osteochondritis dissecans of the humeral capitellum. SUBJECTS AND
      METHODS: Twenty-seven patients with capitellar osteochondritis dissecans (27
      males; range, 11-20 years; mean age, 14 years) underwent radiography and
      sonography performed with a 7.5-MHz mechanical sector probe. Lesions were
      assessed as stable or unstable. The sonographic assessment was compared with
      radiographic assessment in 27 patients, MR assessment obtained in 10, and
      surgical findings in 15. RESULTS: Sonographic assessment agreed with radiographic
      assessment in 23 of the 27 patients, MR assessment in nine of the 10, and
      surgical findings in 14 of the 15. Sonography revealed that two lesions, which
      had been underestimated on radiography, were unstable. CONCLUSION: Sonography
      facilitates the assessment of capitellar lesions so that treatment can be
      optimized.

PMID- 10658718
TI  - Primary tumors of the sacrum: diagnostic imaging.

PMID- 10658719
TI  - Lateral access for CT-guided percutaneous biopsy of the lumbar spine.

PMID- 10658720
TI  - CT evaluation of mesenteric panniculitis: prevalence and associated diseases.
AB  - OBJECTIVE: This study was undertaken to assess the prevalence of mesenteric
      panniculitis on CT and to describe its appearance and associated diseases.
      SUBJECTS AND METHODS: A total of 7620 consecutive abdominal CT examinations were
      prospectively evaluated for features common to mesenteric panniculitis such as a
      well-delineated inhomogeneous hyperattenuated fatty mass at the mesenteric root,
      envelopment of mesenteric vessels, and no evidence of invasion of the adjacent
      small-bowel loops that may be displaced. RESULTS: CT findings of mesenteric
      panniculitis were seen in 49 patients (0.6%). We found a female predominance.
      Mesenteric panniculitis coexisted with malignancy in 34 patients and with benign
      disorders in 11 patients. In the remaining four patients, mesenteric
      panniculitis, verified on histology, was considered to be responsible for the
      patients' clinical manifestations; no other abnormality was identified. Soft
      tissue nodules (n = 39) and a fatty halo surrounding vessels and nodules (n = 42)
      were observed in most patients. Follow-up abdominal CT examinations in 29 of the
      49 patients showed changes in only one patient. CONCLUSION: CT findings of
      mesenteric panniculitis may be seen in patients undergoing abdominal CT for
      various symptoms.

PMID- 10658721
TI  - Comparing contrast-enhanced breath-hold MR angiography and conventional
      angiography in the evaluation of mesenteric circulation.
AB  - OBJECTIVE: Our aim was to compare the results of gadolinium-enhanced breath-hold
      MR angiography with those of conventional angiography for the study of mesenteric
      circulation. SUBJECTS AND METHODS: MR angiography and digital subtraction
      angiography were prospectively performed in 33 patients referred for hepatic,
      pancreatic, or mesenteric disease. MR angiography was performed with four three
      dimensional acquisitions at 0, 30, 60, and 90 sec after injection of 0.1 mmol/kg
      of gadolinium. Selective conventional angiography was used as the standard of
      reference. RESULTS: A pure arterial angiogram (one on which veins could not be
      visualized) was obtained in 27 patients during the second or third acquisition.
      By subtracting the arterial phase from an arteriovenous phase (third or fourth
      acquisition) we obtained a pure venous angiogram (one on which arteries could not
      be visualized) in 28 patients. Agreement was good or excellent for the hepatic
      artery (kappa = 0.78), the superior mesenteric artery (kappa = 0.65), the splenic
      artery (kappa = 0.70), the portal vein (kappa = 1.0), the superior mesenteric
      vein (kappa = 0.88), and the splenic vein (kappa = 0.75). Agreement was poor, and
      vessels were better shown by conventional angiography, for the intrahepatic
      arteries (kappa = 0.006) and the branches of the superior mesenteric artery
      (kappa = 0.14). MR angiography and conventional angiography revealed 29 and 27
      portosystemic collaterals, respectively. CONCLUSION: Dynamic breath-hold contrast
      enhanced MR angiography compared favorably with conventional angiography in
      preoperative assessment of the proximal mesenteric arteries and in the evaluation
      of portal hypertension; however, conventional angiography is still necessary to
      evaluate distal arteries.

PMID- 10658722
TI  - Intraductal papillary mucinous tumors of the pancreas: thin-section helical CT
      findings.
AB  - OBJECTIVE: The purpose of this study was to evaluate the thin-section helical CT
      findings of intraductal papillary mucinous tumors and to investigate whether
      helical CT could distinguish between malignant and benign intraductal papillary
      mucinous tumors. MATERIALS AND METHODS: Twenty-seven patients (nine with
      malignant and 18 with benign intraductal papillary-mucinous tumors) underwent
      thin-section (3- or 5-mm) helical CT. Two-phase enhanced CT was started 30 and 60
      70 sec after injection of contrast material at 3 ml/sec. RESULTS: In six patients
      (22.2%), a bulging papilla was depicted on CT. Twenty-five patients (92.6%) had a
      dilated main pancreatic duct. Cystic lesions were seen in 25 patients (92.6%).
      Thirteen lesions (48%) were located in the uncinate process, seven (25.9%) were
      in the head, two (7.4%) were in the body, and three (11%) were in the tail. The
      cystic lesion was unilocular in five patients (18.5%) and multilocular with a
      lobulated margin in 20 patients (74%). Communication between the main pancreatic
      duct and the cystic lesion was depicted in 19 patients (70.4%). The papillary
      projections corresponding to 3-mm or larger papillary neoplasms were depicted in
      five patients (18.5%). The bulging papilla was more often observed in malignant
      than in benign intraductal papillary mucinous tumors (p < 0.05). The caliber of
      the main pancreatic duct was significantly larger in patients with malignant
      intraductal papillary mucinous tumors (p > 0.001). CONCLUSION: The most
      frequently found feature of intraductal papillary mucinous tumors was a lobulated
      multilocular cystic lesion located in the uncinate process and in contiguity with
      the dilated main pancreatic duct. In some patients, a bulging papilla and
      papillary projections in the ducts, which were specific findings, were visualized
      on CT. The bulging papilla and the caliber of the main pancreatic duct helped
      differentiate malignant from benign intraductal papillary mucinous tumors.

PMID- 10658723
TI  - Cervical osteophytes impinging on the pharynx: importance of size and concurrent
      disorders for development of aspiration.
AB  - OBJECTIVE: This study evaluated the clinical significance of cervical osteophytes
      impinging on the pharynx in patients with dysphagia and the importance of
      concurrent disorders that may affect swallowing function. MATERIALS AND METHODS:
      On videofluoroscopy, anterior cervical osteophytes were found in 55 (32 men, 23
      women; mean age, 69 years) of 3318 patients with dysphagia (1.7%). Coexisting
      diseases that affected swallowing function were found in 28 patients (stroke, n =
      7; thyroidectomy, n = 7; tongue base or laryngeal cancer surgery, n = 5; other
      diseases, n = 9). Swallowing function was assessed with videofluoroscopy
      evaluating epiglottic tilting, laryngeal closure, impression of the hypopharynx,
      pharyngeal residue, and aspiration. RESULTS: With advancing age, the probability
      of aspiration (odds ratio, 1.07; p < 0.05) and of enlarging osteophytes (odds
      ratio, 1.26; p < 0.01) increased; the probability was higher for osteophytes at
      more than one vertebrae (odds ratio, 8.00; p < 0.01) and for concurrent diseases
      (odds ratio, 8.02; p < 0.01). Aspiration was found in 75% of patients with
      osteophytes larger than 10 mm and in 34% with osteophytes smaller than or equal
      to 10 mm. In 88% of patients with small osteophytes who aspirated, other diseases
      affected swallowing function. CONCLUSION: Aspiration is common in patients with
      dysphagia and cervical osteophytes larger than 10 mm. Aspiration is rare in
      patients with osteophytes smaller than or equal to 10 mm unless these patients
      suffer from other disorders that may affect swallowing.

PMID- 10658724
TI  - Helical CT: diagnostic pitfalls of arterial phase imaging of the upper abdomen.

PMID- 10658725
TI  - CT features of metastatic linitis plastica to the rectum in patients with
      peritoneal carcinomatosis.
AB  - OBJECTIVE: We examined the CT features of 22 patients with metastatic linitis
      plastica to the rectum. CONCLUSION: Metastatic linitis plastica to the rectum
      should be considered when CT shows a long segment of circumferential rectal wall
      thickening, especially in patients with peritoneal carcinomatosis from gastric
      cancer. In such patients, CT helps avoid unnecessary extensive surgery.

PMID- 10658726
TI  - Littoral cell angioma of the spleen: imaging features.

PMID- 10658727
TI  - 1999 ARRS Executive Council Award. Contrast-enhanced CT of small hypovascular
      hepatic tumors: effect of lesion enhancement on conspicuity in rabbits. American
      Roentgen Ray Society.
AB  - OBJECTIVE: The purpose of this study was to evaluate the effect of lesion
      enhancement on the conspicuity of small hypovascular hepatic tumors in an animal
      model. MATERIALS AND METHODS: Seven VX2 hepatic tumors in five rabbits were
      imaged. Dynamic contrast-enhanced CT was performed at a single level centered
      over the lesions at 5-sec intervals for 119 sec after injection of 2 ml/kg i.v.
      contrast material at 2 ml/sec. Attenuation was measured over time within regions
      of interest in the tumor and normal liver, aorta, inferior vena cava, and portal
      vein. Lesion conspicuity, defined as the difference between the attenuation of
      the uninvolved liver and neoplasm, was calculated. RESULTS: The mean diameter of
      the tumors on CT was 10 mm (range, 6-15 mm). The tumors appeared as low
      attenuation lesions with progressive enhancement during the arterial phase and
      early portal phase. Peak mean lesion attenuation was 60 +/- 27 H (enhancement, 23
      H) at 64 sec. Peak mean lesion conspicuity was 80 +/- 18 H at 39 sec, occurring
      10 sec before the peak mean hepatic attenuation of 135 +/- 15 H (enhancement, 67
      H) at 49 sec. Relative lesion conspicuity paralleled relative enhancement of the
      liver throughout the imaging period. CONCLUSION: Although low-level tumor
      enhancement during the arterial phase and early portal phase reduced the
      conspicuity of small hypovascular tumors in this animal model, our results
      support the use of maximum liver enhancement as a marker for peak lesion
      conspicuity.

PMID- 10658728
TI  - Addition of gadolinium chelates to heavily T2-weighted MR imaging: limited role
      in differentiating hepatic hemangiomas from metastases.
AB  - OBJECTIVE: The purpose of this study was to determine whether the addition of
      gadolinium-enhanced imaging to heavily T2-weighted MR imaging of the liver is
      valuable in differentiating hemangiomas from metastases. The T2 relaxation time
      was also included in our analysis. SUBJECTS AND METHODS: Fifty-one patients with
      52 proven liver lesions (24 hemangiomas and 28 metastases) larger than 1 cm
      underwent MR imaging at 1.5 T with T2-weighted spin-echo (TR/TE, 3000/80, 160)
      and gadolinium chelate-enhanced dynamic T1-weighted gradient-recalled echo
      (80/2.6, 80) pulse sequences. Images were reviewed by observers who were unaware
      of the patients' clinical history; first, only T2-weighted images were reviewed
      and then T2-weighted plus dynamic images were reviewed together. The T2
      relaxation times were calculated for each lesion. Diagnostic accuracy by each
      method was compared using receiver operating characteristic analysis. RESULTS:
      Mean T2 relaxation times were 76 +/- 26 msec for metastases and 133 +/- 25 msec
      for hemangiomas. The addition of dynamic scanning to the T2-weighted sequence
      made a statistically significant difference for only one observer (p = 0.03).
      However, it did not make a statistically significant contribution for either
      observer when compared with the T2 relaxation time. Although addition of the
      dynamic images resulted in correct diagnosis of six lesions, three lesions were
      misdiagnosed after having been correctly characterized on the T2-weighted images
      alone. CONCLUSION: When optimized T2-weighted images are obtained and the T2
      relaxation time is calculated, routine use of gadolinium enhancement for
      differentiation of hemangiomas from metastases is unnecessary although dynamic
      scanning is valuable in selected cases.

PMID- 10658729
TI  - Helical CT cholangiography with three-dimensional volume rendering using an oral
      biliary contrast agent: feasibility of a novel technique.
AB  - OBJECTIVE: We evaluated the feasibility and image quality of a new noninvasive
      biliary imaging technique: helical CT cholangiography with three-dimensional
      volume rendering using an oral biliary contrast agent. SUBJECTS AND METHODS:
      Nineteen subjects including five healthy volunteers and 14 patients underwent
      helical CT cholangiography. Subjects ingested 6.0 g of iopanoic acid 6-10 hr
      before undergoing imaging. Axial data were used to construct three-dimensional
      volume-rendered cholangiograms. Two radiologists, an endoscopist, and a
      laparoscopic surgeon reviewed the images and evaluated overall image quality. In
      the 14 patients, findings from CT cholangiography were compared with those from
      ERCP, surgery, and intraoperative cholangiography. RESULTS: All segments of the
      biliary tree were opacified in all volunteers except one, in whom the
      intrahepatic ducts were not opacified. Image quality was good to excellent in all
      volunteers. Anomalous cystic duct insertions were seen in two volunteers.
      Opacification of the biliary tree was rated as acceptable to excellent in nine
      patients and suboptimal in five. In five patients with good or excellent
      opacification, the biliary anatomy correlated with findings on intraoperative
      cholangiography or ERCP. CT cholangiography revealed additional conditions
      (gallbladder varices and acute pancreatitis) and variant anatomy in three
      patients. CONCLUSION: Results of this pilot project suggest that obtaining CT
      cholangiograms using an oral biliary contrast agent is a feasible, noninvasive
      method for revealing biliary anatomy. However, visualization of the biliary tree
      was suboptimal in 36% of the patients, which represents a limitation of this
      technique.

PMID- 10658730
TI  - Evaluation of pseudoenhancement of renal cysts during contrast-enhanced CT.
AB  - OBJECTIVE: The purpose of our study was to evaluate renal cyst pseudoenhancement
      during helical CT in a phantom model and in patients. MATERIALS AND METHODS:
      Iodine baths containing water-filled spheres and cylinders were constructed to
      simulate cysts in enhancing renal parenchyma. Iodine concentration, cyst size and
      location, collimation, and peak kilovoltage were varied and cyst attenuation was
      measured. Data were analyzed with the mixed linear models and Mantel-Haenszel
      tests. Subsequently, a paired t test compared CT attenuation values before and
      after contrast material enhancement in 40 patients with 68 renal cysts
      (radiographic stability >3 months). RESULTS: The attenuation values of phantom
      cysts increased when placed in a contrast media bath (p = 0.001). The increase in
      attenuation values became more pronounced with increasing iodine concentrations,
      decreasing peak kilovoltage, and smaller sphere sizes. In patients, mean cyst
      attenuation increased 3.4 +/- 6.2 H after administration of contrast material (p
      = 0.00002). The attenuation did not increase more than 10 H in any of the 37
      cysts larger than 2 cm found in patients. Eight (26%) of the 31 cysts smaller
      than 2 cm found in patients increased by at least 10 H. CONCLUSION: In a phantom
      model, at simulated physiologic levels of renal enhancement, cysts may
      pseudoenhance by more than 10 H. Similarly, in patients, cysts may also
      pseudoenhance; however, most pseudoenhancement does not exceed 10 H. In patients,
      pseudoenhancement of at least 10 H is more likely in cysts smaller than 2 cm.

PMID- 10658731
TI  - Angiotensin-converting enzyme inhibitor-enhanced phase-contrast MR imaging to
      measure renal artery velocity waveforms in patients with suspected renovascular
      hypertension.
AB  - OBJECTIVE: We investigated the usefulness of phase-contrast MR imaging to measure
      renal artery velocity waveforms as an adjunct to renal MR angiography. We also
      examined whether an angiotensin-converting enzyme (ACE) inhibitor improves the
      diagnostic accuracy of waveform analysis. SUBJECTS AND METHODS: Thirty-five
      patients referred for MR angiography of renal arteries underwent non-breath-hold
      oblique sagittal velocity-encoded phase-contrast MR imaging through both renal
      hila (TR/TE, 24/5; flip angle, 30 degrees; signal averages, two; encoding
      velocity, 75 cm/sec) before and after i.v. administration of an ACE inhibitor
      (enalaprilat). We analyzed velocity waveforms using established Doppler
      sonographic criteria. A timing examination with a test bolus of gadolinium
      contrast material was performed to ensure optimal arterial enhancement during
      breath-hold gadolinium-enhanced three-dimensional gradient-echo MR angiography.
      RESULTS: MR phase-contrast waveform pattern analysis was 50% (9/18) sensitive and
      78% (40/51) specific for the detection of renal artery stenosis equal to or
      greater than 60% as shown on MR angiography. Sensitivity (67%, 12/18) and
      specificity (84%, 42/50) increased slightly, but not significantly, after i.v.
      administration of an ACE inhibitor. Also, the accuracy of quantitative criteria
      such as acceleration time and acceleration index did not improve after the
      administration of ACE inhibitor. CONCLUSION: Renal hilar velocity waveforms,
      measured using non-breath-hold MR phase-contrast techniques with or without an
      ACE inhibitor, are insufficiently accurate to use in predicting renal artery
      stenosis.

PMID- 10658732
TI  - Predictors of patient response to pulmonary thromboendarterectomy.
AB  - OBJECTIVE: We sought to identify imaging features that help predict surgical
      success in patients undergoing thromboendarterectomy. MATERIALS AND METHODS:
      Thirty-nine consecutive patients who underwent pulmonary angiography and
      thromboendarterectomy during 1995 and 1996 were included. Thirty-four underwent
      helical CT angiography. Measurements of postoperative pulmonary vascular
      resistance were compared with preoperative imaging features and preoperative
      pulmonary vascular resistance. RESULTS: The best imaging indicators of a
      relatively high postoperative pulmonary vascular resistance were the extent of
      small vessel disease identified on CT angiograms as segments with abnormal
      perfusion but normal segmental arteries (p = 0.005) and the extent of central
      disease (p = 0.015). Combined with preoperative pulmonary vascular resistance,
      these features had a strong correlation with postoperative outcome (p = 0.0005).
      Segmental arterial disease seen on both conventional angiography and CT
      angiography correlated poorly with surgical outcome. CONCLUSION: In patients with
      chronic thromboembolic pulmonary hypertension, CT angiographic evidence of
      extensive central vessel disease and limited small vessel involvement indicates a
      favorable surgical outcome.

PMID- 10658733
TI  - Pulmonary leukemic infiltrates: high-resolution CT findings in 10 patients.
AB  - OBJECTIVE: We assessed the high-resolution CT findings of pulmonary leukemic
      infiltrates. CONCLUSION: High-resolution CT findings of pulmonary leukemic
      infiltrates reflect the predilection of leukemic cells to involve the
      perilymphatic pulmonary interstitium.

PMID- 10658734
TI  - Bronchial anthracofibrosis (inflammatory bronchial stenosis with anthracotic
      pigmentation): CT findings.
AB  - OBJECTIVE: The aim of this study was to describe CT findings of patients with
      bronchial anthracofibrosis. CONCLUSION: Atelectasis caused by smooth bronchial
      narrowing, surrounded by calcified or noncalcified lymph nodes, in elderly and
      nonsmoking women is a typical finding of anthracofibrosis. Calcified lymph nodes
      adjacent to the involved bronchi and multifocal involvement of bronchial
      narrowing may be helpful in differentiating this condition from lung cancer.

PMID- 10658735
TI  - Lateral decubitus CT: a useful adjunct to standard inspiratory-expiratory CT for
      the detection of air-trapping.

PMID- 10658736
TI  - Pulmonary infarction resulting from metastatic osteogenic sarcoma with pulmonary
      venous tumor thrombus.

PMID- 10658737
TI  - Primary inflammatory carcinoma of the breast: retrospective review of
      mammographic findings.
AB  - OBJECTIVE: Our goal was to describe the mammographic characteristics of primary
      inflammatory carcinoma of the breast. MATERIALS AND METHODS: We identified the
      medical records of 43 women who participated in a chemotherapy protocol for
      primary inflammatory carcinoma of the breast between 1994 and 1997. Mammograms
      were available for review in 26 women (age range, 34-78 years; mean age, 56
      years). Two radiologists independently reviewed the 26 mammograms obtained before
      patients underwent treatment. A third observer was the final arbiter when needed.
      RESULTS: Mammographic findings included skin thickening in 24 patients (92%),
      diffusely increased density in 21 patients (81%), trabecular thickening in 16
      patients (62%), axillary lymphadenopathy in 15 patients (58%), architectural
      distortion or focal asymmetric density in 13 patients (50%), and nipple
      retraction in 10 patients (38%). Malignant-appearing calcifications were seen in
      six patients (23%), and a mass was seen in four patients (15%). CONCLUSION:
      Diffuse mammographic abnormalities such as skin thickening, increased density,
      trabecular thickening, and axillary lymphadenopathy are common at presentation in
      patients with primary inflammatory carcinoma of the breast. Mammographic masses
      and malignant-appearing calcifications are uncommon manifestations of this
      disease.

PMID- 10658738
TI  - Sonographically guided clip placement facilitates localization of breast cancer
      after neoadjuvant chemotherapy.

PMID- 10658739
TI  - Sebaceous carcinoma of the breast in a patient with Muir-Torre syndrome.

PMID- 10658741
TI  - Diagnostic accuracy of thin-section CT and chest radiography of pediatric
      interstitial lung disease.
AB  - OBJECTIVE: We assessed the accuracy of thin-section CT and chest radiography to
      diagnose pediatric interstitial lung disease. MATERIALS AND METHODS: We
      identified 20 infants, boys, and girls (age range, 1 month to 14 years) with
      histopathologic confirmation of interstitial lung disease. Six boys and girls
      without interstitial lung disease were also included. Two observers independently
      assessed chest radiograph and CT images. The observers stated the most likely
      diagnosis and a differential diagnosis. We evaluated individual CT features and
      their distribution. RESULTS: Observers' diagnoses on CT images were correct
      (first choice or differential) in 66% of observations versus 45% on chest
      radiographs (p < 0.025). Correct diagnoses were made on first choice in 61% of CT
      observations versus 34% on chest radiographs (p < 0.005). Observers were
      confident (versus uncertain) in 42% of the CT observations versus 18% on chest
      radiographs; of the confident diagnoses made on CT, 91% were correct. CT
      interpretations were most accurate in the diagnosis of pulmonary alveolar
      proteinosis, congenital lymphangiectasia, and idiopathic pulmonary hemosiderosis.
      All healthy patients examined with CT were correctly identified as such. We noted
      a distinctive CT pattern in three patients with nonspecific interstitial
      pneumonitis and one patient with desquamative interstitial pneumonitis; the CT
      pattern consisted of upper zone predominant honeycombing on a background of
      ground-glass attenuation. CONCLUSION: A higher proportion of pediatric
      interstitial lung diseases can be diagnosed on thin-section CT than on chest
      radiographs. In our study, confident and correct diagnoses were made more
      frequently with CT than with chest radiographs.

PMID- 10658740
TI  - Helical and single-slice conventional CT versus electron beam CT for the
      quantification of coronary artery calcification.
AB  - OBJECTIVE: We compared electron beam CT with conventional CT to determine the
      best method for the assessment of the coronary calcium score. We used
      conventional CT to examine symptomatic and asymptomatic patients suspected of
      having coronary artery disease. SUBJECTS AND METHODS: One hundred sixty male
      patients underwent electron beam CT and helical CT with a pitch of 1 (n = 30) and
      2 (n = 30) and using a single-slice mode with (n = 50) and without (n = 50)
      prospective ECG triggering. In another 50 patients, we determined reproducibility
      for repeated scanning using electron beam CT. For all images, we derived the
      calcium score according to the Agatston method. We performed regression analysis
      and determined mean variability. Mean variability was calculated as the ratio of
      the absolute difference to the mean of the corresponding calcium scores. RESULTS:
      The correlation coefficients for electron beam CT and all conventional CT modes
      were very high (range, 0.93-0.98). The mean variability was highest in the
      helical mode with a pitch of 2 (61.4%) and lowest for the single-slice mode with
      prospective ECG triggering (25.4%). For repeated electron beam CT, the
      correlation coefficient and mean variability were 0.99 and 22.1%, respectively.
      CONCLUSION: ECG-triggered single-slice conventional CT had the best agreement
      with electron beam CT calcium scores.

PMID- 10658742
TI  - MR imaging of the pituitary gland in children and young adults with congenital
      combined pituitary hormone deficiency associated with PROP1 mutations.
AB  - OBJECTIVE: The aim of this study was to clarify the relationship between
      morphologic changes of the pituitary gland and the genotype of Prophet of Pit-1
      (PROP1), a newly discovered gene responsible for congenital combined pituitary
      hormone deficiency, in a series of eight humans with this disorder. CONCLUSION:
      Congenital hypoplasia of the anterior pituitary gland is the most common MR
      imaging finding in patients with combined pituitary hormone deficiency. Our
      findings suggest a crucial role for PROP1 in pituitary organogenesis as well as
      anterior pituitary cell differentiation.

PMID- 10658743
TI  - Sonographic visualization of neonatal posterior fossa abnormalities through the
      posterolateral fontanelle.
AB  - OBJECTIVE: This study was performed to determine whether imaging through the
      posterolateral fontanelle in addition to the anterior fontanelle during neonatal
      cranial sonography improves diagnostic accuracy or examiner confidence in the
      diagnosis of neonatal posterior fossa abnormalities. MATERIALS AND METHODS: In
      1995 we changed our protocol of neonatal cranial sonography to include imaging
      through the posterolateral fontanelle in all patients. The reports of all
      sonography performed in the first 15 months of this protocol were reviewed, and
      two radiologists reviewed the images of all patients in whom a posterior fossa
      abnormality was diagnosed with posterolateral fontanelle images masked and then
      with posterolateral fontanelle images available. RESULTS: In total, 1292
      sonograms were obtained in 462 patients. In 200 patients, the sonographic
      findings were abnormal; of these 200 patients, 24 (12%) had posterior fossa
      abnormalities (nine posterior fossa hemorrhages, four Arnold-Chiari malformations
      (type II), two posterior fossa arteriovenous malformations, and nine partial
      vermian defects). The posterolateral fontanelle images showed the posterior fossa
      abnormality better than the anterior fontanelle images did in 23 (96%) of the 24
      patients, increased confidence in the diagnosis of 18 (75%) of the 24 patients,
      and was the only technique to reveal the posterior fossa abnormality in 11 (46%)
      of the 24 patients. Nearly all pathologic correlations with imaging confirmed the
      posterolateral fontanelle findings except for the diagnosis of inferior vermian
      agenesis, which was presumed to be a false-positive diagnosis in four patients in
      whom MR imaging showed no abnormalities. CONCLUSION: Additional imaging through
      the posterolateral fontanelle during routine neonatal cranial sonography added
      considerable benefit. False-positive diagnosis of vermian defects is a troubling
      problem but may be avoided with careful attention to the midline sagittal
      sonographic images of the vermis and fourth ventricle.

PMID- 10658744
TI  - Helical CT and renal calculi.

PMID- 10658745
TI  - Advanced breast biopsy instrumentation results.

PMID- 10658746
TI  - The role of emergent sonography after blunt abdominal trauma.

PMID- 10658747
TI  - Primary liposarcoma of the mediastinum with coexistent mediastinal lipomatosis.

PMID- 10658748
TI  - Extensive bone formation by squamous cell carcinoma in the maxilla.

PMID- 10658749
TI  - MR imaging of hepatic myelolipoma.

PMID- 10658750
TI  - Coexistence of intramuscular hydatid cyst and tapeworm.

PMID- 10658752
TI  - Hooks right, eyes left: brassiere fasteners as a clue to situs.

PMID- 10658751
TI  - Frontal bladder duplication and renal agenesis.

PMID- 10658753
TI  - Implications of vancomycin-resistant Staphylococcus aureus.
AB  - Strains of Staphylococcus aureus with reduced susceptibility to glycopeptides
      have been reported from Japan (multiple strains), the United States (four
      strains), and Europe (France, the UK and Spain) and the Far East (Hong Kong and
      Korea). The isolates from the US, France, and strain Mu50 from Japan, demonstrate
      vancomycin MICs of 8 microg/mL by broth microdilution testing and appear to have
      developed from pre-existing methicillin-resistant S. aureus (MRSA) infections.
      The strain from the UK and other parts of Europe appears heteroresistant to
      vancomycin and has MIICs in the 1-2 microg/mL range. Many of the isolates with
      reduced susceptibility to glycopeptides have been associated with therapeutic
      failures with vancomycin. Although nosocomial spread of the glycopeptide
      intermediate S. aureus (GISA) strains has not been observed in US hospitals or in
      Europe, spread of GISA strains has apparently occurred in Japan. Laboratory
      studies have indicated that the disk diffusion test, the Stoke's method, and
      several automated methods of antimicrobial susceptibility testing do not detect
      GISA strains. The requirement to choose from a relatively small number of
      acceptable techniques for screening may well influence the ability of
      laboratories to conduct surveillance for these organisms. Finally, the isolation
      of such strains in three geographically distinct regions suggests that this
      phenomenon will continue to occur worldwide.

PMID- 10658754
TI  - Residential care and the elderly: the burden of infection.
AB  - Long term care facilities (LTCFs) include a variety of different types of
      healthcare settings, each with their own unique infectious disease problems. This
      report focuses on the epidemiological considerations, risk factors and types of
      infections that occur in elderly patients institutionalized in nursing home
      settings. In the US, the number of patients in nursing homes continues to grow as
      the population ages. Today, patients in nursing homes have more complicated
      medical conditions than they did five years ago as they become even more elderly
      and the trend continues towards shorter and shorter hospital stays in acute care
      facilities. The patient population in nursing homes is uniquely susceptible to
      infections because of the physiological changes that occur with ageing, the
      underlying chronic diseases of the patients and the institutional environment
      within which residents socialize and live. In addition, in nursing home settings,
      problems with infections may be more difficult to diagnose because of their
      subtle presentations, the presence of co-morbid illnesses which obscure the
      symptoms of infection and the lack of on site diagnostic facilities. Delays in
      diagnosing and treating infections allow transmission to occur within the
      facility. Both endemic and epidemic infections occur relatively commonly in
      nursing homes. The incidence of endemic infections, such as catheter-associated
      urinary tract infections, lower respiratory infections and skin infections, is
      influenced by the debility level of the patients. Calculations of infection rates
      are influenced by the intensity of surveillance methods at each institution. Many
      endemic infections are unpreventable. Epidemic infections account for 10-20% of
      nursing home infections. These include clusters of upper or lower respiratory
      infections, gastroenteritis, diarrhoea, and catheter-associated UTI's. Epidemic
      infections are potentially preventable with sound infection control practices.
      Special attention must be paid to promote universal precautions and give certain
      patients, such as those with known infection or colonization with Clostridium
      difficile, MRSA or VRE, special consideration. The potential for epidemic
      infections with antibiotic-resistant organisms is real. In the nursing home
      setting, attention must be given to develop and support strong infection control
      programmes that can monitor the occurrence of institutionally-acquired infections
      and initiate control strategies to prevent the spread of epidemic infections.
      Education in infection control issues and attention to employee health is
      essential to enable staff to care appropriately for today's nursing home
      population and to prepare them for the even more complicated patients who will be
      cared for in this type of setting in future.

PMID- 10658755
TI  - Keeping MRSA out of a district general hospital.
AB  - This study describes a three-year audit of methicillin-resistant Staphylococcus
      aureus (NIRSA) in a district general hospital and surrounding community. Despite
      a continuing increase in new cases of MRSA both nationally and locally, and the
      transfer of patients with MRSA from outside, the hospital remains free from
      endemic MRSA, albeit with occasional sporadic cases. This is attributed to the
      presence of a Control of Infection team who have introduced and implemented
      various policies to control MRSA. These include prompt screening of hospital
      transfers, an effective topical regimen, attention to environmental cleaning,
      treatment for established infection, tailored protocol for colonized urinary
      catheters and an educational programme for staff. Some of these policies have
      been extended into the community. This report also presents data from 172 cases
      of MRSA, including carriage rate, infection site, antibiogram, phage-typing,
      treatment and/or clearance outcome and preliminary evaluation of pathogenicity. A
      questionnaire has been formulated to assess colonization vs infection. Future
      strategies will be required if the status quo is to be maintained.

PMID- 10658756
TI  - Soil, seed and climate: developing a strategy for prevention and management of
      infections in UK nursing homes.
AB  - Most studies of nursing home (NH) infections come from the USA and very few from
      the UK. USA studies lead us to anticipate a rate of 7 infections per 1000 patient
      days with a point prevalence as high as 16% in UK NH residents. Pneumonia, skin
      and urine infections would be the most frequent, followed by enteric infection
      and bacteraemia. Colonization with resistant organisms is increasing in UK NH
      residents (e.g., MRSA in 4-17%). Surveillance studies are needed in UK NHs to
      report incidence of infection, residents' characteristics, existence of and
      adherence to above standards and policies. Trials of effectiveness of different
      infection control programmes and of NH vs hospital management are required.
      Management of infection may be a useful marker of quality of care in NHs and
      therefore of interest to health and local authorities.

PMID- 10658757
TI  - Control of infection in nursing homes: a risk-management approach.
AB  - The concept of risk addresses the probability that an untoward incident will
      occur. In the healthcare setting, professionals have a responsibility to identify
      risks over which they have some control and to take appropriate measures to
      minimise those risks. This process is referred to as risk management when
      actively undertaken. During our work with clinical and non-clinical staff in
      nursing homes, it became increasingly clear that old ritualistic habits remained
      and compromised effective infection control practice. To try to develop a more
      effective management of the risks associated with this environment, we worked
      with a number of homes to enable them to develop and implement a modified risk
      management process in relation to infection control practice. The staff carried
      out a brief risk review, including assessment of: (a) Possible risk exposures;
      (b) Appropriate methods of control; (c) Selecting and implementing the best
      method of control; (d) Evaluating and monitoring improvements in risk reduction
      and patient outcomes. Tools were devised and utilised in three main areas: (1)
      Risks to the patient; (2) Risks to the staff; (3) Environmental risks and
      controls. These interventions are currently being evaluated. As there is little
      baseline data in this type of care environment, evaluation of the impact of these
      interventions will take some time to assess.

PMID- 10658758
TI  - Infection control: the role of disinfection and sterilization.
AB  - Many articles that document infections after improper decontamination of patient
      care items have emphasized the necessity for appropriate disinfection and
      sterilization procedures. This paper provides recommendations on the preferred
      method for disinfection and sterilization of patient-care items based on the
      intended use of the item (i.e., critical, semicritical, noncritical). The
      chemical disinfectants recommended for patient-care items and instruments include
      glutaraldehyde, hydrogen peroxide, peracetic acid, sodium hypochlorite, alcohol,
      iodophors, phenolics, and quaternary ammonium compounds. The choice of
      disinfectant, concentration, and exposure time is based on the risk of infection
      associated with the use of the item. The sterilization methods briefly discussed
      include steam sterilization, ethylene oxide, new low-temperature sterilization
      technologies and dry heat. When properly used, these disinfection and
      sterilization processes can ensure the safe use of invasive and noninvasive
      medical devices. However, this requires strict adherence to current cleaning,
      disinfection, and sterilization guidelines.

PMID- 10658759
TI  - Bacterial resistance to disinfectants: present knowledge and future problems.
AB  - Bacterial resistance to antibiotics is a long-established, widely-studied
      problem. Increasingly, attention is being directed to the responses of various
      types of microbes to biocides (antiseptics, disinfectants and preservatives).
      Different groups of bacteria vary in their susceptibility to biocides, with
      bacterial spores being the most resistant, followed by mycobacteria, then Gram
      negative organisms, with cocci generally being the most sensitive. There are wide
      divergencies within this general classification. Thus, (i) spores of Bacillus
      subtilis are less susceptible to biocides than those of Clostridium difficile:
      (ii) Mycobacterium chelonae strains may show high resistance to glutaraldehyde
      and M. avium intracellulare is generally less sensitive than M. tuberculosis;
      (iii) Gram-negative bacteria such as Pseudomonas aeruginosa, Providencia spp and
      Proteus spp may be difficult to inactivate; (iv) enterococci are less sensitive
      than staphylococci to biocides and antibiotic-resistant strains of Staphylococcus
      aureus might show low-level biocide resistance. The mechanisms involved in
      biocide resistance to biocides are becoming better understood. Intrinsic
      resistance (intrinsic insusceptibility) is found with bacterial spores,
      mycobacteria and Gram-negative bacteria. This resistance might, in some
      instances, be associated with constitutive degradative enzymes but in reality is
      more closely linked to cellular impermeability. The coats(s) and, to some extent,
      the cortex in spores, the arabinogalactan and possibly other components of the
      mycobacterial cell wall and the outer membrane of Gram-negative bacteria limit
      the concentration of active biocide that can reach the target site(s) in these
      bacterial cells. A special situation is found with bacteria present in biofilms,
      which can be considered as being an intrinsic resistance mechanism resulting from
      physiological (phenotypic) adaptation of cells. Acquired resistance to biocides
      may arise by cellular mutation or by the acquisition of genetic elements.
      Plasmid/transposon-mediated resistance to inorganic and organic mercury compounds
      by hydrolases and reductases has been extensively studied. Plasmid-mediated
      resistance to some other biocides in Gram-negative bacteria and in staphylococci
      has been described, but its significance remains uncertain. As to the future,
      there is a need to establish conclusively whether there is a clear-cut linkage
      between antibiotic and biocide resistance in non-sporulating bacteria and whether
      biocides can select for antibiotic resistance. Additionally, the responses to
      biocides of new and emerging pathogens must be assessed. At the same time,
      continuing research is necessary to establish further the underlying mechanisms
      of resistance and to provide more efficient means of bacterial inactivation.

PMID- 10658760
TI  - Inactivation of prions by physical and chemical means.
AB  - Prions are very resistant to inactivation, and accidental transmission has
      occurred through the use of inadequate decontamination procedures. Strong sodium
      hypochiorite solutions achieve inactivation but other chlorine-releasing
      compounds are less effective. 2M sodium hydroxide leads to substantial but
      incomplete inactivation; other chemical procedures such as the use of proprietary
      phenolic disinfectants are much less less effective. Infectivity can survive
      autoclaving at 132-138 degrees C, and under certain conditions the effectiveness
      of autoclaving actually declines as the temperature is increased. The small
      resistant subpopulations that survive autoclaving are not inactivated by simply
      re-autoclaving, and they acquire biological characteristics that differentiate
      them from the main population. Despite the limitations of autoclaving, combining
      autoclaving (even at 121 degrees C) with a sodium hydroxide treatment is
      extremely effective. Protein-fixation (e.g., by ethanol or formalin)
      substantially enhances the thermostability of these agents. This suggests that
      future successful inactivation strategies might best be developed by studying
      procedures that avoid protein-fixation.

PMID- 10658762
TI  - Molecular typing in practice.

PMID- 10658761
TI  - Principles of molecular typing: a guide to the letters.

PMID- 10658763
TI  - Where is typing going?
AB  - The basic premise in any bacterial typing scheme is that epidemiologically
      related isolates are derived from the clonal expansion of a single precursor. In
      simple terms this means that a certain characteristic is more useful than others
      on the basis that it is conserved within a strain but diverse with a species.
      Such a definition is appropriate when considering the spread of a species within
      a ward hospital or even a community. However, as we have developed more and more
      refined molecular techniques for analysis of the bacterial genome, such a
      definition has become stressed when considering the evolution that is occurring
      especially amongst drug-resistant bacteria whose genetic make-up is changing due
      to the selective pressure induced by drug usage in the hospital or community.
      Increased sophistication does not necessarily bring improved typing of bacterial
      strains which might only be variants of the same clonal type. Molecular
      epidemiology is perhaps too exacting to be practical in certain circumstances and
      one should be cautious in its interpretation and extrapolation. It is open to
      debate whether we shall see in the next century unanimity in the choice of pheno-
      or genotypic tests to be used for typing of bacterial strains.

PMID- 10658764
TI  - Surveillance of resistance against antimicrobial agents: a European perspective.

PMID- 10658765
TI  - Nosocomial antimicrobial resistance surveillance.
AB  - The global threat of antimicrobial resistance and potentially untreatable
      infections is a serious matter under review currently by the WHO and many
      countries throughout the world. I consider the optimal surveillance scheme and
      point out the various biases in the systems that we have been using in the UK
      over the last decade. MRSA are used as an example where similar trends have been
      identified in these systems and the information has, once again, proved to be of
      value to the MRSA control working party.

PMID- 10658766
TI  - Prevalence of nosocomial infections in Spain: EPINE study 1990-1997. EPINE
      Working Group.
AB  - From 1990, a study on the prevalence of nosocomial infections has been carried
      out yearly in Spanish hospitals. Acute care hospitals with more than 50 beds were
      involved on a voluntary basis. In 1990, 123 hospitals participated and by 1997
      the number of hospitals had reached 214. The objective of the study is to examine
      the situation in each hospital, and to collect data across the country, by means
      of a common protocol. The overall prevalence of nosocomial infections has
      significantly decreased in Spain. The prevalence of infected patients has been
      about 7% in the three last studies. The prevalences for urinary tract infections
      and surgical wound infections have decreased, while prevalences for lower
      respiratory tract infections and bacteraemia have increased. Urinary tract
      infections have occupied the first position over the eight surveys. Second place
      was taken by surgical wound infections from 1990 to 1995, and by lower
      respiratory tract infections in 1996-1997. With the exception of Intensive Care
      Units, the prevalence of nosocomial infections has been decreasing in all
      hospital areas. The mean age of hospitalized patients has increased, so has the
      proportion of patients with one or more intrinsic risk factors and the proportion
      of those with one or more instrumentations. The proportions of patients with a
      short or a very long hospital stay have increased, revealing a change that no
      doubt reduces nosocomial infection rates. The use of antimicrobial drugs has
      shown a significant increase, from 33.8% of patients in 1990 to 35.8% in 1997.

PMID- 10658767
TI  - Molecular mechanisms of Staphylococcus epidermidis biofilm formation.
AB  - Coagulase-negative staphylococci, mainly Staphylococcus epidermidis, are the
      predominant cause of implanted medical-device related infections. The formation
      of adherent multi-layered biofilms embedded into a glycocalyx composed of
      exopolysaccharides on implanted devices is believed to be essential for the
      pathogenesis of S. epidermidis infections. Biofilm formation may be separated
      into primary attachment of bacteria to native or modified polymer surfaces
      followed by proliferation of attached bacterial cells leading to accumulation of
      multi-layered cell-clusters and glycocalyx formation. Recent progress in the
      understanding of the molecular mechanisms cooperating in S. epidermidis biofilm
      formation is reviewed and current thinking on the relevance of these mechanisms
      for S. epidermidis device-related infections is discussed.

PMID- 10658768
TI  - Novel methods for the prevention of infection of intravascular devices.
AB  - Infections are often caused by bacteria that gain access either from the skin
      during insertion, or by migration from the skin to the surrounding subcutaneous
      tissue, once in situ. It is necessary to understand the pathogenesis with regard
      to sessile or planktonic forms of microorganisms and why they adhere to catheter
      surfaces, and the interactions between host, catheter and bug. To prevent
      colonization two general approaches have been adopted: the first concerns the
      site of insertion-prophylactic antibiotics, tunnelling, intraluminal antibiotic
      locks, topical application of antibiotics or antiseptics, cutaneous disinfection
      pre- and post-insertion with various antiseptics, catheter site care and
      frequency of dressing changes. The second approach considers the physical nature
      of catheter material-silver impregnated subcutaneous collagen cuffs, antiseptic
      hubs, antimicrobial coating of catheters with antibiotics e.g., rifampicin and
      minocycline, silver ions, chlorhexidine, chlorhexidine and silver sulphadiazine.
      Only by understanding the pathogenesis of catheter devices whereby micro
      organisms are embedded in biofilms and are resistant to the action of
      antibiotics, will effective preventative measures be possible. In addition a
      proper risk-management review will be necessary to determine the cost-benefit of
      such modified catheters.

PMID- 10658769
TI  - Viral transmission by blood, organs and tissues.

PMID- 10658770
TI  - Unusual transmissions of blood-borne viruses, with special reference to HIV.
AB  - Containing virus infections in hospital and other clinical contexts depends upon
      a clear understanding of how they may be transmitted. The routes of transmission,
      infectious doses, portals of virus entry and exit, intensity of virus excretion
      and stability of the virus in the environment are all important considerations.
      Although present infection control policies may be based on the best available
      evidence, the risks are in some instances still not well enough defined to be
      sure that all reasonable precautions are in place. One way of improving infection
      control policies is to study unexpected and unusual viral transmissions to see
      whether new or previously unrecognized hazards have arisen. Examples are given
      where transmission of HIV and other blood borne viruses has seemed to occur
      outside recognized risk situations. On closer examination most of these represent
      known transmission modes but, where they do not, current control of infection
      policies may need to be reviewed.

PMID- 10658771
TI  - Foodborne human disease: is it a veterinary problem?

PMID- 10658772
TI  - White Paper: political change and infection control in Scotland.

PMID- 10658773
TI  - White papers, political change in infection control in the UK: a perspective from
      the deep south.

PMID- 10658774
TI  - Infection control and changes in management of hospitals: the European
      experience.
AB  - The general setting for the management of many European hospitals has undergone
      enormous changes during the last five to 10 years, especially with respect to
      economic, personnel and technical resources. This change has had a serious
      influence on the practice of infection control. To get an insight of the problems
      infection control practitioners in Europe today have to face, hospital
      epidemiologists representing nine European countries were asked to answer a
      questionnaire. In most countries, new laws on communicable disease prevention and
      infection control in hospitals have been implemented during the last few years.
      In conjunction with the widespread introduction of quality assurance and the
      accreditation of hospitals, organizational aspects of infection control have
      gained importance. However, budget restrictions and the growing competition
      between institutions are major challenges. In general, there has been a
      remarkable influence of the documented changes on the practice of infection
      control in European hospitals. Facing this situation, infection control
      practitioners should abandon unproven measures and implement those that are
      evidence-based, to prevent hospital acquired infection (HAI). Cost reducing
      initiatives, like the use of well designed multi-use devices and the reuse of
      disposables should be considered and scientifically assessed.

PMID- 10658775
TI  - Infectious diseases and litigation.

PMID- 10658776
TI  - European medical device regulatory law and product liability.
AB  - The regulatory system for medical devices is quite different from that for
      pharmaceuticals and may catch many people unawares. For instance, it does not
      involve the grant of a marketing authorization by a medicines agency. Instead, a
      declaration of conformity is made by the manufacturer, but in many instances this
      is subject to approval by an independent certification house (known as a notified
      body). The Medical Devices Directive 93/42/EEC is applied in each EEA State by
      national Legislation. In the UK, for example, the relevant law is the Medical
      Devices Regulations 1994, and responsibility for enforcement rests with the
      Medical Devices Agency. Non-compliance with the regulations can incur a criminal
      penalty.

PMID- 10658777
TI  - Controlling Escherichia coli O157: the emerging challenge.

PMID- 10658778
TI  - Epidemiology of nosocomial clostridium difficile diarrhoea.
AB  - Clostridium difficile is a frequent and clinically important cause of diarrhoea
      that has been strongly but not exclusively associated with the hospital setting.
      The vast majority of cases of C. difficile diarrhoea are associated with
      antecedent treatment with antibiotics, of which cephalosporins and clindamycin
      appear to pose the highest risk. Within hospitals and chronic-care facilities,
      cross-infection of C. difficile has been related to transient carriage on hands
      of healthcare workers and contamination of diverse environmental surfaces,
      including electronic rectal thermometers. Prospective epidemiologic studies have
      demonstrated that acquisition of C. difficile is common in hospitalized patients.
      Although colonized patients contribute to nosocomial transmission of C.
      difficile, symptom-free carriage of C. difficile appears to reduce risk of
      subsequent development of C. difficile diarrhoea. Antimicrobial treatment with
      oral metronidazole or vancomycin to attempt to eradicate symptomless carriage is
      not recommended. Measures to control nosocomial C. difficile diarrhoea have
      focused on improved handwashing, use of barrier precautions with single rooms for
      symptomatic patients, reduction of environmental contamination, and antibiotic
      restriction. Restricting clindamycin has been particularly successful in
      terminating outbreaks of C. difficile diarrhoea associated with its use. The
      epidemiologic features of C. difficile and strategies for control are similar to
      those for micro-organisms that have acquired antimicrobial resistance. C.
      difficile may be indirectly or directly contributing to spread of resistant
      organisms, for instance, by causing diarrhoea and thereby enhancing environmental
      contamination with other gastrointestinal flora such as vancomycin-resistant
      enterococci. Thus, a consideration of C. difficile in the larger context of the
      world-wide spread of antibiotic resistance offers useful insights that may help
      form the basis for the development of more effective control measures.

PMID- 10658779
TI  - Nosocomial infections in HIV-infected/AIDS patients.
AB  - Several pathogenetic processes are involved in the progression to AIDS in HIV
      infected individuals. These include a gradual, but ultimately profound, depletion
      in CD4 lymphocytes, defects in B lymphocytes, neutrophil dysfunction and the
      breakdown of the integument as a consequence of AIDS-related dermatological
      conditions such as bacterial and fungal dermatoses and Kaposi's sarcoma. Each of
      these factors has important implications regarding host susceptibility to
      nosocomial infections. This review deals with some of the difficulties that are
      encountered in precisely defining the interrelationships between HIV
      infection/AIDS and nosocomial sepsis, and some of the controversies that surround
      respiratory, bloodstream (including central venous catheter-related infections)
      and gastrointestinal infections that may be acquired within healthcare centres.
      Because of the lack of accurate, detailed information on this subject, parallels
      will sometimes be drawn from observations made in other immunologically impaired
      patient groups and from data examining the rates of community-acquired infections
      in HIV-infected patients compared to controls. Appropriate and rational infection
      practice to minimize the risk of acquisition of nosocomial infection is
      highlighted. Finally, some of the common methodological problems commonly
      encountered in the current literature regarding nosocomial infections in this
      population group, and future challenges in the study of these infections, are
      reviewed.

PMID- 10658780
TI  - Controlling airborne infections.

PMID- 10658781
TI  - Meta-analysis and systematic review of antibiotic trials.

PMID- 10658782
TI  - Nosocomial fungal infection: diagnosis and typing.

PMID- 10658783
TI  - Sharps injury! A review of controversial areas in the management of sharps
      accidents.

PMID- 10658785
TI  - The information superhijack.
AB  - Infection control teams are not alone in their need to manipulate data. How best
      can such manipulation be achieved and what tools are available to turn
      information into knowledge. The workshop included discussion and demonstration of
      some methods currently being used by infection control teams. While the workshop
      did not aim to produce all the answers, participants were able to question,
      discuss and learn new ways that they might take their own practice in the future.

PMID- 10658784
TI  - Weighing the consequence of doing nothing versus those of doing something: post
      exposure chemoprophylaxis for occupational exposures to HIV.

PMID- 10658786
TI  - Changing attitudes of healthcare workers to comply with infection control
      procedures.

PMID- 10658787
TI  - Pre-transplantation testing: who, when and why?
AB  - An ever-widening range of human organs and tissues is being transplanted, limited
      currently only by the ingenuity of surgeons and immunologists to overcome the
      physical and immune barriers. Microbiologists are in danger of being left behind.
      Although the major infective risks of human organ transplantation are now well
      understood, many details remain controversial, and the special risks associated
      with tissue banking have received little attention until recently. What should we
      do? Are we making mountains out of molehills? Are there any data on which to base
      a rational decision? Topics covered include: bacteriology of cadaveric heart
      valve transplantation (why are valves not cultured and only dunked in antibiotic
      solution for 24h, whereas endocarditis gets treated for 4 weeks?); screening for
      tissue-born viruses (why does everyone persist with serology when genomic methods
      are so much better?); screening organ donors for CMV (surely we should use the
      optimally sensitive combination of methods?); peripheral blood stem cell
      transplants (should we culture these, and what do the positive results mean if we
      do?); donor sputum screening before heart-lung transplantation (does this aid the
      post-operative management of the recipient?). With active participation from the
      floor some areas of consensus were identified and topics worthy of scientific
      investigation in the future were highlighted.

PMID- 10658788
TI  - Stewardship of antibiotic use and resistance surveillance: the international
      scene.
AB  - Audit is all about education and changing practice. It is well known that doctors
      are both difficult to target with educational initiatives and those who need
      educating are the most difficult to target! Changing established practice is even
      harder and maintaining change in practice is often considered just a dream. This
      emphasises the importance of the cycle of audit, feedback (education), re-audit
      etc. This process has been developed over a twelve-year period in Aberdeen while
      the antibiotic policy has evolved from a 15-page booklet on hospital antibiotic
      prescribing into a 90-page book combining both hospital and general practice
      prescribing. Both successes and failures of the audit process will be described
      in the context of Strategic Goals. The next phase is assessment of performance
      against other policies in Europe to establish the best methods of antibiotic
      stewardship. A European group has recently been formed to begin this process.
      Parameters that can be used to assess the comparative performance of policies
      will be discussed and include antibiotic resistance rates. Several international
      resistance surveillance and quality of antibiotic use programmes are highlighted.

PMID- 10658789
TI  - Antibiotic policies and the role of strategic hospital leadership.
AB  - Operational aspects, programme construction and implementation are all essential
      components of antimicrobial control but are not the direct remit of management
      and must rest with the professional provider. Hospital leaders can influence
      antibiotic control through the priority they give it. This must not be purely
      financially driven and must incorporate an awareness of issues surrounding
      patient care. Such attitudes should encompass the consequences of poor
      prescribing practices in both human and corporate terms. A leader's recognition
      of these elements can be expressed through securing resources in terms of both
      the human and hardware components. The best signalling of the status of this
      activity is through ensuring its inclusion in clinical governance and
      organisational Board reports. The goals for hospital leaders should be evidence
      of effective working practices and the execution of their own responsibilities by
      championing robust structures and procedures are in place. Potent hospital
      leadership delivered to the focus of antimicrobial control programmes is a major
      tool for their success.

PMID- 10658790
TI  - How do you measure the impact of an antibiotic policy?
AB  - The principle aim of antibiotic policies is to bring about a change in
      prescribing which will lead to decreased cost, reduction of resistance and
      improved quality (judicious, safe and appropriate) of antibiotic prescribing.
      Before embarking upon developing, disseminating and subsequently implementing an
      antibiotic policy clinicians and key decision makers need to make explicit at the
      onset of policy development, how they plan to evaluate its impact. Quality
      indicators of the process of implementing policies and their impact on various
      outcomes need to be identified. These number and complexity of these indicators
      is dependent on local resource but they must be specific to the organisation,
      simple, measurable and meaningful. This information needs to be shared and acted
      upon.

PMID- 10658791
TI  - Antibiotic policies in Central/Eastern Europe (CEE) after 1990.
AB  - Significant political and social changes in Eastern Europe have caused dramatic
      changes in healthcare: Centralized state drug policies were decentralized,
      vaccination strategies in some countries changed and directed financing of
      healthcare replaced by one or multiple health management organisations (HMO).
      Centralized Infectious Diseases and/or Antibiotic Resistance surveillance were
      stopped after 1990 in four of six countries but resurrected after 1996 in
      Hungary, Poland and Slovakia. According to antibiotic (ATB) resistance and
      nosocomial infection rates, there are some differences in comparison to Western
      and Northern Europe e.g., a higher incidence of penicillin resistant pneumococci,
      ampicillin resistant H. influenzae and methicillin resistant Staphylococcus
      aureus. Because of increasing consumption of ATB before 1991, due to the free
      market, pharmaceutical marketing and reimbursement policies, several strategies
      to decrease consumption and/or resistance were implemented such as restriction of
      outpatient use, national and hospital formularies and Health Management
      Organizations-based restrictions. Probably due to the short time scale, no
      significant reduction in resistance has been documented although antibiotic
      consumption has declined.

PMID- 10658792
TI  - Automated entry of nosocomial infection surveillance data: use of an optical
      scanning system.
AB  - Surveillance of nosocomial infections is the foundation of any infection control
      programme. One of the main obstacles to surveillance is the speed and accuracy of
      data collection and entry. To overcome this bottleneck, we instituted automated
      data capture and processing in a number of point-prevalence and continuous
      nosocomial infection surveillance programmes. The system incorporated a document
      scanner, form design and processing software (Formic for Windows version 2) and
      statistical analysis software SPSS (Statistical Products and Service Solutions).
      After designing the surveillance questionnaire, it was completed by putting an X
      or a numeral in the the appropriate boxes. Information was collected by the
      infection control nurse and/or by members of clinical staff depending on the type
      of surveillance being undertaken. Once the form was completed it was returned and
      scanned using a document scanner with automatic feed. The software read and
      evaluated the data on each page. Data from 16741 A4 sides of surveillance
      questionnaires were automatically processed in a total time of 37.3 hours. This
      system was found to have a 99.98% accuracy rate and it was estimated to be 22
      times quicker than manual entry of data. Infection control teams who are required
      to carry out surveillance activities should consider automatic data-entry
      systems. The versatility of such systems makes it possible to achieve extensive
      surveillance with limited resources.

PMID- 10658793
TI  - Minimum standards in laboratories for infection control.
AB  - Laboratory services should be available to support every infection control
      programme, whether in a hospital or community setting. The services will depend
      upon available resources and the expectation of the clinicians using the
      services. Equally, resources reflect the level of staff expertise, equipment and
      finances supporting laboratory practice. All information given to the clinical
      staff should be sensible, accurate, comprehensible and in keeping with the
      clinical needs of the healthcare setting. Internal and external quality controls
      should be rigorous. Not all laboratories are expected to provide an all
      encompassing service and therefore primary, secondary and tertiary or referral
      laboratories should be established where necessary. It is essential to have clear
      protocols on laboratory usage, mutually agreed between the laboratory and
      clinical staff to be cost effective.

PMID- 10658795
TI  - What does a clinician expect from a microbiologist? Towards an effective joint
      policy.
AB  - What a clinician needs from a microbiologist and microbiological service depends
      on the specialty. To provide a diagnosis of infection, the service should
      organize and also follow-up the specimen transport, microbiological examination
      and antimicrobial susceptibility testing together with antigen detection and
      other modern test technology. A manual describing the local service and including
      guidelines should be placed in every department. At the same time a clinician
      should be familiar with clinical syndromes and causative micro-organisms, in
      order to be able to ask for the correct investigation. Only with continuous
      interchange of information by both parties is an effective joint policy possible
      in daily routine work.

PMID- 10658794
TI  - Interaction between the microbiology laboratory and clinician: what the
      microbiologist can provide.
AB  - The work of the clinical microbiologist comprises three major areas: diagnostic
      work in the laboratory, advice to clinicians about treatment of infected
      patients, and infection control. By clinical alertness, either from work in the
      laboratory or from clinical contacts, the microbiologist may contribute to the
      recognition of hospital outbreaks. The microbiologist plays a key role in
      implementing a restrictive antibiotic policy in hospital. Experience shows that a
      close personal contact with clinicians in the daily treatment of patients is the
      most efficient way to ensure a rational use of antibiotics and keep the
      consumption low. Other important measures include the elaboration of antibiotic
      guidelines and performance of audits. On basis of periodic summaries of
      laboratory data and data on antibiotic consumption, the microbiologist can keep
      the clinicians informed about antibiotic resistance and compliance with the
      antibiotic guidelines. In addition to informal contacts, the microbiologist also
      interacts with clinicians through participation in infection control and drug and
      therapeutic committees.

PMID- 10658796
TI  - National guidelines for infection control in The Netherlands.
AB  - National guidelines for the prevention of hospital infections in The Netherlands
      were established by the Working Group on Infection Prevention (WIP) in 1981.
      Since 1992 these guidelines have functioned as national standards for infection
      control applicable in all hospitals. The organization of the WIP, the process of
      developing guidelines and the current guidelines are described. The working group
      has also produced guidelines for nursing homes, institutions for the mentally
      handicapped and dentists.

PMID- 10658797
TI  - Guidelines for infection prevention and control in Germany: evidence- or expert
      based?
AB  - Nosocomial infections (NI) are a major problem, and numerous measures are being
      recommended for preventing NIs in Germany. However, the evidence for the efficacy
      of many currently recommended measures is incomplete or has been established for
      certain sub-groups of patients or specific conditions only. In view of this
      situation, it is necessary to improve the established measures for preventing
      NIs. Since many procedures and components of infection control involve additional
      expenditure, their deployment can only be justified if their efficiency has been
      demonstrated or is highly likely on the basis of rational considerations.

PMID- 10658798
TI  - Guidelines for nosocomial infection control in Britain.

PMID- 10658799
TI  - Guidelines for infection control: the French situation.

PMID- 10658800
TI  - What should we do about patients with Clostridium difficile?

PMID- 10658801
TI  - Choosing disinfectants.
AB  - Disinfectant choice is an important part of the role of the infection control
      team. Its importance has increased due to concern over transmission of blood
      borne viruses and the need to identify alternatives to gluteraldehyde. Factors to
      be taken into account when choosing disinfectants include compliance with COSHH
      regulations, user acceptability, instrument compatibility and antimicrobial
      activity. Compounds vary in their suitability for different uses and an agent's
      properties must be fully evaluated before adopting it for a particular purpose.
      This review outlines the main properties that need to be established and covers
      the major characteristics of main classes of disinfectants.

PMID- 10658802
TI  - Low prevalence of nosocomial Clostridium difficile transmission, as determined by
      comparison of arbitrarily primed PCR and epidemiological data.
AB  - An increased prevalence of patients with C. difficile-associated diarrhoea in a
      hospital setting suggested the possible existence of an endemic occurrence. A
      study was therefore designed to determine clonal relatedness among 173 isolates
      of C. difficile, collected consecutively during 1995 from 147 patients (89
      inpatients and 58 outpatients) and to estimate the probability of nosocomial
      transmission. Arbitrarily primed PCR (AP-PCR) with three different primers, AP1,
      AP2 and CLD1, was used for fingerprinting and identified 21, 92 and 70 types,
      respectively. Overall DNA analysis of the combined AP-PCR data yielded 140 types,
      of which 130 were unique, whereas 10 types occurred repeatedly in 36 isolates
      from 33 patients; seven isolates were non-typeable by one of the primers.
      Epidemiological data confirmed that in eight of the 33 patients there was a high
      probability of nosocomial transmission. Despite a high prevalence of C. difficile
      among hospitalized patients, a low frequency of nosocomial transmission was
      suggested by high resolution molecular typing of bacterial isolates in
      conjunction with traditional epidemiological methods.

PMID- 10658803
TI  - Incidence of Clostridium difficile infection: a prospective study in an Indian
      hospital.
AB  - Clostridium difficile is the commonest cause of hospital-acquired diarrhoea. A
      prospective study comprising of 156 patients and 54 healthy controls was
      undertaken to assess C. difficile associated diarrhoea (CDAD) incidence in an
      Indian hospital. Methods used included C. difficile culture and enzyme linked
      immunosorbent assay (ELISA) for Toxin A. Attempts were made to type isolates by
      antibiogram and SDS-PAGE. Of the 210 stool samples tested, 12 gave positive
      results in at least one assay. Of these, 11 were positive by the ELISA method,
      eight by culture, and seven by both methods. Neither the organisms nor the toxin
      was found in healthy controls or neonates. The average disease incidence of CDAD
      estimated by using both methods was 15%. Two antibiotypes of the isolates were
      obtained and of the isolates characterized by SDS-PAGE, two had identical
      patterns. This study shows that CDAD is an emerging problem in Indian hospitals.
      Monitoring should enable the development and implementation of policies and
      procedures that minimize the risk of this nosocomial pathogen.

PMID- 10658804
TI  - Antibiotic and biocide resistance in methicillin-resistant Staphylococcus aureus
      and vancomycin-resistant enterococcus.
AB  - Concern has been growing regarding the potential of antibiotic and disinfectant
      co-resistance in clinically important bacteria. In this study, the
      susceptibilities of methicillin-resistant Staphylococcus aureus (MRSA) and
      methicillin-sensitive Staphylococcus aureus (MSSA) to chlorhexidine (CHX), the
      quaternary ammonium compounds cetylpyridinium chloride (CPC) and benzalkonium
      chloride (BC), triclosan, dibromopropamidine isethionate (DBPI) and triclocarban
      were compared. MRSA exhibited low-level resistance to CHX and the QACs, with MICs
      of 1.5 to 3-fold (CHX), and 2 to 4-fold (QACs) higher than MSSA. However, the MIC
      values for MRSA ranged between 0.025 (the MIC of MSSA) and 1 microg/mL with
      triclosan, and between <5 (the MIC of MSSA) and 75 microg/mL with DPBI.
      Nevertheless, these strains remain relatively sensitive to most of these
      antimicrobial agents. The bactericidal efficacy of CHX, CPC and DBPI (with the
      exception of one strain) correlated with their MIC value. This was not observed
      using triclosan; MRSA and MSSA strains were equally susceptible to its killing
      effect, regardless of MIC. The permeabilizing agent, ethylenediamine tetraacetic
      acid (EDTA) was unable to potentiate the antibacterial activities of the biocides
      against any of the strains tested. Attempts to select for staphylococcal strains
      with increased resistance to triclosan, CPC or CHX, using disc diffusion, step
      wise broth, or repeated exposure/recovery technique, were only partially
      successful, and resistance was found to be unstable. The susceptibilities of
      vancomycin-resistant enterococcus (VRE) and vancomycin-sensitive enterococcus
      (VSE) to the biocides were also compared and found to be similar both in terms of
      MIC testing and time-kill studies.

PMID- 10658805
TI  - Residual glutaraldehyde levels in fiberoptic endoscopes: measurement and
      implications for patient toxicity.
AB  - Most gastroenterology societies recommend glutaraldehyde for fiberoptic endoscope
      disinfection. However, glutaraldehyde toxicity has been suspected in patients
      examined with endoscopes disinfected with this compound. The aim of our study was
      to determine the residual levels of glutaraldehyde in fiberoptic endoscopes after
      either manual or automatic disinfection and to evaluate the extent of toxicity.
      Furthermore, the procedures for disinfection currently performed by the
      department were compared with the new French guidelines. We used both manual and
      automatic disinfection procedures and flushed sterile distilled water through the
      lumens of endoscopes before use. Residual glutaraldehyde levels were determined
      using liquid chromatography coupled to spectrophotometric detection. In a total
      of 92 measurements it was found that residual glutaraldehyde levels were higher
      and more variable after manual disinfection (< 0.2-159.5 mg/L) than after
      automatic disinfection (< 0.2-6.3 mg/L). We conclude that local procedures for
      disinfection need to be improved to conform to the new French guidelines. Since
      thresholds for the toxic dose of glutaraldehyde and international norms for
      levels of residual glutaraldehyde in equipment have not been defined, additional
      studies combining accurate measurements in fiberoptic endoscopes and clinical
      observations of endoscopy patients will be required to draw more definitive
      conclusions.

PMID- 10658806
TI  - An outbreak of neonatal infection with Acinetobacter linked to contaminated
      suction catheters.
AB  - An outbreak of multi-drug resistant Acinetobacter spp. infection in the neonatal
      unit at King Edward VIII hospital in Durban, South Africa, is described. Nine out
      of a total of 218 neonates were infected during the study period. The outbreak
      was characterized by early onset infection [median postnatal age 3 days (range 1
      23 days)] in pre-term babies [median gestational age 33 weeks (range 30-35
      weeks)] with an attributable mortality of 22%. The source of the outbreak,
      determined by ribotyping, was presumed to be contaminated suction bottles and
      catheters in the neonatal admission room. Five neonates were successfully treated
      with ciprofloxacin and amikacin. Enforcement of strict infection control
      practices curtailed the outbreak.

PMID- 10658807
TI  - A comparative study of blood and bone marrow cultures in cadaveric bone donation.
AB  - The results of blood cultures taken from cadaveric bone donors were compared with
      bone marrow and also swab cultures of the procured grafts. In eight of the 95
      donors evaluated, pathogenic micro-organisms were detected in the blood sample.
      In two, identical micro-organisms were cultured from the blood and bone marrow
      sample whilst the swab cultures were negative. Considering the low sensitivity of
      the swab culture, the organisms detected in the blood culture were likely to have
      spread haematogenously and considered to be present in the explanted grafts.
      Bacteriological screening of bone donors is extremely important since the
      transmission of micro-organisms via an allograft can lead to serious
      complications in the recipient. Positive blood cultures provide important
      information on the presence of pathogenic micro-organisms in grafts obtained from
      cadaveric bone donors and are therefore essential in deciding whether a graft is
      bacteriologically acceptable for transplantation.

PMID- 10658808
TI  - An audit of the use of manual handling equipment and their microbiological flora-
      implications for infection control.
AB  - A review of the use of manual handling aids in two hospitals found equipment was
      employed on a multi-patient basis with inadequate cleaning. Sampling with a
      Casella slit sampler demonstrated frequent contamination by methicillin-resistant
      Staphylococcus aureus and Clostridium difficile of fabric aids. Recommendations
      for care of equipment are made.

PMID- 10658809
TI  - Revised guidelines for control of MRSA: applying appropriately-based
      recommendations.

PMID- 10658810
TI  - Screening for methicillin-resistant Staphylococcus aureus (MRSA): one hour versus
      twenty-four hours sampling interval.

PMID- 10658811
TI  - Screening for carriage and nosocomial acquisition of Clostridium difficile by
      culture: a study of 284 admissions of elderly patients to six general hospitals
      in Wales.

PMID- 10658812
TI  - Fungal colonization of filtered water supplied to an automatic washer
      disinfector.

PMID- 10658813
TI  - Bacterial contamination of inhalers.

PMID- 10658814
TI  - Pseudobacteraemia due to Pseudomonas fluorescens.

PMID- 10658815
TI  - Antibiotic prophylaxis in vascular surgery.

PMID- 10658816
TI  - Nosocomial transmission of Bordetella bronchiseptica.

PMID- 10658817
TI  - Hydrogen peroxide: friend of the faux blonde, foe of the cell.

PMID- 10658818
TI  - Cutting to the quick: proteolytic control of oxygen sensors.

PMID- 10658819
TI  - Mitochondria: unravelling the secrets of life and death.

PMID- 10658820
TI  - The ability of mineral dusts and fibres to initiate lipid peroxidation. Part I:
      parameters which determine this ability.

PMID- 10658821
TI  - Hydroxyl radicals detected via brain microdialysis in rats breathing air and
      during hyperbaric oxygen convulsions.
AB  - Microdialysis was done on 300-400 g, awake, male rats with microdialysis probes
      inserted through guide cannulas into the striatum (Bregma co-ordinates A 0.5, L
      2.9, D -4.0 for guide cannulas implanted 5 days previously). Rats were exposed to
      hyperbaric oxygen (HBO; 6 atm absolute, 5 atm gauge pressure of oxygen with
      carbon dioxide absorbed by soda lime). Artificial cerebrospinal fluid (CSF)
      containing 5 mM sodium salicylate was perfused at 1 microl/min and collected over
      sequential 10 min intervals with rats breathing air, then HBO, and after
      decompression. Times to convulsions and duration and severity of convulsions were
      observed and recorded. CSF samples were analyzed for 2,3- and 2,5
      dihydroxybenzoic acid (DHBA), reaction products of hydroxyl radicals with
      salicylate, by HPLC and compared to authentic standards. Recovery of DHBAs was
      48% from fluid surrounding microdialysis probes, based on in vitro tests. The
      average time to the first convulsion was 21 min and rats convulsed an average of
      4 times during 40 min in HBO. There were no significant differences in hydroxyl
      radical production by this protocol during any of the 10 min collection periods
      in air or HBO (average in pmoles for 10 microl of all samples: 2,3-DHBA = 7.0 +/-
      2.5 and 2,5-DHBA = 11.3 +/- 4.1). The failure to detect an increase in hydroxyl
      radicals in HBO prior to or during convulsions appears valid since each rat
      served as its own control.

PMID- 10658822
TI  - Effect of procyanidins from Pinus maritima on glutathione levels in endothelial
      cells challenged by 3-morpholinosydnonimine or activated macrophages.
AB  - The effects of reactive nitrogen species on glutathione homeostasis in human
      endothelial ECV 304 cells challenged by 3-morpholinosydnonimine-N-ethylcarbamide
      (SIN-1) on RAW 264.7 activated macrophages using a co-culture model were
      investigated. SIN-1 or macrophages activated by lipopolysaccharide plus
      interferon-gamma induced a significant glutathione decrease in ECV 304 cells. Pre
      incubation of ECV 304 cells with French maritime pine bark extract containing
      mainly oligomeric procyanidins protected endothelial cells from activated
      macrophage-induced glutathione depletion. Data demonstrate that reactive nitrogen
      species generated with different kinetics and mechanisms impair glutathione
      levels in endothelial cells, and that pine bark extract significantly enhances
      antioxidant defenses.

PMID- 10658824
TI  - Hereditary cancer and developmental abnormalities.
AB  - About 1% of all cancers are hereditary, caused by germ-line mutations in specific
      cancer-related genes. More than 25 different hereditary cancer syndromes are
      known, most of them involving mutations in tumor suppressor genes. These genes,
      which are related to cellular proliferation, might also be involved in
      differentiation. Hence, the phenotype of hereditary cancer syndromes might
      include developmental abnormalities, in addition to cancer predisposition. The
      information summarized here indicates that developmental phenotypes appear in
      both human patients and mouse models of the various hereditary cancer syndromes.
      These developmental abnormalities, which involve a variety of tissues and organs,
      usually lead to embryonic malformation that prevents the birth of viable
      homozygous offspring, but can also be detected in heterozygotes. In some of the
      syndromes a correlation exists between tumor types and developmentally affected
      tissues. Comparison of mice and human phenotypes from both the cancer and the
      developmental aspects indicates that many of the mouse models mimic the human
      syndromes. Our analysis indicates that most tumor suppressor genes participate
      not only in the regulation of cell proliferation, but also in differentiation and
      embryogenesis.

PMID- 10658823
TI  - Nicotinamide (vitamin B3) as an effective antioxidant against oxidative damage in
      rat brain mitochondria.
AB  - Nicotinamide (vitamin B3) an endogenous metabolite, showed significant inhibition
      of oxidative damage induced by reactive oxygen species (ROS) generated by
      ascorbate-Fe2+ and photosensitization systems in rat brain mitochondria. It
      protected against both protein oxidation and lipid peroxidation, at millimolar
      concentrations. Inhibition was more pronounced against oxidation of proteins than
      peroxidation of lipids. Chemically related endogenous compounds, tryptophan and
      isonicotinic acid, showed comparable inhibitory properties. The protective effect
      observed, at biologically relevant concentrations, with nicotinamide was more
      than that of the endogenous antioxidants ascorbic acid and alpha-tocopherol.
      Hence our studies suggest that nicotinamide (vitamin B3) can be considered as a
      potent antioxidant capable of protecting the cellular membranes in brain, which
      is highly susceptible to prooxidants, against oxidative damage induced by ROS.

PMID- 10658825
TI  - Changes in body composition during the initial hours of life in breast-fed
      healthy term newborns.
AB  - Newborns usually lose 5-10% of their initial weight during the first 4 days of
      life. Our aim, using bioelectrical impedance (BI), was to study the body
      composition of healthy term newborns and the nature of the changes which
      accompany this physiological weight loss. Forty-three healthy term newborns, all
      with adequate weight for their gestational age, were studied during the first 3
      days of life. Weight and BI were taken on the 1st, 2nd, and 3rd days of life,
      always at the same time of the day. Total body water (TBW), percentage of total
      body mass hydration (%TBW), and amount of body solids were calculated. Average
      weight at birth was 3,297+/-381 g, length 50.04+/-1.75 cm, and gestational age
      39.9+/-0.84 weeks. Weight, TBW, and body solids decreased progressively during
      the first 3 days of life (p<0.000). By day 3, weight loss represented 5.67+/
      1.98% of birth weight, but %TBW increased slightly (1.72%; p<0.000). These
      results suggest that, during physiological weight loss, body composition
      modifications are produced in the term newborn by a decrease in TBW and loss of
      body solids. The level of body hydration increases slightly, since the loss of
      body solids is greater than the loss of TBW. The use of BI can help us in the
      study of body composition and the short- and/or long-term changes produced
      therein, in the newborn.

PMID- 10658826
TI  - Impaired serum lipids and lipoproteins in fetal macrosomia related to maternal
      obesity.
AB  - The aim of this work was to determine lipoprotein metabolism alterations in
      macrosomic newborns and to see whether these lipoprotein abnormalities are
      parallel or not to those found in their obese or nonobese mothers. Serum lipids,
      apo A-I, apo B100, lipoproteins (VLDL, LDL, HDL2, and HDL3), and LCAT activity
      were investigated in obese and nonobese mothers and cord blood of their
      macrosomic or appropriate-for-gestational-age (AGA) newborns. Serum and VLDL
      triglyceride concentrations were higher in obese mothers of AGA newborns than in
      nonobese mothers. Serum triglyceride, VLDL, and apo B100 levels were higher,
      while serum apo A-I and HDL2 cholesterol concentrations were lower in obese
      mothers of macrosomic newborns than in the other groups. In their macrosomic
      newborns, serum lipid, lipoprotein, apo B100, and apo A-I levels were higher as
      compared with those of other newborns. Macrosomic newborns of nonobese mothers
      had lipoprotein profiles similar to those in AGA newborns. LCAT activity was
      similar in both mother groups and in both newborn groups. In conclusion, maternal
      obesity and fetal macrosomia were associated with lipoprotein abnormalities
      consistent with high atherogenic risk.

PMID- 10658828
TI  - Effect of prenatal glucocorticoid on fetal lung ultrastructural maturation in
      hyt/hyt mice with primary hypothyroidism.
AB  - Glucocorticoids (GC) and thyroid hormones (TH) accelerate fetal lung maturation.
      Though GC are used clinically, the mechanisms of GC-induced fetal lung maturity
      remain unclear. Prenatal GC increase fetal TH activity in humans and in animals.
      Thus, it is possible that increased fetal TH activity after prenatal GC plays a
      role in accelerating fetal lung maturation. However, this hypothesis has remained
      untested due to the lack of a suitable animal model. In the hyt/hyt mouse primary
      hypothyroidism occurs due to a point mutation in the beta subunit of the thyroid
      stimulating hormone receptor of the thyroid gland, and it is transmitted in an
      autosomal recessive manner. We studied the effect of maternal betamethasone on
      fetal lung ultrastructure in hyt/hyt (hypothyroid) and Balb-c (euthyroid) mice.
      Hypothyroid mice were made euthyroid by T3 supplementation and mated to carry
      hypothyroid pups. Vehicle (n = 6) or betamethasone (n = 6) was injected
      intraperitoneally twice daily into the doe on days 16 and 17 of gestation. Fetal
      lungs on 18 days of gestation were subjected to ultrastructural morphometric
      analysis. The number of lamellar bodies per type II cell increased after
      betamethasone in Balb-c (2.10+/-0.31 vs. 3.43+/-0.37) and hyt/hyt (0.77+/-0.28
      vs. 3.85+/-0.26) mice. The alveolar-to-parenchymal ratio was less in the vehicle
      treated hyt/hyt (0.082+/-0.024) as compared with the vehicle-treated Balb-c
      (0.30+/-0.05) mice, while prenatal betamethasone increased the alveolar-to
      parenchymal ratio in the hyt/hyt (0.227+/-0.034) but not in the Balb-c (0.26+/
      0.04) mice. The glycogen-to-nucleus ratio was higher in betamethasone-treated
      hyt/hyt mice (1.46+/-0.20) when compared to vehicle-treated hyt/hyt (0.89+/-0.14)
      or Balb-c (1.01+/-0.17) or betamethasone-treated Balb-c (0.81+/-0.13) mice.
      Though tubular myelin was readily apparent in the airspace lumen of betamethasone
      treated Balb-c mice, it was absent in betamethasone-treated hyt/hyt fetal lungs.
      We conclude that fetal thyroid plays an important role in accelerating some
      aspects of fetal lung ultrastructural maturation from GC stimulation.

PMID- 10658827
TI  - Carnitine supplementation and ketogenesis by small-for-date neonates on medium
      and long-chain fatty acid formulae.
AB  - Carnitine is a key molecule in energy production from various substrates.
      Although it is generally believed that it plays no role in the metabolism of
      medium-chain triglycerides, quite a few data exist to the contrary. In the
      present study we investigated the effect of carnitine on ketogenesis in small-for
      date neonates fed formulae of equal caloric value and fat content that was
      predominantly long-chain triglycerides or medium-chain triglycerides (46% of
      total fat). According to our results there was a statistically significant
      interaction between carnitine and the chain length of the administered fat with
      respect to ketone production. Increased ketogenesis was only shown by the
      neonates receiving medium-chain triglycerides and carnitine. Our results provide
      further evidence for the involvement of carnitine in medium-chain triglyceride
      metabolism.

PMID- 10658829
TI  - Independent and combined effects of prolonged inhaled nitric oxide and oxygen on
      lung inflammation in newborn piglets.
AB  - Clinical use of nitric oxide (NO) is usually in conjunction with high oxygen
      concentrations, the effects of which may include lung neutrophil accumulation,
      apoptosis and upregulation of antioxidant enzyme activity. To define the effects
      of NO on neutrophils from young piglets and its relationship to lung neutrophil
      dynamics during hyperoxia we exposed thirty piglets to room air (RA), RA+NO (50
      ppm NO), O2 (FiO2> or =0.96) or O2+NO for 5 days. Ten additional animals breathed
      RA+NO or O2+NO, then recovered in RA for 3 days before sacrifice. Neutrophil CD18
      and intracellular oxidant production were measured by flow cytometry. Lung
      apoptosis were assessed by TUNEL assay. Lung myeloperoxidase, SOD and catalase
      were measured biochemically. When compared to RA group, there was significant
      reduction in neutrophil CD18 and intracellular oxidant production in the RA+NO
      group, but lung MPO was unchanged. The O2 and O2+NO groups did not differ in CD18
      expression or in intracellular oxidant production, but had significant increase
      in lung myeloperoxidase compared to the RA group. Apoptosis increased
      significantly only in the O2+NO group. The O2 group showed significantly
      increased lung SOD and catalase activity compared to the RA group, whereas the
      RA+NO and O2+NO groups did not. We conclude that inhaled NO at 50 ppm decreases
      neutrophil CD18 expression as well as intracellular oxidant production. However,
      this effect does not impact lung neutrophil accumulation during concurrent
      hyperoxia. The combination of NO and O2 exposure produces an increase in lung
      apoptosis. Finally, NO may prevent upregulation of SOD and catalase activity
      during hyperoxia, potentially increasing injury.

PMID- 10658830
TI  - Chronic bradykinin receptor blockade modulates neonatal renal function.
AB  - Recent data indicate that bradykinin participates in the regulation of neonatal
      glomerular function and also acts as a growth regulator during renal development.
      The aim of the present study was to investigate the involvement of bradykinin in
      the maturation of renal function. Bradykinin beta2-receptors of newborn rabbits
      were inhibited for 4 days by Hoe 140. The animals were treated with 300 microg/kg
      s.c. Hoe 140 (group Hoe, n = 8) or 0.9% NaCl (group control, n = 8) twice daily.
      Clearance studies were performed in anesthetized rabbits at the age of 8-9 days.
      Bradykinin receptor blockade did not impair kidney growth, as demonstrated by
      similar kidney weights in the two groups, nor did it influence blood pressure.
      Renal blood flow was higher, while renal vascular resistance and filtration
      fraction were lower in Hoe 140-treated rabbits. No difference in glomerular
      filtration rate was observed. The unexpectedly higher renal perfusion observed in
      group Hoe cannot be explained by the blockade of the known vasodilator and
      trophic effect of bradykinin. Our results indicate that in intact kallikrein
      kinin system is necessary for the normal functional development of the kidney.

PMID- 10658831
TI  - Influence of mild hypothermia after hypoxia-ischemia on the pharmacokinetics of
      gentamicin in newborn pigs.
AB  - The renal function is often affected in asphyxiated newborn infants. The
      pharmacokinetics of drugs like aminoglycosides eliminated through the kidneys may
      be impaired and require a different than usual dosage regimen. A decrease in body
      temperature is associated with a decrease in glomerular filtration rate and may,
      therefore, impair the elimination of aminoglycosides. When hypothermia is applied
      as neuronal rescue therapy after birth asphyxia, the pharmacokinetics of kidney
      eliminated drugs may be impaired even more. We used our well-established global
      hypoxia-asphyxia newborn pig model to evaluate the effect of mild hypothermia
      after hypoxia-ischemia on gentamicin pharmacokinetics. Newborn pigs underwent
      global hypoxia-ischemia followed by normothermia (39 degrees C) for 72 h (n = 8)
      or mild hypothermia (35 degrees C) for 24 h followed by normothermia (39 degrees
      C) for 48 h (n = 8). Gentamicin pharmacokinetics was studied after three
      gentamicin doses: before hypoxia-ischemia, after hypoxia-ischemia during mild
      hypothermia or normothermia, and during normothermia 48 h after the first dose.
      The gentamicin pharmacokinetics variables were calculated using a SAAM II
      program. Hypoxia-ischemia altered renal function and gentamicin pharmacokinetics.
      The gentamicin clearance correlated with the creatinine plasma concentration (r =
      0.89) and with the kidney pathology score (r = 0.55). There was no significant
      difference in gentamicin pharmacokinetics at 35 and 39 degrees C in newborn pigs
      after hypoxia-ischemia. The gentamicin pharmacokinetics variables were not
      different in the hypothermic or normothermic pigs after all three studied doses.
      Mild hypothermia for 24 h after hypoxia-ischemia does not affect gentamicin
      pharmacokinetics.

PMID- 10658832
TI  - Vascular potassium channels mediate oxygen-induced pulmonary vasodilation in
      fetal lambs.
AB  - The pulmonary vascular resistance decreases at birth secondary to release of
      endothelium-derived nitric oxide (EDNO). EDNO release is a calcium-dependent
      process, and endothelial potassium (K+) channels regulate intracellular calcium
      flux. We investigated the hypothesis that potassium channels mediate oxygen
      induced pulmonary vasodilation and EDNO release in fetal lambs. We instrumented
      18 near-term fetal lambs at 122-126 days of gestation to measure pulmonary
      pressures, flow, and resistance. We studied hemodynamic effects of (1) 100%
      oxygen; (2) pinacidil, an ATP-sensitive K+ (KATP) channel agonist, and (3) S
      nitroso-N-acetylpenicillamine (SNAP), a NO donor. We studied the effects of
      glybenclamide, a K(ATP) channel antagonist, tetraethylammonium chloride (TEA), a
      preferential KCa channel antagonist, and nitro-L-arginine (NLA), an NO synthase
      inhibitor, on the response to some of the above agents. Oxygen-induced pulmonary
      vasodilation was inhibited by both glybenclamide and TEA, indicating that K(ATP)
      and K(Ca) channels mediate pulmonary vasodilator response to oxygen. Blocking NO
      synthesis with NLA inhibited pinacidil-mediated pulmonary vasodilation,
      indicating that K(ATP) channel activation stimulates NO release. SNAP-mediated
      pulmonary vasodilation was inhibited by TEA, but not glybenclamide, indicating
      that K(Ca) channels, but not K(ATP) channels, mediate effects of NO on vascular
      smooth muscle relaxation. In conclusion, K+ channels mediate oxygen-induced
      pulmonary vasodilation in fetal lambs. K(ATP) channels appear to mediate EDNO
      release, while K(Ca) channels probably mediate NO effects on vascular smooth
      muscle.

PMID- 10658833
TI  - Competition for enzymes in metabolic pathways: implications for optimal
      distributions of enzyme concentrations and for the distribution of flux control.
AB  - The structures of biochemical pathways are assumed to be determined by
      evolutionary optimization processes. In the framework of mathematical models,
      these structures should be explained by the formulation of optimization
      principles. In the present work, the principle of minimal total enzyme
      concentration at fixed steady state fluxes is applied to metabolic networks.
      According to this principle there exists a competition of the reactions for the
      available amount of enzymes such that all biological functions are maintained. In
      states which fulfil these optimization criteria the enzyme concentrations are
      distributed in a non-uniform manner among the reactions. This result has
      consequences for the distribution of flux control. It is shown that the flux
      control matrix c, the elasticity matrix epsilon, and the vector e of enzyme
      concentrations fulfil in optimal states the relations c(T)e = e and epsilon(T)e =
      0. Starting from a well-balanced distribution of enzymes the minimization of
      total enzyme concentration leads to a lowering of the SD of the flux control
      coefficients.

PMID- 10658834
TI  - Fitness distributions in evolutionary computation: motivation and examples in the
      continuous domain.
AB  - Evolutionary algorithms are, fundamentally, stochastic search procedures. Each
      next population is a probabilistic function of the current population. Various
      controls are available to adjust the probability mass function that is used to
      sample the space of candidate solutions at each generation. For example, the step
      size of a single-parent variation operator can be adjusted with a corresponding
      effect on the probability of finding improved solutions and the expected
      improvement that will be obtained. Examining these statistics as a function of
      the step size leads to a 'fitness distribution', a function that trades off the
      expected improvement at each iteration for the probability of that improvement.
      This paper analyzes the effects of adjusting the step size of Gaussian and Cauchy
      mutations, as well as a mutation that is a convolution of these two
      distributions. The results indicate that fitness distributions can be effective
      in identifying suitable parameter settings for these operators. Some comments on
      the utility of extending this protocol toward the general diagnosis of
      evolutionary algorithms is also offered.

PMID- 10658835
TI  - A mathematical model predicting the frequency of aberrant rearrangements in the T
      cell receptor gene.
AB  - The T-cell receptor (TCR) genetic loci undergo an orderly process of
      recombination in ontogeny in order to generate a diverse array of antigen
      receptors. Normally occurring, out-of-frame and incomplete rearrangements produce
      non-productive TCR transcripts. Abnormalities in the rearrangement process occur
      at very low frequencies but may predominate in inborn errors of recombination.
      Detecting these abnormalities in surviving pools of lymphocytes is difficult and
      typically focuses on identification of abnormally rearranged alleles or on
      detecting abnormalities in recombinase proteins. Thus, there currently exists no
      rapid screening method to identify aberrant V(D)J recombination. To address this
      issue, a mathematical model was developed to predict the error rate from the
      measured proportions of different non-productive TCR alleles. Since the
      proportions of different non-productive rearrangements vary in a characteristic
      fashion in response to abnormalities in the recombination process, the
      mathematical model presented here provides a tool to indirectly assess the error
      rate of TCR recombination. The model was applied to a group of patients with
      Omenn's syndrome, most of whom had an unknown primary defect. The results
      indicate that these patients had a > 90% rate of aberrant TCR recombination.

PMID- 10658836
TI  - Evolution of the genetic code: the nonsense, antisense, and antinonsense codes
      make no sense.
AB  - According to the molecular recognition theory, the complementarity of the sense
      and nonsense DNA strands is reflected in a complementarity of polypeptides and
      the corresponding nonsense polypeptides. A comparison of the sense and nonsense
      code matrices, and of the antisense and antinonsense code matrices, either by
      visual inspection or by comparing the corresponding hydrophobicity matrices (e.g.
      by simply adding them together), revealed no complementarity of these pairs of
      matrices in terms of possible attractive physical forces. Instead, it was evident
      that the codes divide the amino acids into two major groups: hydrophilic and
      hydrophobic, a division which is directly correlated with the folding property of
      proteins. A simple primordial genetic code distinguishing between these two types
      of amino acids would have been capable of generating three-dimensionally folded
      peptides, which could stabilize coding RNAs by forming ribonucleoprotein
      complexes. This evolutionary scheme is reflected in the present organisation of
      information processing and storage in essentially all organisms. RNAs are
      processed and translated into proteins by ribonucleoproteins, while other steps
      in information retrieval and processing, such as DNA replication, transcription,
      protein folding and posttranslational processing, are catalyzed by proteins. This
      shows that the evolution of DNA as an information storage medium was a secondary
      event, unrelated to the evolution of the genetic code. From the primordial
      hydrophilic/hydrophobic (f.ex. Leu/Arg) code, evolution proceeded by introduction
      of a catalytic amino acid (Ser). The further evolution of the code has mainly
      served to increase the number of functional hydrophilic amino acids, since there
      has not been a great advantage in increasing the number of structural,
      hydrophobic amino acids. At some stage during the evolution of the genetic code,
      double-stranded DNA was introduced as a maximally safe genetic copy of RNA. This
      required the action of highly specific enzymes, and was therefore preceded by the
      refinement of the genetic code. As a conclusion of this evolutionary scheme, it
      can be inferred that, in general only the sense strand encodes proteins.

PMID- 10658837
TI  - Protein evolution drives the evolution of the genetic code and vice versa.
AB  - A model for the developmental pathway of the genetic code, grounded on group
      theory and the thermodynamics of codon-anticodon interaction is presented. At
      variance with previous models, it takes into account not only the optimization
      with respect to amino acid attributes but, also physicochemical constraints and
      initial conditions. A 'simple-first' rule is introduced after ranking the amino
      acids with respect to two current measures of chemical complexity. It is shown
      that a primeval code of only seven amino acids is enough to build functional
      proteins. It is assumed that these proteins drive the further expansion of the
      code. The proposed primeval code is compared with surrogate codes randomly
      generated and with another proposal for primeval code found in the literature.
      The departures from the 'universal' code, observed in many organisms and cellular
      compartments, fit naturally in the proposed evolutionary scheme. A strong
      correlation is found between, on one side, the two classes of aminoacyl-tRNA
      synthetases, and on the other, the amino acids grouped by end-atom-type and by
      codon type. An inverse of Davydov's rules, to associate the amino acid end atoms
      (O/N and non-O/non-N) of 18 amino acids with codons containing a weak base (A/U),
      extended to the 20 amino acids, is derived.

PMID- 10658838
TI  - Dynamic patterns in the locomotion and feeding behaviors by the placozoan
      Trichoplax adhaerence.
AB  - The placozoan Trichoplax adhaerence is one of the most primitive multi-cellular
      organisms, and moves about accompanying perpetual changes in its shape. Changes
      in position, locomotion velocity and the outer shape of the organism were
      monitored quantitatively with use of a computer image analysis, and their dynamic
      patterns in free locomotion and upon feeding were analyzed in terms of non-linear
      dynamics. The organism changed its behavioral patterns discontinuously in
      response to various concentrations of yeast extracts (food). (1) At low
      concentrations, the organism moved fast with perpetual random changes in shape.
      Both locomotion velocity and shape changes exhibited 1/f fluctuations. (2) At
      high concentrations, the shape of the organism as well as the locomotion
      exhibited oscillations with periods of about 8 min. These limit cycle
      oscillations bifurcated into the period 2 at the highest concentration tested.
      The organism flattened more strongly and the locomotion was more reduced on the
      whole at higher concentrations. (3) At the intermediate concentrations, two
      patterns as monitored above appeared: one pattern continued for a while and
      switched to the other abruptly. (4) The average square displacement of the
      organism increased linearly with time in all cases, indicating that the
      locomotion is a Brownian movement. In this way, the feeding behaviors by the
      placozoan are organized as successive co-operative transitions among non-linear
      dynamic states.

PMID- 10658839
TI  - A hypothetical model of the influence of inorganic phosphate on the kinetics of
      pyruvate kinase.
AB  - This paper presents a simple solution to the problem of approximating the
      calculated curve of reaction progress to the measured curve which is usually
      disturbed by initial oscillation of auxiliary lactate dehydrogenase (LDH)
      reaction. The experiments leading to the determination of the apparent Km for
      phosphoenolpyruvate (PEP) and Vm were performed. For precise estimation of
      kinetic parameters (Km and Vm) of the M1 isozyme of pyruvate kinase (PK),
      measured by coupling it to LDH reaction, the sequence of Michaelis-Menten for
      pyruvate kinase and second-order kinetics for lactate dehydrogenase reaction as
      well as a non-zero initial concentration of lactate was assumed. The functions of
      apparent Km and Vm of pyruvate kinase with respect to phosphate concentration,
      computed by an analysis of the total reaction progress curves, indicate that the
      reaction mixture contains an uncompetitive inhibitor of pyruvate kinase, and that
      the phosphate binds this inhibitor. The proposed simple mathematical model of
      pyruvate kinase Km and Vm increase by inorganic phosphate assumes that the
      pyridine nucleotides (NAD-derivatives) are kinase inhibitors. An approximate
      dissociation constant for pyridine nucleotides-phosphate complex and true Km of
      pyruvate kinase for PEP were estimated. The proposed model fits exactly the
      entire measured reaction process.

PMID- 10658840
TI  - Computational modeling of an early evolutionary stage of the nervous system.
AB  - The object of this work is to create a computational model that examines the
      early evolution of the nervous system in relation to adaptive behavior. The main
      questions are: how did the nervous system and the most primitive forms of
      intelligence came into being, how a system can be organized during evolution that
      is able to ensure the adaptive behavior of a being, what are the basic rules of
      construction that are sufficient to create a workable nervous system without
      specifying the details of the construction. The biological bases of the model are
      the phyla Cnidaria and Porifera as they stand at the beginning of the genesis of
      nervous organization. We found in our model that in a network of homogenous
      epithelial-like cells, which is considered the starting point of the genesis of
      the nervous system, the changes that have positive influence on the behavior are
      those that make the spreading of the electric potential more efficient. It can
      cause the increase of the effectiveness of the behavior by itself without
      creating new specific cell-types. There are some alternatives to increasing the
      effectiveness of spreading of stimuli, for example increasing the value of
      biophysical parameters of the cells, or increasing the density of nerve cells and
      the number of synapses. If during the evolution a sort of cell comes into being
      that is able to conduct electrical stimuli--even in a rudimentary way--it can
      increase the adaptivity of behavior by itself without the need for specific
      information of how to organize the construction of this system.

PMID- 10658841
TI  - Learning process by goldfish and its use of a local site as a map.
AB  - The issue we address is whether an animal knows or understands the significance
      of learning. We constructed an animal's own conceptualization via resolving a
      paradox underlying the process of learning. We found a kind of self-similar
      pattern in the behavior of goldfish resolving a paradoxical experimental problem.
      The pattern can be considered as a solution to the paradox in the experiment. An
      animal's own learning should be revised through solving paradoxes. The dualism of
      mechanistic thinking and vitalism can thus be avoided.

PMID- 10658842
TI  - Illness narratives: time, hope and HIV.
AB  - Life threatening illness, such as HIV/AIDS, also threaten people's sense of
      identity and taken-for-granted assumptions about the temporal framing of their
      lives. In response, people often experience transformations in values,
      spirituality and life priorities. Drawing on a combined quantitative and
      qualitative study of people living with HIV/AIDS in Australia, three different
      narratives that people use to make sense of their illness experience are
      identified: linear restitution narratives, linear chaotic narratives and
      polyphonic narratives. Linear illness narratives colonise the future, assuming
      that the future can be controlled through human action. They emphasise a faith in
      medical science, tend to be secular and self-centred and assume the end of life
      to be in the distant future. Hope is focused on concrete outcomes such as
      improved health or material possessions. Linear narratives can be either
      restitutive or chaotic. Restitutive linear narratives anticipate a life that will
      mirror the narrative. Chaotic linear narratives anticipate a life that will fail
      to meet the linear ideal resulting in despair and depression. In contrast,
      polyphonic illness narratives are oriented toward the present, emphasising the
      unpredictability of the future. These narratives tend to include spiritual
      experiences, a communally oriented value system, and to recount increased self
      understanding and the gaining of new insights as a consequence of their illness.
      Hope in polyphonic narratives is more abstract and focused on a celebration of
      mystery, surprise and creativity.

PMID- 10658843
TI  - Social capital, SES and health: an individual-level analysis.
AB  - Stimulated by the finding (Kawachi et al., 1997) that social capital in
      communities may mediate the relationship between income inequality and health
      status, this article describes relationships between individual-level elements of
      social capital--trust, commitment and identity in the social-psychological
      dimension; participation in clubs and associations and civic participation in the
      action dimension--and self-rated health status, before and after controlling for
      human capital (socioeconomic status measured by income and education), using
      survey data collected in Saskatchewan, Canada (n = 534, 40% response rate).
      Income (P = 0.001) and education (P < 0.001) were related to health in the
      expected directions. Both income (P = 0.002) and education (P = 0.004) were
      related to health among the elderly; education (P = 0.035) to health among the
      middle-aged; and neither among the youthful respondents. Frequency of
      socialization with work-mates (P = 0.019) and attendance at religious services (P
      = 0.034) had the strongest (and positive) relationships with health of the social
      engagement questions, even after controlling for human capital, and participation
      in clubs and associations was positively related to health among the elderly (P =
      0.009). But for commitment to one's own personal happiness (P = 0.039), trust,
      commitment and identification of various kinds were not significantly related to
      health. Civic participation was also unrelated to health. The main conclusion is
      that little evidence was found for compositional effects of social capital on
      health. Secondary findings are that the relationship between SES and health was
      the same for men and women and strongest among the elderly; that socialization
      with colleagues from work is relevant and that attendance at religious services
      and participation in clubs are related to health for the elderly.

PMID- 10658844
TI  - Well being, work environment and work accidents.
AB  - We examine factors that influence accident proneness among employees. We agree
      that the determinants of accident proneness include organizational, emotional and
      personal factors. Using logistic regression we estimated three models, and their
      predictability for accident proneness among sample of 200 injured workers
      interviewed upon entering hospital emergency wards in Israel. Work injuries were
      not contingent on age, religion, nor education. The effects of gender were strong
      but non-significant. Subcontracted and higher-paid workers are more likely to get
      repeat injuries. Prior injury experience sensitized employees to stronger
      perceptions of risk associated with unsafe practices. Large family households,
      ameliorates stress feelings and lessens the likelihood of accident proneness
      while poor housing conditions have the opposite effect. The full model
      demonstrates considerable prediction of injuries when focusing on type of
      employment, personal income level, being involved in dangerous jobs, emotional
      distress and a poor housing environment. The model contains most of the
      significant results of interest and provides a high level of predictability for
      work injuries.

PMID- 10658845
TI  - Social class differences in mortality using the new UK National Statistics Socio
      Economic Classification.
AB  - Social class differences in health in the UK have usually been demonstrated by
      the Registrar General's social classification (RGSC). It is being replaced by the
      new UK National Statistics Socio-Economic Classification (NS-SEC). The NS-SEC is
      explicitly based on differences between employment relations and conditions. The
      mechanisms underlying social class differences in health remain debatable. Some
      studies have hypothesised that class differences in work characteristics and
      employment conditions may explain part of the observed class differences in
      health. This study investigates the associations of the NS-SEC and other measures
      of socio-economic status (SES) with mortality outcomes in a 7-year panel study
      representative of British private households and their members (the British
      Household Panel Survey, n = 10264). The NS-SEC was neither significantly
      associated with mortality for respondents of all ages nor with mortality for a
      younger subsample who were under 65 years at the initial survey. Other measures
      of SES, especially income and housing tenure showed significant patterns of
      inequalities in mortality. It may be useful to use other measures of SES along
      with the NS-SEC when analysing social inequalities in health and mortality.

PMID- 10658846
TI  - Menorrhagia in general practice--disease or illness.
AB  - Menorrhagia is a common presentation in primary care. The gynaecological
      literature defines menorrhagia, as the loss of 80 ml or more of blood per period
      and guidelines for treatment are based on this definition. There is extensive
      evidence that the majority of women who complain of heavy bleeding do not fit the
      medical definition. We interviewed women presenting with menorrhagia to explore
      their perceptions and their initial interaction with the medical profession. A
      distinct illness model emerged. Women had a precise understanding of their
      complaint, so that a change in her cycle was indicative of a problem to many
      women, without reference to outside criteria. Women attached particular
      importance to how they felt and to their ability to function and they rejected
      the medical emphasis on blood loss evaluation. Many women were dissatisfied with
      the consultation and experienced doctors as being dismissive of their problem.
      They were seeking an explanation for why their periods had changed and had
      concerns that related to their understanding of menstrual bleeding. Interviewees
      were unsure whether period problems could be described as illness, and what range
      of disturbance was normal. It is suggested that the disease model of menorrhagia
      is not relevant to the majority of women with this complaint. It is proposed that
      the disease model be replaced with illness models.

PMID- 10658847
TI  - Income-related health inequality in Canada.
AB  - This study uses data from the 1994 National Population Health Survey and applies
      the methods developed by Wagstaff and van Doorslaer (1994, measuring inequalities
      in health in the presence of multiple-category morbidity indicators. Health
      Economics 3, 281-291) to measure the degree of income-related inequality in self
      reported health in Canada by means of concentration indices. It finds that
      significant inequalities in self-reported ill-health exist and favour the higher
      income groups--the higher the level of income, the better the level of self
      assessed health. The analysis also indicates that lower income individuals are
      somewhat more likely to report their self-assessed health as poor or less-than
      good than higher income groups, at the same level of a more 'objective' health
      indictor such as the McMaster Health Utility Index. The degree of inequality in
      'subjective' health is slightly higher than in 'objective' health, but not
      significantly different. The degree of inequality in self-assessed health in
      Canada was found to be significantly higher than that reported by van Doorslaer
      et al. (1997, income related inequalities in health: some international
      comparisons, Journal of Health Economics 16, 93-112) for seven European
      countries, but not significantly different from the health inequality measured
      for the UK or the US. It also appears as if Canada's health inequality is higher
      than what would be expected on the basis of its income inequality.

PMID- 10658848
TI  - A multilevel analysis of income inequality and cardiovascular disease risk
      factors.
AB  - Recent research has suggested that inequality in the distribution of income is
      associated with increased mortality, even after accounting for average income
      levels. Using data from the Behavioral Risk Factor Surveillance System (BRFSS),
      we investigated whether inequality in the distribution of income within US states
      is related to the prevalence of four cardiovascular disease risk factors (body
      mass index (BMI), history of hypertension, sedentarism, and smoking). Multilevel
      models (including both state-level and individual-level variables) were used to
      examine associations of state inequality with risk factor levels before and after
      adjustment for individual-level income. For three of the four risk factors
      investigated (BMI, hypertension, and sedentarism), state inequality was
      associated with increased risk factor levels, particularly at low income levels
      (annual household incomes <$25,000), with associations persisting after
      adjustment for individual-level income. Inequality was also positively associated
      with smoking, but associations were either stronger or only present at higher
      income levels. Associations of inequality with the outcomes were statistically
      significant in women but not in men. Although not conclusive, findings for three
      of the four risk factors are suggestive of a contextual effect of income
      inequality, particularly among persons with lower incomes.

PMID- 10658850
TI  - Injections and the fear of death: an essay on the limits of biomedicine among the
      Dagomba of northern Ghana.
AB  - This article offers a cultural ("indigenous") explanation of why people in their
      quest for therapy sometimes reject biomedicine. The argument is that in the
      current debate over the power of biomedicine, there is a lack of scrutiny of its
      "failures", i.e. of why people occasionally refuse to accept the offers of
      biomedicine and its most powerful therapy, injection-therapy. After introducing
      the problem, the relevant literature and the methods used, the article proceeds
      by first using historical material regarding vaccination campaigns and the
      treatment of endemic diseases in Ghana and comparative data from elsewhere in
      Africa to show that people may be ambivalent and have a mixed view of the power
      of biomedicine. In the context of their experiences, people (possibly, in
      particular, older ones) have come to know both the (early) failures as well as
      the successes of injection-therapy. Turning to the ethnographic present (1990
      1997) the record of Dagomba notions of health and illness as well as two cases
      are analyzed to define this ambiguity also among younger members of Dagomba
      culture. Thus, the article oscillates between ethnography and history to define
      people's ambivalence and the conflict between biomedicine and local
      understandings.

PMID- 10658849
TI  - Between fear and relief: how rural pregnant women experience foetal ultrasound in
      a Botswana district hospital.
AB  - Ultrasound technology has achieved almost universal coverage in industrialised
      countries with particular importance in antenatal surveillance. Its routine use
      has, however, been viewed critically from medical as well as from sociological
      perspectives. Studies on women's perception of ultrasound underline the crucial
      role of client provider communication supporting the technical procedure.
      Ultrasound is now increasingly available in developing countries. Little is known
      about how clients in these settings perceive the technology. This study was
      concerned with women's experience of ultrasound scanning in an African district
      hospital setting and how their experience concurs with the health professionals'
      views about the new technology. The study was qualitative and used semi
      structured in-depth interviews with 41 clients and structured non-participant
      observation of the examination process, as well as semistructured interviews with
      health staff. Most women viewed ultrasound as being beneficial. Some expressed
      considerable fear. The quality of client-provider interaction played a decisive
      role in how the procedure was perceived. Many statements, however, reflect
      women's overestimation of the diagnostic power of ultrasound and prenatal
      therapeutic possibilities. Technology and its often expatriate providers tend to
      be mystified and at the same time non-technological procedures provided by local
      staff in the context of normal history taking and antenatal care undervalued.
      Health staff expressed very positive views of ultrasound. They admitted, however,
      that since the availability of ultrasound they were tempted to take histories and
      physical examinations less thoroughly than before. Irrational expectations from
      the clients' side and unindicated overuse of ultrasound by health professionals
      may in the long run interact in a way that possibly undermines the quality and
      rational utilisation of antenatal care and respective referral guidelines.
      Indications for the use of ultrasound must be clearly specified within specific
      societal contexts and mechanism of ensuring adherence to these criteria be
      established. Communication with patients and appropriate information about the
      benefits and limitations of ultrasound are essential to alleviate fear, and to
      discourage irrational expectations and demand.

PMID- 10658851
TI  - Factor and subscale structure of a parental health locus of control instrument
      (parental health beliefs scales) for use in a mainland United States Puerto Rican
      community.
AB  - This study was undertaken to determine whether the subscale structure of an
      instrument used to measure parental health locus of control is a valid
      representation of the concept of locus of control in the Puerto Rican community.
      Ethnocultural differences in values and attitudes may create different
      conceptualizations of questionnaire items, which may impact on the subscale
      factor loadings for these items. Four hundred and twenty parents of Puerto Rican
      ethnicity living in a mainland inner city community in the United States
      completed the Parental Health Beliefs Scales (PHBS) instrument, which was
      developed to measure parental locus of control regarding their children's health.
      Results were subject to exploratory factor analysis. The resultant factor
      structure was then compared to other published factor structures by confirmatory
      factor analysis. Exploratory factor analysis results show a new five factor
      solution. Compared to two previously published factor structures for this
      instrument, the new five factor structure has a better goodness of fit for this
      Puerto Rican study sample. Through item analysis, we were able to refine the
      final structure into a four factor, 15 item instrument. We conclude that the new
      factor structure for the PHBS creates an instrument with subscales that reflect
      Puerto Rican cultural beliefs and values, especially as it pertains to locus of
      control issues (e.g. respect of professionals, collectivism, and the importance
      of fate). When working with ethnocultural minority groups, the health services
      researcher needs to be certain that the research instruments used are culturally
      appropriate and sensitive.

PMID- 10658852
TI  - The sexual behavior of married Mexican immigrant men in North Carolina.
AB  - In the southern United States, North Carolina has attracted an unprecedented
      influx of Hispanic immigrants in the 1990s. Detailed data on the sexual behavior
      of these recent immigrants are lacking. This exploratory study used two methods,
      a survey and qualitative interviews. For both methods, participants were
      recruited using convenience sampling. All study participants were first
      generation Mexican immigrants who had lived in North Carolina for at least six
      consecutive months. The survey, administered face-to-face, explored the sexual
      attitudes and behavior of 43 married Mexican men living in North Carolina. The
      qualitative interviews, conducted with men (n = 20) and women (n = 19), explored
      immigrants' perceptions of extramarital sex and sexually transmitted diseases
      (STDs). The study's results suggest that the sexual behavior of 'unaccompanied'
      married Mexican immigrant men, living alone in North Carolina, differs, at least
      in degree if not in kind, from that of 'accompanied' married men, residing in the
      state with their wives. Unaccompanied men who participated in the survey reported
      more lifetime sexual partners, more partners in the previous year, more
      extramarital partners and more contact with prostitutes than accompanied survey
      respondents. The qualitative interviews suggest that unaccompanied men's peculiar
      status as 'single' men in North Carolina may provide them with both motive and
      opportunity to have extramarital sexual relationships and that few married
      Mexican men and women perceive STDs as relevant to their lives. Overall, the
      study supports the need for male- and couple-focused STD prevention interventions
      for Hispanic immigrants.

PMID- 10658853
TI  - Highway cowboys, old hands, and Christian truckers: risk behavior for human
      immunodeficiency virus infection among long-haul truckers in Florida.
AB  - This paper reports the results of ethnographic research to describe risk for
      human immunodeficiency virus (HIV) infection among long-haul truck drivers and
      the contexts and factors that influence risk and protective behaviors. Drivers
      were selected using purposive and snowball sampling at trucking-related
      businesses along major truck routes in Florida. Interview information was used to
      categorize truckers' levels of potential risk, describe behavioral
      characteristics of each group, identify sex partners, and assess perceptions of
      the risk of HIV infection. One-third of the 71 men interviewed had frequent
      sexual intercourse on the road with multiple partners, but few ever used condoms.
      Commercial sex workers were their most frequent partners for on-the-road sex. The
      risk was compounded by occupational conditions, which motivated truckers to drive
      long hours, often using drugs to stay alert. Sex, alcohol, and drugs were
      perceived as quick, effective stress relievers during downtime on long, lonely
      trips. Despite their high-risk behaviors, truckers tended to consider themselves
      at low risk for HIV infection and expressed a number of misconceptions regarding
      HIV transmission. For example, many truckers did not associate HIV risk with
      heterosexual contact or think that condoms were effective in preventing HIV
      transmission. In addition, many truckers maintained strong homophobic and anti
      government opinions that reinforced their suspicion of safe-sex messages. These
      findings suggest that high-risk sexual behavior is common among long-haul
      truckers in the US, who may be at risk for HIV infection primarily because of
      unprotected sexual intercourse with multiple sex partners. Also, drug use may be
      associated with HIV risk behavior. The authors recommend establishing prevention
      programs that are developed by and for truckers, determining HIV seroprevalence
      rates of truckers, addressing drug and alcohol abuse among truckers, and altering
      industry policy that keeps truckers on the road too long for their own and
      others' safety.

PMID- 10658854
TI  - School counselors' accuracy in identifying adolescents at risk for dropping out.
AB  - School counselors were asked to identify, using qualitative judgments alone,
      adolescents who they believed were at moderate risk for dropping out. These
      students were then administered a dropout prediction scale. Results indicated
      that the school counselors accurately identified potential dropouts. The paper
      concludes with a discussion of the ties between dropout identification and
      consultation with teachers.

PMID- 10658855
TI  - Psychosocial correlates of contraceptive practices during late adolescence.
AB  - This article reviews the literature on psychosocial correlates of contraceptive
      practices among sexually active late adolescents (primarily college
      undergraduates). It seeks to help identify subgroups of adolescents who either do
      not use or misuse contraceptive means, putting them at risk for unwanted
      pregnancy, AIDS, and other sexually transmitted diseases. The intent is to
      promote further research on those variables with the most potential for
      predicting contraceptive behaviors, which will assist in the development and
      implementation of effective prevention and intervention programs.

PMID- 10658856
TI  - What does it take to have a positive impact on minority students' college
      retention?
AB  - This paper describes the Young Scholars Program (YSP), which seeks to expand the
      pool of African American and other underrepresented minority youth who aspire to
      attend college, and to help them meet entrance requirements and successfully
      obtain a college degree. Quarter-by-quarter data for the first two groups of YSP
      students entering The Ohio State University were promising. Their retention rates
      approximated university averages, while comparison groups showed lower levels of
      retention. It was concluded that the many facets of the Young Scholars Program,
      as well as the students' positive reputation among family members, peers, and
      teachers, produced strong motivation, ability, and determination to succeed.

PMID- 10658857
TI  - Racial socialization and racial identity: can they promote resiliency for African
      American adolescents?
AB  - Although there is a rich body of research on resiliency, much of the literature
      fails to include minority youths or does not take into consideration their
      distinctive racial and environmental circumstances. Additionally, limited
      attention has been given to protective factors that are unique to nonmajority
      populations. This article posits that racial socialization and racial identity
      protect urban African American adolescents against some of the harmful effects of
      a discriminatory environment. These factors are hypothesized to influence
      academic achievement-an indicator of resiliency that has been used in many
      studies. A theoretical framework is provided that combines character development
      in a hostile environment, bicultural identity, and urban stress models.
      Implications for practice and future research are discussed.

PMID- 10658858
TI  - Intimidation and violence by males in high school athletics.
AB  - This study examined verbal intimidation (VI), physical intimidation (PI), and
      physical violence (PV) in high school athletics, both by program and by sport.
      Antecedents were identified via principal component analysis; they included
      contextual setting, attitude, pressure, and coaching. Multiple regression
      analysis was used to assess relationships between antecedents and VI, PI, and PV.
      Coaching was the only significant predictor in 9 of 15 regression analyses of
      overall VI, PI, and PV, and one of two significant predictors in 4 of 6
      additional analyses. Coaching was the only significant predictor of VI in
      basketball and football, PI in football and soccer, and PV in basketball and
      soccer. In addition to coaching, contextual setting was a significant predictor
      of PI in basketball, attitude was a significant predictor of PV in football, and
      pressure was a significant predictor of VI in soccer. The implications of these
      findings are discussed.

PMID- 10658859
TI  - Teens' concerns: a national evaluation.
AB  - Previous research found that adolescents in Toledo, Ohio, utilized a peer
      listening phone service predominantly for four reasons: to discuss peer
      relationships, family problems, and sexuality issues, as well as to have someone
      "just to talk to." The present study investigated whether adolescents in other
      areas of the United States used such services for similar reasons. Data were
      collected at four sites-Toledo, Los Angeles (California), Martinsville
      (Virginia), and Syracuse (New York)-over the course of one year. The results
      indicated that the callers were predominantly female and of high school age. The
      most frequently discussed issue was peer relationships (46% to 60%), regardless
      of site. Another frequent topic at all sites was family problems (10% to 20%).
      Other concerns varied by site.

PMID- 10658861
TI  - Sources of self-identity among Turkish adolescents.
AB  - As part of the International Self-Identity Research Project, this study explored
      sources of identity among Turkish adolescents. The interview sample consisted of
      three male and three female high school students in Ankara, Turkey. The results
      indicated that social, familial, personal, physical, and moral-ethical dimensions
      contributed to adolescents' definitions of self, but to different degrees. Social
      and familial dimensions were very influential and were used as reference points
      for defining self in other areas. Physical and personal aspects of identity were
      also apparent, but were not as salient as social and familial dimensions.
      Patriotism and religion played a role in moral-ethical identity. Overall, self
      identity influenced emotional state, cognitive and behavioral functioning, and
      social relations to a significant degree.

PMID- 10658860
TI  - Massage and music therapies attenuate frontal EEG asymmetry in depressed
      adolescents.
AB  - EEG asymmetry, specifically greater relative right frontal activation, is
      associated with negative affect. Depressed adults show stable patterns of this
      asymmetry. The present study assessed the effects of massage therapy and music
      therapy on frontal EEG asymmetry in depressed adolescents. Thirty adolescents
      with greater relative right frontal EEG activation and symptoms of depression
      were given either massage therapy (n = 14) or music therapy (n = 16). EEG was
      recorded for three-minute periods before, during, and after therapy. Frontal EEG
      asymmetry was significantly attenuated during and after the massage and music
      sessions.

PMID- 10658862
TI  - A specialized apperception test for ambulatory-impaired adolescents.
AB  - A specialized apperception test for physically impaired adolescents was
      developed, and a pilot was conducted using ten nonimpaired and ten impaired
      adolescents. Ten cards depicting various scenes with physically impaired male and
      female models were designed to elicit themes that may be particularly relevant
      for this adolescent population. Two raters evaluated how well each card elicited
      issues identified in the literature as pertinent to physically challenged
      adolescents.

PMID- 10658863
TI  - Restrained drinking and cognitive control among adolescents.
AB  - The present study investigated restrained drinking and self-control in relation
      to alcohol consumption and problem drinking in a sample of adolescents. One
      hundred ninety-eight high school students (97 males and 101 females; mean age =
      16.45 years) completed questionnaires that assessed levels of alcohol
      consumption, problem drinking, restrained drinking, and cognitive self-control.
      The findings were similar for males and females: higher levels of restrained
      drinking, as measured by cognitive emotional preoccupation (CEP), predicted
      higher levels of alcohol consumption and problem drinking. Moreover, it was high
      CEP in combination with a low score on a general measure of cognitive self
      control that differentiated problem drinking from high levels of drinking. The
      results are consistent with previous research on young adults. The findings are
      discussed in relation to Baumeister and Heatherton's (1996) model of self
      regulation failure.

PMID- 10658864
TI  - Depression and stress in street youth.
AB  - The present study explored stress and depression levels in Canadian street youth,
      as well as the methods they used to cope. Twenty-seven street youth and 27
      nonrunaway peers responded to a questionnaire investigating history of running
      away, depression level, coping strategies, family history, and stress. Analyses
      revealed that stress and depression were positively correlated for the street
      youth, and that these youth had higher levels, compared with nonrunaways, of
      both. There were also differences in coping strategies: street youth were more
      likely to engage in acts of self-harm and to use drugs and alcohol, while
      nonrunaways more frequently resorted to productive problem solving and
      disclosure/discussion with someone they trust.

PMID- 10658865
TI  - Nondelinquent youths' stealing behavior and their perceptions of parents, school,
      and peers.
AB  - Correlates of stealing behavior were investigated in a sample of 167
      nondelinquent 10- to 15-year-olds. Stealing was related to youths' attitudes
      toward parents and school, as well as reasons for stealing. Stealing was most
      frequent among older males. Attitude toward school was most consistently related
      to stealing behavior, though perceptions of family's values and the consequences
      of stealing were also important. Interventions with youths at risk for continued
      covert antisocial behaviors are discussed.

PMID- 10658866
TI  - School culture: exploring the hidden curriculum.
AB  - Educators frequently overlook school culture. This article encourages teachers
      and administrators to gain a more complete picture of the school environment
      through an exploration of the symbolic nature of the hidden, or implicit,
      curriculum. A historical overview of the influence of the hidden curriculum on
      the educational process is presented. In addition, a checklist for examining
      symbolic aspects of the school environment is provided.

PMID- 10658867
TI  - Identity development of homosexual youth and parental and familial influences on
      the coming out process.
AB  - This paper examines the literature on identity development of homosexual youth,
      and parental and familial influences on the coming out process. Research
      indicates that homosexual adolescents who have a close relationship with their
      parents and families tend to come out at a younger age and to experience more
      positive identities than do those who have a poor relationship.

PMID- 10658868
TI  - Ecological factors associated with adolescent pregnancy: a review of the
      literature.
AB  - Adolescent pregnancy, the disproportionate number of births to unmarried
      adolescents, the potential disadvantages for both mothers and their children, and
      the commensurate costs to society have received the attention of researchers in a
      variety of disciplines. This article reviews and synthesizes the disparate
      literature on psychosocial factors associated with adolescent pregnancy using
      Bronfenbrenner's ecological model. Social influences within the macrosystem,
      mesosystem, and microsystem are examined. Policy and service delivery
      recommendations are offered.

PMID- 10658869
TI  - Anorexic eating attitudes and behaviors of male and female college students.
AB  - This study examined gender differences in eating attitudes and behaviors in a
      sample of 471 undergraduate college students. The prevalence of symptomatology
      indicative of anorexia was determined using the Eating Attitudes Test (EAT-26).
      In addition, the family climate, parent-child dynamics, and self-concept of
      students with and without maladaptive eating attitudes and behaviors were
      compared, and the relationship between eating attitudes/behaviors and current
      psychological distress was examined. Anorexic symptomatology was found for 20% of
      the females and 10% of the males. In general, students without symptomatic
      attitudes and behaviors had a more positive self-concept and reported less
      psychological distress than did those with eating disturbances. The findings
      suggest that eating problems may be more prevalent among males than previously
      estimated.

PMID- 10658870
TI  - A survey of practice patterns and the health promotion and prevention attitudes
      of US chiropractors. Maintenance care: part I.
AB  - OBJECTIVE: To investigate the primary care, health promotion activities
      associated with what has historically been called "maintenance care" (MC) as used
      in the practice of chiropractic in the United States. This includes issues such
      as investigating the purpose of MC, what conditions and patient populations it
      best serves, how frequently it is required, what therapeutic interventions
      constitute MC, how often it is recommended, and what percent of patient visits
      are for prevention and health promotion services. It also investigates the
      economic impact of these services. DESIGN: Postal survey of a randomized sample
      of practicing US chiropractors. The questionnaire was structured with a 5-point
      ordinal Likert scale (28 questions) and brief fill-in questionnaire (12
      questions). The 40-question survey was mailed to 1500 chiropractors selected at
      random from a pool of chiropractors with active practices in the United States.
      The National Directory of Chiropractic database was the source of actively
      practicing chiropractors from which doctor selection was made. The sample was
      derived by using the last numbers composing the zip codes assigned by the US
      Postal Service. This sampling method assured potential inclusion of chiropractors
      from all 50 states, from rural areas and large cities, and assured a sample
      weighting based on population density that might not have been afforded by a
      simple random sample. RESULTS: Six hundred and fifty-eight (44%) of the
      questionnaires were completed and returned. US chiropractors agreed or strongly
      agreed that the purpose of MC was to optimize health (90%), prevent conditions
      from developing (88%), provide palliative care (86%), and minimize recurrence or
      exacerbations (95%). MC was viewed as helpful in preventing both musculoskeletal
      and visceral health problems. There was strong agreement that the therapeutic
      composition of MC placed virtually equal weight on exercise (96%) and
      adjustments/manipulation (97%) and that other interventions, including dietary
      recommendations (93%) and patient education about lifestyle changes (84%), shared
      a high level of importance. Seventy-nine percent of chiropractic patients have MC
      recommended to them and nearly half of those (34%) comply. The average number of
      recommended MC visits was 14.4 visits per year, and the total revenue represents
      an estimated 23% of practice income. CONCLUSIONS: Despite educational,
      philosophic, and political differences, US chiropractors come to a consensus
      about the purpose and composition of MC. Not withstanding the absence of
      scientific support, they believe that it is of value to all age groups and a
      variety of conditions from stress to musculoskeletal and visceral conditions.
      This strong belief in the preventive and health promotion value of MC motivates
      them to recommend this care to most patients. This, in turn, results in a high
      level of preventive services and income averaging an estimated $50,000 per
      chiropractic practice in 1994. The data suggest that the amount of services and
      income generated by preventive and health-promoting services may be second only
      to those from the treatment of low-back pain. The response from this survey also
      suggests that the level of primary care, health promotion and prevention
      activities of chiropractors surpasses that of other physicians.

PMID- 10658871
TI  - Maintenance care: health promotion services administered to US chiropractic
      patients aged 65 and older, part II.
AB  - OBJECTIVE: Health promotion and prevention services provided by the chiropractic
      profession historically have been referred to as maintenance care (MC). The
      primary objective of this investigation was to obtain information regarding
      multiple health issues of patients age 65 years and over who have had a long-term
      regimen of chiropractic health promotion and preventive care. The study also
      sought to explore the nature of the interventions and methods that were most
      commonly used by chiropractors when administering MC and to determine whether
      there were differences between patients who have had long-term exposure to these
      preventive services versus those who have not. DESIGN: This descriptive study was
      accomplished by selecting chiropractic patients (age 65 years and over) who had
      received health-promotion and prevention services for at least 5 years, with a
      minimum of 4 visits per year. To enhance the probability of securing a more
      representative patient sample, selection was made through the participation of
      chiropractors from 6 diverse geographic locations across the United States.
      Doctors were asked to enroll the first 10 consenting patients who met the
      inclusion criteria. A battery of diverse assessment instruments were completed by
      each patient to provide a patient health profile. Information related to each
      patient included answers to the SF-36D survey, patient health habits,
      expenditures of health services, frequency of use of health providers, and
      perceived value of chiropractic prevention and health promotion services.
      RESULTS: A total of 73 chiropractors participated in this investigation from the
      6 study sites. In addition to an average 1.9 manual procedures used per patient,
      it was common to recommend stretching exercises (68.2%), aerobic exercises
      (55.6%), dietary advice (45.3%), and a host of other prevention strategies,
      including vitamins and relaxation. The patients investigated in this study
      reported making only half the annual number of visits to medical providers (4.76
      visits per year) compared with the national average (9 visits per year) for
      individuals age 65 years and over. CONCLUSIONS: On the basis of the response of
      participating chiropractors, this study describes the therapeutic components of
      MC for the elderly patient. For these patients, MC does not simply consist solely
      of periodic visits for joint manipulation, but it involves an eclectic host of
      interventions (e.g., exercise, nutrition, relaxation, physical therapy, and
      manipulation) that are directed at both musculoskeletal and visceral conditions.

PMID- 10658872
TI  - Standardized initial head position in cervical range-of-motion assessment:
      reliability and error analysis.
AB  - OBJECTIVE: To assess the clinical reliability and precision of the OSI CA-6000
      Spinal Motion Analyzer for measurement of range of motion in cervical spines of
      pain-free subjects by using a novel procedure designed to minimize variability
      and quantitatively evaluate sources of errors. METHODS: Twenty asymptomatic
      volunteer subjects were evaluated twice by each of two trained examiners in one
      session. Subject position was carefully standardized. Rotation, lateral bending,
      and flexion-extension were evaluated in repeated movements (cycles) from extreme
      to extreme. ANALYSIS: Descriptive statistics and reliability coefficients
      (interclass correlation coefficients [ICCs]) were calculated for all full- and
      half-cycle motions. Possible sources of systematic errors were evaluated, and
      random errors were estimated. RESULTS: ICCs indicate that the instrument performs
      very reliably for rotation and lateral bending (0.93-0.97) and acceptably for
      flexion-extension (0.75-0.93) measurements. Differences in instrument placement,
      subject posture, or both in different trials correlate neither with differences
      in measured values nor with variances. Within-trial errors did not correlate with
      ranges of motion. Standardizing head position resulted in increases in
      reliability of from 3% to 15% for axial rotation and lateral bending but actually
      decreased the ICCs for flexion-extension (up to 14%) compared with data collected
      under a less-stringent protocol. Errors in clinical use are estimated at 4.5
      degrees. CONCLUSIONS: By using our modifications to the accessories and
      standardization of subject position, the CA-6000 is a highly precise and reliable
      instrument for measuring active cervical motion about the 3 Cartesian axes.
      Individuals can repeat the same patterns of motion in sequential trials on the
      same day with very little variation. Ease of repetitious measurement without
      examiner intervention contributes to the instrument's ability to obtain highly
      reliable data. Changes in instrument placement or subject body posture between
      trials do not give rise to systematic errors. Design of the instrument for
      flexion-extension could be improved.

PMID- 10658873
TI  - An alteration in arterial compliance associated with elevated aerobic fitness.
AB  - OBJECTIVE: To identify a nonpharmacologic method of enhancing arterial
      compliance, a correlate of atherogenesis; to determine the relationship between
      aerobic fitness levels and arterial compliance; and to identify a characteristic
      Doppler analog waveform associated with elevated levels of aerobic fitness.
      DESIGN: A cross-sectional design was used to compare the Doppler studies of
      sedentary subjects and aerobically trained subjects. The trained subjects were
      divided into a moderately trained group and a highly trained group. SETTING AND
      PARTICIPANTS: One hundred subjects consisting of 50 sedentary control subjects
      and 50 aerobically trained subjects in a university-based setting. The mean age
      of the total group of subjects was 36.0+/-8.6 years. Each group had an equal
      number of male and female subjects. Control subjects were sedentary, with normal
      vascular risk factor profiles and a mean aerobic capacity (maximum oxygen
      consumption) of 25.8+/-3.0 mL x kg(-1) x min(-1). Trained subjects were divided
      into a moderately trained group and a highly trained group. The mean aerobic
      capacity for the moderately trained group was 46.0+/-4.4 mL x kg(-1) x min(-1),
      and that for the highly trained group was 63.3+/-6.7 mL x kg(-1) x min(-1). A
      standard Doppler examination, including ankle pressure index was performed on
      each subject. MAIN OUTCOME MEASURE: Arterial compliance measurements were
      recorded by using A-mode Doppler ultrasonography and analyzed by diastolic flow
      analysis. RESULTS: Control subjects had a mean arterial compliance level of
      21.1%+/-2.5%. The moderately trained subjects had a mean compliance level of
      34.8%+/-4.9%, and the highly trained subjects had a mean compliance level of
      46.0%+/-6.7%. An analysis of variance was used for this comparison and was
      significant at a P value of less than .01. CONCLUSION: These results demonstrate
      that elevated aerobic fitness levels are associated with an augmentation in
      arterial compliance. A linear relationship existed in our data between aerobic
      fitness levels and arterial compliance. This study suggests that enhanced
      arterial compliance is another beneficial cardioprotective effect associated with
      aerobic training.

PMID- 10658874
TI  - Stress management: an exploratory study of chiropractic patients.
AB  - BACKGROUND: Stress is a recognized variable in the diagnosis, management, and
      prognosis of musculoskeletal conditions; chiropractic care is reputed to be
      successful in the management of stress-related visceral conditions. It may be
      useful for chiropractors to include stress management as a clinical care option.
      OBJECTIVE: To explore screening tools to aid stress self-assessment, investigate
      patients' perceptions of stress management as a chiropractic care option, and
      examine which stress-management strategies chiropractic patients perceive as most
      useful. DESIGN: A multiphase qualitative study with purposive sampling of
      chiropractic clinics to maximize the diversity of the patient population.
      Convenience sampling of patients was undertaken in a Western Australian case
      study, an inner city, and a national exploratory study. Data for the case study
      were collected by semistructured interview. Questionnaires and a self-assessed
      stress-management task were used to collect data from the inner city and national
      studies. Data was thematically analyzed, and results were triangulated. RESULTS:
      The sample size of chiropractic patients in the West Australian case study was
      48, 15 in the Western Australia exploratory study and 36 in the national study. A
      number of chiropractic patients participating in this study perceive themselves
      to be stressed and were interested in having stress-management strategies
      included in their chiropractic care. Individual patients preferred different
      stress-management options. This qualitative study found little justification for
      routinely using a stress-assessment technique more complex than asking the
      patient to rate his or her stress level as absent, minimal, moderate, or severe.
      Exercise, particularly walking, was found to be a prevalent pasttime among
      participants in the case study. CONCLUSION: This study was too small to warrant
      statistical analysis; nonetheless, the results of this study are relevant because
      some patients believe they would benefit from chiropractic care that includes
      information about stress-management strategies.

PMID- 10658875
TI  - Sitting biomechanics, part II: optimal car driver's seat and optimal driver's
      spinal model.
AB  - BACKGROUND: Driving has been associated with signs and symptoms caused by
      vibrations. Sitting causes the pelvis to rotate backwards and the lumbar lordosis
      to reduce. Lumbar support and armrests reduce disc pressure and
      electromyographically recorded values. However, the ideal driver's seat and an
      optimal seated spinal model have not been described. OBJECTIVE: To determine an
      optimal automobile seat and an ideal spinal model of a driver. DATA SOURCES:
      Information was obtained from peer-reviewed scientific journals and texts,
      automotive engineering reports, and the National Library of Medicine. CONCLUSION:
      Driving predisposes vehicle operators to low-back pain and degeneration. The
      optimal seat would have an adjustable seat back incline of 100 degrees from
      horizontal, a changeable depth of seat back to front edge of seat bottom,
      adjustable height, an adjustable seat bottom incline, firm (dense) foam in the
      seat bottom cushion, horizontally and vertically adjustable lumbar support,
      adjustable bilateral arm rests, adjustable head restraint with lordosis pad, seat
      shock absorbers to dampen frequencies in the 1 to 20 Hz range, and linear front
      back travel of the seat enabling drivers of all sizes to reach the pedals. The
      lumbar support should be pulsating in depth to reduce static load. The seat back
      should be damped to reduce rebounding of the torso in rear-end impacts. The
      optimal driver's spinal model would be the average Harrison model in a 10 degrees
      posterior inclining seat back angle.

PMID- 10658876
TI  - Tortuosity of the vertebral artery resulting in vertebral erosion.
AB  - OBJECTIVE: To discuss the case of a patient with unilateral vertebral artery
      tortuosity and dilatation resulting in vertebral body and transverse foramen
      erosion. An emphasis is placed on diagnostic imaging. CLINICAL FEATURES: A 45
      year-old man had a frozen shoulder and headaches. Previous arm pain, numbness,
      and a cold extremity were the result of occlusion of the subclavian artery and
      had been treated with a subclavian-carotid bypass procedure. INTERVENTION AND
      OUTCOME: As a result of the angiographic detection of the left vertebral artery
      dilatation and tortuosity and the concomitant hypoplastic right vertebral artery,
      high-velocity, low-amplitude manipulation of the cervical spine was
      contraindicated. However, the patient's symptoms were not related to these
      findings. Alternatively, low-force manipulation of the cervical spine, shoulder
      range of motion and muscle techniques were used, and the patient's symptoms
      diminished significantly with improved shoulder range of motion. CONCLUSION:
      Clinicians need to be alert to clinical presentations and appropriate imaging
      protocols in cases of suggested vertebral artery anomaly.

PMID- 10658877
TI  - Pelvic stress fracture: assessment and risk factors.
AB  - OBJECTIVE: To discuss the case of a patient with a pelvic stress fracture and the
      differential considerations among patients presenting with hip and/or groin pain.
      FEATURES: A 42-year-old woman had hip pain after running. Initial radiograph of
      the pelvis was negative. Subsequent films showed a right inferior pubic ramus
      stress fracture. Stress fractures of the pelvis are relatively uncommon,
      accounting for only 1% to 2% of all stress fractures. INTERVENTION AND OUTCOME:
      Treatment included high-velocity, low-amplitude chiropractic manipulation,
      ultrasound, and stretching of the psoas and piriformis muscles. After 8 weeks,
      care was discontinued because the patient's hip pain had resolved. The pelvic
      fracture was left to heal with time. After 1 year, the patient still had delayed
      union of the fracture. CONCLUSION: When predisposing factors are present, such as
      osteoporosis and rheumatoid arthritis, pelvic stress fracture should be suspected
      in patients with groin or hip-area pain. However, because pelvic stress fractures
      are relatively rare, radiographic studies are often postponed, making diagnosis
      difficult.

PMID- 10658878
TI  - Patient education initiatives at the Canadian Memorial Chiropractic College.

PMID- 10658879
TI  - Motion palpation: it's time to accept the evidence.

PMID- 10658880
TI  - Rear-end impacts: vehicle and occupant response.

PMID- 10658881
TI  - The role of organizational behavior in occupational health psychology: a view as
      we approach the millennium.
AB  - This special section of the Journal of Occupational Health Psychology provides
      ample illustration of the increasingly important role of organizational behavior
      research on work-related issues of health and well-being. More specifically, the
      9 articles contained in this special section highlight the varied application and
      potentially widespread benefit of considering the main effects of employee
      physical health and psychological well-being. The authors conclude with a
      discussion of how emerging research issues in occupational health psychology can
      be used to build a stronger science of organizational behavior.

PMID- 10658882
TI  - Stress prevention in bus drivers: evaluation of 13 natural experiments.
AB  - The research aim was to select, compare, and analyze interventions and preventive
      actions from international bus companies to decrease bus drivers' occupational
      stress and sickness absenteeism. Through networking, international surveys, and
      literature study, 13 "natural experiments" were identified with an acceptable
      research design rating. Interventions were both work and person directed.
      Principles of worker participation were often followed. The variety in
      intervention programs, outcome measures, case evaluations, and methodological
      flaws makes it difficult to present a general picture of program effectiveness.
      However, analyses on more objective and more subjective outcomes do point at
      positive effects. This study suggests that stress prevention that combines
      adequate interventions and proper implementation may be beneficial to both the
      employee and the company.

PMID- 10658883
TI  - Two years after a job loss: long-term impact of the JOBS program on reemployment
      and mental health.
AB  - Analyses of data from a randomized field experiment with 1,801 participants (A.D.
      Vinokur, R.H. Price. & Y.Schul, 1995) examined the long-term effects of a job
      search workshop (JOBS) and the independent effects of demographic and
      psychological factors on reemployment and mental health outcomes. Two years after
      the JOBS workshop, the experimental group had significantly higher levels of
      reemployment and monthly income, lower levels of depressive symptoms, lower
      likelihood of experiencing a major depressive episode in the last year, and
      better role and emotional functioning compared with the control group. Baseline
      job-search motivation and sense of mastery had both direct and interactive
      effects (with experimental condition) on reemployment and mental health outcomes,
      respectively. The interactive effects demonstrated larger benefits for those who
      had initial low levels of job-search motivation and mastery.

PMID- 10658884
TI  - Stress management training for military trainees returned to duty after a mental
      health evaluation: effect on graduation rates.
AB  - A significant proportion of people entering the military are discharged within
      the first 6 months of enlistment. Mental health related problems are often cited
      as the cause of discharge. This study evaluated the utility of stress inoculation
      training in helping reduce the attrition of a sample of Air Force trainees at
      risk for discharge from basic military training. Participants were 178 trainees
      referred for a psychological evaluation from basic training. Participants were
      randomly assigned to a 2-session stress management group or a usual-care control
      condition. Compared with past studies that used less rigorous methodology, this
      study did not find that exposure to stress management information increased the
      probability of graduating basic military training. Results are discussed in terms
      of possible reasons for the lack of treatment effects and directions for future
      research.

PMID- 10658885
TI  - Examining a stress-coping model of burnout and depression in extension agents.
AB  - Occupational stressors, coping strategies, and burnout and depression were
      examined in extension agents. Results indicated that a significant proportion of
      extension agents (range = 9.8%-51%) reported burnout symptoms above established
      cut-off scores for the burnout subscales, but fewer than 3% of the sample
      reported significant symptoms on all 3 dimensions of burnout. Depressive symptoms
      based on established cut-off scores were noted in approximately 26% of the
      sample. Stepwise multiple regression indicated that extension agents who used an
      emotion-oriented coping strategy were more likely to (a) display high levels of
      depression, emotional exhaustion, and depersonalization and (b) exhibit low
      levels of personal accomplishment. Furthermore, task-oriented coping strategies
      were found to be negatively associated with the 3 dimensions of burnout.
      Implications for interventional programming to reduce the symptoms of burnout are
      discussed.

PMID- 10658886
TI  - Wedded to the job: moderating effects of job involvement on the consequences of
      job insecurity.
AB  - Two hundred eighty-three public-sector employees experiencing a workplace
      reorganization completed surveys assessing the relationships between job
      involvement and job insecurity on self-report measures of psychological,
      behavioral, and physical outcomes. Using C. L. Hulin's (1991) job adaptation
      theory, differential predictions were made regarding the specific outcomes of job
      insecurity for high job involvement versus low job involvement employees. Results
      indicate that employees who were highly invested in their jobs were most
      adversely affected by job insecurity. Specifically, they reported more negative
      job attitudes, more health problems, and a higher level of psychological distress
      than their less involved counterparts when they perceived their jobs to be
      threatened.

PMID- 10658887
TI  - Distress and boredom among orchestra musicians: the two faces of stress.
AB  - Survey data gathered from 63 professional musicians in a small symphony orchestra
      in the eastern United States were used to examine the effects of work-generated
      stressors on their psychological health and well-being. Lack of artistic
      integrity, task difficulty, and social tension were found to be the 3 most potent
      stressors that evoked 2 types of stress reactions: distress reflecting role
      overload and boredom stress reflecting role underload. Lack of artistic integrity
      and social tension contributed to heightened distress. Lack of artistic integrity
      was also associated with increased boredom stress, whereas task difficulty had
      the opposite effect. Musicians' job involvement and the instrument group in which
      they played moderated the relationship of selected stressors with the 3 outcome
      variables. Limitations of the study and directions for future research are
      discussed.

PMID- 10658888
TI  - Psychological well-being and job satisfaction as predictors of job performance.
AB  - The happy-productive worker hypothesis has most often been examined in
      organizational research by correlating job satisfaction to performance. Recent
      research has expanded this to include measures of psychological well-being.
      However, to date, no field research has provided a comparative test of the
      relative contribution of job satisfaction and psychological well-being as
      predictors of employee performance. The authors report 2 field studies that,
      taken together, provide an opportunity to simultaneously examine the relative
      contribution of psychological well-being and job satisfaction to job performance.
      In Study 1, psychological well-being, but not job satisfaction, was predictive of
      job performance for 47 human services workers. These findings were replicated in
      Study 2 for 37 juvenile probation officers. These findings are discussed in terms
      of research on the happy-productive worker hypothesis.

PMID- 10658889
TI  - Emotion regulation in the workplace: a new way to conceptualize emotional labor.
AB  - The topic of emotions in the workplace is beginning to garner closer attention by
      researchers and theorists. The study of emotional labor addresses the stress of
      managing emotions when the work role demands that certain expressions be shown to
      customers. However, there has been no overarching framework to guide this work,
      and the previous studies have often disagreed on the definition and
      operationalization of emotional labor. The purposes of this article are as
      follows: to review and compare previous perspectives of emotional labor, to
      provide a definition of emotional labor that integrates these perspectives, to
      discuss emotion regulation as a guiding theory for understanding the mechanisms
      of emotional labor, and to present a model of emotional labor that includes
      individual differences (such as emotional intelligence) and organizational
      factors (such as supervisor support).

PMID- 10658890
TI  - Reconceptualizing the work-family interface: an ecological perspective on the
      correlates of positive and negative spillover between work and family.
AB  - Ecological theory was used to develop a more expanded conceptualization of the
      work-family interface and to identify significant correlates of multiple
      dimensions of work-family spillover. Using data from employed adults
      participating in the National Survey of Midlife Development in the United States
      (N = 1,986), negative spillover from work to family, positive spillover from work
      to family, negative spillover from family to work, and positive spillover from
      family to work were found to be distinct work-family experiences. Analyses
      indicated that work and family factors that facilitated development (e.g.,
      decision latitude, family support) were associated with less negative and more
      positive spillover between work and family. By contrast, work and family barriers
      (e.g., job pressure, family disagreements) were associated with more negative
      spillover and less positive spillover between work and family. In some cases,
      results differ significantly by gender.

PMID- 10658891
TI  - Behavioral-diagnostic analysis of compliance with universal precautions among
      nurses.
AB  - This study used the PRECEDE model (L.W. Green, M.W. Kreuter, S.G. Deeds, & K.B.
      Partridge, 1980) to examine individual, job-task, and environmental
      organizational factors related to compliance with universal precautions (UP)
      among nurses. Structural equation modeling showed that the hypothesized model did
      a better job predicting general compliance (R2 = .41) than compliance with
      personal protective equipment (PPE; R2 = .18). All 3 categories of diagnostic
      factors (predisposing, enabling, and reinforcing) influenced general compliance,
      but predisposing factors were relatively unimportant for compliance with PPE.
      With a set of nested models, the greatest improvement in model fit occurred when
      the indirect effects of reinforcing factors were added. A positive safety climate
      may increase the likelihood that the work environment will contain features that
      enable workers to comply with safe work practices.

PMID- 10658892
TI  - The validity and reliability of the Dutch Effort-Reward Imbalance Questionnaire.
AB  - The reliability and validity of the Effort-Reward Imbalance Questionnaire were
      tested in 775 blue- and white-collar workers in the Netherlands. Cronbach's alpha
      revealed sufficient internal consistency of all subscales except Need for
      Control. With exploratory probabilistic scaling (Mokken) analysis, the
      psychometric qualities of the Need for Control scale were improved. With
      confirmatory factor analysis, the factorial validity of the Extrinsic Effort and
      Reward subscales was confirmed. A model with 3 separate dimensions for reward
      (status control, esteem reward, and monetary gratification) proved adequate,
      emphasizing the importance of distinguishing subscales. The congruent validity of
      the subscales and a hypothesized relationship with an external construct, health
      functioning, were confirmed.

PMID- 10658893
TI  - Mediators of change in emotion-focused and problem-focused worksite stress
      management interventions.
AB  - Ninety volunteers in a media organization were randomly allocated to an
      Acceptance and Commitment Therapy (ACT, n = 30) group that sought to enhance
      people's ability to cope with work-related strain, an Innovation Promotion
      Program (IPP, n = 30) that helped individuals to identify and then innovatively
      change causes of occupational strain, or a waitlist control group (n = 30). Both
      interventions lasted 9 hr, spread over 3 months. Improvements in mental health
      and work-related variables were found following both interventions. As
      hypothesized, changes in outcome variables in the ACT condition were mediated
      only by the acceptance of undesirable thoughts and feelings. In the IPP
      condition, outcome change was mediated only by attempts to modify stressors.
      Discussion focused on the importance of understanding the mechanisms underpinning
      change in occupational stress management interventions.

PMID- 10658894
TI  - Biomechanical, psychosocial, and organizational risk factors for WRMSD:
      population-based estimates from the Connecticut upper-extremity surveillance
      project (CUSP).
AB  - In a case-control study of a population-based telephone survey of 3,798 working
      adults, symptoms of work-related musculoskeletal disorder (WRMSD) were associated
      with biomechanical, psychosocial, and organizational factors. In several models,
      biomechanical exposures with strong associations were static postures (odds
      ratios [ORs] = 2.00-5.45); repeated pushing, pulling, lifting (ORs = 1.86-12.75);
      and repeated neck bending (ORs = 1.07-12.8). Psychosocial and organizational
      factors consistently retained in these models were demands (ORs = 1.26-1.59) and
      organizational support (ORs = 0.53-0.79). Decision latitude entered less
      frequently (ORs = 0.30-0.49). This research may have implications for
      intervention strategies. First, reducing both biomechanical and psychosocial risk
      may be more effective than focusing solely on engineering controls. Second,
      organizational culture and policy may have strong implications for WRMSD
      prevalence and control.

PMID- 10658895
TI  - A multilevel analysis of the demands--control model: is stress at work determined
      by factors at the group level or the individual level?
AB  - This study explored the extent to which negative health-related outcomes are
      associated with differences between work groups and with differences between
      individuals within work groups using R.A. Karasek's (1979) demands-control model.
      The sample consisted of 260 employees in 31 working groups of a national bank in
      the Netherlands. Results suggest that job demands and job control should be
      conceptualized as having both group- and individual-level foundations. Support
      for Karasek's demands-control model was found only when these variables were
      split into the 2 parts, reflecting shared perceptions and employees' subjective
      assessment, respectively. One of the most appealing practical implications is
      that absence rates among homogeneous work groups can be reduced by enhancing
      actual control on the job.

PMID- 10658896
TI  - Coping with anger-provoking situations, psychosocial working conditions, and ECG
      detected signs of coronary heart disease.
AB  - This study explored the association among coping, psychosocial work factors, and
      signs of coronary heart disease (CHD) among prison staff (777 men, 345 women).
      Electrocardiogram (ECG) recordings at rest, health examinations, and a
      questionnaire were used. A high level of covert coping in men and a low level of
      open coping in women showed the strongest association with signs of CHD. Among
      several traditional biological and lifestyle risk factors, only age and systolic
      blood pressure in men and none in the case of women were significantly associated
      with CHD signs in the final multivariate regression analyses. A coping style of
      repressed emotions and actions in anger-provoking situations, independent of
      traditional risk factors, seems to be associated with a prevalence of ECG signs
      in male and female prison staff.

PMID- 10658897
TI  - An examination of nonresponse in a work environment questionnaire mailed to
      psychiatric health care personnel.
AB  - Nonresponse to surveys, which seems to plague work environment studies and
      studies of health care personnel in particular, may pose problems of
      generalizability and validity. The aim of this study was to provide an estimate
      of nonresponse error in a self-administered survey concerning the work
      environment of psychiatric health care personnel. A random sample of 10% of the
      original survey population (N = 693) was selected to participate in a telephone
      follow-up of a postal survey that had a response rate of 51%. There were no
      differences between the responders and nonresponders to the postal survey on the
      exposure or outcome variables. There was no evidence of nonresponse bias in this
      study, although recall bias may have been a problem. In those cases in which
      generalizability is deemed important, it is recommended that nonresponse studies
      be regularly carried out when response rates are less than 100%.

PMID- 10658898
TI  - Study of heterocycle rings binding to human serum albumin.
AB  - The binding of drugs to human serum albumin determines the drug distribution
      through the systemic circulation and its pharmacological effects on the organism.
      Then, with the aim of obtaining information concerning the drug structural
      features which favour their binding on seroalbumin we have studied the
      seroalbumin binding to the heterocyclic drugs such as warfarin, propylthiouracil
      and cromoglycate and to similar compounds such as 4-hydroxy-coumarin, 3
      acetylcoumarin, coumarin, benzylthiouracil, propyluracil, thiouracil, chromone
      and chromanol. These compounds were competitively displaced by warfarin at their
      primary binding sites on seroalbumin. The comparative analysis of the binding
      data showed that heterocyclic compounds such as benzopyranes (coumarins and
      chromanol) and benzyl pyrimidines with 4-hydroxyl groups bind specifically in the
      warfarin binding site. Then, 4-hydroxyl-bencene heterocycles will displace other
      ligands from the subdomain IIA of the seroalbumin molecule. Therefore, we can
      predict that the administration concomitant of warfarin, cromoglycate,
      propylthiouracil and analogous heterocyclic drugs involves the displacement of
      the drug without 4-hydroxyl and benzyl groups, increasing their free fraction in
      serum and the amount of active drug.

PMID- 10658899
TI  - Adenine N3 is a main alkylation site of styrene oxide in double-stranded DNA.
AB  - Styrene 7,8-oxide (SO), a major metabolite of styrene, is classified as a
      probable human carcinogen. In the present work, salmon testis DNA was reacted
      with SO and the alkylation products were analysed after sequential depurination
      in neutral or acidic conditions followed by HPLC separation and UV-detection. A
      novel finding was that the N-3 position of adenine was the next most reactive
      alkylation site in double-stranded DNA, comprising 4% of the total alkylation, as
      compared to alkylation at the N-7 position of guanine, 93% of the total
      alkylation. Both alpha- and beta-products of SO were formed at these two sites.
      Other modified sites were N2-guanine (1.5%, alpha-isomer), 1-adenine (0.4%, both
      isomers) and N6-adenine (0.7%, both isomers) as well as 1-hypoxanthine (0.1%,
      alpha-isomer), formed by deamination of the corresponding 1-adenine adduct. The
      results indicated that in double-stranded DNA N-7 of guanine and N-3 of adenine
      account for 97% of alkylation by SO. However, these abundant adducts are not
      stable, the half-life of depurination in DNA for 3-substituted adenines being
      approximately 10 and approximately 20 h, for alpha- and beta-isomers,
      respectively, and 51 h for both isomers of 7-substituted guanines.

PMID- 10658900
TI  - Chemical features of flavonols affecting their genotoxicity. Potential
      implications in their use as therapeutical agents.
AB  - Flavonls are natural compounds present in edible plants and possess several
      biological activities that can be useful in drug design. Conversely some of these
      compounds have been shown to be genotoxic to prokaryotic and eukaryotic cells. In
      this study we tried to establish the chemical features responsible for the
      genotoxicity of flavonols and to study the conditions that can modulate their
      genotoxicity namely pH, the presence of antioxidants and metabolism. We assessed
      the induction of revertants in Salmonella typhimurium TA98 and the induction of
      Chromosomal aberrations in V79 cells by eight different flavonols and one
      catechin in the presence and in the absence of metabolizing systems. We have also
      studied the generation of hydroxyl radical by these flavonoids using the
      deoxyribose degradation assay. The results obtained in this study suggest that
      flavonols having a free hydroxyl group at position 3 of the C ring, a free
      hydroxyl group at position 7 of the A ring and a B ring with a catechol or
      pyrogallol structure, or a structure that after metabolic activation is
      transformed into a catechol or a pyrogallol, are flavonols whose genotoxicity in
      eukaryotic cells depends on their autooxidation. These flavonols can autooxidize
      when the pH value is slightly alkaline, such as in the intestine, and therefore
      can induce genotoxicity in humans. Given the above mentioned considerations it is
      necessary to clarify the mechanisms and the conditions that mediate the
      biological effects of flavonols before considering them as therapeutical agents.

PMID- 10658901
TI  - Inhibition of nitric oxide synthesis in primary cultured mouse hepatocytes by
      alpha-lipoic acid.
AB  - Recent work shows that septic or endotoxic shock is associated with
      lipopolysaccharide and cytokine mixture-induced nitric oxide (NO) synthesis in
      liver. Here we found that DL-alpha-lipoic acid inhibited but other thiol
      containing antioxidants such as glutathione and N-acetylcysteine enhanced
      lipopolysaccharide and cytokine mixture (referred as LPS/CM)-induced NO synthesis
      in hepatocytes. The inhibitory action of alpha-lipoic acid on hepatocyte NO
      synthesis was as potent as that of NG-monomethyl-L-arginine without obvious
      cytotoxicity. Deletion by diethylmaleate or inhibition by buthionine sulfoximine
      of intracellular glutathione caused a significant decrease in hepatocyte NO
      synthesis, implying that increased intracellular reduced glutathione levels could
      not be the reason for alpha-lipoic acid inhibited NO synthesis. alpha-Lipoic acid
      inhibition of NO synthesis seems to be from alpha-lipoic acid improved
      carbohydrate metabolism in hepatocytes. Since alpha-lipoic acid is an essential
      compound existing naturally in physiological systems, it may serve as both a
      research and therapeutic agent for sepsis.

PMID- 10658902
TI  - Kinetics of inhibition of human and rat dihydroorotate dehydrogenase by
      atovaquone, lawsone derivatives, brequinar sodium and polyporic acid.
AB  - Mitochondrially-bound dihydroorotate dehydrogenase (EC 1.3.99.11) catalyzes the
      fourth sequential step in the de novo synthesis of uridine monophosphate. The
      enzyme has been identified as or surmised to be the pharmacological target for
      isoxazol, triazine, cinchoninic acid and (naphtho)quinone derivatives, which
      exerted antiproliferative, immunosuppressive, and antiparasitic effects. Despite
      this broad spectrum of biological and clinical relevance, there have been no
      comparative studies on drug-dihydroorotate dehydrogenase interactions. Here, we
      describe a study of the inhibition of the purified recombinant human and rat
      dihydroorotate dehydrogenase by ten compounds. 1,4-Naphthoquinone, 5,8-hydroxy
      naphthoquinone and the natural compounds juglon, plumbagin and polyporic acid
      (quinone derivative) were found to function as alternative electron acceptors
      with 10-30% of control enzyme activity. The human and rat enzyme activity was
      decreased by 50% by the natural compound lawsone ( > 500 and 49 microM,
      respectively) and by the derivatives dichloroally-lawsone (67 and 10 nM),
      lapachol (618 and 61 nM) and atovaquone (15 microM and 698 nM). With respect to
      the quinone co-substrate of the dihydroorotate dehydrogenase, atovaquone (Kic =
      2.7 microM) and dichloroally-lawsone (Kic = 9.8 nM) were shown to be competitive
      inhibitors of human dihydroorotate dehydrogenase. Atovaquone (Kic = 60 nM) was
      also acompetitive inhibitor of the rat enzyme. Dichloroally]-lawsone was found to
      be a time-dependent inhibitor of the rat enzyme, with the lowest inhibition
      constant (Ki* = 0.77 nM) determined so far for mammalian dihydroorotate
      dehydrogenases. Another inhibitor, brequinar was previously reported to be a slow
      binding inhibitor of the human dihydroorotate dehydrogenase [W. Knecht, M.
      Loffler, Species-related inhibition of human and rat dihyroorotate dehydrogenase
      by immunosuppressive isoxazol and cinchoninic acid derivatives, Biochem.
      Pharmacol. 56 (1998) 1259-1264]. The slow binding features of this potent
      inhibitor (Ki* = 1.8 nM) with the human enzyme, were verified and seen to be one
      of the reasons for the narrow therapeutic window (efficacy versus toxicity)
      reported from clinical trials on its antiproliferative and immunosuppressive
      action. With respect to the substrate dihydroorotate, atovaquone was an
      uncompetitive inhibitor of human dihydroorotate dehydrogenase (Kiu = 11.6 microM)
      and a non-competitive inhibitor of the rat enzyme (Kiu = 905/ Kic = 1,012 nM).
      1.5 mM polyporic acid, a natural quinone from fungi, influenced the activity of
      the human enzyme only slightly; the activity of the rat enzyme was decreased by
      30%.

PMID- 10658903
TI  - The quality of Her-2/Neu predictive immunohistochemistry: something FISHy?

PMID- 10658904
TI  - Sjogren's syndrome and MALT lymphomas of salivary glands: a DNA-cytometric and
      interphase-cytogenetic study.
AB  - Few and conflicting cytogenetic data are available concerning the chromosomal
      constitution of (mainly gastric) extranodal marginal zone B-cell non-Hodgkin's
      lymphoma arising from mucosa-associated lymphoid tissue (MALT)-type lymphoma. The
      majority of salivary gland MALT lymphomas are thought to develop from
      longstanding Sjogren's syndrome/benign lymphoepithelial lesion (BLEL). We tried
      to achieve a better comprehension of related cytogenetic alterations by comparing
      DNA-ploidy and numerical chromosomal (#) aberrations, assessed by different
      techniques of DNA cytometry (image cytometry) and interphase cytogenetics using
      nonradiographic in situ hybridization (centromere specific probes for #3, 7, 12,
      18) on 12 cases of BLEL, 13 low-grade MALT lymphomas (LG-MALT-L) and 4 high-grade
      MALT lymphomas (HG-MALT-L) of salivary gland. Both techniques were applied on
      tissue sections preferentially, enabling a reliable measurement of
      histomorphologically identified areas. No case of BLEL showed cytogenetic
      abnormalities. Three of 4 HG- and 2 of 13 LG-MALT-L exhibited complex chromosomal
      gains in nonisotopic in situ hybridization, which were reflected by DNA
      nondiploidy in image cytometry. In 6 of 13 LG- and lof 4 HG-MALT-L, one or two
      numerical chromosomal aberrations were demonstrated by nonisotopic in situ
      hybridization, which could not be resolved by image cytometry. In the 11 DNA
      diploid LG-MALT-L, trisomies 18, 3, and 12 were found in 36, 12, and 9%,
      respectively. In conclusion, comparing BLEL, which showed no chromosomal
      aberrations, with LG- and HG-MALT-L, an increase in frequency and number of
      numerical aberrations and DNA nondiploidy was seen. Peritetraploid DNA
      nondiploidy might be characteristic for HG-MALT-L of salivary gland as it is a
      rare finding in MALT lymphomas of other sites. It is unclear whether the
      documented chromosomal aberrations in LG-MALT-L, especially increased rate of
      trisomy 18, indicate a pathogenic impact or merely reflect genetic instability.

PMID- 10658905
TI  - Immunohistochemical analysis of Ki-67, p53, p21, and p27 in benign and malignant
      apocrine lesions of the breast: its correlation to histologic findings in 43
      cases.
AB  - We examined Ki-67, p53, p21, and p27 immunolocalization in 43 cases of apocrine
      lesions of the breast and correlated these findings with histologic parameters to
      understand their biologic significance. Twenty cases were benign, 1 case was
      borderline, and 22 cases were diagnosed as malignant, including 9 intraductal and
      13 invasive apocrine carcinomas. Both the ratio of Ki-67-positive cases (17 of 21
      [88.9%] versus 1 of 19 [5.3%]; P < .001) and the Ki-67 labeling index of positive
      cases examined (15.0% versus 2.7%; P < .005) were significantly higher in
      malignant than in benign apocrine lesions. None of the benign or borderline cases
      was immunohistochemically positive for p53, but 15 of 22 malignant cases (68.2%)
      demonstrated p53 (P < .001). In addition, the ratio of p53-positive cases was
      significantly higher in high nuclear grade cases (11 of 13 [84.6%]) than in
      intermediate nuclear grade cases (4 of 9 [44.4%]; P < .05). P53 immunoreactivity
      was also positively correlated with the nuclear grade of carcinoma cases examined
      in this study. Neither p21 nor p27 demonstrated any correlation with histologic
      parameters or findings of the apocrine lesions. Results of these studies suggest
      that Ki-67 and p53 may be good markers for differentiation between benign and
      malignant breast apocrine lesions.

PMID- 10658906
TI  - Non-Hodgkin's lymphomas involving the uterus: a clinicopathologic analysis of 26
      cases.
AB  - Non-Hodgkin's lymphomas (NHL) involving the uterus may be either low-stage
      neoplasms that probably arise in the uterus (primary) or systemic neoplasms with
      secondary involvement. In this study, 26 NHL involving the uterus are reported.
      Ten cases were stage I(E) or II(E) and are presumed to be primary. The mean age
      of patients at presentation was 55 years (range, 35 to 67 years), and abnormal
      uterine bleeding was the most frequent complaint (six patients). Nine of 10
      tumors involved the cervix. Histologically, eight were diffuse large B-cell
      lymphoma (DLBCL); one was follicle center lymphoma, follicular, grade 1; and one
      was marginal zone B-cell lymphoma. At 5 years of clinical follow-up, five of six
      patients were alive after treatment. In 12 cases, uterine involvement was part of
      a systemic disease at diagnosis, either stage III(E) or IV. The mean patient age
      at the time that uterine involvement was detected was 58 years (range, 22 to 75
      years); 6 of 12 had abnormal uterine bleeding. Six tumors involved both cervix
      and corpus, four corpus, and two cervix. Six were DLBCL; two were small
      lymphocytic lymphoma; three were follicle center lymphoma, follicular, grade 1
      (two cases) or grade 2 (one case); and one was precursor T-cell lymphoblastic
      lymphoma. At 5 years of clinical follow-up, two of seven patients were alive
      after treatment. Four DLBCL arose in patients with incomplete clinical
      information; therefore, stage is unknown. We conclude that low-stage (presumably
      primary) uterine NHL are most commonly DLBCL, predominantly arise in the cervix,
      and cause abnormal uterine bleeding. High-stage NHL are a heterogeneous group of
      B-cell neoplasms that can involve the cervix or the corpus.

PMID- 10658907
TI  - Detection of the ETV6-NTRK3 chimeric RNA of infantile fibrosarcoma/cellular
      congenital mesoblastic nephroma in paraffin-embedded tissue: application to
      challenging pediatric renal stromal tumors.
AB  - We report the development of a reverse transcriptase polymerase chain reaction
      assay that reliably detects the ETV6-NTRK3 chimeric RNA characteristic of
      infantile fibrosarcoma and the cellular variant of congenital mesoblastic
      nephroma (CMN) in formalin-fixed, paraffin-embedded tissue blocks. The 188 base
      pair polymerase chain reaction fusion product was detected in 11 of 12 cases of
      cellular CMN from which a larger sized control RNA band could be amplified, and
      even in 7 of 8 cases in which the control band was not detectable. A variety of
      other tumors that are in the histologic differential diagnosis of cellular CMN
      yielded negative results, including four classic CMNs, four rhabdoid tumors of
      the kidney, and four clear cell sarcomas of the kidney, confirming the assay's
      specificity. We further demonstrate the assay's utility by illustrating two cases
      of molecularly confirmed cellular CMN that mimicked rhabdoid tumor and clear cell
      sarcoma of the kidney. In contrast to previous reports, five mixed CMNs that had
      both classic and cellular areas all lacked the ETV6-NTRK3 fusion transcript.
      These results suggest that cases morphologically defined as mixed CMN may
      represent a mixed group of genetically distinct entities.

PMID- 10658908
TI  - Determination of Her-2/Neu status in breast carcinoma: comparative analysis of
      immunohistochemistry and fluorescent in situ hybridization.
AB  - Her-2/neu (H2N) status in breast carcinoma has been considered a prognostic
      factor that may have therapeutic implications; however, the correlation between
      H2N overexpression and gene amplification has not been completely defined. A
      consecutive series of ductal carcinomas (34 invasive and 7 in situ) were analyzed
      by fluorescent in situ hybridization for H2N gene and chromosome 17 copy number
      using touch preps of intact cells and by immunohistochemistry, using three
      different commercial antibodies to H2N protein (Zymed, clone 31G7; Ventana, clone
      CB11; and Dako, polyclonal) in corresponding formalin-fixed, paraffin-embedded
      tissue sections. Gene amplification was classified as unequivocal if more than
      five signals were present in more than 80% of the counted nuclei and absent if
      more than 80% of the nuclei counted contained two or fewer gene copies. Cases
      that did not fulfill the above criteria were considered equivocal for
      amplification. Immunostaining was classified as follows: 0 = no staining; 1+ =
      faint, incomplete membranous pattern; 2+ = moderate, complete membranous pattern;
      3+ = strong membranous pattern. Of the 34 invasive tumors, 10 (29%) had
      unequivocal gene amplification. Furthermore, all had more than 10 copies of the
      gene in more than 60% of the counted nuclei. An additional nine cases (26%) had
      equivocal amplification, which was usually the result of chromosome 17 aneuploidy
      (seven of nine) or heterogeneity. With the Zymed and Dako antibodies, all tumors
      with 3+ staining had unequivocal gene amplification and all cases with 2+, 1+, or
      0 staining were negative or equivocal for gene amplification. With the Ventana
      antibody, all cases with 3+ staining had unequivocal gene amplification, but two
      cases with unequivocal amplification by fluorescent in situ hybridization
      exhibited 1+ staining. Moderate (2+) H2N staining was observed in one case, three
      cases, and five cases with the Ventana, Dako, and Zymed reagents, respectively,
      and did not correlate with H2N gene copy number. Discordance between H2N and
      chromosome 17 copy number was not a useful means of defining amplification. Two
      cases of ductal carcinoma in situ with the Zymed antibody and two with the Dako
      antibody showed 3+ staining despite lack of unequivocal gene amplification. We
      conclude that (1) strong H2N immunostaining is highly associated with gene
      amplification, although there is minor variation in sensitivity between different
      antibodies; (2) a subset of breast carcinomas (3 to 15%) demonstrate moderate H2N
      staining without evidence of amplification, and it is unclear whether they
      represent highly sensitive staining or are a subset of cases that show
      overexpression without amplification; (3) gene amplification, as detected by
      fluorescent in situ hybridization, is associated with at least 10 gene copies per
      nucleus, and lower gene copy duplication (3 to 4/nucleus) is frequent, usually
      the result of chromosome 17 polysomy, and not associated with high-level
      overexpression; (5) overexpression of H2N without amplification may be more
      frequent in ductal carcinoma in situ, implying a different role in the biology of
      preinvasive versus invasive neoplasm.

PMID- 10658909
TI  - Primary seminal vesicle carcinoma: an immunohistochemical analysis of four cases.
AB  - Primary adenocarcinoma of the seminal vesicles is an extremely rare neoplasm.
      Because prompt diagnosis and treatment are associated with improved long-term
      survival, accurate recognition of this neoplasm is important, particularly when
      evaluating limited biopsy material. Immunohistochemistry can be used to rule out
      neoplasms that commonly invade the seminal vesicles, such as prostatic
      adenocarcinoma. Previous reports have shown that seminal vesicle adenocarcinoma
      (SVCA) is negative for prostate-specific antigen (PSA) and prostate-specific acid
      phosphatase (PAP); however, little else is known of its immunophenotype.
      Consequently, we evaluated the utility of cancer antigen 125 (CA-125) and
      cytokeratin (CK) subsets 7 and 20 for distinguishing SVCA from other neoplasms
      that enter the differential diagnosis. Four cases of SVCA-three cases of bladder
      adenocarcinoma and a rare case of adenocarcinoma arising in a mullerian duct cyst
      were immunostained for CA-125, CK7, and CK20. Three of four cases of SVCA were CA
      125 positive and CK7 positive. All four cases were CK20 negative. All bladder
      adenocarcinomas and the mullerian duct cyst adenocarcinoma were CK7 positive and
      negative for CA-125 and CK20. In addition, CA-125 immunostaining was performed in
      neoplasms that commonly invade the seminal vesicles, including prostatic
      adenocarcinoma (n = 40), bladder transitional cell carcinoma (n = 32), and rectal
      adenocarcinoma (n = 10), and all were negative for this antigen. In conclusion,
      the present study has shown that the CK7-positive, CK20-negative, CA-125
      positive, PSA/PAP-negative immunophenotype of papillary SVCA is unique and can be
      used in conjunction with histomorphology to distinguish it from other tumors that
      enter the differential diagnosis, including prostatic adenocarcinoma (CA-125
      negative, PSA/PAP positive), bladder transitional cell carcinoma (CK20 positive,
      CA-125 negative), rectal adenocarcinoma (CA-125 negative, CK7 negative, CK20
      positive), bladder adenocarcinoma (CA-125 negative), and adenocarcinoma arising
      in a mullerian duct cyst (CA-125 negative).

PMID- 10658910
TI  - TIA-1 positive tumor-infiltrating lymphocytes in nevi and melanomas.
AB  - Tumor-infiltrating lymphocytes (TIL) have been shown to be an independent
      prognostic factor in melanomas. To better characterize the host immune response,
      we have classified TIL by their immunoreactivity against lymphoid markers in
      formalin-fixed, paraffin-embedded tissue. Monoclonal antibodies to leukocyte
      common antigen (LCA) and TIA-1 (a granule-associated protein of cytotoxic T cells
      and NK cells) were used to immunostain a series of benign nevi, nontumorigenic
      radial growth phase, and tumorigenic vertical growth phase melanomas and
      metastases. Among nine nevi, few LCA+ TIL were found, among which rare cells were
      positive for TIA-1 (mean, 2.0). Five nontumorigenic radial growth phase melanomas
      also had few total TIL and rare TIA-1+ TIL (mean, 3.4); the nontumorigenic radial
      growth phase component of seven tumorigenic vertical growth phase melanomas had
      higher numbers of TIA-1+ TIL (mean, 11). Twelve cases of tumorigenic vertical
      growth phase melanoma showed a variable but significantly greater number of both
      LCA+ TIL and TIA-1+ TIL (mean, 30.6). Nine cases of metastatic melanoma had a
      wide range of variation in LCA as well as in TIA-1+ TIL (mean, 46). Although the
      mean total number of TIA-1+ TIL increased from nontumorigenic radial growth phase
      to tumorigenic vertical growth phase to metastases, TIA-1+ as a percentage of TIL
      declined across these categories of tumor progression (42%, 31%, and 26%,
      respectively). Our results show that these attributes of TIA-1+ TIL, both
      increasing total number but decreasing percentage, appear to be a marker of tumor
      progression of malignant melanomas. In addition, there was significant
      variability in the number of TIA-1+ TIL among advanced melanomas, raising the
      possibility that an assessment of TIA-1+ TIL may prove a useful prognostic tool
      for the evaluation of primary melanomas.

PMID- 10658911
TI  - Tenascin expression patterns and cells of monocyte lineage: relationship in human
      gliomas.
AB  - Stromal extracellular matrix (ECM) components are thought to play an important
      role in regulating invasion of human gliomas. Macrophages and microglial cells
      may heavily influence the integrity of the extracellular compartment of gliomas,
      and the affected ECM may play a key role in regulating migratory activity of both
      tumor cells and macrophages/microglia. The aim of this investigation was to study
      immunohistochemically the expression patterns of four ECM components:
      fibronectin, laminin, collagen IV, and tenascin (TN) in human gliomas, with
      special attention to TN. Our main goal was to study the possible correlation
      between TN expression and macrophagic/microglial infiltration in gliomas.
      Altogether, 90 gliomas were studied. Tumors included 46 glioblastomas, 19
      anaplastic gliomas, 22 low grade gliomas, and 3 pilocytic astrocytomas. Vascular
      TN prevailed in perinecrotic areas of glioblastomas, whereas interstitial TN was
      more often expressed distant from necrosis and in the ECM of anaplastic and low
      grade gliomas. Double staining with CD68 and anti-TN antibodies showed that
      macrophagic/microglial density was significantly higher in TN-positive areas of
      most of the glioblastomas and anaplastic gliomas, whereas microglial percentage
      from total number of CD68-positive cells was in most of the cases significantly
      higher in TN-negative areas. In addition, we saw a morphologically spatial
      correlation between higher densities of macrophagic/microglial infiltration and
      TN expression in perinecrotic areas in glioblastomas. Attachment of macrophages
      to TN-positive basement membrane zones of newly formed stromal blood vessels was
      evident. On the basis of our results, we conclude that TN may play a crucial role
      in regulating trafficking of cells of monocyte lineage in human gliomas.

PMID- 10658912
TI  - Synovial sarcoma of the upper digestive tract: a report of two cases with
      demonstration of the X;18 translocation by fluorescence in situ hybridization.
AB  - Two cases of synovial sarcoma that arose in the upper digestive tract are
      reported. One case was a polypoid mass that arose at the gastroesophageal
      junction; the other was a large intramural mass that arose in the wall of the
      stomach. Both cases had a classic biphasic pattern. In the stomach tumor, the
      biphasic morphology was focal and there was an abrupt transition to poorly
      differentiated synovial sarcoma. The tumors had immunohistochemical features that
      were consistent with synovial sarcoma. Ultrastructural evaluation of the
      gastroesophageal tumor supported the diagnosis. The diagnostic X;18 translocation
      was demonstrated by fluorescence in situ hybridization on sections from paraffin
      embedded tissue in 86% and 50% of interphase nuclei from the gastroesophageal and
      gastric tumor, respectively. The translocation was present in equal frequency in
      the epithelial and spindle cells in the biphasic areas and the poorly
      differentiated areas of the gastric tumor, indicating that the development of the
      more aggressive subclone was probably due to genetic mutations not encompassing
      the SYT-SSX gene fusion product. We are aware of only five reported cases of
      synovial sarcoma arising in the digestive tract, all in the proximal esophagus.
      These cases are the first reported arising in the gastroesophageal junction and
      stomach and the only cases of synovial sarcoma of the digestive tract in which
      the diagnostic translocation was demonstrated. Sarcomatoid carcinoma
      (carcinosarcoma) and gastrointestinal stromal tumor are the main differential
      diagnoses for synovial sarcoma in this site. Synovial sarcoma of the digestive
      tract may be underdiagnosed, and its recognition may have important clinical
      implications. Fluorescence in situ hybridization is helpful in making this
      distinction.

PMID- 10658913
TI  - Human herpesvirus 8-associated solid lymphomas that occur in AIDS patients take
      anaplastic large cell morphology.
AB  - Human herpesvirus type 8 (HHV-8; Kaposi's sarcoma-associated herpesvirus) is a
      recently isolated human herpesvirus frequently identified in Kaposi's sarcoma,
      primary effusion lymphoma, and multicentric Castleman's disease. Here we report
      three cases of HHV-8-bearing solid lymphomas that occurred in AIDS patients
      (Cases 1-3). All three patients were homosexual men presenting extranodal masses
      in the lungs (Case 1) or skin (Cases 2 and 3), together with the presence of
      Kaposi's sarcoma (Case 1), primary effusion lymphoma (Case 2), or multicentric
      Castleman's disease (Case 3). These solid lymphomas exhibited anaplastic large
      cell morphology and expressed CD30, corresponding to the recent diagnostic
      criteria of anaplastic large cell lymphoma (ALCL). The chromosomal translocation
      t(2;5)-associated chimeric protein p80NPM/ALK was not observed in any of these
      cases. HHV-8 was detected in all of these cases by polymerase chain reaction,
      immunohistochemistry of HHV-8-encoded ORF73 protein, and in situ hybridization of
      T1.1. Epstein-Barr virus was detected only in Cases 2 and 3 by in situ
      hybridization. It is interesting that inoculation of a cell line obtained from a
      primary effusion lymphoma cell in Case 2 to severe combined immunodeficiency mice
      produced HHV-8-positive and Epstein-Barr virus-negative tumors in inoculated
      sites. These tumor cells exhibited phenotypes of ALCL that were identical to the
      subcutaneous tumor cells of this particular patient. These findings clearly show
      that HHV-8 can associate with solid lymphomas and that it can take anaplastic
      large cell morphology. Those lymphomas should be distinguished from the classical
      ALCL as were defined by the revised European-American classification of lymphoid
      neoplasms even though morphology and a part of immunophenotype mimic that of
      classical ALCL.

PMID- 10658914
TI  - Pancreatic mucinous cystic neoplasms with sarcomatous stroma: molecular evidence
      for monoclonal origin with subsequent divergence of the epithelial and
      sarcomatous components.
AB  - Neoplasms with mixed carcinomatous and sarcomatous growth patterns occur in many
      organs and tissues. The pathogenesis of these cancers is thought to be either the
      result of two independent neoplastic processes merging to form a single tumor, or
      a neoplasm of monoclonal origin that develops phenotypic diversity. To address
      this issue, we characterized molecular alterations in separately microdissected
      epithelial and sarcomatous areas in three cases of pancreatic mucinous cystic
      neoplasms with sarcomatous stroma. Using microsatellite markers for six
      chromosomal loci commonly deleted in infiltrating ductal adenocarcinomas of the
      pancreas, we found genetic alterations to be virtually identical between the
      sarcomatous and epithelial components of two of the three neoplasms. In the third
      neoplasm, we found allelic losses and retentions to be identical at five of the
      six chromosomal loci, but at a single locus, we noted allelic loss in the
      neoplastic epithelial component but not the sarcomatous component. The same
      neoplasms were also analyzed for activating point mutations in codon 12 of the K
      ras gene by using mutant-enriched polymerase chain reaction and allele-specific
      oligonucleotide hybridization. A K-ras mutation was identified in the epithelial
      component of one of the three neoplasms (the same tumor with an additional
      allelic loss in the neoplastic epithelial cells), but the sarcomatous component
      of this tumor was wild-type at codon 12 of K-ras, as were both components of the
      other two neoplasms. Overall, these results suggest a monoclonal origin with
      subsequent divergence of the neoplastic epithelial and sarcomatous portions of
      these neoplasms.

PMID- 10658915
TI  - A novel in vitro human model of hemangioma.
AB  - Hemangioma, the most common tumor of infancy, is characterized by a proliferation
      of capillary endothelial cells with multilamination of the basement membrane and
      accumulation of cellular elements, including mast cells. The initial rapid growth
      is followed by an inevitable but slow involution. The currently available
      therapies are empirical and unsatisfactory because what is known of the cellular
      and molecular basis of hemangioma development is rudimentary. Advances in the
      understanding of its programmed biologic behavior has been hampered by the lack
      of a valid human model. We report here a novel in vitro culture system that is a
      useful human model of hemangioma. A small fragment of hemangioma biopsy is
      embedded in fibrin gel in a well of culture plates and incubated in a serum-free,
      buffered-salt, minimal medium. A complex network of microvessels grows out from
      the tissue fragments. Biopsies taken from all three phases of hemangioma
      development were cultured successfully; proliferative phase samples developed
      microvessels in 1 to 4 days, involuting phase in 5 to 7 days, and involuted phase
      in 7 to 12 days. The relative growth rates of the microvessels in the culture of
      biopsies taken from different stages of hemangioma development reflect the growth
      patterns seen clinically. This model has been validated using histochemistry,
      immunohistochemistry, and reverse transcriptase-polymerase chain reaction.
      Comparison of the number, localization, and phenotype of endothelial and mast
      cells and the distribution of basement membrane constituents (type IV collagen,
      perlecan, and laminins) and growth factors (basic fibroblast growth factor,
      vascular endothelial growth factor, transforming growth factor-betas) in the
      biopsy and the tissue after culture shows that many of the characteristics of the
      original tissues were retained in culture. This in vitro human model of
      hemangioma overcomes some of the deficiencies associated with earlier models. It
      offers an opportunity for studying the precise cellular, biochemical, and
      molecular basis of hemangioma It may also help to elucidate the mechanisms of
      action of existing therapies and may lead to the identification of novel
      treatments for hemangioma.

PMID- 10658916
TI  - Rajani B, Smith TA, Reith JD, Goldblum JR: Retroperitoneal leiomyosarcomas
      unassociated with the gastrointestinal tract: a clinicopathologic analysis of 17
      cases. Mod Pathol 1999;12:21-28.

PMID- 10658917
TI  - Correspondence re: Brunning R: Proposed WHO classification of acute myeloid
      leukemia and myelodysplastic syndromes. Mod Pathol 1999;1:102-4.

PMID- 10658918
TI  - Inorganic anions and the renal organic cation transport system.
AB  - During renal secretion, organic cations (OC) have to pass two hydrophobic
      membranes (basolateral and luminal) and the intervening aqueous cytoplasm.
      Furthermore, an uptake in intracellular endosomes may also occur. OC transport
      critically depends on the presence or absence of certain inorganic anions, such
      as Cl-, HCO3-, and others. The interaction between inorganic anions and OC may
      occur during the transport across the membranes or uptake by endosomes, by
      alterations of the transport protein or the substrate and by changes of the
      intracellular pH.

PMID- 10658919
TI  - Liver ischemia, catecholamines and preoperative condition influencing
      postoperative tachycardia in liver surgery.
AB  - The aim of our study was to assess the influence of intraoperative hypoxic stress
      -unavoidably brought about by so called Pringle maneuver - on free and conjugated
      catecholamines during major hepatic resection. Judging from earlier results of
      fatigue-experiments in rats we also wanted to check the relationship between of
      poor general preoperative condition and conspicuously low triglyceride serum
      concentrations. The study included 26 patients with primary and secondary liver
      tumors. The mean age was 54 years (range 27-79). Twenty-one patients had
      segmental liver resections, 3 had hemihepatectomies and 2 hydatid cysts were
      treated by cystectomy. Blood samples were taken 2 days before and throughout
      surgery. Catecholamine plasma values were determined by high performance liquid
      chromatography. Statistical comparisons were made by t-test, ANOVA and chi square
      test. Free plasma catecholamines increased significantly during prolonged
      intraoperative ischemia (Pringle time 50-125 minutes). Patients with elevated
      intraoperative catecholamines had a significant correlation to postoperative
      episodes of tachycardia, and prolonged hospital stay. On the other hand, we could
      also see postoperative tachycardias in patients with short Pringle times (18-49
      minutes) but with decreased preoperative serum triglycerides as an indicator of
      chronic stress and reduced general condition. Intraoperative hypoxic stress is
      associated with increased catecholamine values. Elevated catecholamines may well
      cause postoperative sinus-tachycardias (mean 20 hours) and are strongly related
      to postoperative liver failure and prolonged hospital stay.

PMID- 10658921
TI  - Differential localization of 5-hydroxytryptamine3 and 5-hydroxytryptamine4
      receptors in the human rectum.
AB  - The functions of the 5-hydroxytryptamine3 (5-HT3) and 5-hydroxytryptamine4 (5
      HT4) receptors in gastrointestinal tract are complex depending on the species and
      anatomical regions, and the localization of these receptors in the human rectum
      was unclear. We examined the localization of the 5-HT3 and 5-HT4 receptors in
      human rectum by in vitro receptor autoradiography using [125I](S)iodozacopride
      and [125I] SB207710 as a ligand, respectively. Specific [125I](S)iodozacopride
      binding sites were clearly evident in the myenteric plexus, whereas, low levels
      of [125I]SB207710 binding sites were distributed over the muscle but not to the
      myenteric plexus. The 5-HT3 receptor located on the myenteric plexus and the 5
      HT4 receptor on the smooth muscle may participate in contractility and relaxation
      of human rectum, respectively.

PMID- 10658920
TI  - Suppression of neuropeptides' mRNA expression by herbal medicines in a rat model
      of peripheral inflammation.
AB  - The traditional Chinese medicines have been used clinically for a long time in
      some Asian countries, however, very few studies have been done to demonstrate the
      working mechanisms of these medicines using recently developed biochemical
      methodologies. In this study, we examined the anti-inflammatory effect of Huang
      Lian-Jie-Du-Tang (HLJDT), a combination of herbs used in traditional Chinese
      medicine, on paw edema, thermal hyperalgesia and the mRNA increase of
      neuropeptides in spinal dorsal horn and hypothalamic neurons using a rat model of
      peripheral inflammation and hyperalgesia. The rats that received HLJDT from 3
      days before the injection of complete Freund's adjuvant (CFA) into the plantar
      had significantly less edema and reduced thermal hyperalgesia compared to control
      rats that received CFA injection. The up-regulation of preprodynorphin mRNA in L4
      5 dorsal horn neurons 8 hours after CFA injection that was observed in control
      rats, was also decreased in the HLJDT-treated rats. Moreover, there was a
      significant decrease in mRNA level of corticotropin-releasing factor in the
      paraventricular hypothalamic nucleus in the HLJDT-treated rats. These data
      demonstrate that HLJDT is anti-inflammatory, and produces changes in mRNA
      expression in dorsal horn and hypothalamic neurons. This is the first
      demonstrated that a traditional Chinese medicine can affect the excitability of
      neurons through an anti-inflammatory action.

PMID- 10658922
TI  - Endogenous monoamine oxidase inhibitory activity and HPA activation in the pig.
AB  - Previously we have shown that an increase in endogenous monoamine oxidase A
      inhibitory activity (MAO-AI), measured in human saliva, both precedes and
      predicts psychological stress-induced activation of the hypothalamic pituitary
      adrenal (HPA) axis, as determined by the cortisol response. We now report the
      relationship between endogenous MAO-AI and the cortisol response in the plasma of
      prepubertal pigs (n=5 or 6) under two experimental paradigms of HPA activation.
      In the first condition, pigs were physically restrained (snaring) for 15 minutes.
      Blood samples were taken from indwelling catheters at intervals before and after
      snaring (a sampling period of about 1 hour), and at the same time intervals on a
      separate day to provide baseline measures. Both cortisol concentration and
      percentage MAO-AI were determined in each plasma sample. There was a pronounced
      cortisol response on the snaring day (cortisol peaked 30 minutes after the start
      of the snaring). There was also a significant MAO-AI response to snaring which
      peaked 15 minutes after the start of the stress challenge. In the second
      experimental paradigm, bacterial endotoxin (LPS: 20microg/pig) was used to induce
      HPA activation and plasma cortisol and MAO-AI were determined. This time,
      however, the cortisol response was not preceded by any change in MAO-AI. We
      conclude that generation of MAO-AI, which is associated with HPA activation
      induced by psychological stress, is not a component of the pathways involved in
      immunological stimulation of the HPA axis.

PMID- 10658923
TI  - Tritiated kappa receptor antagonist norbinal torphimine: synthesis and in vitro
      binding in three different tissues.
AB  - Recently a new antagonist with high selectivity for the kappa receptors
      (norbinaltorphimine) was developed and tested in various systems. This compound
      was radiolabelled with tritium resulting in high specific radioactivity (47.2
      Ci/mmol). [3H]Norbinaltorphimine was characterized by in vitro radioligand
      binding assays. The radioligand binds to kappa-opioid receptors with a high
      potency and selectivity in guinea pig, frog and rat brain membranes. Our results
      suggest the kappa1 specificity of the radioligand.

PMID- 10658924
TI  - SR142801 behaves as a tachykinin NK-3 receptor agonist on a spinal nociceptive
      reflex in the rat.
AB  - Effects of two commonly used tachykinin NK-3 receptor antagonists (SR 142801 and
      R820) intrathecally (i.t.) administered were assessed in the rat tail-flick test.
      SR142801 and its (R)-enantiomer SR142806 (1.3, 6.5 and 65 nmol) were found as
      potent as senktide and [MePhe7]NKB (NK-3 selective agonists) to induce transient
      antinociceptive effects. Naloxone (10 microg) and R820 (6.5 nmol) blocked
      reversibly the responses to 6.5 nmol senktide, [MePhe7]NKB, SR142801 and SR142806
      when administered i.t. 15 min earlier. However, the antinociceptive responses
      induced by SR142801 and SR142806 were not affected by i.t. pretreatments with NK
      1 (6.5 nmol SR140333) and NK-2 (6.5 nmol SR48968) receptor antagonists. In
      control experiments, the NK-1 and NK-2 antagonists prevented the hyperalgesic
      effects to NK-1 ([Sar9,Met(O2)11]SP) and NK-2 ([beta-Ala8] NKA(4-10)) receptor
      agonists (6.5 nmol i.t.), respectively. R820 had no direct effect on nociceptive
      threshold and failed to alter angiotensin II-induced antinociception. The data
      suggest that the antinociceptive effect of SR142801 is due to an agonist effect
      at NK-3 receptor in the rat spinal cord that involves a local opioid mechanism.
      These results can be best explained by the existence of inter-species NK-3
      receptor subtypes.

PMID- 10658925
TI  - Opposing actions of angiotensins on angiogenesis.
AB  - Using the murine sponge model of angiogenesis, associated to functional and
      morphological parameters we have demonstrated opposing actions of angiotensin II
      (Ang II) and angiotensin-(1-7;Ang-1-7) in modulating fibrovascular tissue growth.
      Angiogenesis in the implants was assessed at day 7 postimplantation by extracting
      the hemoglobin content, by determining the outflow rate of sodium fluorescein
      applied intraimplant and by histological analysis. Furthermore, the proliferative
      activity of control and angiotensin-treated implants was established using the
      MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2(4 -sulfonyl)2H
      tetrazolium)assay. The hemoglobin content in the control implants was 2.4 +/-
      0.14 (microg/mg wet weight) versus 3.6 +/- 0.27(Ang II;100 ng) and 0.86 +/- 0.07
      Ang-(1-7); 20 ng. Blood flow in the implants as determined by t1/2 values (time
      taken for the fluorescence to reach 50% of the peak in the systemic circulation)
      showed that Ang II stimulated angiogenesis, whereas Ang-(1-7) inhibited it. The
      proliferative activity of the sponge-induced fibrovascular tissue was enhanced by
      Ang II and diminished by Ang-(1-7). These results show the pro-versus anti
      angiogenic effects of these angiotensin molecules, providing evidence for their
      opposing effects on vascular tissue growth and wound healing in vivo.

PMID- 10658926
TI  - Effects of cAMP-dependent protein kinase and ATP on N1-oxidation of 9
      benzyladenine by animal hepatic microsomes.
AB  - N1-Oxidation is a major metabolic pathway for 9-benzyladenine (BA) catalyzed by
      the cytochrome P450 system in animal hepatic microsomes. After normal hamster
      hepatic microsomes or phenobarbital induced rabbit hepatic microsomes were
      preincubated in the presence of cyclic AMP-dependent protein kinase catalytic
      subunit (PKA), MgCl2 and ATP, BA-N1-oxidation was significantly decreased.
      However, further investigation indicated that the decrease of BA-N1-oxidation
      seemed to be a combination of the effects of PKA and ATP, as ATP alone showed a
      biphasic regulatory effect on BA-N1-oxidation when microsomes were preincubated
      in the presence of various concentrations of ATP. In the lower ATP concentration
      range (0.5-2.5mM), BA-N1-oxidation increased along with the increase of ATP
      concentration; whereas BA-N1-oxidation decreased when the ATP concentration was
      higher (>5mM). The biphasic regulatory effects of ATP on BA-N1-oxidation seem
      dependent on the incubation process, as preincubation markedly strengthened the
      effects. When microsomes were incubated at 37 degrees C for different time
      lengths in the absence or presence of ATP (2.5 or 20mM), the activity of BA-N1
      oxidase decreased at similar rates in all groups, but the activity levels of BA
      N1-oxidase were different among the groups. The cytochrome P450 content was not
      changed parallel to the variation of BA-N1-oxidation when microsomes were
      incubated in the presence of ATP, indicating that the effects of ATP on BA-N1
      oxidation were not mediated by affecting CYP stability. In addition, the activity
      of NADPH-cytochrome P450 reductase was not markedly affected by ATP without
      incubation. The result implied that ATP did not inhibit the reductase directly.
      After microsomes were incubated in the presence of low ATP concentration (2.5mM),
      the reductase was slightly inhibited, whilst high ATP concentration (20mM) showed
      marked inhibition (83% of control). This may partially contribute to the down
      regulatory effect of ATP on BA-N1-oxidation. Furthermore, it was found that the
      presence of magnesium ions during preincubation weakened the up-regulatory effect
      of ATP (2.5mM) on BA-N1-oxidation, but showed no effect on the down-regulatory
      effect of ATP (20mM). Since these observed phenomena are not readily explained, a
      possible mechanism, i.e. phosphorylation and dephosphorylation of cytochrome
      P450, is suggested.

PMID- 10658927
TI  - New EIA technique for tyrosinase in human melanocytes and its application.
AB  - The expression of tyrosinase in melanocytes relates to skin pigmentation or
      depigmentation. Although many types of drugs with whitening effects are well
      known, neither the definite effect nor the mechanism underlying the effect has
      been elucidated. In this study, we attempted to develop the rapid and simple EIA
      technique for tyrosinase protein, then this technique was applied to normal human
      cultured melanocytes. When primary antibody and tyrosinase were incubated in non
      coated 96-well microtitre plates for 48 hours at 4 degrees C, then the solution
      in tyrosinase-coated plate was further incubated for another 1 hour at 37 degrees
      C. Thus the best results were obtained. The developed EIA system could detect
      authentic tyrosinase until 0.1-1.0 ng/mL. This EIA technique could also be
      applied to human cultured melanocytes. The melanocytes cultured with endothelin-1
      induced tyrosinase like immune reactive protein. The protein induction with
      endothelin-1 was suppressed by BQ 123, ETa receptor antagonists. The simple EIA
      technique developed for tyrosinase may give a clue to determination of the onset
      mechanisms underlying pigmental diseases of the skin as well as the mechanisms
      underlying the effects of various whitening drugs.

PMID- 10658928
TI  - Small molecular weight heat shock-related protein, HSP20, exhibits an anti
      platelet activity by inhibiting receptor-mediated calcium influx.
AB  - We have shown that Hsp20, one of small molecular weight heat shock protein, which
      is present at a high concentration both in vascular smooth muscle cells and in
      circulating blood in patient with vascular disease, strongly inhibits platelet
      aggregation in vitro and ex vivo. To clarify the mechanism, we investigated the
      effect of Hsp20 on free calcium concentration in human platelet cytoplasm using
      fura 2. Hsp20 inhibited thrombin-induced calcium influx without affecting calcium
      release from intracellular calcium stores. The degree of inhibition is well
      correlated with that of suppression of thrombin-induced platelet aggregation by
      this substance. Hsp20 also inhibited the elevation of cytoplasmic free calcium
      level triggered by collagen, but not that by A-23187. In contrast, Hsp28, another
      type of small molecular weight Hsp, failed to affect the cytoplasmic free calcium
      level. These findings suggest that Hsp20 inhibits the receptor-mediated calcium
      influx of platelets without affecting calcium release from intracellular calcium
      stores, leading to its anti-platelet activity.

PMID- 10658929
TI  - Endothelium-dependent relaxation by tetraoctylammonium ions in rat isolated
      aortic rings.
AB  - Quaternary ammonium ions are common pharmacological blockers of K+ channels. This
      study examined the vasorelaxant effect of tetraoctylammonium ions (TOA+) in rat
      isolated aortic rings. TOA+ caused a concentration-dependent transient relaxation
      of endothelium-intact tissues. Pretreatment with NG-nitro-L-arginine methyl ester
      (L-NAME, 3x10(-5) M) or methylene blue (3 x 10(-6) M) or removal of the
      endothelium abolished the TOA+-induced relaxation. L-arginine (10(-3) M )
      partially antagonized the effect of L-NAME. Glibenclamide (3x10(-6) M),
      charybdotoxin (CTX, 10(-7) M), indomethacin (10(-5) M), or atropine (3x10(-6) M)
      had no effect. Both TOA+ (10(-5) M)- and acetylcholine (ACh, 10(-5) M)-induced
      increase in tissue content of cyclic GMP was significantly attenuated by NG-nitro
      L-arginine (L-NNA, 10(-4) M) and abolished in endothelium-denuded arteries. These
      results indicate that TOA+ induced endothelium-dependent relaxation which is
      likely mediated through nitric oxide but not other endothelium-derived factors.
      This relaxant action seems unique for TOA+ since other quaternary ammonium ions
      did not cause nitric oxide-dependent relaxation.

PMID- 10658930
TI  - Renal angioplasty: better for treating hypertension or for rescuing renal
      function?
AB  - Angioplasty of renal artery stenosis has been used extensively in the last two
      decades for treating renovascular hypertension, and, more recently, for
      preserving the jeopardized renal function. A large body of evidence has
      accumulated indicating that this approach is by far the most convenient for
      patients with fibromuscular stenosis in whom the technical success of the
      procedure is followed by a high cure rate (50%) or at least by some improvement
      of blood pressure (40%). In contrast, in patients with atheromatous stenosis, the
      rate of cure is very low (8-10% at best) and the rate of improvement is between
      40 and 50% irrespective of whether the stenosis is treated with angioplasty or
      with stent implantation. Thus, before undergoing procedures which are not devoid
      of potentially serious side-effects, these patients should be thoroughly
      investigated to select those in whom the benefit actually outweighs the risks.
      Studies investigating the effects of angioplasty on renal function are less
      numerous than those addressing the effects on blood pressure, and, in most cases,
      suffer the limitation of using the levels of serum creatinine as the sole marker
      of the changes in glomerular filtration rate induced by the procedure. These
      investigations have shown that some amelioration can be achieved in one-third of
      patients, with another third having unmodified levels of creatinine at follow-up.
      Radioisotopic techniques, which allow a more precise and separate evaluation of
      the function of the two kidneys, appear to be a promising alternative for the
      investigation of the effects of angioplasty; indeed, preliminary studies which
      took advantage of these methodologies have shown that the function of the
      stenotic kidney can possibly be rescued by slowly reversing the multiple
      mechanisms by which chronic ischaemia damages the kidney.

PMID- 10658931
TI  - The amplifier hypothesis: permission to dissent?

PMID- 10658932
TI  - Associations between heart rate and other risk factors in a large French
      population.
AB  - OBJECTIVES: In a large general French population of 100,000 subjects, the
      relationship of resting heart rate with age, gender, demographic parameters,
      physical activity and classical risk factors was evaluated. POPULATION AND
      METHODS: A population composed of all the subjects who had a free health check-up
      at the IPC Centre between 1992 and 1995 (62,353 men and 35,371 women) was
      analysed. Heart rate was considered either as a continuous parameter or as a
      qualitative parameter. The study population was divided into four heart rate
      classes: < 65, 65-74, 75-84 and > or = 85 beats/min. RESULTS: Women had
      significantly higher heart rate values than men, and this gender difference was
      constant in the different age groups. In both genders, heart rate was positively
      associated with blood pressure, triglycerides, glycaemia and physical inactivity,
      and negatively with body height Heart rate was also correlated with total
      cholesterol but only in men. The only factor having opposite effects on heart
      rate in men and women was tobacco smoking (positive in men and negative in
      women). Among untreated hypertensive men, 21.3% had a heart rate > or = 85
      beats/min compared with only 4.0% among normotensive men. In women, these
      percentages were 23.6 and 7.6%, respectively. Subjects with untreated mild
      hypertension or uncontrolled treated hypertension also showed increased rates of
      tachycardia compared to normotensives. CONCLUSIONS: The present analysis,
      performed in a large French population, shows that high heart rate is associated
      with several other risk factors, especially hypertension, suggesting that
      tachycardic subjects have a high risk profile.

PMID- 10658933
TI  - Genetic and environmental causes of covariation among blood pressure, body mass
      and serum lipids during young adulthood: a twin study.
AB  - OBJECTIVE: To determine the extent to which the correlation of systolic blood
      pressure, diastolic blood pressure, body mass, fasting total cholesterol and
      fasting triglycerides in young adulthood reflects common genetic or environmental
      influences. DESIGN: Cardiovascular risk factors were measured in a community
      sample of 129 monozygotic and 67 dizygotic twin pairs, ages 18-30 years. METHODS:
      Multivariate twin structural equation modelling allows estimation of the extent
      to which the covariation of two or more variables is attributable to common
      genetic and environmental factors and was used to analyse the correlation among
      systolic blood pressure, diastolic blood pressure, body mass index, fasting total
      cholesterol and triglycerides. RESULTS: The covariation of risk factors was
      partially attributable to a single common genetic factor, while the covariation
      of systolic blood pressure, body mass index and triglycerides was also, in part,
      attributable to a common non-shared environmental factor. CONCLUSIONS: Genetic
      and, to a lesser extent, non-shared environmental factors contribute to the
      covariation of cardiovascular risk factors in young adult twins. Nonetheless, it
      should be noted that these common influences account for a relatively small
      percentage of the variance in each risk factor compared to genetic and
      environmental factors that are risk factor-specific.

PMID- 10658934
TI  - Enhanced total peripheral vascular responsiveness in hypertension accords with
      the amplifier hypothesis.
AB  - BACKGROUND: Increases in vascular resistance (or the reciprocal, vascular
      conductance) in response to constrictor drugs are amplified (or attenuated) in
      the hindquarter vascular bed of hypertensive rats and rabbits. However, such
      changes have not been observed for the total peripheral circulation. OBJECTIVE:
      To assess whether the vascular amplifier applies to the total peripheral
      circulation in conscious hypertensive rabbits. METHODS: Rabbits were implanted
      with a flow probe for measuring cardiac output, a left atrial catheter for
      infusing dilator (adenosine) and constrictor (methoxamine) drugs, and ear artery
      and vein catheters for measuring mean arterial pressure (MAP) and for giving
      ganglion blockade. Data from full dose-total peripheral resistance (TPR) or total
      peripheral conductance (TPC) response curves to adenosine and methoxamine were
      combined into a logistic function extending from near full dilatation to near
      maximum constriction. RESULTS: Changes in MAP induced by methoxamine and
      adenosine were markedly greater in the 'wrap' rabbits (those with renal
      cellophane wrapping) compared with the sham animals. In the 'wrap' rabbits, the
      slopes and ranges of the adenosine-TPR response curve and the methoxamine-TPC
      response curve were 200% and 60%, respectively, of sham values. These data show
      that TPR changes are amplified, and TPC changes attenuated, to dilator and
      constrictor stimuli. The relationship between dose-average vascular radius (r;
      based on Poiseuille's law) over the full range of vascular tone showed that r was
      narrower in hypertension, but, in contrast to TPR, the degree of narrowing was
      almost the same between maximum dilatation and constriction. CONCLUSION: The
      total peripheral circulation in experimental hypertension is a TPR amplifier, or
      TPC attenuator, in the rabbit, consistent with well-established data in the major
      vascular beds.

PMID- 10658935
TI  - Stroke-prone spontaneously hypertensive rats lose their ability to auto-regulate
      cerebral blood flow prior to stroke.
AB  - OBJECTIVES: We hypothesized that the loss of cerebral blood flow (CBF) auto
      regulation under hypertensive conditions could promote cerebrovascular over
      perfusion and haemorrhage formation. The possibility that CBF auto-regulation
      becomes defective prior to haemorrhagic stroke development was assessed in Wistar
      Kyoto stroke-prone spontaneously hypertensive rats (SHRsp) and related to the
      myogenic responsiveness of the cerebrovasculature to pressure. METHODS: Laser
      Doppler techniques were used to measure relative CBF in relation to mean arterial
      pressure (MAP 130-260 mmHg) within the perfusion domains of the middle (MCA) and
      posterior (PCA) cerebral arteries. The ability of isolated MCAs and PCAs to
      constrict to a 120 mmHg pressure step (pressure-dependent constriction) was
      measured using a pressure myograph. RESULTS: Two weeks prior to stroke, 10-week
      old pre-stroke SHRsp exhibited near-constant CBF regulation to a 200 mmHg MAP.
      Thirteen-week-old pre-stroke SHRsp and age-matched post-stroke SHRsp lost their
      ability to auto-regulate CBF in the MCA and PCA perfusion domains. CBF increased
      at a high rate and in a linear manner with MAP. A distinct upper limit to CBF
      auto-regulation was absent. Pressure-dependent constriction was attenuated prior
      to stroke, and lost after stroke in isolated MCAs, but not the PCAs, of SHRsp.
      CONCLUSIONS: The loss of CBF auto-regulation prior to stroke in SHRsp could
      enhance cerebral perfusion and facilitate the initiation of haemorrhage. Such
      dysfunction after stroke could produce secondary haemorrhages. Defects in
      pressure-dependent constriction cannot fully account for the pattern of CBF auto
      regulation loss observed in post-stroke SHRsp.

PMID- 10658936
TI  - Effects of nitric oxide blockade and cyclosporin A on cardiovascular and renal
      function in normal man.
AB  - OBJECTIVE: The present study investigated whether the nitric oxide (NO) system is
      involved in cyclosporin A (CsA)-induced changes in cardiovascular and renal
      function in man. SUBJECTS AND METHODS: Ten healthy volunteers were investigated
      twice--with and without intake of a single dose of CsA (8 mg/kg). N(G)-monomethyl
      L-arginine (L-NMMA; 3 mg/kg) was injected 4 h after study start on each day.
      RESULTS: There was no change in glomerular filtration rate (GFR) on the day
      without CsA. CsA alone did not change GFR, but after L-NMMA injection, GFR
      decreased significantly from 101 +/- 4 to 91 +/- 4 ml/min. L-NMMA increased renal
      vascular resistance with no difference between the two study days. CsA increased
      significantly the diastolic blood pressure (BP) by 8 +/- 2% and the heart rate
      (HR) by 30 +/- 4%, without changes in cardiac output L-NMMA further increased BP
      by around 8%, and decreased HR by 11% and cardiac output by 20% on both study
      days. L-NMMA decreased urinary flow rate by around 25% and renal sodium clearance
      from 1.1 to approximately 0.6 ml/min on both study days. CsA decreased plasma
      renin significantly and increased the urinary excretion rate of prostaglandin E2
      (PgE2), 6-keto-prostaglandin F1alpha (6-keto-PgF1alpha) and thromboxane B2(TxB2)
      when compared to the control day. The urinary excretion rate of NOx and cGMP
      declined gradually on the control day. In contrast, there was a minor, non
      significant increase in NOx and cGMP excretion after CsA, followed by a decrease
      (29 +/- 2 and 16 +/- 4%, respectively) after L-NMMA in parallel with the decrease
      in GFR. CONCLUSION: The present findings suggest that NO does not play a major
      role during acute CsA-induced changes in cardiovascular function and renal
      haemodynamics in man. Renal NO synthesis, however, may attenuate the acute CsA
      induced decrease in GFR.

PMID- 10658937
TI  - Haemodynamic mechanisms of corticotropin (ACTH)-induced hypertension in the rat.
AB  - OBJECTIVES: To investigate the roles of cardiac output and systemic and regional
      resistances in corticotropin (ACTH)-induced hypertension in the rat METHODS: This
      study consisted of three series of experiments with eight groups of male Sprague
      Dawley rats (n = 132). Series 1 comprised groups 1-4, where group 1 = sham (0.9%
      NaCl, subcutaneous (s.c.) injection); group 2 = ACTH (0.5 mg/kg per day, s.c.);
      group 3 = atenolol + sham; group 4 = atenolol + ACTH treatments. Series 2
      comprised groups 5 and 6, where group 5 = minoxidil + sham and group 6 =
      minoxidil + ACTH treatments. Series 3 comprised groups 7 and 8, where group 7 =
      ramipril + sham and group 8 = ramipril + ACTH treatments. Systolic blood
      pressure, water and food intakes, urine volume, and body weight were measured
      every second day. After 10 days of treatment, mean arterial blood pressure was
      measured by intra-arterial cannulation, and cardiac output (CO), and renal,
      mesenteric and hindquarter blood flows (RBF, MBF and HBF) determined using
      transonic small animal flowmeters. RESULTS: ACTH treatment increased blood
      pressure (P < 0.001) with a rise in CO (P < 0.01) and renal vascular resistance
      (RVR, P < 0.05), but did not affect total peripheral resistance (TPR). Atenolol
      blocked the rise in CO without affecting the rise in blood pressure produced by
      ACTH treatment Minoxidil lowered TPR, but did not prevent the rise in blood
      pressure or renal vascular resistance. Ramipril blunted the rise in RVR and blood
      pressure without significantly affecting TPR. CONCLUSION: Neither preventing rise
      in CO nor lowering TPR altered the ACTH-induced rise in blood pressure in the rat
      However, both the hypertension and rise in RVR were prevented by ramipril. These
      data suggest that increase in RVR may play a role in the pathogenesis of ACTH
      induced hypertension in the rat.

PMID- 10658938
TI  - Triiodothyronine: a link between the insulin resistance syndrome and blood
      pressure?
AB  - OBJECTIVE: Overall obesity is associated with elevated serum triiodothyronine
      concentrations and insulin resistance. Oral triiodothyronine is known to induce
      hypertension in laboratory rats, while triiodothyronine also increases the
      expression of genes encoding for enzymes involved in the synthesis and secretion
      of insulin by pancreatic beta cells. We investigated the hypothesis that central
      obesity and insulin resistance are linked with an increased blood pressure and
      insulin production through elevated free serum triiodothyronine concentrations.
      DESIGN: A cross-sectional study of 47 healthy euthyroid subjects (17 men, 30
      women; 34 +/- 15 years, mean +/- SD). METHODS: The waist:hip ratio was used as
      measure of central obesity, and insulin-stimulated glucose disposal during a
      hyperinsulinaemic euglycaemic clamp was used as measure of insulin sensitivity.
      Insulin production was calculated from the insulin clearance during the clamp and
      fasting insulin concentrations. RESULTS: Free serum triiodothyronine
      concentrations correlated, independent of age and gender, positively with
      systolic and diastolic blood pressure, insulin production and fasting insulin.
      There was only a borderline significant correlation of free serum
      triiodothyronine with the waist-to-hip ratio, and no correlation with insulin
      sensitivity as assessed during the clamp. The correlations of free serum
      triiodothyronine with blood pressure, insulin production and fasting insulin were
      independent of the waist:hip ratio and insulin sensitivity. CONCLUSION: Our
      hypothesis of free serum triiodothyronine as an intermediate factor in the
      insulin resistance syndrome is refuted by these data, but we identified free
      serum triiodothyronine concentrations as a new determinant of blood pressure,
      insulin production, and fasting insulin in healthy euthyroid subjects.

PMID- 10658939
TI  - Inter-observer variability in the angiographic assessment of renal artery
      stenosis. DRASTIC study group. Dutch Renal Artery Stenosis Intervention
      Cooperative.
AB  - OBJECTIVE: To assess inter-observer agreement in the interpretation of renal
      angiograms. DESIGN: Comparison of the assessment of renal angiograms by three
      experienced radiologists, who evaluated the number of renal arteries and the
      presence, location, aspect and severity of a renal artery stenosis. SETTING:
      General hospital and university hospital serving urban and rural populations.
      PATIENTS: Patients with difficult-to-treat hypertension referred for diagnostic
      work-up; 312 angiograms with the intra-arterial digital subtraction technique
      were obtained from 289 consecutive patients. MAIN OUTCOME MEASURES: Inter
      observer agreement was tested for the following parameters: number of arteries
      per kidney, presence of stenosis, location of stenosis (truncal, ostial), aspect
      of stenosis (concentric, eccentric, post-stenotic dilatation), severity of
      stenosis (reduction of lumen diameter in categories of 30%, 40%, etc. to 100%),
      and overall quality of the angiographic images. Kappa (kappa) values and weighted
      kappa between the three pairs of radiologists were used as estimates of inter
      observer agreement RESULTS: Agreement about the number of renal arteries was
      reasonable (kappa = 0.50-0.72), as was agreement about the presence of stenosis
      (kappa = 0.68-0.86). Agreement about stenosis location and aspect was poor (kappa
      = 0.26-0.47 and kappa = 0.15-0.26, respectively). There was general agreement
      about the severity of stenosis (weighted kappa = 0.65-0.70), but it was not
      possible to distinguish between 50 and 60% stenosis or between 60 and 70%
      stenosis (kappa < 0.40). No correlation was found between agreement on severity
      of stenosis and the quality of the images. CONCLUSIONS: It is not realistic to
      make statements about what degree of renal artery stenosis is clinically
      significant, as long as the intra-arterial angiogram with digital subtraction
      remains the gold standard. It is likewise risky to rely too strongly on stenosis
      morphology as visualized by renal angiography in choosing between balloon
      angioplasty and stent deployment.

PMID- 10658940
TI  - Interpretation of renal angiography by radiologists.
AB  - OBJECTIVE: Different radiologists may show considerable variation in their
      interpretation of renal angiograms. We therefore wished to establish the
      reliability of their interpretation. DESIGN: Assessment of the intra- and inter
      observer agreement of the interpretation of renal angiograms. SETTING: Tertiary
      referral university hospital. PATIENTS: Hypertensive patients suspected of
      renovascular hypertension on clinical grounds or on the basis of renography.
      INTERVENTIONS: Patients were prospectively selected to undergo a renal
      angiography via the femoral approach. MAIN OUTCOME MEASURES: Intra- and inter
      observer agreement of the degree and site of stenosis. RESULTS: The difference
      between two estimates of the degree of stenosis ranged from 0 to 65% for the
      individual readers and from 0 to 75% between two readers. When the site of
      greatest stenosis was in the origin of the renal artery, the intra-observer
      agreement kappa ranged from 0.54-0.71, the inter-observer agreement across
      multiple readers being 0.43. In a post hoc analysis using two different cut-off
      points of stenosis (50 or 70%), the intra- and inter-observer agreement was
      better at the 70% cut-off-point. In a subset of patients with stenosis and a
      renin ratio greater than 1.5, both the intra- and inter-observer agreement were
      much better than when all angiograms were considered. CONCLUSIONS: Assessment of
      the diagnostic performance of three experienced radiologists in their
      interpretation of renal artery angiograms indicates that the intra- and inter
      observer agreement with respect to their estimates of the degree of stenosis and
      the site of greatest stenosis are rather poor but their diagnostic performance
      improves in patients with stenosis and a renin ratio greater than 1.5. There is a
      need for more objective assessment of renal artery lesions.

PMID- 10658941
TI  - Increased cardiovascular mortality in hypertensive patients with renal artery
      stenosis. Relation to sympathetic activation, renal function and treatment
      regimens.
AB  - BACKGROUND: Previous studies in hypertensive patients with renovascular disease
      have shown both elevated sympathetic nerve activity and increased cardiovascular
      mortality. OBJECTIVE: The aim of the present study was to assess long-term
      survival in hypertensive patients with renal artery stenosis in relation to
      sympathetic activation, renal function and treatment regimens. SUBJECTS AND
      METHODS: A total of 169 consecutive patients aged 54 +/- 1 years with
      hypertension underwent a clinical investigation for renovascular hypertension
      including renal angiography and measurement of bilateral renal renin secretion.
      In 107 of these patients, arterial plasma concentrations of noradrenaline were
      measured. The mean follow-up time was 7.1 +/- 0.3 years and survival data were
      available in all patients up to May 1997. For comparison, healthy age-matched
      normotensive controls were examined. RESULTS: Arterial noradrenaline
      concentrations were threefold elevated in hypertensive patients with renal artery
      stenosis compared to healthy controls (P < 0.01). During the follow-up time, 44
      patients died. Cardiovascular mortality accounted for 75% of all deaths. The risk
      ratio for overall mortality in hypertensive patients with renal artery stenosis
      compared to the normal population of Sweden, matched for age, was 3.3 (2.4-4.4),
      whereas the risk ratio for cardiovascular mortality was 5.7 (3.9-8.0). The
      arterial plasma concentration of noradrenaline was 3.11 +/- 0.30 pmol/ml in
      patients who died compared to 3.84 +/- 0.26 pmol/ml in survivors. Reduced renal
      function and age were independent predictors of death. Survival did not differ
      between patients undergoing intervention with either renal angioplasty or
      surgical reconstruction for renal artery stenosis and patients not undergoing
      intervention. CONCLUSIONS: Although sympathetic nerve activity is elevated in
      hypertensive patients with renal artery stenosis, our results do not suggest that
      this adrenergic over-activity is directly linked to the observed high
      cardiovascular mortality. Mortality in hypertensive patients with renovascular
      disease remains high whether an interventional treatment is performed or not,
      possibly due to the concomitant coronary disease.

PMID- 10658942
TI  - Prediction of left ventricular geometry by clinic, pre-dialysis and 24-h
      ambulatory BP monitoring in hemodialysis patients: CREED investigators.
AB  - OBJECTIVE: Arterial hypertension is an established risk factor for left
      ventricular hypertrophy (LVH) in the uremic population. However, whether 24-h
      monitoring is a better predictor of LVH than clinic blood pressure and routine
      pre-dialysis measurements in these patients is still undefined. METHODS: This
      problem was studied in 64 nondiabetic hemodialysis patients without heart
      failure. The echocardiographic study as well as the clinic and 24-h ambulatory
      blood pressure (BP) measurements were performed during the day off-dialysis. Pre
      dialysis arterial pressure was calculated as the average value of the 12 routine
      recordings taken during the month preceding the study. RESULTS: In multivariate
      models, including also sex, body mass index, hematocrit and serum cholesterol,
      pre-dialysis systolic, diastolic and pulse pressures were the only independent BP
      determinants of heart geometry. Twenty-four hour ambulatory BP monitoring (ABPM)
      did add significant (but weak) information to the prediction of left ventricular
      internal dimension, i.e. it increased by 9% (P = 0.01) the variance already
      explained by pre-dialysis diastolic BP and other significant covariates. However,
      24-h ABPM did not add any significant and independent explanatory information to
      the corresponding pre-dialysis measurements for the posterior wall and
      interventricular septum measurements, and for left ventricular mass (-0.6 to
      +3.9%; average +1.1%). CONCLUSIONS: In dialysis patients, pre-dialysis BP is at
      least as strong a predictor of left ventricular mass as 24-h ambulatory
      monitoring. Thus, the average of 12 routine pre-dialysis measurements may be used
      to predict heart geometry in dialysis patients without any loss of information in
      comparison with 24-h ambulatory monitoring.

PMID- 10658943
TI  - Effects of valsartan on left ventricular diastolic function in patients with mild
      or moderate essential hypertension: comparison with enalapril.
AB  - OBJECTIVE: This study compares the effects of an AT1 angiotensin II receptor
      antagonist (valsartan) with those of an ACE inhibitor (enalapril) on left
      ventricular (LV) diastolic function in patients with mild or moderate essential
      hypertension and no evidence of LV hypertrophy at echocardiography. METHODS: A
      total of 24 patients (16 men, mean age 47 +/- 8 years) underwent radionuclide
      ambulatory monitoring (Vest) of LV function at rest and during upright bicycle
      exercise testing before and after two 4-week treatment periods with valsartan (80
      160 mg/day orally) and enalapril (20-40 mg/day orally) according to a double
      blind, crossover randomization scheme. RESULTS: In the overall population no
      differences between the two treatments were found in LV peak filling rate (PFR)
      either at rest or at peak exercise. In a subgroup analysis it was found that
      baseline PFR was normal (= 2.5 EDV/sec) in 12 patients (subgroup A) and impaired
      (< 2.5 EDV/sec) in the remaining 12 (subgroup B). In both subgroups, valsartan
      and enalapril induced a significant and comparable reduction of systolic and
      diastolic blood pressure. In subgroup A, valsartan and enalapril did not induce
      significant changes in PFR. In subgroup B, valsartan increased PFR both at rest
      (from 2.0 +/- 0.3 to 2.4 +/- 0.3 EDV/sec, P < 0.01) and at peak exercise (from
      4.1 +/- 1.1 to 4.4 +/- 1.0 EDV/s, P < 0.05), whereas enalapril did not change PFR
      either at rest (2.0 +/- 0.4 EDV/s, P < 0.01 versus valsartan) or at peak exercise
      (3.7 +/- 1.1 EDV/sec, P < 0.05 versus valsartan). CONCLUSIONS: Valsartan-induced
      renin-angiotensin system blockade is able to improve LV filling in patients with
      mild or moderate essential hypertension and impaired diastolic function. These
      findings support the hypothesis of a contribution of the renin-angiotensin system
      in the control of LV diastolic function in these patients.

PMID- 10658944
TI  - A controlled study of the effects of isosorbide mononitrate on arterial blood
      pressure and pulse wave form in systolic hypertension.
AB  - OBJECTIVE: To determine the effect of an extended-release nitrate preparation on
      the arterial pulse wave and blood pressure of patients in whom systolic blood
      pressure was elevated in part by exaggerated pulse-wave reflectance. DESIGN: A
      double-blind randomized placebo-controlled crossover study was carried out.
      PATIENTS AND METHODS: The subjects were ten elderly patients with systolic
      hypertension resistant to conventional anti-hypertensive therapy. Pharmacodynamic
      responses to 2-week courses of placebo/isosorbide mononitrate (ISMN) were
      assessed in seven subjects by an ambulatory blood pressure monitor, and in all
      ten subjects by standard sphygmomanometry, arterial pulse-wave analysis and
      measurement of plasma nitrate concentration during peak and trough. RESULTS:
      Ambulatory systolic blood pressure was decreased by ISMN (P < 0.02) between 1000
      and 2200 h. Ambulatory diastolic blood pressure fell with ISMN (P < 0.01) during
      the last 4 h of this period. At peak plasma nitrate levels, ISMN decreased the
      aortic systolic blood pressure (P < 0.01), ejection peak (P < 0.02) and
      augmentation component (P < 0.001) of the pulse wave; heart rate increased
      slightly (P < 0.03). CONCLUSION: ISMN has a role as an adjunct in the anti
      hypertensive therapy of patients with refractory systolic hypertension due to
      exaggerated pulse-wave reflectance.

PMID- 10658945
TI  - Posterior calcaneal displacement osteotomy for adult acquired flatfoot.
AB  - The authors retrospectively reviewed 24 patients who underwent posterior
      calcaneal displacement osteotomy (PCDO) for posterior tibial tendon dysfunction
      and adult acquired flatfoot deformity from 1991 to 1996. The average follow-up
      was 27 months. Analysis consisted of preoperative and postoperative evaluation of
      radiographs, as well as postoperative subjective results. Ancillary procedures
      included flexor digitorum longus tendon transfer (n = 19), tendo Achilles
      lengthening (n = 21), tibialis anterior tendon transfer (n = 5),
      naviculocuneiform joint arthrodesis (n = 4), and first metatarsocunieform joint
      arthrodesis (n = 1). The talo-first metatarsal angle on the lateral view
      decreased from a preoperative average of 22.13 degrees to a postoperative average
      of 8.50 degrees. The talo-first metatarsal angle on the anteroposterior view
      decreased from an average preoperative value of 22.96 degrees to a postoperative
      average of 11.04 degrees. In all cases, talar head coverage at the talonavicular
      joint improved. Subjective results were categorized as good (n = 17),
      satisfactory (n = 5), and poor (n = 2). Complications included sural neuritis (n
      = 6), Achilles tendon rupture (n = 2), difficulty with fixation (n = 2), and
      undercorrection of deformity (n = 2). Patients who had higher preoperative and
      postoperative talo-first metatarsal angles on either the anteroposterior or
      lateral radiographs had significantly poorer outcomes (p = .0403, p = .002, p =
      .009, p = .001, respectively). In addition, those patients who had medial column
      fusions had statistically significant poorer subjective results (p = .015).
      Patients who had flexor digitorum longus (FDL) tendon transfers did significantly
      better than those patients who did not have FDL transfer (p = .004). The authors
      conclude that the posterior calcaneal displacement osteotomy is a reasonable
      option for management of posterior tibial tendon dysfunction in the adult
      acquired flatfoot.

PMID- 10658946
TI  - Autogenous bone grafting for the treatment of talar dome lesions.
AB  - This study evaluated a surgical bone grafting technique, which restores the talar
      dome weightbearing articular surface for the repair of a transchondral lesion. An
      autogenous bone graft combined with viable cartilage is used to recreate a normal
      talar articular surface. In a retrospective analysis of talar dome lesions, 14
      patients surgically treated with bone grafts were compared to 17 patients treated
      with curettage and subchondral drilling. Post surgical follow-up was collected at
      71.5 +/- 21.1 months (mean +/- SD). Age, lesion stage, and gender did not differ
      between the groups, but the mean fracture area was selectively smaller in the
      curettage and drilling group (85.2 +/- 58.7 mm2 vs. 156.4 +/- 69.4 mm2). Clinical
      evaluation consisted of an 8-point scale which took into account range of motion,
      the presence of pain and crepitus, and radiographic assessment. Significantly
      better overall clinical scores were observed for the bone graft group (graft, 6.9
      +/- 1.6, curettage plus drilling, 4.5 +/- 1.9; p = .001), due to better results
      for range of motion (1.6 degrees +/- 0.5 degrees; 1.1 degrees +/- 0.4 degrees),
      less pain (2.7 +/- 0.50; 2.0 +/- 0.7), and presence of subchondral bone on x-ray
      (0.9 +/- 0.4; 0.2 +/- 0.4). Patients were also asked their perception of their
      own surgical outcome (considering pain frequency and ability to participate in
      sporting activities or walk at a similar level compared to before the surgery),
      and if they would have the surgery again. No differences in the patients'
      preoperative symptoms or their subjective assessment post surgery were detected
      between the groups. While curettage plus drilling is the most common surgical
      procedure for chronic symptomatic talar dome lesion, our results suggest that
      bone grafting of the lesion yields better long-term clinical results.

PMID- 10658947
TI  - The relationship between articular cartilage degeneration and bone changes of the
      first metatarsophalangeal joint.
AB  - Plain-film radiography is commonly used in the assessment of joints affected by
      osteoarthritis. It has been shown that the condition of articular cartilage in
      the knee, when grossly assessed, does not always correlate well to the
      radiographic evaluation of the joint. The aim of this study was to determine
      whether a relationship existed between the radiographic appearance of the
      subchondral bone and the morphological condition of the articular cartilage
      surfaces of the first metatarsophalangeal joint. Forty-nine pairs of cadaveric
      metatarsals and their respective proximal phalanges were studied in order to
      determine the correlation between articular cartilage degeneration and
      radiographic grade using a modified Kellgren-Lawrence scale. The relationship
      between cartilage degeneration and age, gender, osteophytes, metatarsal length,
      and measured angles (proximal articular set angle, distal articular set angle,
      intermetatarsal angle) was also investigated. It was found that there was a
      significant correlation between radiographic grade and cartilage degeneration on
      both the metatarsal head and the base of the proximal phalange (r2 = .2038 and
      .1733, respectively). However, while useful in the clinical setting, bony changes
      of the first metatarsophalangeal joint, as seen radiographically, fail to provide
      a full representation of the level of cartilage degeneration on the articular
      surfaces of this joint.

PMID- 10658948
TI  - The durability of the Semmes-Weinstein 5.07 monofilament.
AB  - Peripheral neuropathy is a risk factor that predisposes diabetic patients to
      plantar foot ulcerations and lower extremity amputations. Clinicians have
      searched for a reliable, cost-effective, and simple method in the identification
      of diabetic patients who are at increased risk of developing plantar foot ulcers.
      Currently, many diabetic foot clinics utilize the Semmes-Weinstein 5.07/10 g
      monofilament in this identification process. Ten 5.07 monofilaments were placed
      in an Instron Dynamic Testing Instrument and their respective filament forces
      were measured utilizing a Mettler scale after being subjected to repetitive
      applications. After 500 cycles were performed, there was an average filament
      force reduction of 1.2 g. After 1,500 cycles, there was still an average
      reduction of 1.2 g. F-testing and the Duncan test identified a significant
      difference between filament forces at 0, 500, 1,000, and 1,500 cycles. These data
      lead to a conclusion that continual utilization of the nylon filaments may lead
      to a reduced ability to accurately detect peripheral neuropathy and identify
      those who are at risk for the development of plantar foot ulcerations.

PMID- 10658949
TI  - A comparison of radiographic measurements in normal, hallux valgus, and hallux
      limitus feet.
AB  - This study investigated the differences in weightbearing, foot radiographs among
      normal subjects, those with hallux valgus, and those with hallux limitus. An
      intrarater reliability study of various x-ray measurements was conducted,
      utilizing seven dorsoplantar and six lateral measurements. The results showed
      that metatarsus primus adductus, increased metatarsal width, and a positive first
      metatarsal protrusion distance were associated with hallux valgus, whereas
      increased hallux interphalangeal angle was associated with hallux limitus.

PMID- 10658951
TI  - Spiked metallic washer and screw for reattachment of the Achilles tendon after
      repair of a distal rupture.
AB  - The authors review Achilles tendon ruptures and treatment options for the acute
      and chronic rupture. A case is described involving reattachment of a chronic
      distal Achilles tendon rupture repair with a spiked metal washer and fully
      threaded cannulated cancellous screw. Spiked metal washers and their effects on
      soft-tissue pullout strength, and possible complications are discussed. In review
      of the literature, the authors have not found this type of fixation used to
      anchor the Achilles tendon, and feel it may be a viable option when faced with
      distal Achilles reattachment for the acute and chronic rupture.

PMID- 10658950
TI  - The reversal sural artery neurocutaneous island flap in composite lower extremity
      wound reconstruction.
AB  - Reconstruction of the lower third of the leg and the forefoot remains a challenge
      due to a lack of regional muscle units and minimal subcutaneous tissues. Reverse
      island flaps have been applied to similar reconstructive problems in the upper
      extremity. Recently, the reverse sural artery neurocutaneous island flap has been
      utilized to reconstruct complex wounds of the lower extremity and forefoot in
      young and middle-aged individuals. We present our use of the flap in a patient
      cohort 65 years of age or older. Unique among this group was the high prevalence
      of diabetes and peripheral vascular disease. Nonetheless, the reverse sural
      artery neurocutaneous island flap proved a safe and reliable means of achieving
      wound closure.

PMID- 10658952
TI  - Rupture of the tibialis anterior tendon.
AB  - Closed rupture of the tendon of tibialis anterior is an infrequently reported
      entity. A thorough review of the literature was performed with 49 reported cases
      of this condition identified. Those patients who were treated conservatively
      experienced late sequelae, including continued slapping of the foot, mild to
      moderate flatfoot deformity, and ankle arthrosis. Low morbidity associated with
      surgical reconstruction should preclude only the most sedentary of patients from
      operative treatment.

PMID- 10658953
TI  - Utilizing threaded Steinmann pins to resect the talus and calcaneus for ankle
      joint disarticulation (Syme's procedure).

PMID- 10658954
TI  - Neural underpinnings of temporal processing: a review of focal lesion,
      pharmacological, and functional imaging research.
AB  - The mechanisms by which the brain times events and stores them in memory for
      later use is increasingly of interest to neuroscientists. There are a variety of
      neurological disorders in which skilled behaviors are not coordinated and appear
      less than fluent, which may suggest a disorder in temporal processing. In this
      review, two influential models are described which suggest timing deficits may be
      due to impairments in a timekeeping mechanism or various nontemporal processes
      such as motor implementation, memory, and attention. We then review focal lesion,
      pharmacological, and functional imaging approaches to understanding the neural
      underpinnings of temporal processing. Converging findings from these approaches
      provide support for the role of the basal ganglia in timekeeping operations.
      Likewise, focal lesion and some functional imaging studies are compatible with a
      timekeeping role of the cerebellum, though specific regions within the cerebellum
      that control timing operations have not been identified. In contrast, the results
      from recent focal lesion research suggests the right middle-frontal and inferior
      parietal cortices comprise a pathway that supports attention and working memory
      operations, which are crucial for timing. Functional imaging data provide some
      converging evidence for this proposal. Functional imaging work also indicates
      that a right superior-temporal inferior-frontal pathway sometimes aids timing
      through subvocal nonlinguistic rehearsal processes. These distributed pathways
      maintain timekeeping operations in working memory and store representations of
      temporal events, which is crucial for skilled performance.

PMID- 10658955
TI  - Increased cortisol levels and impaired cognition in human aging: implication for
      depression and dementia in later life.
AB  - Perhaps the most prominent feature of human aging is the variability in decline
      of intellectual processes. Although many research avenues have been used to study
      the origin of such an increased variability with aging, new studies show that
      some biological factors may be associated with normal and pathological cognitive
      aging. One biological parameter that came under scrutiny in the past few years is
      the hypothalamic-pituitary-adrenal (HPA) axis, an endocrine closed-loop system
      controlling the secretion of stress hormones (glucocorticoids). In this review,
      we summarize data obtained in both animals and humans suggesting that cumulative
      exposure to high levels of glucocorticoids can be particularly detrimental for
      the aged hippocampus, a brain structure involved in learning and memory in both
      animals and humans. We then analyze the implication of these data for the study
      of dementia and depression in later life, two disorders characterized by
      increased glucocorticoid secretion in a significant proportion of patients.
      Finally, we suggest various factors that could explain the development of
      glucocorticoid hypersecretion in later life.

PMID- 10658956
TI  - Vitamin E as an antioxidant/free radical scavenger against amyloid beta-peptide
      induced oxidative stress in neocortical synaptosomal membranes and hippocampal
      neurons in culture: insights into Alzheimer's disease.
AB  - Amyloid beta-peptide (Abeta), the major constituent in senile plaques in
      Alzheimer's disease (AD) brain, is thought by many researchers to be central to
      neurotoxicity in AD brain. Increasing evidence from many laboratories indicates
      that AD brain is under oxidative stress, with strong evidence of protein
      oxidation, lipid peroxidation, and peroxynitrite damage. A link between the
      central role of Abeta and oxidative stress in AD brain may be Abeta-associated
      free radical oxidative stress. If so, antioxidants such as vitamin E should
      modulate Abeta-induced oxidative damage and neurotoxicity in brain cells. This
      review summarizes studies of Abeta-associated free radical oxidative stress and
      its inhibition by vitamin E in cortical synaptosomal membranes and hippocampal
      neuronal cells in culture. Taken together with the recent report that vitamin E
      slows the progression of AD, this review strongly supports a central role of
      Abeta-associated free radical oxidative stress in neurotoxicity in AD brain.

PMID- 10658957
TI  - The neurobiological basis of time estimation and temporal order.
AB  - Time estimation may be evaluated with the use of four major paradigms: temporal
      discrimination, verbal estimation, temporal production, and temporal
      reproduction. On the basis of testing of normal subjects and patients with brain
      lesions, it has been shown that the cerebellum, the basal ganglia, and the
      prefrontal cortex are involved in time estimation. In particular, studies in
      humans and animals have indicated that facilitation of dopamine transmission
      speeds up the internal clock, while inhibition of dopamine transmission slows it
      down. It has been hypothesized that the central timer is located in the
      cerebellum, while the planning abilities subserving the estimation of longer
      intervals are mediated by the prefrontal cortex. It remains to be determined
      whether time estimation is related to memory of temporal order or context and
      whether time-related tasks are correlated with working memory.

PMID- 10658958
TI  - Enabling, empowering, inspiring: research and mentorship through the years.
AB  - The interrelationship between research and mentorship in an association such as
      the Medical Library Association (MLA) is revealed through the contributions of
      individuals and significant association activities in support of research.
      Research is vital to the well-being and ultimate survival of health sciences
      librarianship and is not an ivory tower academic activity. Mentorship plays a
      critical role in setting a standard and model for those individuals who want to
      be involved in research and, ultimately, for the preparation of the next
      generation of health sciences librarians. Research and mentorship are discussed
      in the context of personal experiences, scholarship, and problem solving in a
      practice environment. Through research and mentorship, we are enabled to enhance
      our services and programs, empowered to look beyond our own operations for
      information puzzles to be solved, and inspired to serve society by improving
      health.

PMID- 10658959
TI  - MEDLINEplus: building and maintaining the National Library of Medicine's consumer
      health Web service.
AB  - MEDLINEplus is a Web-based consumer health information resource, made available
      by the National Library of Medicine (NLM). MEDLINEplus has been designed to
      provide consumers with a well-organized, selective Web site facilitating access
      to reliable full-text health information. In addition to full-text resources,
      MEDLINEplus directs consumers to dictionaries, organizations, directories,
      libraries, and clearinghouses for answers to health questions. For each health
      topic, MEDLINEplus includes a preformulated MEDLINE search created by librarians.
      The site has been designed to match consumer language to medical terminology. NLM
      has used advances in database and Web technologies to build and maintain
      MEDLINEplus, allowing health sciences librarians to contribute remotely to the
      resource. This article describes the development and implementation of
      MEDLINEplus, its supporting technology, and plans for future development.

PMID- 10658960
TI  - Electronic reserves: copyright and permissions.
AB  - Electronic reserves present a new service option for libraries to provide needed
      materials during hours that the library is not open and to user groups located
      some distance from library collections. Possible changes to current copyright law
      and publishers permissions policies have delayed the development of electronic
      reserves in many libraries. This paper reviews the current state of electronic
      reserves materials in the publishing and library communities and presents the
      results of a survey of publishers to determine permissions policies for
      electronic materials. Issues of concern to both libraries and publishers are
      discussed.

PMID- 10658961
TI  - The rise and fall of the medical mediated searcher.
AB  - The relationship between the development of mediated online literature searching
      and the recruitment of medical librarians to fill positions as online searchers
      was investigated. The history of database searching by medical librarians was
      outlined and a content analysis of thirty-five years of job advertisements in MLA
      News from 1961 through 1996 was summarized. Advertisements for online searchers
      were examined to test the hypothesis that the growth of mediated online searching
      was reflected in the recruitment of librarians to fill positions as mediated
      online searchers in medical libraries. The advent of end-user searching was also
      traced to determine how this trend affected the demand for mediated online
      searching and job availability of online searchers. Job advertisements were
      analyzed to determine what skills were in demand as end-user searching replaced
      mediated online searching as the norm in medical libraries. Finally, the trend
      away from mediated online searching to support of other library services was
      placed in the context of new roles for medical librarians.

PMID- 10658962
TI  - A library-based bioinformatics services program.
AB  - Support for molecular biology researchers has been limited to traditional library
      resources and services in most academic health sciences libraries. The University
      of Washington Health Sciences Libraries have been providing specialized services
      to this user community since 1995. The library recruited a Ph.D. biologist to
      assess the molecular biological information needs of researchers and design
      strategies to enhance library resources and services. A survey of laboratory
      research groups identified areas of greatest need and led to the development of a
      three-pronged program: consultation, education, and resource development.
      Outcomes of this program include bioinformatics consultation services, library
      based and graduate level courses, networking of sequence analysis tools, and a
      biological research Web site. Bioinformatics clients are drawn from diverse
      departments and include clinical researchers in need of tools that are not
      readily available outside of basic sciences laboratories. Evaluation and usage
      statistics indicate that researchers, regardless of departmental affiliation or
      position, require support to access molecular biology and genetics resources.
      Centralizing such services in the library is a natural synergy of interests and
      enhances the provision of traditional library resources. Successful
      implementation of a library-based bioinformatics program requires both subject
      specific and library and information technology expertise.

PMID- 10658963
TI  - Applications of informatics in veterinary medicine.
AB  - This study used the peer-reviewed biomedical literature to define the veterinary
      informatics knowledgebase and associated subspecialties, and assesses the level
      of activity in the field over the thirty-year period from 1966 through 1995.
      Grateful Med was used to search the MEDLINE bibliographic database for articles
      that shared one or more Medical Subject Headings (MeSH) keywords from the
      veterinary and medical informatics subject headings. Each of ninety-five MeSH
      medical informatics terms was assigned to one of twelve veterinary informatics
      subspecialties. The number of articles retrieved by each MeSH keyword and
      subspecialty was calculated. A total of 611 articles were retrieved, representing
      the contributions of 1,338 authors published in 153 journals. The field
      experienced slow growth over the twenty-year period from 1966 through 1985. In
      the following decade, the cumulative number of veterinary informatics articles
      almost tripled and the percentage of veterinary-related articles that included an
      informatics component increased almost two-and-one-half fold. Despite this recent
      growth, the number of veterinary-related articles with an informatics component
      has never exceeded 1% of either the veterinary or medical informatics literature
      over the past thirty years, and representation of veterinary subspecialties in
      the literature varied widely.

PMID- 10658964
TI  - AIDS in Haiti: a bibliometric analysis.
AB  - OBJECTIVES: In Haiti, AIDS has become the leading cause of death in sexually
      active adults. Increasingly, AIDS has become a disease of women and children.
      Previous bibliometric studies have shown the emergence of Haiti as a leading
      country in the production of AIDS literature in the Latin American and Caribbean
      regions. No information exists, however, regarding the type of publications
      produced, the collaboration patterns used, or the subject content analysis of
      this production. The purpose of this study was to gain insight into the
      construction of this literature production. METHODS: A bibliometric analysis
      regarding Haitian AIDS research was conducted in the AIDSLINE database for the
      period 1980 to 1998. An attempt was made to identify the patterns of the growth
      in AIDS literature, as well as the types of documents published, authorship,
      institutional affiliations of authors, and subject content. RESULTS: Results
      indicated that most documents were published in periodicals. The International
      Conference on AIDS obtained the highest frequency. The United States, Haiti, and
      Canada were the main productive countries. CONCLUSIONS: While nearly 40% of the
      records corresponded to ethnology-related articles, HIV infections, sex behavior,
      pregnancy, and substance-related disorders headed the Medical Subject Headings
      (MeSH) found. Main aspects of AIDS papers focused on epidemiology, complications,
      and trends issues.

PMID- 10658966
TI  - Electronic access in Russian medical libraries.

PMID- 10658965
TI  - Providing health information to the general public: a survey of current practices
      in academic health sciences libraries.
AB  - A questionnaire was mailed to 148 publicly and privately supported academic
      health sciences libraries affiliated with Association of American Medical
      Colleges (AAMC-accredited medical schools in the United States and Canada to
      determine level of access and services provided to the general public. For
      purposes of this study, "general public" was defined as nonaffiliated students or
      health care professionals, attorneys and other nonhealth-related professionals,
      patients from affiliated or other hospitals or clinics, and general consumers.
      One hundred five (71%) libraries responded. Results showed 98% of publicly
      supported libraries and 88% of privately supported libraries provided access to
      some or all of the general public. Publicly supported libraries saw greater
      numbers of public patrons, often provided more services, and were more likely to
      circulate materials from their collections than were privately supported
      libraries. A significant number of academic health sciences libraries housed a
      collection of consumer-oriented materials and many provided some level of
      document delivery service, usually for a fee. Most allowed the public to use some
      or all library computers. Results of this study indicated that academic health
      sciences libraries played a significant role in serving the information-seeking
      public and suggested a need to develop written policies or guidelines covering
      the services that will be provided to minimize the impact of this service on
      primary clientele.

PMID- 10658967
TI  - Preparing health information professionals for the twenty-first century: the
      Texas Woman's University dual master's degree program.

PMID- 10658968
TI  - Use of print journals in an intracampus exchange program: implications for
      service and electronic journal subscriptions.

PMID- 10658969
TI  - Electronic current awareness for mental health facilities.

PMID- 10658970
TI  - A snapshot in time: citation rankings of the Bulletin of the Medical Library
      Association.

PMID- 10658971
TI  - "Rubber stamping" retracted papers.

PMID- 10658972
TI  - The human natural cytotoxicity receptors (NCR) that induce HLA class I
      independent NK cell triggering.
AB  - The cytolytic activity mediated by human natural killer (NK) cells is the result
      of a balance between signals delivered by inhibitory and activating receptors.
      The inhibitory receptors are represented by different families of HLA-specific
      receptors characterized by immunoreceptor tyrosine-based inhibiting motif(ITIM)
      sequences in their cytoplasmic portion. The function and the specificity of the
      inhibitory receptors imply the existence of triggering receptors specific for non
      HLA ligands that are responsible for the induction of the cytolytic activity
      against HLA class I-deficient target cells. These receptors have remained elusive
      until recently when three distinct NK-specific molecules, termed natural
      cytotoxicity receptors (NCR), were identified and cloned. The different members
      of this novel family of receptors play a complementary role in the recognition
      and lysis of target cells. The NCR family is composed by a heterogeneous group of
      molecules belonging to the Ig superfamily that associate to different
      immunoreceptor tyrosine-based activating motif (ITAM)-containing signal
      transducing polypeptides.

PMID- 10658973
TI  - Paired inhibitory and triggering NK cell receptors for HLA class I molecules.
AB  - Human natural killer (NK) cells specifically interact with major
      histocompatibility complex (MHC) class I molecules employing different receptor
      systems, shared with subsets of alphabeta and gammadelta T lymphocytes. Killer
      cell immunoglobulin-like receptors (KIRs) recognize groups of human leukocyte
      antigen (HLA) class Ia proteins displaying common structural features at the
      alpha-1 domain; among them, KIR2DL4 has been proposed to specifically interact
      with the class Ib molecule HLA-G1. Members of a related family of immunoglobulin
      (Ig)-like receptors (ILT2 or LIR-1 and ILT4 or LIR-2), expressed by other
      leukocyte lineages, interact with a broad spectrum of class Ia molecules and HLA
      G1. On the other hand, CD94/NKG2-A(-C) and NKG2D lectin-like receptors,
      respectively, recognize the class Ib molecules HLA-E and MICA. A recurrent
      finding within the different receptor families is the existence of pairs of
      homologous molecules that often share the same ligands but display divergent
      functions. Inhibitory receptors tend to exhibit an affinity for HLA molecules
      higher than their activating counterparts. Recruitment of SH2 domain-bearing
      tyrosine phosphatases (SHP) by cytoplasmic phosphorylated immunoreceptor tyrosine
      based inhibition motifs (ITIMs) is a crucial event for the inhibitory signalling
      pathway. By contrast, triggering receptors assemble with homodimers of immune
      tyrosine-based activation motif (ITAM)-bearing adaptor molecules (i.e., DAP12,
      CD3 xi) that engage tyrosine kinases (ZAP70 and syk).

PMID- 10658974
TI  - NK cell activation: distinct stimulatory pathways counterbalancing inhibitory
      signals.
AB  - A delicate balance between positive and negative signals regulates NK cell
      effector function. Activation of NK cells may be initiated by the triggering of
      multiple adhesion or costimulatory molecules, and can be counterbalanced by
      inhibitory signals induced by receptors for MHC class I. A common pathway of
      inhibitory signaling is provided by immunoreceptor tyrosine-based inhibitory
      motifs (ITIMs) in the cytoplasmic domains of these receptors which mediate the
      recruitment of SH2 domain-bearing tyrosine phosphate-1 (SHP-1). In contrast to
      the extensive progress that has been made regarding the negative regulation of NK
      cell function, our knowledge of the signals that activate NK cells is still poor.
      Recent studies of the activating receptor complexes have shed new light on the
      induction of NK cell effector function. Several NK receptors using novel adaptors
      with immunoreceptor tyrosine-based activation motifs (ITAMs) and with PI 3-kinase
      recruiting motifs have been implicated in NK cell stimulation.

PMID- 10658975
TI  - Molecular analyses of the interactions between human NK receptors and their HLA
      ligands.
AB  - NK cell cytotoxicity is regulated by the action of multiple families of
      receptors. The interactions of these receptors with their ligands control
      different activating/inhibiting signal pathways and it is the balance of these
      signals which determines the behavior of the NK cell. The major described
      inhibitory pathways begin either with the recognition of a target cell classical
      class I HLA molecule by a killer cell immunologlobulin-like receptor (KIR) or the
      binding of the non-classical class I molecule HLA-E to the CD94/NKG2-A
      heterodimer. Activating counterparts to these inhibitory NK receptors have also
      been described and this review focuses on the molecular details of the binding of
      the inhibitory and activating receptors to their HLA ligands.

PMID- 10658976
TI  - 2B4: an NK cell activating receptor with unique specificity and signal
      transduction mechanism.
AB  - 2B4 is a cell surface glycoprotein of the Ig-superfamily structurally related to
      CD2-like molecules such as CD2, CD48, CD58, CD84, Ly-9, and SLAM. Engagement of
      2B4 on NK cells with specific antibodies or with its ligand CD48 enhances NK cell
      mediated cytotoxicity. 2B4 is also expressed on both CD8+ T cells and myeloid
      cells, but its function in these cells remains unknown. Signal transduction
      through 2B4 involves recruitment of the SH2-containing adapter molecule SAP to
      cytoplasmic tyrosines. SAP is deficient in patients affected by X-linked
      lymphoproliferative disorder (XLP), which is triggered following EBV infection.
      Thus, an interruption of signaling through 2B4 and related molecules may impair
      NK cell recognition of virally infected cells and contribute to XLP.

PMID- 10658977
TI  - Expression of HLA class I-specific inhibitory receptors in human cytolytic T
      lymphocytes: a regulated mechanism that controls T-cell activation and function.
AB  - Different families of major histocompatibility complex (MHC)-specific inhibitory
      receptors (NKRs) play a major role in natural killer (NK) cell function, allowing
      discrimination between normal cells and cells that do not express adequate
      amounts of MHC class I antigens. This occurs in most instances as a consequence
      of viral infection or tumor transformation. In T lymphocytes, expression of NKR
      is mostly confined to activated CD8+ cytolytic T lymphocytes (CTLs). While NKR
      expression by CTLs may be viewed as a mechanism preventing damages to normal
      cells by those CTLs that have acquired NK-like activity, it may also down
      regulate TCR-mediated T cell activation, thus, impairing CTL functions. The
      finding that certain cytokines can modulate killer inhibitory receptor expression
      in CTLs is of major interest and might be instrumental in novel therapeutic
      approaches aimed at the down regulation ofT-cell function in transplantation or
      autoimmunity.

PMID- 10658978
TI  - Early signaling via inhibitory and activating NK receptors.
AB  - This review focuses on recent findings on the structural features of inhibitory
      NK cell receptors containing immunoreceptor tyrosine-based inhibition motif
      (ITIM) and of NK cell activating receptors, both in human and mouse. First, the
      study of the inhibitory killer cell immunoglobulin-like receptors (KIR) unveiled
      the presence of intracytoplasmic ITIM and their capacity to recruit protein
      tyrosine phosphatases such as SHP-1 in vivo. A brief summary of the known SHP-1
      targets may help us to understand the inhibition mediated by the KIR. The
      characterization of ITIM thus allowed the definition of a large group of
      inhibitory cell surface receptors. The second part of the review describes the
      known NK cell activating receptors. Most of them require association with ITAM
      containing polypeptides in order to mediate cell activation.

PMID- 10658979
TI  - The HLA crossroad in tumor immunology.
AB  - It is generally accepted that human and experimental tumor cells can lose major
      histocompatibility complex (MHC) class I molecules. These human leukocyte antigen
      (HLA) losses are detected when the primary tumor breaks the basal membrane,
      invades the surrounding tissues, and starts to metastasize. These altered HLA
      class I phenotypes probably constitute the major tumor escape mechanism facing
      anti-tumor T-cell mediated responses. Thus, it is important to characterize these
      phenotypes in clinical tumor samples, analyze the mechanism(s) responsible for
      them, and counsel patients before and during peptide anti-cancer immunotherapy.
      The present paper summarizes the most relevant altered HLA class I phenotypes
      found in human tumor samples, indicates their frequency, and outlines the
      mechanisms implicated. This review also points out that the natural killer (NK)
      escape mechanism of HLA class I deficient cancer cells is yet to be defined.
      Knowledge accumulated to date reveals that HLA class I molecules are an important
      crossroad in tumor immunology.

PMID- 10658980
TI  - HLA-class I-specific inhibitory receptors in HIV-1 infection.
AB  - One of the most characteristic and, at the same time, puzzling features of the
      cellular immune response towards HIV-1 is represented by an early vigorous HIV
      specific CD8+ CTL response that does not prevent disease progression in the vast
      majority of patients. In this context, there is a striking mismatch over the
      course of disease progression between increasing numbers of activated CD8+ T
      cells and apparent decrease of virus-specific CD8+ CTLs. Inhibitory NK receptors
      (iNKRs) specific for HLA class I molecules can be expressed on CD8+ T-cells of
      healthy individuals and deliver inhibitory signals that determine decreased CTL
      function. Their expression on CD8+ CTL may be induced by IL-15 or TGFP in vitro,
      and may represent an important regulatory function for the fine-tuning of the
      antigen-specific T cell response against tumors and intracytoplasmic pathogens.
      In HIV-1 infected patients, relevant proportions of peripheral blood CD8+ T
      lymphocytes express iNKRs belonging to the Ig superfamily (p58/p70/p140) and
      CD94/NKG2A. Presence of iNKRs on CD8+ CTLs impairs HIV-1-specific cytolytic
      activity in vitro and may allow uncontrolled viral replication and spread
      following functional inhibition of CTL effectors in infected patients.

PMID- 10658981
TI  - Should we establish chest pain observation units in the UK? A systematic review
      and critical appraisal of the literature.
AB  - OBJECTIVES: The chest pain observation unit (CPOU) has been developed in the
      United States to allow rigorous assessment of patients presenting with chest
      pain, thus expediting their discharge if assessment is negative. This review aims
      to examine the evidence for effectiveness and economic efficiency of the CPOU and
      to explore whether data from the United States can be extrapolated to the UK.
      METHOD: Search of the literature using Medline and critical appraisal of the
      validity of the data. RESULTS: Five studies comparing outcomes of CPOU care with
      routine practice showed no significant difference in objective measures including
      mortality or missed pathology. Eleven studies described outcomes of a cohort of
      CPOU patients. Follow up was comprehensive and demonstrated no clinically
      significant evidence of missed pathology. Nine studies comparing CPOU costs with
      routine care demonstrated impressive cost savings that were more modest when
      randomised comparisons were made. CONCLUSION: CPOU care is safe and costs are
      well defined. There is no strong evidence that a CPOU will improve outcomes if
      routine practice is good. Cost savings have been shown when compared with routine
      care in the United States but may not be reproduced the UK.

PMID- 10658982
TI  - Management of eclampsia in the accident and emergency department.
AB  - Eclampsia is defined as the occurrence of seizures in pregnancy or within 10 days
      of delivery, accompanied by at least two of the following features documented
      within 24 hours of the seizure: hypertension, proteinuria, thrombocytopenia or
      raised aspartate amino transferase. Eclampsia complicates approximately one in
      2,000 pregnancies in the United Kingdom and it remains one of the main causes of
      maternal death. Up to 38% of cases of eclampsia can occur without premonitory
      signs or symptoms of pre-eclampsia-that is, hypertension, proteinuria, and
      oedema. Only 38% of eclamptic seizures occur antepartum; 18% occur during labour
      and a further 44% occur postpartum. Rare cases of eclampsia have occurred over a
      week after delivery. Outcome is poor for mother and child. Almost one in 50 women
      suffering eclamptic seizures die, 23% will require ventilation and 35% will have
      at least one major complication including pulmonary oedema, renal failure,
      disseminated intravascular coagulation, HELLP syndrome, acute respiratory
      distress syndrome, stroke, or cardiac arrest. Stillbirth or neonatal death occurs
      in approximately one in 14 cases of eclampsia. Up to one third of eclamptic
      seizures occur out of hospital. For this reason, initial management may involve
      accident and emergency departments. Early involvement of senior obstetric staff
      is crucial. Optimal emergency management of seizures, hypertension, fluid balance
      and subsequent safe transfer is essential to minimise morbidity and mortality.

PMID- 10658983
TI  - Continuing professional development for doctors in accident and emergency.

PMID- 10658984
TI  - High yield criteria for emergency cranial computed tomography in adult patients
      with no history of head injury.
AB  - OBJECTIVES: A recent American study identified clinical factors which effectively
      predicted those patients who would have significant findings on cranial computed
      tomography. It was proposed to apply these criteria in a UK setting and to
      determine whether modifications could be made to improve their efficiency.
      METHODS: A prospective observational study was conducted over a four month period
      including all non-trauma adult patients referred from the accident and emergency
      (A&E) department for urgent cranial computed tomography. Presenting symptoms and
      signs were analysed for ability to predict clinically significant computed
      tomography findings, namely: acute infarct, malignancy, acute hydrocephalus,
      intracranial haemorrhage, or intracranial infection. RESULTS: Sixty two patients
      were included; 22 (35%) had significant findings on computed tomography. Applying
      the original criteria (any of: age 60 years or older, focal neurology, headache
      with nausea or vomiting, altered mental status) to the study population showed
      that no clinically significant tomograms would have been omitted but only 11%
      fewer performed. Modifying the criteria by removing "age 60 years or older" and
      replacing "altered mental status" with a Glasgow coma score <14, still ensured
      100% sensitivity and would have resulted in 19% fewer scans being performed.
      CONCLUSION: Simple clinical criteria can be usefully applied to patients
      presenting to an A&E department in this country to target patients most likely to
      have clinically significant findings on urgent cranial computed tomography.

PMID- 10658985
TI  - Study of choice between accident and emergency departments and general practice
      centres for out of hours primary care problems.
AB  - OBJECTIVES: To determine the reasons for choosing between primary care out of
      hours centres and accident and emergency (A&E) departments for patients with
      primary care problems. METHODS: Interviews using a semistructured approach of
      samples of patients attending A&E departments and general practitioner (GP) out
      of hours centres for primary care problems. RESULTS: 102 patient interviews were
      undertaken. Sixty two per cent of A&E attenders were unemployed compared with 41%
      of out of hours attenders. White people were more likely to attend A&E
      departments and Asians the out of hours centre (p<0.01) and unemployed were more
      likely to attend A&E departments (70% v 30%). Some 46.3% of A&E department
      attenders had not contacted their GP before attending; 81.3% of first time users
      of the out of hours centre found out about it on the day of interview. Those
      attending A&E thought waiting times at the out of hours centre would be 6.3 hours
      (median) compared with a median perceived time of 2.9 hours by those actually
      attending the out of hours centre. Actual time was actually much less.
      CONCLUSION: Once patients have used the GP out of hours centre they are more
      likely to use it again. Education should be targeted at young adults, the
      unemployed and white people. Patients should be encouraged to contact their GP
      before A&E department attendance for non-life threatening conditions. Waiting
      time perception may be an important reason for choice of service.

PMID- 10658986
TI  - Ultrasound imaging of forearm fractures in children: a viable alternative?
AB  - OBJECTIVE: A pilot study to investigate whether ultrasonography can be reliably
      used to demonstrate uncomplicated greenstick and torus fractures in children.
      METHOD: Children between the ages of 2 and 14 years with a high clinical
      suspicion of a non-articular, undisplaced forearm fracture were included.
      Ultrasound imaging of the injury was performed by a consultant radiologist who
      gave an immediate report. Standard radiographs of the forearm were then obtained
      and the patient treated in the normal way. The radiograph was formally reported
      on at a later date. RESULTS: 26 patients were included. There was an absolute
      correlation between the ultrasound and radiographic findings. The procedure was
      well tolerated. CONCLUSION: Ultrasound seems effective for detecting
      uncomplicated forearm fractures in children. The procedure is easy to perform and
      the images easy to interpret. A larger study will now be undertaken to confirm
      these initial findings.

PMID- 10658987
TI  - Accident and emergency department led implementation of ketamine sedation in
      paediatric practice and parental response.
AB  - OBJECTIVE: To evaluate accident and emergency (A&E) department led practice of
      ketamine sedation for painful, short procedures in the paediatric population and
      to ascertain parental response. METHODS: Analysis of retrospective data for all
      children who received ketamine sedation over a 20 month period in a district
      general hospital. A data extraction form was used to record age, sex, dose,
      indication, side effects, and outcome. The parents were contacted by telephone
      afterwards and asked standardised questions about the child's treatment, their
      progress after discharge, and overall satisfaction with the treatment. RESULTS:
      Intramuscular ketamine was administered to 100 children under 12 years of age
      during the study period. The drug caused no adverse events pre-operatively or
      intraoperatively. The main early postoperative complication was vomiting (14%).
      Ninety three per cent of patients were discharged the same day. No reattendance
      or treatment attributable to ketamine related side effects were necessary. Over
      the 24 hours after discharge, vomiting occurred in 12% and ataxia in 15% of
      patients. Ninety nine per cent of parents were either very satisfied or satisfied
      with ketamine sedation and were willing for their child to receive it again, if
      required. CONCLUSION: This study, while confirming the known safety of ketamine
      sedation, established its suitability for "independent" use within A&E
      departments by suitably qualified staff.

PMID- 10658988
TI  - Adult intraosseous infusion in accident and emergency departments in the UK.
AB  - OBJECTIVE: A postal survey was conducted to gain an overview of current opinion
      and practice relating to intraosseous infusion in adult resuscitation in accident
      and emergency (A&E) departments in the UK and to use the results to generate
      debate in light of published and personal experience. METHODS: Questionnaires
      were sent to 559 departments listed in the 1996 British Association for Accident
      and Emergency Medicine directory. Three hundred and thirty two (59%) were
      returned and the 157 (28%) consultant led departments with more than 30,000 new
      patient attendances per year were examined. RESULTS: Seventy four per cent of
      respondents were aware that intraosseous infusion could be used in adult
      resuscitation, while only seven per cent used the technique. All (100%) were
      involved with training their medical staff and 11% said they taught the technique
      for use in adults. The majority of respondents were accredited in at least one of
      the adult resuscitation training courses. CONCLUSIONS: Numerous references appear
      in the literature relating to intraosseous infusion in adult resuscitation and
      represent a wealth of experience. The technique is taught and used in our
      department in contrast with the results of this survey, which demonstrate that it
      is infrequently taught and used in UK A&E departments. The more widespread
      teaching of this technique for adult use is recommended.

PMID- 10658989
TI  - Toxicological screening in trauma.
AB  - OBJECTIVES: To determine the prevalence and patterns of alcohol and drug use in
      patients with major trauma. METHODS: Consecutive trauma patient enrollment, 24
      hours a day, was envisaged with anonymised patient data on gender, age band, and
      mechanism of injury collected. The study group had surplus plasma quantitatively
      analysed for ethanol concentration, and urine samples were initially screened,
      via immunoassay, for opiates, cannabinoids, amphetamines, benzodiazepines,
      cocaine, and methadone. Confirmation and specification of individual positive
      results was then performed using thin layer or gas-liquid chromatography. Drugs
      of treatment given in the resuscitation room, if subsequently detected in the
      urine samples, were excluded from the final results. RESULTS: There were 116
      eligible trauma patients assessed and treated in the resuscitation room over a
      six month period, of which 93 (80%) were enrolled. Altogether 27% of this trauma
      population had plasma ethanol concentrations greater than 80 mg/dl. There was a
      significantly higher prevalence of alcohol intoxication in the group not involved
      in a road traffic accident (RTA) compared with the group who were involved in a
      RTA. Initial screening of urine for drugs revealed a prevalence of 51%. After 12
      exclusions due to iatrogenic administration of opiates, the final confirmed
      prevalence was 35% in this trauma population. The individual drug prevalence was
      13% for cannabinoids, 11% for codeine, 8% for morphine, 6% for amphetamine, 6%
      for benzodiazepines, 3% for cocaine, 1% for dihydrocodeine, and 1% for methadone.
      CONCLUSIONS: There is a notable prevalence of drug and alcohol use in this
      British accident and emergency trauma population. A significantly higher
      prevalence for alcohol intoxication was found in the non-RTA group compared with
      the RTA group. The patterns of drug usage detected reflect local influences and
      less cocaine use is seen compared with American studies. The association between
      alcohol, drugs, and trauma, together with ethically acceptable methods of
      screening, are discussed.

PMID- 10658990
TI  - Mass carbon monoxide poisoning.
AB  - The largest occurrence of carbon monoxide poisoning in Britain demonstrates the
      potential for mass accidental poisoning. It emphasises the need for strict public
      health controls and the importance of good liaison between emergency services to
      ensure that such events are quickly recognised and that the necessary resources
      are organised.

PMID- 10658991
TI  - Electrocardiographic abnormalities encountered in acute myocardial infarction.

PMID- 10658992
TI  - Towards evidence based emergency medicine: best BETs from the Manchester Royal
      Infirmary. Radiological diagnosis of mandibular fracture.

PMID- 10658993
TI  - Towards evidence based emergency medicine: best BETs from the Manchester Royal
      Infirmary. Management of undisplaced Bennett's fracture.

PMID- 10658994
TI  - Towards evidence based emergency medicine: best BETs from the Manchester Royal
      Infirmary. Diagnostic imaging of the hip in the limping child.

PMID- 10658996
TI  - Journal scan. Significance of vomiting after head injury

PMID- 10658995
TI  - Towards evidence based emergency medicine: best BETs from the Manchester Royal
      Infirmary. Immediate anticoagulant management of unstable angina.

PMID- 10658997
TI  - A magnetic nasal attraction.

PMID- 10658998
TI  - Complete open dislocation of the talus.

PMID- 10658999
TI  - Unguarded electric plugs cause penetrating head injuries in children.

PMID- 10659000
TI  - Occult injury in a diabetic.

PMID- 10659001
TI  - Acute myocardial infarction in patients with left bundle branch block.

PMID- 10659002
TI  - Confirmation of correct endotracheal tube placement.

PMID- 10659003
TI  - Anaesthetic training for specialist registrars in accident and emergency.

PMID- 10659004
TI  - Casemix Healthcare Resource Group update.

PMID- 10659005
TI  - Prospective survey to verify the Ottawa ankle rules.

PMID- 10659006
TI  - Fast tracking patients with a proximal femoral fracture--more than a broken bone.

PMID- 10659007
TI  - CS incapacitant spray.

PMID- 10659008
TI  - A rare cause of acute confusional state.

PMID- 10659009
TI  - Retrosigmoid intradural suprameatal approach to Meckel's cave and the middle
      fossa: surgical technique and outcome.
AB  - OBJECT: The goal of this study was to determine whether some petroclival tumors
      can be safely and efficiently treated using a modified retrosigmoid petrosal
      approach that is called the retrosigmoid intradural suprameatal approach (RISA).
      METHODS: The RISA was introduced in 1983, and since that time 12 patients
      harboring petroclival meningiomas have been treated using this technique. The
      RISA includes a retrosigmoid craniotomy and drilling of the suprameatus petrous
      bone, which is located above and anterior to the internal auditory meatus, thus
      providing access to Meckel's cave and the middle fossa. Radical tumor resection
      (Simpson Grade I or II) was achieved in nine (75%) of the 12 patients. Two
      patients underwent subtotal resection (Simpson Grade III). and one patient
      underwent complete resection of tumor at the posterior fossa with subtotal
      resection at the middle fossa. There were no deaths or severe complications in
      this series; all patients did well postoperatively, being independent at the time
      of their last follow-up examinations (mean 5.6 years). Neurological deficits
      included facial paresis in one patient and worsening of hearing in two patients.
      CONCLUSIONS: The approach described here is a useful modification of the
      retrosigmoid approach, which allows resection of large petroclival tumors without
      the need for supratentorial craniotomies. Although technically meticulous, this
      approach is not time-consuming; it is safe and can produce good results. This is
      the first report on the use of this approach for petroclival meningiomas.

PMID- 10659010
TI  - Cortical motor and somatosensory representation: effect of cerebral lesions.
AB  - OBJECT: Changes in cortical representation in patients with cerebral lesions may
      alter the correlation between cortical anatomy and function. This is of potential
      clinical significance when the extent of cortical resection is based on surface
      anatomical landmarks. METHODS: Fifty-one patients with supratentorial lesions
      were studied. Nineteen harbored noncentral lesions (no involvement of pre- or
      postcentral gyrus), whereas 32 had central lesions. Control studies consisted of
      stimulation of the hand contralateral to the unaffected hemisphere. Positron
      emission tomography activation studies were performed using the [15O]H2O tracer.
      Somatosensory stimulation of the hand or foot was performed using a mechanical
      vibrator. Motor activation consisted of hand clenching or foot tapping. The t
      statistic volumes were generated from images showing the mean change in regional
      cerebral blood flow, and coregistered with a T1-weighted magnetic resonance
      image. At the threshold selected, exclusive contralateral primary sensorimotor
      cortex activation was elicited in 100% of the control studies. A different
      pattern of cortical activation was associated with central lesions in 35 (78%) of
      45 patients, which occurred significantly more often than with noncentral lesions
      (eight [31%] of 26 patients). The most common difference in the pattern of
      activation with central lesions was activation of cortical regions outside the
      central area (including the supplementary sensorimotor area and the secondary
      somatosensory cortex). No sensorimotor activation was observed in gyri adjacent
      to the pre- or postcentral gyrus. CONCLUSIONS: Central lesions are more
      frequently associated with altered patterns in activation than lesions in
      noncentral locations. Characteristic patterns include activation of secondary
      sensorimotor areas. The absence of activation in gyri adjacent to the
      sensorimotor strip has clinical significance for the planning of resections in
      the central area.

PMID- 10659011
TI  - Treatment of progressive or recurrent pediatric malignant supratentorial brain
      tumors with herpes simplex virus thymidine kinase gene vector-producer cells
      followed by intravenous ganciclovir administration.
AB  - OBJECT: The outcome for children with recurrent malignant brain tumors is poor.
      The majority of patients die of progressive disease within months of relapse, and
      other therapeutic options are needed. The goal of this Phase I study was to
      evaluate the safety of in vivo suicide gene therapy in 12 children with
      recurrent, malignant, supratentorial brain tumors. METHODS: After optimal
      repeated tumor resection, multiple injections of murine vector-producing cells
      shedding murine replication-defective retroviral vectors coding the herpes
      simplex virus thymidine kinase type 1 (HSV-Tk1) gene were made into the rim of
      the resection cavity. Fourteen days after the vector-producing cells were
      injected, ganciclovir was administered for 14 days. The retroviral vector that
      was used only integrated and expressed HSV-Tk1 in proliferating cells, which are
      killed after a series of metabolic events lead to cell death. The median age of
      the patients was 11 years (range 2-15 years). Treated brain tumors included seven
      malignant gliomas, two ependyminomas, and three primitive neuroectodermal tumors.
      The patients were treated with one of three escalating dose concentrations of
      vector-producer cells. Four transient central nervous system adverse effects were
      considered possibly related to the vector-producing cells. In no child did
      permanent neurological worsening or ventricular irritation develop, and tests for
      replication-competent retroviruses yielded negative findings. CONCLUSIONS: This
      Phase I study demonstrates that in vivo gene therapy in which a replication
      defective retroviral vector in murine vector-producing cells is delivered by
      brain injections can be performed with satisfactory safety in a select group of
      children with localized supratentorial brain tumors.

PMID- 10659013
TI  - Primary intracerebral malignant lymphoma: report of 248 cases.
AB  - OBJECT: The authors present a retrospective analysis of 248 immunocompetent
      patients with primary intracerebral lymphoma treated at 19 French and Belgian
      medical centers between January 1980 and December 1995. METHODS: This study
      involved 127 female and 121 male patients with a median age of 61 years (range 2
      88 years). All tumors available for review were classic diffuse non-Hodgkin's
      lymphoma, for which the phenotype was determined in 220 patients: 212 (96.4%)
      were B-cell and eight (3.6%) were T-cell type tumors. According to the Revised
      European-American classification of lymphoid neoplasms, most lesions were diffuse
      large cell tumors (62%). A total of 196 tumors were reviewed in 127 patients for
      whom preoperative computerized tomography and magnetic resonance studies were
      available. There was a single lesion in 66% of the cases, with a supratentorial
      location in 87%. Tumor location in the basal ganglia, corpus callosum, or fornix,
      infiltration of the periventricular ependyma, or a mirror pattern, were strongly
      suggestive of a lesion of lymphomatous origin. The histological diagnosis was
      obtained after surgical resection in 116 patients, with the remainder undergoing
      biopsy sampling only. Of the 248 patients studied, 129 (52%) received
      chemotherapy plus radiation therapy, 60 (24%) received radiation therapy alone,
      35 (14%) received chemotherapy alone, and 24 (10%) received no postsurgical
      treatment. CONCLUSIONS: Using univariate analysis, the authors determined
      prognostic factors that were significantly associated with a favorable impact on
      survival including age younger than 60 years, radiation therapy (without evidence
      of a dose-response relationship), radiation therapy combined with chemotherapy,
      and chemotherapy consisting of anthracycline. Partial surgical resection was an
      unfavorable prognostic factor. Multivariate analysis was used to confirm the
      independent prognostic value of radiation therapy, age, chemotherapy consisting
      of anthracyclines or methotrexate, and partial surgical resection. This European
      survey provides a reasonable basis for the treatment of primary intracerebral
      lymphoma with the following sequence: stereotactic biopsy sampling, chemotherapy
      with a methotrexate- and anthracycline-based regimen, followed by cranial
      irradiation.

PMID- 10659012
TI  - Phase II evaluation of interferon-alpha-2a for progressive or recurrent
      craniopharyngiomas.
AB  - OBJECT: Craniopharyngiomas originate from the same cells as squamous cell skin
      carcinoma, which can be treated successfully with interferon-alpha (IFNalpha)-2a.
      The authors evaluated the activity and toxicity of systemic IFN in young patients
      with craniopharyngiomas. METHODS: Fifteen patients between the ages of 4.2 and
      19.8 years who had progressive or recurrent craniopharyngiomas were enrolled in
      this study. Nine of these patients had never received external-beam radiation
      therapy. Therapy consisted of 8,000,000 U/m2 IFNalpha-2a administered daily for
      16 weeks (induction phase) followed by the same dose three times per week for an
      additional 32 weeks (maintenance phase). Of the 12 patients who could be
      evaluated, radiological studies demonstrated a response to treatment in three
      with predominantly cystic tumors (one minor response, one partial response, and
      one complete response); one of these patients also showed improvement in visual
      fields. The size of the cystic component of the tumors often increased
      temporarily during the first several months of therapy. Three patients met the
      criteria for progressive disease during therapy. The median time to progression
      was 25 months. The need for radiation therapy in patients treated with IFN was
      delayed for 18 to 35 months (median 25 months) in six patients. All patients
      developed transient flulike symptoms shortly after receiving the first dose of
      IFN. Other toxicities (predominantly hepatic, neurological, and cutaneous) were
      seen in nine (60%) of the 15 patients during the first 8 weeks of treatment but
      resolved after temporary discontinuation and/or dose reduction. CONCLUSIONS:
      Interferon-alpha-2a is active against some childhood craniopharyngiomas; its
      toxicity precludes administration of high daily doses, and the optimum dose level
      and schedule remain to be defined.

PMID- 10659014
TI  - Clinical presentation and management of giant anterior communicating artery
      region aneurysms.
AB  - OBJECT: The authors reviewed their 20-year experience with giant anterior
      communicating artery aneurysms to correlate aneurysm size with clinical
      presentation and to analyze treatment methods. METHODS: In 18 patients, visual
      and cognitive impairment were quantitated and clinical outcome was categorized
      according to the Rankin scale. Statistical analysis was performed using Fisher's
      exact test. CONCLUSIONS: At least 3.5 cm of aneurysm mass effect was required to
      produce dementia in the patient (p = 0.0004). Dementia was usually caused by
      direct brain compression by the aneurysm rather than by hydrocephalus. Optic
      apparatus compression occurred with smaller aneurysms (2.7-3.2 cm) when they
      pointed inferiorly. Aneurysm neck clipping was possible in half of the cases.
      Special techniques, including temporary clipping, evacuation of intraluminal
      thrombus, tandem and/or fenestrated clipping, and clip reconstruction were often
      required. Occlusion of or injury to the anterior cerebral artery (ACA) was the
      main cause of poor outcome or death. Proximal ACA occlusion, even of dominant A1
      segments with small or no contralateral A1 artery, was an effective treatment
      alternative and was well tolerated as a result of excellent leptomeningeal
      collateral circulation.

PMID- 10659015
TI  - Use of spiral computerized tomography angiography in patients with subarachnoid
      hemorrhage in whom subtraction angiography did not reveal cerebral aneurysms.
AB  - OBJECT: Patients with subarachnoid hemorrhage (SAH) in whom angiography does not
      demonstrate diagnostic findings sometimes suffer recurrent disease and actually
      harbor undetected cerebral aneurysms. The management strategy for such cases
      remains controversial, but technological advances in spiral computerized
      tomography (CT) angiography are changing the picture. The purpose of this
      prospective study was to examine how spiral CT angiography can contribute to the
      detection of cerebral aneurysms that cannot be visualized on angiography.
      METHODS: In 134 consecutive patients with SAH, a prospective search for the
      source of bleeding was performed using digital subtraction (DS) and spiral CT
      angiography. In 21 patients in whom initial DS angiography yielded no diagnostic
      findings, spiral CT angiography was performed within 3 days. Patients in whom CT
      angiography provided no diagnostic results underwent second and third DS
      angiography sessions after approximately 2 weeks and 6 months, respectively. Six
      patients with perimesencephalic SAH were included in the 21 cases. Six of the
      other 15 patients had small cerebral aneurysms detectable by spiral CT
      angiography, five involving the anterior communicating artery and one the middle
      cerebral artery. Two patients in whom initial angiograms did not demonstrate
      diagnostic findings proved to have a ruptured dissecting aneurysm of the
      vertebral artery; in one case this was revealed at autopsy and in the other
      during the second DS angiography session. A third DS angiography session revealed
      no diagnostic results in 13 patients. CONCLUSIONS: Spiral CT angiography was
      useful in the detection of cerebral aneurysms in patients with SAH in whom
      angiography revealed no diagnostic findings. Anterior communicating artery
      aneurysms are generally well hidden in these types of SAH cases. A repeated
      angiography session was warranted in patients with nonperimesencephalic SAH and
      in whom initial angiography revealed no diagnostic findings, although a third
      session was thought to be superfluous.

PMID- 10659016
TI  - Efficacy of transluminal angioplasty for the management of symptomatic cerebral
      vasospasm following aneurysmal subarachnoid hemorrhage.
AB  - OBJECT: Transluminal angioplasty has become a widely used adjunct therapy to
      medical management of symptomatic cerebral vasospasm following subarachnoid
      hemorrhage (SAH). Despite anecdotal reports of universal, angiographically
      confirmed reversal of vasospasm and high rates of clinical improvement, no
      rigorous examination of the efficacy of this procedure has been conducted. In
      this study the authors assess the efficacy of the aforementioned procedure.
      METHODS: Thirty-eight patients enrolled as part of the North American trial of
      tirilazad in aneurysmal SAH underwent transluminal angioplasty for symptomatic
      cerebral vasospasm. Fifty-three percent of these patients showed good recovery or
      moderate disability based on their 3-month Glasgow Outcome Scale score. Among the
      38 patients who underwent angioplasty, the severity and type of vasospasm, use of
      papaverine in addition to balloon angioplasty, timing of treatment, and dose of
      study drug did not have an effect on the outcome. The results of their
      neurological examinations improved in only four of the 38 patients immediately
      after the procedure. A conditional logistic regression analysis was performed in
      which these patients were compared with individuals matched for age, sex, dose of
      study drug, admission neurological grade, and modified Glasgow Coma Scale score
      at the time of angioplasty. No effect on favorable outcomes was found for this
      procedure. CONCLUSIONS: Transluminal cerebral angioplasty is very effective in
      reversing angiographically confirmed vasospasm, and anecdotal reports of its
      clinical utility are numerous. However, in this report the authors conclude that
      its superiority to medical management for symptomatic cerebral vasospasm is
      questionable.

PMID- 10659017
TI  - Clinical outcomes after carotid endarterectomy: comparison of the use of regional
      and general anesthetics.
AB  - OBJECT: The authors analyzed their series of carotid endarterectomies (CEAs),
      which were performed after administration of either a general or regional
      anesthetic, to determine whether the choice of anesthetic affected patients'
      clinical outcomes and length of hospital stay. METHODS: A series of 803
      consecutive CEAs performed between July 1990 and February 1999 was reviewed.
      Cases were analyzed for patient demographics, comorbid medical states, and
      perioperative complications. Contingency-table statistical analysis was used to
      compare the incidence of comorbid medical states and perioperative complications
      between patients who underwent CEA in which either a regional or general
      anesthetic was used. Student's t-test was used to compare the length of hospital
      stay and mean patient age. A regional anesthetic was used for 632 CEAs, and a
      general anesthetic was used for 171 operations. There were no statistically
      significant intergroup differences in demographics or comorbid medical states.
      The incidence of perioperative stroke and death did not differ significantly
      between the regional (2.7%) and the general anesthetic groups (2.3%). However,
      the incidence of nonneurological, nonfatal complications was significantly less
      in the regional anesthetic (1.6%) than in the general anesthetic group (14.6%,
      p<0.0001). Patients undergoing CEA in which a regional anesthetic was used had a
      significantly lower incidence of cardiopulmonary complications (myocardial
      infarction and postoperative intubation), cervical complications (neck hematomas
      and cranial nerve injuries), and urological complications (urinary retention)
      than patients who underwent surgery after receiving a general anesthetic.
      CONCLUSIONS: Patients undergoing CEA in which a regional anesthetic was used had
      significantly fewer nonneurological, nonfatal complications, particularly
      cardiopulmonary complications, than similar patients surgically treated after
      induction of general anesthesia.

PMID- 10659018
TI  - Marked inhibition of glioblastoma target cell tumorigenicity in vitro by
      retrovirus-mediated transfer of a hairpin ribozyme against deletion-mutant
      epidermal growth factor receptor messenger RNA.
AB  - OBJECT: The goal of this study was to evaluate the activity of certain hairpin
      ribozymes against deletion-mutant epidermal growth factor receptor (deltaEGFR)
      messenger (m)RNA in glioblastomas multiforme (GBMs). A distinct 801-bp deletion
      mutation associated with amplification of the EGFR gene is present in a large
      subgroup of primary GBMs and confers enhanced tumorigenicity in vivo. As a result
      of the deletion mutation, the fusion junction of the gene is created directly
      upstream of a GTA triplet, which is subsequently transcribed into a ribozyme
      target codon (GUA). METHODS: In attempts to intercept deltaEGFR gene expression
      at the mRNA level, the authors designed three different hairpin ribozymes derived
      from the negative strands of satellite RNAs in tobacco ringspot virus, chicory
      yellow mottle virus (sCYMV1), and arabis mosaic virus against this target and
      evaluated their efficiency and specificity in a cell-free system. The sCYMV1,
      identified as the most active anti-deltaEGFR hairpin ribozyme motif, was cloned
      into the retroviral plasmid N2A+tRNAi(met). High-titer recombinant retrovirus
      containing supernatants (> 10(5) colony-forming units/ml) derived from an
      amphotropic GP+envAM 12 packaging cell line transfected with the N2A+tRNAi(met)
      anti-deltaEGFR-sCYMV1 construct were used to introduce the sCYMV1 hairpin
      ribozyme into U-87MG.deltaEGFR glioblastoma cells, which overexpress exogenous
      deltaEGFR. Using a virus/target cell ratio of 40:1 in the absence of drug
      selection, the ribozyme transfer resulted in a greater than 90% reduction of
      deltaEGFR mRNA levels, a 69% inhibition of deltaEGFR-mediated proliferation
      advantage, and a greater than 95% decrease of colony formation in soft agar under
      relative serum starvation conditions in vitro; transfer of a control mutant
      ribozyme that was rendered incapable of cleaving its target yielded none of these
      effects. CONCLUSIONS: These findings indicate that the anti-deltaEGFR-sCYMV1
      hairpin ribozyme is capable of specifically inhibiting the expression of
      deltaEGFR and reversing the deltaEGFR-associated malignant phenotype of GBM
      cells. This strategy may constitute a promising gene therapy approach for a
      molecularly defined subgroup of GBMs.

PMID- 10659019
TI  - Intracranial injection of human meningioma cells in athymic mice: an orthotopic
      model for meningioma growth.
AB  - OBJECT: Although human meningioma cells have been heterotopically implanted in
      nude mice, introducing these cells into intracranial locations seems more likely
      to reproduce normal patterns of tumor growth. To provide an orthotopic xenograft
      model of meningioma, the authors implanted a controlled quantity of meningioma
      cells at subdural and intracerebral sites in athymic mice. METHODS: Malignant
      (one tumor), atypical (two tumors), or benign (three tumors) meningiomas were
      placed into primary cell cultures. Cells (10(6)/10 microl) from these cultures
      and from an immortalized malignant meningioma cell line, IOMM-Lee, were injected
      with stereotactic guidance into the frontal white matter or subdural space of
      athymic mice. Survival curves were plotted for mice receiving tumor cells of each
      histological type and according to injection site. Other mice were killed at
      intervals and their heads were sectioned whole. Hematoxylin and eosin staining of
      these sections revealed the extent of tumor growth. CONCLUSIONS: The median
      length of survival for mice with malignant, atypical, or benign tumors was 19,
      42, or longer than 84 days, respectively. Atypical and malignant tumors were
      invasive, but did not metastasize extracranially. Malignant tumors uniformly
      showed leptomeningeal dissemination and those implanted intracerebrally grew
      locally and spread noncontiguously to the ventricles, choroid plexus,
      convexities, and skull base. Tumors formed in only 50% of mice injected with
      benign meningioma cells, whereas injection of more aggressive cells was uniformly
      successful at tumor production. The three types of human meningiomas grown
      intracranially in athymic mice maintained their relative positions in the
      spectrum of malignancy. However, atypical meningiomas became more aggressive
      after xenografting and acquired malignant features, implying that there had been
      immune constraint in the original host. Tumor cells injected into brain
      parenchyma migrated to more optimal environments and grew best there. This model
      provides insights into the biology of meningiomas and may be useful for testing
      new therapies.

PMID- 10659020
TI  - Bone regeneration at rabbit skull defects treated with transforming growth factor
      beta1 incorporated into hydrogels with different levels of biodegradability.
AB  - OBJECT: Skull bone regeneration induced by transforming growth factor-beta1
      (TGFbeta1)-containing gelatin hydrogels (TGFbeta1-hydrogels) was investigated
      using a rabbit skull defect model. Different strengths of TGFbeta1 were examined
      and compared: different TGFbeta1 doses in gelatin hydrogels with a fixed water
      content, different water contents in gelatin hydrogels with a fixed TGFbeta1
      dose, and TGFbeta1 in solution form. In addition, regenerated skull bone was
      observed over long time periods after treatment. METHODS: Soft x-ray, dual energy
      x-ray absorptometry, and histological studies were performed to assess the time
      course of bone regeneration at a 6-mm-diameter skull defect in rabbits after
      treatment with TGFbeta1-hydrogels or other agents. The influence of TGFbeta1 dose
      and hydrogel water content on skull bone regeneration by TGFbeta1-hydrogels was
      evaluated. Gelatin hydrogels with a water content of 95 wt% that incorporated at
      least 0.1 microg of TGFbeta1 induced significant bone regeneration at the rabbit
      skull defect site 6 weeks after treatment, whereas TGFbeta1 in solution form was
      ineffective, regardless of dose. The in vivo degradability of the hydrogels,
      which varied according to water content, played an important role in skull bone
      regeneration induced by TGFbeta1 -hydrogels. In our hydrogel system, TGFbeta1 is
      released from hydrogels as a result of hydrogel degradation. When the hydrogel
      degrades too quickly, it does not retain TGFbeta1 or prevent ingrowth of soft
      tissues at the skull defect site and does not induce bone regeneration at the
      skull defect. It is likely that hydrogel that degrades too slowly physically
      impedes formation of new bone at the skull defect. Following treatment with 0.1
      microg TGFbeta1-hydrogel (95 wt%), newly formed bone remained at the defect site
      without being resorbed 6 and 12 months later. The histological structure of the
      newly formed bone was similar to that of normal skull bone. Overgrowth of
      regenerated bone and tissue reaction were not observed after treatment with
      TGFbeta1 -hydrogels. CONCLUSIONS: A TGFbeta1-hydrogel with appropriate
      biodegradability will function not only as a release matrix for the TGFbeta1, but
      also as a space provider for bone regeneration. The TGFbeta1-hydrogel is a
      promising surgical tool for skull defect repair and skull base reconstruction.

PMID- 10659021
TI  - An implantable guide-screw system for brain tumor studies in small animals.
AB  - OBJECT: To overcome the problems associated with using stereotactic techniques to
      establish intracranial xenografts in nude mice and to treat engrafted tumors with
      intratumoral therapies (such as gene or viral therapies), the authors developed
      an implantable guide-screw system. In this study, they describe the guide-screw
      system, its method of implantation, and their experience with establishing
      xenografts and delivering intratumoral therapy. METHODS: The system consists of a
      2.6-mm guide screw with a central 0.5-mm diameter hole that accepts the 26-gauge
      needle of a Hamilton syringe. The screw is implanted into a small drill hole made
      2.5 mm lateral and 1 mm anterior to the bregma. A stylet is used to cap the screw
      between treatments. Tumor cells or therapeutic agents are injected in a freehand
      fashion by using a Hamilton syringe and a 26-gauge needle fitted with a cuff to
      determine the depth of injection. To test this system, guide screws were
      successfully implanted in 44 (98%) of 45 nude mice. After 1 to 2 weeks of
      recovery, 38 mice were inoculated with U87MG cells and killed 5 days later. On
      histological studies in 37 (97%) of these animals, xenografts were evident within
      the caudate nucleus (mean diameter 2.5 mm). To determine whether injections into
      the center of an established xenograft could be reproducibly achieved with the
      guide-screw system, an adenovirus vector containing the beta-galactosidase gene
      was injected 3 days after cell implantation in 15 of the mice. All of these
      animals demonstrated transduced cells within the tumor. To demonstrate that
      engrafted animals have a uniform survival time that is indicative of reproducible
      tumor growth, the survival of six mice was assessed after engraftment with U87MG
      cells. All six animals died within 28 to 35 days. CONCLUSIONS: The guide-screw
      system allows a large number of animals to be rapidly and reproducibly engrafted
      and for intratumoral treatments to be accurately delivered into established
      xenografts.

PMID- 10659022
TI  - Recurrent intraneural ganglion cyst of the tibial nerve. Case report.
AB  - Different theories have evolved to explain the pathogenesis and the cell of
      origin of intraneural ganglion cysts. Reportedly only three cases of intraneural
      ganglion of the tibial nerve have been located within the popliteal fossa, and
      all of these were thought to arise within the nerve. The authors report a case of
      a recurrent tibial intraneural ganglion in which a connection to the proximal
      tibiofibular joint was demonstrated on magnetic resonance (MR) images and at
      surgery. Surgical ligation of the articular branch and evacuation of the cyst led
      to symptomatic relief, and an MR image obtained 1 year after surgery documented
      no recurrence. This case reinforces the fact that surgeons need to consider and
      search for an articular connection in all cases of intraneural ganglia,
      especially in those that have recurred.

PMID- 10659023
TI  - Malignant intracerebral nerve sheath tumor with intratumoral calcification. Case
      report.
AB  - The authors present the clinical, radiological, and pathological features of a
      malignant intracerebral nerve sheath tumor that occurred in the right
      parietooccipital lobe of a 4-year-old girl. Computerized tomography scanning and
      magnetic resonance imaging demonstrated a 5x5x4-cm multiloculated mass with
      considerable enhancement of the irregularly shaped septa and clearly calcified
      areas within the mass. Among five cases reported in the literature, this patient
      is the youngest and represents the first case in which there is radiological
      evidence of intratumoral calcification.

PMID- 10659024
TI  - Malignant peripheral nerve sheath tumors in the setting of segmental
      neurofibromatosis. Case report.
AB  - Approximately 100 cases of segmental neurofibromatosis (NF5) have been reported
      in the recent literature. Patients with NF5 present with cafe-au-lait macules,
      freckles, and/or neurofibromas limited to one or adjacent dermatomes.
      Neurofibromas arising in NF5 have been uniformly considered to be benign;
      patients were thought to have an excellent prognosis without the risk of
      developing malignant peripheral nerve sheath tumors (PNSTs), which are
      characteristic in patients with the generalized form of this disease, von
      Recklinghausen's NF. In this report the authors detail the first observations of
      malignant PNSTs in two patients with NF5. Indications for surgical removal of a
      neurofibroma in a patient with NF include pain. neurological impairment,
      compression of adjacent structures, cosmetic disfigurement, and rapid tumor
      growth suggestive of malignant degeneration. Surgical indications are similar for
      patients with NF5. All patients with neurofibromas should be considered at risk
      for malignant degeneration.

PMID- 10659025
TI  - Continuous intrathecal pump infusion of baclofen with antibiotic drugs for
      treatment of pump-associated meningitis. Case report.
AB  - Intrathecal baclofen administered by means of an implantable pump is being
      increasingly used for successful treatment of spasticity. Meningitis following
      intrathecally administered baclofen is a rare but serious complication that is
      difficult to treat without removal of the pump. Because success rates with
      intravenously administered antibiotic drugs for the treatment of meningitis have
      been low, intrathecal administration of antibiotic agents is often required to
      eradicate the pathogen. The authors report the case of a patient in whom
      Staphylococcus epidermidis meningitis developed after insertion of an intrathecal
      baclofen pump. The patient was successfully treated by intrathecal
      coadministration of vancomycin and baclofen.

PMID- 10659026
TI  - Visual loss associated with fibrous dysplasia of the anterior skull base. Case
      report and review of the literature.
AB  - The authors present a case of visual loss associated with fibrous dysplasia of
      the anterior skull base and the surgical management of this case. Preoperative
      computerized tomography scanning in this patient demonstrated a patent optic
      foramen and a rapidly growing cystic mass within the orbit, which was responsible
      for the patient's visual loss. A literature review revealed that this case is
      typical, in that cystic mass lesions of various types are frequently responsible
      for visual loss associated with fibrous dysplasia. The authors did not find
      significant evidence in the literature to support the notion that visual loss
      associated with fibrous dysplasia is the result of progressive optic canal
      stenosis, thus raising questions about the value of prophylactic optic canal
      decompression. Instead, as demonstrated by this case and those uncovered in the
      literature review, most instances of visual loss result from the rapid growth of
      mass lesions of cystic fibrous dysplasia, mucoceles, or hemorrhage. Findings of
      the literature review and the present case of fibrous dysplasia of the anterior
      skull base support a role for extensive surgical resection in these cases and
      indicate a need for additional prospective analysis of a larger number of
      patients with this disease.

PMID- 10659027
TI  - Early aneurysm recurrence after technically satisfactory Guglielmi detachable
      coil therapy: is early surveillance needed? Case report.
AB  - Guglielmi detachable coil (GDC) therapy was initially intended as a treatment for
      select patients harboring aneurysms deemed to be at high risk for clip ligation.
      As experience with the technique has grown, many centers are now offering GDC
      therapy as a primary treatment to patients who are also good surgical candidates.
      The authors report a case in which a ruptured anterior communicating artery
      aneurysm recurred within 2 weeks of a technically satisfactory GDC procedure. The
      patient subsequently underwent successful surgery for clip ligation of the
      lesion. This is the earliest reported recurrence of an aneurysm after
      angiographically confirmed successful GDC therapy and underscores the need for
      performing early control angiography in patients undergoing this procedure.

PMID- 10659028
TI  - Modification of a nasal speculum for transsphenoidal surgery. Technical note.
AB  - The authors modified a Hardy nasal speculum to improve the access to surgical
      fields and the handling of various instruments during transsphenoidal surgery. A
      section of the inferior edge of the speculum was cut out 2 cm from its orifice on
      both sides. The thickness of the tip of the speculum was also reduced. The
      authors are prepared to operate using a variety of speculum lengths (the distance
      between the tip and the cutting level), and this length is selected depending on
      the distance between the anterior wall of the sphenoid sinus and the surface of
      the gingiva in the individual patient. A modified nasal speculum was used in
      transsphenoidal surgery for a pituitary adenoma. With use of this device, the
      protrusion of the speculum above the gingiva was markedly decreased. Because most
      instruments are inserted into the inferior portion of the speculum orifice, this
      approach facilitated the handling of all surgical instruments through the
      modified nasal speculum. The actual surgical field became shallow and wide, and
      the long surgical instruments that are generally used for transsphenoidal surgery
      were unnecessary in most cases.

PMID- 10659029
TI  - Double pituitary adenomas detected on preoperative magnetic resonance images.
      Case illustration.

PMID- 10659030
TI  - Bone wax as a cause of foreign body granuloma in the cerebellopontine angle. Case
      illustration.

PMID- 10659031
TI  - Development of an arachnoid cyst after ventriculoperitoneal shunt placement. Case
      illustration.

PMID- 10659032
TI  - Densely calcified anterior cerebral arteries. Case illustration.

PMID- 10659033
TI  - Increased intracranial pressure resulting in a pulsatile aneurysm. Case
      illustration.

PMID- 10659034
TI  - High prolactin level.

PMID- 10659035
TI  - Transluminal balloon angioplasty for prevention of vasospasm.

PMID- 10659036
TI  - Terminology confusion in spinal surgery: laminotomy, laminoplasty, laminectomy.

PMID- 10659037
TI  - Tuning of photoreceptor spectral sensitivity in fireflies (Coleoptera:
      Lampyridae).
AB  - Sexual communication between male and female fireflies involves the visual
      detection of species-specific bioluminescent signals. Firefly species vary
      spectrally in both their emitted light and in the sensitivity of the eye,
      depending on the time when each is active. Tuning of spectral sensitivity in
      three firefly species that occupy different photic niches was investigated using
      light and electron microscopy, microspectrophotometry, and intracellular
      recording to characterize the location and spectral absorption of the screening
      pigments that filter incoming light, the visual pigments that receive this
      filtered light, and the visual spectral sensitivity. Twilight-active species had
      similar pink screening pigments, but the visual pigment of Photinus pyralis
      peaked near 545 nm, while that of P. scintillans had a lambdamax near 557 nm. The
      night-active Photuris versicolo, had a yellow screening pigment that was uniquely
      localized, while its visual pigment was similar to that of P. pyralis. These
      results show that both screening and visual pigments vary among species. Modeling
      of spectral tuning indicates that the combination of screening and visual
      pigments found in the retina of each species provides the best possible match of
      sensitivity to bioluminescent emission. This combination also produced model
      sensitivity spectra that closely resemble sensitivities measured either with
      electroretinographic or intracellular techniques. Vision in both species of
      Photinus appears to be evolutionarily tuned for maximum discrimination of
      conspecific signals from spectrally broader backgrounds. Ph. versicolor, on the
      other hand, appears to have a visual system that offers a compromise between
      maximum sensitivity to, and maximum discrimination of, their signals.

PMID- 10659038
TI  - Sensitivity to chemically diverse phagostimulants in a single gustatory neuron of
      a polyphagous caterpillar.
AB  - Caterpillars of the arctiid moth, Grammia geneura, are polyphagous, but species
      of Plantago are amongst their preferred food plants. A neuron in the medial
      styloconic sensillum on the galea has been shown to have a general
      phagostimulatory function. Experiments with binary mixtures and cross-adaptation
      have demonstrated that it responds to some sugars, to several amino acids, and
      also to catalpol. Catalpol is a plant secondary compound in Plantago and a
      phagostimulant for the caterpillars. The possible significance of combining
      sensitivity to nutrient compounds with sensitivity to a secondary compound is
      discussed.

PMID- 10659039
TI  - Detection of object motion by a fly neuron during simulated flight.
AB  - Object detection on the basis of relative motion was investigated in the fly at
      the neuronal level. A representative of the figure detection cells (FD-cells),
      the FD1b-cell, was characterized with respect to its responses to optic flow
      which simulated the presence of an object during translatory flight. The figure
      detection cells reside in the fly's third visual neuropil and are believed to
      play a central role in mediating object-directed turning behaviour. The dynamical
      response properties as well as the mean response amplitudes of the FD1b-cell
      depend on the temporal frequency of object motion and on the presence or absence
      of background motion. The responses of the FD1b-cell to object motion during
      simulated translatory flight were compared to behavioural responses of the fly as
      obtained with identical stimuli in a previous study. The behavioural responses
      could only partly be explained on the basis of the FD1b-cell's responses. Further
      processing between the third visual neuropil and the final motor output has to be
      assumed which involves (1) facilitation of the object-induced responses during
      translatory background motion at moderate temporal frequencies, and (2)
      inhibition of the object-induced turning responses during translatory background
      motion at high temporal frequencies.

PMID- 10659040
TI  - Metabolic correlates of the circadian pattern of suckling-associated arousal in
      young rabbits.
AB  - Young rabbits (Oryctolagus cuniculus) are only nursed for 3-5 min every 24 h.
      They show a circadian increase in activity in anticipation of this, which is
      entrained by suckling. Our aim was to determine whether serum and liver
      metabolites show diurnal fluctuations which could act to regulate this circadian
      pattern. Stomach weight, liver glycogen and serum metabolites were measured every
      3 h in 7- to 8-day-old pups when normally nursed (up to 24 h after suckling) and
      fasted (up to 48 h after suckling). The results suggest: 1. Energy balance
      between feeds was maintained by a cascade in the use of fuels, first glucose from
      the milk, then glycogen stores and gluconeogenesis from circulating products of
      proteins and triglycerides, and finally, in late-fasted animals, the mobilization
      of free fatty acids. 2. The empty stomach and depletion of glycogen 23-24 h after
      the last feed could act to trigger anticipatory arousal in normally nursed pups,
      and the release of free fatty acids 45 48 h after the last feed could trigger
      this in fasted pups. 3. Unmasking of rhythmicity by fasting in serum levels of
      glucose and proteins suggests their regulation by endogenous oscillators, which
      may also be the case for the mobilization of free fatty acids.

PMID- 10659041
TI  - PACAP-38 is a chemorepellent and an agonist for the lysozyme receptor in
      tetrahymena thermophila.
AB  - Pituitary adenylate cyclase activating peptide (PACAP-38) is a peptide hormone
      which functions in many mammalian systems, including the nervous and digestive
      systems. Using in vivo behavioral studies, we have found that this hormone
      functions as a chemore-pellent in Tetrahymena thermophila with an EC50 of 10 nM.
      Cells previously adapted to PACAP-38 were found to be adapted to lysozyme and
      vice versa. Furthermore, the in vivo behavioral activity of PACAP-38 was blocked
      by addition of the anti-lysozyme receptor antibody, 5545. Chemorepellent activity
      of PACAP-38 was also inhibited by the addition of neomycin sulfate (inhibition
      constant Ki = 0.080 micromol x l(-1)), a competitive inhibitor of lysozyme
      binding to its receptor. PACAP-38 is a more potent and specific agonist for the
      lysozyme receptor than either intact lysozyme or CB2, a 24-amino acid fragment of
      lysozyme.

PMID- 10659042
TI  - Optomotor course control in flies with largely asymmetric visual input.
AB  - We have studied freely flying and walking flies as well as flies flying in a
      flight simulator in order to discover how functionally blinding one of the eyes
      affects the fly's ability to move straight. It is hard to tell just by observing
      the animals' movements whether they have been deprived of vision in one eye.
      Statistical analysis is need to show that there are differences in the locomotory
      paths of monocular and binocular flies: monocular flies tend to turn slightly
      towards the side of the seeing eye. It is possible that the superimposed
      translational and rotational optic flow fields, generated on the trajectory of
      monocular flies, sum to zero net flow. This overall flow over the retina of the
      open eye might lead to a state of optomotor equilibrium.

PMID- 10659043
TI  - Mixture interactions of glutamate and betaine in single squid olfactory neurons.
AB  - We used nystatin-patch techniques to characterize the responses of squid
      olfactory receptor neurons to the attractive odorant, L-glutamate, and to study
      mixture interactions between glutamate and the aversive odorant, betaine. We
      report that glutamate activates a cation-selective conductance that is permeable
      to Ca2+, K+, and Na+ and which would depolarize squid olfactory receptor neurons
      under physiological conditions. The responses to glutamate were concentration
      dependent. The EC50 of individual cells ranged from 0.3 mmol x l(-l) to 85.0 mmol
      x l(-l). We found that individual cells were capable of responding to both
      glutamate and betaine, and that the relative magnitudes of these responses varied
      from cell to cell. Finally, we report that current responses to binary mixtures
      of glutamate and betaine are suppressed relative to the sum of the responses to
      the individual odors in single squid olfactory receptor neurons.

PMID- 10659044
TI  - Developmental attenuation of Manduca pre-ecdysis behavior involves neural changes
      upstream of motoneurons and relay interneurons.
AB  - Each molt in the hawkmoth, Manduca sexta, culminates in the shedding of the old
      cuticle at ecdysis. Prior to each larval ecdysis, the old cuticle is loosened by
      pre-ecdysis behavior, which includes rhythmic, synchronous compressions in all
      abdominal segments. Prior to ecdysis to the pupal stage, pre-ecdysis behavior and
      its underlying motor pattern are markedly attenuated. A single pair of
      interneurons located in the terminal abdominal ganglion, the IN-402s, drives
      compression motoneuron activity during the pre-ecdysis motor pattern via
      monosynaptic excitatory connections. The present study tested the hypotheses that
      (1) changes in intrinsic properties (resting membrane potential, spike threshold,
      input resistance and excitability) of compression motoneurons, or (2) changes in
      the strength of synaptic connections from IN-402s to compression motoneurons,
      underlie the developmental attenuation of the pre-ecdysis motor pattern. Membrane
      potential was slightly more hyperpolarized in prepupal as compared to larval
      motoneurons, but no other findings supported the tested hypotheses. These results
      suggest that developmental weakening of the pre-ecdysis motor pattern results
      from changes upstream of the compression motoneurons and their synaptic
      connections from IN-402s.

PMID- 10659045
TI  - Electrical stimulation of the preoptic area in Eigenmannia: evoked interruptions
      in the electric organ discharge.
AB  - The functional role of the basal forebrain and preoptic regions in modulating the
      normally regular electric organ discharge was determined by focal brain
      stimulation in the weakly electric fish, Eigenmannia. The rostral preoptic area,
      which is connected with the diencephalic prepacemaker nucleus, was examined
      physiologically by electrical stimulation in a curarized fish. Electrical
      stimulation of the most rostral region of the preoptic area with trains of
      relatively low intensity current elicits discrete bursts of electric organ
      discharge interruptions in contrast to other forebrain loci. These responses were
      observed primarily as after-responses following the termination of the stimulus
      train and were relatively immune to variations in the stimulus parameters. As the
      duration and rate of these preoptic-evoked bursts of electric organ discharge
      interruptions (approximately 100 ms at 2 per s) are similar to duration and rate
      of natural interruptions, it is proposed that these bursts might be precursors to
      natural interruptions. These data suggest that the preoptic area, consistent with
      its role in controlling reproductive behaviors in vertebrates, may be influencing
      the occurrence of electric organ discharge courtship signals by either direct
      actions on the prepacemaker nucleus or through other regions that are connected
      with the diencephalic pre-pacemaker nucleus.

PMID- 10659046
TI  - Responses of the tropical bont tick, Amblyomma variegatum (Fabricius), to its
      aggregation-attachment pheromone presented in an air stream on a servosphere.
AB  - Male Amblyomma variegatum ticks feeding on a host release a mixture of o
      nitrophenol and methyl salicylate which serves to attract conspecifics. The
      behavioural responses of A. variegatum on a servosphere to these volatiles
      presented in an air stream are detailed here. In still air, ticks walked on all
      eight legs, but with long halts. In contrast, the air stream caused continuous
      walking and induced a reaching response where the forelegs actively sampled the
      air. Such reaching increased the angular velocity and reduced walking speed,
      effects that were amplified in the presence of vapours from o-nitrophenol and
      methyl salicylate in the air flowing over the ticks. Vapour from a 1:1 mixture of
      o-nitrophenol and methyl salicylate was attractive over a 10(4)-fold
      concentration range providing an increase in upwind displacement of 20-40%,
      significantly higher than the natural ratio where o-nitrophenol vapour
      predominates. Although the responses to o-nitrophenol vapour were variable when
      presented alone, this chemical was consistently attractive when delivered with
      steer hair odour unattractive on its own. Moreover, the upwind walk to this
      combination did not cause a change in speed or angular velocity. This supports
      the hypothesis that the response to the pheromone is enhanced by host odour.

PMID- 10659048
TI  - Allelic distribution of CCR5 and CCR2 genes in an Italian population sample.
AB  - Genetic polymorphisms of CCR5 and CCR2 human chemokine receptors have been
      associated with resistance during HIV-1 infection and disease progression. The
      protective effect of mutant alleles at these loci has important implications in
      AIDS pathogenesis. Chemokine receptors have a role in viral entry into target
      cells as well as in immune response modulation. In the present report, we studied
      the frequency of CCR5delta32 and CCR264I allelic variants among a representative
      sample of the Italian population. Observed allelic frequencies were 0.0454 and
      0.0655, respectively. In both cases, genotype distribution was in equilibrium as
      predicted by the Hardy-Weinberg equation. Taken as a whole, about 21% of the
      population sample was found to be heterozygous for one or another of those two
      mutated alleles. Distribution of CCR5delta32 and CCR264I allelic variants within
      a population can be considered as a measure of genetic susceptibility to HIV
      infection and disease progression.

PMID- 10659047
TI  - Recombinant bacillus Calmette-Guerin as a potential vector for preventive HIV
      type 1 vaccines.
AB  - In August 1997, the World Health Organization (WHO) and the Joint United Nations
      Programme on HIV/AIDS (UNAIDS) convened an expert working group to discuss
      current strategies for the development of HIV type 1 vaccines. Based on the
      recent findings of investigators from Japan's National Institute of Infectious
      Diseases (NIID) in Tokyo using recombinant bacillus Calmette-Guerin (rBCG) as a
      potential vectored vaccine for HIV, a recommendation was made that further work
      in this area is a priority. As a result, the working group reconvened in
      September 1998 to discuss the progress to date with this vaccine approach, as
      well as areas of related research to assess the feasibility of a BCG-vectored HIV
      vaccine. This report summarizes the discussions addressing the available
      scientific data on the potential use of rBCG as a vector for preventive HIV
      vaccines, the work necessary to move such candidate vaccines into Phase 1
      clinical trials, and recommendations targeted at facilitating the long-term
      development of rBCG-vectored HIV vaccines.

PMID- 10659049
TI  - AIDS onset at high CD4+ cell levels is associated with high HIV load.
AB  - To identify factors associated with development of AIDS at high CD4+ cell levels
      a nested case-control study using data from the Multicenter AIDS Cohort Study
      (MACS) was conducted. HIV-1-infected men who developed AIDS with > or =300/mm3
      CD4+ cells (AIDS men) were compared to men who had > or =300/mm3 of CD4+ cells,
      but remained AIDS free for at least 2 years. The AIDS men had higher plasma HIV-1
      RNA levels (mean 10(5.02) vs. 10(4.42), p<0.01) and neopterin levels (mean 18.3
      vs. 11.5 units/ml, p<0.05) before the AIDS diagnosis than did the AIDS-free men.
      A significantly higher proportion of the AIDS men reported genital herpes within
      the year prior to their initial AIDS diagnosis than did the AIDS-free men (21.9
      vs. 4.4%, p<0.05). The higher viral load at relatively high CD4+ cell levels in
      men who subsequently developed AIDS within 6 months supports the hypothesis that
      elevated levels of HIV precede CD4+ decline and are the major factor in
      determining risk of AIDS even at high levels of CD4+ cell levels.

PMID- 10659050
TI  - Anti-cell antibodies in exposed seronegative individuals with HIV type 1
      neutralizing activity.
AB  - Despite repeated exposures to HIV-1, some individuals remain seronegative. This
      study reports that sera from a fraction of exposed seronegative (ESN) subjects
      showed HIV-neutralizing activity; 5 of 17 ESN sera and none of 17 controls
      neutralized two different HIV-1 primary isolates (range of neutralizing titers:
      1/20 to 1/60). The neutralizing activity was associated with the IgG fraction of
      4 of 4 neutralizing ESN sera. Moreover, in 11 of 17 and 9 of 17 ESN sera (but
      none of the control sera) we found antibodies against HLA class I and CD4,
      respectively. One of the ESN sera (EU22) neutralized efficiently the primary
      virus derived from the seropositive partner and showed a good broadly cross
      reactive neutralization. Immunoadsorption of two IgG fractions from EU19 and EU22
      on peripheral blood mononuclear cells (PBMC) removed virus-neutralizing
      antibodies. The correlations between the ESN status and neutralizing activity
      (p<0.05), anti-HLA antibodies (p<0.0002), and anti-CD4 antibodies (p<0.001) were
      statistically significant. However, there was no statistically significant
      correlation between neutralizing activity and either anti-HLA or anti-CD4
      antibodies. It can therefore be said that exposure to HIV-1 without
      seroconversion is, in some individuals, associated with HIV-neutralizing
      antibodies (not directed against viral antigens) and/or with anti-cell
      autoantibodies, which are possibly specific for cellular antigens involved in the
      infection/entry process.

PMID- 10659051
TI  - Dependence of CD8+ T-cell-mediated suppression of HIV type 1 on viral phenotypes
      and mediation of phenotype-dependent suppression by viral envelope gene and not
      by beta-chemokines.
AB  - CD8+ T-cell-mediated HIV-1 suppressive activity has been shown against a number
      of strains of HIV-1 and HIV-2. In this study using a semiquantitative assay, we
      showed that CD8+ T cells from seropositive subjects and herpes virus saimiri
      transformed CD8+ T-cell clones from HIV-1-infected subjects exhibited 5 to 100
      fold higher suppressive activity against slow replicating nonsyncytia-inducing
      strains (Slow/NSI) as compared to fast replicating syncytia-inducing strains
      (Fast/SI) of HIV-1. Such differential suppressive activity was not due to beta
      chemokines as evidenced by the lack of blocking activity of antibodies to RANTES,
      MIP-1beta, and MIP-1alpha on the antiviral activities of CD8+ T cells. Moreover,
      there was no correlation between the level of CD8+ T-cell suppression and the
      level of these beta-chemokines in culture supernatant. Results from the CD8+ T
      cell-mediated suppressive activity against two molecular cloned virus ME1
      (Slow/NSI), ME46 (Fast/SI), and their interstrain recombinants indicate that the
      envelope gene carries a major genetic determinant responsible for this phenotypic
      dependent differential suppressive activity.

PMID- 10659052
TI  - Attenuation of human immunodeficiency virus type 1 cytopathic effects by
      replacing a 424-bp region of envelope from a noncytopathic biological clone.
AB  - We analyzed the env genes of cytopathic and noncytopathic biological clones
      derived from two HIV-1-infected children with discordant clinical courses.
      Chimeric viruses were constructed by switching env regions from V2 through V3 of
      the biological clones with the corresponding region from the molecular clone NL4
      3. These HIV-1 chimeric viruses exhibited similar replication kinetics as well as
      syncytium-inducing abilities. The chimeric virus containing the env region of
      noncytopathic biological clone, GC6 8-4, was noncytopathic in an in vitro cell
      killing assay, while the chimeric virus containing the env region of cytopathic
      biological clone, HC4, was cytopathic in the in vitro cell-killing assay. These
      studies suggest the presence of a cytopathicity determinant that maps to the
      envelope sequences contained within the downstream region of V2 and within the V3
      region (nucleotide position 6822 to nucleotide position 7250, based on NL4-3
      sequence).

PMID- 10659054
TI  - Immunogenicity of a vaccine preparation representing the variable regions of the
      HIV type 1 envelope glycoprotein.
AB  - Variability of the major antigenic sites of the envelope glycoprotein of HIV-1
      constitutes a major problem in the formulation of effective vaccines. We have
      prepared a synthetic peptide vaccine that represents the major hypervariable
      epitopes (V1 through V5) of the clade B HIV-1 envelope glycoprotein (gp120). We
      refer to this preparation as variable epitope immunogen or VEI vaccine. This
      construct takes into consideration the type and frequency of amino acid
      substitutions found at each epitope during the evolution of the virus in
      individual patients and in the target population. Immunization of mice, rabbits,
      and rhesus macaques with the VEI vaccine resulted in the induction of long
      lasting, high-titered HIV-1 antibodies, including antibodies that neutralize
      primary isolates. We also documented lymphocyte proliferative responses to the
      VEI vaccine, its individual components, analogs, and subtype-specific peptides
      representing the major hypervariable regions of HIV-1 gp120. Delayed-type
      hypersensitivity responses to these antigens were also demonstrated in mice. Our
      results show that this vaccine is highly immunogenic and safe in animals. Our
      data suggest that this formulation could become an important component of
      combination vaccine approaches against HIV-1 and other antigenically variable
      pathogens.

PMID- 10659053
TI  - Near-full-length genome sequencing of divergent African HIV type 1 subtype F
      viruses leads to the identification of a new HIV type 1 subtype designated K.
AB  - We recently reported a high divergence among African subtype F strains. Three
      well-separated groups (F1, F2, and F3) have been shown based on the phylogenetic
      analysis of the p24 gag and envelope sequences with genetic distances similar to
      those observed for known subtypes. In this study, we characterized the near-full
      length genomes of two strains from epidemiological unlinked individual belonging
      to each of the subgroups: F1 (96FR-MP411), F2 (95CM-MP255 and 95CM-MP257), and F3
      (96CM-MP535 and 97ZR-EQTB11). Phylogenetic analysis of the near-full-length
      sequences and for each of the genes separately showed the same three groups,
      supported by high bootstrap values. Diversity plotting, BLAST subtyping, and
      bootstrap plotting confirmed that the divergent F strains correspond to
      nonrecombinant viruses. The divergence between F1 and F2 is consistently lower
      than that seen in any other intersubtype comparison, with the exception of
      subtypes B and D. Based on all the different analyses, we propose to divide
      subtype F into two subclades, with F1 gathering the known subtype F strains from
      Brazil and Finland, and our African strain (96FR-MP411), and F2 containing the
      95CM-MP255 and 95CM-MP257 strains from Cameroon. The F3 strains, 97ZR-EQTB11 from
      the Democratic Republic of Congo and 96CM-MP535 from Cameroon, meet the criteria
      of a new subtype designated as K. The equidistance of subtype K to the other
      subtypes of HIV-1 suggests that this subtype existed as long as the others, the
      lower distance between B and D, and between F1 and F2 suggest a more recent
      subdivision for these latter strains.

PMID- 10659055
TI  - Rhesus lymphocryptovirus infection during the progression of SAIDS and SAIDS
      associated lymphoma in the rhesus macaque.
AB  - SAIDS-associated lymphoma (SAL) represents a monoclonal expansion of B-cell
      origin in which simian immunodeficiency virus (SIV) infection is not detected.
      However, tumor cells are frequently infected with rhesus lymphocryptovirus
      (RhLCV), a rhesus homologue of Epstein-Barr virus (EBV). In previous studies, the
      incidence of RhLCV infection in SAL was determined to be 89% as measured by
      polymerase chain reaction (PCR) and/or in situ hybridization. The main objective
      of the present study was to ascertain whether the level of RhLCV infection in the
      SIV-infected macaque is influenced as a function of SAIDS progression, and/or
      whether increased levels of RhLCV infection may correlate with the development of
      SAL. To this end, RhLCV infection was evaluated in three independent groups: (1)
      in lymphomas from SIV-infected rhesus macaques, (2) in peripheral blood
      mononuclear cells (PBMC) from a cohort of 69 randomly selected healthy animals,
      and (3) in PBMC collected from 22 SIV-infected animals at various times during
      progression to SAIDS or SAL. The relative levels of RhLCV infection were
      evaluated by PCR/Southern blot analysis, visual comparison to a standard dilution
      series, and assignment of relative signal intensity to a uniform classification
      scheme. The data show that SIV-infected monkeys have a generally higher RhLCV
      load in PBMC than do healthy animals, but that the virus load varies widely among
      animals during disease progression. Increased RhLCV load does not occur uniformly
      during the progression of SAIDS, although evidence indicates an increased RhLCV
      viral load in the development of SAL.

PMID- 10659056
TI  - Differential gene expression in B-cell non-Hodgkin's lymphoma of SIV-infected
      monkey.
AB  - Infection with SIVmac251 in some rhesus monkeys (Macaca mulatta) leads to B-cell
      non-Hodgkin's lymphomas (B-NHL) clinically similar to that of HIV-infected AIDS
      patients. To further characterize the SIV-associated B-NHL we have generated
      genetic profiles of malignant cells by subtractive hybridization and Northern
      blot analysis. We have analyzed 21 clones of a subtracted cDNA library
      corresponding to overexpressed genes in diffuse large B-cell (DLBCL) SIV
      associated monkey lymphoma. Eight of these clones represent a sequence homologous
      to an abundant transcript from KG-1 cells originally established from a human
      myelogenous leukemia. The protein encoded has a 60% similarity to a hypothetical
      glycine-rich transmembrane signal protein of Caenorhabditis elegans and 25%
      similarity to the ret finger protein. The other cDNA clones contained sequences
      of the serum amyloid A gene (SAA), the alpha1-acid glycoprotein gene (AGP), the
      ribosomal protein S3a (RPS3a) and L8 (RPL8) genes, the interferon-inducible gene
      (INF-ind), the metastasin gene (mts1), and the NADH dehydrogenase I gene (ND-I).
      The remaining cDNA clones consisted of yet unknown sequences. In addition, we
      detected an up-regulation of the cytochrome c oxidase II gene (COX-II), the ND-IV
      gene, and the SET oncogene by Northern blot hybridization in three SIV-associated
      NHLs of different histomorphological classification. All these genes have not
      previously been found to be overexpressed in B-NHL.

PMID- 10659057
TI  - Distribution of the CCR5 delta32 allele in Italian HIV type 1-infected and normal
      individuals.

PMID- 10659058
TI  - The challenge of imaging acute stroke in Canada.

PMID- 10659060
TI  - Radiological evaluation of inferior vena cava obstruction: pictorial essay.

PMID- 10659059
TI  - Radial sclerosing lesions of the breast: mammographic and pathologic correlation.
AB  - OBJECTIVE: The purpose of this study was to define the mammographic appearance of
      96 pathologically proven radial sclerosing lesions (RSLs) and to determine the
      frequency of association with malignancy in and around the lesions. METHODS:
      Ninety-three patients with 96 RSLs were identified from the pathology files of
      the BC Cancer Agency, and the reasons for biopsy were obtained. All preoperative
      mammograms were reviewed, and the RSLs were categorized as classic (typical), non
      classic (atypical), or incidental. The histopathologic results were
      retrospectively examined for atypia, ductal carcinoma in situ (DCIS) and invasive
      carcinoma. RESULTS: In 67 of the 96 biopsies, the RSL was the primary
      mammographic abnormality that led to biopsy. In this group, 17 cases (25.4%)
      contained atypia, 17 (25.4%) DCIS, and 4 (6%) invasive carcinoma. Nineteen of
      these RSLs presented as mass-like opacities that mimicked carcinoma. No single
      mammographic feature consistently predicted premalignant or malignant lesions. In
      the remaining 29 patients, biopsy was carried out because of pleomorphic
      calcifications or masses, and RSLs were found incidentally in specimens. These
      specimens included 4 cases (13.8%) of atypia, and 1 case (3.4%) of DCIS.
      CONCLUSION: Of the 67 mammographically detected RSLs, only 48 (71.6%) had a
      typical mammographic appearance. We found a significant amount of atypia (25.4%)
      and malignancy (25.4% DCIS and 6% invasive carcinoma) in mammographically
      detected RSLs. Because of the lack of predictable radiological features, adequate
      open surgical biopsy is recommended for all focal abnormalities in which a RSL is
      a possible diagnosis.

PMID- 10659061
TI  - Thoracoabdominal actinomycosis mimicking metastatic disease: case report.

PMID- 10659062
TI  - Epithelioid hemangioendothelioma of the liver--characteristics on magnetic
      resonance imaging: case report.

PMID- 10659063
TI  - Sonographic appearance of renal transplant osseous metaplasia: case report.

PMID- 10659064
TI  - Computed tomographic and magnetic resonance imaging of ameloblastoma: 2 case
      reports.

PMID- 10659065
TI  - Spine and spinal cord vascular malformations: pictorial essay.

PMID- 10659066
TI  - Neurosarcoidosis presenting as an intrasellar pseudotumoral mass: case report.

PMID- 10659067
TI  - Residents' corner. Answer to case of the month #66. Intravenous pulmonary
      talcosis with complicating massive fibrosis.

PMID- 10659069
TI  - Residents' corner. Answer to case of the month #68. Calcified amyloidoma of the
      larynx.

PMID- 10659068
TI  - Residents' corner. Answer to case of the month #67. Pyeloureteritis cystica.

PMID- 10659070
TI  - Raised scaly and crusted papules.

PMID- 10659071
TI  - Geriatrics photo quiz. Abdominal x-rays.

PMID- 10659072
TI  - Dementia DDx. Office diagnosis of the four major types of dementia.
AB  - The prevalence of dementia increases with age from 1% at age 60 to about 40% at
      age 85. Four types of dementia--Alzheimer's disease, diffuse Lewy body dementia,
      frontotemporal dementia, and vascular dementia--account for 90% of all cases. The
      office-based physician can recognize these dementing illnesses in older patients
      by using existing consensus criteria. Differential diagnosis has an important
      bearing on patient management and prognosis, due to the potential value of
      treatment with some medications, possible drug toxicities in certain
      circumstances, and the complex care needs of patients and their families.

PMID- 10659073
TI  - Neck pain. Primary care work-up of acute and chronic symptoms.
AB  - Acute or chronic neck pain can arise from degenerative processes, musculoskeletal
      trauma, or structural changes. For all patients presenting with neck pain,
      determining the presence of radiculopathy or myelopathy is an important step in
      initial assessment. Depending on the duration of pain, the work-up should include
      appropriate use of traditional and advanced imaging studies. For cases that do
      not suggest traumatic, structural, or rheumatologic origins, alternate
      considerations should include stress, depression, and--because of its increased
      incidence in older persons--cancer. Nonsteroidal anti-inflammatory agents, mild
      oral analgesics, and short-term corticosteroid therapy are the mainstays of
      treatment, although physical therapy and traction can be helpful for some
      patients. The presence of a herniated disk, cord compression (severe stenosis),
      tumor, or other structural lesion may require surgical decompression.

PMID- 10659074
TI  - Clinical practice guidelines. Finding and appraising useful, relevant
      recommendations for geriatric care.
AB  - Practicing effective evidence-based medicine in the geriatric setting depends on
      routine review of the current literature and critical analysis of its relevance
      to the patient and condition in question. Clinical guidelines facilitate this
      approach and are readily available from an array of print and electronic
      resources. The recent growth in the number of published guidelines by medical
      associations, government agencies, and healthcare organizations makes determining
      their validity and applicability a challenging proposition. The Internet provides
      one of the most effective tools for quickly finding evidence-based guidelines.
      Appraisal involves several fundamental steps that can aid in determining whether
      the guidelines are valid--based on "best evidence"--and clinically relevant.

PMID- 10659076
TI  - Safe, effective techniques for cerumen removal.
AB  - Cerumen removal in older patients can prevent serious social withdrawal due to
      hearing loss or infection due to untreated impaction. The recommended procedure
      calls for taking a careful history, examining the patient for prior pathology,
      and using sterile instruments, good lighting, and accepted methods of cerumen
      removal. Knowing when to stop irrigation and to use ceruminolytic drops or refer
      to a specialist is key to maximizing patient comfort and minimizing
      complications.

PMID- 10659075
TI  - Clinical update: how to recognize and treat depression in older patients..
      Interview by Marc E. Webster.
AB  - Geriatrics is pleased to highlight the clinical implications of research topics
      supported by the American Federation for Aging Research (AFAR). AFAR is a leading
      private organization supporting research on the aging process and diseases of
      older populations. More than 900 physicians, scientists, and students have
      received AFAR grants totaling more than $20 million since AFAR was founded by
      Irving S. Wright, MD, in 1981. The articles in the New Frontiers series are
      designed to provide primary care physicians with insight into the pathogenesis,
      diagnosis, prevention, and treatment of the diseases of aging.

PMID- 10659077
TI  - Assumptions of infantile amnesia: are there differences between early and later
      memories?
AB  - Most adults are able to provide few, if any, reports of autobiographical memories
      from the first years of life. Early memories that do exist have been
      characterised as highly emotional, containing an abundance of perceptual as
      opposed to propositional information, and more often in the third than the first
      person perspective. These qualities figure prominently in theories of the source
      of the phenomenon of infantile amnesia. However, early and later memories have
      not been directly compared with regard to these features. In the present
      research, we compared early and later memories in the same individuals, with the
      same methodology. Results indicated few objective differences between the early
      and later memories of women (Experiment 1) and men (Experiment 2). The findings
      are discussed in light of their implications for theories as to the source of
      infantile amnesia.

PMID- 10659078
TI  - Childhood amnesia: on answering questions about very early life events.
AB  - Twenty five young adults were asked about the events surrounding the birth of a
      younger sibling which took place when they were under the age of 2 years.
      Approximately 40% of the participants claimed to have significant memories of the
      events. The mothers of our participants verified that a majority of their answers
      were accurate. Comparing the pattern of data with those previously collected
      (Eacott & Crawley, 1998) suggests that the memories of those who were aged below
      2:0 are qualitatively similar to the memories of those who were older at the time
      of events and dissimilar in type to those who are basing their reports on
      reconstructions from family knowledge. This finding may be evidence that memories
      of events that occurred before the age of 2 years are genuine but rare. This
      conclusion may be useful in assessing theories of childhood amnesia.

PMID- 10659079
TI  - The credibility of a source influences the rate of unconscious plagiarism.
AB  - Three experiments were conducted to investigate the relationship between the
      credibility of information and later unconscious plagiarism of that information.
      In each experiment, ideas concerning ways to reduce traffic accidents were
      presented from a more credible source (traffic planners) and a less credible
      source (college freshmen). After a distractor task, participants were asked to
      generate novel ways to reduce traffic accidents. In Experiments 1 and 2,
      unconscious plagiarism of ideas presented from the more credible source was
      greater than from the less credible source. In neither experiment was explicit
      memory for ideas from each source different in tests of source monitoring or free
      recall. However, the difference in unconscious plagiarism was eliminated in
      Experiment 3 by having participants generate the implications of ideas at study.
      The results are discussed in terms of the explicit factors that affect the
      incidence of unconscious plagiarism.

PMID- 10659080
TI  - The effect of text coherence and modality on metamemory judgements.
AB  - This study examined the effects of text coherence and modality on the metamemory
      judgements of Ease of Learning (EOL) and Judgement of Learning (JOL), and on the
      object-level measure of recall. Previous work found that sentence material set in
      a coherent, ordered text context was not judged as more memorable than that
      presented in a context of sentences in a disordered sequence, even though an
      ordered sequence helped recall (Shaddock & Carroll, 1997). The current study
      modified Shaddock and Carroll's design by changing the texts used from expository
      to narrative text. The metamemory judgements and recall were now found to be
      significantly more sensitive to material learned in an ordered sequence than to
      material learned in a disordered sequence. Also, JOLs and recall were more
      sensitive to material that was originally learned in an auditory mode (spoken
      presentation) than in a visual mode (verbal presentation). The results are
      discussed in terms of a cue-utilisation approach to metamemory judgements.

PMID- 10659081
TI  - Do novel associative word stem completion and cued recall share the same memory
      retrieval processes?
AB  - The aim of this study was to determine whether word stem completion for novel
      associations between cue and target words was mediated by automatic unconscious
      memory processes or effortful memory processes under conscious control. This was
      done by applying full and divided attention conditions at test to stem
      completion, cued recall, and recognition, and by administering a questionnaire
      that probed the memory strategies used by subjects during the completion test.
      Divided attention had no effect on stem completion performance, but did reduce
      associative cued recall. Recognition performance was weakened overall by divided
      attention, but the associative effect was similar under both attention
      conditions. This suggested that novel associative word stem completion was
      mediated by automatic retrieval processes. However, the results of the
      questionnaire indicated that only subjects who attempted to remember the words
      from the study phase during the completion task showed any novel associative
      effect. It is concluded that novel association word stem completion and cued
      recall share automatic retrieval processes, which nevertheless give rise to the
      experience of remembering.

PMID- 10659082
TI  - Categorisation of action speed and estimated event duration.
AB  - Two experiments investigated the relationship between the words used to describe
      event actions and estimates of event duration, and whether this relationship
      might account for some of the variation found in duration estimates. Experiment 1
      manipulated sets of action words within an account of a robbery, and replicated
      the Burt and Popple (1996, Experiment 1) finding that estimated duration
      decreased as the implied action speed of the robbery increased. Experiment 2
      found considerable variation across individuals in the action words they used to
      describe a robbery, and that the number of action words used was negatively
      correlated with estimated duration. Taken together the experiments suggest that
      the interaction between individual differences in action categorisation and the
      use of inferences about the relationship between action speed and event duration,
      may account for some of the between-subject variation found in estimates of event
      duration.

PMID- 10659083
TI  - Long-term retention of theatrical roles.
AB  - Two experiments tested both long-term retention of complex material by
      professional actors, and the contributions made by motoric codes to that
      retention. The first experiment indicated that, during performance, the actors
      rendered the written script with approximately 98% accuracy, making only very
      minor changes, primarily additions or deletions of verbal interjections. The
      second experiment assessed recall three months after the final performance, with
      the actors having learned and performed new roles in the interim. Retention was
      still extremely high with approximately 90% of the text being recalled verbatim
      or within very narrowly defined limits. A repeated trials paradigm (involving
      actors either sitting or moving about as they did in performance) indicated that
      motoric cues aided long-term verbal recall even when the movements did not
      constitute enactments of the literal words.

PMID- 10659084
TI  - Images, memories, and models: introduction to the special issue.

PMID- 10659085
TI  - Mapping cognition to the brain through neural interactions.
AB  - Brain imaging methods, such as positron emission tomography (PET) and functional
      magnetic resonance imaging (fMRI), provide a unique opportunity to study the
      neurobiology of human memory. As these methods can measure most of the brain, it
      is possible to examine the operations of large-scale neural systems and their
      relation to cognition. Two neuroimaging studies, one concerning working memory
      and the other episodic memory retrieval, serve as examples of application of two
      analytic methods that are optimised for the quantification of neural systems,
      structural equation modelling, and partial least squares. Structural equation
      modelling was used to explore shifting prefrontal and limbic interactions from
      the right to the left hemisphere in a delayed match-to-sample task for faces. A
      feature of the functional network for short delays was strong right hemisphere
      interactions between hippocampus, inferior prefrontal, and anterior cingulate
      cortices. At longer delays, these same three areas were strongly linked, but in
      the left hemisphere, which was interpreted as reflecting change in task strategy
      from perceptual to elaborate encoding with increasing delay. The primary
      manipulation in the memory retrieval study was different levels of retrieval
      success. The partial least squares method was used to determine whether the image
      wide pattern of covariances of Brodmann areas 10 and 45/47 in right prefrontal
      cortex (RPFC) and the left hippocampus (LGH) could be mapped on to retrieval
      levels. Area 10 and LGH showed an opposite pattern of functional connectivity
      with a large expanse of bilateral limbic cortices that was equivalent for all
      levels of retrieval as well as the baseline task. However, only during high
      retrieval was area 45/47 included in this pattern. The results suggest that
      activity in portions of the RPFC can reflect either memory retrieval mode or
      retrieval success depending on other brain regions to which it is functionally
      linked, and imply that regional activity must be evaluated within the neural
      context in which it occurs. The general hypothesis that learning and memory are
      emergent properties of large-scale neural network interactions is discussed,
      emphasising that a region can play a different role across many functions and
      that role is governed by its interactions with anatomically related regions.

PMID- 10659086
TI  - The neural correlates of updating information in verbal working memory.
AB  - The aim of the present study was to re-examine cerebral areas subserving the
      updating function of the central executive with a running span task requiring
      subjects to watch strings of consonants of unknown length and then to recall
      serially a specific number of recent items. In order to dissociate more precisely
      the updating process from the storage function, a four-item instead of a six-item
      memory load was used, contrary to our previous study (Salmon et al., 1996). In
      addition, a serial recall procedure was preferred to a recognition procedure in
      order to suppress the use of visuospatial strategies. The most significant
      increase of rCBF occurred in the left frontopolar cortex (Brodmann's area 10),
      spreading to the left middle frontal (Brodmann's area 46). Results suggest that
      frontopolar activation underlies an updating process in working memory.

PMID- 10659087
TI  - Functional neuroimaging correlates of functional amnesia.
AB  - Especially in the field of memory encoding and retrieval, the results of
      functional neuroimaging have provided new insights in anatomico-functional
      interactions. In particular this holds true for the role of the prefrontal cortex
      in mnestic information processing, for the contribution and participation of the
      two hemispheres in various processes of information transmission, and for views
      on disturbed information processing after organically obvious and so-called
      psychogenic forms of memory impairments. This report particularly stresses the
      insights obtained by functional neuroimaging for probably environmentally
      triggered deficiencies in memory processing and discusses possible subtle
      neuroanatomical correlates of functional amnesias. It is especially emphasised
      that stress conditions and depressive states may modify the release of steroids
      (glucocorticoids) and transmitter agonists at the brain level with the
      consequence of selective memory disturbances which may manifest as a "mnestic
      block syndrome".

PMID- 10659088
TI  - Imaging episodic memory: implications for cognitive theories and phenomena.
AB  - Functional neuroimaging studies are beginning to identify neuroanatomical
      correlates of various cognitive functions. This paper presents results relevant
      to several theories and phenomena of episodic memory, including component
      processes of episodic retrieval, encoding specificity, inhibition, item versus
      source memory, encoding-retrieval overlap, and the picture-superiority effect.
      Overall, by revealing specific activation patterns, the results provide support
      for existing theoretical views and they add some unique information which may be
      important to consider in future attempts to develop cognitive theories of
      episodic memory.

PMID- 10659089
TI  - FDG-PET analysis and findings in amnesia resulting from hypoxia.
AB  - The assumptions underlying neuroimaging, and problems in its analysis and
      interpretation, are commonly underestimated in neuropsychology. The ways in which
      fluoro-deoxy-glucose (FDG) positron emission tomography (PET) data can be
      analysed are discussed. PET findings from four patients who had suffered severe
      amnesia, following episodes of acute hypoxia, are presented. These patients had
      shown evidence of medial temporal (hippocampal and parahippocampal) atrophy on
      MRI brain scans. The PET data were analysed in several different ways. The
      converging findings were that the patients showed bilateral thalamic
      hypometabolism, and there was also evidence of retrosplenial hypometabolism
      bilaterally. Cognitively, these patients performed most like other patients with
      medial temporal lesions, but the results indicate that structural lesions can
      have distal metabolic effects on structures elsewhere. These findings are
      interpreted in the light of neuroanatomical observations concerning parallel
      projections between medial temporal lobe structures and the thalamus, some of
      which pass via the retrosplenium.

PMID- 10659090
TI  - The neuroimaging of long-term memory encoding processes.
AB  - There needs to be more crosstalk between the lesion and functional neuroimaging
      memory literatures. This is illustrated by a discussion of episode and fact
      encoding. The lesion literature suggests several hypotheses about which brain
      regions underlie the storage of episode and fact information, which can be
      explored by functional neuroimaging. These hypotheses have been underexplored
      because neuroimaging studies of encoding have been insufficiently hypothesis
      driven and have not controlled encoding-related processes sufficiently well to
      allow clear interpretations of results to be made. Nevertheless, there is good
      evidence that certain kinds of associative encoding and/or consolidation are
      sufficient to activate the medial temporal lobes, and preliminary evidence that
      some kinds of associative priming may reduce activation of this region. It
      remains to be proved that attentional orienting to certain kinds of novel
      information activates the medial temporal lobes. Evidence is growing that the
      HERA model, developed from neuroimaging rather than lesion data, requires
      modification and that frontal cortex encoding activations are probably caused by
      executive processes that are important in effortful memory processing.
      Neuroimaging studies allow the detection of encoding-related activations in
      previously unexpected brain regions (e.g. parietal lobes) and, in turn, these
      findings can be explored with lesion studies.

PMID- 10659091
TI  - Direct comparison of episodic encoding and retrieval of words: an event-related
      fMRI study.
AB  - Functional magnetic resonance imaging (fMRI) was used to compare directly
      episodic encoding and retrieval. During encoding, subjects studied visually
      presented words and reported via keypress whether each word represented a
      pleasant or unpleasant concept (intentional, deep encoding). During the retrieval
      phase, subjects indicated (via keypress) whether visually presented words had
      previously been studied. No reliable differences were found during the
      recognition phase for words that had been previously studied and those that had
      not been studied. Areas preferentially active during encoding (relative to
      retrieval) included left superior frontal cortex, medial frontal cortex, left
      superior temporal cortex, posterior cingulate, left parahippocampal gyrus, and
      left inferior frontal gyrus. Regions more active in retrieval than encoding
      included bilateral inferior parietal cortex, bilateral precuneus, right frontal
      polar cortex, right dorsolateral prefrontal cortex, and right inferior
      frontal/insular cortex.

PMID- 10659092
TI  - A positron emission tomography (PET) study of autobiographical memory retrieval.
AB  - Memory for the experiences of one's life, autobiographical memory (AM), is one of
      the most human types of memory, yet comparatively little is known of its
      neurobiology. A positron emission tomography (PET) study of AM retrieval revealed
      that the left frontal cortex was significantly active during retrieval (compared
      to memory control tasks), together with activation in the inferior temporal and
      occipital lobes in the left hemisphere. We propose that this left frontal lobe
      activation reflects the operation of control processes that modulate the
      construction of AMs in posterior neocortical networks.

PMID- 10659093
TI  - Right prefrontal cortex responds to item familiarity during a memory encoding
      task.
AB  - In a previous word-pair encoding study (Dolan & Fletcher, 1997), we examined the
      effect of introducing novelty, either in studied words or in their mutual
      associations. A left medial temporal lobe (MTL) sensitivity to novel words and
      left prefrontal cortex (PFC) to novel associations was observed. In this further
      report on the data, we explored the extent to which the right PFC, more generally
      implicated in retrieval operations (Fletcher, Frith, & Rugg, 1997), was sensitive
      to these manipulations. Specifically, we characterised changes associated with
      increasing familiarity of study material. We demonstrate that the response in
      right ventrolateral PFC is preferentially sensitive to a condition in which all
      material was familiar (that is, in which all material had been presented prior to
      scanning). A more dorsal region in right PFC was found to be relatively more
      active in association with a condition in which one item in the pair was familiar
      but was paired with a novel associate. Our results suggest that sensitivity to
      stimulus familiarity is expressed in right PFC, even within the context of an
      encoding task. The data also provide further evidence for functional
      heterogeneity within right PFC, with a more ventral region responding to
      familiarity of complete word pairs and a more dorsal region responding to
      familiar single words occurring in the context of new associative relationships.

PMID- 10659095
TI  - Memory, imaging, and the mind-brain: in conclusion.

PMID- 10659094
TI  - The hippocampus and delayed recall: bigger is not necessarily better?
AB  - Healthy young female participants were tested on a measure of delayed verbal
      recall and then received volumetric Magnetic Resonance Imaging (MRI) scans. The
      analysis of the MRI scans focused on the volume of the hippocampus. Left
      hippocampal volume was negatively associated with the level of delayed verbal
      recall performance. This relationship was confirmed in further testing. This
      finding is consistent with a previous report of a similar relationship in healthy
      elderly individuals, but not in patients with Alzheimer's disease, in whom the
      opposite relationship was observed. An explanation of these findings in terms of
      impaired neural pruning of the hippocampus is advanced, whereby insufficient
      pruning of the hippocampus during childhood and adolescence (following adequate
      growth) may lead to reduced mnemonic efficiency.

PMID- 10659096
TI  - The impact of palliative medicine?

PMID- 10659097
TI  - Lay carers' satisfaction with community palliative care: results of a postal
      survey. South Tyneside MAAG Palliative Care Study Group.
AB  - This paper reports the substantive findings of a study that examined the
      feasibility of using postal questionnaires to assess the satisfaction of lay
      caregivers with the care received in the community by those dying of cancer. The
      focus of the analysis was the quality of information provided by health
      professionals, health services used in the final year of the dying person's life
      and the lay carer's views about the quality of these services. The study was a
      retrospective survey of lay carers identified from death certificates over a 9
      month period. Of the 355 people contacted, 156 completed the questionnaires, a
      44% response rate. The results of the survey indicate that information provision
      was deemed unsatisfactory by a large proportion of respondents, and that
      dissatisfaction with care received from hospital, the district nursing service
      and the general practitioner was common. Levels of satisfaction with care were
      clearly related to a range of service factors. Our survey also highlighted clear
      differences in the perceived quality of specialist and generic services for those
      dying of cancer. A comparison of the findings from this postal study with those
      reported in earlier retrospective interview surveys of lay carers suggests that
      the use of the postal questionnaire is a valid and cost-effective approach for
      assessing quality of care. The data provide baseline information against which
      improvements in the quality of care can be measured.

PMID- 10659098
TI  - Feasibility of using postal questionnaires to examine carer satisfaction with
      palliative care: a methodological assessment. South Tyneside MAAG Palliative Care
      Study Group.
AB  - This paper reports on the methodological findings from a project which examined
      the feasibility of using a postal questionnaire to assess lay carer satisfaction
      with palliative care. The focus of this paper is the process of questionnaire
      development and its psychometric evaluation. The questionnaire was derived from
      an interview schedule used in previous national surveys of care for the dying,
      and was refined through qualitative work with recently bereaved lay carers. It
      was then tested in a postal survey of 355 lay carers identified from death
      registration certificates. Overall response rates were low, but significantly
      enhanced by the use of a single reminder sent 3 weeks after the initial mailshot.
      The analysis indicated that in the majority of cases the person targeted to
      receive the questionnaire was the most appropriate informant. Psychometric
      evaluation of the questionnaire against five criteria was encouraging, with low
      item nonresponse and ineligible response, and some evidence of discriminatory
      power, reliability, and face and content validity. Postal approaches appear to
      represent an acceptable means of assessing user satisfaction with palliative
      care, compared with more resource-intensive methods.

PMID- 10659099
TI  - Challenges in palliative care research; recruitment, attrition and compliance:
      experience from a randomized controlled trial.
AB  - Randomized controlled trials (RCTs) in palliative cancer care often experience
      methodological problems. In this paper we discuss issues of major concern,
      including recruitment, patient attrition and compliance, arising from an RCT that
      compared comprehensive palliative care to conventional care. The main criteria
      for trial entry were incurable malignant disease and a survival expectancy of
      between 2 and 9 months. Patients' health-related quality of life (HRQL), self
      assessed by multi-item questionnaires, was a defined endpoint. The planned number
      of patients was successfully recruited, although the patients were referred late
      in the course of their disease so that follow-up tended to be short. Compliance
      in completing HRQL questionnaires was good up to 1 month before the patient's
      death; but in the final weeks it was found to drop substantially. Based on our
      experience, recommendations are given for those planning similar research.
      Procedures for improving patient recruitment are suggested, stressing the need
      for local data management, repeated information to referral sources, extensive
      screening for potentially eligible patients and simple referral routines. Precise
      inclusion criteria, including prognostic factors other than physicians' estimates
      of life expectancy, should be used to ensure a sufficient follow-up period. For
      HRQL assessment, multi-item questionnaires can achieve excellent compliance up to
      1 month before patients' death, but in order to evaluate the very final weeks of
      life we recommend the use of simpler methods.

PMID- 10659100
TI  - A comparison of patient and proxy symptom assessments in advanced cancer
      patients.
AB  - The purpose of this study was to compare patient and proxy (physician and nurse)
      assessments of symptoms in advanced cancer patients. The sample consisted of 49
      patients with advanced cancer admitted to an acute palliative care unit. Three
      independent assessments were completed for each patient on two occasions within
      11 days of admission. On each occasion, symptoms were rated independently by the
      patient and two proxies (treating physician and nurse), using the Edmonton
      Symptom Assessment System (ESAS). The ESAS is a nine-item visual analogue scale
      (VAS) for assessing pain, activity, nausea, depression, anxiety, drowsiness,
      appetite, well-being and shortness of breath. Symptom ratings were compared using
      a repeated-measures ANOVA procedure and correlations. Average physician ratings
      were generally lower than average patient ratings for both occasions. Average
      nurse ratings agreed more closely with patient ratings, with a trend towards
      lower ratings on occasion 1 and higher ratings on occasion 2. There was a
      significant rater (person rating the effects) effect (P < 0.01) for three of the
      nine symptoms: physicians rated drowsiness, shortness of breath and pain
      significantly lower than patients. For drowsiness and shortness of breath, these
      differences were clinically relevant, representing a difference of more than 12
      mm on a 100-mm VAS. The accuracy of assessments amongst those rating the symptoms
      did not improve over time. Proxy assessments of symptom intensity, particularly
      by physicians, were significantly lower than patient assessments for three of the
      nine symptoms. Further research regarding the reliability of patient and proxy
      assessments is needed to assess and manage symptoms in advanced cancer
      effectively.

PMID- 10659101
TI  - The applicability of quality-of-life assessment in palliative care: comparing two
      quality-of-life measures.
AB  - Two self-administered quality-of-life measures, the McGill Quality of Life
      Questionnaire (MQOL) and the Patient Evaluated Problem Scores (PEPS) were
      compared in patients receiving palliative care. The MQOL is a multidimensional
      questionnaire consisting of 16 items in five quality-of-life (QOL) domains:
      physical symptoms, physical well-being, psychological, existential and support
      domains. The PEPS is an individualized questionnaire asking patients to identify
      and rate major problems affecting their QOL. Both questionnaires were completed
      by 36 patients during outpatient clinic visits in three palliative care settings
      in Wales. Of those patients who stated their questionnaire preference 60%
      favoured MQOL due to its comprehensiveness, while others (28%) preferred PEPS due
      to its simplicity. The MQOL showed excellent internal consistency (alpha = 0.90).
      The intrapatient analysis of answers from both questionnaires showed that MQOL
      was better than PEPS in reporting physical symptoms and support domain, while
      PEPS detected more psychosocial issues. The MQOL overall QOL score correlated
      highly with its existential domain (rs = 0.57, P < 0.0005) and the PEPS overall
      quality of life (rs = 0.77, P < 0.0005). Similarly, the PEPS overall QOL
      correlated well with MQOL total score (rs = 0.76, P < 0.0005) and existential
      domain of the MQOL (rs = 0.63, P < 0.0005). The findings support the importance
      of an existential domain in assessing the QOL of this population. Both MQOL and
      PEPS were found to be relevant and acceptable in advanced cancer patients
      receiving palliative care. However, with its favourable psychometric properties
      MQOL may be more suitable for QOL assessment in this population.

PMID- 10659102
TI  - Prospective study of symptom control in 133 cases of palliative care inpatients
      in Shatin Hospital.
AB  - We report a prospective study assessing the prevalence and severity of physical
      and nonphysical symptoms, and the benefits from treatment and intervention, in
      advanced cancer patients presenting to a local palliative care unit in Hong Kong.
      Patients were assessed by a modified version of the support team assessment
      schedule (STAS). The study highlighted some symptoms which needed better control,
      and also reinforced the team morale by demonstrating aspects where there was
      definite improvement. In general, the STAS was found to be practicable and
      acceptable by our patients and staff. The most important benefit gained from the
      study was the successful dissemination of the concept of audit and quality
      assurance throughout the unit, which is essential for continuous improvement in
      the future.

PMID- 10659103
TI  - A longitudinal evaluation of a communication skills programme.
AB  - Communication is an essential component of palliative care, but patients and
      their families are often dissatisfied with their interactions with health
      professionals. Communication difficulties are also a recognized stress factor
      among health professionals. Education and training, however, are said to improve
      communication skills. A communication skills training programme for 110 nurses
      has demonstrated statistically significant improvements in the nurses' skills,
      but no long-term effect was evaluated. This paper presents the results of the
      long-term follow-up study. Of the 110 nurses contacted, 20% refused to
      participate, 45% agreed and 35% did not respond; 33 nurses returned usable data.
      The mean length of time since completing the original study was 2.5 years. Since
      completion of the original course there was no statistically significant
      deterioration or improvement in eight of the nine areas of assessment skills
      evaluated. In the area of psychological assessment there was a statistically
      significant improvement, and overall the nurses maintained their skills and
      improved in this area. The results suggest that over time the nurses became more
      confident in the emotional areas of care as a result of the training. The two key
      elements of the training were audio-tape recordings and feedback, which raised
      self-awareness, and experiential workshops covering ways of handling difficult
      situations. Whether a similar training effect could be achieved by a short 3-5
      day course on communication skills needs addressing, because the integrated
      training skills course evaluated here is costly. Preliminary evidence suggests
      that the 3-5-day course may not be as effective, so the increased costs
      associated with the integrated training skills course may be wisely spent if it
      improves the quality of nurse-patient interaction as evidence here suggests.

PMID- 10659104
TI  - An audit of long-stay patients in an inner city palliative care centre.
AB  - An audit was carried out of patients with long admissions to a palliative care
      centre in central London. The records of patients remaining in the centre for
      more than 28 days were examined to see whether there were particular features
      characteristic of long-stay patients which could be identified to improve future
      admission planning.

PMID- 10659105
TI  - Use of the Hospital Anxiety and Depression Scale (HADS) in the assessment of
      depression in patients with inoperable lung cancer.

PMID- 10659106
TI  - Systematic review of the use of opioid drugs in the palliative treatment of
      dyspnoea.

PMID- 10659107
TI  - Double effect, double bind or double speak?

PMID- 10659108
TI  - Acute care palliative medicine: psychosocial assessment of patients and primary
      caregivers.
AB  - This paper describes the application of an empirically-derived psychosocial
      assessment for use in advanced cancer. The patient population selected for this
      study was those patients no longer pursuing aggressive antitumour treatment, and
      the focus of care was on management of major symptoms and complications, and
      psychosocial support of the patient and family. The physical, cognitive, social
      and emotional dimensions were the framework for the assessment of both patient
      and caregiver functioning. Through this assessment of all patients admitted to
      our inpatient palliative medicine unit, care needs were identified and
      psychosocial interventions planned. The results of 150 assessments are reported,
      as well as observations of the process, implications for psychosocial care and
      modifications of the assessment based on this experience.

PMID- 10659109
TI  - Development of a breathlessness assessment guide for use in palliative care.
AB  - The complex nature of breathlessness in advanced cancer makes it a difficult
      symptom to understand and control. Measurement instruments applied to
      breathlessness have thus far failed to consider the multivariant components of
      this symptom. This study developed a breathlessness assessment guide for use in
      the clinical practice setting, that may be completed by any member of the health
      care team. The guide aims to encourage breathlessness to be addressed as a
      multidimensional problem, in which the emotional experience of breathlessness is
      inseparable from the sensory experience and the causative biological mechanisms.
      This guide provides the foundation for understanding the symptom of
      breathlessness in advanced cancer, and in turn promotes the development of
      management strategies to deal with this complex symptom.

PMID- 10659110
TI  - Optimizing hospital-based home care for dying cancer patients: a population-based
      study.
AB  - Health-related quality of life (HRQL) is difficult to define and measure. It is a
      generic term that includes concepts such as physical health, life satisfaction,
      psychological well-being and self-integrity. Realizing and appreciating the
      importance of HRQL is crucial for physicians if they are to be in a position to
      offer appropriate suggestions in assisting patients and their families in the
      decision-making process regarding cancer treatment and terminal care. In order to
      determine whether Greek physicians take into consideration HRQL when assessing
      different therapeutic options, we conducted a postal survey. A total of 1500
      Greek physicians (internists, oncologists and anaesthesiologists) were asked to
      complete a questionnaire. We received replies from 1280 (85%). In summary, we
      found that Greek physicians: (1) have already started taking HRQL into
      consideration when reviewing their therapeutic options; (2) increasingly include
      HRQL in research studies as an outcome measure; (3) do not yet have thoroughly
      sufficient training in the holistic care of cancer patients and their families;
      (4) mostly do not have the opportunity to work in interdisciplinary therapeutic
      teams where they can exchange ideas and consider different aspects of alternative
      therapeutic methods. It is concluded that HRQL has already been introduced as an
      important determinant of therapeutic choices in cancer care in Greece. However,
      efforts need to be made to allow HRQL to enjoy its appropriate place in cancer
      care.

PMID- 10659111
TI  - Optimizing hospital-based home care for dying cancer patients: a population-based
      study.
AB  - In many reports the percentage of home deaths in cancer is based on selected
      populations. In this population-based study all cancer patients who died within
      12 months within a specified area were studied (n = 108). This area is covered by
      hospital-based home care (HBHC) on a 24-h basis, which doctors available by day
      and at night. Forty people (37%) out of the total cancer population died in their
      own homes. Another 11% would theoretically have been ideal candidates for home
      care at the end of life. Thus, a home death rate of about 50% of the cancer
      patients is a realistic figure, and much higher than the usual 5-15% reported,
      provided that an effective HBHC is offered.

PMID- 10659112
TI  - Screening for psychiatric illness in the palliative care inpatient setting: a
      comparison between the Hospital Anxiety and Depression Scale and the General
      Health Questionnaire-12.
AB  - The objective of this study was to compare the performance of the Hospital
      Anxiety and Depression Scale (HADS) with the 12-item General Health Questionnaire
      (GHQ-12) as a screening instrument for the detection of psychiatric disorders in
      a palliative care inpatient setting. The results from the HADS and GHQ were
      compared to diagnoses generated from a semistructured psychiatric interview
      (Revised Clinical Interview Schedule) using standard receiver operating
      characteristic analysis. The study was conducted at the Marie Curie Centre,
      Edinburgh, a 37-bedded palliative care inpatient facility. Out of a total of 282
      admissions during the study period, 79 took part in the study. The remainder of
      patients either refused (69) or were too unwell to participate (134). The HADS
      was found to be an effective screening tool for identifying depression, with an
      area under the receiver operating characteristic curve of 0.92. A suggested cut
      off of 20 would have a sensitivity of 0.77, a specificity of 0.85 and a positive
      predictive value (PPV) of 0.48. There was no significant difference between the
      two subscales in their ability to detect depressive illnesses, although there was
      a trend for the anxiety subscale to perform better (P < 0.15). The GHQ did not
      perform as well as the HADS in this type of population. In view of this, it can
      be concluded that the HADS is a valid screening tool for psychiatric disorders,
      particularly depression, in a palliative care setting.

PMID- 10659113
TI  - An evaluation of aromatherapy massage in palliative care.
AB  - The use of complementary therapies, such as massage and aromatherapy massage, is
      rising in popularity among patients and healthcare professionals. They are
      increasingly being used to improve the quality of life of patients, but there is
      little evidence of their efficacy. This study assessed the effects of massage and
      aromatherapy massage on cancer patients in a palliative care setting. We studied
      103 patients, who were randomly allocated to receive massage using a carrier oil
      (massage) or massage using a carrier oil plus the Roman chamomile essential oil
      (aromatherapy massage). Outcome measurements included the Rotterdam Symptom
      Checklist (RSCL), the State-Trait Anxiety Inventory (STAI) and a semi-structured
      questionnaire, administered 2 weeks postmassage, to explore patients' perceptions
      of massage. There was a statistically significant reduction in anxiety after each
      massage on the STAI (P < 0.001), and improved scores on the RSCL: psychological
      (P < 0.001), quality of life (P < 0.01), severe physical (P < 0.05), and severe
      psychological (P < 0.05) subscales for the combined aromatherapy and massage
      group. The aromatherapy group's scores improved on all RSCL subscales at the 1%
      level of significance or better, except for severely restricted activities. The
      massage group's scores improved on four RSCL subscales but these improvements did
      not reach statistical significance. Massage with or without essential oils
      appears to reduce levels of anxiety. The addition of an essential oil seems to
      enhance the effect of massage and to improve physical and psychological symptoms,
      as well as overall quality of life.

PMID- 10659115
TI  - Generalized hyperalgesia and allodynia following abrupt cessation of subcutaneous
      ketamine infusion.

PMID- 10659114
TI  - Coeliac plexus block using computed tomography guidance.
AB  - Coeliac plexus blocks have been used successfully in the treatment of abdominal
      pain in advanced cancer and in benign chronic abdominal pain. However, concern
      remains about occasional potentially serious complications. One possible way to
      reduce the risks of this procedure may be to improve imaging during the
      procedure. We report a series of 38 coeliac plexus blocks carried out under
      computer tomographic (CT) guidance, mostly using the anterior approach. The
      technique is described. Effectiveness and side-effect rates were similar to other
      reported series. There were no major complications. Analysis of contrast spread
      would indicate that anterior preaortic or bilateral contrast spread is necessary
      to obtain pain relief. Our experience would indicate that routine CT guidance can
      be a simple aid to coeliac plexus block, and can be achieved easily in a district
      general hospital. Improved imaging allows accurate needle placement, while
      avoiding vital structures such as the aorta and pleura. Accurate placement may
      also allow the use of reduced volumes of neurolytic drugs.

PMID- 10659116
TI  - Octreotide as an agent for the relief of malignant ascites in palliative care
      patients.

PMID- 10659117
TI  - A survey of psychosocial service provision within hospices.

PMID- 10659118
TI  - Meta-analysis.

PMID- 10659119
TI  - Taking responsibility for affecting the time of death.

PMID- 10659120
TI  - Use of external nasal dilator strips in motor neurone disease with upper airways
      obstruction.

PMID- 10659121
TI  - Pseudomyxoma peritonei--a palliative approach.

PMID- 10659122
TI  - Acupuncture in the control of vasomotor symptoms caused by tamoxifen.

PMID- 10659123
TI  - Use of unlicensed medication in palliative medicine.

PMID- 10659124
TI  - Systematic review of the management of late complications arising as a result of
      radiotherapy for carcinoma of the cervix.

PMID- 10659125
TI  - Properties of a novel superoxide dismutase-hemoglobin conjugate of possible value
      in blood substitute formulation.

PMID- 10659126
TI  - Reactions of cross-linked methaemoglobins with hydrogen peroxide.

PMID- 10659127
TI  - A model for evaluation of artificial oxygen carriers regarding circulation,
      respiration and metabolism in anesthetized spontaneously breathing guinea pigs.
AB  - The evaluation of artificial oxygen carriers requires experiments with suitable
      animals. Many investigators do this with the classical laboratory animal, the
      rat, but it has a quite different oxygen pressure of half saturation (p50 = 36
      mmHg) from that of humans (26 mmHg). It was demonstrated that induced changes of
      the p50 value in animals provokes substantial changes in important cardiovascular
      parameters. Therefore, we decided to develop a guinea pig model for evaluation of
      artificial oxygen carriers, because it has a p50 of about 24 mmHg that is very
      similar to that of man. We found an anesthesia combination using
      fentanyl/droperidol/urethane to be very suitable for the narcosis, because
      important cardiovascular and respiratory parameters remain normal. Our model
      allows assessment of arterial pressure, oxygen uptake, carbon dioxide release,
      cardiac output, total peripheral resistance, shock index, blood lactate level,
      and, in particular, it allows to differentiate the oxygen transport in blood. We
      evaluated two hemoglobin-based oxygen carriers: bovine and porcine hemoglobin
      polymerized with glutaraldehyde in isoncotic solution (n = 3). Control
      experiments (n = 4) were done with an isotonic albumin solution. The protocol
      comprised a so-called exchange phase (I) with different degrees of hemodilution
      and a so-called time phase (II), an observation period with a hematocrit of 10%
      over about 3 hours. In the control group substantial changes in mean arterial
      pressure, total peripheral resistance, shock index, oxygen uptake and of blood
      lactate level were seen. All these effects were prevented by the artificial
      oxygen carriers tested. The carriers proved to be very effective, as small
      quantities in blood effectively restored these parameters, presumably via
      synergetic effects. Moreover, the experiments clearly revealed the limitation of
      hemodilution, at least in guinea pigs: below a hematocrit of 20% all parameters
      mentioned above changed significantly. The animal model presented proved to be
      appropriate for the evaluation of artificial oxygen carriers.

PMID- 10659128
TI  - Redox states of cerebral tissues of rats substituted by the liposome-encapsulated
      hemoglobin.

PMID- 10659129
TI  - Cortical blood oxygenation changes in the left and right occipital area induced
      by selective visual stimuli in humans.

PMID- 10659130
TI  - Measurement of arterial, venous, and interstitial pO2 during acute hypoxia in rat
      brain using a time-resolved luminescence-based oxygen sensor.
AB  - This is the first publication using a fiber optic "optode" and a luminescence
      based pO2 detection method for assessing neural tissue oxygenation. The system
      was used to simultaneously monitor pO2 in tissue (PtO2) and venous blood (PvO2)
      during normoxia, hyperoxia and hypoxia. PaO2 was varied by changing inspired
      oxygen (FiO2) from 0.3 to 0.13. Tissue and arterial pO2 were measured in 5 rats
      while the simultaneous venous measurements were undertaken in 3 animals. The PtO2
      was 29 +/- 10 at an arterial pO2 of 116 +/- 10 (mean +/- SE, n = 5). The PvO2 was
      consistently higher than PtO2 although PvO2 approached PtO2 as PaO2 declined to
      50 mmHg and was lower than tissue pO2 during the complete hypoxic period in one
      animal. These data indicate that brain venous pO2 is not representative of brain
      tissue pO2 and support published models predicting that in brain PvO2 is higher
      than PtO2.

PMID- 10659131
TI  - Fractal analysis of spontaneous fluctuations in human cerebral hemoglobin content
      and its oxygenation level recorded by NIRS.

PMID- 10659132
TI  - Oscillations in cerebral haemodynamics. Implications for functional activation
      studies.

PMID- 10659133
TI  - On the oxygenation of hemoglobin in the human brain.
AB  - We test three hypotheses arising from a model of oxygen delivery to brain tissue.
      The hypotheses claim that mitochondrial oxygen is negligible in brain tissue such
      that oxygen consumption depends solely on the mean capillary oxygen tension for a
      given capillary density; that capillary density is adjusted to satisfy the
      average steady-state oxygen requirement; and that sudden changes of brain
      function are subserved by changes of blood flow which adjust the mean capillary
      oxygen tension in the required direction. The results of the tests did not reject
      the two former hypotheses and only partly rejected the latter: Sudden changes of
      blood flow are not always accompanied by increases of oxygen consumption. When
      they are, changes of apparent capillary density (physiological recruitment) can
      occur.

PMID- 10659134
TI  - Reduced dilator and constrictor response of the middle cerebral artery after cold
      lesion of the rat parietal cortex.

PMID- 10659135
TI  - Loss of ETB-receptor-mediated relaxation in basilar artery after cold lesion of
      the rat parietal cortex.

PMID- 10659136
TI  - Regulation of cerebral oxygen delivery.

PMID- 10659137
TI  - A link between vasomotion and spontaneous oscillations of oxygen in rat brain.

PMID- 10659138
TI  - Evaluation of apolipoprotein E genotypes on cerebral blood flow and metabolism
      following traumatic brain injury.

PMID- 10659139
TI  - Cerebral tissue oxygen saturation (SrO2) from near infrared spectroscopy (NIRS)
      measurements following 90 degrees-head-up tilt.

PMID- 10659140
TI  - Optical monitoring of NADH redox state and blood flow as indicators of brain
      energy balance.

PMID- 10659141
TI  - Metabolic and hemodynamic oscillations monitored optically in the brain exposed
      to various pathological states.

PMID- 10659142
TI  - Altered ligand binding of D1 and D2 dopamine receptors in response to hypoxia and
      posthypoxic reoxygenation.

PMID- 10659143
TI  - Regional expression of heat shock protein 72 mRNA following mild and severe
      hypoxia in neonatal piglet brain.
AB  - The present study examined the effect of hypoxia on expression of 72-kDa heat
      shock protein (hsp72) mRNA in the newborn brain. The studies were carried out in
      anesthetized and mechanically ventilated newborn piglets, age 3-5 days. Hypoxic
      insult was induced by decreasing the fraction of inspired oxygen (FiO2) from 21%
      to 6% or 10% for 1 h. Oxygen pressure in the microvasculature of the cortex
      (cortical pO2) was measured by oxygen dependent quenching of the phosphorescence
      of phosphor dissolved in blood. Following the two hours of normoxic recovery,
      regional expression of the 72-kDa heat shock protein (hsp72) mRNA was determined
      using in situ hybridization and autoradiography. Two grades of hypoxia were
      studied. Mild hypoxia (cortical pO2 = 10-30 mm Hg) induced the expression of
      hsp72 mRNA predominantly in the subcortical white matter. In individual animals
      of this group, the extent of expression varied from isolated regions to
      widespread involvement of the white matter. Severe hypoxia (cortical pO2 = 3-10
      mm Hg) induced the expression of hsp72 mRNA in both white and gray matter
      regions, with strong expression occurring in the cerebral cortex of individual
      animals. The present results indicate that immature white matter is more
      sensitive than gray matter to the hypoxia induced expression of hsp72 mRNA.
      Further, increased expression of hsp72 mRNA may be an indicator of a pathologic
      degree of hypoxic stress, and the observed increase may indicate that in the
      newborn brain the immature white matter is particularly sensitive to injury by
      hypoxia-ischemia and reperfusion.

PMID- 10659144
TI  - Excitatory and inhibitory pathways for anoxic preconditioning neuroprotection in
      hippocampal slices.

PMID- 10659145
TI  - Mechanism(s) of mitochondrial hyperoxidation after global cerebral ischemia.

PMID- 10659146
TI  - Oxygen dependency of cerebral CuA redox state during increased oxygen consumption
      produced by infusion of a mitochondrial uncoupler in newborn piglets.

PMID- 10659147
TI  - Effects of ketamine/xylazine and pentobarbital anesthesia on cerebral tissue
      oxygen tension, blood pressure, and arterial blood gas in rats.

PMID- 10659148
TI  - Cerebral blood volume responses to acute PaCO2 changes in humans, assessed with
      near infrared spectroscopy.

PMID- 10659149
TI  - Brain oxygenation after experimental closed head injury. A NIRS study.

PMID- 10659150
TI  - Adenosine improves cerebral recovery in rat after cardiac arrest and
      resuscitation.

PMID- 10659151
TI  - Hemodynamic, metabolic, ionic, and electrical responses to cortical spreading
      depression in aging rats.

PMID- 10659152
TI  - Arteriolar and capillary tissue supply areas in myocardium.

PMID- 10659153
TI  - Role of K+ATP channels in the metabolic adaptation of the coronaries.

PMID- 10659154
TI  - Uneven flow distribution in the heart induced by endothelin.

PMID- 10659155
TI  - Hemodynamic changes caused by glibenclamide in isolated, working, erythrocyte
      perfused rat heart.
AB  - Glibenclamide-induced cardiac hemodynamic changes before and after ischemia have
      been frequently studied. In general a Langendorff buffer perfused heart model was
      used to examine these effects. However these models used protein-free buffer
      perfusates. To improve clinical relevance and thereby enhance extrapolation to
      the in vivo condition we studied the effects of glibenclamide on cardiac
      hemodynamics using a working, erythrocyte perfused, rat heart model, where the
      perfusate was enriched with albumin. The results show a dose-dependent decline in
      CBF in normoxia and at the end of reperfusion (after an ischemic period) with
      glibenclamide treatment compared to control. Cardiac functional recovery improved
      with 1 and 4 mumol.L-1 glibenclamide concentrations. From this study it seems
      that there is a marked decrease in CBF but this did not result in impaired
      myocardial function after a period of ischemia, so it appears that there are no
      startling side effects of glibenclamide in the ischemic rat heart.

PMID- 10659156
TI  - Hyperoxia and hypercapnic acidosis differentially alter nuclear factor-kappa B
      activation in human pulmonary artery endothelial cells.

PMID- 10659157
TI  - Heterogeneity of local metabolism and perfusion. Measuring local myocardial O2
      consumption in situ using frozen samples.

PMID- 10659158
TI  - Estimation of lactate threshold by near infrared spectroscopy.

PMID- 10659159
TI  - Myoglobin and O2 consumption in exercising human gastrocnemius muscle.

PMID- 10659160
TI  - Oxygen transport to muscular tissue under adaptation to hypoxic hypoxia.

PMID- 10659161
TI  - Incomplete oxygen extraction in exercising muscle.

PMID- 10659162
TI  - Quantitative measurement of oxygen consumption and forearm blood flow in patients
      with mitochondrial myopathies.
AB  - Five patients with chronic progressive external ophthalmoplegia (CPEO) and 27
      healthy controls were examined by near-infrared spectroscopy (NIRS) for the non
      invasive and direct quantitative measurement of muscle oxygen consumption during
      rest as well as during static isometric handgrip exercise at 10% of their maximum
      voluntary contraction. In patients with CPEO, we found a significantly decreased
      oxygen consumption during exercise, but more remarkably already during rest. Our
      results suggest that NIRS is able to discriminate between CPEO patients and
      healthy controls, which makes NIRS a promising tool in the diagnostic work-up of
      patients suspected of a mitochondrial myopathy.

PMID- 10659163
TI  - Critical capillary PO2 and the role of lactate production in oxyhemoglobin
      dissociation during exercise.
AB  - During exercise, O2 transport from capillary to myocyte is not diffusion-limited
      until end-capillary PO2 reaches its lowest value (critical capillary PO2).
      Critical capillary PO2 is reached at the mid-level of the subject's work
      capacity, not at Vo2 max. Femoral vein lactate does not increase until the
      critical capillary PO2 is reached. The increase in lactate is essential once the
      critical capillary PO2 is reached because the increase in H+ that accompanies the
      increase in lactate, through the "Bohr Effect", becomes the mechanism for
      oxyhemoglobin dissociation. Both normal subjects and patients with chronic stable
      heart failure have a critical capillary PO2 between 14 and 22 mm Hg. The pattern
      of femoral vein (end capillary) PO2 change as VO2 increases, describes the Vo2 at
      which O2 becomes diffusion limited and the extent to which new muscle capillary
      bed is recruited as Vo2 increases above the lactate threshold.

PMID- 10659164
TI  - NADH fluorimetry to predict ischemic injury in transplant kidneys.

PMID- 10659165
TI  - Effect of hydroxyl radical scavengers in renal cortical cells.

PMID- 10659166
TI  - Effect of furosemide or mannitol before injection of a non-ionic contrast medium
      on intrarenal oxygen tension.
AB  - Oxygen tension (pO2) in rat renal cortex and outer medulla was studied after an
      intravenous injection of mannitol or furosemide, followed 10 minutes later by an
      intravenous injection of the non-ionic X-ray contrast medium (CM) iopromide (370
      mg iodine/ml). Ten minutes after mannitol injection, before injection of CM, pO2
      in the medulla had decreased from a control level of 32 +/- 3 to 28 +/- 4 mm Hg.
      The addition of CM caused a further decrease, to 24 +/- 5 mm Hg, which was a
      significant reduction. Ten minutes after furosemide injection the pO2 in the
      medulla had increased significantly, from a control value of 32 +/- 2 to 44 +/- 4
      mm Hg. Injection of CM caused a significant decrease in pO2 to 37 +/- 3 mm.
      Ringer's solution (n = 6) caused no changes. We conclude that pretreatment with
      mannitol or furosemide does not prevent the CM-induced decrease in pO2 in the
      outer medulla.

PMID- 10659167
TI  - In vitro placental perfusion. Practical parameters and procedural performance.

PMID- 10659168
TI  - Dynamic measurements of oxygen tension in islets of Langerhans.

PMID- 10659169
TI  - Interaction between nitric oxide and thromboxane A2 in the regulation of the
      resting cerebrovascular tone.

PMID- 10659170
TI  - Role of nitric oxide in the control of mitochondrial function.
AB  - In summary, NO is capable of decreasing mitochondrial respiration in a variety of
      mammalian tissues. This effect is mediated primarily via binding of NO to the O2
      binding site of cytochrome oxidase. This highly sensitive interaction presumably
      reflects a remnant homology between cytochrome oxidase and bacterial nitrate
      reductase. This effect has been demonstrated at physiologic levels of NO,
      highlighting the role for NO in the tonic control of cellular respiration. As
      this inhibition is dependent upon the levels figure: see text[ of NO and O2 in
      the tissue, various states of NO production and oxygen supply dictate the
      ultimate respiratory rate of the mitochondria. Furthermore, deviation from a
      physiologic NO: O2 may lead to an exacerbation of pathologic states, such as
      congestive heart failure and septic shock. Thus, NO may play a crucial role in
      the control of cellular respiration, providing an additional mechanism of action
      for this biologically diverse molecule that is distinct yet inseparable from its
      dilator effect on blood vessels.

PMID- 10659171
TI  - Easy quantification of the respiratory and metabolic impact of blood O2-CO2
      exchange interactions in critical illness.

PMID- 10659173
TI  - A pathogenesis-based classification scheme for mitochondrial disorders.

PMID- 10659172
TI  - Enhancement effect of methyl alpha-D-glucoside for inhibitory effects of
      antioxidants on ADP/Fe(2+)-induced lipid peroxidation in rat liver mitochondria.

PMID- 10659174
TI  - A possible new mtrRNA mutation site for aminoglycoside-induced deafness syndrome.

PMID- 10659175
TI  - Effects of different vasodilators on human internal mammary artery in vitro.

PMID- 10659176
TI  - Red blood cell degradation products modify responsiveness of erythropoietin gene
      to hypoxia.

PMID- 10659177
TI  - Principles underlying vascular adaptation/angiogenesis.

PMID- 10659178
TI  - Some aspects concerning the antioxidant capacity of venous blood in lower limbs
      varicose veins.

PMID- 10659179
TI  - Assessment of tissue oxygenation in a cardiovascular ICU with radiometer's ABL
      625, Siggaard Andersen's OSA and ASKIT's NHMS.

PMID- 10659180
TI  - Norepinephrine vs nitric oxide synthase inhibition in endotoxemia.

PMID- 10659181
TI  - Changes in microvascular blood flow patterns and oxygen saturation in breast skin
      during radiotherapy.

PMID- 10659182
TI  - Impact of the antimetastatic drug Batimastat on tumor growth and PO2 measured by
      EPR oximetry in a murine mammary adenocarcinoma.

PMID- 10659183
TI  - Blood perfusion of subcutaneous tumours in mice following the application of low
      level direct electric current.
AB  - Electrotherapy with low-level direct electric current has been proved to be an
      effective local treatment of solid tumours. In the presented study an attempt was
      made to evaluate the effect of a single treatment with electrotherapy on blood
      perfusion of solid subcutaneous fibrosarcoma Sa-1 tumours in A/J mice. The tissue
      staining method with Patent blue-violet dye, the rubidium extraction technique,
      and the noninvasive near-infrared spectroscopy method were used for this purpose.
      Results of all methods indicate that perfusion and subsequently oxygenation of
      tumours were reduced due to application of electrotherapy.

PMID- 10659184
TI  - Effect of breathing carbogen on the oxygen tension of murine and human tumours
      measured using an Eppendorf pO2 histograph.

PMID- 10659185
TI  - Oxygen consumption and its transport in tissues during photodynamic therapy of
      tumors and whole blood.

PMID- 10659186
TI  - Can tumor oxygenation be improved by reducing cellular oxygen consumption.

PMID- 10659187
TI  - Predictive power of the tumor oxygenation status.
AB  - We have previously demonstrated with a prospective study in primary cancer of the
      uterine cervix (clinical size > 2 cm) that tumor hypoxia not only indicates
      decreased radiocurability but is generally associated with malignant progression
      of the disease. This finding also holds true for other tumor entities (soft
      tissue sarcomas, squamous cell carcinomas of the head and neck region), for lymph
      node metastases of head and neck lesions, and for locoregional recurrences of
      cervical cancers. All data available so far support our thesis that in cervical
      cancers (and in other solid tumors as well), tumor hypoxia and clinical
      aggressiveness in terms of resistance to therapy and tumor dissemination, are
      interrelated.

PMID- 10659189
TI  - Computational modeling of oxygen transport from complex capillary networks.
      Relation to the microcirculation physiome.

PMID- 10659188
TI  - The Cardiome Project. An integrated view of cardiac metabolism and regional
      mechanical function.
AB  - The goal, to develop a functioning three-dimensional computational model of the
      excitation, metabolism and contraction of the heart within three years, is one of
      the beginnings for the Cardiome Project. Our first stage will not be likely to
      provide highly accurate prediction of physiological behavior in general, but will
      be focussed so that it is adequate for at least three specific purposes: response
      to regional flow reduction, response to heart rate changes, and response to
      increased metabolic drive. We would like to make the model visualizable by three
      dimensional viewing, with cross-sectional and transparency viewing approaches,
      illustrate the fiber directions, the arteries, the deformation with contraction
      and images of regional functions such as oxygen consumption, preejection strain,
      or lactate concentration. The display techniques developed by Hunter et al. and
      by McCulloch et al. would be excellent for such demonstration and teaching
      purposes, and should be attractive enough for public display. The Physiome
      Project is underway now, with growing government and private support. Now we are
      going from the era of molecular biology, led by the Genome Project, into a new
      era of integrative biology. The goal is to understand biology so deeply and so
      broadly that predictions about interventions can be made. Methods of
      experimentation and of diagnosis are critical to acquiring the data, and
      therefore in making the prediction, and so all aspects of our Society's efforts
      and interests are relevant to undertaking this grand challenge.

PMID- 10659190
TI  - Regulation of local perfusion. Levels of control and contributing factors.

PMID- 10659191
TI  - Modeling in the evaluation/calibration of modern oxygen measuring techniques.

PMID- 10659192
TI  - Mathematical modeling of oxygen transport to skeletal muscle during exercise.
      Hypoxia and VO2max.

PMID- 10659193
TI  - Paradoxical relation of mitochondrial PO2 to Vo2.

PMID- 10659194
TI  - Sensitivity of protein C immunosensor with and without human serum albumin.

PMID- 10659195
TI  - Simultaneous measurements of mechanical pressure and oxygen pressure during
      puncturing of semisolid polymeric networks by polarographic needle electrodes.

PMID- 10659196
TI  - A new combined deep-body-temperature/NIRs probe for noninvasive metabolic
      measurements on human skeletal muscle.

PMID- 10659197
TI  - Laser-assisted optical rotational red cell analyzer (LORCA) in clinical practice.
      Hemorheological kinetics and tissue oxygenation.

PMID- 10659198
TI  - Separation of human protein C from components of transgenic milk using
      immobilized metal affinity chromatography.

PMID- 10659199
TI  - Analysis of phosphorescence decay for nonuniform oxygen tension. Consequences of
      finite excitation flash duration.

PMID- 10659200
TI  - A three wavelength study on arterial occlusion in skin tissue.

PMID- 10659201
TI  - Heterogeneity depth localization using Near Infrared Time Resolved Spectroscopy
      (NIR-TRS).

PMID- 10659202
TI  - Toward absolute quantitation of bold functional MRI.

PMID- 10659203
TI  - Measurement of oxygen diffusion through cultured endothelial cell monolayers.

PMID- 10659204
TI  - Monitoring changes in oxygen tension and microcirculation in a flap with a
      modified oxygen microelectrode and laser-Doppler flowmetry.

PMID- 10659205
TI  - A new measuring device for non-invasive determination of oxygen partial pressure
      and oxygen conductance of the skin and other tissues.
AB  - About fifty percent of the oxygen consumption of the skin is supplied by
      diffusion through the surface. This portion of the skin oxygen supply becomes of
      high importance in case of arterial occlusion. The oxygen permeation coefficient
      (P) of the upper layers and the oxygen pressure field within the skin determine
      the diffusive oxygen uptake from the outside. To our knowledge, the permeation
      coefficient (P) until now was only estimated by indirect methods of little
      practicability (Baumberger et al., 1951; Eberhard et al., 1978). An oxygen
      partial pressure of the skin is conventionally measured by modified CLARK type
      electrodes. A disadvantage of this so-called transcutaneous electrode is its
      oxygen consumption and the fixed coupling of the consumption with the oxygen
      pressure to be determined. Therefore the measurement always induces a systematic
      error (the so-called stirring effect) which depends, among other factors, on the
      oxygen availability of the skin under the electrode. The new device combines a
      consumption-free oxygen partial pressure detector on the basis of luminescence
      quenching by oxygen with an independently working specific oxygen consumer
      realized by an active galvanic chain (silver-lead element). The chain permits
      setting any oxygen mass flow (mO2) in a certain range by varying the electrode
      current choosing different resistors within the electrical circuit. According to
      the diffusion law, the surface oxygen pressure (ePO2) being measured is a linear
      function of the oxygen flow (mO2) directed to the cathode: ePO2 identical to 
      (1/P).(mO2/A) + icPO2; A: area under the cathode. The intracutaneous oxygen
      partial pressure (icPO2) is a virtual quantity defined by the equation given.
      Only by using an active electrode different oxygen mass flows can be set and so
      the oxygen conductance of the upper skin layers can be assessed. First
      experiments on human skin in the gluteal region of an adult delivered an
      estimated value of the permeation coefficient (P): 2.2.10(-5) ml O2
      (STPD)/(atm.s.cm2) at 42 degrees C skin surface temperature; the intracutaneous
      partial pressure obtained was 5.5 kPa (41 mmHg) (STPD: "standard temperature
      pressure dry" conditions of the gas). At 42 degrees C skin temperature no burning
      occurs. The determined O2-conductance is in the same range as estimated formerly
      (see above). The intracutaneous oxygen partial pressure determined seems to be a
      realistic value of the tissue at 42 degrees C. By in vitro measurements with
      technical membranes the new device and procedure was validated giving precise
      values of the oxygen conductance. Hence the new method may be used for
      calibration of the oxygen flux optode (Holst et al., 1993). The O2-permeation
      coefficient (P) could be an important parameter for evaluating dermatological
      applications (which attempt to increase P) in the treatment of local dermal
      oxygen deficiency. The intracutaneous oxygen partial pressure found is a
      reasonable value for a surface temperature of 42 degrees. Because of the
      independence of the O2-partial pressure determined and the O2-consumption the new
      device exhibits no stirring effect and it provides more insight into the
      limitations of conventional transcutaneous oxygen measurement.

PMID- 10659206
TI  - Oxygen transport in 10 microns artificial capillaries.
AB  - In order to further define the influence of microvessel diameter on intraluminal
      oxygen transport a previously described in vitro artificial capillary system was
      modified from a vessel diameter of 25 microns to 10 microns. Oxygen uptake and
      release rates were measured for hemoglobin solutions and red blood cell (Rbc)
      suspensions of the same overall hemoglobin concentration (10 g/dl). The modified
      apparatus was tested by comparing data for the hemoglobin solutions with
      predictive simulations from a validated mathematical model of oxygen transport.
      Preliminary data for oxygen uptake by Rbc suspensions flowing in 10 microns
      diameter capillaries are presented. As observed previously oxygen uptake is
      faster in hemoglobin solutions than in Rbc suspensions.

PMID- 10659207
TI  - A dual wavelength spectrophotometer for use in plastic surgery. Comparison with a
      Hamamatsu NIRO-500 instrument.

PMID- 10659208
TI  - Reusability study of fiber optic based protein C biosensor.

PMID- 10659209
TI  - Oxygen and hydrogen gas transport through living C6 cell suspensions is faster
      than that in dead cells.

PMID- 10659210
TI  - Cerebral blood flow in humans measured with near infrared spectroscopy is not
      reproducible.

PMID- 10659211
TI  - Evaluation of critical oxygen supply in the brain cortex.

PMID- 10659212
TI  - Comparison of cerebral blood volume measured by near infrared spectroscopy and
      contrast enhanced magnetic resonance imaging.
AB  - Cerebral blood volume (CBV) can be quantified by both near infrared spectroscopy
      (NIRS) and magnetic resonance imaging (MRI). The aim is to compare CBV results
      obtained by NIRS and MRI in adult patients. 10 adult patients, 6 females and 4
      males, age median 24 (range 21 to 76) years, were included in this study. All
      needed a MRI investigation with contrast medium for clinical reasons. The NIRS
      instrument, the Cerebral RedOx Monitor 2020 from Critikon, quantifies cerebral
      haemoglobin concentration using a sensor with two receiving channels at different
      distances. Geometrical detector arrangements of this type enable a ratio
      measurement to be achieved, which reduces the contribution of the skull and skin,
      thus allowing quantification. Cerebral haemoglobin concentration can be converted
      in CBV, as the haemoglobin concentration in the blood is known. CBV can be
      quantified by MRI using an indicator dilution method. The method requires an
      injection of a paramagnetic contrast agent. The input function can be measured at
      the throat and thus perfusion images can be quantified. CBV was measured by NIRS
      just before the patient entered the magnet and after he had left it. The sensor
      for the NIRS measurement was applied to the patients front three times for 1
      minute to each side, avoiding the sinuses. CBV was determined by contrast
      enhanced MRI between the NIRS measurements. The mean CBV (NIRS) was 8.6 (SD 1.3)
      ml/100 g and CBV (MRI) was 7.1 (SD 2.5). The correlation between CBV (NIRS) and
      CBV (MRI) was Pearson's correlation coefficient -0.297 (p = 0.204) respectively
      Spearman's rho (nonparametric) -0.266 (p = 0.257). The CBV values obtained by
      NIRS and MRI, even though they are in the same range, do not correlate.

PMID- 10659213
TI  - Bioluminescence for biological sensing in living mammals.

PMID- 10659214
TI  - Monte Carlo Simulation and the spectroscopic analysis of the response to neural
      stimulation in brain.

PMID- 10659215
TI  - Effect of breathing frequency and airflow on pulmonary function in high-intensity
      equine exercise.
AB  - It has been postulated that the hypoxaemia and hypercapnoea that characterize
      strenuous equine exercise are partly due to flow limitations imposed by high
      breathing frequencies (fb), and that gas exchange would be improved if fb could
      be lowered. To evaluate this possibility, 6 Thoroughbred horses underwent 4
      incremental treadmill exercise tests at inclines of 0, 5, 10 and 25%,
      respectively. In the test, horses were given a warm-up for 2 min, then ran
      sequentially for 1 min each at 60, 100 and 115% VO2max. Oxygen consumption (VO2),
      blood gas tensions (PaO2, PaCO2), fb, tidal volume (VT), minute ventilation (Ve),
      transpulmonary pressure (Ptp), peak inspiratory and expiratory airflows (VI, VE)
      and work of breathing (Wrm) were determined during the last 15 s of exercise at
      each intensity. The only effect of fb on PaO2 was seen at 60% VO2max. Also,
      maximal transpulmonary pressure difference (delta Ptpmax), and peak VI, and VE on
      a 25% slope were lower than those recorded at the other 3 inclines at 60% VO2max.
      At 100 and 115% VO2max, the effect of fb was less clear. While fb still differed,
      the only effects of fb at 100% VO2max were on delta Ptpmax. At 115% VO2max, fb on
      a 25% incline was lower than that for 0 and 5% slopes. The only other difference
      noted at this intensity was in VT on 10% slope. However, there was no difference
      between VTS recorded at inclines of 0, 5 or 25% at 115% VO2max. There was no
      effect of fb or exercise intensity on Ve at 100 or 115% VO2max. There was no
      change in PaO2, fb, VT, delta Ptpmax or VI and VE as exercise intensity increased
      from 60-115% VO2max on slopes of 0, 5 or 10%. However, for exercise on the 25%
      incline (i.e. with lower fb), each of these parameters increased (or decreased
      for PaO2) from 60-100%, but not from 100-115% VO2max. Failure of peak airflow and
      VT to increase when intensity increased was associated with the development of
      hypoxaemia and hypercapnoea, regardless of slope or fb. It is concluded that
      while a low fb may have some beneficial effect on gas exchange during submaximal
      exercise at approximately 60% VO2max, this effect disappears as exercise
      intensity increases. There appear to be limits to the peak airflows that can be
      generated by horses during strenuous exercise, and these limits may be reached
      regardless of fb. Flow limitation per se may play a greater role in the
      development of exercise-induced hypoxaemia and hypercapnoea in horses than dose
      fb.

PMID- 10659216
TI  - Blood gas changes during incremental and sprint exercise.
AB  - We investigated and compared arterial blood gas and ventilatory changes during
      rapid acceleration sprint and during incremental treadmill exercise. Seven
      clinically normal racehorses completed standardised incremental exercise tests
      and rapid acceleration tests at speeds calculated to elicit 115% VO2max. Arterial
      oxygen tension decreased (P < 0.001) between 15 s (mean +/- s.d. 103.8 +/- 14.3
      mmHg) and 30 s (85.0 +/- 7.7 mmHg) after the onset of rapid acceleration
      exercise, but did not change significantly during the remainder of the sprint.
      This was accompanied by an increase in PaCO2 of 5.9 mmHg (P < 0.05). Despite
      reductions in SaO2 during exercise, CaO2 did not change due to increases in
      haemoglobin concentration. Heart rate increased rapidly (P < 0.001) during the
      first 15 s of exercise and thereafter remained constant. The mean maximum speed
      during the incremental test (11.4 +/- 0.5 m/s) was not significantly different to
      the speed calculated to elicit 115% VO2max during the sprint test (12.2 +/- 0.8
      m/s). The mean peak HR and Hb during the sprint test were significantly less than
      during the incremental test. However, there were no significant differences in
      the maximum or minimum values achieved for other variables. We conclude that
      rapid acceleration exercise is accompanied by rapid changes in blood gas
      variables, reaching steady state within 45 s. Blood gas responses during the
      simpler incremental test describe maximal changes during high-intensity sprint
      exercise.

PMID- 10659217
TI  - Pulmonary capillary pressure in horses undergoing alteration of pleural pressure
      by imposition of various upper airway resistive loads.
AB  - We hypothesized that changes in pleural pressure induced by resistive breathing
      would affect transmural pulmonary artery, pulmonary capillary, and pulmonary
      wedge pressures. Seven horses were assigned to exercise with each of 4 upper
      respiratory resistive loads in random order at intervals of at least 2 days: 1)
      control--no added resistive loads; 2) inspiratory resistive load (Iobst)--left
      laryngeal hemiplegia; 3) expiratory resistive load (Eobst)--one-way valve in the
      right nostril; and 4) combined inspiratory and expiratory resistive loads
      (CIEobst)--left nostril occlusion. On each occasion, the horses performed an
      incremental exercise protocol consisting of exercise episodes of 3 min duration
      at 75, 90, and 100% of maximal heart rate (HRmax). Pulmonary artery and
      oesophageal pressures were recorded continuously. Subsequent analysis was carried
      out on the pulmonary arterial pressure signal with the oesophageal pressure
      signal subtracted, hence the pulmonary vascular pressures in this paper
      approximate transmural pressures. Pulmonary vascular pressures, heart rate, and
      arterial blood gas tensions were measured at each level of exercise. Pulmonary
      capillary and pulmonary wedge pressures were determined from the pulmonary artery
      waveform after dynamic occlusion of a branch of the pulmonary artery. During
      exercise, peak expiratory oesophageal pressure was more positive in horses with
      Eobst and CIEobst (adjusted means = 43, and 39 mmHg, respectively) compared with
      control (adjusted mean = 23 mmHg) (P = 0.0001). Peak inspiratory oesophageal
      pressure was more negative in horses at exercise with Iobst and CIEobst (adjusted
      means = -42 and -39 mmHg, respectively) compared with control (adjusted mean = 
      26 mmHg) (P = 0.0012). Eobst was associated with an increase in mean oesophageal
      pressure while Iobst was associated with a decrease in mean oesophageal pressure.
      There were significant increases in mean pulmonary artery pressure in horses with
      CIEobst (adjusted means = 82 mmHg) and in pulmonary wedge pressure in horses with
      CIEobst and Iobst (adjusted means = 51, and 55 mmHg, respectively) when compared
      to control (73 and 42 mmHg, respectively) (P = 0.0001). Pulmonary capillary
      pressure was significantly increased in horses with CIEobst or Iobst (adjusted
      means = 61 mmHg, 63 mmHg, respectively) when compared to control (adjusted mean =
      50 mmHg)(P = 0.0001). At maximal exercise intensity with inspiratory obstruction,
      the mean oesophageal (pleural) pressure was -17 mmHg while the mean pulmonary
      capillary pressure was 77 mmHg. The latter exceeds the reported 75 mmHg threshold
      for capillary failure in horses. We conclude that inspiratory resistive breathing
      can lead to a significant increase in transmural pulmonary capillary pressure
      which may contribute to loss of capillary integrity and rupture.

PMID- 10659218
TI  - Modelling impact-initiated wave transmission through lung parenchyma in relation
      to the aetiology of exercise-induced pulmonary haemorrhage.
AB  - Recently we proposed that exercise-induced pulmonary haemorrhage (EIPH) results
      from locomotory-impact-induced trauma by impact of the scapula on the chest wall
      during footfall and the consequent transmission of waves through the lung. A
      computational model has been developed to demonstrate that wave amplification and
      focusing occur in the dorsocaudal tip of the lung for waves originating on the
      anterior subscapular surface. The propagation of an acoustic wave was
      investigated in a simplified 2-dimensional representation of a vertical anterio
      dorsal section of horse lung. It was demonstrated that a complicated pattern of
      waves is transmitted from the scapula to the dorsal region. Wave motion was
      characterised using the instantaneous rate of change of pressure with time
      (dp/dt) which is associated with lung injury. Due to wave reflection and
      focusing, dp/dt is transiently very high on the spinal and diaphragmatic lung
      walls, particularly in the vicinity of the dorsal tip. The model therefore
      predicts that lung injury may occur in the region in which EIPH is reported to
      originate.

PMID- 10659219
TI  - Is ventilation during maximal exercise limited by dynamic airway closure?
AB  - A study was undertaken to find if the reason why horses hypoventilate when
      running is that they experience expiratory flow limitation due to dynamic airway
      closure. To test this hypothesis, we measured peak expiratory flows on a
      Thoroughbred galloping on a treadmill and hypoventilating and compared those
      flows with the peak dynamically-limited flow that the same horse could achieve
      during a forced expiratory flow-volume manoeuvre. At the approximate lung volumes
      at which the horse was ventilating while running, it did not appear to be
      mechanically limited and appeared to have reserve capacity available potentially
      to increase its expiratory flow.

PMID- 10659220
TI  - Pathophysiology of dorsal displacement of the soft palate in horses.
AB  - Dorsal displacement of the soft palate (DDSP) is an intermittent obstructive
      upper airway condition that occurs in athletic horses during high-intensity
      exercise. The pathogenesis of this condition is unknown, but may involve
      epiglottic hypoplasia, malformation, or neuromuscular dysfunction. In this paper,
      we report on investigations into the pathophysiology of DDSP. In 3 separate
      experiments, Standardbred horses were exercised on a high-speed treadmill at
      speeds corresponding to 50, 75 and 100% of maximum heart rate. The upper airway
      was evaluated by videoendoscopy and measurement of tracheal pressures. In
      experiment 1, we examined the effect of bilateral hypoglossal and
      glossopharyngeal nerve block on epiglottic function in exercising horses. This
      nerve block caused epiglottic retroversion and inspiratory upper airway
      obstruction. However, DDSP did not occur. In experiment 2, we evaluated the
      hypothesis that tensor veli palatini muscle dysfunction is involved in the
      pathogenesis of DDSP. Bilateral tensor veli palatini muscle tenectomy did not
      cause DDSP, but caused instability of the rostral half of the soft palate and a
      modest inspiratory upper airway obstruction. In experiment 3, we hypothesised
      that palatinus and palatopharyngeal dysfunction causes DDSP. The pharyngeal
      branch of the vagus nerve was blocked bilaterally in the guttural pouch. This
      block caused DDSP in all horses within 2-15 min after nerve block. Furthermore,
      DDSP created an expiratory nasopharyngeal obstruction. Because the pharyngeal
      branch of the vagus nerve is in close proximity to the retropharyngeal lymph node
      chain, we suggest that retropharyngeal lymphadenopathy may cause neural
      dysfunction and thereby be involved in the pathogenesis of clinical DDSP.

PMID- 10659222
TI  - Influence of girth strap tensions on athletic performance of racehorses.
AB  - Eight horses were exercised at speeds to produce 80% of maximal heart rates, on 4
      occasions using a randomised block design, and girthed at tensions of
      approximately 5, 10, 15 or 20 kg using a standard canvas girth attached to a
      racing saddle. Tension was recorded continuously using an in-line load cell
      connected to a physiograph. Horses ran until fatigued on a treadmill inclined at
      10% slope. Tensions were measured at peak inhalation (T/inh) and exhalation
      (T/exh), recorded at rest (rest) and during exercise (ex). Data were analysed by
      ANOVA and, in addition, least squares linear regression was performed to
      determine the relationship between distance travelled, time to fatigue and the
      recorded maximum tensions at inhalation and minimum tensions at exhalation. For
      T/inhrest, every increase in girth tension by 1 kg was associated with a
      reduction in distance to fatigue by 98.3 +/- 28.6 m and a corresponding reduction
      in run times of 0.24 +/- 0.07 min (P = 0.01). Results for T/exhrest were similar,
      with a reduction of mean +/- s.e. 81.3 +/- 26.9 m and 0.20 +/- 0.07 min per 1 kg
      increase in tension (P = 0.02). The mean distances to fatigue for the T/exhrest
      of 5, 10, 15 and 20 kg were 6624, 5812, 5268 and 5405 m respectively. These data
      indicate that distances to fatigue are similar once T/exhrest equals or exceeds
      10 kg. Based on this study, resting girth tensions less than 10 kg are optimal
      for performance, but from our survey data, tensions exceeding this tension are
      typical for Thoroughbred racing in Victoria.

PMID- 10659221
TI  - Differences in the ventilatory responses of horses and ponies to exercise of
      varying intensities.
AB  - Horses exercising at > or = approximately 90% VO2max develop arterial hypoxaemia
      with concurrent hypercapnoea, whereas ponies exercising at comparative levels
      become hypocapnoeic and maintain arterial oxygen tensions close to resting
      values. We sought to investigate the possibility that these differences relate to
      the ventilatory responses of these animals to exercise. Six Thoroughbred horses
      weighing mean +/- s.e. 501 +/- 27 kg and 5 ponies weighing mean +/- s.e. 164 +/-
      18 kg exercised for 2 min on a 10% slope at speeds calculated to require 60%
      VO2max and for at least 1 min at speeds calculated to require 115% VO2max. Oxygen
      consumption (VO2), arterial oxygen (PaO2) and carbon dioxide (PaCO2) tensions,
      acid-base balance, tidal volume (VT), minute ventilation (VE), peak inspiratory
      (VImax) and expiratory (VEmax) flow, and maximal changes in transpulmonary
      pressures (delta PtPmax) were measured immediately before exercise and in the
      last 15 s of exercise at each intensity. The results confirmed that, unlike
      horses, ponies do not become hypoxaemic or hypercapnoeic during exercise. Despite
      having a higher delta PtPmax, higher VImax and VEmax and VE/kg0.75 at the same
      relative intensities, horses were less capable of mounting an appropriate
      ventilatory response to exercise. This was reflected by lower mass specific and
      metabolic weight-based ventilations at similar absolute workloads, and their
      higher PaCO2 and arterial HCO3-[, and lower ventilatory equivalent for oxygen
      (VE/VO2). This suggests that horses become hypoxaemic and hypercapnoeic at work
      loads > or = approximately 90% VO2max because their metabolic demand surpasses
      the capacity of their ventilatory system to meet this demand. Because ponies are
      less capable athletes, they can match their ventilatory response to their
      metabolic requirements.

PMID- 10659223
TI  - The effects of training on ventilation and blood gases in exercising
      thoroughbreds.
AB  - The effects of training on ventilation and blood gases during exercise were
      investigated in 6 clinically normal, detrained Thoroughbred horses. They
      underwent a 16 week training programme similar to the type frequently used for
      Thoroughbred racehorses in Great Britain. Standardized treadmill exercise tests
      (2 min canter at 8 and 10 m/s C8 and C10[ and 2 min gallop at 12 m/s [G12], on a
      level surface) were performed prior to and after 16 weeks of training.
      Respiratory flow rates were measured using ultrasound flow transducers. Blood
      samples were drawn from a transverse facial artery and the right atrium. Minute
      ventilation, respiratory frequency and tidal volume were not significantly
      altered by training. Peak inspiratory flow rate was lower following training at 8
      and 10 m/s, but not at 12 m/s. Arterial oxygen tension was decreased during trot
      and canter following training. Blood lactate concentration post G12 decreased
      following training (10.5 +/- 2.2 mmol/l vs. 7.7 +/- 2.2 mmol/l; P < 0.05). The
      increase in the degree of exercise-induced arterial hypoxaemia following training
      may reflect a lack of pulmonary adaptation to training in the face of improved
      cardiovascular and muscular function.

PMID- 10659224
TI  - Functional and compositional changes in pulmonary surfactant in response to
      exercise.
AB  - Pulmonary surfactant from bronchoalveolar lavages was obtained from 2 groups of
      horses. A control group consisting of 6 healthy racehorses that were paddock
      rested and lavaged weekly for 6 consecutive weeks were compared with an
      experimental group of 10 healthy racehorses, lavaged weekly the same period,
      consisting of a 5 week incremental-intensity treadmill training programme and one
      week post training paddock rest. Phospholipid content of lavage fluid was
      determined indirectly by phosphorus assay, and surfactant functional activity was
      determined by bubble surfactometry. Total cell counts and differential cell
      percentages of lavage fluid were adjusted to reflect the dilution of alveolar
      epithelial lining fluid (ELF) using the lavage/serum urea ratio, and data were
      analysed per volume of ELF. There was no change in phospholipid content for
      either group, but some horses had consistently greater amounts than did others,
      ranging from 17.2-64.4 micrograms/microliter. From the exercised group ELF had
      both increased nucleated cell numbers due to increased macrophage numbers, and
      increased numbers of erythrocytes. Surface tension increased significantly over
      the exercise protocol, but not in controls. Functional activity of surfactant
      varied between horses, independent of phospholipid content, with average values
      for individuals ranging 10.5-29.5 mN/m. We conclude that exercise of sufficient
      intensity to induce intrapulmonary haemorrhage also leads to functional decrease
      in surfactant activity, without affecting phospholipid content. This study also
      indicates that functional differences in surfactant exist between horses and may
      be a risk factor for development of exercise-induced pulmonary haemorrhage.

PMID- 10659225
TI  - A preliminary study of the effect of inhaled nitric oxide on lung mechanics in
      the standing horse with histamine-induced bronchoconstriction.
AB  - The effect of inhaled nitric oxide on pulmonary mechanics was studied in normal
      standing horses with histamine-induced bronchoconstriction. The respiratory
      health status of 6 normal horses was established on the basis of history,
      clinical and bronchoalveolar lavage examination. Intrathoracic pressures were
      estimated using distal oesophageal pressures. Respiratory gas flows were measured
      using a heated pneumotachograph. Pulmonary mechanics variables were determined
      from these measurements on a breath by breath basis. Bronchoconstriction was
      induced by nebulizing a 0.75% w/v solution of histamine over 5 min. Pulmonary
      function was assessed during 4 periods: 1) while breathing room air prior to
      histamine challenge; 2) 5 min post histamine challenge; 3) 10 min post histamine
      challenge and while breathing 5 ppm nitric oxide; and 4) 14 min post histamine
      challenge while breathing room air. Statistical analysis included Friedman's
      nonparametric repeated measures analysis of variance followed by Dunn's multiple
      comparisons tests, where appropriate. Criteria for demonstration of nitric oxide
      effect on pulmonary mechanics variables were taken as a return of the variable
      value following nitric oxide administration towards control value and subsequent
      restoration of the value toward post histamine levels with discontinuation of
      nitric oxide. Five variables (dynamic compliance, airway resistance, maximum
      developed pressure, work of breathing, and peak expiratory flow) had significant
      changes in response to histamine. Three variables (dynamic compliance, airway
      resistance, and maximum developed pressure) met the above criteria, but only
      dynamic compliance and airway resistance showed statistical significance (P <
      0.05). These results suggest that nitric oxide partly dilates small airways
      constricted by histamine.

PMID- 10659226
TI  - High-altitude effects on respiratory gases, acid-base balance and pulmonary
      artery pressures in equids.
AB  - Arterial and venous blood were analysed at rest and post exercise for pH, PCO2,
      and PO2, and bicarbonate ([HCO3-]), base excess (BE), and strong ion difference
      (SID) were calculated in response to a 10 day sojourn to 3800 m. Pulmonary artery
      pressures (PAP) were measured at rest. Post exercise samples were restricted to
      venous blood. The equids (n = 6) experienced a profound hypoxia-hypocapnia and a
      respiratory alkalosis. PaO2 decreased 42% and PaCO2 41%. PaCO2 increased to 80%
      of initial values after 8 days at altitude. Arterial [HCO3-] decreased by 34%;
      however, it returned to normal by Day 4. Base excess decreased initially, but
      increased at altitude with time. Strong ion difference was decreased during the
      altitude exposure and continued to be depressed even after return to low
      altitude. Pulmonary artery pressure increased 63% on Day 1 of exposure (from 27.9
      +/- 2 to 45.4 +/- 3 mmHg); Days 2 and 6 averaged 36.3 +/- 3 and 37.5 +/- 3 mmHg.
      Thirty-six hours after return to 225 m, most variables (except [SID] and post
      exercise BE) returned to normal. The most profound changes in the indicators of
      gas exchange, at altitude, occurred during the first 3 days and only [HCO3-]
      returned to normal during the subsequent acclimatization to altitude.

PMID- 10659227
TI  - Blood gas, plasma lactate and bronchoalveolar lavage cytology analyses in
      racehorses with respiratory disease.
AB  - The purpose of this study was to evaluate the relationship between
      bronchoalveolar lavage (BAL) cytology, arterial blood gases and plasma lactate
      concentration during a standardised treadmill test (STT) in racehorses with small
      airway inflammation (SAI), or exercise-induced pulmonary haemorrhage (EIPH).
      Sixteen Thoroughbred and 20 Standardbred actively racing racehorses, were divided
      into a control group (n = 10), EIPH group (n = 13) and SAI group (n = 13). Each
      STT consisted of a 2 min trot at 4 m/s followed by 5 x 1 min, incremental speed
      steps (6, 8, 10, 11 and 12 m/s) at 10% incline for Thoroughbred and 5% for
      Standardbred horses, followed by a 15 min recovery period. Blood was collected
      via a transverse facial artery catheter at the end of each step. Total nucleated
      cell count of bronchoalveolar lavage fluid (BALF) collected from horses with EIPH
      was significantly higher than controls. Neutrophil count and percentage in BALF
      collected pre-STT from horses with SAI were significantly higher than controls.
      Horses with EIPH or SAI exhibited a more severe exercise-induced arterial
      hypoxaemia than control horses during the first 4 steps of the STT (P < 0.001).
      Poorly performing horses were more severely hypercapnic than control horses
      during the STT recovery period (P < 0.05). Five and 15 min post exercise, horses
      with SAI and EIPH had higher blood lactate and lower blood bicarbonate
      concentrations than control horses (P < 0.05). The results of this study suggest
      that lung ventilation-perfusion mismatch may be more severe in horses with
      respiratory disease. BALF of horses with SAI and EIPH was characterised by
      neutrophilic and lymphocytic inflammation, respectively. Very few parameters were
      significantly different between groups of good and poor performers.

PMID- 10659228
TI  - Cardiorespiratory measurements and indices of oxidative stress in exercising COPD
      horses.
AB  - The effect of a COPD crisis on arterial blood gases, heart rate, lactate and
      indices of oxidative stress were investigated before, during and 1 h after a 'run
      up to fatigue' in 6 COPD horses. They were investigated twice, randomly: once in
      acute crisis (C) and once in clinical remission (R). Arterial and mixed venous
      blood samples were collected and analysed for partial pressures in O2 and CO2.
      The mixed venous blood was also analysed for plasma lactate (LA) and packed cell
      volume (PCV), as well as for indices of oxidative stress, i.e. reduced
      glutathione, glutathione disulphide, glutathione redox ratio (GRR) and lipid
      hydroperoxides (LPH). The exercise test was an effort of increasing intensity on
      a treadmill at 0% slope, which was stopped when the horses showed signs of
      exhaustion. Their performance was evaluated by the number of steps and the
      running time in the last step. Heart rate was monitored continuously during the
      test. Blood sampling was performed before, just after and 1 h after the end of
      the test. The COPD crisis significantly reduced the time to fatigue. However,
      despite the fact that the exercise intensity and length were lower, peak HR and
      peak LA were similar in C and R, while arterial hypoxaemia and hypercapnia, and
      PCV were significantly higher in C, indicating a higher physiological stress in
      this condition. By contrast, the oxidative stress seemed to be higher in R than
      in C as suggested by the fact that, 1 h after exercise, GRR and LPH were
      significantly increased with regards to their pre-exercise values in R and not in
      C. The fact that exercise did not induce an oxidative stress in C could be partly
      related to (1) the lower exercise intensity reached by the horses, and (2) to the
      more severe hypoxaemia experienced in this condition. In conclusion, COPD horses
      in acute crisis show a significant decrease in performance. The reasons for this
      exercise intolerance remain unclear, but do not appear to be related to any
      increase of the oxidative stress in C.

PMID- 10659229
TI  - Effect of exercise and COPD crisis on isoprostane concentration in plasma and
      bronchoalveolar lavage fluid in horses.
AB  - To test whether isoprostanes could be used as markers of oxidative stress in
      horses, their concentration was determined in plasma and in pulmonary epithelial
      lining fluid (PELF) in 3 models of oxidative stress: (1) strenuous exercise, (2)
      acute COPD crisis and (3) exercise combined with COPD crisis. Four horses were
      investigated twice, once in crisis and once in remission. The animals underwent a
      standardised treadmill exercise test. Isoprostane assessment was performed in
      plasma and bronchoalveolar lavage fluid 24 h before and 1 h after exercise and in
      plasma also immediately after exercise. Exercise in remission induced a
      significant increase of isoprostanes in plasma and in PELF. In horses in crisis,
      the isoprostane concentrations did not increase in plasma, while they did
      increase in PELF. Lastly, exercise in crisis increased plasma levels of
      isoprostanes, but did not change PELF isoprostanes. In conclusion, 1)
      isoprostanes are increased by systemic oxidative stress induced by strenuous
      exercise in COPD horses in remission either in PELF or in plasma; 2) only PELF
      and not plasma isoprostanes are increased by pulmonary oxidative stress induced
      by COPD crisis and 3) unexpectedly, exercise in crisis increased plasma but not
      PELF isoprostanes.

PMID- 10659230
TI  - Effect of exercise on concentrations of immunoreactive endothelin in
      bronchoalveolar lavage fluid of normal horses and horses with chronic obstructive
      pulmonary disease.
AB  - Chronic obstructive pulmonary disease (COPD) represents a major cause of loss of
      performance in the horse. The role of endothelin (ET), a potent
      bronchoconstrictive and vasoactive peptide, is currently being investigated in
      asthma and other obstructive respiratory diseases in man. We have previously
      found elevated systemic and pulmonary endothelin levels in horses during
      exacerbation of COPD. In the present study, our aim was to examine possible
      variations in ET concentrations occurring during exercise in COPD horses. We
      compared the effects of intense treadmill exercise on the recovery of endothelin
      (ET) in the bronchoalveolar lavage fluid (BALF) as well as in arterial and venous
      blood, in a group of 5 healthy horses and a group of 5 COPD horses studied
      alternately in remission and while symptomatic. We also investigated the possible
      correlations between ET levels and pulmonary function tests during the study.
      While exercise did not affect the ET levels recovered in BALF among controls, it
      caused a significant increase (P = 0.02) among symptomatic COPD horses. During
      remission, wide variations of ET levels among horses, at rest and during
      exercise, made any significant interpretation difficult. No correlation could be
      found between exercise-induced changes in ET concentrations and pulmonary
      function tests or changes in arterial oxygen tension with exercise. We conclude
      that exercise appears to affect the release of ET by the airways in COPD horses,
      in contrast to healthy horses. It is still unclear, however, whether these
      differences relate to adjustments of lung function during exercise.

PMID- 10659231
TI  - Gas exchange during exercise in standardbred trotters with mild bronchiolitis.
AB  - To investigate the gas exchange response during exercise in horses with mild
      bronchiolitis (MB), we studied 7 Standardbred trotters. In order to determine
      pulmonary gas exchange and red cell volume in relation to bodyweight (CV/BW),
      submaximal graded exercise tests were performed. VO2 was monitored from an open
      bias flow system without valves. Heart rate, respiratory rate and mean pulmonary
      and systemic artery pressures were measured. Cardiac output and alveolar
      ventilation were calculated. Arterial and mixed venous blood were drawn for blood
      gas analysis and pH measurements. Pulmonary gas exchange was assessed by
      conventional blood gas variables, and the ventilation-perfusion distribution was
      estimated using the multiple inert gas elimination technique. The dispersion of
      perfusion and ventilation distribution and the difference between measured
      arterial oxygen tension and that predicted on the basis of the amount of
      ventilation-perfusion mismatching and shunt were determined in order to reflect
      diffusion limitation. The results were compared, using analysis of variance, with
      data from an earlier study on healthy Standardbred trotters (LH) during a similar
      exercise test. No differences in pulmonary gas exchange were obtained between LH
      and MB. However, CV/BW, pulmonary artery mean pressure (PAP) and systemic
      arterial mean pressure (SAP) were significantly higher in MB than in LH. Lactate
      concentration, arteriovenous oxygen content differences C(av)O2[ and pH were
      significantly lower in MB horses than in LH. We conclude that Standardbred
      trotters with mild subclinical bronchiolitis can achieve an adequate gas exchange
      compared to healthy Standardbred trotters, during a graded exercise test;
      however, the significantly increased CV/BW in MB horses may be a compensatory
      mechanism for hypoxaemia during maximal work.

PMID- 10659232
TI  - Effects of frusemide on pulmonary capillary pressure in horses exercising on a
      treadmill.
AB  - We hypothesised that frusemide would decrease pulmonary capillary pressure in
      horses during strenuous exercise. Seven horses were tested after receiving saline
      or frusemide (2 mg/kg bwt) in random order with an interval of at least one week.
      Measurements were made with the horses standing, exercising at 75, 90 and 100%
      HRmax (maximal heart rate), and then walking 2 min after cessation of 100% HRmax.
      The exercise tests lasted for approximately 3 min with an interval of walking
      between them. Pulmonary artery and oesophageal pressures were recorded
      continuously and subsequent analysis of the pulmonary artery pressure signal was
      carried out after subtraction of the oesophageal pressure signal. Pulmonary
      arterial pressure, pulmonary capillary pressure, pulmonary artery wedge pressure,
      breathing rate, heart rate and arterial blood gas tensions were recorded at each
      level of exercise. Pulmonary arterial wedge and pulmonary capillary pressures
      were determined from the pulmonary arterial waveform after dynamic occlusion of a
      branch of the pulmonary artery. The resulting decay in pressure was submitted to
      exponential curve fitting and the amplitude on this curve at the moment of
      occlusion was recorded as pulmonary capillary pressure. When adjusted for horse
      and exercise intensity, horses receiving frusemide had lower pulmonary capillary
      and wedge pressures (adjusted least-squares means = 36 mmHg and 28 mmHg,
      respectively) when compared with control values (adjusted least-squares means =
      41 mmHg (P = 0.042) and 35 mmHg (P = 0.002), respectively). Pulmonary arterial
      pressure, breathing rate, heart rate and arterial blood gas tensions did not
      differ between treatments at any exercise intensity. We conclude that frusemide
      reduces pulmonary capillary and wedge pressures. This is compatible with reduced
      transcapillary filtration and, therefore, reduced accumulation of lung water at
      exercise. It may also account for the putative protective effect of frusemide
      against exercise-induced pulmonary haemorrhage.

PMID- 10659233
TI  - Ventilation-perfusion relationships during exercise in standardbred trotters with
      red cell hypervolaemia.
AB  - In order to evaluate the pulmonary gas exchange during exercise in Standardbred
      trotters with red cell hypervolaemia (RCHV), 12 horses with RCHV were compared
      with 9 normovolaemic (NV) horses. VO2 and VCO2 were determined with an open bias
      flow system. Cardiovascular and haemodynamic data were recorded during exercise
      at 4 different speeds on a treadmill. Pulmonary gas exchange was assessed by
      conventional blood gas variables (arterial and mixed venous blood gas tensions),
      and the ventilation-perfusion distribution VA/Q was estimated by the multiple
      inert gas elimination technique. VA and AaDO2 were calculated. Dispersions of
      perfusion and ventilation distribution (SDQ, SDV) were determined. HR, RR, Qt,
      VO2, VA, log SDV, C(a-av)O2 and lactate did not differ between groups. The degree
      of hypoxaemia was more pronounced in the RCHV than in the NV (PaO2 = 54 and 59
      mmHg; AaDO2 = 41 and 34 mmHg in RCHV and NV, respectively, at highest workload).
      Further, pH was lower in the RCHV and PaCO2 and VCO2 was significantly higher in
      the RCHV during the course of exercise (pH = 7.24 and 7.29; PaCO2 = 56 and 51
      mmHg; VCO2 = 156 and 135 ml/kg x min in RCHV and NV, respectively, at highest
      workload). The PaO2 predicted from the VA/Q distribution was higher than actually
      measured in blood during heavy exercise which may suggest a certain diffusion
      limitation over the alveolar-capillary membranes in both groups but there was no
      difference between the 2 groups. The more pronounced hypoxaemia observed in RCHV
      trotters was mainly caused by increased VA/Q mismatch expressed as a
      significantly increased log SDQ (0.78 and 0.45 in RCHV and NV, respectively, at
      highest workload).

PMID- 10659234
TI  - Pulmonary vascular resistance of horses decreases with moderate exercise and
      remains unchanged as workload is increased to maximal exercise.
AB  - This study was carried out to examine changes in pulmonary vascular resistance
      (PVR) induced by moderate and strenuous exercise; the objective being to
      understand why pulmonary artery blood pressure of exercising horses increases
      progressively as work intensity increases. Pulmonary arterial and wedge pressures
      (referenced at the point of the left shoulder) were determined simultaneously
      with cardiac output in 2 groups of healthy, sound, exercise-trained horses.
      Horses in Group 1 (n = 8) were studied at rest and during exercise performed at 8
      and 13 m/s; the latter workload eliciting maximal heart rate (mean +/- s.e. 212
      +/- 3 beats/min). Horses in Group 2 (n = 7 Thoroughbreds) were studied at rest
      and during galloping at 14.5 m/s on 5% uphill grade, a workload which elicited
      maximal heart rate (217 +/- 3 beats/min) and could not be sustained for > 90 s.
      Pulmonary vascular resistance was calculated by dividing pulmonary perfusion
      pressure gradient (i.e. mean pulmonary arterial pressure minus mean pulmonary
      wedge pressure) with cardiac output. Pulmonary arterial and wedge pressures,
      pulmonary perfusion pressure gradient and cardiac output increased significantly
      (P < 0.05) with exercise in both groups. There were no differences in PVR between
      the 2 groups of horses at rest. In Group 1 horses PVR decreased significantly (P
      < 0.05) with exercise at 8 m/s, but further pulmonary vasodilation did not occur
      as workload increased to 13 m/s. During exercise at 14.5 m/s on 5% grade, PVR of
      Group 2 horses also decreased significantly and was not different from values for
      8 or 13 m/s in Group 1 horses. It is concluded that PVR reaches its nadir during
      moderate exercise, presumably due to upper limit of recruitment and distension
      having been reached. Therefore, in accordance with Ohm's law (P alpha Q x PVR),
      in going to higher workloads pulmonary blood flow (Q) remained the sole
      determinant of the rise in pulmonary arterial blood pressure (P). Our data also
      indicate that pulmonary artery wedge pressure is another variable that is
      important in determining the absolute value of pulmonary arterial blood pressure.

PMID- 10659235
TI  - Changes in left ventricular dynamics during graded exercise.
AB  - Three mature Thoroughbred horses were prepared surgically with ultrasonic
      sonomicrometer crystals affixed to their ventricular pericardia. Signals from
      crystals recorded dimensions of axes across the left ventricle. Cubic algorithms
      were fitted to dimensional data to generate volume estimates that matched stroke
      volumes simultaneously measured using the Fick principle. As horses stood at rest
      or exercised at various intensities (approx 7, 12, 24, 47 and 100% maximal rate
      of O2 consumption VO2max[), left ventricular dimensions were recorded and 20
      consecutive diastolic and systolic volumes calculated. Although Fick estimates
      detected no difference in stroke volume at different exercise intensities,
      sonomicrometer measurements of stroke volume were significantly lower at rest and
      higher at VO2max. These differences mirrored changes in end-diastolic volume,
      although end-systolic volume did not change. At all exercise intensities, stroke
      volume was most variable and end-diastolic volume the least. The pattern conforms
      to the Frank-Starling mechanism, and indicates that at high exercise intensities
      ventricular myocytes generate high pressures with higher myocardial wall stress
      due to the increased size of the chamber.

PMID- 10659236
TI  - Sequential changes in bronchoalveolar cytology after autologous blood
      inoculation.
AB  - Six horses, free of recent exercise-induced pulmonary haemorrhage (EIPH), each
      had 8 bronchial segments inoculated with 40 ml of autologous blood lavaged on
      Days 3, 5, 7, 10, 14 and 21 after inoculation. The bronchoalveolar lavage (BAL)
      fluid samples were analysed, and total leucocyte counts and differential cell
      percentages determined. Statistical analysis of the differences between the 8
      post inoculation and 1 pre-inoculation (control) lavage sites demonstrated an
      early neutrophilic response, rising from < 5% of alveolar leucocytes to 10% by 24
      48 h post inoculation. As this response waned, macrophage numbers increased and
      persisted at mildly elevated levels for the remainder of the experiment. Small
      numbers of erythrophagocytes were observed prior to 3 days post inoculation, but
      their numbers increased 10-fold by Day 10. In the first 3 days, blood was
      observed endoscopically streaming from inoculated lung regions, suggesting that
      mucociliary clearance is a major mechanism of early erythrocyte clearance.
      However, both free and phagocytosed whole erythrocytes were recovered in lavages
      14 days after inoculation with small numbers of erythrocytes still present at 21
      days. We conclude that intrapulmonary blood provokes a mild, but prolonged
      inflammatory reaction and that the removal of alveolar haemorrhage is dependent
      on a combination of mucociliary clearance and phagocytic mechanisms.
      Erythrophagocytosis is slow to commence and the removal of blood prolonged,
      suggesting that horses in fast work, sufficient to induce EIPH, are unlikely to
      recover fully if intervals between strenuous work are less than 14 days.

PMID- 10659237
TI  - Pre- and post exercise echocardiography in horses performing treadmill exercise
      in cool and hot/humid conditions.
AB  - We hypothesised that exercise in a hot and humid environment would affect
      echocardiographic indices of cardiac dimensions and function more than exercise
      in a cool environment. M-mode echocardiograms were obtained in 5 clinically
      normal horses before, and at 0, 10, 30 and 60 min after a treadmill exercise
      test. The test was performed in a controlled environment at 20 degrees C/40%
      relative humidity (RH) and again at 30 degrees C/80% RH. All the horses completed
      the exercise test in cool conditions, but only one horse completed the exercise
      test in the hot/humid environment. The relaxation time index (RTI) correlated
      significantly and inversely with heart rate (HR). Heart rate was increased and
      RTI was decreased immediately after exercise in cool conditions. HR recovery
      appeared to be prolonged following exercise in hot/humid conditions. Post
      exercise RTI was significantly decreased in hot/humid environment. In hot/humid
      conditions, the left ventricular internal dimensions measured in diastole and
      systole (LVIDd, LVIDs) were reduced following exercise and continued to fall
      throughout the 60 min after exercise. The left ventricular fractional shortening
      (FS%) was lower than resting levels immediately after exercise in hot/humid
      conditions. Significant decreases were found in LVIDs and LVIDd, which may
      reflect a reduction in preload arising from dehydration or re-distribution of
      blood throughout the recovery period following exercise in the hot/humid
      environment. It was concluded that echocardiography was a useful tool in
      assessing cardiac responses to exercise in different climates.

PMID- 10659238
TI  - Feasibility of scintigraphy in exercise-induced pulmonary haemorrhage detection
      and quantification: preliminary studies.
AB  - We hypothesised that scintigraphic imaging of the lungs following injection of
      99mTc labelled red blood cells (99mTc-RBC) in the exercising horse might enable
      exercise-induced pulmonary haemorrhage (EIPH) quantification. Ideally, to favour
      detection of bleeding, circulating 99mTc-RBC not involved in the haemorrhage
      should be removed from the circulation quickly. Altering RBC during labelling to
      stimulate splenic uptake of 99mTc-RBC may encourage this. In order to investigate
      this hypothesis, 99mTc-RBC distribution was followed for 1 h in 2 groups of
      horses. Group 1 was injected i.v., at rest, with radioactive nondenatured RBC
      (99mTc-NDRBC); Group 2 received labelled RBC partly denatured by heating (99mTc
      HDRBC). In Group 2, splenic uptake was higher at all times and radioactivity in
      the lung was proportionally higher and decreased less quickly than in Group 1.
      Hence, the time-consuming 99mTc-HDRBC labelling technique did not demonstrate any
      advantage over the easier 99mTc-NDRBC labelling procedure. Additionally, the
      feasibility of scintigraphic visualisation of a small amount of pulmonary
      bleeding was confirmed with the following trial: using an endoscope, a
      radioactive solution mimicking 50 ml of bleeding was deposited at the usual site
      of EIPH in a live horse. The radioactivity recorded in that area was compared to
      the one obtained in the same region in Group 1 and 2. The activity measured 20
      min post endoscopy corresponded to 33% of the activity obtained in Group 1 vs. 8%
      in Group 2 at that timing. Once again, there was no advantage of using 99mTc
      HDRBC vs. 99mTc-NDRBC. These results demonstrated that small amounts of bleeding
      might potentially be detected with scintigraphy; they also suggest that the
      limiting factor for detecting small amounts of bleeding may be the level of lung
      background radioactivity.

PMID- 10659239
TI  - Effects of phlebotomy and autologous blood transfusion on oxygen transport in the
      racehorse.
AB  - Because the haemoglobin concentration Hb[ during exercise may be at the upper
      limit of blood viscosity for effective oxygen delivery, we hypothesised that
      administration of blood would not further enhance oxygen delivery or exercise
      capacity. Six Thoroughbred geldings were used in 5 incremental treadmill exercise
      tests over a period of 4 weeks. The first test was performed 6 days prior to
      phlebotomy, which involved the removal of 20 ml/kg bwt of venous blood. Exercise
      tests were performed at 1, 8 and 15 days after blood removal. Six days after the
      15 day post phlebotomy exercise test, blood from each horse was reinfused and the
      final test performed 24 h after blood reinfusion. During the 3 weeks following
      blood collection, the blood, collected into acid citrate dextrose, was stored at
      3 degrees C. Each exercise test involved measurements of arterial and mixed
      venous blood gases, plasma lactate concentrations, heart rate and VO2 using an
      open flow system. Cardiac output was measured by direct Fick. The removal and
      reinfusion of blood had significant effects on packed cell volume (PCV) with the
      lowest PCV value during exercise of 0.57 +/- 0.04 l/l being recorded in the
      second post phlebotomy test and the highest value of 0.67 +/- 0.04 l/l found
      after blood reinfusion. There were no significant effects of phlebotomy or blood
      reinfusion on arterial blood gas values. However, arteriovenous oxygen content
      difference was significantly altered by phlebotomy and reinfusion. The maximal
      values during the 3 tests following phlebotomy were significantly lower (P <
      0.05) by about 7% than those before phlebotomy and after blood reinfusion,
      mirroring the alterations in Hb[. There was no significant effect of phlebotomy
      or blood reinfusion on heart rate but stroke volume was significantly higher (P <
      0.01) during the 3 post phlebotomy tests than for the control or blood reinfusion
      tests. There was no significant effect of phlebotomy or blood reinfusion on
      either the submaximal or maximal values for VO2. No significant effect of blood
      removal or reinfusion was found on the treadmill run time to fatigue. We
      concluded that haemodynamic adjustments following phlebotomy or blood reinfusion
      maintained oxygen delivery during exercise. No detrimental effects on exercise
      capacity were found from phlebotomy nor beneficial effects from autologous blood
      transfusion. However, it should be noted that the extent of change induced in Hb[
      was relatively small and with the number of horses in the study, the experimental
      power was not great.

PMID- 10659240
TI  - Cardiac output measurements using sonomicrometer crystals on the left ventricle
      at rest and exercise.
AB  - Eight horses were fitted surgically with 8 ultrasonic sonomicrometer crystals
      each attached to their left ventricular pericardia and a left atrial catheter.
      Three horses returned to treadmill performance with a maximum rate of oxygen
      consumption similar to their presurgical values. These horses were evaluated to
      determine how well sonomicrometer estimates of cardiac output agreed with those
      obtained by a steady-state method, the Fick principle. Variance between the 2 was
      similar to the coefficient of variation (approximately 12.5%) of the Fick
      estimates. We conclude that left ventricular sonomicrometer measurements in
      horses appear to give a reasonable estimate of ventricular dimensions and can,
      therefore, be used potentially to evaluate such variables as diastolic flow.

PMID- 10659241
TI  - Oral nitroglycerin paste did not lower pulmonary capillary pressure during
      treadmill exercise.
AB  - We hypothesised that 22.5 mg of oral nitroglycerin would cause pulmonary
      vasodilation and therefore decrease pulmonary capillary pressure in horses during
      strenuous exercise. Six horses were assigned to exercise twice, once with no
      medication (control) and once with nitroglycerin (22.5 mg orally) in random
      order. Horses were exercised for 3 min each at 75, 90 and 100% of maximal heart
      rate (HRmax) with a 2 min period of walking between each period of exertion.
      Pulmonary artery and oesophageal pressures were recorded continuously. Subsequent
      analysis was carried out on the pulmonary arterial pressure signal with the
      oesophageal pressure subtracted, hence pulmonary vascular pressures reported in
      this paper approximate transmural pressures. Pulmonary arterial pressure,
      pulmonary arterial wedge pressure, pulmonary capillary pressure, heart rate and
      arterial blood gas tensions were determined for each level of exercise. Pulmonary
      arterial wedge and pulmonary capillary pressures were determined from the
      pulmonary artery waveform after dynamic occlusion of a branch of the pulmonary
      artery. The resulting decay in pulmonary artery pressure was submitted to an
      exponential curve fitting and the amplitude at the moment of occlusion on this
      curve was recorded as pulmonary capillary pressure. The effects of nitroglycerin
      on the various parameters were evaluated using a 3-way ANOVA blocked on horse
      treatment, and exercise intensity, followed by Tukey's multiple comparison
      procedure. Resting pulmonary artery pressure decreased from mean +/- s.e. 34.0 +/
      5.5 mmHg to 24.0 +/- 3.9 mmHg 5 min after administration of nitroglycerin (P <
      0.05) but there were no significant effects on pulmonary capillary or wedge
      pressures. Nitroglycerin at this dose resulted in no significant differences in
      pulmonary artery, pulmonary capillary, and pulmonary wedge pressure, heart rate,
      arterial oxygen tension or arterial carbon dioxide tension at 75, 90 and 100% of
      HRmax. This dose of nitroglycerin does not appear significantly to protect the
      pulmonary vascular bed from exercise-induced hypertension. These data do not
      support the use of this dose of oral nitroglycerin in the prevention of EIPH.

PMID- 10659242
TI  - Application of V200 values for evaluation of training effects in the young
      thoroughbred under field conditions.
AB  - The purpose of this investigation was to study, under field conditions, the
      usefulness of an incremental exercise test to measure V200 (running velocity [V]
      at heart rate HR[ of 200 beats/min) for evaluation of training effects in the
      young Thoroughbred. Five to 112 two-year-old Thoroughbreds were used over 4 years
      to investigate the correlation between HR and V, the influence of the track and
      rider's weight to V200, reproducibility of V200 and the changes of V200 as
      training progresses. The high correlation coefficient between HR and V, and V200
      were obtained in horses that exercised smoothly during gait changes and had
      acceleration during the canter in relaxed and nonexcitable states. The
      reproducibility of V200 as statistically significant providing the conditions
      were constant. Furthermore, the regression lines between HR and V gradually
      declined in parallel as training progressed. The average V200 in 2-year-old
      Thoroughbreds significantly increased from 623 +/- 55 m/min to 691 +/- 64 m/min
      after 5 months of training (P < 0.05). We concluded that V200 could easily be
      measured, that it was useful in evaluating treatment effect and that practical
      application under field conditions was possible.

PMID- 10659243
TI  - Relationship between running speed, isoenzymes of serum creatine kinase and
      lactate dehydrogenase and left ventricular function in stallions.
AB  - The purpose of this study was to assess the possible relationship between maximal
      running speed, serum isoenzyme patterns of creatine kinase (CK) and lactate
      dehydrogenase (LDH) and echocardiographic indices of left ventricular function. A
      group of 15 healthy, 3-year-old Maremmano stallions were given a 100 day training
      programme. At the end of this the animals carried out a maximum speed test and
      were divided into 2 groups (A and B) according to whether or not they had
      attained a speed of 15 m/s. Venous blood samples were taken from each horse
      before exercise (T0), 2 min (T1) and 24 h (T2) after exercise. Total serum
      activity of CK and LDH was measured and their isoenzyme distribution pattern
      determined. The day before the speed test echocardiographic examination was
      carried out at rest to assess the left ventricular function by calculating
      telediastolic, telesystolic and stroke volume, ejection fraction and stroke
      index. Statistically significant differences were found for the CK isoenzyme
      pattern at T2, where Group A showed an increase in the MM fraction (P = 0.003)
      and a decrease in the MB fraction (P = 0.014). These changes were thought to be
      linked to an increased membrane leakage due to exercise and not to muscle fibre
      disruption because the CK and LDH total activities remained within the normal
      range. In Group A there was also greater left ventricular telediastolic volume (P
      = 0.044) and length (P = 0.033) at rest as well as a greater stroke index (P =
      0.032). We concluded that the evaluation of CK pattern after exercise and of
      echocardiographic left ventricular function indices at rest made it possible to
      select for the fastest horses (Group A).

PMID- 10659244
TI  - Comparison of exercise variables measured during intensity of simulated training
      to variables at maximal effort in standardbreds.
AB  - The heart rate changes during routine training in a group of 8 actively racing
      Standardbreds were used to simulate the training work on a treadmill (ST) and
      indices of exercise compared to maximal effort (MAX) on the treadmill. The
      following parameters were recorded during treadmill work: heart rate, velocity,
      O2 consumption, respiratory and stride frequency, and stride length. Blood
      lactate concentrations were measured before and after each work test. Heart rate
      during simulated training was mean +/- s.d. 87.8 +/- 5.5% heart rate in MAX, one
      of the 8 horses working < 80% of maximal HR and 2 of the 8 horses working above
      90% maximal heart rate. Mean +/- s.d. oxygen consumption during the ST was 75.1%
      +/- 8.4% MAX, but correlated poorly against percentage heart rate for individual
      horses (r2 = 0.02). At similar velocities for the ST and MAX, only respiratory
      frequency differed significantly (P > 0.05), being higher during the ST. Most
      horses worked at intensities based on heart rate consistent with proposed
      guidelines of 80-90% of maximal heart rate. However, in 3 of the 8 horses work
      intensity of insufficient or excessive amounts may have occurred.

PMID- 10659245
TI  - Influence of frusemide on dynamic cardiac variables during exercise.
AB  - Exercising horses have extremely high right and left atrial pressures. Limitation
      in ventricular function (i.e. relaxation) may play a role in these high
      pressures. We studied relaxation characteristics of the right ventricular
      myocardium and the impact of frusemide (2.0 mg/kg bwt i.v.) on these
      characteristics in horses exercising at 8, 10, 12 and 14 m/s. Exercise tests were
      performed 4 h after administration of frusemide. Right ventricular (RV) pressure
      was analysed using Fast Fourier Transform techniques to remove non cardiac
      components of the pressure signal. Mean right atrial (RA) pressure increased with
      exercise and was significantly attenuated at all speeds by frusemide. RV maximum
      and minimum rates of pressure change with respect to time (RV + dP/dtmax, RV
      dP/dtmax) increased with exercise and RV relaxation time constant (RV tau) and
      time of RV relaxation from 65-20% of the difference between maximum and minimum
      ventricular pressure (delta 65-20) decreased with exercise. Frusemide produced no
      significant differences in +dP/dtmax, -dP/dtmax, RV tau or delta 65-20 except at
      12 m/s where RV tau was longer after frusemide (23.4 ms for frusemide vs. 19.7 ms
      for control). Significant reductions in stroke volume were seen at 8, 10 and 14
      m/s after frusemide. These results suggest that the reduction of atrial pressure
      by frusemide is not due to changes in ventricular relaxation rate.

PMID- 10659246
TI  - Effects of pre-exercise frusemide administration and post exercise anaesthesia on
      cardiopulmonary and acid-base parameters and blood and plasma volumes in horses
      exercised supramaximally to fatigue.
AB  - Six horses were randomly assigned to receive either frusemide (F) (0.5 mg/kg
      i.v.) or an equivalent volume of saline (S) i.v., 4 h prior to treadmill
      exercise. Horses were instrumented to enable measurement of heart rate (HR),
      systolic (SAP), mean (MAP), and diastolic (DAP) carotid arterial pressures,
      pulmonary artery pressure (PAP), central venous pressure (CVP), pulmonary
      arterial temperature (TEMP), blood gases, and cardiac output (CO). Plasma (PV)
      and blood volumes (BV) were measured using 2 injections of Evan's Blue dye.
      Baseline parameters were recorded while the horse stood quietly. Horses were then
      administered F or S. Four hours later, they were warmed up for 3 min at 4 m/s and
      then exercised to the point of fatigue at 115% VO2max. Horses were anaesthetised
      immediately following exercise by administration of detomidine (0.04 mg/kg bwt
      i.v.) followed 5 min later by tiletamine-zolazepam (1.25 mg/kg bwt i.v.). After
      transporting the horse to a recovery stall, anaesthesia was maintained with
      isoflurane in 100% O2. Data were analysed using a 2-way ANOVA with repeated
      measures with post hoc differences identified using the Student-Newman-Keul's
      procedure. Exercise was associated with increases in HR, SAP, MAP, DAP, PAP, CVP,
      TEMP, PCV, and BV, and decreases in PV, pH, arterial bicarbonate and base excess.
      Anaesthesia was associated with marked hypercapnia, a decrease in HR following
      detomidine administration, and persistent pulmonary hypertension despite carotid
      arterial pressure which returned to baseline. No effects attributable to F were
      identified at any time during the study.

PMID- 10659247
TI  - Influence of training on autonomic nervous function in horses: evaluation by
      power spectral analysis of heart rate variability.
AB  - We studied the influence of training on autonomic nervous function in the horse.
      For this purpose, Holter electrocardiogram (ECG) was recorded before and after
      training from 24 Thoroughbred horses (2-year-olds) and autonomic nervous function
      was evaluated by the power spectral analysis of heart rate (HR) variability. We
      obtained HR, low-frequency (LF) power, high-frequency (HF) power, and LF/HF ratio
      from recording. We set LF at 0.01-0.07 Hz and HF at 0.07-0.6 Hz. The HF power is
      thought to reflect primarily parasympathetic nervous function. Both the
      sympathetic and parasympathetic nervous systems have been shown to contribute to
      the LF power. The LF/HF ratio is considered as an index of the cardiac
      sympathovagal balance. Second degree atrioventricular blocks were found in the
      ECG of 3 and 5 horses before and after the training period, respectively.
      Ventricular premature depolarisations were detected in a horse after the training
      period. Heart rate decreased at night. The lowest HR values had a tendency to
      appear in the early morning. Both the LF and HF power tended to be higher at
      night. However, the LF/HF ratio was almost the same throughout the day. The HR
      was significantly decreased by training. Although the LF power and LF/HF ratio
      were significantly increased, the HF power was not changed by training. These
      results suggest that parasympathetic nervous activity may be fully activated even
      before training in this species.

PMID- 10659248
TI  - The effect of supramaximal exercise on equine platelet function.
AB  - When blood is collected into sodium citrate in the proportion of 9 parts blood:1
      part sodium citrate, the concentration of plasma sodium citrate in the sample
      will depend on the packed cell volume (PCV) of the blood sample. This difference
      in plasma sodium citrate concentration secondary to alterations in PCV
      significantly affects human platelet aggregation responses. Since horses attain a
      high PCV in response to high-intensity exercise we investigated the effect of
      differences in sample plasma sodium citrate concentration on equine platelet
      aggregability. In addition, low molecular weight heparin (LMWH) was evaluated as
      an alternative anticoagulant for assessment of platelet aggregability during
      strenuous exercise in horses. Blood samples were collected pre-exercise and at
      fatigue after supramaximal treadmill exercise into either 3.8% sodium citrate (9
      parts blood:1 part sodium citrate) or 20 u LMWH/ml of blood. Platelet aggregation
      responses to 1.25 mumol/l adenosine diphosphate (ADP) were measured via optical
      aggregometry. For samples collected into sodium citrate, aggregability was
      significantly less than pre-exercise values in samples collected at fatigue and
      in pre-exercise samples in which sodium citrate concentrations were adjusted to
      equal those in fatigue samples. However, samples collected into LMWH showed
      significantly increased platelet aggregability in samples collected at fatigue
      when compared to pre-exercise samples. In conclusion, higher plasma sodium
      citrate concentration had a marked inhibitory effect on equine platelet
      aggregation responses. Low molecular weight heparin was a good alternative
      anticoagulant for assessment of equine platelet function and results indicate
      that equine platelet aggregability was enhanced in response to supramaximal
      exercise.

PMID- 10659249
TI  - Plasma atrial natriuretic peptide during and after repeated exercise under heat
      exposure.
AB  - Plasma atrial natriuretic peptide (ANP) responses were studied in horses during
      and after a competition exercise test (CET) designed to simulate the endurance
      test of a 3-day event and including test Phases A-D. CET was repeated 5 times at
      2 week intervals at mean temperature +28 degrees C and relative humidity (RH)
      58%. Heart rate (HR) was monitored during CET. After CET, the horses were
      rehydrated with isotonic glucose-electrolyte solution or water. ANP, NH2-terminal
      pro-atrial natriuretic peptide (NT-ANP), aldosterone, arginine vasopressin (AVP)
      and plasma proteins (PP) were measured during CET and recovery. ANP rose with
      intensity and duration of exercise from 8 pmol/l to 15 pmol/l at a gallop (Phase
      B), remained elevated at Phases C-X, and peaked (23 pmol/l) at a canter (Phase
      D). Thereafter, ANP decreased to the pre-exercise level within 2.5 h irrespective
      of rehydration. Repeated exercise bouts failed to affect plasma ANP, although
      other adaptive changes occurred. No diurnal variation in plasma ANP appeared. In
      NT-ANP, the most marked elevation occurred during Phases C-D. In contrast to ANP,
      the decrease was minor for 1 h after the canter. ANP did not correlate with AVP
      or HR. In conclusion, exercise per se affected equine plasma ANP but the possible
      effect of thermal stress could not be demonstrated. The differences between ANP
      and NT-ANP responses indicate differences in their release or elimination and
      suggest that the cardiac prohormone cleavage may occur intracellularly or
      simultaneously with secretion, not in circulation.

PMID- 10659250
TI  - Relationship between VO2max, heart score and echocardiographic measurements
      obtained at rest and immediately following maximal exercise in thoroughbred
      horses.
AB  - We evaluated the relationships of heart score (HS) and echocardiographic measures
      to maximal oxygen consumption (VO2max), maximal cardiac output (Qmax), and
      maximal stroke volume (SVmax). Six fit, mature Thoroughbred horses weighing (mean
      +/- s.e.) 487 +/- 11 kg were run 4 times on an inclined (10%) treadmill. Each run
      consisted of a 3 min warm-up at 4 m/s followed by completion of an incremental
      exercise test in which each horse ran until VO2max was reached. Arterial and
      mixed venous blood was collected to determine arteriovenous oxygen content
      difference C(a-v)O2[ in the last 15 s of exercise. An ATL HDI 3000 ultrasound
      system and a 3.5 MHz phased array transducer were used to make echocardiographic
      measurements before and within 2 min of run completion. Guided M-mode
      echocardiographic measurements of left ventricular diameter (LVD),
      interventricular septal thickness (IVS) and left ventricular free wall thickness
      (LVFW) during diastole (D) and systole (S) were made from the right parasternal
      short axis view at the level of the chordae, and VO2 and C(a-v)O2 were measured
      as the appropriate M-mode view was recorded. Maximum heart rate (HRmax) was
      determined using a cardiotachometer, and HS was calculated on nonexercise days
      using the established technique. Maximum cardiac output and SVmax were calculated
      from the Fick equation and HRmax. Backward stepwise regression analysis was used
      to relate pre- and post exercise echocardiographic measurements and HS to VO2, Q,
      and SV at the time of measurement, and to VO2max, Qmax, and SVmax. Pre- and post
      exercise LVDD appeared to be the most important variable in these equations. Mean
      pre-exercise HR at the time of measurement was 54.7 +/- 1.9 beats/min, while the
      mean post exercise rate was 111.7 +/- 2.6 beats/min. The mean +/- s.e. VO2max was
      150.4 +/- 13.2 ml/(kg.min). Heart score was not correlated with VO2max, Qmax, or
      SVmax. There was no significant difference between pre- and post exercise
      measurements of LVD, IVSS, and LVFWS.

PMID- 10659251
TI  - Cardiac responses to training in 2-year-old thoroughbreds: an echocardiographic
      study.
AB  - Guided M-mode echocardiography was performed in seven 2-year-old Thoroughbreds
      before commencement of commercial flat-race training, and 18 weeks later, when
      all horses were either racing regularly (5 horses), or at racing fitness (2
      horses). M-mode echocardiography was performed using a 2.5 MHz annular phased
      array ultrasound transducer and a Vingmed 800 Supervision echocardiograph. Images
      were obtained from the right hemithorax; a short axis view of the left ventricle
      (LV) at the level of the chordae tendinae was used to position the M-mode cursor.
      The following variables were measured: left ventricular (LV) internal diameter in
      diastole (LVIDd) and systole (LVIDs) and interventricular septal (IVS) and left
      ventricular free wall thickness (LVFW) in systole and diastole. The following
      variables were also calculated: LV fractional shortening (%FS), LV ejection
      fraction (EF), LV relative and mean wall thickness and muscle mass. Values before
      and after training were compared using a paired Student's t test. Training
      resulted in significant reductions in %FS and EF. Left ventricular internal
      diameter increased from 11.38 s.d = 0.58) cm before training to 12.16 (s.d. =
      0.7) cm after training (P < 0.001). Calculated left ventricular mass also
      increased significantly (mean increase of 33% P < 0.001). Bodyweight was
      unchanged in the present study. Relative wall thickness was significantly
      increased in all horses, suggesting that eccentric cardiac hypertrophy occurs in
      response to commercial flat-race training. The mean post training value for
      relative wall thickness of 0.45 (s.d. = 0.05) for the horses in the present study
      is similar to that of human athletes in power/endurance disciplines.

PMID- 10659252
TI  - Should equine athletes commence training during skeletal development?: changes in
      tendon matrix associated with development, ageing, function and exercise.
AB  - In human athletes, conditioning, training and competition are commenced before
      skeletal maturity. Yet in equine athletics, racing of young (age 2 years) horses
      remains contentious. Tendon injury persists as major causes of wastage in equine
      athletes. Minimising injury and associated welfare issues could involve a radical
      approach to the timing and implementation of conditioning and training. Tendons
      were examined from Thoroughbreds, Dutch Warmblood foals, working horses and also
      a group of wild horses to evaluate effects of age, function and exercise. Gross
      mechanical properties did not differ significantly with age or exercise, but
      showed a high variance within each group. Mechanical properties of tendon tissue
      showed significant differences as a function of age and location. The collagen
      fibril crimp angle and length showed a regional reduction in the central core
      with exercise and age, with a synergistic effect. Regional differences in
      collagen fibril diameter were seen in long-term exercised older horses, but not
      in short-term exercised, or younger, horses. The higher proportion of small
      fibrils in the central region of the long-term exercised horses did not correlate
      with new collagen formation and therefore appear to result from disassembly of
      the larger diameter fibrils. Fibril diameter distributions were influenced by
      exercise regimens in the growing foal. Changes in molecular composition occurred
      in longer-term exercise and older horses, in the centre of the tendon, with
      higher levels of type III collagen and changes in glycosaminoglycan (GAG)
      content. Cartilage Oligomeric Matrix Protein (COMP) levels also appear to be
      modulated by age, function and superimposition of exercise. These changes were
      all exacerbated with age and exercise, suggesting appropriate exercise in young
      horses may lead to a lower incidence of injury than in older horses. An
      hypothesis is advanced that immature tendon can respond to exercise while mature
      tendon has limited, if any, ability to do so. These findings support potentially
      controversial earlier conditioning and racing of younger, rather than older,
      equine athletes.

PMID- 10659253
TI  - Kinematics of the equine back: flexion-extension movements in sound trotting
      horses.
AB  - This study was undertaken to evaluate the flexion-extension movements of the back
      in a group of sound trotting horses. Using a 3-D kinematic analysis system, 13
      clinically sound horses fitted with 5 skin markers placed on the dorsal midline
      of their trunk were recorded while trotting on a track in the conditions of the
      routine lameness examination. These markers were used to calculate 3 back angles
      (thoracic, thoracolumbar and lumbosacral angle). These back angles were then
      filtered using Fourier series. To evaluate the repeatability of flexion-extension
      movements, the intra- and inter-individual variabilities were studied. The angle
      time diagrams showed that the equine back extended during the first part of each
      diagonal stance phase and flexed during the second part of each diagonal stance
      phase. The ranges of motion were less than 4 degrees for the 3 back angles. The
      intra- and inter-individual variability values of maximal extension and maximal
      flexion time points were similar and extremely low. This demonstrates the high
      repeatability of the temporal pattern of flexion-extension movements of the back.
      Intra- and inter-individual variabilities of the range of motion showed that the
      back mobility varies more in-between horses than between trials of the same
      horse. Compared with electromyographic activities of back muscles reported in the
      literature, flexion-extension movements described in this study tend to show
      that, at a slow trot, trunk muscles act mainly to limit flexion-extension
      movements of the back rather than to induce movements.

PMID- 10659254
TI  - Influence of rough track surfaces on components of vertical forces in cantering
      thoroughbred horses.
AB  - No kinetic data are available to indicate the influence of a rough track surface
      and the resultant loss of footing on the components of hoof vertical forces. The
      aim of the present study was to evaluate the influence of rough track surfaces on
      the components of hoof vertical forces. Seven clinically sound 2-year-old
      Thoroughbred horses had instrumented shoes attached to both of the fore hooves to
      obtain the magnitudes of consecutive forces exerted in the hoof. All horses were
      cantered at approximately 10 m/s on straight tracks of smooth and rough surfaces
      of woodchip and dirt. The instrumented shoe indicated in real time 4 component
      forces acting on the hoof via 4 transducers positioned on the lateral and medial
      sides of the toe (LT, MT) and the heel (LH, MH). The peak vertical component
      forces of the heel were about twice that of the toe. The variances of the 4
      components of peak vertical forces significantly increased on the rough track
      surface of both the woodchip (Leading: LH, MH and MT; Trailing: MH and LT) and
      dirt (Leading: LH and LT; Trailing: MH and MT) tracks. The trajectories of the
      position of the resultant force acting on the hoof also tended to increase the
      variance on rough track surfaces. Therefore, running on a rough track changes the
      vertical hoof forces and the balance of the resultant hoof forces. These results
      suggest a mechanism by which the rough track surfaces may influence the soundness
      of the horse.

PMID- 10659255
TI  - The effects of a rider's mass on ground reaction forces and fetlock kinematics at
      the trot.
AB  - Ground reaction force (GRF) measurements are often normalised to body mass to
      facilitate inter-individual comparisons. The objective of this study was to
      explore the effect of a rider on the GRFs and fetlock joint kinematics of
      trotting horses. The subjects were 5 dressage-trained horses and 3 experienced
      dressage riders. Ground reaction force measurements and sagittal view videotapes
      were recorded as the horses trotted at the same velocity in hand (3.49 +/- 0.52
      m/s) and with a rider (3.49 +/- 0.46 m/s). Data were time-normalised to stance
      duration. Ground reaction force measurements were expressed in absolute terms and
      normalised to the system mass (horse or horse plus rider). All the horses showed
      changes in the same direction when comparing the ridden condition with the in
      hand condition. There was an increase in the absolute peak vertical GRFs of the
      fore- and hindlimbs with a rider. However, the mass-normalised peak vertical GRFs
      were lower for the ridden condition, with the peak occurring later in the
      forelimbs and earlier in the hindlimbs compared with the inhand condition.
      Maximal fetlock angle and its time of occurrence were similar for the 2
      conditions, but the fore fetlock joint was more extended during the later part of
      the stance phase in ridden horses. The presence of a rider appeared to affect the
      GRFs and fetlock joint kinematics differently in the fore- and hindlimbs, and the
      ridden horse did not seem to be equivalent to a proportionately larger horse.
      This should be considered when normalising for body mass in studies comparing
      horses in hand and ridden horses.

PMID- 10659256
TI  - Treadmill exercise-induced tendon hypertrophy: assessment of tendons with
      different mechanical functions.
AB  - The equine superficial digital flexor tendon (SDFT) functions as an energy store
      during high-speed gaits reducing the energetic cost of locomotion. To enable the
      SDFT to function effectively, the appropriate mechanical properties are
      essential. We tested the hypothesis that the SDFT does not undergo gross
      hypertrophy in response to high-intensity exercise whereas tendons not involved
      in energy storage undergo adaptive hypertrophy. Two groups (n = 6) of
      Thoroughbred fillies were trained at high-intensity on a high-speed equine
      treadmill for 5 months (short-term study) or 18 months (long-term study). Age
      matched groups (n = 6) of horses undertook low-intensity exercise only for the
      same time period. Throughout the short-term study the SDFT and deep digital
      flexor tendon (DDFT) were ultrasonograpically scanned at mid-metacarpal level and
      cross-sectional area (CSA) calculated. At the end of the short-term study (horse
      age = 2 years) and long-term study (horse age = 3 years) the left SDFT, DDFT,
      suspensory ligament (SL) and common digital extensor tendon (CDET) were harvested
      and CSA calculated. Comparison of the DDFT from 2- and 3-year-old horses revealed
      an age-related increase in CSA which was confirmed by ultrasonographs. Post
      mortem analysis showed a significant hypertrophy of the CDET with high-intensity
      training in the short-term study (younger horses). CSA did not differ
      significantly between training groups for any of the structures following long
      term training. These results suggest a structure specific hypertrophic response
      to the imposed training regime.

PMID- 10659257
TI  - Sedation and antisedation as tools in equine lameness examination.
AB  - A kinematic study was performed to establish the locomotion pattern of horses
      under detomidine sedation and the effects of antagonization for possible use
      during lameness examinations in uncooperative horses. The kinematics of 17
      Warmblood horses (9 sound, 8 lame with chronic forelimb lameness) were recorded
      on 2 days using a high-speed video system while trotting (3.9 m/s) on a
      treadmill. On each day a control measurement was carried out prior to sedation
      with detomidine (10 micrograms/kg bwt) and repeated recordings at 15, 25, 35, 45
      and 60 min after sedation. On the second day, sedation was antagonized using
      atipamezole (100 micrograms/kg bwt) after the 15 min recording. Head height and
      pulse rate documented the level of sedation. The head dropped from mean 1.23 m
      (s.d. 0.13) to 0.50 m (0.26) following sedation to reach again 1.06 m (0.19)
      after 60 min. Antagonization reversed the height significantly at the 25 min
      recording to 1.06 m (0.11). Walking and trotting were possible in all sedated
      horses in response to voice commands only. Forelimb lameness symmetry parameter
      (Head Acceleration Asymmetry: HAAS) in 8 lame horses did not change significantly
      due to sedation. Stride length increased significantly from mean 2.53 m (0.18) to
      2.66 m (0.20) 15 min after sedation and reversed to 2.56 (0.17) m after
      antagonization. Stride and stance durations changed accordingly. In conclusion,
      sedation did not change the degree of lameness, but did alter the general
      locomotion pattern. Antagonization diminished most of these effects, but small
      differences to the unsedated pattern remained.

PMID- 10659258
TI  - EMG activity of the muscles of the neck and forelimbs during different forms of
      locomotion.
AB  - We recorded the electromyographic (EMG) activity of 7 skeletal muscles in the
      forequarters and 1 in the hindquarters of 6 Thoroughbred horses during overground
      walking, swimming in a circular pool, and walking and trotting in a water
      treadmill. Bipolar fine wire electrodes were inserted into the muscles and the
      EMG signals were recorded using a telemetric system. The splenius exhibited tonic
      EMG activity during swimming. The brachiocephalicus showed its highest intensity
      during swimming followed by the walk and trot in the water treadmill and then
      walking overground. The triceps brachii caput longum had a similar activity
      pattern to the brachiocephalicus. The brachialis showed only weak EMG activity in
      all 3 types of locomotion. The extensor digitorum communis had higher intensity
      of EMG activity in the walk in the water treadmill than in other kinds of
      locomotion. The flexor digitorum profundus exhibited the most intense EMG
      activity during swimming. These results indicated that swimming evoked strong EMG
      activity in the antigravity muscles in spite of reduced gravitational force.
      Walking in the water treadmill may require more intensified EMG activity of the
      forelimb than the trot in the same treadmill.

PMID- 10659259
TI  - Forelimb kinematics and net joint moments during the swing phase of the trot.
AB  - The purpose of this study was to calculate net moments of force at the joints of
      the forelimb during the swing phase of the stride. An optoelectronic system was
      used to measure segmental kinematics for 3 strides in 5 sound, Warmblood horses
      trotting at a mean velocity +/- s.d. of 3.03 +/- 0.16 m/s. A link segment model
      was used to determine the net moments of force about the joints of the left
      forelimb. The model combined kinematic data with morphometric data describing the
      inertial parameters of the limb segments of warmblood horses, and incorporated
      correction factors for skin displacement. At each joint the net moment of force
      was on the cranial/dorsal side during the early swing phase and on the
      caudal/palmar side during the later swing phase. The transition (time of zero
      moment) occurred between 35-52% of the swing phase. The peak magnitude of the net
      joint moments decreased progressively in a proximal to distal direction.
      Published electromyographic (EMG) data correlated well with the timing of
      muscular activity required to generate the calculated net joint moments. The
      moments in the proximal limb are indicative of muscular activity accelerating the
      limb forward during the first 30-40% of the swing phase, then decelerating the
      forward swing of the upper limb segments. The net joint moments at all of the
      joints except the elbow work to slow the motion of the joints. The net joint
      moment about the elbow actively flex and then extend the joint. The low net joint
      moments at the distal joints during the first half of swing are consistent with
      their motion being primarily a result of inertial forces. Flexor muscle activity
      during the last half of swing indicate active control in preparation for ground
      contact.

PMID- 10659260
TI  - A comparison between the trot of pony and horse foals to characterize equine
      locomotion at young age.
AB  - The trot at 3 m/s of 24 Shetland foals ('ponies') and 24 Dutch Warmblood foals
      ('horses') was recorded at age 4 months on a treadmill using a modified CODA-3
      apparatus to characterise equine locomotion at young age. Locomotor variables of
      the ponies were qualitatively and, after scaling, quantitatively compared with
      those of horses. Ponies made shorter strides than horses, evidenced by a shorter
      stance and swing duration, although their relative stance durations were similar.
      Neither linear nor dynamic scaling procedures could completely compensate for
      differences in height at the withers comparing ponies and horses. The patterns of
      the joint angle-time curves were similar. Ponies had a larger range of pro- and
      retraction, with a more protracted forelimb and a more retracted hindlimb,
      therefore demonstrating a more extended trot. The horses trotted with more
      extended elbow, stifle and tarsal joints and a more flexed hip joint, which is in
      accordance with the conformation for the Warmblood. The ponies moved with a
      stiffer trot in contrast to the more supple trot of the horses, which showed a
      larger maximal fetlock extension during the stance phase. In conclusion, ponies
      and horses move qualitatively similarly at age 4 months, but characteristic breed
      differences in conformation and gait quality can already be detected. Scaling
      methods to compensate for differences in height at the withers cannot be applied
      when animals move at the same velocity.

PMID- 10659261
TI  - In vitro transmission and attenuation of impact vibrations in the distal
      forelimb.
AB  - An in vitro model was developed and validated in vivo to quantify the attenuation
      of impact vibrations, transmitted through the lower equine forelimb and to assess
      the effects of horseshoeing on this attenuation. The transsected forelimbs of 13
      horses were equipped with custom-made hollow bone screws in the 4 distal bones,
      on each of which a tri-axial accelerometer could be mounted. The limbs were then
      preloaded while the impact was simulated by dropping a weight on the steel plate
      on which the hoof was resting. At the hoof wall, the distal, middle and proximal
      phalanx and at the metacarpal bone, the shock waves resulting from this impact
      were quantified. To assess the damping effects of shoeing, measurements were
      performed with unshod hooves, hooves shod with a normal flat shoe and hooves shod
      with an equisoft pad and a silicone packing between hoof and pad. The in vitro
      model was validated by performing in vivo measurements using one horse, and
      subjecting the limb of this horse to the same in vitro measurements after death.
      Approximately 67% of the damping of impact vibrations took place at the interface
      between the hoof wall and the distal phalanx. The attenuation of impact
      vibrations at the distal and proximal interphalangeal joints was considerably
      less (both 6%), while at the metacarpophalangeal joint 9% of the amplitude of
      that at the hoof wall was absorbed, leaving approximately 13% of the initial
      amplitude at the hoof wall detectable at the metacarpus. Compared to unshod
      hooves the amplitude at the hoof wall is 15% higher in shod hooves. No
      differences could be observed between shoe types. At the level of the first
      phalanx and metacarpus the difference between shod and unshod vanished; it was
      therefore concluded that, although shoeing might influence the amplitude of
      impact vibrations at the hoof wall, the effect of shoeing on the amplitude at the
      level of the metacarpophalangeal joint is minimal.

PMID- 10659262
TI  - The kinematics of loading and fatigue in the standardbred trotter.
AB  - The Standardbred trotter must pull a considerable load when racing and,
      consequently, draught loading is a common method of training in the Standardbred
      and the effects of loading and fatigue due to loading on the locomotor pattern
      was the purpose of this investigation. Four mature healthy Standardbred horses
      trotted with and without a horizontal-pulling loading of 34 kg until the horses
      were no longer willing to keep pace with the treadmill despite encouragement.
      Heart rate was monitored every min using a bipolar electrocardiogram. The
      kinematics for 5 consecutive strides were filmed. Horses exercised on the
      treadmill for 7-10 mins. The mean heart rate was 206 beats/min at the end of the
      exercise. Due to draught loading, the horses reduced significantly the time of
      the stance phase in both the fore- and hindlimb. Three of the 4 horses reduced
      their stride lengths as the result of increased loading. The general movement
      pattern of the horses remained similar. More dramatic changes in the movement
      pattern were observed because of fatigue. The limbs of the horse were
      significantly more compressed as the result of greater joint excursion during the
      stance phase. Furthermore, the length of stride was significantly increased as
      the result of fatigue. The results show that both loading and fatigue change the
      locomotor pattern of the Standardbred trotter. Although the horizontal loading
      was considerable, the horse maintained similar joint movement with increases in
      stride frequency. During fatigue the horse seems to be unable to maintain stride
      frequency, probably due to a compromised power capacity of the muscles. The
      increase in joint excursion due to fatigue may have an important influence on
      certain types of injury to the locomotor system of the racehorse.

PMID- 10659263
TI  - Temporal changes in the trot between the first and third horse inspections at a
      CCI*** 3-day event.
AB  - Kinematic parameters were measured from horses competing in a CCI*** 3-day event.
      The horses were filmed during the first and third horse inspection. This provided
      a repeat sample on 16 horses. The horses were filmed using a panning lateral S
      VHS video camera (50 Hz). Spatial measurements were taken for mean +/- s.d. 5.66
      +/- 0.92 strides for the first inspection and 5.05 +/- 1.27 for the third
      inspection. Within the calibration zone, data of the horses accelerating and
      obtaining a constant velocity were collected. The horses trotted with a higher
      mean velocity during the third inspection (0.26 +/- 0.05 m/s, P < 0.001). During
      the third inspection the horses trotted with a shorter stride length (0.193 +/-
      0.03 m, P < 0.001) and stride duration (31 +/- 42 m/s, P < 0.001). The third
      inspection was characterised by a decrease in retraction percentage for both the
      forelimbs (3.69 +/- 2.39%, P < 0.001) and the hindlimbs (2.48 +/- 2.16%, P <
      0.001). However, no significant difference was found between the 2 inspections
      for other temporal parameters when measured as a percentage of stride. It is
      proposed that the event horses trot with a decreased stride length and duration
      during the third horse inspection but maintain a consistent temporal
      relationship.

PMID- 10659264
TI  - An MRI study of the effect of treadmill training on bone morphology of the
      central and third tarsal bones of young thoroughbred horses.
AB  - Training results in marked modelling of the subchondral bone of the carpus, but
      the effect of training on the subchondral bone of the distal tarsal joints is
      unknown. The aim of this study was to determine whether training influenced
      modelling of the third and central tarsal bones in Thoroughbred horses. Twelve
      untrained Thoroughbred horses were divided into 2 groups. Group 1 underwent a 19
      week progressive training regimen on a high speed treadmill. Group 2 were walked
      for 40 min daily. Images of left tarsi were obtained by magnetic resonance
      imaging (MRI) with a 0.5 Tesla superconducting magnet using a spin echo sequence.
      Sagittal and oblique sagittal slices were made perpendicular to the articular
      surfaces of the intertarsal joints and were analysed using image analysis
      software to measure the proportion of dense subchondral bone in the dorsal facet
      of each bone. Mean +/- s.d. percentage area of dense subchondral bone in the
      dorsal facet of the central tarsal bone in Group 1 was 47 +/- 8 medially, 46 +/-
      4 sagitally and 50 +/- 11 dorsolaterally, whereas in Group 2 it was 39 +/- 16
      medially, 43 +/- 8 sagitally and 53 +/- 7 dorsolaterally. For the third tarsal
      bone mean +/- s.d. percentage area of dense subchondral bone in Group 1 was 32 +/
      10 medially, 39 +/- 11 sagitally and 44 +/- 8 dorsolaterally, whereas in Group 2
      it was 28 +/- 8 medially, 37 +/- 6 sagitally and 41 +/- 9 dorsolaterally. There
      was no significant difference in percentage area of dense subchondral bone
      between the trained and untrained horses. An effect of treadmill training of
      Thoroughbred horses on modelling of the central and third tarsal bones could not
      be demonstrated.

PMID- 10659265
TI  - Radiographic measures of bone shape in young thoroughbreds during training for
      racing.
AB  - The aim of this study was to determine if changes in the shape of the third
      metacarpal bone (MC3) during the first preparation for racing in young
      Thoroughbred racehorses could be measured radiographically. Lateral radiographs
      of each MC3 were taken when the horses commenced training, every 2 weeks for 10
      weeks, and again at 6 months after the start of training. The width of the dorsal
      cortex (DC), palmar cortex (PC), and medulla (M) were measured at a position 2.5
      cm distal to the nutrient foramen before the subject of each radiograph was
      identified. The following ratios were calculated: z = DC/M; RI = (DC + PC)/M[ x
      DC/PC[. The results showed that the shape of the MC3 changed during training for
      racing and that these changes may be measured on standard lateral radiographs.
      The dorsal cortex became proportionately thicker than the rest of the bone
      dimensions in the dorsopalmar plane. The proportionate increases in dorsal cortex
      dimensions were greater in horses that were recorded as shin sore during racing
      than in horses that were racing with no recorded shin soreness.

PMID- 10659266
TI  - Nerve block and intra-articular anaesthesia of the forelimb in the sound horse.
AB  - Nerve blocks and intra-articular anaesthesia are used extensively as routine
      methods in lameness evaluation. The method is based on the assumption that the
      technique itself does not change the movement pattern. The aim of this study was
      to carry out a quantitative kinematic study to confirm or reject the hypothesis
      that high palmar digital nerve block (HPDN) and intra-articular fetlock joint
      anaesthesia (IAF) influence significantly the movement pattern of the horse.
      Seven Standardbred horses trotting at 4.5 m/s were recorded at 240 Hz on a
      treadmill before and after anaesthesia by use of a ProReflex video system. Time
      variables, segment and joint angles were calculated. The high palmar digital
      nerve block (HPDN) resulted in a longer stance time and caused a greater fetlock
      joint angle range and greater maximal pastern joint angle. No systematic
      differences in time and angle variables were observed after intra-articular
      fetlock joint anaesthesia (IAF). In conclusion, HPDN but not IAF affects
      locomotor pattern in sound horses. Distal limb proprioception is important in
      normal movement, while fetlock intra-articular proprioception is apparently not.
      Interpretation of the effect of HPDN in lame individuals should incorporate more
      variables than maximal overextension of the fetlock joint.

PMID- 10659267
TI  - Effects of flunixin on movement and performance of standardbred trotters on the
      track.
AB  - An often discussed and controversial issue is the effect of nonsteroidal anti
      inflammatory drugs (NSAIDs) on performance. The purpose of this study was to
      investigate the effect of the NSAID flunixin on the movement pattern and
      performance capacity of Standardbred trotters using a standardised track model.
      Five adult Standardbred horses in training trotted at 2 occasions with a 2 week
      interval on the same oval dirt track. Before each occasion the horses were either
      injected with flunixin meglumine (Finadyne) or normal saline solution i.m. 4 h
      before the performance test (double blind crossover study). The kinematics for 5
      consecutive strides were filmed. There was no significant difference in maximal
      speed between the saline and flunixin treatment sessions. Significant changes in
      the movement pattern were observed as an effect of the flunixin treatment. The
      horses maintained the same stride duration while significantly decreasing stance
      time and increasing swing time in the forelimbs. The horses' range of limb angle
      decreased significantly. Heart rates were monitored and plasma lactate and
      flunixin concentrations were measured. No significant differences were found in
      heart rate and plasma lactate. The results indicate that flunixin had a
      significant effect on locomotor pattern while it did not effect metabolic
      response in these horses (considered to represent a normal race track
      population). The overall effect on performance in racing horses may therefore be
      related to the anti-inflammatory and analgesic properties of NSAIDs by masking
      pain and lameness.

PMID- 10659268
TI  - The effect of training on the calcified zone of equine middle carpal articular
      cartilage.
AB  - Carpal osteochondral injury is frequently observed in strenuously trained horses.
      It is clear that the integrity of articular cartilage and subchondral bone are
      intimately related, although there is controversy about which component is the
      most important. Calcified cartilage provides the mechanical link between soft
      hyaline cartilage and stiff subchondral bone so it is essential to understand the
      tissue's response to exercise. Middle carpal calcified and uncalcified (hyaline)
      cartilage thickness was investigated in horses undergoing high- and low-intensity
      exercise. Twelve untrained horses (18-21 months) were paired, and randomly
      assigned to an exercise group. Group 1 underwent 19 weeks progressive high
      intensity training on a high-speed treadmill. Group 2 underwent walking exercise
      only. Osteochondral specimens were obtained from 8 test sites per carpus
      immediately after euthanasia. Histomorphometric measurements of total cartilage,
      hyaline layer, and calcified zone thickness were obtained from decalcified and
      undecalcified samples. Mean +/- s.d. (micron) calcified cartilage thickness for
      dorsal cartilage from Group 1 was 271 +/- 73 and from Group 2 was 163 +/- 49; for
      palmar cartilage from Group 1 was 195 +/- 42 and Group 2 was 150 +/- 52. Group 1
      horses had significantly thicker total cartilage (P < 0.0001) and calcified zone
      (P < 0.0001) than Group 2, but there was no difference in hyaline layer. Within
      each group all dorsal sites had thicker calcified cartilage (P < 0.003) than
      palmar sites, but no difference in hyaline or total cartilage. These findings
      indicate that high-intensity exercise leads to greater calcified zone depth
      without alteration in hyaline cartilage thickness, and that this response is
      maximal at sites that withstand high, intermittent loads. Increasing calcified
      cartilage thickness with exercise may maintain the articular surface stiffness
      gradient in the face of alterations in hyaline cartilage and/or subchondral bone
      stiffness.

PMID- 10659269
TI  - The effect of shoeing on kinetics and kinematics during the stance phase.
AB  - The increasing range of of horseshoes and hoofpads makes it important to be able
      to evaluate their influence on performance and stress in the locomotor apparatus.
      The aim of this study was to describe the changes in ground reaction forces and
      locomotion pattern during the stance phase due to the application of a standard
      iron shoe. Six Swedish Warmblood horses were evaluated kinetically and
      kinematically before and after they were shod with an 8 mm iron shoe. Data were
      used to calculate ground reaction forces in the vertical and craniocaudal
      directions, point of application of the force, hoof segment angle and hoof joint,
      pastern joint, fetlock, carpal and tarsal angles. Finally joint angular velocity
      and landing velocity of the hoof were calculated. During the initial phase of the
      stance or the concussion phase, the horses altered the conditions of the limb, as
      reflected by hoof-landing velocities. Concussion-dampening mechanisms of the
      distal limb subsequently were altered. In the nonshod condition, the coffin and
      fetlock joints rotated more rapidly in the forelimb and less rapidly in the
      hindlimb, while earlier proximal off-loading by the carpus and tarsus resulted in
      a decrease in initial horizontal loading at the hoof. It was concluded that
      horses accustomed to standard iron shoes demonstrate slight but significant
      differences in the movement and loading of the distal limb due to shoeing. Though
      the main differences were related to the concussion phase of the stance, even mid
      stance loading and roll-over were altered. The study provides a basis for further
      investigation of the effect of various farriery techniques on the hoof and
      movement of the horse.

PMID- 10659270
TI  - Heritability of percentage of fast myosin heavy chains in skeletal muscles and
      relationship with performance.
AB  - The purpose of this study was to determine the percentage of fast myosin heavy
      chains (fast MHCs = MHC 2A + 2B) in 2 propelling muscles to estimate the
      heritability and to identify any relationship with performance. The gluteus
      medius and the biceps femoris muscles were biopsied in 100 related French Anglo
      Arabian horses. The percentages of slow and fast myosin heavy chains were
      measured using an ELISA technique. The heritability (s.e.) of the fast MHCs
      percentage was estimated at 13% (0.1) using a restricted maximum likelihood
      resolution of a mixed animal model. There were significant (P < 0.05)
      correlations between the performance level and the fast MHCs percentage of the
      gluteus medius and biceps femoris muscles: 0.47 and 0.34 respectively. An
      analysis of variance revealed a significant (P < 0.05) effect of performance
      level in gallop racing and show jumping on the fast MHCs percentage of the
      gluteus medius muscle. The good performers in gallop racing (75.5 > 69.6% fast
      MHCs) and show jumping (74.1 > 67.8% fast MHCs) had a higher percentage of fast
      MHCs in the gluteus medius than poor performers (P < 0.05). This muscular
      analysis could be one of the interesting physiological traits to measure for
      early selection of gallop racing and show jumping horses.

PMID- 10659271
TI  - Exercise that induces substantial muscle glycogen depletion impairs subsequent
      anaerobic capacity.
AB  - The purpose of this study was to develop a model of muscle glycogen depletion and
      to study the effect of this model on aerobic and anaerobic capacity of horses.
      The maximal rate of oxygen consumption (VO2max), maximal accumulated oxygen
      deficit (MAOD), muscle glycogen concentration and blood lactate concentration of
      6 fit Standardbred horses were measured on 3 occasions 7 days apart (Trials 1, 2
      and 3). Between Trials 2 and 3, strenuous exercise intended to deplete muscle
      glycogen was performed by exercising horses on the treadmill on 3 consecutive
      days. Strenuous exercise resulted in reduction of muscle glycogen concentration
      by at least 55% (from mean +/- s.e. 155.1 +/- 5.6 mmol/kg, wet weight, before
      Trial 2 to 55.4 +/- 5.5 mmol/kg before Trial 3; P < 0.05). VO2max was similar in
      Trials 2 and 3 (140.4 +/- 5.4 ml O2/kg bwt and 141.8 ml +/- 6.2 ml O2/kg,
      respectively). Run time to fatigue during a single high-speed exercise test
      (253.9 +/- 33.3 s and 153.8 +/- 16.4 s, P < 0.05), accumulated oxygen deficit (95
      +/- 13.2 ml O2/kg and 35 +/- 13.9 ml O2/kg, P < 0.05) and blood lactate
      concentration at the end of the sprint (17 +/- 1.2 mmol/l and 10.5 +/- 1.1
      mmol/l, P < 0.05) were less during Trial 3 than Trial 2. These data suggested
      that repeated strenuous exercise that causes muscle glycogen depletion results in
      impairment of anaerobic, but not aerobic, metabolism.

PMID- 10659272
TI  - Muscle adenine nucleotide degradation during submaximal treadmill exercise to
      fatigue.
AB  - The aim was to investigate metabolic response in muscle during submaximal
      treadmill exercise to fatigue, with a special emphasis on adenine nucleotide
      degradation products such as inosine monophosphate (IMP) in muscle and
      hypoxanthine, xanthine and uric acid in plasma. Five Standardbred trotters
      performed treadmill exercise on 2 occasions, once at 7 m/s and once at 10 m/s.
      Venous blood samples were taken at rest, during exercise and at the end of
      exercise. Muscle biopsies were taken before and after exercise and muscle
      temperature was measured before and after exercise. Running time differed among
      horses and was 48-58 min at 7 m/s and 10-15.5 min at 10 m/s. Both lactate and
      uric acid concentrations in plasma showed a gradual increase during exercise at
      both 7 and 10 m/s. At the end of exercise, values for uric acid were higher and
      values for lactate lower at 7 m/s compared with at 10 m/s. No marked changes were
      seen in plasma concentrations of hypoxanthine or xanthine with exercise. Muscle
      glycogen decreased after exercise at both 7 and 10 m/s with a marked depletion
      seen in some fibres. Muscle lactate concentrations increased after exercise at
      both 7 m/s and at 10 m/s. No significant changes were seen in adenosine
      triphosphate (ATP), ADP and AMP concentrations, whereas IMP concentrations
      increased after exercise at both 7 m/s and at 10 m/s. The results of this study
      indicate that AMP deamination occurs with submaximal exercise and that
      development of fatigue may be related to adenine nucleotide degradation in
      muscle.

PMID- 10659273
TI  - Skeletal muscle Na(+)-K(+)-ATPase and K+ homeostasis during exercise: effects of
      short-term training.
AB  - The objective of this study was to determine the effects of 10 consecutive days
      of moderate intensity training on 1) the concentration of middle gluteal muscle
      Na(+)-K(+)-ATPase as determined by vanadate-facilitated 3H[ouabain binding; and
      2) plasma potassium regulation before, during and after exercise at 100% of the
      pre-training maximum rate of oxygen consumption (VO2max). Six mature, unfit
      Thoroughbred horses completed both incremental (for determination of VO2max) and
      high-intensity exercise protocols before (HI1) and after (HI2) training. There
      additional horses undertook no training or exercise tests and served as controls
      for determination of middle gluteal muscle Na(+)-K(+)-ATPase concentration.
      Training consisted of 10 consecutive days of running at 55% VO2max for 60 min per
      day (13-14 km/day). For each high intensity exercise protocol, horses completed a
      10 min warm-up at 50% VO2max, followed by exercise at 100% of pre-training VO2max
      (6 degrees incline, mean speed 9.8 m/s) until fatigue. Training resulted in a
      13.8% increase in resting plasma volume (pre: 20.9 +/- 0.8 l; post: 23.8 +/- 0.9
      l; P = 0.03), and an 8.9% increase in VO2max (pre: 142 +/- 4 ml/kg/min; post: 155
      +/- 4 ml/kg/min; P = 0.004) during HI. Peak values for plasma potassium
      concentration and content during exercise decreased by 13% (P = 0.02) and 7% (P =
      0.0002), respectively, after training whereas training had no effect on increases
      in packed cell volume, plasma total solids, and erythrocyte K+ concentration and
      content during exercise. Following training, there was also a significant (23%)
      increase in Na(+)-K(+)-ATPase concentration in biopsies of middle gluteal muscle,
      as measured by vanadate-facilitated 3H[ouabain binding. We conclude that 10 days
      of moderate intensity exercise results in increases in skeletal muscle Na(+)-K(+)
      ATPase and attenuation in the elevation in plasma K+ during high intensity
      exercise at the same absolute workload. The increase in middle gluteal muscle
      Na(+)-K(+)-ATPase concentration is consistent with decreases in K+ efflux from
      working muscle during exercise.

PMID- 10659274
TI  - Muscular and metabolic responses to moderate-intensity short-term training.
AB  - The objectives of this study were to determine the effects of 10 consecutive days
      of moderate-intensity training on 1) the muscular metabolic response to exercise
      at 100% of the pre-training maximum rate of oxygen consumption (VO2max); and 2)
      mitochondrial enzyme markers (citrate synthase, CS; succinate dehydrogenase, SDH;
      3-hydroxy-acyl-CoA dehydrogenase, HAD) of oxidative capacity in middle gluteal
      muscle. Six mature, unfit Thoroughbred horses completed both incremental (for
      determination of VO2max) and high-intensity exercise protocols before (HI1) and
      after (HI2) training. Training consisted of 10 consecutive days of running at 55%
      VO2max for 60 min per day (13-14 km/day). For the HI, horses completed a 10 min
      warm-up, followed by exercise at 100% of pre-training VO2max (mean speed 9.8 m/s)
      until fatigue. Training resulted in an 8.9% increases in VO2max (Pre: 142 +/- 4
      ml/kg bwt/min; Post: 155 +/- 4 ml/kg bwt/min) and a 24% increase in run time to
      fatigue during HI. Whereas VO2 during HI was not altered by training, peak values
      for VCO2 and R were significantly lower following training. Compared to HI1,
      there was a 45% reduction in the net rate of muscle glycogenolysis during HI2.
      Peak (end exercise) values for plasma and muscle lactate concentrations decreased
      by 22 and 23%, respectively, after training. Training also attenuated the
      exercise-associated increase in plasma norepinephrine, but there was no effect on
      plasma epinephrine concentrations. Maximal activities of CS, SDH, and HAD were
      unaltered by training. We conclude that 10 days of moderate-intensity exercise
      results in decreases in muscle glycogenolysis and anaerobic metabolism during
      high-intensity exercise at the same absolute workload. Furthermore, development
      of measurable increases in mitochondrial oxidative potential may not be required
      for expression of these metabolic adaptations in early training.

PMID- 10659275
TI  - Skeletal myosin heavy chain composition and carriage training.
AB  - Three different myosin heavy chain (MHC) isoforms have been identified in the
      equine gluteus medius muscle: the slow or MHC-I and the 2 fast MHC-IIA and MHC
      IIX isoforms. They are distributed in 3 fibre types containing a single MHC (I,
      IIA, IIX) and 2 hybrid types co-expressing 2 isoforms (I + IIA, IIA + IIX). The
      aim of this study was to determine if heavy carriage training alters skeletal MHC
      composition in horses. Fourteen Andalusian mares age 42-46 months were used.
      Seven horses were used as controls to estimate the effects of growth on muscle.
      The remaining 7 horses underwent a training programme based on carriage exercise
      for 8 months. The intensity of exercise was individually adjusted to each horse
      according to a standardised exercise test. Gluteus medius muscle biopsies were
      analysed biochemically for MHC composition by electrophoresis,
      immunohistochemically for fibre types with specific anti-MHC monoclonal
      antibodies, and histochemically for fibre type areas, fibre oxidative capacity
      and capillaries. After training, MHC-IIX decreased and MHC-I increased. The
      percentages of type IIX and IIAX (i.e. fibres co-expressing MHCs IIA and IIX)
      fibres decreased, whereas the percentage of type I fibres increased. Neither MHC
      IIA composition nor type IIA fibre percentage changed with training. The training
      had no significant effect on fibre areas and capillaries, but the percentage of
      fibres with high oxidative capacity increased. The control group showed no
      changes in muscle variables after the 8 month training period. These results
      suggest that carriage training alters MHC composition in equine skeletal muscle,
      reflecting a conversion of MHC isoforms in the order IIX-->IIA-->I and suggesting
      a reduction in the velocity of shortening of the muscle, but an increase in
      fatigue resistance.

PMID- 10659276
TI  - Blood glucose clearance after feeding and exercise in polysaccharide storage
      myopathy.
AB  - Polysaccharide storage myopathy (PSSM) in Quarter Horses (QH) and QH crosses is a
      glycogen storage disorder in which blood glucose clearance and insulin
      sensitivity, following an i.v. or oral glucose challenge, are enhanced. Exercise
      is known also to enhance glucose uptake into skeletal muscle in many animal
      species. Therefore, the purpose of this study was to compare the effect of
      exercise on glucose clearance in PSSM and control horses when an oral
      carbohydrate meal (8 Mcal sweet feed) was fed following either 12 h fasting alone
      (NEX protocol) or following fasting and a standard exercise protocol (EX
      protocol). In the NEX protocol, horses fasted 12 h and then were fed 8
      megacalories (Mcal) of sweet feed (2.3 kg). In the EX protocol, horses were fed
      sweet feed 2 h after an exercise test (SET). Blood glucose was analysed for < 480
      min after feeding. Muscle biopsies were taken before and after the EX protocol.
      With the NEX protocol, the mean of all blood glucose and insulin concentrations
      were significantly lower in fed-PSSM horses than controls (P < 0.013). The EX
      protocol in control horses caused a less pronounced percentage change in glucose
      concentration from baseline following feeding compared to the NEX protocol (mean
      peak EX 26.5% vs. NEX 70.2%, respectively) (P < 0.0003). In PSSM horses, the EX
      protocol also resulted in a lower percent change in glucose concentration
      following feeding compared to the NEX protocol (44.7 vs. 67.5%, respectively) (P
      = 0.021). The magnitude of the difference in percentage change of blood glucose
      concentration with the EX protocol was less in PSSM than that seen for controls
      (mean peak PSSM-EX 44.7% vs. 26.5% for controls, respectively) (P < 0.006). No
      significant differences in the insulin:glucose ratios were found for control
      horses between NEX and EX. In PSSM horses, the insulin:glucose ratio was
      significantly increased in the EX vs. NEX. In conclusion, exercise in normal
      horses results in enhanced glucose clearance following feeding without altering
      insulin:glucose ratios. At rest, PSSM horses have lower insulin:glucose ratios
      after feeding than normal horses, however, exercise in PSSM horses significantly
      increases insulin:glucose ratios. This may explain the beneficial effect of daily
      exercise for preventing rhabdomyolysis in horses with PSSM.

PMID- 10659277
TI  - Effects of conditioning horses with lactate-guided exercise on muscle glycogen
      content.
AB  - The effects of 3 different conditioning programmes on muscle glycogen
      concentration in horses were examined. Speed of exercise was selected according
      to the blood lactate values for each horse derived from a standardised exercise
      test before beginning a conditioning programme. Six 2-year-old Haflinger
      stallions were assigned randomly to one of 3 conditioning programmes according to
      a 6 x 3 latin square design: 45 min at their individual v1.5 or v2.5 and 25 min
      at v4. Each conditioning programme lasted 6 weeks (21 exercise sessions),
      followed by 5 weeks without conditioning (resting period). All exercise was
      carried out on a treadmill inclined at 17%. Muscle biopsies were taken 5 times
      from the gluteus medius muscle at 2 cm and 6 cm depth: before the start and in
      the middle of the conditioning period, then at Days 2, 9 and 35 after the last
      exercise session. It was found that glycogen concentration was not affected by
      conditioning until 9 days after finishing conditioning at v1.5 and v2.5 for 45
      min (P < 0.05). By this time glycogen concentration in the muscle samples taken
      at 6 cm depth increased by 47 and 48%, respectively, and remained elevated until
      the end of the resting period. It was concluded that conditioning at lower
      intensity and for longer duration seemed to increase glycogen stores in the
      muscle while faster intensity but shorter duration exercise did not. To increase
      the likelihood of measuring effects of conditioning programmes on muscle
      variables, sampling should be done at different depths of a muscle and at several
      days after finishing a conditioning programme.

PMID- 10659279
TI  - Incremental treadmill exercise until onset of fatigue and its relationship to
      metabolic response and locomotion pattern.
AB  - The aim was to study metabolic response and locomotion pattern in Standardbred
      trotters during incremental treadmill exercise performed by increasing speed by 1
      m/s in 1 min steps (start 7 m/s) until the onset of fatigue. The test protocol
      included determination of oxygen uptake, heart rate (HR), stride length (SL) and
      stride frequency (SF). Venous blood samples were collected at rest, at the end of
      each exercise step and after 30 min of recovery. Muscle biopsies were taken at
      rest and post exercise and muscle temperature was measured after exercise. As
      horses fatigued at different speed steps (9-11 m/s), variation was seen in
      running time (180-300 s), oxygen uptake (109-170 ml/kg bwt min), HR (200-225
      beats/min), SL (4.4-5.7 m) and SF (116-130 strides/min) at the last speed step.
      Increased mean plasma lactate concentration (20.5 mmol/l) was seen at onset of
      fatigue and increased mean uric acid concentration after 30 min of recovery
      (112.8 mumol/l). After exercise, a decrease was seen in muscle ATP (7.1 mmol/kg
      d.w.), creatine phosphate (43.9 mmol/kg d.w.) and glycogen (160 mmol/kg d.w.),
      and an increase was seen in ADP (0.3 mmol/kg d.w.), AMP (0.18 mmol/kg d.w.), IMP
      (5.8 mmol/kg d.w.) and lactate (100.8 mmol/kg d.w.). At onset of fatigue, muscle
      temperature varied from 39.9-41.4 degrees C. Running time correlated with SL (r =
      0.86), with an increase in IMP (r = 0.79) and AMP (r = 0.70) post exercise and
      with plasma uric acid concentration (r = 0.74) at 30 min of recovery. SF
      correlated negatively with the increase in ADP after exercise (r = 0.85). The
      results of this study indicate that running time during incremental treadmill
      exercise until the onset of fatigue is related to locomotion pattern and to a
      marked degree of anaerobic metabolism, especially adenine nucleotide degradation.

PMID- 10659278
TI  - Metabolic and hormonal changes after exercise in relation to muscle glycogen
      concentrations.
AB  - To test whether, in horses, the concentration of muscle glycogen can be
      influenced by increasing the uptake of glucose into the muscle cells or by
      providing a gluconeogenic precursor, 9 trained half-bred riding horses performed
      on a treadmill a 1.5 h competition exercise test (CET). Each horse performed CET
      3 times and 30 min after CET, each was given one of the following solutions:
      isotonic glucose-electrolyte (GE) solution, GE supplemented with 50 g leucine
      (GEL) to increase insulin secretion, or GE supplemented with 200 ml propionic
      acid (GEP), a gluconeogenic precursor. Administration of GE solutions caused no
      increase in plasma glucose concentration. The highest concentration of insulin
      was measured after GEL, but also in the GE group the concentration of insulin
      increased. GEP completely inhibited the increase in insulin concentration.
      Concentration of glucagon was increased 6 and 22.5 h after CET. None of the post
      exercise treatments influenced significantly the glycogen content at 22.5 h after
      CET. This indicates that neither i) elevation of insulin concentration to
      increase muscle-uptake of glucose, nor ii) increase in the availability of a
      glucose precursor, propionic acid, was able to increase accumulation of glycogen
      in the middle gluteal muscle.

PMID- 10659280
TI  - Standardisation of muscular biopsy of gluteus medius in French trotters.
AB  - Morphometric measurements were taken from 41 French trotters of various ages and
      both sexes. Biopsy location was determined for the dorsal compartment as being
      one-third of the distance from the tuber sacrale to the tuber coxae and for the
      ventral compartment as being one-third of the distance from the tuber coxae to
      the caudal Cd1-Cd2 intervertebral joint. Ten horses were biopsied at these 2
      sites at a sampling depth equal to half the total depth of the compartment as
      measured by ultrasonography. The percentage of slow and fast myosin heavy chain
      fibres was measured by using an immunoenzymatic method. The depth of the dorsal
      and ventral compartments of the gluteus medius was significantly greater in males
      than in females. The depth of the ventral compartment was greater in the case of
      a straight hip than of a wide hip and was greater in young horses than in older
      horses. The ventral and the dorsal compartments were composed in the mid-portion
      of 81.3 and 75.6% of fast myosin heavy chains, respectively. It was concluded
      that the locations and sampling depths in the gluteus medius could be
      standardised in French trotters by taking into account anatomical references,
      sex, age and width of the hip.

PMID- 10659281
TI  - Contributions of equine exercise physiology research to the success of the 1996
      Equestrian Olympic Games: a review.
AB  - Following public concern about the weather conditions for the 1996 Olympic Games
      in Atlanta an international research programme was initiated. The primary
      objective of this effort was to identify strategies for ensuring welfare of
      horses competing in the heat. Field observations of horses during the endurance
      test of 3-day events in Europe, Canada, and the USA characterised the work effort
      of this form of competition; laboratory treadmill studies assessed limitations to
      performance of heat and humidity, explored the relationships of thermoregulatory
      demands to the phases of the competition and documented fluid and electrolyte
      losses. Estimates of energy expenditure and heat production during the endurance
      test were made. Strategies for facilitating heat dissipation were also studied in
      depth. Assessment of the effect of environmental conditions was based upon
      intensive climate monitoring using a modification of the Wet Bulb Globe
      Temperature index. Studies of heat acclimation provided a basis for
      recommendation of acclimatization times for horses before the Games. The results
      of all these studies guided the management of equine athletes at the 1996 Olympic
      Games and significantly advanced knowledge of thermoregulation in competitive
      horses.

PMID- 10659282
TI  - Thermoregulatory strategies during short-term exercise at different intensities.
AB  - Previously we have observed a decline in sweating rate (SR) during high intensity
      exercise in an incremental test protocol. In man, the sweating sensitivity
      (SR/degree C) has been shown to vary with exercise intensity. The aim of the
      present study was to determine if thermoregulatory responses in the horse, a
      prolific sweater with a high rate of metabolic heat production, were modified by
      exercise intensity. The effect of 3 separate exercise intensities (50 (S), 70 (M)
      and 90% (F) VO2peak on neck (SRN) and gluteal sweating rate (SRG), pulmonary
      artery (TPA), rectal (TREC) and skin temperatures on the neck (TSK-N) and gluteal
      region (TSK-G) were investigated. Horses were exercised for approximately 2 min
      at each exercise intensity in a randomised order. The rate of increase in TPA
      increased with exercise intensity (P < 0.05) (0.27 +/- 0.05, 0.43 +/- 0.04 and
      0.77 +/- 0.05 degree C/min during S, M and F, respectively. The TPA and TSK
      temperatures at the onset of sweating were not different between exercise
      intensities (P > 0.05). Despite the increased rate of heat production with
      increasing exercise intensity, sweating sensitivity decreased on both the neck (P
      < 0.05) (18.2 +/- 3.4 (S), 12.0 +/- 3.5 (M) and 2.9 +/- 0.7 (g/m2/min)/degree C
      (F)[ and gluteal region (P < 0.05) (8.9 +/- 2.0 (S), 5.1 +/- 1.7 (M) and 0.8 +/-
      0.3 (g/m2/min)/degree C (F)[. During exercise at 90% VO2peak sweating sensitivity
      and the rate of increase in skin temperature were markedly reduced compared to at
      70% VO2peak. The present investigation demonstrates that the drive to
      thermoregulate is overridden during short-term, high-intensity exercise,
      resulting in greater heat storage (TPA) as a result of a lower SR sensitivity.

PMID- 10659283
TI  - Sweating and skin temperature responses of normal and anhidrotic horses to
      intravenous adrenaline.
AB  - Anhidrosis has been recognised for over half a century, but despite some
      excellent epidemiological studies, there has been little progress in
      understanding the aetiology of the condition. Using a modified ventilated
      capsule, we obtained dynamic, quantitative data on sweating responses in
      anhidrotic horses and normal sweating controls from the same environment. Ten
      horses with current seasonal anhidrosis and 10 matched normal sweating controls
      were selected. Each horse was given two 10 min infusions of 1 and 2
      micrograms/kg/min adrenaline, separated by at least 6 h. Sweating responses and
      skin temperatures on the neck and gluteal region were measured. Plasma and sweat
      for analysis of total protein and electrolytes and plasma for analysis of
      adrenaline were collected. Anhidrotic horses produced significantly less sweat,
      had lower initial and peak sweat rates and a greater neck:gluteal ratio for sweat
      production. Plasma adrenaline at rest or at the time of peak sweating rate was
      not different between groups. In nearly three-quarters of the anhidrotic horses,
      the shape of the sweat rate against time curve was different compared to
      controls. Volume of sweat produced was significantly correlated with skin
      temperature on the neck of controls and anhidrotic horses and on the gluteal
      region of controls, but not anhidrotic horses. Plasma total protein and
      electrolyte concentrations were not different between groups. There were
      significant differences in sweat electrolyte concentrations between controls and
      anhidrotic horses. These differences were reduced when sweat electrolytes were
      expressed per g of total protein, and no differences existed when expressed as
      g/m2. This study has provided insight into the response of anhidrotic horses to
      beta 2 adrenergic stimulation and may be a useful technique to investigate this
      condition.

PMID- 10659284
TI  - Effects of frusemide on electrolyte and acid-base balance during exercise.
AB  - This study was undertaken to evaluate the effects of frusemide on the
      concentration of plasma electrolytes and the relationship between changes in
      electrolyte concentration and the simultaneous changes in acid-base balance in
      arterial and venous blood during intense exercise. Five exercise-conditioned
      Thoroughbred horses were exercised on a high-speed treadmill at a slope of 10% at
      speeds known to exceed VO2max. Horses participated in 3 randomised exercise
      trials in which they received either placebo (control), low-dose frusemide (0.5
      mg/kg bwt), or high-dose frusemide (1.0 mg/kg) 4 h prior to exercise. Arterial
      and mixed venous blood samples were drawn before, during and after intense
      exercise. Packed cell volume (PCV), plasma protein, plasma electrolyte, plasma
      lactate concentrations and acid-base balance were determined. Frusemide at both
      dosages induced a significant metabolic alkalosis associated with a decrease in
      plasma chloride[ in both arterial and mixed venous blood. There was a highly
      significant correlation between the strong ion difference (SID) and bicarbonate[
      in all blood samples. The effects of frusemide on electrolyte concentration and
      acid-base balance were largely due to changes in SID.

PMID- 10659285
TI  - Frusemide and weight carriage alter the acid:base responses of horses to
      incremental and to brief intense exertion.
AB  - We speculated that frusemide would attenuate the acidosis associated with intense
      exertion, and that weight carriage would mitigate this effect. Therefore, in each
      of 2 experiments we measured pulmonary artery and systemic arterial blood pH,
      PCO2, PO2 and pulmonary artery temperature in 9 horses during exertion on a
      treadmill after each of 3 treatments. The treatments were: 1) injection of saline
      solution (C), 2) injection of frusemide (1 mg/kg bwt, i.v. 4 h before running)
      (FU) and 3) injection of frusemide (F) as for FU and the horses carried weight
      equal to that lost in the 4 h after frusemide administration (FL). In Experiment
      1 the horses performed an incremental exercise test of 90 s at each of 4, 7 and 9
      m/s (4 degrees incline). In Experiment 2, the horses ran on a treadmill inclined
      at 4 degrees for 3 min at 3 m/s, at approximately 120% VO2max for 2 min, and 3
      m/s for 5 min. Blood samples for measurement of blood pH, PCO2 and PO2 were
      collected into heparinised glass syringes. Values were adjusted for changes in
      pulmonary artery blood temperature. Data were analysed using a 2 way repeated
      measures ANOVA. There was a consistent pattern in both experiments characterised
      by a mild alkalosis or mitigated acidosis, compared to C, at rest and during
      exercise and recovery after FU (P < 0.05). Weight carriage blunted or inhibited
      the effect of frusemide during exercise and recovery. In experiment 2, at the end
      of the sprint, FU treatment resulted in a less severe acidosis than did C or FI:
      mixed venous pH for C, FU, and FL at the end of the sprint were 6.93, 6.98 and
      6.93, respectively (P interaction = 0.038), mixed venous base excess was -12.4, 
      9.91, and -11.8 mmol/l, respectively, and arterial base excess of -1.44, -12.7
      and -14.1 mmol/l (P interaction = 0.006) respectively. These effects persisted
      into recovery. A similar pattern of responses occurred during the incremental
      exercise test, with weight carriage offsetting the alkalinizing effect of
      frusemide. We conclude that frusemide attenuates the acidosis of intense exertion
      and that carriage of weight prevents this effect.

PMID- 10659286
TI  - Partition of plasma hydrogen ion concentration changes during repeated sprints.
AB  - Increases in blood [H+] and lactic acid [La-] attend fatigue. We applied
      Stewart's physiological model of acid-base status and simple regressions to
      assess the importance of independent variables and [La-] on [H+] during repeated
      sprints. Eight well-conditioned Arabians performed 9 sprints. Plasma from jugular
      vein samples was analysed for pH, PCO2, Na+, K+ and Cl-. Plasma [La-] was
      calculated from blood [La-], plasma [H+] from pH, SID from Na+, K+, Cl- and La-,
      Atot from pH, PCO2 and SID. Peaks for SID, PCO2 and [H+] were reached at sprint
      1, -2 and -3, respectively. At sprint 3, the 5.7 nmol/l peak in [H+] was
      partitioned into 2.3, 2.7 and 0.7 nmol/l for Atot, PCO2 and SID, respectively.
      From sprint 3 to sprint 9, increases in Atot and decreases in SID tended to
      increase [H+] but were counteracted by a steady decrease in PCO2 that determined
      the progressive decrease in [H+]. Therefore PCO2 was the dominant determinant of
      [H+] during 9 repeated sprints, and the expected major effect of [La-] was
      moderated in the SID by opposing increases in [Na+] and [K+]. In the work-adapted
      phase (sprints 3-9), decreasing [H+] was correlated positively with PCO2 (r =
      0.997, P < 0.001) but negatively with La- (r = -0.986, P < 0.001). Respiration
      was therefore completely compensating for the effects of metabolism on [H+].
      During the transition from rest to sprint 3 (peak plasma [H+]), increasing [H+]
      was highly correlated (r = 0.99, P = 0.011) with [La-] but no other variable. The
      empirical and physiological analyses were consistent with one another during the
      work-adapted phase, but emphasis was placed on [La-] by the regression analysis,
      in contrast to PCO2 by the Stewart analysis, during the rest-work transition.

PMID- 10659287
TI  - Effects of electrolyte and glycerol supplementation on recovery from endurance
      exercise.
AB  - Incomplete recovery from endurance exercise after an overnight rest period is
      reflected by persisting weight loss and an elevated plasma aldosterone
      concentration, even in successful competitors. To determine whether
      supplementation with high doses of electrolytes, with or without glycerol,
      enhances recovery, the following were measured in 6 Arabian horses before and
      after completion of a 60 km treadmill exercise test simulating an endurance ride
      and after 12, 24, 48, and 72 h of recovery: bodyweight; plasma osmolality; plasma
      concentrations of protein, electrolytes, aldosterone and cortisol; and urine and
      faecal electrolyte concentrations. Before and during the exercise test, horses
      were supplemented with a total of 2.4 ml/kg bwt of water (W); 0.2 g/kg bwt KCl
      and 0.4 g/kg bwt NaCl in 2.4 ml/kg bwt of water (E); or 0.2 g/kg bwt KCl and 0.4
      g/kg bwt NaCl in 2.4 ml/kg bwt (3 g/kg bwt) of glycerol (GE). Although weight
      loss after completion of the simulated ride was greater (P < 0.01) for W (3.2%)
      than for E and GE (1.0 and 0.9%, respectively), horses supplemented with E or GE
      experienced further weight loss by 24 h after the simulated ride (2.2 and 2.1%
      for E and GE, respectively) while bodyweight with W remained unchanged (3.0%)
      from the finish value. After 48 h of recovery, bodyweight was not different from
      the starting values with E and GE but remained decreased (P < 0.01) with W
      throughout the recovery period (2.2% persisting weight loss after 72 h of
      recovery). Plasma osmolality and plasma Na+ and Cl- concentrations increased (P <
      0.01) and plasma protein concentration decreased (P < 0.01) after the exercise
      test with E and GE but were unchanged with W. Plasma osmolality and protein and
      electrolyte concentrations returned to pre-exercise values within 12 h of
      recovery with the exception of a persistent increase in plasma Na+ concentration
      with GE. The greatest plasma aldosterone concentration was measured after 12 h of
      recovery with W (1357 pmol/l) and was greater (P < 0.02) than that with E and GE
      (24 and 304 pmol/l, respectively). Urine production during the simulated ride
      increased (P < 0.01) with GE and resulted in loss of approximately 20% and
      essentially 100% of supplemented Na+ and K+, respectively. In contrast,
      electrolyte losses in faeces were unaffected by electrolyte or glycerol
      supplementation. In conclusion, supplementation with high doses of electrolytes
      as hypertonic oral pastes attenuated weight loss during a simulated endurance
      ride (by enhancing voluntary water intake); however, it did not prevent
      development of significant weight loss during the initial 24 h of recovery.
      Glycerol administration resulted in no benefits, and actually increased urine
      electrolyte losses, in comparison to supplementation with electrolytes alone.

PMID- 10659288
TI  - Environmental stress and 3-day eventing: effects of altitude.
AB  - Three-day event horses are subject to various external environmental stresses
      including changes in ambient temperature, humidity, altitude, and test severity.
      Considerable research on the adverse effects of increased heat and humidity
      preceded the 1996 Olympic Summer Games in Atlanta, Georgia USA, but no research
      has been done previously on the effects of altitude on 3-day eventing. Physical
      and venous blood gas data were collected on horses (n = 24) competing in the High
      Prairie Preliminary (CCN*) and Intermediate (CCN**) 3-day events and Preliminary
      Horse Trials in Parker, Colorado (1900 m above sea level). Despite the increased
      altitude, only post exercise rectal temperature and pH were higher (P < 0.05)
      whereas heart rate (HR), [K+], and ionized calcium (ICa++) were lower (P < 0.05)
      in 3-day event horses compared to horse trial horses. All other variables
      (respiratory rate [RR], PCV, [Hb], PCO2, [tCO2], [HCO3-], BE, and [Na+]) were not
      different between groups (P > 0.05). When these preliminary horse trial horses in
      Colorado were compared to those previously studied at preliminary horse trials at
      sea level in Arizona, post exercise HR and RR were higher (P < 0.05) and pH,
      PCO2, [tCO2], [HCO3-], BE and [iCa++] were lower (P < 0.05) at altitude. These
      data show that increased altitude (1900 m above sea level) was more stressful for
      3-day event horses, but did not result in the severe physiological changes and
      inability to complete prescribed exercise tests seen in previous studies with
      increased heat and humidity. It is clear from these and previous data that
      increased heat and humidity are the more important environmental stressors in 3
      day eventing.

PMID- 10659289
TI  - Sweat production and localisation of carbonic anhydrase in the equine sweat gland
      during exercise at two ambient temperatures.
AB  - The aim of this investigation was to study sweat production during exercise at 2
      ambient temperatures (20 degrees C and 35 degrees C) and the concurrent
      localisation of carbonic anhydrase (CA) in the sweat gland. Horses develop
      alkalosis during prolonged exercise and the sweat contains HCO3-. Carbonic
      anhydrase is therefore of interest since it catalyses the reaction CO2 + H2O<-
      >HCO3- + H+. Four standardbred trotters performed an exercise test. Skin biopsies
      were taken from the neck, and sweat rate, blood and skin temperatures were
      measured. There was a close relationship between sweat rate, temperatures and
      work intensity at 20 degrees C. Temperatures and sweat rate were higher at 35
      degrees C and did not fall when the work intensity dropped. A significant
      decrease in the sweat gland cell area was found after exercise at 35 degrees C
      with an accompanying decrease of vesicles. Strong CA activity was present at the
      luminal cell membrane and weaker basolaterally. The staining intensity increased
      after exercise. We suggest that CA might be of importance for counteracting the
      alkalosis developed after exercise by delivering HCO3- for generation of the
      alkaline pH in sweat.

PMID- 10659290
TI  - Effect of ambient temperature and humidity on pulmonary artery temperature of
      exercising horses.
AB  - Six healthy Thoroughbred mares were trained to run on a high-speed treadmill and
      were conditioned for approximately 5 weeks. Each horse performed 6 identical
      standardised exercise tests (SET) 5 to 7 days apart. Each SET was performed under
      different ambient laboratory conditions: low temperature/low humidity (LL) 20.2
      degrees +/- 0.6 degree C, 53.6 +/- 4.1%; low temperature/high humidity (LH) 19.7
      +/- 0.6 degrees C, 86.7 +/- 4.2%; medium temperature/low humidity (ML) 24.6 +/-
      0.2 degrees C, 58.7 +/- 3.7%; medium temperature/high humidity (MH) 24.7 +/- 0.3
      degrees C, 87.5 +/- 1.4%; high temperature/low humidity (HL) 31.1 +/- 0.6 degrees
      C, 41.6 +/- 3.5%; and high temperature/high humidity (HH) 30.6 +/- 0.2 degrees C,
      84.4 +/- 3.6%. Horses completed the 46 min SET, became fatigued or exercise was
      terminated when a pulmonary artery temperature (PAT) of 41.5 degrees C was
      reached. During a 30 min recovery period, horses stood quietly on the treadmill.
      Only one trial was terminated due to fatigue; in all other trials horses
      completed the 46 min SET or the trial was terminated when PAT = 41.5 degrees C.
      The relationships among run time (min) or PAT (degree C), ambient temperature and
      % relative humidity were defined by multiple linear regression analysis. Run time
      (min) = 90.9 - (1.39 x ambient temperature degree C) - (0.236 x relative humidity
      %). Approximately 54% of the variation in run times was explained by variation in
      environmental conditions, indicating that ambient temperature and humidity
      contribute substantially to the rate of rise in PAT. Run times to a PAT of 41.5
      degrees C were significantly shorter (P < 0.000001) in HH than in other groups
      during the SET. Approximately 63% of the variation in PAT at the end of exercise
      was due to ambient temperature and humidity. In general, the longer the exercise
      time, the better the correlation among PAT, ambient temperature and relative
      humidity. Rectal temperature increased significantly (P < 0.0001) during the
      recovery period only in horses in the HH group, indicating that heat dissipation
      during recovery may have been impaired by environmental conditions. This study
      demonstrates that hot humid conditions result in more rapid rate of rise in PAT
      for horses undertaking identical exercise tests.

PMID- 10659291
TI  - Effects of potassium intake on potassium, sodium and fluid balance in exercising
      horses.
AB  - The aim of this study was to investigate the adaptation to an increased potassium
      (K+) intake in horses and to study whether the regulation of the post exercise
      K+, sodium (Na+) and fluid balances were altered by an increased K+ intake. Four
      Standardbred horses were fed 2 levels (4.1 and 5.4 mmol/kg bwt/day) of K+ for 17
      days in a crossover design. The effects on K+, Na+ and fluid balance were studied
      both at rest and in response to 29 km exercise. K+, Na+ and fluid intakes and
      outputs were balanced within 24 h after a new diet had been introduced.
      Adaptation consisted primarily of an increased urinary K+ excretion, later
      followed by an increase in faecal excretion. The increased urinary K+ excretion
      was associated with an increased mass of urine (1.2-1.4 kg/day) compensated for
      by an increased water intake. The sweat Na+ concentration was increased on the
      highest K+ intake (from 123 +/- 5 mmol/l to 138 +/- 3 mmol/l) and the urinary Na+
      excretion was lower post exercise on this diet. There were no differences in the
      magnitude of post exercise hypokalaemia between the diets, and plasma K+
      concentration was still reduced 24 h post exercise even when the horses were fed
      the higher K+ diet. Adaptation to an increased K+ intake was rapid in these
      horses and consisted mainly of an increased urinary excretion. The response to
      exercise was unaltered by the increased K+ intake, except for an increased Na+
      concentration in sweat.

PMID- 10659292
TI  - Electrolyte and glycerol supplementation improve water intake by horses
      performing a simulated 60 km endurance ride.
AB  - To replace electrolytes lost in sweat during endurance competitions, riders
      frequently supplement horses with hypertonic oral electrolyte pastes. To
      determine whether this practice and concurrent administration of the so-called
      hyperhydrating substance glycerol are of benefit, weight loss, voluntary water
      intake, plasma osmolality, and plasma protein and electrolyte concentrations were
      measured in 6 Arabian horses supplemented with a total of 2.4 ml/kg bwt of water
      (W); 0.2 g/kg bwt KCl and 0.4 g/kg bwt NaCl in 2.4 ml/kg bwt of water (E); or 0.2
      g/kg bwt KCl and 0.4 g/kg bwt NaCl in 2.4 ml/kg bwt (3 g/kg bwt) of glycerol (GE)
      before and during a treadmill exercise test simulating a 60 km endurance ride.
      Weight loss was greater (P < 0.01) with W (3.2%) than with E and GE (1.0% and
      0.9%, respectively) and was associated (r = -0.85, P < 0.0001) with less (P <
      0.01) water intake with W (12.2 l) than with E or GE (23.5 l and 25.8 l,
      respectively). Plasma osmolality increased to a greater extent (P < 0.01) with GE
      than with E and was unchanged with W. In contrast, plasma protein concentration
      decreased (P < 0.01) in the later stages of the simulated ride with E and GE,
      reflecting plasma volume expansion, but remained unchanged with W. Plasma Na+ and
      Cl- concentrations increased (P < 0.01) with E and GE and were greater (P < 0.01)
      than values for W during the second half of the 60 km simulated ride. Despite
      administration are large amounts of potassium with E and GE, plasma K+
      concentration was decreased (P < 0.01) at the end of the rest breaks during the
      simulated ride and after 60 min of recovery with all supplements. Adverse effects
      of administration of hypertonic oral electrolyte pastes were not observed and
      decreases in plasma protein concentration within 30 min after drinking with all
      supplements suggested that intestinal absorption was well maintained during the
      simulated endurance ride. In conclusion, electrolyte supplementation in the form
      of hypertonic oral pastes improved water intake during endurance exercise but
      concurrent glycerol administration provided no additional benefits in comparison
      to supplementation with electrolytes alone.

PMID- 10659293
TI  - Electrolyte vs. glucose-electrolyte isotonic solutions for oral rehydration
      therapy in horses.
AB  - An isotonic electrolyte solution with a composition similar to equine sweat was
      compared to an isotonic glucose-glycine-electrolyte solution for oral rehydration
      therapy in exercising horses. Ten horses were dehydrated by using frusemide and
      allocated randomly to receive 4 different oral solutions: isotonic sweat-like
      electrolyte solution, half-strength hypotonic electrolyte solution, isotonic
      glucose-glycine-electrolyte solution, and plain water. Solutions were given by
      nasogastric tube using the same volume as the bodyweight lost by each horse.
      Blood samples were collected before and throughout 6 h of the rehydration period.
      Results showed that all solutions recovered pre-frusemide values of packed cell
      volume (PCV) and total plasma protein (TP) in a similar fashion. No changes for
      Na+ values were observed during the rehydration period when the isotonic sweat
      like solution was used. However, a significant hyponatraemia was induced
      throughout rehydration when the other 3 solutions were given, especially when
      hypotonic solution and water were used. Osmolality values did not change when
      both isotonic solutions were administered; but a significant hypotonicity was
      observed when hypotonic solution and water were given. When the isotonic sweat
      like solution was used, plasma Cl-, K+ and creatinine values recovered to
      premedication values significantly faster than the other 3 solutions. In
      conclusion, the isotonic sweat-like electrolyte was the best solution because it
      restored rapidly the fluid and plasma electrolyte imbalances. In contrast, the
      isotonic glucose-glycine-electrolyte solution impaired the plasma electrolyte
      imbalances.

PMID- 10659294
TI  - Chronological changes in superoxide-scavenging ability and lipid peroxide
      concentration of equine serum due to stress from exercise and transport.
AB  - It has been suggested that a variety of stresses on animals may accelerate their
      production of superoxide. Racehorses are considered to be exposed to substantial
      oxide stress due to transport and exercise for training and racing. To determine
      the effect of exercise and transport on racehorses in terms of superoxide and
      antioxidative ability, changes in the superoxide-scavenging ability of equine
      serum were observed using electron spin resonance (ESR). Changes in the
      concentration of lipid peroxide, which is produced in equine serum by superoxide,
      were also examined. The analysis revealed that lipid peroxide concentrations
      increased as a result of stress from exercise and transport. On the other hand,
      the superoxide-scavenging ability of equine serum showed a decline during
      transport, which is in sharp contrast to the increase seen immediately after a
      race due to the severe load exerted in exercise.

PMID- 10659295
TI  - Effect of frusemide and hypertonic saline on electrolytes during post exercise
      anaesthesia.
AB  - This study evaluated the effects of pre-exercise frusemide administration and
      hypertonic saline (H) infusion during anaesthesia on arterial pH, blood gases and
      electrolytes in 6 Thoroughbred horses anaesthetised immediately post exercise.
      Horses received either frusemide (F) (0.5 mg/kg, i.v.) or a saline placebo (P)
      injection 4 h prior to treadmill exercise. Exercise consisted of a 3 min warm-up
      at 40% VO2max followed by exercise to fatigue. Detomidine (40 micrograms/kg,
      i.v.) was given within 5 min of stopping and followed 5 min later by zolazepam
      tiletamine (1.25 mg/kg, i.v.) to induce anaesthesia. During maintenance of
      anaesthesia using isoflurane in O2, either isotonic saline solution (I) or 7.5% H
      (4 ml/kg, i.v.) was administered. Arterial blood was sampled at the following
      times: prior to (Pre-F/P) and 4 h after (Pre-ex) F or P administration, 1 min
      after fatigue (Fatigue), 5 min after induction of anaesthesia (Post-ind), and
      just prior to and 15, 30 and 60 min after beginning isoflurane (ISFL)
      anaesthesia. Arterial pH and blood gas tensions, pulmonary arterial blood
      temperature, plasma [lactate], total protein and plasma [Na+], [K+], and [Cl-]
      were measured. Data were analyzed using 2-way ANOVA for repeated measures (P <
      0.05). There were significant differences over time for all variables except
      total protein. Plasma [Na+] increased at Fatigue compared to Pre-F/P or Pre-ex in
      all treatment groups. Plasma [Na+] and [Cl-] increased during ISFL anaesthesia
      compared to Pre-F/P and Pre-ex in horses given H. During ISFL anaesthesia, plasma
      [Cl-] decreased compared to Pre-F/P in Group F+I horses. We conclude that acid
      base, blood gas, and electrolyte changes associated with F are unlikely to
      influence management of horses anaesthetised immediately following supramaximal
      exercise to fatigue. Hypertonic saline infusion may help restore plasma [Cl-]
      faster in hypochloraemic horses requiring anaesthesia immediately after strenuous
      exercise.

PMID- 10659296
TI  - Weak acid-concentration Atot and dissociation constant Ka of plasma proteins in
      racehorses.
AB  - The plasma proteins are a significant contributor to the total weak acid
      concentration as a net anionic charge. Due to potential species difference,
      species-specific values must be confirmed for the weak acid anionic
      concentrations of proteins (Atot) and the effective dissociation constant for
      plasma weak acids (Ka). We studied the net anion load Atot of equine plasma
      protein in 10 clinically healthy mature Standardbred horses. A multi-step
      titration procedure, using a tonometer covering a titration range of PCO2 from 25
      to 145 mmHg at 37 degrees C, was applied on the plasma of these 10 horses. Blood
      gases (pH, PCO2) and electrolytes required to calculate the strong ion difference
      ([SID] = [(Na(+) + K(+) + Ca(2+) + Mg(2+))-(Cl(-) + Lac(-) + PO4(2-))]) were
      simultaneously measured over a physiological pH range from 6.90-7.55. A nonlinear
      regression iteration to determine Atot and Ka was performed using polygonal
      regression curve fitting applied to the electrical neutrality equation of the
      physico-chemical system. The average anion-load Atot for plasma protein of 10
      Standardbred horses was 14.89 +/- 0.8 mEq/l plasma and Ka was 2.11 +/- 0.50 x 10(
      7) Eq/l (pKa = 6.67). The derived conversion factor (iterated Atot
      concentration/average plasma protein concentration) for calculation of Atot in
      plasma is 0.21 mEq/g protein (protein-unit: g/l). This value compares closely
      with the 0.24 mEq/g protein determined by titration of Van Slyke et al. (1928)
      and 0.22 mEq/g protein recently published by Constable (1997) for horse plasma.
      The Ka value compares closely with the value experimentally determined by
      Constable in 1997 (2.22 x 10(7) Eq/l). Linear regression of a set of experimental
      data from 5 Thoroughbred horses on a treadmill exercise test, showed excellent
      correlation with the regression lines not different from identity for the
      calculated and measured variables pH, HCO3 and SID. Knowledge of Atot and Ka for
      the horse is useful especially in exercise studies and in clinical conditions to
      quantify the mechanisms of the acid-base disturbances occurring.

PMID- 10659297
TI  - Factors affecting accumulation of lactate in red blood cells.
AB  - In horses, both the post exercise distribution of lactate between plasma and red
      blood cells (RBC) and the activity of lactate transporters on the RBC membrane
      vary widely between individuals. In this study, we investigated the effects of
      pH, time and temperature on lactate distribution in vitro, and compared the in
      vitro activity of lactate transporters with the accumulation of lactate into RBC
      in vivo. To accomplish this, we took venous blood samples at rest and after
      trotting races. The post exercise accumulation of lactate into RBC was shown to
      depend on the activity of lactate transporters. The results, in vitro, also
      indicate that pH, incubation time and temperature influence the activity of
      lactate transporters and the accumulation of lactate into RBC, underscoring the
      fact that in practice it is important to standardise the measurement conditions
      of lactate. These results support the view that whole blood lactate
      concentrations should be measured in estimating the accumulation of lactate from
      exercising muscles into the blood, because the effect of blood pH, temperature,
      time to centrifugation of the sample and also interindividual variation in
      lactate transport into RBC are therefore minimised.

PMID- 10659298
TI  - The effects of timing and amount of forage and grain on exercise response in
      thoroughbred horses.
AB  - There is considerable debate among horsemen about how to feed horses before
      exercise. Should horses be fed or fasted before work and when should hay be fed
      relative to grain and/or exercise? Three experiments were conducted to evaluate
      if feeding hay with and without grain affects glycaemic and haematological
      responses in Thoroughbred (TB) horses at rest and during a simulated competition
      exercise test (CET) on a high-speed treadmill. In Experiment 1, 6 TB horses were
      fed hay at 3 different times relative to a grain meal. Time of feeding hay
      affected glycaemic response, plasma protein and water intake post grain feeding.
      During Experiment 2, 4 TB horses were used in a 4 x 4 Latin square design to
      determine whether feeding grain with or without hay prior to a CET would affect
      substrate utilisation and exercise. Feeding grain reduced free fatty acid (FFA)
      availability and increased blood glucose disappearance during exercise (P <
      0.05). Feeding hay either along with grain or ad libitum the night before
      exercise resulted in reduced plasma volume (P < 0.05) and higher lactate
      production (P < 0.05) and heart rates (P < 0.05) during exercise. During
      Experiment 3, 4 TB horses were used in a 4 x 4 Latin square design experiment to
      determine whether feeding forage but no grain prior to CET would affect substrate
      utilisation and performance. Feeding only forage before exercise did not
      adversely affect performance. It was concluded that grain should be withheld from
      horses before exercise, but that small quantities of hay should be fed to ensure
      proper gastrointestinal tract function.

PMID- 10659299
TI  - Effect of diet on thoroughbred horses with recurrent exertional rhabdomyolysis
      performing a standardised exercise test.
AB  - Previous studies have associated recurrent exertional rhabdomyolysis (RER) with a
      diet high in soluble carbohydrate (CHO). The purpose of this study was to
      investigate the effect of 3 diets on clinical and metabolic parameters in 5
      Thoroughbred horses with RER and 3 healthy Thoroughbreds performing a
      standardised exercise test (SET). Two diets were formulated to meet energy
      requirements for the amount of exercise being performed in the form of CHO or fat
      (21.4 Mcal DE/day). The third diet was formulated to provide 135% of the DE of
      the other 2 diets in the form of an excessive amount of carbohydrate (28.8 Mcal
      DE/day). Diets were fed in a crossover design for 3 week blocks and then horses
      performed a near maximal SET. Changes in heart rate (HR), plasma lactate, plasma
      glucose, total plasma solids, packed cell volume (PCV), muscle lactate and muscle
      glycogen concentration were measured immediately prior to, during, and 5 min
      after exercise. Serum creatine kinase (CK) activity was measured prior to and 4 h
      post SET. A 2-way ANOVA was used to examine the effect of group and dietary
      treatment. When dietary treatments were compared, horses fed the high-CHO diet
      had a mean pre-SET PCV and pre-SET HR that was higher than horses fed the fat
      diet (P = 0.06 and P = 0.07, respectively). Pre-SET heart rates were highest in
      RER horses consuming the high-CHO diet compared to RER horses consuming the low
      CHO and fat diets (P = 0.02). Horses with RER had 4 h post SET CK activity
      greater than 400 u/l in 7/14 (50%) measurements compared to control horses which
      had CK activity greater than 400 u/l in 2/7 (29%) measurements. This study did
      not demonstrate a significant effect of diet on rhabdomyolysis, indicated by CK
      activity, or on the metabolic response to exercise. However, diet may have a
      calming effect on Thoroughbred horses with RER as manifested by decreased pre
      exercise heart rates and decreased pre-exercise PCV in horses fed the fat diet.

PMID- 10659300
TI  - Dietary protein influences acid-base responses to repeated sprints.
AB  - Dietary protein during conditioning and exercise must support additional needs
      while avoiding adverse metabolic effects. Ten Arabian horses were assigned
      randomly to 2 diets formulated to contain 7.5 or 14.5% crude protein and 12% fat.
      The low-protein diet (LP) was supplemented with lysine and threonine to match the
      levels of these amino acids in the high-protein diet (HP). Feed intake averaged
      8.1 kg/day. Dietary cation-anion difference was 181.6 and 260.4 mmol/kg for high
      and low protein, respectively. Following 9 weeks conditioning, horses performed a
      repeated sprint test: 3 min walk at 1.5 m/s and zero slope, followed by 3 min
      walk at 1.5 m/s, 5 min trot at 3.5 m/s, then six 1 min sprints at 10 m/s
      separated by 4 min walks all on a 6% slope, concluding with 30 min walk at 1.5
      m/s and zero slope. Blood samples (arterial, A, and venous, V) were taken at
      rest, during the last 15 s of each sprint, and at 5, 10, 20 and 30 min. of
      recovery. Samples were analysed for total protein (TP), lactate (La-), pH, PCO2,
      PO2, HCO3-, Na+, K+ and Cl-. Strong ion difference (SID+) and total weak acids
      (Atot) were calculated. Analysis of variance with repeated measures was used to
      evaluate the effects of exercise and recovery (time), diet and any interactions.
      Comparing LP to HP groups, plasma pH tended to be higher after the first sprint
      (V, P = 0.084; A, P = 0.014), and plasma HCO3- was higher overall (V, P = 0.0023;
      A, P = 0.094) during exercise and recovery. In both groups, pH declined; however,
      LP remained higher than HP. The decline in pH represents an exercise-induced
      acidosis which was attributable mainly to PCO2, especially during recovery, and
      to a tendency for a higher SID+ during most of exercise and recovery. The plasma
      La- response was lower, Cl- higher, suggesting that LP enhanced the lactate
      storage function of erythrocytes. Dietary protein restriction for 9 weeks
      moderated sprint-induced acidosis in fat-adapted horses.

PMID- 10659302
TI  - Dietary fat supplementation and equine plasma lipid metabolism.
AB  - Feeding of a fat-rich diet to horses may enhance the flux of fatty acids, in the
      form of triacylglycerols (TAG), through the circulation into skeletal muscle.
      This hypothesis was tested indirectly by measuring the concentration of plasma
      TAG and the activity of lipoprotein lipase (LPL) in post heparin plasma. Six
      mature horses were fed a high-fat or a control diet according to a crossover
      design with feeding periods of 6 weeks. The control diet contained 1.5% fat in
      the dry matter and the high-fat diet 11.8%. The high-fat diet was formulated by
      adding soybean oil to the control diet at the expense of an isoenergetic amount
      of corn starch plus glucose. Both diets consisted of hay and concentrate and were
      given on a restricted basis. Nine hours after feeding, whole plasma TAG
      concentration decreased significantly by 84% following fat-supplementation,
      whereas the whole plasma concentrations of cholesterol and phospholipids were
      significantly increased by 53% and 26%, respectively. The level of HDL
      cholesterol was raised by 54%. The changes in plasma lipids were accompanied by a
      79% increase in LPL activity in post heparin plasma. These results indicate that
      in the fasting state a high-fat diet raises the flux of fatty acids, in the form
      of TAG, into skeletal muscles as illustrated by the observed decrease in plasma
      TAG concentrations and increase in LPL activity. It is speculated that the
      increased flux of fatty acids is associated with an increased oxidative capacity
      of skeletal muscle which might be advantageous to exercising horses.

PMID- 10659301
TI  - Effect of feeding thoroughbred horses a high unsaturated or saturated vegetable
      oil supplemented diet for 6 months following a 10 month fat acclimation.
AB  - This study looked at the effect of feeding diets supplemented with either a
      predominantly saturated or unsaturated vegetable oil over a prolonged period to
      exercising horses. Eight Thoroughbred horses were assigned to 2 diet treatments
      and for 10 months were fed Timothy hay and oats, together with a fortified sweet
      feed supplemented with either a predominantly unsaturated (Un) or a saturated (S)
      vegetable oil so that approximately 19% DE (Digestible Energy) came from dietary
      fat and approximately 12% from either the Un or S source (AC). An increased
      amount of Un or S fortified sweet feed, replacing the oats, was then fed for a
      further 6 months (HF) so that approximately 27% DE came from fat and
      approximately 20% from the Un or S vegetable oil. Standardised incremental
      treadmill exercise (8-12 m/s) tests (STEP) and duplicate oral glucose tolerance
      tests (TOL) were carried out after 3, 6 and 9 months of the AC diet and after 3
      and 6 months on the HF diet. There was no significant effect of dietary treatment
      or when the tests were undertaken (time) on the insulin or lactate responses to
      the STEP tests. Overall there was a significant (P < 0.05) effect of time and
      treatment on the glucose response, but there was no difference between treatments
      at the first and last tests or between the results for these tests or between the
      endAC and endHF tests. No significant effect of treatment or time was seen on the
      TOL glucose response (% change from Time '0') although there was a trend for the
      glucose concentrations to be lower and the insulin responses higher
      (nonsignificant) in the S treatment group. No significant effect of treatment on
      haematological parameters, monitored monthly, was found. Total protein and gamma
      glutamyl transferase remained within the normal range throughout. There was a
      significant effect of treatment (P < 0.05) on cholesterol and triglycerides with
      higher concentrations in the S group from the first (1 month) sample. Linoleic
      acid was the main fatty acid in all the 4 plasma lipid classes with slightly, but
      significant (P < 0.05), higher concentrations in Un for the cholesterol ester and
      phospholipid classes. There was no effect of time. Overall, the total resting
      plasma fatty acid content was significantly higher (P < 0.05) with S at the
      sample points (endAC and endHF). No adverse effects of feeding either diet on
      apparent coat condition or hoof appearance were seen apart from an apparent
      increase in the grease score. Many of the parameters assessed showed significant
      improvements with time (P < 0.05). In conclusion, no apparent adverse effects of
      feeding a diet supplemented with either an unsaturated or saturated vegetable oil
      for 6 months at approximately 20% DE after 10 months at approximately 12% DE were
      identified and there were no apparent disadvantages of feeding a saturated
      vegetable oil supplemented diet compared with an unsaturated one.

PMID- 10659303
TI  - Time of feeding and fat supplementation affect plasma concentrations of insulin
      and metabolites during exercise.
AB  - Six Thoroughbreds were used to evaluate time of feeding on changes in exercise
      response in horses receiving either a textured feed or a fat-supplemented
      textured feed. Using a crossover design, 3 horses were fed a fat-supplemented
      diet while 3 horses received a control ration of textured feed. Horses performed
      a standardised exercise test (SET) on a high speed treadmill. The SET was
      performed at 3 different times: 1) following an overnight 12 h fast, 2) 3 h after
      feeding and 3) 8 h after feeding. The SET consisted of a 2 min walk at 1.4 m/s,
      800 m trot at 4.2 m/s, 800 m gallop at 7.7 m/s, 1600 m gallop at 11 m/s, 800 m
      trot at 4.2 m/s and 2 min walk at 1.4 m/s. Jugular blood samples were taken
      before feeding, hourly until the beginning of the SET, at the end of each
      exercise step, 15 min post exercise and 30 min post exercise. During the SET,
      heart rate was measured and blood samples collected for analysis of glucose,
      lactate, insulin and nonesterified fatty acids (NEFA). Feeding horses 3 h prior
      to exercise resulted in elevated concentrations of plasma glucose and insulin (P
      < 0.01) at rest. Elevated concentrations of insulin in horses fed 3 h prior to
      exercise decreased plasma glucose (P < 0.01) during exercise and appeared to have
      suppressed fat oxidation during exercise because horses that were either fasted
      or fed 8 h post prandial had a net disappearance of NEFA in the plasma during
      exercise. This study indicates that beginning exercise with elevated plasma
      insulin appeared to be of no benefit during the exercise conducted in this
      experiment.

PMID- 10659304
TI  - A comparison of grain, oil and beet pulp as energy sources for the exercised
      horse.
AB  - High-grain diets for the exercising horse were compared with diets which provided
      15% of the total caloric intake from either vegetable oil or a highly fermentable
      fibre source (beet pulp). Six Thoroughbreds age 3 years were fed one of 3 diets
      or 5 weeks in a replicated 3 x 3 Latin square. The CONTROL diet was 3.65 kg of
      sweet feed (SF), 0.9 kg of a protein/vitamin/mineral pellet and 5.45 kg of hay
      cubes. The FAT diet replaced 1.15 kg of SF with 0.45 kg of soybean oil and the
      FIBRE diet replaced 1.15 kg of SF with 1.36 kg of beet pulp. Horses were
      exercised 3 times per week on a high-speed treadmill. During the last week of
      each period, the horses performed a standardised exercise test (SET). A series of
      blood samples was drawn immediately before feeding and every 0.5 h for 3 h after
      feeding, throughout the exercise bout and 30 min post exercise. Plasma was
      analysed for lactate, glucose, cortisol, insulin, packed cell volume, total
      protein and triglycerides. Water intake was measured at regular intervals during
      SET day. Blood glucose was lower (P < 0.05) in the FAT-fed horses during the 3 h
      post feeding as compared to either CONTROL or FIBRE-fed horses. Insulin was lower
      (P < 0.05) in the FAT-fed both post feeding and throughout exercise. Cortisol was
      lower (P < 0.05) in the FAT than the CONTROL-fed during exercise. Following
      exercise, the FAT-fed drank more water (P < 0.01) than either CONTROL or FIBRE
      fed. Substituting 15% of DE as vegetable oil had a greater effect on metabolic
      response to exercise than a 15% substitution of beet pulp.

PMID- 10659305
TI  - Digestible energy expenditure in grazing activity of growing horses.
AB  - Ten Thoroughbred yearlings (5 females and 5 males) were used to examine the
      effect of time of grazing on pasture forage and digestible energy (DE) intake,
      bodyweight gain and DE expenditure in grazing activity. Five females were grazed
      for 17 h/day (LTG), 5 males were grazed for 7 h/day (STG) and they were fed
      differently. As a result, DE intake from pasture forage of LTG horses and STG
      horses was 27.3 and 12.7-13.9 Mcal/day, respectively. The average daily gain
      (ADG) of LTG and STG horses was 0.37 and 0.39-0.61 kg/day, respectively. The
      regression lines between DE intake and ADG of both groups were parallel and the
      difference in DE intake between them was 10 Mcal of DE. It was suggested that DE
      expenditure in grazing activity (entirely at night) of growing horses was 1
      Mcal/h under the conditions of this study.

PMID- 10659306
TI  - Effect of a post exercise fat-supplemented diet on muscle glycogen repletion.
AB  - Low muscle glycogen at the beginning of exercise may adversely affect
      performance, increase protein degradation and contribute to the onset of fatigue.
      As horses are sometimes required to compete on consecutive days both in racing
      and endurance types of competition, optimal muscle glycogen repletion may improve
      performance on the day following a race day. The purpose of this experiment was
      to study the effects of fat supplementation on repletion of muscle glycogen.
      Twelve Finnhorses performed an exercise test on a treadmill, and 2 and 4 h later
      they received hay and concentrate (Trial A). Two weeks later these horses
      performed the same exercise test and were fed the same diet supplemented with
      either 1000 g of carbohydrate or 400 g of vegetable oil (Trial B). A third trial
      (Trial C) was 3 weeks later, identical to Trial B, except that the fat group had
      already been adapted to dietary fat for 3 weeks. Blood samples were analysed for
      lactate, glucose, glycerol, triglycerides, NEFA, cholesterol, beta-OH-butyrate,
      insulin and glucagon and muscle samples were analysed for glycogen and
      triglycerides. The results indicate that in horses not adapted to fat feeding,
      fat supplementation slows the rate of muscle glycogen repletion, and that after
      an adaptation period, fat supplementation does not alter the rate of muscle
      glycogen repletion compared to the rate with a normal diet.

PMID- 10659307
TI  - Influence of oral beta-alanine and L-histidine supplementation on the carnosine
      content of the gluteus medius.
AB  - The aim of this work was to test the hypothesis that in vivo carnosine
      biosynthesis is dependent upon endogenous beta-alanine availability, by studying
      the effect of sustained dietary beta-alanine supplementation in the horse on the
      carnosine concentration in types I, IIA and IIB skeletal muscle fibres. The diets
      of 6 Thoroughbred horses were supplemented 3 times/day with beta-alanine (100
      mg/kg bwt) and L-histidine (12.5 mg/kg bwt) for a period of 30 days. Percutaneous
      biopsies of the m. gluteus medius from a depth of 6 cm were taken on the days
      immediately before and after the supplementation period. Heparinised blood
      samples were collected at hourly intervals on the first and last days of
      supplementation, and on every sixth day during the supplementation period, 2 h
      after each ration. Individual muscle fibres were dissected from freeze-dried
      biopsies, weighed and characterised histochemically. beta-alanine, histidine and
      carnosine concentrations were measured in plasma. The areas under the plasma
      concentration-time curves (AUC) for beta-alanine and histidine were calculated as
      indicators of the doses absorbed. Carnosine concentrations were measured in types
      I, IIA and IIB muscle fibres. There was an adaptive response to sustained beta
      alanine administration resulting in mean +/- s.d. beta-alanine AUC increasing
      significantly from 1130 +/- 612 mumol/l h (Day 1) to 2490 +/- 1416 mumol/l h (Day
      30) (P < 0.05). This was probably due to increased beta-amino acid transport
      across the gastrointestinal lumen. There was no consistent increase in histidine
      AUC between Days 1 and 30, (mean +/- s.d. values being 757 +/- 447 mumol/l h Day
      1[ and 1162 +/- 1084 mumol/l h Day 30[ P > 0.05[). Type IIA fibre carnosine
      concentrations increased from 59.9-102.6 to 76.2-112.2 mmol/kg dry weight (dw).
      Increases were statistically significant in 2 of the 6 horses (P < 0.05 in both
      instances). Type IIB fibre carnosine concentrations increased from 101.3-131.2 to
      114.3-153.3 mmol/kg dw. Increases were statistically significant in 5 of the 6
      horses (P < 0.05 in 3 horses, P < 0.01 in 1 horse, P < 0.005 in 1 horse). Changes
      in muscle carnosine concentration appeared to be influenced by beta-alanine
      bioavailability. Individual increases in muscle carnosine concentration were
      significantly correlated with individual changes in beta-alanine AUC (r2 = 0.973,
      P < 0.005). Increased muscle carnosine concentrations lead to increased
      intramuscular hydrogen ion (H+) buffering capacity.

PMID- 10659308
TI  - Phytate and phosphorus movements in the digestive tract of horses.
AB  - This experiment was conducted to study phytate degradation and the effect of
      dietary phytate level on phosphorus absorption in the gastrointestinal tract of
      horses. Six Thoroughbred horses were fed diets containing low-phytate diet or
      high-phytate diet for 5 days. The diets were supplemented with Cr2O3 as an
      unabsorbable marker. The horses were killed 3 h after the last feeding and
      digesta in some segments of the intestine were collected. In both dietary groups,
      the daily passage of phytate phosphorus was decreased in the upper small
      intestine and in the lower large intestine. The daily passage of phytate
      phosphorus in the lower large intestine did not differ between these groups.
      Although the passage of total phosphorus increased in the upper small intestine
      and in the upper large intestine of both groups, its passage decreased in the
      lower large intestine. These results suggest that phytate phosphorus is degraded
      in the upper small intestine and in the lower large intestine of both groups.
      Phosphorus is suggested to be mainly absorbed in the lower large intestine.
      Therefore, phytate phosphorus is considered to be easily absorbed in horses
      because the major site of phosphorus is the lower large intestine where most of
      phytate is already degraded.

PMID- 10659309
TI  - The effect of dietary fibre on hydration status after dehydration with frusemide.
AB  - Three diets were fed to 6 horses in a 3 x 6 Latin rectangle experiment to
      determine if dietary fibre could improve hydration status in response to
      dehydration with frusemide. Frusemide was used to simulate dehydration from
      exercise-induced sweat loss. Diets contained similar dry matter (DM), energy,
      protein and electrolyte content, but differed in total dietary fibre (TDF) and/or
      soluble fibre (SDF). The 3 diets were: 1) HIGH-HIGH (high TDF, high SDF); 2) HIGH
      LOW (high TDF, low SDF); and 3) LOW-LOW (low TDF, low SDF). In each 10 day
      period, water intake and faecal moisture content were assessed on Day 7. On Day
      10, feed and water were withheld and horses were dehydrated with frusemide (1
      mg/kg bwt, i.m.). Plasma volume (PV), plasma total protein (TP), packed cell
      volume (PCV) and plasma electrolyte concentrations were determined before and
      after frusemide administration. Water consumption was greater (P < 0.05) when
      horses received diets high in TDF. Faecal moisture content was greatest (P <
      0.01) when horses received the HIGH-HIGH diet. The decline in PV and the rise in
      plasma TP concentration following frusemide administration were similar for all
      diets. When horses received the HIGH-HIGH diet, they had a greater (P < 0.05)
      bodyweight before dehydration and lost more (P < 0.05) bodyweight in response to
      frusemide. A greater loss of bodyweight in response to frusemide without a
      proportional loss of PV when horses received the HIGH-HIGH diet suggests that a
      diet high in SDF may provide the horse with a source of dispensable water in the
      hind gut during dehydration.

PMID- 10659310
TI  - The effect of diet composition and feeding state on the response to exercise in
      feed-restricted horses.
AB  - Eight Thoroughbred horses were used to determine the effects of long-term calorie
      restriction and diet composition on serum T4 and T3 concentrations and metabolic
      responses with exercise. Horses were randomly assigned to 2 treatment groups (n =
      4): Group 1, horses were fed a calorie-restricted diet designed to have 70% of
      the calories from the roughage source (RHR); Group 2, horses were fed a calorie
      restricted diet designed to have 70% of the calories from the concentrate source
      (RHC). Horses then completed 2 step-wise exercise tests; one following a 12 h
      fast and one 2 h after a meal of 2 kg of a grain mix. Glucose concentrations
      declined (P < 0.01) in fed horses on the RHR diet but did not change in fed
      horses on the RHC diet. Fasted horses receiving the RHR diet had a more rapid
      increase in glucose concentration during exercise compared to fasted horses
      receiving the RHC diet (P < 0.01) as well as the highest glucose concentration at
      fatigue (P < 0.05). Insulin concentrations were higher (P < 0.05) at fatigue in
      fed horses on the RHR diet. Fasted horses receiving the RHR diet had higher (P <
      0.01) pre-exercise FFA concentrations and a more rapid decline (P < 0.01) in FFA
      during exercise. Serum T3 concentrations increased (P < 0.01) in response to
      exercise within all treatments. The differences in thyroid hormone, glucose and
      FFA responses to exercise suggest that calorie source may be important in the
      hormonal regulation and energy metabolism of horses consuming calorie deficient
      diets.

PMID- 10659311
TI  - Effects of low- and moderate-intensity training on metabolic responses to
      exercise in thoroughbreds.
AB  - This experiment was undertaken to determine whether there were differences in
      cardiorespiratory, haematological and muscular responses in horses trained at
      either low or moderate intensities. Ten Thoroughbred horses previously rested in
      paddocks for 4 months were trained 5 days/week for 9 weeks. Horses were allocated
      randomly into fast or slow groups and exercised the same distance each day.
      Training distances were 1600 m in Weeks 0 and 1 up to 4000 m in Week 9. The fast
      group were trained at an intensity inducing a post training blood lactate of 4-8
      mmol/l. This intensity was determined for each horse each week. The slow group
      trained at half the speed of the fast group (blood lactate < 2 mmol/l). Horses
      performed a standardised exercise test prior to (Week 0) and on Weeks 1, 2, 3, 4,
      7 and 9 of training. HR, VO2, VCO2 and blood lactate concentration were recorded
      during the last 15 s of each step. Blood samples were collected at the end of
      each test for determination of red cell and plasma volume. Muscle biopsies were
      collected from the middle gluteal muscle before training and after 4 and 9 weeks
      training. Training intensity had few effects on the majority of variables
      measured and results for both groups are combined unless otherwise stated.
      Bodyweight was unaffected by training. Economy of locomotion decreased from 12.0
      +/- 0.4 ml/kg bwt/m prior to training to 13.8 +/- 0.6 ml/kg bwt/m at the end of
      training in the fast group. Run time to fatigue was not affected by training
      intensity. VO2max increased from 120.3 +/- 4.8 to 144.7 +/- 3.5 ml/kg bwt/min
      with a significant correlation between run time and VO2max. Peak HR was 221.4 +/-
      2.5 beats/min prior to training and 226.5 +/- 1.7 beats/min after the first 4
      weeks of training. V200 and VLa4 increased in response to training. Similarly,
      VLa4 increased from 7.0 +/- 0.5 to 9.2 +/- 0.2 m/s with VLa4 correlated to
      VO2max. Plasma volume decreased from 29.1 +/- 1.7 to 25.8 +/- 0.9 l during the
      last 3 weeks of training. Blood volume, red cell volume and/or red cell volume/kg
      were unaffected by intensity or duration of training. The activity of CS in
      muscle increased in the first 5 weeks of training whereas HAD activity was not
      affected by intensity or duration of training.

PMID- 10659312
TI  - Comparison of exercise tests in French trotters under training track, racetrack
      and treadmill conditions.
AB  - Standardised exercise tests were performed at 2 different tracks and on an
      uninclined treadmill during the same week to determine the influence of exercise
      surface on different measured variables such as heart rate (HR), blood lactate
      concentration, packed cell volume, stride frequency, stride length, gait symmetry
      and regularity and on different derived physiological variables such as the speed
      at a HR of 200 beats/min (V200), the speed at a blood lactate concentration of 4
      mmol/l (V4), the speed at a maximal HR (VHRmax). Five French Trotters, age 3
      years, in training for 3 months prior to the test, performed 3 exercise tests on
      a training track (Test 1), a racetrack (Test 2) and an uninclined treadmill (Test
      3). Test 1 utilised 3 steps each of 3 min at speeds of 490, 560 and 630 m/min.
      Tests 2 and 3 utilised the same speeds and a fourth step in which the horse was
      accelerated for 30 s to speed approaching maximal. No significant differences (P
      < 0.05) were found for the physiological and locomotor variables between the 2
      tracks. In contrast, there was a significant difference (P < 0.05) for these
      variables between the tracks and the treadmill, horses showing lower heart rate
      and blood lactate response, reduced stride frequency and increased stride length
      and regularity on the uninclined treadmill. We concluded that this standardised
      exercise test was repeatable on various tracks even when the surface and geometry
      vary. In contrast, both physiological and locomotor variables were different when
      comparing the tracks with the uninclined treadmill.

PMID- 10659313
TI  - Exertional rhabdomyolysis in quarter horses and thoroughbreds: one syndrome,
      multiple aetiologies.
AB  - The purpose of this study was to determine if chronic exertional rhabdomyolysis
      (ER) in Quarter Horses and Thoroughbreds represents one or several distinct
      myopathies. Eighteen Quarter Horses and 18 Thoroughbreds with ER were selected
      from cases presented to the Veterinary Hospital on the basis of a history of ER,
      assessment of muscle histopathology, and serum CK activity before and 4 h post
      exercise. In addition, 2 of 3 of the following parameters were evaluated: muscle
      glycogen concentrations, thyroid hormones (T3, T4), fractional excretion (FE) of
      sodium, potassium and chloride. The CK response to training, the metabolic
      response to a near maximal standardised exercise test (SET), blood glucose
      concentrations after an i.v. glucose challenge and a skeletal muscle in vitro
      caffeine contracture test were performed on 5 of the Quarter Horses, selected
      because of polysaccharide storage myopathy (PSSM), and 5 of the Thoroughbreds.
      Serum T3 and T4 were all within normal limits. Low FE of sodium and potassium
      were seen in < 20% of Quarter Horses and Thoroughbreds. Four hours post exercise,
      CK was increased in 77% of Quarter Horses and 72% of Thoroughbreds with ER.
      Muscle glycogen concentrations in Quarter Horses with ER were significantly
      higher than in normal Quarter Horses and Thoroughbreds with ER. No Thoroughbreds,
      but 15/18 Quarter Horses with ER had abnormal polysaccharide accumulation in
      muscle biopsies consistent with a diagnosis of PSSM. PSSM Quarter Horses had
      higher CK activity during training than Thoroughbreds and higher glycogen
      utilisation with the SET. PSSM Quarter Horses also had significantly enhanced
      glucose clearance compared to normal Quarter Horses and Thoroughbreds with ER.
      Thoroughbreds with ER had significantly lower thresholds for caffeine-induced
      contracture than normal horses and PSSM Quarter Horses. It was concluded that
      there are multiple causes for exertional rhabdomyolysis. In Quarter Horses,
      rhabdomyolysis is commonly due to a glycogen storage disorder, PSSM, and is
      readily expressed in untrained horses. In Thoroughbreds, ER is commonly due to an
      underlying abnormality of muscle contraction. Rhabdomyolysis in Thoroughbreds,
      however, is only expressed intermittently when key stressors are present.

PMID- 10659314
TI  - Repeated administration of frusemide does not offer an advantage over single
      dosing in attenuating exercise-induced pulmonary hypertension in thoroughbred
      horses.
AB  - The objective of the present study was to ascertain whether administration of a
      second dose of frusemide would attenuate exercise-induced pulmonary hypertension
      more than a single dose. Right atrial, right ventricular and pulmonary vascular
      pressures were determined in 7 healthy, sound, exercise-trained Thoroughbred
      horses at rest and during exercise (14.2 m/s + a 3.5% uphill grade) performed at
      maximal heart rate (217 +/- 3 beats/min [mean +/- s.e.]). Horses were studied
      during the following 3 treatments in random order 7 days apart: control (no
      medication), frusemide single dose (250 mg i.v. 4 h pre-exercise), and frusemide
      double dose (250 mg i.v., 4 h pre-exercise + 250 mg i.v. 2 h pre-exercise). In
      the control study, exercise resulted in significant (P < 0.05) right atrial as
      well as pulmonary arterial, capillary and venous hypertension. In the frusemide
      single dose experiments, a significant (P < 0.05) attenuation of the exercise
      induced rise in right atrial and pulmonary vascular pressures was observed.
      However, compared with frusemide single dose experiments, significant changes in
      the exercise-induced right atrial and pulmonary arterial, capillary and venous
      hypertension were not observed in the frusemide double dose experiments.
      Therefore, it is concluded that administration of an additional dose of frusemide
      is unlikely to affect the severity of EIPH in racing Thoroughbred horses more
      than a single dose.

PMID- 10659315
TI  - Plasma ammonia and lactate responses using incremental and constant speed
      exercise tests.
AB  - Plasma NH3, formed during intense exercise, results principally from the
      deamination of AMP in muscle. Its formation during exercise may be influenced
      both by the pool of fibres recruited and by changes in the intracellular
      environment affecting ADP homeostasis. This study compared incremental and
      constant speed exercise as possible protocols for the investigation of plasma NH3
      accumulation with intense exercise. Six trained Thoroughbred horses, one of which
      had recently been operated on for recurrent laryngeal neuropathy, undertook a
      step-wise treadmill test with 1 min incremental steps of 6, 8, 10, 11 and 12 m/s
      (7.5% incline). Two and 4 weeks later horses performed a constant-speed, maximum
      exercise tolerance test at 115% VO2max (7.5% incline). Blood samples from the
      jugular vein were drawn at 20 s intervals in all 3 tests, for plasma NH3 and
      lactate. There were marked differences between and within horses in their time
      dependant lactate and NH3 responses to exercise. Three of the 6 horses studied
      showed a distinct threshold for onset of plasma NH3 accumulation with incremental
      exercise. Distinct thresholds for the onset of NH3 accumulation were apparent
      also in 5 of the 6 horses during exercise at constant rate. The present study
      demonstrates clearly the practicality of measuring NH3 concentration curves, even
      during a short incremental step test which has the advantage that other measures
      relating to cardiovascular and respiratory functions can be measured
      simultaneously.

PMID- 10659316
TI  - Osteoinductive response in the dorsal aspect of the carpus of young thoroughbreds
      in training occurs within months.
AB  - Bone mineral density (BMD) was measured by dual x-ray absorptiometry (DXA) in the
      carpus of 6 Thoroughbreds age 24 months that were exercised on the treadmill for
      4.5 months, and of 6 matched control horses. A sagittal slab of known thickness
      was sawn from one or more of radius, radial carpal (Cr), third carpal (C3), and
      third metacarpal (Mc3) bones. After the 4.5 month treadmill exercise, there was a
      significantly greater volumetric BMD in the dorsal aspect of C3 (P = 0.006).
      Treadmill-exercised horses also had higher BMD in the dorsodistal aspect of the
      radius (P = 0.03), the dorsal half of Mc3 (P = 0.012), and the dorsal aspect of
      Cr (P = 0.04). In other areas of interest (AOI) studied on the palmar aspect of
      the bones, significant increases in exercised horses did not occur. These
      sizeable changes in bone mass occurred within a few months of initiation of
      exercise. With technical development, DXA could be applied in vivo for
      investigation of changes in bone mass of horses which are growing and exercising
      under various regimes. The data are also relevant to the development of
      scientifically based training protocols.

PMID- 10659317
TI  - Effect of exercise on bone density in distal regions of the equine third
      metacarpal bone in 2-year-old thoroughbreds.
AB  - The present study addressed the question of whether training induces changes in
      bone density in the younger racehorse in regions relevant to the genesis of the
      common sagittal condylar fracture pattern and, if so, the nature of such
      alteration. Third metacarpal bones (McIII) were obtained from 12 experimental
      Thoroughbred, unbroken fillies, age 18.1-21.0 months at entry to the study. Six
      (Group E) undertook 19 weeks of progressive high intensity exercise on a high
      speed treadmill at 3% incline. Six (Group C) walked 40 min each day. Clinical
      bone density was studied by Computed Tomography (CT) of the right McIII. 1:1
      aspects of bone density were studied by digital radiography of slices and
      microscopic aspects by backscattered electron (BSE) imaging. There was a distinct
      pattern of regional variation in bone density throughout the distal condyles of
      McIII. Bone density was greater in specimens from Group E than those from Group C
      by CT, by radiographic density and by bone volume fraction as determined from
      backscattered electron images: the latter also showed that the most important
      change was in the increased amount of bone deposited within antecedent marrow
      space in cancellous tissue in Group E compared with Group C, with more extensive
      regional involvement in the highly loaded (distopalmar) aspects of the medial and
      lateral condyles. However, this space-filling bone fraction had a lower degree of
      mineralisation than the prior bone tissue, showing that CT and radiography
      underestimate the resultant increased bone volume fraction. Stress fractures of
      the distal condyles of the McIII are common in Thoroughbred racehorses. We
      propose that excess stiffening within the condyles due to extensive new bone
      formation may lead to concentration of strain at the condylar grooves and
      incipient cracking through calcified cartilage and into the subchondral bone.

PMID- 10659318
TI  - Endocrine response to exercise in young and old horses.
AB  - Six young (mean + s.e., 5.3 +/- 0.8 years, 445 +/- 13 kg bwt) and 6 old (22.0 +/-
      0.4 years, 473 +/- 18 kg bwt) Standardbred and Thoroughbred mares were used to
      test the hypothesis that age would alter the endocrine response to exercise. All
      of the mares were unconditioned but accustomed to the laboratory, to standing
      quietly and running on a treadmill, and to the standardised incremental exercise
      test (SET) used in the experiment. Two weeks prior to the experiment, each horse
      underwent a SET to determine maximal oxygen uptake (VO2max) and the speeds to be
      used in the actual experiment. A second graded exercise test (GXT) was performed
      without instrumentation for the measurement of plasma renin activity (PRA) and
      the plasma concentrations of atrial natriuretic peptide (ANP), arginine
      vasopressin (AVP), aldosterone (ALDO), and endothelin-1 (ET-1). Blood samples (30
      ml) were collected at rest and at the end of each one minute step of the exercise
      test. Plasma concentrations of hormones were measured using radioimmunoassay
      kits. There were no differences (P > 0.05) between old vs. young mares for
      resting PRA (2.2 +/- 0.3 vs. 1.5 +/- 0.3 ng/ml/h), or the plasma concentrations
      of ANP (10.0 +/- 0.9 vs. 10.7 +/- 0.6 pg/ml); AVP (0.7 + 0.7 vs. 1.4 +/- 0.4
      pg/ml); ALDO (39.2 +/- 10.3 vs. 22.7 +/- 4.6 pg/ml); or ET-1 (0.23 +/- 0.04 vs.
      0.18 +/- 0.03 pg/ml). Exercise significantly increased PRA and the concentrations
      of ANP, AVP, and ALDO in both groups of horses; however, ET-1 was not altered (P
      > 0.05) by exercise in either group. There were differences (P < 0.05) between
      means obtained from the old and young groups for PRA (5.4 +/- 0.6 vs. 3.9 +/- 0.8
      ng/ml/h and the concentrations of ANP (14.5 +/- 2.3 vs. 26.5 +/- 9.0 pg/ml), AVP
      (13.6 +/- 0.3 vs. 26.1 +/- 13.9 pg/ml, and ALDO (76.8 +/- 22.0 vs. 41.5 +/- 4.9
      pg/ml) measured in samples obtained at the speed eliciting VO2max. These data
      suggest that older horses have an age-altered endocrine response to exercise.

PMID- 10659319
TI  - Equine plasma beta-endorphin concentrations are affected by exercise intensity
      and time of day.
AB  - Eight mature mares were exercised for 20 min at 60% VO2max and to fatigue at 95%
      VO2max. Plasma beta-endorphin (EN) concentrations were determined before
      exercise, after a 10 min warm-up, and at the end of each exercise test. Mean +/-
      s.e. beta-endorphin concentrations were significantly (P < 0.05) higher following
      work at 95% VO2max when compared to that at 60% VO2max (420.0 +/- 102.7 vs. 269.9
      +/- 30.69 pg/ml). Pre-exercise samples were collected between 1000 and 1500 h. In
      order to evaluate whether any cyclic changes in EN secretion effects may have
      influenced results, a subsequent study was completed using 12 horses to assess
      diurnal fluctuations in EN concentrations, by measuring EN concentration every 2
      h for a 24 h period. There was no statistical difference in mean values at any
      time between 0800 and 2000 h. Whether individual differences in EN concentrations
      reflected varying degrees of stress associated with the exercise could not be
      determined. Any possible link between EN concentration and exercise stress in
      exercising horses awaits clarification.

PMID- 10659320
TI  - Plasma adrenocorticotropin, cortisol and catecholamines response to various
      exercises.
AB  - The responses of plasma adrenocorticotropin (ACTH), cortisol, noradrenaline and
      adrenaline in 5 Thoroughbred horses to an incremental exercise and 2 relative
      workload exercises, at 105 and 80% maximal oxygen consumption (VO2max), on a
      treadmill were examined. These hormone concentrations increased (P < 0.05) with
      each exercise and the maximal plasma concentrations of ACTH, cortisol were
      observed between 5 and 30 min after the end of the exercise, while maximal
      catecholamine concentrations occurred just at exhaustion time. The plasma ACTH,
      noradrenaline and adrenaline responses during exercise were more sensitive to the
      intensity of exercise than that of cortisol and showed a significant correlation
      with blood lactate concentrations (r = 0.605, P < 0.001 for ACTH; r = 0.718, P <
      0.001 for noradrenaline; r = 0.738, P < 0.001 for adrenaline). The plasma
      cortisol response appeared to be connected with the duration of exercise (r =
      0.71, P < 0.05). The recovery of these hormones was related to the exercise
      styles. These results suggest that the autonomic nervous system and the pituitary
      adrenal axis of the horse are efficiently stimulated by various treadmill
      exercises, and these hormones may be used in the evaluation of exercise-induced
      stress.

PMID- 10659321
TI  - Effect of inhaled beta 2 adrenoceptor agonist, albuterol sulphate, on performance
      of horses.
AB  - This study was designed to test the hypothesis that a specific beta 2 adrenergic
      receptor agonist, albuterol sulphate, when delivered by metered-dose inhaler
      (MDI) would affect the performance of Thoroughbred horses during incremental
      exercise testing. Six conditioned Thoroughbred horses were randomly assigned to
      one of 2 treatment groups: Group 1 horses received placebo and Group 2 received
      albuterol. Each horse received both treatments in a crossover design with a 3
      week interval between trials. Horses inspired albuterol (900 micrograms) or
      placebo over a 5 min period followed by an incremental, peak oxygen consumption
      (VO2peak) exercise test. Facial arterial blood gases (PaO2, PaCO2), pHa,
      temperature, haemoximetry (O2Hb, COHb, MetHb, RHb) and electrolytes (Na+, K+,
      iCa2+, Cl-) were measured. Heart rate (HR), VO2peak, CO2 production (VCO2),
      plasma lactate, speed at failure, exercise duration, and urine levels of
      albuterol and metabolites (Alburine) were monitored. The Paratrend7 intravascular
      sensor provided continuous arterial blood gas data. Mixed effects linear
      modelling using generalised least-squares estimation was used to assess treatment
      and speed main effects interaction. Significant differences (P < 0.01) were found
      between placebo and albuterol-treated horses for total run time (mean +/- s.e.
      405.8 +/- 8.8 vs. 430.5 +/- 6.7 s) and run time from completion of 8 m/s until
      fatigue (169.3 +/- 8.6 vs. 187.3 +/- 6.7 s), as well as VO2peak (121.7 +/- 3.7
      vs. 130.3 +/- 3.8 ml/kg/min), respectively. In conclusion, inhaled albuterol
      sulphate has a small but significant effect on the performance of fit
      Thoroughbred horses during incremental, VO2peak exercise testing.

PMID- 10659322
TI  - Maximal exercise transiently disrupts hormonal secretory patterns in standardbred
      geldings.
AB  - Basal concentrations of cortisol (CORT), beta-endorphin (beta EP), growth hormone
      (GH) and testosterone (T) and their disruption during 32 h of recovery after
      treadmill exercise were investigated in 4 geldings. Blood samples were collected
      from resting horses every 20 min between 0600-1000 and 1500-1900 h, and hourly
      between 1000-1500 h on 3 consecutive days. Treadmill exercise tests comprising 2
      min intervals at 30, 50, and 70% VO2max then to fatigue at 100% VO2max were
      conducted between 1020-1130 h on Day 2. Blood was collected before, during and
      15, 30, 60 and 90 min after exercise. Mean (Cav), peak (Cmax) and total (i.e.
      integrated) (Ctot) concentrations were calculated for CORT, beta EP and GH during
      the 20 min sampling sessions, and for CORT, beta EP, GH and T between 1000-1300 h
      on Days 1-3 (incorporating the samples during exercise on Day 2) and 1300-1900 h
      on Days 1-3. Cav, Cmax and Ctot for CORT, beta EP, GH and T were greater during
      exercise and recovery than in the same period on Day 1. Cav and Ctot values for
      plasma T during the 1300-1900 h period were significantly elevated on Day 2 and
      compared to Day 1 (P < 0.05), but there were no differences between Days 1 and 3
      values for these variables. We concluded that plasma T concentration increases in
      response to maximal exercise in geldings, as does plasma CORT, beta EP and GH.
      Furthermore, maximal exercise disrupts basal plasma concentrations of CORT, beta
      EP and GH for up to 24 h and T for 26-32 h post exercise in geldings, therefore
      reflecting the minimum recovery periods required before evaluating normal,
      resting levels of these hormones in horses undergoing training.

PMID- 10659323
TI  - Hyperbolic relationship between time-to-fatigue and workload.
AB  - The power:time-to-fatigue relationship for high-intensity exercise in man is
      useful in determining anaerobic work capacity. The purpose of this study was to
      determine the nature of this relationship in horses. Eight Standardbred horses
      performed 5 or 6 run-to-fatigue trials on a treadmill. Exercise intensities were
      chosen to induce fatigue in 30 to 240 s. The order of trials was randomised for
      each horse, but balanced overall for the first 4 trials. The data for power
      (independent variable) and time-to-fatigue (dependent variable) were tested for
      goodness of fit to hyperbolic, linear and exponential equations by nonlinear
      regression. The best fit to the data was obtained using the hyperbolic
      relationship t = W'(P- phi PA) where t is the time to fatigue, W' is the
      anaerobic work capacity, P is the power and phi PA is the critical power value.
      The values for W' and phi PA were 47,000 +/- 500 J and 2490 +/- 150 watts,
      respectively. We conclude that the power:time-to-fatigue relationship of horses
      is hyperbolic and that this relationship may be useful in assessing anaerobic
      capacity of horses.

PMID- 10659324
TI  - Relationship of body condition score to completion rate during 160 km endurance
      races.
AB  - Three-hundred and sixty horses, primarily of Arabian breeding, age 5-22 years and
      body conditions scores 1.5-5.5 (on 1 to 9 scale as described by Henneke 1985),
      participated in one of two 160 km endurance races over the same course in August
      1995 and July 1996. Condition score, cannon bone circumference, combined rider
      and tack weight, heart girth and body length were measured 11-18 h prior to the
      start of the event and bodyweight estimated according to the formula by Carroll
      and Huntington (1988). A rider weight ratio was calculated as rider weight
      divided by horse bodyweight. Rider weight and rider weight ratio had no effect on
      overall completion rates among all horses (P > 0.05). Among horses successfully
      completing the course, rider weight and rider weight ratio had no effect on
      finish time or placing (P > 0.05). Among horses who were eliminated, rider weight
      and rider weight ratio had no effect on miles completed before failure (P >
      0.05). Condition scores had a significant effect on completion rate (P < 0.001).
      Distance successfully completed increased 31.81 km (19.88 miles) for each
      incremental increase of 1 in condition score (P < 0.001). Within the group of
      unsuccessful horses, there was a significant difference in condition score
      between horses who failed due to metabolic and nonmetabolic factors (P < 0.001).
      It was concluded that condition score is a more important factor in endurance
      performance than has been previously believed, and that condition score is a more
      important factor than is the weight of the rider, or the rider weight in relation
      to the weight of the mount.

PMID- 10659325
TI  - Effects of caffeine and promazine hydrochloride on plasma catecholamines in
      thoroughbreds at rest and during treadmill exercise.
AB  - Our aim was to investigate plasma catecholamine responses to so-called 'doping'
      drugs and exercise in Thoroughbreds. Plasma adrenaline (Ad) and noradrenaline
      (NA) were determined after the administration of caffeine and promazine
      hydrochloride (PRZ) using a high performance liquid chromatographic method.
      Caffeine or PRZ was administered i.m. to Thoroughbreds and its effects on plasma
      catecholamines at rest and during exercise were compared with the saline control.
      The treadmill exercise was performed 1 h after administration. A dose of 5.0
      mg/kg bwt caffeine was found to significantly increase both plasma Ad and NA
      levels but this was not the case for the 2.5 mg/kg bwt dose and their peak levels
      at 1.5 h were about 3 and 2.5 times as compared with the control values at 1.5 h
      (Ad: mean +/- s.e. 21.2 +/- 2.8 pg/ml, NA: 55.5 +/- 4.1 pg/ml), respectively.
      Both 1.0 and 1.5 mg/kg bwt PRZ doses reduced the plasma Ad to below the detection
      limit (10 pg/ml) and significantly reduced the plasma NA. The 2.5 mg/kg bwt
      caffeine dose significantly increased plasma Ad and NA during exercise and
      approximately doubled their maximal values as compared with the saline control
      (Ad: mean +/- s.e. 12.328 +/- 4.733 ng/ml, NA: 9.997 +/- 4.146 ng/ml). The 1.5
      mg/kg bwt PRZ dose decreased the plasma Ad during exercise but the effect was not
      significant. On the other hand, PRZ significantly increased the plasma NA as
      compared with the saline control. In conclusion, the present study demonstrates
      that the plasma catecholamine responses to caffeine and PRZ were modified by
      exercise. It is probable that the modification may be related to exercise-induced
      activation of the sympathetico-adrenal axis.

PMID- 10659326
TI  - Comparison of bone mineral content and biochemical markers of bone metabolism in
      stall- vs. pasture-reared horses.
AB  - Sixteen Arabian yearlings were assigned randomly to 2 groups, confined to stall
      and pastured, to investigate the effects of confinement vs. pasture-rearing on
      bone mineral content and biochemical markers of bone metabolism over a 140 day
      period. Following an 84 day pretraining period, 6 horses from each group were
      selected randomly to complete a 56 day training period. Serum osteocalcin
      concentrations were determined from blood samples collected every 14 days.
      Urinary deoxypyridinoline concentrations and mineral content of the third
      metacarpus, as determined by lateral and medial radiographic bone aluminum
      equivalency (RBAE), were determined every 28 days from 24 h urine samples and
      radiographs of the left forelimb, respectively. In comparison with starting
      values, lateral RBAE was lower in the confined horses at Day 28 and remained
      lower throughout most of the project, while pastured horses had increasing
      lateral RBAE. Horses kept in stalls had lower medial RBAE at Day 28 than pasture
      reared horses. Medial RBAE tended to remain lower in confined horses than in
      pastured horses throughout most of the project. The onset of training failed to
      negate the loss of mineral. Serum osteocalcin concentrations were lower and
      urinary deoxypyridinoline concentrations were higher in the confined horses at
      Days 14 and 28, respectively, compared with the pastured horses, and subsequently
      returned to baseline. These results suggest that housing yearling/2-year-old
      horses in stalls may be associated with a loss of bone mineral content in
      comparison with horses maintained on pasture.

PMID- 10659327
TI  - The effects of an endurance ride on metabolism and neutrophil function.
AB  - The effects of an endurance ride on neutrophil functions in endurance-trained
      horses were evaluated and related to metabolic changes and changes in cortisol
      concentrations. Blood samples were taken from 7 horses (aged 9-15 years) one day
      before, and then 30-60 min, 1 day and 8 days after the ride. The race resulted in
      elevated serum cortisol levels (< 465 nmol/l) and an increased
      neutrophil:lymphocyte ratio. Immediately post race, the neutrophil ability to
      engulf yeast was increased. One day after the race, a decrease in leukotriene B4
      production (approximately 40%) and in the respiratory burst (approximately 75%)
      was observed. Blood glucose concentration remained unchanged, as did serum
      lactate, which was low. After the race, the muscle glycogen stores were about 33%
      of the values noted after 8 days of recovery. Histochemical staining showed that
      22 +/- 2% of the muscle fibres were totally depleted of glycogen. CK activity
      increased significantly from 40 +/- 10 mmol/min pre-race to 228 +/- 38 mmol/min
      post race. It was concluded that both hormonal and metabolic changes occurred
      during an endurance ride, which not only triggered neutrophil activation, but
      also induced alterations in their functional capacities.

PMID- 10659328
TI  - Fragility of red cells during exercise is affected by blood pH and temperature.
AB  - We examined the relationship in horses between osmotic fragility of erythrocytes
      (OFE) measured as the red cell haemolysis rates (HLR) in 0.56% NaCl and certain
      physiological characters. Animals were exercised on a treadmill: warmed up at 30%
      VO2max for 5 min or at 105% VO2max for 1 min, given an exercise test at 80 or
      105% VO2max until fatigued, and then cooled down. The pH and temperature of the
      blood had a significant correlation for the HLR: r = 0.93 and 0.92 (P < 0.01) on
      arterial and mixed venous blood, respectively. In multiple regression analysis,
      heart rate and packed cell volume showed lower coefficients for the HLR. The
      present study suggested that, in exercising horses, 1) the increase of blood flow
      and release of erythrocytes from the spleen into the circulation have little
      effect on changes of OFE; 2) the decrease of blood pH promotes OFE; 3) the
      increase of the pH causes osmotic resistance in the cells and 4) an increase of
      blood temperature during exercise is associated with the decrease in the OFE.

PMID- 10659329
TI  - Plasma glutamine status in the equine at rest, during exercise and following
      viral challenge.
AB  - The variation over 24 h of plasma glutamine concentration in nonexercising horses
      was studied in 3 Thoroughbreds (TB) fed at 1600 h and 0700 h. This indicated a
      small but regular change associated with feeding. Starting at a mean of 482
      mumol/l at 1600 h the concentration increased to 522 mumol/l at 2000 h, falling
      to 476 mumol/l at 1600 h and increasing again to 525 mumol/l at 2000 h. 'Normal'
      values were established in 19 part-bred TB horses, lacking clinical signs or
      remarkable pathology and in light training, by sampling weekly at 1000 h over a
      10 week period. The mean concentration was 491 mumol/l. Values were normally
      distributed with 95% confidence range between horses of 469-512 mumol/l. The s.d.
      of values within-horse was 28 mumol/l. The acute effect of exercise was
      investigated in 5 TB horses during i) an exercise simulating the road and tracks
      phase of a 3-day-event and ii) a sustained high-intensity exercise test (115%
      VO2max until the pace was no longer maintained). In both tests a transient
      increase was produced as a direct result of exercise, followed by a decline to a
      nadir at approximately 3 h post exercise. Pre-exercise resting concentrations,
      following either test, were approaching pre-values by 24 h recovery. The effect
      of viral challenge was studied in 6 TB horses exposed to an aerosol of equine
      influenza virus, subtype H3N8 (A/equine-2 subtype) which caused mild clinical
      signs. A significant fall in the 1000 h plasma glutamine concentration from a
      mean of 463 to 342 mumol/l by the 6th day was seen in 5 horses. A more gradual
      decline was observed in the 6th horse. These findings indicate a similar response
      to viral challenge in the horse to that in man.

PMID- 10659330
TI  - Racing performance in red blood cell hypervolaemic standardbred trotters.
AB  - The association between red blood cell hypervolaemia (RCHV) and racing
      performance was examined in 116 Standardbred trotters referred to the clinic
      during a 5 year period with histories of impaired racing performance. Red cell
      hypervolaemia was the only significant abnormality detected in a thorough
      clinical examination, cell volumes ranging 116-178% of the predicted normal
      values. They were also compared with the performance traits of the contemporary
      Swedish Standardbred trotter population (n = 58,058). The performance traits were
      based on earnings per year and start, best annual racing time, % placings 1 to 3,
      and calculated individual performance indices (PI) published in the Annual
      Statistics for Swedish Trotting. These parameters were transformed to approach
      normal distributions. The results indicated that horses developing RCHV tended to
      have been superior athletes initially compared to the contemporary population
      average. After 3 to 4 years of racing (at mean age +/- s.d. 5.5 +/- 1.5 years)
      their racing performance declined rapidly during the year of diagnosis of RCHV.
      Therefore, both earning and placing traits were reduced and best racing time
      increased. Further, the PI, well above the population average prior to diagnosis,
      was reduced significantly. During the 3 year period following diagnosis, a slight
      improvement in racing performance was noted although it was not restored to
      previous racing form. It was concluded that RCHV in the Standardbred trotter may
      denote the end of a successful racing career.

PMID- 10659332
TI  - Biomechanical analysis of horse shoeing.
AB  - Most of the principles of farriery have been derived from practical experience
      and traditional skills of individual farriers. To date, there has been little
      done in the way of good science and few publications have appeared to advance the
      discipline. Therefore, opinions or policies on horse shoeing vary greatly between
      farriers and members of the veterinary profession. The aim of this workshop was
      to present the latest information on biomechanical analysis of horse shoeing as
      it relates to modern day farriery and could have direct benefits for the future
      of shoeing in performance horses.

PMID- 10659331
TI  - Haematological and biochemical responses to training and overtraining.
AB  - We sought a physiological marker of overtraining in horses, using commonly
      practised field and laboratory tests to allow early prediction and treatment of
      the syndrome. Thirteen Standardbred horses were trained as follows: phase 1
      (endurance, 7 weeks), phase 2 (high intensity, 9 weeks) and phase 3 (overload, 18
      weeks). In phase 3 the horses were divided into 2 groups: overload training (OLT)
      and control (C). The OLT group exercised at greater intensities, frequencies and
      durations than the C group. Overtraining occurred after 31 weeks and was defined
      as a significant decrease in treadmill run time to fatigue (RT) in response to a
      standardised exercise test (SET). Variables measured included: feed intake,
      bodyweight (BWT), resting haematology and plasma biochemistry and treadmill SETs
      to measure RT. The OLT group had a decrease in BWT after week 28 (P < 0.05)
      without a reduction in feed intake and a reduction in RT during the SET after 31
      weeks. Signs persisted after 2 weeks of a reduced training load confirming
      overtraining. Haematology and biochemistry failed to detect any markers of
      overtraining. Although no physiological markers of overtraining were identified,
      empirical observations revealed that the behaviour of horses in the OLT group was
      different from those in the C group during the period of overtraining. This study
      reflects that a model of overtraining has been developed based on measurement of
      a reduction in performance; however, there were no consistent changes in
      haematology or serum biochemical values in association with the decrement in
      performance capacity.

PMID- 10659333
TI  - Pulmonary function testing.

PMID- 10659334
TI  - To evaluate the influence that 'feeding state' may exert on metabolic and
      physiological responses to exercise.

PMID- 10659335
TI  - The physicochemical approach for evaluating acid-base balance in exercising
      horses.

PMID- 10659336
TI  - Upper airway disease: does it affect lower airway mechanics and pulmonary
      haemodynamics?

PMID- 10659337
TI  - Clinical and investigational advances in the prevention of tendonitis.

PMID- 10659338
TI  - Exercise-induced pulmonary haemorrhage workshop.

PMID- 10659339
TI  - Advantages and disadvantages of track vs. treadmill tests.

PMID- 10659340
TI  - Intestinal lymphoepithelial communication.
AB  - The close anatomic juxtaposition of epithelial cells with lymphocytes lining the
      intestinal tract facilitates communication between the two cell types. This
      intercellular dialogue is important for mucosal development and has a
      conditioning effect on mucosal structure, function, and response to tissue
      injury. Lymphoepithelial communication is bi-directional, and mediated in large
      part, by shared ligands and receptors. The chemical messengers involved include
      cytokines, growth factors, local hormones, and products of arachidonate
      metabolism. The interdependency between the epithelium and adjacent lymphoid
      cells is such that the epithelium is considered to have a central role in the
      mucosal immune system and is an active participant in both the afferent and
      efferent limbs of the mucosal immune response. The molecular crosstalk between
      the epithelium and adjacent lymphocytes is just one aspect of a more complex
      network of intercellular signalling within the intestinal mucosa and upon which
      the integrity of the mucosa is dependent. Thus, there are extensive interactions
      between nerve and immune cells and between the enteric flora and the epithelium
      and amongst intestinal mesenchymal cells including fibroblasts and vascular
      endothelial cells. Disruption of any aspect of the mucosal microenvironment, as
      has been achieved with selective genetically engineered murine models, is
      associated with impaired mucosal defence and inflammation.

PMID- 10659341
TI  - Bacterial translocation from the gastrointestinal tract.
AB  - Bacterial translocation is defined as the passage of viable bacteria from the
      gastrointestinal (GI) tract to extraintestinal sites, such as the mesenteric
      lymph node complex (MLN), liver, spleen, kidney, and bloodstream. The three
      primary mechanisms promoting bacterial translocation in animal models are
      identified as: (a) disruption of the ecologic GI equilibrium to allow intestinal
      bacterial overgrowth, (b) increased permeability of the intestinal mucosal
      barrier, and (c) deficiencies in host immune defenses. These mechanisms can act
      in concert to promote synergistically the systemic spread of indigenous
      translocating bacteria to cause lethal sepsis. In animal models in which the
      intestinal barrier is not physically damaged, indigenous bacteria translocate by
      an intracellular route through the epithelial cells lining the intestines and
      then travel via the lymph to the MLN. In animal models exhibiting damage to the
      mucosal epithelium, indigenous bacteria translocate intercellularly between the
      epithelial cells to directly access the blood. Indigenous GI bacteria have been
      cultured directly from the MLN of various types of patients. Thus, evidence is
      accumulating that translocation of indigenous bacteria from the GI tract is an
      important early step in the pathogenesis of opportunistic infections originating
      from the GI tract.

PMID- 10659342
TI  - Interference with virus and bacteria replication by the tissue specific
      expression of antibodies and interfering molecules.
AB  - Historically, protection against virus infections has relied on the use of
      vaccines, but the induction of an immune response requires several days and in
      certain situations, like in newborn animals that may be infected at birth and die
      in a few days, there is not sufficient time to elicit a protective immune
      response. Immediate protection in new born could be provided either by vectors
      that express virus-interfering molecules in a tissue specific form, or by the
      production of animals expressing resistance to virus replication. The mucosal
      surface is the largest body surface susceptible to virus infection that can serve
      for virus entry. Then, it is of high interest to develop strategies to prevent
      infections of these areas. Virus growth can be interfered intracellularly,
      extracellularly or both. The antibodies neutralize virus intra- and
      extracellularly and their molecular biology is well known. In addition,
      antibodies efficiently neutralize viruses in the mucosal areas. The autonomy of
      antibody molecules in virus neutralization makes them functional in cells
      different from those that produce the antibodies and in the extracellular medium.
      These properties have identified antibodies as very useful molecules to be
      expressed by vectors or in transgenic animals to provide resistance to virus
      infection. A similar role could be played by antimicrobial peptides in the case
      of bacteria. Intracellular interference with virus growth (intracellular
      immunity) can be mediated by molecules of very different nature: (i) full length
      or single chain antibodies; (ii) mutant viral proteins that strongly interfere
      with the replication of the wild type virus (dominant-negative mutants); (iii)
      antisense RNA and ribozyme sequences; and (iv) the product of antiviral genes
      such as the Mx proteins. All these molecules inhibiting virus replication may be
      used to obtain transgenic animals with resistance to viral infection built in
      their genomes. We have developed two strategies to target into mucosal areas
      either antibodies to provide immediate protection, or antigens to elicit immune
      responses in the enteric or respiratory surfaces in order to prevent virus
      infection. One strategy is based on the development of expression vectors using
      coronavirus derived defective RNA minigenomes, and the other relies on the
      development of transgenic animals providing virus neutralizing antibodies in the
      milk during lactation. Two types of expression vectors are being engineered based
      on transmissible gastroenteritis coronavirus (TGEV) defective minigenomes. The
      first one is a helper virus dependent expression system and the second is based
      on self-replicating RNAs including the information required to encode the TGEV
      replicase. The minigenomes expressing the heterologous gene have been improved by
      using a two-step amplification system based on cytomegalovirus (CMV) and viral
      promoters. Expression levels around 5 micrograms per 10(6) cells were obtained.
      The engineered minigenomes will be useful to understand the mechanism of
      coronavirus replication and for the tissue specific expression of antigen,
      antibody or virus interfering molecules. To protect from viral infections of the
      enteric tract, transgenic animals secreting virus neutralizing recombinant
      antibodies in the milk during lactation have been developed. Neutralizing
      antibodies with isotypes IgG1 or IgA were produced in the milk with titers of
      10(6) in RIA that reduced virus infectivity by one million-fold. The recombinant
      antibodies recognized a conserved epitope apparently essential for virus
      replication. Antibody expression levels were transgene transgene copy number
      independent and were related to the transgene integration site. This strategy may
      be of general use since it could be applied to protect newborn animals against
      infections of the enteric tract by viruses or bacteria for which a protective MAb
      has been identified. Alternatively, the same strategy could be used to target the
      expression of antibio

PMID- 10659343
TI  - Comparative pathogenesis of enteric viral infections of swine.
AB  - At least 11 enteric viruses belonging to 6 distinct families (Adenoviridae,
      Astroviridae, Caliciviridae, Coronaviridae, Parvoviridae, and Reoviridae) cause
      diarrhea in swine mainly during the nursing and immediate post-weaning period.
      Most infect the small intestinal enterocytes, inducing various degrees of villous
      atrophy and subsequently a malabsorptive, maldigestive diarrhea. In addition
      rotaviruses possess an enterotoxin (NSP4) which induces a secretory diarrhea in
      mice. These viruses have distinct predilections for different vertical
      (villus/crypt) and horizontal (duodenum, jejunum, ileum, colon) replication sites
      in the intestine and the diarrhea intensity is often related to the extent of
      viral replication at these sites. In addition concurrent infections with multiple
      enteric viruses can produce synergistic or additive effects leading to more
      extensive villous atrophy throughout the intestine and more severe and prolonged
      diarrhea. Knowledge of enteric viral replication sites and comparative mechanisms
      of diarrhea induction may lead to new or improved vaccine strategies or
      therapeutic approaches for the prevention or treatment of these viral diarrheas.

PMID- 10659344
TI  - Molecular evolution of corona- and toroviruses.

PMID- 10659345
TI  - A viral enterotoxin. A new mechanism of virus-induced pathogenesis.
AB  - Acute infectious gastroenteritis is a major cause of infant morbidity in
      developed countries and of infant mortality in developing areas of the world.
      Rotavirus is recognized as the most important etiologic agent of infantile
      gastroenteritis, and studies of rotavirus serve as models to understand the
      complex interactions between enteric viruses and the multifunctional cells of the
      gastrointestinal tract. Understanding such interactions is significant for
      microbial pathogenesis because most (> 80%) infections are initiated at mucosal
      surfaces. Rotaviruses are pathogens that infect the mature enterocytes of the
      villi in the intestine and infection appears to be limited to these highly
      differentiated cells in immunologically competent hosts. In such hosts,
      infections are generally acute yet diarrheal disease can be severe and life
      threatening. Disease generally is resolved within 2-5 days after infection if
      affected hosts receive adequate rehydration. In immunocompromised hosts, virus
      infections persist, virus can be detected extraintestinally and virus excretion
      may be detected for extended periods of time (many months). Rotaviruses infect
      almost all mammalian and some avian species and much of our understanding of
      rotavirus pathogenesis has come from studies in animal models, particularly in
      small animal models (mice and rabbits), but also in larger animals (cows and
      piglets). Studies in children are limited due to the difficulty and lack of
      clinical need of obtaining biopsies from infants and the inability to determine
      the precise time of natural infections. In all animal species where naive animals
      can be infected, disease is age-dependent; for example, in mice and rabbits,
      diarrheal disease is the outcome of infections that occur only during the first
      two weeks of life (Ciarlet et al., 1998; Starkey et al., 1986; Ramig 1988; Ward
      et al., 1990; Burns et al., 1995), while animals remain susceptible to viral
      infection into adulthood. Rotavirus infections have been reported to occur
      repeatedly in humans from birth to old age, but the majority of infections after
      the first 2 years of life are asymptomatic or associated with mild
      gastrointestinal symptoms. The age-related resistance to rotavirus-induced
      diarrhea in humans is thought to be mediated primarily by acquired immunity, but
      it is not possible to directly test if humans also exhibit an age-dependent
      resistance to disease based on other factors such as intestinal development and
      maturation. Currently, our best understanding of the mechanisms of rotavirus
      pathogenesis rely on results obtained in animal models.

PMID- 10659346
TI  - Comparative pathology of bacterial enteric diseases of swine.
AB  - Enteric bacterial infections are among the most common and economically
      significant diseases affecting swine production worldwide. Clinical signs of
      these infections include diarrhea, reduced growth rate, weight loss, and death of
      preweaned, weanling, grower-finisher, young and adult age breeding animals. The
      most common etiological agents include Escherichia coli, Clostridium perfringens,
      Lawsonia intracellularis, Salmonella enterica, and Brachyspira (Serpulina) spp.
      With the exception of Brachyspira (Serpulina) hyodysenteriae, the cause of swine
      dysentery, and Lawsonia intracellularis, the cause of proliferative enteropathy,
      the pathological changes seen with these agents closely resemble the diseases
      occurring in human beings. Histological changes in the intestines of swine with
      enteric bacterial infections include bacterial colonization without significant
      damage (e.g., certain enterotoxigenic E. coli and C. perfringens type A),
      attaching and effacing lesions with enteropathogenic E. coli and Brachyspira
      pilosicoli, the cause of colonic spirochetosis, inflammation with S. enterica,
      and necrotizing and hemorrhagic lesions with certain C. perfringens.
      Extraintestinal spread of bacteria and/or toxins occurs with some serotypes of E.
      coli and most serotypes of S. enterica. Enteric bacterial diseases of swine have
      been used as models to study the pathogenesis of similar diseases of human
      beings. Several of these pathogens are also important causes of food-borne
      disease in humans.

PMID- 10659347
TI  - Mechanisms and impact of enteric infections.
AB  - The increased recognition of both old and new enteric pathogens and their
      potential impact requires an improved understanding of pathogenesis and effective
      interventions. While the overwhelming mortality (> 3 million children per year)
      due to diarrheal diseases is well-recognized, the potential long-term impacts of
      enteric infections and early childhood diarrhea morbidity are just beginning to
      be appreciated. Furthermore, several enteric infections are now being recognized
      as causes of growth shortfalls with or without diarrhea; i.e., malnutrition may
      be one of the greatest yet of the "emerging infectious diseases." The increased
      appreciation of this extended impact calls for further quantification and
      improved understanding of the deranged physiology. In particular, persistent
      diarrheal illnesses exhibit common themes of blunted villi, disruption of
      intestinal barrier function and varying degrees of sub-mucosal inflammation for
      which lactulose/mannitol permeability and fecal lactoferrin provide respective
      quantification. Finally, such improved understanding will allow targeted
      interventions among those most vulnerable, which will enable further
      documentation of cost effectiveness and the potential for improved human
      development which is critical to reducing the widening disparity and population
      overgrowth which increasingly threaten our global security.

PMID- 10659349
TI  - Reproduction of lesions and clinical signs with a CNF2-producing Escherichia coli
      in neonatal calves.
AB  - CNF2-producing necrotoxigenic E. coli (NTEC2) are associated with diarrhoea and
      septicaemia in calves. We orally inoculated neonatal calves with a NTEC2 strain
      in order to reproduce clinical signs and lesions. We observed diarrhoea in each
      inoculated calf, bacteraemia (80%), the presence of CNF2+ bacteria in the lungs
      (80%) and in the liver (20%). The observed lesions were inflammation of the
      entire gut, hypertrophy of the mesenteric lymph nodes and hepatisation of the
      lungs. We were unable to detect characteristic lesions that are classical signs
      of septicaemia.

PMID- 10659348
TI  - Insulin modulates intestinal response of suckling mice to the Escherichia coli
      heat-stable enterotoxin.
AB  - Effect of insulin on the response of suckling mice to the enterotoxigenic
      Escherichia coli heat-stable enterotoxin (STa) was studied. Four groups (8-10 in
      each group) of two day old Swiss Webster suckling mice were used. Five, 10, 25,
      and 50 micrograms of insulin were given orally to half the mice in each group
      respectively. The rest of the mice in each group were given normal saline as
      intra-litter controls. After 7 days, the suckling mouse assay for STa was
      performed on three mice from each insulin-treated and control groups. Enterocyte
      suspensions were prepared from mice in all groups. Intestinal tissue samples were
      taken for electron microscopy. Interaction of STa with its putative receptor on
      the enterocytes was evaluated using indirect immunofluorescence and flow
      cytometry. The suckling mouse assay revealed a significant increase in the gut
      weight to body weight ratio in all mice in the insulin treated groups compared to
      control mice (p < 0.05). Flow cytometry and indirect immunofluorescence analyses
      suggested that insulin had an upregulatory effect on the STa receptor level.
      Similarly, insulin was found to increase intestinal brush border membrane
      differentiation as indicated by the increase in the inward movement of milk
      particles through the intestinal mucosa. Insulin seems to modify the structure
      function of the brush border membrane including the response of suckling mice to
      STa. This study may provide further insights into the mechanism of STa/receptor
      interaction in diarrhea in newborn animals and human infants.

PMID- 10659350
TI  - The locus for enterocyte effacement (LEE) of enteropathogenic Escherichia coli
      (EPEC) from dogs and cats.
AB  - Enteropathogenic Escherichia coli (EPEC) produce attaching and effacing lesions.
      The genes responsible for this lesion are clustered on the chromosome forming a
      35.5 kilobase pathogenesis island called LEE. The LEE was identified,
      characterized and completely sequenced from the human EPEC strain E2348/69. The
      LEE carries genes coding for: a type III secretion system (genes esc and sep),
      the translocated intimin receptor (gene tir), the outer membrane protein intimin
      (gene eae) and the E. coli secreted proteins EspA, EspB, and EspD (genes esp). In
      addition to man and farm animals, EPEC are also isolated from dogs and cats. We
      studied structurally and functionally the LEE of dog and cat EPEC. First, we used
      four probes scattered along the LEE to identify the presence of a LEE in canine
      and feline EPEC isolates. Second, by PCR, we checked the presence of genes
      homologous to eae, sep, esp, and tir genes in these strains. Third, since the
      four types of eae and tir genes were described, we developed a multiplex PCR in
      order to determine the type of eae and tir genes present in each strain. Fourth,
      we determined by PCR the site of the LEE insertion on the chromosome. Fifth, we
      tested several of the canine EPEC in their capacity to induce attaching and
      effacing lesions in the rabbit intestinal loop assay. We can conclude from this
      study: first, that the a LEE-like structure is present in all tested strains and
      that it contains genes homologous to esp, sep, tir, and eae genes; second, that
      there is some preferential associations between the type of eae gene and the type
      of tir gene present in a strain; third, that the majority of the tested strains
      contained a LEE located elsewhere on the chromosome in comparison to the human
      EPEC strain E2348/69; and fourth that dog EPEC were able to induce attaching and
      effacing lesions in rabbit ileal loop assay.

PMID- 10659351
TI  - Age-dependent variation in the density and affinity of Escherichia coli heat
      stable enterotoxin receptors in mice.
AB  - Enterotoxigenic strains of Escherichia coli that produce heat-stable enterotoxin
      (STa), are a major cause of diarrheal disease worldwide. Resistance to diarrheal
      disease in human infants and newborn animals has been attributed to a gradual
      turnover in the intestinal brush border membrane receptors to bacterial pili. In
      this study, we demonstrated age-dependent variation in the density and affinity
      of the mouse enterocyte receptors specific for STa. Flow cytometry and
      radiolabeled-STa (125I-STa) assays were used as more reliable quantitative
      measures for the characterization of STa-enterocyte receptor interaction. These
      assays indicated a stronger interaction of STa with its putative receptor on the
      enterocytes of the 2-day-old suckling mice than with enterocytes from 1-week, 2
      week and 2-month-old mice. Scatchard plot analysis of 125I-STa-receptor
      interaction suggested that STa-receptors exist at a higher number on enterocytes
      from the 2-day-old mice than enterocytes of the older mice. Additionally,
      receptors from the 2-day-old mice had a greater affinity for STa ligand than
      receptors from the older mice. Density of STa receptors on enterocytes and their
      affinity to STa may determine the extent of binding and severity of secretory
      response. This may further explain the increased susceptibility of newborn
      animals and human infants to STa-mediated diarrheal disease.

PMID- 10659352
TI  - K88 adhesins of enterotoxigenic Escherichia coli and their porcine enterocyte
      receptors.
AB  - The three antigenic variants of the K88 fimbrial adhesin (K88ab, K88ac, and
      K88ad) of enterotoxigenic Escherichia coli (ETEC) each exhibit unique specificity
      with regard to their hemagglutination characteristics. The variants are also
      unique in the specificity of their binding to the brush borders of enterocytes
      isolated from pigs with different genetic backgrounds. Diversity in enterocyte
      binding specificity suggests the existence of several K88 receptors, expressed
      individually or in various combinations on porcine enterocytes. Three candidate
      receptors have been identified that may explain the adhesion of K88 fimbrial
      variants to various porcine enterocytes. These receptors are an intestinal mucin
      type sialoglycoprotein (IMTGP), an intestinal transferrin (GP74), and an
      intestinal neutral glycosphingolipid (IGLad). The IMTGP binds K88ab and K88ac,
      but not K88ad. The GP74 binds K88ab, but not K88ac or K88ad, and the IGLad binds
      K88ad, but not K88ab or K88ac. Each of the candidate receptors has been found in
      brush borders that are adhesive for the fimbriae that bind the respective
      receptor. They have not been found in brush borders that are not adhesive for
      those same fimbriae. The presence of IMTGP was highly correlated with
      susceptibility of neonatal gnotobiotic pigs to ETEC expressing K88ab or K88ac.

PMID- 10659353
TI  - Edema disease as a model for systemic disease induced by Shiga toxin-producing E.
      coli.
AB  - Edema disease (ED) is a naturally occurring disease of weaned pigs caused by host
      adapted strains of E. coli that produce Shiga toxin (STEC). We determined the
      temporal and quantitative relationships between intestinal colonization by STEC,
      levels of Shiga toxin (Stx2e) in the gut, in the blood, and clinical
      manifestations of ED. Bacterial colonization (10(8) CFU/cm ileum) was highest 4
      days post inoculation (pi) in animals that did not develop clinical disease and 6
      days pi in animals with clinical signs of ED. The mean time for the development
      of clinical signs of ED was 6 days pi (range 4-10). Average peak titers of Stx2e
      in the ileum were 1:16,384 in asymptomatic animals and 1:32,768 in clinical
      animals. Titers of Stx2e in the feces reflected the toxin titers in the ileum but
      were lower. Intestinal titers of Stx2e and the density of bacterial colonization
      were predictive of clinical ED for a group of animals but not for individuals.
      Approximately 50% of the pigs that had Stx2e titers of > or = 1:4096 and a
      bacterial density of > or = 10(6) CFU/cm in their ileum, had clinical ED. Pigs
      that had intestinal Stx2e titers < 1:4096 were asymptomatic. Stx2e was detected
      in the red cell fraction of blood from some of the pigs with clinical ED and in
      some that were asymptomatic. Stx2e was not detected in the serum of any animals.
      ED may be a useful model for predicting the temporal and quantitative
      relationships between bacterial colonization, Stx levels in the gut and blood and
      systemic disease for STEC in other species.

PMID- 10659354
TI  - Ultrastructure and DNA fragmentation analysis of arterioles in swine infected
      with Shiga toxin-producing Escherichia coli.
AB  - Shiga toxins (Stx) produced by E. coli are potent cytotoxins that affect the
      vascular system. In humans, systemic toxemia causes renal glomerular damage
      manifested as hemolytic uremic syndrome. In swine, Stx-producing E. coli (STEC)
      cause edema disease that is characterized microscopically by segmental arteriolar
      smooth muscle cell (SMC) lesions. Our objectives were to characterize
      ultrastructurally and by TUNEL the type of death (apoptosis or necrosis) that
      occurs in SMCs during edema disease. Increased DNA fragmentation consistent with
      apoptosis was detected by TUNEL in arterioles of challenged pigs 14-15 days post
      inoculation. Ultrastructurally 3 grades of SMC lesions were distinguished: 1)
      Partial loss of SMCs, intercellular space filled with granular cellular debris
      admixed with membrane bound vacuoles; 2) Complete loss of SMCs; only granular
      cellular debris and clear vacuoles remained within basement membrane; 3)
      Inflammation of media; SMCs replaced by a rim of cellular debris located in the
      periphery of vessel wall. The most common lesion detected was grade 1 (9 ilea and
      4 brains). We did not find apoptotic nuclear changes in SMCs or apoptotic
      inclusion bodies within resident cells. Our study indicates, that (1) Stx
      produced during edema disease does not cause SMC apoptosis 14-15 dpi; (2) SMCs
      undergo an array of changes from degeneration to necrosis.

PMID- 10659355
TI  - Pathogenesis of Escherichia coli O157:H7 in weaned calves.
AB  - Cattle are an important reservoir of Shiga toxin-producing Escherichia coli
      O157:H7 and other enterohemorrhagic E. coli (EHEC) that cause diarrhea,
      hemorrhagic colitis, and hemorrhagic uremic syndrome in humans. One strategy for
      reducing human foodborne EHEC infections is to reduce the levels of EHEC in
      cattle. Bovine O157:H7 infection models will facilitate identification of
      virulence factors involved in bovine infections. O157:H7 cause severe diarrhea
      and attaching and effacing (A/E) mucosal lesions in colostrum-deprived neonatal
      (< 2 h) calves. We hypothesized that O157:H7 also cause A/E lesions in older
      calves, but these were not detected in earlier studies because intestinal levels
      of O157:H7 were too low (< 10(6) CFU/g of tissue) for detection of focally
      distributed microscopic lesions. Weaned 3- to 4-month-old calves were fasted 48
      h, inoculated via stomach tube with 10(10) CFU of O157:H7 or nonpathogenic E.
      coli, necropsied 4 d pi and examined histologically. Calves inoculated with
      O157:H7 had higher intestinal levels of inoculated E. coli than control animals.
      The rectum was the major site of colonization. A/E lesions were seen in the
      rectum and cecum of calves with high levels of O157:H7. Weaned calves, like
      neonatal calves, are susceptible to intestinal damage induced by EHEC O157:H7.
      The rectum and cecum may be principal sites of EHEC O157:H7 colonization during
      the carrier-shedder state in cattle.

PMID- 10659356
TI  - Distribution of a novel locus called Paa (porcine attaching and effacing
      associated) among enteric Escherichia coli.
AB  - Using TnphoA transposon insertion mutagenesis, we found a porcine EPEC (PEPEC)
      mutant demonstrating as inability to induce AE lesions. The insertion was
      identified in a gene designated paa (porcine attaching and effacing associated).
      The distribution of paa in PEPEC O45 strains revealed that it was associated with
      presence of the eae and its AE phenotype in vivo. On examination of enteric E.
      coli isolates from humans and various animal species, a strong correlation with
      the presence of paa was found in EHEC O157:H7 and O26, and dog, rabbit, and pig
      eae-positive isolates, and to a lesser extent in human EPEC eae-positive
      isolates. Also, among porcine ETEC isolates, a strong association was found with
      the presence of LT encoded genes. In contrast, paa sequence was rarely found in
      enteric E. coli isolates lacking ETEC and AEEC virulence determinants. Thus, our
      results suggest that Paa could play a role in the AE mechanism and other
      mechanisms of enteric disease.

PMID- 10659357
TI  - Potentiation of the effectiveness of Lactobacillus casei in the prevention of E.
      coli induced diarrhea in conventional and gnotobiotic pigs.
AB  - The influence of preventive administration of Lactobacillus casei subsp. casei
      and maltodextrin KMS X-70 on Escherichia coli 08: K88 adhesion in the
      gastrointestinal tract of 11 conventional and 6 gnotobiotic piglets was
      investigated. The preventive administration of L. casei alone had almost no
      inhibitory effect on the adherence of E. coli to the jejunal mucosa of
      gnotobiotic and conventional piglets while the lactobacilli administered together
      with maltodextrin decreased the number of E. coli colonising jejunal mucosa of
      gnotobiotic piglets by 1 logarithm (4.95 log 10/cm2) in comparison with the
      control group (5.96 log 10/cm2). L. casei administered in combination with
      maltodextrin decreased the number of E. coli colonising the jejunum of
      conventional piglets by more than two and half logarithm (4.75 log 10/cm2, p <
      0.05) in comparison with the control (7.42 log 10/cm2). The inhibitory effect of
      Lactobacillus casei and maltodextrin KMS X-70 on the adhesion of E. coli to the
      intestinal mucosa of conventional and gnotobiotic pigs was probably mediated by
      Lactobacillus--produced antibacterial substances and stimulation of immunity.

PMID- 10659358
TI  - Recovery from colonic infection elicits serum IgG antibodies to specific
      Serpulina pilosicoli outer membrane antigens (SPOMA).
AB  - Colonic spirochetosis caused by S. pilosicoli is a disease of human and animals
      characterized by intimate attachment of the spirochete to colonic epithelial
      cells and colitis. To identify antigens that are potentially involved in recovery
      from the disease, whole-cell lysate (WC) and various detergent extracts including
      Sarkosyl-soluble (SS) and insoluble (SI), and Triton X-114 detergent phase (TXD)
      and aqueous phase (TXA) of the human isolate SP16 were examined by Western
      blotting with Serpulina spp. periplasmic flagellar protein FlaB-specific
      monoclonal antibody 7G2 as well as pooled pre-immune serum (PS), hyperimmune
      serum (HS), and convalescent serum (CS) from swine. The HS reacted with several
      antigens that were not identified by the CS, including the periplasmic flagellar
      proteins and some lower molecular weight bands. The CS identified three major
      immunoreactive double (D) or single (S) bands of approximately: (i) 64-kDa in the
      WC(S), SS(D), and TXD/A(S), (ii) 54-kDa in the WC(S), SS/I(S), and TXD(S), and
      (iii) 47-kDa in the SS(S) fraction. The data indicate recovery from colonic
      infection elicits serum IgG antibodies to specific S. pilosicoli outer membrane
      antigens (SPOMA).

PMID- 10659359
TI  - Motility-regulated mucin association of Serpulina pilosicoli, the agent of
      colonic spirochetosis of humans and animals.
AB  - Colonic spirochetosis is a disease of humans and animals characterized by
      colonization of the colonic mucus gel and intimate attachment of Serpulina
      pilosicoli to the apical membrane of enterocytes. Motility-regulated mucin
      association plays a key role in colonic infection by the related spirochete
      Serpulina hyodysenteriae, the cause of swine dysentery. In this study the
      chemotaxis of Serpulina pilosicoli porcine isolate P43/6/78, human isolate SP16,
      and canine isolate 16242-94 was examined by anaerobic incubation of each
      spirochete in control medium or medium containing increasing concentrations of D
      L serine or porcine gastric mucin (PGM). The porcine isolate had a chemotactic
      response towards 10 mM D-L serine, but not towards PGM. By contrast, the human
      and canine isolates were attracted towards 0.1% PGM, but not towards DL-serine.
      The composition of the growth medium appeared to modulate the chemotactic
      response of S. pilosicoli towards PGM; the loss of a chemotactic response of
      spirochetes grown in medium without pig fecal extract was restored by growing the
      spirochetes in medium containing 0.1% PGM. Serpulina pilosicoli displays a
      chemotactic response towards PGM which is modulated by the presence of certain
      substrate during the growth phase of the spirochete.

PMID- 10659360
TI  - Coiling phagocytosis is the predominant mechanism for uptake of the colonic
      spirochetosis bacterium Serpulina pilosicoli by human monocytes.
AB  - Serpulina pilosicoli is a newly identified pathogenic spirochete that establishes
      persistent colonic infections in human beings and animals. Macrophages are one of
      the key defenses against invasion of mucosal surfaces by bacterial pathogens.
      Macrophages engulf many bacteria by conventional phagocytosis; however recent
      studies indicate coiling phagocytosis as a new and important mechanism for
      internalization of Legionella pneumophila and spirochetes of the genus Borrelia,
      Leptospira, and Treponema. In this study, THP-1 human monocytic cells were
      incubated with the human S. pilosicoli strain SP16 and the contribution of
      coiling and conventional phagocytosis to the total number of phagocytic events
      were determined by sequential ultrastructural examination between 5 and 45
      minutes. The frequency of phagocytosis increased over time from 5.1% after 5
      minutes up to 21.9% after 45 minutes with greater than 70% of the events
      involving coiling phagocytosis. The data indicate that coiling phagocytosis may
      be a universal mechanism for uptake of pathogenic spirochetes.

PMID- 10659361
TI  - Identification of proteins required for the internalization of Campylobacter
      jejuni into cultured mammalian cells.
AB  - Clinical and in vitro experimental data suggest that invasion of intestinal
      epithelial cells is an essential step in the pathogenesis of Campylobacter jejuni
      mediated enteritis. However, the molecular mechanism of C. jejuni internalization
      remains poorly defined. The goal of this study was to identify a gene that
      encodes a protein required for the internalization of C. jejuni into host cells.
      A C. jejuni gene, designated ciaB, was identified upon immunoscreening C. jejuni
      genomic DNA-phage libraries with an antiserum generated against C. jejuni co
      cultivated with INT 407 cells. The C. jejuni ciaB gene encodes a protein of 610
      amino acids with a calculated molecular mass of 73,154 Da. The deduced amino acid
      sequence of the CiaB protein shares similarity with type III secreted proteins,
      associated with invasion of host cells, from other more extensively characterized
      bacterial pathogens. In vitro binding and internalization assays revealed that
      the binding of C. jejuni ciaB null mutants was indistinguishable from that of the
      parental isolate, whereas a significant reduction was noted in internalization.
      Immunoblot analysis using an anti-CiaB specific antibody revealed that CiaB is
      secreted into the supernatant fluids upon co-cultivation of C. jejuni with INT
      407 cell conditioned medium. Metabolic labeling experiments revealed that at
      least eight C. jejuni proteins, ranging in size from 12.8 to 108 kDa, are
      secreted into the culture medium. C. jejuni ciaB null mutants were deficient in
      the secretion of all proteins, indicating that CiaB is required for the secretion
      process. Identification of the C. jejuni ciaB gene represents a significant
      advance in understanding the molecular mechanism of C. jejuni internalization.

PMID- 10659362
TI  - Secretion of Campylobacter jejuni Cia proteins is contact dependent.
AB  - Campylobacter jejuni is a common cause of human gastrointestinal disease
      worldwide. Despite the prevalence of C. jejuni infections, the mechanisms of C.
      jejuni pathogenesis remain ill-defined. Invasion of the cells lining the
      intestinal tract is hypothesized to be essential for the development of C. jejuni
      mediated enteritis. Recent studies in our laboratory have revealed that C. jejuni
      secrete proteins, termed Cia for Campylobacter invasion antigens, upon incubation
      with human intestinal cells. A mutation in one of the genes encoding a secreted
      protein resulted in an invasion-deficient phenotype. The purpose of this study
      was to identify a component capable of stimulating the synthesis and secretion of
      the Cia proteins from C. jejuni. Here, we report that these processes can be
      induced upon incubating C. jejuni in medium supplemented with fetal bovine serum.
      The synthesis and secretion of the Cia proteins were not affected by heat
      treatment of the fetal bovine serum, indicating that the stimulating molecule in
      serum is heat stable. The stimulatory molecule was not unique to fetal bovine
      serum as sera from other sources including human, pig, sheep, goat, rabbit,
      mouse, and chicken also induced the synthesis and release of the Cia proteins.
      These findings indicate that the synthesis and secretion of the Cia proteins can
      be induced in a cell-free system by incubating C. jejuni in serum-supplemented
      tissue culture medium.

PMID- 10659363
TI  - Codon usage in the A/T-rich bacterium Campylobacter jejuni.
AB  - Campylobacter jejuni is a Gram negative, microaerophilic pathogen that causes
      gastroenteritis in humans. The genome of C. jejuni is AT-rich, with a mol% G + C
      of 30.4. This high AT content was hypothesized to result in unique codon usage.
      In the present study, we analyzed the codon usage of sixty-seven C. jejuni genes
      and generated a codon frequency table. As predicted, the codon usage of C. jejuni
      revealed a strong bias towards codons ending in A or U. In addition to
      determining codon usage frequencies, the relative synonymous codon usage values
      were calculated to identify rare and optimal codons. Seventeen codons were
      identified as optimal and twelve codons as rare. Thirty-two codons exhibited
      little or no bias. A plot of the effective number of codons versus the third
      position %G + C values for the sixty-seven genes revealed that C. jejuni uses an
      average of 39 of the 61 codons to encode proteins. These data will be useful for
      various molecular analyses including selection of degenerate primers to screen C.
      jejuni-genomic DNA libraries.

PMID- 10659364
TI  - Prevalence of Campylobacter, Salmonella, and Arcobacter species at slaughter in
      market age pigs.
AB  - A survey was conducted to determine the prevalence of Campylobacter, Salmonella,
      and Arcobacter species in market age pigs from an integrated swine operation in
      Texas. Our findings indicate that farms from this commercial operation were
      heavily contaminated with Campylobacter and Salmonella, that the isolation rates
      of C. jejuni were higher than predicted, and that there was a low prevalence of
      Arcobacter.

PMID- 10659365
TI  - Cryptosporidium parvum gene discovery.
AB  - Cryptosporidium parvum is a well-recognized cause of diarrhea in humans and
      animals throughout the world, and is associated with a substantial degree of
      morbidity and mortality in patients with acquired immunodeficiency syndrome
      (AIDS). At the present time, there is no effective therapy for treating or
      preventing infection with C. parvum. This is primarily due to a lack of
      understanding of the basic cellular and molecular biology of this pathogen in
      terms of virulence factors, genome structure, gene expression, and regulation.
      Over the past few years, large-scale sequencing of randomly selected cDNAs or
      fragments of genomic DNA has proven to be an efficient approach for obtaining
      large amount of genomic information. Recently, large-scale sporozoite expressed
      sequence tag (EST) and genomic sequence tag (GST) projects have been initiated
      for C. parvum. These projects have greatly increased the number of C. parvum
      genes identified and demonstrate the usefulness of large-scale sequencing for
      expanding our understanding of C. parvum biology. Continued characterization of
      the C. parvum genome will increase our basic understanding of the cellular and
      molecular biology of C. parvum in terms of gene and genome structure, and will
      identify key metabolic and pathophysiologic features of the organism for future
      development of safe and effective strategies for prevention and treatment of
      disease.

PMID- 10659366
TI  - Norepinephrine stimulates in vitro growth but does not increase pathogenicity of
      Salmonella choleraesuis in an in vivo model.
AB  - Norepinephrine stimulates growth of Escherichia coli, Yersinia enterocolitica,
      and Pseudomonas aeruginosa in serum-supplemented media, and in vivo increases in
      norepinephrine may be important in the pathogenesis of sepsis by gram-negative
      bacteria. Because salmonellosis often is associated with stress, the effects of
      norepinephrine on in vitro growth, and in vivo pathogenicity of the swine
      pathogen Salmonella choleraesuis were investigated. When RPMI 1640 with and
      without pig serum was inoculated with fewer than 100 S. choleraesuis/ml and
      incubated overnight, bacterial numbers were 10(4) to 10(6) lower in RPMI
      containing serum. Norepinephrine restored bacterial growth in RPMI with serum to
      normal levels, but it did not increase growth in serum-free RPMI. Similar results
      were obtained with SAPI, a nutrient-poor medium previously used to study the
      effect of norepinephrine on growth of gram-negative bacteria. Conditioned media
      were produced by growing S. choleraesuis in RPMI containing serum with and
      without norepinephrine and filter sterilizing. Conditioned medium produced with
      norepinephrine stimulated growth of S. choleraesuis but not E. coli, whereas
      conditioned medium produced without norepinephrine stimulated growth of both
      bacteria. To determine the in vivo effects of norepinephrine, rats were implanted
      with tablets that secrete norepinephrine for 20 to 24 hours or with identical
      tablets without norepinephrine and infected intraperitoneally with graded doses
      of S. choleraesuis. The LD-50 of S. choleraesuis was the same in both groups, and
      norepinephrine did not affect the carrier rate at 30 days after infection. We
      concluded that although norepinephrine stimulates in vitro growth of S.
      choleraesuis in serum-based media, the increase in norepinephrine levels in the
      present in vivo system was probably not sufficient to influence the pathogenesis
      of S. choleraesuis infection.

PMID- 10659367
TI  - Of mice, calves, and men. Comparison of the mouse typhoid model with other
      Salmonella infections.
AB  - Numerous Salmonella typhimurium virulence factors have been identified and
      characterized using experimental infection of mice. While the murine typhoid
      model has been used successfully for Salmonella typhi vaccine development and to
      infer virulence mechanisms important during typhoid fever, information derived
      from infection of mice has been of limited value in elucidating the mechanisms by
      which S. typhimurium causes enteritis in humans. Progress in our understanding of
      virulence mechanisms contributing to diarrheal disease comes from recent studies
      of bovine enteritis, a S. typhimurium infection, which manifests as acute
      gastroenteritis. This review compares virulence genes and mechanisms required
      during murine typhoid, typhoid fever, and bovine enteritis. Comparison of
      illnesses caused in different animal hosts identifies virulence mechanisms
      involved in species specific disease manifestations. The determination of the
      relative importance of virulence factors for disease manifestations in different
      host species provides an important link between the in vitro characterization of
      genes and their role during host pathogen interaction.

PMID- 10659368
TI  - Sips, Sops, and SPIs but not stn influence Salmonella enteropathogenesis.
AB  - The virulence factors influencing Salmonella-induced enteropathogenesis remain
      poorly characterised. The interactions of different serotypes of Salmonella with
      bovine ileal mucosa have been characterised in the ligated ileal loop model. In a
      quantitative intestinal invasion assay Salmonella dublin, S. choleraesuis, S.
      gallinarum, and S. abortusovis strains were all recovered from ileal mucosa,
      either with or without Peyer's patches in similar numbers. This observation
      suggests that the magnitude and route of intestinal invasion does not mediate
      Salmonella serotype host specificity. Despite being equally invasive there was a
      clear hierarchy in the enteropathogenicity of these serotypes. The magnitude of
      the enteropathogenic responses did not correlate to serotype host specificity.
      These observations implicate undefined serotype specific factors in influencing
      enteropathogenicity independently of intestinal invasion. Disruption of genes in
      Salmonella Pathogenicity Island (SPI) 1 of S. typhimurium and S. dublin blocked
      the secretion of Salmonella Invasion Proteins (Sips) and Salmonella Outer
      Proteins (Sops). These mutants were significantly less invasive and
      enteropathogenic then the wild type strain in ligated ileal loops. Disruption of
      sopB and sopD significantly reduced enteropathogenesis, but without influencing
      intestinal invasion. These two genes appear to act in concert. Surprisingly,
      disruption of stn, the Salmonella enterotoxin gene cloned on the basis of its
      homology to cholera toxin, did not influence enteropathogenesis. SopB was mapped
      to the 20 centisome of S. typhimurium and is flanked by 5 genes that are
      organised in a manner typical of a pathogenicity island, which we have termed SPI
      5. Mutation of the other genes in SPI-5 also attenuated enteropathogenesis but
      not virulence for mice, suggesting SPI-5 is a key locus specifically influencing
      Salmonella enteropathogenesis.

PMID- 10659369
TI  - Phase variable switching of in vivo and environmental phenotypes of Salmonella
      typhimurium.
AB  - Previously it was shown that S. typhimurium strain 798, which is known to cause
      persistent asymptomatic infections in pigs, exists in two phenotypes. One
      phenotype, which is called adhesive, was shown to produce pili, is adhesive to
      porcine enterocytes, is readily phagocytized, and then survives intracellularly
      in phagocytes. The other phenotype, termed non-adhesive, does not produce pili,
      does not attach to enterocytes, is phagocytized less efficiently, and does not
      survive within the phagocyte. Cells in each phenotype can freely switch to the
      other phenotype at a fairly high frequency and thus the shift between each
      phenotype is phase variation. Further analysis of these phenotypes identified 4
      additional characteristics that were co-regulated by phase variation. The first
      is the enterocyte-specific adhesin, which was shown to be type 1 fimbriae.
      Mutations in fimA, the major pilin molecule, led to a decreased ability to
      colonize the gut of pigs and mice. The second characteristic is O-antigen
      production. Adhesive cells produce a long O-antigen (up to 18 subunits) while non
      adhesive cells do not (only 1-2 subunits). The long O-antigen produced by the
      adhesive cells leads to resistance to serum and appears to be the result of phase
      variable expression of rfaL. A third locus, ebu, has been identified based on
      differential color production of colonies growing on Evans blue-Uranine plates.
      The relationship of this trait to in vivo survival or virulence is not known but
      ebu is genetically related to a family of transcriptional activators. The fourth
      locus, prv is located on the virulence plasmid and a mutation in prv results in
      delayed time to death in mice. It is hypothesized that the adhesive phenotype is
      the in vivo, virulent form, while the non-adhesive phenotype is the
      environmental, avirulent form. By modulating the fraction of cells in each phase,
      persistent asymptomatic infections can be promoted.

PMID- 10659370
TI  - A preliminary survey of antibiotic resistance of Salmonella in market-age swine.
AB  - We conducted an epidemiological survey of antibiotic resistance in Salmonella
      recovered from market-age swine at five different Texas farms. These farms, which
      were visited between October 1997 and June 1998, were completely integrated,
      farrow-to-finish operations. Samples were taken from the lymph nodes and cecal
      contents at the time of slaughter. The Salmonella samples that were recovered
      were sent to the National Veterinary Services Laboratory for serotyping.
      Antibiotic resistance was determined using the Dispens-O-Disc Susceptibility Test
      System using 13 different antimicrobial agents that have been utilized in either
      veterinary medicine, human medicine, or both. Preliminary analysis of the first
      183 samples out of approximately 400 Salmonella samples recovered indicated that
      183 (100%) of the Salmonella samples were resistant to penicillin G, and 122
      (66.7%) were resistent to chlortetracycline. Six (3.3%) were resistant to four
      antibiotics (chlortetracycline, penicillin G, streptomycin, and sulfisoxazole),
      and 25 (13.7%) were resistant to three antibiotics (chlortetracycline, penicillin
      G, and either streptomycin, sulfisoxazole, or ampicillin). Variation was seen
      between serotypes, with four out of five S. agona samples (80.0%) and two out of
      eight S. derby samples (25.0%) resistant to four antibiotics. Variation in
      antibiotic resistance also was seen between farms. There is an increasing concern
      about the prevalent usage of antibiotics in medicine and agriculture and the
      relationship this may have on emerging microbial resistance patterns; therefore,
      continued surveillance on antibiotic resistance in animal production is
      warranted.

PMID- 10659371
TI  - Prophylactic administration of immune lymphokine derived from T cells of
      Salmonella enteritidis-immune pigs. Protection against Salmonella choleraesuis
      organ invasion and cecal colonization in weaned pigs.
AB  - Experiments involving 132 weaned piglets were conducted to evaluate the efficacy
      of a Salmonella enteritidis-immune lymphokine (PILK) derived from the T cells of
      Salmonella enteritidis (SE)-immunized pigs to protect weaned piglets from
      Salmonella choleraesuis (SC) infection. Fourteen-to-seventeen day-old piglets
      were weaned and randomly placed into 1 of 5 groups: (1) noninfected controls, (2)
      PILK 3X noninfected, (3) SC infected controls, (4) PILK 1X SC infected, and (5)
      PILK 3X SC infected. PILK was given orally either one time (PILK 1X) or three
      times (PILK 3X) over 14 days. One hour after the first PILK administration on day
      0, piglets were orally challenged with 10(7) cfu of SC. Weights were recorded on
      day 0, day 7, and day 14. On day 14, pigs in groups 3, 4, and 5 were sacrificed
      and organs and lymph tissue were cultured for the presence of SC. Three
      replicates of this experiment were pooled and anlayzed. A significant reduction
      in the number of pigs positive for SC in the liver, lung, and spleen was found in
      group 5 (PILK 3X) when compared to group 3 (inf. cont. p < 0.001[). The number of
      SC positive cecal contents was dramatically reduced in group 5 group when
      compared to group 3, with the PILK 3X group showing 13% positive pigs versus
      55.2% in the infected controls (p < 0.05). Weight gain over the 14 day study in
      the infected PILK 3X group (group 5) was found to be comparable to the gain
      observed in the group 1 (noninfected controls). The pigs receiving PILK 3X (group
      2) with no SC challenge gained significantly more weight than all other groups,
      including the noninfected controls (group 1 p < 0.05[). The results of these
      experiments indicate that PILK protects against SC infection in weaned pigs while
      enhancing performance in the presence of an SC infection.

PMID- 10659372
TI  - Sialic acid dependence and independence of group A rotaviruses.
AB  - We have found (1), in contrast to previous reports, the human rotavirus Wa strain
      is sialic acid-dependent for binding to and infectivity of MA-104 cells and (2),
      a dual carbohydrate binding specificity is associated with both human Wa and
      Porcine OSU rotaviruses. One carbohydrate binding activity is associated with
      triple-layered virus particles (TLP) and the other with double-layered virus
      particles (DLP). In binding and infectivity studies, we found that gangliosides
      were the most potent inhibitors of both the human and procine rotavirus TLP.
      Furthermore, glycosylation mutant cells deficient in sialylation or neuraminidase
      treated MA104 cells, did not bind rotavirus TLP from either strain. Our results
      show that human Wa binding and infectivity cannot be distinguished from the
      porcine OSU strain and appears to be sialic acid-dependent. Direct binding of
      human or porcine TLP to a variety of intact gangliosides was demonstrated in an
      thin-layer chromatographic (TLC) overlay assay. Human or porcine rotavirus DLP
      did not bind to any of the intact gangliosides but surprisingly bound
      asialogangliosides. This binding was abolished by prior treatment of the
      glycolipids with ceramide glycanase suggesting the intact asialoglycolipid was
      required for DLP binding. After treatment of either human or porcine TLP with
      EDTA to remove the outer shell, virus particles bound only to the immobilized
      asialogangliosides. These results suggest that rotavirus sugar binding
      specificity can be interpreted either as sialic acid-dependent or independent
      based on whether the virus preparation consists primarily of triple-layered or
      double-layered particles. Of perhaps greater interest is the possibility that
      sialic acid-independent carbohydrate binding activity plays a role in virus
      maturation or assembly.

PMID- 10659373
TI  - New approaches to mucosal immunization.
AB  - Every year more than 17 million deaths worldwide are caused by infectious
      diseases. The great majority of these deaths occur in underdeveloped countries
      and are attributed to diseases preventable by existing vaccines, or diseases that
      could potentially be prevented with new vaccines. The fact that most human and
      veterinary pathogens establish infection in the host by initiating contact at a
      mucosal surface, provide the rationale for the development of mucosal vaccines.
      An increasing number of strategies have been proposed to facilitate mucosal
      immunization. Among the most widely investigated strategies are the use of
      attenuated microorganisms; the inclusion of immunizing antigens in lipid-based
      carriers, the genetic creation of transgenic plants and the use of mucosal
      adjuvants derived from bacterial toxins. This review provides a brief summary of
      the most recent advances in the field of mucosal immunization with an special
      emphasis on a promising genetically detoxified mucosal adjuvant, LT(R192G),
      derived from the heat-labile toxin of enterotoxigenic E. coli. We present
      evidence regarding the safety, immunogenicity, and efficacy of LT(R192G) for the
      development of a new generation of mucosal vaccines.

PMID- 10659374
TI  - Acute effects of using a mobile phone on CNS functions.
AB  - Twenty volunteers participated in two experiments exploring the acute effects of
      using the mobile phone Motorola GSM 8700 on the functions of the CNS. When
      speaking (5 minutes reading a text from daily newspapers) the electromagnetic
      fields from the mobile apparatus did not affect the visual evoked potentials.
      Also a 6-min exposure did not reveal any effect of electromagnetic fields on the
      results in two tests (memory and attention) performed while speaking into the
      mobile. On the other hand the phone call itself strongly influenced the
      performance in a secondary task applying a test of switching attention which is a
      good model for driving a car. The response and decision speed were significantly
      worse. This is a proof that even a slight psychological stress involved in
      calling while driving can be a great risk.

PMID- 10659375
TI  - Alternative treatment of the carpal tunnel syndrome.
AB  - Carpal tunnel syndrome (CTS) is a painful disease of the wrist which is usually
      treated with corticoids locally or surgically. In this study combined infusion
      therapy with procain, pentoxyphyllin and magnesium sulphuricum in patients with
      CTS was evaluated retrospectively. 101 manually working patients (65 male, 36
      female) aged 42.8 +/- 8.6 years, initially examined at our department to assess
      professional origin of the disease and who had abnormal conduction to the distal
      section of median nerve on electromyography (EMG), were entrolled. The group of
      patients was heterogenous etiologically. 41% of patients were found to be exposed
      to overlimit vibrations, while 21% of patients were exposed to overload of upper
      extremities and 16% patients to both the risks. The professional hazard was not
      proved in 23% of patients. In these patients 166 CTS were diagnosed of which 144
      improved after the treatment, while the condition remained unchanged in 11 and
      even worsened in another 11 cases. Using the clinical and EMG criteria the
      findings were divided to mild, moderate and severe CTS. 77 mild CTS improved by
      61% in average, 63 moderate CTS were improved by 47% and 26 of severe CTS
      improved by 50%. There was no association between the treatment outcome and sex,
      age or severity of symptoms. Patients with unfavourite outcome and the possible
      causes of treatment failure are discussed in detail.

PMID- 10659376
TI  - Plesiomonas shigelloides in water and fish.
AB  - Plesiomonas shigelloides strains isolated from aquariums, surface water and fish
      were serotyped using the international antigenic scheme and a provisional scheme
      designed for environmental strains, called the "Schubert" scheme. A remarkable
      variety of serovars represented in both schemes was found, namely in surface
      water samples and in fish.

PMID- 10659377
TI  - Status of magnesium, selenium and iodine saturation in the population of seven
      regions in the Czech Republic.
AB  - In seven regions of the Czech Republic the magnesiuria and calciuria were
      determined photometrically using the apparatus Merck Vitalab Eclipse, the
      selenuria fluorimetrically and the ioduria photometrically after alkaline
      mineralization in the morning sample of urine (after night fasting) in subjects
      aged 6-65 years (3,587 probands) selected at random. The lowest magnesiuria was
      found in children in Klatovy district (5.36 nmol/l +/- 0.11) and the highest
      magnesiuria was estimated in children from the Usti nad Labem district (6.59
      mmol/l +/- 0.16). In adults the lowest magnesiuria was in Vsetin region (3.78
      mmol/l +/- 0.08). Selenuria was lowest in Jindrichuv Hradec (7.60 micrograms/l +/
      0.30) and highest in the Vsetin district (15.07 micrograms/l +/- 0.50). Adults
      had the lowest selenuria in the region Jindrichuv Hradec (7.67 micrograms/l +/-
      0.30) and the highest in Usti nad Orlici (11.68 micrograms/l +/- 0.34). The
      lowest ioduria was estimated in children from Usti nad Labem (94.30 micrograms/l
      +/- 2.06) and the highest in the Vsetin region (151.60 micrograms/l +/- 7.55).
      Adults from the district Jindrichuv Hradec had ioduria merely (77.7 micrograms/l
      +/- 2.18) and the highest ioduria was found in probands from the Znojmo region
      (123.30 micrograms/l +/- 4.47). As far as the dependence on age is concerned, the
      magnesiuria significantly decreases both in children and in adults with the
      increasing age. Selenuria decreases in adults significantly with growing age. Sex
      related differences were estimated in children aged 6 years where girls had
      significantly lower selenuria than boys and girls aged 13 years had lower
      ioduria, magnesiuria and selenuria than boys. Women aged 18-35 years had
      significantly lower ioduria, calciuria and magnesiuria in comparison with men of
      the same age. Women have a significantly lower ioduria in comparison with men at
      the age 56-65 years.

PMID- 10659378
TI  - Microbiological control of the water bottling process.
AB  - Psychrophilic and mesophilic bacteria counts were detected in samples taken from
      10 sites in filling line for bottled waters (table and baby waters). Increased
      microorganisms count were located behind the sand filter and the aeration unit
      (10(2) CFU/ml). We recommend intensified sanitation of the aeration columns.

PMID- 10659379
TI  - Spectral coherence between blood pressure and inter-beat intervals in
      hypertension.
AB  - Continuous registration of blood pressure (BP) was obtained in 31 normotensives
      and 76 hypertensives (divided into 3 stages of hypertension) by a method where
      the blood pressure in a human finger was measured non-invasively in a beat-by
      beat fully calibrated manner. From this signal, the power density spectra of
      inter-beat intervals (IBI), systolic blood pressure (SBP) and diastolic blood
      pressure (DBP) were derived. Total spectral power (TP) and low/high spectral
      frequency ratios of all spectra were calculated. Cross-correlation analysis
      between IBI, SBP and DBP spectra showed that the level of amplitude and phase
      spectral coherence (SC) was strongly dependent of the stage of hypertension. SC
      was calculated by means of appropriate mathematical algorithms. Multiple step
      regression analysis pointed out that the observed phenomenon is highly
      significant for both--the amplitude and the phase SC (p < 0.01).

PMID- 10659380
TI  - National Tuberculosis Programme in Romania 1997-2000: how it works.
AB  - Romania displays one of the highest epidemiological parameters of tuberculosis
      among European countries: the incidence reached 113.3 per 100,000 in 1998, the
      prevalence of chronic cases was 18.9 and mortality 11.5 per 100,000 in 1996. A
      National Tuberculosis Programme aimed at decreasing the present burden of the
      disease has been elaborated according to the WHO strategy in 1997 and for its
      implementing. The National Committee on Pneumophtisiology and the Central Unit of
      the National Institute of Pneumophtisiology were made responsible. Tuberculosis
      managers and supervisors were nominated in each of the 48 counties and a total of
      18,000 family doctors were involved in this programme at the primary health care
      level. Tuberculosis has been declared the second health priority in Romania and
      the following budget providers for its effective control were acquired: Ministry
      of Health, World Bank, Open Society Foundation, Funds of Romania and World Health
      Organization. The following achievements can be mentioned so far: A technical
      manual on the National Programme has been published, WHO modules on DOTS strategy
      were translated into Romanian, a training course on the WHO-DOTS strategy was
      organized for tuberculosis managers and laboratory chiefs, a pilot project on the
      WHO-DOTS strategy started in lasi, first control visits in counties and
      pneumophtisiologists were implemented, training for family doctors was organized
      and a project for health education with video shots was presented on the national
      TV channel.

PMID- 10659381
TI  - Drinking water, mortality, and life expectancy: an assessment of the east-west
      mortality gap in Europe.
AB  - The role of the drinking water in public health has been recognised for many
      years. Recent ecological studies of mortality rates in Slovakia when compared to
      indicators of environmental pollution have shown surprising results--areas with
      greater air pollution seem to have lower total mortality rates. This paradox may
      be explained by a number of other factors, including urban/rural occupational
      conditions, socio-economic status, access to health care, and perhaps drinking
      water. Overall population access to safe drinking water is about the same between
      East and West Europe, but more careful evaluation suggest at least one important
      difference. About 35.7% of the people in Central and Eastern European countries
      do not have 100% access to safe drinking water in their rural areas, compared to
      only 18.7% of the rural populations in Western Europe who do not have full access
      to safe drinking water. This study examines access to safe drinking water,
      assesses overall drinking water quality, and utilises an index of drinking water
      quality to perform correlation with total mortality, selected chronic diseases
      which have been associated with drinking water contamination, and life expectancy
      at birth. These methods are applied to data for East-West Europe, Slovakia, and
      detailed urban-rural comparisons for three areas of Slovakia (Trnava, Banska
      Bystrica, and Kosice).

PMID- 10659382
TI  - Problems associated with sterilization using ethylene oxide. Residues in treated
      materials.
AB  - The paper deals with problems associated with reduction of undesirable effects of
      ethylene oxide in polymers in medical devices on the patient's health. The
      authors explain the need of careful elaboration and validation of the
      sterilization and aeration process incl assessment of ethylene oxide (EO)
      residues. The authors investigated the effect of the type of material and
      conditions of sterilization and aeration on the assessed EO concentration. For
      research of the behaviour of different polymers in the sterilization process
      model sterilizations of actual items of medical devices with a known composition
      proved more suitable than assessment in medical devices from medical
      institutions. The main conclusions of the investigation were a classification of
      polymers into those suitable and unsuitable for sterilization or resterilization,
      and attention was also drawn to poor reproducibility of results in old
      sterilizers, in particular those lacking effective aeration in aerators.

PMID- 10659383
TI  - Environmental health and the family doctors.
AB  - Medicine, that is human medicine, has a long tradition of the use of biomarkers
      in assessing multiple departures from the health status: it is assumed that in
      ecosystem health assessment this experience could be helpfully shared with all
      those--from many scientific disciplines--involved in this research, crucial for
      the future of life on earth. The growing importance of ecology is evident in all
      aspects of modern life. Social and economically the ecological analysis cannot be
      ignored in future by politicians or medical doctors alike. Environmental Health
      is thus taking over many responsibilities from the traditional Public Health,
      mainly the significant challenges put by toxic and hazardous substances released
      into the environment which is fundamentally an evaluation of relevant
      environmental data, health outcome and community health concerns associated with
      toxic exposure. The public has become increasingly concerned about the exposure
      to synthetic chemical compounds produced by modern industry. Environmental Health
      is essentially a critical tool to determine the relationship between
      environmental contamination and human adverse health effects. Environmental
      Health aims much further than the traditional Public Health. Although
      Environmental Health has not enjoyed the successes of traditional Public Health
      such as maternal and child health or the eradication of smallpox, an array of
      activities is underway that will enhance the health professional's ability to
      cope with the demanding issue of toxic exposures.

PMID- 10659384
TI  - Defining and assessing health-related quality of life.
AB  - In recent years, there has been an increasing interest in quality of life
      assessment in clinical research and practice, as well as in public health and
      policy analysis. Indicators of health-related quality of life are important not
      only for health professionals and their patients, but also for health
      administrators and health economists in health care planning and policy making.
      Most studies on the outcome of treatments and interventions now include some kind
      of a quality of life measure. This usually takes a form of an assessment of
      symptoms and physical functioning, measurement of psychological well-being, life
      satisfaction, or coping and adjustment. Numerous scales of psychological health,
      physical health status and physical functioning have been developed for use in
      the assessment of health outcomes and a wide range of instruments for measurement
      of health-related quality of life is available. These fall into two broad
      categories of generic and disease-specific instruments. The selection of an
      instrument depends upon its measurement properties but also upon the specific
      context in which the instrument is going to be used. Adequate attention needs to
      be paid to the translation and validation of instruments for use across countries
      and cultural contexts.

PMID- 10659385
TI  - Occupational risks for human reproduction: ELSPAC Study. European Longitudinal
      Study of Pregnancy and Childhood.
AB  - Pregnant women living in Brno who were contacted for the first time at 18th week
      of their pregnancies during the period from February 1990 to January 1992 were
      involved into the ELSPAC group. Among others, the exposure to different
      occupational factors in the three periods was obtained by the self-reported
      questionnaire: 1. the last 9 months before pregnancy, 2. the first, and 3. second
      trimester periods. The women's health status during pregnancy, the history of
      delivery and the developmental and health status of newborns were described in
      details by obstetrics and pediatrics according to another internationally unified
      questionnaire. All data obtained from 3,897 pregnant women living in Brno were
      computered. Smoking women were significantly more often than non-smokers
      occupationally exposed to ergonomic stressors associated with the monotony work,
      and to chemical substances. In the whole group, the intrauterine growth
      retardation has been positively associated with shifting (OR 1.59, p < 0.05) and
      occupational exposure to permanent noise (OR 1.92, < 0.05). Newborns of such
      exposed women had in average lower parameters of head cimcumstances (p < 0.01).
      Non-physiologic, non-spontaneous deliveries have been more often observed among
      VDTs users (OR 1.20-1.28, p < 0.05). Women exposed to organic solvents during 2nd
      trimester of pregnancy delivered more often babies with some congenital
      malformations (OR 2.31, p < 0.05). On the other hand, the different occupational
      factors seemed to be protective for several markers of the women health status,
      as the prevalence of reproductive damages was significantly lower among exposed
      women than in the non-exposed group. After the standardization of the smoking
      habit, more significant associations have occurred in the group of smokers
      occupationally exposed to: shift work (low-birth-weight babies: OR 1.98, p <
      0.05), chemicals (bleeding during pregnancy: OR 2.00, p < 0.05), sedentary work
      (placental abnormalities and congenital malformations: OR 1.59, p < 0.05). Non
      smoking women using VDTs had more often babies with intrauterine growth
      retardation (OR 2.29, p < 0.05). Newborns with different malformations were more
      often born to non-smoking women occupationally exposed to chemicals (OR 2.33, p >
      0.05).

PMID- 10659386
TI  - Quality of water--quality of life.
AB  - Especially in developing countries, the problem of adequate drinking water supply
      is an ever growing one. Public health programmes have been established to improve
      the population's health conditions, but these programmes require big financial
      means for guaranteeing adequate supply of potable water and medical therapy for
      sick people. Too little emphasis is still put on regular testing of drinking
      water for microorganisms such as Aeromonas sp. and Vibrio sp. In a spot check
      analysis in various countries, the importance of Aeromonas sp. is shown--not a
      single sample complied with international norms and guidelines for drinking
      water.

PMID- 10659387
TI  - The biomarkers detecting early changes in the human organism exposed to
      occupational carcinogens.
AB  - Epidemiological studies and clinical data confirm that occupational exposure to
      carcinogenic agents plays an important role in cancer etiology. Recent tremendous
      progress in understanding of the mechanisms of carcinogenesis, and also
      introduction of new tests to recognize changes occurring in the exposed organism
      have made it possible for the occupational medicine to detect the earliest cancer
      stages which occur during the latent phase of the disease. Detecting pre
      neoplastic changes which precede an overt form of cancer and identification of
      measurable indicators of those changes has been one of the fundamental aims of
      molecular biology research. Biomarkers may serve as a research tool which makes
      it possible to achieve this aim. Suitably selected biomarker sets can provide
      information on the extent of the exposure to carcinogenic agents (biomarkers of
      exposure), detect early changes produced by the agents in the exposed organism
      (biomarkers of effects), and identify people with particularly high cancer risk
      (biomarkers of susceptibility). It will soon be possible to use molecular
      biomarkers, capable of detecting increased cancer risk at the molecular level of
      cell structure, in prophylactic action intended to reduce cancer incidence.
      Molecular biomarkers are capable of recording very early health effects of
      exposure to carcinogens, thus making it possible to determine cancer risk at a
      very early stage of cancer development.

PMID- 10659388
TI  - Future challenges and opportunities in child welfare.

PMID- 10659389
TI  - Policy challenges for child welfare in the new century.
AB  - Recent changes in public policy reflect increased efforts to scapegoat poor women
      and children and to polarize the objectives of child protection and family
      preservation. This article challenges various stakeholders in the child welfare
      field to move beyond the quick-fix solutions and bureaucratic overregulation
      precipitated by horror stories of child abuse in the media. The new century
      presents an opportunity to pursue differential intervention strategies that
      protect children while empowering poor families and communities.

PMID- 10659390
TI  - Family preservation: a potential not yet realized.
AB  - When they received widespread promotion and support beginning in the 1980s,
      family preservation services seemed to hold much promise for the child welfare
      field, and for the lives of families and children. Unfortunately, this promise
      has never been fully realized throughout the United States. This article traces
      the recent history of family preservation services, examines some of the reasons
      why efforts to implement family preservation services have been less than
      completely successful, and proposes a strategy for ensuring that these services
      reach their potential in the future.

PMID- 10659391
TI  - Reforming child protective services.
AB  - Child welfare analysts, practitioners, and the general public all agree: the
      child protective services system (CPS) is in crisis and is in urgent need of
      reform. Children at risk are not being adequately protected, and they and their
      families are not receiving the services that they need. This article briefly
      reviews the problems facing CPS today, outlines a vision for reforming CPS, and
      suggests ways to move from today's CPS to the CPS of the future.

PMID- 10659392
TI  - The future of residential group care.
AB  - The author addresses some of the tensions and strains that have affected the
      development of group care in the North American context. An argument is advanced
      for rethinking group care resources within a total continuum of child and family
      services.

PMID- 10659394
TI  - Child welfare education and training: future trends and influences.
AB  - Based on a review of current economic, political, social, and professional
      trends, the authors propose recommendations for child welfare education and
      training. Future partnerships between child welfare agencies and schools of
      social work will need to incorporate cross-system collaboration,
      multiculturalism, and family-centered approaches with a broader conceptualization
      of child well-being.

PMID- 10659393
TI  - In our best interest: three necessary shifts for child welfare workers and
      children.
AB  - In contrast to medicine, technology, and other fields, where great advances have
      been made in the past century, child welfare has yet to reach its full potential.
      The author, a former youth in care, proposes three practical shifts in child
      welfare policy and practice, changes that would cost little but would do much to
      build a better future for children and families: (1) renaming and reclaiming our
      children; (2) emphasizing communities, not agencies; and (3) valuing principles
      more than programs. Suggestions for implementing these shifts are highlighted.

PMID- 10659395
TI  - The future of child and family welfare: selected readings.
AB  - In the decade leading up to the 21st century, a number of authors began focusing
      on the future in the field of child and family welfare. This review summarizes
      selected readings in this area, ranging from examination of such broad topics as
      research and policy issues to indepth analysis of specific topics such as family
      foster care and child protective services.

PMID- 10659397
TI  - Antiemetics for cancer chemotherapy-induced nausea and vomiting. Summary and
      table.

PMID- 10659396
TI  - Antiemetics for cancer chemotherapy-induced nausea and vomiting. A review of
      agents in development.
AB  - Significant progress has been made in recent years in developing more effective
      means of preventing nausea and vomiting induced by cancer chemotherapy. With
      appropriate application of currently available antiemetic regimens, the majority
      of patients with cancer who are receiving chemotherapy can anticipate
      experiencing no emesis during their treatment. Nevertheless, incompletely
      controlled emesis remains a problem for a significant percentage of patients.
      Persistent challenges include delayed emesis and emesis following high-dose
      chemotherapy regimens. The goal of complete prevention of emesis in all patients
      remains elusive. Therefore, there is a strong rationale for investigating new
      antiemetic approaches. New antiemetic agents currently under development target
      the neurotransmitters serotonin (5-hydroxytryptamine; 5-HT) and substance P. A
      number of new selective antagonists of serotonin 5-HT3 receptors are in clinical
      trials. Given the lack of clinically significant differences between the
      available 5-HT3 receptor antagonists, it appears unlikely that any of these new
      agents will have substantial advantages over currently approved agents. Several
      other serotonin receptors have been targeted including the 5-HT4, 5-HT1A and 5
      HT2A receptors. Of these approaches, only agonism of the 5-HT1A receptor has
      produced an agent that has proceeded into clinical testing. The most exciting new
      class of antiemetics currently under development focuses on antagonism of the
      effects of the neurotransmitter substance P. Results of early clinical trials
      with tachykinin neurokinin NK1 receptor antagonists demonstrate enhanced control
      of acute emesis with their addition to currently available agents and promising
      activity in controlling delayed emesis. Available evidence would strongly suggest
      that this class of agents will represent the next important advance in efforts to
      control nausea and vomiting induced by chemotherapy.

PMID- 10659398
TI  - CJ 11974.

PMID- 10659399
TI  - Itasetron. DAU 6215, U 98079.

PMID- 10659400
TI  - Lerisetron. F 0930, F 0930RS.

PMID- 10659401
TI  - Levosulpiride. Levopraid, RV 12309.

PMID- 10659402
TI  - MK 869. L 754030, MK 0869.

PMID- 10659403
TI  - Palonosetron. RS 25259, RS 25259 197.

PMID- 10659404
TI  - Zatosetron. LY 191617, LY 277359.

PMID- 10659405
TI  - Agents in development for the treatment of hepatitis C. Summary and table.

PMID- 10659406
TI  - Acetylcysteine. Fluimucil, Mucomyst, N-acetylcysteine, NAC, NSC 111180.

PMID- 10659407
TI  - Aldesleukin. Interleukin-2 (IL-2), IL-2 (Chiron), Macrolin, Proleukin,
      recombinant IL-2 (Chiron), T cell growth factor.

PMID- 10659408
TI  - Interferon-alpha-n3. Alferon, Alferon LDO, Alferon N, Alferon N Gel, Altemol,
      natural alpha interferon, alpha-n3-IF.

PMID- 10659409
TI  - Maxamine. Histamine dihydrochloride.

PMID- 10659410
TI  - MTH 68/B. Hepatitis vaccine MTH-68/B.

PMID- 10659411
TI  - PEG interferon-alpha-2a. PEG IFN-alpha-2a, Pegasys, RO 253036.

PMID- 10659412
TI  - Ursodeoxycholic acid. Actigall, Urso, Ursobilane, Ursochol, ursodesoxycholic
      acid, ursodiol, Ursolite, Ursolvan.

PMID- 10659413
TI  - [Treatment of stress incontinence by percutaneous bladder neck stabilization
      (Vesica)].
AB  - We experienced 9 cases of percutaneous bladder neck stabilization (Vesica) for
      patients with urinary incontinence who were diagnosed with stress incontinence
      from December 1995 to June 1998. None of the patients were able to control
      continence with any drugs. Chain cystography was performed on all of the patients
      before and after surgery. The posterior urethro-vesical angle before surgery was
      over 130 degrees in all of the patients, and it improved after the operation.
      Moreover, the mean volume of the pad test greatly decreased from 47 g to 1 g. All
      of the patients were treated with epidural anesthesia. The operation time was
      less than 60 minutes. The subjective and objective findings were satisfactory. We
      conclude that percutaneous bladder neck stabilization is a very useful surgical
      treatment for stress incontinence.

PMID- 10659414
TI  - [Flutamide-induced hepatic disorder and serum concentrations of flutamide and its
      metabolites in patients with prostate cancer].
AB  - Severe hepatotoxicity occurred in a prostate cancer patient treated with 375 mg
      of flutamide per day, 125 mg three times a day, for 11 weeks. Serial measurements
      of serum concentrations of flutamide and its metabolites in the patient showed an
      unusually high serum level and delayed elimination of flutamide and suggested
      decreased metabolic activity of oxidation of flutamide to OH-flutamide. In 37
      patients with prostate cancer we periodically monitored the serum concentrations
      of flutamide as well as liver function parameters. In 2 patients, glutamic
      oxaloacetic transaminase (GOT) and glutamic-pyruvic transaminase (GPT) elevated
      over 100 IU/L, and treatment with flutamide was discontinued. Slight elevation of
      GOT and GPT over 40 to 100 IU/L was also detected in 5 patients, and flutamide
      was withdrawn. The elevated GOT and GPT in these 7 patients recovered to the
      pretreatment levels after discontinuation of the treatment. In these patients
      with flutamide-induced hepatic disorders, the average serum concentration of
      flutamide was higher (2.76 times, and that of OH-flutamide was lower (0.76
      times), as compared with patients who maintained normal liver function.

PMID- 10659415
TI  - [Evaluation of serum lipid levels in clinical benign prostatic hyperplasia
      patients with terazosin monotherapy].
AB  - Nine clinical benign prostatic hyperplasia (BPH) patients were treated with oral
      terazoin monotherapy (2 mg daily) for 12 weeks. Serum lipid levels (total
      cholesterol, triglyceride, high density lipoprotein, low density lipoprotein,
      apoproteins) were estimated prior to and every 4 weeks during treatment in 5
      patients. International Prostate Symptom Score (IPSS) and pressure-flow study
      were evaluated before and 12 weeks after treatment in 4 patients. The total
      cholesterol level decreased from a baseline of 210 +/- 36.6 mg/dl by 6.6% at the
      12th week. This result was not significant but suggested a favorable effect of
      terazosin on diminishing the risk of coronary heart disease. This effect was
      marked especially in patients with a total cholesterol level over 200 mg/dl. On
      the other hand, IPSS improved in all cases. The mean change ranged from 19.5 to
      10.0 and the mean peak flow rate from 9.0 to 15.7 ml/s. On Shaffer's nomogram, 1
      patient showed improvement of obstruction and the other 3 patients were diagnosed
      as having week detrusor without obstruction. Clinical BPH patients with
      hyperlipidemia may markedly benefit from terazosin, which is a safe and useful
      initial treatment for BPH.

PMID- 10659416
TI  - [A case of dopamine-secreting pheochromocytoma].
AB  - We report a case of a pheochromocytoma that exclusively secretes dopamine among a
      blend of catecholamines. A 66-year-old female was referred to our hospital for
      further examination of right adrenal tumor. She had no symptoms and no episodes
      of hypertension. Abdominal CT scan showed a large mass, 9 x 8 x 6 cm, in the
      right adrenal region. Plasma and urinary catecholamine measurements were
      repeatedly performed and showed normal adrenaline and noradrenaline but elevated
      dopamine levels. We performed right adrenalectomy. The tumor was completely
      removed surgically and histological examinations revealed it to be a
      pheochromocytoma.

PMID- 10659417
TI  - [Giant psoas abscess with aggressive extension: report of a case].
AB  - We report a case of giant psoas abscess with aggressive extension outside the
      muscles of the iliopsoas component. A 57-year-old man was admitted to our
      hospital, presenting with right flank pain and severe general malaise. He had
      been diabetic, but no treatment had been performed for diabetes. Leukocytosis,
      positive CRP and hyperglycemia were noted, but he was nearly afebrile on
      admission. Computerized tomography revealed a large multilocular mass in the
      right retroperitoneal space involving the ipsilateral psoas muscle. The diagnosis
      was not apparent until the 12th hospital day, when moderate grade fever was noted
      and brownish purulent fluid was obtained by percutaneous puncture of the mass.
      Staphylococcus aureus was isolated on culture. Antibiotic chemotherapy was
      started, and ultrasound-guided percutaneous drainage was then performed under the
      diagnosis of psoas abscess. At that time, the abscess was aggressively extending
      from the iliopsoas component into the pelvic floor, involving the rectus muscle,
      the gluteal muscles and formation of subucutaneous lesions. At 46 days after
      drainage, surgical resection of the abscess with removal of the adjucent tissue
      was performed because of persistent discharge of pus and multiple residual
      lesions. The postoperative course was uneventful, and there has been no
      recurrence. Many cases of psoas abscess have been reported in the Japanese
      literature. Prompt drainage, either percutaneously or surgically are required.
      Surgical resection of the abscess, with not only opening the cavity but also
      removal of the adjacent tissue, may be recommended in some cases, especially
      those diffuse or multilocular lesions.

PMID- 10659418
TI  - [Usefulness of magnetic resonance imaging for the diagnosis of superior lumbar
      hernia: a case report].
AB  - A 48-year-old man consulted us with the chief complaints of right flank mass. On
      examination, there was a soft bulge on the right superior lumbar area. Since
      computed tomographic scanning showed subcutaneous fatty tissue, we suspected a
      superior lumbar hernia. The diagnosis was confirmed by magnetic resonance imaging
      (MRI) that revealed a lumbar muscle defect and prolapsed fatty tissue around the
      kidney. During the operation, a small hernia hiatus, 2 cm in width, opened in the
      superior lumbar triangle. The herniated fatty tissue was excised, and the defect
      of fascia was closed by overlapping the adjacent fascial structure. No signs of
      recurrence were found at 3 months postoperatively. The usefulness of MRI for the
      diagnosis is discussed and previous literature is reviewed.

PMID- 10659419
TI  - [Renal cell carcinoma in a patient with malignant lymphoma: a case report].
AB  - We herein report a case of renal cell carcinoma coexisting with malignant
      lymphoma. A 69-year-old male complained of an obstruction of the right nasal
      cavity due to a solid tumor in the paranasal sinuses. A biopsy of the tumor
      revealed diffuse, large cell and B cell type non-Hodgkin lymphoma. At the same
      time, just before the patient was scheduled to receive therapy, a left renal cell
      carcinoma was found. He therefore underwent a left radical nephrectomy.

PMID- 10659420
TI  - [A case of bladder tumor producing granulocyte colony-stimulating factor].
AB  - A case of bladder tumor producing granulocyte colony-stimulating factor (G-CSF)
      is reported. A 78-year-old male presented with macroscopic hematuria. Cystoscopy
      demonstrated a large bladder tumor. Drip infusion pyelography and computerized
      tomography of the chest, abdomen and pelvis revealed right hydronephrosis, but
      did not reveal any metastasis. Total cystectomy and construction of bilateral
      cutaneous ureterostomy was performed. Histologically, the tumor consisted of
      sarcomatoid carcinoma with foci of transitional cell carcinoma (G3 > G2), showing
      marked infiltration of polymorphonuclear leukocytes. Immunohistochemical
      examination revealed a high concentration of G-CSF in the tumor specimen.
      Preoperatively, the white blood cell, count in the peripheral blood and serum G
      CSF concentration were elevated, 45,400/mm3 and 73.4 pg/ml, respectively. After
      surgery these values became normal. This is the 19th reported case of G-CSF
      producing bladder tumor in Japan. The prognosis of the reported cases of G-CSF
      producing bladder tumor has been very poor. Fourteen of the reported 19 cases
      died within one year. This patient should be carefully followed up.

PMID- 10659421
TI  - [Recurrence of bladder cancer in fossa navicularis 12 years after total
      cystectomy: a case report].
AB  - We report a case of urothelial cancer recurrence in fossa navicularis of urethra
      12 years after total cystourethrectomy for bladder cancer. A 73-year-old man had
      undergone total cystourethrectomy and ureterocutancostomy for multiple bladder
      cancer on June 13, 1986. Histopathological findings showed transitional cell
      carcinoma, G3, pT4 with carcinoma in situ. Twelve years after the cystectomy, he
      was admitted to our hospital complaining of the induration of the glans penis.
      Magnetic resonance imaging showed a high intensity tumor in T1-WI and low
      intensity tumor in T2-WI, which had invaded fossa navicularis of urethra to glans
      penis. Aspiration biopsy of the penile tumor revealed transitional cell
      carcinoma. Therefore, we performed partial penectomy on July 16, 1998, since
      computed tomography showed no lymph node swelling in the inguinal region. Five
      months after the second operation, he was diagnosed with bilateral inguinal lymph
      node metastasis. Then we performed 2-course M-VAC (methotrexate, vinblastine,
      doxorubicin cisplatin) therapy, which showed partial response. Thereafter,
      bilateral inguinal lymphadenectomy with one-course postoperative M-VAC therapy
      was performed.

PMID- 10659422
TI  - [A case of sacral chordoma presenting as urinary retention].
AB  - A 71-year-old man was referred to our hospital complaining of urinary retention.
      He noticed a small mass on his buttocks about one year ago. Computed tomographic
      (CT) scan and magnetic resonance imaging (MRI) showed a large mass of 10 cm in
      diameter located in the retrovesical space. The mass extended to the surface of
      his buttocks and contained many calcified deposits, and was accompanied with a
      sacral bone fracture. Transdermic biopsy revealed the presence of sacral
      chordoma. Chordoma is a rare tumor, arising from remnants of the notochord and is
      locally progressive. Both tumor resection and diverting colostomy were performed
      at another hospital. In that operation his spinal cord was protected down to the
      second sacral level. Unfortunately after the operation, the patient suffered
      total urinary incontinence. At 15 months after surgical treatment, the patient
      presented with lung and bone metastases, and at 2 years after his initial
      operation, he had local recurrence.

PMID- 10659423
TI  - [A case of metastatic tumor of spermatic cord with hydrocele from gastric
      cancer].
AB  - A 70-year-old man, who had undergone total gastrectomy for Borrmann III gastric
      cancer one year previously, was referred to us with a complaint of left scrotal
      swelling. Physical examination showed left scrotal hydrocele and a hard nodule in
      the ipsilateral inguinal area. Excretory pyelography and abdominal computed
      tomography showed mild left hydronephrosis and no stone. A left orchiectomy was
      performed. The mass in the spermatic cord was 2.5 x 1.0 x 1.0 cm in size, and the
      pathological diagnosis was tubular adenocarcinoma, identical to that of the
      previous gastric cancer. Five months after orchiectomy, the patient underwent
      percutaneous nephrostomy to manage postrenal renal failure caused by massive
      metastasis of retroperitoneal lymph nodes. He died one month later. We found a
      total of 84 cases of metastatic tumors of the spermatic cord reported in Japan,
      approximately half of which were metastases from gastric cancer. In 10 cases,
      including ours, the tumor was accompanied by hydrocele of the scrotum or
      spermatic cord. Although this association is rare, cancerous lesions should be
      considered in the management of hydrocele.

PMID- 10659424
TI  - [Clinical statistics at the urological clinic of Sanjukai Hospital--statistics on
      new outpatients over the last five years].
AB  - We herein report the clinical statistics on new outpatients over five years from
      1994 at our hospital. The average number of new outpatients per year was 8,534.4
      (8,366-8,658) and there was only a slight variation in the number over the last
      five years. The male to female ratio was 1.61:1. Twenty-one percent of the
      outpatients were referred to us by other sources. The representative operations
      on outpatients were circumcision, vasectomy, resection of condylomas and
      resection of caruncles. A statistical study was made on new outpatients according
      to the international classification of disease. There were 197.0 (2.3%) malignant
      urogenital tumors per year. There was a tendency for sexually transmitted
      diseases to increase over the last five years. In males, the major diseases were
      upper urinary tract stones (23-27%), benign prostatic hypertrophy (19-26%) and
      prostatitis (15-24%). In females, they were cystitis (57-59%), upper urinary
      tract stones (17-18%) and neurogenic bladder (3-4%). We conclude that our
      hospital plays a major role as a private urological hospital.

PMID- 10659425
TI  - Symbols of time.

PMID- 10659427
TI  - Chromosome classification using backpropagation neural networks.

PMID- 10659426
TI  - The history of MRI.

PMID- 10659428
TI  - Chronic stress evaluation using neural networks.

PMID- 10659429
TI  - Fuzzy neural network-based texture analysis of ultrasonic images.

PMID- 10659430
TI  - Improved detection of breast cancer nuclei using modular neural networks.

PMID- 10659431
TI  - A silicon model of the Hirudo swim oscillator.

PMID- 10659432
TI  - Hybrid fuzzy image processing for situation assessment.

PMID- 10659433
TI  - Situation assessment of glaucoma using a hybrid fuzzy neural network.

PMID- 10659434
TI  - Speaker identification using neural networks and wavelets.

PMID- 10659435
TI  - Nonstationary speech analysis using neural prediction.

PMID- 10659436
TI  - Rectification in biological membranes.

PMID- 10659437
TI  - Palpebral fissure morphology segmentation and measurement using image processing.

PMID- 10659438
TI  - The birth of the first CT scanner.

PMID- 10659439
TI  - An introduction to cellular and tissue engineering.

PMID- 10659440
TI  - Possible health hazards from exposure to power-frequency electric and magnetic
      fields--a COMAR Technical Information Statement.
AB  - In recent years concerns have been raised about the biological effects of
      exposure to electric and magnetic fields at extremely low frequencies (ELF),
      particularly those associated with the distribution and utilization of electric
      power. In 1989, the Institute of Electrical and Electronics Engineers (IEEE)
      issued an "Entity Position Statement" which stated that "there is not enough
      relevant scientific data to establish whether common exposure to power-frequency
      fields should be considered a health hazard" and that "there is general agreement
      that more research is needed to define safe limits of human exposure to power
      frequency fields." After examination of relevant research reports published
      during the last ten years, COMAR concludes that it is highly unlikely that health
      problems can be associated with average 24-hour field exposure to power frequency
      magnetic fields of less than 1 microT (10 mG). Good laboratory evidence shows
      that magnetic fields 100 to 10,000 times higher than this level, either ELF
      sinusoidal or pulsed, can induce a variety of biological effects, including
      beneficial health effects such as bone or tissue healing. Many of the reports of
      effects of weaker fields should be considered preliminary, as some observations
      have not been reproduced in different laboratories, while others, observed in
      cells, have not been clearly connected to effects in intact animals. Also, the
      means of interaction of low-level ELF fields with cells, tissues or laboratory
      animals is not fully understood; therefore the health impacts of such weak fields
      on intact animals and humans, if any, cannot be predicted or explained. Further
      research is needed to confirm or negate reports of effects of weak fields, and to
      determine mechanisms and relevance of these effects to actual health hazards.
      Continued study in this complicated area will enhance our understanding of
      biological systems, as well as help identify levels and types of ELF exposure
      that may be deleterious to human health.

PMID- 10659442
TI  - [Levofloxacin concentrations in serum, sputum and lung tissue: evaluation of its
      efficacy according to breakpoint].
AB  - The levels of levofloxacin (LVFX) in the serum, sputum and lung tissue were
      measured by a high-performance liquid chromatography method, and the penetration
      ratio of LVFX into respiratory tissue was investigated. The subjects of this
      study were 23 patients under pulmonectomy or brochoscopy. LVFX at the dose of 200
      mg was given orally and specimens were collected as follows; serum at 2, 3 and 5
      hours after, sputum at 2 hours after, and lung tissue at 3 and 5 hours after the
      administration, respectively. The mean level of LVFX in lung tissue at 3 hours
      was 3.91 +/- 2.33 micrograms/g, and those in sputum and in serum at 2 hours were
      0.71 +/- 0.63 and 2.08 +/- 1.01 micrograms/ml, respectively. A very strong
      correlation was demonstrated between the level of LVFX in lung tissue and that in
      serum (p < 0.0001), but correlation between those in sputum and in serum was not
      significant. The penetration ratio of LVFX into lung tissue was 217.2% and that
      into sputum was 4.05%. Based on the results of this study, the breakpoints (BPs)
      of LVFX for pneumonia and chronic respiratory tract infections were calculated to
      be 4 micrograms/ml and 1 microgram/ml, respectively. It was concluded that
      penetration of LVFX into lung tissue was satisfactory, and the tissue level of
      LVFX exceeded greatly the MIC90s against the typical pathogenic bacteria of
      respiratory tract infections. Taking the excellent BP for pneumonia, 4
      micrograms/ml, into consideration, it was thought that LVFX is an effective
      antibacterial agent against pneumonia and other respiratory tract infections.

PMID- 10659441
TI  - [Clinical evaluation of biapenem in various infectious diseases].
AB  - The clinical usefulness of injectable biapenem (BIPM) was examined for various
      infectious diseases in the fields of internal medicine, urology, surgery,
      orthopedics, obstetrics and gynecology, otorhinolaryngology, ophthalmology,
      dermatology, oral surgery, and plastic surgery. BIPM was administered by
      intravenous drip infusion at a dose of 150, 300, or 600 mg twice a day. The
      concentrations in various body fluid and tissues were also examined. 1. In the
      total enrollment of 256 cases, the numbers subjected to the analyses for clinical
      efficacy, bacteriological efficacy, side effects and abnormal laboratory findings
      were 214, 170, 252 and 251 cases, respectively. 2. The clinical efficacy rate was
      85.5% (183/214 cases) as a whole, being 2/2 for sepsis, 6/8 for cellulitis and
      lymphangitis, 76.2% (16/21) for traumatic, operative wound and burn infections,
      4/6 for osteomyelitis and arthritis, 92.9% (13/14) for peritonsillar abscess and
      peritonsillitis, 83.3% (15/18) for chronic lower respiratory tract infection, 7/7
      for pneumonia, 83.3% (30/36) for complicated urinary tract infection, 100%
      (14/14) for cholecystitis and cholangitis, 88.2% (15/17) for peritonitis, 86.5%
      (32/37) for internal genital infection, 8/9 for pelvic peritonitis, 2/4 for
      corneal ulcer, orbital infection and panophthalmitis, 1/2 for otitis media, 4/4
      for sinustitis, 93.3% (14/15) for osteitis of jaw and cellulitis of mouth floor.
      The efficacy rate in the poor responders to the pretreatment by other antibiotics
      was 86.4% (70/81). 3. 300 strains of causative organisms were isolated from 170
      cases which contained polymicrobial infections. The elimination rate of causative
      organisms was 85.3% (256/300 strains), in terms of bacteriological efficacy. 4.
      Side effects were noted in 11 of 252 cases (4.4%) with 11 events. The signs and
      symptoms were the skin symptoms (5 cases), gastro-intestinal symptoms (3 cases),
      interstitial pneumonia (2 cases), and feeling bad (1 case), all of which
      disappeared during treatment or after the discontinuation of treatment. The
      abnormal laboratory findings were observed in 31 of 251 cases (12.4%) with 50
      events, and major ones were an increase in eosinophils, and elevations of AST,
      ALT, gamma-GTP and Al-p. 5. The concentrations of BIPM in body fluid and tissues
      were determined in 46 cases (212 samples) most of which were administered 300 mg
      of BIPM by intravenous drip infusion for 60 minutes. The concentrations in the
      sputum within 6 hours after administration were 0.1-2.5 micrograms/g. The maximum
      concentrations in body fluid and tissues were 0.2-1.8 micrograms/g or ml in the
      bile, middle ear mucosa, tonsillar tissue, aqueous humor and bone tissues and
      were 2.0-5.7 micrograms/g or ml in the gallbladder, maxillary sinus mucous
      membrane, ethmoidal sinus mucous membrane, oral tissues, skin, woman genitals,
      synovia, joint tissue, and the eschar. The concentrations in the uterine arterial
      plasma and retroperitoneal fluid were almost similar to those in the cubitl vein
      plasma. From the above-mentioned results of clinical efficacy, bacteriological
      efficacy, and safety, injectable BIPM was confirmed to be useful in the treatment
      of moderate, severe and/or refractory infections in various fields.

PMID- 10659443
TI  - [In vitro antibacterial activities of carbapenems against clinical isolates].
AB  - Antibacterial activities of four carbapenems, imipenem, panipenem, meropenem, and
      biapenem, were determined using 353 strains belonging to 18 bacterial species
      which were isolated from clinical materials at Ehime University Hospital. The MIC
      values of these carbapenems against MRSA were widely distributed between 0.1 and
      100 micrograms/ml, and MIC90 values of these 4 carbapenems were 25-50
      micrograms/ml. Any of these carbapenems prevented the bacterial growth of
      enterobacteriaceae of 8 bacterial species excluding S. macrescens at
      concentrations of 1 microgram/ml or less. The MIC values against P. aeruginosa
      showed relatively wide distribution, being 0.39-25 micrograms/ml for imipenem,
      0.2-25 micrograms/ml for panipenem, 0.1-12.5 micrograms/ml for meropenem, and 0.2
      12.5 micrograms/ml for biapenem. From those results, it was confirmed that any of
      the carbapenems tested had a wide antibacterial spectrum and strong antibacterial
      activities.

PMID- 10659444
TI  - A study of interactivity in educational patient hypermedia.
AB  - This study explores the use of interactive graphics for patients about to undergo
      Ishiki Type I thyroplasty, a surgery for unilateral vocal cord palsy. Steps
      include exploration of previous studies, needs assessment, prototype creation,
      and formative evaluation. Research suggests that interactive graphics should
      include the opportunity for the patients to practice and engage in a relevant,
      realistic scenario. Needs assessment results suggest the need for further studies
      with interactive graphics using larger patient sample sizes.

PMID- 10659445
TI  - Time-course analysis of stretch reflexes in hemiparetic subjects using an on-line
      spasticity measurement system.
AB  - Spasticity after a stroke is usually assessed in a score form by subjectively
      determining the resistance of a joint to an externally imposed passive movement.
      This work presents a spasticity measurement system for on-line quantifying the
      stretch reflex of paretic limbs. Four different constant stretch velocities in a
      ramp-and-hold mode are used to elicit the stretch reflex of the elbow joint in
      spastic subjects. The subjects are tested at supine position with the upper limb
      stretched towards the ground, in contrast with the horizontally stretched
      movement used in other studies. By subtracting the baseline torque, reflex torque
      measured at a selected low stretch velocity of 5 deg/sec, the influence of
      gravity torque and inertial in vertical stretching mode can be minimized. The
      averaged speed-dependent reflex torque (ASRT), defined as the measured torque
      deviated from the baseline torque, is used for quantifying the spastic
      hypertonia. Four subjects having incurred cerebrovascular accident (CVA) are
      recruited for time-course study in which the measurements are taken at 72 hours,
      one week, one month, three months, and six months after onset of stroke. During
      the development of spasticity, the changes of ASRT and velocity sensitivity of
      ASRT of the involved and the intact elbow joints are discussed.

PMID- 10659446
TI  - EMG responses resulting from transient and steady-state dynamic isometric loading
      of the human biceps can be distinguished.
AB  - In order to determine if differences in human muscle EMG response to steady-state
      (STD) dynamic load and transient (TRN) load could be detected, two distinct
      sinusoidal loads having identical amplitude and frequency were applied to the
      forearm, which was held in a fixed posture. The first condition used application
      of a constant amplitude, constant frequency, STD sinusoid, and the second
      condition used application of a single sinusoid of identical amplitude and
      frequency as the STD load. Time-domain parameters of Half-Mass, Dispersion
      Moments, Asymmetry Moments, Peak Ratio (ratio of cycle peak RMS EMG to cycle mean
      RMS EMG) and Time-to-Peak Ratio (ratio of cycle time to reach peak RMS EMG to
      cycle time duration) were used to quantify responses in the time domain. A single
      frequency-domain parameter, Dispersion Moments, was used to quantify responses in
      the frequency domain. Individual ANOVA's of the time domain parameter results
      revealed that p = 0.689 for Dispersion Moments, p = 0.111 for Half-Mass, p =
      0.007 for Asymmetry Moments, p = 0.001 for Peak Ratio, and p = 0.001 for Time-to
      Peak Ratio. The time-domain MANOVA and frequency-domain ANOVA revealed that EMG
      responses resulting from STD and TRN applied loads were statistically different
      in the time domain (p = 0.001), but not in the frequency domain (p = 0.810).
      Thus, use of Asymmetry Moments, Peak Ratio, and Time-to-Peak Ratio parameters can
      distinguish EMG responses to STD and TRN loads.

PMID- 10659447
TI  - Does using an ejector chair affect muscle activation patterns in rheumatoid
      arthritic patients? A preliminary investigation.
AB  - The present study examined knee and arm extensor muscle activation patterns
      displayed by 12 elderly female rheumatoid arthritic patients (mean age = 65.5 +/-
      8.6 yr) rising from an instrumented Eser ejector chair under four conditions:
      high seat (540 mm), low seat (450 mm), with and without ejector assistance.
      Electromyographic (EMG) signals were sampled (1000 Hz) for vastus lateralis (VL),
      vastus medialis (VM), rectus femoris (RF) and triceps brachii (TB) using a
      Noraxon Telemyo System (bandwidth 0-340 Hz). Muscle onset, offset and peak
      activity relative to loss of seat contact (SS), and integrated EMG, were
      calculated for each muscle burst before SS. A high seat significantly (p < or =
      005) decreased VL and TB intensity but did not change muscle activation patterns
      compared with rising from a low seat. Ejector assistance significantly increased
      VM and RF burst duration and RF intensity but had no effect on vastii muscle
      intensity. It was concluded that concerns pertaining to muscle disuse when rising
      with ejector assistance were unfounded in the present study. However, further
      research is required to investigate the effects of habitual use of a mechanical
      ejector device on muscle activation patterns.

PMID- 10659448
TI  - Myoelectric signal measurement during prolonged computer terminal work.
AB  - Myoelectric signal (MES) behaviour was studied during prolonged, sustained, low
      level contractions using a portable system with limited data storage capacity. A
      pre-processing technique is described which overcomes memory and data storage
      limitations in a portable multichannel MES data logger. This technique for data
      reduction was used to study MES behaviour in four muscle groups during prolonged
      computer terminal work. Myoelectric signal parameters were recorded from eighteen
      individuals while they performed computer work both without breaks, and with
      "microbreaks" (short rest breaks of 30 seconds duration) at twenty minute
      intervals. Myoelectric signal (MES) data were collected from the cervical
      paraspinal extensors, the lumbar erector spinae, the upper trapezius, and the
      forearm extensors while participants performed their usual computer work
      activities. No significant slope for either amplitude or mean frequency was
      determined in either the break or no break trials over an eighty minute recording
      period. Instead, most data sets revealed a cyclic trend in terms of frequency and
      amplitude parameters of the MES. Characteristic values were compared between
      trials when subjects did and did not take microbreaks. It was found that the
      overall median value of mean frequency was higher for the "break" than the "no
      break" protocol only in the cervical extensors, although the clinical
      significance of this finding is not well understood. By far, the most interesting
      finding of this work was the discovery of a cyclic trend in the mean frequency of
      the myoelectric signals studied. This trend was present even when participants
      did not take breaks. The trend is a potential indicator of the cyclic recruitment
      of motor units during sustained postural contractions, and is the primary area to
      be investigated in future studies by the authors.

PMID- 10659449
TI  - Transcutaneous FES of the paralyzed quadriceps: is knee torque affected by
      unintended activation of the hamstrings?
AB  - This study addresses the question whether unintended response of the knee flexors
      (hamstrings) accompanies transcutaneous functional electrical stimulation (FES)
      of the quadriceps and whether the knee torque is hereby affected. Transcutaneous
      FES of the right quadriceps of two paraplegic subjects was applied and
      measurements were made of the net torque and of the myoelectric activities of the
      quadriceps and hamstrings muscles of the right leg. A low correlation was
      obtained between the peak-to-peak amplitudes of the M-waves of the two muscles.
      This correlation decreased further with the development of fatigue, which
      indicated that the electromyography (EMG) signals from the hamstrings were not
      the result of cross-talk between adjacent recording sites. The force profile of
      each muscle was determined from a developed model incorporating EMG-based
      activation, muscle anthropometry as obtained from in vivo magnetic resonance
      imaging of the thigh, and metabolic fatigue function, based on data acquired by
      31P nuclear magnetic resonance spectroscopy. A sensitivity analysis revealed that
      the muscle specific tension and the muscle moment arms have a major influence on
      the resulting muscle forces and should therefore be accurately provided. The
      results show that during the unfatigued phase of contraction the estimated
      maximal force in the hamstrings was lower than 20% of that in the quadriceps and
      could be considered to be practically negligible. As fatigue progressed the
      hamstrings-to-quadriceps force ratio increased, reaching up to 45%, and the
      effect of co-activation on the torque partition between the two muscles was no
      longer negligible.

PMID- 10659450
TI  - Relationship between EMG signals and force in human vastus lateralis muscle using
      multiple bipolar wire electrodes.
AB  - This paper describes the relationship between knee extension force and EMG
      signals detected by multiple bipolar wire electrodes inserted into the human
      vastus lateralis muscle under isometric conditions. Six healthy male volunteers
      participated in this study. Eight pairs of bipolar wire electrodes were inserted
      into the right vastus lateralis muscle and the EMG data were simultaneously
      detected and analyzed. The EMG raw data and individual force-IEMG relations were
      influenced by the location of the electrode inserted into the muscle. The force
      and IEMG relationship averaged across subjects detected from the eight
      electrodes, however, showed almost the same linear correlation in spite of
      different electrode locations. No linear correlation was observed between MdF and
      the knee extension force. This result suggests that, if all of the muscle fibers
      participate in the same action at the same time, the averaged normalized IEMG
      from any places using wire electrodes could reflect the total activities of that
      muscle even if the muscle is large.

PMID- 10659451
TI  - A highly sensitive assay for protein using resonance light-scattering technique
      with dibromohydroxyphenylfluorone-molybdenum(VI) complex.
AB  - At pH 2.8 and in the presence of 0.090% p-octylpolyethyleneglycol phenylether,
      the resonance light-scattering (RLS) spectrum of molybdenum(VI) complex with
      dibromohydroxyphenylfluorone (DBHPF) has a sharp peak at 586 nm. If the micro
      protein coexists with Mo(VI) and DBHPF, the RLS intensity of the complex at 586
      nm is significantly enhanced by protein due to the binding interaction between
      protein and DBHPF-Mo(VI) complex. Based on this a new assay for protein is
      described. The dynamic ranges for bovine and human serum albumins are both 0.05
      0.75 mg l-1 with detection limits of 13 and 15 ng ml-1, respectively. Besides
      high sensitivity, the method is characterized by good reproducibility, rapidity
      of reaction, good stability of chemical system, commonality of
      spectrofluorometer, few coexisting substances, especially detergents. The
      determinations of diluted human serum and urine by this method give the results
      very close to these by the Coomassie brilliant blue G-250 colorimetry, with
      relative standard deviations of five duplicates of 1.8-2.5%.

PMID- 10659452
TI  - Spectroscopic properties of Carcinus aestuarii hemocyanin and its structural
      subunits.
AB  - Hemocyanin (Hc) of Carcinus aestuarii contains three major and one minor
      electrophoretically separable polypeptide chains which were purified by fast
      protein liquid chromatography (FPLC) ion exchange chromatography. N-terminal
      amino acid sequences of four structural subunits (SSs) from C. aestuarii were
      compared with known N-terminal sequences from other arthropodan hemocyanins. The
      conformational changes, induced by various treatments, were monitored by far UV,
      CD and fluorescence spectroscopy. The critical temperatures for the structural
      subunits, Tc, determined by fluorescence spectroscopy, are in the region of 52-59
      degrees C and coincide with the melting temperatures, Tm (49-55 degrees C),
      determined by CD spectroscopy. The free energy of stabilization in water, delta
      GDH2O, toward guanidinium hydrochloride is about 1.3 times higher for the
      dodecameric Hc as compared to the isolated subunits and about one time higher for
      Cal, comparing with other SSs. The studies reveal that the conformational
      stability of the native dodecamer towards various denaturants (temperature and
      guanidinium hydrochloride) indicate that the quaternary structure is stabilized
      by oligomerization between structural subunits, and the possibility of a
      structural role of the sugar mojeties cannot be excluded.

PMID- 10659453
TI  - [Infectious diseases in primary care. Improving their management and properly
      using antimicrobials. The working groups on infectious diseases of the Baleares,
      Catalan and Valencian Societies of Family and Community Medicine].

PMID- 10659454
TI  - [Family physicians and unions: a possible and necessary relationship].

PMID- 10659455
TI  - [The degree of control and care for hypertension patients in the Toledo Health
      Area].
AB  - OBJECTIVES: To find how well blood pressure figures of patients with hypertension
      in the Toledo Health District are monitored and how they are followed up. DESIGN:
      Cross-sectional and descriptive, based on review of clinical records. SETTING:
      Primary care in Toledo. PATIENTS: 391 patients diagnosed with hypertension,
      chosen through multi-stage random sampling and followed up at the District's
      Health Centres. INTERVENTIONS: The age and sex of the patient, complications,
      level of blood pressure monitoring (the patient was considered "under control" if
      the mean of the three last blood pressure figures was < 140/90 mmHg), inclusion
      in nursing clinic and how many times monitored for hypertension, were taken from
      the clinical records. MEASUREMENTS AND MAIN RESULTS: 12.3% were classified as
      suffering from serious hypertension, 57.9% of the patients had no visceral
      complication. 22.1% had a cardiac complication, and 14.9% a renal complication.
      26.57% had mean blood pressure < 140/90 mmHg (CI, 22.19-30.94). 93% were followed
      up in the nursing clinic. Average annual hypertension controls was 2.69 with
      doctors and 8.73 with nurses. There was no significant association between the
      percentage of patients under control, and follow-up or otherwise in the nursing
      clinic (27.3% and 24%, respectively). There was greater attendance of patients
      with their blood pressure poorly controlled, both in medical (2.8 vs 2.3; p >
      0.05) and nursing clinics (9.2 vs 7.5; t = 3.03; p < 0.01). CONCLUSIONS: Our
      results confirm the tendency towards an improvement in recent years in the
      monitoring of patients with hypertension in our country. In view of the important
      number of monitoring sessions (especially in nursing clinics) that proper follow
      up requires, we wonder whether such a discreet improvement is not being achieved
      at too high a cost.

PMID- 10659456
TI  - [The prediction of the cancer incidence and mortality rates in Spain for the year
      2000].
AB  - OBJECTIVE: To forecast the cancer incidence and mortality rates in Spain for the
      year 2000, and to estimate the number of new cases and the number of dead
      patients due to the cancer for this year. DESIGN: Ecological study with time
      series analysis. PATIENTS: Cancer mortality rates in Spain was obtained from 1905
      to 1995. MEASUREMENTS AND RESULTS: Brow method was applied in order to forecast
      cancer mortality rates for the year 2000. An estimation of the incidence rates in
      Spain was obtained from the incidence/mortality rate (1.49 for males and 2.07 for
      females), given by the International Agency for Research on Cancer (IARC). INE's
      publications were used in order to estimate the number of new cases and the
      number of dead patients due to the cancer for the year 2000. The forecasting
      about cancer mortality rates in Spain for the year 2000 were 312.93 in men and
      180.56 in women. An increasing in mortality will be produced in the following
      years. 90,000 men and 75,000 women will be diagnosed with cancer; 61,000 men and
      36,000 women will be died due of this disease. CONCLUSION: The trends in cancer
      incidence and mortality are increasing. These results could be interesting in
      health policy in order to plan different actions in the future.

PMID- 10659457
TI  - [Anxiety disorders. The variability and determinants of the therapeutic approach
      of primary care physicians].
AB  - OBJECTIVES: To analyse the influence of independent factors, relating to the
      characteristics of primary care doctors, patients and the illness, on therapeutic
      attitudes and their variability before anxiety disorders. DESIGN: Observational
      study of people attending primary care family medicine clinics who are identified
      as suffering anxiety disorders. SETTING: The autonomous Communities of Castilla
      and Leon, the Basque Country and the Valencian Community. PARTICIPANTS: 3247
      patients over 18 classified by their doctors as suffering an anxiety disorder.
      MEASUREMENTS AND RESULTS: During 1995, 317 primary care doctors collected
      information from patients with anxiety disorders (CIE codes F40 and F41). The
      information was gathered with the same questionnaire in the three communities.
      The data were validated monthly before the final analysis. Women doctors gave
      less medical advice than male doctors (OR: 0.48, 95% CI: 0.36-0.65). Patients
      with anxiety in Castilla and Leon were at greater "risk" of receiving drugs
      treatment than those in the Basque Country (OR: 1.64, CI: 1.31-2.06). When the
      consultation was for any mental symptom or when the kind of anxiety was a panic
      disorder (OR: 2.39, CI: 1.53-3.65), phobic disorder (OR: 2.17, CI: 1.52-3.08) or
      mixed anxiety disorder (OR: 2.20, CI: 1.77-2.73), patients were more likely to be
      referred for specialist treatment. If it was decided to prescribe drugs
      treatment, women doctors used more often than their male colleagues a mixed
      treatment with anti-depressants, anxiolytic drugs and drugs for psychosis (OR:
      1.60, CI: 160-4.28). Castilla and Leon, and the Valencian Community were less
      likely to use mixed treatment than the Basque Country reference group.
      CONCLUSIONS: This study shows the variability in the difficulties encountered in
      diagnosis and finding a common standard of conduct for primary care doctors faced
      with patients suffering anxiety disorders. Although the treatment used for
      anxiety can be considered adequate in most cases, there is high variability,
      which depends mainly on the type and other characteristics of the process, the
      patient and the professional.

PMID- 10659458
TI  - [The recognition of AIDS as a disabling pathology among the members of the
      Special Regime of the Sea in the province of Cadiz].
AB  - OBJECTIVES: To identify the year in which AIDS appeared as a cause of permanent
      disability among the members of the Special Sea Regime (REM), and to evaluate the
      clinical, social and labour characteristics of AIDS patients between 1987 and
      1996. DESIGN: Descriptive study of series of cases. SETTING: Cadiz Province, 1987
      to 1996. PARTICIPANTS: Patients with a disability proposal report from the
      Provincial Medical Inspectorate of the ISM (Fleet Social Institute) in Cadiz
      province between 1987 and 1996. MAIN RESULTS: AIDS appeared as the cause of
      permanent disability for the first time in 1988. 1994 and 1995 were the years
      with most cases. Over 90% of the reports of permanent disability analysed, in
      which AIDS appeared as the cause, belonged to workers professionally classed as
      sailors. AIDS is a highly disabling disease and accounted for 13.26% of all
      absolute permanent disabilities. The risk conduct of patients for whom a
      disability proposal was made was rarely recorded in the reports, which made it
      impossible to specify it in most cases. CONCLUSIONS: There must be health
      education and preventive counselling of REM members who attend the Maritime
      Health Service for their compulsory pre-embarkation check-up.

PMID- 10659460
TI  - [The knowledge and application of regulations on smoking in secondary teaching
      centers].
AB  - OBJECTIVES: Despite the growing body of legal and normative regulations regarding
      promotion, sales and consumption of cigarettes, a few studies have already
      pointed to a low enforcement and commitment of these restrictions. This study
      explores the degree of awareness and compliance of these norms in the secondary
      school. DESIGN: Cross-sectional, observational study. A telephone survey was
      carried out. PARTICIPANTS: A simple of school principals or deputy principal was
      surveyed. MEASUREMENTS: A questionnaire was designed to obtain respondents
      knowledge of the current policies regarding smoking, as well as on the existence
      of visible signals in the school wards. Besides, opinion on tolerance towards
      smoking behavior among the school teachers was ascertained. RESULTS: Virtually at
      the respondents (98.8%) declared to know the existence of the regulations,
      although only 74.4% declared to have specific regulations at the school level.
      Smoking by teachers was allowed in their own offices in 61.6% of the centers. In
      open grounds, only 4.7% of the centers authorized adults to smoke while 18.6%
      permitted to smoke to the students. Public centers were less restrictive than
      private centers. DISCUSSION: Principals of secondary schools are aware of the
      existing, policy, and in most cases largely restrict public consumption. However,
      there are still some important gaps regarding signals, consumption in outdoor
      public spaces and teachers consumption in their own offices. Specific
      interventions seem to be necessary to overcome this situation.

PMID- 10659459
TI  - [The prevalence of juvenile obesity in 2 rural populations. An anthropometric
      study].
AB  - OBJECTIVES: To find the prevalence of obesity in the population under study. To
      prepare tables containing all the pertinent anthropometric variables. DESIGN: A
      descriptive, cross-sectional and prospective study of the entire population
      studied (no sampling). SETTING: The study was run in two places, Las Navas de la
      Concepcion (NC) and EI Pedroso (EP), attended by different professionals from the
      same health district. PARTICIPANTS: 523 children between 3 and 13 from two rural
      towns, from all social and economic backgrounds. MEASUREMENTS AND MAIN RESULTS:
      Anthropometric data of these children were taken, and the variables studied: age,
      sex, height, weight, waist, hip, tricipital cutaneous fold (TCF) and
      circumference of the arm. Quetelet's body mass index (BMI), the waist-hip index
      and the muscular circumference of the arm were also calculated. The BMI and TCF
      were summarised in percentile tables, taking as diagnostic criteria of obesity
      percentile 90 or above on the BMI, or percentile 85 or above on the TCF. Values
      on the BMI were 22.6% (NC) and 23.5% (EP); and on the TCF, 30.3% (NC) and 37.4%
      (EP). CONCLUSIONS: There was 5 times greater child obesity than in previous
      Spanish studies. Mean values of the variables was lightly higher than in other
      studies. The waist-hip index and the hip measurement were associated with sex.
      There is a need to perform valid updated studies throughout the country.

PMID- 10659461
TI  - [Problem-solving therapy: the psychotherapy of choice for primary care].

PMID- 10659462
TI  - [On bioethics and family medicine (I). The Working Group of the semFYC (Sociedad
      Espanola de Medicina Familiar y Comunitaria)].

PMID- 10659463
TI  - [Malignant tumors of the rhinopharynx in a health area. An analysis of the 1992
      1997 period].

PMID- 10659464
TI  - [The Beniajan Cycling Unit: our first year of running in].

PMID- 10659465
TI  - [Venlafaxine and its discontinuation syndrome].

PMID- 10659466
TI  - [A cross-sectional caries study of 12-year-olds from Area 13 of the Valencian
      Health Service].

PMID- 10659467
TI  - [The clinical history: a fundamental tool in primary care].

PMID- 10659468
TI  - [Attendance at emergency services].

PMID- 10659469
TI  - [Neither one extreme nor the other. Hormonal therapy: in medio virtus].

PMID- 10659470
TI  - A complex urologic problem demonstrates how far pediatric urology has progressed.
AB  - OBJECTIVE: We present the experience at Connecticut Children's Medical Center
      (CCMC) with single-system bilateral ectopic ureters (SSBUE), a rare clinical
      entity which continues to challenge the pediatric urologist. Innovative
      diagnostic and reconstructive techniques are utilized in an effort to preserve
      renal function and develop urinary continence in a select group of patients.
      METHODS: A review of the English language literature was performed to identify
      all female patients with SSBUE and evaluate their treatment and outcomes. In
      addition, we present our experience with three cases of SSBUE at CCMC and
      describe the recent advances in the management of such patients. RESULTS: From
      1937 to 1999, 25 articles described 54 female patients with SSBUE. Patients were
      treated with a variety of reconstructive procedures that resulted in a low
      overall continence rate of 20% (eight of 39 reported outcomes). We evaluated
      three patients with SSBUE at CCMC. Our first patient had undergone three previous
      operations prior to her successful procedure at CCMC utilizing a new technique to
      achieve urinary continence in which a portion of the anterior bladder wall is
      used for bladder neck reconstruction. Our last patient was identified antenatally
      by the maternal-fetal obstetrician, evaluated postnatally by the pediatric
      urologist, and underwent formal urodynamics and proximal urinary diversion for an
      obstructed upper collecting system. No previous reports focus on antenatal
      identification, accurate postnatal diagnosis, urodynamic assessment and early
      intervention including upper urinary tract diversion, and staged Pippi Salle
      bladder neck reconstruction. CONCLUSION: The CCMC experience with SSBUE
      demonstrates the recent achievements in complex urinary tract reconstruction that
      have taken place in pediatric urology. We describe diagnostic studies such as
      formal urodynamics and the growing trend to identify urologic problems
      antenatally. A team approach involving the obstetrician, pediatric urologist,
      neonatologist, and the pediatrician has been beneficial. As pediatric urology
      moves into the new millennium there are prospects for even more innovative
      diagnostic and therapeutic options for children with urologic problems.

PMID- 10659471
TI  - Safety and costs of treating neutropenic fever in an outpatient setting.
AB  - PURPOSE: The purpose of this study is to analyze the safety of outpatient
      treatment for cancer patients with chemotherapy-induced neutropenic fever in a
      community hospital setting and to compare the costs of outpatient treatment with
      those of inpatient treatment for such patients. PATIENTS AND METHODS: We reviewed
      charts and charges for 32 consecutive patients initially treated for neutropenic
      fever with broad-spectrum antibiotics in the offices of Hematology/Oncology
      Associates (HOA) at the Bennett Cancer Center in the Stamford Hospital January
      1997-June 1998. We also reviewed charts and charges for eight consecutive HOA
      patients with neutropenic fever who met the criteria for outpatient treatment but
      were initially hospitalized for other reasons during this period. We compared
      these two groups with respect to mean nadir absolute neutrophil count (ANC), mean
      number of days when ANC < 1,000 cells cu mm, and mean number of days of
      intravenous antibiotic treatment. We compared costs for ambulatory and hospital
      care of the two groups using Health Care Financing Administration (HCFA) payments
      in 1998 as a proxy for costs. RESULTS: Of 32 patients with neutropenic fever
      initially treated in the outpatient setting, only four required hospitalization.
      No patients in either group died in connection with neutropenic fever. Although
      outpatients received an average of 3.6 days and inpatients only 2.5 days of
      antibiotic treatment, outpatient treatment was significantly less costly than
      inpatient treatment. CONCLUSION: In a community hospital setting most cancer
      patients with neutropenic fever who meet certain criteria can be safely,
      effectively, and inexpensively treated as outpatients.

PMID- 10659472
TI  - Beta-adrenoceptor blockers in heart failure.

PMID- 10659474
TI  - Goodbye Osler, so long Aristotle, hello quantum physics!

PMID- 10659473
TI  - A surplus of physicians? The view of internists at a single institution.
AB  - BACKGROUND: The sizable increase in the United States physician workforce over
      the last 25 years has led to a concern by health policy analysts that we are
      training too few generalist physicians, too many specialists and too many doctors
      altogether. Nearly all analysts' studies report that the United States currently
      has an adequate or more than adequate supply of physicians; however, few reports
      discuss practicing physicians' view of the issues. OBJECTIVE: To determine
      internists' opinion regarding the current and future physician supply and
      specialty mix. DESIGN: Analysis of results of a mailed questionnaire. SETTING:
      Nine hundred bed academic medical center in southern Connecticut. PARTICIPANTS:
      Three hundred seventy eight internal medicine attendings, fellows and residents.
      MEASURES: Seventeen questions that covered 4 domains: is there or will there be a
      surplus of general internists, internal medicine subspecialists or total
      physicians in Connecticut or the United States; which internal medicine
      subspecialties have a current surplus; what is the correct primary care/specialty
      care mix for our physician workforce; and what subspecialties are current
      internal medicine residents planning to pursue? RESULTS: A total of 378 of 686
      (55%) mailed surveys were returned. The majority of physicians reported that
      there is currently no surplus of physicians (68%) or general internists (90%) in
      the Unites States, but that there is a surplus of internal medicine
      subspecialists (68%). The majority of the physicians who responded that there is
      no current surplus reported that there would not be a surplus in 10 years.
      Subspecialties most frequently indicated to have a surplus in the United States
      were cardiology (70%) and gastroenterology (57%). A majority of internal medicine
      residents (66%) indicated that they planned to pursue subspecialty fellowship;
      the fellowship most commonly indicated was cardiology (23%). CONCLUSIONS: In
      contrast to the opinion of most health policy analysts, the majority of
      internists associated with our institution do not believe that there is or will
      be a physician surplus in the United States. Reasons for a difference of opinion
      between practicing internists and health policy analysts are worthy of further
      study.

PMID- 10659476
TI  - In response to Dr. Katz's question "doesn't anyone sell reasonable insurance any
      more?".

PMID- 10659475
TI  - A question for Mr. Kelly and John J. Phelan, Ph.D.

PMID- 10659477
TI  - Insurance companies rip off Medicare.

PMID- 10659478
TI  - Hepatitis E and intrafamilial transmission.

PMID- 10659479
TI  - Animal model for liver dysfunction using lomustine in Wistar rats.
AB  - AIM: To induce intrahepatic cholestasis in rats using lomustine 1(2-chloroethyl)
      3-cyclohexyl-l-nitrosourea (CCNU). METHODS: Doses of 10 mg, 20 mg and 30 mg/Kg
      body weight of CCNU were injected intraperitoneally in separate groups of
      animals. RESULTS: With 10 mg/Kg body weight of CCNU, serum bilirubin levels
      increased for up to 72 hours and then slowly returned to normal. With a dose of
      20 mg/Kg body weight of CCNU, serum bilirubin, AST, ALT and alkaline phosphatase
      levels increased for 72 hours and then returned to normal over 4-5 weeks. With a
      dose of 30 mg/Kg body weight peak levels of serum bilirubin were reached on day
      17. Pathological studies were carried out after injection of 30 mg/Kg body weight
      of CCNU. After 72 hours hepatocytes were normal, with minimal nonspecific
      inflammation and bile duct proliferation. After 16 days, triaditis was observed
      with deposition of collagen. Focal fibrosis was also noticed. There was no
      significant abnormality of hepatocytes. After 75 days, hepatocytes showed focal
      ballooning. Bile duct proliferation was seen invading the parenchyma. Nodules of
      hepatocytes separated by irregular fibrous bands indicated cirrhosis.
      CONCLUSIONS: An animal model of intrahepatic cholestasis has been developed using
      CCNU; this model may be used to assess the utility of hepatobiliary
      radiopharmaceuticals.

PMID- 10659480
TI  - Non-cirrhotic portal fibrosis in children.
AB  - BACKGROUND AND OBJECTIVES: Non-cirrhotic portal fibrosis (NCPF) is an infrequent
      cause of portal hypertension in children. We report 11 children with NCPF, from
      among 338 with portal hypertension, seen over 6.5 years. METHODS: The diagnosis
      was based on patent splenoportal axis on ultrasonography and/or splenoportal
      venography and liver biopsy showing no evidence of cirrhosis or other diagnosis,
      in children with portal hypertension. Those with variceal bleed were managed with
      endoscopic sclerotherapy and/or shunt surgery. RESULTS: The median age was 11
      years (range 5 to 14), and 8 were boys. Presentation was with variceal bleed in
      6, lump in left upper abdomen in 5 (though all children had splenomegaly) and
      esophageal varices on endoscopy. The median spleen enlargement was 8.5 cm; 8 also
      had hepatomegaly. Hypersplenism was present in 7, and two had developed ascites
      after bleed. Of 6 children presenting with bleed, variceal obliteration was
      achieved on sclerotherapy (average 5.6 sessions) in 4 while two underwent shunt
      surgery for associated hypersplenism. After median follow up of 57.5 months
      (range 12-78) all are alive and well. CONCLUSION: NCPF is an uncommon cause of
      portal hypertension in Indian children. Presentation with variceal bleed is less
      common than in adults; sclerotherapy is effective.

PMID- 10659481
TI  - Role of azathioprine in severe ulcerative colitis: one-year, placebo-controlled,
      randomized trial.
AB  - OBJECTIVE: To investigate the efficacy of azathioprine in treating patients with
      severe ulcerative colitis. DESIGN: One-year, randomized, placebo-controlled
      trial. SUBJECTS: 83 patients with severe ulcerative colitis were enrolled. Fifty
      patients who relapsed within two months on corticosteroid withdrawal were
      randomized into two groups. The azathioprine group received oral sulfasalazine (6
      8 g/day), oral prednisolone (1 mg/Kg/day) and oral azathioprine (2 mg/Kg/day).
      The placebo group received oral sulfasalazine (6-8 g/day), oral prednisolone (1
      mg/Kg/day) and placebo. Corticosteroids were tapered over 12-16 weeks. RESULTS:
      Five patients (2 in azathioprine group, 3 in placebo group) dropped out of the
      study. Three patients in the azathioprine group had side effects. The number of
      patients going into complete remission and partial remission was not
      significantly different in the two groups. The proportion of relapses in the
      azathioprine group was lower than in the placebo group (p < 0.05). CONCLUSIONS:
      In patients with ulcerative colitis, azathioprine had no effect in achieving
      remission, when given in combination with prednisolone; however, it lowers the
      proportion of relapses. Side effects like pancreatitis and hepatitis are mild and
      respond promptly to drug withdrawal.

PMID- 10659482
TI  - Is Crohn's disease rare in India?
AB  - BACKGROUND: Crohn's disease (CD) is believed to be rare in India. OBJECTIVE: To
      analyze the data pertaining to patients with CD seen in a tertiary referral
      center. METHODS: Data on patients with chronic inflammatory bowel disease
      attending our Unit over a 5-year period were analyzed. The diagnosis of CD was
      established by the presence of characteristic segmental bowel involvement,
      consistent histological picture, exclusion of infectious causes, relapsing nature
      of the disease, response to appropriate drug therapy, and lack of evidence for
      another etiological factor. RESULTS: Of the 25 patients (age range 12-52, mean
      31.7, years) 13 were men. Abdominal pain was present in 21 (84%) patients,
      diarrhea in 20 (80%), blood per rectum in 11 (44%) and fever in 4 (16%). The
      ileocecal region was involved in 6 (24%) patients and anal canal in 4 (16%); 19
      (76%) had patchy involvement of different segments of the large bowel.
      Colonoscopic biopsies revealed granulomas in 12 (48%). During a mean follow up of
      36.4 (range 6-54) months, 15 (60%) patients had 21 relapses. Despite initial
      response to 5-aminosalicylic acid in five patients, 23 needed glucocorticoid
      therapy at least once. CONCLUSIONS: CD may not be rare in India. Because of the
      high prevalence of intestinal tuberculosis there is a possibility that CD may be
      under-recognized in India.

PMID- 10659483
TI  - Oxidative stress in gastric mucosa in Helicobacter pylori infection.
AB  - BACKGROUND: Infection with Helicobacter pylori is believed to be associated with
      generation of reactive oxygen molecules which leads to oxidative stress in the
      gastric mucosa; but the relation between oxidative stress and gastrointestinal
      mucosal damage has not been documented. AIM: To look for evidence of oxidative
      stress and lipid peroxidation in the gastric mucosa in H. pylori-associated
      peptic ulcer. METHODS: 34 duodenal ulcer (DU) patients with H. pylori infection,
      14 DU patients without H. pylori infection and 10 healthy subjects without H.
      pylori infection were studied. H. pylori infection was diagnosed by histology and
      rapid urease test on endoscopic biopsies from the gastric body and antrum.
      Reduced glutathione (GSH) and malondialdehyde (MDA) content were measured in
      biopsies taken from the gastric antrum. Statistical analysis was done using
      Student's t test. RESULTS: Tissue levels of GSH were significantly lower (91.7
      [35.4] nmole/100 mg versus 147.3 [41.2] nmole/100 mg; p < 0.001) and MDA higher
      (163.0 [83.4] nmole/100 mg versus 109.2 [51.3] nmole/100 mg; p < 0.01) in
      patients with DU associated with H. pylori infection as compared to those without
      H. pylori infection. GSH levels were significantly lower and MDA levels higher in
      DU patients with or without H. pylori infection as compared to control subjects.
      Serum MDA levels in DU patients with H. pylori infection were also significantly
      higher than in patients without H. pylori infection. CONCLUSION: Depletion of
      gastric mucosal glutathione in H. pylori-infected DU patients may be due to
      failure of the antioxidant defense system. Failure of the glutathione-dependent
      defense system results in accumulation of free radicals which can initiate
      membrane damage by lipid peroxidation.

PMID- 10659484
TI  - Epidemic hepatitis E: serological evidence for lack of intrafamilial spread.
AB  - INTRODUCTION: Hepatitis E presents as epidemic as well as sporadic disease. Fecal
      contamination of drinking water results in epidemics of hepatitis E. The extent
      of intrafamilial spread needs to be assessed employing serological assays. AIMS:
      To understand the dynamics of intrafamilial spread of the disease. METHODS: The
      study was conducted using blood samples collected during the 1988 and 1989
      epidemics of viral hepatitis in Kudal and Atit villages of Maharashtra state; the
      epidemics were subsequently shown to be due to hepatitis E virus (HEV). The one
      time collection carried out at the end of the Kudal epidemic was from 184
      apparently healthy individuals irrespective of family history of jaundice during
      the epidemic. In the Atit epidemic, 153 family contacts of 49 IgM anti-HEV
      positive patients were bled. An additional 151 blood samples were collected from
      apparently healthy individuals irrespective of family history of jaundice during
      the epidemic. One month later, blood samples were collected from 64 of the 153
      family contacts. Relevant history was recorded each time. All serum samples were
      tested for ALT levels and for IgM and IgG antibodies to hepatitis E virus
      employing ELISA. RESULTS: IgM anti-HEV positivity among persons with family
      history of jaundice was not different from those without such a history (8/62
      [12.9%] and 11/122 [9%] at Kudal; 9/57 [15.8%] and 22/94 [23.4%] at Atit; p >
      0.1). Excluding IgG anti-HEV positive samples from the analysis also yielded non
      significant results. Of the 32 follow-up samples collected from family contacts
      without IgG or IgM antibodies to HEV in the initial blood sample, 31 remained IgM
      and IgG anti-HEV negative at the end of 1 month. One of the family contacts was
      found to be IgG anti-HEV positive in the second blood sample. The disease was not
      related to the index case. CONCLUSION: Intrafamilial spread of HEV is negligible.

PMID- 10659485
TI  - Symptomatic chronic calcific pancreatitis in a patient with idiopathic ulcerative
      colitis and sclerosing cholangitis.
AB  - Although sclerosing cholangitis is well recognized to occur in patients with
      idiopathic inflammatory bowel disease, pancreatitis as a complication of
      ulcerative colitis is uncommon. We describe a patient who had idiopathic
      ulcerative colitis, primary sclerosing cholangitis and calcific pancreatitis with
      endocrine pancreatic deficiency, a rare combination.

PMID- 10659486
TI  - Idiopathic hypoparathyroidism and celiac disease in two patients with previous
      history of cataract.
AB  - We report two patients with idiopathic hypoparathyroidism and celiac disease.
      Both had undergone surgery for cataract previously. The patients presented with
      tetany in the absence of gastrointestinal complaints. Investigations showed
      severe hypocalcemia, hypoparathyroidism, flattening of duodenal villi
      histologically, and diffuse cerebral and basal ganglia calcifications on CT scan.
      After a gluten-free diet with calcium supplementation, the clinical situation and
      biochemical values improved.

PMID- 10659487
TI  - Small cell carcinoma of gall bladder.
AB  - Small cell carcinoma of the gall bladder is very rare. We report a 25-year-old
      woman with this tumor. These tumors typically occur in elderly women with
      cholelithiasis; chemotherapy is not known to improve survival.

PMID- 10659488
TI  - Hemangiopericytoma of greater omentum.
AB  - A 67-year-old man presented with a painless abdominal lump. CT scan revealed a
      large vascular intraperitoneal mass. At laparotomy, a large, vascular tumor was
      seen to arise from the greater omentum, which was resected. At histology, this
      tumor was a benign hemangiopericytoma.

PMID- 10659489
TI  - Concurrent renal transitional cell carcinoma and right colon cancer.
AB  - A 45-year-old man who had undergone right radical nephrectomy for transitional
      cell carcinoma 3 months earlier was admitted with right colonic tumor. Review of
      CT done for right kidney tumor was suggestive of right colon pathology. Right
      hemicolectomy was performed, followed by a course of chemotherapy for mucinous
      adenocarcinoma, and he is well a year later.

PMID- 10659490
TI  - Richter's hernia in Spigelian hernia.
AB  - A 75-year-old woman presented with a painful abdominal lump. Clinically and
      sonographically it was diagnosed as an abscess. Surgical exploration revealed a
      Spigelian hernia with Richter's type of strangulation. The strangulated portion
      of the ileum had perforated, leading to abscess formation.

PMID- 10659491
TI  - Neuroendocrine differentiation in hepatocellular carcinoma.
AB  - A patient with hepatocellular carcinoma with neuroendocrine features is reported.
      Identification of this tumor is essential due to its aggressive behavior and the
      differences in the treatment and clinical control of the patient.

PMID- 10659492
TI  - Intestinal giardiasis: an unusual cause for hypoproteinemia.
AB  - Malabsorption is a well-known complication of infection with Giardia lamblia.
      However, selective protein-losing enteropathy is rare. We report a child with
      anasarca due to hypoalbuminemia as a result of gastrointestinal protein loss.
      Investigations established giardiasis as the etiology. The child returned to
      normal health after treatment with metronidazole.

PMID- 10659493
TI  - Iatrogenic esophageal perforation during devascularization procedure managed with
      Thal wrap.
AB  - We describe the successful use of 270 degrees Thal's partial fundal wrap to close
      an iatrogenic esophageal perforation in a patient who underwent devascularization
      and splenectomy after failure of sclerotherapy for bleeding esophageal varices.

PMID- 10659494
TI  - Esophageal metallic stents: initial experience.

PMID- 10659495
TI  - Seroprotection following Enivac-HB, a recombinant hepatitis B vaccine.

PMID- 10659496
TI  - Foreign bodies migrating from gut to liver.

PMID- 10659497
TI  - Foreign bodies migrating from gut to liver.

PMID- 10659498
TI  - Clinicopathologic analysis of 124 cases of adult T-cell leukemia/lymphoma with
      cutaneous manifestations: the smouldering type with skin manifestations has a
      poorer prognosis than previously thought.
AB  - Adult T-cell leukemia/lymphoma (ATLL) commonly involves the skin as well as
      peripheral blood and lymph nodes. During the last 15 years we have studied 124
      cases of ATLL with specific skin manifestations. Twenty-one patients (16.9%) were
      classified as acute, 21 (16.9%) as chronic, 26 (21.0%) as lymphoma, and 56
      (45.2%) as smouldering according to Shimoyama's classification. Many patients had
      nodules/tumors (34.7%), erythematous plaques (22.6%), and erythematous papules
      (19.4%) similar to those occurring with other cutaneous T-cell lymphomas. Some
      patients displayed characteristic skin manifestations resembling non-neoplastic
      cutaneous disorders. The median survival time (MST) of all patients was 12.0
      months. The MSTs of individual clinical types were: acute type, 4 months; chronic
      type, 14 months; lymphoma type, 7 months; and smouldering type, 16 months. In the
      smouldering type, cases with a deeper infiltration pattern (MST, 14 months) had a
      more aggressive course than those with a superficial infiltration pattern (MST,
      24 months) (p < 0.05). The results indicate that smouldering type ATLL with skin
      manifestations may have a worse prognosis than without skin manifestations.
      Moreover, some cases of the smouldering type with specific skin lesions should be
      classified into another group with a much poorer prognosis.

PMID- 10659499
TI  - Congenital ichthyosiform erythroderma: particulate staining pattern of TGK.
AB  - A case of late onset non-bullous congenital ichthyosiform erythroderma (CIE) was
      studied. This patient was not born as a collodion baby and did not have skin
      abnormalities until 9-10 years of age. She gradually developed erythroderma and
      fine scales, callosities of her feet, and a mild ectropion. Since recent work has
      revealed that in the majority of CIE patients, transglutaminase (TGK) is
      distributed in the cytoplasm of granular cells and horny cells (11), TGK was
      studied in our case. It was found that TGK was distributed along the cell
      periphery of horny cells and also in the cytoplasm of granular cells. In the
      control skins, TGK was stained along the cell periphery of horny cells and
      granular cells. The marginal band formation was normal. Involucrine and loricrin,
      the building materials of the marginal band whose-cross-linking is mediated by
      TGK, were normally stained in the upper epidermis. Cytoplasmic TGK of granular
      cells and normal development of the marginal band may serve as a helpful
      diagnostic marker of CIE, particularly because the often confusing collodion baby
      of lamellar ichthyosis may lack TGK staining and the marginal band altogether.

PMID- 10659501
TI  - Characteristics of Streptococcus species isolated from infectious skin diseases.
AB  - During the period from January of 1995 to June of 1998, 27 beta-hemolytic
      streptococci were isolated from 25 cases of infectious skin diseases including
      secondary infections, impetigo, phlegmone, and paronychia. The rate of beta
      hemolytic streptococci among all kinds of the isolates was found to be similar
      during those 4 years, ranging from 3.5% to 5.6%. Staphylococcus aureus were found
      to coexist with beta-hemolytic streptococci in 20 (80%) out of 25 cases. beta
      hemolytic streptococci were also often associated with coagulase-negative
      staphylococci, gram-positive rods, or other species. Twelve cases (48%) carried
      beta-hemolytic streptococci predominantly. Most beta-hemolytic streptococci
      showed high susceptibilities to all antimicrobials tested; however S. agalactiae
      showed no susceptibility to gentamicin. The evaluation of characteristics of
      Streptococcus species is very important for selecting the right antimicrobial
      agents and the proper term of chemotherapy.

PMID- 10659500
TI  - Characterization of infiltrating T cells in human scalp explants from alopecia
      areata to SCID nude mice: possible role of the disappearance of CD8+ T
      lymphocytes in the process of hair regrowth.
AB  - T cells may play a role in the pathogenesis of alopecia areata (AA). We attempted
      to elucidate the linkage between infiltrating T cells and hair regrowth processes
      by grafting scalp skin from the affected region of patients with AA onto severe
      combined immune deficiency (SCID) nude mice. When the AA scalp was grafted into
      the mice, the grafts were accepted, and normal hair regrowth was observed. Before
      grafting, CD4+ and CD8+ T cells had infiltrated into the peribulb area. After
      grafting, the telogen hair shifted to anagen hair, and the CD4+ and CD8+ T cell
      infiltrates in the bulb area decreased in all cases. CD8+ T cells had almost
      disappeared from all portions of the follicles. It has been suggested that CD8+ T
      cells play a crucial role in the pathogenesis of AA. The absence of CD8+ T
      lymphocytes that responded to follicular autoantigens may induce hair regrowth in
      the grafted skin. In addition, the CD4+ human T cells that had infiltrated or
      still remained in the upper-middle portions including the bulge area accompanied
      the HLA-DR expression after grafting. Infiltrating or surviving T cell phenotypes
      and locations changed during the hair cycle in the grafts. These results indicate
      that the location of infiltrated T cells and their phenotypes may participate not
      only in hair loss but also in regrowth of hair in AA.

PMID- 10659502
TI  - Encephalocraniocutaneous lipomatosis: a new case report and review of the
      literature.
AB  - Encephalocraniocutaneous lipomatosis is a rare neurocutaneous syndrome
      characterized by lipomatous hamartomas ranging in size from a few millimeters to
      several centimeters and affecting the head. Ocular anomalies and a variable
      degree of mental retardation with or without convulsions are usually observed.
      This disorder should be distinguished from other mosaic neurocutaneous phenotypes
      such as Proteus syndrome, oculocerebrocutaneous syndrome, and nevus sebaceous
      syndrome. We report the clinicopathologic findings of a 4-year-old Brazilian girl
      affected by this syndrome and review the literature. To our best knowledge, this
      is the first documented case of encephalocraniocutaneous lipomatosis occurring
      sporadically in South America.

PMID- 10659503
TI  - Vascular tumors arising in port-wine stains: two cases of pyogenic granuloma and
      a case of acquired tufted angioma.
AB  - Three female patients affected by intradermal vascular tumors were presented. The
      lesions were acquired and developed from preexisting port-wine stains (PWS).
      Among the three patients observed, two had a pyogenic granuloma (PG) and the
      third patients had tufted angiomas. As reported earlier, formation of a PG within
      the lesion of a PWS supports the assumption that arteriovenous anastomoses are
      associated with its pathogenesis. Occurrence of tufted angioma from a PWS, as
      well as coexisting but separate PWS has been reported. However, the tufted
      angiomas of our patient were located in different sites, one in the PWS and
      others separate from the PWS. This has never previously been reported.

PMID- 10659504
TI  - Livedo vasculitis associated with regional cytophagic histiocytoses.
AB  - We report a 70-year-old woman who developed recurrent multiple ulcers and
      residual atrophic scars on her legs and feet. The histology showed fibrinoid
      material in the dermal vessel walls causing partial to complete occlusion of the
      lumina. Capillary tufting and dilatation were also noted in the dermis. There was
      no vasculitis or panniculitis. Extravasated red blood cells were seen throughout
      the dermis; these were engulfed by benign-appearing histiocytes around the dermal
      fat junction. As she was generally well and there was no evidence of the presence
      of cytophagic cells in her extracutaneous organs, she was diagnosed with regional
      phagocytic histiocytoses supposedly triggered by extravasated red blood cells.

PMID- 10659505
TI  - A case of generalized morphea with a high titer of anti-Borrelia burgdorferi
      antibodies.
AB  - A 69-year-old male had noticed pruritus on the back for the previous 3-4 years
      and cutaneous sclerosis with swelling of the dorsum of the neck had developed in
      the last one and a half years. However, he had never complained of Raynaud's
      phenomenon of the fingers, dry mouth, or dry eyes. At this first visit to our
      hospital, he complained of erythematous cutaneous sclerosis with swelling of the
      dorsum of the neck. Histopathological findings biopsied from the neck showed
      epidermal hyperplasia with elongation of rete ridges and homogeneous and
      fibromatous changes of the dermis with dense perivascular cell infiltration
      consisting of mononuclear cells or lymphocytes with several nests of
      incontinentia pigmenti. However, there were no sclerotic changes in blood vessels
      in the upper dermis biopsied from the forearm skin, although slightly homogeneous
      and fibromatous changes of the dermis were seen. In the clinical course, the
      cutaneous sclerotic change enlarged to extend to the bottom of the cheek,
      forearm, and lower legs. These clinical features and histopathological findings
      led to the diagnosis of generalized morphea. Hematologic examination showed
      positive anti-Borrelia burgdorferi IgM antibodies, although there were no
      positive anti-Borrelia burgdorferi IgG antibodies. These results revealed that
      there can be a close association of localized scleroderma with Borrelia
      burgdorferi and that generalized morphea may also represent a Borrelia infection.

PMID- 10659506
TI  - Primary cutaneous mucormycosis in a trauma patient.
AB  - We report a rare case of primary cutaneous mucormycosis caused by Rhizopus oryzae
      that occurred in an immunocompetent trauma patient. The patient had encrusted
      erythematous plaques with pustules on the left shin, which had been abraded in a
      traffic accident. Histologic examination revealed widespread granulomatous
      inflammation and characteristic broad, non-septate hyphae with right-angle
      branching in the dermis. The infection was cured with intravenous amphotericin B
      therapy.

PMID- 10659507
TI  - Subcutaneous nocardial abscesses in a patient with bullous pemphigoid during
      immunosuppressive therapy: report of a case and review of the Japanese
      literature.
AB  - We describe a rare case of multiple, subcutaneous nocardial abscesses. A 67-year
      old Japanese male with bullous pemphigoid was admitted to our hospital, and
      systemic prednisolone and double filtration plasmapheresis were administered.
      During the combination treatment, he noted a solitary subcutaneous nodule on the
      right upper arm. The lesions gradually increased in number and disseminated. The
      microbial diagnosis was thought to be a Nocardia species. Administration of
      combination chemotherapy with minocycline and diamino-diphenyl sulfone failed to
      eliminate the nodules completely, so he was treated with daily injection of
      amikacin sulfate into the nodules. The lesions dramatically responded to this
      therapy and resolved in four weeks.

PMID- 10659508
TI  - Port-wine-stain (nevus flammeus), congenital Becker's nevus, cafe-au-lait-macule
      and lentigines: phakomatosis pigmentovascularis type Ia--a new combination.
AB  - A 16-year-old male had brown macules in a geographic pattern with increased
      terminal hair on the back and dusky red partially blanchable non progressing
      macules on his left thigh since birth. Clinical diagnoses of Becker's nevus and
      port-wine-stain were made and confirmed histopathologically. In addition, he had
      multiple lentigines on the face and trunk and a single cafe-au-lait-macule on his
      chest.

PMID- 10659509
TI  - Prognostic significance of expression of p53 protein and Ki-67 antigen in well
      differentiated squamous cell carcinoma of the skin.

PMID- 10659510
TI  - Enhancing global health through nursing.

PMID- 10659511
TI  - Education. Help wanted--faculty.

PMID- 10659512
TI  - International affairs. Journey toward quality.

PMID- 10659513
TI  - Legal and ethical issues. Diversity in nursing education--Part II.

PMID- 10659514
TI  - Tips for scholarly writing in nursing.
AB  - Professional nurses, and certainly those in academia and nursing service
      leadership positions, are experiencing an increasing need for writing skills.
      Among the most important skills required for scholarly writing are those relating
      to critical thinking. With this in mind, suggestions for scholarly writing in
      nursing are presented in this article, organized according to Paul's criteria for
      critical thinking: clarity, precision, specificity, accuracy, relevance,
      consistency, logicalness, depth, completeness, significance, fairness, and
      adequacy for purpose. Although becoming proficient in scholarly writing takes
      time and effort, the rewards in terms of career advancement, professional
      contributions, and personal satisfaction and enjoyment are considerable.

PMID- 10659515
TI  - Nurses on-line: career mobility for registered nurses.
AB  - The demands of a dynamic health care environment have altered the roles and
      responsibilities of nurses, creating employment situations where distinctions
      across educational levels are becoming increasingly important. The 1995 Pew
      Foundation Report projected that, in the next decade, there would exist a
      shortage of registered nurses with baccalaureate and higher degree preparation.
      This deficit creates a unique opportunity to provide innovative approaches to
      career mobility for registered nurses. Constraints related to juggling the
      demands of home life, child rearing, and employment have been obstacles for
      diploma and associate degree nurses wishing to continue their education. Web
      based instruction offers exciting possibilities for a new paradigm in nursing
      education that takes advantage of both the interactivity and substantial
      resources of the internet. On-line registered nurse completion programs offer
      flexible, cost-effective, and easily accessible alternatives to traditional
      education. This article describes the application of adult learning theory for
      use in re-engineering courses for on-line instruction. Hardware and software
      needs, technical support, development of an instructional model, teaching
      learning considerations, and program evaluation also are discussed.

PMID- 10659516
TI  - An educational intervention for advance directives.
AB  - In spite of the passage of the Patient Self-Determination Act in 1991, research
      indicates that providing information alone has not brought about a significant
      increase in the completion rates of advance directive (AD) documents. The purpose
      of this pilot study was to design, implement, and evaluate an interactive
      multimedia CD-ROM educational program on AD. Study subjects consisted of 31
      volunteer elderly men and women in a senior citizens center. An interactive
      multimedia CD-ROM program was developed in phase I of the study. Subjects were
      administered on-line pretests and posttests. The effectiveness of the CD-ROM
      intervention was measured by AD attitude and knowledge changes. A program
      satisfaction scale was used, and an observer rated the subjects' use of the
      computer program. Subjects had a statistically significant change in posttest
      knowledge scores and a high degree of satisfaction and ease in using the computer
      program. The use of an interactive multimedia CD-ROM program with a touch
      sensitive monitor to operate a computer-based AD program for senior citizens
      shows future promise.

PMID- 10659517
TI  - Health communications: nursing education for increased visibility and
      effectiveness.
AB  - The media play an influential role in American society. The challenge for health
      professionals, including nurses, is to translate and transmit complex health
      information for the public through many channels. Although nurses are trained to
      be effective communicators in practice, a recent study demonstrates that nurses
      are virtually invisible in the media. This lack of visibility limits nursing's
      ability to communicate important health information, impedes nursing's ability to
      define its role and contributions in the health care delivery system, and
      restricts nursing's ability to advocate for health policy. One option to improve
      nurses' ability to communicate effectively in all media venues is to integrate
      health communications content into nursing programs, which would provide nurses
      with the opportunity to develop advanced communication skills, media expertise,
      and new strategies for educating the public. Health communications programs exist
      in several colleges and universities, but not within nursing programs. Because
      nursing curricula are in a period of transition as changes in the health care
      environment are accommodated, health communications courses could be integrated
      into nursing programs as elective courses, graduate certificate programs, or a
      field of graduate study. Without creative educational strategies, nursing will
      remain invisible to the public and ineffective in its ability to influence the
      health care environment.

PMID- 10659518
TI  - Nursing's epistemology revisited in relation to professional education
      competencies.
AB  - As nursing continues to debate entry-into-practice issues, it is important to re
      examine patterns of knowing as well as their end products for the discipline in
      relation to the overall competencies of liberal and professional education. The
      changing landscape of society, along with the needed skills to provide
      comprehensive care that promotes the health and well-being of the people nursing
      serves, requires a close examination of what institutions of higher education can
      provide the discipline of nursing. A discussion of the epistemology of the
      nursing profession, needed competencies, and the goals of higher education are
      presented in this article. Patterns of knowing distinguish disciplines from one
      another. Nursing patterns of knowing and subsequent clinical, conceptual, and
      empirical knowledge require placement in institutions of higher learning that
      promotes both professional competencies and attitudes.

PMID- 10659519
TI  - From nurse to nurse anesthetist: the influence of age and gender on professional
      socialization and career commitment of advanced practice nurses.
AB  - The purpose of this study was to identify the influence of age and gender on
      professional socialization and career commitment of student registered nurse
      anesthetists. A 78-item, self-administered questionnaire was mailed to the United
      States population of student nurse anesthetists (n = 2,008). Responses were
      received from 1,106 (55 per cent response rate). Forty per cent of the
      respondents were male, and 60 per cent were female. Thirty-nine per cent of
      respondents were age 20 to 30 years; 48 per cent were 31 to 40 years old; and 13
      per cent were older than 40 years. Demographic data and scales identifying the
      three dimensions of socialization were analyzed with Chi square and GSK analysis
      of variance to measure responses and differences to all Guttman-scaled items. Age
      and gender both correlated significantly (P < .05) with the socioeconomic rewards
      of the profession. Increasing age was negatively correlated with professional
      socioeconomic rewards and attraction and the dimension of relatedness to the
      professional role. Male gender was positively correlated with a bureaucratic
      orientation and administrative/supervisory roles, and female gender was
      positively correlated with holistic patient care. Men achieved socialization more
      readily in the dimension of occupational orientation. Nurses, particularly
      advanced practice nurses, are socialized into a hierarchy that has implicit
      values and roles. The influence of age and gender must be considered in the
      professional socialization process.

PMID- 10659520
TI  - Endowed chairs and professorships in schools of nursing: a 1999 update.

PMID- 10659521
TI  - Violence as a public health problem. American Association of College of Nursing.

PMID- 10659522
TI  - Procedures and lifestyle changes that can enhance the lives of diabetic patients.
AB  - This article emphasizes to primary care physicians the importance of maintaining
      a diabetic patient's blood sugar level within the normal range. Additionally, it
      aims to impress on those who care for diabetic patients some of the adverse
      consequences of surgical and dental procedures that can be avoided by proper
      precautionary measures taken before the procedures.

PMID- 10659523
TI  - Herbal products and supplemental nutrients used in the management of diabetes.
AB  - As companies, including large pharmaceutical houses, try to market supplemental
      nutrients and herbal products to ever-increasing numbers of consumers, diabetics
      will start to approach their physicians about these alternative remedies. A whole
      new industry know as "neutraceuticals" has evolved. This new industry is a
      combination of the vitamin supplement and herbal industries trying to work with
      regulatory agents to develop good manufacturing processes to ensure that
      consumers obtain good products. In fact, some diabetics may be taking herbal or
      nutritional supplements without their physician's knowledge. Therefore, it is
      important to query diabetic patients at least once a year as to whether they are
      using any herbal or nutritional products. Once it is determined that a patient is
      using these products, physicians must decide if they or someone else should
      address the issue of taking these products. Physicians who have a good comfort
      level with herbal products by all means should recommend them to their patients.
      If such a comfort level is lacking or low, patients can be referred for a
      consultation on the use of supplements or told that information will be forwarded
      to them after contact is made with someone who has knowledge of diabetes and use
      of appropriate supplements. This article reviews nine nutrient and herbal
      remedies commonly used for diabetes to facilitate such patient education.

PMID- 10659524
TI  - Complications of type 2 diabetes mellitus: a brief overview.
AB  - The recent findings of the United Kingdom Prospective Diabetes Study (UKPDS) have
      focused attention on the need to prevent complications in type 2 diabetes
      mellitus. Understanding the pathogenesis and physiologic mechanisms that lead to
      complications in the patients with type 2 diabetes mellitus is imperative to
      prevent their progression and improve treatment. This article discusses the more
      common complications and their possible etiologies, progression, and contribution
      to the morbidity of the diabetic population. It also reviews treatment of these
      complications and recent advances. In addition, some of the less common
      complications will be identified so that primary care physicians and specialists
      will be aware and not overlook these in patients who can be treated early and
      aggressively.

PMID- 10659526
TI  - The effect of foot orthoses on transverse tibial rotation during walking.
AB  - The purpose of this study was to determine the effectiveness of two types of foot
      orthoses in controlling the magnitude and rate of internal tibial rotation,
      measured by the tibial pointer device, during walking. Ten subjects between the
      ages of 23 and 43 years volunteered to participate in the study. Prior to data
      collection, each subject was issued two types of foot orthoses: a pair of rigid,
      plastic orthoses with posting in either the forefoot or the rearfoot, and a pair
      of soft, accommodative, premolded orthoses with no posting. All subjects wore
      standardized footwear. Following a controlled break-in period for both footwear
      and orthoses, each subject was asked to walk at a self-selected speed over a 12-m
      walkway while the movement of internal tibial rotation was recorded with a video
      camera during five trials. The results indicated that both the rigid plastic and
      the accommodative foot orthoses significantly reduced the magnitude and the rate
      of internal tibial rotation. No significant difference was noted between the soft
      and rigid foot orthoses conditions.

PMID- 10659525
TI  - Pharmacologic management of diabetes mellitus.
AB  - Recently, the number of agents to treat type 2 diabetes has increased markedly.
      In the past, the only agents practitioners had available to treat patients with
      type 2 diabetes mellitus were insulin and sulfonylureas. Today, three additional
      classes of agents with a total of six new drugs are available: acarbose, migital,
      repaglinide, metformin hydrochloride, troglitazone, and rosiglitazone. In the not
      too-distant future, several other agents will be available for treating patients
      with diabetes. These new agents will allow physicians to control their diabetic
      patients' blood sugar levels without the need for insulin injections. This
      article reviews the new agents and provides practical suggestions regarding their
      use as monotherapy or in combination therapy.

PMID- 10659527
TI  - Biomechanics of the tarsal mechanism. A key to the function of the normal human
      foot.
AB  - This article describes the function of the tarsal complex as a constrained
      mechanism. The relationship between the interdependence of the motions of the
      tarsal joints and the special nature of tarsal joint function is explained, with
      emphasis on the midtarsal joint and its presumed two axes of motion.

PMID- 10659528
TI  - Timing of peak plantar pressure during the stance phase of walking. A study of
      patients with diabetes mellitus and transmetatarsal amputation.
AB  - High plantar pressures contribute to skin breakdown in patients with diabetes
      mellitus and peripheral neuropathy. The primary purpose of this study was to
      determine the point during the stance phase of walking that corresponds with
      forefoot peak plantar pressures. Results indicate that peak plantar pressures
      occurred at 80% +/- 5% of the stance phase of gait in subjects with diabetes and
      transmetatarsal amputation, as well as in control subjects. Improved methods of
      footwear design or walking strategies proposed to patients should focus on the
      demands of the foot during the late stance phase of walking in order to increase
      available weightbearing area or to decrease forces, which will minimize plantar
      pressures and reduce trauma to the neuropathic foot.

PMID- 10659529
TI  - Dynamic foot orthoses. Principles and application.
AB  - Previous research has identified areas under the foot where stimulation evokes
      specific tonic reflexes. The term "tonic" is used because these reflex movements
      occur slowly, as if tonus or tension were accumulating, in contrast to the abrupt
      phasic response of a tendon jerk. The concept of tonic reactions has now been
      incorporated into the design of dynamic foot orthoses to help provide improved
      orthotic treatment with a better functional outcome. This article describes the
      background of this technique, briefly describes the manufacture of the dynamic
      orthosis, and outlines some of its uses.

PMID- 10659530
TI  - Biomechanics of the normal and abnormal foot.
AB  - The foot is an engineering marvel that allows the body to perform many physical
      activities over a wide variety of terrain with remarkable efficiency. The
      functions of the foot and the lower extremity are biomechanically integrated;
      thus normal lower-extremity function requires normal foot function and vice
      versa. Because the subtalar joint is the main pedal joint allowing the triplanar
      translation of motion between the foot and lower extremity, normal subtalar joint
      function is critical to normal foot and lower-extremity function. This article
      provides an overview of the interrelationships between foot and lower-extremity
      function and mechanically based pathology of the foot and lower extremity, with
      an emphasis on the subtalar joint.

PMID- 10659531
TI  - The windlass mechanism of the foot. A mechanical model to explain pathology.
AB  - This article presents a mechanical model that can be used to understand the foot,
      to help develop methods of treatment of foot pathology, and to provide direction
      for future research in foot mechanics and pathology. The anatomy and mechanical
      function of the windlass mechanism of the foot are analyzed using principles of
      mechanical engineering. The principles of force couples and free-body diagrams
      are explained and then applied to the foot. The relationship of the windlass
      mechanism to plantar fasciitis or heel spur syndrome, hallux abducto valgus, and
      hallux limitus is discussed.

PMID- 10659532
TI  - Sagittal plane biomechanics. American Diabetes Association.
AB  - During walking, the center of body mass must pass from behind the weightbearing
      foot to in front of it. For this to take place, the foot must function as a
      sagittal plane pivot. Because the range required for this motion is approximately
      five times as great as both frontal and transverse plane motion, its evaluation
      should become an essential part of a podiatric biomechanical assessment. Lack of
      proper sagittal plane motion and its sequelae are described.

PMID- 10659533
TI  - Preventive foot care in people with diabetes.

PMID- 10659534
TI  - E-doc approach opens lines to patients.

PMID- 10659535
TI  - Kimberly Ferguson Garner, MD

PMID- 10659536
TI  - Providing culturally sensitive care to Hispanic patients in Arkansas.
AB  - Providing culturally sensitive care to Hispanic patients can lead to a better
      patient-physician relationship. Greater compliance, improved health care delivery
      and treatment efficacy also are enhanced when health care providers understand
      the Hispanic patient's expectation of care and health paradigm. An inability to
      understand the Hispanic patient's health beliefs, social system and barriers to
      health care may lead to a communication breakdown and compromise maximal delivery
      of care.

PMID- 10659537
TI  - The waves of the electrocardiogram: Part 4: The T wave.

PMID- 10659538
TI  - Meconium peritonitis.
AB  - Meconium peritonitis is an unusual and often fatal form of neonatal peritonitis
      characterized by intraperitoneal calcification, numerous fibrosis with or without
      pseudocyst formation due to antenatal extravasation of meconium. This report is a
      retrospective study of 32 pediatric patients who were treated at the Surgical
      Department of the Children's Hospital from 1987 to 1996. The purposes of this
      study emphasize clinical manifestations, radiological findings, operative
      procedures and results of treatment. Twenty seven were neonates and five were
      older infants. The most common clinical presentation was abdominal distension at
      birth. The abdominal X-rays showed abnormal calcification and mass lesion in the
      peritoneal cavity in 71.9 and 46.9 per cent respectively. Only one patient was
      not treated surgically because he had no evidence of gut obstruction and
      inflammation. Thirty-one patients were operated on. At laparotomy, all of them
      had numerous inflammatory adhesion bands and matted bowel loops. Giant
      pseudocysts and intestinal perforations were noted in 64.5 and 54.8 per cent
      respectively. The obvious causes of meconium peritonitis were ileal atresia in 4,
      jejunal atresia in 3 and appendiceal perforation in 1. In the other 23 patients,
      no apparent cause of perforation was noted. Only lysis of the adhesion with or
      without drainage was done in 9 patients and one of these died. Partial resection
      of pseudocysts and exteriorization of the perforated bowel were done in 10
      patients and 2 of these babies died. Primary anastomosis after resection of the
      perforated bowel was done in 12 patients and 5 of these cases died. The overall
      survival rate was 75 per cent. Our data from this study suggested that partial
      resection of the pseudocyst and temporary enterostomy should be done in cases
      with bowel perforation and severe meconium contamination. Early diagnosis, proper
      operative procedure and meticulous postoperative care offer the best opportunity
      for survival of patients with meconium peritonitis.

PMID- 10659539
TI  - Resection of hepatocellular carcinoma: personal experience with 67 patients and
      long-term results.
AB  - Hepatocellular carcinoma (HCC) is the most common cancer in Thailand. Hepatic
      resection has been accepted as the only chance for cure. However; very limited
      information about the operative treatment and survival of HCC in Thailand has
      been documented. The author reviewed the experiences of surgical treatment of HCC
      at the National Cancer Institute, Bangkok and reports herein the long term
      outcome. From January 1986 to January 1996 a total of 884 primary liver cancers
      admitted in our institute were reviewed. 112 consecutive hepatic resections were
      performed by the author. 67 of 112 patients were HCC of which clinical features,
      survival rate and recurrence were studied. Liver cirrhosis was associated in 49
      patients (73.1%). HBsAg was positive in 58 patients (86.6%). Preoperative AFP
      level was more than 400 ng/ml in 35 patients. The resectability for HCC was 11.0
      per cent. In 50 of 67 hepatic resection, major hepatic resection were carried
      out. Postoperative major complications were found in 14 patients (20.9%).
      Postoperative mortality rate of 5 patients was 7.5 per cent. Survival curve was
      calculated by Kaplan-Meier with the overall survival rate at 1, 2, 3, 4, 5 years
      was 63.2 per cent, 28.6 per cent, 21.1 per cent, 14.5 per cent and 11.5 per cent
      respectively. 1, 3, 5 years survival rate for a tumor less than 5 cm was 91.0 per
      cent, 57.0 per cent, 49.4 per cent, tumor size of 5-10 cm was 57.5 per cent, 16.0
      per cent, 9.0 per cent and tumor size more than 10 cm was 52.2 per cent, 0 per
      cent, 0 per cent. A significant difference in survival rate was observed by size.
      Postoperative recurrences were observed in 45 patients (67.2%) and 82.8 per cent
      of the patients had intrahepatic recurrence within 2 years. Hepatic resection is
      an appropriate treatment for a tumor less than 10 cm. However, a tumor larger
      than 10 cm should be considered for multimodality approaches. Intrahepatic
      recurrence is high and similar to the reports from the Orient. Close follow-up
      with prompt treatment for recurrence is the important factor to obtain better
      results.

PMID- 10659540
TI  - The first 100 cases of intracoronary stent implantation in cardiac center, King
      Chulalongkorn Memorial Hospital.
AB  - At King Chulalongkorn Memorial Hospital from July 1994 to December 1996, 123
      stents were implanted in 75 males and 25 females. Average age of the patients was
      61.3 +/- 9.6 years. Fifty-five per cent of the cases were performed in stable
      angina, 26 per cent in post myocardial infarction angina. 17 per cent in unstable
      angina and 2 per cent in acute myocardial infarction. Seventy stents were
      implanted in the left anterior descending artery, 25 in the left circumflex
      artery, 27 in the right coronary artery and one stent in the left main. The
      indications for stent implantation were abrupt closure in thirteen sites, mild
      dissection in 58, suboptimal dilatation in 19, restenosis in 23 and de novo in
      10. Mean size of the stents was 2.99 +/- 0.49 mm and mean inflation pressure was
      11.9 atmosphere. Palmaz-Schatz stent was the most commonly used (53.6%) followed
      by AVE Microstent II (42.3%). There were 3 stents loss in the right femoral
      artery without any complications. Two stents were misplaced, one stent dislodged
      in the left main and needed emergency coronary bypass graft surgery. Two patients
      developed acute stent thrombosis and were successfully reopened with
      intracoronary urokinase. No patient had major bleeding complication, subacute
      thrombosis, acute myocardial infarction or death. CONCLUSION: Stent implantation
      can be performed rather safely with a high success rate and minimal
      complications.

PMID- 10659541
TI  - Separation of labial fusion under topical anesthesia.
AB  - A prospective study from August 1987 to April 1996 at the Outpatient Pediatric
      Surgical Unit, Ratchaburi Hospital, of labial separations performed under topical
      analgesic cream in 31 labial fusions. The ages ranged from 5 months to 5 years.
      Topical analgesic cream (EMLA cream) produces adequate anesthesia for labial
      separation in children without causing pain. It is a simple, safe and effective
      technique including a very short duration of therapy that should be performed in
      children with labial fusion.

PMID- 10659542
TI  - Fetomaternal hemorrhage after midtrimester genetic amniocentesis at King
      Chulalongkorn Memorial Hospital.
AB  - Midtrimester genetic amniocentesis has become an accepted part of modern
      obstetric care. Although its accuracy is well established, the risk of
      fetomaternal hemorrhage remains controversial. This prospective study was
      conducted to determine how effective continuous ultrasound guided amniocentesis
      is in preventing fetomaternal hemorrhage. The authors investigated 30 patients
      undergoing midtrimester genetic amniocentesis at our institution. Amniocentesis
      was performed under continuous real-time ultrasound guidance using a 21-gauge,
      3.5-inch long spinal needle. Maternal serum alpha-fetoprotein (AFP) levels were
      determined before, at 5 minutes and at 1 hour after amniocentesis. There were no
      significant changes in maternal serum AFP levels either at 5 minutes or at 1 hour
      after amniocentesis. Midtrimester genetic amniocentesis performed by a trained
      and experienced operator under continuous ultrasound guidance does not
      significantly increase the risk of fetomaternal hemorrhage after the procedure.

PMID- 10659543
TI  - Somatic growth and clinical manifestation in formula fed infants born to HIV-
      infected mothers during the first year of life.
AB  - This was a comparative study of the growth and clinical manifestation between
      infected and uninfected HIV infants both of whom were fed with a limited quantity
      of powder milk from birth until one year of age. HIV-infected pregnant women were
      enrolled from the second trimester or the beginning of the third trimester. After
      birth, infants had physical examinations, body weight and height were recorded at
      2, 4, 6, 9 and 12 month visits. All mothers were given 7 kilograms of infant
      formula at each infant visit until the infant was one year old. Diagnosis for HIV
      infection in these infants was made by two positive concordant results of DNA PCR
      or RNA PCR or HIV RNA. One hundred and two infants were diagnosed for HIV status
      and 21.5 per cent were infected. The infected infants showed signs of
      malnutrition. From 2-4 months of age, the averages of their weights and heights
      were lower than those of non-infected infants. Abnormal clinical signs were found
      in most infected infants by the time they were 9-12 months old. In conclusion for
      the infants born to HIV- infected mothers, monitoring signs and symptoms
      including their weight and height from birth till 9-12 months old, is predictive
      of the infectious status of most infected infants. The administration and
      management of infant formula in a limited quantity to HIV infected mothers in
      upper northern provinces of Thailand is possible without causing abnormal infant
      growth.

PMID- 10659544
TI  - The diagnostic value of anorectal manometry as a screening test for
      Hirschsprung's disease.
AB  - The diagnostic accuracy of anorectal manometry as a screening test for
      Hirschsprung's disease (HD) was assessed in 46 children suspected of having HD on
      clinical grounds. Among 33 children in whom a rectosphincteric reflex (RSR) was
      not demonstrated on manometric recordings, 31 were later proven to have HD by
      full thickness rectal biopsy: the remaining 2 children were shown not to have HD.
      None of the 12 children who had a normal RSR had HD. Thus, two false positive
      diagnoses were observed in this study, giving an overall diagnostic accuracy by
      anorectal manometry of 95 per cent and diagnostic sensitivity of 100 per cent.
      Anorectal manometry is an accurate, non-invasive test which has a place as the
      screening test of choice for HD.

PMID- 10659545
TI  - Preoperative laparoscopy in the management of the nonpalpable testis.
AB  - The purpose of laparoscopy in the management of the nonpalpable testis is to
      provide information regarding testicular presence and location to facilitate
      overall surgical management. Laparoscopy was performed at operation in 20
      patients between 14 months to 21 years old (average 63 months), who had 22
      nonpalpable testes. Of the testes 13 (59 per cent) were in the inguinal region or
      just proximal to the inguinal ring, 8 (36 per cent) were in a high intra
      abdominal position and 1 (5 per cent) were absent. Anatomical localization of
      nonpalpable testes facilitated accurate planning of operative repair and the
      laparoscopy rendered exploration unnecessary in patients with intraabdominal
      vanishing testes syndrome, and laparoscopic orchiectomy is the treatment for the
      unilateral intraabdominal testes in patients more than 10 years old.

PMID- 10659546
TI  - Photodynamic therapy for residual or recurrent cancer of the nasopharynx.
AB  - Adequate or effective treatments are not always available for most recurrent or
      residual nasopharyngeal cancers (NPC). Photodynamic therapy (PDT) using
      hematoporphyrin derivative (HpD) was evaluated for its effectiveness in treating
      patients, who conventionally failed, with curative or palliative intent. Thirteen
      patients were treated from March 1994 to November 1998. PDT was given to
      eradicate tumor cells, debulk tumor mass for other treatment options, and to
      resolve obstruction. Long-term tumor control could be achieved in 6 patients with
      localized lesions at T1-T2 stages. The mean disease free survival time was 25.8
      months (range 5-61 months). For tumors beyond T2 stage (7 cases), PDT in
      combination with chemotherapy, laser surgery or radiotherapy induced complete
      response in 1 out of 5 patients (survival time = 40 months) and partial response
      in the rest (survival time = 16-37 months). In two patients who refused or were
      in tolerable to further treatment, PDT yielded useful palliative results (i.e.
      resolve nasal obstruction and epistaxis). On an overall basis, the average
      survival time for these patients with relatively advanced diseases was 24.7
      months (range 9-40 months). Our study demonstrated that HpD-PDT could effectively
      control locally recurrent or residual NPC at T1-T2 stages and offered good
      palliation for more advances. Combined PDT and chemotherapy seemed to prolong
      survival time for a period longer than 2 years in T3-T4 tumors.

PMID- 10659547
TI  - Efficacy of high dose interferon--alpha treatment of chronic hepatitis B.
AB  - Fifteen consecutive Hepatitis B virus chronic hepatitis patients were treated
      with interferon alfa-2B 10 mu tiw for 5-6 months. All patients could tolerate the
      side effects without serious complications throughout the treatment period.
      Overall, 12 cases had normalization of ALT (80%), 7 cases had loss of HbeAg with
      appearance of anti-Hbe (58.33%) and 2 cases had loss of HbsAg with the presence
      of antiHBs (13.33%). The response usually associated with improvement in
      histology and decrease in viral load. These results seemed to be better than
      other studies with a lower dose. Further study with more patients should be done
      in the future.

PMID- 10659548
TI  - Pharmacokinetics of levofloxacin in healthy Thai male volunteers.
AB  - The pharmacokinetics of levofloxacin, a new fluoroquinolone, were investigated in
      12 healthy Thai male volunteers with an average age (SD) of 22.92 (2.50) years. A
      single oral dose of 300 mg or 500 mg levofloxacin was given to subjects following
      an 8- hour overnight fast. The drug was given in a controlled, randomized, 2 x 2
      crossover design with a 1 week washout period. Venous blood samples were drawn
      prior to and from 0.25 up to 48 hours after dosing. Plasma levofloxacin
      concentrations were determined by HPLC assay. The pharmacokinetics of
      levofloxacin were well described by a linear, 2-compartment open model with first
      order absorption with lag time and first-order elimination. Mean +/- SEM of Cmax
      after 300 mg and 500 mg dose was 4.83 +/- 0.33 and 7.75 +/- 0.71 micrograms/mL,
      respectively. Tmax ranged from 0.7 to 0.8 hours for both doses. Mean +/- SEM of
      AUC0-infinity was 35.77 +/- 2.06 micrograms x h/mL for 300 mg dose and 61.57 +/-
      2.84 micrograms x h/mL for 500 mg dose. High distribution with VSS/F value of
      approximately 1.5 L/kg was demonstrated after both doses. Mean +/- SEM of CL/F
      value was 8.64 +/- 0.41 L/h and 8.31 +/- 0.37 L/h for a 300-mg and a 500-mg dose,
      respectively. Long t1/2 beta of 7 to 8 hours with the mean residence time of
      10.43 +/- 0.43 hours and 10.49 +/- 0.38 hours after 300 mg and 500 mg dose,
      respectively, was observed. The results suggested that an oral 300 mg dose once
      daily provides sufficient Cmax to cover most Gram-negative and atypical bacteria
      (median MIC90 0.032-0.5 microgram/mL) common in mild to moderate respiratory
      tract infections or complicated urinary tract infections and Gram-positive
      bacteria (median MIC90 0.5 microgram/mL) common in skin and soft tissue
      infections. For severe cases or Streptococcus pneumoniae (MIC90 2 micrograms/mL)
      infection, a 500-mg dose should be recommended.

PMID- 10659549
TI  - Reference value for urinary deoxypyridinoline as a specific marker for measuring
      bone resorption in Thais.
AB  - In the next century, the increasing number of elderly and rising healthcare costs
      will bring with it metabolic bone problems, particularly osteoporosis.
      Deoxypyridinoline: Dpd in urine is a sensitive and specific marker for screening
      and monitoring of bone resorption in a variety of diseases affecting bone
      turnover and in risk groups especially in the postmenopause. The reference value
      among aging (21-60 years) of a healthy well defined group was studied by
      collecting the urine between 700-1000 hours and using the ELISA technique to
      determine the level of Dpd. The reference value of Dpd in 113 males and 298
      females 1.3-6.5 and 1.5-6.9 nm Dpd/nm Creatinine respectively. The level of Dpd
      in females was significantly higher than in males at p < 0.028. However, the
      average value of deoxypyridinoline in postmenopause was higher than premenopause
      but not different at p = 0.05. There are many factors which influence the results
      so the overall reference value is only a guideline for screening in bone
      resorption.

PMID- 10659550
TI  - Effects of different biopsy methods on the development of preimplantation mouse
      embryos, in vitro and in vivo: implication for preimplantation genetic diagnosis.
AB  - The aim of this study was to investigate the efficacy of two different embryo
      biopsy techniques, direct aspiration and partial zona dissection (PZD)-push, on
      subsequent in vitro and in vivo development of 8-cell stage mouse embryos. It was
      found that the rates of normal blastocyst formation and hatching blastocysts of
      direct aspiration, PZD-push, solution control and control embryos were not
      significantly different (80.8%, 81.6%, 84.5%, 86.7% and 71.9%, 72.3% and 74.6%)
      respectively. There was, however, a significant reduction in rate of complete
      hatching blastocysts (P < 0.1) (72.9% aspiration versus 85.2 per cent solution
      control and 86.4% control) and rate of live-born fetuses (24.2% aspiration versus
      43.3% solution control and 41.2% control) (P < 0.05) in the direct aspiration
      group but no significant difference in the PZD-push group (80.3% of complete
      hatched blastocysts and 33.8% of live-born fetuses). These findings indicated
      that embryo biopsy with PZD-push was superior to the direct aspiration method.
      This mouse embryo biopsy model was useful in advancing development of biopsy
      technique for human preimplantation genetic diagnosis.

PMID- 10659551
TI  - Comparative bioavailability of paracetamol.
AB  - Prescribing brand name versus generic drugs continues to be a controversial
      issue. The harmful effects of nonequivalence result from either too little or too
      much drug reaching the patient which will cause either failure of treatment or
      adverse drug reactions. On the other hand, if physicians prescribe higher priced
      original drugs instead of therapeutically equivalent lower cost generic drugs to
      their patients, the patients then have to pay for the added cost. This study was
      designed to compare the bioavailability of paracetamol of a generic versus
      original drug. The original brand (Tylenol, Cilag) which was assigned as the
      reference standard against another generic formulation (Sara, Thai Nakorn
      Patana). Ten healthy male volunteers aged 20 to 45 years participated in this
      study. The study was conducted as a cross-over experimental design. The dose was
      2 tablets of 500 mg. In conclusion, based on the concentration-time curve and
      pharmacokinetic analysis there were no statistically significant differences
      between T1/2 absorption and Cmax. Although AUC of Sara was marginally
      statistically greater than Tylenol, this magnitude of difference probably has no
      clinical significance. All these parameters are within the accepted 20 per cent
      difference, indicating these products are bioequivalent.

PMID- 10659552
TI  - Syndrome of progressive ataxia and palatal myoclonus: a case report.
AB  - A 46-year old man presented with progressive cerebellar ataxia for 5 years.
      Physical examination revealed palatal and tongue myoclonus, cerebellar gait, limb
      ataxia and spasticity of the lower extremities. The imaging studies including CT
      scan and MRI of the brain revealed progressive pancerebellar atrophy and
      bilateral hypertrophic degeneration of inferior olives. The clinical course was
      slowly progressive. Various medications included anticonvulsants, benzodiazepines
      and antispasticity failed to abolish the abnormal palatal movement and ataxic
      syndrome. The syndrome of progressive ataxia and palatal myoclonus is a rare and
      unique neurodegenerative syndrome. The pathogenesis and treatment are still
      unknown.

PMID- 10659553
TI  - Fixed drug eruption due to atenolol: a case report.
AB  - We report a case of (generalized) fixed drug eruption induced by atenolol, a beta
      adrenoreceptor blocking agent. Atenolol has been shown to be effective treatment
      for hypertension, angina pectoris and cardiac arrhythmia. However, adverse skin
      reactions are very rare. We present a case of (generalized) fixed drug eruption
      due to atenolol and review the cutaneous reaction to the drug.

PMID- 10659554
TI  - Hepaticojejunostomy after excision of choledochal cyst in two children with
      previous biliary surgery.
AB  - Hepaticojejunostomy Roux-en-Y after excision of choledochal cyst is the treatment
      of choice for children with choledochal cyst, to prevent the risk of
      postoperative cholangitis, stone formation and malignancy. The author reports two
      children with previous biliary surgery for choledochal cyst, one with
      cystojejunostomy without cholecystectomy and the other with cholecystectomy
      alone. Two children were admitted to the Pediatric Surgical Unit, Ratchaburi
      Hospital, with the complaint of chronic abdominal pain. After investigation the
      two children had cyst excision and hepaticojejunostomy Roux-en-Y. After six and
      one year follow-up the patients remain asymptomatic. The aim of this report was
      to show the complication of two previous biliary surgeries for choledochal cyst
      and support total cyst excision combined with hepaticojejunostomy Roux-en-Y being
      the treatment of choice for choledochal cyst.

PMID- 10659555
TI  - Brain abscess in a patient with atrial septal defect.
AB  - Brain abscess rarely occurs in adults with congenital heart disease. A 59-year
      old man who presented with headache, fever and stiffness of the neck was
      reported. The patient had a atrial septal defect with pulmonary hypertension and
      atrial fibrillation. CT scan of the brain demonstrated an abscess at the right
      parieto-occipital lobe. The patient was successfully treated with appropriate
      antibiotics.

PMID- 10659556
TI  - Simultaneous bilateral painful ophthalmoplegia and exudative retinal detachment
      in rheumatoid arthritis.
AB  - A 47-year-old woman who suffered from chronic rheumatoid arthritis presented with
      bilateral painful ophthalmoplegia with proptosis and exudativeretinal detachment.
      The painful ophthalmoplegia with proptosis might have been caused by
      pachymeningitis involving the cavernous sinus bilaterally, or bilateral posterior
      scleritis spreading to the extraocular muscles and tendons. The exudative retinal
      detachment might have been a result of bilateral posterior scleritis which had
      spread to the choroid. These two unusual complications of rheumatoid arthritis
      occurred simultaneously in this case. Both complications responded to
      corticosteroid treatment.

PMID- 10659557
TI  - Medical ethics in the changing cultural milieu of Thai society.
AB  - Thai Society is changing from an agrarian one to a more individualistic one based
      on rule of law and impersonal relationships. This has far reaching implications
      on the relation between doctors and their patients and especially on medical
      ethics. Traditional communal ties and the honor accorded doctors by the public
      can no longer be relied on as sole measures enforcing ethical principles.
      Measures have shifted from one based on honor to one based on law. One
      implication of this is that medical ethics have to change from the traditional to
      one based on rational discourse. Measures must be found in order that ethics
      based on rational discourse become ingrained in Thai culture. One such measure is
      that radical separation of arts and science in the schools be demolished, and
      that medical students interact academically and substantively with their peers in
      other disciplines.

PMID- 10659558
TI  - Percutaneous transluminal coronary angioplasty in King Chulalongkorn Memorial
      Hospital: a four-year experience.
AB  - From January 1993 to December 1996, 461 cases (743 lesions) of percutaneous
      transluminal coronary angioplasty (PTCA) were performed at King Chulalongkorn
      Memorial Hospital. Seventy eight per cent of the patients were male. Mean age was
      61.1 +/- 9.6 yrs and mean ejection fraction was 0.59 +/- 0.18. The indications
      for PTCA were chronic stable angina (53%), post myocardial infarction (MI) angina
      (26.6%), unstable angina (17.4%) and acute MI (3%). Emergency PTCA was performed
      on 15 cases with 5 patients in cardiogenic shock. Fifty four per cent of the
      cases were performed in single vessel disease, 33 per cent in double vessel
      disease and 13 per cent in tripple vessel disease. The vessels dilated were the
      left anterior descending artery (44.2%), right coronary artery (27.8%), left
      circumflex artery (26.7%), left main (0.9%) and saphenous vein graft (0.4%). Mean
      balloon size was 2.48 mm. The overall success rate of PTCA, defined as residual
      diameter stenosis less than 50 per cent, was 91.5 per cent. In addition to PTCA,
      123 stent implantations with mean stent size 2.98 mm and 15 rotational athrectomy
      were done in 114 cases. Complications of PTCA occurred in 32 cases (6.9%). Ten
      patients (2.2%) had abrupt closure, 1 of these needed emergency coronary bypass
      graft surgery (CABG). One patient (0.2%) had cerebral embolism with minor
      residual neurological deficit. One patient (0.2%) had toe gangrene which
      eventually needed amputation. One patient (0.2%) who presented with acute
      extensive anterior wall MI and failure of thrombolytic therapy died 8 hours after
      successful PTCA due to refractory cardiogenic shock. In the patients who also had
      stent implantation, there were 6 stent misplacements: 3 in the right femoral
      artery without any complication, 2 were misplacements in the coronary system and
      1 dislodged in LM necessitating emergency CABG. CONCLUSION: PTCA is the coronary
      interventional procedure that can be performed with a high success rate and
      minimal complications.

PMID- 10659559
TI  - Recovery of joint position sense after total knee replacement: the effects of
      soft tissue dissection.
AB  - To find out the effect of sharp dissection compared to electrocautery for soft
      tissue release and balancing in total knee replacement on proprioceptive sense,
      the study was carried out as a parellel double blind trial with 2 year follow-up.
      There were 52 patients in the sharp dissection group and 42 patients in the
      electrocautery group. Position sense of the operated knees was evaluated by the
      ability to reproduce the same angles as the non operative knees which acted as
      reference knees. The absolute different angles were used to evaluate the position
      sense. Before the operation, the patients in both groups had similar biographic
      data, pathology, and absolute different angles of knee positioning. After the
      operation, both groups had improvement in knee position sense; however, the sharp
      dissection group had more rapid improvement in the 1st post operative year. There
      was no significant difference at the 2 year follow-up.

PMID- 10659560
TI  - The use of the stabilization period in ECT research in schizophrenia: I. A pilot
      study.
AB  - Electroconvulsive therapy (ECT) has been used to control schizophrenic patients
      since 1938. At the present time, the role of ECT treatment in schizophrenia is
      still controversial. This is because of the paucity of research of both acute and
      long term ECT uses, which has also been characterized by serious methodological
      flaws. The main problems of these difficulties are: 1) lacking standard of ECT
      techniques, 2) using heterogeneous groups of patients, and, 3) no proper outcome
      measurements. The author hypothesized the 3-week-stabilization-period in order to
      use as: 1) a response criterion to delineate the ECT responders from non
      responders, 2) a screening method to obtain a homogeneous group of patients for
      continuation treatment study in schizophrenia, and 3) a method to terminate acute
      ECT treatment. This pilot study was done prospectively on 35 schizophrenic
      patients suffering psychotic exacerbations. Twenty three patients passed the
      stabilization period and there were a clear distinction between responders and
      non-responders. This study could identify a homogeneous group of patients, which
      might be suitable for continuation treatment study. Critical questions regarding
      the ECT methodological issues are extensively discussed.

PMID- 10659561
TI  - Development of the Thai Depression Inventory.
AB  - The Thai Depression Inventory was developed as a self-rating instrument for
      measuring the severity of depression. The items used were based on widely used
      Western scales and on common manifestations and idioms of distress among
      depressed Thai subjects. The scale was tested with 50 depressed patients using
      the Hamilton Rating Scale for Depression as an external standard. The internal
      reliability and concurrent validity were good (Cronbach alpha = 0.858; r = 0.72).
      The items of psychomotor retardation and loss of libido were poorly correlated
      with the total score. Factor analysis revealed five distinct factors which
      accounted for 59.8 per cent of the total variance. Anxiety-insomnia factor was
      the predominant factor. For major depressive patients, the Thai Depression
      Inventory total score is 35 or above. The Thai Depression Inventory is a
      culturally appropriate instrument for measuring the severity of depression with
      satisfactory reliability and validity.

PMID- 10659562
TI  - Somatostatin receptor tumor imaging (Tc 99m P829) in pituitary adenoma.
AB  - Technetium 99m P829 (99mTc P829) is a somatostatin like structure labelled with
      Technetium-99m. Somatostatin receptor positive tumors such as pituitary tumors,
      neuroendocrine tumors, and lymphomas show positive scintigraphy. Eleven patients
      suspected of having a pituitary mass (12 studies) were studied with 99mTc P829.
      Three pituitary adenoma patients (4 studies) showed positive somatostatin
      receptor tumor imaging. Eight negative somatostatin receptor scintigraphy were
      one hypothyroid induced pituitary hyperplasia, one craniopharyngioma, one normal
      pituitary tissue with focal hyperplasia, one ACTH secreting pituitary tumor, one
      GH, PRL secreting pituitary tumor post transphenoidal partial tumor removal, and
      no surgery in 3 patients. Finally, somatostatin receptor imaging may be useful as
      a tumor localizing technique in addition to conventional CT and MRI imaging and
      identify patients who might potentially benefit from octreotide treatment. In
      addition, the development of peptide analogs coupling to beta-emitting
      radiopharmaceutical may lead to a situation in which diagnosis peptide receptor
      scintigraphy can be followed by radionuclide therapy.

PMID- 10659563
TI  - Lack of association between a polymorphism of human thyrotropin receptor gene and
      autoimmune thyroid disease.
AB  - A polymorphism in codon 52 of the human thyrotropin receptor results in a proline
      to threonine substitution in the extracellular domain of the receptor, but the
      association with autoimmune thyroid disease has been uncertain and there is no
      report the prevalence of this polymorphism in Orientals. To investigate this
      polymorphism and the association with autoimmune thyroid disease, we studied 113
      normal unrelated individuals, 142 autoimmune thyroid disease patients including
      112 Graves' disease and 30 Hashimoto's thyroiditis in the Thai population. We
      screened genomic DNAs of these subjects for the presence of A253 by PCR
      amplification using a degenerate oligonucleotide primer which produces a Tth111 I
      restriction site only in the presence of A253. The variant allele was present in
      5.3 per cent of normal and 3.5 per cent of autoimmune thyroid disease, 2.7 per
      cent of Graves' disease and 6.7 per cent of Hashimoto's thyroiditis. The allele
      distribution in autoimmune thyroid disease patients did not differ significantly
      from that observed in controls. No association was found between this TSH-R
      polymorphism and the occurrence of autoimmune thyroid disease.

PMID- 10659564
TI  - Myringoplasty: a simple procedure for out-patients.
AB  - The standard treatment of tympanic membrane perforation is myringoplasty. We
      describe a new myringoplasty technique requiring only a partial removal of skin
      on the ear drum remnant followed by lateral placing of fascia and free skin
      graft. The overall cure rate in our series is 97 per cent. The hearing gains for
      the overall cases are 13.9 dB (p < 0.001) for the AC, 13.6 dB (p < 0.001) for the
      air bone gap closure, 13.1 dB (p < 0.001) for the SRT and 4.2 per cent (p =
      0.005) for the SDS. Minor complications are observed in only 14 per cent. Our
      technique is simple, effective and can be performed on an out-patient basis.

PMID- 10659565
TI  - Fine needle aspiration cytology of thymoma.
AB  - Thymoma is the 2nd most common mediastinal tumor found in Thai people.
      Cytologically it has a characteristic biphasic cell pattern and can be
      differentiated from other mediastinal lesions. We reviewed 14 aspirated samples,
      initially diagnosed as thymoma among a total of 80 mediastinal aspirations,
      obtained during a period of 6 years. Revised cytologic diagnosis was made and
      compared with histopathology from needle biopsy, surgical biopsy and surgical
      removal in each case. All cytologic samples revealed a mixture of epithelial
      cells and lymphocytes in varying proportions. Histopathologic samples were
      available in 13 patients and showed 12 thymomas and 1 immature teratoma. While
      all thymomas revealed characteristic cytologic features, a case of mediastinal
      immature teratoma with unsatisfactory aspirated sample revealed resembling
      features and it was very difficult to differentiate such a tumor from thymoma.

PMID- 10659566
TI  - Reduction of urinary stone in children from north-eastern Thailand.
AB  - Bladder stones in children have decreased now compared with the previous decade.
      If we promote good nutrition for children, bladder stones will decrease and might
      be eradicated in the future. A seminar of doctors and health personnel from 19
      hospitals in the north-eastern provinces of Thailand was conducted to survey
      bladder stones in children by weighting and interviewing bladder stone symptoms
      then giving supplementary diet milk and vitamins and teaching health education
      about nutrition and urinary stones through referring children with bladder stones
      to hospitals in north-eastern Thailand for surgery. The findings of the stone
      patients from October 1995 to June 1996 from hospitals in northern Thailand were:
      Total number of patients was 6671 of which 287 patients (4.3%) were 10 years old
      or younger. Of these children there were 135 renal stone operations (2.0%), 29
      ureteric stone operations (0.4%), 106 bladder stone operations (1.6%) and 17
      urethral stone operations (0.3%). There were 6384 patients aged more than 10
      years. (95.7%) The total number of operations was 5373.

PMID- 10659567
TI  - A risk scoring system to predict outcome of non-variceal upper gastrointestinal
      bleeding in Thai patients.
AB  - The purpose of this study was to determine the predictors for poor outcome in
      patients with upper gastrointestinal bleeding (UGIB) by constructing a risk
      scoring system based on retrospective data analysis and validating the scoring
      system prospectively. In the first phase of the study, 264 patients with acute
      non-variceal UGIB were retrospectively reviewed, and likely predictors of poor
      outcome, including major re-bleeding, need for emergency surgery to control
      bleeding and hospital death, were ranked into a risk scoring system. In the
      second phase, this scoring system was prospectively validated in 107 patients.
      The characteristics of the retrospective and the prospective groups were not
      significantly different. Four predictors of outcome were found to be significant,
      namely concurrent illnesses, the presence of at least one disease (score 1),
      heart rate above 110 beat/min (score 1), blood transfusion over 6 units (score 2)
      and the presence of visible vessels on endoscopic examination (score 1). Patients
      with a total score of less than 2 had good outcome whereas scores of 2 or more
      were associated with a poor outcome. The accuracy of the test was 82.5 per cent.
      The positive and negative predictive values were 46.3 per cent and 92.7 per cent
      respectively. The likelihood ratio was 4.5. It is concluded that the risk scoring
      system constructed in this study represents a good predictor of poor clinical
      outcome in patients presenting with non-variceal UGIB.

PMID- 10659568
TI  - Fast liver alkaline phosphatase isoenzyme in diagnosis of malignant biliary
      obstruction.
AB  - Fast liver alkaline phosphatase isoenzyme was measured by cellulose acetate
      electrophoresis in the sera obtained from 84 patients with specific hepatobiliary
      diseases and 10 control subjects. The mean value of this isoenzyme in patients
      with malignant extrahepatic obstruction was 130.58 +/- 107.08 U/L, significantly
      higher than that of patients with benign extrahepatic obstruction (65.63 +/-
      34.14 U/L), as well as patients with intrahepatic cholestasis and infiltrative
      liver cancers (65.31 +/- 38.11 U/L and 48.47 +/- 36.85 U/L, respectively).
      Furthermore, we could not detect this isoenzyme in normal individuals. When 100
      U/L was used as a cut-off value to discriminate between patients with malignant
      extrahepatic obstruction and the remaining hepatobiliary disorders, the
      sensitivity, specificity and accuracy of the test were 63 per cent, 84 per cent
      and 80 per cent, respectively. It is concluded that the fast liver isoenzyme
      could be a useful marker in diagnosis of malignant extrahepatic obstruction.

PMID- 10659569
TI  - Interlaboratory results for blood lead proficiency testing program in Thailand.
AB  - Between December 1994 to 1995, Faculty of Medical Technology, Mahidol University
      have a thirteen laboratory to participate in Blood Lead Proficiency Testing
      Program (BLPT). Every-month the Toxicology Unit in Faculty of Medical Technology
      Mahidol University which served for Reference Laboratory Center for BLPT send the
      three lots of whole blood sample which made from bovine blood to the participants
      by EMS. After evaluation in term of accuracy: using 75 per cent correctly when
      compared with the target value. There are nine laboratory which have successful
      in blood lead below 20 micrograms/dL and three laboratory which passing the
      analysed when the concentration of blood lead at 21-50 micrograms/dL and 51-80
      micrograms/dL. In term of precision evaluation the planning process will show
      that laboratory using Graphite Furnace Atomic Absorption Spectrophotometer
      (GFAAS) reported reliability than using Flame Atomic Absorption Spectrophotometer
      (FAAS). From joining with this program the participants will get three
      advantages, First the target value from the reference laboratory in Thailand and
      Singapore are similar with the Center for Disease Control (CDC) from the United
      State of America which known world wide for Reference Laboratory. In the second
      participants will develop the analysis and solve the problem by himself, The
      third advantage: will showing the superior, methodology and instruments which
      guarantee for quality assurance and guideline to standardized blood lead analysis
      in the International level.

PMID- 10659570
TI  - Down's syndrome presented with clubfoot deformity: a case report.
AB  - A 1 month old girl was referred to the orthopaedic clinic with bilateral clubfoot
      deformities. At birth, clinical examination showed the typical characters of
      Down's syndrome and the diagnosis was confirmed by chromosome study. These two
      conditions appear improbable as their basic pathologies are entirely different.
      In our patient, the translocation type at the long arm of chromosome 21 was
      determined in the chromosome study. This result has never been reported in the
      literature.

PMID- 10659571
TI  - Abdominal incisional endometrioma following cesarean section: a case report.
AB  - A 34 year old woman underwent a cesarean section for placenta previa when she was
      25 years old, after that she took oral contraceptives regularly for 8 years and
      remained asymptomatic. Upon entering our hospital, the patient stopped taking the
      oral contraceptives and had a one year history of cyclic bleeding from the lower
      midline abdominal incision scar. Surgical excision was done and pathological
      findings revealed endometrioma.

PMID- 10659572
TI  - Acute pancreatitis following resection of juxtarenal abdominal aortic aneurysm.
AB  - A case of acute pancreatitis following resection of a juxtarenal abdominal aortic
      aneurysm is reported. The patient was a 73 year old man who underwent resection
      of a juxtarenal abdominal aortic aneurysm. The aneurysm was repaired with a 20
      mm. gelatin coated Dacron graft. Proximal control of the aneurysm was performed
      with supraceliac aortic cross clamping. The clamping time was 50 minutes.
      Postoperatively, he developed progressive abdominal distension with deterioration
      of renal and pulmonary function necessitating relaparotomy on the 7th
      postoperative day. The second operation revealed evidence of saponification and
      fat necrosis in the omentum. The pancreas was edematous and swollen compatible
      with acute pancreatitis. The aortic graft and other intraabdominal organs
      appeared normal. Despite intensive supportive care, the patient died 2 weeks
      later from multiple system organ failure. The possible causes of acute
      pancreatitis following aortic surgery described in the literature are 1. systemic
      and regional hypoperfusion, 2. atheromatous emboli to arteries supplying the
      pancreas and 3. direct trauma to the pancreas during the operation from
      retractors or surgical dissection. All of which may be the etiology of acute
      pancreatitis in our patient. Avoidance of such factors during aortic surgery is
      recommended to prevent this potentially fatal complication.

PMID- 10659573
TI  - Intra- and extra-uterine pregnancies following repeated sterilization in a case
      of HIV seropositive patient.
AB  - A 24-year-old woman, HIV seropositive, LMP ten weeks previously, para 2-0-0-2,
      presented with complaints of left sided pelvic pain. Her previous pregnancies
      were terminated by cesarean section with tubal sterilization (Pomeroy technique)
      in the first pregnancy and by cesarean section with repeated tubal sterilization
      (Pomeroy technique) in the second one. The pelvic examination revealed cervical
      motion tenderness and a tender sausage-like mass of about 3 x 4 cm in the left
      adnexa. Both previously ligated fallopian tubes and a hematosalpinx lying distal
      to the ligated site of the left tube were revealed in the exploratory laparotomy
      after a positive culdocentesis. Bilateral salpingectomy was performed. The
      histological examination confirmed the diagnosis of tubal pregnancy in the left
      tube and the status post tubal sterilization in the right one. The postoperative
      course was uneventful.

PMID- 10659574
TI  - Hypophosphatasia: the importance of alkaline phosphatase in bone mineralization.
AB  - The authors describe a neonate who was diagnosed with "perinatal
      hypophosphatasia". The clinical manifestations in this patient were small head
      size, soft calvarium (caput membranaceum), and short bowing forearms and legs.
      Laboratory investigations revealed hypercalcemia at 12.7 mg/dl, hyperphosphatemia
      8.6 mg/dl, and extremely low alkaline phosphatase 0 unit/L. Roentgenographic
      studies of the skull showed calcification only at frontal bone and base of the
      skull. Spines were small and flattened. Long bones were hypomineralized and
      deformed. The functions of alkaline phosphatase to bone development and
      mineralization were reviewed. Because perinatal hypophosphatasia is a fatal
      condition and inherited as an autosomal recessive pattern, prenatal diagnosis is
      necessary. The most reliable and suitable method in our facility is serial
      ultrasonography from which the diagnosis can be made by the second trimester.

PMID- 10659575
TI  - Appendectomies that almost went wrong.

PMID- 10659576
TI  - [The production and coexistence of neurotransmitters in the neurons of the rat's
      locus coeruleus].
AB  - The production and coexistence of neurotransmitters in the locus coeruleus is
      reviewed. Immunocytochemical and in situ hybridization evidence demonstrated that
      the LC consists mainly of a single cell population that is producing GABA and 5
      HT in addition to noradrenaline (NA) simultaneously in single neurons. The
      coexistence of GABA, 5-HT and NA in single LC neurons was proved by identifying
      the same neurons in adjacent sections alternately immunostained by different
      antisera. In situ hybridization detected the signals of glutamic acid
      decarboxylase mRNA and tryptophan hydroxylase mRNA indicating the presence of
      GABA/GAD system and the ability to produce 5-HT in many LC neurons.
      Neuroanatomical studies strongly suggest that a single NA cell population
      produces multiple transmitters so that the LC can play a role in mechanism
      controlling the human's adaptation to environmental changes. The present author
      introduces three different recent works concerning the LC. Caffe concluded that
      the concept of a NA-ergic cell population in all mammals is questionable. In
      similar cases to the domestic pig's LC, acetylcholinesterase activity, muscarinic
      and nicotinic receptor proteins should be checked. Tohyama et al. examined
      various receptor proteins in the LC and found localization of GAGAA, glutamate
      and glycine receptors. Maeda et al. reported that doaminergic neurons in the
      hypothalamus play a powerful role in mechanisms controlling the activity of NA
      ergic neurons in the LC. Senile dementia of Alzheimer type causes marked atrophy
      and cell loss in the LC as well as the frontal lobe of the cerebrum. Molecular
      biology of the cell has been devoted to clarify the pathology of this fatal
      disease.

PMID- 10659577
TI  - Sural--lateral plantar nerve communications in Japanese macaque.
AB  - It is generally accepted that the sural nerve in humans contains exclusively
      sensory and autonomic fibers. Recently, however, a few clinical reports have
      suggested that the human sural nerve contains motor fibers. On the other hand, it
      is known that motor fibers are present in the sural nerve of rats and dogs, and
      that the fibers reach intrinsic muscles of the foot via a communicating branch to
      the lateral plantar nerve. The author investigated the communicating branch
      between the sural and lateral plantar nerves in Japanese macaques, and examined
      both nerves by the fiber analysis method, removing the perineurium under a
      stereoscopic microscope. The communicating branch was found in all examined
      macaques. Nerve fibers which derived from the sural nerve via the branch reached
      the abductor digiti quinti, the flexor digiti quinti brevis, the contrahentes
      digitorum, the adductor hallucis, the interosseous and the lumbrical muscles.
      Furthermore, these fibers supplied the lateral part of the skin of the sole and
      the metatarsophalangeal joints. These findings in the Japanese macaques suggest
      that we may encounter the communicating branch between the sural and lateral
      plantar nerves in other primates including humans as in rats and dogs.

PMID- 10659578
TI  - Lumbosacral plexus in Hoxa9 knockout mice with special reference to their nerve
      variations identified according to whether they were interphenotypic or
      intergenotypic differences.
AB  - The lumbosacral plexus in specific Hox gene mutant mice originating from
      C57bl/60, i.e., Hoxa9 +/+, +/- and -/- genotypes (10 specimens of each), were
      dissected minutely and detailed examinations were made of the eight nerves in the
      plexus and the lowest intercostal nerve. We identified three types of nerve
      variation in mice with Hox mutations: interphenotypic variations, intergenotypic
      variations and common variations regardless of the genotype axial phenotype. The
      interphenotypic variations involved a caudal shift of the nerve origin in mice
      with the Hoxa9 -/- axial phenotype. We divided these variations into three
      patterns according to whether or not nerve configurations in mice with the wild
      and/or Hoxa9 -/- axial phenotypes were consistent, as follows: 1) the
      iliohypogastric and pudendal nerve morphologies of either of the phenotypes were
      consistent; 2) the femoral, obturator and sciatic nerve morphologies of the wild
      axial phenotype were consistent, but those of the -/- phenotype showed several
      variations and 3) both phenotypes showed several variations of the ilioinguinal
      and genitofemoral nerves. The intergenotypic variations, were limited to two
      examples: the common trunk formation of the ilioinguinal and iliohypogastric
      nerves in mice with the +/- and -/- genotypes, regardless of their axial
      phenotypes, and the territory of the ilioinguinal nerve touched the lateral
      margin of the thigh in the wild genotype, but extended beyond the margin onto the
      posterior aspect in the -/- genotype. The common variations regardless of either
      axial phenotype or genotype, included the lateral cutaneous nerve of the thigh
      which showed a limited, common variation in both of the nerve origin,
      ramification pattern and territory among either the three genotypes or two axial
      phenotypes. We consider the interphenotypic variations to be consistent with
      previous experimental findings showing a discrepancy between the nerve origins
      and their cues for nerve pathfinding. However, this developmental sequence did
      not seem to apply to the intergenotypic or common variations.

PMID- 10659579
TI  - A possible barrier function of the articular surface.
AB  - Since MacConaill first reported the existence of a thin additional layer of the
      articular cartilage and named it the lamina splendens, there have been various
      opinions as to the role of this layer in the lubrication of the articular
      surface. We studied the superficial portion of the articular cartilage in the 20
      day-old and 30 day-old rats using light and transmission electron microscopy.
      Furthermore, we studied the articular cartilage of the rat whose "cover layer"
      had been removed mechanically. Also, intraarticular latex beads injection,
      intraarticular dye injection using lithium carmine and supravital staining
      experiments were performed. On day 20, dye injected intraarticularly was clearly
      observed by light microscopy in chondrocytes situated in the deeper layers. The
      dye injected in the 30 day-old rats, however, was not seen in the chondrocytes
      but was found only in the superficial layer. Dye was found in the chondrocytes
      when supravital staining was performed in the articular cartilage of 30 day-old
      rats after mechanical removal of the cover layer. By transmission electron
      microscopy, a superficial layer consisted of fine filamentous structures was
      observed on the articular surface of the 30 day-old rats. The cover layer was
      destroyed by intraarticular injected latex beads in 30 day-old rats. These
      findings strongly support the idea that the cover layer acts as a barrier against
      substances which invade from the surface of the articular cartilage. The
      development period of the cover layer coincides with the initiation of weight
      bearing, and joint cartilage debris and pressure changes might further promote
      maturation.

PMID- 10659580
TI  - Morphometric analyses of the development of dermis in human fetuses.
AB  - In this study, the morphometric differences of the different dermis regions
      during the development of the human fetus were investigated. The different dermis
      regions, namely, cranial, femoral and plantar (sole) parts of 40 fetuses which
      were between 12th-23.5th week gestation age were obtained from maternity hospital
      and after the routine H&E histological procedure, the measurement was performed
      with ocular micrometer. The first sharp increase was observed in the dermis of
      cranial region. It has been suggested that the thickness of the dermis is
      dependent on the collagen and elastic fibres, but the flexibility of the dermis
      is dependent on the number and the structure of the elastic fibres. The early
      beginning of the increase of the dermis thickness in the cranial part may be due
      to the effect of the cranio-caudal stimulation on the production of the collagen
      and elastic fibres in the embryonic term.

PMID- 10659581
TI  - [Visualization of normal organs in whole-body FDG-PET imaging].
AB  - It is important to know FDG accumulation in the normal distributions for
      interpreting whole-body PET imaging for tumor detection. Twenty-eight normal
      subjects were studied with whole-body PET imaging and were examined the intensity
      of FDG uptake in major organs and the factors which caused it's variety. Emission
      images were acquired and images were reconstructed without attenuation
      correction. The intensity of FDG uptake was classified into 4 grades visually. No
      accumulation was found in the thyroid, the esophagus and the spleen. The oral
      cavity, the liver, the stomach, and the colon were visualized in all subjects.
      The laryngeal muscle, the cervical muscle, and the heart accumulated FDG with
      various grade from 1 to 4 grades. No association was found between the intensity
      of uptake in the organs and volunteer's age. The fasting time was shorter in
      volunteers whose heart showed "high" grade than those showed less accumulation (p
      < 0.05). Serum concentration of free fatty acid was significantly lower in them,
      too (p < 0.05). Various FDG uptake was observed in many organs, especially the
      laryngeal muscle, the cervical muscle, and the heart. In our study, there was no
      facter which caused FDG uptake in organs except for the fasting time and the
      value of free fatty acid in the heart. Such analysis of whole-body FDG
      distributions in the normal subjects is valuable for tumor detection with FDG
      PET.

PMID- 10659582
TI  - [Characteristics of myocardial ischemia in patients with chronic renal failure
      and its relation to cardiac sympathetic activity].
AB  - In order to clarify the characteristics of myocardial ischemia in patients with
      chronic renal failure (CRF), we performed exercise stress myocardial perfusion
      imaging with 99mTc-MIBI in 36 patients with CRF. In 18 patients myocardial
      imaging with 123I-MIBG (MIBG) and 201Tl was performed at rest to evaluate
      myocardial sympathetic activities: cardiac uptake of MIBG normalized by
      myocardial perfusion (Uptake Ratio, UR) and myocardial washout rate of MIBG (WO).
      Exercise-induced perfusion abnormality was observed in 25 patients, and coronary
      angiography was performed in 19 of them. Among 25 diseased coronary arteries, 18
      developed perfusion abnormalities in the myocardial segments which were supplied
      by each coronary artery. However in 5 patients without coronary artery stenosis
      and 2 patients with left anterior descending coronary artery disease, transient
      perfusion abnormalities were observed in the inferior segments. In 6 of them,
      MIBG imaging was obtained (Group A). MIBG imaging was also performed in 5
      patients with transient inferior perfusion abnormality with coronary artery
      stenosis which supplied the inferior wall (Group B), and 7 patients without
      perfusion abnormality (Group C). In the patients of Group B, inferior UR was
      significantly lower than in Group C (0.58 +/- 0.07 vs. 0.68 +/- 0.08, p = 0.0485)
      and inferior WO was more accelerated than in Group C (18.6 +/- 7.7 vs. 12.1 +/-
      6.0%, NS). However anterior UR and Wo levels were identical with those in Group
      C. In Group A, inferior UR (0.43 +/- 0.05) was significantly lower than in Group
      B and C, and WO in Group A (27.2 +/- 8.3%) was accelerated significantly compared
      to that in Group C. Besides in Group A, anterior UR was significantly smaller and
      WO was greater than in Group B and C. These findings suggested that in some
      patients with CRF, myocardial ischemia could arise without coronary artery
      stenosis, and this phenomenon might be related to abnormalities of cardiac
      sympathetic activity.

PMID- 10659583
TI  - [Assessment of regional quantitative analysis by ECG-gated myocardial SPECT after
      coronary artery bypass surgery].
AB  - PURPOSE: ECG-gated myocardial SPECT (G-SPECT) was performed before and after
      coronary artery bypass surgery (CABG) to investigate how this operation would
      affect the assessment of regional quantitative analyses. METHODS: Nineteen
      patients with coronary artery disease underwent G-SPECT before and 1 month after
      uncomplicated CABG. 99mTc-MIBI 740 MBq was injected at rest, then G-SPECT was
      performed 60 min later. Regional ejection fraction (rEF), wall motion (WM),
      systolic wall thickening (WT) and % tracer uptake were evaluated by quantitative
      gated SPECT program (QGS). Parameters were obtained quantitatively in 16 segments
      based on the functional bull's eye map. RESULTS: Percent tracer uptake increased
      in septum from 75 +/- 11% to 78 +/- 11% (p < 0.001), while WT did not change (40
      +/- 19% to 41 +/- 20%) after CABG. However, in septum rEF decreased from 17 +/-
      13% to 6 +/- 9% (p < 0.001) and WM decreased in septum from 1.6 +/- 1.1 mm to 0.6
      +/- 0.9 mm (p < 0.001). CONCLUSION: Significant reduction of rEF and WM despite
      of no deterioration of WT and % tracer uptake suggested that rEF and WM were
      affected by pseudoparadoxical asynergy after uncomplicated CABG. For the
      evaluation of regional function after CABG by G-SPECT, WT might be the preferred
      parameter.

PMID- 10659584
TI  - [Practical compensation method of downscattered component due to high energy
      photon in 123I imaging].
AB  - We looked into the problem that the quantitative values of 123I data vary
      according to collimator type. First, we made the assumption that the quantitative
      values of 123I data are degraded by the scattered photons from the 529 keV
      component which contaminate the 159 keV imaging data. Then, the 123I Dual Window
      (IDW) method was proposed to improve the quantitative values of the 123I data.
      The IDW method uses the energy window on the high-energy side to estimate the
      amount of scattered 529 keV photons which contaminate the 159 keV data. Since
      only a dual-energy window acquisition and a simple image processing are needed,
      the IDW method can be performed in most conventional gamma camera systems. In the
      torso phantom studies, the IDW method reduced the error in the semi-quantitative
      value 'heart/mediastinum (H/M) ratio' in 123I-MIBG myocardial scintigraphy from
      22% to 1%. The results of the phantom studies indicate that the IDW method can
      improve the quantitative values of 123I data.

PMID- 10659585
TI  - [Compartment analysis of 123I-iomazenil brain SPECT in patients with moyamoya
      disease].
AB  - We investigated 11 patients with moyamoya disease about 123I-Iomazenil kinetics
      in the brain using three-compartment, two-parameter model. The transition rate
      constant (K1) from the blood to the brain and the binding potential (BP) of the
      benzodiazepine to the receptors were calculated for every ROI (right and left
      side of cerebellum, frontal lobe, parietal lobe, occipital lobe and temporal
      lobe; 10 ROIs a case). The K1 value correlated with BP value significantly, but
      not so closely (r = 0.639). And there is no significant difference in BP value
      among low-K1 group (mean (of K1) -S.D. < or = K1 < or = mean) and high-K1 group
      (mean < K1 < or = mean + S.D.). This means that CBF and BP do not correlate
      closely in the average Moyamoya disease patients. And we showed a case with
      IMP/IMZ discrepancy. The nerve cell in the hypoperfused area which has almost
      normal BP value is ischemic but viable. IMZ-SPECT presents an important
      information about the viability of the hypoperfused area in Moyamoya disease
      patients' brain.

PMID- 10659586
TI  - [Phase 1 clinical study of 123I-FP-CIT, a new radioligand for evaluating dopamine
      transporter by SPECT (II): Tracer kinetics in the brain].
AB  - The kinetics of 123I-FP-CIT in the brain for healthy subjects were studied.
      Twelve dynamic SPECT data sets (0- to 6-hr after an intravenous injection) from a
      Phase 1 clinical trial of 123I-FP-CIT were analyzed. Tracer concentrations in the
      striatum, midbrain, cerebellum and cerebral cortex were measured on the SPECT
      images co-registered with the corresponding MR images. High tracer accumulation
      was observed in the striatum, which peaked at 60 min post-injection, followed by
      slow elimination (3%/hr). The kinetics were similar both in the cerebellum and in
      the cerebral cortex, which peaked at 15 min post-injection, followed by rapid
      elimination. Tracer accumulation in the midbrain was higher than in the
      cerebellum and cerebral cortex. The striatal specific/nonspecific binding ratio
      ((striatal-occipital)/occipital concentration ratio) was stable at 3-hr post
      injection and later at a value of 3, suggesting that the specific binding of 123I
      FP-CIT could be evaluated from a single SPECT image at 3- to 6-hr post-injection.
      The specific/nonspecific binding ratio at 4-hr post-injection showed a negative
      correlation with aging (r = -0.70, p = 0.01), with a decrease rate of 11%/decade
      (95% confidence interval: 3%-19%/decade).

PMID- 10659587
TI  - [Investigation of radiation safety management of nuclear medicine facilities in
      Japan; contamination of radioactivity in the draining-water system. A Working
      Group of Japanese Society of Nuclear Medicine for the Guidelines of Nuclear
      Medicine Therapy].
AB  - Radiation safety management condition in Japanese nuclear medicine facilities
      were investigated by the questionnaire method. The first questionnaire was asked
      in all Japanese 1,401 Nuclear Medicine facilities. Answers from 624 institutes
      (44.5%) were received and analyzed. The radiation-safety management in nuclear
      medicine institutes was considered to be very well performed everyday. Opinion
      for the present legal control of nuclear medicine institutes was that the
      regulation in Japan was too strict for the clinical use of radionuclides. The
      current regulation is based on the assumption that 1% of all radioactivity used
      in nuclear medicine institutes contaminates into the draining-water system. The
      second questionnaire detailing the contamination of radioactivity in the draining
      water system was sent to 128 institutes, and 64 answers were received. Of them,
      42 institutes were considered to be enough to evaluate the contamination of
      radioactivity in the draining-water system. There was no difference between 624
      institutes answered to the first questionnaire and 42 institutes, where the
      radioactivity in the draining-water system was measured, in the distribution of
      the institute size, draining-water system equipment and the radioactivity
      measuring method, and these 42 institutes seemed to be representative of Japanese
      nuclear medicine institutes. Contamination rate of radioactivity into the
      draining system was calculated by the value of radioactivity in the collecting
      tank divided by the amount of radionuclides used daily in each institute. The
      institutes were divided into two categories on the basis of nuclear medicine
      practice pattern; type A: in-vivo use only and type B: both in-vivo and in-vitro
      use. The contamination rate in 27 type A institutes did not exceed 0.01%, whereas
      in 15 type B institutes the contamination rate distributed widely from
      undetectable to above 1%. These results indicated that the present regulation for
      the draining-water system, which assumed that 1% of all radioactivity used in
      nuclear medicine institutes contaminated into draining-water system, should be
      reconsidered in nuclear medicine facilities where radionuclides are used only in
      in-vivo studies.

PMID- 10659588
TI  - Effects of indomethacin and hyperventilation on cerebral hemodynamics and
      oxygenation in newborn piglets.
AB  - We investigated the effect of indomethacin (INDO) and hyperventilation (HV) on
      cerebral hemodynamics and oxygenation in newborn piglets using near-infrared
      spectroscopy (NIRS). A total of 10 piglets aged 7-10 days were divided into 2
      groups. INDO (Experimental group; 0.2 mg/kg i.v.) or saline (Control group) was
      administered after steady state, then each group was hyperventilated (pCO2; 20 mm
      Hg). Cerebral oxyhemoglobin concentrations (HbO2) significantly decreased
      immediately after INDO administration compared to controls (p < 0.01). This
      decrease continued for 15 min. During HV, HbO2 remained low compared to the
      steady state (p < 0.05) in the experimental group. Total hemoglobin
      concentrations (HbT) decreased simultaneously with HbO2. In the control group, no
      changes in HbO2 or HbT were observed after saline administration, and only a
      slight decrease in HbO2 was observed during the 5 minutes' HV compared to the
      steady state. No changes in cytochrome aa3 (Cytaa3) were observed in either group
      during 100% O2 inhalation. We conclude that INDO decreased HbO2 and HbT by
      vasoconstriction, but that HV did not further aggravate this tendency. Great care
      should be taken when using INDO for newborn neonates.

PMID- 10659589
TI  - Effects of interleukin-1 beta on neurons in mammalian pelvic ganglia.
AB  - The effects of interleukin-1 beta (IL-1 beta) on the membrane potential and
      synaptic transmission were examined in neurons of mammalian pelvic ganglia. Bath
      application of recombinant human IL-1 beta (6-300 pM) for 10 s-5 min produced a
      long-lasting hyperpolarization associated with increased input resistance in 11
      neurons of rat major pelvic ganglia (MPG). In other 8 neurons, IL-1 beta (300 pM)
      produced a biphasic response that consists of an initial depolarization followed
      by a long-lasting hyperpolarization. IL-1 beta 163-171 (10-100 pM), a synthetic
      nonapeptide analog that contains the active domain of human IL-1 beta, mimicked
      the effect of IL-1 beta in MPG neurons. gamma-Aminobutyric acid (GABA, 300
      microM) produced a depolarization followed by a hyperpolarization that was
      blocked by picrotoxin (100 microM). Db-cyclic guanosine monophosphate (db-cyclic
      GMP, 100 microM) also produced an initial depolarization followed by a long
      lasting hyperpolarization. These results suggest that the IL-1 beta-induced
      biphasic response is mediated by a GABA receptor-cyclic GMP pathway. IL-1 beta
      and IL-1 beta 163-171 caused an initial facilitation followed by a long-lasting
      depression of the excitatory postsynaptic potential (EPSP) in rabbit VPG. The
      data suggest that IL-1 beta presynaptically depressed the EPSP by reducing the
      release of acetylcholine (ACh) from the pelvic nerve terminals.

PMID- 10659590
TI  - Differential diagnosis between tumor-forming pancreatitis and pancreatic cancer
      by percutaneous transhepatic portography and selective direct pancreatic
      venography.
AB  - In 32 patients with tumor-forming pancreatitis and 109 patients with pancreatic
      cancer, the usefulness of percutaneous transhepatic portography (PTP) and
      selective pancreatic venography (SPV) for differential diagnosis of the two
      diseases was evaluated. The PTP images were type I in 53.1%, type II in 21.9%,
      type III in 12.5%, and type IV in 12.5% of the patients with tumor-forming
      pancreatitis and type I in 20.2%, type II in 23.9%, type III in 37.6%, and type
      IV in 18.3% of the patients with pancreatic cancer. Advanced images (type III or
      type IV) were observed in more than half the patients with pancreatic cancer.
      Mild images classified as type II were observed slightly more frequently in the
      patients with pancreatic cancer, but the differential diagnosis of the two
      diseases was difficult in patients showing type II PTP images. SPV findings were
      primarily hypervascularization (78.1%) and vasodilation (68.8%) in the patients
      with tumor-forming pancreatitis. Although encasement (smooth encasement) was
      noted in 31.3%, obstruction was found in only 3.1%. In the patients with
      pancreatic cancer, obstruction was observed in 85.3%, and encasement (irregular
      encasement) was noted in 78.9%. However, hypervascularization or vasodilatation
      was infrequent, and the tumor was characteristically imaged as a hypovascular
      area. PTP and SPV were considered to be useful for the differential diagnosis of
      tumor-forming pancreatitis and pancreatic cancer.

PMID- 10659591
TI  - The role of protein kinase C and [Ca2+]i in superoxide anion synthesis and
      myeloperoxidase degranulation of human neutrophils.
AB  - A chemiluminescence procedure has been developed to determine superoxide anion
      (O2-) generation and myeloperoxidase (MPO) release from human activated
      neutrophils. By using this procedure, the role of protein kinase C (PKC) and
      cytosolic calcium ion (Ca2+[i) for O2- generation and MPO release was examined.
      Activation of Fc gamma R on neutrophils with IgG-coated zymosan (IgGZ) caused a
      transient rise of Ca2+[i, followed by O2- generation and MPO release. A PKC
      inhibitor suppressed completely the O2- generation and slightly the MPO release.
      Direct activation of PKC by a specific PKC activator, phorbol myristate acetate
      (PMA), induced a remarkable O2- generation and a small MPO release, indicating
      that PKC may regulate entirely O2- synthesis and partially MPO degranulation.
      Influx of extracellular Ca2+ induced by the calcium ionophore A23187 provoked MPO
      release only. Complete inhibition of this MPO release with a Ca2+/calmodulin
      (CaM)-coupling inhibitor and a CaM inhibitor provides evidence that Ca2+[i may
      regulate MPO degranulation through direct activation of CaM, but not PKC. The
      Ca2+/CaM inhibitors significantly prevented IgGZ-induced O2- generation and MPO
      release, while they did not affect PMA-induced O2- generation and MPO release.
      These results suggest that in Fc gamma R-stimulated neutrophils, Ca2+[i activates
      CaM, which in turn mediates not only activation of PKC-induced O2- synthesis and
      MPO degranulation, but also MPO degranulation without PKC intermediate.

PMID- 10659592
TI  - An in vitro chemosensitivity test for colorectal cancer using collagen-gel
      droplet embedded cultures.
AB  - This study evaluated in vitro assay for chemosensitivity test using a collagen
      gel droplet embedded culture drug sensitivity test (CD-DST) for colorectal
      cancer. CD-DST was performed in 24 patients with Dukes B, C colorectal cancer.
      Primary cultures of tumor cell samples from 87.5% (21/24) patients with
      colorectal cancer were successful. The efficacy rates assessed by CD-DST of five
      anticancer drugs evaluated were: 60.4% for adriamycin, 58.9% for etoposide, 56.7%
      for cisplatin, 53.4% for 5-fluorouracil, for 31.1% for mitomycin C, and 9.5% for
      vindesine. The present study demonstrated the clinical usefulness of CD-DST in
      evaluating the response to chemotherapy in colorectal cancer.

PMID- 10659593
TI  - Histopathological findings of the lower esophagus after total gastrectomy in rat.
AB  - It is now accepted that the incidence of esophageal carcinoma is highest in the
      middle thoracic region. Esophageal carcinoma after gastrectomy, however, has a
      tendency to develop in the lower region. This study was designed to investigate
      the role of reflux of gastroduodenal juice in the genesis of carcinoma in the
      esophagus. We found a possible correlation between the development of esophageal
      carcinoma and gastrectomy, related to alkaline reflux into the esophagus. To
      elucidate this correlation, the role of alkaline reflux of duodenal contents in
      the development of esophageal squamous cell carcinoma was investigated in Wister
      rats. Gastrectomized rats with regurgitation of duodenal contents into the
      esophagus were not administered any carcinogen and were sacrificed some at the
      end of 8 weeks and others at 50 weeks for pathological examination. Hyperplasia
      was found in rats at 8 weeks, and the esophageal squamous cell carcinoma was
      found in rats at 50 weeks. The carcinomas were found exclusively in the area of
      the reflux esophagitis and were accompanied by severe dysplasia. These results
      suggested that alkaline reflux of duodenal contents was strongly correlated to
      the development of the esophageal squamous cell carcinoma.

PMID- 10659594
TI  - Submucosal gastric cancer with lymph node metastasis--a clinicopathological
      study.
AB  - We have reviewed the clinicopathological features of submucosal gastric cancer
      with lymph node metastasis. The degree of vertical submucosal infiltration was
      classified into three stages as sm1, sm2 or sm3. The number of cases with lymph
      node metastasis of sm3 was significantly more than that of sm1 or sm2. We found
      no correlation between the tumor size and the rate of lymph node metastasis from
      submucosal invasive cancer. Accordingly, we concluded that the vertical
      submucosal infiltration was a more important factor for lymph node metastasis
      than horizontal infiltration. Minimal invasive surgery was recommended for a
      tumor measuring 1 cm or less in size with vertical submucosal invasion of sm1 or
      sm2.

PMID- 10659595
TI  - A so-called carcinosarcoma of the gallbladder in a patient with multiple
      anomalies--a case report.
AB  - The patient was a 65-year-old woman with a chief complaint of right upper
      quadrant pain. Under the diagnosis of gallbladder tumor, preduodenal portal vein
      and absence of the pancreatic tail, cholecystectomy was performed. Intraoperative
      findings resulted in a diagnosis of gallbladder tumor, absence of the pancreatic
      tail, presence of preduodenal portal vein, and malrotation of the intestine.
      Histological examination of the resected specimens showed a so-called
      carcinosarcoma. Carcinosarcoma of the gallbladder is a rare tumor of the
      hepatobiliary region. The present case differs from previously reported cases in
      its presentation with multiple anomalies including the presence of preduodenal
      portal vein. Many cases of preduodenal portal vein in an association with
      duodenal stenosis in children have been reported, but reports of cases of
      preduodenal portal vein in adult patients are rarely seen in the literature.

PMID- 10659596
TI  - A case of Turner's syndrome complicated with desmoid tumor of the transverse
      colon.
AB  - The association of Turner's syndrome and endometrial carcinoma has been
      previously established, but has never been described in conjunction with a
      desmoid tumor of the colon. A case is described of a colonic desmoid tumor
      developing in a 38-year-old female with Turner's syndrome. The association has
      not been previously reported. In this report, we describe a 38-year-old woman who
      has Turner's syndrome with a colonic desmoid and review the literature.

PMID- 10659597
TI  - Bronchial amyloidosis successfully treated with low-dose long-term erythromycin
      therapy.
AB  - A 69-year-old man was admitted for evaluation of an abnormal chest X-ray. A
      diagnosis of primary bronchial amyloidosis was made on the basis of the chest X
      ray, CT scans and bronchial biopsy specimens. The patient was treated with low
      dose long-term erythromycin therapy (600 mg/day). After four months of therapy,
      chest CT scans, bronchoscopic findings and bronchial biopsy specimens revealed
      significant improvement of inflammatory changes. Low-dose erythromycin therapy
      may be helpful in terms of its anti-inflammatory effects for patients with
      bronchial amyloidosis.

PMID- 10659598
TI  - A case of intraabdominal bleeding following pancreatoduodenectomy successfully
      treated by transcatheter arterial embolization.
AB  - A 58-year-old male underwent pancreatoduodenectomy based on a diagnosis of middle
      bile duct cancer. Because abdominal drainage revealed bile leakage 5 days
      postoperatively, leakage at the site of cholangiojejunostomy was diagnosed, and
      continuous aspiration was performed. Seventeen days postoperatively, pus was
      discharged through the abdominal drain. Because bleeding was detected by
      abdominal drainage, and shock ensued 20 days postoperatively, emergency abdominal
      angiography was carried out to identify the bleeding site. A false aneurysm in
      the proper hepatic artery and extravasation from the gastroduodenal artery stump
      were recognized, and therefore, the proper hepatic artery and common hepatic
      artery were embolized at a site distal to the false aneurysm using microcoils.
      Celiac arteriography after transcatheter arterial embolization (TAE) did not show
      extravasation, and revealed blood flow from the right inferior phrenic artery to
      the liver. Liver function was normal after TAE, and the patient recovered and was
      discharged from the hospital 54 days postoperatively. This paper presents a
      patient in whom intraabdominal bleeding due to leakage at the site of
      cholangiojejunostomy complicated by infection was successfully treated by
      hemostasis with TAE.

PMID- 10659599
TI  - A case of lymphoepithelial cyst of the pancreas.
AB  - We report a relatively rare case of lymphoepithelial cyst of the pancreas. The
      patient, a 43-year-old man with no subjective symptoms, was found to have a
      pancreatic tumor during a physical examination. Based on the ultrasonographic and
      abdominal computed tomographic findings, a pancreatic cystic tumor was diagnosed.
      Endoscopic retrograde pancreatography showed a normal duct system. Enucleation
      was easily performed. Macroscopically, the cyst resembled an atheroma.
      Histopathologic examination disclosed lymphoepithelial cyst of the pancreas.

PMID- 10659600
TI  - [Treatment of multiple sclerosis].
AB  - In recent years there have been important advances in the treatment of multiple
      sclerosis (MS), on the demonstration that specific therapies may modify the long
      term evolution of this disease. There is however still no treatment which
      definitively stops its evolution and thus there are numerous ongoing studies
      searching for new therapeutic options. For the acute phase of this disease there
      is generalized consensus on the use of corticoids. Nonetheless it is not
      unanimous as to the type, dose or therapeutic schedule of these drugs although
      the most commonly used drug at present is intravenous methylprednisolone. To
      prevent the evolution of remittent MS beta interferon is considered as the
      treatment of choice. However there are questions as to which cases would benefit
      most and when it should be used in addition to the type of beta interferon, the
      dose and the route of administration, etc. A possible alternative may be the use
      of copolimere-1 or azathioprine. The use of interferon beta 1-b has recently been
      shown to be useful in the secondarily progressive forms of MS. Up to the present
      the therapies used for primarily progressive MS have been deceiving since no drug
      has shown clear benefits despite their side effects. In cases of rapid evolution
      mitozantrone, methotrexate or cyclophosphamide may be considered (with periodic
      maintenance schedules). Current studies are aimed at: a) combining different
      treatments which have shown partial effects when used separately, b) searching
      for immunomodulators which are more specific than indiscriminated
      immunosuppression, or c) finding therapies promoting remyelinization. The
      symptomatic, pharmacologic or rehabilitation treatment continue to be fundamental
      in the quality of life of patients with MS.

PMID- 10659601
TI  - [New treatments in epilepsy].
AB  - In recent years the treatment of epilepsies has significantly evolved. The
      launching of six new antiepileptic drugs--vigabatrin, lamotrigine, felbamate,
      gabapentin, topiramate and tiagabin--has considerably increased the available
      therapeutic options. On the other hand, the use of no pharmacologic treatments
      such as surgery of epilepsy, the implantation of the vagal stimulator or
      cetogenic diets has increased. In the next decade new antiepileptic drugs will
      probably be available with different mechanisms of actions which will improve the
      treatment of epilepsy.

PMID- 10659602
TI  - [New treatments in brain tumors].
AB  - The current situation of the treatment of cerebral tumors in Spain may be
      summarized in two events: a) most neurologists do not participate in the
      management of cerebral tumors, and b) the treatment of cerebral tumors, as a
      multidisciplinary activity requiring the coordinated work of different
      specialists and which integrates all the needs of the patient, remains far from
      being carried out in our hospitals. Only the creation of competitive highly
      qualified, multidisciplinary groups including a reasonable number of hospitals
      will allow reaching the new challenges in the treatment of cerebral tumors
      present to be rapidly and successfully undertaken in a medium term. These
      challenges may be summarized as follows: a) the design of less neurotoxic and
      more effective protocols for chemosensitive tumors (lymphomas, meduloblastomas,
      germinomas and anaplastic oligodendrogliomas), b) the development of better
      response evaluation techniques, and c) the identification of subgroups of more
      homogeneous tumors within the malignant gliomas defined by molecular alterations
      which confers them a prognosis similar to the treated studied.

PMID- 10659603
TI  - [New prospects in the treatment of migraine].
AB  - The options for migraine treatment have increased in the recent years and will
      expand in the near future. In this work both recent and future options for
      migraine treatment are critically reviewed. Firstly the late advances in the
      symptomatic treatment of migraine, including the new 5-HT1B/D agonists "triptans"
      appeared after sumatriptan, are reviewed. Possible alternative, such as selective
      5-HT1D and 5-HT1F agonists, are also discussed. In the second part of this
      manuscript the new, possible options for the preventive treatment of migraine
      comprising "antiepileptics", such as valproic acid, gabapentin and topiramate,
      calcium-antagonists, such as cyclandelate and dotarizin, and a miscellany,
      including riboflavin, are analysed. Finally, possible compounds for the future,
      such as the selective inhibitors of neurokinin receptors or drugs acting upon
      neuronal calcium channels, are commented. From this review we conclude that while
      there have been relevant advances in the symptomatic treatment of migraine, there
      is a need for the development of better preventive compounds.

PMID- 10659604
TI  - [Therapeutic advances in neuromuscular diseases].
AB  - The etiology of neuromuscular diseases varies widely as does their treatment.
      This study reports the treatment of patients with neuromuscular disease of
      autoimmune origin in addition to the therapy of muscular dystrophies. The
      mechanisms of action of the immunosuppressive drugs (glucocorticoids,
      azathiaprin, cyclosporin, methotrexate, chlorambucil, cyclophosphamide) and
      immunomodulators (plasmapheresis, Ig ev) currently used are analyzed, as are
      their indications, management and the methods which allow the control of
      therapeutic efficacy. The immunotherapies presently in experimental phases are
      also reviewed (oral tolerance, inhibition of cytokines, chemokines, etc.). Both
      molecular therapy (myoblast transplantation, genetic therapy, gentamycin) and
      anabolizing drugs administered after the favorable results of clinical trials
      (glucocorticoids, oxandrolone) and undergoing controlled clinical studies
      (albuterol, creation, etc.) on the treatment of muscular dystrophies are
      evaluated. Lastly, symptomatic treatments which improve the quality of life of
      patients with muscular dystrophy are analyzed.

PMID- 10659605
TI  - [New treatments in movement disorders].
AB  - In recent years there have been considerable advances in the field of movement
      disorders which have decisively transformed not only the comprehension of the
      genetics and the pathophysiology of different diseases but have also improved the
      quality of life of these patients. Examples of these already available advances
      include the introduction of new treatments for previously untreatable diseases,
      such as botulinum toxin for dystonia, new therapeutic options or new forms of
      administration of levodopa for Parkinson disease, such as delayed levodopa,
      catecol-O-methyl transferase inhibitors and monotherapy with the classical and
      new dopaminergic agonists or new surgical techniques for previously
      unapproachable complications, such as dyskinesias in advanced Parkinson's
      disease. This study reviews the current treatment of Parkinson's disease,
      essential tremor, dystonia and different forms of choreas and indicates some of
      the experimental therapies which open renewed perspectives for neurodegenerative
      diseases, mainly Huntington's chorea and Parkinson's disease, such as the drugs
      with possible neuroprotective action, glutamatergic transmission reducers,
      neurotrophic factors and neuronal implants.

PMID- 10659606
TI  - [New treatments in dementia].
AB  - The advances in the treatment of Alzheimer's disease, mainly related to
      anticholinesterase drugs (tacrine, donepezil, metriphonate and rivastigmine) and
      the methodology of their application in clinical studies and in everyday
      neurologic practice are reviewed. Recent discoveries with the immunization with
      Abeta-42 of transgenic rats expressing a mutation related to Alzheimer's disease
      may lead to new possibilities of etiopathogenic treatments.

PMID- 10659607
TI  - [New treatments in cerebrovascular diseases].
AB  - Acute stroke is a neurologic emergency which should be preferentially treated in
      a Stroke Unit. The applications of general therapeutic measures in these units
      decreases the mortality or dependence in 29% of the cases. Thrombolytic treatment
      with rt-PA in the first 3 hours of cerebral ischemia reduces the risk of
      mortality or dependence at 3 months by 51%. This treatment should be used in
      centers with an adequate organization and experience in the management of stroke.
      Careful patient selection allows a favorable conscious risk/benefit when rt-PA is
      used in clinical practice. In the last decade numerous neuroprotector drugs have
      been developed which, despite decreasing the volume of the infarction in animal
      models, have not currently achieved a reduction in the mortality and morbidity of
      cerebral infarction in clinical trials. Ebselen, citicoline, piracetam and
      clomethiazol have shown beneficial effects in preliminary studies or in some
      subgroups of patients, but their use based on evidence is not recommendable.
      Anticoagulants and antiplatelet drugs have not been shown to be effective in the
      acute phase of cerebral infarction. The neuroprotector effect of unfractionated
      heparin and glycoprotein IIb IIIa antagonists is still under study. Clopidogrel
      and the association of aspirin and dipiridamol are new alternatives to aspirin in
      the secondary prevention of cerebral infarction. Both options provide a lower
      risk of recurrence, and clopidogrel also shows better tolerance. The preventive
      effect of low intensity anticoagulation and statins is being analyzed in clinical
      studies.

PMID- 10659608
TI  - [Acetaldehyde adducts in the cerebral cortex of long-term ethanol-fed mice].
AB  - It is assumed that the acetaldehyde binds to the proteins after the consumption
      of ethanol to form an adduct. Such acetaldehyde adducts are related to organ
      diseases. We examined 8-week-old female BALB/cAJcl mice which had been on a
      liquid diet for six months. The alcohol-fed mice's liquid diet comprised
      vitamins, minerals, amino acid and a ethanol solution. The five groups of mice
      examined were 1.5% ethanol-fed, 2% ethanol-fed, 2.5% ethanol-fed, 3% ethanol-fed,
      and 3.5% ethanol-fed mice respectively. All mice fed by 2.5% or more ethanol died
      within a month. Tissue samples were taken from the 1.5% and 2% ethanol-fed mice
      to investigate the distribution of acetaldehyde adducts in various organs. We
      demonstrated the immunohistochemical staining of the cerebral cortex and liver
      from the ethanol-fed mice with antibodies against acetaldehyde adducts. In the 2%
      ethanol-fed mice, the protein epitope related to acetaldehyde was found in the
      cerebral cortex and the liver. There was a significant difference in the amount
      of cell degeneration between the 1.5% and 2% ethanol-fed mice. The results
      suggest that the neurotoxicity of ethanol starts to cause serious cell
      degeneration in concentrations of more than 1.5%. The neurotoxicity of ethanol in
      the cerebral cortex was found to be more prominent than in the liver, resulting
      in more cell degeneration.

PMID- 10659609
TI  - [Mental and physical symptoms in alcoholics after alcohol withdrawal--comparing
      with involutional melancholia patients].
AB  - As a factor of recurrence of drinking in patients with alcoholic dependence,
      emotional disorders accompanied by alcohol dependence has been noted in many
      reports. Particularly, it is noted to be very likely that depression after
      abstinence is an incentive to re-start drinking. In this study, we investigated
      depressive feeling in aspects of psychiatric and physical subjective symptoms
      after abstinence in patients with alcohol dependence, and compared the symptoms
      with those in patients with involutional depression. On analysis of the major
      component of psychiatric subjective symptoms, a sense of alienation, emotional
      instability, anxiety, and aggressiveness were observed. In involutional
      depression, depressive feeling, somnipathy, anxiety, self accusation/sense of
      guilt, delusion of culpability were observed. On analysis of the major component
      of physical subjective symptoms, autonomic nervous symptoms accompanied by
      feebleness, hysterical neurosis-like autonomic nervous symptoms, reduced sexual
      libido, anorexia, hydrodipsia/sweating were observed. Similarly, in patients with
      involutional depression, hysterical neurosis-like autonomic nervous symptoms,
      anorexia, elevation of tonus, general malaise, and hydrodipsia were noted.
      Differences in status were emphasized in comparison between the two groups in
      both analyses. Unlike involutional depression that exhibits the current features
      of depression, patients with alcohol dependence showed a sense of alienation,
      emotional instability, anxiety, and aggressiveness, reflecting self-uncertainty
      and loss of self-respect. Drinking may be re-started to relieve or reduce tension
      and frustration in such conditions.

PMID- 10659610
TI  - M. leprae infection of vascular and lymphatic endothelial cells of the epineurium
      and perineurium in experimental lepromatous neuritis.
AB  - Infection of peripheral nerve by M. leprae, the histopathologic hallmark of
      leprosy, is a major factor in this disease, but the route and mechanisms by which
      bacilli localize to peripheral nerve are unknown. Experimentally infected
      armadillos have recently been recognized as a model of lepromatous neuritis; the
      major site of early accumulation of M. leprae is epineurial. To determine the
      epineurial cells involved, 1 cm. segments of 44 nerves from armadillos were
      screened for acid-fast bacilli (AFB), and thin sections were examined
      ultrastructurally. Of 596 blocks containing nerve, 36% contained AFB. Overall, M.
      leprae were found in endothelial cells in 40% of epineurial blood vessels and 75%
      of lymphatics, and in 25% of endoneurial vessels. Comparison of epineurial and
      endoneurial findings suggested that colonization of epineurial vessels preceded
      endoneurial infection. Such colonization of epineurial nutrient vessels may
      greatly increase the risk of endoneurial M. leprae bacteremia, and also enhance
      the risk of ischemia following even mild increases in inflammation or mechanical
      stress. These findings also raise the possibility that early, specific mechanisms
      in the localization of M. leprae to peripheral nerve may involve adhesion events
      between M. leprae (or M. leprae-parasitized macrophages) and the endothelial
      cells of the vasa nervorum.

PMID- 10659611
TI  - [For the growth of Mycobacterium lepraemurium in cell-free liquid medium, the key
      essential factor may be the pH (optimal 6.0-6.2) of the culture medium, rather
      than the presence of alpha-ketoglutaric acid].
AB  - Since the success of the multiplication of Mycobacterium lepraemurium in cell
      free liquid medium by the author in 1972, various factors affecting its growth
      have been reported. In particular, it was emphasized that the key essential
      factor for the growth was alpha-ketoglutaric acid(alpha-kg). However, recent data
      now indicate that the critical factor for the growth of M. lepraemurium is not
      alpha-kg, but the optimal pH of the liquid culture medium, quite similar to the
      condition of egg-yolk solid medium. The recent experimental results clearly
      indicated that an abundant multiplication of M. lepraemurium took place in an
      acid liquid medium containing egg-yolk extract, without alpha-kg. This finding
      means that the cells of M. lepraemurium can multiply in a liquid medium, if the
      pH of the medium is adjusted to 6.0-6.2. The reason why the cells of M.
      lepraemurium multiplied in NC medium, and NC-5 medium, containing alpha-kg was
      that the pH of neutral liquid base medium of the NC or NC-5 medium, was adjusted
      to 6.0-6.2, optimal for the growth of M. lepraemurium by addition of the 10%
      alpha-kg (where 10% alpha-kg is strongly acidic; pH:1.22). Other supplements,
      such as cytochrome c, l-cysteine, and hemin, which are routinely added to the
      base medium of NC and NC-5 medium, have shown stimulatory effects on
      multiplication of M. lepraemurium, rather than a key essential effect. In
      addition, recent experimental data have suggested a second key essential
      component for growth present in egg-yolk extract.

PMID- 10659612
TI  - Serodiagnosis of Hansen's disease/leprosy by enzyme-linked immunosorbent assay
      using cord factor (trehalose 6,6'-dimycolate) as an antigen.
AB  - IgG and/or IgM antibodies against mycobacterial cord factor (trehalose 6,6'
      dimycolate, TDM) in sera of 65 patients of Hansen's disease (21 cases with smear
      positive and 44 cases with smear-negative) and 60 healthy individuals were tested
      by enzyme-linked immunosorbent assay (ELISA) with TDM purified from Mycobacterium
      tuberculosis H37Rv as an antigen. Of 65 patients with Hansen's disease, 58 cases
      (89.2%) had positive results (21 samples from 21 patients, 100% with acid-fast
      bacilli positive in the lesion, and 37 samples from 44 patients, 84.0% with acid
      fast bacilli negative Hansen's disease diagnosed clinically). The sensitivity and
      specificity of anti-cord factor ELISA were higher than those of anti-phenolic
      glycolipid-I (PGL-I) agglutination test. Among the total, 34 patients were
      classified clinically into three types of the disease, lepromatous leprosy (LL),
      borderline lepromatous (BL) and borderline tuberculoid (BT). The antibody titer
      showed LL > BL > BT, indicating that the elevation of anti-cord factor antibody
      titers appeared to be parallel with the degree of humoral immune response against
      M. leprae. By using semisynthetic cord factor consisting of a single subclass of
      mycolic acid from M. tuberculosis, it was revealed that sera from patients with
      Hansen's disease were highly reactive against alpha-mycoloyl cord factor (alpha
      TDM) and less reactive against methoxy mycoloyl TDM (methoxy TDM), differed from
      sera of tuberculosis patients, which were highly reactive against both methoxy
      and alpha-mycoloyl cord factor (alpha-TDM). Most of sera from patients with
      Hansen's disease were more reactive against TMM than TDM, differed from sera of
      tuberculosis patients which were highly reactive against TDM. ELISA using TDM as
      an antigen is simple, reproducible and useful for the rapid serodiagnosis of
      Hansen's disease, especially for smear-negative cases.

PMID- 10659613
TI  - [Present status of Buruli ulcer in Ghana, West Africa].
AB  - Recently, Buruli ulcer is emerging from the West and Central African countries.
      The disease come up with necrotizing and immno-suppressive type ulcer in the
      skin, subcutaneous tissue and bone, infected by Mycobacterium ulcerans, and shows
      indolent chronic course as mycobacterial infection, like tuberculosis and
      Hansen's disease. After the transmission to human, the lesion is usually single
      and begin as firm, painless, subcutaneous nodule and on any area of human body
      skin, though most frequently on lower limbs. In countries of West Africa, it is
      suspected that the disease should be spreading most widely in Ghana. During April
      and June 1999, Ghana Health Service pick up the new patients by nation-wide
      examination. The author visited Ghana twice at March and September 1999 and made
      on-the-spot inspections not only at a community and Ga district Health Service
      Center in Accra region but also at St. Martin's hospital in Agroyesum, Amanse
      west district, Ashanti region. At the time, the author did see the present state
      of Buruli ulcer, i.e. health and medical enlightenment. This report, includes the
      results due to undergoing nation-wide examination on Buruli ulcer at 2 District
      in Ghana (List 1 and 2), the present states of the patients and the enlightenment
      provided by the staffs of Ga district Health Service Center (Photografs 1-14).
      Staffs working for WHO and Ghana Health Service are tackling to Buruli ulcer
      problems, but conditions of the patients are very hard because these patients
      must live in tropical wetlands, poor health, poor medical and poor economic
      conditions.

PMID- 10659614
TI  - Shedding of soluble receptor for tumor necrosis factor alpha induced by M. leprae
      or LPS from human mononuclear cells.
AB  - Cell surface expression and release of the tumor necrosis factor receptor (TNFR
      type I) was analyzed after stimulation of peripheral blood mononuclear cells
      (PBMC) with Mycobacterium leprae (M. leprae) or lipopolysaccharide (LPS). A
      transient spontaneous expression of TNFR type I on the surface of PBMC was
      observed. Two hr after activation with LPS, a significant reduction of TNFR type
      I expression was detected: Release of TNFR type I by M. leprae or LPS-stimulated
      PBMC was evaluated with an enzyme-linked immunoabsorbent assay. This release
      occurred relatively later (20 to 40 hr) than the secretion of TNF alpha which
      reached high levels between 8 to 20 hr after activation. Thalidomide, a potent
      drug for the treatment of erythema nodosum leprosum episodes by inhibiting TNF
      alpha production, had no influence on the TNFR type I expression. Similar results
      were obtained with pentoxifylline. It is concluded that the release of TNFR type
      I by M. leprae or LPS-stimulated PBMC may counteract the pro-inflammatory
      activities of TNF alpha, by reducing the systemic toxicity of this cytokine in
      leprosy.

PMID- 10659615
TI  - A recurrent case of BT leprosy with widely spread skin lesions showing a
      histopathology of indeterminate group after 4.5-years irregular treatment,
      Bangladesh.
AB  - A 29 year-old Bengali male case is presented in this paper which was a borderline
      tuberculoid leprosy (BT) at detection. His father contracted a lepromatous
      leprosy of G = 2 deformity. He took anti-leprosy drugs including MDT/MB regimen
      irregularly and had maculae widely-spread with anesthesia 16 months after being
      released from treatment (RFT). The histopathology of the maculae unexpectedly
      showed that of an indeterminate group of leprosy. The recurrent skin lesions were
      susceptive to a four-week regimen of Rifampicin and Ofloxacin. This case can not
      be defined as a relapsed case, because slit skin smears were always negative. It
      would be called a recurrent case after MDT/MB regimen. Though the reason
      recurrent skin lesions occur is unknown, it is reasonable to assume that the
      recurrent lesions are caused by dormant persisters which are originally drug
      sensitive. The recurrent skin lesions can not be classified because the clinical
      features can not be matched to their histology. Such recurrent cases might occur
      among the defaulters of MDT in future.

PMID- 10659616
TI  - A case of reconstruction of saddle nose deformity in leprosy.
AB  - A case of reconstructive surgery for saddle nose deformity is presented in this
      paper. A 22 year-old Bengali female who had completed WHO/MB regimen for 27
      months underwent reconstructive surgery for saddle nose deformity. Since a saddle
      nose is one of the symbols of leprosy, it often causes serious psychological and
      social troubles to patients. This happens more often when the patient is a young
      unmarried woman. In this case the saddle nose seemed to be very serious. After
      being discharged from hospital she got married and had a baby. This operation
      gave the patient great relief to live in the community, because she no longer had
      serious visible evidence of leprosy on the body. Though the correction of the
      deformity without any dysfunction does not always have priority over other
      surgeries at a busy leprosy control project in Bangladesh, it has merit both in
      patients themselves and in the society around them because it leads to the
      elimination of the stigma of leprosy.

PMID- 10659617
TI  - [Projects for improving the health services and the leprosy control in Myanmar].

PMID- 10659618
TI  - [Blood-flow measurements in glaucoma].

PMID- 10659619
TI  - [Combined effect of topical latanoprost and timolol on retinal blood flow and
      tissue circulation in the optic nerve head in cynomolgus monkeys].
AB  - PURPOSE: To evaluate the combined effect of topical latanoprost and timolol on
      the retinal blood flow and the tissue circulation of the optic nerve head (ONH)
      in cynomolgus monkeys. MATERIALS AND METHODS: 30 microliters of latanoprost
      (0.005%) was instilled once daily and timolol (0.5%) twice daily into one eye,
      and physiological saline as a control into the other eye of 8 cynomolgus monkeys
      for 6 days. Blood velocity through the retinal veins was measured using a KOWA
      Laser Speckle Blood Flow Meter. The ONH tissue blood velocity normalized blur
      (NBONH) was measured using a Laser Speckle Tissue Circulation analyzer. Retinal
      blood flow, NBONH, intraocular pressure (IOP), blood pressure, and pulse rate
      were measured before the first instillation, 4 hours after the first instillation
      on the 2nd experimental day, and 4 hours after the last instillation. RESULTS:
      After the first instillation on the 2nd experimental day, the retinal blood flow
      was decreased to below the baseline, but 6-day instillation caused no significant
      change from the baseline. Six-day instillation increased the NBONH in the treated
      eyes by 10% from the baseline and by 7% from that in the fellow control eye.
      After 6-day instillation, the IOP was lowered by 7.8 +/- 2.7 (mean +/- standard
      deviation) mmHg and 3.6 +/- 4.3 mmHg in the treated and control eyes,
      respectively. CONCLUSION: The results suggest that 6-day instillation of
      latanoprost once daily and timolol twice daily has no significant effect on the
      retinal blood flow, and significantly increases the ONH tissue blood velocity in
      monkey eyes.

PMID- 10659620
TI  - [Neuroprotective effect of N-methyl-D-aspartate receptor antagonists in an
      experimental glaucoma model in the rat].
AB  - PURPOSE: To evaluate the neuroprotective effect of memantine and dizocilpine,
      which are noncompetitive open-channel blockers of the N-methyl-D-aspartate (NMDA)
      receptor, on glaucomatous optic neuropathy in an experimental glaucoma model in
      the rat. METHODS: Experimental glaucoma was induced in the right eyes of 30
      Wistar albino rats by intracameral injection of India ink followed by laser
      trabecular photocoagulation 4 days later. The left eye served as a control.
      Either memantine, dizocilpine, or phosphate-buffered saline (PBS) was injected
      intraperitoneally just before trabecular photocoagulation. Five days later, 3%
      fast blue was injected into both superior colliculi. The eyes were enucleated
      another 3 days later and flat mounts of the retinas were prepared. Labeled
      ganglion cells were counted in the area 1 mm away from the optic disc. RESULTS:
      Five days after laser application, no significant intraocular pressure (IOP)
      change in the right eye was found among the 3 groups. In eyes treated with
      memantine or dizocilpine, significantly more ganglion cells were labeled.
      CONCLUSION: Systemically applied memantine and dizocilpine had a neuroprotective
      effect against experimental glaucomatous optic neuropathy in the rat.

PMID- 10659621
TI  - [Changes in isolated ciliary muscle caused by repeated instillation of carbachol
      ointment in rabbits and effect of topically applied amlexanox].
AB  - PURPOSE: We investigated changes in ciliary muscle caused by continual
      contraction in rabbits and evaluated the efficacy of topically applied amlexanox,
      which relaxes the ciliary muscle, on such changes. SUBJECTS AND METHODS: After
      topical application of carbachol ointment 5 times daily for 2 weeks, the
      contractile responses of isolated ciliary muscles to carbachol were measured
      isometrically, and the ciliary smooth muscle fibers were stained with
      phosphotungstic acid and hematoxylin and observed histologically. 1% amlexanox
      solution was instilled 5 minutes before every instillation of carbachol ointment.
      RESULTS: Repeated topical carbachol ointment caused decreases in both contractile
      responses of isolated ciliary muscles to carbachol and number of ciliary smooth
      muscle fibers stained by phosphotungstic acid and hematoxylin. Amlexanox
      inhibited these changes. CONCLUSION: We found that continual contraction of the
      ciliary muscle caused functional and histological changes in it. These changes
      are thought to occur in some diseases which cause excessive contraction of the
      ciliary muscle. Topical amlexanox might be useful for these diseases.

PMID- 10659622
TI  - [Comparison of scleral buckling and vitrectomy for superior retinal detachment
      caused by flap tears].
AB  - PURPOSE: We compared the surgical results of vitrectomy and scleral buckling for
      uncomplicated superior retinal detachment caused by flap tears. SUBJECTS AND
      METHODS: Included in the study were 225 phakic eyes of 225 patients undergoing
      primary surgery from January 1990 to December of 1996 for superior retinal
      detachment caused by flap tears; all eyes had been followed for longer than six
      months after surgery. The choice of procedures was based on each surgeon's
      preference. The cases were evaluated retrospectively and the surgical outcome and
      the rate of complications compared between the two groups of eyes. RESULTS:
      Initial and final anatomical success rate were 92% and 100% after each procedure.
      Redetachment after the first procedure was due to new retinal breaks in 5 eyes,
      reopening of original breaks in 2 eyes of vitrectomy cases, and malpositioned
      buckle in 11 eyes of scleral buckling cases. Proliferative vitreoretinopathy
      occurred in 3 eyes of vitrectomy cases. CONCLUSION: Primary vitrectomy was as
      successful as scleral buckling for superior rhegmatogenous retinal detachment.
      Although a high incidence of postoperative cataract formation was a major
      drawback, vitrectomy had some advantages over to scleral buckling.

PMID- 10659623
TI  - [Effect of stellate ganglion block on human retinal blood flow].
AB  - PURPOSE: The effect of stellate ganglion block (SGB) on human retinal blood flow
      was evaluated. METHODS: We measured the diameter of the retinal artery and vein,
      and retinal venous flow rate by laser speckle retinal blood flow meter
      simultaneously in 11 eyes of 11 normal volunteers. RESULTS: The reliable data
      from 9 eyes of 9 person were used for analysis. SGB did not change the blood
      pressure, heart rate, retinal arterial diameter, or venous diameter. However SGB
      increased retinal blood velocity significantly from 9.9 +/- 1.6 (mean +/-
      standard deviation) mm/s to 11.1 +/- 1.5 mm/s (p < 0.01). Intraocular pressure
      decreased from 12.3 +/- 2.1 (mean +/- standard deviation)mmHg to 9.4 +/- 2.2 mmHg
      after SGB (p < 0.01). There was no relationship between the change of ocular
      perfusion pressure and that of retinal venous blood velocity. CONCLUSION: SGB
      increased the retinal venous blood velocity without changing the retinal vessel
      diameter.

PMID- 10659624
TI  - [Evaluation of extraocular muscle enlargement in dysthyroid ophthalmopathy].
AB  - PURPOSE: To evaluate the extraocular muscle enlargement in dysthyroid
      opthalmopathy. METHOD: Extraocular muscle enlargement was assessed by orbital
      computed tomography (CT) in 573 patients with dysthyroid ophthalmopathy in order
      to investigate the frequency and exact location of extraocular muscle enlargement
      and the clinical features of related ocular symptoms in patients with dysthyroid
      ophthalmopathy. RESULTS AND CONCLUSION: 187 patients (38% of the total) showed
      evidence of extraocular muscle enlargement on CT images, and this disorder were
      more frequent in male patients than in female patients. Extraocular muscle
      enlargement was also more frequently seen in older patients than in younger
      patients. Enlargement of a single muscle was found in 55% of the 187 patients,
      with the most frequently affected muscle being the inferior rectus muscle. When
      multiple muscles were enlarged, the inferior rectus muscle was the most
      frequently affected, followed by the medial rectus muscle. Of the clinical
      findings specific to dysthyroid ophthalmopathy examined in the present study, the
      incidence of exophthaomos, upper lid swelling, superior limbic
      keratoconjunctivitis, keratitis, diplopia, and dysthyroid optic neuropathy were
      significantly increased in patients with dysthyroid ophthalmopathy, indicating a
      close relationship between these findings and the underlying disease, but the
      incidence of upper lid retraction was not significantly increased.

PMID- 10659625
TI  - [Long-term effect of topically applied isopropyl unoprostone on microcirculation
      in the choroid-retina].
AB  - PURPOSE: To study the long-term effect of topically applied 0.12% isopropyl
      unoprostone (unoprostone, Rescula) on microcirculation in the ocular fundus.
      MATERIALS AND METHODS: Using a laser speckle tissue circulation analyzer,
      normalized blur (NB), a quantitative index of blood flow velocity and tissue
      blood flow, was measured in the optic nerve head (ONH) and choroid-retina before
      and 4.5 hours after an instillation of placebo into both eyes in 11 normal human
      volunteers. Intraocular pressure (IOP), blood pressure, and pulse rate were also
      measured. A drop of unoprostone or the placebo was instilled into each eye in a
      double-blind manner twice a day for 21 days (the treated or untreated eye).
      RESULTS: Twenty-one days later, NB values in the ONH and the choroid-retina
      increased significantly and the IOP decreased significantly only in the treated
      eyes. Ocular perfusion pressure showed no significant changes. CONCLUSIONS: These
      results suggest that the increase of the blood flow in the microcirculation in
      the human ocular fundus following the relatively long-term topical application of
      unoprostone may be due to reduction in vascular resistance.

PMID- 10659626
TI  - [Histological study of gelatinous drop-like dystrophy following excimer laser
      phototherapeutic keratectomy].
AB  - PURPOSE: Investigation of effects of excimer laser phototherapeutic keratectomy
      (PTK) on gelatinous drop-like dystrophy. OBJECT AND METHODS: The patient was a 28
      year-old woman with gelatinous drop-like dystrophy. She had a history of
      penetrating keratoplasty and underwent PTK for recurrent lesions by spot mode
      several times. Finally her sight deteriorated and she underwent lamellar
      keratoplasty. We divided the corneal specimen into 2 halves, the non-ablated area
      and the ablated area. The corneal specimens were investigated histologically.
      RESULTS: Light microscopy showed a decrease in thickness of the epithelial layer,
      absence of Bowman's layer, and amyloid positive materials at the subepithelial
      layer in both areas. Electronmicroscopy showed irregularly arranged amyloid
      fibrils in the subepithelial layer of the non-ablated area. In the ablated area,
      two different types of amyloid fibrils were identified. In the middle and deep
      stromal layer, the collagen lamellar structure was intact and keratocytes were
      normal in both areas. CONCLUSIONS: In the subepithelial layer, two different
      types of amyloid fibrils were identified in the ablated area. These findings
      might show that the original disease was affected by excimer laser ablation. In
      the middle and deep stromal layer, collagen lamellar structure was intact and
      keratocytes were normal in both areas. These findings suggest that PTK has less
      effect on the tissue beneath the ablated area, indicating that PTK is a useful
      and safe technique to remove corneal opacities.

PMID- 10659628
TI  - [Present state and future prospect of endoscopic surgery in the treatment of
      gastrointestinal cancers].

PMID- 10659627
TI  - [Laser photocoagulation for choroidal neovascularization developed in a patient
      with optic disc drusen and angioid streaks].
AB  - BACKGROUND: Optic disc drusen accompanied by angioid streaks is rarely seen in
      Japan. Laser photocoagulation for choroidal neovascularization (CNV) in patients
      with angioid streaks is controversial. CASE: A 45-year-old woman presented with
      bilateral papilledema. Clinical examination revealed optic disc drusen and
      angioid streaks. During the follow-up period, juxtapapillary CNV developed in
      both eyes. CNV in the right eye developed progressively towards the fovea and was
      eventually treated by laser, but the CNV in the left eye regressed spontaneously.
      CONCLUSION: These are the first precise clinical records on optic disc drusen
      with angioid streaks to be reported. The outcome of laser treatment for CNV in
      this case was favorable, because alteration of Bruch's membrane was mild, in the
      form of angioid streaks.

PMID- 10659629
TI  - [Current topics of medical treatment for ulcerative colitis].

PMID- 10659630
TI  - [Studies of gastric acid secretion and gastric mucosal change after Helicobacter
      pylori eradication--the short and long-term observation].
AB  - We studied the gastric acid secretion and the histological findings of gastric
      mucosa in 48 patients with peptic ulcer before and after successful Helicobacter
      pylori (H. pylori) eradication. The pH of fasting gastric juice significantly
      decreased from 2.46 to 1.65 four weeks after eradication (p < 0.001). The factors
      such as disease, atrophic border, inflammatory cell involvement and histological
      atrophy were analyzed by logistic regression. Only the atrophic border was a
      significant and independent factor to convert the acidity after eradication, and
      the pH of gastric juice prominently decreased in the patients with widespread
      atrophic mucosal area. In the 24-hour intragastric pH monitoring, the pH3 holding
      time overnight remarkably decreased from 54.1% to 22.3% after eradication (p <
      0.005). In the long follow-up of 17 patients (the mean follow-up period was 15.2
      months), the pH of gastric juice kept a lower titer of 1.66. The mean atrophic
      scores in the upper body reduced from 1.5 to 0.9 (p < 0.05). In addition to the
      functional recovery of parietal cells after eradication, it was considered that
      the histological improvement of atrophy in oxyntic mucosa was associated with the
      recovery of pH.

PMID- 10659631
TI  - [Jejunal villous tumor presenting with entero-enteric intussusception: report of
      a case].

PMID- 10659632
TI  - [A case of primary small bowel volvulus with a jejunal diverticulum].

PMID- 10659633
TI  - [A case of (CIIP) chronic idiopathic intestinal pseudoobstruction diagnosed with
      the aid of manometric study of the intestinal tract].

PMID- 10659634
TI  - [A case of colonic muco-submucosal elongated polyp (CMSEP) with colonic
      diverticulosis].

PMID- 10659635
TI  - [A case of follicle center lymphoma of the small intestine with multiple
      lymphomatous polyposis].

PMID- 10659636
TI  - [A case of hepatocellular carcinoma developed in a patient with alcoholic liver
      cirrhosis with primary biliary cirrhosis].

PMID- 10659637
TI  - [A case of acute alcoholic fatty liver recovered immediately from severe liver
      dysfunction].

PMID- 10659638
TI  - [A resected case of gallbladder carcinoma which was left untreated for 4 years
      after being detected as a gallbladder polypoid lesion measuring over 2.0 cm in
      diameter].

PMID- 10659639
TI  - [A case of inflammatory obstruction of the common bile duct due to acute
      pancreatitis].

PMID- 10659640
TI  - [Mucin producing pancreatic tumor, arising in the accessory pancreatic duct].

PMID- 10659641
TI  - [Evidence based reevaluation of primary screening tests].
AB  - Preventive medicine consists of all efforts which delay the development of
      diseases (primary prevention), make early detection possible (secondary
      prevention) as well as rehabilitation of patients (tertiary prevention). The aim
      to reduce premature morbidity and mortality and increase life expectancy and
      quality of life. The authors summarize the secondary preventive interventions of
      asymptomatic individuals namely primary screening methods, with special regard to
      so-called "western diseases": hypertension, hyperlipidemia, colorectal cancer,
      neoplasms of breast, cervix, prostata, also considering type 2 diabetes and
      osteoporosis on the basis of the supporting evidence and the recommendation of
      certain national committees.

PMID- 10659642
TI  - [Pathologic diagnosis of mantle cell lymphoma based on histologic, cytologic,
      immunohistologic and genetic characteristics].
AB  - Mantle cell lymphoma (MCL) is a clinocopathologic entity representing a broad
      histologic and cytologic spectrum from cystic to the blastic form. The
      histologic, cytologic heterogeneity of MCLs may lead to diagnostic confusion. The
      aim of this study was to reclassify NHLs registered as centrocytic lymphoma and
      centrocytoid-centroblastoma by the Lymphoma Reference Centrum at the Department
      of Pathology, University Medical School of Pecs between 1988 and 1995. 63 of 67
      selected cases have been classified as mantle cell lymphoma according to
      histological, cytological appearance, and the pheno- and genotype of tumour
      cells. 48% of the cases showed diffuse while 52% showed nodular histological
      pattern. 27% of diffuse MCLs composed of classic MCL cells (small to medium-size
      cells) 40% blastic and 33% both small and blastic lymphoma cells. In 76% of the
      nodular MCLs the tumour consisted of small to medium-size cells 15% blastic while
      9% both small and blastic lymphoma cells. In 99% of MCL the diagnosis was
      supported by CD5, CD20 and CD23 positivity and in 67% by the presence of cyclin
      D1-overexpression. The t(11;14) chromosome translocation PCR amplification was
      positive in 3 of 17 cases investigated. The authors conclude that MCLs represent
      a heterogeneous disease based on the cytology of the tumour cells. The nodular
      architecture was associated with classic MCL cells while the diffuse form was
      more frequently associated with blastic or combined cytological appearance. The
      correct diagnosis of MCL could be reached by tumour cell immunophenotyping, while
      molecular genetic methods proved to be informative only in part of the cases
      studied.

PMID- 10659643
TI  - [Minimal invasive lumbar sympathectomy].
AB  - Forty-four lumbar sympathectomies have been made on 42 patients by ROMICRO-set at
      the authors' department. This method--made by a specially developed lighting
      retractor system--ensures the same exposure as the traditional approach, but the
      visibility of the operative field is much better. The costs of the material
      character are low. Technique of the operation is discussed. Authors have got good
      experiences: there were no complications, postoperative pain is minimal, the time
      of the hospitalization is shortened. A special advantage of this new approach is
      that it can be even made on patients-belonging to ASA IV., and they can be
      operated on in epidural anesthesia. The authors recommend this new method only
      for those surgeons who are experienced in the technique of traditional lumbar
      sympathectomies.

PMID- 10659645
TI  - [The death of Endre Ady 80 years ago, its location, the Liget Sanatorium].

PMID- 10659644
TI  - [Catastrophic antiphospholipid antibody syndrome in a cancer patient].
AB  - Antiphospholipid syndrome is characterized by the presence of antiphospholipid
      antibodies resulting in arterial and venous thromboembolism. Apart from primary
      cases, this syndrome is often associated with autoimmune diseases. Around 50
      cases of catastrophic antiphospholipid antibody syndrome have been reported as
      yet. Authors describe a case of a female patients with catastrophic
      antiphospholipid syndrome associated with gastric cancer. This may be the first
      case of such association in the literature. Authors also discuss the possible
      pathomechanism of this disorder, as well as the available therapeutic approaches.

PMID- 10659646
TI  - [Timely anniversary of an international medical congress].

PMID- 10659647
TI  - [What is the effect of the patient's condition after a stroke on his capacity of
      composing a last will?].

PMID- 10659648
TI  - [Newcastle disease virus vaccine (MTH-68/H) in a high-grade glioblastoma
      patients].

PMID- 10659649
TI  - [The predictive factors of intra-stent restenosis].
AB  - INTRODUCTION AND OBJECTIVE: Stenting has contributed to improve the early
      angiographic result, the restenosis rate and the problem of acute and subacute
      coronary occlusion. In spite of this, the restenosis phenomenon still remains a
      problem to be completely solved. The aim of the study was to identify clinical,
      angiographical and procedural factors that are predictive of in-stent restenosis
      after successful implantation of coronary stent. MATERIAL AND METHODS: We
      retrospectively analyzed 202 lesions, in 176 consecutive patients who underwent
      stent implantation with success in our hospital between January 1995 and August
      1998. All patients had a clinical follow-up and an angiography after six months
      of stent implantation. RESULTS: From 202 lesions evaluated, 47 evolved with
      restenosis (23%). The only independent predictive variables were: to be receiving
      hypolipemiant treatment before stenting (OR: 0.3; IC: 0.1-0.8), the use of high
      pressure for stent implantation (OR: 0.4; IC: 0.2-0.9), to implant stent in < 3.1
      mm (OR: 2.2; IC: 1.1-4.5) and to have a residual stenosis > 30% after stenting
      (OR: 13; IC: 1.5-120). CONCLUSIONS: The only statistical variables associated
      with in-stent restenosis phenomenon were: be under hypolipemiant treatment before
      the procedure and the use of high pressures for stent implantation; while risk
      factors arose: to implant stent in vessels < 3.1 mm and suboptimal angiography
      result after stenting.

PMID- 10659650
TI  - [The prevalence of angina and cardiovascular risk factors in the different
      autonomous communities of Spain: the PANES Study. Prevalencia de Angina en
      Espana].
AB  - INTRODUCTION AND OBJECTIVE: The study of angina prevalence has received little
      attention in the analysis of the dimension of coronary heart disease. The aim of
      this study was to determine the prevalence of angina and cardiovascular risk
      factors in the 45- to 74-year-old population of the different autonomous regions
      of Spain. METHODS: A sample of 10,248 subjects was recruited. Sampling was
      stratified by gender and age groups (45-54, 55-64 and 65 to 74 years), and
      proportional to the population distribution of the different autonomous regions.
      A multistage sampling was performed, firstly 200 villages were randomly selected,
      secondly three different socio-economic household were chosen. Sample unit was
      neighbouring households. Rose questionnaire of angina and a structured
      questionnaire to collect socio-demographic and risk factor variables were
      administered. RESULTS: Angina prevalence in the 45- to 74-year-old Spanish
      population was 7.5%. The autonomous regions with the higher and lower prevalence
      were Baleares (11.4%) and Basque Country (3.1%), respectively. The Pearson
      correlation coefficient between angina prevalence and ischemic heart disease or
      cardiovascular disease mortality in men and women was 0.52 and 0.55, and 0.31 and
      0.44, respectively. The self reported prevalence of hypertension, dyslipemia,
      diabetes and smoking was 31.1%, 24.2%, 14.3% and 34.6% respectively. CONCLUSIONS:
      Angina prevalence in Spain is similar to that of developed countries although
      significant differences were observed among the autonomous regions of Spain.
      These differences correlate with those observed in ischemic heart disease or
      cardiovascular mortality among them and are associated with the cardiovascular
      risk factors prevalence which also varies among communities.

PMID- 10659651
TI  - [The prevalence of angina and coronary risk factors].

PMID- 10659652
TI  - [The influence of sex on the performance of dobutamine echocardiography for the
      diagnosis of ischemic cardiopathy].
AB  - OBJECTIVE: To compare the usefulness of dobutamine-atropine stress
      echocardiography in the diagnosis of coronary artery disease among men and women.
      METHODS: We have consecutively studied 137 men and 99 women without a previous
      history of coronary artery disease who underwent dobutamine-atropine stress
      echocardiography and coronary angiography afterwards. RESULTS: Significant
      coronary artery disease was detected in 102 men and 42 women (74% and 42%
      respectively; p < 0.001). 64% of the women had single-vessel versus 45% of the
      men (p < 0.05). Dobutamine-atropine stress echocardiography was positive in 78
      men and 35 women. Sensitivity, specificity and diagnostic accuracy of the test
      were 72%, 88% and 76% for men and 69%, 89% and 83% for women (p = NS). Positive
      predictive value was higher in men (95% in men versus 83% in women; p < 0.05) and
      negative predictive value was significantly greater in women than in men (79%
      versus 52%; p < 0.01). CONCLUSION: Sensitivity, specificity and diagnostic
      accuracy of dobutamine-atropine stress echocardiography is not affected by
      gender. Positive predictive value is higher in men and negative in women owing to
      the differences in both sexes of the prevalence of coronary artery disease.

PMID- 10659653
TI  - [Arrhythmia recurrence in patients with an old myocardial infarct treated by
      implantable defibrillator: an analysis according to the initial clinical
      presentation].
AB  - INTRODUCTION AND OBJECTIVES: The importance of the clinical presentation in the
      frequency and type of recurrences of ventricular arrhythmias in patients that
      received an automatic implantable defibrillator is not well known. The purpose of
      this study was to analyze the frequency and type of recurrences in patients with
      an old myocardial infarction that received an automatic implantable defibrillator
      with electrogram recording. METHODS AND RESULTS: We analyzed 100 patients
      classified in 3 groups according to their clinical presentation: Sustained
      Monomorphic Ventricular Tachycardia (VT Group n = 65), Cardiac Arrest (CA Group =
      19), and Syncope (Syncope Group n = 16). There were no significant differences in
      the clinical variables among the different groups, nor in the inducibility of
      arrhythmia at the electrophysiologic study. In a follow-up 27 +/- 14 months, 54%
      of patients presented at last one episode of sustained ventricular arrhythmia.
      All recurrences except one were as sustained monomorphic ventricular tachycardia
      (776 episodes). 81% of episodes of sustained monomorphic ventricular tachycardia
      (630) were treated with antitachycardia pacing with an effectiveness of 89%.
      There were no differences in the probability of arrhythmic recurrence among
      groups but death probability was higher in the ventricular fibrillation group at
      36 follow-up months (38% vs 7% and 12% in the sustained monomorphic ventricular
      tachycardia and syncope groups respectively, p = 0.0113). CONCLUSIONS: In the
      patients with an old myocardial infarction and malignant ventricular arrhythmias,
      most of recurrences are due to sustained monomorphic ventricular tachycardia
      independently of the clinical presentation. The antitachycardia pacing is not
      only effective in patients with documented sustained monomorphic ventricular
      tachycardia but also in those that are presented as cardiac arrest or syncope.

PMID- 10659654
TI  - [Combined perioperative ultrafiltration in pediatric cardiac surgery. The
      preliminary results].
AB  - INTRODUCTION AND OBJECTIVES: Recently, ultrafiltration techniques are used more
      and more as a treatment for the inflammatory response of cardiopulmonary bypass.
      It also provides fine control of fluids. The purpose of this study is to present
      a technique which combines conventional and modified ultrafiltration and to
      analyze the obtained results. PATIENTS AND METHODS: 22 patients (mean weight 13.1
      +/- 8.4 kg) operated on cardiopulmonary bypass. Combined ultrafiltration was
      performed during cardiopulmonary bypass (conventional) and after pump (modified
      ultrafiltration). We analyzed cardiopulmonary bypass variables, the first 24-hour
      hemodynamics, biological variables (arterial blood gases, cell counts, IL-6,
      adhesion molecules ICAM-1 and VCAM-1, and coagulation profiles). RESULTS: A total
      amount of 1,399 +/- 680 ml/m2 of mean combined ultrafiltrate volume was obtained
      (657 +/- 386 ml/m2 during cardiopulmonary bypass and 845 +/- 358 ml/m2 post
      cardiopulmonary bypass). After modified ultrafiltration, hematocrit rose from 23
      +/- 2.3 to 32 +/- 4.1, arterial systolic blood pressure rose from 74 +/- 13 to 98
      +/- 20 mmHg, heart rate decreased from 133 +/- 22 to 126 +/- 23 bpm, and central
      versus pressure did not change. A statistically significant relationship
      (multivariable), was shown between modified ultrafiltration time and VCAM-1 post
      ultrafiltration levels. Platelet count was lower and diuresis rose related to
      cardiopulmonary bypass ultrafiltration volume and diuresis increased.
      CONCLUSIONS: Perioperative combined ultrafiltration is feasible without undue
      morbidity and provides adequate hemoconcentration and excellent postoperative
      hemodynamic results. More studies with control groups are necessary to better
      define the therapeutic influence in antiinflammatory properties of this
      technique.

PMID- 10659655
TI  - [The clinical practice guidelines of the Sociedad Espanola de Cardiologia on the
      automatic implantable defibrillator].
AB  - Since the first implantation in man in 1980 implantable cardioverter
      defibrillator technology has greatly improved and the number of devices implanted
      has increased considerably every year. Non thoracotomy lead systems and biphasic
      shocks are now the approach of choice, offering an almost 100% success rate. This
      document reviews the recommendations for qualification of personnel and for the
      centres implanting and carrying out follow-ups on defibrillators. The current
      indications for the implantation of implantable cardioverter defibrillator are
      also addressed.

PMID- 10659656
TI  - [The Registry of the Activities of the Hemodynamics and Interventional Cardiology
      Section in 1998].
AB  - The results of the Spanish Registry of Hemodynamic and Interventional Cardiology
      of the Spanish Society of Cardiology in 1998 are hereby presented. The Registry
      collects the activity of 82 centers, which constitutes all the cardiac
      catheterization laboratories in Spain. The main activity was adult cardiac
      catheterization in 75 centers, and exclusively pediatric cardiac catheterization
      in 7. A total of 74,364 diagnostic catheterization procedures, 80% coronary
      angiographies (59,321; 1,498 per million inhabitants), were performed, which
      represents a 2.8% total increase compared to 1997. Coronary intervention
      increased by 8.6% compared to 1997, for a total number of 20,146 procedures. The
      ratio of coronary interventions per million inhabitants was 509. Success rates of
      coronary interventions (94%) and complications (2.3%) are similar to those
      registered in previous years, and in 9.7% of the cases, IIb-IIIa glicoprotein
      inhibitors were used. A 8.6% of the procedures were performed in order to treat
      an acute myocardial infarction. Coronary stenting is, continues to be the main
      device for coronary intervention. In 1998, coronary stents were employed in
      14,497 cases (a 27% increase compared to 1997) which represents the 72% of all
      coronary revascularizations procedures. A total of 19,378 prosthesis were
      implanted, 83% in a elective way and 12.9% primary stenting, with a low rate of
      complications (1.5% subacute closure, 1.5% myocardial infarction and 0.94%
      mortality). Compared to 1997, directional coronary atherectomy (83 procedures)
      showed a slight decrease, whereas rotational atherectomy (549 procedures) has
      stabilized the number of procedures and centers performing this technique. As in
      previous years, a slight decrease (9% compared to 1997) in adult valvuloplasties
      (505 vs 559) were noted. Pediatric interventional procedures increased by 20%
      (557 vs 465 procedures) compared to the 1997 Registry.

PMID- 10659657
TI  - [The Spanish Registry of Heart Transplantation. The 10th Official Report (1984
      1998). Spanish Heart Transplantation Groups. The Section of Heart Transplantation
      of the Spanish Society of Cardiology].
AB  - The results of the Spanish Registry of Heart Transplantation are hereby
      presented. A total of 349 transplants were performed in 1998--representing a net
      2756 transplants since 1984. The number of procedures increased again in the last
      year, with a 9.8% rise over the preceding year. This was probably due to an
      increase in the number of available organs, combined with less restrictive
      acceptance conditions imposed by the prolonged waiting list. Early mortality
      improved compared to 1997 (11% versus 16%), despite an increase in the proportion
      of urgent transplants performed (26% versus 22%). Overall survival increased for
      all transplant types and situations (urgent, pediatric, elderly and combined with
      kidney, liver or lung) on incorporating the 1998 data to the previous year
      (survival at 1 and 5 years: 74% and 62% versus 73% and 60%). Mean patient
      survival also increased from 8.6 to 9.5 years. As in the previous year, over 100
      variables per patient have been analyzed to establish predictors of early and
      late mortality. In conclusion, heart transplantation in Spain has not yet reached
      a plateau, and year after year the number of procedures increases, with improved
      results.

PMID- 10659658
TI  - [The treatment of intra-stent restenosis. The current situation and future
      outlook].
AB  - In-stent restenosis is an increasing problem due to the frequent use of coronary
      stent as a form of percutaneous revascularization. The global incidence is near
      to 28%, and it is well document that a neointimal hyperplasia is its principal
      mechanism. The most commonly related factors for its appearance are diabetes
      mellitus, a longer length of the original lesion, a smaller diameter of the
      reference vessel, the left anterior descending artery location and a smaller
      luminal diameter at the end of the procedure. Due to a different long term
      evolution in-stent restenosis has been classified as focal or diffuse, according
      to the length of the restenotic lesion (focal < 10 mm and diffuse > or = 10 mm).
      Some strategies have been proven for its treatment, but no randomized-controlled
      trials have been published comparing these different treatments. In focal in
      stent restenosis the practice of a conventional balloon angioplasty is associated
      with high initial clinical success with a favourable long term evolution (target
      lesion revascularization between 11-15%). But on the contrary, in diffuse in
      stent restenosis, in spite of a high initial success rate, an elevated target
      lesion revascularization has been detected at the follow-up (up to 43%). Other
      proved such as atherectomy or excimer laser are associated with a significant
      procedural non-Q-wave infarction (near to 9%) and a long term target lesion
      revascularization during follow-up (23-31%). The implantation of an additional
      stent has been performed with low procedural complications and with a long term
      target lesion revascularization near to 27%. Patients treated with intracoronary
      radiation as a complementary technique seem to have a better long term evolution
      than those having had the other strategies alone. In conclusion, in-stent
      restenosis is a new and progressively more frequent problem, requiring complex
      treatment and of which as been established. Comparative controlled studies need
      to be performed in order to determine the best treatment for this new entity.

PMID- 10659660
TI  - [Fever after an acute myocardial infarct].

PMID- 10659659
TI  - [Sudden death (IV). Sudden death in the athlete. The minimal requirements before
      performing a competitive sport].
AB  - In our society, athletes project the ultimate image of well being in the health
      status spectrum. Though very uncommon, the sudden death of a young athlete has
      always great impact on the community and the athlete's surroundings (physicians,
      athletes, coaches, etc.). Due both to this and to the growing number of physical
      exercise practitioners, there is an increasing demand for more and precise
      information on the recommendations of participation in certain sports with the
      minimum possible risk. Together with the most recent and detailed statistics
      concerning the cardiovascular causes of sudden death in athletes, the objective
      of the present article is to review the present controversy regarding the
      preparticipation medical examination as a useful method to identify those
      athletes with greater potential risk, as well as to propose a few and simple
      recommendations concerning the tests that should be performed in each case.

PMID- 10659661
TI  - [The electrocardiogram in apical hypertrophic myocardiopathy. A case report with
      unique manifestations].
AB  - We report the case of a 63-year-old female patient with apical hypertrophic
      cardiomyopathy, diagnosed by the presence of localized apical hypertrophy in the
      echocardiogram and a typical "spade like" left ventricular angiographic image,
      but with unique electrocardiographic features, characterized by chronic ST
      segment elevation, and T wave inversion, in the anterolateral leads. These
      changes were initially interpreted as a manifestation of acute ischemic heart
      disease. Chronic ST segment elevation has been occasionally described in patients
      with hypertrophic cardiomyopathy complicated with apical necrosis and aneurysm
      formation, but not in uncomplicated cases of apical hypertrophic cardiomyopathy.
      Its knowledge by the physician could allow avoidance of problems of differential
      diagnosis with more frequent heart diseases, especially acute atherosclerotic
      ischaemic heart disease.

PMID- 10659662
TI  - [Syncope and a negative electrophysiological study. The usefulness of an
      implantable Holter monitor for the diagnosis of ventricular arrhythmias].
AB  - Currently the insertable loop recorder is usually indicated when the patient has
      recurrent syncopes and conventional Holter and electrophysiological testing have
      been negative. We report the case of a patient with dilated cardiomyopathy,
      admitted to our hospital due to a single episode of syncope. After performing
      conventional diagnostic procedures, including continuous electrocardiographic
      monitoring for 48 hours, 24-hour Holter and electrophysiological study, no
      abnormalities were detected. Therefore, a insertable loop recorder was implanted,
      which was activated by the patient one month later after a pre-syncopal
      situation. The Holter reading evidenced self-limited monomorphic ventricular
      tachycardia, confirming the arrhythmic origin of the syncope. In patients with
      severe structural heart disease, in whom syncope can be caused by a malignant
      ventricular arrhythmia, the insertable loop recorder can be indicated in a single
      episode of syncope when the electrophysiological study is negative.

PMID- 10659663
TI  - [The right coronary artery with an anomalous origin and pathway and myocardial
      ischemia].
AB  - We present the case of a 59-year-old man, with exertional angina, atrial
      fibrillation, electrocardiographic and scintigraphic signs of inferior necrosis
      and anterior ischemia. An abnormally high take off of the right coronary artery,
      with anomalous intraaortic initial pathway, was objectified in the patient by
      means of angiography and magnetic resonance imaging. The patient did not have
      coronary atherosclerosis or intracoronary lesions.

PMID- 10659664
TI  - [A complete atrioventricular block and polymorphic ventricular tachycardia as the
      initial manifestation of secondary amyloidosis].
AB  - Cardiac injury is a frequent characteristic in primary, senile and myeloma
      related amyloidosis, but it is unusual in secondary amyloidosis. We report a
      patient with complete atrioventricular block and polymorphic ventricular
      tachycardia as the initial manifestation of secondary amyloidosis. Necropsy
      demonstrated amyloidosis deposits in the specific conduction system.

PMID- 10659665
TI  - [Atrial standstill and rheumatic mitral valvulopathy].
AB  - Atrial standstill is a very rare form of bradyarrhythmia and consists of a
      transitory or permanent loss of the electrical and mechanical activity of the
      atria. We report a series of 8 patients, all of them with rheumatic valve disease
      (5 of them with a prosthetic valve) with symptomatic bradyarrhythmia secondary to
      atrial standstill, requiring an implantable pacemaker.

PMID- 10659666
TI  - [Giant-cell myocarditis simulating an apical myocardial infarct].
AB  - We present a case of a 57-year-old man with a giant-cell myocarditis that made
      its debut as a sustained ventricular polymorphic tachycardia interpreted in the
      context of old apical myocardium infarct, with a posterior evolution towards
      refractory heart failure, which finally needed urgent cardiac transplantation. We
      explain the characteristics of this unusual myocarditis, which has a poor
      prognosis, and also the results of the laboratory techniques that led to an
      equivocal diagnosis in this patient.

PMID- 10659667
TI  - [Prevalence of Trypanosoma cruzi infection in opossum (Didelphis albiventris) in
      Santiago del Estero, Argentina].
AB  - The opossum of the genus Didelphis is one of the principal wild reservoirs of
      Trypanosoma cruzi and is widely distributed in the Western Hemisphere. Didelphis
      albiventris is the most common marsupial in Amama and Trinidad, two communities
      in the province of Santiago del Estero, Argentina. The D. albiventris population
      is replaced every year, and the opossum normally has two reproductive periods,
      one at the beginning of the spring and another at the beginning of the summer.
      The two litters are weaned, and they leave the mother's marsupial pouch to join
      the population, the first (G1) at the beginning of the summer and the second (G2)
      at the beginning of the fall. Between 1988 and 1991 409 D. albiventris opossums
      were studied, and xenodiagnoses showed that 35% of them were infected with T.
      cruzi. Annual cycles of renewed infection were observed, with prevalences that
      ranged between 22% and 43%. The acquisition of the parasite occurred over the
      entire year, from the summer through the spring. The prevalence of infection
      increased with age. The G1 individuals tended to present higher prevalences than
      the G2 individuals, probably from being exposed to transmission for a longer
      period of time. In the first two (younger) age categories for the opossums, G2
      individuals showed higher prevalences than did the G1 individuals. This indicates
      a significant increase in transmission intensity during the fall. Opossums should
      be regarded as a potential source of T. cruzi entry to the domestic transmission
      cycle.

PMID- 10659668
TI  - Hepatitis B seroprevalence in Latin America.
AB  - The seroprevalence of hepatitis B was investigated in over 12,000 subjects in six
      countries of Latin America: Argentina, Brazil, Chile, the Dominican Republic,
      Mexico, and Venezuela. Each study population was stratified according to age,
      gender, and socioeconomic status. Antibodies against hepatitis B core antigen
      (anti-HBc) were measured in order to determine hepatitis B infection. The highest
      overall seroprevalence was found in the Dominican Republic (21.4%), followed by
      Brazil (7.9%), Venezuela (3.2%), Argentina (2.1%), Mexico (1.4%), and Chile
      (0.6%). In all the countries an increase in seroprevalence was found among
      persons 16 years old and older, suggesting sexual transmission as the major route
      of infection. In addition, comparatively high seroprevalence levels were seen at
      an early age in the Dominican Republic and Brazil, implicating a vertical route
      of transmission.

PMID- 10659669
TI  - [Acute effects of the breathing of industrial waste and of sulfur dioxide on the
      respiratory health of children living in the industrial area of Puchuncavi,
      Chile].
AB  - This study investigated the acute effect of air pollution on the respiratory
      health of children living in the industrial area of Puchuncavi, in Region V of
      Chile. The 114 children studied were from 6 to 12 years old; 57 of them had
      chronic respiratory symptoms and 57 did not. Each day for 66 days the air was
      checked for levels of sulfur dioxide (SO2) and of breathable particles that were
      < 10 microns (PM10). The children were selected and classified according to their
      susceptibility to chronic respiratory disease by means of a questionnaire used
      with 882 children living within the area of the emissions from a copper foundry
      and a thermoelectric plant. Each day, each studied child's peak expiratory flow
      (PEF) and incidence of respiratory symptoms were checked and recorded. Using
      regression models (generalized estimation equations), estimates were made of the
      association of SO2 and PM10 levels with PEF and the incidence of cough,
      expectoration, episodes of wheezing, dyspnea, and use of bronchodilators. Among
      the children who were initially symptomatic, an increase of 50 micrograms/m3 in
      the daily mean level of SO2 caused a reduction of -1.42 L/min (95% confidence
      interval (95% CI): -2.84 to -0.71) in the PEF of the following day. An increase
      of 30 micrograms/m3 in the cumulative concentration of PM10 over three days
      produced a PEF reduction of -2.84 L/min (95% CI: -4.26 to 0.00). With respect to
      symptoms, an increase of 30 micrograms/m3 in the weekly mean level of PM10 was
      related with a 26% increase (odds ratio (OR) = 1.26; 95% CI: 1.01 to 1.57) in the
      incidence of cough and of 23% (OR = 1.23; 95% CI: 1.00 to 1.50) in the incidence
      of expectoration. An increase of 50 micrograms/m3 in the mean level of SO2 for
      three days was associated with a 5% increase (OR = 1.05; 95% CI: 1.00 to 1.10) in
      the incidence of expectoration. An increase of 30 micrograms/m3 in the daily
      average of PM10 increased the use of bronchodilators two days later by 10% (OR =
      1.10; 95% CI: 1.03 to 1.18). Among the initially asymptomatic children, a
      significant effect from PM10 exposure was found after an increase of 30
      micrograms/m3 in the mean daily PM10 level, with a reduction of -1.34 L/min (95%
      CI: -2.68 to -0.67) in the PEF of the following day. A similar increase in the
      cumulative exposure over three days was associated with an increase of 9% in the
      incidence of episodes of wheezing (OR = 1.09; 95% CI: 1.01 to 1.31). It is
      concluded that high levels of PM10 and SO2 affect the respiratory health of
      children living in the industrial area of Puchuncavi.

PMID- 10659670
TI  - Hemoglobin correction factors for estimating the prevalence of iron deficiency
      anemia in pregnant women residing at high altitudes in Bolivia.
AB  - This study had two primary objectives: 1) to derive a method to determine
      hemoglobin cutoffs that could be used to better estimate the prevalence of iron
      deficiency anemia in pregnancy at high altitudes and 2) to estimate the
      prevalence of anemia in a sample of pregnant women residing in two cities in
      Bolivia, La Paz (3,600 meters) and El Alto (4,000 meters). We derived a
      hemoglobin-altitude curve from previously published data on the mean hemoglobin
      concentrations of nonanemic women of childbearing age at various altitudes. In
      addition, we abstracted data on hemoglobin concentration during pregnancy from
      medical records of women from La Paz and El Alto who had given birth at a
      maternity hospital in La Paz between January and June of 1996. Using our approach
      and two other previously published, currently used methods, we calculated and
      compared prevalences of iron deficiency anemia in this population using
      hemoglobin cutoffs determined from a hemoglobin-altitude curve corrected for
      pregnancy. The hemoglobin-altitude curve derived in this study provided a better
      fit to data for women of childbearing age than the two other models. Those models
      used cutoffs based on non-iron-replete populations of children or men, both of
      which were residing below 4,000 m, and then extrapolated to women and higher
      altitudes. The estimated prevalences of iron deficiency anemia in pregnancy using
      the hemoglobin cutoffs determined in this study were higher than those estimated
      by the two other approaches.

PMID- 10659671
TI  - [Educational level of mothers and their knowledge, attitude and practices
      concerning respiratory infections of their children].
AB  - An evaluation was performed on the influence of different variables on the
      knowledge, attitudes, and practices that mothers of children under the age of 5
      have concerning acute respiratory infections (ARIs). Two groups of mothers were
      interviewed: 1) mothers of children seen in a polyclinic in the province of
      Havana (n = 221) and 2) mothers whose children were hospitalized in the
      respiratory unit of a pediatric hospital in the city of Havana (n = 200). The
      five variables analyzed were the educational level of the mother, her age, place
      of residence, number of children, and whether or not she was employed in the
      health service sector, as well as the interactions between the first variable and
      the other four variables. A questionnaire was used to measure the ARI knowledge,
      attitudes, and practices (KAP) of the mothers. Two levels of KAP sufficiency were
      taken into account, "Adequate I" for obtaining 70% or more of the maximum
      possible score and "Adequate II" for achieving at least a 50% score. For both
      levels of adequacy, the KAP of the mothers working in the health sector was
      significantly higher than that of the mothers interviewed in the secondary health
      care center. This suggests that the poorer knowledge, attitudes, and practices of
      mothers with hospitalized children may have contributed to the children's
      hospitalization. The most important variable associated with sufficient knowledge
      was educational level, which highlights the fundamental and positive influence
      education exerts on the preventive and curative care that mothers provide their
      children with ARI.

PMID- 10659672
TI  - [The Brazilian Universal Health System and the delivery of nursing care in a
      Brazilian hospital].
AB  - There are few studies on the delivery of nursing services in hospitals
      participating in the Brazilian universal public health system (Sistema Unico de
      Saude), which was put in place in 1988. This study, which examined possible
      changes in the delivery of these services since universal health care was
      implemented, was based on interviews carried out between July and September 1995
      with 31 nurses working at a teaching hospital in the city of Ribeirao Preto, in
      the state of Sao Paulo. The nurses had begun working at the hospital between May
      1980 and May 1987. Thematic analysis was used to assess their answers. According
      to the nurses, patients treated after the universal system was implemented have
      had more complex medical needs and a higher socioeconomic status. In addition,
      nurses reported an increase in the complexity of patient demands and in the
      variety of medical specialties offered by the hospital, as well as a decrease in
      the length of inpatient stays. Forty-six percent of the interviewees reported a
      change in the work done by nursing staff (for example, nurses have less time
      available for each patient). Not all of the problems the nurses mentioned are
      related to the public health system (understaffing is one example). It is
      essential that nurses examine national health policy and that they engage in the
      (re)construction of the practice of health care delivery. Nurses ought to
      understand the reality of their institutions and carry out a management process
      geared towards the expectations of patients and of health care workers.

PMID- 10659673
TI  - [Stress related to administrative tasks in nursing].
AB  - According to several studies, nursing, especially in hospital settings, is one of
      the most stressful professions. The objective of this study was to identify the
      sources of stress related to the administrative tasks of nurses working in a
      hospital, as well as the main health changes that stress caused these
      professionals. The quantitative survey was carried out in 1996 with a sample of
      207 nurses at a university hospital in the city of Porto Alegre, in the state of
      Rio Grande do Sul, Brazil. A questionnaire was used to collect data on stress
      sources and symptoms. The questionnaire also gathered demographic data, as well
      as information on the nurses' feelings about their working conditions. The
      average age of the study participants was 35.8 years, and the average time
      working at the hospital was 8.5 years. Among participants, 48% were considered to
      be stressed. Work overload was the stress source that best predicted relative
      risk of stress (6.1). In terms of stress symptoms, the most commonly reported
      ones were cardiovascular changes. However, gastrointestinal changes were related
      to a higher risk of stress (5.3). Managing other staff was the stress source that
      had the greatest number of significant correlations with stress symptoms. On the
      other hand, immunologic changes were the symptoms that had the highest
      correlation with stress sources. Our results suggest that stress related to
      administrative tasks in nursing may trigger changes in nurses' health.

PMID- 10659674
TI  - [Activation mechanism of matrix metalloproteinases].

PMID- 10659675
TI  - [Evaluation of factors that contribute to conformational stability of a protein
      using data base of stability/structure].

PMID- 10659676
TI  - [Molecular architecture of hemidesmosomes and desmosomes].

PMID- 10659677
TI  - [Induction of apoptosis by isoprenoids].

PMID- 10659678
TI  - [Basic studies for the formation of artificial organ in vitro].

PMID- 10659679
TI  - The monoclonal antibody HB1 recognizes an adhesion molecule for macrophages in
      the brain.
AB  - The brain environment exerts a powerful influence on macrophage phenotype, as
      exemplified by microglia, but the mechanisms mediating this control are nuclear.
      Since adhesion molecules are known to transmit signals across cell membranes, we
      investigated adhesion receptors involved in macrophage interaction with brain
      tissue. We have demonstrated previously that macrophages adhere specifically to
      CNS neurones in an in vitro assay. Here we show that this adhesion is inhibited
      by lectins, including Griffonia simplicofolia isolectin B4 (GSI), which has been
      used as a microglial marker for many years. Adhesion is unaffected by antibodies
      to several known adhesion molecules but is markedly inhibited by a new monoclonal
      antibody: HB1. HB1 recognizes microglia in the normal brain and activated
      microglia and recruited monocytes during CNS pathology. It labels a subset of
      resident macrophages and recruited monocytes in other tissues. Using this
      antibody, we isolated a protein of about 110 kDa from macrophage cell lysates.
      This protein is recognized by GSI, providing the first evidence of a functional
      role for the antigen labelled by this lectin. Further study of the HB1 antigen
      may provide important information about the influence of the brain environment on
      the phenotype of monocytic cells.

PMID- 10659680
TI  - TH-, NPY-, SP-, and CGRP-immunoreactive nerves in interscapular brown adipose
      tissue of adult rats acclimated at different temperatures: an immunohistochemical
      study.
AB  - Interscapular brown adipose tissue (IBAT), a site of nonshivering thermogenesis
      in mammals, is neurally controlled. The co-existence of sympathetic and
      peptidergic innervation has been demonstrated in different brown adipose depots.
      We studied the morphological profile of IBAT innervation and tested by
      immunohistochemical methods whether cold and warm stimulation are accompanied by
      modifications in the density of parenchymal noradrenergic nerve fibers. We also
      studied the immunoreactivity of afferent fibers--which contain calcitonin gene
      related peptide (CGRP) and substance P (SP)--in different functional conditions.
      IBAT was obtained from adult rats (6 weeks old) acclimated at different
      temperatures (4 degrees, 20 degrees, and 28 degrees C). Tissue activity was
      evaluated by studying the immunolocalization of uncoupling protein (UCP-1), a
      specific marker of brown adipose tissue. Noradrenergic and peptidergic
      innervation were seen to arise from morphologically different nerves. Fibers
      staining for tyrosine hydroxylase (TH) were thin, unmyelinated hilar nerves, and
      CGRP- and SP-positive fibers were in thick nerves containing both myelinated and
      unmyelinated fibers. Under cold stimulation, noradrenergic neurons produce
      greater amounts of TH, and their axons branch, resulting in increased parenchymal
      nerve fibers density. Neuropeptide Y (NPY) probably co-localizes with TH in
      noradrenergic neurons, but only in the perivascular nerve fiber network. The
      parenchymal distribution of NPY to interlobular arterioles and capillaries
      suggests that this peptide must have other functions besides that of innervating
      arteriovenous anastomoses, as hypothesized by other researchers. The different
      distribution of CGRP and SP suggests the existence of different sensory neuronal
      populations. The detection of CGRP at the parenchymal level is in line with the
      hypothesis of a trophic action of this peptide.

PMID- 10659681
TI  - The nuclear/mitotic apparatus protein NuMA is a component of the somatodendritic
      microtubule arrays of the neuron.
AB  - Neurons are terminally post-mitotic cells that utilize their microtubule arrays
      for the growth and maintenance of axons and dendrites rather than for the
      formation of mitotic spindles. Recent studies from our laboratory suggest that
      the mechanisms that organize the axonal and dendritic microtubule arrays may be
      variations on the same mechanisms that organize the mitotic spindle in dividing
      cells. In particular, we have identified molecular motor proteins that serve
      analogous functions in the establishment of these seemingly very different
      microtubule arrays. In the present study, we have sought to determine whether a
      non-motor protein termed NuMA is also a component of both systems. NuMA is a
      approximately 230 kDa structural protein that is present exclusively in the
      nucleus during interphase. During mitosis, NuMA forms aggregates that interact
      with microtubules and certain motor proteins. As a result of these interactions,
      NuMA is thought to draw together the minus-ends of microtubules, thereby helping
      to organize them into a bipolar spindle. In contrast to mitotic cells, post
      mitotic neurons display NuMA both in the nucleus and in the cytoplasm. NuMA
      appears as multiple small particles within the somatodendritic compartment of the
      neuron, where its levels increase during early dendritic differentiation. A
      partial but not complete colocalization with minus-ends of microtubules is
      suggested by the distribution of the particles during development and during drug
      treatments that alter the microtubule array. These observations provide an
      initial set of clues regarding a potentially important function of NuMA in the
      organization of microtubules within the somatodendritic compartment of the
      neuron.

PMID- 10659682
TI  - A possible role of SchistoFLRFamide in inhibition of adipokinetic hormone release
      from locust corpora cardiaca.
AB  - The distribution and actions of FMRFamide-related peptides (FaRPs) in the corpora
      cardiaca of the locust Locusta migratoria were studied. Antisera to FMRFamide and
      SchistoFLRFamide (PDVDHVFLRFamide) label neuronal processes that impinge on
      glandular cells in the glandular lobe of the corpora cardiaca known to produce
      adipokinetic hormones. Electron microscopic immunocytochemistry revealed that
      these FaRP-containing processes form synaptoid contacts with the glandular cells.
      Approximately 12% of the axon profiles present in the glandular part of the
      corpus cardiacum contained SchistoFLRFamide-immunoreactive material. Retrograde
      tracing of the axons in the nervus corporis cardiaci II with Lucifer yellow
      revealed 25-30 labelled neuronal cell bodies in each lateral part of the
      protocerebrum. About five of these in each hemisphere reacted with the
      SchistoFLRFamide-antiserum. Double-labelling immunocytochemistry showed that the
      FaRP-containing processes in the glandular lobe of the corpora cardiaca are
      distinct from neuronal processes, reacting with an antiserum to the neuropeptide
      locustatachykinin. The effect of the decapeptide SchistoFLRFamide and the
      tetrapeptide FMRFamide on the release of adipokinetic hormone I (AKH I) from the
      cells in the glandular part of the corpus cardiacum was studied in vitro. Neither
      the deca- nor the tetrapeptide had any effect on the spontaneous release of AKH
      I. Release of AKH I induced by the phosphodiesterase inhibitor IBMX, however, was
      reduced significantly by both peptides. These results point to an involvement of
      FaRPs as inhibitory modulators in the regulation of the release of adipokinetic
      hormone from the glandular cells.

PMID- 10659683
TI  - Axon-glial relations during regeneration of axons in the adult rat anterior
      medullary velum.
AB  - The anterior medullary velum (AMV) of adult Wistar rats was lesioned in the
      midsagittal plane, transecting all decussating axons including those of the
      central projection of the IVth nerve. At selected times up to 200 days after
      transection, the degenerative and regenerative responses of axons and glia were
      analyzed using transmission and scanning electron microscopy and
      immunohistochemistry. In particular, both the capacity of oligodendrocytes to
      remyelinate regenerated fibers and the stability of the CNS/PNS junctional zone
      of the IVth nerve rootlet were documented. Transected central AMV axons exhibited
      four patterns of fiber regeneration in which fibers grew: rostrocaudally in the
      reactive paralesion neuropil (Group 1); randomly within the AMV (Group 2); into
      the ipsilateral IVth nerve rootlet, after turning at the lesion edge and growing
      recurrently through the old degenerated contralateral central trochlear nerve
      trajectory (Group 3); and ectopically through paralesion tears in the ependyma
      onto the surface of the IVth ventricle (Group 4). Group 1-3 axons regenerated
      unperturbed through degenerating central myelin, reactive astrocytes,
      oligodendrocytes, microglia, and large accumulations of hematogenous macrophages.
      Only Group 3 axons survived long term in significant numbers, and all became
      myelinated by oligodendrocytes, ultimately establishing thin sheaths with
      relatively normal nodal gaps and intersegmental myelin sheath lengths. Schwann
      cells at the CNS/PNS junction of the IVth nerve rootlet did not invade the CNS,
      but astrocyte processes grew across the junction into the PNS portion of the IVth
      nerve. The basal lamina of the junctional glia limitans remained stable
      throughout the experimental period.

PMID- 10659684
TI  - Developmental regulation of NF1 tumor suppressor gene in human peripheral nerve.
AB  - Mutations of the NF1 tumor suppressor gene cause type 1 neurofibromatosis,
      characterized by multiple tumors of the peripheral nerves, as well as other tumor
      types. The NF1 protein, neurofibromin, is intricately linked to the cell growth
      regulatory signalling pathways, e.g. by possessing RAS-GTPase activity. The
      regulation and role of neurofibromin are not known in normal human development.
      We addressed this issue by studying the regulation of neurofibromin in normal
      human peripheral nerves, from early fetal development to adulthood. The barely
      detectable neurofibromin immunosignal in peripheral nerves during the first
      trimester of gestation contrasted dramatically to its increase in Schwann cells,
      perineurial cells, and axons during the second and third trimesters.
      Interestingly, the type I and II isoforms of neurofibromin, differing in their
      RAS oncoprotein inactivation capacity, displayed clearly different expression
      profiles throughout these periods. This suggests distinct cellular functions for
      these neurofibromin isoforms. The results also revealed distinct species-specific
      differences in neurofibromin expression, potentially bearing relevance to the
      lack of human neurofibromatosis-like disorders in other species.

PMID- 10659685
TI  - Different strokes for different folks: are differences in physician practices
      good for older persons with diabetes?

PMID- 10659686
TI  - More than provider specialty.

PMID- 10659687
TI  - Specialty differences in the care of older patients with diabetes.
AB  - OBJECTIVES: To determine differences in health status, quality of care, and
      resource utilization among older diabetic Medicare patients cared for by
      endocrinologists, internists, family practitioners, and general practitioners.
      METHODS: The authors analyzed 1,637 patients with diabetes age 65 years or older
      in the 1994 Medicare Current Beneficiary Survey, a database that links patient
      surveys to 12 months of Medicare claims data. MEASURES: Measures of morbidity
      were Basic and Instrumental Activities of Daily Living, health perception,
      Charlson Comorbidity Index score, and diabetic complications. Quality of care
      markers were measurement of ophthalmologic visit, lipid testing, glycosylated
      hemoglobin measurement, mammography, influenza vaccination, early hospital
      readmission, outpatient follow-up, and patient satisfaction. Resource utilization
      included reimbursement, relative value units, physician and emergency department
      visits, and hospitalizations. Age, gender, race, and education were adjusted for
      in multivariable analyses. RESULTS: Compared with patients of family
      practitioners, patients of endocrinologists and internists had more comorbidity
      and diabetic complications but similar health perception and deficiencies in
      activities of daily living. The patients of endocrinologists also had higher
      utilization of ophthalmologic screening, lipid testing, and glycosylated
      hemoglobin measurement than the patients of generalist physicians, but similar
      rates of influenza vaccination. Patients of endocrinologists and internists had
      higher total reimbursement than those of family practitioners and general
      practitioners. Patient satisfaction was generally similar. CONCLUSIONS: Older
      diabetic patients of endocrinologists had higher utilization of diabetes-specific
      process of care measures and had similar functional status despite more diabetic
      complications. However, they received a more costly style of care than patients
      of family practitioners and general practitioners. Future work needs to explore
      the optimal coordination of care of diabetic patients among different health
      providers.

PMID- 10659688
TI  - To buy, or not to buy: factors associated with the purchase of nongroup, private
      health insurance.
AB  - BACKGROUND: Employment-based health insurance coverage is declining in the United
      States. Many recent efforts to increase coverage have promoted the individual
      purchase of insurance, with or without subsidies. OBJECTIVES: To study the
      associations of factors including minority group membership, education, income,
      wealth, and health status with the voluntary purchase of nongroup, private health
      insurance. DESIGN: Analysis of the 1987 National Medical Expenditure Survey
      (NMES). SUBJECTS: Adult respondents to the NMES who were younger than 65 years of
      age in 2,574 health-insurance eligibility units (HIEUs) and who either were
      uninsured or who purchased nongroup, private health insurance for all of 1987.
      MEASURES: Adjusted odds ratios and marginal effects for the associations of
      minority group membership, educational attainment, income, and wealth with the
      purchase of nongroup insurance. RESULTS: Lower-income and less-wealthy HIEUs were
      much less likely to purchase insurance than higher-income and wealthier HIEUs,
      with income and wealth measures having relatively independent effects. With
      simultaneous adjustment for income, wealth, and other factors, members of
      minority groups had less than half the odds of non-Hispanic whites and persons
      with less than a high school education had less than half the odds of college
      graduates of purchasing nongroup insurance. CONCLUSIONS: Minorities and the less
      educated are much less likely to buy their own health insurance, even after
      adjustment for income and wealth. Programs encouraging the voluntary purchase of
      health insurance are likely to widen coverage gaps between historically
      disadvantaged groups and others.

PMID- 10659689
TI  - Discussion between reviewers does not improve reliability of peer review of
      hospital quality.
AB  - OBJECTIVES: Peer review is used to make final judgments about quality of care in
      many quality assurance activities. To overcome the low reliability of peer
      review, discussion between several reviewers is often recommended to point out
      overlooked information or allow for reconsideration of opinions and thus improve
      reliability. The authors assessed the impact of discussion between 2 reviewers on
      the reliability of peer review. METHODS: A group of 13 board-certified physicians
      completed a total of 741 structured implicit record reviews of 95 records for
      patients who experienced severe adverse events related to laboratory
      abnormalities while in the hospital (hypokalemia, hyperkalemia, renal failure,
      hyponatremia, and digoxin toxicity). They independently assessed the degree to
      which each adverse event was caused by medical care and the quality of the care
      leading up to the adverse event. Working in pairs, they then discussed
      differences of opinion, clarified factual discrepancies, and rerated the record.
      The authors compared the reliability of each measure before and after discussion,
      and between and within pairs of reviewers, using the intraclass correlation
      coefficient for continuous ratings and the kappa statistic for a dichotomized
      rating. RESULTS: The assessment of whether the laboratory abnormality was
      iatrogenic had a reliability of 0.46 before discussion and 0.71 after discussion
      between paired reviewers, indicating considerably improved agreement between the
      members of a pair. However, across reviewer pairs, the reviewer reliability was
      0.36 before discussion and 0.40 after discussion. Similarly, for the rating of
      overall quality of care, reliability of physician review went from 0.35 before
      discussion to 0.58 after discussion as assessed by pair. However, across pairs
      the reliability increased only from 0.14 to 0.17. Even for prediscussion ratings,
      reliability was substantially higher between 2 members of a pair than across
      pairs, suggesting that reviewers who work in pairs learn to be more consistent
      with each other even before discussion, but this consistency also did not improve
      overall reliability across pairs. CONCLUSIONS: When 2 physicians discuss a record
      that they are reviewing, it substantially improves the agreement between those 2
      physicians. However, this improvement is illusory, as discussion does not improve
      the overall reliability as assessed by examining the reliability between
      physicians who were part of different discussions. This finding may also have
      implications with regard to how disagreements are resolved on consensus panels,
      guideline committees, and reviews of literature quality for meta-analyses.

PMID- 10659690
TI  - Dimensions of consumer-assessed quality of Medicare managed-care health plans.
AB  - OBJECTIVES: We investigated relationships at the health-plan level among member
      ratings of and reports on plans in the Consumer Assessment of Health Plans Survey
      (CAHPS). We sought a more parsimonious description of the reports that can be
      used in analyses of the distribution and correlates of consumer-assessed quality.
      SUBJECTS: There were 89,419 Medicare beneficiaries enrolled in 212 Medicare
      managed-care health plans who responded to CAHPS in 1998. MEASURES: There were 39
      survey items measuring consumer ratings of and reports on care. METHODS: We
      adjusted correlations for sampling variability in the plan means and performed a
      principal factor analysis of the report items with oblique rotation. We grouped
      items that loaded heavily on the different factors, formed composites, and
      regressed rating items on the report composites. RESULTS: Four factors explained
      75% of the variance in the reports. The corresponding groups of items were
      concerned with the following subjects: (1) interactions around delivery of care
      in the doctor's office; (2) customer service from the plan; (3) access to medical
      services provided by the plan, such as specialist care, equipment, therapy, or
      drugs; and (4) advice on health-promoting activities. Corrected Cronbach alpha
      for composites were 0.97, 0.93, 0.86, and 0.60. The "delivery" composite was
      strongly predictive of overall ratings of care, doctor, and specialist; the
      "customer" composite was strongly predictive of overall ratings of the plan.
      CONCLUSIONS: CAHPS distinguishes among dimensions of between-plan variability of
      consumer-assessed quality. Different global ratings are related to distinct
      groups of consumer reports on their experiences.

PMID- 10659691
TI  - Provision of feedback on perceived health status to health care professionals: a
      systematic review of its impact.
AB  - OBJECTIVE: To assess the impact on the process and the outcomes of care of
      feeding back information on perceived health status to health care professionals
      in clinical practice. DESIGN: Systematic review of controlled trials. DATA
      IDENTIFICATION: Search in electronic databases (MEDLINE 1966-1997), manual
      searches, and requests to experts in the field. DATA ANALYSIS: Differences
      between intervention and control group were considered in process of care (use of
      health services, diagnosis, and treatment), patient outcomes (health status), and
      patient satisfaction. In a subgroup of 13 interventions that dealt with the
      provision of feedback about the patient's mental health, the impact on the
      process of care was subjected to meta-analysis. RESULTS: We identified 21 studies
      that satisfied the selection criteria. Eleven of 20 (55%) found significant
      differences (P <0.05) in at least 1 of the process indicators in favor of the
      intervention group. Of 11 trials that assessed patient outcomes, only 4 (36%)
      detected significant improvements. A similar trend but lower percentages were
      observed among the 8 interventions that provided general health status
      information. Eleven interventions that evaluated feedback information about the
      patient's mental health status showed a higher rate of diagnosis in the
      intervention group (combined odds ratio [OR]=1.91; 95% confidence interval [CI]
      1.28 to 2.83). Seven of 9 studies evaluating treatment failed to show an effect
      on this indicator (combined OR=1.15; 95% CI 0.76 to 1.75). CONCLUSIONS: The
      provision of feedback on perceived health status to health professionals seems to
      have an effect on the process of care but not on patient functional or health
      status. This is especially true with regard to mental health status information.
      Nevertheless, there is still need for a more through evaluation of this type of
      intervention.

PMID- 10659692
TI  - Tracking clinical preventive service use: a comparison of the health plan
      employer data and information set with the behavioral risk factor surveillance
      system.
AB  - BACKGROUND: There is a need for meaningful and accurate ways of tracking
      preventive service delivery among different sectors of the US population.
      OBJECTIVES: To compare methodologies of and clinical preventive service use
      estimates obtained from 2 data sets: the Health Plan Employer Data and
      Information Set (HEDIS 3.0) and the Behavioral Risk Factor Surveillance System
      (BRFSS). METHODS: HEDIS used a combination of mailed-survey, administrative, and
      medical-record data to measure preventive service use among commercial enrollees
      of 320 HMOs in 42 states during 1996. BRFSS data are from insured respondents
      (excluding those reporting Medicare or Medicaid coverage) to a random-digit
      dialed telephone survey conducted in the same 42 states during 1996. RESULTS: The
      median state-specific mammography, Papanicolaou smear, and retinal examination
      rates reported by HEDIS were consistently and substantially lower than those
      reported by BRFSS. For mammography, the median HEDIS rate was 72.4%, compared
      with 81.1% for BRFSS. For Papanicolaou smear and retinal examinations, HEDIS
      rates were 72.7% and 40.8%, respectively, compared with 91.2% and 61.6% for
      BRFSS. The median state rates of advice to quit smoking reported by HEDIS were
      similar to those for BRFSS: 62.1% versus 62.2%, respectively. For each measure,
      the absolute difference between HEDIS and BRFSS rates varied substantially both
      within a state and between states. CONCLUSIONS: It does not appear that the BRFSS
      and HEDIS data can be compared directly to accurately track progress toward
      national preventive health objectives. This study highlights some of the problems
      with comparing these data and possible means for addressing the discrepancies.

PMID- 10659693
TI  - Did recent expansions in Medicaid narrow socioeconomic differences in
      hospitalization rates of infants?
AB  - OBJECTIVE: To test whether socioeconomic differences in the ratio of infant
      hospitalizations to births, a proxy for infant hospitalization rates, and
      hospital lengths of stay for infants narrowed between 1988 and 1992: a period of
      large increases in the numbers of low-income infants enrolled in Medicaid.
      RESEARCH DESIGN: Before and after comparison of socioeconomic differences in the
      ratio of infant hospitalizations to births (ie, infant hospitalization rates) and
      lengths of stay between 1988 and 1992. By use of ICD-9 codes, hospitalizations
      were categorized as mandatory or discretionary. The difference between the 2 is
      that discretionary hospitalizations are potentially avoidable with appropriate
      primary care. Difference-in-differences techniques were used to assess the
      differential change in the rates of hospitalizations and lengths of stay for
      infants from low-income, compared with high-income, zip codes. SETTING AND
      PARTICIPANTS: Discharges of infants <2 years of age at 326 nonfederal, short
      term, general, and other specialty hospitals in 8 states. OUTCOME MEASURES:
      Ratios of discretionary and mandatory hospitalizations to births (ie,
      hospitalization rates) and hospital lengths of stay of infants <2 years of age.
      RESULTS: Infants from the poorest zip codes had ratios of discretionary
      hospitalizations to births (discretionary hospitalization rate) that were 3.1%
      points higher than infants from the wealthiest zip codes and ratios of mandatory
      hospitalizations to births (mandatory hospitalization rates) that were 0.2%
      points higher. Poor versus nonpoor differences in lengths of stay were 0.3 and
      1.9 days for discretionary and mandatory hospitalizations, respectively. No
      narrowing in the socioeconomic gradients about ratios of hospitalizations to
      births (ie, rates of hospitalization) or lengths of stay was observed.
      CONCLUSIONS: Expansions in the Medicaid program from 1988 to 1992 did not result
      in a decrease in ratios of discretionary hospitalizations to births (ie,
      discretionary hospitalization rate) or hospital length of stay for infants from
      low-income areas.

PMID- 10659694
TI  - Assessing the impact of total quality management and organizational culture on
      multiple outcomes of care for coronary artery bypass graft surgery patients.
AB  - OBJECTIVES: To assess the impact of total quality management (TQM) and
      organizational culture on a comprehensive set of endpoints of care for coronary
      artery bypass graft surgery (CABG) patients, including risk-adjusted adverse
      outcomes, clinical efficiency, patient satisfaction, functional health status,
      and cost of care. METHODS: Prospective cohort study of 3,045 eligible CABG
      patients from 16 hospitals using risk-adjusted clinical outcomes, functional
      health status, patient satisfaction, and cost measures. Implementation of TQM was
      measured by a previously validated instrument based on the Baldridge national
      quality award criteria. Organizational culture was measured by a previously
      validated 20-item instrument. Generalized estimating equations were used to
      control for potential selection bias, repeated measures, and intraclass
      correlation. RESULTS: A 2- to 4-fold difference in all major clinical CABG care
      endpoints was observed among the 16 hospitals, but little of this variation was
      associated with TQM or organizational culture. Patients receiving CABG from
      hospitals with high TQM scores were more satisfied with their nursing care (P =
      0.005) but were more likely to have lengths of stay >10 days (P = 0.0003). A
      supportive group culture was associated with shorter postoperative intubation
      times (P = 0.01) but longer operating room times (P = 0.004). A supportive group
      culture was also associated with higher patient physical (P = 0.005) and mental
      (P = 0.01) functional health status scores 6 months after CABG. CONCLUSIONS:
      There was little effect of TQM and organizational culture on multiple endpoints
      of care for CABG patients. There is a need to examine further the relationships
      among individual professional skills and motivations, group and microsystem team
      processes, specifically tailored interventions, and organization-wide culture,
      decision support processes, and incentives. Assessing the impact of such
      multifaceted approaches is an important area for further research.

PMID- 10659695
TI  - The effect of automated calls with telephone nurse follow-up on patient-centered
      outcomes of diabetes care: a randomized, controlled trial.
AB  - OBJECTIVE: We evaluated the impact of automated telephone disease management
      (ATDM) calls with telephone nurse follow-up as a strategy for improving outcomes
      such as mental health, self-efficacy, satisfaction with care, and health-related
      quality of life (HRQL) among low-income patients with diabetes mellitus. RESEARCH
      DESIGN: This was a randomized, controlled trial. SUBJECTS: Two hundred forty
      eight primarily English- and Spanish-speaking adults with diabetes enrolled at
      the time of visits to a county health care system. INTERVENTION: In addition to
      usual care, intervention patients received biweekly ATDM calls with telephone
      follow-up by a diabetes nurse educator. Patients used the ATDM calls to report
      information about their health and self-care and to access self-care education.
      The nurse used patients' ATDM reports to allocate her time according to their
      needs. MEASURES: Patient-centered outcomes were measured at 12 months via
      telephone interview. RESULTS: Compared with patients receiving usual care,
      intervention patients at follow-up reported fewer symptoms of depression (P =
      0.023), greater self-efficacy to conduct self-care activities (P = 0.006), and
      fewer days in bed because of illness (P = 0.026). Among English-speaking
      patients, those receiving the intervention reported greater satisfaction with
      their health care overall and with the technical quality of the services they
      received, their choice of providers and continuity of care, their communication
      with providers, and the quality of their health outcomes (all P <0.042).
      Intervention and control patients had roughly equivalent scores for established
      measures of anxiety, diabetes-specific HRQL, and general HRQL. CONCLUSIONS: This
      intervention had several positive effects on patient-centered outcomes of care
      but no measurable effects on anxiety or HRQL.

PMID- 10659696
TI  - The association between hospital type and mortality and length of stay: a study
      of 16.9 million hospitalized Medicare beneficiaries.
AB  - OBJECTIVES: To examine the association between hospital type and mortality and
      length of stay using hospitalized Medicare beneficiaries for a 10-year period.
      METHODS: The retrospective cohort study included 16.9 million hospitalized
      Medicare beneficiaries > or = 65 years of age admitted for 10 common medical
      conditions and 10 common surgical procedures from 1984 to 1993. A total of 5,127
      acute-care hospitals in the United States were grouped into 6 mutually exclusive
      hospital types based on teaching status and financial structure (for-profit [FP],
      not-for-profit [NFP], osteopathic [OSTEO], public [PUB], teaching not-for-profit
      [TNFP], and teaching public [TPUB]) as reported in the 1988 American Hospital
      Association database. Logistic and linear regression methods were used to examine
      risk-adjusted 30-day and 6-month mortality and length of stay. RESULTS: During
      the 10-year study period, 10.6 million patients were admitted with 1 of the 10
      selected medical conditions, and 6.3 million patients were hospitalized for 1 of
      the 10 selected surgical procedures. Patients at TNFP hospitals had significantly
      lower risk-adjusted 30-day mortality rates than patients at other hospital types
      when all diagnoses or procedures were combined (combined diagnoses: RR(TNFP) =
      1.00 [reference], RR(TPUB) = 1.40, RR(OSTEO) = 1.14, RR(PUB) = 1.07, RR(FP) =
      1.03, RR(NFP) = 1.02; combined procedures: RR(TNFP) = 1.00 [reference], RR(OSTEO)
      = 1.36, RR(TPUB) = 1.30, RR(PUB) = 1.16, RR(FP) = 1.13, RR(NFP) = 1.08). The
      results were mostly consistent when diagnoses and procedures were examined
      separately. After adjustment for patient characteristics, patients at other
      hospital types had 10% to 20% shorter lengths of stay (LOS) than patients at TNFP
      hospitals for most diagnoses and procedures studied. CONCLUSION: As measured by
      the risk-adjusted 30-day mortality, TNFP hospitals had an overall better
      performance than other hospital types. However, patients at TNFP hospitals had
      relatively longer LOS than patients at other hospital types, perhaps reflecting
      the medical education and research activities found at teaching institutions.
      Future research should examine the empirical evidence to help elucidate the
      adequate LOS for a given condition or procedure while maintaining the quality of
      care.

PMID- 10659697
TI  - The nuclear-receptor interacting protein (RIP) 140 binds to the human
      glucocorticoid receptor and modulates hormone-dependent transactivation.
AB  - The glucocorticoid receptor (GR) regulates target gene expression in response to
      corticosteroid hormones. We have investigated the mechanism of transcriptional
      activation by the GR by studying the role of the receptor interacting protein
      RIP140. Both in vivo and in vitro protein-protein interaction assays revealed a
      ligand-dependent interaction between the GR and RIP140. The ligand binding domain
      of the GR was sufficient for this interaction, while both the N- and C-terminal
      regions of RIP140 bound to the receptor. In a yeast transactivation assay RIP140
      and SRC-1, a member of the steroid receptor coactivator family of proteins, both
      enhanced the transactivation activity of a GR protein (GRA-1) in which the potent
      N-terminal tau1 transactivation domain has been deleted. In contrast, in COS-7
      cells increasing amounts of RIP140 significantly inhibited GRdeltatau1 function.
      In cotransfection studies in COS-7 cells, RIP140 also inhibited receptor activity
      in presence of both SRC-1 and the coactivator protein CBP together. Thus, in
      yeast cells a stimulation of receptor activity was observed, while in mammalian
      cells RIP140 repressed GR function. Taken together, these data suggest that, (1)
      RIP140 is a target protein for the GR and (2) RIP140 can modulate the
      transactivation activity of the receptor.

PMID- 10659698
TI  - Expression of five steroidogenic genes including aromatase gene at early
      developmental stages of chicken male and female embryos.
AB  - In the course of avian embryo development, estrogen has been indicated to play a
      key role in gonadal differentiation by the inhibition of aromatase (P-450arom)
      that synthesizes estrogen from androgen. Biosynthesis of estrogen requires not
      only P-450arom but also other enzymes for a steroidogenic pathway. To elucidate
      gonadal differentiation, the steroidogenic pathway should be studied
      comprehensively in the early developmental stages including that of sex
      differentiation. Therefore, in the present study, the expressions of the
      steroidogenic genes, P-450scc, 3beta-HSD, P-450c17, 17beta-HSD and P-450arom,
      were measured at the developmental stages (days 2-9 of incubation) of chicken
      embryos by quantitative RT-PCR. Transcripts for all the genes studied, except for
      P-450arom were detected in all the developmental stages examined, indicating that
      mRNAs for the steroidogenic enzymes required to convert cholesterol to androgens
      are present in the avian embryo before gonadal differentiation. In contrast, P
      450arom mRNA was detected in female embryos during days 5-9 of incubation but not
      in male embryos throughout incubation. The onset of P-450arom gene expression at
      day 5 coincides with the stage of gonadal differentiation, corroborating the role
      of estrogen in the process of gonadal differentiation in chicken.

PMID- 10659699
TI  - Enhanced biological activity of 1alpha,25-dihydroxy-20-epi-vitamin D3, the C-20
      epimer of 1alpha,25-dihydroxyvitamin D3, is in part due to its metabolism into
      stable intermediary metabolites with significant biological activity.
AB  - 1alpha,25-dihydroxy-20-epi-vitamin D3 (1alpha,25(OH)2-20-epi-D3), the C-20 epimer
      of the natural hormone 1alpha,25(OH)2D3, is several fold more potent than the
      natural hormone in inhibiting cell growth and inducing cell differentiation. At
      present, the various mechanisms responsible for the enhanced biological
      activities of this unique vitamin D3 analog are not fully understood. In our
      present study we compared the target tissue metabolism of 1alpha,25(OH)2D3 with
      that of 1alpha,25(OH)2-20-epi-D3 using the technique of isolated perfused rat
      kidney. The results indicated that the C-24 oxidation pathway plays a major role
      in the metabolism of both compounds in the rat kidney. However, it was noted that
      the concentrations of two of the intermediary metabolites of 1alpha,25(OH)2-20
      epi-D3, namely, 1alpha,24(R),25(OH)3-20-epi-D3 and 1alpha,25(OH)2-24-oxo-20-epi
      D3 in the kidney perfusate, exceeded the concentrations of the corresponding
      intermediary metabolites of 1alpha,25(OH)2D3. Furthermore, 1alpha,25(OH)2-24-oxo
      20-epi-D3 induces the conformation of the vitamin D receptor similar to that
      induced by its parent analog and is nearly as potent as its parent in inducing
      transactivation of a gene construct containing the human osteocalcin vitamin D
      responsive element. We conclude that 1alpha,25(OH)2-20-epi-D3 by itself is not
      metabolically stable when compared to 1alpha,25(OH)2D3, but it acquires its
      metabolic stability because of the reduced rate of catabolism of its intermediary
      metabolites. Furthermore, 1alpha,25(OH)2-24-oxo-20-epi-D3, the stable bioactive
      intermediary metabolite plays a significant role in generating the enhanced
      biological activities ascribed to 1alpha,25(OH)2-20-epi-D3.

PMID- 10659700
TI  - Correlation between PAP-dependent steroid binding activity and substrate
      specificity of mouse and human estrogen sulfotransferases.
AB  - Estrogen sulfotransferase (EST) is a cytosolic enzyme that catalyzes the
      sulfoconjugation and inactivation of estrogens using 3'-phosphoadenosine-5'
      phosphosulfate (PAPS) as an activated sulfate donor. A finding of undetermined
      significance in the study of EST has been that the guinea pig EST is able to bind
      pregnenolone and estradiol with high affinity in the presence of PAP, the
      reaction by-product of the sulfate donor PAPS. This finding has raised the
      possibility that EST may have other physiological functions independent of its
      enzymatic activity as a sulfotransferase. To determine if the PAP-dependent
      steroid binding activity is a common property shared by other estrogen
      sulfotransferases, we have expressed the mouse and human EST in bacteria and used
      the purified protein to address this question. We found that, in the presence of
      PAP, both recombinant mouse and human EST were able to bind estradiol with high
      affinity but only the human EST was able to bind pregnenolone. In addition, we
      show that human but not the mouse EST was also able to bind
      dehydroepiandrosterone, a property that was not described for the guinea pig EST.
      Furthermore, we demonstrate that the promiscuity of human EST in steroid binding
      is mirrored by a correspondingly low substrate specificity in its enzymatic
      activity as a sulfotransferase. Reversely, the lack of stable binding of
      pregnenolone and dehydroepiandrosterone by the mouse EST is paralleled by a lack
      of sulfotransferase activity of this enzyme toward these two steroids.
      Mutagenesis of mouse EST within a domain critical for PAPS binding abolished both
      its sulfotransferase and PAP-dependent estrogen binding activity. These data
      suggest that stable binding of steroids such as pregnenolone or estrogen is not
      an independent property of estrogen sulfotransferases but rather is related to
      their catalytic activity.

PMID- 10659701
TI  - 7Beta-OH-DHEA counteracts dexamethasone induced suppression of primary immune
      response in murine spleenocytes.
AB  - The effect of dexamethasone and of three potential antiglucocorticoids, namely
      dehydroepiandrosterone (DHEA) and its 7alpha-and 7beta-hydroxylated metabolites,
      on primary immune response has been studied by measuring the number of plaque
      forming cells (NPFC) and their viability in a cell culture of murine
      spleenocytes. As expected, dexamethasone suppressed considerably the NPFC as well
      as their viability. Surprisingly, DHEA as well as its 7alpha-hydroxylated
      metabolite decreased significantly the NPFC, while the effect of 7beta-hydroxy
      DHEA was different: at low doses it decreased the NPFC, but this effect was less
      pronounced at higher concentrations. In addition, 7beta-hydroxy-DHEA was able to
      counteract the effect of dexamethasone on the NPFC. None of the natural steroids
      affected the cell viability.

PMID- 10659702
TI  - 11beta-hydroxysteroid dehydrogenase functions reversibly as an oxidoreductase in
      the rat hippocampus in vivo.
AB  - The localization in the brain and metabolism of 3H-labeled corticosterone (B) and
      11-dehydrocorticosterone (A) of high specific radioactivity was determined after
      stereotaxic injection into the hippocampus of anesthetized rats. [3H]B was
      cleared very rapidly with, on average, only about 7% being recovered after 5 min
      and 0.5% after 30 min. Most of this 3H-radioactivity was localized in the area
      surrounding the site of injection with little diffusion to adjacent areas. These
      findings make it possible to compare the short term metabolism of [3H]A and [3H]B
      in different lobes of the hippocampus in the same animal and establish their
      local equilibrium point in vivo. Under these conditions, about 5% conversion of
      each steroid to the other was observed in contrast to the situation in cultured
      hippocampal cells where 11beta-hydroxysteroid dehydrogenase (11-HSD) has been
      shown by others to act primarily as a reductase catalyzing the conversion of A to
      B. This method can also be used to study the effect of inhibitors such as 11alpha
      hydroxyprogesterone, applied locally in the brain, on the metabolism of
      corticosteroids. The rate of conversion [3H]B or [3H]A to their dihydro- and
      tetrahydro-derivatives capable of modulating the GABAa receptor in the
      hippocampus was much lower than their interconversion. Thus, factors which
      influence the direction of the 11-HSD catalyzed reaction are important in
      regulating not only salt appetite and blood pressure but also the levels of
      neuroactive metabolites of corticosterone.

PMID- 10659704
TI  - Microbial transformations of steroids-XI. Progesterone transformation by
      Streptomyces roseochromogenes-purification and characterisation of the 16alpha
      hydroxylase system.
AB  - Streptomyces roseochromogenes, NCIB 10984, contains a cytochrome P450 which, in
      conjunction with two indigenous electron transfer proteins, roseoredoxin and
      roseoredoxin reductase, hydroxylates exogenous progesterone firstly to 16alpha
      hydroxyprogesterone and thereafter in a second phase bioconversion to
      2beta,16alpha-dihydroxyprogesterone. The progesterone 16alpha-hydroxylase P450
      and the two electron transfer proteins have been purified to homogeneity. A
      reconstituted incubation containing these three purified proteins and NADH, the
      natural electron donor, produced identical hydroxy-progesterone metabolites as in
      intact cells. Peroxy and hydroperoxy compounds act in a shortened form of the
      cycle known as the 'peroxide shunt' by replacing the natural pathway requirement
      for the electron donor NADH, the electron transfer proteins and molecular O2, the
      terminal electron acceptor. In an NaIO4 supported incubation, the initial rate of
      progesterone hydroxylation was marginally higher (1.62 mmol progesterone/mmol P
      450/h) than in the reconstituted natural incubation (1.18 mmol progesterone/mmol
      P-450/h) but the product yield was significantly lower, 0.45 mol
      hydroxyprogesterone produced/mol P-450 compared to 6.0 mol hydroxyprogesterone
      produced/mol P-450. These yield data show that in the reconstituted natural
      pathway, progesterone 16alpha-hydroxylase P450 supports multiple rounds of
      hydroxylation in contrast to a likely single oxygenation by a minority of P450s
      in the peroxide shunt pathway.

PMID- 10659703
TI  - Effects of novel 17-azolyl compounds on androgen synthesis in vitro and in vivo.
AB  - 17-Azolyl steroids were synthesized and evaluated as inhibitors of androgen
      synthesis in vitro and in vivo. Several of the novel compounds exhibit potent
      noncompetitive inhibition of human 17alpha-hydroxylase/C17,20-lyase with IC50
      values ranging from 7 to 90 nM, and Ki values from 1.2 to 41 nM. VN/85-1 and
      VN/108-1 were the most potent inhibitors against this enzyme with IC50 value of 8
      nM (Ki of 1.2 nM) and 7 nM (Ki of 1.9 nM), respectively. VN/107-1, VN/108-1 and
      VN/109-1 also showed moderate inhibition of 5alpha-reductase in human prostatic
      microsomes. Normal adult male rats were treated with these novel 17-azolyl
      steroidal compounds at a dose level of 50 mg/kg, s.c., for 14 consecutive days,
      sacrificed 1-2 h after the last administered dose and blood, prostate and other
      tissues were collected. The organs were weighed and tissue concentrations of
      testosterone (T) and dihydrotestosterone (DHT) were measured. Tissue T levels
      were significantly (p<0.05) lower in rats treated with the novel 17-azolyl
      steroids by more than 50% compared to the control group. Similarly, the
      concentration of DHT in the serum and prostates was significantly (p<0.05)
      diminished in rats treated with the 17-azolyl steroids by 39-80% compared to the
      control group. Furthermore, the wet weights of the prostates and seminal vesicles
      were significantly (p<0.05) reduced by several of the novel steroids. Although
      only one dose was evaluated in these studies, VN/85-1 was the most effective
      compound and reduced prostatic androgen levels by more than 80% and the wet
      weights of the prostate and seminal vesicles in rats by about 50%. These findings
      suggest that these novel compounds may provide useful leads for the research and
      development of suitable agents for the treatment of androgen dependent prostate
      cancer.

PMID- 10659705
TI  - Hypaphorine from the ectomycorrhizal fungus Pisolithus tinctorius counteracts
      activities of indole-3-acetic acid and ethylene but not synthetic auxins in
      eucalypt seedlings.
AB  - Very little is known about the molecules regulating the interaction between
      plants and ectomycorrhizal fungi during root colonization. The role of fungal
      auxin in ectomycorrhiza has repeatedly been suggested and questioned, suggesting
      that, if fungal auxin controls some steps of colonized root development, its
      activity might be tightly controlled in time and in space by plant and/or fungal
      regulatory mechanisms. We demonstrate that fungal hypaphorine, the betaine of
      tryptophan, counteracts the activity of indole-3-acetic acid (IAA) on eucalypt
      tap root elongation but does not affect the activity of the IAA analogs 2,4-D
      ((2,4-dichlorophenoxy)acetic acid) or NAA (1-naphthaleneacetic acid). These data
      suggest that IAA and hypaphorine interact during the very early steps of the IAA
      perception or signal transduction pathway. Furthermore, while seedling treatment
      with 1-amincocyclopropane-1-carboxylic acid (ACC), the precursor of ethylene,
      results in formation of a hypocotyl apical hook, hypaphorine application as well
      as root colonization by Pisolithus tinctorius, a hypaphorine-accumulating
      ectomycorrhizal fungus, stimulated hook opening. Hypaphorine counteraction with
      ACC is likely a consequence of hypaphorine interaction with IAA. In most plant
      microbe interactions studied, the interactions result in increased auxin
      synthesis or auxin accumulation in plant tissues. The P. tinctorius / eucalypt
      interaction is intriguing because in this interaction the microbe down-regulates
      the auxin activity in the host plant. Hypaphorine might be the first specific IAA
      antagonist identified.

PMID- 10659706
TI  - Fungal development and induction of defense response genes during early infection
      of wheat spikes by Fusarium graminearum.
AB  - Fusarium head blight (FHB) of wheat is a crippling disease that causes severe
      economic losses in many of the wheat-growing regions of the world. Temporal
      patterns of fungus development and transcript accumulation of defense response
      genes were studied in Fusarium graminearum-inoculated wheat spikes within the
      first 48 to 76 h after inoculation (hai). Microscopy of inoculated glumes
      revealed that the fungus appeared to penetrate through stomata, exhibited
      subcuticular growth along stomatal rows, colonized glume parenchyma cells, and
      sporulated within 48 to 76 hai. No major differences in the timing of these
      events were found between Sumai 3 (resistant) and Wheaton (susceptible)
      genotypes. In complementary experiments, RNA was extracted from spikes at several
      time intervals up to 48 hai and temporal expression patterns were determined for
      defense response genes encoding peroxidase, PR-1, PR-2 (beta-1,3-glucanase), PR-3
      (chitinase), PR-4, and PR-5 (thaumatin-like protein). In both genotypes,
      transcripts for the six defense response genes accumulated as early as 6 to 12
      hai during F. graminearum infection and peaked at 36 to 48 hai. Greater and
      earlier PR-4 and PR-5 transcript accumulation was observed in Sumai 3, compared
      with Wheaton. Our results show that the timing of defense response gene induction
      is correlated with F. graminearum infection.

PMID- 10659707
TI  - Rhizobia can induce nodules in white clover by "hijacking" mature cortical cells
      activated during lateral root development.
AB  - We examined a range of responses of root cortical cells to Rhizobium sp.
      inoculation to investigate why rhizobia preferentially nodulate legume roots in
      the zone of emerging root hairs, but generally fail to nodulate the mature root.
      We tested whether the inability to form nodules in the mature root is due to a
      lack of plant flavonoids to induce the bacterial genes required for nodulation or
      a failure of mature cortical cells to respond to Rhizobium spp. When rhizobia
      were inoculated in the zone of emerging root hairs, changes in beta-glucuronidase
      (GUS) expression from an auxin-responsive promoter (GH3), expression from three
      chalcone synthase promoters, and the accumulation of specific flavonoid compounds
      occurred in cortical cells prior to nodule formation. Rhizobia failed to induce
      these responses when inoculated in the mature root, even when co-inoculated with
      nod gene-inducing flavonoids. However, mature root hairs remained responsive to
      rhizobia and could support infection thread formation. This suggests that a
      deficiency in signal transduction is the reason for nodulation failure in the
      mature root. However, nodules could be initiated in the mature root at sites of
      lateral root emergence. A comparison between lateral root and nodule formation
      showed that similar patterns of GH3:gusA expression, chalcone synthase gene
      expression, and accumulation of a particular flavonoid compound occurred in the
      cortical cells involved in both processes. The results suggest that rhizobia can
      "hijack" cortical cells next to lateral root emergence sites because some of the
      early responses required for nodule formation have already been activated by the
      plant in those cells.

PMID- 10659708
TI  - Harpin-induced hypersensitive cell death is associated with altered mitochondrial
      functions in tobacco cells.
AB  - Mitochondria play important roles in animal apoptosis and are implicated in
      salicylic acid (SA)-induced plant resistance to viral pathogens. In a previous
      study, we demonstrated that SA induces rapid inhibition of mitochondrial electron
      transport and oxidative phosphorylation in tobacco cells. In the present study,
      we report that plant programmed cell death induced during pathogen elicitor
      induced hypersensitive response (HR) is also associated with altered
      mitochondrial functions. Harpin, an HR elicitor produced by Erwinia amylovora,
      induced inhibition of ATP synthesis in tobacco cell cultures. Inhibition of ATP
      synthesis occurred almost immediately after incubation with harpin and preceded
      hypersensitive cell death induced by the elicitor. Diphenylene iodonium, an
      inhibitor of the oxidative burst, did not block harpin-induced inhibition of ATP
      synthesis or cell death, suggesting that oxidative burst was not the direct cause
      for these two harpin-induced processes. Unlike SA, harpin had no significant
      effect on total respiratory O2 uptake of treated cells. However, respiration of
      harpin-treated tobacco cells became very sensitive to the alternative oxidase
      inhibitors salicyl-hydroxamic acid and n-propyl gallate. Thus, harpin treatment
      resulted in reduced capacity of mitochondrial cytochrome pathway electron
      transport, which could lead to the observed inhibition of ATP synthesis. Given
      the recently demonstrated roles of mitochondria in apoptosis, this rapid
      inhibition of mitochondrial functions may play a role in harpin-induced
      hypersensitive cell death.

PMID- 10659709
TI  - NPR1 differentially interacts with members of the TGA/OBF family of transcription
      factors that bind an element of the PR-1 gene required for induction by salicylic
      acid.
AB  - NPR1 is a critical component of the salicylic acid (SA)-mediated signal
      transduction pathway leading to the induction of defense genes, such as the
      pathogenesis-related (PR)-1 gene, and enhanced disease resistance. Using a yeast
      two-hybrid screen, we identified several NPR1-interacting proteins (NIPs). Two of
      these NIPs are members of the TGA/OBF family of basic leucine zipper (bZIP)
      transcription factors; this family has been implicated in the activation of SA
      responsive genes, including PR-1. Six TGA family members were tested and shown to
      differentially interact with NPR1: TGA2 and TGA3 showed strong affinity for NPR1;
      TGA5 and TGA6 exhibited weaker affinity; and TGA1 and TGA4 displayed little or no
      detectable interaction with NPR1, respectively. Interestingly, the amino-termini
      of these factors were found to decrease their stability in yeast and
      differentially affect their apparent affinity toward NPR1. The interacting
      regions on NPR1 and the TGA factors were also defined. Each of four point
      mutations in NPR1 that disrupt SA signaling in Arabidopsis completely blocked
      interaction of NPR1 with TGA2 and TGA3. TGA2 and TGA3 were also found to bind the
      SA-responsive element of the Arabidopsis PR-1 promoter. These results directly
      link NPR1 to SA-induced PR-1 expression through members of the TGA family of
      transcription factors.

PMID- 10659710
TI  - Beticolins, nonpeptidic, polycyclic molecules produced by the phytopathogenic
      fungus Cercospora beticola, as a new family of ion channel-forming toxins.
AB  - Beticolins are toxins produced by Cercospora beticola, a phytopathogenic fungus
      responsible for the leaf spot disease of sugar beet. They form a family of 20
      nonpeptidic compounds (named B0 to B19) that share the same polycyclic skeleton
      but differ by isomeric configuration (ortho- or para-) and by a variable residue
      R (bridging two carbons in one of the six cycles). It has been previously shown
      that B0 assembles itself into a multimeric structure and forms ion channels into
      planar lipid bilayers (C. Goudet, A.-A. Very, M.-L. Milat, M. Ildefonse, J.-B.
      Thibaud, H. Sentenac, and J.-P. Blein, Plant J. 14:359-364, 1998). In the present
      work, we investigate pore formation by three ortho-beticolins, B0, B2, and B4,
      and their related (i.e., same R) para-isomers, B13, B1, and B3, respectively,
      using planar lipid bilayers. All beticolins were able to form ion channels with
      multiple conductance states, although the type of cyclization (ortho- or para-)
      and residue (R) result in variations of channel conductance and ionic
      permeability, respectively. Channel formation by beticolins is likely to be
      involved in the biological activity of these toxins.

PMID- 10659711
TI  - An HR-induced tobacco peroxidase gene is responsive to spermine, but not to
      salicylate, methyl jasmonate, and ethephon.
AB  - In Tobacco mosaic virus (TMV)-infected tobacco plants carrying the N resistance
      gene, a hypersensitive reaction or response (HR) occurs to enclose the virus in
      the infected tissue. Although a contribution of peroxidases to the resistance has
      been proposed, no evidence has been presented that tobacco peroxidase genes
      respond to HR. Here, we describe the HR-induced expression of a tobacco
      peroxidase gene (tpoxC1) whose induction kinetics were slightly different from
      those of acidic and basic tobacco pathogenesis-related (PR) protein genes.
      Interestingly, tpoxC1 was insensitive to the inducers of PR genes such as
      salicylic acid, methyl jasmonate, and ethephon. Spermine activated tpoxC1 gene
      expression at a low level and both acidic and basic PR gene expression at a
      considerably higher level. These results indicate that the induced expression of
      tpoxC1 is regulated differently from that of classical tobacco PR genes in the N
      gene-mediated self-defense system in tobacco plants.

PMID- 10659713
TI  - The purMN genes of Rhizobium leguminosarum and a superficial link with
      siderophore production.
AB  - We isolated a mutant of R. leguminosarum initially on the basis of reduced
      production of the siderophore vicibactin on chrome azurol sulfonate (CAS)/agar
      indicator plates. The mutation was in the purMN operon and the mutant was shown
      to be an adenine auxotroph and defective for nodulation of peas. The siderophore
      defect appears to be trivial, being due to diminished growth of the auxotroph on
      agar-based minimal medium, which contains unknown contaminant(s) that allow it
      grow poorly. Transcriptional fusions showed that purMN was transcribed at
      relatively high levels in media containing purines. Expression was enhanced,
      approximately twofold, if purines were omitted.

PMID- 10659712
TI  - Mapping of avirulence genes in the rice blast fungus, Magnaporthe grisea, with
      RFLP and RAPD markers.
AB  - Three genetically independent avirulence genes, AVR1-Irat7, AVRI-MedNoi; and AVR1
      Ku86, were identified in a cross involving isolates Guy11 and 2/0/3 of the rice
      blast fungus, Magnaporthe grisea. Using 76 random progeny, we constructed a
      partial genetic map with restriction fragment length polymorphism (RFLP) markers
      revealed by probes such as the repeated sequences MGL/MGR583 and Pot3/MGR586,
      cosmids from the M. grisea genetic map, and a telomere sequence oligonucleotide.
      Avirulence genes AVR1-MedNoi and AVR1-Ku86 were closely linked to telomere RFLPs
      such as marker TelG (6 cM from AVR1-MedNoi) and TelF (4.5 cM from AVR1-Ku86).
      Avirulence gene AVR1-Irat7 was linked to a cosmid RFLP located on chromosome 1
      and mapped at 20 cM from the avirulence gene AVR1-CO39. Using bulked segregant
      analysis, we identified 11 random amplified polymorphic DNA (RAPD) markers
      closely linked (0 to 10 cM) to the avirulence genes segregating in this cross.
      Most of these RAPD markers corresponded to junction fragments between known or
      new transposons and a single-copy sequence. Such junctions or the whole sequences
      of single-copy RAPD markers were frequently absent in one parental isolate.
      Single-copy sequences from RAPD markers tightly linked to avirulence genes will
      be used for positional cloning.

PMID- 10659714
TI  - Small, stable shuttle vectors based on the minimal pVS1 replicon for use in gram
      negative, plant-associated bacteria.
AB  - The minimal replicon of the Pseudomonas plasmid pVS1 was genetically defined and
      combined with the Escherichia coli p15A replicon, to provide a series of new,
      oligocopy cloning vectors (5.3 to 8.3 kb). Recombinant plasmids derived from
      these vectors were stable in growing and nongrowing cells of root-colonizing P.
      fluorescens strains incubated under different environmental conditions for more
      than 1 month.

PMID- 10659715
TI  - Is a fully established arbuscular mycorrhizal symbiosis required for a
      bioprotection of Pisum sativum roots against Aphanomyces euteiches?
AB  - Bioprotection of pea roots against Aphanomyces euteiches by the arbuscular
      mycorrhizal fungus G. mosseae was demonstrated to depend on a fully established
      symbiosis. This was related with induction of mycorrrhiza-related chitinolytic
      enzymes. Possible mechanisms implicated in bioprotection are discussed.

PMID- 10659716
TI  - Alcohol misuse as a health and social issue in the Baltic Sea region. A summary
      of findings from the Baltica Study.
AB  - The Baltic Sea region today is a scene of a double transition: the eastern
      transformation and the western integration. As a consequence, alcohol-related
      issues are undergoing extensive changes. As part of a study of prevalence and
      perception of social problems around the Baltic Sea (the Baltica Study), alcohol
      issues have been studied from four perspectives: official statistics, mass media,
      public opinion and views of influential groups. The Baltic Sea region contains
      countries from the top and from the bottom of the European statistics on alcohol
      consumption (Latvia and Sweden respectively). Alcohol has been an important
      political issue in the transition of many countries (Russia and Poland just
      before the transition, Sweden and also Finland in their processes of European
      Union integration). For the medically oriented alcohol research community, the
      most important finding is that the medical profession and medical and
      epidemiological arguments play a secondary role in most of the countries when it
      comes to the definition of the problem.

PMID- 10659717
TI  - Alcohol in Russia.
AB  - The contribution that alcohol has made to the large fluctuations in mortality in
      Russia in recent years is now widely recognized. An association between heavy
      drinking and Russia is part of popular culture. But what is the reality? This
      paper reviews the evidence on historical patterns of consumption in Russia,
      highlighting the difficulties of obtaining valid statistics during the Soviet
      period (1917-1991). It notes how the state, at various times, encouraged alcohol
      sales. By the early 1980s, the social cost of heavy drinking was becoming
      apparent. This led, in 1985, to the imposition of the wide-ranging and initially
      highly effective anti-alcohol campaign by Mikhail Gorbachev. The features of this
      campaign and of its subsequent collapse are described. In the 1990s, consumption
      of alcohol increased rapidly. There has, however, been a recent reduction in
      alcohol-related deaths. It is concluded that heavy drinking is not an inevitable
      feature of Russian life and that, as the state has done much to create the
      present problem, it also has a role to play in resolving it.

PMID- 10659718
TI  - Consequences of alcohol consumption on host defence.
AB  - This communication reviews recent literature and summarizes current views on the
      immunomodulatory effects of acute and chronic alcohol consumption. Chronic and
      even acute, moderate alcohol use can increase host susceptibility to infections
      caused by bacterial and viral pathogens. Impaired host defence after alcohol
      exposure appears to be linked to a combination of decreased inflammatory
      response, altered cytokine production, and abnormal reactive oxygen intermediate
      generation. Furthermore, cellular immunity, particularly antigen-specific immune
      response, is impaired by both acute and chronic alcohol use. Although T
      lymphocyte functions can be directly affected by ethanol, decreased antigen
      presenting cell function appears to be a key element in the ethanol-induced
      decrease in cell-mediated immunity. In addition, a preferential induction of Th2
      vs Th1 immune response has been suggested, based on the increased immunoglobulin
      levels seen in chronic alcoholics. The effects of chronic and acute alcohol
      consumption in humans, animal models and in vitro systems on host defence and
      immunity are discussed in the context of the functional abnormalities of T and B
      lymphocytes, natural killer cells and monocytes/macrophages resulting in the
      altered immune response seen after alcohol use.

PMID- 10659719
TI  - Inhibitory effect of melatonin on products of lipid peroxidation resulting from
      chronic ethanol administration.
AB  - Despite decades of research, the role of free radicals in alcohol-induced organ
      injury is still a matter of debate. The present work was designed to investigate
      the potential protective effect of melatonin, a reported radical scavenger and
      antioxidant, on free radical toxicity induced by chronic ethanol administration.
      The major end-point of oxidative damage measured in this report was lipid
      peroxidation. Four groups of male Sprague-Dawley rats were used. The first group
      served as untreated controls and received a daily injection of alcoholic (<1%
      ethanol) saline. The second group of rats received daily at 18:00 a single
      subcutaneous injection of melatonin (10 mg/kg). Group 3 rats received only
      ethanol (3 g/kg) for 30 consecutive days; the ethanol was given at 18:30. The
      final group of rats was given both melatonin and ethanol with melatonin preceding
      ethanol by 30 min. Products of lipid peroxidation [malondialdehyde (MDA) and 4
      hydroxyalkenals (4-HDA)] were measured in the brain, heart, liver, lung and
      testes. At the conclusion of the study, MDA + 4-HDA levels were significantly
      increased in brains, hearts, lungs and testes, but not livers, of alcohol-treated
      compared with control rats. The percentage increases in lipid peroxidation
      products were 21.8%, 28.8%, 35.9% and 45.3% for brain, heart, lung and testes,
      respectively. In animals given melatonin 30 min before ethanol, the increases in
      MDA + 4-HDA levels were significantly reduced in all organs investigated, with
      levels not different from those in control rats. Based on these findings, it is
      speculated that melatonin's direct and indirect antioxidative actions inhibited
      alcohol-induced lipid peroxidation. These results suggest a new strategy for the
      treatment of alcohol-related diseases using melatonin as an antioxidant to reduce
      the damage inflicted by aggressive radical species.

PMID- 10659720
TI  - Effect of local intracerebral corticosterone implants on alcohol intake in the
      rat.
AB  - Corticosterone acts within the brain to stimulate alcohol consumption in the rat.
      The experiments reported here were aimed at identifying where in the brain
      corticosterone acts to facilitate ethanol drinking. The daily fluid intake of
      male Wistar rats with simultaneous access to 6% ethanol and water was determined
      during a 1-week pre-operative baseline period and following implantation of
      corticosterone in various brain areas. Animals bearing unilateral or bilateral
      implants of corticosterone in the ventral striatum showed increased ethanol
      consumption compared to cholesterol-treated controls. Ethanol intake was not
      affected when corticosterone was implanted into septum, hippocampus, or thalamus.
      Neither were changes in fluid intake detected in animals bearing ventral striatal
      implants of two related steroid hormones, aldosterone and testosterone. These
      results indicate that corticosterone partly acts within the ventral
      striatopallidal system to facilitate alcohol consumption in the rat.

PMID- 10659721
TI  - A survey of the current clinical practice of psychiatrists and accident and
      emergency specialists in the United Kingdom concerning vitamin supplementation
      for chronic alcohol misusers.
AB  - Although it is well known that B-vitamin deficiencies directly affecting the
      brain are common in alcohol misuse, no concise guidelines on the use of vitamin
      supplements in alcohol misusers currently exist in the UK. The purpose of this
      study was to assess current practice and opinion among UK physicians.
      Questionnaires were completed by a total of 427 physicians comprising Accident
      and Emergency (A&E) specialists and psychiatrists, with a response rate of 25%.
      The main findings were that vitamin deficiency was perceived as being uncommon
      amongst alcohol misusers (<25%) and there was no consensus as to which B vitamins
      are beneficial in treatment or the best method of administration of B-vitamin
      supplementation. The majority of psychiatrists favoured oral administration for
      prophylaxis against the Wernicke-Korsakoff syndrome in chronic alcohol misusers
      and parenteral therapy in patients with signs of Wernicke-Korsakoff syndrome.
      Whilst only just over half the A&E specialists expressed a preference, most
      favoured parenteral therapy in both cases. Most respondents did not currently
      have a unit policy/protocol on the management of vitamin supplementation in
      chronic alcohol misusers. Overall, the findings suggest that there is wide
      variation in current practice and highlight the need for guidelines in this area.

PMID- 10659722
TI  - Was the fetal alcohol syndrome recognized by the Greeks and Romans?
AB  - Ancient Greek and Roman philosophers/scientists are frequently quoted as
      expressing an awareness of potential harm associated with drinking during
      pregnancy. However, the statements attributed to these authors were not made by
      them. Instead, they are interpretations, presented in the form of verbatim
      statements, of their views relating to procreation. Although they did have
      something to say about the role of alcohol in procreation, it was the effects of
      drinking on the male body at the time of conception, and especially alcohol's
      effects on male body temperature, that concerned them. A cold body at the time of
      conception was believed to enhance the likelihood of conceiving a female, which
      to the Greeks and Romans was a 'deformity'.

PMID- 10659723
TI  - Outcome variables in the evaluation of alcoholics' treatment: lessons from the
      Italian Assessment of Alcoholism Treatment (ASSALT) Project.
AB  - The observational evaluation of alcoholics' treatments requires a combined
      analysis of alcoholic behaviour during treatment and of adherence to therapeutic
      programmes. The application of survival analysis techniques in this setting has
      been explored in this study. Two hundred and seventy alcoholics admitted to 15
      Italian treatment units in a 1-year period were followed-up for 2 years,
      recording date and length of every recurrence episode and of definitive or
      transitory interruption of the planned treatment. An extensive use of several
      survival analysis techniques was made. The length of time between the start of
      the treatment and the first episode of relapse did not give a reliable measure of
      frequency of failures. Conversely, the length of time between the start of
      treatment and withdrawal appeared to be unbiased. The cumulative proportions of
      treatment-compliant patients (and the corresponding 95% confidence intervals)
      were 71% (66-76%), 63% (57-69%) and 53% (47-60%) after 6 months, 1 year and 2
      years respectively from the start of treatment. Cumulative abstinence duration
      before withdrawal was significantly and positively associated with the risk of
      first, of definitive, and of every episode of treatment interruption. This first
      application of survival analysis techniques to the combined study of alcoholic
      behaviour and of adherence to treatment can improve our knowledge of treatment
      evaluation. Our results suggest that compliance to treatment is an objective and
      versatile outcome measure. Long-term follow-up studies aimed to elucidate the
      determinants of withdrawal should be performed.

PMID- 10659724
TI  - Alcohol-Use Disorders Identification Test: a comparison between paper and pencil
      and computerized versions.
AB  - The use of screening questionnaires to detect early problem drinking has been
      stimulated by the development of the AUDIT (Alcohol-Use Disorders Identification
      Test). A comparison of a computerized version of the test and its paper and
      pencil original was conducted on 110 consecutive attenders at an alcoholism day
      treatment facility. The findings suggest that the computer version is as
      acceptable as the paper and pencil one and that scores on the two formats are
      comparable.

PMID- 10659725
TI  - Truancy and perceived school performance: an alcohol and drug study of UK
      teenagers.
AB  - This study is based on a subsample of 15- and 16-year-old school students from
      the UK, part of the European School Project on Alcohol and Other Drugs (ESPAD).
      Information was available on truancy rates, perceived school performance, family
      structure, lifestyle, and usage of alcohol, cigarettes and illicit drugs in 6409
      teenagers. Living in a single-parent family, lack of constructive hobbies,
      presence of psychiatric symptoms, and an aggressive outgoing delinquent lifestyle
      bore the strongest associations to truancy and to perceived school performance.
      There were also strong relationships between both these last two variables and
      use of alcohol, cigarettes, and illicit drugs. However, the effects of alcohol,
      cigarettes, and illicit drugs were largely accounted for by other variables.
      Having at least one parent who both supported the respondent and who exercised
      some control was predictive of better perceived school performance.

PMID- 10659726
TI  - Gender differences in the relationship between alcohol consumption and drink
      problems are largely accounted for by body water.
AB  - It is widely reported that women drink less and have a lower prevalence of drink
      problems than men, but the gender differences in the relationship between level
      of drinking and drink problems have rarely been investigated quantitatively. This
      paper reports results from the Medical Research Council National Survey of Health
      and Development (the 1946 British Cohort) when the subjects were 43 years old.
      Using 7-day recall for alcohol consumption and CAGE scores of 2, 3 or 4 for drink
      problems, it was found that the prevalence of drink problems increased with level
      of alcohol consumption. Women were more likely than men to report drink problems
      at the same level of alcohol consumption. However, this gender difference was
      largely accounted for by individual differences in weight of body water. Beer
      accounted for the excess of men's drinking over women's and the proportion of
      alcohol consumed as beer was inversely related to drink problems. Eighty per cent
      of women and 52% of men who had drink problems in the past year reported drinking
      less than an average of 3 U (women) or 4 U (men) a day in the past week. As
      drinking levels in women begin to approach those in men, rates of drink problems
      in women are likely to overtake those in men because of women's greater
      physiological sensitivity to the effects of alcohol.

PMID- 10659727
TI  - Sex hormone-binding globulin in non-cirrhotic alcoholic patients during early
      withdrawal and after longer abstinence.
AB  - In recently intoxicated non-cirrhotic male alcohol-misusing and -dependent
      patients, we studied, during early withdrawal and more prolonged abstinence, the
      rate of changes of sex hormones and their binding globulin (SHBG), the prevalence
      of hypo-androgenism and possible determinant factors of SHBG increase. Twenty-one
      alcoholics and 21 controls were studied. SHBG plasma levels, sex hormones (SH),
      cortisol, insulin and thyroid hormones were measured at admission and discharge.
      SHBG and SH were also determined on days 2, 4 and 7 after admission and on weeks
      2, 6 and 12 after discharge. SHBG showed a 3-fold increase, decreasing slowly
      during the first 10 days, but remaining above control values. Luteinizing hormone
      was also increased. Free testosterone (Tf) was low at admission and correlated
      negatively with SHBG during the first 10 days. By day 10, Tf reached normal
      values, despite SHBG remaining elevated. The other sex hormones were normal.
      Neither insulin nor thyroid hormones correlated with SHBG. Cortisol was high at
      admission and then normalized. Clinical hypo-androgenism was found in 33-50% of
      patients, but did not correlate with SHBG or SH. During follow-up, nine patients
      relapsed. In those remaining abstinent, SHBG continued decreasing, reaching
      normal levels in the 12th week. In those who relapsed, SHBG remained high or even
      increased further. Gamma-glutamyltransferase showed similar but faster changes.
      We conclude that excessive alcohol ingestion is associated with marked increases
      of SHBG which slowly revert during abstinence. High SHBG does not fully explain
      the low Tf values or the presence of clinical hypo-androgenism in alcoholics.
      This SHBG response to ethanol makes it a potential marker of excessive alcohol
      intake.

PMID- 10659728
TI  - Identifying alcohol-related harm in young drinkers: the role of accident and
      emergency departments.
AB  - Data are presented from a screening study of ambulant attendees at two London
      Accident and Emergency (A&E) departments. Among young people (aged 16-24 years),
      37.2% were drinking harmfully [an Alcohol-Use Disorders Identification Test
      (AUDIT) score of 8 or more]; 17.3% admitted to drinking alcohol in the 6 h prior
      to attendance; and 14.6% considered that their attendance was alcohol related.
      Young women were as likely as men to score 8 or over. This age group had nearly
      twice the odds of scoring highly on the AUDIT, compared to those over 25 years
      old, and were more likely to report that their attendance was alcohol related.
      Screening in A&E departments would identify considerable numbers of young people
      who might benefit from brief intervention, but the problems of doing so are
      acknowledged.

PMID- 10659729
TI  - Secondary depression in weaned alcoholics: implications of Lesch's typology of
      chronic alcoholism.

PMID- 10659731
TI  - The Joint Commission for the Accreditation of Healthcare Organizations should
      require that all physicians who perform fluoroscopy be credentialed in radiation
      management by their healthcare facility.

PMID- 10659730
TI  - Intravenous injection of alcohol by drug injectors: report of three cases.

PMID- 10659732
TI  - Computerized analysis of mammographic parenchymal patterns for breast cancer risk
      assessment: feature selection.
AB  - Our purpose in this study was to identify computer-extracted, mammographic
      parenchymal patterns that are associated with breast cancer risk. We extracted 14
      features from the central breast region on digitized mammograms to characterize
      the mammographic parenchymal patterns of women at different risk levels. Two
      different approaches were employed to relate these mammographic features to
      breast cancer risk. In one approach, the features were used to distinguish
      mammographic patterns seen in low-risk women from those who inherited a mutated
      form of the BRCA1/BRCA2 gene, which confers a very high risk of developing breast
      cancer. In another approach, the features were related to risk as determined from
      existing clinical models (Gail and Claus models), which use well-known
      epidemiological factors such as a woman's age, her family history of breast
      cancer, reproductive history, etc. Stepwise linear discriminant analysis was
      employed to identify features that were useful in differentiating between "low
      risk" women and BRCA1/BRCA2-mutation carriers. Stepwise linear regression
      analysis was employed to identify useful features in predicting the risk, as
      estimated from the Gail and Claus models. Similar computer-extracted mammographic
      features were identified in the two approaches. Results show that women at high
      risk tend to have dense breasts and their mammographic patterns tend to be coarse
      and low in contrast.

PMID- 10659733
TI  - Segmentation of suspicious clustered microcalcifications in mammograms.
AB  - We have developed a multistage computer-aided diagnosis (CAD) scheme for the
      automated segmentation of suspicious microcalcification clusters in digital
      mammograms. The scheme consisted of three main processing steps. First, the
      breast region was segmented and its high-frequency content was enhanced using
      unsharp masking. In the second step, individual microcalcifications were
      segmented using local histogram analysis on overlapping subimages. For this step,
      eight histogram features were extracted for each subimage and were used as input
      to a fuzzy rule-based classifier that identified subimages containing
      microcalcifications and assigned the appropriate thresholds to segment any
      microcalcifications within them. The final step clustered the segmented
      microcalcifications and extracted the following features for each cluster: the
      number of microcalcifications, the average distance between microcalcifications,
      and the average number of times pixels in the cluster were segmented in the
      second step. Fuzzy logic rules incorporating the cluster features were designed
      to remove nonsuspicious clusters, defined as those with typically benign
      characteristics. A database of 98 images, with 48 images containing one or more
      microcalcification clusters, provided training and testing sets to optimize the
      parameters and evaluate the CAD scheme, respectively. The results showed a true
      positive rate of 93.2% and an average of 0.73 false positive clusters per image.
      A comparison of our results with other reported segmentation results on the same
      database showed comparable sensitivity and at the same time an improved false
      positive rate. The performance of the CAD scheme is encouraging for its use as an
      automatic tool for efficient and accurate diagnosis of breast cancer.

PMID- 10659734
TI  - An iterative approach to the beam hardening correction in cone beam CT.
AB  - In computed tomography (CT), the beam hardening effect has been known to be one
      of the major sources of deterministic error that leads to inaccuracy and artifact
      in the reconstructed images. Because of the polychromatic nature of the x-ray
      source used in CT and the energy-dependent attenuation of most materials, Beer's
      law no longer holds. As a result, errors are present in the acquired line
      integrals or measurements of the attenuation coefficients of the scanned object.
      In the past, many studies have been conducted to combat image artifacts induced
      by beam hardening. In this paper, we present an iterative beam hardening
      correction approach for cone beam CT. An algorithm that utilizes a tilted
      parallel beam geometry is developed and subsequently employed to estimate the
      projection error and obtain an error estimation image, which is then subtracted
      from the initial reconstruction. A theoretical analysis is performed to
      investigate the accuracy of our methods. Phantom and animal experiments are
      conducted to demonstrate the effectiveness of our approach.

PMID- 10659735
TI  - Three-dimensional computed tomographic reconstruction using a C-arm mounted XRII:
      image-based correction of gantry motion nonidealities.
AB  - The image quality of 3D reconstructions produced using a C-arm mounted XRII
      depends on precise determination of the geometric parameters that describe the
      detector system in the laboratory frame of reference. We have designed a
      simplified calibration system that depends on images of a metal sphere, acquired
      during rotation of the gantry through 200 degrees. Angle-dependent shift
      corrections are obtained, accounting for nonideal motion in two directions:
      perpendicular to the axis of rotation and tangential to the circular trajectory
      (tau), and parallel to the axis of rotation (xi). Projection images are corrected
      prior to reconstruction using a simple shift-interpolation algorithm. We show
      that the motion of the gantry is highly reproducible during acquisitions within
      one day (mean standard deviation in tau and xi is 0.11 mm and 0.08 mm,
      respectively), and over 21 months (mean standard deviation in tau and xi is 0.10
      mm and 0.06 mm, respectively). Reconstruction of a small-bead phantom
      demonstrates uniformity of the correction algorithm over the full volume of the
      reconstruction [standard deviation of full-width-half-maximum of the beads is
      approximately 0.25 pixels (0.13 mm) over the volume of reconstruction]. Our
      approach provides a simple correction technique that can be applied when
      trajectory deviations are significant relative to the pixel size of the detector
      but small relative to the detector field of view, and when the fan angle of the
      acquisition geometry is small (<20 degrees). A comparison with other calibration
      techniques in the literature is provided.

PMID- 10659736
TI  - Efficient correction for CT image artifacts caused by objects extending outside
      the scan field of view.
AB  - The purpose of this paper is to develop a method of eliminating CT image
      artifacts generated by objects extending outside the scan field of view, such as
      obese or inadequately positioned patients. CT projection data are measured only
      within the scan field of view and thus are abruptly discontinuous at the
      projection boundaries if the scanned object extends outside the scan field of
      view. This data discontinuity causes an artifact that consists of a bright
      peripheral band that obscures objects near the boundary of the scan field of
      view. An adaptive mathematical extrapolation scheme with low computational
      expense was applied to reduce the data discontinuity prior to convolution in a
      filtered backprojection reconstruction. Despite extended projection length, the
      convolution length was not increased and thus the reconstruction time was not
      affected. Raw projection data from ten patients whose bodies extended beyond the
      scan field of view were reconstructed using a conventional method and our
      extended reconstruction method. Limitations of the algorithm are investigated and
      extensions for further improvement are discussed. The images reconstructed by
      conventional filtered backprojection demonstrated peripheral bright-band
      artifacts near the boundary of the scan field of view. Images reconstructed with
      our technique were free of such artifacts and clearly showed the anatomy at the
      periphery of the scan field of view with correct attenuation values. We conclude
      that bright-band artifacts generated by obese patients whose bodies extend beyond
      the scan field of view were eliminated with our reconstruction method, which
      reduces boundary data discontinuity. The algorithm can be generalized to objects
      with inhomogeneous peripheral density and to true "Region of Interest
      Reconstruction" from truncated projections.

PMID- 10659737
TI  - Contralateral subtraction: a novel technique for detection of asymmetric
      abnormalities on digital chest radiographs.
AB  - A novel contralateral subtraction technique has been developed to assist
      radiologists in the detection of asymmetric abnormalities on a single chest
      radiograph. With this method, the lateral inclination is first corrected by
      rotating and shifting the original chest image so that the midline of the thorax
      is aligned with the vertical centerline of the original chest image. The rotated
      image is then flipped laterally to produce a reversed "mirror" image. Finally,
      the mirror image is warped and subtracted from the original image for derivation
      of the contralateral subtraction image. The three key techniques which are
      employed in this study are applied successively to the initial contralateral
      subtraction technique for acquisition of improved subtraction images. One hundred
      PA chest radiographs, including 50 normals and 50 abnormals, were used as the
      database for this study. The percentage of chest images, which were rated as
      being adequate, good, or excellent quality of subtraction images by employing a
      subjective evaluation method, was improved from 73% to 91% by use of the three
      key techniques. The contralateral subtraction technique can be used for detection
      of any asymmetric abnormalities, such as lung nodules, pneumothorax, pneumonia,
      and emphysema, on a single chest radiograph, and therefore has potential utility
      in a high proportion of abnormal cases.

PMID- 10659738
TI  - Digital radiography enhancement by nonlinear multiscale processing.
AB  - Today's digital radiography systems mostly use unsharp maskinglike enhancement
      algorithms based on splitting input images into two or three frequency channels.
      This method allows fine detail enhancement as well as processing of global
      contrast (harmonization). However, structures of medium size are not accessible.
      In extension of a standard algorithm of such type, we develop and test a new
      enhancement algorithm based on hierarchically repeated unsharp masking, resulting
      in a multiscale architecture allowing consistent access to structures of all
      sizes. Our algorithm decomposes a radiograph by a pyramid-architecture, dividing
      it into eight or more channels representing structures of different sizes, known
      as "scales." At each scale, weakly contrasting structures are then enhanced by
      suitable nonlinear processing. We emphasize two points: first, backward
      compatibility to the standard algorithm which is used routinely in clinical
      practice. This allows reuse of current parametrization know-how as well as a
      smooth transition from current to new processing. Second, our enhancement is
      noise-resistant in the sense that it prevents unacceptable noise amplification. A
      prototype implementation of the algorithm is undergoing trials in the clinical
      routine of radiology departments of major German hospitals. Results strongly
      indicate the superior performance and high acceptance of the new processing.

PMID- 10659739
TI  - A lesion detectability simulation method for digital x-ray imaging.
AB  - A simulation method is described in this work that aids in quantifying the upper
      limits of lesion detectability as a function of lesion size, lesion contrast,
      pixel size, and x-ray exposure for digital x-ray imaging systems. The method
      entails random lesion placement with subsequent simulated imaging on idealized x
      ray detectors with no additive noise and 100% quantum detective efficiency.
      Lesions of different size and thickness were simulated. Mean (expectation) lesion
      signal-to-noise ratios (LSNRs) were calculated and receiver operating
      characteristic (ROC) curves were constructed based on LSNR ensembles. Mean
      (expectation) values of the areas under the ROC curves were calculated for
      lesions of varying size on pixel arrays of varying size at different exposures.
      Analyses were performed across several parameters, including lesion size, pixel
      size, and exposure levels representative of various areas of radiography. As
      expected, lesion detectability increased with lesion size, contrast, pixel size,
      and exposure. The model suggests that lesion detectability is strongly dependent
      on the relative alignment (phase) of the lesion with the pixel matrix for lesions
      on the order of the pixel size.

PMID- 10659740
TI  - Computerized analysis of radiographic bone patterns: effect of imaging conditions
      on performance.
AB  - We are developing computerized methods for characterizing the bone texture
      pattern from digitized skeletal radiographs. For this method to be useful
      clinically, it must be able to distinguish between weak and strong bone under the
      range of exposure conditions potentially encountered in the clinical setting. In
      this study, we examined the effect of exposure conditions on Fourier-based
      texture features. Thirty-four femoral specimens from total hip arthroplasties
      were radiographed multiple times under different exposure conditions. The
      specimens underwent mechanical strength testing from which load to failure values
      were obtained. The performance of the texture features were investigated in the
      task of distinguishing between strong and weak bone as characterized by the load
      to failure values. The texture features showed no dependence upon focal spot size
      of the x-ray tube or magnification. The texture features did show a dependence
      with relative exposure, peak kilovoltage, and amount of scattering material.

PMID- 10659742
TI  - Statistical approach for image quality evaluation in daily medical practice.
AB  - The ROC method usually used for image quality evaluation in medical diagnostics
      has a lot of advantages, however it is too complicated and inconvenient for daily
      medical practice. In this paper, a simple, rapid, and unbiased statistical
      approach is suggested as a method for evaluation of detectability of pathology
      simulators with small size and low contrast. The method takes into consideration
      both erroneous and true interpretations; within each are two types: false
      positive P(Y/n) and false-negative P(N/s), and true-positive P(Y/s) and true
      negative P(N/n). The methodology consists of the following steps: obtaining an
      image of a phantom, evaluation of the image by estimating the likelihood of test
      element presence in each of the numbered phantom areas (in percentage), comparing
      the real disposition of test elements with the results of the estimation, and
      calculating the various interpretation probabilities with very simple formulas.
      Assuming the distribution of photons corresponding to test elements and
      background are both Gaussian, one can obtain receiver operating characteristics
      (ROC) curves and curves of observer bias for over- and under-reading of test
      elements presence. Each of these curves is determined by the measurement of a
      single point. The suggested statistical method can be used for checking and
      adjusting imaging systems, selecting the physical and technical conditions of a
      diagnostic procedure, as well as for training and testing operators and
      physicians. Various designs of statistical phantoms are considered, and the
      merits of the suggested method and possibilities for its usage in quality
      assurance medical practice, particularly in x-ray diagnostics, are described.

PMID- 10659741
TI  - Signal-to-noise ratio and spatial resolution in x-ray electronic imagers: is the
      MTF a relevant parameter?
AB  - In most imaging detectors, the modulation transfer function (MTF) is regarded as
      a good parameter to describe spatial resolution. This is undoubtedly valid for
      visual observation. However, the detectability of a detail is essentially a
      matter of signal-to-noise ratio, which is not accounted for by the MTF. In x-ray
      imaging, signal-to-noise ratio in the image is generally limited by incident
      photons statistics, often larger than readout noises. Therefore, the MTF of the
      detector applies to both signal and noise, and does not impair the image content.
      Contrast can easily be restored by image processing without altering the signal
      to-noise ratio. However, a number of effects may alter very differently noise and
      signal: (i) If the MTF significantly extends beyond half the sampling frequency,
      the aliasing introduced by spatial sampling can severely enhance the noise and
      cancel the benefit of the good signal transfer. This is illustrated by synthetic
      images which simulate the response of imagers with different MTFs to the same
      test pattern in the presence of quantum noise. (ii) Parallax and blurring by the
      x-ray spot size or motion are shown to degrade the transfer properties of signal,
      but do not affect the quantum noise; they must be treated separately. Contrary to
      the x-ray converter MTF, parallax directly impacts the detective quantum
      efficiency (DQE). Finally, it is shown that only the detective quantum efficiency
      can reliably describe the spatial resolution of an x-ray imaging detector in the
      presence of noise, parallax and blurring.

PMID- 10659744
TI  - Bandpass optical flow for tagged MRI.
AB  - MR tagging has shown great promise for detailed noninvasive cardiac motion
      imaging. Our research uses low-frequency tags coupled with gradient-based optical
      flow estimation to compute cardiac motion. We develop here a novel, fast, fully
      automated optical flow method for tagged MRI by exploiting the Fourier content of
      the tagged images. This new method, called bandpass optical flow, works by
      extracting various subband images from tagged cardiac data, and then formulating
      multiple optical flow constraints for each subband. The resulting system is
      solved by least squares pseudo-inversion. The proposed method is validated on
      simulated and real tagged data.

PMID- 10659743
TI  - Elasticity reconstruction from experimental MR displacement data: initial
      experience with an overlapping subzone finite element inversion process.
AB  - The determination of the elastic property distribution in heterogeneous gel
      samples with a finite element based reconstruction scheme is considered. The
      algorithm operates on small overlapping subzones of the total field to allow for
      a high degree of spatial discretization while maintaining computational
      tractability. By including a Maxwellian-type viscoelastic property in the model
      physics and optimizing the spatial distribution of this property in the same
      manner as elasticity, a Young's modulus image is obtained which reasonably
      reflects the true distribution within the gel. However, the image lacks the
      clarity and accuracy expected based on simulation experience. Preliminary
      investigations suggest that transient effects in the data are the cause of a
      significant mismatch between the inversion model, which assumes steady-state
      conditions, and the actual displacements as measured by a phase contrast MR
      technique.

PMID- 10659745
TI  - Validation of K x-ray fluorescence bone lead measurements by inductively coupled
      plasma mass spectrometry in cadaver legs.
AB  - K x-ray fluorescence (KXRF) systems are being used in a growing number of
      epidemiologic studies to measure bone lead levels as a biological marker of
      accumulated lead exposure. Although validation of the KXRF technique in lead
      doped phantoms and bare bone specimens has been repeatedly demonstrated, few
      studies have compared KXRF to chemical measurements of actual intact cadaver
      limbs (with skin and soft tissues). In this study, lead levels in eight amputated
      human legs were measured by KXRF; after dissection, levels in the bare bones were
      again measured by KXRF and then by inductively coupled plasma mass spectrometry
      (ICP-MS). We observed close agreement between the KXRF and ICP-MS measurements
      with correlation coefficients for both the tibia and patella greater than 0.9. In
      this study we provide further support for the validity of KXRF measurements,
      particularly with respect to the patella.

PMID- 10659746
TI  - Limitations of the point and line source approximations for the determination of
      geometry factors around brachytherapy sources.
AB  - Geometry factors were calculated around commercially available pellets and
      elongated brachytherapy sources taking into account their actual active core
      geometries. These calculations were compared with corresponding ones derived
      using the point and line source approximations commonly used for the
      determination of geometry factors, as proposed by AAPM Task Group 43. The point
      source approximation was found to be efficient for the determination of geometry
      factors around single active pellets, even at radial distances very close to the
      source. It is also valid for the determination of geometry factors at radial
      distances r>2L from elongated brachytherapy sources of length L. For smaller
      radial distances, however, this approximation introduces significant errors,
      >50%, around elongated source designs, thus being unacceptable for the
      determination of geometry factors in this case. The line source approximation was
      found to accurately reproduce geometry factors around elongated brachytherapy
      source designs. Errors greater than 3%, due to the fact that the line source
      approximation ignores the radial dimension d of the source, are observed only at
      radial distances very close to the source (r< or =L/2), at polar angles far away
      from their transverse bisectors. These errors depend on the ratio d/L and
      increase as this ratio increases.

PMID- 10659747
TI  - Size and positioning reproducibility of an 192Ir brachytherapy stepping source.
AB  - In this paper we describe techniques for measuring the dimensions and position
      reproducibility of an 192Ir brachytherapy stepping source. Measurements were
      carried out using a 0.25x10x152 mm3 collimator placed in front of a detector of
      our own design. The brachytherapy source was translated past the collimator in
      0.025 mm increments using a stepper motor. The source was found to be 3.58 mm
      long and 0.69 mm wide, which is in good agreement with the manufacturer's values
      of 3.5x0.6 mm2. The source position was reproducible to within 0.12 mm.

PMID- 10659748
TI  - Monte Carlo calculations of dose rate distributions around the Amersham CDCS-M
      type 137Cs source.
AB  - The Amersham CDCS-M-type 137Cs stainless-steel encapsulated source is widely used
      in low dose rate brachytherapy with manual afterloading. However there is a need
      for more accurate dosimetry data. In this study we present Monte Carlo
      calculations of absolute dose rate in water around this source using the Monte
      Carlo code GEANT, discuss dosimetric features of these data, and compare them
      with Krishnaswamy's results for 137Cs intracavitary sources. Dose rate
      distributions are presented in the form of along-away tables and in the TG43
      formalism. Simulated absolute dose rate values can be used as benchmark data to
      verify the treatment planning system calculation results or directly as input
      data for treatment planning. Best-fit values of attenuation coefficients suitable
      for use in Sievert integral type calculations have been derived comparing dose
      rate distributions calculated using this algorithm with those obtained from Monte
      Carlo calculations.

PMID- 10659749
TI  - A simple technique for alignment of perineal needle template to ultrasound image
      grid for permanent prostate implants.
AB  - Proper alignment of a needle template and ultrasound software grid is required to
      accurately deliver permanent prostate seed implants optimized using pretreatment
      volume studies. Correct alignment may also reduce tissue edema, morbidity, and
      the time and labor required to deliver permanent prostate seed implants. A
      technique has been developed to rapidly assess (and, if necessary, improve) the
      alignment using a custom-designed water phantom. Verification of needle positions
      can be conducted within 1 mm and requires less than ten minutes. We have
      instituted the technique as a part of our periodic quality assurance program.

PMID- 10659750
TI  - Toward a statistically relevant calibration end point for prostate seed implants.
AB  - Interstitial brachytherapy for carcinoma of the prostate is achieved through the
      use of a configuration of radioactive seeds placed in a manner that delivers a
      customized, reasonably uniform dose to the target volume. Accurate dose delivery
      depends on both precise seed placement and reliable seed strength in the
      implanted configuration. This study assumes the independence of the two issues,
      and quantifies the reduction in the minimum dose to the surface of the gland due
      only to variability in individual seed strengths. Current AAPM guidelines
      pertaining to the acceptable limits on seed-to-seed variability are prudent for
      small configurations of seeds, yet are likely to be overly stringent for
      applications such as prostate seed implantation. In this study we determine the
      reduction in the minimum peripheral dose (mPD) caused by the introduction of
      source strength variability, and provide statistical insight into this effect. It
      is concluded that the current guidelines limit the reduction in mPD to < or =0.4%
      relative to the prescription value, for an average configuration, due to the
      inclusion of strength variability. The maximum observed reduction in mPD would be
      < or =1.5%. This value is an order of magnitude lower than the recommendations of
      the AAPM Task Group 40 for the overall accuracy of brachytherapy procedures,
      which suggests that seed strength variability is of limited concern and that
      constraints on this factor should perhaps be reevaluated.

PMID- 10659751
TI  - Limitations of the straight-line assumption for endobronchial HDR brachytherapy
      treatments.
AB  - It is useful to expedite high dose rate brachytherapy endobronchial treatments by
      using standardized dwell weights and worksheets, avoiding computerized planning
      where possible. Such methods assume the treatment catheter is straight. This
      study uses inverse-square considerations to quantify the curvature that
      invalidates the straight-line approximation. The ratio of the distance between
      end dwell positions and the active length can be used as a measure of the
      curvature. The variation in mean dose and maximum dose at the prescription points
      is presented as a function of active length and curvature, allowing the planner
      to determine quickly when a pre-treatment computer plan is necessary.

PMID- 10659752
TI  - Automated Gamma Knife dose planning using polygon clipping and adaptive simulated
      annealing.
AB  - The Gamma Knife (Elekta Instruments, Inc., Norcross, GA), a neurosurgical, highly
      focused radiation delivery device, is used to eradicate deep-seated anomalous
      tissue within the human brain by delivering a lethal dose of radiation to target
      tissue. This dose is the accumulated result of delivering sequential "shots" of
      radiation to the target, where each shot is approximately three-dimensional (3-D)
      Gaussian in shape. The size and intensity of each shot can be adjusted by varying
      the time of radiation exposure and by using one of four collimator sizes ranging
      from 4-18 mm. Current dose planning requires that the dose plan be developed
      manually to cover the target, and only the target, with a desired minimum
      radiation intensity using a minimum number of shots. This is a laborious and
      subjective process that typically leads to suboptimal conformal target coverage
      by the dose. We have previously presented a forward-direct-method, which, using
      adaptive simulated annealing and Nelder-Mead simplex optimizers, automates the
      selection and placement of generic Gaussian-based kernels or "shots" to form a
      simulated dose plan. In order to make the computation of the problem tractable,
      the algorithm exploits 2-D contouring and polygon clipping and takes a 2 1/2-D
      approach to defining the problem. In the current paper we present the results of
      four experiments on two historical clinical datasets, where the generic kernels
      have been replaced by patient specific kernels calculated by Elekta's Leksell
      Gamma Plan software. For these experiments the user only selects the maximum
      number of shots to use and the optimizers are then given the freedom to vary the
      number of shots as well as the weight, collimator size, and 3-D location of each
      shot. Highly conformal and competitive dose plans were generated for these two
      difficult cases.

PMID- 10659754
TI  - A virtual source model for Monte Carlo modeling of arbitrary intensity
      distributions.
AB  - A photon virtual source model was developed for simulating arbitrary, external
      beam, intensity distributions using the Monte Carlo method. The source model
      consists of a photon fluence grid composed of a matrix of square elements,
      located 25-cm downstream from the linear accelerator target. Each particle
      originating from the fluence map is characterized by the seven phase space
      parameters, position (x, y, z), direction (u, v, w), and energy. The map was
      reconstructed from fluence and energy spectra acquired by modeling components of
      the linear accelerator treatment head using the Monte Carlo code MCNP4B. The
      effect of contaminant electrons is accounted for by the use of a sub-source
      derived from a phase-space simulation of a 25-MV linac treatment head using the
      code BEAM. The BEAM sub-source was incorporated into the MCNP4B phase-space model
      and is sampled using a field-size dependent sampling ratio. A Gaussian blurring
      kernel is convolved with the photon fluence map to account for the finite focal
      spot size and scattering effects from structures such as the flattening filter
      and MLC leaves. Depth dose and profile source calculations for 6-MV and 25-MV
      photon beams, for 5 x 5 cm2, 10 x 10 cm2, and 15 x 15 cm2 field sizes, are in
      good agreement with measurement and are well within acceptability criteria
      suggested by the AAPM Task Group Report No. 53. Irregular field calculations
      compared with film measurement and with a 3-D pencil beam algorithm show that the
      source model is capable of accurately simulating arbitrary MLC fields.

PMID- 10659753
TI  - Superficial doses from serial tomotherapy delivery.
AB  - Serial tomotherapy patients are treated using a commercial computer-controlled
      treatment planning and delivery system and a linear accelerator in arc mode.
      Target volumes are irradiated using sequential 1.68-cm-thick slices with the
      patient moved between each successive slice delivery. Due to the method of
      delivery, superficial doses from a course of intensity modulated radiation
      therapy may be significantly different from doses delivered with conventional
      radiation therapy. An experimental investigation was conducted to determine the
      superficial depth-dose distribution for geometric target volumes. Treatment plans
      were conducted for 5-cm-diam, 5-cm-long right cylindrical target volumes embedded
      in a 16-cm-diam, 12-cm-long water-equivalent cylindrical phantom. Three
      experiments were conducted with centrally located, off-centered, and superficial
      targets. Doses at superficial depths were measured using 3 x 3 x 1 mm3
      thermoluminescent dosimetry chips. For all three targets, the measured doses were
      slightly greater than the calculated doses. Doses measured in the buildup region
      for the superficial target indicated that bolus would be required to provide the
      prescribed dose at the phantom surface.

PMID- 10659755
TI  - A language for generating tomographic images of mathematical phantoms.
AB  - A computer language is presented that can be used to generate image files, as if
      the images are created with a CT or a MR scanner. The language defines objects in
      the "scanner's" coordinate system, as sets of quadratic inequalities. Each of
      these objects, e.g., an ellipsoid or a half-plane or a cylinder, has its own
      density. Objects can be superimposed and collections of objects are allowed to
      translate and rotate. The language allows for a concise way of describing complex
      objects with precisely defined geometries and densities. An implementation of the
      language can be used for testing, developing, and analyzing diagnostic software,
      treatment planning systems, etc. A software module that is based on the language
      can be made available. The utility of the module for acceptance testing of
      radiation therapy treatment planning systems is described.

PMID- 10659756
TI  - Electron beam modeling and commissioning for Monte Carlo treatment planning.
AB  - A hybrid approach for commissioning electron beam Monte Carlo treatment planning
      systems has been studied. The approach is based on the assumption that
      accelerators of the same type have very similar electron beam characteristics and
      the major difference comes from the on-site tuning of the electron incident
      energy at the exit window. For one type of accelerator, a reference machine can
      be selected and simulated with the Monte Carlo method. A multiple source model
      can be built on the full Monte Carlo simulation of the reference beam. When
      commissioning electron beams from other accelerators of the same type, the energy
      spectra in the source model are tuned to match the measured dose distributions. A
      Varian Clinac 2100C accelerator was chosen as the reference machine and a four
      source beam model was established based on the Monte Carlo simulations. This
      simplified beam model can be used to generate Monte Carlo dose distributions
      accurately (within 2%/2 mm compared to those calculated with full phase space
      data) for electron beams from the reference machine with various nominal
      energies, applicator sizes, and SSDs. Three electron beams were commissioned by
      adjusting the energy spectra in the source model. The dose distributions
      calculated with the adjusted source model were compared with the dose
      distributions calculated using the phase space data for these beams. The
      agreement is within 1% in most of cases and 2% in all situations. This
      preliminary study has shown the capability of the commissioning approach for
      handling large variation in the electron incident energy. The possibility of
      making the approach more versatile is also discussed.

PMID- 10659757
TI  - A Monte Carlo dosimetry-based evaluation of the 7Li(p,n)7Be reaction near
      threshold for accelerator boron neutron capture therapy.
AB  - Advanced methods of boron neutron capture therapy (BNCT) use an epithermal
      neutron beam in conjunction with tumor-targeting boron compounds for irradiation
      of glioblastomas and metastatic melanomas. A common neutron-producing reaction
      considered for accelerator-based BNCT is 7Li(p,n)7Be, whose cross section
      increases very rapidly within several tens of keV of the reaction threshold at
      1.88 MeV. Operation in the proton energy region near threshold will have an
      appreciable thick target neutron yield, but the neutrons produced will have
      relatively low energies that require little moderation to reach the epithermal
      range desirable for BNCT. Because of its relatively low projected accelerator
      cost and the portability of the neutron source/target assembly, BNCT based on the
      near-threshold technique is considered an attractive candidate for widespread
      hospital use. A systematic Monte Carlo N-Particle (MCNP) investigation of the
      dosimetric properties of near-threshold neutron beams has been performed. Results
      of these studies indicate that accelerator proton energies between 1.93 and 1.99
      MeV, using 5 cm of H2O moderator followed by thin 6Li and Pb shields, can provide
      therapeutically useful beams with treatment times less than one hour and
      accelerator currents less than 5 mA.

PMID- 10659759
TI  - IORT apparatus design improvement through the evaluation of electron spectral
      distributions using Monte Carlo methods.
AB  - Clinically used IORT electron beam characteristics may vary with respect to
      typical external beams due to the decrease of lateral scatter equilibrium and the
      addition of the IORT apparatus itself. Additionally, chamber size effects may
      lead to inaccurate measurements of the changes in electron beam characteristics.
      The causal components of these beam characteristics are often difficult or
      impossible to measure using experimental techniques. For this reason, and for
      potential design improvement, the electron beams were modeled using the
      OMEGA/BEAM Monte Carlo software for radiation transport. The IORT electron beam
      characteristics of the Varian Clinac 1800 were studied for 6, 12, and 20 MeV
      electrons and 1-4 in. diameter flat-end applicators. The characteristics studied
      include electron energy spectra, percentage depth dose, and cross-plane profiles.
      It was found that by increasing the thickness of the aluminum base plate of the
      main attachment, the dose at d(max) outside the primary field could be reduced
      from approximately 9% to 1% of maximum.

PMID- 10659758
TI  - Development and construction of a neutron beam line for accelerator-based boron
      neutron capture synovectomy.
AB  - A potential application of the 10B(n, alpha)7Li nuclear reaction for the
      treatment of rheumatoid arthritis, termed Boron Neutron Capture Synovectomy
      (BNCS), is under investigation. In an arthritic joint, the synovial lining
      becomes inflamed and is a source of great pain and discomfort for the afflicted
      patient. The goal of BNCS is to ablate the synovium, thereby eliminating the
      symptoms of the arthritis. A BNCS treatment would consist of an intra-articular
      injection of boron followed by neutron irradiation of the joint. Monte Carlo
      radiation transport calculations have been used to develop an accelerator-based
      epithermal neutron beam line for BNCS treatments. The model includes a
      moderator/reflector assembly, neutron producing target, target cooling system,
      and arthritic joint phantom. Single and parallel opposed beam irradiations have
      been modeled for the human knee, human finger, and rabbit knee joints. Additional
      reflectors, placed to the side and back of the joint, have been added to the
      model and have been shown to improve treatment times and skin doses by about a
      factor of 2. Several neutron-producing charged particle reactions have been
      examined for BNCS, including the 9Be(p,n) reaction at proton energies of 4 and
      3.7 MeV, the 9Be(d,n) reaction at deuteron energies of 1.5 and 2.6 MeV, and the
      7Li(p,n) reaction at a proton energy of 2.5 MeV. For an accelerator beam current
      of 1 mA and synovial boron uptake of 1000 ppm, the time to deliver a therapy dose
      of 10,000 RBEcGy ranges from 3 to 48 min, depending on the treated joint and the
      neutron producing charged particle reaction. The whole-body effective dose that a
      human would incur during a knee treatment has been estimated to be 3.6 rem or
      0.75 rem, for 1000 ppm or 19,000 ppm synovial boron uptake, respectively,
      although the shielding configuration has not yet been optimized. The Monte Carlo
      design process culminated in the construction, installation, and testing of a
      dedicated BNCS beam line on the high-current tandem electrostatic accelerator at
      the Laboratory for Accelerator Beam Applications at the Massachusetts Institute
      of Technology.

PMID- 10659760
TI  - Reliability of water proton chemical shift temperature calibration for focused
      ultrasound ablation therapy.
AB  - Our purpose in this work was to assess the reliability of the calibration
      coefficient for magnetic resonance water proton chemical shift temperature
      mapping. Over a six month period, the calibration coefficient was measured 15
      times in several different phantoms. A highly linear relationship between water
      proton chemical shift and temperature change was found. The average temperature
      calibration coefficient determined from all studies was 0.009+/-0.001 ppm/degrees
      C. Four of the 15 studies were conducted on the same day using the same phantom.
      The average temperature calibration coefficient of these four studies was
      0.0096+/-0.0001 ppm/degrees C.

PMID- 10659761
TI  - Evaluation of the contribution of capture gamma rays, x-ray leakage, and scatter
      to the photon dose at the maze door for a high energy medical electron
      accelerator using a Monte Carlo particle transport code.
AB  - A Monte Carlo simulation of the photon dose due to scattered x rays, head leakage
      photons, and capture gamma rays in the maze of an 18 MeV accelerator facility was
      carried out. The results of the Monte Carlo simulation were compared with dose
      measurements made in the maze and also with values calculated using an empirical
      equation. Agreement within +/-26% was found among the three techniques used to
      evaluate the capture gamma ray dose. It was found that the empirical equation
      overestimated the scattered x ray plus head leakage photon dose by a factor as
      large as 2.9 as compared to the other methods. It was concluded that the photon
      dose, for mazes greater than 3 m in length, is produced predominately by capture
      gamma rays.

PMID- 10659762
TI  - Estimation of the dose at the maze entrance for x-rays from radiotherapy linear
      accelerators.
AB  - Recent measurements have shown that the NCRP formula to estimate the x radiation
      dose at the maze entrance of high energy radiotherapy rooms underestimates the
      dose by an order of magnitude. In the present work the Monte Carlo Code MCNP was
      used to model a radiotherapy room and investigate the NCRP formula. The dose of
      the scattered photons was calculated for 6-MV and 10-MV x-rays for the following
      situations: primary beam in vacuum, primary beam with air in the room, collimated
      primary beam (by the jaws) with air in the room and primary beam collimated with
      air in the room, and phantom at 100-cm SSD. It was found that for 6-MV x-rays the
      dose, when these materials were present in the beam path, was 1.2, 1.6, 5.3, and
      13.1 x 10(-22) Gy photon(-1), respectively. Therefore the presence of all these
      materials together increased the dose by a factor of 11. The dose due to leakage
      was calculated separately to be 9.1 x 10(-22) Gy photon(-1). This adds another
      factor of 8. The 10-MV results were similar to those at 6 MV. There was good
      agreement between MCNP calculations and the published measurements. The spectrum
      and average energy of scattered photons at different locations in the
      radiotherapy room and the maze were also calculated by MCNP.

PMID- 10659763
TI  - Improved spatial resolution by MOSFET dosimetry of an x-ray microbeam.
AB  - Measurement of the lateral profile of the dose distribution across a narrow x-ray
      microbeam requires a dosimeter with a micron resolution. We investigated the use
      of a MOSFET dosimeter in an "edge-on" orientation with the gate insulating oxide
      layer parallel to the direction of the beam. We compared results using this
      technique to Gafchromic film measurements of a 200 micrometer wide planar x-ray
      microbeam. The microbeam was obtained by using a vernier micrometer-driven
      miniature collimator attached to a Therapax DXT300 x-ray machine operated at 100
      kVp. The "edge-on" application allows utilization of the ultra thin sensitive
      volume of the MOSFET detector. Spatial resolution of both the MOSFET and
      Gafchromic film dosimeters appeared to be of about 1 micrometer. The MOSFET
      dosimeter appeared to provide more uniform dose profiles with the advantage of on
      line measurements.

PMID- 10659764
TI  - Optical density changes of Gafchromic MD-55 film resulting from laser light
      exposure at wavelengths of 671 nm and 633 nm.
AB  - Laser-based scanners provide a sensitive means for measuring optical density (OD)
      of Gafchromic films. Such instruments were reviewed in a recent AAPM report (task
      group 55) which provided recommendations and information on OD measurements
      (effect of wavelength, temperature, etc.). The present article reports that
      variable rate scanners and spot densitometers using laser diodes (671 nm) and
      HeNe lasers (633 nm) can cause polymerization of Gafchromic film. The light
      induced polymerization depends on light power, wavelength, beam spot size, dwell
      time, and prior radiation dose of the film. Measurements were made with a custom
      built scanner that provided accurate control of light power, light polarization,
      dwell time, and film position in relation to the beam focus. The results
      demonstrate that lasers operating with powers of 0.1, 0.5, 1.0, and 1.5 mW
      produce a nonlinear increase in OD of Gafchromic film. The measured change in OD
      after 1 min of exposure ranges from 0.150 to 0.244 for a laser diode operating at
      0.5 and 1.5 mW, respectively. Tables are included that tabulate the increase in
      OD for laser power, dwell time, and prior dose. Laser light induced
      polymerization can have a significant impact on dosimetry measurements acquired
      using these laser-based systems.

PMID- 10659766
TI  - Response to "Comment on 'Dosimetry of interstitial brachytherapy sources:
      recommendation of the AAPM Radiation Therapy Committee Task Group 43' " [Med.
      Phys. 26, 2514 (1999)]. American Association of Physicists in Medicine.

PMID- 10659765
TI  - The finite element model for the propagation of light in scattering media: a
      direct method for domains with nonscattering regions.
AB  - We present a method for handling nonscattering regions within diffusing domains.
      The method develops from an iterative radiosity-diffusion approach using Green's
      functions that was computationally slow. Here we present an improved
      implementation using a finite element method (FEM) that is direct. The
      fundamental idea is to introduce extra equations into the standard diffusion FEM
      to represent nondiffusive light propagation across a nonscattering region. By
      appropriate mesh node ordering the computational time is not much greater than
      for diffusion alone. We compare results from this method with those from a
      discrete ordinate transport code, and with Monte Carlo calculations. The
      agreement is very good, and, in addition, our scheme allows us to easily model
      time-dependent and frequency domain problems.

PMID- 10659767
TI  - Broad-sense sexual selection, sex gene pool evolution, and speciation.
AB  - Studies of sexual selection have traditionally focused on explaining the extreme
      sexual dimorphism in male secondary sexual traits and elaborate mating behaviors
      displayed by males during courtship. In recent years, two aspects of sexual
      selection have received considerable attention in the literature: an extension of
      the sexual selection concept to other traits (i.e., postcopulatory behaviors,
      external and internal genital morphology, gametes, molecules), and alternative
      mechanistic explanations of the sexual selection process (i.e., coevolutionary
      runaway, good-genes, sexual conflicts). This article focuses on the need for an
      extension of sexual selection as a mechanism of change for courtship and (or)
      mating male characters (i.e., narrow-sense sexual selection) to all components of
      sexuality not necessarily related to courtship or mating (i.e., broad-sense
      sexual selection). We bring together evidence from a wide variety of organisms to
      show that sex-related genes evolve at a fast rate, and discuss the potential role
      of broad-sense sexual selection as an alternative to models that limit speciation
      to strict demographic conditions or treat it simply as an epiphenomenon of
      adaptive evolution.

PMID- 10659768
TI  - Molecular analysis of a 21.1-kb fragment of wheat chloroplast DNA bearing RNA
      polymerase subunit (rpo) genes.
AB  - The entire nucleotide sequence of a 21.1-kb fragment of wheat chloroplast (ct)
      DNA was determined. This fragment carries 18 intact genes and parts of two
      additional genes, including the three RNA polymerase genes rpoB, rpoC1, and
      rpoC2. The gene arrangement of this region is conserved in wheat, rice, and
      maize, but not in non-grass species. Comparison of these 20 genes in wheat, rice,
      and maize showed that tRNA genes evolved more slowly than protein-coding genes in
      the chloroplast genome. Intergenic regions evolved much faster than both types of
      genes. Although the 19 genes of wheat, except for orf42, showed high identity to
      those of other plants, there were three novel structural features in the wheat
      rpoC2 gene; a deletion of 81 bp in the middle region, a variable insertion (408
      bp), and a nonsense mutation in the 3' terminal region, resulting in truncation
      of a sequence of ca. 10 amino acids. An intermolecular recombination between the
      stretches of CTTAT and CTTTT was suggested as the mechanism of the 81-bp deletion
      in the wheat rpoC2 gene. Evolutionary distance between the chloroplast genomes of
      wheat and maize was larger than those between wheat and rice and between rice and
      maize.

PMID- 10659769
TI  - Isolation of microsatellite and RAPD markers flanking the Yr15 gene of wheat
      using NILs and bulked segregant analysis.
AB  - Microsatellite and random amplified polymorphic DNA (RAPD) primers were used to
      identify molecular markers linked to the Yr15 gene which confer resistance to
      stripe rust (Puccina striiformis Westend) in wheat. By using near isogenic lines
      (NILs) for the Yr15 gene and a F2 mapping population derived from crosses of
      these lines and phenotyped for resistance, we identified one microsatellite
      marker (GWM33) and one RAPD marker (OPA19(800)) linked to Yr15. Then, bulked
      segregant analysis was used in addition to the NILs to identify RAPD markers
      linked to the target gene. Using this approach, two RAPD markers linked to Yr15
      were identified, one in coupling (UBC199(700)) and one in repulsion phase
      (UBC212(1200)). After MAPMAKER linkage analysis on the F2 population, the two
      closest markers were shown to be linked to Yr15 within a distance of about 12 cM.
      The recombination rates were recalculated using the maximum likelihood technique
      to take into account putative escaped individuals from the stripe rust resistance
      test and obtain unbiased distance estimates. As a result of this study, the
      stripe rust resistance gene Yr15 is surrounded by two flanking PCR markers,
      UBC199(700) and GWM33, at about 5 cM from each side.

PMID- 10659772
TI  - Sequence analysis of a rice BAC covering the syntenous barley Rpg1 region
AB  - In the course of map-based cloning of the barley stem rust resistance gene Rpg1,
      we identified a rice bacterial artificial chromosome (BAC) containing the Rpg1
      flanking markers. Based on the excellent gene order colinearity between barley
      and rice in this region, we expected that this rice BAC would contain the barley
      Rpg1 homologue. In order to identify the putative rice homologue, we sequenced
      ca. 35 kb of the rice BAC at random and then an additional 33 kb of contiguous
      sequence between the two most closely spaced Rpg1 flanking markers. Sequence
      analysis revealed a total of 15 putative genes, 5 within the 33-kb contiguous
      region. A rice Rpg1 homologue was not identified, although a gene encoding a
      hypothetical polypeptide with similarity to a membrane protein could not be
      eliminated as a candidate. Surprisingly, four of the genes identified in the 33
      kb contiguous rice sequence showed a high degree of similarity with genes on
      Arabidopsis chromosome 4. The genome regions harboring these genes showed some
      relatedness, but many rearrangements were also evident. These data suggest that
      some genes have remained linked even over the long evolutionary separation of
      Arabidopsis and rice, as has also been reported for mammals and invertebrates.

PMID- 10659771
TI  - MFASAT: a new alphoid DNA sequence isolated from Macaca fascicularis
      (Cercopithecidae, Primates).
AB  - A new highly repeated DNA fragment isolated from Macaca fascicularis (MFASAT) is
      described. Our findings obtained by sequencing, Southern blot analysis, and
      fluorescent in situ hybridization (FISH) on metaphasic chromosomes strongly
      suggest that MFASAT can be considered as a member of the alphoid DNA family
      characteristic of Old World monkeys. The chromosomal localization of MFASAT,
      obtained by FISH, showed that this alphoid DNA is present in the peri-centromeric
      area of all the chromosomes. MFASAT showed a high degree of conservation when
      compared, by sequence alignment, to other Macaca species and Papio papio as
      expected for species with considerable genome conservation. A low degree of
      homology has been found comparing M. fascicularis alphoid DNA with a more
      distantly related Cercopithecidae species such as Cercopithecus aethiops.

PMID- 10659770
TI  - Microsatellites in the silkworm, Bombyx mori: abundance, polymorphism, and strain
      characterization.
AB  - We have isolated and characterized microsatellites (simple sequence repeat (SSR)
      loci) from the silkworm genome. The screening of a partial genomic library by the
      conventional hybridization method led to the isolation of 28 microsatellites
      harbouring clones. The abundance of (CA)n repeats in the silkworm genome was akin
      to those reported in the other organisms such as honey bee, pig, and human, but
      the (CT)n repeat motif is less common compared to bumble bee and honey bee
      genomes. Detailed analysis of 13 diverse silkworm strains with a representative
      of 15 microsatellite loci revealed a number of alleles ranging from 3 to 17 with
      heterozygosity values of 0.66-0.90. Along with strain-specific microsatellite
      markers, diapause and non-diapause strain-specific alleles were also identified.
      The repeat length did not show any relationship with the degree of polymorphism
      in the present study. The co-dominant inheritance of microsatellite markers was
      demonstrated in F1 offspring. A list of primer sequences that tag each locus is
      provided. The availability of microsatellite markers can be expected to enhance
      the power and resolution of genome analysis in silkworm.

PMID- 10659773
TI  - Sequence and phylogenetic analysis of the SNF4/AMPK gamma subunit gene from
      Drosophila melanogaster.
AB  - To optimize gene expression under different environmental conditions, many
      organisms have evolved systems which can quickly up- and down-regulate the
      activity of other genes. Recently, the SNF1 kinase complex from yeast and the AMP
      activated protein kinase complex from mammals have been shown to represent
      homologous metabolic sensors that are key to regulating energy levels under times
      of metabolic stress. Using heterologous probing, we have cloned the Drosophila
      melanogaster homologue of SNF4, the noncatalytic effector subunit from this
      kinase complex. A sequence corresponding to the partial genomic sequence as well
      as the full-length cDNA was obtained, and shows that the D. melanogaster SNF4 is
      encoded in a 1944-bp cDNA representing a protein of 648 amino acids (aa).
      Southern analysis of Drosophila genomic DNA in concert with a survey of mammalian
      SNF4 ESTs indicates that in metazoans, SNF4 is a duplicated gene, and possibly
      even a larger gene family. We propose that one gene copy codes for a short (330
      aa) protein, whereas the second locus codes for a longer version (<410 aa) that
      is extended at the carboxy terminus, as typified by the Drosophila homologue
      presented here. Phylogenetic analysis of yeast, invertebrate, and multiple
      mammalian isoforms of SNF4 shows that the gene duplication likely occurred early
      in the metazoan lineage, as the protein products of the different loci are
      relatively divergent. When the phylogeny was extended beyond the SNF4 gene
      family, SNF4 shares sequence similarity with other cystathionine-beta-synthase
      domain-containing proteins, including IMP dehydrogenase and a variety of
      uncharacterized Methanococcus proteins.

PMID- 10659775
TI  - Genome size variation in Hordeum spontaneum populations
AB  - Populations of wild barley, Hordeum spontaneum (C. Koch), originating from 10
      ecologically and geographically different sites in Israel, were assessed for
      genome size. Measurements were obtained by flow cytometry using propidium iodide
      staining. Genome sizes ranged from 9.35 to 9.81 pg. Variance analysis indicated a
      significant difference between populations. Genome sizes were positively
      correlated with mean January temperature. Our results corroborate previous
      findings of intraspecific variation in genome size from different plant species.
      The positive correlations between climate and genome size suggest that the latter
      is adaptive and determined by natural selection.

PMID- 10659774
TI  - Within- and between-individual length heterogeneity of the rDNA-IGS in Miscanthus
      sinensis var. glaber (Poaceae): phylogenetic analyses.
AB  - The variability in the intergenic spacer (IGS) region between 17S and 25S rRNA
      genes of ribosomal DNA (rDNA) gene family was surveyed in Miscanthus sinensis
      var. glaber. Length heterogeneity, with sizes from 1782 to 2212 base pairs, of
      the IGS resulted from the variation of copy numbers of the A and B subrepeats.
      These repeated elements were located upstream of the presumptive polymeraseII
      promoter, which was the region corresponding to the nontranscribed spacer (NTS).
      Length heterogeneity was detected both within and between individuals of
      Miscanthus sinensis var. glaber. Neighbor-joining analyses of repetitive A
      elements indicated that both unequal crossing-over and preferential conversion
      may have affected the hot-spot regions of the IGS in concert. Within-individual
      polymorphism and the reconstructed phylogeny suggested that interspecific
      hybridization has also contributed to length heterogeneity.

PMID- 10659776
TI  - Disease resistance gene analogs as candidates for QTLs involved in pepper
      pathogen interactions.
AB  - Whereas resistance genes (R-genes) governing qualitative resistance have been
      isolated and characterized, the biological roles of genes governing quantitative
      resistance (quantitative trait loci, QTLs) are still unknown. We hypothesized
      that genes at QTLs could share homologies with cloned R-genes. We used a PCR
      based approach to isolate R-gene analogs (RGAs) with consensus primers
      corresponding with conserved domains of cloned R-genes: (i) the nucleotide
      binding site (NBS) and hydrophobic domain, and (ii) the kinase domain. PCR
      amplified fragments were sequenced and mapped on a pepper intraspecific map. NBS
      containing sequences of pepper, most similar to the N gene of tobacco, were
      classified into seven families and all mapped in a unique region covering 64 cM
      on the Noir chromosome. Kinase domain containing sequences and cloned R-gene
      homologs (Pto, Fen, Cf-2) were mapped on four different linkage groups. A QTL
      involved in partial resistance to cucumber mosaic virus (CMV) with an additive
      effect was closely linked or allelic to one NBS-type family. QTLs with epistatic
      effects were also detected at several RGA loci. The colocalizations between NBS
      containing sequences and resistance QTLs suggest that the mechanisms of
      qualitative and quantitative resistance may be similar in some cases.

PMID- 10659777
TI  - Development of a CAPS marker for the Pvr4 locus: a tool for pyramiding potyvirus
      resistance genes in pepper.
AB  - The Pvr4 resistance gene in pepper confers a complete resistance to the three
      pathotypes of potato virus Y (PVY) and to pepper mottle virus (PepMoV). In order
      to use this gene in a marker-assisted selection (MAS) program and to permit the
      pyramiding of several potyvirus resistance genes in the same cultivar, tightly
      linked amplified fragment length polymorphism (AFLP) markers were obtained by the
      bulked segregant analysis method. Eight linked AFLP markers were mapped in an
      interval from 2.1 +/- 0.8 to 13.8 +/- 2.9 cM around this locus. The closest
      codominant AFLP marker was converted into a codominant CAPS (cleaved amplified
      polymorphic sequence) marker using data from the alignment of the two allele
      sequences. We have further characterized the relevance of the CAPS marker for MAS
      programs in different pepper breeding lines.

PMID- 10659778
TI  - Geographic dimorphism of the wild silkworm, Bombyx mandarina, in the chromosome
      number and the occurrence of a retroposon-like insertion in the arylphorin gene.
AB  - Individuals of the wild silkworm, Bombyx mandarina, collected in South Korea
      (Taegu City) and Japan (Tsushima Islands and Fukuoka City) had the chromosome
      number of 2n = 54, while those collected in China (Hangzhou City) had the
      chromosome number of 2n = 56. Analysis by PCR (polymerase chain reaction) showed
      that the 66-bp-long retroposon-like insertion known in the arylphorin gene was
      present in the B. mandarina specimens with 2n = 54, but not in those with 2n =
      56. Thus, dimorphism in the chromosome number coincided with the occurrence of
      the insertion. It is likely that the boundary dividing the two geographic B.
      mandarina populations lies somewhere in the northern part of the Korean
      Peninsula.

PMID- 10659780
TI  - Molecular changes at Rrn loci in barley (Hordeum vulgare L.) hybrids with H.
      bulbosum (L.)
AB  - Southern blots of restriction fragments of genomic DNAs from Hordeum vulgare
      (L.), H. bulbosum (L.), and interspecific hybrids and their derivatives were
      hybridized with rDNA probe to identify locus-specific modifications at Rrn loci.
      H. bulbosum rDNA revealed a single EcoRV site per repeat compared with two sites
      in H. vulgare rDNA repeats. H. bulbosum accessions possessed at least two rDNA
      repeat lengths, indicating heterozygosity at the Rrn locus. Hybrids possessed
      both H. vulgare and H. bulbosum rDNA repeats. Two of the hybrid derivatives
      possessed bulbosum-specific Sau3AI and HaeIII rDNA fragments, while amphiploid
      and doubled haploid derivatives lacked H. bulbosum rDNA repeat units and (or)
      fragments. Two hybrid derivatives, one amphiploid and a doubled haploid derived
      from the same parental combination, lacked the vulgare Rrn2-specific 9.0-kb rDNA
      repeat. This is the first conclusive evidence for the elimination of vulgare
      genetic material in vulgare-bulbosum hybrids. The ratios of 9.0- to 9.9-kb
      vulgare repeats and H. vulgare to H. bulbosum rDNA repeats indicate partial loss
      of the vulgare-specific 9.0-kb rDNA repeat among the hybrids. Differences in MboI
      and Sau3AI fragments and the ratios of 9.0 to 9.9 kb vulgare rDNA repeats
      revealed differential methylation at Rrn1 and Rrn2 loci. Hybrids and derivatives
      showed differential distribution of methylation of EcoRI, BglII, and SacI sites
      at the Rrn1 locus. Two of the hybrid derivatives exhibited extensive CpG-biased
      methylation. Data presented here are indicative of the differences in the onset
      of events triggered by the interaction of the component genomes and enabled
      detection of differential methylation among Rrn loci, loss of H. vulgare genetic
      material, and development of doubled haploids with the Rrn1 locus.

PMID- 10659779
TI  - Genomic organization of the 260 kb surrounding the waxy locus in a Japonica rice
AB  - The present study was carried out to characterize the molecular organization in
      the vicinity of the waxy locus in rice. To determine the structural organization
      of the region surrounding waxy, contiguous clones covering a total of 260 kb were
      constructed using a bacterial artificial chromosome (BAC) library from the
      Shimokita variety of Japonica rice. This map also contains 200 overlapping
      subclones, which allowed construction of a fine physical map with a total of 64
      HindIII sites. During the course of constructing the map, we noticed the presence
      of some repeated regions which might be related to transposable elements. We
      divided the 260-kb region into 60 segments (average size of 5.7 kb) to use as
      probes to determine their genomic organization. Hybridization patterns obtained
      by probing with these segments were classified into four types: class 1, a single
      or a few bands without a smeared background; class 2, a single or a few bands
      with a smeared background; class 3, multiple discrete bands without a smeared
      background; and class 4, only a smeared background. These classes constituted
      6.5%, 20.9%, 3.7%, and 68.9% of the 260-kb region, respectively. The distribution
      of each class revealed that repetitive sequences are a major component in this
      region, as expected, and that unique sequence regions were mostly no longer than
      6 kb due to interruption by repetitive sequences. We discuss how the map
      constructed here might be a powerful tool for characterization and comparison of
      the genome structures and the genes around the waxy locus in the Oryza species.

PMID- 10659781
TI  - Genome plasticity during the acquisition of embryogenic competence
AB  - Hypocotyl explants from carrot and other species experience concomitant
      segregation events and differentiation of homeotic structures during the first 20
      days of culture on 2,4-dichlorophenoxyacetic acid (2,4-D). In addition to these
      cyto-morphological changes, significant amounts of nuclear DNA are lost, the
      molecular details of which we investigate in this paper. We have developed a slot
      blot analysis assay to study the DNA content of a series of carrot samples;
      besides the leaves, this survey ranged over different culture timepoints:
      hypocotyls, cell lines, and somatic embryo stages. We carried on to study the
      relationship between this DNA loss and sequence complexity modulation. Results
      from probing sequences that correspond to different degrees of complexity, such
      as medium repetitive and unique sequences as well as sequences belonging to both
      classes (ribosomal cistrons, ubiquitin, actin, and chalcone synthase),
      consistently manifested a reduction in DNA levels during the acquisition of
      embryogenic competence. In some cases, the cultured cells would contain only 10%
      of the gene copies observed in the reference tissues. Modulation trends also
      showed that DNA levels of most sequences recover at the torpedo-plantlet stage,
      which again correlates DNA modulation and the acquisition of embryogenic
      competence. These results suggest that similar DNA variations may occur in plants
      in vivo during meiosis, possibly so that meiotic division may be properly
      completed.

PMID- 10659783
TI  - Mouse genetic model for left-right hand usage: context, direction, norms of
      reaction, and memory.
AB  - Asymmetry of paw usage in the laboratory mouse is an experimental model for left
      right asymmetry of hand usage. Given a set number of reaches into a centrally
      placed food tube (an unbiased or U-world test), individual mice exhibit a number
      of left and right paw reaches that is reliably expressed on retesting. Whereas
      different inbred strains appear to have equal numbers of individual mice with a
      left- or a right-preferred paw after a U-world test, there are significant
      differences among strains in the degree or strength of lateralization of the
      preferred paw. We report here a systematic series of tests of paw usage with
      naive mice and retests of the individuals in test chambers with the food tube
      biased to the left or to the right, contrasting the highly lateralized C57BL/6J
      and the very weakly lateralized (or ambilateral) CDS/Lay inbred strains and their
      (B6 x CDS) F1 generation. The results caused a shift in the paradigm of paw
      usage. There is an unexpected qualitative difference in paw usage between
      C57BL/6J and CDS/Lay. C57BL/6J is random in its left-right paw usage, but it is
      conditioned by the left or right direction of the initial biased-world test and
      by usage. CDS/Lay is constitutively equal-pawed, responds very little to
      direction of the test chamber, and is not conditioned by it. The probability of
      left-paw versus right-paw usage depends on both the genotype and the context of
      the test. The (B6 x CDS) F1 generation suggests that constitutive equal-paw usage
      of CDS/Lay is dominant to experience-conditioned paw usage of C57BL/6J. There is
      also an apparent quantitative difference between the very weakly lateralized
      (ambilateral) preferred paw usage in CDS/Lay and the highly lateralized preferred
      paw usage in C57BL/6J. The difference in degree of lateralization of preferred
      paw usage between the constitutively equal-pawed CDS/Lay strain and (B6 x CDS) F1
      generation must originate from allelic differences at other gene loci between the
      CDS/Lay and C57BL/6J parental strains. The SWV and NOD/Lt strains were also
      assessed in asymmetrical tests because they were known to be weakly lateralized
      and similar to each other in a U-world test and to be significantly different
      from both C57BL/6J and CDS/Lay. SWV is experience-conditioned and weakly
      lateralized; NOD/Lt is constitutively equal-pawed and weakly lateralized. Further
      analysis will determine the genetic cause of the qualitative difference between
      constitutive equal-paw and experience-conditioned paw usage and the genetic cause
      of the quantitative differences in degree of lateralization of the preferred paw
      within each type of paw usage.

PMID- 10659782
TI  - Genetic organization of the ci-M-pan region on chromosome IV in Drosophila
      melanogaster.
AB  - The genes cubitus interruptus (ci), ribosomal protein S3A (RpS3A), and pangolin
      (pan) are localized within 73 kb in the cytological region 101F-102A on
      chromosome IV in Drosophila melanogaster. A region of 13 kb harbours the
      regulatory regions of both ci and pan, transcribed in opposite directions, and a
      1.1-kb gene encoding RpS3A. This dense clustering gives rise to very complicated
      complementation patterns between different alleles in these loci. We investigated
      this region genetically and molecularly by use of an enhancer trap line (IA5),
      where the P-element was found to be inserted into the first intron of pan.
      Screens for imprecise excisions of the P-element were performed, and
      complementations between new and old established mutant lines were investigated.
      We found that when mutated or deleted the RpS3A gene gives rise to a Minute
      phenotype, and we conclude that M(4)101 encodes the ribosomal protein S3A.

PMID- 10659784
TI  - Evolution of a functionally related lactate dehydrogenase and pyruvate
      decarboxylase pseudogene complex in maize.
AB  - A large proportion of the maize genome is repetitive DNA (60-80%) with
      retrotransposons contributing significantly to the repetitive DNA component. The
      majority of retrotransposon DNA is located in intergenic regions and is organized
      in a nested fashion. Analysis of an 8.2-kb segment of maize genomic DNA
      demonstrated the presence of three retrotransposons of different reiteration
      classes in addition to lactate dehydrogenase and pyruvate decarboxylase
      pseudogenes. Both of the pseudogenes were located within a defective
      retrotransposon element (LP-like element) which possessed identical long terminal
      repeats (LTRs) with inverted repeats at each end, a primer binding site, a
      polypurine tract, and generated a 5-bp target site duplication. A model
      describing the events leading to the formation of the LP-like element is
      proposed.

PMID- 10659785
TI  - Construction and characterization of a bacterial artificial chromosome (BAC)
      library for the A genome of wheat.
AB  - A genomic bacterial artificial chromosome (BAC) library of the A genome of wheat
      has been constructed. Triticum monococcum accession DV92 was selected for this
      purpose because it is a cultivated diploid wheat and one of the parental lines
      used in the construction of a saturated genetic map. Leaves from this accession
      were used to isolate high-molecular-weight DNA from nuclei. This DNA was
      partially digested with restriction enzyme Hind III, subjected to double size
      selection, electroeluted and cloned into the pINDIGO451 BAC vector. The library
      consists of 276,480 clones with an average insert size of 115 kb. Excluding the
      1.33% of empty clones and 0.14% of clones with chloroplast DNA, the coverage of
      this library is 5.6 genome equivalents. With this genome coverage the probability
      of having any DNA sequence represented in this library is higher than 99.6%.
      Clones were sorted in 720,384-well plates and blotted onto 15 high-density
      filters. High-density filters were screened with several single or low-copy
      clones and five positive BAC clones were selected for further analysis. Since
      most of the T. monococcum BAC ends included repetitive sequences, a modification
      was introduced into the classical end-isolation procedure to select low copy
      sequences for chromosome walking.

PMID- 10659787
TI  - Identification of wheat and tritordeum chromosomes by genomic in situ
      hybridization using total Hordeum chilense DNA as probe
AB  - Total genomic Hordeum chilense DNA probe was hybridized to somatic chromosome
      spreads of Triticum aestivum 'Chinese Spring' and to four advanced tritordeum
      lines, the latter being the fertile amphiploid between H. chilense and durum
      wheat (2n = 6x = 42, AABBH(ch)H(ch)). The probe hybridized strongly to the B
      genome chromosomes and to one or two bands on the A-genome chromosomes present in
      both wheat and tritordeum alloploids. Bands on chromosomes 1D, 2D, and 7D from
      hexaploid wheat were also detected. Genomic H. chilense DNA probe identified 16
      chromosome pairs of the chromosome complement of hexaploid wheat and all A- and B
      genome chromosomes present in the tritordeum amphiploids. The in situ
      hybridization patterns observed correspond to those previously reported in wheat
      by both N-banding and in situ hybridization with the GAA-satellite sequence
      (Pedersen and Langridge 1997), allowing the identification of these chromosomes.
      Variation among the tritordeum amphiploids for hybridization sites on chromosomes
      2A, 4A, 6A, 7A, 4B, 5B, and 7B was observed. Despite of this polymorphism, all
      lines shared the general banding pattern. When used as probe, total H. chilense
      genomic DNA labeled the H. chilense chromosomes over their lengths allowing the
      identification of 14 H. chilense chromosomes present in the tritordeum
      amphiploids. In addition, chromosome-specific telomeric, interstial, and
      centromeric hybridization sites were observed. These hybridization sites coincide
      with N-banded regions in H. chilense allowing the identification of the
      individual H. chilense chromosomes in one of the amphiploid. The N-banded
      karyotypes of H. chilense (accessions H1 and H7) are presented.

PMID- 10659788
TI  - Genomic relationships between maize and its wild relatives
AB  - Recent molecular studies confirm the long-held theory that maize is a tetraploid,
      but the identity of the ancestral diploid species remains an enigma. The various
      hypotheses were investigated using genomic in situ hybridization (GISH). Total
      genomic DNA from 10 wild relatives of maize were used as probes onto maize
      chromosomes to see if this could identify the ancestral genome donors in maize.
      While none of the taxa hybridized to a subset of chromosomes, genomic DNA from
      Zea mays ssp. mexicana, Z. mays ssp. parviglumis, Z. diploperennis, Tripsacum
      dactyloides and Coix lacryma-jobi all showed a similar hybridization pattern
      consisting of a dispersed signal over all maize chromosomes. Moreover, the first
      four species also showed highly localized subtelomeric signal on the long arms of
      maize chromosomes 5, 6, 7, and 8. In contrast, three Sorghum species tested (S.
      bicolor, S. halapense, and S. versicolor) only showed hybridization at the
      nucleolar organizer region. In light of recent data on retrotransposon occurrence
      in maize, the results may provide insights into the timing of speciation of Zea,
      Tripsacum, and Coix. Data obtained from the tetraploid Z. perennis strongly
      supported its taxonomic separation from the diploid Z. diploperennis.

PMID- 10659786
TI  - A genetic and molecular characterization of the garnet gene of Drosophila
      melanogaster.
AB  - The garnet gene was one of the first genes to be identified in Drosophila
      melanogaster. Mutations in the garnet gene affect both of the biochemically
      distinct types of pigments in the eye and disrupt pigmentation of other organs.
      As an initial step in the analysis of this gene, we have analyzed the
      pigmentation defects in several of the garnet alleles. We have also cloned the
      gene and examined its expression in various tissues and at different stages of
      development. The garnet gene is expressed throughout development and in all
      tissues examined. Structurally related sequences can be detected in a variety of
      other eukaryotes. The predicted protein sequence of the garnet product resembles
      clathrin and nonclathrin adaptin proteins and is highly similar to the delta
      subunit of the newly isolated mammalian AP-3 adaptin complex, which is associated
      with the trans-Golgi network and endosomes. This suggests that garnet encodes a
      protein that acts in the intracellular sorting and trafficking of vesicles from
      the trans-Golgi network to endosomes, and related specialized organelles such as
      the pigment granule. This finding provides an explanation for the phenotype of
      garnet mutations and predicts that other Drosophila eye-colour genes will be a
      rich resource for the genetic dissection of intracellular vesicle transport.

PMID- 10659789
TI  - Random amplified polymorphic DNA analysis, genome size, and genomic in situ
      hybridization of triploid viviparous onions
AB  - Triploid viviparous onions (Allium cepa L. var. viviparum Metzg. (ALEF.), auct.),
      (2n = 3x = 24), are known in some countries only as a rare relic crop, while in
      other parts of the world they are still traditionally or even commercially
      cultivated. Results indicating an identical random amplified polymorphic DNA
      (RAPD) banding pattern and the same DNA content (2C = 43.4 pg) establish the high
      genetic similarity and the unique origin of the Croatian clone Ljutika and the
      Indian clone Pran. In order to determine the parental Allium species of these
      natural triploid hybrids, genomic fluorescent in situ hybridization (GISH) was
      applied. Biotinylated genomic DNAs from six diploid Allium species (A. cepa L.,
      A. fistulosum L., A. roylei Stearn, A. vavilovii M. Pop. et Vved., A. galanthum
      Kar. et Kir., A. oschaninii O. Fedtsch.) were used as probes in this study. While
      probes obtained from genomic DNA of A. cepa, A. vavilovii, and A. roylei
      hybridized to somatic chromosomes of Ljutika probes from A. fistulosum, A.
      galanthum, and A. oschaninii did not. The DNA probes of A. cepa and A. roylei
      each completely or predominantly labelled one genome (eight chromosomes). A few
      chromosomes, the markers of the triploid karyotype, were not completely labelled
      by any probe applied. Our GISH results indicate that triploid viviparous onions
      might possess a complex triparental genome organization.

PMID- 10659790
TI  - Genomic in situ hybridization analysis of Thinopyrum chromatin in a wheat-Th.
      intermedium partial amphiploid and six derived chromosome addition lines
AB  - The genomic origin of alien chromosomes present in a wheat-Thinopyrum intermedium
      partial amphiploid TAF46 (2n = 8x = 56) and six derived chromosome addition lines
      were analyzed by genomic in situ hybridization (GISH) using S genomic DNA from
      Pseudoroegneria strigosa (2n = 2x = 14, SS) as a probe. The GISH analysis clearly
      showed that the chromosome complement of the partial amphiploid TAF46 consists of
      an entire wheat genome plus one synthetic genome consisting of a mixture of six S
      genome chromosomes and eight J (=E) genome chromosomes derived from Th.
      intermedium (2n = 6x = 42, JJJ(s)J(s)SS). There were no Js genome chromosomes
      present in TAF46. The J genome chromosomes present in TAF46 displayed a unique
      GISH hybridization pattern with the S genomic DNA probe, in which S genome DNA
      strongly hybridized at the terminal regions and weakly hybridized over the
      remaining parts of the chromosomes. This provides a diagnostic marker for
      distinguishing J genome chromosomes from Js or S genome or wheat ABD genome
      chromosomes. The genomic origin of the alien chromosomes present in the six
      derived chromosome addition lines were identified by their characteristic GISH
      hybridization patterns with S genomic DNA probe. GISH analysis showed that
      addition lines L1, L2, L3, and L5 carried one pair of J genome chromosomes, while
      addition lines L4 and L7 each carried one pair of S genome chromosomes. GISH
      patterns detected by the S genome probe on addition line of L1 were identical to
      those of the J genome chromosomes present in the partial amphiploid TAF46,
      suggesting that these chromosomes were not structurally altered when they were
      transferred from TAF46 to addition lines.

PMID- 10659792
TI  - Variations in the maize Ac transposase transcript level and the Ds excision
      frequency in transgenic wheat callus lines
AB  - To investigate the excision of a maize transposable element in wheat cells,
      plasmid DNAs containing a Dissociation (Ds) element located between a rice actin
      1 gene promoter and a beta-glucuronidase (GUS) gene (gus) were introduced into
      wheat callus lines by microprojectile bombardment, and transient GUS expression
      was assayed. The gus-expressing cells after Ds excision were detected only when
      the Activator (Ac) transposase gene was co-transformed. To further examine a
      relationship between the amount of Ac mRNA and the Ds excision frequency, the Ds
      containing plasmids were introduced into 15 independent transgenic callus lines
      transformed with the Ac transposase gene. Ten lines expressed the Ac transposase
      gene under the control of either the cauliflower mosaic virus 35S promoter or the
      Ac native promoter. The gus gene expression that indicated the Ds excision was
      observed only in the transgenic callus lines stably expressing the Ac transposase
      gene. The number of blue spots reflecting the frequency of Ds excision was
      variable among them. Northern-blot analysis also showed a large variability in
      the amount of Ac transposase transcripts among the lines. It was however noted
      that the excision frequency was decreased at a high level of the Ac transposase
      transcripts, supporting the hypothesis that Ds excision is inhibited above a
      certain level of the Ac transposase as observed in maize and transgenic tobacco.

PMID- 10659791
TI  - Quantitative karyotyping and dual-color FISH mapping of 5S and 18S-25S rDNA
      probes in the cultivated Phaseolus species (Leguminosae)
AB  - Double-color fluorescence in situ hybridization (FISH) followed by DAPI
      counterstaining allowed the chromosomal assignment of 5S and 18S-25S rRNA genes
      in the four cultivated Phaseolus Species; P. vulgaris, P. coccineus, P.
      acutifolius, and P. lunatus (all: 2n = 2x = 22). The rRNA gene loci display
      variation between species as reflected in differences of signal size and (or)
      number. From one to three pairs of 5S sites and one to seven pairs of 18S-25S
      sites were found in the diploid complements of the four taxa studied.
      Intraspecific variation was studied in P. vulgaris, and it is shown that the
      number of 18S-25S rDNA sites differs between cultivars. Cytogenetic mapping was
      complemented by karyotype analyses. Each of the four cultivated Phaseolus species
      exhibits a characteristic heterochromatin endowment, with P. acutifolius var.
      latifolius having the highest amount of C-band material. Quantitative karyotyping
      in combination with cytogenetic mapping allowed the identification of homeologous
      chromosomes in the different species.

PMID- 10659793
TI  - The Ha locus of wheat: identification of a polymorphic region for tracing grain
      hardness in crosses.
AB  - The grain softness proteins or friabilins are known to be composed of three main
      components: puroindoline a, puroindoline b, and GSP-1. cDNAs for GSP-1 have
      previously been mapped to group-5 chromosomes and their location on chromosome 5D
      is closely linked to the grain hardness (Ha) locus of hexaploid wheat. A genomic
      DNA clone containing the GSP-1 gene (wGSP1-A1) from hexaploid wheat has been
      identified by fluorescent in situ hybridization as having originated from the
      distal end of the short arm of chromosome 5A. A genomic clone containing the gene
      (wGSP1-D1) was also isolated from Aegilops tauschii, the donor of the D genome to
      bread wheat. There are no introns in the GSP-1 genes, and there is high sequence
      identity between wGSP1-A1 and wGSP1-D1 up to 1 kb 5' and 300 bp 3' to wGSP1-D1.
      However, regions further upstream and downstream of wGSP1-D1 share no significant
      sequence identity to corresponding sequences in wGSP1-A1. These regions therefore
      identified potentially valuable sequences for tracing the Ha locus through
      assaying polymorphic DNA sequences. The sequence from 300 to 500 bp 3' to wGSP1
      D1 (wGSP1-D13) was mapped to the Ha locus in a mapping population. wGSP1-D13 was
      also tightly linked to genes for puroindoline a and puroindoline b which have
      been previously mapped to be at the Ha locus. In addition wGSP1-D13 was used to
      detect RFLPs between near isogenic soft and hard Falcon lines and in a random
      selection of soft and hard wheats.

PMID- 10659794
TI  - Distribution of TGG repeat-related sequences in 'Trovita' orange (Citrus sinensis
      Osbeck) chromosomes
AB  - The clone pAS"C" is a sequence related to M13 phage minisatellite sequences
      isolated from bovine DNA. It contains TGG repeats, and related sequences are
      abundant in the Citrus genome. Fluorescent in situ hybridization (FISH) signals
      detected using this clone as a probe showed that the TGG repeat-related sequences
      are found on all the Citrus chromosomes, but are not found in Citrus-specific
      CMA+/DAPI- heterochromatic regions located at the extreme ends of each
      chromosome. These data suggest that the TGG-repeated sequences are evolutionarily
      conserved and that the CMA+/DAPI- heterochromatic regions were added to the
      chromosome ends at a recent stage in Citrus evolution.

PMID- 10659795
TI  - Chromosomal location and genetic mapping of the mismatch repair gene homologs
      MSH2, MSH3, and MSH6 in rye and wheat
AB  - The efficiency of homeologous recombination is influenced by mismatch repair
      genes in bacteria, yeast, and mammals. To elucidate a possible role of these
      genes in homeologous pairing and cross-compatibility in plants, gene probes of
      wheat (Triticum aestivum) specific for the mismatch repair gene homologues MSH2,
      MSH3, and MSH6 were used to map them to their genomic positions in rye (Secale
      cereale). Whereas MSH2 was mapped to the short arm of chromosome 1R, MSH3 was
      mapped to the long arm of chromosome 2R and MSH6 to the long arm of chromosome
      5R. Southern blots with nullisomic-tetrasomic (NT) lines of wheat indicated the
      presence of the sequences on the respective homeologous group of wheat
      chromosomes. Additionally, an MSH6-specific homologue could also be detected on
      homoeologous group 3 of wheat. However, in the well-known, highly homoeologous
      pairing wheat mutant ph1b the MSH6-specific sequence is not within the deleted
      part of chromosome 5BL, indicating that the pairing phenotype is not due to a
      loss of one of the mismatch repair genes tested.

PMID- 10659796
TI  - Tandem repetitive Afa-family sequences from Leymus racemosus and Psathyrostachys
      juncea (Poaceae)
AB  - Tandem repetitive Afa-family sequences of 340 bp are known to occur in wheat and
      related species of tribe Triticeae. We isolated six and three Afa-family
      sequences from Leymus racemosus and Psathyrostachys juncea, respectively, both of
      which are perennial species. The sequences account for 0.5% and 0.2% of L.
      racemosus and P. juncea genomes, respectively, and using in situ hybridization
      were located in subtelomeric and interstitial regions of L. racemosus
      chromosomes. These sequences are clustered with those of Elymus trachycaulus in
      the phylogenetic tree. Our findings indicate that the Afa-family sequences have
      been amplified at least twice in the lineage of L. racemosus, P. juncea, and E.
      trachycaulus.

PMID- 10659797
TI  - New discovery equals change in clinical practice.

PMID- 10659798
TI  - Issues of importance reported by persons with lower limb amputations and
      prostheses.
AB  - The purpose of this paper is to report prosthesis-related issues of importance
      that were identified by a diverse group of persons living with lower limb
      amputations (LLA) and prostheses. These perceptions and themes validate some old
      assumptions and challenge others, report both common and unusual experiences, and
      indirectly identify the information level of our respondents concerning
      prostheses. Persons with LLA were identified from computerized rosters at a level
      one regional trauma center and at the VA Puget Sound Health Care System-Seattle,
      Division. Inclusion criteria specified that respondents were to: 1) be one or
      more years post-unilateral amputation at the Syme's level (ankle disarticulation)
      or higher, 2) use their prosthesis at least 5 days a week, 3) read English, and
      4) be able to provide informed consent. Respondents completed the Prosthesis
      Evaluation Questionnaire-field version (PEQ) and the standard form (SF)-36, a
      health status measure. Of 114 persons who agreed to participate, 92 (85% male,
      mean age 55 years) responded to the questionnaire and graded the personal
      importance of various characteristics and qualities of their prosthesis. The
      number of years since their last amputation ranged from 1 to 53 years. Four
      Themes of Interest were identified from responses to open-ended questions about
      living with a prosthesis. These themes included the fit of the socket with the
      residual limb, aspects of the mechanical functioning of the prosthesis, other
      nonmechanical qualities, and advice about adaptation to life with a prosthesis
      with support from others. Future research is recommended to adjust aspects of the
      fit of the prosthesis with the residual limb. Implementing periodic check-up
      visits could uncover problems and eliminate unnecessary suffering.

PMID- 10659799
TI  - Prosthetic loading during kneeling of persons with transfemoral amputation.
AB  - Observations in the field of lower limb prosthetic rehabilitation have shown that
      several transfemoral prostheses show signs of wear on some components of the knee
      unit. This is thought to be a result of severe loading developed during
      activities associated with kneeling. Some prostheses may have failed due to
      repetitive action of such loading. In order to determine the nature and magnitude
      of the loads developed during kneeling by persons with transfemoral amputation,
      and to investigate the influence of various prosthetic parameters, an analysis of
      the results of 162 tests in prosthetic knee hyperflexion was undertaken. The
      services of four males with amputation were enlisted. The measurements involved
      simultaneous use of two Kistler force platforms, a six-channel strain gauge
      transducer mounted on the prosthetic shank, and a data acquisition system. The
      critical loads for this configuration were found to be the shear force on the
      knee hinge, the shear force imposed by the knee chassis on the shin, and the
      bending moment tending to hyperflex the knee. These loads ranged from 0.6 to 6.2
      kN, 0.9 to 6.7 kN, and from 18.3 to 155.7 Nm, respectively. To achieve a
      comfortable kneeling position, some prostheses permit foot rotation about the
      pylon axis of 90 infinity to allow the shank to be approximately parallel to the
      ground. Tests were also conducted with the prostheses in this configuration and
      the most influential prosthetic parameter was found to be the external rotation
      of the foot (toe-out angle). During kneeling, it was found that the loading was
      dependent upon the position of the torso relative to the prosthesis, but loads
      were much higher than those developed during level walking.

PMID- 10659801
TI  - Gait characteristics of individuals with multiple sclerosis before and after a 6
      month aerobic training program.
AB  - Individuals who have multiple sclerosis (MS) typically experience problems with
      physical activities such as walking, resulting from the combined effects of
      skeletal muscle weakness, sensory disturbances, spasticity, gait ataxia, and
      reduction in aerobic capacity. The aim of this study was to determine whether a 6
      mo exercise program designed for aerobic conditioning might also affect gait
      abnormalities in individuals with MS. Subjects included 18 individuals with MS
      who presented a range of disability. Passive range of motion (PROM) in the lower
      limbs was measured and gait analyzed before and after exercise conditioning.
      Three-dimensional kinematics, ground reaction forces (GRF), and electromyographic
      information were acquired as subjects walked at self-selected velocities. Hip
      PROM increased following conditioning. Mean walking velocity, cadence, and
      posterior shear GRF (push-off force) decreased. During walking, maximum ankle
      dorsiflexion decreased and ankle plantarflexion increased. Total knee
      flexion/extension range during the walking cycle decreased slightly as did
      maximum hip extension. Results suggest this 6-mo training program had minimal
      effect on gait abnormalities.

PMID- 10659800
TI  - Effects of age and functional limitation on leg joint power and work during
      stance phase of gait.
AB  - It is commonly accepted that leg muscle power is an important component of
      functional ability. Paced gait data for 20 healthy young women (27+/-4.2 yrs), 16
      healthy old women (72.5+/-5.6 yrs), and 24 functionally limited old women (73.5+/
      7.2 yrs) were analyzed during stance phase to investigate whether power
      calculations from motion analysis data were sensitive to impairments beyond the
      differences expected with aging. Healthy women included in the study functioned
      at a high/moderate level with no limitations, while functionally limited women
      functioned at a much lower level and exhibited one or more functional limitations
      as defined by the SF36 physical function scale. Single support time (SSUP),
      stance duration (SDUR), average forward center of gravity velocity (GVEL), and
      three-dimensional net power and work of the ankle (APOW/AWRK), knee (KPOW/KWRK),
      and hip (HPOW/ HWRK) were computed for the stance limb during the stance phase of
      gait. Univariate ANCOVA was used to examine which variables were most sensitive
      to functional limitations. We found that SDUR and SSUP were not different among
      the three groups when controlling for height and weight. Although differences in
      CG velocity between healthy and functionally limited old women were not
      significant, both elderly groups translated their CG slower than did the younger
      women (p<0.0001) when walking at the same cadence. Controlling for CG velocity
      eliminated all significant differences among groups except for APOW and AWRK in
      late stance phase between healthy and functionally limited elderly women
      (p<0.003). These results suggest that decreased ankle plantar-flexor power in
      late stance of gait may be an impairment-related characteristic more than an age
      related characteristic.

PMID- 10659803
TI  - Transcutaneous oxygen tension in subjects with tetraplegia with and without
      pressure ulcers: a preliminary report.
AB  - This study compared transcutaneous oxygen tension (TcpO2) in subjects with
      paraplegia and pressure ulcers (PU), those with paraplegia and no pressure ulcer
      (NPU), and ambulatory controls. TcpO2 was measured using a surface-electrode
      monitoring system, recorded at 1-min intervals for 5 min and averaged. Mean TcpO2
      was significantly lower in the PU than the NPU and control groups (23.53+/-1.83
      vs. 58.93+/-2.53 and 79.70+/-6.77 mmHg, respectively, p<0.05). In a PU subgroup
      (n=4) mean TcpO2 of the pressure ulcer and nonpressure ulcer sides (trochanter or
      ischium) were significantly different (21.05+/-2.98 vs. 67.65+/-2.11 mmHg,
      respectively, p<0.001). Additionally, the NPU group demonstrated significantly
      lower TcpO2 than the controls. PUs had a greater reduction in TcpO2 levels
      relative to controls than NPUs. No association was found between TcpO2 and
      duration of injury, completeness of lesion, or smoking history. Thus, TcpO2 may
      be an effective method to identify individuals who are susceptible to pressure
      ulcers. The further attenuation of TcpO2 observed in the PU group may be useful
      to help predict whether ulcers will heal with local care or will require
      additional treatment.

PMID- 10659802
TI  - Temperature effects on surface pressure-induced changes in rat skin perfusion:
      implications in pressure ulcer development.
AB  - The effect of varying local skin temperature on surface pressure-induced changes
      in skin perfusion and deformation was determined in hairless fuzzy rats (13.5+/-3
      mo, 474+/-25 g). Skin surface pressure was applied by a computer-controlled
      plunger with corresponding skin deformation measured by a linear variable
      differential transformer while a laser Doppler flowmeter measured skin perfusion.
      In Protocol I, skin surface perfusion was measured without heating (control, T=28
      degrees C), with heating (T=36 degrees C), for control (probe just touching skin,
      3.7 mmHg), and at two different skin surface pressures, 18 mmHg and 73 mmHg.
      Heating caused perfusion to increase at control and 18 mmHg pressure, but not at
      73 mmHg. In Protocol II, skin perfusion was measured with and without heating as
      in Protocol I, but this time skin surface pressure was increased from 3.7 to 62
      mmHg in increments of 3.7 mmHg. For unheated skin, perfusion increased as skin
      surface pressure increased from 3.7 to 18 mmHg. Further increases in surface
      pressure caused a decrease in perfusion until zero perfusion was reached for
      pressures over 55 mmHg. Heating increased skin perfusion for surface pressures
      from 3.7 to 18 mmHg, but not for pressures greater than 18 mmHg. After the
      release of surface pressure, the reactive hyperemia peak of perfusion increased
      with heating. In Protocol III, where skin deformation (creep and relaxation) was
      measured during the application of 3.7 and 18 mmHg, heating caused the tissue to
      be stiffer, allowing less deformation. It was found that for surface pressures
      below 18 mmHg, increasing skin temperature significantly increased skin perfusion
      and tissue stiffness. The clinical significance of these findings may have
      relevance in evaluating temperature and pressure effects on skin blood flow and
      deformation as well as the efficacy of using temperature as a therapeutic
      modality in the treatment of pressure ulcers.

PMID- 10659804
TI  - Knee kinetics during functional electrical stimulation induced cycling in
      subjects with spinal cord injury: a preliminary study.
AB  - The purpose of this preliminary study was to describe pedal effectiveness
      parameters and knee-joint reaction forces generated by subjects with chronic
      spinal cord injury (SCI) during functional electrical stimulation (FES)-induced
      bicycling. Three male subjects (age 33-36 years old), who were post-traumatic SCI
      (ASIA-modified level A, level T4-C5) and enrolled in an FES rehabilitation
      program, signed informed consent forms and participated in this study. Kinematic
      data and pedal forces during bicycling were collected and effective force, knee
      joint reaction forces, knee generalized muscle moments, and knee-joint power and
      work were calculated. There were three critical findings of this study: 1)
      pedaling effectiveness was severely compromised in this subject population as
      indicated by a lack of overall positive crank work; 2) knee-joint kinetics were
      similar in magnitude to data reported for unimpaired individuals pedaling at
      higher rates and workloads, suggesting excessive knee-joint loading for subjects
      with SCI; and 3) shear reaction forces and muscle moments were opposite in
      direction to data reported for unimpaired individuals, revealing an energetically
      unfavorable knee stabilizing mechanism. The critical findings of this study
      suggest that knee-joint kinetics may be large enough to produce a fracture in the
      compromised lower limbs of individuals with SCI.

PMID- 10659805
TI  - The robotized workstation "MASTER" for users with tetraplegia: description and
      evaluation.
AB  - The rehabilitation robotics MASTER program was developed by the French Atomic
      Energy Commission (CEA) and evaluated by the APPROCHE Rehabilitation centers. The
      aim of this program is to increase the autonomy and quality of life of persons
      with tetraplegia in domestic and vocational environments. Taking advantage of its
      experience in nuclear robotics, the CEA has supported studies dealing with the
      use of such technical aids in the medical area since 1975 with the SPARTACUS
      project, followed by MASTER 10 years later, and its European extension in the
      framework of the TIDE/RAID program. The present system is composed of a fixed
      robotized workstation that includes a six-axis SCARA robot mounted on a rail to
      allow horizontal movement and is equipped with tools for various tasks. The
      Operator Interface (OI) has been carefully adapted to the most severe
      tetraplegia. Results are given following a 2-year evaluation in real-life
      situations.

PMID- 10659806
TI  - Multiresolutional modification of speech signals for listeners with hearing
      impairment.
AB  - A new method, the multiresolutional modification algorithm (MMA), which modifies
      speech signals in frequency and time domains, is proposed for listeners with
      hearing impairment and early clinical results are reported. Unlike other methods,
      this algorithm modifies the wavelet coefficients of the speech signal in order to
      obtain a modified version of the original signal instead of modifying the speech
      waveform itself. The speech signal is first divided into subbands using an 11
      level quadrature mirror filter (QMF) bank. These subbands are then modified using
      the modification algorithm. Finally, the inverse Wavelet transform is applied to
      these modified subband coefficients in order to reconstruct a modified version of
      the input signal. The efficacy of the MMA was evaluated using subjects with
      hearing impairment and subjects with no such impairment. Listening tests showed
      that the proposed algorithm increases the quality and intelligibility of the
      modified speech over the well-known modification algorithms.

PMID- 10659807
TI  - Constraint-Induced Movement Therapy: a new family of techniques with broad
      application to physical rehabilitation--a clinical review.
AB  - A new family of rehabilitation techniques, termed Constraint-Induced Movement
      Therapy or CI Therapy, has been developed that controlled experiments have shown
      is effective in producing large improvements in limb use in the real-world
      environment after cerebrovascular accident (CVA). The signature therapy involves
      constraining movements of the less-affected arm with a sling for 90% of waking
      hours for 2 weeks, while intensively training use of the more-affected arm. The
      common therapeutic factor in all CI Therapy techniques would appear to be
      inducing concentrated, repetitive practice of use of the more-affected limb. A
      number of neuroimaging and transcranial magnetic stimulation studies have shown
      that the massed practice of CI Therapy produces a massive use-dependent cortical
      reorganization that increases the area of cortex involved in the innervation of
      movement of the more-affected limb. The CI Therapy approach has been used
      successfully to date for the upper limb of patients with chronic and subacute CVA
      and patients with chronic traumatic brain injury and for the lower limb of
      patients with CVA, incomplete spinal cord injury, and fractured hip. The approach
      has recently been extended to focal hand dystonia of musicians and possibly
      phantom limb pain.

PMID- 10659808
TI  - Three-dimensional foot modeling and analysis of stresses in normal and early
      stage Hansen's disease with muscle paralysis.
AB  - The models of the foot available in the literature are either two- or three
      dimensional (3-D), representing a part of the foot without considering different
      segments of bones, cartilages, ligaments, and important muscles. Hence, there is
      a need to develop a 3-D model with sufficient details. In this paper, a 3-D, two
      arch model of the foot is developed, taking foot geometry from the X-rays of
      nondisabled controls and a Hansen's disease (HD) subject, and taking into
      consideration bones, cartilages, ligaments, important muscle forces, and foot
      sole soft tissue. The stress analysis is carried out by finite element (FE)
      technique using NISA software for the foot models, simulating quasi-static
      walking phases of heel-strike, midstance, and push-off. The analysis shows that
      the highest stresses occur during push-off phase in the dorsal central part of
      the lateral and medial metatarsals, the dorsal junction of the calcaneus, and the
      cuboid and plantar central part of the lateral metatarsals in the foot. The
      stresses in push-off phase in critical tarsal bone regions, for the early stage
      of HD with muscle paralysis, increase by 25-50% as compared with the control foot
      model. The model calculated stress results at the plantar surfaces are of the
      same order of magnitude as the measured foot pressures (0.2-0.5 MPa). The high
      stress concentration areas in the foot bones indicated above are of great
      importance, since it is found from clinical reports that in some subjects with
      pathogenic decrease in the mechanical strength of the bone from HD, these areas
      of bone are disintegrated. Therefore, this investigation could possibly provide
      an insight into the factors contributing to disintegration of tarsal bones in HD.

PMID- 10659810
TI  - In praise of open software.

PMID- 10659811
TI  - A step up for a few postdocs.

PMID- 10659809
TI  - New on-line parameters for analysis of dynamic foot pressures in neuropathic feet
      of Hansen's disease subjects.
AB  - Pressures on the foot during walking are affected by the weight of the person and
      the walking velocity. It is also found that both the magnitude and duration of
      the dynamic foot pressures are important in ulcer formation in the neuropathic
      feet of persons with Hansen's disease (HD). Therefore, new parameters, Normalized
      Peak Pressure (NPP) and Pressure Contact Ratio (PCR), are calculated from dynamic
      foot pressure data in 10 defined areas of the feet of 52 nonimpaired controls and
      108 persons with HD with different pathologies, using a long barograph that could
      accommodate at least two foot prints in one walking cycle. Statistical study of
      these new parameters, for various classes of HD subjects, shows significantly
      different mean values in the foot areas and hence could aid the clinician in
      better diagnosis and therapy planning. The second part of the article deals with
      on-line calculations and gray scale display of these parameter transforms for all
      the points on the plantar surfaces of both feet in a way that could help the
      clinician in quick analysis and better management and care of neuropathic feet.

PMID- 10659813
TI  - Merger of Glaxo Wellcome and SmithKline Beecham creates pharmaceutical giant.

PMID- 10659812
TI  - Celera genome licensing terms spark concerns over 'monopoly'.

PMID- 10659814
TI  - NASA ponders termination of gamma-ray observatory

PMID- 10659815
TI  - Global-warming sceptics left out in the cold

PMID- 10659816
TI  - DIY microarrayers promise DNA chips with everything.

PMID- 10659817
TI  - Dutch institute forced to respond to crisis in recruitment of postdoctoral
      researchers.

PMID- 10659818
TI  - Appointment of UK food standards chief under fire.

PMID- 10659819
TI  - Mouse geneticists call for unified rules of exchange.

PMID- 10659820
TI  - NIH under fire over gene-therapy trials...

PMID- 10659822
TI  - Local data are vital to worldwide conservation.

PMID- 10659821
TI  - As panel seeks help for trial host nations.

PMID- 10659823
TI  - There's a place for the theory of everything

PMID- 10659824
TI  - ECT damage is easy to find if you look for it.

PMID- 10659825
TI  - Full effects of oil rigs on corals are not yet known.

PMID- 10659826
TI  - Cover adds fuel to the fire in evolution battle.

PMID- 10659827
TI  - Seeking the great transition.

PMID- 10659828
TI  - Tycho and the ton of gold

PMID- 10659829
TI  - Cognitive ability and the light bulb

PMID- 10659830
TI  - A central control for cell growth.

PMID- 10659831
TI  - Engineering decoherence

PMID- 10659832
TI  - Neurobiology. Finding the lost target.

PMID- 10659833
TI  - Better budgets for methyl halides?

PMID- 10659834
TI  - Evolutionary biology. Protamine wars.

PMID- 10659835
TI  - Ultrasonic hearing in nocturnal butterflies.

PMID- 10659836
TI  - Atomic structure of the quasicrystal Al72Ni20Co8

PMID- 10659837
TI  - Circadian clocks limited by noise.

PMID- 10659838
TI  - Decoherence of quantum superpositions through coupling to engineered reservoirs
AB  - The theory of quantum mechanics applies to closed systems. In such ideal
      situations, a single atom can, for example, exist simultaneously in a
      superposition of two different spatial locations. In contrast, real systems
      always interact with their environment, with the consequence that macroscopic
      quantum superpositions (as illustrated by the 'Schrodinger's cat' thought
      experiment) are not observed. Moreover, macroscopic superpositions decay so
      quickly that even the dynamics of decoherence cannot be observed. However,
      mesoscopic systems offer the possibility of observing the decoherence of such
      quantum superpositions. Here we present measurements of the decoherence of
      superposed motional states of a single trapped atom. Decoherence is induced by
      coupling the atom to engineered reservoirs, in which the coupling and state of
      the environment are controllable. We perform three experiments, finding that the
      decoherence rate scales with the square of a quantity describing the amplitude of
      the superposition state.

PMID- 10659840
TI  - Polarization rotation mechanism for ultrahigh electromechanical response in
      single-crystal piezoelectrics
AB  - Piezoelectric materials, which convert mechanical to electrical energy (and vice
      versa), are crucial in medical imaging, telecommunication and ultrasonic devices.
      A new generation of single-crystal materials, such as Pb(Zn1/3Nb2/3)O3-PbTiO3
      (PZN-PT) and Pb(Mg1/3Nb2/3)O3-PbTiO3 (PMN-PT), exhibit a piezoelectric effect
      that is ten times larger than conventional ceramics, and may revolutionize these
      applications. However, the mechanism underlying the ultrahigh performance of
      these new materials-and consequently the possibilities for further improvements
      are not at present clear. Here we report a first-principles study of the
      ferroelectric perovskite, BaTiO3, which is similar to single-crystal PZN-PT but
      is a simpler system to analyse. We show that a large piezoelectric response can
      be driven by polarization rotation induced by an external electric field. Our
      computations suggest how to design materials with better performance, and may
      stimulate further interest in the fundamental theory of dielectric systems in
      finite electric fields.

PMID- 10659839
TI  - Direct protein-protein coupling enables cross-talk between dopamine D5 and gamma
      aminobutyric acid A receptors.
AB  - GABA(A) (gamma-aminobutyric-acid A) and dopamine D1 and D5 receptors represent
      two structurally and functionally divergent families of neurotransmitter
      receptors. The former comprises a class of multi-subunit ligand-gated channels
      mediating fast interneuronal synaptic transmission, whereas the latter belongs to
      the seven-transmembrane-domain single-polypeptide receptor superfamily that
      exerts its biological effects, including the modulation of GABA(A) receptor
      function, through the activation of second-messenger signalling cascades by G
      proteins. Here we show that GABA(A)-ligand-gated channels complex selectively
      with D5 receptors through the direct binding of the D5 carboxy-terminal domain
      with the second intracellular loop of the GABA(A) gamma2(short) receptor subunit.
      This physical association enables mutually inhibitory functional interactions
      between these receptor systems. The data highlight a previously unknown signal
      transduction mechanism whereby subtype-selective G-protein-coupled receptors
      dynamically regulate synaptic strength independently of classically defined
      second-messenger systems, and provide a heuristic framework in which to view
      these receptor systems in the maintenance of psychomotor disease states.

PMID- 10659841
TI  - Dynamics of supercooled water in confined geometry
AB  - As with most liquids, it is possible to supercool water; this generally involves
      cooling the liquid below its melting temperature (avoiding crystallization) until
      it eventually forms a glass. The viscosity and related relaxation times (tau) of
      glass-forming liquids typically show non-Arrhenius temperature (T) dependencies.
      Liquids with highly non-Arrhenius behaviour in the supercooled region are termed
      'fragile'. In contrast, liquids whose behaviour is close to the Arrhenius law (In
      tau infinity 1/T) are termed 'strong'. A unique 'fragile-strong' transition
      around 228 K has been proposed for supercooled water; however, experimental
      studies of bulk supercooled water in this temperature range are generally
      hampered because crystallization occurs. Here we use broad-band dielectric
      spectroscopy to study the relaxation dynamics of supercooled water in a wide
      temperature range, including the usually inaccessible temperature region. This is
      possible because the supercooled water is held within a layered vermiculite clay
      the geometrical confinement and presence of intercalated sodium ions prevent most
      of the water from crystallizing. We find a relaxational process with an Arrhenius
      temperature dependence, consistent with the proposed strong nature of deeply
      supercooled bulk water. Because water that is less supercooled has been
      established as highly fragile, our results support the existence of a fragile
      strong transition.

PMID- 10659842
TI  - Molecular imprinting of bulk, microporous silica
AB  - Molecular imprinting aims to create solid materials containing chemical
      functionalities that are spatially organized by covalent or non-covalent
      interactions with imprint (or template) molecules during the synthesis process.
      Subsequent removal of the imprint molecules leaves behind designed sites for the
      recognition of small molecules, making the material ideally suited for
      applications such as separations, chemical sensing and catalysis. Until now, the
      molecular imprinting of bulk polymers and polymer and silica surfaces has been
      reported, but the extension of these methods to a wider range of materials
      remains problematic. For example, the formation of substrate-specific cavities
      within bulk silica, while conceptually straightforward, has been difficult to
      accomplish experimentally. Here we describe the imprinting of bulk amorphous
      silicas with single aromatic rings carrying up to three 3
      aminopropyltriethoxysilane side groups; this generates and occupies microporosity
      and attaches functional organic groups to the pore walls in a controlled fashion.
      The triethoxysilane part of the molecules' side groups is incorporated into the
      silica framework during sol-gel synthesis, and subsequent removal of the aromatic
      core creates a cavity with spatially organized aminopropyl groups covalently
      anchored to the pore walls. We find that the imprinted silicas act as shape
      selective base catalysts. Our strategy can be extended to imprint other
      functional groups, which should give access to a wide range of functionalized
      materials.

PMID- 10659843
TI  - Biomimetic synthesis of ordered silica structures mediated by block
      copolypeptides.
AB  - In biological systems such as diatoms and sponges, the formation of solid silica
      structures with precisely controlled morphologies is directed by proteins and
      polysaccharides and occurs in water at neutral pH and ambient temperature.
      Laboratory methods, in contrast, have to rely on extreme pH conditions and/or
      surfactants to induce the condensation of silica precursors into specific
      morphologies or patterned structures. This contrast in processing conditions and
      the growing demand for benign synthesis methods that minimize adverse
      environmental effects have spurred much interest in biomimetic approaches in
      materials science. The recent demonstration that silicatein-a protein found in
      the silica spicules of the sponge Tethya aurantia--can hydrolyse and condense the
      precursor molecule tetraethoxysilane to form silica structures with controlled
      shapes at ambient conditions seems particularly promising in this context. Here
      we describe synthetic cysteine-lysine block copolypeptides that mimic the
      properties of silicatein: the copolypeptides self-assemble into structured
      aggregates that hydrolyse tetraethoxysilane while simultaneously directing the
      formation of ordered silica morphologies. We find that oxidation of the cysteine
      sulphydryl groups, which is known to affect the assembly of the block
      copolypeptide, allows us to produce different structures: hard silica spheres and
      well-defined columns of amorphous silica are produced using the fully reduced and
      the oxidized forms of the copolymer, respectively.

PMID- 10659844
TI  - Natural methyl bromide and methyl chloride emissions from coastal salt marshes.
AB  - Atmospheric methyl bromide (CH3Br) and methyl chloride (CH3Cl), compounds that
      are involved in stratospheric ozone depletion, originate from both natural and
      anthropogenic sources. Current estimates of CH3Br and CH3Cl emissions from
      oceanic sources, terrestrial plants and fungi, biomass burning and anthropogenic
      inputs do not balance their losses owing to oxidation by hydroxyl radicals,
      oceanic degradation, and consumption in soils, suggesting that additional natural
      terrestrial sources may be important. Here we show that CH3Br and CH3Cl are
      released to the atmosphere from all vegetation zones of two coastal salt marshes.
      We see very large fluxes of CH3Br and CH3Cl per unit area: up to 42 and 570
      micromol m(-2) d(-1), respectively. The fluxes show large diurnal, seasonal and
      spatial variabilities, but there is a strong correlation between the fluxes of
      CH3Br and those of CH3Cl, with an average molar flux ratio of roughly 1:20. If
      our measurements are typical of salt marshes globally, they suggest that such
      ecosystems, even though they constitute less than 0.1% of the global surface
      area, may produce roughly 10% of the total fluxes of atmospheric CH3Br and CH3Cl.

PMID- 10659845
TI  - A strong source of methyl chloride to the atmosphere from tropical coastal land.
AB  - Methyl chloride (CH3Cl), the most abundant halocarbon in the atmosphere, has
      received much attention as a natural source of chlorine atoms in the
      stratosphere. The annual global flux of CH3Cl has been estimated to be around 3.5
      Tg on the grounds that this must balance the loss through reaction with OH
      radicals (which gives a lifetime for atmospheric CH3Cl of 1.5 yr). The most
      likely main source of methyl chloride has been thought to be oceanic emission,
      with biomass burning the second largest source. But recent seawater measurements
      indicate that oceanic fluxes cannot account for more than 12% of the estimated
      global flux of CH3Cl, raising the question of where the remainder comes from.
      Here we report evidence of significant CH3Cl emission from warm coastal land,
      particularly from tropical islands. This conclusion is based on a global
      monitoring study and spot measurements, which show enhancement of atmospheric
      CH3Cl in the tropics, a close correlation between CH3Cl concentrations and those
      of biogenic compounds emitted by terrestrial plants, and OH-linked seasonality of
      CH3Cl concentrations in middle and high latitudes. A strong, equatorially located
      source of this nature would explain why the distribution of CH3Cl is uniform
      between the Northern and Southern hemispheres, despite their differences in ocean
      and land area.

PMID- 10659846
TI  - Halocarbons produced by natural oxidation processes during degradation of organic
      matter.
AB  - Volatile halogenated organic compounds (VHOC) play an important role in
      atmospheric chemical processes-contributing, for example, to stratospheric ozone
      depletion. For anthropogenic VHOC whose sources are well known, the global
      atmospheric input can be estimated from industrial production data. Halogenated
      compounds of natural origin can also contribute significantly to the levels of
      VHOC in the atmosphere. The oceans have been implicated as one of the main
      natural sources, where organisms such as macroalgae and microalgae can release
      large quantities of VHOC to the atmosphere. Some terrestrial sources have also
      been identified, such as wood-rotting fungi, biomass burning and volcanic
      emissions. Here we report the identification of a different terrestrial source of
      naturally occurring VHOC. We find that, in soils and sediments, halide ions can
      be alkylated during the oxidation of organic matter by an electron acceptor such
      as Fe(III): sunlight or microbial mediation are not required for these reactions.
      When the available halide ion is chloride, the reaction products are CH3Cl,
      C2H5Cl, C3H7Cl and C4H9Cl. (The corresponding alkyl bromides or alkyl iodides are
      produced when bromide or iodide are present.) Such abiotic processes could make a
      significant contribution to the budget of the important atmospheric compounds
      CH3Cl, CH3Br and CH3I.

PMID- 10659847
TI  - Annual fluxes of carbon from deforestation and regrowth in the Brazilian Amazon.
AB  - The distribution of sources and sinks of carbon among the world's ecosystems is
      uncertain. Some analyses show northern mid-latitude lands to be a large sink,
      whereas the tropics are a net source; other analyses show the tropics to be
      nearly neutral, whereas northern mid-latitudes are a small sink. Here we show
      that the annual flux of carbon from deforestation and abandonment of agricultural
      lands in the Brazilian Amazon was a source of about 0.2 Pg Cyr(-1) over the
      period 1989-1998 (1 Pg is 10(15) g). This estimate is based on annual rates of
      deforestation and spatially detailed estimates of deforestation, regrowing
      forests and biomass. Logging may add another 5-10% to this estimate, and fires
      may double the magnitude of the source in years following a drought. The annual
      source of carbon from land-use change and fire approximately offsets the sink
      calculated for natural ecosystems in the region. Thus this large area of tropical
      forest is nearly balanced with respect to carbon, but has an interannual
      variability of +/- 0.2 PgC yr(-1).

PMID- 10659848
TI  - Rapid evolution of male reproductive genes in the descent of man.
AB  - A diverse body of morphological and genetic evidence has suggested that traits
      pertaining to male reproduction may have evolved much more rapidly than other
      types of character. Recently, DNA sequence comparisons have also shown a very
      high level of divergence in male reproductive proteins between closely related
      Drosophila species, among marine invertebrates and between mouse and rat. Here we
      show that rapid evolution of male reproductive genes is observable in primates
      and is quite notable in the lineages to human and chimpanzee. Nevertheless, rapid
      evolution by itself is not necessarily an indication of positive darwinian
      selection; relaxation of negative selection is often equally compatible with the
      DNA sequence data. By taking three statistical approaches, we show that positive
      darwinian selection is often the driving force behind this rapid evolution. These
      results open up opportunities to test the hypothesis that sexual selection plays
      some role in the molecular evolution of higher primates.

PMID- 10659849
TI  - Voice-selective areas in human auditory cortex.
AB  - The human voice contains in its acoustic structure a wealth of information on the
      speaker's identity and emotional state which we perceive with remarkable ease and
      accuracy. Although the perception of speaker-related features of voice plays a
      major role in human communication, little is known about its neural basis. Here
      we show, using functional magnetic resonance imaging in human volunteers, that
      voice-selective regions can be found bilaterally along the upper bank of the
      superior temporal sulcus (STS). These regions showed greater neuronal activity
      when subjects listened passively to vocal sounds, whether speech or non-speech,
      than to non-vocal environmental sounds. Central STS regions also displayed a high
      degree of selectivity by responding significantly more to vocal sounds than to
      matched control stimuli, including scrambled voices and amplitude-modulated
      noise. Moreover, their response to stimuli degraded by frequency filtering
      paralleled the subjects' behavioural performance in voice-perception tasks that
      used these stimuli. The voice-selective areas in the STS may represent the
      counterpart of the face-selective areas in human visual cortex; their existence
      sheds new light on the functional architecture of the human auditory cortex.

PMID- 10659850
TI  - Functional regeneration of sensory axons into the adult spinal cord.
AB  - The arrest of dorsal root axonal regeneration at the transitional zone between
      the peripheral and central nervous system has been repeatedly described since the
      early twentieth century. Here we show that, with trophic support to damaged
      sensory axons, this regenerative barrier is surmountable. In adult rats with
      injured dorsal roots, treatment with nerve growth factor (NGF), neurotrophin-3
      (NT3) and glial-cell-line-derived neurotrophic factor (GDNF), but not brain
      derived neurotrophic factor (BDNF), resulted in selective regrowth of damaged
      axons across the dorsal root entry zone and into the spinal cord. Dorsal horn
      neurons were found to be synaptically driven by peripheral nerve stimulation in
      rats treated with NGF, NT3 and GDNF, demonstrating functional reconnection. In
      behavioural studies, rats treated with NGF and GDNF recovered sensitivity to
      noxious heat and pressure. The observed effects of neurotrophic factors
      corresponded to their known actions on distinct subpopulations of sensory
      neurons. Neurotrophic factor treatment may thus serve as a viable treatment in
      promoting recovery from root avulsion injuries. I

PMID- 10659851
TI  - Glutamate release in severe brain ischaemia is mainly by reversed uptake.
AB  - The release of glutamate during brain anoxia or ischaemia triggers the death of
      neurons, causing mental or physical handicap. The mechanism of glutamate release
      is controversial, however. Four release mechanisms have been postulated:
      vesicular release dependent on external calcium or Ca2+ released from
      intracellular stores; release through swelling-activated anion channels; an
      indomethacin-sensitive process in astrocytes; and reversed operation of glutamate
      transporters. Here we have mimicked severe ischaemia in hippocampal slices and
      monitored glutamate release as a receptor-gated current in the CA1 pyramidal
      cells that are killed preferentially in ischaemic hippocampus. Using blockers of
      the different release mechanisms, we demonstrate that glutamate release is
      largely by reversed operation of neuronal glutamate transporters, and that it
      plays a key role in generating the anoxic depolarization that abolishes
      information processing in the central nervous system a few minutes after the
      start of ischaemia. A mathematical model incorporating K+ channels, reversible
      uptake carriers and NMDA (N-methyl-D-aspartate) receptor channels reproduces the
      main features of the response to ischaemia. Thus, transporter-mediated glutamate
      homeostasis fails dramatically in ischaemia: instead of removing extracellular
      glutamate to protect neurons, transporters release glutamate, triggering neuronal
      death.

PMID- 10659852
TI  - Blocker protection in the pore of a voltage-gated K+ channel and its structural
      implications.
AB  - The structure of the bacterial potassium channel KcsA has provided a framework
      for understanding the related voltage-gated potassium channels (Kv channels) that
      are used for signalling in neurons. Opening and closing of these Kv channels
      (gating) occurs at the intracellular entrance to the pore, and this is also the
      site at which many open channel blockers affect Kv channels. To learn more about
      the sites of blocker binding and about the structure of the open Kv channel, we
      investigated here the ability of blockers to protect against chemical
      modification of cysteines introduced at sites in transmembrane segment S6, which
      contributes to the intracellular entrance. Within the intracellular half of S6 we
      found an abrupt cessation of protection for both large and small blockers that is
      inconsistent with the narrow 'inner pore' seen in the KcsA structure. These and
      other results are most readily explained by supposing that the structure of Kv
      channels differs from that of the non-voltage-gated bacterial channel by the
      introduction of a sharp bend in the inner (S6) helices. This bend would occur at
      a Pro-X-Pro sequence that is highly conserved in Kv channels, near the site of
      activation gating.

PMID- 10659853
TI  - KIR expression on self-reactive CD8+ T cells is controlled by T-cell receptor
      engagement.
AB  - Natural killer cell tolerance is maintained by the interaction of killer
      inhibitory receptors (KIRs) with self-major histocompatibility complex class I
      gene products. A subset of T cells also expresses inhibitory receptors, but the
      functional significance of these receptors on T cells is unclear. Here we show
      that, in the absence of T-cell receptor (TCR) engagement, KIRs expressed on CD8+
      T cells are slowly downregulated by KIR ligands expressed on antigen-presenting
      cells. The resulting expression levels of KIR are no longer able to inhibit T
      cell function. In contrast, TCR engagement sustains KIR expression, and re
      induces functional levels of KIR expression after ligand-induced downregulation
      of KIR. Our data indicate that KIR expression on CD8+ T cells in vivo may be
      maintained through continuous encounters with antigen. As KIR-mediated inhibition
      of T-cell activation can be bypassed at high antigen concentrations, dynamic KIR
      expression may mediate T-cell tolerance to self-antigens by sparing self-reactive
      T cells, thus enabling them to mediate potentially useful immune functions to
      quantitatively or qualitatively different antigens.

PMID- 10659854
TI  - Regulation of carbamoyl phosphate synthetase by MAP kinase.
AB  - The de novo synthesis of pyrimidine nucleotides is required for mammalian cells
      to proliferate. The rate-limiting step in this pathway is catalysed by carbamoyl
      phosphate synthetase (CPS II), part of the multifunctional enzyme CAD. Here we
      describe the regulation of CAD by the mitogen-activated protein (MAP) kinase
      cascade. When phosphorylated by MAP kinase in vitro or activated by epidermal
      growth factor in vivo, CAD lost its feedback inhibition (which is dependent on
      uridine triphosphate) and became more sensitive to activation (which depends upon
      phosphoribosyl pyrophosphate). Both these allosteric regulatory changes favour
      biosynthesis of pyrimidines for growth. They were accompanied by increased
      epidermal growth factor-dependent phosphorylation of CAD in vivo and were
      prevented by inhibition of MAP kinase. Mutation of a consensus MAP kinase
      phosphorylation site abolished the changes in CAD allosteric regulation that were
      stimulated by growth factors. Finally, consistent with an effect of MAP kinase
      signalling on CPS II activity, epidermal growth factor increased cellular uridine
      triphosphate and this increase was reversed by inhibition of MAP kinase. Hence
      these studies may indicate a direct link between activation of the MAP kinase
      cascade and de novo biosynthesis of pyrimidine nucleotides.

PMID- 10659855
TI  - The joining of ribosomal subunits in eukaryotes requires eIF5B.
AB  - Initiation of eukaryotic protein synthesis begins with the ribosome separated
      into its 40S and 60S subunits. The 40S subunit first binds eukaryotic initiation
      factor (eIF) 3 and an eIF2-GTP-initiator transfer RNA ternary complex. The
      resulting complex requires eIF1, eIF1A, eIF4A, eIF4B and eIF4F to bind to a
      messenger RNA and to scan to the initiation codon. eIF5 stimulates hydrolysis of
      eIF2-bound GTP and eIF2 is released from the 48S complex formed at the initiation
      codon before it is joined by a 60S subunit to form an active 80S ribosome. Here
      we show that hydrolysis of eIF2-bound GTP induced by eIF5 in 48S complexes is
      necessary but not sufficient for the subunits to join. A second factor termed
      eIF5B (relative molecular mass 175,000) is essential for this process. It is a
      homologue of the prokaryotic initiation factor IF2 (re and, like it, mediates
      joining of subunits and has a ribosome-dependent GTPase activity that is
      essential for its function.

PMID- 10659856
TI  - A synthetic oscillatory network of transcriptional regulators.
AB  - Networks of interacting biomolecules carry out many essential functions in living
      cells, but the 'design principles' underlying the functioning of such
      intracellular networks remain poorly understood, despite intensive efforts
      including quantitative analysis of relatively simple systems. Here we present a
      complementary approach to this problem: the design and construction of a
      synthetic network to implement a particular function. We used three
      transcriptional repressor systems that are not part of any natural biological
      clock to build an oscillating network, termed the repressilator, in Escherichia
      coli. The network periodically induces the synthesis of green fluorescent protein
      as a readout of its state in individual cells. The resulting oscillations, with
      typical periods of hours, are slower than the cell-division cycle, so the state
      of the oscillator has to be transmitted from generation to generation. This
      artificial clock displays noisy behaviour, possibly because of stochastic
      fluctuations of its components. Such 'rational network design may lead both to
      the engineering of new cellular behaviours and to an improved understanding of
      naturally occurring networks.

PMID- 10659857
TI  - Construction of a genetic toggle switch in Escherichia coli.
AB  - It has been proposed' that gene-regulatory circuits with virtually any desired
      property can be constructed from networks of simple regulatory elements. These
      properties, which include multistability and oscillations, have been found in
      specialized gene circuits such as the bacteriophage lambda switch and the
      Cyanobacteria circadian oscillator. However, these behaviours have not been
      demonstrated in networks of non-specialized regulatory components. Here we
      present the construction of a genetic toggle switch-a synthetic, bistable gene
      regulatory network-in Escherichia coli and provide a simple theory that predicts
      the conditions necessary for bistability. The toggle is constructed from any two
      repressible promoters arranged in a mutually inhibitory network. It is flipped
      between stable states using transient chemical or thermal induction and exhibits
      a nearly ideal switching threshold. As a practical device, the toggle switch
      forms a synthetic, addressable cellular memory unit and has implications for
      biotechnology, biocomputing and gene therapy.

PMID- 10659858
TI  - Casting stones.

PMID- 10659859
TI  - Treatment selection in ductal carcinoma in situ.

PMID- 10659860
TI  - Medicine--public health collaboration tested.

PMID- 10659861
TI  - Enhancing diabetes care in a low-income, high-risk population.

PMID- 10659862
TI  - Music hath charms for care of preemies.

PMID- 10659863
TI  - From the Centers for Disease Control and Prevention. Hypertrophic pyloric
      stenosis in infants following pertussis prophylaxis with erythromycin--Knoxville,
      Tennessee, 1999.

PMID- 10659864
TI  - From the Centers for Disease Control and Prevention. Global measles control and
      regional elimination, 1998-1999.

PMID- 10659865
TI  - Predicting cardiovascular risk using ambulatory blood pressure.

PMID- 10659866
TI  - Predicting cardiovascular risk using ambulatory blood pressure.

PMID- 10659867
TI  - Blood lead level and dental caries.

PMID- 10659868
TI  - Blood lead level and dental caries.

PMID- 10659869
TI  - Central venous catheters and bloodstream infection.

PMID- 10659870
TI  - Central venous catheters and bloodstream infection.

PMID- 10659871
TI  - Prognostic value of pololike kinase expression in melanomas.

PMID- 10659872
TI  - A 13-year-old boy with transient ischemic attacks.

PMID- 10659873
TI  - Effectiveness of a journal intervention to improve abstract quality.

PMID- 10659874
TI  - Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer
      risk.
AB  - CONTEXT: Whether menopausal hormone replacement therapy using a combined estrogen
      progestin regimen increases risk of breast cancer beyond that associated with
      estrogen alone is unknown. OBJECTIVE: To determine whether increases in risk
      associated with the estrogen-progestin regimen are greater than those associated
      with estrogen alone. DESIGN: Cohort study of follow-up data for 1980-1995 from
      the Breast Cancer Detection Demonstration Project, a nationwide breast cancer
      screening program. SETTING: Twenty-nine screening centers throughout the United
      States. PARTICIPANTS: A total of 46355 postmenopausal women (mean age at start of
      follow-up, 58 years). MAIN OUTCOME MEASURE: Incident breast cancers by recency,
      duration, and type of hormone use. RESULTS: During follow-up, 2082 cases of
      breast cancer were identified. Increases in risk with estrogen only and estrogen
      progestin only were restricted to use within the previous 4 years (relative risk
      [RR], 1.2 [95% confidence interval [CI], 1.0-1.4] and 1.4 [95% CI, 1.1-1.8],
      respectively); the relative risk increased by 0.01 (95% CI, 0.002-0.03) with each
      year of estrogen-only use and by 0.08 (95% CI, 0.02-0.16) with each year of
      estrogen-progestin-only use among recent users, after adjustment for mammographic
      screening, age at menopause, body mass index (BMI), education, and age. The P
      value associated with the test of homogeneity of these estimates was .02. Among
      women with a BMI of 24.4 kg/m2 or less, increases in RR with each year of
      estrogen-only use and estrogen-progestin-only use among recent users were 0.03
      (95% CI, 0.01-0.06) and 0.12 (95% CI, 0.02-0.25), respectively. These
      associations were evident for the majority of invasive tumors with ductal
      histology and regardless of extent of invasive disease. Risk in heavier women did
      not increase with use of estrogen only or estrogen-progestin only. CONCLUSION:
      Our data suggest that the estrogen-progestin regimen increases breast cancer risk
      beyond that associated with estrogen alone.

PMID- 10659875
TI  - Nucleoside analogs plus ritonavir in stable antiretroviral therapy-experienced
      HIV-infected children: a randomized controlled trial. Pediatric AIDS Clinical
      Trials Group 338 Study Team.
AB  - CONTEXT: Although protease inhibitors are used routinely in adults with human
      immunodeficiency virus (HIV) infection, the role of these drugs in the treatment
      of clinically stable HIV-infected children is not clear. OBJECTIVE: To evaluate
      the safety, tolerance, and virologic response produced by a change in
      antiretroviral therapy in HIV-infected children who were clinically and
      immunologically stable while receiving previous therapy. DESIGN: The Pediatric
      AIDS Clinical Trials Group 338, a multicenter, phase 2, randomized, open-label
      controlled trial conducted from February 6 to April 30, 1997 (patient entry
      period); patients were followed up for 48 weeks. SETTING: Pediatric HIV research
      clinics in the United States and Puerto Rico. PATIENTS: Two hundred ninety-seven
      antiretroviral-experienced, protease inhibitor-naive, clinically stable HIV
      infected children aged 2 to 17 years. INTERVENTIONS: Children were randomized to
      receive zidovudine, 160 mg/m2 3 times per day, plus lamivudine, 4 mg/kg 2 times
      per day (n = 100); the same regimen plus ritonavir, 350 mg/m2 2 times per day (n
      = 100); or ritonavir, 350 mg/m2 2 times per day, and stavudine, 4 mg/kg 2 times
      per day (n = 97). MAIN OUTCOME MEASURE: Plasma HIV-1 RNA levels at study weeks 12
      and 48, compared among the 3 treatment groups. RESULTS: At study week 12, 12% of
      patients in the zidovudine-lamivudine group had undetectable plasma HIV RNA
      levels (<400 copies/mL) compared with 52% and 54% of patients in the 2- and 3
      drug ritonavir-containing groups, respectively (P<.001). Through study week 48,
      70% of children continued receiving their ritonavir-containing regimen. At study
      week 48, 42% of children receiving ritonavir plus 2 nucleosides compared with 27%
      of those receiving ritonavir and a single nucleoside had undetectable HIV RNA
      levels (P = .04); however, similar proportions in each group continuing initial
      therapy had HIV RNA levels of less than 10000 copies/mL (58% vs 48%,
      respectively; P = .19). CONCLUSIONS: In our study, change in antiretroviral
      therapy to a ritonavir-containing regimen was associated with superior virologic
      response at study week 12 compared with change to a dual nucleoside analog
      regimen. More children receiving ritonavir in combination with 2 compared with 1
      nucleoside analog had undetectable HIV RNA levels at study week 48.

PMID- 10659876
TI  - Impact of respiratory virus infections on persons with chronic underlying
      conditions.
AB  - CONTEXT: While hospitalization rates have declined overall, hospitalizations for
      acute lower respiratory tract infections have increased steadily since 1980.
      Development of new approaches for prevention of acute respiratory tract
      conditions requires studies of the etiologies of infections and quantification of
      the risk of hospitalization for vulnerable patients. OBJECTIVE: To determine the
      frequency of specific virus infections associated with acute respiratory tract
      conditions leading to hospitalization of chronically ill patients. DESIGN:
      Analysis of viral etiology of patients hospitalized with acute respiratory tract
      conditions between July 1991 and June 1995. SETTING: Four large clinics and
      related hospitals serving diverse populations representative of Harris County,
      Texas. PATIENTS: A total of 1029 patients who were hospitalized for pneumonia,
      tracheobronchitis, bronchiolitis, croup, exacerbations of asthma or chronic
      obstructive pulmonary disease, and/or congestive heart failure. MAIN OUTCOME
      MEASURE: Virus infection, defined by culture, antigen detection, and significant
      rise in serum antibodies, by underlying condition; hospitalization rates by low-
      vs middle-income status. RESULTS: Ninety-three percent of patients older than 5
      years had a chronic underlying condition; a chronic pulmonary condition was most
      common. Patients with chronic pulmonary disease from low-income populations were
      hospitalized at a rate of 398.6 per 10000, almost 8 times higher than the rate
      for patients from middle-income groups (52.2 per 10000; P<.001). Of the 403
      patients (44.4% of adults and 32.3% of children) who submitted convalescent serum
      specimens for antibody testing, respiratory tract virus infections were detected
      in 181 (44.9%). Influenza, parainfluenza, and respiratory syncytial virus (RSV)
      infections accounted for 75% of all virus infections. CONCLUSIONS: Our study
      suggests that respiratory virus infections commonly trigger serious acute
      respiratory conditions that result in hospitalization of patients with chronic
      underlying conditions, highlighting the need for development of effective
      vaccines for these viruses, especially for parainfluenza and RSV.

PMID- 10659877
TI  - Mental disorders and use of cardiovascular procedures after myocardial
      infarction.
AB  - CONTEXT: A number of studies have found race- and sex-based differences in rates
      of cardiovascular procedures in the United States. Similarly, mental disorders
      might be expected to be associated with lower rates of such procedures on the
      basis of clinical, socioeconomic, patient, and provider factors. OBJECTIVE: To
      assess whether having a comorbid mental disorder is associated with a lower
      likelihood of cardiac catheterization and/or revascularization after acute
      myocardial infarction. DESIGN: Retrospective cohort study using data from medical
      charts and administrative files as part of the Cooperative Cardiovascular
      Project. SETTING: Acute care nongovernmental hospitals in the United States.
      PATIENTS: National cohort of 113653 eligible patients 65 years or older who were
      hospitalized for confirmed acute myocardial infarction between February 1994 and
      July 1995. MAIN OUTCOME MEASURES: Likelihood of cardiac catheterization,
      percutaneous transluminal coronary angioplasty (PTCA), or coronary artery bypass
      graft (CABG) surgery during the index hospitalization, comparing patients with
      and without mental disorders (classified as schizophrenia, major affective
      disorder, substance abuse/dependence disorder, or other mental disorder).
      RESULTS: Compared with the remainder of the sample, patients with any comorbid
      mental disorder (n = 5365; 4.7%) were significantly less likely to undergo PTCA
      (11.8% vs 16.8%; P<.001) or CABG (8.2% vs 12.6%; P<.001). After adjusting for
      demographic, clinical, hospital, and regional factors, individuals with mental
      disorders were 41% (for schizophrenia) to 78% (for substance use) as likely to
      undergo cardiac catheterization as those without mental disorders (P<.001 for
      all). Among those undergoing catheterization, rates of PTCA or CABG for patients
      with mental disorders were not significantly different from rates for patients
      without mental disorders (for those with any mental disorder, P = .12 for PTCA
      and P = .06 for CABG). In multivariate models, the 30-day mortality did not
      differ between patients with and without mental disorders. CONCLUSIONS: In this
      study, individuals with comorbid mental disorders were substantially less likely
      to undergo coronary revascularization procedures than those without mental
      disorders. Further research is needed to understand the degree to which patient
      and provider factors contribute to this difference and its implications for
      quality and long-term outcomes of care.

PMID- 10659878
TI  - Quality of the last year of life of older adults: 1986 vs 1993.
AB  - CONTEXT: The population is aging and life expectancy is increasing, but whether
      morbidity and disability late in life also increase is unknown. OBJECTIVE: To
      examine whether the use of health care services, disability and cognitive
      function, and overall quality of life in the year before death among older adults
      has changed over time. DESIGN AND SETTING: The 1986 and 1993 National Mortality
      Followback Surveys, which were probability samples of all deaths in the United
      States with response rates of next of kin of 90% and 88% for those aged 65 years
      and older. PARTICIPANTS: Next of kin were asked to report the health status of a
      total of 9179 decedents who were 65 years and older in 1986 and 6735 in 1993,
      representing 1.5 and 1.6 million decedents aged 65 years and older. MAIN OUTCOME
      MEASURES: Days of hospital or nursing home stays, number and length of disability
      in 5 activities of daily living, duration of impairment in 3 measures of
      cognitive function, and an overall sickness score among individuals aged 65
      through 84 years and those aged 85 years and older. RESULTS: Women used
      significantly fewer hospital and nursing home services in the last year of life
      in 1993 vs 1986 (mean reduction, 3.3 nights for both age groups for hospital
      services; mean reduction 18.4 nights for nursing home for women aged 65-84 years
      and 42.3 nights for women > or =85 years). Men had no changes except those aged
      85 years and older had a decline in nursing home nights of 32.6. The proportion
      of women aged 85 years and older with restriction of at least 2 activities of
      daily living decreased from 62.5% in 1986 to 52.1% in 1993 (P<.01), and those
      with normal cognitive function increased from 50.3% to 56.2% (P<.05). Their mean
      overall sickness score decreased and quality-of-life improved. Among women aged
      65 through 84 years, the number with normal cognitive function increased and the
      mean sickness score decreased, but those with at least 2 activities of daily
      living impairments increased and the overall quality of life declined. A similar
      pattern of change was found in the oldest-old men except that cognitive function
      worsened. Most parameters for men aged 65 through 84 years did not change
      significantly. CONCLUSIONS: Men and women at least 85 years old in the US
      experienced a better overall quality of life in the last year of life in 1993
      than those in 1986. Most measures for men and women aged 65 through 84 years
      improved or did not change.

PMID- 10659879
TI  - Recommendations to guide revision of the Guides to the Evaluation of Permanent
      Impairment. American Medical Association.
AB  - The American Medical Association's Guides to the Evaluation of Permanent
      Impairment, Fourth Edition, is the most commonly used tool in the United States
      for rating permanent impairments for disability systems. The Guides, currently
      undergoing revision, has been the focus of considerable controversy. Criticisms
      have focused on 2 areas: internal deficiencies, including the lack of a
      comprehensive, valid, reliable, unbiased, and evidence-based system for rating
      impairments; and the way in which workers' compensation systems use the ratings,
      resulting in inappropriate compensation. We focus on the internal deficiencies
      and recommend that the Guides remains a tool for evaluation of permanent
      impairment, not disability. To maintain wide acceptance of the Guides, its
      authors need to improve the validity, internal consistency, and comprehensiveness
      of the ratings; document reliability and reproducibility of the results; and make
      the Guides easily comprehensible and accessible to physicians.

PMID- 10659881
TI  - A 73-year-old woman with osteoporosis, 1 year later.

PMID- 10659880
TI  - A 55-year-old woman with rheumatoid arthritis.

PMID- 10659882
TI  - Improving the evaluation of permanent impairment.

PMID- 10659883
TI  - Postmenopausal estrogens--opposed, unopposed, or none of the above.

PMID- 10659884
TI  - JAMA Patient Page: Aging.

PMID- 10659885
TI  - Material properties of commonly-used interface materials and their static
      coefficients of friction with skin and socks.

PMID- 10659886
TI  - Enabling veterans: the challenge and the promise of the next millenium.

PMID- 10659887
TI  - Reflections on a half century as we approach the millennium.

PMID- 10659888
TI  - Working in Pasteur's quadrant.

PMID- 10659889
TI  - A method of residual limb stiffness distribution measurement.
AB  - A method of recording a residual limb indentation stiffness map was developed for
      possible use as an aid in calculating prosthetic socket rectifications. The
      method was tested to determine the level of repeatability attainable. A hand
      held, pencil-like device was used, with an air-driven piston that indented the
      tissue 10 times per second. The indentor tip contained an electromagnetic
      digitizer element that sensed position and orientation 120 times per second. The
      examiner moved the device around the limb; sampling was variable in density, and
      typically concentrated on critical areas. An interactive visual display of
      sampled data quality was used to guide sampling. The indentation maps typically
      contained approximately 4,000 locations, in a cylindrical coordinate system, with
      sampling locations spaced every 3.2 mm vertically, and every 0.087 radians
      tangentially. The behavior of the system was characterized using six test
      subjects on whom recorded indentations ranged from 1.5 to 21 mm. The largest
      range of indentations (i.e., worst disagreement) recorded at a single location
      was 5.4 mm. The average standard deviation on repeated measurement ranged from 7
      to 15%, and averaged 0.67 mm in absolute terms. Many of the structurally
      significant anatomical features of the limbs were visible, including the patella
      and patellar tendon, fibular head, shin, biceps femoris tendon, semitendinosus,
      and popliteal area.

PMID- 10659890
TI  - Step activity monitor: long-term, continuous recording of ambulatory function.
AB  - In many areas of research and medicine, objective data describing an individual's
      ambulatory function are sought as useful indicators of that person's condition.
      Normally, detailed measurements are taken over short periods of time within a
      controlled laboratory setting. To complement this approach, Prosthetics Research
      Study has developed a small, unobtrusive instrument that continuously records a
      simple measure--step counts per unit time--as an individual goes about normal
      daily life. The Step Activity Monitor (SAM) is approximately the size and weight
      of a pager and is worn at the ankle. It can detect steps with better than 99%
      accuracy across a wide range of gait styles for adults, children, and large
      animals. During monitoring, step counts are recorded at consecutive, adjustable
      time intervals over weeks to months at a time. Recording at 1-min intervals for a
      minimum of 2 weeks is recommended. Once monitoring is completed, the data are
      transferred to a computer, and the levels and patterns of step activity can be
      analyzed. This article provides a detailed description of the SAM, guidelines for
      use, results of accuracy and reliability testing, case study descriptions
      demonstrating the ability to measure differences that result from medical
      interventions or changes in health status, and a discussion of considerations
      pertinent to long-term monitoring of activity.

PMID- 10659891
TI  - New horizons in stroke rehabilitation research.
AB  - To promote health services research in stroke rehabilitation, we gathered
      information about stroke rehabilitation structures, processes, and outcomes
      (SPO), using extant databases and the Donabedian theoretical model of health
      services evaluation. We found that, in the United States, over S3.6 billion was
      spent by third-party payers in 1992 on rehabilitation, including stroke. Total
      disability-related costs now amount to over $170 billion per year. However, there
      are few studies identifying cost-effective stroke rehabilitation practices.
      Existing studies indicate that the organizational structure of rehabilitation
      influences stroke outcomes, but it is less clear exactly what organizational
      practices constitute optimal stroke rehabilitation. Data about specific,
      beneficial rehabilitation processes are scanty for stroke. There are a number of
      valid and reliable outcome measures pertinent to stroke rehabilitation health
      services research. We conclude that health services research in stroke
      rehabilitation is sparse. To be more informative, rehabilitation health services
      research should be guided by the SPO model.

PMID- 10659892
TI  - Testing and evaluation of wheelchair caster assemblies subjected to dynamic crash
      loading.
AB  - Wheelchair designs based upon loads applied quasi-statically during normal
      mobility use are apt to be inadequate to handle the increased level of dynamic
      crash forces that may be encountered when using the wheelchair as a motor vehicle
      seat. The purpose of this study was to characterize the integrity of wheelchair
      caster assemblies under simulated crash conditions. This study utilized dynamic
      drop (DD) testing, with loading levels and rates adjusted to match those found
      previously in sled impact testing and computer crash simulations. The results
      verify that current caster assembly designs may not be able to withstand forces
      associated with a crash. Five of seven evaluated caster assemblies failed when
      loaded to 8,007 N, or less, at loading rates seen in sled testing. DD testing
      used in this study is a valuable tool that can be used in the design of transport
      wheelchair components.

PMID- 10659893
TI  - A steering linkage for short wheelbase vehicles: design and evaluation in a
      wheelchair power base--a technical note.
AB  - An Ackerman steering linkage for short wheelbase, four-wheel vehicles has been
      developed. The linkage coordinates the steering angle of each wheel through a
      range of 180 degrees with minimal misalignment between wheels. Control of
      steering angles is accomplished using a single linear actuator. Control
      complexity is lower compared to four-wheel systems using individually controlled
      steering actuators for each wheel. A prototype linkage that provides a minimum
      turning radius while maintaining maximum stability has been developed and
      evaluated for a power wheelchair base. The single-actuator linkage is well suited
      for this application, due to the cost-sensitive nature of wheelchair products.

PMID- 10659894
TI  - Augmentation of the 100 kg ISO wheelchair test dummy to accommodate higher mass:
      a technical note.
AB  - Most of the 22 approved or developing ISO standards rely on a wheelchair test
      dummy, a specialized device described in ISO 7176-11. The purpose of this study
      was to develop a means for modifying the design of the ISO 7176-11 test dummy to
      be suitable for testing with higher masses. The changes are based upon published
      data for obese individuals. With these data, we derived equations for determining
      the distribution of the additional mass among the test dummy components, and the
      locations of the centers of mass. The results of this study provide guidelines
      for adding mass to the 100 kg wheelchair test dummy to accommodate testing of
      wheelchairs designed for obese individuals.

PMID- 10659895
TI  - Diabetic amputations in the VA: are there opportunities for interventions?
AB  - Lower limb amputation (LLA) is a devastating complication experienced by some
      veterans with diabetes. The Veterans Affairs (VA) Healthcare system has
      identified the prevention of LLA as a priority goal. This study was designed to
      describe the sources of outpatient care received by veterans with diabetes who
      have undergone LLA, to determine whether these persons would have been impacted
      by a VA amputation prevention program. This study was also designed to describe
      prior amputation history, footwear history, and the pivotal events that led to
      these amputations. We found that the vast majority of these subjects identified
      the VA as their primary source of care, and thus would have been available for
      enrollment in a prevention program. Since over one-half of them had had a prior
      amputation, diabetics with a prior amputation should be particularly targeted for
      foot care interventions. Lastly, prescription of protective footwear has the
      potential to reduce the incidence of shoe-related ulcers and amputations.

PMID- 10659896
TI  - Uterine and fetal Doppler flow changes after misoprostol and oxytocin therapy for
      induction of labor in post-term pregnancies.
AB  - OBJECTIVES: To compare the effect of misoprostol vs. oxytocin on blood flow in
      uteroplacental circulation during labor induction. METHODS: Ninety-one women with
      indications for induction of labor were assigned to receive either misoprostol 50
      microg per vagina every 4 h as needed or intravenous oxytocin by means of a
      randomization table generated by computer. Doppler velocimetry of umbilical,
      uterine and arcuate arteries was performed immediately before and 2-3 h after
      administration of misoprostol or oxytocin. Pulsatility index (PI), resistance
      index (RI) and systolic/diastolic (S/D) ratios were measured for these arteries.
      The SAS system was used to perform statistical analysis. RESULTS: There were no
      significant changes of PI, RI and S/D ratios in umbilical arteries during
      misoprostol and oxytocin inductions. Vaginal application of misoprostol
      significantly increased PI, RI and S/D ratios in arcuate arteries and S/D ratio
      in uterine arteries. CONCLUSIONS: Our results indicate that intravaginal
      misoprostol administration increases uteroplacental resistance but probably does
      not substantially affect placental perfusion.

PMID- 10659898
TI  - Perforation in single- and double-gloving methods for cesarean section.
AB  - OBJECTIVE: To compare glove perforation between the single- and double-gloving
      method in cesarean section. METHOD: Three hundred primary surgeons selected at
      random to be two equal groups--single and double gloving in cesarean section--at
      Rajavithi Hospital from 1 November 1997 to 31 March 1998. The gloves were tested
      by immersing in water. The level of statistical significance was noted at P <
      0.05. RESULT: The prevalence of glove perforation was 10.67% and 2% in single-
      and double-inner glove, respectively, with significant difference. CONCLUSION:
      The double-gloving method had a significant benefit in protecting the primary
      surgeons' hands from exposure to blood compared with the single-gloving method in
      cesarean section.

PMID- 10659897
TI  - Plasma lipid concentrations in pre-eclamptic and normotensive Peruvian women.
AB  - OBJECTIVES: Dyslipidemia is thought to be of etiological importance in pre
      eclampsia. We studied the relationship between maternal plasma lipid
      concentrations and risk of pre-eclampsia. METHODS: A total of 125 pre-eclampsia
      cases and 179 normotensive control subjects were included in this case-control
      study conducted in Lima, Peru, between August 1997 and January 1998.
      Postdiagnosis, antepartum plasma lipid profiles were determined by standard
      enzymatic methods. Logistic regression procedures were used to calculate odds
      ratios (OR) adjusted for potential confounders. RESULTS: Mean plasma total
      cholesterol and triglyceride concentrations were, on average, 6% and 21% higher
      in pre-eclamptics than controls, respectively. High-density lipoprotein (HDL)
      cholesterol concentrations were, on average, 9% lower in cases than controls.
      After adjusting for maternal age, prepregnancy body mass index, education, parity
      and other potential confounders, the risk of pre-eclampsia increased with
      successively higher quartiles of plasma triglyceride (adjusted OR: 1.00, 1.62,
      2.21, 5.00, with the lowest quartile as referent; P-value for trend < 0.001). The
      association between pre-eclampsia risk and plasma total cholesterol was much less
      pronounced. In general, there was an inverse association between pre-eclampsia
      risk and HDL cholesterol concentration (adjusted OR: 1.00, 0.41, 0.50, 0.38, with
      the first quartile as the referent group; P-value for trend = 0.02). CONCLUSIONS:
      These findings suggest that high triglyceride and low HDL cholesterol
      concentrations are important risk factors for pre-eclampsia among Peruvian women.

PMID- 10659899
TI  - Prevalence and genotyping of HPV in cervical cancer among Australian women.
AB  - OBJECTIVE: To investigate the association between HPV DNA detection and
      histological examination of tumor biopsies from women with cervical cancer.
      METHOD: A total of 186 women with cervical cancer were screened for HPV infection
      using MY09/MY11 primer based PCR. The status of HPV infection was correlated with
      histological and demographic characteristics by Fisher's exact test or Chi square
      test. RESULT: The prevalence of HPV infection in this Australian population was
      91.9% (171). Among these 53.8% (100) were HPV type 16, 17.2% (32) HPV type 18,
      and 21.0% (39) other HPV types. Three significant associations were identified:
      (1) HPV genotype 18 and adenocarcinomas/adenosquamous carcinomas (P < 0.001); (2)
      HPV DNA negativity and postmenopausal status (P = 0.02); and (3) HPV DNA
      positivity and lymphocyte infiltration of tumor tissues (P = 0.03). CONCLUSION:
      HPV infection is present in the vast majority of cervical cancer patients.
      However, its presence or genotyping does not seem to have a major influence on
      the pathogenesis of cervical cancer, such as tumor grade, FIGO staging and
      metastasis (P > 0.1).

PMID- 10659900
TI  - Effect of Korean red ginseng on psychological functions in patients with severe
      climacteric syndromes.
AB  - OBJECTIVE: To evaluate the degree of psychological dysfunction and levels of
      stress hormones in postmenopausal women with climacteric syndromes and effect of
      Korean red ginseng (RG) on them. METHODS: ACTH, cortisol and DHEA-S in peripheral
      blood from 12 postmenopausal women with climacteric syndromes or 8 postmenopausal
      women without any climacteric syndrome were measured before and 30 days after
      treatment with daily oral administration of 6 g RG. Blood samples were collected
      in the early morning on the bed-rest. In postmenopausal women with climacteric
      syndromes such as fatigue, insomnia and depression, psychological tests using the
      Cornell Medical Index (CMI) and the State-Trait Anxiety Inventory (STAI) were
      performed before and 30 days after treatment with RG. RESULTS: CMI score as well
      as anxiety (A)-state in STAI score in postmenopausal women with climacteric
      syndromes was significantly higher than that without climacteric syndrome, while
      DHEA-S levels in postmenopausal women with climacteric syndromes were about a
      half of those without climacteric syndrome. Consequently, cortisol/DHEA-S (C/D)
      ratio was significantly higher in postmenopausal women with climacteric syndromes
      than in those without climacteric syndrome. When postmenopausal women with
      climacteric syndromes were treated with daily oral administration of 6 g RG for
      30 days, CMI and STAI A-state scores decreased within normal range. Although the
      decreased DHEA-S levels were not restored to the levels in postmenopausal women
      without climacteric syndrome, the C/D ratio decreased significantly after
      treatment with RG. CONCLUSIONS: Improvement of CMI and STAI scores in
      postmenopausal women suffering climacteric syndromes, particularly fatigue,
      insomnia and depression, by RG seemed to be brought about in part by effects of
      RG on stress-related hormones as shown by a decrease in C/D ratio.

PMID- 10659901
TI  - Prenatal diagnosis of giant hemangioma of the thigh.

PMID- 10659902
TI  - Pregnancy-induced hypertension and placenta previa: a racial and geographical
      perspective.

PMID- 10659903
TI  - Changes in service organization: antenatal care policy to improve attendance and
      reduce maternal mortality.
AB  - High cost and delay in service purchase are major contributory factors to the
      decline of utilization of maternity services at the UBTH.

PMID- 10659904
TI  - Uncommon adverse maternal effects with indomethacin for tocolysis.

PMID- 10659905
TI  - Maternal age as an independent risk factor for cesarean delivery.

PMID- 10659906
TI  - Myomectomy during cesarean section.

PMID- 10659907
TI  - Ovarian ectopic gestation carried to term.

PMID- 10659908
TI  - ACOG practice bulletin. Prophylactic oophorectomy. Number 7, September 1999
      (replaces Technical Bulletin Number 111, December 1987). Clinical management
      guidelines for obstetrician-gynecologists. American College of Obstetricians and
      Gynecologists.

PMID- 10659909
TI  - Direct cost of single dose methotrexate for unruptured ectopic pregnancy.
      Prospective comparison with laparoscopy.
AB  - OBJECTIVES: to compare the direct cost of single dose methotrexate (MTX) and
      laparoscopy in the treatment of unruptured ectopic pregnancy (unruptured EP).
      STUDY DESIGN: A prospective nonrandomized study. Thirty-two women received
      intramuscular MTX (1 mg/kg) on an out-patient basis when they fulfilled the
      following requirements: human chorionic gonadotropin (hCG) level <5000 IU/l,
      hematosalpinx diameter <3 cm and peritoneal fluid <100 cc. Follow-up consisted of
      clinical controls and hCG assays. Twenty-seven women eligible for MTX therapy
      according to the above conditions underwent laparoscopic salpingectomy because
      some of them refused the therapy while others had contraindications to MTX. We
      recorded all the medical expenses related to the out-patient and in-patient
      management for the two treatment options. The cost was calculated according to
      the French General Nomenclature of Professional Acts and expressed in Euros.
      RESULTS: MTX resulted in a significantly lower mean direct cost in comparison
      with surgery (E 1145 vs. 2442, P=0.006) that was mainly due to shortened hospital
      stay (1.1 vs. 2.8 days, P=0.007). Conversely MTX required a significantly higher
      number of medical acts during the follow-up. Costs for MTX therapy were closely
      related to the length of hospitalization and to the duration of the follow-up.
      CONCLUSION: Single dose MTX provides significant cost-savings when compared to
      laparoscopy. Savings reach a peak for small unruptured EP because hospitalization
      is not required and the length of follow-up reduced.

PMID- 10659910
TI  - A prospective study examining the association between the symptoms of anxiety and
      depression and severity of urinary incontinence.
AB  - OBJECTIVE: To investigate the association of the presence or absence of the
      symptoms of anxiety and depression compared with the 48 h pad test as an
      objective measure of incontinence. DESIGN: Prospective study. SETTING:
      Urodynamics clinic in a large teaching hospital. SUBJECTS: All patients with
      urinary incontinence attending for urodynamic assessment from 23.4.96 to
      29.10.96. INTERVENTIONS: 48 h pad test, Hospital Anxiety and Depression scale
      (HAD scale). MAIN OUTCOME MEASURES: Urodynamic diagnosis of cause of
      incontinence. Urinary loss over 48 h as measured by weight change in pads.
      Presence of symptoms of anxiety or depression as defined by HAD scale score of 8
      or more. RESULTS: Urodynamic investigation was performed for incontinence on 133
      patients. Of these 127 (95.4%) completed the HAD scale questionnaire. Of the 43
      patients (32.2%) who returned the pads 18 (41.8%) patients were found to have
      symptoms of anxiety and six patients (13.9%) had symptoms of depression. Patients
      with symptoms of anxiety had lower mean measured urinary loss over a 48 h period
      compared to women with no symptoms of anxiety (median loss 44.2 ml range 6.8
      622.4 versus 97.1 ml range 8.2-4384.4 ml) (P=0.05). There was no significant
      association between symptoms of depression and pad test results. CONCLUSIONS:
      Patients presenting with incontinence who have symptoms of anxiety are on average
      less incontinent compared to than those without symptoms of anxiety. It suggests
      that anxious patients present with a lesser degree of incontinence than
      nonanxious patients.

PMID- 10659911
TI  - Estroprogestin vs. gonadotrophin agonists plus estroprogestin in the treatment of
      endometriosis-related pelvic pain: a randomized trial. Gruppo Italiano per lo
      Studio dell'Endometriosi.
AB  - OBJECTIVE: This is a randomized clinical trial comparing estroprogestin (E/P)
      pill given for 12 months vs. gonadotrophin releasing hormone agonist (GNRHa)
      given for 4 months followed by E/P pill treatment for 8 months in the relief of
      endometriosis-related pelvic pain. METHODS: Eligible for the study were women
      with laparoscopically confirmed endometriosis and pelvic pain lasting 3-12 months
      after diagnosis. Eligible women were randomly assigned to treatment with E/P pill
      (gestroden 0.75 mg and ethynlestradiol 0.03 mg) for 12 months (47 patients) vs.
      tryptorelin 3.75 mg slow release every 28 days for 4 months followed by E/P pill
      for 8 months (55 patients). RESULTS: At baseline, dysmenorrhea was reported in 46
      women allocated to E/P pill only (97.9%), and in all the 55 women allocated to
      GNRHa+E/P pill. The corresponding value at the 12 months follow-up visit was 14
      subjects (35.9%) and 16 subjects (34.8%). The baseline median values of the
      multidimensional and analog scale were for dysmenorrhea 4 and 6 in the EP only
      and 3 and 6 in the GNRHa+E/P group. The corresponding value at the 12 months
      follow-up visit were 2 and 6 and 0 and 5. Non-menstrual pain was reported,
      respectively, at baseline and 12 month visit by 46 (97.9%) and 15 (38.5%)
      subjects in the E/P pill group and 49 (89.1%) and 17 (37.0%) of the GNRHa+E/P
      pill one. The baseline median values of the multidimensional and analog scale
      were for non-menstrual pain 3 and 5 in the E/P only and 2 and 6 in the GNRHa+E/P
      group. The corresponding values at the 12 month follow-up visit were 0 and 4 and
      0 and 4. These differences between the two groups were not statistically
      significant. CONCLUSIONS: 1 year after randomization, the two treatment schedules
      show similar relief of pelvic pain in women with endometriosis.

PMID- 10659912
TI  - Risks and benefits of beta-receptor blockers for pregnancy hypertension: overview
      of the randomized trials.
AB  - OBJECTIVE: Examine the benefits/risks of beta-blockers for pregnancy
      hypertension. STUDY DESIGN: Meta-analysis of relevant trials identified by
      comprehensive literature review (1966-97). RESULTS: Included were 30 trials for
      pregnancy hypertension, and four others for perinatal outcomes only. For mild
      chronic hypertension treated throughout pregnancy (n=2 trials), oral beta
      blockers (compared with no therapy) were associated with an inconsistent increase
      in small for gestational age (SGA) infants (OR 2.46 [1.02, 5.92]). For mild
      moderate 'late-onset' pregnancy hypertension (i.e. either chronic treated only
      late in pregnancy, or pregnancy-induced) (n=8 trials), oral beta-blockers
      (compared with no therapy) were associated with a decrease in severe hypertension
      (OR 0.27 [0.16, 0.451), borderline decrease in development of proteinuria (OR
      0.69 [0.48, 1.02]), decrease in RDS (OR 0.33 [0.13, 0.85]), but a borderline
      increase in SGA infants (OR 1.47 [0.96, 2.26]). Beta-blockers were equivalent to
      other agents (n=15 trials). For severe 'late-onset' pregnancy hypertension (n=5
      trials), i.v. labetalol produced less maternal hypotension (OR 0.13 [0.03, 0.71])
      and fewer cesareans (OR 0.23 [0.13, 0.63]) than i.v. hydralazine/diazoxide.
      CONCLUSIONS: It is not clear that the benefits outweigh the risks when beta
      blockers are used to treat mild to moderate chronic or pregnancy-induced
      hypertension, given the unknown overall effect on perinatal outcomes. For severe
      'late-onset' pregnancy hypertension, i.v. labetalol is safer than i.v.
      hydralazine or diazoxide.

PMID- 10659913
TI  - A population-based case-control teratologic study of oral oxytetracycline
      treatment during pregnancy.
AB  - OBJECTIVE: To study human teratogenic potential of oral oxytetracycline treatment
      during pregnancy. MATERIALS AND METHODS: The pair analysis of cases with
      congenital abnormalities and matched healthy controls in the large population
      based dataset of the Hungarian Case-Control Surveillance of Congenital
      Abnormalities, 1980-1996. RESULTS: Of 38,151 pregnant women who had babies
      without any defects in the study period (control group), 214 (0.6%) were treated
      with oral oxytetracycline. Of 22,865 pregnant women who had offspring with
      congenital abnormalities, 216 (0.9%) were treated with oxytetracycline (OR with
      95%: 1.7, 1.4-2.0). Different approaches in the study showed a higher rate of
      medically documented oxytetracycline treatment in the second months of gestation
      in neural-tube defects (OR with 95%: 9.7, 2.0-47.1), cleft palate (17.2, 3.5
      83.5) and multiple congenital abnormalities (12.9, 3.8-44.3) including mainly the
      combination of neural-tube defects and cardiovascular malformations. CONCLUSION:
      Treatment with oxytetracycline during the second months of pregnancy presents a
      teratogenic risk to the fetus.

PMID- 10659914
TI  - Perceived quality of care in pregnancy assessment before and after delivery.
AB  - OBJECTIVE: To assess the perceived quality of care in a group of pregnant women
      attended in a public Hospital. STUDY DESIGN: All pregnant women seen at the
      Hospital Clinic of Barcelona in 1996. Two study groups were defined: group A,
      women seen at the outpatient clinic as a regular follow-up visit for pregnancy,
      and group B, women seen at the outpatient clinic for follow-up after delivery. A
      satisfaction questionnaire survey was used in a random sample of both groups of
      women. RESULTS: Total number of interviews performed was 174. Both groups, A and
      B were comparable. Scores recorded in both groups were significantly different
      (P<0.01) for the clinical follow-up and privacy variables (regarded as better
      than expected). The difference in scores for the information supplied was also
      statistically significant (P<0.01), but regarded as worst than expected.
      CONCLUSIONS: The analysis of satisfaction does not seem to follow a linear,
      straightforward explanation. The differences seen strongly suggest the need of
      patient's satisfaction surveys to be specific by dimension and tailored to
      patients' expectations.

PMID- 10659915
TI  - Improving intrapartum surveillance: an individualised T/QRS ratio?
AB  - OBJECTIVES: To test the T/QRS ratio of the fetal electrocardiogram for normal
      distribution and assess the potential value of an individualised T/QRS ratio
      threshold to depict abnormality in the detection of fetal compromise during
      labour. STUDY DESIGN: A retrospective analysis of twenty intrapartum fetal
      electrocardiogram recordings obtained on the labour ward of the Queen's Medical
      Centre, Nottingham. RESULTS: In two of the twenty cases the T/QRS ratio was
      normally distributed. An increase in the T/QRS ratio over the 97.5th and 99.5th
      centile for 2 consecutive minutes, calculated on an individual basis, would
      appear to discriminate best between biochemically compromised and non-compromised
      fetuses. In no case was the T/QRS ratio seen to exceed 0.25 for periods
      previously described to be related to poor outcome. CONCLUSION: T/QRS ratio
      changes with individually calculated criteria for abnormality may be of benefit
      in the detection of fetal compromise but the effect on the intervention rate
      remains to be established. The use of an absolute threshold for T/QRS ratio
      abnormality which is based on the assumption of a normal distribution needs to be
      viewed with caution.

PMID- 10659916
TI  - The triple-marker test in predicting fetal aneuploidy: a compromise between
      sensitivity and specificity.
AB  - OBJECTIVE: to review the contribution of unconjugated estriol in Down's syndrome
      detection, and influence of maternal age, cut-off choice, and population
      specificity on the balance between triple-marker test sensitivity and
      specificity. STUDY DESIGN: Prenatal karyotyping was performed in 2833 pregnant
      women, 73% of them over the age of 34. Duration of gestation was determined by
      ultrasound in 98% of women. Prior to amniocentesis, the serum levels of alpha
      fetoprotein, human chorionic gonadotropin and unconjugated estriol were evaluated
      and corrected for weight. The risk of trisomy 21 was calculated for the first 986
      subjects using default medians, and for 1847 by our population-specific medians.
      The cut-off was initially 1:300 at term, but the 1:100 and 1:200 risks were also
      tested. Down syndrome risk was calculated with alpha-fetoprotein and human
      chorionic gonadotropin combination as well. Linear logistic regression model was
      performed to test the ability of aneuploidy markers to classify patients into
      normal and trisomic groups. RESULTS: There were twelve cases of Down's syndrome,
      seven of trisomy 18, four of trisomy 13, and one trisomy 22. Four cases of
      aneuploidy (16.7%) referred to women younger than 35. With the cut-off risk of
      1:300, detection rate was 87.5% and specificity 63.3%, and with 1:100, 66.7% and
      79.5%, respectively. The sensitivity for Down's syndrome was from 75% for cut
      off=1:100 to 92% for cut-off=1:300, while detection of other trisomies was less
      successful (58% and 83%, respectively). Exclusion of unconjugated estriol MoM
      from the risk calculations reduced detection rate by 33% and improved specificity
      by 4% independently of cut-off choice. Linear logistic regression analysis showed
      that only unconjugated estriol was able to correctly classify patients between
      normal and trisomy 21 (p=0.011, odds ratio=1.445), and normal and trisomy 18
      (p=0.0023, odds ratio=1.96) groups. CONCLUSIONS: The unconjugated estriol
      significantly contributes in Down's syndrome detection with cost of slightly
      reduced specificity. The 1:300 risk caused an unfavorable compromise between
      sensitivity and specificity. A higher cut-off, 1:100, would indicate performance
      of amniocentesis in women aged 39 years and older, and in those aged 35-39 only
      after the screen-positive result.

PMID- 10659918
TI  - Dating biometry during the first trimester: accuracy of an every-day practice.
AB  - OBJECTIVE: The goal of this study was to determine the accuracy of an every-day
      practice for assessing gestational age by ultrasound measurement of the greatest
      embryonic length (GEL). DESIGN: This retrospective study used measurements taken
      during the first trimester. SUBJECTS: We considered all births in this hospital
      between 1 January 1992 and 31 December 1994 from pregnancies that began by an in
      vitro fertilization procedure (IVF). We examined 143 consecutive files,
      containing 257 measurements made by 72 different operators. METHODS: The
      precision of seven embryo growth curves was compared. We calculated for each
      curve its ability to predict (95% prediction interval) the date the pregnancy
      began, using these dated pregnancies. RESULT: For GEL measurements between 3 and
      80 mm, which includes most of our population, Robinson and Wisser (2) were the
      most appropriate curves. The 95% prediction interval was 9.5 and 10.2 days
      respectively. CONCLUSION: Dating pregnancies in every-day practice with GEL is
      nearly as accurate as prospective studies with only one or two scanners.

PMID- 10659917
TI  - Maternal serum interleukin 1, 2, 6, 8 and interleukin-2 receptor levels in
      preterm labor and delivery.
AB  - OBJECTIVE: To determine the concentrations of maternal serum interleukins (ILs)
      1, 2, 6, 8 and IL-2 receptors (IL-2R) in patients in their second and third
      trimesters of pregnancy and in preterm labor and delivery without evidence of
      chorioamnionitis. STUDY DESIGN: The study was conducted in La Paz Maternal
      Hospital, Madrid. Maternal serum IL concentrations were measured in 103 gravidas
      during preterm labor and delivery. The Mann-Whitney U test was used for analysis.
      RESULTS: Women in preterm labor and delivery had significantly higher median IL
      2R concentration. Women who responded to tocolysis had significantly lower serum
      concentrations of IL-6. IL-2R and IL-6 serum concentrations predict delivery in
      48 h and before 34 weeks gestation. CONCLUSIONS: Compared with non-laboring
      gravidas, those in idiopathic preterm labor or delivery had significantly higher
      concentrations of maternal serum IL-2R. Both IL-6 and IL-2R may predict failure
      of tocolysis. IL-2 does not seem to play an important role in pregnancy.

PMID- 10659919
TI  - Perinatal audit on avoidable mortality in a Dutch rural region: a retrospective
      study.
AB  - OBJECTIVE: To analyse the mode and cause of perinatal mortality. SETTING: a rural
      Dutch region. STUDY DESIGN: Over a two-year period (1994-1995), data were
      collected in the 's Hertogenbosch region. A perinatal audit group investigated
      and classified the cause of death in an "intention to treat" and concensus model.
      We then analyzed who was responsible for the patient at the moment perinatal
      death occurred, or became inevitable. RESULTS: Out of 8509 newborns, 73 died
      between the 24th week of pregnancy till the 7th day post-partum (8.58 promille).
      Twenty-three cases (31.50%) were classified as probably or possibly avoidable. In
      the primary health care group (midwives, general practitioners) 6 out of 32
      (18.75%), in the secondary care group (obstetricians) 15 out of 35 (44.86%) and
      in the tertiary care group 1 out of 4 (25.00%) were judged as probably or
      possibly avoidable. The degree of concensus in the perinatal audit committee was
      high (Kappa=0.9). IMPACT: The analysis of perinatal mortality identifies the
      cause of death and may help to improve perinatal health care. CONCLUSION: In this
      study, 31.55% of perinatal mortality was avoidable in the three levels of care.
      Intra-uterine growth retardation, congenital malformations and antepartum
      haemorrhage were the most determinant factors for perinatal mortality. The Dutch
      obstetrical care system as such, for example home deliveries, did not effect the
      perinatal mortality rate. Perinatal mortality rates presented by the Dutch
      Central Bureau of Statistics still shows a slight underregistration.

PMID- 10659920
TI  - Rectal cancer in pregnancy: a new management based on blended anesthesia and
      monitoring of fetal well being.
AB  - Colorectal carcinoma presenting during pregnancy is an extremely rare condition
      associated with a poor prognosis. In this report we studied a patient referred to
      our hospital at 26 weeks of gestation with the diagnosis of rectal
      adenocarcinoma. Tumor resection with a colostomy was planned in the attempt to
      preserve pregnancy until fetal viability could be reached. Blended anesthesia
      (general and epidural) was chosen to avoid surgical and anesthesiological risks;
      in fact this technique allows either an optimal block of neurohormonal response
      or a good control of surgical stress to be obtained. In order to monitor fetal
      well being during surgery, Doppler evaluations of fetal heart rate and umbilical
      artery flow velocity waveforms were performed. The patient was dismissed in good
      health and then rehospitalized at 32 weeks of gestation in order to perform an
      elective cesarean section. In conclusion we suggest that, with the choice of a
      good anesthesiological technique and monitoring of fetal well being, surgical
      treatment in case of rectal cancer could be performed without affecting the
      course of pregnancy.

PMID- 10659922
TI  - Hysteroscopic metroplasty for septate uterus and repetitive abortions:
      reproductive outcome.
AB  - OBJECTIVES: The aim of this study is to assess fertility outcome and obstetrical
      prognosis of 63 patients after hysteroscopic section of uterine septa. MATERIALS
      AND METHODS: This is a retrospective study about 63 patients consulting for
      septate uterus and repeated pregnancy loss or abnormal fetal presentation between
      January 1988 and December 1996 in La Conception hospital in Marseille. Septal
      lysis was performed with microscissors or resectoscope. Statistical analysis was
      performed using the CHI2-test. RESULTS: The anatomical result was considered
      satisfactory in 57.1% of cases. Forty-five pregnancies were obtained, two after
      an IVF-program in 56 patients. Twenty-eight living children were born: twenty-six
      at term. Twenty patients delivered normally. Two women are still pregnant.
      Obstetrical prognosis of these patients is statistically improved by the
      treatment (P=0.001). CONCLUSION: Obstetrical prognosis of patients presenting
      repeated pregnancy loss and septate uterus is statistically improved by
      hysteroscopic metroplasty.

PMID- 10659921
TI  - Effect of grade on disease-free survival and overall survival in FIGO stage I
      adenocarcinoma of the endometrium.
AB  - OBJECTIVE: To analyse the effect of differentiation on disease-free survival
      (DFS) and overall survival (OS) in patients with stage I adenocarcinoma of the
      endometrium. PATIENTS AND METHODS: From 1979 to 1995, 350 patients with FIGO
      stage IA-IC with well (G1), moderately (G2) or poorly (G3) differentiated tumors
      were treated with surgery and high dose-rate brachytherapy with or without
      external radiation. Median age was 65 years (39-86 years). RESULTS: The 5-year
      DFS was 88+/-3% for the G1 tumors, 77+/-4% for the G2 tumors, and 67+/-7% for the
      G3 tumors (P=0.0049). With regard to the events contributing to DFS, the 5-year
      cumulative percentage of local relapse was 4.6% for the G1 tumors, 9.0% for the
      G2 tumors, and 4.6% (P=0.027) for the G3 tumors. Cumulative percentage of
      metastasis was 1.4, 6.3 and 7.2% (P<0.001), respectively, whereas percentages of
      death were 6.0, 7.9 and 20.7% (P<0.001). The 5-year OS was 91+/-3, 83+/-4 and
      76+/-7%, respectively (P=0.0018). In terms of multivariate hazard ratios (HR),
      the relative differences between the three differentiation groups correspond to
      an increase of 77% of the risk of occurrence of either of the three events
      considered for the DFS (HR=1.77, 95% CI [0.94-3.33]), (P=0.078) for the G2 tumors
      and of 163% (HR=2.63, 95% CI [1.27-5.43]), (P=0.009) for the G3 tumors with
      respect to the G1 tumors. The estimated relative hazards for OS are,
      respectively, in line with those for DFS: HR=1.51 (P=0.282) for the G2 tumors;
      and HR=3.37 (P=0.003) for the G3 tumors. CONCLUSION: Patients with grade 1 tumors
      are those least exposed to either local relapse, metastasis, or death. In
      contrast patients with grade 2 tumors seem to be at higher risk of metastasis,
      whereas patients with grade 3 tumors appear at higher risk of death. Since we
      have looked at the first of three competing events (local relapse, metastasis and
      death), this suggests that patients with grade 3 tumors probably progress to
      death so fast that local relapse, if any, cannot be observed.

PMID- 10659923
TI  - Fertility after hysteroscopic myomectomy: effect of intramural myomas associated.
AB  - OBJECTIVE: The aims of this retrospective study were to evaluate the subsequent
      fertility and outcome of pregnancies after hysteroscopic myomectomy according to
      (a) the characteristics of submucous myomas and (b) the association with
      intramural myomas. MATERIALS AND METHODS: From July 1994 to June 1997, 119
      patients had hysteroscopic myomectomy including 31 infertile women. Among these
      31 patients, the mean number of removed myomas by hysteroscopy was 1.4 (range 1
      4) and the mean diameter of fibroid was 20 mm (range 10 to 50). RESULTS: Eleven
      out of 31 women (35.5%) became pregnant. Thirteen pregnancies were observed
      including nine term deliveries, three miscarriages and one premature labor at 24
      weeks of amenorrhea. A difference in delivery rate was found between patients
      with one submucous myoma resected and those with two or more (p=0.02). No
      difference in pregnancy and in delivery rates was observed according to size and
      location of submucous myomas. In contrast, in patients without intramural myomas,
      the delivery rate (p<0.03) was significantly greater and the delay of conception
      (p=0.05) was significantly shorter than those found in patients with intramural
      myomas. CONCLUSION: Our study suggest that fertility after hysteroscopic
      myomectomy depend on (a) the number of submucous myomas resected and (b) the
      association with intramural fibroids.

PMID- 10659924
TI  - A randomized study of the effects of tibolone and transdermal estrogen
      replacement therapy in postmenopausal women with uterine myomas.
AB  - OBJECTIVE: To evaluate the effects of two types of hormone replacement therapy,
      an estrogen-progestin combination and tibolone, on uterine myomas in menopausal
      women. STUDY DESIGN: Thirty-eight menopausal women with one or more uterine
      myomas were randomized to treatment with a transdermal system continuously
      releasing estradiol 50 microg/day combined with oral medroxyprogesterone acetate
      (MPA) 10 mg/day for 12 days/month or tibolone tablets 2.5 mg/day. The scheduled
      duration of both treatments was 12 months. Physical examination and
      abdominal/transvaginal ultrasonography were performed before entering the study
      and at 3, 6 and 12 months of treatment. At each ultrasonography the overall
      uterine volume was determined as well as the size of each myoma and the
      endometrial thickness and characteristics. RESULTS: No statistically significant
      difference was detected between the two groups at any time during treatment.
      However, within-group analysis showed a significant increase of uterine volume
      and of myoma number and size in the estrogen-progestin group, whereas no such
      increase occurred in the patients treated with tibolone. Also, the mean
      endometrium width increased significantly from baseline to the end of treatment
      in the estrogen-progestin group, but not in the tibolone group. CONCLUSIONS:
      Tibolone seems a valid alternative in menopausal patients with uterine myomas as
      it provides adequate relief from menopausal symptoms and avoids volume increase
      of the uterus and myomas.

PMID- 10659925
TI  - Transverse uterine incision non-closure versus closure: an experimental study in
      dogs.
AB  - This study was conducted to test the hypothesis that non-closure of all layers of
      the uterus during low transverse cesarean section is not associated with
      increased intra-operative or immediate and late postoperative complication.
      Eleven pregnant dogs underwent cesarean section for the evaluation of non-closure
      and closure of all layers of the uterus on immediate or early and late
      postoperative complication and the effect of suture in tissue. Statistical
      analysis was performed using Student's t-test for continuous variables and
      analysis for qualitative variables. Significance was defined as P < 0.05. The
      ranges of wound infection, other morbidity, and mortality were similar between
      the groups. The average operating time was significantly less for the non-closure
      group (71.00+/-7.11 min) than for the closure group (92.00+/-6.12 min; P <
      0.005). Adhesion was significantly less (P < 0.001) for the non-closure group
      than for the closure group. The ranges of myometrial necrosis (5/5: 100% versus
      0/5: 00%; P < 0.001) and fibrosis (2/5: 40% versus 0/5: 00%; P < 0.01) were
      significantly higher for the closure group than for the open group. It was found
      that non-closure of all layers of the uterus at low transverse cesarean incision
      had no adverse effect on immediate and late postoperative complication in dogs.
      Our data show that non-closure of all layers of the uterus at low transverse
      cesarean incision results in significantly less muscular necrosis and fibrosis
      than in the closure group. We suggest that non-closure and/or at least non
      vigorous locking but very simple closure of all layers of the uterus at low
      transverse cesarean incision may be preferential in appropriate cases.

PMID- 10659926
TI  - Subsequent successful pregnancy and delivery after intracytoplasmic sperm
      injection in a patient with XY gonadal dysgenesisms.
AB  - Report of a rare case of subsequent twin delivery after intracytoplasmic sperm
      injection (ICSI) into donated oocytes in a 30-year-old woman with a diagnosis of
      XY dysgenesis, who underwent a gonadectomy at the age of 13 years. Her husband
      suffers from severe oligo-astheno-terato-spermia.

PMID- 10659927
TI  - Polypoid endocervical stromal sarcoma with heterologous elements. Report of a
      case with review of the literature.
AB  - A 44 year old woman presented with six recurrent endocervical polyps within the
      span of 28 months. The last two of these polyps exhibited sarcomatous changes
      within the endocervical stroma with heterologous cartilagenous elements.
      Abdominal hysterectomy with bilateral salpingo-oophorectomy was performed. No
      chemotherapy or radiotherapy was administered. The patient is alive and free of
      recurrent disease 9 years following surgery.

PMID- 10659928
TI  - A case of postpregnancy osteoporosis.
AB  - A puerperant woman, who was previously healthy and had no disease known to affect
      bone metabolism, experienced lower back pain and lumbar vertebral fractures
      during lactation. Both bone formation markers and resorption markers were
      markedly elevated. Bone mineral density of the lumbar spine as measured by dual
      energy X-ray absorptiometry was extremely low. She stopped lactation through the
      use of bromocriptine because of the large volume of milk secretion. After
      treatment with calcitonin injections and the use of a corset, her back pain
      gradually disappeared. This case appears to be postpregnancy osteoporosis.

PMID- 10659929
TI  - IMIA Working Group 13: organizational impact of medical informatics.
AB  - In 1993 the International Medical Informatics Association approved a working
      group whose purpose focused on the people and organizational issues surrounding
      the use of computers in health care. This article outlines two key concepts that
      act as the guiding principles for the working group's efforts. The concepts are:
      applying the knowledge of human behaviors toward the use of information or
      information technology within a health care environment and effectively
      incorporating human factors, culture, change, and organizational and human
      engineering in the medical informatics processes. These concepts are further
      supported by functional statements and a strategy to ensure the principles are
      effectively diffused in the medical informatics community. The concepts,
      functional statements and process were adopted by the working group and are
      outlined in this article.

PMID- 10659930
TI  - IMIA Working Group 15: technology assessment and quality development in health
      informatics.
AB  - The working group on technology assessment and quality development in health
      informatics was established as a follow-up to the recommendations made at the
      IMIA-ISTAHC working conference in 1990. The working group was approved by the
      IMIA General Assembly at Kyoto, September, 1993. The working group aims to
      further develop the field of technology assessment and quality development in
      health informatics, by: promoting consensus development on methodological issues;
      promoting comprehensive assessment of health care information technologies, for
      instance by providing expertise; demonstrating the value and importance of
      assessment of health care information technologies, to health care decision
      makers, health care providers and developers of information technologies.

PMID- 10659931
TI  - Information systems evaluation and subjectivity.
AB  - This paper claims that, when evaluation of information systems is at stake, it is
      impossible in most cases to discard human subjectivity in the same way that one
      cannot discard quality of life when a therapeutic strategy is to be evaluated.

PMID- 10659932
TI  - Cultural aspects of information technology implementation.
AB  - Culture sets our values and norms. It is a way of thinking that determines our
      behaviours, decisions, actions and knowledge. Technology transfer and integration
      are basically the exchange of the knowledge, know-how and skills through which
      technology was created and on which its use depends. Culture is deeply rooted in
      ourselves. We are usually unaware of its influence on our professional activity.
      Cultures are diverse, and their encounter through technology exchange triggers
      conflicts that are expressed in objective terms. We need to detect and resolve
      those conflicts at the right level, i.e. at the cultural level instead of only
      focusing on the visible 'obstacles' to the deployment of telematics applications.
      This paper summarises the basic concepts on which we ground a practical approach
      to detecting and resolving culture-based conflicts in technology transfer and
      integration. It investigates the relation between cultural preferences and
      actions. Culture is translated and reduced to a seven dimensions framework.
      Cultural preferences influence the decision-making process that leads to tangible
      actions. The structure and dynamics of that process are described as a Change
      Governance Framework. It considers the control aspects of decision making that
      are sensitive to cultural preferences, i.e. the way decisions are taken, why, by
      whom.

PMID- 10659933
TI  - Using a descriptive model of change when implementing large scale clinical
      information systems to identify priorities for further research.
AB  - In this paper we identify domains for research based on a model that describes
      the stages of change when designing and implementing large scale information and
      communication technology throughout a healthcare organization. We use the model
      in the case of the electronic patient record systems. We suggest that the
      research agenda should include approaches from the social and business sciences.

PMID- 10659934
TI  - The contextual nature of medical information.
AB  - Successful design of information systems in health care starts with a thorough
      understanding of the practices in which the systems are to function. In this
      paper, we discuss the nature of 'medical information' from a sociological
      perspective. We focus on the (im)possibilities of the utilization of primary
      health care data for secondary purposes such as research and administration. In
      much of the literature on EPRs, this secondary utilization is only seen to depend
      on the question whether the IT connections are in place. It is then simply a
      matter of selecting which information to transport and to where. In this article,
      we argue that this view of medical information is mistaken. Information should be
      conceptualized as always entangled with the context of its production. The
      disentangling of information from its production context is possible, but that
      entails work. We propose the following 'law of medical information': the further
      information has to be able to circulate (i.e. the more diverse contexts it has to
      be usable in), the more work is required to disentangle the information from the
      context of its production. The question that then becomes pertinent is; who has
      to do this work, and who reaps the benefits?

PMID- 10659935
TI  - Organisational learning within health care organisations.
AB  - The demands on the health care sector are increasing both from the outside, e.g.
      political push for cost containment, improved service and quality, and from
      within as new technologies and procedures are introduced. This calls for an
      organisation that can adjust to new conditions through flexibility and
      creativeness. The concept of organisational learning has been introduced as a
      potential way to meet these challenges. The objectives for this paper are to
      focus on central topics within the concept of organisational learning relevant
      for health care organisations and discuss the consequences of these applied to
      health care organisations.

PMID- 10659936
TI  - Methodology for constructive assessment of IT-based systems in an organisational
      context.
AB  - Even if painted in black and white, there is no doubt that the assumptions for
      the application of traditional approaches for user requirements specification are
      more or less unfulfilled. This indicates a need for evolutionary system
      development combined with constructive assessment throughout the life-cycle of an
      IT-based solution. A methodology for constructive technology assessment is
      presented, which 1) covers the entire system life-cycle; 2) has users from the
      application domain of the future system, or their representatives, as the target
      users of the assessment methodology; 3) enables constructive assessment during
      the development of an IT-based solution; 4) is applicable independently of the
      system development approach; and 5) provides users of the IT-based solution with
      information enabling them to decide whether or not to take the system into real
      life clinical usage.

PMID- 10659937
TI  - Inventory of validation approaches in selected health telematics projects.
AB  - This paper presents the results from an inventory of validation approaches and
      methodologies which have been used in selected health telematics projects. The
      inventory was performed in the VATAM Validation of Telematic Applications in
      Medicine project, HC1115HC. The purpose of the inventory was to analyse the
      methodologies and their application assumptions in order to identify
      possibilities for harmonization and consolidation. The inventory was performed
      using five validation dimensions: IT-development; quality; user; technology
      assessment and marketing. The inventory results show that possibilities exist to
      synthesise methodologies and to provide practical guidance and support for
      projects that are developing health telematics applications. All stakeholders in
      health telematics projects, i.e. users, health care decision-makers, developers,
      suppliers and IT-industries, can benefit from practical validation guidelines and
      support for validation when guidelines are represented in a usable, easy to
      access and informative way.

PMID- 10659938
TI  - Methodological approaches of health technology assessment.
AB  - In this era of evolving health care systems throughout the world, technology
      remains the substance of health care. Medical informatics comprises a growing
      contribution to the technologies used in the delivery and management of health
      care. Diverse, evolving technologies include artificial neural networks, computer
      assisted surgery, computer-based patient records, hospital information systems,
      and more. Decision-makers increasingly demand well-founded information to
      determine whether or how to develop these technologies, allow them on the market,
      acquire them, use them, pay for their use, and more. The development and wider
      use of health technology assessment (HTA) reflects this demand. While HTA offers
      systematic, well-founded approaches for determining the value of medical
      informatics technologies, HTA must continue to adapt and refine its methods in
      response to these evolving technologies. This paper provides a basic overview of
      HTA principles and methods.

PMID- 10659939
TI  - The VATAM guidelines.
AB  - Evaluation and assessment of the impact of information and communication
      technology in medicine is gaining interest. Unfortunately, till now there were no
      agreed upon approaches. The objective of the VATAM project is to develop
      guidelines that will assist assessors to set-up and execute studies. This paper
      describes the background of the VATAM project and provides an account of the
      current state of the guidelines. It concludes with an indication of the
      developments that will take place in the short term to further elaborate the
      guidelines and some considerations for consolidation of VATAM's results.

PMID- 10659940
TI  - The behavioral side of information technology.
AB  - Exposure to technologies is becoming more prevalent in healthcare technologies.
      Few strategies have been developed that work reliably to successfully implement
      information technologies. Information technology enables, but does not guarantee
      organizational change. A theoretical model has been developed identifying several
      areas that have been found important in information technology implementation.
      The information technology adoption model is described, and provides a framework
      for implementors of information technologies. It provides a structure to
      categorize areas that may benefit from the development of implementation
      strategies and the development of evaluation techniques. Implementation and
      evaluation strategies are discussed as they pertain to end-user fit, user
      perceptions of innovation usefulness and ease of use, and adoption and
      utilization.

PMID- 10659941
TI  - IT, change and evaluation: an overview of the role of evaluation in health
      services.
AB  - Effective evaluation is important for appropriate deployment and use of
      information technology, especially in the current environment of changing health
      services. However, the broad range of roles and environments in which technology
      is used challenges traditional evaluation approaches. As technology has
      progressed, these roles have developed to the extent that information technology
      is now often playing a very complex role in health service organisations. In such
      cases there are many uncertainties in decisionmaking that are difficult to
      address with traditional formal evaluation techniques. There is a need to
      recognise and work with more complex, socially constructed decisionmaking process
      relying substantially on a variety of human judgements. The need for this
      recognition is demonstrated by exploring the difference in our ability to analyse
      a range of different systems, considering the role of complexity, uncertainty,
      theory, change and control. There is the need, then, for evaluation processes to
      complement these social decisionmaking processes, rather than to replace them.
      The nature of these processes needs to be effectively understood to enable the
      most appropriate types of evaluations to be undertaken. A number of different
      scenarios are explored to demonstrate the types of roles that evaluation may need
      to take.

PMID- 10659942
TI  - Information technology as tool for change.
AB  - It looks that networking welfare thinking and implementations of network projects
      only follow the development of data transfer possibilities. It is a danger that
      seamless chain of care in health care is just a data transferring generator based
      on easy connections, only creating needs for new data transferring. This is an
      'illusion of core skills' that does not extend to the development of the contents
      of services. Easy access to the system makes more contacts and need for more also
      clinical services. New needs for data transfer burden the personnel with
      unnecessary information and networking functional model does not emancipate them
      to use their substantial skills. It means more costs and it is also a danger that
      normal life will be medicated. Public sector cannot finance all these new
      possibilities and consequences of modern technology. Does all this create a new
      combination of public and private sector and push them to allocate
      responsibilities in developing work? If the public and private sectors do not
      find the balance in controlling this development, also actors outside health care
      get to influence the choices and health care loses its autonomy. It becomes a
      business means for companies producing data transfer and network services. From
      the prioritization point of view this is not a good vision for financing and
      delivery of health care services either in public or private sector.

PMID- 10659943
TI  - Health informatics as a tool to improve quality in non-acute care--new
      opportunities and a matching need for a new evaluation paradigm.
AB  - Whilst most health care is delivered to people living at home, the focus of
      innovation in health informatics concepts has been largely on acute hospitals.
      However, delivery of services in community settings, and often related to long
      term conditions, is complex, and involves multiple professions and agencies,
      delivery of care in several locations including home settings, and individually
      tailored care for episodes lasting over long periods of time. This challenge is
      poorly supported by current information systems. However, computer-based record
      systems have a major potential to improve quality of care by enabling integrated
      care delivery through multi-professional electronic patient records, whilst also
      providing quality assurance processes. In turn, though, this requires a new
      evaluation paradigm. Firstly, the multi-disciplinary and holistic ideal of
      integrated care requires an as yet inadequately developed framework to give
      structure to assessment of the value and utility of the data recorded and the way
      in which they are processed and presented, mapped to clinical processes and to
      the views of consumers as prime stakeholders. Secondly, a deeper and longer-term
      evaluation philosophy is needed which does not stop after the initial
      confirmation of system functioning, but continues on with a deepening into the
      effects on the individual clinical services, and then on the host user
      organisation. This paper maps out the new paradigm, and suggests specific issues
      which merit practical research to reset evaluation and assessment tools to this
      new setting and viewpoints.

PMID- 10659944
TI  - The use of clinical information to help develop new services in a district
      general hospital.
AB  - This paper describes a case study of the use of clinical information to improve
      gastroenterological services in a district general hospital. The clinical
      information has been derived from aggregation and analysis of operational
      clinical data collected in coded, structured form on a clinical information
      system over a period of 8 years. The monitoring of activity, referral patterns
      and administrative and clinical outcomes, and the use of this information to
      develop new services to improve access to patients are described. It is concluded
      that the secondary use of clinical information derived from electronically
      captured data can have a significant impact on the development of services by a
      provider organisation, and on professional teamworking.

PMID- 10659945
TI  - Criteria for the evaluation of district health information systems.
AB  - A comprehensive set of evaluation criteria for District Health Information
      Systems (DHISs) in South Africa (SA) have been developed. The criteria are
      organised in the following eight categories: philosophy and objectives, policy
      and procedures, functionality, facilities and equipment, DHIS management and
      staffing, user/patient interaction, staff development and education, and
      evaluation and quality improvement. A handbook of evaluation criteria has been
      compiled by restating the evaluation criteria to include mechanisms for measuring
      whether or not criteria have been met.

PMID- 10659946
TI  - Considerations on the quality of medical software and information services.
AB  - Fast developments in information and communication technology have made it
      possible to develop new services for citizens. One of the most interesting areas
      is health care. Medical knowledge is usually valid all over the world that makes
      the market global. Information services and decision support software are
      becoming important tools for medical professionals but also ordinary citizens are
      interested in health related information. It has been estimated that by the year
      2010 the turnover of health care telematics industry may be close to that of the
      drug industry today. The nature of this global information industry is very
      different from any industry in history. Since there are no frontiers, no clear
      products and no shops in the information market, it is difficult to develop any
      effective legislation. However, the history of medicine has shown that health
      care sector cannot be free from regulation without risking citizens' health. The
      huge commercial potential of the Internet has already been used to promote
      products and services that have no proven effect on health and that may sometimes
      be even dangerous. In this paper we discuss the needs and possibilities to assess
      the quality of medical decision support software and information services. For
      brevity the terms medical software and medical knowledge are used, but the issues
      also relate to informatics systems used by any health professional, and to
      computerised systems used to schedule care or to organise record systems.

PMID- 10659947
TI  - Results of discussions at the IMIA WG 13 and 15 working conference.

PMID- 10659948
TI  - Molecular modelling of human CYP2E1 by homology with the CYP102 haemoprotein
      domain: investigation of the interactions of substrates and inhibitors within the
      putative active site of the human CYP2E1 isoform.
AB  - 1. The construction of a three-dimensional model of human CYP2E1 is reported. It
      is based on homology with the haemoprotein domain of the unusual bacterial P450,
      CYP102, which is of known crystal structure. 2. Interactive docking of a number
      of human CYP2E1 substrates is consistent with their known positions of CYP2E1
      mediated metabolism, where specific interactions with key active site amino acid
      side-chains appear to rationalize the binding and orientation of substrate
      molecules. 3. Amino acid residues within the putative active site of human
      CYP2E1, including those associated with the binding of substrates and inhibitors,
      are shown to correspond with those identified by site-directed mutagenesis
      experiments conducted on CYP2 family isoforms, and they are known to affect
      substrate metabolism regioselectivity. 4. Consequently, it was found that the
      CYP2E1 active site exhibits complementarity with the structural characteristics
      of known substrates and inhibitors of this enzyme, including their relatively low
      molecular weights and disposition of hydrogen bond-forming groups.

PMID- 10659949
TI  - Cytochrome P450 enzyme activity and protein expression in primary porcine
      enterocyte and hepatocyte cultures.
AB  - 1. A method for the isolation and cultivation of porcine hepatocytes and porcine
      duodenal enterocytes for the investigation of drug oxidation reactions has been
      established. 2. Hepatocytes as well as enterocytes metabolized ethoxyresorufin
      (EROD) and ethoxycoumarin (ECOD) effectively, the rate being 31+/-17 pmol/h x
      dish (EROD) and 9530+/-4062 pmol/h x dish (ECOD) in the case of hepatocytes, and
      9+/-4 pmol/h x dish (EROD) and 510+/-467 pmol/h x dish (ECOD) in the case of
      enterocytes. Diazepam, another CYP monooxygenase substrate, was also metabolized
      by porcine hepatocytes but not with porcine enterocytes, thus indicating
      differences in the metabolic competence of the liver and the gut. 3. The ability
      to induce enzymes responsible for the metabolism of ethoxyresorufin and
      ethoxycoumarin was investigated in vitro on treatment of the cell cultures with
      either 50 microM 3-methylcholanthrene (3-MC) or 50 microM beta-naphthoflavone
      (beta-NF). With enterocyte cultures, ECOD activity was inducible up to 20-fold,
      whereas EROD remained unchanged following treatment with either 3-MC or beta-NF.
      4. Western blotting provided additional evidence for the expression of CYP1A1 and
      CYP3A4 at the protein level and treatment of cultured enterocytes with 30 microM
      Aroclor 1254 or 50 microM beta-NF resulted in enhanced expression of the CYP1A
      protein, and CYP3A4 protein expression was induced following treatment with 50
      microM DEX, 2 mM PB, 30 microM Aroclor 1254 or 50 microM beta-NF. 5. The
      metabolism of diazepam was also investigated with baculovirus-expressed human CYP
      enzymes (2C8, 2C9-ARG, 2C9-CYS, 2C19, 3A4, 3A4+cytochrome b5 and 3A5) and
      evidence was obtained to suggest the formation of temazepam and oxazepam by
      enzymes of the CYP3A subfamily. Small amounts (32+/-12 ng/ml) of
      desmethyldiazepam were additionally recovered in microsomal preparations of all
      CYP-transfected cell lines. 6. In conclusion, porcine duodenal enterocytes can
      successfully be cultured for a short period and may be used as a tool for
      studying intestinal metabolism, whereas porcine hepatocytes can be cultured for
      prolonged periods (>10 days) reliably to investigate hepatic drug oxidation
      reactions.

PMID- 10659951
TI  - In vitro inhibitory effects of troglitazone and its metabolites on drug oxidation
      activities of human cytochrome P450 enzymes: comparison with pioglitazone and
      rosiglitazone.
AB  - 1. Investigated were the effects of a new oral antidiabetic drug, troglitazone,
      and its three metabolites and antidiabetic drug candidates pioglitazone and
      rosiglitazone on xenobiotic oxidations catalyzed by nine recombinant human
      cytochrome P450 (P450 or CYP) enzymes and by human liver microsomes. 2.
      Troglitazone (5 microM) significantly inhibited CYP2C8-dependent paclitaxel
      6alpha-hydroxylation and CYP2C9-dependent S-warfarin 7-hydroxylation. On the
      other hand, pioglitazone and rosiglitazone (50 microM) only slightly inhibited
      these xenobiotic oxidation activities catalyzed by CYP2C enzymes. 3. The
      inhibitory potential of troglitazone (50% inhibition concentration, IC50) was
      approximately 5 microM for drug oxidations catalyzed by CYP2C9 and CYP2C8 and
      approximately 20 microM for activities catalyzed by CYP2C19 and CYP3A4
      respectively. For the three metabolites of troglitazone tested, a quinone-type
      metabolite (M3) was the most potent inhibitor for CYP2C enzymes, followed by a
      sulphate conjugate (M1); effects of a glucuronide (M2) were very weak. The
      inhibitory effects of the parent drug were more potent than those of metabolites.
      Troglitazone and M3 inhibited P450 activities mainly through a competitive manner
      with Ki = 0.2-1.7 microM and 1.4-8.8 microM respectively. 4. In three human liver
      microsomes, troglitazone and its metabolites also inhibited paclitaxel 6alpha
      hydroxylation, S-warfarin 7-hydroxylation, S-mephenytoin 4'-hydroxylation, and
      testosterone 6beta-hydroxylation with similar IC50, as observed for the
      recombinant P450 enzyme systems. 5. These results suggest that xenobiotic
      oxidations by P450 enzymes are more substantially affected by troglitazone and
      its metabolites than pioglitazone or rosiglitazone, and that drug interactions
      may be of much importance to understand the basis for the pharmacological and
      toxicological actions of this new oral antidiabetic drug.

PMID- 10659950
TI  - Interspecies comparison and role of human cytochrome P450 and flavin-containing
      monooxygenase in hepatic metabolism of L-775,606, a potent 5-HT(1D) receptor
      agonist.
AB  - 1. Quantitative species differences and human liver enzymes involved in the
      metabolism of L-775,606, a potent and selective 5-HT1D receptor agonist developed
      for the acute treatment of migraine headache, have been investigated in vitro. 2.
      In human, monkey, dog and rat liver microsomes, formation of the hydroxylated M1
      and the N-dealkylated M2 was mediated by enzyme(s) of high-affinity (apparent Km
      approximately 1-6 microM), and that of the two N-oxide isomers (M3) was catalysed
      by those of low affinity (apparent Km approximately 50-110 microM). In dog, M3
      constituted a major pathway (approximately 40%), whereas in all other species it
      was a minor metabolite (< 5%). 3. In human liver microsomes, a marked inhibition
      (> or =80%) of M1 and M2 formation was observed by SKF525-A, troleandomycin,
      ketoconazole and anti-CYP3A antibodies, whereas the inhibition was modest
      (approximately 20-40%) with quercetin. Of seven cDNA-expressed human P450 tested,
      only CYP3A4 and CYP2C8 were capable of oxidizing L-775,606, resulting primarily
      in M1 and M2. However, CYP3A4 possessed much higher affinity (> or = 20-fold) and
      much higher intrinsic activity (> 100-fold) than CYP2C8. 4. In contrast, N
      oxidation was not inhibited by any inhibitors of P450 tested, but rather was
      reduced significantly by heat treatment and methimazole, and was increased
      substantially with an incubation pH>7.4. Human flavin-containing monooxygenase
      form 3 (FMO3) catalysed exclusively the N-oxidation to M3, with apparent Km and
      optimum pH comparable with those observed in human liver microsomes. 5. These
      results demonstrated quantitative interspecies differences in the metabolism of L
      775,606. In human, metabolism of L-775,606 to the principal metabolites, M1 and
      M2, was mediated primarily by CYP3A4 with minimal contribution from CYP2C8,
      whereas the minor N-oxidative pathway was catalysed mainly by FMO3.

PMID- 10659953
TI  - Pronounced differences in inhibition potency of lactone and non-lactone compounds
      for mouse and human coumarin 7-hydroxylases (CYP2A5 and CYP2A6).
AB  - 1. The structural requirements for a compound to be a potent inhibitor for mouse
      CYP2A5 and human CYP2A6 enzymes catalysing coumarin 7-hydroxylase activity have
      been studied. 2. The IC50 of 28 compounds for the pyrazole-treated male DBA/2
      mouse and human liver microsomal coumarin 7-hydroxylation were determined at 10
      microm coumarin concentration 15 times over Km of coumarin. 3. The three most
      potent inhibitors for CYP2A5 were gamma-nonanoic lactone, gamma-decanolactone and
      gamma-phenyl-gamma-butyrolactone with an IC50 = 1.9+/-0.4, 2.1+/-0.2 and 2.4+/
      0.3 microM and for CYP2A67-methylcoumarin, butylcyclohexane and indan with an
      IC50. = 30+/-3.2, 43+/-9 and 50+/-11 microM. 4. Among the 28 compounds studied,
      only 2-benzoxazolinone, 2-indanone and gamma-valerolactone showed similar
      inhibitory activity in both species. Indan had a lower IC50 for human than for
      mouse coumarin 7-hydroxylation, whereas the IC50 of 24 other compounds was higher
      for human than for mouse coumarin 7-hydroxylation. 5. The largest difference in
      IC50 between mouse and human activity was observed with 5-substituted phenyl,
      pentyl, hexyl, heptyl or octyl gamma-lactones or 6-substituted delta-lactones.
      IC50 of gamma-undecanolactone and gamma-decanolactone was 500 times lower for
      mouse than human coumarin 7-hydroxylation. 6. The difference in the IC50 between
      human and mouse coumarin 7-hydroxylation decreased substantially with the
      corresponding compounds without the lactone ring. 7. It is concluded that certain
      5- or 6-position substituted gamma- and delta-lactones are potent inhibitors for
      mouse CYP2A5 but not for the orthologous human CYP2A6 and that the active site of
      CYP2A6 could be smaller than the active site of CYP2A5.

PMID- 10659952
TI  - Identification of CYP3A4 as the predominant isoform responsible for the
      metabolism of ambroxol in human liver microsomes.
AB  - 1. In humans, ambroxol is metabolized to dibromoanthranilic acid (DBAA) and 6,8
      dibromo-3-(trans-4-hydroxycyclohexyl)-1,2,3,4-tetrahydroquinazoli ne (DHTQ). The
      formation of DHTQ proceeds non-enzymatically, whereas that of DBAA requires
      NADPH. Studies have been performed to identify the CYP isozyme(s) involved in the
      formation of DBAA using human liver microsomes and microsomes expressing
      recombinant human CYP isozymes (1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4
      and 4A11). 2. The apparent Vmax and Km for the formation of DBAA were 472+/-192
      pmol/ min/mg protein and 248+/-40.6 microM respectively (mean +/- S.D., n = 3).
      3. Of the recombinant CYP examined, only CYP3A4 metabolized ambroxol to DBAA. The
      apparent Vmax and Km were 1.42 pmol/min/pmol P450 and 287 microM respectively. 4.
      Among the CYP inhibitors examined (furafylline, sulphaphenazole, quinidine,
      diethyldithiocarbamic acid, ketoconazole), only ketoconazole inhibited the
      production of DBAA (> 80%) at 1 microM and anti-CYP3A antiserum almost completely
      inhibited the formation of DBAA. 5. These results suggest that CYP3A4 is
      predominantly involved in the metabolism of ambroxol to DBAA in humans.

PMID- 10659954
TI  - Comparison of the pharmacokinetics of verapamil in the pregnant and non-pregnant
      rabbit: study of maternal and foetal tissue levels.
AB  - 1. The comparison of the pharmacokinetics of verapamil (VER) has been studied
      between the non-pregnant and pregnant rabbit following VER intravenous (i.v.)
      bolus administration. Also studied has been VER tissue distribution in the non
      pregnant and pregnant rabbit and its foetuses following an i.v. infusion of VER.
      2. When the pharmacokinetic variables were compared between the pregnant and non
      pregnant rabbit, it was observed that t(1/2)lambda2 V1 and V(D) were
      significantly higher in the non-pregnant than in the pregnant rabbit. Moreover,
      lambda(z) was significantly lower in the non-pregnant than in the pregnant
      rabbit. However, AUC and CL showed no significant differences between the
      pregnant and non-pregnant rabbit. 3. When tissue concentrations were examined, it
      was found that in most of the tissues studied high concentrations of VER were
      found both in the pregnant and non-pregnant rabbit. Furthermore, VER
      concentrations in the uterus, heart, spleen and kidney were significantly higher
      in the non-pregnant than in the pregnant rabbit. 4. The results suggest that VER
      diffuses poorly through the placenta, given that VER blood concentrations were
      lower in blood foetuses than in maternal blood. Moreover, the concentrations of
      VER in the selected foetal tissues were either similar (brain and liver) or lower
      than those observed in maternal tissues.

PMID- 10659955
TI  - Biotransformation of the xanthine oxidase inhibitor BOF-4272 and its metabolites
      in the liver and by the intestinal flora in rat.
AB  - 1. BOF-4272, (+/-)-8-(3-methoxy-4-phenylsulfinylphenyl) pyrazolo[1,5-a]-1,3,5
      triazine-4(1H)-one), is a new drug intended for the treatment of hyperuricaemia.
      2. This paper describes the detailed biotransformation of BOF-4272 and its
      metabolites in the liver and by the intestinal flora in rat. 3. Only the
      sulphoxide metabolite (M6) was detected in plasma in small amounts after the
      intravenous administration of M4 (hydroxy-BOF-4272) and in culture medium after
      the addition of M4. 4. Only M3 (the sulphide metabolite of M4) was detected in
      faeces, and its amount was approximately 50% of the administered dose within 1
      day after the intravenous administration of M4. 5. These findings suggest that
      M4, which is excreted in the bile, is metabolized mainly to M3 (the corresponding
      sulphide of M4) by the intestinal flora in rat, whereas little M4 is metabolized
      to the sulphoxide (M6) in the rat liver. 6. M2, which is the demethylated form of
      BOF-4269, was detected in faeces after the oral administration of BOF-4272 to rat
      in which the common bile duct was cannulated, suggesting that BOF-4272 is
      metabolized to BOF-4269 and then to M2 by the intestinal flora. 7. These findings
      suggest that in rat the sulphoxide of BOF-4272 and its metabolites are
      demethylated and reduced by the intestinal flora, with other types of
      biotransformation occurring in the liver.

PMID- 10659956
TI  - Whiteness change during heating and cooling of Mozzarella cheese.
AB  - Whiteness (L-value) changes in low-fat and low-moisture, part-skim Mozzarella
      cheeses during heating (7 to 60 degrees C) and cooling (60 to 7 degrees C) were
      evaluated. In low-fat Mozzarella, a large increase in whiteness was observed
      during heating, and a decrease in whiteness was observed during cooling. In low
      moisture, part-skim Mozzarella, the whiteness changes during heating and cooling
      were smaller. Serum phase was removed from low-fat and low-moisture, part-skim
      Mozzarella cheeses. White protein gels were formed when the isolated serum phase
      from either low-fat or low-moisture, part-skim Mozzarella was heated. The white
      gel that formed was composed predominantly of casein and casein proteolysis
      products. The gel might have been produced by heat-induced, hydrophobic protein
      protein interactions, and it tended to dissociate when cooled. Formation of a gel
      during heating increased light scattering, which increased the L-value. The gel
      dissociated during cooling and no longer scattered light, which decreased the L
      value. We hypothesized that a gel, which was reversible, formed in the serum
      phase of cheese during heating and might have been responsible for the observed
      changes in the L-value of low-fat Mozzarella cheese during heating and cooling.
      The additional fat in low-moisture, part-skim Mozzarella compared with low-fat
      Mozzarella masked some of the color changes in the serum phase of low-moisture,
      part-skim Mozzarella. A model was developed to describe the contributions of the
      casein matrix plus serum phase of Mozzarella cheese and the contribution of fat
      to the changes in whiteness of Mozzarella cheese during heating and cooling.

PMID- 10659957
TI  - Analysis of major caprine milk proteins by reverse-phase high-performance liquid
      chromatography and electrospray ionization-mass spectrometry.
AB  - Major proteins from caprine milk were separated by preparative gel permeation and
      cation-exchange fast protein liquid chromatography and were characterized by flow
      injection analysis by electrospray ionization mass spectrometry. In addition,
      proteins from whole skim milk and whole casein were analyzed by coupling reverse
      phase HPLC and electrospray ionization mass spectrometry by two different
      chromatographic methods. These methods successfully resolved the major caprine
      milk proteins and main casein variants. The experimental molecular masses of
      major milk proteins and variants were: 19,302 for kappa-CN 2P; 25,599 for alphas2
      CN A-11P; 25,514 for alphas2-CN B-10P; 23,370 for alphas1-CN A-8P; 23,345 for
      alphas1-CN B-8P; 23,264 for alphas1-CN E-8P; 18,817 for alphas1-CN F-3P; 23,835
      for beta-CN 6P; 18,181 for beta-LG; 14,180 for alpha-LA and 66,318 for serum
      albumin.

PMID- 10659958
TI  - Short communication: concentration of conjugated linoleic acid from milk fat with
      a continuous supercritical fluid processing system.
AB  - A continuous pilot-scale supercritical carbon dioxide system was utilized for the
      concentration of conjugated linoleic acids (cis-9, trans-11 C18:2) from anhydrous
      milk fat, which was separated into five fractions (S1 to S5) in the pressure and
      temperature range of 2.4 to 24.1 MPa (350 to 3500 psi) and 40 to 60 degrees C,
      respectively. The highest concentration of CLA attained showed an increase of
      about 89% and occurred in the raffinate fraction (S1) when the solvent to feed
      ratio was 65. This was followed by a gradual decrease in the concentration of
      this fatty acid from S2 to S5. This study shows the feasibility of selectively
      enhancing the CLA concentration in one of the fractions of milk fat with a benign
      solvent in a one-step process. Other unique attributes of the CLA-rich fraction
      are also listed.

PMID- 10659959
TI  - Effects of diet and injection of bovine somatotropin on prepubertal growth and
      first-lactation milk yields of Holstein cows.
AB  - To determine effects of rapid prepubertal growth on first-lactation milk
      production, Holstein heifers were randomly assigned to one of three treatments.
      Thirty-five heifers were fed a standard diet to meet NRC recommendations and
      produce 0.8 kg of body weight (BW) gain/d (standard). Thirty-five heifers were
      fed a diet with higher energy (2.8 Mcal of metabolizable energy/kg) and protein
      (19.7% crude protein; high diet) to produce 1.2 kg of BW gain/d (high). Thirty
      five heifers were fed the high diet and injected daily with bovine somatotropin
      (bST) (25 microg/kg of BW; high-bST). Diets were fed and bST was injected from
      135 kg of BW until pregnancy was confirmed. Heifers were inseminated after BW
      exceeded 363 kg. Pregnant heifers were commingled and fed similar diets through
      gestation, parturition, and lactation. High and high-bST heifers had greater
      prebreeding average BW gains than standard heifers. Conversely, standard heifers
      had a greater average BW gain during gestation than high and high-bST heifers.
      High and high-bST heifers were approximately 90 d younger than standard heifers
      at first insemination and first parturition. Postpartum BW, body condition
      scores, and withers heights at parturition, and calving ease scores were not
      different among treatments. Standard heifers produced 14% more milk than high
      heifers but not more than high-bST heifers. The high-protein, high-energy diet
      decreased age at first parturition and first-lactation milk production, but did
      not affect reproduction. Injection of bST during the prepubertal growth period
      combined with the high diet decreased age at first parturition without reducing
      milk production.

PMID- 10659960
TI  - Regulation of local synthesis of insulin-like growth factor-I and binding
      proteins in mammary tissue.
AB  - Our objective was to investigate the mammary expression of insulin-like growth
      factor-I (IGF-I) and IGF-binding proteins in prepubertal heifers and regulation
      of IGF-I by bovine somatotropin (bST) and feeding level. Twenty-four prepubertal
      Friesian heifers were divided into six blocks according to genotype and starting
      date for the experiments. Within blocks, heifers were assigned to daily bST
      treatment (0 or 15 mg/d) at low or high feeding level (0.55 kg/d or 1.1 kg/d
      average daily gain, respectively) for 5 wk so that the mean body weight and
      standard error was approximately equal for all four treatment groups. At high
      feeding level, content of IGF-I protein in mammary tissue extracts was increased
      46% by somatotropin compared with placebo. Somatotropin tended to increase
      abundance of IGF-binding protein-3 (40 to 43 kD) in mammary extracts. High
      feeding level increased abundance of a 24-kD binding protein and reduced
      abundance of IGF-binding protein-2 (32 kD) in mammary extracts. High feeding
      level reduced abundance of IGF-binding protein-1 mRNA in mammary tissue, but
      there was no significant effect of feeding level or somatotropin on mRNA levels
      of other IGF-binding proteins. These results suggest that effects of somatotropin
      treatment and feeding level on the prepubertal mammary gland are mediated in part
      by alterations in local synthesis of IGF-I and IGF-binding proteins.

PMID- 10659961
TI  - Glucocorticoid receptor expression profiles in mononuclear leukocytes of
      periparturient Holstein cows.
AB  - Cortisol-activated glucocorticoid receptors modulate cellular responses to stress
      by translocating from the cytosol to the nucleus and enhancing or repressing the
      transcription of target genes. The functional capacity of mononuclear leukocytes
      is inhibited in parturient dairy cows at a time when blood cortisol
      concentrations are high. Because the glucocorticoid receptor is autoregulatory in
      many cell types, the hypothesis of the current study was that glucocorticoid
      receptor expression by mononuclear leukocytes is altered around parturition in
      association with elevated blood cortisol. If true, the glucocorticoid receptor
      could be involved in suppressed functions of mononuclear leukocytes in parturient
      cows. The objectives of this study were to determine effects of parturition on
      lymphocyte and monocyte glucocorticoid receptor expression and to correlate
      expression with serum cortisol concentrations. Objectives were achieved by using
      fluorescence staining and flow cytometric analyses to monitor glucocorticoid
      receptors in peripheral blood mononuclear leukocytes collected multiple times
      from 13 periparturtient test cows (eight multi- and five primiparous) and 10
      midgestation control cows (five multi- and five primiparous). Serum cortisol
      concentrations were determined by radioimmunoassay. Based on intensity of the
      fluorescent glucocorticoid receptor stain, parturition caused 42 and 47%
      reductions in lymphocyte and monocyte glucocorticoid receptor expression,
      respectively, compared with mean expression in corresponding cells from control
      cows. When mean prepartum values were compared with nadir values at parturition
      in the test cows, glucocorticoid receptor expression was reduced by 67% in
      lymphocytes and by 54% in monocytes. Mononuclear cell expression of
      glucocorticoid receptors was negatively correlated with serum cortisol
      concentrations. Results suggest that glucocorticoid receptors are down-regulated
      in bovine mononuclear leukocytes in association with increased adrenal secretion
      of cortisol at calving. It is possible that glucocorticoid receptor down
      regulation is also associated with altered phenotype or function (or both) of
      lymphocytes and monocytes. This possibility should be substantiated because it
      could explain increased disease susceptibility in periparturient dairy cows.

PMID- 10659962
TI  - Short communication: effects of isolation stress on mammary tight junctions in
      lactating dairy cows.
AB  - Eighteen cows had been selected for their responsiveness to psychological stress
      during the first lactation and were classified as having low (n = 10) or high (n
      = 8) cortisol concentrations in response to isolation-induced stress. In the
      present study these cows, now in their second lactation, were used to determine
      the effect of social isolation stress on the permeability of mammary tight
      junctions. During the experiment, each cow was isolated from the rest of the herd
      for 55 h. After the 1st h of isolation, each cow received a bolus infusion of
      endotoxin in one hind quarter in order to challenge tight junctions. Blood
      samples were taken throughout to measure lactose, which was used as an indicator
      of tight-junction leakiness. After 1 h of isolation, stress caused an increase in
      tight junction permeability in both groups, which was further enhanced by the
      endotoxin treatment. Although the permeability did not differ significantly
      between the two groups, it was consistently higher in the high-cortisol group,
      which was also the most stress-responsive group. Thus, psychological stress may
      adversely affect milk quality by allowing serum components to leak into milk.

PMID- 10659964
TI  - Short communication: effects of prepartum milking on dry matter intake, liver
      triglyceride, and plasma constituents.
AB  - An experiment was conducted to determine if initiation of milking 10 d prior to
      expected calving could prevent fatty liver by circumventing intake depression and
      by providing an alternative route for fatty acid metabolism. Prepartum milking
      tended to increase DMI before calving; liver triglyceride, plasma nonesterified
      fatty acids, and milk yield were not affected.

PMID- 10659963
TI  - Interrelation of fatty acid composition in adipose tissue, serum, and liver of
      dairy cows during the development of fatty liver postpartum.
AB  - We investigated the composition of fatty acids in adipose tissue, serum, and
      liver of cows that were fed at restricted energy intake or were overfed during
      the dry period. Overfed cows had higher concentrations of serum nonesterified
      fatty acids and consequently accumulated greater amounts of triacylglycerols in
      the liver than did cows that were fed at restricted energy intake. The
      percentages of the different fatty acids present in adipose tissue were similar
      for both groups and did not change during sampling intervals. Before parturition,
      concentrations of the individual fatty acids present in serum were similar
      between groups. After parturition, concentrations of major fatty acids in serum,
      including palmitic, stearic, oleic, and linoleic acids significantly increased in
      both groups and were higher in overfed cows than in cows that were fed at
      restricted energy intake. The shift of concentrations of the different fatty
      acids present in the liver--as a result of increased lipolysis-was observed in
      palmitic, oleic, and linoleic acids but not stearic acid, suggesting that stearic
      acid is used by the liver (i.e., oxidation) or is considerably secreted through
      the milk, thereby not increasing in accumulation in the liver. In conclusion,
      different feeding regimens during the dry period do not influence the composition
      of fatty acids in adipose tissue. More intensive lipolysis results in increased
      concentrations of palmitic, stearic, oleic, and linoleic acids in the blood;
      subsequently, these fatty acids, excluding stearic acid, greatly accumulated in
      the liver.

PMID- 10659965
TI  - Energy balance of dairy cattle in relation to milk production variables and
      fertility.
AB  - Variables derived from milk yield records were investigated to find an easy to
      measure and readily available indicator of the energy balance status of a
      lactating cow. Weekly energy balances during the first 180 d in milk (DIM) were
      calculated from weekly yield, live weight, and energy intake records for 470
      first lactation heifers. The energy balance curve for each cow was estimated
      using a random regression model. From each curve, three measures were calculated
      to describe the energy balance status: 1) total energy deficit in early
      lactation, 2) interval for return to positive energy balance, and 3) lowest value
      (nadir) for energy balance. Mean energy deficit per lactation was 776.8 MJ of
      NE(L)/d, interval for return to positive energy balance was 41.47 d, and nadir
      was -33.72 MJ of NE(L)/d. Regression analysis to relate these variables to
      interval to start of luteal activity (measured using progesterone profiles)
      showed that a low nadir of energy balance was related to delayed resumption of
      luteal activity. In general, a 10 MJ of NE(L)/d lower nadir of energy balance
      corresponded to a delay of ovulation of 1.25 d. A relatively strong decrease in
      fat percentage during early lactation was significantly correlated with lower
      nadir of energy balance, larger energy deficit, and later return to positive
      energy balance. The maximal correlation was between nadir of energy balance and a
      decrease of milk fat percentage. This correlation remained above 0.60 throughout
      the first 26 DIM but dropped to 0.14 at 180 DIM. Large decreases in milk fat
      percentage were related to high initial fat percentages at the start of lactation
      and slightly lower fat percentages later during lactation. Hence, we concluded
      that a decrease in fat percentage during early lactation might serve as an
      indicator of energy balance.

PMID- 10659966
TI  - Outcome of clinical mastitis in dairy heifers assessed by reexamination of cases
      one month after treatment.
AB  - Heifers that were treated for clinical mastitis prior to parturition or within 14
      d postpartum were reexamined approximately 1 mo after treatment. Clinical
      examination of the heifers and microbiological examination of quarter milk
      samples were carried out on both occasions. Of the 1000 heifers included in the
      study, 10.9% were culled within 28 d after treatment. Udder damage caused by
      mastitis was the only or main reason for culling in 96% of those heifers. In
      comparison, 4.5% of nonmastitic heifers from the same herds were culled within 30
      d postpartum. Twenty-five percent of those heifers that were not culled at d 28
      after treatment had at least one nonfunctional quarter at that time. One thousand
      one hundred twenty-two quarters that were clinically affected at the time of
      treatment were reexamined; 22% were nonfunctional, 14% were still affected by
      clinical mastitis, 12% had subclinical mastitis, 5% had a latent infection with
      coagulase-positive staphylococci or Streptococcus dysgalactiae, and 46% were
      bacteriologically negative and had a normal cell count at the time of
      reexamination. High percentages of nonfunctional quarters were observed among
      those quarters that were infected with Arcanobacterium pyogenes or with coagulase
      positive staphylococci at treatment. When all quarters that were clinically
      affected at treatment were considered, 40% of quarters were cured and were still
      in lactation at reexamination. Quarters infected with coagulase-negative
      staphylococci had a higher cure rate than quarters infected with other organisms.
      At reexamination, clinical signs of thelitis were observed in many of those
      quarters that were nonfunctional following the episode of clinical mastitis and
      also in 25% of lactating quarters in which clinical mastitis persisted.

PMID- 10659967
TI  - Effects of milkline vacuum, pulsator airline vacuum, and cluster weight on milk
      yield, teat condition, and udder health.
AB  - The influence of milkline vacuum, pulsator airline vacuum, and cluster weight on
      complete lactation milk yield performance, teat condition, and udder health were
      studied in 241 cows by using three separate factorial experiments. The first
      experiment had milkline vacuum set at 38 and 48 kPa, pulsator airline was vacuum
      was set at 0 and 8 kPa above milkline vacuum, and cluster weight was 1.6 and 2.3
      kg. The second experiment had milkline vacuum set at 38 and 48 kPa and cluster
      weight was 1.6 and 2.3 kg. The third experiment had milkline vacuum set at 32 and
      42 kPa and pulsator airline vacuum 0 and 8 kPa above milk line vacuum. The first
      two experiments were carried out with a high-level milking and the third with a
      low-level milking system. The average vacuums in the short milk tube during
      milking for low and high milkline vacuum in the high-level system were 26 and 33
      kPa, and 30 and 39 kPa for the low-level milking system, respectively. Milking at
      low vacuum increased the machine-on time and frequency of liner slip, decreased
      milk flow rate, but had no influence on teat condition and udder health. The milk
      yield of high producing cows with long machine-on time was reduced by 5% when
      milked at a low vacuum. A higher pulsator airline vacuum than milkline vacuum had
      no influence on milking performance. The use of the light cluster reduced machine
      on time. We recommend that mean vacuum in the short milk tube should not be lower
      than 32 kPa.

PMID- 10659968
TI  - Delayed colostrum feeding affects IGF-I and insulin plasma concentrations in
      neonatal calves.
AB  - In the neonatal calf, insulin-like growth factor I (IGF-I) concentrations are
      markedly influenced by the amount of colostrum intake after birth, although
      colostral IGF-I is barely absorbed. In this study we have investigated effects of
      delayed colostrum intake in neonatal calves on metabolic traits and on IGF-I, IGF
      binding proteins (IGFBP), growth hormone (GH), and insulin concentrations in
      plasma. Calves received colostrum of first milking starting at 2 (GrA), 6 (GrB),
      12 (GrC), and 24 h (GrD) after birth. Before third colostrum intake plasma total
      protein concentrations were higher in GrA than in GrD and plasma glucose
      concentrations were higher in GrC than GrD. Plasma IGF-I concentrations at first
      and third colostrum intake were higher in GrA than in GrD. Plasma IGFBP-2
      concentrations before first colostrum intake were higher in GrD than in GrA and
      GrC, and were higher before third colostrum intake in GrD than in GrA. Plasma
      IGFBP-3 concentrations before first colostrum intake were lower in GrD than in
      GrA, and before third colostrum intake were lower in GrD than in GrA and GrB.
      Postprandial plasma insulin concentrations after first colostrum intake were
      higher in GrA than in GrC and GrD. In conclusion, the plasma IGF-I and insulin
      status are markedly, albeit transiently, decreased in calves fed colostrum with a
      delay of 12 to 24 h, and the decreased concentrations of plasma IGF-I were
      associated with decreased IGFBP-3/IGFBP-2 ratios.

PMID- 10659969
TI  - Effects of insulin and postruminal supply of protein on use of amino acids by the
      mammary gland for milk protein synthesis.
AB  - We examined the relationships between amino acid supply, net utilization of amino
      acid by the mammary gland, and milk protein yield, in investigations that
      utilized a hyperinsulinemic-euglycemic clamp. A two-way crossed factorial design
      was employed. There were two 12-d periods involving abomasal infusions of either
      water or a mixture of casein (500 g/d) plus branched-chain amino acids (88 g/d),
      with a hyperinsulinemic-euglycemic clamp during the last 4 d of each period.
      During the clamp, insulin was infused at 1.0 microg x kg BW(-1) x h(-1) to
      increase circulating levels fourfold, and euglycemia was maintained by infusion
      of glucose. The insulin clamp treatments increased milk protein yield by 15 and
      25% during abomasal infusion of water or casein plus branched-chain amino acids,
      respectively. Circulating concentrations of essential amino acids were reduced
      (33%) during insulin clamp treatments, especially branched-chain amino acids
      (41%). Arteriovenous difference of essential amino acids across the mammary gland
      was linearly related to their arterial concentrations. However, milk protein
      yield was not related to either arterial concentration or arteriovenous
      difference, for any of the essential amino acids. During insulin clamp
      treatments, the mammary gland was able to support the increased milk protein
      yields by increasing extraction efficiency of essential amino acids, mammary
      blood flow, and glucose uptake. Furthermore, a positive mammary balance of total
      amino nitrogen and carbon was maintained for all treatments. These adaptations
      demonstrate the unique ability of the mammary gland to adjust local conditions to
      allow for an adequate nutrient supply.

PMID- 10659970
TI  - Effect of replacing alfalfa silage with high moisture corn on nutrient
      utilization and milk production.
AB  - Twenty-four multiparous lactating Holstein cows were blocked by days in milk and
      assigned to treatment sequences in a replicated 4x4 Latin square with 21-d
      periods. The four diets, formulated from alfalfa silage plus a concentrate mix
      based on ground high moisture ear corn, contained [dry matter (DM) basis]: 1) 20%
      concentrate, 80% alfalfa silage (24% nonfiber carbohydrates; NFC), 2) 35%
      concentrate, 65% alfalfa silage (30% NFC), 3) 50% concentrate, 50% alfalfa silage
      (37% NFC), or 4) 65% concentrate, 35% alfalfa silage (43% NFC). Soybean meal and
      urea were added to make diets isonitrogenous with equal nonprotein N (43% of
      total N). Intake of DM and milk yield indicated that adaptation was complete
      within 7 d of changing the diets within the Latin square. There were linear
      increases in apparent digestibility of DM and organic matter, and a linear
      decrease in neutral detergent fiber (NDF) digestibility with increasing dietary
      NFC. Solutions of significant quadratic equations yielded estimated maxima for
      intake of DM, organic matter, digestible organic matter, and NDF at,
      respectively, 37, 38, 43, and 27% dietary NFC. There were linear increases in
      yields of milk, protein, lactose, and solids not fat with increasing dietary NFC.
      Feed efficiency (milk/DM intake) yielded a quadratic response with a minimum at
      27% dietary NFC. Maxima for milk fat content, fat yield, and fat-corrected milk
      yield were estimated to occur at, respectively, 30, 34 and 38% dietary NFC. In
      this short-term trial, maximal DM intake and fat-corrected milk yield indicated
      that the optimum concentrate for cows fed high moisture ear corn plus alfalfa
      silage as the only forage was equivalent to 37 to 38% dietary NFC; however,
      yields of milk, protein and solids not fat were still increasing at 65% dietary
      concentrate (43% NFC).

PMID- 10659971
TI  - The effect of treating forages with fibrolytic enzymes on its nutritive value and
      lactation performance of dairy cows.
AB  - Forages (corn silage and alfalfa hay) were sprayed with liquid enzymes prior to
      combining with a concentrate to form a total mixed ration (50% forage:50%
      concentrate, dry matter basis) and fed to lactating cows. In the first year,
      treatments were 1) no enzymes, 2) an enzyme complex containing 3500 carboxymethyl
      cellulase (CMCase) and 16,000 xylanase units per kilogram of forage dry matter,
      or 3) an enzyme complex containing 8800 CMCase units and 40,000 xylanase units.
      In the second year, the treatments were 1) no enzymes, 2) an enzyme complex as in
      yr 1 containing 3700 CMCase and 14,000 xylanase units, or 3) an enzyme complex
      using an alternative cellulase and containing 3600 CMCase and 11,000 xylanase
      units. In the first year, cows fed diet 2 tended to produce more milk (39.5 kg/d)
      than those fed diet 1 (37.0 kg/d) or those fed diet 3 (36.2 kg/d). The high level
      of enzyme treatment in diet 3 decreased the output of milk protein and fat
      compared to the low level of enzyme treatment. In the second year, cows fed diet
      3 produced more milk (35.4 kg/d) than did those fed diet 1 (32.9 kg/d) and
      numerically more than those fed diet 2 (33.6 kg/d). Milk fat and protein were
      similar among treatments but numerically lower for cows fed enzyme-treated
      forages. Dry matter intake (kg/d) was similar among treatments in both years.
      Spraying certain doses and combinations of enzymes directly onto forages prior to
      feeding can improve milk yields but enzyme sources and dose levels are of
      critical importance.

PMID- 10659972
TI  - Effects of yeast culture (Saccharomyces cerevisiae) on prepartum intake and
      postpartum intake and milk production of Jersey cows.
AB  - Yeast cultures (Saccharomyces cerevisiae; YC) have been added to diets for dry
      and lactating dairy cows to attempt to improve ruminal fermentation, potentially
      increasing dry matter intake (DMI) and milk yield. Jersey cows (14 primigravid
      and 25 multigravid) were fed total mixed rations prepartum and postpartum that
      were either supplemented or not supplemented with YC. The YC was a dried product
      that was top-dressed at 60 g/d for approximately 21 d prepartum and 140 d
      postpartum. The DMI was increased by YC during both the last 7 d prepartum (9.8
      vs. 7.7 kg) and during the first 42 d of lactation (13.7 vs. 11.9 kg). The
      treatment-by-day interaction was significant for DMI during the first 21 d
      postpartum, indicating that cows supplemented with YC increased DMI more rapidly
      than did nonsupplemented cows. A significant treatment-by-day interaction
      indicated that cows supplemented with YC lost body weight less rapidly postpartum
      than did non-supplemented cows. A significant interaction of treatment by day
      indicated that cows supplemented with YC reached peak milk production more
      quickly than did nonsupplemented cows. However, total milk produced during the
      first 140 d of lactation did not differ. Concentrations of fat, protein, lactose,
      total solids, and urea N in milk, as well as somatic cell count, were not
      significantly affected by YC. Supplementation of YC increased DMI during the
      transition period and increased DMI postpartum.

PMID- 10659973
TI  - Estimation of parameters describing lipid metabolism in lactation: challenge of
      existing knowledge described in a model of metabolism.
AB  - We have been conducting research to improve quantitative descriptions of
      metabolism in lactating dairy cows depicted in an existing mechanistic, computer
      assisted model. The model is dynamic and deterministic and is based on
      biochemical equations describing ruminal fermentation and chemical interactions
      in body tissues. The objective was to challenge this model with data collected in
      in vivo and in vitro experiments on high producing dairy cattle fed a range of
      energy. Cows that varied in genetic propensity for milk production (7045 to
      12,909 kg of milk/305 d), lactation number (1 to 4), stage of lactation (-30 to
      345 d in milk), and rate of intake (14 to 29 kg/d of dry matter) and that were
      fed various energy-yielding feedstuffs were used. Dietary inputs, milk component
      outputs, body fat, nutrient concentrations in blood, and maximal velocity and
      substrate sensitivity of adipose tissue metabolic reactions were observed. Model
      simulations were conducted; simulated yields of milk components for a 305-d
      lactation were within 5% of observed means. Simulated lipid metabolism and
      accumulation of body fat were adequate in many situations; however, the model
      response to changes in energy intake was too sensitive. This inadequacy was
      especially noticeable in later lactation because of inadequate representation of
      dynamic responses over periods more than a few weeks long. The model behaves
      consistently with biochemical principles, behavior was in the correct direction,
      and precision was adequate for many variables. Lack of precision in long-term
      dynamic changes indicates that the parameters describing energy-utilizing
      reactions are inadequate. This severe challenge of the model supports its
      functionality. Further experiments must be designed to determine how nutrients in
      viscera, muscle, and adipose tissue are used; these experiments must encompass
      sufficient range in genetic ability, nutrient input, and time to adequately
      describe the dynamic and integrated nature of metabolic reactions.

PMID- 10659974
TI  - Profitabilities of some mating systems for dairy herds in New Zealand.
AB  - The aim of this study was to evaluate the profitability of dairy herds under
      three mating systems involving the Holstein-Friesian, Jersey, and Ayrshire
      breeds. Mating systems were straight breeding and rotational cross-breeding using
      two or three breeds. A deterministic model was developed to simulate the
      nutritional, biological, and economic performance of dairy herds under New
      Zealand conditions. Expected performances per cow were obtained using estimates
      of breed group and heterosis effects, age effects, and age distribution in the
      herd. Requirements for dry matter in feed were estimated per cow for maintenance,
      lactation, pregnancy, and growth of the replacements. Stocking rate was
      calculated by assuming 12,000 kg of dry matter utilized annually per hectare.
      Productivity per hectare was calculated as performance per cow multiplied by
      stocking rate. Profitability was the difference between income (sale of milk and
      salvage value of animals) and costs (related to the number of cows in the herd
      and the land area farmed). Under current market values for milk and meat, all of
      the rotational crossbred herds showed superior profitability to the straightbred
      herds (Holstein-Friesian x Jersey, NZ$505/ha; Holstein-Friesian x Jersey x
      Ayrshire NZ$493/ha; Jersey x Ayrshire, NZ$466/ha; Holstein-Friesian x Ayrshire,
      NZ$430/ha; Jersey, NZ$430/ha; Holstein-Friesian, NZ$398/ha; and Ayrshire,
      NZ$338/ha). Changes in the value for fat relative to protein affected
      profitability more significantly in herds using the Jersey breed, and changes in
      the value for meat affected profitabiity more significantly in herds using the
      Holstein-Friesian and Ayrshire breeds. Results suggested that, under New Zealand
      conditions, the use of rotational crossbreeding systems could increase
      profitability of dairy herds under the conceivable market conditions.

PMID- 10659975
TI  - Possible effects of 25 years of selection and crossbreeding on the genetic merit
      and productivity of New Zealand dairy cattle.
AB  - A deterministic model was developed to evaluate the concurrent effects of
      selection and crossbreeding on the rate of genetic gain and productivity of New
      Zealand dairy cattle over 25 yr. Selection was based on an index, which included
      estimated breeding values for mature cow live weight and lactation yields of
      milk, fat, and protein. Mating strategies involving Holstein-Friesian, Jersey,
      and Ayrshire breeds were evaluated. Effects of heterosis and age were included to
      calculate live weight and yields of milk, fat, and protein per cow. Feed
      requirements were estimated for maintenance, lactation, and pregnancy and for
      replacement heifers. Stocking rate was calculated by assuming 12,000 kg of dry
      matter annually utilized per hectare. Upgrading to either Jersey or Holstein
      Friesian increased the number of potential bull mothers and resulted in genetic
      gains of 0.27 genetic standard deviations/yr for both options. Rotational
      crossbreeding of Holstein-Friesian x Jersey decreased the number of potential
      bull mothers and resulted in a genetic gain of 0.24 genetic standard
      deviations/yr. Upgrading to Jersey resulted in the least increase in milk (5%)
      and the greatest increase in fat (16%) and protein (27%) per hectare with a small
      decrease in stocking rate (0.4%). Upgrading to Holstein-Friesian reduced the
      stocking rate by 11% and increased production of milk, fat, and protein per
      hectare by 10, 8, and 21%, respectively. Rotational crossbreeding of Holstein
      Friesian x Jersey resulted in greater production per hectare than the
      intermediate production between upgrading to Jersey and upgrading to Holstein
      Friesian. Crossbreeding can be used in combination with selection to exploit the
      effects of heterosis while maintaining genetic diversity to cover changes in
      market conditions.

PMID- 10659976
TI  - Effects of selection and crossbreeding strategies on industry profit in the New
      Zealand dairy industry.
AB  - The effects of selection and crossbreeding on the New Zealand dairy industry net
      income were evaluated with a deterministic model over a 25 yr planning horizon.
      Several mating strategies involving Holstein-Friesian, Jersey and Ayrshire cattle
      were evaluated. These strategies were straight breeding, upgrading to Holstein
      Friesian, upgrading to Jersey, upgrading to Ayrshire, use of the best bulls
      irrespective of breed and two- and three-breed rotational crossbreeding. Industry
      productions of milk, fat, protein, and lactose were calculated assuming that
      12,000 kg of dry matter per hectare was utilized from 1,224,911 hectares of
      pasture. Profitability was the difference between income (international sale of
      whole milk powder, casein, butter, and beef from salvage animals) and costs (farm
      expenses, milk collection, manufacture, and marketing). Casein and whole milk
      powder were valued at NZ$8.345 and NZ$3.306/ per kilogram, respectively, over 25
      yr. Butter was valued at NZ$2.995/kilogram for base year production levels and
      NZ$0.45/kilogram for marginal increases in production. Upgrading to Holstein
      Friesian resulted in the highest industry net income (NZ$1119 million) followed
      by straight breeding (NZ$1086 million) and two-breed rotational Holstein-Friesian
      x Jersey (NZ$1076 million). However, if the marginal value of extra butter
      production was assumed equal to the average base value, then upgrading to Jersey
      resulted in the highest industry net income (NZ$1185 million) followed by two
      breed rotational Holstein-Friesian x Jersey (NZ$1177 million) and use of the best
      bulls (NZ$1173 million). Future costs and prices of dairy products have major
      impact on mating strategies.

PMID- 10659977
TI  - Selective genotyping to detect quantitative trait loci for multiple traits in
      outbred populations.
AB  - Selective genotyping (i.e., genotyping of individuals that are extreme for a
      quantitative trait) has been undertaken in many studies but has usually been
      limited to one trait of interest. This paper outlines the implications of
      selective genotyping when applied to a daughter design. Formulas are presented
      that enable unbiased estimation of QTL effects for the selectively genotyped and
      correlated traits. Formulas were verified using simulation. Further, formulas are
      presented to enable power calculations to be undertaken for the selectively
      genotyped trait and correlated traits. These algorithms are demonstrated with a
      numerical example.

PMID- 10659978
TI  - Effect of misidentification on genetic gain and estimation of breeding value in
      dairy cattle populations.
AB  - The effect of pedigree errors on estimated breeding value and genetic gain for a
      sex-limited trait with heritability of 0.25 was evaluated. Ten populations of
      100,000 milking cows were simulated with correct paternity identification for all
      animals, and 10 populations were simulated with 10% incorrect paternal
      identification. The initial populations consisted of 100,000 unrelated
      individuals, and simulations were continued for 20 yr. The BLUP genetic
      evaluations were computed every year by an animal model analysis for each
      complete population. Estimated breeding values for the populations with 10%
      incorrect paternity were biased, especially in the later generations. Genetic
      gains were 4.3% higher with correct paternity identification. Reduction of
      pedigree errors by paternity confirmation of daughters of test sires by DNA
      microsatellites may result in considerable economic benefits, depending on the
      cost of testing in each country.

PMID- 10659979
TI  - Endocrine effects of lithium carbonate in healthy premenopausal women:
      relationship with body weight regulation.
AB  - The mechanisms involved in Li-induced weight gain remain unclear. The higher
      frequency of obesity in women than in men under Li treatment, suggests a role for
      reproductive hormones. The serum levels of the following hormones were evaluated
      in healthy young women at diverse stages of a control menstrual cycle, and during
      Li carbonate (900 mg/day) or placebo administration: prolactin, luteinizing
      hormone, follicle-stimulating hormone, 17-1 estradiol, progesterone, thyroxine,
      thyrotropin, cortisol, dehidroepiandrosterone sulfate, free testosterone, leptin
      and an oral glucose tolerance test, in order to measure the areas under the
      glucose and insulin curve. The body weight was assessed the day before and the
      last day of treatment. The Li serum levels 15 hours after the last dose were 0.31
      +/- 0.1 mEq/L. No significant changes in body weight and in the normal
      fluctuations of the reproductive hormones along the menstrual cycle were observed
      during Li administration. An increase in the serum levels of thyrotropic hormone
      ( p = 0.0001) was the only significant effect of Li, which may predispose to
      excessive weight gain after prolonged administration of the cation. The
      remarkable lack of effects of Li on these hormones, question the pertinence of
      studies conducted in healthy volunteers for the comprehension of the obesity
      observed in psychiatric patients who may be particularly prone to gain weight
      under prolonged treatment with high dose of Li.

PMID- 10659980
TI  - Forms of knowledge, cognitive impairment and drug abuse: a demonstration.
AB  - Chronic abusers of alcohol and other drugs often exhibit persistent deficits on
      neuropsychological tests. These deficits are usually attributed to drug-induced
      brain dysfunction or to familial factors that depress performance independent of
      drug abuse. The aim of this study was to determine the plausibility of a third
      explanation: namely that some neuropsychological deficits of drug abusers arise
      because they acquire different forms of knowledge from non-drug abusers. This
      hypothesis predicts that drug abusers should excel on tests of knowledge that is
      related to their lifestyle. Sixty-three clients from a local methadone clinic and
      a comparison group of 24 non-abusing subjects who were knowledgeable about drugs
      listened to a song about cocaine addiction. They were asked to identify the
      title, artist, year the song was first popular and the meaning of the song. There
      were no significant differences between the groups in identifying the song title,
      artist or year, but the drug-abusers were significantly more likely to state that
      the song was about cocaine or drug addiction. In interpreting deficits by drug
      abusers on neuropsychological tests, differences in knowledge acquired should be
      considered.

PMID- 10659981
TI  - Red blood cell triiodothyronine uptake in unipolar major depression: effect of a
      chronic antidepressant treatment.
AB  - The evolution of kinetic parameters (Vmax, maximal velocity, and Km, Michaelis
      constant) of red blood cell (RBC) triiodothyronine (L-T3) initial uptake was
      followed in 19 inpatients suffering from unipolar depression after 1 week (D7)
      and 4 weeks (D28) of a chronic administration of fluvoxamine, in relation with
      the clinical efficacy of the drug. In a drug-free state (DO), Vmax (in
      pmol/min/10(8) cells) and Km (in nM) were significantly increased in depressed
      patients (Vmax +/- S.D.= 1.02 +/- 0.29, p< 0.01 and Km +/- S.D.= 68.8 +/-15.4, p<
      0.05; n=19) compared to healthy volunteers matched for age and sex (Vmax +/-
      S.D.= 0.82 +/- 0.15 and Km S.D.= 58.8 +/- 9.0; n= 19). When patients were
      dichotomized on the basis of their treatment response, responders had kinetic
      parameters significantly increased (Vmax +/-S.D.= 1.03 +/- 0.26, p< 0.01 and Km
      +/- S.D.= 71.7 +/- 18.7, p< 0.05, n= 10) compared to controls, whereas non
      responders had not (Vmax +/- S.D.= 1.00 +/- 0.33, NS and Km +/- S.D.= 65.7 +/-
      10.9, NS, n= 9). At D7, Vmax differed from the one of controls only in the
      responders (Vmax +/- S.D.= 1.03 +/-0.26, p< 0.01). In addition, the percentage of
      variation of the individual Vmax values during the first week of treatment was
      significantly lower in responders than in non-responders (deltaVmax(D7-D0) +/-
      S.D. in % = 10.7 +/- 6.0 and 22.0 +/- 11. 1, p< 0.05, respectively). At D28,
      kinetics of L-T3 uptake normalized only in the responders (Vmax +/- S.D.= 0.91 +/
      0.13, NS; Km+/-S.D.= 65.7 +/- 7.4, NS). The results indicate that both RBC L-T3
      uptake at the pretreatment level and its change during the first week of
      fluvoxamine treatment were related to the further clinical response to the
      antidepressant. RBC L-T3 uptake seems to be a biological correlate of the
      depressive symptomatology since the disturbances disappear only with the clinical
      remission.

PMID- 10659982
TI  - Decreased locomotor activity after microinjection of dopamine D2/D3 receptor
      agonists and antagonists into lobule 9/10 of the cerebellum: a D3 receptor
      mediated effect?
AB  - The restricted localization of dopamine (DA) D3 receptors in the rat cerebellum
      lobule 9/10 appears to provide a method for investigating the in vivo selectivity
      of dopaminergic compounds for the D3 receptor subtype. Sprague-Dawley rats
      implanted with a cannula aimed at lobule 9/10 were microinjected with DA receptor
      ligands and immediately placed into activity chambers to record their spontaneous
      locomotor activity for short term (0 to 20 min) and delayed (20 to 40 min)
      effects. The DA D2/D3 receptor agonists quinelorane (0.1 to 2.5 microg) and 7-OH
      DPAT (0.1 to 10 microg) decreased locomotor activity in the first 20 min post
      microinjection. In contrast, the DAD1, receptor agonist 6-Br-APB (0.1 to 10
      microg) did not affect locomotor activity during this time period, but markedly
      increased locomotion between 20 and 40 min at the highest dose tested. The DA
      receptor antagonists haloperidol and raclopride (1 to 10 microg) were also found
      to reduce locomotor activity. Furthermore, quinelorane and 7-OH-DPAT, but not
      haloperidol, when microinjected into lobules 1/2 or 6/7 (where no DA D3 receptors
      have been detected) decreased locomotor scores. These results show that both DA
      receptor agonists and antagonists decrease locomotor activity when microinjected
      into lobule 9/10 of the cerebellum. Additionally, DA receptor agonists can reduce
      spontaneous locomotion when microinjected outside of lobule 9/10. This would
      suggest that, at least for quinelorane and 7-OH-DPAT, the locomotor decreasing
      effects following microinjection into cerebellar lobule 9/10 may not be mediated
      by activity at DA D3 receptors, and that this behavioural assay is unlikely to
      provide a means for studying the in vivo pharmacology of the DA D3 receptor.

PMID- 10659983
TI  - Guinea-pigs treated with beta-endorphin fragments DTgammaE and DEgammaE exhibit
      reduced morphine inhibition of electrically-induced contractions.
AB  - The effect exerted by two gamma-endorphin derivatives (DTgammaE and DEgammaE) was
      investigated on morphine-induced inhibition on the electrically contractions of
      guinea pig ileum in vitro. Morphine (1x10(-8)-5x10(-8)-1x10(-7) M) dose
      dependently and significantly reduced the E.C. of guinea pig ileum, IC50=6.5x10(
      8) M (Confidence limits: 3.7x10(-8)-9.1x10(-8)). DTgammaE and DEgammaEper se
      (1x10(-6)-5x10(-6)-1x10(-5) M) did not modify significantly the E.C. of guinea
      pig ileum. Furthermore, DTgammaE or DEgammaE injection 10-30-60 min before
      morphine, did not affect the inhibitory effect of morphine on the E.C. of guinea
      pig ileum. By contrast, ilea from guinea-pigs treated for 4 days with DTgammaE or
      DEgammaE (1 mg/Kg/i.p.) resulted less sensitive to the inhibitory effect of
      morphine, IC50=8.3x10(-7) M (Confidence limits: 1.4x10(-6)-3.5x10(-7)) for
      DTgammaE and IC50=7.7x10(-7) M (Confidence limits: 2.7x10(-6)-8.7x10(-7)) for
      DEgammaE. Our results indicate that chronic treatment of guinea pigs with
      DTgammaE or DEgammaE induces a significant reduction of the inhibitory effect of
      morphine on the E.C. of guinea-pig ileum thus confirming an important functional
      interaction between gamma-endorphin derivatives and opioid system.

PMID- 10659984
TI  - Open field locomotion and neurotransmission in mice evaluated by principal
      component factor analysis-effects of housing condition, individual activity
      disposition and psychotropic drugs.
AB  - Effects of housing condition and individual disposition on dopaminergically and
      GABAergically influenced open field locomotion and neurochemistry were studied in
      mice. Mice characterized as high active (HAM) and low active (LAM) by a running
      wheel test were housed in groups or isolated for 1 day, 1 week, 3, 6, 12 or 18
      weeks before an open field test was performed with saline, apomorphine (0.75
      mg/kg) or diazepam (1.00 mg/kg) administration. Immediately afterwards animals
      were decapitated and brain sections were frozen for subsequent HPLC-analysis of
      dopaminergic and serotonergic transmitter metabolism. Principal component factor
      analysis (PCA) of locomotion variables provided three factors explaining 78.5% of
      total variance. Variables related to the amount of locomotion loaded highly on
      Factor 1 (F1-Activity), variables related to place utilization loaded highly on
      Factor 2 (F2-Exploration) and variables related to immobility and place
      preference loaded highly on Factor 3 (F3-Irritation). Apomorphine decreased F1
      Activity with smaller effects in HAM and without changes in F2-Exploration and F3
      Irritation independent on housing conditions. Diazepam exerted a decrease in F2
      Exploration with a small increase in FI-Activity and no effects in F3-Irritation.
      Diazepam induced changes depended on housing conditions and were especially
      pronounced in isolated HAM. PCA of considerable locomotion and neurochemical data
      revealed interrelationships between striatal dopamine metabolism and F1-Activity,
      between cortical dopamine and serotonin metabolism and F2-Exploration as well as
      between cerebellar, hippocampal and striatal serotonin metabolism and F3
      Irritation. The authors concluded that the application of PCA is a useful method
      to provide functionally relevant characteristics of behaviors and functionally
      relevant descriptions of interrrelationships between behavior and appropriate
      central nervous mechanisms. Furthermore the received behavioral characteristics
      (F1, F2, F3) of open field locomotion were sensitive to reveal housing and drug
      effects.

PMID- 10659985
TI  - Lithium chloride inhibits thrombin-induced intracellular calcium mobilization in
      C6 rat glioma cells.
AB  - In this study, the authors have demonstrated the effect of lithium, a typical
      mood stabilizer, on thrombin-evoked Ca2+ mobilization in C6 cells to elucidate
      the action mechanisms of the drug. Thrombin-induced Ca2 mobilization was reduced
      24 hr after 1 or 10 mM lithium chloride (LiCl) pretreatment. The Ca2+ rise was
      reduced in a time-dependent manner, and the significant inhibition was observed 9
      hr pretreatment with 10 mM LiCl. On the other hand, pretreatment of the cells
      with 10 mM LiCl for 24 hr did not alter the amount of Galphaq/11 significantly.
      Pretreatment with 10 mM LiCl for 24 hr failed to reduce the 5-HT-induced Ca2+
      mobilization or to affect the desensitization of the 5-HT signal. Finally,
      thrombin-elicited Ca2+ rise was markedly inhibited in the presence of 0.05 U/ml
      plasmin, however, the Ca2+ rise was not further attenuated in the presence of
      plasmin in C6 cells pretreated with LiCl for 24 hr. These results indicate that
      pretreatment with LiCl attenuated thrombin-evoked intracellular Ca2+ mobilization
      in plasmin sensitive manner in C6 rat glioma cells. Thus, it is important to
      investigate the effect of lithium on thrombin-induced cellular responses to
      clarify the action mechanism of lithium in relation to some abnormality in
      thrombin-evoked Ca2+ rise observed in bipolar disorders.

PMID- 10659986
TI  - Pertussis vaccine and pertussis toxin increase lithium levels in rats: possible
      role of G-proteins.
AB  - A single dose of lithium was injected intravenously or intraperitoneally in rats.
      Lithium levels in serum and tissues 5 or 24 hours later were elevated when the
      rats were pretreated with pertussis vaccine (PV). The vaccine was effective
      whether given locally (subcutaneous) or systemically (intravenous). Tests of
      heated (inactivated) PV suggested that pertussis toxin might be responsible for
      the effects of PV. Injection of purified pertussis toxin (PT) confirmed this
      suggestion. Elevation of serum urea nitrogen suggested that lithium levels were
      increased because the combination of PV or PT with lithium reduced renal
      excretory function which could cause retention of lithium. Inasmuch as PV and PT
      are known to inactivate the inhibitory G-proteins, these data suggest G-protein
      involvement in the elevation of lithium levels by PV and PT.

PMID- 10659987
TI  - Long photoperiod regimen may produce antidepressant actions in the male rat.
AB  - The exposure to bright light reverts the depressive symptoms of seasonally
      affective disorder. Rats received tricyclic antidepressants or were submitted to
      two photoperiod regimens. After treatments, the rats were forced to swim or were
      submitted to the differential reinforcement of the low-rate 72s schedule. Two
      animal models designed to testing the antidepressant effects of drugs.
      Clomipramine, desipramine or the long photoperiod decreased immobility in rats
      forced to swim. In the differential reinforcement of the low-rate 72s schedule,
      clomipramine, desipramine or the long photoperiod increased the reinforcers
      obtained by the rats. It is concluded that the long photoperiod regimen may
      produce antidepressant effects in male Wistar rats.

PMID- 10659988
TI  - Anxiolytic-like actions of melatonin, 5-metoxytryptophol, 5-hydroxytryptophol and
      benzodiazepines on a conflict procedure.
AB  - Male Wistar rats (120-230 g) were used in these experiments. Some rats were
      deprived of water for 48 h before testing in a conflict procedure. Then, after 20
      licks from a water bottle with a metal drinking tube, the animal received an
      electric shock (0.5 mA/500 msec). The effects of two classical anxiolytic drugs,
      DIAZ (1.0, 2.0 and 4.0 mg/Kg b.wt), and CDP (5.0 and 10.0 mg/Kg b.wt) were
      compared to those produced by MEL (0.1, 0.2, 0.5, 1.0 and 2.0 mg/Kg b.wt), 5
      MTOPHOL (1.0 and 2.0 mg/Kg b.wt), 5-HTOPHOL (1.0 and 2.0 mg/Kg b.wt) and vehicle
      solution. Anxiolytic drugs as well as MEL produced a dose-dependent increase in
      the number of shocks received. The results suggest that the three pineal indoles
      are involved in the modulation of the stress responses. MEL showed a higher
      potency than the other indoles.

PMID- 10659989
TI  - Acute and subchronic effects of pimozide on isolation-induced aggression in male
      mice.
AB  - The aim of this study was to examine the effects of pimozide (0.25-1.25 mg/kg),
      administered acutely or subchronically for 10 days, on agonistic behavior
      elicited by isolation in male mice. Individually housed mice were exposed to
      anosmic "standard opponents" 90 min after pimozide injections, and the encounters
      were videotaped and evaluated using an ethologically based analysis. 3. After
      acute treatment pimozide did not affect significantly aggression and immobility.
      However, mice treated subchronically with pimozide (0.75 and 1.25 mg/kg) showed a
      significant reduction in offensive behaviors (threat and attack) and an increase
      of immobility (1.25 mg/kg). The antiaggressive and motor actions of pimozide were
      more marked after subchronic treatment than after acute treatment. It might
      reflect an accumulation of the drug over time, an effect also described with
      other neuroleptics such as amisulpride.

PMID- 10659990
TI  - Changes of metallothionein I + II proteins in the brain after 1-methyl-4
      phenylpyridinium administration in mice.
AB  - 1-methyl-4-phenylpyridinium (MPP+) is a drug that induces a Parkinson's-like
      syndrome in several species. Oxidative stress resulting from either excess
      generation or reduced scavenging of free radicals has been proposed to play a
      role in its neurotoxicity. It has been suggested that metallothionein (MT)
      protects against oxidative damage of the central nervous system produced by
      overproduction of free radicals. This study examined the effect of MPP+ on
      metallothionein I+II protein content in different brain regions. NIH mice were
      injected with MPP+ (4.5, 9.0 or 18 microg/3 microl) into their right lateral
      ventricle. Corpus striatum, cerebellum, midbrain, frontal cortex and hippocampus
      were dissected out and their metallothionein concentrations were analyzed by
      radioimmunoassay. MPP+ reduced the concentration of MT I+II proteins (38%) only
      in the striatum. The results suggest that changes in MT I+II content may be
      associated with MPP+ neurotoxicity.

PMID- 10659991
TI  - Acute stress does not alter 5-HT1A receptor density.
AB  - Previous research suggests that 5-HT1A receptors are altered with exposure to
      chronic stress. No previous studies have examined the effect of acute stress on 5
      HT1A. Using receptor autoradiography it was observed that there were no
      differences in [3H]-8-OH-DPAT binding between control rats and rats that received
      20 minutes of restraint stress 2 hours prior to sacrifice. This study suggests
      that the changes in 5-HT1A receptor density associated with chronic stress
      develop over the course of repeated stress.

PMID- 10659992
TI  - A model for the cytoplasmic trafficking of signalling proteins involving the
      hsp90-binding immunophilins and p50cdc37.
AB  - A number of transcription factors and protein kinases involved in signal
      transduction exist in heterocomplexes with the ubiquitous and essential protein
      chaperone hsp90. These signalling protein x hsp90 heterocomplexes are assembled
      by a multiprotein chaperone system comprising hsp90, hsp70, Hop, hsp40, and p23.
      In the case of transcription factors, the heterocomplexes with hsp90 also contain
      a high molecular weight immunophilin with tetratricopeptide repeat (TPR) motifs,
      such as FKBP52 or CyP-40. In the case of the protein kinases, the heterocomplexes
      contain p50cdc37. The immunophilins bind to a single TPR acceptor site on hsp90,
      and p50cdc37 binds to an adjacent site so that binding is exclusive for p50cdc37
      or an immunophilin. Direct interaction of immunophilins with the transcription
      factors or p50cdc37 with the protein kinases leads to selection of different
      heterocomplexes after their assembly by a common mechanism. Studies with the
      glucocorticoid receptor, for which translocation from the cytoplasm to the
      nucleus is under hormonal control, suggest that dynamic assembly of the
      heterocomplexes is required for rapid movement of the receptor through the
      cytoplasm along cytoskeletal tracts. As for the similar short-range trafficking
      of vesicles along microtubules, there must be a mechanism for linking the
      signalling protein solutes to the molecular motors involved in movement. We
      present here a model in which the immunophilins and p50cdc37 target,
      respectively, the retrograde or anterograde direction of signalling protein
      movement by functioning as connectors that link the signalling proteins to the
      movement machinery.

PMID- 10659993
TI  - Pharmacological and functional characterization of bradykinin receptors in rat
      cultured vascular smooth muscle cells.
AB  - The pharmacological properties of bradykinin receptors were characterized in rat
      cultured vascular smooth muscle cells (VSMCs) using [3H]-bradykinin as a ligand.
      Analysis of binding isotherms gave an apparent equilibrium dissociation constant
      (K(D)) of 1.2 +/- 0.2 nM and a maximum receptor density (Bmax) of 47.3 +/- 4.4
      fmol/mg protein. The specific binding of [3H]-bradykinin to VSMCs was inhibited
      by the B2 receptor-selective agonists (bradykinin and kallidin) and antagonists
      ([D-Arg0, Hyp3, Thi5, D-Tic7, Oic8]-bradykinin (Hoe 140) and [D-Arg0, Hyp3,
      Thi(5,8), D-Phe7]-bradykinin) with an order of potency as kallidin = bradykinin =
      Hoe 140 > [D-Arg0, Hyp3, Thi(5,8), D-Phe7]-bradykinin, but not by a B1 receptor
      selective agonist (des-Arg9-bradykinin) and antagonist ([Leu8, des-Arg9]
      bradykinin). Stimulation of VSMCs by bradykinin produced a concentration
      dependent inositol phosphate (IP) accumulation, and initial transient peak of
      [Ca2+]i with half-maximal responses (pEC50) were 7.53 and 7.69, respectively. B2
      receptor-selective antagonists (Hoe 140 and [D-Arg0, Hyp3, Thi(5,8), D-Phe7]
      bradykinin) significantly antagonized the bradykinin-induced responses with pK(B)
      values of 8.3-8.7 and 7.2-7.9, respectively. Pretreatment of VSMCs with pertussis
      toxin (100 ng/ml, 24 h) did not alter the bradykinin-induced inositol phosphate
      accumulation and [Ca2+]i changes in VSMCs. Removal of external Ca2+ led to a
      significant attenuation of responses induced by bradykinin. Influx of external
      Ca2+ was required for the bradykinin-induced responses, since Ca2+-channel
      blockers, nifedipine, verapamil, and Ni2+, partially inhibited the bradykinin
      induced IP accumulation and Ca2+ mobilization. These results demonstrate that
      bradykinin stimulates phosphoinositide hydrolysis and Ca2+ mobilization via a
      pertussis toxin-insensitive G-protein in rat VSMCs. Bradykinin B2 receptors may
      be predominantly mediating IP accumulation and subsequently induction of Ca2+
      mobilization may function as the transducing mechanism for bradykinin-stimulated
      contraction of vascular smooth muscle.

PMID- 10659994
TI  - Activation of arachidonate release and cytosolic phospholipase A2 via
      extracellular signal-regulated kinase and p38 mitogen-activated protein kinase in
      macrophages stimulated by bacteria or zymosan.
AB  - The mitogen-activated protein kinases (MAP kinases), extracellular signal
      regulated kinase (ERK) and p38, can both contribute to the activation of
      cytosolic phospholipase A2 (cPLA2). We have investigated the hypothesis that ERK
      and p38 together or independent of one another play roles in the regulation of
      cPLA2 in macrophages responding to the oral bacterium Prevotella intermedia or
      zymosan. Stimulation with bacteria or zymosan beads caused arachidonate release
      and enhanced in vitro cPLA2 activity of cell lysate by 1.5- and 1.7-fold,
      respectively, as well as activation of ERK and p38. The specific inhibitor of MAP
      kinase kinase, PD 98059, and the inhibitor of p38, SB 203580, both partially
      inhibited cPLA2 activation and arachidonate release induced by bacteria and
      zymosan. Together, the two inhibitors had additive effects and completely blocked
      cPLA2 activation and arachidonate release. The present results demonstrate that
      ERK and p38 both have important roles in the regulation of cPLA2 and together
      account for its activation in P. intermedia and zymosan-stimulated mouse
      macrophages.

PMID- 10659995
TI  - Co-expression of human Kir3 subunits can yield channels with different functional
      properties.
AB  - To date, no comprehensive study has been done on all combinations of the human
      homologues of the Kir3.0 channel family, and the human homologue of Kir3.3 has
      not yet been identified. To obtain support for the contention that most of the
      functional data on non-human Kir3.0 channels can be extrapolated to human
      channels, we have cloned the human homologues of the Kir3.0 family, including the
      yet unidentified human Kir3.3, and the human Kir4.1. The expression pattern of
      these channels in various human brain areas and peripheral tissues, analysed by
      Northern blot analysis, allows for the existence of various homomeric and
      heteromeric forms of human Kir3.0 channels. Expression studies of all possible
      combinations in Xenopus oocytes indicated that in homomeric Kir3.2c and
      heteromeric Kir3.1/3.2c channels mediate, in our studies, inward currents with
      largest amplitude of any other Kir3.0 channel combinations, followed by
      heteromeric Kir3.1/3.4 and homomeric Kir4.1 channels. Channel combinations which
      include Kir3.3 are detrimental to the formation of functional channels. The co
      expression experiments with different Kir channel subunits indicate the selective
      formation of certain channel combinations, suggesting that channel specificity is
      not solely dependent on spatial and temporal regulation of Kir subunit
      expression.

PMID- 10659997
TI  - Novel kinetics, behaviour and cell-type specificity of CD157-mediated tyrosine
      kinase signalling.
AB  - CD157, a recently characterized leukocyte surface antigen, has recently been
      shown to induce tyrosine phosphorylation of a 130-kDa protein (p130) when cross
      linked with its antibody (ligand). We have further investigated the detailed
      kinetics, behaviour and cell-type specificity of this CD157-stimulated p130
      phosphorylation. We demonstrate that CD157-mediated p130 phosphorylation is
      ligand independent in recombinant CD157-expressing CHO, MCA102 and COS-7 cells
      but is ligand dependent in HL-60-differentiated monocytes (mHL-60) having
      enhanced CD157 expression. This p130 phosphorylation is activated only at lower
      temperatures (0-4 degrees C) in MCA102, COS-7 and mHL-60 cells but is temperature
      insensitive in CHO cells. We further demonstrate that the CHO/CD157 cell clones
      have approximately 22-28% slower rates of proliferation than that of a CHO/mock
      clone. But the MCA102 cell proliferation remains unaffected by CD157 expression.
      We postulate that the difference in the temperature sensitivity of p130
      phosphorylation can be responsible for the discrepancy in the rates of
      MCA102/CD157 and CHO/CD157 cell proliferation.

PMID- 10659996
TI  - Phosphatidylinositol 3-kinase contributes to Erk1/Erk2 MAP kinase activation
      associated with hepatocyte growth factor-induced cell scattering.
AB  - MAP kinase cascade-dependent responses were investigated during scattering of
      HepG2 human hepatoma cells stimulated by HGF or phorbol ester. Inhibition of
      phosphatidylinositol 3-kinase with LY294002 prevented completely the dissociation
      of cells. Inhibition of MAP kinase kinase (MEK) with PD98059 prevented the
      development of characteristic morphological changes associated with cell
      migration. EGF, which failed to induce cell scattering, caused a short-term
      increase in the phosphorylation of Erk1/Erk2 MAP kinases. On the contrary, HGF or
      phorbol ester stimulated the phosphorylation of MAP kinases for a long time.
      Experiments performed with LY294002 indicated that phosphatidylinositol 3-kinase
      contributed to the HGF-stimulated phosphorylation of Erk1/Erk2. This finding was
      confirmed by the demonstration that the MAP kinase cascade-dependent expression
      of a high-Mr (>300 kDa) protein pair appearing in the course of cell scattering
      was inhibited by LY294002 in HGF-induced cells but was not inhibited in phorbol
      ester-treated cells.

PMID- 10659998
TI  - Inhibition of bradykinin-induced phosphoinositide hydrolysis and Ca2+
      mobilisation by phorbol ester in rat cultured vascular smooth muscle cells.
AB  - Regulation of the increase in inositol phosphate (IP) production and
      intracellular Ca2+ concentration ([Ca2+]i by protein kinase C (PKC) was
      investigated in cultured rat vascular smooth muscle cells (VSMCs). Pretreatment
      of VSMCs with phorbol 12-myristate 14-acetate (PMA, 1 microM) for 30 min almost
      abolished the BK-induced IP formation and Ca2+ mobilisation. This inhibition was
      reduced after incubating the cells with PMA for 4 h, and within 24 h the BK
      induced responses were greater than those of control cells. The concentrations of
      PMA giving a half-maximal (pEC50) and maximal inhibition of BK induced an
      increase in [Ca2+]i, were 7.8 +/- 0.3 M and 1 microM, n = 8, respectively. Prior
      treatment of VSMCs with staurosporine (1 microM), a PKC inhibitor, inhibited the
      ability of PMA to attenuate BK-induced responses, suggesting that the inhibitory
      effect of PMA is mediated through the activation of PKC. Paralleling the effect
      of PMA on the BK-induced IP formation and Ca2+ mobilisation, the translocation
      and downregulation of PKC isozymes were determined by Western blotting with
      antibodies against different PKC isozymes. The results revealed that treatment of
      the cells with PMA for various times, translocation of PKC-alpha, betaI, betaII,
      delta, epsilon, and zeta isozymes from the cytosol to the membrane were seen
      after 5 min, 30 min, 2 h, and 4 h of treatment. However, 24-h treatment caused a
      partial downregulation of these PKC isozymes in both fractions. Treatment of
      VSMCs with 1 microM PMA for either 1 or 24 h did not significantly change the
      K(D) and Bmax of the BK receptor for binding (control: K(D) = 1.7 +/- 0.2 nM;
      Bmax = 47.3 +/- 4.4 fmol/mg protein), indicating that BK receptors are not a site
      for the inhibitory effect of PMA on BK-induced responses. In conclusion, these
      results demonstrate that translocation of PKC-alpha, betaI, betaII, delta,
      epsilon, and zeta induced by PMA caused an attenuation of BK-induced IPs
      accumulation and Ca2+ mobilisation in VSMCs.

PMID- 10659999
TI  - Should data and safety monitoring boards share confidential interim data?
AB  - Consider the following situation: Two clinical trials are underway, closely
      related in terms of the interventions being compared and the target populations.
      In preparing for a planned interim analysis, the statistician for trial 1 finds
      that the results support a recommendation to stop the trial early. Should the
      statistician ask the investigators for trial 2 to make interim results of their
      trial available to the data and safety monitoring board (DSMB) for trial 1? If
      so, in what form? Would the answers change if the trial 1 results showed a strong
      but not convincing trend? What is the obligation of the trial 2 investigators to
      respond to such a request? What role do the two DSMBs have, either in initiating
      a request or in agreeing to respond to it? In this article, we examine this
      situation in some detail, having faced it occasionally in our own experience with
      clinical trials and DSMBs. The chief argument in favor of sharing data is that
      data from trial 2 are obviously relevant to the question being addressed by trial
      1 and therefore ought to be available to those who must interpret the results
      from that trial. On the other hand, there are several reasons for not sharing
      interim data. For example, sharing is incompatible with the independence of the
      trials; the time for synthesizing evidence from both trials is after the two
      teams of investigators have presented the full analysis and interpretation of
      their separate trials. For this and other conceptual and practical reasons we
      conclude that it is better, in most cases, for DSMBs to consider only information
      that has already been made public in some form.

PMID- 10660000
TI  - Clinical trials in the genomic era: effects of protective genotypes on sample
      size and duration of trial.
AB  - It is well known that individuals can vary widely in their disease
      susceptibilities. One potential source of this variation is the genetic makeup of
      individuals, which can confer either protection or susceptibility to disease.
      Here we examine the effects of protective genotypes on the sample sizes and time
      required to detect differences between clinical trial arms. We show that
      including individuals with protective genotypes in a clinical trial can increase
      required sample sizes and trial duration. One can deal with this issue by
      pregenotyping subjects and selectively enrolling them based on their genotype.
      Thus we also calculate the number of individuals that must be recruited and
      pregenotyped to fulfill sample size requirements. The benefits of genotypically
      screening study subjects will depend on numerous factors, including ease of
      patient recruitment, cost of genotyping, long-term costs of study (or long-term
      cost per subject), and the strength of the protective effect. We present several
      examples that show the potential value of incorporating information about
      protective genotypes into a clinical trial.

PMID- 10660001
TI  - General linear models for multicenter clinical trials.
AB  - The use of generalized linear models (GLM) in the analysis of multicenter
      clinical trials is commonplace. Currently, diverse opinion exists as to the
      proper modeling approach in this setting. This paper provides a description of
      the technical backdrop underlying the model selection and discusses the pros and
      cons of the usual parameter estimators. Arguments are given favoring a model
      incorporating a term for interaction effect while attenuating the effects of
      small centers.

PMID- 10660002
TI  - Selection of quality-of-life measures for a prevention trial: a psychometric
      analysis.
AB  - Quality-of-life (QoL) outcomes have become increasingly important in the
      evaluation of health interventions. The objective of the present study was to
      determine which of three generic QoL instruments was most suitable for use in an
      8-year nutritional primary prevention trial. We compared the Duke Health Profile,
      the Nottingham Health Profile, and the Short Form Health Survey Questionnaire
      (SF36). We conducted the comparison in two stages: (1) a statistical analysis of
      data from a pilot study (n = 963) comparing the psychometric properties of the
      three instruments; and (2) an assessment of the practicality of the tools. With
      regard to psychometric properties, convergent validity was comparable for the
      three scales, and the correlation with Global Health Assessment ranged from 0.24
      to 0.72. Discriminant validity was best for the SF36, with a difference between
      scores in healthy subjects and those with chronic disease in the range of 4.4 to
      15.8 (scores could range from 0 to 100, where 100 indicates perfect health).
      Reproducibility was good for all three instruments, with a test-retest intraclass
      correlation coefficient of over 0.60 for most dimensions. DHP and SF36 performed
      best in terms of responsiveness. We judged the practicality of the three tools as
      satisfactory. We chose the SF36 for its high responsiveness. We also selected the
      Duke Health Profile for its practicality and favorable psychometric properties.

PMID- 10660003
TI  - Dynamically allocating treatment when the cost of goods is high and drug supply
      is limited.
AB  - Large-scale production of proteins by cell culture and subsequent purification
      for use in novel medical therapies is a slow and complex process. During the
      early phases of development of manufacturing processes, contamination and
      replication errors cause entire batches of material to be wasted. As a result,
      the cost of goods for large-molecule therapies in early clinical development can
      be significant, and the supply limited. When designing clinical trials to test
      expensive biological compounds with limited supply, sponsoring companies want to
      minimize the waste of drug, that is, to maintain small inventories of drug at the
      investigational hospitals. We must, however, weigh the benefits of smaller
      inventories against the costs of increased numbers of shipments to resupply when
      rapid enrollment causes shortages of drug. A well-planned randomization scheme
      may be able to balance these objectives. This paper demonstrates how a dynamic
      randomization algorithm can be used to maintain smaller drug inventory at
      hospitals than a typical permuted block randomization list plan, and how well it
      automatically restores balance when the shortage of drug causes assignment of
      alternate treatments.

PMID- 10660005
TI  - Henry Kempe's Legacy

PMID- 10660004
TI  - A design for testing interventions to improve adherence within a hypertension
      clinical trial.
AB  - The Potassium Adherence Clinical Trial (PACT) incorporates one randomized
      clinical trial within another. A randomized trial of interventions to increase
      adherence to medication is nested within a second randomized clinical trial
      testing hypotensive effect of supplemental oral potassium. The trial aims
      principally to compare the effects of three intervention strategies: two sessions
      of individual patient counseling, two telephone contacts, or standard care. The
      trial aims secondarily to evaluate the effect of 60 mEq supplemental oral
      potassium daily on sitting systolic and diastolic blood pressure in hypertensive
      patients on established drug therapy. Therefore, it organizes the patients given
      potassium into three study groups for adherence interventions, and the patients
      assigned to placebo into a further three. We evaluate adherence primarily by
      means of the Medication Event Monitoring System (MEMS), an electronic system that
      records the date and time that the container of study medication is opened.
      Additional measurements, such as assessments of change in levels of urinary
      potassium, pill counts, appointment records, self-reporting by patients, and
      estimates by physician of adherence, are used and correlated with MEMS data. At a
      single center, the trial enrolled 107 participants between the ages of 26 and 80.
      This paper describes the background to this trial within a trial, details its
      design, documents the baseline characteristics of participants enrolled, and
      describes issues experienced during implementation of the trial.

PMID- 10660006
TI  - Extrafamilial sexual abuse: treatment for child victims and their families.
AB  - OBJECTIVES: To decrease the emotional distress of child victims of extrafamilial
      sexual abuse (ESA) and their families. To provide crisis intervention, individual
      and group treatment in response to an expressed need in the community. To pilot
      the use of group treatment for child victims of ESA under age 10. METHOD: This
      discussion describes intervention with a sample of 246 child victims, ages 2-14
      years, and 323 parents who participated in the program from 1984 to 1991. This
      pilot project operated at a university medical facility and was located off
      campus in an outpatient child abuse center. Priority was given to child victims
      under age 7. Child victims and their families were evaluated after investigative
      interviews by law enforcement agencies were completed. A treatment plan was
      developed based on clinical assessment. Families participated in crisis
      counseling, individual treatment for the child victim and/or parent, Children's
      Treatment Groups, Parent Support Groups, or were referred to other resources.
      Clinical assessment of treatment progress included weekly case review by child
      and parent therapists, video analysis and observation of Children's Treatment
      Group sessions, consultation with parents and collateral contacts. RESULTS: A
      family approach and services for parents in addition to intervention for child
      victims were determined to be key components in facilitating recovery. Clinical
      observations and client feedback showed positive outcomes for child victims and
      parents with crisis counseling, Children's Treatment groups, and Parent Support
      Groups. The extent of intervention ranged from one session to 24 months with an
      average participation of 6-9 months. Follow up surveys were returned by parents
      for 48 child victims and results are reported. Themes, parallels in responses,
      and recovery factors for child victims and parents are discussed. CONCLUSIONS:
      The need for intervention and a community-based program was demonstrated by (1)
      the significant disruption in functioning that occurred for child victims of ESA
      and their families, (2) the risk for long term sequelae, (3) the high incidence
      of extrafamilial sexual abuse, and 4) the consistent, large number of requests
      for services. Family-centered crisis services, Children's Treatment Groups, and
      Parent Support Groups can be effectively based at child advocacy centers, out
      patient care clinics, or other community agencies. The results of formal outcome
      measures and longitudinal studies is needed to determine how child victims and
      parents benefit from specific treatment modalities and to better guide the use of
      limited resources.

PMID- 10660007
TI  - Academic progress of children who attended a preschool for abused children: a
      follow-up of the keepsafe project.
AB  - OBJECTIVE: This study was undertaken to assess academic progress of children 1 to
      5 years after graduating from the C. Henry Kempe Center's Therapeutic Preschool
      Day Treatment Program. METHOD: Information was gathered through chart review;
      telephone surveys of care providers, relatives, and social service workers; as
      well questionnaires on all children who attended the therapeutic preschool day
      treatment program between 1984 and 1989, including the 24 children reported on by
      Oates, Gray, Schweitzer, Kempe, and Harmon, 1995. RESULTS: Classroom placement
      was determined for 27 of the 44 graduates (61.4%), 14 of whom (51.9%) were in a
      regular classroom, 10 (37.0%) in special education, two (7.4%) in residential
      treatment, and one (3.7%) was receiving home schooling. Twenty-two of the 27
      children (81.5%) improved or remained in the same grade and type of classroom as
      they had been staffed into at the time of their graduation from the preschool day
      treatment program. Factors thought to affect stability of classroom placement
      were studied, of which frequency of family moves was the only significant
      variable. Its significance was in the direction opposite to that expected. The
      most effective method of locating families was to contact the Department of
      Social Services who provided information used to find 60% of them. CONCLUSIONS:
      Intervention in a therapeutic preschool day treatment program was found to be
      beneficial, as it enabled most of the children to progress appropriately in
      public school.

PMID- 10660008
TI  - Childhood sexuality: a decade of study. Part I--research and curriculum
      development.
AB  - OBJECTIVE: One goal of the Kempe Center's Perpetration Prevention Program has
      been to increase the awareness and competence of professionals and parents in
      understanding and responding to the sexual behaviors of children in order to
      reduce the risk of children developing sexually abusive patterns of behavior. A
      decade of exploration and the development of curricula is reviewed in this paper.
      METHOD: The evolving body of literature relevant to childhood sexuality and
      sexually abusive behaviors in childhood was reviewed. Several new sources of
      information and development of a teaching model for adults are described.
      RESULTS: Children engage in a wide range of sexual behaviors, some of which may
      be observed by or reported to adults. Research encompassing diverse samples and
      methods converges to describe what is developmentally expected and what might be
      problematic. Professionals need to be trained to evaluate and respond to these
      behaviors objectively, without relying on the personal beliefs or values of
      individuals. CONCLUSION: Children have a legitimate need for validation and
      correction of sexual learning. Adults often have not been trained to respond
      consistently to children's behaviors, but are eager to obtain more information.

PMID- 10660009
TI  - Childhood sexuality: a decade of study. Part II--dissemination and future
      directions.
AB  - OBJECTIVE: One goal in perpetration prevention has been to increase the awareness
      and competence of professionals and parents in understanding and responding to
      the sexual behavior of children in order to reduce the risk of children
      developing sexually abusive behavior. A decade of experience in disseminating
      information about children's sexual development and behavior is reviewed in this
      paper. METHOD: Curricula developed at the Kempe Children's Center, University of
      Colorado Health Science Center, were used to provide training to professionals
      and paraprofessional caregivers. The information has evolved into a variety of
      models for different purposes in different settings. RESULTS: Children engage in
      a wide range of sexual behaviors, some of which adults observe or are told about
      by other children. Adults can be trained to evaluate what is developmentally
      expected or problematic, and to respond consistently on the basis of objective
      definitions and universal goals, rather than relying on the personal beliefs and
      values of individuals. CONCLUSION: Because children's sexual behaviors may pose a
      risk to themselves or others, there is a legitimate need for adults to respond to
      what they see and hear in order to validate or correct sexual learning in
      childhood. Adults are often not well informed about childhood sexuality and are
      eager to access objective information to inform their decision making in the care
      of children.

PMID- 10660010
TI  - Elevated picture completion scores: a possible indicator of hypervigilance in
      maltreated preschoolers.
AB  - OBJECTIVE: The Picture Completion subtest of the Wechsler Preschool and Primary
      Scales of Intelligence-Revised (WPPSI-R) measures visual alertness and the
      ability to differentiate essential from nonessential details. In children who are
      hypervigilant as a result of maltreatment, these skills may be over-functioning.
      It was hypothesized that the Picture Completion subtest scores of these children
      would be significantly elevated in comparison to their other nonverbal scores and
      their overall intellectual functioning. METHOD: Fourteen children from a
      therapeutic day treatment preschool program for maltreated children were
      administered the WPPSI-R. Standardized discrepancy scores between Picture
      Completion scores and Performance mean scores (PC-Performance Discrepancy) and
      the mean of all subscale scores (PC-Overall IQ Discrepancy) were formed and then
      analyzed. RESULTS: The abused preschoolers scored significantly lower than the
      population mean on four of the five WPPSI-R Performance subscales. Only on
      Picture Completion did they score significantly higher. Average PC-Performance
      Discrepancy and PC-Overall IQ Discrepancy scores were greater than one,
      indicating that the mean difference of children's Picture Completion score from
      either their Performance mean score or all of their mean scores was more than one
      standard deviation. CONCLUSION: Elevated Picture Completion score may serve as a
      marker for hypervigilance and/or PTSD in children with histories of maltreatment.

PMID- 10660011
TI  - Client evaluation of a consultation team on crimes against children.
AB  - OBJECTIVE: Cases of child abuse filed in court as crimes against children
      represent a small percentage of the total numbers of children maltreated.
      However, studying crimes of maltreatment against children is important for
      individual victims and their families, and for theory and policy in order to
      assure that these cases are managed as well as possible. Forensic consultation
      teams can perform several functions related to child abuse crimes: provide
      multidisciplinary expertise in the evaluation of maltreatment cases, offer a
      method for allocating resources between cases managed by the criminal justice and
      child protection systems, and provide important research and teaching
      opportunities. This study reviews the role played by multidisciplinary team
      consultations based on the perception of client professionals whose agencies pay
      for an outside consulting forensic team. METHOD: Professionals referring to a
      forensic team for consultative assistance were asked to evaluate the service
      during telephone interviews, responding to both structured and unstructured
      questions. RESULTS: Responding professionals (N= 18) stated that the team
      increased their confidence that the approach being taken to a case was correct
      (94%), that missing expertise was provided (100%), that progress was made in
      cases that might otherwise not have been made (55%), and that ambiguity was
      reduced (in 83% of referred cases). Using the team sometimes caused delays. Some
      delays were unacceptable administrative delays while others were considered
      necessary to assure completeness of the evaluation. CONCLUSION: The use of the
      team did not result in resolution of all of the cases referred, but referral to
      the team consistently provided closure for referring professionals. In one-third
      of the cases studied, if it had not been for the START consultation the cases
      would not have proceeded to an appropriate criminal or civil resolution.

PMID- 10660012
TI  - Characteristics of volunteers and families in a neonatal home visitation project:
      the Kempe Community Caring Program.
AB  - OBJECTIVE: The purpose of this paper is to review literature related to home
      visitation support for new families using volunteer visitors and to describe
      characteristics of volunteers of the Kempe Community Caring Program, a home
      visitor support program for first time parents. Suggestions for effectively
      utilizing volunteers in family support programs are made. METHOD: Program data
      was collected and reviewed on 592 volunteer home visitors and the 1,144 families
      they served. Several evaluations and assessments were performed in order to
      attempt to measure the success of the intervention. Motivation for volunteering,
      longevity with program, and the extent of sociodemographic match between visitor
      and client were reviewed and discussed. RESULTS: Information on matched volunteer
      client pairs was limited; however, speculations were made that neither motivation
      to participate nor sociodemographic match were critical factors in determining
      success of the intervention. Duration of volunteer participation was influenced
      by marital status, but not by age. Married volunteers stayed with the program
      significantly longer than unmarried volunteers. Low risk families demonstrated
      slightly improved confidence in parental function after receiving home visitation
      by a volunteer. CONCLUSION: This program suggests that new mothers may benefit
      from receiving the services of a volunteer home visitor; specifically, their
      confidence as parents and ability to establish positive relationships show slight
      improvement. Likewise, volunteers and families felt satisfied with the supportive
      relationships generated. In addition, a volunteer profile emerged which may be
      beneficial to similar programs' recruiting efforts.

PMID- 10660013
TI  - Children's story stem responses: a measure of program impact on developmental
      risks associated with dysfunctional parenting.
AB  - OBJECTIVE: This paper will explore how a new research tool, the MacArthur Story
      Stem Battery (MSSB), enables investigations into the interior life of children,
      its potential usefulness in evaluating effectiveness of interventions geared to
      prevent dysfunctional parenting, and how the method has been adapted for use with
      low income African American children in the Memphis New Mothers Study. METHOD: A
      literature review provides justification for assessing children's representations
      of their parenting experience to evaluate the effectiveness of an early
      intervention program. Case examples are used to illustrate children's
      representations of themes in narrative responses that are indicative of
      behavioral regulation and dysregulation and specific adaptations for use with
      African American children. RESULTS: Case examples support the method's
      application. CONCLUSIONS: The story stem technique can play an important role in
      evaluating children's emotion regulation, social skills, and early experience in
      the family.

PMID- 10660014
TI  - The role of acculturation in explaining ethnic differences in the prenatal health
      risk behaviors, mental health, and parenting beliefs of Mexican American and
      European American at-risk women.
AB  - OBJECTIVE: To assess: (1) ethnic differences in the health-risk behaviors, mental
      health problems, and adverse parenting beliefs during pregnancy of low-income
      Mexican American and European American women; and, (2) the extent to which these
      risks varied with levels of acculturation among low-income Mexican American
      women. METHOD: Participants were 594 primiparous, low-income, urban women. A
      cross-sectional design was used to compare the 331 Mexican American women to the
      263 European American. Language was used to assess the level of acculturation of
      the Mexican American women. Interviews were used to evaluate health-risk
      behaviors, mental health problems, and adverse parenting beliefs. RESULTS: In
      comparison to European American women, Mexican American women were at lower risk
      for cigarette smoking during pregnancy and higher risk for adverse parenting
      beliefs. Among Mexican American women, Spanish speakers were at lower risk for
      cigarette smoking and mental health problems during pregnancy, and higher risk
      for adverse parenting beliefs than bilingual and English speakers. CONCLUSIONS:
      The findings indicate that ethnic differences in cigarette smoking and parenting
      beliefs during pregnancy were concentrated on the less acculturated, low-income,
      and primarily unmarried Spanish speaking Mexican American women. Moreover,
      acculturation is differentially related to cigarette smoking and parenting
      beliefs. Therefore, acculturation needs to be considered in the development of
      preventive interventions in order to appropriately target the specific needs of
      different sub-populations of Mexican Americans.

PMID- 10660016
TI  - Volunteer services for vulnerable families and at-risk elderly.
AB  - OBJECTIVE: The purpose of this paper is to explore the role of the volunteer with
      vulnerable populations, specifically, new parents and their infants and at-risk
      elderly. As demand for volunteer services increases due to budgetary and
      personnel reductions, a better understanding of volunteers as service providers
      is imperative. METHOD: A review of the literature related to volunteers who work
      with these two populations was conducted. Volunteer characteristics, roles, needs
      of populations served, recruitment, and training issues were addressed,
      specifically as they relate to the two populations. RESULTS: Studies indicate
      that the socio-demographic range of volunteers is wide, as are the motivations
      for volunteering. Similarities between the needs of new families and the elderly
      exist, and volunteers for both populations often provide supportive and pragmatic
      services. Volunteers for both populations are further challenged to maintain a
      client-focused intervention, a task which may be more difficult in the home.
      Training of volunteers was found to be both client and volunteer driven, with the
      needs of the population being served and the role of the volunteer within a
      specific service domain of prime importance. CONCLUSION: Similarities between
      infant and elder populations exist, as do volunteer interventions with these
      populations. A theoretical framework for defining motivation, designing need
      based training, and addressing the role of volunteers is discussed. The use of
      volunteers as compassionate and cost-effective service providers for populations
      across the lifespan not only provides an increase in the number of skilled
      workers involved with these vulnerable populations, but also allows professional
      staff to expand the care which they are able to provide.

PMID- 10660015
TI  - The Kempe Family Stress Inventory: a review.
AB  - OBJECTIVE: The objective of this article is to review the Kempe Family Stress
      Inventory (KFSI), a 10-item scale that measures risk for parenting difficulties
      based upon responses to a thorough psychosocial interview. The article provides a
      historical overview, as well as reviewing research regarding its reliability and
      validity. METHOD: Research and documentation regarding the KFSI were gathered
      from journals, book chapters, presentations, workshops, and intervention
      evaluation reports. RESULTS: The KFSI has been used to predict parents' future
      risk of maltreating their children. The scale covers a variety of domains,
      including psychiatric history, criminal and substance abuse history, childhood
      history of care, emotional functioning, attitudes towards and perception of
      child, discipline of child, and level of stress in the parent's life. Although
      construct validity has been demonstrated with the KFSI, questions remain about
      its specificity and sensitivity. In addition, there has been minimal reliability
      work done on the measure. CONCLUSIONS: It is concluded that the KFSI may have
      clinical utility, but should be used as part of a more comprehensive risk
      assessment that includes multiple measures. Acceptable accuracy in predicting
      child abuse and neglect when used by itself has not been demonstrated. There is a
      need for more demonstration of reliability and validity. Suggestions for future
      research are noted.

PMID- 10660017
TI  - Erroneous concerns about child sexual abuse.
AB  - AIM: To assess the incidence and nature of concerns about sexual abuse, with
      particular reference to erroneous concerns of sexual abuse made by children.
      METHODS: A review of case notes of all child sexual abuse reports to the Denver
      Department of Social Services over 12 months. Cases were put into four groups:
      substantiated, not sexual abuse, inconclusive and erroneous accounts by children.
      RESULTS: 551 cases were reviewed. Forty-three percent were substantiated, 21%
      were inconclusive and 34% were not considered to be abuse cases. There were 14
      (2.5%) erroneous concerns emanating from children. They comprised three cases of
      allegations made in collusion with a parent, three cases where an innocent event
      was misinterpreted as sexual abuse and eight cases (1.5%) of false allegations of
      sexual abuse. CONCLUSION: Erroneous concern of sexual abuse from children are
      uncommon. The four categories of concern in this study, in contrast to the simple
      classification of substantiated and unsubstantiated, provide a means of
      encouraging open minded assessments of the typical concerns which a child
      protection agency receives.

PMID- 10660018
TI  - A systems perspective on research and treatment with abused and neglected
      children.
AB  - OBJECTIVE: To discuss two systems-level changes in the organization and financing
      of mental health and child welfare services that will increasingly affect abused
      and neglected children: the implementation of managed care processes and the
      incorporation of accountability mechanisms in the management of mental health and
      child welfare services, particularly the use of systematic outcomes assessments.
      A central goal of the paper is to identify critical research questions which will
      help us to understand the impact of these changes on maltreated children. METHOD:
      These two systems-level changes are described, and ways they may affect
      maltreated children are addressed. RESULTS: Both managed care and the growing
      focus on managing services by monitoring outcomes may positively or negatively
      affect maltreated children. Both of these trends are affecting the mental health
      and child welfare systems. It is likely that they will affect maltreated
      children's access to and the quality, cost, and outcomes of mental health and
      child welfare services. CONCLUSIONS: Systematic research on the impact of these
      large-scale changes can increase the likelihood that these changes will benefit
      maltreated children. A number of critical areas are identified for future
      research.

PMID- 10660019
TI  - Percutaneous transpedicular biopsy of thoracic and lumbar vertebrae--method and
      diagnostic validity.
AB  - BACKGROUND: Percutaneous transpedicular needle biopsy was performed on thoracic
      and lumbar vertebral bodies with a thin trocar (2.0 mm outer diameter) under
      observation with a conventional X-ray image intensifier in order to establish a
      correct histopathological diagnosis. We also evaluated the clinical validity of
      this less invasive diagnostic method in terms of the accuracy of the pathological
      diagnosis. METHODS: Twenty-eight thoracic or lumbar vertebrae of 26 patients with
      abnormalities observed on routine X-ray, CT, or MRI images underwent percutaneous
      transpedicular needle biopsy under local anesthesia. A threaded trocar with an
      outer diameter of 2.0 mm was screwed into the intra-vertebral lesion through the
      pedicle from the posterior side under control of X-P imaging, and a small amount
      of tissue or fluid was collected. RESULTS: For all patients but two, where
      inadequate specimens were obtained, correct diagnoses were made, which were
      confirmed by pathological diagnoses of massive tissue obtained during subsequent
      reconstructive surgery. CONCLUSIONS: The accuracy rate of diagnosis with this
      biopsy method was 92% without significant intra- or postoperative complications.
      Therefore, it can be concluded that this less invasive biopsy method used in
      conjunction with conventional X-ray apparatus has good potential to result in
      correct preoperative diagnosis of thoracic and lumbar lesions so that more
      effective treatment can be determined.

PMID- 10660020
TI  - Surgical results for spinal meningiomas.
AB  - Among a series of 782 spinal tumors, 130 spinal meningiomas in 117 patients were
      operated in the Department of Neurosurgery at the Nordstadt Hospital in Hannover,
      Germany, between 1977 and 1998. Patients were followed postoperatively for up to
      13 years (mean 20 +/- 33 months). Comparing the period of 1977 through 1987,
      before magnetic resonance imaging (MRI) was available, to the period of 1988 to
      1998 revealed that the average history until diagnosis shortened by about 6
      months during the second decade of this study (24 +/- 33 to 18 +/- 29 months; not
      significant). Consequently, the preoperative Karnofsky Score increased
      significantly (59 +/- 15 and 66 +/- 16; p < 0.05). The rates of complete
      resection and the postoperative neurological outcome, however, remained
      unchanged. Even though the overall prognosis of neurological deficits is
      favorable after complete resection of a meningioma, a subset of 18 patients had
      either en plaque growing or recurrent tumors that were more likely to be removed
      incompletely and to cause postoperative neurological problems, with a
      significantly worse Karnofsky Score after 1 year (57 +/- 12 and 77 +/- 12,
      respectively; p < 0.01) and a significantly higher recurrence rate after 5 years
      (86.7% and 20.4%, respectively; log rank test p = 0.0014). In conclusion, a
      favorable postoperative neurological outcome requires complete resection of the
      spinal meningioma. The advent of MRI has shortened the time until diagnosis and
      made it possible to perform surgery before severe deficits have occurred, but did
      not have a major impact on postoperative results. En plaque and recurrent
      meningiomas remain surgical challenges, as infiltration of surrounding structures
      and associated arachnoid scarring may render complete resection difficult to
      achieve.

PMID- 10660021
TI  - Outcomes of medical treatment of neurocysticercosis: a study of 65 cases in Cheju
      Island, Korea.
AB  - BACKGROUND: Although cysticidal drugs hasten the death and disappearance of the
      parasite, the long-term prognosis of NCC is still not satisfactory. METHODS: In
      this study, 65 patients with active neurocysticercosis (NCC) treated with
      praziquantel or albendazole were retrospectively reviewed to evaluate
      radiological and clinical outcome. According to worm location, patients were
      divided into two groups: parenchymal (n = 42) and extraparenchymal NCC (n = 23).
      The average duration of follow-up was 23 months. RESULTS: In terms of cysticidal
      effectiveness (73% vs. 50%), seizure control (60% vs. 43%) and symptomatic
      improvement of non-seizure patients (64% vs. 44%), the outcome of treatment was
      better in the parenchymal NCC than in the extraparenchymal. Repeated cysticidal
      treatment was needed in 26% of parenchymal and 39% of extraparenchymal NCC. After
      treatment, 38% of parenchymal NCC complained of seizure and 35% suffered from
      headache. Likewise, 27% and 36% of extraparenchymal NCC complained of seizure and
      headache, respectively. During the follow-up, 7 of 30 patients without initial
      seizure developed new seizures after medical treatment. CONCLUSION: Despite the
      development of cysticidal drugs, a considerable number of patients suffer from
      late neurologic sequelae such as seizure and headache. Therefore continuous
      attention should be given to the patients after cysticidal treatment. Prevention
      by health education is emphasized.

PMID- 10660022
TI  - Medically treated intraspinal "Brucella" granuloma.
AB  - BACKGROUND: Although there have been reports of Brucella granuloma or abscess in
      the literature, they were all localized extradurally except one, and most
      patients underwent surgery. CASE REPORT: A 40-year-old female presented with
      urinary and fecal incontinence and a two-month history of progressive weakness of
      the right leg and numbness of the left leg. Four months previously, she had been
      diagnosed with systemic brucellosis with a period of radiculomeningoencephalitis;
      she was treated successfully with rifampicin, doxycycline,
      trimethoprim/sulfamethoxazole (TMP/SMZ), and streptomycin, and was discharged
      symptom-free on rifampicin and doxycycline. Neurological examination revealed
      spastic paraparesis, globally hyperactive deep tendon reflexes (DTRs) and sensory
      level at T6. Magnetic resonance imaging (MRI) of the spinal cord revealed a 10 x
      30 mm intradural-intramedullary mass lesion at the T5 level with surrounding
      edema that enhanced with contrast. The cerebrospinal fluid (CSF) was
      xanthochromic with lymphocytic pleocytosis and elevated levels of albumin,
      immunoglobulins, and antibody titers for Brucella. The medications were modified
      to rifampicin 1200 mg, doxycycline 400 mg, and TMP/SMZ 480/2400 mg daily, and
      methylprednisolone 100 mg in decremental doses (for 6 weeks). After 2 months, the
      patient was almost symptom-free and her medication doses were decreased. After 5
      months, the mass lesion resolved almost completely. The treatment was
      discontinued after 2 years. CONCLUSIONS: The case is presented because of its
      uniqueness. In cases of Brucella granuloma, the authors recommend a trial of
      medical treatment with adequate dosages for a reasonable length of time before
      considering surgical intervention.

PMID- 10660023
TI  - Vasospasm after cranial base tumor resection: pathogenesis, diagnosis, and
      therapy.
AB  - OBJECTIVE: Cerebral vasospasm is well known to occur after various cerebral
      neurosurgical events that cause subarachnoid hemorrhage. However, cerebral
      vasospasm can occur after cranial base tumor resection. We present a series of
      nine patients with angiographically evident vasospasm that was clinically
      symptomatic in eight of them. METHODS: A total of 470 consecutive patients with
      cranial base tumors were operated in our institution between April 1993 and
      December 1996. Nine had evidence of cerebral vasospasm postoperatively (1.9% of
      the total population), of whom eight were asymptomatic. There were seven males
      and two females with an age range of 33 to 65 years (average 48.5 years). There
      were seven meningiomas, one chordoma, and one trigeminal schwannoma. RESULTS:
      Vasospasm manifested clinically 1 to 30 days postoperatively in eight patients.
      Most patients were symptomatic within 7 days. In the ninth case, surgery was
      delayed when asymptomatic vasospasm was noted on an angiogram before second stage
      surgery. Symptoms included altered mental status in four patients, hemiparesis in
      three patients (one patient had both hemiparesis and altered mental status), and
      monoparesis in two patients. Factors that were found to correlate with a higher
      incidence of vasospasm were tumor size, total operative time, vessel encasement,
      vessel narrowing, and preoperative embolization. All eight patients with
      symptomatic vasospasm were treated with hypertensive, hypervolemic,
      hemodilutional (HHH) therapy. Five patients also underwent intraluminal
      angioplasty, in conjunction with papaverine in one case. One patient received
      intraarterial papaverine alone. Angiographic results were good in all patients.
      Significant clinical improvement was seen in six of the eight symptomatic cases.
      CONCLUSION: Delayed neurological deterioration in a patient who has undergone
      cranial base tumor surgery not explained by an intracranial mass lesion should be
      promptly investigated with angiography. If vasospasm is diagnosed, it should be
      treated aggressively with hypertensive, hypervolemic, hemodilutional therapy and
      early angioplasty.

PMID- 10660025
TI  - Postoperative MRI appearance after transsphenoidal pituitary tumor resection.
AB  - BACKGROUND: Knowledge of the magnetic resonance imaging (MRI) appearance of the
      pituitary fossa following transsphenoidal resection of a pituitary adenoma, in
      the early and late postoperative period, is important for detecting complications
      and for assessing extent of tumor excision. Few prospective studies have
      addressed this issue. METHODS: Fourteen patients with pituitary macroadenomas
      were prospectively studied with MRI. Maximal tumor resection was accomplished in
      each patient, and the postoperative histological diagnoses included non-secreting
      adenoma in 11 patients, prolactinoma in 2 and necrosis in one. Early
      postoperative scans were obtained within 14 days after surgery, and late studies
      between 3 and 4 months, in all patients. Four patients also had delayed scans
      between 8 months and a year. The maximum coronal dimension (MCTD) of the sellar
      and suprasellar contents was measured on T1-weighted contrast enhanced scans.
      RESULTS: All patients had normal or improved visual examinations and normal or
      improved hormonal function postoperatively. The preoperative MCTD ranged from 11
      mm to 59 mm in height (mean 30.3 mm). There was little change in MCTD on the
      early postoperative MRI scans (range 7-49 mm, mean 23.5 mm). However, in all
      patients the MCTD decreased in height by 4 months (range 2-35 mm, mean 12.7 mm).
      This change represented a 58% mean reduction in size compared to the preoperative
      measurements. CONCLUSIONS: We conclude that the appearance of the sellar contents
      on early postoperative MRI may appear remarkably similar to that seen before
      surgery, even after technically adequate resection. The postoperative mass may
      represent a combination of residual tumor, edema, postoperative hemorrhage and
      hemostatic material. Routine follow-up MRI after transsphenoidal resection of
      pituitary tumors may be delayed until at least 4 months after surgery in patients
      who are clinically stable.

PMID- 10660024
TI  - Direct intraoperative micromethod for hormone measurements of pituitary tissue in
      Cushing's disease.
AB  - BACKGROUND: During transsphenoidal surgery (TSS) for Cushing's disease, the
      surgeon depends on experience to find minute adenomas. Cytological slide
      preparations or frozen sections, even when successful, are not specific
      concerning the hormone activity. In an attempt to improve accurate localization
      of minute ACTH adenomas, we evaluated a new intraoperative method of ACTH
      measurements in adenoma and anterior lobe microsamples. As most ACTH adenomas are
      monohormonal, the possible benefit of a GH measurement was investigated. METHODS:
      We included pituitary tissue of 32 patients, 22 with Cushing's disease and 10
      endocrine inactive pituitary adenomas as control. All patients underwent TSS by
      one surgeon. Preoperative data, intraoperative and perioperative hormone
      measurements of homogenized, weighed pituitary tissue samples, and histological
      findings are presented. RESULTS: In ACTH adenomas, the median ACTH content was
      found to be 1,688 ng/mg, minimum 345 ng/mg. The median GH was measured at 36
      ng/mg. Anterior lobe tissue contained median 80 ng ACTH/mg, maximum 279 ng/mg.
      Median GH was 2,200 ng/mg. In hormonally inactive adenomas ACTH was less than 0.1
      ng/mg, median GH was 5.5 ng/mg. There was no overlap of ACTH content in the
      tissues investigated. Therefore, by adopting 300 ng ACTH/mg as a cutoff level, a
      clear discrimination is given. Additional GH measurements are not necessary.
      CONCLUSION: This new intraoperative method permits a clear differentiation
      between adenoma and pituitary tissue. In addition to intraoperative cytology and
      histology, this method can serve as a specific proof that the ACTH adenoma has
      been identified during surgery. This may be valuable in difficult cases with
      unclear intraoperative findings, especially after previously negative
      exploration.

PMID- 10660026
TI  - Amyloidoma in the gasserian ganglion: case report.
AB  - BACKGROUND: Amyloidoma in the central nervous system is extremely rare. We
      describe a rare case of amyloidoma in the gasserian ganglion manifesting as
      trigeminal neuropathy. METHODS: A 41-year-old woman was admitted to our hospital
      with progressive numbness and hypalgesia in the distribution of the second and
      third divisions of the left trigeminal nerve. There was no evidence of chronic
      inflammatory disorder or immunological abnormalities. Magnetic resonance images
      showed a mass in the left Meckel's cave that was brightly enhanced with
      gadolinium. RESULTS: A reddish, firm mass was successfully removed via a left
      temporal craniotomy. Histologically, the tumor was composed of larger acellular
      deposits of eosinophilic material. The acellular deposits were positive for
      potassium permanganate-resistant Congo red staining, showing apple-green
      birefringence under polarized light and expression of immunoglobulin lambda light
      chain-derived proteins (A lambda) immunohistochemically. CONCLUSION: The present
      case revealed an A lambda amyloidoma in the left gasserian ganglion. Although the
      incidence is rare, amyloidoma should be suspected in patients who complain of
      progressive trigeminal neuropathies and show an enhanced lesion in the gasserian
      ganglion on MR images.

PMID- 10660027
TI  - Posterior fossa chondroma arising from the tentorium: a case report.

PMID- 10660028
TI  - Dural waisting as a sign of subarachnoid extension of cavernous carotid
      aneurysms: a follow-up case report.
AB  - OBJECTIVE: Even when augmented by CT and MRI, it can be difficult on angiography
      to predict which intracavernous carotid artery aneurysms (ICCAA) have
      subarachnoid extension and therefore pose a higher risk of subarachnoid
      hemorrhage. Previously we reported a case of an ICCAA, which on angiogram had a
      focal tapering of the dome that we termed a "waist." At surgery this lesion was
      found to have subarachnoid extension. We postulated that this dural "waisting" on
      the arteriogram was a predictor of subarachnoid extension. Herein we report a
      second case of an ICCAA with the angiographic appearance of a waist that was also
      confirmed to have subarachnoid extension at surgery, thereby strengthening our
      original hypothesis. CLINICAL PRESENTATION: A 40-year-old woman presented with a
      3-month history of bitemporal headache, diplopia, and a left sixth nerve palsy.
      MRI showed a lesion in the vicinity of the left cavernous carotid sinus and an
      arteriogram confirmed the presence of a large cavernous carotid aneurysm. As in
      the previous case, the aneurysm fundus was indented, creating a waist on the
      aneurysm dome. INTERVENTION: After passing a trial balloon occlusion of the
      involved carotid artery, the patient was brought to the operating room for lesion
      trapping. The aneurysm fundus was seen to extend beyond the falciform ligament
      and with subsequent dissection, the neck of the aneurysm was seen to incorporate
      the carotid artery distal to the ophthalmic artery. The aneurysm was trapped by
      ligating the internal carotid artery in the neck and by placing a clip on the
      intracranial carotid proximal to the posterior communicating artery. CONCLUSION:
      The presence of subarachnoid extension of an ICCAA can be difficult to elucidate
      on an arteriogram. This is an additional case in which a focal narrowing or
      "waisting" of the aneurysm dome seen on an angiogram served as a marker of
      subarachnoid extension.

PMID- 10660030
TI  - A case of posterior cerebral artery aneurysm associated with idiopathic bilateral
      internal carotid artery occlusion: case report.
AB  - BACKGROUND: Aneurysms of the posterior circulation are challenging lesions to
      neurosurgeons, despite improvements in microsurgical techniques and advances in
      skull base approaches. We present a rare case of a posterior cerebral artery
      (PCA)-posterior communicating artery (PcomA) junction aneurysm associated with
      bilateral internal carotid artery (ICA) occlusion successfully treated with an
      endovascular procedure. CASE DESCRIPTION: A 57-year-old female presented with
      sudden onset of severe headache and loss of consciousness. CT scan showed diffuse
      subarachnoid hemorrhage and acute hydrocephalus. The patient developed severe
      neurogenic pulmonary edema and shock. Although her neurogenic pulmonary edema did
      not resolve, she recovered from shock. However, her general condition was so
      critical and her vital signs so unstable, that direct surgery under general
      anesthesia was considered too risky. A cerebral angiogram showed complete
      occlusion of both internal carotid arteries without any Moyamoya vessels. A
      saccular aneurysm located at the right PCA-PcomA junction was seen. To obliterate
      the aneurysm and prevent rerupture, the patient underwent coil embolization via
      an endovascular approach under sedation with local anesthesia. The balloon
      remodeling technique was useful to prevent occlusion of parent arteries. Finally,
      four interlocking detachable coils (IDC) with a total length of 44 cm were used
      to completely obliterate the aneurysm using the balloon remodeling technique. The
      patient made a full recovery after treatment and the aneurysm remained
      obliterated 2 years after coil embolization. CONCLUSIONS: We emphasize the
      advantages of the endovascular approach for the patient in critical condition. We
      believe that this is the first report of a PCA-Pcom junction aneurysm associated
      with bilateral ICA occlusion without moyamoya disease.

PMID- 10660029
TI  - Antegrade recanalization of completely embolized internal carotid artery after
      treatment of a giant intracavernous aneurysm: a case report.
AB  - BACKGROUND: Parent artery occlusion is one of the traditional methods of
      treatment for unclippable aneurysms. However, parent artery occlusion may not
      result in permanent exclusion of the aneurysm from the systemic circulation. We
      present a case of cerebral aneurysm treated by proximal embolization of the
      parent artery, which recanalized during the follow-up period. CASE DESCRIPTION: A
      69-year-old woman presented with a right blepharoptosis and diplopia. A large
      aneurysm arising from the cavernous portion of the right internal carotid artery
      was found and endovascularly excluded from the cerebral circulation by proximal
      internal carotid artery occlusion with balloons. Eleven days after treatment,
      occlusion of the parent artery and obliteration of the aneurysm were
      angiographically confirmed. However, the parent artery was found to be
      recanalized with nearly total obliteration of the aneurysm at the follow-up 6
      months after treatment. CONCLUSION: Angiography suggested that recanalization
      took place through the vaso vasorum. We believe that recanalization was induced
      by marginal cerebral blood flow in the ipsilateral hemisphere.

PMID- 10660031
TI  - Cerebral aneurysm rupture after r-TPA thrombolysis for acute myocardial
      infarction.
AB  - BACKGROUND: Intracranial hemorrhage is the most dreaded risk of thrombolytic
      therapy for acute myocardial infarction because of the high mortality and
      disability rates associated with this complication. Brain structural lesions may
      predispose a patient to bleeding. To date, aneurysm rupture has not been
      described as a complication of such therapy. CASE DESCRIPTION: A 66-year-old
      hypertensive woman was admitted because of chest pain. Myocardial infarction was
      diagnosed and fibrinolytic therapy with recombinant tissue plasminogen activator
      (r-TPA) was initiated. Eight hours after admission she became unconscious. Brain
      computed tomography scan showed subarachnoid hemorrhage, and a cerebral
      arteriography showed an anterior communicating artery aneurysm. Because of her
      poor clinical condition treatment was postponed. Death occurred 7 days later
      because of multiorgan failure. CONCLUSIONS: Cerebral aneurysms should be
      considered as a possible contributing factor to intracranial bleeding after
      thrombolytic therapy.

PMID- 10660032
TI  - Spontaneous resolution of bilateral traumatic carotid cavernous fistulas and
      development of trans-sellar intercarotid vascular communication: case report.
AB  - BACKGROUND: Bilateral carotid cavernous fistulas may complicate head injury.
      Spontaneous resolution of post-traumatic direct carotid cavernous fistula is
      rare. CASE DESCRIPTION We present a case of a 42-year-old female who developed
      post-traumatic high flow bilateral carotid cavernous fistulas with cortical and
      deep venous drainage, who had a spontaneous resolution with thrombosis of the
      cavernous sinus outlets bilaterally and development of a trans-sellar
      intercarotid vascular communication. To our knowledge this is the first reported
      case in the literature describing such a phenomenon. CONCLUSION Bilateral direct
      carotid cavernous fistulas may undergo spontaneous resolution and form a benign
      trans-sellar intercarotid vascular communication.

PMID- 10660033
TI  - Elevated cerebral perfusion pressure and low colloid osmotic pressure as a risk
      factor for subdural space-occupying hygromas?
AB  - BACKGROUND: Space-occupying subdural hygromas are a late complication of severe
      traumatic brain injury (TBI) and may delay the patient's recovery. To evaluate
      the risk factors involved, we performed a semiretrospective, -prospective
      analysis of three groups of patients, which differed with regard to the
      techniques used in the management of their cerebral perfusion pressure (CPP) and
      colloid osmotic pressure (COP) to determine the occurrence of space-occupying
      subdural hygromas. PATIENTS AND METHODS: Between 1989 and 1997 we examined 696
      patients after a severe TBI: Group 1. 1989-1994 mean CPP: 67 (elevated for
      therapeutic reasons by catecholamines, if necessary), mean COP: 19. Group 2.
      January 1995-October 1996, mean CPP: 77, mean COP: 20. Group 3. November 1996
      December 1997, mean CPP: 79, mean COP: 23 (elevated for therapeutic reasons by
      infusions of colloids). The groups were comparable for other criteria. RESULTS:
      Compared to Group 1, Group 2, with a high CPP but lower COP, showed a
      significantly higher (p < 0.01; chi2-test with correction of Yates) percentage of
      posttraumatic subdural hygromas with space-occupying aspects, clinical signs of
      bradycardia, hypertension and impaired consciousness requiring surgery (Group 1:
      1.75%; Group 2: 10.46%; Group 3: 0%). In Group 3 we saw no patient with a space
      occupying hygroma. CONCLUSION: We conclude that iatrogenic elevated CPP, which
      has been reported to be helpful in preventing secondary ischemic damage after a
      severe TBI, may be harmful to a patient if the COP is not maintained within
      physiological ranges.

PMID- 10660034
TI  - An unusual cause of depressed skull fracture: case report.
AB  - BACKGROUND: Camel collision accidents are a common occurrence in Saudi Arabia,
      with a high rate of mortality and morbidity. Isolated injuries are rare because
      of the nature of impact sustained by the person. CASE DESCRIPTION: A 4-year-old
      child with an isolated depressed skull fracture resulting from a camel collision
      is described. The other occupants of the car were crushed to death. The child
      sustained only an impact to his head, causing a compound depressed skull fracture
      with localized cortical damage. CONCLUSIONS: Camel collision accidents are a
      common cause of mortality and morbidity in Saudi Arabia. Isolated skull injuries
      are rare and result from a localized impact. This is the first report of a
      compound depressed skull fracture from such an incident. The extent of the
      problem and efforts toward prevention are described.

PMID- 10660035
TI  - Survey on neurosurgery subspecialty fellowship training. Congress of Neurological
      Surgeons Education Committee.
AB  - BACKGROUND: The ongoing controversy on the certification of neurosurgery
      subspecialties has not been settled. There has been no detailed report on why a
      resident chooses to undergo further training in the form of a postgraduate
      fellowship. A survey was devised to investigate the reasons, as well as factors,
      that prompt the resident to pursue fellowship training. METHODS: The names of the
      surveyed residents were obtained from the Congress of Neurological Surgeons
      database, and the names of the neurosurgery fellows were obtained from individual
      program coordinators by phone. A survey, a cover letter, and a return envelope
      were mailed to each prospective respondent. The data were entered on the Paradox
      for Windows program, and multiple queries were run to obtain tabulated results.
      RESULTS: The overwhelming majority (84.6%) of the resident respondents considered
      fellowship a possibility. Academic medicine was also the choice of career for
      most (60.3%). The most popular reported fellowships were spine (25.6%), pediatric
      (16.5%), and vascular (16.1%). The three top reasons for pursuing fellowship
      training were "personal interest for knowledge," "job market demand," and
      "academic prestige." "Inadequate training during residency" was a distant fourth.
      For respondents citing "inadequate training during residency" as one of the top
      three reasons, there were proportionally higher respondents in the fields of
      peripheral nerve, endovascular, and skull base neurosurgeries. CONCLUSION: A
      significant number of residents consider fellowship a way to further their
      personal interest and knowledge, as well as increase their marketability.
      Relatively few from the surveyed group considered their residency training
      experience deficient in the subspecialty areas, with the exception of peripheral
      nerve, endovascular, and possibly skull base neurosurgery.

PMID- 10660036
TI  - What are those soldiers doing? They're holding the horses!

PMID- 10660037
TI  - Craniopagus twins.

PMID- 10660038
TI  - Neuronavigation in pituitary surgery.

PMID- 10660039
TI  - PICA aneurysms and posterior fossa AVMs.

PMID- 10660040
TI  - More surprises in the Hedgehog signaling pathway.

PMID- 10660041
TI  - Regulation of Smad activity.

PMID- 10660042
TI  - GroEL-substrate interactions: molding the fold, or folding the mold?

PMID- 10660043
TI  - Leptin inhibits bone formation through a hypothalamic relay: a central control of
      bone mass.
AB  - Gonadal failure induces bone loss while obesity prevents it. This raises the
      possibility that bone mass, body weight, and gonadal function are regulated by
      common pathways. To test this hypothesis, we studied leptin-deficient and leptin
      receptor-deficient mice that are obese and hypogonadic. Both mutant mice have an
      increased bone formation leading to high bone mass despite hypogonadism and
      hypercortisolism. This phenotype is dominant, independent of the presence of fat,
      and specific for the absence of leptin signaling. There is no leptin signaling in
      osteoblasts but intracerebroventricular infusion of leptin causes bone loss in
      leptin-deficient and wild-type mice. This study identifies leptin as a potent
      inhibitor of bone formation acting through the central nervous system and
      therefore describes the central nature of bone mass control and its disorders.

PMID- 10660044
TI  - Directed actin polymerization is the driving force for epithelial cell-cell
      adhesion.
AB  - We have found that epithelial cells engage in a process of cadherin-mediated
      intercellular adhesion that utilizes calcium and actin polymerization in
      unexpected ways. Calcium stimulates filopodia, which penetrate and embed into
      neighboring cells. E-cadherin complexes cluster at filopodia tips, generating a
      two-rowed zipper of embedded puncta. Opposing cell surfaces are clamped by
      desmosomes, while vinculin, zyxin, VASP, and Mena are recruited to adhesion
      zippers by a mechanism that requires alpha-catenin. Actin reorganizes and
      polymerizes to merge puncta into a single row and seal cell borders. In
      keratinocytes either null for alpha-catenin or blocked in VASP/Mena function,
      filopodia embed, but actin reorganization/polymerization is prevented, and
      membranes cannot seal. Taken together, a dynamic mechanism for intercellular
      adhesion is unveiled involving calcium-activated filopodia penetration and
      VASP/Mena-dependent actin reorganization/polymerization.

PMID- 10660045
TI  - Phosphatidylinositol 4,5-bisphosphate functions as a second messenger that
      regulates cytoskeleton-plasma membrane adhesion.
AB  - Binding interactions between the plasma membrane and the cytoskeleton define cell
      functions such as cell shape, formation of cell processes, cell movement, and
      endocytosis. Here we use optical tweezers tether force measurements and show that
      plasma membrane phosphatidylinositol 4,5-bisphosphate (PIP2) acts as a second
      messenger that regulates the adhesion energy between the cytoskeleton and the
      plasma membrane. Receptor stimuli that hydrolyze PIP2 lowered adhesion energy, a
      process that could be mimicked by expressing PH domains that sequester PIP2 or by
      targeting a 5'-PIP2-phosphatase to the plasma membrane to selectively lower
      plasma membrane PIP2 concentration. Our study suggests that plasma membrane PIP2
      controls dynamic membrane functions and cell shape by locally increasing and
      decreasing the adhesion between the actin-based cortical cytoskeleton and the
      plasma membrane.

PMID- 10660046
TI  - OAZ uses distinct DNA- and protein-binding zinc fingers in separate BMP-Smad and
      Olf signaling pathways.
AB  - We have identified the 30-zinc finger protein OAZ as a DNA-binding factor that
      associates with Smads in response to BMP2, forming a complex that
      transcriptionally activates the homeobox regulator of Xenopus mesoderm and neural
      development, Xvent-2. OAZ contains a BMP signaling module formed by two clusters
      of fingers that bind Smads and the Xvent-2 BMP response element, respectively.
      Previously implicated as a transcriptional partner of Olf-1/EBF in olfactory
      epithelium and lymphocyte development in the rat, OAZ fulfills this role through
      clusters of fingers that are separate from the BMP signaling module. The mutually
      exclusive use of OAZ by the BMP-Smad and Olf pathways illustrates the dual role
      of a multi-zinc finger protein in signal transduction during development.

PMID- 10660047
TI  - 15 A resolution model of the monomeric kinesin motor, KIF1A.
AB  - A two-headed structure has been widely believed to be essential for the kinesin
      molecular motor to move processively on the track, microtubules. However, we have
      recently demonstrated that a monomeric motor domain construct of KIF1A (C351), a
      kinesin superfamily protein, moves processively, taking about 700 steps before
      being detached from microtubules. To elucidate the mechanism of its single-headed
      processivity, we examined the C351 -MT interaction by mutant analysis and high
      resolution cryo-EM. Mutant analysis indicated the importance of a highly
      positively charged loop, the "K loop," for such processivity. A 15 A resolution
      structure unambiguously docked with the available atomic models revealed "K loop"
      as an extra microtubule-binding domain specific to KIF1A, and bound to the C
      terminus of tubulin. The site-specific cross-linking further confirmed this
      model.

PMID- 10660048
TI  - Maturation dynamics of a viral capsid: visualization of transitional intermediate
      states.
AB  - Typical of DNA bacteriophages and herpesviruses, HK97 assembles in two stages:
      polymerization and maturation. First, capsid protein polymerizes into closed
      shells; then, these precursors mature into larger, stabler particles. Maturation
      is initiated by proteolysis, producing a metastable particle primed for expansion
      the major structural transition. We induced expansion in vitro by acidic pH and
      monitored the resulting changes by time-resolved X-ray diffraction and cryo
      electron microscopy. The transition, which is not synchronized over the
      population, proceeds in a series of stochastically triggered subtransitions.
      Three distinct intermediates were identified, which are comparable to
      transitional states in protein folding. The intermediates' structures reveal the
      molecular events occurring during expansion. Integrated into a movie (see Dynamic
      Visualization below), they show capsid maturation as a dynamic process.

PMID- 10660049
TI  - E. coli hemolysin E (HlyE, ClyA, SheA): X-ray crystal structure of the toxin and
      observation of membrane pores by electron microscopy.
AB  - Hemolysin E (HlyE) is a novel pore-forming toxin of Escherichia coli, Salmonella
      typhi, and Shigella flexneri. Here we report the X-ray crystal structure of the
      water-soluble form of E. coli HlyE at 2.0 A resolution and the visualization of
      the lipid-associated form of the toxin in projection at low resolution by
      electron microscopy. The crystal structure reveals HlyE to be the first member of
      a new family of toxin structures, consisting of an elaborated helical bundle some
      100 A long. The electron micrographs show how HlyE oligomerizes in the presence
      of lipid to form transmembrane pores. Taken together, the data from these two
      structural techniques allow us to propose a simple model for the structure of the
      pore and for membrane interaction.

PMID- 10660050
TI  - Molecular basis of a yeast prion species barrier.
AB  - The yeast [PSI+] factor is inherited by a prion mechanism involving self
      propagating Sup35p aggregates. We find that Sup35p prion function is conserved
      among distantly related yeasts. As with mammalian prions, a species barrier
      inhibits prion induction between Sup35p from different yeast species. This
      barrier is faithfully reproduced in vitro where, remarkably, ongoing
      polymerization of one Sup35p species does not affect conversion of another.
      Chimeric analysis identifies a short domain sufficient to allow foreign Sup35p to
      cross this barrier. These observations argue that the species barrier results
      from specificity in the growing aggregate, mediated by a well-defined epitope on
      the amyloid surface and, together with our identification of a novel yeast prion
      domain, show that multiple prion-based heritable states can propagate
      independently within one cell.

PMID- 10660051
TI  - Transient transformation of the rust fungus Puccinia graminis f. sp. tritici.
AB  - The biotrophic rust fungus Puccinia graminis f. sp. tritici (Pgt) was transformed
      by particle bombardment. The promoter from the Pgt translation elongation factor
      1alpha (EF-1alpha) gene was fused to the bacterial marker genes hygromycin B
      phosphotransferase (hpt) and beta-glucuronidase (GUS). Transformation constructs
      were introduced into uredospores of Pgt, an obligate pathogen of wheat, by
      biolistic bombardment. Uredospores transformed with the construct containing the
      hpt gene germinated and initiated branching on selective medium, indicating that
      they had acquired resistance to hygromycin B. However, transformants stopped
      growing 5 days after bombardment. GUS activity in uredospores and germlings was
      histochemically detected 4-16 h after bombardment. GUS expression was also
      obtained using the INF24 promoter from the bean rust fungus Uromyces
      appendiculatus, demonstrating that heterologous genes can be expressed in P.
      graminis under the control of regulatory sequences from closely related
      organisms.

PMID- 10660052
TI  - Controlled expression of tagged proteins in Drosophila using a new modular P
      element vector system.
AB  - We have developed a new modular vector system that facilitates the combination of
      various DNA fragments as functional modules for P element-mediated transformation
      of Drosophila melanogaster. The basic vector pP?GS? contains unique sites for 17
      restriction enzymes, including three 8-bp cutters, that allow one to combine
      various promoter elements, cDNAs and genomic DNA fragments, as well as protein
      tags and selectable marker genes, for a wide spectrum of transgene analyses. With
      this new vector system we analysed the chromosomal distribution of the Drosophila
      SU(VAR)3-9 protein tagged with EGFP, using hsp70-cDNA and genomic Su(var)3-9
      constructs. We found preferential association of the tagged SU(VAR)3-9 with
      centric heterochromatin.

PMID- 10660053
TI  - The alm1+ gene from Schizosaccharomyces pombe encodes a coiled-coil protein that
      associates with the medial region during mitosis.
AB  - We have isolated a cDNA that encodes a 142 kDa protein by immunoscreening of a
      Schizosaccharomyces pombe expression library with a new antibody, mAb8, that
      reveals spindle poles and equatorial ring-like structures in several organisms.
      This cDNA encodes a putative protein which we termed Alm (for abnormal long
      morphology). The protein is predicted to be a coiled-coil protein, containing a
      central alpha-helical domain flanked by non-helical terminal domains.
      Immunofluorescence analysis showed that Alm1 is localized in the medial region of
      the cell from anaphase to the end of cytokinesis. Cells carrying an alm1::ura4+
      disruption are viable and exhibit an elongated morphology. Homozygous alm1::ura4+
      diploids sporulated normally but the spores did not germinate. Spores that have
      inherited the disruption allele from a heterozygous alm1+/ alm1::ura4+ diploid
      germinated but generated smaller colonies. We propose that Alm1 participates in
      the structural organization of the medial region in S. pombe.

PMID- 10660054
TI  - Mer22-related sequence elements form pericentric repetitive DNA families in
      primates.
AB  - We describe a novel repetitive DNA element isolated from three primate species
      belonging to the family Cercopithecidae. The unusually long 2.6-kb repeat unit of
      this DNA element is present in high copy number in the pericentromeric region of
      one pair of chromosomes in both baboon and macaque, forming chromosome-specific
      satellite-like DNA families. Besides these two very closely related species, the
      novel DNA element was also detected in the more distantly related African green
      monkey. However, the copy number of the repeat unit in this species is
      significantly lower than in macaque and baboon. Sequence analysis revealed that
      the repeat units of the new repetitive element show similarity to the human MER22
      repeat and the Y chromosome-specific TTY2 element, which also exhibits
      retroelement-like features. Database searches indicate that tandemly arranged
      MER22-related DNA sequences can also be found in human, raising the possibility
      that these DNA elements may correspond to a novel primate-specific repetitive DNA
      group. Recent studies indicate that chromosome-specific pericentric repetitive
      elements, besides their potential involvement in centromere function, also
      facilitate homolog recognition during meiosis. In addition, rapid expansion of
      retroelements in the pericentric regions of chromosomes during interspecific
      hybridization has been described. In light of these data, we hypothesize that the
      novel repetitive element described here might have been involved in the
      speciation of the family Cercopithecidae.

PMID- 10660055
TI  - Extragenic suppressors that rescue defects in the heat stress response of the
      budding yeast mutant tom1.
AB  - The TOM1 gene codes for a so-called HECT protein, a putative ubiquitin ligase, in
      Saccharomyces cerevisiae. Deletion of the entire gene (tom1-10) or the sequence
      encoding the HECT domain (tom1-2) causes temperature sensitivity for growth. Here
      we report the isolation of extragenic, recessive suppressors of tom1-2, which
      were designated tmr (for tom1 revertant) mutations. These were classified into
      eight complementation groups and six of the genes were identified: tmr1/cyr1,
      tmnr2/sch9, tmr3/zuo1, tmr4, tmr5/mot1, tmr6/sse1, tmr7 and tmr8/kre6. These
      results suggested that the tom1 phenotype can be rescued by down-regulating the
      cAMP/PKA pathway. It was found that the temperature sensitivity of the tom1-2
      mutant is indeed suppressed by multiple copies of PDE2 or BCY1, which encode
      negative regulators of the cAMP/PKA pathway. The MSN2 gene, which encodes a zinc
      finger transcription factor involved in the general stress response is also a
      multicopy suppressor of tom1. It was found that induction levels of both STRE
      mediated (general stress response) and HSE-mediated gene expression (heat shock
      response) upon shift to high temperature are reduced by more than half in the
      tom1 mutant. Most of the isolated tmr mutations rescued one of the defects seen
      in both types of heat stress response in the tom1 mutant.

PMID- 10660056
TI  - Involvement of a natural transport system in the process of efflux-mediated drug
      resistance in Mycobacterium smegmatis.
AB  - The phosphate-specific transporter (Pst) in bacteria is a multi-subunit system
      which belongs to the ABC family of transporters. The gene forms part of an operon
      and it is involved in phosphate uptake in prokaryotes. Its import function is
      known to be operative only under conditions of phosphate starvation. However, we
      found overexpression of this transporter in a Mycobacterium smegmatis strain
      selected for ciprofloxacin resistance (CIPr) which was grown under conditions in
      which the phosphate-scavenging function of this operon was inoperative. In CIPr
      cells, active efflux of the drug plays a predominant role in conferring high
      levels of fluoroquinolone resistance. We therefore investigated the role of this
      transporter in the process of efflux-mediated drug resistance by inactivating the
      pst operon in the CIPr strain. Phenotypic characterization of the resulting
      strain, CIPrd, showed a striking reduction in the minimal inhibitory
      concentration (MIC) of ciprofloxacin and in the drug extrusion profile as well.
      Genotype analysis, on the other hand, revealed partial disruption of the pst
      operon in CIPrd as a consequence of transporter gene amplification. Furthermore,
      disruption of this operon in wild-type cells resulted in hypersensitivity to
      ciprofloxacin and other xenobiotics to which CIPr cells exhibited cross
      resistance. Thus our results provide strong evidence that Pst is a natural
      membrane transport system that has the ability to promote drug efflux in addition
      to its phosphate-scavenging function in the CIPr strain.

PMID- 10660057
TI  - Cloning of the gene encoding 3-hydroxy-3-methylglutaryl coenzyme A reductase from
      terpenoid antibiotic-producing Streptomyces strains.
AB  - We have isolated a mutant lacking 3-hydroxy-3-methylglutaryl CoA (HMG-CoA)
      reductase activity from a terpenoid antibiotic (terpentecin) producer,
      Streptomyces griseolosporeus MF730-N6, which uses both the mevalonate and
      nonmevalonate pathways for the formation of isopentenyl diphosphate, by screening
      terpentecin non-producing mutants. Terpentecin is known to be synthesized via the
      mevalonate pathway. The gene encoding HMG-CoA reductase (hmgg) was cloned and
      identified by complementation of the mutant, using a self-cloning system
      developed in this study for strain MF730-N6. The corresponding hmgs gene for HMG
      CoA reductase was also cloned from Streptomyces sp. KO-3988, which produces the
      terpenoid antibiotic furaquinocin. Sequence analysis of hmgg and hmgs showed that
      both genes encode polypeptides of 353 amino acids which are 84% identical to each
      other. A search of protein sequence databases revealed that both gene products
      were also similar to HMG-CoA reductases from a variety of other organisms,
      including Streptomyces sp. CL190 (hmgg is 89% and hmgs 85% identical to its CL190
      homolog), sea urchin (40.3 and 40.5%), German cockroach (37.6 and 38.4%), and
      Camptotheca acuminata (39.7 and 40.8%).

PMID- 10660058
TI  - Genetic organisation of the M protein region in human isolates of group C and G
      streptococci: two types of multigene regulator-like (mgrC) regions.
AB  - In addition to beta-haemolytic streptococci belonging to Lancefield group A
      (Streptococcus pyogenes, GAS), human isolates of group C (GCS) and group G (GGS)
      streptococci (S. dysgalactiae subsp. equisimilis) have been implicated as
      causative agents in outbreaks of purulent pharyngitis, of wound infections and
      recently also of streptococcal toxic shock-like syndrome. Very little is known
      about the organisation of the genomic region in which the emm gene of GCS and GGS
      is located. We have investigated the genome sequences flanking the emm gene in
      GCS by sequencing neighbouring fragments obtained by inverse PCR. Our sequence
      data for GCS strains 25287 and H46A revealed two types of arrangement in the emm
      region, which differ significantly from the known types of mga regulon in GAS. We
      named this segment of the genome mgrC (for multigene regulon-like segment in
      group C streptococci). In strains belonging to the first mgrC type (prototype
      strain 25287) the emm gene is flanked up-stream by mgc, a gene that is 61%
      identical to the mga gene of GAS. A phylogenetic analysis of the deduced protein
      sequences showed that Mgc is related to Mga proteins of various types of GAS but
      forms a distinct cluster. Downstream of emm, the mgrC sequence region is bordered
      by rel. This gene encodes a protein that functions in the synthesis and
      degradation of guanosine 3',5' bipyrophosphate (ppGpp) during the stringent
      regulatory response to amino acid deprivation. In the second mgrC type (prototype
      strain H46A), the genes mgc and emm are arranged as in type 1. But an additional
      ORF (orf) is inserted in opposite orientation between emm and rel. This orf shows
      sequence homology to cpdB, which is present in various microorganisms and encodes
      2',3' cyclo-nucleotide 2'-phosphodiesterase. PCR analysis showed that these two
      mgrC arrangements also exist in GGS. Our sequence and PCR data further showed
      that both types of mgrC region in GCS and GGS are linked via rel to the
      streptokinase region characterised recently in strain H46A. A gene encoding C5a
      peptidase, which is present at the 3' end of the mga regulon in GAS, was not
      found in the mgrC region identified in the GCS and GGS strains investigated here.

PMID- 10660059
TI  - Identification by RNA fingerprinting of genes differentially expressed during the
      development of the basidiomycete Lentinula edodes.
AB  - As part of an ongoing project to understand the molecular mechanisms of fruit
      body development in Lentinula edodes (Shiitake mushroom), RNA fingerprinting by
      arbitrarily primed PCR (RAP-PCR) was used to identify differentially expressed
      genes in RNA populations from four stages of L. edodes development vegetative
      mycelium, primordium, young fruit body and mature fruit body. From 30 RNA
      fingerprints, we cloned and sequenced 33 RAP fragments after their differential
      expression patterns had been verified by reverse Northern dot-blot hybridization.
      Thirteen RAP fragments show high sequence similarity to known gene products which
      are involved in (1) transport across the plasma membrane (drug efflux pump and
      sugar transporter); (2) cell cycle control (cyclin B); (3) signal transduction
      and transcriptional regulation (mitogen-activated protein kinase, Cdc39/Not1,
      PriA, Jun-D); (4) intracellular molecule trafficking (ubiquitin, plasma membrane
      proton ATPase, and alpha-adaptin); (5) mitochondrial biogenesis (mitochondrial
      processing peptidase beta-subunit, mitochondrial glycerol-3-phosphate
      dehydrogenase); and (6) intermediary metabolism (fructose 1,6 bisphosphatase).
      The transcript levels for plasma membrane proton ATPase and alpha-adaptin
      remained constant, whereas the other eleven genes were differentially expressed
      during L. edodes. development. The expression profiles of the genes suggest that
      transport across the plasma membrane is important in the mycelial stage. Specific
      signal transduction and transcriptional controls may play important roles during
      the initiation of primordia and the formation of young fruiting bodies. When the
      mushroom matures, expression of genes involved in metabolic pathways becomes
      prominent. The isolation of these genes indicates their involvement in
      homobasidiomycete development and suggests new directions for molecular studies
      on mechanisms of mushroom development.

PMID- 10660060
TI  - Characterization of two glycosyltransferases involved in early glycosylation
      steps during biosynthesis of the antitumor polyketide mithramycin by Streptomyces
      argillaceus.
AB  - A 2,580-bp region of the chromosome of Streptomyces argillaceus, the producer of
      the antitumor polyketide mithramycin, was sequenced. Analysis of the nucleotide
      sequence revealed the presence of two genes (mtmGIII and mtmGIV) encoding
      proteins that showed a high degree of similarity to glycosyltransferases involved
      in the biosynthesis of various antibiotics and antitumor drugs. Independent
      insertional inactivation of both genes produced mutants that did not synthesize
      mithramycin but accumulated several mithramycin intermediates. Both mutants
      accumulated premithramycinone, a non-glycosylated intermediate in mithramycin
      biosynthesis. The mutant affected in the mtmGIII gene also accumulated
      premithramycin A1, which contains premithramycinone as the aglycon unit and a D
      olivose attached at C-12a-O. These experiments demonstrate that the
      glycosyltransferases MtmGIV and MtmGIII catalyze the first two glycosylation
      steps in mithramycin biosynthesis. A model is proposed for the glycosylation
      steps in mithramycin biosynthesis.

PMID- 10660061
TI  - Developmental and metabolic regulation of the phosphoglucomutase-encoding gene,
      pgmB, of Aspergillus nidulans.
AB  - We have isolated the pgmB gene from Aspergillus nidulans, which encodes a
      phosphoglucomutase, one of the key enzymes in carbohydrate metabolism. The pgmB
      gene is located on chromosome VII and its ORF encodes 557 amino acids. Mutant
      phenotypes were analysed by expression of high levels of pgmB antisense RNA,
      which lead to a loss of detectable levels of sense RNA. Under conditions of
      antisense RNA expression, a 30% reduction in the growth rate was observed in
      comparison to wild-type. On the enzyme level, expression of pgmB antisense RNA
      resulted in a 35% reduction in total phosphoglucomutase activity. Two pgmB mRNAs
      were observed under all conditions tested and differ with respect to the location
      of the poly(A) site. Expression of pgmB driven by the GAL1 promoter in
      Saccharomyces cerevisiae complemented the growth phenotype of a pgm2delta mutant
      strain and suppressed the sensitivity of a gcn4delta mutant strain to amino acid
      starvation in the presence of galactose. Cultivation of A. nidulans in the
      presence of glucose or galactose as carbon source did not affect transcription of
      pgmB. However, amino acid starvation conditions resulted in a six-fold reduction
      in the level of pgmB mRNA, while genes for amino acid biosynthesis showed
      increased transcription. Transcription of pgmB was low during hyphal growth and
      in the sexual phase of development, but was significantly increased during the
      asexual stage of the A. nidulans life cycle.

PMID- 10660062
TI  - A novel gene is transcribed in the chicken alpha-globin gene domain in the
      direction opposite to the globin genes.
AB  - A novel gene transcribed in the direction opposite to that of the globin genes
      was found in the chicken alpha-globin gene domain. Northern hybridisation with
      single-stranded riboprobes revealed that a 4.5-kb poly(A)+ RNA is transcribed in
      antisense polarity with respect to the globin genes. The transcription unit
      encoding this RNA seems to overlap the entire cluster of alpha-globin genes and
      extends at least 15 kb upstream from pi, the first of the alpha-globin genes.
      This new transcript shows partial sequence homology with that encoded by the
      human "-14" gene. An oligonucleotide based on part of a restriction fragment of
      chicken DNA that is 80% homologous to exon 4 of the human "-14" gene hybridises
      with a 4.5-kb RNA molecule. In situ hybridisation of globin-antisense probes,
      that detect polyribosomal mRNAs of 1.7 and 2.5 kb on Northern blots, shows these
      "antisense" transcripts to be present in the cytoplasm. The 4.5-kb RNA is absent
      in polyribosomal poly(A)+ RNA and may, hence, represent a nuclear pre-mRNA
      transcribed from the chicken gene that is homologous to the human "-14" gene. The
      expression of this gene is not specific to erythroid cells; analogous transcripts
      were also detected in poly(A)+ RNA extracted from a chicken lymphoblastoma cell
      line (HP50). Taken together, these data allow us to postulate the existence in
      the chicken genome of a novel gene, for which we suggest the name "ggPRX" in
      analogy to the murine mProx1, a gene identified in the upstream region of the
      alpha-globin gene domain in mice.

PMID- 10660063
TI  - An osmotic-remedial, temperature-sensitive mutation in the allosteric activity
      site of ribonucleotide reductase in Neurospora crassa.
AB  - An osmotic-remedial, temperature-sensitive conditional mutant (un-24) was
      generated by Repeat Induced Point mutation (RIP) from a cross between a wild-type
      N. crassa strain and a strain carrying a approximately 250-kb duplication of the
      left arm of linkage group II (LGII). The mutation was mapped to the duplicated
      segment, within 2.6 map units of the heterokaryon incompatibility locus het-6.
      DNA transformation identified a 3.75-kb fragment that complemented the
      temperature-sensitive phenotype. A large ORF within this fragment was found to
      have a high degree of sequence identity to the large subunit of ribonucleotide
      reductase (RNR) from diverse organisms. Conserved amino acids at the active site
      and the allosteric activity sites are also evident. An unusual feature of the
      Neurospora sequence is a large insertion near the C-terminus relative to
      otherwise homologous sequences from other organisms. Three transition mutations,
      indicative of RIP, were identified in the N-terminal region of the temperature
      sensitive mutant allele. One of these mutations results in a non-conservative
      amino acid substitution within the four-helix bundle that is important in the
      allosteric control of ribonucleotide reductase activity. This substitution
      appears to disrupt proper folding of the allosteric activity site during
      synthesis of the protein.

PMID- 10660065
TI  - Molecular analysis of the NAC gene family in rice.
AB  - Genes that encode products containing a NAC domain, such as NO APICAL MERISTEM
      (NAM) in petunia, CUP-SHAPED COTYLEDON2 (CUC2) and NAP in Arabidopsis thaliana,
      have crucial functions in plant development. We describe here molecular aspects
      of the OsNAC genes that encode proteins with NAC domains in rice (Oryza sativa
      L.). Sequence analysis revealed that the NAC genes in plants can be divided into
      several subfamilies, such as the NAM, ATAF, and OsNAC3 subfamilies. In rice,
      OsNAC1 and OsNAC2 are classified in the NAM subfamily, which includes NAM and
      CUC2, while OsNAC5 and OsNAC6 fall into the ATAF subfamily. In addition to the
      members of these subfamilies, the rice genome contains the NAC genes OsNAC3,
      OsNAC4 (both in the OsNAC3 subfamily), OsNAC7, and OsNAC8. These results and
      Southern analysis indicate that the OsNAC genes constitute a large gene family in
      the rice genome. Each OsNAC gene is expressed in a specific pattern in different
      organs, suggesting that this family has diverse and important roles in rice
      development.

PMID- 10660064
TI  - In vivo analysis of mutated initiation codons in the mitochondrial COX2 gene of
      Saccharomyces cerevisiae fused to the reporter gene ARG8m reveals lack of
      downstream reinitiation.
AB  - To examine normal and aberrant translation initiation in Saccharomyces cerevisiae
      mitochondria, we fused the synthetic mitochondrial reporter gene ARG8m to codon
      91 of the COX2 coding sequence and inserted the chimeric gene into mitochondrial
      DNA (mtDNA). Translation of the cox2(1-91)::ARG8m mRNA yielded a fusion protein
      precursor that was processed to yield wild-type Arg8p. Thus mitochondrial
      translation could be monitored by the ability of mutant chimeric genes to
      complement a nuclear arg8 mutation. As expected, translation of the cox2(1
      91)::ARG8m mRNA was dependent on the COX2 mRNA-specific activator PET111. We
      tested the ability of six triplets to function as initiation codons in both the
      cox2(1-91)::ARG8m reporter mRNA and the otherwise wild-type COX2 mRNA.
      Substitution of AUC, CCC or AAA for the initiation codon abolished detectable
      translation of both mRNAs, even when PET111 activity was increased. The failure
      of these mutant cox2(1-91)::ARG8m genes to yield Arg8p demonstrates that
      initiation at downstream AUG codons, such as COX2 codon 14, does not occur even
      when normal initiation is blocked. Three mutant triplets at the site of the
      initiation codon supported detectable translation, with efficiencies decreasing
      in the order GUG, AUU, AUA. Increased PET111 activity enhanced initiation at AUU
      and AUA codons. Comparisons of expression, at the level of accumulated product,
      of cox2(1-91)::ARG8m and COX2 carrying these mutant initiation codons revealed
      that very low-efficiency translation can provide enough Cox2p to sustain
      significant respiratory growth, presumably because Cox2p is efficiently assembled
      into stable cytochrome oxidase complexes.

PMID- 10660066
TI  - In vitro recruitment of the RfaH regulatory protein into a specialised
      transcription complex, directed by the nucleic acid ops element.
AB  - An unusual regulatory mechanism that controls transcription elongation in long
      fertility and virulence operons in bacteria is effected by two specialised
      components, the RfaH protein and the nucleic acid ops element. Without direct
      interaction, ops acts to reduce the concentration of RfaH required to stimulate
      distal gene transcription, and we have proposed that ops recruits RfaH to the
      transcription machinery. To provide direct experimental evidence for this view,
      we used gel fitration to identify potential RfaH complexes assembled in
      Escherichia coli cell extracts that carry out RfaH-dependent transcription. This
      novel molecular weight shift assay revealed that RfaH-dependent transcription
      elongation occurs concomitantly with recruitment of RfaH into a high molecular
      weight transcription complex, and that this recruitment is specifically directed
      by the ops element. Assembly of this complex required RNA polymerase and
      nucleotide hydrolysis, but not processive transcription. Neither assembly of the
      complex nor RfaH-dependent transcription was observed in in vitro reactions
      containing only ops, RfaH and purified core (alphabetabeta') RNA polymerase; both
      processes required the combination of subcellular fractions containing the RNA
      polymerase complex, the cytoplasmic membrane and ribosomes. The data confirm that
      the ops element directs recruitment of RfaH into a multi-component RNA polymerase
      complex that resists transcription termination.

PMID- 10660068
TI  - The replication origin of Azotobacter vinelandii.
AB  - The putative replication origin of Azotobacter vinelandii was cloned as an
      autonomously replicating fragment after ligation to an antibiotic resistance
      cartridge. The resulting plasmids could be isolated and labelled by Southern
      hybridisation with the antibiotic resistance cartridge as probe and also
      visualised by electron microscopy. These plasmids integrated into the chromosome
      after a few generations, even in the recA mutant of A. vinelandii. The integrated
      copy of the plasmid was re-isolated from the chromosome and the DNA and its
      subfragments were cloned in the plasmid vector pBR322. A 200-bp DNA fragment was
      sufficient to allow the replication of pBR322 in an Escherichia coli polA strain.
      Electron microscopic analysis of this plasmid showed that replication initiated
      mostly within the A. vinelandii DNA fragment. The nucleotide sequence of the
      putative replication origin and its flanking regions was determined. In the
      sequence of the 200-bp fragment many of the distinctive features found in other
      replication origins are lacking. A greater variation from the consensus DnaA
      binding sequence was observed in A. vinelandii. Direct sequencing of the relevant
      genomic fragment was also carried after amplifying it from A. vinelandii
      chromosomal DNA by PCR. This confirmed that no rearrangements had taken place
      while the cloned fragment was resident in E. coli. It was shown by hybridisation
      that the 200-bp chromosomal origin fragment of A. vinelandii was present in three
      other field strains of Azotobacter spp.

PMID- 10660067
TI  - Expression and use of the green fluorescent protein as a reporter system in
      Legionella pneumophila.
AB  - The gene encoding the green fluorescent protein (GFP) was used as a reporter gene
      in Legionella pneumophila. To analyze GFP expression in Legionella,
      transcriptional fusions of gfp with the Legionella-specific mip (Macrophage
      Infectivity Potentiator) promoter (P(mip)) and the sod (SuperOxide Dismutase)
      promoter (P(sod)) derived from Listeria monocytogenes were constructed. Following
      transformation into the virulent L. pneumophila strain JR 32, strong GFP-mediated
      fluorescence was detected with both plasmids, although the sod promoter was
      associated with a 1ten-fold higher intensity. No fluorescence was observed in L.
      pneumophila transformed with the promoterless gfp gene. Comparison of
      fluorescence yields between various L. pneumophila strains that differ in their
      virulence characteristics and were transformed with the P(mip)-gfp carrying
      plasmid revealed no differences in GFP expression. Infection studies using
      Acanthamoeba castellanii as host and recombinant L. pneumophila strains carrying
      the P(mip)-gfp and P(sod)-gfp fusions indicated that the mip promoter was
      expressed when the bacteria replicated intracellularly. GFP expression was also
      used to monitor, in infected A. castellanii cells, the intracellular survival of,
      and incidence of host-cell killing by. L. pneumophila strains that vary in their
      virulence properties. As quantified by flow cytometry the highly virulent L.
      pneumophila strain Corby was twice as infectious to A. castellanii as the
      Philadelphia strain JR 32. Using the avirulent Philadelphia derivative 25D
      invasion but no intracellular multiplication was observed. In addition, we
      examined by flow cytometry the influence of cytochalasin D, cycloheximide, and
      methylamine on the uptake of Legionella by A. castellanii. In conclusion, gfp
      appears to be a convenient reporter gene whose expression in Legionella can be
      followed in real time and allows analysis of promoter activities in Legionella
      and monitoring of the infection process.

PMID- 10660070
TI  - Structure and regulation of the dnaA promoter region in three Streptomyces
      species.
AB  - The regulatory region of the Streptomyces dnaA gene comprises a single promoter
      and two DnaA boxes that are located upstream of the promoter. Comparative
      analysis of the dnaA promoter region from S. chrysomallus, S. lividans and S.
      reticuli revealed that the location, spacing and orientation of the DnaA boxes
      are conserved. In vitro studies demonstrated that efficient binding of the
      Streptomyces DnaA protein to DNA requires the presence of two DnaA boxes. In vivo
      analysis of dnaA promoter mutants deleted for one or both DnaA boxes indicated
      that the dnaA gene is autoregulated. However, the degree of derepression observed
      is relatively modest.

PMID- 10660069
TI  - Functional analysis of RRD1 (YIL153w) and RRD2 (YPL152w), which encode two
      putative activators of the phosphotyrosyl phosphatase activity of PP2A in
      Saccharomyces cerevisiae.
AB  - In the context of the cooperative project for functional analysis of novel genes
      uncovered during the systematic sequencing of the Saccharomyces cerevisiae
      genome, we deleted two paralogous ORFs: YIL153w and YPL152w. Based on the
      resulting phenotypes, the corresponding genes were named RRD1 and RRD2,
      respectively. Rrd proteins show significant similarity to the human
      phosphotyrosyl phosphatase activator (PTPA). Both single mutants, rrd1delta and
      rrd2delta, were viable. Deletion of RRD1 caused pleiotropic phenotypes under a
      wide range of conditions, including sensitivity to Ca2+, vanadate, ketoconazole,
      cycloheximide and Calcofluor white, and resistance to caffeine and rapamycin. The
      only phenotypes found for rrd2delta - resistance to caffeine and rapamycin - were
      weaker than the corresponding phenotypes of rrd1delta. The double mutant
      rrd1,2delta was inviable on rich glucose medium, but could grow in the presence
      of an osmotic stabilizer. The rrd1,2delta mutant was partially rescued by
      inactivation of HOG1 or PBS2, suggesting an interaction between the RRD genes and
      the Hog1p signal transduction pathway. Introduction of slt2delta into the
      rrd1,2delta background improved the growth of rrd1,2delta on sorbitol-containing
      medium, indicating that the Rrd proteins also interact with the Slt2p/Mpk1p
      signaling pathway. Suppression of the lethal phenotype of the rrd1,2delta mutant
      by overexpression of PPH22 suggested that the products of the RRD genes function
      positively with catalytic subunits of PP2A. The synthetic lethality was also
      suppressed by the "viable" allele (SSD1-v1) of the SSD1 gene.

PMID- 10660071
TI  - Rna14p, a component of the yeast nuclear cleavage/polyadenylation factor I, is
      also localised in mitochondria.
AB  - RNA14 was identified as a gene involved in premessenger RNA cleavage and
      polyadenylation. These processing steps take place in the nucleus, but the Rna14p
      protein is distributed in both the nucleus and the cytoplasm. By subcellular
      fractionation, we show here that the cytoplasmic fraction is localised in the
      mitochondria. In order to understand the role played by Rna14p in mitochondria,
      we have searched for new thermosensitive alleles of RNA14. We isolated thirteen
      new mutants. Some of them are deficient in mRNA cleavage and polyadenylation at
      the restrictive temperature - like the first mutant identified (rna14-1).
      However, others do not appear to be impaired in any of the steps in RNA
      metabolism investigated, nor do they appear to be involved in the replication or
      expression of mitochondrial DNA or in respiration. The localisation data strongly
      suggest that, besides an essential function in mRNA polyadenylation, the Rna14p
      protein has a non essential function in mitochondrial metabolism.

PMID- 10660072
TI  - Multiple copies of MRG19 suppress transcription of the GAL1 promoter in a GAL80
      dependent manner in Saccharomyces cerevisiae.
AB  - A plasmid clone that suppresses galactose toxicity in a gal7 yeast strain has
      been isolated from a multicopy genomic DNA library. Molecular analysis revealed
      that the region responsible for the suppression of galactose toxicity corresponds
      to the ORF YPR030w, which was named MRG19. A CEN-based plasmid carrying the above
      ORF was unable to suppress the toxicity. Galactokinase activity was substantially
      reduced in cell extracts obtained from transformants bearing multiple copies of
      MRG19. Multiple copies of MRG19 were also able to suppress galactokinase
      expression driven by the CYC1 promoter but not the TEF1 promoter. Multiple copies
      of MRG19 could not suppress GAL1-driven galactokinase expression in a gal80
      strain. However, MRG19-mediated suppression of CYC1-driven galactokinase
      expression was independent of GAL80 function. These results imply that multiple
      copies of MRG19 suppress galactokinase expression probably at the level of
      transcription. In agreement with this idea, multiple copies of MRG19 also
      suppress beta-galactosidase expression driven by the GAL1 promoter in a GAL80
      dependent manner. Disruption of MRG19 leads to an increase in the cell density at
      stationary phase in synthetic complete medium. MRG19 encodes a previously
      uncharacterised 124-kDa protein that shows no sequence homology to any known
      proteins.

PMID- 10660073
TI  - Three-partner conversion induced by the P-element transposase in Drosophila
      melanogaster.
AB  - Conversion of one P-derived transposon into another has already been shown to
      occur with a measurable frequency. However, the mechanism responsible for such
      replacements has remained controversial. We previously proposed a mechanism
      involving three partners. We assumed that after excision of the P-element
      inserted at the target site, the double-strand break was repaired using, first,
      the homologous P sequences on the sister chromatid, and second, a remote
      template, the donor P-derived transposon. However, two other mechanisms have been
      proposed. The first involves two partners only, the broken end and the remote
      template, while the second involves transposition of the donor into the target P
      element, followed by a double recombination event. Here we describe the
      conversion of a defective P-element using as a remote template an enhancer-trap
      element that is itself unable to transpose because it lacks 21 bp at its 5' end.
      This result makes it possible to exclude the possibility that this conversion
      event occurred after transposition. The new allele was molecularly and
      genetically characterized. The occurrence of a polymorphism at position 33 of the
      P-element sequence and of an imperfect copy of the template on the 3' side of the
      converted transposon confirmed that the sister chromatid was absolutely necessary
      as a partner for repair. Our results show that targeting of a marked P-element is
      possible, even when this element is unable to transpose. This provides a means of
      improving recovery of conversion events by eliminating unwanted transpositions
      catalyzed by the P transposase.

PMID- 10660074
TI  - Characterization of a Saccharomyces cerevisiae homologue of Schizosaccharomyces
      pombe Chk1 involved in DNA-damage-induced M-phase arrest.
AB  - Chk1 is an evolutionarily conserved protein kinase that plays an essential role
      in mediating G2 arrest in response to DNA damage in Schizosaccharomyces pombe and
      human cells. It functions by maintaining the inhibition (by phosphorylation of a
      specific tyrosine residue) of the cyclin-dependent kinase Cdc2 that initiates the
      G2/M transition. Here, we characterize a structural homologue of Chk1 in the
      budding yeast Saccharomyces cerevisiae. In this organism, G2/M arrest following
      DNA damage is considered to be independent of tyrosine phosphorylation of the
      Cdc2 homologue Cdc28. Nevertheless, a partial defect in G2/M-phase arrest
      following treatment with ionizing radiation, but not UV radiation, is associated
      with deletion of CHK1. The fact that such an effect remains detectable in cells
      synchronized with the microtubule inhibitor nocodazole prior to gamma irradiation
      implies the existence of a CHK1-dependent checkpoint in M phase. We conclude from
      epistasis analysis that Chk1 participates in the Pds1-dependent subpathway of M
      phase arrest. In spite of the partial checkpoint defect of the chk1 mutant, the
      survival of colony-forming cells is not notably decreased following UV and gamma
      irradiation. In two-hybrid screens, we identified a heme-binding stress protein
      (encoded by the yeast ORF YNL234W), a protein involved in genomic silencing
      (Sas3) and Chk1 itself as interacting partners of Chk1.

PMID- 10660076
TI  - Empowering the aged--a postmodern approach.
AB  - With the growth of the elderly population, the theme of empowerment and its
      actual negotiation will emerge as an issue of great importance. The aged are
      vulnerable in many ways and occupy still relatively limited social roles with
      restricted access to social goods. They are often undermined in their desire for
      self-determination. It is suggested that by introducing a postmodern approach in
      helping this group, the basic principles of social work can be enriched.
      Empowerment that includes opportunities for growth, mastery, significance, and
      meaning can be substantially increased. This article outlines the rationale for
      this approach and discusses the process of collaboration, the therapeutic
      relationship, and intervention strategies. While this article is limited to the
      elderly, the appreciation of the postmodern approach has implications for people
      in need for other populations as well.

PMID- 10660075
TI  - SLG1 plays a role during G1 in the decision to enter or exit the cell cycle.
AB  - Saccharomyces cerevisiae cells decide to divide during G1. If nutrients are
      abundant, cells pass through START and coordinately undergo DNA replication, bud
      emergence, and spindle pole body duplication. Phenotypic analysis of the
      slg1delta mutant revealed that this mutation uncouples post-START events. At the
      nonpermissive temperature, slg1delta cells that have undergone bud emergence but
      not DNA replication or SPB duplication accumulate. Furthermore, while wild-type
      cells arrest in GO when starved, the slg1delta mutant fails to arrest at this
      point; instead, cells with small buds accumulate. The slg1delta mutation
      displayed genetic interactions with cdc34, which encodes a regulator of exit from
      G1. This is consistent with a role of SLG1 in G1 regulation. Epitope-tagged Slg1p
      cofractionated with the plasma membrane, suggesting that Slglp may function by
      integrating external cues and relaying them to the interior of the cell. We
      propose that SLG1 plays a regulatory role in bud emergence or stationary phase.

PMID- 10660077
TI  - Caregiver stress: a failed negotiation? A qualitative study in South West France.
AB  - The purpose of this work is to analyze the various negotiations involved in
      setting up and developing a caregiving relationship with a disabled elderly
      person, to understand the processes inducing caregiver stress. Within the
      conceptual framework defined by the paradigm of negotiation, this study uses the
      theoretical contributions of the parallelist theory and the theory of the gift.
      It is based on a qualitative inquiry including fifty-four caregivers conducted in
      Toulouse (South West France). The analysis focuses on two undersystems of the
      caregiver's relationships: 1) the caregiver/cared-for's relationship, which is
      characterized by the establishment and maintenance of a "tacit contract" and 2)
      the relationships with other eligible caregivers, which are marked by the
      "designation" of the principal caregiver. This analysis shows that a failure in
      the negotiation process can induce a designation and/or a weak tacit contract-the
      result of which is the caregiver's expression of stress. This expression is
      closely linked to the caregiver's perception of a negative balance in his/her
      exchanges with the partners. This study should help break away from the one-way
      arrow model currently dominating the field of caregiver stress research.

PMID- 10660078
TI  - Old age support in China: the role of the state and the family.
AB  - This study investigates the relationship between some support factors and the
      well-being of the elderly in China. The analytical models identify and compare
      the effects of each type of factor on the sense of well-being of elderly Chinese
      across rural and urban settings. Pension, health care, size of family, and living
      arrangements are the factors found to be significantly related to the perception
      of happiness among aged people in general. The strength of the effects of
      children and living arrangements varies depending on places of residency. The
      findings indicate the continuous role of the family support, and the increasingly
      important role of state support in promoting a sense of well-being among elderly
      Chinese.

PMID- 10660079
TI  - Changing status and roles of older Korean immigrants in the United States.
AB  - This study examines the current status of older Korean immigrants and their
      changing roles in their families. Interviews were conducted with fifty elderly
      and forty adult children from Korean-American families residing in the
      Philadelphia area. The results suggest that a decrease in power and resources
      placed the elderly Koreans in an unfavorable position to remain valued members of
      their family. Older Korean immigrants have experienced many unexpected changing,
      and often less prestigious, roles in their old age. However, their modified
      beliefs on "filial piety" and a relative financial independence supported by the
      United States government may have been of significant influence to prevent
      intergenerational conflicts in Korean-American families.

PMID- 10660080
TI  - Perceived youth: appraisal and characterization.
AB  - Results from a mail survey of respondents aged sixty to ninety-four suggest that
      psychographic dimensions of youthfulness and identification with old age
      constitute effective inner-age research variables, especially to those seeking to
      study older populations. The two specific dimensions explored are: "perceived
      youth," a magnitude measure of the proportional discrepancy between chronological
      and cognitive ages; and "feeling-old," which inversely measured youth through
      reliance on a six-point Likert agree/disagree statement: "I feel old...." In
      addition to the obvious inverse relationship between these inner-ages, research
      established trait covariation relative to an increase in perceived youth
      coincidental with a rejection of a feeling-old identity, corresponding to
      increases in "happiness, own-health rating, being venturesome, giving advice,
      self-esteem, social activity, and keeping-in-shape," as well as decreases in
      "taking advice, being a homebody, and having health worries."

PMID- 10660081
TI  - Assessment of aniline derivatives-induced DNA damage in the liver cells of B6C3F1
      mice using the alkaline single cell gel electrophoresis ('comet') assay.
AB  - The alkaline single cell gel electrophoresis (SCGE) or 'comet' assay under
      alkaline conditions was used to measure DNA damage in the liver cells of B6C3F1
      male mice exposed to 2,4-dimethylaniline and 2,4,6-trimethylaniline. Cells
      embedded in agarose were lysed, subjected briefly to an electric field, stained
      with a fluorescent DNA-binding stain, and viewed using a fluorescence microscope.
      The effect of 2,4-dimethylaniline and 2,4,6-trimethylaniline was studied after
      single intraperitoneal injections at doses equal to 100, 200 mg/kg and 150, 300
      mg/kg body wt., respectively. It was found that 2,4-dimethylaniline and 2,4,6
      trimethylaniline were able to damage DNA in the liver cells of the mice. As has
      been published elsewhere, the DNA damaging effect of the studied compounds was
      also observed in bone marrow cells of the mice. In conclusion, taking into
      account the results mentioned above and the results obtained by the other
      researchers who reported mutagenic activity of 2,4-dimethylaniline and 2,4,6
      trimethylaniline in a Salmonella typhimurium assay and DNA repair test using
      Chinese hamster hepatocytes, it can be stated that both aromatic amines are
      genotoxic.

PMID- 10660082
TI  - Antiproliferative activity of conditioned medium from lymphocytes of
      neuroblastoma (NB) patient and inhibition with NB serum.
AB  - Neuroblastoma (NB) is a pediatric malignancy and results in high mortality rate.
      Cellular immunity has been shown to play an important role in killing tumors 'in
      vitro'. Human lymphocytes were activated in vitro with phytohaemagglutinin (PHA)
      and the effect of supernatants collected at 24, 48, 72 and 96 h were tested on
      proliferation of human NB cell line-SK-N-MC and glioma cell line U87-MG. The SK-N
      MC cells were observed to be more susceptible to the supernatants compared to U87
      MG with higher inhibition of proliferation as evaluated by [3H]thymidine
      incorporation (P < 0.05 for 24 and 72 h and P < 0.0005 for 48 and 96 h).
      Conditioned medium from lymphocytes of NB patient collected at 48 and 96 h after
      activation inhibited proliferation (P < 0.005) of SK-N-MC cells. The presence of
      serum from NB patient decreased the antiproliferative activity of supernatants
      from normal lymphocytes and NB patient's autologous lymphocytes (P < 0.01). This
      preliminary data demonstrates the capability of the activation of lymphocytes
      from NB patient undergoing aggressive multiagent chemotherapy and controlling
      proliferation of tumor cells on one hand and the role of serum from NB patient in
      abrogating to a certain extent the effect of activated immune cells thereby
      protecting tumor cells, on the other hand. Both these aspects need to considered
      with equal importance to study mechanisms in designing strategies for immune
      therapies.

PMID- 10660084
TI  - Roxithromycin and clarithromycin, 14-membered ring macrolides, potentiate the
      antitumor activity of cytotoxic agents against mouse B16 melanoma cells.
AB  - We previously reported antiangiogenic activity of roxithromycin and
      clarithromycin, 14-membered ring macrolide antibiotics. In the present study, we
      examined the antitumor effects of roxithromycin and clarithromycin, alone and in
      combination with several cytotoxic drugs, on mouse B16BL6 melanoma cells in vivo
      and in vitro. Both roxithromycin and clarithromycin potentiated the inhibition of
      tumor growth induced by cyclophosphamide, cis-diamminedichloroplatinum(II),
      Adriamycin and vindesine in vivo. However, neither roxithromycin nor
      clarithromycin, altered the cytotoxicity of 4-hydroperoxycyclophosphamide, cis
      diamminedichloroplatinum(II), Adriamycin or vindesine in an in vitro cell
      proliferation assay. These results suggest that the antiangiogenic activity of
      roxithromycin and clarithromycin may provide beneficial effects in combination
      with cytotoxic therapies against solid tumors.

PMID- 10660083
TI  - Cancer chemopreventive activity of majonoside-R2 from Vietnamese ginseng, Panax
      vietnamensis.
AB  - In the course of our continuing search for novel cancer chemopreventive agents
      from natural sources, several kinds of Panax plants were screened. Consequently,
      the ocotillol-type saponin, majonoside-R2 (MR2), was obtained from the rhizome
      and root of Panax vietnamensis (Vietnamese ginseng) as an active constituent. MR2
      exhibited potent anti-tumor-promoting activity on two-stage carcinogenesis test
      of mouse hepatic tumor using N-nitrosodiethylamine (DEN) as an initiator and
      phenobarbital (PB) as a promoter. Further, MR2 exhibited the remarkable
      inhibitory effect on two-stage carcinogenesis test of mouse skin induced by
      nitric oxide (NO) donor/12-O-tetradecanoylphorbol-13-acetate (TPA) or
      peroxynitrite/TPA.

PMID- 10660085
TI  - Secretion and dual regulation between epidermal growth factor and transforming
      growth factor-beta1 in MDA-MB-231 cell line in 42-hour-long cultures.
AB  - MDA-MB-231 is a breast cancer cell line which possesses large quantities of
      epidermal growth factor (EGF) receptors and specific high-affinity transforming
      growth factor-beta1 (TGF-beta1) receptors. We have established that these cells
      secrete constitutively measurable levels of EGF and TGF-beta1 in conditioned
      medium. The constitutive secretion of EGF decreased over time in culture (42 h),
      while the constitutive secretion of TGF-beta1 remained constant. TGF-beta1
      secretion in EGF-treated cells was lower than in controls (P < 0.0001), but EGF
      concentrations were not modified after TGF-beta1 supplement. We postulate that in
      MDA-MB-231 cell line there is a dual regulation between both growth factors.

PMID- 10660086
TI  - Ezrin, a membrane-cytoskeletal linking protein, is involved in the process of
      invasion of endometrial cancer cells.
AB  - In order to study ezrin function in tumor growth and invasion, we used two cell
      lines of human endometrial cancers. Ishikawa, the low-metastatic endometrial
      cancer cell line, and its subclone (mEIIL) with high-metastatic activity and
      higher ezrin expression were treated with a ezrin antisense phosphorothioate
      oligonucleotides (ePONs) pulse four times before the in vitro growth assay and
      Matrigel invasion assay. ePONs significantly suppressed the number of both cells
      that penetrated through Matrigel membrane (inhibition rate; 40.1 +/- 7.5%
      (Ishikawa), 42.7 +/- 2.4% (mEIIL), mean +/- SD, n = 6, P < 0.05, Student's t
      test), whereas they showed no effect on cell proliferation. Ezrin expression at
      the protein level was inhibited by ePONs. These data suggest that ezrin
      expression is required for invasion. The association of high ezrin expression in
      mEIIL and its higher ability to migrate through Matrigel may at least in part
      indicate functional significance of ezrin in endometrial cancer metastasis.

PMID- 10660087
TI  - Modulation of NDEA activated ras expression and protein kinase C activity by
      nicotinamide.
AB  - Nicotinamide, an amide derivative of vitamin B3, was found to inhibit the
      increase in ras expression, protein kinase C (PKC) activity, and diacylglycerol
      (DAG) levels in rats treated with N-nitrosodiethylamine (NDEA). It effectively
      modulated the carcinogen induced increase in the cytosol and the particulate PKC
      activities but not the nuclear PKC activity. The DAG levels were also modulated
      by the endobiotic. It may serve as an ideal modulator of carcinogenesis.
      Nicotinamide is currently under trial as a radio sensitizer, and inhibition of
      these parameters may be one of the ways in which it confers radiosensitivity.

PMID- 10660088
TI  - Chromosomal integration of adeno-associated parvovirus DNA limits proliferation
      and dispersal of human MKr melanoma cells in co-cultures with human fibroblasts.
AB  - Adeno-associated parvoviruses (AAVs) possess onco-suppressive potential and
      inhibit proliferation of cells derived from malignant human tumors in culture.
      Growth inhibition of human melanoma cells can be achieved when the cells are
      infected with these viruses but continues subsequent to infection when viral DNA
      is chromosomally integrated. Integration of AAV2 DNA into the genome of the human
      melanoma cell line MKr alters the cellular phenotype towards that of diploid
      cells in culture, and leads to density-arrested growth, strong reduction of the
      ability to form colonies from single cells and to an increased number of
      terminally differentiating cultures. The present study aimed at the question
      whether the altered growth properties were retained upon prolonged co-cultivation
      with fibroblasts, i.e. under conditions that occur in invasive growth and
      colonization of distant tissues. The results show that despite the known
      possibility of growth stimulation by fibroblasts the potential of melanoma cells
      to proliferate and the potential to further scatter in the fibroblast cultures
      remain limited when AAV DNA is integrated.

PMID- 10660090
TI  - Lymphadenectomy in primary carcinoma of the Fallopian tube.
AB  - OBJECTIVE: The bad prognosis of primary carcinoma of the Fallopian tube is
      ascribed to early lymphogenous metastasis. Due to the rarity of cases, there
      exist only few and divergent results on the importance of lymph node metastasis
      in the relevant literature. Thus, our study aimed at detecting the incidence of
      lymph node metastases and their influence on overall survival, as well as at
      evaluating the therapeutic effect of radical lymphadenectomy. METHODS: We studied
      158 cases of primary carcinoma of the Fallopian tube in a retrospective
      multicenter analysis. Group I (n = 38) consisted of patients who were subjected
      to radical pelvic and para-aortic lymphadenectomy in addition to total abdominal
      hysterectomy, bilateral adenectomy and omentectomy. The control group II (n = 71)
      underwent the same surgical procedures but without radical lymphadenectomy.
      Patients who received post-operative irradiation (n = 49) were excluded from the
      study. RESULTS: On average, 38 lymph nodes (range 12-68) were extirpated. In
      group I 42.1% of the cases showed lymph node metastases. Lymphatic dissemination
      was observed only after the carcinoma had spread beyond the organ (intraabdominal
      stage II); the incidence of lymph node metastases rose significantly (P = 0.02)
      with growing intraperitoneal tumour masses. Pelvic and para-aortic metastases
      occur simultaneously. Overall survival with tumour of equal size is markedly, but
      not significantly reduced (P = 0.18) if the lymph nodes are involved. If,
      however, radical lymphadenectomy is performed (group I) the median survival time
      increases to 43 months (95% confidence-interval 20-66), compared with 21 months
      (95% confidence-interval 10-32) in group II (P = 0.095). CONCLUSION: Correct
      staging is obtained only on the basis of pelvic and para-aortic lymphadenectomy.
      Radical lymphadenectomy in tumours of equal size may markedly prolong survival.

PMID- 10660089
TI  - Mesotheliomas induced in rats by the fibrous mineral erionite are independent
      from p53 alterations.
AB  - The development of human malignant mesothelioma (MM) is strongly associated with
      occupational or environmental exposure to certain natural mineral fibers,
      although the genetic mechanisms underlying this malignancy remain unclear.
      Although the p53 gene is frequently mutated in various tumors, human asbestos
      associated MMs appear to develop independently from p53 alterations. The high
      mesotheliomagenic potency of natural fibrous mineral erionite is well established
      in humans and rodents, but no data regarding genetic alterations in erionite
      associated tumors are currently available. Previous speculations that the
      oncogenic mechanisms underlying asbestos and erionite carcinogenesis may differ
      led us to examine whether the p53 gene is targeted in erionite carcinogenesis.
      Fifteen erionite-induced rat MMs as well as six cell lines derived from asbestos
      induced and spontaneous rat MM were analyzed for p53 mutations by direct DNA
      sequencing and immunohistochemical analysis. Both approaches did not reveal p53
      alterations in rat MM samples used in the study indicating that, similar to
      asbestos carcinogenesis, erionite carcinogenesis does not target the p53 tumor
      suppressor gene.

PMID- 10660091
TI  - The potentiated antileukemic effects of doxorubicin and interleukin-12
      combination are not dependent on nitric oxide production.
AB  - In our recent study we described a significant antileukemic efficacy of a
      combination therapy with interleukin-12 (IL-12) and doxorubicin (DOX) in the
      L1210 leukemia model. This therapeutic effect was abrogated by elimination of
      activated macrophages. Activated macrophages produce a variety of factors that
      can contribute to the elimination of tumor cells in vivo, including proteases,
      TNF, reactive oxygen intermediates, and nitric oxide (NO). Based on the results
      of previous reports, the contribution of NO in potentiated antileukemic effects
      of IL-12 + DOX combination seemed to be highly possible. Both DOX and IL-12 given
      alone increased the production of NO by peritoneal macrophages, however,
      macrophages derived from the mice treated with the combination of those agents
      produced significantly less NO than macrophages from IL-12-alone-treated mice.
      Production of NO by spleen macrophages after IL-12 + DOX treatment was higher
      than it was in controls, IL-12-alone or DOX-alone-treated groups. In serum,
      concentrations of NOx- in IL-12- or IL-12 + DOX-treated mice were significantly
      higher in comparison with controls, however not significantly different from each
      other. Addition of L-NAME treatment to the IL-12 + DOX therapy in leukemia
      bearing mice did not significantly change the antileukemic efficacy of this
      therapy. Thus, our results indicate that the augmented antileukemic effects of IL
      12 + DOX combination therapy in L1210 model are NO-independent. Therefore,
      further studies on the possible mechanisms of potentiated antileukemic activity
      of combination of IL-12 and DOX would be worth pursuing.

PMID- 10660092
TI  - Inhibition of human carcinoma cell growth and DNA synthesis by silibinin, an
      active constituent of milk thistle: comparison with silymarin.
AB  - Several studies from our laboratory have shown the cancer chemopreventive and
      anti-carcinogenic effects of silymarin, a flavonoid antioxidant isolated from
      milk thistle, in long-term tumorigenesis models and in human prostate, breast and
      cervical carcinoma cells. Since silymarin is composed mainly of silibinin with
      small amounts of other stereoisomers of silibinin, in the present communication,
      studies were performed to assess whether the cancer preventive and anti
      carcinogenic effects of silymarin are due to its major component silibinin.
      Treatment of different prostate, breast, and cervical human carcinoma cells with
      silibinin resulted in a highly significant inhibition of both cell growth and DNA
      synthesis in a time-dependent manner with large loss of cell viability only in
      case of cervical carcinoma cells. When compared with silymarin, these effects of
      silibinin were consistent and comparable in terms of cell growth and DNA
      synthesis inhibition, and loss of cell viability. Based on the comparable results
      of silibinin and silymarin, we suggest that the cancer chemopreventive and anti
      carcinogenic effects of silymarin reported earlier are due to the main
      constituent silibinin.

PMID- 10660094
TI  - Effects of sulindac, sulindac metabolites, and aspirin on the activity of
      detoxification enzymes in HT-29 human colon adenocarcinoma cells.
AB  - Non-steroidal anti-inflammatory drugs (NSAIDs) have been found to reduce cancer
      rates in various segments of the gastro-intestinal tract in both animals and
      humans. In this study we examined the effect of sulindac, sulindac sulfide,
      sulindac sulfone and aspirin on QR and GST activity. We found that sulindac
      itself increased QR activity as much as 2-fold over controls but had no effect on
      GST activity. Sulindac sulfone, a metabolite of sulindac which lacks the ability
      to inhibit prostaglandin (PG) synthesis, increased QR and GST to 1.5-fold over
      controls in both cases. Aspirin increased QR and GST to 1.5-fold and 3.5-fold
      over controls respectively. These data indicate that NSAIDs increase phase II
      enzyme detoxification enzyme activity. Consequently, this effect may contribute
      to the protective effect of NSAIDs against colon cancer and may be an
      anticarcinogenic effect of these drugs that is distinct from their ability to
      inhibit PG synthesis.

PMID- 10660093
TI  - Clofilium, a potassium channel blocker, induces apoptosis of human promyelocytic
      leukemia (HL-60) cells via Bcl-2-insensitive activation of caspase-3.
AB  - We have demonstrated that clofilium, a potassium channel blocker, induces
      apoptosis on human promyelocytic leukemia (HL-60) cells. Cells treated with
      clofilium led to suppression of viability and proliferation in both time and
      concentration-dependent manners. Nuclear DAPI staining and electronmicroscopic
      examination revealed typical nuclear features of apoptosis in cells treated with
      clofilium that was further verified in DNA fragmentation analysis. Flow cytometry
      analysis with FITC-annexin V and propidium iodide (PI) revealed that apoptotic
      cell population with Annexin V+/PI- increased gradually from < 2% at 0 h, to 20%
      at 4 h and 29% at 16 h after exposure to 10 microM clofilium in HL-60 cells.
      Furthermore, fluorometric immunosorbent enzyme assay for activity of caspase-3
      showed approximately a 10-fold increase of activity in cells treated with 10
      microM of clofilium for 2-3 h compared with the basal level of its activity in
      untreated control cells. Immunoblotting analysis revealed proteolytic cleavage of
      caspase-3 and subsequent cleavage of PARP. However, there was no significant
      change of Bcl-2 and Bax proteins. These results indicate that clofilium exerts
      antiproliferative action and growth inhibition on HL-60 through induction of
      apoptosis which is mediated via Bcl-2-insensitive activation of caspase-3, and
      suggest chemotherapeutic and cytostatic potentials of this compound in human
      leukemias.

PMID- 10660095
TI  - An intragenic deletion of nuclear localization signal-1 of p53 tumor suppressor
      gene results in loss of apoptosis in murine fibroblasts.
AB  - We established mouse lines containing either full-length wild-type p53 or nuclear
      localization signal-I (NLS-I) deleted p53 to study the role of NLS-I in p53
      translocation and function. Induction of apoptosis in response to DNA damage, a
      primary function of p53, was tested in these cell lines. After exposure to gamma
      ionizing radiation or hydrogen peroxide, DNA ladders and labeling of nucelosomal
      fragments were detected in cells with wild-type p53 gene, but not in p53 null
      cells or NLS-I deleted cells, suggesting that the NLS-I of p53 protein is
      necessary for apoptosis. Analysis of p53 protein from subcellular fractions
      indicated that NLS-I deprived p53 remained in the cytoplasmic fraction, which may
      explain why NLS-I deleted p53 failed to induce apoptosis.

PMID- 10660096
TI  - N-acetylcysteine suppression of the proliferative index in the colon of patients
      with previous adenomatous colonic polyps.
AB  - This investigation is part of an effort to develop chemoprevention for
      carcinogenesis of the large bowel. The agent investigated is N-acetylcysteine
      (NAC). We used as a predictive biomarker, the proliferative index (PI), in a
      short-term human study. Patients with previous adenomatous colonic polyps are a
      cohort with increased risk for colon cancer and an increased PI of colonic
      crypts. They were randomly assigned to an experimental group given 800 mg/day of
      NAC for 12 weeks or a placebo group. Using proliferative cell nuclear antigen
      immunostaining, the PI of colonic crypts was measured prior to and after the
      treatments. The PI of the NAC group was decreased significantly (P < 0.02) while
      the placebo group showed no difference (P > 0.45). Since this decrease in PI may
      be an indicator of decreased risk of colon cancer, more extensive studies of the
      potential of NAC as a chemopreventive agent for colon cancer appear warranted.

PMID- 10660097
TI  - Involvement of Ca2+ influx in the mechanism of tamoxifen-induced apoptosis in
      HepG2 human hepatoblastoma cells.
AB  - The signaling mechanism of tamoxifen (TAM)-induced apoptosis was investigated in
      HepG2 human hepatoblastoma cells which do not express the estrogen receptor (ER).
      TAM induced cytotoxicity and DNA fragmentation, a hallmark of apoptosis, in a
      dose-dependent manner. TAM increased the intracellular concentration of Ca2+.
      This effect was completely inhibited by the extracellular Ca2+ chelation with
      EGTA. TAM also induced a Mn2+ influx, indicating that TAM activated Ca2+ influx
      pathways. This action of TAM was significantly inhibited by flufenamic acid (FA),
      a known non-selective cation channel blocker. Quantitative analysis of apoptosis
      by flow cytometry revealed that treatment with either FA or BAPTA, an
      intracellular Ca2+ chelator, significantly inhibited TAM-induced apoptosis. These
      results suggest that intracellular Ca2+ signals may play a central role in the
      mechanism of the TAM-induced apoptotic cell death in ER-negative HepG2 cells.

PMID- 10660098
TI  - Inhibitory effects of freeze-dried milk fermented by selected Lactobacillus
      bulgaricus strains on carcinogenesis induced by 1,2-dimethylhydrazine in rats and
      by diethylnitrosamine in hamsters.
AB  - Fermented milk products might be used for cancer chemoprevention due to their
      putative anticarcinogenic and antitumor activities. The diet was supplemented
      with freeze-dried milk fermented by Lactobacillus bulgaricus strain LBB.B 144
      (product FFM.B 144) added throughout the experiment at doses of 1.3 g and 2.5 g
      per rat, 5 times a week starting 3 weeks before the first carcinogen injection.
      This treatment significantly inhibited, by 26.2-28.6% and by 34.2%, the total
      intestinal carcinogenesis induced by 1,2-dimethylhydrazine (DMH, 21 mg/kg, s.c.,
      once per week for 20 weeks) in male and female BD6 rats, respectively. FFM.B144
      decreased the tumor incidence and multiplicity in large bowel, caecum, and
      duodenum. Protective effects were better expressed in female animals, with
      exception of that observed in duodenum. Supplementation of diet with freeze-dried
      milk fermented by Lactobacillus bulgaricus strain LBB.B5 (product FFM.B5)
      inhibited DMH-induced carcinogenesis only in the large bowel, but had no
      significant protective effect when all intestinal tumors were taken into account.
      However, both freeze-dried products favorably shifted the differentiation of
      large bowel tumors by increasing the proportion of benign and highly
      differentiated malignant tumors and decreasing in parallel the number of poorly
      differentiated carcinomas without influencing the tumor size. A lower number of
      cases with visible mesenterial metastasis was also observed in FFM-treated rats.
      In addition, both FFM.B 144 and FFM.B5 significantly inhibited, by 26-33%, the
      induction in the same rats of ear-duct tumors. FFM.B144 but not FFM.B5 was also
      effective in inhibiting the tracheal carcinogenesis induced in Syrian golden
      hamsters by diethylnitrosamine (DEN, 100 mg/kg, two s.c. injections), the
      protective effect being better expressed in female animals. The anticarcinogenic
      potential of some fermented milk products might be exploited in chemoprevention
      of cancer in humans.

PMID- 10660099
TI  - A new member of the GTPase superfamily that is upregulated in highly metastatic
      cells.
AB  - Two sublines of B16 melanoma cells, F10 and BL6, are metastatic after intravenous
      injection, but only BL6 cells are metastatic after subcutaneous injection. We
      found a new member of the GTPase superfamily, namely TIB929, which displayed an
      induction of expression in BL6 cells. It conserved three consensus sequences for
      GTP-binding site motifs and showed a significant homology to the yeast Gtr2 gene
      throughout the coding sequence. TIB929 was expressed ubiquitously in human tumor
      cells, with a marked expression in highly metastatic cells. TIB929 was mapped on
      mouse chromosome 4D, syntenic to human chromosome 1p. The results suggested an
      involvement of TIB929 in malignant progression.

PMID- 10660100
TI  - Primary brain tumor incidence in mice exposed to split-dose ionizing radiation
      and circularly polarized 60 Hz magnetic fields.
AB  - Three sections of brain tissue from 2,657 female C57BL/6 mice were stained with
      hematoxylin and eosin and evaluated microscopically for proliferative lesions.
      Mice had been treated with either split-dose ionizing radiation (0, 3.0, 4.0 and
      5.1 Gy), chronic lifetime 60 Hz circularly polarized magnetic field exposure
      (ambient or 14.2 G, 1.4 mT), or both, and were evaluated after natural death or
      euthanasia for humane reasons. Among 950 mice which were not treated with
      ionizing radiation, two benign spontaneous lipomatous hamartomas were observed.
      Seven primary brain tumors of various types not found in untreated animals were
      observed among the 1,707 irradiated mice. Possible promotional effects of
      magnetic field exposure on primary brain tumor development and incidence could
      not be assessed due to the low number of tumors observed.

PMID- 10660101
TI  - Reduced expression of p33(ING1) and the relationship with p53 expression in human
      gastric cancer.
AB  - p33(ING1) is a novel growth inhibitor candidate for a tumor suppressor gene.
      p33(ING1) cooperates with p53 and negatively regulates cell growth by activating
      transcription from the p21/WAF1 promoter even though it has no significant
      sequence similarity to p53. We first compared p33(ING1) expression in human
      gastric cancers and matched normal tissues using quantitative RT-PCR and real
      time 'Taqman TM' technology. A significant decrease in p33(ING1) expression was
      evident in 15 of 20 gastric cancers. In immunohistochemical analysis, p53 protein
      expression was detected in 4 of 20 (20%) tumors, and 12 of 15 (80%) tumors with
      decreasing p33(ING1) expression in RT-PCR had the wild type p53. When we examined
      the sequence of p33(ING1) in 12 gastrointestinal carcinoma cell lines, we found
      mutation in only one cell line, HCT116. Our findings are interpreted to mean that
      p33(ING1) may function as a tumor suppressor in gastric carcinogenesis, even
      though the gene is preserved in the majority of gastrointestinal carcinomas. It
      should be noted that expression of p33 decreased in many cancer patients, and the
      biological effects of p33(ING1) and p53 are interrelated and require the activity
      of both genes.

PMID- 10660102
TI  - Enhancement of methylcholanthrene-induced neoplastic transformation in murine C3H
      10T1/2 fibroblasts by antisense phosphorothioate oligodeoxynucleotide sequences.
AB  - Antisense phosphorothioate oligodeoxynucleotides (ODNs) are increasingly used to
      target specific proteins for inhibition. Previous reports of antisense inhibition
      of the inducible nitric oxide synthase (iNOS) gene suggested its utility in
      defining the role of nitric oxide (NO) in carcinogenesis, as NO is mutagenic and
      chemical inhibitors of iNOS block neoplastic transformation in C3H 10T1/2
      fibroblasts. Treatment with ODNs (0.025-25 microM) directed against 15mer
      sequences in the iNOS coding region decreased NO production consistent with a
      reduction of iNOS protein and iNOS mRNA, however, control ODNs (2.5 microM) also
      showed considerable nonspecific inhibition of NO synthesis. Treatment with both
      iNOS antisense and missense ODNs during the promotional phase of the C3H10T1/2
      transformation assay significantly increased the number of neoplastic foci in 3
      methylcholanthrene (MCA) treated cells which corresponded with the ability of the
      ODN to inhibit NO production. Enhanced neoplastic transformation and non-specific
      inhibition of NO synthesis resulting from exposure to antisense ODNs suggest
      limitations to their long-term use in humans at higher doses.

PMID- 10660103
TI  - Decreased phagocytic capacity of rat peritoneal macrophages following photon
      abdominal irradiation.
AB  - Photon irradiation of the abdomen may be accompanied by complications due to a
      decrease in the immune defense of the recipient. Since peritoneal macrophages are
      an important component of the immune system, we examined the phagocytic activity
      and oxygen superoxide anion generation by peritoneal macrophages from rats 2 and
      4 weeks after abdominal irradiation with 6 MV photons applying a single dose of 2
      Gy. Two and 4 weeks after irradiation, peritoneal macrophages were harvested and
      their capacity to engulf latex particles and to produce oxygen superoxide anions
      was determined. Non-irradiated rats, treated identically otherwise, served as
      controls. Two weeks after irradiation the phagocytic capacity and oxygen
      superoxide anion generation decreased by 61 and 70%, respectively, compared with
      controls. This tendency persisted after 4 weeks post irradiation, the decrease in
      both functions being 50 and 74%, respectively. It is suggested that the altered
      function of peritoneal macrophages following irradiation may further compromise
      the immune defense in patients receiving abdominal radiotherapy.

PMID- 10660104
TI  - Analysis of Li-Fraumeni syndrome and Li-Fraumeni-like families for germline
      mutations in Bcl10.
AB  - The Li-Fraumeni syndrome (LFS) is a dominant disease whose hallmark is an
      increased risk of breast cancers, brain tumours, sarcomas, leukaemia and adrenal
      carcinoma. Some, but not all LFS and Li-Fraumeni-like (LFL) families are caused
      by TP53 mutations. Bcl10 is a recently identified tumour suppressor reported to
      be commonly mutated in a wide range of cancers. To investigate the possibility
      that Bcl10 is a susceptibility gene for LFS and LFL we have analysed 27 LFS/LFL
      families. No mutations were observed. This indicates that Bcl10 is unlikely to
      act as a susceptibility gene for LFS and LFL.

PMID- 10660105
TI  - Termination of piroxicam treatment and the occurrence of azoxymethane-induced
      colon cancer in rats.
AB  - Piroxicam has been shown to prevent azoxymethane (AOM)-induced colon cancer when
      administered during the promotion/ progression phase. The requirement for
      continued treatment with piroxicam in order to maintain prevention of colon
      cancer was investigated. Male F344 rats were administered 15 mg/kg AOM at 7 and 8
      weeks of age and started to receive piroxicam (200 mg/kg) in their diet at 11
      weeks after the second dose of AOM. Piroxicam was removed from the diet of some
      of the rats at weeks 19 and 28 and the animals were held until week 47. Other
      rats continued to receive piroxicam until sacrificed at week 47. Treatment with
      piroxicam from week 11-47 reduced the yield of colon tumors. When treatment was
      terminated at week 19 or 28 the yield of tumors at week 47 was not reduced.
      Within 1 week of the start of piroxicam treatment, the number of aberrant crypt
      foci (ACF)/animal was decreased. Termination of treatment resulted in the
      recurrence of ACF. Apoptosis in adenomas was increased when piroxicam treatment
      was continued to week 47 but not when treatment was terminated earlier at week 19
      or 28. The proliferating cell nuclear antigen-labeling index in adenomas was not
      affected by piroxicam even when treatment was from week 11 to 47. In summary,
      termination of treatment resulted in the occurrence of ACF and colon cancer
      indicating that prevention by piroxicam was reversible. Furthermore, enhancement
      of apoptosis and not decreased cell proliferation correlated with prevention of
      colon cancer.

PMID- 10660106
TI  - Changes in serum diamine oxidase activity during chemotherapy in patients with
      hematological malignancies.
AB  - Serum diamine oxidase (DAO) activity is very low, but is considered to reflect
      quantitative changes in small intestinal mass. Therefore, we measured DAO
      activity during chemotherapy in patients with hematological malignancies in order
      to evaluate mucosal injury. DAO activity decreased from 1-3 weeks after
      chemotherapy but returned to initial levels after 4 weeks. As the dosage of anti
      cancer drugs increased, DAO activity decreased more, but its activity was not
      related to other parameters. These findings suggest that serum DAO could be used
      as an indicator of mucosal injury during chemotherapy.

PMID- 10660107
TI  - Potentially lethal damage repair and its inhibitory effect of caffeine in two
      yolk sac tumor cell lines with different radiosensitivities.
AB  - PURPOSE: In order to investigate the role of potentially lethal damage repair
      (PLDR) in cellular radiosensitivity, PLDR and its inhibitory effect by caffeine
      was examined. In addition, cell cycle distribution was also examined. MATERIALS
      AND METHODS: Two rat yolk sac tumor cell lines, NMT-1 and NMT-1R, with different
      radiosensitivities in vitro were used. The capacity for PLDR was examined using
      confluent-phase cells, and evaluated by calculating the recovery ratio.
      Inhibitory effect of caffeine on PLDR was examined with doses of 1, 5 and 10 mM.
      RESULTS: The capacity of PLDR in two cell lines reflected radiosensitivity. The
      recovery ratio after irradiation of 5 Gy was 2.8 in the radiosensitive NMT-1 and
      5.2 in the radioresistant NMT-1R, and recovery reached its peak level at 6 h in
      both cell lines. The degree of inhibition of PLDR was weaker in NMT-1R than that
      in NMT-1 at the same dose level, and was correlated with reduction of G2-arrested
      cells by caffeine. CONCLUSIONS: The results of this study suggest that the
      capacity of PLDR may be one of the determinant factors for radiosensitivity in
      the two cell lines used, and the inhibitory effect of caffeine on PLDR was in
      part attributable to the modification of the cell cycle progression.

PMID- 10660108
TI  - Effect of chromogranin A (pancreastatin) fragment on invasion of prostate cancer
      cells.
AB  - We investigated the effect of chromogranin A (pancreastatin) fragment on the
      invasion of PC-3, DU-145 and LNCaP prostate cancer cells through a reconstituted
      basement membrane (Matrigel) using a Transwell cell culture chamber assay.
      Chromogranin A fragment increased the invasive capacity of both PC-3 and DU- 145
      cells, whereas it had no significant effect of LNCaP cells. Chromogranin A
      fragment also increased the haptotactic migration of both PC-3 and DU-145 cells
      to fibronectin. Furthermore chromogranin A fragment increased the fibrinolytic
      activities of urokinase-type plasminogen activator (u-PA) in fibrin zymograms of
      both PC-3 and DU-145 cells and the expression of u-PA mRNA of PC-3 cells.
      However, the growth of these tumor cells was not affected by chromogranin A
      fragment at any concentrations used in this study. These results indicate that
      chromogranin A fragment increased the invasive potential of both PC-3 and DU-145
      cells probably through enhancement of cell motility and the production of u-PA.

PMID- 10660110
TI  - Post-initiation effects of a super critical extract of propolis in a rat two
      stage carcinogenesis model in female F344 rats.
AB  - Post-initiation modifying effects of dietary administration of a super critical
      extract of propolis on major organs were examined using a two-stage
      carcinogenesis model. Groups of 21 or 22 F344 female rats were treated
      sequentially with 2,2'-dihydroxy-di-n-propylnitrosamine (DHPN, i.g.), 7,12
      dimethylbenz[a]anthracene (DMBA, i.g.), 1,2-dimethylhydrazine (DMH, s.c.) and N
      butyl-N-(4-hydroxybutyl)nitrosamine (BBN, in drinking water) during the first 3
      weeks for initiation, and then administered diet containing 0.1 or 0.01% propolis
      for 33 weeks. Further groups were treated with the carcinogens alone, 0.1%
      propolis alone or basal diet alone. All surviving animals were killed at week 36,
      and major organs were examined histopathologically for development of
      preneoplastic and neoplastic lesions. The incidence and multiplicity of mammary
      carcinomas were significantly decreased by the 0.1 and 0.01% propolis treatments.
      In the urinary bladder, the incidence of PN hyperplasia but not tumors was, in
      contrast, significantly increased by 0.1% propolis. Similarly, the number and
      area of glutathione S-transferase placental form (GST-P)-positive liver foci were
      significantly elevated with this high dose. The results indicate that a low dose
      of a super critical extract of propolis may find application as a potent
      chemopreventor of mammary carcinogenesis.

PMID- 10660109
TI  - Fas-resistance in ATL cell lines not associated with HTLV-I or FAP-1 production.
AB  - A preventive role for human T-cell leukemia virus type-I (HTLV-I) and Fas
      associated phosphatase-1 (FAP-1) in Fas-mediated apoptosis has been reported in
      HTLV-I-infected cells. In the present study, we examined whether these molecules
      increased during the acquisition of Fas-resistance in adult T-cell leukemia (ATL)
      cell lines. SO4, ST1 and KK1 are Fas-sensitive ATL cell lines, and produce small
      amounts of HTLV-I in vitro. Although their subclones RSO4 and RST1 are completely
      Fas-resistant, they produced an equivalent amount of HTLV-I to SO4 and ST1.
      Moreover, FAP-1 mRNA was not detected in these cell lines irrespective of Fas
      sensitivity. Thus, Fas resistance in ATL cells was not directly associated with
      the increased production of HTLV-I or FAP-1.

PMID- 10660111
TI  - A role for the cell adhesion molecule CD44 and sulfation in leukocyte-endothelial
      cell adhesion during an inflammatory response?
AB  - CD44 is a widely expressed cell adhesion molecule that has been implicated in a
      variety of biological processes including lymphopoiesis, angiogenesis, wound
      healing, leukocyte extravasation at inflammatory sites, and tumor metastasis. The
      adhesive function of CD44, like other molecules involved in inducible adhesion,
      is tightly regulated. Post-translational modifications, isoform expression,
      aggregation state, and protein associations all can affect the ligand binding
      properties of CD44, and these can vary depending on the cell type and the
      activation state of the cell. The most extensively characterized ligand for CD44
      is hyaluronan, a component of the extracellular matrix. Interactions between CD44
      and hyaluronan can mediate both cell-cell and cell-extracellular matrix adhesion.
      In the immune system, both the selectin molecules and CD44 have been implicated
      in the initial binding of leukocytes to endothelial cells at an inflammatory
      site. Sulfation is required for selectin-mediated leukocyte-endothelial cell
      interactions, and, recently, inducible sulfation also was shown to regulate CD44
      mediated leukocyte adhesion to endothelial cells. Sulfation, therefore, may be
      important in the regulation of cell adhesion at inflammatory sites. In this
      commentary we have reviewed the molecular aspects of CD44 and the mechanisms that
      regulate its binding to hyaluronan. In addition, we have summarized the role of
      CD44 and hyaluronan in mediating leukocyte-endothelial cell interactions and have
      discussed how this interaction may be regulated. Finally, we examined the
      potential role of sulfation as an inducible means to regulate CD44-mediated
      leukocyte adhesion and as a more general mechanism to regulate leukocyte
      endothelial cell interactions.

PMID- 10660113
TI  - Stimulatory effect of Daidzein in osteoblastic MC3T3-E1 cells.
AB  - Daidzein is a natural isoflavone found in Leguminosae. The effect of daidzein on
      osteoblastic MC3T3-E1 cells was investigated. Cells were cultured in a serum-free
      medium for 48 hr in the presence of daidzein (10(-7)-10(-5) M). Daidzein (10(-6)
      and 10(-5) M) caused a significant elevation of protein content, alkaline
      phosphatase activity, and DNA content in cells; those increases were about 1.4-,
      1.5-, and 2.0-fold, respectively. The ability of daidzein (10(-5) M) to increase
      protein content, alkaline phosphatase activity, and DNA content in cells was
      prevented completely by the presence of cycloheximide (10(-6) M), an inhibitor of
      protein synthesis, indicating that the isoflavone has a stimulatory effect on
      cellular protein synthesis. The anabolic effect of daidzein (10(-6) or 10(-5) M)
      in cells was not distinguishable from that of genistein (10(-6) or 10(-5) M).
      Meanwhile, cell protein showed an additive effect of 17beta-estradiol and
      daidzein, but their effects on alkaline phosphatase were not additive. Moreover,
      the effect of daidzein (10(-5) M) in elevating cellular protein content and
      alkaline phosphatase activity was inhibited completely by the presence of
      tamoxifen (10(-6) M), suggesting that the effect of the isoflavone is mediated
      partly through estrogen action. This study demonstrates that daidzein has an
      anabolic effect in osteoblastic MC3T3-E1 cells.

PMID- 10660112
TI  - Coordinate induction by antioxidants of UDP-glucuronosyltransferase UGT1A6 and
      the apical conjugate export pump MRP2 (multidrug resistance protein 2) in Caco-2
      cells.
AB  - Treatment of Caco-2 cells with the antioxidants quercetin or t-butylhydroquinone
      led to induced protein levels of UDP-glucuronosyltransferase UGT1A6 (ca. 3-fold
      over controls) and of the apical conjugate export pump multidrug resistance
      protein 2 (MRP2; 1.9-fold over controls). In contrast to UGT1A6, MRP2 (symbol
      ABCC2) was not inducible by 2,3,7,8-tetrachlorodibenzo-p-dioxin.
      Immunocytochemistry demonstrated that MRP2 was only expressed at the brush border
      domain of Caco-2 cell monolayers. The results indicate that UGT1A6 and MRP2 are
      coordinately induced by antioxidants, facilitating chemoprotection against
      phenolic toxins and excretion of conjugates into the intestinal lumen.

PMID- 10660114
TI  - Stimulation of nucleoside efflux and inhibition of adenosine kinase by A1
      adenosine receptor activation.
AB  - Adenosine is produced intracellularly during conditions of metabolic stress and
      is an endogenous agonist for four subtypes of G-protein linked receptors.
      Nucleoside transporters are membrane-bound carrier proteins that transfer
      adenosine, and other nucleosides, across biological membranes. We investigated
      whether adenosine receptor activation could modulate transporter-mediated
      adenosine efflux from metabolically stressed cells. DDT1 MF-2 smooth muscle cells
      were incubated with 10 microM [3H]adenine to label adenine nucleotide pools.
      Metabolic stress with the glycolytic inhibitor iodoacetic acid (1AA, 5 mM)
      increased tritium release by 63% (P < 0.01), relative to cells treated with
      buffer alone. The IAA-induced increase was blocked by the nucleoside transport
      inhibitor nitrobenzylthioinosine (1 microM), indicating that the increased
      tritium release was primarily a purine nucleoside. HPLC verified this to be
      [3H]adenosine. The adenosine A1 receptor selective agonist N6-cyclohexyladenosine
      (CHA, 300 nM) increased the release of [3H]purine nucleoside induced by IAA
      treatment by 39% (P < 0.05). This increase was blocked by the A1 receptor
      antagonist 8-cyclopentyl-1,3-dipropylxanthine (10 microM). Treatment of cells
      with UTP (100 microM), histamine (100 microM), or phorbol-12-myristate-13-acetate
      (PMA, 10 microM) also increased [3H]purine nucleoside release. The protein kinase
      C inhibitor chelerythrine chloride (500 nM) inhibited the increase in [3H]purine
      nucleoside efflux induced by CHA or PMA treatment. The adenosine kinase activity
      of cells treated with CHA or PMA was found to be decreased significantly compared
      with buffer-treated cells. These data indicated that adenosine A1 receptor
      activation increased nucleoside efflux from metabolically stressed DDT1 MF-2
      cells by a PKC-dependent inhibition of adenosine kinase activity.

PMID- 10660115
TI  - Differential effects of retinoic acid on growth and apoptosis in human colon
      cancer cell lines associated with the induction of retinoic acid receptor beta.
AB  - Retinoids are well known as potential chemopreventive and chemotherapeutic agents
      against a variety of human cancers. Here, we report that retinoic acid (RA)
      induced differential growth inhibition in human colon cancer cell lines: while
      DLD-1, HT-29, and WiDr were relatively resistant, HCT-15 and Colo201 were
      relatively sensitive. All-trans-retinoic acid caused morphological and
      biochemical changes such as membrane shrinkage, chromatin condensation, and DNA
      cleavage, which are typical features of cells undergoing apoptosis in sensitive
      cell lines. Although retinoic acid receptor (RAR)alpha, beta, gamma and retinoid
      X receptor alpha were expressed in all cell lines examined, a significant
      induction of RARbeta by all-trans-RA was observed only in sensitive cell lines,
      suggesting important roles of RARbeta in RA sensitivity. When a vector containing
      the RARbeta gene was introduced into a relatively resistant cell line, DLD-1, the
      cells acquired RA sensitivity. Further, we found that the RARbeta transfectants
      of DLD-1 expressed an enhanced level of c-Myc and Bax proteins, which may result
      in the increased susceptibility of the cells to all-trans-RA-induced apoptosis.
      In summary, our data demonstrated that RA induced growth inhibition and apoptosis
      in human colon cancer cells and that the induction of RAR3 may mediate the
      retinoid action.

PMID- 10660116
TI  - Unique biochemical, cytotoxic, and antitumor activity of camptothecin and 4beta
      amino-4'-O-demethylepipodophyllotoxin conjugates.
AB  - Two compounds having a camptothecin (CPT) analog conjugated to the 4beta-amino-4'
      O-demethylepipodophyllotoxin analog were evaluated for their biochemical and
      biological activities. W1[camptothecin-(para)-4beta-amino-4'-O
      demethylepipodophyllotoxin] had no activity against topoisomerase II (TOP II),
      but inhibited topoisomerase I (TOP I) with an IC(50) value 2-fold higher than
      CPT. W2 [camptothecin-(ortho)-4beta-amino-4'-O-demethylepipodophyllotoxin] had
      inhibitory activity against TOP I and TOP II with IC(50) values 1.5-fold higher
      than either CPT or etoposide (VP-16). Both conjugates had similar cytotoxicity
      against the KB cell line, although the protein-linked DNA breaks (PLDBs)
      generated by W2 in KB cells were about 4-fold more than those of W1. No cross
      resistance with the two conjugates was seen in a VP-16-resistant KB subline,
      which showed down-regulation of TOP II and overexpression of the multiple drug
      resistance-associated protein, or in a vincristine-resistant KB subline with
      overexpression of gp-170/mdr-1. The CPT-resistant KB variant (KB CPT 100), which
      has a reduction in TOP I content and another mechanism that occurs post-PLDB
      formation, was partially resistant to both compounds. W1 was not affected by this
      post-PLDB resistance mechanism. Cell cycle analysis demonstrated that W1 and W1
      had similar cell cycle effects on KB and KB CPT 100 cells, which accumulated in S
      phase upon drug treatment. These results suggested that W1 and W2 exerted their
      cytotoxicity through TOP I. In CPT-resistant cells, however, an unidentified
      target also may be involved in the cytotoxic action of W1 and TOP II may still be
      a target for W1. In vivo, W1 was more effective against the growth of human
      prostate cancer cells in nude mice than VP-16, CPT, or W2. Given its antitumor
      activity and unique biochemical mechanism of action, W1 warrants exploration as
      an antitumor compound.

PMID- 10660117
TI  - Inducible nitric oxide synthase in P11 cells: expression in the presence of
      interferon-gamma, lipopolysaccharide, and modified serum.
AB  - P11 cells, derived from the transplantahle rat pituitary tumor 7315a, have been
      used previously ias a model system to study the regulation of serotonin2A (5
      HT2A) receptor expression. As our laboratory has been interested in
      characterizing the interactions between the 5-HT2A receptor and inducible nitric
      oxide synthase (iNOS), we have analyzed the Pl I cell line for iNOS expression.
      Treatment of P ll cells with interferon-gamma and lipopolysaccharide resulted in
      a 23-fold increase in nitrite production and induced expression of iNOS protein.
      The increase in nitrite levels was attenuated by the non-selective nitric oxide
      synthase (NOS) inhibitor N i-nitro-L-arginine methyl ester, hut not the neuronal
      NOS inhibitor 7-nitroindazole. Typically, Pl 11 cells have been grown in either
      charcoal-stripped or dialyzed serum-containing medium. We have observed that Pl 1
      cells grown under these culture conditions express basal iNOS activity, as
      evidenced by a 5-fold increase in nitrite accumulation over a 48-hr period,
      compared with that in cells grown in non-modified serum, which was inhibited by
      the selective iNOS inhibitor L.N6-(1-iminoethyl)-lysine. Conditioned medium from
      Pll cells was ahle to stimulate nitrite accumulation in C6 glioma cells,
      suggesting that the Pl I cells may produce a pro-inflammatory-like factor. As pro
      inflammatory cytokines have been shown to modify hormone secretion from the
      anterior pituitary, the P11 cell line may be a useful in vitro model by which to
      characterize the function of cells from this organ. In addition, our data suggest
      that alteration of the microenvironment of the anterior pituitary may result in
      iNOS expression, possibly altering the function of the hypothalamic-pituitary
      adrenal axis.

PMID- 10660118
TI  - Biochemical and functional characterization of 1-benzyl substituted trimetoquinol
      affinity analogs on rat and human beta-adrenoceptors.
AB  - The site of interaction for the 1-(3',4',5'-trimethoxybenzyl) group of
      trimetoquinol (TMQ) with beta-adrenoceptors (beta-ARs) is important for the
      rational design of highly potent and beta3-AR-selective analogs. 1-Benzyl ring
      substituted TMQ analogs were evaluated for binding affinities and biochemical
      activities (cyclic AMP accumulations) in Chinese hamster ovary (CHO) cells
      expressing the rat and human beta3-AR, and for functional activities on isolated
      rat tissues. Binding affinities (K1 approximately 0.055 to 1.5 microM) for the
      rat beta3-AR and potencies for adenylyl cyclase activation (K(act) approximately
      0.43 to 2;5 nM) of the 3'-monoiodo or 3',5'-diiodo derivatives with 4'
      isothiocyanato-, 4'-amino, 4'-acetamido, or 4'-alpha-haloacetamido substitutions
      were higher than those of (-)-isoproterenol, and comparable to those of BRL 37344
      [(+/-)-(R*,R*-[4-[2-[[2-(3-chlorophenyl)-2-hydroxy-ethyl]amino]propyl]ph enoxy]
      acetic acid sodium]. A similar rank order of binding affinities (K(i)
      approximately 0.11 to 2.5 microM) and potencies (K(act) approximately 0.45 to 9.5
      nM) was obtained for TMQ analogs on the human beta3-AR. The 4'-acetamido and 4'
      alpha-chloroacetamido analogs of 3',5'-diiodoTMQ were more potent than (-)
      isoproterenol in rat atria (beta1-AR) and rat trachea (beta2-AR) and exhibited
      partial agonist activities, whereas full agonist activities were observed in rat
      esophageal smooth muscle (EC50 approximately 2-8 nM, beta3-AR). 4'-alpha
      Chloroacetamido-3',5'-diiodoTMQ-mediated chronotropic responses in atria were
      sustained and resistant to washout. Further, the 4'-alpha-chloroacetamido and 4'
      alpha-bromoacetamido analogs of 3',5'-diiodoTMQ demonstrated significant
      concentration-dependent irreversible binding to the rat beta3-AR. Reversible beta
      AR agonists such as (-)-isoproterenol, BRL 37344, and 4'-acetamido-3',5'
      diiodoTMQ or nucleophilic 1-amino acids (lysine, glutathione, cysteine) did not
      protect against this irreversible binding. Thus, the lipophilic 1-benzyl ring of
      TMQ analogs interacts with a hydrophobic region of the beta-AR that may represent
      an exo-site or an allosteric binding site.

PMID- 10660119
TI  - Role of cytochrome P450 and glutathione S-transferase alpha in the metabolism and
      cytotoxicity of trichloroethylene in rat kidney.
AB  - The toxicity and metabolism of trichloroethylene (TRI) were studied in renal
      proximal tubular (PT) and distal tubular (DT) cells from male Fischer 344 rats.
      TRI was slightly toxic to both PT and DT cells, and inhibition of cytochrome P450
      (P450; substrate, reduced-flavoprotein:oxygen oxidoreductase [RH-hydroxylating or
      -epoxidizing]; EC 1.14.14.1) increased TRI toxicity only in DT cells. In
      untreated cells, glutathione (GSH) conjugation of TRI to form S-(1,2
      dichlorovinyl)glutathione (DCVG) was detected only in PT cells. Inhibition of
      P450 transiently increased DCVG formation in PT cells and resulted in detection
      of DCVG formation in DT cells. Formation of DCVG in PT cells was described by a
      two-component model (apparent Vmax values of 0.65 and 0.47 nmol/min per mg
      protein and Km values of 2.91 and 0.46 mM). Cytosol isolated from rat renal
      cortical, PT, and DT cells expressed high levels of GSH S-transferase (GST;
      RX:glutathione R-transferase; EC 2.5.1.18) alpha (GSTalpha) but not GSTpi. Low
      levels of GSTmu were detected in cortical and DT cells. Purified rat GSTalpha2-2
      exhibited markedly higher affinity for TRI than did GSTalpha1-1 or GSTalpha1-2,
      but each isoform exhibited similar VmaX values. Triethyltinbromide (TETB) (9
      microM) inhibited DCVG formation by purified GSTalpha-1 and GSTalpha2-2, but not
      GSTalpha1-2. Bromosulfophthalein (BSP) (4 microM) only inhibited DCVG formation
      by GSTalpha2-2. TETB and BSP inhibited approximately 90% of DCVG formation in PT
      cytosol but had no effect in DT cytosol. This suggests that GSTalpha1-1 is the
      primary isoform in rat renal PT cells responsible for GSH conjugation of TRI.
      These data, for the first time, describe the metabolism of TRI by individual GST
      isoforms and suggest that DCVG feedback inhibits TRI metabolism by GSTs.

PMID- 10660120
TI  - Effects of inhibitors of guanine nucleotide synthesis on membrane potential and
      cytosolic free Ca2+ levels in insulin-secreting cells.
AB  - Adenine nucleotides play an important role in the control of membrane potential
      by acting on ATP-sensitive K+ (K(ATP)) channels and, in turn, modulating the open
      probability of voltage-gated Ca2+ channels in pancreatic islet beta-cells. Here,
      we provide evidence that guanine nucleotides (GNs) also may be involved in the
      modulation of these events in vivo. GNs were depleted by treatment of HIT-T15
      cells with mycophenolic acid (MPA). Resting membrane potential was more
      depolarized in cells treated for 3 and 6 hr with MPA than in control cells, and
      this effect was inhibited by diazoxide. After 6 hr of exposure to MPA, basal
      cytosolic free Ca2+ concentrations ([Ca2+]i) were elevated by 20%. Increments in
      [Ca2+]i induced by submaximal concentrations of K+ (10-15 mM) or bombesin were
      enhanced by > 50%. Opening K(ATP) channels with diazoxide lowered basal [Ca2+]i
      in MPA-treated cells to normal and abrogated the enhanced [Ca2+]i responses.
      However, an L-type Ca2+ channel blocker only abolished the enhanced [Ca2+]i
      response to stimuli and had no effect on the elevated basal [Ca2+]i, in contrast
      to EGTA, which obliterated both, implying that the latter was due to Ca2+ influx
      via non-L-type Ca2+ channels. These effects on ion fluxes were attributable
      specifically to GN depletion, since guanosine, which restores GTP content and the
      GTP/GDP ratio, but not adenosine, prevented all MPA-induced ion changes;
      furthermore, the latter were mimicked by mizoribine (a structurally dissimilar
      GTP synthesis inhibitor). It is concluded that, in addition to adenine
      nucleotides, GNs might contribute to the modulation of K(ATP) channels in intact
      beta-cells. In addition, GN depletion appeared to be able to reduce stimulated
      insulin secretion by a mechanism largely independent of the changes of ion fluxes
      observed above.

PMID- 10660121
TI  - Nitric oxide-independent effects of nitric oxide donors on energy metabolism in
      erythrocytes.
AB  - In order to study the roles of nitric oxide (NO) in various biological events,
      several types of NO-releasing agents have been extensively used. Although both NO
      and its donors and/or their decomposed products may have biological activities,
      most of the cellular responses to these donors have been postulated to reflect NO
      dependent events. Among the various NO donors, 1-hydroxy-2-oxo-3-(N-methyl
      aminopropyl)-3-methyl-l-triazene (NOC7), 3-morpholinosydnonimine N-ethylcarbamide
      (SIN-1), S-nitrosoglutathione, S-nitrosocysteine (CysNO), and related
      nitrosothiols are commonly used agents. To investigate the biological activities
      of these donors and their decomposed products, we tested their effects on energy
      metabolism in erythrocytes. When incubated with freshly prepared erythrocytes,
      NOC7, Cys-NO, and their decomposed products, but not NO and its oxidized
      metabolites, nitrite and nitrate, decreased cellular ATP levels. Although SIN-1
      generates both NO and superoxide radical thereby forming peroxynitrite (ONOO-),
      this donor had no appreciable effect on cellular ATP levels, even in the presence
      of superoxide dismutase. These results indicate that NOC7 and CysNO and/or their
      decomposed product(s), but not NO and its oxidized metabolites, are responsible
      for the decrease in cellular ATP levels. Thus, the effects of not only NO and its
      oxidized metabolites (NO2, NO3 ), but also NO donors and their decomposed
      products, should be taken into account when attempting to understand the
      mechanism of biological responses induced by NO donors.

PMID- 10660123
TI  - Multiple forms of cytochrome P450 and associated monooxygenase activities in
      human brain mitochondria.
AB  - We have investigated cytochrome P450 (P450) and associated monooxygenase
      activities in human brain mitochondria isolated from eight regions of four human
      brain samples obtained at autopsy. P450-associated monooxygenase activities
      including aminopyrine N-demethylase (APD), 7-ethoxycoumarin O-deethylase (ECD), p
      nitrophenol hydroxylase (PNPH), and N-nitrosodimethylamine N-demethylase (ND-MAD)
      were detectable in the mitochondria from human brain regions. Immunoblot
      experiments using antisera to purified rat liver microsomal P450, namely
      P4502B1/2, P4501A1/2, and P4502E1, revealed immunoreactive bands in isolated
      mitochondria from different regions of the human brain. The antibody to P4502B1/2
      and P4501A1/2 inhibited the human brain mitochondrial APD and ECD activities,
      respectively. The addition of antiserum to microsomal NADPH cytochrome P450
      reductase did not affect the mitochondrial P450-associated monooxygenase
      activities, although it completely inhibited the corresponding activities in
      brain microsomes. Overall, the present study demonstrates, in human brain
      mitochondria, the presence of multiple forms of P450 belonging to the 1A, 2B, and
      2E subfamilies that are involved in xenobiotic metabolism.

PMID- 10660122
TI  - Stimulation of dichlorofluorescin oxidation by capsaicin and analogues in RAW 264
      monocyte/macrophages: lack of involvement of the vanilloid receptor.
AB  - In studies into the oxidative burst in RAW 264 monocyte/macrophages, it was
      observed that capsaicin, a vanilloid receptor agonist, stimulated
      dichlorofluorescin (DCFH) oxidation in a concentration-dependent manner, which
      could be blocked by capsazepine, a vanilloid receptor antagonist. However, by use
      of a number of vanilloid agonists (including N-octyl-3-chloro-4
      hydroxyphenylacetamide, 4m), we demonstrated that there was no relationship
      between vanilloid agonist potency and the capacity to stimulate DCFH oxidation.
      The oxidative burst stimulators Tween 20 and phorbol myristyl acetate (PMA) also
      stimulated reactive oxygen species generation, which again was inhibited by
      capsazepine. Use of the selective inhibitor diphenyliodonium iodide ruled out a
      role for plasma membrane NAD(P)H oxidase as the site of capsaicin- and 4m
      stimulated DCFH oxidation. However, this DCFH oxidation was modulated by a number
      of inhibitors of mitochondrial respiration. Rotenone enhanced DCFH oxidation
      induced by capsaicin and 4m, whilst malonic acid and potassium cyanide inhibited
      this response. 2,4-Dinitrophenol, an inhibitor of oxidative phosphorylation, was
      without effect. The antioxidant trolox c inhibited DCFH oxidation stimulated by
      capsaicin, 4m, and PMA, whereas N-acetylcysteine, a precursor of glutathione, was
      without effect. Capsazepine inhibited DCFH oxidation in unstimulated cells and in
      cells treated with menadione, a redox-cycling quinone. Capsazepine was also a
      potent antioxidant when measured in a Fe3+ reduction assay. We concluded that
      DCFH oxidation stimulated by vanilloid analogues was not mediated via a vanilloid
      receptor, but rather by impairment of mitochondrial electron transport.

PMID- 10660124
TI  - Growth hormone-regulated periportal expression of CYP2C7 in rat liver.
AB  - Most drug- and steroid-metabolizing cytochrome P450 (CYP) enzymes are expressed
      in the mammalian liver in a characteristic zonated pattern, with high expression
      in the downstream perivenous (centrilobular) region. Here, we report that CYP2C7,
      a member of the rat CYP2 family, is expressed preferentially in the opposite,
      periportal region. CYP2C7 mRNA, as detected by reverse transcription-polymerase
      chain reaction, was detected almost exclusively in cell lysates obtained from the
      periportal region, indicating a very steep acinar gradient. The amount of
      immunoreactive CYP2C7 protein in periportal cell lysates was also higher than in
      samples from the perivenous region. This gradient was reversed by hypophysectomy,
      which markedly and selectively reduced the periportal CYP2C7 protein content.
      Subsequent growth hormone infusion by osmotic minipumps restored the zonation by
      selectively increasing the amount of periportal CYP2C7 protein. Although
      hypophysectomy suppressed CYP2C7 mRNA and growth hormone counteracted it,
      regulation at this level did not appear to occur in a zone-specific fashion. This
      indicates that growth hormone-mediated zonal regulation of CYP2C7 protein has
      additional translational or posttranslational components. Ethanol treatment,
      which has been shown to affect growth hormone levels, significantly induced
      CYP2C7 mRNA, but not zone specifically. Our results demonstrate that growth
      hormone up-regulates the CYP2C7 gene by enhancing the expression of the protein
      specifically in the periportal liver region. Growth hormone may up-regulate other
      periportally expressed liver genes in a similar fashion.

PMID- 10660125
TI  - Selective binding of the truncated form of the chemokine CKbeta8 (25-99) to CC
      chemokine receptor 1(CCR1).
AB  - Human CC chemokine receptor 1 (CCR1) has been proposed as a receptor for CKbeta8.
      To obtain conclusive evidence, binding-displacement studies of 125I-CKbeta8 (25
      99) were performed on membranes of Chinese hamster ovary cells expressing human
      CCR1. The Ic50 for displacement of 125I-CKbeta8 (25-99) with CKbeta8 (25-99) was
      0.22 nM. The longer forms of CKbeta8 (24-99 and 1-99) also displaced 125I
      CKbeta8, with Ic50 values of 6.5 and 16 nM, respectively. Displacement profiles
      of 125I-CKbeta8 (25-99) on freshly prepared human monocytes indicated that CCR1
      was the major receptor for CKbeta8. We conclude that CCR1 is a receptor for
      different-length CKbeta8 and that CKbeta8 (25-99) has a similar affinity for CCR1
      as macrophage inflammatory protein-1alpha (MIP-1alpha). The longer variants of
      CKbeta8 are significantly less potent than CKbeta8 (25-99) and MIP-1a on CCR1 and
      monocytes (P < 0.05).

PMID- 10660126
TI  - Perspectives in dermatopathology: telomeres and telomerase in ageing and cancer;
      with emphasis on cutaneous disease.
AB  - Shortening of telomeres occurs with cell proliferation and correlates well with
      ageing in humans. Telomerase is a ribonucleoprotein, and is the body's most
      widely studied mechanism for extension of telomeres to circumvent cellular
      ageing. Telomerase levels remain at low or unmeasurable levels in most somatic
      cell populations with only a few exceptions. However, in transformed cell
      populations, upregulation of telomerase or some other mechanism for telomere
      extension is required for immortality. The telomere-telomerase system has been
      proposed to be an adaptation of organisms with prolonged lifespan to avoid
      malignant tumors, at the cost of the cellular dysfunctions associated with the
      aged phenotype. Therapies to modulate telomere length and telomerase levels hold
      promise for therapy of cancer and ageing as well as for genetic conditions that
      predispose to an aged phenotype.

PMID- 10660127
TI  - Encapsulated fat necrosis--a clinicopathological study of 8 cases and a
      literature review.
AB  - Eight cases of encapsulated fat necrosis are described. The patients were two
      males and six females from 10 to 77 years of age. The majority of the lesions
      clinically presented as asymptomatic, multiple, mobile, small nodules. All
      patients were treated by simple excisions of the nodules. Grossly, the lesions
      were whitish-yellow in color, smoothly-surfaced, round nodules measuring 3 to 20
      mm in the greatest diameter. Histopathologically, the nodules were basically
      composed of variably degenerated and necrotic fatty tissue covered by fibrous
      connective tissue capsule associated with occasional calcification and
      inflammatory cell infiltrates. Among several terms proposed for this disease,
      encapsulated fat necrosis is considered most preferable term based on the
      clinical and histological findings of the present and reported cases.

PMID- 10660128
TI  - Expression of desmoglein I and plakoglobin in skin carcinomas.
AB  - Reduction or absence of cell-cell adhesion molecules has been reported in various
      carinomas and the abnormal expression of these molecules contributes to the
      invasive and metastatic behavior of malignant tumor cells. In epidermal
      keratinocytes, the main cell-cell adhesion systems are adherens junctions and
      desmosomes. Previous studies have shown that, in skin carcinomas, the decreased
      expression of E-cadherin, major constitutional glycoprotein of adherens
      junctions, is associated with the invasive and metastatic ability of the tumor
      cells. In the present study, we examined the expression of desmoglein I and
      plakoglobin, the constitutional components of desmosomes, in various skin
      carcinomas such as basal cell carcinoma (BCC), squamous cell carcinoma (SCC),
      extramammary Paget's disease and Bowen's disease by an immunofluorescence method.
      In normal human skin, desmoglein I and plakoglobin were strongly expressed in the
      intercellular space of the epidermis except for the basal cell layer. In BCC and
      SCC, the expression of desmoglein I and plakoglobin was markedly reduced or
      absent in tumor cells. In carcinoma in situ of Paget's disease, compared with the
      normal epidermal cells surrounding tumor cell nests, the expression of these
      molecules was reduced in tumor cells. In Paget's disease with dermal infiltration
      of tumor cells, the expression of these molecules was almost absent throughout
      the epidermis. In Bowen's disease, the expression of desmoglein I was reduced in
      the dumping cells and dyskeratotic cells. These results suggest that the
      expression of desmosomal cadherin is reduced or absent in human skin carcinomas,
      and that reduction of these molecules may also contribute to the invasiveness and
      metastasis of skin carcinomas.

PMID- 10660129
TI  - Genetic changes in sweat gland carcinomas.
AB  - The molecular pathogenesis of malignant appendageal tumors is poorly understood.
      Immunohistochemical staining, polymerase chain reaction (PCR)-based loss of
      heterozygosity (LOH) and sequencing analyses were performed in a mixed group of
      21 sweat gland carcinomas. LOH was mostly confined to the chromosome arm 17p.
      None of the remaining 17 tumors showed LOH at any loci. Nuclear accumulation of
      p53 protein was observed in 3 tumors, all of which also showed LOH of 17p. One
      eccrine gland adenocarcinoma showed allelic loss of 17p and a Cys 176 Arg
      mutation in the p53 gene. The other three tumors that showed LOH of 17p, however,
      had wild-type p53 genes. A clear transition from benign eccrine poroma to
      porocarcinoma that was associated with p53 protein stabilization and allelic loss
      was observed in one tumor. One eccrine porocarcinoma/undifferentiated adnexal
      carcinoma showed prominent microsatellite instability, probably reflecting an
      underlying defect in DNA mismatch repair. Overexpression of erbB-2 was observed
      in three tumors. The low frequencies of LOH and p53 alterations in sweat gland
      carcinomas contrasted with the multiple genetic defects normally observed in
      cutaneous squamous cell carcinomas, and may be partly explained by the relative
      protection of cutaneous appendages from ultraviolet light and other environmental
      mutagens.

PMID- 10660130
TI  - Dermatofibroma is a clonal proliferative disease.
AB  - Benign fibrous histiocytoma of the skin or dermatofibroma (DF) has been regarded
      as a fibrohistiocytic tumor. Whether DF is a neoplastic growth or a reactive
      process has not been settled. Since a neoplastic process is clonal in nature,
      clonal analysis of DF was conducted to see if DF is a clonal disease. Fresh
      specimens of 13 DFs and 2 hypertrophic scars obtained from female patients were
      studied. The adjacent nonlesional skin tissues served as controls. The clonal
      analysis was based on the methylation pattern of the polymorphic X-chromosome
      linked androgen-receptor gene (HUMARA). Eight DFs and 1 hypertrophic scar were
      heterozygous at the androgen receptor gene and could be analyzed. All 8
      informative DFs showed a significant reduction in one of the allelic bands
      compared with the corresponding bands of the nonlesional tissue after Hha I
      digestion. Therefore, DF is a clonal proliferative disease. In contrast, 1
      hypertrophic scar showed a polyclonal pattern of X-chromosome inactivation. We
      conclude that DF is a clonal disease favoring a neoplastic process.

PMID- 10660131
TI  - Cutaneous collagenous vasculopathy with generalized telangiectasia: an
      immunohistochemical and ultrastructural study.
AB  - We report a 54-year-old male, with a 5-year history of spreading asymptomatic
      generalized cutaneous telangiectases. The patient had no mucosal or nail
      involvement, no positive family history and no clinical evidence of systemic
      disease or bleeding diathesis. Histologically, the superficial small dermal blood
      vessels were dilated and showed thickened walls with hyaline perivascular
      material, staining as collagen. The vessel walls were PAS and colloidal iron
      stain positive, and immuno-histochemically lacked actin staining. Collagen IV,
      fibronectin and laminin antibodies showed the material deposited around the
      basement membrane zone. Ultrastructurally, the vessels were post-capillary
      venules (PCV) and showed marked collagen deposition around the basal lamina.
      There were many abnormally banded widely spaced fibres with 100-150 nm
      periodicity (Luse bodies), in addition to regular banded collagen. Pericytes were
      sparse and lacked intracytoplasmic filaments, and few veil or fibroblastic cells
      were seen embedded within the collagen. We believe this is a form of cutaneous
      microangiopathy not previously described, with distinct morphology and unique
      ultrastructural features. It may be due to a genetic defect with erroneous
      production of disorganized collagen in the cutaneous microvasculature.
      Dermatologists and Dermatopathologists should be aware of this unusual cutaneous
      vasculopathy.

PMID- 10660132
TI  - Lipedematous alopecia: a clinicopathologic, histologic and ultrastructural study.
AB  - Lipedematous alopecia is a rare condition of unknown etiology characterized by a
      thick, boggy scalp with varying degrees of hair loss that occurs in adult black
      females, with no clearly associated medical or physiologic conditions. The
      fundamental pathologic finding consists of an approximate doubling in scalp
      thickness resulting from expansion of the subcutaneous fat layer in the absence
      of adipose tissue hypertrophy or hyperplasia. Observations by light and electron
      microscopy detailed in this report suggest that this alteration principally
      manifests by localized edema with disruption and degeneration of adipose tissue.
      Some diminution in the number of follicles as well as focal bulb atrophy is
      noted. Aberrant mucin deposition such as that seen in myxedema or other cutaneous
      mucinoses is not a feature. The histologic findings bear some resemblance to
      those seen in lipedema of the legs, a relatively common but infrequently
      diagnosed condition. We present a case of lipedematous alopecia with emphasis on
      histologic and ultrastructural features. The etiology is unknown.

PMID- 10660133
TI  - Multiple eruptive dermatofibromas in a patient with HIV infection: case report
      and literature review.
AB  - Multiple eruptive dermatofibromas have been reported in the setting of autoimmune
      diseases treated with immunosuppressive drugs and more recently in the course of
      human immunodeficiency virus (HIV) infection. We report herein the ninth case of
      multiple eruptive dermato fibromas associated with HIV infection. The relevant
      literature is reviewed and the differences of these lesions from "ordinary"
      dermatofibromas are discussed.

PMID- 10660134
TI  - Is streptolysin S of group A streptococci a virulence factor?
AB  - The possible role played by streptolysin S (SLS) of group A streptococci in the
      pathophysiology of streptococcal infections and in post-streptococcal sequelae is
      discussed. The following properties of SLS justify its definition as a distinct
      virulence factor: 1) its presence on the streptococcus surface in a cell-bound
      form, 2) its continuous and prolonged synthesis by resting streptococci, 3) its
      non-immunogenicity, 4) its extractability by serum proteins (albumin, alpha
      lipoprotein), 5) its ability to become transferred directly to target cells while
      being protected from inhibitory agents in the milieu of inflammation, 6) its
      ability to bore holes in the membrane phospholipids in a large variety of
      mammalian cells, 7) its ability to synergize with oxidants, proteolytic enzymes,
      and with additional host-derived proinflammatory agonists, and 8) its absence in
      streptococcal mutants associated with a lower pathogenicity for animals. Because
      tissue damage in streptococcal and post-streptococcal sequelae might be the end
      result of a distinct synergism between streptococcal and host-derived
      proinflammatory agonists it is proposed that only cocktails of anti-inflammatory
      agents including distinct inhibitors of SLS (phospholipids), gamma globulin,
      inhibitors of reactive oxygen species, proteinases, cationic proteins cytokines
      etc., will be effective in inhibiting the multiple synergistic interactions which
      lead to fasciitis, myositis and the flesh-eating syndromes, and often develop
      into sepsis, septic shock and multiple organ failure. The creation of mutants
      deficient in SLS and in proteases will help shed light on the specific role
      played by SLS in the virulence of group A hemolytic streptococci.

PMID- 10660135
TI  - Low occurrence of antibiotic resistance in Escherichia coli and staphylococci
      isolated from blood cultures in two Norwegian hospitals in 1991-92 and 1995-96.
AB  - The aim of this study was to investigate the antibiotic resistance rates of major
      bacterial pathogens causing bloodstream infections in two very different types of
      hospital in Norway. We examined all Escherichia coli and staphylococci (330
      isolates) causing bloodstream infections from one general county hospital and one
      specialist national cancer hospital during the periods 1991-92 and 1995-96.
      Minimal inhibitory concentrations (MICs) were determined using the E-test. E.
      coli and staphylococci constituted 46.7% of all isolates from bloodstream
      infections in the two hospitals. Overall, E. coli isolates were resistant to
      amoxicillin (21%), trimethoprim (21%), doxycycline (20%) and trimethoprim
      sulphamethoxazole (17%), while Staphylococcus aureus strains were resistant to
      benzylpenicillin (66%). No methicillin-resistant S. aureus was detected.
      Coagulase-negative staphylococci were often multiresistant, but remained fully
      sensitive to vancomycin. For a few antibiotics, significantly more resistance was
      found in the specialist hospital. In our material we found no significant
      increase in resistance between 1991-92 and 1995-96. In conclusion, antimicrobial
      resistance still remains low in important bacterial pathogens causing bloodstream
      infections in Norway.

PMID- 10660136
TI  - Serological response to Helicobacter pylori recombinant antigens in Chilean
      infected patients with duodenal ulcer, non-ulcer dyspepsia and gastric cancer.
AB  - We have previously cloned 10 Helicobacter pylori antigen genes from a Chilean
      strain including: cytotoxin VacA, a truncated region of CagA (called A17), a
      species-specific protein (Ag26), urease subunits (UreA, UreB), a flagellin,
      (FlaB), heat shock proteins (HspA and HspB), an adhesin (HpaA) and a lipoprotein
      (Lpp20). Immunogenicity of these antigens was tested by immunoblot with sera of
      Chilean infected patients, revealing that HpaA, A17, HspB and VacA were more
      frequently recognized (86%, 82%, 68% and 68%, respectively). According to the
      clinical condition, it was determined that Lpp20 was preferentially recognized by
      sera from non-ulcer dyspepsia patients (80%), A17 and VacA by patients with
      duodenal ulcer (92% and 83% respectively), and HspB by patients with duodenal
      ulcer (83%) and gastric cancer (90%). An ELISA was developed with a purified
      mixture of A17 and VacA antigens to test the different groups of patients. It was
      found that sera from duodenal ulcer patients showed higher values than those from
      non-ulcer dyspepsia patients, but this difference was not significant (p<0.2).
      Moreover, sera from gastric cancer patients showed values lower than those from
      non-ulcer dyspepsia patients (p<0.019). These results indicate that, in the
      Chilean population, antibodies raised against VacA and A 7 are not markers either
      for duodenal ulcer or for gastric cancer.

PMID- 10660137
TI  - The discriminatory power of ribo-PCR compared to conventional ribotyping for
      epidemiological purposes.
AB  - Molecular typing techniques have become increasingly important for confirmation
      of epidemiological relationships and delimitation of nosocomial outbreaks. The
      discriminatory power of the two DNA-based typing methods, conventional ribotyping
      and ribo-PCR, was assessed to distinguish between selected strains of
      Acinetobacter calcoaceticus, Enterobacter cloacae, Serratia marcescens and
      Pseudomonas aeruginosa. Overall, conventional ribotyping was more discriminatory
      than ribo-PCR.

PMID- 10660138
TI  - Clinical and histopathological tumour progression in ECL cell carcinoids
      ("ECLomas").
AB  - AIMS: The aims of this study were to illustrate the malignant potential of
      gastric enterochromaffin-like (ECL) cell carcinoids (ECLomas) associated with
      hypergastrinemia, and the gradual neoplastic progression of such tumours. In
      addition, we examined whether the tyramide signal amplification (TSA) technique
      could visualize immunohistochemical (IHC) neuroendocrine (NE) features in the
      dedifferentiated neoplastic ECL cells which were not detected by conventional
      methods. METHODS: Conventional histopathological and IHC methods for visualizing
      ECL cells and cell proliferation were used in addition to the TSA technique.
      OBSERVATIONS: Our patient was followed for 5 years. During that period, her
      ECLoma displayed all the signs of classical tumour progression, ultimately with
      the appearance of metastases in the regional lymph nodes, the liver and the skin.
      The neoplastic ECL cells became progressively dedifferentiated with an increasing
      number of Ki-67 immunoreactive (IR) cell nuclei. In addition, there was a
      substantial decrease in argyrophil and IR NE cells that could be visualized by
      conventional methods. By applying the TSA technique, however, the number of IR
      tumour cells increased considerably. CONCLUSIONS: ECLomas secondary to
      hypergastrinemia should be closely followed for signs of clinical and
      histopathological tumour progression. Such ECLomas deserve early, active, radical
      surgical treatment. The TSA technique is a valuable tool for visualizing the
      characteristic IHC features in dedifferentiated NE cells.

PMID- 10660139
TI  - Early immune response in susceptible and resistant mice strains with chronic
      Pseudomonas aeruginosa lung infection determines the type of T-helper cell
      response.
AB  - Most cystic fibrosis (CF) patients become chronically infected with Pseudomonas
      aeruginosa in the lungs. The infection is characterized by a pronounced antibody
      response and a persistant inflammation dominated by polymorphonuclear
      neutrophils. Moreover a high antibody response correlates with a poor prognosis.
      We speculated that a change from this Th2-like response to a Th1-like response
      might decrease the lung inflammation and thus improve the prognosis in CF
      patients. To investigate this, we infected C3H/HeN and BALB/c mice
      intratracheally with P. aeruginosa. In addition, we studied the early immune
      response leading to different Th responses. Mortality was lower in the C3H/HeN
      mice (p<0.005), they cleared the bacteria faster (day 3 p<0.01, day 7 p<0.02),
      had a milder lung inflammation (day 7 p<0.01, day 14 p< or =0.0005) and had a Th1
      like IgG subclass switch. At day 3, the C3H/HeN mice produced less NO and TNF
      alpha, (p<0.01 and p<0.03) and had the lowest IL-10/IL-12 ratio (p< or =0.05). At
      day 7, the C3H/HeN mice had the highest IFN-gamma (p<0.02), and the lowest IL-4
      (p<0.02) production in the lungs. In conclusion, these results show that the Th1
      reacting C3H/HeN mice with chronic P. aeruginosa lung infection have a better
      disease outcome compared to the Th2-reacting BALB/c mice, indicating that a Th1
      response might be beneficial in CF patients with chronic P. aeruginosa lung
      infection.

PMID- 10660140
TI  - Immunohistochemical localization of FAP-1, an inhibitor of Fas-mediated
      apoptosis, in normal and neoplastic human tissues.
AB  - Fas, a death receptor, is widely expressed in human tissue, but its expression,
      although a prerequisite for the induction of apoptosis, does not predict its
      biological function. To understand the mechanisms of Fas resistance in human
      tissues in vivo, we performed immunohistochemistry using an antibody against Fas
      associated phosphatase-1 (FAP-1), which interacts with the cytosolic domain of
      Fas and inhibits Fas-mediated apoptosis. In normal human tissues, FAP-1
      immunostaining was easily detected, for example, in renal tubules, skeletal
      muscle, myocardiocytes, pituitary gland, parathyroid gland, pancreatic islets,
      hepatocytes, testicular germ cells, prostatic glands, neurons, epithelium of
      fallopian tube, endometrial glands, trophoblasts, bronchial epithelial cells, and
      some types of gastrointestinal epithelial cells. In 123 (78%) of 158 cancers of
      various origins, including breast carcinomas, stomach carcinomas, colon
      carcinomas, lung carcinomas and several types of sarcomas, variable intensities
      of FAP-1 expression were evident. Taken together, these findings demonstrated
      that FAP-1 is widely expressed in normal human tissues and partly overlapped with
      Fas expression described in earlier reports, suggesting that FAP-1 may have an
      important role in the regulation of apoptosis in vivo. In addition, FAP-1
      expression in cancers suggests that many cancers may be resistant to Fas-mediated
      apoptosis through the action of FAP-1 in vivo.

PMID- 10660141
TI  - Rapid identification of mutations in a multidrug efflux pump in Pseudomonas
      aeruginosa.
AB  - The gene mexR regulates negatively the expression of the MexA-MexB-OprM efflux
      pump in Pseudomonas aeruginosa, and mutations in mexR cause a multiple antibiotic
      resistance phenotype. Five hundred and forty resistant clones of P. aeruginosa
      PAO503 were isolated after selection for resistance to chloramphenicol or
      tetracycline. All isolates showed similar phenotypes and were resistant to
      tetracycline, chloramphenicol and norfloxacin. Nineteen randomly selected
      isolates were analyzed. Since mutational analysis by direct sequencing of all
      regions of interest in several strains is time-consuming and expensive, a
      screening method, Non-Isotopic RNase Cleavage Assay (NIRCA), was applied to
      identify mutant genes so that they could be targeted for DNA sequencing. NIRCA is
      a simple but rapid method for mutational analysis and can be performed in 3-4 h.
      Results of NIRCA analysis were compared with DNA sequencing. Both NIRCA and DNA
      sequencing analysis showed mexR gene mutations in 11 of 19 isolates but no
      alterations in 8 strains. An immunoblot assay showed overexpression of OprN, a
      component of another multidrug efflux pump, MexE-MexF-OprN, in those eight
      isolates. Nucleotide sequencing of quinolone resistance-determining regions of
      DNA gyrase (gyrA) or topoisomerase IV (parC) showed no alterations in any of the
      19 mutants. The data indicate that two efflux pump systems, MexA-MexB-OprM and
      MexE-MexF-OprN, were involved in multidrug resistance including quinolones and
      that NIRCA is a sensitive method for screening mutations.

PMID- 10660142
TI  - Proinflammatory activation of neutrophils and monocytes by Helicobacter pylori is
      not associated with cagA, vacA or picB genotypes.
AB  - Chronic Helicobacter pylori infection is associated with mucosal inflammation.
      The aim of the present study was to assess human neutrophil and monocyte
      activation induced by H. pylori strains with different virulence genotypes.
      Bacterial sonicates from 12 strains were used to induce phagocyte up-regulation
      of adherence molecule CD11b, assessed by fluorescence flow cytometry, and
      oxidative burst responses, assessed by chemiluminescence. A dose-dependent
      induction of the expression of CD11b was observed with sonicate from all H.
      pylori strains on both neutrophils and monocytes. Strains negative for cagA and
      picB genes had the same inducing activity of upregulation of CD11b as strains
      positive for these genes. A vacA-S2 type strain had the same activity as vacA-S1
      type strains. The induction of toxic oxygen radicals by H. pylori-activated
      neutrophils gave higher median values for the cagA-positive strains than for the
      cagA-negative strains. For the monocyte chemiluminescence response, cagA-negative
      strains gave higher median values compared to cagA-positive strains. We conclude
      that upregulation of the neutrophil and monocyte adherence molecule CD11b induced
      by H. pylori sonicates is not associated with the presence of cagA, picB or
      mosaic pattern of vacA, and that cagA, picB-negative strains and vacA-S2 strains
      retain their inflammatory capacity.

PMID- 10660143
TI  - Blood levels of CD11b+ memory T lymphocytes are selectively upregulated in
      patients with active rheumatoid arthritis.
AB  - The adhesion molecules CD11b (a beta2-integrin component) and CD54 (ICAM-1) on
      blood leukocytes were studied by flow cytometry in patients with rheumatoid
      arthritis (RA). The fractions of CD4+ cells co-expressing CD11b were elevated in
      16 patients with active RA compared with those in 16 RA patients who improved
      during therapy and 8 healthy controls: 0.8+/-0.12% (mean+/-SEM) versus 0.3+/
      0.06% (p<0.002) and 0.3+/-0.06% (p<0.005), respectively. Increased levels of
      CD11b+CD45R0+ cells were observed in patients with active RA compared to those
      with improved RA and controls: 12.6+/-3.9% versus 4.8+/-2.7% (p<0.002) and 6.1+/
      1.2% (p<0.003), respectively. Disease activity, determined by C-reactive protein,
      correlated with the numbers of CD11b+CD45R0+ cells: r=0.62 (p<0.001). Seven
      patients were followed during induction of remission with methotrexate and
      glucocorticoids. The numbers of CD11b+CD4+ and CD11b+CD45R0+ cells fell
      significantly after clinical improvement. The levels of CD11b+CD14+ cells
      (monocytes) did not differ between the groups. The number of CD11b+CD15+ cells
      (neutrophils) was elevated in patients with RA irrespective of disease activity.
      The levels of CD54+ cells were not different between the RA and control groups.
      We conclude that the increased numbers of CD11b+ memory T cells may arise from
      exposure to stimuli outside the synovial compartment.

PMID- 10660144
TI  - Internal carotid artery dissection.
AB  - The purpose of this review is to increase the awareness of internal carotid
      artery dissection (ICAD), a potentially serious and probably underdiagnosed
      condition. ICAD is a not uncommon cause of stroke in young patients. ICAD may
      occur spontaneously or as a result of trauma. However, the "spontaneous"
      dissection is often preceded by a trivial trauma. The typical patient presents
      with ipsilateral headache or neck pain, ipsilateral Horner's syndrome and delayed
      ischemic symptoms from the ipsilateral hemisphere or retina. Conventional
      angiography, the gold standard for diagnosis, tends to be replaced by non
      invasive diagnostic methods. There are no evidence-based guidelines for therapy
      although anticoagulation is most commonly used. The references are selected from
      the Medline database for the years 1966-1997.

PMID- 10660145
TI  - Crossed cerebellocerebral diaschisis in patients with cerebellar stroke.
AB  - OBJECTIVES: We performed single-photon emission computed tomography (SPECT) to
      investigate crossed cerebellocerebral diaschisis (CCCD) in patients with
      cerebellar stroke. MATERIAL AND METHODS: Fifteen patients with unilateral
      cerebellar stroke underwent SPECT of the brain with N-isopropyl-p-[123I]
      iodoamphetamine (123I-IMP). Regional cerebral blood flow (rCBF) was measured by
      the autoradiographic method. Regions of interest were defined in the cerebral
      cortex, striatum, thalamus and cerebellum to compare structures (contralateral to
      the cerebellar lesion) with counterparts ipsilateral to the stroke. RESULTS: In
      the frontal and parietal cortices, especially the posterior superior frontal,
      anterior midfrontal, precentral, postcentral, and supramarginal areas, rCBF
      contralateral to the lesion was significantly lower than on the side of the
      lesion (showing CCCD). CONCLUSION: This CCCD phenomenon is important to be aware
      of in clinical reading of images.

PMID- 10660146
TI  - Predictive value of clinical lacunar syndromes for lacunar infarcts on magnetic
      resonance brain imaging.
AB  - OBJECTIVE: We prospectively investigated the predictive value of clinical and CT
      supported lacunar syndromes for lacunar infarcts on magnetic resonance (MR) brain
      imaging. PATIENTS AND METHODS: The 54 prospective, consecutive patients had
      clinical lacunar syndromes of acute onset and early computed tomography (CT; on
      admission day, i.e. < or =48 h after onset of symptoms) showing either a small
      deep infarct or no corresponding lesion. Taking MR (at day 2 to 4 after
      admission) as the gold standard, the positive predictive value of the CT
      supported clinical syndrome for corresponding lacunar lesions was calculated.
      RESULTS: In 27 (50%) patients, early CT showed a lacunar infarct corresponding to
      the clinical syndrome, a further 27 (50%) patients had no fresh ischemic lesion.
      In 51 patients (94%), MR showed a recent lacunar infarct (hyperintense lacune in
      T2-weighted scans, no demarcation on T1-weighted scans and/or positive gadolinium
      enhancement) corresponding to the clinical syndrome (positive predictive value
      0.94, 95%, CI: 0.88 to 0.98). In 3 (6%) patients MR was normal. Aside from old
      unrelated ischemic (macro- and/or microangiopathic) lesions, MR revealed no acute
      non-lacunar infarct. CT and MR sites of lacunar lesions were matching. Compared
      to gold standard MR, the sensitivity of early CT for suspected lacunar lesions
      was 0.53 (95% CI: 0.38 to 0.67). CONCLUSION: Lacunar syndromes were highly
      predictive for small deep infarcts on MR. Magnetic resonance brain imaging may be
      redundant in the setting of a lacunar syndrome supported by a CT that excludes
      non-ischemic causes of stroke; it may therefore be abandoned in order to reduce
      costs in the health care system.

PMID- 10660147
TI  - Ischemic stroke in Korean young adults.
AB  - OBJECTIVES: To evaluate the characteristics of ischemic stroke in Korean young
      adults. MATERIAL AND METHODS: We prospectively studied 149 consecutive patients
      with acute ischemic stroke aged between 15 to 44 years who were admitted to Asan
      Medical Center. All patients underwent brain CT/MRI and the majority of them
      underwent cerebral anglogram, echocardiography and laboratory studies for
      coagulopathy and vasculitis. Stroke subtypes were classified according to TOAST
      criteria. RESULTS: In our study, men (75.2%) significantly outnumbered women.
      Stroke subtypes were: large artery atherosclerosis 20.8%), small artery occlusive
      disease 17.4%), cardioembolism 18.1%, undetermined causes 16.8%, and other
      determined etiologies 26.8%. The prevalence of hypertension, cigarette smoking
      and habitual alcohol consumption was significantly higher in men than in women.
      CONCLUSIONS: Compared to the western studies, the deviation of sex ratio and the
      relative proportion of large artery atherosclerosis/small artery occlusion was
      higher. Heavy exposure to risk factors such as hypertension and cigarette smoking
      in Korean young men may explain these differences.

PMID- 10660148
TI  - Lacunar infarcts in patients aged 85 years and older.
AB  - OBJECTIVES: To compare the occurrence of lacunar infarcts in the very elderly ( >
      or = 85 years of age) and in patients below 85. MATERIAL AND METHODS: Data of 374
      consecutive patients with lacunar infarcts were collected from a prospective
      hospital-based stroke registry in which 2000 patients are included. Distinctive
      clinical features of lacunar infarct in the very elderly were assessed by
      multiple logistic regression analysis. RESULTS: Lacunar infarcts were diagnosed
      in 39 (15%) of the 262 very elderly patients of our stroke registry. Lacunar
      infarcts in the very elderly accounted for 10.5% of all lacunes. There was no
      statistical difference in the occurrence of different lacunar syndromes between
      the very elderly patients and patients below 85. However, the very old group with
      lacunar infarct showed a significantly higher proportion of the female sex (56.4%
      vs 37.3%) and history of atrial fibrillation (28.2% vs 8.7%), chronic renal
      disease and pathologic condition and a significantly lower proportion of
      hypertension (61.5% vs 77.3%), diabetes (7.7%) vs 28.4%), ischemic heart disease,
      hypercholesterolemia, and absence of neurologic deficit at discharge from the
      hospital than patients below 85. After multivariate analysis only atrial
      fibrillation (OR = 3.77), female gender (OR =2.52), hypertension (OR = 0.35), and
      diabetes (OR = 0.16) were independent clinical factors for developing lacunar
      infarction in the very elderly. CONCLUSION: In the very elderly the higher
      occurrence of atrial fibrillation, the lower prevalence of hypertension and
      diabetes, and the greater focal neurological impairment suggest that the
      cardioembolic pathogenetic mechanisms may be more frequent than generally
      established for lacunar infarcts in stroke patients.

PMID- 10660149
TI  - Interferon-alpha2a effects on complement activation and regulation in MS
      patients.
AB  - OBJECTIVES: To evaluate the treatment effect of recombinant interferon-alpha2a
      (rIFN-alpha2a) on complement activation and regulation in MS patients. MATERIAL
      AND METHODS: Plasma levels of the complement activation products C3bc and
      terminal complement complex (TCC) and serum levels of the complement regulatory
      proteins, complement receptor 1, CR1 (CD35) and the membrane inhibitor of
      reactive lysis, protectin (CD59), were determined by enzyme-linked immunosorbent
      assay (ELISA) in MS patients treated with IFN-alpha2a (14 patients) or placebo (7
      patients). RESULTS: The level of soluble CD35 decreased while the level of TCC
      and to a lesser degree C3bc increased in the IFN-alpha2a treated patients during
      the initial part of the treatment. There was also a concomitant reduction of
      leukocytes in the same patients. CONCLUSIONS: The results indicate that
      complement is activated during the initial phase of rIFN-alpha2a treatment. This
      could partly be due to a concomitant reduction in soluble CD35.

PMID- 10660150
TI  - Autoimmune diseases in families of French patients with multiple sclerosis.
AB  - Multiple sclerosis (MS) is associated with autoimmune disorders (AIDs) in
      individual patients, and limited data suggest a possible familial association of
      MS and AIDs; however, no systematic study has been conducted on the occurrence of
      AIDs in the families of MS patients. Using a standardized interview focused on
      AIDs, we obtained the family histories of 357 consecutive patients from our MS
      clinic. Adequate information was obtained on 1971 first-degree relatives. Fifty
      five patients (15.4%) had first-degree relatives with MS (n=22, 6.2%) another AID
      (n = 30, 8.4%), or both (n = 3, 0.8%). In 16 families (4.5%), at least 3 first
      degree relatives had MS or another AID. MS, Grave's disease, rheumatoid
      arthritis, vitiligo, type 1 insulin-dependent diabetes mellitus, and uveitis,
      were the most common AIDs in these families. Such multiplex families (families
      with MS plus AID) are appropriate for identifying susceptibility genes that may
      be common to MS and other AIDs.

PMID- 10660151
TI  - Myasthenia gravis: a retrospective study comparing thymectomy to conservative
      treatment.
AB  - OBJECTIVES: To study the effectiveness of thymectomy (TY) in a group of patients
      with myasthenia gravis compared to a group of patients submitted to conservative
      treatment (CT) at a similar clinical stage. METHODS: Among 153 patients with
      myasthenia gravis, we paired 28 patients who underwent TY, with 28 cases under
      CT. The following data were analyzed: gender, age, and age at the beginning of
      symptoms, illness duration, follow-up time and type of medical treatment. There
      was no statistical difference between these 2 groups. The mean time for TY was
      2.5 (0.2-13) years after the onset of the disease. The cases were evaluated
      through a functional scale at the beginning and at the end of the study. RESULTS:
      We found complete remission in 15 cases (TY 6, CT 9), improved (normal life with
      or without minimal symptoms and with or without medication) 9 cases (TY 8, CT 1),
      improved with partial control and minimal limitation 32 cases (TY 14, CT 18), and
      poor control 2 cases (TY 2). No death was found in this group. CONCLUSION: There
      was no statistical difference between the conservative treatment and thymectomy
      groups, regarding remission or improvement. Furthermore TY done in the first year
      of the disease or latter, did not change the final outcome.

PMID- 10660152
TI  - Polyneuropathy in late Lyme borreliosis - a clinical, neurophysiological and
      morphological description.
AB  - In a prospective study, detailed clinical and neurophysiological examinations
      were performed in 17 patients with polyneuropathy associated with the late
      borrelial manifestation acrodermatitis chronica atrophicans (ACA). Similar
      clinical and neurophysiological signs were found in most of the patients. The
      findings were those of a sensory polyneuropathy, mainly affecting large nerve
      fibres. Marked abnormality of vibration threshold was a common finding and in 4
      patients this raised a suspicion of spinal cord engagement, in addition to a
      polyneuropathy. Sural nerve biopsy, performed in 3 of the patients, showed a
      mainly axonal neuropathy. Biopsy findings did not confirm earlier reports of
      vasculitis of epineural vessels in ACA-associated polyneuropathy.

PMID- 10660153
TI  - The electroencephalogram in dementia with Lewy bodies.
AB  - OBJECTIVES: Dementia with Lewy bodies (DLB) is the second commonest
      neurodegenerative cause of dementia. While there is consensus on the clinical
      diagnostic criteria for DLB, the use of EEG to increase the diagnostic
      sensitivity has not been substantiated. MATERIAL AND METHODS: We studied the
      resting EEG findings in 18 consecutive patients with DLB and compared them with a
      control group of 20 patients with "probable" Alzheimer's disease (AD). We aimed
      to evaluate the use of EEG in a representative sample of patients with DLB.
      RESULTS: All patients with DLB fulfilled accepted clinical criteria for DLB. The
      DLB group had a more severe dementia than the AD group, as measured by the Mini
      Mental State Examination (MMSE) test (DLB mean MMSE 9.4 and AD mean MMSE 17.2)
      despite a similar duration of overall severity of illness. The EEG was slow in
      both groups, predominantly in the 4-7 Hz range. Although there was no
      statistically significant difference in the EEG findings between the DLB and AD
      groups, there was a correlation between the EEG score and MMSE score (Spearman
      Rank correlation rs = -0.61, P < 0.001). CONCLUSION: These findings suggest that
      although patients with DLB have a more aggressive course than AD, EEG
      abnormalities do not differ in the 2 groups. However, we believe the EEG provides
      important supporting diagnostic information in DLB.

PMID- 10660154
TI  - Analysis of effector CD4 (OX-40+) and CD8 (CD45RA+CD27-) T lymphocytes in active
      multiple sclerosis.
AB  - OBJECTIVE: Recently, effector T-cell subpopulations have been identified that can
      be distinguished by expression of members of the TNF-R family: CD4+OX-40+ cells
      are CD4 helper-effector cells CD8+CD45RA+CD27 cells are CD8-killer-effector
      cells. We investigated whether these lymphocyte subsets were increased in the
      active phase of multiple sclerosis (MS). MATERIAL AND METHODS: Multiple colour
      immunofluorescence staining was performed on peripheral blood lymphocytes of 28
      patients with active MS and of 29 healthy controls, followed by FACS analysis.
      RESULTS: Frequencies of CD8-killer-effector cells showed a wide interindividual
      range in both groups and percentages of CD4 helper-effector cells were low. No
      significant difference between the groups was observed for these subsets, but
      CD8+CD45RA-CD27 were increased in MS. In healthy individuals, CD4 helper-effector
      cells correlated with the total percentages of memory cells. Moreover, CD4+ and
      CD8 memory cells were strongly correlated. CONCLUSION: The here described
      recently identified effector CD4 and CD8 lymphocyte subpopulations were not
      increased in clinically active MS. It is however still possible that in MS,
      myelin-specific encephalitogenic cells reside within these subsets.

PMID- 10660155
TI  - Rapid diagnosis of tuberculous meningitis by a dot-immunobinding assay.
AB  - In this study, a dot-immunobinding assay (Dot-Iba) was standardized to measure
      circulating antimycobacterial antibodies in the cerebrospinal fluid (CSF)
      specimens for the rapid laboratory diagnosis of tuberculous meningitis (TBM).
      Specific CSF-IgG antibody to Mycobacterium tuberculosis from a culture proven
      patient with TBM was isolated and coupled with activated Cynogen bromide
      Sepharose 4B. Using an immunoabsorbent affinity chromatography, 14 kDa antigen
      present in the culture filtrates of M. tuberculosis was isolated and this antigen
      was used in the Dot-Iba, to quantitate specific antimycobacterial antibodies in
      CSF specimens. The Dot-Iba gave positive results in all the 5 culture proven
      patients with TBM and gave no false positive results in CSFs from patients with
      partially treated pyogenic meningitis. Dot-Iba developed in our laboratory is a
      simple, rapid and specific method and more importantly suited for the routine
      application in laboratories with limited resources.

PMID- 10660156
TI  - Absence of maternal A3243G mtDNA mutation and reversible hyperglycemia in a
      patient with MELAS syndrome.
AB  - We report the unusual features of a female patient who had MELAS-specific A3243G
      mutation in mitochondrial DNA (mtDNA) and diabetes mellitus (DM). The patient
      showed mitochondrial myopathy, encephalopathy, lactic acidosis, and deafness but
      lacked the stroke-like episode. Acute hyperglycemia was noted after one attack of
      status epilepticus. Molecular genetic analysis demonstrated a heteroplasmic
      A3243G point mutation in the mtDNAs of muscle, blood cells and hair follicles.
      Glucagon stimulation test exhibited marked depression of pancreatic beta-cell
      function. However, in a further study neither this mutation, nor MELAS syndrome
      or DM, was found in all of her maternal relatives. A series of follow-up studies
      for beta-cell function also showed gradual improvement. The pedigree study led us
      to believe that this A3243G mutation arose from the germ line cells or occurred
      later in somatic tissues of the patient. We also suggest that the A3243G mutation
      of mtDNA may elicit the pathogenesis of a subtype of DM. Nevertheless,
      environmental stress may be another important factor for provocation of the
      disease.

PMID- 10660157
TI  - Inline skating as a possible cause of consecutive bilateral vertebral artery
      dissection.

PMID- 10660158
TI  - The effect of prosthetic valve type on survival after aortic valve surgery.
AB  - A number of recent reports have suggested that valve design has an influence on
      long-term survival after aortic valve replacement (AVR). The present study
      examines the clinical results of two large multicenter trials of the Hancock II
      stented and Medtronic Freestyle stentless bioprosthetic valves. In all cases a
      subcoronary implant technique was used. All patients were operated on between
      1991 and 1994, and all patients were monitored for 5 years. The 5-year actuarial
      survival rate was 86% for Freestyle and 77% for Hancock patients (P<.05). Late
      mortality occurred in 40 Freestyle patients (8.8%) compared with 36 Hancock II
      patients (16.1%, P = .0074). Cox's proportional hazard models were used to
      identify independent predictors of 5-year survival for the two groups. Hazard
      ratio (HR) and P value are presented in parentheses. The final analysis included
      the interactive variable valve*age. The resultant model indicates that the
      interaction of age and valve type has a significant effect on outcome. In
      patients < or =60 years of age at the time of operation, AVR with a Hancock II
      valves was associated with nearly a fivefold risk of death compared with patients
      of the same age who received a Freestyle valve (HR = 4.97, P = .0004). However,
      this survival advantage decreased by 50% with each decade thereafter (valve*age
      interaction HR = 0.50, P = .0027). Our data indicate that AVR with a stentless
      valve confers a survival advantage to the patient. The probability of dying
      within 5 years of surgery is 50% greater in patients who received a Hancock II
      versus a Freestyle valve (HR = 1.50, P = .0442). However, this survival advantage
      is most prominent in younger patients (<60 years of age) where the probability of
      death is fivefold greater with Hancock than Freestyle valves. With advancing age
      the benefits of stentless valves are diminished.

PMID- 10660159
TI  - Aortic valve replacement with stentless porcine aortic valve: a pioneer series.
AB  - Durability of stentless porcine aortic valves is determined by the resistance of
      the cusps to mechanical fatigue and reactions by the host. This study examines
      the role of mismatch between the size of the valve and the diameter of the
      sinotubular junction on durability of the valve. A custom-made stentless porcine
      aortic valve designed for implantation in the subcoronary position was used for
      aortic valve replacement in 29 patients. There were 15 men and 14 women, with a
      mean age of 58 years (range 26 to 72 years). In addition to aortic valve
      replacement, 6 patients had mitral valve surgery, 10 patients had coronary artery
      bypass graft, 1 patient had closure of an atrial septal defect, and 1 had
      concomitant aortobi-iliac bypass graft. Follow-up time extended from 10.3 to 11.5
      years and was complete. The selection of size of valve implanted was based solely
      on the diameter of the aortic annulus. Because the diameter of the sinotubular
      junction plays an important role in leaflet motion and valve competence, the size
      of valves was compared with the diameter of the sinotubular junction of the
      aortic roots where they were implanted. There was one operative death and five
      late deaths. There were no valve-related deaths. The actuarial survival at 10
      years was 76%+/-5%. There were only two transient ischemic attacks and no
      strokes. One patient developed endocarditis 4 years' postoperatively and was
      successfully treated with aortic valve re-replacement. One patient with
      cardiomyopathy had heart transplantation. Thus, the stentless valve was at risk
      of failure in 21 patients. Nine patients developed echocardiographic evidence of
      valve dysfunction: seven had aortic valve re-replacement and two continue to be
      observed because the dysfunction is not severe. The function of the stentless
      valve remained normal in 12 patients. Patients with bioprosthetic valve
      dysfunction had a sinotubular junction 3.2+/-1.3 mm larger than the size of the
      valve, whereas patients with normal bioprosthetic valve function had a
      sinotubular junction 0.8+/-1.2 mm larger than the size of the valve (P = .01).
      The durability of stentless porcine aortic valve implanted in the subcoronary
      position is affected by discrepancies in diameters between the xenograft valve
      and the sinotubular junction of the aortic root. Sinotubular junction greater
      than the size of the stentless valve probably increases mechanical stress on the
      cusps and causes premature valve failure.

PMID- 10660160
TI  - An exceedingly low operative mortality given by stentless autologous, homologous,
      and heterologous aortic valves for aortic valve replacement.
AB  - Homologous, autologous, and heterologous stentless valves were implanted into 663
      patients undergoing aortic valve replacement by standard conventional methods. An
      exceedingly low mortality rate was achieved for the whole series, with the last
      consecutive 311 patients experiencing zero mortality. This analysis encompasses
      the hospitals' total experiences with these three stentless valves and examines
      only the low and zero mortalities. The three stentless valves were the aortic
      allograft used as a root replacement in 374 patients (mean age 43 years, 8.8% for
      active endocarditis), the pulmonary autograft used as a root replacement (22
      patients, mean age 34 years) and the Cryolife O'Brien Model 300 stentless
      composite porcine glutaraldehyde-preserved aortic xenograft (267 patients, mean
      age 73 years, 16% 80 years or older, 55% concomitant procedures). Overall
      mortality rate was 1.1%. The seven deaths were essentially non-valve- and non
      procedure-related. Of the last consecutive 311 patients, the mortality rate has
      been zero (166 allografts, 22 autografts, and 123 stentless xenografts). As a
      result of a careful, planned introduction of each valve and good experience and
      training in implant techniques, this low mortality and consecutive zero mortality
      suggest a "modern-day gold standard."

PMID- 10660161
TI  - Regression of left ventricular hypertrophy after stentless versus conventional
      aortic valve replacement.
AB  - The goal of this study was to analyze regression of left ventricular hypertrophy
      after randomization to conventional biological versus stentless aortic valve
      replacement. Stentless (Freestyle, Toronto, n = 106) or conventional biological
      aortic valves (Carpentier-Edwards, n = 74) were evaluated prospectively.
      Preoperatively there were no differences with regard to aortic valve pathology,
      left ventricular function, and pressure gradients between the two patient groups.
      The patient annulus index (13.55 vs. 13.46 mm; NS) measured intraoperatively was
      used as baseline for further comparison. Postoperatively, left ventricular mass
      index was 213+/-77 g/m2 (stentless) compared with 202+/-72 (conventional group)
      g/m2 (NS), whereas after 6 months it was 141+/-41 g/m2 in the stentless and 170+/
      43 g/m2 in the conventional group (P<.05). Regression of left ventricular
      hypertrophy occurs in all patients after aortic valve replacement. Nevertheless,
      the use of stentless bioprostheses leads to a significant enhancement, which may
      result in a reduction of the cardiac risk profile for the patient.

PMID- 10660162
TI  - Midterm follow-up of unstented biological valves.
AB  - We have used the stentless aortic biosprosthesis for aortic valve replacement
      during the last 10 years. Since 1988, 647 stentless aortic prosthesis were
      implanted: 384 unstented heterografts, 176 Ross procedures, and 87 homografts.
      Patients up to age 50 were offered the Ross procedure, those between the ages of
      50 and 60 a homograft, and patients 60 years old and older received heterografts.
      All patients were evaluated at our clinic. An echocardiogram was obtained before
      discharge from the hospital, at 3 to 6 months postoperatively, and yearly
      thereafter. Gradients, regurgitation, and effective orifice area were recorded at
      each visit. The patient was also evaluated clinically. Early mortality rate was
      5.4%, 1.7%, and 5.8% for heterograft, autograft, and homograft, respectively. The
      mean gradient for the unstented porcine valve was 7.6 mm Hg at 3 to 6 month but 5
      mm Hg or less for the homografts or autografts. Unstented valves are relatively
      new but they showed superior hemodynamic performance compared with either
      mechanical or biological stented valves. Anticoagulation is not mandatory, which
      should decrease the number of complications. They are the replacement of choice
      for young and old patients with a small aortic root and are the best alternative
      to the natural valve.

PMID- 10660163
TI  - Twenty-year follow-up of aortic valve replacement with antibiotic sterilized
      homografts in 200 patients.
AB  - The aim of this study was to determine long-term results from one unit of
      subcoronary homograft aortic valve replacement (AVR) using the same sterilization
      and preservation techniques in each case. Between 1973 and 1983, 200 patients
      underwent AVR using an unstented homograft previously sterilized in antibiotics
      and preserved at 4 degrees C. Surviving patients were monitored for a minimum of
      15 years to the end of 1998. Mean age was 50.0+/-14 (1 standard deviation) years;
      121 patients were men (60.5%). Mean patient follow-up time was 15.6+/-6.7 years,
      with a total follow-up time of 3,115 patient years. Follow-up was 95.6% complete.
      There were three early deaths (1.5%). At autopsy, the homograft was anatomically
      normal and in a satisfactory position. Kaplan-Meier survival, including early
      death, was 81.2%+/-2.8% (1 standard error) at 10 years, 68.1%+/-3.4% at 15 years,
      and 58.0%+/-3.7% at 20 years. Repeat AVR was undertaken in 74 patients, giving a
      freedom from reoperation for any reason of 86.5%+/-2.6%, 69.6%+/-3.8%, and
      38.8%+/-5.3% at 10, 15, and 20 years, respectively. Freedom from structural valve
      degeneration at 10, 15, and 20 years was 81.1%+/-2.9%, 61.7%+/-3.9%, and 31.2%+/
      4.7%, respectively. Freedom from endocarditis at 10, 15, and 20 years was 98.7%+/
      0.9%, 96.0%+/-1.8%, and 94.6%,+/-2.3%, respectively. Homograft AVR with an
      antibiotic-sterilized valve stored at 4 degrees C and implanted in the
      subcoronary position offers low operative mortality and good long-term outcome
      for patients.

PMID- 10660164
TI  - Aortic valve replacement with Medtronic Freestyle bioprosthesis: 5-year results.
AB  - The Medtronic Freestyle aortic root bioprosthesis has been implanted in patients
      since August 1992. This study reviews clinical and echocardiographic results at
      midterm (5 years) after implantation. The Freestyle bioprosthesis was implanted
      in 1,100 patients in a 21-center Food and Drug Administration clinical trial from
      August 1992 to October 1998. The device was implanted (1) as a subcoronary valve
      replacement, (2) as a complete aortic root replacement (full-root), or (3) as a
      root inclusion. Patients were followed annually by clinical examination and
      echocardiography. There were 47 deaths early after operation (7.1%). There were
      2,478 patient-years of follow-up during which there were 99 deaths or 4.0/pt.-yr.
      Before implantation, 73% of patients were in New York Heart Association
      functional class III or IV. After operation, 95% were in class I or II.
      Transvalvular gradient 4 years after operation was low (7.5+/-5.3 mm Hg) for all
      valve sizes (subcoronary implant). Small valves (19 and 21 mm) had mean gradients
      (10.2+/-3.0, 9.1+/-4.4 mm Hg). There was no or mild valve insufficiency in 98% of
      patients. Actuarial analysis at 5 years showed the rate for freedom from
      thromboembolism of 86% in subcoronary implant and 93% in full root replacement.
      Freedom from endocarditis was 98%. Freedom from reoperation for explant of the
      valve highest in patients having full root replacement (98%) and lower with root
      inclusion (94%). There were 20 bioprostheses explanted; 10 for endocarditis, 8
      for technical reasons, and 2 for structural deterioration. The Medtronic
      Freestyle bioprosthesis (1) has excellent hemodynamic performance, (2) techniques
      for insertion that result in a competent valve, (3) low rates of thromboembolism
      and endocarditis, and (4) a rare rate of structural deterioration at 5 years.

PMID- 10660165
TI  - Will stentless valves be durable? The Toronto valve (TSPV) at 5 to 6 years.
AB  - The early hemodynamic benefits of stentless aortic valves have been well
      documented. The issue of long-term functional integrity remains unanswered. We
      report the clinical results of a multicenter registry with prospective data on
      621 patients monitored for 7.1 years. Patient data were collected and analyzed at
      St Jude Medical Inc, St Paul, Minnesota. In all, 66% of patients were male; the
      average age was 65.9 years +/-11.0 years, with 39% older than 70 years. Native
      aortic valves were bicuspid in 40.6%, 91.5% were calcified and 65.7% stenotic.
      Most valves implanted (83.1%) were sizes 25, 27, or 29 mm. Concomitant coronary
      bypass was performed in 42% of patients. Total follow-up time for the 621
      patients was 1,944.5 valve years (mean 3.1 years per patient). At 5 years, 86.1%
      (n = 137) and at 6 years 80.4% (n = 51) were in New York Heart Association class
      I, and 78% had no or trivial atrial insufficiency. The average mean systolic
      gradient for all valves at 6 years was 4.0 mm Hg, and the peak gradient was 8.6
      mm Hg. The effective orifice area varied from 1.4 cm2 (23-mm valve) to 2.7 cm2
      (29-mm valve). The decrease in left ventricular mass index was significant and
      sustained. Actuarial survival at 6 years was 84.2%, and freedom from cardiac
      related deaths was 90.1%. Freedom from valve-related deaths was 95.7%, and
      freedom from prosthetic endocarditis was 98.6%. There were no instances of
      primary tissue valve failure during follow-up, with 97.2% freedom from
      reoperation. The early hemodynamic benefits of the TSPV are well maintained
      during more than 6 years of follow-up, without evident valvular dysfunction.
      Longer follow-up time is required to validate durability, but there is increasing
      evidence for well-maintained structural and functional integrity.

PMID- 10660166
TI  - Ross operation and aneurysm or dilation of the ascending aorta.
AB  - Aortic valve disease and aneurysmal dilation of the ascending aorta are managed
      by prosthetic valve conduit replacement or homograft replacement. Requirement of
      anticoagulation, risk of thromboembolism or bleeding, and increased risk for
      homograft degeneration in young patients suggest that a Ross root replacement
      with replacement or reduction of the ascending aorta could be a preferred
      alternative. To assess efficacy, the present review was undertaken. Between April
      19, 1995, and February 1999, 64 patients (age, 8 months to 59 years; median age,
      37 years) had a Ross operation, with resection of the ascending aorta in 30 and
      reduction aortoplasty in 34. Annular fixation was performed in 57 patients, with
      aortic annulus reduction in 39. Clinical evaluation with echocardiogram was
      completed within 1 year of closure in 62 patients. There was one operative death
      and one non-valve-related late death. Autograft valve insufficiency (AI) was 0 to
      trace in the perioperative period in all patients. One patient developed
      progressive annular dilation with moderate AI at 2 months. Reoperation with
      annular reduction and fixation restored autograft valve function. Postoperative
      mean aortic annulus diameter was 22.5+/-0.4 mm (Z-value, -0.2+/-0.2) and 23.2+/
      0.8 mm (Z-value, -0.02+/-0.5) at 1 year. Aortic sinus diameter was 33+/-6
      postoperative and 36+/-5 at 1 year. The autograft root sinus diameter was greater
      than 39 mm in 11 patients at the most recent echocardiogram. Mean
      echocardiography measurements of the aortic root have been constant during the
      postoperative follow-up period. Two patients have required reoperation for
      homograft obstruction 1.3 and 2.1 years after operation. Ross root replacement of
      the aortic valve with resection or reduction aortoplasty can be performed with a
      low operative risk and limited morbidity. Its early durability appears to be
      similar to other Ross operations.

PMID- 10660167
TI  - Critical analysis of the Ross procedure: do its problems justify wider
      application?
AB  - The Ross procedure has shown superior hemodynamic results in young patients with
      aortic root pathology. Wider application of the procedure is restricted by its
      technical complexity and potential associated problems. The mortality/morbidity
      associated with 130 consecutive patients who have had the Ross procedure using
      the root replacement implantation technique between October 29, 1990, and October
      8, 1998 is summarized. New York Heart Association (NYHA) preoperatively was class
      I, 23.5%; class II, 64.7%; and class III, 11.8%; mean age was 36 years (range 3
      to 67 years). Men accounted for 73.8% and women 26.2% of the series. Preoperative
      diagnosis was congenital, 80.7%; rheumatic, 5.3%; failed prosthesis, 7.0%;
      degenerative, 2.6%; and endocarditis, 4.4% with preoperative aortic insufficiency
      (AI) 7.9% 1+, 19.8% 2+, 29.7% 3+, and 42.6% 4+, respectively. At operation mean
      cross-clamp time was 201 minutes (range 102 to 280 minutes). Patient follow-up
      was 99.2% (1 patient lost to follow-up), and 94.4% were NYHA class I at follow-up
      and 5.6% class II. Postoperative AI was 0 to 1 + in 93.6% and 2+ or greater in
      6.4%. Mean time to patient follow-up was 436 days (range, 20 days to 2,878 days).
      Thirty-day mortality rate was 1.5%; one patient died of mediastinal bleeding, and
      one from complications of acute pancreatitis. There was no late mortality. Early
      autograft explant occurred in one patient secondary to iatrogenic injury to the
      pulmonary autograft at the time of harvesting, and one late explant occurred
      secondary to proximal suture line dehiscence. Late autograft repair occurred in
      one patient secondary to a false aneurysm along the proximal suture line; one
      patient was reoperated for left main coronary stenosis relative to iatrogenic
      injury at the time of the procedure. Right ventricular outflow tract replacement
      has occurred in two patients. Postoperative morbidity and mortality for the Ross
      procedure, as shown in this series, remains low and supports broader application
      of the procedure.

PMID- 10660168
TI  - The Sorin stentless pericardial valve: implant technique and hemodynamic profile.
AB  - Stentless porcine xenografts have had significant impact on the hemodynamics,
      left ventricular remodeling, and survival after aortic valve replacement. We
      sought to establish a similar trend for the stentless pericardial valve. In a
      consecutive unselected series of 54 patients over 65 years of age, we refined the
      implant method for the stentless aortic pericardial valve and defined the
      pitfalls. We used a detailed echocardiographic study designed by the Food and
      Drug Administration to define the early valve hemodynamics and changes in left
      ventricular function. The valve is user friendly. With an easily reproducible
      implant technique, very low mean (7.1+/-3.4 mm Hg) and peak (13.6+/-6.3 mm Hg)
      transvalvular gradients were obtained, which did not decline significantly with
      time. Left ventricular mass index declined accordingly over 6 months (147+/-49
      g/m2 to 125+/-39 g/m2). Mild aortic regurgitation, which did not influence left
      ventricular mass regression, occurred (26%) predominantly in the first half of
      the series because of size discrepancy between the annulus and a dilated
      sinotubular junction. Aortic regurgitation was virtually eliminated by tailoring
      of the sinotubular junction in the noncoronary sinus. The stentless pericardial
      valve provides excellent early hemodynamics and is a realistic alternative to the
      stentless porcine xenograft or aortic homograft for subcoronary aortic valve
      replacement in elderly patients. Valve durability is yet to be defined.

PMID- 10660169
TI  - Comparison of results using "freestyle" stentless porcine aortic root
      bioprosthesis with cryopreserved aortic allograft.
AB  - Aortic valve replacement with natural heart valves offer the advantages of
      superior hemodynamics, laminar flow patterns, lack of need for anticoagulation,
      and perhaps improved durability. This study compares 5-year results for two
      stentless aortic valves. In 1992, two prospective clinical trials using two
      different stentless aortic valves were initiated at our center. The Freestyle
      stentless porcine aortic root bioprosthesis (SPB) was placed in 106 patients, and
      cryopreserved aortic allografts (CAA) were placed in 174 patients using a
      freestanding total root replacement technique in each series. The mean systolic
      gradient for the SPB was 7.5+/-4.4 mm Hg at discharge and 5.9+/-3.1 mm Hg at 5
      years. The mean systolic gradient for the CAA was 6.4+/-3.3 mm Hg at discharge
      and 5.0+/-2.2 mm Hg at 5 years. At discharge 92.2% of SPB patients had no aortic
      insufficiency (AI) and 7.8% had trivial AI. In all, 92.9% of CAA patients had no
      AI at discharge, and 7.1% had mild AI. At 5-year follow-up, 100% of the SPB had
      no AI, and only 20% of the allograft patients had no AI. The remainder, 80%, had
      mild AI. Excellent hemodynamic function was seen with both SPB and CAA. A lower
      incidence of nonhemodynamically significant AI was observed in the SPB group.
      Preoperative factors such as chronic renal failure and endocarditis may have
      adversely affected durability in the allograft group, but long-term follow-up is
      still required to determine durability.

PMID- 10660170
TI  - Use of Toronto stentless porcine valve in patients with aortic dilation.
AB  - One of the contraindications for a stentless aortic valve is dilation of the
      aorta such that the sinotubular ridge is more than 2 mm larger than the annulus.
      Since May of 1994, 134 patients have had their aortic valve replaced with St Jude
      Toronto SPV valves; of these, 38 patients have required sinotubular ridge
      reduction. This was done by using one or more pleats in the aorta between the
      commisural posts. There were 20 patients with one pleat, 12 patients with two
      pleats, 5 patients with three pleats, and 1 patient with four pleats. In
      addition, three Toronto SPV valves were used in patients with significant
      calcification in the native coronary sinuses. All of the valves have had trace or
      no aortic insufficiency and have not developed aortic insufficiency in follow-up
      evaluation. Mean gradients remain low (<10 mm Hg). These valves have been much
      more versatile than originally expected and can be used in patients with mild to
      moderate aortic dilation and calcification.

PMID- 10660171
TI  - The impact of new technology on a clinical practice.
AB  - The use of xenograft stentless tissue valves has increased because of excellent
      hemodynamics and availability. This article describes the impact of the
      incorporation of this new technology into a single institutional practice over
      time. A time span for continual usage of the new stentless Freestyle valve was
      divided into four distinct chronological groups and evaluated. Data on 266
      consecutive patients receiving the Freestyle prosthesis were analyzed with regard
      to demographics, degree of illness, complexity of surgery, and outcomes to
      discover any distinct changes over time with respect to experience and acquired
      confidence and surgical expertise. Findings among the four groups were compared
      using Student's t-test. The only change in patient demographics was younger age
      (mean age decreased from 70 to 62 years). The number of procedures rose steadily,
      and the degree of illness increased as noted in the increase between groups in
      the percentage of patients with comorbidities (from 45% to 92%). The complexity
      of surgery score steadily increased (from 1.9 to 2.5); however, the mean cross
      clamp time did not change. The surgical mortality rate for the entire study was
      3.4%. In group 1, the mortality was 7.5% but decreased rapidly and remained
      steady throughout the rest of the study. The use of the Freestyle stentless
      conduit in a single practice over time shows a distinct learning curve. With
      experience, valves are placed in younger, sicker patients who require more
      complex surgery. Surgical outcomes and efficiency improve with acquired surgical
      expertise.

PMID- 10660172
TI  - Simultaneous myocardial revascularization and aortic valve replacement: stentless
      versus stented bioprostheses.
AB  - Implantation of stentless aortic valve prostheses is more time-consuming than
      implantation of conventional stented bioprostheses. Simultaneous myocardial
      revascularization can result in a considerably prolonged operation time. We
      reviewed our patients with regard to surgical aspects in the specific patient
      cohorts. From April 1996 to April 1999, 303 patients were operated for aortic
      valve disease with or without concomitant coronary artery revascularization. Mean
      age was 75 years, ranging between 36 and 90 years. Using the Medtronic Freestyle
      valve, the following techniques of implantation were used: subcoronary technique,
      163 patients, 61.5%; root inclusion technique, 7 patients, 3.5%; total root
      replacement, 30 patients, 15%. Total hospital mortality rate was 5.6%, reflecting
      age and concomitant disease of these patients. For isolated aortic valve
      replacement, the mortality rate was 4.7% and 6.7% for combined procedures.
      Coronary artery patients who are not suitable for stentless valve implantation
      owing to extensive aortic root calcification have a higher perioperative
      mortality rate. Compared with the isolated valve replacement and despite more
      extensive surgery and prolonged operative time, simultaneous myocardial
      revascularization in patients with stentless prostheses implantation can be
      performed without an increased risk.

PMID- 10660173
TI  - Impact of intraoperative post-pump aortic regurgitation with stentless aortic
      bioprostheses.
AB  - Stentless aortic bioprosthesis performance may be affected by geometric
      distortion, and intraoperative echocardiography typically is used to assess
      prosthetic valve function. The impact of minimal or mild post-pump aortic
      regurgitation has not been previously investigated. Intraoperative post-pump
      transesophageal echocardiograms and follow-up transthoracic echocardiograms (up
      to 3 years' postoperatively) were reviewed for 96 patients who underwent
      implantation of Freestyle (Medtronic) stentless aortic bioprostheses. Minimal or
      mild aortic regurgitation was present post-pump in 50 of 96 (52%) patients. On
      early follow-up examination (n = 80), no patient had more than mild aortic
      regurgitation. Aortic regurgitation had completely resolved in 24 of 39 (62%)
      patients with post-pump aortic regurgitation, including 15 of 19 (79%) patients
      with minimal paravalvular regurgitation. The incidence of mild aortic
      regurgitation at 2 and 3 years did not appear different between patients with and
      those without post-pump aortic regurgitation. Minimal or mild aortic
      regurgitation is common on intraoperative post-pump transesophageal
      echocardiography immediately after implantation of stentless aortic
      bioprostheses. Resolution is common, especially of small paravalvular jets.
      Minimal or mild post-pump aortic regurgitation infrequently results in even mild
      aortic regurgitation on early follow-up evaluation and does not appear to predict
      clinically significant progression of aortic regurgitation on long-term follow-up
      evaluation.

PMID- 10660174
TI  - Randomized controlled trial of stented and stentless aortic bioprotheses:
      hemodynamic performance at 3 years.
AB  - A randomized prospective trial was undertaken to compare the hemodynamic
      performance and left ventricular regression after aortic valve replacement with
      the Toronto SPV stentless bioprosthesis and the Carpentier Edwards SAV (CE)
      bioprosthesis. Forty patients were randomized after the annular and sinotubular
      diameters had been measured. Early hemodynamic measurements were made with a
      thermodilution cardiac output catheter, and echocardiography was used thereafter.
      Left ventricular mass was assessed using magnetic resonance imaging (MRI) at 1
      week, 6 months, and 32 months. The mean annular size was 25.3+/-2.2 mm (CE) and
      25.5+/-1.5 mm (Toronto), although it was possible to implant valves with a mean
      diameter 3 mm larger in the stentless group (26.0+/-1.7 mm cf. 23.0+/-1.7 mm).
      Hemodynamic performance in the first 24 hours showed no significant difference
      between the groups, but there was a trend for shorter ventilation time and
      shorter stays in the intensive therapy unit in the stentless group.
      Echocardiography showed superior transvalvular gradients in the stentless group
      at 1 week (mean 5.5+/-3.1 mm Hg cf. 8.9+/-2.5 mm Hg), and this difference was
      maintained at a mean follow-up time of 32 months (3.5+/-0.6 mm Hg cf. 6.3+/-0.6
      mm Hg). Similar regression of left ventricular mass was seen in both groups at 6
      months, but at 32 months, measurement in diastole showed a reduction of 38%
      (P<.01) in the stentless group compared with 20% (P = ns) in the stented group,
      and measurements in systole showed a 23% (P<.01) and 13% (P = ns) reduction,
      respectively. This study confirms that a larger stentless valve can be implanted
      into a given size of aortic annulus with superior residual aortic valve
      gradients. These lower gradients seem to result in improved long-term regression
      of left ventricular mass as measured by MRI.

PMID- 10660175
TI  - Prosthesis-patient mismatch: hemodynamic comparison of stented and stentless
      aortic valves.
AB  - Several centers have reported excellent clinical performance of stentless aortic
      xenografts. This study reports a hemodynamic comparison of the Medtronic
      Freestyle stentless and Mosaic stented valves. The prosthetic hemodynamics at
      discharge and 1 year after insertion in 95 patients who underwent aortic valve
      replacement with the Freestyle stentless bioprosthesis at Southern California
      Kaiser Permanente Medical Center were compared retrospectively with 115 unmatched
      individuals who received the Mosaic stented valve at the University of British
      Columbia. As assessed by echocardiography, there were no differences in the mean
      transvalvular gradient, effective orifice area (EOA), or EOA indexed to body
      surface area (EOAI) at discharge between the two groups. However, after 1 year,
      all corresponding Freestyle valve sizes had larger EOAs and lower gradients.
      Furthermore, fewer patients receiving Freestyle xenografts had prosthesis-patient
      mismatch (19% vs. 64%, P<.001) as defined by EOAI <0.85 cm2/m2. Although the
      Mosaic stented valve provides comparable immediate hemodynamic performance after
      implantation, there is significant improvement with the Freestyle bioprosthesis
      in terms of gradient, EOA, and prosthetic-patient mismatch at 1 year.

PMID- 10660176
TI  - Left ventricular remodeling after aortic valve replacement with the Toronto-SPV
      prosthesis.
AB  - The remarkable hemodynamic features of the aortic Toronto SPV prosthesis have
      been reported. To assess the efficacy of these characteristics to produce a
      favorable left ventricular remodeling and to test the limits of the dobutamine
      stress test to check these results, 25 consecutive patients, who had undergone
      aortic valve replacement with Toronto SPV, were monitored with dobutamine and
      exercise stress tests for 1 year. Among the prosthetic and left ventricular
      morphological and functional parameters evaluated, dobutamine infusion produced
      an overestimation of prosthetic and left ventricular outflow tract gradients,
      effective orifice area, and prosthetic resistance compared with the more
      physiological exercise test (P<.01). These misleading results were probably due
      to the inotropic and unloading effects of dobutamine in still hypertrophied
      hearts. Indexed myocardial mass and wall thickness decreased significantly during
      the follow-up period (P<.01), whereas left ventricular diastolic diameter and
      ejection fraction showed no significant variations. These data show that the
      positive left ventricular remodeling is due only to the regression of the
      hypertrophy and not to the reduction of left ventricular diameters. Based on
      results from this study, the dobutamine stress test should be avoided to evaluate
      patients with aortic valve prostheses and still present left ventricular
      hypertrophy. The Toronto SPV produces a favorable left ventricular remodeling
      during the first year of follow-up, and is likely to improve.

PMID- 10660177
TI  - The Toronto SPV: hemodynamic data at 1 and 5 years' postimplantation.
AB  - The Toronto-SPV (T-SPV) bioprosthesis has been used for aortic valve replacement
      (AVR) since July 1991. There is no published data on its mid-term hemodynamic
      performance. This study compares the hemodynamic data of a consecutive series of
      patients at 1 and 5 years after AVR. The first 109 consecutive patients who had
      AVR with a T-SPV have been monitored for a minimum of 5 years and have had annual
      Doppler echocardiographic studies. There were 80 men and 29 women in the study;
      mean age was 62 years (range 34 to 80 years). Concomitant coronary artery bypass
      surgery was done in 35 patients. One operative and nine late deaths occurred. The
      mean systolic gradient across the T-SPV in all patients was 3.9+/-2.4 mm Hg at 1
      year and 4.1+/-3.3 mm Hg at 5 years (P = .27). The mean aortic valve area was
      2.2+/-0.6 cm2 at 1 year and 2.3+/-0.7 cm2 at 5 years (P = .43). The mean left
      ventricular mass index (LVMI) was 104+/-31 g/m2 at 1 year and 97+/-24 g/m2 at 5
      years (P = .08). Multivariate linear regression analysis showed that preoperative
      coronary artery disease (P<.0001) and hypertension (P<.01) were independent
      predictors of higher LVMI over time. Aortic insufficiency was none/trivial in 94%
      of patients and mild in 6% at 1 year. At 5 years, aortic insufficiency was
      none/trivial in 88% of patients, mild in 10%, and moderate in 2%. The aortic
      leaflets remained thin and pliable in all patients as assessed by
      echocardiography. Most patients (85%) were in New York Heart Association
      functional class I. The hemodynamic performance of the T-SPV remained unchanged
      during the first 5 years after implantation. The LVMI continued to decrease after
      the first year and tended to normalize in most patients. The aortic valve
      remained competent, and the leaflets did not change their thickness or show
      evidence of calcification.

PMID- 10660178
TI  - Factors affecting left ventricular mass regression after aortic valve replacement
      with stentless valves.
AB  - The hemodynamic benefits of using stentless valves for replacement of the human
      aortic valve have become more well known. These devices are associated with
      significant decrease in left ventricular (LV) mass and LV remodeling in the early
      postoperative period. However, no large study has examined patient-related and
      valve-related factors that may contribute to this phenomenon. This study examined
      1,103 patients who underwent aortic valve replacement (AVR) with a stentless
      porcine valve (Freestyle = 840, SPV = 263). In all cases, a subcoronary implant
      technique was used. Valve performance was assessed by serial echocardiograms. At
      3 years' post-AVR, mean gradient was 6.3+/-5.0 mm Hg, and effective orifice area
      (EOA) was 2.0+/-0.7 cm2. Indexed EOA was 1.2+/-0.4 cm2/m2. There was an
      association between indexed EOA and the extent of LV mass regression. At 3 years
      after surgery, LV mass index (LVMI) was reduced to 76.3% to 78.7% of baseline in
      patients whose indexed EOA was >0.8 cm2/m2. In contrast, for patients with an
      indexed EOA that was <0.8 cm2/m2, LVMI at 3 years was 95.5% of baseline (P =
      .0001). Multiple linear regression models were used to identify parameters that
      predicted the 3-year LVMI. Baseline LVMI (P<.0001), prior myocardial infarction
      (P = .0009), male gender (P = .0036), and carotid stenosis (P = .022) were
      independent predictors of LV mass regression. Valve type, valve size,
      preoperative New York Heart Association class symptoms, coronary disease, prior
      bypass surgery, chronic obstructive pulmonary disease, or underlying valve
      pathology had no effect on LV mass regression. Data indicate that baseline LVMI
      and patient-prosthetic mismatch have major effects on the extent of LV mass
      regression post-AVR. Long-term hemodynamic benefits of AVR can be optimized by
      proper selection of the prosthesis so as to avoid mismatch. Furthermore, because
      the baseline LVMI affects the extent of regression post-AVR, early intervention
      may result in more complete resolution of LV mass postoperatively, which may have
      important prognostic implications.

PMID- 10660179
TI  - Implantation technique of the Cryolife-O'Brien stentless xenograft aortic valve:
      the simple, rapid, and correct way to implant and the errors to avoid.
AB  - Implantation of the Cryolife-O'Brien Model 300 stentless composite porcine aortic
      xenograft valve for aortic valve replacement is different from that of other
      stentless valves. The valve is a symmetrical, composite, three noncoronary
      leaflet assembly, with a broad coaptive leaflet surface. Because the valve has
      only a small superior aortic wall cuff and no inferior cuff, a single continuous
      suture line of 3-0 polypropylene provides a rapid safe implantation in the supra
      annular position. Consequently ideal recipients are elderly patients, who benefit
      from the short cardiopulmonary bypass time. This report describes the step-by
      step technique of implantation and outlines the principles of maintaining
      symmetry during implantation. Errors to avoid are also discussed. This stentless
      valve has been used for aortic valve replacement in 267 elderly patients since
      1992, with a 1.1% mortality, low morbidity, and excellent valve function.

PMID- 10660180
TI  - Risk factors for coronary complications after stentless aortic root replacement.
AB  - Coronary complications after aortic root replacement (ARR) with pulmonary
      autografts have been reported to be more common than with other stentless
      biological conduits (homografts, xenografts). To verify this hypothesis, results
      with 84 consecutive patients having stentless ARR between January 1992 and
      January 1999 were reviewed. Fifty patients had autograft (Group 1) and 34 either
      homograft or xenograft (Group 2) ARR. Comparison of age (27+/-9 vs. 38+/-22
      years, P = ns), prevalence of male sex (86% vs. 79%, P = ns), aortic root disease
      (30% vs. 44%, P = ns), congenital coronary anomalies (10% vs. 3%, P = ns), prior
      aortic procedure (16% vs. 15%), and need for associated procedures (26% vs. 24%,
      P = ns), did not disclose significant differences. Bicuspid aortic valve was more
      prevalent in Group 1 (56% vs. 9%, P = .001). Mean aortic crossclamp (154+/-28 vs.
      120+/-24 minutes, P = .05) and bypass (216+/-30 vs. 192+/-58 minutes, P = .05)
      times were longer in Group 1. Early mortality was comparable (2% vs. 3%, P = ns)
      and caused by right ventricular ischemia in both groups. Overall prevalence of
      coronary complications was higher in Group 1 (10% vs. 3%, P = .04), all resulting
      in right heart ischemia. Intraoperative partial takedown of repair in 5 Group 1
      patients, associated with CABG in 1, resulted in prompt resolution of myocardial
      ischemia in 4 (80%) and prolonged in 1, which ultimately died as a result of
      sepsis. Recovery was prompt in all 4 patients (mean ICU stay 35+/-28 hours) with
      no metabolic or echocardiographic evidence of myocardial infarction. At discharge
      echocardiography, satisfactory biventricular kinetics was found in all patients.
      Analysis of preoperative variables showed bicuspid aortic valve (83% vs. 33%, P =
      .01) and coronary anomalies (67% vs. 3%, P = .001) to be more prevalent in
      patients suffering from coronary complications. Stentless ARR is a safe procedure
      with low operative mortality, regardless of the type of biological conduit.
      Autograft ARR may be at greater risk of right ventricular ischemia in patients
      with bicuspid aortic valve and coronary anomalies. An aggressive intraoperative
      approach including partial takedown of repair may limit the morbidity of coronary
      complications.

PMID- 10660181
TI  - Dehiscence of the Freestyle stentless bioprosthesis.
AB  - This study aimed to identify and characterize patients who developed prosthetic
      dehiscence after aortic valve replacement with the Freestyle Stentless
      bioprosthesis. Review of patients' records and preoperative echocardiogram was
      performed. Prosthetic dehiscence developed in 10 patients after 2.5 to 49 months
      (mean 19). Most patients were symptomatic at presentation. Nine patients were
      reoperated. Dehiscence was typically located at the inflow suture line beneath
      the noncoronary cusp. Four patients died. The cause of dehiscence is assumed to
      be related primarily to surgical technique.

PMID- 10660182
TI  - Stentless aortic xenograft valve replacement: lessons learned after 300 implants.
AB  - Early results after aortic valve replacement (AVR) with three different types of
      stentless xenografts suggested less satisfactory outcome with a simplified
      implant model (Cryolife-O'Brien) compared with two standard implant models
      (Biocor PSB, Toronto SPV). To assess the impact of experience on mid-term outcome
      after stentless AVR, results with 322 implants were reviewed. Between July 1992
      and February 1999, 106 patients underwent operations to implant the Biocor PSB
      (group 1), 139 patients the Toronto SPV (group 2), and 77 patients the Cryolife
      O'Brien valve (group 3). Mean age (70+/-6 years; 70+/-7 years; 71+/-7 years; P =
      .7), prevalence of male gender (56 patients, 53%; 72 patients, 55%; 38 patients,
      49%; P = .4), prevalence of aortic stenosis (72 patients, 68%; 77 patients, 55%;
      38 patients, 49%; P = .7), and need for associated procedures (51 patients, 48%;
      54 patients, 39%; 33 patients, 43%; P = .7) were similar among all three groups,
      respectively. Mean aortic cross-clamp time was shorter in group 3 (96+/-24 min;
      98+/-24 min; 78+/-22 min; P = .02). Early deaths (3/106, 3%; 4/139, 3%; 2/77; 3%,
      P = .8) and late survival were comparable (89%+/-5%, 93%+/-4%, and 85%+/-7% at 5
      years, P = .1) among groups. Follow-up ranged from 1 to 84 months (mean 52+/-20
      months). Five-year freedom from valve deterioration (95%+/-5%, 96%+/-3%, and
      85%+/-7%, P = .008) and from reoperation (98%+/-2%, 98%+/-2%, 92%+/-4%, P = .01)
      was significantly poorer in group 3 patients. When valve failure resulting from
      technical mishaps (none in the last 60 implants) with the Cryolife-O'Brien valve
      was excluded, no significant difference in freedom from valve deterioration was
      noted (98%+/-2%, 96%+/-3%, and 95%+/-4%, P = .1). Late functional status of 290
      survivors was satisfactory and comparable among groups (1.3+/-0.8, 1.1+/-0.4, and
      1.4+/-0.7 New York Heart Association class, P = .5). After an initial learning
      curve, simplified implant stentless xenografts offer satisfactory mid-term
      results, which are comparable to two-suture-line implant valves. Owing to the
      shorter grafting time, simplified implant xenografts such as the Cryolife-O'Brien
      may be particularly suited for complex operations where associated procedures are
      required.

PMID- 10660183
TI  - Aortic root geometry and stentless porcine valve competence.
AB  - The goal of this study was to characterize medium-term changes in aortic root
      geometry after stentless aortic valve replacement, the relationship between
      aortic sinotubular junction and the competence of stentless valves. A total of
      205 consecutive patients (mean age 73+/-6 years; 120 men, 85 women) received a
      Freestyle stentless porcine aortic valve and were studied prospectively by
      echocardiography from 1 week to 5 years. Internal diameters of outflow tract,
      annulus, sinus, sinotubular junction, and ascending aortic root were measured at
      early ejection and indexed to stentless valve size. The degree of stentless valve
      regurgitation was semiquantified by color Doppler echocardiography. A total of
      701 echocardiographic studies were obtained and analyzed; 73% showed a fully
      competent stentless valve (nAR) and 13% and 14%, respectively, showed a trivial
      (tAR) or mild (mAR) regurgitation. Sinotubular junction of tAR or mAR was
      significantly greater than that of nAR (111+/-1.9, 117+/-2.2 vs. 104+/-1.0,
      percentage of valve size, P<.001). A preoperative diagnosis of aortic
      regurgitation (110+/-2.6 vs. 104+/-1.0, percentage of valve size, P<.001) and 4
      to 5-year follow-up time (116+/-2.2 vs. 107+/-2.9, percentage of valve size, P =
      .023) were associated with a greater sinotubular junction, although the incidence
      and mean grade of stentless valve regurgitation did not change significantly
      during the follow-up period. Up to medium-term follow-up evaluation, the
      incidence of moderate stentless aortic regurgitation is less than 5%. The nature
      of valve disease and age-related increase in sinotubular junction may have
      reduced the cusp coaptation area of the stentless valve and may predict the
      presence of a trivial or mild regurgitation. Understanding the interrelations
      between the stentless valve and remodeling of the aging aorta has important
      implications for both surgical technique and long-term follow-up outcome.

PMID- 10660184
TI  - Pathological analysis of nonstented Freestyle aortic root bioprostheses treated
      with amino oleic acid.
AB  - We examined 67 explanted Medtronic Freestyle (MF) valves of 0 to 1,490 days of
      implantation from 66 patients, including 9 full-root, 17 root inclusion, and 41
      subcoronary implants derived from a multicenter trial composed of 1,100 patients
      at 27 centers worldwide (58 valves) and other removed specimens (9 valves).
      Macroscopic, radiographic and histological examination was performed to establish
      clinicopathological correlations in retrieved MF stentless aortic bioprostheses.
      Indications for 30 explants obtained at reoperation were perioperative technical
      (1 bleeding, 3 iatrogenic valve damage), endocarditis (11), sterile perivalvular
      leak (4), valve stenosis (1) regurgitation (3), fistula (2), or degeneration (2
      cuspal tears, 1 cusp separation). Autopsy specimens were obtained after valve
      related (9), non-valve-related (22), or perioperative death (6). Most non-valve
      related deaths were cardiac. Valve-related deaths included endocarditis (4),
      paravalvular leak (1), thrombus (2), subannular occlusion (1), and tamponade (1).
      No excessive pannus was present. Macroscopic valve thrombosis was noted in two
      subcoronary implants of 180 and 279 days' duration. Histological analysis on all
      valves of more than 10 days implant duration or with macroscopic abnormality
      revealed variable but progressive flattening of the valve cusps; focal,
      plaquelike unorganized mural thrombus; cuspal fluid insudation; and generalized,
      nonspecific degenerative changes typical of explanted porcine valves. Aortic wall
      calcification was seen in two explants of 47 and 49 months' duration, the later
      with associated cuspal tear. Cusp mineralization was limited to infected valves.
      No excessive inflammation or fibrosis at the host-device interface was noted.
      Pathological findings were generally similar to those seen in clinically used
      glutaraldehyde-fixed xenografts. Potential pathology related to stentless design
      including pannus, aortic wall calcification, and host-tissue interaction were not
      clinically significant. Nevertheless, examination of many explanted valves at
      extended intervals and ongoing clinical data are needed to confirm the long-term
      efficacy, safety, and characteristic modes of failure of stentless bioprostheses.

PMID- 10660185
TI  - The Toronto SPV bioprosthesis: review of morphological findings in eight valves.
AB  - The morphological findings in eight explanted Toronto SPV bioprostheses were
      described. Clinical records were reviewed for patient information and data
      regarding the explanted bioprosthesis, all of which were analyzed in detail by
      gross and histological examination. All valves were also examined radiologically
      and detailed specimen photographs obtained. When warranted, tissue cultures were
      taken and special stains for microorganisms obtained. The Toronto SPV
      bioprosthesis has been used for aortic valve replacement in 270 patients since
      its introduction in 1991. The follow-up evaluation was 99.5% complete. Eight
      valves have been explanted: three at surgery and five at autopsy. Patient age
      ranged from 35 to 69 years, with five male and three female patients. Indications
      for aortic valve replacement were aortic stenosis in all cases. Implant duration
      ranged from 5 weeks to just over 6 years (mean 38 months). Early failures (2)
      were due to infective endocarditis. Two patients died of acute myocardial
      infarction, related to pre-existing coronary artery disease, and two died from
      lung cancer. All late explants showed host tissue growth (grade 2-3), with
      variable extension onto both the proximal and distal suture lines, as well as
      extension onto the cusps and commissures on the flow and nonflow surfaces.
      Extension of pannus onto native aortic tissues was seen but did not encroach on
      the coronary ostia. Tissue degenerative changes were present, as were small tears
      (type 1) in two valves. Mild calcification was seen in two valves. The Toronto
      SPV has excellent clinical performance at up to 8 years of follow-up evaluation.
      In this series, early failures are related to infective endocarditis, and later
      explants (6 of 8) are associated with mild tissue degeneration and an occasional
      cusp tear. At up to 5 years, only minimal/mild calcification was seen in two of
      the eight valves.

PMID- 10660186
TI  - Deformation of the stentless porcine valve scaffold enhances accelerated leaflet
      fibrosis and calcification in juvenile sheep.
AB  - Stent mounting of xenografts induces a loss of mobility and reduces the effective
      valve orifice. By contrast, the higher surgical technical expertise required for
      stentless procedures is a major obstacle for many surgeons. To facilitate the
      insertion of the Toronto SPV (St Jude Medical Inc, St Paul, Minneapolis, MN)
      stentless aortic valve, we tried to alter the porcine design by lowering the
      invasive profile at the depth of the sinuses on both coronary sites. This
      technique could theoretically facilitate implantation of the modified stentless
      valve with an easygoing single-layer suture at the challenging subcoronary level
      and make it more attractive for the surgeon. The standard model was modified by
      lowering the profile at the depth of the sinuses on both coronary sites, whether
      by plication (in 3 specimens, one of each size) or excision (in 3 others) of the
      protruding porcine aortic wall at the nadir of each coronary sinus. Animal
      implants in juvenile sheep (6 standard Toronto versus 6 modified valves of 21,
      23, and 25 mm) were studied for durability and biocompatibility for 3 to 6
      months. All valves were evaluated by postoperative echocardiography and after
      explantation examined macroscopically, radiographically, histologically, and
      electron microscopically. The standard valves performed well, although at 6
      months after implantation, marked fibrosis was found at the outflow parts with
      scattered calcifications, essentially in the porcine aortic wall. The leaflets
      remained mobile and contained scant mineralization. By contrast, the modified
      specimen showed markedly accelerated fibrosis and significant cusp calcifications
      at distance from the altered zones. Severe restriction of the mobility of the
      leaflets was visible 3 months after implantation in the juvenile sheep model. The
      more pronounced the deformation of the modified scaffold, the faster and more
      intense the degradation and calcification of the leaflets far from the altered
      zones (worse in the heavily deformed, plicated cusps). Because all valve types
      were prepared by identical preservation techniques, this study shows that loss of
      mobility by distortion of the natural scaffold induces early failure. It is
      extremely important to correct implantation of stentless valves to prevent early
      degeneration.

PMID- 10660187
TI  - The No-React anticalcification treatment: a comparison of Biocor No-React II and
      Toronto SPV stentless bioprostheses implanted in sheep.
AB  - Calcification of stentless aortic heterografts still limits the use of these
      bioprostheses in young patients despite their superior hemodynamic profile. The
      No-React treatment is described as an anticalcification treatment for
      biomaterials. We compared the Biocor No-React treated stentless bioprosthesis
      with the routine glutaraldehyde-fixed Toronto SPV bioprosthesis in a juvenile
      sheep model. Toronto SPV or Biocor No-React valves were implanted in pulmonary
      position in juvenile sheep (n = 6). The valves were explanted after 3 months and
      analyzed by gross inspection, x-ray studies, histological examination, and
      transmission electron microscopy. The Toronto SPV valve showed calcification of
      the aortic wall portion at both the inflow and outflow sides of the valve. No
      significant calcification of the cusps was found by gross inspection or by
      radiographic or histological examinations. Calcification was visible with
      electron microscopy in cell remnants and between collagen fibers in the cusps.
      The Biocor No-React valve showed extensive calcification of the residual aortic
      wall portion that is contained in the valve. With x-ray and histological
      examinations, clear calcification of the pericardial wrap, largely replacing the
      aortic wall tissue, was seen. Calcification scattered throughout the cusp was
      seen by electron microscopy. We conclude that the Biocor No-React process did not
      prevent calcification of glutaraldehyde-fixed stentless bioprostheses in a
      juvenile sheep experimental model. Furthermore, replacement of a large part of
      the aortic wall by a pericardial wrap did not prevent calcification of the
      stentless valve "wall."

PMID- 10660188
TI  - Are stentless aortic heterografts suitable for right ventricular outflow tract
      reconstruction? An experimental study in juvenile sheep.
AB  - Allograft valved conduits are used routinely for reconstruction of the right
      ventricular outflow tract in children with congenital heart disease; however,
      allografts are scarce. The purpose of this study was to evaluate two stentless
      aortic valves that might be suitable alternatives for right ventricular outflow
      tract reconstruction. Twelve juvenile sheep underwent implantation of stentless
      aortic heterografts as an interposition in the pulmonary artery: six porcine
      aortic valves (Freestyle) and six fully pericardial valves (Pericarbon
      stentless). In each series, three valves were explanted after 3 months, the other
      three after 6 months. Valves were analyzed by gross inspection, radiography, and
      light microscopy. The porcine aortic stentless valve (Freestyle) showed extensive
      calcification of its aortic wall portion, with perfectly functioning, pliable
      cusps without calcification or fibrous overgrowth up to 6 months. The pericardial
      valves (Pericarbon stentless) showed extensive fibrous sheathing, causing
      progressive retraction of the leaflets and severe regurgitation. After 3 months,
      minimal calcification was seen in the pericardial wall. Calcification was more
      pronounced after 6 months, sometimes causing complete calcification of
      pericardial wall and leaflets, leading to a significant stenosis. We conclude
      that the pericardial stentless valve becomes rapidly dysfunctional after right
      sided implantation as a result of fibrous sheathing and severe calcification. The
      porcine aortic stentless valve remains functional, but severe calcification of
      the aortic wall portion is problematic.

PMID- 10660190
TI  - Stentless mitral valve replacement using the quattro valve.
AB  - This study analyzed early clinical results after stentless mitral valve
      (Quadrileaflet Mitral Valve (QMV)/Quattro) implantation. A total of 28 patients
      have received a Quattro valve since August 1997. Patient age was 69+/-8 years;
      the underlying disease was mitral incompetence (14) and stenosis (13).
      Preoperative New York Heart Association functional class was 3.2+/-0.4 and
      cardiac index was 1.8+/-0.6. Mean cross-clamp duration was 58+/-19 minutes.
      Twenty patients received a 28-mm prosthesis, and eight patients received a 30-mm
      prosthesis. Four patients had myocardial revascularization, two had tricuspid
      valve repair, and six had radiofrequency ablation therapy to restore sinus
      rhythm. Mortality (1) was nonvalve related. Reoperation was necessary in two
      patients for posterior paravalvular leakage (1) and for functional stenosis (1).
      Echocardiography showed satisfactory hemodynamic function. By stentless mitral
      valve implantation the annuloventricular continuity is preserved to stabilize
      left ventricular function. The Quattro valve resembles native mitral valve
      function and is well suited for mitral valve replacement.

PMID- 10660189
TI  - The quadrileaflet mitral valve: follow-up in rheumatic heart disease.
AB  - This prospective study evaluated the clinical performance of a novel stentless
      quadrileaflet bovine pericardial mitral valve implanted at one center since
      December 1996. After giving informed consent, patients were included in the study
      if they required isolated mitral valve replacement. All underwent comprehensive
      clinical evaluation, as well as transthoracic M-mode, two-dimensional and Doppler
      (pulsed, continuous, and color) echocardiography preoperatively and
      postoperatively at 1 month, 3 months, and annually thereafter. Mitral valve area
      was derived by planimetry, the pressure half-time method, and the continuity
      equation. The degree of mitral regurgitation was semi-quantitated using color
      Doppler. In all 38 patients with rheumatic valvular heart disease (mean age 35+/
      13 years) were monitored for 13.8+/-7.5 months (range, 1 to 29 months). All but
      three patients are alive and symptomatically improved (functional New York Heart
      Association class I or II). One valve was explanted because of early prosthetic
      valve endocarditis. There were no episodes of thromboembolism or anticoagulation
      related hemorrhage. Left ventricular function was maintained with increased
      cardiac output and low transmitral pressure gradients. The mitral valve area was
      larger when measured by pressure half-time and planimetry than by the continuity
      equation (P<.05). In an independent clinical evaluation of a subset of 30
      patients, mitral stenosis was considered absent in 33%, mild in 30%, mild to
      moderate in 26%, and moderate in 10% of cases. No or less than or equal to mild
      mitral regurgitation was noted in the majority of patients postoperatively, both
      clinically and echocardiographically. We are encouraged by the clinical
      performance of the quadrileaflet mitral valve and with patient outcome. Long-term
      follow-up data are needed to assess durability.

PMID- 10660191
TI  - Mitral valve replacement with homograft.
AB  - The purpose of this study was to review the results of mitral valve replacement
      with mitral valve homograft, applying the method described by Acar, to determine
      if the method could be reproduced and was safe to use. Fourteen patients had
      replacement of the mitral valve with homograft. The diseased valve was excised
      and replaced with a cryopreserved homograft. The papillary muscles of the graft
      were attached to the papillary muscles of the patient in side-to-side fashion,
      using multiple stitches of fine monofilament suture. The annulus of the graft was
      attached to the patient annulus by continuous suture. The repair was supported by
      annuloplasty ring. All patients had intraoperative echocardiography. Patients
      were monitored clinically for up to 1.5 years. There were five men and nine women
      ranging in age from 16 to 70 years (mean = 43 years). Seven had rheumatic, six
      had degenerative, and one congenital morphology. Concomitant Maze III procedure
      was performed in three patients. All patients survived and are currently alive
      and in New York Heart Association functional class I. Thirteen patients have
      normal sinus rhythm. Only one patient has intermittent atrial fibrillation and is
      taking digoxin and warfarin. One patient had dehiscence of the recipient
      papillary muscle that required reoperation for mitral valve replacement with
      prosthesis. Three patients have moderate mitral valve regurgitation. Mitral valve
      replacement with homograft may be accomplished safely and reproducibly using the
      Acar method. Good short-term functional results and maintenance of normal sinus
      rhythm may be expected. Anticoagulant therapy should not be required.

PMID- 10660192
TI  - The SynerGraft valve: a new acellular (nonglutaraldehyde-fixed) tissue heart
      valve for autologous recellularization first experimental studies before clinical
      implantation.
AB  - The durability of current bioprosthetic heart valves is diminished by
      glutaraldehyde-associated leaflet calcification or by the associated absence of a
      cellular component capable of repair of wear-related damage. As a novel tissue
      engineering approach to improving replacement heart valve durability, we have
      developed a decellularization process to replace the use of cross-linking to
      limit xenograft antigenicity. The effectiveness of this process was assessed in a
      weanling sheep right ventricular outflow tract reconstruction model where valve
      function, calcification, and recellularization were examined. Porcine aortic
      valves were decellularized by a process designed to remove all histologically
      demonstrable leaflet cells. Stentless, bioprosthetic valves were fabricated from
      acellular tissues, cryopreserved, sterilized, and then implanted as pulmonary
      valve replacements in 4- to 6-month old female Suffolk sheep. Sheep aortic valves
      were implanted as allograft control subjects. After 150 days, the grafts were
      explanted and assessed histologically and by atomic absorption spectrophotometry
      for calcium content. All valves were hemodynamically functional at explant.
      Histological examination showed intact leaflets with in-growth of host
      fibroblastoid cells in all explanted porcine valves and no evidence of
      calcification. Porcine leaflet calcium content was unchanged over the duration of
      the implant (1.0+/-1.2 vs 1.5+/-1.8 mg/g dry weight, P = ns). Decellularization
      can stabilize xenogenic heart valves. Lack of calcification of acellular aortic
      leaflets suggests that prolonged durability of such valves is attainable without
      the use of cross-linking agents. The repopulation of the leaflet matrix offers
      additional promise of durability based on revitalization of the graft in vivo.

PMID- 10660193
TI  - Fatigue-induced changes to the biaxial mechanical properties of glutaraldehyde
      fixed porcine aortic valve leaflets.
AB  - Circumferential extension is a direct measure of the preservation of functional
      collagen crimp in the fibrosal layer of aortic valve leaflets. The aim of this
      study was to determine whether the elastic properties of zero-pressure,
      glutaraldehyde-fixed leaflets are changed by mechanical fatigue. Nine Medtronic
      Freestyle bioprostheses were subjected to 200x10(6) cycles of accelerated fatigue
      and then biaxially tested to quantify the elastic properties of the leaflets. At
      physiological load (60 Nm(-1)) the radial extensibility was approximately halved
      relative to controls (P<10(-4)); there were also lesser reductions in the
      circumferential extensions (P<.01). The pulsatile regurgitant volume showed no
      change relative to the control leaflets. The natural corrugations of the fibrosal
      layer were flattened by the fatigue cycling, but this was not related to an
      increase in the radial size of the leaflets. Valve competency was maintained.

PMID- 10660194
TI  - The Carbomedics "Oxford" Photofix stentless valve (PSV).
AB  - The hemodynamic superiority of first-generation stentless xenografts over their
      stented equivalents is now clearly defined. Issues of durability remain. In light
      of considerable early experience, we sought to provide an "ideal" stentless valve
      design with the potential for improved durability by eliminating glutaraldehyde.
      The Carbomedics Oxford Photofix stentless valve (PSV) is a composite xenograft
      root constructed from three selected porcine noncoronary cusps fixed by the
      photofix process. The valve inflow has a low pericardial cuff. Consequently there
      are no coronaries, cloth, or muscle bar in the structure. The valve was tested in
      the descending aorta and subcoronary positions of juvenile sheep to compare the
      influence on calcification of photofixation and the alpha-amino-oleic-acid
      treated Freestyle valve. There was a substantial difference between the valves,
      both in radiographic imaging of calcification and the elemental analysis of
      calcium and phosphorus. In the valve cusp, calcium content of PSV was 3.98+/-5.77
      mg/g versus 14.3+/-19.29 mg/g for the Freestyle valve. Equivalent calcium values
      for the aortic wall were 1.99+/-3.39 mg/g versus 130.79+/-56.29 mg/g. We consider
      the composite root configuration without cloth, coronaries, or muscle bar to be a
      promising valve design. The photofix process minimizes xenograft tissue
      calcification and appears superior to existing methods.

PMID- 10660195
TI  - Revealing morbidity.

PMID- 10660196
TI  - Late complications after a combined pre and postoperative (sandwich) radiotherapy
      for rectal cancer.
AB  - BACKGROUND AND PURPOSE: The purpose of this study was to analyse the treatment
      related side effects, the outcome and the prognostic significance of clinical
      parameters in two groups of patients with rectal cancer receiving either
      preoperative or pre and postoperative radiotherapy after radical resection. The
      authors of this study were not involved in the radiation treatments. PATIENTS AND
      METHODS: From 1986 to 1990, 63 patients received a combined pre and postoperative
      (sandwich) radiotherapy. Preoperative irradiation was given in four fractions of
      5 Gy each applied within 2 or 3 days. Postoperative irradiation consisted mostly
      of 15 x 2 Gy (31 patients) but the range was 20-40 Gy. The results were compared
      with those on 73 patients who only received preoperative radiotherapy in the same
      time period. The distribution of prognostic factors was not very different
      between treatment groups. Out of 63 patients in the sandwich group, 22 received
      concurrent chemotherapy and 18 also received radiotherapy to the liver. Radical
      surgery usually followed on the day after the last preoperative radiotherapy
      session. Median follow-up of survivors was 6 years. RESULTS: Local tumour control
      was 88% after 5 years and 84% after 8 years in the sandwich group, and 90 and
      85%, respectively, in the preoperative radiotherapy group. Thus, tumour control
      was similar for the two radiotherapy regimens applied. However, the percentage of
      patients suffering from one or more complications after 5 years was 84% in the
      sandwich and 17% in the preoperative radiotherapy group. The incidence of severe
      late complications (grade > or = 3) was recorded as a function of time after
      start of treatment. In the sandwich group the actuarial rates of late
      complications at 5 years (and the median time to diagnosis) were 53% (27 months)
      for anorectum, 43% (37 months) for bladder, 28% (51 months) for bone, 19% (36
      months) for dermis, 47% (48 months) for ileum, 41% (32 months) for lymphatic and
      soft tissue, and 44% (53 months) for ureters. CONCLUSIONS: Severe late reactions
      did not occur within a certain period of time, but continued to appear for at
      least 10 years after radiotherapy. Sandwich therapy, as given in this series, did
      not appear to give a greater tumour control than preoperative radiotherapy alone,
      whereas the rate of complications was drastically enhanced. Thus, the rationale
      of a sandwich therapy with a long time interval between surgery and postoperative
      irradiation appears questionable.

PMID- 10660197
TI  - Bone marrow doses and leukaemia risk in radiotherapy of prostate cancer.
AB  - BACKGROUND AND PURPOSE: As more and more patients with prostate cancer are cured
      and survive with only minor chronic morbidity, other potentially treatment
      related morbidity, in particular second cancers, becomes an urgent problem which
      may influence decisions on treatment strategy and treatment plan optimisation.
      Epidemiological data suggest a radiotherapy associated risk of AML in prostate
      cancer patients of approximately 0.1% in 10 years. The aim of the study was to
      determine the range of bone marrow doses from different treatment plans and in
      different patients in order to develop criteria for optimisation of treatment
      plans in conformal radiotherapy of prostate cancer to further minimise the small
      risk of secondary leukaemia. MATERIALS AND METHODS: Doses to the pelvic bone
      marrow were calculated for eight different plans used in radiotherapy of prostate
      cancer to determine the variability of bone marrow doses in radiotherapy of
      prostate cancer. Computer tomography (CT) slices of the entire pelvic region of
      an Alderson phantom were acquired and transferred to the TPS. Critical bone
      marrow structures were outlined in each slice. Different treatment plans were
      evaluated on this phantom and dose-volume histograms (DVH) for the pelvic bone
      marrow were obtained. Similarly, the DVH for the bone marrow of 14 patients who
      received conformal radiotherapy for prostate cancer was determined. RESULTS: Mean
      total bone marrow doses ranged from 3.4 to 5.6 Gy in the phantom study.
      Approximately 99% of the mean dose to the total bone marrow comes from the dose
      to bone marrow located in the pelvic bones and lumbar vertebrae. Mean bone marrow
      doses of 14 patients given the same conformal radiotherapy plan ranged from 3.5
      to 7.7 Gy. CONCLUSIONS: No correlation was found between the rectum normal tissue
      complication probability (NTCP) and the mean bone marrow dose. This means that in
      the process of treatment planning, exposure to both critical organs, the rectum
      as well as the bone marrow, should be minimised independently to arrive at the
      optimal treatment plan.

PMID- 10660198
TI  - Risk assessment of radiation-induced malignancies based on whole-body equivalent
      dose estimates for IMRT treatment in the head and neck region.
AB  - BACKGROUND AND PURPOSE: Intensity modulated radiation therapy (IMRT) has been
      introduced in our department for treatment of the head and neck region with the
      intention of reducing complications without compromising treatment outcome.
      However, these new treatment modalities inevitably require a substantial increase
      in monitor units per target dose yielding an increased risk of secondary
      malignancies induced by the treatment. This study aims at assessing the increased
      risk by means of in vivo measurements of the whole-body equivalent dose of both
      the conventional and the IMRT treatment techniques for head and neck lesions.
      MATERIAL AND METHODS: A conventional technique using parallel opposed, wedged
      treatment fields has been compared with a slice-by-slice arc rotation technique
      for IMRT. Both techniques were used to treat head and neck lesions with a 6-MV
      photon beam. Thermoluminescent badges and neutron bubble detectors designed for
      personnel monitoring have been applied to obtain the estimated whole-body
      equivalent dose on three patients for each treatment technique. The nominal
      probability coefficient for a lifetime risk of excess fatal cancer, recommended
      by the ICRP 60 has been used for risk estimates based on the estimated dose
      values. RESULTS: An estimated whole-body equivalent dose per monitor unit equal
      to 1.2 x 10(-2) mSv/MU and 1.6 x 10(-2) mSv/MU have been obtained with the
      conventional and IMRT technique, respectively. Applying the average amount of MU
      necessary to realize a 70 Gy target dose the estimated whole-body equivalent dose
      for both treatment techniques becomes 242 mSv (conventional) and 1969 mSv (IMRT),
      yielding an increase in the risk for secondary malignancies with a factor 8.
      CONCLUSIONS: Historically the risk of secondary malignancies has been accepted to
      take advantage of the possible benefits of improved local control and treatment
      outcome. However, the introduction of new and sophisticated treatment techniques
      will also increase the risk of radiation induced malignancies. Therefore, these
      risk estimates become important to assess whether the benefits of the treatment
      technique outweigh the possible risks.

PMID- 10660199
TI  - Assessment of a carcinogenic risk for treatment of Graves' ophthalmopathy in
      dependence on age and irradiation geometry.
AB  - In view of the probable carcinogenic risk due to the irradiation of Graves'
      ophthalmopathy in young patients the effective dose was assessed for two
      geometries. Adjusting the field to the conical outline of the orbit resulted in
      appreciable reduction in dose to uninvolved areas such as brain and bone marrow.
      In Leiden and in Essen the initial target dose was 20 Gy in 10 fractions of 2 Gy.
      Since 1996 the target dose in Essen was lowered to 10 fractions of 1.6 Gy with
      equal positive results. The combined effect of field optimization and 20%
      reduction in target dose has lowered the effective dose from 65 to 34 mSv. The
      attributable lifetime risk for fatal malignancies of 0.3% as a population average
      will be considerably reduced when the exposure occurs at older age.

PMID- 10660200
TI  - Pathological prognostic factors in a series of 137 stage I TNM/UICC endometrial
      carcinomas.
AB  - PURPOSE: We report on the long-term results of combination surgery-radiotherapy
      in cT1 carcinoma of the endometrium according to prognostic factors. PATIENTS AND
      METHODS: From 1974 to 1993, 130 women suffering from cT1Nx-O Mo endometrial
      carcinoma, underwent surgical resection. The median age was 62 years. Thirteen
      received pre-operative irradiation, two pre-operative brachytherapy followed by
      post-operative external irradiation and 115 patients (88.35%) underwent post
      operative irradiation therapy by brachytherapy or external beam irradiation.
      RESULTS: The median follow-up is 67 months. Overall and specific survival rates
      for patients with cT1pT1 tumours were 71.1 and 85% at 10 years. For overall
      survival, lymph node invasion was the most powerful prognostic factor in the
      multivariate analysis (P = 0.02). If lymph node invasion is not taken into
      account, the WHO histological grade exerts a significant prognostic impact (P =
      0.001). CONCLUSION: For stage cT1 endometrial carcinoma, primary surgery allows
      radiotherapy to be adjusted according to the WHO histological grade, myometrial
      invasion and the pelvic lymph node status.

PMID- 10660201
TI  - Is there place for radiotherapy in the treatment of advanced ovarian cancer?
AB  - BACKGROUND AND PURPOSE: Irradiation of advanced ovarian cancer has been performed
      during the years 1976-1984 with six-field technique. Results of this treatment in
      a long follow-up have never before been evaluated. MATERIAL AND METHODS: Seventy
      five patients with stage IIb-IV of invasive ovarian cancer have been treated with
      a combination of surgery, radiotherapy and chemotherapy. The results of the
      treatment were compared with 98 patients treated during the year 1991-1992 with
      surgery and chemotherapy only. RESULTS: After controlling for the differences in
      background factors between the groups considered, there was still a significantly
      better survival rate for the patients treated with radiotherapy. CONCLUSION: The
      results suggest that the role of radiotherapy in advanced ovarian cancer should
      be investigated in a prospective randomized trial.

PMID- 10660202
TI  - Repair halftimes estimated from observations of treatment-related morbidity after
      CHART or conventional radiotherapy in head and neck cancer.
AB  - BACKGROUND AND PURPOSE: The CHART (Continuous Hyperfractionated Accelerated
      Radiotherapy) head and neck cancer fractionation schedule delivered 54 Gy in 36
      fractions on 12 consecutive days and this was compared in a randomised controlled
      trial with conventional fractionation delivering 66 Gy in 33 fractions over 6-7
      weeks. Patients receiving CHART experienced statistically significantly less
      treatment-related morbidity after 6 months than patients receiving conventional
      fractionation. However, this improved tolerance was much less than anticipated
      from existing knowledge of dose-fractionation effects on late-responding normal
      tissues. Here, the experience from the CHART study is analysed and repair
      halftimes for three types of late treatment-related morbidity of human tissues
      are estimated. PATIENTS AND METHODS: The CHART trial was open for patient accrual
      from March 1990 to April 1995 and a total of 918 patients in 11 participating
      centres were randomised. All patients were followed at regular intervals for a
      minimum of 5 years or until the time of death. At each follow-up, a number of
      treatment-related morbidity items were evaluated and scored prospectively. Data
      for three late endpoints are analysed here: laryngeal oedema, skin telangiectasia
      and subcutaneous fibrosis. Differences in the incidence of these endpoints in the
      two trial arms were quantified by means of the ratio of hazard rates in a Cox
      proportional hazards model. Monte Carlo sampling was performed from distributions
      of fractionation sensitivity (quantified by the alpha/beta-ratio) and steepness
      of the dose-response curve (quantified by the normalised dose-response gradient,
      gamma50) with means and standard deviations derived from the literature. Each
      pair of values were used to convert a Monte Carlo sampled estimate of the
      difference in biological effect into an estimate of the repair halftime. From the
      distribution of 1000 Monte Carlo samples, the mean repair halftime and its 95%
      confidence interval were estimated. RESULTS: The estimated repair halftimes, with
      95% confidence intervals in parentheses, were 4.9 h (3.2, 6.4) for laryngeal
      oedema, 3.8 h (2.5, 4.6) for skin telangiectasia and 4.4 h (3.8, 4.9) for
      subcutaneous fibrosis. Calculations show that these repair halftimes are
      consistent with the observations from two published randomised controlled trials
      of altered fractionation in head and neck cancer, the EORTC 22791 and 22851
      trials. CONCLUSIONS: These long repair halftimes for late effects in human normal
      tissues have to be considered in order to gain the full benefit from
      fractionation schedules employing multiple fractions per day.

PMID- 10660203
TI  - How valid is the assumption of equal effect per fraction?
AB  - BACKGROUND AND PURPOSE: The validity of the assumption of equal biological effect
      with dose per fraction in fractionated radiotherapy has been examined for the
      acute skin reaction in a rat foot model using a variable number of 2-Gy daily
      fractions followed by graded top-up doses. MATERIAL AND METHODS: Mature female
      rats were used. Both hind feet of each rat were irradiated with a range of
      fractionated and top-up doses of 60Co gamma-rays. The dose-related incidence of
      moist desquamation was used as an end-point. Quantal data for the incidence of
      moist desquamation were analysed using probit analysis and ED50 (+/-SE) values
      were obtained. The results were also compared with predicted values obtained from
      the application LQ-model. RESULTS: After a single 2-Gy fraction followed by top
      up doses 24 h later, the dose effect curve for the top-up doses used was shifted
      to lower doses as expected and the ED50 for moist desquamation of 19.78 +/- 0.13
      Gy was 1.16 Gy less than the ED50 of 20.94 +/- 0.15 Gy for large single dose
      exposure alone. This implied that only approximately 58% of the initial 2-Gy
      fraction was effective, and the rest was repaired within a 24-h interval between
      the 2 Gy and top-up doses. However, after two or three 2-Gy daily fractions the
      dose effect curves for the subsequent top-up doses moved to the higher doses
      again and the ED50 for top-up dose increased to 20.33 +/- 0.21 and 20.75 +/- 0.11
      Gy, respectively. A further increase in the number of 2-Gy daily fractions
      shifted the dose effect curves for the top-up doses to lower doses and ED50
      values for the top-up doses decreased progressively. CONCLUSIONS: The findings
      were not in keeping with values predicted based on the assumption of equal effect
      per fraction and could not be explained by the use of a single alpha/beta ratio
      in the LQ-model.

PMID- 10660204
TI  - Acute and late toxicity, tumour control and intrinsic radiosensitivity of primary
      fibroblasts in vitro of patients with advanced head and neck cancer after
      concomitant boost radiochemotherapy.
AB  - BACKGROUND AND PURPOSE: The existence of hereditary factors influencing the
      cellular response to ionising radiation has led to the hypothesis that the inter
      patient variability of clinical radiation reactions may, at least in part, be
      attributable to an individual, or intrinsic, radiosensitivity. Considerable
      effort has been spent in the development of test systems that would determine
      individual radiosensitivity before or early during radiotherapy to possibly
      predict treatment outcome, but the results are still conflicting. The present
      explorative study was therefore aimed at the detection of associations between
      acute and late radiation effects, tumour control and in vitro radiosensitivity of
      primary normal tissue fibroblasts. PATIENTS AND METHODS: Sixty-eight patients
      with squamous cell carcinoma of the head and neck (93% UICC stage IV) were
      treated with a simultaneous concomitant boost radiochemotherapy with Carboplatin
      as part of a prospective non-randomised multicenter study at the University of
      Heidelberg. Primary fibroblasts were obtained from skin biopsies prior to
      treatment from 25 unselected patients of this study and the SF2 was determined
      using the colony forming assay and high dose-rate irradiation. The median follow
      up was 21 months (range 2.5-81 months). RESULTS: The locoregional control rate at
      three years was 32%. No significant association between acute (mucosa reaction
      grade 1 or 2 vs. grade 3 and 4), late radiation effects (subcutaneous fibrosis,
      osteonecrosis, larynx oedema), locoregional tumour control and SF2 of primary
      fibroblasts was found using Cox proportional hazards regression analysis, log
      rank test and Mann-Whitney U-test. Although a steep dose-response relationship
      was observed for the radiation-induced severe larynx oedema, Cox proportional
      hazards regression analysis could not fully explain the occurrence of severe
      radiation-induced larynx oedema with the dose to the larynx (P = 0.09). In the
      subgroup of twenty-five patients, where the SF2 was determined, bivariate
      analysis revealed about the same non-significant influence of the dose to the
      larynx on the larynx oedema (P = 0.1) and no influence of the SF2 (P = 0.5).
      CONCLUSIONS: In our study of patients with advanced cancer of the head and neck,
      neither the normal fibroblast SF2 nor the severity of acute radiation effects
      were able to predict late radiation effects or locoregional tumour control.

PMID- 10660205
TI  - Evaluation of a target contouring protocol for 3D conformal radiotherapy in non
      small cell lung cancer.
AB  - BACKGROUND: A protocol for the contouring of target volumes in lung cancer was
      implemented. Subsequently, a study was performed in order to determine the intra
      and inter-clinician variations in contoured volumes. MATERIALS AND METHODS: Six
      radiation oncologists (RO) contoured the gross tumour volume (GTV) and/or
      clinical target volume (CTV), and planning target volume (PTV) for three patients
      with non-small cell lung cancer (NSCLC), on two separate occasions. These were,
      respectively, a well-circumscribed T1N0M0 lesion, an irregularly shaped T2N0M0
      lesion, and a T2N2M0 tumour. Detailed diagnostic radiology reports were provided
      and contours were entered into a 3D planning system. The target volumes were
      calculated and beams-eye view (BEV) plots were generated to visualise differences
      in contouring. A software tool was used to expand the GTV and CTV in three
      dimensions for an automatically derived PTV. RESULTS: Significant inter-RO
      variations in contoured target volumes were observed for all patients, and these
      were greater than intra-RO differences. The ratio of the largest to smallest
      contoured volume ranged from 1.6 for the GTV in the T1N0 lesion, to 2.0 for the
      PTV in the T2N2 lesion. The BEV plots revealed significant inter-RO variations in
      contouring the mediastinal CTV. The PTV's derived using a 3D margin programme
      were larger than manually contoured PTV's. These variations did not correlate
      with the experience of ROs. CONCLUSIONS: Despite the use of an institutional
      contouring protocol, significant interclinician variations persist in contouring
      target volumes in NSCLC. Additional measures to decrease such variations should
      be incorporated into clinical trials.

PMID- 10660206
TI  - Clinical implementation of wedge filter optimization in three-dimensional
      radiotherapy treatment planning.
AB  - BACKGROUND AND PURPOSE: To describe a wedge filter optimization technique which
      automatically chooses the beam weights and wedge filters and to demonstrate the
      implementation of the algorithm in clinical three-dimensional (3D) radiotherapy
      treatment planning. MATERIAL AND METHODS: Given the incident directions and beam
      energies of J beams, the dose distribution is a function of the beam weights,
      wedge angles, and wedge orientations. Instead of decomposing an incident field
      into a superposition of an open and two nominal wedged fields and then optimizing
      their weights, the algorithm optimizes the objective function with respect to the
      beam weights, wedge angles and wedge orientations directly. A salient feature of
      the algorithm is that no planner intervention was required in the selection of
      wedge filters during the optimization process. A dose-based objective function
      which incorporated the relative importance of structures was adopted in this
      work. The objective function was minimized by the method of simulated annealing.
      The technique was demonstrated by using a phantom study and two clinical cases.
      RESULTS: For the phantom case, the classical wedge pair result was obtained,
      providing a useful test of the algorithm. Dose distributions and dose volume
      histograms for the target and surrounding organs were presented for the two
      clinical cases. It was also shown that dose homogeneity to the target could be
      compromised by increasing the relative importance factors to the surrounding
      organs. CONCLUSIONS: A 3D wedge filter optimization algorithm has been developed.
      The technique has the potential to fully automate the 3D radiotherapy treatment
      planning process. In addition, treatment planning time and efforts were
      significantly reduced.

PMID- 10660207
TI  - Inhibition of Ca2+ release channel (ryanodine receptor) activity by sphingolipid
      bases: mechanism of action.
AB  - Sphingosine inhibits the activity of the skeletal muscle Ca2+ release channel
      (ryanodine receptor) and is a noncompetitive inhibitor of [3H]ryanodine binding
      (Needleman et al., Am. J. Physiol. 272, C1465-1474, 1997). To determine the
      contribution of other sphingolipids to the regulation of ryanodine receptor
      activity, several sphingolipid bases were assessed for their ability to alter
      [3H]ryanodine binding to sarcoplasmic reticulum (SR) membranes and to modulate
      the activity of the Ca2+ release channel. Three lipids, N,N-dimethylsphingosine,
      dihydrosphingosine, and phytosphingosine, inhibited [3H]ryanodine binding to both
      skeletal and cardiac SR membranes. However, the potency of these three lipids and
      sphingosine was lower in rabbit cardiac membranes when compared to rabbit
      skeletal muscle membranes and when compared to sphingosine. Like sphingosine, the
      lipids inhibited [3H]ryanodine binding by greatly increasing the rate of
      dissociation of bound [3H]ryanodine from SR membranes, indicating that these
      three sphingolipid bases were noncompetitive inhibitors of [3H]ryanodine binding.
      These bases also decreased the activity of the Ca2+ release channel incorporated
      into planar lipid bilayers by stabilizing a long closed state. Sphingosine-1-PO4
      and C6 to C18 ceramides of sphingosine had no significant effect on [3H]ryanodine
      binding to cardiac or skeletal muscle SR membranes. Saturation of the double bond
      at positions 4-5 decreased the ability of the sphingolipid bases to inhibit
      [3H]ryanodine binding 2-3 fold compared to sphingosine. In summary, our data
      indicate that other endogenous sphingolipid bases are capable of modulating the
      activity of the Ca2+ release channel and as a class possess a common mechanism of
      inhibition.

PMID- 10660208
TI  - Enzymatic fatty acid exchange in digalactosyldiacylglycerol.
AB  - Six different lipases were screened for their ability of acidolysis between
      digalactosyldiacylglycerol (DGDG) and heptadecanoic acid in toluene. Lipases from
      Geotrichum candidum, Alcaligenes sp. and Penicillium camembertii did not catalyse
      the acidolysis reaction. Rhizopus arrhizus and Rhizomucor miehei (Lipozyme)
      catalysed the acidolysis but produced a mixture of DGMG, DGDG, acyl-DGMG and acyl
      DGDG. The extra acyl group is bound to the primary hydroxyl of the digalactosyl
      moiety. Candida antarctica also catalysed the acidolysis but the TLC analysis
      showed bands with higher Rf values than acyl-DGDG, these probably being different
      tetra and higher esters. R. arrhizus lipase was the most promising enzyme under
      the conditions used, with no tetra esters being formed and giving the highest
      reaction rate of the enzymes investigated. Low water activity (0.06 or 0.11) and
      high fatty acid concentration (400 mM) increased the formation of acyl-DGDG
      whilst higher water activities (0.33 and 0.54) increased the amount of DGMG when
      R. arrhizus lipase was used as catalyst. At a water activity of 0.11 and a fatty
      acid concentration of 400 mM a yield of 24% modified DGDG was obtained. In this
      product the fatty acid originally present in the sn-1 position had been exchanged
      by heptadecanoic acid.

PMID- 10660209
TI  - Solid state molecular motion in sucrose octapalmitate as studied by deuterium NMR
      spectroscopy.
AB  - Sucrose octapalmitate-d11, d24 and d248 have been synthesized. Using 2H NMR T1
      and analyses of the temperature dependence of the lineshapes, a detailed
      description of the solid state molecular motional modes is presented. Activation
      energies for methyl and methylene group rotation in the fatty acyl chains have
      been determined. The sucrose moiety is found to be static on the solid state
      deuterium NMR timescale.

PMID- 10660210
TI  - Molecular interactions of peptides with phospholipid vesicle membranes as studied
      by fluorescence correlation spectroscopy.
AB  - Interactions of the peptides melittin and magainin with phospholipid vesicle
      membranes have been studied using fluorescence correlation spectroscopy.
      Molecular interactions of melittin and magainin with phospholipid membranes are
      performed in rhodamine-entrapped vesicles (REV) and in rhodamine-labelled
      phospholipid vesicles (RLV), which did not entrap free rhodamine inside. The
      results demonstrate that melittin makes channels into vesicle membranes since
      exposure of melittin to vesicles causes rhodamine release only from REV but not
      from RLV. It is obvious that rhodamine can not be released from RLV because the
      inside of RLV is free of dye molecules. In contrast, magainin breaks vesicles
      since addition of magainin to vesicles results in rhodamine release from both REV
      and RLV. As the inside of RLV is free of rhodamine, the appearance of rhodamine
      in solution confirms that these vesicles are broken into rhodamine-labelled
      phospholipid fragments after addition of magainin. This study is of
      pharmaceutical significance since it will provide insights that fluorescence
      correlation spectroscopy can be used as a rapid protocol to test incorporation
      and release of drugs by vesicles.

PMID- 10660211
TI  - Kinetics of lipid peroxidation in compartmentalized systems initiated by a water
      soluble free radical source.
AB  - Kinetic rate laws arising from theoretical expectations for the oxidation of
      lipids initiated by water-soluble free radicals in compartmentalized systems
      under different experimental conditions are deduced. In particular, the
      predictions for the kinetic reaction orders in: (a) intra-particle oxidizable
      compound concentration (at fixed number of particles and particle size), alpha;
      (b) number of particles or analytical lipid concentration (at fixed intra
      particle concentration and particle size), beta and (c) initiator, gamma, are
      obtained. The reaction orders beta and gamma are determined by the fraction of
      initiator derived radicals captured by the particles (f) and the mean number of
      chain carrying radicals per particle (<n>) when the system reaches the steady
      state condition. Predicted orders in initiator range from 0 (<n> = 0.5) to 0.5 (f
      ->1; <n> > > 1), while the order in number of particles ranges between 0.5 (f-
      >1; <n> > > 1) and 1. These predictions are tested by measuring the kinetic law
      for the oxidation of SUV's egg yolk phosphatidylcholine vesicles initiated by the
      thermal decomposition of ABAP. The results indicate that, under the conditions
      employed, beta = 0.68 +/- 0.05 and gamma = 0.46 +/- 0.04. These values are close
      to those expected for a system in which <n> > > 1 and the efficiency of capture
      is relatively high. This last condition is confirmed by estimating the efficiency
      of capture from a comparison of induction times elicited by similar
      concentrations of Trolox and alpha-tocopherol.

PMID- 10660212
TI  - 1,3-Diacylglycero-2-phosphocholines--synthesis, aggregation behaviour and
      properties as inhibitors of phospholipase D.
AB  - A series of 1,3-diacylglycero-2-phosphocholines (1,3-PCs) with acyl chain lengths
      of C8-C18 were synthesised by chemical introduction of the phosphocholine moiety
      into the regioisomerically pure 1,3-diacylglycerols, which were obtained from
      glycerol and the vinyl esters of fatty acid by means of lipase from Rhizomucor
      mihei. The 1,3-PCs being regioisomers of the natural glycerophospholipids were
      studied with respect to their aggregation behaviour in the absence and in the
      presence of sodium dodecylsulfate (SDS) as well as their properties as substrates
      and inhibitors of phospholipase D (PLD) from cabbage. While the main structures
      of the pure 1,3-PCs were micelles (C8), liposomes (C10, C12) or planar bilayers
      (C14, C16, C18), the addition of SDS resulted in the formation of mixed micelles
      (C8, C10) and mixed liposomes (C12, C14, C16, C18). None of the 1,3-PCs was found
      to be hydrolysed by PLD, whereas all of them showed inhibitory properties in the
      standard assay for PLD. The inhibitory power was strongest with 1,3
      didecanoylglycero-2-phosphocholine (IC50 = 43 microM).

PMID- 10660213
TI  - Synthesis, structure, and thermal properties of 1,2-dipalmitoylgalloylglycerol
      (DPGG), a novel self-adhering lipid.
AB  - A novel diacyl glycerol-based lipid with a polyphenolic head group has been
      synthesized and characterized. X-ray diffraction experiments show that this
      lipid, 1,2-dipalmitoylgalloylglycerol (DPGG), hydrates to form gel phase bilayers
      at 20 degrees C with extremely narrow interbilayer fluid separations, indicating
      that apposing DPGG bilayers strongly adhere to each other. Differential scanning
      calorimetry shows that fully hydrated DPGG exhibits a pretransition exotherm (3.7
      kcal/mol) at 52 degrees C and a high enthalpy (11.3 kcal/mol) main endothermic
      transition at 69 degrees C. These thermal properties are similar to those of
      galactosylceramides with similar hydrocarbon chain compositions. The adhesive and
      thermal properties of DPGG are likely due to both intermolecular hydrogen-bonding
      and hydrophobic interactions between the aromatic rings on the gallic acids.

PMID- 10660214
TI  - Thermotropic and lyotropic properties of long chain alkyl glycopyranosides. Part
      I: monosaccharide headgroups.
AB  - A systematic structure variation of a classical amphiphile (dodecyl-beta-D
      glucopyranoside) is performed, demonstrating the influence of anomeric linkage,
      configuration, ring size and flexibility as well as electric charges on the
      mesophase behaviour. In addition, we have investigated the thermotropic and
      lyotropic properties of some long chain alkyl glycosides with monosaccharide
      headgroups. The thermotropism was measured with polarizing microscopy and
      differential scanning calorimetry, and additionally the lyotropism with FTIR
      spectroscopy and X-ray diffraction.

PMID- 10660215
TI  - Surface properties of unsaturated non-oxidized and oxidized free fatty acids
      spread as monomolecular films at an argon/water interface.
AB  - The interfacial properties of monomolecular films of stearic acid (SA) oleic acid
      (OA), linoleic acid (LA), ricinoleic acid (RA), 13(S)-hydroperoxyoctadeca-9Z,11E
      dienoic acid (13-HPODE) and 13(S)-hydroxyoctadeca-9Z,11E-dienoic acid (13-HODE)
      were studied by recording the changes occurring in response to monomolecular film
      compression in their surface pressure and surface potential at the argon/water
      interface. The oxidized free fatty acids are more expanded than the parent non
      oxidized free fatty acids, reflecting a higher hydrophilic-lipophilic balance.
      The lift-off values of the molecular area of 13-HODE, 13-HPODE and RA were 68, 74
      and 106 A2 molecule(-1), respectively, as compared to 47 and 40 A2 molecule(-1)
      in the case of LA and OA, respectively. Variations in the molecular orientation
      of free fatty acids can result in large changes in the dipole moment which are
      not accompanied by appreciable changes in the surface pressure. In the case of
      the oxidized free fatty acids, the spontaneous desorption into the aqueous phase
      was found to increase at increasing surface pressures. The desorption rates of OA
      and LA increased dramatically in the presence of beta-cyclodextrin (beta-CD);
      whereas the presence of beta-CD only slightly increased the desorption rates of
      the oxidized free fatty acids.

PMID- 10660216
TI  - Effects of soybean diet on the beta cells in the streptozotocin treated rats for
      induction of diabetes.
AB  - Certain dietary components have been reported to potentially suppress the
      initiation of experimental insulin-dependent diabetes mellitus (IDDM) in animal
      models. In the present study, we showed that dietary soybean prevents induction
      of experimental hyperglycemia by retaining beta cell activity. In rats fed raw
      soybean, expression of insulin mRNA in pancreatic beta cells was significantly
      increased compared to those fed with normal diet. In those rats and upon
      injection of streptozotocin, only few beta cells underwent cell death, most of
      them demonstrating active viability with enhanced mRNA expression and insulin
      content. This is consistent with the fact that blood glucose level was normalized
      (72.51 +/- 1.54 mg/dl) after a transitory hyperglycemic state (> 300 mg/dl). It
      implies the dietary soybean can prevent beta cell injury by streptozotocin.
      Moreover, a prolonged hyperglycemia was not observed in rats fed raw soybean even
      when this was substituted by the normal diet after streptozotocin injection. In
      contrast, in streptozotocin-treated rats fed normal diet, most beta cells were
      destroyed and severe hyperglycemia was observed. Although the protective effect
      was not recorded in the rats fed with heated soybean, some beta cells were found
      to retain their cell organelles for insulin secretion indicating that some heat
      stable components of soybean might prevent the cytotoxic insult. Therefore, we
      suggest that dietary soybean protected the streptozotocin-induced beta cell
      damage and restrained the development of hyperglycemia in rats.

PMID- 10660218
TI  - Haemostasis and carotid artery wall thickness in non-insulin dependent diabetes
      mellitus.
AB  - The purpose of this study was to examine the associations of carotid artery
      intima-media wall thickness (IMT) with hemostatic proteins and cardiovascular
      risk factors (CVRFs) in participants with and without non-insulin dependent
      diabetes mellitus (NIDDM). IMT measurements were determined by high resolution B
      mode ultrasound imaging of the carotid arteries in 921 participants with NIDDM
      and 11,964 non-diabetic participants aged 45-64 years. Fasting glucose, serum
      lipids and activated partial thromboplastin time, factor VIII fibrinogen, factor
      VII, antithrombin III, protein C, and von Willebrand factor measurements were
      made. Compared to non-diabetic participants, participants with NIDDM had a more
      adverse pattern of CVRFs and a more procoagulatory profile. Participants with
      NIDDM had 0.06 mm (8.1%) higher mean IMT compared to non-diabetic participants
      after adjusting for age and gender (P < 0.001). However, only plasma fibrinogen
      concentrations showed statistically significant positive associations with IMT in
      both groups. After adjusting for CVRFs and fibrinogen, mean IMT remained 0.04 mm
      (5.4%) higher in diabetic compared to non-diabetic participants. Despite the more
      procoagulatory profile in participants with NIDDM, only plasma fibrinogen
      concentrations were independently associated with mean IMT. The association of
      NIDDM with mean IMT was only partly explained by CVRFs.

PMID- 10660217
TI  - Changes of glucose transporters in the cerebral adaptation to hypoglycemia.
AB  - Repeated hypoglycemia increases the glycemic thresholds of responses of
      counterregulatory hormones and of symptoms to subsequent hypoglycemia. This may
      in part be due to cerebral adaptation to hypoglycemia, which involves glucose
      transporter-1 (GLUT1) and glucose transporter-3 (GLUT3). To investigate the role
      of brain GLUT1 and GLUT3 in cerebral adaptation to chronic hypoglycemia, GLUT1
      and GLUT3 mRNA and protein expressions were determined in rat brain using RT-PCR
      and Western blot analyses after 4- and 8-day hypoglycemic insults. Hypoglycemia
      was induced in rats by twice daily subcutaneous injection of intermediate-acting
      insulin with dosage adjustment according to the blood glucose levels. Target
      level of hypoglycemia (< 2.5 mmol/l) was achieved at least once a day in all rats
      included. Control rats received saline injections. Blood glucose levels during
      the 4 and 8 days of insulin treatment were 2.18 +/- 0.12 and 2.68 +/- 0.07
      mmol/l, respectively. Following the 4 and 8 days of hypoglycemia, GLUT1 mRNA
      levels did not significantly change. GLUT3 mRNA expressions after the 4 days of
      hypoglycemia increased by 36.9 +/- 9.4% compared with that in control rats (P =
      0.031), but after the 8 days of hypoglycemia, did not change. On Western blot
      analysis of total particulate rat brain membrane, amount of 55-kDa isoform of
      GLUT1 protein did not change after 4- and 8-day hypoglycemia (88.1 +/- 4.9% of
      control, P = 0.240; 92.1 +/- 1.4% of control, P = 0.096, respectively). In
      contrast, the expression of GLUT3 protein in the 4-day hypoglycemic rats
      increased by 51.4 +/- 8.4% compared with that in control rats (P = 0.004). After
      the 8 days of hypoglycemia, the expression also tended to increase by 44.9 +/-
      14.4% (P = 0.119). There was an inverse correlation between the amount of GLUT3
      protein expression and mean blood glucose levels in 4-day hypoglycemic and
      control rats (r = -0.886, P = 0.019). These data suggest that GLUT3 isoform plays
      a role in the cerebral adaptation to chronic hypoglycemia.

PMID- 10660219
TI  - High incidence of silent myocardial ischemia in elderly patients with non insulin
      dependent diabetes mellitus.
AB  - The present study was designed to reveal the incidence of silent myocardial
      ischemia in asymptomatic elderly non-insulin-dependent diabetic (NIDDM) patients
      (aged over 60 years). As a first step screening, maximal treadmill exercise test
      was performed. Of 140 patients studied, 54 (38.6%) were unable or not expected to
      achieve diagnostic levels of exercise during treadmill testing. A positive
      exercise test was noted in 39 of 86 (45.3%) subjects. As a second step
      examination, dipyridamole thallium scintigraphy was performed for 93 subjects who
      exhibited a positive exercise test and could not perform a maximal exercise test.
      Abnormal perfusion pattern was found in 39 of 93 (41.9%), who were finally
      considered to have a silent myocardial ischemia. Coronary angiography was
      performed in 18 subjects with diagnosis of silent myocardial ischemia, who gave
      their consent. Significant coronary artery stenosis was in fact found in 17 of 18
      (94.4%) subjects studied, confirming a very high positive predictive value of
      this diagnostic procedure. In conclusion, elderly NIDDM patients (aged over 60
      years) had an extremely high prevalence (estimated 26.3%) of silent myocardial
      ischemia. This evidence suggests that early and intensive detection may be needed
      as a part of routine care for this group.

PMID- 10660220
TI  - Association of Chlamydia pneumoniae infection with diabetic nephropathy.
AB  - We evaluated the association of Chlamydia pneumoniae (CP) infection with
      progression of diabetic nephropathy. Type 2 diabetic patients (60) were divided
      into two groups, those with incipient nephropathy and those with advanced
      nephropathy, based on the severity of diffuse glomerular lesions using Gellman's
      criteria. Type 2 (34) diabetic patients without nephropathy (normoalbuminuria)
      and 59 nondiabetics served as control groups. Serum IgG-antibody against CP was
      measured using ELISA. CP antibody was detected in 45.8% of nondiabetic controls,
      in 47.1% of diabetic patients without nephropathy, in 52.6% of diabetic patients
      with incipient nephropathy, and 78% of diabetic patients with advanced
      nephropathy. There was 4.22-fold increase in the risk of advanced nephropathy
      associated with the presence of CP antibody. Our findings indicate an association
      between chronic CP infection and advanced diabetic nephropathy.

PMID- 10660221
TI  - HLA DPB1*0201 gene confers disease susceptibility in japanese with childhood
      onset type I diabetes, independent of HLA-DR and DQ genotypes.
AB  - HLA is an important etiologic genetic factor in Type I diabetes and specific HLA
      class II genes are closely related to the onset of the disease. Many differences
      in the patterns of susceptible and resistant DRB1, DQA1, and DQB1 genes have been
      observed among various ethnic groups. We have previously shown that DRB1*0405,
      DRB1*0901 and DQA1*0301-DQB1*0302 were the major susceptible alleles or haplotype
      to Type I diabetes while DR-DQ haplotype studies suggested the important role of
      DR and DQ alleles in susceptibility and resistance in Japanese patients. Based on
      the analysis of 90 Japanese patients with childhood onset Type I diabetes and 136
      unrelated healthy Japanese controls by polymerase chain reaction-restriction
      fragment polymorphism method (PCR-RFLP), we report here the association of Type I
      diabetes with DPB1*0201 (relative risk = 2.29; Pc = 0.027) in this population.
      Comparison of linkage disequilibrium patterns between patients and controls
      showed that the significantly high prevalence of DPB1*0201 among patients cannot
      be attributed simply to linkage disequilibrium with susceptible DRB1 alleles and
      DQA1-DQB1 haplotypes. Our results suggest that in addition to alleles at the
      DRB1, DQA1, DQB1 loci, polymorphism at DPB1 locus also influences the risk of
      Type I diabetes.

PMID- 10660223
TI  - Association of sex hormone-binding globulin and insulin resistance among Japanese
      American subjects.
AB  - An association between sex hormone-binding globulin (SHBG) and insulin resistance
      expressed by the homeostasis model (HOMA-R), and the significance of both
      variables as risk factors for the development of type 2 diabetes were
      investigated in 483 Japanese-American subjects. The serum SHBG level was
      significantly higher in women (68.7 nmol/l) than in men (45.1 nmol/l). This
      difference was also significant independently of age, body mass index (BMI),
      waist to hip ratio (WHR), and HOMA-R. When multiple regression analysis was
      performed after adjustment for age and BMI, SHBG was not correlated with HOMA-R
      in men. In women, SHBG was not significantly correlated with HOMA-R after
      adjustment for age, BMI, and WHR. In a 3-year prospective analysis, HOMA-R was
      significantly higher in converters to type 2 diabetes than non-converters in both
      men and women which was independent of age, BMI and WHR. However, after adjusting
      these variables, SHBG was not a significant risk factor either in men or women.
      These results indicate that SHBG might be related to insulin resistance
      secondarily via BMI and/or WHR in both men and women among Japanese-Americans.
      HOMA-R is a useful index for both men and women as a risk factor of type 2
      diabetes when only fasting blood samples can be obtained.

PMID- 10660222
TI  - Sociodemographic determinants of glycaemic control in young diabetic patients in
      peninsular Malaysia.
AB  - Recent studies have shown that good glycaemic control can prevent the development
      of diabetic complications in type 1 and type 2 diabetes. We wished to observe the
      glycaemic control in patients from different centres in Peninsular Malaysia and
      the factors that determine it. We recruited 926 patients with diabetes diagnosed
      before age 40 years from seven different centres, with proportionate
      representation from the three main ethnic groups. Clinical history and physical
      examination were done and blood taken for HbA1c and fasting glucose. The overall
      glycaemic control was poor with geometric mean HbA1c of 8.6% whilst 61.1% of the
      patients had HbA1c greater than 8%. Glycaemic control in patients with type 2
      diabetes varied between various centres and ethnic groups, with the best control
      obtained in Chinese patients. Significant predictors of HbA1c in both type 1 and
      type 2 diabetes include access to nurse educators, ethnic background and WHR. In
      type 2 diabetes, use of insulin was a significant predictor, while in type 1
      diabetes, household income was a significant predictor. Socioeconomic status did
      not have a significant effect in type 2 diabetes. There were no significant
      differences in the glycaemic control in patients with different educational
      status. In conclusion, glycaemic control in big hospitals in Malaysia was poor,
      and was closely related to the availability of diabetes care facilities and
      ethnic group, rather than socioeconomic status.

PMID- 10660224
TI  - The functional anatomy of visual-tactile integration in man: a study using
      positron emission tomography.
AB  - The integration of neural signals from different sensory modalities is a
      prerequisite for many cognitive and behavioural functions. In this study, we have
      mapped the functional anatomy of the integration of sensory signals across the
      tactile and visual modalities. Using the PET radiotracer H2(15)O, regional
      cerebral blood flow (rCBF) changes were measured in eight normal volunteers
      performing crossmodal recognition of simultaneously presented visual and tactile
      stimuli using a modified version of the 'arc-circle test'. Whilst intramodal
      matching within the visual modality led to relative rCBF increases in the visual
      association cortex, crossmodal matching (visual-tactile), when compared to
      intramodal matching, was accompanied by relative rCBF increases in the anterior
      cingulate cortex, inferior parietal lobules, the left dorsolateral prefrontal
      cortex (DLPFC) and the left claustrum/insular cortex. The pattern of brain
      activation is congruent with areas of heteromodal and supramodal cortex and
      indicates that activation of multimodal areas is required to solve the crossmodal
      problem.

PMID- 10660225
TI  - The role of speech production in auditory-verbal short-term memory: evidence from
      progressive fluent aphasia.
AB  - We report investigations of auditory-verbal short-term memory (AVSTM) in a
      patient with progressive fluent anomic aphasia. Despite having apparently normal
      AVSTM as measured by digital span, FM was significantly impaired in immediate
      serial recall of short sequences of familiar words, and even in reproducing a
      single word after a filled delay of just a few seconds. In both tasks, unlike
      normal subjects, she produced numerous phonological errors, often consisting of
      phonological segments from the intended target word concatenated with segments
      from other words in the stimulus sequence. Her success in these tasks was
      modulated (i) consistently by word frequency (high > low), (ii) inconsistently by
      word imageability (high > low), and (iii) most dramatically by 'nameability':
      that is, FM was much more likely to reproduce a word correctly in AVSTM if it was
      a word that she could also produce successfully in picture-naming tasks. On the
      basis of these and additional experiments designed to exclude other
      interpretations, we conclude that AVSTM may be crucially supported by activation
      of the lexical phonological representations responsible for production of content
      words in speech.

PMID- 10660226
TI  - The impact of semantic memory impairment on spelling: evidence from semantic
      dementia.
AB  - We assessed spelling and reading abilities in 14 patients with semantic dementia
      (with varying degrees of semantic impairment) and 24 matched controls, using
      spelling-to-dictation and single-word reading tests which manipulated regularity
      of the correspondences between spelling and sound, and word frequency. All of the
      patients exhibited spelling and reading deficits, except at the very earliest
      stages of disease. Longitudinal study of seven of the patients revealed further
      deterioration in spelling, reading, and semantic memory. The performance of both
      subject groups on both spelling and reading was affected by regularity and word
      frequency, but these effects were substantially larger for the patients. Spelling
      of words with exceptional (or more precisely, unpredictable) sound-to-spelling
      correspondences was most impaired, and the majority of errors were phonologically
      plausible renderings of the target words. Reading of low frequency words with
      exceptional spelling-to-sound correspondences was also significantly impaired.
      The spelling and reading deficits were correlated with, and in our interpretation
      are attributed to, the semantic impairment.

PMID- 10660227
TI  - fMRI study of bimanual coordination.
AB  - Eleven right-handed subjects performed uni- and bimanual tapping tasks.
      Hemodynamic responses as measured with functional magnetic resonance imaging
      (fMRI) in the primary somato-motor cortex (SMC) showed that during bimanual
      activity the SMC contralateral to the hand taking the faster rate was more
      strongly activated than the SMC contralateral to hand taking the slower rate.
      There were no asymmetries, left SMC activation during the right fast/left slow
      tapping condition was comparable to the right SMC activation during the left
      fast/right slow condition. A given SMC showed similar activation levels for
      bimanual and unimanual activity (i.e. left SMC activation for right fast/left
      slow was similar to left SMC activation for the right fast unimanual condition).
      In contrast, a given supplementary motor area (SMA) showed significantly more
      activation for the bimanual than for the unimanual activity. In addition, an
      asymmetry was observed during bimanual activities: during the right fast/left
      slow activity, the left SMA showed more activation than the right SMA, but during
      the left fast/right slow activity, the right SMA was not significantly more
      activated than the left SMA. For unimanual activities, a clear rate effect
      (greater activation for faster rate) was seen in the SMC but not in the SMA.

PMID- 10660228
TI  - Spontaneous confabulations, disorientation, and the processing of 'now'.
AB  - We have previously demonstrated that spontaneous confabulations and
      disorientation in amnesia emanate from temporal context confusion in memory
      characterised by intrusion of previously acquired information into ongoing
      thinking. This failure appears to be due to an inability to suppress previously
      activated memory traces of events dating back hours, weeks or even years. In the
      present study, the possibility was explored that spontaneous confabulators also
      have a problem in processing information in the very short-term range of the
      psychological present (the 'now'), which has been defined as the duration of an
      experiential process. Tasks assessing the processing of time within the
      psychological present were devised to test this possibility. In experiment 1,
      spontaneous confabulators, in comparison with other amnestic patients, failed to
      discriminate brief, visually presented intervals in the now. In experiment 2,
      they failed to make motion-associated time estimations within the now. These
      deficits also correlated with disorientation. Although these results do not prove
      a causal relationship, they indicate that spontaneously confabulating and
      disorientated patients typically do fail to process information within the 'now'.

PMID- 10660229
TI  - Classical anomia: a neuropsychological perspective on speech production.
AB  - We present data collected from two anomic aphasics. Thorough assessment of
      comprehension, oral reading and repetition revealed no underlying impairments
      suggesting that both patients were examples of classical anomia--word-finding
      difficulties without impaired semantics or phonology. We describe a series of
      experiments in which the degree of anomia was both increased and decreased, by
      cueing or priming with either a semantically related word or the target item. One
      of the patients also presented with an 'acquired' tip-of-the-tongue phenomenon.
      He was able to indicate with a high-degree of accuracy the syllable length of the
      target, and whether or not it was a compound word. Neither patient could provide
      the first sound/letter. The data are discussed in terms of discrete two-stage
      models of speech production, an interactive-activation theory and a distributed
      model in which the positive and negative computational consequences of the
      arbitrary relationship between sound and meaning are emphasised.

PMID- 10660230
TI  - Movement accuracy constraints in Parkinson's disease patients.
AB  - This study examined the hypothesis that the kinematics of movements performed by
      PD (Parkinson's disease) patients are differentially affected depending on
      whether or not the aiming movement has an accuracy constraint. The aiming
      movements required elbow extension in the horizontal plane on a digitizer. There
      were two movement conditions: (1) one having a spatial accuracy requirement in
      which the subjects moved to the defined target and stopped on it; and (2) one
      requiring the subjects to move toward the defined target without stopping
      precisely on it. Subjects were instructed to make their movements as fast and as
      accurate as possible in response to the auditory imperative signal. PD patients
      modified the movement speed and kinematics depending on the two accuracy
      conditions. However, when the accuracy constraint was imposed, movement slowness
      observed in the patients was much more pronounced. The most revealing result was
      localized to the deceleration phase, particularly as the target was approached.
      The patients also were found to make a higher number of acceleration zero
      crossings from negative to positive to reach the target, indicating that the
      movements were more irregular. For the patients, the first acceleration zero
      crossing from negative to positive occurred much earlier in the movement than
      that for the controls. In addition, when movement accuracy was constrained, the
      number of zero crossings was accentuated. These data show that when PD patients
      make aiming movements to a target, their deceleration phase becomes longer and
      more variable.

PMID- 10660231
TI  - Nurturing syndrome: a form of pathological bereavement with delusions in
      Alzheimer's disease.
AB  - We report the history and neuroimaging profile of two patients, CS and KC who
      developed an unusual bereavement reaction with delusions following the deaths of
      their husbands. Their neuropsychological profiles met criteria for dementia of
      Alzheimer type. The delusions about their husbands' existence were persistent
      despite a considerable passage of time after their deaths. SPECT investigation
      showed reduction of blood flow in the frontal area in both patients when compared
      with demented controls and in particular a significant reduction in perfusion was
      observed in the right frontal regions. We argue that this significant reduction
      of blood flow in the right frontal area, in the context of severe cognitive
      deterioration, might be responsible for their delusional reaction to bereavement
      which we interpret as result of reality monitoring and episodic memory failure.

PMID- 10660232
TI  - Pain--final common pathways: pathophysiology and pragmatism.

PMID- 10660233
TI  - Should we administer epidural or spinal clonidine during labor?

PMID- 10660234
TI  - The importance of combining anatomy and image in Regional Anesthesia and Pain
      Medicine.

PMID- 10660235
TI  - 1996 Labat lecture: pain--a persistent problem.

PMID- 10660236
TI  - Cell death in the central nervous system: therapeutic possibilities?

PMID- 10660237
TI  - August Bier 1861-1949. A tribute to a great surgeon who contributed much to the
      development of modern anesthesia on the 50th anniversary of his death.

PMID- 10660238
TI  - Patient-controlled epidural analgesia in labor: the addition of clonidine to
      bupivacaine-fentanyl.
AB  - BACKGROUND AND OBJECTIVES: Epidural clonidine has not been evaluated as a
      component of patient-controlled epidural analgesia (PCEA) solutions during labor.
      A randomized, double-blind trial was conducted to investigate the efficacy and
      side effects of PCEA using bupivacaine and fentanyl, with or without clonidine.
      METHODS: Seventy-five healthy parturients in active labor were assigned to a PCEA
      solution of 0.0625% bupivacaine and fentanyl 2 microg/mL (4 mL demand bolus, 15
      min lockout), with or without clonidine 4.5 microg/mL. The primary outcome
      measure was parturient rating of analgesia; others assessments included pain
      scores, drug utilization, supplementation and side effects. RESULTS: Thirty-one
      parturients received clonidine (group BFC) and 38 received control solution
      (group BF). Eight (6 group BF, 2 group BFC, P = .28) failed to achieve
      satisfactory epidural analgesia. There was a trend for parturient ratings of pain
      relief to be higher in group BFC, with significantly more reporting excellent
      first-stage analgesia (81% v. 57%, P<.05). Pain scores were similar. Clonidine
      (median dose, 28 microg/h) reduced total bupivacaine and fentanyl use (P<.01),
      and reduced supplementation (P<.01). Maternal blood pressure (BP) and recordings
      of systolic BP below 100 mm Hg did not differ. Group BFC had higher sedation
      scores (P<.01), but no one appeared oversedated. Shivering was reduced in group
      BFC (P<.01). CONCLUSIONS: The addition of clonidine to epidural bupivacaine and
      fentanyl for PCEA in labor improved analgesia, reduced the supplementation rate,
      and reduced shivering. Increased sedation and lower BP were not clinically
      important.

PMID- 10660239
TI  - 1,001 subclavian perivascular brachial plexus blocks: success with a nerve
      stimulator.
AB  - BACKGROUND AND OBJECTIVES: Among the supraclavicular approaches to the brachial
      plexus, the subclavian perivascular technique is a well-established method of
      anesthesia of the upper extremity. Ever since Kulenkampf described his technique,
      eliciting a paresthesia has been almost mandatory ("no paresthesia, no
      anesthesia"). Lately, nerve stimulators have become more popular. However, up to
      the present time, clinical studies involving the nerve stimulator have failed to
      show success rates comparable to paresthesia techniques. METHODS: Data from 1,001
      consecutive, subclavian perivascular blocks were prospectively gathered over 2.5
      years. All blocks were performed according to Winnie's technique, but using a
      nerve stimulator instead of a paresthesia. When an adequate response was
      obtained, 35 to 40 mL of local anesthetic solution was injected. RESULTS: Nine
      hundred seventy-three blocks (97.2%) were completely successful; 16 blocks (1.6%)
      were incomplete and needed supplementation; and 12 blocks (1.2%) failed and
      required general anesthesia, giving a success rate for regional anesthesia of
      98.8%. CONCLUSIONS: The subclavian perivascular block consistently provides an
      effective block for surgery on the upper extremity. At the site of injection with
      this technique, the plexus is reduced to its smallest components and the sheath
      is reduced to its smallest volume, which explains in great part the success
      obtained with this block. We believe that we have demonstrated a nerve stimulator
      technique that is both highly successful and safe; no clinical pneumothorax was
      found nor did any other major complications develop.

PMID- 10660240
TI  - Evaluation of efficacy and plasma concentrations of ropivacaine in continuous
      axillary brachial plexus block: high dose for surgical anesthesia and low dose
      for postoperative analgesia.
AB  - BACKGROUND AND OBJECTIVES: Ropivacaine is a potent local anesthetic that,
      experimentally at low concentrations, produces an effective block of pain
      conducting nerve fibers. Therefore, it was hypothesized that 0.1% and 0.2%
      ropivacaine would provide clinically adequate postoperative analgesia in
      continuous axillary plexus block. METHODS: Sixty patients (ASA I-II) scheduled
      for elective hand or forearm surgery received 5 mg/kg of 0.75% ropivacaine for
      axillary block using nerve stimulator technique. One hour later, in random order,
      a continuous infusion of either 0.1% ropivacaine (0.125 mg/kg/h), 0.2%
      ropivacaine (0.25 mg/kg/h) or saline 6 to 11 mL/h was started. RESULTS: The mean
      total ropivacaine dose for the surgical block was 5.1 to 5.2 mg/kg with the
      supplementation. All patients were pain free for the first 12 to 15 hours after
      the block. The need for postoperative analgesics during the infusion was similar
      in all groups. After the initial block, the maximum plasma concentrations (mean
      2.5 microg/mL) were measured at 45 or 60 minutes after injection. The highest
      individual plasma concentration was 4.2 microg/mL. Despite the high venous peak
      concentration, no toxic reactions were observed. The mean peak plasma
      concentration (Cmax) was 2.2+/-0.5 microg/mL for saline, 2.6+/-0.8 microg/mL for
      0.1% ropivacaine, and 2.6+/-0.7 microg/mL for 0.2% ropivacaine. During the
      continuous infusion of 24 hours, the ropivacaine concentration declined steadily.
      CONCLUSIONS: Ropivacaine is safe and effective for axillary brachial plexus
      block. The continuous infusion of 0.1% or 0.2% ropivacaine was no more beneficial
      than an infusion of saline in relieving postoperative pain in patients having
      elective hand surgery. None of the infusions were sufficient to adequately treat
      the patients' pain without the addition of adjunct agents.

PMID- 10660241
TI  - The local anesthetic properties and toxicity of saxitonin homologues for rat
      sciatic nerve block in vivo.
AB  - BACKGROUND AND OBJECTIVES: Saxitoxin and its homologues are naturally occurring
      compounds that block the sodium channel with high potency. They have the
      potential for providing prolonged duration local anesthesia when coinjected with
      vasoconstrictors or conventional local anesthetics and are devoid of local
      neurotoxicity. Here, we compare sciatic nerve block with saxitoxin to those with
      neosaxitoxin, decarbamoyl saxitoxin, and tetrodotoxin (TTX), in a search for even
      safer compounds. METHODS: Rats received percutaneous sciatic nerve block with
      toxins. The compounds were compared in terms of lethality, onset and duration of
      action for thermal analgesia (hot-plate testing), and motor block (weight
      bearing). Data were expressed as medians with 25th and 75th percentiles, and
      median effective concentrations were determined. RESULTS: The median
      concentrations at which analgesia of 60 minutes duration was achieved were
      neosaxitoxin, 34+/-2 micromol/L; saxitoxin, 58+/-3 micromol/L; TTX, 92+/-5
      micromol/L; and decarbamoyl saxitoxin, 268+/-8 micromol/L. Similar trends were
      observed for other measures of effectiveness (block duration of 90 minutes,
      maximal block), and for lethality so that the therapeutic indices were similar.
      No toxin had a marked predominance of sensory or motor block. The potency of TTX
      was intermediate between those of the saxitoxins, and its therapeutic index was
      slightly better. No difference was observed in time to onset of nerve blockade
      among the toxins. CONCLUSIONS: Substitutions on the saxitoxin nucleus result in
      large differences in incidence and duration of block, and toxicity. The
      therapeutic indices of the saxitoxins are similar; that of TTX is slightly
      better.

PMID- 10660242
TI  - Supraspinal pupillary effects of intravenous and epidural fentanyl during
      isoflurane anesthesia.
AB  - BACKGROUND AND OBJECTIVES: Epidural fentanyl has been shown to gain rapid access
      to the circulation resulting in supraspinal effects. We compared the supraspinal
      effects of fentanyl via epidural versus intravenous (IV) routes, during
      isoflurane anesthesia. Supraspinal fentanyl effect was evaluated as a reduction
      of pupillary reflex dilation (PRD) measured with infrared pupillometry. METHODS:
      Eighteen patients undergoing abdominal procedures were studied during combined
      epidural and general anesthesia. General anesthesia was provided by 0.55 to 0.70%
      end-tidal isofurane in air:oxygen (50:50). Sensory block of the surgical field
      was established with bupivacaine 0.375% and confirmed by absence of PRD to
      cutaneous stimulation. A high cervical dermatome was then stimulated (60 to 70
      mA) at 5-minute intervals via cutaneous needle electrodes, and PRD was measured
      with each stimulation, using infrared pupillometry. Baseline PRD was determined
      and then a randomized injection of cpidueral saline (n = 6), epidural fentanyl 3
      microg/kg (n = 6), or IV fentanyl 3 microg/kg (n = 6) was given. Subsequently,
      PRD was measured at 5, 10, 20, 30, 40, 60, and 80 minutes. Maximum change in PRD
      and time to maximum change were calculated for each group. RESULTS: Following
      epidural injection, suppression of PRD was highly variable among subjects. The
      maximum suppression was 70+/-15% at 23.3+/-10.3 minutes for the epidural group
      and 96+/-3% at 10.8+/-7.4 min for the IV group (P<.0001). Epidural saline
      produced no effect. CONCLUSIONS: Supraspinal effects of epidural fentanyl can be
      assessed during general anesthesia using infrared pupillometry. Epidural fentanyl
      3 microg/kg produces significant but variable supraspinal effects during 0.5
      minimum alveolar concentration isoflurane anesthesia.

PMID- 10660243
TI  - Prolonged suppression of tinnitus after peripheral nerve block using bupivacaine
      and lidocaine.
AB  - OBJECTIVE: The local anesthetic lidocaine has been shown to suppress tinnitus,
      albeit very temporarily, when administered intravenously. Long-term suppression
      by local anesthetics has not been reported. Bupivacaine has not been studied.
      Here we report a case of prolonged (1-month) suppression of tinnitus following a
      peripheral nerve block performed with lidocaine and bupivacaine. CASE REPORT: A
      57-year-old man undergoing facet and sacroiliac infiltration with lidocaine and
      bupivacaine experienced symptoms of systemic local anesthetic toxicity. He
      described significant perioral numbness. Shortly after this the patient noted
      that his long-standing and severe tinnitus was completely gone. Follow-up 1 month
      later revealed the tinnitus had not returned. Longer-term follow-up was not
      possible because the patient died. CONCLUSIONS: There are no reports regarding
      the use of bupivacaine for suppression of tinnitus. Although previous reports
      studying lidocaine for this purpose have shown only a brief effect, the use of
      bupivacaine or a combination of lidocaine and bupivacaine, as in this case, may
      represent a treatment for tinnitus that is worth further investigation. There
      currently is no effective long-term therapy for this debilitating problem.

PMID- 10660244
TI  - Upper extremity pain of 10 years duration caused by a glomus tumor.
AB  - BACKGROUND AND OBJECTIVES: Long-standing limb pain typically has a multifactorial
      etiology not amenable to causal therapy. We present a case of chronic progressing
      upper extremity pain caused by a glomus tumor; the excision was curative.
      METHODS: A 39-year-old woman presented with 10-year history of constant deep
      internal throbbing, aching pain localized to the radial aspect of the left index
      finger and additional intermittent shooting pains radiating up the arm toward the
      shoulder. Pain was increased after minor local trauma, following cold exposure,
      and for unknown reasons. A blotchy, bluish skin discoloration could appear on the
      radial aspect of the index finger during severe pain. Nonsteroidal
      antinflammatory drugs, narcotics, amitriptyline, local heat, bracing, and a
      sympathetic nerve block had all been ineffective. The physical examination was
      characterized by exquisite pressure tenderness over the radial aspect of the left
      index finger, most pronounced just distal to the distal interphalengeal joint.
      RESULTS: Inflation of a left arm blood pressure cuff to above systolic pressures
      abolished pain. A glomus tumor was suspected and confirmed by histologic
      examination. CONCLUSIONS: Glomus tumors are rare, benign neoplasms (1 to 5% of
      all hand tumors), developing from neuromyoarterial glomus bodies. They usually
      present with pain and may mimic other painful conditions, delaying the average
      time until diagnosis for up to 10 years. The classic diagnostic triad consists of
      local pain, pressure tenderness, and cold hypersensitivity. Abolition of pain
      following inflation of a blood pressure cuff to above systolic levels (ischemia
      test) is highly diagnostic. We suggest routine use of this test in cases of upper
      limb pain of unclear etiology.

PMID- 10660245
TI  - Epidural hematoma following epidural analgesia in a patient receiving
      unfractionated heparin for thromboprophylaxis.
AB  - BACKGROUND AND OBJECTIVES: The practice of providing postoperative epidural
      analgesia for patients receiving deep venous thromboprophylaxis with
      unfractionated heparin is common. This case report is intended to heighten
      awareness of comorbid risk factors for epidural hematoma and to bring attention
      to the new ASRA consensus guidelines on the management of neuraxial anesthesia in
      the presence of standard heparin. CASE REPORT: A 79-year-old woman with
      apparently normal coagulation and receiving no antiplatelet agents required an
      abdominoperineal resection for recurrent squamous cell carcinoma of the anus.
      Approximately 2 hours after her preoperative dose of 5,000 U unfractionated
      heparin, an epidural catheter was placed on the third attempt. Subcutaneous
      heparin was subsequently administered every 12 hours. Her international
      normalized ratio became slightly elevated during surgery while the partial
      thromboplastin time and platelet count remained normal. The catheter was removed
      on postoperative day 3, 6 hours after the last dose of heparin. The patient
      developed signs of an epidural hematoma requiring surgical evacuation on
      postoperative day 4. The presence of previously undiagnosed spinal stenosis may
      have contributed to her symptoms. CONCLUSION: Management of postoperative
      epidural analgesia in the patient receiving thromboprophylaxis with
      unfractionated heparin requires appropriate timing of epidural insertion and
      removal, monitoring of coagulation status and vigilance.

PMID- 10660246
TI  - Cranial nerve palsy and intracranial subdural hematoma following implantation of
      intrathecal drug delivery device.
AB  - BACKGROUND AND OBJECTIVES: Complications related to cerebrospinal fluid (CSF)
      leak and low CSF pressure can occur following placement of an intrathecal drug
      delivery device. METHODS: A 58-year-old man with chronic, intractable lower back
      pain underwent implantation of an intrathecal drug delivery device. On the fourth
      postoperative day, he developed a postural headache and diplopia with findings
      compatible with left sixth cranial nerve palsy. The headache subsequently became
      constant and nonpostural. Cranial magnetic resonance imaging was obtained that
      showed the presence of a posterior subdural intracranial hematoma. Conservative
      treatment for postdural puncture headache did not improve the symptomatology.
      Therefore, an epidural blood patch was performed that produced rapid improvement
      and eventual resolution of symptoms. CONCLUSIONS: Intrathecal catheter
      implantation can result in CSF loss that might not resolve promptly with
      conservative therapy. In this case, epidural blood patch proved to be a safe and
      effective form of treatment.

PMID- 10660247
TI  - Epidural abscess following epidural analgesia.

PMID- 10660248
TI  - Neurologic complications of spinal and epidural anesthesia.

PMID- 10660249
TI  - Medical resources for the anesthesiologist on the Internet.
AB  - BACKGROUND AND OBJECTIVES: The Internet may be the most powerful information tool
      currently available to medical professionals. The first article in this Internet
      series (Reg Anesth Pain Med 1999;24:369-374) served as an introduction to the
      World Wide Web, while this article describes specific resources available to
      anesthesiologists searching for medical information. EDITOR'S NOTE: This series
      of articles on information technology describes a number of resources. Inclusion
      in this article does not imply endorsement or support by the American Society of
      Regional Anesthesia and Pain Medicine (ASRA-PM). Each reader is encouraged to
      personally evaluate specific websites because of the rapidly changing content and
      location of information on the Internet. This article is available on the ASRA-PM
      website (www.ASRA.com) with updated links to websites in this article.

PMID- 10660250
TI  - Axillary block complicated by hematoma and radial nerve injury.

PMID- 10660251
TI  - Is ropivacaine a culprit?

PMID- 10660252
TI  - Alleged problems with combined spinal and epidural anesthesia.

PMID- 10660253
TI  - Serotypes of verotoxin-producing (Shiga toxin-producing) Escherichia coli
      isolated from healthy sheep.
AB  - Using PCR techniques Shiga toxin-producing strains of Escherichia coli were
      isolated from the faeces of 45 out of 101 healthy sheep. These strains were
      serotyped and found to include O5:H-, O91:H- and O163:H19, which had previously
      been reported as being associated with human disease including haemolytic uraemic
      syndrome.

PMID- 10660254
TI  - Reptilian paramyxoviruses induce cytokine production in human leukocytes.
AB  - The reptilian paramyxoviruses FDLV and GOV initiated the production and release
      of cytokines like IL-1alpha, IL-1beta, IL-2, TNF-alpha and IFN-alpha in human
      peripheral blood mononuclear cells (PBMC) at 37 degrees C. The target cells
      produced the cytokines without replication of virus.

PMID- 10660256
TI  - Isolation and evaluation of immunological adjuvant activities of saponins from
      Polygala senega L.
AB  - We have identified saponins in the root of Polygala senega L., a plant indigenous
      to the Canadian prairies, which display immunopotentiation activity to protein
      and viral antigens. By two-step extraction and hemolytic activity-guided
      fractionation by silica flush chromatography six saponin fractions were generated
      and their HPLC profiles determined. Two dominant fractions, designated as PS-1
      and PS-2, were tested for adjuvant activity in mice immunized with ovalbumin, and
      hens immunized with rotavirus. The resulting adjuvant activity was compared with
      that of Quil A saponin. The P. senega saponins increased specific antibody levels
      to the antigens, in both mice and hens. In mice, there was a preferential
      increase of the IgG2a subclass, and upon in vitro secondary antigen stimulation,
      high IL-2 and IFN-gamma levels were observed in spleen cell cultures from P.
      senega saponins-immunized animals. The saponins were tested for their toxicity by
      lethality in mice and were found to be less toxic at the same dose than their
      counterpart Quil A. The results of this study indicated the potential of P.
      senega saponins as vaccine adjuvants to increase specific immune responses.

PMID- 10660255
TI  - The response of pigs inoculated with a thymidine kinase-negative (TK-)
      pseudorabies virus to challenge infection with virulent virus.
AB  - 12 Large-White-Landrace piglets were subdivided in four groups of 3 and housed in
      separate units. The piglets of three groups were inoculated with the 86/27V 6C2
      thymidine kinase negative (TK-) mutant of pseudorabies virus (PRV), by different
      routes. A second inoculation with the same mutant was given to the pigs 21 days
      later. The animals of a fourth group were left as uninoculated controls. 21 days
      following the second inoculation with the TK- mutant all pigs were challenge
      infected with the virulent PRV. On post challenge day (PCD) 30 all pigs were
      killed and samples for virus detection and histology were taken from several
      organs. The inoculated TK- mutant of PRV did not induce any ill effects in the
      pigs except a transient febrile reaction in some animals. Virus was recovered
      from nasal swabbings from one pig 2 days after the first inoculation of the
      mutant. After challenge exposure with virulent PRV, the TK- mutant-inoculated
      pigs were apparently protected, whereas the control pigs all were severely
      affected and recovered very slowly over 3 weeks. Virus was isolated from the
      nasal swabbings from the TK- mutant-inoculated pigs on PCDs 2 and 4, whereas the
      nasal swabbings from the control piglets were all positive for virus from PCD 2
      through PCD 10. DNA analysis of the virus recovered showed a pattern identical to
      that of the virulent PRV. Histologic lesions were found in the respiratory and
      the central nervous systems, however, the lesions in the TK- mutant-inoculated
      pigs were much milder compared to those registered for the control pigs. Virus
      was not isolated from any of the tissue samples that were tested, but viral DNA
      with sequences typical of PRV genome was detected by PCR in all samples of
      trigeminal ganglia from either the TK- mutant-inoculated pigs or from the
      controls.

PMID- 10660257
TI  - Isolation, biochemical and serological characterisation of Plesiomonas
      shigelloides from freshwater in Northern Europe.
AB  - Isolation and characterisation of Plesiomonas shigelloides from fresh water in
      Northern Europe is reported in this study. The organisms were isolated from two
      lakes and a river in Sweden. All isolates of P. shigelloides showed an identical
      biochemical profile and belonged to different serotypes, namely, O18, O23, O26,
      O58 and O60. The study indicates that P. shigelloides may occur in the aquatic
      environment of cold climates and as a result, it is likely to be associated with
      human infections caused by waterborne pathogens in geographical areas with
      similar climatic conditions.

PMID- 10660258
TI  - Prevalence and diversity of Aeromonas and Vibrio spp. in coastal waters of
      Southern Italy.
AB  - A survey was undertaken to examine sea water and sediment for the presence of
      Vibrio and Aeromonas spp. along approximately 900 km of coast in Southern Italy
      during early and late summer. A quantitative analysis was also done to evaluate
      the water fecal contamination at the stations examined. The results indicate that
      all the investigated areas were submitted to a wide spatial fluctuation of fecal
      contamination and that Vibrio and Aeromonas spp. were present in both high and
      low fecal-contaminated stations. Sixty two percent of the investigated samples
      were positive for Aeromonas spp., while 42% of samples were positive for Vibrio
      spp. It was interesting to note that 38% of the positive stations for both
      Aeromonas and Vibrio spp. showed a fecal coliform contamination of water at <
      10(2) cells 100 ml(-1). Thus, these findings support the hypothesis that the
      bacterial indicators (such as fecal coliforms) do not always satisfactorily
      reflect the hygienic quality of water. The presence of Vibrionaceae on copepods
      was also investigated. Copepods were sampled at a station located inside the
      harbour of the city of Naples and were found contaminated by V. cholerae non-O1,
      V. alginolyticus, V. fluvialis and A. caviae. Furthermore, the antibiotic
      resistance patterns of isolated bacteria showed the presence of a number of
      resistant strains among the isolates. In order to discriminate the isolates on
      the basis of their biochemical profiles and/or antibiotic resistance patterns,
      cluster analysis was carried out which showed that no unique assay could fully
      discern these isolates. However, the best discrimination resulted from complete
      pattern profile based on both biochemical profiles and antibiotic resistance
      patterns.

PMID- 10660259
TI  - Increased severity of Candida vaginitis in BALB/c nu/nu mice versus the parent
      strain is not abrogated by adoptive transfer of T cell enriched lymphocytes.
AB  - The role of the host immune system in combating candidal infections in the vagina
      is poorly understood. A murine model of Candida vaginitis was used to elucidate
      the role of T cells in a candidal infection. Athymic BALB/c nu/nu mice or normal
      BALB/c mice were induced into estrus and then infected with 1 x 10(6) Candida
      albicans intravaginally. The infection was monitored over 1 week. Samples from
      blood, small intestine, tongue, kidney, spleen, liver, uterus and vagina were
      tested for recoverable C. albicans. Histology of the vagina was assessed for both
      inflammation and extent of infection. Results indicated that the BALB/c nu/nu
      mice had similar levels of vaginal yeast load to the normal BALB/c mice. In 25
      30% of nude mice Candida was also recovered from extra vaginal sites (kidney,
      liver, small intestine), however, extra vaginal dissemination was not observed in
      any normal BALB/c animals. Histologically, both the nu/nu and control BALB/c had
      similar levels of vaginal inflammation; however, the nu/nu mice had more florid
      fungal growth in the vaginal epithelium. Adoptive transfer of either immune or
      non-immune BALB/c T cells into nude mice had no affect on either infection or
      vaginal inflammation. Immunohistochemical staining of vaginal tissues from normal
      BALB/c mice or nude mice adoptively transferred with either immune or non-immune
      T cells with anti-CD3 monoclonal antibody revealed no significant difference
      between groups in the numbers of CD3+ vaginal T cells. However, in mice receiving
      either immune or non-immune T cells no yeast was recovered from any tissues
      except the vagina. These data show that T cells have a limited role in protecting
      the vagina from C. albicans infection.

PMID- 10660261
TI  - The effect of restricted nutrition on uterine macrophage populations in mice.
AB  - The abundant macrophage populations present in the endometrium are implicated in
      the tissue remodelling events and immunological changes necessary for pregnancy.
      Using two regimens of restricted nutrition (95 and 88% of ad libitum intake for
      19 days), we have shown that moderately reduced food consumption can dramatically
      alter the number of endometrial macrophages and their immunoaccessory function in
      mice. Restricted nutrition also interfered with the estrous cycle, but the
      effects on endometrial macrophages were more extensive and qualitatively
      different than could be explained by diminished ovarian steroid hormone activity.
      Significantly less F4/80+ and Ia+ cells were found in the endometrium of food
      restricted mice than in ad libitum mice at the same estrous cycle stage. In the
      more severely restricted mice the losses were even greater than those seen after
      ovariectomy. In ad libitum fed animals, uterine but not peritoneal macrophages
      showed an ovarian hormone-dependent inhibitory phenotype in a splenocyte
      mitogenesis assay. Macrophages derived from both locations exhibited greater
      immunostimulatory activity following restricted nutrition. We conclude that
      endometrial macrophage populations are influenced by nutritional status and this
      may be mediated through both steroid hormone-dependent and -independent
      mechanisms. Nutritionally induced aberrations in the number or behaviour of
      endometrial macrophages during the estrous cycle or in early pregnancy could have
      important implications for the quality of the pre- and peri-implantation
      environment and the maternal immune response to pregnancy.

PMID- 10660260
TI  - Antigen phenotype of cultured decidual stromal cells of human term decidua.
AB  - We previously reported that decidual stromal cells (DSC) from early human decidua
      express antigens associated with hematopoietic cells and develop different immune
      functions. Here we study the antigenic phenotype of DSC from term decidua and
      compare it with the phenotype reported for DSC from early decidua. Decidual
      stromal cells were isolated from human term deciduas and maintained in culture
      until highly purified DSC cultures were obtained. Most term DSC, like most early
      DSC, expressed CD10. Term DSC expressed antigens specific for follicular
      dendritic cells (FDC), such as DRC-1 (CD21L) and HJ2, together with CD21, CD23
      and CD80, which are detected on FDC as well. Also like early DSC, term DSC were
      negative for CD3, CD14, CD15 and CD45. Although early DSC were reported to be HLA
      DR-positive and CD86-positive, these antigens were not expressed by term DSC.
      These discrepant results suggest that two types of cells, or cells at different
      stages of differentiation (decidualization) were selected during culture of
      decidual cells from different periods of gestation. This possibility was further
      supported by the finding that term DSC expressed desmin and prolactin, two
      markers of decidualization, whereas these molecules have not previously been
      detected in early DSC.

PMID- 10660262
TI  - Maternal immunopotentiation affects the teratogenic response to hyperthermia.
AB  - Immune responses occurring between the embryo and mother have been shown to
      influence the embryo's tolerance to teratogens, including chemical teratogens and
      diabetes-induced teratogenic insult. In this study, we tried to evaluate whether
      maternal immunostimulation alters the embryo's response to heat shock, one of few
      teratogens which directly affect the embryo. In order to induce structural
      anomalies, both intact ICR female mice and mice which had been immunostimulated
      with xenogeneic rat splenocytes before mating, were exposed to two consecutive
      exposures to heat (43.6 +/- 0.2 degrees C) for 10 min on day 9 of pregnancy. The
      number of malformed fetuses, resorptions, and fetal weight were assessed on day
      19 of pregnancy. Heat shock-induced apoptosis, and the level of heat shock
      protein (HSP) 60 expression, were examined in embryonic cells at different time
      points within 24 h after heating. All these indices differed dramatically in
      immunized and non-immunized heat shocked females. Heat shocked non-immunized
      females demonstrated an increased level of resorptions (approximately, 21% versus
      8.6% in controls) and the proportion of fetuses with such anomalies as
      encephalocele and open eyes reached 28% and 21%, respectively. Maternal
      immunostimulation was associated with a significant decrease in the proportion of
      fetuses with encephalocele (12.8%), open eyes (8.9%), and resorptions (8%). The
      maximum level of heat shock-induced apoptosis in cell populations from the
      embryos of non-immunized females, was approximately, 30% versus 7% in cells of
      embryos of immunized mice. Heat shock was also followed by a significant increase
      in HSP60 expression, but only in the cells of embryos of non-immunized females.
      Together, these findings suggest that the tolerance of mouse embryos to a heat
      shock-induced teratogenic insult may, to some extent, depend on the character of
      the maternal immune responses.

PMID- 10660264
TI  - Change in paternity: a risk factor for preeclampsia in multiparous women?
AB  - BACKGROUND: Preeclampsia is often thought of as being a disease of first
      pregnancies. The incidence of preeclampsia in subsequent pregnancies, after a
      previous normal pregnancy is lower. However, it has been reported that this
      beneficial effect of multiparity is lost with a change in paternity. The aim of
      this study was to assess the impact of change in paternity on the incidence of
      preeclampsia in Dutch multiparous pregnant women. METHODS: 364 Multiparous
      patients with hypertension (diastolic blood pressure > or = 100 mmHg) were
      identified in the obstetric database of the Academic Hospital Vrije Universiteit
      Amsterdam for the period 1989-1996. The diagnosis in their obstetrical history
      (Preeclampsia, HELLP-syndrome, chronic hypertension) was defined in a pragmatic
      way in view of the retrospective nature of the study. The control group consisted
      of 281 multiparous women from a midwife clinic, with normotensive pregnancies in
      the same period. Patients and controls were asked, by telephone, if the index
      pregnancy was from the same partner as the previous pregnancy and what the sex of
      the newborns had been in each pregnancy. Fisher's Exact test was used for
      statistical analysis and P < 0.05 was considered significant. RESULTS: The final
      study group consisted of 333 multiparous patients with hypertension. The control
      group consisted of 182 multiparous women without hypertension. The prevalence of
      new paternity was significantly higher (P < 0.0001) both for preeclamptic and
      HELLP patients in comparison with the controls, with an odds ratio of 8.6 (95%CI:
      3.1-23.5) and 10.9 (95%CI: 3.7-32.3), respectively. CONCLUSION: This study
      confirms that change of partner raises the risk for preeclampsia in subsequent
      pregnancies. Immune maladaptation on the fetal maternal interface could be an
      underlying mechanism. Multiparous women with a new partner should be approached
      as being primigravid women.

PMID- 10660265
TI  - The genetic algorithm applied to haplotype data at the LDL receptor locus.
AB  - Conventional statistical methods based upon single restriction fragment length
      polymorphisms often prove inadequate in studies of genetic variation. Cladistic
      analysis has been suggested as an alternative, but requires basic assumptions
      that usually cannot be met. We wanted to test whether it could be a workable
      approach to apply the genetic algorithm, an artificial intelligence method, to
      haplotype data. The genetic algorithm creates in-computer artificial
      'individuals', all having 'genes' coding for solutions to a problem. The
      individuals are allowed to compete and 'mate', individuals with genes coding for
      better solutions mating more often. Genes coding for good solutions survive
      through generations of the genetic algorithm. At the end of the run, the best
      solutions can be extracted. We applied the genetic algorithm to data consisting
      of cholesterol values and haplotypes made up of seven restriction sites at the
      LDL receptor locus. The persons included were 114 FH (familial
      hypercholesterolemia) patients and 61 normals. The genetic algorithm found the
      restriction sites 1 (Sph1 in intron 6), 2 (StuI in exon 8), and 7 (ApaLI site in
      the 3' flanking region) were associated with high cholesterol levels. As a
      validity check we used runs of the genetic algorithm applied to 'artificial
      patients', i.e. artificially generated haplotypes linked to artificially
      generated cholesterol values. This demonstrated the genetic algorithm
      consistently found the appropriate haplotype. We conclude that the genetic
      algorithm may be a useful tool for studying genetic variation.

PMID- 10660263
TI  - Expression and hormonal regulation of rat ovarian interleukin-1beta converting
      enzyme, a putative apoptotic marker: endocrine- and paracrine-dependence.
AB  - It is the purpose of this paper to assess the expression, cellular localization,
      and hormonal regulation of rat ovarian interleukin (IL)-1beta converting enzyme
      (ICE), a putative apoptotic marker. In agreement with previous observations ICE
      transcripts were noted in relatively increased abundance in the thymus, lung,
      spleen and small intestine. Although ICE transcripts were barely expressed in the
      untreated, immature rat ovary, they were apparent throughout a simulated estrous
      cycle. The in vivo expression of ovarian ICE rose gradually from 6 h after
      ovulation triggering to a peak (1.74-fold increase versus control, P < 0.05) 24 h
      after human chorionic gonadotropin administration, a marked and significant
      decrease to baseline being noted 24 h later. To examine the effect of in vitro
      culture on ovarian ICE gene expression, whole ovarian dispersates from immature
      rats were cultured without treatment for 72 h. ICE gene expression significantly
      (P < 0.01) increased to a maximum 24 h post plating (2.55-fold increase as
      compared with time zero). Treatment with IL-1beta was associated with a small but
      statistically insignificant increase in ovarian ICE gene expression. Similarly,
      provision of IL-RA resulted in a modest, albeit statistically insignificant,
      decrease in ovarian ICE gene expression. Treatment with GnRH (but not FSH, LH or
      PMSG) significantly (P < 0.05) increased ovarian ICE gene expression (41.5%
      increase versus control). Treatment with dexamethasone (but not
      diethylstilbestrol, R5020 or R1881) produced a significant (P < 0.05) 42.3%
      decrease in ovarian ICE gene expression as compared with untreated controls.
      Treatment with TNF alpha (but not ET-1, TGF alpha, TGF beta, IGF-I or bFGF)
      produced a significant (P < 0.01) 2.5-fold increase in ovarian ICE gene
      expression as compared with untreated controls. Taken together, our present
      findings: (1) reaffirm the ovarian expression of the ICE gene, (2) document a
      periovulatory increase in ovarian ICE gene expression, (3) show the inhibitory
      effect of glucocorticoids in this regard, and (4) establish TNF alpha as an
      upregulator. Taken together, these findings suggest a role for ovarian ICE either
      in the context of apoptosis/atresia or in the context of the ovulatory process.

PMID- 10660266
TI  - Automation of the use of fluorescent microspheres for the determination of blood
      flow.
AB  - Fluorescent-labeled microspheres (FM) are a new tool for the determination of
      organ blood flow. However, the FM-method is labor intensive, because of the
      necessity to recover the microspheres from the tissue samples. The aim of this
      study was to automate the FM-method. A Zymate-Robotic System (Zymark, Idstein,
      Germany) was modified to handle a novel filtration device. The robot is
      surrounded by 12 different stations which are necessary to process the samples.
      It performs the sequential steps which are needed to recover the microspheres
      from the samples. The dyes are finally released from the FM with a solvent and
      their fluorescent intensity is measured online using a spectrophotometer (Perkin
      Elmer, Uberlingen, Germany). The robotic system is able to recover the FM through
      digestion and filtration of the tissue samples using the new filter, to dissolve
      the FM and to release the dyes so that their fluorescent intensities can be
      measured for the calculation of organ blood flow.

PMID- 10660267
TI  - Region based techniques for segmentation of volumetric histo-pathological images.
AB  - In this article we have presented the application of three region based
      segmentation techniques namely, seeded volume growing, constrained erosion
      dilation techniques and 3-D watershed algorithm. The algorithms are suitably
      extended to apply on 3-D histo-pathological images. Suitable modifications and
      extension for each algorithm is done to obtain better segmentation. A
      quantitative as well as qualitative comparison of the three methods is presented.
      Modifications to these algorithms for obtaining better results are discussed. The
      modifications include, (1) design of adaptive similarity measures to control the
      seeded volume growing and (2) rule-based merging of the over-segmented cells in
      the case of the 3-D watershed algorithm. Some results and quantitative study is
      also presented.

PMID- 10660268
TI  - Trial summary software.
AB  - Medical practice is most strongly founded when based on the results of well
      conducted clinical trials. Clinical trial results normally enter the domain of
      medical knowledge and practice through their publication in scientific journals.
      This in itself poses problems of accessibility and selection. The results of this
      is a slow and selective diffusion of new medical facts which has a consequent
      cost in human lives and human suffering. In an attempt to shorten this
      information path initiatives such as the Cochrane collaboration produce and
      maintain systematic reviews by speciality of the current state of knowledge. The
      ability to store a representation of a clinical trial in a standard form seems to
      us to be a necessary condition for the efficient and reproducible preparation of
      systematic reviews. Furthermore the consequent increased accessibility of
      research results due to the existence of the summaries would itself be of great
      use. In this aim a relational database client server system was developed and we
      publish here the results of our preliminary findings, including the data model,
      which we feel is an important contribution to the future discussion and
      development of computer based representations of clinical trial protocols and
      results and their use in clinical decision making.

PMID- 10660270
TI  - Debbie's nurse.

PMID- 10660271
TI  - Abuse during pregnancy.

PMID- 10660269
TI  - A program for the optimization of cyclosporine therapy using population kinetics
      modeling.
AB  - Cyclosporine is one of the most widely used immunosuppressive agents in organ
      transplantation. Due to large inter- and intra-individual variations, its
      behavior in the specific patient is still difficult to predict. Dosage
      optimization is thus mainly performed on a trial-and-error basis. In this paper,
      we present a new program based on the population kinetics approach, which was
      designed to help physicians in the difficult task of adjusting patient specific
      cyclosporine dosing regimens. Dose optimization is carried out by model
      simulation, using a two-compartment mathematical model of cyclosporine kinetics
      to predict the drug behavior in the patient. Two of the model parameters are
      assumed from the literature, the other two are estimated from the patient data
      through a Bayesian estimation procedure. Previous information needed by the
      Bayesian algorithm is derived by a population analysis, performed beforehand and
      based on a nonlinear mixed effect model. A user-friendly graphical interface
      written in Delphi under Windows makes the program easily accessible to
      physicians. A preliminary retrospective validation of the program, performed on
      data from 18 renal transplanted patients, yielded very satisfactory results.

PMID- 10660272
TI  - Continence for women: evaluation of AWHONN's third research utilization project.
      Association of Women's Health Obstetric and Neonatal Nurses.
AB  - OBJECTIVE: To develop an evidence-based protocol for initial evaluation and
      treatment of urinary incontinence and to design procedures that would facilitate
      the protocol's implementation into clinical practice. DESIGN: Descriptive report
      of the Association of Women's Health, Obstetric and Neonatal Nurses (AWHONN)
      Continence for Women Project. SETTING: Twenty-one public, private, and other
      women's health sites. PARTICIPANTS: Women in ambulatory care settings (N = 1,474)
      provided demographic statistics. METHODS: The protocol was developed, sites were
      selected, site coordinator training was provided, data collection was facilitated
      by project-specific teleforms, and the overall process was evaluated by the
      science team. MAIN OUTCOME MEASURES: Site representation, patient representation,
      site coordinator feedback on the training program, and site coordinator
      experience during project implementation. RESULTS: The process yielded a
      representative mix of site and patient diversity appropriate for testing of the
      protocol. Site coordinators felt well-prepared to implement the protocol and
      experienced increased professional satisfaction because of therapeutic benefits
      achieved for patients and positive collaboration with physicians. CONCLUSIONS:
      The Continence for Women Project demonstrated the potential for developing and
      testing evidence-based protocols for clinical practice when the resources of an
      organization such as AWHONN and the research community are combined.

PMID- 10660273
TI  - Continence for women: a test of AWHONN's evidence-based protocol in clinical
      practice. Association of Women's Health Obstetric and Neonatal Nurses.
AB  - OBJECTIVE: To test the effectiveness of an evidence-based protocol for urinary
      incontinence in increasing identification of women with the condition and
      improving their outcomes. DESIGN: Prospective formative evaluation study.
      SETTING: Twenty-one public, private, and other women's health care sites.
      PARTICIPANTS: Women in ambulatory care settings (N = 1,474) provided descriptive
      statistics. Clinical outcomes were tested in 132 cases for whom pre- and
      posttreatment data were available. INTERVENTIONS: Standardized screening and
      baseline follow-up forms were used to minimize time burden on clinicians; bladder
      and pelvic floor muscle training materials were provided to clinicians for
      distribution. MAIN OUTCOME MEASURES: Self-reported frequency, volume, and quality
      of life related to incontinence and cost of self-management were used to assess
      protocol effectiveness. RESULTS: Frequency of incontinence episodes, estimated
      volume lost per episode, and the cost of self-management decreased. Quality of
      life improved, as reflected in decreased bother attributed to incontinence and in
      the number of women avoiding activities such as shopping, exercising, or travel
      because of incontinence. CONCLUSIONS: This simple program of pelvic floor muscle
      and bladder training, as it has been systematically implemented in a variety of
      ambulatory women's health care settings, has benefited women's continence status.
      The results of this project strongly support widespread application.

PMID- 10660274
TI  - The effect of timing of initial bath on newborn's temperature.
AB  - OBJECTIVE: To determine the effect of the early timing of an initial bath on
      newborn temperature. DESIGN: Random assignment to group, comparative study.
      SETTING: Newborn nursery of a 20-bed obstetric unit in a regional hospital in the
      Midwest. PATIENTS: 80 healthy, full-term newborns. INTERVENTIONS: 40 neonates
      were bathed at 1 hour of age and 40 were bathed at 2 hours of age. MAIN OUTCOME
      MEASURES: Axillary temperatures were measured before the admission bath and at
      10, 20, and 60 minutes after the bath with disposable thermometers; the maximum
      drop in temperature also was determined. RESULTS: No significant differences were
      noted in axillary temperatures between the two groups before the bath or at 10,
      20, or 60 minutes after the bath. The groups did not differ significantly by
      gender, birth weight, length of bath in minutes, room temperature during bath,
      Apgar score at 5 minutes, or gestational age. CONCLUSION: Healthy full-term
      newborns with an axillary temperature > or = 36.8 degrees C (98.2 degrees F) can
      be bathed after 1 hour of age when appropriate care is taken to support thermal
      stability.

PMID- 10660275
TI  - Hysterectomy: what do women need and want to know?
AB  - OBJECTIVE: The purpose of this article is to describe women's experiences of
      hysterectomy and to identify their fears, concerns, and met as well as unmet
      health care needs. DESIGN: Narrative data of women's hysterectomy experiences
      were collected via a written survey. SETTING: Data were collected from women
      living in southeastern Wisconsin. PARTICIPANTS: Participants were 102 women who
      had undergone hysterectomy within the previous 2 years. The mean age of the women
      was 43 and mean time since hysterectomy was 13 months. Eighty percent of the
      women had undergone both hysterectomy and oophorectomy, and 78% were taking
      hormone replacement therapy. MAIN OUTCOME MEASURES: A questionnaire of women's
      hysterectomy needs and a demographic questionnaire were used to collect data via
      mail. The data from three open-ended questions were content analyzed. RESULTS:
      Seven themes about women's experiences of hysterectomy were identified: (a)
      positive aspects, (b) hormone replacement therapy, (c) insufficient information,
      (d) changes in sexual feelings and functioning, (e) emotional support, (f)
      psychologic sequelae, and (g) feelings of loss. CONCLUSIONS: Women wanted
      treatment choices, a part in decision-making, accurate and useful information at
      an appropriate time, provider support, and access to professional and lay support
      systems. The essentials for hysterectomy care are outlined and include the
      characteristics of care that women desire, the informational content that women
      want, health care systems that support patient satisfaction, and the outcomes
      women want.

PMID- 10660276
TI  - Nutrition for the childbearing years.
AB  - OBJECTIVE: To review the literature on preconceptional nutrition and nutrition
      during pregnancy and lactation, focusing on recommendations from the Institute of
      Medicine. DATA SOURCES: Computerized searches on MEDLINE, CINAHL, National
      Institutes of Health and Institute of Medicine web sites. STUDY SELECTION:
      Articles from indexed journals and reports from government sources relevant to
      the topics of this review and published after 1990 (except for classic findings)
      were evaluated. DATA EXTRACTION: Data were analyzed under the headings of
      preconceptional nutrition, prenatal nutrition, nutrition during lactation, and
      nursing implications. DATA SYNTHESIS: The nutrition a woman receives before
      conception, during pregnancy, and during lactation affects her health and the
      health of her child. Information on the amount and timing of prenatal weight
      gain, recommended intakes of vitamins and minerals, and nutrition and activity
      during lactation have been revised in the last 10 years. CONCLUSIONS: The health,
      size, and growth of the infant are dependent on the timing and amount of weight
      gain during pregnancy and on maternal nutrition during lactation. Prenatal weight
      gain also affects a woman's future risk of obesity.

PMID- 10660277
TI  - History of the Women's Health Movement in the 20th century.
AB  - The Women's Health Movement (WHM) emerged during the 1960s and the 1970s with the
      primary goal to improve health care for all women. Despite setbacks in the area
      of reproductive rights during the 1980s, the WHM made significant gains in
      women's health at the federal policy level during the 1980s and 1990s. The WHM
      became a powerful political force. The achievements of the movement in improving
      women's health during the 20th century were numerous and significant.

PMID- 10660278
TI  - The hospital and the postpartum experience: a historical analysis.
AB  - In the United States, use of hospitals for childbearing started in the early 19th
      century for women who did not have suitable homes. Since then, the purpose and
      structure of hospital-based postpartum care changed several times. The trend
      toward shorter stays began almost 50 years ago. Although the economy was a
      driving force both now and 50 years ago, the purposes for changes were different.
      Knowing the history of postpartum care gives insight into the state of care at
      the turn of the millennium.

PMID- 10660279
TI  - This most dangerous instrument: propriety, power, and the vaginal speculum.
AB  - The vaginal speculum is an instrument in a contested technology. As the oldest
      instrument in the technology of obstetric surveillance and diagnosis, the vaginal
      speculum provoked serious debates about the propriety and power of looking at
      women's bodies. Contemporary devices, such as the ultrasound machine and the
      electronic fetal monitor, continue to engender debates about looking. Nurses are
      key participants in technologically mediated spectatorship, as nursing practice
      with women increasingly comprises looking at and through them with instruments.

PMID- 10660280
TI  - The evolution of advanced practice nursing in the United States: caring for women
      and newborns.
AB  - The evolution of advanced practice nurses to care for women and newborns has its
      roots in public health nursing of the latter decades of the 19th century. As we
      consider the challenges of practicing as advanced practice nurses in the 21st
      century, it is instructive to look back on 100 years of creating new programs and
      systems for delivering care. Such reflection helps us to clear our vision to
      imagine the future.

PMID- 10660281
TI  - Trendsetter: Celeste Phillips, the mother of family-centered maternity care.
AB  - Celeste Phillips has been a proponent of family-centered maternity care and the
      single-room model of maternity care for her entire career. As a young nurse, she
      developed a strong philosophy that the childbearing experience belongs to the
      family, not the caregivers. To spread this philosophy to others and facilitate
      change, she has been a labor and delivery nurse, a nurse educator, an author, a
      consultant, and the principal of a leading women's health consulting firm. Her
      influence on clinical practice has made her a trendsetter.

PMID- 10660282
TI  - Trendsetter: Ruth Watson Lubic.
AB  - A visionary who has developed and successfully instituted the birthing center as
      a means to improve the lives of childbearing families, Ruth Watson Lubic shows a
      philosophy that is one way of meeting the challenges found in the health care
      system. She stresses the need to look to families and their communities and for
      making the focus the concept of their empowerment to enrich their lives. Ruth's
      undaunted pursuit of this vision has led her to the nation's capital to involve
      government in this cause.

PMID- 10660283
TI  - The real challenge: lessons from obstetric nursing history.
AB  - The successes, failures, and ongoing dilemmas within nursing derive directly from
      the earliest nursing practices. The conflicting requirements between strictly
      prescribed scientific medical treatment and the nurturing care needed by mothers
      and infants have shaped the practice of obstetric nursing throughout the past
      century. The historical challenge, relevant to current practice, is that nurses
      not become so focused on techniques and routines that they forget the patients'
      needs for comfort and support.

PMID- 10660284
TI  - Recognition of pathogens by plants.

PMID- 10660285
TI  - Origins of modern humans still look recent.

PMID- 10660286
TI  - Signal transduction: hair brains in bacterial chemotaxis.
AB  - The conserved cytoplasmic domains of bacterial chemotaxis receptors are a fibrous
      arrangement of alpha-helical coiled coils that look a lot like hair. Such bundles
      of alpha-helical filaments mediate sensory-motor responses in all prokaryotic
      cells. How do they work? Very nearly perfectly is probably as good an answer as
      any.

PMID- 10660287
TI  - Visual neuroscience: illuminating the dark corners.
AB  - Recent experiments suggest that our perception of lightness involves a
      sophisticated interpretation of illumination and shadow. This finding challenges
      common notions about hierarchical processing and the neural basis of perception.

PMID- 10660289
TI  - Speckle microscopy: when less is more.
AB  - Fluorescent speckle microscopy is a new and simplified method for generating
      fiduciary marks on cellular structures. It promises to become the method of
      choice for studying polymer movement and dynamics in vivo.

PMID- 10660288
TI  - RNA-binding proteins: TRAPping RNA bases.
AB  - In Bacillus subtilis, tryptophan biosynthesis is regulated by a mechanism called
      attenuation. The new crystal structure of the 'trp RNA binding attenuation
      protein', TRAP, in complex with RNA has provided new structural insights into how
      proteins can bind RNA to regulate transcription and translation.

PMID- 10660290
TI  - Sliding clamps: a (tail)ored fit.
AB  - New structural information on the architecture of a DNA replisome provides
      insights into a number of DNA metabolic processes and their modulation by
      circular 'sliding damps', which form rings around DNA that play an Important role
      in processive processes such as replication.

PMID- 10660292
TI  - Neuropsychology: the touchy, feely side of vision.
AB  - Some visual attributes, such as colour, are purely visual, but others, such as
      orientation and movement, can be perceived by touch or audition. A magnetic
      stimulation study has now shown that the perception of tactile orientation may be
      influenced by visual Information.

PMID- 10660291
TI  - Leukocyte migration: scent of the T zone.
AB  - Recent studies show that the chemokine receptor CCR7 helps T lymphocytes and
      dendritic cells to navigate into the T-cell zone of lymphoid organs. Furthermore,
      down-modulation of CCR7 redirects some activated T cells from these zones into
      other lymphoid tissue compartments.

PMID- 10660293
TI  - Animal phylogeny: root and branch surgery.
AB  - Our view of how-many phyla relate to each other is being radically revised by
      molecular phylogenetics. For example, arthropods and annelids are no longer
      placed together, but are now considered to be in separate clades. The new tree
      has important ramifications for developmental biology and genomics.

PMID- 10660294
TI  - Epithelial polarity: sorting out the sorters.
AB  - Epithelial cell polarity depends on the continuous sorting of plasma membrane
      proteins. While various sorting signals and pathways have been identified, only
      recently has a protein been identified that recognizes such sorting determinants
      and mediates sorting to a specific cell-surface domain.

PMID- 10660295
TI  - Head-head/tail-tail relative orientation of the pore-forming domains of the
      heterodimeric ABC transporter TAP.
AB  - BACKGROUND: The transporter associated with antigen processing (TAP) is a
      heterodimeric member of the large family of ABC transporters. The study of
      interactions between the subunits TAP1 and TAP2 can reveal the relative
      orientation of the transmembrane segments, which form a translocation pore for
      peptides. This is essential for understanding the architecture of TAP and other
      ABC transporters. RESULTS: The amino-terminal six transmembrane segments (TMs) of
      human TAP1, TAP1 (1-6), and the amino-terminal five TMs of TAP2, TAP2(1-5), are
      thought to constitute the pore of TAP. Two new approaches are used to define
      dimer interactions. We show that TM6 of TAP1 (1-6) is able to change topology
      post-translationally. This TM, along with a cytoplasmic tail, is translocated
      into the endoplasmic reticulum lumen, unless TAP2 is expressed. Coexpression of
      TM(4-5) of TAP2 stabilizes the topology of TAP1 (1-6), even when the TM1 of TAP1
      is subsitituted with another sequence. This suggests that the carboxy-terminal
      TMs of the pore-forming domains TAP1 (1-6) and TAP2(1-5) interact. An alternative
      assay uses photobleaching in living cells using TAP1 (1-6) tagged with the green
      fluorescent protein (GFP). Coexpression with TAP2(1-5) results in reduced
      movement of the heterodimer within the endoplasmic reticulum membrane, as
      compared with the single TAP1 (1-6) molecule. In contrast, TAP2(1-4) has no
      effect on the mobility of TAP1 (1-6)-GFP, indicating the importance of TM5 of
      TAP2 for dimer formation. Also, TM1 of both TAP1 and TAP2 is essential for
      formation of a complex with low mobility. CONCLUSIONS: Dimerization of the pore
      forming transmembrane domains of TAP1 (TM1-6) with its TAP2 counterpart (TM1-5)
      prevents the post-translational translocation of TM6 of TAP1 and results in a
      complex with reduced mobility within the endoplasmic reticulum membrane compared
      with the free subunit. These techniques are used to show that the pore-forming
      domains of TAP are aligned in a head-head/tail-tail orientation. This positions
      the following peptide-binding segments of the two TAP subunits to one side of the
      pore.

PMID- 10660296
TI  - Microscopic properties of elementary Ca2+ release sites in non-excitable cells.
AB  - BACKGROUND: Elementary Ca2+ signals, such as 'Ca2+ puffs', that arise from the
      activation of clusters of inositol 1 ,4,5,-trisphosphate (InsP3) receptors are
      the building blocks for local and global Ca2+ signalling. We previously found
      that one, or a few, Ca2+ puff sites within agonist-stimulated cells act as
      'pacemakers' to initiate global Ca2+ waves. The factors that distinguish these
      pacemaker Ca2+ puff sites from the other Ca2+ release sites that simply
      participate in Ca2+ wave propagation are unknown. RESULTS: The spatiotemporal
      properties of Ca2+ puffs were investigated using confocal microscopy of fluo3
      loaded HeLa cells. The same pacemaker Ca2+ puff sites were activated during
      stimulation of cells with different agonists. The majority of agonist-stimulated
      pacemaker Ca2+ puffs originated in a perinuclear location. The positions of such
      Ca2+ puff sites were stable for up to 2 hours, and were not affected by
      disruption of the actin cytoskeleton. A similar perinuclear distribution of Ca2+
      puff sites was also observed when InsP3 receptors were directly stimulated with
      thimerosal or membrane-permeant InsP3 esters. Immunostaining indicated that the
      perinuclear position of pacemaker Ca2+ puffs was not due to the localised
      expression of InsP3 receptors. CONCLUSIONS: The pacemaker Ca2+ puff sites that
      initiate Ca2+ responses are temporally and spatially stable within cells. These
      Ca2+ release sites are distinguished from their neighbours by an intrinsically
      higher InsP3 sensitivity.

PMID- 10660297
TI  - The functional neuroanatomy of implicit-motion perception or representational
      momentum.
AB  - BACKGROUND: When we view static scenes that imply motion - such as an object
      dropping off a shelf - recognition memory for the position of the object is
      extrapolated forward. It is as if the object in our mind's eye comes alive and
      continues on its course. This phenomenon is known as representational momentum
      and results in a distortion of recognition memory in the implied direction of
      motion. Representational momentum is modifiable; simply labelling a drawing of a
      pointed object as 'rocket' will facilitate the effect, whereas the label
      'steeple' will impede it. We used functional magnetic resonance imaging (fMRI) to
      explore the neural substrate for representational momentum. RESULTS: Subjects
      participated in two experiments. In the first, they were presented with video
      excerpts of objects in motion (versus the same objects in a resting position).
      This identified brain areas responsible for motion perception. In the second
      experiment, they were presented with still photographs of the same target items,
      only some of which implied motion (representational momentum stimuli). When
      viewing still photographs of scenes implying motion, activity was revealed in
      secondary visual cortical regions that overlap with areas responsible for the
      perception of actual motion. Additional bilateral activity was revealed within a
      posterior satellite of V5 for the representational momentum stimuli. Activation
      was also engendered in the anterior cingulate cortex. CONCLUSIONS: Considering
      the implicit nature of representational momentum and its modifiability, the
      findings suggest that higher-order semantic information can act on secondary
      visual cortex to alter perception without explicit awareness.

PMID- 10660298
TI  - Cactus-independent regulation of Dorsal nuclear import by the ventral signal.
AB  - Rel-family transcription factors function in a variety of biological processes,
      including development and immunity. During early Drosophila development, the Toll
      Cactus-Dorsal pathway regulates the establishment of the embryonic dorsoventral
      axis. The last step in this pathway is the graded nuclear import of the Rel
      protein Dorsal. Dorsal is retained in the cytoplasm by the IkappaB-family protein
      Cactus. Phosphorylation of both Dorsal and Cactus is regulated by a Toll-receptor
      dependent ventral signal relayed by the Tube and Pelle proteins. Phosphorylation
      of Cactus leads to its degradation and to the release of Dorsal to form a ventral
      to-dorsal nuclear Dorsal gradient. To understand how the ventral signal regulates
      the nuclear import and activity of Dorsal, we deleted its conserved nuclear
      localization signal (NLS). The truncated protein remained in the cytoplasm and
      could antagonize the function of wild-type Dorsal, suggesting that Dorsal forms a
      dimer in the cytoplasm. Further, the nuclear import of a mutant Dorsal protein
      that failed to interact with Cactus was still regulated by the ventral signal.
      Our results are consistent with a model in which ventral signal-dependent
      modification of both Cactus and Dorsal is required for the graded nuclear import
      of Dorsal.

PMID- 10660299
TI  - The HP1 chromo shadow domain binds a consensus peptide pentamer.
AB  - Heterochromatin-associated protein 1 (HP1) is thought to affect chromatin
      structure through interactions with other proteins in heterochromatin. Chromo
      domains located near the amino (amino chromo) and carboxy (chromo shadow) termini
      of HP1 may mediate such interactions, as suggested by domain swapping, in vitro
      binding and 3D structural studies . Several HP1-associated proteins have been
      reported, providing candidates that might specifically complex with the chromo
      domains of HP1. However, such association studies provide little mechanistic
      insight and explore only a limited set of potential interactions in a largely non
      competitive setting. To determine how chromo domains can selectively interact
      with other proteins, we probed random peptide phage display libraries using
      chromo domains from HP1. Our results demonstrate that a consensus pentapeptide is
      suffident for specific interaction with the HP1 chromo shadow domain. The
      pentapeptide is found in the amino acid sequence of reported HP1-associated
      proteins, including the shadow domain itself. Peptides that bind the shadow
      domain also disrupt shadow domain dimers. Our results suggest that HP1
      dimerization, which is thought to mediate heterochromatin compaction and
      cohesion, occurs via pentapeptide binding. In general, chromo domains may
      function by avidly binding short peptides at the surface of chromatin-associated
      proteins.

PMID- 10660300
TI  - A structurally defined mini-chromosome vector for the mouse germ line.
AB  - Yeast artificial mini-chromosomes have helped to define the features of
      chromosome architecture important for accurate segregation and replication and
      have been used to identify genes important for chromosome stability and as large
      fragment cloning vectors. Artificial chromosomes have been developed in human
      cells but they do not have defined, experimentally predictable structures.
      Fragments of human chromosomes have also been introduced into mice and in one
      case passed through the germ line. In these experiments, however, the structure
      and sequence organization of the fragments was not defined. Structurally defined
      mammalian mini-chromosome vectors should allow large tracts of DNA to be
      introduced into the vertebrate germ line for biotechnological purposes and for
      investigations of features of chromosome structure that influence gene
      expression. Here, we have determined the structure and sequence organization of
      an engineered mammalian mini-chromosome, ST1, and shown that it is stably
      maintained in vertebrate somatic cells and that it can be transmitted through the
      mouse germ line.

PMID- 10660301
TI  - The human visual system is optimised for processing the spatial information in
      natural visual images.
AB  - A fundamental tenet of visual science is that the detailed properties of visual
      systems are not capricious accidents, but are closely matched by evolution and
      neonatal experience to the environments and lifestyles in which those visual
      systems must work. This has been shown most convincingly for fish and insects.
      For mammalian vision, however, this tenet is based more upon theoretical
      arguments than upon direct observations. Here, we describe experiments that
      require human observers to discriminate between pictures of slightly different
      faces or objects. These are produced by a morphing technique that allows small,
      quantifiable changes to be made in the stimulus images. The independent variable
      is designed to give increasing deviation from natural visual scenes, and is a
      measure of the Fourier composition of the image (its second-order statistics).
      Performance in these tests was best when the pictures had natural second-order
      spatial statistics, and degraded when the images were made less natural.
      Furthermore, performance can be explained with a simple model of contrast coding,
      based upon the properties of simple cells in the mammalian visual cortex. The
      findings thus provide direct empirical support for the notion that human spatial
      vision is optimised to the second-order statistics of the optical environment.

PMID- 10660302
TI  - A novel Rad24 checkpoint protein complex closely related to replication factor C.
AB  - Rad24 functions in the DNA damage checkpoint pathway of Saccharomyces cerevisiae.
      Here, analysis of Rad24 in whole cell extracts demonstrated that its mass was
      considerably greater than its predicted molecular weight, suggesting that Rad24
      is a component of a protein complex. The Rad24 complex was purified to
      homogeneity. In addition to Rad24, the complex included polypeptides of 40 kDa
      and 35 kDa. The 40 kDa species was found by mass spectrometry to contain Rfc2 and
      Rfc3, subunits of replication factor C (RFC), a five subunit protein that is
      required for the loading of polymerases onto DNA during replication and repair
      [3]. We hypothesised that other RFC subunits, all of which share sequence
      homologles with Rad24, might also be components of the Rad24 complex. Reciprocal
      co-immunoprecipitation studies were performed using extracts prepared from
      strains containing epitope-tagged RFC proteins. These experiments showed that the
      small RFC proteins, Rfc2, Rfc3, Rfc4 and Rfc5, interacted with Rad24, whereas the
      Rfc1 subunit did not. We suggest that this RFC-like Rad24 complex may function as
      a structure-specific sensor in the DNA damage checkpoint pathway.

PMID- 10660303
TI  - Phospholipase D regulation and localisation is dependent upon a
      phosphatidylinositol 4,5-biphosphate-specific PH domain.
AB  - The signalling pathway leading, for example, to actin cytoskeletal
      reorganisation, secretion or superoxide generation involves phospholipase D (PLD)
      catalysed hydrolysis of phosphatidylcholine to generate phosphatidic acid, which
      appears to mediate the messenger functions of this pathway. Two PLD genes (PLD1
      and PLD2) with similar domain structures have been doned and progress has been
      made in identifying the protein regulators of PLD1 activation, for example Arf
      and Rho family members. The activities of both PLD isoforms are dependent on
      phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and our sequence analysis
      suggested the presence of a pleckstrin homology (PH) domain in PLD1, although its
      absence has also been daimed. Investigation of the inositide dependence showed
      that a bis-phosphorylated lipid with a vicinal pair of phosphates was required
      for PLD1 activity. Furthermore, PLD1 bound specifically and with high affinity to
      lipid surfaces containing PI(4,5)P2 independently of the substrate
      phosphatidylcholine, suggesting a key role for the PH domain in PLD function.
      Importantly, a glutathione-S-transferase (GST) fusion protein comprising GST and
      the PH domain of PLD1 (GST-PLD1-PH) also bound specifically to supported lipid
      monolayers containing PI(4,5)P2. Point mutations within the PLD1 PH domain
      inhibited enzyme activity, whereas deletion of the domain both inhibited enzyme
      activity and disrupted normal PLD1 localisation. Thus, the functional PH domain
      regulates PLD by mediating its interaction with polyphosphoinositide-containing
      membranes; this might also induce a conformational change, thereby regulating
      catalytic activity.

PMID- 10660304
TI  - Serine phosphorylation and maximal activation of STAT3 during CNTF signaling is
      mediated by the rapamycin target mTOR.
AB  - Neuropoletic cytokines such as ciliary neurotrophic factor (CNTF) can activate
      multiple signaling pathways in parallel, including those involving Janus kinase
      (JAK)-signal transducers and activators of transcription (STATs), mitogen
      activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI 3-kinase) and
      mammalian target of rapamydn (mTOR)-p70 S6 kinase . Crosstalk occurs between
      these pathways, because studies have shown that STAT3 requires phosphorylation on
      tyrosine and serine residues by independent protein kinase activities for maximal
      activation of target gene transcription. Members of the JAK/Tyk family of
      tyrosine kinases mediate phosphorylation of STAT3 at Tyr705 during CNTF
      signaling; however, the kinase responsible for phosphorylation at STAT3 Tyr727
      appears to depend on both the extracellular stimulus and the cellular context.
      Here we investigate the kinase activity responsible for phosphorylation of STAT3
      on Ser727 in CNTF-stimulated neuroblastoma cells. We found that CNTF-induced
      phosphorylation of Ser727 was inhibited by the mTOR inhibitor rapamycin, but not
      by inhibitors of MAPK and protein kinase C (PKC) activation. A STAT3 peptide was
      efficiently phosphorylated on Ser727 in a CNTF-dependent manner by mTOR, but not
      by a kinase-inactive mTOR mutant or by p70 S6 kinase. In agreement with these
      biochemical studies, rapamycin treatment of cells transfected with a STAT
      responsive promoter reporter decreased activation of the reporter to the same
      degree as a STAT3 Ser727Ala mutant The ability of mTOR to contribute to
      activation of STAT3 extends the function of mTOR in mammalian cells to include
      transcriptional regulation.

PMID- 10660305
TI  - Receptor tyrosine kinase signaling regulates different modes of Groucho-dependent
      control of Dorsal.
AB  - Transcriptional control of the Drosophila terminal gap gene huckebein (hkb)
      depends on Torso (Tor) receptor tyrosine kinase (RTK) signaling and the
      Rel/NFkappaB homolog Dorsal (DI). DI acts as an intrinsic transcriptional
      activator in the ventral region of the embryo, but under certain conditions, such
      as when it is associated with the non-DNA-binding co-repressor Groucho (Gro), it
      is converted into a repressor. Gro is recruited to the enhancer element in the
      vicinity of DI by sequence-specific transcription factors such as Dead Ringer
      (Dri). We examined the interplay between DI, Gro and Dri on the hkb enhancer and
      show that when acting over a distance, Gro abolishes rather than converts DI
      activator function. Reducing the distance between DI- and Dri-binding sites,
      however, switches DI into a Gro-dependent repressor that overrides activation of
      transcription. Both of the distance-dependent regulatory options of Gro -
      quenching and silencing of transcription - are inhibited by RTK signaling. These
      data describe a newly identified mode of function for Gro when acting in concert
      with DI. RTK signaling provides a way of modulating DI function by interfering
      either with Gro activity or with Dri-dependent recruitment of Gro to the
      enhancer.

PMID- 10660306
TI  - The p24 family member p23 is required for early embryonic development.
AB  - The p24 family of type I integral-membrane proteins, which are localised in the
      endoplasmic reticulum (ER), the intermediate compartment and the Golgi apparatus,
      are thought to function as receptors for cargo exit from the ER and in transport
      vesicle formation. Members of the p24 family have been found in a molecular
      complex and are enriched in COPI-coated vesicles, which are involved in membrane
      traffic between the ER and Golgi complex. Although expressed abundantly,
      simultaneous deletion of several family members does not appear to affect cell
      viability and protein secretion in yeast. In order to gain more insights into the
      physiological roles of different p24 proteins, we generated mice deficient in the
      expression of one family member, p23 (also called 24delta1, see for alternative
      nomenclature). In contrast to yeast genetics, in mice disruption of both p23
      alleles resulted in early embryonic lethality. Inactivation of one allele led not
      only to reduced levels of p23 itself but also to reduced levels of other family
      members. The reduction in steady-state protein levels also induced structural
      changes in the Golgi apparatus, such as the formation of dilated saccules. The
      generation of mice deficient in p23 expression has revealed an essential and non
      redundant role for p23 in the earliest stages of mammalian development. It has
      also provided genetic evidence for the participation of p24 family members in
      oligomeric complexes and indicates a structural role for these proteins in
      maintaining the integrity of the early secretory pathway.

PMID- 10660307
TI  - The structure of two fengycins from Bacillus subtilis S499.
AB  - The structures of the two fengycins, lipopeptides from Bacillus subtilis, were
      elucidated by spectroscopic methods and chemical degradation. They show a close
      structural relationship to the plipastatins from Bacillus cereus differing only
      in the stereochemistry of the Tyr residues.

PMID- 10660308
TI  - Immune tolerance and gene therapy in transplantation.

PMID- 10660309
TI  - Was it worth it?

PMID- 10660310
TI  - MFGDP clarified. Membership of the Faculties of General Dental Practice.

PMID- 10660311
TI  - Uveitis associated with parvovirus infection.

PMID- 10660312
TI  - Management of corneal opacification associated with epibulbar choristomata.

PMID- 10660313
TI  - Herpes simplex virus (HSV-1) infection in a donor cornea.

PMID- 10660314
TI  - A case of acquired iris depigmentation as a possible complication of levobunolol
      eye drops.

PMID- 10660315
TI  - Horner's syndrome in yolk sac tumour of the mediastinum.

PMID- 10660316
TI  - Phacoemulsification combined with silicone oil removal through posterior
      capsulorhexis.

PMID- 10660317
TI  - Modified Sheridan-Gardiner vision test with a semitransparent card.

PMID- 10660318
TI  - Corneal fleck dystrophy in an English family.

PMID- 10660319
TI  - Horizontal transfer of DNA and the "genometastasis hypothesis".

PMID- 10660320
TI  - FANCA protein binds FANCG proteins in an intracellular complex.

PMID- 10660321
TI  - C-kit mutations in core binding factor leukemias.

PMID- 10660322
TI  - Circulating endothelial cells in acute coronary syndromes.

PMID- 10660323
TI  - Neonatal Screening in the New Millennium. Proceedings of the 4th International
      Society for Neonatal Screening. Stockholm, Sweden, 13-16 June 1999.

PMID- 10660324
TI  - Commentary: an inconclusive study?

PMID- 10660325
TI  - Commentary: report of statistical referee.

PMID- 10660326
TI  - Commentary: a warning to complementary medicine practitioners: get empirical or
      else.

PMID- 10660327
TI  - New mutations in XNP/ATR-X gene: a further contribution to genotype/phenotype
      relationship in ATR/X syndrome. Mutations in brief no. 176. Online.
AB  - The molecular causes of ATR-X syndrome reside in mutations involving the XNP/ATR
      X gene, which maps in the Xq13.3 region. Mutational analysis of this gene in two
      unrelated affected patients allowed us to identify two new molecular defects in
      two distinct regions of the gene. The first is a A-->G splice mutation in the
      acceptor site of the intron 11 that removes most of the 3' part of the protein,
      including the helicase domains and the glutamic acid stretch. Three cryptic
      acceptor splice sites are activated by this point mutation with consequent
      production of three types of abnormal mRNA: two with intronic insertions and a
      smaller one, approximately 10% of the total transcript, which is shorter than
      normal mRNA by one amino acid residue (E). Since the physiopathological
      characteristics of the patient carrying the splice mutation do not exhibit severe
      urogential abnormalities despite the lack of the -COOH end of the protein, a
      residual function of this third transcript is to be suspected. The second
      encountered nucleotide change (G-->T) leads to an R246L amino acid substitution
      in the putative zinc finger DNA-binding domain in the -NH2 terminal part of the
      protein.

PMID- 10660328
TI  - Noval mutation (Y184C) in exon 4 of the beta-sarcoglycan gene identified in a
      Portuguese patient. Mutations in brief no. 177. Online.
AB  - We report a novel beta-sarcoglycan gene mutation identified in a 21-year-old
      Portuguese male with a progressive myopathy of intermediate severity, who had
      been misdiagnosed as Becker Muscular Dystrophy (BMD) based on clinical
      observations and muscle immunocytochemical anaylsis with dystrophin antibodies
      only. Since no detectable deletions or duplications were found in the dystrophin
      gene, we screened for mutations in the sarcoglycan genes by PCR-SSCP. The
      patient's sample showed a band of increased mobility in exon 4 of the beta
      sarcoglycan gene which, upon sequencing, was found to represent a homozygous A-
      >G transversion at nucleotide 551, resulting in a tyrosine to cysteine
      substitution at position 184 (Y184C). Carrier status was ascertained in both
      parents and a sister. These aberrant conformers were not detected in 85 unrelated
      control individuals screened by PCR-SSCP analysis. All seven beta-sarcoglycan
      mutations reported to date are associated with a severe phenotype and occur in
      exons 3 and 4, which correspond to the immediate extracellular domain of the
      protein. This region contains five conserved cysteine residues. In our patient,
      the presence of an extra cysteine residue could interefere with intra- and/or
      inter-molecular disulphide bond formation. The intermediate phenotype could
      perhaps result from the assembly of both normal and abnormal complexes, depending
      on the formation of the disulphide bonds.

PMID- 10660329
TI  - Characterization of ten novel and 13 recurring BRCA1 and BRCA2 germline mutations
      in Italian breast and/or ovarian carcinoma patients. Mutations in brief no. 178.
      Online.
AB  - Germline mutations in the BRCA1 and BRCA2 genes are associated with approximately
      80% of families with a high incidence of breast and/or ovarian cancers (OMIM
      database reference numbers: 113705, 600185). Furthermore, constitutional
      mutations in the these genes have been reported in women with early-onset breast
      carcinoma and without family history of cancer. We analyzed by protein truncation
      test (PTT) and single strand conformation polymorphism (SSCP) followed by
      sequence analysis, BRCA1 exons 11 and 20 and BRCA2 exons 10 and 11 in 142 Italian
      cancer patients. These included six male breast cancer cases, 61 women with
      breast carcinoma diagnosed before 36 years old and selected independently of
      family history of breast cancer and 75 familial breast and/or ovarian cancer
      patients. In a previous report, we described 11 different BRCA1 mutations in a
      subset of 70 cases. Here, we report the characterization of 23 additional
      mutations, 14 in BRCA1 and 9 in BRCA2, subsequently identified. Ten mutations
      were not previously described, while the other 13 were recurrent. Of the 61 women
      with early-onset breast cancer, 11 carried a germline mutation in BRCA1 (18.0%)
      and four in BRCA2 (6.6%). These frequencies indicate that BRCA1/BRCA2 genetic
      tests should be advised to women with breast cancer diagnosed at early age,
      independently of family history of cancer.

PMID- 10660330
TI  - Truncating somatic mutation in exon 15 of the APC gene is a rare event in human
      breast carcinomas. Mutations in brief no. 179. Online.
AB  - Inactivation of the adenomatous polyposis coli (APC) gene is an early event in
      sporadic colorectal cancer. Somatic mutations have also been detected in cancers
      of the stomach, pancreas, thyroid, ovary and breast. Over 95% of the mutations
      reported in the APC gene are frameshift and nonsense mutations. The large exon 15
      accounts for 77% of the coding sequence. The APC gene product interacts with
      cytoplasmic beta-catenin, mediates its degradation and thereby downregulates
      transcription exerted by the beta-catenin-Tcf complex. In the absence of a
      functional APC protein, beta-catenin is stabilized and accumulates in the
      cytoplasm. This results in uncontrolled transcriptional activation of Tcf
      responsive genes which may contribute to cancer progression. In order to
      investigate whether this pathway is disrupted by APC mutations in breast
      carcinoma cells, we screened 227 breast tumors for truncating mutations in exon
      15 using the protein truncation test (PTT). Only one mutation, 4678delA, which
      was shown to be somatic, was detected by this approach. The mutation resided just
      outside the mutation cluster region (MCR) and resulted in a premature stop in
      codon 1564. Our findings do not indicate that the suppressive function of APC is
      commonly abrogated by truncating mutations in human breast carcinomas.

PMID- 10660331
TI  - A common beta ig-h3 gene mutation (delta f540) in a large cohort of Sardinian
      Reis Bucklers corneal dystrophy patients. Mutations in brief no. 180. Online.
AB  - Reis-Bucklers' corneal dystrophy (RBCD) is a relatively rare autosomal dominant
      disease originating in the Bowman's membrane, which causes severe visual
      impairment. Recently RBCD, together with lattice corneal dystrophy type I (LCDI),
      granular corneal dystrophy (CDGG1) and Avellino stromal dystrophy (ASD), all
      mapped on 5q31, were found to be associated to four different mutations in the
      beta ig-h3 gene which codify for kerato-epithelin. We identified several cases of
      RBCD in Sardinia. We reconstructed through genealogical search two eight
      generation-families, originating from the same village (Arbus), indicating a
      common ancestor for RBCD in Sardinia. Linkage studies on these families confirmed
      the association of the disease with the 5q31 region. Sequence analysis of beta ig
      h3 gene revealed a trinucleotide deletion in exon 12, corresponding to the loss
      of F540 in the protein sequence (delta F540). Our data describe a new mutation in
      the beta ig-h3 gene causing RBCD. This dominant negative mutation is located in
      the fourth internal repeat of kerato-epithelin which is a protein domain highly
      conserved across species. This suggests the basic role of this domain in
      maintaining the proper kerato-epithelin structure which when altered can cause
      the typical precipitates in the RBCD cornea.

PMID- 10660332
TI  - 18 bp insertion/duplication with internal missense mutation in human hepatic
      lipase gene exon 3. Mutations in brief no. 181. Online.
AB  - Human hepatic lipase (hHL) plays an important role in hydrolysis of triglycerides
      from plasma lipoproteins. The enzyme also hydrolyzes HDL2 lipids resulting in
      smaller HDL particles with a lower cholesterol content and properties similar to
      HDL3. hHL is localized in liver sinusoids, ovary and adrenal gland. These
      findings propose an influence on processing of cholesterol. Here we report an
      insertion mutation in exon 3 of hHL. The 18 bp duplication contains an additional
      internal point mutation (GenBank-Accession #AF037404). The female mutation
      carrier suffered from severe adiposity with total cholesterol of 291,6mg/dl, HDL
      cholesterol of 55,3mg/dl, LDL-cholesterol of 206,8mg/dl and triglycerides of
      80,8mg/dl. Following cloning of a PCR-amplified fragment the mutation was
      confirmed by cycle sequencing. Sequence analysis revealed an inserted repeat of
      18 nucleotides. Furthermore the patient carries an additional missense mutation A
      ->G at nucleotide 9 of the repeat which results in an amino acid exchange from
      Ile-->Val at codon 4 of the repeat. These data enable us to report the insertion
      of HisTyrThrValArgVal which might be responsible for the moderate shift in lipid
      metabolism of the heterozygous patient.

PMID- 10660334
TI  - Compound heterozygosity for a new (S259G) and a previously described (G188E)
      mutation in lipoprotein lipase (LpL) as a cause of chylomicronemia. Mutations in
      brief no. 183. Online.
AB  - Familial chylomicronemia is an autosomal recessive disease characterised by
      fasting triglyceridemia and an absence of lipoprotein lipase (LpL) activity in
      post-heparin plasma. The disease is a result of mutation in either the
      lipoprotein lipase (Lpl) gene or in the apoCII gene which codes for an essential
      co-factor. To date, over 80 mutations in the LpL gene have been reported. The
      proband, a 30 month old female, presented with fasting triglycerides of 3192
      mg/dl, and no detectable LpL mass or activity in post-heparin plasma. Sequencing
      of all of the exons and exon/intron boundaries of the LpL gene showed that she
      was a compound heterozygote with G-A transitions in codon 188 (G188E:GGG to GAG)
      generating an avall restriction site and in codon 259 (S259G:AGT to GGT)
      generating a bssKI site. Restriction digests confirmed the mutations and
      determined the incidence within the family. The father (55%LPL activity),
      paternal aunt (82%) and paternal grandmother (29%) were all heterozygous for the
      S259G mutation whilst her sister (55%), mother (73%) and maternal grandfather
      (45%) were heterozygous for the G188E mutation. The maternal grandmother (114%)
      was unaffected.

PMID- 10660333
TI  - hMLH1 mutations in hereditary nonpolyposis colorectal cancer kindreds. Mutations
      in brief no. 182. Online.
AB  - Hereditary nonpolyposis colorectral cancer (HNPCC), an autosomal dominantly
      inherited predisposition for early onset colorectal cancer, accounts for at least
      6% of all colorectal malignancies. HNPCC results from germ-line mutations in DNA
      mismatch repair (MMR) genes (hMSH2, hMLH1, hPMS1 and hPMS2) and is associated
      with a high rate of replication errors in tumor cells. Using PCR-SSCP, the
      protein truncation test and DNA sequencing we have analyzed the hMSH2 and hMLH1
      genes in 10 Italian families that met the standard diagnostic criteria for HNPCC.
      We have identified three new mutations in the hMLH1 gene. One mutation consists
      in a deletion of one base pair at nucleotide 954 (954delC) in exon 11 that
      creates an early stop at codon 366 and is predicted to abolish normal protein
      function. The other two are missense mutations. Cys77Arg and Ser193Pro, that
      cause dramatic amino acid substitutions in two highly conserved MLH domains. The
      Cys77Arg mutation occurs within a domain (1-114 residues) that is very critical
      for MMR function. The Ser193Pro mutation occurs in a highly conserved central
      region of the MLH1 protein. No functional domains have yet been identified in
      this region. All mutant alleles cosegregate with the cancer phenotype.

PMID- 10660335
TI  - Novel intragenic polymorphisms in the tuberous sclerosis 2 (TSC2) gene. Mutations
      in brief no. 184. Online.
AB  - Twenty-three unrelated patients with tuberous sclerosis have been screened for
      the presence of mutations in six regions of the TSC2 gene. Eight novel intragenic
      polymorphisms have been found, one in intron 36 and seven in intron 4, with the
      use of SSCP analysis. Four of these polymorphisms alter the recognition sequence
      of specific restriction enzymes and can be detected as RFLPs. Study in a random
      sample of unrelated individuals from Northern Greece, showed that these
      polymorphisms have mean observed and expected heterozygosity values of 0.2996 and
      0.3349, respectively and could be useful for linkage analysis. It is most likely
      that the wild type alleles from two pairs of these polymorphisms are strongly
      associated. A 667 bp segment of intron 4 (954 bp) and an additional 75 bp of
      intron 36 (352bp) were sequenced, thus completing the sequence of both introns.

PMID- 10660336
TI  - Molecular analysis of northwestern Mexican patients with cystic fibrosis:
      screening of 10 known mutations. Mutations in brief no. 185. Online.
AB  - We have analyzed 45 unrelated Northwestern Mexican patients with Cystic Fibrosis
      for 10 known CF mutations (DF508, G542X, G551D. R553X, W1282X, NI303K, R334W,
      R347H, S549R, and R1162X). Screening was performed on exons 7, 10, 11, 19, 20 and
      21 using standard methods such as polymerase chain reactions, reverse dot blot
      hybridization (non-radioactive), and restriction enzyme digestion. The analysis
      for these ten mutations permitted the identification of only two mutations in
      37.7% of CF chromosomes in this sample. The major mutation, delta F508, accounts
      for 34.4% of CF chromosomes. Of the 45 CF patients 9 (20.0%) were homozygous
      delta F508 deletion, 11 (24.4%) were heterozygous for the delta F508 mutation and
      an unknown mutation. One additional mutation G542X was also found in 3
      chromosomes in our population (3.3%). Two patients were documented to be a
      compound heterozygote for DF508/G542X, and other one heterozygous for G542X and
      an unknown mutation. Therefore 62.2% of chromosomes remain uncharacterized.

PMID- 10660337
TI  - Identification of two rare variants (G-->A at nucleotide 721; C-->T at nucleotide
      5200) in the rhodopsin gene. Mutations in brief no. 187. Online.
AB  - The authors report two new rare DNA sequence variants in the Rhodopsin gene. This
      gene is involved in the pathogenesis of some retinal hereditary disorders as
      Retinitis Pigmentosa. These rare variants are G-->A at nucleotide 721 of the non
      coding region and C-->T at nucleotide 5200 within codon 323 which does not alter
      the aminoacid cysteine. Therefore, they are not implicated in the development of
      the Retinitis Pigmentosa disease.

PMID- 10660338
TI  - The minisatellite expansion mutation in EPM1: resolution of an initial
      discrepancy. Mutatations in brief no. 186. Online.
AB  - Mutations in the cystatin B (CSTB) gene underlie progressive myoclonus epilepsy
      of Unverricht-Lundborg type (EPM1) (Pennacchio et al., 1996). We previously
      described an unstable minisatellite expansion mutation in the putative promoter
      region of CSTB that accounts for the majority of EPM1 patients. Sequencing of a
      genomic lambda clone, generated from a Finnish EPM1 patient homozygous for an
      enlarged restriction fragment, revealed a 15- to 18-mer minisatellite repeat
      expansion (Virtaneva et al., 1997). Later, sequencing of plasmid clones generated
      from Swiss and French patients revealed a dodecamer repeat expansion (Lalioti et
      al., 1997a). By restriction enzyme analysis of our original patient clone and a
      clone generated from an Italian patient, we now show that the expansion is
      neither a 15-mer nor an 18-mer contrary to our initial results. Moreover, direct
      sequencing of the Finnish patient clone with Pfu exo polymerase confirmed that
      the expanded repeat is a dodecamer. Based on this finding and additional
      experiments, we suggest that the discrepancy between the two studies was due to
      errors caused by the combination of native Pfu polymerase and modified guanosine
      deaza-7-dGTP used in the PCR reaction.

PMID- 10660339
TI  - Five novel mutations in the familial multiple endocrine neoplasia type 1 (MEN1)
      gene. Mutations in brief no. 188. Online.

PMID- 10660340
TI  - Two novel mutations consisting in minor gene rearrangements in the human low
      density lipoprotein receptor gene in Italian patients affected by familial
      hypercholesterolemia. Mutations in brief no. 194. Online.
AB  - Mutations in the low density lipoprotein (LDL)-receptor gene cause familial
      hypercholesterolemia (FH), an autosomal dominant disease associated to an
      increased risk of premature atherosclerosis. We describe two novel mutations
      found in Italian families and consisting in minor gene rearrangements. The first
      one (FH-Pisa) is a tetranucleotide insertion occurring in exon 8, which causes a
      frameshift and a premature stop codon. The second one (FH-Chieti3) occurs at the
      3'-end of exon 4 and consists in a trinucleotide deletion replaced by a six-base
      insertion, so that the reading frame is maintained with a glutamic acid-to
      cysteine substitution at codon 207 and the insertion of a lysine at codon 208.
      Both mutations occur in regions of the LDL-receptor gene which can be considered
      hotspots for minor rearrangements.

PMID- 10660341
TI  - Different ocular abnormalities in individuals of a three-generation family caused
      by a new nonsense mutation in the PST domain of the PAX6 gene. Mutations in brief
      no. 189. Online.
AB  - PAX6 is a candidate gene for familial aniridia. We have carried out a mutational
      analysis of the PAX6 gene in a three-generation family from Germany, containing 5
      individuals affected with ocular abnormalities. In all affected individuals, a
      heterozygous mutation was detected in the PAX6 gene, exchanging tyrosine 369 by a
      stop codon. The mutation is located in the 3' moiety of the PST domain, at the C
      terminus of the PAX6 protein. In the affected family members, the same
      heterozygous mutation leads to distinct phenotypes of varying severity. Most
      notably, no aniridia was observed in one of the family members carrying the
      mutation, although other ocular abnormalities (underdeveloped iris and cataracts)
      were present. We discuss the possibility that small C terminal truncations of the
      PAX6 protein might lead to less severe or more divergent phenotypes than
      trancations at internal positions.

PMID- 10660342
TI  - Laminin 5 genes and Herlitz junctional epidermolysis bullosa: novel mutations and
      polymorphisms in the LAMB3 and LAMC2 genes. Mutations in brief no. 190. Online.
AB  - Herlitz junctional epidermolysis bullosa (H-JEB; OMIM #226700) is a lethal,
      autosomal recessive blistering disorder characterized by fragility of the skin
      and other specialized epithelia. Previously, mutations in the laminin 5 genes
      (LAMA3, LAMB3, and LAMC2) have been disclosed, most of them in LAMB3. In this
      study, we have examined the genetic basis of H-JEB in three families utilizing
      heteroduplex analysis and automated nucleotide sequencing. In one family, the
      proband was compound heterozygote for previously unpublished LAMB3 mutations,
      1482delC and W95X. In two other families, the probands were found to be
      homozygous for novel nonsense mutations C553X and K822X in the LAMC2 gene. These
      mutations result in premature termination codons and predict truncation of the
      corresponding polypeptides. Also, during the search of laminin 5 mutations, 18
      LAMB3 and LAMC2 polymorphisms were discovered, 9 of them being previously
      undescribed. Delineation of novel homozygous nonsense mutations in the LAMB3 and
      LAMC2 genes, with previous demonstrations of LAMA3 mutations, re-emphasizes the
      concept that stop codon mutations in both alleles of any of the three laminin 5
      genes result in the severe H-JEB phenotype.

PMID- 10660343
TI  - Characterization of an allelic variant in the nifedipine-specific element of
      CYP3A4: ethnic distribution and implications for prostate cancer risk. Mutations
      in brief no. 191. Online.
AB  - CYP3A4 is involved in the metabolism of numerous biologically active compounds,
      including testosterone. A genetic variant located in the P450NF (nifedipine)
      specific element (NFSE) has been identified that disrupts a transciptional
      regulatory element located in the 5' regulatory region of CYP3A4. The CYP3A4
      variant (CYP3A4-V) is associated with the clinical presentation of prostate
      cancer. There are significant differences in CYP3A4 metabolism and rates of
      prostate cancer across ethnic groups that may be associated with CYP3A4
      genotypes. Therefore, we estimated the frequency of the CYP3A4 variant in three
      ethnic groups with different prostate cancer incidence rates. The frequency (q)
      of CYP3A4-V was significantly different (p<0.0001) in African Americans (q=0.53),
      U.S. Caucasians (q=0.09), and Taiwanese (q=0.0). CYP3A4-V segregated in a
      Mendelian manner in one large African American family, and 7 of 16 (44%)
      biologically unrelated "marry-ins" carried a CYP3A4 variant allele. Reflecting
      population-specific prostate cancer incidence rates, our results suggest a high
      frequency of this variant in African Americans compared with U.S. Caucasians and
      Taiwanese.

PMID- 10660344
TI  - T426I a new mutation in the thyroid hormone receptor beta gene in a sporadic
      patient with resistance to thyroid hormone and dysmorphism. Mutations in brief
      no. 192. Online.
AB  - Resistance to thyroid hormone (RTH) is a rare inherited autosomal syndrome caused
      by mutations in the thyroid hormone receptor beta (TRb) gene. Although RTH is
      generally a familiar disease, 15% of sporadic cases have been also reported. So
      far, about 80 different mutations of TRb gene have been identified in patients
      affected by RTH. All these mutations localize to the binding domain and most of
      them cluster within two "hot spots" (codons 310-349 and codons 429-460). Here we
      describe in a patient with RTH, a new mutation in codon 426 (T426I) of the TRb
      gene leading to a threonine to isoleucine substitution. This is a "de nova"
      mutation which localizes in the so-called "cold" region, outside the two known
      "hot spots". The patient had the hallmark of RTH: elevated FT3 and FT4, normal
      TSH, and clinical features of both hypo and hyperthyroidism. Moreover, several
      dysmorphisms were present including triangular face appearance, synophris, low
      set ears, micrognathia with malocclusion, large upper incisors and apparent lack
      of lower cuspids which have not previously described in RTH patients.

PMID- 10660346
TI  - Proceedings of the 3rd Annual Meeting of the Japanese Research Society for
      Helicobacter pylori--Related Gastroduodenal Diseases. Beppu, Japan, July 18-19,
      1997.

PMID- 10660345
TI  - Polymorphisms in the human ornithine transcarbamylase gene useful for allele
      tracking. Mutations in brief no. 193. Online.
AB  - Sequences of amplified DNA fragments from the ornithine transcarbamylase (OTC)
      genes were screened for 10 polymorphic single base substitutions in order to
      determine their frequency in the population. Six of the polymorphisms showed a
      frequency of 0.02 or less. The remaining four polymorphisms showed a range in
      frequency from 0.125 to 0.5. Based on the allele frequencies of the four common
      polymorphisms, we calculated that a female has an 87% chance of being
      heterozygous for at least one locus. These intragenic sequence variations can be
      used for tracking of deleterious OTC  alleles whenever the deleterious mutation
      cannot be found and should also prove useful for prenatal diagnosis.

PMID- 10660348
TI  - Evaluating local and international trends in the quality field.

PMID- 10660347
TI  - Problems of anticoagulation within a palliative care setting-- correction.

PMID- 10660349
TI  - Prospective study of symptoms and gastro-oesophageal reflux 10 years after
      posterior partial fundoplication.

PMID- 10660350
TI  - Multimodal therapy for squamous carcinoma of the oesophagus.

PMID- 10660351
TI  - Prevalence of aortic aneurysm in men with a history of inguinal hernia repair.

PMID- 10660352
TI  - Value of splenic preservation during distal pancreatectomy for chronic
      pancreatitis.

PMID- 10660353
TI  - [Recent findings on the etiology of systemic sclerosis].

PMID- 10660354
TI  - Case report: French West Indies-a tourist destination at risk for Plasmodium
      falciparum transmission?

PMID- 10660355
TI  - Reconstructive hand surgery.

PMID- 10660357
TI  - Web alert: patent information.

PMID- 10660356
TI  - Innovations: bug warfare. IntraBiotics Pharmaceuticals, Inc.

PMID- 10660358
TI  - Model-based analysis of medical images.

PMID- 10660359
TI  - The 'Malone Group' meeting, October 1998.

PMID- 10660360
TI  - Report from the 20th Congress of the European Society of Cardiology, Vienna, 22
      26 August 1998.

PMID- 10660362
TI  - Proceedings of the symposium on rhodopsins and phototransduction. Kyoto, Japan,
      26-28 October 1998.

PMID- 10660361
TI  - Report from the 8th European Respiratory Society Annual Congress, Geneva,
      Switzerland, September 1998.

PMID- 10660363
TI  - How deterministic can the angiogram be?

PMID- 10660364
TI  - Reactions to prescribed drugs kill thousands annually.

PMID- 10660365
TI  - [The procedure in suspected occupational disease].

PMID- 10660366
TI  - ["Vitality took up the pen here"!--Julius Schwalbe and the DMW (Deutsche
      Medizinische Wochenschrift) 1894-1930].

PMID- 10660367
TI  - [Ear surgery].

PMID- 10660369
TI  - [Microsurgical preparation of isolated outer hair cells of the inner ear from the
      adult guinea pig cochlea].

PMID- 10660368
TI  - [Comments on the discussion of the book by J. Maurer (Hrsg.): Neurootology--with
      emphasis on examination techniques].

PMID- 10660370
TI  - [Medical jurisprudence events from November 1888 to April 1999].

PMID- 10660371
TI  - Choosing a, please con't call it an alternative, alternative career in science.

PMID- 10660372
TI  - [Infections of the anterior chamber].

PMID- 10660373
TI  - [Our limitations and choices].

PMID- 10660374
TI  - [Retina].

PMID- 10660375
TI  - Midwifery in the 21st century.

PMID- 10660376
TI  - What accounts for physician opinions about midwifery in Canada.

PMID- 10660377
TI  - [Ambulatory surgery--foreign body removal (from the nasal cavity, external ear,
      pharynx, and esophagus)].

PMID- 10660378
TI  - The Epididymis: Cellular and Molecular Aspects. Proceedings of the Boden
      Conference. Robertson, NSW, Australia. February 1998.

PMID- 10660379
TI  - London Hypertension Society 9th Annual Symposium. 15 October 1998. Abstracts.

PMID- 10660380
TI  - Annual Scientific Meeting of the British Hypertension Society. Glasgow, United
      Kingdom, 13-15 September 1999. Abstracts.

PMID- 10660381
TI  - Xenotransplantation: A Solution for the Future? Proceedings of an international
      meeting. Madrid, Spain, February 9-10, 1999.

PMID- 10660382
TI  - Proceedings of the International Space Lifesciences Working Group on Radiation
      Biology workshop. Banff, Canada, November 1997.

PMID- 10660383
TI  - International Workshop on Radiation Biology.

PMID- 10660384
TI  - Body-mass index and mortality.

PMID- 10660385
TI  - Body-mass index and mortality.

PMID- 10660386
TI  - Dofetilide for atrial fibrillation.

PMID- 10660387
TI  - Dofetilide for atrial fibrillation.

PMID- 10660388
TI  - Hepatitis C in children.

PMID- 10660389
TI  - Case 28-1999: Creutzfeldt-Jakob disease.

PMID- 10660390
TI  - Central sleep apnea and heart failure.

PMID- 10660391
TI  - Central sleep apnea and heart failure.

PMID- 10660392
TI  - Angiographic visualization of an atrial myxoma.

PMID- 10660393
TI  - Right ventricular myxoma.

PMID- 10660394
TI  - Early identification of refractory epilepsy.
AB  - BACKGROUND: More than 30 percent of patients with epilepsy have inadequate
      control of seizures with drug therapy, but why this happens and whether it can be
      predicted are unknown. We studied the response to antiepileptic drugs in patients
      with newly diagnosed epilepsy to identify factors associated with subsequent poor
      control of seizures. METHODS: We prospectively studied 525 patients (age, 9 to 93
      years) who were given a diagnosis, treated, and followed up at a single center
      between 1984 and 1997. Epilepsy was classified as idiopathic (with a presumed
      genetic basis), symptomatic (resulting from a structural abnormality), or
      cryptogenic (resulting from an unknown underlying cause). Patients were
      considered to be seizure-free if they had not had any seizures for at least one
      year. RESULTS: Among the 525 patients, 333 (63 percent) remained seizure-free
      during antiepileptic-drug treatment or after treatment was stopped. The
      prevalence of persistent seizures was higher in patients with symptomatic or
      cryptogenic epilepsy than in those with idiopathic epilepsy (40 percent vs. 26
      percent, P=0.004) and in patients who had had more than 20 seizures before
      starting treatment than in those who had had fewer (51 percent vs. 29 percent,
      P<0.001). The seizure-free rate was similar in patients who were treated with a
      single established drug (67 percent) and patients who were treated with a single
      new drug (69 percent). Among 470 previously untreated patients, 222 (47 percent)
      became seizure-free during treatment with their first antiepileptic drug and 67
      (14 percent) became seizure-free during treatment with a second or third drug. In
      12 patients (3 percent) epilepsy was controlled by treatment with two drugs.
      Among patients who had no response to the first drug, the percentage who
      subsequently became seizure-free was smaller (11 percent) when treatment failure
      was due to lack of efficacy than when it was due to intolerable side effects (41
      percent) or an idiosyncratic reaction (55 percent). CONCLUSIONS: Patients who
      have many seizures before therapy or who have an inadequate response to initial
      treatment with antiepileptic drugs are likely to have refractory epilepsy.

PMID- 10660395
TI  - Placebo surgery in trials of therapy for Parkinson's disease.

PMID- 10660396
TI  - Placebo surgery in trials of therapy for Parkinson's disease.

PMID- 10660397
TI  - Placebo surgery in trials of therapy for Parkinson's disease.

PMID- 10660398
TI  - Placebo surgery in trials of therapy for Parkinson's disease.

PMID- 10660399
TI  - Placebo surgery in trials of therapy for Parkinson's disease.

PMID- 10660400
TI  - Outbreaks of enterovirus 71 infection.

PMID- 10660401
TI  - Enterovirus 71 infection and neurologic complications.

PMID- 10660402
TI  - Acute myeloid leukemia.

PMID- 10660403
TI  - Growth hormone therapy in adults and children.

PMID- 10660404
TI  - Growth hormone therapy in adults and children.

PMID- 10660405
TI  - Acute eosinophilic hepatitis from trovafloxacin.

PMID- 10660406
TI  - [Current Problems of Developmental Biology, conference dedicated to the 275th
      anniversary of the Russian Academy of Sciences. Moscow, 26-28 April 1999.
      Abstracts].

PMID- 10660407
TI  - Strength of discourse context as a determinant of the subordinate bias effect.
AB  - Two experiments examined the influence of strength of discourse bias on lexical
      ambiguity resolution. Short passages were constructed to bias polarized ambiguous
      words (homonymous) strongly or weakly toward the dominant or subordinate
      meanings. Using a self-paced reading task in Experiment 1, it was demonstrated
      that in strongly biased discourse, reading times for homonyms in dominant
      discourse did not differ from those in subordinate discourse. However, when the
      discourse was weakly biased, homonyms were read faster in dominant discourse than
      in subordinate discourse. Experiment 2 combined the reading paradigm with a
      naming task in order to provide an assessment of specific word-meaning
      activation. Reading times on ambiguous words replicated the results of Experiment
      1. In addition, naming latencies for probe words revealed that only the
      contextually appropriate sense of a homonym was activated in strongly biased
      discourse. In contrast, both contextually appropriate and inappropriate senses
      were activated following a weakly biased subordinate discourse, whereas only the
      dominant sense was activated following weakly biased dominant discourse. The
      results demonstrate (1) an immediate influence of prior discourse information on
      lexical processing; and (2) that the strength of discourse constraints can play a
      governing role in lexical ambiguity resolution. The results were interpreted
      within the framework of a context-sensitive model of lexical ambiguity
      resolution.

PMID- 10660408
TI  - XVIII International Symposium of the Society of Toxicologic Pathologists:
      Toxicologic Pathology of the Nervous System. Abstracts.

PMID- 10660410
TI  - Young Investigators session abstracts.

PMID- 10660409
TI  - Mechanisms of Toxicity, Carcinogenesis, and Cancer Prevention. The 14th Aspen
      Cancer Conference. Aspen, Colorado, USA, July 18-21, 1999. Abstracts.

PMID- 10660411
TI  - Prostate--the central organ--and its diseases. Symposium proceedings. November
      1998.

PMID- 10660412
TI  - Accumulation of heavy metals and As in wetland birds in the area around Donana
      National Park affected by the Aznalcollar toxic spill.
AB  - The impact of the spill from the mine in Aznalcollar (Seville, Spain) on
      waterfowl in the Donana National Park is assessed. The concentrations of Cu, Pb,
      Cd, Zn nd As in the liver and eggs of 16 species of waterfowl found dead in the
      Park between April and November 1998 were determined. The highest levels were
      found for Zn, followed by Cu, Pb, Cd and As. The main parameters related to the
      accumulation of these elements in the waterfowl studied were species and trophic
      level. The other variables studied--distance from the spill, days of exposure,
      sex, size, and age--are important, although this depends on the element studied.
      Zn and Cu from the spill have entered the food chain of the aquatic birds
      studied, but Cd, Pb and As have not. There is currently no evidence to suggest
      that the trace element concentrations measured have reached toxic levels.

PMID- 10660413
TI  - Trace elements in blood collected from birds feeding in the area around Donana
      National Park affected by the toxic spill from the Aznacollar mine.
AB  - A long-term monitoring plan was established to study if bird populations around
      Donana National Park were affected by the toxic spill from the Aznalcollar mine.
      The concentrations of Zn, Pb, As, Cu, Sb, Co, Tl and Cd in the blood of 11 bird
      species feeding in the area were determined. The parameters which most affect the
      accumulation of trace elements in the birds studied are, firstly, species and
      secondly, trophic position, sex, days of exposure and weight. In some
      individuals, Zn and Cu occurred at higher levels than the reference values for
      contaminated areas. Concentrations of Pb and Cd in a considerable number of
      individuals were higher than those found in birds from uncontaminated areas. The
      present data, together with the lack of data on blood metal concentration prior
      to the spill, do not offer any conclusive evidence of the influence of the spill
      on avian blood metal concentrations.

PMID- 10660414
TI  - Fetal tissue research. Antiabortion groups target neuroscience study at Nebraska.

PMID- 10660415
TI  - Evolution. Nature steers a predictable course.

PMID- 10660416
TI  - Designer labs: architecture discovers science.

PMID- 10660417
TI  - The endless pathways of discovery.

PMID- 10660418
TI  - Of chimps and men.

PMID- 10660419
TI  - Social "mentalizing" abilities in mental patients.

PMID- 10660420
TI  - Biosphere management: some tools of the trade.

PMID- 10660421
TI  - Biosphere management: some tools of the trade.

PMID- 10660422
TI  - Waiting for organ transplantation. Institute of Medicine Committee on Organ
      Transplantation.

PMID- 10660423
TI  - Perspectives: plant biology. The green revolution strikes gold.

PMID- 10660424
TI  - Perspectives: neurobiology. Diversity in inhibition.

PMID- 10660425
TI  - Pathways of discovery. Deconstructing the "science wars" by reconstructing an old
      mold.

PMID- 10660426
TI  - Proceedings of the XVII Congress of the International Society of Thrombosis and
      Haemostasis.

PMID- 10660427
TI  - [All-Russia symposium on issues in establishing and development of cancer
      registries].

PMID- 10660428
TI  - [Reports of the German Society of Cardiology-Heart and Cardiovascular Research.
      Report of activities of the Cardiovascular Ultrasound Study Group 1998/99].

PMID- 10660429
TI  - Aluminium chelation in chronic haemodialysis and aluminium adjuvanted vaccines.

PMID- 10660430
TI  - Vaccines against H5N1 influenza.

PMID- 10660431
TI  - Glucocorticoid Hormone Action in Rheumatic Autoimmune Diseases. International
      conference. Bad Nauheim, Germany, October 14-16, 1999. Abstracts.

PMID- 10660432
TI  - [Controversies. On the separation of the SGR/SGPMR Professional Society].

PMID- 10660434
TI  - Proceedings of the 11th International Hypoxia Symposium. Jasper, Alberta, Canada.
      February 28-March 3, 1999.

PMID- 10660433
TI  - [Special issue dedicated to the 100th birthday of Evgenii Mikhailovich Kreps].

PMID- 10660435
TI  - Hypoxia and the blood-brain barrier: introduction.

PMID- 10660436
TI  - World wide interest in herpes virus-associated lymphoproliferation in humans.

PMID- 10660437
TI  - Application of a macrocycle immobilized silica gel sorbent to flow injection on
      line microcolumn preconcentration and separation coupled with flame atomic
      absorption spectrometry for interference-free determination of trace lead in
      biological and environmental samples.
AB  - A simple and highly selective flow injection on-line pre-concentration and
      separation-flame atomic absorption spectrometric method was developed for routine
      analysis of trace amounts of lead in biological and environmental samples. The
      selective preconcentration of lead was achieved in a wide range of sample acidity
      (0.075 to > or = 3 mol L(-1)HNO3) on a microcolumn (145 microL) packed with a
      macrocycle immobilized on silica gel. The lead retained on the column was
      effectively eluted with an EDTA solution (0.03 mol L(-1), pH 10.5). Three kinds
      of potential interferences, i.e., preconcentration inferences from metal ions
      with an ionic radius similar to that of Pb(II) due to their competition for the
      cavity of the macrocyle, elution kinetic interferences from ions which form
      stable complexes with EDTA due to their competition for EDTA, and interferences
      in the atomizer from residual matrix, were evaluated and compared in view of the
      read-out mode of the analyte response (peak area vs peak height), column wash
      step (with vs without), column capacity (50 vs 145 microL), and column shape
      (conical vs cylindrical). The results showed that a combination of increase in
      column capacity, quantitation based on peak area, and use of dilute nitric acid
      for column wash before elution efficiently avoid the above-mentioned potential
      interferences. With the use of a 145 microL column the present system tolerated
      up to 0.1 g L(-1) Ba(II), 1 g L(-1) Sr(II), and at least 10 g L(-1) Fe(III),
      Cu(II), Ni(II), Zn(II), Cd(II), Al(III), K(I), Na(I), CaII), and Mg(II) in the
      sample digest. Further improvement of the interference tolerance can be achieved
      by increasing column capacity if more complicated samples need to be analyzed. At
      a sample loading rate of 3.9 mL min(-1) with 30-s preconcentration, an enrichment
      factor of 52, a detection limit (3s) of 5 micrograms L(-1) Pb in the digest and a
      sampling frequency of 63 h(-1) were obtained. The precision (RSD, n = 11) at the
      200 micrograms L(-1) level was 1.9%. The enrichment factor and the detection
      limit can be further improved by increasing sample loading rate without
      degradation in the efficiency due to the favorable kinetics and low hydrodynamic
      impedance of the present system. The analytical results obtained by the proposed
      method for a number of biological and environmental standard reference materials
      were in good agreement with the certified and recommended values.

PMID- 10660438
TI  - A prototype electrochemical chromatographic column for use with proteins.
AB  - We developed electrochemical hardware and media targeted for protein
      chromatography. Two types of stationary phases were investigated. The first
      comprised gold-plated stainless 316L beads coated with a self-assembled monolayer
      of 6-mercaptohexan-1-ol and was expected to behave like an ion-exchange resin in
      the presence of an electric field. The secondary stationary phase comprised the
      first stationary phase with further functionalization with immobilized heme
      moieties and was expected to behave like immobilized metal affinity resin. We
      tested apparatus with both stationary phases using ribonuclease A as a model
      protein and applied potentials from -0.3 to +0.3 V versus the saturated calomel
      electrode. Despite low binding capacities, we demonstrated that protein retention
      on both stationary phases could be controlled with an applied potential. The
      greatest extent of electromodulation was achieved with the mercaptohexanol-based
      ion-exchange media.

PMID- 10660439
TI  - Scanning electrochemical microscopy. 38. Application of SECM to the study of
      charge transfer through bilayer lipid membranes.
AB  - The use of the scanning electrochemical microscope (SECM) to probe the kinetics
      of charge-transfer processes at bilayer lipid membranes (BLM) is presented.
      Analysis of the SECM tip response demonstrates that an unmodified BLM behaves as
      an insulator, whereas a BLM doped with iodine shows some positive feedback. The
      SECM technique thus allows one to probe processes at a BLM and determine the
      kinetics of the charge-transfer process. The SECM can also be used to determine
      the shape of the BLM.

PMID- 10660440
TI  - On-line coupling flow injection microcolumn separation and preconcentration to
      electrothermal atomic absorption spectrometry for determination of (ultra)trace
      selenite and selenate in water.
AB  - A flow injection manifold with an air-segmented and air-transported operational
      sequence for on-line coupling of microcolumn separation and preconcentration to
      electro-thermal atomic absorption spectrometry (ETAAS) was developed for the
      determination of (ultra)trace selenite and selenate in water. The determination
      of selenite was achieved by selective reaction with pyrrolidine dithiocarbamate
      (PDC), sorption of the resultant Se-PDC compound onto a conical microcolumn (10.2
      microL) packed with RP C18 sorbent, elution with ethanol, and detection by ETAAS.
      The concentration of selenate was obtained as the difference between the
      concentrations of selenite after and before prereduction of selenate to selenite.
      With the developed manifold and operation sequence,the dispersion during elution
      and eluate transport and the eluent volume required for complete elution of the
      sorbed analyte were minimized. As a result, the sorbed analyte was quantitatively
      eluted from the column with only 26 microL of ethanol, and all the eluate was
      automatically introduced into the graphite tube by an air flow without the need
      of preheating the graphite tube or precise timing. Pretreatment of the graphite
      tube with iridium as a long-term "permanent" modifier effectively prevented
      analyte loss arising from the high volatility of the Se-PDC compound and greatly
      improved the precision, sensitivity, and detection limit. One thermal
      pretreatment of the graphite tube with injection of 150 microgram of iridium made
      possible at least 200 repetitive atomization cycles. With a preconcentration time
      of 180 s and a sample flow rate of 1.4 mL min(-1), an enhancement factor of 112
      was achieved in comparison with direct injection of 30 microL of aqueous
      solution. The detection limit (3s) was 4.5 ng L(-1)Se. The RSD (n = 7) was 3.8%
      at 20 ng L(-1)Se. The concentrations of selenite and selenate determined in
      synthetic aqueous mixtures were in good agreement with the expected values. The
      recoveries for selenite from spiked seawater samples ranged from 98 to 102%. The
      concentrations of selenite in several seawater reference materials obtained with
      simple aqueous standard solutions for calibration agreed well with the certified
      and information values, respectively. In addition, the developed method was
      successfully applied to the certification of selenite and selenate in water.

PMID- 10660441
TI  - Spin-stretching of DNA and protein molecules for detection by fluorescence and
      atomic force microscopy.
AB  - We have developed a rapid and efficient way of stretching DNA and denatured
      protein molecules for detection by fluorescence microscopy and atomic force
      microscopy (AFM). In the described method, a viscous drag created by transient
      rotational flow stretches randomly coiled DNA molecules or denatured proteins.
      Stretching is achieved by dispensing a droplet of sample solution containing DNA
      or denatured protein on a MgCl2-soaked mica surface. We present fluorescent
      images of straightened lambdaDNA molecules and AFM images of stress-shared,
      reduced von Willebrand factor as well as straightened lambdaDNA. The described
      quick and reliable spin-stretching technique will find wide applications in the
      analysis of single biopolymer molecules.

PMID- 10660442
TI  - Proceedings of the 1st International Symposium on Disease Prevention by IP6, and
      Other Rice Components. Kyoto, Japan, 8-9 June 1998.

PMID- 10660443
TI  - Caring makes a difference.

PMID- 10660444
TI  - 1999-2000 legislative update.

PMID- 10660445
TI  - Common sense--a key component of decision making.

PMID- 10660446
TI  - History corner: A hunting we will go!

PMID- 10660447
TI  - Do we need a new word for patients? Continue to call them patients but treat them
      like customers.

PMID- 10660448
TI  - Biomechanical stress-induced apoptosis in vein grafts involves p38 mitogen
      activated protein kinases.
AB  - The present study was designed to investigate whether apoptosis occurs in early
      stage vein grafts and to determine the mechanisms by which mechanical stress
      contributes to apoptosis in vascular smooth muscle cells (SMCs). Apoptosis in
      vessel walls of mouse vein grafts was confirmed by morphological changes and by
      terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling
      (TUNEL). TUNEL(+) cells in vein grafts 1, 4, and 8 wk postoperatively was 13%,
      29%, and 21%, respectively, and apoptosis occurred mainly in veins grafted to
      arteries, remaining unchanged in vein-to-vein grafts. When mouse, rat, and human
      arterial SMCs were cultured on a flexible membrane and subjected to cyclic strain
      stress, apoptosis was observed in a time- and strength-dependent manner. All
      three types of SMCs showed apoptotic death as confirmed by TUNEL, propidium
      iodide, and annexin V staining. To further study the signal pathways leading to
      apoptosis, activities of p38, a subfamily of mitogen-activated protein kinases
      (MAPKs), were determined. Mechanical stress resulted in p38 MAPK activation,
      reaching high levels within 8 min. SB 202190, a specific inhibitor for p38 MAPKs,
      prevented SMC apoptosis in response to mechanical stress. SMC lines stably
      transfected with a dominant negative rac, an upstream signal transducer, or
      overexpressing MAPK phosphatase-1, a negative regulator for MAPKs, completely
      inhibited mechanical stress stimulated p38 activation and abolished mechanical
      stress-induced apoptosis. Thus, we provide solid evidence that one of the
      earliest events in venous bypass grafts is apoptosis, in which mechanical stress
      induced p38-MAPK activation is responsible for transducing signals leading to
      apoptosis.-Mayr, M., Li, C., Zou, Y., Huemer, U., Hu, Y., Xu, Q. Biomechanical
      stress-induced apoptosis in vein grafts involves p38 mitogen-activated protein
      kinases.

PMID- 10660449
TI  - Quantitative, high-throughput cell-based assays for inhibitors of trkA receptor.
AB  - Two quantitative, high-throughput cell-based assays for evaluating inhibitors of
      NGF-stimulated trkA phosphorylation in trkA-transfected NIH3T3 cells have been
      established. Both assays involve capture of the trkA receptor from cell lysates
      in microtiter plates coated with an anti-trk antibody. The amount of trkA
      phosphorylation is then measured using either an anti-phosphotyrosine antibody
      with a colorimetric readout or a lanthanide (europium)-labeled anti
      phosphotyrosine antibody with a fluorometric detection. The two assay formats
      exhibited at least a fivefold increase in phosphorylated trkA signal in trkA
      transfected cells compared to vector control. Inhibition plots generated for trkA
      kinase inhibitors using the two detection systems yielded comparable IC(50)
      values. Overall, the two assays represent a marked improvement over the standard
      gel-based/western blot method in terms of throughput, quantitation, and
      amenability to automation.

PMID- 10660450
TI  - Direct detection of crosslinks of collagen and elastin in the hydrolysates of
      human yellow ligament using single-column high performance liquid chromatography.
AB  - Collagen and elastin are recognized as two major connective tissue proteins of
      human yellow ligament. In both collagen and elastin there are many kinds of intra
      or intermolecular crosslinks. Pyridinoline (Pyr) and deoxypyridinoline (Dpyr)
      are mature crosslinks which maintain the structure of the collagen fibril.
      Desmosine (Des) and isodesmosine (Isodes) represent the major crosslinking
      components of elastin. Pentosidine (Pen), which is a senescent crosslink and one
      of the advanced glycation end products, accumulates with age in tissue proteins
      including collagen. We developed a direct and one-injection HPLC method to
      measure Pyr, Dpyr, Des, Isodes, and Pen in the hydrolysate of human yellow
      ligament. This method used one column and two detectors. Recovery rates of Pyr,
      Dpyr, Pen, Des, and Isodes were 86.4-98.3, 83.6-96.8, 78.7-95.6, 83.6-97.9, and
      85.6-99.3%, respectively (n = 8). The intraassay coefficients of variation for
      Pyr, Dpyr, Pen, Des, and Isodes were 3.7, 4.1, 5.4, 4.5, and 4.7%, respectively
      (n = 8), and the interassay coefficients of variation for Pyr, Dpyr, Pen, Des,
      and Isodes were 4.4, 5.1, 4.9, 4.6 and 4.1%, respectively. Linear regression
      analysis showed the linearity (r = 0.99, P = 0.0001) of calibration line for each
      Pyr, Dpyr, Pen, Des, and Isodes. Using this method, we investigated age-related
      changes in the crosslinks of collagen and elastin in human yellow ligament. There
      was a significant correlation between Pen and age, but no correlations with Pyr,
      Dpyr, Des, and Isodes. We believe that this method is useful for investigating
      the content of these crosslinks in both collagen and elastin under various
      conditions.

PMID- 10660451
TI  - Determination of the substrate specificity of the phospholipase D from
      Streptomyces chromofuscus via an inorganic phosphate quantitation assay.
AB  - The substrate specificity for phospholipase D from Streptomyces chromofuscus
      (PLD(Sc)) has been determined utilizing an assay based on the quantitation of
      inorganic phosphate. 1,2-Di-n-hexanoyl phosphatidylcholine (C6PC),
      phosphatidylethanolamine (C6PE), phosphatidylserine (C6PS), phosphatidylglycerol
      (C6PG), and an unnatural phospholipid bearing a neohexyl headgroup (C6PDB) were
      examined as substrates. The assay relies on the quenching of the PLD(Sc)
      catalyzed hydrolysis of the phospholipid substrates with EDTA followed by the
      hydrolysis of the phosphatidic acid product with alkaline phosphatase. The
      inorganic phosphate thus released is quantitated through the formation of a
      complex with ammonium molybdate, which has an absorbance maximum at 700 nm. To
      minimize the time involved and the reagents consumed, the assay is conducted in
      96-well plates. The results of this study indicate that the catalytic efficiency
      for PLD(Sc) on the substrates is C6PC >> C6PS approximately C6PE > C6PG >> C6PDB.

PMID- 10660452
TI  - Selective organic precipitation/extraction of released N-glycans following large
      scale enzymatic deglycosylation of glycoproteins.
AB  - A major difficulty with isolating enzymatically or chemically released
      oligosaccharides from large-scale glycoprotein deglycosylation reactions is the
      time-consuming chromatography, desalting, and concentration steps required to
      prepare a glycan fraction of manageable proportions. To overcome these time and
      preparative chromatography equipment requirements, we have developed a rapid
      organic solvent precipitation/extraction procedure that allows sequential
      isolation of endo-beta-N-acetylglucosaminidase H (EC 3.2.1.96)-released high
      mannose and hybrid, peptide-N(4)-(N-acetyl-beta-glucosaminyl) Asn amidase (EC
      3.5.1. 52)-released complex, and beta-eliminated O-linked glycans without the
      need for intermediate chromatography, desalting, or concentration steps. The
      method involves precipitation of protein and released glycans at -20 degrees C in
      80% acetone and extraction of the glycans from the pellet with 60% aqueous
      methanol after each deglycosylation step. Three pools of essentially salt- and
      detergent-free oligosaccharides (high-mannose/hybrid, complex, and O-linked) can
      be isolated in a high yield in 4 days with this protocol, which has been
      extensively tested using bovine RNase B, human bile salt-stimulated lipase
      expressed in Pichia pastoris, hen ovalbumin, bovine fetuin, bovine thyroglobulin,
      and several invertase preparations from wild-type and mutant yeast strains.

PMID- 10660454
TI  - Application of high-density optical microwell arrays in a live-cell biosensing
      system.
AB  - In this paper, we use optical imaging fibers to fabricate a chemical and
      biochemical sensor that utilizes the ability of living cells to respond to
      biologically significant compounds. The sensor is created by randomly dispersing
      single NIH 3T3 mouse fibroblast cells into an optically addressable fiber-optic
      microwell array such that each microwell accommodates a single cell. The cells
      are encoded to identify their location within the array and to correlate changes
      or manipulations in the local environment to responses of specific cell types.
      The entire array can be simultaneously measured, yielding a rapid, repetitive,
      and high-density analysis method.

PMID- 10660453
TI  - Protein microchips: use for immunoassay and enzymatic reactions.
AB  - Different proteins such as antibodies, antigens, and enzymes were immobilized
      within the 100 x 100 x 20-microm gel pads of protein microchips. A modified
      polyacrylamide gel has been developed to accommodate proteins of a size up to
      400,000 daltons. Electrophoresis in the microchip reaction chamber speeded up
      antigen-antibody interactions within the gel. Protein microchips were used in
      immunoassays for detection of antigens or antibodies, as well as to carry out
      enzymatic reactions and to measure their kinetics in the absence or presence of
      an inhibitor. A protein microchip can be used several times in different
      immunoassays and enzymatic kinetic measurements.

PMID- 10660455
TI  - Critical factors in the radioimmunoassay of endothelin-1, endothelin-3, and big
      endothelin-1 in human plasma.
AB  - The possible diagnostic or prognostic significance of changes in circulating
      level of endothelins in a variety of pathological conditions is currently of
      interest. Unfortunately, no consensus regarding optimization of sensitivity and
      extraction procedures for the reliable radioimmunoassay of endothelin-1 (ET-1),
      big endothelin-1 (BigET-1), and endothelin-3 (ET-3) currently exists. The object
      of the present study was to evaluate aspects of currently used extraction and
      assay procedures that limit accurate determination of ET in human plasma and
      define criteria to reduce variability. Critical parameters include the
      selectivity of commercial antibodies and the ability to remove interfering
      material after Sep-Pak absorption by selective washing with 24% ethanol in 4%
      acetic acid or methylene chloride in 0.1% trifluoroacetic acid. Assay sensitivity
      and specificity in the physiological range is improved by optimizing total
      binding parameters for the antibodies to give approximately 15-20% binding of
      radiolabeled peptide. With these modifications normal plasma values for ET-1,
      BigET-1, and ET-3 averaged 1.7 +/- 0.06, 2.5 +/- 0.3, and 5.8 +/- 0.2 pg/ml,
      respectively. These data suggest that such modifications may help to resolve many
      of the earlier difficulties concerning the role of ET under normal and
      pathological conditions.

PMID- 10660456
TI  - Development of improved high-performance liquid chromatography conditions for
      nonisotopic detection of isoaspartic acid to determine the extent of protein
      deamidation.
AB  - A rapid and accurate ion-pairing reversed-phase high-performance liquid
      chromatography (IP-RP-HPLC) procedure has been developed for nonisotopic
      detection of isoaspartic acid residues in protein or peptides resulting from
      deamidation of asparagine residues. The IP-RP-HPLC procedure specifically detects
      and quantifies S-adenosylhomocysteine (SAH). SAH is a by-product of the reaction
      between protein isoaspartyl methyltransferase (PIMT), S-adenosylmethionine (SAM),
      and isoaspartic acid residues. The HPLC conditions described in this paper have
      been demonstrated to offer significantly better reproducibility compared to
      earlier studies. The HPLC method allows determination of the extent of protein
      deamidation without the use of radioisotopes and therefore offers significant
      advantages for biopharmaceutical development laboratories.

PMID- 10660457
TI  - 13C gas chromatography-combustion isotope ratio mass spectrometry analysis of N
      pivaloyl amino acid esters of tissue and plasma samples.
AB  - We present the analysis of the stable carbon isotope compositions of 14
      individual N-pivaloyl-isopropyl (NPP) amino acid esters by gas chromatography
      combustion isotope ratio mass spectrometry (GC-C-IRMS). The mean reproducibility
      of derivatization procedure and GC-C-IRMS analysis was 0.45 per thousand (range,
      0.12-0.68), whereas the mean analytical error was 0.26 per thousand delta(13)C
      (range, 0.13-0.42). Furthermore, the delta(13)C values of N-pivaloyl-isopropyl
      and N-acetyl-n-propyl (NAP) amino acid esters were compared. Due to a
      reproducible isotopic fractionation introduced by the derivatization process an
      empirical correction factor for each individual amino acid was derived separately
      for both derivatives (NPP, -1.13 to -2.52 (lysine, +2.09) per thousand
      delta(13)C; NAP, -2.36 to -3.97 (lysine, +1.91) per thousand delta(13)C), and the
      original delta(13)C value of the underivatized amino acid was calculated.
      Further, we performed an animal study where rats (n = 5) ingested a mixed meal
      containing uniformly (13)C-labeled casein (indispensable amino acids 1.3 to 1.7
      at.%). One hour after the meal delta(13)C values of protein-bound amino acids
      from small intestinal mucosa and liver and of free amino acids from mucosa and
      plasma were determined. Significant (13)C enrichments of indispensable amino
      acids of the free pools of mucosa and plasma (range, 0.0518 to 0.1700 at.%
      excess) and in mucosa and liver proteins (range, 0.0021 and 0.0161 at.% excess)
      were observed. The feasibility of various derivatives for the measurement of
      carbon isotopic composition is discussed.

PMID- 10660458
TI  - Screening hypermethylated regions by methylation-sensitive single-strand
      conformational polymorphism.
AB  - DNA methylation is an important epigenetic modification that alters transcription
      in those genes containing CpG islands. In this report we demonstrate that the
      familiar technique single-strand conformation polymorphism (SSCP) can be easily
      applied to bisulfite-treated DNA to detect methylation differences over large (
      approximately 250 bp) CG-enriched regions. In the methylation-sensitive SSCP (Ms
      SSCP) technique, sodium bisulfite modification of DNA converts unmethylated
      cytosine to uracil under conditions in which 5-methylcytosine remains unaltered.
      Amplification of these regions to be tested is then performed using primers
      specific for bisulfite-treated DNA. The resulting products are then subjected to
      nondenaturing gel analysis. Based on differential band mobility, Ms-SSCP is able
      to sensitively detect alterations in methylation density and determine if
      unmethylated alleles are present in a sample. Ms-SSCP is a rapid and simple
      technique for screening multiple samples for methylation changes. It has several
      advantages over existing techniques, including the utilization of nanogram
      amounts of DNA, the avoidance of difficulties in sequencing CG-enriched regions,
      and the screening of multiple sites for methylation across large regions of DNA.

PMID- 10660459
TI  - Control and statistical analysis of in vitro reporter gene assays.
AB  - The use of in vitro gene reporter assays is becoming increasingly widespread in
      biology and particularly in drug metabolism, where the need for rapid screening
      of novel compounds is a driving factor. There is, however, little standardization
      of technique in the control of such assays, nor in the interpretation of results.
      This leads to confusion in the literature, with the possibility of a single piece
      of data being interpreted by several different methods, potentially giving vastly
      differing results. We have developed a reporter gene assay methodology that
      controls for many biological and experimental variables in the system and allows
      the application of a mathematical model to determine statistical significance
      between groups. Use of this methodology, we feel, allows an accurate and
      reproducible method of analyzing in vitro reporter gene assay data and increases
      its value as a biological tool.

PMID- 10660460
TI  - Quantitation of dihydropyrimidine dehydrogenase expression by real-time reverse
      transcription polymerase chain reaction.
AB  - Several recent studies have reported a correlation between intratumor
      dihydropyrimidine dehydrogenase (DPD) messenger RNA (mRNA) levels and sensitivity
      to 5-fluorouracil (5-FU). However, significant tissue requirements and labor
      intensive methodology have limited the large-scale studies necessary for
      statistical validation. In addition, the semiquantitative results obtained by
      these methods further limit their application. We have developed a real-time
      reverse transcription-PCR (RT-PCR) assay, based on TaqMan fluorescence
      methodology, capable of rapid and accurate quantitation of DPD mRNA levels in
      biopsy-sized tissue samples. Results obtained with this approach indicate a
      linear dynamic range of 10(8)-10(3) DPD mRNA copies, with an intra-assay
      variation of <5%. We evaluated the data using three different methods (absolute
      standard curve, relative standard curve, and comparative C(T)) and show them to
      be equivalent. This RT-PCR assay was validated by quantitative comparison to
      Northern blot analysis in five tissues. In addition, analysis of 18 colorectal
      tumor and liver tissue specimens demonstrated a significant correlation (r(2) =
      0.90) between DPD enzyme activity and mRNA levels. This method provides the first
      high-throughput, reproducible, and sensitive technique capable of determining DPD
      mRNA expression levels in nanogram amounts of total RNA.

PMID- 10660461
TI  - Characterization of a selective protein kinase C substrate derived from the
      MARCKS phosphorylation site domain for use in brain tissue homogenates.
AB  - Protein kinase C (PKC) isozymes play crucial roles in neuronal signal
      transduction and can regulate transmitter release, ion channels, neural
      development, and plasticity. In vitro assays of PKC are frequently used to
      associate PKC activity with cellular function, and the availability of selective
      PKC substrates can facilitate such studies. We have characterized a commercially
      available 12 amino acid peptide derived from the myristoylated alanine-rich C
      kinase substrate (MARCKS-PSD, Calbiochem) for use in crude rat brain homogenates.
      Assays were performed at 25 degrees C for 10 min (linear up to 12 min) using
      optimal concentrations of calcium and lipid cofactors. Kinetic analysis of MARCKS
      PSD phosphorylation by PKC purified from rat brain gave a K(m) of 2.3 microM,
      which was similar to the K(m) of 2.8 microM obtained using rat brain cortical
      homogenates. The selective PKC inhibitor bisindolylmaleimide reduced
      phosphorylation of MARCKS-PSD in a concentration-dependent manner, with greater
      than 95% inhibition at 1.0 microM. MARCKS-PSD was more potent than another widely
      used selective PKC substrate (neurogranin((28-43)) and was a good substrate for
      human recombinant PKC alpha, delta, and epsilon but not zeta. The ontogeny of PKC
      activity was examined in the cortex and cerebellum. PKC activity was low at birth
      and reached adult levels by 21 days of age in both regions. Calcium-independent
      PKC activity in brain homogenates could be measured with MARCKS-PSD and accounted
      for approximately 25 and 10% of total activity in 1-day-old and adult rat cortex,
      respectively. These results suggest that the MARCKS-PSD peptide can be used as a
      selective PKC substrate in rat brain homogenates.

PMID- 10660462
TI  - Development of an assay method for activities of serine/threonine protein
      phosphatase type 2B (calcineurin) in crude extracts.
AB  - Despite the physiological importance of serine/threonine protein phosphatase type
      2B (PP2B/calcineurin), an accurate assay method of PP2B in crude tissue extracts
      has not been established. By using recombinant protein phosphatase inhibitor-1 as
      a substrate and ascorbic acid as an antioxidant, we developed an improved assay
      method for PP2B activity in crude extracts from mouse tissues and investigated
      tissue distribution of its activity. Under the assay conditions, the PP2B
      activities were stable for at least 30 min with more than 100-fold higher
      sensitivity than those previously reported. The specific activities of PP2B were
      22.3, 0.85, 2.9, 0.36, and 1.5 mU/mg protein in mouse brain, heart, spleen,
      liver, and testis, respectively, and furthermore in each region of the brain they
      were 26.1, 13.7, 42.8, 40.5, 15.1, and 8.6 mU/mg protein in cerebrum, midbrain
      plus interbrain, striatum, hippocampus, cerebellum, and brain stem, respectively.
      This is the first paper to demonstrate a close correlation between tissue
      distributions and content of PP2B. These results showed that the present assay
      method is extremely powerful for precise measurement of a wide range of PP2B
      activities including not only high PP2B activity in the brain but also low PP2B
      activities in other tissues.

PMID- 10660463
TI  - Rapid method for determining the rate of DNA synthesis and cellular
      proliferation.
AB  - A new method has been developed for determination of DNA synthesis during cell
      proliferation. The method is based on the metabolism of [U-(13)C(6)]glucose to
      deoxyribose (DR) and then incorporation of [U-(13)C(5)]DR into newly synthesized
      DNA. Extracted cellular DNA is subjected to HCl hydrolysis (2 h at 100 degrees
      C), which converts DR into levulinic acid. The (13)C enrichment in DR is
      determined in the trimethylsilyl derivative of levulinate using gas
      chromatography-mass spectrometry. The method is rapid and sensitive. It can
      precisely determine (13)C enrichment below 1 at.% excess in as little as 4 ng
      DNA. We have used this method to determine the rate of cell proliferation in
      vitro and the level of DR in a given amount of DNA. The current approach has
      significant advantages over previously described methods and overcomes several
      difficulties related to the determination of DNA synthesis both in vivo and in
      vitro.

PMID- 10660464
TI  - Detection of phosphopeptides by fluorescence polarization in the presence of
      cationic polyamino acids: application to kinase assays.
AB  - We have studied the interaction of several phosphopeptides with cationic
      polyamino acids such as polyarginine and polylysine by fluorescence polarization.
      The phosphopeptides used were labeled with fluorescein, and their net charges at
      the experimental pH of 7. 5 were 0, -1, -2, and -3. These phosphopeptides
      represent the products of enzymatic phosphorylation reactions of the
      corresponding nonphosphorylated precursors by the protein kinase A, Akt1 (protein
      kinase Balpha), and protein kinase C. We found that these phosphopeptides bind
      more strongly to the cationic polyamino acids studied than their
      nonphosphorylated analogs. This preferential binding of the phosphorylated
      peptides could be conveniently detected by an increase in the fluorescence
      polarization signal of the attached fluorescein residue. We have exploited this
      observation to develop a new approach for the detection of kinase activity that
      does not require radioactivity or separation of substrate from product. We have
      successfully used this method to perform K(m) determinations of the kinase
      enzymes for their substrates and K(i) determinations of one of their inhibitors.
      This method for measuring kinase activity might be particularly useful for high
      throughput screening applications.

PMID- 10660465
TI  - Assay of glycoamidases and endo-beta-N-acetylglucosaminidases by lectin capture
      and dissociation-enhanced lanthanide fluorescence immunoassay.
AB  - We have developed an assay system for endo-beta-N-acetylglucosaminidase and
      glycoamidase (PNGase), using Eu(3+)-labeled Man(9)GlcNAc(2) glycopeptides as
      substrates in combination with lectin capture. Two glycopeptides of different
      peptide lengths, derived from soybean agglutinin, were labeled with Eu(3+) via a
      diethylenetriaminepentaacetate (DTPA) chelating linker and served as substrates
      for two types of enzymes: one with (Man(9)GlcNAc(2))Asn for endo-beta-N
      acetylglucosaminidase and the other with Ala-Ser-Phe-(Man(9)GlcNAc(2))Asn-Phe-Thr
      for glycoamidase activities. Following enzymatic hydrolysis, concanavalin A,
      immobilized or soluble, was added to the mixture to bind unreacted substrate and
      unlabeled hydrolysis product. The labeled peptide product could then be separated
      from the lectin-bound complexes by filtration for quantification by dissociation
      enhanced lanthanide fluorescence immunoassay. Activities as low as 2 fmol min(-1)
      could be rapidly quantified for both types of enzymes, and enzymological
      parameters could be determined within minutes. Applicability of the assay was
      tested for identification of a glycoamidase activity peak in the fractionation of
      sweet almond emulsin, a classic example. This assay offers sensitivity, ease of
      use, and high throughput. In addition, it is versatile and should be applicable
      to other glycobiology enzyme systems.

PMID- 10660466
TI  - A cell viability assay based on monitoring respiration by optical oxygen sensing.
AB  - A cell viability assay based on monitoring of the metabolic activity of living
      cells via their consumption of dissolved oxygen has been developed. It uses a
      microwell plate format and disposable phosphorescent sensor inserts incorporated
      into each sample. The wells are subsequently sealed from ambient oxygen using a
      layer of mineral oil, and periodically scanned from underneath with a simple
      fiber-optic phosphorescent phase detector. Thus, dissolved oxygen levels and time
      profiles of cell respiration can be determined noninvasively and compared to each
      other. The system was tested by monitoring the viability of the fission yeast
      Schizosaccharomyces pombe. In comparison with the conventional cell densitometry
      assay, the optical oxygen sensor method could reliably monitor lower numbers of
      cells (10(4)-10(5) vs 10(6)-10(7) cells/ml for densitometry), and accurately
      determine culture viability within 1 h. The assay was then applied to determine
      the viability of samples treated with toxic agents such as azide and in response
      to expression of a physiological inducer of cell death, the Bcl-2 family member
      Bak. The results obtained confirm that measurement of cell respiration by this
      assay can serve as a predictable, reliable, and fast method for high-throughput
      determination of cell viability and growth.

PMID- 10660467
TI  - Plant DNA extraction based on grinding by reciprocal shaking of dried tissue.

PMID- 10660468
TI  - Microscale synthesis of glycoconjugate series and libraries.

PMID- 10660469
TI  - Choosing the proper organic solvent for the determination of lipid hydroperoxides
      by the ferric thiocyanate assay.

PMID- 10660470
TI  - Multiple probing of an immunoblot membrane using a non-block technique:
      advantages in speed and sensitivity.

PMID- 10660471
TI  - Documentation of negatively stained polyacrylamide gels.

PMID- 10660472
TI  - Use of hydrophobic interaction chromatography to separate recombinant antibody
      fragments from associated bacterial chaperone protein GroEL.

PMID- 10660473
TI  - Isomorphism of quasispecies and percolation models.
AB  - Population dynamics of tRNA-like macromolecules and viruses have been interpreted
      by Eigen (1971, Naturwissenschaften58, 465-526) on the basis of the
      "quasispecies" model. The present paper contains a qualitative analysis of the
      similarities between Eigen's quasispecies model and percolation models. In fact,
      different phenomena characterized by an analogous inner structure can conceivably
      be described by quite similar mathematical formalisms. The occurrence of a
      threshold in specific processes predicted by the models is considered first.
      Secondly, Ising's model of ferromagnetism is taken into account in the last
      section. An interpretation of the above-mentioned biological theory in terms of
      percolation, implying a zeroth-order approximation to the real situation, might
      be a point of departure to a deeper insight obtainable with more refined
      approaches. A better comprehension of biological phenomena might in any case
      arise from a percolative approach, even if the description of the systems is
      simplified. An overview of some quasispecies results and some plausible
      applications are presented.

PMID- 10660474
TI  - Testing character correlation using pairwise comparisons on a phylogeny.
AB  - In comparative biology, pairwise comparisons of species or genes (terminal taxa)
      are used to detect character associations. For instance, if pairs of species
      contrasting in the state of a particular character are examined, the member of a
      pair with a particular state might be more likely than the other member to show a
      particular state in a second character. Pairs are chosen so as to be
      phylogenetically separate, that is, the path between members of a pair, along the
      branches of the tree, does not touch the path of any other pair. On a given
      phylogenetic tree, pairs must be chosen carefully to achieve the maximum possible
      number of pairs while maintaining phylogenetic separation. Many alternative sets
      of pairs may have this maximum number. Algorithms are developed that find all
      taxon pairings that maximize the number of pairs without constraint, or with the
      constraint that members of each pair have contrasting states in a binary
      character, or that they have contrasting states in two binary characters. The
      comparisons chosen by these algorithms, although phylogenetically separate on the
      tree, are not necessarily statistically independent.

PMID- 10660475
TI  - A model of photoinhibition related to mRNA instability in ethylene production by
      a recombinant cyanobacterium.
AB  - Photoinhibition mechanism is studied for ethylene production by a recombinant
      cyanobacterium. The kinetic pattern of the production is similar to that of
      substrate inhibition in enzyme reactions, whereas the photoinhibition is believed
      not to be substrate-related, but to originate from the enzyme for ethylene
      formation. In a proposed model, the inhibition is attributed to the process of
      enzyme synthesis, where light-dependent mRNA decomposition affects enzyme
      concentration. A mathematical formula derived accordingly for light dependence of
      ethylene production rate gives the same form as a well-known equation of
      substrate inhibition. The model also predicts ethylene production under dark
      condition, which has been observed experimentally.

PMID- 10660476
TI  - Evolutionary stable strategy: a test for theories of retroviral pathology which
      are based upon the concept of molecular mimicry.
AB  - The genetic makeup of animal and plant populations is determined by established
      principles and concepts. Ecology and evolution provide a basic theoretical
      framework for understanding how genetic changes occur in populations. Whether
      these rules can be applied to host retroviral populations is unknown. Individuals
      infected with the human immunodeficiency virus (HIV) contain within their bodies
      a viral population. This population is known as a viral quasispecies. Located in
      the transmembrane protein of HIV-1 is the viral sequence Gly-Thr-Asp-Arg-Val.
      Previous immunological studies have shown that viral antibody is produced in
      response to this five-amino-acid sequence. Antibody to this viral sequence also
      crossreacts and binds to a related peptide sequence found on certain immune
      cells. This related sequence, Gly-Thr-Glu-Arg-Val, is found on immune cells
      bearing a structure known as the major histocompatibility complex (MHC). The
      viral transmembrane sequence, Gly-Thr-Asp-Arg-Val, can be substituted with
      alanine residues utilizing site-directed mutagenesis. This creates a viral clone
      devoid of the genetic similarity with the MHC. Chimpanzees progressing to AIDS
      contain both sequences of interest. Suppression of the chimpanzee quasispecies
      utilizing anti-retroviral drugs is proposed. This action serves to suppress the
      presence of the viruses containing the sequence Gly-Thr-Asp-Arg-Val. When viral
      load has been reduced significantly, a drug resistant, alanine altered clone is
      to be introduced in large numbers. The concept of evolutionary stable strategy
      predicts that a viable HIV clone with alanine residues can genetically dominate
      the viral population. Immune system recognition of the alanine sequence is likely
      to result in renewed antibody production. Antibodies to the alanine containing
      viral sequence should not recognize or bind to the MHC. Immunological parameters
      can then be measured to determine the physiological impact of eliminating a
      sequence responsible for molecular mimicry between virus and host.

PMID- 10660477
TI  - Turbulent transport of suspended particles and dispersing benthic organisms: the
      hitting-time distribution for the local exchange model.
AB  - Fine particles suspended in turbulent water exhibit highly irregular trajectories
      as they are buffeted by fluid eddies. The Local Exchange Model provides a
      stochastic diffusion approximation to the randomlike motion of such particles
      (e.g. dispersing benthic organisms in a stream). McNair et al. (1997, J. theor.
      Biol.188, 29) used this model to derive equations governing the mean hitting
      time, which is the expected time until a particle hits bottom for the first time
      from a given initial elevation. The present paper derives equations governing the
      probability distribution of the hitting time, then studies the distribution's
      dependence on a particle's initial elevation and two dimensionless parameters.
      The results show that for fine particles suspended in moderately to highly
      turbulent water, the hitting-time distribution is strongly skewed to the right,
      with mode<median<mean. Because of the distribution's thick upper tail, there is a
      significant probability that a particle's hitting time will greatly exceed the
      mean. The results also show that the position of the mode depends strongly on a
      particle's initial elevation but, compared to the median or mean, is relatively
      insensitive to the particle's fall velocity.

PMID- 10660478
TI  - Lineage-restricted expression of bone morphogenetic protein genes in human
      hematopoietic cell lines.
AB  - To explore the possibility that bone morphogenetic proteins (BMPs) are
      autocrine/paracrine regulators of hematopoietic differentiation and function, we
      screened a panel of human cell lines encompassing the hematopoietic lineages for
      expression of members of this family of genes. Expression of BMP-2, BMP-4, BMP-6,
      BMP-7, Growth and Differentiation Factor-1 (GDF-1), Placental Bone Morphogenetic
      Protein (PLAB), and Transforming Growth Factor-beta3 (TGF-beta3) was detected in
      one or more cell lines. BMP-2, BMP-4, BMP-7, and TGF-beta3 expression was also
      found in normal hematopoietic tissue. Expression of BMP-5 and BMP-8 was not seen.
      Lineage-restricted patterns of expression were found for BMP-4 (T-lymphoid), BMP
      7 (lymphoid), PLAB (macrophage/monocyte), and GDF-1 (myeloid). Expression of BMP
      2, GDF-1, and PLAB could be modulated by treatment with differentiating agents.
      Marked variations in the levels of BMP-4, BMP-7, and PLAB expression were
      encountered, indicating that disorders in BMP signaling pathways may play a role
      in the development of hematopoietic neoplasia.

PMID- 10660479
TI  - Mutation analysis of the HFE gene in Brazilian populations.
AB  - We analyzed the frequency of the C282Y and H63D mutations in the HFE gene in 227
      individuals from Brazil comprising 71 Caucasians, 91 racially mixed Caucasian
      African-derived Amerindians (both populations from Southeast Brazil), 85 African
      derived subjects (from Northeast Brazil) and 75 Parakana Indians. Allelic
      frequency of the mutation C. 845G(A (C282Y) was 1.4% in the Caucasian population,
      1.1% in the African-derived population, 1.1% in the racially mixed normal
      controls and 0% in the Parakana Indians. In the African-derived population, the
      C282Y mutation was present on chromosomes bearing the haplotype 6/1h according to
      Beutler and West (1997). Allelic frequency of the mutation C. 187C(G (H63D) was
      16.3% in the Caucasian population, 7.5% in the African-derived population, 9.8%
      in the racially mixed controls and 0% in the Amerindians. The presence of these
      mutations in the African-derived population reflects the fact that these subjects
      may have undergone a non-identified racial admixture in their past history. The
      absence of both defects in the Amerindians suggests that these mutations have
      emerged after the migration of Polynesians to America, or that they may not have
      reached the Polynesian population until after the migration to America had
      occurred.

PMID- 10660480
TI  - Analysis of Tlr4-mediated LPS signal transduction in macrophages by mutational
      modification of the receptor.
AB  - In mouse macrophages (RAW 264.7 cells), toll-like receptor 4 (Tlr4) is a limiting
      factor in lipopolysaccharide (LPS) signal transduction. The expression of only 1
      2 x 10(4) copies of recombinant Tlr4 per cell enhances sensitivity to LPS,
      shifting the EC50 by 30-fold to the left. Expression of the Tlr4(Lps-d) isoform
      of Tlr4 (found in C3H/HeJ mice) shifts the EC50 2600-fold to the right,
      essentially abolishing LPS responses. A truncated form of Tlr4, lacking a
      cytoplasmic domain, exerts only a weak inhibitory effect on signal transduction.
      Similarly, the normal or Tlr4(Lps-d) forms of protein lacking an ectodomain
      [corrected], cause modest inhibition of LPS signaling. Manipulations of Tlr4
      structure and expression cause changes in LPS sensitivity that range over 3 to 4
      orders of magnitude. These findings support the view that Tlr4 is an integral
      component of a solitary pathway for LPS signal transduction in macrophages and
      permit inferences related to the mechanism of signaling and its blockade.

PMID- 10660481
TI  - Kinetic model for erythrocyte aggregation.
AB  - It is well known that light transmission through blood is the most widely
      utilized method for the study of erythrocyte aggregation. The curves obtained had
      been considered empirically as exponential functions. In consequence, the process
      becomes characterized by an only parameter that varies with all the process
      factors without discrimination. In the present paper a mathematical model for RBC
      aggregation process is deduced in accordance with von Smoluchowski's theory about
      the kinetics of colloidal particles agglomeration. The equation fitted the
      experimental pattern of the RBC suspension optical transmittance closely and
      contained two parameters that estimate the most important characteristics of the
      aggregation process separately, i.e., (1) average size of rouleaux at equilibrium
      and (2) aggregation rate. The evaluation of the method was assessed by some
      factors affecting erythrocyte aggregation, such as temperature, plasma dilutions,
      Dextran 500, Dextran 70 and PVP 360, at different media concentrations, cellular
      membrane alteration by the alkylating agent TCEA, and decrease of medium
      osmolarity. Results were interpreted considering the process characteristics
      estimated by the parameters, and there were also compared with similar studies
      carried out by other authors with other methods. This analysis allowed us to
      conclude that the equation proposed is reliable and useful to study erythrocyte
      aggregation.

PMID- 10660482
TI  - Mutations of the HFE gene and the risk of hepatocellular carcinoma.
AB  - The discovery of the C282Y and H63D point mutations in the hereditary
      hemochromatosis-associated HFE gene allows us to study the molecular basis of
      congenital and acquired iron overload disorders. In hereditary hemochromatosis an
      increased frequency of the C282Y and, to a lesser extent, of the H63D mutations
      has been established, but their role in other conditions associated with iron
      overload and their prevalence in the normal population are still under
      investigation. We sought to determine the presence of such mutations, and their
      possible involvement in the multi-step neoplastic transformation of the
      hepatocytes, in patients diagnosed with hepatocellular carcinoma, a frequent
      complication of iron-induced liver cirrhosis occurring in untreated hereditary
      hemochromatosis subjects. The frequency of the C282Y and H63D mutations was
      determined in DNA from 12 patients with hepatocellular carcinoma and with no
      clinical signs of hereditary hemochromatosis. The frequency of the mutations was
      also determined in 130 normal subjects. A germline C282Y mutation was found in
      none of the hepatocellular carcinoma patients; the frequency of the H63D mutation
      was not increased, compared to the 130 controls. The allele frequencies of the
      C282Y and H63D mutations in the normal population were 0.042 and 0.185,
      respectively. In conclusion, we suggest that the hereditary hemochromatosis
      related mutations of the HFE gene do not play a significant role in the
      pathogenesis of hepatocellular carcinoma.

PMID- 10660483
TI  - HFE S65C variant is not associated with increased transferrin saturation in
      voluntary blood donors.
AB  - Two amino acid variants in the HFE gene, C282Y and H63D, have been reported in
      most cases of hereditary hemochromatosis. A recently discovered novel amino acid
      variant of HFE, namely S65C, has been implicated to be responsible for a mild
      form of iron overload. We determined genotypes of the HFE S65C variant in 230
      voluntary blood donors with a transferrin saturation >45%, who did not carry the
      HFE C282Y variant. The control group consisted of 248 first time blood donors who
      had a transferrin saturation < 45%. We also determined genotypes of the HFE H63D
      variant in the two groups. For the HFE S65C variant, the frequency of the HFE C65
      allele was 1. 7% and 2.2% in the high and low transferrin saturation groups,
      respectively (p = 0.65). In contrast, for the HFE H63D variant, the frequency of
      the HFE D63 allele was 24.8% and 14.7% in the high and low transferrin saturation
      groups, respectively (p = 0.0009). This study demonstrates no association of the
      HFE C65 allele with the phenotype of high transferrin saturation. The results do
      not support the use of DNA genotyping for the HFE S65C mutation in population
      screening studies for hemochromatosis.

PMID- 10660484
TI  - Commentary on HFE S65C variant is not associated with increased transferrin
      saturation in voluntary blood donors by Naveen Arya, Subrata Chakrabrati, Robert
      A. Hegele, Paul C. Adams.

PMID- 10660485
TI  - Multi-ribozyme targeting of human alpha-globin gene expression.
AB  - One approach to gene therapy for the treatment of hemoglobinopathies has been
      focused on increasing normal globin gene expression. However, because of the high
      concentration of hemoglobin in the red blood cell (32-34 g/dl), merely
      introducing the normal globin gene may not be enough to counteract the effect of
      an abnormal globin. We propose that in addition to strategies to add normal beta-
      or gamma-globin production to sickle erythrocytes, a decrease in overall
      hemoglobin concentration would further decrease the polymerization potential and
      should be considered with other gene therapy approaches. Ribozymes offer the
      potential to target a selected gene product. A model system has been set up using
      the human alpha-globin gene for specific gene suppression by ribozymes by
      cleaving alpha-globin mRNA transcripts. Ribozymes, specifically targeted to five
      different sites in the 5' portion of human alpha-globin mRNA, have been designed
      and tested in vitro. Cleavage of 32P-labeled alpha-globin mRNA by these ribozymes
      has been observed in vitro and the highest level of activity has been found for a
      multi-ribozyme combining all five ribozymes. The multi-ribozyme gene along with
      promoters with varying activities in erythroid cells was transfected into human
      erythroleukemia K562 cells. The multi-ribozyme gene, under the control of human
      alpha-2-globin promoter alone and combined with the locus control region
      enhancer, caused a decrease in the level of alpha-globin mRNA of 50-75% compared
      to the control, determined by RNase protection and by real-time quantitative PCR.
      The decrease in alpha-globin transcripts has been found to be correlated with
      expression of the multi-ribozyme in a dose-dependent manner and does not appear
      to be mediated by an antisense effect. These results suggest that the multi
      ribozyme may be useful in gene therapy as an effective suppressor of a specific
      globin gene.

PMID- 10660487
TI  - Publishers announcement

PMID- 10660488
TI  - Radioimmunodiagnosis and therapy.
AB  - Although promising results with radioimmunotherapy and radioimmunodiagnosis in
      haematological diseases, have been reported, they are less encouraging results in
      solid tumours. Experimental mathematical models suggest that optimization of
      antibody-based therapy and diagnosis is possible and that further research
      towards improvement is warranted. In this review, the major problems of
      radioimmunotherapy and diagnosis are discussed. Particular items adressed include
      tumour uptake of antibodies and antibody-fragments, the target/non-target ratio,
      immunogenicity and the selection of radionuclides.

PMID- 10660486
TI  - The effect of transferrin polymorphisms on iron metabolism.
AB  - The effect of five different transferrin variants (TFv1, TFv2, TFv3, TFv4, and
      TFv5) on the hemoglobin level, mean corpuscular volume (MCV), ferritin level,
      percent transferrin saturation (%TS), and the unsaturated iron binding capacity
      (UIBC) was investigated in subjects with defined HFE haplotypes, 919 persons
      undergoing health screening and 113 patients with clinical hemochromatosis. The
      most common variant is TFv4; the population distribution of this variant was also
      studied. None of the variants were found to have an effect on any of the
      parameters of iron metabolism that were investigated. Moreover, the frequency of
      these variants in patients with clinically significant hemochromatosis was no
      different from that in the general population. We conclude that these
      polymorphisms in transferrin do not play a role in the expression of
      hemochromatosis, nor do they produce any other significant changes in iron
      metabolism.

PMID- 10660489
TI  - Tumour progression and angiogenesis in bone metastasis from breast cancer: new
      approaches to an old problem.
AB  - Breast cancer metastasizes frequently to the skeleton and causes considerable
      morbidity and deterioration of the quality of life. The clinical consequences of
      skeletal metastases are bone pain, pathological fractures, hypercalcaemia and
      nerve compression syndromes. From the moment breast cancer cells are located in
      the bone microenvironment, they may release factors which stimulate bone
      resorption and angiogenesis leading to growth of skeletal metastases and a
      subsequent selective increase in the attraction of new cancer cells to bone. In
      this review, emerging new concepts of breast cancer-bone interactions, in
      particular the involvement of angiogenesis, proteolysis and the role of cancer
      induced bone resorption in skeletal metastasis are discussed. Better
      understanding of the processes involved in the metastasis of cancer cells to
      bone, local tumour growth and subsequent destruction of skeletal architecture can
      lead to optimal methods for the prevention and treatment of metastatic bone
      disease.

PMID- 10660490
TI  - Molecular biology of pancreatic cancer; oncogenes, tumour suppressor genes,
      growth factors, and their receptors from a clinical perspective.
AB  - Pancreatic cancer represents the fourth leading cause of cancer death in men and
      the fifth in women. Prognosis remains dismal, mainly because the diagnosis is
      made late in the clinical course of the disease. The need to improve the
      diagnosis, detection, and treatment of pancreatic cancer is great. It is in this
      type of cancer, in which the mortality is so great and the clinical detection so
      difficult that the recent advances of molecular biology may have a significant
      impact. Genetic alterations can be detected at different levels. These
      alterations include oncogene mutations (most commonly, K-ras mutations, which
      occur in 75% to more than 95% of pancreatic cancer tissues), tumour suppressor
      genes alterations (mainly, p53, p16, DCC, etc.), overexpression of growth factors
      (such as EGF, TGF alpha, TGF beta 1-3, aFGF, bTGF, etc.) and their receptors
      (i.e., EGF receptor, TGF beta receptor I-III, etc.). Insights into the molecular
      genetics of pancreatic carcinogenesis are beginning to form a genetic model for
      pancreatic cancer and its precursors. These improvements in our understanding of
      the molecular biology of pancreatic cancer are not simply of research interest,
      but may have clinical implications, such as risk assessment, early diagnosis,
      treatment, and prognosis evaluation.

PMID- 10660491
TI  - Bone marrow and lymph node assessment for minimal residual disease in patients
      with breast cancer.
AB  - The immunocytological detection of disseminated epithelial cells in bone marrow
      in patients with breast cancer has been performed at many hospitals and
      institutes since the early 1980s. Despite numerous publications in this field, it
      has not been possible to standardize the method and establish the 'ideal'
      antibody, either nationally or internationally. Molecular biological methods
      using PCR technology could extend the diagnostic spectrum. However, one of the
      major problems in breast cancer is the lack of a disease-specific marker gene. As
      a result, immunocytology is still the standard procedure for tumour cell
      detection. The detection of disseminated single cells in bone marrow in primary
      breast cancer (also known as minimal residual disease) is a new prognostic factor
      for disease-free and overall survival. This has been demonstrated in two large (N
      > 300) groups and several small to medium groups (N = 50-300). As a marker of
      dissemination in a target organ for metastasis this prognostic factor corresponds
      much more closely to the tendency of breast cancer to early haematogenic spread.
      Tumour cell detection may predict the course of the disease better than the
      axillary lymph node status. Bone marrow aspiration and detection of disseminated
      cells might replace lymph node dissection, at least in those patients with small
      tumours and no clinical signs of lymph node involvement. This strategy will soon
      be investigated in appropriate studies. Another possible clinical use might be in
      deciding on whether or not to give adjuvant systemic therapy to node-negative
      patients. Patients with positive tumour cell detection are at a higher risk of
      subsequent metastasis, even if the axillary nodes are histologically normal. The
      immunohistological or molecular biological detection of tumour cells in axillary
      lymph nodes might also be very useful, now that it has been shown that a
      considerable subset of patients determined to be node-negative by means of
      conventional methods, are positive according to these new techniques. These
      methods could be a useful supplement to sentinel node biopsy. A further potential
      use of this method is in monitoring therapy with new treatment modalities such as
      gene therapy and immunotherapy. Repeated bone marrow aspiration can provide
      information on the success of therapy in minimal residual disease
      (cytoreduction). Immunocytochemical investigation of individual cells may be
      useful in studying the pathogenesis of metastasis, in particular in the skeleton.
      Phenotyping of cells might allow statements to be made on the metastatic
      potential of cells and the question of cell dormancy. It remains to be hoped that
      this aspect of minimal residual disease will be granted more attention in future.

PMID- 10660492
TI  - The challenge of p53 as prognostic and predictive factor in gliomas.
AB  - In recent years, increasing interest in genetic abnormalities and biologic
      factors such as the tumour suppressor gene p53 as possible predictive and
      prognostic factor in gliomas has emerged. Inactivation of p53 can result in
      resistance to apoptosis, one of the mechanisms thought to explain the failure to
      respond to DNA-damaging agents. Thus, inactivation of p53 might be associated
      with a worse prognosis. Considering the inconsistent results of several recent
      studies, it has remained controversial whether p53 actually can be related to
      response to treatment and patients' prognosis. Therefore, a systematic review of
      the literature was performed, which included 28 publications. Techniques for
      assessing the inactivation of p53 varied widely. Overall, approximately 50% or
      more of astrocytoma specimens evaluated by immunohistochemistry stained
      positively for p53, regardless of histologic grade. Eight studies were restricted
      to comparably treated patients within a single histologic group. In most
      instances, non-restrictive inclusion criteria and use of statistical methods,
      which were not sufficient to correct the possible bias, make it difficult to
      reach unequivocal conclusions. However, it appears that the prognostic
      information of p53 is at best marginal, especially when compared to established
      parameters such as grading, age, etc. Its predictive value, which most likely is
      rather limited too, can hardly be judged without prospective studies also
      evaluating other biological factors as well as end-points other than time to
      radiological progression.

PMID- 10660493
TI  - Is interruption of HIV therapy always harmful?

PMID- 10660494
TI  - MecI represses synthesis from the beta-lactamase operon of Staphylococcus aureus.
AB  - Plasmid diploids were constructed in Staphylococcus aureus to study the effect of
      the repressor of methicillin resistance (MecI) on the synthesis of both beta
      lactamase and the beta-lactamase repressor (BlaI). MecI-mediated repression of
      the synthesis of beta-lactamase was shown by reduction in the specific activity
      of nitrocefinase in bacteria containing a plasmid carrying mecI but not when
      containing the same plasmid deleted for mecI. Antisera prepared against purified
      MecI and against purified BlaI were used in Western blots which showed that MecI
      repressed the synthesis of BlaI in these diploids. The interactions between the
      mec operon and the bla operon are discussed.

PMID- 10660495
TI  - Cytological changes in chlorhexidine-resistant isolates of Pseudomonas stutzeri.
AB  - Transmission electron microscopy (TEM), scanning electron microscopy (SEM) and
      energy-dispersive analysis of X-ray (EDAX) have been used to examine
      chlorhexidine diacetate (CHA)-sensitive and -resistant isolates of Pseudomonas
      stutzeri and to determine the effects of CHA on the cells. Significant
      differences were observed in the structure, size and elemental composition of CHA
      sensitive and -resistant cells. Treatment with CHA produced considerably greater
      changes in CHA-sensitive cells, with widespread peeling of the outer membrane, a
      substantial loss of cytoplasmic electron-dense material and extensive lysis.
      Cells from the resistant isolates showed no blebbing of the outer membrane and no
      structural damage. X-ray mapping confirmed the difference in CHA uptake between
      CHA-sensitive and CHA-resistant cells. It is proposed that changes in the outer
      membrane form a major mechanism of resistance to CHA in P. stutzeri.

PMID- 10660496
TI  - The effect of triclosan toothpaste on enamel demineralization in a bacterial
      demineralization model.
AB  - Triclosan has been incorporated into toothpaste to enhance inhibitory effects on
      bacterial metabolism in dental plaque. Many studies have confirmed these effects
      by showing a reduction of accumulation of dental plaque, gingivitis and calculus.
      However, there is no evidence for triclosan having an inhibitory effect on the
      dental plaque-induced demineralization of the dental hard tissues. Therefore, the
      effect of 0.3% triclosan added to non-fluoride and fluoride toothpaste was tested
      in an in vitro model, in which bovine enamel specimens were to be demineralized
      by acids produced in overlaying Streptococcus mutans suspensions. In a first set
      of experiments the toothpastes were added to the S. mutans suspensions at 1:100,
      1:1000 and 1:10,000 (w/v) dilutions. After 22 h incubation at 37 degrees C the
      suspensions were removed and assessed for calcium and lactate content, and pH. In
      this set of experiments, triclosan had no additive protective effect to the non
      fluoride or fluoride toothpaste. In a second set of experiments, the enamel
      specimens were immersed daily for 3 min in 30% (w/v) slurries of the toothpastes
      before the 22 h incubation with the S. mutans suspensions. Under these
      conditions, triclosan showed an additional protective effect compared with non
      fluoride toothpaste at a low concentration of S. mutans cells (0.07 mg cells dry
      weight per 600 microL suspension). It is concluded that the enamel surface may
      act as a reservoir for triclosan, which may protect the enamel surface against a
      mild acid attack. In combination with fluoride, however, as in toothpaste,
      triclosan has no additional protective effect against demineralization.

PMID- 10660497
TI  - Accumulation of rifampicin by Mycobacterium aurum, Mycobacterium smegmatis and
      Mycobacterium tuberculosis.
AB  - The characteristics of the accumulation of 2 mg/L [(14)C]rifampicin by wild-type
      strains of Mycobacterium aurum (A(+)), Mycobacterium smegmatis (mc(2)155) and
      Mycobacterium tuberculosis (H37Rv) were determined. After 10 min exposure M.
      aurum had accumulated 220 ng rifampicin/mg cells, M. smegmatis had accumulated
      120 ng rifampicin/mg cells and M. tuberculosis had accumulated 154 ng
      rifampicin/mg cells. A steady-state concentration (SSC) of rifampicin was
      accumulated rapidly by M. aurum and M. tuberculosis within minutes of drug
      exposure, unlike M. smegmatis, which accumulated rifampicin more slowly. With an
      increase in the concentration of rifampicin from 0.12 mg/L to 2 mg/L there was an
      increase in the concentration of rifampicin accumulated by M. tuberculosis, with
      no detectable loss of viability over the 20 min of the accumulation experiment.
      With an increase in temperature there was also an increase in the concentration
      of rifampicin accumulated by M. tuberculosis; between 15 and 30 degrees C the
      increase was linear. For all three species sub-inhibitory concentrations of
      ethambutol increased the concentration of rifampicin accumulated. However, both
      growth and accumulation of rifampicin were lower in the presence of 0.05% Tween
      80. Accumulation of rifampicin by M. smegmatis was unaffected by the presence of
      the proton motive force inhibitor, 2,4-dinitrophenol (1 mM), whether added before
      or after the addition of rifampicin to the mycobacterial culture. For all three
      species, the Gram-positive bacterial efflux inhibitor reserpine (20 mg/L)
      slightly increased the SSC of rifampicin, but the increase was not statistically
      significant. Addition of glucose to energize a putative efflux pump had little
      effect on the accumulation of rifampicin in the presence or absence of reserpine
      for M. tuberculosis; however, for M. aurum and M. smegmatis the reserpine effect
      was abolished by the addition of glucose. These data suggest that rifampicin may
      be removed from wild-type mycobacteria by efflux, but that the pump(s) is
      expressed at low level.

PMID- 10660498
TI  - Macrolide resistance and erythromycin resistance determinants among Belgian
      Streptococcus pyogenes and Streptococcus pneumoniae isolates.
AB  - Resistance of streptococci to macrolide antibiotics is caused by target-site
      modification or drug efflux. The phenotypic expression of target-site
      modification can be inducible or constitutive. The prevalence of the three
      phenotypes among Belgian erythromycin-resistant Group A streptococci (GAS) and
      Streptococcus pneumoniae isolates was surveyed, their MICs for seven antibiotics
      were determined and the clonality of the isolates was explored. Of the 2014 GAS
      isolates tested 131(6.5%) were erythromycin resistant (MIC > 1 mg/L): 110 (84.0%)
      showed the M-resistance phenotype whereas the remaining 21 strains (16.0%) were
      constitutively resistant. No inducibly resistant strains were detected. Of 100 S.
      pneumoniae isolates, 33 were erythromycin resistant (MIC > 1 mg/L). In contrast
      to the GAS isolates, only 9.1% of the 33 erythromycin-resistant S. pneumoniae
      isolates showed the M-resistance phenotype. The presence of mefA/E and ermB genes
      in the M-resistant and constitutively and inducibly resistant strains,
      respectively, was confirmed by PCR analysis. Genomic analysis based on pulsed
      field gel electrophoresis (PFGE) using the restriction enzyme SfiI, revealed 54
      different PFGE patterns among the 131 erythromycin-resistant GAS isolates, of
      which an M6 clone represented 16.0% of the strains; all other clones, exhibiting
      different M-types, represented <7% of the strains. The S. pneumoniae isolates
      also appeared to be polyclonally based, as determined by arbitrarily primed PCR.
      The macrolides miocamycin and rovamycin, the lincosamide clindamycin and the
      ketolide HMR 3647 showed excellent activity against the M-resistant GAS and S.
      pneumoniae strains.

PMID- 10660499
TI  - Long-term trends in susceptibility of Moraxella catarrhalis: a population
      analysis.
AB  - A retrospective, population analysis of antimicrobial susceptibility patterns was
      performed on Moraxella catarrhalis isolates recovered from a single medical
      centre to detect temporal trends and infer potential mechanisms of reduced
      susceptibility. The duration of this study, June 1984 to July 1994, encompassed
      the period during which the frequency of beta-lactamase production expanded from
      30 to 96% in the population. MICs of penicillin G, cefamandole, ceftriaxone,
      amoxycillin/clavulanate, imipenem, clarithromycin, tetracycline, ciprofloxacin
      and trimethoprim/sulphamethoxazole for a representative sample of 375 isolates
      were determined. Analyses were conducted to test for variation in susceptibility
      among isolates, correlations of susceptibility levels among different
      antimicrobial agents, and temporal patterns in susceptibility. All antimicrobials
      except clarithromycin displayed significant differences among isolates within
      years, and mean MICs of all antimicrobial agents except tetracycline and
      clarithromycin varied significantly between years. Temporal trends to a reduction
      in susceptibility were detected to four of five beta-lactam antimicrobials (all
      except cefamandole). Significant correlations in MICs were uncovered among all
      pairs of four beta-lactam antimicrobials in both producers and non-producers of
      beta-lactamase. In contrast, cefamandole MICs were correlated only with
      ceftriaxone and penicillin, and these were limited to beta-lactam producing
      isolates; cefamandole and amoxycillin/clavulanate showed a correlation limited to
      non-producing isolates. For some antimicrobials, trends toward decreasing
      susceptibility may have been caused by an increased proportion of beta-lactamase
      producing isolates in the population, but the observation of significant
      decreases in susceptibility limited to beta-lactamase-producing isolates suggests
      that the underlying factors were different forms of beta-lactamase, beta
      lactamase-dependent modifiers and/or additional factors.

PMID- 10660500
TI  - Antimicrobial resistance amongst Klebsiella spp. collected from intensive care
      units in Southern and Western Europe in 1997-1998.
AB  - A 1994 survey of 35 intensive care units (ICUs) in Western and Southern Europe
      found extended-spectrum beta-lactamases (ESBLs) in 220/966 (23%) klebsiellae. A
      follow-up survey from May 1997 to October 1998 collected klebsiellae from 24
      ICUs, including 23 that participated in 1994. Twenty-one ICUs sent 433 eligible
      isolates, of which 110 (25%) had ESBLs. The prevalence of ESBLs had not changed
      significantly from 1994 but the proportion of ESBL-producers resistant to
      piperacillin/tazobactam had risen from 31% to 63% (P < 0.001), and most of this
      resistance was high level (MICs >/= 128 + 4 mg/L). The proportion of Klebsiella
      oxytoca isolates hyperproducing K1 beta-lactamase rose from 8% in 1994 to 21% in
      1997-1998 (P < 0. 001). Most klebsiellae (99%) were very susceptible to meropenem
      (mode MIC 0.03 mg/L) but three had decreased susceptibility (MICs 2-4 mg/L).
      These could not hydrolyse carbapenems. Aminoglycoside resistance was not
      significantly changed in prevalence from 1994; ciprofloxacin resistance occurred
      in 31% of ESBL-producers in both years, but had increased among non-producers (2%
      in 1994 versus 7% in 1997-1998, P < 0.001).

PMID- 10660501
TI  - The Alexander Project 1996-1997: latest susceptibility data from this
      international study of bacterial pathogens from community-acquired lower
      respiratory tract infections.
AB  - The Alexander Project was established in 1992 to examine antimicrobial
      susceptibilities of bacterial isolates from community-acquired infections of the
      lower respiratory tract. Testing of a range of compounds was undertaken in a
      central laboratory. From 1992 to 1995, isolates were collected from
      geographically separated areas in countries in the European Union and various
      states in the USA. In 1996, the study was extended to include centres in Mexico,
      Brazil, Saudi Arabia, South Africa, Hong Kong and other European countries not
      included previously. Data generated by the project during 1996-1997 confirm
      France and Spain as European centres with high rates of resistance to penicillin
      among isolates of Streptococcus pneumoniae. Both intermediate (MIC 0. 12-1 mg/L)
      and resistant (MIC 2 mg/L) phenotypes are present. Combined resistance rates
      (intermediate and resistant) were >/=50% in 1997. Combined resistance rates in
      excess of 20% were found in the Republic of Ireland, Portugal, the Slovak
      Republic and Hungary. Penicillin resistance continues to evolve in the USA, with
      combined resistance rates of 16.4% (1996) and 18.6% (1997). In the new, non
      European centres, e.g. Mexico and, in particular, Hong Kong (where resistant
      strains accounted for 50% of all isolates of S. pneumoniae in 1996 and 55.5% in
      1997), there are centres where rates of resistance are high. Macrolide resistance
      is increasing generally among both penicillin-resistant and penicillin
      susceptible isolates of S. pneumoniae. There is variation between countries, and
      in four out of the 16 centres for which both 1996 and 1997 data are available,
      rates of macrolide resistance have fallen. Overall, the percentage of S.
      pneumoniae strains that is resistant to macrolides exceeds the percentage that is
      resistant to penicillin. In 1996, 16. 5% of all S. pneumoniae isolates were
      resistant to macrolides compared with 10.4% resistant to penicillin, and in 1997
      respective rates were 21.9% and 14.1%. beta-Lactamase production was the
      principal mechanism of resistance observed among isolates of Haemophilus
      influenzae. However, considerable variation in the percentage of isolates
      producing beta-lactamase (0-37.1%) was observed within this species. Within
      Europe, in the Republic of Ireland, France and Belgium, more than 15% of isolates
      were beta-lactamase producers. In Spain rates were as high as 31.7%. Outside
      Europe and the USA high rates were described in Mexico (25%), Saudi Arabia
      (27.9%, 16.7%) and Hong Kong (37.1%, 28.9%). Of H. influenzae from the USA, 30.4%
      were beta-lactamase producers in 1996 and 23.3% in 1997. beta-Lactamase
      production among isolates of Moraxella catarrhalis was observed in >90% of the
      isolates tested in 1996 and 1997.

PMID- 10660502
TI  - Are routine sensitivity test data suitable for the surveillance of resistance?
      Resistance rates amongst Escherichia coli from blood and CSF from 1991-1997, as
      assessed by routine and centralized testing.
AB  - Surveillance of antibiotic resistance can be undertaken by compilation of routine
      data or by central testing of isolates. Routine results can be obtained cheaply
      and in sufficient quantities for correlation with population and prescribing
      denominators but there is concern about their quality. As one of a series of
      ongoing studies to assess this quality, we compared the proportions of resistance
      amongst Escherichia coli from patients with bacteraemia or meningitis between
      1991 and 1997 (i) as recorded in routine data reported to the PHLS and (ii) as
      found in tests performed at the PHLS Laboratory of Enteric Pathogens (LEP). These
      two data sets both showed an overall upward trend in the proportion of isolates
      resistant to ampicillin, trimethoprim, gentamicin and ciprofloxacin. The average
      annual percentage increase in resistance was estimated in separate logistic
      regression models, and 95% confidence intervals (CI) were determined. The annual
      percentage increases in the proportions of isolates reported resistant were
      similar in the two data sets for trimethoprim, gentamicin and ciprofloxacin but
      differed for ampicillin. The upward trends were statistically significant except
      for gentamicin resistance in the LEP data set, where the 95% CI straddled zero.
      The proportions of resistant isolates for each antibiotic in the two data sets
      each year were in poorer agreement than the trends; however, the 95% CI of the
      difference of proportions resistant between the routine and LEP data sets
      straddled zero in 4 or 5 of the 7 years studied. Some discrepancies might be
      explained by geographical bias in the sampling or by differences in definitions
      of resistance. Thus (i) the proportion of resistant isolates tested at LEP almost
      always fell within the ranges bounded by the highest and lowest proportions for
      individual Regional Health Authorities, as recorded in the routine data, and (ii)
      the fact that LEP consistently recorded less gentamicin resistance but more
      ciprofloxacin resistance than the routine could be explained by breakpoint
      differences. We conclude that routine susceptibility data for ampicillin,
      ciprofloxacin, gentamicin and trimethoprim appear sound for E. coli and might be
      suitable for correlation with other data, e.g. for prescribing.

PMID- 10660503
TI  - Penetration of cefpirome into the anterior chamber of the human eye after
      intravenous application.
AB  - The penetration of intravenously administered cefpirome into the anterior chamber
      of the non-inflamed human eye was investigated in this study. A total of 42
      patients, all hospitalized for cataract extraction, received a dosage of 1 g or 2
      g of cefpirome by iv infusion 1, 2 or 6 h preoperatively. An aqueous humour
      sample was collected immediately after paracentesis and a blood specimen was
      simultaneously obtained from each patient. All samples were analysed for
      cefpirome concentrations using high-pressure liquid chromatography. Mean aqueous
      humour levels of cefpirome in patients receiving a dosage of 1 g were 1.33 mg/L
      (1 h), 1.67 mg/L (2 h) and 1.29 mg/L (6 h after application), respectively. When
      patients received a dosage of 2 g cefpirome the resulting mean aqueous humour
      concentrations were 1.60 mg/L (1 h), 2.27 mg/L (2 h) and 2.39 mg/L (6 h after
      application), respectively. A statistically significant difference in aqueous
      humour concentrations between patients receiving 1 g or 2 g of cefpirome could
      not be proven. In conclusion, cefpirome penetrates well into the anterior chamber
      of the non-inflamed human eye in concentrations that are therapeutic for many
      gram-positive and gram-negative organisms, frequently responsible for anterior
      segment eye infections.

PMID- 10660504
TI  - Antimicrobial effects of lidocaine in bronchoalveolar lavage fluid.
AB  - The antimicrobial activity of lidocaine in bronchoalveolar lavage fluid (BAL(f))
      was investigated. Clinical respiratory isolates were added to BAL(f) suspensions
      containing lidocaine and to normal saline. The growth of two of four isolates of
      Streptococcus pneumoniae was significantly reduced in the presence of lidocaine
      BAL(f) compared with controls in saline. Growth of Moraxella catarrhalis isolates
      was reduced in normal saline when compared with BAL(f) containing lidocaine.
      There was no effect upon the growth of Haemophilus influenzae, Pseudomonas
      aeruginosa and Candida albicans isolates. The recovery of isolates of S.
      pneumoniae may be reduced below the critical threshold of 10(5) cfu/mL during
      bronchoscopy when using lidocaine as a local anaesthetic.

PMID- 10660505
TI  - Antibacterial activity of antibiotic-soaked polyvinylpyrrolidone-grafted silicon
      elastomer hydrocephalus shunts.
AB  - If shunts, inserted for the relief of hydrocephalus, are pretreated with
      antimicrobials, the incidence of shunt-associated infections (SAI) may be
      reduced. The duration of the antibacterial activity of shunts, made from
      conventional silicon elastomer (SE) or from SE grafted with the hydrogel
      polyvinylpyrrolidone (SEpvp), which had been soaked in various antibiotics, was
      assessed in vitro. For any antibiotic or combination, using an arbitrary
      breakpoint (aBP), SEpvp remained antibacterially active for longer periods than
      SE. Bacterial adherence to either shunt was prevented during the period of
      antibacterial activity. Thus, the aBP is a good indicator of the capacity of
      antimicrobial-treated shunts to prevent bacterial colonization in vitro. Hydrogel
      grafting of shunts may be useful in preventing SAI.

PMID- 10660506
TI  - Activity of linezolid against multi-resistant gram-positive bacteria from diverse
      hospitals in the United Kingdom.
AB  - The in vitro activity of linezolid, an oxazolidinone, was assessed against 374
      gram-positive cocci, with an emphasis on testing multi-resistant,
      epidemiologically unrelated isolates. MICs of linezolid for staphylococci,
      pneumococci and streptococci had a narrow range, from 0.5 to 2 mg/L, whereas MICs
      for enterococci were uniformly 4 mg/L. For all the species tested, the MICs of
      linezolid were unrelated to those of other antimicrobials. Linezolid appears to
      be a potentially useful drug for infections caused by gram-positive cocci.

PMID- 10660507
TI  - In vitro activity of ciprofloxacin, sparfloxacin, ofloxacin, amikacin and
      rifampicin against Ghanaian isolates of Mycobacterium ulcerans.
AB  - MICs of ciprofloxacin, sparfloxacin, ofloxacin, amikacin and rifampicin were
      determined for 14 primary clinical isolates and three reference isolates of
      Mycobacterium ulcerans by modifying a standard agar dilution method for testing
      Mycobacterium tuberculosis sensitivity. All these antimicrobials were active
      against every isolate of M. ulcerans. Sparfloxacin exhibited the highest activity
      and ofloxacin was the least effective. Rifampicin exhibited the broadest range of
      activity.

PMID- 10660508
TI  - Anticandidal activity of SPA-S-843, a new polyenic drug.
AB  - The activity of a new, soluble and stable polyene (SPA-S-843) against Candida
      albicans was assessed by contact and culture tests and by inhibition of germ-tube
      formation. The drug demonstrated a higher contact activity and lower MICs than
      amphotericin B. This antimicrobial activity was more evident under acid pH and
      low ionic strength. In addition, the ability of SPA-S-843 to inhibit Candida sp.
      conversion from yeast to mycelial form was evident at low drug concentrations
      (0.25-0.62 mg/L).

PMID- 10660509
TI  - In vitro susceptibility studies of Cryptococcus neoformans isolated from patients
      with no clinical response to amphotericin B therapy.
AB  - The in vitro activities of three antifungal drugs alone and in combination were
      evaluated against five isolates of Cryptococcus neoformans using time-kill curves
      (TKC). The isolates were from AIDS patients who had either died or had failed to
      show a clinical response during amphotericin B (AMB) treatment. AMB, fluconazole
      (FCZ) and flucytosine (5FC), and combinations of the drugs (AMB plus 5FC, AMB
      plus rifampicin (RIF) and FCZ plus 5FC), were evaluated. With all five isolates
      AMB did not show fungicidal activity; instead, a persistent or tolerant effect
      was observed. Combinations of AMB plus 5FC and AMB plus RIF showed a clear
      synergic effect, except for one isolate tested with AMB plus RIF. In contrast,
      the FCZ plus 5FC combination did not inhibit growth of any isolate.

PMID- 10660510
TI  - Pharmacokinetics and tissue penetration of vancomycin in patients undergoing
      prosthetic mammary surgery.
AB  - Vancomycin concentrations in periprosthetic breast tissues were evaluated in 24
      women undergoing reconstructive surgery after mastectomy for breast cancer.
      Patients were given a single prophylactic dose of vancomycin (1 g iv) 1-8 h
      before surgery, and mean capsular and pericapsular tissue concentrations were
      measured by HPLC. Vancomycin was not detectable in the majority of patients
      belonging to the 1-3 h post-dose groups, whereas in the 4-8 h post-dose groups,
      mean capsular and pericapsular concentrations were as follows: at 4 h, 4.0 mg/kg
      and 5.9 mg/kg; at 6 h, 4.1 mg/kg and 4. 8 mg/kg; at 8 h, 5.9 mg/kg and 11.1
      mg/kg, respectively. Vancomycin tissue concentrations thus were equal to or
      exceeded the breakpoint of 4 mg/L in most samples collected 4-8 h after dosing.
      In conclusion, our data suggest that appropriate timing of vancomycin prophylaxis
      should be considered to allow the maintenance of adequate tissue concentrations
      throughout the surgical procedure.

PMID- 10660511
TI  - Use of meropenem 3 g once daily for outpatient treatment of infective
      exacerbations of bronchiectasis.
AB  - Meropenem administered as a single iv 3 g dose once every 24 h was used to treat
      nine ambulatory patients with infective exacerbations of bronchiectasis. Serum
      meropenem concentrations were measured before dosing and at 30 min after each 30
      min infusion. Mean pre-dose concentrations were <0.1 mg/L and mean post-dose
      concentrations 93.9 +/- 29.5 mg/L (95% confidence interval (CI) 86. 2-101.6, n =
      59). A pathogen was cultured from sputum in six patients and eradicated (<100
      cfu/g sputum) in all but one by day 6 of therapy. Previous work on animals has
      shown that a bacteriostatic effect is seen with meropenem when t > MIC is greater
      than 20-30% of the dose interval. In these nine patients, this could be achieved
      and was associated with successful outcome for pathogens for which MICs are </=
      0.5 mg/L. Therefore, once-a-day meropenem therapy may be a useful option for
      outpatient treatment for isolates for which MICs are </= 0.5 mg/L.

PMID- 10660512
TI  - Antibiotic use in Dutch hospitals 1991-1996.
AB  - The use of antibiotics in Dutch hospitals between 1991 and 1996 was investigated.
      A total of 54 hospitals responded to the enquiry, representing over 70% of all
      hospital beds in The Netherlands. The use of antibiotics in Dutch hospitals,
      expressed as defined daily doses (DDD) per hundred bed days, gradually increased
      from 37.2 DDD per 100 bed days in 1991 to 42.5 DDD per 100 bed days in 1996. The
      antibiotic that showed the largest increase in use was co-amoxiclav. Its use
      increased more than three-fold from 3.93 DDD per 100 bed days in 1991 to 12.5 DDD
      per 100 bed days in 1996. The increase in use of co-amoxiclav exceeded the
      increase in total antibiotic consumption. The use of cephalosporins remained
      fairly constant during the study period, but there were changes in the relative
      use of the different cephalosporin groups. The use of earlier cephalosporins
      gradually decreased, whereas the use of the more recently developed
      cephalosporins increased between 1991 and 1996. Ciprofloxacin and norfloxacin
      were the most commonly used fluoroquinolones throughout the study period. The use
      of ofloxacin increased significantly between 1991 and 1996, approaching the
      levels of use of ciprofloxacin and norfloxacin. There may be complex reasons for
      the increases, which need further analysis, but they mirror those few data
      available from elsewhere in the world. Possible explanations include more
      intensive treatment to expedite patient discharges, sicker patients with more
      serious infections and more resistant organisms.

PMID- 10660513
TI  - Comparison of the Etest with a conventional agar dilution method in evaluating
      the in vitro activity of moxifloxacin.

PMID- 10660514
TI  - Vancomycin resistance among epidemic strains of methicillin-resistant
      Staphylococcus aureus in England and wales.

PMID- 10660515
TI  - Establishing MIC breakpoints for coagulase-negative Staphylococci to oxacillin.

PMID- 10660516
TI  - Substitution of protease inhibitors during treatment of patients with human
      immunodeficiency virus infection: frequency, mode, reasons and mid-term outcome.

PMID- 10660517
TI  - Cystic fibrosis transmembrane conductance regulator. Structure and function of an
      epithelial chloride channel.

PMID- 10660518
TI  - Both coactivator LXXLL motif-dependent and -independent interactions are required
      for peroxisome proliferator-activated receptor gamma (PPARgamma) function.
AB  - Nuclear receptor activation is dependent on recruitment of coactivators,
      including CREB-binding protein (CBP/p300) and steroid receptor coactivator-1 (SRC
      1). A three-dimensional NMR approach was used to probe the coactivator binding
      interface in the peroxisome proliferator-activated receptor gamma (PPARgamma)
      ligand binding domain (LBD). In the presence of a CBP peptide, peaks
      corresponding to 20 residues in helices 3, 4, 5, and 12 of the LBD were
      attenuated. Alanine mutants revealed that K301A, V315A, Y320A, L468A, and E471A
      were required for binding of both CBP and SRC-1 and for cell-based transcription.
      Several additional amino acids in helix 4 of the PPARgammaLBD were defective with
      respect to CBP recruitment, but retained relatively normal SRC-1 recruitment.
      Thus these amino acid residues may be important determinants of specificity for
      nuclear receptor LBD interactions with discrete coactivator molecules.

PMID- 10660519
TI  - Formation of the Ras dimer is essential for Raf-1 activation.
AB  - Although it is well established that Ras requires membrane localization for
      activation of its target molecule, Raf-1, the reason for this requirement is not
      fully understood. In this study, we found that modified Ras, which is purified
      from Sf9 cells, could activate Raf-1 in a cell-free system, when incorporated
      into liposome. Using a bifunctional cross-linker and a protein-fragmentation
      complementation assay, we detected dimer formation of Ras in the liposome and in
      the intact cells, respectively. These results suggest that dimerization of Ras in
      the lipid membrane is essential for activation of Raf-1. To support this, we
      found that, when fused to glutathione S-transferase (GST), unprocessed Ras
      expressed in Escherichia coli could bypass the requirement for liposome. A Ras
      dependent Raf-1 activator, which we previously reported (Mizutani, S., Koide, H.,
      and Kaziro, Y. (1998) Oncogene 16, 2781-2786), was still required for Raf-1
      activation by GST-Ras. Furthermore, an enforced dimerization of unmodified
      oncogenic Ras mutant in human embryonic kidney (HEK) 293 cells, using a portion
      of gyrase B or estrogen receptor, also resulted in activation of Raf-1. From
      these results, we conclude that membrane localization allows Ras to form a dimer,
      which is essential, although not sufficient, for Raf-1 activation.

PMID- 10660521
TI  - Selective membrane recruitment of EEA1 suggests a role in directional transport
      of clathrin-coated vesicles to early endosomes.
AB  - The molecular mechanisms ensuring directionality of endocytic membrane
      trafficking between transport vesicles and target organelles still remain poorly
      characterized. We have been investigating the function of the small GTPase Rab5
      in early endocytic transport. In vitro studies have demonstrated a role of Rab5
      in two membrane fusion events: the heterotypic fusion between plasma membrane
      derived clathrin-coated vesicles (CCVs) and early endosomes and in the homotypic
      fusion between early endosomes. Several Rab5 effectors are required in homotypic
      endosome fusion, including EEA1, which mediates endosome membrane docking, as
      well as Rabaptin-5 x Rabex-5 complex and phosphatidylinositol 3-kinase hVPS34. In
      this study we have examined the localization and function of Rab5 and its
      effectors in heterotypic fusion in vitro. We report that the presence of active
      Rab5 is necessary on both CCVs and early endosomes for a heterotypic fusion event
      to occur. This process requires EEA1 in addition to the Rabaptin-5 complex.
      However, whereas Rab5 and Rabaptin-5 are symmetrically distributed between CCVs
      and early endosomes, EEA1 is recruited selectively onto the membrane of early
      endosomes. Our results suggest that EEA1 is a tethering molecule that provides
      directionality to vesicular transport from the plasma membrane to the early
      endosomes.

PMID- 10660520
TI  - Specific requirement for the p85-p110alpha phosphatidylinositol 3-kinase during
      epidermal growth factor-stimulated actin nucleation in breast cancer cells.
AB  - We have studied the role of phosphatidylinositol 3-kinases (PI 3-kinases) in the
      regulation of the actin cytoskeleton in MTLn3 rat adenocarcinoma cells.
      Stimulation of MTLn3 cells with epidermal growth factor (EGF) induced a rapid
      increase in actin polymerization, with production of lamellipodia within 3 min.
      EGF-stimulated lamellipodia were blocked by 100 nM wortmannin, suggesting the
      involvement of a class Ia PI 3-kinase. MTLn3 cells contain equal amounts of
      p110alpha and p110beta, and do not contain p110delta. Injection of specific
      inhibitory antibodies to p110alpha induced cell rounding and blocked EGF
      stimulated lamellipod extension, whereas control or anti-p110beta antibodies had
      no effect. In contrast, both antibodies inhibited EGF-stimulated DNA synthesis.
      An in situ assay for actin nucleation showed that EGF-stimulated formation of new
      barbed ends was blocked by injection of anti-p110alpha antibodies. In summary,
      the p110alpha isoform of PI 3-kinase is specifically required for EGF-stimulated
      actin nucleation during lamellipod extension in breast cancer cells.

PMID- 10660522
TI  - Conditional and unconditional inhibition of calcium-activated potassium channels
      by reversible protein phosphorylation.
AB  - Large conductance, calcium-activated potassium channels (BK(Ca) or maxi-K) are
      important determinants of membrane excitability in many cell types. We used patch
      clamp techniques to study the biochemical regulation of native BK(Ca) channel
      proteins by endogenous Ser/Thr-directed protein kinases and phosphatases in cell
      free membrane patches from rat pituitary tumor cells (GH(4)C(1)). When protein
      kinase activity was blocked by removing ATP, endogenous protein phosphatases
      slowly increased BK(Ca) channel activity approximately 3-fold. Dephosphorylated
      channels could be activated fully by physiological increases in cytoplasmic
      calcium or membrane depolarization. In contrast, endogenous protein kinases
      inhibited BK(Ca) channel activity at two functionally distinct sites. A closely
      associated, cAMP-dependent protein kinase rapidly reduced channel activity in a
      conditional manner that could be overcome completely by increasing cytoplasmic
      free calcium 3-fold or 20 mV further depolarization. Phosphorylation at a
      pharmacologically distinct site inhibited channel activity unconditionally by
      reducing availability to approximately half that of maximum at all physiological
      calcium and voltages. Conditional versus unconditional inhibition of BK(Ca)
      channel activity through different protein kinases provides cells with a powerful
      computational mechanism for regulating membrane excitability.

PMID- 10660523
TI  - The biosynthesis of methylated amino acids in the active site region of methyl
      coenzyme M reductase.
AB  - The global production of the greenhouse gas methane by methanogenic archaea
      reaches 1 billion tons per annum. The final reaction releasing methane is
      catalyzed by the enzyme methyl-coenzyme M reductase. The crystal structure of
      methyl-coenzyme M reductase from Methanobacterium thermoautotrophicum revealed
      the presence of five modified amino acids within the alpha-subunit and near the
      active site region. Four of these modifications were C-, N-, and S-methylations,
      two of which, 2-(S)-methylglutamine and 5-(S)-methylarginine, have never been
      encountered before. We have now confirmed these modifications by mass
      spectrometry of chymotryptic peptides. With methyl-coenzyme M reductase purified
      from cells grown in the presence of L-[methyl-D(3)]methionine, it was shown that
      the methyl groups of the modified amino acids are derived from the methyl group
      of methionine rather than from methyl-coenzyme M, an intermediate in methane
      formation. The D(3) labeling pattern was found to be qualitatively and
      quantitatively the same as in the two methyl groups of the methanogenic coenzyme
      F(430), which are known to be introduced via S-adenosylmethionine. From the
      results, it is concluded that the methyl groups of the modified amino acids in
      methyl-coenzyme M reductase are biosynthetically introduced by an S
      adenosylmethionine-dependent post-translational modification. A mechanism for the
      methylation of glutamine at C-2 and of arginine at C-5 is discussed.

PMID- 10660524
TI  - Gelsolin in complex with phosphatidylinositol 4,5-bisphosphate inhibits caspase-3
      and -9 to retard apoptotic progression.
AB  - Apoptosis, or programmed cell death, occurs because of the activation of a
      protease cascade amplification circuit that includes the critical effector
      caspase-3. Previously, we identified the widely expressed actin modulatory
      protein gelsolin as a prominent substrate of caspase-3 and demonstrated that the
      N-terminal gelsolin cleavage product promotes apoptosis. Here we show that
      phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3, 4-bisphosphate
      in pure micelles or mixed vesicles prevent caspase-3 cleavage of gelsolin.
      Moreover, phosphatidylinositol 4, 5-bisphosphate-gelsolin strongly inhibits
      caspase-3 and -9 activity through the formation of a stable phosphatidylinositol
      4, 5-bisphosphate-gelsolin-caspase complex. In addition, phosphatidylinositol 4,5
      bisphosphate-gelsolin prevents apoptotic progression mediated by caspase-3 in a
      cell-free system, and phosphatidylinositol 4,5-bisphosphate-gelsolin-caspase-9
      and phosphatidylinositol 4,5-bisphosphate-gelsolin-caspase-3 complexes form in
      mouse embryonic fibroblasts during apoptosis induction when stimulated with
      fibronectin, to delay cell death. The results suggest that gelsolin can act as
      both an effector and an inhibitor of caspase-3, the latter in concert with
      phosphatidylinositol 4, 5-bisphosphate, and other membrane phospholipids to
      regulate the onset and progression of apoptosis.

PMID- 10660525
TI  - Synthesis and characterization of a peptide identified as a functional element in
      alphaA-crystallin.
AB  - Eye lens alpha-crystallin is a member of the small heat shock protein (sHSP)
      family and forms large multimeric structures. Earlier studies have shown that it
      can act like a molecular chaperone and form a stable complex with partially
      unfolded proteins. We have observed that prior binding of the hydrophobic protein
      melittin to alpha-crystallin diminishes its chaperone-like activity toward
      denaturing alcohol dehydrogenase, suggesting the presence of mutually exclusive
      sites for these proteins in alpha-crystallin. To investigate the mechanism of the
      interaction between alpha-crystallin and substrate proteins, we determined the
      melittin-binding sites in alpha-crystallin by cross-linking studies. Localization
      of melittin-binding sites in alpha-crystallin resulted in the identification of
      RTLGPFYPSR and FVIFLDVKHFSPEDLTVK of alphaA-crystallin and FSVNLDVK of alphaB
      crystallin as the chaperone sites. Of these sites, FVIFLDVKHFSPEDLTVK and
      FSVNLDVK were identified earlier as 1,1'-bi(4-anilino) naphthalene-5,5'
      disulfonic acid (bis-ANS)-binding hydrophobic sites. Here we also report the
      synthesis and characterization of the peptide, KFVIFLDVKHFSPEDLTVK, having the
      melittin as well as bis-ANS-binding sequence of alphaA-crystallin. We show that
      this peptide has characteristics similar to that of alphaA-crystallin by in vitro
      thermal aggregation assay, gel filtration study, CD spectroscopy, and bis-ANS
      interaction studies. The peptide sequence corresponds to the beta3 and beta4
      region present in the alpha-crystallin domain of sHSP 16.5. We hypothesize that
      the alpha-crystallin domain in other sHSPs may have a similar function and would
      likely possess the anti-aggregation property even when separated from the native
      protein.

PMID- 10660526
TI  - Differential localization and operation of distinct Mg(2+) transporters in apical
      and basolateral sides of rat liver plasma membrane.
AB  - Upon activation of specific cell signaling, hepatocytes rapidly accumulate or
      release an amount of Mg(2+) equivalent to 10% of their total Mg(2+) content.
      Although it is widely accepted that Mg(2+) efflux is Na(+)-dependent, little is
      known about transporter identity and the overall regulation. Even less is known
      about the mechanism of cellular Mg(2+) uptake. Using sealed and right-sided rat
      liver plasma membrane vesicles representing either the basolateral (bLPM) or
      apical (aLPM) domain, it was possible to dissect three different Mg(2+) transport
      mechanisms based upon specific inhibition, localization within the plasma
      membrane, and directionality. The bLPM possesses only one Mg(2+) transporter,
      which is strictly Na(+)-dependent, bi-directional, and not inhibited by
      amiloride. The aLPM possesses two separate Mg(2+) transporters. One, similar to
      that in the bLPM because it strictly depends on Na(+) transport, and it can be
      differentiated from that of the bLPM because it is unidirectional and fully
      inhibited by amiloride. The second is a novel Ca(2+)/Mg(2+) exchanger that is
      unidirectional and inhibited by amiloride and imipramine. Hence, the bLPM
      transporter may be responsible for the exchange of Mg(2+) between hepatocytes and
      plasma, and vice versa, shown in livers upon specific metabolic stimulation,
      whereas the aLPM transporters can only extrude Mg(2+) into the biliary tract. The
      dissection of these three distinct pathways and, therefore, the opportunity to
      study each individually will greatly facilitate further characterization of these
      transporters and a better understanding of Mg(2+) homeostasis.

PMID- 10660527
TI  - Ultrastructure and function of the fractalkine mucin domain in CX(3)C chemokine
      domain presentation.
AB  - Fractalkine (FKN), a CX(3)C chemokine/mucin hybrid molecule on endothelium,
      functions as an adhesion molecule to capture and induce firm adhesion of a subset
      of leukocytes in a selectin- and integrin-independent manner. We hypothesized
      that the FKN mucin domain may be important for its function in adhesion, and
      tested the ability of secreted alkaline phosphatase (SEAP) fusion proteins
      containing the entire extracellular region (FKN-SEAP), the chemokine domain (CX3C
      SEAP), or the mucin domain (mucin-SEAP) to support firm adhesion under flow. CX3C
      SEAP induced suboptimal firm adhesion of resting peripheral blood mononuclear
      cells, compared with FKN-SEAP, and mucin-SEAP induced no firm adhesion. CX3C-SEAP
      and FKN-SEAP bound to CX(3)CR1 with similar affinities. By electron microscopy,
      fractalkine was 29 nm in length with a long stalk (mucin domain), and a globular
      head (CX(3)C). To test the function of the mucin domain, a chimeric protein
      replacing the mucin domain with a rod-like segment of E-selectin was constructed.
      This chimeric protein gave the same adhesion of peripheral blood mononuclear
      cells as intact FKN, both when immobilized on glass and when expressed on the
      cell surface. This implies that the function of the mucin domain is to provide a
      stalk, extending the chemokine domain away from the endothelial cell surface to
      present it to flowing leukocytes.

PMID- 10660528
TI  - DNA strongly impairs the inhibition of cathepsin G by alpha(1)-antichymotrypsin
      and alpha(1)-proteinase inhibitor.
AB  - This paper explores the possibility that neutrophil-derived DNA interferes with
      the inhibition of neutrophil cathepsin G (cat G) and proteinase 3 by the lung
      antiproteinases alpha(1)-proteinase inhibitor (alpha(1)PI), alpha(1)
      antichymotrypsin (ACT), and mucus proteinase inhibitor (MPI). A 30-base pair DNA
      fragment ((30bp)DNA), used as a model of DNA, tightly binds cat G (K(d), 8.5 nM)
      but does not react with proteinase 3, alpha(1)PI, ACT, and MPI at physiological
      ionic strength. The polynucleotide is a partial noncompetitive inhibitor of cat G
      whose K(i) is close to K(d). ACT and alpha(1)PI are slow binding inhibitors of
      the cat G-(30bp)DNA complex whose second-order rate constants of inhibition are
      2300 M(-1) s(-1) and 21 M(-1) s(-1), respectively, which represents a 195-fold
      and a 3190-fold rate deceleration. DNA thus renders cat G virtually resistant to
      inhibition by these irreversible serpins. On the other hand, (30bp)DNA has little
      or no effect on the reversible inhibition of cat G by MPI or chymostatin or on
      the irreversible inhibition of cat G by carbobenzoxy-Gly-Leu-Phe
      chloromethylketone. The polynucleotide neither inhibits proteinase 3 nor affects
      its rate of inhibition by alpha(1)PI. These findings suggest that cat G may cause
      lung tissue destruction despite the presence of antiproteinases.

PMID- 10660529
TI  - Decreased binding to proteins and cells of polymeric gene delivery vectors
      surface modified with a multivalent hydrophilic polymer and retargeting through
      attachment of transferrin.
AB  - Binding of serum proteins to polyelectrolyte gene delivery complexes is thought
      to be an important factor limiting bloodstream circulation and restricting access
      to target tissues. Protein binding can also inhibit transfection activity in
      vitro. In this study a multivalent reactive hydrophilic polymer has been used to
      inhibit protein binding. This polymer is based on poly-[N-(2
      hydroxypropyl)methacrylamide] (pHPMA) bearing pendent oligopeptide (Gly-Phe-Leu
      Gly) side chains terminated in reactive 4-nitrophenoxy groups (8.6 mol%). The
      polymer reacts with the primary amino groups of poly(L-lysine) (pLL) and produces
      a hydrophilic coating on the surface of pLL.DNA complexes (as measured by
      fluorescamine). The resulting pHPMA-coated complexes show a decreased surface
      charge (from +14 mV for pLL.DNA complexes to -25 mV for pHPMA-modified complexes)
      as measured by zeta potential analysis. The pHPMA-coated complexes also show a
      slightly increased average diameter (approximately 90 nm compared with 60 nm for
      pLL. DNA complexes) as viewed by atomic force and transmission electron
      microscopy and around 100 nm as viewed by photon correlation spectroscopy. They
      are completely resistant to protein interaction, as determined by turbidometry
      and SDS-polyacrylamide gel electrophoresis analysis of complexes isolated from
      plasma, and show significantly decreased nonspecific uptake into cells in vitro.
      Spare reactive ester groups can be used to conjugate targeting ligands (e.g.
      transferrin) on to the surface of the complex to provide a means of tissue
      specific targeting and transfection. The properties of these complexes therefore
      make them promising candidates for targeted gene delivery, both in vitro and
      potentially in vivo.

PMID- 10660530
TI  - Disruption of the 14-3-3 binding site within the B-Raf kinase domain uncouples
      catalytic activity from PC12 cell differentiation.
AB  - A number of Raf-associated proteins have recently been identified, including
      members of the 14-3-3 family of phosphoserine-binding proteins. Although both
      positive and negative regulatory functions have been ascribed for 14-3-3
      interactions with Raf-1, the mechanisms by which 14-3-3 binding modulates Raf
      activity have not been fully established. We report that mutational disruption of
      14-3-3 binding to the B-Raf catalytic domain inhibits B-Raf biological activity.
      Expression of the isolated B-Raf catalytic domain (B-Rafcat) induces PC12 cell
      differentiation in the absence of nerve growth factor. By contrast, the B-Rafcat
      14-3-3 binding mutant, B-Rafcat S728A, was severely compromised for the induction
      of PC12 cell differentiation. Interestingly, the B-Rafcat 14-3-3 binding mutant
      retained significant in vitro catalytic activity. In Xenopus oocytes, the
      analogous full-length B-Raf 14-3-3 binding mutant blocked progesterone-stimulated
      maturation and the activation of endogenous mitogen-activated protein kinase
      kinase and mitogen-activated protein kinase. Similarly, the full-length B-Raf 14
      3-3 binding mutant inhibited nerve growth factor-stimulated PC12 cell
      differentiation. We conclude that 14-3-3 interaction with the catalytic domain is
      not required for kinase activity per se but is essential to couple B-Raf
      catalytic activity to downstream effector activation.

PMID- 10660531
TI  - Identification of the transactivation domain of the transcription factor Sox-2
      and an associated co-activator.
AB  - The importance of interactions between Sox and POU transcription factors in the
      regulation of gene expression is becoming increasingly apparent. Recently, many
      examples of the involvement of Sox-POU partnerships in transcription have been
      discovered, including a partnership between Sox-2 and Oct-3. Little is known
      about the mechanisms by which these factors modulate transcription. To better
      understand the molecular interactions involved, we mapped the location of the
      transactivation domain of Sox-2. This was done in the context of its interaction
      with Oct-3, as well as its ability to transactivate as a fusion protein linked to
      the DNA-binding domain of Gal4. Both approaches demonstrated that Sox-2 contains
      a transactivation domain in its C-terminal half, containing a serine-rich region
      and the C terminus. We also determined that the viral oncoprotein E1a inhibits
      the ability of the Gal4/Sox-2 fusion protein to transactivate, as well as the
      transcriptional activation mediated by the combined action of Sox-2 and Oct-3. In
      contrast, a mutant form of E1a, unable to bind p300, lacks both of these effects.
      Importantly, we determined that p300 overcomes the inhibitory effects of E1a in
      both assays. Together, these findings suggest that Sox-2 mediates its effects, at
      least in part, through the co-activator p300.

PMID- 10660532
TI  - Release of insulin receptor substrate proteins from an intracellular complex
      coincides with the development of insulin resistance.
AB  - Insulin receptor substrate (IRS) proteins are major substrates of the insulin
      receptor (IR). IRS-1 associates with an insoluble multiprotein complex, possibly
      the cytoskeleton, in adipocytes. This localization may facilitate interaction
      with the IR at the cell surface. In the present study, we examined the hypothesis
      that the release of IRS proteins from this location may be a mechanism for
      insulin desensitization. We show that a second IRS protein, IRS-2, is associated
      with a multiprotein complex in adipocytes with similar characteristics to the IRS
      1 complex. Insulin treatment (15-60 min) caused the release of IRS-1 and IRS-2
      from this complex (high speed pellet; HSP) into the cytosol, whereas the level of
      tyrosyl-phosphorylated IRS proteins remained constant. Chronic insulin treatment
      resulted in a dramatic reduction in IRS-1 and IRS-2 in the HSP, eventually (>2 h)
      leading to IRS protein degradation and decreased levels of tyrosyl-phosphorylated
      IRS proteins. Okadaic acid, which rapidly induces insulin resistance in
      adipocytes independently of IR function, caused an almost quantitative release of
      IRS-1 into the cytosol commensurate with a significant reduction in tyrosyl
      phosphorylated IRS proteins. Platelet-derived growth factor, a factor known to
      compromise insulin signaling, caused a more moderate release of IRS proteins from
      the HSP. Collectively, these results suggest that the assembly of IRS-1/IRS-2
      into a multiprotein complex facilitates coupling to the IR and that the regulated
      release from this location may represent a novel mechanism of insulin resistance.

PMID- 10660533
TI  - Dipeptidyl peptidase IV (DPIV/CD26) degradation of glucagon. Characterization of
      glucagon degradation products and DPIV-resistant analogs.
AB  - Over the past decade, numerous studies have been targeted at defining structure
      activity relationships of glucagon. Recently, we have found that glucagon(1-29)
      is hydrolyzed by dipeptidyl peptidase IV (DPIV) to produce glucagon(3-29) and
      glucagon(5-29); in human serum, [pyroglutamyl (pGlu)(3)]glucagon(3-29) is formed
      from glucagon(3-29), and this prevents further hydrolysis of glucagon by DPIV (H.
      U. Demuth, K. Glund, U. Heiser, J. Pospisilik, S. Hinke, T. Hoffmann, F. Rosche,
      D. Schlenzig, M. Wermann, C. McIntosh, and R. Pederson, manuscript in
      preparation). In the current study, the biological activity of these peptides was
      examined in vitro. The amino-terminally truncated peptides all behaved as partial
      agonists in cyclic AMP stimulation assays, with Chinese hamster ovary K1 cells
      overexpressing the human glucagon receptor (potency: glucagon(1-29) >
      [pGlu(3)]glu- cagon(3-29) > glucagon(3-29) > glucagon(5-29) > [Glu(9)]glu-
      cagon(2-29)). In competition binding experiments, [pGlu(3)]glucagon(3-29) and
      glucagon(5-29) both demonstrated 5-fold lower affinity for the receptor than
      glucagon(1-29), whereas glucagon(3-29) exhibited 18-fold lower affinity. Of the
      peptides tested, only glucagon(5-29) showed antagonist activity, and this was
      weak compared with the classical glucagon antagonist, [Glu(9)]glucagon(2-29).
      Hence, DPIV hydrolysis of glucagon yields low affinity agonists of the glucagon
      receptor. As a corollary to evidence indicating that DPIV degrades glucagon
      (Demuth, et al., manuscript in preparation), DPIV-resistant analogs were
      synthesized. Matrix-assisted laser desorption/ionization-time of flight mass
      spectrometry was used to assess DPIV resistance, and it allowed kinetic analysis
      of degradation. Of several analogs generated, only [D-Ser(2)] and
      [Gly(2)]glucagon retained high affinity binding and biological potency, similar
      to native glucagon in vitro. [D-Ser(2)]Glucagon exhibited enhanced hyperglycemic
      activity in a bioassay, whereas [Gly(2)]glucagon was not completely resistant to
      DPIV degradation.

PMID- 10660534
TI  - Resting lymphocyte kinase (Rlk/Txk) targets lymphoid adaptor SLP-76 in the
      cooperative activation of interleukin-2 transcription in T-cells.
AB  - Rlk/Txk is a T-cell-specific member of the Btk/Tec family of tyrosine kinases,
      whereas SLP-76 is a lymphoid adaptor that is essential for pre-TcR and mature TcR
      signaling. Although Rlk deficient T-cells show partial defects in T-cell
      proliferation, Rlk can complement ITK-/- cells with multiple defects in TcR
      initiated early events and interleukin (IL)-2 production. A key question is the
      nature of the target of Rlk responsible for bridging the TcR with the activation
      of IL-2 transcription. In this study, we identify a pathway in which Rlk
      phosphorylates SLP-76 leading to the phosphorylation of PLCgamma1, activation of
      ERKs, and the synergistic up-regulation of TcR-driven IL-2 NFAT/AP-1
      transcription. Rlk phosphorylated the N-terminal region of SLP-76, a region that
      has been previously shown to serve as a target for ZAP-70. Loss of N-terminal
      YESP/YEPP sites of SLP-76 or the Rlk kinase activity attenuated cooperativity
      between Rlk and SLP-76. These observations support a model where the TcR can
      utilize Rlk (as well as ZAP-70) in the phosphorylation of key sites in SLP-76
      leading to the up-regulation of Th1 preferred cytokine IL-2.

PMID- 10660535
TI  - Role of the suppressor of cytokine signaling-3 in mediating the inhibitory
      effects of interleukin-1beta on the growth hormone-dependent transcription of the
      acid-labile subunit gene in liver cells.
AB  - During catabolic diseases such as sepsis, inflammation, and infection, a state of
      growth hormone (GH) resistance develops in liver. This has been attributed in
      part to increased production of the proinflammatory cytokine interleukin-1beta
      (IL-1beta). To determine how IL-1beta induces GH resistance, we studied the acid
      labile subunit (ALS) gene whose hepatic transcription is increased by GH via the
      Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway.
      IL-1beta reduced the ability of GH to stimulate ALS mRNA in rat primary
      hepatocytes and ALS promoter activity in H4-II-E rat hepatoma cells. This
      inhibition was dependent on ALSGAS1, an element resembling a gamma-interferon
      activated sequence that mediates the transcriptional effects of GH. Inhibition by
      IL-1beta was also associated with a reduction of GH-dependent binding of STAT5 to
      this element after chronic (8 and 24 h), but not after acute treatment (15 min).
      Because these results indicated that the inhibition by IL-1beta was indirect,
      expression of the recently discovered suppressors of cytokine action (SOCS) was
      examined in liver cells. IL-1beta did not alter the expression of SOCS1, SOCS2,
      and CIS, indicating that they are not involved. In contrast, IL-1beta increased
      SOCS3 mRNA by 8-fold after 24 h of treatment, whereas GH had no effect. Forced
      expression of SOCS3 was just as effective as IL-1beta in reducing the GH
      induction of ALS promoter activity in H4-II-E rat hepatoma cells. Similar results
      were observed in primary rat hepatocytes. We conclude that the induction of SOCS3
      by IL-1beta contributes to the development of GH resistance in liver, and
      represents a mechanism by which cytokines such as IL-1beta cross-talk with
      cytokines using the JAK-STAT pathway.

PMID- 10660536
TI  - Rab24 is an atypical member of the Rab GTPase family. Deficient GTPase activity,
      GDP dissociation inhibitor interaction, and prenylation of Rab24 expressed in
      cultured cells.
AB  - The function of Rab24 is currently unknown, but other members of the Rab GTPase
      family are known to participate in various protein trafficking pathways. Rab
      proteins are thought to cycle on and off vesicle membranes in conjunction with
      changes in their guanine nucleotide state. The present studies indicate that
      Rab24 possesses several unusual characteristics that distinguish it from other
      Rab proteins. 1) Based on [(32)P]orthophosphate labeling of protein-bound
      nucleotide, Rab24 exists predominantly in the GTP state when expressed in
      cultured cells. The low GTPase activity is related to the presence of serine
      instead of glutamine at the position cognate to Ras Gln-61. 2) Posttranslational
      geranylgeranylation of Rab24, determined by metabolic labeling or detergent
      partitioning assays, is inefficient when compared with other Rabs ending with the
      common CXC and CC carboxyl-terminal motifs. This is partly due to the presence of
      two histidines distal to the target cysteines, but also involves other
      unidentified features. 3) Most of the Rab24 in the cytoplasmic compartment of
      cultured cells is not associated with Rab GDP dissociation inhibitors. These
      findings indicate that, if Rab24 functions in vesicular transport processes, it
      may operate through a novel mechanism that does not depend on GTP hydrolysis or
      GDP dissociation inhibitor-mediated recycling.

PMID- 10660537
TI  - Identification of a novel signal sequence that targets transmembrane proteins to
      the nuclear envelope inner membrane.
AB  - Herpesvirus maturation requires translocation of glycoprotein B homologue from
      the endoplasmic reticulum to the inner nuclear membrane. Glycoprotein B of human
      cytomegalovirus was used in this context as a model protein. To identify a
      specific signal sequence within human cytomegalovirus glycoprotein B acting in a
      modular fashion, coding sequences were recombined with reporter proteins.
      Immunofluorescence and cell fractionation demonstrated that a short sequence
      element within the cytoplasmic tail of human cytomegalovirus glycoprotein B was
      sufficient to translocate the membrane protein CD8 to the inner nuclear membrane.
      This carboxyl-terminal sequence had no detectable nuclear localization signal
      activity for soluble beta-Galactosidase and could not be substituted by the
      nuclear localization signal of SV40 T antigen. For glycoprotein B of herpes
      simplex virus, a carboxyl-terminal element with comparable properties was found.
      Further experiments showed that the amino acid sequence DRLRHR of human
      cytomegalovirus glycoprotein B (amino acids 885-890) was sufficient for nuclear
      envelope translocation. Single residue mutations revealed that the arginine
      residues in positions 4 and 6 of the DRLRHR sequence were essential for its
      function. These results support the view that transmembrane protein transport to
      the inner nuclear membrane is controlled by a mechanism different from that of
      soluble proteins.

PMID- 10660538
TI  - Human and mouse Fas (APO-1/CD95) death receptor genes each contain a p53
      responsive element that is activated by p53 mutants unable to induce apoptosis.
AB  - p53 is a tumor suppressor protein that induces apoptosis at least in part through
      its ability to act as a sequence-specific transactivator. This work reports that
      intron 1 of the mouse Fas death receptor gene contains a p53-responsive element
      (p53RE) that matches the p53 consensus sequence and that is located between
      nucleotides +1704 and +1723 from the transcription initiation site. This element
      is specifically bound by p53 and functions as a p53-dependent enhancer in
      mammalian or in yeast reporter gene assays. Contrary to bax, another known pro
      apoptotic p53-target gene, both mouse and human FAS p53REs are still activated by
      the discriminatory p53 mutants Pro-175 and Ala-143, a class of mutants unable to
      induce apoptosis. We propose that p53-dependent up-regulation of Fas does not
      induce apoptosis per se but sensitizes the cell to other pro-apoptotic signal(s).
      The functional conservation of p53-dependent Fas up-regulation argues strongly in
      favor of its biological importance and suggests that murine models may be used to
      study further the in vivo role of Fas in the p53 response.

PMID- 10660539
TI  - The ATP hydrolytic activity of purified ZntA, a Pb(II)/Cd(II)/Zn(II)
      translocating ATPase from Escherichia coli.
AB  - ZntA, a soft metal-translocating P1-type ATPase from Escherichia coli, confers
      resistance to Pb(II), Cd(II), and Zn(II). ZntA was expressed as a histidyl-tagged
      protein, solubilized from membranes with Triton X-100, and purified to
      homogeneity. The soft metal-dependent ATP hydrolysis activity of purified ZntA
      was characterized. The activity was specific for Pb(II), Cd(II), Zn(II), and
      Hg(II), with the highest activity obtained when the metals were present as
      thiolate complexes of cysteine or glutathione. The maximal ATPase activity of
      ZntA was approximately 3 micromol/(mg x min) obtained with the Pb(II)-thiolate
      complex. In the absence of thiolates, Cd(II) inhibits ZntA above pH 6, whereas
      the Cd(II)-thiolate complexes stimulate activity, suggesting that a metal
      thiolate complex is the true substrate in vivo. These results are consistent with
      the physiological role of ZntA as mediator of resistance to toxic concentrations
      of the divalent soft metals, Pb(II), Cd(II), and Zn(II), by ATP-dependent efflux.
      Our results confirm that ZntA is the first Pb(II)-dependent ATPase discovered to
      date.

PMID- 10660540
TI  - The contribution of a conformationally mobile, active site loop to the reaction
      catalyzed by glutamate semialdehyde aminomutase.
AB  - The behavior of glutamate semialdehyde aminomutase, the enzyme that produces 4
      aminolevulinate for tetrapyrrole synthesis in plants and bacteria, is markedly
      affected by the extent to which the central intermediate in the reaction, 4,5
      diaminovalerate, is allowed to dissociate. The kinetic properties of the wild
      type enzyme are compared with those of a mutant form in which a flexible loop,
      that reversibly plugs the entrance to the active site, has been deleted by site
      directed mutagenesis. The deletion has three effects. The dissociation constant
      for diaminovalerate is increased approximately 100-fold. The catalytic efficiency
      of the enzyme, measured as k(cat)/K(m) in the presence of saturating
      concentrations of diaminovalerate, is lowered 30-fold to 2.1 mM(-1) s(-1). During
      the course of the reaction, which begins with the enzyme in its pyridoxamine
      form, the mutant enzyme undergoes absorbance changes not seen with the wild-type
      enzyme under the same conditions. These are proposed to be due to abortive
      complex formation between the pyridoxal form of the enzyme (formed by
      dissociation of diaminovalerate) and glutamate semialdehyde itself.

PMID- 10660541
TI  - The Asp(272)-Glu(282) region of platelet glycoprotein Ibalpha interacts with the
      heparin-binding site of alpha-thrombin and protects the enzyme from the heparin
      catalyzed inhibition by antithrombin III.
AB  - Platelet glycoprotein Ib (GpIb) mediates interaction with both von Willebrand
      factor and thrombin. Thrombin binds to GpIb via its heparin-binding site (HBS)
      (De Candia, E., De Cristofaro, R., De Marco, L., Mazzucato, M., Picozzi, M., and
      Landolfi, R. (1997) Thromb. Haemostasis 77, 735-740; De Cristofaro, R., De
      Candia, E., Croce, G., Morosetti, R., and Landolfi, R. (1998) Biochem. J. 332,
      643-650). To identify the thrombin-binding domain on GpIbalpha, we examined the
      effect of GpIbalpha(1-282), a GpIbalpha fragment released by the cobra venom
      mocarhagin on the heparin-catalyzed rate of thrombin inhibition by antithrombin
      III (AT). GpIbalpha(1-282) inhibited the reaction in a dose-dependent and
      competitive fashion. In contrast, the GpIbalpha(1-271) fragment, produced by
      exposing GpIbalpha(1-282) to carboxypeptidase Y, had no effect on thrombin
      inhibition by the heparin-AT complex. Measurements of the apparent equilibrium
      constant of the GpIbalpha(1-282) binding to thrombin as a function of different
      salts (NaCl and tetramethyl-ammonium chloride) concentration (0.1-0.2 M)
      indicated a large salt dependence (Gamma(+/-) = -4.5), similar to that pertaining
      to the heparin binding to thrombin. The importance of thrombin HBS in its
      interaction with GpIbalpha was confirmed using DNA aptamers, which specifically
      bind to either HBS (HD22) or the fibrinogen recognition site of thrombin (HD1).
      HD22, but not HD1, inhibited thrombin binding to GpIbalpha(1-282). Furthermore,
      the proteolytic derivative gamma(T)-thrombin, which lacks the fibrinogen
      recognition site, binds to GpIbalpha via its intact HBS in a reaction that is
      inhibited by HD22. Neither alpha- nor gamma(T)-thrombin bound to GpIbalpha(1
      271), suggesting that the Asp(272)-Glu(282) region of GpIbalpha may act as a
      "heparin-like" ligand for the thrombin HBS, thereby inhibiting heparin binding to
      thrombin. It was also demonstrated that intact platelets may dose-dependently
      inhibit the heparin-catalyzed thrombin inhibition by AT at enzyme concentrations
      <5 nM. Altogether, these findings show that thrombin HBS binds to the region of
      GpIbalpha involving the Asp(272)-Glu(282) segment, protecting the enzyme from the
      inactivation by the heparin-AT system.

PMID- 10660542
TI  - Biosynthesis of ganglioside mimics in Campylobacter jejuni OH4384. Identification
      of the glycosyltransferase genes, enzymatic synthesis of model compounds, and
      characterization of nanomole amounts by 600-mhz (1)h and (13)c NMR analysis.
AB  - We have applied two strategies for the cloning of four genes responsible for the
      biosynthesis of the GT1a ganglioside mimic in the lipooligosaccharide (LOS) of a
      bacterial pathogen, Campylobacter jejuni OH4384, which has been associated with
      Guillain-Barre syndrome. We first cloned a gene encoding an alpha-2, 3
      sialyltransferase (cst-I) using an activity screening strategy. We then used
      nucleotide sequence information from the recently completed sequence from C.
      jejuni NCTC 11168 to amplify a region involved in LOS biosynthesis from C. jejuni
      OH4384. The LOS biosynthesis locus from C. jejuni OH4384 is 11.47 kilobase pairs
      and encodes 13 partial or complete open reading frames, while the corresponding
      locus in C. jejuni NCTC 11168 spans 13.49 kilobase pairs and contains 15 open
      reading frames, indicating a different organization between these two strains.
      Potential glycosyltransferase genes were cloned individually, expressed in
      Escherichia coli, and assayed using synthetic fluorescent oligosaccharides as
      acceptors. We identified genes encoding a beta-1, 4-N-acetylgalactosaminyl
      transferase (cgtA), a beta-1, 3-galactosyltransferase (cgtB), and a bifunctional
      sialyltransferase (cst-II), which transfers sialic acid to O-3 of galactose and
      to O-8 of a sialic acid that is linked alpha-2,3- to a galactose. The linkage
      specificity of each identified glycosyltransferase was confirmed by NMR analysis
      at 600 MHz on nanomole amounts of model compounds synthesized in vitro. Using a
      gradient inverse broadband nano-NMR probe, sequence information could be obtained
      by detection of (3)J(C,H) correlations across the glycosidic bond. The role of
      cgtA and cst-II in the synthesis of the GT1a mimic in C. jejuni OH4384 were
      confirmed by comparing their sequence and activity with corresponding homologues
      in two related C. jejuni strains that express shorter ganglioside mimics in their
      LOS.

PMID- 10660543
TI  - Mechanism of type 3 capsular polysaccharide synthesis in Streptococcus
      pneumoniae.
AB  - The glycosidic linkages of the type 3 capsular polysaccharide of Streptococcus
      pneumoniae ([3)-beta-D-GlcUA-(1-->4)-beta-D-Glc-(1-->](n)) are formed by the
      membrane-associated type 3 synthase (Cps3S), which is capable of synthesizing
      polymer from UDP sugar precursors. Using membrane preparations of S. pneumoniae
      in an in vitro assay, we observed type 3 synthase activity in the presence of
      either Mn(2+) or Mg(2+) with maximal levels seen with 10-20 mM Mn(2+). High
      molecular weight polymer synthesized in the assay was composed of Glc and
      glucuronic acid and could be degraded to a low molecular weight product by a type
      3-specific depolymerase from Bacillus circulans. Additionally, the polymer bound
      specifically to an affinity column made with a type 3 polysaccharide-specific
      monoclonal antibody. The polysaccharide was rapidly synthesized from smaller
      chains and remained associated with the enzyme-containing membrane fraction
      throughout its synthesis, indicating a processive mechanism of synthesis. Release
      of the polysaccharide was observed, however, when the level of one of the
      substrates became limiting. Finally, addition of sugars to the growing type 3
      polysaccharide was shown to occur at the nonreducing end of the polysaccharide
      chain.

PMID- 10660544
TI  - Opposite effects of Ca(2+) and GTP binding on tissue transglutaminase tertiary
      structure.
AB  - Tissue transglutaminase (tTG) belongs to a class of enzymes that catalyze a cross
      linking reaction between proteins or peptides. The protein activity is known to
      be finely tuned by Ca(2+) and GTP binding. In this study we report the effects of
      these ligands on the enzyme structure, as revealed by circular dichroism, and
      steady-state and dynamic fluorescence measurements. We have found that calcium
      and GTP induced opposite conformational changes at the level of the protein
      tertiary structure. In particular the metal ions were responsible for a small
      widening of the protein molecule, as indicated by anisotropy decay measurements
      and by the binding of a hydrophobic probe such as 1-anilino-8-naphthalenesulfonic
      acid (ANS). Unlike Ca(2+), the nucleotide binding increased the protein dynamics,
      reducing its rotational correlation lifetime from 32 to 25 ns, preventing also
      the binding of ANS into the protein matrix. Unfolding of tTG by guanidinium
      hydrochloride yielded a three-state denaturation mechanism, involving an
      intermediate species with the characteristics of the so-called "molten globule"
      state. The effect of GTP binding (but not that of Ca(2+)) had an important
      consequence on the stability of tissue transglutaminase, increasing the free
      energy change from the native to the intermediate species by at least
      approximately 0.7 kcal/mol. Also a greater stability of tTG to high hydrostatic
      pressure was obtained in presence of GTP. These findings suggest that the
      molecular mechanism by which tTG activity is inhibited by GTP is essentially due
      to a protein conformational change which, decreasing the accessibility of the
      protein matrix to the solvent, renders more difficult the exposure of the active
      site.

PMID- 10660545
TI  - The role of mismatched nucleotides in activating the hMSH2-hMSH6 molecular
      switch.
AB  - We have previously shown that hMSH2-hMSH6 contains an intrinsic ATPase which is
      activated by mismatch-provoked ADP-->ATP exchange that coordinately induces the
      formation of a sliding clamp capable of hydrolysis-independent diffusion along
      the DNA backbone (1,2). These studies suggested that mismatch repair could be
      propagated by a signaling event transduced via diffusion of ATP-bound hMSH2-hMSH6
      molecular switches to the DNA repair machinery. The Molecular Switch model
      (Fishel, R. (1998) Genes Dev. 12, 2096-2101) is considerably different than the
      Hydrolysis-Driven Translocation model (Blackwell, L. J., Martik, D., Bjornson, K.
      P., Bjornson, E. S., and Modrich, P. (1998) J. Biol. Chem. 273, 32055-32062) and
      makes additional testable predictions beyond the demonstration of hydrolysis
      independent diffusion (Gradia, S., Subramanian, D., Wilson, T., Acharya, S.,
      Makhov, A., Griffith, J., and Fishel, R. (1999) Mol. Cell 3, 255-261): (i)
      individual mismatch-provoked ADP-->ATP exchange should be unique and rate
      limiting, and (ii) the k(cat x DNA) for the DNA-stimulated ATPase activity should
      decrease with increasing chain length. Here we have examined hMSH2-hMSH6 affinity
      and ATPase stimulatory activity for several DNA substrates containing mispaired
      nucleotides as well as the chain length dependence of a defined mismatch under
      physiological conditions. We find that the results are most consistent with the
      predictions of the Molecular Switch model.

PMID- 10660546
TI  - Invariance of the nucleoside triphosphate pools of Escherichia coli with growth
      rate.
AB  - The ATP and GTP pools of Escherichia coli have recently been reported to increase
      approximately 10-fold with increasing growth rates in the range from 0.4 to 1.4
      generations/hour (Gaal, T., Bartlett, M. S., Ross, W., Turnbough, C. L., and
      Gourse, R. L. (1997) Science 278, 2092-2097). Moreover, it was proposed that this
      variation of the nucleotide pools, particularly the ATP pool, might be
      responsible for the well known growth rate-dependent regulation of rRNA synthesis
      in E. coli. To test this hypothesis we have measured the nucleoside triphosphate
      pools as a function of growth rate for several E. coli strains. We found that the
      size of all four RNA precursor pools are essentially invariant with growth rate,
      in the range from 0.5 to 2.3 generations/hour. Nevertheless we observed the
      expected growth rate-dependent increase of RNA accumulation in these strains. In
      light of these results, it seems unlikely that nucleotide pool variations should
      be responsible for the growth rate-dependent regulation of rRNA synthesis.

PMID- 10660547
TI  - Protein-induced fusion can be modulated by target membrane lipids through a
      structural switch at the level of the fusion peptide.
AB  - Regulatory features of protein-induced membrane fusion are largely unclear,
      particularly at the level of the fusion peptide. Fusion peptides being part of
      larger protein complexes, such investigations are met with technical limitations.
      Here, we show that the fusion activity of influenza virus or Golgi membranes is
      strongly inhibited by minor amounts of (lyso)lipids when present in the target
      membrane but not when inserted into the viral or Golgi membrane itself. To
      investigate the underlying mechanism, we employ a membrane-anchored peptide
      system and show that fusion is similarly regulated by these lipids when inserted
      into the target but not when present in the peptide-containing membrane. Peptide
      induced fusion is regulated by a reversible switch of secondary structure from a
      fusion-permissive alpha-helix to a nonfusogenic beta-sheet. The "on/off"
      activation of this switch is governed by minor amounts of (lyso)-phospholipids in
      targets, causing a drop in alpha-helix and a dramatic increase in beta-sheet
      contents. Concomitantly, fusion is inhibited, due to impaired peptide insertion
      into the target membrane. Our observations in biological fusion systems together
      with the model studies suggest that distinct lipids in target membranes provide a
      means for regulating membrane fusion by causing a reversible secondary structure
      switch of the fusion peptides.

PMID- 10660548
TI  - Engineered salt-insensitive alpha-defensins with end-to-end circularized
      structures.
AB  - We designed a retro-isomer and seven circularized "beta-tile" peptide analogs of
      a typical rabbit alpha-defensin, NP-1. The analogs retained defensin-like
      architecture after the characteristic end-to-end, Cys(3,31) (C I:C VI), alpha
      defensin disulfide bond was replaced by a backbone peptide bond. The retro-isomer
      of NP-1 was as active as the parent compound, suggesting that overall topology
      and amphipathicity governed its antimicrobial activity. A beta-tile design with
      or without a single cross-bracing disulfide bond sufficed for antimicrobial
      activity, and some of the analogs retained activity against Escherichia coli and
      Salmonella typhimurium in NaCl concentrations that rendered NP-1 inactive. The
      new molecules had clustered positive charges resembling those in protegrins and
      tachyplesins, but were less cytotoxic. Such simplified alpha-defensin analogs
      minimize problems encountered during the oxidative folding of three-disulfide
      defensins. In addition, they are readily accessible to a novel thia zip
      cyclization procedure applicable to large unprotected peptide precursors of 31
      amino acids in aqueous solutions. Collectively, these findings provide new and
      improved methodology to create salt-insensitive defensin-like peptides for
      application against bacterial diseases.

PMID- 10660549
TI  - Apolipoprotein B, a paradigm for proteins regulated by intracellular degradation,
      does not undergo intracellular degradation in CaCo2 cells.
AB  - Studies in different liver-derived cells in culture indicate that apolipoprotein
      (apo) B-100 production is regulated largely by intracellular degradation and the
      ubiquitin-proteasome pathway is a major mechanism for the degradation. The
      proteasomal degradation of apoB-100 was postulated to be an intrinsic property of
      the protein that occurs even in the presence of optimal amounts of lipids
      supplied to the cell. We examined apoB-100 and apoB-48 biogenesis in CaCo2, a
      human colon carcinoma cell line. To our surprise, apoB-100 and apoB-48 were
      quantitatively secreted by CaCo2 cells; essentially none of the newly synthesized
      apoB was degraded before secretion in a 2-h period whether the cells were
      cultured on filter or on plastic. Furthermore, although ubiquitin
      immunoreactivity was readily detected in the intracellular apoB isolated from
      HepG2 cells, little or no ubiquitin was detectable in the intracellular apoB from
      CaCo2 cells. The amounts of free ubiquitin and total and non-apoB ubiquitinated
      proteins were comparable in HepG2 and CaCo2 cells, indicating that CaCo2 cells
      have the necessary machinery for tagging ubiquitin chains onto cellular proteins
      for proteasomal degradation. Incubation in lipoprotein-deficient serum did not
      induce apoB degradation, but the addition of a microsomal triglyceride transfer
      protein inhibitor led to apoB degradation in CaCo2 cells. Finally, similar
      proportions of apoB polypeptide in isolated microsomes from CaCo2 and HepG2 cells
      were accessible to exogenously added trypsin, indicating that the mere exposure
      of apoB nascent chains to the cytosolic compartment is insufficient to cause the
      proteasomal degradation. Therefore, the intracellular degradation of apoB is not
      an intrinsic property of the protein, and the phenomenon is neither universal nor
      inevitable. The unconditional use of apoB as a paradigm for intracellular protein
      degradation is not warranted.

PMID- 10660550
TI  - Calcium-dependent human serum homocysteine thiolactone hydrolase. A protective
      mechanism against protein N-homocysteinylation.
AB  - Homocysteine thiolactone is formed in all cell types studied thus far as a result
      of editing reactions of some aminoacyl-tRNA synthetases. Because inadvertent
      reactions of thiolactone with proteins are potentially harmful, the ability to
      detoxify homocysteine thiolactone is essential for biological integrity. This
      work shows that a single specific enzyme, present in mammalian but not in avian
      sera, hydrolyzes thiolactone to homocysteine. Human serum thiolactonase, a 45-kDa
      protein component of high density lipoprotein, requires calcium for activity and
      stability and is inhibited by isoleucine and penicillamine. Substrate specificity
      studies suggest that homocysteine thiolactone is a likely natural substrate of
      this enzyme. However, thiolactonase also hydrolyzes non-natural substrates, such
      as phenyl acetate, p-nitrophenyl acetate, and the organophospate paraoxon. N
      terminal amino acid sequence of pure thiolactonase is identical with that of
      human paraoxonase. These and other data indicate that paraoxonase, an
      organophosphate-detoxifying enzyme whose natural substrate and function remained
      unknown up to now, is in fact homocysteine thiolactonase. By detoxifying
      homocysteine thiolactone, the thiolactonase/paraoxonase would protect proteins
      against homocysteinylation, a potential contributing factor to atherosclerosis.

PMID- 10660551
TI  - Permeation and gating properties of the novel epithelial Ca(2+) channel.
AB  - The recently cloned epithelial Ca(2+) channel (ECaC) constitutes the Ca(2+)
      influx pathway in 1,25-dihydroxyvitamin D(3)-responsive epithelia. We have
      combined patch-clamp analysis and fura-2 fluorescence microscopy to functionally
      characterize ECaC heterologously expressed in HEK293 cells. The intracellular
      Ca(2+) concentration in ECaC-expressing cells was closely correlated with the
      applied electrochemical Ca(2+) gradient, demonstrating the distinctive Ca(2+)
      permeability and constitutive activation of ECaC. Cells dialyzed with 10 mM 1,2
      bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid displayed large inward
      currents through ECaC in response to voltage ramps. The corresponding current
      voltage relationship showed pronounced inward rectification. Currents evoked by
      voltage steps to potentials below -40 mV partially inactivated with a
      biexponential time course. This inactivation was less pronounced if Ba(2+) or
      Sr(2+) replaced Ca(2+) and was absent in Ca(2+)-free solutions. ECaC showed an
      anomalous mole fraction behavior. The permeability ratio P(Ca):P(Na) calculated
      from the reversal potential at 30 mM [Ca(2+)](o) was larger than 100. The
      divalent cation selectivity profile is Ca(2+) > Mn(2+) > Ba(2+) approximately
      Sr(2+). Repetitive stimulation of ECaC-expressing cells induced a decay of the
      current response, which was greatly reduced if Ca(2+) was replaced by Ba(2+) and
      was virtually abolished if [Ca(2+)](o) was lowered to 1 nM. In conclusion, ECaC
      is a Ca(2+) selective channel, exhibiting Ca(2+)-dependent autoregulatory
      mechanisms, including fast inactivation and slow down-regulation.

PMID- 10660552
TI  - Rad51 uses one mechanism to drive DNA strand exchange in both directions.
AB  - The Rad51 protein of Saccharomyces cerevisiae, like its bacterial counterpart
      RecA, promotes strand exchange between circular single-stranded DNA (ssDNA) and
      linear double-stranded DNA (dsDNA) in vitro. However, the two proteins differ in
      the requirement for initiating joint molecules and in the polarity of branch
      migration. Whereas RecA initiates joint molecules from any type of ends on the
      dsDNA and branch migration proceeds exclusively in the 5'- to 3'-direction with
      respect to the single strand DNA substrate, initiation mediated by Rad51 requires
      a complementary 3' or 5' overhanging end of the linear dsDNA and branch migration
      proceeds in either direction. Here we report that the rates of Rad51-mediated
      branch migration in either the 5'- to 3'- or 3'- to 5'-directions are affected to
      the same extent by temperature and MgCl(2). Furthermore, branch migration in both
      directions is equally impeded by insertions of non-homologous sequences in the
      dsDNA, inserts of 6 base pairs or more being completely inhibitory. We have also
      found that the preference of strand exchange in the 5'- to 3'-direction does not
      change if RPA is replaced by Escherichia coli SSB or T4 gene 32 proteins,
      suggesting that the preference for the direction of strand exchange is intrinsic
      to Rad51. Based on these results, we conclude that Rad51-promoted branch
      migration in either direction occurs fundamentally by the same mechanism, quite
      probably by stabilizing successively formed heteroduplex base pair.

PMID- 10660553
TI  - The multiple activities of polyphosphate kinase of Escherichia coli and their
      subunit structure determined by radiation target analysis.
AB  - Polyphosphate kinase (PPK), the principal enzyme required for the synthesis of
      inorganic polyphosphate (polyP) from ATP, also exhibits other enzymatic
      activities, which differ significantly in their biochemical optima and responses
      to chemical agents. These several activities include: polyP synthesis (forward
      reaction), nATP --> polyP(n) + nADP (Equation 1); ATP synthesis from polyP
      (reverse reaction), ADP + polyP(n) --> ATP + polyP(n - 1) (Equation 2); general
      nucleoside-diphosphate kinase, GDP + polyP(n) --> GTP + polyP(n - 1) (Equation
      3); linear guanosine 5'-tetraphosphate (ppppG) synthesis, GDP + polyP(n) -->
      ppppG + polyP(n - 2) (Equation 4); and autophosphorylation, PPK + ATP --> PPK-P +
      ADP (Equation 5). The Mg(2+) optima are 5, 2, 1, and 0.2 mM, respectively, for
      the activities in Equations 1, 2, 3, and 4. Inorganic pyrophosphate inhibits the
      activities in Equations 1 and 3 but stimulates that in Equation 4. The kinetics
      of the activities in Equations 1, 2, and 3 are highly processive, whereas the
      transfer of a pyrophosphoryl group from polyP to GDP (Equation 4) is distributive
      and demonstrates a rapid equilibrium, random Bi-Bi catalytic mechanism. Radiation
      target analysis revealed that the principal functional unit of the homotetrameric
      PPK is a dimer. Exceptions are a trimer for the synthesis of ppppG (Equation 4)
      and a tetrameric state for the autophosphorylation of PPK (Equation 5) at low ATP
      concentrations. Thus, the diverse functions of this enzyme involve different
      subunit organizations and conformations. The highly conserved homology of PPK
      among 18 microorganisms was used to determine important residues and conserved
      regions by alanine substitution, by site-directed mutagenesis, and by deletion
      mutagenesis. Of 46 single-site mutants, seven exhibit none of the five enzymatic
      activities; in one mutant, ATP synthesis from polyP is reduced relative to GTP
      synthesis. Among deletion mutants, some lost all five PPK activities, but others
      retained partial activity for some reactions but not for others.

PMID- 10660554
TI  - Retention of subunits of the oligosaccharyltransferase complex in the endoplasmic
      reticulum.
AB  - Membrane proteins of the endoplasmic reticulum (ER) may be localized to this
      organelle by mechanisms that involve retention, retrieval, or a combination of
      both. For luminal ER proteins, which contain a KDEL domain, and for type I
      transmembrane proteins carrying a dilysine motif, specific retrieval mechanisms
      have been identified. However, most ER membrane proteins do not contain easily
      identifiable retrieval motifs. ER localization information has been found in
      cytoplasmic, transmembrane, or luminal domains. In this study, we have identified
      ER localization domains within the three type I transmembrane proteins,
      ribophorin I (RI), ribophorin II (RII), and OST48. Together with DAD1, these
      membrane proteins form an oligomeric complex that has oligosaccharyltransferase
      (OST) activity. We have previously shown that ER retention information is
      independently contained within the transmembrane and the cytoplasmic domain of
      RII, and in the case of RI, a truncated form consisting of the luminal domain was
      retained in the ER. To determine whether other domains of RI carry additional
      retention information, we have generated chimeras by exchanging individual
      domains of the Tac antigen with the corresponding ones of RI. We demonstrate here
      that only the luminal domain of RI contains ER retention information. We also
      show that the dilysine motif in OST48 functions as an ER localization motif
      because OST48 in which the two lysine residues are replaced by serine (OST48ss)
      is no longer retained in the ER and is found instead also at the plasma membrane.
      OST48ss is, however, retained in the ER when coexpressed with RI, RII, or
      chimeras, which by themselves do not exit from the ER, indicating that they may
      form partial oligomeric complexes by interacting with the luminal domain of
      OST48. In the case of the Tac chimera containing only the luminal domain of RII,
      which by itself exits from the ER and is rapidly degraded, it is retained in the
      ER and becomes stabilized when coexpressed with OST48.

PMID- 10660555
TI  - Muscle-specific transcriptional regulation of the slowpoke Ca(2+)-activated K(+)
      channel gene.
AB  - Transcriptional regulation of the Drosophila slowpoke calcium-activated potassium
      channel gene is complex. To date, five transcriptional promoters have been
      identified, which are responsible for slowpoke expression in neurons, midgut
      cells, tracheal cells, and muscle fibers. The slowpoke promoter called Promoter
      C2 is active in muscles and tracheal cells. To identify sequences that activate
      Promoter C2 in specific cell types, we introduced small deletions into the
      slowpoke transcriptional control region. Using transformed flies, we asked how
      these deletions affected the in situ tissue-specific pattern of expression.
      Sequence comparisons between evolutionarily divergent species helped guide the
      placement of these deletions. A section of DNA important for expression in all
      cell types was subdivided and reintroduced into the mutated control region, a
      piece at a time, to identify which portion was required for promoter activity. We
      identified 55-, 214-, and 20-nucleotide sequences that control promoter activity.
      Different combinations of these elements activate the promoter in adult muscle,
      larval muscle, and tracheal cells.

PMID- 10660556
TI  - Molecular structure and tissue distribution of matrilin-3, a filament-forming
      extracellular matrix protein expressed during skeletal development.
AB  - Matrilin-3 is a recently identified member of the superfamily of proteins
      containing von Willebrand factor A-like domains and is able to form hetero
      oligomers with matrilin-1 (cartilage matrix protein) via a C-terminal coiled-coil
      domain. Full-length matrilin-3 and a fragment lacking the assembly domain were
      expressed in 293-EBNA cells, purified, and subjected to biochemical
      characterization. Recombinantly expressed full-length matrilin-3 occurs as
      monomers, dimers, trimers, and tetramers, as detected by electron microscopy and
      SDS-polyacrylamide gel electrophoresis, whereas matrilin-3, purified from fetal
      calf cartilage, forms homotetramers as well as hetero-oligomers of variable
      stoichiometry with matrilin-1. In the matrix formed by cultured chondrosarcoma
      cells, matrilin-3 is found in a filamentous, collagen-dependent network
      connecting cells and in a collagen-independent pericellular network. Affinity
      purified antibodies detect matrilin-3 expression in a variety of mouse
      cartilaginous tissues, such as sternum, articular, and epiphyseal cartilage, and
      in the cartilage anlage of developing bones. It is found both inside the lacunae
      and in the interterritorial matrix of the resting, proliferating, hypertrophic,
      and calcified cartilage zones, whereas the expression is lower in the superficial
      articular cartilage. In trachea and in costal cartilage of adult mice, an
      expression was seen in the perichondrium. Furthermore, matrilin-3 is found in
      bone, and its expression is, therefore, not restricted to chondroblasts and
      chondrocytes.

PMID- 10660557
TI  - A novel family of cyclic peptide antagonists suggests that N-cadherin specificity
      is determined by amino acids that flank the HAV motif.
AB  - The classical cadherins (e.g. N-, E-, and P- cadherin) are well established
      homophilic adhesion molecules; however, the mechanism that governs cadherin
      specificity remains contentious. The classical cadherins contain an
      evolutionarily conserved His-Ala-Val (HAV) sequence, and linear peptides
      harboring this motif are capable of inhibiting a variety of cadherin-dependent
      processes. We now demonstrate that short cyclic HAV peptides can inhibit N
      cadherin function. Interestingly, the nature of the amino acids that flank the
      HAV motif determine both the activity and specificity of the peptides. For
      example, when the HAV motif is flanked by a single aspartic acid, which mimics
      the natural HAVD sequence of N-cadherin, the peptide becomes a much more
      effective inhibitor of N-cadherin function. In contrast, when the HAV motif is
      flanked by a single serine, which mimics the natural HAVS sequence of E-cadherin,
      it loses its ability to inhibit the N-cadherin response. Our results demonstrate
      that subtle changes in the amino acids that flank the HAV motif can account for
      cadherin specificity and that small cyclic peptides can inhibit cadherin
      function. An emerging role for cadherins in a number of pathological processes
      suggests that the cyclic peptides reported in this study might be developed as
      therapeutic agents.

PMID- 10660558
TI  - Role of Niemann-Pick type C1 protein in intracellular trafficking of low density
      lipoprotein-derived cholesterol.
AB  - Niemann-Pick type C (NPC) is a disease that affects intracellular cholesterol
      trafficking pathways. By cloning the hamster ortholog of NPC1, we identified the
      molecular lesions in two independently isolated Chinese hamster ovary cell
      mutants, CT60 and CT43. Both mutants lead to premature translational terminations
      of the NPC1 protein. Transfecting hamster NPC1 cDNA complemented the defects of
      the mutants. Investigation of the CT mutants, their parental cells, and an NPC1
      stable transfectant allow us to present evidence that NPC1 is involved in a post
      plasma membrane cholesterol-trafficking pathway. We found that the initial
      movement of low density lipoprotein (LDL)-derived cholesterol to the plasma
      membrane (PM) did not require NPC1. After reaching the PM and subsequent
      internalization, however, cholesterol trafficking back to the PM did involve
      NPC1. Both LDL-derived cholesterol and cholesterol originating from the PM
      accumulated in a dense, intracellular compartment in the CT mutants. Cholesterol
      movement from this compartment to the PM or endoplasmic reticulum was defective
      in the CT mutants. Our results functionally distinguish the dense, intracellular
      compartment from the early endocytic hydrolytic organelle and imply that NPC1 is
      involved in sorting cholesterol from the intracellular compartment back to the PM
      or to the endoplasmic reticulum.

PMID- 10660559
TI  - Effects of activated ADP-ribosylation factors on Golgi morphology require neither
      activation of phospholipase D1 nor recruitment of coatomer.
AB  - Nine mutations in the switch I and switch II regions of human ADP-ribosylation
      factor 3 (ARF3) were isolated from loss-of-interaction screens, using two-hybrid
      assays with three different effectors. We then analyzed the ability of the
      recombinant proteins to (i) bind guanine nucleotides, (ii) activate phospholipase
      D1 (PLD1), (iii) recruit coatomer (COP-I) to Golgi-enriched membranes, and (iv)
      expand and vesiculate Golgi in intact cells. Correlations of activities in these
      assays were used as a means of testing specific hypotheses of ARF action,
      including the role of PLD1 activation in COP-I recruitment, the role of COP-I in
      Golgi vesiculation caused by expression of the dominant activating mutant
      [Q71L]ARF3, and the need for PLD1 activation in Golgi vesiculation. Because we
      were able to find at least one example of a protein that has lost each of these
      activities with retention of the others, we conclude that activation of PLD1,
      recruitment of COP-I to Golgi, and vesiculation of Golgi in cells are
      functionally separable processes. The ability of certain mutants of ARF3 to alter
      Golgi morphology without changes in PLD1 activity or COP-I binding is interpreted
      as evidence for at least one additional, currently unidentified, effector for ARF
      action at the Golgi.

PMID- 10660560
TI  - A functional interaction between dorsal and components of the Smt3 conjugation
      machinery.
AB  - To identify proteins that regulate the function of Dorsal, a Drosophila Rel
      family transcription factor, we employed a yeast two-hybrid screen to search for
      genes encoding Dorsal-interacting proteins. Six genes were identified, including
      two that encode previously known Dorsal-interacting proteins (Twist and Cactus),
      three that encode novel proteins, and one that encodes Drosophila Ubc9 (DmUbc9),
      a protein thought to conjugate the ubiquitin-like polypeptide Smt3 to protein
      substrates. We have found that DmUbc9 binds and conjugates Drosophila Smt3
      (DmSmt3) to Dorsal. In cultured cells, DmUbc9 was found to relieve inhibition of
      Dorsal nuclear uptake by Cactus, allowing Dorsal to enter the nucleus and
      activate transcription. The effect of DmUbc9 on Dorsal activity was potentiated
      by the overexpression of DmSmt3. We have also identified a DmSmt3-activating
      enzyme, DmSAE1/DmSAE2 and found that it further potentiates Dorsal-mediated
      activation.

PMID- 10660561
TI  - Comparison of covalent with reversible inhibitor binding sites of the gastric H,K
      ATPase by site-directed mutagenesis.
AB  - The gastric H,K-ATPase is covalently inhibited by substituted pyridyl
      methylsulfinyl-benzimidazoles, such as omeprazole, that convert to thiophilic
      probes of luminally accessible cysteines in the acid space. The K(+) competitive
      inhibitor, SCH28080, prevented inhibition of acid transport by omeprazole. In
      stably expressing HEK293 cells, the benzimidazole-reactive cysteines, Cys-321
      (transmembrane helix (TM) 3), Cys-813 and Cys-822 (TM5/6), and Cys-892 (TM7/8)
      were mutated to the amino acids found in the SCH28080-resistant Na,K-ATPase and
      kinetic parameters of H,K-ATPase activity analyzed. Mutations of Cys-822 and Cys
      892 had insignificant effects on the K(i(app)), K(m(app)) or V(max), but
      mutations of Cys-813 to threonine and Cys-321 to alanine decreased the affinity
      for SCH28080. Mutation of Cys-321 to alanine produced mixed kinetics of
      inhibition, still with higher affinity for the cation-free form of phosphoenzyme.
      Since the phenylmethoxy ring of the imidazo-pyridine inhibitors binds to TM1/2,
      as shown by earlier photoaffinity studies, and the mutations in TM6 (Cys-813 -->
      Thr) as well as the end of TM3 (Cys-321 --> Ala) decrease the affinity for
      SCH28080, the TM1/2, TM3, and TM6 helices lie within approximately 16 A of each
      other based on the size of the active, extended conformation of SCH28080.

PMID- 10660562
TI  - Cloning and functional identification of a neuronal glutamine transporter.
AB  - Glutamine is the preferred precursor for the neurotransmitter pool of glutamate,
      the major excitatory transmitter in the mammalian central nervous system. We have
      isolated a complementary DNA clone (designated GlnT) encoding a plasma membrane
      glutamine transporter from glutamatergic neurons in culture, and its properties
      have been examined using the T7 vaccinia system in fibroblasts. When GlnT is
      transfected into CV-1 cells, L-glutamine is the preferred substrate. Transport is
      Na(+)-dependent and inhibited by alpha-methylaminoisobutyric acid, a specific
      inhibitor of neutral amino acid transport system A. Kinetic analysis of glutamine
      uptake by GlnT is saturable, with a Michaelis constant (K(m)) of 489 +/- 88
      microM at pH 7.4. Glutamine uptake mediated by GlnT is pH-sensitive with a 5-fold
      greater efficiency of uptake at pH 8.2 than at pH 6.6. Only the maximal velocity
      of transport increases without a significant change in K(m). The distribution of
      GlnT mRNA and protein in the central nervous system is widespread and is
      expressed on neurons that use glutamate as their neurotransmitter. In cultured
      cerebellar granule cells, GlnT is expressed only on neurons and is absent from
      astrocytes. GlnT expression increases concomitantly with the morphologic and
      functional differentiation of these cells in vitro, consistent with its role of
      supplying glutamatergic neurons with their neurotransmitter precursor. GlnT is
      the first member of the system A family of neutral amino acid transporters with
      11 putative membrane-spanning domains and is a potential target to modulate
      presynaptic glutamatergic function.

PMID- 10660563
TI  - Identification of a highly diverged class of S-adenosylmethionine synthetases in
      the archaea.
AB  - S-adenosylmethionine is the primary alkylating agent in all known organisms.
      ATP:L-methionine S-adenosyltransferase (MAT) catalyzes the only known
      biosynthetic route to this central metabolite. Although the amino acid sequence
      of MAT is strongly conserved among bacteria and eukarya, no homologs have been
      recognized in the completed genome sequences of any archaea. In this study, MAT
      has been purified to homogeneity from the archaeon Methanococcus jannaschii, and
      the gene encoding it has been identified by mass spectrometry. The peptide mass
      map identifies the gene encoding MAT as MJ1208, a hypothetical open reading
      frame. The gene was cloned in Escherichia coli, and expressed enzyme has been
      purified and characterized. This protein has only 22 and 23% sequence identity to
      the E. coli and human enzymes, respectively, whereas those are 59% identical to
      each other. The few identical residues include the majority of those constituting
      the polar active site residues. Each complete archaeal genome sequence contains a
      homolog of this archaeal-type MAT. Surprisingly, three bacterial genomes encode
      both the archaeal and eukaryal/bacterial types of MAT. This identification of a
      second major class of MAT emphasizes the long evolutionary history of the
      archaeal lineage and the structural diversity found even in crucial metabolic
      enzymes.

PMID- 10660564
TI  - The bifunctional active site of S-adenosylmethionine synthetase. Roles of the
      basic residues.
AB  - S-adenosylmethionine (AdoMet) synthetase catalyzes a unique two-step enzymatic
      reaction leading to formation of the primary biological alkylating agent. The
      crystal structure of Escherichia coli AdoMet synthetase shows that the active
      site, which lies between two subunits, contains four lysines and one histidine as
      basic residues. In order to test the proposed charge and hydrogen bonding roles
      in catalytic function, each lysine has been changed to an uncharged methionine or
      alanine, and the histidine has been altered to asparagine. The resultant enzyme
      variants are all tetramers like the wild type enzyme; however, circular dichroism
      spectra show reductions in helix content for the K245*M and K269M mutants. (The
      asterisk denotes that the residue is in the second subunit.) Four mutants have
      k(cat) reductions of approximately 10(3)-10(4)-fold in AdoMet synthesis; however,
      the k(cat) of K165*M variant is only reduced 2-fold. In each mutant, there is a
      smaller catalytic impairment in the partial reaction of tripolyphosphate
      hydrolysis. The K165*A enzyme has a 100-fold greater k(cat) for tripolyphosphate
      hydrolysis than the wild type enzyme, but this mutant is not activated by AdoMet
      in contrast to the wild type enzyme. The properties of these mutants require
      reassessment of the catalytic roles of these residues.

PMID- 10660565
TI  - Structural basis for substrate specificity of protein-tyrosine phosphatase SHP-1.
AB  - The substrate specificity of the catalytic domain of SHP-1, an important
      regulator in the proliferation and development of hematopoietic cells, is
      critical for understanding the physiological functions of SHP-1. Here we report
      the crystal structures of the catalytic domain of SHP-1 complexed with two
      peptide substrates derived from SIRPalpha, a member of the signal-regulatory
      proteins. We show that the variable beta5-loop-beta6 motif confers SHP-1
      substrate specificity at the P-4 and further N-terminal subpockets. We also
      observe a novel residue shift at P-2, the highly conserved subpocket in protein-
      tyrosine phosphatases. Our observations provide new insight into the substrate
      specificity of SHP-1.

PMID- 10660566
TI  - Characterization of a novel alanine-rich protein located in surface microdomains
      in Trypanosoma brucei.
AB  - Heterologous expression in COS cells followed by orientation-specific polymerase
      chain reaction to select and amplify cDNAs encoding surface proteins in
      Trypanosoma brucei resulted in the isolation of a cDNA ( approximately 1.4
      kilobase) which encodes an acidic, alanine-rich polypeptide that is expressed
      only in bloodstream forms of the parasite and has been termed bloodstream stage
      alanine-rich protein (BARP). Analysis of the amino acid sequence predicted the
      presence of a typical NH(2)-terminal leader sequence as well as a COOH-terminal
      hydrophobic extension with the potential to be replaced by a
      glycosylphosphatidylinositol anchor. A search of existing protein sequences
      revealed partial homology between BARP and the major surface antigen of procyclic
      forms of Trypanosoma congolense. BARP migrated as a complex, heterogeneous series
      of bands on Western blots with an apparent molecular mass ( approximately 50-70
      kDa) significantly higher than predicted from the amino acid sequence (
      approximately 26 kDa). Confocal microscopy demonstrated that BARP was present in
      small discrete spots that were distributed over the entire cellular surface.
      Detergent extraction experiments revealed that BARP was recovered in the
      detergent-insoluble, glycolipid-enriched fraction. These data suggested that BARP
      may be sequestered in lipid rafts.

PMID- 10660567
TI  - Random mutagenesis and functional analysis of the Ran-binding protein, RanBP1.
AB  - Ran GTPase is required for nucleocytoplasmic transport of many types of cargo.
      Several proteins that recognize Ran in its GTP-bound state (Ran x GTP) possess a
      conserved Ran-binding domain (RanBD). Ran-binding protein-1 (RanBP1) has a single
      RanBD and is required for RanGAP-mediated GTP hydrolysis and release of Ran from
      nuclear transport receptors (karyopherins). In budding yeast (Saccharomyces
      cerevisiae), RanBP1 is encoded by the essential YRB1 gene; expression of mouse
      RanBP1 cDNA rescues the lethality of Yrb1-deficient cells. We generated libraries
      of mouse RanBP1 mutants and examined 11 mutants in vitro and for their ability to
      complement a temperature-sensitive yrb1 mutant (yrb1-51(ts)) in vivo. In 9 of the
      mutants, the alteration was a change in a residue (or 2 residues) that is
      conserved in all known RanBDs. However, 4 of these 9 mutants displayed
      biochemical properties indistinguishable from that of wild-type RanBP1. These
      mutants bound to Ran x GTP, stimulated RanGAP, inhibited the exchange activity of
      RCC1, and rescued growth of the yrb1-51(ts) yeast cells. Two of the 9 mutants
      altered in residues thought to be essential for interaction with Ran were unable
      to rescue growth of the yrb1(ts) mutant and did not bind detectably to Ran in
      vitro. However, one of these 2 mutants (and 2 others that were crippled in other
      RanBP1 functions) retained some ability to co-activate RanGAP. A truncated form
      of RanBP1 (lacking its nuclear export signal) was able to complement the yrb1(ts)
      mutation. When driven from the YRB1 promoter, 4 of the 5 mutants most impaired
      for Ran binding were unable to rescue growth of the yrb1(ts) cells; remarkably,
      these mutants could nevertheless form ternary complexes with importin-5 or
      importin-beta and Ran-GTP. The same mutants stimulated only inefficiently RanGAP
      mediated GTP hydrolysis of the Ran x GTP x importin-5 complex. Thus, the
      essential biological activity of RanBP1 in budding yeast correlates not with Ran
      x GTP binding per se or with the ability to form ternary complexes with
      karyopherins, but with the capacity to potentiate RanGAP activity toward GTP
      bound Ran in these complexes.

PMID- 10660568
TI  - Serine 380 (P14) --> glutamate mutation activates antithrombin as an inhibitor of
      factor Xa.
AB  - Heparin regulates the inhibitory activity of antithrombin. It has been proposed
      that residues P15 and P14 are expelled from beta-sheet A of antithrombin by
      heparin binding, permitting better interaction of the reactive center loop with
      factor Xa. We have made a P14 antithrombin variant (S380E) to create an activated
      inhibitory form of antithrombin in which P14 is already expelled from beta-sheet
      A. S380E antithrombin fluorescence is enhanced 35 +/- 5% compared with control
      antithrombin. There is minimal further increase in antithrombin fluorescence upon
      heparin binding. The variant has a 5 degrees C lower T(m) than control
      antithrombin. The variant is an inhibitor of proteinases and has a nearly 200
      fold increased basal rate of inhibition of factor Xa, after correction for an
      increased stoichiometry of inhibition. This is comparable to that of antithrombin
      activated by high affinity heparin pentasaccharide. Full-length high affinity
      heparin causes only a 7-fold additional increase in rate and a large increase in
      stoichiometry of inhibition. In contrast, the basal rate of inhibition of
      thrombin is similar to that of control antithrombin but is increased 300-fold by
      heparin. These findings suggest that the native state of the S380E variant exists
      in a loop-expelled conformation that is consequently highly reactive toward
      factor Xa.

PMID- 10660569
TI  - Mutational analysis of Escherichia coli topoisomerase IV. I. Selection of
      dominant-negative parE alleles.
AB  - In order to define regions of ParE, one of the two subunits of topoisomerase IV,
      that are involved in catalysis during topoisomerization, we developed a selection
      procedure to isolate dominant-negative parE alleles. Both wild-type parC and
      mutagenized parE were expressed from a tightly-regulated lac promoter on a
      moderate-copy plasmid. Mutated parE alleles were rescued from those plasmids that
      caused IPTG-dependent cell death. The mutant ParE proteins could be divided into
      two groups when reconstituted with ParC to form topoisomerase IV, those that
      elicited hyper-DNA cleavage and those that affected covalent complex formation.

PMID- 10660570
TI  - Mutational analysis of Escherichia coli topoisomerase IV. II. ATPase negative
      mutants of parE induce hyper-DNA cleavage.
AB  - ParE is the ATP-binding subunit of topoisomerase IV (Topo IV). During
      topoisomerization, the ATP-binding and hydrolysis cycle must be coordinated with
      the cycle of DNA cleavage and religation. We have isolated three dominant
      negative mutant alleles of parE that encode ParE proteins that fail to hydrolyze
      ATP when reconstituted with ParC to form Topo IV. ParE G110S Topo IV and ParE
      S123L Topo IV failed to bind ATP at all, whereas ParE T201A could bind ATP. All
      three mutant Topo IV proteins exhibited an elevated level of spontaneous DNA
      cleavage that could be associated with a decreased rate of DNA resealing. In ParE
      T201A Topo IV, this defect appeared to result from an increased likelihood that
      the tetrameric enzyme would fall apart after DNA cleavage. Thus, while ATP is not
      required for DNA cleavage, the properties of these mutant enzymes suggests that
      ATP-hydrolysis informs DNA religation.

PMID- 10660571
TI  - Mutational analysis of Escherichia coli topoisomerase IV. III. Identification of
      a region of parE involved in covalent catalysis.
AB  - The products of three dominant-negative alleles of parE, encoding the ATP-binding
      subunit of topoisomerase IV (Topo IV), were purified and their activities
      characterized when reconstituted with ParC to form Topo IV. The ability of the
      ParE E418K, ParE G419D, and ParE G442D mutant Topo IVs to bind DNA, hydrolyze
      ATP, and close their ATP-dependent clamp was relatively unaffected. However,
      their ability to relax negatively supercoiled DNA was compromised significantly.
      This could be attributed to severe defects in covalent complex formation between
      ParC and DNA. Thus, these residues, which are far from the active site Tyr of
      ParC, contribute to covalent catalysis. This indicates that a dramatic
      conformational rearrangement of the protein likely occurs subsequent to the
      binding of the G segment at the DNA gate and prior to its opening.

PMID- 10660572
TI  - Formation of 20-hydroxyeicosatetraenoic acid, a vasoactive and natriuretic
      eicosanoid, in human kidney. Role of Cyp4F2 and Cyp4A11.
AB  - 20-hydroxyeicosatetraenoic acid (20-HETE), an omega-hydroxylated arachidonic acid
      (AA) metabolite, elicits specific effects on kidney vascular and tubular function
      that, in turn, influence blood pressure control. The human kidney's capacity to
      convert AA to 20-HETE is unclear, however, as is the underlying P450 catalyst.
      Microsomes from human kidney cortex were found to convert AA to a single major
      product, namely 20-HETE, but failed to catalyze AA epoxygenation and midchain
      hydroxylation. Despite the monophasic nature of renal AA omega-hydroxylation
      kinetics, immunochemical studies revealed participation of two P450s, CYP4F2 and
      CYP4A11, since antibodies to these enzymes inhibited 20-HETE formation by 65. 9
      +/- 17 and 32.5 +/- 14%, respectively. Western blotting confirmed abundant
      expression of these CYP4 proteins in human kidney and revealed that other AA
      oxidizing P450s, including CYP2C8, CYP2C9, and CYP2E1, were not expressed.
      Immunocytochemistry showed CYP4F2 and CYP4A11 expression in only the S2 and S3
      segments of proximal tubules in cortex and outer medulla. Our results demonstrate
      that CYP4F2 and CYP4A11 underlie conversion of AA to 20-HETE, a natriuretic and
      vasoactive eicosanoid, in human kidney. Considering their proximal tubular
      localization, these P450 enzymes may partake in pivotal renal functions,
      including the regulation of salt and water balance, and arterial blood pressure
      itself.

PMID- 10660573
TI  - Interaction of Pex5p, the type 1 peroxisome targeting signal receptor, with the
      peroxisomal membrane proteins Pex14p and Pex13p.
AB  - Pex5p, a receptor for peroxisomal matrix proteins with a type 1 peroxisome
      targeting signal (PTS1), has been proposed to cycle from the cytoplasm to the
      peroxisomal membrane where it docks with Pex14p and Pex13p, the latter an SH3
      domain-containing protein. Using in vitro binding assays we have demonstrated
      that binding of Pex5p to Pex14p is enhanced when Pex5p is loaded with a PTS1
      containing peptide. In contrast, Pex5p binding to Pex13p, which involves only the
      SH3 domain, occurs at 20-40-fold lower levels and is reduced when Pex5p is
      preloaded with a PTS1 peptide. Pex14p was also shown to bind weakly to the Pex13p
      SH3 domain. Site-directed mutagenesis of the Pex13p SH3 domain attenuated binding
      to Pex5p and Pex14p, consistent with both of these proteins being binding
      partners for this domain. The SH3 binding site in Pex5p was determined to lie
      within a 114-residue peptide (Trp(100)-Glu(213)) in the amino-terminal region of
      the protein. The interaction between this peptide and the SH3 domain was
      competitively inhibited by Pex14p. We interpret these data as suggesting that
      docking of the Pex5p-PTS1 protein complex at the peroxisome membrane occurs at
      Pex14p and that the Pex13p SH3 domain functions as an associated component
      possibly involved in sequestering Pex5p after relinquishment of the PTS1 protein
      cargo to components of the translocation machinery.

PMID- 10660574
TI  - Identification and characterization of a novel Golgi protein, golgin-67.
AB  - In the course of screening a lambdagt11 human leukemic T-cell cDNA expression
      library with an antibody specific to the mitotic target of Src, Sam68, we
      identified and cloned a cDNA encoding a novel protein with a predicted molecular
      mass of 51.4 kDa. Polyclonal antibodies raised to a His(6)-tagged construct of
      this protein, detected a approximately 67-kDa protein in immunoprecipitation
      experiments, and cytological studies showed that this protein localized to the
      Golgi complex, through colocalization experiments with specific Golgi markers.
      Therefore, we designated this protein golgin-67. Sequence analysis revealed that
      golgin-67 is a highly coiled-coil protein, with potential Cdc2 and Src kinase
      phosphorylation motifs. It has sequence homologies to other Golgi proteins,
      including the coatamer complex I vesicle docking protein, GM130. Structurally,
      golgin-67 resembles, golgin-84, an integral membrane Golgi protein with an N
      terminal coiled-coil domain and a single C-terminal transmembrane domain. The C
      terminal region of golgin-67, which contains a predicted transmembrane domain,
      was demonstrated to be essential for its Golgi localization.

PMID- 10660575
TI  - Follicle-stimulating hormone inhibits all-trans-retinoic acid-induced retinoic
      acid receptor alpha nuclear localization and transcriptional activation in mouse
      Sertoli cell lines.
AB  - The regulation of retinoic acid receptor alpha (RARalpha) signal transduction has
      not been well characterized. In this study, we determined whether all-trans
      retinoic acid (tRA) and follicle-stimulating hormone (FSH) modulate RARalpha
      receptor subcellular localization, leading to changes in its transcriptional
      activity and protein expression in mouse Sertoli cell lines. We found that tRA
      induced the nuclear localization of RARalpha within 30 min and that longer term
      exposure increased the receptor transcriptional activity and RARalpha protein
      expression. Conversely, FSH suppressed the tRA-induced nuclear localization,
      transcriptional transactivation, and protein expression of RARalpha. Treatment
      with two different protein kinase A-selective antagonists reversed the inhibitory
      actions of FSH on tRA-dependent RARalpha nuclear localization and transcriptional
      activity. These results are consistent with the involvement of protein kinase A
      in mediating the inhibitory effects of FSH. For the first time, we demonstrate a
      unique signaling convergence between the RARalpha and the FSH-mediated signaling
      pathways, which may have significant implications in the testis because both are
      critical regulators of testis physiology.

PMID- 10660576
TI  - Nucleolin, a novel partner for the Myb transcription factor family that regulates
      their activity.
AB  - To unravel the mechanisms of action of transcriptional regulation by the Myb
      family of transcription factors, we have set out to isolate their protein
      partners. We identify nucleolin as one of the nuclear polypeptides that interact
      specifically with the A-Myb and c-Myb, but not B-Myb DNA-binding domains. We show
      unambiguously that this interaction is direct and takes place in vivo, as
      demonstrated by co-immunoprecipitation of the endogenously and exogenously
      expressed proteins. The minimal DNA-binding domain containing only the R2R3 c-Myb
      repeats is sufficient for nucleolin binding. Computer analysis of the R2R3 three
      dimensional structure, as well as extensive mutational analysis within this
      region, reveals that the Arg(161) residue, present in c-Myb and A-Myb, but not B
      Myb, is crucial for this interaction. We show that the interaction of nucleolin
      with Myb is functional because co-transfection of nucleolin down-regulates Myb
      transcriptional activity. Nucleolin is a multifunctional phosphoprotein present
      in both nucleoplasm and more abundantly in the nucleolus and shows helicase and
      chromatin decondensing activities. This is the first demonstration of nucleolin
      binding to a transcription factor.

PMID- 10660577
TI  - HIV-1 Tat-mediated inhibition of the tyrosine hydroxylase gene expression in
      dopaminergic neuronal cells.
AB  - Treatment of dopaminergic rat PC12 cells with human immunodeficiency virus, type
      1 (HIV-1) Tat protein or tat cDNA inhibited the expression of tyrosine
      hydroxylase (TH), the rate-limiting enzyme for the dopamine biosynthetic pathway,
      as well as the production and release of dopamine into the culture medium.
      Moreover, the Tat addition to PC12 cells up-regulated the expression of the
      inducible cAMP early repressor (ICER), a specific member of the cAMP-responsive
      element modulator transcription factor family, in a cAMP-dependent manner. In
      turn, ICER overexpression abrogated the transcription activity of the TH promoter
      in PC12 cells, strongly suggesting ICER involvement in Tat-mediated inhibition of
      TH gene expression. In vivo injection of synthetic HIV-1 Tat protein into the
      striatum of healthy rats induced a subclinical Parkinson's-like disease that
      became manifested only when the animals were treated with amphetamine. As early
      as one week postinjection, the histochemical examination of the rat substantia
      nigra showed a reduced staining of neurons expressing TH followed by a loss of
      TH(+) neurons at later time points. As Tat protein can be locally released into
      the central nervous system by HIV-1-infected microglial cells, our findings may
      contribute to the explanation of the pathogenesis of the motorial abnormalities
      often reported in HIV-1 seropositive individuals.

PMID- 10660578
TI  - Coupling of the muscarinic m2 receptor to G protein-activated K(+) channels via
      Galpha(z) and a receptor-Galpha(z) fusion protein. Fusion between the receptor
      and Galpha(z) eliminates catalytic (collision) coupling.
AB  - G protein-activated K(+) channel (GIRK), which is activated by the G(betagamma)
      subunit of heterotrimeric G proteins, and muscarinic m2 receptor (m2R) were
      coexpressed in Xenopus oocytes. Acetylcholine evoked a K(+) current, I(ACh), via
      the endogenous pertussis toxin (PTX)-sensitive G(i/o) proteins. Activation of
      I(ACh) was accelerated by increasing the expression of m2R, suggesting a
      collision coupling mechanism in which one receptor catalytically activates
      several G proteins. Coexpression of the alpha subunit of the PTX-insensitive G
      protein G(z), Galpha(z), induced a slowly activating PTX-insensitive I(ACh),
      whose activation kinetics were also compatible with the collision coupling
      mechanism. When GIRK was coexpressed with an m2R x Galpha(z) fusion protein
      (tandem), in which the C terminus of m2R was tethered to the N terminus of
      Galpha(z), part of I(ACh) was still eliminated by PTX. Thus, the m2R of the
      tandem activates the tethered Galpha(z) but also the nontethered G(i/o) proteins.
      After PTX treatment, the speed of activation of the m2R x Galpha(z)-mediated
      response did not depend on the expression level of m2R x Galpha(z) and was faster
      than when m2R and Galpha(z) were coexpressed as separate proteins. These results
      demonstrate that fusing the receptor and the Galpha strengthens their coupling,
      support the collision-coupling mechanism between m2R and the G proteins, and
      suggest a noncatalytic (stoichiometric) coupling between the G protein and GIRK
      in this model system.

PMID- 10660579
TI  - HIV-2 and SIV nef proteins target different Src family SH3 domains than does HIV
      1 Nef because of a triple amino acid substitution.
AB  - The nef gene is required for optimal viral spread of human and simian
      immunodeficiency viruses. However, the molecular mechanisms underlying the action
      of the Nef proteins may not be identical for all viral families. Here we
      investigate the interaction between the Nef protein of human and simian
      immunodeficiency viruses and SH3 domains from Src family kinases. Using the yeast
      two-hybrid system and immunoblotting we show that, in contrast to HIV-1 Nef, SIV
      and HIV-2 Nef poorly interact with Hck SH3 but bind to Src and Fyn SH3 domains.
      The molecular basis of these differences in SH3 targeting was revealed by
      sequence analysis and homology modeling of the putative SH3-Nef structures. Three
      amino acids (Trp-113, Thr-117, and Gln-118) that localize in a "hydrophobic
      pocket" implicated in SH3 binding of HIV-1 Nef, are systematically substituted in
      SIV/HIV-2 alleles (by Tyr, Glu, and Glu, respectively). We demonstrate that site
      directed mutagenesis of these residues in SIV(mac239) Nef suffices to restore Hck
      SH3 binding and co-immunoprecipitation with full-length Hck from transfected
      cells. Our findings identify fundamental mechanistic differences in targeting of
      Src family kinases by HIV and SIV Nef. The herein described mechanism of SH3
      selection by Nef via a "pocket" proximal to the canonical proline-rich motif may
      be a common feature for SH3 recognition by their natural ligands.

PMID- 10660580
TI  - Catalytic activities of mitochondrial ATP synthase in patients with mitochondrial
      DNA T8993G mutation in the ATPase 6 gene encoding subunit a.
AB  - We investigated the biochemical phenotype of the mtDNA T8993G point mutation in
      the ATPase 6 gene, associated with neurogenic muscle weakness, ataxia, and
      retinitis pigmentosa (NARP), in three patients from two unrelated families. All
      three carried >80% mutant genome in platelets and were manifesting clinically
      various degrees of the NARP phenotype. Coupled submitochondrial particles
      prepared from platelets capable of succinate-sustained ATP synthesis were studied
      using very sensitive and rapid luminometric and fluorescence methods. A sharp
      decrease (>95%) in the succinate-sustained ATP synthesis rate of the particles
      was found, but both the ATP hydrolysis rate and ATP-driven proton translocation
      (when the protons flow from the matrix to the cytosol) were minimally affected.
      The T8993G mutation changes the highly conserved residue Leu(156) to Arg in the
      ATPase 6 subunit (subunit a). This subunit, together with subunit c, is thought
      to cooperatively catalyze proton translocation and rotate, one with respect to
      the other, during the catalytic cycle of the F(1)F(0) complex. Our results
      suggest that the T8993G mutation induces a structural defect in human F(1)F(0)
      ATPase that causes a severe impairment of ATP synthesis. This is possibly due to
      a defect in either the vectorial proton transport from the cytosol to the
      mitochondrial matrix or the coupling of proton flow through F(0) to ATP synthesis
      in F(1). Whatever mechanism is involved, this leads to impaired ATP synthesis. On
      the other hand, ATP hydrolysis that involves proton flow from the matrix to the
      cytosol is essentially unaffected.

PMID- 10660581
TI  - Heparan sulfate proteoglycans as extracellular docking molecules for matrilysin
      (matrix metalloproteinase 7).
AB  - Many matrix metalloproteinases (MMPs) are tightly bound to tissues; matrilysin
      (MMP-7), although the smallest of the MMPs, is one of the most tightly bound. The
      most likely docking molecules for MMP-7 are heparan sulfate proteoglycans on or
      around epithelial cells and in the underlying basement membrane. This is
      established by extraction experiments and confocal microscopy. The enzyme is
      extracted from homogenates of postpartum rat uterus by heparin/heparan sulfate
      and by heparinase III treatment. The enzyme is colocalized with heparan sulfate
      in the apical region of uterine glandular epithelial cells and can be released by
      heparinase digestion. Heparan sulfate and MMP-7 are expressed at similar stages
      of the rat estrous cycle. The strength of heparin binding by recombinant rat
      proMMP-7 was examined by affinity chromatography, affinity coelectrophoresis, and
      homogeneous enzyme-based binding assay; the K(D) is 5-10 nM. Zymographic
      measurement of MMP-7 activity is greatly enhanced by heparin. Two putative
      heparin-binding peptides have been identified near the C- and N-terminal regions
      of proMMP-7; however, molecular modeling suggests a more extensive binding track
      or cradle crossing multiple peptide strands. Evidence is also found for the
      binding of MMP-2, -9, and -13. Binding of MMP-7 and other MMPs to heparan sulfate
      in the extracellular space could prevent loss of secreted enzyme, provide a
      reservoir of latent enzyme, and facilitate cellular sensing and regulation of
      enzyme levels. Binding to the cell surface could position the enzyme for directed
      proteolytic attack, for activation of or by other MMPs and for regulation of
      other cell surface proteins. Dislodging MMPs by treatment with compounds such as
      heparin might be beneficial in attenuating excessive tissue breakdown such as
      occurs in cancer metastasis, arthritis, and angiogenesis.

PMID- 10660582
TI  - Inhibition of protein phosphatase-1 by clavosines A and B. Novel members of the
      calyculin family of toxins.
AB  - Site-directed mutagenesis was used to investigate the mechanism of interaction
      between the catalytic subunit of human protein phosphatase-1 (PP-1cgamma) and
      members of the calyculin family of toxins. Clavosines A and B are related to
      calyculins but are glycosylated with a trimethoxy rhamnose group. We provide
      experimental evidence implicating Tyr-134 as an important residue in PP-1cgamma
      that mediates interactions with the calyculins. Mutation of Tyr-134 to Phe, to
      prevent hydrogen bond formation, resulted in a slight increase in sensitivity of
      PP-1cgamma to clavosines A and B and calyculin A. In contrast, a Y134A mutant was
      10-fold less sensitive to inhibition by all three inhibitors. The greatest effect
      on inhibition was found by substituting an Asp for Tyr-134 in the phosphatase.
      Clavosine B inhibited PP-1cgamma Y134D with a 310-fold decrease in potency.
      Clavosine A and calyculin A were also markedly poorer inhibitors of this mutant.
      These results suggest that a hydrogen bond between Tyr-134 and the calyculins is
      unlikely to be essential for inhibitor binding to the phosphatase. The clavosines
      and calyculin A were tested for their ability to inhibit other mutants of PP
      1cgamma (including Ile-133, Val-223, and Cys-291). Our mutagenesis studies
      provide an experimental basis for assessing models of calyculin binding found in
      the literature (Lindvall, M. K., Pihko, P. M., and Koskinen, A. M. (1997) J.
      Biol. Chem. 272, 23312-23316; Gupta, V., Ogawa, A. K., Du, X., Houk, K. N., and
      Armstrong, R. W. (1997) J. Med. Chem. 40, 3199-3206; Gauss, C. M., Sheppeck, I.
      J., Nairn, A. C., and Chamberlain, R. (1997) Bioorg. Med. Chem. 5, 1751-1773). A
      new model for clavosine and calyculin A binding to PP-1c is presented that is
      consistent with previous structure-function experiments and which accommodates
      key structural features of the clavosines, including the novel rhamnose moiety.

PMID- 10660583
TI  - Ca(2+) binding and energy coupling in the calmodulin-myosin light chain kinase
      complex.
AB  - We have previously shown that 3 Ca(2+) ions are released cooperatively and 1
      independently from the complex between (Ca(2+))4-calmodulin and skeletal muscle
      myosin light chain kinase or a peptide containing its core calmodulin-binding
      sequence. We now have found that three Ca(2+)-binding sites also function
      cooperatively in equilibrium Ca(2+) binding to these complexes. Replacement of
      sites I and II in calmodulin by a copy of sites III and IV abolishes these
      cooperative effects. Energy coupling-dependent increases in Ca(2+)-binding
      affinity in the mutant and native calmodulin complexes with enzyme are
      considerably less than in the peptide complexes, although the complexes have
      similar affinities. Ca(2+) binding to three sites in the native calmodulin-enzyme
      complex is enhanced; the affinity of the remaining site is slightly reduced. In
      the mutant enzyme complex Ca(2+) binding to one pair of sites is enhanced; the
      other pair is unaffected. In this complex reversal of enzyme activation occurs
      when Ca(2+) dissociates from the pair of sites with enhanced affinity; more rapid
      dissociation from the other pair has no effect, although both pairs participate
      in activation. Ca(2+)-independent interactions with calmodulin clearly play a
      major role in the enzyme complex, and appear to weaken Ca(2+)-dependent
      interactions with the core calmodulin-binding sequence.

PMID- 10660584
TI  - Mapping the collagen-binding site in the I domain of the glycoprotein Ia/IIa
      (integrin alpha(2)beta(1)).
AB  - The I domain present within the alpha2 chain of the integrin alpha(2)beta(1)
      (GPIa/IIa) contains the principal collagen-binding site. Based on the crystal
      structure of the alpha2-I domain, a hypothetical model was proposed in which
      collagen binds to a groove on the upper surface of the I domain (Emsley, J.,
      King, S. L., Bergelson, J. M., and Liddington, R. C. (1997) J. Biol. Chem. 272,
      28512-28517). We have introduced point mutations into 13 residues on the upper
      surface of the domain. Recombinant mutant proteins were assayed for binding to
      monoclonal antibodies 6F1 and 12F1, to collagen under static conditions, and for
      the ability to retain adhesive activity under flow conditions. The mutations to
      residues surrounding the metal ion-dependent adhesion site that caused the
      greatest loss of collagen binding under both static and flow conditions are N154S
      in the betaA-alpha1 turn, N190D in the betaB-betaC turn, D219R in the alpha3
      alpha4 turn, and E256V and H258V in the betaD-alpha5 turn. Mutation in one of the
      residues that coordinate the metal binding, S155A, completely lost the adhesive
      activity under flow but bound normally under static conditions, whereas the
      mutation Y285F had the converse effect. We conclude that the upper surface of the
      domain, including the metal ion-dependent adhesion site motif, defines the
      collagen recognition site.

PMID- 10660585
TI  - Low resolution structure of the sigma54 transcription factor revealed by X-ray
      solution scattering.
AB  - The sigma54 RNA polymerase holoenzyme functions in enhancer-dependent
      transcription. The structural organization of the sigma54 subunit of bacterial
      RNA polymerase in solution is analyzed by synchrotron x-ray scattering.
      Scattering patterns are collected from the full-length protein and from a large
      fragment able to bind the core RNA polymerase, and their low resolution shapes
      are restored using two ab initio shape determination techniques. The sigma54
      subunit is a highly elongated particle, and the core binding fragment can be
      unambiguously positioned inside the full-length protein. The boomerang-like shape
      of the core binding fragment is similar to that of the atomic model of a fragment
      of the Escherichia coli sigma70 protein, indicating that, although the sigma54
      and sigma70 factors are unrelated by primary sequence, they may share some
      structural similarity. Potential DNA binding surfaces of sigma54 are also
      predicted by comparison with the sigma54 core binding fragment.

PMID- 10660586
TI  - Regulation of P311 expression by Met-hepatocyte growth factor/scatter factor and
      the ubiquitin/proteasome system.
AB  - P311 is a mouse cDNA originally identified for its high expression in late-stage
      embryonic brain and adult cerebellum, hippocampus, and olfactory bulb. The
      protein product of P311, however, had not been identified previously, and its
      function remains unknown. We report here that P311 expression is regulated at
      multiple levels by pathways that control cellular transformation. P311 mRNA
      expression was decreased sharply in both neural and smooth muscle cells when the
      cells were transformed by coexpression of the oncogenic tyrosine kinase receptor
      Met and its ligand hepatocyte growth factor/scatter factor. The P311 mRNA was
      found to encode an 8-kDa polypeptide that was subject to rapid degradation by the
      lactacystin-sensitive ubiquitin/proteasome system and an unidentified
      metalloprotease, resulting in a protein half-life of about 5 min. These data
      suggest that P311 expression is dramatically decreased by several pathways that
      regulate cellular growth.

PMID- 10660587
TI  - Critical role of micelles in pancreatic lipase activation revealed by small angle
      neutron scattering.
AB  - In the duodenum, pancreatic lipase (PL) develops its activity on triglycerides by
      binding to the bile-emulsified oil droplets in the presence of its protein
      cofactor pancreatic colipase (PC). The neutron crystal structure of a PC-PL
      micelle complex (Hermoso, J., Pignol, D., Penel, S., Roth, M., Chapus, C., and
      Fontecilla-Camps, J. C. (1997) EMBO J. 16, 5531-5536) has suggested that the
      stabilization of the enzyme in its active conformation and its adsorption to the
      emulsified oil droplets are mediated by a preformed lipase-colipase-micelle
      complex. Here, we correlate the ability of different amphypathic compounds to
      activate PL, with their association with PC-PL in solution. The method of small
      angle neutron scattering with D(2)O/H(2)O contrast variation was used to
      characterize a solution containing PC-PL complex and taurodeoxycholate micelles.
      The resulting radius of gyration (56 A) and the match point of the solution
      indicate the formation of a ternary complex that is similar to the one observed
      in the neutron crystal structure. In addition, we show that either bile salts,
      lysophospholipids, or nonionic detergents that form micelles with radii of
      gyration ranging from 13 to 26 A are able to bind to the PC-PL complex, whereas
      smaller micelles or nonmicellar compounds are not. This further supports the
      notion of a micelle size-dependent affinity process for lipase activation in
      vivo.

PMID- 10660588
TI  - Structure of the influenza C virus CM2 protein transmembrane domain obtained by
      site-specific infrared dichroism and global molecular dynamics searching.
AB  - The 115-residue protein CM2 from Influenza C virus has been recently
      characterized as a tetrameric integral membrane glycoprotein. Infrared
      spectroscopy and site-directed infrared dichroism were utilized here to determine
      its transmembrane structure. The transmembrane domain of CM2 is alpha-helical,
      and the helices are tilted by beta = (14.6 +/- 3.0) degrees from the membrane
      normal. The rotational pitch angle about the helix axis omega for the 1-(13)C
      labeled residues Gly(59) and Leu(66) is omega = (218 +/- 17) degrees, where omega
      is defined as zero for a residue pointing in the direction of the helix tilt. A
      detailed structure was obtained from a global molecular dynamics search utilizing
      the orientational data as an energy refinement term. The structure consists of a
      left-handed coiled-coil with a helix crossing angle of Omega = 16 degrees. The
      putative transmembrane pore is occluded by the residue Met(65). In addition
      hydrogen/deuterium exchange experiments show that the core is not accessible to
      water.

PMID- 10660589
TI  - Structure-activity relationship study of antimicrobial dermaseptin S4 showing the
      consequences of peptide oligomerization on selective cytotoxicity.
AB  - To understand how peptide organization in aqueous solution might affect the
      activity of antimicrobial peptides, the potency of various dermaseptin S4 analogs
      was assessed against human red blood cells (RBC), protozoa, and several Gram
      negative bacteria. Dermaseptin S4 had weak antibacterial activity but potent
      hemolytic or antiprotozoan effects. K(4)K(20)-S4 was 2-3-fold more potent against
      protozoa and RBC, yet K(4)K(20)-S4 was more potent by 2 orders of magnitude
      against bacteria. K(4)-S4 had similar behavior as K(4)K(20)-S4, but K(20)-S4 and
      analogous negative charge substitutions were as active as dermaseptin S4 or had
      reduced activity. Binding experiments suggested that potency enhancement was not
      the result of increased affinity to target cells. In contrast, potency correlated
      well with aggregation properties. Fluorescence studies indicated that K(20)-S4
      and all negative charge substitutions were as aggregated as dermaseptin S4,
      whereas K(4)-S4 and K(4)K(20)-S4 were clearly less aggregated. Overall, the data
      indicated that N-terminal domain interaction between dermaseptin S4 monomers is
      responsible for the peptide's oligomerization in solution and, hence, for its
      limited spectrum of action. Moreover, bell-shaped dose-response profiles obtained
      with bacteria but not with protozoa or RBC implied that aggregation can have
      dramatic consequences on antibacterial activity. Based on these results, we
      tested the feasibility of selectivity reversal in the activity of dermaseptin S4.
      Tampering with the composition of the hydrophobic domains by reducing
      hydrophobicity or by increasing the net positive charge affected dramatically the
      peptide's activity and resulted in various analogs that displayed potent
      antibacterial activity but reduced hemolytic activity. Among these, maximal
      antibacterial activity was displayed by a 15-mer version that was more potent by
      2 orders of magnitude compared with native dermaseptin S4. These results
      emphasize the notion that peptide-based antibiotics represent a highly modular
      synthetic antimicrobial system and provide indications of how the peptide's
      physico-chemical properties affect potency and selectivity.

PMID- 10660590
TI  - Interaction of Xenopus Cdc2 x cyclin A1 with the origin recognition complex.
AB  - The initiation of DNA replication in eukaryotes is regulated in a minimum of at
      least two ways. First, several proteins, including origin recognition complex
      (ORC), Cdc6 protein, and the minichromosome maintenance (MCM) protein complex,
      need to be assembled on chromatin before initiation. Second, cyclin-dependent
      kinases regulate DNA replication in both a positive and a negative way by
      inducing the initiation of DNA replication at G(1)/S transition and preventing
      further rounds of origin firing within the same cell cycle. Here we characterize
      a link between the two levels. Immunoprecipitation of Xenopus origin recognition
      complex with anti-XOrc1 or anti-XOrc2 antibodies specifically co
      immunoprecipitates a histone H1 kinase activity. The kinase activity is sensitive
      to several inhibitors of cyclin-dependent kinases including 6-dimethylaminopurine
      (6-DMAP), olomoucine, and p21(Cip1). This kinase activity also copurifies with
      ORC over several fractionation steps and was identified as a complex of the Cdc2
      catalytic subunit and cyclin A1. Neither Cdk2 nor cyclin E could be detected in
      ORC immunoprecipitations. Reciprocal immunoprecipitations with anti-Xenopus Cdc2
      or anti-Xenopus cyclin A1 antibodies specifically co-precipitate XOrc1 and XOrc2.
      Our results indicate that Xenopus ORC and Cdc2 x cyclin A1 physically interact
      and demonstrate a physical link between an active cyclin-dependent kinase and
      proteins involved in the initiation of DNA replication.

PMID- 10660591
TI  - Regulation of inducible cAMP early repressor expression by gastrin and
      cholecystokinin in the pancreatic cell line AR42J.
AB  - The CREM gene encodes both activators and repressors of cAMP-induced
      transcription. Inducible cAMP early repressor (ICER) isoforms are generated upon
      activation of an alternative, intronic promoter within the CREM gene. ICER is
      proposed to down-regulate both its own expression and the expression of other
      genes that contain cAMP-responsive elements such as a number of growth factors.
      Thus, ICER has been postulated to play a role in proliferation and
      differentiation. Here we show that ICER gene expression is induced by gastrin,
      cholecystokinin (CCK), and epidermal growth factor in AR42J cells. The time
      course of gastrin- and CCK-mediated ICER induction is rapid and transient,
      similar to forskolin- and phorbol 12-myristate 13-acetate-induced ICER
      expression. The specific CCK-B receptor antagonist L740,093 blocks the gastrin
      but not the CCK response, indicating that both the CCK-B and the CCK-A receptor
      can mediate ICER gene activation. Noteworthy, CREB is constitutively
      phosphorylated at Ser-133 in AR42J cells, and ICER induction proceeds in the
      absence of increased CREB Ser(P)-133. Gastrin-mediated ICER induction was not
      reduced in the presence of the protein kinase A inhibitor H-89, indicating a
      protein kinase A-independent mechanism. This is the first report on ICER
      inducibility via G(q)/G(11) protein-coupled receptors.

PMID- 10660592
TI  - Modification defect at anticodon wobble nucleotide of mitochondrial
      tRNAs(Leu)(UUR) with pathogenic mutations of mitochondrial myopathy,
      encephalopathy, lactic acidosis, and stroke-like episodes.
AB  - The mitochondrial tRNA(Leu)(UUR) (R = A or G) gene possesses several hot spots
      for pathogenic mutations. A point mutation at nucleotide position 3243 or 3271 is
      associated with mitochondrial myopathy, encephalopathy, lactic acidosis, and
      stroke-like episodes and maternally inherited diabetes with deafness. Detailed
      studies on two tRNAs(Leu)(UUR) with the 3243 or 3271 mutation revealed some
      common characteristics in cybrid cells: (i) a decreased life span, resulting in a
      70% decrease in the amounts of the tRNAs in the steady state, (ii) a slight
      decrease in the ratios of aminoacyl-tRNAs(Leu)(UUR) versus uncharged
      tRNAs(Leu)(UUR), and (iii) accurate aminoacylation with leucine without any
      misacylation. As a marked result, both of the mutant tRNA molecules were
      deficient in a modification of uridine that occurs in the normal tRNA(Leu)(UUR)
      at the first position of the anticodon. The lack of this modification may lead to
      the mistranslation of leucine into non-cognate phenylalanine codons by mutant
      tRNAs(Leu)(UUR), according to the mitochondrial wobble rule, and/or a decrease in
      the rate of mitochondrial protein synthesis. This finding could explain why two
      different mutations (3243 and 3271) manifest indistinguishable clinical features.

PMID- 10660593
TI  - TFIIH with inactive XPD helicase functions in transcription initiation but is
      defective in DNA repair.
AB  - TFIIH is a multisubunit protein complex involved in RNA polymerase II
      transcription and nucleotide excision repair, which removes a wide variety of DNA
      lesions including UV-induced photoproducts. Mutations in the DNA-dependent
      ATPase/helicase subunits of TFIIH, XPB and XPD, are associated with three
      inherited syndromes as follows: xeroderma pigmentosum with or without Cockayne
      syndrome and trichothiodystrophy. By using epitope-tagged XPD we purified
      mammalian TFIIH carrying a wild type or an active-site mutant XPD subunit.
      Contrary to XPB, XPD helicase activity was dispensable for in vitro
      transcription, catalytic formation of trinucleotide transcripts, and promoter
      opening. Moreover, in contrast to XPB, microinjection of mutant XPD cDNA did not
      interfere with in vivo transcription. These data show directly that XPD activity
      is not required for transcription. However, during DNA repair, neither 5' nor 3'
      incisions in defined positions around a DNA adduct were detected in the presence
      of TFIIH containing inactive XPD, although substantial damage-dependent DNA
      synthesis was induced by the presence of mutant XPD both in cells and cell
      extracts. The aberrant damage-dependent DNA synthesis caused by the mutant XPD
      does not lead to effective repair, consistent with the discrepancy between repair
      synthesis and survival in cells from a number of XP-D patients.

PMID- 10660594
TI  - The accumulation of Man(6)GlcNAc(2)-PP-dolichol in the Saccharomyces cerevisiae
      Deltaalg9 mutant reveals a regulatory role for the Alg3p alpha1,3-Man middle-arm
      addition in downstream oligosaccharide-lipid and glycoprotein glycan processing.
AB  - N-Glycans in nearly all eukaryotes are derived by transfer of a precursor
      Glc(3)Man(9)GlcNAc(2) from dolichol (Dol) to consensus Asn residues in nascent
      proteins in the endoplasmic reticulum. The Saccharomyces cerevisiae alg
      (asparagine-linked glycosylation) mutants fail to synthesize oligosaccharide
      lipid properly, and the alg9 mutant, accumulates Man(6)GlcNAc(2)-PP-Dol. High
      field (1)H NMR and methylation analyses of Man(6)GlcNAc(2) released with peptide
      N-glycosidase F from invertase secreted by Deltaalg9 yeast showed its structure
      to be Manalpha1,2Manalpha1,2Manalpha1, 3(Manalpha1,3Manalpha1,6)
      Manbeta1,4GlcNAcbeta1, 4GlcNAcalpha/beta, confirming the addition of the alpha1,3
      linked Man to Man(5)GlcNAc(2)-PP-Dol prior to the addition of the final upper-arm
      alpha1,6-linked Man. This Man(6)GlcNAc(2) is the endoglycosidase H-sensitive
      product of the Alg3p step. The Deltaalg9 Hex(7-10)GlcNAc(2) elongation
      intermediates were released from invertase and similarly analyzed. When compared
      with alg3 sec18 and wild-type core mannans, Deltaalg9 N-glycans reveal a
      regulatory role for the Alg3p-dependent alpha1,3-linked Man in subsequent
      oligosaccharide-lipid and glycoprotein glycan maturation. The presence of this
      Man appears to provide structural information potentiating the downstream action
      of the endoplasmic reticulum glucosyltransferases Alg6p, Alg8p and Alg10p,
      glucosidases Gls1p and Gls2p, and the Golgi Och1p outerchain alpha1,6-Man branch
      initiating mannosyltransferase.

PMID- 10660595
TI  - Mutation of a unique aspartate residue abolishes the catalytic activity but not
      substrate binding of the mouse N-methylpurine-DNA glycosylase (MPG).
AB  - N-Methylpurine-DNA glycosylase (MPG) initiates base excision repair in DNA by
      removing a variety of alkylated purine adducts. Although Asp was identified as
      the active site residue in various DNA glycosylases based on the crystal
      structure, Glu-125 in human MPG (Glu-145 in mouse MPG) was recently proposed to
      be the catalytic residue. Mutational analysis for all Asp residues in a
      truncated, fully active MPG protein showed that only Asp-152 (Asp-132 in the
      human protein), which is located near the active site, is essential for catalytic
      activity. However, the substrate binding was not affected in the inactive Glu
      152, Asn-152, and Ala-152 mutants. Furthermore, mutation of Asp-152 did not
      significantly affect the intrinsic tryptophan fluorescence of the enzyme and the
      far UV CD spectra, although a small change in the near UV CD spectra of the
      mutants suggests localized conformational change in the aromatic residues. We
      propose that in addition to Glu-145 in mouse MPG, which functions as the
      activator of a water molecule for nucleophilic attack, Asp-152 plays an essential
      role either by donating a proton to the substrate base and, thus, facilitating
      its release or by stabilizing the steric configuration of the active site pocket.

PMID- 10660596
TI  - Tyrosine dephosphorylation and deactivation of insulin receptor substrate-1 by
      protein-tyrosine phosphatase 1B. Possible facilitation by the formation of a
      ternary complex with the Grb2 adaptor protein.
AB  - Regulation of the steady-state tyrosine phosphorylation of the insulin receptor
      and its postreceptor substrates are essential determinants of insulin signal
      transduction. However, little is known regarding the molecular interactions that
      influence the balance of these processes, especially the phosphorylation state of
      postinsulin receptor substrates, such as insulin receptor substrate-1 (IRS-1).
      The specific activity of four candidate protein-tyrosine phosphatases (protein
      tyrosine phosphatase 1B (PTP1B), SH2 domain-containing PTPase-2 (SHP-2),
      leukocyte common antigen-related (LAR), and leukocyte antigen-related
      phosphatase) (LRP) toward IRS-1 dephosphorylation was studied using recombinant
      proteins in vitro. PTP1B exhibited the highest specific activity (percentage
      dephosphorylated per microg per min), and the enzyme activities varied over a
      range of 5.5 x 10(3). When evaluated as a ratio of activity versus IRS-1 to that
      versus p-nitrophenyl phosphate, PTP1B remained significantly more active by 3.1
      293-fold, respectively. Overlay blots with recombinant Src homology 2 domains of
      IRS-1 adaptor proteins showed that the loss of IRS-1 binding of Crk, GRB2, SHP-2,
      and the p85 subunit of phosphatidylinositol 3'-kinase paralleled the rate of
      overall IRS-1 dephosphorylation. Further studies revealed that the adaptor
      protein GRB2 strongly promoted the formation of a stable protein complex between
      tyrosine-phosphorylated IRS-1 and catalytically inactive PTP1B, increasing their
      co-immunoprecipitation from an equimolar solution by 13.5 +/- 3.3-fold (n = 7; p
      < 0.01). Inclusion of GRB2 in a reaction mixture of IRS-1 and active PTP1B also
      increased the overall rate of IRS-1 tyrosine dephosphorylation by 2.7-3.9-fold (p
      < 0.01). These results provide new insight into novel molecular interactions
      involving PTP1B and GRB2 that may influence the steady-state capacity of IRS-1 to
      function as a phosphotyrosine scaffold and possibly affect the balance of
      postreceptor insulin signaling.

PMID- 10660597
TI  - Purification and characterization of beta-adrenergic receptor mRNA-binding
      proteins.
AB  - Beta-adrenergic receptors (beta-ARs), like other G-protein-coupled receptors, can
      undergo post-transciptional regulation at the level of mRNA stability. In
      particular, the human beta(1)- and beta(2)-ARs and the hamster beta(2)-AR mRNA
      undergo beta-agonist-mediated destabilization. By UV cross-linking, we have
      previously described an approximately M(r) 36,000 mRNA-binding protein, betaARB,
      that binds to A/C+U-rich nucleotide regions within 3'-untranslated regions.
      Further, we have demonstrated previously that betaARB is immunologically distinct
      from AUF1/heterogeneous nuclear ribonucleoprotein (hnRNP) D, another mRNA-binding
      protein associated with destabilization of A+U-rich mRNAs (Pende, A., Tremmel, K.
      D., DeMaria, C. T., Blaxall, B. C., Minobe, W., Sherman, J. A., Bisognano, J.,
      Bristow, M. R., Brewer, G., and Port, J. D. (1996) J. Biol. Chem. 271, 8493
      8501). In this report, we describe the peptide composition of betaARB. Mass
      spectrometric analysis of an approximately M(r) 36,000 band isolated from
      ribosomal salt wash proteins revealed the presence of two mRNA-binding proteins,
      hnRNP A1, and the elav-like protein, HuR, both of which are known to bind to A+U
      rich nucleotide regions. By immunoprecipitation, HuR appears to be the
      biologically dominant RNA binding component of betaARB. Although hnRNP A1 and HuR
      can both be immunoprecipitated from ribosomal salt wash proteins, the composition
      of betaARB (HuR alone versus HuR and hnRNP A1) appears to be dependent on the
      mRNA probe used. The exact role of HuR and hnRNP A1 in the regulation of beta-AR
      mRNA stability remains to be determined.

PMID- 10660598
TI  - Nuclear import of adenovirus DNA in vitro involves the nuclear protein import
      pathway and hsc70.
AB  - Adenovirus, a respiratory virus with a double-stranded DNA genome, replicates in
      the nuclei of mammalian cells. We have developed a cytosol-dependent in vitro
      assay utilizing adenovirus nucleocapsids to examine the requirements for
      adenovirus docking to the nuclear pore complex and for DNA import into the
      nucleus. Our assay reveals that adenovirus DNA import is blocked by a competitive
      excess of classical protein nuclear localization sequences and other inhibitors
      of nuclear protein import and indicates that this process is dependent on hsc70.
      Previous work revealed that the hexon (coat) protein of adenovirus is the only
      major protein on the surface of the adenovirus nucleocapsid that docks at the
      nuclear pore complex. This, together with our finding that in vitro nuclear
      import of hexon is inhibited by an excess of classical nuclear localization
      sequences, suggests a role for the hexon protein in adenovirus DNA import.
      However, recombinant transport factors that are sufficient for hexon import in
      permeabilized cells do not support DNA import, indicating that there are other as
      yet unidentified factors required for this process.

PMID- 10660599
TI  - Alternative RNA splicing generates a glycosylphosphatidylinositol-anchored form
      of ceruloplasmin in mammalian brain.
AB  - Ceruloplasmin is a copper-containing ferroxidase that is essential for normal
      iron homeostasis. Whereas ceruloplasmin in plasma is produced and secreted by
      hepatocytes, in the brain a glycosylphosphatidylinositol (GPI)-anchored form of
      ceruloplasmin is expressed on the surface of astrocytes. By using a cDNA cloning
      approach, we have now determined that the GPI-anchored form of ceruloplasmin is
      generated by alternative RNA splicing. The splicing occurs downstream of exon 18
      and replaces the C-terminal 5 amino acids of the secreted form with an
      alternative 30 amino acids that signal GPI anchor addition. RNase protection
      analysis demonstrates that the GPI-anchored form is the major form in the brain,
      whereas the secreted form predominates in the liver. Individuals with
      aceruloplasminemia, a hereditary deficiency of ceruloplasmin, have severe iron
      deposition in a number of organs, including the brain where it results in
      neurodegeneration. Therefore, this novel GPI-anchored form of ceruloplasmin is
      likely to play an important role in iron metabolism in the central nervous
      system.

PMID- 10660600
TI  - PSK, a novel STE20-like kinase derived from prostatic carcinoma that activates
      the c-Jun N-terminal kinase mitogen-activated protein kinase pathway and
      regulates actin cytoskeletal organization.
AB  - Degenerate polymerase chain reaction against conserved kinase catalytic
      subdomains identified 15 tyrosine and serine-threonine kinases expressed in
      surgically removed prostatic carcinoma tissues, including six receptor kinases
      (PDGFBR, IGF1-R, VEGFR2, MET, RYK, and EPH-A1), six non-receptor kinases (ABL,
      JAK1, JAK2, TYK2, PLK-1, and EMK), and three novel kinases. Several of these
      kinases are oncogenic, and may function in the development of prostate cancer.
      One of the novel kinases is a new member of the sterile 20 (STE20) family of
      serine-threonine kinases which we have called prostate-derived STE20-like kinase
      (PSK) and characterized functionally. PSK encodes an open reading frame of 3705
      nucleotides and contains an N-terminal kinase domain. Immunoprecipitated PSK
      phosphorylates myelin basic protein and transfected PSK stimulates MKK4 and MKK7
      and activates the c-Jun N-terminal kinase mitogen-activated protein kinase
      pathway. Microinjection of PSK into cells results in localization of PSK to a
      vesicular compartment and causes a marked reduction in actin stress fibers. In
      contrast, C-terminally truncated PSK (1-349) did not localize to this compartment
      or induce a decrease in stress fibers demonstrating a requirement for the C
      terminus. Kinase-defective PSK (K57A) was unable to reduce stress fibers. PSK is
      the first member of the STE20 family lacking a Cdc42/Rac binding domain that has
      been shown to regulate both the c-Jun N-terminal kinase mitogen-activated protein
      kinase pathway and the actin cytoskeleton.

PMID- 10660601
TI  - Plasma membrane Ca(2+) pump isoform 3f is weakly stimulated by calmodulin.
AB  - Isoform 3f of the plasma membrane Ca(2+) pump is a major isoform of this pump in
      rat skeletal muscle. It has an unusual structure, with a short carboxyl-terminal
      regulatory region of only 33 residues when compared with the 77 to 124 residues
      found in the other isoforms. Also, whereas the regulatory regions of the other
      isoforms, downstream of the alternative splice, consist of two homologous groups,
      the sequence of 3f is not related to either group. A synthetic peptide
      representing the calmodulin binding domain of isoform 3f had a much lower
      calmodulin affinity (with a K(d) of 15 nM) than the corresponding peptide of
      isoform 2b (K(d) value was 0.2 nM). The characteristics of this domain were
      further studied by making chimeras of the 3f regulatory region with the catalytic
      core of isoform 4 and by making the full-length isoform 3f. Both constructs bound
      to calmodulin-Sepharose. The chimera was fully active without calmodulin, showing
      no stimulation of activity when calmodulin was added. The full-length isoform 3f
      was slightly activated by calmodulin. These data show that the regulatory region
      of isoform 3f is only a weak autoinhibitor of the enzyme, in contrast to the
      properties of all the other isoforms studied so far. Rather, this isoform is a
      special-purpose, constitutively active form of the enzyme, expressed primarily in
      skeletal muscle and as a minor isoform in brain.

PMID- 10660602
TI  - Effect of ADP and ionic strength on the kinetic and motile properties of
      recombinant mouse myosin V.
AB  - Mouse myosin V is a two-headed unconventional myosin with an extended neck that
      binds six calmodulins. Double-headed (heavy meromyosin-like) and single-headed
      (subfragment 1-like) fragments of mouse myosin V were expressed in Sf9 cells, and
      intact myosin V was purified from mouse brain. The actin-activated MgATPase of
      the tissue-purified myosin V, and its expressed fragments had a high V(max) and a
      low K(ATPase). Calcium regulated the MgATPase of intact myosin V but not of the
      fragments. Both the MgATPase activity and the in vitro motility were remarkably
      insensitive to ionic strength. Myosin V and its fragments translocated actin at
      very low myosin surface densities. ADP markedly inhibited the actin-activated
      MgATPase activity and the in vitro motility. ADP dissociated from myosin V
      subfragment 1 at a rate of about 11.5 s(-1) under conditions where the V(max) was
      3.3 s(-1), indicating that, although not totally rate-limiting, ADP dissociation
      was close to the rate-limiting step. The high affinity for actin and the slow
      rate of ADP release helps the myosin head to remain attached to actin for a large
      fraction of each ATPase cycle and allows actin filaments to be moved by only a
      few myosin V molecules in vitro.

PMID- 10660603
TI  - Activation of p70 ribosomal protein S6 kinase is an essential step in the DNA
      damage-dependent signaling pathway responsible for the ultraviolet B-mediated
      increase in interstitial collagenase (MMP-1) and stromelysin-1 (MMP-3) protein
      levels in human dermal fibroblasts.
AB  - Ultraviolet B (UVB) irradiation has been shown to stimulate the expression of
      matrix-degrading metalloproteinases via generation of DNA damage and/or reactive
      oxygen species. Matrix-degrading metalloproteinases promote UVB-triggered
      detrimental long term effects like cancer formation and premature skin aging.
      Here, we were interested in identifying components of the signal transduction
      pathway that causally link UVB-mediated DNA damage and induction of matrix
      degrading metalloproteinase (MMP)-1/interstitial collagenase and MMP
      3/stromelysin-1 in human dermal fibroblasts in vitro. The activity of p70
      ribosomal S6 kinase, a downstream target of the FK506-binding protein
      12/rapamycin-associated protein kinase (FRAP) kinase (RAFT1, mTOR), was
      identified to be 4.8 +/- 0.8-fold, and MMP-1 and MMP-3 protein levels 2.4- and
      11.5-fold increased upon UVB irradiation compared with mock-irradiated controls.
      The FRAP kinase inhibitor rapamycin and the DNA repair inhibitor aphidicolin
      significantly suppressed the UVB-mediated increase in p70 ribosomal S6 kinase
      activity by 50-65% and MMP-1 and MMP-3 protein levels by 34-68% and 42-88%
      compared with UVB-irradiated fibroblasts. By contrast, the interleukin-1beta
      mediated increase in MMP-1 and MMP-3 protein levels could not be suppressed by
      rapamycin. Collectively, our data suggest that the FRAP-controlled p70 ribosomal
      S6 kinase is an essential component of a DNA damage-dependent, but not of the
      interleukin-1/cell membrane receptor-dependent signaling.

PMID- 10660604
TI  - The peroxisome proliferator response element of the gene encoding the peroxisomal
      beta-oxidation enzyme enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase is a
      target for constitutive androstane receptor beta/9-cis-retinoic acid receptor
      mediated transactivation.
AB  - The genes encoding the first two enzymes of the peroxisomal beta-oxidation
      pathway, acyl-CoA oxidase (AOx) and enoyl-CoA hydratase/3-hydroxyacyl-CoA
      dehydrogenase (HD), contain upstream cis-acting regulatory regions termed
      peroxisome proliferator response elements (PPRE). Transcription of these genes is
      mediated through the binding of peroxisome proliferator-activated receptor alpha
      (PPARalpha), which binds to a PPRE as a heterodimer with the 9-cis-retinoic acid
      receptor (RXRalpha). Here we demonstrate that the HD-PPRE is also a target for
      the constitutive androstane receptor beta (CARbeta). In vitro binding analysis
      showed that CARbeta bound the HD-PPRE, but not the AOx-PPRE, as a heterodimer
      with RXRalpha. Binding of CARbeta/RXRalpha to the HD-PPRE occurred via
      determinants that overlap partially with those required for PPARalpha/RXRalpha
      binding. In vivo, CARbeta/RXRalpha activated transcription from an HD-PPRE
      luciferase reporter construct. Interestingly, CARbeta was shown to also modulate
      PPARalpha/RXRalpha-mediated transactivation in a response element-specific
      manner. In the presence of the peroxisome proliferator, Wy-14,643, CARbeta had no
      effect on PPARalpha/RXRalpha-mediated transactivation from the HD-PPRE but
      antagonized transactivation from the AOx-PPRE in both the presence and the
      absence of proliferator. Our results illustrate that transcription of the AOx and
      HD genes is differentially regulated by CARbeta and that the HD gene is a
      specific target for regulation by CARbeta. Overall, this study proposes a novel
      role for CARbeta in the regulation of peroxisomal beta-oxidation.

PMID- 10660605
TI  - Characterization of structural features that mediate the tethering of
      Caenorhabditis elegans protein kinase A to a novel A kinase anchor protein.
      Insights into the anchoring of PKAI isoforms.
AB  - Caenorhabditis elegans protein kinase A (PKAI(CE)) is tethered to organelles in
      vivo. A unique A kinase anchor protein (AKAP(CE)) avidly binds the RI-like
      regulatory subunits (R(CE)) of PKAI(CE) and stringently discriminates against
      RIIalpha and RIIbeta subunits, the preferred ligands for classical AKAPs. We
      elucidated structural features that stabilize AKAP(CE).R(CE) complexes and confer
      atypical R isoform specificity on the anchor protein. Three large aliphatic amino
      acids (Leu(236), Ile(248), and Leu(252)) in the tethering domain of AKAP(CE)
      (residues 236-255) are crucial for ligation of R(CE). Their side chains
      apparently generate a precisely configured hydrophobic binding pocket that
      accommodates an apolar surface on R(CE) dimers. Basic residues (His(254)-Arg(255)
      Lys(256)) at the C terminus of the tethering site set an upper limit on affinity
      for R(CE.) A central dipeptide (Phe(243)-Ser(244)) contributes critical and
      distinctive properties of the tethering site. Ser(244) is essential for selective
      binding of R(CE) and exclusion of RII isoforms. The aromatic hydrophobic
      character of Phe(243) ensures maximal R(CE) binding activity, thereby supporting
      a "gatekeeper" function of Ser(244). Substitution of Phe(243)-Ser(244) with Leu
      Val generated an RII-specific AKAP. R(CE) and RII subunits contain similar
      dimerization domains. AKAP-binding domains of R(CE) (residues 23-47) and RII
      differ markedly in size, amino acid sequence, and docking specificity. Four
      hydrophobic residues (Cys(23), Val(27), Ile(32), and Cys(44)) in R(CE) are
      crucial for avid binding with AKAP(CE), whereas side chains from Leu(20),
      Leu(35), Val(36), Ile(40), and Ile(41) have little impact on complex formation.
      Tyr(26) is embedded in the docking domain, but its aromatic ring is required for
      R(CE)-R(CE) dimerization. Residues 236-255 in AKAP(CE) also constitute a binding
      site for mammalian RIalpha. RIalpha (PKAIalpha) is tightly sequestered by
      AKAP(CE) in vitro (K(D) = approximately 10 nM) and in the environment of intact
      cells. The tethering domain of AKAP(CE) provides a molecular module for
      manipulating intracellular localization of RI and elucidating functions of
      anchored PKAI in eukaryotes.

PMID- 10660606
TI  - Requirement for prolonged action in the cytosol for optimal protein synthesis
      inhibition by diphtheria toxin.
AB  - Diphtheria toxin A-fragment enters the cytosol of target cells, where it inhibits
      protein synthesis by catalyzing ADP-ribosylation of elongation factor 2 (EF-2).
      We have here analyzed toxin-induced protein synthesis inhibition in single cells
      by autoradiography and compared it with inhibition of protein synthesis in the
      whole cell culture. The data show that half-maximal protein synthesis inhibition
      in the whole cell population after a short incubation time is achieved by
      partially inhibiting protein synthesis in basically all the cells, while half
      maximal protein synthesis inhibition after a long incubation time is due to a
      complete protein synthesis block in about half the cells in the population. We
      have also compared stable and unstable A-fragment mutants with respect to the
      kinetics of cell intoxication. While the toxicity of the stable mutants increased
      with time, the unstable mutants showed a similar toxicity at early and late time
      points. When studying the kinetics of cell intoxication by toxins with short
      cytosolic half-life, we could not detect any recovery of protein synthesis at
      late time points when all the mutant A-fragments should be degraded. This
      indicates that the ADP-ribosylation of EF-2 cannot be reversed by an endogenous
      activity in the cells. The data indicate that entry of toxin into a cell is not
      associated with an immediate block in protein synthesis, and that prolonged
      action of single A-fragment molecules in the cytosol is sufficient to obtain
      complete protein synthesis inhibition at low toxin concentrations.

PMID- 10660607
TI  - Vicinal dithiol-binding agent, phenylarsine oxide, inhibits inducible nitric
      oxide synthase gene expression at a step of nuclear factor-kappaB DNA binding in
      hepatocytes.
AB  - Inflammatory cytokine interleukin 1beta induces inducible nitric-oxide synthase
      (iNOS) mRNA and its protein, which are followed by increasing the production of
      nitric oxide, in primary cultures of rat hepatocytes. Nuclear factor-kappaB (NF
      kappaB), an important transcription factor for iNOS gene expression, is also
      activated and translocated to the nucleus. In the present study, we found that
      vicinal dithiol-binding agent, phenylarsine oxide (PAO), inhibited the induction
      of iNOS protein and mRNA as well as the release of nitrite (nitric oxide
      metabolite) into the culture medium. Simultaneous addition of a vicinal dithiol
      compound, 2, 3-dimercaptopropanol, with PAO completely abolished these
      inhibitions. PAO could not prevent either degradation of an inhibitory protein,
      IkappaB, of NF-kappaB or translocation of NF-kappaB to the nucleus. However,
      electrophoretic mobility shift assay demonstrated that PAO decreased the
      interaction between NF-kappaB and its binding consensus oligonucleotide.
      Transfection experiments with iNOS promoter-luciferase construct revealed that
      PAO inhibited NF-kappaB binding to DNA. These results indicate that PAO inhibits
      iNOS gene expression at a step of NF-kappaB binding to DNA by modifying its
      vicinal dithiol moiety, which may play a crucial role for the iNOS regulation in
      hepatocytes.

PMID- 10660608
TI  - Secreted frizzled-related protein-1 binds directly to Wingless and is a biphasic
      modulator of Wnt signaling.
AB  - Secreted Frizzled-related protein-1 (sFRP-1) contains a cysteine-rich domain
      homologous to the putative Wnt-binding site of Frizzleds. To facilitate the
      biochemical and biological analysis of sFRP-1, we developed a mammalian
      recombinant expression system that yields approximately 3 mg of purified
      protein/liter of conditioned medium. Using this recombinant protein, we
      demonstrated that sFRP-1 and Wg (wingless) interact in enzyme-linked
      immunosorbent and co-precipitation assays. Surprisingly, a derivative lacking the
      cysteine-rich domain retained the ability to bind Wg. Cross-linking experiments
      performed with radioiodinated sFRP-1 provided definitive evidence that sFRP-1 and
      Wg bind directly to each other. Besides detecting a cross-linked complex
      consistent in size with 1:1 stoichiometry of sFRP-1 and Wg, we also observed a
      larger complex whose size suggested the presence of a second sFRP-1 molecule. The
      formation of both complexes was markedly enhanced by an optimal concentration of
      exogenous heparin, emphasizing the potential importance of heparan-sulfate
      proteoglycan in Wnt binding and signaling. sFRP-1 exerted a biphasic effect on Wg
      activity in an armadillo stabilization assay, increasing armadillo level at low
      concentrations but reducing it at higher concentrations. These results provide
      new insights about the Wnt binding and biological activity of sFRPs.

PMID- 10660609
TI  - Inhibition of nuclear factor-kappaB-mediated transcription by association with
      the amino-terminal enhancer of split, a Groucho-related protein lacking WD40
      repeats.
AB  - The amino-terminal enhancer of split (AES) encodes a 197-amino acid protein that
      is homologous to the NH(2)-terminal domain of the Drosophila Groucho protein but
      lacks COOH-terminal WD40 repeats. Although the Drosophila Groucho protein and its
      mammalian homologs, transducin-like enhancer of split proteins, are known to act
      as non-DNA binding corepressors, the role of the AES protein remains unclarified.
      Using the yeast two-hybrid system, we have identified the protein-protein
      interaction between AES and the p65 (RelA) subunit of the transcription factor
      nuclear factor kappaB (NF-kappaB), which activates various target genes involved
      in inflammation, apoptosis, and embryonic development. The interaction between
      AES and p65 was confirmed by in vitro glutathione S-transferase pull down assay
      and by in vivo co-immunoprecipitation study. In transient transfection assays,
      AES repressed p65-driven gene expression. AES also inhibited NF-kappaB-dependent
      gene expression induced by tumor necrosis factor alpha, interleukin-1beta, and
      mitogen-activated protein kinase/extracellular signal-regulated kinase kinase
      kinase 1, which is an upstream kinase for NF-kappaB activation. These data
      indicate that AES acts as a corepressor for NF-kappaB and suggest that AES may
      play a pivotal role in the regulation of NF-kappaB target genes.

PMID- 10660610
TI  - A human REV7 homolog that interacts with the polymerase zeta catalytic subunit
      hREV3 and the spindle assembly checkpoint protein hMAD2.
AB  - Widespread alteration of the genomic DNA is a hallmark of tumors, and alteration
      of genes involved in DNA maintenance have been shown to contribute to the
      tumorigenic process. The DNA polymerase zeta of Saccharomyces cerevisiae is
      required for error-prone repair following DNA damage and consists of a complex
      between three proteins, scRev1, scRev3, and scRev7. Here we describe a candidate
      human homolog of S. cerevisiae Rev7 (hREV7), which was identified in a yeast two
      hybrid screen using the human homolog of S. cerevisiae Rev3 (hREV3). The hREV7
      gene product displays 23% identity and 53% similarity with scREV7, as well as 23%
      identity and 54% similarity with the human mitotic checkpoint protein hMAD2.
      hREV7 is located on human chromosome 1p36 in a region of high loss of
      heterozygosity in human tumors, although no alterations of hREV3 or hREV7 were
      found in primary human tumors or human tumor cell lines. The interaction domain
      between hREV3 and hREV7 was determined and suggests that hREV7 probably functions
      with hREV3 in the human DNA polymerase zeta complex. In addition, we have
      identified an interaction between hREV7 and hMAD2 but not hMAD1. While
      overexpression of hREV7 does not lead to cell cycle arrest, we entertain the
      possibility that it may act as an adapter between DNA repair and the spindle
      assembly checkpoint.

PMID- 10660611
TI  - The SH2 inositol 5-phosphatase Ship1 is recruited in an SH2-dependent manner to
      the erythropoietin receptor.
AB  - Ship1 (SH2 inositol 5-phosphatase 1) has been shown to be a target of tyrosine
      phosphorylation downstream of cytokine and immunoregulatory receptors. In
      addition to its catalytic activity on phosphatidylinositol substrates, it can
      serve as an adaptor protein in binding Shc and Grb2. Erythropoietin (EPO), the
      primary regulator of erythropoiesis, has been shown to activate the tyrosine
      phosphorylation of Shc, resulting in recruitment of Grb2. However, the mechanism
      by which the erythropoietin receptor (EPO-R) recruits Shc remains unknown. EPO
      activates the tyrosine phosphorylation of Ship1, resulting in the interdependent
      recruitment of Shc and Grb2. Ship1 is recruited to the EPO-R in an SH2-dependent
      manner. Utilizing a panel of EPO-R deletion and tyrosine mutants, we have
      discovered remarkable redundancy in Ship1 recruitment. EPO-R Tyr(401) appears to
      be a major site of Ship1 binding; however, Tyr(429) and Tyr(431) can also serve
      to recruit Ship1. In addition, we have shown that EPO stimulates the formation of
      a ternary complex consisting of Ship1, Shc, and Grb2. Ship1 may modulate several
      discrete signal transduction pathways. EPO-dependent activation of ERK1/2 and
      protein kinase B (PKB)/Akt was examined utilizing a panel of EPO-R deletion
      mutants. Activation of ERK1/2 was observed in EPO-RDelta99, which retains only
      the most proximal tyrosine, Tyr(343). In contrast, EPO-dependent PKB activation
      was observed in EPO-RDelta43, but not in EPO-RDelta99. It appears that EPO
      dependent PKB activation is downstream of a region that indirectly couples to
      phosphatidylinositol 3-kinase.

PMID- 10660612
TI  - Reversible inhibition of the calcium-pumping ATPase in native cardiac
      sarcoplasmic reticulum by a calmodulin-binding peptide. Evidence for calmodulin
      dependent regulation of the V(max) of calcium transport.
AB  - Calmodulin (CaM) and Ca(2+)/CaM-dependent protein kinase II (CaM kinase) are
      tightly associated with cardiac sarcoplasmic reticulum (SR) and are implicated in
      the regulation of transmembrane Ca(2+) cycling. In order to assess the importance
      of membrane-associated CaM in modulating the Ca(2+) pump (Ca(2+)-ATPase) function
      of SR, the present study investigated the effects of a synthetic, high affinity
      CaM-binding peptide (CaM BP; amino acid sequence, LKWKKLLKLLKKLLKLG) on the ATP
      energized Ca(2+) uptake, Ca(2+)-stimulated ATP hydrolysis, and CaM kinase
      mediated protein phosphorylation in rabbit cardiac SR vesicles. The results
      revealed a strong concentration-dependent inhibitory action of CaM BP on Ca(2+)
      uptake and Ca(2+)-ATPase activities of SR (50% inhibition at approximately 2-3
      microM CaM BP). The inhibition, which followed the association of CaM BP with its
      SR target(s), was of rapid onset (manifested within 30 s) and was accompanied by
      a decrease in V(max) of Ca(2+) uptake, unaltered K(0.5) for Ca(2+) activation of
      Ca(2+) transport, and a 10-fold decrease in the apparent affinity of the Ca(2+)
      ATPase for its substrate, ATP. Thus, the mechanism of inhibition involved
      alterations at the catalytic site but not the Ca(2+)-binding sites of the Ca(2+)
      ATPase. Endogenous CaM kinase-mediated phosphorylation of Ca(2+)-ATPase,
      phospholamban, and ryanodine receptor-Ca(2+) release channel was also strongly
      inhibited by CaM BP. The inhibitory action of CaM BP on SR Ca(2+) pump function
      and protein phosphorylation was fully reversed by exogenous CaM (1-3 microM). A
      peptide inhibitor of CaM kinase markedly attenuated the ability of CaM to reverse
      CaM BP-mediated inhibition of Ca(2+) transport. These findings suggest a critical
      role for membrane-bound CaM in controlling the velocity of Ca(2+) pumping in
      native cardiac SR. Consistent with its ability to inhibit SR Ca(2+) pump
      function, CaM BP (1-2.5 microM) caused marked depression of contractility and
      diastolic dysfunction in isolated perfused, spontaneously beating rabbit heart
      preparations. Full or partial recovery of contractile function occurred gradually
      following withdrawal of CaM BP from the perfusate, presumably due to slow
      dissociation of CaM BP from its target sites promoted by endogenous cytosolic
      CaM.

PMID- 10660613
TI  - Activated cardiac adenosine A(1) receptors translocate out of caveolae.
AB  - The cardiac affects of the purine nucleoside, adenosine, are well known.
      Adenosine increases coronary blood flow, exerts direct negative chronotropic and
      dromotropic effects, and exerts indirect anti-adrenergic effects. These effects
      of adenosine are mediated via the activation of specific G protein-coupled
      receptors. There is increasing evidence that caveolae play a role in the
      compartmentalization of receptors and second messengers in the vicinity of the
      plasma membrane. Several reports demonstrate that G protein-coupled receptors
      redistribute to caveolae in response to receptor occupation. In this study, we
      tested the hypothesis that adenosine A(1) receptors would translocate to caveolae
      in the presence of agonists. Surprisingly, in unstimulated rat cardiac
      ventricular myocytes, 67 +/- 5% of adenosine A(1) receptors were isolated with
      caveolae. However, incubation with the adenosine A(1) receptor agonist 2
      chlorocyclopentyladenosine induced the rapid translocation of the A(1) receptors
      from caveolae into non-caveolae plasma membrane, an effect that was blocked by
      the adenosine A(1) receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine. An
      adenosine A(2a) receptor agonist did not alter the localization of A(1) receptors
      to caveolae. These data suggest that the translocation of A(1) receptors out of
      caveolae and away from compartmentalized signaling molecules may explain why
      activation of ventricular myocyte A(1) receptors are associated with few direct
      effects.

PMID- 10660614
TI  - Three aromatic amino acid residues critical for galactose transport in yeast Gal2
      transporter.
AB  - Tyr(446) in putative transmembrane segment 10 (TM10) of the yeast galactose
      transporter Gal2 has previously been identified as essential for galactose
      recognition. In the present study, alignment of the amino acid sequences of 63
      sugar transporters or related proteins revealed 14 aromatic sites, including
      Tyr(446) of Gal2, that are conserved in >75% of these proteins. The importance of
      the remaining 13 conserved aromatic amino acids was examined individually by
      random mutagenesis using degenerate primers. Galactose transport-positive clones
      were identified by plate selection and subjected to DNA sequencing. For those
      transport-positive clones corresponding to Tyr(352), and Phe(504) mutants, all
      the amino acid substitutions comprised aromatic residues. The importance of the
      aromatic residues at these sites was further investigated by replacing them
      individually with each of the other 19 amino acids and measuring the galactose
      transport activity of the resulting mutants. Among both Tyr(352) and Phe(504)
      mutants, the other aromatic amino acids supported galactose transport; no other
      amino acids conferred high affinity transport activity. Thus, at least three
      aromatic sites are critical for galactose transport: one at the extracellular
      boundary of putative TM7 (Tyr(352)), one in the middle of putative TM10
      (Tyr(446)), and one in the middle of putative TM12 (Phe(504)).

PMID- 10660615
TI  - Disruption of the A(3) adenosine receptor gene in mice and its effect on
      stimulated inflammatory cells.
AB  - The A(3) adenosine receptor (A3AR) is one of four receptor subtypes for adenosine
      and is expressed in a broad spectrum of tissues. In order to study the function
      of A3AR, a mouse line carrying a mutant A(3) allele was generated. Mice
      homozygous for targeted disruption of the A3AR gene, A3AR(-/-), are fertile and
      visually and histologically indistinguishable from wild type mice. The lack of a
      functional receptor in the A3AR(-/-) mice was confirmed by molecular and
      pharmacological analyses. The absence of A3AR protein expression in the A3AR(-/-)
      mice was demonstrated by lack of N(6)-(4-amino-3-[(125)I]iodobenzyl)adenosine
      binding to bone marrow-derived mast cell membranes that were found to express
      high levels of A3AR in wild type mice. In A3AR(-/-) mice, the density of A(1) and
      A(2A) adenosine receptor subtypes was the same as in A3AR(+/+) mice as determined
      by radioligand binding to brain membranes. Additionally, A(2B) receptor
      transcript expression was not affected by ablation of the A3AR gene. A3AR(-/-)
      mice have basal heart rates and arterial blood pressures indistinguishable from
      A3AR(+/+) mice. Functionally, in contrast to wild type mice, adenosine and the
      A3AR-specific agonist, 2-chloro-N(6)-(3-iodobenzyl)-adenosine-5'-N-methyl
      carboxamide (2-Cl-IB-MECA), elicit no potentiation of antigen-dependent
      degranulation of bone marrow-derived mast cells from A3AR(-/-) mice as measured
      by hexosaminidase release. Also, the ability of 2Cl-IB-MECA to inhibit
      lipopolysaccharide-induced tumor necrosis factor-alpha production in vivo was
      decreased in A3AR(-/-) mice in comparison to A3AR(+/+) mice. The A(2A) adenosine
      receptor agonist, 2-p-(2-carboxyethyl)phenylamino)-5'-N
      ethylcarboxamidoadenosine, produced inhibition of lipopolysaccharide-stimulated
      tumor necrosis factor-alpha production in both A3AR(-/-) and A3AR(+/+) mice.
      These results show that the inhibition in vivo can be mediated by multiple
      subtypes, specifically the A(3) and A(2A) adenosine receptors, and A3AR
      activation plays an important role in both pro- and anti-inflammatory responses.

PMID- 10660616
TI  - Stable expression of a dominant negative mutant of CCAAT binding factor/NF-Y in
      mouse fibroblast cells resulting in retardation of cell growth and inhibition of
      transcription of various cellular genes.
AB  - The heterotrimeric CCAAT-binding factor CBF specifically interacts with the CCAAT
      motif present in the proximal promoters of numerous mammalian genes. To
      understand the in vivo function of CBF, a dominant negative mutant of CBF-B
      subunit that inhibits DNA binding of wild type CBF was stably expressed in mouse
      fibroblast cells under control of tetracycline-responsive promoter. Expression of
      the mutant CBF-B but not the wild-type CBF-B resulted in retardation of
      fibroblast cell growth. The analysis of cell growth using bromodeoxyuridine
      labeling showed that expression of the mutant CBF-B decreased the number of cells
      entering into S phase, and also delayed induction of S phase in the quiescent
      cells after serum stimulation, thus indicating that the inhibition of CBF binding
      prolonged the progression of S phase in fibroblasts. These results provide direct
      evidence for the first time that CBF is an important regulator of fibroblast
      growth. The inhibition of CBF binding reduced expression of various cellular
      genes including the alpha2(1) collagen, E2F1, and topoisomerase IIalpha genes
      which promoters contain the CBF-binding site. This result implied that expression
      of many other genes which promoters contain CBF-binding site was also decreased
      by the inhibition of CBF binding, and that the decreased expression of multiple
      cellular genes possibly caused the retardation of fibroblast cell growth.

PMID- 10660617
TI  - A consensus sequence for long-chain fatty-acid alcohol oxidases from Candida
      identifies a family of genes involved in lipid omega-oxidation in yeast with
      homologues in plants and bacteria.
AB  - The yeast Candida cloacae is capable of growing on alkanes and fatty acids as
      sole carbon sources. Transfer of cultures from a glucose medium to one containing
      oleic acid induced seven proteins of M(r) 102,000, 73,000, 61,000, 54,000, and
      46,000 and two in the region of M(r) 45,000 and repressed a protein of M(r)
      64,000. The induction of the M(r) 73,000 protein reached a 7-fold maximum 24 h
      after induction. The protein was confirmed by its enzyme activity to be a long
      chain fatty-acid alcohol oxidase (LC-FAO) and purified to homogeneity from
      microsomes by a rapid procedure involving hydrophobic chromatography. An internal
      peptide of 30 amino acids was sequenced. A 1100-base pair cDNA fragment
      containing the LC-FAO peptide coding sequence was used to isolate a single exon
      genomic clone containing the full-length coding sequence of an LC-FAO (fao1). The
      fao1 gene product was expressed in Escherichia coli and was translated as a
      functional long-chain alcohol oxidase, which was present in the membrane
      fraction. In addition, full-length coding sequences for a Candida tropicalis LC
      FAO (faoT) and a second C. cloacae LC-FAO (fao2) were isolated. The DNA sequences
      obtained had open reading frames of 2094 (fao1), 2091 (fao2), and 2112 (faoT)
      base pairs. The derived amino acid sequences of fao2 and faoT showed 89.4 and
      76.2% similarities to fao1. The fao1 gene is much more highly induced on alkane
      than is fao2. Although this study describes the first known DNA sequences
      encoding LC-FAOs from any source, there are unassigned Arabidopsis sequences and
      an unassigned Mycobacterium sequence in the GenBank(TM) Data Bank that show
      strong homology to the described LC-FAO sequences. The conservation of sequence
      between yeast, plants, and bacteria suggests that an as yet undescribed family of
      long-chain fatty-acid oxidases exists in both eukaryotes and prokaryotes.

PMID- 10660618
TI  - MAPK pathways activate and phosphorylate the osteoblast-specific transcription
      factor, Cbfa1.
AB  - The bone-specific transcription factor, Cbfa1, regulates expression of the
      osteocalcin (OCN) gene and is essential for bone formation. However, little is
      known about the mechanisms regulating Cbfa1 activity. This work examines the role
      of the MAPK pathway in regulating Cbfa1-dependent transcription. Stimulation of
      MAPK by transfecting a constitutively active form of MEK1, MEK(SP), into MC3T3-E1
      preosteoblast cells increased endogenous OCN mRNA, while a dominant negative
      mutant, MEK(DN), was inhibitory. MEK(SP) also stimulated activity of a 147-base
      pair minimal OCN promoter, and this stimulation required an intact copy of OSE2,
      the DNA binding site for Cbfa1. Effects of MEK(SP) were specific to Cbfa1
      positive osteoblast-like cells. A purified His-tagged Cbfa1 fusion protein was
      directly phosphorylated by activated recombinant MAPK in vitro. Furthermore,
      (32)P metabolic labeling studies demonstrated that MEK(SP) clearly enhanced
      phosphorylation of Cbfa1 in intact cells, while MEK(DN) decreased
      phosphorylation. The specific MEK1/MEK2 inhibitor, PD98059, inhibited
      extracellular matrix-dependent up-regulation of the OCN promoter, indicating that
      the MAPK pathway and, presumably, Cbfa1 phosphorylation are also required for
      responsiveness of osteoblasts to extracellular matrix signals. This study is the
      first demonstration that Cbfa1 is controlled by MAPKs and suggests that this
      pathway has an important role in the control of osteoblast-specific gene
      expression.

PMID- 10660619
TI  - FEN1 stimulation of DNA polymerase beta mediates an excision step in mammalian
      long patch base excision repair.
AB  - In mammalian cells, single-base lesions, such as uracil and abasic sites, appear
      to be repaired by at least two base excision repair (BER) subpathways: "single
      nucleotide BER" requiring DNA synthesis of just one nucleotide and "long patch
      BER" requiring multi-nucleotide DNA synthesis. In single-nucleotide BER, DNA
      polymerase beta (beta-pol) accounts for both gap filling DNA synthesis and
      removal of the 5'-deoxyribose phosphate (dRP) of the abasic site, whereas the
      involvement of various DNA polymerases in long patch BER is less well understood.
      Recently, we found that beta-pol plays a role in mammalian cell extract-mediated
      long patch BER, in that formation of a key excision product, 5'-dRP-trinucleotide
      (5'-dRP-N(3)), is dependent upon beta-pol (Dianov, G. L., Prasad, R., Wilson, S.
      H., and Bohr, V.A. (1999) J. Biol. Chem. 274, 13741-13743). The structure
      specific endonuclease flap endonuclease 1 (FEN1) has also been suggested to be
      involved in long patch BER excision. Here, we demonstrate by immunodepletion
      experiments that 5'-dRP-N(3) excision in long patch BER of uracil-DNA in a human
      lymphoid cell extract is, indeed, dependent upon FEN1. Next, we reconstituted the
      excision step of long patch BER using purified human proteins and an
      oligonucleotide substrate with 5'-dRP at the margin of a one-nucleotide gap.
      Formation of the excision product 5'-dRP-N(3) was dependent upon both strand
      displacement DNA synthesis by beta-pol and FEN1 excision. FEN1 stimulated strand
      displacement DNA synthesis of beta-pol. FEN1 acting either alone, or without DNA
      synthesis by beta-pol, produced a two-nucleotide excision product, 5'-dRP-N(1),
      but not 5'-dRP-N(3). These results demonstrate that human FEN1 and beta-pol can
      cooperate in long patch BER excision and specify the predominant excision product
      seen with a cell extract.

PMID- 10660620
TI  - PILRalpha, a novel immunoreceptor tyrosine-based inhibitory motif-bearing
      protein, recruits SHP-1 upon tyrosine phosphorylation and is paired with the
      truncated counterpart PILRbeta.
AB  - SHP-1-mediated dephosphorylation of protein tyrosine residues is central to the
      regulation of several cell signaling pathways, the specificity of which is
      dictated by the intrinsic affinity of SH2 domains for the flanking sequences of
      phosphotyrosine residues. By using a modified yeast two-hybrid system and SHP-1
      as bait, we have cloned a human cDNA, PILRalpha, encoding a 303-amino acid
      immunoglobulin-like transmembrane receptor bearing two cytoplasmic tyrosines
      positioned within an immunoreceptor tyrosine-based inhibitory motif. Substrate
      trapping in combination with pervanadate treatment of 293T cells confirms that
      PILRalpha associates with SHP-1 in vivo upon tyrosine phosphorylation. Mutation
      of the tyrosine residues in PILRalpha indicates the pivotal role of the Tyr-269
      residue in recruiting SHP-1. Surface plasmon resonance analysis further suggests
      that the association between PILRalpha-Tyr-269 and SHP-1 is mediated primarily
      via the amino-terminal SH2 domain of the latter. Polymerase chain reaction
      amplification of cDNA in combination with genomic sequence analysis revealed a
      second gene, PILRbeta, coding for a putative activating receptor as suggested by
      a truncated cytoplasmic tail and a charged lysine residue in its transmembrane
      region. The PILRalpha and PILRbeta genes are localized to chromosome 7 which is
      in contrast with the mapping of known members of the inhibitory receptor
      superfamily.

PMID- 10660621
TI  - Phosphorylation of steroid receptor coactivator-1. Identification of the
      phosphorylation sites and phosphorylation through the mitogen-activated protein
      kinase pathway.
AB  - Steroid receptor coactivator-1 (SRC-1) is a member of a coactivator family that
      enhance the activation of the steroid/nuclear receptor superfamily of ligand
      stimulated transcription factors. To study the regulation of SRC-1 by signaling
      pathways in the cell, the major phosphorylation sites of SRC-1 were identified in
      COS-1 cells using a combination of in vivo labeling with [(32)P]H(3)PO(4),
      modified manual Edman degradation, phosphoamino acid analysis, endoproteinase
      digestion, and mutagenesis of the SRC-1 phosphorylation sites. Seven
      phosphorylation sites were identified in SRC-1: serine 372, serine 395, serine
      517, serine 569, serine 1033, threonine 1179, and serine 1185. All the sites
      contained consensus sequences for the serine/threonine-proline-directed family of
      protein kinases, and two sites (serine 395 and threonine 1179) contained a
      perfect consensus sequence for the mitogen-activated protein kinase family (Erk-1
      and Erk-2). Furthermore, Erk-2 phosphorylated threonine 1179 and serine 1185 (and
      to a lesser extent, serine 395) in vitro, suggesting the importance of this
      pathway for SRC-1 regulation. Treatment of cells expressing SRC-1 with epidermal
      growth factor enhanced the ligand-dependent, progesterone receptor-mediated
      activation of a target reporter gene. These results identify phosphorylation as a
      regulatory modification of SRC-1 and provide a basis upon which to identify
      signaling pathways that regulate SRC-1 function and, consequently, modify
      steroid/nuclear receptor action.

PMID- 10660622
TI  - Polysialyltransferase-1 autopolysialylation is not requisite for polysialylation
      of neural cell adhesion molecule.
AB  - Polysialyltransferase-1 (PST; ST8Sia IV) is one of the alpha2, 8
      polysialyltransferases responsible for the polysialylation of the neural cell
      adhesion molecule (NCAM). The presence of polysialic acid on NCAM has been shown
      to modulate cell-cell and cell-matrix interactions. We previously reported that
      the PST enzyme itself is modified by alpha2,8-linked polysialic acid chains in
      vivo. To understand the role of autopolysialylation in PST enzymatic activity, we
      employed a mutagenesis approach. We found that PST is modified by five Asn-linked
      oligosaccharides and that the vast majority of the polysialic acid is found on
      the oligosaccharide modifying Asn-74. In addition, the presence of the
      oligosaccharide on Asn-119 appeared to be required for folding of PST into an
      active enzyme. Co-expression of the PST Asn mutants with NCAM demonstrated that
      autopolysialylation is not required for PST polysialyltransferase activity.
      Notably, catalytically active, non-autopolysialylated PST does not polysialylate
      any endogenous COS-1 cell proteins, highlighting the protein specificity of
      polysialylation. Immunoblot analyses of NCAM polysialylation by polysialylated
      and non-autopolysialylated PST suggests that the NCAM is polysialylated to a
      higher degree by autopolysialylated PST. We conclude that autopolysialylation of
      PST is not required for, but does enhance, NCAM polysialylation.

PMID- 10660623
TI  - Selective activation of MAPK(erk1/2) by laminin-1 peptide alpha1:Ser(2091)
      Arg(2108) regulates macrophage degradative phenotype.
AB  - Components of the extracellular matrix contain cryptic domains, which are exposed
      by proteolysis and elicit biological responses distinct from intact molecules.
      The disparate cellular response to extracellular matrix fragments and parent
      intact molecules suggests differential recognition and signaling pathways. In
      experiments reported here, we demonstrate that urokinase and matrix
      metalloproteinase-9 expression by RAW264.7 macrophages is stimulated by a
      synthetic laminin peptide derived from the alpha1-chain (SRARKQAASIKVAVSADR),
      whereas intact laminin-1 has no effect on proteinase expression by macrophages.
      Incubation of macrophages with alpha1:SRARKQAASIKVAVSADR stimulates tyrosine
      phosphorylation of several proteins including mitogen-activated protein kinase
      (MAPK)(erk1/2). In contrast, neither intact laminin-1 nor the beta1-chain peptide
      CDPGYIGSR stimulated protein tyrosine phosphorylation in these cells. Inhibition
      of tyrosine kinases or protein kinase C blocked alpha1-chain peptide-induced
      phosphorylation of MAPK(erk1/2) and the up-regulation of steady state levels of
      urokinase mRNA and matrix metalloproteinase-9 activity. A MAPK kinase inhibitor
      blocked alpha1-chain-induced phosphorylation of MAPK(erk1/2) and the induction of
      proteinase expression. Intact laminin-1, which was unable to induce macrophage
      proteinase expression, failed to stimulate the phosphorylation of MAPK(erk1/2).
      These data demonstrate that incubation of macrophages with
      alpha1:SRARKQAASIKVAVSADR, but not intact laminin-1, triggers protein kinase C
      dependent activation of MAPK(erk1/2), leading to the up-regulation of proteinase
      expression.

PMID- 10660624
TI  - The caudal-related homeodomain protein Cdx1 inhibits proliferation of intestinal
      epithelial cells by down-regulation of D-type cyclins.
AB  - Cdx1 is a homeodomain transcription factor that regulates intestine-specific gene
      expression. Experimental evidence suggests that Cdx1 may be involved in cell
      cycle regulation, but its role is ill defined and the mechanisms have not been
      explored. We used stable transfection of inducible constructs and transient
      expression with a replication-deficient adenovirus to induce Cdx1 expression in
      rat IEC6 cells, a non-transformed intestinal epithelial cell line that does not
      express Cdx1 protein. Expression of Cdx1 markedly reduced proliferation of IEC6
      cells with accumulation of cells in the G(0)/G(1) phase of the cell cycle. Cell
      cycle arrest was accompanied by an increase in the hypophosphorylated forms of
      the retinoblastoma protein (pRb) and the pRb-related p130 protein. Protein levels
      of multiple cyclin-dependent kinase inhibitors were either unchanged (p16, p18,
      p21, p27, and p57) or were not detected (p15 and p19). Most significantly, levels
      of cyclins D1 and D2 were markedly diminished with Cdx1 expression, but not
      cyclins D3, E, or the G(1) kinases. Additionally, cyclin-dependent kinase-4
      activity was decreased in association with decreased cyclin D protein. We
      conclude that Cdx1 regulates intestinal epithelial cell proliferation by
      inhibiting progression through G(0)/G(1), most likely via modulation of cyclin D1
      and D2 protein levels.

PMID- 10660625
TI  - Molecular cloning and characterization of multispecific organic anion transporter
      4 expressed in the placenta.
AB  - A cDNA encoding a novel multispecific organic anion transporter, OAT4, was
      isolated from a human kidney cDNA library. The OAT4 cDNA consisted of 2210 base
      pairs that encoded a 550-amino acid residue protein with 12 putative membrane
      spanning domains. The amino acid sequence of OAT4 showed 38 to 44% identity to
      those of other members of the OAT family. Northern blot analysis revealed that
      OAT4 mRNA is abundantly expressed in the placenta as well as in the kidney. When
      expressed in Xenopus oocytes, OAT4 mediated the high affinity transport of
      estrone sulfate (K(m) = 1.01 microM) and dehydroepiandrosterone sulfate (K(m) =
      0.63 microM) in a sodium-independent manner. OAT4 also mediated the transport of
      ochratoxin A. OAT4-mediated transport of estrone sulfate was inhibited by several
      sulfate conjugates, such as p-nitrophenyl sulfate, alpha-naphthyl sulfate, beta
      estradiol sulfate, and 4-methylumbelliferyl sulfate. By contrast, glucuronide
      conjugates showed little or no inhibitory effect on the OAT4-mediated transport
      of estrone sulfate. OAT4 interacted with chemically heterogeneous anionic
      compounds, such as nonsteroidal anti-inflammatory drugs, diuretics,
      sulfobromophthalein, penicillin G, and bile salts, whereas tetraethylammonium, an
      organic cation, did not. OAT4 is the first member of the multispecific organic
      anion transporter family, which is expressed abundantly in the placenta. OAT4
      might be responsible for the elimination and detoxification of harmful anionic
      substances from the fetus.

PMID- 10660627
TI  - Effects of mutations in the L-tryptophan binding pocket of the Trp RNA-binding
      attenuation protein of Bacillus subtilis.
AB  - The Bacillus subtilis tryptophan biosynthetic genes are regulated by the trp RNA
      binding attenuation protein (TRAP). Cooperative binding of L-tryptophan activates
      TRAP so that it can bind to RNA. The crystal structure revealed that L-tryptophan
      forms nine hydrogen bonds with various amino acid residues of TRAP. We performed
      site-directed mutagenesis to determine the importance of several of these
      hydrogen bonds in TRAP activation. We tested both alanine substitutions as well
      as substitutions more closely related to the natural amino acid at appropriate
      positions. Tryptophan binding mutations were identified in vivo having unchanged,
      reduced, or completely eliminated repression activity. Several of the in vivo
      defective TRAP mutants exhibited reduced affinity for tryptophan in vitro but did
      not interfere with RNA binding at saturating tryptophan concentrations. However,
      a 10-fold decrease in TRAP affinity for tryptophan led to an almost complete loss
      of regulation, whereas increased TRAP affinity for tryptophan had little or no
      effect on the in vivo regulatory activity of TRAP. One hydrogen bond was found to
      be dispensable for TRAP activity, whereas two others appear to be essential for
      TRAP function. Another mutant protein exhibited tryptophan-independent RNA
      binding activity. We also found that trp leader RNA increases the affinity of
      TRAP for tryptophan.

PMID- 10660626
TI  - Identification of amino acids involved in the functional interaction between DnaA
      protein and acidic phospholipids.
AB  - DnaA protein, the initiator of chromosomal DNA replication in Escherichia coli,
      seems to be regulated through its binding to acidic phospholipids, such as
      cardiolipin. In our previous paper (Hase, M., Yoshimi, T., Ishikawa, Y., Ohba,
      A., Guo, L., Mima, S., Makise, M., Yamaguchi, Y., Tsuchiya, T., and Mizushima, T.
      (1998) J. Biol. Chem. 273, 28651-28656), we found that mutant DnaA protein
      (DnaA431), in which three basic amino acids (Arg(360), Arg(364), and Lys(372))
      were mutated to acidic amino acids showed a decreased ability to interact with
      cardiolipin in vitro, suggesting that DnaA protein binds to cardiolipin through
      an ionic interaction. In this study, we construct three mutant dnaA genes each
      with a single mutation and examined the function of the mutant proteins in vitro
      and in vivo. All mutant proteins maintained activities for DNA replication and
      ATP binding. A mutant protein in which Lys(372) was mutated to Glu showed the
      weakest interaction with cardiolipin among these three mutant proteins. Thus,
      Lys(372) seems to play an important role in the interaction between DnaA protein
      and acidic phospholipids. Plasmid complementation analyses revealed that all
      these mutant proteins, including DnaA431 could function as an initiator for
      chromosomal DNA replication in vivo.

PMID- 10660628
TI  - Binding of octamer factors to a novel 3'-positive regulatory element in the mouse
      interleukin-5 gene.
AB  - The development of eosinophilia is regulated by interleukin (IL)-5. The
      biological specificity of eosinophilia suggests a tight and independent
      regulation of IL-5 expression. A number of regulatory regions in the 5'-end of
      the IL-5 gene have been described; many of them are involved in the regulation of
      other genes, and it is not clear how the specific expression of IL-5 is
      regulated. In this study, we report the finding of a novel 3'-regulatory element.
      Data base analysis of a 2-kilobase fragment of the 3'-end of the mouse IL-5 gene
      revealed the presence of a 40-base pair-long repetitive sequence that consists of
      four direct repeats of ATGAATGA distributed in a symmetrical manner. This
      sequence, named mouse downstream regulatory element-1 (mDRE1), was shown to be
      protected in DNase I footprinting assays in vitro. Electrophoretic mobility shift
      assays using specific antibodies identified the transcription factors Oct-1 and
      Oct-2 as responsible for the formation of the specific complexes with mDRE1 and
      nuclear extracts from both EL4 and primary T-cells. Competition electrophoretic
      mobility shift assays with oligonucleotides containing different numbers of
      ATGAATGA repeats showed that Oct-1 and Oct-2 bind to different motifs in the
      mDRE1 sequence. Deletion of mDRE1 from a 9.5-kilobase IL-5 gene construct
      significantly decreased the expression of the luciferase reporter gene,
      suggesting that it plays a positive role in the expression of the IL-5 gene.

PMID- 10660630
TI  - Testing for allergy.

PMID- 10660629
TI  - Regulation of BRCA1 expression by the Rb-E2F pathway.
AB  - Inheritance of a mutant allele of the breast cancer susceptibility gene BRCA1
      confers increased risk of developing breast and ovarian cancers. Likewise,
      inheritance of a mutant allele of the retinoblastoma susceptibility gene (RB1)
      results in the development of retinoblastoma and/or osteosarcoma, and both
      alleles are often mutated or inactivated in sporadic forms of these and other
      cancers. We now demonstrate that the product of the RB1 gene, Rb, regulates the
      expression of the murine Brca1 and human BRCA1 genes through its ability to
      modulate E2F transcriptional activity. The Brca1 gene is identified as an in vivo
      target of E2F1 in a transgenic mouse model. The Brca1 promoter contains E2F DNA
      binding sites that mediate transcriptional activation by E2F1 and repression by
      Rb. Moreover, ectopic expression of cyclin D1 and Cdk4 can stimulate the Brca1
      promoter in an E2F-dependent manner, and this is inhibited by coexpression of the
      p16(INK4a) cyclin-dependent kinase inhibitor. The human BRCA1 promoter also
      contains a conserved E2F site and is similarly regulated by E2F1 and Rb. This
      functional link between the BRCA1 and Rb tumor suppressors may provide insight
      into the mechanism by which BRCA1 inactivation contributes to cancer development.

PMID- 10660631
TI  - Herbs in pediatric and adolescent medicine.

PMID- 10660632
TI  - Prevention of neural tube defects by periconceptional use of folic acid.

PMID- 10660633
TI  - Index of suspicion. Case 1. Diagnosis: arteriovenous malformation.

PMID- 10660635
TI  - [Dermatophytes from animals].
AB  - Dermatophytes from animal dermatophytoses were investigated, especially for their
      teleomorphs and molecular characteristics. Microsporum canis, M. equinum, M.
      gypseum, M. nanum, Trichophyton equinum, T. mentagrophytes complex, T. rubrum and
      T. verrucosum were isolated as the etiological agents of animal ringworm in
      Japan. They were morphologically and biochemically identified and their perfect
      states were examined. The teleomorph of M. canis was first obtained and reported
      as Nanizzia otae in 1975. The isolates of M. canis of which the teleomorph was
      confirmed were all "-" excepted two Japanese isolates. Mating experiments
      indicated that the isolates of M. gypseum were "+" or "-" of A. gypseum and A.
      incurvatum, respectively. Most of the isolates of T. mentagrophytes complex of
      which a perfect state was detected were A. vanbreuseghemii. One isolate from a
      monkey was A. simii and one from a rabbit was A. benhamiae. However, the
      teleomorph remained unknown in many isolates. Molecular characteristics in random
      amplification of polymorphic DNA and Southern hybridization analyses were found
      to be effective to differentiate the species of Microsporum. Nucleotide sequences
      of chitin synthase 1 (CHS1) gene of dermatophytes were also analyzed for their
      phylogenetic relatedness. The phylogenetic analysis revealed four clusters: the
      first cluster consisted of A. benhamiae, A. simii, A. vanbreuseghemii, T.
      mentagrophytes var. interdigitale, T. rubrum and T. violaceum; the second of A.
      fulvum, A. gypseum and A. incurvatum; the third of A. grubyi and A. otae; and the
      fourth of Epidermaphyton floccosum, providing useful information for the
      classification and understanding of their evolution.

PMID- 10660636
TI  - [Effect of temperature, humidity and minor injury to the penetration of
      dermatophytes into human stratum corneum].
AB  - We evaluated the minimum period for penetration of Trichophyton mentagrophytes
      into human stratum corneum using an experimental model of tinea pedis. Fungal
      elements were applied to the surface of stratum corneum which were obtained from
      a healthy human heel, and samples were incubated under a designated condition of
      temperature and humidity. Thirty-five degrees, which is the approximate
      temperature of the surface of human skin, seemed more suitable for penetration
      than 27C. The result also indicated that humidity was a more significant factor
      than temperature. In the following examination using T. mentagrophytes and T.
      rubrum, the minimum period for penetration at 100% humidity was 1 day with the
      former and 1.5 days with the latter. At 95% humidity, T. mentagrophytes
      penetrated into human stratum corneum on day 1.5 and T. rubrum penetrated on day
      4. Humidity of the 4th interdigital space in daily life was calculated to be
      below 95% using a hygro-thermometer. Therefore, to wash the feet daily can
      prevent development of tinea pedis. When we applied fungal elements to a cut side
      of stratum corneum, fungi penetrated within a day at 100% and 95% humidity. In
      addition, fungi were able to penetrate at below 85% humidity, which they were
      unable to do when applied them to the surface side. We stress that minor injury
      of stratum corneum is also a significant factor of the development of tinea
      pedis.

PMID- 10660637
TI  - Molecular analysis of DNA polymorphism of Sporothrix schenckii.
AB  - Partial cDNA cloning of a putative membrane transporter protein gene expressed in
      Sporothrix schenckii and DNA polymorphism of the isolated gene are described
      here. DNA fragments were isolated from S. schenckii, and the deduced amino acid
      sequence from one of the fragments contained a region homologous to the conserved
      sequence of the membrane transporter protein family. 188-bp fragments encoding
      the homologous region were amplified from many strains of S. schenckii, and were
      subjected to polymerase chain reaction single strand conformation polymorphism
      (PCR-SSCP) analysis. The results demonstrated that the strains of S. schenckii
      were divided into three groups, and several base substitutions among these groups
      were observed. This finding agreed with the classification of S. schenckii
      strains based on the mitochondrial DNA diversity, because the three groups were
      clearly located on the branches of the phylogenetic tree constructed by digestion
      profiles of mitochondrial DNA with restriction enzymes. The correlation of the
      results of PCR-SSCP analysis with the mitochondrial DNA diversity might indicate
      linkage of the mutation of the membrane transporter protein gene with the
      evolution of S. schenckii, suggesting the protein plays an essential role in S.
      schenckii.

PMID- 10660638
TI  - A case of cutaneous Exophiala spinifera infection.
AB  - A 66-year-old female had a solitary dark-red nodule measuring 1 cm in diameter on
      her left forearm. She often had trauma to her hands and arms. A histopathologic
      examination demonstrated granulomatous changes in the dermis. Under the high
      power magnification yeast-like cells and short toruloid hyphal elements were
      observed in the granuloma. A few giant cells contained fungal elements. No
      sclerotic cells were found. On the basis of the histopathologic and mycologic
      findings, the lesion was diagnosed as a dematiaceous fungal infection caused by
      Exophiala spinifera. She was treated with oral itraconazole (200 mg/day) and
      topical heat therapy. The lesion was clinically improved within 58-days. However,
      E. spinifera was still isolated from the excisional specimen 92-days later. We
      believe that surgical excision is the choice of therapy if the lesion is small.

PMID- 10660639
TI  - A case of Penicillium marneffei infection in an AIDS patient: the first case in
      Japan.
AB  - A 38-year-old Japanese AIDS patient developed papular lesions which rapidly
      increased in number, eroded and crusted, and spread over not only skin but also
      the mucosal surface. High fever, sore throat, malaise and hepatosplenomegaly were
      also noted, and he died despite 2 months of intensive treatment. An autopsy
      revealed numerous histiocytes infected with Penicillium marneffei in the lymph
      nodes, liver, spleen, bone marrow, skin, and mucosal surface of the oral cavity
      to the pharynx. This case is thought to be the first Japanese case of
      penicilliosis marneffei.

PMID- 10660640
TI  - [Statistical surveillance of mucocutaneous candidiasis in Showa University
      Fujigaoka Hospital in the past 5 years].
AB  - We investigated the epidemiology of 618 patients of mucocutaneous candidiasis who
      visited our outpatient clinic between 1993 and 1997. Compared with previous
      reports in Japan, the incidence of candida intertrigo increased and that of
      erythema mycoticum infantile decreased. The incidence of "others", such as nail
      candidiasis and candidiasis developed under plaster increased. We identified the
      species of Candida from patients in 496 recent cases, and these species were
      cultured successfully in 79.2%. As reported by previous authors, a majority or
      our results were Candida albicans serotype A. We also investigated the risk
      factors such as diseases or conditions which might be related to immunodeficiency
      (neoplasm, AIDS) and that might force a patient to restrict himself to bed for a
      long period (neurological disease). The former was found in 22.7%, and the latter
      in 23.3% of patients.

PMID- 10660641
TI  - Serum itraconazole and hydroxyitraconazole concentrations and interaction with
      digoxin in a case of chronic hypertrophic pachymenigitis caused by Aspergillus
      flavus.
AB  - A patient treated with itraconazole (ITCZ) under the diagnosis of Aspergillus
      flavus-induced chronic hypertrophic pachymeningitis is presented. The reason for
      the successful cure of this patient was investigated by the pharmacokinetic
      analysis of serum levels of ITCZ. Concurrently administered digoxin was also
      investigated for its drug-drug interaction. The patient (a 75-year-old male)
      developed ophthalmopathy, and was diagnosed as having A. flavus hypertrophic
      pachymeningitis by pachymeninx biopsy. After admission, he was treated with FLCZ,
      AMPH, 5-FC and MCZ. The infection tended to subside with the AMPH administration.
      Since renal insufficiency was induced by AMPH and the other antifungal drugs were
      ineffective, daily administration of 200 mg of ITCZ was initiated, and the
      inflammatory signs and symptoms gradually subsided. The symptoms did not recur
      during the 36 months of itraconazole treatment after discharge, and it was
      concluded that ITCZ was effective for A. flavus hypertrophic pachymeningitis.
      Pharmacokinetic parameters of ITCZ and OH-ITCZ as follows: ITCZ: Cmax 93.2 ng/ml,
      T1/2 beta 11 hours, AUC0-24 999 ng.h/ml, OH-ITCZ: Cmax 159.4 ng/ml, T1/2 beta 16.
      2 hours, AUC0-24 of 1391 ng.h/ml. Both ITCZ and OH-ITCZ reached steady states
      seven days after administration began. The ITCZ and OH-ITCZ levels in serum
      collected 36 months after the initiation of administration were 452.9 ng/ml and
      1233.6 ng/ml, respectively. Cmax and AUC0-24 of ITCZ and OH-ITCZ on the second
      day were markedly lower than those in healthy adults reported by Oguchi et al.,
      and hypoalbuminemia observed at administration on that day was considered the
      most probable cause. It was assumed that the most plausible reason for a
      successful cure even at a low dose of ITCZ was the increase of distribution to
      tissue by the increase of the unbound form. Digoxin was concurrently given to
      this patient at 0. 125 mg/day, but the blood digoxin level was not elevated.
      Consideration of the blood level of albumin is believed to be important for
      evaluating the blood concentration of ITCZ.

PMID- 10660642
TI  - Evaluation of miconazole activity contained in human serum to hypha of
      Aspergillus fumigatus.
AB  - Aspergillus fumigatus is an opportunistic pathogen, especially in an
      immunocompromised host. This fungus grows in a hyphal form in infected tissues;
      therefore, new tests to examine hyphal susceptibility are needed. In this study,
      we measured the mycotic activity of miconazole (MCZ) contained in human serum
      against A. fumigatus using the BioCell-Tracer method. Three serum samples were
      obtained from the same patient who was injected with 600 mg b.i.d. MCZ daily for
      2 days. The concentrations of MCZ in the serum sample were 8.8, 3.5, and 1.6
      micro g/ml, respectively. The serum containing 8.8 micro g/ml of MCZ inhibited
      hyphal growth 90 minutes after administration, and the hypha stopped growing. The
      serum containing 3.5 micro g/ml MCZ stopped hypha growth 100 minutes after
      administration, but re-growth of the hypha was observed at this concentration of
      MCZ. Serum containing 1.6 micro g/ml did not inhibite hyphal growth, nor did
      control serum have any inhibitory activity foward hyphae. Based on these results,
      we conclude that the BioCell-Tracer is a useful method for determining the
      effects on filamentous fungi of antifungal agents in the serum.

PMID- 10660643
TI  - [In memory of Professor Pierre Amalric].

PMID- 10660644
TI  - [Exploration of visual memory by functional MRI].
AB  - PURPOSE: The aim of our study was to evidence the location of the cortical area
      triggered by visual memory tasks by he mean of functional magnetic resonance
      imaging examination (fMRI). METHODS: Twelve healthy volunteers underwent fMRI
      examination on a 1.5 Tesla magnet with echoplanar imaging sequence during
      figurative and non-figurative memory tasks. An area was considered to be
      activated if at least 10 contiguous voxels activation was noted. Activated areas
      were defined for both tasks and the brain mapping was realized according to
      Talairach atlas. RESULTS: For all examinations a bilateral activity was evidenced
      (area 17 and 18). In addition, a frontal activation was also noted in 83% of the
      cases for both tasks. However, frontal activation was bilateral in 9/10 cases for
      the figurative task and 6/10 cases for the non-figurative task. CONCLUSION: FMRI
      was able to evidence activation of cerebral areas during visual memory tasks in
      all our study cases. Frontal activation was not discriminative of figurative or
      non figurative memory. This might be probably explain by inappropriate non
      figurative tests. FMRI should allow a better knowledge of memory mechanisms as
      well as an enhancement of functional cerebral mapping before surgery.

PMID- 10660645
TI  - [Evaluation of functional and anatomical changes in the macula after surgery for
      retro-foveal neovascularization of membranes in age-related macular
      degeneration].
AB  - PURPOSE: The aim of this study was to evaluate the direct effect of surgical
      treatment of subfoveolar neovascular membranes in age related macular
      degeneration to macular functions. PATIENTS AND METHODS: Thirteen eyes of 13
      patients were included in this study. Macular function was assayed by visual
      acuity and central visual field using the Octopus perimeter before surgery and in
      the first three post operative months. Pre and post operative fluorescein
      angiography frames were digitalized and the size of each lesions were compared.
      RESULTS: After a 3 months follow up, visual acuity remained stable or improved in
      66% of the patients. However, visual acuity was better than 0.1 in 15% of the
      patients. Central visual field comparison disclosed a significant worsening of
      the retinal sensitivity in the 3 degree field surrounding the central point. On
      fluorescein frames, submacular scar was 141% of the size of the neovascular
      membrane. After a mean follow up of 6.9 months (range 3-14), one case of
      recurrence occurred. A cataract was observed in 85% of the phakic patients
      followed for more than six months. CONCLUSION: After a short term follow up,
      surgery can stabilise visual acuity, even though it remains poor. A worsening of
      the scotoma in the 3 degrees surrounding the central point is observed. However,
      patients noticed a subjective visual improvement in 62% of the case.

PMID- 10660646
TI  - [Correlation between neuroretinal rim and optic disc areas in normal melanoderm
      and glaucoma patients].
AB  - BACKGROUND: To evaluate optic disc size and its relationship with neuroretinal
      rim areas. MATERIAL AND METHODS: The study was prospective; 400 hundred patients
      with 292 glaucomatous and 108 non glaucomatous were enrolled in this study. Optic
      disc size quantification was assessed by the use of Goldmann 3 mirror contact
      lens; diameter reading were adjusted by the magnification factor of the lens,
      squares of the disc and the cupping were calculated using an ellipse formula, the
      neuroretinal rim area was then obtained by reducing the cupping area from the
      whole optic disc area. RESULTS: The mean age of the sample was 36.80 years (sd:
      15.68 years).The average value of the vertical disc diameter was 2.045 mm (sd:
      0.254) for glaucoma patients and 1.966 mm (sd: 0.237) in the control group;
      p<0.001. Neuroretinal rim area was 1.886 mm(2) (sd: 0.675) in the glaucoma group;
      and 2.165 mm(2) (sd: 0.425) in the control one; p<0. 004. In the glaucoma group,
      72.97% of large optic disc were found (vertical diameter over 1.90 mm); and
      63.80% in the control one. In the control group, neuroretinal rim area was wider
      in the large optic discs compared to the small discs, p<0.001, Anova test.
      Neuroretinal rim area was thinner in the glaucoma large disc compared to the
      control, p<0.005, Student test. Meanwhile, there was no difference in the medium
      and the small discs in the glaucoma and control groups; p > 0.005, Student
      Newmann test. CONCLUSION: Neuroretinal rim areas are thinner in the large
      glaucoma discs compared to the non glaucoma large discs. In Africa, this
      parameter could be helpful in the diagnosis and survey of glaucoma patients.

PMID- 10660647
TI  - [Central retinal vein occlusion in a patient treated with antiandrogenic drug].
AB  - Central retinal vein occlusion (CRVO) is usually seen in older adults and is
      often associated with systemic vascular disease, this is much less evident in
      young people. A case report of a 28-year-old woman presented a central retinal
      vein occlusion in her left eye. This young woman was treated with antiandrogenic
      drug. Investigations revealed an abnormality of the hemostatic system. The
      central retinal vein occlusion was resolved and the fundus assumed a normal
      appearance one-month after the primary episode. Retinal vascular occlusions with
      antiandrogenic drug may be due to three mechanisms: increased platelet cell
      aggregation, alteration of fibrinolytic system and vascular endothelium
      hyperplasia.

PMID- 10660648
TI  - [Laser photocoagulation of occult choroidal neovascularization guided by
      angiography using indocyanine green. A pilot study].
AB  - PURPOSE: Age related macular degeneration (AMD) is the most common cause of legal
      blindness in the Western world in people over 50 years of age. The most severe
      visual loss occurs in patients with AMD complicated by choroidal neovascular
      membranes (CNV). Indocyanine green angiography (ICG) account for visualization in
      up to 60% of the cases that are classified as occult on fluorescein angiography
      (up to 70% of the cases). ICG-guided laser photocoagulation of CNV is currently a
      mater of debate. We conducted a pilot study to determine wether it could be
      beneficial for patients presenting with occult CNV on fluorescein angiography.
      MATERIAL AND METHODS: Twenty consecutive patients (20 eyes) with occult CNV in
      AMD were included. All showed occult CNV on fluorescein angiography and a well
      defined juxta- or extrafoveal hot spot or plaque hyperfluorescence on ICG.
      Fibrovascular retinal pigment epithelial detachments were excluded. The patients
      had serial controls, including fluorescein angiography and ICG, at 15 days, 1, 2,
      3, 6, 9 and 12 months after photocoagulation. RESULTS: At the end of follow-up
      visual acuity (VA) was stable (within +/- 3 lines) compared to the initial one in
      80% (16) of the cases. A complete resolution of exudative signs was observed in
      75% (15) of the cases. CONCLUSIONS: ICG-guided laser photocoagulation of occult
      CNV in AMD account for better visual acuity than natural course of the disease at
      12 months follow-up. However, a prospective randomized clinical trial is
      warranted to evaluate definitively this treatment approach.

PMID- 10660649
TI  - [Cockayne's syndrome with unusual retinal involvement (report of one family)].
AB  - Cockayne's syndrome is a very rare autosomal recessive affection. Ocular
      involvement is an essential element for positive diagnosis; the retina shows a
      typical salt and pepper retinitis with optical atrophy. We report a family with
      four brothers who had Cockayne's syndrome with unusual retinal involvement. The
      patients' parents were first cousins. Ophthalmologic examination of the mother
      showed unilateral left pigmentary retinopathy localized in the peripapillary
      region. The father's ophthalmological examination was normal. The four brothers
      presented disharmonious dwarfism, cutaneous hyperpigmentation of skin areas
      exposed to sun with old-appearance of the skin, sensorineural deafness,
      kyphoscoliosis, a cerebellar syndrome and mental retardation. The
      ophthalmological examination showed hypermetropia in all four brothers and
      bilateral maculopathy with no papillary or vascular abnormalities. The
      electroretinogram was in favor of cone dystrophy. Computed tomography showed one
      case of calcifications of the basal ganglia and cerebral atrophy. The karyotypes
      of the four brothers and the mother were normal. We discuss the ocular symptoms
      and the etiopathogenesis of this syndrome.

PMID- 10660659
TI  - Chemiluminescent measurement of peroxidase activity and its application using a
      lucigenin CT-complex.
AB  - Luminol (3-aminophthaloylhydrazine) is well known as a chemiluminescent reagent
      that can be used to measure peroxidase (POD) activity. We have developed a more
      sensitive assay for POD using a new chemiluminescent reagent based on 10,10'
      dimethyl-9, 9'-biacridinium nitrate (lucigenin). This new reagent was obtained
      from lucigenin by light irradiation in an organic polar solvent such as N,N
      dimethylacetamide (DMAc). The detection limit for POD activity using this reagent
      is 10(-19) mol/assay. In an application for enzyme immunoassay based on a POD
      label, we were able to detect human alpha-fetoprotein (AFP) at 1pg/mL. The
      characterization of this chemiluminescent reagent was obtained by optical
      measurements, and the formation of lucigenin charge transfer complex (CT-complex)
      was confirmed. We also investigated the stability of lucigenin CT-complex as a
      chemiluminescent reagent for the measurement of POD activity, and confirmed that
      the reagent was stable for more than a year.

PMID- 10660660
TI  - Chemiluminescence of adzuki bean and soybean seedlings.
AB  - The chemiluminescence of extracts from leguminous seedlings (adzuki bean and
      soybean) was investigated. In an H(2)O(2)/gallic acid/water extract system, the
      photon intensities of adzuki bean seedlings were increased after germination and
      in the hypocotyls it reached a maximum level during the first 4 days of
      germination. On day 4 after germination, chemiluminescence in the primary leaf
      part exhibited the strongest intensity. Emission spectra showed a main peak at
      510 nm, with shoulders at 660 nm. Mechanical injuries to the stems and cotyledons
      resulted in about a 1.5- and 6.8-fold increase of chemiluminescence,
      respectively. In an H(2)O(2)/70% EtOH extract/HRP system, photon intensities
      increased after germination and reached a maximum level during the first 2 days
      of germination. On day 4 after germination, chemiluminescence in the root and
      leaf area was stronger than in any other area. Emission spectra showed a main
      peak at around 570 nm, with shoulders at around 660 nm. The photon intensities of
      stems and cotyledons after mechanical injuries resulted in about an 0.72-fold
      decrease and an 8.8-fold increase in the presence of H(2)O(2) and acetaldehyde
      (MeCHO), respectively.

PMID- 10660661
TI  - Effect of exhaustive exercise on human neutrophils in athletes.
AB  - In order to investigate the effect of exercise on the capacity of neutrophils to
      produce reactive oxygen species (ROS), eight male cross-country skiers underwent
      maximal exercise. Peripheral blood samples were taken pre-exercise, 0 h, 1 h, and
      2 h after finishing maximal exercise. Leukocyte counts significantly increased (p
      < 0. 05), particularly lymphocytes (p < 0.05), just after the exercise period (0
      h) and significantly increased again (p < 0.05), particularly neutrophils (p <
      0.05), 2 h after the exercise compared with pre-exercise values. The capacity of
      isolated neutrophils to produce ROS was assessed by lucigenin (Lg)-dependent
      chemiluminescence (CL) and luminol (Lm)-dependent CL on stimulation with
      opsonized zymosan (OZ) and phorbol myristate acetate (PMA). Just after exercise,
      the LgCL response was not affected, while the response of LmCL mixed with sodium
      azide, which inhibits catalase and myeloperoxidase (MPO) activity, was
      significantly enhanced (p < 0.05). In addition, just after exercise, the level of
      serum growth hormone increased significantly (p < 0.05). The serum cortisol level
      also increased significantly just after and 1 h after exercise (p < 0.05). These
      data indicated that maximal exercise not only mobilized neutrophils from
      marginated pools into the circulation, but also caused increased ROS generation.

PMID- 10660662
TI  - Detection of luciferase having two kinds of luminescent colour based on optical
      filter procedure: application to an enzyme immunoassay.
AB  - This paper reports on our study using several optical filters known to be
      efficient in separating compounds having various levels of maximum luminescence,
      to separate information from three kinds of Luciola lateralis luciferase with a
      maximum luminescence of 559 nm, 604 nm and 607 nm. Simultaneous luminescence of
      Luciola lateralis luciferase was determined by measuring the luminescence through
      a band pass filter or sharp cut filter (BPB50, 53, 58, No.58, SC58, 60, 62, 64).
      It was possible to determine luciferase with a maximum luminescence lambda(max)
      of 559 nm (yellow-green) utilizing the band pass filter (BPB 50), described here.
      Meanwhile, luciferase with a lambda(max) of 607 nm (red) could be determined by
      calculations based on the bioluminescent intensity through the band pass filter
      and sharp cut filter (SC58). In addition, we also applied a simultaneous
      bioluminescent enzyme immunoassay of pepsinogen I (PGI) and pepsinogen II (PGII)
      in which two kinds of biotinylated luciferase (Luciola lateralis) labelled as an
      enzyme producing yellow-green light (lambda(max) = 559 nm) and red light
      (lambda(max) = 607 nm) were used. In the proposed method, PGI and PGII in serum
      were simultaneously captured in a sandwich-type immune reaction between anti-PGI
      and anti-PGII monoclonal antibody-coated magnetic particles, and streptavidin
      biotinylated luciferase biotinylated anti-PGI and anti-PGII monoclonal antibodies
      triplexes, respectively. The result was a calibration range for PGI of 2-200
      ng/mL, and for PGII of 1-100 ng/mL. In conclusion, the correlation of PG values
      in serum between the proposed method (simultaneous assay) and an individual
      specific bioluminescent immunoassay (specific assay) were satisfactory.

PMID- 10660663
TI  - Mechanoluminescence: lymphocyte analysis after exposure to ionizing radiation.
AB  - Lymphocyte mechanoluminescence (ML) develops as a result of mechanochemical
      activation of cells. This paper describes devices (tribogenerators) and
      techniques for lymphocyte mechanoluminescence analysis. At different stages of
      the cellular cycle the ML of non-irradiated peripheral blood lymphocytes (PBL)
      showed characteristic differences. After (60)Co gamma -irradiation of PBL in
      vitro at 0.25 Gy and 1 Gy an alteration of ML was observed with a relationship
      between ML values of lymphocytes, and also of mitochondria (MT), and the dose of
      ionizing radiation used. By using bioluminescence techniques it was shown that
      gamma-irradiation reduces the amount of ATP synthesized by PBL in the stationary
      phase.

PMID- 10660664
TI  - Green tea extract and its polyphenols markedly inhibit luminol-dependent
      chemiluminescence activated by peroxynitrite or SIN-1.
AB  - This study is based on a simple chemical interaction of peroxynitrite (OONO-) and
      luminol, which produces blue light upon oxidation. Since peroxynitrite has a half
      life of less than 1 s, a drug known as SIN-1 is used as a peroxynitrite
      generator. In addition peroxynitrite itself was used directly with a fast
      injection-mixing system to ascertain whether there are differences between it and
      the peroxynitrite-generating system (SIN-1) which mimics the natural production
      of (OONO-). Peroxynitrite is a potent oxidizing compound (1000 times more active
      than equidose hydrogen peroxide) and it can oxidize carbohydrates, lipids,
      proteins and nucleic acids. Upon stimulation by inflammation and/or infection,
      macrophages and neutrophils can be activated to produce large amounts of
      peroxynitrite. We are interested in simple chemicals that are non-toxic that
      could inhibit or destroy peroxynitrite, which might otherwise cause inappropriate
      damage to blood and tissues. Green tea is a complex mixture containing several
      potent major antioxidant constituents, eg flavins and/or polyphenols. The
      constituents in green tea may react directly or indirectly with peroxynitrite or
      its constituents through the process of antioxidation to inhibit light.
      Alternatively, compounds could produce superoxide which, when reacted with nitric
      oxide, could produce more peroxynitrite and hence more light with luminol.
      Therefore, as the tea or antioxidants from tea are diluted, while the
      peroxynitrite or its precursors are kept at a constant concentration, one can
      observe unusual behaviour regarding light emission. Initially, at high doses of
      tea or antioxidant, one observes clear inhibition of the light generated from the
      reaction of peroxynitrite and luminol. However, at dilute concentrations of
      antioxidants, one can often observe stimulation of light. Possible reasons for
      these observations are discussed.

PMID- 10660665
TI  - Visualizing and quantifying protein secretion using a Renilla luciferase-GFP
      fusion protein.
AB  - We have shown previously that an engineered form of Renilla luciferase (SRUC) can
      be secreted as a functional enzyme by mammalian cells, and that fusing wild-type
      Renilla luciferase with the green fluorescent protein from Aequorea victoria
      (GFP) yields a chimeric protein retaining light-emission properties similar to
      that of unfused Renilla luciferase and GFP. In the work presented here, SRUC was
      fused with GFP to determine whether it could be used to both visualize and
      quantify protein secretion in mammalian cells. Simian COS-7 and Chinese hamster
      ovary (CHO) cells were transiently transfected with gene constructs encoding a
      secreted or an intracellular version of a Renilla luciferase-GFP fusion protein.
      Renilla luciferase activity was measured from COS-7 cell lysates and culture
      media, and GFP activity was detected in CHO cells using fluorescence microscopy.
      Data indicated that the SRUC-GFP fusion protein was secreted as a chimeric
      protein that had both Renilla luciferase and GFP activity. This fusion protein
      could be a useful marker for the study of protein secretion in mammalian cells.

PMID- 10660666
TI  - Light-emitters involved in the luminescence of coelenterazine.
AB  - Coelenterazine emits light by chemi-and bioluminescence reactions, decomposing
      into coelenteramide and CO(2). To ascertain the light emitters involved, the
      fluorescence of coelenteramide and five analogues were studies in four kinds of
      solvent. The results showed that coelenteramides can form five kinds of light
      emitters, ie unionized (lambda(max) 386-423 nm), phenolate anion (lambda(max) 480
      490 nm), phenolate anion temporarily formed from the ion-pair state (lambda(max)
      465-479 nm), amide anion (lambda(max) 435-458 nm) and pyrazine-N(4) anion
      (lambda(max) 530-565 nm). The chemiluminescence light emitter of coelenterazine
      in the presence of alkali (lambda(max) 530-550 nm) was found to be the pyrazine
      N(4) anion and not the dianion (ie phenolate anion/amide anion), as previously
      believed. In chemiluminescence, the normal light emitter is the amide anion, and
      the pyrazine-N(4) anion emission may occur in the presence of alkali, but light
      emission from any other emitters has not been observed. In the bioluminescence
      reaction, the normal light emitter is the amide anion, but no other light emitter
      was observed except the unionized form found in the Ca-triggered luminescence of
      semisynthetic aequorins prepared with an e-type coelenterazine instead of
      coelenterazine.

PMID- 10660667
TI  - Mus musculus in the SWISS-PROT database: its relevance to developmental research.

PMID- 10660668
TI  - Heterogeneous populations of ES cells in the generation of a floxed Presenilin-1
      allele.
AB  - Generation of a floxed Presenilin-1 (PS1) allele involved two recombination
      events in the embryonic stem (ES) cells. First, a targeting vector containing a
      loxP site in intron 1 and a floxed CMV-HYG/TK double selection cassette in intron
      3 was integrated into the PS1 locus by homologous recombination. The use of a
      negative selection cassette, PGK-DTA, dramatically increased the recombination
      efficiency within the targeted locus (75-fold). Second, an expression vector
      encoding Cre recombinase was introduced to excise the floxed CMV-HYG/TK cassette
      via site-specific recombination. However, all five ES cell clones testing
      positive for the proper removal of the CMV-HYG/TK cassette also contained a
      proportion of ES cells in which recombination had occurred between the distal
      loxP sites in introns 1 and 3, resulting in excision of the entire floxed region.
      It is therefore critical to screen for possible recombination events involving
      all 3 loxP sites, in order to identify ES cells clones bearing high proportions
      of the desired ES cells. genesis 26:5-8, 2000.

PMID- 10660669
TI  - Differential gene expression during elongation in the preimplantation pig embryo.
AB  - On day 12-13 of gestation, the preimplantation pig conceptus undergoes a dramatic
      morphologic change from an approximately 1-cm sphere to a nearly 1-m long thread.
      This transformation, referred to as elongation, occurs in just 12-24 h.
      Elongation is primarily the result of trophectodermal cell shape changes, as
      there is relatively little mitosis during this stage of development. Thus far,
      descriptions of elongation have been limited to histologic and immunofluorescent
      studies of cell morphology and gross biochemical evaluations. We hypothesized
      that the changes in trophectoderm morphology likely involves significant changes
      in gene expression. Therefore, we used RNA arbitrarily primed-PCR (RAP-PCR) to
      characterize potential differential gene expression by trophectodermal cells
      during pig conceptus elongation. We found that the porcine heterogeneous nuclear
      ribonucleoprotein (hnRNP) A2/B1 was shown to be differentially expressed by
      trophectodermal cells during elongation. We suggest that regulated alternative
      splicing may contribute to the morphogenetic process of elongation. genesis 26:9
      14, 2000. Published 2000 Wiley-Liss, Inc.

PMID- 10660671
TI  - The polo-like kinase PLK-1 is required for nuclear envelope breakdown and the
      completion of meiosis in Caenorhabditis elegans.
AB  - The Polo-like kinases are key regulatory molecules required during the cell cycle
      for the successful completion of mitosis. We have cloned a C. elegans homolog of
      the Drosophila melanogaster polo gene (designated plk-1 for C. elegans polo-like
      kinase-1) and present the subcellular localization of the PLK-1 protein during
      the meiotic and mitotic cell cycles in C. elegans oocytes and embryos,
      respectively. Disruption of PLK-1 expression by RNA-mediated interference (RNAi)
      disrupts normal oocyte and embryonic development. Inspection of oocytes revealed
      a defect in nuclear envelope breakdown (NEBD) before ovulation. This defect in
      NEBD was also observed in oocytes that were depleted of the cyclin-dependent
      kinase NCC-1 (C. elegans homolog of Cdc2). The plk-1 RNAi oocytes were
      fertilized; however the resulting embryos were unable to separate their meiotic
      chromosomes or form and extrude polar bodies. These defects led to embryonic
      arrest as single cells. genesis 26:26-41, 2000. Published 2000 Wiley-Liss, Inc.

PMID- 10660670
TI  - LMX1B, a LIM homeodomain class transcription factor, is necessary for normal
      development of multiple tissues in the anterior segment of the murine eye.
AB  - Proper development of the anterior segment of the mammalian eye is critical for
      normal ocular function. Indeed, several congenital syndromes associated with
      anterior segment anomalies can lead to impaired vision and glaucoma. One such
      syndrome is nail patella syndrome (NPS), caused by haploinsufficiency for the LIM
      homeodomain transcription factor LMX1B. Although mutations in LMX1B cosegregate
      with NPS, whether these mutations cause the glaucoma associated with NPS is not
      known. Here, we provide evidence that the LIM-homeodomain transcription factor
      lmx1b is an essential regulator of murine anterior segment development. Mice that
      are homozygous for a targeted mutation of lmx1b display iris and ciliary body
      hypoplasia, and cornea stromal defects. In addition, two cDNAs normally
      downregulated in presumptive cornea, mf1 and mfh1, exhibit persistent expression,
      while keratocan, a keratin sulfate proteoglycan expressed by keratocytes, is not
      detected in mutant corneas. Moreover, ultrastructural examination of homozygous
      mutants indicates that corneal collagen fibrillogenesis is perturbed. Taken
      together, our studies suggest a developmental etiology for glaucoma in NPS
      patients and highlight lmx1b as an essential regulator of anterior segment
      morphogenesis and patterning. genesis 26:15-25, 2000.

PMID- 10660672
TI  - LEUNIG has multiple functions in gynoecium development in Arabidopsis.
AB  - The Arabidopsis gene LEUNIG was previously found to regulate floral organ
      identity. In this work we describe gynoecial phenotypes of newly isolated strong
      leunig alleles, leunig-101, leunig-102, and leunig-103. Gynoecia of these strong
      leunig mutants are united only at the basal part, leaving four unfused parts at
      the apex. Among them two medial ones are styles capped with stigmas, and two
      lateral ones are protrusions from valves. The gynoecium with unfused apex in
      leunig arises as a unit from a basal meristematic zone, suggesting that LEUNIG is
      required for normal congenital gynoecium fusion. The epidermal cells on growing
      inner surfaces of leunig gynoecium failed to fuse after they contact each other,
      indicating that LEUNIG is essential for the proper postgenital fusion. The
      epidermal cells at the very distal portion of protruded valves mimic those on
      wild-type styles, and those valves occasionally also have stigma-like tissues,
      indicating that LEUNIG function is required for the valve identity determination.
      We have also analyzed clavata1-4 leunig-101, clavata2-1 lug-101, fruitfull-1
      leunig-101, and pinoid-1 leunig-101 double mutants. clavata1-4 leunig-101 and
      clavata2-1 leunig-101 exhibited additive phenotypes of single mutants, suggesting
      that LEUNIG and CLAVATA genes function in different pathways. In contrast,
      FRUITFULL and PINOID genes interact with LEUNIG to regulate gynoecium
      development. genesis 26:42-54, 2000.

PMID- 10660673
TI  - Cardiac enhancer activity of the homeobox gene tinman depends on CREB consensus
      binding sites in Drosophila.
AB  - The Drosophila homeobox gene tinman plays a critical role in subdividing the
      early mesoderm. In particular, tinman is absolutely required for formation of the
      heart and visceral mesoderm. tinman expression is initiated throughout the
      mesoderm of the trunk region under the control of the bHLH transcription factor
      encoded by the twist gene, a determinant of all mesoderm. Later, tinman
      expression is restricted to the dorsal portion of the mesoderm, a process that is
      directed by decapentaplegic (dpp) whose product (a TGF-beta-related protein) is
      secreted by the overlaying ectoderm. Further restriction of tinman expression to
      the cardiac progenitors, in which it will persist throughout development,
      involves the secreted segmentation gene product encoded by wingless (wg, a
      Drosophila Wnt gene). Here, we show that strong early expression depends on the
      synergistic action of an enhancer element at the 5' end of the gene in
      conjunction with an element in the first intron. Moreover, two distinct enhancer
      regions are responsible for tinman expression in the heart: one region confers
      expression in the heart-tube-associated pericardial cells, the other element
      drives expression in the contractile, myocardial cells. The latter element
      contains two CREB consensus binding sites that are essential for cardiac-specific
      expression. genesis 26:55-66, 2000.

PMID- 10660674
TI  - Mouse homolog of the Drosophila Pc-G gene esc exerts a dominant negative effect
      in Drosophila.
AB  - The Polycomb group genes are involved in maintaining long term transcriptional
      repression of the homeotic genes in both Drosophila and mammals. The mouse eed
      locus encodes the highly conserved ortholog of the Drosophila ESC protein. To
      test the functional conservation between the two genes, eed was introduced into
      the fly to determine whether it could rescue the esc mutant phenotype. eed
      exerted a dominant negative effect on the leg transformation phenotype associated
      with the esc mutation. This result is interpreted in light of in vitro protein
      protein binding data and in vivo polytene chromosome staining indicating the lack
      of significant interaction between Eed and fly E(Z), a molecular partner of ESC.
      genesis 26:67-76, 2000

PMID- 10660675
TI  - The pan-neural bHLH proteins DEADPAN and ASENSE regulate mitotic activity and cdk
      inhibitor dacapo expression in the Drosophila larval optic lobes.
AB  - Developmental regulators and cell cycle regulators have to interface in order to
      ensure appropriate cell proliferation during organogenesis. Our analysis of the
      roles of the pan-neural genes deadpan and asense defines critical roles for these
      genes in regulation of mitotic activities in the larval optic lobes. Loss of
      deadpan results in reduced cell proliferation, while ectopic deadpan expression
      causes over-proliferation. In contrast, loss of asense results in increased
      proliferation, while ectopic asense expression causes reduced proliferation.
      Consistent with these observations endogenous Deadpan is expressed in mitotic
      areas of the optic lobes, and endogenous Asense is expressed in cells that will
      become quiescent. Altered Deadpan or Asense expression results in altered
      expression of the cyclin dependent kinase inhibitor gene dacapo. Thus, regulation
      of mitotic activity during optic lobe development may, at least in part, involve
      deadpan and asense mediated regulation of the cyclin dependent kinase inhibitor
      gene dacapo. genesis 26:77-85, 2000.

PMID- 10660676
TI  - Genes dependent on zebrafish cyclops function identified by AFLP differential
      gene expression screen.
AB  - Zebrafish cyclops (cyc) encodes a Transforming Growth Factor beta (TGFbeta)
      signaling factor closely related to mouse Nodal. By comparing amplified fragment
      length polymorphisms (AFLP) from cyc mutant and wild-type cDNA pools, we devised
      a differential gene expression screen to isolate genes whose expression is
      dependent on Cyc signaling. We report two genes not previously described in the
      zebrafish that were identified using this approach. The first gene, crestin, is
      expressed predominantly in premigratory and migrating neural crest cells during
      somitogenesis stages. crestin expression is reduced in cyc mutants initially but
      recovers by late somitogenesis. The second gene encodes the zebrafish homologue
      of the calcium-binding protein, calreticulin. Zebrafish calreticulin is highly
      expressed in the hatching gland and in the floor plate, tissues that are affected
      in cyc mutants. During gastrulation, calreticulin transcripts are found in the
      dorsal mesendoderm, in the same cells that express the cyc gene. Expression is
      reduced in cyc mutants and is abolished by the one-eyed pinhead (oep) mutation
      that is presumed to prevent Nodal signaling. The identification of calreticulin
      suggests that a differential screen between wild-type and mutant cDNA is a useful
      approach to reveal regulation of unexpected gene expression in response to
      cellular signals. genesis 26:86-97, 2000.

PMID- 10660677
TI  - Editor's note

PMID- 10660678
TI  - Methionine-independent initiation of translation in the capsid protein of an
      insect RNA virus.
AB  - Protein synthesis is believed to be initiated with the amino acid methionine
      because the AUG translation initiation codon of mRNAs is recognized by the
      anticodon of initiator methionine transfer RNA. A group of positive-stranded RNA
      viruses of insects, however, lacks an AUG translation initiation codon for their
      capsid protein gene, which is located at the downstream part of the genome. The
      capsid protein of one of these viruses, Plautia stali intestine virus, is
      synthesized by internal ribosome entry site-mediated translation. Here we report
      that methionine is not the initiating amino acid in the translation of the capsid
      protein in this virus. Its translation is initiated with glutamine encoded by a
      CAA codon that is the first codon of the capsid-coding region. The nucleotide
      sequence immediately upstream of the capsid-coding region interacts with a loop
      segment in the stem-loop structure located 15-43 nt upstream of the 5' end of the
      capsid-coding region. The pseudoknot structure formed by this base pair
      interaction is essential for translation of the capsid protein. This mechanism
      for translation initiation differs from the conventional one in that the
      initiation step controlled by the initiator methionine transfer RNA is not
      necessary.

PMID- 10660679
TI  - Alternatively spliced N resistance gene transcripts: their possible role in
      tobacco mosaic virus resistance.
AB  - The N gene, a member of the Toll-IL-1 homology region-nucleotide binding site
      leucine-rich repeat region (LRR) class of plant resistance genes, encodes two
      transcripts, N(S) and N(L), via alternative splicing of the alternative exon
      present in the intron III. The N(S) transcript, predicted to encode the full
      length N protein containing the Toll-IL-1 homology region, nucleotide binding
      site, and LRR, is more prevalent before and for 3 hr after tobacco mosaic virus
      (TMV) infection. The N(L) transcript, predicted to encode a truncated N protein
      (N(tr)) lacking 13 of the 14 repeats of the LRR, is more prevalent 4-8 hr after
      TMV infection. Plants harboring a cDNA-N(S) transgene, capable of encoding an N
      protein but not an N(tr) protein, fail to exhibit complete resistance to TMV.
      Transgenic plants containing a cDNA-N(S)-bearing intron III and containing 3' N
      genomic sequences, encoding both N(S) and N(L) transcripts, exhibit complete
      resistance to TMV. These results suggest that both N transcripts and presumably
      their encoded protein products are necessary to confer complete resistance to
      TMV.

PMID- 10660680
TI  - The elasticity and failure of fluid-filled cellular solids: theory and
      experiment.
AB  - We extend and apply theories of filled foam elasticity and failure to recently
      available data on foods. The predictions of elastic modulus and failure mode
      dependence on internal pressure and on wall integrity are borne out by
      photographic evidence of distortion and failure under compressive loading and
      under the localized stress applied by a knife blade, and by mechanical data on
      vegetables differing only in their turgor pressure. We calculate the dry modulus
      of plate-like cellular solids and the cross over between dry-like and fully fluid
      filled elastic response. The bulk elastic properties of limp and aging cellular
      solids are calculated for model systems and compared with our mechanical data,
      which also show two regimes of response. The mechanics of an aged, limp beam is
      calculated, thus offering a practical procedure for comparing experiment and
      theory. This investigation also thereby offers explanations of the connection
      between turgor pressure and crispness and limpness of cellular materials.

PMID- 10660681
TI  - High relatedness and inbreeding at the origin of eusociality in gall-inducing
      thrips.
AB  - Within the haplodiploid eusocial gall-inducing thrips, a species-level phylogeny
      combined with genetic data for five eusocial species enables an inference of
      levels of relatedness and inbreeding values for lineages at the origin of
      eusociality. Character optimization using data from five eusocial species
      indicates that the lineage or lineages where eusociality is inferred to have
      originated exhibit relatedness of 0.64-0.92, and F(IS) of 0.33-0.64. The high
      inbreeding coefficients found in these eusocial thrips have increased relatedness
      among and within both sexes and have reduced the haplodiploidy-induced
      relatedness asymmetries [Hamilton, W. D. (1964) J. Theor. Biol. 7, 1-52]. These
      results indicate that unusually high relatedness is associated with the origin of
      eusociality, and they suggest a role for inbreeding in the evolution of bisexual
      helping.

PMID- 10660682
TI  - A novel precursor recognition element facilitates posttranslational binding to
      the signal recognition particle in chloroplasts.
AB  - Signal recognition particles (SRPs) in the cytosols of prokaryotes and eukaryotes
      are used to target proteins to cytoplasmic membranes and the endoplasmic
      reticulum, respectively. The mechanism of targeting relies on cotranslational SRP
      binding to hydrophobic signal sequences. An organellar SRP identified in
      chloroplasts (cpSRP) is unusual in that it functions posttranslationally to
      localize a subset of nuclear-encoded thylakoid proteins. In assays that
      reconstitute thylakoid integration of the light harvesting chlorophyll-binding
      protein (LHCP), stromal cpSRP binds LHCP posttranslationally to form a cpSRP/LHCP
      transit complex, which is believed to represent the LHCP form targeted to
      thylakoids. In this investigation, we have identified an 18-aa sequence motif in
      LHCP (L18) that, along with a hydrophobic domain, is required for transit complex
      formation. Fusion of L18 to the amino terminus of an endoplasmic reticulum
      targeted protein, preprolactin, led to transit complex formation whereas wild
      type preprolactin exhibited no ability to form a transit complex. In addition, a
      synthetic L18 peptide, which competed with LHCP for transit complex formation,
      caused a parallel inhibition of LHCP integration. Translocation of proteins by
      the thylakoid Sec and Delta pH transport systems was unaffected by the highest
      concentration of L18 peptide examined. Our data indicate that a motif contained
      in L18 functions in precursor recruitment to the posttranslational SRP pathway,
      one of at least four different thylakoid sorting pathways used by chloroplasts.

PMID- 10660683
TI  - Defensive extrusive ectosymbionts of Euplotidium (Ciliophora) that contain
      microtubule-like structures are bacteria related to Verrucomicrobia.
AB  - Epixenosomes, ectosymbionts on hypotrich ciliates (genus Euplotidium) defend
      their host against the ciliate predator Litonotus lamella. Although here only
      Euplotidium itoi and Euplotidium arenarium from tide pools along a rocky shore
      near Leghorn (Ligurian sea) were studied in detail, these epibionts are certainly
      present on specimens of E. itoi and on other Euplotidium species in similar north
      coastal habitats. The complex life history of epixenosomes has two main stages.
      In stage I, cells with typical prokaryotic structure divide by binary fission.
      Stage II cells show complex organization with different cytoplasmic compartments
      where an extrusive apparatus within a proteinaceous matrix, although not membrane
      bounded, differs from the remaining cytoplasm. The ejection process is involved
      in defense; extrusive apparatus is surrounded by a basket consisting of bundles
      of tubules. These tubules, 22 +/- 3 nm in diameter, delimited by a wall made up
      of globular structures, are sensitive to inhibitor of tubulin polymerization
      (nocodazole/4 degrees C temperature) and react positively with different
      antitubulin antibodies, two of which are monoclonal. The prokaryotic vs.
      eukaryotic nature of epixenosomes was resolved by comparative sequence analysis
      of amplified small subunit rRNA genes and in situ hybridization with
      fluorescently labeled rRNA-targeted polynucleotide probes. These unique
      ectosymbionts are phylogenetically related to Verrucomicrobia. Epixenosomes
      represent marine symbionts in this recently discovered division of the Bacteria.

PMID- 10660684
TI  - Femtosecond observation of benzyne intermediates in a molecular beam: Bergman
      rearrangement in the isolated molecule.
AB  - In this communication, we report our femtosecond real-time observation of the
      dynamics for the three didehydrobenzene molecules (p-, m-, and o-benzyne)
      generated from 1,4-, 1,3-, and 1, 2-dibromobenzene, respectively, in a molecular
      beam, by using femtosecond time-resolved mass spectrometry. The time required for
      the first and the second C-Br bond breakage is less than 100 fs; the benzyne
      molecules are produced within 100 fs and then decay with a lifetime of 400 ps or
      more. Density functional theory and high-level ab initio calculations are also
      reported herein to elucidate the energetics along the reaction path. We discuss
      the dynamics and possible reaction mechanisms for the disappearance of benzyne
      intermediates. Our effort focuses on the isolated molecule dynamics of the three
      isomers on the femtosecond time scale.

PMID- 10660685
TI  - Femtosecond resolution of ligand-heme interactions in the high-affinity quinol
      oxidase bd: A di-heme active site?
AB  - Interaction of the two high-spin hemes in the oxygen reduction site of the bd
      type quinol oxidase from Escherichia coli has been studied by femtosecond
      multicolor transient absorption spectroscopy. The previously unidentified Soret
      band of ferrous heme b(595) was determined to be centered around 440 nm by
      selective excitation of the fully reduced unliganded or CO-bound cytochrome bd in
      the alpha-band of heme b(595). The redox state of the b-type hemes strongly
      affects both the line shape and the kinetics of the absorption changes induced by
      photodissociation of CO from heme d. In the reduced enzyme, CO photodissociation
      from heme d perturbs the spectrum of ferrous cytochrome b(595) within a few ps,
      pointing to a direct interaction between hemes b(595) and d. Whereas in the
      reduced enzyme no heme d-CO geminate recombination is observed, in the mixed
      valence CO-liganded complex with heme b(595) initially oxidized, a significant
      part of photodissociated CO does not leave the protein and recombines with heme d
      within a few hundred ps. This caging effect may indicate that ferrous heme b(595)
      provides a transient binding site for carbon monoxide within one of the routes by
      which the dissociated ligand leaves the protein. Taken together, the data
      indicate physical proximity of the hemes d and b(595) and corroborate the
      possibility of a functional cooperation between the two hemes in the dioxygen
      reducing center of cytochrome bd.

PMID- 10660686
TI  - Suppression of chromosome segregation defects of Escherichia coli muk mutants by
      mutations in topoisomerase I.
AB  - Escherichia coli muk mutants are temperature-sensitive and produce anucleate
      cells. A spontaneously occurring mutation was found in a DeltamukBkan mutant
      strain that suppressed the temperature-sensitive phenotype and mapped in or near
      topA, the gene that encodes topoisomerase I. Previously characterized topA
      mutations, topA10 and topA66, were found to be general suppressors of muk
      mutants: they suppressed temperature sensitivity and anucleate cell production of
      cells containing null or point mutations in mukB and null mutations in mukE or
      mukF. The suppression correlated with excess negative supercoiling by DNA gyrase,
      and the gyrase inhibitor, coumermycin, reversed it. Defects in topA allow 99% of
      cell division events in muk null mutants to proceed without chromosome loss or
      loss of cell viability. This observation imposes important limitations on models
      for Muk activity and is consistent with a role for MukBEF in chromosome folding
      and DNA condensation.

PMID- 10660687
TI  - Enzyme plus light therapy to repair DNA damage in ultraviolet-B-irradiated human
      skin.
AB  - Ultraviolet-B (UVB) (290-320 nm) radiation-induced cyclobutane pyrimidine dimers
      within the DNA of epidermal cells are detrimental to human health by causing
      mutations and immunosuppressive effects that presumably contribute to
      photocarcinogenesis. Conventional photoprotection by sunscreens is exclusively
      prophylactic in nature and of no value once DNA damage has occurred. In this
      paper, we have therefore assessed whether it is possible to repair UVB radiation
      induced DNA damage through topical application of the DNA-repair enzyme
      photolyase, derived from Anacystis nidulans, that specifically converts
      cyclobutane dimers into their original DNA structure after exposure to
      photoreactivating light. When a dose of UVB radiation sufficient to induce
      erythema was administered to the skin of healthy subjects, significant numbers of
      dimers were formed within epidermal cells. Topical application of photolyase
      containing liposomes to UVB-irradiated skin and subsequent exposure to
      photoreactivating light decreased the number of UVB radiation-induced dimers by
      40-45%. No reduction was observed if the liposomes were not filled with
      photolyase or if photoreactivating exposure preceded the application of filled
      liposomes. The UVB dose administered resulted in suppression of intercellular
      adhesion molecule-1 (ICAM-1), a molecule required for immunity and inflammatory
      events in the epidermis. In addition, in subjects hypersensitive to nickel
      sulfate, elicitation of the hypersensitivity reaction in irradiated skin areas
      was prevented. Photolyase-induced dimer repair completely prevented these UVB
      radiation-induced immunosuppressive effects as well as erythema and sunburn-cell
      formation. These studies demonstrate that topical application of photolyase is
      effective in dimer reversal and thereby leads to immunoprotection.

PMID- 10660688
TI  - Neuropeptide Y (NPY) potentiates phenylephrine-induced mitogen-activated protein
      kinase activation in primary cardiomyocytes via NPY Y5 receptors.
AB  - Neuropeptide Y (NPY) has been shown to participate in the cardiovascular response
      mediated by the sympathetic system. In this report, we investigate the growth
      factor properties of NPY on cardiac myocytes. Mitogen-activated protein kinases
      (MAPK) are key signaling molecules in the transduction of trophic signals.
      Therefore, the role of NPY in inducing MAPK activation was studied in mouse
      neonatal cardiomyocytes. Exposure of neonatal cardiomyocytes to either NPY,
      phenylephrine, or angiotensin II induces a rapid phosphorylation of the
      extracellular responsive kinase, the c-jun N-terminal kinase, and the p38 kinase
      as well as an activation of protein kinase C (PKC). Moreover, NPY potentiates
      phenylephrine-induced MAPK and PKC stimulation. In contrast, NPY has no
      synergistic effect on angiotensin II-stimulated MAPK phosphorylation or PKC
      activity. NPY effects are pertussis toxin-sensitive and calcium-independent and
      are mediated by NPY Y5 receptors. Taken together, these results suggest that NPY,
      via G(i) protein-coupled NPY Y5 receptors, could participate in the development
      of cardiac hypertrophy during chronic sympathetic stimulation by potentiating
      alpha-adrenergic signals.

PMID- 10660689
TI  - Atmospheric energy for subsurface life on Mars?
AB  - The location and density of biologically useful energy sources on Mars will limit
      the biomass, spatial distribution, and organism size of any biota. Subsurface
      Martian organisms could be supplied with a large energy flux from the oxidation
      of photochemically produced atmospheric H(2) and CO diffusing into the regolith.
      However, surface abundance measurements of these gases demonstrate that no more
      than a few percent of this available flux is actually being consumed, suggesting
      that biological activity driven by atmospheric H(2) and CO is limited in the top
      few hundred meters of the subsurface. This is significant because the available
      but unused energy is extremely large: for organisms at 30-m depth, it is 2,000
      times previous estimates of hydrothermal and chemical weathering energy and far
      exceeds the energy derivable from other atmospheric gases. This also implies that
      the apparent scarcity of life on Mars is not attributable to lack of energy.
      Instead, the availability of liquid water may be a more important factor limiting
      biological activity because the photochemical energy flux can only penetrate to
      100- to 1,000-m depth, where most H(2)O is probably frozen. Because both
      atmospheric and Viking lander soil data provide little evidence for biological
      activity, the detection of short-lived trace gases will probably be a better
      indicator of any extant Martian life.

PMID- 10660691
TI  - [The DACA].

PMID- 10660692
TI  - [DNA-dependent protein kinase: a major protein involved in the cellular response
      to ionizing radiation].
AB  - DNA-dependent protein kinase (DNA-PK) is a DNA-activated nuclear serine/threonine
      protein kinase. DNA-PK consists of a regulatory sub-unit, the heterodimeric Ku
      protein (composed of a 70- and a 86-kDa subunit) which binds DNA ends and targets
      the catalytic sub-unit, DNA-PKcs to DNA strand breaks. DNA-PK plays a major role
      in the repair of double-strand breaks induced in DNA after exposure to ionizing
      radiation as shown by the extreme radiosensitivity of cells with mutations in
      Ku86, Ku70 or DNA-PKcs genes. Cells deficient in DNA-PK activity also exhibit
      hypersensitivity to genotoxic drugs such as cisplatin and nitrogen mustards. In
      the first part of this review, the current knowledge on the biochemical
      characteristics of DNA-PK, its mechanism of action in DNA repair and the
      phenotype of DNA-PK deficient cells is summarized. These results suggest that DNA
      PK might play a role in the acquisition of a resistant phenotype of human tumors
      to radiotherapy, chemotherapy using genotoxic drugs or to both treatments. In the
      second part of this review, the studies devoted to inhibition of DNA-PK in order
      to enhance cancer therapy by DNA-damaging agents are presented.

PMID- 10660690
TI  - Positive and negative regulation of endogenous genes by designed transcription
      factors.
AB  - Gene regulation by imposed localization was studied by using designed zinc finger
      proteins that bind 18-bp DNA sequences in the 5' untranslated regions of the
      protooncogenes erbB-2 and erbB-3. Transcription factors were generated by fusion
      of the DNA-binding proteins to repression or activation domains. When introduced
      into cells these transcription factors acted as dominant repressors or activators
      of, respectively, endogenous erbB-2 or erbB-3 gene expression. Significantly,
      imposed regulation of the two genes was highly specific, despite the fact that
      the transcription factor binding sites targeted in erbB-2 and erbB-3 share 15 of
      18 nucleotides. Regulation of erbB-2 gene expression was observed in cells
      derived from several species that conserve the DNA target sequence. Repression of
      erbB-2 in SKBR3 breast cancer cells inhibited cell-cycle progression by inducing
      a G(1) accumulation, suggesting the potential of designed transcription factors
      for cancer gene therapy. These results demonstrate the willful up- and down
      regulation of endogenous genes, and provide an additional means to alter
      biological systems.

PMID- 10660693
TI  - [Wound infection in head and neck cancer surgery].
AB  - Wound infections (WIs) are the main cause of post-surgical morbidity in head and
      neck surgery. They arise with an especially immunocompromised predisposition and
      mainly involve oropharyngeal flora bacteria. However, the assessment of the
      incidence of these infections differs in the literature (0 to 87%). This in part
      accounts for the lack of a real consensus as to the definition (do all
      mucocutaneous fistulae attest to WIs?). For this reason, the analysis of their
      risk factors and the means of the prevention is difficult. In class 1 surgery,
      the incidence of WIs ranges 0 to 6%. In this case, antiobioprophylaxis does not
      seem to be justified. In surgery opening the mucosa, it is difficult to classify
      the surgical procedures in Altemeier's classes 2 and 3. There are many arguments,
      in particular physiopathological arguments, to consider that the contamination of
      surgical bed of surgery does continue after the operation. The incidence of WIs
      varies widely from one study to the next. Without antibiotic prophylaxis, from 40
      to 87% WIs are observed. With preventive antibiotherapy, the incidence ranges
      between 3.4 to 47%. Various risk factors have been described, in particular:
      tumour size and node extension, tracheotomy prior to surgery. Four multi-factor
      studies have shown, in multivariate analysis, totally different risk factors. The
      prevention of these WIs is currently based on hospital hygiene rules and
      antibiotic prophylaxis. The optimum conditions have still not been determined.
      Reliable data to define, the incidence and risk factors of these WIs are missing.
      New prospective studies are definitely required.

PMID- 10660694
TI  - [Good clinical practice in nutritional management in cancer patients:
      malnutrition and nutritional assessment].
AB  - CONTEXT: The "Standards, Options and Recommendations" (SOR) project, started in
      1993, is a collaboration between the Federation of the French Cancer Centres
      (FNCLCC), the 20 French Cancer Centres and specialists from French Public
      Universities, General Hospitals and Private Clinics. The main objective is the
      development of clinical practice guidelines to improve the quality of health care
      and outcome for cancer patients. The methodology is based on literature review
      and critical appraisal by a multidisciplinary group of experts, with feedback
      from specialists in cancer care delivery. OBJECTIVES: To develop clinical
      practice guidelines according to the definitions of the Standards, Options and
      Recommendations project for the nutritional evaluation of cancer patients.
      METHODS: Data were identified by searching Medline and personal reference lists
      of members of the expert groups. Once the guidelines were defined, the document
      was submitted for review to 83 independent reviewers, and to the medical
      committees of the 20 French Cancer Centres. RESULTS: The main recommendations for
      the nutritional evaluation of cancer patients are: 1) Clinical and anthropometric
      evaluation should measure height, current weight, ideal weight, weight lost and
      rate of loss, and Body Mass Index. Social and economic data, details of previous
      history, current treatment and clinical examination results should also be
      collected. Gastrointestinal disorders and energetic needs should be assessed. 2)
      Nutritional intervention is recommended for all patients with a weight loss of
      10% or more. 3) A multidimensional assessment can be performed using three
      validated nutritional and clinical scales: the Subjective Global Assessment, the
      Scored PG-SGA and the Mini Nutritional assessment. 4) The predictive value of
      biological factors (albumin) is not sufficient individually, risk scales
      combining several factors should be used: the Prognostic Inflammatory and
      Nutritional Index (PINI), the Nutritional Risk Index (NRI), the Prognostic
      Nutritional Index (Mullen) or the Sadan. 5) Minimal nutritional assessment should
      include clinical data, patient interview, height, current weight, ideal weight
      and weight change. 6) The efficacy of the nutrional management should be followed
      by assessing weight, and the presence of oedema and ascitis. The ratio of calorie
      to nitrogen intake should be calculated regularly.

PMID- 10660695
TI  - [High-dose ifosfamide in patients with stage IV non-small cell lung cancer: phase
      II trial from the Groupe francais de pneumo-cancerologie (GFPC)].
AB  - PURPOSE: To assess the toxicity and efficacy of high dose ifosfamide in stage IV
      NSCLC. METHODS: In a previous trial, we have determined maximum tolerated dose
      for 3-days ifosfamide treatment by 3-weeks schedule as 9 g/m2 according to
      hematologic tolerance. We therefore set up a phase II to study the toxicity and
      efficacy of this schedule in chemotherapy naive metastatic NSCLC. Ifosfamide (+
      mesna 1 g/m2) was administered by a two hour infusion (3 g/m2) for three days
      every three weeks. Patients received three mesna bolus infusions (1 g/m2) at 4, 8
      and 12 hours after the end of ifosfamide infusion. Antitumoral efficacy was
      performed after 2 cycles and treatment could be pursued for responding patients
      until disease progression. From september 1995 to January 1997, 31 patients have
      been included in this study. Median age was 60.7 years +/- 1.33 (41-70) for 27
      males and 4 females. Patients (pts) presented metastases in lung for 10 pts, bone
      for 10 pts, liver for 6 pts, adrenal for 4 pts and multiorgan metastatic
      localisation for 1 patient. Seven patients were unassessable: 1 lost for follow
      up, 1 sudden death, 5 treatment interruptions before evaluation time and 3 toxic
      deaths (9.6%). TOXICITY: neutropenia grade 4 (10 pts and 1 death), cardiotoxicity
      grade 4 (1 pt) and 2 deaths following neurotoxicity grade 4. We achieve 4 partial
      responses (13%, 95CI: 3.6-29.8), 10 progressive diseases (32.3%, 95CI: 16.7-51.4)
      and 10 stabilizations (32.3%, 95CI: 16.7-51.4). Median response duration was 91
      days +/- 55 d. Median survival was 9.3 months, e.g. 280 days (8-863). Overall
      survival at one year is 48%. CONCLUSION: This modality of high dose ifosfamide is
      as effective as standard monotherapy schedules in stage IV NSCLC. Unexpected
      toxicities particularly hematological ones could be due to a short duration of
      fractionated treatment. Results in term of survival leads us to further evaluate
      ifosfamide monotherapy treatment on a 5-day schedule basis.

PMID- 10660696
TI  - [Medical ethics and therapeutic progress in lung cancer: with help,
      Hippocrates!].

PMID- 10660697
TI  - Capsulectomy for the relief of flexion contractures of the elbow following
      fracture. 1944.

PMID- 10660698
TI  - Imaging of posttraumatic and soft tissue dysfunction of the elbow.
AB  - The inherent obliquity of the elbow produces a challenge to the radiologist. In
      the treatment of elbow trauma, comprehensive evaluation includes detection of
      bone, cartilage, ligament, and tendon injury. In most cases, plain radiographs
      remain the initial imaging mainstay for evaluation of the elbow, followed by
      properly performed magnetic resonance imaging with thin (1.5-2 mm) sections and
      appropriate pulse sequencing to provide differential contrast between subchondral
      bone, cartilage, and joint fluid. Vigilant attention to imaging technique
      obviates the need for additional intraarticular contrast agent, which converts
      the magnetic resonance imaging to an invasive procedure and, in many cases,
      increases the cost. The advent of magnetic resonance angiography has provided an
      important noninvasive diagnostic means to detect associated vascular injury. In
      addition, computed tomography imaging, particularly with concomitant three
      dimensional reformations, provides comprehensive fracture assessment.
      Postprocessing capabilities include rotation of three-dimensional models and
      subtraction programs that may be useful in disclosing subtle fracture components.
      Finally, ultrasound increasingly is being accepted as an important imaging
      modality by which to detect tendinous and soft tissue injury and has the distinct
      advantage of being able to impart dynamic load to muscle tendon units.

PMID- 10660699
TI  - Surgical approaches to the elbow.
AB  - The recent explosion of interest in the elbow and the need for better surgical
      approaches, has produced numerous new approaches and the modification of other
      approaches, the result of which is a much shorter but more useful list of
      surgical approaches. Surgeons who perform a large number of elbow procedures have
      found that these approaches permit them to perform the majority of elbow
      procedures with only one skin incision, usually a straight posterior midline
      incision. Knowledge of the deep intermuscular and internervous intervals allows
      the surgeon to expose the elbow circumferentially through one skin incision. This
      approach has been associated with fewer wound complications and has allowed
      immediate active motion of the elbow.

PMID- 10660700
TI  - Classification and evaluation of recurrent instability of the elbow.
AB  - The clinical presentation, diagnosis, radiographic features, mechanism,
      pathologic changes, and treatment of elbow instability are understood better now.
      Elbow instability can be classified according to five criteria: (1) the timing
      (acute, chronic or recurrent); (2) the articulation(s) involved (elbow versus
      radial head); (3) the direction of displacement (valgus, varus, anterior,
      posterolateral rotatory); (4) the degree of displacement (subluxation or
      dislocation); and (5) the presence or absence of associated fractures.
      Posterolateral rotatory instability is the most common pattern of elbow
      instability, particularly that which is recurrent. Posterolateral rotatory
      instability can be considered a spectrum consisting of three stages according to
      the degree of soft tissue disruption. Patients typically present with a history
      of recurrent painful clicking, snapping, clunking, or locking of the elbow and
      careful examination reveals that this occurs in the extension portion of the arc
      of motion with the forearm in supination. There are four principle physical
      examination tests. The most sensitive is the lateral pivot-shift apprehension
      test, or posterolateral rotatory apprehension test, just as the anterior
      apprehension test of the shoulder is the most sensitive test for a patient with
      shoulder instability. Next is the lateral pivot-shift test, or posterolateral
      rotatory instability test. Reproducing the actual subluxation and the clunk that
      occurs with reduction usually can be accomplished only with the patient under
      general anesthesia or occasionally after injecting local anesthetic into the
      elbow. The third test is the posterolateral rotatory drawer test, which is a
      rotatory version of the drawer or Lachman test of the knee. The final test is the
      stand up test as reported by Regan. The patient's symptoms are reproduced as he
      or she attempts to stand up from the sitting position by pushing on the seat with
      the hand at the side and the elbow fully supinated. A lateral stress radiograph
      can show the rotatory subluxation.

PMID- 10660701
TI  - Reconstruction of posttraumatic elbow instability.
AB  - Successful reconstruction of posttraumatic elbow instability depends on
      restoration of the anatomic contributors to stability. The osseous and articular
      structures are paramount. The radial head and coronoid should be repaired or
      reconstructed and the olecranon (proximal ulna) should be repaired in anatomic
      alignment so that the contour and dimensions of the trochlear notch are restored
      and the radiocapitellar joint is aligned appropriately. The lateral collateral
      ligament complex is commonly disrupted and usually can be reattached to its
      origin from the lateral epicondyle. Patients with longstanding subluxation or
      dislocation may require temporary hinged external fixation or reconstruction of
      the collateral ligaments with tendon grafts.

PMID- 10660702
TI  - Surgical treatment of extraarticular elbow contracture.
AB  - The problem of the contracted elbow is well-recognized for the circumstances
      under which it develops and the difficulty of operative and non-operative
      treatment. Earlier studies report this problem in an unfavorable manner; however,
      current studies suggest that posttraumatic stiffness of the elbow, particularly
      when the articular surface is left intact, may be treated reliably. The authors
      present a specific surgical approach to the elbow that has posttraumatic motion
      limitation described as extrinsic, that is, primarily attributable to contracture
      of the capsule and periarticular soft tissues. The limited surgical exposure
      termed the column procedure allows anterior capsular exposure through an interval
      in the brachioradialis and extensor carpi radialis longus. Using this procedure
      the authors report the treatment of 38 elbows (38 patients) with sufficient
      followup to accurately describe the postoperative course. At a mean of 3.5 years
      after surgery the total postoperative arc of motion improved from approximately
      50 degrees to approximately 90 degrees. There were minimal complications. A
      static adjustable splint rather than physical therapy is used postoperatively. It
      is concluded that newer surgical techniques with carefully described programs can
      be successful in the majority of patients undergoing surgical release for
      extrinsic contracture of the elbow.

PMID- 10660703
TI  - Treatment of ectopic ossification about the elbow.
AB  - The surgical treatment of elbow ectopic ossification associated with elbow
      stiffness has progressed significantly in the past decade. Although previous
      reports describe inconsistent results and high complication rates, numerous
      recent reports document not only good results, but also lower complication rates.
      The current study outlines the authors' treatment of patients with ectopic bone
      about the elbow. Various modalities have been used for prophylaxis against elbow
      ectopic ossification in the patient with elbow trauma. However, despite these
      prophylaxis efforts, periarticular ossification may form and result in disabling
      elbow stiffness. If ectopic ossification and stiffness develop, operative
      intervention may be indicated to restore motion. It has been long suggested that
      operative intervention be delayed for at least 1 year, with earlier intervention
      thought to predispose to recurrence. Recent reports, however, have documented
      good results with earlier intervention, from 3 to 6 months after injury. The
      evaluation of posttraumatic elbow stiffness associated with ectopic ossification
      is described, followed by a discussion regarding anatomic and functional
      classifications. Surgery is based on multiple factors including the location of
      ectopic ossification, the plane(s) of elbow stiffness, and the presence of
      associated nerve compression. A limited or extended Kocher approach may be used
      to release most contractures; however, other approaches may be necessary.
      Surgical technique is described in detail. Meticulous surgical technique is
      necessary to avoid complications, including triceps avulsion, recurrent elbow
      stiffness, and hematoma.

PMID- 10660704
TI  - Operative treatment of nonunions about the elbow.
AB  - Nonunions about the elbow present a great challenge to the orthopaedic surgeon.
      Recent advances have enabled the surgeon to achieve much improved results. The
      current study outlines the treatment of nonunions of the distal humerus, proximal
      ulna (including olecranon, Monteggia, and coronoid nonunions), and radial head
      and neck nonunions. The historic problems of treating these nonunions included
      the use of inadequate fixation, the poor understanding of the role of soft tissue
      surgery in the treatment of the stiff elbow, and the failure of previous
      postoperative rehabilitation protocols. Advances made in the techniques of soft
      tissue treatment, modern methods of stable internal fixation, and early
      postoperative rehabilitation all have made an exceptional difference in the
      surgeon's ability to treat these most complex problems. The current study will
      provide the reader with a greater understanding of nonunions about the elbow,
      clinical and technical details for their treatment, and the expected results
      after treatment.

PMID- 10660705
TI  - Total elbow arthroplasty in the treatment of posttraumatic conditions of the
      elbow.
AB  - Posttraumatic arthritis, arthritis secondary to instability, and nonunion or
      malunion about the elbow may be treated by various methods. Recommended first
      line treatment in the younger, more active patient population is nonprosthetic
      techniques. Total elbow arthroplasty should be considered primarily as a salvage
      procedure for these patients. Careful patient selection will determine whether
      total elbow arthroplasty is an acceptable choice, despite its inherent risks and
      complications. Prosthetic replacement is more applicable for patients with low
      physical demands who are older than 60 years of age with pain, stiffness, and/or
      instability of the elbow who will more likely be able to comply with
      postoperative rehabilitation and strict activity restrictions. Previous
      incisions, gross instability, periarticular fibrosis with ulnar nerve encasement,
      loss of bone and/or soft tissue, and previous infections represent obstacles for
      prosthetic reconstruction in these patients. The use of unlinked total elbow
      designs require good bone stock with little deformity and stable
      capsuloligamentous support, which uncommonly is found in elbows after trauma.
      Linked semiconstrained prostheses have been used most frequently with good short
      term results reported in the literature. Reported failure rates after longer
      followup have led to a search for improvements in prosthetic design, cementing
      techniques, and better patient selection.

PMID- 10660706
TI  - Posttraumatic reconstruction of the elbow in the pediatric patient.
AB  - The elbow in a pediatric patient does not usually have the propensity for
      stiffness like that of the elbow in an adult. There are some posttraumatic
      conditions of the elbow in the pediatric patient that do require reconstruction.
      These include reconstruction for malunion after supracondylar humerus fractures
      and after Monteggia fractures. Nonunion of lateral condyle fractures also may
      require reconstruction. The posttraumatic elbow contracture in the pediatric
      patient is an operative challenge when the patient does not respond to
      conservative treatment. Patients with osteochondritis dissecans resulting in
      osteochondral loose bodies, significant loss of motion, or radiocapitellar
      subluxation will benefit from surgery. An entrapped median nerve or medial
      epicondyle after an elbow fracture or dislocation is an impending disaster that
      requires reconstruction immediately on recognition.

PMID- 10660707
TI  - Treatment of soft tissue problems about the elbow.
AB  - The treatment of soft tissue problems about the elbow should be directed toward
      early coverage and functional rehabilitation. The current study reviews some of
      the available treatment options, with emphasis on the treatment of large soft
      tissue defects. The role of prophylactic soft tissue coverage also is discussed.
      For large defects not extending more than 8 cm below the elbow and for
      prophylactic soft tissue coverage, the authors recommend the pedicled latissimus
      flap, which provides reliable coverage and a generous blood supply that promotes
      healing at the site of injury.

PMID- 10660708
TI  - The assessment and treatment of nerve dysfunction after trauma around the elbow.
AB  - Nerve dysfunction after trauma around the elbow can lead to significant long-term
      pain and functional deficit. Fortunately, most of these injuries are neurapraxias
      that will recover spontaneously after conservative treatment. The necessity and
      time frame for surgical intervention for specific patterns of nerve dysfunction
      remains controversial. Often surgical exploration exacerbates rather than
      alleviates the presenting nerve problem. Distal humeral shaft fractures, elbow
      dislocations, Monteggia fracture-dislocations, supracondylar fractures in
      children, and proximal forearm trauma all have been associated with various types
      of nerve injuries with a variable degree of recovery. The early recognition of
      nerve dysfunction combined with appropriate treatment measures is the key to
      successful outcome.

PMID- 10660709
TI  - Magnetic resonance-based motion analysis of the shoulder during elevation.
AB  - Changes in shoulder motion patterns are relevant in various shoulder diseases,
      but no in vivo information exists about the relative positions in vivo of the
      shoulder girdle bones and the supraspinatus muscle in three-dimensional space.
      Thus, the objective of this study was to perform a motion analysis of these
      structures during passive arm elevation using open magnetic resonance imaging and
      three-dimensional image processing. Fourteen volunteers were examined in five
      positions of abduction (30 degrees-150 degrees) with an open magnetic resonance
      system. After segmentation and three-dimensional reconstruction, the axis of the
      supraspinatus, humerus, clavicle, and the plane of the glenoid were determined,
      and the relative movements were calculated. The ratio for glenohumeral to
      scapulothoracic motion was 1.5:1 at 60 degrees and 2.4:1 at 120 degrees
      abduction. At 30 degrees, the axis of the supraspinatus was nearly horizontal,
      and during abduction a continuous elevation (+123 degrees at 150 degrees
      abduction) was measured. In the transverse plane, the angle between the
      supraspinatus and the clavicle axes became larger during abduction because of an
      increasing retroversion of the clavicle. The study shows specific three
      dimensional motion patterns for each bone of the shoulder girdle and the
      supraspinatus muscle during passive elevation. The technique and results can be
      used for future studies in patients with pathologic changes of shoulder girdle
      motion.

PMID- 10660711
TI  - Cost analyses of extended prophylaxis with enoxaparin after hip arthroplasty.
AB  - Venous thromboembolic complications occur in 50% to 70% of patients undergoing
      total hip arthroplasty if no prophylactic regimen is used. Because enoxaparin and
      warfarin are useful for extended outpatient prophylaxis, the objective of this
      study was to determine which of these agents is most cost effective in preventing
      venous thromboembolic complications. A decision tree analysis was developed to
      simulate a hypothetical cohort of patients with total hip arthroplasty. The
      analysis considered home health care services to perform monitoring and
      compliance verification. Accounting for prophylactic failures and treatment
      complications, results showed that enoxaparin maintained a cost effective
      advantage over warfarin for extended prophylaxis in the time after discharge and
      total hip arthroplasty ranging from 19 to 31 days after the patient was
      discharged from the hospital. The duration of cost effectiveness of enoxaparin
      was reduced to 14 to 17 days when home care services were excluded. These results
      indicated that approximately 3 weeks of outpatient therapy with enoxaparin is
      cost effective. With the cornerstone of managed care being cost efficiency in the
      provision of quality care, this conclusion warrants the development of integrated
      care strategies for the patient having orthopaedic surgery to achieve cost
      effective patient management.

PMID- 10660710
TI  - Trapeziometacarpal arthroplasty using the entire flexor carpi radialis tendon.
AB  - Fifty-eight patients (62 joints) with arthritis of the thumb carpometacarpal
      joint were treated with resection arthroplasty, ligament reconstruction, and
      tendon interposition with the entire flexor carpi radialis tendon. The mean age
      of the patients at the time of surgery was 58.4 years (range, 28-80 years), and
      the average followup was 42.5 months (range, 21-86 months). The entire flexor
      carpi radialis tendon was used for reconstruction and interposition. In 32 of the
      62 joints, a partial trapezoidectomy was performed for scaphotrapezoidal
      arthritis. Finger-tip pinch improved by 88%, key pinch improved by 86%, and grip
      strength improved by 69%. Palmar and radial abduction also improved by 8% and
      10%, respectively. Fifty-five (95%) patients reported excellent pain relief,
      whereas three patients reported only mild pain. No patients experienced an
      increase in pain. All thumbs were stable radiographically. This study indicated
      ligament reconstruction with tendon interposition, accompanied by partial
      trapezoidectomy when indicated, provides excellent pain relief and restoration of
      function. No morbidity was observed with use of the entire flexor carpi radialis
      tendon.

PMID- 10660712
TI  - Effect of low-friction ion-treated femoral heads on polyethylene wear rates.
AB  - Polyethylene wear is a major contributor to osteolysis and subsequent aseptic
      loosening of prosthetic components in total hip arthroplasty. Use of ion
      implantation as a surface modification to the metallic bearing component of
      orthopaedic implants may be an effective means of reducing wear debris at the
      bearing interface. In July 1991, low friction ion treated femoral heads were
      introduced. This study evaluates the effect of the low friction ion treated
      femoral head on polyethylene wear. Fifty-five total hip arthroplasties (53
      patients) with low friction ion treated femoral heads followed up a minimum of 3
      years were matched with 55 total hip arthroplasties (47 patients) without low
      friction ion treated femoral heads for the same postoperative period. Socket wear
      was evaluated radiographically. Case matching and strict inclusion criteria were
      used to control for known factors influencing polyethylene wear. These criteria
      included: (1) cases matched for gender and age within 2 years; (2) diagnosis
      limited to osteoarthritis or avascular necrosis of the femoral head only; (3)
      femoral head diameter limited to 26 or 28 mm only; (4) hydroxyapatite coated
      femoral stem of the same design and a metal backed socket of the one of two
      designs with the same polyethylene insert; and (5) minimum followup of 3 years.
      The linear wear rate of polyethylene was 0.161 +/- 0.095 mm per year in the group
      without the low friction ion treated heads and 0.116 +/- 0.101 mm per year in the
      low friction ion treated group. The volumetric wear rates were 74.5 +/- 44.3 mm3
      per year for the group without the low friction ion treated heads and 57.8 +/-
      51.1 mm3 per year for the low friction ion treated group. Assuming the
      sensitivity of these measurements can detect these small differences in wear
      accurately, these results suggest low friction ion treated prosthetic heads are
      useful in reducing polyethylene wear at 3-year minimum followup.

PMID- 10660713
TI  - Hydroxyapatite-enhanced tibial prosthetic fixation.
AB  - Sixty-two knees (60 patients) were randomized to four noncemented groups. In
      Groups 1, 3, and 4, the bone cuts were made with a cooled saw blade. In Group 1,
      15 patients were operated on with the porous coated Osteonic 7000 tibial
      component. In Group 2, 15 patients were operated on with the same tibial
      component as in Group 1 but with the use of a standard saw blade. In Group 3, 16
      patients were operated on with the hydroxyapatite-coated Osteonic tibial
      component, and in Group 4, 16 patients were operated on with the hydroxyapatite
      Duracon tibial component. All patients were followed up clinically and with
      roentgenstereometric analysis. There were no differences among the groups
      regarding clinical outcome. One knee was revised (Group 2) after 1 year because
      of loosening of the tibial component. The maximum migration at 1 year was 1.7 mm
      in Group 1, 1.9 mm in Group 2, 1.3 mm in Group 3, and 1 mm in Group 4. At the 2
      year followup, the migrations were 1.8 mm, 1.5 mm, 1.4 mm, and 1 mm in Groups 1,
      2, 3, and 4, respectively. The inducible displacement that occurred at 1 year was
      0.6 mm in Group 1, 0.5 mm in Group 2, 0.4 mm in Group 3, and 0.4 mm in Group 4.
      The hydroxyapatite coating had a strong positive effect on the tibial component
      fixation. No prosthesis in the hydroxyapatite groups showed continuous migration.

PMID- 10660714
TI  - Human patellar tendon strain. A noninvasive, in vivo study.
AB  - This study showed the assumption of patellar tendon inextensibility was not
      valid, and the strain in the patellar tendon was higher than previously reported
      for other human tendons. The in vivo three-dimensional velocity profiles for the
      patella, femur, and tibia were measured noninvasively in 18 healthy knees during
      a low load extensor task using cine phase contrast magnetic resonance imaging.
      These data were used to calculate patellar tendon elongation and strain. Average
      maximum strains of 6.6% were found for a low load extension task at relatively
      small knee angles.

PMID- 10660715
TI  - Distal clavicle osteolysis unrelated to trauma, overuse, or metabolic disease.
AB  - Osteolysis of the distal clavicle has been reported to occur from traumatic,
      atraumatic (overuse), or systemic causes. Three patients with bilateral
      osteolysis of the distal clavicles whose osteolysis did not fit these etiologic
      categories were evaluated. Clinical, imaging, and laboratory evaluations were
      nonspecific, and histologic sections of the distal clavicle showed evidence of
      chronic inflammation with reactive change of the articular surface. Patients
      either had complete resolution or marked improvement of their symptoms after
      bilateral distal clavicle resection at mean followup of 5 years 3 months. These
      cases of osteolysis of the distal clavicle represent a category of this disorder
      not previously described.

PMID- 10660716
TI  - Aggressive aneurysmal bone cyst of the proximal humerus. A case report.
AB  - The case of an 11-year-old girl with a rapidly expanding, massive lesion in the
      right proximal humerus is reported. After biopsy, surgical treatment of the
      aneurysmal bone cyst consisted of aggressive intralesional resection with
      autogenous tibial strut grafting for reconstruction. After followup of 17 years
      with no recurrence of disease, there is excellent graft incorporation and
      remodeling and excellent function of the shoulder.

PMID- 10660717
TI  - Computed tomography image-guided surgery in complex acetabular fractures.
AB  - Eleven complex acetabular fractures in 10 patients were treated by open reduction
      with internal fixation incorporating computed tomography image guided software
      intraoperatively. Each of the implants placed under image guidance was found to
      be accurate and without penetration of the pelvis or joint space. The setup time
      for the system was minimal. Accuracy in the range of 1 mm was found when
      registration was precise (eight cases) and was in the range of 3.5 mm when
      registration was only approximate (three cases). Added benefits included reduced
      intraoperative fluoroscopic time, less need for more extensive dissection, and
      obviation of additional surgical approaches in some cases. Compared with a series
      of similar fractures treated before this image guided series, the reduction in
      operative time was significant. For patients with complex anterior and posterior
      combined fractures, the average operation times with and without application of
      three-dimensional imaging technique were, respectively, 5 hours 15 minutes and 6
      hours 14 minutes, revealing 16% less operative time for those who had surgery
      using image guidance. In the single column fracture group, the operation time for
      those with three-dimensional imaging application, was 2 hours 58 minutes and for
      those with traditional surgery, 3 hours 42 minutes, indicating 20% less operative
      time for those with imaging modality. Intraoperative computed tomography guided
      imagery was found to be an accurate and suitable method for use in the operative
      treatment of complex acetabular fractures with substantial displacement.

PMID- 10660718
TI  - Fractures in large-segment allografts.
AB  - Segment skeletal defects that result from resection of a malignant bone neoplasm
      commonly are reconstructed with large segment allografts. Excellent functional
      results after these reconstructions and significant complications have been
      reported. Although it is known that a common complication seen with the use of
      allografts is allograft fracture, the factors associated with allograft fracture
      are not entirely clear. In this study, the hypothesis was examined that allograft
      reconstructions, which use internal fixation devices that penetrate the cortex of
      the allograft, are associated with an increased risk of fracture. Findings from
      large segment allograft reconstructions in 74 patients with a minimum followup of
      36 months were studied. These 74 patients include 35 patients whose outcomes were
      reported previously and now have additional followup and 39 patients whose
      outcomes are being reported for the first time. Thirty-one of the 74 (42%)
      allografts fractured, and the mean time to fracture was 26 months. When the
      fixation techniques resulted in cortical penetration of the allograft, fractures
      occurred in 27 of the 43 (63%) allografts, and when fixation of the graft to the
      host bone required no cortical penetration, only four of the 31 (13%) allografts
      fractured. Fractures occurred in 12 of 15 (80%) tibial allografts and in only two
      of 17 (12%) proximal femoral allografts; however, the anatomic site was not
      statistically independent of method of fixation because 14 of the 15 tibial
      grafts had cortical penetration and 15 of the 17 proximal femoral grafts had no
      cortical penetration. The authors' analysis indicates that internal fixation
      devices that require cortical penetration are associated with an increased risk
      of allograft fracture.

PMID- 10660719
TI  - The mechanism of joint capsule thermal modification in an in-vitro sheep model.
AB  - The purpose of this study was to understand the mechanism responsible for joint
      capsule shrinkage after nonablative laser application in an in-vitro sheep model.
      Femoropatellar joint capsular tissue specimens harvested from 20 adult sheep were
      treated with one of three power settings of a holmium:yttrium-aluminum-garnet
      laser or served as a control. Laser treatment significantly shortened the tissue
      and decreased tissue stiffness in all three laser groups, whereas failure
      strength was not altered significantly by laser treatment. Transmission electron
      microscopic examination showed swollen collagen fibrils and loss of membrane
      integrity of fibroblasts. A thermometric study revealed nonablative laser energy
      caused tissue temperature to rise in the range of 64 degrees C to 100 degrees C.
      Electrophoresis after trypsin digestion of the tissue revealed significant loss
      of distinct alpha bands of Type I collagen in laser treated samples, whereas
      alpha bands were present in laser treated tissue without trypsin digestion. The
      results of this study support the concept that the primary mechanism responsible
      for the effect of nonablative laser energy is thermal denaturation of collagen in
      joint capsular tissue associated with unwinding of the triple helical structure
      of the collagen molecule.

PMID- 10660720
TI  - Medial cortex strain distribution during noncemented total hip arthroplasty.
AB  - Intraoperative proximal femur fractures are a significant concern during
      noncemented total hip arthroplasty. The current study was performed to
      investigate the hypothesis that broaching the femur and inserting the stem
      without using mallet applied impact loads will reduce the risk of intraoperative
      fracture. Rosette strain gauges were applied to the medial and anteromedial
      cortex of six human anatomic specimen femurs to compare the strain distribution
      for broaching and stem insertion. Eight additional femurs were used to compare
      the strain distribution for stem insertion using impact loading and constant rate
      stem insertion. For the impact loading stem insertions, the soft tissues
      surrounding the femur were modeled. Constant rate stem insertions were performed
      using a mechanical testing machine. The largest strains measured at the medial
      and anteromedial sites primarily were aligned with the femur hoop axis. The
      largest strain magnitude, orientation, and sign (tensile or compressive) varied
      widely among femurs. The stem insertion strains were significantly larger than
      the broaching strains (two-way analysis of variance with replication). The impact
      stem insertion strains were not significantly different from the constant rate
      stem insertion strains. The results indicate that the femur geometry and material
      properties have a greater influence on the strain distribution than does the
      implantation technique.

PMID- 10660721
TI  - Cervical intervertebral disc space narrowing and size of intervertebral foramina.
AB  - Computer-assisted simulation of C4-C5, C5-C6, and C6-C7 intervertebral disc space
      narrowing was performed on 16 anatomic specimen cervical spines to determine the
      relationship of the cross sectional foraminal areas with the degree of narrowing
      of the cervical intervertebral disc space. Compared with normal foraminal area
      values, reduction of 20% to 30% of the foraminal area was found after 1 mm
      narrowing of the intervertebral disc spaces; reduction of 30% to 40% of the
      foraminal area was found after 2 mm narrowing of the intervertebral disc space;
      and reduction of 35% to 45% of the foraminal area was found after 3 mm narrowing
      of the intervertebral disc space. Statistically significant differences were
      found among the remaining cross sectional foraminal areas after different degrees
      of intervertebral disc space narrowing. Compression of the nerve root within the
      intervertebral foramina after the collapse of the intervertebral disc space
      cannot be ignored, and an appropriate surgical procedure to maintain the normal
      height of the disc space is essential. The size of the intervertebral foramen is
      related directly to the height of the intervertebral disc space. A 3-mm vertical
      reduction of the intervertebral disc space is associated more frequently with
      severe narrowing of the neuroforamen.

PMID- 10660722
TI  - Occult hypoxia after femoral neck fracture and elective hip surgery.
AB  - The incidence of hypoxia after femoral neck and total hip arthroplasty was
      investigated. In addition, the incidence of preoperative and postoperative
      delirium was assessed. Oxygen saturation and mental status were tested before and
      after surgery in patients undergoing surgery for a femoral neck fracture or total
      hip arthroplasty. Hypoxia was present before surgery in five of 50 patients who
      underwent total hip replacement and 17 of 50 patients with femoral neck
      fractures. On Day 1 after surgery, 20 patients who underwent total hip
      replacement and 36 with femoral neck fractures had hypoxia; on Day 3 after
      surgery, 12 patients who underwent total hip replacement and 17 with femoral neck
      fractures had hypoxia. Respiratory recovery was quicker in patients after total
      hip replacement with 39 who recovered by Day 3 after surgery, compared with 31
      patients with femoral neck fractures. Preoperatively, patients with femoral neck
      fracture had significantly lower mental test scores than did patients who had
      undergone total hip replacement, and this continued on Day 1 after surgery.
      However, by Day 3 after surgery, there was no significant difference between the
      groups. Although the scores for the patients with femoral neck fractures were
      lower, delirium developed in only three patients with total hip replacements and
      six patients with femoral neck fracture. Hypoxia after hip surgery, particularly
      after femoral neck fracture, is common. The incidence of delirium was much lower
      than reported previously, and it is suggested that supplemental oxygen, when
      indicated and monitored by pulse oximetry, was the cause for the reduction in
      delirium.

PMID- 10660723
TI  - Use of growth factors to improve muscle healing after strain injury.
AB  - Muscle injuries represent a large number of professional and recreational sports
      injuries. Muscle strains habitually occur after an eccentric contraction, which
      often leads to an injury located in the myotendinous junction. Treatment varies
      widely, depending on the severity of the trauma, but has remained limited mostly
      to rest, ice, compression, elevation, antiinflammatory drugs, and mobilization.
      The authors' research group aims to develop new biologic approaches to improve
      muscle healing after injuries, including muscle strains. To achieve this goal,
      the authors investigated several parameters that will lead to the development of
      new strategies to enhance muscle healing. The authors first evaluated natural
      muscle healing after strain injuries and showed that muscle regeneration occurs
      in the early phase of healing but becomes impaired with time by the development
      of tissue fibrosis. Several growth factors capable of improving muscle
      regeneration were investigated; basic fibroblast growth factor, insulin-like
      growth factor, and nerve growth factors were identified as substances capable of
      enhancing muscle regeneration and improving muscle force in the strained injured
      muscle. The current study should aid in the development of strategies to promote
      efficient muscle healing and complete recovery after strain injury.

PMID- 10660724
TI  - Adhesive force of chondrocytes to cartilage. Effects of chondroitinase ABC.
AB  - Chondrocyte transplantation is a clinical procedure for cartilage repair.
      Transplanted cells may have difficulty attaching to the surface of chondral
      lesions because of the anti-adhesive properties of the proteoglycan rich matrix.
      This study used micromanipulation methods to determine if pretreatment of
      cartilage with chondroitinase ABC affects chondrocyte adhesion to cartilage and
      if chondrocytes adhere preferentially to the superficial, middle, or deep layers
      of cartilage. Bovine chondrocytes were transplanted in vitro on articular
      cartilage sections cut perpendicular to the articular surface. At various times
      between 15 and 75 minutes after seeding, a micropipette micromanipulation system
      was used to measure the adhesion force of individual chondrocytes to cartilage.
      The chondrocyte adhesion force increased with chondroitinase ABC treatment and
      seeding time but generally was similar for the different regions of articular
      cartilage (superficial, middle, deep layer) to which the cells were attached. For
      normal cartilage, the adhesion force increased from 1.29 +/- 0.24 mdyne after 15
      to 30 minutes seeding to 5.29 +/- 0.25 mdyne after 60 to 75 minutes. Treatment
      with chondroitinase ABC at certain concentrations and durations (1.0 U/mL for 5
      minutes or 0.5 or 1 U/mL for 15 minutes) led to an increase in adhesion force,
      whereas relatively low concentration or treatment time (0.25 U/mL for 15 minutes
      or 0.5 U/mL for 5 minutes) had little or no detectable effect. The increase in
      adhesion attributable to chondroitinase ABC treatment appeared most marked (+144%
      to +292%) for short (15 to 30 minutes) seeding durations but was still
      significant (+46%) for the longest seeding period (60 to 75 minutes) studied
      after the 1 U/mL for 15 minute treatment condition. These results provide direct
      biomechanical evidence that enzymatic treatment of a cartilage surface can
      enhance chondrocyte adhesion.

PMID- 10660725
TI  - The Nicolas Andry award. The pathogenesis and prevention of steroid-induced
      osteonecrosis.
AB  - The effects of steroids on a cloned pluripotential cell from bone marrow stroma
      were examined in vitro in culture and in vivo after the cells were transfected
      with a traceable gene and transplanted into host mice. Bipedal chickens were
      treated with steroids to establish a model for osteonecrosis. The effects of a
      lipid lowering agent, lovastatin, on the prevention of steroid induced
      adipogenesis in vitro in cell culture, and on adipogenesis and osteonecrosis in
      vivo in chickens, were evaluated. On treatment with dexamethasone, cloned
      pluripotential cells began to differentiate into adipocytes and expressed a fat
      specific gene, whereas the expression of Type I collagen and osteocalcin
      messenger ribonucleic acid decreased. Addition of lovastatin in culture inhibited
      steroid induced fat gene expression and counteracted the inhibitory effect of
      steroids on osteoblastic gene expression. Cloned pluripotential cells were
      transduced with a traceable retrovirus vector encoding the beta-galactosidase and
      neomycin resistance genes. The transfected cells were administered to mice either
      by tail vein or by direct intramedullary injection. Half of the animals in each
      group were treated with steroids. Histologic sections showed the appearance of
      transplanted cells in the marrow. Analysis of marrow blowouts by flow cytometry
      revealed that steroid treatment produced adipogenesis in transplanted cells.
      Evidence of osteonecrosis was observed in steroid treated chickens, whereas
      sections from animals treated with steroids and lovastatin showed less
      adipogenesis and no bone death. The results indicate that steroid induced
      adipogenesis in the marrow may contribute to osteonecrosis and that lovastatin
      may be helpful in preventing the development of steroid induced osteonecrosis.

PMID- 10660727
TI  - Biomechanical assessment of compression screws.

PMID- 10660726
TI  - Painless enlarging subcutaneous mass in a 58-year-old woman.

PMID- 10660728
TI  - [A summary report of response evaluation criteria in solid tumors (RECIST
      criteria)].
AB  - The World Health Organization definitions for objective tumor response published
      in the 1979 WHO Handbook have been the most commonly used criteria around the
      world. However, some problems developed with the use of WHO criteria. These
      issues led to various modifications to the WHO criteria, resulting in a situation
      in which response criteria were no longer comparable among research organizations
      or researchers. However, because the efficacy of novel therapies and drugs is
      estimated according to tumor regression, it is very important to unify the
      definitions of objective tumor response. A revised version of the WHO criteria,
      Response Evaluation Criteria in Solid Tumors (RECIST criteria), was published in
      1999 to deal with these issues. However, some problems concerning the evaluation
      of non-cytotoxic drugs and unidimensional measurements remain in the new
      criteria.

PMID- 10660729
TI  - [Evidence-based medicine in cancer chemotherapy].
AB  - Recently, evidence-based medicine (EBM) has been introduced into medical practice
      and developed to assist practitioner and patient decisions for appropriate
      medical care in specific clinical circumstances, including cancer chemotherapy.
      At present, cancer chemotherapy is still considered an incomplete anticancer
      therapy, because it rarely results in cure of advanced cancers. Most cancer
      chemotherapy is therefore considered palliative. Moreover, cancer chemotherapy is
      toxic due to the side effects of anticancer drugs. Given this situation, evidence
      based cancer chemotherapy may contribute to the clinical practice of medical
      oncology. EBM in cancer chemotherapy consists of four steps, just as in EBM in
      general practice. The first step is the formulation of clinical problems, the
      second step is to survey the literature, the third step a critical review of the
      literature, and the fourth step application to patient. If valid, reliable,
      reproducible, clinically flexible evidence for cancer chemotherapy are found in
      this process, it can be applied to a patient with cancer in clinical practice. It
      is important to realize, however, that EBM cannot always account for individual
      variation among patients. Furthermore, there is another big problem in obtaining
      evidence, since there are very few reports of randomized comparative studies of
      cancer chemotherapy which were carried out in Japan with Japanese patients. Most
      evidence is therefore derived from patients from other countries. This means that
      the evidence obtained in cancer chemotherapy should be applied to our patients
      with due caution. Given doses of drugs or administration schedules may not be
      suitable to Japanese people. According, we should undertake large scale clinical
      studies for the various evidences of cancer chemotherapy in our country.

PMID- 10660730
TI  - [Chemotherapy based on EBM in the field of hematological malignancies].
AB  - In the field of hematology/oncology, there are reasonable number of chemotherapy
      related reports with level 1 evidences based on the analysis of the evidence
      based medicine (EBM). Following reasons may be pointed out; the first is that the
      history of chemotherapy has been initiated in the field of in hematology/oncology
      so it has more than 50 years' experience. The second is that leukemia and
      lymphoma are very chemosensitive diseases to compare with solid tumor, so the
      ultimate goal of their therapy is increase of the cure rate. The third is
      hematologists with high specialty only can manage such serious patients. Thus
      they have proposed plenty well-designed and well-organized clinical protocols and
      have performed some of them in this field. We have learned several recommended
      therapy of some hematological malignancies with level 1 evidences. It is not so
      easy, however, to treat all patients according to the best recommended therapy
      for Japanese patients, because of some limitations of using Japanese health
      insurance. This is very crucial problem for the patients. We should settle the
      issue from the scientific and social aspects as soon as possible.

PMID- 10660731
TI  - [Evidence based chemotherapy for lung cancer].
AB  - There is often little foundation for decisions in experience-based or impression
      based medicine. Therapy, however, should be based on the highest level of
      available evidence. In many clinical cancer practices, "uncertainty" exists. When
      no evidence is available, it is important that we perform clinical trials to
      generate new evidence. Organizing multi-institutional clinical trials in Japan is
      an urgent necessity. Limited disease SCLC Concurrent radiotherapy in combination
      with cisplatin and etoposide is considered to be a standard treatment in limited
      disease SCLC. Extensive disease SCLC Chemotherapy regiments such as PE or CAV/PE
      are standard therapy for ED SCLC. There is no current evidence for alternating
      chemotherapy, dose intensive chemotherapy, high dose chemotherapy, late
      intensification chemotherapy or maintenance chemotherapy in extensive disease
      SCLC. New drugs in combination with cisplatin have been reported to show
      promising antitumor activity in extensive disease SCLC. The impact of CPT-11 +
      CDDP on survival may be discussed at the 2000 ASCO meeting. Surgically
      unresectable stage III NSCLC In a recent meta-analysis, cisplatin-based
      chemotherapy plus radiotherapy was compared with radiotherapy alone in prolonging
      survival. Cisplatin-based chemotherapy with or followed by radiation was proven
      to enhance survival. However, the optimal sequencing of chemotherapy and
      radiation has not been definitively established. Chemoradiotherapy with new drugs
      (paclitaxel, docetaxel, vinorelbine, gemicitabine, CPT-11) has been evaluated for
      activity and efficacy. Metastatic stage IV NSCLC Compared with the best
      supportive care alone, cisplatin-based chemotherapy yields an absolute
      improvement in survival. New drugs in combination with cisplatin or carboplatin
      have been reported to show promising antitumor activity. There is no combination
      therapy including a new anti-cancer agent which can be recommended as a "gold
      standard". There is no current evidence that either confirms or refutes non
      platinum-based combination chemotherapy. Second line chemotherapy Second line
      chemotherapy (docetaxel 75 mg/m2) improves survival in patients previously
      treated with platinum-based chemotherapy.

PMID- 10660732
TI  - [Cancer chemotherapy based on evidence--metastatic breast cancer].
AB  - Breast cancer is relatively sensitive to chemotherapy. However, although response
      rate to chemotherapy is reported to be from 50 to 70% in metastatic breast
      cancer, it is incurable. Current standard chemotherapeutic regimens do not
      provide a large survival benefit according to the evidence obtained from clinical
      studies. Before developing a treatment program, we should therefore realize that
      the aims of chemotherapy for metastatic breast cancer are improvement of quality
      of life through relief of symptoms, and prolonging survival.

PMID- 10660733
TI  - [Gynecologic cancer-evidenced based chemotherapy].
AB  - Among gynecologic cancers, ovarian cancer is treated with chemotherapy as a
      routine practice. Recent studies have shown that paclitaxel or docetaxel combined
      chemotherapy is selected because of its better antitumor effect and favorable
      effect for the long term prognosis.

PMID- 10660734
TI  - [Non-randomized study on the effects of preoperative radiotherapy and daily
      administration of low-dose cisplatin against those of radiotherapy alone for oral
      cancer--effects on local control, control of metastases, and overall survival].
AB  - Cisplatin is a known radiation modifier. Our previous study suggested that daily
      administration of low-dose cisplatin enhanced the efficacy of radiotherapy
      against primary oral squamous carcinoma. In this paper, we follow the patients
      who participated in the previous study and survey the benefit of combination low
      dose cisplatin in improving local control, prevention of metastases, and overall
      survival. This study included patients with surgically resectable advanced oral
      tumors. Ten patients underwent preoperative radiotherapy of 30-40 Gy/15-20 days
      with concomitant daily administration of low-dose cisplatin (5 mg/body or 5
      mg/m2). Ten other patients received external radiotherapy alone. All patients
      then underwent a planned radical tumor resection. No significant difference was
      see in loco-regional control rates (primary: 86 vs. 88%, neck: 83 vs. 78% at 48
      months) or incidence of metastasis (70 vs. 64%) between the two groups. Nor was
      there a significant difference in the overall survival rate (60 vs. 66%). The
      results of this study suggest that the concomitant use of daily administration of
      low-dose cisplatin with preoperative radiation brings no statistically
      significant benefit in improving local control and survival rate in patients with
      advanced resectable oral cancer.

PMID- 10660735
TI  - [Clinical effects of adjuvant therapy using Z-100 (Ancer 20 injection) for oral
      cancer--prevention of stomatitis and hematopoietic impairment].
AB  - A combination of radiotherapy and chemotherapy is a usual treatment method for
      malignant head and neck tumors, however chemoradiotherapy is associated with
      hematopoietic impairment and serious stomatitis in patients. The clinical effects
      and evaluation of hematopoietic activity (e.g., leukocyte count) and the degree
      of stomatitis under adjuvant therapy using Z-100 (Ancer 20 injection) for oral
      cancer were investigated for preoperative cancer therapy. In order to evaluate
      the clinical effects of Ancer 20 injection with regard to hematopoietic activity
      and the degree of stomatitis, a clinical study was performed for 18 patients with
      oral cancer in our department. The 18 patients, who had oral squamous cell
      carcinomas (5 of the tongue, 4 of the mandibular gingiva, 3 of the maxillary
      gingiva, 1 of the floor of the mouth, 3 of the buccal mucosa, and 2 others), were
      treated with this combination of adjuvant therapy with Ancer 20 injection, from
      March, 1991 to March, 1997. They were injected with Ancer 20 (twice a week, 40
      micrograms) during the cancer treatment period. We investigated hematopoietic
      activity, (e.g., leukocyte and platelet counts) and the degree of stomatitis
      periodically, before and after the combined radiotherapy and chemotherapy
      treatment period. It was found that in the patients who were treated with Ancer
      20 injection, the decrease in leukocyte and platelet counts was prevented and the
      condition of stomatitis was improved. These results suggest that Ancer 20
      injection may generally improve various dysfunctions due to hematopoietic
      impairment by radiotherapy combined with chemotherapy, and improve immunological
      factors. We conclude that Ancer 20 injection is a useful adjuvant treatment for
      oral cancer.

PMID- 10660736
TI  - [A double-blind randomized comparative study of oral 5-fluorouracil (5-FU),
      cyclophosphamide (CPA), and 5-FU + CPA in advanced breast cancer].
AB  - A randomized trial was performed comparing the effects of oral 5-fluorouracil (5
      FU), 300 mg/day, cyclophosphamide (CPA), 150 mg/day and 5-FU + CPA in advanced
      breast cancer. Some 181 patients were entered in the trial, with 1 ineligible,
      and 14 incomplete cases. Then 166 were evaluated for their rates of response in
      the treatment groups: 14.0% (8/57) in 5-FU, 23.6% (13/55) in CPA, and 37.0%
      (20/54) in 5-FU + CPA, with a P value of 0.019. The difference in response rates
      between 5-FU and 5-FU + CPA was shown to be significant (p = 0.005). When long NC
      was included in the comparison, there was a significant difference (p = 0.006)
      between the groups. A higher incidence of adverse effects was noted in the
      combination group. A significant difference was noted in TTP (time to
      progression) among the 3 groups (p = 0.0144), and between 5-FU and 5-FU + CPA (p
      = 0.0061). There were no significant differences in the overall survival among
      the groups (p = 0.6808). In conclusion, the combination oral treatment of 5-FU
      and CPA appears effective as a first line therapy for advanced breast cancer, and
      also in the postoperative adjuvant setting.

PMID- 10660737
TI  - [A late phase II study of raltitrexed (ZD 1694) in chemotherapy-naive patients
      with advanced colorectal cancer].
AB  - A multicenter co-operative late phase II study of raltitrexed (ZD1694), a
      specific thymidylate synthase (TS) inhibitor, was conducted in chemotherapy-naive
      patients with advanced colorectal cancer. Raltitrexed was infused intravenously
      over 15 minutes once every three weeks. Between April 1996 and September 1998, 61
      patients were enrolled and 58 were eligible. Fourteen patients experienced a
      partial response (PR), 22 no change (NC), 20 progressive disease (PD) and 2 no
      evaluable (NE). The overall response rate was 24.1% (95% CI: 13.9-37.2%).
      Responses were seen in lung (22.7%), liver (22.9%) and deep lymph nodes (10.0%).
      Median survival was 11.6 months. Grade 3 or 4 toxicities were: leukopenia
      (13.8%), neutropenia (24.1%), hemoglobin decrease (15.5%), FBC decrease (6.9%),
      hematocrit decrease (6.9%), thrombocytopenia (6.9%), transient SGPT increase
      (6.9%), nausea/vomiting (20.7%), anorexia (15.5%), and asthenia (6.9%). These
      adverse reactions were considered to be manageable. Only one death was associated
      with drug treatment. These results suggest that raltitrexed provides an effective
      and convenient treatment for patients with advanced and previously untreated
      colorectal cancer.

PMID- 10660738
TI  - [Anti-angiogenic activities of UFT and its metabolites, GHB and GBL, in the
      dorsal air sac (DAS) model in mice].
AB  - We investigated the effects of UFT and its metabolites, GHB and GBL, on
      angiogenesis induced by tumor cells in a dorsal air sac (DAS) assay in mice. Five
      tumor cell lines (murine renal carcinoma; RENCA, human gastric cancer; 4-1ST,
      human small-cell lung carcinoma; LX-1, and human colon carcinoma; DLD-1, KM-20C)
      were used in the DAS assay. In this model, UFT demonstrated a significant anti
      angiogenic activity in a dose-dependent manner while 5-FU (19 mg/kg/day) and 5'
      DFUR (200 mg/kg/day) were less effective. Moreover, tegafur (FT), a component of
      UFT, and gamma-hydroxybutyric acid (GHB) and gamma-butyrolactone (GBL), in vivo
      metabolites of UFT, inhibited angiogenesis induced by RENCA cells. The inhibitory
      effects of 5-FU, GHB, and GBL on angiogenesis were increased with administration
      by continuous infusion, providing a suitable pharmacokinetic profile. These
      results suggest that GHB and GBL are involved in the expression of anti
      angiogenic activity of UFT.

PMID- 10660739
TI  - [Syndrome of inappropriate secretion of antidiuretic hormone in a patient with
      myeloid antigen positive acute lymphoblastic leukemia after systemic chemotherapy
      including vincristine].
AB  - We report a case of syndrome of inappropriate secretion of antidiuretic hormone
      (SIADH) after the patient had received several anti-cancer drugs, including
      vincristine (VCR), in a patient with myeloid antigen positive acute lymphoblastic
      leukemia (My(+)-ALL). A 53-year-old woman presented at the hospital complaining
      of high-grade fever and general lassitude. Further examination revealed that she
      had My(+)-ALL. On admission, she was treated with anti-cancer drugs, including
      VCR. On day 24, after the first administration of VCR, a conscious disturbance
      suddenly occurred and she was diagnosed with SIADH. A plain head CT scan showed a
      low density lesion through the gray matter to the white matter in the bilateral
      occipital lobe, as well as diffuse swelling of the cerebrum. This was not seen on
      the follow up CT scan, and we concluded that it had been a transient abnormal
      finding due to SIADH. She achieved complete remission after induction
      chemotherapy and 3 added courses of consolidation chemotherapy. VCR was also
      administered 4 times in the second consolidation chemotherapy, but hyponatremia
      did not occur. This case suggests that a head CT scan is a useful procedure for
      the diagnosis and monitoring of SIADH, and that VCR may still be used in a
      patient who has suffered from VCR-induced SIADH.

PMID- 10660740
TI  - [A case of advanced gastric cancer with lung and liver metastasis responding
      remarkably to combination chemotherapy with CDDP and CPT-11].
AB  - A 56-year-old male patient with upper epigastric discomfort was introduced to our
      hospital from the previous clinic due to gastric cancer on July 8, 1998. Several
      examinations showed massive lung and liver metastases from Type-I gastric cancer
      beneath the esophagogastric mucosal junction. First we tried transcatheter
      arterial embolization (TAE) with a single agent, CDDP 20 mg/day for 4 days, but
      there was no change in the metastatic lesions. We then tried combination
      chemotherapy of CPT-11 40 mg/day a day with CDDP 15 mg/day for 4 days. After a 6
      week interval, we added 4 courses at the same doses. The primary stomach lesion
      was reduced and was visible as a small nodular flat mass. Moreover, we found that
      the lung and liver metastatic lesions were already reduced. Three months have
      passed since CDDP-CPT-11 combination therapy, and we have not found any recurrent
      tumors so far.

PMID- 10660741
TI  - [A case of advanced gastric cancer (type 3) with pyloric stenosis, multiple liver
      and lymph node metastases responding to UFT-E granules and lentinan].
AB  - The patient was a 80-year-old male with advanced gastric cancer (Type 3)
      accompanied by multiple liver and lymph node metastases. Histological findings in
      the stomach showed poorly differentiated adenocarcinoma. He had nausea, vomiting
      and anorexia due to pyloric stenosis, and was treated with 600 mg of UFT E
      granules/day orally for 5 consecutive days followed by 2 drug-free days (weekly-5
      method), and 2 mg of lentinan intravenously twice a week. After 4 weeks of
      treatment, the primary tumor and metastatic lesions of the liver and lymph nodes
      were markedly reduced. His symptoms had completely disappeared along with
      lessening of the pyloric stenosis after 6 weeks of treatment. The patient
      survived for 7 months in a state of CR and PR. The adverse effects were very mild
      and negligible. A weekly-5 method of UFT, in comparison with conventional daily
      administration, may induce maximal antitumor effects with minimal adverse
      effects.

PMID- 10660742
TI  - [Two cases of recurrent gastric cancer for which combination chemotherapy with
      pirarubicin, cis-platinum and 5-fluorouracil were markedly effective].
AB  - In the treatment of 2 patients with recurrent gastric cancer who showed bone
      metastasis and lymph node recurrence, we administered 30 mg/body of pirarubicin
      (THP) on the first day of treatment, and 30 mg/body of cis-platinum (CDDP) and
      500 mg/m2 of 5-fluorouracil (5-FU) for 3 days (FP therapy). Marked effects were
      achieved. Gastric cancer of Borrmann IV type was diagnosed in Case 1, and total
      gastrectomy was performed. The histological type was poorly differentiated
      adenocarcinoma, and the histological classification was II. A bone metastasis was
      found three years after operation. The patient was CR after three courses of
      treatment, and has survived for 2 years. In Case 2, advanced gastric cancer was
      treated with neoadjuvant chemotherapy and distal gastrectomy. The histological
      type was moderately differentiated adenocarcinoma, and the histological
      classification was IIIa. Obstructive jaundice due to lymph node recurrence
      developed 6 years after operation. Two courses of treatment were provided after
      PTCD, and PR was observed. The patient has survived for 3 months. Both patients
      exhibited mild side effects such as anemia and leukocytopenia, but no serious
      complications were observed. Although various dosage regimens of FP therapy have
      been investigated, there has been a certain limit to the response rate achieved
      by this therapy, and new protocols have been explored. We achieved marked effects
      in 2 patients by adding THP to FP therapy. These cases are reported here together
      with some discussion of cases reported in the literature.

PMID- 10660744
TI  - [A case of recurrent pancreatic cancer brought into a complete response by a
      multimodal treatment with intraarterial chemotherapy and radiotherapy].
AB  - We achieved a complete response of recurrent pancreatic cancer using a multimodal
      treatment with intravenous, oral and intraarterial chemotherapies and
      radiotherapy. A 55-year-old female patient had a recurrent pancreatic cancer,
      which had invaded the portal vein, 2 years after pancreatoduodenectomy.
      Angiography demonstrated prominent stenosis of the portal vein, which was
      enlarged by the insertion of a metalic stent to maintain blood flow to the liver.
      Chemotherapy included intravenous mitomycin C, 5-FU and 4'-epirubicin (EPI), oral
      UFT and cyclophosphamide, and intraarterial cisplatin, 5-FU and EPI through a
      catheter inserted into the celiac artery. Furthermore, the patient received a
      total of 50 Gy radiotherapy. Four months after the initiation of therapy, a
      computed tomography image demonstrated a complete disappearance of the recurrent
      tumor and a prominent decrease in the serum CA19-9 level. At present, 11 months
      have passed after the initiation of therapy, and she has been followed at our
      outpatient department without any symptoms of recurrence.

PMID- 10660743
TI  - [A case of unresectable gallbladder cancer responding to combination therapy with
      hyperthermia and local chemotherapy].
AB  - A 78-year-old woman was admitted to our hospital for the control of gallbladder
      cancer. A peritoneal metastasis, diagnosed as unresectable cancer, was detected
      during surgery in a previous hospital, and a biliary stent was introduced and
      gastrojejunostomy was performed. In our hospital she was treated weekly with
      local chemotherapy (PFL; cisplatin 2.5-5 mg/body ia, fluorouracil 300 mg/body ia,
      and calcium folinate 30 mg/body ia, via the common hepatic arterial port) at the
      time of hyperthermia. Hyperthermia was performed with a Thermox 500 (HEH-500 C)
      at the power of 500 watts for 45-60 minutes. To enhance the hyperthermia effect,
      mitomycin C 2-4 mg/body ia via the common hepatic arterial port and 500 ml of
      7.5% glucose infusion were given. As a result of the combination therapy, the
      volume of the whole tumor was reduced to 60.9% on computed tomography, and
      diagnosed as PR. The serum level of CA19-9 decreased from 3,000 U/ml to 300 U/ml.
      The patient continued to receive the therapy for 1 year, and is now well.
      Therefore, we conclude that combination therapy with hyperthermia and local
      chemotherapy seems beneficial in managing unresectable advanced gallbladder
      cancer, especially for the elderly.

PMID- 10660745
TI  - [Successful treatment of a patient with recurrent ovarian clear cell
      adenocarcinoma under combination chemotherapy of 5-FU (civ) and low-dose CDDP
      (i.v.)].
AB  - Resistance to conventional chemotherapy including CDDP is the most important
      therapeutic problem in ovarian cancer. The combination chemotherapy of 5-FU (civ)
      and low-dose CDDP (i.v.) was applied to a patient with recurrent ovarian clear
      cell adenocarcinoma (stage IIa), which is often more resistant to systemic
      chemotherapy than other ovarian adenocarcinomas and is a poor prognostic factor.
      The patient underwent cytoreductive surgery. Then, 5-FU 375 mg/m2/day civ (days 1
      5, 8-12, 15-19, 22-26) and CDDP 3.75 mg/m2/day i.v. (days 1-5, 8-12, 15-19, 22
      26) were administered. After four courses of this treatment, there is no sign of
      recurrence. This result indicates that the combination of 5-FU and CDDP is useful
      in the treatment of recurrent ovarian cancers.

PMID- 10660746
TI  - [Long-term complete response in a case of unresectable rectal cancer following
      chemoradiation].
AB  - We report a case of unresectable rectal cancer in a 53-year-old male treated with
      chemoradiation. Radiation therapy was delivered with a total pelvic dose of 45 Gy
      together with oral administration of 5'-DFUR (1,200 mg/day). The patient received
      one course of combination chemotherapy consisting of cisplatin, 100 mg/body x 1
      day, and 5-FU, 1,000 mg/body x 5 days, followed by radiation therapy. Oral
      administration of tegafur-uracil (300 mg/day) was continued for five years
      following the chemoradiation. The patient is now disease-free 75 months after the
      initial surgery. Chemoradiation can be managed to obtain a complete remission of
      some locally advanced rectal cancers.

PMID- 10660747
TI  - [A long-term survivor of extensive-stage small cell lung cancer].
AB  - A 53-year-old man was admitted for evaluation of multiple hepatic tumors. A
      thoracic CT scan revealed a mass lesion in the right middle lobe. Transcutaneous
      needle aspiration cytology from the lung tumor and transcutaneous hepatic tumor
      biopsy were performed, from which the cytohistological diagnosis was small cell
      lung cancer with liver metastasis. The patient was treated with 3 courses of high
      dose cisplatin with vindesine and mitomycin and 5 courses of carboplatin with
      etoposide, and achieved a complete response. We herein report a long-term
      survivor of extensive-stage small cell lung cancer.

PMID- 10660748
TI  - [A case of squamous cell lung cancer in a nonsmoking female, successfully treated
      with docetaxel and cisplatin].
AB  - A 62-year-old nonsmoking female was admitted to our hospital in May, 1998
      complaining of marked cough accompanied by repeated hemosputa. Chest X-ray and CT
      examinations revealed a large tumor, located adjacent to a cystic lesion in the
      left lower lung field, in association with a clearly recognizable swelling of the
      ipsilateral hilar as well as the mediastinal lymph nodes. Sputum cytology after
      bronchofiberscopy led to the diagnosis that the patient suffered from squamous
      cell lung cancer of Stage IIIA with bulky N2 (T2N2M0). Chemotherapy was selected
      as the most reasonable treatment for this patient. The new chemotherapeutic agent
      docetaxel (60 mg/m2) in combination with cisplatin (CDDP: 80 mg/m2) was tried,
      resulting in a remarkable reduction in tumor size by 60% after the initial course
      of chemotherapy was completed, which fulfilled the definition of a partial
      response (PR). Furthermore, after 4 courses of the chemotherapy, the hilar and
      mediastinal lymphadenopathy had conspicuously abated and only scar tissue was
      visible at the site where the lung cancer was thought to have originally
      developed. We herein report a case in which squamous cell lung cancer sprouted in
      a nonsmoking female, who was successfully treated by the combined chemotherapy of
      docetaxel and CDDP. The present case may suggest the efficacy of newly developed
      docetaxel in treating non-small cell lung cancer.

PMID- 10660750
TI  - Invited commentary: artificial neural networks--an introduction.

PMID- 10660749
TI  - [A trial for neoadjuvant chemotherapy of transarterial infusion of docetaxel in
      locally advanced breast cancer].

PMID- 10660751
TI  - Artificial neural networks.

PMID- 10660752
TI  - Invited commentary: surgical residency training.

PMID- 10660753
TI  - General surgery and fellowship training: opinions of surgical intern applicants
      and fellowship directors.
AB  - BACKGROUND: Given the pressures that exist today to modify surgical training
      programs, this study was undertaken to ascertain the opinions of surgical intern
      applicants and fellowship program directors with regard to the length of surgical
      training. METHODS: Surveys were sent to fourth-year medical students who were
      applying for categorical surgical training during a 2-year period at a single
      university medical center and to fellowship program directors in 6 surgical
      subspecialties. RESULTS: Ninety-three percent of the applicants planned to pursue
      fellowship training. Sixty-eight percent of the applicants did not feel that 5
      years of general surgery are necessary before beginning a fellowship. Seventy-one
      percent of the applicants indicated that they would be willing to "short track"
      into a subspecialty to reduce training time. Virtually all fellowship directors
      in pediatric surgery (94%), transplantation surgery (94%), and oncologic surgery
      (100%) felt that 5 years of general surgery training are necessary before
      entering a fellowship. Significantly fewer fellowship directors in vascular
      surgery (53%), cardiothoracic surgery (30%), and plastic surgery (17%) felt that
      5 years of general surgery are essential before beginning a fellowship (P < or =
      .001). CONCLUSIONS: For some general surgery subspecialties, a shortened,
      integrated training program may be desirable from the point of view of both
      trainees and fellowship directors. Vascular, cardiothoracic, and plastic surgery
      appear to be those subspecialties that are most amenable to such programs.

PMID- 10660754
TI  - Sentinel node localization in primary melanoma: preoperative dynamic
      lymphoscintigraphy, intraoperative gamma probe, and vital dye guidance.
AB  - BACKGROUND: Sentinel node (SN) biopsy can be used to select patients with primary
      melanoma for therapeutic lymphadenectomy. The aim of the study was to assess the
      efficacy of 3 methods to locate the SN: preoperative dynamic lymphoscintigraphy,
      intraoperative patent blue dye (PBD), and gamma-detecting probe (GDP). METHODS:
      We studied 133 patients with cutaneous melanoma and clinically negative lymph
      nodes. Within 24 hours before surgery, colloid labeled with technetium 99m was
      injected intradermally around the site of the primary melanoma. The patients were
      studied before their operations by using dynamic lymphoscintigraphy. A total of
      208 SNs were found in 164 lymph node basins. In addition, all the patients had
      PBD injected immediately before the surgical procedure. When the blue-stained
      node was identified intraoperatively, its radioactivity level was measured with
      the GDP. In the absence of blue coloration, the GDP was used to trace the SN.
      RESULTS: Of 208 SNs, 168 (80.8%) were identified in the regional draining basin
      during intraoperative lymphatic mapping by using PBD. By using the GDP method,
      202 (97.1%) of 208 were identified (GDP vs PBD; P < .01). By combining the 2
      methods, 206 (99%) of 208 SNs were detected. Of the 133 patients, 29 (21.8%) had
      pathologically positive SNs, and were subsequently subjected to regional
      lymphadenectomy. In 26 (89.7%) of 29 patients, the SN was the only node with
      metastasis. Three cases (10.3%) of recurrence in patients with microscopic SN
      metastasis and 7 cases (6.7%) of recurrence in patients without SN metastasis
      were found during a median follow-up of 566 days. CONCLUSIONS: Preoperative
      dynamic lymphoscintigraphy and intraoperative mapping with PBD and GDP offer
      simple and reliable methods of staging regional lymph nodes without subjecting
      every patient to a regional lymphadenectomy.

PMID- 10660755
TI  - Standardized probe-directed sentinel node dissection in melanoma.
AB  - BACKGROUND: Radiopharmaceutical agents appear to improve the accuracy of sentinel
      node (SN) identification in patients with early-stage melanoma, but the optimal
      radiopharmaceutical agent and its timing from injection to surgery remain
      controversial. We undertook this investigation to examine the utility of 3
      methods of intraoperative lymphatic mapping with radiopharmaceutical-directed
      sentinel lymphadenectomy (LM/SL). We suspected that concurrent injection of
      radiopharmaceutical and blue-dye would lead to the greatest success of SN
      identification. METHODS: The study was composed of 247 consecutive patients who
      had American Joint Committee on Cancer stage I or II melanoma. Before LM/SL, all
      patients underwent cutaneous lymphoscintigraphy by 1 of 3 techniques: technetium
      99m (Tc 99m) human serum albumin (HSA) injected at least 24 hours before LM/SL
      (124 patients), Tc 99m filtered sulfur colloid (SC) injected no more than 4 hours
      before LM/SL (same-day SC, 95 patients), or Tc 99m SC injected at least 18 hours
      before LM/SL (prior-day SC, 28 patients). At the time of LM/SL, isosulfan blue
      dye was injected alone (SC groups) or with a second dose of HSA (HSA group). A
      hand-held gamma probe was used to determine the radioactive (hot) counts of blue
      stained and nonstained nodes, and the in vivo and ex vivo node-to-background
      count ratios of the nodes were compared. RESULTS: Preoperative LS identified 299
      drainage basins; LM/SL identified at least 1 SN in 119 (98%) of 121 basins using
      same-day SC, 142 (97%) of 146 basins using HSA, and 32 (100%) of 32 basins using
      prior-day SC. There was no difference (P = .62) in the accuracy rate between the
      3 techniques. The total number of SNs was 463. Same-day SC yielded higher
      intraoperative node-to-background count ratios than did either of the other
      techniques (P < .0001). Same-day SC also had the greatest relative change in
      radioactivity between the blue sentinel node and the post-excision basin (P <
      .0001), and the highest rate of SNs that were both blue and hot (in vivo or ex
      vivo ratio > or = 2, P = .05). CONCLUSIONS: LS and LM/SL performed on the same
      day with a single injection of filtered Tc 99m SC serves as the most useful
      method for probe-directed LM/SL. This technique demonstrated the highest in vivo
      and ex vivo count ratios, fall-off of radioactivity between the excised nodes and
      post-excision basin, and concordance between blue dye and hot nodes. It should be
      recommended as the method of choice for probe-directed LM/SL.

PMID- 10660756
TI  - Micrometastasis in lymph nodes and microinvasion of the muscularis propria in
      primary lesions of submucosal gastric cancer.
AB  - BACKGROUND: It is important to clarify the clinicopathologic characteristics of
      micrometastasis in lymph nodes and microinvasion in primary lesions for the
      treatment options with regard to submucosal gastric cancer. METHODS: We examined
      1945 lymph nodes and 68 primary tumors resected from 79 patients with submucosal
      gastric cancer. Two consecutive sections were prepared for simultaneous staining
      with ordinary hematoxylin and eosin and immunostaining with anticytokeratin
      antibody (CAM 5.2), respectively. RESULTS: The incidence of nodal involvement in
      79 patients with submucosal gastric cancer increased from 13% (10/79 patients) by
      hematoxylin and eosin staining to 34% (27/79 patients) by cytokeratin
      immunostaining. Micrometastases in the lymph nodes were found in 17 of 69
      patients (25%), with cancer-free nodes examined by hematoxylin and eosin.
      Microinvasion to the muscularis propria was found in 11 of 68 patients (16%) who
      were histologically diagnosed with submucosal gastric cancer. Survival analysis
      demonstrated a lesser 5-year survival in the patients with micrometastasis in
      lymph nodes (82%) and with microinvasion to muscularis propria (73%). A high
      incidence of nodal involvement was found in submucosal cancers of large size (> 2
      cm; 43%), a depressed type (48%), lymphatic invasion (73%), and deeper submucosal
      invasion (submucosal 3, 53%). A higher incidence of microinvasion was found with
      the diffuse-type carcinoma (33%). CONCLUSIONS: Cytokeratin immunostaining is
      useful for detecting micrometastasis and microinvasion in submucosal gastric
      cancer. Tumor size, macroscopic type, lymphatic invasion, and the depth of
      submucosal invasion are strongly associated with lymph node involvement.

PMID- 10660757
TI  - Significance of immunohistochemically demonstrated micrometastases to lymph nodes
      in esophageal cancer with histologically negative nodes.
AB  - BACKGROUND: We examined the prevalence, patterns, and clinical significance of
      nodal micrometastases in patients with esophageal cancer. METHODS: Cervical,
      mediastinal, and abdominal lymph nodes systematically removed from 37 patients
      without conventional histologic evidence of lymph node metastasis from esophageal
      squamous cell carcinoma were immunohistochemically examined to detect cells that
      were stained for cytokeratins by the monoclonal antibody cocktail AE1/AE3.
      Postoperative care and survival were compared in cases with and without such
      micrometastases. RESULTS: Nodal micrometastases were found in 14 of 37 patients
      (38%). Among these patients, 9, 7, and 4 had micrometastases to abdominal,
      mediastinal, and cervical lymph nodes, respectively. Postoperative tumor
      recurrence was significantly more frequent in patients with micrometastases (50%)
      than in those without (9%, P = .008). Overall and relapse-free survival in the
      former group was significantly worse than in the latter group (P = .042 and P =
      .002, respectively). Nodal micrometastases had an independent prognostic
      importance for relapse-free survival as determined by multivariate analysis.
      CONCLUSIONS: Metastatic tumor cells are frequently present in lymph nodes, even
      in patients without histologic evidence of nodal metastasis from esophageal
      cancer. Nodal micrometastases indicates a poorer prognosis after a curative
      esophagectomy procedure in histologically node-negative cases.

PMID- 10660758
TI  - Immunosuppressive therapy using FTY720 combined with tacrolimus in rat liver
      transplantation.
AB  - BACKGROUND: FTY720 (FTY) exerts its effects through a reduction of peripheral
      lymphocytes. This unique mechanism allows for a possible combination effect with
      other immunosuppressants. We investigated therapy with FTY combined with
      tacrolimus (FK) in rat liver transplantation. METHODS: Different doses of FK,
      FTY, or both were orally administered to the recipients for 15 days. Expression
      of cytokine mRNAs using RT-PCR and appearance of lymphocyte apoptosis by
      immunohistologic staining were studied in the allografts. RESULTS: Recipients
      treated with a low dose of FK (0.3 mg/kg) or FTY (0.03 mg/kg) showed a slightly
      prolonged survival time, although combination therapy with these drugs prolonged
      survival time similar to the duration obtained by an optimal dose of each drug
      alone. A marked suppression of lymphocyte infiltration and decreased levels of
      mRNAs for IL-2, IFN-gamma, and granzyme B were seen in the grafts with
      combination therapy. Grafts with combination therapy showed an increased number
      of cells double-stained with TUNEL and CD2 in infiltrated lymphocytes.
      CONCLUSIONS: Allografts that underwent combination therapy demonstrated markedly
      reduced lymphocyte infiltration; a number of cells had induced apoptosis and an
      inhibition of IL-2, IFN-gamma, and granzyme B mRNA transcription, but not IL-4
      and IL-10 transcripts, accounting for powerful mutual effect of FTY and FK.

PMID- 10660759
TI  - Apoptotic cell death of hepatocytes in rat experimental severe acute
      pancreatitis.
AB  - BACKGROUND: Apoptosis of hepatocytes has been reported to be involved in liver
      failure complicated with systemic manifestations such as endotoxemia. We
      hypothesized that hepatocyte apoptosis occurs in severe acute pancreatitis.
      METHODS: Induction of apoptosis was evaluated in the liver from rats with
      necrotizing pancreatitis. Apoptosis-inducing activity of the pancreatitis
      associated ascitic fluid on hepatocytes was evaluated in vivo by intraperitoneal
      injection of the ascitic fluid and in vitro using rat primary hepatocyte culture.
      RESULTS: Apoptosis was detected in hepatocytes in the rats both with severe acute
      pancreatitis and with the intraperitoneal injection of the ascitic fluid by in
      situ nick-end labeling and DNA fragmentation. Apoptotic change and hepatic injury
      were ameliorated by administration of an interleukin-1 beta-converting enzyme
      inhibitor. The ascitic fluid exhibited cytocidal activity in rat primary
      hepatocyte culture via apoptosis, which was confirmed by DNA fragmentation, by
      cell cycle analysis, and by nuclear fragmentation. The neutralizing antibody for
      transforming growth factor-beta 1 partially blocked the apoptosis induction but
      the antibody to tumor necrosis factor-alpha had no effect. CONCLUSIONS: Apoptotic
      cell death occurs in hepatocytes in severe acute pancreatitis partially via
      transforming growth factor-beta 1 in the pancreatitis-associated ascitic fluid.

PMID- 10660760
TI  - Cell-mediated immune response is better preserved by laparoscopy than laparotomy.
AB  - BACKGROUND: This study compares the effects of carbon dioxide pneumoperitoneum
      versus laparotomy on cellular-mediated immune response in a murine model.
      METHODS: Sixty-eight female C3H/He mice were sensitized to keyhole limpet
      hemocyanin (KLH) and to a mouse mammary carcinoma cell line (MC2) before surgery.
      Animals were randomized into 4 groups: group I, anesthesia (control); group II,
      pneumoperitoneum with carbon dioxide; group III, extraperitoneal wound; group IV,
      laparotomy. All animals were challenged subsequently with KLH and MC2 tumor
      cells. Delayed-type hypersensitivity skin reaction (DTH) to KLH was measured on
      postoperative days (PODs) 1, 2, 4, and 5. Tumor growth was assessed weekly as an
      indicator of postoperative cellular immune response. RESULTS: Compared with
      preoperative values, postoperative DTH skin reactions were significantly less for
      all PODs in groups III and IV (P < .05), on POD 1 and 4 in group II (P < .05) and
      POD 4 for group I (P < .05). Group IV showed significantly fewer DTH skin
      reactions for all PODs compared with groups I and II (P < .05) and all PODs
      except on day 2 compared with group III (P < .05). Tumor growth was significantly
      increased at postoperative week 2 (n = 3/17 mice) and 3 (n = 4/17 mice) in group
      IV, when compared with groups I and II (P < .05). CONCLUSIONS: Cellular immunity
      is preserved after carbon dioxide pneumoperitoneum compared with extraperitoneal
      incisions and laparotomy as measured by DTH and the ability to reject an
      immunogenictumor.

PMID- 10660761
TI  - Nicotine induces platelet-derived growth factor release and cytoskeletal
      alteration in aortic smooth muscle cells.
AB  - BACKGROUND: Cigarette smoking is implicated in atherosclerotic plaque formation,
      but the role of nicotine in this process is not completely understood. The
      release of platelet-derived growth factor (PDGF) by the bovine aortic smooth
      muscle cell (SMC) after nicotine administration at a concentration similar to
      that ingested by active and passive smokers and the role of PDGF in SMC
      cytoskeletal modification were studied. METHODS: SMC, harvested with enzymatic
      digestion from calf aorta, were stimulated in a serum-free medium for 72 hours
      with (-)-nicotine (from 6 x 10(-4) mol/L to 6 x 10(-8) mol/L). The release of
      PDGF was assessed by inhibition antibody-binding assay and confirmed by Western
      blotting. Mitogenic activity of nicotine on SMCs was also determined. The SMC
      cytoskeleton was studied with specific antibodies anti-alpha-actin fibers, anti
      vimentin, and anti-beta-tubulin, and the modification induced by PDGF was
      assessed by blocking PDGF activity with specific antibodies. RESULTS: The
      greatest PDGF release (1.24 +/- 0.14 ng/10(4) cells vs control 0.43 +/- 0.07
      ng/10(4) cells) was noted at a (-)-nicotine concentration of 6 x 10(-7) mol/L (P
      < .001). The addition of monoclonal antibody anti-PDGF decreased the tritiated
      thymidine uptake of SMCs exposed to (-)-nicotine compared with the control (29%
      vs 5%-P < .001). SMCs exposed to (-)-nicotine concentration of 6 x 10(-7) mol/L
      and 6 x 10(-8) mol/L had a significant alteration in the expression of alpha
      actin fibers, vimentin, and beta-tubulin compared with control. The
      administration of antibody anti-PDGF in the culture medium reversed cytoskeletal
      alteration. CONCLUSIONS: Nicotine enhanced the release of platelet-derived
      growth, which in turn caused an alteration in cytoskeletal organization.

PMID- 10660762
TI  - Effect of the 21-aminosteroid on nuclear factor-kappa B activation of Kupffer
      cells in endotoxin shock.
AB  - BACKGROUND: The 21-aminosteroid (U-74389G) is a nonglucocorticoid steroid that
      was synthesized to inhibit lipid peroxidation without the glucocorticoid
      activity. We recently demonstrated that the 21-aminosteroid administered to
      endotoxin shock mice reduces liver injury and improves the survival rate of mice
      through inhibition of nuclear factor-kappa B activation in the liver. The study
      was undertaken to determine whether the 21-aminosteroid could suppress pro
      inflammatory gene up-regulation through inhibition of nuclear factor-kappa B
      activation in Kupffer cells. METHODS: Kupffer cells were isolated from rats by
      collagenase perfusion followed by pronase digestion. After a lipopolysaccharide
      addition, each assay was performed for tumor necrosis factor-alpha, interleukin
      6, tumor necrosis factor-alpha messenger RNA, nuclear factor-kappa B, and I kappa
      B proteins. RESULTS: After the lipopolysaccharide addition, Kupffer cells
      released both tumor necrosis factor-alpha and interleukin-6. The 21-aminosteroid
      treatment suppressed the release of tumor necrosis factor-alpha in a dose
      dependent manner. The 21-aminosteroid also inhibited the increase of tumor
      necrosis factor-alpha messenger RNA expression and nuclear factor-kappa B
      activation in Kupffer cells 1 hour and 30 minutes, respectively, after
      lipopolysaccharide addition. Furthermore, the 21-aminosteroid treatment
      suppressed the degradation of I kappa B proteins in lipopolysaccharide-stimulated
      Kupffer cells. CONCLUSIONS: These results suggest that the 21-aminosteroid
      inhibits release of the tumor necrosis factor-alpha and interleukin-6 from
      lipopolysaccharide-stimulated Kupffer cells by inhibiting nuclear factor-kappa B
      activation. This is accomplished by inhibiting I kappa B degradation in endotoxin
      shock and this may prove useful for the treatment of endotoxin shock.

PMID- 10660763
TI  - Modulation of platelet aggregation after percutaneous transluminal angioplasty of
      the iliac artery for atherosclerosis obliterans.
AB  - BACKGROUND: Platelet aggregation is modulated by blood flow. We investigated
      whether platelet function is altered during percutaneous transluminal balloon
      angioplasty in patients with atherosclerosis obliterans. METHODS: Blood samples
      were obtained from the iliac artery in 9 lower limbs of 7 patients undergoing
      percutaneous balloon angioplasty of the iliac artery. An agonists-induced
      platelet aggregation test was performed with an aggregometer. Femoral blood flow
      was measured with a Doppler velocimeter before and after the procedure. RESULTS:
      Before dilatation, the maximum platelet aggregation rates (+/- SEM) induced by
      adenosine phosphate, epinephrine, and arachidonic acid were 54.7% +/- 5.8%, 64.8%
      +/- 4.3%, and 60.5% +/- 6.1%, respectively. After angioplasty, these values
      reduced to 36.7% +/- 4.1%, 36.1% +/- 8.6%, and 40.1% +/- 5.0%, respectively (P <
      .05). The pre-procedural ankle-brachial pressure index, mean flow rate, mean
      velocity, and shear stress variation were 0.63 +/- 0.1, 218.1 +/- 32.1 mL/min,
      9.4 +/- 1.1 cm/sec, and 60.6 +/- 17.7 dyne/cm2, respectively. The mean velocity
      at the stenotic lesion was 215.1 +/- 83.9 cm/sec, which was significantly greater
      than those of the distal artery or after angioplasty (P < .01). Both ankle
      brachial pressure index and shear stress variation increased after angioplasty to
      0.99 +/- 0.07 (P < .05) and 139.8 +/- 17.0 (P < .05) dyne/cm2, but the mean flow
      rate and the mean velocity (198.3 +/- 24.5 mL/min and 8.8 +/- 1.2 cm/sec after
      angioplasty) did not change significantly. CONCLUSIONS: These results indicate
      that activated platelet function at a stenosed artery was decreased after
      angioplasty, possibly because of normalized blood flow with reduction of stenotic
      lesion.

PMID- 10660764
TI  - End-to-side pudendal nerve anastomosis for the creation of a new reinforcing anal
      sphincter in dogs.
AB  - BACKGROUND: An ideal reinforcing neo-sphincter should be innervated by the
      pudendal nerve to work in coordination with the external anal sphincter. The aim
      of this study was to create a skeletal muscle innervated by the pudendal nerve
      without inducing external anal sphincter morbidity. METHODS: Seven dogs were
      used. On the right side of each dog, the distal end of the transected nerve
      innervating the biceps femoris muscle was anastomosed to the perineural window of
      the pudendal nerve, where the epineurium was excised over a small area without
      injuring the funiculus. Reinnervation was studied 5 months after the operations.
      The left side of the dogs was used as a control. RESULTS: For all 7 dogs, there
      was no macroscopic difference detected in the external anal sphincter. For 6
      dogs, the biceps femoris muscle was preserved after end-to-side pudendal nerve
      anastomosis. After the pudendal nerve central to the anastomosis site was
      electrically stimulated, the external anal sphincter contracted in all dogs.
      After end-to-side pudendal nerve anastomosis, the biceps femoris muscle
      contracted with the evoked potential in 5 dogs (71%) and demonstrated electric
      activity at rest in 3 dogs (43%), but there was no reflex activity after anal
      stimulation. The ratio of type 1 to type 2 muscle fiber in the biceps femoris
      muscle after end-to-side pudendal nerve anastomosis significantly changed and
      became the same as that in the external anal sphincter. The diameter of type 2
      muscle fibers in the biceps femoris muscle significantly decreased after surgery.
      In addition, regenerated myelinated axons were observed in a cross section of the
      anastomosed nerve in 6 dogs. CONCLUSIONS: End-to-side pudendal nerve anastomosis
      is a promising technique for the creation of an anal sphincter in patients who
      have fecal incontinence. The technique preserved the original external anal
      sphincter and created a skeletal muscle that was innervated by the pudendal nerve
      in 71% of the dogs studied. This newly innervated skeletal muscle was capable of
      contracting in coordination with the original external anal sphincter on electric
      stimulation and also demonstrated characteristics closely similar to those of the
      external anal sphincter.

PMID- 10660765
TI  - Goiter recurrence in patients submitted to thyroid-stimulating hormone
      suppression: possible role of insulin-like growth factors and insulin-like growth
      factor-binding proteins.
AB  - BACKGROUND: It is known that factors other than thyroid-stimulating hormone, such
      as insulin-like growth factor-I (IGF-I) and epidermal growth factor, have a
      goitrogenic effect. It has been established that insulin-like growth factor
      binding proteins (IGFBPs) may play a role as autocrine/paracrine factors in
      regulating the local actions of IGFs. Both an inhibitory and a stimulatory effect
      for different IGFBPs have been shown in several cell systems. The aim of this
      study was to assess the involvement of IGFBPs in the goitrogenic process in
      patients with goiter recurrence. METHODS: The IGFBP-1 and -3 content in normal
      and nodular tissues obtained at the time of thyroidectomy from 10 patients with
      recurrent goiters, unresponsive to thyroid-stimulating hormone suppressive
      therapy, was studied. In all patients, a fragment of normal tissue was also
      obtained. The IGF-I, IGFBP-1, and -3 content was evaluated by specific
      immunoassays and/or immunoblotting with anti-IGFBP specific antiserum. RESULTS:
      The IGF-I content was significantly higher (P < .05) in nodular tissues (8.0 +/-
      1.6 ng/g of tissue) than what was found in normal tissue (4.8 +/- 0.9 ng/g).
      Radioimmunoassay IGFBP-3 concentration in nodular tissue was 111.5 +/- 18.2 ng/g
      significantly higher (P < .001) than values found in normal tissue (77.5 +/- 18.6
      ng/g). By immunoblot, IGFBP-1 appeared higher in all but 1 nodular tissue.
      CONCLUSIONS: These data raise the possibility that IGFBPs are important in the
      proliferative activities entailed in the goitrogenic process. Three mechanisms
      are potentially involved: (1) reduction of the potency of locally produced IGF
      peptide to downregulate type I receptors (potentiating effect on the
      autocrine/paracrine mitogenic action of IGFs); (2) increase of the IGF-I tissue
      concentration restraining its passage to circulation; and (3) protection of IGF-I
      from degradation. Further studies are needed to define a more precise link
      between these factors and the recurrence of goiter.

PMID- 10660766
TI  - Long-term survival of peripheral intrahepatic cholangiocarcinoma with metastasis
      to the para-aortic lymph nodes.

PMID- 10660767
TI  - Primary malignant melanoma of the adrenal gland.

PMID- 10660768
TI  - Laparoscopic intracavitary debridement of peripancreatic necrosis: preliminary
      report and description of the technique.

PMID- 10660769
TI  - Adverse events.

PMID- 10660770
TI  - Femoral nerve entrapment following appendectomy.

PMID- 10660771
TI  - Survey of studies on how spaceflight affects rodent skeletal muscle.
AB  - Rodent muscles have been examined in more than 89 spaceflight studies over the
      last 25 years with much variation in the procedures and results. Mission duration
      ranged from four days to three weeks, postflight data collection ranged from a
      few hours to two days after landing, and there is great diversity in the number,
      size, and age of the rats that have flown. Several different types and sizes of
      animal enclosures have also been used--a significant factor because cage design
      affects animal activity and muscle loading. Only a small percentage
      (approximately 16%) of the total number of striated muscles in the rat have been
      examined. We have identified both substantial redundancy and inconsistencies in
      the results from studies to date. However, many of these appear unavoidable due
      to the great variation in experimental protocol of the different missions.
      Nevertheless these studies repeatedly confirm that exposure to spaceflight
      decreases the mass of limb muscles and leads to muscle atrophy. The majority of
      missions were flown by the former Soviet Union, but the majority of papers have
      been published by U.S. researchers. A relatively small number of investigators
      (about 50) clustered into fewer than 15 identifiable research groups worldwide
      account for most of the results to date. These groups have had access to rodent
      muscle tissue from two to seven spaceflights each. International cooperation in
      the post-cold war era and the publication of future work in peer-reviewed
      international journals should help greatly in reducing redundancy and enriching
      our knowledge of how gravity affects biological systems.

PMID- 10660772
TI  - Is skeletal muscle ready for long-term spaceflight and return to gravity?
AB  - It is now clear that prevention of muscle debilitation during spaceflight will
      require a broader approach than simple exercise aimed at strengthening of the
      muscle fibers. The levels of several hormones and receptors are altered by
      unloading and must be returned to homeostasis. Pharmacotherapy and gene transfer
      strategies to raise the relative level of structural proteins may minimize the
      problems faced by astronauts in readapting to Earth-gravity. Up to now, we have
      only minimally exploited microgravity for advancing our understanding of muscle
      biology. A research laboratory in the space station with a centrifuge facility
      (gravity control) is essential for conducting basic research in this field.
      Microgravity has proven an excellent tool for noninvasively perturbing the
      synthesis of muscle proteins in the search for molecular signals and gene
      regulatory factors influencing differentiation, growth, maintenance and atrophy
      of muscle. Understanding the relation between blood flow and interstitial edema
      and between workload and subsequent structural failure are but two important
      problems that require serious attention. The roles of hormones and growth factors
      in regulating gene expression and their microgravity-induced altered production
      are other urgent issues to pursue. These types of studies will yield information
      that advances basic knowledge of muscle biology and offers insights into
      countermeasure design. This knowledge is likely to assist rehabilitation of
      diseased or injured muscles in humans on Earth, especially individuals in the
      more vulnerable aging population and persons participating in strenuous sports.
      Will the skeletal muscle system be prepared for the increased exposure to
      microgravity and the return to gravity loading without injury when space station
      is operational? The answer depends in large part on continued access to space and
      funding of ground-based models and flight experiments. The previous two decades
      of spaceflight research have described the effects of microgravity on multiple
      systems. The next generation of experiments promises to be even more exciting as
      we are challenged to define the cellular and molecular mechanisms of microgravity
      induced changes.

PMID- 10660773
TI  - Nutrition and muscle loss in humans during spaceflight.
AB  - The protein loss in humans during spaceflight is partly due to a normal adaptive
      response to a decreased work load on the muscles involved in weight bearing. The
      process is mediated by changes in prostaglandin release, secondary to the
      decrease in tension on the affected muscles. On missions, where there is a high
      level of physical demands on the astronauts, there tends to be an energy deficit,
      which adds to the muscle protein loss and depletes the body fat reserves. While
      the adaptive response is a normal part of homeostasis, the additional protein
      loss from an energy deficit can, in the long run, have a negative effect on
      health and capability of humans to live and work in space and afterward return to
      Earth.

PMID- 10660774
TI  - Hormonal changes in humans during spaceflight.
AB  - Readers of this review may feel that there is much more that we do not know about
      space endocrinology than what we know. Several reasons for this state of affairs
      have been given: 1. the complexity of the field of endocrinology with its still
      increasing number of known hormones, releasing factors and precursors, and of the
      interactions between them through various feedback mechanisms 2. the difficulty
      in separating the microgravity effects from the effects of stress from launch,
      isolation and confinement during flight, reentry, and postflight re-adaptation 3.
      the experimental limitations during flight, such as limited number of subjects,
      limited number of samples, impossibility of collecting triple samples for
      pulsatile hormones like growth hormone 4. the disturbing effects of
      countermeasures used by astronauts 5. the inadequacy of postflight samples for
      conclusions about inflight values 6. limitations of conclusions from animal
      experiments and space simulation studies The endocrinology field is divided in to
      nine systems or axes, which are successively reviewed: 1. Rapid bone
      demineralization in the early phase of spaceflight that, when unopposed, leads to
      catastrophic effects after three months but that slows down later. The endocrine
      mechanism, apart from the effect of exercise as a countermeasure, is not yet
      understood. 2. The hypothalamic-pituitary-adrenal axis is involved in stress
      reactions, which complicate our understanding and makes postflight analysis
      dubious. 3. In the hypothalamic-pituitary-gonadal axis, pulsatility poses a
      problem for obtaining representative values (e.g., for luteinizing hormone).
      Reproduction of rats in space is possible, but much more needs to be known about
      this aspect, particularly in women, before the advent of space colonies, but also
      in males because some evidence for reversible testicular dysfunction in space has
      been found. 4. The hypothalamic-pituitary-somato-mammotrophic axis involves
      prolactin and growth hormone. The latter also acts as a stress hormone and its
      secretion is greatly decreased in spaceflown rats, but not in astronauts, which
      may be due to differences in the regulation of growth hormone secretion between
      rats and humans. 5. The hypothalamic-pituitary-thyroid axis involves the thyroid
      hormones thyroxine and triiodothyronine, which are lowered in space, suggesting
      mild hypothyroidism. 6. The renin-angiotensin-aldosterone axis, which regulates
      water and electrolytes, involves antidiuretic hormone and two natriuretic
      peptides and shows paradoxical behavior in space. 7. Erythrocyte mass regulation
      involves erythropoietin, and space anemia is still not explained. 8. The
      endocrine pancreas involves insulin and glucagon, with loss of insulin
      sensitivity in space due to lack of exercise, which phenomenon requires more
      study before the advent of space colonies. 9. The sympathetic system acts through
      epinephrine, norepinephrine and dopamine and seems to have an increased activity
      in space in contrast to what had been widely believed. From the foregoing
      conclusions, it is clear that much further study is needed in all fields of space
      endocrinology. On the other hand, future studies will allow us to understand what
      happens in a given endocrine subsystem in the absence of the "gravity factor",
      the perturbing factor to which the human race has become adapted through
      thousands of years of evolution. This should provide us with a fuller
      understanding of the internal homeostatic mechanisms. An important point is that
      some endocrine systems seem to undergo changes in space that resemble those
      observed during senescence, but after spaceflight, recovery always occurs within
      weeks or months after return. This is particularly true for the systems
      regulating bone and muscle metabolism and reproduction, exactly as happens with
      the immune, neurosensory, and cardiovascular systems. Further space research may
      help us find new insights in the pathophysiology of aging and hopefully define
      novel prev

PMID- 10660775
TI  - Growing crops for space explorers on the moon, Mars, or in space.
AB  - An option in the long-duration exploration of space, whether on the Moon or Mars
      or in a spacecraft on its way to Mars or the asteroids, is to utilize a
      bioregenerative life-support system in addition to the physicochemical systems
      that will always be necessary. Green plants can use the energy of light to remove
      carbon dioxide from the atmosphere and add oxygen to it while at the same time
      synthesizing food for the space travelers. The water that crop plants transpire
      can be condensed in pure form, contributing to the water purification system. An
      added bonus is that green plants provide a familiar environment for humans far
      from their home planet. The down side is that such a bioregenerative life-support
      system--called a controlled environment life-support system (CELSS) in this paper
      -must be highly complex and relatively massive to maintain a proper composition
      of the atmosphere while also providing food. Thus, launch costs will be high.
      Except for resupply and removal of nonrecycleable substances, such a system is
      nearly closed with respect to matter but open with respect to energy. Although a
      CELSS facility is small compared to the Earth's biosphere, it must be large
      enough to feed humans and provide a suitable atmosphere for them. A functioning
      CELSS can only be created with the help of today's advanced technology,
      especially computerized controls. Needed are energy for light, possibly from a
      nuclear power plant, and equipment to provide a suitable environment for plant
      growth, including a way to supply plants with the necessary mineral nutrients.
      All this constitutes the biomass production unit. There must also be food
      preparation facilities and a means to recycle or dispose of waste materials and
      there must be control equipment to keep the facility running. Humans are part of
      the system as well as plants and possibly animals. Human brain power will often
      be needed to keep the system functional in spite of the best computer-driven
      controls. The particulars of a CELSS facility depend strongly on where it is to
      be located. The presence of gravity on the Moon and Mars simplifies the design
      for a facility on those bodies, but a spacecraft in microgravity is a much more
      challenging environment. One problem is that plants, which are very sensitive to
      gravity, might not grow and produce food in the virtual absence of gravity.
      However, the experience with growing super-dwarf wheat in the Russian space
      station Mir, while not entirely successful because of the sterile wheat heads,
      was highly encouraging. The plants grew well for 123 days, producing more biomass
      than had been produced in space before. This was due to the high photon flux
      available to the plants and the careful control of substrate moisture. The
      sterile heads were probably due to the failure to remove the gaseous plant
      hormone, ethylene, from the Mir atmosphere. Since ethylene can easily be removed,
      it should be possible to grow wheat and other crops in microgravity with the
      production of viable seeds. On the ground Biosphere-2 taught us several lessons
      about the design and construction of a CELSS facility, but Bios-3 came much
      closer to achieving the goals of such a facility. Although stability was never
      completely reached, Bios-3 was much more stable than Biosphere-2 apparently
      because every effort was made to keep the system simple and to use the best
      technology available to maintain control. Wastes were not recycled in Bios-3
      except for urine, and inedible plant materials were incinerated to restore CO2 to
      the atmosphere. Since much meat (about 20% of calories) was imported, closure in
      the Bios-3 experiments was well below 100%. But then, a practical CELSS on the
      Moon might also depend on regular resupply from Earth. Several important lessons
      have been learned from the CELSS research described in this review.

PMID- 10660776
TI  - Electrophoresis in space.
AB  - Programs for free flow electrophoresis in microgravity over the past 25 years are
      reviewed. Several studies accomplished during 20 spaceflight missions have
      demonstrated that sample throughput is significantly higher in microgravity than
      on the ground. Some studies have shown that resolution is also increased.
      However, many cell separation trials have fallen victim to difficulties
      associated with experimenting in the microgravity environment such as microbial
      contamination, air bubbles in electrophoresis chambers, and inadequate facilities
      for maintaining cells before and after separation. Recent studies suggest that
      the charge density of cells at their surface may also be modified in
      microgravity. If this result is confirmed, a further cellular mechanism of
      "sensing" the low gravity environment will have been found. Several free fluid
      electrophoresis devices are now available. Most have been tried at least once in
      microgravity. Newer units not yet tested in spaceflight have been designed to
      accommodate problems associated with space processing. The USCEPS device and the
      Japanese FFEU device are specifically designed for sterile operations, whereas
      the Octopus device is designed to reduce electroosmotic and electrohydrodynamic
      effects, which become dominant and detrimental in microgravity. Some of these
      devices will also separate proteins by zone electrophoresis, isotachophoresis, or
      isoelectric focusing in a single unit. Separation experiments with standard test
      particles are useful and necessary for testing and optimizing new space hardware.
      A cohesive free fluid electrophoresis program in the future will obviously
      require (1) flight opportunities and funding, (2) identification of suitable
      cellular and macromolecular candidate samples, and (3) provision of a proper
      interface of electrophoresis processing equipment with biotechnological
      facilities--equipment like bioreactors and protein crystal growth chambers. The
      authors feel that such capabilities will lead to the production of commercially
      useful quantities of target products and to an accumulation of new knowledge
      relating to the complexities of electrostatic phenomena at the cell surface.

PMID- 10660777
TI  - Teaching of space life sciences.
AB  - Space life sciences is not really a new life sciences discipline such as
      immunology was some decades ago and it may never be so. Rather it is a field that
      will provide each existing life sciences discipline with new and more information
      gathered from space research. In fact, the danger is that space research will be
      confined in a separate discipline, and thus it will be cut off from classical
      ground research. Conversely, scientists should increasingly consider spaceflight
      as a tool and should integrate the findings of space research into their
      traditional disciplines. A brief survey of topics and main findings in the
      various subdisciplines of space life sciences is provided. This is followed by a
      discussion of typical problems encountered such as access to space, controls,
      ground-based simulations, medical care in space, extravehicular activity, and
      environmental control and life support. As many space life sciences courses are
      initiated around the world either by space agencies or universities or jointly,
      there is a need to consider the international, intercultural, and
      interdisciplinary aspects of such programs. It is argued that the growing
      knowledge derived from space research should be integrated into the regular
      teaching of life sciences rather than leaving it confined to a separate field.
      Teaching of space life sciences is a prime candidate for the application of the
      new techniques of "cyberspace education", where interactive learning and
      globalization of the learning process will take a leading place. The experts and
      student body are dispersed over many nations, research is of necessity conducted
      on a basis of international cooperation. The conduct of tele-education is
      discussed and existing information sources and courses are listed.

PMID- 10660778
TI  - Travel medicine. Movement and health in the new millennium.

PMID- 10660779
TI  - Marginalized patients. A challenge for family physicians.

PMID- 10660780
TI  - Are you a "risk-minimizer" or a "test minimizer"?

PMID- 10660781
TI  - A bit of Canadian medical history...

PMID- 10660782
TI  - [The expansion of research, a sign of great vitality].

PMID- 10660783
TI  - A step in the right direction.

PMID- 10660784
TI  - Supply and distribution of family physicians.

PMID- 10660785
TI  - A day in the life.

PMID- 10660786
TI  - Zopiclone use during pregnancy.
AB  - QUESTION: One of my patients, whom I had treated with a 2-week course of
      zopiclone for insomnia, conceived while using the medication. She is concerned.
      How should I advise her? ANSWER: Based on available, albeit limited, evidence,
      zopiclone does not appear to be a major human teratogen.

PMID- 10660787
TI  - Reporting intoxicated drivers.

PMID- 10660788
TI  - Triquetrum fracture.

PMID- 10660789
TI  - Practice tips. Surveillance for type 2 diabetes and its complications. Committee
      on Utilization Review and Education.

PMID- 10660790
TI  - Does raloxifene reduce postmenopausal women's risk of breast cancer?

PMID- 10660791
TI  - Montelukast. No current use for asthma.
AB  - Montelukast (Singulair), an antiasthma drug belonging to the leukotriene
      antagonist family, has two indications: as adjunctive treatment for mild-to
      moderate chronic asthma when regular inhaled steroid therapy and short-acting
      inhaled beta2 stimulants "on demand" are inadequate; and in prevention of effort
      induced asthma. The clinical file on montelukast contains no methodologically
      acceptable comparisons with reference treatments. Several placebo-controlled
      trials have shown the efficacy of montelukast, with improvement in clinical
      scores and respiratory function tests in those with chronic asthma and prevention
      of effort-induced asthma. For chronic asthma, montelukast has not been compared
      with oral or inhaled long-acting beta2 stimulants or with sustained-release
      theophylline in patients inadequately controlled by steroid therapy. For effort
      induced asthma, only two trials have compared montelukast with salmeterol. On the
      basis of preliminary results, the authors of both studies concluded that
      montelukast was superior. Clinical trials showed no clear difference in the
      frequency of side effects in patients taking montelukast and patients taking
      placebo. Montelukast, however, might be associated with Churg-Strauss syndrome in
      rare cases. Montelukast is expensive.

PMID- 10660792
TI  - The pond is wider than you think! Problems encountered when searching family
      practice literature.
AB  - OBJECTIVE: To explain differences in the results of literature searches in
      British general practice and North American family practice or family medicine.
      DESIGN: Comparative literature search. SETTING: The Department of Family and
      Community Medicine at the University of Toronto in Ontario. METHOD: Literature
      searches on MEDLINE demonstrated that certain search strategies ignored certain
      key words, depending on the search engine and the search terms chosen. Literature
      searches using the key words "general practice," "family practice," and "family
      medicine" combined with the topics "depression" and then "otitis media" were
      conducted in MEDLINE using four different Web-based search engines: Ovid,
      HealthGate, PubMed, and Internet Grateful Med. MAIN OUTCOME MEASURES: The number
      of MEDLINE references retrieved for both topics when searched with each of the
      three key words, "general practice," "family practice," and "family medicine"
      using each of the four search engines. RESULTS: For each topic, each search
      yielded very different articles. Some search engines did a better job of matching
      the term "general practice" to the terms "family medicine" and "family practice,"
      and thus improved retrieval. The problem of language use extends to the variable
      use of terminology and differences in spelling between British and American
      English. CONCLUSION: We need to heighten awareness of literature search problems
      and the potential for duplication of research effort when some of the literature
      is ignored, and to suggest ways to overcome the deficiencies of the various
      search engines.

PMID- 10660793
TI  - Use of walk-in clinics by rural and urban patients.
AB  - OBJECTIVE: To compare use of walk-in clinics by rural and urban family practice
      patients and to describe patients' perceptions of the quality of care in
      physicians' offices. DESIGN: Questionnaire completed by patients in family
      physicians' offices. SETTING: Nine community-based family practices located in
      rural and urban areas of Alberta. PARTICIPANTS: Patients who had visited their
      family physicians' offices during April, May, June, or July 1997. Response rate
      was 89.6% (403 of 450 questionnaires were completed). MAIN OUTCOME MEASURES: Use
      of walk-in clinics, patients' perceptions of the quality of care in physicians'
      offices. RESULTS: Overall, 27.5% of patients (22.2% of rural, 35.5% of urban
      patients) attended walk-in clinics in the 6 months before visiting their family
      physicians' offices: 43.3% went during weekdays when their family physicians'
      offices were open. Significantly more rural (91.1%) than urban (60.7%) patients
      felt they could contact their doctors during evenings and weekends (P.004).
      Significantly more urban (67.2%) than rural (33.3%) patients did not call their
      own physicians before going to walk-in clinics (P.002). Patients who attended
      walk-in clinics were more likely (P.01) than patients who did not to rate their
      family physicians' office hours poor to good (27.9% vs 15.6%). CONCLUSIONS: Many
      patients attending the offices of community-based family physicians in both urban
      and rural areas of Alberta also attend walk-in clinics. Family practice patients
      attend walk-in clinics primarily because their own physicians' offices are less
      convenient.

PMID- 10660794
TI  - From Livingstone to ecotourism. What's new in travel medicine?
AB  - OBJECTIVE: To review recent developments in the field of travel medicine and to
      outline the knowledge and resources family physicians need for providing health
      advice to travelers headed for tropical or developing countries. QUALITY OF
      EVIDENCE: Personal files; references from review articles and from a recent
      textbook of travel medicine; current guidelines on pretravel advice; and a review
      of the 1996 to 1999 MEDLINE database using "travel medicine" as a term and
      subject heading, "trave(l)lers' diarrhea" as a text word and subject heading,
      "immunization + travel," and "malaria + chemo prevention" were used as
      information sources. Priority was given to randomized controlled trials and
      recommendations of expert or national bodies. MAIN MESSAGE: Some elements of
      travel medicine, such as malaria chemoprophylaxis, have become more complex. Some
      valuable new preventive measures, such as hepatitis A vaccine, treated bed nets,
      and antimalarial drugs, have become available. Some health risks, such as
      cholera, have been overemphasized in the past, whereas others, such as
      tuberculosis and sexually transmitted diseases, have been underemphasized.
      Information sources relevant for providing travel health advice have improved and
      expanded. Canadian evidence-based guidelines addressing most important travel
      health issues are now available. CONCLUSIONS: Travel medicine is a rapidly
      evolving field. Physicians intending to provide health advice to travelers to
      high-risk parts of the world should be well prepared and have access to good, up
      to-date information.

PMID- 10660795
TI  - Preparing patients to travel abroad safely. Part 1: Taking a travel history and
      identifying special risks.
AB  - OBJECTIVE: To present for family physicians without access to a travel clinic and
      the Internet the questions to ask about the medical history and itinerary of
      their patients traveling abroad. To suggest ways to identify and advise high-risk
      patients. QUALITY OF EVIDENCE: MEDLINE searches from 1990 to November 1998
      located 51 articles on travel and diabetes, 37 on travel and chronic obstructive
      pulmonary disease (COPD), 63 on travel and heart disease, 192 on travel and
      pregnancy, and 298 on travel with infants or children. Additional searches were
      undertaken in September 1999. The quality of evidence in most articles is level
      III (expert opinion). There are no randomized controlled trials of the best
      advice for family physicians to give travelers. MAIN MESSAGE: A history should
      include countries to be visited, planned activities, previous tropical travel,
      medical history, vaccination status, whether children are traveling, pregnancy
      status, and patients' opinions of the risks and precautions needed. Detailed
      advice should be given to reduce risks. The main causes of mortality abroad are
      existing cardiovascular conditions and accidents. High-risk conditions to be
      identified in travelers are cardiovascular illness, COPD, diabetes,
      immunodeficiency, pregnancy, and traveling with children. CONCLUSIONS: Patients
      with cardiovascular illness or COPD should be advised to avoid too much exertion
      while traveling. Detailed instruction should be given to diabetic patients on how
      to maintain stable glucose levels, to pregnant women on avoiding malarial
      infection, and to parents on protecting their children from infections and
      accidents.

PMID- 10660796
TI  - DriveABLE: new clinical tool measures driving competency. Saint Elizabeth Health
      Care.

PMID- 10660797
TI  - Children and youth new to Canada. Canadian Paediatric Society's health care
      guide.

PMID- 10660798
TI  - Hepatitis A and B. Two-pronged protection in one vaccine. Laboratory Centre for
      Disease Control.

PMID- 10660799
TI  - Forming habits of healthy eating.

PMID- 10660800
TI  - Environmental threats to health. Environmental Committee of the Ontario College
      of Family Physicians.

PMID- 10660801
TI  - We had it tough! Evolution of the family medicine residency program.

PMID- 10660802
TI  - [Small malaria, large malaria. Extracts].

PMID- 10660803
TI  - Establishment of quantitative reverse transcription--polymerase chain reaction
      assays for human telomerase-associated genes.
AB  - Telomerase is an enzyme that synthesizes and adds repetitive telomeric sequences
      of (TTAGGG)n to the ends of chromosomes. Recently, several telomerase-associated
      genes have been cloned, making it possible to study the expression of these
      genes. Quantitative comparisons of the expression of these genes and of
      telomerase activity might help clarify the regulation of telomerase activity.
      Therefore, we established the validity of a quantitative reverse transcription
      polymerase chain reaction (RT-PCR) assay for the human telomerase catalytic
      subunit (hTERT) mRNA and telomerase associated protein (TEP1) mRNA using the
      TaqMan fluorogenic detection system. Using this assay, we quantitated hTERT mRNA
      and TEP1 mRNA expression in two human pancreatic cancer cell lines, AsPC-1 and
      PANC-1. Our results indicated that the levels of hTERT mRNA and TEP1 mRNA
      expression in AsPC-1 were 1.50 and 2.31 times higher than in PANC-1 cells. This
      TaqMan RT-PCR assay appears to be useful in determining the quantities of hTERT
      and TEP1 mRNAs in clinical specimens. Taken together, our results indicate that
      it is possible to measure the expression of the major telomerase genes subunits.
      Furthermore it is possible to apply this technique to determine the amount of
      other types of mRNA.

PMID- 10660804
TI  - A new quantitative RT-PCR assay for thymidylate synthase mRNA in blood leukocytes
      applied to cancer patients and healthy controls.
AB  - Thymidylate synthase (TS) is the target enzyme for 5-fluorouracil (5-FU). TS mRNA
      and protein levels in colorectal tumours are among the most important
      determinants for tumour response to 5-FU. TS mRNA levels in blood leukocytes may
      give information on pharmacokinetic and pharmacodynamic actions of 5-FU on TS as
      it has previously been shown that inhibition of TS levels by 5-FU in bone marrow
      leukocytes resembles the degree of TS inhibition in colorectal tumours. The aim
      of this study was to develop a quantitative high-throughput RT-PCR assay for TS
      mRNA expression in blood leukocytes (CURT-PCR). Furthermore the TS mRNA levels in
      blood of patients with colorectal cancer and healthy controls was compared. TS
      mRNA levels in 17 patients with colorectal cancer did not differ from 20 matched
      controls whereas a group of 14 younger controls had significantly lower TS mRNA
      expression than patients and matched controls. In order to investigate the
      sensitivity of the assay towards cellular reactions such as proliferative
      stimuli, isolated blood leukocytes were stimulated with phytohemagglutinin both
      in mitogenic and non-mitogenic concentrations and an induction of TS mRNA
      expression was measured in both cases. TS activity and cellular proliferation
      also increased but only at mitogenic concentrations, suggesting that TS mRNA
      expression is an early leukocyte activation marker. This new CURT-PCR assay may
      allow improved studies of functional kinetics of drugs with impact upon TS.
      Further studies are required to establish the possible clinical benefit of TS
      mRNA measurements in blood leukocytes.

PMID- 10660805
TI  - Optimization of adenosine deaminase assay by response surface methodology.
AB  - The effect of four variables (adenosine, glutamate dehydrogenase, phosphate
      buffer, and pH) on the measured catalytic concentration of adenosine deaminase
      (EC 3.5.4.4) was studied by Response Surface Methodology (RSM). This multivariate
      methodology offers an empirical approach to the study of enzyme assays and allows
      to detect the interaction between different variables of the system. Response
      surface data showed maximum adenosine deaminase catalytic concentration at pH
      7.2, adenosine 20 mmol/l, phosphate buffer 200 mmol/l and glutamate dehydrogenase
      850 mu kat/l when pleural fluids were used as samples. Optimum conditions for a
      material containing purified adenosine deaminase from human erythrocytes differed
      only slightly from that obtained for the pleural fluid.

PMID- 10660806
TI  - Pentagalloylglucose, an antisecretory component of Paeoniae radix, inhibits
      gastric H+, K(+)-ATPase.
AB  - We purified a compound with strong inhibitory effect on H+, K(+)-ATPase from
      Paeoniae radix, which has been used in Japan for the treatment of gastritis and
      peptic ulcers. The compound was identified as 1,2,3,4,6,-penta-o-galloyl-beta-D
      glucose by proton nuclear magnetic resonance, carbon-13 nuclear magnetic
      resonance, and fast atomic bombardment mass spectrometry. The IC50 of the
      compound for H+, K(+)-ATPase was 166 nmol/l. Kinetic analyses indicated that the
      inhibition of the enzyme by pentagalloylglucose was noncompetitive with respect
      to K+. Pentagalloylglucose had relatively weak inhibitory effects for Mg(+)
      ATPase (IC50: > 10 mumol/l) and Na+, K(+)-ATPase (IC50: 2.7 mumol/l).
      Pentagalloylglucose also inhibited the accumulation of [14C]aminopyrine in
      parietal cells that had been isolated from guinea pig stomach and stimulated by
      10 mumol/l histamine (IC50: 7.8 mumol/l) and 1 mmol/l dbc-AMP (IC50: 10 mumol/l).
      These results suggest that pentagalloylglucose is a potent inhibitor of H+, K(+)
      ATPase and may be responsible for inhibition of acid secretion by Paeoniae radix.

PMID- 10660807
TI  - Age-related change of plasma extracellular-superoxide dismutase.
AB  - Extracellular-superoxide dismutase (EC-SOD) is a secretory protein that is the
      major SOD isozyme in extracellular fluids. Plasma EC-SOD mass concentrations in
      individuals were distributed in two discrete groups with the rare group (2.9%)
      having a variant of the enzyme with about 15-fold higher plasma levels. The EC
      SOD level of the common phenotype in children/youths was significantly higher
      than that in their parents, and decreased with age, with an average decrease of
      about 2% per year to age 20. On the other hand, the parents' EC-SOD increased
      slightly with age. The cord EC-SOD level was the lowest. We observed no
      significant age-dependent changes in mass concentrations of copper- and zinc
      containing SOD (Cu,Zn-SOD) or manganese-containing SOD (Mn-SOD). The total SOD
      activity in children/youths was significantly higher than that in parents and
      decreased with age. Three SOD isozymes function together in a complementary
      manner as a consequence of different cellular and subcellular distributions.
      However, the results suggest that the changes in EC-SOD levels may be the most
      sensitive biomarker for age-related changes in the antioxidant capacity.

PMID- 10660808
TI  - Guanidinoacetate methyltransferase (GAMT) deficiency: non-invasive enzymatic
      diagnosis of a newly recognized inborn error of metabolism.
AB  - Guanidinoacetate methyltransferase deficiency is a newly recognized inborn error
      of creatine biosynthesis. Manifestation of neurologic symptoms occurs in infancy
      and is partly reversible upon oral substitution of creatine. In the first two
      index patients, enzymatic diagnosis was established in a liver biopsy, and the
      underlying molecular defect in the GAMT gene has been identified. In order to
      provide non-invasive biochemical diagnosis, we have developed an enzyme assay
      based on the formation of radiolabeled creatine from 14C guanidinoacetate and S
      adenosylmethionine in concentrated and dialyzed extracts from cultivated skin
      fibroblasts, Epstein-Barr virus transformed lymphoblasts, and cultivated amniotic
      cells. Cells were investigated from controls, from 1 index patient with proven
      GAMT deficiency and from 3 additional patients with clinical and biochemical
      signs of GAMT deficiency. Separation of 14C guanidinoacetate from 14C creatine in
      the reaction mixture was accomplished by HPLC on Hypersil ODS column and
      radioactivity was determined in fractions according to respective UV signals.
      GAMT activities in control fibroblasts (n = 7), lymphoblasts (n = 8) and in
      amniotic cells (n = 2) were 0.38-0.56, 0.61-0.84 and 0.38-0.56 nmol/h/mg protein.
      Apparent Km values were 9.5-14.8 microM for guanidinoacetate and 68-78 microM for
      S-adenosylmethionine. In the index patient and in the three additional patients
      at risk, GAMT activity was < 0.1 nmol/h/mg protein. The assay described here
      allows non-invasive diagnosis of GAMT deficiency in patients at risk.

PMID- 10660809
TI  - Parathyroid hormone-related protein, parathyroid hormone, and vitamin D in
      hypercalcemia of malignancy.
AB  - The pathogenesis of cancer-associated hypercalcemia is not yet completely
      understood. In the majority of cancer patients, hypercalcemia appears to be a
      consequence of the tumor production of parathyroid hormone (PTH)-related protein
      (PTHrP). However, patients with humoral hypercalcemia of malignancy, in contrast
      to those with primary hyperparathyroidism, have an uncoupled bone turnover, and
      they usually have low circulating levels of 1.25(OH)2D3. We performed a case
      control study to assess the relationship of plasma PTHrP, PTH and 1.25(OH)2D3
      with hypercalcemia in cancer patients with a variety of tumors. Sixty of these
      patients had hypercalcemia, and 45 were normocalcemic. We measured PTHrP and PTH
      by immunoradiometric assay (Nichols), and 1.25(OH)2D3 by radioreceptor assay
      (Nichols), in plasma in both groups of cancer patients. Using a logistic
      regression analysis, we found that the higher PTHrP in plasma, the higher
      association with hypercalcemia occurred in these patients. In addition, the
      decreased plasma levels of PTH and 1.25(OH)2D3 in the majority of cancer patients
      were found to be significantly associated with hypercalcemia. Our results
      indicate that the combined determination of PTH, PTHrP and 1.25(OH)2D3 in plasma
      represents a more comprehensive approach to the investigation of hypercalcemia in
      cancer patients. Our data also support the role of PTHrP as a humoral factor
      responsible for hypercalcemia in these patients.

PMID- 10660810
TI  - Robotic automation performs a nested RT-PCR analysis for HCV without introducing
      sample contamination.
AB  - The Polymerase Chain Reaction (PCR) is a popular method to amplify and detect
      specific RNA and DNA sequences. To obtain maximum performance of PCR, it is best
      performed by highly skilled technologists because of the complexity of the assay
      and the potential for laboratory contamination from the amplification products
      produced. We chose to automate this nested RT-PCR for hepatitis C assay to
      significantly reduce the need for manual pipetting while preserving the excellent
      non-contamination performance of the corresponding manual test. A three axis
      cartesian robotic pipetting station was equipped to perform RT-PCR using an on
      board automated thermal cycling device. 104 sera were analyzed using this
      modified pipetting station and we found a very close agreement (100% sensitivity
      and 98% specificity) with results previously obtained by corresponding manual RT
      PCR analysis. This study demonstrated a user-programmed robotic pipetting system
      could successfully automate a complex PCR assay without contamination. Our
      results suggest that use of robotic pipetting station can provide cost efficient
      alternative to performance of molecular diagnostic assays while demonstrating
      minimal inter sample contamination.

PMID- 10660811
TI  - The possible association of decreased total cholesterol and severity of disease
      in elderly hospitalized patients.
AB  - The object of our study was to determine if any association exists between low
      serum cholesterol (< 4.14 mmol/l) and adverse outcomes in elderly patients > 60
      years. Patients with low serum cholesterol were compared to a patient population
      with high serum cholesterol (> 6.22 mmol/l) and normal cholesterol (> or = 4.14
      to < or = 6.22 mmol/l). Only hospitalized patients > 60 years, who were not on
      cholesterol lowering drugs, and did not have cardiovascular or liver disease were
      included in this study. The study group was 157 patients (79 with low, 78 with
      high, and 23 with normal cholesterol concentrations). Using the Kruskal-Wallis
      tests, the low cholesterol group was found to have statistically (p < 0.05)
      longer length of stay (average difference of > 11.1 days), higher hospital re
      admission rate over a 1-year period (average difference of > 0.4 re-admissions),
      greater use of acute care services (average difference of > 0.6 days), and more
      emergency room (ER) visits over 1 year (average difference of > 0.5 admissions).

PMID- 10660812
TI  - Levels of nitric oxide are markedly increased in cerebrospinal fluid from
      patients with severe head injury.

PMID- 10660813
TI  - Managing pediatric atopic dermatitis.
AB  - Although atopic dermatitis is a very common inflammatory skin condition in
      children and results in many pediatric healthcare visits, its exact cause is
      unknown. No single laboratory test can reliably diagnose atopic dermatitis, but a
      relatively simple set of diagnostic criteria was recently validated for use by
      practicing physicians. Because existing remedies for atopic dermatitis do not
      cure the disorder, a program of disease control and management should be pursued.
      Patients and their caregivers should be advised that current therapies are
      primarily preventive and palliative. However, a comprehensive plan that includes
      routine general skin care, medical management of symptoms, identification and
      avoidance of aggravating factors (including psychological factors), and attention
      to quality-of-life issues can reduce the occurrence of skin flares. Successful
      treatment of acute flare-ups can be achieved with appropriate use of topical
      corticosteroids, but occasionally children afflicted with severe atopic
      dermatitis require more intensive therapies (e.g., ultraviolet light exposure
      systemic corticosteroids, and cyclosporine) that need close physician monitoring.
      Physicians must remain mindful of the psychological and quality-of-life burdens
      imposed on children with atopic dermatitis and their families and tailor
      treatments to the needs of each individual patient.

PMID- 10660814
TI  - A pilot study of methylphenidate, clonidine, or the combination in ADHD comorbid
      with aggressive oppositional defiant or conduct disorder.
AB  - A pilot comparison of the safety and efficacy of methylphenidate (MPH) combined
      with clonidine, clonidine monotherapy, or MPH monotherapy in 6- to 16-year-old
      children diagnosed with attention deficit hyperactivity disorder (ADHD) and
      comorbid aggressive oppositional defiant disorder or conduct disorder was
      completed. Study design was a 3-month, randomized, blinded, group comparison with
      eight subjects per group. No placebo comparison was used. All three treatment
      groups showed significant improvements in attention deficits, impulsivity,
      oppositional, and conduct disordered symptoms as assessed by parent and teacher
      rating scales and laboratory measures. Significant differences among treatment
      groups were found only on a few measures. Only the clonidine monotherapy group
      showed significantly decreased fine motor speed. These results suggest the safety
      and efficacy of clonidine alone or in combination with MPH for the treatment of
      ADHD and aggressive oppositional and conduct disorders.

PMID- 10660815
TI  - Pulmonary function following blastomycosis in childhood.
AB  - In order to determine the pulmonary outcome following blastomycosis during
      childhood, we compiled a case series of hospitalized patients from a
      retrospective review with later recall for pulmonary function testing, coupled
      with prospective measurements of pulmonary function in three patients, at a
      tertiary care children's hospital. A convenience sample of five of 17 patients
      hospitalized with pulmonary blastomycosis, whose mean age at the time of
      diagnosis was 10.6 +/- 5.5 years, was recalled at a mean of 4.5 +/- 3.5 years
      after diagnosis. Three patients more recently hospitalized underwent serial
      pulmonary function testing (PFT) prospectively from as soon after the acute
      infection as their condition permitted. All but two patients had normal PFT when
      last seen. The two patients with persistent pulmonary sequelae were among those
      followed up prospectively and had more severe clinical and radiographic pictures
      at the outset. Pulmonary function in children who suffered from pulmonary
      blastomycosis is normal in most patients at follow-up years later. Severe
      radiographic disease and slow recovery over months portend long-term sequelae.

PMID- 10660816
TI  - Child abuse and domestic violence in families of children seen for suspected
      sexual abuse.
AB  - We surveyed families of children seen in a sexual abuse evaluation clinic
      regarding domestic violence in the child's home and physical and sexual abuse
      during childhood among the mothers. Domestic violence occurred in 54% (216/402)
      of the children's homes; 28% (111/392) of mothers reported childhood physical
      abuse, and 42% (167/395) reported sexual abuse. There were no differences in the
      rates of domestic violence (chi 2 = 0.42, 2 df, p = 0.8), maternal physical abuse
      (chi 2 = 2.40, 2 df, p = 0.3), or maternal sexual abuse (chi 2 = 2.11, 2 df, p =
      0.3) based on whether our current, patient was at high, medium, or low risk for
      having actually experienced sexual abuse. Neither domestic violence in the
      child's home nor the mother's childhood experience of abuse was increased if the
      child's perpetrator was a relative or lived in the home. Domestic violence in the
      child's home was more frequent if the mother had experienced physical abuse
      during childhood (65% 70/107) than if she had not (48%, 130/271; chi 2 = 8.69, p
      < 0.01). Child sexual abuse is part of a global pattern of victimization, and
      clinicians must address other forms of family violence when evaluating a child
      for allegations of sexual abuse.

PMID- 10660817
TI  - Everything's not o.k. at home.

PMID- 10660818
TI  - Gonococcal bacteremia in a neonate.

PMID- 10660819
TI  - Suprasellar dysplasia: a pediatric perspective.

PMID- 10660820
TI  - Compliance with initiation of a sequential schedule for polio immunization.

PMID- 10660821
TI  - Eosinophilic gastroenteritis masquerading as pyloric stenosis.

PMID- 10660822
TI  - Focus on the foreskin, not its destruction.

PMID- 10660823
TI  - The circumcision issue.

PMID- 10660824
TI  - Congenital malaria: diagnosis and therapy.

PMID- 10660825
TI  - Should pediatric hospitalists replace the staff/ward attending?

PMID- 10660826
TI  - Accessing information on medical/health web sites by Italian families: a pilot
      study.

PMID- 10660827
TI  - Risk factors in school shootings.
AB  - Nine incidents of multiple-victim homicide in American secondary schools are
      examined and common risk factors are identified. The literature dealing with
      individual, family, social, societal, and situational risk factors for youth
      violence and aggression is reviewed along with existing risk assessment methods.
      Checklists of risk factors for serious youth violence and school violence are
      used in reviewing each school shooting case. Commonalties among the cases and
      implications for psychologists practicing in clinical and school settings are
      discussed.

PMID- 10660828
TI  - On the classification and diagnosis of pathological grief.
AB  - It has been suggested that pathological grief should become either a separate
      category of mental disorder or be integrated within existing, extended
      classifications in systems such as the Diagnostic and Statistical Manual of
      Mental Disorders. Despite strong arguments for inclusion, and advancements by
      scientists toward development of diagnostic classification, there has been a lack
      of critical evaluation. Several issues need further scrutiny and clarification.
      These concern the definition of pathological grief, the distinction of
      pathological from normal grief, its relationship with other disorders, and the
      lack of agreement among scientists about criteria for pathological grief. Further
      research needs to focus on delineation of syndromes that comprise "pathological
      grief," and on derivation of acceptable, valid, diagnostic criteria. Evaluation
      of the ramifications--both positive and potentially negative--associated with the
      revision of the diagnostic status of pathological grief needs also to be
      undertaken.

PMID- 10660829
TI  - Childhood disintegrative disorder: should it be considered a distinct diagnosis?
AB  - First termed Dementia Infantilis by Theodore Heller in 1908, Childhood
      Disintegrative Disorder (CDD) has had a history longer than that of Autistic
      Disorder. Presently, CDD is classified as a Pervasive Developmental Disorder in
      the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders.
      The characteristics most often cited as distinguishing CDD from Autistic
      Disorder, another one of the Pervasive Developmental Disorders, is the age of
      onset and evidence of normal development prior to the presence of symptomatology.
      Otherwise, the behavioral symptoms of CDD and Autistic Disorder are strikingly
      similar. The purpose of this article is to provide a historical background on
      CDD, examine the evolution of diagnostic criteria, review the existing literature
      pertaining to the disorder, and, finally, to draw conclusions regarding the
      validity of CDD as a distinct diagnosis with reference to current and alternative
      classification approaches.

PMID- 10660830
TI  - Are cultic environments psychologically harmful?
AB  - This article is the first critical review of research that addresses the question
      of whether cult membership is psychologically harmful. The available evidence
      warrants three conclusions: (a) persons entering cults do not necessarily exhibit
      psychopathology; (b) current cult members appear psychologically well-adjusted
      generally, and demonstrate few conspicuous symptoms of psychopathology. However,
      pathology may be masked by conformity pressures and demand characteristics
      associated with the cultic environment; (c) a small but growing body of research
      indicates that at least a substantial minority of former cult members experience
      significant adjustment difficulties. There also are indications that these
      difficulties cannot be ascribed to demand characteristics. Although the review
      highlights definitional and methodological issues and problems that temper
      conclusions that can be drawn from the literature, no evidence indicates that
      cults improve adjustment after members leave the cultic environment.

PMID- 10660831
TI  - A meta-analytic review of the relation between antisocial behavior and
      neuropsychological measures of executive function.
AB  - Previous narrative reviews of the relation between antisocial behavior (ASB) and
      neuropsychological tests of executive functioning (EF) have raised numerous
      methodological concerns and produced equivocal conclusions. By using meta
      analytic procedures, this study attempts to remedy many of these concerns and
      quantifies the relation between ASB and performance on six reasonably well
      validated measures of EF. Thirty-nine studies yielding a total of 4,589
      participants were included in the analysis. Overall, antisocial groups performed
      .62 standard deviations worse on EF tests than comparison groups; this effect
      size is in the medium to large range. Significant variation within this effect
      size estimate was found, some of which was accounted for by differences in the
      operationalizations of ASB (e.g., psychopathy vs. criminality) and measures of
      EF. Evidence for the specificity of EF deficits relative to deficits on other
      neuropsychological tasks was inconsistent. Unresolved conceptual problems
      regarding the association between ASB and EF tests, including the problem of
      localizing EF tests to specific brain regions, are discussed.

PMID- 10660832
TI  - Inhaled ATP causes mucin release from goblet cells of intact rats.
AB  - Secretion of mucins from airway epithelial cells has been studied almost
      exclusively using in vitro cell culture systems. Our understanding of in vivo
      secretion is greatly limited due to the unavailability of both suitable model
      systems and adequate assays. It has been reported that ATP induces mucin release
      from the cultured primary tracheal surface epithelial cell, but there is no clear
      demonstration of the effect of ATP on mucin release in vivo, which is important
      to understand the mechanism of mucin release in vivo and also to devise means for
      regulation of mucin release. The objective of this experiment was to see if
      inhaled ATP could stimulate airway mucin release in intact rats using both enzyme
      linked immunosorbent assay (ELISA) and immunohistochemistry. The results were:
      (1) a new monoclonal antibody (mAbRT03) developed against purified rat mucins
      specifically recognized high-molecular-mass mucins; (2) ELISA results with
      conventional gel-filtration assay results are virtually superimposable; (3)
      inhalation of ATP in intact rats resulted in a dose-independent increase in the
      amount of mucins in the tracheal lavage fluid with a concomitant decrease in the
      number of mucin-positive cells in the trachea. We conclude that extracellular ATP
      can stimulate mucin release from the airway in vivo, and the present rat
      inhalation system combined with ELISA of the airway secretions should serve a
      useful model for studying the pharmacology of airway mucin secretion in vivo.

PMID- 10660833
TI  - Activation of ERK2 by respiratory syncytial virus in A549 cells is linked to the
      production of interleukin 8.
AB  - The airway inflammation that results from respiratory syncytial virus infection
      is associated with a marked increase in interleukin 8 and neutrophils in the
      infected sites of the lung. In this study, the relationship between production of
      interleukin 8, infection of A549 cells by the virus, and activation of mitogen
      activated protein kinases (MAPKs) was investigated. Infection of A549 cells by
      the virus caused an increase on the activity of extracellular signal-regulated
      kinase 2 (ERK2) by about 10-fold compared with the noninfected cells. The
      increase in the activity of ERK2 during the viral infection was an immediate
      event and occurred prior to the viral replication process. PD98059, which blocks
      the activation of MAPK/ERK kinase 1 (MEK1), inhibited the increase in the
      activity of ERK2 by infection of respiratory syncytial virus by about 50% at 10
      microM. Pretreatment of A549 cells with PD98059 before the viral infection also
      inhibited the increase in the production of interleukin 8 by 50%, but had little
      effect on the mRNA level. The viral infection had no effect on the activities of
      p38 and c-jun N-terminal kinase (JNK). These observations suggest that activation
      of ERK2 by respiratory syncytial virus infection may be one of the mechanisms
      that result in the increase of the production of interleukin 8.

PMID- 10660834
TI  - Bronchial casts of human lungs using negative pressure injection.
AB  - Negative-pressure casting techniques have been used for obtaining silicone rubber
      casts of the avian respiratory system, which contains minute air capillaries,
      noncompressible hollow bones, and highly flexible air sacs. The possibilities of
      this technique for the study of human airway diseases, which present technical
      difficulties similar to those of avian lungs, are investigated here. Left lungs
      from patients with various obstructive lung diseases or with normal lungs were
      fixed at autopsy under 25 cm H2O airway pressure with 2.5% phosphate-buffered
      glutaraldehyde. Cannulated, isolated lobes were placed in a vacuum chamber, and
      Dow Corning 734 RTV silicone elastomer, diluted with 10% low-viscosity silicone
      oil, was introduced into the airways at--10 kPa. Following complete
      polymerization, the tissue was microdissected to reveal the lung cast in situ,
      and histological sections were obtained for correlative studies. The tissue was
      then macerated in 5.25% sodium hypochlorite. The total time from fixation to
      finished cast was 3-4 days. Linear shrinkage of the elastomer was less than 1% in
      glutaraldehyde or water and between 1 and 2% in bleach. The negative-pressure
      injection technique enabled complete and accurate filling of airways to the
      alveolar duct level at physiological pressures and provided good delineation of
      blind cavities such as obstructed airways or ecstatic mucous gland ducts. The
      technique proved useful for the study of obstructive lung disease and should also
      prove useful for modelling aerosol deposition in diseased lungs.

PMID- 10660835
TI  - Asbestos stimulation triggers differential cytokine release from human monocytes
      and alveolar macrophages.
AB  - Inhalation of asbestos fibers results in a variety of lung diseases, including
      pulmonary fibrosis. Various animal models have demonstrated the importance of
      cytokines in the pathogenesis of pulmonary fibrosis. Alveolar macrophages from
      patients exposed to asbestos spontaneously release increased amounts of
      cytokines. The purpose of these studies was to determine whether asbestos
      directly stimulates cytokine release from human alveolar macrophages after in
      vitro exposure. We demonstrate that, although asbestos triggers cytokine release
      from blood monocytes, normal alveolar macrophages do not respond to asbestos
      stimulation with cytokine release. However, normal alveolar macrophages are
      activated by asbestos particles, in vitro, as determined by the upregulation of
      mRNAs for cytokines, and activation of the p38 kinase, which has been shown to be
      important in the translation of cytokine message into protein. These studies
      demonstrate that asbestos stimulates both normal blood monocytes and normal
      alveolar macrophages, but that there is a block in translation of cytokine mRNAs
      in the macrophages.

PMID- 10660837
TI  - Do we need intermediate care units?

PMID- 10660836
TI  - Increased expression of cyclooxygenase 2 mediates oil fly ash-induced lung
      injury.
AB  - We have previously shown that in vitro exposure to the combustion-derived ambient
      air pollutant residual oil fly ash (ROFA) induces the expression of prostaglandin
      H synthase 2 (COX2) in human airway epithelial cells. To determine the role of
      prostaglandins and COX2 expression in ROFA-induced lung injury in vivo, we have
      examined the effect of intratracheal ROFA instillation on COX2 expression,
      prostaglandin synthesis, and indices of pulmonary injury and inflammation in
      adult Sprague-Dawley rats. ROFA treatment induced a marked increase in the level
      of prostagladin E2 (PGE2) recovered in the bronchoalveolar lavage fluid (BALF),
      which was effectively decreased by pretreating the animals with the specific COX2
      inhibitor NS398. Immunohistochemical analyses of rat airways showed concomitant
      expression of COX2 in the proximal airway epithelium of rats treated with ROFA.
      Increases in BALF protein, but not interleukin 6 (IL-6) increases or ROFA-induced
      polymorphonuclear neutrophils (PMN) influx into the airway, were blunted by
      administration of NS398 prior to ROFA instillation. These data demonstrate that
      prostaglandins mediate lung injury induced by exposure to ROFA and implicate
      increased expression of COX2 as a mechanism that contributes to the toxicity of
      metal-laden ambient particulate matter.

PMID- 10660838
TI  - Monitoring alarms--the key to patient's safety in the ICU?

PMID- 10660839
TI  - Health systems research & intensive care.

PMID- 10660840
TI  - Noninvasive positive pressure ventilation for weaning from invasive mechanical
      ventilation.

PMID- 10660841
TI  - Heterogeneity of human albumin preparations.

PMID- 10660842
TI  - Multicentric study of monitoring alarms in the adult intensive care unit (ICU): a
      descriptive analysis.
AB  - OBJECTIVES: To assess the relevance of current monitoring alarms as a warning
      system in the adult ICU. DESIGN: Prospective, observational study. SETTINGS: Two
      university hospital, and three general hospital, ICUs. PATIENTS: Hundred thirty
      one patients, ventilated at admission, from different shifts (morning, evening,
      night) combined with different stages of stay, early (0-3 days), intermediate (4
      6 days) and late (> 6 days). INTERVENTIONS: Experienced nurses were asked to
      record the patient's characteristics and, for each alarm event, the reason, type
      and consequence. MEASUREMENTS AND MAIN RESULTS: The mean age of the patients
      included was 59.8 +/- 16.4 and SAPS1 was 15.9 +/- 7.4. We recorded 1971 h of
      care. The shift distribution was 78 mornings, 85 evenings and 83 nights; the
      stage distribution was 88 early, 78 intermediate and 80 late. There were 3188
      alarms, an average of one alarm every 37 min: 23.7% were due to staff
      manipulation, 17.5% to technical problems and 58.8% to the patients. Alarms
      originated from ventilators (37.8%), cardiovascular monitors (32.7%), pulse
      oximeters (14.9%) and capnography (13.5%). Of the alarms, 25.8% had a consequence
      such as sensor repositioning, suction, modification of the therapy (drug or
      ventilation). Only 5.9% of the alarms led to a physician's being called. The
      positive predictive value of an alarm was 27% and its negative predictive value
      was 99%. The sensitivity was 97% and the specificity 58%. CONCLUSIONS: The study
      confirms that the level of monitoring in ICUs generates a great number of false
      positive alarms.

PMID- 10660843
TI  - Impact of standard procedures and clinical standards on cost-effectiveness and
      intensive care unit performance in adult patients after cardiac surgery.
AB  - OBJECTIVE: To investigate the impact of organizational procedures on intensive
      care unit (ICU) performance and cost-effectiveness after cardiac surgery. DESIGN:
      Prospective study. SETTING: Cardiothoracic ICU at a university hospital.
      PATIENTS: Thousand five hundred twenty-six consecutive patients over a period of
      18 months. INTERVENTIONS: The first 6 months were used as the control period.
      Afterwards selected organizational changes were introduced, such as written
      standard procedures, time schedules and discharge reports. MEASUREMENTS:
      Demographic data, surgical procedures, length of ICU and hospital stay and
      hospital outcome were recorded. Severity of illness was assessed daily using
      Acute Physiology and Chronic Health Evaluation (APACHE II), Simplified Acute
      Physiology Score (SAPS II) and Organ Failure Score (OFS). Intensity of treatment
      and nursing care was monitored by the Therapeutic Intervention Scoring System
      (TISS). RIYADH ICU Program (RIP 5.0) was used to determine the relationship of
      observed to predicted mortality (standardized mortality ratio SMR) and the
      effective costs per survivor. MAIN RESULTS: SMR decreased continuously after the
      establishment of new management procedures while all other factors all other
      factors remained unchanged. Comparing outcome according to APACHE II on ICU
      admission demonstrated a significantly increased ICU performance in high risk
      patients with an APACHE II of 20-30 points (p < 0.05) while effective costs per
      survivor decreased significantly from DM 29,988 to DM 13,568 DM (p < 0.05).
      CONCLUSIONS: Organizational changes can improve ICU performance and cost
      effectiveness after cardiac surgery. The RIP may be used to monitor the clinical
      and economical effects of change.

PMID- 10660844
TI  - Effects of noninvasive positive pressure ventilatory support in non-COPD patients
      with acute respiratory insufficiency after early extubation.
AB  - OBJECTIVE: To investigate the effects of noninvasive positive pressure
      ventilation (NPPV) on pulmonary gas exchange, breathing pattern, intrapulmonary
      shunt fraction, oxygen consumption, and resting energy expenditure in patients
      with persistent acute respiratory failure but without chronic obstructive
      pulmonary disease (COPD) after early extubation. DESIGN: Prospective study.
      SETTING: Multidisciplinary intensive care unit of a university hospital.
      PATIENTS: 15 patients after prolonged mechanical ventilation (> 72 h) with acute
      respiratory insufficiency after early extubation. INTERVENTIONS: Criteria for
      early extubation were arterial oxygen tension (PaO2) > or = 40 mm Hg (fractional
      inspired oxygen 0.21), arterial carbon dioxide tension (PaCO2) < or = 55 mm Hg,
      pH > 7.32, respiratory rate < or = 40 breaths per min, tidal volume (VT) > or = 3
      ml/kg, rapid shallow breathing index < or = 190 and negative inspiratory force >
      or = 20 cmH2O. After extubation, two modes of NPPV were applied [continuous
      positive airway pressure (CPAP) of 5 cmH2O and pressure support ventilation (PSV)
      with 15 cmH2O pressure support]. MEASUREMENTS AND MAIN RESULTS: Oxygenation and
      ventilatory parameters improved during both modes of NPPV (p < 0.05): increase in
      PaO2 of 11 mm Hg during CPAP and 21 mm Hg during PSV; decrease in intrapulmonary
      shunt fraction of 7% during CPAP and 12% during PSV; increase in tidal volume of
      1 ml/kg during CPAP and 4 ml/kg during PSV; decrease in respiratory rate 6
      breaths/min during CPAP and 9 breaths/min during PSV. Oxygen consumption (15%
      during CPAP, 22% during PSV) and resting energy expenditure (12% during CPAP, 20%
      during PSV) were reduced (p < 0.05). PaCO2 decreased, whereas minute ventilation
      and pH increased during PSV (p < 0.05). The median duration of NPPV was 2 days.
      Two patients had to be reintubated. CONCLUSIONS: In non-COPD patients with
      persistent acute respiratory failure after early extubation, NPPV improved
      pulmonary gas exchange and breathing pattern, decreased intrapulmonary shunt
      fraction, and reduced the work of breathing.

PMID- 10660845
TI  - Certain batches of albumin solutions influence the expression of endothelial cell
      adhesion molecules.
AB  - OBJECTIVE: Increased levels of soluble adhesion molecules, a decreased PO2/FIO2
      ratio and a tendency to worsened outcome have been reported following the use of
      human albumin in critical illness. The reasons are not yet understood. Since
      albumin solutions have previously been shown to contain proinflammatory
      mediators, a direct upregulation of adhesion molecules by contaminated batches
      may explain these findings. To examine this, we studied the effects of different
      albumin preparations on endothelial cell adhesion molecules in vitro. DESIGN:
      Experimental study. SETTING: Laboratory for cell biology. METHODS: Human
      umbilical venous endothelial cell cultures (n = 4) were incubated for 6 h at 5
      mg/ml with four different human albumin solutions (HA1-4) from different
      manufacturers. Medium served as the control. Using flow cytometry, the effects on
      E-selectin, ICAM-1 and VCAM-1 expression were determined on unstimulated cells
      and on cells stimulated with tumour necrosis factor alpha at 0.5 ng/ml for 4 h.
      MEASUREMENTS AND RESULTS: On unstimulated cells, HA1 and HA4, two different
      batches from the same manufacturer, increased ICAM-1 by 22% and 15%,
      respectively. After stimulation, both solutions resulted in a 19% increased
      expression of E-Selectin. In addition, HA4 decreased VCAM-1 on stimulated cells
      (p < or = 0.05). Two albumin preparations from other manufacturers did not
      produce significant effects. CONCLUSIONS: Some albumin solutions directly
      modulate adhesion molecule expression on endothelial cells. This may, at least in
      part, explain the previous finding of increased soluble adhesion molecules and a
      decreased PO2/FIO2 ratio in critically ill patients undergoing volume replacement
      with human albumin.

PMID- 10660846
TI  - Kinetics and characteristics of an acute phase response following cardiac arrest.
AB  - OBJECTIVE: Inflammation and hypoxia are frequently associated, but their
      interaction is poorly understood. In vitro studies have shown that hypoxia
      stimulates the genes of acute phase proteins (APP) and cytokines known to induce
      APP. We decided to determine kinetics and potential determinants of an acute
      phase response after cardiac arrest and to assess whether isolated moderate
      hypoxia can induce APP in humans in vivo. DESIGN: Prospective, observational
      study in patients and human experiment. SETTING: Tertiary care university
      hospital. PATIENTS AND PARTICIPANTS: 22 patients after primarily successful
      cardiopulmonary resuscitation (CPR) and 7 healthy volunteers. INTERVENTIONS: None
      in patients; exposure of volunteers to simulated altitude (460 torr/6 h).
      RESULTS: Following CPR, type-1 APP (C-reactive protein, alpha 1-acidglycoprotein,
      serum amyloid A) and type-2 APP (haptoglobin, alpha 1-antitrypsin) increased
      consistently within 1-2 days and the 'negative' APP transferrin was
      downregulated. This APP response occurred irrespective of the cause of arrest,
      the estimated time of anoxia, clinical course or patient outcome and was not
      different in patients with and without infectious complications. Exposure of
      healthy volunteers to less severe but more prolonged hypoxia did not induce APP,
      although a time dependent increase of serum erythropoietin (EPO) was measurable
      under these conditions, indicating the activation of oxygen dependent gene
      expression. CONCLUSIONS: (i) A marked acute phase response occurs regularly after
      cardiac arrest, but within the complexity of this situation the severity of
      hypoxia is not a predominant determinant of this response. (ii) Despite in vitro
      evidence for similarities in the oxygen dependent regulation of APP and EPO
      production, the oxygen sensitivity of these proteins in vivo is different. (iii)
      Measurements of APP are not revealing regarding infectious complications in the
      early phase after CPR.

PMID- 10660847
TI  - Changing use of intensive care for hematological patients: the example of
      multiple myeloma.
AB  - OBJECTIVE: Intensivists generally view patients with hematological malignancies
      as poor candidates for intensive care. Nevertheless, hematologists have recently
      developed more aggressive treatment protocols capable of achieving prolonged
      complete remissions in many of these patients. This change mandates a reappraisal
      of indications for ICU admission in each type of hematological disease. Improved
      knowledge of the prognosis is of assistance in making treatment decisions.
      PATIENTS AND METHODS: The records of 75 myeloma patients consecutively admitted
      to our ICU between 1992 and 1998 were reviewed retrospectively and predictors of
      30-day mortality were identified using stepwise logistic regression. RESULTS: The
      median age was 56 years (37-84). Chronic health status (Knaus scale) was C or D
      in 39 cases. Fifty-five patients (73%) had stage III disease and 17 had a
      complete or partial remission. Autologous bone marrow transplantation had been
      performed in 28 patients (37%). ICU admission occurred between 1992 and 1995 in
      41 patients (54.7%), and between 1996 and 1998 in 34 patients (45.3%). The median
      SAPS II and LOD scores were 60 (23-107) and 7 (0-21), respectively. Reasons for
      ICU admission were acute respiratory failure in 39 patients (52%) and shock in 31
      (41%). Forty-six patients (61%) required mechanical ventilation. Fifty patients
      (66%) received vasopressors and 24 dialysis. Thirty-day mortality was 57%. Only
      five parameters were independently associated with 30-day mortality in the
      multivariate model: female gender (OR = 5.12), mechanical ventilation (OR = 16.7)
      and use of vasopressor agents (OR = 5.67) were associated with a higher mortality
      rate, whereas disease remission (OR = 0.16) and ICU admission between 1996 and
      1998 (OR = 0.09) were associated with a lower one. CONCLUSION: The prognosis for
      myeloma patients in the ICU is improving over time. This may reflect either
      recent therapeutic changes in hematological departments and ICUs or changes in
      patient selection for ICU admission. Hematologists and intensivists should work
      closely together to select hematological patients likely to benefit from ICU
      admission.

PMID- 10660848
TI  - Activation of the hypothalamo-pituitary-adrenal axis in response to septic or non
      septic diseases--implications for the euthyroid sick syndrome.
AB  - OBJECTIVE: To determine whether cytokine release or activation of the hypothalamo
      pituitary-adrenal (HPA) axis is predominantly involved in the development of the
      euthyroid sick syndrome (ESS). DESIGN: Prospective observational study. SETTING:
      Intensive care unit at a tertiary care medical center in Germany. PATIENTS: Nine
      patients with sepsis of different causes and eight patients with acute myocardial
      infarction. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Immediately on
      admission and on day 7 the following parameters were determined: total thyroxine
      (T4), free thyroxine (FT4), total triiodothyronine (T3), thyrotropin (TSH),
      interleukin-1 beta (IL-1 beta), interleukin-2 (IL-2), soluble interleukin-2
      receptor (sIL-2R), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha),
      serum cortisol and plasma adrenocorticotropin (ACTH). On admission,
      concentrations of all thyroid hormones and TSH were significantly lower in septic
      patients compared to non-septic patients, whereas all cytokines except IL-2 were
      significantly elevated in the sepsis group. By contrast, there was no difference
      in serum cortisol and plasma ACTH levels between the two groups. On day 7, T4 and
      T3 were still lower in the septic group, whereas IL-1 beta, sIL-2R and IL-6 were
      still elevated. Again, no differences were found with regard to cortisol and ACTH
      levels. CONCLUSIONS: Euthyroid sick syndrome occurs very early during the course
      of septic diseases. Significantly decreased levels of total T4, FT4, T3 and TSH
      in septic patients suggest central suppression of TSH as well as inhibition of
      thyroid hormone release in ESS. The HPA axis is activated in septic patients and
      in non-septic patients and does not contribute to the development of ESS.

PMID- 10660849
TI  - Economic impact of a rational use of antibiotics in intensive care.
AB  - OBJECTIVE: To evaluate the economic impact of a rational policy in antibiotic
      treatment. DESIGN: Comparative study with a retrospective and a prospective part.
      SETTING: An 11-bed intensive care unit (ICU) in a general hospital. PATIENTS: All
      patients admitted to the unit in 1994, 1995 and 1996. INTERVENTIONS: In 1995, a
      program of cost control was started and a contract of agreed objectives signed
      with the director of the hospital. This contract included a commitment to refund
      the eventual savings in order to improve the quality of care. Prescribing
      protocols were established by consensus as guidelines for a rational policy in
      antibiotic therapy. MEASUREMENTS AND RESULTS: The cost of antibiotic therapy, the
      patients' characteristics and the incidence of nosocomial infection were compared
      prior to and during the program. The expenses for antibiotic drugs decreased by
      19% in 1995 and by 22% in 1996. Most of the savings were refunded to the ICU and
      contributed to the employment of an additional nurse and the purchase of new
      material. In number of patients, type of disease, mean age, Simplified Acute
      Physiology Score, occupancy rate, length of stay, omega score, artificial
      ventilation, readmission within 7 days, mortality and incidence of nosocomial
      infection, no significant difference was found. CONCLUSIONS: We proved a positive
      economic impact of a rational policy in antibiotic therapy realized with a
      contract of agreed objectives. The savings made while applying our program of
      cost control were used to improve the quality of care.

PMID- 10660850
TI  - Effects of pulmonary blood volume on vascular reactivity in the lung.
AB  - OBJECTIVE: Pulmonary flow resistance is mainly determined by vessel calibres,
      resulting from the interaction of volume-passive distension and active
      vasomotion. However, quantitative information on the interplay between these
      counteracting forces in the lung is lacking. Therefore, we aimed at quantifying
      (1) the effects of vasomotor tone on pulmonary blood volume (Qp) and (2) the
      influence of Qp on vascular reactivity. DESIGN: Experimental study in isolated
      zone III rabbit lungs perfused with autologous blood. SETTING: Research
      department of experimental anaesthesiology. INTERVENTIONS: Stepwise changes of
      pulmonary blood flow (Q = 0-200 ml.min-1) and Qp (10-30 ml) were applied
      independently of each other during normoxia (control), hypoxic vasoconstriction
      (3% O2) and vasodilation by papaverine (10(-4) M). MEASUREMENTS: The
      arteriovenous pressure gradient (delta P) was calculated as the difference
      between the pressures in the pulmonary artery and the left atrium. Qp was
      continuously measured as reciprocal volume changes in the blood reservoir.
      RESULTS: Vasomotor interventions did not alter Qp despite substantial changes in
      pulmonary artery pressure. Vasoconstriction and decreasing Qp shifted the
      pressure/flow curves to greater delta P, whereas vasodilation, as well as
      increasing Qp, had the opposite effect. Analysis of the pressure/flow relations
      by the equation delta P = K.Qm revealed that both parameters (K and m) were
      functions of Qp but only K was affected by vasoconstriction and vasodilation. K,
      an indicator of flow resistance, decreased hyperbolically to one-sixth and
      approached each other as Qp was tripled, whereas m increased only 1.5-fold (0.5
      0.8). The factorial changes of K from constricted to dilated states varied from 2
      to 2.9 and attained a maximum at Qp = 20 ml. CONCLUSIONS: Pulmonary blood volume,
      although not affected by vasomotor interventions, attenuates vascular reactivity
      in the lung.

PMID- 10660851
TI  - Stressors in ICU: perception of the patient, relatives and health care team.
AB  - OBJECTIVE: To compare the evaluation of the stressors present in the intensive
      care unit (ICU) from the point of view of the patient, relatives and the
      multiprofessional team and to identify differences and similarities with regard
      to the perception of stressors in order to optimize patient care. DESIGN: Cross
      sectional analytical survey. SETTING: General ICU of a private hospital. PATIENTS
      AND PARTICIPANTS: From April 1st to June 30th, 1996, 50 ICU patients during the
      first week of their ICU stay, 50 of their respective relatives and 50 members of
      the professional team directly involved in the care of these patients.
      MEASUREMENTS AND RESULTS: The Intensive Care Unit Environmental Stressor Scale
      (ICUESS) was administered to all patients. The relatives and health care
      professionals were asked to complete the ICUESS on the basis of their perception
      of the patient's stressors. Being in pain, having tubes in the nose or mouth,
      being restrained by tubes and being unable to sleep were considered by the
      patients, relatives and health care professionals as the main stressors. The
      professional team evaluated the intensity of the stressors higher than either the
      family or the patient. No statistical significance was detected between the
      intensity of the stressors as evaluated by the patient and the intensity
      evaluated by relatives and by the professional team. CONCLUSIONS: Being in pain,
      being unable to sleep and having tubes in the nose and/or mouth were pointed out
      as the major stressors by the three groups. There was no statistically
      significant correlation between the total stress scores of the patients and their
      relatives (r = 0.193), between the patients and the team (r = -0.002), or between
      the total scores of the team and the relatives (r = -0.185). The results suggest
      that the views of the relatives and the professional team concerning the
      stressors have some similar points compared to the evaluation made by the patient
      himself, although the intensity of the evaluation for each group corresponds to
      its own perception.

PMID- 10660852
TI  - Pharmacokinetics of cefpirome in critically ill patients with renal failure
      treated by continuous veno-venous hemofiltration.
AB  - OBJECTIVE: To study the cefpirome pharmacokinetics of patients with sepsis and
      multiple organ failure treated with CVVH. DESIGN: Measurements of serum and
      ultrafiltrate (UF) concentrations and in vitro sensitivity testing of isolated
      micro-organisms. SETTING: University hospital-based, single ICU. PATIENTS: Six
      critically ill CVVH-dependent patients with sepsis and multiple organ dysfunction
      syndrome in need of antimicrobial therapy. Age range: 60-75 years; APACHE II
      score for severity of illness on admission: 19-30. One patient survived.
      INTERVENTIONS: Cefpirome i.v. was started at 2 g in 30 min, then continued 1 g
      i.v.b.i.d. MEASUREMENTS: The UF rate was 27 +/- 7 ml/min on day 1 and 34 +/- 2
      ml/min on day 2. Serum and ultrafiltrate samples were measured by a validated
      high performance liquid chromatography assay. Volume of distribution: 23 x 5(SD
      +/- 4 x 6) l. Total cefpirome clearance was 32 +/- 6 x 3 ml/min; cefpirome CVVH
      clearance (ClCVVH): 17 +/- 4.2 ml/min; mean serum half-life (t1/2): 8.8 +/- 2.3
      h; mass transfer on day 1: 660 +/- 123 mg/12 h (33 +/- 6% of administered dose)
      and day 2: 642 +/- 66 mg/12 h (64 +/- 7%). Estimated sieving coefficient
      (ClCVVH/UF rate): 64 +/- 11%. In vitro sensitivity of isolated microbes was
      excellent except for two non-sensitive enterococci and Candida spp. CONCLUSIONS:
      The sieving coefficient (64%) indicates that a substantial fraction of the drug
      is not filtered; clearance by pathways other than CVVH mounted to 50% of the
      total clearance and increased on day 2, indicating that the dosing schedule used
      is appropriate for this setting. Cefpirome appeared to be safe in these patients
      and effective for most of the nosocomial microbial isolates. During more than 90%
      of the time, serum levels were maintained above killing concentrations for
      susceptible micro-organisms.

PMID- 10660853
TI  - Autonomic instability and hypertension resulting in subarachnoid haemorrhage in
      the Guillain-Barre syndrome.
AB  - We report the case of a 47-year-old woman with Guillain-Barre syndrome who
      developed autonomic instability and hypertension and subsequently developed a
      subarachnoid haemorrhage. This was manifested clinically by a seizure which began
      focally and became generalised. Computer tomography demonstrated a localised
      haemorrhage in the left central sulcus. Control of the hypertension was achieved
      with intravenous labetolol. Autonomic instability and hypertension are frequently
      reported in Guillain-Barre syndrome. Subarachnoid haemorrhage is an uncommon but
      serious complication.

PMID- 10660855
TI  - Reversible tetraplegia due to polyneuropathy in a diabetic patient with
      hyperosmolar non-ketotic coma.
AB  - Critical illness polyneuromypathy has not previously been reported as a
      complication of diabetic coma. We describe a patient with hyperosmolar non
      ketotic coma (HONK) complicating gram-negative sepsis in whom persistent coma and
      profound tetraplegia caused considerable concern. Although, initially, it was
      feared that the patient had suffered a central neurological complication such as
      stroke or cerebral oedema, a diagnosis of critical illness motor syndrome (CIMS)
      was subsequently confirmed neurophysiologically. Profound limb weakness
      associated with HONK is not necessarily due to a catastrophic cerebral event,
      rather it may be a result of CIMS, which has an excellent prognosis for full
      neurological recovery.

PMID- 10660854
TI  - Prolonged sedation requiring mechanical ventilation and continuous flumazenil
      infusion after routine doses of clorazepam for alcohol withdrawal syndrome.
AB  - We report the cases of two patients who developed prolonged sedation after
      routine doses of clorazepam for alcohol withdrawal syndrome. They required
      prolonged mechanical ventilation (10 days for both patients) followed by
      continuous flumazenil infusion (16 days for one patient and 3 days for the other)
      to avoid reintubation. In the two patients, nordazepam accumulation (main active
      metabolite of clorazepam) was demonstrated as the cause of the coma. This
      accumulation could be attributed, in one case, to impaired hepatic cytochrome P
      450 3A4 activity. Caution is required when prescribing benzodiazepines to
      alcoholic patients and the use of benzodiazepine which do not undergo hepatic
      oxidation by cytochrome P 450 such as oxazepam or lorazepam is suggested.

PMID- 10660856
TI  - Recommendations for intra-hospital transport of the severely head injured
      patient. Working Group on Neurosurgical Intensive Care of the European Society of
      Intensive Care Medicine.

PMID- 10660857
TI  - International consensus conferences in intensive care medicine. Ventilator
      associated lung injury in ARDS. American Thoracic Society, European Society of
      Intensive Care Medicine, Societe de Reanimation Langue Francaise.

PMID- 10660858
TI  - Prone position in a spontaneously breathing near-drowning patient.

PMID- 10660859
TI  - Aborted sudden death caused by delayed ventricular arrhythmia in a patient with
      vasospastic angina.

PMID- 10660860
TI  - Plasmapheresis in fatal overdose with verapamil.

PMID- 10660861
TI  - Combination of inhaled nitric oxide and intravenous prostacyclin for successful
      treatment of severe pulmonary hypertension in a patient with ARDS.

PMID- 10660862
TI  - Is SjvO2 monitoring useful in the management of head trauma patients?

PMID- 10660863
TI  - Assessment of medication errors: methodological details.

PMID- 10660864
TI  - Acute carbohydrate consumption does not influence resistance exercise performance
      during energy restriction.
AB  - The effect of acute carbohydrate consumption on performance and metabolism of
      resistance-trained males was determined. Twenty-two subjects, assigned to either
      carbohydrate (C, n = 8), placebo (P, n = 8), or control (N, n = 6), performed
      standardized workouts every other day for a week prior to testing and throughout
      the testing period. Three of these workouts (T1, T2, and T3) were the performance
      test in that the last bouts of leg extension and bench press were done to failure
      at 80% of 10 repetition maximum. A carbohydrate or placebo beverage was consumed
      30 min prior to T3. Blood samples were drawn before and after T2 and T3. There
      was no effect of carbohydrate or energy restriction on number of repetitions done
      during the leg extension performance test. Carbohydrate intake prior to a
      resistance exercise bout done in negative energy balance state did not affect
      performance or evidence of muscle damage.

PMID- 10660865
TI  - Inosine supplementation has no effect on aerobic or anaerobic cycling
      performance.
AB  - The two basic aims of this study were to add to the limited literature concerning
      Inosine as an ergogenic aid, and to determine the effects of Inosine
      supplementation over a period of 5 and 10 days, at a dosage of 10,000 mg.d-1 on
      measures associated with aerobic and anaerobic performance. Seven trained,
      volunteer male subjects (body mass = 63.0 +/- 8.7 kg, VO2max = 67.9 +/- 3.3 ml.kg
      1.min-1) participated in this study. The subjects completed three test sessions,
      each comprising three tests (5 x 6-s sprint, 30-s sprint, and 20-min time trial).
      Supplementation was carried out in a random, double-blind manner, and the test
      sessions were undertaken prior to (Baseline, B), on Day 6, and on Day 11. Blood
      was sampled prior to supplementation as well as on Days 6 and 11 and was analyzed
      for uric acid and 2,3 DPG. An analysis of the data indicated no performance
      benefit of supplementation and no improvement in 2,3 DPG concentration. Uric acid
      concentration increased significantly after both Days 6 and 11 (p < 0.03 and p <
      0.004, respectively). It is concluded that Inosine has no ergogenic effects but
      may cause possible health problems if taken over long periods of time.

PMID- 10660866
TI  - Nutritional and physiological status of U.S. national figure skaters.
AB  - This study assessed the nutrient intake, body composition and biochemical indices
      of National Figure Skating Championship competitors. Four-day diet records,
      fasting blood samples, and anthropometric measurements were obtained 2 months
      after the National Championships from 41 figure skaters 11-18 years of age.
      Energy, carbohydrate, fat, dietary fiber and cholesterol intake were
      significantly lower compared to the NHANES III averages for adolescents in the
      U.S. In general, the mean intakes for most vitamins except vitamin D and E were
      above the recommended intake. But the athletes had lower intakes of vitamin E and
      B12, and higher intakes of vitamin C, and thiamin (females only) compared with
      NHANES III. The mean intakes of magnesium, zinc, and iodine by the male skaters
      were below the recommended levels, as were the mean intakes of calcium, iron,
      phosphorus, magnesium, and zinc by the female skaters. Also, the number of
      servings from vegetable, fruit, dairy, and meat groups were below the recommended
      levels. Biochemical indices of nutritional status were within normal limits for
      all skaters. But plasma electrolyte concentrations were indicative of potential
      dehydration status. The results suggest there is a need to develop dietary
      intervention and educational programs targeted at promoting optimal nutrient and
      fluid intakes by these athletes to maintain performance and improve long-term
      health status.

PMID- 10660867
TI  - Influence of caffeine on metabolic and cardiovascular functions during sustained
      light intensity cycling and at rest.
AB  - This study assessed the influence of caffeine on metabolic and cardiovascular
      functions during sustained, light intensity cycling and at rest. Eight healthy,
      recreationally active adults participated in four randomly assigned, double-blind
      experimental trials of 60 min upright seated cycle exercise (30% VO2 max) or
      equivalent rest with caffeine (5 mg.kg-1) or placebo consumed 60 min prior to
      data collection. Gas exchange was measured by open-circuit spirometry indirect
      calorimetry. Global blood flow was evaluated by thoracic impedance cardiography
      and arterial blood pressure by auscultation. A repeated measures ANOVA indicated
      that pretrial caffeine increased oxygen uptake and energy expenditure rate (p <
      0.05) but did not change respiratory exchange ratio. Systolic, diastolic, and
      mean arterial blood pressure were elevated following caffeine intake (p < 0.05).
      Cardiac output, heart rate, stroke volume, and systemic vascular resistance were
      not significantly different between caffeine and placebo sessions. For each of
      the metabolic and hemodynamic variables examined, the effects of caffeine were
      similar during constant-load, light intensity cycling and at rest. These data
      illustrate that caffeine's mild thermogenic influence can be mediated without a
      major shift in substrate oxidation mixture. Caffeine at this dosage level alters
      cardiovascular dynamics by augmenting arterial blood pressure.

PMID- 10660868
TI  - Ginseng treatment improves psychomotor performance at rest and during graded
      exercise in young athletes.
AB  - This study was designed to determine the effect of ginseng treatment on multiple
      choice reaction time (RT) during exercise. Fifteen soccer players (age 19.07 +/-
      0.62 yrs) were placed in a double-blind manner into one of two groups: ginseng (n
      = 7), receiving 350 mg of ginseng daily for 6 weeks, or placebo (n = 8),
      receiving a placebo daily for 6 weeks. Before and after the treatment all the
      subjects performed an incremental bicycle ergometer exercise with intensity
      increasing 50 W every 3 min until volitional exhaustion. RT was measured before
      exercise, and then in the last 2 min of each exercise load. Maximal oxygen uptake
      (VO2max) and lactate threshold (LAT) were also determined from the exercise test.
      Ginseng treatment was found to shorten RT at rest and during exercise, shifting
      the exercise load associated with the shortest RT toward higher exercise loads.
      Neither ginseng nor placebo influenced VO2 max and LAT. In conclusion, ginseng
      extract does improve psychomotor performance during exercise without affecting
      exercise capacity.

PMID- 10660869
TI  - Resting metabolic rate and thermogenic effect of glucose in trained and untrained
      girls age 11-15 years.
AB  - Twelve girls who trained in rowing were examined twice a year for 4 years. Their
      initial age was 11.7 +/- (SD) 0.2 yrs. Control groups consisted of 13 girls age
      11.5 +/- 0.3 yrs and 18 girls age 14.4 +/- 0.3 yrs examined simultaneously with
      trained girls in the first and last year of the study, respectively. The
      examination involved basic anthropometry, estimation of sexual maturation (Tanner
      scale), 2-day food records, measurements of resting metabolic rate, energy
      expenditure following glucose ingestion (50 g), and determinations of blood
      glucose and plasma insulin concentrations prior to and 2 hrs after glucose load.
      Body mass, height, and fat content were slightly greater in trained girls. None
      of the subjects reported disturbances in menstrual function, and the age of
      menarche was similar for all. Both trained and untrained girls reported similar
      daily energy intake closer to the lower limit or slightly below the estimates of
      energy requirements for adolescents. Resting metabolic rate calculated per kg of
      total body mass or lean body mass was lower in trained girls, while the
      thermogenic effect of glucose was greater. Plasma insulin concentrations measured
      2 hrs after glucose ingestion were lower in trained girls. The results suggest
      that in circumpubertal girls, increased physical activity leads to energy
      conservation at rest in postabsorptive state and a tendency toward enhancement of
      food-induced thermogenesis.

PMID- 10660870
TI  - Patterns of vitamin/mineral supplement usage by adolescents attending athletic
      high schools in Korea.
AB  - An excessive use of vitamin/mineral supplements is considered by many to be a
      common health problem. We surveyed 1,355 adolescent boys and girls attending
      athletic high schools in Korea for their usage patterns of vitamin/mineral
      supplements. The usage rate of the vitamin/mineral supplements was 35.8%. The
      most favored supplements were vitamin C, multivitamins, and calcium. The reasons
      most cited for taking supplements were "to recover from fatigue," and "to
      maintain health." Vitamin and mineral intakes occurred over a wide range; mean
      intake values were typically higher than the Korean RDA. Vitamins B1, B12 and C
      were consumed in very high amounts at 29.7, 17.9 and 11.1 times the Korean RDA,
      respectively. When the intakes of nutrients from supplements and diet were
      combined, it was observed that the intakes of niacin, folic acid, vitamin C, and
      iron exceeded levels that have been proposed as upper safe limits. The above data
      underscore the need to provide sound nutritional education to athletic
      adolescents and their coaches with respect to the use of vitamin/mineral
      supplements and the links between adequate diet, good health, and physical
      performance.

PMID- 10660871
TI  - Glycogen replenishment and repeated maximal effort exercise: effect of liquid
      carbohydrate.
AB  - We investigated the effects of carbohydrate ingestion on glycogen replenishment
      and subsequent short duration, high intensity exercise performance. During
      Session 1, aerobic power was determined and each subject (N = 6) was familiarized
      with the 100-kJ cycling test (100KJ-Test). During the treatment sessions, the
      subjects performed a 100KJ-Test (Ride-1), then consumed 0.7 g.kg body mass-1 of
      maltodextrin (CHO) or placebo (PLC), rested 60 min, and then performed a second
      100KJ-Test (Ride-2). Muscle tissue was collected before (Pre-1) and after Ride-1
      (Post-1), and before (Pre-2) and after Ride-2 (Post-2), and analyzed for glycogen
      concentration. Both treatments yielded a significant increase in glycogen levels
      following the 60-min recovery, but there was no difference between treatments.
      Time to complete the 100KJ-Test increased significantly for PLC, but not for CHO.
      These data indicate that the decrease in performance during Ride-2 in PLC was not
      the result of a difference in glycogen concentration.

PMID- 10660872
TI  - A report of vitamin and mineral supplement use among university athletes in a
      division I institution.
AB  - The influences of gender, ethnicity, and sport of varsity athletes on their
      vitamin/mineral supplementation habits were examined. Subjects included 145
      females and 266 males from 22 varsity teams; 80% were Caucasian; 12% African
      American; and 8% Combined-Other. Over half of the subjects took supplements.
      Males were more likely than females to give "too expensive" as a reason for not
      taking supplements, and "improve athletic performance" and "build muscle" as
      reasons for taking supplements. The most common supplement was multivitamins plus
      minerals. Females were more likely to take calcium and iron, and males vitamins
      B12 and A. African Americans were the most likely to take vitamin A. Males were
      more likely to get supplement information from nutritionists/dietitians and self,
      and females from family members or friends and physicians or pharmacists.
      Football players were more likely to get supplement information from
      nutritionists/dietitians, and males in other sports from coaches/trainers. There
      were some differences in vitamin/mineral supplement habits of the athletes by
      gender, ethnicity, and sport.

PMID- 10660873
TI  - Intestinal permeability in runners in the 1996 Chicago marathon.
AB  - Abdominal cramping, nausea, diarrhea, and GI bleeding are often reported in long
      distance runners. This study set out to determine the effects of prolonged (2-4
      hrs) exercise and NSAID ingestion on gastric and intestinal permeability during
      the first 5 hrs following the 1996 Chicago Marathon. Thirty-four healthy
      volunteers (20 M, 14 F; ages 30-50) completed the race and ingested the test
      solution (5 g sucrose, 5 g lactulose, 2 g rhamnose, in 40 ml water) within 10-15
      min. The urinary excretion ratio of lactulose/rhamnose was used to assess small
      intestine permeability; sucrose excretion was used to evaluate gastric
      impairment. There were no significant differences for mean training mileage,
      postrace rectal temperature, and percent dehydration between runners who ingested
      NSAIDs and those who did not. In all, 75% of subjects reported aspirin or
      ibuprofen ingestion before or during the race. Runners who ingested ibuprofen had
      significant elevations in urinary lactulose excretion and lactulose/rhamnose
      ratio, whereas those who ingested aspirin or who did not ingest either NSAID had
      no significant differences in urinary excretion of lactulose, rhamnose, sucrose,
      or lactulose/rhamnose ratio compared to resting controls. Thirteen of the 26
      NSAID users and 4 of the 8 non-users reported GI symptoms. It is concluded that
      (a) ibuprofen but not aspirin ingestion during prolonged exercise may increase
      gastrointestinal permeability and lead to GI symptoms, and (b) prolonged exercise
      alone can produce GI symptoms.

PMID- 10660874
TI  - Effect of ENDUROX on metabolic responses to submaximal exercise.
AB  - Claims that ENDUROX enhances performance by altering metabolic responses to
      exercise were tested. In a double-blind crossover design, 10 male subjects were
      randomly assigned to consume 400 mg of placebo or 800 mg ENDUROX for 7 days.
      Cycle ergometry was performed for 30 minutes at 25%, followed by 10 min at 65% of
      peak oxygen consumption. After a 1-week washout period, subjects performed the
      identical exercise protocol following 7 days of reciprocal supplemental
      conditions. Expired gases were collected and analyzed continuously for oxygen
      consumption, minute ventilation, and respiratory exchange ratio. Heart rate,
      blood pressure, rating of perceived exertion, blood lactate, and serum glycerol
      data were also collected at regular intervals. A two-way ANOVA with repeated
      measures revealed no significant main or interaction effects involving group
      differences (p > 0.05) between trials for any variable during rest, 25% or 65%
      (VO2 peak), or recovery. Our findings do not support the ergogenic claims for
      ENDUROX.

PMID- 10660875
TI  - RXR gamma gene is expressed by discrete cell columns within the alar plate of the
      brainstem of the chicken embryo.
AB  - With in situ hybridization assays, we mapped the distribution of retinoid X
      receptor gamma (RXR gamma) gene transcripts in the central nervous system of the
      chicken embryo. Previous studies have demonstrated the presence of RXR gamma
      transcripts in migrating neural crest and in neural crest derivatives throughout
      the peripheral nervous system, implicating RXR gamma as an early pan-neural crest
      marker (Rowe et al. 1991. Development 111:771-778), and in the retina (Hoover et
      al. 1998. J Comp Neurol 391:204-213). Here we report the presence of RXR gamma
      transcripts in discrete regions of the developing neural tube, within the
      hindbrain, the cerebellar plate, the optic tectum, and the diencephalon. At stage
      10, when migrating neural crest expresses RXR gamma transcripts, we detect no
      transcripts in the neural tube. By stage 13, RXR gamma transcripts accumulate to
      detectable levels along the midline of the posterior optic tectum, where the
      neural crest-derived sensory neurons of the mesencephalic trigeminal nucleus are
      located. By stage 15, RXR gamma transcripts also appear in an intermittent
      longitudinal cell column within the mantle zone of the alar plate of the
      hindbrain, eventually extending into the cerebellar plate rostrally and into the
      cervical spinal cord caudally, with a gap at about rhombomere 3. By stage 19,
      transcripts appear in a discrete population of cells within the diencephalon.
      Expression in these cell populations continues until at least stage 22.5, when
      many neuron populations have been generated in the hindbrain. The localization of
      the RXR gamma-positive cells to the mantle zone suggests that they are
      postmitotic and are probably neurons. Their specific alar locations indicate that
      they reside within sensory columns and potential downstream targets, evidently
      corresponding to some of the central components of the trigeminal system.

PMID- 10660876
TI  - Rostral wulst in passerine birds. I. Origin, course, and terminations of an avian
      pyramidal tract.
AB  - An avian "pyramidal tract" was defined in zebra finches and green finches by
      making injections of neuronal tracers into the hyperstriatum accessorium (HA) of
      the rostral Wulst. Extratelencephalic projections of rostral HA traveled in the
      septomesencephalic tract (TSM) and gave rise to nuclear-specific terminal fields
      in the precerebellar medial spiriform nucleus of the posterior thalamus, the red
      nucleus in the mesencephalon, the medial pontine nucleus in the pons, and the
      subtrigeminal, external cuneate, cuneate, gracile, and inferior olivary nuclei in
      the medulla. Extensive but more diffuse terminal fields were also present in the
      stratum cellulare externum of the posterior hypothalamus, the central
      periaqueductal gray, the prerubral field, and the lateral and ventrolateral
      tegmentum of the pons and medulla. There was also a sparse projection to the
      dorsal thalamic nucleus intermedius ventralis anterior, which supplies the
      somatosensory input to the rostral Wulst, and distinct projections to the
      intercollicular region surrounding the central nucleus of the inferior
      colliculus, where they partly overlapped the projections of the dorsal column
      nuclei. Projections from HA to the cerebellum via the TSM are described
      separately. In the brainstem the ventral ramus of TSM was situated ventral to the
      medial lemniscus at the base of the brain, entered the spinal cord in the inner
      margin of the lateral funiculus, predominantly ipsilaterally, and terminated
      bilaterally but predominantly contralaterally in the medial part of the base of
      the dorsal horn of the upper six or seven cervical segments. After injections of
      tracers into putative targets, numerous retrogradely labeled cells were found in
      the rostral HA, predominantly ventrally. The results confirm the presence of a
      major descending fiber system in passerine birds that resembles in its brainstem
      course and several of its terminations the pyramidal tract of mammals. The
      reciprocal projections of HA with the hypothalamus suggest that rostral HA may
      also incorporate neuronal components that in mammals would be considered parts of
      prefrontal cortex.

PMID- 10660877
TI  - Origins of cholinergic inputs to the cell bodies of intestinofugal neurons in the
      guinea pig distal colon.
AB  - Integration of function between gut regions is mediated by means of hormones and
      long neuronal reflex pathways. Intestinofugal neurons, which participate in one
      of these pathways, have cell bodies within the myenteric plexus and project their
      axons from the gut with the mesenteric nerves. They form excitatory synapses on
      neurons in prevertebral ganglia that in turn innervate other gut regions. The aim
      of the present study was to characterise immunohistochemically the synaptic input
      to intestinofugal neurons. The cell bodies of intestinofugal neurons that project
      from the distal colon were labelled with Fast Blue that was injected into the
      inferior mesenteric ganglia. Varicosities surrounding Fast Blue-labelled neurons
      were analysed for immunoreactivity for the vesicular acetylcholine transporter,
      vasoactive intestinal peptide, and bombesin. Most intestinofugal neurons were
      surrounded by nerve terminals immunoreactive for the vesicular acetylcholine
      transporter; many of these terminals also contained vasoactive intestinal peptide
      and bombesin immunoreactivity. This combination of markers occurs in axons of
      descending interneurons. Extrinsic denervation had no effect on the distribution
      of cholinergic terminals around intestinofugal neurons. A decrease in the number
      of vesicular acetylcholine transporter and vasoactive intestinal peptide
      immunoreactive terminals occurred around nerve cells immediately anal, but not
      oral, to myotomy operations. Consistent with previous physiological studies, it
      is concluded that intestinofugal neurons receive cholinergic synaptic input from
      other myenteric neurons, including cholinergic descending interneurons. Thus,
      intestinofugal neurons are second, or higher, order neurons in reflex pathways,
      although physiological data indicate that they also respond directly to
      distension of the gut wall.

PMID- 10660878
TI  - Embryonic development of the nervous system of the rhabdocoel flatworm Mesostoma
      lingua (Abilgaard, 1789).
AB  - We have analyzed the embryonic development of the Mesostoma nervous system, using
      a combination of histology, transmission electron microscopy, and wholemount
      immunohistochemistry. Neural progenitors are formed at an early stage when the
      Mesostoma embryo constitutes a multilayered mesenchymal mass of cells. A
      neurectoderm as in vertebrates or arthropods is absent. Only after neurons in the
      deep layers of the embryo have started differentiating do superficial cells
      reorganize into an epithelium that will give rise to the epidermis. Neurons are
      clustered in two anterior, bilaterally symmetric brain hemispheres. An antibody
      against acetylated beta-tubulin (anti-acTub) that labels neurotubules reveals an
      invariant pattern of pioneer neurons in the brain of midstage embryos. Pioneer
      neurons are grouped in several small clusters at characteristic positions. They
      pioneer several commissural tracts of the brain and two pairs of ventral and
      dorsal connectives, respectively.

PMID- 10660879
TI  - Differential expression of gamma-aminobutyric acid type B receptor-1a and -1b
      mRNA variants in GABA and non-GABAergic neurons of the rat brain.
AB  - To understand the heterogeneity of gamma-aminobutyric acid type B receptor
      (GABABR)-mediated events, we investigated expression of GABABR1a and 1b mRNA
      variants in GABA and non-GABAergic neurons of the rat central nervous system
      (CNS), by using nonradioactive in situ hybridization histochemistry and, in
      combination with GABA immunocytochemistry, double labeling. In situ hybridization
      with a pan probe, which recognizes a common sequence of both GABABR1a and
      GABABR1b mRNA variants, demonstrated widespread expression of GABABR1 mRNA at
      various levels in the CNS. Both GABABR1a and GABABR1b were expressed in the
      neocortex, hippocampus, dorsal thalamus, habenula, and septum, but only GABABR1a
      was detected in cerebellar granule cells, in caudate putamen, and most hindbrain
      structures. A majority of GABA neurons in cerebral cortex showed hybridization
      signals for both GABABR1a and GABABR1b, whereas those in most subcortical
      structures expressed either or neither of the two. GABA neurons in thalamic
      reticular nucleus and caudate putamen hybridized primarily for GABABR1a. Purkinje
      cells in the cerebellar cortex expressed predominantly GABABR1b. GABA neurons in
      dorsal lateral geniculate nucleus did not display significant levels of either
      GABABR1a or GABABR1b mRNAs. These data suggested widespread availability of
      GABABR-mediated inhibition in the CNS. The differential but overlapping
      expression of GABABR1 mRNA variants in different neurons and brain structures may
      contribute to the heterogeneity of GABABR-mediated inhibition. Some GABA neurons
      possessed, but others might lack the molecular machinery for GABABR-mediated
      disinhibition, autoinhibition, or both.

PMID- 10660880
TI  - Differential innervation of parvalbumin-immunoreactive interneurons of the
      basolateral amygdaloid complex by cortical and intrinsic inputs.
AB  - In the basolateral (BL) amygdaloid complex, the excitability of projection cells
      is regulated by intrinsic inhibitory interneurons using gamma-aminobutyric acid
      (GABA) as a transmitter. A subset of these cells are labeled in a Golgi-like
      manner by Parvalbumin (PV) immunohistochemistry. Recently, we have shown that the
      overwhelming majority of axon terminals contacting these PV-immunoreactive
      neurons form asymmetric synapses. The present study was undertaken to identify
      the source(s) of these inputs. Since previous work had revealed that thalamic
      axons form very few synapses on BL interneurons (< 1%), we focused on cortical
      and intra-amygdaloid inputs. Iontophoretic injections of the anterograde tracers
      Phaseolus vulgaris-leucoagglutinin or biotinylated dextran amine were performed
      in various cortical fields in cats (perirhinal, entorhinal, pre/infralimbic
      cortices) and monkeys (orbitofrontal region) or in the BL amygdaloid nucleus in
      cats. These injections resulted in a large number of anterogradely labeled
      terminals forming asymmetric synapses in the BL complex. Following cortical
      injections, numerous anterogradely labeled terminals were found in the vicinity
      of PV-immunoreactive interneurons in the BL amygdala. However, only approximately
      1% of these terminals formed synaptic contacts with PV-immunoreactive profiles.
      In contrast, as many as 11% of the terminals contributed by the intranuclear axon
      collaterals of BL projection cells established synapses with PV-immunoreactive
      elements. Since the axon terminals of PV-immunoreactive interneurons are enriched
      in GABA and they exclusively form symmetric synapses, these results suggest that
      PV-immunoreactive interneurons are predominantly involved in feedback inhibition
      in the BL amygdaloid complex.

PMID- 10660881
TI  - Relative distribution of synapses in the A-laminae of the lateral geniculate
      nucleus of the cat.
AB  - Previous electron microscopic studies of synaptic terminal distributions in the
      lateral geniculate nucleus have been flawed by potential sampling biases favoring
      larger synapses. We have thus re-investigated this in the geniculate A-laminae of
      the cat with an algorithm to correct this sampling bias. We used serial
      reconstructions with the electron microscope to determine the size of each
      terminal and synaptic type. We observed that RL (retinal) terminals are largest,
      F (local, GABAergic, inhibitory) terminals are intermediate in size, and RS
      (cortical and brainstem) terminals are smallest. We also found that synapses from
      RL terminals are largest, and thus most oversampled, and we used synaptic size
      data to correct for sampling errors. Doing so, we found that the relative
      synaptic percentages overall are 11.7% for RL terminals, 27.5% for F, and 60.8%
      for RS. Furthermore, we distinguished between relay cells and interneurons with
      post-embedding immunocytochemistry for GABA (relay cells are GABA negative and
      interneurons are GABA positive). Onto relay cells, RL terminals contributed 7.1%,
      F terminals contributed 30.9%, and RS terminals contributed 62.0%. Onto
      interneurons, RL terminals contributed 48.7%, F terminals contributed 24.4%, and
      RS terminals contributed 26.9%. We also found that RL terminals included many
      more separate synaptic contact zones (9.1 +/- 1.6) than did F terminals (2.6 +/-
      0.2) or RS terminals (1.02 +/- 0.02). We used these data plus the calculation of
      overall percentages of each synaptic type to compute the relative percentage of
      each terminal type in the neuropil: RL terminals represent 1.8%, F terminals
      represent 14.5%, and RS terminals represent 83.7%. We argue that this relative
      synaptic paucity is typical for driver inputs (from retina), whereas modulator
      inputs (all others) require many more synapses to achieve their function.

PMID- 10660882
TI  - Multiple somatosensory areas in the anterior parietal cortex of the California
      ground squirrel (Spermophilus beecheyii).
AB  - Multiunit electrophysiological recording techniques were used to explore the
      somatosensory cortex of the California ground squirrel (Spermophilus beecheyii).
      Cortex rostral and caudal to the primary somatosensory area (SI) contained
      neurons that responded to stimulation of deep receptors and to muscle and joint
      manipulation. The region of cortex rostral to SI was termed the rostral field (R)
      because of possible homologies with a similar field described in other mammals.
      Cortex caudal to SI had neurons that responded to stimulation of deep receptors
      and has been termed the parietal medial area (PM), as in previous investigations
      in squirrels. Like SI, both R and PM contained a complete or almost complete
      representation of the body surface, although the receptive field size for
      clusters of neurons in these regions was somewhat larger than those for clusters
      of neurons in SI. Electrophysiological recording results were correlated with
      histologically processed tissue that had been sectioned tangentially. Although SI
      was clearly identified as a myelin-dense region, both R and PM stained much less
      densely for myelin. Our results indicate that as in a number of other mammals
      including monotremes, marsupials, carnivores, and primates, the anterior parietal
      cortex of the California ground squirrel contains multiple representations of the
      sensory epithelium. This work, as well as a growing body of studies of
      somatosensory cortex organization in a variety of mammals, indicates that
      anterior parietal fields other than SI existed early in mammalian evolution, and
      were present in the common ancestor of all mammals.

PMID- 10660883
TI  - Expression of EphA5 during development of the olfactory nerve pathway in rat.
AB  - The olfactory neuroepithelium is a highly plastic region of the nervous system
      that undergoes continual turnover of primary olfactory neurons throughout life.
      The mechanisms responsible for persistent growth and guidance of primary
      olfactory axons along the olfactory nerve are unknown. In the present study, we
      used antibodies against the Eph-related receptor, EphA5, to localise EphA5, and
      recombinant EphA5-IgG fusion protein to localise its ligands. We found that
      although both EphA5 and its ligands were both expressed by primary olfactory
      neurons within the embryonic olfactory nerve pathway, there was no graded or
      complementary expression pattern. In contrast, the expression patterns altered
      postnatally such that primary olfactory neurons expressed the ligands, whereas
      the second-order olfactory neurons, the mitral cells, expressed EphA5. The role
      of EphA5 was analysed by blocking EphA5-ligand interactions in explant cultures
      of olfactory neuroepithelium using anti-EphA5 antibodies and recombinant EphA5.
      These perturbations reduced neurite outgrowth from explant cultures and suggest
      that intrafascicular axon repulsion may serve to limit adhesion and optimise
      conditions for axon growth.

PMID- 10660884
TI  - Temporal, spatial, and morphologic features of hair cell regeneration in the
      avian basilar papilla.
AB  - Hair cell-selective antibodies were used in combination with the nucleotide
      bromode-oxyuridine (BrdU) to examine the temporal, spatial, and morphologic
      progression of auditory hair cell regeneration in chicks after a single
      gentamicin injection. New hair cells are first identifiable with an antibody to
      class III beta (beta) tubulin (TuJ1) by 14 hours after BrdU incorporation, but
      progenitor cells in S phase and M phase are TuJ1-negative. TuJ1 labeling reveals
      that new hair cells are first detected at 3 days after gentamicin, in the base,
      and the emergence and maturation of regenerating hair cells spreads apically over
      time. Differentiation of regenerating hair cells consists of a progressive series
      of morphologic changes. During early differentiation (14 hours to 1 day after
      BrdU), regenerating hair cells are round or fusiform and remain near the lumen,
      where they are generated. During intermediate differentiation (2-4 days after
      BrdU), regenerating hair cells resemble support cells; their somata are
      elongated, their nuclei are in the support cell layer, and they appear to contact
      both the lumenal surface and the basal lamina. The 275-kDa hair cell antigen is
      first expressed in regenerating hair cells during this period. During late
      differentiation (7 days after BrdU and later), TuJ1-positive cells acquire the
      globose shape of mature hair cells. Labeling with antibodies to hair cell
      antigen, calmodulin, and ribosomal RNA confirms this morphologic progression.
      Examination of sister cells born at 3 days post-gentamicin reveals that there is
      equal likelihood that they will assume the hair cell or support cell fate (i.e.,
      both asymmetric and symmetric differentiation occur).

PMID- 10660885
TI  - Single-axon tracing study of neurons of the external segment of the globus
      pallidus in primate.
AB  - Axonal projections arising from the external segment of the globus pallidus (GPe)
      in cynomolgus monkeys (Macaca fascicularis) were mapped after labeling small
      pools (5-15 cells) of neurons with biotinylated dextran amine. Seventy-six single
      axons were reconstructed from serial sagittal sections with a camera lucida. The
      majority of labeled GPe cells displayed long, aspiny, and poorly branched
      dendrites that arborized mostly along the sagittal plane, whereas others showed
      dendrites radiating in all directions. Numerous GPe axons emitted short,
      intranuclear collaterals that arborized close to their parent cell body. Based on
      their axonal targets, four distinct types of GPe projection neurons have been
      identified: 1) neurons that project to the internal segment of the globus
      pallidus (GPi), the subthalamic nucleus (STN), and the substantia nigra, pars
      reticulata (SNr; 13.2%); 2) neurons that target the GPi and the STN (18.4%); 3)
      neurons that project to the STN and the SNr (52.6%); and 4) neurons that target
      the striatum (15.8%). Labeled GPe axons displayed large varicosities that often
      were closely apposed to the somata and proximal dendrites of STN, GPi, and SNr
      neurons. At striatal levels, however, GPe axons displayed small axonal
      varicosities that did not form perineuronal nets. These results suggest that the
      GPe is an important integrative locus in primate basal ganglia. This nucleus
      harbors several subtypes of projection neurons that are endowed with a highly
      patterned set of collaterals. This organization allows single GPe neurons to
      exert a multifarious effect not only on the STN, which is the claimed GPe target,
      but also on the two major output structures of the basal ganglia, the SNr and the
      GPi.

PMID- 10660886
TI  - Theta ganglion cell type of cat retina.
AB  - We define a new bistratified ganglion cell type of cat retina using intracellular
      staining in vitro. The theta cell has a small soma, slender axon, and delicate,
      highly branched dendritic arbor. Dendritic fields are intermediate in size among
      cat ganglion cells, with diameters typically two to three times those of beta
      cells. Fields increase in size with distance from the area centralis, ranging in
      diameter from 70 to 150 microns centrally to a maximum of 700 microns in the
      periphery. Theta cells have markedly smaller dendritic fields within the nasal
      visual streak than above or below it and smaller fields nasally than temporally.
      Dendritic arbors are narrowly bistratified. The outer arbor lies in the lower
      part of sublamina a (OFF sublayer) of the inner plexiform layer where it
      costratifies with the dendrites of OFF alpha cells. The inner arbor occupies the
      upper part of sublamina b (ON sublayer), where it costratifies with ON alpha
      dendrites. The outer and inner arbors are composed of many relatively short
      segments and are densely interconnected by branches that traverse the a/b
      sublaminar border. Experiments combining retrograde labeling with intracellular
      staining indicate that theta cells project to the superior colliculus and to two
      components of the dorsal lateral geniculate nucleus (the C laminae and medial
      interlaminar nucleus). Theta cells project contralaterally from the nasal retina
      and ipsilaterally from the temporal retina. They apparently correspond to a
      sluggish transient or phasic W-cell with an ON-OFF receptive field center.

PMID- 10660887
TI  - Remodeling of hippocampal synapses after hippocampus-dependent associative
      learning.
AB  - The aim of this study was to determine whether hippocampus-dependent associative
      learning involves changes in the number and/or structure of hippocampal synapses.
      A behavioral paradigm of trace eyeblink conditioning was used. Young adult
      rabbits were given daily 80 trial sessions to a criterion of 80% conditioned
      responses in a session. During each trial, the conditioned (tone) and
      unconditioned (corneal airpuff) stimuli were presented with a stimulus-free or
      trace interval of 500 msec. Control rabbits were pseudoconditioned by equal
      numbers of random presentations of the same stimuli. Brain tissue was taken for
      morphological analyses 24 hours after the last session. Synapses were examined in
      the stratum radiatum of hippocampal subfield CA1. Unbiased stereological methods
      were used to obtain estimates of the total number of synapses in this layer as
      well as the area of the postsynaptic density. The data showed that the total
      numbers of all synaptic contacts and various morphological subtypes of synapses
      did not change in conditioned animals. The area of the postsynaptic density,
      however, was significantly increased after conditioning in axospinous
      nonperforated synapses. This structural alteration may reflect an addition of
      signal transduction proteins (such as receptors and ion channels) and the
      transformation of postsynaptically silent synapses into functional ones. The
      findings of the present study indicate that cellular mechanisms of hippocampus
      dependent associative learning include the remodeling of existing hippocampal
      synapses. Further studies examining various time points along the learning curve
      are necessary to clarify the issue of whether these mechanisms also involve the
      formation of additional synaptic contacts.

PMID- 10660888
TI  - Plastic changes and nitric oxide synthase induction in neurons that innervate the
      regenerated tail of the lizard Gekko gecko: I. Response of spinal motoneurons to
      tail amputation and regeneration.
AB  - The lizard tail regenerates after autotomy or amputation. After horseradish
      peroxidase injections in the regenerate, motoneurons were retrogradely labeled
      only in the three spinal segments rostral to the amputation, whose spinal nerves
      are severed by tail loss. The changes in these motoneurons, compared to those of
      lizards with original intact tails, were investigated 5, 15, and 30 days after
      caudotomy and at 8 months in lizards with mature regenerates. Morphometric
      analysis of Nissl-stained motoneurons rostral to the amputation revealed marked
      hypertrophy, peaking at 15 days, when chromatolysis and nuclear eccentricity were
      also evident; motoneuron perikarya remained significantly larger than in controls
      after tail regeneration. The dUTP nick-end labeling (TUNEL) stain for apoptotic
      neurons did not reveal labeled cells in the spinal cord 5 and 15 days after
      caudotomy. Nitric oxide synthase (NOS) expression was studied with nicotinamide
      adenine-dinucleotide phosphate (NADPH)-diaphorase histochemistry and evaluated
      quantitatively with densitometry. A few caudal spinal motoneurons were lightly
      stained in lizards with intact tails. Induction of NADPH-diaphorase positivity
      was evident in the vast majority of these cells 5 days after caudotomy and was
      very marked at 15 and 30 days, during tail regrowth. These data were confirmed by
      neuronal NOS immunohistochemistry. After tail regeneration, histochemical
      positivity was markedly down-regulated in the tail spinal motoneurons but
      persisted in the majority of these cells. The findings show that in the lizard
      caudotomy elicits in axotomized caudal spinal motoneurons NOS induction
      associated with plasticity phenomena and in particular with vigorous regeneration
      of axons that innervate the regrowing tail.

PMID- 10660889
TI  - Does the visual system of the flying fox resemble that of primates? The
      distribution of calcium-binding proteins in the primary visual pathway of
      Pteropus poliocephalus.
AB  - It has been proposed that flying foxes and echolocating bats evolved
      independently from early mammalian ancestors in such a way that flying foxes form
      one of the suborders most closely related to primates. A major piece of evidence
      offered in support of a flying fox-primate link is the highly developed visual
      system of flying foxes, which is theorized to be primate-like in several
      different ways. Because the calcium-binding proteins parvalbumin (PV) and
      calbindin (CB) show distinct and consistent distributions in the primate visual
      system, the distribution of these same proteins was examined in the flying fox
      (Pteropus poliocephalus) visual system. Standard immunocytochemical techniques
      reveal that PV labeling within the lateral geniculate nucleus (LGN) of the flying
      fox is sparse, with clearly labeled cells located only within layer 1, adjacent
      to the optic tract. CB labeling in the LGN is profuse, with cells labeled in all
      layers throughout the nucleus. Double labeling reveals that all PV+ cells also
      contain CB, and that these cells are among the largest in the LGN. In primary
      visual cortex (V1) PV and CB label different classes of non-pyramidal neurons.
      PV+ cells are found in all cortical layers, although labeled cells are found only
      rarely in layer I. CB+ cells are found primarily in layers II and III. The
      density of PV+ neuropil correlates with the density of cytochrome oxidase
      staining; however, no CO+ or PV+ or CB+ patches or blobs are found in V1. These
      results show that the distribution of calcium-binding proteins in the flying fox
      LGN is unlike that found in primates, in which antibodies for PV and CB label
      specific separate populations of relay cells that exist in different layers.
      Indeed, the pattern of calcium-binding protein distribution in the flying fox LGN
      is different from that reported in any other terrestrial mammal. Within V1 no PV+
      patches, CO blobs, or patchy distribution of CB+ neuropil that might reveal
      interblobs characteristic of primate V1 are found; however, PV and CB are found
      in separate populations of non-pyramidal neurons. The types of V1 cells labeled
      with antibodies to PV and CB in all mammals examined including the flying fox
      suggest that the similarities in the cellular distribution of these proteins in
      cortex reflect the fact that this feature is common to all mammals.

PMID- 10660890
TI  - On the problem of lamination in the superficial dorsal horn of mammals: a
      reappraisal of the substantia gelatinosa in postnatal life.
AB  - Although it is one of the most distinctive and earliest recognized features in
      the spinal cord, the substantia gelatinosa (SG) remains among the most enigmatic
      of central nervous system regions. The present neuroanatomical studies employed
      transganglionic transport of horseradish peroxidase conjugates of choleragenoid
      (B-HRP) and the B4 isolectin of Bandeiraea simplicifolia (IB4-HRP) on opposite
      sides to compare the projection patterns of myelinated and unmyelinated cutaneous
      primary afferents, respectively, within the superficial dorsal horn of the spinal
      cord in postnatal mice, from shortly after birth to adulthood. Putative
      unmyelinated afferents labeled with IB4-HRP gave rise to a dense sheet of
      terminal-like labeling restricted to the outer half of the SG. In contrast,
      myelinated inputs labeled with B-HRP gave rise to a similarly dense sheet of
      terminal-like labeling that occupied the inner half of the SG. This adult
      organization, with two dense sheets of terminal labeling in the superficial
      dorsal horn, was clearly evident shortly after birth using these markers, prior
      to the emergence of the SG. Furthermore, the location of the SG proper varied
      considerably within the dorsoventral plane of the dorsal horn according to
      mediolateral and segmental locations, a finding that was also seen in comparative
      studies in rat and cat. These findings caution against equating the SG in
      particular, and the superficial dorsal horn in general, with nociceptive
      processing; at minimum, the SG subserves a clear duality of function, with only a
      thin portion of its outermost aspect devoted to pain.

PMID- 10660891
TI  - Evidence for coexistence of enkephalin and glutamate in axon terminals and
      cellular sites for functional interactions of their receptors in the rat locus
      coeruleus.
AB  - The authors previously showed that a subset of axon terminals in the locus
      coeruleus (LC) contains methionine5-enkephalin (ENK) and gamma-aminobutyric acid
      (GABA) immunoreactivities. However, numerous ENK-labeled terminals lacked GABA
      and exhibited synaptic specializations that were characteristic of excitatory
      type transmitters. To determine whether ENK coexists with glutamate in the LC,
      preembedding immunoperoxidase detection of ENK or immunogold-silver was combined
      with postembedding identification of glutamate using a gold marker. Indeed, 28%
      of the ENK-labeled axon terminals examined (n = 250 axon terminals) also
      contained glutamate. To define further sites for functional interactions between
      opiate ligands and excitatory amino acid receptors, the ultrastructural
      localization of the mu-opioid receptor (MOR) was examined with respect to either
      the kainate receptor (KAR) or the R1 subunit of the N-methyl-D-aspartate (NR1)
      type glutamate receptor in the LC. Gold-silver labeling for MOR and peroxidase
      labeling for either KAR or NR1 indicated that the MOR often was localized to the
      plasma membrane of dendrites that also exhibited immunolabeling for either
      glutamate receptor subtype. In contrast to the KAR, which was identified
      primarily in somata and dendrites, NR1 immunoreactivity also was found frequently
      in axon terminals as well as in glial processes. Glial processes containing NR1
      occasionally exhibited immunolabeling for MOR and sometimes were directly apposed
      to MOR-containing dendrites in the LC. Furthermore, NR1-labeled receptors in axon
      terminals sometimes were presynaptic to MOR-labeled dendrites. The authors
      concluded that ENK and glutamate may be cotransmitters in LC afferents. Moreover,
      ligands at the KAR may modulate directly MOR-containing neurons in the LC,
      whereas actions at NR1 receptors may affect opioid-sensitive neurons through
      multiple cellular mechanisms, i.e., through presynaptic, postsynaptic, or glial
      actions.

PMID- 10660892
TI  - Ontogeny of the tectorotundal pathway in chicks (Gallus gallus): birthdating and
      pathway tracing study.
AB  - The avian tectorotundal system has been suggested as a homologue of the mammalian
      colliculopulvinar system. In the tectorotundal system, neurons of the stratum
      griseum centrale (SGC) of the optic tectum send their axons bilaterally to the
      nucleus rotundus (Rt). In transit to the Rt, the axons of the SGC neurons
      collateralize in the nuclei posteroventralis thalami (PV), subpretectalis (SP),
      and interstitiopretectosubpretectalis (IPS) of the tectothalamic tract (TT). The
      current study used birthdating and pathway-tracing methods to investigate the
      neurogenesis and time course of neuronal connections of the tectorotundal pathway
      in chicks during embryogenesis. By using tritiated thymidine autoradiography, we
      observed that the SGC neurons of the tectum were generated by embryonic days 3.0
      5.5 (E3.0-E5.5), the Rt by E3.5-E5.0, and the nuclei of TT by E3.5-4.5. To trace
      the tectorotundal pathway, we injected cholera toxin B subunit (CTb) into the
      tectum, and the CTb-like immunoreactivity was examined. By E4.5-E5.5, some CTb
      like immunoreactive (CTb-LI) axons terminated in the ipsilateral SP/IPS. By E6.0
      E6.5, CTb-LI axon bundles were seen ipsilaterally in the TT. Increased numbers of
      labeled axons were seen terminating in the SP/IPS. By E7.0-E7.5, heavily labeled
      axons in the TT were observed with diffuse terminals in areas ventral to the
      presumptive Rt and PV. By E7.5-E8.0, the tectal axons innervated the ipsilateral
      Rt, in which some of the collaterals crossed the midline to the contralateral
      diencephalon. The crossed tectorotundal projection was seen first by E8.0-E8.5.
      Also, during this stage, a few CTb-LI collaterals terminated in the contralateral
      SP/IPS. Between E10 and E13, the pattern of bilateral tectorotundal projections
      became more regionalized, whereas labeling continued to increase in the SP/IPS.
      At E16, the labeling pattern of all tectorecipient structures resembled that of
      the hatchling. The current study revealed the temporal order of development of
      the tectorotundal pathway during embryogenesis. The SGC cells first innervate
      ipsilaterally the SP/IPS and then the Rt/PV. The schedule of the crossed
      tectorotundal connections coincides with the schedule of tectal projections onto
      the contralateral intrinsic nuclei of the TT. We conclude that E8.0 (+/- E0.5) is
      a critical stage for the development of the tectofugal pathway. Moreover, the
      current study provides important insights into the relative ontogeny of the
      mammalian tectofugal pathway.

PMID- 10660893
TI  - Lingual BDNF and NT-3 mRNA expression patterns and their relation to innervation
      in the human tongue: similarities and differences compared with rodents.
AB  - Brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT-3) mRNAs are
      expressed in developing and adult rodent tongue and are important for the proper
      development of lingual gustatory and somatosensory innervation in rodents. Here,
      we wished to determine whether the findings in rodents apply to humans. By using
      in situ hybridization histochemistry, distinct, specific, and in some instances
      overlapping patterns of BDNF and NT-3 mRNA expression were found in the
      developing and adult human tongue, gustatory papillae, and taste buds. BDNF mRNA
      was expressed in the superior surface epithelium of the developing fungiform
      papillae (i.e., developing taste buds), in the epithelium covering the
      circumvallate papillae, and in the subepithelial mesenchyme. Interestingly, BDNF
      mRNA was expressed in the lingual epithelium before nerve fibers reached the
      epithelium, indicating a prespecialization of the gustatory epithelium before the
      arrival of nerves. In the adult fungiform papillae, BDNF mRNA labeling was found
      in taste buds and in restricted areas in the non-gustatory lingual epithelium. NT
      3 mRNA was found in the developing lingual epithelium and gustatory papillae. NT
      3 mRNA labeling was observed in the adult fungiform taste buds, overlapping with
      BDNF mRNA labeling, in contrast to what was seen in rodents. NT-3 mRNA was
      additionally found in restricted areas in filiform papillae. Protein gene product
      9.5 (PGP) antibodies were used to investigate a possible correlation between
      lingual innervation and sites of neurotrophin gene activity. Adult human tongue
      innervation differed from that of rodents, possibly in part due to a different
      neurotrophin expression pattern in the human tongue. Based on these findings, we
      suggest that BDNF and NT-3 are important for the initiation and maintenance of
      the gustatory and somatosensory innervation also in humans. The broader and
      somewhat overlapping expression patterns of BDNF and NT-3 mRNAs, compared with
      rodents, suggest additional and possibly somewhat overlapping roles for BDNF and
      NT-3 in the human tongue and also indicate differences between species. It is
      important that interspecies differences be taken into consideration.

PMID- 10660894
TI  - Expression of chondroitin sulfate proteoglycans in the chiasm of mouse embryos.
AB  - Chondroitin sulfate (CS) proteoglycans have been implicated as molecules that are
      involved in axon guidance in the developing neural pathways. The spatiotemporal
      expression of CS was investigated in the developing retinofugal pathway in mouse
      embryos by using the CS-56 antibody. Immunoreactive CS was detected in inner
      regions of the retina as early as embryonic day 11 (E11). Its expression in
      subsequent stages of development followed a centrifugal, receding gradient that
      appeared to correlate with the sequence of axogenesis in the retina. In the
      chiasm, immunoreactive CS was expressed at E12, before the arrival of retinal
      axons. When the retinal axons navigated in the chiasm at E13-E14, immunoreactive
      CS remained at a low level in the optic fiber layer of the chiasm but was
      observed prominently in the caudal parts of the ventral diencephalon. This
      pattern followed closely the array of stage-specific-embryonic-antigen-1-positive
      neurons in the ventral diencephalon, with a V-shaped configuration that bordered
      the posterior boundary of the retinal axons, and a rostral raphe extension that
      ran across the decussating axons in the chiasm. Thus, the CS epitope is
      implicated in patterning the course of early retinal axons and in regulating axon
      divergence in the chiasm. At the lateral region of the chiasm, where the retinal
      axons cross the midline and approach the optic tract, a CS-immunopositive region
      coincided with the region in which active sorting of dorsal retinal axons from
      ventral retinal axons occurs. Moreover, at the threshold of the optic tract, the
      immunoreactive CS was restricted only to the deep part of the optic fiber layer,
      suggesting an inhibitory role of the CS epitope in repelling newly arrived axons
      to superficial regions of the optic tract during the development of chronotopic
      order at this part of the retinofugal pathway.

PMID- 10660895
TI  - Pallidal and cerebellar afferents to pre-supplementary motor area thalamocortical
      neurons in the owl monkey: a multiple labeling study.
AB  - In the present study, we determined where thalamic neurons projecting to the pre
      supplementary motor area (pre-SMA) are located relative to pallidothalamic and
      cerebellothalamic inputs and nuclear boundaries. We employed a triple-labeling
      technique in the same owl monkey (Aotus trivirgatus). The cerebellothalamic
      projections were labeled with injections of wheat germ agglutinin conjugated to
      horseradish peroxidase, and the pallidothalamic projections were labeled with
      biotinylated dextran amine. The pre-SMA was identified by location and movement
      patterns evoked by intracortical microstimulation and injected with the
      retrograde tracer cholera toxin subunit B. Brain sections were processed
      sequentially using different chromogens to visualize all three tracers in the
      same section. Alternate sections were processed for Nissl cytoarchitecture or
      acetylcholinesterase chemoarchitecture for nuclear boundaries. The cerebellar
      nuclei primarily projected to posterior (VLp), medial (VLx), and dorsal (VLd)
      divisions of the ventral lateral nucleus; the pallidum largely projected to the
      anterior division (VLa) of the ventral lateral nucleus and the parvocellular part
      of the ventral anterior nucleus (VApc). However, we also found zones of
      overlapping projections, as well as interdigitating foci of pallidal and
      cerebellar label, particularly in border regions of the VLa and VApc. Thalamic
      neurons labeled by pre-SMA injections occupied a wide band and were especially
      concentrated in the VLx and VApc, cerebellar and pallidal territories,
      respectively. Labeled thalamocortical neurons overlapped cerebellar inputs in the
      VLd and VApc and overlapped pallidal inputs in the VLa and the ventral medial
      nucleus. The results demonstrate that inputs from both the cerebellum and globus
      pallidus are relayed to the pre-SMA.

PMID- 10660896
TI  - Somatodendritic localization of 5-HT1A and preterminal axonal localization of 5
      HT1B serotonin receptors in adult rat brain.
AB  - The 5-HT1A and 5-HT1B receptors of serotonin play important roles as auto- and
      heteroreceptors controlling the release of serotonin itself and of other
      neurotransmitters/modulators in the central nervous system (CNS). To determine
      the precise localization of these receptors, we examined their respective
      cellular and subcellular distributions in the nucleus raphe dorsalis and
      hippocampal formation (5-HT1A) and in the globus pallidus and substantia nigra (5
      HT1B), using light and electron microscopic immunocytochemistry with specific
      antibodies. Both immunogold and immunoperoxidase preembedding labelings were
      achieved. In the nucleus raphe dorsalis, 5-HT1A immunoreactivity was found
      exclusively on neuronal cell bodies and dendrites, and mostly along extrasynaptic
      portions of their plasma membrane. After immunogold labeling, the density of
      membrane-associated 5-HT1A receptors could be estimated to be at least 30-40
      times that in the cytoplasm. In the hippocampal formation, the somata as well as
      dendrites of pyramidal and granule cells displayed 5-HT1A immunoreactivity, which
      was also prominent on the dendritic spines of pyramidal cells. In both substantia
      nigra and globus pallidus, 5-HT1B receptors were preferentially associated with
      the membrane of fine, unmyelinated, preterminal axons, and were not found on axon
      terminals. A selective localization to the cytoplasm of endothelial cells of
      microvessels was also observed. Because the 5-HT1A receptors are somatodendritic,
      they are ideally situated to mediate serotonin effects on neuronal firing, both
      as auto- and as heteroreceptors. The localization of 5-HT1B receptors to the
      membrane of preterminal axons suggests that they control transmitter release from
      nonserotonin as well as serotonin neurons by mediating serotonin effects on
      axonal conduction. The fact that these two receptor subtypes predominate at
      extrasynaptic and nonsynaptic sites provides further evidence for diffuse
      serotonin transmission in the CNS.

PMID- 10660898
TI  - Cell proliferation and cell death in the developing chick inner ear: spatial and
      temporal patterns.
AB  - Morphogenesis of the inner ear is a complex process in which the balance of cell
      division and death is presumed to play an important role. Surprisingly, there are
      no reports of a systematic comparison of these two processes in individual ears
      at different stages of development. This study presents such an analysis for the
      chicken otocyst at stages 13-29 (embryonic days 2.5-6). To detect proliferating
      cells, we used exposure to bromodeoxyuridine. To detect apoptotic cells, we used
      nuclear condensation and fragmentation or terminal dUTP nick-end labeling
      (TUNEL). The spatial and temporal locations of proliferating and dying cells were
      mapped across serial sections, revealing regional differences in proliferation
      within the otocyst epithelium that are more complex than previously reported. In
      addition, almost all of the previously identified "hot spots" of cell death
      correspond spatially to regions of reduced cell proliferation. An exception is
      the ventromedial hot spot of cell death, which is intermingled with proliferating
      cells when it first appears at stages 19-23 before becoming a cold spot of
      proliferation. The results further show that the inferior part of the otocyst has
      a high level of proliferation, whereas the superior part does not. Since the
      superior part of the otocyst demonstrates outward expansion that is comparable to
      the inferior part, it appears that regional outgrowth of the otic vesicle is not
      necessarily coupled to cell proliferation. This study provides a basis for
      exploring the regulation and function of cell proliferation and cell death during
      inner ear morphogenesis.

PMID- 10660897
TI  - Lateralized and widespread brain activation during transient blood pressure
      elevation revealed by magnetic resonance imaging.
AB  - The location and possible lateralization of structures mediating autonomic
      processing are not well-described in the human. Functional magnetic resonance
      imaging procedures were used to demonstrate signal changes in multiple brain
      sites during blood pressure challenges. Magnetic resonance signals in brain
      tissue were visualized with a 1.5 Tesla scanner in 11 healthy volunteers (22-37
      years), by using echo-planar procedures. Images were collected during baseline
      states and three pressor challenges: cold application to the hand or forehead,
      and a Valsalva maneuver. Image values from experimental conditions were compared
      with corresponding baseline values on a voxel-by-voxel basis to identify brain
      regions responsive to physiologic activation. Probability maps (P < 0.01) of
      voxel changes, with Bonferroni corrections for multiple comparisons, were
      determined, and amplitude of signal changes associated with significance maps
      were pseudocolored and overlaid on anatomic images. The time courses and extent
      of signal alterations in defined unilateral regions were followed and compared
      with changes in corresponding regions on the contralateral side. Pressor
      challenges elicited significant regional signal intensity changes within the
      orbitomedial prefrontal cortex, temporal cortex, amygdala, hippocampal formation,
      thalamus, and hypothalamus. Cerebellar, midbrain, and pontine areas were also
      recruited. Signal changes, especially at forebrain sites, were often highly
      lateralized. The findings indicate that (1) transient, behaviorally-coupled
      cardiovascular challenges elicit discrete activity changes over multiple brain
      sites, and (2) these activity changes, especially in specific prefrontal and
      temporal forebrain regions and cerebellum, are often expressed unilaterally, even
      to a bilateral challenge.

PMID- 10660899
TI  - Human nuclear respiratory factor 2 alpha subunit cDNA: isolation, subcloning,
      sequencing, and in situ hybridization of transcripts in normal and monocularly
      deprived macaque visual system.
AB  - Nuclear respiratory factor 2 (NRF-2) has been shown to contribute to the
      transcriptional regulation of a number of subunits of respiratory chain enzymes,
      including cytochrome c oxidase (CO). Our recent study demonstrated a parallel
      distribution of the alpha subunit proteins of NRF-2 (NRF-2 alpha) with CO in the
      monkey striate cortex, and that it can be regulated by neuronal activity. To
      determine whether this regulation is at the transcriptional level, the present
      study examined the expression of NRF-2 alpha mRNA in normal and monocularly
      deprived adult monkeys. A partial NRF-2 alpha cDNA was isolated from a human
      brain cDNA library. Sequence analysis revealed that it shared 99% identity with
      the published sequence from human HeLa cells. Riboprobes of NRF-2 alpha was
      generated and labeled with digoxigenin-11-UTP for in situ hybridization. The
      expression pattern of NRF-2 alpha mRNA in the normal striate cortex paralleled
      that of CO activity. It was highly expressed in layers IVC and VI, which
      contained high levels of CO, and more densely expressed in puffs of layers II and
      III than in interpuffs. In monkeys monocularly treated with tetrodotoxin for 1
      day to 2 weeks, both NRF-2 alpha expression and CO activity were reduced in
      deprived ocular dominance columns of the visual cortex and in deprived layers of
      the lateral geniculate nucleus. These data indicate that, in the normal and
      visually deprived adult monkeys, NRF-2 alpha is regulated by neuronal activity at
      the transcriptional level.

PMID- 10660900
TI  - Morphological and electrophysiological properties of neurones in the dorsal vagal
      complex of the rat activated by arterial baroreceptors.
AB  - This study physiologically identifies and anatomically describes arterial
      baroreceptive neurones in the nucleus tractus solitarii of the rat. Neurones were
      recorded using neurobiotin-containing whole cell patch electrodes in a working
      heart-brainstem preparation and characterized physiologically as arterial
      baroreceptive in response to stimulation of the aortic arch and/or ipsilateral
      carotid sinus. Fifteen of 84 neurones tested were arterial baroreceptive, 7 of 8
      were morphologically identified as located in the solitary tract nucleus (NTS),
      and 1 of 8 was located in the dorsal vagal nucleus. The seven NTS neurones had a
      resting membrane potential of -52 +/- 3.6 mV and a membrane input resistance of
      233 +/- 38 M omega. Action potential height was 62 +/- 4.2 mV, width at half
      amplitude 1.46 +/- 0.38 ms, and duration of after-hyperpolarization 1.7 +/- 2.33
      ms. In six of eight neurones labelled there was an invariant excitatory synaptic
      input (latency 3.95 +/- 0.3 ms) to stimulation of the solitary tract. Labelled
      somata were dorsomedial or medial to the solitary tract from -0.3 mm to +1.5 mm
      with regard to obex. Neurones had three to eight primary dendrites, and branches
      often entered the solitary tract and also extended across the ipsilateral NTS.
      Axons, which were mostly unmyelinated with boutons of the en passant variety,
      could ramify within the NTS while the main axon exited the NTS (n = 4/6), in the
      direction of the ipsilateral ventral medulla (n = 5/6). This is the first
      morphological and localisation data of physiologically characterised arterial
      baroreceptive NTS neurones in the rat. By comparing labelled cells with each
      other as well as with other unidentified cells, we conclude that NTS arterially
      baroreceptive neurones are morphologically and physiologically heterogenous.

PMID- 10660901
TI  - Sequence and distribution of pro-opiomelanocortin in the pituitary and the brain
      of the chicken (Gallus gallus).
AB  - Although pro-opiomelanocortin (POMC) is a well-known hormone precursor in many
      species, molecular information about avian POMCs is still relatively scarce. In a
      former study (Berghman et al., [1998] Mol Cell Endocrinol. 142:119-130) the
      nucleotide and amino acid sequence of N-terminal POMC in the chicken were
      reported. To complete the nucleotide sequence of the precursor, rapid
      amplification of 3' and 5' cDNA end reactions were performed and the polymerase
      chain reaction (PCR) products were cloned and sequenced. The chicken POMC coding
      region appears to consist of 678 base pairs in the pituitary and also in the
      hypothalamus, as assessed by reverse transcriptase PCR. Overall nucleotide
      sequence homology with other species ranges from 41% (in bovine) to 57% (in rat).
      The distribution of the POMC mRNA in pituitary and brain was analyzed by in situ
      hybridization by using 33P-labelled oligonucleotides. Expression of POMC mRNA in
      the pituitary was restricted to the cephalic lobe, whereas in the brain, the
      signal was limited to the hypothalamic region. As assessed by Northern blot
      analysis, the length of the POMC mRNA in both the pituitary and the hypothalamus
      was approximately 1,200 nucleotides. By using antisera to N-terminal POMC, alpha
      melanotropin and beta-endorphin, POMC-containing cells were observed in the
      cephalic lobe of the pituitary and immunopositive perikarya were localized in the
      infundibular nucleus and median eminence of the hypothalamus. Immunoreactive
      fibers were found in the preoptic area and in the medial basal hypothalamus
      surrounding the third ventricle and more dorsally in the thalamus. Double
      staining experiments in the pituitary clearly indicated a complete overlap of the
      signals generated by these antisera.

PMID- 10660902
TI  - Dissociating automatic and intentional processes in children's eyewitness memory.
AB  - Two experiments investigated the contribution of automatic and intentional memory
      processes to 5- and 8-year-old children's acceptance of misinformation. Children
      were presented with a picture story followed by misleading postevent details that
      either were read to participants or were self-generated in response to semantic
      and perceptual hints. Children were then given a recognition test under 2
      instructional conditions. In the inclusion condition children reported whether
      they remembered items from either of the previous phases. In the exclusion
      condition children were instructed to exclude postevent suggestions. Children
      were more likely to accept misled-generate items compared to misled-read items in
      the inclusion condition, but the opposite was the case under exclusion
      instructions. Both automaticity and recollection (cf. L. L. Jacoby, 1991)
      influenced misinformation acceptance, but the role of automatic processes
      declined with age.

PMID- 10660903
TI  - Sequential pointing in children and adults.
AB  - The development of visuomotor control in sequential pointing was investigated in
      6- to 10-year-old children and in adults. In 3 experiments we manipulated task
      difficulty by changing the number, the size, and the spacing of the targets in
      the sequences. In Experiment 4, only 1 movement was required; we varied
      independently the distance between targets and the distance of the starting point
      from the participant's body. Children's temporal and spatial parameters of the
      motor sequences showed large age-dependent trends, but did not reach the adult
      values. Comparison of performance across levels of difficulty and ages suggests
      that motor development is not a uniform fine-tuning of stable strategies.
      Instead, we argue that each stage of development is best characterized by the set
      of strategic components potentially available at that stage, and by the (age
      dependent) rules for the selection of components in a given context.

PMID- 10660904
TI  - The effect of Kana literacy acquisition on the speech segmentation unit used by
      Japanese young children.
AB  - Three experiments were undertaken to investigate whether young children's
      segmentation units would change as they learned to read kana letters, which
      represent morae (subsyllabic rhythmic units). The first 2 experiments used a
      vocal-motor segmentation task to examine whether 4- to 6-year-olds preferred to
      segment spoken words containing the special syllables CVN, CVQ, or CV: into
      syllables or into morae. The third experiment used a target monitoring task for
      CVN to examine whether children's detection of the target syllable in a series of
      words would vary depending on the moraic constitution of the target and the
      moraic-syllabic status of the word initial in which the target was embedded.
      Results indicated that the children's conscious segmentation of words, except for
      those having a geminate stop consonant (CVQ), developed from being a mixture of
      syllable- and mora-based to being predominantly mora-based as they learned to
      read kana letters. The tendency toward mora-based segmentation was also found in
      the target monitoring task, which required segmentation at a less conscious
      level.

PMID- 10660905
TI  - Molecular scaffold-based design and comparison of combinatorial libraries focused
      on the ATP-binding site of protein kinases.
AB  - Compound libraries were designed to target specifically the ATP cofactor-binding
      site in protein kinases by combining knowledge- and diversity-based design
      elements. A key aspect of the approach is the identification of molecular
      building blocks or scaffolds that are compatible with the binding site and
      therefore capture some aspects of target specificity. Scaffolds were selected on
      the basis of docking calculations and analysis of known inhibitors. We have
      generated 75 molecular scaffolds and applied different strategies to compute
      diverse compounds from scaffolds or, alternatively, to screen compound databases
      for molecules containing these scaffolds. The resulting libraries had a similar
      degree of molecular diversity, with at most 12% of the compounds being identical.
      However, their scaffold distributions differed significantly and a small number
      of scaffolds dominated the majority of compounds in each library.

PMID- 10660906
TI  - Binning schemes for partition-based compound selection.
AB  - Partition-based approaches to the selection of structurally diverse sets of
      compounds involve allocating compounds to the individual elements of a
      multidimensional grid that spans the available chemical space. The space is
      defined by an appropriate set of chemical properties, with subranges of the
      values of these properties being used to define the constituent elements, or
      bins. This article compares several binning schemes in terms of their ability to
      provide an even distribution of compounds across the available space and to
      maximise the numbers of active molecules identified in simulated assay
      experiments.

PMID- 10660907
TI  - Solution conformation of phakellistatin 8 investigated by molecular dynamics
      simulations.
AB  - Phakellistatin 8 is a cyclic decapeptide that inhibits cancer cell growth and has
      sequence and structure similar to antamanide. In molecular dynamics simulations
      of phakellistatin 8 in water, the decapeptide ring undergoes a conformational
      change from the saddle-like crystal structure to a more elongated conformation by
      a transition of the Tyr9 main chain from the alpha L to an extended structure.
      This is coupled to the loss of the NH9-O6 beta-turn hydrogen bond and the
      transient dissociation of the Pro7-Tyr9 side-chain packing. Furthermore, the
      water molecule acting as a transannular bridge forms an additional hydrogen bond
      with phakellistatin 8, namely with the NH group of Val5 besides those already
      present in the crystal structure, i.e., with the NH of Ile10 and the CO of Leu6.
      The alpha-turn hydrogen bond between the Phe4 amide hydrogen and the Ile10
      carbonyl oxygen is always present. The solution conformations of the two cyclic
      decapeptides are similar, in particular in the region involving the NH4-O10 alpha
      turn of phakellistatin 8 and the NH5-O1 alpha turn of antamanide. The simulation
      results suggest that in aqueous solution the conformation of phakellistatin 8 is
      more extended than in the crystalline state, and on a nanosecond time scale
      phakellistatin 8 is more flexible than antamanide.

PMID- 10660908
TI  - A novel approach to the analysis of substituent effects: quantitative description
      of ionization energies and gas basicity of amines.
AB  - In this work, a new topological approach based on simple matrix algebra is
      introduced to explore substituent effects at the level of atomic additivity in
      the absence of significant resonance contributions. In the framework of the
      suggested method, all atoms are classified according to element and valence
      state. The sums of the inverse squared distances between the substituent atoms
      and the reaction centre of the molecule are used as operational parameters in the
      present method. The approach implies atomic level of consideration of inductive
      and steric effects and allows for quantification of substituent effects without
      the use of pre-established group substituent constants. The practical application
      of the model is illustrated by the quantitative interpretation of ionization
      energies and gas basicity of a broad range of amines. Further development of the
      elaborated approach is also discussed.

PMID- 10660909
TI  - Three-dimensional pharmacophore hypotheses of octopamine receptor responsible for
      the inhibition of sex-pheromone production in Helicoverpa armigera.
AB  - Three-dimensional pharmacophore hypotheses were built on the basis of a set of
      nine octopamine (OA) agonists responsible for the inhibition of sex-pheromone
      production in Helicoverpa armigera. Of the 10 models generated by the program
      Catalyst/Hypo, hypotheses including hydrogen-bond acceptor (HBA), hydrophobic
      (Hp), and hydrophobic aliphatic (HpAl) features were considered important and
      predictive in evaluating OA agonists. An HBA and four hydrophobic features are
      the minimum components of an effective OA agonist-binding hypothesis, which
      resembles the results of binding activity to locust OAR3. Active agonists mapped
      well onto all of the features of the hypothesis, such as HBA, Hp, and HpAl
      features. On the other hand, inactive compounds lacking binding affinity were
      shown to be poorly capable of achieving an energetically favorable conformation
      shared by the active molecules in order to fit the 3D chemical feature
      pharmacophore models. Those hypotheses are considered useful in designing new
      leads for more active compounds. Further research on the comparison of models
      from agonists may help elucidate the mechanisms of OA receptor-ligand
      interactions.

PMID- 10660910
TI  - The art of molecular graphics. The 1998 Molecular Graphics Art Show.

PMID- 10660911
TI  - Python: a programming language for software integration and development.

PMID- 10660912
TI  - Quantum Chemistry Program Exchange.

PMID- 10660913
TI  - New millennium, old dilemmas.

PMID- 10660914
TI  - Managing hot flashes after breast cancer.

PMID- 10660915
TI  - The Clinical Trials Office as a shared resource.

PMID- 10660916
TI  - The evolution of an institution-based cancer information program.

PMID- 10660917
TI  - Research nurses play a vital role in clinical trials.

PMID- 10660918
TI  - How to best use a protocol development liaison.

PMID- 10660919
TI  - A computerized database assists in the management of clinical trials.

PMID- 10660920
TI  - Reorganizational plan helps staff manage workloads.

PMID- 10660921
TI  - Evaluation of nurses and genetic counselors as providers of education about
      breast cancer susceptibility testing.
AB  - PURPOSE/OBJECTIVES: To compare outcomes of pretest education about breast cancer
      susceptibility testing provided by nurses and genetic counselors. DESIGN: Two
      group, post-test only evaluation of an educational intervention. SETTING: A
      tertiary care hospital. SAMPLE: 87 women who had a first-degree relative with
      premenopausal breast cancer; six specially-trained providers (four genetic
      counselors and two nurses). METHODS: Self-administered questionnaire completed
      immediately following education sessions. MAIN RESEARCH VARIABLES: Subjects'
      understanding of the limitations of testing, perceived autonomy in decision
      making, and satisfaction; partnership as perceived by subjects and providers.
      FINDINGS: After the sessions, 62% of subjects understood the limitations of
      testing, 98% reported a high degree of perceived autonomy in decision making, 81%
      were highly satisfied with the session, and 91% reported forming a partnership
      with their providers. Lower perceived partnership reported by genetic counselors
      was the only significant difference by provider type. CONCLUSIONS: With training
      and supervision, nurses and genetic counselors can be equally effective in
      providing education about genetic testing for breast cancer susceptibility in
      research settings. Additional research is needed to determine the outcomes of
      education provided in clinical settings. IMPLICATIONS FOR NURSING PRACTICE: As
      the demand for education about genetic testing for cancer susceptibility
      increases, nurses need to be educated and trained to provide this service.

PMID- 10660922
TI  - Acupressure for nausea: results of a pilot study.
AB  - PURPOSE/OBJECTIVES: To compare differences in nausea experience and intensity in
      women undergoing chemotherapy for breast cancer between those receiving usual
      care plus acupressure training and treatment and those receiving only usual care.
      DESIGN: Single-cycle, randomized clinical trial. SETTING: Outpatient oncology
      clinic in a major teaching medical center and a private outpatient oncology
      practice. SAMPLE: Seventeen women participated in the study. The typical
      participant was 49.5 years old (SD = 6.0), Caucasian (59%), not married/partnered
      (76%), on disability (53%), born a U.S. citizen (76%), and heterosexual (88%);
      lived alone (59%); had at least graduated from high school (100%); and had an
      annual personal income of $50,000 or greater (65%). METHODS: The intervention
      included finger acupressure bilaterally at P6 and ST36, acupressure points
      located on the forearm and by the knee. Baseline and poststudy questionnaires
      plus a daily log were used to collect data. MAIN RESEARCH VARIABLES: Nausea
      experience measured by the Rhodes inventory of Nausea, Vomiting, and Retching and
      nausea intensity. FINDINGS: Significant differences existed between the two
      groups in regard to nausea experience (p < 0.01) and nausea intensity (p < 0.04)
      during the first 10 days of the chemotherapy cycle, with the acupressure group
      reporting less intensity and experience of nausea. CONCLUSIONS: Finger
      acupressure may decrease nausea among women undergoing chemotherapy for breast
      cancer. IMPLICATIONS FOR NURSING PRACTICE: This study must be replicated prior to
      advising patients about the efficacy of acupressure for the treatment of nausea.

PMID- 10660923
TI  - Rituximab: a new monoclonal antibody therapy for non-Hodgkin's lymphoma.
AB  - PURPOSE/OBJECTIVES: To review the use of monoclonal antibodies (MAbs),
      specifically rituximab, in the treatment of non-Hodgkin's lymphoma (NHL) and to
      describe the nursing management of patients receiving rituximab. DATA SOURCES:
      Published articles, abstracts, book chapters, drug manufacturer, lectures, and
      personal experience with rituximab. DATA SYNTHESIS: NHL ranks sixth among
      malignancies in incidence and mortality in the United States. The most common
      subtype, low-grade follicular lymphoma, is considered incurable. Lack of
      specificity may limit the usefulness of chemotherapy for low-grade follicular
      NHL. However, MAb therapy may deliver a cytotoxic effect specifically to the
      targeted cancer cell. Rituximab is the first MAb approved for cancer therapy.
      Clinical trials indicate that rituximab is efficacious and safe for recurrent or
      chemotherapy-resistant, B-cell, low-grade NHL. Infusion-related side effects are
      the most common and can be managed effectively by following the infusion rate
      recommendations. CONCLUSIONS: Monoclonal antibody therapy is an effective and
      safe treatment modality for cancer. Infusion-related side effects are managed
      effectively by following infusion rate recommendations. IMPLICATIONS FOR NURSING
      PRACTICE: Nurses need to be knowledgeable about MAb therapy to educate patients
      and families regarding the mechanism of action and side-effect profiles of these
      agents, which often differ from those of chemotherapy or radiation therapy.
      Nurses should be familiar with the unique side effects of rituximab and also
      specific infusion-rate instructions, measures to reduce the incidence of side
      effects, and criteria for stopping the infusion when necessary.

PMID- 10660925
TI  - Mother and child interactions about the mother's breast cancer: an interview
      study.
AB  - PURPOSE/OBJECTIVES: To describe mothers' reported methods of interacting with the
      mothers' school-age children about their breast cancer. DESIGN: Qualitative.
      SETTING/SAMPLE: 19 mothers newly diagnosed with breast cancer. Mothers received
      treatment for their illness in the Pacific Northwest. Mothers had at least one
      child between 7 and 12 years old at the time of diagnosis. METHODS: Case
      intensive, in-home, semistructured interviews were audiotaped, transcribed, and
      inductively coded into four conceptual domains and 16 categories of behavioral
      strategies used by the mothers to interact with their children about the breast
      cancer. MAIN RESEARCH VARIABLES: Behavioral strategies used by mothers when
      interacting with the children about the breast cancer and when providing children
      with support. FINDINGS: Mothers used a number of methods to bring children into
      the mothers' breast cancer experience. The conceptual domains included talking
      about the breast cancer, explaining treatment and care, providing experiences,
      and doing things to help children cope. CONCLUSIONS: The dominant pattern in the
      interview data was for mothers to assume a teacher/educator role with the
      children about the cancer, not an interactive, emotive-expressive parenting role.
      Most mothers used technical biomedical language; did not give evidence of
      systematically checking on the children's understanding of what they were told;
      did not elicit the children's concerns; and exposed the children to emotionally
      laden or potentially frightening images, words, or experiences. IMPLICATIONS FOR
      NURSING PRACTICE: Programs and materials need to be developed that help mothers
      work from a model of parenting that includes developmentally appropriate
      language, facilitates the children's expression of questions and feelings, links
      the mothers with the children's understanding of the illness, and assists the
      children to better manage what is happening related to the breast cancer.

PMID- 10660924
TI  - The effects of foot reflexology on anxiety and pain in patients with breast and
      lung cancer.
AB  - PURPOSE/OBJECTIVES: To test the effects of foot reflexology on anxiety and pain
      in patients with breast and lung cancer. DESIGN: Quasi-experimental, pre/post,
      crossover. SETTING: A medical/oncology unit in a 314-bed hospital in the
      southeastern United States. SAMPLE: Twenty-three inpatients with breast or lung
      cancer. The majority of the sample were female, Caucasian, and 65 years or older;
      had 12 or fewer years of education and an annual income of $20,000 or more; and
      were receiving regularly scheduled opioids and adjuvant medications on the
      control and intervention day. METHODS: Procedures included an intervention
      condition (foot reflexology to both feet for 30 minutes total by a certified
      reflexologist) and a control condition for each patient (with at least a two-day
      break). No changes were made in patients' regular schedule or medications. MAIN
      RESEARCH VARIABLES: Anxiety and pain. FINDINGS: Following the foot reflexology
      intervention, patients with breast and lung cancer experienced a significant
      decrease in anxiety. One of three pain measures showed that patients with breast
      cancer experienced a significant decrease in pain. CONCLUSIONS: The significant
      decrease in anxiety observed in this sample of patients with breast and lung
      cancer following foot reflexology suggests that this may be a self-care approach
      to decrease anxiety in this patient population. IMPLICATIONS FOR NURSING
      PRACTICE: Professionals and lay people can be taught reflexology. Foot
      reflexology is an avenue for human touch, can be performed anywhere, requires no
      special equipment, is noninvasive, and does not interfere with patients' privacy.

PMID- 10660926
TI  - Focus on health promotion: self-efficacy in oncology nursing research and
      practice.
AB  - PURPOSE/OBJECTIVES: To discuss self-efficacy in oncology nursing research and
      practice in promoting health for people with cancer. DATA SOURCES: Published
      articles, abstracts, and books; consultations. DATA SYNTHESIS: Self-efficacy has
      much merit as a concept to guide oncology nursing research and practice related
      to health promotion. It has strong predictive capability in nononcology
      populations for determining the likelihood of individuals engaging in health
      promotion behaviors. In oncology, it has been an effective determinant to predict
      disease prevention and early-detection behaviors and adaptation to cancer.
      CONCLUSIONS: Self-efficacy provides prescriptive specificity to guide clinical
      interventions to promote health in people with cancer. IMPLICATIONS FOR NURSING
      PRACTICE: Exercise for people with cancer recently has been emphasized, and
      specific examples of cancer nursing research and practice using self-efficacy to
      increase participation in this health-promotion behavior have been suggested.
      Research that tests this concept further as a basis for health promotion in
      people with cancer is needed.

PMID- 10660927
TI  - The nursing interventions classification: a language to define nursing.
AB  - PURPOSE/OBJECTIVES: To discuss the Nursing Interventions Classification (NIC)
      framework and its relationship to oncology nursing. DATA SYNTHESIS: NIC is a
      standardized language that identifies all interventions performed by nurses. The
      three-tiered taxonomy consists of six domains, 27 classes, and 433 interventions
      with related nursing activities. Each intervention consists of a label describing
      the concept, the definition of the concept, and a set of representative
      activities or actions. CONCLUSIONS: Although differences exist in the core
      interventions identified by the Oncology Nursing Society and the Association of
      Pediatric Oncology Nurses as critical to their practice, the NIC research team,
      after surveying both organizations, found numerous similarities in the
      possibilities for clinical application. IMPLICATIONS FOR NURSING PRACTICE: NIC
      provides a standardized language to enable oncology nurses to describe and
      demonstrate their work and contributions to lawmakers, healthcare policy makers,
      and the public.

PMID- 10660928
TI  - The diagnosis of prion diseases.
AB  - Prion diseases of humans and other animals have clinical, economic and political
      significance. Pre-mortem diagnosis is therefore of great importance. Clinical
      diagnostic criteria and the current status of the available diagnostic tests are
      reviewed and possible future developments discussed. Presently, most diagnostic
      tests are indirect, relying on findings that may not be confined to prion
      diseases rather than on their particular intrinsic nature. They are therefore not
      absolutely specific nor are they 100% sensitive. The electroencephalogram (EEG),
      cerebral imaging and cerebrospinal fluid (CSF) analysis are the main techniques
      employed. However, there is hope that useful blood tests could be developed which
      would be simpler and less invasive. Also, there is hope that more specific tests
      will become available.

PMID- 10660929
TI  - The evolution of immunoassay technology.
AB  - Since they were first utilized, immunoassays have witnessed phenomenal growth in
      the range and scope of their applications. A vast array of different labels and
      assay strategies has been developed to meet the requirements of sensitivity,
      accuracy and convenience. The development of increasingly sensitive labels and
      detection equipment has seen a drastic improvement in the sensitivity of
      immunoassay systems, allowing an ever-increasing range of analytes to be measured
      accurately. At the same time, simple to use, inexpensive assay systems have been
      developed with the necessary reliability, accuracy and sensitivity to bring
      immunoassay technology to much more diverse areas such as home testing, near
      patient monitoring, and large screening programmes in developing countries.
      Recent developments in molecular biology techniques have made possible the
      production of fusion antibody conjugates, which can lead to further improvements
      in sensitivity and cost of reagents, as well as possibly revolutionizing the
      production of monoclonal antibodies. However, dissatisfaction with various
      aspects of existing immunoassay technology will necessarily lead to the continued
      development of this already widely diverse subject.

PMID- 10660930
TI  - Detection of viruses in livestock.
AB  - Diseases caused by viruses are a constant and major problem for livestock
      production world wide. The diseases range from highly contagious acute forms with
      high mortality, to chronic disabling diseases with an insidious effect on
      production. Such diseases cannot be regarded as static in nature due to the
      highly mutable nature of viruses and their direct selection at the host level and
      indirect selection in vectors, inducing changes in pathogenicity. Considerable
      efforts are needed to control these diseases including accurate and rapid
      diagnosis using both classical and emerging technologies. The methods used are
      based on both serological and molecular biological based methods. The ELISA and
      use of monoclonal antibodies are significant in the serological field whereas the
      Polymerase Chain reaction (PCR) and its direct and indirect uses for identifying
      (sequencing) and amplification of gene products, is vital to both research and
      applied fields. Both areas have to be used in a complementary way in the
      diagnosis of virus diseases.

PMID- 10660931
TI  - Diagnosis of schistosomiasis: antibody detection, with notes on parasitological
      and antigen detection methods.
AB  - Schistosomiasis remains a serious world-wide public health problem with a still
      unfulfilled need for routine cost-effective methods of diagnosis. Such methods
      are required not only for people in endemic areas, but increasingly for tourists
      who may have become infected during visits to such places. This article reviews
      the wide range of immunoassays and antigenic preparations that have been shown to
      have potential for diagnosis of schistosomiasis by the indirect method of
      antibody detection. Antigens in native form derived from cercariae, adult worms
      and eggs are considered, as well as schistosome antigens produced by recombinant
      DNA technology and the schistosome cross-reactive antigen, keyhole limpet
      haemocyanin (KLH). Respective advantages and disadvantages of antibody detection,
      circulating antigen detection and parasitological methods of diagnosis are
      analysed. It is suggested that due to the relative insensitivity of both
      parasitology and antigen detection, antibody detection methods could find
      increasing use in situations of low infection intensity.

PMID- 10660932
TI  - Molecular and immunodiagnosis of human filarial nematode infections.
AB  - The filarial nematodes Wuchereria bancrofti, Brugia malayi and Onchocerca
      volvulus represent major public health problems in the Tropics. Effective
      diagnosis of infection with these parasites is required both for administration
      of drugs to infected individuals and for monitoring of control programs. However
      parasitological diagnosis is associated with a number of problems including
      frequently inadequate sensitivity, long pre-patency of infection and
      inconvenience for patients. For these reasons there has been considerable effort
      expended in developing other forms of diagnosis, in particular immunoassays for
      measuring antibody and circulating parasite antigen as well as molecular-biology
      based assays for detecting parasite DNA. This article reviews the progress and
      achievements obtained to date. The latter include the development of ELISAs
      employing recombinant antigen for detection of antibody to O. volvulus which have
      both high sensitivity and specificity, the commercial availability of
      immunoassays to measure circulating antigen in W. bancrofti infection and the
      generation of specific DNA-based detection systems for all three parasites.

PMID- 10660933
TI  - Molecular detection of parasitic protozoa.
AB  - The development of molecular diagnostic methods, particularly those utilizing PCR
      for the detection of parasitic protozoa will contribute greatly to the
      identification and control of these pathogens, by increasing speed of diagnosis,
      specificity and sensitivity, reproducibility and case of interpretation. PCR
      methods are not without their problems however, and there is a need for
      laboratory procedures to be refined before PCR-based assays are accepted as the
      tools of choice for the routine detection of protozoan parasites. The application
      of PCR detection to various parasites is discussed.

PMID- 10660934
TI  - Molecular diagnosis of parasitic nematodes.
AB  - There is an essential requirement for highly sensitive tools that will
      differentiate nematode parasites of animals and plants to the species level. For
      studying host range, genetic variation, virulence and resistance, the
      availability of well defined populations is vital. Many nematode species cannot
      be identified with certainty using traditional morphological or morphometric
      techniques. This is particularly the case for the more accessible developmental
      stages that, depending on the particular group concerned, live as eggs and larvae
      in the environment or as micro-filariae that circulate in the blood or inhabit
      the skin. Morphological identification of these stages requires specialized
      expertise and is extremely time consuming. Immunological assays have their place
      in nematode identification but they do not discriminate between current and
      previous infections, an essential requirement in many epidemiological and
      prevalence studies. In addition to being highly sensitive, DNA-based methods of
      detection define present over past infection and are not dependent on the
      parasite stage. Many types of methodology are available for the detection and
      definition of nematode DNA. This paper reviews these methods citing examples that
      have been used with success in the laboratory as well as the field.

PMID- 10660935
TI  - Detection of parasites in food.
AB  - The importance of foodborne parasitic zoonoses remains high in many regions of
      the world. Although control efforts have been exerted for quite some time,
      overall progress has not been satisfactory, even in many well developed
      countries. An important drawback in control programmes for parasites such as
      Trichinella, Toxoplasma and Taenia has been the absence of rapid, accurate and
      sensitive diagnostic tests for these meatborne parasites. However, the rapid
      advances in the molecular biology of these organisms has yielded concomitant
      gains in precision of detection. This review highlights these advances and their
      impact or potential application to the control of foodborne parasites.

PMID- 10660936
TI  - Detection of parasites in the environment.
AB  - The environmental route of transmission is important for many protozoan and
      helminth parasites, with water, soil and food being particularly significant.
      Both the potential for producing large numbers of transmissive stages and their
      environmental robustness (with the ability to survive in moist microclimates for
      prolonged periods of time) pose persistent threats to public and veterinary
      health. Increased demands made on natural resources increase the likelihood of
      encountering environments and produce contaminated with parasites. In the last 30
      years, endemic and epidemic waterborne and foodborne outbreaks in developed
      countries have led to a reappraisal of conventional isolation and detection
      methods. While these methods have proved invaluable in our understanding of
      environmental transmission routes for helminths, they have been less effective
      for the parasitic protozoa. Robust, efficient detection, viability and typing
      methods are required to assess risk and to further epidemiological understanding.
      Greater awareness of parasite contamination of our environment and its impact on
      health has precipitated the development of better detection methods. Currently,
      nowhere is this more apparent than with Cryptosporidium, with a broad range of
      immunological, microscopical and molecular methods available. The upsurge in
      molecular techniques, particularly the polymerase chain reaction, for determining
      occurrence and viability have brought with them the added benefits of increased
      sensitivity and specificity, yet many methods still have to be shown to address
      these issues consistently in the field. Rapid commercialization of reagents and
      standardization of methods provide consistency. The advances identified in non
      destructive and destructive methods for the protozoa have application for
      helminths and emerging pathogens and should determine the importance of the
      matrices involved in the environmental transmission of parasites, further
      safeguarding public and veterinary health.

PMID- 10660937
TI  - Emerging pathogens: Isospora, Cyclospora and microsporidia.
AB  - Isospora belli, Cyclospora cayetanensis as well as several species of
      microsporidia are recognized as emerging protozoan pathogens of humans. All are
      obligate intracellular parasites, with Isospora and the microsporidia being
      primarily associated with immunocompromised hosts. Cyclospora is a cause of
      traveller's diarrhoea, and is responsible for water-borne and food-borne
      outbreaks of disease. Drug treatment is available for these infections. Improved
      diagnostic methods including the autofluorescence of I. belli and C. cayetanensis
      oocysts have assisted in the routine detection of these pathogens. Since the
      recognition of immunosuppression due to HIV infection, microsporidia have become
      recognized as important human pathogens with a continuing expansion of the
      parasite-associated clinico-pathological spectrum. The small size, intracellular
      nature and poor staining properties with many histological stains result in under
      reporting of microsporidial infections. Trichrome stain and optical brighteners
      are used to detect spores in faeces, urines, respiratory secretions and other
      aspirates. Electron microscopy remains an important diagnostic method but its
      sensitivity is relatively poor. Molecular techniques should overcome current
      diagnostic limitations. The ability to extract DNA and amplify by PCR directly
      from clinical samples has increased the usefulness of molecular methods.
      Restriction fragment length polymorphism analysis of amplicons can be used to
      determine genus, species and strain types of various microsporidia. Increased
      specificity is required in primer design because current primers used for
      amplifying non-microsporidian DNA also amplify microsporidian DNA. Diagnosis and
      pathogen characterisation rely increasingly on PCR-based approaches, and the
      sequence analysis approach becomes increasingly feasible and affordable. However,
      robust, reliable and sensitive methods are still required for dissecting
      pathogenesis, epidemiology, transmission routes and sources of infections.

PMID- 10660938
TI  - Overview and significance of molecular methods: what role for molecular
      epidemiology?
AB  - In this chapter, the contribution of molecular tools in understanding the
      aetiology and ecology of infectious diseases is examined in the context of
      molecular epidemiology (ME). ME is seen as providing the 'tools', both laboratory
      and analytical, which have predictive significance in epidemiological
      investigations of the causation of disease. A diversity of questions can be
      addressed with these tools which can conveniently be viewed as particular regions
      of DNA and grouped according to the different hierarchical levels of specificity
      by which infectious agents can be characterized. These groupings and the
      applications of the different molecular tools are described, and consideration
      given to the most appropriate methods of analysing data from ME investigations.

PMID- 10660939
TI  - Electrorotation and dielectrophoresis.
AB  - Using microelectrode structures, various forms of electric fields, such as non
      uniform, rotating and travelling wave, can be imposed on particles of sizes
      ranging from proteins and viruses to micro-organisms and cells. Each type of
      particle responds to the forces exerted on them in a unique way, allowing for
      their controlled and selective manipulation as well as their characterization.
      Moreover, particles of the same type but of different viability can be
      distinguished in a simple, reliable manner. This review outlines the principles
      that govern the way in which bioparticles respond to these various field types,
      and how they can be exploited. Examples of current and potential biotechnological
      and biomedical applications are given, along with a critical comparison of
      current techniques.

PMID- 10660940
TI  - Future trends in diagnosis using laboratory-on-a-chip technologies.
AB  - There has been an enormous growth in the development of biotechnological
      applications, where advances in the techniques of microelectronic fabrication and
      the technologies of miniaturization and integration in semiconductor industries
      are being applied to the production of Laboratory-on-a-Chip devices. The aim of
      this development is to create devices that will perform the same processes that
      are currently carried out in the laboratory in reduced timescales, at a lower
      cost, requiring less reagents, and with a greater resolution of detection and
      specificity. The expectations of this Laboratory-on-a-Chip revolution is that
      this technology will facilitate rapid advances in gene discovery, genetic mapping
      and gene expression with broader applications ranging from infectious diseases
      and cancer diagnostics to food quality and environmental testing. A review of the
      current state of development in this field reveals the scale of the ongoing
      revolution and serves to highlight the advances that can be perceived in the
      development of Laboratory-on-a-Chip technologies. Since miniaturization can be
      applied to such a wide range of laboratory processes, some of the sub-units that
      can be used as building blocks in these devices are described, with a brief
      description of some of the fabrication processes that can be used to create them.

PMID- 10660941
TI  - Risk assessment of waterborne protozoa: current status and future trends.
AB  - Throughout the past decade much research has been directed towards identifying
      the occurrence, epidemiology, and risks associated with waterborne protozoa.
      While outbreaks are continually documented, sporadic cases of disease associated
      with exposure to low levels of waterborne protozoa are of increasing concern.
      Current methodologies may not be sensitive enough to define these low levels of
      disease. However, risk assessment methods may be utilised to address these low
      level contamination events. The purpose of this article is to provide an
      introduction to microbial risk assessment for waterborne protozoa. Risk
      assessment is a useful tool for evaluating relative risks and can be used for
      development of policies to decrease risks. Numerous studies have been published
      on risk assessment methods for pathogenic protozoa including Cryptosporidium and
      Giardia. One common notion prevails: microbial risk assessment presents
      interesting complications to the traditional chemical risk assessment paradigm.
      Single microbial exposures (non-threshold) are capable of causing symptomatic
      illness unlike traditional chemical exposures, which require a threshold to be
      reached. Due to the lack of efficient recovery and detection methods for
      protozoa, we may be underestimating the occurrence, concentration and
      distribution of these pathogenic micro-organisms. To better utilize the tool of
      microbial risk assessment for risk management practices, future research should
      focus in the area of exposure assessment.

PMID- 10660942
TI  - Fumonisin B1-induced DNA damage in rat liver and spleen: effects of pretreatment
      with coenzyme Q10, L-carnitine, alpha-tocopherol and selenium.
AB  - Active oxygen radical species are reported to cause organ damage. This study was
      designed to determine whether oxidative stress contributed to the initiation or
      progression of hepatic and splenic cell DNA damage induced by fumonisin B1 (FB1)
      in rats. Another aim was to investigate the protective effects of the
      antioxidants coenzyme Q10 (CoQ10), L-carnitine, vitamin E (alpha-tocopherol) and
      selenium against DNA damage in the liver and spleen of rats treated with FB1.
      Fasted rats were injected intravenously with a single dose of fumonisin B1 at
      1.55 mg kg-1 body wt. into the tail vein. Treatment with FB1 led to splenic and
      hepatic DNA fragmentation in 85% of the test animals. DNA fragmentation was
      investigated as a critical event in toxic cell death by testing total Ca2+ in
      liver. FB1 administration caused total Ca2+ in liver to increase within 4 h (204%
      of control). Measurement of liver enzyme activities showed an increase in
      aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT). FB1 also
      markedly decreased splenic and hepatic glutathione (GSH) levels. Pretreatment
      with CoQ10 (30 mg CoQ10 kg-1 diet) together with L-carnitine (2.8 mg carnitine kg
      1 diet), alpha-tocopherol (30 IU vitamin E kg-1 diet) and selenium (1 mg selenium
      as sodium selenite kg-1 diet), decreased DNA damage and the activities of Ca2+,
      ASAT and ALAT in the liver. On the other hand, the level of GSH was slightly
      increased. The CoQ10 alone did not significantly protect against toxic cell death
      and glutathione depletion caused by FB1. Oxidative damage caused by FB1 may be
      one of the underlining mechanisms of FB1-induced cell injury and DNA damage.

PMID- 10660943
TI  - Effects of general anaesthetics on the activity of the Na,K-ATPase of canine
      renal medulla.
AB  - Several previous studies have reported inhibition of Na,K-ATPase activity by
      chlorpromazine, phenobarbital and pentobarbital, thiopental, and monoketones. The
      purpose of this study is to investigate the influences of other general
      anaesthetics on Na,K-ATPase activity. The ATPase activity of Na,K-ATPase-enriched
      membranes from canine renal medulla was determined at 37 degrees C in the absence
      and in the presence of hexanol, diethylether, halothane, and propofol. The
      influence of hexanol on stimulation of Na,K-ATPase activity by Na+ and K+ was
      investigated. Hexanol, diethylether, halothane, and propofol inhibited the
      activity at 37 degrees C of the Na,K-ATPase of canine renal medulla. The IC50
      values at 37 degrees C were: hexanol, 12.3 mM; diethylether, 170 mM; halothane,
      7.35 mM; propofol, 0.127 mM. Hexanol increased the K0.5 of the Na,K-ATPase for K+
      at 37 degrees C, but did not affect the K0.5 for Na+. At lower [K+] hexanol was a
      more potent inhibitor than at higher [K+].

PMID- 10660944
TI  - Long-term effects of glibenclamide and nateglinide upon pancreatic islet function
      in normal and diabetic rats.
AB  - Both control and hereditarily diabetic (Goto-Kakizaki) rats were administered
      twice daily for 7 days with an oral solution of carboxymethylcellulose
      containing, when required, glibenclamide (1.0 microgram g-1 body wt.) or
      nateglinide (50.0 micrograms g-1 body wt.). The increase in plasma D-glucose
      concentration and decrease in insulinogenic index caused by the bleeding and
      handling of the rats prior to sacrifice was more pronounced in the hyperglycaemic
      and hyperinsulinemic diabetic rats than in the control animals. Eighteen hours
      after the last oral loading, a sizeable fall in plasma D-glucose concentration
      and increase in plasma insulin concentration was only observed in the
      glibenclamide-treated control rats, indicating a more prolonged biological effect
      of the hypoglycaemic sulphonylurea, as compared to the meglitinide analog. This
      coincided with the fact that the insulin content of the islets, their secretory
      response to a high concentration of D-glucose and their basal biosynthetic
      activity were more severely affected in glibenclamide than nateglinide-treated
      animals, especially in the control rats. It is proposed, therefore, that the
      meglitinide analog, considered as a new insulinotropic tool for the treatment of
      non-insulin-dependent diabetic subjects, may offer the far-from-negligible
      advantage of minimising the risk of a sustained decrease in both islet insulin
      content and glycaemia.

PMID- 10660945
TI  - Cyclosporine A pharmacokinetics in rheumatoid arthritis patients after 6 months
      of methotrexate therapy.
AB  - To evaluate the effects of a 6-month methotrexate (MTX) treatment period on
      cyclosporine A (CsA) pharmacokinetics were subsequently added in patients with
      rheumatoid arthritis (RA) in comparison with patients treated with CsA only, CsA
      was administered to 30 subjects with RA (group A) treated with MTX (10 mg week-1
      i.m.) for 6 months and to 30 patients (group B) who received no MTX treatment.
      The mean doses +/- SD of CsA used in groups A and B were 3.2 +/- 0.5 and 3.3 +/-
      0.4 mg kg-1, respectively. CsA levels were determined in whole blood by means of
      a fluorescence polarization immunoassay (FPIA) method with a specific monoclonal
      antibody. The following pharmacokinetics parameters were calculated: area under
      the curve from 0 to 24 h (AUC0-24), half-life of the elimination phase (T1/2
      beta), total body clearance CL.F-1; V.F-1 and apparent volume of distribution (Vd
      beta). The mean blood concentrations and the pharmacokinetic parameters
      calculated in group A did not present significant statistical differences in
      comparison to group B. In conclusion, a 6-month MTX therapy does not produce
      liver function modifications to such an extent as to modify the pharmacokinetics
      of CsA subsequently added. Therefore, from a clinical pharmacological point of
      view, an MTX-CsA cotreatment appears feasible.

PMID- 10660946
TI  - Protective effects of sodium tanshinone IIA sulphonate against adriamycin-induced
      lipid peroxidation in mice hearts in vivo and in vitro.
AB  - Protective effects of sodium tanshinone IIA sulphonate against adriamycin-induced
      lipid peroxidation were investigated. Data showed that treatment with sodium
      tanshinone IIA sulphonate could prevent mice from decrease in body weight caused
      by adriamycin. It was found that myocardial lipid peroxidation in sodium
      tanshinone IIA sulphonate-treated mice was lower compared with that in adriamycin
      treated ones. The activities of some endogenous antioxidant enzymes, such as
      superoxide dismutase, glutathione peroxidase and catalase, were higher in the
      sodium tanshinone IIA sulphonate group than that in the adriamycin group. In
      vitro experiments showed that sodium tanshinone IIA sulphonate could inhibit
      adriamycin-induced mitochondrial lipid peroxidation and swelling. Sodium
      tanshinone IIA sulphonate could scavenge adriamycin semiquinone free radical in
      heart homogenate dose-dependently. Thus, protective effects of sodium tanshinone
      IIA sulphonate may not only be related to its antioxidant activity but also to
      its regulation of antioxidant enzyme activities in the heart.

PMID- 10660947
TI  - Hypolipidaemic effects of naringenin, rutin, nicotinic acid and their
      associations.
AB  - Atherosclerosis can be defined as being a disease of coronary circulation. The
      present work evaluates the action of the naringenin, rutin, nicotinic acid,
      isolated and in association, on the metabolism of lipids. Cholesterol,
      cholesterol HDL, and triacylglycerols have been dosed after retreat of blood,
      following the administration of the compounds dissolved in propylene glycol by
      intraperitoneal route in doses of 5 mg kg-1 body wt. Results evidence that
      naringenin and nicotinic acid, isolated as well as their association with
      naringenin and nicotinic acid-rutin, present the largest percentual reduction of
      cholesterol. On the other hand, the best results for cholesterol-HDL have been
      obtained with naringenin, while rutin has shown the best triacylglycerols levels.

PMID- 10660948
TI  - Maharishi Amrit Kalash rejuvenates ageing central nervous system's antioxidant
      defence system: an in vivo study.
AB  - The oxygen-free radical involvement in various deteriorative processes and in
      ageing is unquestionably established. In the present study age-related changes in
      antioxidant enzyme activity in the different regions of CNS of 10-month and 32
      month-old guinea pigs were studied. Maharishi Amrit Kalash has shown promise in
      inhibiting the in vitro and in vivo lipid peroxidation. Therefore in the present
      study the effect of MAK on the activity of antioxidant enzymes was checked. Our
      results indicate that the activity of superoxide dismutase and glutathione
      peroxidase, was found to be reduced (P < 0.05) in all the regions of CNS studied,
      The activities of catalase declined significantly only in the cerebral cortex,
      hypothalamus and the cerebellum. Whereas glutathione reductase activity declined
      in the cerebral cortex and hypothalamus. It is concluded that the age-related
      decline in the activities of antioxidant enzymes is region-specific as well as
      enzyme-specific. The endogenous lipid peroxide was found to be increased
      significantly (P < 0.05) in the 32-month-old animals. Whereas the lipid
      peroxidation after incubating the tissue homogenate in the air was found to be
      decreased (P < 0.05) in the older animals. The results indicate that the
      accumulation of lipid peroxides take place with age but the susceptibility of
      lipid peroxidation decreases in the older animals. The treatment of MAK 500 mg kg
      1 body wt. for 2 months could augment the activities of antioxidant enzymes (P <
      0.05). The effect of MAK was more pronounced in older than younger animals. It is
      concluded that the MAK can be used in compensating the decline in the activities
      of antioxidant enzymes in CNS and thereby it reduces the risks of lipid
      peroxidation.

PMID- 10660949
TI  - Changes in monoamine metabolites concentrations in rat cerebrospinal fluid after
      acute and long-term administration of a selective serotonin reuptake inhibitor,
      trazodone.
AB  - In order to clarify the mechanism of the antidepressive effects of trazodone, a
      selective serotonin reuptake inhibitor, we investigated the dynamics of monoamine
      metabolites in cerebrospinal fluid (CSF) of free-moving conscious rats by acute
      and long-term treatment with trazodone. When 100 mg kg-1 p.o. of trazodone were
      administered, a significant increase of 3-methoxy-4-hydroxyphenylglycol (MHPG)
      concentration was soon observed in the light period of the light/dark cycle, and
      a significant decrease of dihydroxy phenyl acetic acid (DOPAC) concentration was
      observed during the 2 days after administration of trazodone; in contrast, the
      homovanilic acid (HVA) level was increased. However, we detected no significant
      changes in the 5-hydroxy indole-3-acetic acid (5-HIAA) concentration during the 3
      days. In the case of long-term treatment with 50 mg kg-1, p.o. of trazodone, the
      levels of MHPG, DOPAC and HVA exhibited no difference when compared with values
      obtained during saline treatment in either the light or dark period, whereas the
      levels of 5-HIAA showed a significant increase during the light period. These
      findings suggest that a long-term treatment with trazodone enhances the
      serotonergic neurons.

PMID- 10660950
TI  - Influence of 3-PPP, a sigma receptor ligand, on the anticonvulsive action of
      conventional antiepileptic drugs.
AB  - (+)-3-(3-Hydroxyphenyl)-N-(1-propyl)-piperidine (3-PPP; a sigma receptor ligand),
      administered at 30 mg kg-1, 30 min before the test, significantly decreased the
      electroconvulsive threshold in mice, being ineffective in lower doses. 3-PPP (20
      mg kg-1) diminished the protective activity of diphenylhydantoin, phenobarbital
      and valproate, but not that of carbamazepine against maximal electroshock. The
      effect of 3-PPP upon the electroconvulsive threshold and the 3-PPP-induced
      inhibition of the protective action of antiepileptics was reversed by haloperidol
      (0.5 mg kg-1). Moreover, 3-PPP did not alter the total and free plasma levels of
      antiepileptic drugs, so a pharmacokinetic interaction is not probable. The
      combined treatment of 3-PPP with antiepileptic drugs, providing a 50% protection
      against maximal electroshock, did not affect motor performance in mice, although
      resulted in significant long-term memory deficits. Our data indicate that sigma
      receptor-mediated events may play some role in seizure processes in the central
      nervous system and can modulate the protective activity of some conventional
      antiepileptic drugs.

PMID- 10660951
TI  - Roles of enterobacteria, nitric oxide and neutrophil in pathogenesis of
      indomethacin-induced small intestinal lesions in rats.
AB  - Roles of enterobacteria, nitric oxide (NO) and neutrophil in indomethacin-induced
      small intestinal lesions were examined in rats. Indomethacin (10 mg kg-1),
      administered s.c. as a single injection, caused haemorrhagic lesions in the small
      intestine, mostly in the jejunum and ileum. The lesions were first observed 6 h
      after administration of indomethacin, the severity increasing progressively with
      time up to 24 h later. Following indomethacin, the enterobacterial numbers,
      inducible NO synthase (iNOS) activity and NO production in the intestinal mucosa
      were also increased with time, and changes in the former preceded those in the
      latter two as well as the occurrence of intestinal damage. Treatment of the
      animals with both NG-nitro-L-arginine methyl ester (L-NAME) and aminoguanidine
      prevented intestinal lesions induced by indomethacin, with suppression of NO
      production. Both dexamethasone and FR167653 (an inhibitor of interleukin-1
      beta/tumour necrosis factor-alpha production) also reduced the severity of
      intestinal lesions as well as the increase in iNOS activity following
      administration of indomethacin. Likewise, the occurrence of intestinal lesions
      was attenuated by pretreatment of the animals with anti-neutrophil serum (ANS).
      None of these treatments, however, affect the translocation of enterobacteria in
      the mucosa. By contrast, ampicillin (an anti-bacterial agent) suppressed the
      increase in mucosal iNOS activity as well as the enterobacterial numbers invaded
      in the mucosa and inhibited the occurrence of intestinal lesions after
      administration of indomethacin. These results strongly suggest that
      enterobacterial translocation in the mucosa is the first step required for
      activation of various factors such as iNOS/NO and neutrophils, all involved in
      the pathogenesis of indomethacin-induced intestinal lesions.

PMID- 10660952
TI  - Differential inhibition of polymorphonuclear leucocyte functions by cloricromene.
AB  - Leucocytes play an essential role in the pathogenesis of ischaemia and
      reperfusion injury and inhibition of their adhesion and of mediator release can
      reduce vascular and tissue damage. Previous studies have shown that cloricromene
      modifies several granulocyte as well as monocyte/macrophage functions and it has
      been shown that cloricromene administration exerts a clear protective action in
      several experimental models of ischaemia. The present work describes new data on
      polymorphonuclear leukocyte (PMN) inhibition exerted by cloricromene and compares
      these observations with earlier ones. Human washed PMN and human whole blood
      (HWB) were studied in vitro upon stimulation with f-MLP in the presence of
      cytochalasin B, with opsonized zymosan and with a phorbol ester (PMA). Amongst
      free radicals, superoxide anions were chosen as index of oxidative burst.
      Phagocytosis and beta-glucuronidase, as lysosomal release indicators, were
      measured to characterize PMN function: cloricromene inhibited concentration
      dependently all the parameters upon stimulation by each activator tested.
      Experiments performed in rabbit whole blood (RWB) showed that cloricromene
      inhibited free radical generation with IC50 values similar to those obtained in
      human whole blood. Comparing the action of cloricromene on human cells in
      different tests, we found that some parameters were more sensitive than others,
      even when the same stimulus was used. In particular, free radical generation was
      inhibited by cloricromene with IC50 values below 36 microM, while other
      functions, like lysosomal release and phagocytosis were inhibited with IC50
      values over 100 microM. These data confirm that cloricromene exerts a notable
      inhibitory effect on PMN and may explain the activity of the compound, observed
      in vivo in several experimental models of ischaemia-reperfusion and shock.

PMID- 10660953
TI  - Preimplantation genetic diagnosis (PGD)

PMID- 10660954
TI  - Recent advances and future developments in PGD.
AB  - PGD has now been practised for a decade. The basic techniques currently used
      involve embryo biopsy, polymerase chain reaction (PCR) and fluorescent in situ
      hybridization (FISH). Recent advances in molecular diagnostic techniques have
      included the use of fluorescent PCR, multiplex PCR and whole genome
      amplification. For cytogenetic analysis, many centres are now using five or more
      chromosome probes to examine for chromosome abnormalities, sexing and aneuploidy.
      Future improvements in molecular diagnosis include the use of quantitative PCR,
      DNA fingerprinting and microarray technology. Developments in methods to analyse
      chromosomes from a single cell have included interphase chromosome conversion,
      which has already been clinically applied, and the use of comparative genomic
      hybridization, which is still being developed. These methods will hopefully
      enable more accurate and a greater number of diseases to be diagnosed at the
      single cell level.

PMID- 10660955
TI  - The role of the preimplantation geneticist in human cloning.
AB  - If human cloning is to become a reality, the preimplantation geneticist must be
      responsible for determining the indications for undertaking cloning and for
      establishing the risks and benefits of human cloning. The unresolved issue is
      whether a compelling argument can be made for cloning a human for therapeutic
      reasons while outweighing legal, moral and ethical objections. At present, 'whole
      person' cloning does not seem justified under any circumstance, whereas cloning
      for the replacement of diseased cells, tissues or organ systems, i.e. 'spare
      parts', seems to be a likely, acceptable application of cloning strategies for
      humans.

PMID- 10660956
TI  - An analysis of the demand for and cost of preimplantation genetic diagnosis in
      the United Kingdom.
AB  - Research in the field of preimplantation genetic diagnosis (PGD) has concentrated
      on increasing the number of diseases diagnosed, different strategies for single
      cell analysis and improving efficiency and reliability. Of equal importance are
      clinical issues such as the demand for and cost of PGD. This study assesses
      patient awareness of PGD and its potential benefits; additionally the awareness,
      attitudes and referral patterns of Assisted Conception Units, Regional Genetics
      Centres and Health Authorities (funding bodies) have been analysed to establish
      the demand for PGD within the United Kingdom. The licensed units are able to
      perform 128 cycles of PGD annually, however 256 cases were referred within the
      last year. It is clear that the currently licensed units operating at their
      present capacity are unable to meet the demand for PGD in the U.K. Concerns
      raised by this study include the unequal geographical distribution of PGD
      services and the lack of a uniform funding policy by Health Authorities. The
      investment in personnel and technology to establish a PGD service is considered
      and a costing provided. We estimate an initial investment in the region of
      139,000 Pounds with annual running costs of 55,000 Pounds. This information
      should contribute towards an appropriate allocation of resources at a national
      level in the U.K.

PMID- 10660957
TI  - A widely applicable strategy for single cell genotyping of beta-thalassaemia
      mutations using DGGE analysis: application to preimplantation genetic diagnosis.
AB  - Preimplantation genetic diagnosis (PGD) allows the selection of unaffected IVF
      embryos for transfer in couples that are at risk for transmitting genetic
      diseases. For monogenic diseases, polymerase chain reaction (PCR)-based diagnosis
      is usually performed on single blastomeres. In Greece, up to 10 per cent of the
      population are carriers for beta-thalassaemia and related haemoglobinopathies,
      and more than 20 pathological mutations in the beta-globin gene have been
      described. In this study we report a strategy which includes a first round of
      PCR, allowing subsequent nested PCR and DGGE analysis for at least 95 per cent of
      beta-thalassaemia major genotypes in the Greek population. The use of DGGE for
      beta-globin genotype analysis is advantageous: it facilitates simultaneous
      analysis of more than one mutation in a single PCR fragment, it detects the
      presence of normal alleles and monitors the occurrence of allelic drop-out (ADO)
      through the expectation that heterozygous samples have more than one
      electrophoretic band on DGGE analysis. The optimization, accuracy and reliability
      of the method was evaluated by genotyping 325 single blastomeres, 110 amniocytes
      and 55 lymphocytes. Results confirmed that PCR efficiency and occurrence of ADO
      are improved by higher denaturation temperatures in the first cycles of first
      round PCR, influenced by the size of the fragment amplified in the first round of
      PCR and additionally by the quality and type of cells being genotyped. The
      proposed strategy was accurate and reliable, and thus for application to PGD
      should ensure the transfer of unaffected embryos. Furthermore it is widely
      applicable in most of the populations worldwide where beta-thalassaemia is
      common.

PMID- 10660958
TI  - Preimplantation genetic diagnosis in 10 couples at risk for transmitting beta
      thalassaemia major: clinical experience including the initiation of six singleton
      pregnancies.
AB  - Preimplantation genetic diagnosis (PGD) offers couples at risk for transmitting
      an inherited disorder the possibility to avoid the need to terminate affected
      pregnancies, since it allows the selection of unaffected IVF embryos for
      transfer. PGD for monogenic diseases is most commonly accomplished by blastomere
      biopsy from cleavage stage embryos, followed by polymerase chain reaction (PCR)
      based DNA analysis. However, PCR-based DNA analysis of single cells is subject to
      several problems including sample contamination, total PCR failure, or failure of
      one allele to amplify--a phenomenon known as allelic drop-out (ADO). Furthermore,
      the molecular heterogeneity of many monogenic diseases requires a diagnostic
      strategy capable of detecting a spectrum of mutations and compound genotypes.
      With the above considerations we developed an accurate and reliable strategy for
      analysis of beta-globin gene mutations, applicable for PGD for the wide spectrum
      of beta-thalassaemia major genotypes in the Greek population. The strategy
      involves nested PCR followed by denaturing gradient gel electrophoresis (DGGE)
      analysis. DGGE is an advantageous method for mutation detection since it
      facilitates simultaneous analysis of more than one mutation in a single PCR
      fragment, it identifies the presence of normal alleles and in addition can
      monitor the occurrence of ADO. This report describes the application of the DGGE
      based diagnostic strategy in 11 clinical IVF/PGD cycles, in 10 couples at risk
      for transmitting beta-thalassaemia major. The transfer of at least one embryo
      diagnosed as unaffected for beta-thalassaemia major in nine couples has resulted
      in the initiation of six pregnancies. Four pregnancies have so far been confirmed
      as unaffected for beta-thalassaemia major by first or second-trimester prenatal
      diagnosis, two of which have resulted in the birth of two healthy babies. Three
      singleton pregnancies are still on-going and one ectopic pregnancy was
      terminated.

PMID- 10660959
TI  - Preimplantation diagnosis for fragile X syndrome based on the detection of the
      non-expanded paternal and maternal CGG.
AB  - Fragile X syndrome is the most common monogenic cause of mental retardation in
      boys. It is always characterized clinically by moderate mental retardation and
      often by a long face with large everted ears and macro-orchidism. The causal
      mutation is an expansion of a CGG triplet repeat in a 5' exon of the FMR-1 gene
      in Xq27.3. We report here for the first time a method for preimplantation genetic
      diagnosis (PGD) for fragile X syndrome based on the amplification of the CGG
      triplet in the normal allele. Our candidate-patient population, as well as two
      clinical preimplantation genetic diagnosis (PGD) cycles which led to a pregnancy
      with an unaffected fetus, are presented in this paper.

PMID- 10660960
TI  - Single cell detection of inherited retinoblastoma predisposition.
AB  - Retinoblastoma susceptibility is an autosomal dominantly inherited cancer
      predisposition which also confers a life-long increased risk for various non
      ocular malignancies. We developed a protocol for single cell detection of this
      disorder which enables its preimplantation genetic diagnosis as an alternative to
      prenatal diagnosis with attendant pregnancy termination. The presented method
      detects the underlying mutation of the disease, a linked intragenic polymorphism
      (p88PR0.6) and an independent marker (D21S1411) for genetic fingerprinting
      allowing detection of contamination. The strategy is based on the combination of
      nested triplex polymerase chain reaction, single strand conformation polymorphism
      analysis by conventional polyacrylamide gel electrophoresis and fragment size
      determination with automated laser fluorescence.

PMID- 10660961
TI  - Confirmation of diagnosis in preimplantation genetic diagnosis (PGD) through
      blastocyst culture: preliminary experience.
AB  - Three cases of preimplantation genetic diagnosis (PGD) (two for sexing and one
      for aneuploidy screening) are presented. Embryo biopsy was performed at day 3 and
      diagnosis was established with fluorescent in situ hybridization (FISH). Embryos
      not used for replacement were cultured in sequential media for blastocyst
      development. Blastocyst rate was 39.3 per cent. Confirmations of diagnosis were
      established with FISH in blastocysts and arrested embryos. Mosaicism was observed
      in 7/8 blastocysts (mean number of cells analysed: 55.5) and 5/8 arrested
      embryos. The percentage of abnormal cells was 17.1 per cent for blastocysts and
      54 per cent for arrested embryos. Polypoid cells were observed in 4/8
      blastocysts. Confirmation of diagnosis at the blastocyst stage is a useful tool
      in PGD.

PMID- 10660962
TI  - Improvement of preimplantation genetic diagnosis (PGD) for the cystic fibrosis
      mutation delta F508 by fluorescent polymerase chain reaction.

PMID- 10660963
TI  - Primary coronary angioplasty in acute myocardial infarction excluded from
      thrombolysis: in-hospital and mid-term results.
AB  - The clinical, in-hospital and mid-term (14 +/- 12 months), results of primary
      percutaneous coronary angioplasty (PTCA) were investigated in 74 consecutive
      patients (pts) with acute myocardial infarction excluded from thrombolysis, of
      whom 9 pts with cardiogenic shock. In pts without cardiogenic shock at admission,
      the success rate of primary PTCA was high (92.3%) and the in-hospital mortality
      was low (3%). There were 89.2% asymptomatic pts during the in-hospital period.
      During the mid-term follow-up, pts without cardiogenic shock at admission had a
      mortality of only 4%, 66% of them remained asymptomatic, 24% developed angina
      pectoris and 6% had a new myocardial infarction. In pts with cardiogenic shock at
      admission to the hospital, the success rate of primary PTCA was of only 55.5% and
      the in-hospital mortality was high, 77.7%. In conclusion, primary PTCA in acute
      myocardial infarction excluded from thrombolysis is particularly useful in
      patients without cardiogenic shock.

PMID- 10660964
TI  - Correlation between left ventricular diastolic function and exercise testing in
      patients with old myocardial infarction.
AB  - There is no correlation between left ventricular (LV) systolic function and
      effort capacity of the patients with acute or old myocardial infarction (MI). On
      the other hand, some recent studies suggest such a relationship for LV diastolic
      function. Twenty-five patients with old MI were submitted to a maximal symptoms
      limited exercise testing (ET) and to an echo Doppler examination; functional
      aerobic impairment (FAI), myocardial aerobic impairment (MAI), maximal exercise
      capacity (METs NYHA class), isovolumic relaxation time (IVRT), E and A wave
      velocity, E/A rate being calculated. There is a negative significant correlation
      between MAI and E velocity (r = -0.68), but not between MAI and A velocity or
      IVRT. The data sustained the correlation between LV diastolic dysfunction and
      myocardial ischemia, but not with effort capacity of the patients, the last one
      being determined mainly by other factors. The LV diastolic function indices were
      modified in anterior but not in inferior MI, in relation with the amount of
      myocardial necrosis. It is concluded that, like LV systolic function, LV
      diastolic function does not correlate with the effort capacity of the patients
      with MI, but it represents a good predictor of the severity of myocardial
      ischemia mainly in anterior MI.

PMID- 10660965
TI  - Effect of exercise training upon left ventricular systolic performance and effort
      capacity in patients with old myocardial infarction.
AB  - Recent studies suggested an improving of left ventricular (LV) systolic function
      during exercise training in patients with old myocardial infarction. Twenty
      patients with old myocardial infarction (3-6 weeks) were included in an exercise
      training programme (mainly cycloergometer) for 2 to 8 weeks. Before and after the
      exercise training programme, the effort capacity and LV systolic function were
      determined through exercise testing on cycloergometer and echocardiography. The
      peak effort raised from 4.39 to 5.27 METs (p < 0.05) and the difference DAF-DAM
      was reduced from 25% to 12% (p < 0.05). The double product (DP) at peak effort
      raised nonsignificantly (4.91%, p > > 0.05), but at submaximal effort levels DP
      decreased significantly on each effort step (12.16%, p < < 0.05). In turn, LV
      systolic function calculated parameters were practically the same before and
      after the exercise training programme. (EDD 54.3 vs 5.3 mm, ESD 39.3 vs 38 mm,
      EDV 160 vs 169 ml, ESV 60.6 vs 54.8 ml, EF 54.1% vs 57.8%, SF 27.6% vs 31.2%). It
      is concluded that exercise training raised the effort capacity in patients with
      old myocardial infarction, mainly through peripheral mechanisms, LV systolic
      function being unchanged. It is also important that exercise training have not
      any detrimental effect upon LV systolic function and consequently exercise
      training programmes can be applied and can be useful also in patients with old
      myocardial infarction and impaired LV systolic function.

PMID- 10660966
TI  - Treatment of atrial flutter and rapid atrial tachycardia with endocavitary atrial
      pacing.
AB  - Fourteen patients with atrial flutter (AFL) and rapid atrial tachycardia (AT) (8
      AFL type I, 2 AFL type II and 4 AT) were treated with endocavitary atrial pacing
      (EAP). In 10 patients no antiarrhythmic agent was during this study and in 4
      patients digoxin and/or verapamil was administered before. Conversion to sinus
      rhythm was successfully achieved in 7 patients, 50% (4 AFL type I and 3 AT).
      Primary success rate (return to sinus rhythm either immediately or after < 10 min
      of atrial fibrillation) was 71% (5/7) (2 AFL type I and 3 AT); delayed success
      (conversion to sinus rhythm in > 10 min, but < 24 h) was observed in 2 cases
      (29%) with AFL type I. At five patients AFL was converted in stable atrial
      fibrillation (4 AFL type I and 1 AFL type II). EAP failed to terminate the
      arrhythmia in 1 patient with uncommon AFL (type II) and 1 case with AT. EAP
      included single extrastimuli, coaction, single decremental atrial extrastimuli
      and incremental atrial pacing (burst) during AFL or AT. In conclusion, EAP is a
      method with few complications and has efficacy for converting AFL and rapid AT
      sinus rhythm or to atrial fibrillation.

PMID- 10660967
TI  - The monophasic action potential: a simple in vivo model to evaluate the effects
      of antiarrhythmic drugs at atrial level.
AB  - Monophasic action potential (MAP) represents an extracellular recording of
      electrical potentials variations produced simultaneously by several cells. Even
      if it does not represent the real cellular action potential, monophasic action
      potential generally reproduces with accuracy that aspect, being useful especially
      in the assessment of myocardial repolarisation phases. Monophasic action
      potential recording was performed with a quadripolar catheter designed by Franz;
      the quality of recordings was good and the procedure is safe. In clinical
      electrophysiology, monophasic action potential may be helpful in the study of
      certain aspects that cannot be evaluated adequately by standard
      electrophysiological techniques. The study was performed on six patients, in drug
      free state. The duration of monophasic action potential at 90% of repolarisation
      and the atrial effective refractory period, at three basic cycle lengths (600,
      500 and 400 msec) were determined. Both monophasic action potential duration at
      90% of repolarisation and the atrial effective refractory period shortening at
      short cycle length and a linear correlation between these two parameters were
      seen. We conclude that the correlation between monophasic action potential
      duration and the effective atrial refractory period may be a simple and useful
      model to characterise in vivo the electrophysiologic profile of antiarrhythmic
      drugs.

PMID- 10660968
TI  - Increased plasma levels of interleukin-8 in patients with unstable angina
      pectoris.
AB  - Interleukin-8 is a proinflammatory cytokine with chemo-attractive and major
      activator properties on neutrophils. The very few studies in literature on the IL
      8 behaviour in myocardial ischaemia refer only to acute myocardial infarction.
      This study investigates the IL-8 behaviour in stable angina pectoris after
      myocardial ischaemia induced by dipyridamole (14 patients) and in unstable angina
      pectoris, Braunwald's class III (35 patients). In stable exercise angina
      following dipyridamole-induced myocardial ischaemia, the plasma IL-8 levels did
      not increase. In unstable angina pectoris increased plasma IL-8 levels were
      evidenced in 25 of the 35 patients, after an average interval of 20 +/- 1.2 hours
      from the last spontaneous episode of angina pectoris. The IL-8 behaviour was
      different in class III B patients as compared to class III A: only 30% of the
      patients in class III A presented transient increase of IL-8, while 70% of the
      class III B presented increased IL-8 with a median value of 900 pg/ml within the
      first 24 hours from the last spontaneous episode of angina pectoris. The
      increased plasma IL-8 levels within the first 24 hours from the spontaneous
      episode could represent a marker of primary angina pectoris, Braunwald's class
      III B.

PMID- 10660969
TI  - Comparison between reverse transcription-polymerase chain reaction and immune
      enzyme assays in the diagnosis of hepatitis C virus infection.
AB  - This is the first study of HCV infection performed in Romania by reverse
      transcription-polymerase chain reaction (RT-PCR). We set up our own protocol,
      using "nested" primers located in the 5' UTR of HCV. Thirty two patients, 16 with
      chronic hepatitis, 7 with hepatic cirrhosis and 9 without chronic hepatic disease
      were investigated. The assignment of each patient to one of the groups was based
      on clinical and laboratory criteria, especially transaminase levels and hepatic
      biopsy findings. In 14 out of 16 (87.5%) chronic hepatitis cases and in 6 cases
      of hepatic cirrhosis out of 7 (85.7%), there was good agreement between RT-PCR
      and ELISA results. Transaminase levels were concordant with RT-PCR results in 27
      of 29 cases (93.1%) but in only 21 of 29 cases (72.4%) transaminase levels were
      in agreement with ELISA results. In two patients treated with interferon,
      transaminase levels and the other clinical and laboratory parameters fell in the
      normal range in parallel with the disappearance of viremia, whereas anti-HCV
      antibodies were still detectable. RT-PCR has a higher specificity in detecting
      the etiology of hepatic diseases if compared to ELISA and an at least equal
      sensitivity. The method proves to be the best means for the confirmation of HCV
      infection, and for the monitoring of interferon therapy.

PMID- 10660970
TI  - Lipoproteins, lipidic peroxidation and total antioxidant capacity in serum of
      aged subjects suffering from hyperglycemia.
AB  - Quantitative alterations of serum lipoproteins were studied as well as lipidic
      peroxidation level and total antioxidant capacity in the serum of 265 subjects
      ranging in age between 60-70 years, out of which 97 showed levels of glycemia
      higher than normal. Increase of LDL and VLDL was found in 74.6% respectively 67%
      of the old-aged subjects researched, without also finding significant differences
      between sexes. Frequent association between the two metabolic disorders is seen
      without there being a statistical correlation between degree of dyslipidemia and
      blood glucose level. The level of lipid peroxidation, determined by serum
      malondialdehyde (MDA) concentration, is higher in subjects with dyslipidemia
      where glycemia level exceeds 200 mg%. Total antioxidant defence in old aged
      hyperglycemic patients decreases by 18% as against the value seen in the
      controls. The normally glycemic patients show a decrease in this activity by only
      12%. Significant frequency of dyslipidemia in the old aged studied is associated
      with hyperglycemia and can be accounted for beyond biologic mechanisms
      characteristic of aging, through a deficient diet. Association of dyslipidemia
      with hyperglycemia, the high level of lipidic peroxides and the diminution of
      body capacity of annihilating them, actually represents an increase in risk
      factors for onset of vascular attacks.

PMID- 10660971
TI  - Value of the lymphoblastic transformation in patients with silicosis.
AB  - The authors verify whether in silicosis the accumulation of silicon dioxide
      (SiO2) particles in the lung can induce changes of the activated T lymphocytes in
      the peripheral blood. The lymphoblastic transformation of lymphocytes stimulated
      with phytohemagglutinin (PHA), concanavalin A (Con A), Mycobacterium tuberculosis
      (Mt) and purified protein derivative (PPD) was studied using the classical
      methods. It was observed that in patients exposed to SiO2 lymphocyte reactivity
      to the above stimulants decreases. Significant differences between patients and
      controls were observed only in the response to PHA (p < 0.001).

PMID- 10660972
TI  - Considerations on the changes of certain immunologic parameters in occupational
      allergic bronchial asthma due to textile fibers.
AB  - The changes of some immunologic parameters such as IgG, IgA and IgM, the C3
      complement, the circulating immune complexes and alpha 1--antitrypsin were
      investigated in 75 patients with occupational allergic bronchial asthma to
      textile fibers as compared with 50 apparently healthy controls with no
      occupational exposure to textile fibers. It was observed that IgG and IgA
      decreased significantly while IgM increased. Likewise C3 decreased in all
      patients with occupational allergic bronchial asthma (OABA) as compared with the
      controls an CIC increased significantly. The determinations carried out
      demonstrated a parallelism of action in the immune response.

PMID- 10660973
TI  - Safety and efficacy of insulin lispro in patients with diabetes mellitus.
AB  - Lispro is a human insulin analogue with a very rapid onset of action, and a
      shorter duration of activity than soluble insulin. In order to assess the
      therapeutical value of lispro, we have had an open-label, non-comparative study,
      for 12 weeks, involving 19 IDDM patients. The treatment regimen with lispro and
      Humulin N has been adapted depending on each patient characteristics. Patients
      attended three visits, and the main metabolic control parameters included values
      of hemoglobin Alc, fasting and postprandial blood glucose monitoring. The
      patients themselves monitored their blood glucose using a glucometer. The mean
      age value of 19 patients (8 females and 11 males) was 22.32 (+/- 13.59) years. In
      patients previously receiving insulin treatment, therapy with lispro insulin
      significantly reduced postprandial glucose values. Lispro has been administered
      t.i.d. in 14 patients, and b.i.d. in 5 patients. At visit 1, mean value of HbAlc
      was 10.32% (+/- 1.63%); at visit 3, mean HbAlc was 9.90% (+/- 1.59%). Total
      insulin daily dose and the rate of short and long acting insulin did not change
      from visit 1 to visit 3. There has been reported only one serious adverse event
      during the study: a ketoacidosis due to a technical dosing error. Ten patients
      have reported mild hypoglycemic episodes. The outcomes of clinical study and of
      Quality of Life Questionnaire suggests that lispro--the first human insulin
      analogue used in humans--is effective, safe, and it is broadening beneficially
      the spectrum of insulins.

PMID- 10660974
TI  - The effect of metoclopramide on antral emptying of a semisolid meal in patients
      with functional dyspepsia. A randomized placebo controlled sonographic study.
AB  - The aim of this study was to investigate the effect of metoclopramide on the
      antral emptying of a semisolid meal. Twenty-five patients with functional
      dyspepsia received in a prospective randomized trial either metoclopramide 10 mg
      t.i.d. (n = 14) or placebo (n = 11) for 7 days. The antral emptying was measured
      by real-time ultrasound with a 3.5 MHz probe from the antral area recordings in
      the aorto-mesenteric plane. The measurements were carried out in fasting
      condition and at 0, 15, 30, 45, 60 min after a standardized semisolid meal. The
      symptoms quantified in a symptom score were also recorded. Metoclopramide was
      superior to placebo in improving the symptom score. Antral emptying was
      accelerated by metoclopramide compared with placebo. Fasting antral emptying was
      not changed by metoclopramide and the postprandial antral area had a trend to
      decrease. These data suggest that the effect of metoclopramide is less due to the
      enhancement of antral motility but rather to the reduction of postprandial fundus
      relaxation.

PMID- 10660975
TI  - Study of fluticasone propionate efficacy in the treatment of patients with
      bronchial asthma not controlled by other inhaled corticosteroids.
AB  - The aim of the study was to test the fluticasone propionate (FP) efficacy in the
      treatment of patients with bronchial asthma (BA), not controlled by high doses
      (more than 1 mg) of other inhaled corticosteroids. Asthma symptoms (degree of
      dyspnea on Sadoul scale, percentage of symptom-free days and nights), and drug
      consumption were measured and lung function tests were performed in 20 patients
      (11 women and 9 men, mean age 47 years) for a 2 months period. Biochemical
      measurements were done referring to oxidant/antioxidant imbalance, which is
      characteristic to inflammatory diseases of respiratory system. We evaluated
      lipoperoxidation (LPO) in the plasma and the blood, before and after FP
      treatment, by determining malondialdehyde (MDA) status, superoxide-dismutase and
      ceruloplasmine activity and non-protein SH groups (essential glutathione) status.
      The biochemical measurements showed a significant decrease in lipid peroxides
      level in the plasma and the blood and a slight increase of glutathione after 2
      months treatment with FP. Lung function tests were performed on a Flow Streen
      Jaeger and we determined: peak expiratory flow (PEF), vital capacity (VC), forced
      expiratory volume in 1 sec. (FEV1) and mid-expiratory flow at 50% VC (MEF50). The
      measurements were done before FP administration, after 3 days, 7 days, 1 month
      and 2 months. The dose of FP was equivalent to 50-75% of the daily dose of
      Beclomethasone dipropionate (BD) previously administered. The degree of dyspnea
      diminished from 3-4 to 0-1. The percentage of symptom-free days and nights
      improved from 12% to 78% and 25% to 95% respectively. The use of short acting
      beta agonists diminished with 75% and no patients required i.v. corticotherapy or
      theophylline. PEF increased with a mean of 25%, VC with a mean of 23%, FEV1 with
      a mean of 30% and MEF50 with a mean of 36%. Our results demonstrate improved
      efficacy of FP vs high doses of other inhaled corticosteroids in the treatment of
      moderate persistent and severe forms of BA.

PMID- 10660976
TI  - Lack of effect of salmon calcitonin on serum level of soluble form of E-selectin
      (CD 62E) in patients with atopic bronchial asthma.
AB  - The effect of salmon calcitonin on serum level of soluble form of E-selectin was
      investigated in patients with atopic bronchial asthma. A slight decrease in serum
      soluble E-selectin level was shown in patients with mild asthma. There was no
      effect of calcitonin (100 units, s.c., daily for three days) on serum E-selectin.

PMID- 10660977
TI  - Primary aldosteronism and adrenal incidentaloma.
AB  - Adrenal incidentaloma are usually found during the assessment of non adrenal
      disease. In this paper we report the association between a bilateral adrenal
      hyperplasia and a macronodule of adrenal cortex (adrenal incidentaloma) which is
      a rare and misleading cause of primary aldosteronism. In the light of this
      association even if it is likely to remain rare and of those previously
      published, its existence is an additional reason for suggesting surgical
      treatment of primary aldosteronism only to patients who satisfy the following
      criteria: 1) satisfactory control with spironolactone; 2) poor spironolactone
      tolerance and poor control with other drugs; 3) accept to be operated on and the
      risk of a possible error.

PMID- 10660978
TI  - Proposal for a new classification of diabetes mellitus.
AB  - Diabetes mellitus is a complex metabolic syndrome characterised by varying
      degrees of insulin deficiency, either absolute or relative, and impaired insulin
      action on protein, lipid and carbohydrate metabolism. Although hyperglycemia is
      always present during the course of the disease, at least in the early phase it
      must not be a unique criterion for diagnosis. A normoglycemic patient with
      hyperinsulinemia associated with obesity or dyslipidemia could be considered as a
      case of "normoglycemic diabetes" which will develop in time toward hyperglycemia.

PMID- 10660979
TI  - Recognition for fission yeast.

PMID- 10660980
TI  - A new manicure table for applying artificial fingernails.

PMID- 10660981
TI  - Office ergonomics resources on the World Wide Web.

PMID- 10660982
TI  - Occupational exposure to crystalline silica during tuckpointing and the use of
      engineering controls.

PMID- 10660983
TI  - Control of exposure to perchloroethylene in commercial drycleaning (machine
      design).

PMID- 10660984
TI  - Exposure assessment must stop being local.
AB  - Exposure assessment activities today are hampered by a narrow focus that is
      detrimental to preventive occupational health goals. Exposure data useful for
      disease prevention are not adequately collected, and exposure surveillance tools
      do not receive adequate attention. Professional recommendations to improve this
      state of affairs have been in existence since the early 1990s, but have not been
      widely adopted. Although the Government Performance and Results Act could help
      address these shortcomings--by enhancing exposure surveillance activities in the
      OSHA and NIOSH Strategic Plans--the agencies have not taken advantage of this
      opportunity. Their strategic plans rely largely on accident data to measure
      performance, despite the fact that occupational disease has a much larger toll.
      This article makes recommendations to address these shortcomings by increasing
      the role of exposure surveillance tools in the agency strategic plans.

PMID- 10660985
TI  - Effect of different grouping strategies in developing estimates of personal
      exposures: specificity versus precision.
AB  - There has been increasing interest in recent years in developing strategies in
      epidemiology for the summarization of occupational exposures, strategies that
      serve to clarify observed relationships between occupational exposure and health
      outcomes. Where source occupational exposure data are scarce, it is common to
      assemble exposure groups with the goal of increasing the extent to which data
      based exposure estimates are available for an entire cohort. There has been
      little guidance, however, on the effect of different grouping strategies on the
      observed fit between exposure and health outcome. This investigation examined the
      effect of the use of different exposure summarization strategies on observed
      relationships between dust exposure and lung function decline among coal mine
      workers. The dust exposure and spirometry data employed were gathered in the
      National Study of Coalworkers' Pneumoconiosis. An analysis of variance procedure
      was carried out to characterize the variability of the dust exposure data,
      employing single variables relating to mine identity, occupation, and year, as
      well as two- and three-way multivariate combinations of these variables. The
      resulting combinations were ranked according to the standard deviation of the
      observed exposure range to reflect the relative specificity of the various
      approaches. Sequential arrangements of single- and multiple-variable combinations
      were constructed, alternately employing highly specific codes or broad categories
      for mine, occupation, and year. Annual exposure estimates were constructed on the
      basis of these sequences and used in tandem with longitudinal change in forced
      expiratory volume (FEV1) in linear multiple regression procedures. Height, age,
      smoking status, and dust exposure were employed as predictor variables. The
      results show that the use of broad categorization approaches had a substantial
      impact on observed regression coefficients. The largest change was observed for
      categorization according to occupation, which resulted in two- to three-fold
      increases in the magnitude of observed regression coefficients. These results
      suggest that the use of highly specific exposure summarization approaches may
      result in regression outcomes which are marked by a high degree of attenuation,
      and that consideration of the precision of summarized exposure estimates is an
      important component of an effective exposure assessment strategy.

PMID- 10660986
TI  - The use of a task-based exposure assessment model (T-BEAM) for assessment of
      metal fume exposures during welding and thermal cutting.
AB  - Elevated disease rates have been documented among construction workers for
      cancer, pneumonoconiosis, asbestosis, and silicosis. However, methodologies for
      exposure assessment in construction are not well described in the U.S.
      literature. Working through a cooperative agreement with the National Institute
      for Occupational Safety and Health (NIOSH), the Center to Protect Workers' Rights
      -a research arm of the Building and Construction Trades Department, AFL-CIO--has
      developed and used a "Task-Based Exposure Assessment Model (T-BEAM)" for
      construction. The characteristic elements of T-BEAM are: (1) an emphasis on the
      identification, implementation, and evaluation of engineering and work practice
      controls; and (2) use of experienced, specially trained construction workers
      (construction safety and health specialists) in the exposure assessment process.
      A task-based approach was used because tasks, or specialized skills, form the
      single greatest thread of continuity in the dynamic environment of construction.
      Workers in the construction industry come from several crafts and are typically
      employed by a large number of contractors throughout their career. Project types
      (e.g., residential or industrial rehabilitation) are also highly variable and
      present unique health risks. Finally, because construction involves building,
      renovating, or dismantling physical surroundings, the work site is constantly
      changing. Between 1995 and 1996, T-BEAM was applied to the collection of
      approximately 200 personal exposure measurements associated with "hot work tasks"
      -welding and thermal cutting. Data were collected with the assistance of
      specially trained, journeyman ironworkers, pipe fitters, and boilermakers on nine
      construction sites located throughout the United States. Portable local exhaust
      ventilation was provided to participating contractors with the intent of
      measuring its impact on exposure. Results indicate that data collected in a
      standardized, systematic fashion from multiple work sites can be used to
      characterize exposures among sampled trades. Comparison of results to American
      Conference of Governmental Industrial Hygienists (ACGIH) threshold limit values
      (TLVs) demonstrate a significant health hazard among sampled trades posed by
      welding and thermal cutting fume, manganese, nickel, and chromium VI. Direct
      estimates of the probability of exceeding the ACGIH TLV for respirable
      particulate suggests that boilermakers (100%) and ironworkers (71%) are at
      greatest risk. Other task variables evaluated with respect to exposure include
      task, whether work was performed indoors or outdoors, intermittency of work, and
      use of ventilation. Use of local or mechanical ventilation reduced mean exposures
      to fumes significantly.

PMID- 10660987
TI  - Real-time monitoring of particles, PAH, and CO in an occupied townhouse.
AB  - Beginning in October 1996, indoor and sometimes outdoor air at an occupied house
      in a suburban area of Virginia has been monitored continuously for particles,
      PAH, and CO. Two Climet monitors have been used to count particles in six size
      ranges between 0.3 and > 10 microns, with 1-minute averages being collected every
      5 minutes. Two Ecochem PAH monitors have been used to sample for particle-bound
      PAHs once every minute. Also, two Langan CO monitor-data loggers have measured CO
      once each minute while logging the PAH data. Two Aethalometers measure black
      carbon. A single Scanning Mobility Particle Sizer (SMPS) measures ultrafine
      particles. The pairs of monitors are set up either to provide an indoor/outdoor
      or an upstairs office/downstairs kitchen comparison. Air exchange is occasionally
      measured using a Bruel & Kjaer 1302 SF6 monitor, as a parameter necessary for
      estimating deposition rates for particles and PAH. Results from the first 16
      months of monitoring (approximately 10 M observations) include: neighborhood
      woodburning and morning rush hour traffic are the most important sources of PAH
      and black carbon outdoors; candles, matches, incense, and frying, sauteeing,
      broiling, deep-frying, and stir-frying are additional important indoor sources of
      PM. One citronella candle was an extremely powerful PAH source. Neither
      woodburning nor vehicles appears to be an important source of particles indoors,
      but frying, grilling, and sauteeing are extremely strong indoor sources, together
      with combustion events such as use of matches and candles. Physical movement was
      an important source of coarse but not fine particles. Use of the gas stove for
      extended periods of time led to increased CO concentrations--vehicles and
      woodburning were relatively minor sources in comparison. The gas oven, gas
      burners, and electric toaster oven were important sources of ultrafine particles
      (< 0.1 micron). A source-proximity effect was noted with the kitchen monitor
      reading two to five times higher than the upstairs monitor for particles from
      kitchen events, while the upstairs monitor often read higher than the kitchen
      monitor for events caused by physical activity alone.

PMID- 10660988
TI  - Computer-aided video exposure monitoring.
AB  - A computer-aided video exposure monitoring system was used to record exposure
      information. The system comprised a handheld camcorder, portable video cassette
      recorder, radio-telemetry transmitter/receiver, and handheld or notebook
      computers for remote data logging, photoionization gas/vapor detectors (PIDs),
      and a personal aerosol monitor. The following workplaces were surveyed using the
      system: dry cleaning establishments--monitoring tetrachoroethylene in the air and
      in breath; printing works--monitoring white spirit type solvent; tire
      manufacturing factory--monitoring rubber fume; and a slate quarry--monitoring
      respirable dust and quartz. The system based on the handheld computer, in
      particular, simplified the data acquisition process compared with earlier systems
      in use by our laboratory. The equipment is more compact and easier to operate,
      and allows more accurate calibration of the instrument reading on the video
      image. Although a variety of data display formats are possible, the best format
      for videos intended for educational and training purposes was the review-preview
      chart superimposed on the video image of the work process. Recommendations for
      reducing exposure by engineering or by modifying work practice were possible
      through use of the video exposure system in the dry cleaning and tire
      manufacturing applications. The slate quarry work illustrated how the technique
      can be used to test ventilation configurations quickly to see their effect on the
      worker's personal exposure.

PMID- 10660989
TI  - Development of a continuous monitoring system for PM10 and components of PM2.5.
AB  - While particulate matter with aerodynamic diameters below 10 and 2.5 microns
      (PM10 and PM2.5) correlate with excess mortality and morbidity, there is evidence
      for still closer epidemiological associations with sulfate ion, and experimental
      exposure-response studies suggest that the hydrogen ion and ultrafine (PM0.15)
      concentrations may be important risk factors. Also, there are measurement
      artifacts in current methods used to measure ambient PM10 and PM2.5, including
      negative artifacts because of losses of sampled semivolatile components (ammonium
      nitrate and some organics) and positive artifacts due to particle-bound water. To
      study such issues, we are developing a semi-continuous monitoring system for
      PM10, PM2.5, semivolatiles (organic compounds and NH4NO3), particle-bound water,
      and other PM2.5 constituents that may be causal factors. PM10 is aerodynamically
      sorted into three size-fractions: (1) coarse (PM10-PM2.5); (2) accumulation mode
      (PM2.5-PM0.15); and (3) ultrafine (PM0.15). The mass concentration of each
      fraction is measured in terms of the linear relation between accumulated mass and
      pressure drop on polycarbonate pore filters. The PM0.15 mass, being highly
      correlated with the ultrafine number concentration, provides a good index of the
      total number concentration in ambient air. For the accumulation mode (PM2.5
      PM0.15), which contains nearly all of the semivolatiles and particle-bound water
      by mass, aliquots of the aerosol stream flow into system components that
      continuously monitor sulfur (by flame photometry), ammonium and nitrate (by
      chemiluminescence following catalytic transformations to NO), organics (by
      thermal-optical analysis) and particle-bound water (by electrolytic hygrometer
      after vacuum evaporation of sampled particles). The concentration of H+ can be
      calculated (by ion balance using the monitoring data on NO3-, NH4+, and SO4=).

PMID- 10660990
TI  - The international conventions for health-related sampling of aerosols--a review
      of current status and future evolution.
AB  - This review article discusses the status of international conventions for size
      selective sampling of particles and the extent to which they have been
      implemented worldwide. Some of the problems that have arose in the implementation
      process are addressed and solutions proposed. The article concludes that it is
      too early to revise the sampling conventions at this time, although there may be
      a case to do so in the future.

PMID- 10660991
TI  - Multicomponent error model for mass measurement based size fractionating aerosol
      samplers.
AB  - A mass based size fractionating aerosol sampling device such as an impactor has a
      number of experimental measurement errors that can affect the size distribution
      determination. These errors are not necessarily additive, such as weighing
      errors, multiplicative such as airflow errors, or a power function such as
      bounce. In general, the cumulative errors are a combination of different
      relational scales and they are likely to have different functional forms across
      the full range of measurements. A complete theory of errors must consider a
      diverse set of functional relationships between mass, flow, size distribution,
      and other non-linear parameters such as entry losses and bounce to estimate the
      error bounds for a measured size distribution and aerosol concentration. In
      addition, aerosol exposure measurements are single sample events. The theoretical
      multi-compartment error model is an extension of the Rocke and Lorenzato model of
      measurement errors in analytical chemistry and it includes generalized parameters
      for all empirically meaningful transformations. Although the general theory is
      complicated, heuristic reductions can be made to reduce the estimation process to
      a manageable size. The numerical examples of error analysis of a hypothetical
      impactor show that the measured distribution related error bound estimation
      process is not difficult to perform.

PMID- 10660992
TI  - Detecting H+ in ultrafine ambient aerosol using iron nano-film detectors and
      scanning probe microscopy.
AB  - Recent epidemiological evidence strongly suggests that ambient-particle
      associated acidity is more closely correlated with total mortality and hospital
      admissions for respiratory disease than indices of total particulate mass. In
      addition, evidence is accumulating to support the hypothesis that the number of
      ultrafine (d < or = 200 nm) acid particles, rather than ambient mass, is an
      important determining factor affecting lung injury. Both outdoor and indoor air
      environments are dominated by nanometer-sized particles. However, no data are
      currently available on the size distribution or number concentration of acidic
      ambient ultrafine particles largely because there are no suitable methods for
      measuring these important quantities. We have developed a method to accomplish
      these measurements based on the use of iron nano-films for detection of acid
      droplets. Detectors were prepared by vapor deposition of iron onto 12-mm-diameter
      glass cover slips. The detectors develop reaction sites when exposed to H2SO4 or
      NH4HSO4 particles. Exposures to non-acidic particle (NaCl and [(NH4)]2SO4) result
      in no detectable surface deformations. The nano-films are examined with scanning
      probe microscopy (SPM) for the enumeration of reaction sites. Until recently,
      direct visualization of individual objects smaller than 200 nm has been possible
      only with electron microscopy. The advancement of SPM provides the opportunity to
      examine the detector surface features with high quality three dimensional
      imaging.

PMID- 10660993
TI  - Modeling evaporative loss of oil mist collected by sampling filters.
AB  - Oil mists can cause respiratory distress and have been linked to skin and
      gastrointestinal cancers in workers. Standard concentration assessment methods
      call for sampling these mists with fibrous or membrane filters. Previous
      experimental studies using glass fiber (GF) filters and polyvinyl chloride and
      polytetrafluoroethylene membrane filters indicate that mist sampled onto filters
      may volatilize. A model has been developed to predict the evaporation of mist
      collected on a fibrous sampling filter. Evaporation of retained fluid from
      membrane filters can be modeled by treating the filter as though it is a fibrous
      filter. Predictions from the model exhibit good agreement with experimental
      results. At low mist concentrations, the model indicates that evaporation of
      retained mineral oil occurs readily. At high mist concentrations, significant
      evaporation from the filters is not expected because the vapor accompanying the
      airborne mist is already saturated with the compounds in the oil. The findings
      from this study indicate that sampling mineral oil mist with filters in
      accordance with standard methods can lead to estimates of worker exposure to oil
      mist that are too low.

PMID- 10660994
TI  - Gas and vapor exposure assessment methods.
AB  - Developing methods for making exposure assessment measurements for gases and
      vapors is a well-developed, active research field. Industry, academia, and
      government agencies have worked in this field for several decades, resulting in
      many sampling and analytical methods for gases and vapors for use in
      occupational, environmental, and indoor air applications. Consensus groups such
      as the International Standards Organization (ISO) and the American Society for
      Testing and Materials (ASTM) have contributed to the standard (methods) bank as
      well. There is much being done and much remaining to be done in methods
      development for gases and vapors. Additionally, consideration is now being given
      to issues like exposure to mixtures (noise and solvent vapors), mixed exposures
      (asphalt, diesel exhaust), and ethical acceptability--areas that before were, for
      a variety of reasons, largely ignored. This presentation focuses on method
      availability for exposure assessment, on research opportunities relative to gas
      and vapor analytical methods, and on avenues for accomplishing such work, and
      discusses some of the newer considerations for developing methods for exposure
      assessment.

PMID- 10660995
TI  - New European legislation and its relation to methods performance criteria and
      standardization.
AB  - In the European context, two new directives, in particular, are under
      development, namely a Chemical Agents Directive and an Ambient Air Directive. The
      first concerns the workplace and the second outdoor air, but both require an
      assessment of air quality and imply a requirement for actual measurement. If
      measurement results are to be comparable across Europe, there is also a
      requirement for standardization of such measurements, either as defined reference
      methods or as method performance requirements. The task of standardization in the
      field of measurement is ultimately the responsibility of the European Commission,
      but it usually devolves this responsibility to Scientific Expert Groups,
      reporting to the Commission, or to Technical Committees of CEN, the Comite
      Europeen de Normalisation. The development of standard measurement procedures,
      ideally meeting the CEN performance criteria, is also the responsibility of ISO,
      the International Organisation for Standardisation. In practice, CEN TC 137 has
      developed method performance requirements for measuring workplace air quality and
      CEN TC 264 has developed reference methods for measuring ambient air quality.
      However, these approaches are not entirely incompatible, because in most cases a
      reference method can only be established if it meets certain performance criteria
      and equivalent procedures are allowed. Most methods actually adopted by CEN as
      reference methods have previously been standardized by ISO, but a few are being
      developed within CEN.

PMID- 10660996
TI  - Mapping the air in real-time to visualize the flow of gases and vapors:
      occupational and environmental applications.
AB  - This article describes a new method for measuring and mapping pollutants in air
      in real-time which can be used for visualizing the flow of gases and vapors in
      both indoor industrial and outdoor environmental applications. This method uses
      open-path Fourier Transform Infrared (OP-FTIR) spectrometry and computed
      tomography for real-time mapping of concentrations of chemicals in air. These
      maps may be used to evaluate human exposures, source emissions and air dispersion
      models; thus, this method can be used for both industrial and environmental
      sampling. It is being developed using computer simulations, and chamber and field
      studies. Computer simulations used simulated test concentration data to create
      maps; the original maps of concentrations were compared with the tomographic
      reconstructed maps. In the chamber studies, tracer gas was released into the
      chamber and measurements from a tomographic system were compared with point
      sample measurements taken at the same time. When sulfur hexafluoride was injected
      in a stable flow field position in the chamber, the concentrations reconstructed
      by the concentration maps were within +/- 15.9 percent of the measured point
      samples; overall, they were within +/- 27 percent of the measured point samples.
      On a 12-foot by 14-foot grid of cells used to model the chamber, the average peak
      location error was within one foot. The peak location error refers to the error
      involved in locating the point of highest concentration in the plume. For the
      field study, field-generated tomographic maps were compared with concentrations
      estimated using the Industrial Source Complex-Short Term (ISCST) model. Fairly
      good correlation (R2 = 0.67) was found between the five-minute overall-average
      cell concentrations in the tomographic and ISCST model maps. Overall, the
      tomographic map concentrations over-predicted the ISCST model concentrations by
      24 percent. Optical remote sensing and computed tomography shows promise as a
      method to produce spatially and temporally resolved two-dimensional concentration
      maps indoors and outdoors. These maps would provide near real-time visualization
      of contaminant generation, movement, concentrations, and emission rates for
      multiple chemicals simultaneously at low limits of detection.

PMID- 10660997
TI  - Can depression be de-medicalized in the 21st century: scientific revolutions,
      counter-revolutions and the magnetic field of normal science.
AB  - This article is about our scientific investigations of the change mechanisms in
      cognitive therapy (CT) for depression. In a previous clinical trial, we found
      that so-called 'cognitive' interventions were not necessary for the success of
      CT: the behavioral activation (BA) component, a treatment precluding attempts to
      change thinking, worked as well as the entire CT package, both in maximizing
      acute treatment response and in relapse prevention over a two year period. We
      tentatively suggested at the time of publication [Jacobson, N. S., Dobson, K. S.,
      Truax, P. A., Addis, M. E., Koerner, K., Gollan, J. K., Gortner, E. T., & Prince,
      S. E. (1996). A component analysis of cognitive-behavioral treament for
      depression. Journal of Consulting and Clinical Psychology, 64, 295-304; Gortner,
      E. T., Gollan, J. K., Dobson, K. S., & Jacobson, N. S. (1998). Cognitive
      behavioral treatment for depression: relapse prevention. Journal of Consulting
      and Clinical Psychology, 66, 377-384.] that the 'cognitive' components of CT may
      not only be unnecessary but potentially a liability, since they result in a less
      parsimonious treatment package that may be not be cost effective. In this
      article, we not only defend this contention, but counteract the skepticism
      expressed by some CT advocates that the quality of our CT was deficient. Finally,
      we describe a study designed to confirm our conclusions from the earlier trial
      and, in the process, reintroduce a contextual perspective on depression, one
      which counters the currently dominant defect models reflected in both Beck's
      cognitive model and in theories that emphasize biological causation.

PMID- 10660998
TI  - Functional and dysfunctional perfectionists: are they different on compulsive
      like behaviors?
AB  - Both perfectionism and excessive responsibility have been linked to obsessive
      compulsive disorder (OCD). Up to now however, a greater number of studies have
      focused on the role of responsibility. The present study compared compulsive-like
      behavior of people with different styles of perfectionism. Sixteen functional
      perfectionists (FP) and 16 dysfunctional perfectionists (DP) were compared on
      three different tasks in order to explore OC type behavior such as doubting,
      checking and intrusions. Results show that DP participants, compared to FP
      participants, scored higher on an OC behavior scale, took significantly more time
      to complete a precision task and precipitated their decision when confronted with
      ambiguity. The two groups also tended to differ in their intrusive thoughts
      following an unsolved problem; FP participants were more preoccupied about
      solving the problem than about the quality of their performance, contrary to DP
      subjects. Results are discussed according to theoretical models of OCD.

PMID- 10660999
TI  - Effect of worrisome and relaxing thinking on fearful emotional processing.
AB  - This study replicated and extended previous data suggesting that worry inhibits
      emotional processing of fearful imagery. Female participants categorized as
      either victimization-fearful (N = 24) or victimization and speech-fearful (N =
      27) completed trials of worrisome or relaxing thinking and tone-cued imagery. For
      each trial, participants engaged in 30 s of relaxing or worrisome (speech or
      victimization) thinking and then imagined speech or victimization fear scenes for
      15 s. Heart rate and facial electromyography activity at the corrugator
      supercilii region were measured during the think and imagery periods to estimate
      degree of emotional processing of the fear imagery. Consistent with earlier
      findings, there was greater heart rate suppression during fearful imagery after a
      period of worry as opposed to relaxation. This finding, however, may have been
      the result of physiological differences between worrisome and relaxation
      thinking. Corrugator activation during thinking showed a similar pattern as the
      heart rate data while corrugator activation during fearful imagery was dependent
      on the baseline employed. These data, in combination with the imagery ratings
      data, suggest that worry may be an unsuccessful strategy for avoiding the
      physiological activation associated with emotional processing.

PMID- 10661000
TI  - Outcome of group cognitive-behavior therapy for bulimia nervosa: the role of core
      beliefs.
AB  - It is hypothesized that individuals who benefit less from CBT will be those who
      have more pathological core beliefs (unconditional beliefs, unrelated to food,
      shape and weight). Twenty bulimic women were treated using 12 sessions of
      conventional group CBT. Eating behavior and attitudes were assessed pre- and
      posttreatment. Core beliefs were assessed at the beginning of the programme, and
      were used as predictors of change across treatment (once any effect of
      pretreatment psychopathology was taken into account). Group CBT was effective,
      with reductions of over 50% in bulimic symptoms. Outcome on most indices was
      associated with pretreatment levels of pathological core beliefs. Possible
      reasons for these findings are discussed.

PMID- 10661001
TI  - Differences and similarities between obsessive intrusive thoughts and worry in a
      non-clinical population: study 1.
AB  - Worry is the central characteristic of Generalized Anxiety Disorder (GAD) and
      obsessions are a central feature of Obsessive-Compulsive Disorder (OCD). There
      are strong similarities between these disorders: repetitive cognitive intrusions,
      negative emotions, difficulty dismissing the intrusion and finally, loss of
      mental control. Direct comparisons between obsessions and worries are almost non
      existent in the literature but key distinctions have been proposed. The study
      attempted to specify the differences between obsessive intrusive thoughts and
      worry in a nonclinical population across a series of variables drawn from current
      models (appraisal, general descriptors and emotional reactions). 254 students
      participated in the study. They first identified an obsession-like intrusion and
      a worry and then evaluated them with the Cognitive Intrusion Questionnaire.
      Within-subject comparisons demonstrated significant differences on several
      variables: frequency, duration, percentage of verbal and image content,
      interference, egodystonic nature, stimuli awareness, emotions, etc. Most of these
      differences remained significant after controlling for frequency of thought.
      Discriminant analysis demonstrated a low classification error rate when using
      nine variables to categorize thoughts as obsessions or worries. Results generally
      support the differences postulated in the literature with the exception that
      obsessive intrusive thoughts are better controlled. The egodystonic/egosyntonic
      dimension emerged as an important variable in understanding obsessions and worry.

PMID- 10661002
TI  - Differences and similarities between obsessive intrusive thoughts and worry in a
      non-clinical population: study 2.
AB  - Differences between obsessions and worry have been clearly demonstrated on
      several variables [Langlois, F., Freeston, M. H., & Ladouccur, R. (2000).
      Differences and similarities between obsessive intrusive thoughts and worry in a
      non-clinical population: study 1. Behaviour Research and Therapy, 38, 157-173.].
      Previous factor analysis of obsessions or worries have typically been used in
      developing measures for OCD and GAD symptoms. These studies generally support the
      distinctiveness of obsessions and worries but there have been no direct
      comparisons of the factor structure of obsession and worry on the same measure.
      This study aimed to compare the general structure of worry and obsessional
      intrusions. It also attempted to identify the relations between the respective
      factors identified in the appraisals of intrusions and the factor structures of
      coping strategies used in reaction to the thoughts. 254 students participated in
      the study. They first identified an obsession-like intrusion and a worry and then
      evaluated them with the Cognitive Intrusion Questionnaire. Different factor
      structures were obtained for worry and obsessive intrusive thoughts. However, the
      factor structure for the strategies used to counter the thoughts were highly
      similar for both types of thought. Furthermore, regression analysis identified
      interesting relationships between the strategies, the thought characteristics and
      appraisal. Thus, despite the ability to find differences between obsessive
      intrusive thoughts and worry, and even to accurately categorize them based on
      these differences, there may in fact exist common processes that are shared over
      much of a continuum. Sharp differences in the processes involved may only become
      clear in prototypical cases. The implications for models of cognitive intrusion
      are discussed.

PMID- 10661003
TI  - Factors associated with outcome of cognitive-behavioural treatment of chronic
      post-traumatic stress disorder.
AB  - The study examined factors that were associated with outcome in the treatment of
      PTSD. A trial of cognitive therapy compared to imaginal exposure of chronic PTSD
      showed that although clinical improvements were obtained after treatment and at 6
      month follow-up one type of treatment was not significantly superior to the
      other. Characteristics of the patient, the trauma and treatment and of
      pretreatment clinical measures were investigated as predictors of PTSD outcome.
      Eleven variables were significantly associated with the pre- to post-treatment
      change in CAPS severity scores. Of these, three (duration of therapy, gender and
      suicide risk) were selected into a step-wise multiple regression equation to
      explain 36.5% of the outcome. Similarly, nine variables were significant
      associated with the pretreatment to follow-up change with three variables (number
      of missed therapy sessions, residential status and co-morbid GAD) being selected
      into the equation and explaining 36.9% of the outcome. The best predictor of
      outcome was inconsistent attendance at therapy.

PMID- 10661004
TI  - Dimensionality of posttraumatic stress symptoms: a confirmatory factor analysis
      of DSM-IV symptom clusters and other symptom models.
AB  - Recent exploratory [Taylor, S., Kuch, K., Koch, W. J., Crockett, D. J., & Passey,
      G. (1998). The structure of posttraumatic stress symptoms. Journal of Abnormal
      Psychology, 107, 154-160.] and confirmatory [Buckley, T. C., Blanchard, E. B., &
      Hickling, E. J. (1998). A confirmatory factor analysis of posttraumatic stress
      symptoms. Behaviour Research and Therapy, 36, 1091-1099; King, D. W., Leskin, G.
      A., King, L. A., & Weathers, F. W. (1998). Confirmatory factor analysis of the
      clinician-administered PTSD scale: evidence for the dimensionality of
      posttraumatic stress disorder. Psychological Assessment, 10, 90-96.] factor
      analytic investigations suggest that the three symptom clusters of posttraumatic
      stress disorder (PTSD) as defined in the Diagnostic and Statistical Manual [4th
      ed.; DSM-IV; American Psychiatric Association (1994). Diagnostic and statistical
      manual of mental disorders (4th ed.). Washington, DC: Author.] may not provide
      the best conceptualization of symptom dimensionality. However, the alternative
      models have not been in agreement, nor have they been compared against each other
      or models based on the DSM-IV. The purpose of the present investigation was to
      test a series of dimensional models suggested by these recent factor analytic
      investigations and the DSM-IV. Using data collected with the PTSD Checklist-
      Civilian Version [Weathers, F. W., Litz, B. T., Huska, J. A., & Keane, T. M.
      (1994). PCL-C for DSM-IV. Boston: National Center for PTSD--Behavioral Science
      Division.] from 349 referrals to a primary care medical clinic, we used
      confirmatory factor analysis to evaluate a: (1) hierarchical four-factor model,
      (2) four-factor intercorrelated model, (3) hierarchical three-factor model, (4)
      three-factor intercorrelated model, and (5) hierarchical two-factor model. The
      hierarchical four-factor model (comprising four first-order factors corresponding
      to reexperiencing, avoidance, numbing, and hyperarousal all subsumed by a higher
      order general factor) provided the best overall fit to the data; although, all
      models met some standards specified for good model fit. More research is needed
      to establish the dimensional nature of PTSD symptoms and to assess whether
      identified dimensions differ as a function of the trauma experience. Implications
      for assessment, diagnosis, and treatment are also discussed.

PMID- 10661005
TI  - The rising menace of environmental tobacco smoke.

PMID- 10661006
TI  - Raman Viswanathan Memorial Lecture. Host response in tuberculosis.

PMID- 10661007
TI  - Prognostic scoring for critically ill hospitalized patients.
AB  - The objective of the study was to validate and refine the APACHE II (acute
      physiology and chronic health evaluation II) prognostic system in the Indian
      context. We prospectively collected data on 79 patients admitted in the medical
      intensive care unit. We have studied APACHE II and 11 other physiological
      variables and sought to improve the risk prediction by developing a new score to
      be governed by the rule of thumb at the bed side. The new score included the
      following five variables: pH and serum albumin at admission and heart rate,
      bilirubin and Glasgow coma scale at 48 hours. A score below 3.5 was independently
      associated with a statistically significant increase in the risk of hospital
      death. This model resulted in a pseudo r2 of 0.43 in comparison to pseudo r2 of
      0.02 and 0.12 for APACHE II scores on the day of admission and after 48 hours,
      respectively.

PMID- 10661008
TI  - Effectiveness of salmeterol in stable COPD.
AB  - Thirty patients of stable chronic obstructive pulmonary disease (COPD) were
      studied for evaluation of effectiveness of inhaled salmeterol in a double blind,
      randomised, placebo controlled trial for seven days. Baseline spirometery and
      breathlessness score after 6 minutes walk test were assessed in all patients.
      Bronchial asthma was excluded in each patient by reversibility test with 200 ug
      of salbutamol inhalation. After inhalation of two puffs from a given inhaler
      through spacer device in the morning, spirometery was carried out 1, 3, 6 and 12
      hrs after inhalation on day 1, 3 and 7 of trial. Six minutes walk test and
      breathlessness score were assessed after 3 hrs of inhalation on days 1, 3 and 7.
      The maximum bronchodilator response to salmeterol was observed on 7th day at
      three hours after inhalation. The mean increase in FEV1 was 29.2% of baseline
      value, which was significant as compared to placebo where the mean increase in
      FEV1 was 3.3% of the baseline value. The peak rise in FEV1 was observed at three
      hours after inhalation on all the three days. The bronchodilator effect of
      salmeterol persisted for upto 12 hours. The mean maximum increase in walking
      distance in 6 minutes walk test was observed on 7th day in salmeterol group,
      which was 50.7 metres whereas in placebo group it was 12.2 meters. The patients
      in salmeterol group perceived less breathlessness after the six minutes walk
      test. The study concluded that salmeterol 50 micrograms twice a day is effective
      in improving lung functions in patients with stable COPD and can be recommended
      as maintenance therapy for stable COPD patients.

PMID- 10661009
TI  - Role of transbronchial lung biopsy in diffuse pulmonary disease: a review of 25
      cases during one year.
AB  - Transbronchial lung biopsy using the fibreoptic videobronchoscope was carried out
      in 25 patients with diffuse pulmonary disease. There were no serious
      complications. Satisfactory specimens were obtained in 20 of the 25 patients. A
      histological diagnosis was made in 10 patients. The problems of interpreting
      pulmonary fibrosis have been highlighted. Fibreoptic transbronchial lung biopsy
      is a safe and useful adjunct to the diagnosis of diffuse parenchymal pulmonary
      disease.

PMID- 10661010
TI  - The "half-moon sign" in saccular aortic aneurysm.

PMID- 10661011
TI  - Acute respiratory distress syndrome complicating typhoid fever.
AB  - We report a case of a young female patient with typhoid fever whose clinical
      course was complicated by hypotension, thrombocytopenia, encephalopathy and acute
      respiratory distress syndrome (ARDS). She recovered with prompt mechanical
      ventilatory support. ARDS in typhoid fever has generally proved to be fatal in
      reported cases.

PMID- 10661012
TI  - Adenoid cystic carcinoma of trachea.
AB  - Adenoid cystic carcinoma of trachea is a rare but distinct salivary gland-type
      malignant neoplasm. This paper described such a case in a young female in whom
      the mass that progressed to cause almost complete obstruction before it was
      diagnosed.

PMID- 10661013
TI  - BOOP presenting as pseudo-lymphadenopathy.
AB  - A case of BOOP presenting with hilar pseudo-lymphadenopathy is reported. Atypical
      radiology should not preclude diagnosis of BOOP.

PMID- 10661014
TI  - Environmental tobacco smoke seriously endangers children's health.

PMID- 10661015
TI  - Malignant pleural mesothelioma without asbestos exposure.

PMID- 10661016
TI  - [Patent ductus arteriosus in neonatal intensive care].
AB  - OBJECTIVE: In this study we evaluated the prevalence of symptomatic patent ductus
      arteriosus (PDA) in newborns, admitted to a neonatal intensive care unit (NICU),
      as well as the clinical features and the outcome of medical or surgical
      treatment. METHODS: We carried out a retrospective medical chart review of 42
      newborns admitted to an NICU between May 1996 and May 1998. Data regarding birth
      weight, sex, gestational age, prenatal corticotherapy and surfactant needs were
      gathered. Clinical evolution was assessed based on mechanical ventilation,
      morbidity and mortality. The therapeutic options and their results where
      analysed. RESULTS: Of the 1,195 newborns admitted to an NICU, 42 had symptomatic
      PDA. The prevalence was higher in newborns with a low birth weight. There was no
      significant difference regarding the administration of steroids prenatally in the
      newborns with PDA compared to the remaining newborns without PDA. Surfactant
      therapy, mechanical ventilation, bronchopulmonary dysplasia, necrotizing
      enterocolitis and intraventricular hemorrhage were found to be more frequent in
      patients with PDA, especially among those with a lower birth weight, with
      statistical significance for newborns weighing less than 2,500 g (p < 0.05). The
      therapy most frequently used was indomethacin, with a success rate of 22/23
      (95.6%) and with two cases of acute renal failure as side effects. Only one
      infant required surgical ligation of PDA. Mortality was similar in both groups
      (PDA vs. no PDA). CONCLUSION: PDA was probably underdiagnosed in our NICU.
      Morbidity, but not mortality, was higher in newborns with symptomatic PDA. We
      conclude that treatment with indomethacin is preferred to surgical ligation as an
      initial approach in those infants. Our data show the importance of early
      screening with echocardiogram for "silent" PDA in low birth weight neonates.

PMID- 10661017
TI  - [Absence of cardiac hypoplasia in an experimental model of congenital
      diaphragmatic hernia].
AB  - INTRODUCTION: Congenital diaphragmatic hernia (CDH) is a rare malformation in
      newborns. Amongst the various prenatal prognostic criteria, it is suggested that
      heart weight could be useful in evaluating the severity of lung hypoplasia. In
      this work we studied heart development in a rat model with nitrofen-induced CDH.
      MATERIAL AND METHODS: Pregnant female Wistar rats were treated on day 9 1/2 of
      gestation with 100 mg of nitrofen dissolved in 1 ml of olive oil. The control
      group was only treated with 1 ml of olive oil. The foetuses were delivered by
      caesarean section on day 21 1/2 of gestation. The weight of the foetuses was
      recorded. Under microscopy, the foetuses were dissected and the diaphragm was
      inspected. The wet weight of the heart and lung were recorded. The results are
      presented as a mean +/- standard deviation. A statistical analysis was made with
      the one-way ANOVA test on Ranks, and the Dunn test for post-test analysis. The
      statistical significance was set at a p < 0.05. RESULTS: The foetuses with CDH (n
      = 16) were lighter and had a smaller left lung/body weight ratio when compared
      with animals exposed to nitrofen without CDH (n = 18) and with controls (n = 12)
      (p < 0.05). The heart/ body weight ratio was smaller in foetuses exposed to
      nitrofen (p < 0.05), but we could not find any differences between nitrofen
      treated treated foetuses with vs without CDH (n.s.). CONCLUSIONS: In spite of the
      lung hypoplasia, we could not demonstrate the presence of heart hypoplasia in
      rats with CDH when compared to nitrofen-treated foetuses without CDH.

PMID- 10661018
TI  - [Comparative study of Toronto SPV prosthesis and bileaflet mechanical aortic
      prosthesis with 2D-Doppler echocardiography].
AB  - AIM: The aim of this study was to make a noninvasive comparison, by means of
      Doppler echocardiography, of the hemodynamic performance of biological stentless
      xenografts and mechanical bileaflet (MB) prostheses (P) in aortic position.
      METHODS: We studied 20 patients (pts) with normofunctional (nf) aortic Toronto
      (T) Stentless Porcine valves (SPV)--Group I--8 males, aged 69 +/- 12 years, 32 +/
      9 months after surgery, and 30 pts with nf MB aortic P (Carbomedics or St. Jude
      Medical)--Group II--17 males (p = NS vs G I), aged 61 +/- 12 years (p < 0.01 vs G
      I), 30 +/- 12 months after implantation (p = NS vs G I). Both groups were
      comparable with regard to body surface area and surgical indication. P diameters
      ranged from 21 to 25 mm (G I: 22.9 +/- 1.7; G II: 22.8 +/- 1.7 - p = NS), the
      number of pts with the same P diameter in each group being similar. We analysed,
      at rest: aortic orifice diameter (AoOd - cm), maximal (GMax) and mean (GMean)
      transprosthesic pressure gradients, P functional area (PFA) and P resistance
      (PRes). Gradients (mm Hg) were calculated by means of the Bernoulli equation, PFA
      (cm2) by means of the continuity equation and PRes (dynes.s.cm-5) as 1333 x Gmean
      x SEP/SV (SEP = systolic ejection period; SV = stroke volume). RESULTS: AoOd (G I
      vs G II): P 21--1.78 +/- 0.04 vs 2.00 +/- 0.10 (p < 0.001); P 23--1.91 +/- 0.10
      vs 2.19 +/- 0.10 (p = 0.01); P 25--2.22 +/- 0.24 vs 2.29 +/- 0.19 (NS). Doppler
      parameters: [table: see text] CONCLUSIONS: P T SPV show better hemodynamic
      performance when compared to P MB with the same diameter, in aortic position. In
      addition, our results suggest that P T SPV allow the use of larger valve sizes
      for the same aortic orifice diameter.

PMID- 10661019
TI  - [Severe ventricular dysfunction. When should is surgery not indicated?].
AB  - The decision to operate in the presence of severe ventricular dysfunction is one
      of the most difficult medical judgements because ventricular dysfunction is, as
      we know, the leading risk factor for morbidity and mortality in cardiac surgery.
      However, despite the greater surgical risk in some pathologies, the patients with
      severe cardiac dysfunction are those who will most likely benefit from surgery
      when we compare medical and surgical survival curves. Although ejection fraction
      is the parameter usually used to quantify ventricular systolic function and to
      stratify patients according to risk, we should not ignore the limitations of this
      parameter in the evaluation of myocardial function. Therefore, besides ejection
      fraction, other criteria should be considered in the process of patient selection
      for surgery. Taking these facts into consideration, the author seeks to establish
      criteria for different cardiac pathologies for the surgical treatment of patients
      with severe left ventricular dysfunction.

PMID- 10661020
TI  - [Serum markers for ischemic myocardial damage].
AB  - Assays of serum enzymes, such as aspartate aminotransferase (AST), lactate
      dehydrogenase (LDH), creatine kinase (CK) and isoenzyme MB, are widely performed
      in the early phase of suspected ischemic myocardial injury. However, these
      enzymes are not restricted to cardiac muscle tissue and increases in their serum
      concentrations have been observed in non-cardiac conditions. The levels of CK,
      and especially those of the myocardial specific isoform (CK-MB), have served as
      essential components for clinical decision in emergency rooms for over 25 years.
      This standard diagnostic test is far from perfect in specificity and the time
      delay necessary for the detection of a rise in levels. The clinician needs
      specific and sensitive biological parameters that can be rapidly measured in
      serum immediately after ischemic damage. In the last years, several new serum
      markers of myocardial damage have been developed. Currently, an important place
      is reserved for some non-enzyme muscle constituents, such as myoglobin and
      troponin sub-units, which have better specificity and allow an earlier detection
      of myocardial damage. The immunoassay of human cardiac troponin is a specific and
      sensitive diagnostic method for acute and sub-acute myocardial damage. It is
      ideal for the detection of myocardial necrosis in complex clinical situations
      when the usual enzymatic markers may be ineffective. An important prognostic
      value of troponin levels, especially troponin T, is currently under
      investigation. Myoglobin is a protein with low molecular weight that is
      abnormally high in serum two hours after myocardial infarction. Despite their
      high sensitivity, the use of serum measurements in the emergency room is
      controversial because of their low specificity, requiring the exclusion of
      skeletal muscle damage. Sensitivity could be lost in patients with renal function
      damage. The measurement of CK-MB protein weight (CK-MBmass) is another marker
      that has been confirmed as more accurate than CK-MB activity assays, especially
      in patients presented within four hours after the onset of chest pain, but could
      be inaccurate in several circumstances. In this research article, the authors
      describe the most important parameters of enzymatic and non-enzymatic markers,
      the kinetics of serum release, the clinical applications and the problems.

PMID- 10661021
TI  - The natural history of closed mitral commissurotomy--a 20 year follow-up.
AB  - AIM: To study the natural history of mitral stenosis in a Portuguese population
      submitted to closed commissurotomy. METHODS-POPULATION: All the patients
      submitted to closed mitral commissurotomy in Pulido Valente Hospital. The
      commisurotomies were performed from 1956 to 1978 and included a total of 1,134
      patients (220 males). Based on the clinical records, we studied the baseline
      characteristics of all the patients (n = 1134) at the time of surgery. An average
      of 20 years after surgery, we sent a questionnaire to all these patients. The
      patients who filled out the questionnaire (n = 352) represented the total
      Population in terms of the principal clinical characteristics. Based on these
      answers, we studied the long-term results of closed commissurotomy. RESULTS:
      Closed commissurotomy was performed before the age of 20 in about 10% of the
      patients and after the age of 49 in only 1.6%. The initial symptoms occurred at
      22.0 years and commissurotomy was performed at 30.4 years (averages). The
      procedure was successful: 99% of patients improved significantly after
      commissurotomy and two thirds had major or total improvement. CONCLUSIONS: In the
      natural history of these commissurotomized patients the events were early, with
      symptoms in their twenties and surgery in their thirties. The events occurred
      earlier in males than in females. Closed commissurotomy presented, in this study
      and with these patients, very good results with improvement in 99% of the
      patients. The positive results the commissurotomies were important and long
      lasting: there was a low rate of re-intervention (16%) and hospitalization (35%)
      twenty years after surgery and 53% of the patients are still alive. These good
      results can be, at least in part, explained by the low age of this population at
      the time of surgery.

PMID- 10661022
TI  - Determinants of survival after aortic valve replacement.
AB  - The aim of this study to was evaluate the surgical results of Aortic Valve
      Replacement (AVR) and to identify the predictive variables associated to risk. A
      total of 650 consecutive patients underwent isolated AVR at the Thoracic Surgery
      Centre, S. Joao Hospital, Oporto, between January 1976 and December 1996. There
      were 29 (4.5%) early operative deaths and 108 follow-up deaths (64 cardiac and 44
      non cardiac), which represents a linearized rate of 2.3% patients per year. The
      5, 10 and 15 year cumulative survival rates for the 650 patients were 85 +/- 3%;
      76 +/- 4.1% and 64 +/- 6.6, respectively. According to data in the literature,
      six preoperative variable and four operative variables were selected to be tested
      for association to risk. Multivariate analysis identified advanced age and the
      year of operation as the most important predictors of mortality followed by the
      type of the prosthesis (the mechanical valves performing better than the
      biological ones) and the prosthetic valve size (the small prosthesis performing
      worse than the others). We concluded that AVR is currently a low risk procedure
      at our Centre. The patient's age emerges as the main risk factor for overall
      mortality; a mechanical prosthesis should be preferred, at least before the age
      of 60, and prostheses with a ring size below 21-mm should be avoided.

PMID- 10661024
TI  - [Role of exercise test in the assessment of heart failure: update].

PMID- 10661023
TI  - [Prevalence of heart failure in Portugal].
AB  - The incidence and prevalence of heart failure are increasing, which presents an
      enormous problem for health care systems. In Portugal, there are no studies
      assessing this issue. The EPICA study was designed to estimate the prevalence of
      chronic heart failure in Portugal in 1998. This is a community-based
      epidemiological survey involving 13,000 primary care recipients, selected through
      a two-stage sampling procedure: each GP, from a random sample of 500, with
      proportionality to district population, will include 26 primary care recipients
      recruited sequentially within each age group. The cases will be identified
      according to ESC Guidelines: symptoms and signs of heart failure and
      echocardiographic evidence of cardiac dysfunction. The individuals will be
      screened for echo examination on the basis of a structured questionnaire (EPICA
      questionnaire) that was drafted from seven questionnaires previously used in
      epidemiological surveys for heart failure. Age and gender adjusted estimates of
      the prevalence of chronic heart failure will be obtained as well as a prevalence
      estimate for the whole population. The study will also estimate the test
      statistics (sensitivity, specificity and predictive values) for the EPICA
      questionnaire compared to echo data, as well as the seven other questionnaires
      used for the diagnosis of chronic heart failure. Their agreement will also be
      evaluated. PRELIMINARY RESULTS: 93% of the GPs recruited have participated. The
      final data will be available in early 2000.

PMID- 10661025
TI  - [Right ventricular dysfunction in left dysfunction caused by ischemia:
      conditioning factors and implications].

PMID- 10661027
TI  - Long-term clinical and echocardiographic follow-up after percutaneous mitral
      valvuloplasty with the Inoue balloon.

PMID- 10661026
TI  - [Prolapse of right ventricular mass into the right atrium producing right
      ventricular outflow obstruction].

PMID- 10661028
TI  - Preclinical evaluation of prototype products.
AB  - Preclinical evaluation of medical devices (prototype products) offers the
      opportunity to investigate and study the intended use of device materials.
      Preclinical evaluation programs are designed to determine the efficacy, safety,
      and biocompatibility of biomaterials, prostheses, and medical devices. The
      purpose of safety testing is to determine if a material presents potential harm
      to the human; it evaluates the interaction of the material with the in vivo
      environment and determines the effect of the host on the implant. Preclinical
      evaluation is the determination of the ability of the prototype product to
      perform with appropriate host response in a specific application, considered from
      the perspective of human clinical use. Therefore, preclinical data should include
      materials science and engineering, biology, biochemistry, medicine, host
      reactions and their evaluation, the testing of biomaterials, and the degradation
      of materials in a biological environment.

PMID- 10661029
TI  - Electric and laser energy for endoscopic surgery.
AB  - Improvements in surgery have focused on refinements in the ability to dissect and
      limit blood loss. The electrosurgery unit (ESU) and laser (light amplification by
      stimulated emission of radiation) have been widely used in recent endoscopic
      surgery. ESU is a form of surgery in which high-frequency (100 kHz-5 MHz)
      electric currents are used to incise, destroy, and remove tissue and to seal
      blood vessels in order to maintain hemostasis. The use of lasers in surgery has
      added a new dimension to operative technique through increased precision,
      improved hemostasis, and less tissue manipulation. This paper aims to explain the
      basic principles and applications of electrosurgery and lasers.

PMID- 10661030
TI  - Ultrasonic energy in endoscopic surgery.
AB  - The Harmonic Scalpel made by Ultracision is a system for endoscopic cutting. The
      energy source is vibration. The power box is attached to a forceps or blade, and
      the vibrational frequency of the blade approaches 55,500 cycles/second. This
      causes a knife-like action of the blade through tissue, with enough heating to
      create coagulation of small vessels. When this vibration energy is applied to the
      forceps configuration, coagulation occurs. By rotating the bottom blade of the
      forceps, the instrument becomes like a pair of scissors, and the tissue can
      divide. The Harmonic Scalpel allows the operator to cut using a tactile tissue.
      No smoke is created, only microaromized water droplets which are rapidly absorbed
      by the peritoneak surface. The instrument is extremely safe in that only tissue
      which is touched is cut; the energy source cannot travel through air, such as can
      happen with electrosurgery and laser surgery.

PMID- 10661031
TI  - Newly developing endoscopic devices--shadow optics and micromachine.
AB  - Based on the newly-developed engineering technologies, many kinds of useful
      equipment have been available for minimally invasive surgery. Recently the time
      to connect clinical needs and advanced technologies has become faster. In this
      article, we have summarized the recent technologies for endoscopic surgeries.
      Shadow optic technologies for better geometric perception using dual illumination
      in a conventional 2-D monitor and "Overview optics" for a panoramic view with an
      additional visual system are introduced. Micromachine technology is very close to
      practical implementation for minimally invasive surgeries. Virtual Biopsy is the
      one of the hottest topics for the next generation of endoscopy. Stereoscopic and
      volumetric vision systems are still on the way, which should overcome the
      irritating goggles and stereo display devices. As well as operational theater
      that integrates all the required equipment with a computer-based system,
      including voice recognition, still requires the standard protocols to connect
      many kinds of devices from different manufacturers.

PMID- 10661032
TI  - Current status of product for endoscopic surgery in Korea.
AB  - Endoscopic surgeries are popularly performed these days because of the advantages
      in rehabilitation and cosmetic aspects. But some accompanying disadvantages
      should not be neglected. For surgeons unfamiliar with the endoscopic surgery
      techniques, the operation takes more time and dangerous complications may occur
      more frequently. Most endoscopic surgery techniques, also called minimal invasive
      surgery techniques, were developed and disseminated from Europe and the U.S. They
      require specialized equipment and instruments that are expensive, and for this
      reason the total operation cost compared to conventional open surgery is higher.
      Despite all the advantages of endoscopic surgery, the high cost due to the of
      imported specialized instruments is holding back its spread in Korea. The
      development of self-supporting endoscopic instruments in Korea is mandatory for
      reducing the expense, and in this regard I have designed trocars of various size,
      specimen retrieval bags, suction and irrigation tubing sets, gasless laparoscopic
      surgery sets, scissors of various types, and forceps. Instruments used in suture
      and ligation which are currently under development will also soon be introduced.

PMID- 10661034
TI  - Technical evolution of arthoscopic knee surgery.
AB  - The widespread growth of arthroscopic techniques and their use has dramatically
      changed the practice of orthopaedic surgery. A high degree of clinical accuracy
      and minimally invasive procedure with a low surgical morbidity have encouraged
      the use of arthroscopy to assist in diagnosis, to determine prognosis and to
      provide treatment. In particular, the knee is the proper joint in which
      arthroscopy has its diagnostic and intraarticular surgical application. The rapid
      advancement of arthroscopic techniques has demonstrated a variety of surgical
      techniques in procedures such as meniscectomy, meniscal repair and cruciate
      ligament reconstruction during the last decade. This article reviews the past
      history of arthroscopy and technical evolution of arthroscopy in knee surgery in
      our department.

PMID- 10661033
TI  - Endoscopic treatment of upper gastrointestinal tumors.
AB  - The art and science of gastrointestinal endoscopy will continue to evolve at an
      amazing pace, with both endoscopists and industry providing new techniques and
      technologies for us to learn, investigate and apply to the benefit of our
      patients. It is not difficult to imagine that the next decade may see the
      maturation of a distinct specialty of gastrointestinal endoscopic surgery,
      currently in its adolescence, which crosses traditional boundaries. Practitioners
      will originate from a variety of backgrounds--gastroenterological, surgical or
      radiological--but must be trained specifically to perform the wide range of
      endoscopic procedures already in existence and those continually being
      introduced. Such 'endotherapists' will be an integral part of multidisciplinary
      units where optimal management strategies are planned based on available
      scientific evaluation of techniques irrespective of who performs them. Currently,
      numerous gastroinestinal diseases including both benign and malignant conditions
      have been managed using only endoscopic measurements. Control of gastrointestinal
      bleeding (variceal and non-variceal), dilation of benign and malignant
      strictures, antireflux management for esophagogastric reflux, endoscopic curative
      resection of premalignant and malignant lesions, treatment of submucosal tumors,
      percutaneous endoscopic gastrostomy or jejunostomy, stenting for malignant
      stricture of hollow viscus or pancreaticobiliary diseases, tumor ablation, and
      removal of biliary or pancreatic duct stones, etc. have been widely performed and
      various fascinating techniques and instruments have been continuously developed.
      It would be difficult to handle all of these various treatment modalities in a
      limited space. In this review we would like to discuss the fields of
      gastrointestinal tumors.

PMID- 10661035
TI  - Laparoscopic splenectomy for immune thrombocytopenic purpura--long-term result of
      40 laparoscopic splenectomies.
AB  - Laparoscopic surgery has recently extended its indications and it has also become
      an acceptable surgical approach for splenectomy. In the last five years, we have
      performed 40 laparoscopic splenectomies for immune thrombocytopenic purpura.
      Thirty-five patients were female and 5 patients were male. The mean age was 34,
      varying from 17 to 56. After learning to perform laparoscopic splenectomy with
      five ports, we are now usually using three or four ports in a right lateral
      kidney position. There was no case of conversion to exploratory laparotomy. The
      mean hospital stay was 7 days. There was no perioperative mortality; but in 2
      cases we had postoperative subphrenic abscesses which were successfully managed
      by catheter drainage. Since undergoing laparoscopic splenectomy, 28 patients
      (70%) were weaned effectively from their steroid medications. Eight patients
      (20%) have been on small doses of steroid, and 4 patients (10%) have been on the
      same doses of steroid with no response. The patient group with rapidly increasing
      platelet count after splenectomy showed a statistically significant relation with
      the complete response group (p < 0.001). Laparoscopic splenectomy is a safe and
      reasonable operative procedure for patients with immune thrombocytopenic purpura.

PMID- 10661036
TI  - Endoscopic management of uterine myoma.
AB  - This study was undertaken to evaluate the various gynecologic endoscopic surgical
      techniques including resectoscopic myomectomy, laparoscopic myomectomy, and
      laparoscopy assisted vaginal hysterectomy (LAVH) used in the treatment of uterine
      myomas. The medical records of 136 cases of uterine myomas treated using one or
      more of the gynecologic endoscopic surgical techniques in the Department of
      Obstetrics and Gynecology at Yonsei University were retrospectively reviewed from
      March 1997 to September 1998. Of the 136 cases reviewed, there were 40 submucosal
      myomas and 96 intramural and subserosal myomas. For statistical analysis,
      Student's t-test was used. Submucosal myomectomy using the resectosope was
      performed in 35 cases (mean age: 39 +/- 1.5 years), laparoscopic myomecotmy in 35
      cases (mean age: 36 +/- 1.9 years), and LAVH in 66 cases (mean age: 42 +/- 1.1
      years). In cases of huge myomas, the GnRH agonist was used prior to surgery, and
      in cases of heavy uterine bleeding, angioblock of the uterine artery was
      undertaken before the endoscopic procedures. The mean operating time was
      significantly shorter in resectoscopic myomectomy (41 +/- 12 min), followed by
      laparoscopic myomectomy (85.0 +/- 10.3 min) and LAVH (123 +/- 5.3 min). The mean
      hospital stay for resectoscopic myomectomy, laparoscopic myomectomy, and LAVH was
      1.9 +/- 0.5, 2.5 +/- 0.5, and 3.4 +/- 0.8 days (p < 0.001), respectively. There
      were 3 cases of complications including pulmonary edema and uterine perforation
      in the resectoscopic myomectomy group, and 4 cases of complications including
      bladder, ureter, and epigastric vessel injury in the LAVH group. In conclusion,
      the therapeutic effect of various gynecologic endoscopic surgical techniques can
      be maximized in terms of shorter operation time, shorter hospital stay, faster
      recovery, and less blood loss by the appropriate management of uterine myoma in
      well-chosen patients.

PMID- 10661037
TI  - Thoracoscopic sympathetic surgery for hyperhidrosis.
AB  - Resectional surgery of sympathetic nerves has been known to be the most effective
      treatment for essential hyperhidrosis and the application of thoracoscopic
      electrocauterization has provided a minimally-invasive procedure with the least
      morbidity and a resultant higher satisfaction rate. This paper describes our
      experience on the 1,167 cases of thoracoscopic sympathetic surgery for the
      treatment of essential hyperhidrosis. A total of 1,167 patients (674 males (58%)
      and 493 females (42%), mean age of 26.4 years with palmar (930), craniofacial
      (190) or axillary (47) hyperhidrosis underwent thoracoscopic sympathetic surgery
      from July 1992 to March 1999. Since the T2-4 sympathectomy, first performed in
      July 1992 for a patient of palmar hyperhidrosis, the operative methods have been
      altered to achieve a higher satisfaction level with the least complication by
      adopting less invasive procedures. Our current standard procedures being
      performed are T3 and T2 clipping for palmar and craniofacial hyperhidrosis and
      T3,4 sympathicotomy for axillary hyperhidrosis, all using a 2 mm needle
      thoracoscope. As the surgical procedures have been transited to a less invasive
      method with limited resection using the newest endoscopic devices, the average
      operation time and complications such as Horner's syndrome and compensatory
      hyperhidrosis have gradually decreased and thus the long-term satisfaction rate
      has been raised up to 98% for palmar hyperhidrosis, 92% for craniofacial
      hyperhidrosis and 89% for axillary hyperhidrosis. The recurrent cases (14/1167)
      were treated successfully with reoperations of thoracoscopic sympathetic surgery.
      The optimal goal of therapy could be achieved by complete elimination of the
      hyperhidrotic symptom, by decreasing the incidence and degree of compensatory
      hyperhidrosis through a selective and limited resection, and by adopting the
      least invasive procedures. Sympathicotomy has provided the advantages of a
      limited extent of denervation and the resultant decrease of compensatory
      hyperhidrosis compared to sympathectomy. The reversible method of clipping may be
      an effective, provisionary means for cases of severe, intractable compensatory
      sweating. For craniofacial hyperhidrosis, T2 sympathicotomy or clipping has been
      proven to be superior to the T1 sympathectomy due to the decreased occurrence of
      Horner's syndrome and T3,4 sympathicotomy providing a satisfactory outcome with
      less compensatory hyperhidrosis for axillary hyperhidrosis.

PMID- 10661038
TI  - Laparoscopy-assisted urologic surgery through minilaparotomy.
AB  - Minimally invasive surgery has gained wide acceptance as a method of reducing
      postoperative pain and curtailing the convalescence period. We have devised a
      modified surgical technique of laparoscopy-assisted surgery through
      minilaparotomy. It is a hybridized form of conventional open and laparoscopic
      surgery and it combines the benefits of both techniques by reducing postoperative
      pain and scarring as in laparoscopy, but at the same time maintaining the safety
      of conventional open surgery. From January 1992 to September 1999, we performed
      laparoscopy-assisted surgery through minilaparotomy in 167 patients. The
      operative time for laparoscopy-assisted surgery through minilaparotomy ranged
      from 79 to 290 minutes (mean 125). There was no conversion to open surgery, no
      peri- or postoperative complications, and only 3 patients needed a blood
      transfusion at any stage. Pain was significant on the first day but resolved
      quickly. All patients resumed consistent oral intake on the second day. All
      patients commenced ambulation by the second postoperative day and were able to
      resume full ambulatory activity by the fourth postoperative day. The final would
      size did not exceed 10 cm in size and all patients expressed satisfaction with
      their wounds. In conclusion, we believe that laparoscopy-assisted minilaparotomy
      surgery is a truly minimally invasive technique maintaining the advantages of
      conventional surgery. Our method could become a first-line approach for simple
      nephrectomy, living donor nephrectomy and radical nephrectomy, as well as surgery
      for kidney and ureter stones.

PMID- 10661039
TI  - Endoscopic surgery for obstructive hydrocephalus.
AB  - Endoscopic surgery is popular in the neurosurgical field. The purpose of this
      study was to determine the role of endoscopy in obstructive hydrocephalus. From
      1989 to 1999, we performed 81 endoscopic third ventriculostomies and 10
      septostomies. Seventy-one of 81 operations were performed with endoscopic third
      ventriculostomy alone and 10 patients had endoscopic third ventriculostomy and
      ventriculoperitoneal shunt simultaneously. Age distribution varied from 2 months
      to 62 years of age. Our selection criteria included aqueductal stenosis (39
      patients) and obstructive hydrocephalus due to tumor or cyst (42 patients). The
      most common candidate for endoscopic septostomy was atresia of the foramen of
      Monro (4 patients). Endoscopic septostomy was also performed to simplify shunting
      in patient; with multiseptated ventricle due to shunt infection, germinoma,
      thalamic tumor, craniopharyngioma, cyst and brain abscess. Sixty-five of 71
      patients who were treated with endoscopic third ventriculostomy alone showed
      successful results (91.5%). However, 6 patients had unsatisfactory results and
      they needed a ventriculoperitoneal shunt. With no mortality, transient surgical
      complications were observed in 7 patients: 2 transient diabetes insipidus from
      electrical injury to the pituitary stalk, 1 epidural hematoma from sudden
      drainage of CSF, 1 delayed intraventricular hemorrhage. 2 obstruction of
      fenestration site and 1 transient memory disturbance from injury to the fornix.
      Endoscopic septostomy was useful in simplifying shunting in all cases with
      complicated hydrocephalus. Endoscopic surgery is straightforward and effective in
      appropriately selected cases with obstructive by drocephalus.

PMID- 10661040
TI  - Operative laparoscopy in treating benign ovarian cysts.
AB  - This study was undertaken to evaluate the clinical usefulness of operative
      laparoscopy in treatment of benign ovarian cysts. A retrospective study was
      carried on 468 operative laparoscopy cases performed from September 1995 to
      September 1998 at Yonsei University College of Medicine, Department of Obstetrics
      and Gynecology. Patient characteristics, specimen pathology, perioperative
      morbidity, and perioperative complications were reviewed. The percentage of
      operative laparoscopy increased steadily from 20.7% in 1996, 33.9% in 1997, to
      49.7% in 1998. The mean age of patients was 33.66.5 (mean +/- SD) years and the
      mean hospital stay was less than 2 days. Types of surgery performed were
      cystectomy (n = 234), salpingo-oophorectomy (n = 126), oophorectomy (n = 63), and
      fulguration (n = 45), in decreasing order. Depending on the pathology of the
      ovarian cyst, the mean operation time was in the range of 80 to 110 minutes.
      Perioperative complications included 5 cases of subcutaneous emphysema, 10 cases
      of abdominal wall hematoma, 7 cases of trocar site bleeding, 3 cases of bowel
      injury, and 1 case of bladder injury. In conclusion, operative laparoscopy in
      treating benign ovarian cysts provides advantages such as less need to perform
      laparotomy, smaller skin incision, less perioperative discomfort, minimal tissue
      handling and trauma, and shorter hospital stay. Nevertheless, the risk of
      unrecognized ovarian malignancy cannot be absolutely excluded, therefore careful
      patient selection is mandated.

PMID- 10661041
TI  - AAOHN Advisory. Work fitness impairment evaluation in occupational and
      environmental health.

PMID- 10661042
TI  - Worksite influenza immunization. Successful program.
AB  - The planning, implementation, and evaluation of worksite health promotion
      programs can benefit from adapting and using the steps in each phase of the
      PRECEDE-PROCEED model. The model provides a framework to build and sustain
      support from employers and employees, and a valuable tool to increase program
      efficiency, effectiveness, and accountability. During the PRECEDE phases of
      planning, the model provides opportunities for continuous communication and
      feedback to all levels of management. The evaluation phases in PROCEED provide
      occupational health nurses with valuable information to share with corporate
      planners, influence management behavior, and contribute to evidence based
      decisions for future programming.

PMID- 10661043
TI  - A worksite influenza immunization program. Impact on lost work days, health care
      utilization, and health care spending.
AB  - Using a randomized, retrospective case control survey approach, this study
      compared employees immunized (cases) to a group of non immunized employees
      (controls) between the months of October and December 1994. In May 1995, a self
      administered questionnaire was distributed to employees working at the Hanford
      nuclear reservation located in eastern Washington State. Bivariate analysis
      included chi-square tests to study the association between influenza vaccine and
      rates of influenza like illness and related complications, rates of employee
      absenteeism, rates of physician visits, use of prescribed medication, and rates
      of hospitalization. To assess the economic benefits associated with vaccination,
      analysis included estimating the direct and indirect costs associated with
      immunization and influenza like illnesses, and complications related to influenza
      like illnesses. Responses to the survey resulted in 789 employees in the
      vaccinated group and 931 employees in the nonvaccinated group. As compared to
      vaccinated employees, nonvaccinated employees reported significantly higher rates
      of episodes of influenza like illness (78 per 100 compared to 59 per 100, p < 0),
      influenza related complications (8.0 compared to 5.0, p < .01), lost work days
      (63 per 100 compared to 35 per 100, p < 0), use of prescription medication (18.6
      per 100 compared to 8.7 per 100, p < 0), physician visits (18.6 per 100 compared
      to 8.7 per 100, p < 0), and inpatient hospital. Cost savings were estimated to be
      $83.84 per person vaccinated. The results of this study suggest this worksite
      influenza vaccination program produced significant health related and economic
      benefit to employee participants and their employers.

PMID- 10661044
TI  - Building a successful ergonomics team. Case report in a manufacturing
      environment.
AB  - 1. With sufficient educational preparation, occupational and environmental health
      nurses can facilitate ergonomics teams. 2. The diverse vocational and educational
      backgrounds of the team members are a major asset of an ergonomics team. 3. In
      this case report, the incidence of musculoskeletal injuries decreased within the
      first year of the team's inception. In addition, employees voiced their
      appreciation that their concerns were addressed and resolved through the
      ergonomics team. 4. Ergonomics teams should be a permanent part of a
      comprehensive corporate health and safety program.

PMID- 10661045
TI  - Reducing perceived physical stress while transferring residents. An ergonomic
      approach.
AB  - The purpose of this small study was to compare the physical exertion felt by
      nursing staff while transferring non-weight bearing residents from bed to chair
      and chair to bed using various methods of transfer. Another goal was to compare
      the residents' feelings of comfort and security using these transfer methods.
      Transfers using a specially designed chair that included a friction reducing
      transfer pad with handles were compared with transfers using a mechanical lift
      and a gait belt. Nursing personnel rated their perceived exertion immediately
      after the transfers; residents rated their feelings of comfort and security
      immediately after the transfer. Perceived physical exertion to shoulders, upper
      back, low back, and body were significantly decreased when using the chair and
      transfer pad. Residents reported feeling more comfortable and more secure while
      being transferred via the chair and pad versus the traditional methods of
      transfer in and out of bed.

PMID- 10661046
TI  - Transitional duty. An overview of program management and placement process.
AB  - Transitional duty is an effective means to return employees to work after an
      injury or illness. Provision of transitional duty may facilitate earlier return
      to work. It also helps in retaining an experienced work force, and decreases
      disability related costs. The occupational and environmental health nurse plays a
      major role in developing and maintaining a transitional duty program. Essential
      to programmatic responsibility is the ability to determine organizational
      culture, involve key stakeholders, and develop a program proposal that "sells"
      the program to a variety of customers. The ability to consistently evaluate and
      demonstrate program outcomes, once formal support is attained, is crucial to
      continued program support. The transitional duty placement process is a vital
      component of a comprehensive disability program and ensures employees are
      identified and placed appropriately according to their functional capacity.
      Routine evaluation of employees on transitional duty is essential to allow for
      progressive placement. The nurse plays a vital part in counseling and supporting
      employees and supervisors involved in the transitional duty process.

PMID- 10661047
TI  - Gertrude Stewart, AAIN president from 1957-1959. Interview by Eileen Lukes.

PMID- 10661048
TI  - Travel health information on the Internet.

PMID- 10661049
TI  - AAOHN Foundation awards first grants.

PMID- 10661050
TI  - The occupational health nurse as case manager--Part 2.

PMID- 10661051
TI  - Case management services for injured workers. Providers' perspectives.
AB  - The perceptions of service providers involved in case management services are
      described here. The service providers included claims managers, occupational
      nurse consultants, attending physicians, and nurse case managers. The purposes of
      this phase of the study were to describe these providers' perceptions about the
      case management program; to organize findings according to the quality assessment
      model that guided this study (including structure, function, and outcomes); and
      to identify barriers and facilitators to satisfaction with case management
      services. Structural factors that affected services included the workers'
      compensation system, construction of the service team, roles within the program,
      and individual attributes of service providers. Process factors were conflicts
      among parties, role of communication, and interaction with workers. Outcomes were
      described in terms of program efficiency and effectiveness. Data are used to
      illustrate and explain each of these themes.

PMID- 10661052
TI  - Case management for injured workers. A descriptive study using a record review.
AB  - A record review was used to examine case management services provided to 36
      workers who sustained a catastrophic or medically complex injury, and who were
      referred to a case management program. The aims of this phase of the evaluation
      were to identify and describe: Workers' demographics and personal attributes, The
      structures and processes that affected the course of these cases, and The role of
      the nurse case manager (NCM). A data collection instrument was developed to
      collect quantitative and qualitative information. Structural factors that emerged
      as most consequential included the quality and quantity of the injured worker's
      social support and the employment situation, including the availability of a job
      post-injury, employer support, and worker motivation. Process variables
      identified included the interactions of service providers including
      communication, and collaboration. The NCM was described as a monitor,
      coordinator, supporter, and advocate for the worker. Additionally, the NCM served
      as a consultant to other service providers and played a key role in the
      implementation of cost containment strategies.

PMID- 10661053
TI  - Evaluation of a case management program. Summary and integration of findings.
AB  - 1. Occupational health nurses can advocate for fair and equitable policies for
      both workers and employers. Assisting workers to understand and negotiate through
      the workers compensation system can minimize suspicion among workers and service
      providers, and can increase the effectiveness and efficiency of service
      provision. 2. Occupational health nurses can work with the team of service
      providers and the injured worker to develop appropriate and realistic goals for
      service provision. Make sure there is clarity related to the roles and
      responsibilities of all persons on the team (including the injured worker) is
      essential. Consistency and continuity of services throughout the life of the case
      is crucial. 3. The injury and its sequelae have personal meaning to the worker
      that may profoundly affect the outcome of their case. The OHN/CM must be
      sensitive and responsive to the worker's issues and concerns, and respectful of
      their views. Workers must be assisted to identify and tap into their social
      support systems. 4. Occupational health nurse/case managers should take an active
      role in developing and advocating for strategies that will assure effective and
      meaningful communication among all parties involved in a case.

PMID- 10661054
TI  - Behavior based safety. A different way of looking at an old problem.
AB  - 1. The occupational and environmental health nurse role in behavioral safety
      initiatives can very to include: serving as a leader, change agent, collaborator
      with safety professionals, consultant, team participant, educator, coach, and
      supporter to employees and management. 2. Behavior based safety and health
      initiatives add to existing knowledge and techniques for improving the health and
      safety of workers. 3. Behavior based safety relies on employee involvement and
      places a strong emphasis on observation, measurement, feedback, positive
      reinforcement, and evaluation. It focuses on identification of system
      improvements and prevention.

PMID- 10661055
TI  - Light treatment for sleep disorders in shift workers.

PMID- 10661056
TI  - Recent issues in physician-assisted suicide.

PMID- 10661057
TI  - Science, hospice, and terminal dehydration.

PMID- 10661058
TI  - Perceptions and decision-making on rehydration of terminally ill cancer patients
      and family members.
AB  - Although the appropriateness of forced rehydration for terminally ill cancer
      patients has been actively discussed, few studies have investigated its
      psychological aspects. To clarify patients' and family members' perceptions about
      rehydration and identify contributing factors for decision-making, a prospective
      structured survey was performed on 121 hospice inpatients with insufficient oral
      intake. Physicians did not recommend rehydration in 78 percent of patients, and
      75 percent decided not to receive artificial fluid therapy. Various concerns
      affected decision-making: 76 percent of patients and 85 percent of family members
      believed patients could not get appropriate nutrition without artificial
      rehydration. Some 56 percent of patients and 84 percent of family members said
      that withholding rehydration would cause premature death, while more than half
      agreed that forced rehydration might worsen the patients' suffering. Patients'
      performance status, fluid retention signs, denial, physicians' recommendations,
      patients' and family members' beliefs about the effect of hydration on patients'
      distress, and family members' anxiety about withholding rehydration were
      significantly associated with decision-making. Multiple regression analyses
      revealed patients' denial, physicians' recommendations determined by patients'
      performance status and fluid retention symptoms, and family members' belief that
      rehydration could worsen patients' distress as independent determinants for
      rehydration. In conclusion, hospice care receivers had various concerns about
      rehydration, related to patients' nutrition, survival, and distress. The main
      determinants for rehydration therapy were patients' performance status, fluid
      retention symptoms, denial, and care receivers' beliefs about the effect of
      hydration on the patients' distress.

PMID- 10661059
TI  - Symptom management algorithms for palliative care.
AB  - In order to develop standards of care that alleviate pain and other distressing
      symptoms among dying patients, the Providence Hospice of Yakima team has
      developed and utilized pain and nonpain symptom management algorithms. In use
      since late 1993, the system is a success, as demonstrated by positive
      satisfaction surveys among physicians, staff, and family members. This article
      offers an introduction to the algorithmic process, key components of its success,
      and guidelines for further improvement in the care provided to dying patients.

PMID- 10661060
TI  - The Minimum Data Set 2.0: a functional assessment to predict mortality in nursing
      home residents.
AB  - Measures of functional assessment, such as the Karnofsky Scale, the Modified ADL
      Scale, and the Descriptive Scale, have been used to predict appropriateness for
      hospice care. A tool is needed to assess functional status across all treatment
      settings, including acute care, long-term care, and hospice. The objective of
      this paper is to determine whether the Minimum Data Set, when utilized in
      conjunction with physical assessment tools to determine prognosis, is accurate in
      predicting short-term mortality in nursing home residents. The paper has been
      designed as a retrospective study of residents in 24 Minnesota nursing homes who
      were referred to a hospice program. The study included 199 patients from 30 to
      107 years of age. Functional variables, as triggered by the Minimum Data Set,
      have a direct correlation to patient mortality within three months of the
      documented observation of the triggered variable, and are the main outcome
      measure. Of a total of 199 patients, 147 patients (74 percent) died within 15
      days of a documented significant decline in the Minimum Data Set in areas of
      cognitive function, communication, activities of daily living, incontinence, and
      nutrition. Age, gender, diagnosis, and significant medical data received from the
      nursing home staff at the time of referral to hospice were applied to the
      Karnofsky Scale, the Modified ADL Scale, the Descriptive Scale, and the Minimum
      Data Set to determine if a resident assessment protocol (RAP) would be triggered
      by these data. The data were then analyzed to determine whether there existed a
      correlation between a significant change, as documented on the Minimum Data Set,
      and subsequent death of the patient. If there existed a correlation, the data
      were further studied to determine consistency in the categories of change that
      might demonstrate predictors of short-term mortality in nursing home residents. A
      decline in functional status, as documented on the Minimum Data Set 2.0 in the
      areas of cognitive functioning, communication, activities of daily living,
      incontinence, and nutrition, are strong predictors of short-term mortality in
      nursing home residents, independent of age, gender, and diagnosis.

PMID- 10661061
TI  - Family surveys: measuring more than just satisfaction.
AB  - A satisfaction survey can be beneficial to an agency if it is carefully planned
      and designed to facilitate quality feedback. The survey should be as short as
      possible and not appear to the respondent as an ominous task to complete. Care
      should be taken in developing the appropriate questions, asked in an objective
      manner that invites a positive or negative response. If possible, the capability
      should be developed to associate individual responses with the patient's
      demographic information. This linkage allows for further analysis and
      identification of characteristics of those who respond favorably and those who do
      not. Length of stay, patient days, a specific county, a staff team, or particular
      staff members are but a few examples of analysis criteria that might produce
      valuable information and possible focus for improvements.

PMID- 10661062
TI  - Lung cancer, malignant melanoma, multiple myeloma.
AB  - This is the fourth of a six-part series on the metastatic spread and natural
      history of 18 common tumors. Part one summarized symptom/problem anticipation,
      cancer metastasis, and the 18 tumors that each cause more than 6000 deaths per
      year in the United States. Bladder and brain cancer were discussed, with
      information given on tumor types, metastatic spread and invasion, and common
      symptoms. Parts two and three charted the natural histories, problems, and
      assessment parameters of advanced cancers of the breast, colon and rectum,
      esophagus, kidney, and liver; and leukemia. Part four provides corresponding
      information on lung cancer, malignant melanoma, and multiple myeloma. Each of
      these cancers is presented separately, with information given on mortality rates,
      the most common tumor types, sites of metastases, common problems, and common
      oncology emergencies. Sites of spread, resulting problems (including site
      specific symptoms), and assessment parameters are presented as tables. Material
      is presented so that clinicians will be able anticipate the spread of these
      cancers and can thus identify problems early in their development so that the
      problems are more easily managed.

PMID- 10661063
TI  - Pain control at the end.

PMID- 10661064
TI  - Cooperation, not competition, engenders success.

PMID- 10661065
TI  - Investigating the educational needs of licensed nursing staff and certified
      nursing assistants in nursing homes regarding end-of-life care.
AB  - Nursing homes care for people at the end of life (EOL). There is evidence to
      suggest, however, that nursing staff in these settings is often unprepared to
      provide a high level of EOL care. This article reports the findings from three
      preliminary studies that investigated the needs of licensed staff and certified
      nursing assistants in nursing homes regarding EOL care. The studies involved
      needs assessment surveys, focus group interviews with staff members, and
      telephone interviews with nursing home administrators. Data show that the major
      needs included a lack of knowledge and skills in symptom management;
      communication difficulties; conflicts with families and physicians; and emotional
      distress in dealing with time constraints and attachment to residents.
      Implications for nursing home staff education are described.

PMID- 10661066
TI  - Intermittent subcutaneous injections of pain medication: effectiveness,
      manageability, and satisfaction.
AB  - This study describes the use of intermittent subcutaneous injections of
      medications for pain control in a home hospice program. Six questionnaires were
      used to collect data over a one-year time period on the 52 patients who received
      medications by this route. Eighty-four percent of those patients had a diagnosis
      of cancer; patients received hospice care for a mean of 25 days. On average,
      intermittent subcutaneous medications were instituted three days prior to the
      patient's death. The main indication for this route was difficulty swallowing.
      Morphine was the most frequently used drug; side effects from the medication and
      problems with the route were rarely reported. Demographic information was
      collected on both the nursing staff and patients' caregivers; analysis indicated
      that caregivers were able to manage the injections and were satisfied with the
      method. Assessment of pain prior to and following the injections demonstrated the
      effectiveness of this method in controlling patients' pain.

PMID- 10661067
TI  - Central post-stroke ('thalamic syndrome') and other central pains.

PMID- 10661068
TI  - Love is as strong as death: meeting the pastoral needs of the Jewish hospice
      patient.

PMID- 10661069
TI  - Non-Hodgkin's lymphoma, oral cavity and pharynx, and ovary.
AB  - This is the fifth of a six-part series on metastatic spread and natural history
      of 18 common tumors. Part 1 summarized symptom/problem anticipation, cancer
      metastasis, and the 18 tumors that each cause more than 6000 deaths/year in the
      United States. Bladder and brain cancer were discussed, with information given on
      tumor types, metastatic spread and invasion, and common symptoms. Parts two,
      three, and four charted the natural histories, problems, and assessment
      parameters of advanced cancers of the breast, colon and rectum, esophagus,
      kidney, liver, and lung; and leukemia, melanoma, and multiple myeloma. Part five
      provides corresponding information on non-Hodgkin's lymphoma and cancers of the
      oral cavity (and pharynx) and ovary. Each of these cancers is presented
      separately, with information given on mortality rates, the most common tumor
      types, sites of metastases, common problems, and common oncologic emergencies.
      Sites of spread, resulting problems (including site-specific symptoms), and
      assessment parameters are presented as tables. Material is presented so that
      clinicians will be able to anticipate the spread of these cancers and can thus
      identify problems early in their development so that the problems are more easily
      managed.

PMID- 10661070
TI  - Spiritual competency: an open letter to hospice colleagues.

PMID- 10661071
TI  - Suicide prevention: a public health approach.
AB  - This article proposes a model for developing a national or regional suicide
      prevention strategy. Suicide is examined from the perspectives of stress, coping
      behaviours, lethality and multiple causation. Public health concepts of primary,
      secondary and tertiary prevention are applied to suicide with minor
      modifications. This exercise facilitates clarity with respect to planning
      strategies. Conceptual clarity may improve prospects for success but ultimately
      evaluation will elucidate the outcome.

PMID- 10661072
TI  - Nursing staff satisfaction on a mental health unit.
AB  - The present study set out to assess the level of nurses' job satisfaction in an
      acute in-patient mental health setting. All but one (n = 22) of the full-time
      nursing staff employed on the unit took part in the study. Unlike many previous
      studies where the level of job satisfaction was assessed using predetermined
      questionnaire items but without providing an understanding for workers' choices,
      the present study sought an estimation of what job characteristics nurses saw as
      important, an estimation regarding their current satisfaction with each
      characteristic and, importantly, the reasons behind their choices.

PMID- 10661073
TI  - Preliminary results from an Australian psychosocial rehabilitation program for
      people with serious mental illness.
AB  - Psychosocial rehabilitation, for those with a serious mental illness, is of
      significant importance due to both its frequency and cost to government. This
      paper describes the implementation and preliminary assessments of a new
      psychosocial rehabilitation program in New South Wales. Of particular urgency was
      the requirement to establish baseline measures for ongoing service evaluation at
      the unit. An extensive array of assessment tools (Brief Psychiatric Rating Scale,
      BPRS; Scale for the Assessment of Negative Symptoms, SANS; Quality Of Life Scale,
      QOLS) was applied to determine the functioning of clients prior to the program.
      Following the initial assessments, subsequent measures were undertaken on
      completion of the program and then at 1 year follow-up. It was hypothesized that
      the clients would demonstrate significant improvements on these measures with a
      reduction in their psychopathology as assessed by the BPRS, improvement in their
      quality-of-life as measured by the QOLS and improvement in their negative
      symptoms as measured by the SANS. The final outcome demonstrated improvement in
      the assessment scores by 34%. A positive correlation to the above results showed
      a 54% reduction in the re-admission rate of clients and length of stay in
      hospital. The paper describes further developments regarding this psychosocial
      rehabilitation unit and suggests other psychosocial rehabilitation initiatives.

PMID- 10661074
TI  - Deliberate self-harm in rural Western Australia: results of an intervention
      study.
AB  - This study evaluates an intervention program in its first 2 years of operation in
      rural Western Australia. The program was effective in producing a systems change
      within the hospital by implementing a protocol of best practice and in improving
      the inter-sectoral liaison between community-based referrals and treatment
      agencies through professional and community education. The early indications
      suggest a reduction in the rate of hospital admissions for repeated suicide
      attempts for cases who were managed by the suicide intervention counsellor
      through a high-intervention approach.

PMID- 10661075
TI  - Collaboration or chaos: a consumer perspective.
AB  - Consumer participation in all levels of mental health service provision is now
      government policy throughout Australia. However, effective participation by
      consumers requires collaboration between mental health nurses and consumers.
      Effective collaboration and the partnership between those who provide and receive
      services requires trust and respect on both sides. Accompanying consumers on
      their 'journey' of wellness and recovery is likely to also provide mental health
      nurses with opportunities for personal and professional growth.

PMID- 10661076
TI  - The 4th quinquennial national community mental health nursing census of England
      and Wales.
AB  - Since 1980, a survey of community mental health nursing has been conducted in the
      United Kingdom, at five-yearly intervals. These three data sets have been
      uniquely useful in plotting trends in Community Mental Health Nursing (CMHN)
      activity over time. Substantial administrative changes to the National Health
      Service have taken place in England and Wales since 1990, however, and these have
      impacted on the nature of mental health service provision. These changes have
      implications for all mental health service personnel and, in particular, the work
      of community mental health nurses. This article presents selected findings from
      the national census, conducted between 1996 and 1997. It sets these findings
      within the context of data derived from the three previous national studies in
      the series and within the contemporary national policy context and discusses the
      substantive implications which flow from the changes detected over time in the
      practice, organisation and management, and education of community mental health
      nurses in England and Wales.

PMID- 10661077
TI  - Mental health nursing and cultural diversity.
AB  - The focus of this article is on ethnic cultural difference. The establishment of
      a bi-cultural model of health care delivery has been a recent priority in New
      Zealand. Bi-culturalism has become an important concept for Maori and Pakeha
      (Europeans), working in partnership in the planning and implementation of mental
      health services in New Zealand. Adoption of the principles of respect and
      recognition of the uniqueness of different cultural identities, by nurses, has
      meant that clients who use mental health services in New Zealand are beginning to
      benefit from nursing care that is culturally competent.

PMID- 10661078
TI  - Collaborative education and social stereotypes.
AB  - The purpose of this paper is to present results from a two-year collaborative
      education project conducted with people with a serious mental illness and senior
      undergraduate students of nursing at the Centre for Mental Health Nursing
      Research at Queensland University of Technology. The study was funded by the
      Australian Commonwealth Government and was completed in June 1998. The results
      suggest that collaborative education is an effective means for breaking down
      social stereotypical thinking about people with a mental illness. A similar
      finding with respect to the stigmatization of undergraduates supports this
      hypothesis. Implications for psychiatric rehabilitation and the undergraduate
      education of students of nursing are explored.

PMID- 10661079
TI  - Staff confidence in dealing with aggressive patients: a benchmarking exercise.
AB  - Interacting with potentially aggressive patients is a common occurrence for
      nurses working in psychiatric intensive care units. Although the literature
      highlights the need to educate staff in the prevention and management of
      aggression, often little, or no, training is provided by employers. This article
      describes a benchmarking exercise conducted in psychiatric intensive care units
      at two Western Australian hospitals to assess staff confidence in coping with
      patient aggression. Results demonstrated that staff in the hospital where regular
      training was undertaken were significantly more confident in dealing with
      aggression. Following the completion of a safe physical restraint module at the
      other hospital staff reported a significant increase in their level of confidence
      that either matched or bettered the results of their benchmark colleagues.

PMID- 10661080
TI  - Factors influencing nurse-patient interaction in the acute psychiatric setting:
      an exploratory investigation.
AB  - Nurse-patient interaction in acute psychiatric in-patient facilities has been the
      subject of much discussion in the literature and remains a contentious issue. How
      and why nurses interact with patients in the acute care setting requires
      definition within the current dynamic environment of mental health service
      provision. Factors which impact on the manner in which nurses care for patients
      also require investigation. This article presents the findings of a collaborative
      research study that investigates factors that influence nurse-patient interaction
      in the acute psychiatric setting. Ten nurses on the study ward were given
      opportunity, through semi-structured interviews, to outline and describe the
      factors perceived to influence nurse-patient interaction. Factors identified as
      influencing interaction included the ward environment, something always comes up,
      nurses' attributes, patient factors, instrumental support and focus of nursing.
      Issues which emerged from the study provide managers and clinical nurses with an
      opportunity for generating new possibilities for nurse-patient interaction.
      However, these issues must be addressed in a sensitive way that takes into
      account the complex and dynamic nature of acute care settings.

PMID- 10661081
TI  - Perioperative roles.

PMID- 10661082
TI  - Nurse education has had a bad press.

PMID- 10661083
TI  - A different kind of theatre nurse. Interview by Kate Lancaster.

PMID- 10661084
TI  - CJD under the microscope.

PMID- 10661085
TI  - Theatre nurses' attitudes towards their role--a phenomenological enquiry.

PMID- 10661086
TI  - When is blowing the whistle not whistle blowing?

PMID- 10661087
TI  - A rare breed: exploring the role of the lecturer practitioner in perioperative
      practice.

PMID- 10661088
TI  - Patient care in the operating department (1).
AB  - Judging by the positive feedback I have received about this series it is a timely
      reminder--or introduction--to the perioperative area. It has been suggested that
      universities and colleges should be made aware of the existence of this series in
      order that students may benefit prior to the theatre placement. So why don't you
      recommend it to your tutors, universities and colleges? This article will
      introduce three aspects of patient care, undertaken in the operating department.
      These are prevention of errors in surgical procedures, patient positioning and
      pressure area care.

PMID- 10661089
TI  - Changing the game in the intensive care unit: letting nature take its course.

PMID- 10661090
TI  - Music therapy in critical care: indications and guidelines for intervention.
AB  - Music therapy is an effective intervention for critically ill patients for such
      purposes as anxiety reduction and stress management. The therapy is readily
      accepted by patients and is an intervention patients thoroughly enjoy. The MAIT
      is one resource that nurses caring for critically ill patients can use to
      implement music therapy in clinical practice. Patients can be given the
      opportunity to select a musical tape they prefer and to negotiate with the nurse
      for uninterrupted music-listening periods. Allowing patients control over music
      selection and providing uninterrupted time for music listening gives the patients
      an enhanced sense of control in an environment that often controls them.

PMID- 10661091
TI  - Implementation of a pet visitation program in critical care.
AB  - We have no quantitative research data to document that these visits are actually
      helpful to patients in any measurable way, although we certainly hope to have
      some soon. However, observations of staff members and evaluations from
      participants in the program have been quite positive thus far. The program has
      been in place for more than 2 years, and about 30 pets have visited so far,
      including 28 dogs and 2 cats. Implementing a pet visitation program for
      critically ill patients affords healthcare providers the opportunity to offer a
      unique and humanistic therapeutic intervention to appropriate patients. Although
      it is a time-consuming endeavor, it has been well received by those patients and
      families that have participated in pet visits. Critically ill patients are often
      denied many simple pleasures because they are in physiological crisis. Such
      patients experience loneliness, isolation, depression, and lack of emotional
      support. Pet visitation is one way to address these common problems of ICU
      patients. For this reason, pet visitation will remain a therapeutic option for
      the support of our critically ill patients.

PMID- 10661092
TI  - Psychiatric aspects of transplantation, II: Preoperative issues.

PMID- 10661093
TI  - Developing trust and connection with patients and their families.

PMID- 10661094
TI  - Munchausen syndrome by proxy: literature review and implications for critical
      care nurses.

PMID- 10661095
TI  - The day the lights went out: one charge nurse's nightmare.
AB  - The synergy model can be applied to many clinical situations. As nursing leaders
      evolve, competencies required to effectively respond to unexpected events
      silently develop. Applying the Synergy Model to this exemplar helped to
      articulate the charge nursing's leadership in ensuring a safe practice
      environment. The model provides a framework to more fully describe the multiple
      dimensions of a charge nurse's role, and acknowledges the richness of knowledge
      and competence that charge nurses often contribute to complex clinical
      situations.

PMID- 10661096
TI  - Family and pet visitation in the critical care unit.

PMID- 10661097
TI  - Should continuous intravenous (i.v.) heparin be infused via a Y site?

PMID- 10661098
TI  - Making the wait more bearable.

PMID- 10661099
TI  - Heart failure: the physiologic basis for current therapeutic concepts.

PMID- 10661100
TI  - Nontraditional musings.

PMID- 10661101
TI  - Complementary/alternative therapies. So many choices.
AB  - Several forms of complementary and alternative medicine (CAM) can be used to
      promote healthy aging. The choice to use them often is a matter of personal
      preference and/or availability. Most CAM therapies have little or no side effects
      under certain conditions. However, patients should be strongly encouraged to let
      their health care providers know which CAM and conventional therapies they are
      using. This notification will inhibit any potential untoward reaction from mixing
      different therapies. If health care providers are caring for patients who are
      using CAM, they must be knowledgeable of the risks and benefits of these
      therapies. This article provides some of this information.

PMID- 10661102
TI  - Practicalities of an alternative pathway. The yellow brick road or a minefield?
AB  - The title of this article is a metaphor of how two consumers turned to self-care
      to maintain health through alternative pathways in the burgeoning field of
      natural healing. We describe practical information on how we became involved and
      our results, how to select practitioners, and how gerontologic nurses can enhance
      the interest in and credibility of self-care.

PMID- 10661103
TI  - Using complementary and alternative therapies wisely.
AB  - Growing numbers of consumers are using complementary and alternative medicine
      (CAM). Many of these therapies offer effective approaches to the management of
      chronic conditions and the promotion of health. However, they are not without
      risks. This article discusses the risks associated with common CAM therapies and
      offers practical suggestions to promote the safe integration of CAM with
      conventional care.

PMID- 10661104
TI  - Spirituality and the elderly: nursing implications with nursing home residents.
AB  - Spiritual care is integral to quality nursing care for nursing home residents.
      Spirituality can be defined as dynamic principles developed throughout the
      lifespan that guide a person's view of the world; influence his or her
      interpretation of a higher power, hope, morals, loss, faith, love, and trust; and
      provide structure and meaning to everyday activities. Spiritually focused nursing
      interventions include silent witnessing, serving as a liaison, and active
      listening. Nursing interventions for spiritual care can be divided into four
      dynamic phases: self-comfort, assessment, intervention, and evaluation. Spiritual
      well-being helps residents' total well-being and inner peace.

PMID- 10661105
TI  - Standard of practice protocol: acute confusion/delirium. NICHE Faculty.
AB  - Acute confusion, also known as delirium, is a prevalent disorder that contributes
      to poor outcomes of care. Because of their inability to think clearly, delirious
      patients are unable to care for themselves and often exhibit unsafe behaviors,
      resulting in an increased use of physical and pharmacologic restraints.
      Consequently, the goal of this article is to delineate prevention and treatment
      guidelines for acutely confused patients and thereby improve nursing care for
      this vulnerable patient population.

PMID- 10661106
TI  - Care of the patient with gout.

PMID- 10661107
TI  - Embracing the Eden Alternative in long-term care environments.
AB  - As we move toward the new millennium, 76 million Baby Boomers are on the brink of
      retirement. For some seniors, long-term care will be a necessity. Older adults
      value independence, physical activity, intellectual curiosity, caring, and
      spirituality. The long-term care culture is being revolutionized by The Eden
      Alternative, which strives to decrease loneliness, helplessness, and boredom by
      developing healthy habitats in a home-like environment. Three key components are
      children, plants, and companion animals that provide variety and spontaneity in
      life.

PMID- 10661109
TI  - Drug/food/food supplements interactions.

PMID- 10661108
TI  - Charlotte Eliopoulos, RNC, PhD. Holistic nurse: teacher, leader, author.

PMID- 10661110
TI  - A little art in home care: poetry and storytelling for the soul.

PMID- 10661111
TI  - The supplement dilemma.

PMID- 10661112
TI  - Assessing and planning primary care at college and university health centers.
AB  - The student body in colleges and universities is no longer homogeneous but
      represents many age groups and life styles. The results of the first national
      college health risk behavior survey reveal problem behaviors matched to
      demographic descriptions of these groups. Nurse practitioners can use this
      information along with relevant health care research to plan and provide
      preventive services as part of the student health center.

PMID- 10661113
TI  - Developing and implementing a Healthy Heart program for women in a parish
      setting.
AB  - Designed for implementation in a parish setting, the "Hearts To God" project
      integrates spirituality, stewardship, and wholeness into a cardiovascular health
      promotion program. This program fills a health education void regarding
      cardiovascular disease and women. The program and accompanying manual incorporate
      heart healthy education with a spirituality message to encourage behavior change.
      It can be adapted to suit the educational context and adult population. Exercises
      included in the manual enable women to assess, develop, and evaluate their own
      plan for heart health. Participants found the program to be relevant.

PMID- 10661114
TI  - Advanced practice community health nursing in community nursing centers: a
      holistic approach to the community as client.
AB  - Community nursing centers are unique arenas for advanced practice community
      health nursing. These innovative nurse-managed delivery models are grounded in a
      holistic approach to the community-as-client. They provide the public with direct
      access to a range of advanced practice professional nursing services that are not
      otherwise available. Community Nursing Centers are collaborative with other
      health professions and organizations. They aim to meet the assessed needs of
      underserved populations using extant resources to achieve optimal health for all
      members of the community. This article discusses the underlying conceptual basis
      for development of community nursing centers and provides a case study example.

PMID- 10661115
TI  - The Arkansas AHEC model of community-oriented primary care.
AB  - This article explicates the Arkansas Area Health Education Center (AHEC) model of
      community-oriented primary care (COPC) and the role of the family nurse
      practitioner (FNP) in its implementation. The AHECs collaborate with local
      agencies to provide comprehensive, accessible, quality health care to specific
      patient populations, and offer learning opportunities to a wide variety of health
      professions students. The FNP demonstrates organizational and role competencies
      that include directing patient care, providing professional leadership, and
      developing the advanced practice nursing role. Two case studies are used to
      illustrate the FNPs' approach to COPC: (1) selection of interdisciplinary,
      multidisciplinary, and transdisciplinary approaches to management of a patient
      with chronic illnesses, and (2) the Sexual Assault Nurse Examiners Training
      Project.

PMID- 10661116
TI  - Primary care ... where?
AB  - Corporate-based nurse managed centers are not the national norm. More prevalent
      is the use of an occupational health or physician-directed medical model of care.
      The author describes how a 14-year-old primary care center at a North Carolina
      computer software company is just "business as usual" when viewed in the context
      of the company's philosophy, goals, and culture. Included are considerations for
      nurse practitioners interested in the successful transplantation of this primary
      care model to other settings.

PMID- 10661117
TI  - 21st century house call: the Internet and the World Wide Web.
AB  - Changes in health care delivery and the explosion of health information available
      on the Internet are affecting primary care practice in America. The provider is
      no longer the distributor, interpreter, and filter of information in the health
      care setting. Clients are becoming informed about their treatment options via the
      World Wide Web and are eager to discuss their therapeutic alternatives, gleaned
      from a variety of sources, with their practitioners. The shifting paradigm of
      practitioners as information provider to information broker is explored. Useful
      sites for primary care providers and guidelines for obtaining and evaluating
      electronically available information is provided. Additionally, caveats in this
      era of electronic communication are presented.

PMID- 10661118
TI  - Effective promotion of breastfeeding among Latin American women newly immigrated
      to the United States.
AB  - Across the United States, advance practice nurses (APNs) are increasingly
      encountering recently immigrated Latin American populations. This article
      provides an overview of the situation of Latin Americans in the United States and
      discusses aspects of Latin American culture such as, respeto (respect), confianza
      (confidence), the importance of family, and the value of a personal connection.
      Strategies that will assist practitioners to incorporate culturally holistic
      principles in the promotion of breastfeeding among Latin American women who are
      new arrivals in the United States are described. If practitioners are to respond
      to the increasing numbers of Latin American women who need health care services,
      and also provide thorough, holistic health care then health care activities must
      be integrated with cultural competence.

PMID- 10661119
TI  - Evaluating change in quality of life from the perspective of the person: advanced
      practice nursing and Parse's goal of nursing.
AB  - Advanced practice nurses (APNs) are challenged to evaluate their practice in
      light of goals guided by nursing theory. In this specific case study, a nurse
      consultant, using Parse's theory of human becoming, evaluated changes in the
      quality of life from the perspective of the person for patients suffering from
      genital herpes. The nurse consultant met with the group before (presession) and
      after (postsession) an APN's 10-week series of seven sessions (person/group
      perspective intervention). Analysis of pre- and postsession data uncovered three
      patterns. These are described with implications for research and practice.

PMID- 10661120
TI  - African-American women's perceptions of weight: paradigm shift for advanced
      practice.
AB  - To identify African-American women's definitions and descriptions of body weight,
      using King's General Systems Framework and Combs and Snygg's concept of
      perception as a guide, focus group methodology was utilized. These women's frame
      of reference for "normal body weight" was much larger than the standard indicator
      for weight and defined weight, normal weight, ideal weight, underweight,
      overweight, and obesity in terms of their cultural, social, and individual
      context. By understanding individual perceptions of weight, advanced practice
      nurses can devise strategies to facilitate weight management in African-American
      women who may want to lose or need to lose weight for such health-related
      illnesses as diabetes, cardiovascular disease, or hypertension.

PMID- 10661121
TI  - Health promoting organizations: a systems model for advanced practice.
AB  - Nursing and other health care providers are challenged to create the future of
      health care. Health is synonymous with well-being framed holistically, mind,
      body, and spirit. Disparities are growing in health status for vulnerable
      population groups and the percentage of people who are uninsured is rising. New
      approaches to health care are needed in the current age of uncertainty. A
      comprehensive health promoting organization (HPO) model within an ecological
      systems framework is described. An operational example is delineated, Welcome
      Home Ministries HPO.

PMID- 10661122
TI  - Nurse practitioners' information needs and information seeking: implications for
      practice and education.
AB  - This report is an exploratory study of the information needs and information
      seeking in a sample of nurse practitioners (NPs) approved to practice in North
      Carolina. A search and review of relevant literature revealed no studies on this
      topic. In this study, NPs report their most frequent information needs relate to
      drug therapy, diagnosis, and other therapy. Their most frequently used
      information resources are physicians, drug reference manuals, and textbooks. They
      most frequently confer with physicians on diagnosis and other therapy and other
      NPs on psychosocial issues.

PMID- 10661123
TI  - An election promise to be kept.

PMID- 10661124
TI  - [Caring for a patient with retrosternal pain].

PMID- 10661125
TI  - [Interview with a remarkable woman: Ginette Rodger] [In Process Citation]

PMID- 10661126
TI  - [When the mental state of a person turns dangerous, do you know the new
      legislation?].

PMID- 10661127
TI  - [Managing pain in children. A team work activity].

PMID- 10661129
TI  - [The Club of the Little Wonder Mothers; a good start in life].

PMID- 10661128
TI  - [Plans for practice guidelines in geriatrics. The first knowledge bank in
      geriatric nursing].

PMID- 10661130
TI  - A new era of visibility and influence.

PMID- 10661131
TI  - [Mme. Marois: when is it the nurses' turn?] [In Process Citation]

PMID- 10661132
TI  - [Episode of care of an arthroplasty following hip fracture].

PMID- 10661133
TI  - [Laparoscopic cholecystectomy in day surgery thanks to nurses' supervision at
      home].

PMID- 10661134
TI  - [Karine Labarre, president of the youth committee of the Quebec Order of Nurses.
      A breath of fresh air. Interview by Danielle Stanton].

PMID- 10661135
TI  - [Systematic follow-up of patient and family within the health care reform].

PMID- 10661136
TI  - [Systematic follow-up of patients in Singapore. A process for the improvement of
      nursing practice].

PMID- 10661137
TI  - [For better political expertise of nurses].

PMID- 10661138
TI  - Hypotension and bedside leukocyte reduction filters.

PMID- 10661139
TI  - It's a small world after all: the global community of emergency and trauma
      nurses.

PMID- 10661140
TI  - Happy Orthopedic Nurse's Day.

PMID- 10661141
TI  - Perioperative registered nurses make a world of difference.

PMID- 10661142
TI  - Trauma outreach education: assessing the needs of rural health care providers.
AB  - Trauma centers find it a challenge to provide appropriate, cost-effective
      outreach education. A needs assessment of rural health care providers was
      conducted to determine "what," "how," and "where" was preferred. The results
      showed that multidisciplinary rural providers were consistent with their
      preferences, that they considered case reviews the most effective method, that
      weekday evenings were the most convenient time, and that their lack of experience
      was their greatest barrier to learning.

PMID- 10661143
TI  - Web sites for pediatric injury prevention.

PMID- 10661144
TI  - Forensic documentation in trauma resuscitations: practical considerations.

PMID- 10661145
TI  - Development of the Crash Injury Research and Engineering Network.
AB  - The Crash Injury Research and Engineering Network has developed a computer
      database and wide area network for data sharing and analysis among 8 trauma
      centers. The computer database extends the National Highway Traffic Safety
      Administration's National Automotive Sampling System with medical- and trauma
      related variables in a relational/object database system. The medical data
      include injury location details, injury subclassification systems, and medical
      images for better biomechanical injury evaluation. Key data elements are migrated
      to a core repository so that all centers can review the status of case
      acquisition across the network. Cases, whole or in part, may be migrated between
      centers so that individual center expertise may be shared in evaluating the cause
      of injury. Electronic rounds, where cases are reviewed simultaneously across
      multiple centers, are possible.

PMID- 10661146
TI  - Important drug information: immune globulin intravenous (human).

PMID- 10661147
TI  - Preventing medication errors with neuromuscular blocking agents: recommendations
      of the United States Pharmacopeia Advisory Panel on Medication Errors.

PMID- 10661148
TI  - Newly approved devices for preventing and diagnosing exposure to blood-borne
      pathogens.

PMID- 10661149
TI  - The privilege of publishing.

PMID- 10661150
TI  - Nutrition support for malnourished, acutely ill adults.
AB  - As the acuity of the hospitalized patient increases, so does the need for nurses
      to become knowledgeable about nutritional support for the acutely ill. The nurse
      clinician provides safe and comprehensive enteral and parenteral nutritional
      support to the malnourished patient.

PMID- 10661151
TI  - Coronary artery bypass surgery in women and men: preoperative profile and
      postoperative outcomes.
AB  - The incidence and presentation of symptoms of coronary heart disease differ in
      women and men. Gender variations also have been documented in their postoperative
      recovery after coronary artery bypass surgery. Women undergoing this procedure
      are older and have more preoperative co-morbidities. The presence of these health
      problems translates into unequal rates of morbidity and mortality for women and
      men during their postoperative recovery in the hospital and has implications for
      adult-health nurses.

PMID- 10661152
TI  - Practice behaviors of RNs related to hazardous risks within the clinical setting.
AB  - A practice behavior survey was distributed to 250 RNs in the Metropolitan Detroit
      area. Seventy percent of the RNs responded to questions focused on needle-stick
      and splash injuries, handwashing, gloving, and other available measures that
      prevent injuries and infection. Respondents reported a larger than expected
      number of sticks (34.5%) and splashes (40.8%), but most of these instances were
      handled to the nurses' satisfaction. The nurses reported that while
      occupationally acquired hepatitis B/C, along with AIDS, are serious concerns, a
      large majority (75%) had not heard of the Campaign For Health Care Safety. The
      results of this survey have implications for research, practice, management, and
      public policy. This exploratory pilot survey raises numerous professional issues.

PMID- 10661153
TI  - A pilot program to increase self-care of adult asthma patients.
AB  - An exploratory pilot study was conducted to test the effectiveness of an
      educational program designed to enhance asthma patients' self-efficacy,
      knowledge, and self-care skills.

PMID- 10661154
TI  - Living with Lyme disease.
AB  - The occurrence of Lyme disease is rising steadily in the United States. The
      majority of health care providers are unfamiliar with this complex syndrome.
      Nurses lack accurate clinical information to provide comprehensive nursing care
      to these patients. The progression of Lyme disease is addressed through three
      stages. Untreated or poorly managed, Lyme disease may become a chronic,
      debilitating illness. The author's personal story is interwoven and serves to
      highlight the pathophysiology of the disease and the emotional and physical costs
      to the patient.

PMID- 10661155
TI  - Building confidence and competence: self-learning modules.

PMID- 10661156
TI  - New recommendations: intensify control of patient blood pressure.

PMID- 10661158
TI  - Recognizing and improving health literacy.

PMID- 10661157
TI  - OASIS: measuring outcomes in home care.

PMID- 10661159
TI  - Central venous catheter occlusion: successful management strategies.
AB  - Catheter occlusion is the most common noninfectious complication seen with
      longterm central venous access devices. Medical-surgical nurses frequently
      encounter these devices both in the hospital and home and are in a key position
      to recognize catheter occlusions and institute appropriate treatments. The
      etiology of catheter occlusion, its clinical evaluation, prevention, and
      treatment strategies will be reviewed.

PMID- 10661160
TI  - Development of a decision tree for support surfaces: a tool for nursing.
AB  - The use of specialty support surfaces can be clinically beneficial for at-risk
      patients, but can prove costly if their use is not closely monitored. A decision
      tree can guide health care providers in selecting the most appropriate support
      surface based on the patient's condition. The process used by one medical center
      to develop and test a decision tree for specialty support surfaces selection is
      described.

PMID- 10661161
TI  - Complementary, alternative, integrative: have nurses kept pace with their
      clients?
AB  - While medical literature reflects an interest in the use of complementary
      therapies, there is a paucity of studies in the nursing literature addressing the
      use of therapies by nurses, either on themselves or on their clients. While the
      utilization rate of complementary therapies by the general population has been
      estimated to be as high as 45%, and nurses are interacting with clients who use
      these therapies on a daily basis, little is known about nurses' attitudes,
      knowledge, or perceived efficacy of the therapies.

PMID- 10661162
TI  - Current management of AIDS and related opportunistic infections.
AB  - Significant changes in acquired immunodeficiency syndrome (AIDS) epidemiology and
      AIDS treatment strategies have emerged in the 17 years since the first case of
      this disease was reported. In the United States, the human immunodeficiency virus
      (HIV) is now primarily acquired through heterosexual relationships and
      intravenous drug use. As a result, dramatic increases in the number of AIDS cases
      in the female, African American, and Hispanic populations are evident. Treatment
      strategies now focus on maximal viral suppression and preventing drug resistance.
      Advances in anti-retroviral therapy and chemoprophylaxis of opportunistic
      infections have increased the long-term survival of AIDS patients by 10 to 20
      years. However, despite abundant research and advances in medical care, AIDS
      continues to be a devastating epidemic worldwide.

PMID- 10661163
TI  - Clinical pathways: from the hospital to the home.

PMID- 10661164
TI  - Principles for selecting the right wound dressing.

PMID- 10661165
TI  - Sharing clinical excellence and AMSN: alive and well.

PMID- 10661166
TI  - Nutritional strategies to reduce the risk of osteoporosis.
AB  - Osteoporosis is a risk for as many as 28 million Americans, with the risk being
      higher in women than men. Osteoporosis is frequently not diagnosed until a
      fracture occurs. Early screening and detection are critical to prevent fractures
      and subsequent debilitation. Proper nutrition and exercise are vital to
      preventing and treating osteoporosis.

PMID- 10661167
TI  - Vascular access devices: meeting patients' needs.
AB  - The traditional approach to vascular access involves peripheral venipuncture
      until all veins are exhausted. If therapy is to continue, a central venous
      catheter is inserted. Currently, the process now emphasizes making an appropriate
      assessment early in the course of therapy. Selecting and inserting the device
      which has the greatest potential for reaching the therapeutic endpoint minimizes
      the number of devices and insertion procedures needed, and reduces risks and
      patient discomfort.

PMID- 10661168
TI  - Improving smooth sailing between hospital and home.
AB  - A unique, collaborative project was undertaken by a large acute care facility and
      its affiliated multisite home health agency. Educational practices within the
      network were evaluated and improved, resulting in increased patient and staff
      outcomes.

PMID- 10661169
TI  - Nursing assessment of patient readiness for ambulation after cardiac
      catheterization.
AB  - Although nurses routinely perform activities that prevent or detect vascular
      complications following a cardiac catheterization, determining patient readiness
      for ambulation has received minimal research attention. Educating nurses to
      determine patient readiness for ambulation is a safe and effective way to promote
      patient comfort.

PMID- 10661170
TI  - Empowering staff nurses: shared governance at work.

PMID- 10661171
TI  - Leukotriene antagonists offer a new mechanism for asthma control.

PMID- 10661172
TI  - Correcting pretentious pronouns.
AB  - If pronouns following prepositions or verbs sound lofty or pretentious, they
      probably are. Without attention to grammar rules, nurse authors and editors can
      make common mistakes by selecting the wrong form of the pronoun. Pronouns
      following prepositions and transitive verbs should be the objective form of the
      pronoun, not the subjective form. These experienced editors describe the rule,
      suggest a quick-fix tip, and provide several practice items followed by answers.

PMID- 10661173
TI  - Getting heard: writing opinion pieces for the newspaper.
AB  - Many nurse authors think about writing in terms of articles or book chapters.
      Skilled writers should also consider writing letters to the editor and short
      opinion pieces as a way to promote nursing and educate the public. In this
      article, the author shares tips on getting letters to the editor or short opinion
      articles published in local or national newspapers.

PMID- 10661174
TI  - Publishing "cutting-edge" information.
AB  - Making sure material is accurate in nursing journal and book manuscripts has been
      a responsibility of authors and editorial board reviewers. With more complex
      information and a fast-paced environment where clinical standards change rapidly,
      using external experts to insure accurate and timely information is critical.
      This experienced author recommends five steps for assuring that nursing
      publications include accurate and state-of-the-art information.

PMID- 10661175
TI  - Avoiding publication delays: author and editor responsibilities.
AB  - Authors, editors, readers, and the profession benefit by having manuscripts
      published in a timely manner. Yet there are many problems that can occur that
      cause delays as a manuscript moves from acceptance to printing. These experienced
      authors identify publication steps where delays are common and suggest ways for
      authors and editors to prevent extensive delays during the publication path of an
      article.

PMID- 10661176
TI  - Parallel format: making life easier for the reader.
AB  - Use parallel style to show the similarity between items in a series. When
      headings, bullet lists, and sentence phrases that relate to each other are
      written in a similar style, the reader can understand the information faster than
      when they are written in different styles.

PMID- 10661177
TI  - A model of mental health.

PMID- 10661178
TI  - Net profits.

PMID- 10661179
TI  - Frame by frame.

PMID- 10661180
TI  - Wales to go all-graduate?

PMID- 10661181
TI  - Streets ahead. Interview by Alison Moore.

PMID- 10661182
TI  - Protecting the whistle blower.

PMID- 10661183
TI  - Hospice pioneer. Interview by Gill Oliver.

PMID- 10661184
TI  - Right on course.

PMID- 10661185
TI  - Get back to basics.

PMID- 10661186
TI  - Nurses and PAMs in innovative roles: job satisfaction and its contributing
      factors.

PMID- 10661187
TI  - Do respiratory patients receive adequate analgesia?
AB  - This literature review demonstrates that hospitalised patients may not be
      receiving adequate pain relief due to health professionals' belief that optimum
      doses of analgesia may affect patients' respiratory capability.

PMID- 10661188
TI  - Critical pathways: an efficient way to manage care.
AB  - Liz Herring argues that care pathways provide a change in the traditional
      approach to planning and documenting care. She suggests that they provide
      opportunities for the more efficient use of nursing time and resources.

PMID- 10661189
TI  - Measuring services: a district nursing dependency tool.
AB  - The government has highlighted the importance of reducing inequalities in health
      and providing an equal and high quality service to all patients. The district
      nursing service in Wolverhampton monitors the provision of services across the
      town to ensure high quality care for all patients.

PMID- 10661190
TI  - Obesity management.
AB  - Recent national initiatives to reduce the numbers of people classified as obese
      appear to have failed. Norma Crombie summarises some current thinking on the
      subject and outlines the role of the nurse in helping obese people to set and
      meet realistic targets for their weight management.

PMID- 10661191
TI  - Meeting the nutritional needs of people with mental health problems.
AB  - In these days of holistic care, it is perhaps surprising that the nutritional
      needs of people with mental health problems may still be overlooked. Alison
      Sullivan and Rick Tucker describe the role of the nurse in this neglected area of
      care.

PMID- 10661192
TI  - Patient individuality in the breast clinic.

PMID- 10661193
TI  - Learning disability nursing.

PMID- 10661194
TI  - Acting to help your career.

PMID- 10661195
TI  - Urine testing.
AB  - Urine testing using reagent strips is a simple, non-invasive, reliable method of
      finding potential signs and symptoms of a number of diseases in their early
      stages. Urine testing can be carried out easily in the home, GP surgery or
      hospital setting.

PMID- 10661196
TI  - Fast forward your career.

PMID- 10661197
TI  - You're nicked!

PMID- 10661198
TI  - Changing childbirth proves a late starter.

PMID- 10661200
TI  - Ruined by red tape. Interview by Jo Carlowe.

PMID- 10661199
TI  - Get real.

PMID- 10661201
TI  - Tailor made. Interview by Charlotte Alderman.

PMID- 10661202
TI  - A nurse's nurse.

PMID- 10661203
TI  - A little learning.

PMID- 10661204
TI  - Play it again sister.

PMID- 10661205
TI  - A risky business.

PMID- 10661206
TI  - The work of the Foundation of Nursing Studies.

PMID- 10661207
TI  - Seclusion in psychiatry.
AB  - The subject of seclusion will always generate professional, legal and moral
      debate. Lawrence Savage and Emad Salib examined the continuing and regular use of
      seclusion in a secure mental health unit, and suggest that the seclusion of some
      patients may continue to be a safe and effective intervention to control
      incidents of disturbed behaviour.

PMID- 10661208
TI  - Meetings: the challenge.
AB  - Attending meetings can be a daunting task, but with the right attitude they can
      be made to work for you. This article describes how to maximise their
      effectiveness, including advice on chairing a meeting and making a presentation.

PMID- 10661209
TI  - Improving the care of patients with dysphagia.

PMID- 10661210
TI  - Funding the future.

PMID- 10661211
TI  - Special delivery.

PMID- 10661212
TI  - Forced to quit.

PMID- 10661213
TI  - Independence day.

PMID- 10661214
TI  - Decisions decisions.

PMID- 10661215
TI  - Stress can be positive.

PMID- 10661216
TI  - Class of '99.

PMID- 10661217
TI  - The estate we're in.

PMID- 10661218
TI  - Housing problems make you sick.

PMID- 10661219
TI  - Out of sight, out of mind.

PMID- 10661220
TI  - The age of discontent.

PMID- 10661221
TI  - The routine of hospital life often prevents nurses from seeing the wonder of
      their work.

PMID- 10661222
TI  - New ideas, strangely familiar.

PMID- 10661223
TI  - How to be happy at work.

PMID- 10661224
TI  - Wake-up call. Interview by Alex Mathieson.

PMID- 10661225
TI  - Primary case. Full steam ahead.

PMID- 10661226
TI  - Pink knickers beat the blitz.

PMID- 10661227
TI  - Face to face. Interview by Eileen Fursland.

PMID- 10661228
TI  - Service users are gaining strength by sharing their insights into the mental
      health service.

PMID- 10661229
TI  - Burns assessment and initial management.

PMID- 10661231
TI  - Good Practice network. Spreading the news.

PMID- 10661230
TI  - Colorectal cancer: diagnosis and treatment.

PMID- 10661232
TI  - Infection control. Standard practice.

PMID- 10661233
TI  - Infection control. A long time coming.
AB  - This article presents the case of a doctor who developed multidrug-resistant
      tuberculosis in his right lung. Development of the disease was attributed to
      treatment errors and resulted in surgical intervention to effect a cure. The
      isolation and management of this patient spanned a total of 12 months. Infection
      control interventions to minimise the effects of sensory deprivation, given the
      length of stay of the patient, appear to have been satisfactory, with no
      treatment for any clinical depression required. The availability of negative
      pressure ventilation and the then controversial use of masks prevented any
      nosocomial transmission of MDR TB. Use of masks resulted in a two-tier system of
      infection control. It was difficult to make such a decision in the absence of any
      published UK guidelines. Guidelines have subsequently been published.

PMID- 10661234
TI  - Infection control. Return of the silent killer.

PMID- 10661235
TI  - Infection control. Antenatal antiseptics.

PMID- 10661236
TI  - Staying safe by working within the established set of rules.

PMID- 10661237
TI  - Open to scrutiny.

PMID- 10661238
TI  - Forewarned is forearmed.

PMID- 10661239
TI  - The breath of the nation.

PMID- 10661240
TI  - A shot in the dark.

PMID- 10661241
TI  - Immunising children is difficult for parents, but it is worse for nurses.

PMID- 10661242
TI  - 'Euphemasia' is the widespread practice of calling a spade a manual digging
      implement.

PMID- 10661243
TI  - Parents shouldn't have to do our jobs.

PMID- 10661244
TI  - Polio strikes back.

PMID- 10661245
TI  - The sting in the tail.

PMID- 10661246
TI  - Rest for the wicked.

PMID- 10661247
TI  - The Hexthorpe rail disaster.

PMID- 10661248
TI  - Sex on wheels.

PMID- 10661249
TI  - Spirituality. Record breakers.

PMID- 10661250
TI  - Letter from America.

PMID- 10661252
TI  - Colorectal cancer: a nurse puts a patient perspective.
AB  - Following last week's article on colorectal cancer this is a health visitor's
      reflective view of her experience coping with the diagnosis and treatment of
      colorectal cancer while being the main carrier for her elderly mother.

PMID- 10661251
TI  - Western governments must promote the development of indigenous anti-HIV drugs.

PMID- 10661253
TI  - Skin cultures in burns care nursing.

PMID- 10661254
TI  - A degree in community children's nursing.

PMID- 10661255
TI  - Switched on.

PMID- 10661256
TI  - Clear as mud.

PMID- 10661257
TI  - Mothering module.

PMID- 10661258
TI  - The challenge ahead.

PMID- 10661259
TI  - [More than just salary negotiations].

PMID- 10661260
TI  - [Vera Henrici; profession, pediatric nurse. Interview by Eva-Maria Krampe].

PMID- 10661261
TI  - [Professional approach to parents. Interview by Sabine Keller-Kuhn].

PMID- 10661262
TI  - [Being aware of parents' concerns. Interview by Ingrid Kollak and Hans Kupper].

PMID- 10661263
TI  - [Death at the start of life].

PMID- 10661264
TI  - [Nursing care in Santiago, Chile].

PMID- 10661265
TI  - [Problems of transcultural communication in the hospital].

PMID- 10661267
TI  - [Feeding of patients with Alzheimer's disease].

PMID- 10661266
TI  - [A day at the intensive care unit].

PMID- 10661268
TI  - [Patient interests--patients' rights].

PMID- 10661269
TI  - [A tripartite model].

PMID- 10661270
TI  - [Patients as partners in The Netherlands].

PMID- 10661271
TI  - [Patients' rights and obligations in the German Federal Republic].

PMID- 10661272
TI  - [Age discrimination is no small matter].

PMID- 10661273
TI  - [Evidence-based practice--what is it?].

PMID- 10661274
TI  - [The errors of bioethics].

PMID- 10661275
TI  - [For discussion: models for new structures in the German Nursing Society].

PMID- 10661276
TI  - [The hospital as a service organization].

PMID- 10661277
TI  - [Health care reform 2000--the "out" for hospitals].

PMID- 10661278
TI  - [Hospital certification as an instrument for quality assurance].

PMID- 10661279
TI  - [The nightmare hospital].

PMID- 10661280
TI  - [What can a hospital offer?].

PMID- 10661282
TI  - [100 years of International Council of Nurses--at the congress in London].

PMID- 10661281
TI  - [Health promotion in nursing].

PMID- 10661283
TI  - [Don't ever say "it is nothing"].

PMID- 10661284
TI  - [A new look at the methodology of the professional project: modeling of the
      complex and paradoxical object].

PMID- 10661285
TI  - [The initial and continuing education of hospital nursing personnel: alternating
      practical work with education].
AB  - Who, as a trainer, has never heard this irritating leitmotiv on the lips of those
      who work in the area? Therefore, each of them is convinced that the other is
      wrong or does not do what he should. Beyond the anecdote, the problem of the
      difficult conjunction between school and the real world is posed. Two places and
      two logics: the first one is concerned with learning, the second one considers
      production as its daily objective. But the words of our imaginary interlocutor
      also remind us of the confrontation between two fields: theory and practice and
      their apparently irrecondilable nature. Two disconnected worlds in which the
      students come and go with the frequent impression that they live two lives. There
      is a lot of professional literature on the subject of the "hands on" theory of
      education. The pedagogical device to which we refer enables the trainee to
      eventually make a link between what he learns at school and what he does during
      his training period. Once this has been asserted, it seems to us that the problem
      still remains unresolved. How can you create links between theory and practice?
      Which skills are required for the trainers? Which training device is necessary?
      The hypothesis of the paper we are presenting is that the question of work is at
      the centre of the problematics of "hands on" education. Work appears as the
      interface between the world of school and the one of field work. This assertion
      means that the practive produces knowledge just as research does and we must
      therefore accept that the practitioners carry on their work thanks to the
      accumulation, the construction and the transmission of this practical knowledge.
      Assuming that the question of work serves as a link between theory and practive
      means reconciling the vision of the teacher and the one of the practitioner. It
      implies that the trainer must make the effort of going on the field to observe,
      to understand and formalize what this knowledge coming from the daily experience
      is made of. This know-how is the result of the mobilization of the intelligence
      of the operators who are faced all the time with the hazards of real life. In the
      following work, we intend to put a pedagogical practice to the test of reality,
      according to the above mentioned hypothesis, to test its effectivity, to sort out
      the possibilities of change it enables it imposes and to mark its limits. Our
      wish is not to make the absolute proof of the validity of a point of view. We
      know by experience that the reality often escapes its observer and that trying to
      get in contact with it to possibly change it, means that you must be faced with
      it through action, and you must admit that success will not always be the result
      of your attempts.

PMID- 10661286
TI  - [Importance, indications and limitations in the use of behavior and cognitive
      scales].

PMID- 10661287
TI  - [French validation of the "Exercise of self-care agency" scale for heart
      patients].
AB  - Self-care agency is the practice of health-related activities that individuals
      deliberately initiate and perform in order to maintain life, health and well
      being (OREM, 1987). A tool measuring self-care agency is useful to nurses for
      identifying patients lacking knowledge, motivation, and for those with limited
      self-care agency. KEARNEY and FLEISCHER (1979) have developed the Exercise of
      Self-care Agency (ESCA) scale to asses the extent to which individuals take
      action toward their health care. Several studies suggest that the ESCA scale
      possesses adequate psychometric properties (KEARNEY & FLEISCHER, 1979; LUCAS,
      MORRIS & ALEXANDER, 1988; MCBRIDE, 1987; RIESCH & HAUCK, 1988). The lack of a
      validated tool measuring self-care agency among french speaking populations, led
      us to translate the ESCA scale and to examine its psychometric properties in a
      sample of French Canadian individuals who have survived a recent non-complicated
      myocardial infarction (MI). At 8 and 14 weeks after their MI, 83 subjects aged 52
      +/- 10 years with a 1,857 +/- 1,605 U/L MI and an ejection fraction of 51 +/- 10%
      completed the french-ESCA scale. Mean scores were 112.6 +/- 13.3 at 8 weeks and
      117.9 +/- 14.0 at 14 weeks post-MI. Internal consistency coefficients of the
      french-ESCA scale (at 8 and 14 weeks post-MI) are acceptable (0.84 and 0.88,
      respectively). Internal consistency coefficients are similar to those obtained in
      previous studies whereas mean scores on the ESCA scale are somewhat higher
      (RIESCH & HAUCK, 1988). Cronbach alphas for the french-ESCA scale's sub-scales
      are generally lower: Self-concept (0.57 and 0.69), Initiative/responsibility
      (0.72 and 0.80), Knowledge/information seeking (0.80 and 0.79), and Taking
      actions (0.49 and 0.62). The french-ESCA scale appears stable within the 6 weeks
      period (r = 0.77, p < 0.001). We recommend to further assess the french-ESCA
      scale's psychometric properties using larger samples of subjects with or without
      various health problems.

PMID- 10661288
TI  - [From concept to practice ... didactic approach to education in nursing education
      institutes: towards education of the spirit].

PMID- 10661289
TI  - [Patients' rights].

PMID- 10661290
TI  - [Pain management by nursing teams: exploratory research in 9 wards of the Vaud
      University Hospital Center (CHUV, Lausanne, Switzerland) 2].
AB  - Using both nursing documents and verbal reports as well as client interviews, the
      authors review pain management by nursing teams in 9 wards of a university
      hospital. The results were obtained using descriptive and inferential analyses.
      Looking at each situation from three different view-points reveals the absence of
      a systematic approach to the reporting and evaluation of pain and the usage of a
      sometimes very vague language. In addition, the preponderance of medically
      oriented interventions in the reports considerably overshadowed the autonomous
      nursing role. The authors propose a basic structure for pain reporting which
      should help to improve its overall management.

PMID- 10661291
TI  - [Clinical nursing research: education and practice].

PMID- 10661292
TI  - [Analysis and teaching experience in the education of clinical specialist
      nurses].

PMID- 10661293
TI  - [Information, a resource for future bone marrow allografts].
AB  - From a legislative point of view, the allograft of bone marrow is considered as
      an organ transplant. It consists in "replacing a diseased or deficient marrow
      with a healthy marrow removed on a compatible living donor." This treatment has
      significant repercussions for the patient. Will he find, in his circle, the
      resources which will enable him to face the changes imposed by the marrow graft?
      The information can then be a way to meet the needs of the patient. Our study is
      based on questionnaires sent to 55 adults who underwent an allograft. Thanks to
      the results, we could highlight the most favourable moment for information, the
      person most capable of giving it, the precise content and the way best suited to
      the needs of the patient.

PMID- 10661294
TI  - [Multicenter nursing study on the importance of nutritional support for the
      prevention of bedsores in the elderly at risk].
AB  - Bedsores prevention is part of the specific role of the nurse, as defined namely
      in the order 84-869 of the 17. July 1984. The analysis of the risk factors for
      the appearance of bedsores shows that immobilization, reduction of mobility
      linked to vigilance disorders and the urinary and faecal incontinence are major
      elements which justify protocols of well defined local cares. More recently, the
      role of undernutrition was highlighted but the recommendations lack accuracy. The
      proteino-energizing undernutrition is frequent among the elderly patients in
      hospital, reaching 60% of all the patients in the department of acute affections.
      The association of a constituted bedsore and of clinical and/or biological scars
      of protein-energizing undernutrition is demonstrated and justifies a re-feeding
      of the patients suffering from bedsores. On the other hand, although a bad
      nutrition state seems to favour the appearance of a bedsore, it is not proved
      that the nutrition intensification associating the diagnosis of an under
      nutrition and the starting of an adapted re-feeding (with enriched food or
      assistance) decreases the actual incidence of the bedsores. A prospective,
      multicentered, randomized survey was therefore proposed. Its aim was to study the
      Influence of Nutrition in the Bedsores Prevention among the Elderly Patients in
      hospitals, suffering from acute affections. This research follows upon the
      preventions audits of bedsores and the nutrition protocol started up in a
      department of geriatrics intern medicine in the Regional Center of Geriatrics of
      Bordeaux. CONCLUSION: Two results must be retained in this nursing survey. It
      gave the possibility of calling into question the professional experience of the
      nursing teams which participated to the research and to update their knowledge in
      the field of the bedsores prevention. They could thus be acquainted with the
      existence of the grids which evaluate the risk of bedsore, the dependence or even
      the nutrition supply and to assess the interest for improving the cares quality.
      On the other hand, we highlighted the possibility of increasing the energy and
      protein supply by a distribution of enriched food supplements. Moreover, this
      action has had a beneficial influence in the bedsores prevention among the old
      people.

PMID- 10661296
TI  - [Teaching clinical nursing research].

PMID- 10661295
TI  - [Patients with arterial hypertension: approach to their experiences].
AB  - The study aims at exploring the experience of the patients suffering from high
      blood pressure, analysing the difficulties they evoke and trying to generate
      similarities. It is a qualitative study, based on the phenomenological method.
      The interviews highlight the fact that the patients are preoccupied only by the
      symptoms of high blood pressure. They also show that all the patients live
      through the disease with a lot of emotions, with feelings of frustration, stress,
      anxiety and helplessness. A better understanding of the patients' experience must
      enable the nurses to have better targeted actions.

PMID- 10661297
TI  - [Nurses' behavior regarding responsibility: its effect on their way of treating
      their patients].
AB  - We have noticed that if the different orders (order n(o): 93-221 of the 16.
      February related to the professional rules, order n(o): 93-345 of the 15. March.
      1993 related to the professional acts) had indeed been brought to the nurses'
      attention, the latter did not seem to have integrated the content of these texts
      into their professional experience. We have chosen as conceptual pattern the
      theory of Ajzen and Fishbein (1980) linked to the human behaviours. Thanks to the
      results obtained from the questionnaires (or measuring instruments) we can evoke
      the fact that, despite a precise legislation, there are still many situations
      where the position of the nurse faced with responsibility is not clear. This work
      permitted a new approach of the behaviour of the nurses faced with problems of
      responsibility, with a constant concern for the improvement of the quality of
      medical care.

PMID- 10661298
TI  - [When social inequality handicaps the multiply disabled].

PMID- 10661299
TI  - [The supervisor of home hospitalization: referent and promoter for the quality of
      care].

PMID- 10661300
TI  - [Treatments of leg ulcers].

PMID- 10661301
TI  - [Asthma: definition and clinical aspects].

PMID- 10661302
TI  - [Practical use of inhalation treatment in children].

PMID- 10661303
TI  - [Asthma education nurses in the hospital].

PMID- 10661304
TI  - [The Asthma Association, a true mission in public health].

PMID- 10661305
TI  - [Asthma: knowing is preventing] [In Process Citation]

PMID- 10661306
TI  - [Asthma: the essentials to remember].

PMID- 10661307
TI  - [Professionalization: from the first teachings to continuing education].

PMID- 10661308
TI  - Privacy threats are no cause for hysteria.

PMID- 10661309
TI  - Ethics in action. The postop orders for a patient who is also a substance abuser.

PMID- 10661310
TI  - Is it an MI? A lab primer.

PMID- 10661311
TI  - Communicate with CARE.

PMID- 10661312
TI  - Ventilation without intubation.

PMID- 10661313
TI  - Antibiotics to treat RA.

PMID- 10661314
TI  - A practical guide to wound care.

PMID- 10661315
TI  - Wound care products.

PMID- 10661316
TI  - If you have to give a deposition.

PMID- 10661317
TI  - Office nursing: does it pay?

PMID- 10661318
TI  - Genetic variability of foetal bovine myoblasts in primary culture.
AB  - Selected strains of adult bovines and those which either have high muscle growth
      capacity or are double-muscled present particular characteristics of muscle
      fibres and collagen at slaughter that favour meat tenderness. For double-muscled
      bovines, it has been shown that these characteristics originated during foetal
      life. However, no studies have been done to determine the origin of muscle growth
      superiority in bovine with high muscle growth capacity compared to those with a
      low muscle growth capacity. Therefore, the objective of this study was to examine
      the proliferation and differentiation phases of myoblasts in primary culture
      taken from high and low muscle growth capacity foetuses at 110 days post
      conception. These cultures were analysed on 1, 2, 3, 4, 6, 8, 10 days of culture.
      The proliferation phase was monitored by appropriate marker antibodies. The
      differentiation was studied by immunocytochemistry with specific antibodies for
      foetal, I, II (IIa and IIb), I and IIb, I and IIa myosin heavy chains (MHCs) and
      connectin respectively, and by immunoblotting with desmin antibody. A higher
      proliferation, a lower fusion and a delayed differentiation of the 'late markers'
      namely MHCs fast (IIa and IIb) and connectin were shown in high muscle growth
      capacity foetuses compared to low capacity ones. The results indicate that the
      muscle growth superiority of high muscle growth capacity bovines seems,
      therefore, to have a similar foetal origin to that of double-muscled ones.

PMID- 10661319
TI  - Stromelysin-1 (MMP-3) in forming enamel and predentine in rat incisor-coordinated
      distribution with proteoglycans suggests a functional role.
AB  - Stromelysin-1 (matrix metalloproteinase-3) or proteoglycanase was visualized by
      light and electron microscopy immunolabelling in the forming zone of rat
      incisors. In predentine, labelling was more dense at the transition zone between
      the inner proximal third and the two outer thirds. Odontoblast processes were
      also positively stained, mostly in predentine and to a lesser degree in dentine.
      The dentine-enamel junction was intensely labelled, whereas dentine and forming
      enamel were only faintly stained. Gold-antibodies complexes were seen inside
      secretory ameloblasts and odontoblasts in cytosolic locations. The distribution
      of stromelysin-1 was compared with the distribution of 2-B-6 epitope, an antibody
      recognizing chondroitin-4-sulphate/dermatan sulphate and which showed a
      decreasing gradient from the proximal zone to the distal part of predentine. In
      contrast, both 5-D-4, an anti-keratan sulphate antibody and an anti-lumican
      antibody displayed a reversed distribution, with an increase seen from the
      proximal and central thirds to the distal part of predentine. This coordinated
      distribution suggests that stromelysin-1 may have a functional role, being
      implicated in predentine in the degradation of chondroitin-4-sulphate/dermatan
      sulphate-containing proteoglycans, and consequently allowing keratan sulphate
      proteoglycan concentration to increase near the border where mineralization is
      initiated.

PMID- 10661320
TI  - Immunohistochemical evidence for a mesothelial contribution to the ventral wall
      of the avian aorta.
AB  - We report morphological and immunohistochemical evidence for a translocation of
      cells from the coelomic mesothelium to the aortic wall between the developmental
      stages HH16 and HH22 of the quail embryos. The coelomic mesothelial cells closest
      to the aorta showed, at these stages, increased mitotic activity, reduced
      intercellular adhesion, loss of tight junctions, and long basal cytoplasmic
      processes. Coinciding with these morphological traits, cytokeratin
      immunoreactivity was found in the mesothelium, in cells of the aortic wall and
      throughout the ventral periaortic mesenchyme (but not in the lateral and dorsal
      aortic regions). Vimentin immunoreactivity colocalized with cytokeratin in the
      mesothelial cells adjacent to the aorta. In the ventral aortic wall, cytokeratin
      colocalized with smooth muscle alpha-actin and with the 1E12 antigen (a smooth
      muscle-specific alpha-actinin isoform). We think that the morphological and
      immunolocalization data observed are compatible with an epithelial-mesenchymal
      transition by which mesothelial-derived cells contribute to the splanchnic
      mesoderm and aortic wall. The precise coincidence between the mesothelial
      contribution and the emergence of the aortic smooth muscle cells progenitors, as
      well as the immunolocalization data, suggest a potential relationship of the
      mesothelial-derived cells with this cell lineage. This may explain the observed
      ventrodorsal asymmetry in the distribution of smooth muscle cells progenitors in
      the aortic wall.

PMID- 10661322
TI  - Morphological phenotypes and functional capabilities of submandibular parenchymal
      cells of the ferret investigated by protein, mucosubstance and enzyme
      histochemistry.
AB  - Submandibular glands obtained post-mortem from mature ferrets of both sexes were
      examined with the use of light microscopical histochemical methods for proteins,
      mucosubstances and enzymes associated with cell functions or organelles.
      Demilunar cells showed carboxylated mucosubstances that were mainly non
      sulphated, and diffuse activity for peroxidase, E600-sensitive esterase and acid
      phosphatase. Thiol groups were also detected in these cells. Central acinar cells
      showed sulphated mucosubstances, disulphides and reticular staining for thiamine
      pyrophosphatase. Intercalary ducts showed diffuse activity for NADH and NAD(P)H
      dehydrogenases. Striated ducts contained protein, tryptophan, disulphides,
      neutral mucosubstances and E600-sensitive esterase periluminally. Basally, the
      striated ductal cells showed variable activity for peroxidase, cytochrome
      oxidase, succinate dehydrogenase and acid phosphatase. Basolateral plasma
      membranes of these cells exhibited ouabain-sensitive Na,K-ATPase activity. The
      collecting ducts were characterized by variable periluminal staining for acid
      phosphatase, beta-glucuronidase, acid beta-galactosidase and E600-resistant
      esterase. The results suggest that the histological appearances of the acini of
      the submandibular gland of the ferret are dependent on the synthesis of secretory
      acid glycoproteins, that the striated ducts are involved with the secretion of
      tryptophan-rich product comprising neutral glycoproteins and showing esterase
      activity and with marked transport of ions and that the collecting ducts are
      involved with absorption.

PMID- 10661321
TI  - Immunochemical localisation of proliferating cells in mussel digestive gland
      tissue.
AB  - The distribution of proliferating cells in the digestive gland of the common
      marine mussel, Mytilus galloprovincialis Lmk, was investigated by means of
      immunochemical techniques employing PC10, a commercial monoclonal antibody to the
      proliferating cell nuclear antigen (PCNA). Immunoblot analysis of digestive gland
      whole homogenates revealed a single crossreactive band of 36-37 kDa, identical to
      the corresponding protein of rat liver and murine melanoma cells. A band of
      slightly higher electrophoretic mobility (34-35 kDa) was found in fish liver. In
      mussel digestive gland, the samples obtained from young specimens presented a
      more intense signal for PCNA than in those obtained from old mussels, suggesting
      that the digestive gland cells of young mussels exhibit a higher proliferative
      activity. In paraffin sections, PC10 specifically labelled nuclei of all cell
      types, but only a smaller number of cells lining the different digestive
      epithelia. PCNA expression was more intense in digestive cells than in basophilic
      cells. Hemocytes circulating along the interdiverticular spaces also presented
      immunoreactive nuclei. Electron microscopy revealed a specific and moderate PC10
      labelling in nuclei. Thus, single gold particles appeared disseminated throughout
      the nuclei with accumulations of particles in the sites of DNA replication. Taken
      together, these data reveal that the capacity to proliferate resides within all
      cell types in the digestive diverticula and do not support the hypothesis of the
      existence of one stem cell in this epithelium. As opposed to the hepatopancreas
      of the crab, Carcinus maenas, where mitotic figures and PCNA immunoreactivity are
      only observed in the embryonic cells within the distal portions of the digestive
      diverticula, apparently there are not discrete regions of cell proliferation in
      the digestive gland of mussels.

PMID- 10661324
TI  - Survey: interpolation methods in medical image processing.
AB  - Image interpolation techniques often are required in medical imaging for image
      generation (e.g., discrete back projection for inverse Radon transform) and
      processing such as compression or resampling. Since the ideal interpolation
      function spatially is unlimited, several interpolation kernels of finite size
      have been introduced. This paper compares 1) truncated and windowed sinc; 2)
      nearest neighbor; 3) linear; 4) quadratic; 5) cubic B-spline; 6) cubic; g)
      Lagrange; and 7) Gaussian interpolation and approximation techniques with kernel
      sizes from 1 x 1 up to 8 x 8. The comparison is done by: 1) spatial and Fourier
      analyses; 2) computational complexity as well as runtime evaluations; and 3)
      qualitative and quantitative interpolation error determinations for particular
      interpolation tasks which were taken from common situations in medical image
      processing. For local and Fourier analyses, a standardized notation is introduced
      and fundamental properties of interpolators are derived. Successful methods
      should be direct current (DC)-constant and interpolators rather than DC
      inconstant or approximators. Each method's parameters are tuned with respect to
      those properties. This results in three novel kernels, which are introduced in
      this paper and proven to be within the best choices for medical image
      interpolation: the 6 x 6 Blackman-Harris windowed sinc interpolator, and the C2
      continuous cubic kernels with N = 6 and N = 8 supporting points. For quantitative
      error evaluations, a set of 50 direct digital X rays was used. They have been
      selected arbitrarily from clinical routine. In general, large kernel sizes were
      found to be superior to small interpolation masks. Except for truncated sinc
      interpolators, all kernels with N = 6 or larger sizes perform significantly
      better than N = 2 or N = 3 point methods (p << 0.005). However, the differences
      within the group of large-sized kernels were not significant. Summarizing the
      results, the cubic 6 x 6 interpolator with continuous second derivatives, as
      defined in (24), can be recommended for most common interpolation tasks. It
      appears to be the fastest six-point kernel to implement computationally. It
      provides eminent local and Fourier properties, is easy to implement, and has only
      small errors. The same characteristics apply to B-spline interpolation, but the 6
      x 6 cubic avoids the intrinsic border effects produced by the B-spline technique.
      However, the goal of this study was not to determine an overall best method, but
      to present a comprehensive catalogue of methods in a uniform terminology, to
      define general properties and requirements of local techniques, and to enable the
      reader to select that method which is optimal for his specific application in
      medical imaging.

PMID- 10661323
TI  - The expression of the fibrillar collagen genes during fracture healing:
      heterogeneity of the matrices and differentiation of the osteoprogenitor cells.
AB  - The cells that express the genes for the fibrillar collagens, types I, II, III
      and V, during callus development in rabbit tibial fractures healing under stable
      and unstable mechanical conditions were localized. The fibroblast-like cells in
      the initial fibrous matrix express types I, III and V collagen mRNAs.
      Osteoblasts, and osteocytes in the newly formed membranous bone under the
      periosteum, express the mRNAs for types I, III and V collagens, but osteocytes in
      the mature trabeculae express none of these mRNAs. Cartilage formation starts at
      7 days in calluses forming under unstable mechanical conditions. The
      differentiating chondrocytes express both types I and II collagen mRNAs, but
      later they cease expression of type I collagen mRNA. Both types I and II
      collagens were located in the cartilaginous areas. The hypertrophic chondrocytes
      express neither type I, nor type II, collagen mRNA. Osteocalcin protein was
      located in the bone and in some cartilaginous regions. At 21 days, irrespective
      of the mechanical conditions, the callus consists of a layer of bone; only a few
      osteoblasts lining the cavities now express type I collagen mRNA. We suggest that
      osteoprogenitor cells in the periosteal tissue can differentiate into either
      osteoblasts or chondrocytes and that some cells may exhibit an intermediate
      phenotype between osteoblasts and chondrocytes for a short period. The finding
      that hypertrophic chondrocytes do not express type I collagen mRNA suggests that
      they do not transdifferentiate into osteoblasts during endochondral ossification
      in fracture callus.

PMID- 10661325
TI  - Fourier rebinning applied to multiplanar circular-orbit cone-beam SPECT.
AB  - We study the application of Fourier rebinning methods to dual-planar cone-beam
      SPECT. Dual-planar cone-beam SPECT involves the use of a pair of dissimilar cone
      beam collimators on a dual-camera SPECT system. Each collimator has its focus in
      a different axial plane. While dual-planar data is best reconstructed with fully
      three-dimensional (3-D) iterative methods, these methods are slow and have
      prompted a search for faster reconstruction techniques. Fourier rebinning was
      developed to estimate equivalent parallel projections from 3-D PET data, but it
      simply expresses a relationship between oblique projections taken in planes not
      perpendicular to the axis of rotation and direct projections taken in those that
      are. We find that it is possible to put cone-beam data in this context as well.
      The rebinned data can then be reconstructed using either filtered backprojection
      (FBP) or parallel iterative algorithms such as OS-EM. We compare the Feldkamp
      algorithm and fully 3-D OSEM reconstruction with Fourier-rebinned reconstructions
      on realistically-simulated Tc-99m HMPAO brain SPECT data. We find that the
      Fourier-rebinned reconstructions exhibit much less image noise and lower variance
      in region-of-interest (ROI) estimates than Feldkamp. Also, Fourier-rebinning
      followed by OSEM with nonuniform attenuation correction exhibits less bias in ROI
      estimates than Feldkamp with Chang attenuation correction. The Fourier-rebinned
      ROI estimates exhibit bias and variance comparable to those from fully 3-D OSEM
      and require considerably less processing time. However, in areas off the axis of
      rotation, the axial-direction resolution of FORE-reconstructed images is poorer
      than that of images reconstructed with 3-D OSEM. We conclude that Fourier
      rebinning is a practical and potentially useful approach to reconstructing data
      from dual-planar circular-orbit cone-beam systems.

PMID- 10661326
TI  - MRI simulation-based evaluation of image-processing and classification methods.
AB  - With the increased interest in computer-aided image analysis methods, there is a
      greater need for objective methods of algorithm evaluation. Validation of in vivo
      MRI studies is complicated by a lack of reference data and the difficulty of
      constructing anatomically realistic physical phantoms. We present here an
      extensible MRI simulator that efficiently generates realistic three-dimensional
      (3-D) brain images using a hybrid Bloch equation and tissue template simulation
      that accounts for image contrast, partial volume, and noise. This allows image
      analysis methods to be evaluated with controlled degradations of image data.

PMID- 10661327
TI  - Models for the comparative equivalence of scattering properties of elemental
      filters used in diagnostic radiology.
AB  - While the equivalence of different filter materials commonly considered useful in
      diagnostic radiology can be obtained in terms of the overall transmitted primary
      photons, the scattering characteristics are not the same. In this work,
      comparative models that relate the scattered photons produced from one-filter
      material with those from another have been developed. The comparison of the
      results of simulation of the scattering properties of these equivalent filter
      materials using the Monte Carlo technique with those from the models developed in
      the study are in reasonable agreement.

PMID- 10661328
TI  - Microwave imaging using the finite-element method and a sensitivity analysis
      approach.
AB  - A method for reconstructing the constitutive parameters of two-dimensional (2-D)
      penetrable scatterers from scattered field measurements is presented. This method
      is based on the differential formulation of the forward scattering problem, which
      is solved by applying the finite-element method (FEM). Given a set of scattered
      field measurements, the objective is to minimize a cost function which consists
      of two terms. The first is the standard error term, which is related to the
      measurements and their estimates, while the second term, which is related to the
      Tikhonov regularization, is used to heal the ill posedness of the inverse
      problem. The iterative Polak-Ribiere nonlinear conjugate gradient algorithm is
      applied to the minimization of the cost function. During each iteration of the
      algorithm, the direction of correction is computed by using a sensitivity
      analysis approach, which is carried out by an elaborate finite-element scheme.
      The adoption of the finite-element method results in sparse systems of equations,
      while the computational burden is further reduced by applying the adjoint state
      vector methodology. Finally, a microwave medical imaging application, which is
      related to the detection of proliferated bone marrow, is examined, while the
      robustness of the proposed technique in the presence of noise and for different
      regularization levels is investigated.

PMID- 10661329
TI  - Medulloblastoma--challenges in radiation therapy and the addition of
      chemotherapy.

PMID- 10661330
TI  - The challenge of conformal radiotherapy in the curative treatment of
      medulloblastoma.

PMID- 10661331
TI  - Sphincter preservation in rectal cancer-continued evidence of success.

PMID- 10661332
TI  - Postoperative neoadjuvant chemotherapy before radiotherapy as compared to
      immediate radiotherapy followed by maintenance chemotherapy in the treatment of
      medulloblastoma in childhood: results of the German prospective randomized trial
      HIT '91.
AB  - PURPOSE: The German Society of Pediatric Hematology and Oncology (GPOH) conducted
      a randomized, prospective, multicenter trial (HIT '91) in order to improve the
      survival of children with medulloblastoma by using postoperative neoadjuvant
      chemotherapy before radiation therapy as opposed to maintenance chemotherapy
      after immediate postoperative radiotherapy. METHODS AND MATERIALS: Between 1991
      and 1997, 158 patients were enrolled and 137 patients randomized. Seventy-two
      patients were allocated to receive neoadjuvant chemotherapy before radiotherapy
      (arm I, investigational). Chemotherapy consisted of ifosfamide, etoposide,
      intravenous high-dose methotrexate, cisplatin, and cytarabine given in two
      cycles. In arm II (standard arm), 65 patients were assigned to receive immediate
      postoperative radiotherapy, with concomitant vincristine followed by 8 cycles of
      maintenance chemotherapy consisting of cisplatin, CCNU, and vincristine
      ("Philadelphia protocol"). All patients received radiotherapy to the craniospinal
      axis (35.2 Gy total dose, 1.6 Gy fractionated dose / 5 times per week followed by
      a boost to posterior fossa with 20 Gy, 2.0 Gy fractionated dose). RESULTS: During
      chemotherapy Grade III/IV infections were predominant in arm I (40%). Peripheral
      neuropathy and ototoxicity were prevailing in arm II (37% and 34%, respectively).
      Dose modification was necessary in particular in arm II (63%). During
      radiotherapy acute toxicity was mild in the majority of patients and equally
      distributed in both arms. Myelosuppression led to a mean prolongation of
      treatment time of 11.5 days in arm I and 7.5 days in arm II, and interruptions in
      35% of patients in arm I. Quality control of radiotherapy revealed correct
      treatment in more than 88% for dose prescription, more than 88% for coverage of
      target volume, and 98% for field matching. At a median follow-up of 30 months
      (range 1.4-62 months), the Kaplan-Meier estimates for relapse-free survival at 3
      years for all randomized patients were 0.70+/-0.08; for patients with residual
      disease: 0.72+/-0.06; without residual disease: 0.68+/-0.09; M0: 0.72+/-0.04; M1:
      0.65+/-0.12; and M2/3: 0.30+/-0.15. For all randomized patients without M2/3
      disease: 0.65+/-0.05 (arm I) and 0.78+/-0.06 (arm II) (p < 0.03); patients
      between 3 and 5.9 years: 0.60+/-0.13 and 0.64+/-0.14, respectively, but patients
      between 6 and 18 years: 0.62+/-0.09 and 0.84+/-0.08, respectively (p < 0.03). In
      a univariate analysis the only negative prognostic factors were M2/3 disease (p <
      0.002) and an age of less than 8 years (p < 0.03). CONCLUSIONS: Maintenance
      chemotherapy would seem to be more effective in low-risk medulloblastoma,
      especially in patients older than 6 years of age. Neoadjuvant chemotherapy was
      accompanied by increased myelotoxicity of the subsequent radiotherapy, causing a
      higher rate of interruptions and an extended overall treatment time. Delayed
      and/or protracted radiotherapy may therefore have a negative impact on outcome.
      M2/3 disease was associated with a poor survival in both arms, suggesting the
      need for a more intensive treatment. Young age and M2/3 stage were negative
      prognostic factors in medulloblastoma, but residual or M1 disease was not,
      suggesting a new stratification system for risk subgroups. High quality of
      radiotherapy may be a major contributing factor for the overall outcome.

PMID- 10661333
TI  - Posterior fossa boost in medulloblastoma: an analysis of dose to surrounding
      structures using 3-dimensional (conformal) radiotherapy.
AB  - PURPOSE: The purpose of this study was to compare three different techniques of
      delivering the posterior fossa boost in patients with medulloblastoma. METHODS
      AND MATERIALS: Five patients underwent CT simulation for treatment planning of
      the posterior fossa boost. For each slice, the posterior fossa was contoured in
      addition to the cochlea, non-posterior fossa brain, pituitary gland, mandible,
      parotid glands, thyroid gland, pharynx, and cervical spinal cord. For each
      patient, plans for three techniques of delivering the posterior fossa boost were
      compared. Technique A utilized parallel-opposed lateral fields using bony
      landmarks (2-dimensional radiotherapy); the other two techniques were planned
      using 3-dimensional radiotherapy. Technique B utilized a pair of coplanar wedged
      posterior oblique beams, whereas Technique C utilized a pair of posterior oblique
      fields and a vertex field. Dose-volume histograms (DVH) were obtained for each of
      the organs contoured and for each technique and patient. The maximum, minimum,
      and mean dose to each organ were determined using the DVH program in our
      treatment planning system. RESULTS: In 3 of 5 patients, the planning target
      volume (PTV) was not included in the treatment field with Technique A. The
      cochlea received 100%, 50%, and 42% of the prescribed posterior fossa dose using
      Techniques A, B, and C respectively. The mean dose to the non-posterior fossa
      brain was highest with Technique C, intermediate with Technique A, and lowest for
      Technique B. The mean dose to the non-posterior fossa brain with Technique B was
      comparable to the mean non-posterior fossa brain dose delivered using parallel
      opposed lateral fields based on the CT definition of the PTV. Likewise, mean dose
      to the pituitary gland was lowest for Technique B. Both Techniques B and C were
      associated with a higher mean dose to the thyroid gland, mandible, parotid
      glands, and pharynx. CONCLUSIONS: The use of Technique B minimized the
      radiotherapy dose to the cochlea, pituitary gland, and non-posterior fossa brain.
      Contrary to what one may expect, conformal radiotherapy using Technique B did not
      deliver a higher dose to the non-posterior fossa brain over standard parallel
      opposed lateral fields. Other advantages of conformal techniques B and C over 2
      dimensional radiotherapy are the inclusion of the PTV in all patients and a lower
      mean dose to the pituitary gland. The main disadvantage of conformal Techniques B
      and C employed in our patients is a higher mean dose to the thyroid gland and
      other tissues in the neck.

PMID- 10661334
TI  - Combined postoperative irradiation and chemotherapy for anaplastic ependymomas in
      childhood: results of the German prospective trials HIT 88/89 and HIT 91.
AB  - PURPOSE: To evaluate the outcome in children with anaplastic ependymomas after
      surgery, irradiation, and chemotherapy; and to identify prognostic factors for
      survival. METHODS AND MATERIALS: Fifty-five children (n = 27 girls, 28 boys;
      median age at diagnosis, 6.2 years) with newly diagnosed anaplastic ependymomas
      were treated in the multicenter, prospective trials HIT 88/89 and HIT 91.
      Macroscopic complete resection was achieved in 28 patients; 27 patients underwent
      incomplete resection. All patients received chemotherapy before (n = 40) or after
      irradiation (n = 15). The irradiation volume encompassed either the neuraxis
      followed by a boost to the primary tumor site (n = 40) or the tumor region only
      (n = 13). No radiotherapy was administered in two patients. RESULTS: Median
      follow-up was 38 months. The overall survival rate at 3 years after surgery was
      75.6%. Disease progression occurred in 25 children with local progression
      occurring in 20. The median time to disease progression was 45 months. The only
      significant prognostic factor was the extent of resection (estimated progression
      free survival [EPFS] after 3 years was 83.3% after complete resection and 38.5%
      after incomplete resection) and the presence of metastases at the time of
      diagnosis (0% vs. 65.8% 3-year EPFS in localized tumors). Age, sex, tumor site,
      mode of chemotherapy, and irradiation volume did not influence survival.
      CONCLUSIONS: Treatment centers should be meticulous about surgery and diagnostic
      workup. Because the primary tumor region is the predominant site of failure it is
      important to intensify local treatment. Dose escalation by hyperfractionation or
      stereotactic radiotherapy might be a promising approach in macroscopically
      residual disease. The role of adjuvant chemotherapy requires further study.

PMID- 10661335
TI  - Prognostic factors in brain metastases: should patients be selected for
      aggressive treatment according to recursive partitioning analysis (RPA) classes?
AB  - PURPOSE: To determine whether or not Radiation Therapy Oncology Group (RTOG)
      recursive partitioning analysis (RPA) derived prognostic classes for patients
      with brain metastases are generally applicable and can be recommended as rational
      strategy for patient selection for future clinical trials. Inclusion of time to
      non-CNS death as additional endpoint besides death from any cause might result in
      further valuable information, as survival limitation due to uncontrolled
      extracranial disease can be explored. METHODS: We performed a retrospective
      analysis of prognostic factors for survival and time to non-CNS death in 528
      patients treated at a single institution with radiotherapy or surgery plus
      radiotherapy for brain metastases. For this purpose, patients were divided into
      groups with Karnofsky performance status (KPS) <70% and KPS > or =70%, as
      proposed by the RTOG. RESULTS: Median overall survival was 2.9 months (2.0 months
      for patients with KPS <70% and 3.6 months for patients with KPS > or =70%, p <
      0.001). We did not find other variables splitting patients with KPS <70% in
      different prognostic groups. However, advanced age, multiple brain metastases,
      presence of extracranial metastases, and uncontrolled primary tumor each
      predicted shorter survival in patients with KPS > or =70%. When grouped into the
      original RTOG RPA classes, our data set split into three subgroups with different
      prognosis and median survival times of 10.5, 3.5, and 2 months, respectively (p <
      0.05). Only 3% of patients fell into the most favorable group. Median time to non
      CNS death was 4.1 months (12.9 months in RPA class I, 4.9 months in RPA class II,
      and 3.8 months in RPA class III, respectively, p > 0.05 for RPA class II versus
      III). However, it was 8.5 months in RPA class II patients with controlled primary
      tumor, which was found to be the only prognostic factor for time to non-CNS death
      in patients with KPS > or =70%. In patients with KPS <70%, no statistically
      significant prognostic factors were identified for this endpoint. CONCLUSIONS:
      Despite some differences, this analysis essentially confirmed the value of RPA
      derived prognostic classes, as published by the RTOG, when survival was chosen as
      endpoint. RPA class I patients seem to be most likely to profit from aggressive
      treatment strategies and should be included in appropriate clinical trials.
      However, their number appears to be very limited. Considering time to non-CNS
      death, our results suggest that certain patients in RPA class II also might
      benefit from increased local control of brain metastases.

PMID- 10661336
TI  - Neurobehavioral toxicity of total body irradiation: a follow-up in long-term
      survivors.
AB  - PURPOSE: Total body irradiation (TBI) in preparation for bone marrow
      transplantation (BMT) is a routine treatment of hematological malignancy. A
      retrospective and a prospective group study of long-term cerebral side effects
      was performed, with a special emphasis on neurobehavioral toxicity effects.
      METHODS AND MATERIALS: Twenty disease-free patients treated with
      hyperfractionated TBI (14.4 Gy, 12 x 1.2 Gy, 4 days), 50 mg/kg cyclophosphamide,
      and autologous BMT (mean age 38 years, range 17-52 years; age at TBI 35 years, 16
      50 years; follow-up time 32 months, 9-65 months) participated in a
      neuropsychological, neuroradiological, and neurological examination. Data were
      compared to 14 patients who were investigated prior to TBI. Eleven patients with
      renal insufficiencies matched for sex and age (38 years, 20-52 years) served as
      controls. In a longitudinal approach, neuropsychological follow-up data were
      assessed in 12 long-term survivors (45 years, 23-59 years; follow-up time 8.8
      years, 7-10.8 years; time since diagnosis 10.1 years, 7.5-14.2 years). RESULTS:
      No evidence of neurological deficits was found in post-TBI patients except one
      case of peripheral movement disorder of unknown origin. Some patients showed
      moderate brain atrophy. Neuropsychological assessment showed a subtle reduction
      of memory performance of about one standard deviation. Cognitive decline in
      individual patients appeared to be associated with pretreatment (brain
      irradiation, intrathecal methotrexate). Ten-years post disease onset, survivors
      without pretreatment showed behavioral improvement up to the premorbid level.
      CONCLUSION: The incidence of long-term neurobehavioral toxicity was very low for
      the present TBI/BMT regimen.

PMID- 10661337
TI  - Anal sphincter conservation for patients with adenocarcinoma of the distal
      rectum: long-term results of radiation therapy oncology group protocol 89-02.
AB  - PURPOSE: To assess the outcome of a multi-institutional, national cooperative
      group study attempting functional preservation of the anorectum for patients with
      limited, distal rectal cancer. METHODS AND MATERIALS: Between September 21, 1989
      and November 1, 1992, a Phase II trial of sphincter-sparing therapy was conducted
      for patients with clinically mobile rectal cancers located below the pelvic
      peritoneal reflection. Protocol treatment was designed for patients who were, in
      the judgement of their attending surgeon, unsuitable for anal sphincter
      conservation in the context of anterior resection, and would have required
      abdominoperineal resection (APR) as conventional surgical therapy. Primary
      cancers were estimated to be 4 cm or less in largest clinical diameter, and
      occupied 40% or less of the rectal circumference. Chest radiography and
      computerized axial tomography (CT) of the abdomen and pelvis excluded patients
      with overt lymphatic or hematogenous metastases. Protocol surgery was intended to
      remove the primary cancer by en-bloc, transmural excision of an ellipse of rectal
      wall by transanal, transcoccygeal, or trans-sacral technique, while conserving
      the anal sphincter. Based on tumor size, T classification, grade, and adequacy of
      surgical margins, patients were allocated to one of three treatment assignments:
      observation, or adjuvant treatment with 5-fluorouracil (5-FU) and one of two
      different dose levels of local-regional radiation. After completion of protocol
      therapy, patients were observed with follow-up that included periodic general
      physical and rectal examination, determinations of CEA, abdominopelvic CT, chest
      radiography, and surveillance endoscopy. Sixty-five eligible and analyzable
      patients were registered. RESULTS: With minimum follow-up of 5 years and median
      follow-up of 6.1 years, 11 patients have failed: 3 patients recurred local
      regionally only, 3 patients had distant failure alone, and 5 patients manifested
      local-regional and distant failure. Eight patients died of intercurrent illness.
      Local-regional failure correlated with T-category revealed: T1 1/27 (4%), T2 4/25
      (16%), and T3 3/13 (23%). Local-regional failure escalated with percentage
      involvement of the rectal circumference: 2/31 (6%) among patients with cancers
      involving 20% or less of the rectal circumference, and 6/34 (18%) among patients
      with cancers involving 21-40% of the circumference. Distant dissemination rose
      with T-category with 1/27 (4%) T1, 3/25 (12%) T2, and 4/13 (31%) T3 patients
      manifesting hematogenous spread. Eight patients (12%) required temporary or
      permanent colostomy. Five of 8 patients with local-regional recurrence achieved
      local-regional control with management including surgery, although 4 of these
      patients subsequently developed distant dissemination. Three patients (5%) had
      persistent, uncontrolled, local disease. Actuarial freedom from pelvic relapse at
      5 years is 88% based on the entire study population, and 86% for the less
      favorable patients treated with adjuvant radiation and 5-FU. CONCLUSION:
      Conservative, sphincter-sparing therapy is a feasible alternative treatment for
      selected patients with limited cancer involving the middle and lower rectum. Risk
      of both local and distant failure appears to escalate with increasing T-category
      (depth of invasion). Results achieved in the multi-institutional, cooperative
      group setting approximate results reported from single institutions.

PMID- 10661338
TI  - Preoperative radiochemotherapy in rectal cancer: long-term results of a phase II
      trial.
AB  - PURPOSE: To assess toxicity and long-term results of preoperative
      chemoradiotherapy in rectal cancer. METHODS AND MATERIALS: Between 1989 and 1997,
      as a phase II study, 66 patients with T3 M0, rectal cancer received
      preoperatively a 45 Gy dose pelvic radiotherapy (XRT) combined with two 5-day
      chemotherapy courses (CT) of 5-Fluorouracil (5-FU) and Leucovorin (LV) delivered
      the first and fifth week of XRT. For each CT course, LV:20 mg/m2/d1-d5,. While
      the 5-FU dose was variable from 450 to 350 mg/m2/d first course and 370 to 350
      mg/m2/d second course. Surgery was planned 3 weeks later. RESULTS: XRT-CT was
      stopped in 1 patient due to progressive disease. CT was stopped in 1 patient due
      to toxicity. Grades 2 and 3 diarrhea were observed in 8 and 3 patients,
      respectively. One patient died from acute diarrhea due to deviation from
      recommendations; 60 patients went to surgery. Among the 58 patients operated on
      for cure, 5 had an R1-resection. After a 4.5-year median follow-up, the 5-year
      pelvic disease-free survival was 92% for the whole group and 96% in the R0
      resection group. CONCLUSION: Preoperative combined XRT-5-FU-LV is feasible if
      optimal XRT and patients are carefully managed. The recommended 5-FU daily dose
      is 350 mg/m2 for both CT courses. This approach is currently tested in a large
      EORTC phase III trial.

PMID- 10661339
TI  - Extracranial stereotactic radiation therapy: set-up accuracy of patients treated
      for liver metastases.
AB  - PURPOSE: Patients with liver metastases might benefit from high-dose conformal
      radiation therapy. A high accuracy of repositioning and a reduction of target
      movement are necessary for such an approach. The set-up accuracy of patients with
      liver metastases treated with stereotactic single dose radiation was evaluated.
      METHODS AND MATERIALS: Twenty-four patients with liver metastases were treated
      with single dose radiation therapy on 26 occasions using a self-developed
      stereotactic frame. Liver movement was reduced by abdominal pressure. The
      effectiveness was evaluated under fluoroscopy. CT scans were performed on the
      planning day and directly before treatment. Representative reference marks were
      chosen and the coordinates were calculated. In addition, the target displacement
      was quantitatively evaluated after treatment. RESULTS: Diaphragmal movement was
      reduced to median 7 mm (range: 3-13 mm). The final set-up accuracy of the body
      was limited to all of median 1.8 mm in latero-lateral direction (range: 0.3-5.0
      mm) and 2.0 mm in anterior-posterior direction (0.8-3.8 mm). Deviations of the
      body in cranio-caudal direction were always less than the thickness of one CT
      slice (<5 mm). However, a repositioning was necessary in 16 occasions. The final
      target shift was median 1.6 mm (0.2-7.0 mm) in latero-lateral and 2.3 mm in
      anterior-posterior direction (0.0-6.3 mm). The median shift in cranio-caudal
      direction was 4.4 mm (0.0-10.0 mm). CONCLUSIONS: In patients with liver
      metastases, a high set-up accuracy of the body and the target can be achieved.
      This allows a high-dose focal radiotherapy of these lesions. However, a control
      CT scan should be performed directly before therapy to confirm set-up accuracy
      and possibly prompt necessary corrections.

PMID- 10661340
TI  - Importance of radiation therapy for breast cancer patients treated with high-dose
      chemotherapy and stem cell transplant.
AB  - PURPOSE: To determine local-regional failure rates in breast cancer patients
      treated with surgery and high-dose chemotherapy with stem cell transplant and to
      relate local-regional failure to the use and timing of radiation treatment.
      METHODS AND MATERIALS: We retrospectively reviewed the records of 165 breast
      cancer patients treated on institutional protocols with surgery and high-dose
      chemotherapy with stem cell transplant. All patients had either Stage III
      disease, 10 or more positive axillary lymph nodes, or 4 or more positive axillary
      lymph nodes following neoadjuvant chemotherapy. Twelve patients had inflammatory
      breast cancer. Thirteen patients treated with breast preservation and 5 patients
      who died from toxicity within 30 days of transplant were excluded from the
      analyses of local-regional recurrences. In the remaining 147 patients, 108 were
      treated with adjuvant radiation and 39 were not. The disease stage distribution
      for these two groups was comparable. The median follow-up for surviving patients
      was 35 months. RESULTS: The 3- and 5-year actuarial disease-free survival (DFS)
      for the entire group was 60% and 51%, respectively. The 5-year rates of freedom
      from isolated local-regional recurrence were 95% in the patients treated with
      adjuvant radiation and 86% in the patients who did not receive radiation (p =
      0.014, log rank comparison). The 5-year rates of any local-regional recurrence as
      a first event (isolated recurrences plus those with simultaneous local-regional
      and distant recurrences) were 92% versus 82%, respectively for patients whose
      treatment did and did not include radiation (p = 0.038). We could not demonstrate
      a correlation of the timing of radiation with the risk of local-regional
      recurrence. CONCLUSIONS: These data indicate that high-dose chemotherapy does not
      negate the importance of radiation in optimizing local-regional control in
      patients with high-risk breast cancer. Given the results of recent randomized
      trials studying postmastectomy radiation, which show that improving local
      regional control improves overall survival (OS), we believe that all breast
      cancer patients with high-risk primary breast cancer who are treated with high
      dose chemotherapy with stem cell transplant should receive radiation as a
      component of their treatment.

PMID- 10661341
TI  - A population-based study of the effectiveness of breast conservation for newly
      diagnosed breast cancer.
AB  - PURPOSE: Our objective was to evaluate the effectiveness of breast conservation
      for newly diagnosed breast cancer. Effectiveness was operationalized as two
      outcomes within 5 years of the diagnosis of breast cancer: the probability of
      mastectomy-free survival (either death or mastectomy count as event, whichever
      comes first), and the probability of mastectomy conditional on survival
      (mastectomy counts as event, observations censored at death). METHODS AND
      MATERIALS: We linked records of 46,687 new cases of breast cancer from 1982 to
      1991 in the Ontario Cancer Registry to records of surgery from 1982 to 1995,
      radiotherapy (RT) from 1982 to 1992, and median household income from the 1986
      census. We labeled breast surgery within 4 months and postoperative RT within 12
      months of diagnosis as treatment for newly diagnosed breast cancer. Surgery was
      categorized as mastectomy, lumpectomy plus RT, lumpectomy alone, or no surgical
      procedure. Among cases that did not undergo mastectomy within 4 months of
      diagnosis, we labeled mastectomy subsequent to 4 months after diagnosis as
      treatment failure. We performed life-table analysis and Cox proportional hazards
      regression, to describe the probability of mastectomy conditional on survival and
      the probability of mastectomy-free survival. RESULTS: A total of 16,279 cases
      underwent lumpectomy as the maximum procedure on the breast within 4 months of
      diagnosis, and 49.7% of these received postoperative RT. Compared to the
      provincial mean, regions with higher rates of lumpectomy plus RT have higher
      probability of mastectomy-free survival and lower probability of mastectomy
      conditional upon survival 5 years after diagnosis of breast cancer. CONCLUSIONS:
      These findings are consistent with a hypothesis that breast conservation is
      effective in the overall breast cancer population of Ontario within the first 5
      years after diagnosis.

PMID- 10661342
TI  - Locoregional first recurrence after mastectomy: prospective cohort studies with
      and without immediate chemotherapy.
AB  - PURPOSE: To evaluate prospectively the impact of combination chemotherapy in the
      combined modality treatment of isolated first locoregional recurrence (LRR)
      following mastectomy for breast cancer. METHODS AND MATERIALS: Between 1979 and
      1989, 120 chemotherapy-naive women with isolated LRR as first failure after
      mastectomy were prospectively identified, uniformly staged, and systematically
      followed. Treatment consisted of excision if feasible, radical locoregional
      radiotherapy, and a hormonal maneuver (unless estrogen receptor negative). The
      initial chemotherapy cohort also received 8 cycles of doxorubicin and
      cyclophosphamide. This was compared to a subsequent control cohort. RESULTS: For
      all patients, the 10-year actuarial relapse-free survival +/- 95% confidence
      interval was 42.1+/-9.2%, and overall survival was 56.8+/-9.1%. No difference was
      seen in locoregional control between cohorts. At 5 years, distant recurrence-free
      survival for chemotherapy and control cohort respectively was 75.4+/-10.8% and
      60.7+/-12.5% (p = 0.33) and overall survival was 81.9%+/-9.6 and 74.3%+/-11.2 (p
      = 0.24). Univariate analysis showed no prognostic importance for any imbalance
      between cohorts. Cox modeling confirmed that complete resection was strongly
      associated with fewer LRR (hazard ratio [HR] 0.32, p = 0.001) and also with
      better overall survival (HR 1.82, p = 0.019). Chemotherapy produced a substantial
      reduction in risk of death (HR 0.72 CI 0.421-1.235, p = 0.23). CONCLUSIONS: In
      this prospective but nonrandomized study of treatment for first LRR, the risk of
      death in the later control cohort was 1.39 times the risk in the chemotherapy
      cohort but failed to reach statistical significance. The results justify further
      study.

PMID- 10661343
TI  - Effect of time interval between breast-conserving surgery and radiation therapy
      on ipsilateral breast recurrence.
AB  - PURPOSE: To examine the effect of the time interval (interval) between breast
      conserving surgery (BCS) and the start of radiation therapy (RT) on the
      subsequent risk of ipsilateral breast cancer recurrence (IBR). METHODS AND
      MATERIALS: We reviewed interval and a number of prognostic and treatment factors
      among 1,962 women treated with BCS and RT for invasive breast cancer diagnosed
      between January 1, 1989 and December 31, 1993 in British Columbia, Canada.
      Subjects were female, less than 90 years old at diagnosis, not treated with
      chemotherapy, not stage T4 or M1, and had survived more than 30 days from
      diagnosis. The cumulative incidence of IBR was estimated in four interval groups:
      0-5, 6-8, 9-12, and 13+ weeks. Only 23 women had an interval of greater than 20
      weeks between BCS and start of RT. To assess whether an imbalance of prognostic
      and treatment factors could be obscuring real differences between the interval
      groups, Cox proportional hazards regression analyses were conducted. RESULTS:
      Median follow-up was 71 months. The crude incidence of IBR for the entire sample
      was 3.9%. The cumulative incidence of IBR in the 6-8, 9-12, and 13+ week groups
      was not statistically significantly different from the cumulative incidence of
      IBR in the 0-5 week group. Multivariate analyses demonstrated that patients not
      using tamoxifen p = 0.027) and those with grade 3 histology (p = 0.003) were more
      likely to recur in the breast. Interval between BCS and RT was not a
      statistically significant predictor of breast recurrence when entered into a
      model incorporating tamoxifen use and tumor grade (0-5 vs. 6-8 weeks, p = 0.872;
      0-5 vs. 9-12 weeks, p = 0.665; 0-5 vs. 13+ weeks, p = 0.573). CONCLUSIONS: We
      found no univariate or multivariate difference in ipsilateral breast cancer
      recurrence between intervals of 0 to 20 weeks from breast conserving surgery to
      start of radiation therapy, in a population-based, low risk group of women not
      receiving adjuvant chemotherapy, after controlling for other factors important in
      predicting ipsilateral breast cancer recurrence.

PMID- 10661344
TI  - Radiation pneumonitis after breast cancer irradiation: analysis of the
      complication probability using the relative seriality model.
AB  - BACKGROUND: Toxicity of the respiratory system is quite common after radiotherapy
      of thoracic tumors; breast cancer patients represent one of the groups for which
      there is also a long expected survival. The quantification of lung tissue
      response to irradiation is important in designing treatments associated with a
      minimum of complications and maximum tumor control. METHODS: The study population
      consisted of 68 patients who received irradiation for breast cancer at Stage II.
      Radiation pneumonitis was retrospectively assessed on the basis of clinical
      symptoms and radiological findings. For each patient, a measure of the exposure
      (i.e., the lung dose-volume histogram [DVH]) and a measure of the outcome was
      available. Based on these data, a maximum likelihood fitting to the relative
      seriality model was performed. The uncertainties of the model parameters were
      calculated and their impact on the dose-response curve was studied. The optimum
      parameter set was then applied to 5 other patient groups treated for breast
      cancer, and the normal tissue complication probability (NTCP) was calculated.
      Each group was individuated by the radiotherapy treatment technique used; the
      dose distribution in the lung was described by a mean DVH and the incidence of
      radiation pneumonitis in each group was known. Lung radiosensitivity was assumed
      to be homogeneous through all of the calculations. RESULTS: The relative
      seriality model could describe the dataset. The volume effect was found to be
      relevant in the description of radiation pneumonitis. Age was found to be
      associated with increased risk of radiation pneumonitis. Two distinct dose
      response curves were obtained by splitting the group according to age. The impact
      of the parameter uncertainties on the dose-response curve was quite large. The
      parameter set determined could be used predictively on 3 of the 5 patient groups.
      CONCLUSION: The complication data could be modeled with the relative seriality
      model. However, further independent datasets, classified according to the same
      endpoint, must be analyzed before introducing NTCP modeling in clinical practice.

PMID- 10661345
TI  - An analysis of 78 breast sarcoma patients without distant metastases at
      presentation.
AB  - PURPOSE: A retrospective review of a single cancer center experience was
      undertaken to identify clinical or treatment prognostic factors for these unusual
      tumors, to allow for a recommendation regarding management. METHODS AND
      MATERIALS: The charts of 76 women and 2 men with breast sarcoma and without
      distant metastases at presentation registered from 1958 to 1990 were reviewed.
      Pathology was centrally reviewed in 54 cases. Histology, tumor size, grade, nodal
      status, age, menopausal status, history of benign breast disease, extent of
      surgery, resection margins, and radiation dose were each examined as potential
      prognostic factors by univariate analysis. To allow an analysis of radiation
      dose, total dose was normalized to a daily fraction size of 2 Gy. RESULTS: The
      median age at diagnosis was 50.5 years (13-82 years). The pathologic diagnosis
      was found to be malignant cystosarcoma phyllodes in 32 patients, with the
      remainder being stromal sarcoma (14), angiosarcoma (8), fibrosarcoma (7),
      carcinosarcoma (5), liposarcoma (4), other (8). Eighteen patients had grade I or
      II tumors, 43 had grade III or IV, and 18 were not evaluable. The 5- and 10-year
      actuarial rates for all 78 patients were 57% and 48% for cause-specific survival
      (CSS), and 47% and 42% for the relapse-free rates (RFR), respectively. The local
      relapse-free rate (LRFR) was 75% at both 5 and 10 years. The 5-year CSS for grade
      I or II tumors was 84% versus 55% for grade III or IV tumors (p = 0.01).
      Conservative surgery versus mastectomy did not lead to statistically significant
      different outcomes for CSS, RFR, or LRFR. The comparison of positive versus
      negative margins showed a 5-year LRFR of 33% versus 80% (p = 0.009). Pairwise
      comparisons of the 5-year CSS of 91% for > 48 Gy versus either 50% for < or = 48
      Gy or 50% for no radiation showed p-values of 0.03 and 0.06, respectively.
      CONCLUSION: The authors propose that if negative surgical margins can be
      achieved, breast sarcoma should be managed by conservative surgery with
      postoperative irradiation to a microscopic tumoricidal dose (50 Gy) to the whole
      beast, and at least 60 Gy to the tumor bed. The decision to treat should be
      preceded by a preoperative multidisciplinary assessment. It is also recommended
      that an axillary lymph node dissection is not indicated, with the possible
      exception of patients with carcinosarcoma.

PMID- 10661346
TI  - Preliminary report of toxicity following 3D radiation therapy for prostate cancer
      on 3DOG/RTOG 9406.
AB  - PURPOSE: A prospective Phase I dose escalation study was conducted to determine
      the maximally-tolerated radiation dose in men treated with three-dimensional
      conformal radiation therapy (3D CRT) for localized prostate cancer. This is a
      preliminary report of toxicity encountered on the 3DOG/RTOG 9406 study. METHODS
      AND MATERIALS: Each participating institution was required to implement data
      exchange with the RTOG 3D quality assurance (QA) center at Washington University
      in St. Louis. 3D CRT capabilities were strictly defined within the study
      protocol. Patients were registered according to three stratification groups:
      Group 1 patients had clinically organ-confined disease (T1,2) with a calculated
      risk of seminal vesicle invasion of < 15%. Group 2 patients had clinical T1,2
      disease with risk of SV invasion > or = 15%. Group 3 (G3) patients had clinical
      local extension of tumor beyond the prostate capsule (T3). All patients were
      treated with 3D techniques with minimum doses prescribed to the planning target
      volume (PTV). The PTV margins were 5-10 mm around the prostate for patients in
      Group 1 and 5-10 mm around the prostate and SV for Group 2. After 55.8 Gy, the
      PTV was reduced in Group 2 patients to 5-10 mm around the prostate only. Minimum
      prescription dose began at 68.4 Gy (level I) and was escalated to 73.8 Gy (level
      II) and subsequently to 79.2 Gy (level III). This report describes the acute and
      late toxicity encountered in Group 1 and 2 patients treated to the first two
      study dose levels. Data from RTOG 7506 and 7706 allowed calculation of the
      expected probability of observing a > or = grade 3 late effect more than 120 days
      after the start of treatment. RTOG toxicity scores were used. RESULTS: Between
      August 23, 1994 and July 2, 1997, 304 Group 1 and 2 cases were registered; 288
      cases were analyzable for toxicity. Acute toxicity was low, with 53-54% of Group
      1 patients having either no or grade 1 toxicity at dose levels I and II,
      respectively. Sixty-two percent of Group 2 patients had either none or grade 1
      toxicity at either dose level. Few patients (0-3%) experienced a grade 3 acute
      bowel or bladder toxicity, and there were no grade 4 or 5 toxicities. Late
      toxicity was very low in all patient groups. The majority (81-85%) had either no
      or mild grade 1 late toxicity at dose level I and II, respectively. A single late
      grade 3 bladder toxicity in a Group 2 patient treated to dose level II was
      recorded. There were no grade 4 or 5 late effects in any patient. Compared to
      historical RTOG controls (studies 7506, 7706) at dose level I, no grade 3 or
      greater late effects were observed in Group 1 and Group 2 patients when 9.1 and
      4.8 events were expected (p = 0.003 and p = 0.028), respectively. At dose level
      II, there were no grade 3 or greater toxicities in Group 1 patients and a single
      grade 3 toxicity in a Group 2 patient when 12.1 and 13.0 were expected (p =
      0.0005 and p = 0.0003), respectively. Multivariate analysis demonstrated that the
      relative risk of developing acute bladder toxicity was 2.13 if the percentage of
      the bladder receiving > or = 65 Gy was more than 30% (p = 0.013) and 2.01 if
      patients received neoadjuvant hormonal therapy (p = 0.018). The relative risk of
      developing late bladder complications also increased as the percentage of the
      bladder receiving > or = 65 Gy increased (p = 0.026). Unexpectedly, there was a
      lower risk of late bladder complications as the mean dose to the bladder and
      prescription dose level increased. This probably reflects improvement in
      conformal techniques as the study matured. There was a 2.1 relative risk of
      developing a late bowel complication if the total rectal volume on the planning
      CT scan exceeded 100 cc (p = 0.019). CONCLUSION: Tolerance to high-dose 3D CRT
      has been better than expected in this dose escalation trial for Stage T1,2
      prostate cancer compared to low-dose RTOG historical experience. With strict
      quality assurance standards and review, 3D CRT can be safely studied in a co

PMID- 10661347
TI  - Prognostic factors in invasive bladder carcinoma treated by combined modality
      protocol (organ-sparing approach).
AB  - PURPOSE: The results of bladder sparing approach for the treatment of muscle
      invasive bladder cancer, using a combination of transurethral resection (TUR),
      chemotherapy, and radiotherapy, are encouraging. The survival of patients treated
      by this method is similar to the survival of patients treated by radical
      cystectomy. The aim of our study was to find out which pretreatment
      characteristics influence the survival of patients treated by organ sparing
      approach that would enable us to identify the patients most suitable for this
      type of treatment. METHODS AND MATERIALS: The prognostic value of different
      factors, such as age, gender, performance status, hemoglobin level, clinical
      stage, histologic grade, presence of obstructive uropathy, and completeness of
      TUR, has been studied in 105 patients with invasive bladder cancer, who received
      a bladder sparing treatment in the period from 1988 to 1995. They were treated
      with a combination of TUR, followed by 2-4 cycles of methotrexate, cisplatinum,
      and vinblastine polychemotherapy. In complete responders the treatment was
      completed by radiotherapy (50 Gy to the bladder and 40 Gy to the regional lymph
      nodes), whereas nonresponders underwent cystectomy whenever feasible. RESULTS:
      Our study has confirmed an independent prognostic value of performance status,
      histologic grade, and obstructive uropathy, for the disease-specific survival
      (DSS) of bladder cancer patients treated by a conservative approach. We believe
      that performance status best reflects the extent of disease and exerts
      significant influence on the extent and course of treatment, while obstructive
      uropathy is a good indicator of local spread of the disease, better than clinical
      T-stage. Our finding that histologic grade is one of the strongest prognostic
      factors shows that tumor biology also is a very important prognostic factor in
      patients treated by conservative approach. CONCLUSION: Patients with muscle
      invasive bladder cancer who are most likely to benefit from conservative
      treatment approach include those with good performance status, absence of
      hydronephrosis, and histologic low grade transitional cell carcinoma.

PMID- 10661348
TI  - Radiation-induced gadd45 expression correlates with clinical response to
      radiotherapy of cervical carcinoma.
AB  - BACKGROUND: Recent work has identified a category of genes devoted to the control
      of genomic stability and prevention of cellular evolution. They encode components
      of cell cycle checkpoint, i.e., regulatory pathways committed to ordered cell
      cycle transition and fidelity of replicated DNA under adverse environmental
      conditions, such as those following exposure to genotoxic agents. Gadd45 belongs
      to the class II family of DNA damage-inducible (DDI) gene, and its role in DNA
      repair has been proved in many experimental models. The aim of our study was to
      correlate gadd45 radio-induction with the responsiveness to radiotherapy of
      cervical carcinomas, a type of cancer most commonly treated with radiotherapy
      alone. METHODS: By means of a competitive polymerase chain reaction strategy, we
      compared in 14 patients the gene expression levels before and during external
      beam radiotherapy, when a dose ranging from 18 to 25 Gy was delivered to the
      target. RESULTS: We found a correlation between the lack of gadd45 induction and
      a good clinical response to radiotherapy, in terms of both local control and
      disease-free survival. CONCLUSION: Our results support the measure of the
      induction of gadd45, and possibly of other genes required for regulated G1-S
      checkpoint, as a method useful for prognostic evaluation of cervical carcinoma
      patients.

PMID- 10661349
TI  - High-dose-rate postoperative vaginal cuff irradiation alone for stage IB and IC
      endometrial cancer.
AB  - PURPOSE: To evaluate the effectiveness of postoperative high-dose-rate (HDR)
      vaginal cuff irradiation alone (1500 cGy in 3 fractions) in patients with Stage
      Ib and Ic endometrial cancer. METHODS AND MATERIALS: This is a retrospective
      review of 102 patients with Stage Ib and Ic endometrial cancer treated with a
      hysterectomy and postoperative HDR intracavitary therapy alone during the period
      of 1/1/90-12/31/96. Each patient received 1500 cGy in 3 weekly treatments, dosed
      to a depth of 0.5 cm. Pathologic features such as depth of invasion, tumor grade,
      lower uterine segment (LUS) involvement, and lymphvascular invasion (LVI) were
      evaluated for their impact on recommended postoperative treatment. All survival
      curves were generated utilizing Kaplan-Meier methods and all statistical
      comparisons were via a Wilcoxon rank sum test. RESULTS: The 5-year actuarial
      overall survival (OS) is 84% and the 5-year disease-free survival (DFS) is 93%.
      Locoregional disease control (pelvic control) was excellent with 97% of the
      patients free of pelvic disease at 5 years. Of the three pelvic failures only one
      was in the vaginal cuff. LVI, LUS involvement, Grade 3 and/or outer third
      myometrial involvement were identified in 41 patients. Thirty-one of these
      patients underwent a lymphadenectomy and there were two regional failures within
      this increased-risk group. CONCLUSIONS: We obtained an excellent level of
      locoregional control with minimal morbidity and minimal time commitment for
      treatment with vaginal HDR brachytherapy alone. Our dose per fraction and total
      dose is lower than most reported series and there is no apparent loss in
      locoregional control. In addition, intermediate-risk patients and patients with
      an increased risk of recurrence (Grade 3, outer third myometrial involvement,
      LVI, LUS) may be treated with cuff irradiation alone, after surgical staging and
      a negative lymphadenectomy.

PMID- 10661350
TI  - Brachytherapy for pediatric soft-tissue sarcoma.
AB  - PURPOSE: To review the use of brachytherapy (BRT) to treat soft-tissue sarcoma
      (STS) in pediatric patients at St. Jude Children's Research Hospital. METHODS AND
      MATERIALS: Thirty-one patients, median age 11 years (range 1-21 years) with
      Pediatric Oncology Group (POG) Grade 2-3 soft-tissue sarcoma (excluding
      rhabdomyosarcoma and Ewing's sarcoma) were treated with BRT initially (n = 27) or
      at the time of recurrence (n = 4) using I-125 or Ir-192 in a temporary (n = 29)
      or permanent implant (n = 2). Twelve patients were treated with BRT alone and the
      remaining 19 were treated with a combination of BRT and external beam irradiation
      (EBRT). The majority of patients had involved margins of resection (n = 20) and
      tumors less than 5 cm (n = 17). RESULTS: Twenty-seven patients were treated with
      BRT at the time of presentation. Among the 10 patients treated with BRT alone,
      one patient developed metastases (4 months) and died of metastatic disease (12
      months after presentation); there were no local or regional failures among the
      remaining 9 patients. Among the 17 patients treated with a combination of BRT and
      EBRT, there was one local (17 months), two regional (both at 8 months), and 3
      distant failures (12, 15, 66 months). The median survival for the surviving 25
      patients was 34 months. Wound dehiscence, fibrosis/telangectasia, pigment
      changes, and cellulitis were the most common side effects. CONCLUSIONS: BRT is an
      excellent treatment option for pediatric patients with STS. Disease control may
      be achieved with a high rate of success when BRT is used alone or in combination
      with EBRT. BRT should be considered for patients with STS who require radiation
      therapy with the objective of reducing the dose to normal tissues and shortening
      the overall treatment time. Limb preservation, functional outcome, and toxicity
      assessment require careful assessment in a prospective study.

PMID- 10661351
TI  - Cutaneous and subcutaneous Ewing's sarcoma: an indolent disease.
AB  - PURPOSE: The occurrence of extraosseous Ewing's sarcoma (ES) in deep soft tissues
      has been well described, but cases in which this tumor occurs in a primary
      cutaneous or subcutaneous site have rarely been reported. The superficial variant
      may be less aggressive than are the more common bony and deep soft tissue
      counterparts with an apparently favorable outcome. A retrospective review of
      patients with cutaneous or subcutaneous ES was conducted to analyze outcome and
      patterns of failure. METHODS AND MATERIALS: Between July 1985 and March 1997, 14
      patients with cutaneous or subcutaneous ES were treated at St. Jude Children's
      Research Hospital. The median age at presentation was 16 years (range 7-21
      years). Anatomic locations included trunk and pelvis (7), upper or lower
      extremity (4), and head and neck (3). The median size of the lesion was 3 cm
      (range, 1-12 cm). Thirteen had definitive surgical resections, and one had biopsy
      of the mass at the time of referral. They were enrolled on institutional (12) or
      cooperative group (2) protocols. All patients received chemotherapy, composed of
      vincristine, doxorubicin, cyclophosphamide, ifosfamide, etoposide, and
      dactinomycin. Patients on institutional protocols received radiation (36 Gy) to
      the operative bed (150-180 cGy/fraction/day). Postoperative radiotherapy was
      omitted for 2 patients who had complete resection on the cooperative group study.
      RESULTS: No patients had metastatic disease at presentation. Thirteen patients
      had wide local excision of the primary tumors prior to enrollment on
      chemotherapy; surgical margins were negative (10), microscopically positive (2),
      and indeterminate (1). Eleven patients received radiotherapy to the tumor bed; 2
      with clear surgical margins were treated without irradiation. The patient who had
      biopsy only received induction chemotherapy followed by definitive surgical
      resection and postoperative radiotherapy. The median follow-up was 77 months
      (range 17-111 months). None of the patients has developed local recurrence or
      distant metastasis. Several of the patients developed treatment-related sequelae,
      including veno-occlusive disease of the lung and hemorrhagic cystitis (1),
      myelodysplastic syndrome (1), chemotherapy-induced ovarian failure (1), moist
      desquamation (1), and dermatofibroma within the radiotherapy volumes (1).
      CONCLUSIONS: Cutaneous and subcutaneous ES are associated with an indolent course
      and a favorable prognosis when treated with combined modality therapy.
      Elimination of radiation therapy following complete resection has been tested in
      the POG 9354 trial. The high rate of local control, low rate of metastatic
      disease, and excellent overall outcome may suggest a role for less intensive
      chemotherapy, as well as tailoring to diminish or avoid radiation therapy in
      completely resected cases, with a goal to minimize toxicity while maintaining a
      high cure rate.

PMID- 10661352
TI  - Primary therapeutic decision-making in inoperable non-small cell lung cancer.
AB  - PURPOSE: To test the accuracy of our treatment decisions for patients with
      inoperable non-small cell lung cancer (NSCLC) using a prototype decision-support
      system (DSS) and a prognostic index (PI). METHODS AND MATERIALS: To predict
      patient outcome and select optimal treatment, the systems protocol was tested
      retrospectively in 242 patients with Stage I-IV disease. The PI was determined in
      184 patients with Stage I-IIIa,b disease. Survival was the final determinant of
      the accuracy of our treatment decisions. RESULTS: Until 1996 it was our treatment
      policy to treat all Stage III patients with radical intent unless they had
      symptoms requiring palliation. In 1997, after the palliation concept of the DSS
      and the PI were changed to include all Stage III disease, there was considerable
      discordance between the rates of palliative treatment indicated by the DSS and
      the PI (69% and 99%, respectively) as well as that observed in our practice (30%
      in the DSS group and 20% in the PI group, respectively). There was also a
      significant difference in survival between the patients in the low- and high-risk
      categories defined by the PI (median survival of 12 versus 6 months,
      respectively; p = 0.0001). In the group that received radical radiotherapy, there
      was also a significant difference in the duration of survival between the low-
      and high-risk groups (median survival of 12 versus 8 months, respectively; p =
      0.01). In addition, the risk categories proved to be the most important predictor
      of survival in the patients receiving radiotherapy longer than 2 weeks (median
      survival of 12 versus 7 months, respectively; p = 0.0001). In high-risk patients,
      however, the duration of radiotherapy did not have a significant impact on
      survival (p = 0.25). CONCLUSION: Our data indicate that the PI is a useful method
      for selecting radical or palliative treatment modalities as well as for
      determining treatment duration.

PMID- 10661353
TI  - Intracavitary brachytherapy significantly enhances local control of early T-stage
      nasopharyngeal carcinoma: the existence of a dose-tumor-control relationship
      above conventional tumoricidal dose.
AB  - PURPOSE: To study the efficacy of intracavitary brachytherapy (ICT) in early T
      stage nasopharyngeal carcinoma (NPC). METHODS AND MATERIALS: All T1 and T2 (nasal
      infiltration) NPC treated with a curative intent from 1984 to 1996 were analyzed
      (n = 509). One hundred sixty-three patients were given ICT after radical external
      radiotherapy (ERT) (Group A). They were compared with 346 patients treated by ERT
      alone (Group B). The ERT delivered the tumoricidal dose (uncorrected BED-10 > or
      =75 Gy) to the primary tumor and did not differ between the two groups in
      technique or dosage. The ICT delivered a dose of 18-24 Gy in 3 fractions over 15
      days to a point 1 cm perpendicular to the midpoint of the plane of the sources.
      ICT was used to treat local persistence diagnosed at 4-6 weeks after ERT (n =
      101) or as an adjuvant for the complete responders to ERT (n = 62). RESULTS: The
      two groups did not differ in patients' age or sex, rate of distant metastasis,
      rate of regional failure, overall survival, or the follow-up duration. However,
      Group A had significantly more T2 lesions and Group B had significantly more
      advanced N-stages. Local failure was significantly less (crude rates 6.75% vs.
      13.0%; 5-year actuarial rates 5.40% vs. 10.3%) and the disease-specific mortality
      was significantly lower (crude rates 14.1% vs. 21.7%; 5-year actuarial rates
      11.9% vs. 16.4%) in Group A compared to Group B. Multivariate analysis showed
      that the ICT was the only significant prognostic factor predictive for fewer
      local failures (Cox regression p = 0.0328, risk ratio = 0.49, 95% confidence
      interval (95% CI) = 0.256-0.957). However, when ICT was excluded from the Cox
      regression model, the total physical dose or the total BED-10 uncorrected for
      tumor repopulation during the period of radiotherapy became significant in
      predicting ultimate local failure rate. The two groups were comparable in the
      incidence rates of each individual chronic radiation complication and the
      actuarial cumulative rate of the chronic radiation complications, with the
      exception of chronic radiation nasopharyngeal ulceration/necrosis which occurred
      in 10 patients in Group A and 1 patient in Group B. Headache (n = 4) and foul
      smell (n = 8) consequential to ulceration/necrosis were mild and manageable by
      conservative means. A significant dose-tumor-control relationship existed when
      local failure was studied as a function of the total physical dose or the total
      biological equivalent dose (linear quadratic equation, alpha/beta = 10)
      uncorrected for tumor repopulation during the time course of the radiotherapy.
      CONCLUSIONS: Supplementing ERT which delivered tumoricidal dose (uncorrected BED
      10 > or =75 Gy), ICT significantly enhanced ultimate local control and avoided
      the necessity for morbid salvage treatments in early T-stage (T1/T2 nasal
      infiltration) NPC. The slight increase in chronic radiation ulceration/necrosis
      after ICT was acceptable with mild and manageable symptoms. Other late
      complications were not increased. A significant dose-tumor-control relationship
      exists above the conventional tumoricidal dose level.

PMID- 10661354
TI  - Severe anemia is associated with poor tumor oxygenation in head and neck squamous
      cell carcinomas.
AB  - PURPOSE: To investigate the relationship between tumor oxygenation and the blood
      hemoglobin (Hb) concentration in patients with squamous cell carcinoma of the
      head and neck (SCCHN). METHODS AND MATERIALS: A total of 133 patients with SCCHN
      underwent pretreatment polarographic pO2 measurements of their tumors. In 66
      patients measurements were also made in sternocleidomastoid muscles. The patients
      were divided into three groups according to their Hb concentration-severe anemia
      (Hb < 11.0 g/dl), mild anemia (female: Hb 11.0-11.9 g/dl; male: Hb 11.0-12.9
      g/dl), and normal Hb concentration (female: Hb > or =12.0 g/dl; male: > or =13.0
      g/dl). RESULTS: No significant difference in tumor oxygenation could be detected
      between mildly anemic patients and patients with a normal Hb level. However, the
      tumor oxygenation in the severely anemic group was significantly below that of
      each of the other two groups (p < 0.0001). There was no significant difference
      between the Hb groups in oxygenation of sternocleidomastoid muscles. In a
      multivariate analysis including Hb group, tumor volume, smoking habits, gender, T
      stage, N-stage, and histologic grade a Hb level < 11 g/dl was found to be the
      strongest predictor for a poor tumor oxygenation. Smoking also had a marginal
      influence on median pO2. CONCLUSION: Our data suggest that a low Hb concentration
      and cigarette smoking contribute to inadequate oxygenation of SCCHN and thus for
      increased radioresistance. Consequently, Hb correction and abstinence from
      smoking may significantly improve tumor oxygenation.

PMID- 10661355
TI  - Nodal basin recurrence following lymph node dissection for melanoma: implications
      for adjuvant radiotherapy.
AB  - PURPOSE: To analyze patterns of failure in malignant melanoma patients with lymph
      node involvement who underwent complete lymph node dissection (LND) of the nodal
      basin. To determine prognostic factors predictive of local recurrence in the
      lymph node basin in order to select patients who may benefit from adjuvant
      radiotherapy. METHODS AND MATERIALS: A retrospective analysis of 338 patients
      undergoing complete LND for melanoma between 1970 and 1996 who had pathologically
      involved lymph nodes was performed. Mean follow-up from the time of LND was 54
      months (range: 12-306 months). Lymph node basins dissected included the neck (56
      patients), axilla (160 patients), and groin (122 patients). Two hundred fifty
      three patients (75%) underwent therapeutic LND for clinically involved nodes,
      while 85 patients (25%) had elective dissections. Forty-four percent of patients
      received adjuvant systemic therapy. No patients received adjuvant radiotherapy to
      the lymph node basin. RESULTS: Overall and disease-specific survival for all
      patients at 10 years was 30% and 36%, respectively. Overall nodal basin
      recurrence was 30% at 10 years. Mean time to nodal basin recurrence was 12 months
      (range: 2-78 months). Site of nodal involvement was prognostic with 43%, 28%, and
      23% nodal basin recurrence at 10 years with cervical, axillary, and inguinal
      involvement, respectively (p = 0.008). Extracapsular extension (ECE) led to a 10
      year nodal basin failure rate of 63% vs. 23% without ECE (p < 0.0001). Patients
      undergoing a therapeutic dissection for clinically involved nodes had a 36%
      failure rate in the nodal basin at 10 years, compared to 16% for patients found
      to have involved nodes after elective dissection (p = 0.002). Lymph nodes larger
      than 6 cm led to a failure rate of 80% compared to 42% for nodes 3-6 cm and 24%
      for nodes less than 3 cm (p < 0.001). The number of lymph nodes involved also
      predicted for nodal basin failure with 25%, 46%, and 63% failure rates at 10
      years for 1-3, 4-10, and > 10 nodes involved (p = 0.0001). There was no
      significant difference in nodal basin control in patients with synchronous or
      metachronous lymph node metastases, nor in patients receiving or not receiving
      adjuvant systemic therapy. Nodal basin failure was predictive of distant
      metastasis with 87% of patients with nodal basin recurrence developing distant
      disease compared to 54% of patients without nodal failure (p < 0.0001). On
      multivariate analysis, number of positive nodes and type of dissection (elective
      vs. therapeutic) were significant predictors of overall and disease-specific
      survival. Size of the largest lymph node was also predictive of disease-specific
      survival. Site of nodal involvement and ECE were significant predictors of nodal
      basin failure. CONCLUSIONS: Malignant melanoma patients with nodal involvement
      have a significant risk of nodal basin failure after LND if they have cervical
      involvement, ECE, >3 positive lymph nodes, clinically involved nodes, or any node
      larger than 3 cm. Patients with these risk factors should be considered for
      adjuvant radiotherapy to the lymph node basin to reduce the incidence of nodal
      basin recurrence. Patients with nodal basin failure are at higher risk of
      developing distant metastases.

PMID- 10661356
TI  - The situation of radiation oncology practice training programs and their
      graduates in 1998.
AB  - PURPOSE: To keep the profession apprised of current trends in the job market, the
      American College of Radiology (ACR) studied the employment situation of 1998
      radiation oncology graduates and the status and plans of radiation oncology
      training programs in the United States. METHODS AND MATERIALS: In April-May 1998,
      and again in a December 1998-January 1999 follow-up, the ACR surveyed all
      radiation oncology residency directors in the U.S. about the employment situation
      of their 1998 residency and fellowship graduates as well as changes in their
      programs. Eighty-five percent (71/84) of those surveyed responded. We compare
      current findings with similar 1997 and earlier surveys and report statistically
      significant differences (p < or = 0.05). RESULTS: By 6 months after graduation,
      there were no graduating residents or fellows who had not secured a position,
      although the status of two was unknown. At that time, about 93% of all graduates
      had secured positions that directors said reasonably matched graduates' training
      and personal goals. Program directors reported that accomplished and planned
      changes in their programs will reduce the annual number of residency graduates by
      about one-fifth since 1993. However, the number of beginning residency positions
      offered in 1998 was 149, up from 116 in 1997 and only a few percent below the
      1993 level. By the December 1998-January 1999 follow-up, fill rates for offered
      training positions were 94% for residencies and 80% for fellowships, figures that
      are similar to those reported for past years. Directors' perceptions of the job
      market are much more positive. For example, only 11% of residency directors
      viewed the market as more difficult this year than typical of recent years, as
      against 48% in 1997 and 82% in 1996. CONCLUSION: Unemployment continues to be
      low, and another, "softer" indicator, the job market perceptions of residency
      program directors, continues to improve. Possibly as a result, plans for program
      reductions are evaporating.

PMID- 10661358
TI  - Radiation and/or hyperthermia sensitivity of human melanoma cells after several
      days of incubation in media lacking serum or certain serum components.
AB  - PURPOSE: Complete serum and single growth factors have been reported to protect
      cells against the effects of hyperthermia. The phenomenon is not very well
      understood, especially with regard to the relative importance of the various
      serum components. There is also a need to clarify the possible involvement of
      changes in proliferation. The influence of serum and growth factors on radiation
      sensitivity has not been studied in detail. The present communication is an
      attempt to at least partly fill these gaps. Cells were exposed to X-rays and/or
      heat after incubation in sufficiently supplemented medium and media lacking
      certain serum components. Differences in clonogenic survival were recorded and
      related to the proliferative status under the various conditions. METHODS AND
      MATERIALS: Human melanoma cells (MeWo) were used throughout. Cells were incubated
      for 3 or 6 days (a) in Ham's F12 medium with 20% fetal calf serum; (b) in medium
      without serum, but supplemented with the following components: insulin,
      transferrin, Na-selenite, and a lipid-protein complex; (c) to (f) in media
      lacking one or the other of these components; (g) in unsupplemented medium.
      Colony formation ability served as a measure of cell survival after exposure to
      radiation (250 kV X-rays) and/or hyperthermia (heating at 43 degrees C). In
      parallel, cell proliferation was characterized by the bromodeoxyuridine (BrdU)
      labeling index and the Ki-67 growth fraction, both determined by two-parameter
      flow cytometry. RESULTS AND CONCLUSIONS: Sensitivity was hardly influenced by 3
      days of incubation in medium containing no supplement at all, whereas after 6
      days under the same conditions survival curves both of irradiated and
      hyperthermia-treated cells had a strongly reduced shoulder or were considerably
      steeper. Experiments with media lacking only one or the other serum component,
      showed that deprivation of insulin, transferrin, and sodium selenite led to no
      more than a modest increase in cell killing, whereas the effects in medium
      lacking lipid-protein complex were about the same as in medium containing no
      supplement at all. Sensitivity changes did not seem to be due to the lack of
      serum or certain of its components per se, but were very well correlated with
      changes in proliferation as characterized by BrdU labeling index or the Ki-67
      growth fraction.

PMID- 10661357
TI  - Relationship between DNA double-strand breaks, cell killing, and fibrosis studied
      in confluent skin fibroblasts derived from breast cancer patients.
AB  - PURPOSE: To investigate the relationship between DNA double-strand breaks (dsbs),
      cell killing, and fibrosis using skin fibroblasts derived from breast cancer
      patients who received postmastectomy radiotherapy. METHODS AND MATERIALS:
      Experiments were performed with 12 lines of normal skin fibroblasts derived from
      recurrence-free breast cancer patients. Cells were irradiated in confluence and
      cell survival was determined either after immediate or delayed (14 h) plating
      using a colony-forming assay. Dsbs were measured by constant-field gel
      electrophoresis. The "excess risk of fibrosis" was previously scored by Johansen
      et al. (IJRB 1994;66:407-412). RESULTS: The 12 cell lines showed a typical
      spectrum of radiosensitivity. The mean value of surviving fraction after 3.5 Gy
      (SF3.5) was 0.063 for immediate and 0.174 for delayed plating with a coefficient
      of variation (CV) of 44 and 39%, respectively. There was also a broad variation
      in the extent of recovery from potentially lethal damage (RPLD), which was not
      correlated with the immediate sensitivity. The number of initial dsbs as well as
      the half-times of dsb repair showed little variation, whereas there were
      considerable differences in the number of residual dsbs (CV = 29%). The number of
      residual dsbs after 100 Gy was correlated significantly only with SF3.5 after
      delayed (r2 = O.59; p = 0.006) but not after immediate plating (r2 = 0.21, p =
      0.16). There was also no significant relationship between residual dsbs and the
      "excess risk of fibrosis" determined for the respective patients. CONCLUSION: It
      is shown that the number of residual dsbs measured in confluent human fibroblast
      lines can be used to predict the cellular radiosensitivity after delayed but not
      after immediate plating and also not to predict the excess risk of fibrosis of
      the respective breast cancer patients.

PMID- 10661359
TI  - On-line set-up corrections during radiotherapy of patients with gynecologic
      tumors.
AB  - PURPOSE: Positioning of patients with gynecologic tumors for radiotherapy has
      proven to be relatively inaccurate. To improve the accuracy and reduce the
      margins from clinical target volume (CTV) to planning target volume (PTV), on
      line set-up corrections were investigated. METHODS AND MATERIALS: Anterior
      posterior portal images of 14 patients were acquired using the first six monitor
      units (MU) of each irradiation fraction. The set-up deviation was established by
      matching three user-defined landmarks in portal and simulator image. If the two
      dimensional deviation exceeded 4 mm, the table position was corrected. A second
      portal image was acquired using 30 MU of the remaining dose. This image was
      analyzed off-line using a semiautomatic contour match to obtain the final set-up
      accuracy. To verify the landmark match accuracy, the contour match was
      retrospectively performed on the six MU images as well. RESULTS: The standard
      deviation (SD) of the distribution of systematic set-up deviations after
      correction was < 1 mm in left-right and cranio-caudal directions. The average
      random deviation was < 2 mm in these directions (1 SD). Before correction, all
      standard deviations were 2 to 3 mm. The landmark match procedure was sufficiently
      accurate and added on average 3 min to the treatment time. The application of on
      line corrections justifies a CTV-to-PTV margin reduction to about 5 mm.
      CONCLUSIONS: On-line set-up corrections significantly improve the positioning
      accuracy. The procedure increases treatment time but might be used effectively in
      combination with off-line corrections.

PMID- 10661360
TI  - A simple method of obtaining equivalent doses for use in HDR brachytherapy.
AB  - PURPOSE: To develop a simple program that can be easily used by clinicians to
      calculate the tumor and late tissue equivalent doses (as if given in 2 Gy/day
      fractions) for different high-dose-rate (HDR) brachytherapy regimens. The program
      should take into account the normal tissue sparing effect of brachytherapy.
      METHODS AND MATERIALS: Using Microsoft Excel, a program was developed
      incorporating the linear-quadratic (LQ) formula to calculate the biologically
      equivalent dose (BED). To express the BED in terms more familiar to all
      clinicians, it was reconverted to equivalent doses as if given as fractionated
      irradiation at 2 Gy/fraction. Since doses given to normal tissues in HDR
      brachytherapy treatments are different from those given to tumor, a normal tissue
      dose modifying factor (DMF) was applied in this spreadsheet (depending on the
      anticipated dose to normal tissue) to obtain more realistic equivalent normal
      tissue effects. RESULTS: The spreadsheet program created requires the clinician
      to enter only the external beam total dose and dose/fraction, HDR dose, and the
      number of HDR fractions. It automatically calculates the equivalent doses for
      tumor and normal tissue effects, respectively. Generally, the DMF applied is < 1
      since the doses to normal tissues are less than the doses to the tumor. However,
      in certain circumstances, a DMF of > 1 may need to be applied if the dose to
      critical normal tissues is higher than the dose to tumor. Additionally, the
      alpha/beta ratios for tumor and normal tissues can be changed from their default
      values of 10 Gy and 3 Gy, respectively. This program has been used to determine
      HDR doses needed for treatment of cancers of the cervix, prostate, and other
      organs. It can also been used to predict the late normal tissue effects, alerting
      the clinician to the possibility of undue morbidity of a new HDR regimen.
      CONCLUSION: A simple Excel spreadsheet program has been developed to assist
      clinicians to easily calculate equivalent doses to be used in HDR brachytherapy
      regimens. The novelty of this program is that the equivalent doses are expressed
      as if given at 2 Gy per fraction rather than as BED values and a more realistic
      equivalent normal tissue effect is obtained by applying a DMF. Its ease of use
      should promote the use of LQ radiobiological modeling to determine doses to be
      used for HDR brachytherapy. The program is to be used judiciously as a guide only
      and should be correlated with clinical outcome.

PMID- 10661361
TI  - Lactation after conservative treatment for breast cancer.

PMID- 10661362
TI  - Non-small cell lung tumors repopulate rapidly during radiation therapy.

PMID- 10661363
TI  - Bone metastasis: review and critical analysis of random allocation trial of local
      field treatment: regarding Ratanatharathorn et al. IJROB 44(1):1-18; 1999.

PMID- 10661364
TI  - Vicarious emotional experience and emotional expression in group psychotherapy.
AB  - Emotional arousal is a key concept in most theories of change. To be able to
      understand the role of emotional expression better, two treatments, cognitive
      therapy (CT) and focused expressive psychotherapy (FEP; a manualized form of
      Gestalt therapy), with opposite process assumptions about the expression of
      emotions were compared. Additionally vicarious emotional experience in the sense
      of an underlying emotional contagion was examined. Clients suffering from major
      depression were rated for the expression of emotion in three randomly selected
      sessions of a 20-session treatment course. While the types of emotions generally
      experienced by CT clients and FEP clients did not differ significantly,
      differences in the subgroups of active and observing-group members were found.
      This indicated that the process assumptions made by the respective treatments
      were only valid for the actively participating clients and not for the observing
      group members. Emotional contagion as a process was not supported.

PMID- 10661365
TI  - Attacking anxiety: a naturalistic study of a multimedia self-help program.
AB  - The effects of a commercial multimedia self-help program (Attacking Anxiety) were
      evaluated by examining the outcome of 176 individuals who participated in the
      treatment. Results suggested that 62 individuals suffering from anxiety achieved
      clinically significant improvement. An additional 40 achieved reliable change,
      despite the fact that these individuals had suffered from anxiety-based problems
      for years prior to their participation. Only one participant experienced negative
      change. These results are discussed in relation to the growing literature on self
      help interventions and the limitations imposed by the naturalistic nature of the
      investigation.

PMID- 10661366
TI  - Quid pro quo: fee for services delivered in a psychology training clinic.
AB  - The present study evaluated the use of a sliding-fee scale at a training clinic
      for doctoral students in clinical psychology. A chart review of 209 individual
      therapy clients and a follow-up telephone interview of 87 of these clients were
      conducted. Results of the chart review revealed a client group of relatively low
      income, with only a very small number receiving social assistance or a disability
      pension. The follow-up survey found that the large majority of clients were
      satisfied with the fees charged. Service use (i.e., frequency and number of
      sessions), client satisfaction with services, and treatment outcome did not vary
      with out-of-pocket costs incurred by clients. Overall, findings suggest that
      training clinics can charge fees without affecting services, although future
      research needs to examine the extent that fee charging by training clinics may be
      an obstacle to service access for the poorest segments of the population.

PMID- 10661367
TI  - Interaction of psychosocial and physical risk factors in the causation of mammary
      cancer, and its prevention through psychological methods of treatment.
AB  - Some 8059 healthy women (mean age 58 years) were studied in 1973 with the aim of
      establishing the presence or absence of a variety of physical and psychological
      risk factors for mammary cancer. Mortality was established in 1988. factor
      predictors were highly significant. Physical risk factors were more predictive
      than psychological ones, but both interacted synergistically to predict
      mortality. Alone, psychological (stress) factors had little effect, while
      physical factors did. However, psychological factors seemed to potentiate the
      effect of physical factors, particularly in the middle range. The causal
      relevance of psychological factors was established in a special intervention
      study using autonomy training as a method of prophylactic therapy and comparing
      outcome with the effects of no therapy (control).

PMID- 10661368
TI  - Shame and guilt in women with eating-disorder symptomatology.
AB  - The relationship of shame and guilt to eating-disorder symptomatology was
      investigated in a sample of 97 Australian women. In terms of the objective of
      predicting the severity of eating disturbance, the study explored the predictive
      utility of proneness to shame and guilt in a global sense, shame and guilt
      associated specifically with eating contexts, and shame associated with the body.
      The study also sought to determine if shame is a more prominent emotion than
      guilt among women who have eating difficulties. Shame associated with eating
      behavior was the strongest predictor of the severity of eating-disorder
      symptomatology. Other effective predictors were guilt associated with eating
      behavior and body shame. Eating disturbance was unrelated to proneness to shame
      and guilt in a global sense. Discussion of these findings focuses on the issue of
      determining whether self-conscious affects are best regarded as causes or as
      consequences of eating disturbance.

PMID- 10661369
TI  - Hypochondriasis and somatization: two distinct aspects of somatoform disorders?
AB  - We investigated boundaries and overlap between somatization and hypochondriasis
      on different levels of psychopathology: (1) comorbidity between hypochondriasis
      and somatization on the level of diagnoses in the Diagnostic and Statistical
      Manual of Mental Disorders, Fourth Edition (DSM-IV; American Psychiatric
      Association, 1994): (2) comorbidity with other mental disorders; (3) differences
      in clinical characteristics: and (4) overlap on the level of psychometric
      measures. The sample consisted of 120 psycho somatic inpatients. Somatoform,
      hypochondriacal, and depressive symptomatology, cognitions about body and health,
      and further aspects of general symptomatology were investigated. Diagnoses of
      Axis I and II were based on DSM-IV Our results suggest a large overlap on the
      level of DSM-IV-diagnoses: only 3 of 31 hypochondriacal patients had no multiple
      somatoform symptoms, while 58 of 86 patients with multiple somatoform symptoms
      had no hypochondriasis. However, the overlap between hypochondriacal and
      somatization symptomatology on the level of psychometric measurement is only
      moderate, indicating that hypochondriasis is a markedly distinct aspect of
      somatoform disorders.

PMID- 10661370
TI  - Do the DSM decision trees improve diagnostic ability?
AB  - Experiment 1 examined whether the use of the DSM-III-R decision trees increased
      the accuracy of DSM-III-R diagnoses. Results indicated that the use of the
      decision trees interacted with the level of DSM-III-R experience to affect
      diagnostic accuracy. The use of the decision trees resulted in a modest increase
      in diagnostic accuracy for participants with less DSM-III-R experience; for
      participants with more DSM-III-R experience, the use of the decision trees had no
      significant effect on diagnostic accuracy. Experiment 2 examined whether the use
      of the DSM-III-R decision trees increased the accuracy and confidence and
      decreased the time of DSM-IlI-R diagnosis across participants with varying levels
      of DSM-III-R experience. The primary analyses consisted of a 3 x 2 x 2
      multivariate analysis of variance (MANOVA) to determine whether the use of the
      decision trees increased diagnostic accuracy and diagnostic confidence and
      decreased diagnostic time. Results indicated (1) the experienced participants
      made more accurate diagnoses than the less-experienced and no-experience
      participants: (2) the decision trees, combined with practice, increased class
      diagnostic accuracy and decreased diagnostic time; and (3) participants were more
      confident in their diagnosis when they used the decision trees than when they did
      not use the decision trees. Supplementary analyses consisted of two one-way
      analysis of variance (ANOVA) procedures and indicated that participants'
      preference for and knowledge of how to use the decision trees did not
      significantly affect their diagnostic accuracy.

PMID- 10661371
TI  - A measurement model of perinatal stressors: identifying risk for postnatal
      emotional distress in mothers of high-risk infants.
AB  - A measurement model of perinatal stressors was first evaluated for reliability
      and then used to identify risk factors for postnatal emotional distress in high
      risk mothers. In Study 1, six measures (gestational age of the baby, birthweight,
      length of the baby's hospitalization, a postnatal complications rating for the
      infant, and Apgar scores at 1 and 5 min) were obtained from chart reviews of
      preterm births at two different hospitals. Confirmatory factor analyses revealed
      that the six measures could be accounted for by three factors: (a) Infant
      Maturity, (b) Apgar Ratings, and (c) Complications. In Study 2, a modified
      measurement model indicated that Infant Maturity and Complications were
      significant predictors of postnatal emotional distress in an additional sample of
      mothers. This measurement model may also be useful in predicting (a) other
      measures of psychological distress in parents, and (b) measures of cognitive and
      motor development in infants.

PMID- 10661372
TI  - The measurement and diagnostic utility of intrasubtest scatter in pediatric
      neuropsychology.
AB  - Intrasubtest scatter (ISS) is a measure of person's tendency toward inconsistency
      when responding to test items. It has been claimed that ISS may be suggestive of
      intellectual inefficiency, difficulty with recall of specific information, or
      fluctuating levels of arousal/attention. The research investigating these claims
      has been inconclusive, possibly because traditional indices of ISS may not
      adequately measure inconsistent responding. Item Response Theory (IRT) approaches
      to the detection of unusual response sequences appear to have a much firmer
      psychometric foundation but have been largely ignored in the neurodiagnostic
      literature. This study compares the utility of traditional and IRT-based indices
      of ISS in identifying children known to be experiencing information-processing
      difficulties. The WISC-R item responses of 100 children who have received cranial
      irradiation treatment for leukemia are compared with those of 100 healthy
      children. Results confirm the diagnostic utility of an IRT-based measure of
      unusual test behavior in this clinical group.

PMID- 10661373
TI  - Bedside evaluation of learning and memory: descriptive information on a shortened
      version of the Luria Memory Words Test.
AB  - Descriptive information on the shortened version of the Luria Memory Words Test
      (LMWT-SF), a serial word-learning list of seven items, administered across five
      trials with a three-minute delay, is presented. The purpose of the investigation
      was to determine what constituted adequate performance among nondemented elderly
      inpatients, and to compare the results to traditional bedside memory measures
      among elders diagnosed with dementia. Results revealed significant group
      differences on Trials 3, 4, 5, total learning score, and the delay trial among
      demented and non-demented geriatric inpatients. Sensitivity and specificity
      ratings for the LMWT-SF delay trial were 80% and 72%, respectively, at a cut-off
      of 3 / 4, and 71% and 60%, respectively, for the total learning score, at a cut
      off of 26 / 27. While this measure cannot take the place of a comprehensive
      evaluation of memory and learning, LMWT-SF performance can suggest when a more
      comprehensive evaluation is required, and may provide value as a cost-effective
      screening tool.

PMID- 10661374
TI  - Personality traits, coping styles, and mood in patients awaiting lumbar-disc
      surgery.
AB  - The objective of this study was to characterize personality traits, coping
      styles, and mood state in patients with lumbar-disc disorders. In two studies (N
      = 112; N = 84) patients expecting lumbar-disc surgery were compared to patients
      awaiting another kind of surgery. Personality traits and coping styles were
      assessed with a personality inventory (FPI-R) and a stress-coping questionnaire
      (SVF). Mood was measured several times before surgery using a multidimensional
      self-report inventory [BSKE (EWL)]. The same inventory was used by anesthetists
      to rate the patient's mood. Heart rate and blood pressure also were measured. The
      groups did not differ with regard to personality traits, coping styles, self
      reported mood state, or somatic variables. The physicians rated lumbar-disc
      patients as being in a better mood than control patients. Significant
      correlations between self-ratings and physician ratings were not observed. The
      results characterize lumbar-disc patients as a subgroup that is not different
      from other surgery patients and, therefore, does not need a specific form of
      psychological management prior to surgery. The importance of using patients
      expecting another type of surgery as a control group rather than healthy
      individuals is clearly demonstrated.

PMID- 10661375
TI  - Relocation of the institutionalized aged.
AB  - The effects of relocation and institutionalization upon frail older people have
      been studied extensively for the past several decades and have been a topic of
      some controversy. Because of varying methodologies, differing populations,
      overlooked variables, and mistakes in interpretation, this area of
      epidemiological research has resulted in debate among scholars in the field. It
      may be helpful to review some of the research that has been done, examine a
      theory of why mortality seems to increase when older people are involuntarily
      relocated, speculate upon how this effect might be minimized, and introduce some
      data that seemingly would confirm that careful planning for relocation might, in
      fact, reduce subsequent morbidity and mortality.

PMID- 10661376
TI  - Are the MMPI subtle subscales subtle measures of their scales?
AB  - This study investigated the ability of the MMPI Wiener-Harmon subtle subscales
      (on scales D. Hy, Pd, Pa, and Ma) to serve as subtle or unobtrusive measures of
      their scales. Forty outpatients completed the MMPI under standard instructions,
      followed by a fake-good or fake-bad instructional set. First, we investigated the
      paradoxical effect found in the MMPI faking literature (in which, overall, the
      subtle subscale T-scores change in a direction opposite of the faking
      instructions) and found that not every subtle subscale shows this effect.
      Secondly, the subtle subscale T-scores achieved under faking conditions showed no
      significant relationship to their respective full-scale T-scores achieved under
      standard conditions. Therefore, our results do not support the Wiener-Harmon
      subtle subscales as subtle measures of their scales.

PMID- 10661377
TI  - Boredom proneness: its relationship to psychological- and physical-health
      symptoms.
AB  - The relationship between boredom proneness and health-symptom reporting was
      examined. Undergraduate students (N = 200) completed the Boredom Proneness Scale
      and the Hopkins Symptom Checklist. A multiple analysis of covariance indicated
      that individuals with high boredom-proneness total scores reported significantly
      higher ratings on all five subscales of the Hopkins Symptom Checklist (Obsessive
      Compulsive, Somatization, Anxiety, Interpersonal Sensitivity, and Depression).
      The results suggest that boredom proneness may be an important element to
      consider when assessing symptom reporting. Implications for determining the
      effects of boredom proneness on psychological- and physical-health symptoms. as
      well as the application in clinical settings, are discussed.

PMID- 10661378
TI  - Laryngoplasty: a novel prosthesis.

PMID- 10661379
TI  - Equine dental disease. Part 3: A long-term study of 400 cases: disorders of wear,
      traumatic damage and idiopathic fractures, tumours and miscellaneous disorders of
      the cheek teeth.
AB  - Of 400 horses referred because of dental disorders, 349 cases were diagnosed as
      suffering from primary disorders of their cheek teeth. Details of 104 of these
      cases are presented, including 44 cases with abnormalities of wear, 26 cases with
      traumatic damage, 24 cases with idiopathic fractures and 10 cases with
      miscellaneous cheek teeth disorders including oral tumours. The long-term
      response to treatment was excellent in most cases, even in cases with residual
      secondary periodontal disease.

PMID- 10661380
TI  - Topographical mapping of biochemical properties of articular cartilage in the
      equine fetlock joint.
AB  - The aim of this study was to evaluate topographical differences in the
      biochemical composition of the extracellular matrix of articular cartilage of the
      normal equine fetlock joint. Water content, DNA content, glycosaminoglycan (GAG)
      content and a number of characteristics of the collagen network (total collagen
      content, levels of hydroxylysine- (Hyl) and the crosslink
      hydroxylysylpyridinoline, (HP) of articular cartilage in the proximal 1st phalanx
      (P1), distal 3rd metacarpal bone (MC), and proximal sesamoid bones (PSB) were
      determined in the left and right fetlock joint of 6 mature horses (age 5-9
      years). Twenty-eight sites were sampled per joint, which included the clinically
      important areas often associated with pathology. Biochemical differences were
      evaluated between sampling sites and related with the predisposition for
      osteochondral injury and type of loading. Significant regional differences in the
      composition of the extracellular matrix existed within the joint. Furthermore,
      left and right joints exhibited biochemical differences. Typical topographic
      distribution patterns were observed for each parameter. In P1 the dorsal and
      palmar articular margin showed a significantly lower GAG content than the more
      centrally located sites. Collagen content and HP crosslinks were higher at the
      joint margins than in the central area. Also, in the MC, GAG content was
      significantly lower at the (dorsal) articular margin compared with the central
      area. Consistent with findings in P1, collagen and HP crosslinks were
      significantly lower in the central area compared to the (dorsal) articular
      margin. Biochemical and biomechanical heterogeneity of articular cartilage is
      supposed to reflect the different functional demands made at different sites. In
      the present study, GAG content was highest in the constantly loaded central areas
      of the joint surfaces. In contrast, collagen content and HP crosslinks were
      higher in areas intermittently subjected to peak loading which suggests that the
      response to a certain type of loading of the various components of the
      extracellular matrix of articular cartilage are different. The differences in
      biochemical characteristics between the various sites may help to explain the
      site specificity of osteochondral lesions commonly found in the equine fetlock
      joint. Finally, these findings emphasise that the choice of sampling sites may
      profoundly influence the outcome of biochemical studies of articular cartilage.

PMID- 10661381
TI  - The effect of replacing nonstructural carbohydrates with soybean oil on the
      digestibility of fibre in trotting horses.
AB  - The hypothesis tested was that the intake of extra fat at the expense of an
      isoenergetic amount of nonstructural carbohydrates reduces fibre utilisation in
      horses. In a crossover trial with feeding periods of 42 days each, 6 mature
      trotting horses (age 4-12 years, bodyweight 340-476 kg) were given either a
      control or test diet. The test concentrate was formulated to contain 37% of net
      energy in the form of soybean oil. The control concentrate contained an
      isoenergetic amount of corn starch plus glucose. The concentrates were fed in
      combination with the same amount of hay so that the control and test diet
      contained 25.13 and 86.66 g crude fat/kg dry matter, respectively. Apart from the
      amounts of fat and nonstructural carbohydrates, the 2 diets were identical. The
      test diet reduced the apparent total tract digestibilities of crude fibre,
      neutral and acid detergent fibre by 8.0 (P = 0.007), 6.2 (P = 0.022) and 8.3 (P =
      0.0005) percentage units, respectively. It is suggested that a high fat intake by
      horses may increase the amount of fat entering the large intestine to levels that
      depress fermentation by cellulolytic bacteria. The observed interaction between
      fat content of the diet and fibre utilisation may have consequences for practical
      horse feeding in that calculating the energy content of test diets on the basis
      of feedstuff tables leads to overestimating the amount of energy provided by the
      high-fibre ingredients of the diets.

PMID- 10661382
TI  - Clinical and neuropathological features of West Nile virus equine
      encephalomyelitis in Italy.
AB  - West Nile (WN) virus infection is a mosquito-borne flavivirosis endemic in Africa
      and Asia. Clinical disease is usually rare and mild and only in a few cases the
      infection causes encephalomyelitis in horses, fever and meningoencephalitis in
      man. We report here the clinical and pathological findings in an epidemic of the
      disease involving 14 horses from Tuscany, Italy. All cases were observed from
      August to October 1998. Affected horses showed ataxia, weakness paresis of the
      hindlimbs and, in 6 cases, there was paraparesis progressing to tetraplegia and
      recumbency within 2 to 9 days. Eight animals recovered without any important
      consequences. Serological investigations revealed positivity to WN virus in all
      the 14 horses and the agent was isolated from the cerebellum and spinal cord of
      an affected horse. Postmortem examination was carried out on 6 horses. The
      neuropathological pattern was that of a mild to moderate, nonsuppurative
      polioencephalomyelitis with constant involvement of the ventral horns of the
      thoracic and lumbar spinal cord, where focal gliosis and haemorrhage were also
      apparent in some cases. Differential diagnoses with other equine viral
      encephalomyelitides are discussed. Climatological and environmental
      characteristics of the geographic area in which the outbreaks occurred suggest
      the existence of suitable conditions for the development of the disease. This is
      the first report of WN virus equine encephalomyelitis in Italy.

PMID- 10661383
TI  - Postmortem findings of gastric ulcers in Swedish horses older than age one year:
      a retrospective study of 3715 horses (1924-1996).
AB  - The present study was performed to estimate retrospectively the prevalence of
      gastric ulceration in necropsied Swedish horses and to evaluate some potential
      risk factors. Horses (n = 3715) older than age one year and necropsied 1924-1996
      were included. Information about breed, gender, age, season of death, clinical
      signs of colic, Gasterophilus larvae and documentation of diseases in different
      organs was recorded. Data on size, number and anatomical distribution of gastric
      ulcers were also obtained. The cold-blooded horses and the Standardbreds were the
      2 most dominating breeds in our material. Gastric ulcers/erosions were seen in
      633 (17%) of the horses. The highest prevalence was found in Thoroughbreds (19%)
      and Standardbreds (19%), whereas only 7% of the cold-blooded horses were
      affected. The cutaneous region along the margo plicatus was the most commonly
      affected area (52%). Multiple ulcers were seen in 62% of the horses with gastric
      ulcers and concurrent ulcers in the oesophagus were reported in 6%. In the
      bivariate analysis, significant associations were found between gastric ulcers
      and signs of colic (P<0.001) and gender (P<0.001), as well as between concomitant
      bowel (P<0.001), liver (P<0.05) and oesophageal (P<0.01) lesions. Using a
      multivariate logistic regression model, only year of necropsy and breed were
      found significantly to influence the risk of gastric ulceration by decreasing the
      Log Likelihood test value. The present study shows clearly that gastric
      ulceration has been present in Swedish horses throughout the 20th century, which
      also may be the situation worldwide.

PMID- 10661384
TI  - In vitro evaluation of a novel prosthesis for laryngoplasty of horses with
      recurrent laryngeal neuropathy.
AB  - A prosthesis, composed of a steel cable and stress-reducing washers, was
      developed to prevent failure of laryngoplasty, a common treatment for horses
      affected by recurrent laryngeal neuropathy. Laryngoplasties were performed on 15
      cadaveric larynges using a polyester suture on one side and the cable prosthesis
      on the other. Each prosthesis was distracted at a displacement rate of 20 mm/s
      using a servohydraulic materials testing machine until laryngoplasty failed.
      Distraction force and actuator displacement were recorded and analysed. All 15
      laryngoplasties performed with a suture failed at the muscular process at a mean
      +/- s.d. force of 55.8 +/- 13.1 N. Six laryngoplasties performed with the cable
      prosthesis failed at the muscular process at mean force 219.6 +/- 125.0 N. In the
      other 9, the arytenoid cartilage was avulsed from the larynx at mean force 206.4
      +/- 75.3 N, and the cable then tore through the muscular process at mean force
      357.0 +/- 32.0 N. The difference in force required to cause failure of
      laryngoplasty was significant (P<0.0001). Although the prosthesis resisted
      substantially higher forces than did the suture, the effects of the prosthesis in
      vivo must be evaluated.

PMID- 10661385
TI  - Equine carpal articular cartilage fibronectin distribution associated with
      training, joint location and cartilage deterioration.
AB  - Processes involved in equine carpal osteochondral injury have not been
      established. In other species, fibronectin appears important in chondrocyte
      matrix interactions, and levels are increased in osteoarthritis. This
      investigation aimed to (a) describe fibronectin immunoreactivity in the middle
      carpal joint of 2-year-old Thoroughbreds, (b) determine topographical variations,
      (c) compare strenuously trained (Group 1) or gently exercised horses (Group 2)
      and (d) describe sites with early osteoarthritis. Group 1 (n = 6) underwent a 19
      week high intensity treadmill training programme. Group 2 (n = 6) underwent 40
      min walking until euthanasia. Dorsal and palmar sites on radial, intermediate and
      third carpal articular surfaces were prepared. Immunohistochemistry was performed
      using a biotin-streptavidin/peroxidase method. Cross-reactivity of rabbit
      antihuman fibronectin antiserum with equine fibronectin was confirmed using
      Western blotting. Results showed: (a) fibronectin was present primarily in
      pericellular and interterritorial matrix locations, (b) dorsal sites had zonal
      immunoreactivity compared to palmar sites, (c) Group 1 dorsal radial carpal
      cartilage had increased superficial staining compared to Group 2 and (d)
      fibrillated cartilage showed increased intracellular and local matrical
      immunoreactivity (superficial zone). These findings suggest topographical and
      exercise-related variations in fibronectin distribution, and indicate equine
      fibronectin is localised at sites of cartilage degeneration and released into the
      matrix by chondrocytes in the local area.

PMID- 10661386
TI  - Cartilage oligomeric matrix protein (COMP) levels in digital sheath synovial
      fluid and serum with tendon injury.
AB  - Cartilage oligomeric matrix protein (COMP) is a noncollagenous extracellular
      matrix protein found predominantly in cartilage, but also in tendon, ligament and
      meniscus. Studies in man have demonstrated that it may be used as a prognostic
      marker in rheumatoid arthritis and osteoarthritis. The present study investigated
      whether tendon injury contributes to serum and tendon sheath synovial fluid
      levels of COMP in horses. COMP levels, analysed by competitive ELISA, in the
      digital sheath synovial fluid were more than 10-fold higher than in the serum.
      Levels were significantly raised when tendon damage or sepsis was present within
      the tendon sheath but showed only mild, statistically insignificant, elevation in
      cases of tenosynovitis alone. COMP concentrations in serum were found to vary
      with age. Foals (age < or = 1 year) had significantly (P<0.001) higher levels in
      comparison to older control horses. Total COMP concentrations in an age-matched
      group with tendinitis were not significantly different from the control group.
      Measurements of COMP levels in tendon sheath synovial fluid are therefore useful
      in depicting processes in tendon tissue, while elevated serum levels are likely
      to be more representative of joint disease than tendinitis.

PMID- 10661387
TI  - Assessment of muscle oxygenation in the horse by near infrared spectroscopy.
AB  - This study examined the ability of near infrared spectroscopy (NIRS) to
      noninvasively determine changes to muscle oxygenation in the resting horse. Five
      horses had (NIRS) performed over extremity muscle while under general
      anaesthesia, first with 8 min limb ischaemia, then systemic hypoxaemia for 5 min.
      A second group of 6 awake horses had NIRS performed over extremity muscle while
      being administered hypoxic gas (F(I)O2 0.10) for 5 min, and after return to
      steady state, limb ischaemia was induced for an additional 5 min. In the
      anaesthetised horses' ischaemia induced marked and significant muscle
      deoxygenation of haemoglobin/myoglobin (P<0.01), with corresponding arterial
      saturation decreasing from 98.9 to 81.9%. Hypoxaemia induced small yet
      significant muscle deoxygenation (P<0.01) that was 3.2% of the ischaemia
      deoxygenation signal, with a corresponding decrease in arterial saturation from
      98.6 to 90.4%. In the awake horses muscle deoxygenation was not detectable during
      hypoxia despite reduction of arterial saturation from 97.8 to 86.8%, whereas
      ischaemia induced rapid and significant deoxygenation of muscle (P<0.05), with
      corresponding reduction of venous saturation from 78.4 to 75.4%. In neither group
      of horses was there evidence of cytochrome aa3 reduction, despite complete
      ischaemia for up to 8 min. NIRS changes in the resting horse muscle clearly
      differed between ischaemia and hypoxaemia, and can readily show muscle
      deoxygenation in clinically relevant hypoxaemia in the horse under anaesthesia.
      Further, as the deoxygenation signal induced by ischaemia was clearly detectable
      above a background movement artefact, NIRS application to study of muscle
      oxygenation in the working horse should be explored.

PMID- 10661389
TI  - The influence of the lunar cycle on fertility on two Thoroughbred studfarms.

PMID- 10661388
TI  - Immunity to equine influenza: relationship of vaccine-induced antibody in young
      Thoroughbred racehorses to protection against field infection with influenza
      A/equine-2 viruses (H3N8).
AB  - Field outbreaks of influenza that occurred in vaccinated Thoroughbred racehorses
      in Newmarket in 1995 and 1996 were investigated by nucleoprotein ELISA and
      serology. Investigations showed that serum levels of vaccine-induced single
      radial haemolysis (SRH) antibody correlated closely with protective immunity
      against equine influenza and were consistent with observations made in previous
      experimental studies using nebulised aerosol challenge. In the second part of
      this study, antibody levels stimulated by vaccination were investigated to
      examine probable protection in high risk groups, such as yearlings and horses in
      training. Results for yearlings correlated closely with experimentally derived
      antibody profiles described for several equine influenza vaccines. The horses in
      training had levels of antibody immediately prior to revaccination, which were
      higher than those measured in the yearlings. In conclusion, SRH antibody, used in
      the investigation of outbreaks and surveillance of post vaccination responses,
      was shown to correlate with and validate experimental vaccination and challenge
      models currently used in ponies in the licensing of modern vaccines. There may be
      benefit from serological monitoring of horses following vaccination through
      identification of susceptible periods to infection and demonstration of poor
      vaccine responders. This would allow appropriate and timely amendment of
      vaccination strategies to maximise protective immunity against influenza.

PMID- 10661390
TI  - SRY-negative, XX intersex horses: the need for pedigree studies to examine the
      mode of inheritance of the condition.

PMID- 10661391
TI  - The inability of some synthetic progestagens to maintain pregnancy in the mare.

PMID- 10661392
TI  - Cutaneous lymphangioma in a young Standardbred mare.

PMID- 10661393
TI  - A novel approach based on computerized image analysis for traditional Chinese
      medical diagnosis of the tongue.
AB  - This research is aimed at building a computerized tongue examination system
      (CTES) based on computerized image analysis for the purpose of quantizing the
      tongue properties in traditional Chinese medical diagnosis. The chromatic
      algorithm is developed to identify the colors of the tongue and the thickness of
      its coating. The textural algorithm is used to detect the grimy coating. CTES is
      shown to be significantly consistent within itself with P > 0.05 using the
      Hotelling multivariate statistical test. The overall rate of correctness for CTES
      to identify the colors of tongue, verifying the thickness of its coating and
      detecting of any grimy coating exceeds 86%. Therefore, the CTES is helpful to
      provide the physicians a systematic and objective diagnostic standard for the
      tongue diagnosis in the clinical practice and research.

PMID- 10661394
TI  - Identification of reliable spike templates in multi-unit extracellular recordings
      using fuzzy clustering.
AB  - A method for extracting single-unit spike trains from extracellular recordings
      containing the activity of several simultaneously active cells is presented. The
      technique is particularly effective when spikes overlap temporally. It is capable
      of identifying the exact number of neurons contributing to a recording and of
      creating reliable spike templates. The procedure is based on fuzzy clustering and
      its performance is controlled by minimizing a cluster-validity index which
      optimizes the compactness and separation of the identified clusters. Application
      examples with synthetic spike trains generated from real spikes and segments of
      background noise show the advantage of the fuzzy method over conventional
      template-creation approaches in a wide range of signal-to-noise ratios.

PMID- 10661395
TI  - Parametric cure models of relative and cause-specific survival for grouped
      survival times.
AB  - With parametric cure models, we can express survival parameters (e.g. cured
      fraction, location and scale parameters) as functions of covariates. These models
      can measure survival from a specific disease process, either by examining deaths
      due to the cause under study (cause-specific survival), or by comparing all
      deaths to those in a matched control population (relative survival). We present a
      binomial maximum likelihood algorithm to be used for actuarial data, where follow
      up times are grouped into specific intervals. Our algorithm provides simultaneous
      maximum likelihood estimates for all the parameters of a cure model and can be
      used for cause-specific or relative survival analysis with a variety of survival
      distributions. Current software does not provide the flexibility of this unified
      approach.

PMID- 10661396
TI  - AVS/express for the PC implementation of a 3D visualization module for
      radiotherapy.
AB  - Treatment planning systems (TPS) are nowadays of great help in cancer
      radiotherapy. Basically, they allow the pair physician/physicist to simulate the
      beams' irradiation effects on tumors as well as healthy tissues in terms of
      delivered radiation doses and finally to assess the validity of a beam setup. The
      state of the art in TPS leads to the following evidence concerning the future of
      such softwares: an access to a 3D visualization at each step of the design and
      verification of a plan has become necessary. Moreover, the fast increasing
      performances of personal computers (PC) will make possible in a near future the
      implementation at a lower cost of a complete 3D TPS. One of the keys of such an
      ambition is the compatibility between the implementation tools and the needs for
      power and flexibility. A first implementation on Open VMS of a simple 3D
      visualization for Institut Curie's TPS ISIS using Advanced Visual Systems' AVS 5
      has been achieved. Their next generation tool, AVS/Express, seemed to meet the
      needs of a wide scale development. The use of AVS/Express working together with
      Microsoft Visual C++ in the implementation on Windows NT of a 3D visualization
      module is exposed.

PMID- 10661397
TI  - Eliminating bias in randomized cluster trials with correlated binomial outcomes.
AB  - Clustered or correlated samples with binary data are frequently encountered in
      biomedical studies. The clustering may be due to repeated measurements of
      individuals over time or may be due to subsampling of the primary sampling units.
      Individuals in the same cluster tend to behave more alike than individuals who
      belong to different clusters. This exhibition of intracluster correlation
      decreases the amount of information about the effect of the intervention. In the
      analysis of randomized cluster trials one must adjust the variance of estimator
      of the mean for the effect of the positive intraclass correlation p;. We review
      selected alternative methods to the typical Pearson's chi2 analysis, illustrate
      these alternatives, and out line an alternative analysis algorithm. We have
      written and tested a FORTRAN program that produces the statistics outlined in
      this paper. The program is available in an executable format and is available
      from the author on request.

PMID- 10661398
TI  - MASTER: a Windows program for recording multiple auditory steady-state responses.
AB  - MASTER is a Windows-based data acquisition system designed to assess human
      hearing by recording auditory steady-state responses. The system simultaneously
      generates multiple amplitude-modulated and/or frequency-modulated auditory
      stimuli, acquires electrophysiological responses to these stimuli, displays these
      responses in the frequency-domain, and determines whether or not the responses
      are significantly larger than background electroencephalographic activity. The
      operator can print out the results, store the data on disk for more extensive
      analysis by other programs, review stored data, and combine results. The system
      design follows clear principles concerning the generation of acoustic signals,
      the acquisition of artifact-free data, the analysis of electrophysiological
      responses in the frequency-domain, and the objective detection of signals in
      noise. The instrument uses a popular programming language (LabVIEW) and a
      commercial data acquisition board (AT-MIO-16E-10), both of which are available
      from National Instruments.

PMID- 10661399
TI  - Development of computerized screening system for dementia and its preliminary
      field test.
AB  - The population of aged persons is increasing along with an extension of the
      average span of human life. Therefore, the number of persons who suffer from
      dementing disorders is also increasing. Because the various psychotic symptoms
      and behavioral problems are frequently observed in persons with dementia, the
      families taking care of such people require help to reduce their mental and
      physical load. Therefore, maintenance and enhancement of the social support
      system for aged persons are urgent issues. Early identification is important
      because immediate recognition of dementia people and appropriate follow up
      treatment can prevent the progress of the disease. Clinical interviews are one
      general method for detecting patients with dementing disorders, and the Hasegawa
      Dementia Scale is one of the most popular methods in Japan. The test takes about
      10 min per person, but it requires a lot of time and burden for medical staff to
      screen patients with dementia from the increasing number of aged persons.
      Therefore, new methods for assessing cognitive functions are requested. A
      computerized assessment system was developed for dementia which is based on the
      Hasegawa Dementia Scale. This system was designed for aged persons with no
      previous computer experience to operate easily by making efficient use of
      multimedia. In this paper, the system and preliminary results of the field-test
      are reported.

PMID- 10661400
TI  - BLNK: connecting Syk and Btk to calcium signals.

PMID- 10661401
TI  - RAC1/P38 MAPK signaling pathway controls beta1 integrin-induced interleukin-8
      production in human natural killer cells.
AB  - The MAP kinase (MAPK) p38 plays a key role in regulating inflammatory responses.
      Here, we demonstrate that beta1 integrin ligation on human NK cells results in
      the activation of the p38 MAPK signaling pathway, which is required for integrin
      triggered IL-8 production. In addition, we identified some of the upstream events
      accompanying the beta1 integrin-mediated p38 MAPK activation, namely, the
      activation of the Rac guanine nucleotide exchange factor (GEF) p95 Vav, the small
      G protein Rac1, and the cytoplasmic kinases Pak1 and MKK3. Finally, we provide
      direct evidence that p95 Vav and Rac control the activation of p38 MAPK triggered
      by beta1 integrins.

PMID- 10661402
TI  - Thymocyte selection is regulated by the helix-loop-helix inhibitor protein, Id3.
AB  - E2A, HEB, E2-2, and daughterless are basic helix-loop-helix (bHLH) proteins that
      play key roles in multiple developmental pathways. The DNA binding activity of
      E2A, HEB, and E2-2 is regulated by a distinct class of inhibitor HLH proteins,
      the Id gene products. Here, we show that Id3 is required for major
      histocompatability (MHC) class I- and class II-restricted thymocyte positive
      selection. Additionally, H-Y TCR-mediated negative selection is severely
      perturbed in Id3 null mutant mice. Finally, we show that E2A and Id3 interact
      genetically to regulate thymocyte development. These observations identify the
      HLH inhibitory protein Id3 as an essential component required for proper
      thymocyte maturation.

PMID- 10661403
TI  - Stat6-independent GATA-3 autoactivation directs IL-4-independent Th2 development
      and commitment.
AB  - The initial source of IL-4-inducing Th2 development and the mechanism of stable
      Th2 commitment remain obscure. We found the reduced level of IL-4 production in
      Stat6-deficient T cells to be significantly higher than in Th1 controls. Using a
      novel cell surface affinity matrix technique, we found that IL-4-secreting Stat6
      deficient T cells stably expressed GATA-3 and Th2 phenotype. Introducing GATA-3
      into Stat6-deficient T cells completely restored Th2 development, inducing c-Maf,
      Th2-specific DNase I hypersensitive sites in the IL-4 locus, and Th2 cytokine
      expression. The fact that GATA-3 fully reconstitutes Th2 development in Stat6
      deficient T cells indicates it is a master switch in Th2 development. Finally,
      GATA-3 exerts Stat6-independent autoactivation, creating a feedback pathway
      stabilizing Th2 commitment.

PMID- 10661404
TI  - Positive selection from newly formed to marginal zone B cells depends on the rate
      of clonal production, CD19, and btk.
AB  - Using immunoglobulin heavy chain transgenic mice, we show that B cell clones
      reaching the long-lived pool are heterogeneous: some are enriched in the
      CD21(high) compartment (mostly marginal zone [MZ]), others reside primarily in
      the follicles (FO). Altering the composition of the B cell receptor through N
      region additions decreases the rate of clonal production and the MZ enrichment.
      This process can be recapitulated by purified CD21(low) B cells and is due to a
      preferential clonal survival that requires a functional btk tyrosine kinase. We
      also show that generation of the MZ population is dependent on CD19. These
      findings suggest that the MZ B cell repertoire is positively selected and have
      functional implications for antigenic responses effected by B cells from this
      microenvironment.

PMID- 10661405
TI  - Structure and dimerization of a soluble form of B7-1.
AB  - B7-1 (CD80) and B7-2 (CD86) are glycoproteins expressed on antigen-presenting
      cells. The binding of these molecules to the T cell homodimers CD28 and CTLA-4
      (CD152) generates costimulatory and inhibitory signals in T cells, respectively.
      The crystal structure of the extracellular region of B7-1 (sB7-1), solved to 3 A
      resolution, consists of a novel combination of two Ig-like domains, one
      characteristic of adhesion molecules and the other previously seen only in
      antigen receptors. In the crystal lattice, sB7-1 unexpectedly forms parallel, 2
      fold rotationally symmetric homodimers. Analytical ultracentrifugation reveals
      that sB7-1 also dimerizes in solution. The structural data suggest a mechanism
      whereby the avidity-enhanced binding of B7-1 and CTLA-4 homodimers, along with
      the relatively high affinity of these interactions, favors the formation of very
      stable inhibitory signaling complexes.

PMID- 10661406
TI  - Tat competes with CIITA for the binding to P-TEFb and blocks the expression of
      MHC class II genes in HIV infection.
AB  - AIDS and the bare lymphocyte syndrome (BLS) are severe combined
      immunodeficiencies. BLS results from mutations in genes that regulate the
      expression of class II major histocompatibility (MHC II) determinants. One of
      these is the class II transactivator (CIITA). HIV and its transcriptional
      transactivator (Tat) also block the expression of MHC II genes. By binding to the
      same surface in the cyclin T1, which together with CDK9 forms the positive
      transcription elongation factor b (P-TEFb) complex, Tat inhibits CIITA. CIITA can
      also activate transcription when tethered artificially to RNA. Moreover, a
      dominant-negative CDK9 protein inhibits the activity of MHC II promoters. Thus,
      CIITA is a novel cellular coactivator that binds to P-TEFb for the expression of
      its target genes.

PMID- 10661407
TI  - Langerin, a novel C-type lectin specific to Langerhans cells, is an endocytic
      receptor that induces the formation of Birbeck granules.
AB  - We have identified a type II Ca2+-dependent lectin displaying mannose-binding
      specificity, exclusively expressed by Langerhans cells (LC), and named Langerin.
      LC are uniquely characterized by Birbeck granules (BG), which are organelles
      consisting of superimposed and zippered membranes. Here, we have shown that
      Langerin is constitutively associated with BG and that antibody to Langerin is
      internalized into these structures. Remarkably, transfection of Langerin cDNA
      into fibroblasts created a compact network of membrane structures with typical
      features of BG. Langerin is thus a potent inducer of membrane superimposition and
      zippering leading to BG formation. Our data suggest that induction of BG is a
      consequence of the antigen-capture function of Langerin, allowing routing into
      these organelles and providing access to a nonclassical antigen-processing
      pathway.

PMID- 10661408
TI  - Dissecting the multifactorial causes of immunodominance in class I-restricted T
      cell responses to viruses.
AB  - Following influenza virus infection, the numbers of mouse TCD8+ cells responding
      to five different determinants vary more than 50-fold in primary responses but
      less so in secondary responses. Surprisingly, each determinant elicits a highly
      diverse and highly sensitive TCD8+ response. Inefficient antigen processing by
      virus-infected cells accounts for the poor immunogenicity of just one of the
      subdominant determinants. Overexpressing class I-peptide complexes using vaccinia
      virus revealed that the poor immunogenicity of two subdominant determinants
      reflects limitations in T cell responses unrelated to TCR diversity or
      sensitivity. Despite greatly enhanced expression, the immunodominant determinant
      is actually less immunogenic when overexpressed by vaccinia virus.
      Immunodominance is also modulated by determinant-specific variations in the
      capacity of TCD8+ to suppress responses to other determinants.

PMID- 10661409
TI  - Dissection of signaling cascades through gp130 in vivo: reciprocal roles for
      STAT3- and SHP2-mediated signals in immune responses.
AB  - We generated a series of knockin mouse lines, in which the cytokine receptor
      gp130-dependent STAT3 and/or SHP2 signals were disrupted, by replacing the mouse
      gp130 gene with human gp130 mutant cDNAs. The SHP2 signal-deficient mice
      (gp130F759/F759 were born normal but displayed splenomegaly and lymphadenopathy
      and an enhanced acute phase reaction. In contrast, the STAT3 signal-deficient
      mice (gp130FXQ/FXXQ) died perinatally, like the gp130-deficient mice (gp130D/D).
      The gp130F759/F759 mice showed prolonged gp130-induced STAT3 activation,
      indicating a negative regulatory role for SHP2. Th1-type cytokine production and
      IgG2a and IgG2b production were increased in the gp130F759/F759 mice, while they
      were decreased in the gp130FXXQ/FXXQ immune system. These results indicate that
      the balance of positive and negative signals generated through gp130 regulates
      the immune responses.

PMID- 10661411
TI  - Morphology of eyes of turkeys reared under commercial lighting regimens at
      different light intensities.

PMID- 10661410
TI  - Processing of some antigens by the standard proteasome but not by the
      immunoproteasome results in poor presentation by dendritic cells.
AB  - By stimulating human lymphocytes with an autologous renal carcinoma, we obtained
      CTL recognizing an antigen derived from a novel, ubiquitous protein. The CTL
      failed to lyse autologous EBV-transformed B cells, even though the latter express
      the protein. This is due to the presence in these cells of immunoproteasomes,
      which, unlike standard proteasomes, cannot produce the antigenic peptide. We show
      that dendritic cells also carry immunoproteasomes and fail to present this
      antigen. This may explain why the relevant CTL escape thymic deletion and are not
      regularly activated in the periphery. Lack of cleavage by the immunoproteasome
      was also observed for melanoma differentiation antigen Melan-A26-35/HLA-A2,
      currently used for antitumoral vaccination. For immunization with such antigens,
      proteins should be less suitable than peptides, which do not require proteasome
      digestion in dendritic cells.

PMID- 10661412
TI  - Use of colour cue to determine the appetite of laying hens for methionine in
      drinking water.

PMID- 10661413
TI  - Does video stimulation have an important role to play in poultry behaviour
      research?

PMID- 10661414
TI  - Tests of consistency of dominance ranking in laying hens and influence of perch
      treatment on frequencies of interaction.

PMID- 10661415
TI  - Effects of four different environmental enrichment treatments on pecking
      behaviour in turkeys.

PMID- 10661416
TI  - Social signalling in the domestic fowl: role of UV(A) light in mating and mate
      choice.

PMID- 10661417
TI  - Is development of pecking damage in layer pullets influenced by dietary protein
      source?

PMID- 10661418
TI  - Effects of qualitative and quantitative food restriction treatments on feeding
      motivational state of growing broiler breeders.

PMID- 10661420
TI  - Intraspecific variation in muscle and organ growth in three strains of chicken
      with differential genetic selection for fast growth rate.

PMID- 10661419
TI  - Estimate of the heritability of plasma troponin T in broiler chickens.

PMID- 10661421
TI  - Inheritance of broodiness in the domestic fowl.

PMID- 10661422
TI  - Effect of strain and flock age on fertility and early embryonic mortality of
      broiler breeder eggs.

PMID- 10661423
TI  - Application of current ultrastructural eggshell quality assessment in captive
      breeding programmes: observations on hatched and unhatched eggs of the Saker
      falcon (Falco cherrug).

PMID- 10661424
TI  - Material properties, ultrastructural integrity and protein chemistry of broiler
      breeder eggshells.

PMID- 10661425
TI  - Nutritive value of Camelina sativa meal for poultry.

PMID- 10661426
TI  - Effect of diets containing alfalfa seed screenings on performance of layer hens.

PMID- 10661427
TI  - Apparent digestibility and endogenous amino acids in birds fed enzyme treated and
      untreated L. angustifolius diets.

PMID- 10661428
TI  - Effect of exogenous enzymes fed with a wheat or wheat rye-based diet on the
      performance of female broiler breeders.

PMID- 10661429
TI  - Effect of enzyme supplementation on the growth and food conversion efficiency of
      broiler chicks on lupin-based diets.

PMID- 10661430
TI  - Effect of photoperiod and feeding schedules on food usage during early life in
      male broilers.

PMID- 10661431
TI  - Effects of providing dietary wood charcoal to broiler chicks of different ages.

PMID- 10661432
TI  - Effects of wheat variety and bushel weight on dietary AME concentration and on
      performance of broilers from 7 to 28 d.

PMID- 10661433
TI  - Effects of diet formulation and enzyme inclusion on apparent metabolisable energy
      (AME) concentration in wheat-based diets and on broiler performance.

PMID- 10661434
TI  - Comparison of food intake, body weight gain and food conversion efficiency on
      broiler starter diets formulated on metabolisable and net energy.

PMID- 10661435
TI  - Effects of Yucca schdigera extract, Saccharomyces boulardii and enzyme
      supplementation of wheat-based diets on broiler performance and diet
      metabolisability.

PMID- 10661436
TI  - Investigation into the possible use of olive pulp in commercial layer diets.

PMID- 10661437
TI  - Neuropeptide Y gene expression in the brain is stimulated by fasting and food
      restriction in chickens.

PMID- 10661438
TI  - Relationships between vaginal collagen, plasma oestradiol and uterine prolapse in
      turkeys.

PMID- 10661439
TI  - Myoprotective action of oestrogen: effects of tamoxifen at sexual maturity in
      laying hens.

PMID- 10661440
TI  - Directional asymmetry in laying hen humeral breaking strength.

PMID- 10661441
TI  - Assessing the effect of mating ratio in broiler breeder flocks by quantifying
      sperm-egg interaction.

PMID- 10661442
TI  - Wetting of broilers during cold weather transport: a major source of
      physiological stress?

PMID- 10661444
TI  - Comparison of thermoregulatory ability in fast and slow growing strains of turkey
      during acute heat stress.

PMID- 10661443
TI  - Detection and assay of polymorphism in the growth hormone receptor gene locus in
      a commercial broiler breeder population.

PMID- 10661445
TI  - Corticosterone, dietary fat source and diet selection in relation to body
      composition.

PMID- 10661446
TI  - Effect of corticosterone on diet selection for protein in relation to egg
      production by laying hens.

PMID- 10661447
TI  - Differential sensitivity to monensin-induced myopathy in fast and slow growing
      lines of broiler chicken?

PMID- 10661448
TI  - Dietary Ca and P requirements and skeletal quality in broiler chickens.

PMID- 10661449
TI  - Effects of whole wheat substitution in broiler diets and viscosity on a coccidial
      infection in broilers.

PMID- 10661450
TI  - Effect of lowering dietary protein concentration on feathering in modern and
      traditional turkeys.

PMID- 10661451
TI  - The BSE inquiry: chairman's closing statement.

PMID- 10661452
TI  - Government announces withdrawal of OP sheep dips.

PMID- 10661453
TI  - Salmonella dublin continues to cause problems in Scottish cattle.

PMID- 10661454
TI  - Clinical, pathological and epidemiological findings in three outbreaks of ovine
      protozoan myeloencephalitis.
AB  - Ovine protozoan myeloencephalitis is a disease of sheep associated with the
      apicomplexan protozoan Sarcocystis tenella. This paper describes the clinical,
      pathological and epidemiological findings in three affected flocks from a well
      defined geographical area. Clinical signs were restricted to sheep under one year
      old in their first winter and were first observed at least 42 days after they had
      been moved off the hill grazing areas to low ground pasture, or after they were
      given conserved forage. The findings are discussed in relation to the timescale
      of the life cycle of S. tenella and it is suggested that clinical disease was
      precipitated by the change from a low level of exposure to infection on the hill
      to a high level of exposure through contaminated pasture or forage. Possible
      preventive strategies are discussed.

PMID- 10661455
TI  - Ultrasonography of spontaneous lesions of the genital system of three rams, and
      their influence on semen quality.
AB  - Three young Suffolk ram lambs had lesions which rendered them reproductively
      unsound. One had a unilateral scrotal hernia, detected by palpation, and two had
      sperm granulomas which were detected by trans-scrotal ultrasonography at 18 to 20
      weeks of age, before they could be detected by palpation. Changes in the lesions
      were monitored ultrasonographically at two-week intervals with a 7.5 MHz linear
      array transducer. On the day of each examination, semen was collected from the
      rams with sperm granulomas by using an artificial vagina, and their libido was
      assessed. Semen could rarely be collected from the third ram. Comparisons were
      made with similar data obtained from two normal rams. When the rams were 20 to 21
      months of age, they were vasectomised on the normal side, so that the influence
      of the lesions on semen composition and libido could be assessed, and semen was
      collected and evaluated until they were euthanised at approximately 24 months of
      age, when the genital system was examined for gross lesions. The sperm granulomas
      changed in size (one of them increased in size by about 30 times) and echotexture
      over the 19-month period of the study, whereas the scrotal hernia, which
      contained omental fat, remained fairly constant. The libido of the two rams with
      sperm granulomas was comparable with the two normal controls. The total mean
      (sem) number of sperm in the ejaculates were 1.11 (0.10) x 10(9) and 2.03 (0.17)
      x 10(9) sperm/ml in the affected rams and 4.11 x 10(9) sperm/ml in the normal
      rams over the same period; the differences were significant (P<0.05). After
      unilateral vasectomy, the ejaculates from these two rams contained small numbers
      of dead spermatozoa, mostly with degenerate heads. Postmortem examination
      confirmed the gross lesions identified ultrasonographically.

PMID- 10661456
TI  - Retrospective study of clinical complications occurring after arterial punctures
      in 111 dogs.
AB  - The clinical complications occurring after 111 dogs had undergone arterial
      punctures were reviewed in relation to the dogs' breed, bodyweight, age, sex and
      underlying diseases. Seven of the dogs had moderate to extensive ecchymoses,
      which were significantly more common in dogs under 3.5 kg in bodyweight and in
      dogs with disorders of the cardiovascular system.

PMID- 10661457
TI  - Deletrocephalus dimidiatus in greater rheas (Rhea americana) in the UK.

PMID- 10661458
TI  - Intestinal chlamydial infection concurrent with postweaning multisystemic wasting
      syndrome in pigs.

PMID- 10661459
TI  - Hepatic sinusoidal dilatation in a Pearsei cichlid (Cichlasoma pearsei).

PMID- 10661460
TI  - Comparison of two intrauterine treatments for bovine endometritis.

PMID- 10661461
TI  - Cattle identification.

PMID- 10661462
TI  - Availability of equine medicines.

PMID- 10661464
TI  - Year 2000 and practice records.

PMID- 10661463
TI  - Metaphyseal osteomyelitis.

PMID- 10661465
TI  - Reindeer concerns.

PMID- 10661466
TI  - A radiobiological basis for the treatment of arteriovenous malformations.

PMID- 10661467
TI  - Bacterial outer membrane proteins: topological analyses and biotechnological
      perspectives.
AB  - The outer membrane proteins (OMPs) from gram-negative bacteria form a distinct
      group of integral membrane proteins with unusual primary, secondary and tertiary
      structures. Unlike typical prokaryotic and eukaryotic membrane proteins,
      bacterial OMPs contain primarily polar sequences, arranged in amphipathic
      antiparallel beta-barrels, and inclined to the plane of the membrane. Due to
      their unique structure, OMPs have recently become the subject of extensive study.
      This article reviews (i) experimental and theoretical approaches of topological
      analyses used in the study of OMPs, and (ii) the applications of OMPs.

PMID- 10661468
TI  - Nocodazole, vinblastine and taxol at low concentrations affect fibroblast
      locomotion and saltatory movements of organelles.
AB  - Microtubules (MTs) are essential for the maintenance of asymmetric cell shape and
      motility of fibroblasts. MTs are considered to function as rails for organelle
      transport to the leading edge. We investigated the relationship between the
      motility of Vero fibroblasts and saltatory movements of particles in their
      lamella Fibroblasts extended their leading edges into the experimental wound at a
      rate of 20+/-11 microm/h. Intracellular particles in the front parts of the
      polarized fibroblasts moved saltatorily mainly along the long axis of the cells.
      MT depolymerization induced by the nocodazole at a high concentration (1.7
      microM) resulted in the inhibition of both fibroblast motility and saltatory
      movements of the particles. Taxol (1 microM) inhibited the fibroblast locomotion
      but not the saltatory movements. The saltatory movement pattern was disorganized
      by taxol by decreasing the portion of longitudinal saltations and consequently by
      increasing the part of saltations perpendicular to the cell long axis. This
      effect may be explained by disorganization of the MT network resulting from the
      inhibition of dynamic instability. To further investigate the relationships
      between the MT dynamics instability, saltatory movements, and fibroblast
      locomotion, we treated fibroblasts with microtubule drugs at low concentration
      (nocodazole, 170 nM; vinblastine, 50 nM; and taxol, 50 nM). All these drugs
      induced rapid disorganization of the saltatory movements and decreased the rate
      of cell locomotion. Simultaneously, the amount of acetylated (stable) MTs
      increased. The treatment also induced reversible changes in the actin meshwork.
      We suggest that decrease in the fibroblast locomotion rate in the case of MT
      stabilization occurred because of the appearance of numerous free MTs. Saltations
      along free MTs are poorly organized and, as a result, the number of organelles
      reaching the fibroblast leading edge decreases.

PMID- 10661469
TI  - The effect of temperature on the interaction of Yersinia pseudotuberculosis
      lipopolysaccharide with chitosan.
AB  - The mechanism of binding of lipopolysaccharide (LPS) from Yersinia
      pseudotuberculosis to low-molecular-weight chitosan was investigated using
      sedimentation analysis, centrifugation in glycerol and percoll density gradients,
      and isopicnic centrifugation in cesium chloride. The LPS interaction with
      chitosan was shown to be a multistage process that depended on time and reaction
      temperature. A stable LPS-chitosan complex could be formed only after preliminary
      incubation of the initial components at an elevated temperature (37 degrees C).
      This temperature caused the LPS dissociation and promoted its binding to
      chitosan. The LPS binding to chitosan results in further dissociation of the
      endotoxin and formation of the complex with a molecular weight that is tens of
      times less than the initial molecular weight of LPS. The obtained complex
      remained stable in solutions of high ionic strength.

PMID- 10661470
TI  - Different modes of ozone-induced lipid oxidation in Candida utilis yeast cells
      and isolated membrane preparations.
AB  - Significant differences in the development of ozonolysis of lipids in membrane
      preparations and intact cells of the Candida utilis yeast were revealed. First,
      unlike isolated membranes, in which lipid modifications can be initiated by low
      ozone doses (< 0.5 micromol O3/mg protein) and develop proportionally to the
      treatment dose, in intact yeast cells, even the most ozone-sensitive sterols and
      nitrogen-containing phospholipids (phosphatidylcholine and
      phosphatidylethanolamine) did not undergo oxidative destruction at doses up to
      6.0 micromol O3/mg protein. Second, the peculiarity of the ozone-initiated lipid
      modification in intact cells was that different classes of lipids exhibited
      different sensitivity to ozone. With an increase in the ozone dose, neutral
      lipids (sterols) and nitrogen-containing phospholipids (phosphatidylcholine,
      phosphatidylethanolamine, and sphingomyelin) were modified to a greater extent.
      Third, the accumulation of lipid peroxidation products upon ozone treatment of
      cells, in contrast to the isolated membranes, was absent at low ozone doses and
      was recorded only after the lethal damage. It is suggested that these differences
      are related to both the function of antioxidative enzymes (catalase, superoxide
      dismutase, peroxidase, etc.) and the difference between the structural states
      (i.e., stability and accessibility to oxidation) of lipids in the isolated
      membranes and the intact cells.

PMID- 10661471
TI  - The role of membrane structure in activation of mitochondrial phospholipases. 2.
      Mechanism of crambin action on the activities of mitochondrial membrane
      phospholipases and microviscosity.
AB  - Effects of crambin on the phospholipase activity, lipid peroxidation and
      structure of mitochondrial membranes have been investigated. Crambin has been
      shown to inhibit lipid peroxidation and phospholipase activity induced by Ca2+
      and freezing-thawing of mitochondria. As shown by ESR studies, these effects are
      based on the ability of crambin to cause changes in mitochondrial membrane
      structure.

PMID- 10661473
TI  - A theoretical analysis of pH dependence of sodium channel conductance.
AB  - A new theory termed tunnel-acid-group-potential (TAGPT), which explains the
      effects of pHo and pHi on the ion conductance through different membrane
      channels, is presented. It is suggested that shifts in pHo and pHi change the
      values of negative charges generated by acid groups of side chains of some polar
      (Glu, Asp) amino acid residues lining the tunnel part of the channel. The
      resulting electrostatic field modification affects the heights of rate-limiting
      energy barriers (for ion transport) in the transition zones between the tunnel
      and the vestibules, which changes the channel conductance.

PMID- 10661472
TI  - Molecular size and hydrophobicity as factors which determine the efficacy of the
      blocking action of amino-adamantane derivatives on NMDA channels.
AB  - Neurons isolated from the CA-1 region of rat hippocampal slices by the
      "vibrodissociation" method were voltage-clamped in the whole cell configuration.
      The currents through NMDA channels were recorded in response to rapid application
      (solution exchange time <30 ms) of 100 microM aspartate (ASP) in a Mg2+-free
      solution in the presence of 3 microM glycine. When added to the ASP solution,
      amantadine as well as other amino-adamantane derivatives (AAD) produced an open
      channel blockade of NMDA channels. Membrane hyperpolarization enhanced the AAD
      block. The affinity between NMDA channels and AAD was different for various AAD.
      The analysis of the experimental data led us to conclude that this affinity
      depended both on the molecular size of the blocker (calculated using HyperChem
      molecular modeling program) and on the blocker's hydrophobicity (calculated
      according to Hansch and Leo, 1979). The affinity between NMDA channels and AAD
      diminished with an increase in molecular size and raised with an increase in
      blocker's hydrophobicity. We propose an empirical equation which describes the
      dependence of affinity on the size and hydrophobicity of the blocker. The
      estimated critical diameter of the NMDA channel pore where the AAD blocking site
      is located proved to be about 17 A.

PMID- 10661474
TI  - Effect of dipole modifiers on the kinetics of sensitized photoinactivation of
      gramicidin channels in bilayer lipid membranes.
AB  - Photodynamic inactivation of gramicidin channels in bilayer lipid membranes
      induced by single flashes of the visible light in the presence of phthalocyanine
      has been studied. The kinetic curves of the flash-induced decrease in the
      gramicidin-mediated electric current are used for determination of the rate
      constants of formation and termination of gramicidin channels in terms of the
      channel dimer model. It is revealed that the kinetics of the sensitized
      photoinactivation of gramicidin in the membrane is altered by agents which modify
      the dipole potential drop at the membrane-water interface. Addition of phloretin,
      which is known to decrease the dipole potential drop, slows down the kinetics,
      whereas the addition of RH421 or 6-ketocholestanol, which increase the dipole
      potential drop, accelerates the kinetics. It is shown that the photoinactivation
      kinetics is also slowed down upon the addition of the thyroid hormone L
      thyronine, which reduces the dipole potential drop similar to phloretin, as it
      was found earlier (M. V. Tsybulskaya, Yu. N. Antonenko, A. E. Tropsha, and L. S.
      Yaguzhinsky, Biofizika 29:801-805 (1984) (in Russian)). It is demonstrated that
      the changes in the dissociation rate constant of gramicidin dimers under the
      action of different dipole modifiers correlate with the changes in the dipole
      potential drop. It is concluded that the process of the gramicidin channel
      termination corresponding to the dimer dissociation is sensitive to the dipole
      potential drop. This conclusion is supported by the data on the effect of dipole
      modifiers on the lifetime of single gramicidin channels.

PMID- 10661475
TI  - Study of conductance changes of bilayer lipid membrane induced by electric field.
AB  - Changes in the bilayer lipid membrane (BLM) conductance induced by electric field
      were studied. BLMs were formed from diphytanoylphosphocholine (DPhPC) solution in
      squalene. Certain time after a constant voltage (200-500 mV) was applied to the
      BLM in the voltage-clamp mode, the BLM conductance started to grow up to
      approximately 10 nS until the BLM ruptured. The conductance often changed
      abruptly (with the front duration of less than 33 micros) and then stabilized for
      a relatively long time (up to 10; 300 ms on average) thus resembling the ion
      channel activity. The mean amplitude of conductance steps was 650 pS. However, in
      some cases a slow conductance drift was recorded. When N-methyl-D
      glucamine/glutamate ions were used instead of KCl, the conductance changes became
      5 times smaller. We suggest that formation in the BLM of single pores
      approximately 1 nm in diameter should result in the observed changes in BLM
      conductance. The BLM conductance growth was due to consecutive opening of several
      such pores. When the electric field amplitude was abruptly decreased (down to 50
      100 mV), the conductance dropped rapidly to the background value. When we
      increased the voltage again, the BLM conductance right after the increase
      depended on the time BLM spent under "weak" electric field. If this time exceeded
      500 ms, the conductance was at the background level, but when the time was
      diminished, the conductance reached the value recorded before the voltage
      decrease. These data imply that the closure of the pores should lead to the
      formation in BLM of small defects (prepores) that can be easily transformed into
      pores when the voltage is increased. The lifetimes of such prepores did not
      exceed 500 ms.

PMID- 10661476
TI  - Combination therapy using prednisolone and cyclophosphamide slows the progression
      of moderately advanced IgA nephropathy.
AB  - AIM: We retrospectively examined the effect of combination therapy using
      prednisolone (PSL) and cyclophosphamide (CPA) on the progression of IgA
      nephropathy (IgAN) in 45 patients with moderate to severe histological changes.
      PATIENTS AND METHODS: Patients were recruited from 129 consecutive patients with
      IgAN seen over 10 years based on semiquantitative histological grading. They were
      divided into two groups: PSL+CPA group (n = 26, male/female = 11/15, age 40+/-3
      years (SEM)) or control group undergone conventional therapy with or without
      antiplatelet agents (n = 19, male/female = 10/9, age 41+/-3). In PSL+CPA group,
      PSL and CPA treatment commenced using a dose of 30 and 50 mg/day, respectively.
      PSL was reduced by 5 mg every month. RESULTS: The clinical parameters at the
      start of treatment such as age, gender, histological score, blood pressure,
      urinary protein excretion and serum creatinine concentration (SCr) were not
      different between the groups. The mean observation period in PSL+CPA group (3.3+/
      0.3 years) was not different from the control group (4.0+/-0.7 years). In PSL+CPA
      group, urinary protein excretion, defined as the ratio of urinary protein to
      creatinine concentration (UP/UCr), significantly decreased from 3.9+/-0.4 to 1.3
      +/-0.2 (p<0.01), whereas it remained high in the control group (3.8+/-0.7 to
      2.7+/-0.8). The progression rate (PR), which was determined by the slope of the
      correlation between time after renal biopsy and reciprocal SCr, was significantly
      lower in PSL+CPA (0.054+/-0.014) than in the control group (0.172+/-0.032
      dl/mg/year, p<0.001). Our results indicated that PSL+CPA combination therapy was
      effective in slowing the progression of moderately advanced IgAN. CONCLUSION: We
      suggest that the immunosuppressive treatment with CPA is sometimes necessary to
      preserve renal function in patients with histologically advanced IgAN.

PMID- 10661477
TI  - Prognostic value of a new scoring system for hospital mortality in acute renal
      failure.
AB  - AIM AND METHODS: In order to define a prognostic scoring system for hospital
      mortality of individual patients with acute renal failure (ARF), data were
      collected prospectively in a single centre study (Stuivenberg General Hospital,
      Antwerp, Belgium) on 197 adult patients consecutively admitted to the intensive
      care unit (ICU) during one year. Mean age was 69.8 (+/- 14.7), male/female ratio
      was 118/79. RESULTS: Hospital mortality was 53%, 26% of the patients who were
      treated with renal replacement therapy. For developing the model all parameters
      showing a significant difference between survivors and non-survivors were entered
      in the multivariate analysis. Two SHARF scores (= Stuivenberg Hospital Acute
      Renal Failure scores) were developed, one at the time of diagnosis of ARF (T0)
      and the other 48 hours later (T48): SHARF T0 (7 x age) + (6 x alb0) + (3 x PTT0)
      + (39 x vent0) + (9 x heartf0) + 52 SHARF T48 (7 x age) + (6 x alb0) + (3 x PTT0)
      + (43 x vent48) + (16 x heartf48) + 52 age, albumin (alb0) and prothrombine time
      (PTT0) at T0 are expressed as categories, respiratory support (vent) and heart
      failure (heartf) at T0 and T48 are presented as absent (0) or present (1). In the
      linear regression model, r2 was, respectively, 0.36 and 0.43. The area under the
      receiver operator characteristic (ROC) curves, judging the discrimination ability
      between survivors and non-survivors, for T0 and T48 were, respectively, 0.87 and
      0.90. The Hosmer-Lemeshow goodness-of-fit C statistic for T0 was C = 8.47; df8; p
      = 0.3 89 and for T48 C = 11.05; df = 8; p = 0.199. CONCLUSION: We conclude that
      this scoring system, developed for all types of ARF, compares favorably with
      published scores and can become useful as a bedside tool for predicting hospital
      mortality in individual patients. A second measuring point increased the
      predictive value of the model. The results have to be confirmed in an ongoing
      prospective multicentre study.

PMID- 10661478
TI  - Cardiac function in dialysis patients evaluated by Doppler echocardiography and
      its relation to intradialytic hypotension: a new index combining systolic and
      diastolic function.
AB  - AIM, PATIENTS AND METHODS: Cardiac function of 40 patients on maintenance
      dialysis was examined using a new Doppler index combining systolic and diastolic
      function. Immediately before dialysis, ultrasonic pulsed Doppler was used to
      measure right and left ventricular inflow and outflow waveforms. The sum of the
      isovolumetric contraction time (ICT) and isovolumetric relaxation time (IRT) was
      calculated by subtracting the ejection time from the interval between the end of
      an inflow waveform and the start of the next inflow waveform. The new index was
      obtained by dividing the sum of the two isovolumetric times by the ejection time.
      Cardiac function was evaluated in dialysis patients and healthy controls using
      new indices of the right and left heart systems. RESULT: Indices of the right and
      left heart systems in dialysis patients were significantly higher than those in
      healthy controls. With respect to hypotension during dialysis, patients were
      divided into two groups, a group with decreased blood pressure (group A: 27
      patients) and a group with normal blood pressure (group B: 13 patients). Only the
      left heart system index in group A was significantly higher. There were no
      significant differences in other M-mode Doppler indices between the two groups.
      CONCLUSION: The new index was a more sensitive evaluator of cardiac function and
      predictor of hypotension during dialysis compared to standard echocardiographic
      indices.

PMID- 10661479
TI  - Changes in cardiac muscle mass and function in hemodialysis patients during
      growth hormone treatment.
AB  - BACKGROUND: Adult patients with chronic renal failure (CRF) often show symptoms
      as fatigue, wasting, and reduced working capacity with concomitant findings of
      reduced cardiac performance and muscle mass. This state may in part be caused by
      an imbalance in the somatostatin/somatomedine axis resulting in increased
      catabolism. During an attempt to correct this catabolic state by administration
      of exogenous growth hormone, cardiac muscle mass and performance were studied.
      METHODS: In a double-blind, placebo-controlled 6-month study comprising 20 adult
      enfeebled hemodialysis patients, 9 patients were treated with a single daily
      subcutaneous injection of recombinant human growth hormone (rhGH) 4 IU/m2 and 11
      with placebo injections. Left ventricular muscle mass (LVM) and ejection fraction
      (EF) were evaluated by echocardiography and the maximal working capacity (MWC)
      was measured by a bicycle exercise test performed before and after the treatment
      period. Supplementary electrocardiography (ECG) was performed before and after 6
      month treatment. RESULTS: Median LVM increased significantly from 172 to 220 g (p
      = 0.03) in the rhGH-treated group, while an insignificant decrease was observed
      in the placebo group from 281 to 200 g (p = 0.3). The EF showed no significant
      changes in the two groups. MWC showed a slight, insignificant decrease in both
      groups. From ECG no significant ST deviations were found and no significant
      changes regarding B-Hb, blood pressure or pulse were observed in the two groups.
      Irregular heart rhythm aggravated in one patient during the first month of
      treatment with rhGH, but was overcome by a -blocking agent. CONCLUSION: The
      treatment with rhGH of adult chronic hemodialysis patients for 6 months increased
      the left ventricular mass significantly, but without any effect on ejection
      fraction or maximal working capacity. No electrocardiographic signs of ischemia
      were associated with the increasing muscle mass and only one patient developed
      symptoms that might relate to ischemia. No changes in B-Hb, blood pressure or
      pulse were observed during the treatment period.

PMID- 10661480
TI  - Carotid artery stiffness in patients with end-stage renal disease: no effect of
      long-term homocysteine-lowering therapy.
AB  - BACKGROUND: The excess of cardiovascular disease in end-stage renal disease
      (ESRD) patients is unexplained, but could relate to altered intrinsic vascular
      wall properties, such as increased arterial stiffness, which could be mediated by
      hyperhomocysteinemia. We investigated potential determinants of carotid artery
      stiffness in ESRD patients and the effect of long-term homocysteine-lowering
      treatment. PATIENTS AND METHODS: Fifty-four patients on maintenance dialysis
      treatment were studied at baseline. Fourty-one patients completed the treatment
      protocol, which consisted of a 12-week treatment with folic acid 5 mg daily with
      or without betaine 4 g per day, and of 1 or 5 mg of folic acid thereafter for 40
      weeks. Both phases were randomized. Compliance and distensibility coefficients
      (CC and DC) and the stiffness index (beta) of the common carotid artery were
      determined at baseline and after 52 weeks of treatment using a non-invasive
      vessel wall movement detector system. RESULTS: At baseline, plasma total
      homocysteine was elevated (44.1+/-33.7 micromol/l), but showed no relationship
      with CC, DC or beta. Age and mean arterial pressure (MAP) were the only
      independent determinants of CC and DC, whereas beta was associated with age only.
      Plasma homocysteine showed a sustained decrease after therapy (20.7+/-9.0
      micromol/l at week 52). No significant changes occurred in CC (from 0.59+/-0.21
      to 0.60+/-0.22 mm2/kPa; p = 0.47), in DC (from 14.9+/-6.1 to 15.3+/-6.2 10(
      3)/kPa; p = 0.55), or in beta (from 10.9+/-4.7 to 11.2+/-4.4; p = 0.64). No
      independent determinants were detected for the change in CC, whereas the change
      in DC was inversely related to the change in MAP (stand. r = -0.58; p<0.0002).
      The decrease in MAP after therapy was significant (p = 0.003) and was related to
      the dialysis mode (p = 0.003) and smoking status (p = 0.02). CONCLUSION: Folic
      acid treatment of hyperhomocysteinemia has no major effect on carotid artery
      stiffness in chronic dialysis patients. The results do, however, emphasize the
      importance of tight blood pressure control in these patients.

PMID- 10661481
TI  - Limited value of zinc protoporphyrin as a marker of iron status in chronic
      hemodialysis patients.
AB  - BACKGROUND: In an attempt to find new parameters able to evaluate the actual iron
      availability by bone marrow cells, zinc protoporphyrin (ZnPP), a metabolic
      intermediate generated in the red blood cell by the incorporation of zinc instead
      of iron, has been proposed. ZnPP is a good marker of iron-deficiency anemia in
      non-uremic people, as red blood cell ZnPP concentration rises specifically
      (except for lead intoxication) in this condition. Existing data on ZnPP as a
      marker of iron deficiency in uremic patients comes mainly from cross sectional
      studies on chronic hemodialysis and has produced conflicting results. SUBJECTS
      AND METHODS: Therefore, we prospectively studied 42 HID patients, 28-88 years
      old, 13-346 months of dialysis age, beginning from a period of maximal iron
      deficiency, due to the lack of parenteral iron compounds (T0) up to the end of
      more than one year of follow-up with continuous parenteral iron supplementation
      (T4). ZnPP, hemoglobin, transferrin saturation and ferritin were serially
      determined before and after six weeks (T1), four months (T2), seven months (T3)
      and 14 months (T4) of parenteral iron supplementation at a maintenance dose of
      0.5-1 mg/kg/week. RESULTS: In comparison with baseline values (95+/-37
      micromol/mol heme) there were no significant changes in ZnPP levels at T1 and T2
      despite a continuous increase in both transferrin saturation and ferritin values,
      while ZnPP significantly decreased at T4 (63+/-37 micromol/mol heme, p<0.001).
      There was no correlation between ZnPP and both transferrin saturation and
      ferritin at any time during the study, the same was true for ZnPP and zinc and
      lead serum concentration, fibrinogen and reactive C protein levels at T1 and T4,
      respectively. At T4, only 2/10 patients who still showed ZnPP levels >80
      micromol/mol heme had absolute or functional iron deficiency, when the percentage
      of hypochromic red cells were measured. CONCLUSION: We conclude that ZnPP
      untimely parallels a change in iron balance in only a proportion of uremic
      people, in as much as confounding factors, such as chronic inflammation and
      uremia in itself may obscure its relationship with iron status. Therefore, ZnPP
      cannot be assumed to be a first-line diagnostic marker of iron balance in uremic
      patients.

PMID- 10661482
TI  - Erythropoietin, folic acid deficiency and hyperhomocysteinemia: is there a
      possible relationship in chronically hemodialyzed patients?
AB  - AIMS: To examine the possible relationships between recombinant human
      erythropoietin (rhEPO) therapy, serum folic acid and homocysteine levels in a
      cohort of stable, chronically hemodialyzed patients. MATERIAL AND METHODS: The
      study was cross-sectional in its first phase and consisted of 3 groups of
      subjects (group 1:6 healthy controls; group 2:7 dialyzed patients not receiving
      rhEPO; group 3: 14 patients on rhEPO therapy). Hematological and biochemical
      parameters were taken after an overnight fast in all subjects. The second phase
      of the study was prospective, and included 8 dialyzed patients, and investigated
      the effects of a 6-month period of folic acid supplementation (10 mg, 3 times a
      week) on the same parameters examined in the first phase of the study. RESULTS:
      In the first part of the study hemoglobin levels were near-normal, or normal, in
      all patients. No differences in hemoglobin or hematocrit values were observed in
      the 3 groups. 80% of all hemodialyzed patients had low serum folic acid levels,
      irrespective of whether they were receiving rhEPO. Serum erythropoietin level was
      elevated in group 3 (23.3+/-10.4 mIU/ml). In group 2, serum erythropoietin level
      was not different from that of the healthy controls (13.5+/-11.2 vs. 8.0+/-5.4
      mIU/ml, p = n.s.). Total serum homocysteine levels were elevated in all dialyzed
      patients (group 2: 24.7+/-9.2 micromol/l; group 3: 31.6+/-14.4 micromol/l), with
      a significant difference seen when comparing controls and those dialyzed patients
      on rhEPO therapy (8.7+/-2.2 vs. 31.6+/-14.4 micromol/l; p<0.05). Significant
      correlations (ANOVA) were observed between serum erythropoietin and folic acid
      levels (r = -0.382; p = 0.049), and between folic acid and homocysteine levels (r
      = -0.560; p = 0.002). In the second part of the study folic acid supplementation
      led to a highly significant reduction in homocysteine levels (20.9+/-4.9 vs.
      11.9+/-2.5 micromol/l; p<0.0005). Two of 3 patients receiving rhEPO therapy, had
      rhEPO discontinued after commencing folic acid, as hemoglobin levels remained
      adequate, even without rhEPO. CONCLUSIONS: In hemodialyzed patients, the presence
      of a near-normal hemoglobin level, irrespective of rhEPO therapy, implies
      efficient erythropoiesis. Without adequate folic acid reserves, folic acid
      deficiency may develop in these patients and this will aggravate already high
      homocysteine levels. Therefore, folic acid supplementation is warranted in
      hemodialyzed patients, especially in those patients with hemoglobin levels
      approaching normal. This treatment is safe and effective in reducing homocysteine
      levels, especially when given in high doses for prolonged periods of time.

PMID- 10661483
TI  - Factors affecting system clotting in continuous renal replacement therapy:
      results of a randomized, controlled trial.
AB  - BACKGROUND: System clotting and the anticoagulation techniques employed to
      prevent it are important causes of morbidity in continuous renal replacement
      therapy (CRRT). Different means have been employed in attempts to prolong system
      lifespan while minimizing complications. SUBJECTS, MATERIALS AND METHODS: To
      determine whether augmenting blood flow and flush frequency could reduce clotting
      frequency, we compared system lifespan in a standard blood flow and saline flush
      group (125 ml/min and 100 ml once hourly, respectively) to an augmented blood
      flow and saline flush group (200-250 ml/min and 100 ml twice hourly). A total of
      34 patients treated with continuous venovenous hemodialysis were randomized to
      receive either the standard or augmented regimens in a prospective trial
      conducted between August 1995 and March 1997. A total of 130 systems were
      studied. RESULTS: Based on intention-to-treat analysis, there was no difference
      in time to clot between the two groups. In a multivariate analysis of the
      outcome, red blood cell and platelet transfusion during CRRT were significantly
      associated with decreased clotting, and systemic heparin infusion significantly
      prolonged lifespan of CRRT systems. CONCLUSION: Increasing blood flow and flush
      frequency does not prevent clotting in CRRT. Since this intervention is more
      costly than standard treatment, its use cannot be justified.

PMID- 10661484
TI  - Fatal hypermagnesemia.
AB  - Severe symptomatic hypermagnesemia is a rare clinical problem that predominantly
      results from excess exogenous magnesium intake in patients with renal failure.
      This report describes an elderly woman who was given a magnesium-containing
      cathartic for pre-operative bowel preparation in the context of unrecognized
      acute renal failure. She subsequently developed one of the highest serum
      magnesium concentrations ever reported. The hypermagnesemia was successfully
      treated with continuous arteriovenous hemodialysis, but she ultimately died from
      complications of hypermagnesemia, that included junctional bradycardia,
      myocardial infarction and respiratory failure. This case illustrates the
      importance of ensuring intact renal function prior to administering large
      quantities of oral magnesium. More specifically, large doses of magnesium salts
      should be avoided in patients with acute renal failure.

PMID- 10661485
TI  - Saline-resistant metabolic alkalosis, severe hypokalemia and hypertension in a 74
      year-old woman.
AB  - The case of a 74-year-old woman with past history of hypertension and
      cerebrovascular accident admitted with pneumonia, dehydration, hypernatremia and
      severe hypokalemic alkalosis is presented. After correction of the hypertonic
      dehydration, the hypokalemia and alkalosis persisted in spite of aggressive
      potassium supplementation and the patient became hypertensive. Mineralocorticoid
      excess was suspected and excluded after extensive endocrinological testing. The
      use of aldactone failed to revert the abnormalities. Triamterene administration
      corrected the electrolytes and acid base aberrations, and dramatically improved
      the blood pressure control. This clinical picture is compatible with the
      diagnosis of Liddle's syndrome. Our patient exemplifies the unique occurrence of
      hypokalemic metabolic alkalosis in association with volume contraction at the
      start of the hospitalization and volume expansion later on her course.

PMID- 10661486
TI  - Retroperitoneal fibrosis and membranous nephropathy.
AB  - We report on a patient with a past history of Pott's abscess who suffered both
      from a retroperitoneal fibrosis and a membranous glomerulonephritis. Five cases
      of retroperitoneal fibrosis and immune complex glomerulonephritis are already
      reported in the literature. These associations might result from a particular
      systemic immune response to an unknown antigen. Consequently, we consider the
      role of tuberculosis in our case.

PMID- 10661487
TI  - Elevated urinary excretion of thromboxane B2 in adults with minimal-change
      nephrotic syndrome.

PMID- 10661488
TI  - An effective "transluminal balloon angioplasty" therapy for pediatric chronic
      fatigue syndrome with nutcracker phenomenon.

PMID- 10661489
TI  - Regions in the brainstem and frontal cortex where electrical stimulation elicits
      parotid and submandibular saliva secretion in sheep.
AB  - Acute experiments were conducted in sheep anaesthetized with sodium pentobarbital
      to identify regions in the brain where electrical stimulation would elicit
      secretion by the parotid and submandibular salivary glands. This was a
      prerequisite for single unit studies in the future. In the brainstem, parotid and
      submandibular secretions were evoked on average between 7 and 16 mm rostral to
      obex and from 1 to 11 mm lateral to midline, with the parotid gland being active
      on the caudal and the submandibular on the rostral sides of this region. Overlap
      of the two sites was common. The combined region was either between cranial
      nerves VII and IX or adjacent to either one of them. Stimulating the caudal edge
      of the parotid sites evoked relatively high parotid secretion rates compared with
      other areas whereas secretions were uniform throughout the submandibular sites.
      The combined sites were from 2 to 5 mm deep, the dorsal edge being 1 mm below the
      floor of the fourth ventricle near midline and 6 mm below it at the lateral
      extremes. From a dorsal perspective, their orientation was essentially in the
      lateral plane except that the submandibular site angled slightly rostrally from
      midline. Profuse parotid secretion was also consistently evoked by stimulating
      the frontal cortex 15-20 mm from midline and 0-15 mm under the apex. Weak
      submandibular responses were observed in about half of the sheep. There were no
      effects on either gland of stimulating the olfactory bulbs. This is the first
      report of the regions in the brain which increase parotid and submandibular
      saliva secretion in ruminants. The three-dimensional representation of both sites
      in the brainstem of individual animals is more precise than the composite
      representations published to date for other species.

PMID- 10661490
TI  - Adenosine A1 receptors inhibit Ca2+ channels coupled to the release of ACh, but
      not of GABA, in cultured retina cells.
AB  - We investigated the effect of adenosine A1 receptors on the release of
      acetylcholine (ACh) and GABA, and on the intracellular calcium concentration
      ([Ca2+]i) response in cultured chick amacrine-like neurons, stimulated by KCl
      depolarization. The KCl-induced release of [3H]ACh, but not the release of
      [14C]GABA, was potentiated when adenosine A1 receptor activation was prevented by
      perfusing the cells with adenosine deaminase (ADA) or with 1,3-dipropyl-8
      cycloentylxanthine (DPCPX). The changes in the [Ca2+]i induced by KCl
      depolarization, measured in neurite segments of single cultured cells, were also
      modulated by endogenous adenosine, acting on adenosine A1 receptors. Our results
      show that adenosine A1 receptors inhibit Ca2+ entry coupled to ACh release, but
      not to the release of GABA, suggesting that the synaptic vesicles containing each
      neurotransmitter are located in different zones of the neurites, containing
      different VSCC and/or different densities of adenosine A1 receptors.

PMID- 10661491
TI  - In situ and immunocytochemical localization of E-FABP mRNA and protein during
      neuronal migration and differentiation in the rat brain.
AB  - The present study compares the temporal-spatial expression and tissue
      localization of the rat epidermal type fatty acid binding protein (E-FABP)
      (DA11/C-FABP/S-FABP/LEBP/KLBP) in the developing rat central nervous system
      (CNS). In situ hybridization (ISH) and immunocytochemistry (ICC) studies
      demonstrate that mRNA E-FABP and protein are expressed at high levels during
      neurogenesis, neuronal migration, and terminal differentiation. Migrating
      pyramidal cells in the cerebral cortex, Purkinje cells and deep nuclear neurons
      in the cerebellum, and neurons in the olfactory bulb and retina exhibited a
      strong E-FABP-like immunoreactivity (E-FABP-LI) throughout the entire process of
      differentiation and migration. The levels of E-FABP mRNA and protein were
      dramatically higher in prenatal and early postnatal neurons, as compared to adult
      neurons. The E-FABP antibody immunoreacted with growing neurites, and nuclear and
      cytoplasmic regions of neurons. The intracellular multiregional pattern of
      localization of E-FABP and its differential temporal expression during
      development, are consistent with its proposed role in transporting long chain
      free fatty acids and/or other hydrophobic ligands during neuronal differentiation
      and axon growth.

PMID- 10661492
TI  - Prolactin regulation of tuberoinfundibular dopaminergic neurons:
      immunoneutralization studies.
AB  - The purpose of this study was to determine the effects of acute hypoprolactinemia
      on tuberoinfundibular dopamine (DA) neurons using a rabbit anti-rat prolactin
      antiserum (PRL-AB) to immunoneutralize circulating prolactin under basal
      conditions and at various times after haloperidol-induced hyperprolactinemia. The
      specificity of PRL-AB for prolactin was determined by examining the ability of
      unlabelled hormone to displace binding of 125I-labelled prolactin to PRL-AB.
      Tuberoinfundibular DA neuronal activity was estimated by measuring the
      concentrations of the DA metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the
      median eminence which contains terminals of these neurons. Systemic (i.v.)
      administration of 200 microl of PRL-AB decreased plasma prolactin concentrations
      below detectable levels for at least 4 h, and this was accompanied by a
      pronounced decrease in DOPAC concentrations in the median eminence of females,
      but not males. Central (i.c.v.) administration of 2 microl PRL-AB diluted up to
      1:100 mimicked the inhibitory effect of systemic administration of PRL-AB on
      median eminence DOPAC concentrations suggesting that the tonic stimulatory effect
      of prolactin on the basal activity of tuberoinfundibular DA neurons in females
      occurs via a central site of action. In male rats, blockade of anterior pituitary
      DA receptors with haloperidol (1 mg/kg; s.c.) caused an prompt (by 1 h) increase
      in plasma prolactin concentrations which was maintained for at least 12 h.
      Haloperidol-induced hyperprolactinemia also caused a delayed (at 6 and 12 h)
      increase in median eminence DOPAC concentrations in these animals which was
      blocked by PRL-AB. Exposure of rats to initial priming periods of endogenous
      hyperprolactinemia of up to 6 h duration (followed by 6 h or more of PRL-AB
      induced hypoprolactinemia) failed to alter median eminence DOPAC concentrations
      unless prolactin exposure was reinstated by an i.c.v. injection of prolactin.
      These results confirm that prolactin mediates the stimulatory effects of
      haloperidol on tuberoinfundibular DA neurons, and reveal that delayed induced
      activation of these neurons by prolactin is dependent upon a priming period of
      sustained hyperprolactinemia longer than 3 h for initiation and maintenance of
      this response.

PMID- 10661493
TI  - Dicyclomine, an M1 muscarinic antagonist, reduces infarct volume in a rat
      subdural hematoma model.
AB  - The rat subdural hematoma (SDH) model produces a zone of ischemic brain damage
      within the hemisphere beneath the SDH. Previous studies have measured large
      increases in extracellular acetylcholine during cerebral ischemia in the rat. We
      examined infarct volume after selectively blocking muscarinic M1 receptors with
      dicyclomine during SDH. Rats were anesthetized with isoflurane (2%), intubated,
      and femoral artery and vein cannulated. Autologous blood (0.375 ml) was injected
      (0.05 ml/min) under the dura of the right parietal cortex. Dicyclomine (5 mg/kg,
      i.v.) was injected at 5 min after and again at 2 h after completion of the
      subdural blood infusion. Blood pressure and intracranial pressure (ICP) were
      continuously measured. At 4 h after SDH rats were euthanized, brains sectioned,
      and immunoreacted with glia fibrillary acidic protein. Cortical infarct volume
      was quantified in coronal brain sections at 0.7-mm intervals from +1.0 mm to -3.9
      mm relative to bregma. Infarct volume in drug-treated rats (n = 10) 22.1 +/- 6.99
      mm3 was significantly smaller (p < 0.02) than vehicle treated rats (n = 10) 56.7
      +/- 9.59 mm3. ICP, blood pressure and cerebral perfusion pressure were not
      significantly different between groups. These data suggest that activation of M1
      muscarinic receptors during an ischemic event may contribute to the development
      of subsequent pathology.

PMID- 10661494
TI  - Aberrant expression of nNOS in pyramidal neurons in Alzheimer's disease is highly
      co-localized with p21ras and p16INK4a.
AB  - Aberrancies of growth and proliferation-regulating mechanisms might be critically
      involved in the processes of neurodegeneration in Alzheimer's disease (AD).
      Expression of p21ras and further downstream signalling elements involved in
      regulation of proliferation and differentiation as, for example, MEK, ERK1/2,
      cyclins, cyclin-dependent kinases and their inhibitors such as those of the
      p16INK4a family, are elevated early during the course of neurodegeneration.
      Activation of p21ras can also directly be triggered by nitric oxide (NO),
      synthesized in the brain by various isoforms of nitric oxide synthase (NOS) that
      might be differentially involved into the pathomechanism of AD. To study the
      potential link of NO and critical regulators of cellular proliferation and
      differentiation in the process of neurofibrillary degeneration, we analyzed the
      expression pattern of NOS-isoforms, p21ras and p16INK4a compared to
      neurofibrillary degeneration in AD. Additionally to its expression in a subtype
      of cortical interneurons that contain the nNOS-isoform also in normal brain, nNOS
      was detected in pyramidal neurons containing neurofibrillary tangles or were even
      unaffected by neurofibrillary degeneration. Expression of nNOS in these neurons
      was highly co-localized with p21ras and p16INK4a. Because endogenous NO can
      activate p21ras in the same cell which in turn leads to cellular activation and
      stimulation of NOS expression [H.M. Lander, J.S. Ogiste, S.F.A. Pearce, R. Levi,
      A. Novogrodsky, Nitric oxide-stimulated guanine nucleotide exchange on p21 ras,
      J. Biol. Chem. 270 (1995) 7017-7020], the high level of co-expression of NOS and
      p21ras in neurons vulnerable to neurofibrillary degeneration early in the course
      of AD thus provides the basis for an autocrine feedback mechanism that might
      exacerbate the progression of neurodegeneration in a self-propagating manner.

PMID- 10661495
TI  - Endogenous mechanisms of neuroprotection: role of zinc, copper, and carnosine.
AB  - Zinc and copper are endogenous transition metals that can be synaptically
      released during neuronal activity. Synaptically released zinc and copper probably
      function to modulate neuronal excitability under normal conditions. However, zinc
      and copper also can be neurotoxic, and it has been proposed that they may
      contribute to the neuropathology associated with a variety of conditions, such as
      Alzheimer's disease, stroke, and seizures. Recently, we demonstrated that
      carnosine, a dipeptide expressed in glial cells throughout the brain as well as
      in neuronal pathways of the visual and olfactory systems, can modulate the
      effects of zinc and copper on neuronal excitability. This result led us to
      hypothesize that carnosine may modulate the neurotoxic effects of zinc and copper
      as well. Our results demonstrate that carnosine can rescue neurons from zinc- and
      copper-mediated neurotoxicity and suggest that one function of carnosine may be
      as an endogenous neuroprotective agent.

PMID- 10661497
TI  - Bradycardic and hypotensive responses to microinjection of L-glutamate into the
      lateral aspect of the commissural NTS are blocked by an NMDA receptor antagonist.
AB  - Baroreflex activation by phenylephrine infusion produces a bradycardic response
      while microinjection of L-glutamate into the most lateral aspect of the
      commissural nucleus tractus solitarius (NTS, 0.8 mm lateral to the midline)
      produces bradycardic and hypotensive responses. In the present study we
      investigated the role of NMDA receptors in the lateral aspect of the commissural
      NTS (0.8 mm lateral to the midline) in the bradycardic and hypotensive responses
      to microinjection of L-glutamate as well as in the processing of the bradycardic
      response to the baroreflex activation. The hypotensive and bradycardic responses
      to L-glutamate microinjection into the NTS were blocked by methyl-atropine
      (intravenous, i.v.), indicating that the hypotensive response was secondary to
      the bradycardia. Microinjection of L-glutamate (1 nmol/50 nl) into the NTS was
      performed before and after microinjection of increasing doses of phosphonovaleric
      acid (AP-5, a selective NMDA antagonist) at the same site. The microinjection of
      AP-5 [0.5 (n = 9), 2.0 (n = 8) and 10.0 nmol/50 nl (n = 7)] into the NTS (0.8 mm
      lateral to the midline) produced a dose-dependent blockade of the bradycardic and
      hypotensive responses to L-glutamate. In a specific group of rats the
      microinjection of 10 nmol/50 nl of AP-5 produced a significant reduction in
      baroreflex sensitivity 2 min after microinjection into the lateral NTS [gain = 
      1.48 +/- 0.12 vs. -0.5 +/- 0.2 beats/mmHg, (n = 5)], which was reversible. The
      data show that the bradycardic responses produced by microinjection of L
      glutamate into the most lateral aspect of the commissural NTS or by activation of
      the baroreflex were blocked by microinjection of AP-5, indicating that the
      neurotransmission of the parasympathetic component of the baroreflex in the
      neurons of the lateral aspect of the commissural NTS involves NMDA receptors.

PMID- 10661496
TI  - High pressure enhanced NMDA activity in the striatum and the globus pallidus:
      relationships with myoclonia and locomotor and motor activity in rat.
AB  - In mammals high pressure of helium-oxygen (He-O2) breathing mixture leads to the
      high pressure neurological syndrome (HPNS) which includes a set of behavioural
      disorders such as locomotor and motor hyperactivity (LMA) and myoclonia. In rats,
      i.c.v. administrations of competitive NMDA antagonists decrease some of these
      symptoms suggesting that He-O2 pressure could enhance NMDA neurotransmission
      within the central nervous system. More recently, we have shown using
      microdialysis that the extracellular glutamate level is increased in the striatum
      by He-O2 pressure. Neurochemical data have suggested that this structure is
      probably involved in the LMA development but not in the myoclonia expression.
      When considering myoclonia, recent neuropathological studies performed at normal
      pressure in humans suggest that the globus pallidus extern (equivalent to the
      globus pallidus in the rat) could be involved in this behavioural disorder. The
      aim of this study was to compare the role of striatal and pallidal NMDA activity
      on the LMA development and the myoclonia expression in the model of rat exposed
      to 8 MPa of He-O2 mixture. The intrastriatal administration of D(-)-2-amino-7
      phosphonoheptanoic acid (2-APH) (10 nmol/slide) reduced the LMA development but
      only slightly reduced myoclonia. In contrast, the intrapallidal administration of
      2-APH (10 nmol/slide) reduced both LMA and myoclonia. These results suggest that
      the LMA development requires NMDA activity at both striatal and pallidal level.
      In contrast, the myoclonia expression mainly requires NMDA activity at pallidal
      level. Consequently, NMDA neurotransmission at input and output levels of the
      striato-pallidal pathway play different roles in some of the behavioural
      disorders induced by He-O2 pressure.

PMID- 10661498
TI  - Prevention of precipitated withdrawal symptoms by activating central cholinergic
      systems during a dependence-producing schedule of morphine in rats.
AB  - Previous studies in this and other laboratories have suggested an important role
      for central cholinergic neurons in the expression of morphine withdrawal
      symptoms. This study was designed to determine whether the symptoms of withdrawal
      could be mitigated by normalization of the effect of morphine on cholinergic
      neurons. Since this effect is generally inhibitory, we used centrally acting
      cholinergic agonists to augment central cholinergic tone during chronic morphine
      infusion. Rats were made dependent following the intra-arterial (i.a.) infusion
      of increasing concentrations (35-100 mg kg(-1) day(-1)) of morphine over 5 days.
      I.a. injection of 0.5 mg/kg of naloxone precipitated a profound withdrawal
      response that included a dramatic increase in mean arterial pressure (MAP) which
      was maintained over the 60-min observation period, a short duration increase in
      heart rate (HR), and characteristic opiate withdrawal symptoms. In separate
      groups of rats, non-toxic doses (50 and 250 microg/kg) of the
      acetylcholinesterase (AChE) inhibitor, diisopropylflurophosphate (DFP) were
      administered as single daily injections concomitant with the morphine infusion.
      DFP treated rats, exhibited significantly reduced expression of the naloxone
      evoked pressor response. The apparent anti-withdrawal effect of DFP was not
      reproduced by the selective peripherally acting AChE inhibitor, echothiophate,
      although both compounds effectively reduced the expression of certain other
      withdrawal symptoms. The centrally acting muscarinic cholinergic receptor
      agonist, arecoline, resulted in an even more impressive suppression of withdrawal
      symptoms. While not all symptoms associated with morphine withdrawal are mediated
      via central cholinergic pathways, these results suggest that physical dependence
      on morphine can be suppressed to a significant degree by the augmentation of
      central cholinergic activity during morphine administration.

PMID- 10661499
TI  - C-fos gene expression in rat brain around birth: effect of asphyxia and
      catecholamines.
AB  - At birth, the mammalian nervous system must adapt rapidly to the new conditions
      it encounters in the extra-uterine environment. One aspect of this adaptation,
      known as arousal, is mediated by catecholamines, the levels of which in the brain
      increase rapidly after birth. The pattern of gene expression also changes.
      Shortly after birth, expression of the immediate early gene c-fos, known to
      reflect general neural activity, is up-regulated. Furthermore, asphyxia often
      occurs in connection with birth. In order to examine the effects of this
      phenomenon on the expression of c-fos, as well as on the rate of noradrenaline
      (NA) turnover, asphyxia was induced in rat pups delivered by caesarean section.
      Northern blot analysis and in situ hybridization revealed that the increase in
      expression of c-fos in certain areas of the brain was greatly enhanced by
      asphyxia of moderate duration; whereas more prolonged asphyxia lowered the level
      of c-fos mRNA. Asphyxia had a similar effect on the rate of NA turnover.
      Adrenergic receptor antagonists administered prior to birth attenuated the birth
      related induction of c-fos mRNA. However, the potentiation of c-fos expression by
      asphyxia was not altered by these antagonists. Therefore, we propose that while
      catecholamines play an important role in the induction of c-fos in the brain at
      birth, the effects of asphyxia involve a different mechanism.

PMID- 10661500
TI  - Angiotensin AT1 receptors in the preoptic area negatively modulate the
      cardiovascular and ACTH responses induced in rats by intrapreoptic injection of
      prostaglandin E2.
AB  - We previously reported that brain angiotensin II type 2 (AT2) receptors
      contribute to the hyperthermia induced by intrahypothalamic (intrapreoptic
      (i.p.o.)) administration of prostaglandin E2 (PGE2) in rats. The present study
      was carried out to investigate the role of angiotensin II (ANG II) receptors in
      the cardiovascular and adrenocorticotropic hormone (ACTH) responses induced in
      rats by i.p.o. injection of PGE2. PGE2 (100 ng) produced marked increases in
      blood pressure, heart rate, and plasma ACTH concentration. These changes were
      significantly enhanced by i.p.o. treatment with an AT1-receptor antagonist,
      losartan, while an AT2-receptor antagonist, CGP 42112A, had no effect. In
      contrast, losartan, but not CGP 42112A, reduced the pressor and ACTH responses to
      i.p.o. injection of a large dose of "exogenous" ANG II (25 ng). These results
      suggest that while "endogenous" ANG II exerts inhibitory effects on both the
      cardiovascular and the ACTH responses to i.p.o. PGE2 by way of preoptic AT1
      receptors, a large dose of exogenous ANG II produces effects opposite to those
      induced by the endogenous ANG II that is released locally and in small amounts by
      i.p.o. PGE2.

PMID- 10661501
TI  - Noradrenergic control of locomotor networks in the in vitro spinal cord of the
      neonatal rat.
AB  - In this paper, we address the role of noradrenaline (NA) in the control of
      locomotor networks in the neonatal rat. Using an in vitro isolated spinal cord
      preparation, we observed that bath application of NA elicited an extremely slow
      alternating motor pattern (period around 80-90 s) alternating between
      contralateral sides, which was recorded in the lumbar ventral roots but not
      between flexor and extensor units. These effects of NA were mimicked by the
      alpha1 agonists methoxamine and phenylephrine, whereas alpha2 and beta receptors
      bath-applied alone did not elicit any activity. NA slightly affected the
      locomotor-like activity induced by the activation of NMDA receptors, whereas the
      alpha1 agonists speeded up the locomotor activity. Both the activation of alpha2
      and beta agonist receptors slowed down the motor rhythm while simultaneously
      increasing the burst amplitude in the case of the beta agonists. NA depolarized
      the motoneurones and increased their input membrane resistance. It was concluded
      that NA does not trigger locomotor activity, but modulates the activity of the
      locomotor networks. This multimodal control is mediated by the activation of a
      variety of receptor types.

PMID- 10661502
TI  - Increased adrenocorticotropin responses to acute stress in Otsuka Long-Evans
      Tokushima Fatty (type 2 diabetic) rats.
AB  - The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is a new diabetic strain of
      rats whose disease closely resembles human type 2 diabetes. We measured plasma
      adrenocorticotropic hormone (ACTH) and corticostrone levels, and iodine-125
      labeled ovine corticotropin-releasing factor ([125I]oCRF) binding in the anterior
      pituitary after ether-laparotomy stress in OLETF rats to examine the alteration
      of the hypothalamic-pituitary-adrenal (HPA) axis. In addition, we examined ACTH
      secretion following CRF administration in vivo and in vitro to characterize the
      mechanisms regulating the HPA axis in OLETF rats. Body weight, plasma glucose and
      insulin levels in OLETF rats were significantly higher than that in Long-Evans
      Tokushima Otsuka (LETO) rats. Basal plasma ACTH levels tended to be higher in
      OLETF rats than in LETO but it did not reach statistical significance. Ether
      laparotomy stress dramatically increased plasma ACTH levels at 2 h after the
      stress both in either OLETF and LETO rats; the peak plasma ACTH level in OLETF
      rats following the stress was significantly greater than in LETO rats. Plasma
      ACTH levels following CRF (2 microg/kg, i.v.) in OLETF and LETO rats showed
      statistically significant increases at 10 and 30 min after CRF administration
      compared to ACTH levels at 0 min, however, the peak plasma ACTH level in OLETF
      rats at 10 min after CRF administration was significantly greater than in LETO
      rats. In contrast to ACTH levels, no significant differences in corticosterone
      levels between OLETF and LETO were observed at any of the time points. CRF (10
      ng/ml) significantly increased ACTH secretion in pituitary cultures from OLETF
      compared to LETO rats. These data reveal a complex regulation of the endocrine
      system in this diabetic condition and suggest that HPA axis may be more
      stimulated during acute stress in diabetes mellitus than in unaffected subjects.

PMID- 10661503
TI  - Disruption of mdr1a p-glycoprotein gene results in dysfunction of blood-inner ear
      barrier in mice.
AB  - P-glycoprotein (p-gp), a drug transporter in multidrug-resistant cancer cells, is
      a transmembrane protein encoded by mdr1a, mdr1b and mdr2 genes in mice. In our
      previous report, high level p-gp was immunohistochemically detected in capillary
      endothelial cells of the guinea pig inner ear, supporting a possible role as an
      extrusion pump in the blood-inner ear barrier (BIB). We investigated the
      functional involvement of p-gp in the inner ear using mdr1a gene knock-out mice
      [mdr1a(-/-) mice]. Pharmacokinetic analyses showed that mdr1a(-/-) mice displayed
      obviously increased accumulations of the p-gp-transported drugs doxorubicin
      (adriamycin, ADM) and vinblastine in the inner ear tissues compared with those in
      mdr1a(+/+) mice. Subsequent functional studies using auditory-evoked brainstem
      responses showed hearing impairment only in mdr1a(-/-) mice after administering
      these drugs. Furthermore, inhibition of p-gp function by co-administration of
      cyclosporin A (CsA) with doxorubicin (ADM) in mdr1a(+/+) mice resulted in
      increased accumulation of ADM in inner ear tissues and hearing impairment similar
      to that noted in mdr1a(-/-) mice. We conclude that mdr1a p-gp, which acts as an
      efflux pump in the inner ear, prevents ototoxicity induced by p-gp substrate
      drugs and contributes to a new functional mechanism in the BIB.

PMID- 10661504
TI  - BDNF regulation of androgen receptor expression in axotomized SNB motoneurons of
      adult male rats.
AB  - Brain-derived neurotrophic factor (BDNF) prevents the axotomy-induced loss of
      androgen receptor-like immunoreactivity (AR-LI) in the spinal nucleus of the
      bulbocavernosus (SNB) motoneurons of adult male rats. In this report, we
      investigated the dose-response effect of BDNF on androgen receptor expression in
      axotomized SNB motoneurons, and examined whether delayed application of BDNF to
      the cut SNB axons can completely reverse the axotomy-induced loss of androgen
      receptor expression. We also used autoradiography to test whether axotomy
      decreases the ability of SNB motoneurons to accumulate androgens. SNB motoneurons
      were axotomized bilaterally and BDNF or PBS was applied to the proximal ends of
      the axons. The percentage of SNB motoneurons expressing medium or high AR-LI was
      the major measure of androgen receptor expression. AR-LI was significantly higher
      on the BDNF-treated side than on the contralateral side treated with phosphate
      buffered saline (PBS) for all three doses of BDNF (1.45, 2.9, and 5.8 mg/ml) and
      was higher than in rats treated bilaterally with PBS. Moreover, AR-LI at the
      highest dose of BDNF was not different from that in intact SNB motoneurons.
      Delayed application of BDNF to the axotomized SNB motoneurons restored the AR-LI
      to the intact level. The AR-LI decreased by axotomy started to increase
      significantly 4 days after BDNF application and returned to the intact level by
      10 days. Furthermore, axotomy significantly decreased the percentage of SNB
      motoneurons to accumulate tritiated testosterone or its metabolites. In
      conclusion, our data demonstrate that BDNF completely prevents and reverses the
      axotomy-induced loss of AR-LI. Moreover, decrease of AR-LI by axotomy reflects
      the decrease in the ability of SNB motoneurons to accumulate androgens.

PMID- 10661505
TI  - Olivocochlear efferent vs. middle-ear contributions to the alteration of
      otoacoustic emissions by contralateral noise.
AB  - The medial olivocochlear efferent bundle is the key element of a bilateral
      efferent reflex activated by sound in either ear and acting directly on cochlear
      outer hair cells (OHC) via numerous cholinergic synapses. It probably contributes
      to regulating the mechanical activity of the cochlea. Otoacoustic emissions,
      being sounds emitted by the cochlea as a reflection of its activity and
      suppressed by efferent activation, are increasingly considered to be the
      privileged tool for a noninvasive assessment of the efferent reflex. However,
      confounding effects on otoacoustic emissions can occur. A primary influence is
      middle-ear muscle reflex activation, which shares common features with the
      effects of cochlear efferent activation. We report a systematic comparison of the
      responses of human otoacoustic emissions to efferent activation by low-level
      noise in the contralateral ear to various middle-ear manipulations (reflex
      contractions of the stapedius muscle induced by high-level contralateral noise;
      moderate middle-ear pressure changes). The profiles of level and phase changes of
      otoacoustic emissions as a function of frequency were highly specific to the
      origin of the effects. The changes induced by middle-ear manipulations matched
      the predictions computed from a standard lumped-element middle-ear model, with
      one or two peaks around the resonance frequency(ies) of the involved subsystem,
      stapes or tympanic membrane. In contrast, the efferent effect was completely
      different, exhibiting a broadband-level suppression associated with a small phase
      lead. We propose that a careful vector analysis of otoacoustic emission
      modifications enables the identification of the contribution of the efferent
      reflex without ambiguity even when it is mixed with middle-ear effects. Thereby,
      otoacoustic emissions can be used more reliably as noninvasive probes of efferent
      olivocochlear function.

PMID- 10661506
TI  - A novel phenylaminotetralin (PAT) recognizes histamine H1 receptors and
      stimulates dopamine synthesis in vivo in rat brain.
AB  - A series of novel phenylaminotetralins (PATs) previously was shown to recognize
      discrete binding sites that are stereoselectively labeled by [3H]-(-)-trans-1
      phenyl-3-N,N-dimethylamino-1,2,3,4-tetrahydronaphthalen e (H2-PAT) and highly
      localized in catecholaminergic nerve terminal regions in guinea pig forebrain.
      Furthermore, certain PATs stimulate tyrosine hydroxylase and dopamine synthesis
      in guinea pig and rat brain in vitro. In the current studies, we characterized
      sites labeled by [3H]-(-)-trans-H2-PAT and measured effects of PATs on dopamine
      synthesis in vivo in rat brain. [3H]-(-)-Trans-H2-PAT binds saturably (Bmax
      approximately 13 fmol/mg protein) and with high affinity (K(D) approximately 0.5
      nM) to a single population of sites in rat brain. The ligand binding profile of
      [3H]-(-)-trans-H2-PAT labeled sites is very similar to histamine H1 receptors
      labeled with [3H]-mepyramine. After i.c.v. injection to rats, (+/-)-trans H2-PAT
      (4-40 nmoles/kg) stimulates dopamine synthesis (to about 180% of control levels)
      selectively in the limbic brain region nucleus accumbens vs. the extrapyramidal
      region striatum; this effect is fully blocked by (+/-)-cis-H2-PAT and the H1
      antagonist triprolidine. At higher doses (> 40 nmoles/kg), the observed
      stimulation of dopamine synthesis is attenuated to control levels, likely due to
      activation of feedback mechanisms resulting from non-receptor mediated
      displacement of intraneuronal dopamine. We propose that PATs represent a novel
      class of ligands for H1 receptors that can modulate tyrosine hydroxylase activity
      and dopamine synthesis in the limbic region of mammalian forebrain.

PMID- 10661507
TI  - Spectrin (betaSpIIsigma1) is an essential component of synaptic transmission.
AB  - The cellular mechanism that underlies the regulated release of synaptic vesicles
      during neurotransmission is not fully known. Our previous data has shown that
      brain spectrin (alphaSpIIsigma1/betaSpIIsigma1)2 is localized in axons and nerve
      terminals and we have shown that the beta subunit (betaSpIIsigma1) contains a
      synapsin-binding domain capable of interacting with synapsin and small synaptic
      vesicles in vitro and in vivo. These findings suggested a role for brain beta
      spectrin in synaptic neurotransmission. To examine this possibility further,
      peptide-specific antibodies directed against epitopes within the synapsin-binding
      domain of brain beta-spectrin, or against flanking regions, were injected into
      the presynaptic neuron of synaptically paired rat hippocampal neurons in culture.
      Here, we show that the antibodies directed against the synapsin-binding domain
      specifically blocked synaptic neurotransmission.

PMID- 10661508
TI  - Azotemia (48 h) decreases the risk of brain damage in rats after correction of
      chronic hyponatremia.
AB  - Brain myelinolysis complicates excessive correction of chronic hyponatremia in
      man. Myelinolysis appear in rats for correction levels deltaSNa) > 20 mEq/l/24 h.
      We previously showed in rats that when chronic hyponatremia was corrected with
      urea, the incidence and the severity of brain lesions were significantly reduced
      compared to hypertonic saline. In man, hyponatremia is frequently associated with
      azotemia and hemo-dialysis usually corrects rapidly the serum sodium (SNa) but
      only few patients apparently develop demyelination. We hypothesize that uremic
      state protects brain against myelinolysis. This hypothesis was evaluated in rats
      developing azotemia by administration of mercuric chloride (HgCl2, 1.5 mg/kg).
      Severe (SNa < 120 mEq/l) hyponatremia (3 days) was induced by S.C. AVP and i.p.
      2.5% D-glucose for 3 days. HgCl2 was injected on day 2. Hyponatremia was
      corrected on day 4 by i.p. injections of 5% NaCl in order to obtain a correction
      level largely above the toxic threshold for brain (deltaSNA approximately 30
      mEq/l/24 h). Surviving rats were decapitated on day 10 for brain analysis. In the
      group with renal failure (Group I, n = 15, urea 59 mmol/l) the outcome was
      remarkably favourable with only three rats (3/15) dying before day 10 and only
      one of them (1/3) presenting myelinolysis-related neurologic symptoms. The 12
      other rats (80%) survived in Group I without symptoms and brain analysis was
      normal in all of them despite large correction level (deltaSNa: 32 mEq/l/24 h).
      On the contrary in nine rats in which HgCl, did not produce significant azotemia
      (control 1, n = 9, urea: 11 mmol/l), all the rats developed severe neurologic
      symptoms and eight of them died before day 10. Similar catastrophic outcome was
      observed in the non-azotemic controls (control 2, no HgCl2 administration, n =
      15, urea: 5 mmol/l). All of them developed myelinolysis-related neurologic
      symptoms and only four of them survived with severe brain lesions (survival 12/15
      in Group I vs. 5/24 in pooled controls 1 and 2, p < 0.001). In conclusion, we
      showed for the first time that chronic hyponatremic rats with azotemia (48 h)
      tolerated large increases in SNa (approximately 30 mEq/l/24 h) without
      significant brain damage.

PMID- 10661509
TI  - Pregnenolone sulfate increases hippocampal acetylcholine release and spatial
      recognition.
AB  - The pregnenolone sulfate is a neurosteroid with promnesic properties. Recently, a
      correlation between endogenous levels of pregnenolone sulfate in the hippocampus
      and performance in a spatial memory task has been reported in aged rats.
      Cholinergic transmission is known to modulate memory processes and to be altered
      with age. In the present experiment we investigated the effect of increasing
      doses of pregnenolone sulfate on hippocampal acetylcholine release. Our results
      show that intracerebroventricular administrations of this neurosteroid induced a
      dose-dependent increase in acetylcholine release. Administration of 12 and 48
      nmol of pregnenolone sulfate induced a short lasting (20 min) enhancement of
      acetylcholine output with a maximum around 120% over baseline and the
      administration of 96 and 192 nmol doses induced a long-lasting (80 min) increase
      that peaked around 300% over baseline. In a second experiment we have observed
      that the 12 nmol dose enhanced spatial memory performance, whereas the 192 nmol
      dose was inefficient. These results are consistent with previous work suggesting
      that, a modest increase in acetylcholine release facilitates memory processes,
      while elevation beyond an optimal level is ineffective. Nevertheless,
      neurosteroids may be of value for reinforcing depressed cholinergic transmission
      in certain age-related memory disorders.

PMID- 10661510
TI  - Downregulation of melanocortin receptors in brain areas involved in food intake
      and reward mechanisms in obese (OLETF) rats.
AB  - The melanocortin (MC)4 receptor is important for food intake and weight
      homeostasis as it mediates the orexigenic and anorexigenic effects of the MCs.
      OLETF (Otsuka-Long-Evans-Tokushima-Fatty) rats are a selective inbred strain of
      polygenic variant rats which overeat and develop obesity with elevated leptin
      levels. We investigated by autoradiography if the expression of MC receptors were
      altered in ovariectomized estradiol-replaced female OLETF rats compared to their
      controls (Long-Evans-Tokushima-Otsuka (LETO) rats). We found that OLETF rats show
      a reduction in total [125I]NDP-MSH MC receptor binding in the ventromedial
      hypothalamic nucleus, perhaps reflecting an increased release of MC peptides in
      this region. The levels of MC receptors in the arcuate nucleus and the
      paraventricular hypothalamic nucleus were not changed. Interestingly, the OLETF
      rats also showed reduced MC-receptor binding in areas such as the nucleus
      accumbens shell, and the ventral tegmental area, both of which are believed to be
      involved in reward systems. Similarities in the changes of MC receptor expression
      in obese animals and in animals treated with opiates may suggest a
      neurobiological link between food intake mediated through the MC receptors and
      reward.

PMID- 10661511
TI  - Histological distribution of class III alcohol dehydrogenase in human brain.
AB  - The distributions of class III alcohol dehydrogenase (ADH), a glutathione
      dependent formaldehyde dehydrogenase, and class I ADH in the human brain were
      examined immunohistochemically. The most intense immunostaining of class III ADH
      was observed in the dendrites and cytoplasm of cerebellar Purkinje cells.
      Scattered cerebral cortical neurons in layers IV and V, and some hippocampal
      pyramidal neurons were also immunopositive. The neuronal distribution of class
      III ADH resembled that of the vulnerable neurons in patients with hypoxic
      encephalopathy, which in view of the intense staining in the Purkinje cells,
      raises the possibility that this enzyme contributes to the hypoxia and cerebellar
      degeneration suffered by chronic alcoholics. Perivascular and subependymal
      astrocytes, which contribute to the maintenance of the cerebral cellular milieu
      and isolate the brain from the systemic circulation and cerebrospinal fluid, were
      also class III ADH positive. As the substrates of this enzyme include intrinsic
      toxic formaldehyde, inflammatory intermediate of 20-hydroxy-leukoteiene B4, and
      possibly ethanol, the distribution of class III ADH immunostaining indicates this
      enzyme contributes to the defence of the brain against degenerative processes.
      The finding that, unlike ependymal cells, subependymal astrocytes were class III
      ADH positive, suggests this enzyme may be useful for differentiating astrocytes
      and ependymal cells.

PMID- 10661512
TI  - Expression of gamma-glutamyl transpeptidase in mouse perivascular astrocytes and
      in a protoplasmic-like astroglial cell clone.
AB  - Gamma-glutamyl transpeptidase (GGT) is known to be present in the central nervous
      system (CNS) but its cellular localization is still subject to controversy. In
      this report, we have investigated, with a specific antiserum, the immunolabelling
      pattern of GGT in the adult mouse CNS at the light and electron microscopic (EM)
      levels. At the optical level, GGT immunoreactivity ensheathes the majority of
      vessels in the grey matter. Immunoelectron microscopy shows that labelling is
      essentially due to the presence of GGT in the astrocytic endfeet which surround
      vessels. In addition, some pericytes and periendothelial cells are also clearly
      labelled. We then investigated GGT activity in astroglial cell clones which may
      represent the in vitro counterpart of the main astroglial cell types. The
      striking result is that a protoplasmic-like astroglial cell clone shows a
      noticeable GGT activity, while, in contrast, no activity was detected in the
      fibrous and the Golgi-Bergmann-like astroglial clones. Taken together, these data
      indicate that, in the mouse CNS, GGT is essentially present in protoplasmic
      astrocytes.

PMID- 10661513
TI  - Behavioral responses to cocaine and amphetamine administration in mice lacking
      the dopamine D1 receptor.
AB  - Cocaine and amphetamine can induce both short-term and long-term behavioral
      changes in rodents. The major target for these psychostimulants is thought to be
      the brain dopamine system. To determine whether the dopamine D1 receptor plays a
      crucial role in the behavioral effects of psychostimulants, we tested both the
      locomotor and stereotyped behaviors in D1 receptor mutant and wild-type control
      mice after cocaine and amphetamine treatments. We found that the overall
      locomotor responses of D1 receptor mutant mice to repeated cocaine administration
      were significantly reduced compared to those of the wild-type mice and the
      responses of the D1 receptor mutant mice to cocaine injections were never
      significantly higher than their responses to saline injections. D1 receptor
      mutant mice were less sensitive than the wild-type mice to acute amphetamine
      stimulation over a dose range even though they exhibited apparently similar
      behavioral responses as those of the wild-type mice after repeated amphetamine
      administration at the 5 mg/kg dose. Immunostaining experiments indicated that
      there was no detectable neurotoxicity in the nucleus accumbens in both D1
      receptor mutant and wild-type mice after repeated amphetamine administration. The
      data suggest that the D1 receptor plays an essential role in mediating cocaine
      induced behavioral changes in mice. Moreover, the D1 receptor also participates
      in behavioral responses induced by amphetamine administration.

PMID- 10661514
TI  - Long-term potentiation in the insular cortex enhances conditioned taste aversion
      retention.
AB  - Long-lasting changes in synaptic strength, such as long-term potentiation (LTP),
      are thought to underlie memory formation. Recent studies on the insular cortex
      (IC), a region of the temporal cortex implicated in the acquisition and retention
      of conditioned taste aversion (CTA), have demonstrated that tetanic stimulation
      of the basolateral nucleus of the amygdala (Bla) induce LTP in the IC of adult
      rats in vivo, as well as, that blockade of N-methyl-D-aspartate (NMDA) receptors
      disrupts CTA and IC-LTP induction in vivo. Here, we present experimental data
      showing that induction of LTP in the Bla-IC projection previous to CTA training
      enhances the retention of this task. These findings are of particular interest
      since they provide support for the view that the neural mechanisms underlying
      neocortical LTP may contribute to memory related functions performed by the IC.

PMID- 10661515
TI  - Lateral tegmental field neurons with activity correlated to the 10-Hz rhythm in
      sympathetic nerve discharge.
AB  - Neurons in the lateral tegmental field (FTL) has been previously reported to have
      activity only minimally correlated (< 1% of neurons tested) with the 10-Hz rhythm
      of the slow wave of the sympathetic nerve discharge. We report here that 10% of
      the neurons recently tested in the FTL could be shown to correlate with the 10-Hz
      rhythm. The neuron-to-nerve coherence is weaker than in other medullary areas,
      but is nonetheless significant.

PMID- 10661516
TI  - Ganglion cells of the rat retina show osteopontin-like immunoreactivity.
AB  - Osteopontin (OPN) is a negatively charged, highly acidic glycosylated
      phosphoprotein that contains an GRGDS amino acid sequence, characteristic of
      proteins that bind to integrin receptors, thereby playing crucial roles in a
      number of physiological processes. This study was conducted to examine the
      expression of OPN in the rat retina by Northern blot analysis, Western blot
      analysis and immunocytochemistry. The expression of OPN was identified in the
      retina and OPN-like immunoreactivity was present in a number of ganglion cells.
      Thus, OPN appears to be important in the retinal homeostasis.

PMID- 10661517
TI  - In vivo hydroxyl radical generation in the striatum following systemic
      administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice.
AB  - We investigated the in vivo hydroxyl radical (OH) generation in the striatum of
      mice following intraperitoneal (i.p.) administration of 1-methyl-4-phenyl-1,2,3,6
      tetrahydropyridine (MPTP). This resulted in a time (1.5-6.5 h) and dose dependent
      (0-45 mg/kg) increase in the content of 2,3-dihydroxybenzoic acid (DHBA), a
      reliable indicator of OH adduct of salicylate, as measured by HPLC and
      electrochemical detector. Severe depletion of dopamine (DA: 65%), glutathione
      (50%), and increase (170%) in catalase activity were observed by 7 days. The
      present study for the first time provides direct evidence for the generation of
      OH in brain following systemic administration of MPTP and suggests involvement of
      oxidative stress in the neurotoxic action of MPTP.

PMID- 10661518
TI  - c-Fos induction in response to saccharin after taste aversion learning depends on
      conditioning method.
AB  - Increases in c-Fos-like immunoreactivity (FLI) in the intermediate nucleus of the
      solitary tract (iNTS) have been seen consistently as a correlate of the
      expression of a conditioned taste aversion (CTA) when conditioning occurs using
      taste delivery through intraoral (I/O) infusions. The present study examined
      whether a similar FLI response would occur when conditioning was accomplished by
      presenting the taste solution in a bottle. I/O and bottle methods generated
      aversions that were comparable, when judged by the behavioral response of
      solution rejection. However, elevations in FLI were seen only in animals
      conditioned with the I/O method. This finding adds to evidence that the neural
      pathways underlying CTA learning differ as a function of the type of conditioning
      method used.

PMID- 10661519
TI  - Loss of dopamine uptake sites and dopamine D2 receptors in striatonigral
      degeneration.
AB  - To explore the mechanisms underlying L-dopa response, we studied, by postmortem
      autoradiography, selective makers of dopamine presynaptic terminals, [3H]WIN
      35428, and dopamine D2 receptors, [3H]nemonapride, in the putamen of four
      Parkinson's disease (PD) and one striatonigral degeneration (SND)
      neuropathologically confirmed brains as compared with six matched control brains.
      Dopamine uptake transporter was dramatically decreased (> 90%) both in PD and SND
      striatum. Dopamine D2 receptors were preserved in PD, but clearly reduced (> 76%)
      in the SND putamen. These data confirm that L-dopa response is closely associated
      with the preservation of striatal dopamine D2 receptors.

PMID- 10661520
TI  - Arachidonic acid and prostaglandin D2 cooperatively accelerate desensitization of
      nicotinic acetylcholine receptor channel in mouse skeletal muscles.
AB  - To clarify the effects of arachidonic acid (AA) and its metabolites on
      desensitization of nicotinic acetylcholine (ACh) receptor channel in mouse
      skeletal muscle cells, we investigated the time-dependent decrease in the channel
      opening frequency of ACh (1 microM)-activated channel currents by the cell
      attached patch clamp technique. AA (30-100 microM) applied to a patched membrane
      or to non-patched membrane accelerated the decrease in the channel opening
      frequency. A cyclooxygenase inhibitor, indomethacin (10 microM), prevented the
      acceleration elicited by 30 microM AA, but not by 100 microM AA. A lipoxygenase
      inhibitor, nordihydroguaiaretic acid (10 microM), and a cytochrome P-450
      inhibitor, ketoconazole (3 microM), did not affect the acceleration by 30 microM
      AA. Prostaglandin (PG) D2 at 10 microM alone and at 25 nM in combination with 10
      microM AA accelerated the decrease in the channel opening frequency. No
      acceleration was observed with PGE2 at 10 microM alone and at 25 nM in
      combination with 10 microM AA. Pretreatment with a protein kinase (PK) C
      inhibitor, staurosporine (10 nM), but not with a PKA inhibitor, H-89 (3 microM),
      prevented the acceleration elicited by AA + PGD2. These results suggest that AA,
      and PGD2 of its metabolites, cooperatively accelerate desensitization of
      nicotinic ACh receptor channel. The activation of PKC by AA and PGD2 may be
      involved in the mechanism of the cooperative acceleration of desensitization.

PMID- 10661521
TI  - Temporal and anatomical distribution of nitric oxide synthase mRNA expression and
      nitric oxide production during central nervous system inflammation.
AB  - Nitric oxide (NO) has important roles in inflammatory processes. It was the aim
      of this study to ascertain whether changes in nitric oxide synthase (NOS) mRNA
      expression lead to similar temporal and anatomical changes in NO production in an
      experimental model of CNS inflammation. NOS-II (inducible NOS) mRNA expression
      was analyzed 2, 4, 6 and 24 h after intracerebroventricular (i.c.v.) injection of
      interleukin-1beta (IL-1beta) or vehicle. Increased expression of NOS-II mRNA was
      observed surrounding the microinjection site and meninges. The changes were
      significantly higher than controls at 4 and 6 h, returning to baseline at 24 h.
      Using the novel fluorometric NO detection system, 4,5-Diaminofluorescein
      diacetate (DAF-2/DA), for the direct detection of NO production, we observed a
      significant increase in NO production after 4 and 6 h. NO production was observed
      in areas surrounding the injection site, meninges surrounding the brain and
      perivascular cells and neuron-like cells throughout the cortex. However,
      increases in NO production in these areas remained significantly higher than
      controls at 24 h. These findings demonstrate for the first time that, in fresh
      frozen tissue, that the anatomical distribution of NOS-II mRNA is consistent with
      the distribution of NO production. We conclude that increases in NOS-II mRNA
      following i.c.v. administration of IL-1beta lead to increases in NO production.
      While the mRNA is degraded by 24 h post treatment, the enzyme remains active. We
      propose that the DAF-2/DA method can be used as a potential marker in the
      diagnosis of CNS inflammation.

PMID- 10661522
TI  - Aging in America.

PMID- 10661523
TI  - Objective assessment of limb tissue elasticity: development of a manual
      indentation procedure.
AB  - An ultrasound indentation system with a pen-size hand-held probe was developed
      and used to obtain the effective Young's moduli of forearm and lower limb soft
      tissues in 12 subjects. Since the probe is manually driven, the alignment of the
      probe and control of the rate of indentation are parameters upon which the
      results obtained depend. This paper addresses whether manual indentation tests
      with the probe are sufficiently acceptable and repeatable for objective
      biomechanical characterization of limb tissues. Forearms of three normal subjects
      were tested in two states of muscular contraction. Six different indentation
      rates, ranging from 0.75 mm/s to 7.5 mm/s, were imposed. The load-indentation
      responses obtained were shown to be well represented by quadratic functions. A
      linear elastic indentation solution was used to extract the effective Young's
      modulus. The material parameters extracted were repeatable and rather rate
      insensitive for the range of rates used. The effective Young's modulus obtained
      was found to significantly increase as a result of contraction of the underlying
      muscles. Indentor misalignment experiments demonstrated that misalignment affects
      the measurement from which the effective Young's modulus of soft tissues is
      calculated. This effect, however, was found to decrease as the tissue thickness
      increased. With the investigation of the above issues, a procedure has been
      established for the extraction of effective Young's moduli of limb soft tissues
      from manual cyclic indentation responses. Tests on experimental subjects' lower
      limbs further demonstrated that the ultrasonic indentor is a feasible instrument
      for characterization of the biomechanical properties of limb soft tissues. Paired
      t tests showed that the effective Young's moduli of the lower limb soft tissues
      of three elderly persons with transtibial amputation were significantly smaller
      than those of six unimpaired young subjects.

PMID- 10661524
TI  - Test of a vertical scan mode in 3-D imaging of residual limbs using ultrasound.
AB  - We have developed a new ultrasound system for imaging residual limbs that employs
      two scan modes: a vertical scan mode (VSM) primarily used for capturing the skin
      surface, and a horizontal compound scan mode (HCSM) primarily used for imaging
      the internal tissue structures. Since the HCSM was described previously (J
      Rehabil Res Dev 1997;34(3):269-78), the main purpose of this article is to
      elucidate the principle of reconstructing the skin surface using the new VSM and
      to report the accuracy of volumetric measurement based on this reconstruction
      method. For a residual limb with a length of up to 26 cm, the vertical scan takes
      about 80 s. The acquired skin surface has a resolution of 144 points per
      circumference in the transverse direction and a resolution of 28 points per cm in
      the longitudinal direction. The measurement accuracy of the system is tested
      using a cylindrical phantom and a custom-made limb model. The diameter of the
      phantom measured by the ultrasound method is 113.8 +/- 0.23 mm, compared with a
      value of 113 mm measured by a caliper. For the limb model, cumulative segment
      volumes measured by the ultrasound method are compared with those measured by the
      hydrostatic weighing method. The relative errors are <1%. This study demonstrates
      the feasibility of using ultrasound to perform limb measurement for prosthetic
      CAD/CAM applications.

PMID- 10661525
TI  - Comparison of upper limb muscle activity in four walking canes: a preliminary
      study.
AB  - It is hypothesized that the cane and forearm can be aligned to reduce muscular
      activity needed during ambulation. In this prospective study, 10 nonimpaired
      control subjects were tested both in stationary and dynamic weight-bearing states
      while using different cane prototypes and the platform cane (PC) as compared to
      the standard cane (SC). The outcome measures were: 1) root mean square (RMS)
      voltage (&micro;V) of electromyographic (EMG) signal as a measure of muscle power
      and 2) distance of ambulation. Results of stationary cane use showed that
      Prototype 1 decreased RMS output by 19 percent (p=0.01), Prototype 2 with wrist
      splint decreased it by 23 percent (p=0.003), and the PC decreased it by 68
      percent (p<0.0001) as compared to the SC (ANOVA, posthoc LSM). In conclusion, the
      two prototypes and the PC significantly decrease RMS voltage muscle output in the
      upper limb, compared to the SC.

PMID- 10661526
TI  - Utilization of prostheses among US veterans with traumatic amputation: a pilot
      survey.
AB  - No random surveys have been done to determine how effectively veterans with
      amputation can utilize their prostheses, and only one limited survey has been
      done of Scandinavians' use of lower-limb prostheses. A pilot survey of prosthetic
      problems was sent to all 170 US veteran soldiers who had traumatic amputations
      over the last 10 years, whose addresses could be supplied by the VA, and whose
      medical synopses showed them to be otherwise healthy when leaving the military.
      This subpopulation was selected as a "best case" group: those most likely to be
      active, young, and healthy enough to use their prostheses, as well as close
      enough to the military and veterans medical systems to get adequate treatment. If
      they have problems, the rest of the veterans with amputation, relatively older
      and more debilitated, are very likely to have far worse problems. Although only
      45 responded (26%), all had significant problems using their prostheses for work.
      Most problems were related to the attachment method. Even if all nonrespondents
      were problem free, at least a quarter had very significant problems using their
      prostheses. This means that there are significant problems with current methods
      for attaching prostheses that need to be addressed. The first step should be a
      large survey of veterans with amputation to get an accurate assessment of the
      extent of prosthesis-related problems.

PMID- 10661527
TI  - Skin perfusion responses to surface pressure-induced ischemia: implication for
      the developing pressure ulcer.
AB  - This study describes alterations in skin perfusion in response to step increases
      in surface pressure, before and after long-term (5 hr) exposure to pressure
      induced ischemia. A provocative test was developed in which surface pressure was
      increased in increments of 3.7 mmHg until perfusion reached an apparent minimum
      by a computer-controlled plunger that included a force cell, a laser Doppler
      flowmeter to determine perfusion, and a thermistor to monitor skin temperature.
      Force was applied to the greater trochanters of adult male fuzzy rats. Skin
      perfusion (n=7) initially increased with low levels of surface pressure (up to
      13.9+/-1.9 mmHg) and then decreased with further increases in pressure, reaching
      minimum (zero) perfusion at 58.2+/-3.64 mmHg. After pressure release, reactive
      hyperemia (3 x normal) was observed, with levels returning to normal within 15-30
      min. The provocative test was then applied after a 5-hr ischemic episode
      (produced by 92 mmHg) and 3 hr of recovery. A comparison of responses between
      stressed and unstressed skin revealed: elevated (63%) control perfusion levels;
      loss of the initial increase in perfusion with low levels of increasing pressure;
      a depression (45%) in the hyperemic response with delayed recovery time; and a
      decrease (54%) in amplitude of low frequency (<1 Hz) rhythms in skin perfusion.
      Skin surface temperature gradually increased both during the control period and
      the period of incremental increases in surface pressure (total DT=3.3 degrees C).
      The results suggest a compromised vasodilator mechanism(s). The provocative test
      developed in this study may have clinical potential for assessing tissue
      viability in early pressure ulcer development.

PMID- 10661528
TI  - Postural stability of wheelchair users exposed to sustained, external
      perturbations.
AB  - The postural stability of wheelchair users experiencing external perturbations
      was examined. Rotation of a tilt platform generated moments in the trunks of
      subjects seated in a manual wheelchair on the platform. The magnitude and
      duration of the moments were on the order of those that might be encountered in
      the sagittal plane during controlled braking maneuvers in a vehicle. Four
      subjects with tetraplegia, four with paraplegia, and five controls participated
      in experimental trials on the platform. As input, four different Disturbance
      profiles with either a 0.2 g (gravitational acceleration) or 0.4 g maximal level
      were imposed. The majority of the subjects with spinal cord injury lost balance
      at Disturbance levels below 0.2 g. The results suggest that the rate of change of
      the applied perturbation may also affect stability. The use of a stability index
      based on normalized motion of the center of pressure with respect to the seat
      showed efficacy in characterizing the response.

PMID- 10661529
TI  - Mechanical characteristics of human skin subjected to static versus cyclic normal
      pressures.
AB  - Several hypotheses exist for the etiology of decubitus ulcers, with external
      pressures exceeding internal capillary pressures over bony prominences claimed to
      be the major factor. This investigation evaluated the mechanical changes that
      occurred in human skin as a result of its exposure to static versus cyclic normal
      pressures of the magnitudes earlier recorded for the heels of human subjects on
      various support surfaces. The skin was characterized through uniaxial tensile
      testing. Static pressure alone altered the tissue's mechanical properties more
      than dynamic pressure cycles. Tissue subjected to pressure prior to uniaxial
      tensile testing always was less stiff than control tissue. Damage to the
      initially randomly oriented tissue collagen fiber bundles in the fibrous matrix,
      which may occur as a result of sustained compression, may be the cause of a
      decrease in stiffness of tissue subjected to prior pressure loading. This is the
      first report of compressive-pre-load-induced strain softening (Mullins effect) of
      a biological material.

PMID- 10661531
TI  - A new system for the cultivation of keratinocytes on acellular human dermis with
      the use of fibrin glue and 3T3 feeder cells.
AB  - The growth of human keratinocytes on human acellular dermis in 4 different
      culture systems was compared. Epidermis was completely separated and removed from
      dermis after skin samples had been soaked in 0.1% trypsin at 4 degrees C for 1
      week. Forty pieces of saline-washed dermis, 1 cm2 each, were randomized into 4
      groups: in group A, human keratinocytes that had undergone 2 to 3 cell passages
      were seeded (30 x 10(4) cell/cm2) onto the dermis and sprayed with a thin layer
      of fibrin glue and proliferative 3T3 feeder cells that had been growing
      separately on the culture dish; in group B, the dermis was only sprayed with
      fibrin glue; in group C, the dermis was treated with 3T3 cells only; and in group
      D, the dermis was not sprayed with anything. The dermis samples in all groups
      were raised on a grid to provide an air-liquid culture system. Histology results
      of the composite grafts at 2 weeks were assessed as having either scanty colonies
      of keratinocytes (SCK), continuous stratified epithelium (CSE), or no observable
      keratinocyte growth. Eight out of the ten dermis samples (80%) in group A
      demonstrated CSE, and 30% of the samples in group B showed SCK. There were 10%
      SCK and 20% CSE in group C, and in group D, 30% SCK and 10% CSE were found. The
      good results in group A indicated that the fibrin glue facilitated the seeding
      efficiency of the keratinocytes on the dermis and that the vital factors released
      from the 3T3 feeder cells enhanced the growth and differentiation of the
      keratinocytes. This model provides an optimal system for the cultivation of
      keratinocytes on acellular dermis.

PMID- 10661530
TI  - Research on physical activity and health among people with disabilities: a
      consensus statement.
AB  - Research is required to advance the understanding of issues related to the effect
      of physical activity on health and disease prevention among people with
      disabilities. This report is the result of a consensus process using selected
      experts in health and exercise. The purpose of the consensus conference was to
      identify research priorities for physical activity and health among people with
      disabilities. Priorities were established by 30 participants, who were selected
      by the principal investigators to achieve balance in the areas of engineering,
      epidemiology, medicine, nutrition, exercise physiology, and psychology. Experts
      summarized relevant data from their research and from comprehensive review of the
      scientific literature on the topic areas chosen for the conference. Public
      commentary was provided by participants in the 1996 Paralympic Congress. Panel
      members discussed openly all material presented to them in executive session.
      Commentary from open discussion periods were recorded and transcribed. Selected
      panelists prepared first drafts of the consensus statements for each research
      priority question. All of these drafts were distributed to the panelists and
      pertinent experts. The documents were edited by the drafting committee to obtain
      consensus. This research priority setting process revealed that greater emphasis
      must be placed on determining the risks and benefits of exercise among people
      with disabilities. Exercise must be studied from the perspective of disease
      prevention while mitigating risk for injury. Five areas were identified as focal
      points for future work: epidemiological studies; effects of nutrition on health
      and ability to exercise; cardiovascular and pulmonary health; children with
      disabilities; and accessibility and safety of exercise programs. As people with
      disabilities live longer, the need for addressing long-term health issues and
      risk for secondary disability must receive greater attention. As a consequence of
      the consensus process, specific recommendations for future research regarding the
      impact of exercise on the health and quality of life of persons with disabilities
      were defined.

PMID- 10661532
TI  - Efficacy of growth factors in the accelerated closure of interstices in explanted
      meshed human skin grafts.
AB  - Meshed split-thickness skin grafts, especially when required to be widely spread,
      do not obtain immediate biologic wound closure. In cases of patients with burns
      that cover a large percentage of the body surface area, this leaves the patient
      at risk for metabolic problems and life-threatening infection. Several cytokines
      and growth factors could theoretically affect the rate of epithelialization and,
      therefore, the rate of meshed graft interstitial closure. With the use of human
      meshed skin grafts explanted onto athymic "nude" rats, the epithelialization
      kinetics of interleukin-4 (IL-4), macrophage colony-stimulating factor (MCSF),
      keratinocyte growth factor-1 (KGF-1), keratinocyte growth factor-2 (KGF-2), basic
      fibroblast growth factor (bFGF), and transforming growth factor beta-2 (TGF(B2))
      were investigated; the results were compared with the rates of epithelialization
      of grafts treated with a vehicle control. On postoperative day 3, wounds treated
      with IL-4, KGF-2, bFGF, and TGF(B2) showed a significantly increased rate of
      interstitial closure (P < .05). On postoperative days 5 and 7, wounds treated
      with KGF-2, bFGF, and TGF(B2) all exhibited a significantly higher rate of
      interstitial closure than the grafts in the control group (P < .05). These data
      suggest that epithelialization kinetics can be accelerated with the use of
      several topical growth factors, and they provide support for a future clinical
      trial.

PMID- 10661533
TI  - Site-specific immunosuppression: mechanisms of cellular immunosuppression that
      are operative at local and systemic levels.
AB  - The cellular mechanisms by which topical cyclosporine A (tCsA) induces site
      specific immunosuppression were investigated. Experiments were designed to
      elucidate how cyclosporine A (CsA) suppresses activated immunocytes in animals
      that are undergoing local alloactivation and concomitant tCsA immune suppression.
      Lewis rats received dual Lewis x Brown Norway rat skin allografts; the rats were
      treated with systemic CsA (sCsA) at 8 mg/kg/day for 10 days after grafting and
      then tCsA and vehicle thereafter. CsA added to mixed lymphocyte reactions 24
      hours after culture initiation modeled the local effects of CsA on alloactivated
      immunocytes, and tCsA in conjunction with limited sCsA prolonged local skin
      allograft survival. CsA inhibited both antigen-specific and nonspecific activated
      alloresponses of immunocytes from animals that had received allografts and that
      underwent limited sCsA treatment only in a dose-dependent manner. When tCsA had
      been applied, immunocyte responses to a nonspecific antigen were extremely CsA
      resistant as compared with those induced by antigen-specific suppression.
      However, this nonspecific alloresponse was fully suppressible with the use of
      elevated CsA doses (66 microg/mL); thus alloresponding immunocytes were
      significantly more sensitive to CsA if they were challenged with the donor
      antigen and preexposed to limited sCsA followed by tCsA in vivo.

PMID- 10661534
TI  - In vivo visualization of cerebral microcirculation in systemic thermal injury.
AB  - We present a model used to describe the effects of systemic thermal injury in
      cerebral permeability with the use of an open, acute pial window technique.
      Sprague-Dawley rats were anesthetized, and an open pial window was constructed.
      The area was then bathed with artificial cerebrospinal fluid with a pH adjusted
      to 7.4 that was heated to a constant temperature of 37 degrees C, which was
      allowed to circulate into a reservoir at a rate of 2 cc/min. The fluid was
      infused with a gas mixture of 5% carbon dioxide and 95% nitrogen. A warming
      blanket was placed under the animal's ventral surface, and the animal's
      temperature was maintained at 37 degrees C and monitored with a rectal thermal
      probe. Experimental animals were submerged to the xiphoid process in 100 degrees
      C water bath for a total of 6 seconds, which produced a 70% total body surface
      area third degree burn. Control animals were submerged in 37 degrees C water for
      6 seconds. The animals were then injected with a constant infusion of bovine
      albumin coupled with fluorescein isothiocyanate. Recordings were taken every 15
      minutes for 6 hours. The vascular albumin leakage was determined from the ratio
      of interstitium to vascular fluorescence and expressed as a percentage. The
      percent albumin leakage in the control group was found to be significantly
      different from that in the experimental group at all periods measured. The mean
      increase in permeability ranged from 20% at 15 minutes to 104% at 6 hours. These
      changes were found to be statistically significant with the use of unpaired t
      test at a P value of .0001. The model presented is the first to demonstrate
      changes in cerebral permeability after acute severe systemic thermal injury.

PMID- 10661535
TI  - Triage of minor burn wounds: avoiding the emergency department.
AB  - Many patients with minor burn wounds will initially be evaluated in an emergency
      department (ED) and incur unnecessary costs that could be avoided through a
      direct referral to a burn center. In June 1997, use of an ED burn triage protocol
      was begun at our hospital. Adults with uncomplicated burns that covered more than
      1% and less than 15% of total body surface area (TBSA) and children with burns
      that covered more than 1% and less than 10% of TBSA were to be triaged directly
      to the outpatient clinic of the burn center without registering in the ED. From
      1996 to 1997, 653 patients were seen in the ED for burn injuries. Approximately
      500 patients fit the present criteria for direct triage to the burn center. Since
      the triage protocol began, the percentage of patients triaged to the burn center
      has increased from 27% in the first month of use (July 1997) to 73% in December
      1997. At least 33% of ED patients were eligible by protocol but not triaged. The
      average ED visit time for these patients was 103 minutes versus 44 minutes for
      patients who were sent directly to the burn clinic. An estimated $125,000 per
      year decrease in charges would occur with use of the protocol. Implementation of
      an ED triage protocol leads to avoidance of emergency room visits for the
      majority of patients with minor burn injuries, which results in more efficient,
      less expensive, faster care.

PMID- 10661536
TI  - American Burn Association/Shriners Hospitals for Children burn outcomes
      questionnaire: construction and psychometric properties.
AB  - To develop a standardized, practical, self-administered questionnaire to monitor
      pediatric patients with burns and to evaluate the effectiveness of comprehensive
      pediatric burn management treatments, a group of experts generated a set of items
      to measure relevant burn outcomes. Children between the ages of 5 and 18 years
      were assessed in a cross-sectional study. Both parent and adolescent responses
      were obtained from children 11 to 18 years old. The internal reliability of final
      scales ranged from 0.82 to 0.93 among parents and from 0.75 to 0.92 among
      adolescents. Mean differences between parent and adolescent were small; the
      greatest difference occurred in the appearance subscale. Parental scales showed
      evidence of validity and potential for sensitivity to change. In an effort to
      support the construct validity of the new scales, they were compared with the
      Child Health Questionnaire and related to each other in clinically sensible ways.
      These burn outcomes scales reliably and validly assess function in patients with
      burns, and the scales have been developed in such a way that they are likely to
      be sensitive to change over time.

PMID- 10661537
TI  - Anhydrous ammonia burns: case presentation and literature review.
AB  - Anhydrous ammonia, a caustic compound commonly used in industry, can cause severe
      burns, even with brief contact. As with other alkali burns, early irrigation to
      remove the ammonia from burned areas is crucial to limit tissue damage. Two cases
      of identical exposure to industrial strength ammonia are presented. Each patient
      was exposed to ammonia liquid and vapors simultaneously when a tank containing
      this compound exploded. One patient showered at the scene immediately after
      exposure, whereas the other deferred irrigation until he arrived at the hospital.
      The first patient suffered minor burns with a 2-day, uncomplicated hospital stay.
      The second patient suffered 14% total body surface area burns and a significant
      inhalation injury. He required intubation, mechanical ventilation, and skin
      grafting during his 13-day hospitalization. Although much is written about the
      management of chemical burns, few articles address ammonia burns. Aggressive
      initial management significantly reduces morbidity of ammonia burns.

PMID- 10661538
TI  - Physical and psychologic rehabilitation outcomes for pediatric patients who
      suffer 80% or more TBSA, 70% or more third degree burns.
AB  - Advances in medical management have dramatically decreased the mortality of
      children with massive burn injuries, which raises many questions about the
      expected quality of life for these young survivors. In this article, we address
      this issue by examining the functional and psychological adaptation of 41 young
      survivors with 88% mean total body surface area (TBSA) burns and 85% mean third
      degree TBSA burns. Patient scores were compared with normative data on
      standardized psychological measures of adjustment and on performance of age
      appropriate activities of daily living (ADL) skills. Thirty-three of the 41
      patients (80%) were independent in basic ADL skills. Eighty-six percent of the
      patients who were aged 10 years and older were independent in advanced ADL
      skills. Patients with amputated fingers were significantly more dependent in ADL
      skills than those without amputations (P < .05). Mean psychosocial adjustment
      scores were within normal limits and were not significantly related to functional
      independence in ADL skills.

PMID- 10661539
TI  - The treatment of hypopigmented lesions with cultured epithelial autograft.
AB  - Hypopigmentation may be a significant problem after burn injury. It is often
      difficult to predictably repair with conventional surgical techniques. It has
      been our experience that epidermal cells cultured from patients with dark skin
      produce pigment within the epidermal cell sheets, which indicates the presence of
      melanocytes. The presence of melanocytes and melanin in these cell sheets was
      demonstrated with the use of histochemical techniques. The results indicate that
      repigmentation with cultured epithelial autograft is possible. We describe a
      novel technique of dermabrasion and a co-culture of epidermal cells and
      melanocytes.

PMID- 10661540
TI  - Assessment with the dermal torque meter of skin pliability after treatment of
      burns with cultured skin substitutes.
AB  - The assessment of visco-elastic (V-E) properties in cutaneous scars is critical
      to reduction of impairment and restoration of function after grafting of excised
      burns. Cultured skin substitutes (CSS) that consist of autologous keratinocytes
      and fibroblasts attached to biopolymer substrates are alternatives for permanent
      closure of excised, full-thickness burns, but assessment of scarring has been
      subjective. V-E properties of CSS were measured with a Dia-Stron Dermal Torque
      Meter (DTM 310, Dia-Stron, Ltd, Broomall, Pa), which applies a constant torque
      (10 mNm) for a fixed interval (10 seconds) and measures rotational deformation
      and recovery. Parameters of skin deformation were measured in patients (n = 10)
      after grafting of CSS or meshed skin autograft. Native human skin (NHS) of
      healthy volunteers (n = 13) served as the control. Skin healed after treatment
      with CSS or autograft was evaluated for 1 year or longer after grafting. Elastic
      stretch (Ue), viscous stretch (Uv), total extensibility (Uf), elastic recovery
      (Ur), total recovery (Ua), and residual plasticity (R) were measured as degrees
      of rotation, were tested for significance (P < .05) by Student t test comparisons
      between treatment groups and controls, and were subjected to regression analysis.
      Assessment of burn scar with the Dermal Torque Meter detected time-dependent
      increases of all individual parameters of V-E properties for both CSS and
      autograft during the first year after grafting. At 1 year or later, no
      statistical differences were found between CSS and autograft for individual
      parameters, but Ue and Ur for autograft were significantly lower than for NHS. At
      1 year or longer, autograft was significantly different from CSS or NHS, with a
      greater ratio of Uv to Ue, and both graft types had a lower ratio of Ur to Uf
      than NHS had. These results suggest that instrumental measurement of scar
      pliability may increase objectivity in assessment of patient recovery and
      establish an absolute scale for quantitative analysis of V-E properties in skin
      after grafting of conventional or alternative skin substitutes.

PMID- 10661541
TI  - Macrophage mediated suppression of granulocyte and macrophage growth after burn
      wound infection reversal by means of anti-PGE2.
AB  - The production and release of granulocytes and macrophages, crucial elements of
      the host defense system, are significantly impaired after burn injury and sepsis.
      Prostaglandin E2 (PGE2) is known to be myelosuppressive. We hypothesized that the
      macrophages contributed to myelopoietic suppression by means of increased PGE2
      production, which is induced by thermal injury and sepsis. In this study,
      peritoneal macrophages were elicited at day 3 from normal mice and from mice who
      underwent a 15% total body surface area dorsal scald burn with or without
      Pseudomonas aeruginosa burn wound infection. The macrophages were incubated with
      or without endotoxin and with or without PGE2 polyclonal antiserum (anti-PGE2)
      for 18 hours. Macrophage supernatants were then used in co-cultures of bone
      marrow cells in a clonogenic assay of granulocyte-macrophage colony-forming cells
      (GM-CFCs) to determine the effect of burn wound infection on the alteration of
      the proliferative status of the GM-CFCs. Burn wound infection and endotoxin both
      caused marked reductions in GM-CFC growth in culture (20%-40% as compared with
      normal, P < .05-.01). The inhibition of GM-CFC growth induced by burn, burn plus
      infection, or endotoxin was significantly reversed by the addition of anti-PGE2
      to the cultures (30%-40% increase in GM-CFC colony growth as compared with
      cultures without anti-PGE2). These results suggest that PGE2 is a key mediator in
      the gram-negative sepsis-induced macrophage suppression of granulocyte and
      macrophage production. The ability of anti-PGE2 to neutralize PGE2 activity may
      provide a useful means of mitigating myeloid depression that follows postburn
      sepsis.

PMID- 10661542
TI  - "Supersplint": a new dynamic combination splint for the burned hand.
AB  - Dynamic splinting for the burned hand is used worldwide. We previously presented
      a home hand therapy program. This program included a series of dynamic splints
      made by the occupational therapist for daily use by the patient. The
      "supersplint" evolved from the need to reduce the time required to manufacture
      the splints for the home therapy program; it also reduced patient-therapist
      sessions in the occupational therapy unit. The supersplint provides active
      resistive movements of the fingers and thumb. As range of motion progresses,
      resistance can be increased to strengthen muscles and tendons. The supersplint
      provides tendon gliding, helps control edema, prevents muscle disuse, prevents
      skin and capsular contracture, minimizes complications, and helps prevent
      deformities. The patient uses the supersplint daily as part of an occupational
      therapy program that includes activities of daily living, prevention of shoulder
      hand syndrome, and scar therapy (including pressure garments).

PMID- 10661544
TI  - Psychiatric status, prevention, and outcome in patients with burns: a prospective
      study.
AB  - One hundred consecutive patients admitted to the Tampa Bay Regional Burn Center
      were assessed to determine cause of injury, preburn psychiatric status, and
      outcome (survival, length of stay in the hospital, and emergence of new
      psychiatric or physiologic disorders). Patients with psychiatric disorders were
      more likely to have injuries that were preventable, and there was a trend for
      this group to have more emergent psychiatric disorders and longer lengths of
      hospital stay. We suggest that the Burn Severity Index might be revised to
      include the presence of preburn psychiatric disorders and then be evaluated in a
      larger group with use of the Burn Registry.

PMID- 10661543
TI  - The epidemiology of fire-related deaths in Alabama, 1992-1997.
AB  - The state of Alabama has one of the highest fire-related fatality rates in the
      nation. The goal of this study was to present the epidemiology of fire-related
      deaths in the state of Alabama. Fatality reports for all fire-related deaths in
      the state of Alabama from 1992 to 1997 were obtained from the State Fire
      Marshall's Office. Fatality rates were calculated and compared according to age,
      sex, and race. Descriptive statistics were generated for population and fire
      characteristics. Fatality rates were higher among black people, men, children,
      and older people. Approximately half (48.8%) of the deaths occurred between the
      months of November and March; July had the lowest proportion of deaths (5.0%).
      Residential fires accounted for the largest proportion of deaths. Fatality rates
      were higher for mobile home residents. Overall, smoke detectors were present in
      only 32.5% of the residential fires. The presence of smoke detectors was more
      common with deaths in urban locations (41.8%) than with deaths in rural locations
      (20.8%). The most frequently reported cause of fatal fires was misuse of
      cigarettes. More than half of the victims aged 18 years and older tested positive
      for alcohol. Fire prevention efforts should focus on smoke detectors, fire-safe
      cigarettes, and alcohol. Mobile home residents should also be targeted for fire
      prevention initiatives.

PMID- 10661545
TI  - Structurally diverse quantitative structure--property relationship correlations
      of technologically relevant physical properties

PMID- 10661546
TI  - Fullerene data mining using bibliometrics and database tomography
AB  - Database tomography (DT) is a textual database analysis system consisting of two
      major components: (1) algorithms for extracting multiword phrase frequencies and
      phrase proximities (physical closeness of the multiword technical phrases) from
      any type of large textual database, to augment (2) interpretative capabilities of
      the expert human analyst. DT was used to derive technical intelligence from a
      fullerenes database derived from the Science Citation Index and the Engineering
      Compendex. Phrase frequency analysis by the technical domain experts provided the
      pervasive technical themes of the fullerenes database, and phrase proximity
      analysis provided the relationships among the pervasive technical themes.
      Bibliometric analysis of the fullerenes literature supplemented the DT results
      with author/journal/institution publication and citation data. Comparisons of
      fullerenes results with past analyses of similarly structured near-earth space,
      chemistry, hypersonic/supersonic flow, aircraft, and ship hydrodynamics databases
      are made. One important finding is that many of the normalized bibliometric
      distribution functions are extremely consistent across these diverse technical
      domains and could reasonably be expected to apply to broader chemical topics than
      fullerenes that span multiple structural classes. Finally, lessons learned about
      integrating the technical domain experts with the data mining tools are
      presented.

PMID- 10661547
TI  - Is the dominance of even carbon atom molecules odd?
AB  - The unexpected higher frequency of occurrence of even carbon atom molecules over
      odd carbon atom ones revealed through previous database searches is shown to be a
      consequence of the predominantly bimolecular nature of bond formation processes
      and the fact that combinations of odd and odd as well as even and even atom
      molecules result in even atom products whereas odd and even atom molecule
      combinations alone lead to odd atom products.

PMID- 10661548
TI  - Comparative evaluation of chemical and environmental online and CD-ROM databases
AB  - In a constantly expanding world of chemical and environmental information
      sources, the need for their evaluation gains more and more importance. This paper
      presents a comparative evaluation of datasources of online databases and
      databases on CD-ROM (called CD-ROMs in this paper) in the field of environmental
      chemicals. The approach is based on research results gained in the years
      1996/1997. The authors are aware that changes in the database industry may lead
      to different results. Before the actual evaluation process can be carried out,
      two major procedures are necessary, namely, the selection of sets of datasources
      and the definition of evaluation criteria. In order to perform the difficult task
      of an evaluation based on several criteria, a general order relation has to be
      introduced. Methods of partially ordered set theory are applied, and the results
      are visualized by the technique of Hasse diagrams. On the basis of these
      evaluation results, the datasources are grouped and then evaluated. It will be
      shown that there are groups of datasources with quite specific property profiles,
      and only two groups turn out to be relatively better than the others.

PMID- 10661549
TI  - Condensed representation of DNA primary sequences.
AB  - With rapid reporting of DNA sequences derived from automated DNA sequencing
      techniques, the problem of reviewing and ordering such information has become
      acute. We have introduced a condensed representation of primary sequences of DNA
      that offers an alternative method of registering DNA. The advantage of the
      condensed codes for DNA is that it not only offers fast, qualitative comparisons
      of DNA but also allows quantitative comparisons of DNA from different sources.
      The approach is outlined for a particular human beta globin sequence extract.
      Using the condensed representation of the primary DNA sequences, comparisons are
      made between primary sequences for Exon 1 of human beta globin and seven other
      beta globins.

PMID- 10661550
TI  - A comparative QSAR study using Wiener, Szeged, and molecular connectivity indices
AB  - In this study we have investigated the relative correlation potential of Wiener
      (W), Szeged (Sz), and molecular connectivity indices (0chiR, 1chiR and 2chiR) in
      developing quantitative structure-activity relationships, QSAR; log P values of
      benzoic acid and its nuclear-substituted derivatives were used for this purpose.
      The statistical analyses for univariate and multivariate correlations had
      indicated that both W and Sz are closely related to the connectivity indices
      (mchiR) and that the W, the Sz, and the 1chiR indices have similar modeling
      potentials. 1chiR gives slightly better results than both W and Sz. Other
      connectivity indices 0chiR and 2chiR correlate poorly with log P.

PMID- 10661551
TI  - Evaluation of reagent-based and product-based strategies in the design of
      combinatorial library subsets.
AB  - With the current and ever-growing offering of reagents along with the vast
      palette of organic reactions, virtual libraries accessible to combinatorial
      chemists have dramatically increased in size. Yet, extracting representative
      subsets for experimentation is an essential step in the design of combinatorial
      libraries. There has been some controversy whether it is necessary to consider
      product properties, at some computational expense, or whether sufficiently
      representative sets can be identified from considerations of the reagent space
      alone. This study compares the efficiency of reagent-based selections and that of
      product-based combinatorial subsetting in the identification of representative
      library subsets. Quantitative estimates reported herein show that the advantage
      of working in product space is descriptor dependent. For some descriptors,
      product-based approaches provide a distinct advantage, whereas for others results
      from reactant pools offer comparable results. Hence the behavior of descriptors,
      in mapping diversity from reagent space to product space, should be investigated
      prior to embarking into lengthy product-based considerations. Several classes of
      descriptors are studied including two-dimensional fingerprints (ISIS and
      Daylight) and physicochemical descriptors.

PMID- 10661552
TI  - Estimation of molecular linear free energy relationship descriptors by a group
      contribution approach. 2. Prediction of partition coefficients
AB  - A previously published method for the prediction of molecular linear free energy
      relationship descriptors is tested against experimentally determined partition
      coefficients in various solvent systems. Sets of partition data between water and
      octanol, cyclohexane, and chloroform were taken from the literature. For each set
      of partition data used, r2 values ranged from 0.8 to 0.9 and RMS errors from 0.7
      to 1.0 log unit, comparable to errors obtained with previously published models
      for octanol-water partition. Modified solvation equations for water-octanol and
      water-cyclohexane partition are presented, and their implications discussed. The
      possibility of applying the current approach to a wide range of solvation and
      transport properties is put forward.

PMID- 10661553
TI  - Development of a quantitative structure--property relationship model for
      estimating normal boiling points of small multifunctional organic molecules.
AB  - Computer-assisted quantitative structure-property relationship techniques are
      applied in the development of a robust and accurate model of normal boiling
      points (boiling at 760 mmHg) for a very diverse set of 268 small organic
      molecules. Most of the molecules included in this study contain two or more
      functional groups. The final model yields a tight fit to the training set data
      (R2 = 0.963), with a fit error of 6.5%. More importantly, the model is also shown
      to perform well in external prediction. The mean prediction error for boiling
      points for a 78-member external test set was 12.3 degrees C, or 8.3%. A detailed
      analysis of the small number of compounds that were either outliers or not well
      predicted illustrates areas for potential improvement of the methodology used.

PMID- 10661554
TI  - Use of weighted least-squares splines for calibration in analytical chemistry
AB  - Weighted least-squares spline functions are discussed and applied for calibration
      processes in analytical chemistry. Different weighting techniques are also
      considered, and for the evaluation of the results some quality coefficients are
      proposed. Depending upon the structure of the data, some weighting procedures may
      improve the results dramatically. Considering the results obtained in the case of
      TLC densitometry, it seems that nonlinear weighting procedures based upon the
      distance to the function are the best ones, with a plus for the y-distance type.
      It is difficult to give general rules regarding the optimal parameters of the
      weighted calibration splines-function order (m), number (N) and distribution of
      knots, and weighting technique. These depend upon the structure of the data.
      However, higher order splines are not recommended since the result might become
      extremely unstable. The example used to illustrate the performances of the
      procedures discussed here involved only a single independent variable. The method
      is general and extends practically to any number of variables, thus resulting in
      a multivariate approach.

PMID- 10661555
TI  - Walk counts, labyrinthicity, and complexity of acyclic and cyclic graphs and
      molecules
AB  - It is demonstrated how the complexity of a (molecular) graph can be quantified in
      terms of the walk counts, extremely easily obtained graph invariants that depend
      on size, branching, cyclicity, and edge and vertex weights (unsaturation,
      heteroatoms). The influence of symmetry is easily accounted for. The term
      labyrinthicity is proposed for what is measured by walk counts alone, neglecting
      symmetry. The total walk count and recently advanced measures of labyrinthicity
      or complexity are compared with respect to the ordering of structures and to the
      computational effort required to obtain numerical values.

PMID- 10661556
TI  - Topological organic chemistry. 12. Whole-molecule Schultz topological indices of
      alkanes.
AB  - A whole-molecule modified Schultz index was devised from the application of
      linear filtration to the constant interval reciprocal distance matrix. The
      resultant descriptors of alkanes were unique within the environment of the 39 C2
      C8 alkane studies. The utility of the descriptors was briefly examined with
      quantitative structural-physical relationship studies.

PMID- 10661557
TI  - The multiplicative version of the Wiener index
AB  - The classical Wiener index, W(G), is equal to the sum of the distances between
      all pairs of vertexes of a (molecular) graph, G. We now consider a related
      topological index, pi(G), equal to the product of distances between all pairs of
      vertexes of G. The basic properties of the pi index are established and its
      possible physicochemical applications examined. In the case of alkanes, pi and W
      are highly correlated; a slightly curvilinear correlation exists between In pi
      and W.

PMID- 10661558
TI  - Pharmacophore fingerprinting. 2. Application to primary library design.
AB  - A methodology for pharmacophore fingerprinting (PharmPrint), previously described
      in the context of QSAR, has been used to address the issues involved in primary
      library design. A subset of the MDDR (MDDR9104) has been used to define a
      reference set of bioactive molecules. A statistic has been devised to measure the
      discriminating power of molecular descriptors using the target class assignments
      for this set, for which the PharmPrint fingerprint outperformed other
      descriptors. A principal components analysis (PCA) of the fingerprints for the
      MDDR9104 produces a low dimensional representation within which molecular
      properties and other libraries can be visualized and explored. PCA calculations
      on subsets of classes show that this space is robust to the addition of new
      classes, suggesting that pharmacophoric space is finite and rapidly converging.
      We demonstrate the application of the PharmPrint methodology to the analysis and
      design of virtual combinatorial libraries using common scaffolds and building
      blocks.

PMID- 10661559
TI  - Quasi-orthogonal basis sets of molecular graph descriptors as a chemical
      diversity measure
AB  - In the pharmaceutical industry, the virtual screening of combinatorial libraries
      is used to rationally select compounds for biological testing from databases of
      hundreds of thousands of compounds. In addition to structural descriptors, such
      as fingerprints and pharmacophores, the application of relatively simple
      structural descriptors traditionally used in quantitative structure-activity
      studies offers speed and efficiency for rapidly measuring the molecular diversity
      of such collections. We explore new topological indices computed from the
      molecular graph as potential structural descriptors for the characterization of
      molecular diversity. A database of 2000 compounds randomly selected from the
      National Cancer Institute AIDS database was used to measure the intercorrelation
      of the descriptors. The initial collection of 240 structural descriptors was
      reduced to several quasi-orthogonal sets of up to 9 descriptors, using different
      thresholds for the maximum intercorrelation coefficient.

PMID- 10661560
TI  - Systematic enumeration of nonrigid isomers with given ligand symmetries
AB  - A new method for enumerating nonrigid isomers with rotatable ligands has been
      developed so as to take the symmetries of the ligands into consideration. The
      method has been based on extended partial cycle indices and has been applied to
      the enumeration of methyl ether derivatives, tetramethylallene derivatives, and
      2,2-dimethylpropane derivatives. These results have been compared with the
      enumeration results of the corresponding promolecules. The factorization of terms
      in generating functions has been discussed so that the new method is capable of
      examining the relationship between promolecules and molecules quantitatively.

PMID- 10661561
TI  - Use of artificial neural networks in a QSAR study of anti-HIV activity for a
      large group of HEPT derivatives.
AB  - Anti-HIV activity for a set of 107 inhibitors of the HIV-1 reverse transcriptase,
      derivatives of 1-[2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT), was
      modeled with the aid of chemometric techniques. The activity of these compounds
      was estimated by means of multiple linear regression (MLR) and artificial neural
      network (ANN) techniques and compared with the previous works. The results
      obtained using the MLR method indicate that the anti-HIV activity of the HEPT
      derivatives depends on the reverse of standard shadow area on the YZ plane and
      the ratio of the partial charges of the most positive atom to the most negative
      atom of the molecule. The best computational neural network model was a fully
      connected, feed-forward method with a 6-6-1 architecture. The mean-square error
      for the prediction set using this network was 0.372 compared with 0.780 obtained
      using the MLR technique. Comparison of the quality of the ANN of this work with
      different MLR models shows that ANN has a better predictive power.

PMID- 10661562
TI  - Comparison of 2D fingerprint types and hierarchy level selection methods for
      structural grouping using Ward's clustering
AB  - Four different two-dimensional fingerprint types (MACCS, Unity, BCI, and
      Daylight) and nine methods of selecting optimal cluster levels from the output of
      a hierarchical clustering algorithm were evaluated for their ability to select
      clusters that represent chemical series present in some typical examples of
      chemical compound data sets. The methods were evaluated using a Ward's clustering
      algorithm on subsets of the publicly available National Cancer Institute HIV data
      set, as well as with compounds from our corporate data set. We make a number of
      observations and recommendations about the choice of fingerprint type and cluster
      level selection methods for use in this type of clustering

PMID- 10661563
TI  - Combinatorial preferences affect molecular similarity/diversity calculations
      using binary fingerprints and Tanimoto coefficients
AB  - A combinatorial method was developed to calculate complete distributions of the
      Tanimoto coefficient (Tc) for binary fingerprint (FP) representations of
      specified length, regardless of the chemical parameters they reflect. Theoretical
      Tc distributions were calculated for FPs consisting of up to 67 bit positions
      which revealed significant statistical preferences of certain Tc values.
      Calculation of Tc distributions in a large compound database using different FPs
      mirrored the effects identified by our general analysis. On the basis of these
      findings, an average Tc is biased by statistically preferred values.

PMID- 10661564
TI  - An efficient projection protocol for chemical databases: singular value
      decomposition combined with truncated-newton minimization.
AB  - A rapid algorithm for visualizing large chemical databases in a low-dimensional
      space (2D or 3D) is presented as a first step in database analysis and design
      applications. The projection mapping of the compound database (described as
      vectors in the high-dimensional space of chemical descriptors) is based on the
      singular value decomposition (SVD) combined with a minimization procedure
      implemented with the efficient truncated-Newton program package (TNPACK).
      Numerical experiments on four chemical datasets with real-valued descriptors
      (ranging from 58 to 27 255 compounds) show that the SVD/TNPACK projection duo
      achieves a reasonable accuracy in 2D, varying from 30% to about 100% of pairwise
      distance segments that lie within 10% of the original distances. The lowest
      percentages, corresponding to scaled datasets, can be made close to 100% with
      projections onto a 10-dimensional space. We also show that the SVD/TNPACK duo is
      efficient for minimizing the distance error objective function (especially for
      scaled datasets), and that TNPACK is much more efficient than a current popular
      approach of steepest descent minimization in this application context.
      Applications of our projection technique to similarity and diversity sampling in
      drug design can be envisioned.

PMID- 10661565
TI  - Discrimination and molecular design of new theoretical hypolipaemic agents using
      the molecular connectivity functions
AB  - The molecular topology model and discriminant analysis have been applied to the
      prediction and QSAR interpretation of some pharmacological properties of
      hypolipaemic drugs using multivariable regression equations with their
      statistical parameters. Regression analysis showed that the molecular topology
      model predicts these properties. The corresponding stability (cross-validation)
      studies done on the selected prediction models confirmed the goodness of the
      fits. The method used for hypolipaemic activity selection was a linear
      discriminant analysis (LDA). We make use of the pharmacological distribution
      diagrams (PDDs) as a visualizing technique for the identification and design of
      new hypolipaemic agents.

PMID- 10661566
TI  - Novel variable selection quantitative structure--property relationship approach
      based on the k-nearest-neighbor principle
AB  - A novel automated variable selection quantitative structure-activity relationship
      (QSAR) method, based on the kappa-nearest neighbor principle (kNN-QSAR) has been
      developed. The kNN-QSAR method explores formally the active analogue approach,
      which implies that similar compounds display similar profiles of pharmacological
      activities. The activity of each compound is predicted as the average activity of
      K most chemically similar compounds from the data set. The robustness of a QSAR
      model is characterized by the value of cross-validated R2 (q2) using the leave
      one-out cross-validation method. The chemical structures are characterized by
      multiple topological descriptors such as molecular connectivity indices or atom
      pairs. The chemical similarity is evaluated by Euclidean distances between
      compounds in multidimensional descriptor space, and the optimal subset of
      descriptors is selected using simulated annealing as a stochastic optimization
      algorithm. The application of the kNN-QSAR method to 58 estrogen receptor ligands
      as well as to several other groups of pharmacologically active compounds yielded
      QSAR models with q2 values of 0.6 or higher. Due to its relative simplicity, high
      degree of automation, nonlinear nature, and computational efficiency, this method
      could be applied routinely to a large variety of experimental data sets.

PMID- 10661567
TI  - Isolation of primary and immortalized CD34-hematopoietic and mesenchymal stem
      cells from various sources.
AB  - Based on historical radiation experiments in rodents, the hematopoietic stem cell
      was defined by its biological properties and later by the expression of certain
      surface antigens (e.g., CD34), as well as the absence of lineage-specific markers
      (e.g., DR). Quite recently it was shown that hematopoietic reconstitution can
      also be achieved by CD34- stem cells, which can be isolated from the bone marrow,
      peripheral blood and cord blood cells. CD34-stem cells are considered to be
      predominately part of the quiescent stem cell pool of hematopoietic and
      mesenchymal stem cells. Due to novel techniques, CD34-stem cells can be expanded
      on the level of a true stem cell but also directed towards their differentiation
      into specified tissues or organ systems. This requires the establishment of
      primary fibroblast-like CD34- stem cells in vitro and their possible reversible
      and transient immortalization with optimized vector systems.

PMID- 10661568
TI  - T-cell immunodeficiency following cytotoxic antineoplastic therapy: a review.
AB  - Although cancer itself is immunosuppressive, cytotoxic antineoplastic therapy is
      the primary contributor to the clinical immunodeficiency observed in cancer
      patients. The immunodeficiency induced by cytotoxic antineoplastic therapy is
      primarily related to T-cell depletion, with CD4 depletion generally more severe
      than CD8 depletion. Myeloablative therapy, dose-intensive alkylating agents,
      purine nucleoside analogs, and corticosteroids substantially increase the risk of
      therapy-induced immunosuppression. Restoration of T-cell populations following
      cytotoxic antineoplastic therapy is a complex process. Efficient recovery of CD4+
      T cell populations requires thymic-dependent pathways which undergo an age
      dependent decline resulting in prolonged CD4+ T-cell depletion in adults
      following T-cell-depleting therapy. Total CD8+ T-cell numbers recover in both
      children and adults relatively quickly post-therapy; however, CD8+ subset
      disruptions often remain for a prolonged period. The clinical management of
      patients with therapy-induced T-cell depletion involves the maintenance of a high
      index of suspicion for opportunistic pathogens, irradiation of blood products,
      prophylaxis for viral infections, and reimmunization in selected clinical
      circumstances. Future research avenues include efforts to rapidly rebuild
      immunity following cytotoxic antineoplastic therapy so that immune-based
      therapies may be utilized immediately following cytotoxic therapy to target
      minimal residual neoplastic disease.

PMID- 10661569
TI  - Latest developments in gene transfer technology: achievements, perspectives, and
      controversies over therapeutic applications.
AB  - Over the last decade, more than 300 phase I and phase II gene-based clinical
      trials have been conducted worldwide for the treatment of cancer and monogenic
      disorders. Lately, these trials have been extended to the treatment of AIDS and,
      to a lesser extent, cardiovascular diseases. There are 27 currently active gene
      therapy protocols for the treatment of HIV-1 infection in the USA. Preclinical
      studies are currently in progress to evaluate the possibility of increasing the
      number of gene therapy clinical trials for cardiopathies, and of beginning new
      gene therapy programs for neurologic illnesses, autoimmuno diseases, allergies,
      regeneration of tissues, and to implement procedures of allogeneic tissues or
      cell transplantation. In addition, gene transfer technology has allowed for the
      development of innovative vaccine design, known as genetic immunization. This
      technique has already been applied in the AIDS vaccine programs in the USA. These
      programs aim to confer protective immunity against HIV-1 transmission to
      individuals who are at risk of infection. Research programs have also been
      considered to develop therapeutic vaccines for patients with AIDS and generate
      either preventive or therapeutic vaccines against malaria, tuberculosis,
      hepatitis A, B and C viruses, influenza virus, La Crosse virus, and Ebola virus.
      The potential therapeutic applications of gene transfer technology are enormous.
      However, the effectiveness of gene therapy programs is still questioned.
      Furthermore, there is growing concern over the matter of safety of gene delivery
      and controversy has arisen over the proposal to begin in utero gene therapy
      clinical trials for the treatment of inherited genetic disorders. From this
      standpoint, despite the latest significant achievements reported in vector
      design, it is not possible to predict to what extent gene therapeutic
      interventions will be effective in patients, and in what time frame.

PMID- 10661570
TI  - Extended activity in cynomolgus monkeys of a granulocyte colony-stimulating
      factor mutein conjugated with high molecular weight polyethylene glycol.
AB  - The activity of a granulocyte colony-stimulating factor (G-CSF) mutein
      (nartograstim; [NTG]) conjugated with an average of two polyethylene glycol (PEG)
      chains per protein molecule was examined in cynomolgus monkeys following a single
      s.c. injection. Groups of monkeys were given 10 microg/kg, 30 microg/kg, or 100
      microg/kg. For comparison, one group of monkeys was given 5 microg/kg of
      recombinant human G-CSF (rHuG-CSF) daily for six days. In monkeys given 100
      microg/kg of PEG-NTG, neutrophil levels reached a peak one day after injection
      approximately 20-fold higher than baseline levels. Neutrophil numbers in these
      animals were still significantly elevated six days after injection. In contrast,
      peak neutrophil levels in monkeys given six injections of rHuG-CSF reached a peak
      only on day 6 and were approximately the same as that in monkeys given a single
      dose of PEG-NTG six days before. Pharmacokinetics of PEG-NTG in these monkeys
      indicated that the area under the plasma concentration time curve (AUC) increased
      with increasing the dose from 497 ng x h/ml at 10 microg/kg, 6,140 ng x h/ml at
      30 microg/kg to 27,900 ng x h/ml at 100 microg/kg. In a separate study, the
      effects of single doses of 100 microg/kg of PEG-NTG, rHuG-CSF, and unmodified NTG
      were compared. In this experiment, peak numbers of neutrophils were reached two
      days after injection in animals receiving PEG-NTG and one day after in animals
      given unmodified proteins. The pharmacokinetic parameters demonstrated increased
      exposure for PEG-NTG relative to the unmodified proteins with an AUC0. of 21,012
      ng x h/ml compared with 5,492 ng x h/ml for rHuG-CSF and 5,153 ng x h/ml for NTG.
      These results demonstrate that conjugation of a G-CSF mutein with high molecular
      weight PEG results in a preparation that can induce prolonged elevation of
      neutrophils in normal nonhuman primates following a single injection.

PMID- 10661571
TI  - Characterization of the adherent cells developed in Dexter-type long-term
      cultures from human umbilical cord blood.
AB  - We have previously shown that when human umbilical cord blood (UCB) cells are
      cultured in standard Dexter-type long-term cultures (D-LTC), adherent cells
      develop forming a discrete net on the bottom of the culture flask. The identity
      of such cells, however, has not been defined. Accordingly, the major goal of the
      present study was to characterize the adherent cells developed in standard UCB D
      LTC. Cultures were established from 14 UCB samples and from nine bone marrow (BM)
      samples, as controls. Both UCB and BM cultures were initiated with the same
      number of mononuclear cells (MNC) (2.5 x 10(6) MNC/ml). After three weeks in
      culture, adherent cell numbers in UCB D-LTC were 24%-30% of the numbers found in
      BM cultures. More than 90% of the adherent cells in UCB D-LTC expressed the acid
      phosphatase enzyme, whereas no alkaline phosphatase-positive cells were observed.
      This was in contrast to BM D-LTC, in which alkaline and acid phosphatase were
      expressed by 60%-75% and 20%-45% of the adherent cells, respectively.
      Immunochemical analysis showed that CD61 (osteoclast marker) and Factor VIII
      (endothelial cell marker) were not expressed by the adherent cells developed in
      UCB cultures. Interestingly, the majority of such cells expressed CD1a (dendritic
      cell marker), CD14, CD68 and CD115 (antigens mainly expressed by macrophagic
      cells). When the cultures were supplemented with the recombinant cytokines
      epidermal growth factor, basic fibroblast growth factor, platelet-derived growth
      factor or granulocyte-macrophage colony-stimulating factor (GM-CSF), only GM-CSF
      had a significant positive effect on adherent cell number. In order to test for
      some functional properties of the adherent cells developed in culture, production
      of stem cell factor (SCF), interleukin 6 (IL-6) and tumor necrosis factor-alpha
      (TNF-alpha) was assessed. IL-6 and TNF-alpha showed elevated levels in UCB D-LTC,
      whereas SCF levels were always below detection. Finally, analysis of fibroblast
      progenitors (fibroblast colony-forming units [CFU-F]) showed that these cells
      were present in BM samples (6 CFU-F/10(5) MNC) and were totally absent in UCB
      samples. Taken together, the results of the present study indicate that the vast
      majority of the adherent cells developed in standard UCB D-LTC belong to the
      macrophage lineage and that fibroblasts seem to be absent. Interestingly, the
      high proportion of CD1a+ cells suggests that dendritic cells are also present in
      these cultures.

PMID- 10661572
TI  - Development of mouse dendritic cells from lineage-negative c-kit(low) pluripotent
      hemopoietic stem cells in vitro.
AB  - Dendritic cells (DCs) are essential for the presentation of antigens in the
      primary immune response. To examine the generation of DCs from hemopoietic stem
      cells in the bone marrow (BM), lineage-negative (Lin-)/CD71- bone marrow cells
      (BMCs) from C57BL/6 mice were separated into major histocompatibility complex
      (MHC) class Ihigh/ c-kit(low) and MHC class Ihigh/c-kit(low)(phenotypically c-kit
      negative, but c-kit message only detected by reverse transcriptase-polymerase
      chain reaction) populations. A large number of cells with the morphological,
      phenotypical, and functional characteristics of DCs was generated from both c
      kit(low) and c-kit(low) populations when cultured with a combination of cytokines
      (GM-CSF, tumor necrosis factor-a [TNF-a], interleukin 7 [IL-7], IL-3, stem cell
      factor [SCF], and flt3 ligand); the cytokine combination studies revealed that
      SCF and IL-3 in addition to GM-CSF and TNF-a are essential for DCs to be
      generated from these primitive populations. To our surprise most (>80%) generated
      cells expressed high levels of DC surface markers such as DEC205 and MHC class
      II, and they were potent stimulators in the primary allogeneic T cell activation.
      The development of DCs from c-kit(<low) cells was slower than that from c
      kit(low) cells. These results indicate that c-kit(<low) cells are more primitive
      than c-kit(low) cells, although both c-kit*(low) cells and c-kit(<low) cells can
      differentiate into DCs. It should be noted that the combination of these
      cytokines selectively induces DCs from both c-kit(<low) and c-kit(low) cells in
      vitro, suggesting that the ex vivo expansion of DCs using these primitive cells
      would be applicable to immunotherapy.

PMID- 10661573
TI  - The interleukin 13 receptor complex.

PMID- 10661574
TI  - Eph receptors and ephrins.

PMID- 10661575
TI  - The role of MCP-1 in atherosclerosis.

PMID- 10661576
TI  - Chemokines induce moesin interaction with ICAM-3.

PMID- 10661577
TI  - Viral cytokines.

PMID- 10661578
TI  - The molecular perspective: matrix metalloproteinase 2.

PMID- 10661579
TI  - Electron contamination from the lead cutout used in kilovoltage radiotherapy.
AB  - In kilovoltage radiotherapy, low-energy electrons are generated on the lead
      cutout plate frequently used to shape the x-ray field. They can cause surface
      dose enhancement and affect the percentage depth dose (PDD) and cutout factor
      when these parameters are measured with a parallel plate chamber. Although many
      previous studies concerning a similar surface dose enhancement have suggested
      using a thin electron filter to eliminate the effect of these low-energy
      electrons, no details have been given regarding the adequacy of the filter. This
      paper describes the procedures required to test an electron filter for our Darpec
      2000 superficial x-ray machine. A piece of plain paper was found to be an
      adequate electron filter, which could block all the low-energy electrons without
      affecting the PDD and cutout factor measurement. The surface dose enhancement
      caused by the presence of the cutout plate was studied with such a filter. The
      enhancement was found to increase with x-ray energy and decrease with cutout size
      as well as applicator size. At the highest x-ray energy in this study (120 kV,
      HVL 8.6 mmAl), the enhancement ranges from less than 1% for a 8 cm diameter
      cutout to a maximum of 14% for a 2 cm diameter cutout with a 10 cm applicator.
      For a 5 cm diameter applicator it ranges from about 1% to about 11%. The
      difference between the measured and predicted cutout factor displays similar
      characteristics. Since the low-energy electrons do not generate any useful
      treatment dose but their presence can lead to potential dosimetry problems, we
      suggest that a filter tested with the procedure described in this paper should be
      used when percentage depth dose and cutout factor for kilovoltage x-ray are
      measured with a parallel-plate chamber.

PMID- 10661580
TI  - Implementation of pencil kernel and depth penetration algorithms for treatment
      planning of proton beams.
AB  - The implementation of two algorithms for calculating dose distributions for
      radiation therapy treatment planning of intermediate energy proton beams is
      described. A pencil kernel algorithm and a depth penetration algorithm have been
      incorporated into a commercial three dimensional treatment planning system (Helax
      TMS, Helax AB, Sweden) to allow conformal planning techniques using irregularly
      shaped fields, proton range modulation, range modification and dose calculation
      for non-coplanar beams. The pencil kernel algorithm is developed from the Fermi
      Eyges formalism and Moliere multiple-scattering theory with range straggling
      corrections applied. The depth penetration algorithm is based on the energy loss
      in the continuous slowing down approximation with simple correction factors
      applied to the beam penumbra region and has been implemented for fast,
      interactive treatment planning. Modelling of the effects of air gaps and range
      modifying device thickness and position are implicit to both algorithms. Measured
      and calculated dose values are compared for a therapeutic proton beam in both
      homogeneous and heterogeneous phantoms of varying complexity. Both algorithms
      model the beam penumbra as a function of depth in a homogeneous phantom with
      acceptable accuracy. Results show that the pencil kernel algorithm is required
      for modelling the dose perturbation effects from scattering in heterogeneous
      media.

PMID- 10661581
TI  - Experimental partial and total kerma coefficients for aluminium at incident
      neutron energies from reaction thresholds to 65 MeV.
AB  - For nine incident neutron energies in the range 25 to 65 MeV, the double
      differential cross sections (energy spectra) for the (n, px), (n, dx), (n, tx)
      and (n, alpha x) reactions on aluminium have been measured at lab angles between
      20 degrees and 160 degrees in steps of 10 degrees. The partial and total kerma
      coefficients have been determined from the experimental energy-differential cross
      sections. The resulting partial kerma coefficients for the incident neutron
      energy range of 25-65 MeV are extrapolated to the threshold energy of each
      registered reaction product type. Only illustrative results of the experimental
      double-differential, energy-differential and total cross sections are presented.
      The deduced partial and total kerma coefficients of the present work are compared
      with results of previous integral measurements and theoretical predictions.

PMID- 10661582
TI  - On the optimal energy of epithermal neutron beams for BNCT.
AB  - The optimal neutron energy for the treatment of deep-seated tumours using boron
      neutron capture therapy is studied by analysing various figures of merit. In
      particular, analysis of the therapeutic gain as a function of the neutron energy
      indicates that, with the currently available 10B carriers, the most useful
      neutrons for the treatment of deep-seated tumours, in particular glioblastoma
      multiforme, are those with an energy of a few keV. Based on the results of the
      simulations, a method is presented which allows us to evaluate the quality of
      epithermal neutron beams of known energy spectrum, thus allowing us to compare
      different neutron-producing reactions and beam-shaping assembly configurations
      used for accelerator-based neutron sources.

PMID- 10661583
TI  - Study of moderator thickness for an accelerator-based neutron irradiation
      facility for boron neutron capture therapy using the 7Li(p,n) reaction near
      threshold.
AB  - Accelerator neutron sources for epithermal neutron capture therapy utilizing the
      7Li(p,n) nuclear reaction will require a moderator even in the threshold range of
      1.89 to 1.95 MeV. The corresponding neutron energies allow for a thinner
      reflector and moderator, with less reduction of the epithermal flux. To estimate
      the useful neutron flux within the epithermal range (4 eV-40 keV), the optimal
      thickness of a heavy water moderator was determined using the two-dimensional
      neutron transport S(N) code DORT. Optimized results are compared with the
      epithermal fluxes reported for the higher proton energy range, and are found to
      be inferior. Thus, this study supports the 2.5-3.0 MeV proton energy range for
      accelerator boron neutron capture therapy.

PMID- 10661584
TI  - Iterative approaches to dose optimization in tomotherapy.
AB  - This paper will present the results of an investigation into three iterative
      approaches to inverse treatment planning. These techniques have been examined in
      the hope of developing an optimization algorithm suitable for the large-scale
      problems that are encountered in tomotherapy. The three iterative techniques are
      referred to as the ratio method, iterative least-squares minimization and the
      maximum-likelihood estimator. Our results indicate that each of these techniques
      can serve as a useful tool in tomotherapy optimization. As compared with other
      mathematical programming techniques, the iterative approaches can reduce both
      memory demands and time requirements. In this paper, the results from small- and
      large-scale optimizations will be analysed. It will also be demonstrated that the
      flexibility of the iterative techniques can be greatly enhanced through the use
      of dose-volume histogram based penalty functions and/or through the use of
      weighting factors assigned to each region of the patient. Finally, results will
      be presented from an investigation into the stability of the iterative
      techniques.

PMID- 10661585
TI  - Variance in parametric images: direct estimation from parametric projections.
AB  - Recent work has shown that it is possible to apply linear kinetic models to
      dynamic projection data in PET in order to calculate parameter projections. These
      can subsequently be back-projected to form parametric images--maps of parameters
      of physiological interest. Critical to the application of these maps, to test for
      significant changes between normal and pathophysiology, is an assessment of the
      statistical uncertainty. In this context, parametric images also include simple
      integral images from, e.g., [O-15]-water used to calculate statistical parametric
      maps (SPMs). This paper revisits the concept of parameter projections and
      presents a more general formulation of the parameter projection derivation as
      well as a method to estimate parameter variance in projection space, showing
      which analysis methods (models) can be used. Using simulated pharmacokinetic
      image data we show that a method based on an analysis in projection space
      inherently calculates the mathematically rigorous pixel variance. This results in
      an estimation which is as accurate as either estimating variance in image space
      during model fitting, or estimation by comparison across sets of parametric
      images--as might be done between individuals in a group pharmacokinetic PET
      study. The method based on projections has, however, a higher computational
      efficiency, and is also shown to be more precise, as reflected in smooth variance
      distribution images when compared to the other methods.

PMID- 10661586
TI  - Oxygen consumption through metabolism and photodynamic reactions in cells
      cultured on microbeads.
AB  - Oxygen consumption by cultured cells, through metabolism and photosensitization
      reactions, has been calculated theoretically. From this result, we have derived
      the partial oxygen pressure PO2 in the perfusion medium flowing across sensitized
      cultured cells during photodynamic experiments. The PO2 variations in the
      perfusate during light irradiation are related to the rate of oxygen consumption
      through photoreactions, and to the number of cells killed per mole of oxygen
      consumed through metabolic processes. After irradiation, the reduced metabolic
      oxygen consumption yields information on the cell death rate, and on the
      photodynamic cell killing efficiency. The aim of this paper is to present an
      experimental set-up and the corresponding theoretical model that allows us to
      control the photodynamic efficiency for a given cell-sensitizer pair, under well
      defined and controlled conditions of irradiation and oxygen supply. To
      demonstrate the usefulness of the methodology described, CHO cells cultured on
      microbeads were sensitized with pheophorbide a and irradiated with different
      light fluence rates. The results obtained, i.e. oxygen consumption of about 0.1
      microM s(-1) m(-3) under a light fluence rate of 1 W m(-2), 10(5) cells killed
      per mole of oxygen consumed and a decay rate of about 1 h(-1) of living cells
      after irradiation, are in good agreement with the theoretical predictions and
      with previously published data.

PMID- 10661587
TI  - Influence of thyroid volume reduction on calculated dose in radioiodine therapy
      of Graves' hyperthyroidism.
AB  - Administration of radioactive iodine (131I) is an effective treatment for
      hyperthyroidism due to Graves' disease. Recently several investigators have shown
      that the success of this therapy may depend on the absorbed dose to the thyroid.
      Thyroid dose varies inversely with the mass of the gland. Much experimental
      evidence demonstrates that a reduction of the thyroid volume (mass) may occur
      after radioiodine therapy. In this work we evaluate the influence of the volume
      reduction on the calculation of the absorbed dose to the thyroid. A mathematical
      model of thyroid mass reduction after 131I therapy is presented, based on masses
      evaluated with ultrasonography of ten patients treated in the endocrinology
      department of our hospital. This model was applied to the general formula for
      calculation of the thyroid doses in these patients. The dose values obtained
      considering a reduction of thyroid mass after the treatment are often quite
      different from those obtained without considering change in mass (from 9% to 30%
      greater). We conclude that the consideration of thyroid mass reduction is
      important for an accurate estimation of the calculated dose.

PMID- 10661588
TI  - Towards the elimination of Monte Carlo statistical fluctuation from dose volume
      histograms for radiotherapy treatment planning.
AB  - The Monte Carlo calculation of dose for radiotherapy treatment planning purposes
      introduces unavoidable statistical noise into the prediction of dose in a given
      volume element (voxel). When the doses in these voxels are summed to produce dose
      volume histograms (DVHs), this noise translates into a broadening of differential
      DVHs and correspondingly flatter DVHs. A brute force approach would entail
      calculating dose for long periods of time--enough to ensure that the DVHs had
      converged. In this paper we introduce an approach for deconvolving the
      statistical noise from DVHs, thereby obtaining estimates for converged DVHs
      obtained about 100 times faster than the brute force approach described above.
      There are two important implications of this work: (a) decisions based upon DVHs
      may be made much more economically using the new approach and (b) inverse
      treatment planning or optimization methods may employ Monte Carlo dose
      calculations at all stages of the iterative procedure since the prohibitive cost
      of Monte Carlo calculations at the intermediate calculation steps can be
      practically eliminated.

PMID- 10661590
TI  - Determining clinical photon beam spectra from measured depth dose with the
      Cimmino algorithm.
AB  - A method to determine the spectrum of a clinical photon beam from measured depth
      dose data is described. At shallow depths, where the range of Compton-generated
      electrons increases rapidly with photon energy, the depth dose provides the
      information to discriminate the spectral contributions. To minimize the influence
      of contaminating electrons, small (6 x 6 cm2) fields were used. The measured
      depth dose is represented as a linear combination of basis functions, namely the
      depth doses of monoenergetic photon beams derived by Monte Carlo simulations. The
      weights of the basis functions were obtained with the Cimmino feasibility
      algorithm, which examines in each iteration the discrepancy between predicted and
      measured depth dose. For 6 and 15 MV photon beams of a clinical accelerator, the
      depth dose obtained from the derived spectral weights was within about 1% of the
      measured depth dose at all depths. Because the problem is ill conditioned,
      solutions for the spectrum can fluctuate with energy. Physically realistic smooth
      spectra for these photon beams appeared when a small margin (about +/- 1%) was
      attributed to the measured depth dose. The maximum energy of both derived spectra
      agreed with the measured energy of the electrons striking the target to within 1
      MeV. The use of a feasibility method on minimally relaxed constraints provides
      realistic spectra quickly and interactively.

PMID- 10661589
TI  - Treatment plan comparison using equivalent uniform biologically effective dose
      (EUBED).
AB  - With the continuing improvement in computer speed, dose distributions can be
      calculated quickly with confidence. However, the resulting biological effect is
      known with much less certainty, despite its critical importance when assessing
      treatment plans. To assess plans accurately, biologically based methods of
      ranking plans are necessary. Many authors have suggested the use of dose volume
      histograms with reduction schemes and Niemierko has recently introduced another
      method based on the cell kill occurring in the tumour. This study presents an
      investigation into this value and suggests a use in prescribing dose. Equivalent
      uniform dose (EUD) can obviously be used for assessing treatment plans, although
      in its current form it is not adequate for assessing normal tissues; however, it
      can also be used to adjust the prescription dose ensuring all plans deliver the
      same EUD to the tumour. Once this is performed, plans can more easily be assessed
      on the effects to the normal tissues. In calculating the EUD another concept is
      introduced--the equivalent uniform biologically effective dose (EUBED). This
      value considers the distribution of dose and dose per fraction when comparing
      plans. Reduced dose per fraction at the edge of the target volume will exacerbate
      the effect of reduced dose on cell kill. Two methods are suggested for
      calculating the necessary prescription dose: one using an iterative method and
      one using the gradient of the EUBED function. A comparison was made for a series
      of stereotactic cases using different collimator sizes. Interestingly, using this
      method, although the maximum doses were different, the dose volume histograms
      (DVHs) for the brainstem were similar in all cases.

PMID- 10661591
TI  - Traceable calibration of ultraviolet meters used with broadband, extended
      sources.
AB  - A calibration system has been developed to provide increased accuracy in the
      measurement of the irradiance responsivity appropriate for UV meters used with
      broadband, extended sources of the type employed in phototherapy. The single
      wavelength responsivity of the test meter is obtained in the wavelength range 250
      400 nm by intercomparison with a transfer standard meter in a narrow,
      monochromatic beam. Traceability to primary standard irradiance scales is
      provided via the National Measurement System with a best uncertainty of 7% (at
      95% confidence). The effective responsivity of the test meter, when used with
      broadband extended sources, is calculated using the measured spectral and angular
      response of the meter and tabulated data on the spectral and spatial
      characteristics of the source radiance. The uncertainty in the effective
      responsivity, independent of the source variability, is estimated to be 10% (at
      95% confidence). The advantages of this calibration system over existing
      approaches are discussed.

PMID- 10661592
TI  - Characterization of a high-elbow, fluoroscopic electronic portal imaging device
      for portal dosimetry.
AB  - The application of a newly developed fluoroscopic (CCD-camera based) electronic
      portal imaging device (EPID) in portal dosimetry is investigated. A description
      of the EPID response to dose is presented in terms of stability, linearity and
      optical cross-talk inside the mechanical structure. The EPID has a relatively
      large distance (41 cm on-axis) between the fluorescent screen and the mirror
      (high-elbow), which results in cross-talk with properties quite different from
      that of the low-elbow fluoroscopic EPIDs that have been studied in the
      literature. In contrast with low elbow systems, the maximum cross-talk is
      observed for points of the fluorescent screen that have the largest distance to
      the mirror, which is explained from the geometry of the system. An algorithm to
      convert the images of the EPID into portal dose images (PDIs) is presented. The
      correction applied for cross-talk is a position dependent additive operation on
      the EPID image pixel values, with a magnitude that depends on a calculated
      effective field width. Deconvolution with a point spread function, as applied for
      low-elbow systems, is not required. For a 25 MV beam, EPID PDIs and ionization
      chamber measurements in the EPID detector plane were obtained behind an
      anthropomorphic phantom and a homogeneous absorber for various field shapes. The
      difference in absolute dose between the EPID and ionization chamber measurements,
      averaged over the four test fields presented in this paper, was 0.1 +/- 0.5% (1
      SD) over the entire irradiation field, with no deviation larger than 2%.

PMID- 10661593
TI  - Estimating achievable signal-to-noise ratios of MRI transmit-receive coils from
      radiofrequency power measurements: applications in quality control.
AB  - The inverse relationship between the radiofrequency (RF) power needed to transmit
      a 90 degree RF pulse, and the signal-to-noise ratio (SNR) available from a
      transmit-receive RF coil is well known. The theory is restated and a formula
      given for the signal-to-noise ratio from water, achievable from a single-shot MRI
      experiment, in terms of the net forward RF power needed for a rectangular 90
      degree RF pulse of known shape and duration. The result is normalized to a signal
      bandwidth of 1 Hz and a sample mass of 1 g. The RF power information needed is
      available on most commercial scanners, as it is used to calculate specific
      absorption rates for RF tissue heating. The achievable SNR figure will normally
      be larger that that actually observed, mainly because of receiver noise, but also
      because of inaccuracies in setting RF pulse angles, and relaxation effects.
      Phantom experiments were performed on the transmit-receive RF head coil of a
      commercial MRI system at 0.95 T using a projection method. The measured SNR
      agreed with that expected from the formula for achievable SNR once a correction
      was made for the noise figure of the receiving chain. Comparisons of measured SNR
      figures with those calculated from RF power measurements are expected to be of
      value in acceptance testing and quality control.

PMID- 10661594
TI  - Contamination of in vivo bone-lead measurements.
AB  - This paper addresses one aspect of the calibration of a 109Cd based K-shell x-ray
      fluorescence measurement system, namely the treatment of the calibration line
      intercept. Under circumstances of contamination, the intercept may warrant
      statistical treatment different from that currently performed. This paper
      proposes refinements to the existing method of subtracting the phantom
      calibration line intercept from in vivo responses in the calculation of in vivo
      concentrations. These refinements are recommended because the existing method can
      underestimate in vivo concentrations by a small amount under normal operating
      conditions. Contamination of the calibration standard matrix of plaster of Paris
      by both lead and non-lead contaminants is addressed.

PMID- 10661596
TI  - Patients' beliefs about treatment: the hidden determinant of treatment outcome?

PMID- 10661595
TI  - Stochastic risk estimate for barium radiological examinations in Malaga (Spain).
AB  - The aim of this research work has been the estimation of the stochastic risk for
      five barium examinations. The sample was the population attending the
      Radiological Service of the 'Nuestra Senora de la Victoria' University Hospital,
      who had been treated with some barium examinations, set in five different groups:
      oesophagus tract, oesophagus-gastric-duodenal tract, intestinal tract,
      enteroclysis and double enema. To estimate the stochastic risk, it is necessary
      to know the organ dose. This can be calculated from the dose-area product which
      allows us to determine the effective dose using software. The dose-area product
      is the most suitable quantity to measure in these types of examination. We have
      evaluated the contribution that each procedure provides to the genetically
      significant dose, somatically significant dose, collective effective dose, annual
      effective dose 'per capita' and detriment, which are useful for assessing the
      population risk of cancer or hereditary effects after x-ray exposure. The
      contribution to the genetically significant dose is 6.7 microGy, to the
      somatically significant dose 8.82 mSv-yr, 16.07 person-Sv for the collective
      effective dose, 0.03 mSv for the 'per capita' annual effective dose and the
      annual aggregated detriment is 0.33.

PMID- 10661597
TI  - Surviving cancer: do psychosocial factors count?

PMID- 10661598
TI  - Anxiety disorders in Parkinson's disease: insights into the neurobiology of
      neurosis.

PMID- 10661599
TI  - What is behind "I'm so tired"? Fatigue experiences and their relations to the
      quality and quantity of external stimulation.
AB  - In the present study, it is hypothesized that both low quality and high quantity
      of external stimulation are related to elevated levels of fatigue. This is
      proposed by the Quality-Quantity model for understanding fatigue (QQuF model).
      The relations between the quality and quantity of external information and the
      Multidimensional Fatigue Inventory (MFI-20) are examined. Moreover, the role of
      depression (measured with the CES-D) in relation to the QQuF model is explored.
      The results show low quality of external stimulation, that is, low
      "attractiveness of external stimulation," relating to all five dimensions of
      fatigue. A high quantity of external stimulation, that is, high "experienced
      overload," related primarily to general and mental fatigue. The QQuF model was
      only slightly moderated by depression, but depression directly and strongly
      related to all dimensions of fatigue. It is concluded that fatigue related to low
      quality of external stimulation can be distinguished from fatigue related to a
      high quantity of external stimulation. This distinction is useful when
      considering theoretical issues and treatment of fatigue.

PMID- 10661601
TI  - Positive effects of illness reported by myocardial infarction and breast cancer
      patients.
AB  - This study investigated the positive effects or changes that patients identified
      in their lives following a myocardial infarction (MI) or breast cancer. One
      hundred and forty-three patients were assessed in hospital following a first-time
      MI and 52 breast cancer patients were assessed on referral for radiotherapy.
      Approximately 3 months later both groups were asked if any positive changes had
      taken place in their lives following their illness. Patients' written responses
      to a single open-ended question were read independently by three judges who
      identified seven major positive themes. Approximately 60% of each patient group
      reported positive changes from their illness and the reporting of such changes
      was unrelated to illness severity. The most common theme reported by MI patients
      was healthy lifestyle change (68%), whereas, for breast cancer patients, it was
      improved close relationships with others (33%). These results are discussed in
      terms of the way patients make sense of and adapt to chronic illness.

PMID- 10661600
TI  - Fenfluramine challenge test predicts outcome in pharmacological treatment of
      patients with functional gastrointestinal disorder.
AB  - We investigated if response to the fenfluramine challenge test could predict
      outcome in 47 nonpsychiatric patients with chronic functional gastrointestinal
      disorder (FGD) treated with mianserin, a drug closely related to mirtazepine, or
      placebo. Sixty milligrams of fenfluramine was given orally in the morning on
      nonfasting basis. Serum cortisol (COR) and prolactin (PRL) were analyzed at
      baseline, and after 120, 180, and 240 minutes. Patients were then randomized into
      a 7-week double-blind treatment trial with mianserin or placebo. Response to
      treatment with mianserin (76% vs.18% for placebo) was closely linked to a high
      increase in PRL and COR following a fenfluramine challenge test (positive
      predictive power=72%). Adding length of illness history increased both positive
      and negative predictive power to 92%. Our results indicate that the fenfluramine
      challenge test may be a potentially useful tool to identify nonpsychiatric
      subjects with FGD, who will most likely respond to treatment with a combined
      alpha2 and 5HT-2 and -3 antagonist.

PMID- 10661602
TI  - Psychological characteristics of people with perceived food intolerance in a
      community sample.
AB  - In most adults who believe themselves to be food intolerant there is no objective
      supporting evidence. It has therefore been proposed that the misperception of
      intolerance to food is linked to psychiatric illness or personality disorder.
      This hypothesis was tested in a community-derived sample of individuals who
      attributed an adverse symptom to a type of food. A random mailing recruited 955
      participants aged > or =18 years, of whom 232 perceived themselves to be food
      intolerant (PFI). All recruits were sent two questionnaires, the General Health
      Questionnaire-28 (GHQ-28) and the shortened version of the Eysenck Personality
      Questionnaire (EPQ-R). A total of 535 GHQ-28 and 518 EPQ-R forms were returned
      that were correctly completed, an overall response rate of 55%. For the subscales
      of the EPQ-R, neuroticism was greater in those with a PFI than those without.
      Women with a PFI were more extroverted than control women. For the GHQ-28
      subscales, women with a PFI had significantly higher scores than control women on
      somatic symptoms, anxiety, insomnia, and severe depression. There was a greater
      percentage of psychiatric caseness among women with a PFI than among men with a
      PFI or control women. Nevertheless, this percentage was no greater than that
      reported among a reference sample derived from NHS and university staff. It is
      concluded that perceived food intolerance is associated with psychological
      distress in women with a PFI, and neurotic symptoms in both men and women with a
      PFI, but there is no greater prevalence of psychiatric disorder among women or
      men with a PFI than there is in some professional groups.

PMID- 10661603
TI  - Patients' beliefs about prescribed medicines and their role in adherence to
      treatment in chronic physical illness.
AB  - The aim of this cross-sectional study was to quantify patients' personal beliefs
      about the necessity of their prescribed medication and their concerns about
      taking it and to assess relations between beliefs and reported adherence among
      324 patients from four chronic illness groups (asthma, renal, cardiac, and
      oncology). The findings revealed considerable variation in reported adherence and
      beliefs about medicines within and between illness groups. Most patients (89%)
      believed that their prescribed medication was necessary for maintaining health.
      However, over a third had strong concerns about their medication based on beliefs
      about the dangers of dependence or long-term effects. Beliefs about medicines
      were related to reported adherence: higher necessity scores correlated with
      higher reported adherence (r=0.21, n=324, p<0.01) and higher concerns correlated
      with lower reported adherence (r=0.33, n=324, p<0.01). For 17% of the total
      sample, concerns scores exceeded necessity scores and these patients reported
      significantly lower adherence rates (t=-4.28, p<0.001). Stepwise multiple linear
      regression analysis showed that higher reported adherence rates were associated
      with higher necessity-concerns difference scores (beta=0.35, p<0.001), a
      diagnosis of asthma (beta= -0.31, p<0.001), a diagnosis of heart disease
      (beta=0.19, p<0.001), and age (beta=0.22, p<0.001). Gender, educational
      experience, or the number of prescribed medicines did not predict reported
      adherence. Medication beliefs were more powerful predictors of reported adherence
      than the clinical and sociodemographic factors, accounting for 19% of the
      explained variance in adherence. These data were consistent with the hypothesis
      that many patients engage in an implicit cost-benefit analysis in which beliefs
      about the necessity of their medication are weighed against concerns about the
      potential adverse effects of taking it and that these beliefs are related to
      medication adherence.

PMID- 10661604
TI  - Repressed anger and patterns of cardiovascular, self-report and behavioral
      responses: effects of harassment.
AB  - We hypothesized that anger repressors would show discrepancies between self
      reported anger and cardiovascular and behavioral responses only during
      harassment. Subjects (N=102) were assigned randomly to condition. In the
      nonharassment condition, subjects told stories about eight Thematic Apperception
      Test cards without any harassment. In the harassment condition, subjects told
      four stories without harassment, and then told four more stories with harassment.
      Words connoting aggressive behavior and angry/hostile affect were coded from
      story content. Subjects were classified into low anger expressor, anger
      repressor, high anger expressor, and defensive anger expressor categories based
      on median splits of the Anger-Out Subscale and Marlowe-Crowne Social Desirability
      Scale. Results showed that harassed anger repressors reported anger comparable to
      that of low anger expressors but less than high expressors, whereas their heart
      rate (HR) reactivity was comparable to high expressors, but greater than low
      anger expressors. Increases in anger words did not distinguish repressors from
      other groups. Repressed anger may represent a distinct anger management style
      characterized by a discrepancy between acknowledged anger and cardiovascular
      reactivity--effects that become fully manifest only during interpersonal
      provocation.

PMID- 10661605
TI  - Psychological correlates of sleep apnea.
AB  - Relationships were examined between psychological and sleep variables in
      individuals with sleep apnea (n=72, 24 with hypertension; Respiratory Disturbance
      Index=15) and without sleep apnea (n=40, 16 with hypertension; respiratory
      disturbance index<15). Subjects were 32-64 years old, 100-150% of ideal weight,
      with no other major illness. For subjects with sleep apnea, depression, anger,
      and total mood disturbance correlated positively with deep sleep, rapid eye
      movement sleep, and/or hypoxemia. For subjects without sleep apnea, vigor
      correlated positively with sleep quantity and negatively with hypoxemia. When
      age, body mass, and hypertension were controlled, results changed little for
      subjects without sleep apnea; for subjects with sleep apnea, depression and total
      mood disturbance no longer correlated with sleep measures. Although various
      psychological measures correlate with sleep variables in sleep apnea subjects,
      many are explained by controlling age, body mass, and hypertension. Anger and
      vigor, however, remain associated with sleep variables.

PMID- 10661606
TI  - Examination of Cloninger's basic dimensions of personality in fatiguing illness:
      chronic fatigue syndrome and multiple sclerosis.
AB  - Relatively few studies have examined the personality characteristics of patients
      with chronic fatigue syndrome (CFS). The personality profiles of 38 CFS subjects
      were compared with 40 healthy controls and 40 subjects with multiple sclerosis
      (MS), a chronic illness that shares many symptoms with CFS (e.g., fatigue), but
      has a known neurological substrate. Subjects were examined within Cloninger's
      biosocial theory of personality, which delineates basic dimensions of
      temperament. Both illness groups displayed similarly elevated levels of Harm
      Avoidance, and lower levels of Reward Dependence as compared with healthy
      controls. The MS group showed a lower level of Persistence than controls and CFS
      subjects. Implications for the relationship between chronic illness and
      personality are discussed.

PMID- 10661607
TI  - Variations in stress levels over the course of pregnancy: factors associated with
      elevated hassles, state anxiety and pregnancy-specific stress.
AB  - This prospective study tracked hassles, pregnancy-specific stress, and state
      anxiety during pregnancy. A second objective was to identify predictors of each
      stress dimension. Pregnant women (n=161) completed the Hassles Scale, the
      Pregnancy-Specific Stress Questionnaire (PEQ), and the state-anxiety scale (STAI
      state) monthly, beginning in the third month of pregnancy. Hassles were found to
      be stable throughout the pregnancy. Women reported significantly higher pregnancy
      specific stress in the first and third trimester of pregnancy, whereas state
      anxiety increased in the third trimester compared with the first and second
      trimesters. Poorer marital adjustment predicted higher Hassles during pregnancy
      and higher PEQ and STAI-state in the third trimester. Women who reported that the
      pregnancy would have a negative impact on their career scored higher on Hassles
      during pregnancy and higher on the PEQ in the third trimester. The occurrence of
      a gestational complication during pregnancy was related to higher pregnancy
      specific stress in the third trimester. Younger women also reported higher PEQ
      results in the third trimester. The data provide support for a multidimensional
      conceptualization of stress during pregnancy.

PMID- 10661608
TI  - Psychosocial predictors of adherence to nutritional recommendations and growth
      outcomes in children with cystic fibrosis.
AB  - This study aimed to elucidate the relationship between maternal psychosocial
      factors related to dietary adherence and growth outcomes in their children with
      cystic fibrosis (CF). Twenty-five children with CF and mild lung disease, aged 7
      12 years, were weighed and measured and completed detailed food records. Mothers
      completed questionnaires that measured general nutritional knowledge, nutritional
      knowledge specific to CF, coping strategies, dieting behaviors, self-efficacy
      about the ability to provide the correct diet, and attitudes and beliefs about
      CF. Of the cohort, only 16% adhered to the dietary recommendations. Dietary
      adherence was positively correlated with weight. Maternal nutritional knowledge
      specific to CF significantly predicted children's dietary adherence score. There
      was a significant negative correlation between the child's weight and mothers who
      were dieting successfully. Other psychosocial factors assessed were not related
      to dietary adherence. Improving the mother's knowledge about nutritional needs in
      CF appears worthwhile and may have an impact on growth.

PMID- 10661609
TI  - Alexithymia and health behaviors in healthy male volunteers.
AB  - The association between alexithymia and maladaptive health behaviors was
      evaluated in 118 young, healthy men, aged 18-45 years. Subjects completed the
      Toronto Alexithymia Scale (TAS-26), and a health behaviors questionnaire,
      measuring alcohol and drug use, sedentary lifestyle, poor nutritional
      consumption, and risky sexual practices. In forced hierarchical regression
      analyses, the association between alexithymia and health behaviors was evaluated
      after adjusting for age, body mass index, social support, ambivalence over
      expression of emotion, and the expression of emotion. Results indicated that: (1)
      the TAS-26 and difficulty identifying feelings was associated with poor
      nutritional consumption; (2) difficulty identifying feelings was associated with
      greater alcohol and drug use; and (3) difficulty communicating feelings was
      associated with a more sedentary lifestyle. There was no association between
      risky sexual practices and alexithymia. These results suggest that, in young men,
      difficulties with identifying emotions and communicating emotions are associated
      with maladaptive nutritional habits, a sedentary lifestyle, and substance abuse,
      even after adjusting for other psychosocial and demographic variables. Such
      maladaptive health behaviors may help explain the association between alexithymia
      and premature mortality.

PMID- 10661610
TI  - Current perspectives on the benefits of HRT in menopausal women.
AB  - AIMS: Women in the West can now expect to live one third of their life in a
      postmenopausal state, and consequently in a state of estrogen deficiency. This
      can have a number of consequences, and many women suffer vasomotor symptoms
      during the climacteric. Estrogen deficiency can also result in changes to the
      skin, hair, urogenital, cardiovascular and skeletal systems. This article reviews
      some of the main actions of replacement estrogen in postmenopausal women, and
      discusses the major benefits of estrogen replacement therapy (ERT) and hormone
      replacement therapy (HRT). REVIEW: HRT is well documented to reduce vasomotor
      symptoms in women suffering from estrogen deficiency, and can have beneficial
      effects on the skin and the prevention of skin aging. HRT has beneficial effects
      on urogenitary function including reductions in urinary incontinence and vaginal
      atrophy. HRT is used as a first-line treatment to prevent or reverse the
      development of postmenopausal osteoporosis and can reduce the risk of fractures
      if taken for 5-10 years from the menopause. In epidemiological studies, ERT was
      associated with a reduction in the risk of coronary heart disease. Estrogens seem
      to affect the cardiovascular system directly and indirectly such as reducing some
      of the coronary risk factors. In recent years, estrogen has been linked to
      beneficial effects in the CNS including an association with a reduction in the
      risk of developing Alzheimer's Disease. Despite these benefits, HRT compliance
      remains low, and physicians need to address this if patients are to gain the
      benefits.

PMID- 10661611
TI  - Strategies for effectively addressing women's concerns about the menopause and
      HRT.
AB  - HRT has many benefits for postmenopausal women yet acceptance and compliance with
      therapy is low. This paper sets out some of the main concerns women have
      regarding HRT and highlights ways that physicians can effectively deal with these
      concerns. Physicians dealing with women concerned about starting or continuing
      HRT should conduct patient-centered consultations employing good counseling
      skills. Dealing effectively with women's concerns means addressing their attitude
      to HRT, listening to the patients' fears in an understanding and non-dismissive
      way, and focusing on good communication. Common concerns relating to unwanted
      effects such as bleeding, fear of cancer, weight gain, thrombosis, general
      systemic effects, and the use of medical intervention generally, can be dealt
      with if the physician follows the principles for conducting a patient-centered
      interview. When it comes to decisions about starting and continuing on HRT, it is
      important that women are treated with understanding, their concerns are taken
      seriously, and they are given time to air their views and ask questions.
      Tailoring treatments to individual patients can overcome many of the problems
      women have with HRT, however it is important that the decision to start HRT, and
      the most suitable regimen and delivery system to use, be decided in partnership
      with the patient. This should result in the patient having a better understanding
      of HRT, and may improve compliance.

PMID- 10661612
TI  - Moderation of the daily dose of HRT: benefits for patients.
AB  - INTRODUCTION: Hormone replacement therapy (HRT) has many benefits yet compliance
      rates remain low. One of the main reasons for discontinuing therapy is
      hyperestrogenic side effects which may be dose related, and the initiation of
      treatment is critical to a patient's chances of gaining long-term benefits. The
      introduction of low dose HRT means that physicians have an option to initiate or
      titrate patients to a low dose. The purpose of this review is to examine current
      literature on the benefits for patients of low dose HRT. RESULTS: Low dose
      estrogen (25 mcg/day transdermally or 0.3 mg/day orally) are effective in
      controlling postmenopausal symptoms, reducing bone loss and reducing
      cardiovascular risk factors. Low dose therapy is also effective at reducing
      vasomotor symptoms in highly symptomatic women. In one study, patients on a daily
      dose of 25 mcg estrogen experienced an 86% reduction in vasomotor symptoms
      compared to a 55% reduction in patients on placebo. In addition, many adverse
      events related to estrogens were reduced using a low dose. CONCLUSION: Compliance
      with traditional doses of HRT is currently a problem for many women who may stop
      taking therapy because they experience hyperestrogenic side effects. Low dose HRT
      is effective at reducing vasomotor symptoms and controlling symptoms even in
      highly symptomatic women. Hyperestrogenic side effects may be reduced by
      initiating treatment at the lowest dose and titrating upwards if necessary. This
      may have benefits for patients in terms of offering effective control of symptoms
      whilst minimising hyperestrogenic effects.

PMID- 10661613
TI  - Optimising delivery systems for HRT.
AB  - INTRODUCTION: HRT has been used to alleviate vasomotor symptoms for more than 50
      years, and since its introduction, ways have been sought to improve delivery
      methods, patient acceptability and tolerability. This paper reviews the benefits
      and disadvantages of some of the main HRT delivery systems currently available.
      RESULTS: Oral methods of administration use high doses of estrogen because they
      are subject to metabolism in the intestine and liver. This results in systemic
      and physiological changes which can result in unwanted effects. Transdermal
      methods administer lower doses of estrogen to achieve the same therapeutic effect
      as oral methods. However, problems of adhesion and skin tolerability with
      conventional transdermal patches can lead to poor compliance with this method.
      Local administration by percutaneous gel or subcutaneous implant can use
      physiological doses of estrogen, but can be difficult to titrate, and may not
      offer the long term benefits associated with some oral and transdermal systems.
      Newer transdermal matrix systems are now available which offer improved skin
      tolerability and adhesion properties compared to some conventional transdermal
      systems. CONCLUSIONS: There are a wide variety of delivery systems currently
      available and the choice of therapy must be made in consultation with women to
      aid compliance. Whilst oral administration has been a traditional first-line
      choice, it is not suitable for certain women. Newer generation transdermal matrix
      patches are usually suitable as a first line treatment in most women and can
      offer optimum profiles in terms of adhesion, tolerability and comfort, essential
      for good compliance and long-term treatment.

PMID- 10661614
TI  - OESCLIM: an advanced delivery system for HRT.
AB  - AIMS: Transdermal estradiol offers a number of advantages over traditional oral
      routes of hormone replacement therapy (HRT) because it is not subject to the
      hepatic first-pass effect. However, transdermal systems need to balance adhesion,
      tolerability, and flux if they are to be effective. OESCLIM is a transdermal 17
      beta estradiol HRT system designed to address the problems of conventional
      transdermal patches and offer optimal adhesion and tolerability in an effective
      HRT system. This paper reviews some of the data on OESCLIM with reference to its
      delivery system. RESULTS: The innovative technology used in OESCLIM results in a
      smooth pharmacokinetic profile throughout the 3-4 day application period. In
      recent pharmacokinetic studies, OESCLIM 50 provided a more consistent release of
      hormone than Estraderm TTS 50 and higher mean estradiol levels than Systen and
      Vivelle. This smooth pharmacokinetic profile is also maintained whether OESCLIM
      is attached to different body sites. The local skin tolerability of OESCLIM is
      good. One study reported that OESCLIM 50 caused less than half the number of skin
      reactions as Estraderm TTS 50 (4.2% compared to 9.5%). OESCLIM has also been
      shown to have fewer detachments than Estraderm TTS (6% compared to 11%). Both
      differences were statistically significant (P < 0.001). A study has shown OESCLIM
      to be as effective as Estraderm TTS at reducing vasomotor symptoms even in highly
      symptomatic women. CONCLUSION: OESCLIM is a very good first-line choice for
      estrogen replacement therapy (ERT) or HRT providing effective therapy with
      optimum adhesion, flux and tolerability profiles.

PMID- 10661615
TI  - OESCLIM: pre-clinical and clinical profile.
AB  - INTRODUCTION: The majority of women will suffer some form of vasomotor symptoms
      at the menopause. Hormone replacement therapy (HRT) has been shown to reduce the
      incidence of these symptoms although compliance with HRT is still poor. OESCLIM
      is a transdermal estrogen-replacement therapy for the treatment of estrogen
      deficiency. METHODS: In this paper, the main pre-clinical and clinical data
      relating to OESCLIM are reviewed. RESULTS: OESCLIM has a stable pharmacokinetic
      profile over the treatment period of 3-4 days and has been shown to have advanced
      pharmacokinetics when compared to other leading transdermal systems. It has been
      shown to reduce vasomotor symptoms by 94% in post-menopausal women, with near
      maximal reduction in symptoms after 4 weeks of treatment. In highly symptomatic
      women, low dose (25 microg/day) OESCLIM therapy resulted in a statistically
      significant reduction in symptoms compared to placebo from week 3. OESCLIM also
      has good local skin tolerability, and is significantly better tolerated than
      Estraderm TTS 50. It is also well accepted among patients. In long-term studies,
      79.8% of patients wished to continue OESCLIM therapy at the end of a 3-year
      study. CONCLUSION: OESCLIM is an innovative first-line transdermal estrogen
      replacement therapy with good efficacy and tolerability. The ability to initiate
      treatment at a low dose (25 microg/day) may have advantages for the patient
      starting therapy by reducing symptoms of hyperestrogenism whilst allowing for
      dose titration upwards if necessary.

PMID- 10661616
TI  - Moderation of the daily dose of HRT: prevention of osteoporosis.
AB  - INTRODUCTION AND METHODS: Osteoporosis is the most common bone disease in
      clinical practice. Between 30% and 50% of postmenopausal women and almost 50% of
      all people over the age of 75 are estimated to have osteoporosis. HRT is well
      known for reducing the risk of osteoporosis in postmenopausal women but
      compliance with long-term HRT therapy remains low. The use of low dose HRT
      reduces the estrogenic adverse events which often cause patients to stop therapy.
      In this paper, the current literature on the benefits of low dose HRT and
      osteoporosis prevention are reviewed. RESULTS: Various studies have assessed the
      efficacy of low-dose HRT (25 mcg/day transdermally; 0.3 mg/day orally) in the
      prevention of osteoporosis. Low dose HRT is effective at reducing bone loss in
      postmenopausal and oophorectomised women. In one study of 218 postmenopausal
      women, a dose of 0.3 mg/day of esterified estrogen resulted in a small but
      significant increase in whole body BMD compared to a decrease in the placebo
      group. The addition of calcium supplements may have a synergistic effect on the
      reduction of bone loss. CONCLUSION: Low dose estrogen, taken either orally or
      transdermally, can prevent or reverse postmenopausal bone loss and appears to be
      a useful alternative to higher dosages in the prevention and treatment of
      osteoporosis. The option of starting HRT at low dose gives physicians the ability
      to titrate doses to suit individual patients whilst ensuring adequate bone
      protection and the minimum of hyperestrogenic side effects.

PMID- 10661617
TI  - HRT and cancer risk: separating fact from fiction.
AB  - INTRODUCTION AND METHODS: The benefits of hormone replacement therapy (HRT) in
      postmenopausal women are well known including control of vasomotor symptoms and
      long-term benefits on the cardiovascular, skeletal and central nervous systems.
      However, some studies have reported a link between long-term HRT use and cancer.
      This paper reviews some of the data related to HRT and major gynaecological
      cancers. RESULTS: Appropriate HRT regimens can reduce the risk of endometrial
      hyperplasia in non-hysterectomised women and can reduce the incidence of
      colorectal cancer. There is no consensus on a link between HRT and ovarian
      cancer, and the data relating to HRT and breast cancer presents differing risk
      analyses. However, it is generally accepted that HRT taken for 5 years or less
      does not increase the risk of breast cancer. When HRT is taken for 10 years or
      more, the relative risk of being diagnosed with breast cancer is 1.46. Individual
      risk must be weighed against the benefits offered by HRT, especially in terms of
      the long-term beneficial effects on the cardiovascular, skeletal and central
      nervous systems. Whilst one in 8-12 women may contract breast cancer in the
      western world, one in 3 women over 65 will have cardiovascular disease and 30-50%
      of postmenopausal women will have osteoporosis. CONCLUSION: Fear of cancer is one
      of the main reasons why women object to HRT. Physicians must be able to
      counteract this fear with fact, and counsel patients on their individual risk, as
      well as putting any cancer risk into perspective with other long-term benefits.

PMID- 10661618
TI  - The long-term tolerability and efficacy of OESCLIM: results of a 1-year study.
AB  - OBJECTIVES: A 1-year, open-label, non-comparative study evaluated the long-term
      tolerability and acceptability of a new generation matrix patch in post
      menopausal women with estrogen deficiency. METHODS: Menopausal women (224) from
      37 centres in five European countries received OESCLIM 50 microg/d (17-beta
      estradiol) for 3 months, titrated if necessary to either 25 or 100 microg/d for a
      further 9 months. Patients received either a continuous or discontinuous
      estradiol regimen with concomitant sequential progestogen (except hysterectomised
      patients). Skin tolerability was assessed by patient diaries and questionnaires.
      Global tolerability, efficacy, laboratory parameters and global acceptability
      were also monitored. RESULTS: Almost two-thirds of women did not experience any
      kind of skin reaction and only 4.3% of all applications (752/17,702) caused site
      reactions. Of these, the majority caused only slight or no discomfort (63.2%).
      Only 0.37% of total applications required patch removal; none required therapy. A
      low percentage of patients withdrew due to tolerability issues: 2.7% due to skin
      reactions; 7.5% due to hyperestrogenism. The mean number of hot flushes
      experienced by symptomatic women reduced by 91% from 4.0 at baseline to 0.4 after
      2 months. Total cholesterol reduced by 3.9% and LDL cholesterol by 5.1%, with no
      increase in triglyceride levels. Investigators assessed treatment as effective in
      96.8% of cases; well tolerated locally in 93.1% and well tolerated generally in
      89.5%. At the end of this 1 year study, 79% of patients wished to continue
      therapy. CONCLUSION: OESCLIM is well tolerated locally and systemically in long
      term therapy with a high proportion of patients wishing to continue therapy after
      1 year.

PMID- 10661619
TI  - OESCLIM: summary of tolerability and safety.
AB  - INTRODUCTION: The benefits of transdermally administered estradiol have been well
      documented in a number of studies. OESCLIM is a new transdermal matrix system
      which has been developed with the objective of providing improved local skin
      tolerability and adhesion, whilst minimising hyperestrogenic effects. METHODS:
      Data relating to OESCLIM's tolerability and safety profile were reviewed.
      RESULTS: In a randomised, controlled comparative clinical trial, OESCLIM resulted
      in less than half as many application site reactions than Estraderm TTS (4.3
      compared to 9.5%). In addition, the duration of reactions was significantly lower
      in the OESCLIM group. OESCLIM has been well tolerated in all clinical trials and
      was reported to have comparable estrogen-specific tolerability as Estraderm TTS.
      Low dose OESCLIM (25 microg/day) is associated with a reduction in
      hyperestrogenic side effects compared to higher doses. In a study of long term
      OESCLIM therapy, 79% of patients wished to continue therapy after 1 year, and in
      a follow up study 79.8% wished to continue at the end of the 3 year study.
      CONCLUSION: OESCLIM offers doctors an alternative to current transdermal therapy
      that is safe and effective and suitable for the majority of women. It has a
      better local tolerability and safety profile than Estraderm TTS and its safety
      has been proven in both short and long-term trials. The extensive range of
      OESCLIM doses available means doctors have a large flexibility and choice when it
      comes to deciding on an appropriate regimen including the option to initiate
      therapy at a low dose.

PMID- 10661620
TI  - Interphase cytogenetics: at the interface of genetics and morphology.

PMID- 10661621
TI  - Immunocytochemistry and DNA-image cytometry in diagnostic effusion cytology I.
      Prevalence of markers in tumour cell positive and negative smears.
AB  - To determine the prevalence of immunocytochemical positivities for a panel of
      antibodies in benign and malignant cells in effusions with known follow-up in
      order to use these as diagnostic markers. Besides their ability to identify
      malignant epithelial cells their contribution to the differential diagnosis
      between carcinomatoses and mesotheliomas was investigated. 101 tumour cell
      positive and 53 negative effusions were stained with 12 different antibodies.
      Results were scored semiquantitatively per cell type. Furthermore, DNA-image
      cytometry was performed. While prevalence of Ber-EP4 positivity was 95.4% in
      metastatic carcinoma cells, it was 0% in those from mesotheliomas. No cell type
      reacted with this marker in benign effusions (0%). Ber-EP4 correctly
      differentiated between metastatic carcinoma and mesothelioma in 98.0%. Prevalence
      of DNA-aneuploidy was 95.4% in metastatic carcinomas, 57.1% in mesotheliomas and
      0% in reactive effusions. Combining immunocytochemistry (Ber-EP4 positivity) and
      DNA-image cytometry (aneuploidy) results in a 100% detection of metastatic
      carcinomatoses and 57.1% of mesotheliomas. Both markers furthermore allowed a
      correct differentiation of these entities in 98%.

PMID- 10661622
TI  - The use of fractal features from the periphery of cell nuclei as a classification
      tool.
AB  - A polygonization-based method is used to estimate the fractal dimension and
      several new scalar lacunarity features from digitized transmission electron
      micrographs (TEM) of mouse liver cell nuclei. The fractal features have been
      estimated in different segments of 1D curves obtained by scanning the 2D cell
      nuclei in a spiral-like fashion called "peel-off scanning". This is a venue to
      separate estimates of fractal features in the center and periphery of a cell
      nucleus. Our aim was to see if a small set of fractal features could discriminate
      between samples from normal liver, hyperplastic nodules and hepatocellular
      carcinomas. The Bhattacharyya distance was used to evaluate the features.
      Bayesian classification with pooled co-variance matrix and equal prior
      probabilities was used as the rule for classification. Several single fractal
      features estimated from the periphery of the cell nuclei discriminated samples
      from the hyperplastic nodules and hepatocellular carcinomas from normal ones. The
      outer 25-30% of the cell nuclei contained important texture information about the
      differences between the classes. The polygonization-based method was also used as
      an analysis tool to relate the differences between the classes to differences in
      the chromatin structure.

PMID- 10661623
TI  - K-ras2 activation and genome instability increase proliferation and size of FAP
      adenomas.
AB  - The possible role of K-ras2 mutations and aneuploidy toward increase of
      proliferation and adenoma size in Familial Adenomatous Polyposis (FAP) adenomas
      is not known. The present study addresses these issues by investigating 147
      colorectal adenomas obtained from four FAP patients. The majority of adenomas had
      size lower than or equal to 10 mm (86%), low grade dysplasia (63%), and were
      preferentially located in the right colon (60%). Normal mucosa samples were
      obtained from 19 healthy donors. Three synchronous adenocarcinomas were also
      investigated. K-ras2 mutation spectrum was analysed by PCR and Sequence Specific
      Oligonucleotide (SSO) hybridization, while flow cytometry (FCM) was used for
      evaluating degree of DNA ploidy and S-phase fraction. Overall, incidences of K
      ras2 mutations, DNA aneuploidy and high S-phase values (>7.2%) were 6.6%, 5.4%
      and 10.5%, respectively. In particular, among the adenomas with size lower than 5
      mm, K-ras2 mutation and DNA aneuploidy frequencies were only slightly above 1%.
      Statistically significant correlations were found between K-ras2 and size, DNA
      ploidy and size and K-ras2 and S-phase (p < 0.001). In particular, among the wild
      type K-ras2 adenomas, high S-phase values were detected in 8% of the cases versus
      57% among the K-ras2 mutated adenomas (p = 0.0005). The present series of FAP
      adenomas indicates that K-ras2 activation and gross genomic changes play a role
      toward a proliferative gain and tumour growth in size.

PMID- 10661624
TI  - Measurement of section thickness: are PAS prestained celloidin control cylinders
      the ultimate solution?

PMID- 10661625
TI  - Measurement of section thickness: bias and absolute versus comparative results.

PMID- 10661626
TI  - European consensus on standardized AgNOR analysis in cytopathology.

PMID- 10661627
TI  - EASCP adopts the new EUROQUANT server fully developed by members of the society.

PMID- 10661629
TI  - Early experience using duplex ultrasonography in the diagnosis of deep venous
      thrombosis; a prospective evaluation.
AB  - Duplex ultrasound is used in many radiology departments as the first line of
      investigation for symptomatic deep venous thrombosis. Before changing the
      practice of our department from venography to duplex ultrasonography, we wanted
      to assess our ability to identify deep venous thrombosis on ultrasound. Thirty
      eight patients were investigated for suspected deep venous thrombosis by
      venography and duplex ultrasound. The results were compared using venography as
      the 'gold standard'. Duplex ultrasound correctly identified 13 out of 16 limbs
      with deep venous thrombosis. Four of the 38 duplex ultrasound examinations (11%)
      were described as inadequate at the time of examination, and when these are
      excluded from the analysis a sensitivity of 93 %, and specificity of 80 % are
      achieved. We conclude that there is a significant learning curve when performing
      duplex ultrasound of the lower limb, and that change-over from venography to
      ultrasound should include a period during which both examinations are routinely
      performed.

PMID- 10661628
TI  - Ultrasonography of intratesticular lesions: its role in clinical management.
AB  - Ultrasound is the primary imaging modality in the investigation of patients with
      symptoms related to the scrotum, and is pivotal to the diagnosis of suspected
      testicular malignancy. This retrospective study analysed the results of
      testicular ultrasound at a large teaching hospital over a five year period. We
      wished to examine the clinical consequences for patients in whom ultrasound
      findings were suspicious of testicular cancer, and the accuracy of the ultrasound
      diagnosis. Real time ultrasound examinations were performed, providing
      multiplanar imaging of the testis and para testicular tissues. Over a five year
      period 661 examinations were carried out. An intratesticular lesion was
      identified in 44 patients; nineteen of these patients were shown to have
      testicular malignancy following tissue diagnosis. When ultrasound was used to
      identify testicular malignancy in those patients with an intratesticular lesion,
      it had a sensitivity of 94.7% and a specificity of 59.1%. A tissue diagnosis was
      obtained in 93% of those patients thought likely to have a testicular malignancy
      on sonographic assessment, and in 40% of those in whom a diagnosis of malignancy
      was possible, but less likely. Our study shows that this modality can be used to
      aid the clinician in deciding which patients should undergo orchidectomy,
      invasive biopsy or clinical surveillance.

PMID- 10661630
TI  - Laparoscopic cholecystectomy: experience with 303 patients over the initial four
      years.
AB  - A total of 303 patients underwent attempted laparoscopic cholecystectomy (LC)
      over a four-year period by two consultant surgeons or a senior trainee under
      their supervision. The procedure was completed in 291 with a conversion rate to
      open cholecystectomy of 3.9% and a median postoperative length of stay of two
      days, range zero to nine days. In eighteen patients the indication for LC was
      failure of symptoms to settle, two of whom required conversion (11.1%). Diathermy
      dissection was avoided in Calot's triangle and dissection started at the junction
      of Hartmann's pouch and cystic duct with full mobilisation of this area prior to
      clip application. Pre-operative endoscopic retrograde cholangiopancreatography
      ERCP was performed in patients suspected of having common bile duct stones
      without routine intra-operative cholangiography. There was one death in this
      series (0.3%) and an overall complication rate of 6.3 %. There was no incidence
      of either bile duct injury or leak. LC can be performed with a low complication
      rate with attention to careful dissection technique in the region of Calot's
      triangle.

PMID- 10661631
TI  - A prospective randomised study comparing polyethylene glycol and sodium phosphate
      bowel cleansing solutions for colonoscopy.
AB  - Polyethylene glycol (Klean-Prep, Norgine) is widely used for bowel cleansing in
      the United Kingdom. This study compares the efficacy, acceptability and adverse
      effects of a polyethylene glycol (PEG) solution with sodium phosphate (Fleet
      Phospho-soda, De Witt) for bowel preparation prior to colonoscopy. Two hundred
      and nine consecutive patients were prospectively randomised to either PEG or
      sodium phosphate (SP) preparation. The endoscopist was blinded to the
      randomisation process. Fifty patients were excluded from the study because of
      previous colectomies or incomplete data. Of the remaining 159 patients, 88 had
      been randomised to the PEG group and 71 to the SP group. There was no difference
      in sex distribution between the groups. There were no significant differences
      between groups in terms of patient acceptability, side effects (nausea/vomiting
      and abdominal cramps), adequacy of bowel preparation and colonoscopy completion
      rates. 74% of the PEG and 70.4% of the SP group were rated by the endoscopist as
      having good or excellent bowel preparation. Sodium phosphate is well tolerated
      without additional side effects when compared with PEG solution. Both solutions
      were found to be equally effective in bowel cleansing.

PMID- 10661632
TI  - A comparison of open access endoscopy and hospital-referred endoscopy in a
      district general hospital.
AB  - Open access endoscopy (OAE) is widely used in many hospitals. The aim of this
      study was to compare the upper gastrointestinal endoscopies referred to as "OGDs"
      performed under the OAE service and those referred from hospital outpatient
      clinics (HR) during the initial year in which an OAE service was provided in a
      district general hospital. A retrospective review of medical records from all
      patients undergoing OGD during the first year of OAE to identify the waiting time
      for OGD, the extent of pre-treatment at the time of OGD, the endoscopic findings
      and the number of endoscopies in which oesophageal or gastric neoplasia was
      detected. Follow-up endoscopies (n = 41) were excluded. Of 739 OGDs included, 384
      (177 male; mean age 48.0 yrs.) were performed under the OAE service, 346 (149
      male; mean age 50.7 yrs.) were referred from outpatient clinics and 9 could not
      be accurately classified. The waiting time was significantly lower in the OAE
      group compared to the HR group (24.5 v. 29.8 days, p<0.001). Pre-treatment at the
      time of OGD was significantly more frequent in the OAE group compared to the HR
      group (295 v. 186, p<0.001). Frequencies of the main endoscopic diagnoses did not
      differ significantly between the two groups. The OAE service provided faster
      access to OGD than the HR group and the endoscopic findings were similar in the
      two groups.

PMID- 10661633
TI  - A home from hospital service for older people.
AB  - Current policy and practice emphasises much more than ever before a need for
      purchasers and providers to reduce appropriately the length of hospital stay.
      Consequently, a number of early discharge "schemes" have been developed. This
      paper presents the findings from an evaluation of a "home from hospital" (HFH)
      scheme. The HFH service provides a maximum of six weeks' intensive domiciliary
      care for older people on their discharge from hospital. The aim of the service is
      to facilitate early discharge from hospital and to assist patients to regain
      independence. The study reported here elicited the views and perceptions of
      clients and professionals involved in the HFH scheme about the quality,
      efficiency and effectiveness of the service. Seventy-five patients were
      discharged from hospital to the HFH scheme during a two month period and those
      who consented to participate in the study were interviewed after discharge from
      the HFH service (n = 40). Participants had attended hospital for various
      conditions but the largest group were fracture patients. Hospital staff and
      community based professionals completed a questionnaire about the service.
      Overall, patients and professionals perceived the HFH scheme as a beneficial
      service, though some minor problems existed at an individual level. Clients'
      dependency levels generally decreased during their time on the scheme. Research
      using a controlled design is necessary in order to draw firm conclusions about
      the cost-effectiveness of a HFH service. Overall, home-from-hospital appears to
      be an effective model of an early discharge scheme worthy of further attention.

PMID- 10661634
TI  - None so deaf. 171st annual oration. Royal Victoria Hospital, Belfast 1st October
      1998.

PMID- 10661635
TI  - Intracranial haemangioma: clinical features and radiological appearances.

PMID- 10661636
TI  - Rapid idiopathic osteolysis of the shoulder.

PMID- 10661637
TI  - Rectus sheath haematoma.

PMID- 10661638
TI  - Extramedullary gastric plasmacytoma.

PMID- 10661639
TI  - Hereditary benign telangiectasia--first family in Northern Ireland.

PMID- 10661640
TI  - Benign neoplastic polyp of the caecum as a rare cause of intussusception in
      adults.

PMID- 10661641
TI  - Small bowel intussusception in metastatic endometrial carcinoma.

PMID- 10661642
TI  - Incidental bile duct adenomas in a patient with obstructive jaundice.

PMID- 10661643
TI  - Body fat distribution and obesity in pre- and postmenopausal breast cancer.
AB  - BACKGROUND: Excessive body weight is known to increase the risk of
      postmenopausal, but not premenopausal breast cancer. Some studies have suggested
      that being overweight is protective against premenopausal breast cancer, but the
      evidence is not compelling. Much less is known about the role of body fat
      distribution in either pre- or postmenopausal breast cancer. METHODS: Breast
      cancer risk was examined in relation to body weight, height, Quetelet index
      (kg/m2), and waist/hip ratio (WHR) in the New York University Women's Health
      Study, a prospective cohort study. Cases were 109 premenopausal and 150
      postmenopausal women diagnosed with breast cancer between 1985 and 1994. Non
      cases were 8,157 cohort members free of breast cancer. RESULTS: Among
      premenopausal women, there was an increasing risk of breast cancer with
      increasing WHR. The relative risk (RR) of breast cancer increased to 1.72 (95%
      confidence interval [CI]: 1.0-3.1) in the upper quartile of WHR. The association
      was limited to subjects who had elevated Quetelet index, but not among those with
      lower weight. Overall, Quetelet index itself was not related to breast cancer
      risk in the premenopausal group, but there was a protective association among
      those ranking below the median WHR. In postmenopausal women, the RR for breast
      cancer increased to 2.36 (95% CI: 1.4-3.9) in the upper quartile of Quetelet
      index, but there was no association with WHR. Height was not associated with
      breast cancer in this study. CONCLUSIONS: The study confirms that excessive body
      weight increases breast cancer risk in postmenopausal women. On the contrary, in
      premenopausal women, excessive body weight may be protective among women who have
      a lower-body type of fat accumulation (low WHR). An upper-body fat accumulation
      (high WHR) is a predictor of breast cancer risk in premenopausal women, and this
      effect is especially pronounced among subjects who are overweight.

PMID- 10661644
TI  - Cohort analysis of cigarette smoking and lung cancer incidence among Norwegian
      women.
AB  - BACKGROUND: Cancer registries have for decades surveyed the development of cancer
      diseases. Data on incident cases includes demographic variables. Knowledge of the
      temporal distribution of risk factors on the same variables makes it possible to
      model the relationship between disease and risk factor. The results of such
      analyses might be difficult to interpret since they are based on aggregated data.
      But the availability of these data sources should encourage further exploration
      of its possibilities and limitations. METHODS: The temporal pattern of smoking
      habits in 5-year birth cohorts from 1890-1949 was established, with data on the
      proportions of current smokers, former smokers and non-smokers and estimated
      average daily consumption of tobacco and average duration of smoking. The lung
      cancer incidence among the cohorts in 1953-1992 was analysed by a model which
      included an additive excess risk for smokers that depended on daily dose and
      duration of smoking. RESULTS: The lung cancer incidence in later decades was
      adequately described by the model, which showed a simple relationship with
      smoking behaviour in the cohorts. For both current smokers and former smokers,
      the excess risk was about proportional to the daily amount smoked and the 4.5
      power of duration of smoking. The age-specific rates for non-smokers were close
      to a fifth-power curve of age. CONCLUSIONS: Even if lung cancer incidence is not
      determined separately for groups with known smoking habits, plausible estimates
      of the effect of smoking can be derived if appropriate information is available
      on temporal smoking habits in the population.

PMID- 10661645
TI  - Occupational risk factors for mortality from stomach and lung cancer among rubber
      workers: an analysis using internal controls and refined exposure assessment.
AB  - OBJECTIVES: To determine occupational risk factors for stomach and lung cancer
      among workers in the German rubber industry. METHODS: A cohort of all male German
      rubber workers (n = 11,633) who had been employed for at least one year in one of
      five study plants and who were alive and actively employed or retired on 1
      January 1981 was followed for mortality from 1 January 1981 through December
      1991. A subcohort of n = 8,933 workers who were hired after 1 January 1950 was
      defined to focus on working conditions in the more recent rubber industry. Work
      histories were reconstructed using routinely documented 'cost centre codes' and
      classified into six work areas as well as subgroups of some work areas. The work
      areas are: 1. preparation of materials, 2. production of technical rubber goods,
      3. production of tyres, 4. storage and dispatch, 5. maintenance, 6. others.
      Standardized mortality ratios (SMR) and Cox proportional hazards models were
      calculated for each of the work areas (>1 year of employment in the respective
      work area). Hazard rate ratios were adjusted for age (time marker) and stratified
      for year of hire (1950-1959, > or =1960) and years of employment in the
      respective work area (1-9 years, > or =10 years); years of employment were lagged
      10 years to account for latency. RESULTS: Compared to the national reference
      population mortality from cancer of stomach (observed 44, SMR = 117; 95% CI: 85
      157) and lung (observed 154, SMR = 123; 95% CI: 104-144) was slightly increased.
      Using internal controls we observed excess deaths from stomach cancer in work
      area 1 (relative risk [RR] = 2.3; 95% CI: 1.2-4.2) and from lung cancer in work
      areas 1 (RR = 1.7; 95% CI: 1.2-2.3), 2 (RR = 1.5; 95% CI: 1.1-2.1), and 3 (RR =
      1.3; 95% CI: 0.9-1.8). On the basis of cumulative years of employment an exposure
      response relationship was observed for mortality from both cancer sites among a
      subcategory of work area 1: weighing and mixing. Increased risks were also seen
      for lung cancer among workers employed in production of technical rubber goods.
      CONCLUSION: Our results support an association between an excess mortality from
      stomach and lung cancer and employment in early production stages of rubber
      manufacturing, especially weighing and mixing. This may point to an aetiologic
      role of asbestos or carbon black. For stomach cancer additional risk factors,
      e.g. exposure to dust and talc, deserve further investigation. The results of the
      present study do not support a causal role of nitrosamines for stomach or lung
      cancer.

PMID- 10661646
TI  - Coronary heart disease mortality trends in men in the post World War II birth
      cohorts aged 35-44 in Japan, South Korea and Taiwan compared with the United
      States.
AB  - BACKGROUND: Since World War II, people in Japan, South Korea, and Taiwan have
      been exposed to a westernized lifestyle. It is most likely that the post World
      War II cohorts (1950+) have been more exposed. We hypothesize that there would be
      an increase in mortality from coronary heart disease (CHD) in men aged 35-44 in
      these countries. METHODS AND RESULTS: Mortality from CHD in men aged 35-44 in
      South Korea and Taiwan has recently increased, and in Japan it has decreased.
      Mortality from CHD in men aged 35-44 is lower in Japan than in either South Korea
      or Taiwan, and much lower than in the US. National sample data and several
      epidemiological studies have shown that risk factors for CHD including
      hypercholesterolaemia and hypertension in the past decade were not much different
      between young adult men in Japan and the US. Based upon these risk factors, CHD
      death rates among post World War II cohorts should be similar in Japan and the
      US. However, the rates are five times higher in the US for men aged 35-44. The
      majority of deaths in the category of diseases of the heart were from heart
      failure in men in this age group in Japan; the mortality from heart failure was
      about three times higher than the mortality from CHD. Heart failure was rarely
      used in men aged 35-44 in the US. CONCLUSIONS: The continued low mortality rates
      from CHD in young men in Japan may be an artifact. It is possible that CHD death
      rates in post World War II birth cohort in Japan are similar to US rates.

PMID- 10661647
TI  - Trends and geographical disparities in coronary heart disease in France: are
      results concordant when different definitions of events are used?
AB  - OBJECTIVES: To assess whether different definitions of acute coronary events
      yielded concordant results concerning trends and geographical disparities in
      coronary heart disease (CHD) mortality and morbidity in France. STUDY DESIGN:
      Data from three French CHD registries participating in the WHO MONICA Project
      during the period 1985-1992. SETTING: Three areas of about one million
      inhabitants each in the North, South and East of France. SUBJECTS: About 2,000
      acute coronary events each year. MAIN OUTCOME MEASURES: Mortality, annual rate of
      fatal and non-fatal events, incidence of first and recurrent events, case
      fatality rates. RESULTS: For incidence and mortality, the broader the broader the
      definition of the acute event, the higher the reported rates. The same tendency
      was not observed for case-fatality rates. Comparing between-registry rates for
      mortality, 28-day case-fatality and hospital case fatality yielded relatively
      concordant results whatever the definition of event. As a whole, the higher
      mortality rate in Lille and its intermediate rank in Strasbourg were related more
      to disparities in case-fatality rates, with only small variations in incidence
      rates, independently of the definition used. Comparing temporal trends in rates
      within and between regions, a consistent decrease in annual mortality rates and
      case-fatality rates was observed, whatever the definition. In contrast, the
      incidence of non-fatal probable myocardial infarction did not change during the
      period in any register. CONCLUSIONS: Although the absolute estimates of rates
      were variable with the definition of the event, major findings in relation to
      trends and geographical disparities were fairly consistent across the
      definitions: the North-South gradient in mortality observed in France was found
      to be much more pronounced for case fatality than for incidence. The proportion
      of milder acute myocardial infarction is currently increasing and this element
      should be taken into account when analysing CHD rates.

PMID- 10661648
TI  - Stroke incidence and case fatality in Shiga, Japan 1989-1993.
AB  - BACKGROUND: This paper describes incidence rates and case-fatality for sub-types
      of stroke using data collected in Takashima, Shiga, Japan, from 1989 to 1993 and
      compares these with similar registers in other parts of Japan. METHODS:
      Registered patients included all residents of the county who experienced a first
      ever stroke. Stroke was defined as sudden onset of neurological symptoms which
      continued for a minimum of 24 hours or led to death. Almost all such patients are
      hospitalized in this country. Early case fatality was defined as patients who
      died within 28 days of stroke onset. Diagnosis of stroke type was based on
      clinical symptoms as well as computed tomography (CT) scans. RESULTS: Age
      adjusted incidence rates for stroke per 100,000 population aged 35 years and
      older were 268.7 for men and 167.5 for women. The age-specific incidence rate of
      both cerebral infarction and cerebral haemorrhage increased with advancing age.
      The occurrence of cerebral infarction in men was twice as high as in women. The
      28-day case fatality for all sub-types of stroke was 16.1% in men and 15.8% in
      women. Case fatality for cerebral infarction, cerebral haemorrhage, and
      subarachnoid haemorrhage was 10.7%, 22.4% and 28.6% respectively. CONCLUSIONS:
      Takashima County has a moderately high stroke incidence rate and case fatality
      compared with other similar studies in Japan. The incidence rate of cerebral
      infarction in men is twice that in women, while other sub-types of stroke showed
      smaller differences. In order to decrease the incidence of stroke in Japan,
      greater efforts at primary prevention will be necessary, in particular, it is
      important to prevent cerebral infarction in men.

PMID- 10661649
TI  - The relationship between alcohol consumption, health indicators and mortality in
      the German population.
AB  - BACKGROUND: The patterns of total alcohol, beer and wine consumption were
      evaluated in the German National Health Surveys. The impact of these habits on
      cardiovascular and all-cause mortality as well as cardiovascular risk factors and
      liver disease parameters was estimated. METHODS: Independent representative
      samples of the German population (15,400 people), and regional samples of the
      Berlin-Spandau population (2,370 in total), aged 25-69 years, were analysed. The
      amount and frequency of alcohol consumption was assessed with standardized
      questionnaires. Biochemical analyses included serum lipids and gamma-glutamyl
      transpeptidase (Gamma GT). Multiple analyses of variance were used to determine
      the relationship between alcohol intake and biochemical parameters. A mortality
      follow-up of about 7 years was conducted for the Berlin-Spandau population.
      Proportional hazard models were used to estimate hazard ratios (HR) for all-cause
      and cardiovascular mortality. RESULTS: Over 80% of men and 55% of women in
      Germany drink alcohol on a regular base. The majority of the consumers (65% of
      men, 87% of women) are light (1-20 g/day) or moderate (21-40 g/day) drinkers.
      Higher serum high density lipoprotein (HDL)-cholesterol and Gamma GT levels were
      observed with increasing alcohol intake. In light and moderate drinkers no
      significant relationship was seen with non-HDL-cholesterol, triglycerides, blood
      pressure and body mass index, compared to teetotallers. Men who consumed 1-20 g
      alcohol/day had a significantly lower all-cause and cardiovascular mortality. As
      compared to nondrinkers, the risk was almost 50% lower. CONCLUSION: The results
      suggest that light (and possibly moderate) alcohol consumption reduces the risk
      of cardiovascular and total mortality risk and is favourably related to HDL
      cholesterol.

PMID- 10661650
TI  - Change in lifestyle factors and their influence on health status and all-cause
      mortality.
AB  - BACKGROUND: The purpose of this study was to analyse both cross-sectional
      associations and how longitudinal changes in lifestyle factors from one state in
      1980-1981 to another in 1988-1989 influence self-reported health status. Another
      aim was to estimate the hazard ratios for all-cause mortality for the changes in
      lifestyle factors and self-reported hypertension during the same period of time.
      METHOD: The cross-sectional and the longitudinal analyses are based on the same
      simple random sample of 3,843 adults, aged 25-74, interviewed in 1980-1981 and
      1988-1989 and is part of the Swedish Annual Level-of-Living Survey. About 85% of
      the respondents in the first interview participated in a second interview in 1988
      1989. Cross-sectional odds ratios, based on a marginal model, were estimated
      using the generalized estimating equations. The transitional models were analysed
      using unconditional logistic regression. A proportional hazard model was applied
      to investigate the influence of lifestyle transitions on mortality. RESULTS:
      Physical inactivity, being a current or former smoker and obesity (women only)
      were strong risk factors for poor health either as main effects and/or combined
      (interactions). There was a strong interaction between physical activity and
      smoking, and for women, also between body mass index (BMI) and physical activity.
      Smoking, physically inactive and obese women had about a ten times higher risk of
      poor health status than non-smoking, physically active, and normal-weight women.
      The corresponding risk for men was about five times higher. Physically active,
      but smoking and obese individuals showed only moderately increased risks for poor
      health status. The transitional model showed that those who were physically
      inactive in 1980-1981, but did exercise in 1988-1989, improved their health after
      adjustments for sociodemographic and other lifestyle factors. Continuing to smoke
      or being physically inactive or having hypertension at both points in time were
      all associated with higher hazard ratios for all-cause mortality (1.6, 1.9 and
      1.8, respectively) than those who reported that they were in good status at both
      points in time. CONCLUSIONS: We found that physical activity protects against
      poor health irrespective of an increased BMI and smoking. The major clinical
      implications are the long-standing benefits of physical activity and not smoking.

PMID- 10661651
TI  - Diagnostic accuracy of physician review, expert algorithms and data-derived
      algorithms in adult verbal autopsies.
AB  - BACKGROUND: The verbal autopsy (VA) is used to collect information on cause
      specific mortality from bereaved relatives. A cause of death may be assigned by
      physician review of the questionnaires, or by an algorithm. We compared the
      diagnostic accuracy of physician review, an expert algorithm, and data-derived
      algorithms. METHODS: Data were drawn from a multicentre validation study of 796
      adult deaths that occurred in hospitals in Tanzania, Ethiopia, and Ghana. A 'gold
      standard' cause of death was assigned using hospital records and death
      certificates. The VA interviews were carried out by trained fieldworkers 1-21
      months after the subject's death. A cause of death was assigned by physician
      review and an expert algorithm. Data-derived algorithms that most accurately
      estimated the cause-specific mortality fraction (CSMF) for each cause of death
      were identified using logistic regression. RESULTS: The most common causes of
      death were tuberculosis/AIDS (CSMF = 18.6%), malaria (CSMF = 10.7%), meningitis
      (CSMF = 8.3%), and cardiovascular disorders (CSMF = 8.2%). The CSMF obtained
      using physician review was within +/-20% of the gold standard value for 12 causes
      of death including the four common causes. The CSMF obtained using the expert
      algorithm was within +/-20% of the gold standard for eight causes of death,
      including tuberculosis/AIDS, malaria, and meningitis. The CSMF obtained using the
      data-derived algorithms was within +/-20% of the gold standard for seven causes
      of death, including tuberculosis/ AIDS, meningitis, and cardiovascular disorders.
      All three methods yielded a specificity of at least 80% for all causes of death,
      and a sensitivity of at least 80% for deaths due to injuries and rabies.
      CONCLUSIONS: For those settings where physician review is not feasible, expert
      and data-derived algorithms provide an alternative approach for assigning many
      causes of death. We recommend that the algorithms proposed herein are validated
      further.

PMID- 10661652
TI  - Prenatal or early postnatal events predict infectious deaths in young adulthood
      in rural Africa.
AB  - BACKGROUND: Research over the past decade has suggested that prenatal and early
      postnatal nutrition influence the risk of developing chronic degenerative
      diseases up to 60 years later. We now present evidence that risk of death from
      infectious diseases in young adulthood is similarly programmed by early life
      events. METHODS: In three rural Gambian villages, affected by a marked annual
      seasonality in diet and disease, we have kept detailed demographic,
      anthropometric and health records since 1949. Fate was known with certainty for
      3,162 individuals (2,059 alive/1,103 dead, most dying in childhood). For this
      case-control analysis of antecedent predictors of premature mortality, all adult
      deaths (n = 61) were paired with two randomly selected controls matched for sex
      and year of birth. RESULTS: Mean age at death was 25 (SD: 8) years. Adult death
      was associated with a profound bias in month of birth with 49 cases born in the
      nutritionally-debilitating hungry season (Jul-Dec) versus 12 in the harvest
      season (Jan-Jun). Relative to harvest season the hazard ratio for early death in
      hungry-season births rose from 3.7 (for deaths >14.5 years, P = 0.000013) to 10.3
      (for deaths >25 years, P = 0.00002). Anthropometric and haematological status at
      18 months of age was identical in cases and controls, indicating an earlier
      origin to the defect. Most deaths for which cause was known had a definite or
      possible infectious aetiology; none were from degenerative diseases of affluence.
      CONCLUSIONS: Early life exposures, correlated with season of birth, strongly
      influence susceptibility to fatal infections in young adulthood. The evidence
      suggests that nutritionally-mediated intrauterine growth retardation may
      permanently impair the development of immune function.

PMID- 10661653
TI  - Are very low birthweight births among American Indians and Alaska Natives
      underregistered?
AB  - BACKGROUND: International infant mortality rates vary widely. This variation has
      been attributed to many factors, including differential reporting. In the US,
      American Indians and Alaska Natives (AI/AN), who generally have low socioeconomic
      status, have a low neonatal mortality rate. One possible explanation is
      underregistration of very low birthweight (VLBW, < 1,500 g) births. We
      hypothesized that underregistration may occur disproportionately among AI/AN
      residing on or near reservations (areas controlled by an American Indian group).
      We estimated infant mortality in these areas. METHODS: Linked birth-infant death
      files for 1989-1991 were used to compare VLBW and neonatal mortality among AI/AN
      infants in counties with reservations with those in non-reservation counties. The
      VLBW rates for non-reservation counties were applied to the reservation risk
      distribution to calculate directly adjusted VLBW and neonatal mortality rates for
      reservation counties. This method assumes that greater registration in non
      reservation counties yields a more accurate estimate of the relationship between
      risk factors and outcomes. RESULTS: Despite a higher prevalence in reservation
      counties of risk factors, the reported VLBW rate was 0.84% in reservation and
      1.17% in non-reservation counties. The neonatal mortality rate was 5.4 per 1,000
      in reservation counties and 6.0 in non-reservation counties. Direct adjustment
      yielded a VLBW rate of 1.28% (95% CI: 1.14-1.39) and a neonatal mortality rate of
      6.7-9.8 per 1,000 in reservation counties. CONCLUSIONS: Reported neonatal
      mortality among AI/AN may understate the true rate due to underregistration of
      VLBW births. Direct adjustment may be useful in estimating infant mortality rates
      for populations with incomplete vital registration.

PMID- 10661654
TI  - Adult nutrient intake as a risk factor for Parkinson's disease.
AB  - BACKGROUND: This population-based case-control study evaluated nutrient intake as
      a risk factor for Parkinson's disease (PD) among people aged > or =50 years in
      metropolitan Detroit. METHODS: Cases (n = 126) were diagnosed between 1991 and
      1995 and neurologist-confirmed. Controls (n = 432) were frequency-matched for
      sex, age (+/-5 years) and race. Using a standardized food frequency
      questionnaire, subjects reported the foods they ate within the past year.
      RESULTS: Estimating the association between PD and risk of being in the highest
      versus the lowest intake quartile, there were elevated odds ratios for total fat
      (OR 1.94, 95% confidence interval [CI] : 1.05-3.58), cholesterol (OR 2.11, 95%
      CI: 1.14-3.90), lutein (OR 2.52, 95% CI: 1.32-4.84) and iron (OR 1.88, 95% CI:
      1.05-3.38). CONCLUSIONS: These results suggest an association of PD with high
      intake of total fat, saturated fats, cholesterol, lutein and iron.

PMID- 10661655
TI  - Trends in dementia-free life expectancy among elderly members of a large health
      maintenance organization.
AB  - BACKGROUND: This study examined the secular trends of life expectancy without
      dementia among elderly American members of a health maintenance organization, and
      observed if an increased life expectancy is accompanied by an increase in the
      duration of life with dementia. METHODS: The data derived from two chronological
      9-year prospective cohort studies of members of the Kaiser Permanente Medical
      Care Program of Northern California. The first and second cohorts included 2,702
      and 2,926 people aged > or =65 years free from dementia at baseline. Life
      expectancy without dementia or dementia-free life expectancy (DemFLE) is defined
      as the average number of years a person is expected to live without dementia.
      Total life expectancy is equal to the sum of DemFLE and life expectancy with
      dementia. Estimations of DemFLE were based on mortality data and incidence of
      dementia, using double-decrement life tables. RESULTS: Between the first and
      second cohorts, all-cause mortality rates declined, while the incidence of
      dementia remained constant in both men and women. Among the males, total life
      expectancy increased at a higher rate than DemFLE. Consequently, the duration of
      life with dementia was extended in the second cohort. Conversely, among the
      females DemFLE increased at a higher rate than total life expectancy, thus the
      duration of life with dementia decreased in the second cohort. The median age of
      dementia onset was postponed by 2-3 years in the second cohort for females, and
      did not show any specific difference between the two cohorts in males.
      CONCLUSION: The trends of health expectancies suggest an extension of the
      duration of life with dementia for males and a compression of dementia for
      females. A decreased incidence of risk factors for dementia among females in the
      second cohort such as stroke may explain these trends.

PMID- 10661656
TI  - Diabetes mellitus among South Asian inhabitants of The Hague: high prevalence and
      an age-specific socioeconomic gradient.
AB  - BACKGROUND: The prevalence of diabetes mellitus is known to be high among South
      Asians. The Municipal Health Service in The Hague investigated the prevalence of
      self-reported diabetes among South Asian inhabitants of The Hague, and the
      relationship between diabetes prevalence and socioeconomic status in this
      population. METHODS: A total of 3,131 South Asians >30 years of age, randomly
      selected (stratified according to age and sex) from the municipal register, were
      included in a postal survey with subsequent telephone interviews with non
      respondents. RESULTS: Self-reported diabetes prevalence varies from 6.4% in the
      31-49 year age group to 37.1% in the over 60s age group. The relationship with
      age varies across the different socioeconomic strata. There are only a few people
      with diabetes in the 31-39 year age group in the highest stratum, whereas in the
      lowest stratum at the same age the prevalence of self-reported diabetes
      approximates 20%. In the over 60s age group the prevalence of diabetes does not
      significantly differ between the higher and lower socioeconomic strata.
      CONCLUSIONS: Diabetes is an extremely common disease among South Asian
      inhabitants of The Hague. In this population, the relationship between diabetes
      prevalence and socioeconomic status varies with age. Cohort and age effects may
      account for this variation.

PMID- 10661657
TI  - Assessing disaster-attributed mortality: development and application of a
      definition and classification matrix.
AB  - BACKGROUND: A useful step in developing and implementing sound policies to
      prevent disaster-attributed mortality is to classify the relationship between
      disasters and mortality. While there are classification methods for specific
      health outcomes, there is no standard method that includes all potential outcomes
      from exposure to a natural disaster. Without standards, our ability to assess
      health effects from disasters and implement prevention programmes is limited.
      METHODS: We present a method for ascertaining and classifying disaster-attributed
      mortality which includes a case definition, flow chart, and matrix. The matrix is
      used for coding, reporting, and evaluating information about manner, cause, and
      circumstance of disaster-attributed deaths and geographical location and time of
      the disaster. To illustrate its use, two readers determine and classify deaths
      attributed to Hurricane Andrew (1992, USA). RESULTS: Of 322 deaths investigated
      by the Dade County Medical Examiner's Office, our readers showed 97% (313/322)
      agreement on case status and 83% (35/42) agreement on case classification.
      CONCLUSIONS: Our definition allows for a liberal interpretation of what
      constitutes disaster-related circumstances and the conditions or diseases that
      might arise from these circumstances. The inclusion of the flow chart and matrix
      provides a framework for consistent case classification and reporting. It also
      provides information about relationships between exposures and health effects,
      thereby identifying prevention policy needs.

PMID- 10661658
TI  - Secondary matching: a method for selecting controls in case-control studies on
      environmental risk factors.
AB  - BACKGROUND: The problem of control selection was considered in a population-based
      case-control study on pleural mesothelioma in Spain. Random sampling from the
      population was discarded because of potential selection bias due to low
      participation. Selection of hospital controls by matching them to cases by
      hospital seemed unsuitable for investigating environmental exposures, as the
      choice of hospital may be related to the place of residence; controlling for
      residence may avoid bias but could produce overmatching. METHODS: A three-step
      procedure was proposed. First, a random sample of primary controls from the
      population census of the province of Barcelona was obtained. Second, the hospital
      closest to the residence of the primary control was identified as the control
      hospital. Third a secondary control was chosen among patients admitted to the
      hospital matched to the primary control by sex, age and municipality. RESULTS: An
      overall participation rate of 85% was achieved. The hospital control group showed
      a distribution of residences similar to that of the general population, and
      independent of the distribution of cases. CONCLUSIONS: This procedure may be
      considered as an alternative for control selection when studying environmental
      factors or, generally, when matching cases and controls by hospital is to be
      avoided. Its validity was assessed according to the principles of comparability
      with cases regarding the study base, accuracy of information, deconfounding and
      efficiency.

PMID- 10661659
TI  - The impact of response bias on estimates of health care utilization in a
      metropolitan area: the use of administrative data.
AB  - BACKGROUND: Surveys among the general population are an important method for
      collecting epidemiological data on health and utilization of health care in that
      population. Selective non-response may affect the validity of these data. This
      study examines the impact of response bias on estimates of health care
      utilization and on risk estimates for utilization in relation to demographic and
      socioeconomic characteristics, using administrative data on use of health care.
      METHODS: Data on registered health care utilization were extracted from a health
      insurance register and linked to respondents (2,934; 62.7%) and non-respondents
      (1,744) in a personal health interview survey among adult residents from the
      lower two-thirds income bracket in Amsterdam, the Netherlands. RESULTS: Estimates
      of registered health care utilization are higher if based on respondents only,
      than if they are based on the entire target sample. This goes for prescription
      drugs, specialist medical care, paramedical care, dental care and medical aids,
      but not for hospital care. Most risk estimates of registered utilization for
      background characteristics (gender, family composition, marital status, year of
      settlement, affluence of neighbourhood and ethnicity) differ only slightly and
      without statistical significance. If different, most estimates based on
      respondents only are somewhat higher. The largest differences are found for age
      (average overestimation of risks for age groups 35-64 and 65+ years compared to
      that of 16-34 years: 16% and 17%, respectively). CONCLUSIONS: In this study,
      response bias affects estimates of registered health care utilization but hardly
      affects risk estimates of utilization by background characteristics.

PMID- 10661660
TI  - An age-period-cohort analysis of 50,875 AIDS cases among injecting drug users in
      Europe.
AB  - BACKGROUND: The long average incubation time from HIV infection to AIDS makes it
      difficult to estimate recent HIV transmission from AIDS incidence data. Age
      period-cohort (APC) analysis can separate out the effects of age, calendar time
      and birth cohort to provide a clearer picture of transmission trends. METHODS:
      AIDS incidence data from 1981 to 1994 among intravenous drug users (IDU) for 12
      Western European countries were used. Yearly incidences per 100,000 population or
      100,000 person-years were calculated by age at diagnosis and 5-year birth cohort
      (1950-1954, 1955-1959, 1960-1964, 1965-1969 and 1970-1974), and corrected for
      reporting delay. Incidence patterns were compared between birth cohorts and
      countries. RESULTS: For most countries the impact was greatest on the cohort born
      1960-1964. Comparing incidence patterns in the 1965-1969 to 1960-1964 cohorts
      suggest the epidemic has plateaued at low to intermediate levels in Austria,
      Greece and the North-Western European countries, and at high levels in France,
      Italy and Switzerland. For most countries transmission amongst the 1970-1974 as
      compared to the 1965-1969 cohorts could not be assessed due to small numbers and
      short follow-up time. In Spain the epidemic was uncontrolled with a high
      incidence among recent birth cohorts. In Portugal the epidemic was still at an
      early and expanding phase. CONCLUSIONS: The APC analysis revealed large country
      differences in the dynamics of the HIV/AIDS epidemic among IDU. Full
      interpretation of these differences is dependent on information from other
      sources about the local public health response and trends in drug injecting
      behaviours. Earlier introduction of the virus and higher prevalence of injecting
      drug use may explain some of the generally higher incidence in Southern European
      countries, but the larger part of it is most likely explained by local
      characteristics of drug users, such as younger age and more frequent sharing of
      needles and syringes, and a less effective public health response.

PMID- 10661661
TI  - Trends in HIV and AIDS based on HIV/AIDS surveillance data in Japan.
AB  - BACKGROUND: In recent years a decline in the number of new AIDS cases has been
      observed in several industrialized countries. It is important to know whether
      these recent trends observed in North America and Europe are also occurring in
      Japan. METHODS: The number of people reported with HIV and AIDS by nationality,
      route of infection, and sex was calculated based on the HIV/AIDS surveillance
      data available in Japan through December 1997. The effect of reporting delay,
      which was defined as those HIV and AIDS cases reported in the calendar year
      following diagnosis, on the trends was examined. The coverage rate in reporting
      HIV cases was estimated as the ratio of the reported AIDS cases with prior report
      as an HIV-positive to the total number of reported AIDS cases. RESULTS: The
      cumulative number of reported cases of HIV among Japanese and non-Japanese
      residents of Japan up to the end of 1997 were 1,300 and 1,190, respectively. The
      cumulative number of reported cases of AIDS among Japanese and non-Japanese up to
      the end of 1997 were 758 and 298, respectively. The number of reported cases of
      HIV among Japanese was found to be still increasing, with the major contribution
      from male cases. The increasing trend in the number of reported AIDS cases among
      Japanese began to slow in 1996 and 1997. The number of reported cases of HIV
      among non-Japanese residents of Japan peaked in 1992, and has decreased since
      then, and remained constant after 1994. In contrast, the number of reported AIDS
      cases among these non-Japanese tended to increase gradually. There was a slight
      reporting delay for people with HIV and AIDS. The estimated coverage rate in
      reporting HIV cases tended to decrease in 1996 and 1997 (1/7.2, 1/10.2,
      respectively). We point out several reasons for this recent decline and suggest
      the possibility of an ostensible decline in the estimates. CONCLUSIONS: We
      suggest that the number of people with HIV among Japanese has continued to
      increase, and that the increase in the number of AIDS cases among Japanese is now
      slowing.

PMID- 10661662
TI  - AIDS incidence and survival in a hospital-based cohort of asymptomatic HIV
      seropositive patients in Sao Paulo, Brazil.
AB  - BACKGROUND: In spite of the high incidence of AIDS in Brazil, few studies have
      tried to evaluate the prognosis of asymptomatic HIV seropositive Brazilian
      patients. METHODS: A hospital outpatient facility-based cohort of HIV
      seropositive asymptomatic subjects was followed to determine their probability of
      remaining AIDS-free at 2 and 4 years of follow-up, as well as the one-year
      estimated cumulative probability of survival for the AIDS incident cases. The
      cohort was made up of all asymptomatic HIV seropositive subjects referred to the
      Immunology Branch of a large university hospital in Sao Paulo, Brazil, between
      1985 and June 1997. RESULTS: The cumulative probability of remaining free from
      AIDS was 79% (+/- 3.7% SE) at 2 years, and 64.4% (+/- 5.1% SE) at 4 years after
      first known positive anti-HIV serology. Women had a marginally significant better
      probability of remaining AIDS-free after both 2 and 4 years of known
      seropositivity, as compared with men. There were no significant differences in
      the prognosis of the infection by age; the only single parameter associated with
      better prognosis was an initial CD4+ count > or =350/microl. The probability of
      survival one year after the diagnosis of AIDS was 78%, and the 50% estimated
      probability of survival was 19 months. Older patients (aged > or =35 years) had a
      better prognosis, as suggested by their longer survival estimates (P = 0.06).
      CONCLUSIONS: The probability of survival with AIDS observed in this study was
      higher than in the few previously published estimates for Brazil. However, since
      the time frame was so wide, it may not be entirely comparable with earlier
      studies. Some likely explanations for this possibly better prognosis could
      include more efficient prophylaxis for opportunistic diseases, as well as an
      increase in the availability of anti-retroviral drugs. The 8% incidence of AIDS
      at 2 years observed in this study for those individuals whose initial CD4+ count
      was > or =350/ml was close to that found in a large international epidemiological
      study of seroconverters.

PMID- 10661664
TI  - Incidence of trichiasis in a cohort of women with and without scarring.
AB  - BACKGROUND: Blindness from trachoma is a significant problem for many
      underdeveloped countries. While active trachoma is common in children,
      trichiasis, the potentially blinding sequella, develops in adulthood and affects
      mainly women. Little is known about factors associated with the development of
      trichiasis. METHODS: The 7-year incidence of trichiasis and its association with
      ocular chlamydia infection was examined in a cohort of women from a hyperendemic
      area. A total of 4,932 women 18 years and older, living in 11 villages in Central
      Tanzania, were examined in 1989. A follow-up examination in 1996 was performed on
      all women with scars living in six of the 11 villages and on a random sample of
      women without scars from the same villages. Trachoma was graded clinically,
      chlamydia infection was ascertained at follow-up using polymerase chain reaction
      enzyme immunoassay (PCR-EIA). RESULTS: A total 523 of the women with scars and
      503 of the women without scars were re-examined. Forty-eight of the women with
      scars (incidence, 9.2%) and three of the women without scars (0.6%) developed
      trichiasis in the 7-year period. Prevalence of chlamydia infection was
      significantly higher in the group with scars (11.7% versus 7.1%). Trichiasis
      cases were more likely to be older, and to have chlamydia infection at follow-up
      odds ratio (95% confidence interval) 2.5 (1.1-5.7). CONCLUSION: The 7-year
      incidence rate in the population with scars was high, over 1% per year. Ocular
      chlamydia infection was more common in the group with scars at baseline and was
      also associated with being a trichiasis case, suggesting the importance of
      potentially long-term chlamydia infection in the progression to trichiasis.
      Antibiotic distribution programmes for trachoma control should include women with
      scars.

PMID- 10661663
TI  - Broader vaccination of expatriates against HBV infection: do we reach those at
      highest risk?
AB  - BACKGROUND: The effects of the implementation of a new Dutch hepatitis B virus
      (HBV) vaccination strategy (1991) for expatriates on HBV vaccination status and
      HBV infection prevalence were evaluated in a group of 864 expatriates returning
      from HBV-endemic areas. METHODS: During a routine medical examination at the
      participating medical centres Dutch expatriates were asked to complete a
      questionnaire and to donate a serum sample for HBV testing. Blood was tested for
      antibodies against the hepatitis B core (anti-HBc) and surface antigens (anti
      HBs). The serological data were related to information gathered on aspects of
      residence, sexual risk behaviour and occupational risks. RESULTS: A significantly
      higher percentage of expatriates (37%) were vaccinated compared to a previous
      study in 1987-1989 (14%). However, the percentage of expatriates with HBV
      infection markers (5%) had not decreased significantly. Moreover, the risk for
      HBV infection, as determined with a questionnaire, was still affected by well
      known risk factors such as homosexual contacts (odds ratio [OR] = 6.6, 95% CI:
      1.7-26), more than five casual local partners (OR = 3.6, 95% CI: 1.2-11) and more
      than five occupational accidents in the last 3 years (OR = 20, 95% CI: 2-187).
      Detailed analysis of the vaccination status indicated that especially young
      female expatriates with low risk behaviour (65%) were protected, while older male
      expatriates with high risk behaviour were less protected (20%). CONCLUSION: We
      conclude that the new vaccination strategy has resulted in a higher percentage of
      expatriates protected. However, only a small proportion was reached of those at
      highest risk for HBV infection.

PMID- 10661665
TI  - Neonatal tetanus associated with topical umbilical ghee: covert role of cow dung.
AB  - BACKGROUND: Previous studies in Pakistan have shown that ghee (clarified butter)
      is commonly applied to umbilical wounds of neonates, and have documented that
      such applications are a risk factor for neonatal tetanus (NNT). In-use
      contamination of ghee with Clostridium tetani has been demonstrated, but
      mechanisms underlying the risk of ghee have been incompletely evaluated
      epidemiologically. METHODS: Detailed information on ghee usage, including fuels
      used to heat it, was obtained from cases of NNT (n = 229) and their matched
      controls (n = 687) from a population-based study of NNT in Punjab Province,
      Pakistan. Design variables were created to evaluate the impact of different fuel
      sources on risk of ghee applications. RESULTS: Nearly one-third of all infants
      had ghee applied, and it was nearly always heated before application to umbilical
      wounds of newborns. After controlling for all factors found to be significantly
      associated with NNT in conditional logistic regression, only ghee that had always
      been heated with dried cow dung fuel was significantly associated with NNT.
      Topical antimicrobials and ghee were never applied together. CONCLUSIONS: Ghee
      applications to umbilical wounds, when heated with 'clean' fuels, appear to pose
      no increased risk of NNT, although handling practices undoubtedly result in
      hazardous microbial contamination. In contrast, ghee heated with dung fuel was
      significantly associated with NNT. The effective promotion of topical
      antimicrobials might help reduce ghee use, since the intended purpose of each is
      to enhance healing.

PMID- 10661666
TI  - Modelling the incidence of congenital rubella syndrome in developing countries.
AB  - BACKGROUND: As of 1997, less than one-third of developing countries included
      rubella vaccine in their national immunization programme. In countries that have
      achieved high coverage of measles vaccine, an ideal opportunity exists to include
      control of rubella and congenital rubella syndrome (CRS) in enhanced measles
      control activities. Data on the burden of congenital rubella syndrome are
      important to guide rubella vaccination policies. METHODS: We reviewed the
      literature to identify studies of rubella antibody prevalence in developing
      countries that were conducted on populations with no major selection bias, prior
      to wide-scale rubella vaccination in the country. We used a simple catalytic
      model to describe the age-specific prevalence of susceptibility to rubella virus
      infection in given populations. Estimates of the incidence of infection among
      pregnant women were calculated using expressions for the average prevalence of
      susceptibility to infection and the incidence of infection during gestation. To
      estimate the number of cases of CRS, we assumed an overall risk of 65% after
      infection in the first 16 weeks of pregnancy and zero risk thereafter. These
      estimates were derived for each country for which data were available, then for
      each World Health Organization region, excluding Europe. RESULTS: The estimated
      mean incidence of CRS per 100,000 live births was lowest in the Eastern
      Mediterranean region (77.4, range 0-212) and highest in the Americas (175, range
      0-598). The mean of the estimates of the total number of cases of CRS in
      developing countries in 1996 was approximately 110,000. The range was, however,
      very wide, from as few as 14,000 to as many as 308,000 cases. CONCLUSIONS:
      Congenital rubella syndrome is an under-recognized public health problem in many
      developing countries. There is an urgent need for collection of appropriate data
      to estimate the cost-effectiveness of a potential global rubella control
      programme.

PMID- 10661667
TI  - Prior use of killed vaccine as a factor in measles incidence in Canada.

PMID- 10661668
TI  - Presence of illegal drugs in drivers involved in fatal road traffic accidents in
      Spain.
AB  - This study investigated the presence of illegal drugs in the blood of 285 fatally
      injured drivers in Spain. Illegal drugs were detected in 10.2% of all samples.
      Illicit drugs alone were detected in 2.5% and together with other substances in
      7.7%. Cocaine was the most common drug detected. The mean number (+/- S.D.) of
      substances detected was 2.6 +/- 1.2: consisting of 46 illegal drugs, 14 alcohol
      cases and 16 medicines. Three concentration levels of the different substances
      have been established: low, medium and high-toxic. In 68.9% of the samples in
      which an illegal drug was detected, a substance was also found at the high-toxic
      level. The results show that illegal drugs are commonly detected in road accident
      victims.

PMID- 10661669
TI  - Perceived risk of cocaine use and experience with cocaine: do they cluster within
      US neighborhoods and cities?
AB  - This study investigates whether experience with cocaine and the perception of
      risk associated with cocaine use might tend to cluster within neighborhoods and
      cities in the US. Population-based data from six years of the National Household
      Surveys on Drug Abuse public use files are employed. The alternating logistic
      regressions model is used to quantify the extent of geographic concentration.
      Perceptions of the harm associated with cocaine use and actual experience with
      cocaine tend to cluster within neighborhoods; once within-neighborhood
      concentration is taken into account, there is little evidence of residual
      concentration within cities.

PMID- 10661670
TI  - Hardcore drug users claim to be occasional users: drug use frequency
      underreporting.
AB  - Self-reports of drug use frequency are central to treatment outcome evaluations,
      estimates of the prevalence of heavy use, estimates of treatment need, and other
      questions with direct relevance to drug policies. Nevertheless, surprisingly
      little is known about the validity of these self-reports. This study examines the
      accuracy of 701 frequency self-reports made by a sample of methadone maintenance
      clients. Self-report accuracy is evaluated by comparing rates of positive
      urinalyses found for each case with rates that would be expected had drug use
      occurred only as often as reported. Expected rates of positive urinalyses are
      derived from conservative Monte Carlo models of drug use for each case. This
      procedure reveals extensive heroin and cocaine use frequency underreporting.
      After adjusting for frequency underreporting, 51% of 279 cases reporting only
      occasional heroin use (1-10 days in the past 30), and 22% of the 157 cases
      reporting occasional cocaine use, are found to be using these drugs with
      frequencies corresponding to what the Office of National Drug Control Policy
      defines as 'hardcore use' (more than 10 days in the past 30). Drug use frequency
      underreporting appears substantial, and might constitute an important threat to
      the validity of some treatment outcome evaluations, needs assessments and other
      analyses that rely on drug use frequency self-reports.

PMID- 10661671
TI  - Reliability of substance use disorder diagnoses among African-Americans and
      Caucasians.
AB  - Cross cultural research on substance use disorders (SUD) demands diagnostic
      measures and criteria that apply equally well to persons of different ethnic
      backgrounds. To evaluate the reliability of SUD in different ethnic groups,
      comparisons were made of the one week test/retest agreement on DSM-IV lifetime
      dependence disorders for 196 African-American (AA) and 107 Caucasian (C)
      respondents using the Composite International Diagnostic Interview-Substance
      Abuse Module (CIDI-SAM). Overall we found excellent reliability, using kappa (k)
      statistics, in diagnosing both AA and C respondents with alcohol dependence (AA k
      = 0.78; C k = 0.80) and opiate dependence (AA k = 0.77; C k = 0.71), good
      reliability for diagnosing both AA respondents (k = 0.63) and C respondents with
      cocaine dependence (k = 0.67), and to good reliability for both AA and C
      respondents with cannabis dependence (AA k = 0.50; C k = 0.69). Reliability of
      the dependence/abuse criteria was consistent with the overall diagnostic
      reliability but some variation was noted. No significant differences in the
      kappas were found between the two ethnic groups for any of the substance
      dependence diagnoses, and only one dependence or abuse criterion (continued use
      of cocaine despite physical/psychological problems) differed significantly
      between AA and C respondents. These initial results indicate that DSM-IV
      dependence diagnoses as measured by the CIDI-SAM apply equally well to AA and C
      respondents.

PMID- 10661672
TI  - Reinforcement-based intensive outpatient treatment for inner city opiate abusers:
      a short-term evaluation.
AB  - We evaluated 3-month outcomes for reinforcement-based intensive outpatient
      treatment (RBT), a new relapse prevention behavior therapy for inner city opiate
      abusers. The therapy provides abstinence-contingent partial support of housing,
      food and recreational activities, abstinence-contingent access to social skills
      and job finding group therapy and non-contingent individual counseling, all in
      the context of a day treatment program. Heroin abusers (n = 52), contacted at a 3
      day detoxification unit, were randomly assigned to RBT (n = 28) or referred to
      community treatment resources (n = 24) after a staff escort from the
      detoxification unit. For RBT patients, treatment began on the day of discharge;
      61% received partial rent support in a recovery house based on the need for drug
      free housing; the remainder were eligible for partial support of utility payments
      where they lived. Abstinence-based contingencies were in effect for 1 month with
      three times per week counseling available for an additional 2 months. One month
      after detoxification, 61% of RBT versus 17% of referral patients were enrolled in
      outpatient treatment (P < 0.01); RBT patients were significantly less likely than
      controls to have returned to any drug use; and 50% of RBT versus 21% of controls
      reported 30 days of abstinence from heroin and cocaine with confirmatory negative
      urine (P < 0.05). RBT patients had significantly lower scores on the Beck
      Depression Inventory at 1 month (M = 9.0 versus 17.6 for controls; P < 0.05) and
      showed evidence of less alcohol use and higher rates of employment. These results
      establish the short-term efficacy for RBT and support continued development and
      evaluation of this new outpatient behavioral treatment.

PMID- 10661673
TI  - A general system for evaluating therapist adherence and competence in
      psychotherapy research in the addictions.
AB  - The Yale Adherence and Competence Scale (YACS) is a general system for rating
      therapist adherence and competence in delivering behavioral treatments for
      substance use disorders. The system includes three scales measuring 'general'
      aspects of drug abuse treatment (assessment, general support, goals of
      treatment), as well as three scales measuring critical elements of three
      treatments that are frequently implemented as control or comparison treatments in
      clinical research in the addictions (clinical management (CM), twelve step
      facilitation (TSF), and cognitive behavioral therapy (CBT)). Validation of the
      YACS using data from a randomized clinical trial indicated that the scales have
      excellent reliability, factor structure, concurrent and discriminant validity.
      Correlations between adherence and competence scores within scales were in the
      moderate range, indicating independence (and thus nonredundancy) of these
      dimensions. Strategies for using the YACS in both psychotherapy and
      pharmacotherapy research in the addictions are described.

PMID- 10661674
TI  - Predictors of cardiovascular response to smoked cocaine in humans.
AB  - The purpose of this study was to examine the predictors of heart rate and blood
      pressure changes following cocaine administration. Sixty-two smoked cocaine users
      received a single 0.4 mg/kg dose of smoked cocaine. Male sex, African American
      race, higher body weight and current marijuana use predicted a greater
      cardiovascular response to cocaine. In contrast, higher baseline blood pressure,
      heart rate, amount and frequency of current cocaine use and presence of current
      cocaine snorting predicted a diminished cardiovascular response to cocaine.
      Whether these predictors of the cardiovascular response to smoked cocaine in the
      laboratory also predict cardiovascular complications from long-term cocaine use
      needs to be studied further.

PMID- 10661675
TI  - Trends in opiate-related deaths in the United Kingdom and Australia, 1985-1995.
AB  - This paper compares data on rates of opiate overdose mortality in the UK and
      Australia between 1985 and 1995. Data on rates of ICD 9-coded overdose mortality
      were obtained from the Office of National Statistics in the UK and from the
      Australian Bureau of Statistics mortality register. The proportion of all deaths
      attributed to opioid overdose increased in both countries between 1985 and 1995.
      The proportion of all deaths attributed to opioid overdose was substantially
      higher in Australia than in the UK, but methadone appeared to contribute to more
      opioid overdose deaths in the UK (50%) than in Australia (18%). Given
      deficiencies in the available data, the reasons for these differences between the
      two countries are uncertain but a plausible hypothesis is that the greater
      availability and ease of access to methadone maintenance in the UK contributes to
      both the lower rate of opioid overdose mortality and the greater apparent
      contribution that methadone makes to opioid overdose deaths in that country.

PMID- 10661676
TI  - Subsensitive alpha-2-adrenoceptor function in male alcohol-dependent individuals
      during 6 months of abstinence.
AB  - Postsynaptic alpha-2-receptor function, as assessed by growth hormone (GH)
      response to clonidine (CLON), has been shown to be downregulated in patients
      investigated in acute but also in late withdrawal after heavy alcohol intake. The
      results are however sometimes conflicting. The question whether this changed
      receptor function is a trait or state marker is not fully investigated so far. A
      total of seven male patients with alcohol dependence according to DSM-IV were
      assessed for the postsynaptic alpha-2-receptor function with the CLON/GH test
      (2.0 microg/kg body weight; i.v.) starting immediately after a period of heavy
      drinking. Neuroendocrine tests were repeated after 7 days, 2 and 6 months. A
      total of six healthy males were used as controls. The maximum GH responses to
      CLON were significantly lower on all four test occasions in the patient group as
      compared to the controls. Furthermore, in the patient group all neuroendocrine
      test results showed blunted GH responses to CLON. Thus, patients with
      downregulated alpha-2-receptor function during acute withdrawal after heavy
      alcohol intake showed similar subsensitive receptor function abnormality after a
      prolonged period of abstinence. The findings in this study indicate that alcohol
      dependent individuals have a persistent subsensitive alpha-2-adrenoceptor
      function which may constitute a trait factor for alcohol dependence.

PMID- 10661677
TI  - Dopamine receptor responsivity in alcoholic patients before and after
      detoxification.
AB  - OBJECTIVE: To assess central dopamine receptor responsivity in alcoholic patients
      during their usual alcohol consumption and after detoxification. METHOD: Plasma
      prolactin levels were measured at 0, 30, 60, and 90 min after administration of 5
      mg haloperidol i.m. in 21 hospitalized male alcoholic patients during usual
      alcohol consumption, and 13 days later (mean, range 7-17 days), after
      detoxification. The test was also performed in seven healthy male volunteers. The
      patterns of prolactin responses were compared using repeated measures analysis of
      variance. RESULTS: The prolactin responses to haloperidol increased significantly
      after detoxification compared to those during usual alcohol consumption (state x
      time interaction P < 0.01; planned comparisons for times 0 and 90 min between
      states P = 0.03). Compared to controls, the responses of the patients before
      detoxification were lower (group-time interaction P = 0.001), and the difference
      was not significant after detoxification (P = 0.19). The magnitude of plasma
      prolactin (PRL) responses were not related to duration of alcohol abuse, score in
      the Brief Michigan Alcoholism Screening Test (BMAST) scale, or family history of
      alcoholism. CONCLUSIONS: Alcohol detoxification is accompanied by a normalization
      of the low responsivity of central dopaminergic receptors during alcohol abuse.
      The data support the hypothesis of a participation of the central dopaminergic
      system in alcohol dependence.

PMID- 10661678
TI  - The significance of apoptosis in the liver.
AB  - Apoptosis is a form of cell death which occurs in normal as well as in
      pathological tissues. We provide a description of the morphological changes
      during apoptosis and an overview of the role of apoptosis dysregulation in the
      pathogenesis of non-neoplastic liver diseases.

PMID- 10661679
TI  - Enhanced expression of interleukin-6 in chronic hepatitis C.
AB  - AIMS/BACKGROUND: There is a possibility that proinflammatory cytokines such as
      interleukin-6 (IL-6) are involved in the inflammatory process of chronic
      hepatitis C. This study was undertaken to investigate the possible role of IL-6
      in the pathophysiology of chronic hepatitis C. METHODS: Serum IL-6 levels in 63
      patients with chronic hepatitis C and in 26 normal controls were measured. Light
      and electron immunostaining studies to localize IL-6 protein as well as in situ
      hybridization to localize IL-6 messenger RNA were performed on 10 liver biopsy
      specimens. RESULTS: Serum IL-6 levels were significantly (p<0.01) elevated in
      chronic hepatitis C compared to those in normal controls. Although no
      statistically significant correlation was found between serum IL-6 levels and
      hepatobiliary enzyme levels, a significant correlation (p<0.01) was found between
      serum IL-6 levels and category II of Knodell's histological activity index score.
      Non-parenchymal cells in hepatic sinusoids and the cells infiltrating enlarged
      fibrous portal tracts were definitely positive for IL-6 protein and mRNA by
      immunohistochemistry and in situ hybridization. In addition, immunoelectron
      microscopy revealed a weak and occasional positive reaction in the cytoplasm of
      hepatocytes. The majority of the positive cells in hepatic sinusoids showed CD68
      immunoreactivity in consecutive sections indicating that these were Kupffer
      cells. Sinusoidal endothelial cells and hepatic stellate cells also exhibited a
      weak reaction. CONCLUSION: These results strongly suggest that Kupffer cells in
      liver parenchyma and macrophages infiltrating in portal tracts are the main
      producers of elevated IL-6 in serum. Moreover, there is a possibility that IL-6
      produced by hepatocytes could also act as a regenerative stimulus to hepatocytes
      themselves in an autocrine fashion.

PMID- 10661680
TI  - Role of Th1 and Th2 cytokines in regulating the liver injury induced by delayed
      type hypersensitivity to picryl chloride.
AB  - AIMS/BACKGROUND: We have previously reported that a new model of liver injury
      induced in mice by delayed-type hypersensitivity (DTH) to picryl chloride (PCl)
      mimicks the pathogenesis of human hepatitis. This liver injury is mediated by
      CD4+ T cells. The interaction between lymphocyte function associated antigen 1
      (LFA-1) and intercellular adhesion molecule 1 (ICAM-1) is an essential process
      for hepatocyte (HC) damage. The present study was undertaken to reveal the role
      of Th1 and Th2-like cytokines in regulating the liver injury. METHODS: The
      kinetics of cytokine production were examined by ELISA and RT-PCR after the
      elicitation of liver injury for both serum protein and liver mRNA expression,
      respectively. A co-culture assay between liver nonparenchymal cells (NPC) and HC
      was conducted to evaluate the cytokine regulation on the cell-cell interaction.
      Expression of LFA-1 on NPC and ICAM-1 on HC were examined by FACScan and ELISA,
      respectively. RESULTS: Serum IL-2 and IFN-gamma showed a peak production at 6 and
      12 h, while IL-5 and IL-4 reached their maximum levels at 18 and 24 h after
      induction of liver injury, respectively. Liver mRNA expression of IFN-gamma and
      IL-4 had a similar time course to their corresponding products. Both recombinant
      murine IFN-gamma and IL-2 triggered the hepatotoxicity of NPC or spleen cells at
      0 h. In this case, an increased expression of both LFA-1 on NPC and ICAM-1 on HC
      was also observed. In contrast, IL-4 and IL-5 completely abolished the
      hepatotoxicity of NPC at 12 h without influencing the adhesion molecules.
      CONCLUSION: Th1 and Th2 may be involved in regulating liver injury. Th1/Th2
      balance may critically contribute to the production of the liver injury or
      recovery from it.

PMID- 10661681
TI  - Effects of nicotinamide-related agents on the growth of primary rat hepatocytes
      and formation of small hepatocyte colonies.
AB  - AIMS/BACKGROUND: We report in this study that, 10 mM nicotinamide can stimulate
      the proliferation of primary rat hepatocytes in serum-free Dulbecco's modified
      Eagle's medium supplemented with 10 ng/ml epidermal growth factor and that small
      hepatocyte colonies appear from 4 to 5 days after plating. We examined the
      effects of nicotinamide-related agents on the growth and differentiation of
      primary rat hepatocytes and on the appearance of small hepatocyte colonies.
      METHODS: As nicotinamide is an aqueous vitamin named niacin and known to act as
      an inhibitor of poly (ADP-ribose) polymerase (PARP), we therefore chose to
      examine the effects on hepatocytes of three nicotinamide-related agents,
      nicotinic acid (NA) which is also a niacin, 3-aminobenzamide (3-AB) which is a
      strong inhibitor of PARP but is not a niacin, and 3-acetylpyridine (3-AP) which
      is a weak inhibitor of PARP and also not a niacin. To examine their effects on
      the growth of the cells and on the formation of the colony, immunocytochemistry
      for BrdU was carried out. Expression of albumin, tryptophan 2,3-dioxygenase (TO),
      and connexin 32 (Cx32) mRNAs were used as marks of hepatic differentiation.
      Intracellular NAD+ content was also measured. RESULTS: At concentration of 10 mM,
      NA could not enhance the proliferation of mature hepatocytes but induced the
      appearance of small hepatocyte colonies. At concentration of 5 mM, 3-AB enhanced
      the proliferation of the hepatocytes but did not induce small hepatocyte
      colonies. On the other hand, although 10 mM 3-AP remarkably inhibited the DNA
      synthesis of the cells, the expression not only of albumin but also of TO and
      Cx32 mRNAs in the cells was well maintained for more than one week. The
      intracellular NAD+ concentration was correlated with the proliferation of the
      hepatocytes. CONCLUSION: These results suggest that the intracellular NAD+
      content may be correlated with the proliferation of primary hepatocytes and that
      the supplementation of niacin in the medium may be important for the appearance
      of small hepatocyte colonies.

PMID- 10661682
TI  - Expression of nerve growth factor in hepatolithiasis.
AB  - AIMS/BACKGROUND: Nerve growth factor (NGF) has recently been shown to influence
      the survival and function of non-neuronal inflammatory cells, possibly through
      its activity as a colony-stimulating factor. It may also play an important role
      in acute inflammation and tissue repair. However, no prior report has focused on
      NGF in chronic inflammatory diseases of the gastrointestinal and biliary tracts.
      The aim of this study was to examine the expression of NGF in hepatolithiasis.
      METHODS: Twenty-six liver specimens resected from 22 patients with intrahepatic
      calcium bilirubinate stones and from 4 patients with intrahepatic cholesterol
      stones were examined immunohistochemically. RESULTS: The 22 patients with calcium
      bilirubinate stones demonstrated NGF immunoreactivity associated with surrounding
      inflammatory cells that was localized to the epithelia of proliferative
      peribiliary glands in the ductal wall. However, neither the surface lining of the
      bile duct nor hepatocytes expressed detectable NGF immunoreactivity. In the
      cholesterol stones cases in contrast, peribiliary glandular elements and
      inflammatory cell infiltration were less extensive than those observed in cases
      of calcium bilirubinate stones, and NGF immunoreactivity was not noted.
      CONCLUSIONS: These observations suggest that proliferative peribiliary glands
      express NGF protein in chronic proliferative cholangitis. This is characteristic
      of intrahepatic calcium bilirubinate stones.

PMID- 10661683
TI  - Visualization of oxygen radical production in mouse liver in response to
      infection with Schistosoma mansoni.
AB  - BACKGROUND/AIMS: The tropical parasite S. mansoni induces granulomatous
      inflammation in the liver, following the lodging of eggs in this organ. In vitro
      studies suggested that the host's response might involve the production of oxygen
      radicals. METHODS: In an attempt to investigate the situation at the site of
      inflammation, under disease conditions, livers of infected mice were treated with
      dichlorodihydrofluorescein diacetate which fluoresces after oxidation. RESULTS:
      Fluorescence of the oxidized tracer revealed that oxygen radicals were produced
      by granulomatous inflammatory cells. The phenomenon reached its highest intensity
      close to the eggs. The membranes of the cells were strongly labelled, probably
      reflecting membrane-associated NADPH oxidase activity. The cytoplasm of
      hepatocytes was also fluorescent but with lower intensity; hepatocyte membranes
      or nuclei were not labelled. Fluorescence was reduced drastically by treatment
      with catalase and antioxidants, indicating the occurrence of H2O2. Treatment with
      superoxide dismutase had no effect. Neither the livers of uninfected animals nor
      those of infected animals before parasite egg deposition were labelled.
      Eosinophil peroxidase activity was released in the areas of inflammatory cells,
      but was not found in hepatocytes. CONCLUSIONS: The H2O2/peroxidase system, which
      is the cornerstone of the antimicrobial defense associated with inflammation, is
      activated in close contact with parasite eggs. The process does contribute to egg
      killing in vivo. Moreover, hepatocytes undergo oxidative stress in the entire
      organ. This finding is in agreement with the parasite-induced decrease of liver
      antioxidant defenses demonstrated previously.

PMID- 10661684
TI  - CA 19-9 and CEA are unreliable markers for cholangiocarcinoma in patients with
      primary sclerosing cholangitis.
AB  - AIMS/BACKGROUND: Diagnosis of early cholangiocarcinoma (CC) in patients with
      primary sclerosing cholangitis with available radiological methods is very
      difficult. This type of tumor is the second most common cause of mortality after
      liver failure in these patients. The recognition of CC is important for the
      selection of patients for, and the results of, liver transplantation (Ltx). In
      this study our aim was to investigate the value of measuring cancer markers (CA
      19-9 and CEA) in patients with PSC for early diagnosis of CC. METHODS: 72 PSC
      patients who were followed at our institution for a long period were included in
      the study; 9 with CC and 63 without CC. Furthermore, nine patients with CC but
      without concomitant PSC were included, as well as 24 patients with various
      cholestatic liver diseases. Serum levels of CA 19-9 and CEA were measured, in 39
      PSC patients without CC, on multiple occasions. Moreover, bile was collected
      during a diagnostic ERCP from 20 patients for measurements of CA 19-9 and CEA.
      RESULTS: In those PSC patients without CC during the follow-up and with more than
      one year of follow-up, 15 patients had increased values of CA 19-9 (>37 ng/ml) on
      some of the occasions. Four of them demonstrated large fluctuations (more than
      100 ng/ml difference at different occasions) in serum levels of Ca 19-9. A
      significant correlation between high CA 19-9 values and serum alkaline
      phosphatase levels was observed in these patients. The sensitivity of CA 19-9 in
      detecting CC in PSC patients was only 63%. The sensitivity of CEA and the
      combination of CA 19-9 and CEA (marker product; King's College formula) were
      still lower (33%) although the specificity was relatively high (85%). Bile levels
      of the tumor markers did not demonstrate any clinically useful differences
      between the different patient groups. CONCLUSIONS: Tumor markers as a diagnostic
      tool in diagnosing CC in patients with PSC are unfortunately not as valuable as
      previously reported. The serum levels of CA 19-9 can rise temporarily in
      association with a "biochemical relapse" of PSC (increased values of serum
      alkaline phosphatase). The marker product of CA 19-9 and CEA has a low
      sensitivity but a relatively high specificity for the detection of CC in PSC
      patients.

PMID- 10661685
TI  - Expression of the mucosal vascular addressin, MAdCAM-1, in inflammatory liver
      disease.
AB  - AIMS/BACKGROUND: The integrin alpha4beta7 and mucosal addressin cell adhesion
      molecule-1 (MAdCAM-1) are involved in normal recirculation of lymphocytes between
      the blood and the tissues of the gastrointestinal tract. In this study we have
      examined the expression of MAdCAM-1 in human liver. METHODS: MAdCAM-1 expression
      was determined in archival human liver tissues by immunohistochemistry. RESULTS:
      While MAdCAM-1 was not detected in normal fetal or adult human liver, expression
      was observed in association with portal tract inflammation in a variety of liver
      diseases. Detailed analysis of liver biopsies from patients with hepatitis C
      showed a positive correlation between the portal/periportal component of the
      histological activity index (HAI) grade and the presence or absence of MAdCAM-1
      expression. CONCLUSION: MAdCAM-1 expression may be important in the recruitment
      of lymphocytes to the liver during inflammation.

PMID- 10661687
TI  - Transverse hepatectomy for symptomatic polycystic liver disease.
AB  - Polycystic liver disease can result in massive enlargement of the liver with
      resultant debilitating symptoms of abdominal pain, chronic fatigue, and severely
      compromised functional status. Fenestration of hepatic cysts has been advocated
      as a treatment for polycystic disease. However, in patients with predominant
      small cyst replacement, fenestration alone often results in limited hepatic
      volume reduction without improvement in patient functional status. Liver
      transplantation has also been previously advocated for polycystic liver disease
      with predominant small cyst replacement, but, with the severe shortage of donor
      organs, alternative treatment should be considered. In this report we present a
      case of massive enlargement of the liver with severe clinical debilitation due to
      polycystic liver disease. Transverse hepatectomy provided a safe and effective
      alternative to fenestration or liver transplantation.

PMID- 10661686
TI  - Hepatic stimulator substance activity in the liver of thioacetamide-intoxicated
      rats.
AB  - AIMS/BACKGROUND: Hepatic stimulator substance (HSS) is a known hepatic growth
      factor which appears to be organ-specific but species non-specific. We have
      recently shown that the administration of HSS enhanced hepatocyte proliferation
      occurring due to thioacetamide (TAA)-induced liver injury in rats (Theocharis SE,
      et al., Scand J Gastroenterol 1998; 33: 656-63). In the present study, we
      examined the activity of the endogenously produced HSS in the liver of TAA
      administered rats during injury and regeneration. METHODS: TAA at a dose of 300
      mg/kg of body weight was injected intraperitoneally in male Wistar rats. The
      animals were sacrificed at 0, 12, 24, 36, 48, 60 and 72 h after TAA
      administration. The rate of tritiated thymidine incorporation into hepatic DNA,
      the enzymatic activity of liver thymidine kinase and the assessment of mitotic
      index in hepatocytes were used to estimate liver regeneration. HSS extract was
      obtained from the livers of TAA-treated rats, sacrificed at the above mentioned
      time points. This HSS extract was injected in 34% partially hepatectomized rats,
      to assess its activity. The ability of the injected HSS extract to increase
      hepatocellular proliferation over that normally occurring 24 h following 34%
      partial hepatectomy was used to express the activity of HSS by determining the
      above mentioned indices of liver regeneration. RESULTS: The administration of TAA
      caused severe hepatic injury recognized histopathologically as well as by the
      increased activities of serum hepatic enzymes aspartate and alanine
      aminotrasferases. The hepatic injury, which peaked at 24 and 36 h post-TAA
      treatment (p<0.001), was followed by hepatocyte proliferation, presenting peaks
      at 48 and 60 h (p<0.001). The activity of the endogenously produced HSS from
      livers of TAA-treated rats increased at 36 h after TAA administration as well as
      being highly expressed at 48 and 60 h thus coinciding with the peak of hepatocyte
      proliferation. At other time points, HSS activity was decreased. CONCLUSIONS: The
      observed variations of HSS activity in rat liver suggest active participation of
      this growth factor in hepatocyte replication which follows toxin-induced liver
      injury as a repair mechanism process.

PMID- 10661688
TI  - Long-term administration of heterogenous interferon results in a loss of its
      biological effect.

PMID- 10661689
TI  - Control error statistics.
AB  - Control in general, and manual control in particular, are traditional topics in
      ergonomics. Numerous studies on these topics have focused on vehicular control or
      tracking, as experimenters have attempted to describe control performance in
      terms of control errors, typically using the 'root-mean-square' (RMS) error. The
      authors of this study believe that this and related statistics are not well
      understood by the ergonomics community and that additional or alternative
      performance measurements would be more appropriate as measurements of the
      particular criteria of concern. Accordingly, this paper shows some background of
      the RMS and similar statistics of control error, some new statistics, and their
      interrelationships. This development is intended as a guide to selection of
      criteria for use in tracking and manual control and their measurement.

PMID- 10661690
TI  - Effects of alcohol and caffeine on maritime navigational skills.
AB  - Twelve experienced navigators participated in an experiment to determine the
      effects of alcohol, caffeine, and an alcohol+caffeine mixture on performance
      during the following tasks: visual search, the search and location of items on a
      navigational chart (chartsearch) and the solving of maritime navigational
      problems. Alcohol (75 ml) produced impairment in performance on visual search
      (p<0.05) and navigational problem-solving (p<0.01). Caffeine was found to enhance
      performance on visual search (p<0.05) but not on the chartsearch, although a
      significant correlation was found between performance on the two tests (p<0.05).
      Caffeine was not found to improve the accuracy of navigational problem-solving
      (p>0.05). Neither alcohol nor caffeine had any significant effect on the speed of
      problem-solving (p>0.05).

PMID- 10661691
TI  - Effect of driving experience on drivers' decoding process of roadway
      interpersonal communication.
AB  - Sixty-three participants (32 novice, 31 experienced drivers) evaluated meanings
      of road users' signals in 24 traffic situations such as blinkers, headlights,
      hazard lamps and hand gestures. The traffic scenes were projected with a slide
      projector in a laboratory. Confidence in answers was also evaluated by using a
      five-point scale. The signals were classified into three categories: Formal
      Device-based Signal (Formal Signal), Informal Device-based Signal (Informal
      Signal), and Informal Gesture-based Signal (Everyday Signal). The total
      comprehension scores demonstrated that experienced drivers could understand the
      signals better than novice drivers. There was a large difference in the
      comprehension scores for Informal Signal between experienced and novice drivers.
      Novice drivers could understand Formal Signal and Everyday Signal better than
      Informal Signal. Similar results were also obtained in the confidence scores.
      Experienced drivers were more confident in their answers than novice drivers. An
      effect of gender was found in the scores of confidence. The discussion focuses on
      how driver's skill in interpersonal communication on roads develops in real
      traffic situations.

PMID- 10661692
TI  - Measurement of specific movement power application: evaluation of weight lifters.
AB  - A new dynamometer was developed for the measurement of specific movement power
      (SMP) exerted by mono- or multi-articular movements. To determine the
      reproducibility of SMP, two identical test protocols were carried out on separate
      days for six movement types on seven adult males. The movement types were arm
      pull (AP), leg rise (LR), knee extension (KE), elbow flexion (EF), hip extension
      (HE) and squat movement (SQ). Variations in peak power obtained in two tests
      ranged from 0.7% (AP) to 9.6% (SQ). Coefficients of the test-re-test correlation
      in peak power ranged from 0.805 (SQ) to 0.961 (AP) and standard errors ranged
      from 4 W (EF) to 14 W (SQ). SMP in upper extremities increased from 166 W (EF) to
      307 W (AP) resulting from the increase in velocity. However, in the movements of
      lower extremities, SMP increased from 506 W (KE) to 1351 W (SQ) as a result of
      the increase in force. To evaluate the validity of the SMP, a pull movement in
      weightlifting was tested and related to the athletic performance on
      weightlifters. Positive linear correlation (r = 0.862, p<0.001) was observed
      between SMP and the total weight best records. It is concluded that this newly
      developed dynamometer has enough reproducibility and validity for evaluating the
      SMP, which is developed by various joint movement patterns related to the sport.
      The feasibility of applying this measuring protocol to the testing and training
      programmes for improving the daily living activities and athletic performances
      should now be assessed.

PMID- 10661693
TI  - An evaluation of the ergonomics of three computer keyboards.
AB  - The influence of keyboard design on hand position, typing productivity and
      keyboard preference was evaluated by comparing two segmented alternative designs
      with the linear standard keyboard. The FIXED alternative keyboard featured a
      split angle of 12 degrees and a moderate lateral inclination angle of 10 degrees.
      The adjustable OPEN alternative keyboard was used with a 15 degrees split
      setting, which resulted in a marked 42 degrees of demiboard lateral inclination.
      Sixteen typists, who completed 10 h of training on both alternative keyboards,
      were videotaped while typing set texts on all three keyboards. Forearm and wrist
      angles based on three-dimensional video analyses were significantly different
      (p<0.05) among the three designs tested. Both alternative keyboards placed the
      forearm and wrist closer to neutral positions than did the standard keyboard.
      While the OPEN keyboard reduced pronation, it simultaneously increased radial
      deviation. The FIXED keyboard kept the forearm in moderate pronation and the
      wrist closer to neutral. More time was spent in neutral and moderate ranges of
      wrist motion when subjects typed on the FIXED compared with the other two
      designs. With respect to the standard keyboard, typing productivity was reduced
      by 10% on the FIXED and 20% on the OPEN designs. No significant difference in
      preference was found between the standard and FIXED keyboards, both of which were
      preferred over the OPEN. It was concluded that, of the three keyboards evaluated,
      the FIXED design incorporated moderate changes to the standard keyboard. These
      changes promoted a more natural hand position while typing thereby reducing the
      potential for cumulative trauma disorders of the wrist. In addition, the FIXED
      design preserved a reasonable level of productivity and was well accepted by
      users.

PMID- 10661694
TI  - Development of physical selection procedures for the British Army. Phase 2:
      relationship between physical performance tests and criterion tasks.
AB  - This paper is the second in a series of three to describe the development of
      physical selection standards for the British Army. The first paper defined
      criterion tasks (single lift, carry, repetitive lift and carry, and loaded march
      tasks) and set standards on the criterion tasks for all British Army trades. The
      principal objective was to determine which combination of physical performance
      tests could be best used to predict criterion task performance. Secondary
      objectives included developing so-called 'gender-free' and 'gender-unbiased'
      models. The objectives were met by analysing performance data on the criterion
      tasks and a large battery of physical performance tests collected from 379
      trained soldiers (mean age 23.5 (SD 4.45) years, stature 1734 (SD 79.5) mm, body
      mass 71.4 (SD 10.58) kg). Objective 1 was met: the most predictive physical
      performance tests were identified for all criterion tasks. Both single lift tasks
      were successfully modelled using muscle strength and fat free mass scores. The
      carry model incorporated muscle endurance and body size data, but the errors of
      prediction were large. The repetitive lift models included measures of muscle
      strength and endurance, and body size, but errors of prediction were also large.
      The loaded march tasks were successfully modelled incorporating indices of
      aerobic fitness, supplemented by measures of strength, endurance or body size and
      composition. The secondary objectives were partially fulfilled, though
      limitations in the data hampered the process. Although only one model (a loaded
      march) was gender-free, three models were gender-related (i.e. contained 'gender'
      explicitly in the model). The remaining six were gender-specific (i.e. were
      appropriate for men or for women). Owing to both a lower accuracy of prediction
      in women's scores and a greater tendency for the women's scores to be distributed
      around the pass standards, a greater percentage of women than men were
      misclassified as passing or failing, resulting in indirect discrimination. A
      validation of the models in a separate sample of the user population of recruits
      is reported in the third paper in this series.

PMID- 10661695
TI  - Comparison between using spectral analysis of electrogoniometer data and
      observational analysis to quantify repetitive motion and ergonomic changes in
      cyclical industrial work.
AB  - Spectral analysis of continuously measured joint angles using an
      electrogoniometer was considered as a potentially efficient method for
      quantifying exposure to physical stress in repetitive manual work. The method was
      previously demonstrated in the laboratory but has not yet been tested extensively
      in the field. Spectral analysis was compared against observational analysis,
      consisting of time-and-motion study and posture classification. Six industrial
      jobs were selected: (1) press operation, (2) large parts hanging, (3) product
      packaging, (4) small parts hanging, (5) parts counting and sorting and (6)
      construction vehicle operation. The posture angle data were synchronized with
      activities on the video using an interactive multimedia video data acquisition
      system. Motion for every joint was analyzed using both spectral analysis and
      observational analysis. Joint angles for the wrist, elbow and shoulder were
      directly measured using electrogoniometers. Visual posture classification
      involved determining joint angles from a frozen videotape image sampled three
      times per s. Repetitiveness was quantified for observational analysis using time
      study to measure the frequency that specific motions repeat, while spectral
      analysis measured repetitiveness as the frequency where spectral peaks occurred.
      Spectral analysis agreed closely with observational analysis. Correlation between
      the repetition frequencies obtained using time study and spectral analysis was
      0.97, with no statistically significant difference observed. Average sustained
      posture was quantified as the mean, and posture deviation as the RMS angle of
      joint motion. No statistically significant differences between data obtained
      using posture classification or spectral analysis were observed for either
      posture deviation or sustained posture. Since posture classification was very
      limited in resolution and often contained measurement errors caused by poor joint
      visibility, the correlation between the postural classification and spectral
      analysis was 0.77 for sustained posture and 0.53 for posture deviation. When
      considering only large motions that exceeded the posture classification angle
      precision, the correlation between postural classification and spectral analysis
      was 0.81 for sustained posture and 0.81 for posture deviation. Spectral analysis
      of electrogoniometer data were, therefore, an efficient method for analyzing
      repetitive manual work that obtained equivalent results, and was more precise
      than observational analysis.

PMID- 10661696
TI  - The effect of glycogen depletion on the curvature constant parameter of the power
      duration curve for cycle ergometry.
AB  - For high-intensity cycle ergometer exercise, the relation between power (P) and
      its tolerable duration (t) has been well characterized by the hyperbolic
      relationship: (P-thetaF) t = W', or P = W' (1/t)+thetaF, where thetaF may be
      termed the 'fatigue threshold'. The curvature constant (W') reflects a constant
      amount of work which is postulated to be equivalent to a finite energy store that
      relates to the oxygen-deficit: phosphagen pool, anaerobic glycolysis and oxygen
      stores. Compared to thetaF, the physiological nature of W' has received little
      consideration. The purpose of this study was therefore to establish the
      parameters of the power-duration curve (thetaF and W') for subjects in normal
      glycogen (NG) and glycogen depleted (GD) states. Seven healthy male subjects
      (aged 22 to 41 years) each performed four high-intensity square-wave exercise
      bouts on an electrically braked cycle ergometer under two different muscular
      glycogen content conditions, i.e. NG and GD states. Subjects performed the
      following exercise on the evening before the trial day to induce the GD state.
      Initially, they performed a 75-min cycling exercise at 60% of VO2max. After a 5
      min rest period, they subsequently repeated a 1-min cycling bout at 115% of
      VO2max (separated by 1-min rest periods) until the subject could no longer
      maintain the prescribed pedal rate for the full minute. Subjects then reported to
      the laboratory after an overnight fast and performed a single high-intensity
      exercise bout. The GD procedure was repeated four times at 1-week intervals. In
      the GD state, the respiratory exchange ratio (RER) (VO2/VCO2) value during a
      recumbent control period prior to the trial was significantly lower than that in
      the NG state [GD: 0.84+/-0.02, NG: 0.94+/-0.04, mean +/- SD]. There was no
      significant difference for thetaF between GD and NG state [NG: 197.1+/-31.9 W,
      GD: 190.6+/-28.2 W]. W' in contrast was significantly reduced by the GD procedure
      [NG: 12.83+/-2.21 kJ, GD: 10.33+/-2.41 kJ]. The present results indicate that the
      muscular glycogen store seems to be an important determinant of the curvature
      constant (W') of the power-duration curve for cycle ergometry.

PMID- 10661697
TI  - Postoperative acute refractory right ventricular failure: incidence,
      pathogenesis, management and prognosis.
AB  - Isolated acute refractory right ventricular failure is extremely uncommon. There
      are greater prospects of seeing a right dominant biventricular failure, as the
      two ventricular chambers are contiguous. The overall clinical spectrum is
      determined by the relative ischemic involvement of the right or left ventricle.
      The postoperative acute refractory right ventricular failure that develops after
      cardiotomy, heart transplant, or during a left ventricular assist device support,
      may have somewhat dissimilar elements of origin, but the resultant clinical
      picture and the management are essentially similar. In this collective review,
      the authors have summarized the incidence, pathogenesis, management and prognosis
      of postoperative acute refractory right ventricular failure, in adult cardiac
      surgical practice. The incidence of post-cardiotomy acute refractory right
      ventricular failure ranges from 0.04 to 0.1%. Acute refractory right ventricular
      failure has also been reported in 2-3% patients after a heart transplant and in
      almost 20-30% patients who receive a left ventricular assist device support. The
      main contributor to this problem is a disproportionate ischemic involvement of
      the right ventricle. Other pertinent contributors to this problem are pulmonary
      hypertension and an altered interventricular balance. The latter component is
      predominant in recipients of a left ventricular assist device support.
      Postoperative acute refractory right ventricular failure has been successfully
      managed with conventional pulmonary vasodilators, mechanical support with a
      pulmonary artery balloon pump, a right ventricular assist device, or
      cavopulmonary diversion. Unfortunately, the reported initial salvage rate is only
      25-30%. This problem is often underestimated. Support measures are often started
      late or terminated prematurely. These factors have contributed to a poor initial
      salvage rate in this group of patients.

PMID- 10661698
TI  - Comparative results of staged and simultaneous bilateral carotid endarterectomy:
      a clinical study and surgical treatment.
AB  - OBJECTIVE: Bilateral carotid stenoses are actually managed by staged
      endarterectomy. The present study compares the results of the above surgical
      procedure with simultaneous bilateral carotid endarterectomy. METHODS: Sixty-four
      carotid endarterectomies were carried out on two groups of thirty-two patients
      with bilateral carotid stenoses. Fifteen patients (group A) were subjected to
      staged and 17 patients (group B) who were subjected to simultaneous bilateral
      carotid endarterectomies. RESULTS: The mortality rate was zero in both groups; no
      statistically significant difference was found concerning complications related
      to the heart, neurological deficit and postoperative hypertension. CONCLUSIONS:
      Simultaneous carotid endarterectomy is a challenging and technically demanding
      operation but with limited indications in strictly selected patients. The
      development of methods of more effective monitoring and protection of the
      cerebral cells might broaden the indications of such a surgical tactic in the
      future. Staged carotid endarterectomy, however, remains the method of choice for
      the management of bilateral carotid occlusive disease.

PMID- 10661699
TI  - Importance of cardiovascular interventions before surgery for abdominal aortic
      aneurysms.
AB  - Preoperative screening, and interventional and surgical therapy of cardiovascular
      diseases are of pivotal importance for successful outcome after abdominal aortic
      aneurysm surgery. In a retrospective study, all patients who underwent surgery
      for abdominal aortic aneurysm were reevaluated by preoperative diagnostic and
      therapeutic interventions for cardiovascular disease. Two study periods (1980
      1989 and 1990-1996) were compared. Of 603 patients operated upon for abdominal
      aortic aneurysm between 1980 and 1996, 449 had surgery on an elective basis and
      154 as an emergency. Preoperative diagnostic studies for coronary artery disease
      were performed on elective patients and were positive in 76.8% (1980-1989, 76.1%,
      1990-1996, 77.5%). Coronary angiography was performed in 108 patients (29.6%).
      Medical therapy of coronary artery disease declined by 2.3%, and interventional
      procedures by 18.8%. In contrast, myocardial revascularization with subsequent
      aneurysm resection increased by 26.6% and 12 patients (16%) required urgent
      simultaneous cardiac and aortic surgery. Early mortality after abdominal aortic
      aneurysm surgery decreased from 4.2 to 2.9%, and the frequency of primary cardiac
      failure as the cause of death was reduced from 33.3 to 22.2% (P < 0.05). It was
      concluded that 42.6% more cardiac surgical procedures were performed before
      abdominal aortic aneurysm surgery since 1990 compared with the period 1980-1989.
      In contrast, the number of interventional procedures fell by 18.8%. Surgical
      therapy of cardiac disease reduces early mortality after elective abdominal
      aortic aneurysm surgery.

PMID- 10661700
TI  - Coronary and major vascular disease: aggressive screening and priority-based
      therapy.
AB  - It is well know that atherosclerosis can simultaneously affect different vascular
      subsystems, and patients with diffuse atherosclerosis can be a major management
      problem both for preoperative evaluation and for intraoperative management. The
      authors have conducted a prospective study to evaluate the prevalence of coronary
      artery disease in arteriopathic patients, and vice versa, to assess the
      effectiveness of aggressive screening together with a priority-based approach.
      Study 1 consisted of 1,000 consecutive non-emergent patients who were affected by
      abdominal aortic or carotid disease and were screened for the presence of
      coronary artery disease before surgery with a newly developed clinical risk
      assessment. They were stratified into three risk categories with different
      preoperative evaluation strategies. When coronary artery disease was
      concomitantly demonstrated in these patients, the choice of surgical method was
      based on priorities, and the use of combined surgical procedures as required. In
      study 2, 1,000 consecutive patients that required coronary angiography for
      suspected coronary artery disease were screened for the presence of carotid or
      abdominal aortic pathology, directly in the cardiac catheter laboratory during
      coronary angiography, by obtaining views of the aortic arch and abdominal aorta.
      Surgical approaches paralleled those of study 1. The results for study 1 showed
      that 720 patients (72%) were affected by abdominal aortic disease, 238 (24%) by
      carotid disease and 42 (4%) by both pathologies. Significant coronary artery
      disease was found in 152 patients (15%), of these 123 (81.5%) were affected by
      abdominal aortic disease and 29 (18.5%) by carotid artery disease. Abdominal
      aortic surgery was performed directly or after myocardial revascularization, with
      an overall mortality rate of 4/718 (0.6%), and a perioperative myocardial
      infarction rate of 10/718 (1.4%). For patients with carotid artery disease, the
      completed screening and possible therapy for coronary artery disease resulted in
      an in-hospital mortality rate of 2/238 (0.8%), and a perioperative myocardial
      infarction rate of 2/238 (0.8%). There were no significant differences in these
      rates between patients with or without coronary artery disease. Results for study
      2 showed that of the 1000 consecutive patients enrolled for suspicion of coronary
      artery disease, 767 (77%) were affected by significant coronary artery disease.
      Among these, 38 (4.9%) had a surgically correctable aortic disease and 31 (4%) a
      surgically correctable carotid disease, which was monolateral and bilateral in 22
      (74%) and nine (26%) patients, respectively, and four (0.5%) were diagnosed with
      both pathologies. These arteriopathic patients were treated for their coronary
      and vascular disease with no in-hospital mortality nor perioperative myocardial
      infarction. In patients with multiple vascular involvement, both coronary and
      vascular surgery can be performed with low risk when aggressive screening and
      priority-based therapy are adopted.

PMID- 10661701
TI  - Simultaneous carotid endarterectomy and coronary artery bypass grafting in 313
      patients.
AB  - The coincidence of coronary and carotid artery disease (uni- or bilateral, with
      or without involvement of the supra-aortic branch) is still a problem with
      regards to surgical strategy. Since the opening of the Heart Centre Duisburg in
      1989 the authors have favoured a simultaneous approach to lesions in both
      arterial systems in order to avoid myocardial infarction or stroke. The aim of
      this retrospective study was to review the early and late results of the combined
      procedures for the endpoints of death, myocardial infarction and stroke. During a
      7-year period (1990-1997) a total of 18,050 patients underwent cardiac surgery
      and extracorporeal circulation. Simultaneous intervention in both arterial
      systems was performed in 313 patients (1.73%). All patients underwent
      preoperative ultrasonic diagnostics, digital subtraction angiography,
      neurological examination and cardiac catheterization. The principal indication
      was the need for myocardial revascularization, and symptomatic or asymptomatic
      carotid stenosis of 80% diameter reduction or more (with or without contralateral
      disease). The mean age was 66.4 +/- 6.9 years; 240 patients (76.7%) were male, 73
      patients (23.3%) female; 243 patients (77.6%) had triple-vessel disease, 82
      patients (26.2%) had left main stenosis and 94 patients (43.5%) had a reduced
      ejection fraction. A total of 171 patients (54.6%) had a previous myocardial
      infarction, 54 patients (17.3%) presented with unstable angina and nine patients
      (2.9%) had prior coronary artery bypass grafts. Eighty-seven patients (27.8%) had
      an internal carotid artery stenosis on the right side, 75 patients (24%) on the
      left side and 151 patients (48.2%) lesions in both carotid arteries. Prior
      carotid endarterectomy was performed in 14 patients (4.5%), and the contralateral
      carotid was occluded in 24 patients (7.7%). Fifty patients had a previous stroke
      (16%) and 185 patients (59.1%) were asymptomatic. During surgery, the the carotid
      artery was first exposed, followed by median sternotomy, systemic heparinization,
      cannulation and cardiopulmonary bypass. After achieving mild hypothermia (30
      degrees C), endarterectomy was performed with a venous patch closure. An occluded
      contralateral carotid artery was always an indication for shunting. Coronary
      artery bypass grafting was carried out with intermittent cross-clamping under
      moderate hypothermia (22-27 degrees C). Ten patients suffered a myocardial
      infarction (3.2%), seven patients (2.2%) had an apoplectic insult perioperatively
      ( < 30 days) and one patient (0.3%) had an event during long-term follow-up.
      Early overall mortality was 28 (8.9%), of which 13 were cardiac related (4.2%).
      Overall late mortality was eight (2.6%), of which six were cardiac related
      (1.9%). Mean survival time was 6.18 years. Simultaneous carotid endarterectomy
      and myocardial revascularization can be justified as a routine surgical
      management of severe lesions in both arterial systems. The risk of myocardial
      infarction, apoplectic stroke or mortality was not significantly different than
      isolated procedures.

PMID- 10661702
TI  - Intensive care is cost-effective in carotid endarterectomy.
AB  - The purpose of this study was to analyze the utilization, cost profile, and
      predictors of intensive care unit (ICU) services after carotid endarterectomy. A
      retrospective medical record review of all patients undergoing isolated carotid
      endarterectomy by a vascular surgery service at one university hospital during a
      12-month period was performed. Eighty-four patients undergoing 91 carotid
      endarterectomies were identified for review. All carotid endarterectomy patients
      at the authors' institution were routinely admitted to an ICU postoperatively.
      Sixty-five of the 91 patients (71.4%) required ICU interventions, the majority of
      which were intravenous antihypertensive therapy. There were no deaths in the
      group. There was one non-fatal stroke (1.1%), and one non-fatal myocardial
      infarction (1.1%). There were three reoperations (3.3%): two for hematoma and one
      for a change in neurological status. One patient required reintubation. Five of
      the six major adverse events after carotid endarterectomy occurred within 12
      hours postoperatively. No preoperative factors predicted a significant risk for
      complications following carotid endarterectomy. There is no reliable predictor
      that carotid endarterectomy patients will require postoperative interventions or
      develop adverse outcomes. Mandatory intensive care immediately after carotid
      endarterectomy upholds high safety standards, avoids the uncertainty of
      preoperative ICU planning, and avoids the high cost of a recovery room stay to
      determine the need for intensive care. In addition, costs may be further reduced
      as the ICU length of stay may be decreased if there are no necessary
      interventions or complications after 12 hours of intensive care.

PMID- 10661703
TI  - Is there carotid artery aneurysm formation following saphenous vein patch
      endarterectomy?
AB  - The use of saphenous vein patching following carotid endarterectomy is reported
      to produce aneurysmal dilatation with the risk of thrombosis and possible
      rupture. The authors have studied patients who have had saphenous vein patch
      angioplasty following carotid endarterectomy to assess whether there is any
      progressive arterial dilatation. Thirty-five patients who had undergone saphenous
      vein patch carotid endarterectomy were age- and sex-matched with 31 subjects that
      had direct closure endarterectomy. All participants underwent carotid duplex
      scanning. The external diameters of the mid common carotid artery, the bulb and
      the proximal internal carotid artery were measured bilaterally. The diameters of
      the endarterectomized carotid were compared with the contralateral side using a
      paired t-test. Using an unpaired t-test, the saphenous vein angioplasty group was
      compared with the directly closed group. A graph was plotted of the ratio of
      internal carotid artery diameter of the saphenous vein angioplasty group
      (endarterectomized artery to the contralateral artery) against the length of
      follow-up, and the Pearson correlation coefficient was calculated. When the
      saphenous vein angioplasty group was compared with the directly closed group
      there was a significant difference between the carotid bulb (11.6 versus 9.7mm, P
      < 0.001) and internal carotid artery diameters (9.0 versus 7.0mm, P < 0.001).
      Longitudinal analysis of the saphenous vein angioplasty group showed that the
      increased diameter of the endarterectomized internal carotid artery progressed
      with time after surgery (r = 0.51, P < 0.005, and r = 0.56, P < 0.001). Vein
      patching increases the diameter of the internal carotid artery, and this may
      further increase with time possibly predisposing to aneurysm formation. Further
      longitudinal studies of paired data are required.

PMID- 10661704
TI  - Open saphenectomy complications following lower extremity revascularization.
AB  - A review of saphenectomy site complications following lower extremity
      revascularization was conducted. Leg incisions used for 133 consecutive
      infrainguinal bypass procedures were categorized by location. Patient and
      procedural risk factors were analyzed for risk of wound complications. Procedure,
      limb and patient outcome were reported via life table analysis. Incisional wound
      complications followed 32/133 procedures (24%), including 15 groin, eight
      saphenectomy, five distal and four vein/distal incisions. There were five grade I
      and three grade II saphenectomy complications. Only weight (body mass index)
      predicted the likelihood of wound complication (P < 0.05). The 6-month primary
      patency rate was 79% (mean follow-up 22 months). Four-year assisted primary
      patency, limb salvage and survival rates were 75, 87 and 57%, respectively. Most
      bypass-related wound complications (24/32, 75%) involve arterial access
      incisions. Incisional complications are related to body mass index. Only 6% of GS
      vein bypass procedures develop saphenectomy site complications. Limiting
      saphenectomy size may not significantly reduce incisional morbidity following
      bypass grafting.

PMID- 10661705
TI  - Two different techniques of retrograde cerebral perfusion for thoracic aortic
      surgery through a left thoracotomy.
AB  - The authors used profound hypothermic circulatory arrest and continuous
      retrograde cerebral perfusion for aortic surgery that involved the distal arch
      through a left thoracotomy. For the first seven patients, oxygenated blood from
      cardiopulmonary bypass was perfused retrogradely through a venous cannula
      positioned into the right atrium. In the last 11 cases, venous blood, provided by
      a perfusion from the lower body, was circulated passively in the brain with the
      descending aorta clamped. The period of profound hypothermic circulatory arrest
      was 34.6 +/- 11.1 min, and continuous retrograde cerebral perfusion was 31.3 +/-
      11.1 min. Seventeen patients survived, but there was one early death. Two
      patients with a severely atherosclerotic aneurysm developed permanent
      neurological dysfunction. The combination of profound hypothermic circulatory
      arrest, continuous retrograde cerebral perfusion and open aortic anastomosis
      through a left thoracotomy protects the brain adequately, and facilitates
      evacuation of debris and air in the aortic arch. It produces satisfactory results
      for aortic surgery that involves the distal arch.

PMID- 10661706
TI  - Ischaemic complications with intra-aortic balloon counter-pulsation: incidence
      and management.
AB  - The most important limitation of the use of the intra-aortic balloon pump is the
      risk of vascular complications. The aim of this study was to identify risk
      factors and aspects of diagnosis and management that may decrease the risk of
      vascular morbidity associated with intra-aortic balloon pumps. Risk factors,
      surgical techniques, complications and other variables were retrospectively
      evaluated in 524 patients who had an intra-aortic balloon pump inserted between
      January 1988 and December 1998. Of the total, 140 (26.7%) patients with an intra
      aortic balloon pump had ischaemic complications that needed surgery. The mean age
      was 65.2 +/-12.3 years (66.7% men and 27.5% women). The mortality rate was 28.1%.
      The mortality for patients with ischaemic vascular complications was
      significantly higher than in those patients without (59.6 versus 30.1%, P =
      0.001). One-hundred and eight (77.2%) ischaemic complications occurred during
      therapy with an intra-aortic balloon pump and 32 (22.8%) complications after
      intra-aortic balloon pumping had been stopped. Thromboembolectomy was required in
      71 (50.7%) patients. Associated surgical procedures were performed in 69 (49.3%)
      patients. A history of peripheral vascular disease (43.6 versus 23.6%, P < 0.05)
      and the presence of diabetes mellitus (49.2 versus 16.9%, P < 0.05) increased the
      risk of limb ischaemia significantly. Limb ischaemia remains the major
      complication after intra-aortic balloon pump insertion. Independent predictors
      for vascular complications included peripheral vascular disease and diabetes.
      Intra-aortic balloon pump removal and thrombectomy is usually sufficient to
      provide revascularization. Identification of subclinical disease may aid in the
      management of subsequent acute limb ischaemia.

PMID- 10661707
TI  - Complex traumatic dissection of right vertebral and bilateral carotid arteries: a
      case report and literature review.
AB  - A 27-year-old female motorcycle passenger was admitted with bruises and
      concussion after a motor-vehicle accident. After a lucid interval of several
      hours she became stuporous and progressed to an acute comatose state. Computed
      tomography demonstrated extensive cerebral ischaemia in the territory of the
      right middle cerebral artery. Angiography after transfer to the authors' hospital
      revealed dissections of both carotid arteries and of the right vertebral artery.
      The patient underwent surgical reconstruction of the left internal carotid artery
      with saphenous vein. The management of this patient is discussed and the
      literature reviewed.

PMID- 10661709
TI  - Fatal fungal infection complicating aortic dissection following coronary artery
      bypass grafting.
AB  - The case of a 52-year-old man with severe coronary atheroma/ischaemic heart
      disease, who underwent successful triple vessel coronary artery bypass grafting
      is described. One month later this was complicated by aortic dissection arising
      at the aortic cannulation site. An emergency resection and Dacron graft placement
      were performed. Five weeks later he represented with haemoptysis. Despite
      inconclusive investigations the patient went on to suffer a massive fatal
      haemoptysis. Autopsy revealed Candida infection of the graft with a secondary
      aortobronchial fistula.

PMID- 10661708
TI  - Emergency repair of type A aortic dissection in type IV Ehlers-Danlos syndrome.
AB  - Ehlers-Danlos syndrome type IV is a distinctive syndrome in which thin and
      fragile skin, premature ageing, bruising and scarring are combined with lethal or
      life-threatening arterial weakness. Aortic rupture either at the aortic root and
      arch, or sometimes lower down the artery, are particularly characteristic. Even
      quite minor injury can produce dangerous vascular tearing and damage. Technical
      difficulties encountered in arterial repair or venous ligature are particularly
      worrying. The authors report the treatment of a ruptured type A aortic dissection
      associated with Ehlers-Danlos syndrome where the extreme fragility of the tissues
      and tendency to bleed posed a difficult task for the surgeon.

PMID- 10661710
TI  - Potential risks in coronary artery bypass grafting via mini-thoracotomy: a case
      report.
AB  - This paper describes a patient with an occluded left internal thoracic artery,
      possibly as a result of the proximal 'steal phenomena', following coronary artery
      bypass grafting via mini-thoracotomy without cardiopulmonary bypass.

PMID- 10661711
TI  - Non-atherosclerotic saccular aneurysmal degeneration of a saphenous-vein graft
      inserted for repair of a popliteal aneurysm.
AB  - The Authors describe a case of a saccular aneurysm formation in a femoropopliteal
      autologous saphenous vein graft, inserted 12 years before. The patient was
      initially treated for a popliteal aneurysm. The graft revealed no microscopic
      signs of atherosclerosis. In spite of the widespread use of the autologous
      saphenous vein as arterial substitute, this complication is extremely rare.

PMID- 10661712
TI  - Surgical management of extensive lipomatous hypertrophy of the right atrium.
AB  - Lipomatous hypertrophy of the right atrium is a rare lesion that is usually
      limited to the interatrial septum. The authors report on a patient that suffered
      from an extensive lipomatous hypertrophy, which protruded into the right and left
      atrium as well as the superior vena cava and caused inflow obstruction.
      Therapeutic management is discussed.

PMID- 10661714
TI  - Enhanced testicular antioxidant system by ascorbic acid in alloxan diabetic rats.
AB  - The diabetic subject is at significantly increased risk of developing testicular
      changes. Its etiology may involve oxidative damage by free radicals and
      protection against such damage can be offered by antioxidant supplementation.
      Alloxan elicited significant inhibition of antioxidants including superoxide
      dismutase, catalase and glutathione reductase activities and decreased
      glutathione content in testis. These effects were accompanied by significant
      elevation of testicular lipid peroxidation, decreased plasma testosterone level
      and a drop in copper and zinc concentrations in testis. The administration of
      ascorbic acid after alloxan treatment interfered and prevented alloxan action.
      Ascorbic acid blunted the increased testicular lipid peroxidation and the
      decreased plasma testosterone level probably by protecting antioxidants and the
      loss of copper and zinc from testes. The data suggested that ascorbic acid has a
      protective effect on alloxan-induced damage by maintaining the activity of
      cellular antioxidants.

PMID- 10661713
TI  - Comparative insecticide susceptibility and detoxification enzyme activities among
      pestiferous blattodea.
AB  - Topical bioassays using propoxur, chlorpyrifos, and lambda-cyhalothrin were
      conducted on eight cockroach species. Based on lethal dose values, the relative
      toxicities of the insecticide classes were generally pyrethroid > carbamate >
      organophosphorous. Lambda-Cyhalothrin and propoxur were more toxic toward the
      Blattidae as compared with the Blattellidae. The order of lambda-cyhalothrin
      toxicity was Periplaneta americana > Periplaneta brunnea = Periplaneta
      australasiae = Periplaneta fuliginosa = Blatta orientalis > Blattella asahinai =
      Blattella germanica > Blattella vaga. The order of propoxur toxicity was B.
      orientalis > P. americana > P. brunnea = P. australasiae > B. asahinai > P.
      fuliginosa = B. germanica > B. vaga. The order of chlorpyrifos toxicity was P.
      americana > B. asahinai = B. vaga > B. orientalis = P. australasiae = P. brunnea
      > B. germanica = P. fuliginosa. Detoxification enzyme activities for each species
      also were measured and compared with insecticide toxicity. Propoxur LD50 was
      significantly (P = 0.01; r = 0.81) correlated with glutathione S-transferase
      activity. Lambda-Cyhalothrin LD50 correlated with methoxyresorufin O-demethylase
      activity (P = 0.01; r = 0.81), carboxylesterase activity (P = 0.03; r = - 0.75),
      general esterase activity (P = 0.02; r = - 0.79), and cockroach weight (P = 0.01;
      r = -0.95).

PMID- 10661716
TI  - Assessment of the toxicity of a pesticide with a two-generation reproduction test
      using Daphnia magna.
AB  - Daphnia magna (F0 generation) were exposed during 21 days to different diazinon
      concentrations. Offspring (animals from the first and third brood: F1 (1st) and
      F1 (3rd), respectively) were transferred to a free pesticide medium during a 21
      day recovery period. The algae Nannochloris oculata (5x10(5) cells/ml) were used
      as food. In this recovery study, survival, growth and reproduction (mean total
      young per female, mean brood size, onset of reproduction and mean number broods
      per female) were assessed as individual parameters, and the intrinsic rate of
      natural increase (r) as population parameter for F1 (1st and 3rd broods)
      daphnids. Reproduction as well as survival was still reduced in F1 (1st)
      generation daphnids from parentals (F0) exposed to the highest diazinon
      concentration. However, F1 (1st) and F1 (3rd) individuals from parentals exposed
      to pesticide concentrations below 0.5 ng/l were able to restore reproduction and
      survival when a recovery period of 21 days was allowed.

PMID- 10661715
TI  - Induction of xenobiotic metabolising enzymes in the common brushtail possum,
      Trichosurus vulpecula, by Eucalyptus terpenes.
AB  - The mixed function oxidase (MFO) activity and content was studied in the liver of
      common brushtail possums fed for 10 days on a diet containing a mixture of
      terpenes found in Eucalyptus leaves on which possums commonly browse. The MFOs
      were compared to the MFOs in possums fed a control diet of fruits and cereals
      only. The terpenes chosen were 1,8-cineole, p-cymene, alpha-pinene and limonene.
      The selected terpenes caused induction of P450 enzymes, as shown by a 53% higher
      cytochrome P450 content and a 45% increase in aminopyrine demethylase activity in
      the test animals. Aniline hydroxylase activity was significantly increased, with
      levels of 2.95 and 1.43 nmol min(-1) mg(-1) microsomal protein in the test and
      control animals, respectively. There was also a significant increase in
      androstenedione 16alpha-hydroxylase activity in the test group, 0.85 as compared
      to 0.50 nmol mg(-1) min(-1) in the control group. Western blot studies using
      human CYP2E1 and rat CYP2C11 and CYP2C6 antibodies gave CYP2E, CYP2C11 and CYP2C6
      immunoreactive bands of greater intensity in the test animals as compared to the
      control group. This study has shown experimentally that dietary terpenes cause
      enzyme induction in folivorous marsupials. It also confirms the importance of
      knowledge of diet when studying xenobiotic metabolising enzymes, particularly in
      wild animals such as the brushtail possum.

PMID- 10661717
TI  - Temperature and KClO(4)-induced metamorphosis in the sea lamprey (Petromyzon
      marinus).
AB  - Larval sea lampreys (Petromyzon marinus) were exposed to either a warm (18
      degrees C) or a cold (3 degrees C) water temperature and either with (treated) or
      without (untreated) the presence of potassium perchlorate (KClO4). After 23
      weeks, larvae were examined for signs of metamorphosis and serum samples were
      collected to assay thyroxine (T4) and 3,5,3'-triiodothyronine (T3)
      concentrations. Water temperature did not significantly affect serum T4 or T3
      concentrations in untreated larvae and no metamorphosis occurred in these groups.
      Serum T4 concentrations were not significantly different between the two
      temperature groups treated with KClO4. However, serum T3 concentrations were
      significantly higher in the cold water, KClO4-treated larvae (5.4 nmol/l) than in
      the warm water, KClO4-treated larvae (1.2 nmol/l). KClO4 treatment at a warm
      water temperature induced metamorphosis in all larvae and resulted in serum T4
      and T3 concentrations which were 66 and 95% lower, respectively, than untreated
      larvae in warm water. Despite having significantly lower serum T4 and T3
      concentrations (73 and 80%, respectively) than untreated cold water larvae,
      metamorphosis was not observed in cold water, KClO4-treated larvae. The results
      of this study indicate that warm water is a requirement for the successful
      induction of metamorphosis with KClO4, and provide further evidence of water
      temperature as an important factor in the metamorphosis of lampreys.

PMID- 10661718
TI  - The effects of silver on intestinal ion and acid-base regulation in the marine
      teleost fish, Parophrys vetulus.
AB  - Exposure to elevated silver (as AgNO3) concentrations (6-9 microM) in seawater
      was associated with comparably high silver concentrations in the intestinal
      fluids of the lemon sole (Parophrys vetulus), and a tendency for reduced drinking
      rate. The effects of silver on intestinal ion and acid-base regulation were
      studied using in situ perfusion of the intestine. Intestinal net Cl- uptake was
      reduced from 0.4 to 0.1 and intestinal net Na+ uptake from 0.2 to 0 mmol kg(-1) x
      h(-1) during silver exposure (9 microM). At the same time, intestinal HCO3- net
      efflux was reduced from 0.2 to 0.1 mmol kg(-1) x h(-1). Both intestinal Na+ and
      Cl- uptake and Cl-/HCO3- exchange are thus sensitive to silver, but to different
      extents. None of the observed effects were reversible during 24 h of recovery.
      Intestinal water transport was highly variable in vivo in the perfused
      preparation, and no significant effect of silver exposure was observed. However,
      in vitro intestine preparations exhibited reduction of intestinal net water flux
      from 4 to 1 microl cm(-2) x h(-1) during silver exposure together with reduced
      unidirectional Cl- influx. Reduced water intake and transepithelial water
      transport in silver-exposed fish resulted in moderate hemoconcentration evident
      from higher hematocrit values, but not in increased plasma ion levels. The latter
      could reflect a compensatory response via increased branchial Na+/K+-ATPase
      levels, observed in silver-exposed fish, indicative of increased branchial ion
      transport capacity. Impairment of intestinal ion and water transport as a result
      of silver intake via drinking could be an important part of the fatal cascade of
      physiological effects observed in marine fish during acute silver exposure.

PMID- 10661719
TI  - Seasonal variations in the activities of selected hepatic biotransformation and
      antioxidant enzymes in eelpout (Zoarces viviparus).
AB  - The eelpout (Zoarces viviparus) is used in Swedish and German environmental
      monitoring of pollutant effects in fish and is being considered for the same
      purpose in other countries, mainly around the Baltic Sea. The activities of
      several hepatic biotransformation and antioxidant enzymes were monitored during
      the period of 12 months from August 1996 to July 1997, using newly caught feral
      eelpout from Kattegat, off the west coast of Sweden. In females, the
      biotransformation enzyme activities showed significant seasonal variations,
      although the amplitude of the changes was limited; CYP1A-activity, measured as
      ethoxyresorufin-O-deethylase (EROD), was highest in February-March and decreased
      afterwards, possibly due to rising estrogen levels. UDP-glucuronosyltransferase
      activity was lowest in November, while the glutathione-S-transferase activity
      markedly decreased during the winter. The antioxidant enzymes, catalase,
      glutathione peroxidase and glutathione reductase showed small variations in their
      activity. The number of male fish was limited and the seasonal variations less
      clear. However, in both sexes, glutathione reductase and peroxidase activities
      were highest in autumn and May, respectively. This study establishes a baseline
      for the activities of the selected enzymes in female eelpout, which is important
      for the environmental monitoring using this fish species.

PMID- 10661720
TI  - Non-selectivity of yohimbine for adrenergic receptors in fish liver.
AB  - Most studies on adrenergic receptors (AR) have been performed on mammalian
      tissues, but the adrenergic ligands routinely utilized seem not always suitable
      for specific interaction with fish tissues. Here we report that in isolated
      catfish hepatocytes, yohimbine, usually thought to act as a specific antagonist
      for AR of the alpha2 subtype, at high concentrations, increases adenylyl cyclase
      activity and synergistically enhances the forskolin-induced enzyme stimulation.
      Such effects are counteracted by the beta-AR antagonist propranolol, but not by
      the alpha-AR antagonist phentolamine. Moreover, yohimbine seems to antagonize
      both alpha1- and alpha2-adrenergic ligand-binding in catfish liver membrane in a
      manner somewhat different from the mammalian systems. Together with previous
      evidence that yohimbine blocks the rise of intracellular calcium induced by
      epinephrine via alpha1-AR, the present results seem to indicate that this
      compound is not a suitable tool for studying alpha2-AR in fish liver.

PMID- 10661721
TI  - Neurotransmitter levels in two populations of larval Fundulus heteroclitus after
      methylmercury exposure.
AB  - The effects of methylmercury (MeHg) exposure on neurotransmitter (NT) levels in
      larval mummichogs (Fundulus heteroclitus) obtained from a mercury-polluted site
      (Piles Creek (PC), NJ) and a reference site (Tuckerton (TK), NJ) were examined.
      Population differences between PC and TK larvae in neurochemical composition and
      in neurochemical changes in response to MeHg intoxication were found. Heads of
      untreated PC larvae (7 days posthatch (dph)) contained considerably higher levels
      of dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and
      homovanillic acid (HVA) than TK. However, they had comparable levels of serotonin
      (5-hydroxytryptamine (5-HT)) and 5-hyroxy-3-indoleacetic acid (5-HIAA)/5-HT
      ratios. Changes in NTs with age were noticed, especially in PC larvae. Exposure
      of larvae to 10 microg/l MeHg induced neurochemical alterations. A significant
      increase in DA and 5-HT, as well as depressed dopaminergic and serotonergic
      activity (i.e. decreased DOPAC/DA, HVA/DA and 5-HIAA/5-HT ratios) were seen in TK
      larvae. Exposure of PC larvae to 10 microg/l MeHg reduced 5-HT at 14 dph,
      increased serotonergic activity at 7 dph, and altered dopaminergic activity (i.e.
      increased DOPAC/DA ratios, but decreased HVA/DA ratios). Changes in DA levels
      were inconsistent over time. The DA level, which was considerably higher than the
      control at 7 dph, was significantly lower than the control at 14 dph. For the two
      populations, the level of 5-HT and serotonergic activity, as well as DOPAC and
      HVA levels, were correlated with previously noted spontaneous activity. The
      changes in NT levels after exposure to MeHg are an indication of neurological
      dysfunction in larvae.

PMID- 10661722
TI  - Chemical characterisation of six oligosaccharides in a sample of colostrum of the
      brown capuchin, Cebus apella (Cebidae: primates).
AB  - Carbohydrates were extracted from a sample of brown capuchin colostrum and six of
      the component oligosaccharides were separated and purified by gel filtration and
      preparative thin layer chromatography. Their structures were determined by 1H-NMR
      to be as follows: Gal beta 1-->4[Fuc alpha 1-->3]Glc (3-fucosyllactose) Gal beta
      1-->3Gal beta 1-->4Glc (beta-3'-galactosyllactose) Gal beta 1-->6Gal beta1-->4Glc
      (beta-6'-galactosyllactose) Gal beta-->3[Gal beta 1-->4GlcNAc beta 1-->6]Gal beta
      1-->4Glc (lacto-N-novopentaose I) Gal beta 1-->4GlcNAc beta 1-->3[Gal beta 1-
      >4GlcNAc beta 1-->6]Gal beta 1-->4Glc (lacto-N-neohexaose) Neu5Ac alpha 2-->3Gal
      beta 1-->4Glc (3'-N-acetylneuraminyllactose) Of these, all except lacto-N
      novopentaose I have been previously found in human milk or colostrum.

PMID- 10661723
TI  - In vitro hepatic metabolism of a CYP3A-mediated drug, quinine, in Adelie
      penguins.
AB  - Very little is known about Antarctic animals' ability to metabolise or detoxify
      xenobiotics. The activity of cytochromes P450 subfamily 3A (CYP3A) in Adelie
      penguin liver was studied by incubating penguin liver microsomes with a human
      CYP3A substrate, quinine, and results were compared with those from human liver
      microsomes. The mean maximum rate of metabolism (Vmax) for quinine in penguin
      livers was approximately five times less (160+/-72 versus 574+/-416 pmol/mg/min;
      P<0.01), and the mean Km (substrate affinity) for the formation of quinine's
      major metabolite (3-hydroxyquinine) was significantly greater than that observed
      in human livers (160+/-73 versus 83+/-19 microM; P<0.01). The mean intrinsic
      clearance (Vmax/Km) was 1.1+/-0.4 microl/min (penguin), i.e. sevenfold less than
      in human livers (7.4+/-5.9 microl/min, P<0.005), suggesting that penguins have
      much less ability than humans to eliminate xenobiotics having a similar metabolic
      nature to quinine (i.e. CYP3A substrates). 3-Hydroxyquinine formation in penguin
      liver was inhibited by specific CYP3A inhibitors, midazolam and troleandomycin,
      but not by other CYP inhibitors, indicating that quinine metabolism to 3
      hydroxyquinine in Adelie penguin liver is likely to be catalysed by a CYP isoform
      resembling human CYP3A. Adelie penguin liver CYP isoforms could serve as
      biomarkers for the impact of environmental pollution.

PMID- 10661724
TI  - Dietary L-arginine level alters plasma nitric oxide and apha-1 acid glycoprotein
      concentrations, and splenocyte proliferation in male broiler chickens following
      Escherichia coli lipopolysaccharide injection.
AB  - Experiments were conducted to determine the effect of dietary arginine (Arg) on
      nitric oxide (NO) production following injection with Escherichia coli
      lipopolysaccharide (LPS) and splenocyte proliferative response to concanavalin A
      in broilers. Birds were fed experimental diets containing Arg at levels of 6.5,
      14.4 or 24.4 g/kg diet in experiment 1, and 6.5, 14.4 or 19.3 g/kg diet in
      experiment 2, respectively, for 7 days and were then intraperitoneally injected
      with LPS (2 mg/kg body weight) after 16 h fasting. Maximum NO production
      estimated by plasma nitrite concentration was observed 6 or 10 h after LPS
      injection in all Arg groups. Dietary Arg level and/or intake were positively
      associated with NO production. NO production at 6 or 10 h after LPS injection
      coincided with changes in plasma alpha-1 acid glycoprotein concentration, an
      acute phase substance, at 10 or 24 h post-LPS injection. Splenocyte proliferation
      in chicks fed on Arg-sufficient (14.4 g/kg) diet was greater that that in chicks
      fed Arg-deficient or -excess diets. The results suggest that dietary Arg level
      and/or intake proportionally affect NO production, and acute phase inflammatory
      responses following LPS injection, and that marginal deficiency or excess of
      dietary Arg might reduce splenocyte proliferative responses.

PMID- 10661725
TI  - Effects of bilobalide, a sesquiterpene in Ginkgo biloba leaves, on population
      spikes in rat hippocampal slices.
AB  - The effects of bilobalide, a sesquiterpene isolated from the leaves of Ginkgo
      biloba L., were investigated in a rat hippocampal slice preparation. Bilobalide
      (10-500 microM) significantly increased the amplitude of population spikes evoked
      by electrical stimulation of Schaffer collateral/commissural fibers in a
      concentration-dependent manner. Paired-pulse inhibition at interpulse intervals
      of 10-50 ms was significantly reduced in the presence of bilobalide (50 microM).
      The inhibitory action of muscimol (1 microM) was attenuated by bilobalide (100
      microM). These results suggest that bilobalide induces an enhancement of
      excitability of CA1 pyramidal neurons, which involves, at least in part, a
      reduction in GABAergic inhibition in rat hippocampus.

PMID- 10661726
TI  - Changes in serum concentrations and pituitary content of the two prolactins and
      growth hormone during the reproductive cycle in female tilapia, Oreochromis
      mossambicus, compared with changes during fasting.
AB  - Patterns of change in serum concentrations and pituitary content of GH and two
      tilapia prolactins (PRL177 and PRL188) were examined during the reproductive
      cycle of female tilapia, Oreochromis mossambicus, adapted to fresh water and to
      seawater. Changes in these hormones during fasting were examined to elucidate
      whether changes observed during brooding could be attributed to a reduction in
      feeding during brooding. Serum concentrations of GH increased prior to pituitary
      content during the brooding phase of the reproductive cycle. In contrast,
      pituitary content of GH increased prior to serum concentrations during fasting.
      There was no consistent pattern of change in serum or pituitary PRL levels during
      the reproductive cycle, among experiments. Serum concentrations of PRL177 were
      elevated in all fasted fish, whereas PRL188 was elevated during fasting in males
      but not females. The increases in the serum concentration of PRLs and GH, and in
      the pituitary content of GH in response to fasting support the notion that these
      hormones are involved in the regulation of the use of metabolic substrates in
      tilapia. We conclude that reduced food intake during brooding may contribute to
      changes in serum and pituitary levels of the PRLs and GH observed during the
      reproductive cycle. Nevertheless, differences between changes in serum and
      pituitary GH during brooding and fasting suggest GH has actions in reproduction,
      and changes in GH during brooding are not only in response to fasting.

PMID- 10661727
TI  - Comparative effect of fenitrothion treatment on intracellular protease activities
      in insecticide-resistant and susceptible strains of Musca domestica L.
AB  - In order to further elucidate the biochemical mechanisms responsible for
      insecticide resistance in insects, we have determined changes in the activity
      levels of a comprehensive range of proteolytic enzymes (cytoplasmic and lysosomal
      proteinases and peptidases, which play a key role in normal cell functioning) in
      fenitrothion-resistant (571ab) and susceptible (Cooper) strains of Musca
      domestica following in vivo exposure to the insecticide fenitrothion. Untreated
      insects of the resistant strain had significantly higher levels (20-100%) of
      activity for many protease types compared to the susceptible strain (whole body
      analysis). Exposure to fenitrothion resulted in further activity increases for
      most proteases at some point during the subsequent 24 h period in resistant
      strain insects; susceptible strain insects were also capable of similar increases
      in protease activities. We therefore suggest that it must be the combination of
      intrinsically higher protease levels (prior to pesticide exposure), together with
      the capacity to further increase protease activities following insecticide
      exposure, which is important in the mechanism by which proteases may confer
      survival advantages in insecticide resistant insects. We further speculate that
      this mechanism may involve increased supply of precursor amino acids from
      proteolytic degradation products to the intracellular pool, prior to de novo
      synthesis of detoxifying enzymes following insecticide exposure.

PMID- 10661728
TI  - Patterns of N-acetyl-beta-glucosaminidase isoenzymes in the epidermis and
      hepatopancreas and induction of N-acetyl-beta-glucosaminidase activity by 20
      hydroxyecdysone in the fiddler crab, Uca pugilator.
AB  - A new staining method for detection of N-acetyl-beta-glucosaminidase on
      denaturing SDS polyacrylamide gels was developed. The isoenzyme pattern of N
      acetyl-beta-glucosaminidase in the epidermis of the fiddler crab, Uca pugilator,
      is different from that in the hepatopancreas. Two isoforms of N-acetyl-beta
      glucosaminidase, with molecular weights of 89 and 45.6 kDa, are present in the
      hepatopancreas while there is only one form of N-acetyl-beta-glucosaminidase, 89
      kDa, in the epidermis. No sexual dimorphism was found in these patterns of N
      acetyl-beta-glucosaminidase isoenzymes. The characteristic isoenzyme patterns in
      the epidermis and hepatopancreas occurred consistently throughout the molting
      cycle. Injections of the molting hormone, 20-hydroxyecdysone, at 25 microg/g live
      weight, into crabs in premolt substage D1, significantly increased N-acetyl-beta
      glucosaminidase activity in the epidermis by 86%. Since only one form of N-acetyl
      beta-glucosaminidase, 89 kDa, is present in the epidermis, the elevation in
      epidermal enzymatic activity after 20-hydroxyecdysone administration is entirely
      accounted for by this N-acetyl-beta-glucosaminidase isoenzyme. The results
      reported herein are the first direct evidence that in a crustacean N-acetyl-beta
      glucosaminidase activity is regulated by the steroid molting hormone.

PMID- 10661729
TI  - Proceedings of the 2nd International Meeting on Bacterial Vaginosis. Aspen,
      Colorado, USA. September 17-19, 1998.

PMID- 10661730
TI  - BV public policy: issues and challenges.

PMID- 10661731
TI  - The epidemiology of bacterial vaginosis.

PMID- 10661732
TI  - Diagnostic methods for bacterial vaginosis.

PMID- 10661734
TI  - A public health approach to adverse outcomes of pregnancy associated with
      bacterial vaginosis.

PMID- 10661733
TI  - Gynecologic sequelae of bacterial vaginosis.

PMID- 10661735
TI  - The future of bacterial vaginosis-related research.
AB  - Various ways and criteria are used to diagnose BV. Guidelines should be redrawn
      and they should embody greater uniformity. The etiology of BV remains enigmatic.
      However, various observations suggest that host factors, possibly hormonal, cause
      an imbalance in the vaginal microflora. Exogenous factors, such as semen and
      antibiotics, may then help to bring about a more prolonged change. This forms a
      working hypothesis for further exploration. The role of the lactobacillus phage
      in the development of BV also needs to be determined. Various conditions may
      occur as a consequence of BV in non-pregnant and pregnant women and BV may also
      affect men. A subjective assessment of the extent to which these associations
      occur or are likely to be shown to occur by further investigations is presented
      in Table 1. The ability to cure acute BV needs to be improved as does the
      treatment of chronic BV, for which vaginal recolonization with exogenous
      lactobacilli is an approach to be evaluated further.

PMID- 10661736
TI  - Contraception-21.
AB  - A Contraception-21 strategy was adopted by the Rockefeller Foundation in 1993.
      The objective of the strategy is to mobilize and lift up the whole field of
      contraceptive research, to develop novel contraceptive approaches for the next
      century. The premise of the strategy is that, in spite of technological advances
      in the past few decades, current contraceptive choices are still inadequate to
      meet present and rapidly expanding future needs, particularly in developing
      countries. The central theme of the strategy is that it should be driven by the
      unmet needs of women, and not by a demographic imperative or by scientific
      opportunity alone. Two essential requirements are: mobilization of the science,
      particularly the new advances in cell and molecular biology, to provide the
      needed tools; and mobilization of industry to provide the needed resources.

PMID- 10661737
TI  - Public/private-sector collaboration in contraceptive research and development:
      summary and historical perspective.
AB  - This summary and historical perspective relates exclusively to contraceptive
      research and development during the period between the early 1970s and the
      present. This paper covers the raison d'etre for public/private-sector
      collaboration in this field, provides definitions and summarizes the issues
      motivating and confronting both sectors, discusses and outlines a generic
      memorandum of understanding (MOU) that can be used to initiate collaborative
      research activities, and presents a time line of selected milestones in
      public/private-sector collaboration, many of which were initiated by the
      Rockefeller Foundation. Public and private-sector collaboration takes advantage
      of the unique strengths of both sectors and offers good opportunities for a 'win
      win' situation in product development.

PMID- 10661738
TI  - The promise of public/private sector collaboration in the development of new
      contraceptives: the experience of CICCR.
AB  - The Consortium for Industrial Collaboration in Contraceptive Research (CICCR) was
      established in 1995 with funding from two philanthropic foundations. Now just
      over 3 years later, it is supported by five foundations and a United Nations
      agency. Work in three priority areas of male methods, vaginal methods and monthly
      methods for women is progressing well. Collaboration with 10 industrial entities
      has been established, and more than 60 contracts with investigators at not-for
      profit institutions have been funded. It can be concluded that CICCR has provided
      an efficient and effective mechanism for promoting industrial collaboration in
      contraceptive R&D, and fills a need not covered by other agencies active in the
      field.

PMID- 10661739
TI  - The promise of public/private sector collaboration in the development of vaginal
      microbicides.
AB  - This paper describes the efforts of the public sector, primarily the CONRAD
      Program and its Consortium for Industrial Collaboration in Contraceptive Research
      (CICCR), to work with industry in the development of vaginal microbicides for the
      prevention of transmission of STDs including HIV. The results of a meeting on
      this topic held in Durham, NC, USA in October 1998, as well as market surveys,
      are also included. The projects described illustrate the opportunities for
      collaboration and the resulting progress.

PMID- 10661740
TI  - A new model for collaboration: the alliance for microbicide development.
AB  - Vaginal microbicides for preventing sexually-transmitted infection and/or
      conception are a novel, much needed technology, yet not seen by industry as
      having attractive market potential. Nor is the public sector acting with the
      urgency, priority, and investment that would compensate for lack of private
      financing, shape the necessary basic and applied research agendas, and spur the
      dedicated development crucial to advancing this field. The Alliance for
      Microbicide Development was constituted through a Rockefeller Foundation grant to
      advocate for and educate about microbicide development, track and communicate
      product development and regulatory status, contribute to enhanced efficiency in
      preclinical and clinical processes and, later, help establish a base for matching
      funds to support combination and comparative studies. After 1 year of existence,
      the Alliance has proved its value as an innovative collaborative model, having
      generated and catalyzed a large volume of activity towards its objectives in all
      priority areas identified by its members.

PMID- 10661741
TI  - Collaboration with academia in the development of vaginal microbicides.
AB  - Advanced Care Products has been active in the development of vaginal
      microbicides, with public sector support. Currently, nonoxynol-9 gel is being
      evaluated in two Phase-III studies. Work has been conducted on polystyrene
      sulfonate, with the aim of filing an investigational new drug application (IND)
      in the USA. This paper discusses the challenges in development of an over-the
      counter (OTC) product for the USA. Public sector support has been pivotal in the
      progress shown to date. Further challenges lie ahead, vis-a-vis an OTC approval.

PMID- 10661742
TI  - A new model for collaboration--making emergency contraceptives available in
      developing countries.
AB  - Private/public-sector collaboration in contraceptive research and development
      offers a fresh opportunity to consider a holistic approach to making emergency
      contraception (EC) available in developing countries. Emergency contraception has
      been available since the 1970s but has remained under-utilized. Emergency
      contraception may be used by women who want to prevent a pregnancy and therefore
      has a specific use, in a specific situation. This paper highlights the distinct
      and reciprocal advantages of a collaborative approach between the Consortium for
      Emergency Contraception (the public sector) and a pharmaceutical company (the
      private sector), to the introduction of EC in developing countries. The
      importance of cultivating a public/private-sector collaborative approach, which
      serves the interests of both parties concerned, in order to foster progress in
      this important initiative, is highlighted.

PMID- 10661743
TI  - Collaborative research and development on mifepristone in China to reduce
      unwanted pregnancies and recourse to abortion.
AB  - A program proposed and executed by The Concept Foundation and funded by the
      Rockefeller Foundation demonstrates the feasibility of using private/public
      sector collaboration for making mifepristone widely available. The application of
      mifepristone to emergency, luteal phase and menstrual induction contraception is
      being assessed in clinical research programs conducted in accordance with
      international standards for good clinical research. Opportunities for
      introduction of mifepristone in developing countries are being pursued using
      mifepristone produced in China in accordance with international standards of good
      manufacturing practice.

PMID- 10661744
TI  - Collaboration with academia in the development of post ovulatory methods.
AB  - The 0.75-mg levonorgestrel-containing 'morning after' contraceptive tablet
      Postinor was developed by Gedeon Richter Ltd., Hungary. The product was first
      launched in 1979 and registered later in approximately 40 countries. In 1994, the
      World Health Organization offered the company participation in a multinational
      clinical trial to prove the superiority of the product over existing (Yuzpe-type)
      emergency contraceptive products. Based on these data the company was able to
      redesign the 'morning after' type Postinor into an 'emergency' pill, Postinor-2.
      During further clinical trials a close working relationship was formed between
      the Department of Obstetrics and Gynaecology at the Albert Szent-Gyorgyi Medical
      University in Szeged, Hungary, and Gedeon Richter. The advantages and challenges
      of cooperation between public- and private-sector institutions are analyzed in
      the paper.

PMID- 10661745
TI  - Collaboration between industry and academia--prospects for male fertility
      control.
AB  - Drug development within the pharmaceutical industry is probably the field with
      the highest level of regulations. Due to the complexity of the different
      components of drug development and drug surveillance the need for a sophisticated
      organization and infrastructure is obvious. In addition, there is a necessity for
      sufficient resources and long-term commitment as well as logistic and long-term
      knowledge management. In order to secure high professional standards at all
      levels of this highly complex value creating chain, the number of cooperative
      arrangements in the pharmaceutical industry are increasing. The identification of
      new targets in the drug finding process calls in particular for outside partners.
      At the same time the preparedness of non-industrial researchers to cooperate with
      industry has also increased significantly. The area of fertility control,
      especially male fertility control, provides an excellent example for this kind of
      cooperation between industrial and non-industrial partners. Here a cooperative
      network is described which probably meets practically all relevant criteria for
      both the non-industrial but also the industrial partner. Some principles for the
      management of such a cooperative network are discussed. We believe that this kind
      of network can serve as a model for similar networks in other fields.

PMID- 10661746
TI  - Pushing the frontiers of science: reflections on an Institute of Medicine study.
AB  - A women-centered contraceptive research agenda was the focus of a 1996 Institute
      of Medicine Committee report. Priority was given to research on methods that act
      as a chemical or physical barrier to conception and to STDs including HIV; to
      menses inducers and once-per-month methods; and to male contraceptive methods.
      Much progress has been made since the 1996 report. This paper summarizes this
      progress. New research has been developed in the three priority areas,
      collaboration activities have been developed between the public and private
      sectors, and emergency contraception has been introduced to the US. Controversies
      are discussed in relation to immunocontraception, stem cell research and fetal
      tissue research. Finally there is a brief report on the lessons to be learned
      from the experience of the introduction of the implant, Norplant, in the US.

PMID- 10661747
TI  - Pushing the frontiers of science--the Mellon reproductive biology centers.
AB  - The 20-year history of the Andrew W. Mellon Foundation's support for US
      reproductive biology centers and junior investigators is summarized. The main
      results of the Foundation's program during the 1990s are described under the
      following headings: research generated by seed money, research generated by the
      twinning program, and commercial partnerships. The twinning program supports
      research collaborations between US centers and reproductive biology centers in
      developing countries, and was recently reviewed by an external panel. Both the
      seed money and twinning mechanisms were judged to have been successful in
      promoting research relevant to contraception which, in many instances, resulted
      in publications in peer-reviewed journals and in follow-on funding from other
      sources. The Foundation established a new program in 1998. The paper lists the US
      centers included in the new program and the 'target' areas of research that will
      be emphasized.

PMID- 10661748
TI  - Pushing the frontiers of science--the WHO/Rockefeller Foundation Initiative on
      implantation.
AB  - One approach to fertility regulation for which there is still a large unmet need
      is a once-a-month method that can be taken at the end of the luteal phase as a
      menses-inducer. Such a method would have a number of logistical and economic
      advantages for many women over other currently available methods. However, to be
      acceptable, menses-inducers of this type must not produce disturbances in
      subsequent menstrual cycles that would lead to unpredictable menstrual patterns
      or advance or delay subsequent ovulations. A number of structural and functional
      factors associated with the cyclical development and demise of the endometrium
      and corpus luteum in fertile and infertile women have been identified and the
      opportunity is now presented for interfering with implantation by disrupting the
      function of these factors at the local level in these tissues without systemic
      involvement or prolonged activity. The Rockefeller Foundation and WHO are
      supporting six centers and investigators around the world, as an international
      collaborative research initiative, to investigate the molecular biology of these
      factors and the effect on fertility of their manipulation. It is intended that
      promising leads identified and selected in this way will be developed into new
      products with industry.

PMID- 10661749
TI  - Pushing the frontiers of science--the Population Council's Microbicide Basic
      Science Network on vaginal microbicide research.
AB  - Microbicides are the new frontier of products for the prevention of sexually
      transmitted infections (STIs). Twelve years ago, scientists realized that
      existing spermicides had some anti-microbial activity and perhaps could be
      improved or reformulated with new compounds to provide a complete barrier against
      STIs. However, the development and successful marketing of an effective, non
      toxic, convenient and affordable vaginal microbicide that women can use on a long
      term basis hinges on a close collaboration between research institutions and the
      pharmaceutical industry. The Population Council has recently taken the first step
      in instituting a multifaceted strategy for the development of a microbicide by
      establishing the Microbicide Basic Science Network, comprising of scientists with
      diverse backgrounds and expertize.

PMID- 10661750
TI  - Public- and private-sector partnerships in contraceptive research and
      development: guiding principles.
AB  - The objective was to review and analyze practices of preferential pricing and
      royalties for products resulting from collaboration between the public and
      private sectors. A wide variety of practices and experience exist, and
      collaboration depends on the product being developed and its potential markets.
      Guiding principles in preferential pricing, royalty provisions, and long-term
      collaboration are presented that can be mutually beneficial to both the public
      and private sector.

PMID- 10661751
TI  - Liability concerns in contraceptive research and development.
AB  - The history of liability claims in the US against contraceptive products is among
      the issues that discourage manufacturers from investing in discovery and
      development in this field. Other factors are the high cost of new drug
      development, elevated insurance rates for contraceptives, and the desire to avoid
      controversy that can disturb corporate tranquility. General features of the
      American legal system influence the large number and cost of product liability
      claims in the US compared to Europe. These differences pertain to issues such as
      the role of judges, how lawyers receive their compensation, and the use of expert
      scientific testimony. The history of litigation in the US against pharmaceutical
      products and devices pertaining to women's health suggests that interventions
      that involve the reproductive system are held to different standards or elicit
      different emotional responses than other pharmaceutical products or devices.

PMID- 10661752
TI  - The past, present and future.
AB  - My generation has seen more progress in science and technology than all preceding
      generations together. We have also witnessed several intellectual, technological,
      medical and social revolutions spearheaded by the contraceptive revolution and
      followed by those in reproductive health, gender equity, information,
      communication, globalization, international assistance, etc. The results of the
      first contraceptive revolution were spectacular, by 1990 some 900 million couples
      used contraception, which became a global lifestyle. When this revolution lost
      momentum, a new departure took place: the Rockefeller Foundation's Contraception
      21 initiative. The major achievements of this initiative are presented in this
      volume. All papers represent a significant contribution also to the ultimate
      objective: the achievement of human dignity for every woman. The revolutions
      mentioned above profoundly changed the world and our perception of it. They will
      also assist humankind in deconstructing the deterministic worldview of past
      centuries and replacing it with a science-driven anthropocentric philosophy.

PMID- 10661753
TI  - Chronic pain management: a qualitative study of elderly people's preferred coping
      strategies and barriers to management.
AB  - Although the majority of pain complaints, in Australia, are among the elderly
      population, the focus of treatment is not on this age group. In order to achieve
      effective management of elderly people's chronic pain, their perspective of pain
      and coping strategies used needs to be understood. This qualitative study
      explored the preferred strategies of elderly people and the barriers they
      encountered in trying to manage their pain. Elderly people (n = 72) with chronic
      pain, over 65 years of age and living in the community, were interviewed for the
      study. Data were collected using six focus group and 12 in-depth interviews and a
      biographical questionnaire. Preferred coping strategies were those that could be
      self-administered and included both physical and cognitive elements. Elderly
      people wished to be active in their treatment, make informed choices and were
      willing to try new methods. Least-preferred strategies were the conventional
      treatments of medications, exercise and physiotherapy. Many barriers have to be
      overcome to achieve relief for their pain such as cost, access to health care,
      related disorders, attitudes of health professionals, lack of communication and
      fear of losing independence. Health professionals need to be aware of elderly
      people's perspective of pain and their preferred strategies and reasons for these
      choices. Health services must meet their specific needs.

PMID- 10661754
TI  - Impacts of illness and disability on the well-being of older people.
AB  - This study examined ways in which aspects of activity may mediate relationships
      between physical illness and well-being among older people. Data were from the
      Health Status of Older People survey of 1000 people aged 65 and over who lived in
      the community in Melbourne, Australia. After controlling for gender, marital
      status, and perceived social support, multivariate analyses showed that the major
      impacts of illness and pain were through their effects on activity limitations,
      which in turn were related to lowered well-being. Limitations with instrumental
      activities were associated most with lower positive affect, while perceived
      activity limitations due to major illness had more impact on increased negative
      affect and depressive symptoms. However, most older people with major illness
      still scored highly on well-being, and there was individual variability in well
      being. Research on the impacts of illness needs to take more account of impacts
      on daily living and differences in individual interpretation of illness and
      disability. Health promotion and treatment can enhance the well-being of older
      people by maintaining and regaining independence and activity when individuals
      experience major illness.

PMID- 10661755
TI  - Can simultaneous bilateral movement involve the undamaged hemisphere in
      reconstruction of neural networks damaged by stroke?
AB  - Normalization of upper limb movement remains a difficult problem for a
      significant subpopulation of hemiplegic stroke patients. Clinical observations
      prompted investigation of a novel approach using simultaneous identical bilateral
      movements performed independently. We briefly report 12 controlled single-case
      experiments using multiple-baseline designs across three separate grasp/reach
      activities. Unilateral performance tests with the hemiplegic arm using the
      bilaterally trained actions demonstrated clinically and statistically significant
      improvements in movement patterns. These improvements were specific to the
      trained movement and well maintained. Using recent literature we develop a
      theoretical model proposing that bilateral simultaneous movement promotes
      interhemispheric disinhibition likely to allow reorganization by sharing of
      normal movement commands from the undamaged hemisphere. Disinhibition may also
      encourage recruitment of undamaged neurones to construct new task-relevant neural
      networks. The potential contribution of spared ipsilateral pathways in the
      damaged hemisphere, indirect corticospinal pathways and ipsilateral pathways from
      the undamaged hemisphere is discussed.

PMID- 10661756
TI  - Post-polio syndrome: assessments, pathophysiology and progression.
AB  - While there have been many reports of the decline in motor function in patients
      with prior-polio, there have been few reports of quantitative changes in muscle
      function and the pathophysiological mechanisms for the deterioration are poorly
      understood. This paper describes the establishment of a postpolio clinic and the
      principles adopted in quantitative muscle testing using twitch interpolation.
      Peripheral endurance and/or voluntary drive to muscles is impaired in about 30%
      of prior-polio patients attending the clinic. Progression of these deficits is
      slow and not easily predicted by factors associated with the original illness.

PMID- 10661757
TI  - Recent Chinese migrants' health, adjustment to life in New Zealand and primary
      health care utilization.
AB  - A community survey of 271 Chinese migrants aged 15 years and older living in
      Auckland was conducted to assess self-rated adjustment and health. The majority
      of respondents came from Hong Kong and Taiwan. Despite significant changes in
      their lives, including the absence of family members, unemployment and
      underemployment, most did not report major adjustment problems or regret having
      come to New Zealand. Few considered their health to be poor. Forty-two per cent
      reported having consulted a doctor within the past 12 weeks. Factors
      significantly associated with having experienced major problems included being
      aged 26-35 years, rejection from locals and having low English proficiency.
      Factors associated with poor adjustment included expectations not having been
      met, regretting coming, low proficiency in English, recent arrival in New
      Zealand, unemployment, younger age and lower levels of education. Self-rated fair
      or poor health was found to be associated with Chinese-only reading knowledge,
      residency of more than 5 years and regretting having come to New Zealand.

PMID- 10661758
TI  - Harm minimization or abstinence: an evaluation of current policies and practices
      in the treatment and control of intravenous drug using groups in Australia.
AB  - The past decade has seen Australia cited as a significant leader in the
      development of harm-minimization policies towards illicit drug use. Such policies
      have been developed on the premise that harm minimization would lead to
      substantial long-term gains to society in the areas of: (1) decreased health
      costs for intravenous drug users (IDU); (2) decreased mortality rates for IDU
      groups; (3) increases in social productivity of IDU (through such things as
      gaining and retaining employment); and (4) decreased criminal activity leading to
      substantial gains in law enforcement budgets, and reduced community crime costs
      (theft and burglaries, etc. Evaluation of the success of harm minimization is
      notoriously difficult. By its nature success often means there are no ways of
      comparing potential losses against potential gains. An alternative to harm
      minimization, abstinence models, exist. In Australia the harm minimization policy
      has come under review in some States, and has never been fully implemented in the
      Northern Territory. This paper reviews the merits and demerits of both
      approaches, and initiates discussion regarding the development of future services
      for IDU groups in Australian society.

PMID- 10661759
TI  - Novel speech patterns and the treatment of stuttering.
AB  - Variants of rhythmic speech and legato speech have been used for centuries to
      treat stuttering. Despite considerable empirical and theoretical inquiry, the
      reason for the effectiveness of these novel speech patterns in suppressing
      stuttering is unknown. Recent acoustic research conducted at the University of
      Sydney suggests that a reduction in the variability of syllabic stress is a
      critical feature of these two speech patterns, and that this reduction suppresses
      stuttering by stabilizing the speech motor system. This paper reviews what is
      known about rhythmic speech and legato speech from this perspective, and the
      theoretical and clinical implications of reconceptualizing them in this way are
      discussed.

PMID- 10661760
TI  - Episodes of allied health outpatient care: an investigation of service delivery
      in acute public hospital settings.
AB  - This paper describes 'episodes of allied health outpatient care' by linking
      related clinical allied health outpatient contacts. Episodes were tracked on
      10095 patients in 46 public hospital outpatient services in eight hospitals over
      a 10-month period during 1996, as part of a Commonwealth Ambulatory Care Reform
      project. Fifty-one per cent of patients completed at least one 'episode of allied
      health outpatient care' during the period of the study. An episode theoretically
      comprised all those occasions of service provided to the one patient for the one
      condition in the one allied health outpatient service, using the one referral.
      There were difficulties in flagging the beginning and end of episodes, as
      services used specific ways of defining and recording episode characteristics.
      Describing allied health outpatient service usage by episode has implications for
      developing funding models that are appropriate to the core business of allied
      health services.

PMID- 10661761
TI  - Motor accident and workers' compensation insurance design for high-quality health
      outcomes and cost containment.
AB  - This paper studies scheme structure and information concerning rehabilitation
      outcome for claimants under the NSW Motor Accidents Scheme and the NSW Workers'
      Compensation Scheme. It argues that to ensure effective rehabilitation there is a
      need for consistent, national accident schemes which provide services regardless
      of fault. In general, health outcomes will be improved if dispute resolution and
      estimation of level of disability occur in a context which avoids adversarialism.
      On the other hand, negligence could best be punished and compensation provided to
      victims as a result of prosecution for breach of duty of care under the relevant
      protective legislation. Other vital elements in injury prevention and
      rehabilitation are more effective risk management, worker representation and
      information provision at the workplace level. Comparable performance measures for
      rehabilitation and other service providers are also necessary for the attainment
      of quality management and evidence-based medicine.

PMID- 10661762
TI  - An automated form of video image analysis applied to classification of movement
      disorders.
AB  - Video image analysis is able to provide quantitative data on postural and
      movement abnormalities and thus has an important application in neurological
      diagnosis and management. The conventional techniques require patients to be
      videotaped while wearing markers in a highly structured laboratory environment.
      This restricts the utility of video in routine clinical practise. We have begun
      development of intelligent software which aims to provide a more flexible system
      able to quantify human posture and movement directly from whole-body images
      without markers and in an unstructured environment. The steps involved are to
      extract complete human profiles from video frames, to fit skeletal frameworks to
      the profiles and derive joint angles and swing distances. By this means a given
      posture is reduced to a set of basic parameters that can provide input to a
      neural network classifier. To test the system's performance we videotaped
      patients with dopa-responsive Parkinsonism and age-matched normals during several
      gait cycles, to yield 61 patient and 49 normal postures. These postures were
      reduced to their basic parameters and fed to the neural network classifier in
      various combinations. The optimal parameter sets (consisting of both swing
      distances and joint angles) yielded successful classification of normals and
      patients with an accuracy above 90%. This result demonstrated the feasibility of
      the approach. The technique has the potential to guide clinicians on the relative
      sensitivity of specific postural/gait features in diagnosis. Future studies will
      aim to improve the robustness of the system in providing accurate parameter
      estimates from subjects wearing a range of clothing, and to further improve
      discrimination by incorporating more stages of the gait cycle into the analysis.

PMID- 10661764
TI  - Regression of melanoma, but not keratoacanthoma, is associated with increased HLA
      B22 and decreased HLA-B27 and HLA-DR1.
AB  - Sixty three Caucasian patients with either melanoma, keratoacanthoma or squamous
      cell carcinoma were human leucocyte antigen (HLA) typed. The regressing tumour
      groups were compared with their non-regressing counterparts, and the patient
      groups were compared with a control Caucasian population. Melanoma patients
      showing histological regression were more likely to be HLA-B22 positive, and HLA
      B27 and -DR1 negative, than those without features of regression. When compared
      with a control population, the group of melanoma patients were more likely to be
      HLA-B22 positive. Comparison of the group of keratoacanthomas, a self-regressing
      tumour, and the group of squamous cell carcinomas, a non-regressing tumour, did
      not show any significant differences in HLA typing.

PMID- 10661763
TI  - Characterization of a human melanoma cell line with non-oestrogen receptor
      dependent tamoxifen resistance.
AB  - While investigating the mechanism of synergistic cytotoxicity between tamoxifen
      (TAM) and cisplatin (DDP) we developed a TAM-resistant variant of the human
      melanoma cell line T-289. We sought to characterize this cell line with respect
      to the effect of TAM resistance on a variety of different intracellular cell
      cycle control and apoptotic pathways. A TAM-resistant variant cell line (289
      TAMs) was developed and the technique of Western analysis was to determine the
      changes in protein expression that occurred as a result of the development of TAM
      resistance. In this model, TAM resistance resulted in an increase in the
      detectable basal levels of cyclin E, GADD 153, p16, BAX, Bcl-XL, and wild-type
      and mutant p53, an increase in TAM induction of p16, and a decrease in the
      detectable basal levels of cyclin D1, p21 and p27. There were no detectable
      changes in the levels of pRb. In the TAM-resistant variant, p21 levels were
      essentially undetectable, while p27 was present and maintained its response to
      TAM Induction, albeit at a much lower level. This investigation demonstrates that
      the development of TAM resistance is associated with a change in the detectable
      levels of a variety of cell cycle control and apoptosis-related proteins. While
      the exact role that each change plays in the development of tamoxifen resistance
      remains to be determined, these data suggest that the development of resistance
      to a particular agent results in changes in multiple, seemingly unrelated
      pathways. These data have implications for future studies in both the laboratory
      and the clinic.

PMID- 10661765
TI  - Efficient in vivo targeting of malignant melanoma by single-chain Fv antibody
      fragments.
AB  - Single-chain antibody fragments (scFvs) have superior pharmacokinetic and
      biodistribution characteristics compared with larger antibody fragments when used
      for radioimaging of human tumours. An scFv specific for malignant melanoma (B4
      scFv) was tested in a mouse xenograft model for human melanoma and compared with
      the monoclonal antibody (MAb) LHM2. LHM2 is specific for the high molecular
      weight proteoglycan melanoma-associated antigen (HMW-MAA), while B4 scFv binds a
      novel melanoma-specific antigen. The B4 scFv was cleared rapidly from the
      circulation (t(1/2)alpha = 7 min) compared with LHM2 MAb (t(1/2)alpha = 37 min).
      However, the B4 scFv had an unusually long t(1/2)beta (437 min compared with 384
      min for LHM2 MAb). Biodistribution studies showed that B4 accumulated
      specifically in the tumour grafts. Although non-specific accumulation in the
      liver, lung, spleen and blood was lower than with LHM2, non-specific accumulation
      of B4 in the kidney was higher. Despite this, the overall targeting efficiency in
      this study, as determined by tumour:normal tissue ratios, showed that B4 was
      superior to whole antibody. Immunoscintigraphy images showed good correlation
      with the biodistribution data for B4 and LHM2. This study represents the first
      use of an anti-melanoma scFv in vivo.

PMID- 10661766
TI  - Evaluation of S-100beta assays for the prediction of recurrence and prognosis in
      patients with AJCC stage I-III melanoma.
AB  - We performed prospective serial studies on 266 melanoma patients undergoing
      surgery for high risk primary or lymph node metastases to assess the predictive
      value for recurrence of melanoma of S-100beta detection in the serum using
      immunoradiometric assay (IRMA) or Immunoluminometric assay (LIA-mat). The tests
      for S-100beta were most frequently positive in the first 3 months after surgery.
      Results of the assays did not show a strong correlation with clinical stage of
      the disease. Studies on a cohort of 147 patients who had been followed for a
      minimum of 2 years post-surgery were carried out to assess the sensitivity of the
      assays for identifying patients who develop recurrence of their melanoma. The LIA
      mat and IRMA assays detected S-100beta in the serum of 47.5% and 23%,
      respectively, of the subset of 61 patients who developed recurrence of disease.
      By Kaplan Meler analysis, patients positive for S-100beta by LIA-mat assay in the
      first 3 months post-surgery were shown to have an approximately 2.7 times shorter
      disease-free survival (DFS) period than patients negative for S-100beta. This was
      significant by log rank analysis. Multivariate analysis indicated that the
      presence of S-100beta was an independent prognostic determinant of DFS, and was
      independent of tumour thickness and lymph node status. This prospective analysis
      in a large number of patients suggests that assays for S-100beta in patients
      following surgical resection of AJCC stage I-III melanoma are of limited value
      for identifying patients who will develop recurrence of their disease. The
      results of the LIA-mat assays, but not the IRMA assays, do however provide an
      additional measure of prognosis that is independent of existing measures.

PMID- 10661767
TI  - Non-invasive assessment of tumour cell proliferation with positron emission
      tomography and [76Br]bromodeoxyuridine.
AB  - In oncology, a number of new potential therapeutic modalities, including gene
      targeting, are currently under investigation. To evaluate their response at a
      preclinical level, a non-invasive method providing information about cell
      proliferation would be highly valuable. The growth fraction can be assessed by
      the incorporation of thymidine into the DNA of S-phase cells. We report the use
      of the thymidine analogue bromodeoxyuridine (BrUdR) labelled with bromide-76
      (76Br) in positron emission tomography (PET). PET scans using [76Br]BrUdR were
      performed in seven patients with metastatic melanoma. The in vitro cell
      proliferation in these metastases (n = 7) was compared with immunohistochemically
      evaluated cell proliferation using anti-bromo-deoxyuridine and MIB-1 antibodies
      after excision. Blood samples were taken to analyse the kinetics of the
      radiopharmaceutical. The accumulation of [76Br]BrUdR in PET correlated
      significantly with the immunohistochemically assessment of S-phase and cycling
      cells. In one patient a clinically unexpected metastases was found on [76Br]BrUdR
      PET which became evident 4 weeks later. Analysis of blood samples showed a fast
      disappearance of [76Br]BrUdR; 30 min after injection free bromide was the main
      form of radioactivity, resulting in a high background activity. Assessment of
      cell proliferation using [76Br]BrUdR is hampered because of fast debromation and
      high background activity. The results are thus rather the effect of the increased
      circulation in more rapidly proliferating metastases than Incorporation of
      [76Br]BrUdR into proliferating cells.

PMID- 10661768
TI  - Uveal melanoma: natural history and treatment options for metastatic disease.
AB  - In order to evaluate the natural history, prognostic parameters and treatment
      modalities for metastatic uveal melanoma, a review of the clinical data from the
      current literature was performed based on a Medline database search. Uveal
      melanoma represents approximately 5% of all melanomas. It is a distinct clinico
      pathological entity, differing in many aspects from cutaneous melanoma. The
      clinical course is unpredictable and metastatic disease can develop very late
      after a long disease-free interval. Uveal melanoma metastasizes haematogenously,
      predominantly to the liver. The most Important prognostic parameters for primary
      uveal melanoma are tumour diameter, the patient's age and gender, histological
      features and tumour location. Systemic chemotherapy that is effective in
      cutaneous melanoma has failed to show activity in uveal melanoma. So far only the
      BOLD chemotherapy regimen (dacarbazine, lomustine, vincristine and bleomycin)
      combined with interferon-alpha has been shown to produce an objective tumour
      response in approximately 20% of previously untreated patients. For metastatic
      disease localized to the liver, intra-arterial application of fotemustine or
      carboplatin or chemoembolization with cisplatin have shown useful activity,
      resulting in a response in up to 40% of patients. Selected patients may benefit
      from palliative surgery. Immunotherapy with interleukin-2 or interferon-alpha has
      not shown consistent activity in metastatic uveal melanoma. In conclusion,
      patients with uveal melanoma metastatic to the liver should undergo one of the
      local treatment options. Carefully selected patients with extrahepatic disease or
      patients failing local treatment may benefit from systemic therapy using the BOLD
      regimen combined with interferon.

PMID- 10661769
TI  - Small melanomas: a clinical study on 270 consecutive cases of cutaneous melanoma.
AB  - The ABCD (asymmetry, border, colour, dimension) criteria represent a commonly
      used clinical guide for the diagnosis of early cutaneous melanoma (CM). This
      guide stipulates that CMs usually are more than 6 mm in diameter. The purpose of
      this retrospective study was to establish the frequency of occurrence of small (<
      or =6 mm) melanomas in a clinical context. Our series consisted of 270
      consecutive CMs (39 in situ and 231 invasive) in 267 patients. Of these 270
      lesions, 47 (17%) were small lesions, ranging from 2 to 6 mm in maximum linear
      extent, with a median value of 5 mm. Of these small lesions, 14 were in situ and
      33 Invasive CMs. The median thickness of the 33 small invasive lesions was 0.31
      mm. The clinical features of CMs were sufficiently distinctive to suggest a
      diagnosis of CM in half of the cases, irrespective of the invasiveness or not of
      the lesions. Dermatoscopy was performed on 36 of the small lesions and achieved a
      correct diagnosis in 72% of the cases. The combination of simple visual
      examination with dermatoscopy allowed a higher rate of recognition (86%) than
      when the two methods were considered separately. Results of our study show that
      small CMs represent a considerable clinical subset of all CMs. Clinicians must be
      aware of this fact in their diagnostic activity.

PMID- 10661770
TI  - Sentinel node localization in primary melanoma: learning curve and results.
AB  - Ninety primary melanoma patients were studied to investigate the importance of
      adopting the simultaneous use of patent blue dye (PBD) and lymphoscintigraphy
      plus gamma detection probe to locate the sentinel node (SN). In total 135 SNs in
      105 basins were visualized preoperatively under a gamma camera after
      lymphoscintigraphy. When a SN was identified intraoperatively, its radioactivity
      level and colour were verified and documented. Two of the SNs seen on
      lymphoscintigraphy were not found. Using PBD 78.52% of the SNs were identified;
      95.5% were identified using the gamma detection probe. Using both methods
      together 98.5% of the SNs were detected. Twenty-two patients (24.4%) had
      pathologically positive SNs. The surgical learning curve was assessed for the two
      techniques. The learning curve associated with the methodology was important in
      finding the SN when using PBD associated with lymphoscintigraphy, but not when
      the gamma detection probe was used; we found a statistically significant
      reduction in the percentage of stained SNs found using PBD in the initial 14 SNs
      biopsied compared with the subsequent 121 nodes. This is important as not all
      institutions have access to a gamma probe. The time required to identify each SN
      was documented and analysed. The duration of the procedure was significantly
      shorter for stained SNs than for non-stained SNs, which support the use of both
      PBD and the gamma probe. In conclusion, SN biopsy should be performed by surgeons
      and nuclear medicine doctors in co-operation, both methods being adopted
      simultaneously to reduce the percentage of procedure failures.

PMID- 10661771
TI  - Resection of metastatic melanoma following wire localization guided by computed
      tomography or ultrasound.
AB  - Melanoma is an aggressive tumour with the propensity to metastasize through the
      lymphatic system and blood. Patients at high risk for developing metastatic
      disease are evaluated clinically together with chest X-rays and when indicated
      computed tomography (CT) scans. Wire localization is routinely used in non
      palpable breast cancer to facilitate surgical resection. This study demonstrates
      the applicability of wire localization and surgical resection of non-palpable,
      deep subcutaneous or Intramuscular metastatic melanoma detected by CT or
      ultrasound. The medical records of six patients with malignant melanoma were
      retrospectively reviewed. Each patient with malignant melanoma developed
      metastatic involvement detected by CT scan or ultrasound at the UCSF/Mount Zion
      Medical Center, California, USA. A Copanz needle was inserted into the tumours
      under local anaesthesia. The patients were transported to the operating room and
      underwent wire-guided surgical resection of the tumour under general anaesthesia
      or intravenous sedation. In all six patients the tumour was successfully resected
      following CT- or ultrasound-guided wire localization of the metastatic foci. In
      conclusion, nonpalpable metastatic melanoma may be resected using CT-or
      ultrasound-guided wire localization. This technique offers several advantages,
      Including minimal surgical dissection, shorter operative times and decreased
      postoperative morbidity.

PMID- 10661772
TI  - Treatment of patients with metastatic melanoma with bryostatin-1--a phase II
      study.
AB  - Bryostatin-1 is a protein kinase C regulator which has shown antitumour activity
      against B16 melanoma in animal models. Safety trials revealed this agent to be
      minimally toxic, thus a phase II trial of bryostatin-1 was conducted to determine
      its efficacy In patients with melanoma. Eighteen patients with metastatic
      melanoma, seven of whom had been previously treated, were enrolled in the study.
      Patients received bryostatin-1 25 microg/m2 intravenously weekly over 1 h for 3
      out of 4 weeks. No objective responses were observed. One patient who had not
      previously received chemotherapy had stable disease for 4 months, and two
      patients (one previously treated) had a marked decrease in the skin component of
      their disease. The major toxicity was myalgia (one patient with grade III, two
      patients with grade II and five patients with grade I), with no grade IV
      toxicities reported. To Indirectly evaluate the stimulation of protein kinase C,
      a sensitive assay that measures the upregulation of the activated form of CD62
      (glycoprotein IIb/IIIa) on platelets was performed. There was a statistically
      significant upregulation of this antigen 1 h after bryostatin-1 therapy. A
      bioassay based on the ability of bryostatin-1 to bind protein kinase C was used
      to measure bryostatin-1 levels in serum. This assay showed that bryostatin-1 has
      a volume of distribution of 2.1 l/m2, an elimination clearance of 32.9 ml/min per
      m2 and a half-life of 43.9 min. In conclusion, this phase II trial demonstrates
      that, although it is relatively non-toxic, bryostatin-1 therapy had minimal
      activity in metastatic melanoma.

PMID- 10661773
TI  - Results of a phase II trial with cystemustine at 90 mg/m(2) as a first- or second
      line treatment in advanced malignant melanoma: a trial of the EORTC Clinical
      Studies Group.
AB  - From May 1991 to January 1996, 54 patients with advanced malignant melanoma were
      enrolled into a phase II trial testing the new nitrosourea cystemustine,
      administrated intravenously as a 15 min infusion every 2 weeks at 90 mg/m2 for
      three cycles followed by 60 mg/m2. Out of the 54 enrolled patients, 10 were
      Ineligible, leaving 44 fully evaluable patients (World Health Organization
      criteria). Twenty one patients had already received first-line palliative
      chemotherapy and/or immunotherapy. The median age was 62 years (range 30-74
      years) and the median performance status was 0 (grade 0, 19 patients; grade 1, 21
      patients; grade 2, 4 patients). Five patients with partial responses (lasting 16
      29 weeks, mean duration 24 weeks), nine with stable disease and 28 showing
      progression were observed, giving an overall response rate of 11% (confidence
      interval 3.8-24.6%). Toxicity was mild and consisted mainly of neutropenia (39%
      grade III-IV), thrombocytopenia (42% grade III-IV); febrile aplasia was rare.
      Cystemustine administered to this schedule appears to have limited clinical
      activity and acceptable toxicity in untreated or second-line advanced malignant
      melanoma.

PMID- 10661774
TI  - Radiotherapy as palliative treatment for metastatic melanoma.
AB  - This study aimed to assess the response rate and efficacy of palliative radiation
      therapy in patients with metastatic melanoma. From 1993 to 1999, 28 patients with
      35 irradiated areas were treated with palliative radiotherapy for metastatic
      melanoma in the Radiotherapy Department of the Henri Mondor University Hospital,
      Creteil, France. Of these, 19 (68%) patients had bone and soft tissue metastases,
      seven (25%) patients had brain metastases and two (7%) patients had both types of
      metastases. Most of the patients were treated with 30 Gy of irradiation in 10
      fractions over 2 weeks or 20 Gy in five fractions over 1.5 weeks. Of those with
      bone metastases, 67% responded to palliative bone treatment with good pain relief
      and/or decompression. Of the patients with brain metastases, 57% had amelioration
      of neurological function deficits, 29% did not respond, and one patient showed
      aggravation of his disease and did not finish the course of irradiation. Two
      patients with unresectable disease obtained partial remission and good palliation
      of symptoms. In conclusion, short-course radiotherapy has a role to play in the
      palliation of metastatic melanoma, with good relief of symptoms.

PMID- 10661775
TI  - The melanoma burden in Belgium; premature morbidity and mortality make melanoma a
      considerable health problem.
AB  - The aim of this study was to investigate the impact of melanoma on public health
      in Belgium. Melanoma incidence and mortality rates were analysed relative to
      those of other cancers. These cancers were then evaluated for premature morbidity
      and mortality by studying age-specific incidence rates, years of potential life
      lost before 65, and years of potential life lost per death. Melanoma accounts for
      1.23% of all incident cancer cases and 0.7% of all cancer deaths in Belgium. It
      is the seventeenth most common cancer in men and the sixteenth most common cancer
      in women. Compared with other, more frequent cancers, melanoma seems to affect
      patients at a younger age; in the 20-39 age group melanoma is the third most
      common cancer in both sexes. It is the second most important cancer in terms of
      years of potential life lost per death, preceded only by tumours of the central
      nervous system. These findings show that melanoma incidence and mortality rates
      are exceeded by many other cancers. Nevertheless, melanoma poses an important
      health problem because of its predilection for young and middle-aged people. We
      suspect that these observations are not specific for Belgium and will also apply
      to other European countries.

PMID- 10661776
TI  - Sentinel node biopsy (SNB) was proposed to stage epidemoid cancer of the male
      genitals.

PMID- 10661777
TI  - The emerging role of low-molecular-weight heparin in cardiovascular medicine.
AB  - Although unfractionated heparin is widely used in the treatment of acute coronary
      syndromes, it has several pharmacokinetic, biophysical, and biological
      limitations. The practical advantages and success of low-molecular-weight heparin
      administered subcutaneously without laboratory monitoring for the treatment of
      venous thromboembolism have prompted a number of randomized studies investigating
      the efficacy and safety of these agents in patients with acute coronary
      syndromes. This article will review the limitations of unfractionated heparin and
      the mechanisms by which low-molecular-weight heparin overcomes these limitations,
      as well as the results of recent trials involving low-molecular-weight heparin in
      the management of patients with acute coronary syndromes.

PMID- 10661778
TI  - Heparin-induced thrombocytopenia and thrombosis.
AB  - Heparin remains the most commonly used parenteral medication in hospitalized
      patients. Heparin induced thrombocytopenia (HIT) and heparin induced
      thrombocytopenia with thrombosis syndrome or the white clot syndrome are
      important complications of heparin use. This article provides an in-depth review
      of the etiopathogenesis, clinical manifestations, diagnosis, and management
      options in patients with HIT. Clinical problems associated with HIT such as
      antiphospholipid antibody syndrome and venous gangrene are described. The
      management options of HIT patients during cardiac interventional procedures and
      coronary surgery as well as recent advances in therapeutic options are
      summarized.

PMID- 10661779
TI  - Detection of pulmonary embolism by D-dimer assay, spiral computed tomography, and
      magnetic resonance imaging.
AB  - Pulmonary embolism (PE) remains difficult to diagnose. Ventilation perfusion lung
      scan, the standard diagnostic test for PE, has poor overall sensitivity. The gold
      standard examination, pulmonary angiography, is invasive and has some risk,
      making clinicians reluctant to refer patients. In recent years, new diagnostic
      modalities have been investigated, including D-Dimer assays, spiral computed
      tomography (CT), and magnetic resonance imaging (MRI). The authors reviewed the
      literature and noted that the D-Dimer assays by ELISA or rapid ELISA design are
      approximately 90% to 95% sensitive, but are not specific for the diagnosis of
      pulmonary embolism. Spiral CT has been studied with conflicting results; however,
      in the largest studies the reported sensitivities are greater than approximately
      85%. Electron beam CT is an alternative technique, which has not been as
      extensively studied. MRI is also useful for imaging the pulmonary arterial
      vasculature, but remains experimental. Although a more accurate assessment of the
      sensitivity of these new modalities will need to wait until a large
      angiographically controlled study, such as the planned PIOPED II, can be done, D
      Dimer assay and spiral CT are often useful in the detection of pulmonary
      embolism. The authors make recommendations for their use in a diagnostic
      algorithm, as alternatives to the standard ventilation perfusion lung scan.

PMID- 10661780
TI  - Risk stratification after acute myocardial infarction in the reperfusion era.
AB  - Historically, risk stratification for survivors of acute myocardial infarction
      (AMI) has centered on 3 principles: assessment of left ventricular function,
      detection of residual myocardial ischemia, and estimation of the risk for sudden
      cardiac death. Although these factors still have important prognostic
      implications for these patients, our ability to predict adverse cardiac events
      has significantly improved over the last several years. Recent studies have
      identified powerful predictors of adverse cardiac events available from the
      patient history, physical examination, initial electrocardiogram, and blood
      testing early in the evaluation of patients with AMI. Numerous studies performed
      in patients receiving early reperfusion therapy with either thrombolysis or
      primary angioplasty have emphasized the importance of a patent infarct related
      artery for long-term survival. The predictive value of a variety of noninvasive
      and invasive tests to predict myocardial electrical instability have been under
      active investigation in patients receiving early reperfusion therapy. The current
      understanding of the clinically important predictors of clinical outcomes in
      survivors of AMI is reviewed in this article.

PMID- 10661781
TI  - The Casey Holter lecture. Non-selective intervention in newborn babies with open
      spina bifida: the outcome 30 years on for the complete cohort.
AB  - The disability in neural tube defect is determined by the neurological deficit.
      The sensory level is a reliable measure of this deficit and predicts the
      disability. Achievement at the age of 30 related as well as to IQ and disability
      events in the history of CSF shunt. Episodes of raised intracranial pressure may
      damage the brain and visual pathways. They may also reduce achievement and
      enterprise. Blockage of the CSF shunt, when symptomatic, should be treated
      urgently, especially when it occurs after infancy. Blockage of the CSF shunt when
      asymptomatic was not usually associated with a low IQ or poor achievement.

PMID- 10661782
TI  - The Pippi Salle procedure for neurogenic urinary incontinence in childhood: a
      three-year experience.
AB  - AIM: A three-year retrospective study was performed to assess the place of the
      Pippi Salle bladder neck repair in the treatment of neurogenic bladder
      incontinence in both sexes in childhood. METHOD: All children who underwent the
      procedure between November 1995 and November 1998 were studied retrospectively.
      There were 18 children: 12 with spina bifida, 5 with sacral agenesis and 1 with
      an idiopathic neurogenic bladder. There were 11 boys and 7 girls. Their age was 3
      14 years (median 7 years) and the length of follow-up was 7 months to 3 years
      (median 2 years). A midline bladder wall flap was fashioned in all patients. The
      procedure was performed alone (n = 5) or in combination with a sigmoid
      colocystoplasty (n = 9) or a Mitrofanoff catheterisable stoma (n = 2) or both (n
      = 2). RESULTS: Diurnal continence (3 hours or more) was achieved in 11 of the 18
      children (61%); 2 are dry for 2-2.5 hours and 5 are incontinent. Eight of the 18
      children (44%) are completely dry during the night, 2 are damp and 8 are
      incontinent. Twelve children (67%) needed oxybutynin to maintain a good result.
      Complications arose in 5 children (28%): difficulty with catheterisation (n = 4)
      and pelvic abscess (n = 1). Seven children (39%) subsequently required further
      operations: exploration of bladder for urine leak (n = 2), reinsertion of
      dislodged catheter (n = 1), drainage of pelvic abscess (n = 1), bladder neck
      injection with macroplastique (n = 1) and bladder neck closure (n = 2).
      CONCLUSIONS: The Pippi Salle bladder neck repair has an undoubted place in the
      management of neurogenic urinary incontinence in childhood. However, in our
      experience, it has a relatively high complication rate and failure rate.

PMID- 10661783
TI  - 19-year follow-up of fetal myelomeningocele brought to term.
AB  - We conducted a 19-year follow-up study of 223 infants with myelomeningocele born
      by cephalic presentation, 68 born by pre-rupture of amniotic membranes cesarean
      section (PRAM C/S) and 155 born vaginally to determine outcome. We recorded
      radiographic level as the last intact vertebral arch at the cephalad end of the
      spinal defect from standard AP films of the spine. Protrusions of the lesions
      dorsal to the back were obtained from medical records or parental recall.
      Subsequent spinal cord abnormalities (hydromyelia, tethered cord and hypoplasia)
      were determined by patient's symptoms and verified by MRI. Data were from our
      Patient Data Management System and analyzed using Microsoft Excel and Epi Info 6.
      Flat lesions protruding less than 1.0 cm beyond the plane of the back and those
      associated with breech position or kyphus were not benefited by PRAM CIS
      (Fisher's Exact, p = 0.58 between the two types of delivery for motor level).
      Flat lesions were more common in the vaginally delivered group (p = 0.01).
      Lesions protruding equal to 1.0 cm or beyond were associated with less paralysis
      after PRAM C/S (p = 0.01). Although tethered cord syndrome was more common in the
      PRAM C/S group (p = 0.02), there was no difference in the muscle strength loss
      between the PRAM C/S and the vaginally delivered groups. Symptomatic hydromyelia
      was equally distributed but spinal cord hypoplasia was more common in the PRAM
      C/S group (p = 0.03). Due to the limited numbers of patients in each group
      available for analysis, we recommend further study to ascertain the appropriate
      management of fetal myelomeningocele diagnosed in utero and brought to term.

PMID- 10661784
TI  - A comparison of hip guidance with reciprocating gait orthoses in children with
      spinal paraplegia: results of a ten-year prospective study.
AB  - Twenty-two children with spinal paraplegia were entered into a prospective
      randomised study to assess the efficacy of two reciprocating orthoses and to
      identify any prognostic factors that might affect continuing use of the devices.
      Thirteen received a hip guidance orthosis (HGO) and nine a reciprocating gait
      orthosis (RGO). They were followed for a mean of ten years. At one year follow-up
      there were three statistically significant differences between the two groups at
      the 5% level: repairs were commoner in the RGO group, the RGO group improved in
      their ability to walk over difficult outdoor surfaces and the HGO group improved
      more in their ability to rise from a sitting to standing position. At one year
      follow-up there was a positive parental and child's view of the benefits of the
      orthoses, but by ten years only 24% of the patients were still using the
      orthoses. We were not able to show any definite advantage of one device over the
      other or any statistically significant prognostic factors for walking in the
      longer term with a reciprocating orthosis. We question whether or not the routine
      provision of these types of orthosis is justifiable when it appears that, in the
      longer term, the patients we studied preferred wheelchair mobility.

PMID- 10661785
TI  - A classification of CSF shunt malfunction.
AB  - A classification of dysfunctional shunts is proposed and clarification of the
      terminology discussed. This is based on experience of successive shunt
      malfunctions over a 3-year period with the aid of ventricular pressure
      measurements, imaging and clinical semiology. The classification system is both
      anatomical and functional.

PMID- 10661786
TI  - New valves--new dangers? 22 valves (38 probes) designed in the 'nineties in
      ultralong-term tests (365 days)'.
AB  - In the nineties, more than 30 valves have been launched, most are "clones", but
      some introduce new concepts (Diamond, SiphonGuard, PaediGAV). Of the 22 designs
      we tested, 20 have no previous tests and 3 are low-cost valves from Mexico
      (Dewimed), Zimbabwe (Harare-shunt) and England (Nottingham Shunt). 27 were tested
      using non-stop-perfusions for 365 days, 8 for 168-294 and 3 for 2 days. RESULTS:
      Ranking of the mean relative deviation: adjustable valves 19%, gravitational 34%,
      simple ball 51%, diaphragm 73%, distal slit 74% and autoregulating valves 121%.
      Ranking of physiological flow properties: gravitational > Equiflow >
      autoregulating > adjustable > ball > diaphragm > distal slit. SAFETY: The
      Equiflow were highly susceptible to external pressure. CONCLUSION: Most valves
      designed in the nineties showed inaccuracy, long-term-drifts, safety deficits and
      hydraulic mismanagement similar to more than 400 previously tested probes. With
      regard to accuracy and drift the ball designs were superior, but simple and
      adjustable ball valves are at risk of overdrainage. The gravitational ball valves
      (Cordis GCA, Miethke valves) showed the closest relation to physiological flow
      requirements.

PMID- 10661787
TI  - Fetal arachnoid cysts: their site, progress, prognosis and differential
      diagnosis.
AB  - Arachnoid cysts are lined by arachnoid membranes and filled with cerebrospinal
      fluid. Etiologically, they are thought to be due to maldevelopment of the
      arachnoid or secondary to trauma or infection. Postnatally, many are asymptomatic
      and remain quiescent for years, although others expand and cause symptoms by
      compressing adjacent brain and/or expanding the overlying skull. Being
      congenital, it should be possible to identify them in the fetus, and this has
      proved to be so. But are they anatomically similar and do they behave the same as
      those detected postnatally? Fifteen fetuses with fluid-filled cysts were
      identified from the database of the Fetal Management Unit at St. Mary's Hospital
      in Manchester. Five were diagnosed at or before 20 weeks of gestation, 4 between
      21 and 30 weeks, and 6 at 31 weeks or more. Thirteen cysts were in the
      supratentorial compartment, and 2 in the posterior fossa. Eleven fetuses were
      delivered, and 4 pregnancies were terminated. One of the born children had
      Pallister-Hall syndrome and died on day 19, and another had Aicardi's syndrome,
      is retarded and has fits, 1 with a posterior fossa cyst developed hydrocephalus
      in utero and was delivered early for the insertion of a ventriculoperitoneal
      shunt, he is moderately mentally delayed. Of the remaining 8 children, 1 has been
      lost to follow-up, and 7 appear to be reaching their early milestones on time.
      The 4 terminated fetuses had a postmortem examination, 2 did not have arachnoid
      cysts; 1 had an expanding glioependymal cyst which had destroyed most of the
      cerebral hemispheres, and the other had a sagittal sinus thrombosis with
      extensive cavitation of one cerebral hemisphere. The diagnosis of an arachnoid
      cyst in the fetus can be difficult and may be confused with other fluid-filled
      cysts.

PMID- 10661788
TI  - Chronic pyelonephritis in association with neuropathic bladder.
AB  - Progressive chronic pyelonephritis (CPN) leading to renal failure was, in the
      past, a mode of death in children with meningomyelocele (MMC). With more
      sophisticated management modalities, renal failure is now uncommon, but the
      problem of CPN still remains. In this series of 100 children with MMC, 39% have
      CPN. It is significantly more common in girls than in boys. There is a strong
      relationship between CPN and vesico-ureteric reflux (VUR). There is no
      association with raised bladder pressure. The majority of CPN arises in children
      under the age of 4 years, but damaged kidneys can continue to deteriorate.
      Although chronic renal failure is rarely seen in children with MMC, there is a
      risk that this may merely be postponed into adulthood.

PMID- 10661789
TI  - Factors affecting mortality and morbidity in adult spina bifida.
AB  - We studied 695 patients with spina bifida over 16 years old. 56 of these are
      deceased. The cause of death of 30 of these patients could be ascertained from
      the records kept at the unit. The leading cause of death was renal failure
      secondary to complications of the renal tract (10 patients). 8 patients died due
      to cardiac causes and 5 due to respiratory complications. Of the remaining, 3
      patients committed suicide and 1 died of malignancy. METHOD: This is a
      retrospective study from review of index cards. Individual case notes were
      scrutinised of patients who were deceased.

PMID- 10661790
TI  - Periurethral Goretex sling in lower urinary reconstruction.
AB  - Urethral incontinence in patients with neuropathic bladders remains a management
      problem not only to urologists but also to the primary carers of these patients.
      It impairs quality of life and encourages social withdrawal, but also leads to
      perineal soreness and inflammation. A number of surgical techniques have been
      described to increase bladder outlet resistance in order to render patients with
      neuropathic bladders perineally dry. We report our experience in achieving
      dryness with a periurethral Goretex sling in 17 patients.

PMID- 10661791
TI  - TGF-beta1 expression is reduced in hydrocephalic H-Tx rat brain.
AB  - Transforming growth factor-beta1 (TGF-beta1) is a cytokine with diverse
      biological effects. Overexpression of TGF-beta1 in mice has been shown to induce
      progressive hydrocephalus. We have used a quantitative RT-PCR method to analyze
      the TGF-beta1 expression in the brains of H-Tx rat, a model of congenital
      hydrocephalus. Our studies have shown that rather than increased expression, the
      3- and 10-day hydrocephalic H-Tx rats have significantly lower TGF-beta1 levels
      than their normal siblings (p < 0.01). This difference became insignificant in
      the 21-day group. Besides, both hydrocephalic and normal H-Tx rats have
      significantly lower TGF-beta1 levels in all three age groups of 3-, 10- and 21
      days than SD control rats (p < 0.01 in all three groups) although the difference
      tends to become less significant with development. We also tested the expression
      of another cytokine, the epidermal growth factor, and observed a similar
      reduction. This suggests that the TGF-beta1 expression change is not unique to
      the development of hydrocephalus in this rat model. Our hypothesis is that the
      TGF-beta1 expression decrease in the H-Tx rat is not the cause of the disease.
      Rather it might be the result of feedback inhibition by increase in the
      expression of the gene it regulates, including an extracellular matrix component.
      Effort is currently being made to test this hypothesis.

PMID- 10661792
TI  - Bladder augmentation surgery--what about the malignant risk?
AB  - Augmentation cystoplasty has become a common surgical treatment for the
      neuropathic bladder. However, malignancy in bladder augmentations has been well
      described and in time is estimated to occur in 1.3% of cases. We surveyed 36
      paediatric surgeons from the UK with a special interest in paediatric urology to
      ascertain how many bladder augmentations were being performed in children each
      year and whether the surgeons were warning patients/parents of the malignant
      risks involved with this surgery. Over 150 bladder augmentations were being
      performed in the UK each year. Surgeons surveyed were concerned about the
      malignant risks and nearly all agreed that a Central Registry of patients with
      bladder augmentations should be established to keep track of developments.

PMID- 10661793
TI  - Brainstem diffusion-weighted MRI in boys with L1CAM mutations.

PMID- 10661794
TI  - Breeding characteristics and genetic analysis of the H-Tx rat strain.

PMID- 10661795
TI  - The effects of CSF blockage in early-onset hydrocephalus on the activity of the
      germinal epithelium.

PMID- 10661796
TI  - Aqueduct stenosis in hydrocephalus: ultrastructural investigation in neonatal H
      Tx rat brain.

PMID- 10661797
TI  - Congenital hydrocephalus: occurrence and outcome. A population-based study in the
      North of England, 1985-1996. Northern Congenital Abnormality Survey Steering
      Group.

PMID- 10661798
TI  - Prevention of CSF shunt infection: effect of the use of hybrid shunt systems
      which include antibacterial catheters.

PMID- 10661799
TI  - Percutaneous tube caecostomy for antegrade continence enema (ACE).

PMID- 10661800
TI  - Normal growth of the spinal cord.

PMID- 10661801
TI  - Pattern of IgE antibodies against latex allergens in children with spina bifida.

PMID- 10661802
TI  - The use of transendoscopic Doppler ultrasound as a safety-enhancing measure
      during neuroendoscopic third ventriculostomy.

PMID- 10661803
TI  - About the rate of shunt complications in patients with hydrocephalus and
      myelomeningocele.

PMID- 10661804
TI  - RITA--Registry of Industrial Toxicology Animal-data: optimization of
      carcinogenicity bioassays.

PMID- 10661805
TI  - RITA/Registry of Industrial Toxicology Animal data: a comparative
      immunohistochemical study of 77 islet cell carcinomas in Sprague-Dawley and
      Wistar rats using antibodies against insulin, glucagon, somatostatin and gastrin.
AB  - The objective of this study was to investigate spontaneous islet cell carcinomas
      with particular reference to possible existing strain differences between Sprague
      Dawley (SD) and Wistar (W) rats in incidence and immunohistochemical staining
      pattern. Secondly the occurrence of somatostatin and/or gastrin-positive islet
      cell tumors should be tested. Islet cell adenocarcinomas (34 from SD, 43 from W
      rats) were selected from the RITA-data base and company in-house data base out of
      an animal pool of 3915 (1681 SD, 2234 W-rats). They were untreated or sham
      treated (vehicle) control animals from carcinogenicity studies and whole life
      span experiments. Islet cell carcinomas occurred in a higher incidence in male
      rats (2.98% for SD, 3.23% for W) than in female rats (1.07% for SD, 0.63% for W).
      All specimens were immunohistologically stained with antibodies against insulin,
      glucagon, somatostatin and gastrin and, selected specimens with additional
      antibodies (pancreatic polypeptide, lipase, chymotrypsin, S100-protein, actin and
      cytokeratin). 94% (SD) and 93% (W), respectively, were insulin-positive and the
      mean staining intensity (on a scale ranging from 0-4) for insulin was 3.58 (SD)
      versus 3.37 (W). This high insulin staining incidence and intensity characterized
      most islet cell carcinomas as malignant insulinomas. 24% (SD) and 37% (W),
      respectively, were glucagon-positive. Except two tumors in W-rats with a focal
      strong glucagon expression, the mean staining intensity for glucagon was low
      (0.38 SD, 0.72 W). 38% (SD) and 44% (W), respectively, were somatostatin
      positive, but except for five cases having a focal to multifocal, moderate to
      marked staining, only a few tumor cells were positive for somatostatin in the
      other cases and the mean staining intensity for somatostatin was low (0.50 SD,
      0.84 W). 6% (SD) and 23% (W), respectively, were gastrin-positive, but only one
      case of a male Wistar rat exhibited a focal strong staining in parts of the
      tumor. The other cases showed only a few tumor cells which were positive for
      gastrin. The mean staining intensity for gastrin was low (0.06 SD, 0.35 W). In
      all tumors with marked glucagon, somatostatin or gastrin expression, the
      immunostaining for insulin was still predominating. Thus, insulin was the major
      hormone produced by most of the tumor cells. Five out of 77 tumors evaluated were
      immunohistologically negative with all applied antibodies. CONCLUSION: This study
      presents the first immunohistochemical survey on spontaneous islet cell
      carcinomas in SD and Wistar rats stained with antibodies against the endocrine
      pancreas hormones insulin, glucagon, somatostatin and gastrin. No major
      differences in incidence or immunohistochemical staining pattern between SD and W
      rats could be detected. In contrast to SD rats, Wistar rats had multihormonal
      coexpression in 16.3%. The multihormonal appearance of the neoplasms is well
      comparable with the findings in other animal species and human insulinomas.
      Moreover, this is the first study in rats which reports five cases with a marked
      co-expression of somatostatin and one case with marked focal co-expression of
      gastrin in malignant islet cell adenocarcinomas.

PMID- 10661806
TI  - CULTEX--a new system and technique for the cultivation and exposure of cells at
      the air/liquid interface.

PMID- 10661807
TI  - Radiation pneumonitis: the model of interstitial edema.
AB  - We used the measurement of the thickness of alveolar septa in the lungs in
      (C57BI/6xDBA/2)F1 mice irradiated locally in the area of the thorax with absorbed
      doses of 14, 16 and 18 Gy of gamma rays. The thickness of alveolar septa of the
      pulmonary tissue was measured using a computer image analysis. 24 weeks after
      irradiation we found a significant increase in the thickness of alveolar septa in
      direct relation to the dose within a range of 14 to 18 Gy. This indicator can be
      used for observation of the radioprotective and remedial interventions against
      the inception and the development of radiation pneumonitis.

PMID- 10661808
TI  - Intratracheally applied rSP-C surfactant exhibits no anaphylactic shock reactions
      in a guinea pig model of acute lung hypersensitivity.
AB  - The effect of the intratracheal administration of the recombinant SP-C surfactant
      apoprotein (rSP-C) with phospholipids (PL) in comparison to an ovalbumin induced
      anaphylactic shock reaction was studied in guinea pigs lungs. Narcotized guinea
      pigs were challenged by intratracheal administration on test day 24/25 once with
      a suspension of rSP-C/PL (reconstituted suspension). These animals were priorily
      sensitized on test day 1, 3 and 5 intraperitoneally with rSP-C/PL suspension or
      with Ovalbumin (OV) respectively. The following groups were used to assess the
      anaphylactic lung shock symptoms: group 1: positive control, 1 mg/kg OV protein,
      2 ml/kg application volume, (Appl. vol.), N: 5 animals; group 2: 1 mg rSP-C/50 mg
      PL/0.5 ml/kg Appl. vol., N: 10; group 3: 2 mg rSP-C/100 mg PL/1.0 ml/kg Appl.
      vol., N: 10; group 4: 4 mg rSP-C/200 mg PL/2.0 ml/kg Appl. vol., N: 10. Clinical
      signs, mortality, lung weights and histopathological changes were evaluated.
      Additionally the lungs were investigated immunohistologically with polyclonal
      antibodies against rSP-C to determine the pulmonary distribution of the
      intratracheal applied rSP-C. In the OV-treated positive control group, all
      animals died within 4 minutes after intratracheal challenge, while only 1 animal
      of group 4 died probably due to an narcosis related respiratory arrest. In the
      rSP-C/PL treated groups, the lung weights showed a dose-related increase, but
      nevertheless all these rSP-C-treated groups showed a significant lower lung
      weight in comparison to the OV treated positive control group. The histopathology
      assessment of the lungs in the OV-treated animals revealed a severe generalised
      bronchoconstriction and a hyperemia in connection with a slight interstitial
      edema in all five animals. The rSP-C/PL-treated animals, which were sacrificed
      after 3 days, showed no bronchoconstriction but a slight increase in the severity
      of bronchus-associated infiltration with eosinophilic granulocytes and in the
      formation of peripheral emphysema, but with no dose-dependency. A slight dose
      dependent increase in the deposition of peribronchiolar eosinophilic foreign
      material was evident. In contrast to this, the number of lipid-laden alveolar
      macrophages seemed to decrease with increasing doses of rSP-C/PL. The
      immunohistological investigation with a polyclonal antibody against rSP-C showed
      an intraalveolar distribution of the intratracheally applied rSP-C which is
      mainly located in the peribronchiolar alveolar parenchyma. A rSP-C-positive
      staining was visible within the cytoplasm of alveolar histiocytes, type II
      pneumocytes and also as an extracellularly rim along the alveolar walls. The
      polyclonal antibody showed no cross reaction with natural occuring SP-C-protein
      of the guinea pigs. We conclude that the intratracheal application of the rSP-C
      surfactant containing phospholipids (PL) exhibits no significant risk of an
      anaphylactic shock reaction in this guinea pig lung hypersensitivity model. The
      immunohistological investigation with polyclonal antibodies against rSP-C
      demonstrated clearly the distribution of intratracheal applied material in this
      toxicological animal model.

PMID- 10661809
TI  - Differential effects of orally versus parenterally administered qinghaosu
      derivative artemether in dogs.
AB  - Artemether (AM) is an antimalarial drug derived from artemisinin (Qinghaosu), an
      extract of the herb Artemisia annua L., sweet wormwood. Its antiparasitic effect
      is that of a schizontocide and is explained by rapid uptake by parasitized
      erythrocytes and interaction with a component of hemoglobin degradation resulting
      in formation of free radicals. It has been shown to exhibit a high clinical cure
      rate. Previous animal safety studies with Qinghaosu derivatives revealed dose
      dependent neurotoxicity with movement disturbances and neuropathic changes in the
      hindbrain of intramuscularly treated dogs, rats and monkeys. Such effects have
      not been seen in man. The objective of our present studies was to compare the
      effects of high levels of AM administered to dogs p.o. versus i.m. In a pilot
      study 20 mg/kg/day of AM was given i.m. to groups of 3 male Beagle dogs for 5 and
      30 days, respectively. Clinical signs of neurotoxicity were noted in some
      individual dogs from test day 23 on. One dog had to be sacrificed pre-term.
      Hematologic findings indicated a hypochromic, microcytic anemia. Microscopic
      examination demonstrated neuropathic changes only at 30 days, but not at 5 days.
      The animals had neuronal and secondary axonal damage, most prominent in the
      cerebellar roof, pontine and vestibular nuclei, and in the raphe/paralemniscal
      region. The affected neurons showed loss of Nissl substance, cytoplasmic
      eosinophilia, shrinkage of the nucleus and in advanced stages scavenging by
      microglia. In a subsequent experiment, AM was administered to groups of 4 male
      and 4 female dogs, respectively, at 8 daily doses of 0, 20, 40 and 80 mg/kg i.m.,
      or 0, 50, 150 and 600 mg/kg p.o. Neurologic signs were seen at high i.m. doses
      only. In most animals they were inconspicuous and consisted of reduced activity
      with convulsions seen in single dogs shortly before death. Neuronal damage
      occurred in all animals at 40 and 80 mg/kg following i.m. treatment. At 20 mg/kg
      minimal effects occurred in 5/8 dogs only, indicating that this level was close
      to tolerated exposure. No comparable lesions were observed after oral
      administration. Both i.m. and p.o. exposure at high dose levels was associated
      with a prolongation of mean QT interval of ECG, suggesting slowing of
      repolarization of the myocardium. Individual data indicated that in 1 of 4
      females at 80 mg/kg i.m. this prolongation was above the 25% level considered as
      threshold for concern. After intramuscular administration pharmacokinetics
      indicated peak plasma levels of AM at 2 to 4 hours post-dose, slow elimination
      and a tendency to accumulate after repeated administration. Only low levels of
      the major metabolite, dihydroartemisinin (DHA), were found. AM levels in the
      cerebrospinal fluid (CSF) were < 10% of plasma levels. After oral administration
      AM concentrations were considerably lower than after i.m. administration. The
      concentration of DHA was high on day 1 but almost nil on day 7 indicating its
      fast inactivation in dogs. Two hours after the 8th oral administration neither AM
      nor DHA was detected in CSF which may explain the absence of neurotoxicity in
      dogs after oral administration of AM.

PMID- 10661810
TI  - Involvement of superoxide and/or nitric oxide in renal tissue injury.
AB  - We examined the influence of superoxide (O2-) and/or nitric oxide (NO) on renal
      tissue injury estimated from the levels of lipid peroxidation and sulfhydryl (SH)
      oxidation. Pyrogallol, an O2- generator and precursor of hydrogen peroxide,
      produced marked tissue injury, but this was prevented by superoxide dismutase
      (SOD)/catalase (CAT). Hemoglobin (Hb), a NO scavenger, provided protection from
      tissue injury caused by sodium nitroprusside (SNP). The tissue injury produced by
      3-morpholinosydnonimine (SIN-1), which is thought to form peroxynitrite (ONOO-)
      as a simultaneous O2- and NO generator, was blocked by SOD/CAT or Hb. On the
      other hand, protein-SH and nonprotein-SH were significantly increased by addition
      of SOD/CAT or Hb. These data suggest that the renal tissue injury induced by O2-,
      NO and ONOO- can be blocked by SH, suggesting an important protective role
      against these reactive oxygen species in the mechanism of tissue defense.

PMID- 10661811
TI  - Trends in mortality, body weights and tumor incidences of Wistar rats over 20
      years.
AB  - Historical data of more than 8,000 Wistar rats (designation: WISW SPF Cpb) used
      as controls in seventy 2-year studies terminated between 1975 and 1994 were
      analyzed for time trends in food consumption, terminal body weight, mortality,
      and tumor incidences. In males there was a significant (p < 0.01) time trend
      towards higher terminal body weight and a tendency (p > 0.05) to lower incidences
      of pituitary tumors and adrenal pheochromocytomas, while mortality remained
      stable. Leydig cell tumors showed a significant (p = 0.0005) positive trend. In
      females, terminal body weight did not increase over time but pituitary and
      mammary tumors showed a marked and highly significant (p = 0.0001) increase,
      which explains a significant (p = 0.0045) positive trend in mortality. There was
      a significant (p = 0.0001) negative time trend for uterine adenomas/carcinomas
      and a slight tendency (p = 0.4135) towards a decreased incidence of endo-metrial
      stromal polyps. Since the average food intake data do not indicate a time trend
      the changes observed might probably not be related to higher caloric intake. In
      contrast to other authors we could not find a positive correlation between either
      body weight and incidences of pituitary tumors or body weight and mortality.
      Certain selection measures at breeding and/or a genetic drift over time might
      explain the time trends observed. This data does not yet indicate a need for a
      change in ad-libitum feeding of these animals.

PMID- 10661812
TI  - Hepatoprotection by dimethyl sulfoxide. II. Characterization of optimal dose and
      the latest time of administration for effective protection against chloroform and
      bromobenzene induced injury.
AB  - Dimethyl sulfoxide (DMSO) has previously been shown to attenuate chloroform
      (CHCl3) and bromobenzene (BB) induced hepatotoxicity in the rat when a dose of
      2.0 ml/kg is given 24 hr after the toxicants. However, the optimal dose of DMSO
      and the latest time at which DMSO can be administered and still provide effective
      protection have not been determined. In order to determine the latest time at
      which DMSO can interrupt the development of necrosis, male Sprague Dawley rats
      received either 0.75 ml/kg CHCl3 or 0.5 ml/kg BB, 20% in corn oil, p.o., followed
      by single dose of 2 ml/kg DMSO, 50% in saline, i.p., at 24, 26, 28 or 30 hr
      later. Positive control groups received either CHCl3 or BB and then 4.0 ml/kg
      saline, i.p., 24 hr later. All of the animals were then killed 48 hr after
      toxicant dosing. The extent of liver injury present when DMSO was administered
      was examined by killing animals at 24, 26, 28 or 30 hr after toxicant dosing. The
      optimal dose of DMSO for providing protection was estimated by administering
      either 0, 1.0, 2.0, 3.0 or 4.0 ml/kg DMSO at 24 hr after toxicant dosing and then
      killing the animals at 48 hr. Delaying DMSO administration to times later than 24
      hr after toxicant dosing led to a loss of protection as indicated by both plasma
      ALT activity and the light microscopic appearance of liver tissue. The
      distinctive liver lesions present at 24 hr after CHCl3 or BB dosing rapidly
      expanded from being limited around central veins to bridging between
      centrilobular areas in only a few hours. This was accompanied by large increases
      in plasma ALT. With both toxicants, doses of DMSO greater than 2 ml/kg did not
      enhance its protective action while the lower dose of 1 ml/kg DMSO was not as
      effective. The loss of DMSO's antidotal action when given at times later than 24
      hr after the toxicants indicates irreversible changes were underway as the
      centrilobular lesions progressed from being limited to more bridging in nature.
      Hopefully, further elucidation of the mechanism(s) by which DMSO interrupts the
      rapid progression of injury will both help to understand the steps involved in
      lesion development and provide insights into therapeutic interventions for drug
      and chemical induced hepatitis.

PMID- 10661813
TI  - Morphometric and biochemical characteristics of short-term effects of ethanol on
      rat cardiac muscle.
AB  - Alcoholism is a very important cause of congestive cardiomyopathy in man. The aim
      of this study was to examine a short-term effect of ethanol in rat cardiac
      muscle, using histologic, morphometric and biochemical methods. Experiments were
      carried out in Wistar male albino rats, divided into two groups: the control
      group consisting of eight animals receiving tap water, and the experimental group
      comprising eight animals received ethyl alcohol for ten days, in a single daily
      dose of 3 g ethanol/kg body weight, per os, using esophageal intubation. The mean
      volume weighted nuclear volume of cardiac myocytes was estimated by point sampled
      intercept method, by objective x 100. The mean cubed nuclear intercept length was
      multiplied by pi and divided by 3. For biochemical analysis, a 10% water tissue
      homogenate from the left ventricle was made. In the experimental group, the mean
      volume-weighted nuclear volume (15.08 +/- 5.20 microm3) was significantly lower
      than in the control group (51.32 +/- 7.83 microm3) (p < 0.001). The treatment of
      experimental animals with ethanol caused significant increase of aldolase (p <
      0.0001) and aspartate transaminase (p < 0.05) activity in the rat cardiac tissue;
      at the same time, the enzyme activity of creatine phosphokinase, alanine
      transaminase and alkaline phosphatase were not changed in the experimental group
      compared to the control values. The amount of the glucose in the cardiac muscle
      was greater in the experimental group compared to the control animals. Our
      results suggest that there is depression of cardiomyocyte nuclei in experimental
      animals treated with ethanol. Alcohol intake results in the loss of Krebs cycle
      enzymes and as a consequence there is greater utilization of fatty acids for
      energy production.

PMID- 10661814
TI  - A toxicity study of simultaneous administration of Tamoxifen and Diazepam to
      female Wistar rats.
AB  - Tamoxifen (TAM) is used in the treatment of breast cancer and decreases the
      incidence of breast cancer when given to healthy women for different therapeutic
      purposes. This expansion of its use calls for further studies of its own
      potential side effects and those in combination with other prescription drugs.
      Diazepam (DP) is one such drug normally administered to patients who are under
      cancer treatment and those who suffer from insomnia. The present study examines
      the effect of individual and simultaneous administration of TAM and DP at
      therapeutic dose level of 0.8 mg/Kg/day of TAM and 0.3 mg/Kg/day of DP to normal
      female Wistar rats for a period of 12 weeks. The drugs were administered orally
      by mixing it in pellet made by wheat dough. There was no significant change in
      the terminal body weight and liver weights of animals. The ovary weights in TAM +
      DP treated animals were significantly decreased. The serum succinate
      dehydrogenase (SDH) levels were significantly lower in TAM, DP and TAM + DP
      treated rats and comparatively were lowest in TAM and TAM + DP treated animal
      groups. Serum glutamate oxaloacetate transaminase (GOT) and glutamate pyruvate
      transaminase (GPT), acid and alkaline phosphatase (ACP & ALP) levels were
      significantly higher in the three treated groups, but comparatively lower in TAM
      + DP treated animals when compared to TAM or DP alone treated rats. There was
      marked increase in liver triglyceride and cholesterol levels in the three treated
      groups but remarkable decrease in liver glycogen. Total serum cholesterol levels
      were significantly high in DP and TAM + DP treated rats and total serum
      triglyceride levels were significantly high only in TAM treated rats. As a whole
      it can be concluded that DP does not enhance TAM toxicity on simultaneous
      administration, but on its own when administered individually brings about
      perturbation in lipid storage and metabolism.

PMID- 10661815
TI  - Repeat-assessment of 1,4-dioxane in a rat-hepatocyte replicative DNA synthesis
      (RDS) test: evidence for stimulus of hepatocyte proliferation.
AB  - 1,4-Dioxane is a nongenotoxic hepatocarcinogen but in our previous replicative
      DNA synthesis (RDS) studies with the [3H]thymidine (TdR)-technique, it failed to
      increase hepatocyte RDS values when given by gavage to male F344 rats as a single
      2000 mg/kg body weight dose. However, in a current series of trials with TdR, it
      showed equivocal responses 24 or 48 hr following treatment with 2000 mg/kg in
      time-course experiments, and positive responses 24 hr following 1000, 1500 and
      2000 mg/kg in dose-response experiments. An increased RDS incidence was also
      observed at the dose of 2000 mg/kg with data for 5-bromo-2'-deoxyuridine (BrdU)
      incorporation. These present findings thus support the hypothesis that a capacity
      to induce cell proliferation may play a key role in 1,4-dioxane
      hepatocarcinogenesis.

PMID- 10661816
TI  - Exocrine cell mitochondria of the rat pancreas after lead intoxication.
AB  - The aim of the study was to evaluate alterations in exocrine cell mitochondria of
      the rat pancreas after lead acetate intoxication. The experiment used 45 rats
      divided into 2 experimental groups receiving lead acetate to drink, of lead
      concentration 50 and 500 mg/dm3 (ppm), and a control group given tap water. The
      animals from the experimental group were decapitated after 2, 4, 6 and 8 weeks, 5
      rats from the control group after 8 weeks of the experiment. Rats from
      experimental groups decapitated after 8 weeks had lead administration stopped
      after six weeks and then, for two weeks tap water was given. Pancreatic sections
      were examined with biochemical methods for the activity of cytochrome oxidase and
      succinic dehydrogenase. Ultrastructural and morphometric examinations were also
      performed. It was demonstrated that: a) exocrine cell mitochondria are
      particularly predisposed to lead effect, b) intoxication of rats with lower lead
      doses (50 ppm) causes reversible adaptative or compensatory changes in these
      organelles, c) intoxication of rats with higher lead doses (500 ppm) induces
      irreversible ultrastructural alterations in numerous mitochondria, including
      damage to inner and to outer mitochondrial membranes, d) structural changes in
      the mitochondria in the course of lead intoxication are the morphological
      expression of the impairment of metabolic processes, associated with the
      inhibited activity of the respiratory enzymes: succinic dehydrogenase and
      cytochrome oxidase.

PMID- 10661818
TI  - Survival.

PMID- 10661817
TI  - A new sensitive cardiac Troponin T rapid test (TROPT) for the detection of
      experimental acute myocardial damage in rats.
AB  - Cardiac Troponin T (cTnT) is a cardiac structural protein which is released in
      the circulation during myocardial cell damage. In this study we addressed the
      question of whether beta-sympathomimetic induced myocardial cell damage in rats
      can be detected in blood by the TROPT sensitive rapid test strip which is
      primarily manufactured for the detection of acute myocardial infarction in
      humans. Sixteen male rats and 16 female animals were treated once with
      orciprenalinesulphate s.c. to induce tachycardia. The control group which
      consisted of 16 rats of both sexes received vehicle (physiological saline). The
      heart rate of two groups of 10 rats (5 of each sex) was measured after
      orciprenaline or saline treatment. After 1-2 hours we could demonstrate an
      increased heart rate in the orciprenaline group. Furthermore in this group we
      could show elevated cTnT levels in peripheral blood measured with the enzyme
      linked immunosorbent assay (ELISA) Enzymun-Test Troponin T for troponin T and a
      positive reaction of the TROPT sensitive test strip. When compared with the ELISA
      method, the test strip showed a positive reaction at cTnT levels of 0.64 ng/ml
      upwards. After 24 hours and 96 hours half of the animals were sacrificed for
      histological examination of the heart tissue. After 24 hours all orciprenaline
      treated and examined animals showed myofibrillar degeneration of the myocardial
      cells. The second half of the animals sacrificed 96 hours after treatment with
      the sympathomimetic drug showed reparative fibrosis of the myocardium. All
      animals with myocardial damage due to orciprenaline showed a positive test strip
      result 2 hours after injection. Twenty-four hours after injection only 8 of the
      16 animals had a positive test strip result although histological cell damage was
      demonstrated. All animals treated with physiological saline had negative results
      of the test strip and showed no signs of myocardial cell damage. We conclude that
      the TROPT sensitive test strip is a rapid and reliable screening tool for
      detecting myocardial cell alteration in rats without the need of an expensive and
      time-consuming ELISA procedure if it is used in early phases of the experiment
      because all animals with myocardial damage were identified by the test 2 hours
      after induction of the damage. If the time range between the induction of the
      injury and the use of the test strip or the ELISA procedure is too wide, in our
      experiments 24 h, false negative results may occur.

PMID- 10661819
TI  - Prognostic factors in invasive lobular carcinoma of the breast: a multivariate
      analysis. A multicentre study after seventeen years of follow-up.
AB  - BACKGROUND AND GOALS: The purpose of this study was to characterize the biologic
      determinants that affect the behavior of invasive lobular carcinoma of the
      breast. MATERIAL AND METHODS: A prospectively accrued data base containing 9,619
      breast cancer cases was queried for specific pathological features. From this
      data base, 390 patients with invasive lobular carcinoma of the breast treated and
      followed at any of these three centers: San Carlos Hospital, Doce de Octubre
      Hospital or The Jimenez Diaz Foundation in Madrid (Spain) were reviewed and
      results, in terms of overall survival and disease-free survival were recorded for
      a long-term follow-up of 206 months (17 years). RESULTS: The parameters that
      showed an important statistical influence on survival were the stage at
      diagnosis, the tumor size and nodal status, as well as the tumor grade. Age
      showed a limited influence, and multicentricity, or the type of surgical
      procedure had no statistical impact on survival. CONCLUSIONS: Our analysis
      specifies the clinico-pathological features that influence the prognosis of
      invasive lobular carcinoma of the breast, and confirms that conservative therapy
      may be an appropriate treatment for this type of cancer.

PMID- 10661820
TI  - Short and long term outcome after laparoscopic cholecystectomy.
AB  - BACKGROUND: As an audit of patients undergoing laparoscopic cholecystectomy this
      study not only reports the short term results, but attempted to assess the long
      term effect of the operation on the symptom profiles of the patients. METHODS:
      Three hundred unselected consecutive patients underwent elective laparoscopic
      cholecystectomy from January 1991 to July 1994. Short term outcome was analysed
      by reviewing patient files for operation details, postoperative morbidity,
      complications, and gallbladder histology. Long term (median 2 years) outcome was
      evaluated by a detailed postal questionnaire. Symptomatic benefit ratios (BR)
      accruing from the laparoscopic removal of the gallbladder were calculated.
      RESULTS: Twelve operations (4.0%) were converted to open surgery and were
      excluded from long term outcome analyses. Median operation time was 93 (range 40
      245) minutes. There were no deaths. Overall morbidity was 13 %. Median
      postoperative hospital stay was 2 days (range 1-18 days) and median time-off work
      15 days (range 2-49 days). The overall response rate to the questionnaire was
      87%. Only one of the 261 patients (0.4%) suffered from recurrent common bile duct
      stones so far. As shown by the benefit ratios the symptoms most effectively
      relieved by laparoscopic cholecystectomy were biliary pain (0.97), nausea (0.95),
      vomiting (0.96) and jaundice (0.94). Most patients with diarrhoea (0.70) and
      heartburn (0.66) felt relief. Constipation (0.39) and food intolerance (0.57)
      were unaffected. Most patients (90%) felt that the operation-initiating symptom
      had disappeared and 98 percent of the patients considered that they had obtained
      overall symptomatic improvement by the operation. CONCLUSIONS: Laparoscopic
      cholecystectomy appears to be a safe and effective way of treating the most
      common symptoms related to gallstone disease.

PMID- 10661821
TI  - Intraarterial chemoembolisation with lipiodol and epirubicin in hepatocellular
      cancer--improved survival in some patients?
AB  - BACKGROUND AND AIMS: Arterial chemoembolisation with lipiodol and a cytotoxic
      drug is reported to give equivocal results in irresectable primary hepatocellular
      cancer (HCC). In order to further elucidate the possible response to this
      treatment, we analysed the results of all patients with irresectable HCC treated
      with chemoembolisation at our hospital. MATERIAL AND METHODS: 58 consecutive
      patients with HCC were treated with lipiodolepirubicin chemoembolisation between
      February 1988 - October 1994 and followed until death or October 1998. RESULTS:
      The average survival was 11.7 months and median survival was 6 months. 17
      patients had only one treatment mostly due to death within 6 weeks after the
      first treatment. Patients with an open portal system at inclusion (50% of all)
      were found to have significantly increased survival after 6 and 12 months
      compared to those with portal obstruction. The subgroup of patients displaying a
      decrease in tumour size as judged by repeated CT scan 6 months after inclusion
      had significantly increased survival; all survived more than 12 months (median
      survival 30 months). CONCLUSIONS: Chemoembolisation with lipiodol-epirubicin may
      have an impact on survival on selected patients with irresectable hepatocellular
      cancer. The treatment may justifiably be offered patients with an open portal
      venous system and without liver failure.

PMID- 10661822
TI  - Axillofemoral bypass operations in Kuopio University Hospital 1985-1996.
AB  - BACKGROUND AND AIMS: Axillofemoral bypass has been used since the 1960's in poor
      risk patients with aortoiliac atherosclerotic occlusive disease to improve
      arterial circulation in the lower extremities. This article describes the outcome
      of 84 consecutive operations in our hospital. MATERIAL AND METHODS: During the
      period 1.1.1985-31.5.1996, 84 axillofemoral bypass operations were performed in
      our hospital. In this retrospective study, information was based on patient
      records and clinical follow-up examination for surviving patients living in the
      area of Kuopio province and operated before the end of 1995. Patencies and
      survivals were established using the life table method. RESULTS: The primary
      patency rate was 81.1 % at one year, 64.3 % at three years and 56.7 % at five
      years. The secondary patency rates were 92.1%, 67.1% and 57.7 %, respectively.
      The operative mortality rate was 6.0%. Eighty-five percent of the patients were
      alive one year after the operation, compared to 50 % after five years. Serious
      complications were rare, but local wound complications occurred in 29 %. Vascular
      reoperations were needed in 29 %, particularly thrombectomies. CONCLUSIONS:
      Axillofemoral bypass gives acceptable results in the treatment of lower leg
      ischaemia in elderly poor-risk patients.

PMID- 10661823
TI  - Can reactive hyperemia be used instead of exercise test in assessment of mild
      intermittent claudication.
AB  - BACKGROUND AND AIMS: Purpose of the study was to find out if reactive hyperemia
      stress test could serve as an alternative for treadmill exercise test in
      assessment of mild intermittent claudication (IC). MATERIAL AND METHODS: A total
      of 22 claudicants with resting ankle brachial index (ABI) ranging from 0.61 to
      1.23 were stressed with progressive treadmill exercise test and suprasystolic
      thigh occlusion test to provoke reactive hyperemia. Immediate pressure
      measurements were obtained after the test. RESULTS: ABI drop after progressive
      exercise test was in average 0.29 and after reactive hyperemia 0.16. The
      pressures indices after these stress tests correlated well (r = 0.82). The tests
      were equally good in detecting mild arteriosclerotic disease. CONCLUSIONS: In
      conclusion, although postexercise ABI was able to detect mild atherosclerotic
      disease as the reason for IC with a better marginal than hyperemia test both
      methods are useful. In circumstances where the patient is for some reason unable
      to carry out treadmill test reactive hyperemia test is an alternative for
      differential diagnosis. This enables vascular surgeons to improve their
      diagnostics without vascular laboratory.

PMID- 10661824
TI  - Risk factors for ascending aortic atheromatosis--a retrospective analysis of
      2,263 patients undergoing coronary artery bypass surgery.
AB  - BACKGROUND AND AIMS: Ascending aortic atherosclerosis has been recognised as a
      potential source of atheroembolization during coronary artery bypass operation. A
      set of possible predictive preoperative factors for ascending aortic
      atheromatosis was studied to find the patients at greatest risk for aortic
      atheromatosis. MATERIAL AND METHODS: The records of 2,263 patients undergoing
      first-time coronary bypass operation from January 1993 to December 1995 were
      reviewed. Ascending aortic atheromatosis was considered to be present if the
      operating surgeon detected atheromatosis in ascending aorta by palpation or by
      sight while making aortotomies. RESULTS: Ascending aortic atheromatosis was found
      in 9.1% of the patients. Significant predictors in the multivariate model were
      age, tobacco use, diabetes, peripheral vascular disease, renal failure, chronic
      obstructive pulmonary disease, x-ray calcifications of the thoracic aorta and
      subclavian artery stenosis at minimum 50 %. The loose variety of atheromatosis
      was detected by sight while making aortotomies in 1.1% of patients. Significant
      predictors in the multivariate model for this loose variety were age,
      hyperlipidemia and renal failure. Patients with ascending aortic atheromas
      suffered significantly more perioperative myocardial infarcts and central
      neurological defects as well as succumbed more often. CONCLUSION: This study
      defines some groups of coronary bypass patients that have increased risk for
      ascending aortic atheromatosis. Special attention should be paid to them during
      coronary bypass operation in order to minimise the otherwise increased risk for
      adverse neurological and cardial outcome.

PMID- 10661825
TI  - Open distal anastomosis in conjunction with partial cardiopulmonary bypass and
      mild hypothermia for repair of descending thoracic aortic aneurysms.
AB  - The duration of spinal cord ischemia is probably the most important single factor
      in the pathogenesis of paraplegia after repair of descending thoracic aortic
      aneurysms. We describe a modification of open distal anastomosis technique
      originally presented by Dr. Cooley, in which we use partial cardiopulmonary
      bypass with femoral cannulation and mild hypothermia. Cardiopulmonary bypass is
      interrupted after lowering patient's temperature to 32 degrees C and the aorta is
      clamped using one proximal clamp. During the suturing of the distal anastomosis
      blood is sucked to reservoire and returned oxygenated to the patient via the
      venous line using a shunt which is installed between the arterial and venous
      lines. After completion of the distal anastomosis the graft is clamped and
      cardiopulmonary bypass reinstituted. Rewarming is started as bleeding intercostal
      arteries are sutured and proximal anastomosis performed. This modification
      shortens the distal ischemia time, but supports the circulation of the kidneys
      and splanchnic area immediately after the distal anastomosis is finished.
      Lowering the temperature should give additional protection for the spinal cord
      and the blood can be returned oxygenated to the patient. In our opinion, this
      combination of femoro-femoral perfusion, mild hypothermia, and open distal
      anastomosis offers several benefits and can be used in dissections and aneurysms,
      which extend up to aortic hiatus.

PMID- 10661826
TI  - Conservative treatment of scaphoid fractures: a follow up study.
AB  - BACKGROUND AND AIMS: This investigation was made to elucidate the outcome of
      conservatively treated scaphoid fractures. MATERIAL AND METHODS: 63 patients with
      a scaphoid fracture were treated initially conservatively and examined
      retrospectively. The mean follow up time was 54 months. RESULTS: In this group
      bone union was achieved in 56 cases (89%). Three of the patients ended up to
      operation because of delayed union soon after conservative treatment and three
      nonunions were found in the follow up appointment. One fracture did not heal
      because of dislocation during cast treatment and was treated with operation.
      Incidence of osteoarthrosis and residual symptoms were studied in the group with
      totally conservative treatment. Osteoarthrosis was found in 19 (32%) wrists, but
      no correlation with wrist problems (pain, reduced grip strength or problems at
      work) was found. 20 (34%) of the patients complained residual symptoms. Most of
      the symptoms were mild and did not impair their ability to work or cause serious
      problems during free time. CONCLUSION: According to the present study
      conservative treatment is a safe method for the treatment of undislocated stabile
      scaphoid fractures.

PMID- 10661827
TI  - Biodegradable screw fixation of the syndesmosis together with metallic
      osteosynthesis. Preliminary experience of 7 ankles.
AB  - BACKGROUND AND AIMS: In ankle fractures with separation of the tibiofibular
      mortise a metallic syndesmosis screw is generally used. As a rule, this
      transfixing screw is removed by a separate operation 6 to 8 weeks later. Usually
      the fracture fixation implants are removed by a second operation later on. In
      order to eliminate separate removal of the transfixing screw, we used a
      biodegradable syndesmosis screw in a pilot clinical study. PATIENTS AND METHODS:
      We treated seven consecutive patients with malleolar fractures and separation of
      the syndesmosis by an ordinary metallic plating and screw fixation of the
      fractures and biodegradable polyglycolic acid (PGA) screw transfixation of the
      syndesmosis. RESULTS AND CONCLUSIONS: All the patients ended up with an
      acceptable result and stable ankle mortise. One of the ankles, which was the only
      one fixed by two transfixing PGA screws instead of one screw, had transient sinus
      formation and intraosseal osteolysis. The final result was good also in this
      case. The ankle mortise can be fixed safely by biodegradable screws in connection
      with metallic osteosynthesis of malleolar fractures. Thus a separate removal of
      the transfixing material is possible to eliminate.

PMID- 10661828
TI  - Finasteride following balloon dilatation of the prostate. A double-blind, placebo
      controlled, multicenter study.
AB  - BACKGROUND AND AIMS: To evaluate the efficacy, safety and tolerability of
      finasteride administered for 24 months following successful balloon dilatation in
      patients with benign prostatic hyperplasia (BPH). PATIENTS AND METHODS: 75
      patients with moderate to severe symptoms of benign prostatic hyperplasia were
      first treated with balloon dilatation. After a 4-week placebo runin period, 64
      patients with successful dilatation and over 50 % reduction in symptoms were
      randomized to receive either finasteride (33 pts.) at 5 mg/day or placebo (31
      pts.) for 24 months. Altogether 12 patients dropped out at some stage, and the
      final analysis hence included 27 patients in the finasteride group and 25
      patients in the placebo group. RESULTS: The symptom scores increased by an
      average of 3.2 points in the finasteride group and 4.4 points in the placebo
      group during two years. The mean maximum flow in the finasteride group remained
      constant: 13.7 ml/s at baseline and 13.9 ml/s at 24 months. In the placebo group
      the mean maximum flow decreased from 13.3 ml/sec to 11.2 ml/s. During the two
      year study period, neither of the groups displayed any changes in residual urine.
      The above mentioned changes were not statistically significant, however. Prostate
      volume and serum PSA were significantly lower in the finasteride group (p <
      0.001). The groups did not differ with regard to side-effects. CONCLUSIONS: On
      the basis of the findings, BPH patients with moderate to severe symptoms can be
      treated with balloon dilatation. The effect of balloon dilatation is quick, and
      it alleviates the patients' symptoms immediately. Finasteride treatment maintains
      the positive effect of balloon dilatation. This combination of treatment is
      tolerated well and side-effects are rare. The favourable effect of balloon
      dilatation was maintained for at least two years. Finasteride treatment
      diminished significantly both prostate volume and serum prostate-specific antigen
      after balloon dilatation compared to placebo treatment.

PMID- 10661829
TI  - BTA test is superior to voided urine cytology in detecting malignant bladder
      tumours.
AB  - BACKGROUND AND AIMS: In a prospective study, Bard BTA (bladder tumour antigen)
      test was compared to voided urine cytology (VUC) in detecting primary and
      recurrent bladder cancer (BC). MATERIALS AND METHODS: 407 control cystoscopies,
      BTA test and VUC were performed on 150 patients, of which 96 (23.6%) recurrent
      tumours were found, and 43 patients with a new BC were noticed. RESULTS: BTA test
      was superior to VUC in detecting superficial Ta (23% vs. 3%, p < 0.001) and grade
      1 (16% vs. 0%, p < 0.001) as well as grade 2 (35% vs. 11%, p < 0.01) tumours. In
      Tis and T2-T4 tumours as well as in grade 3 tumours both tests performed
      similarly. The sensitivity of BTA test compared to VUC in detecting recurrent
      tumours was higher (24 % vs. 9%, p < 0.01), but VUC had more specificity than BTA
      test (99% vs. 80%, p < 0.001). CONCLUSIONS: BTA test was superior to VUC in
      detecting BC and its recurrence. The simultaneous use of the BTA test and VUC did
      not add any information in detecting tumour growth in the bladder as compared to
      the BTA test alone.

PMID- 10661830
TI  - Evaluation of self-reinforced polyglycolide membrane implanted in the subcutis of
      rabbits.
AB  - BACKGROUND: Self-reinforced absorbable implants have been developed recently to
      use in hard tissue reconstructive surgery. Polyglycolide is a biocompatible
      polymer from which the suture Dexon is made and widely used. AIMS: To study
      histologically the behaviour of self-reinforced polyglycolide membrane (SR-PGA)
      in rabbits' ears. MATERIAL AND METHODS: SR-PGA membranes, 0.4 mm thick, were
      implanted in the subcutis of the ears of 24 New Zealand white rabbits. Sham
      operations were carried out on the contralateral ear of each rabbit. The rabbits
      were followed-up for 4, 12 and 20 weeks. Attention was directed towards external
      macroscopic changes in the rabbits' ears. After sacrifice, the ears were taken as
      specimens, inspected for any evidence of infection, sinus formation or fluid
      accumulation and histological examination was carried out. RESULTS: No
      complications such as infection, fluid accumulation or sinus formation were
      observed. Histologically, the membranes induced a foreign-body reaction involving
      fibrous tissue encapsulation, macrophages and giant cells. Fibrous tissue and
      inflammatory cells were seen between the PGA fibres. The membranes underwent
      progressive degradation throughout the follow-up period. However, PGA material
      could be still seen 20 weeks postoperatively, with a small amount of fibrous
      tissue and macrophages and giant cells. The implant-cartilage interface comprised
      fibrous and fatty tissue. CONCLUSIONS: SR-PGA membranes are biocompatible when
      implanted in the subcutis of the ears of rabbits.

PMID- 10661831
TI  - Histological evaluation of poly(L-lactide/epsilon-caprolactone) membrane
      implanted subcutaneously in rats.
AB  - BACKGROUND: Poly(L-lactide/epsilon-caprolactone) [P(L-LA/epsilon-CL)] 50/50
      membranes is an absorbable membrane which has been developed recently for
      possible use in tissue engineering. AIMS: To look at histological tissue
      reactions to the membrane and its behaviour upon its in vivo implantation in
      rats. MATERIAL AND METHODS: P(L-LA/e-CL) 50/50 membranes, 0.4 mm thick, were
      implanted subcutaneously in the dorsal neck of 20 Wistar rats. The rats were
      followed-up for 1, 3, 6, 12 and 28 months. After sacrifice, subcutaneous tissues
      with implants were taken as specimens, inspected for any gross abnormality and
      histological examination was carried out. RESULTS: No significant macroscopic
      changes were noticed except for two implants that were grossly rounded.
      Histologically, the membranes had undergone cracking, fragmentation and
      progressive degradation. Cracks appeared initially at the periphery of the
      implant. Large cracks progressed mainly in longitudinal planes. Cracks occurred
      in the middle of implants and led to membrane bending in some cases.
      "Neomembrane" formation, comprised of fibrous tissue and the implant, was seen.
      The foreign-body reaction to the membrane involved macrophages and foreign-body
      giant cells. In one case an acute type of polymorphonuclear cell reaction was
      observed and in a second case a predominantly lymphocytic reaction was seen at
      three months. They were thought to be the results of infection. No other adverse
      effects were seen. CONCLUSIONS: P(L-LA/e-CL) 50/50 membrane was found to be
      biocompatible when implanted subcutaneously in rats. It was degraded to a great
      extent but not completely in 28 months.

PMID- 10661832
TI  - Comparison of self-reinforced poly-L-lactide and steel wire in fixation of
      sternotomy in rabbits.
AB  - BACKGROUND AND AIMS: To investigate the healing of sternotomies fixed with
      biodegradable self-reinforced poly-L-lactide (SR-PLLA) wire and comparing it with
      steel wire fixation. MATERIAL AND METHODS: Sixteen rabbits (15 Chinchilla and one
      New Zealand White rabbit) were operated on. Two parallel holes of 1.5 mm in
      diameter were drilled in the sternum at the level of the second and third rib and
      similar holes of 0.8 mm were drilled at the level of the third and fourth rib. A
      transverse sternotomy was created between both drill hole pairs. The sternotomy
      with larger drill holes was fixed with 1.1-mm thick SR-PLLA wire. The sternotomy
      between the smaller drill holes was fixed using 2.0 steel wire. The animals were
      sacrificed at 2, 7, 26 and 52 weeks postoperatively and specimens were taken,
      radiographed and studied by both light and scanning electron microscopy. RESULTS:
      One rabbit died at four months postoperatively as a result of gastrointestinal
      problems. No other complications were seen. The SR-PLLA wire was slowly degraded.
      There was no disturbance of bone healing. The implants were surrounded by a
      fibrous tissue capsule, which also contained chronic inflammatory cells. Both SR
      PLLA and steel wires provided sufficient fixation security. No differences in the
      healing of the sternotomies were observed between SR-PLLA and steel wire
      fixation. CONCLUSIONS: SR-PLLA wires are biocompatible and useful for sternotomy
      fixation. They may be suitable for use in clinical applications.

PMID- 10661833
TI  - A report of three cases with an oesophageal perforation treated with a coated
      self-expanding stent.
AB  - A perforation of distal oesophagus in benign cases occurs usually as a
      complication of endoscopic procedures or due to perforating external trauma.
      Perforations caused by blunt trauma are rare and usually involve high-energy
      accidents. The time of diagnosis, severity of the perforation, degree of
      mediastinal and pleural contamination and treatment are the most important
      factors predicting the outcome. Treatment may be conservative, comprise primary
      suturation or include oesophageal resection. We present three cases with a benign
      oesophageal perforation, which we have treated with a coated stent. One of the
      cases suffered from a thoracic oesophageal perforation due to a lesser trauma,
      while the other two cases are perforations caused by complications of endoscopy.

PMID- 10661834
TI  - Survival analysis: caveats and pitfalls.
AB  - BACKGROUND: Survival analysis in clinical studies is important to assess the
      effectiveness of a given treatment and to understand the effect of various
      disease characteristics. A number of methods exist to estimate the survival rate
      and its standard error. However, one cannot be certain that these methods have
      been handled appropriately. The widespread use of computers has made it possible
      to carry out survival analysis without expert guidance, but using inappropriate
      methods can give rise to erroneous conclusions. The majority of the biomedical
      journals now recommend that a statistical review of each manuscript should be
      carried out by an experienced bio-statistician, in addition to obtaining expert
      referees' comments on the article. The problem is compounded in papers from third
      world countries where bio-statisticians may not be available in all institutions
      to guide clinicians as to the selection of proper techniques. METHODS: The
      present paper deals with the various techniques of survival analysis and their
      interpretation, using a modal data set of malignant upper-aerodigestive tract
      melanoma patients treated in the Regional Cancer Centre, Trivandrum since 1982.
      RESULTS: The Kaplan-Meier method was found to be the most suitable for survival
      analysis. The median survival time is a better method of summarizing data than
      the mean. Rothman's method of estimation of the confidence limit is better than
      Peto's method as the confidence limit for survival probability tends to go beyond
      the range of 0-1.0 when calculated by Peto's method, especially when the sample
      size is small. CONCLUSION: The results from the present study suggest that
      survival analysis should be carried out by the Kaplan-Meier method. The median
      survival time should be provided wherever possible, rather than relying on mean
      survival. Confidence limits should be calculated as a measure of variability. A
      suitable rank test should be used to compare two or more survival curves, rather
      than a Z-test. Stratified analysis and Cox's model, when stratified analysis
      fails, can be used to define the impact of prognostic factors on survival.

PMID- 10661835
TI  - Differential gene expression between human neurons and neuronal progenitor cells
      in culture: an analysis of arrayed cDNA clones in NTera2 human embryonal
      carcinoma cell line as a model system.
AB  - To elucidate the highly complex expression pattern of the genes involved in human
      neuronal differentiation, differential gene expression between human neurons and
      neuronal progenitor cells was investigated by analysis of a cDNA expression array
      in a pluripotent human embryonal carcinoma cell line NTera2 (NT2), a model system
      of human neuronal differentiation. Among 588 arrayed cDNA clones, 87 genes showed
      a differential expression pattern between undifferentiated neuronal progenitor
      cells (NT2-U) and NT2-derived differentiated neurons induced by treatment with
      retinoic acid (RA) (NT2-N), while 26 genes could not be analyzed due to high
      background signals. The levels of expression of 76 genes, including those
      encoding a group of transcription factors, intracellular signal-transducing
      proteins, cell death-regulatory proteins, and growth
      factors/cytokines/neurotransmitters and their receptors, were elevated after
      neuronal differentiation, while the levels of 11 genes, including those coding
      for cellular proliferation-related proteins, were decreased. Among the
      differentially expressed genes following induction of neuronal differentiation,
      significant up-regulation of the growth-associated protein (GAP-43), low-affinity
      nerve growth factor receptor p75 (LNGFR), and defender against apoptotic cell
      death (DAD1) mRNAs and substantial down-regulation of the proliferation
      associated gene (PAG), fibroblast growth factor receptor-1 (FGFR-1), and cellular
      RA-binding protein-II (CRABP-II) mRNAs were verified by Northern blot analysis.
      These results indicate that the analysis of cDNA expression arrays provides a
      useful approach for screening and identification of a set of distinct genes that
      undergo highly complex regulation during human neuronal differentiation.

PMID- 10661836
TI  - Mapping of fiber orientation in human internal capsule by means of polarized
      light and confocal scanning laser microscopy.
AB  - The nervous fibers in the human internal capsule were mapped according to their
      three-dimensional orientation. Four human cadaver brains were cut into comparable
      and standardized sections parallel to the ACPC-plane, stained with DiI, and
      analyzed using a combination of confocal and polarized light microscopy at the
      same time. This combination provides information about the structure and
      orientation of the fibers in great detail with confocal microscopy, and
      information about the localization and orientation of long myelinated fiber
      tracts with polarization microscopy. The internal capsule was parcellated in the
      areas CI 1 to CI 4 containing fibers of distinct orientation and structure, which
      enriches the macroscopically definable parcellation in the anterior and posterior
      limb. Fibers of the anterior thalamic peduncle intermingle with frontopontine
      tract fibers. Single fibers connect the caudate and the lentiform nucleus. The
      pyramidal tract is located in the anterior half of the posterior limb
      intermingled with fibers of the superior thalamic peduncle.
      Parietooccipitopontine fibers are located in the posterior part of the posterior
      limb. The slopes of the different systems of fibers change continuously in the
      anterior posterior direction of the internal capsule. Using the 3D orientation of
      fibers as a criterion for parcellation, as well as the description of bundles as
      a collection of fibers belonging to particular tracts leads to a more function
      related description of the anatomy of the internal capsule. The method can be
      used for interindividual, sex- or age-related comparisons of particular systems
      of fibers.

PMID- 10661837
TI  - Analysis of tyrosine hydroxylase gene transcription using an intron specific
      probe.
AB  - The nuclear run-on assay is the most commonly used technique to determine
      transcription rates of specific genes such as tyrosine hydroxylase. Its
      application to studies in the nervous system is problematic, however, as a result
      of limitations in sensitivity and the loss of anatomical integrity. We observed
      that the relative levels of tyrosine hydroxylase intron 2-containing RNA using a
      ribonuclease protection assay in the adrenal medulla changed in response to
      pharmacological treatments consistently with changes shown by the nuclear run-on
      assay. Our results indicate that measures of tyrosine hydroxylase primary
      transcript levels offer an alternative to the nuclear run-on assay and validate
      the application of intron-specific in situ hybridization as a means of assessing
      the relative transcriptional activity of the tyrosine hydroxylase gene. Similar
      quantitative results were obtained using intron-specific in situ hybridization
      with oligonucleotide probes specific for rat tyrosine hydroxylase intron 2.
      Furthermore, we observed that intron-specific in situ hybridization could be used
      to measure tyrosine hydroxylase transcription rates in the locus coeruleus,
      providing resolution at the level of single neurons. Thus, measuring the levels
      of tyrosine hydroxylase intron 2 provides a sensitive measure of tyrosine
      hydroxylase transcription rate that can be applied to the study of brain
      catecholaminergic neurons.

PMID- 10661838
TI  - Spectrophotometric measurement of experimental brain injury.
AB  - Freshly sampled brain tissue exposed to 2,3,5-triphenyltetrazolium chloride (TTC)
      acquires a red color because mitochondrial enzymes reduce the colorless TTC to a
      red, water-insoluble formazan deposit. Pan-necrotic areas remain uncolored, which
      enables quantitation of experimental brain injury by optical scanning and image
      analysis of serial slices to determine the relative volume of red versus
      infarcted, non-stained, tissue. The accuracy of this method can be challenged,
      however, when infarction is accompanied by areas of partial, scattered injury
      where differences in coloration are difficult to see or quantify. We tested the
      feasibility of measuring scattered injury using a principle which underlies
      standard assays for in vitro cell survival, namely extracting deposited formazan
      with a solvent and measuring its level by spectrophotometry. Anesthetized, adult
      Sprague Dawley rats were subjected to 12 min of cerebral ischemia to produce
      selective, delayed neuronal death in hippocampus, striatum and cortex. Some rats
      also received 6 h of whole-body hypothermia treatment (31.5-32.5 degrees C)
      immediately after ischemia. Ischemia rats and non-operated controls were
      sacrificed 1 week later. Hippocampus and portions of cerebrum were incubated 90
      min in a 2% TTC solution and then soaked in a measured volume of 50:50 ethanol
      and dimethylsulfoxide to extract the red formazan product. Spectrophotometric
      measurements of the extract showed a diminished formazan coloration (absorbance/g
      brain) in all samples from the untreated ischemia group compared to non-operated
      controls. This apparent brain injury was attenuated in the group of ischemia rats
      that received hypothermia treatment. We conclude that solvent extraction and
      spectrophotometric quantitation of formazan has potential utility as an objective
      way to index experimental brain injury even if this is diffuse in nature and not
      amenable to measurement by conventional image analysis techniques.

PMID- 10661839
TI  - Field potential analysis of synaptic transmission in spiking neurons in a sparse
      and irregular neuronal structure in vitro.
AB  - Extracellular field potential (FP) recording of dendritic depolarizations evoked
      by afferent stimulation is widely used as a quantitative measure of excitatory
      synaptic transmission in brain slices in-vitro for structures with high neuronal
      density and regularity such as hippocampus, neocortex and cerebellum. On the
      other hand, FP recordings of somatic depolarizations induced by orthodromic or
      antidromic stimulation of afferent or efferent nerves have been used in some in
      vivo preparations for mapping the central projections of these nerves. In this
      study, we examined the applicability of somatic FPs as a measure of excitatory
      synaptic transmission in a sparse and irregular brain structure. Excitatory FPs
      were induced in nucleus tractus solitarius (NTS) in the dorsal medulla by
      electrical impulse stimulation of primary afferent fibers in the tractus
      solitarius (TS) in rat brainstem slices in vitro. The evoked FP was rapid and
      biphasic, and was stimulus-intensity dependent and saturable. The morphology of
      these somatic FPs resembled the dendritic FPs found in hippocampal and
      neocortical slices, with an excitatory postsynaptic component that exhibited
      similar pharmacological and stimulus frequency-dependent properties as found in
      NTS cells with intracellular or whole-cell recordings. Simultaneous FP and whole
      cell recordings revealed that the postsynaptic component of FP was associated
      with neuronal firing rather than subthreshold membrane depolarizations. We
      conclude that somatic FP recording provides a simple and reliable measure of
      excitatory neurotransmission in the TS-NTS pathway and is a useful alternative or
      adjunct to intracellular or whole-cell recordings especially for studies of long
      term synaptic plasticity in spiking neurons. This technique may also be
      applicable to other brain regions that lack the regular and dense organization of
      hippocampal and neocortical structures.

PMID- 10661840
TI  - A method for measuring colocalization of presynaptic markers with anatomically
      labeled axons using double label immunofluorescence and confocal microscopy.
AB  - Information concerning the location and distribution of presynaptic
      neurotransmitter release sites within anatomically labeled axons would be of
      value for a large number of studies in functional anatomy, development, and
      plasticity. Here we report a method for localizing presynaptic sites within
      identified arbors of interest using anterograde anatomical tracer injections to
      label axonal projections and synaptic vesicle protein (SVP) antibodies to label
      presumptive presynaptic terminals. The axons and presynaptic sites are
      independently visualized with double label immunofluorescence and confocal
      microscopy. Stacks of images representing adjacent focal planes are collected,
      and image processing techniques are applied to identify the location of each
      axonal branch segment and each cluster of SVP label in three-dimensional space.
      Segmentation of the SVP label into distinct pixel clusters in three-dimensional
      space, followed by colocalization of these clusters with the labeled axons
      (object-based analysis), yields much more reliable and sensitive measures of
      colocalization than a simple determination of the number (or summed intensities)
      of colocalized pixels in a single optical section (pixel-based analysis). The
      method has been extended to measure the colocalization of antigens that are not
      located at the presynaptic terminal with a labeled population of axons.

PMID- 10661841
TI  - Basal signaling activity of human dopamine D2L receptor demonstrated with an
      ecdysone-inducible mammalian expression system.
AB  - Basal signaling activity of the dopamine D2L (long isoform) receptor was
      investigated using an ecdysone-inducible mammalian expression system. Whereas
      basal signaling activity had been demonstrated for the D1, D2S (short isoform),
      D3, and D5 receptor subtypes, this issue has yet to be clearly resolved for the
      D2L receptors. An ecdysone-inducible mammalian expression system was used to
      express the dopamine D2L receptor in human embryonic kidney cells (HEK293). The
      two ecdysone analogs, muristerone A and ponasterone A, induced D2L receptor
      expression dose-dependently from 120 (non-induced) to 2000 fmol/mg protein which
      is similar to physiological D2 receptor density in dopaminergic brain regions.
      With this approach, we demonstrate significant basal D2L receptor activity. Basal
      and agonist-stimulated signaling activity, determined with assays of cAMP levels
      and [35S]GTPgammaS binding to assess G protein coupling, correlated with the
      level of receptor expression. Furthermore, among several antagonists tested, only
      fluphenazine and trifluoperazine exhibited clearly detectable inverse agonist
      activity. This differs from the D2S receptors, where most antagonists were
      reported to display full inverse agonism. Differences between inverse agonist
      effects of D2L and D2S antagonists may be relevant to the treatment of diseases
      involving dopamine D2 receptors.

PMID- 10661842
TI  - Pituitary gland and axial skeletal malformations in human fetuses with spina
      bifida.
AB  - The purpose of the present study was to describe the pituitary gland and axial
      skeleton, including the sella turcica, in human fetuses with spina bifida. Ten
      fetuses with gestational ages (GA) 15 1/2-28 weeks were investigated
      radiographically (Faxitron X-ray apparatus) and immunohistochemically. Four of
      the fetuses have been described previously. The study showed that nine fetuses
      had minor or no skeletal abnormalities in the vertebral bodies of the spine, and
      one fetus had severely malformed vertebral bodies. In all cases the sella turcica
      and the pituitary gland were malformed. Adenopituitary tissue was in all cases
      located in both the sella turcica and the pharyngeal submucosa. The most severe
      sella turcica/pituitary gland malformation was seen in the fetus with the
      malformed spine. The connection between the prenatally registered sella
      turcica/pituitary gland malformation and the endocrinological status of children
      with spina bifida should be emphasized in future studies.

PMID- 10661843
TI  - Differentiated thyroid cancer in children and adolescents: the importance of
      adequate surgery and review of literature.
AB  - Within 25 years, 13 girls and 5 boys between the ages of 9 to 20 years were
      treated for differentiated thyroid cancer (DTC) at our institution. In 67% of the
      cases the diagnosis was made at an advanced stage indicated by cervical lymphnode
      metastases, two children showed metastases of the lung. Except for one girl, all
      patients underwent a total thyroidectomy with various forms of lymph node
      dissections. All were treated post-surgically with radio-iodine (131I) and all
      patients received levothyroxine in suppressive doses. The complication rate was
      low (laryngeal nerve injury in only 3 cases and no permanent hypoparathyroidism)
      and after a follow-up period of 26 years all patients are alive and without
      disease. In the case of DTC in children and adolescents, a total thyroidectomy
      with an appropriate lymph node dissection is the best surgical management.
      Besides the rather high incidence of local and distant recurrence, particularly
      in this age group, the detection and treatment of the metastases with radio
      iodine are significantly facilitated by this surgical procedure. Additionally it
      allows the use of serum thyroglobulin as a reliable indicator of recurrence. To
      prevent high complication rates, surgical treatment should be performed in
      centers with skilled and experienced endocrine surgeons.

PMID- 10661844
TI  - Congenital cystic disease of the lung in infants and children (experience with 57
      cases).
AB  - A retrospective analysis of 57 consecutive cases with congenital cystic disease
      of the lung admitted to King Faisal Specialist Hospital and Research Center and
      King Khalid University Hospital, Riyadh, between 1985-1995 is presented. There
      were 37 congenital lobar emphysema (CLE), 7 cystic adenomatoid malformation
      (CAM), 8 bronchogenic cyst (BC) and 5 pulmonary sequestrations (PS). There were
      39 males and 18 females with ages ranging from 1 day to 5 years. All patients
      were symptomatic except three. Respiratory distress, repeated chest infections,
      and cystic changes noted in chest x-ray were the commonest presentation. Five of
      eight patients with BC presented with symptoms related to pressure effect of the
      cyst on the surrounding structures, these included bronchiectasis in two
      patients, bronchopleural fistula in one, pulmonary artery stenosis and
      bronchomalacia in one, airway obstruction mimicking bronchial asthma in one.
      Seven patients (12.2%) were treated conservatively, the remaining underwent
      surgery. Surgery included excision of the bronchogenic cyst and lobectomy for
      CLE, CAM, and intralobar sequestration. The post-operative course in most cases
      was uneventful. There were no deaths in this series, and the majority of patients
      had a satisfactory outcome with follow-up ranging from 1-72 months (mean 24
      months). It appears that lobectomy for symptomatic CLE, CAM, and intralobar
      sequestration and excision for bronchogenic cyst offer the best treatment
      modality and is well tolerated by pediatric patients. Careful search for
      associated anomalies is important to obtain better outcome.

PMID- 10661845
TI  - Primary repair of long-gap esophageal atresia by mobilization of the distal
      esophagus.
AB  - Long-gap esophageal atresia remains a difficult problem for the pediatric
      surgeon. Several strategies for lengthening of the proximal esophageal segment
      have been used with relative success. Autogenous tissue conduits have resulted in
      less than optimal long-term results. Five patients since 1991 with long gap
      esophageal atresia (2 with distal tracheo-esophageal fistula [Type C], and 3 with
      isolated esophageal atresia [Type A]) underwent mobilization of the distal
      esophagus to the level of the diaphragm in order to perform a primary
      anastomosis. A retrospective analysis evaluated the timing of repair, when oral
      feeds were successfully begun, with particular attention to any ischemic sequelae
      related to the distal esophageal dissection. Two patients underwent immediate
      repair, three had delayed repair. There were no anastomotic leaks. Three patients
      healed without stricture. Of four patients who survived long-term, three patients
      are eating well and only one still requires jejunoenteric supplementation.
      Classic teaching dictates that dissection of the distal esophagus should not be
      done because of disruption of its segmental blood supply. In this series, distal
      esophageal mobilization was successful in facilitating a primary anastomosis.
      These results are encouraging as an alternative to the high morbidity and
      marginal long-term results of interposition grafting or gastric transposition.

PMID- 10661846
TI  - Diagnosing hypertrophic pyloric stenosis: does size matter?
AB  - This retrospective study examines the size of the pyloric tumour at the time of
      surgery in 100 patients (76 boys, 24 girls) operated over a 2.75 years period
      from June 1993 to March 1996. The size of the pyloric tumour was classified into
      one of three categories (short, moderate or large) by the operating consultant
      and documented in the operation note. This study supports the view that the
      pyloric tumour increases in size with the progressing age of a baby. Nowadays the
      diagnosis of hypertrophic pyloric stenosis (HPS) is made on average 2 weeks
      earlier than in a similar study 4 decades ago. Two thirds of the patients in the
      subgroup with short- and moderate-size pyloric tumours did not require any
      imaging technique to arrive at the diagnosis. Unexpectedly a more frequent use of
      imaging techniques was required in the subgroup of large pyloric tumours; large
      tumours tend to present as an ill-defined fullness in the right upper quadrant
      rather than a distinct olive.

PMID- 10661847
TI  - In-utero defecation: fact or fiction?
AB  - An experimental study was performed to investigate the gastrointestinal motility
      and in-utero defecation by radionuclide techniques. Forty-eight New-Zealand white
      rabbit fetuses at 25 days' gestation (fullterm, 31 to 32 days) were divided into
      two groups as A (n: 24) and B (n: 24). 0.1 ml of Technetium-99m (99mTC)-HIDA (a
      derivative of iminodiacetic acid) containing 1 mCi of radioactivity was injected
      into the gluteus muscle of each fetus, which had been exposed through the uterus.
      This procedure was used for all fetuses and additionally surgical closure of anus
      by a purse string suture was performed in Group B fetuses. After replacing the
      fetus and uterus into the abdomen, and beginning 1 hour after injection, a live
      fetus was killed each hour for 24 hours. Tissue samples from the reference organs
      (lung, heart, stomach, kidney, bladder), liver, meconium in the proximal, mid and
      distal bowel, and amniotic fluid were taken. The radioactivity of each sample was
      determined by a gamma counter and the percentage injected dose (uptake) per gram
      of tissue is calculated. 99mTc-HIDA was predominantly trapped by the liver via
      systemic circulation and excreted into the gastrointestinal tract in both groups
      through which it passed into the amniotic fluid only in Group A. The very low
      radioactivity levels detected in the amniotic fluid of Group B originated from
      urinary tract and indicated the in-vivo stability of 99mTc-HIDA, thus reliability
      of the experimental model. Intestinal transport of a radiopharmaceutical agent in
      both groups and demonstrated passage into the amniotic fluid only in Group A
      strongly suggest that fetal defecation is a physiologic event.

PMID- 10661848
TI  - Congenital colonic hypoganglionosis in murine trisomy 16--an animal model for
      Down's syndrome.
AB  - Human trisomy 21 (Down's syndrome) affects the development of multiple organ
      systems frequently including gastrointestinal anomalies such as Hirschsprung's
      disease. To elucidate the underlying morphogenetical mechanisms a murine model
      (trisomy 16 mouse) for Down's syndrome has been established. However, previous
      studies on trisomy 16 (TS 16) mice have been confined to non-enteric
      developmental disorders. Therefore, the aim of the present study was to assess
      the enteric nervous system and the morphology of the terminal colon in TS 16 mice
      during late intrauterine development. Immunohistochemical examination (protein
      gene product 9.5) revealed a reduction of myenteric ganglionic size and density
      as well as the presence of ectopic ganglia, thus resembling typical features of
      colonic hypoganglionosis and myenteric heterotopia. Enzyme histochemistry for
      NADPH-diaphorase showed a remarkable decrease of NADPH-positive neurons in TS 16
      mice, whose sparse distribution was confined to a minor portion of the
      oligoneuronal myenteric ganglia. Electron microscopical studies of TS 16 mice
      confirmed the myenteric hypoganglionosis and, additionally, demonstrated the
      absence of submucosal neurons. Whereas neurons of controls were characterized by
      arborizing neuronal processes, neurons of TS 16 mice were reduced in size and
      exhibited only few and shortened cytoplasmic protrusions. Additionally, prominent
      bundles of parallel nerve fibers passed through the intermuscular zone and lacked
      the arborization pattern of normal neuropil. They were not observed in controls
      and resembled features of extrinsic nerves. Approximately one third of TS 16 mice
      developed a colonic dilatation proximally to an obstructed segment characterized
      by a pronounced hypoganglionosis. Although TS 16 mice did not develop complete
      aganglionosis, the abundance of nerve fiber bundles and the colonic dilatation
      were consistent with the morphological characteristics of Hirschsprung's disease.
      The findings suggest that even a hypoganglionosis characterized by
      ultrastructurally altered and NADPH-diaphorase-deficient neurons may be capable
      of provoking a functional intestinal obstruction. Similar abnormalities of the
      enteric nervous system as observed in TS 16 mice may also be present in such
      trisomy 21 patients who suffer from chronic intestinal motility disorders which
      are not caused by complete aganglionosis.

PMID- 10661849
TI  - Rehbein's procedure for Hirschsprung's disease. An appraisal of 45 years.
AB  - A retrospective follow-up study of all children treated for Hirschsprung's
      disease over the last 45 years at the Department of Pediatric Surgery, Children's
      Hospital, Bremen was done to evaluate the results of Rehbein's procedure. A total
      of 416 children underwent Rehbein's lower anterior resection. The postoperative
      outcome was analysed in detail for early and late complications like wound
      infection, pelvic abscess, anastomotic stenosis, anastomotic insufficiency,
      postoperative enterocolitis, persistence of constipation, fecal and urinary
      incontinence, recurrent achalasia, need for reoperation, adhesion ileus and
      mortality. On the basis of the data analysed and review of literature it was
      concluded that Rehbein's procedure is a well-established method in the treatment
      of Hirschsprung's disease with excellent results and few complications.

PMID- 10661850
TI  - Functional ileus in neonates: Hirschsprung's disease-allied disorders versus
      meconium-related ileus.
AB  - Sixty-eight neonates with functional ileus were reviewed. Twelve required
      laparotomy; in seven, histological studies revealed decreased ganglia and
      ganglion cells of the myenteric plexus (MP) (Group A), and in five, MP was normal
      (Group B). In the remaining 56 cases, obstructive symptoms were relieved
      following conservative therapy (Group C). All Group A cases except one had normal
      birth weight, while Group B and C cases showed significantly lower birth weights.
      A marked caliber change of the small intestine and/or small-caliber distal
      intestine with meconium stagnation in the proximal intestine was commonly
      demonstrated at operation in Group A and B, or on contrast enema in Group C. Four
      Group A cases died of enteritis, and three survivors suffered from prolonged
      obstructive symptoms. The grade of histological abnormality of MP correlated with
      the clinical outcome. In Group B, three died of sepsis shortly after surgery, but
      two survivors have been free from symptoms. Group A can be categorized as
      Hirschsprung's disease-allied disorders (HAD). Group B and C can be categorized
      as meconium-related ileus (MRI). The similarity of the macroscopic findings of
      HAD and MRI, and the occurrence of MRI exclusively in low birth weight neonates,
      strongly suggest that functional immaturity of MP plays a role in the etiology of
      MRI.

PMID- 10661851
TI  - Conservative treatment of neonatal primary megaureter.
AB  - The growing agreement toward the conservative treatment of primary megaureter
      (PM) is supported by the increasingly frequent reports in the literature of
      spontaneous resolution of this pathology after few years of attendance. If the PM
      is asymptomatic without the presence of parenchymatous damage, and the diuretic
      scintiscan does not show a definite obstruction of the uretero-vesical junction,
      the conservative treatment should be the choice for the neonatal forms of PM. We
      report our experience of 14 neonatal PM, conservatively managed out of a total of
      22 PM observed between 1990 and 1996. All the patients have been controlled with
      serial ultrasonography and Tc99 DTPA scintigraphy. Three of them underwent a
      surgical operation because of persistence or impairment of the clinical and
      scintigraphic pictures after a 12-18 months' follow-up. Some of the remainders
      are completely recovered while others are going toward resolution. The
      conservative treatment of neonatal PM is therefore confirmed to be sure and
      effective, and in spite of the different attitudes expressed by reliable authors
      in the up-to-date literature we believe it should be undertaken for the
      asymptomatic forms in which there is no documented uretero-vesical obstruction.

PMID- 10661852
TI  - Long-term outcome of the fetal adrenal gland transplantation in rats.
AB  - Three experimental groups have been constructed to evaluate the long-term outcome
      of fetal adrenal transplantation in rats. In Group 1 (n = 10), rats underwent
      bilateral adrenalectomy. In Group 2 (n = 10), rats underwent a sham procedure
      which included flank incision and arterial canulization. In Group 3 (n = 20), a
      left adrenalectomy was performed followed immediately by transplantation of a
      fetal adrenal graft into the greater omentum and marked with a prolene suture
      (Stage 1). One year later, the right adrenal gland of the recipient was removed
      followed by a determination of the fetal adrenal graft function (Stage 2). Graft
      function was evaluated by measuring ACTH and corticosterone levels; and a
      histologic examination of the transplanted fetal adrenal gland was obtained at
      autopsy. In Group 1, all the rats died within first 8 hours, following bilateral
      adrenalectomy. In Group 2, and Group 3, all rats survived after Stage 1
      operation. During the Stage 2 operation, it was observed that three rats (15%)
      had neither fetal adrenal transplant nor prolene suture, seven rats (35%) had a
      well vascularized and developed fetal adrenal graft and a prolene suture. There
      was no visible fetal adrenal graft but the prolene suture was present in the
      remaining rats (50%) in Group 3. After removal of the right adrenal gland (6 and
      12 hours later), the mean plasma level of ACTH increased with a decline in mean
      serum corticosterone level in Group 3 compared to the sham-operated animals (p <
      0.001). In spite of visible, and viable transplants, all rats died within 48
      hours following Stage 2 operation. The mean weight of the fetal adrenal
      transplant showed a sixteen-fold increase compared to the initial weight (p <
      0.001) and histologic examination showed all 3 zones of adrenal cortex, but there
      were no medullary cells noted. Although the transplanted fetal adrenal grafts
      survived, their hormonal function was not enough to maintain host viability.
      Based on these results it is concluded that, insufficiency of the transplanted
      fetal adrenal gland may be secondary to either graft rejection or suppression of
      the transplanted tissue by the functional recipient adrenal despite the fetal
      adrenal transplant survival.

PMID- 10661853
TI  - Cricopharyngeal achalasia--a cause of major dysphagia in a newborn. A case
      report.
AB  - Cricopharyngeal achalasia is a rare cause of neonatal dysphagia. Its treatment is
      based on surgical myotomy, which is to be avoided in the presence of prematurity
      and neurological diseases. The authors report a case of cricopharyngeal achalasia
      in a full-term four-month-old female baby. Coughing and choking during feeds were
      the major symptoms. The diagnosis was made peroperatively although barium meal
      and endoscopic findings were suggestive. After cricopharyngeal myotomy, symptoms
      took several weeks to disappear. Seven months after surgery, she feeds normally
      and weighs 7,700 g. Neonatal cricopharyngeal achalasia could be a foregoing state
      to cricopharyngeal diverticula in adult. Some cases may remain undiagnosed either
      due to lack of symptoms or sudden infant death.

PMID- 10661854
TI  - Lung cancer in a child with a substantial family history of cancer.
AB  - The occurrence of primary lung cancer is rare in childhood. The case of an 11
      year-old boy with primary lung cancer is presented in this report. He had a
      substantial family history of cancer. His chief complaint was coughing with right
      chest pain. A chest radiograph showed a coin lesion in the right lower lung. A
      right lower lobectomy revealed a squamous cell carcinoma (stage IIIA at Japanese
      TNM classification). Systemic chemotherapy using cisplatin, vindesine, THP
      adriamycin and cyclophosphamide was performed. Six months after surgery, a
      recurrent tumor occurred. An analysis of the familial cancer related genes (p53
      gene and mismatch repair gene) showed no abnormality.

PMID- 10661855
TI  - Ectopic gastric mucosa causing dysphagia due to strictures in a boy.
AB  - Ectopic gastric mucosa in the upper esophagus has been reported previously in
      neonatal autopsy series and encountered in adult esophagoscopies. Despite the
      usual asymptomatic course of the disease, symptomatic adults have been reported.
      However there is no report of a symptomatic child with ectopic gastric mucosa in
      the literature. A 12-year-old boy presenting with dysphagia due to strictures
      resulting from circular patches of ectopic gastric mucosa located in the mid
      esophagus is reported.

PMID- 10661856
TI  - Papillary cystic and solid tumor of the pancreas--surgical therapy with the use
      of CUSA, and a review of the pediatric literature.
AB  - Papillary cystic and solid tumor of the pancreas (PCSTP), so-called Frantz tumor,
      is a very rare tumor in children. Only 62 cases, 57 girls and 5 boys, have been
      reported in children since 1959. The tumor presents usually as a slowly growing
      abdominal mass with or without abdominal pain. Surgical resection of the tumor is
      an adequate mode of treatment, and the prognosis is excellent. The authors
      present 4 girls and 1 boy with PCSTP and demonstrate that the Cavitron Ultrasonic
      Surgical Aspirator (CUSA, Valleylab) is successfully used in surgical therapy.

PMID- 10661857
TI  - Laparoscopic bilateral adrenalectomy in a child.
AB  - Laparoscopic adrenalectomy is an established technique--in adults. This report
      describes a bilateral laparoscopic adrenalectomy in a child. As in adults, it
      indicates that the technique is superior in anatomic exposure and postoperative
      recovery, and is well suited for children.

PMID- 10661858
TI  - Aggressive congenital fibromatosis of the small intestine in the newborn. Report
      of a case and review of the literature.
AB  - A case of so-called congenital fibro(leio)myosarcoma of the small intestine in a
      18-day-old female baby, treated only with surgical resection, was studied by
      immunohistochemistry and electron microscopy in order to investigate the
      proliferating cell type. The tumour cells showed positivity only for vimentin and
      CD 34 and were negative for smooth muscle actin, desmin, alpha-sarcomeric actin,
      factor VIIIR: Ag and S-100 protein. Ultrastructural findings showed oval nuclei
      with prominent nucleoli, rare intracytoplasmic mitochondria and well developed
      rough endoplasmic reticulum. According to histoimmunological and electron
      microscopy findings the proliferating cells were likely to be of fibroblastic
      origin. A 7-year follow-up showed a favourable clinical evolution thus confirming
      that surgical resection can be a sufficient therapeutic approach. The
      morphological findings and clinical behaviour suggest that more appropriate
      terminology for this tumour would be "aggressive congenital fibromatosis" which
      better highlights its local progressive invasion without metastases.

PMID- 10661859
TI  - Multifocal omental mesenteric inflammatory pseudotumor (plasma cell granuloma).
AB  - Inflammatory pseudotumor (IP) is an uncommon benign tumor during childhood. The
      most common location is lung, and sporadic cases of IP with extrapulmonary
      involvement such as liver and abdomen are reported. However, the IP among the
      reported cases have appeared as solitary masses. A multifocal IP in a 14-year-old
      girl presumed to result following an Entamoeba histolytica infestation is
      reported.

PMID- 10661861
TI  - A chimpanzee millennium.

PMID- 10661860
TI  - Ondine's curse and Hirschsprung's disease: neurocristopathic syndrome.
AB  - We report a female newborn with Ondine's curse and Hirschsprung's disease-
      neurocristopathic syndrome. The female infant required endotracheal intubation
      and mechanical ventilation due to apnea which developed soon after birth. She had
      abdominal distension with bilious vomiting. A barium enema revealed a caliber
      change at the rectum and rectal biopsies showed no ganglion cells. Colostomy was
      performed at the age of 17 days. Hypoxemia with hypercapnia was noted during her
      sleep, and tracheostomy was performed at the age of 55 days. In addition,
      deafness and pupillary autonomic dysfunction were observed. The definitive
      surgery for Hirschsprung's disease was performed at the age of 4 months. She is
      now 2 years old with normal growth but needs ventilator support at home. In this
      case, we detected no mutation in the RET gene and EDNRB gene.

PMID- 10661862
TI  - Molecular genetics of dopa-responsive dystonia.
AB  - The causative genes of two types of hereditary dopa-responsive dystonia (DRD) due
      to dopamine (DA) deficiency in the nigrostriatum DA neurons have been elucidated.
      Autosomal dominant DRD (AD-DRD) was originally described by Segawa as hereditary
      progressive dystonia with marked diurnal fluctuation (HPD). We cloned the human
      GTP cyclohydrolase I (GCH1) gene, and mapped the gene to chromosome 14q22.1-q22.2
      within the HPD/DRD locus, which had been identified by linkage analysis. GCH1
      isthe rate-limiting enzyme for the biosynthesis of tetrahydrobiopterin (BH4), the
      cofactor for tyrosine hydroxylase (TH), which is the first and rate-limiting
      enzyme of DA synthesis. We proved that the GCH1 gene is the causative gene for
      HPD/DRD based on the identification of mutations of the gene in the patients and
      decreases in the enzyme activity expressed in mononuclear blood cells to 2-20% of
      the normal value. About 60 different mutations (missense, nonsense, and
      frameshift mutations) in the coding region or in the exon-intron junctions of the
      GCH1 gene have been reported in patients with AD-DRD all over the world. Recent
      findings indicate that the decreased GCH1 activity in AD-DRD may be caused by the
      negative interaction of the mutated subunit with the wild-type one, i.e., a
      dominant negative effect, and/or by decreases in the levels of GCH1 mRNA and
      protein caused by inactivation of one allele of the GCH1 gene. Autosomal
      recessive DRD (AR-DRD) with Segawa's syndrome was discovered in Germany. The AR
      DRD locus was mapped to chromosome 11p15.5 in the chromosomal site of the TH
      gene. In the AR-DRD with Segawa's syndrome, a point mutation in TH (Gln381Lys)
      resulted in a pronounced decrease in TH activity to about 15% of that of the wild
      type. Several missense mutations in the TH gene have been found in AR-DRD in
      Europe. The phenotype of AR-DRD with the Leu205Pro mutation in the TH gene, which
      produces a severe decrease in TH activity to 1.5% of that of the wild type, was
      severe, not dystonia/Segawa's syndrome, but early-onset parkinsonism. However, a
      marked improvement of all clinical symptoms with a low dose of L-dopa was
      reported in AR-DRD/parkinsonism patients. These findings on DRD indicate that the
      nigrostriatal DA neurons may be most susceptible to the decreases in GCH1
      activity, BH4 level, TH activity, and DA level, and that DRD is the DA deficiency
      without neuronal death in contrast to juvenile parkinsonism or Parkinson's
      disease with DA cell death.

PMID- 10661863
TI  - In vitro transcription of a TATA-less promoter: negative regulation by the Not1
      protein.
AB  - Genetic experiments in the yeast Saccharomyces cerevisiae have identified the
      five Not proteins as global repressors of transcription which preferentially
      repress core promoters which do not contain a canonical TATA sequence. Recently,
      the Ccr4 and Caf1 proteins, required for non-fermentative gene expression, were
      found to be associated with the five Not proteins in 1.2 and 2 MDa Ccr4-Not
      complexes. These Ccr4-Not complexes, as many other global regulators of
      transcription, appear to regulate transcription both positively and negatively in
      vivo. To further characterize the activity of Not1p, the only essential known
      protein of the Ccr4-Not complex, and determine whether it can act directly as a
      transcriptional repressor, we established an in vitro transcription system in
      which the HIS3 TATA-less promoter can be efficiently transcribed. We demonstrate
      that transcription from the HIS3 TATA-less promoter can be specifically increased
      in vitro by preparing nuclear extracts from a conditional mutant of the NOT1 gene
      and analyzing transcription after shifting the nuclear extracts to the
      restrictive temperature. This result is the first demonstration that one of the
      Not proteins directly represses transcription. Moreover, it now defines an
      experimental system in which TATA-less transcription initiation and repression by
      the Ccr4-Not complex can be studied further.

PMID- 10661864
TI  - Fast control of DNA replication in response to hypoxia and to inhibited protein
      synthesis in CCRF-CEM and HeLa cells.
AB  - In order to elucidate whether data about the fast regulation of DNA replication
      in dependence on oxygen supply and on a functioning protein synthesis, previously
      elaborated with Ehrlich ascites cells, are valid for human cells too, we repeated
      key experiments with CCRF-CEM and HeLa cells. The most important techniques
      employed were DNA fibre autoradiography and alkaline sedimentation analyses of
      growing (pulse-labeled) daughter strand DNA. It was found that CCRF-CEM and HeLa
      cells responded to transient hypoxia and to transient inhibition of protein
      synthesis in an almost identical fashion. Scheduled replicon initiations were
      reversibly suppressed and the progress rates of replication forks, which were
      already active before the respective inhibitory conditions were established, were
      reversibly slowed down. The inclusion of the fork progress rate in the response
      differs from Ehrlich ascites cells, which respond only by suppressing initiation.
      Further circumstances of the fast oxygen dependent response, concerning the
      behaviour of ribonucleotide reductase and of the dNTP pools, revealed no
      significant differences among the three cell lines. The striking identity of the
      response of each of the cell lines to hypoxia and to inhibited protein synthesis
      prompts the suspicion that converging fast regulatory pathways act on the
      cellular replication machinery. The phenomena as such seem to be rather
      widespread among mammalian cells.

PMID- 10661865
TI  - The inhibition of NF-kappaB activation pathways and the induction of apoptosis by
      dithiocarbamates in T cells are blocked by the glutathione precursor N-acetyl-L
      cysteine.
AB  - Nuclear factor-kappaB regulates genes that control immune and inflammatory
      responses and are involved in the pathogenesis of several diseases, including
      AIDS and cancer. It has been proposed that reactive oxygen intermediates
      participate in NF-kappaB activation pathways, and compounds with putative
      antioxidant activity such as N-acetyl-L-cysteine (NAC) and pyrrolidine
      dithiocarbamate (PDTC) have been used interchangeably to demonstrate this point.
      We examined their effects, separately and combined, on different stages of the NF
      kappaB activation pathway, in primary and in transformed T cells. We show that
      NAC, contrary to its reported role as an NF-kappaB inhibitor, can actually
      enhance rather than inhibit IkappaB degradation and, most importantly, show that
      in all cases NAC exerts a dominant antagonistic effect on PDTC-mediated NF-kappaB
      inhibition. This was observed at the level of IkappaB degradation, NF-kappaB DNA
      binding, and HIV-LTR-driven reporter gene expression. NAC also counteracted
      growth arrest and apoptosis induced by dithiocarbamates. Antagonistic effects
      were further observed at the level of jun-NH2-terminal kinase, p38 and ATF-2
      activation. Our findings argue against the widely accepted assumption that NAC
      inhibits all NF-kappaB activation pathways and shows that two compounds,
      previously thought to function through a common inhibitory mechanism, can also
      have antagonistic effects.

PMID- 10661866
TI  - Xylose utilisation: cloning and characterisation of the Xylose reductase from
      Candida tenuis.
AB  - Xylose reductases catalyse the initial reaction in the xylose utilisation
      pathway, the NAD(P)H+H+ dependent reduction of xylose to xylitol. In this work,
      the xylose reductase gene from Candida tenuis CBS 4435 was cloned and
      successfully expressed in E. coli. From the purified and partially sequenced
      protein primers were deduced for PCR. The fragment obtained was used for Southern
      blot analysis and screening of a subgenomic library. The clone containing the
      open reading frame was sequenced; the gene consisted of 969 nucleotides coding
      for a 322 amino acids protein with a molecular mass of 36 kDa. Putative
      regulatory signals were identified with the help of a Saccharomyces cerevisiae
      regulatory sequence database. In order to express the xylose reductase in E.
      coli, the gene was placed under positive and negative control. At low
      temperatures, the xylose reductase was expressed in soluble and active form up to
      about 10% of the soluble protein; with rising temperatures formation of visible
      inclusion bodies occurred. In refolding experiments we were able to recover the
      major portion of xylose reductase activity from the pellet fraction.

PMID- 10661867
TI  - Xylose utilisation: cloning and characterisation of the xylitol dehydrogenase
      from Galactocandida mastotermitis.
AB  - We cloned and successfully expressed the gene for xylitol dehydrogenase from
      Galactocandida mastotermitis in Escherichia coli. The amino acid sequence
      revealed that the enzyme belongs to the superfamily of zinc containing, medium
      chain alcohol dehydrogenases. The enzyme catalyses the second step in the xylose
      utilising pathway converting xylose to xylulosephosphate. Xylulose-phosphate is
      further degraded by the transaldolase and transketolase reactions of the pentose
      phosphate pathway. The purified xylitol dehydrogenase from G. mastotermitis was
      subjected to partial amino acid sequence analysis. The resulting amino acid
      information was then used to construct oligonucleotide probes for PCR
      amplification. The PCR product was used to screen a genomic library. The
      identified xdh gene includes one short intron at its 5' end. Putative regulatory
      signals were identified with the help of Saccharomyces cerevisiae regulatory
      sequence databases. An intronless xdh transcript, cloned by RT-PCR, was actively
      expressed in pBTac1 at 37 degrees C to approximately 8% of the soluble E. coli
      protein. Furthermore, the kinetic parameters were determined and conditions were
      found to stabilise the soluble and active protein.

PMID- 10661868
TI  - Thermodynamic properties and DNA binding of the ParD protein from the broad host
      range plasmid RK2/RP4 killing system.
AB  - ParD is a small, acidic protein from the partitioning system of the plasmid
      RK2/RP4. The ParD protein exhibits specific DNA binding activity and, as the
      antidote component of a toxin-antidote plasmid addiction system, ParD forms a
      tight complex in solution with its toxin antagonist, the ParE protein. Unopposed
      ParE acts as a toxin that causes growth retardation and killing of plasmid cured
      cells. ParD negatively autoregulates its expression by binding to an operator
      sequence in the parDE promoter region. This DNA binding activity is crucial for
      the regulation of the relative abundance of toxin and antidote which ultimately
      determines life or death for the bacterial host and its daughter cells. In light
      scattering studies and gel filtration chromatography we observed the existence of
      a stable dimer of ParD in solution. The stoichiometry of ParD-DNA complex
      formation appeared to be 4:1, the molecular mass of the complex was 72.1 kDa. The
      alpha-helical content of ParD as determined by CD-spectrometry was 35%. The
      protein exhibited high thermostability with a T(M) of 64 degrees C and deltaH of
      25 kcal/mol as shown by differential scanning calorimetry. Upon complex formation
      the T(M) increased by 10 degrees C. The thermal unfolding of the ParD protein was
      highly reversible as observed in repeated DSC scans of the same sample. The
      recovery of the native fold was proven by CD-spectroscopy.

PMID- 10661869
TI  - Dipeptidyl peptidase III from rat liver cytosol: purification, molecular cloning
      and immunohistochemical localization.
AB  - Dipeptidyl peptidase III (DPP III) was purified to homogeneity from rat liver
      cytosol. The calculated molecular weight of the purified enzyme was 82845.6
      according to TOF-MS and 82000 on non-denaturing PAGE, and 82000 on SDS-PAGE in
      the absence or presence of beta-mercaptoethanol. These findings suggest that the
      enzyme exists in a monomeric form in rat liver cytosol. The enzyme rapidly
      hydrolyzed the substrate Arg-Arg-MCA and moderately hydrolyzed Gly-Arg-MCA in the
      pH range of 7.5 to 9.5. The Km, k(cat) and k(cat)/Km values of DPP III at optimal
      pH (pH 8.5) were 290 microM, 18.0 s(-1) and 62.1 s(-1) x nM(-1) for Arg-Arg-MCA
      and 125 microM, 4.53 s(-1) and 36.2 s(-1) x nM(-1) for Ala-Arg-MCA, respectively.
      DPP III was potently inhibited by EDTA, 1,10-phenanthroline, DFP, PCMBS and NEM.
      These findings suggest that DPP III is an exo-type peptidase with characteristics
      of a metallo- and serine peptidase. For further information on the molecular
      structure, we screened a rat liver cDNA library using affinity-purified anti-rat
      DPP III rabbit IgG antibodies, determined the cDNA structure and deduced the
      amino acid sequence. The cDNA, designated as lambdaRDIII-11, is composed of 2640
      bp and encodes 738 amino acids in the coding region. Although the enzyme has a
      novel zinc-binding motif, HEXXXH, DPP III is thought to belong to family 1 in
      clan MA in the metalloprotease kingdom. The DPP III antigen was detected in
      significant amounts in the cytosol of various rat tissues by immunohistochemical
      examination.

PMID- 10661870
TI  - Genomic expansion across the albumin gene family on human chromosome 4q is
      directional.
AB  - The albumin gene family arose in a series of duplication events which gave rise
      to symmetry in its structure. The four genes are tandemly linked on human
      chromosome 4q in the order: 5'ALB-5'AFP-5'ALF-5'DBP-centromere, and their introns
      display a symmetrical and repetitive pattern that is shared by members of the
      gene family. These repetitive motifs provide an internal reference, allowing
      observations of evolutionary changes within a single line (human) of evolutionary
      descent. The four genes and three intergenic regions between them increase in
      size as they get closer to the centromere. An invasion by multiple repetitive DNA
      elements may account, in part, for this expansion.

PMID- 10661871
TI  - Comparison of the tamoxifen regulated chimeric Cre recombinases MerCreMer and
      CreMer.
AB  - The site-directed recombinase Cre can be employed to delete or assemble genes in
      the genome of living cells. We have constructed expression vectors for chimeric
      Cre recombinases carrying a mutated hormone binding domain either at the C
      terminus only (CreMer) or at both the N and C-termini (MerCreMer). The chimeric
      Cre proteins can be activated by culturing transfected cells with 4
      hydroxytamoxifen. In transfected embryonic stem (ES) cells, we compared the
      extent of recombination of a floxed gene with the expression levels of the
      chimeric Cre proteins. Our data demonstrate that the bulky MerCreMer protein is
      not less active than the CreMer protein. Thus, the tighter control and low
      background activity of the MerCreMer enzyme is not due to a generally low
      recombinase efficiency.

PMID- 10661872
TI  - The human cathepsin F gene--a fusion product between an ancestral cathepsin and
      cystatin gene.
AB  - Human cathepsin F is a novel papain-like cysteine protease of unknown function.
      Here, we describe the complete human cathepsin F (CTSF) gene which is composed of
      13 exons. In addition to a previous report, two novel upstream located exons
      whose splice sites interrupted the propeptide of cathepsin F within the 'cystatin
      like' domain, recently described by Nagler et al. (Biochem. Biophys. Res. Comm.
      257, 313-318, 1999) were identified. A comparison of the genomic structures
      between this novel part of the cathepsin F gene and those of several cystatin
      genes revealed striking similarities, supporting the hypothesis that the
      cathepsin F gene resulted from a gene fusion between an ancestral cystatin and
      cathepsin gene.

PMID- 10661873
TI  - Characterization of a new member of the TNF family expressed on antigen
      presenting cells.
AB  - The TNF family is involved in the regulation of the immune system, and its
      members have been implicated in a variety of biological events such as apoptosis,
      cell proliferation, differentiation and survival. Here we present a new member of
      the TNF family, tumor necrosis factor superfamily member 20 (TNFSF20) that we
      have identified from the expressed sequence tag (EST) database and characterized.
      The human protein is a 285 amino acid long type II transmembrane protein and is
      19% homologous to TNF in its extra-cellular domain. TNFSF20 is expressed at the
      surface of antigen presenting cells such as cells of the macrophagemonocyte
      lineage and dendritic cells. After treatment with bacterial lipopolysaccharide
      (LPS), TNFSF20 expression is downregulated at the surface of the expresssing
      cells, suggesting that the membrane-bound protein gets cleaved, and that a
      soluble factor is released in the extra-cellular compartment. The soluble form of
      the recombinant TNFSF20 induces proliferation of resting peripheral blood
      monocytes (PBMC) and cell death of activated lymphocytes. TNFSF20 might therefore
      play a critical role in the regulation of cell-mediated immune responses.

PMID- 10661874
TI  - Vascular endothelial growth factor (VEGF) and its receptors in tumor-bearing
      dogs.
AB  - The molecular biology of the angiogenic growth factor, vascular endothelial
      growth factor (VEGF), has been studied in the dog. All major isoforms of VEGF are
      present in the dog. The amino acid sequences are identical between human and dog
      in the loop regions that are responsible for receptor binding. Accordingly, the
      VEGF receptors of dogs and humans are very similar and permit functional exchange
      of the growth factor. Here we show that canine VEGF activates human endothelial
      cells to the same extent as human VEGF. Similarly, the two proteins display
      identical cell binding properties. The VEGF receptor 1 (Flt-1) shows the same
      alternative splicing in humans and dogs and is overexpressed in the majority of
      tumors in both species. VEGF occurs also in canine tumors in similar relative
      quantities as in human malignancies. Based on the literature and our study we
      suggest that the molecular biology and the function of the VEGF signaling system
      are virtually identical in humans and canines and in healthy as well as in
      disease conditions.

PMID- 10661875
TI  - Molecular cloning and characterization of a cDNA encoding a transferrin homolog
      from Bombyx mori.
AB  - We isolated a cDNA representing a message that was strongly induced by injection
      with E. coli in Bombyx mori. The 2160 bp cDNA has an open reading frame of 644
      amino acids and the deduced product a predicted molecular mass of 71 kDa. The
      cDNA sequence shared high homology with the transferrins known so far, and its
      deduced peptide had unique features of transferrins, that is, sites of cystein
      residues and iron binding. We suggest that the B. mori transferrin plays an
      important role in the self-defense system.

PMID- 10661876
TI  - Mitochondria-derived and extra-mitochondrial human type-1 porin are identical as
      revealed by amino acid sequencing and electrophysiological characterisation.
AB  - In mammalian cells porin channels are localised in both mitochondrial outer
      membranes and extra-mitochondrial membranes. We isolated mitochondria-derived
      porin of a human lymphoblastoid B cell line, determined its amino acid sequence
      and characterised its channel properties. Interestingly, the amino acid sequence
      of this porin preparation and, correspondingly, its electrophysiological
      characteristics in a reconstituted system were identical to those of 'Porin
      31HL', the human type-1 porin purified from a crude membrane preparation of the
      same cell line using a different purification protocol. The results raise
      questions about targeting, insertion and orientation of human type-1 porin in
      different membranes.

PMID- 10661877
TI  - Effects of red ginseng saponins and nootropic drugs on impaired acquisition of
      ethanol-treated rats in passive avoidance performance.
AB  - Effects of single and repeated administration of red ginseng total saponins
      (ROTS) and nootropic drugs were examined on impairment of acquisition induced by
      single oral administration of 3 g/kg ethanol (EtOH) in a step through test. The
      inhibitory effect of EtOH on acquisition was significantly reduced following
      single or repeated RGTS administration. The nootropic drugs, piracetam and N
      methyl-D-glucamine, given orally significantly reduced impairment of acquisition
      induced by EtOH. On the other hand, the inhibitory effect of repeated RGTS on the
      EtOH-induced amnesia was blocked by the pretreatment of alpha-methyl-p-tyrosine
      (alpha-MT), an inhibitor of catecholamine synthesis, in a dose-dependent manner
      but not p-chlorophenylalanine (PCPA), an inhibitor of serotonin synthesis,
      whereas the inhibitory effect of repeated N-methyl-D-glucamine on the EtOH
      induced amnesia was blocked neither by alpha-MT nor PCPA. These results suggest
      that repeated RGTS and N-methyl-D-glucamine ameliorate the impairing effect of
      EtOH on acquisition, and the effect of RGTS on EtOH-induced amnesia is dependent
      on the catecholaminergic but not serotonergic neuronal activity, while RGTS and N
      methyl-D-glucamine seem to have a different mechanism on EtOH-induced amnesia.

PMID- 10661878
TI  - Toxic studies on biochemical parameters carried out in rats with Serankottai nei,
      a siddha drug-milk extract of Semecarpus anacardium nut.
AB  - A toxicological study was carried out in rats with a Siddha preparation, milk
      extracts of Semecarpus anacardium nuts. The effect of acute (72 h) and subacute
      (30 days) treatment of the drug with different dosage on liver and kidney
      functions and hematological parameters were studied. The acute toxicity studies
      with this drug did not produce mortality at any dose level given (75-2000 mg/kg
      body weight). No marked adverse alterations were observed in hematological and
      biochemical parameters during the subacute toxicity studies (50, 100, 250 and 500
      mg/kg body weight). In the subacute treatment, the highest dose (500 mg/kg body
      weight) alone showed a moderate increase in the level of blood glucose, plasma
      urea, uric acid, and creatinine. In addition, alteration in lipid profiles were
      observed which may be attributed to the ghee preparation of the drug. Decrease in
      urinary urea, uric acid and creatinine levels were also observed.
      Histopathological examination of vital organs showed normal architecture
      suggesting no morphological disturbances.

PMID- 10661879
TI  - The hypoglycemic activity of Zygophyllum gaetulum extracts in alloxan-induced
      hyperglycemic rats.
AB  - The aqueous infusion of the aerial parts of Zygophyllum gaetulum Emb. and Maire
      was tested orally (1 g/kg body weight) for hypoglycemic activity in alloxan
      induced diabetic rats. The infusion was partitioned between water and butanol to
      yield a butanol soluble fraction (B), and an aqueous fraction (W) which on
      reduction in volume gave a precipitate (WP) and supernatant (WS). Fractions (B)
      and (WP) caused significant reduction in blood glucose concentration, while the
      ingestion of (WS) produced no significant reduction in blood glucose level.

PMID- 10661880
TI  - Hypocholesterolemic effects of crude extract of leaf of Moringa oleifera Lam in
      high-fat diet fed wistar rats.
AB  - The leaves of Moringa oleifera Lam (Moringaceae) are used by the Indians in their
      herbal medicine as a hypocholesterolemic agent in obese patients. The scientific
      basis for their use in hypercholesterolemia was therefore examined. It was found
      that administration of the crude leaf extract of Moringa oleifera along with high
      fat diet decreased the high-fat diet-induced increases in serum, liver, and
      kidney cholesterol levels by 14.35% (115-103.2 mg/100 ml of serum), 6.40% (9.4
      8.8 mg/g wet weight) and 11.09% (1.09-0.97 mg/g wet weight) respectively. The
      effect on the serum cholesterol was statistically significant. No significant
      effect on serum total protein was observed. However, the crude extract increased
      serum albumin by 15.22% (46-53 g/l). This value was also found to be
      statistically significant. It was concluded that the leaves of Moringa oleifera
      have definite hypocholesterolemic activity and that there is valid
      pharmacological basis for employing them for this purpose in India.

PMID- 10661881
TI  - In vitro antimalarial activity of limonoids from Khaya grandifoliola C.D.C.
      (Meliaceae).
AB  - The crude extract from the bark and seeds of Khaya grandifoliola was active in
      vitro against Plasmodium falciparum with an IC50 value of 13.23 microg/ml. The
      extract was purified to obtain seven limonoids--methylangolensate (1), 6
      methylhydroxyangolensate (2), gedunin (3), 7-deacetylkhivorin (5), 1
      deacetylkhivorin (6), swietenolide (7), 6-acetylswietenolide (8)--and one
      flavonoid, catechin (4). Five limonoids (1, 3, 5, 6, 8) were active with IC50
      values between 1.25 and 9.63 microg/ml. Catechin was practically devoid of
      activity. The most active limonoid, gedunin, exhibited an additive effect when
      combined with chloroquine.

PMID- 10661882
TI  - The production of nitric oxide and TNF-alpha in peritoneal macrophages is
      inhibited by Dichroa febrifuga Lour.
AB  - Nitric oxide (NO) and tumor necrosis factor-alpha (TNF-alpha) have been suggested
      to play an important role in endotoxin-mediated shock and inflammation. In this
      study, we investigated the effect of aqueous extract of Dichroa febrifuga Lour.
      (Saxifragaceae) roots, a traditional antimalarial drug, on the production of NO
      and TNF-alpha. The aqueous extract of D. febrifuga roots (AEDF) inhibited the
      secretion of NO and TNF-alpha in lipopolysaccharide (LPS) and/or interferon-gamma
      (IFN-gamma)-stimulated mouse peritoneal macrophages, without affecting cell
      viability. The protein level of inducible nitric oxide synthase (iNOS) in
      peritoneal macrophages was also decreased by AEDF. In addition, the serum level
      of NO was reduced by i.p. administration of AEDF. These results suggest that AEDF
      suppresses the endotoxin-induced inflammatory responses through inhibiting the
      production of NO and TNF-alpha, and could be used as an anti-inflammatory drug.

PMID- 10661883
TI  - Folk use of medicinal herbs of Margalla Hills National Park, Islamabad.
AB  - This paper is based on the results of an ethnobotanical research project
      conducted in Margalla Hills National Park. The inhabitants of the park have
      always used medicinal herbs for various ailments and have for a long time been
      dependent on surrounding plant resources for their food, shelter, fodder, health
      care, and other cultural purposes. However, encroaching industrialisation and the
      accompanying changes in their life styles are responsible for the decrease of
      practice in the local use of herbs for medicine. It is, therefore, felt
      worthwhile to record the native uses of these herbs before the information is
      lost. About 100 informants were interviewed in this regard. In total 50 species
      of herbs belonging to 27 families were recorded as used medicinally by
      inhabitants of the park, among which ten species are being sold in the local
      market. Asparagus adescendens Roxb., and Viola canesence Wall. ex Roxb. are found
      vulnerable to harvesting.

PMID- 10661884
TI  - Antiulcerogenic activity of crude hydroalcoholic extract of Rosmarinus
      officinalis L.
AB  - Rosmarinus officinalis L. crude hydroalcoholic (70%) extract was evaluated for
      antiulcerogenic activity employing different experimental models. The crude
      hydroalcoholic extract (CHE) decreased the ulcerative lesion index produced by
      indomethacin, ethanol and reserpine in rats. No antisecretory activity was
      observed on pyloric ligation model. The previous administration of L-NAME, a NO
      synthase inhibitor, did not reduce the antiulcerogenic activity of CHE in ethanol
      induced ulcer model, suggesting that the pharmacological mechanism has no
      relationship with nitric oxide (NO). Whereas when the animal groups were treated
      with indomethacin, using the same experimental model, CHE did not reduce the
      antiulcerogenic activity, suggesting that the pharmacological mechanism has no
      relationship with prostaglandins. The previous treatment with N-ethymaleimide, a
      thiol blocker, including mucosal nonprotein sulfhydryl groups, reduced the
      anitulcerogenic activity of CHE on ethanol induced ulcer model. This result
      suggests that the crude hydroalcoholic extract of R. officinalis L. has active
      substances that increase the mucosal nonprotein sulfhydryl groups content. In
      another hypothesis, the pharmacological mechanism could be attributed to the
      activity of antioxidant compounds found in the crude hydroalcoholic extract which
      can react with N-ethylmaleimide.

PMID- 10661885
TI  - Antibacterial activity of some folklore medicinal plants used by tribals in
      Western Ghats of India.
AB  - A series of 30 Indian folklore medicinal plants used by tribal healers to treat
      infections, were screened for antibacterial properties at 10 mg/ml concentration
      by using disc diffusion method against Bacillus subtilis, Escherichia coli,
      Klebsiella aerogenes, Proteus vulgaris, Pseudomonas aerogenes and Staphylococcus
      aureus. Twenty plant species showed activity against one or more species of
      bacteria used in this assay; among them the leaf extracts of Cassia occidentalis
      and Cassia auriculata exhibited significant broad spectrum activity against B.
      subtilis and S. aureus. Ten plant species were not found active against all
      tested bacteria. These results were compared with results obtained using standard
      antibiotics, chloramphenicol (30 microg/disc) and streptomycin (30 microg/disc)
      which served as a reference for inhibition zone diameter.

PMID- 10661886
TI  - Protective effects of Orostachys japonicus A. Berger (Crassulaceae) on H2O2
      induced apoptosis in GT1-1 mouse hypothalamic neuronal cell line.
AB  - Oxidative stress is a major cause of neurodegenerative diseases, so the
      protection of neuronal cells from reactive oxygen species can be beneficial for
      the prevention and treatment of these diseases. Methanol extract of Orostachys
      japonicus A. Berger (Crassulaceae), a traditional oriental medical herb, was
      shown to have a protective effect on H2O2-induced apoptosis in GT1-1 mouse
      hypothalamic neuronal cell line which was detected by flow cytometry after
      propidium iodide staining. Among fractions of O. japonicus, chloroform fraction
      had the highest protective effect, and water fraction had no protective effect
      suggesting that the active ingredients might be hydrophobic compounds.

PMID- 10661887
TI  - Antihepatotoxic activity of bergenin, the major constituent of Mallotus
      japonicus, on carbon tetrachloride-intoxicated hepatocytes.
AB  - To determine the antihepatotoxic activity of bergenin from Mallotus japonicus,
      carbon tetrachloride (CCl4)-induced cytotoxicity in primary cultured rat
      hepatocytes has been adopted as an assay system. Bergenin significantly reduced
      the activities of glutamic pyruvic transaminase and sorbitol dehydrogenase
      released from the CCl4-intoxicated hepatocytes. The antihepatotoxicity of
      bergenin was also evidenced by elevating the activities of glutathione S
      transferase and glutathione reductase, and content of glutathione in the CCl4
      intoxicated hepatocytes. From these results, it is assumed that bergenin exerted
      antihepatotoxicity against CCl4-induced cytotoxicity through glutathione-mediated
      detoxification as well as free radical suppressing activity.

PMID- 10661889
TI  - Calpains and muscular dystrophies.
AB  - Calpains are a ubiquitous, well-conserved family of calcium-dependent, cysteine
      proteases. Their function in muscle has received increased interest because of
      the discoveries that the activation and concentration of the ubiquitous calpains
      increase in the mouse model of Duchenne muscular dystrophy (DMD), but null
      mutations of muscle specific calpain causes limb girdle muscular dystrophy 2A
      (LGMD2A). These findings indicate that modulation of calpain activity contributes
      to muscular dystrophies by disrupting normal regulatory mechanisms influenced by
      calpains, rather than through a general, nonspecific increase in proteolysis.
      Thus, modulation of calpain activity or expression through pharmacological or
      molecular genetic approaches may provide therapies for some muscular dystrophies.

PMID- 10661888
TI  - Antinociceptive properties of the methanolic extract obtained from Ipomoea pes
      caprae (L.) R. Br.
AB  - Ipomoea pes-caprae is a medicinal plant used in many countries for the treatment
      of several ailments, including inflammatory and algesic processes. The present
      study describes the antinociceptive effects of the methanolic extract and two
      fractions obtained from aerial parts of this plant. The results indicated that
      both methanolic extract and two fractions (ethyl acetate and aqueous) exhibited
      considerable antinociceptive activity against two classical models of pain in
      mice. Methanolic extract presented a calculated ID50 value of 33.8 mg/kg, i.p.
      against writhing test and also inhibited both phases of pain (neurogenic and
      inflammatory) of the formalin test with ID50 of 37.7 and 12.5 mg/kg, i.p. for the
      first and second phase, respectively. Preliminary phytochemical analysis
      suggested the presence of steroids, terpenoids, alkaloids and flavonoids. These
      findings support, at least in part, the popular use of I. pes-caprae to treat
      dolorous processes.

PMID- 10661890
TI  - Eph receptors and ephrins.
AB  - The Eph receptors are the largest known family of receptor tyrosine kinases. The
      Eph receptors and their membrane-attached ligands, ephrins, show diverse
      expression patterns during development. Recent studies have demonstrated that Eph
      receptors and ephrins play important roles in many developmental processes,
      including neuronal network formation, the patterning of the neural tube and the
      paraxial mesoderm, the guidance of cell migration, and vascular formation. In the
      nervous system, Eph receptors and ephrins have been shown to act as positional
      labels to establish topographic projections. They also play a key role in pathway
      finding by axons and neural crest cells. The crucial roles of Eph receptors and
      ephrins during development suggest involvement of these genes in congenital
      disorders affecting the nervous system and other tissues. It has also been
      suggested that Eph receptors and ephrins may be involved in carcinogenesis. It is
      therefore of clinical importance to further analyse the function of these
      molecules, as manipulation of their function may have therapeutic applications.

PMID- 10661891
TI  - The transport machinery for the import of preproteins across the outer
      mitochondrial membrane.
AB  - In order for proteins to be imported into subcellular compartments, they must
      first traverse the organellar membranes. In mitochondria, hydrophilic protein
      channels in both the outer and inner membranes serve such a purpose. Recently,
      the channel protein of the outer mitochondrial membrane was identified to be
      Tom40. Tom40 is found in a high molecular weight complex termed the general
      import pore (GIP) complex where it is tightly associated with the receptor
      protein Tom22 along with Tom7, Tom6 and Tom5. Tom7 and Tom6 seem to modulate the
      dynamics of the GIP complex while Tom5 is involved in preprotein transfer from
      receptors to Tom40. The receptor proteins Tom70 and Tom20 associate with this
      complex in a weaker manner where they are involved in the initial recognition of
      preproteins. This review focuses on the identification and characterisation of
      the transport machinery of the outer mitochondrial membrane and how they are
      involved in the co-ordination and regulation of events required for the
      translocation of preproteins into mitochondria.

PMID- 10661892
TI  - Molecular mechanisms of extinction: old findings and new ideas.
AB  - Fusion experiments between somatic cells have been used for a long time as a
      means to understand the regulation of gene expression. In hybrids between
      differentiated cells such as hepatocytes or lymphocytes and undifferentiated
      cells such as fibroblasts a phenomenon called extinction has been described. In
      such hybrids expression of cell-specific genes derived from the more
      differentiated parental cell is selectively turned off (extinguished), whereas
      genes expressed from both cells like housekeeping genes remain active after
      fusion. Study of the molecular basis of extinction of the liver-specifically
      expressed tyrosine aminotransferase gene and of the B-cell-specifically expressed
      immunoglobulin genes has revealed that in hybrids the transcriptional program of
      the differentiated cells is reset. This is accompanied by a loss of expression or
      activity of many of the regulatory molecules that were operating in the
      differentiated cells. In the light of new insights in eukaryotic gene regulation
      we speculate that molecular mechanisms such as chromatin remodelling, recruitment
      to heterochromatin or subnuclear localization could underly the extinction
      process.

PMID- 10661893
TI  - Endothelins and the lung.
AB  - Since endothelins were discovered by Yanasigawa in 1988 it has been recognised
      that they may have an important role in lung pathophysiology. Despite their
      biological importance as vasoconstrictors the physiological role of endothelin
      has not yet been defined within the lungs. This review explores their role in
      acute and chronic disease. During acute inflammation and ischaemia-reperfusion
      injury cytokines may induce release of endothelin. This is important in the realm
      of acute lung injury and during surgical procedures such as cardiopulmonary
      operations including lung resections and transplantation. Complications of
      surgery including primary organ failure resulting in poor gas exchange as well as
      increased pulmonary vascular resistance have been linked to the presence of
      excessive endothelin. Endothelin may have an important role in transplantation
      biology. The complex process leading to successful lung transplantation includes
      optimising the donor with brain death, harvesting the lungs, managing acute and
      chronic rejection, and protecting the vital organs from toxic effects of
      immunosuppressants. During chronic disease processes, the mitotic action of
      endothelin may be important in vascular and airway remodelling by means of smooth
      muscle cell proliferation. We also explore recent advances in drug development,
      animal models and future directions for research.

PMID- 10661894
TI  - Isolation and characterization of myotoxin II from Atropoides (Bothrops) nummifer
      snake venom, a new Lys49 phospholipase A2 homologue.
AB  - Myotoxic phospholipases A2 of class II are commonly found in the venoms of
      crotalid snakes. As an approach to understanding their structure-activity
      relationship, diverse natural variants have been characterized biochemically and
      pharmacologically. This study describes a new myotoxic phospholipase A2
      homologue, isolated from the venom of Atropoides (Bothrops) nummifer from Costa
      Rica. A. nummifer myotoxin 1 is a basic protein, with an apparent subunit
      molecular mass of 16 kDa, which migrates as a dimer in sodium dodecylsulfate
      polyacrylamide gel electrophoresis under nonreducing conditions. It is strongly
      recognized by antibodies generated against Bothrops asper myotoxin II, by enzyme
      immunoassay. The toxin induces rapid myonecrosis upon intramuscular injection in
      mice (evidenced by an early increase in plasma creatine kinase activity), and
      significant edema in the footpad assay. It also displays cytolytic activity upon
      cultured murine endothelial cells. The toxin (up to 50 microg) has no detectable
      phospholipase A2 activity on egg yolk phospholipids, and does not show an
      anticoagulant effect on sheep platelet-poor plasma in vitro. N-terminal sequence
      determination (53 amino acid residues) demonstrated that A. nummifer myotoxin II
      is a new Lys49 variant of the family of myotoxic, class II phospholipases A2.
      Sequence comparison with other phospholipases A2 revealed Asn53 as a novel
      substitution. In addition, this myotoxin is the first Lys49 variant presenting
      Asn in its N-terminus. Consequently, these findings suggest that neither Ser1 or
      Lys53, usually found in this family of proteins, are essential amino acid
      residues for their myotoxic, cytolytic, or edema-inducing effects.

PMID- 10661895
TI  - Non-enzymatic lipid peroxidation of microsomes and mitochondria isolated from
      liver and heart of pigeon and rat.
AB  - Studies were carried out to determine the level of ascorbate-Fe2+ dependent lipid
      peroxidation of mitochondria and microsomes isolated from liver and heart of rat
      and pigeon. Measurements of chemiluminescence indicate that the lipid
      peroxidation process was more effective in mitochondria and microsomes from rat
      liver than in the same organelles obtained from pigeon. In both mitochondria and
      microsomes from liver of both species a significant decrease of arachidonic acid
      was observed during peroxidation. The rate C18:2 n6/C20:4 n6 was 4.5 times higher
      in pigeon than in rat liver. This observation can explain the differences noted
      when light emission and unsaturation index of both species were analysed. A
      significant decrease of C18:2 n6 and C20:4 n6 in pigeon liver mitochondria was
      observed when compared with native organelles whereas in pigeon liver microsomes
      only C20:4 n6 diminished. In rat liver mitochondria only arachidonic acid C20:4
      n6 showed a significant decrease whereas in rat liver microsomes C20:4 n6 and
      C22:6 n3 decreased significantly. However changes were not observed in the fatty
      acid profile of mitochondria and microsomes isolated from pigeon heart. In the
      heart under our peroxidation conditions the fatty acid profile does not appear to
      be responsible for the different susceptibility to the lipid peroxidation
      process. The lack of a relationship between fatty acid unsaturation and
      sensitivity to peroxidation observed in heart suggest that other factor/s may be
      involved in the protection to lipid peroxidation in microsomes and mitochondria
      isolated from heart.

PMID- 10661896
TI  - Presenilin-1 protein specifically expressed in Leydig cells with its expression
      level increased during rat testis development.
AB  - Presenilin-1, mutations of which cause the early-onset of Alzheimer's disease,
      was shown to be abundantly expressed in the testis as well as the brain. In spite
      of the high expression level of this protein in the testis, no further analysis
      has been undertaken. We aimed to study the distribution and developmental changes
      in presenilin-1 protein, and to provide clues so as to elucidate the role of this
      protein in the rat testis. To evaluate the specificity of the anti presenilin-1
      antibody, rat presenilin-1 protein was expressed in COS-7 cells and the
      recombinant protein was used for western blot analysis. A positive band of
      approximately 20 kDa corresponding to the C-terminal fragment of proteolyzed
      presenilin-1 protein was observed. Using testis and brain tissue samples, a 20
      kDa band was detected in both tissues suggesting a similar proteolytic process,
      but the expression level in the testis was higher than that in the brain. The
      expression level increased significantly during postnatal testis development. By
      an immunohistochemical analysis of the rat testis, a strong signal was observed
      in interstitial cells and further study with cultured TM3 murine Leydig cells
      revealed an abundant expression of presenilin-1 in Leydig cells. Our study
      suggests that presenilin-1 expression in Leydig cells may play an important role
      in Leydig cell function and testis development.

PMID- 10661897
TI  - Purification and characterization of liver catalase in acatalasemic beagle dog:
      comparison with normal dog liver catalase.
AB  - Catalase from acatalasemic dog liver was purified to homogeneity and its
      properties were compared with those of normal dog liver catalase. The purified
      acatalasemic and normal dog liver catalases were found to have the same molecular
      weight (230,000 Da) and isoelectric point (pI: 6.0-6.2) and both enzymes
      contained four hematins per molecule. The catalytic activity of catalase from
      acatalasemic dog was normal. Furthermore, there was no difference between the
      acatalasemic and normal dog catalases in the binding affinity to NADPH (apparent
      Kd: 0.11-0.12 microM) and in the sensitivity to oxidative stress by hydrogen
      peroxide, the normal substrate of catalase. The acatalasemic dog enzyme was
      stable only in a narrow pH range (pH 6-9) although the normal enzyme was stable
      in a wide pH range (pH 4-10). Acatalasemic dog liver catalase also showed a
      slight low thermal stability at 37 degrees C and the heat-lability was remarkable
      at 45 degrees C, compared to the normal dog enzyme. These results indicated that
      the acatalasemic dog catalase is catalytically normal although it is associated
      with an unstable molecular structure.

PMID- 10661898
TI  - Characterization of two mu class glutathione S-transferases from guinea pig lens.
AB  - Glutathione S-transferase (GST) plays an important role in the detoxifications of
      foreign electrophiles. Two GSTs of class mu from guinea pig lens were purified
      with Sephacryl S-100 gelfiltration, S-Hexyl glutathione Agarose affinity and Q
      Sepharose anion exchange chromatographies. These GSTs (GST-A and B) showed
      similar relative molecular masses of 22.9 and 22.5 kDa, respectively. Two protein
      bands which crossreacted with anti GSTYb1 (GST 3-3) were detected in lens
      cytosolic crude extract on Western blotting and they showed Mrs corresponding to
      the purified enzymes. These GSTs showed a strong resistance against H2O2, 1,2
      naphthoquinone and superoxide anion consistent with the other GSTs in class mu
      from animal tissues.

PMID- 10661899
TI  - Effect of protein-modifying reagents on ecto-apyrase from rat brain.
AB  - We have tested several chemical modifiers to investigate which amino acid
      residues, present in the primary structure of the ecto-apyrase, could be involved
      in catalysis. Synaptosomes from cerebral cortex of rats were prepared and the ATP
      diphosphohydrolase activity was assayed in absence or the presence of the
      modifiers. Percentages of residual activity for ATPase and ADPase obtained when
      the following reagents were tested, are respectively: phenylglyoxal (an arginine
      group modifier) 17 and 30%; Woodward's reagent (a carboxylic group modifier) 33
      and 23%; Koshland's reagent (a tryptophan group modifier) 10 and 12%; maleic
      anhidride (an amino group modifier) 11 and 25% and carbodiimide reagent (a
      carboxylic group modifier) 56 and 72%. Otherwise, PMSF, a seryl protein modifier
      and DTNB, a SH-group modifier did not affect either ATPase or ADPase activity.
      Inhibitions observed after treatment with phenylglyoxal and Woodward's reagent
      were significantly prevented when the synaptosomal fraction was preincubated with
      ATP and ADP, indicating that the arginine and the side chain of glutamate or
      aspartate (carboxyl groups) participate in the structure of the active site. This
      interpretation was confirmed by using GTP and GDP, two other apyrase substrates.
      Phenylglyoxal and Woodward's reagent also inhibited the GTPase and GDPase
      activities and this inhibition was prevented by preincubation with these
      substrates.

PMID- 10661903
TI  - Congenital abnormalities in the United Arab Emirates.

PMID- 10661904
TI  - New genetics of hearing loss.

PMID- 10661905
TI  - Myelocystocele-cloacal exstrophy in a pedigree with a mitochondrial 12S rRNA
      mutation, aminoglycoside-induced deafness, pigmentary disturbances, and spinal
      anomalies.
AB  - A large Filipino-American family with progressive matrilineal hearing loss,
      premature graying, depigmented patches, and digital anomalies was ascertained
      through a survey of a spina bifida clinic for neural crest disorders. Deafness
      followed a matrilineal pattern of inheritance and was associated with the A1555G
      mutation in the 12S rRNA gene (MTRNR1) in affected individuals as well as
      unaffected maternal relatives. Several other malformations were found in carriers
      of the mutation. The proband had a myelocystocele, Arnold-Chiari type I
      malformation, cloacal exstrophy, and severe early-onset hearing loss. Several
      family members had premature graying, white forelock, congenital leukoderma with
      or without telecanthus, somewhat suggestive of a Waardenburg syndrome variant. In
      addition to the patient with myelocystocele, two individuals had scoliosis and
      one had segmentation defects of spinal vertebrae. The syndromic characteristics
      reported here are novel for the mitochondrial A1555G substitution, and may result
      from dysfunction of mitochondrial genes during early development. However, the
      mitochondrial A1555G mutation is only rarely associated with neural tube defects
      as it was not found in a screen of 218 additional individuals with spina bifida,
      four of whom had congenital hearing loss.

PMID- 10661906
TI  - Normal development of the male anterior urethra.
AB  - A histological study was performed on serially sectioned human and mouse embryos
      to study the influences of programmed cell death (PCD) during morphogenesis for
      clarifying the existing controversies on the morphology and basic processes
      involved in the embryonic development of the male anterior urethra. The following
      new insights into the development of the anterior urethra could be established.
      The formation of the urethra starts with the early adhesion of the arms of the
      genital tubercle. In this way an epithelial plate is formed, located in the
      ventral midline, that is in continuity with the cloacal membrane. Male sex
      differentiation takes place following rupture of this cloacal membrane through
      programmed cell death. Fusion of the urogenital swellings with primary
      luminization gives rise to the penile urethra, whereas the glandular part of the
      urethra is formed through secondary luminization of the epithelial cord that is
      formed during fusion of the arms of the genital tubercle, i.e., the glans. In
      both fusion processes, apoptosis plays a key role. The consequence of fusion of
      the urogenital swellings is that their mesodermal cores unite on the ventral
      aspect of the penile urethra, where they differentiate into the integumental
      structures. The prepuce starts to develop as a fold of ectoderm with a mesodermal
      core after complete fusion of the entire urethra. Finally, the scrotum was found
      to develop through merging of the labioscrotal swellings and not by fusion.

PMID- 10661907
TI  - Experimental study of umbilical cord length as a marker of fetal alcohol
      syndrome.
AB  - Umbilical cord length has long been investigated as a potential marker of
      intrauterine events that may place the neonate at risk for future adverse
      developmental sequelae. Experimentally, significantly shortened cords have been
      reported in association with prenatal exposure to common drugs of abuse. This
      study in rats reports the time course of effects on umbilical cord length of a
      daily maternal ethanol gavage (3,200 mg/kg) from gestational day 6 through
      termination of pregnancy at either day 17, 18, 19, or 20. A total of 786 fetuses
      derived from 60 litters were examined. Control fetuses demonstrated a linear
      increase in umbilical cord length and body weight gain during late gestation,
      findings that support previous studies. The body weights of the ethanol-exposed
      fetuses were reduced significantly on all gestational days examined, indicating
      intrauterine growth retardation, a characteristic of fetal alcohol syndrome.
      Similarly, acute fetal akinesia as well as long-term sequelae stemming from
      impaired neurological development would result from the elevated blood ethanol
      levels achieved in this study. The umbilical cords of ethanol-exposed fetuses
      were significantly shorter on gestational days 19 and 20 in comparison to their
      controls, while cord lengths on days 17 and 18 were not shortened significantly.
      A stretch hypothesis has been proposed suggesting that the degree of fetal
      activity is the main determinant of umbilical cord length. In rats, there is a
      physiologic diminution of the volume of amniotic fluid (oligohydramnios) in late
      gestation (day 19 to term), which restricts fetal movements but does not appear
      to alter the linear relationships between gestational age and cord length in
      controls, thus arguing against the stretch hypothesis. However, cord lengths in
      the ethanol-exposed fetuses plateaued in late gestation, suggesting possible
      adherence to a stretch hypothesis. This dichotomy is discussed emphasizing fetal
      growth and activity as well as intrauterine space.

PMID- 10661908
TI  - Hypothesis: thalidomide embryopathy-proposed mechanism of action.
AB  - We propose that thalidomide affects the following pathway during limb
      development: Growth factors (FGF-2 and IGF-I) attach to receptors on limb bud
      mesenchymal cells and initiate some second messenger system (perhaps SP-1), which
      activates alphav and beta3 integrin subunit genes. The resulting alphav beta3
      integrin proteins stimulate angiogenesis in the developing limb bud. Several
      steps in this pathway depend on the activation of genes with primarily GC
      promoters (GGGCGG). Thalidomide, or a hydrolysis or metabolic breakdown product,
      specifically binds to GC promoter sites and inhibits the transcription of those
      genes. Inhibition of the genes interferes with normal angiogenesis, which results
      in truncation of the limb.

PMID- 10661909
TI  - Intelligence and physical features of children of women with epilepsy.
AB  - The teratogenicity of maternal epilepsy has been attributed to several factors,
      including the antiepileptic drugs taken to prevent seizures during pregnancy, the
      occurrence of seizures during pregnancy, and the factors in the mother that
      caused her to have epilepsy. We have addressed the hypothesis that the children
      of women who have a history of epilepsy (seizure history), but who took no
      antiepileptic drugs (AED) and had no tonic-clonic seizures in pregnancy, have an
      increased risk of malformations and diminished intelligence. The frequency of
      cognitive dysfunction was determined in 57 seizure history and 57 matched control
      children aged 6-l6 years. The masked evaluation of the children included a
      physical and neurologic examination and testing with the Wechsler Intelligence
      Scale for Children-Revised (WISC-R) and a systematic physical examination for the
      features of the fetal AED syndrome. The evaluation of both parents of each child
      included a test of reasoning (Ravens Progressive Matrix) and a physical
      examination. There were no differences between the two groups of children in
      either IQ scores or physical features; none of the seizure history children was
      judged to have the "anticonvulsant face" or digit hypoplasia. This study had 80%
      power to rule out a difference of seven or more IQ points between the two groups,
      based on a two-sided test at a 5% level of significance. Our confidence in
      concluding that there was no difference between seizure history and control
      infants was strengthened by the fact that no statistically significant
      differences were observed with respect to multiple outcomes, including eight
      related measures of intelligence. Thirty (53%) of the seizure history mothers
      resumed taking AED after the birth of the child we evaluated. Additional studies
      are needed to address the teratogenicity of the antiepileptic drugs as
      monotherapy.

PMID- 10661910
TI  - Comparison of cleft palate induction by Nicotiana glauca in goats and sheep.
AB  - The induction of cleft palate by Nicotiana glauca (wild tree tobacco) during the
      first trimester of pregnancy was compared between Spanish-type goats and
      crossbred western-type sheep. Cleft palate was induced in 100% of the
      embryonic/fetal goats when their pregnant mothers were gavaged with N. glauca
      plant material or with anabasine-rich extracts from the latter, during gestation
      days 32-41. Seventy-five percent of newborn goats had cleft palate after maternal
      dosing with N. glauca during gestation days 35-41, while no cleft palates were
      induced when dosing periods included days 36-40, 37-39, or day 38 only. The
      induced cleft palates were bilateral, involving the entire secondary palates with
      complete detachment of the vomer. Eleven percent of the newborn goats from does
      gavaged during gestation days 32-41 had extracranial abnormalities, most often
      contractures of the metacarpal joints. Most of these contractures resolved
      spontaneously by 4-6 weeks postpartum. One newborn kid also had an asymmetric
      skull due to apparent fetal positioning. No cleft palates were induced in lambs
      whose mothers were gavaged with N. glauca plant or anabasine-rich extracts during
      gestation days 34-41, 35-40, 35-41, 36-41, 35-51, or 37-50. Only one of five
      lambs born to three ewes gavaged with N. glauca plant material during gestation
      days 34-55 had a cleft palate, but all five of these lambs had moderate to severe
      contractures in the metacarpal joints. The slight to moderate contracture defects
      resolved spontaneously by 4-6 weeks postpartum, but the severe contractures
      resolved only partially. Embryonic/fetal death and resorption (determined by
      ultrasound) occurred in 25% of pregnant goats fed N. glauca compared to only 4%
      of pregnant sheep. Nicotiana glauca plant material contained the teratogenic
      alkaloid anabasine at 0.175% to 0.23%, dry weight, demonstrating that Spanish
      type goats are susceptible to cleft palate induction by the natural toxin
      anabasine, while crossbred western-type sheep are resistant. However, clinical
      signs of toxicity were equally severe in goats and sheep, even though maternal
      alkaloid tolerance was generally lower in sheep. We postulate that an alkaloid
      induced reduction in fetal movement during the period of normal palate closure is
      the cause of the cleft palate and multiple flexion contractures. Teratology
      61:203-210, 2000. Published 2000 Wiley-Liss, Inc.

PMID- 10661911
TI  - Benzofuranyl ureas with potent cardiovascular teratogenicity in rats.
AB  - Studies of embryo-fetal development in rats were conducted with two 5
      lipoxygenase inhibitors. SB-202235 (1,000 mg/kg/day) or SB-210661 (50, 100, or
      500 mg/kg/day) was administered orally by gavage to female rats on days 6-17
      postcoitus (pc) or days 7-16 pc. SB-202235 (1,000 mg/kg/day) and SB-210661 (100
      mg/kg/day) reduced maternal body weight gain for the treatment period by 16% and
      21%, respectively, relative to controls. SB-202235 (1,000 mg/kg/day) or SB-210661
      (50 or 100 mg/kg/day), did not affect numbers of resorptions, dead or live
      fetuses/litter, but 500 mg/kg/day of SB-210661 caused 100% embryo lethality. SB
      202235 (1,000 mg/kg/day) and SB-210661 (50 and 100 mg/kg/day) reduced fetal body
      weight by 15-30% and produced extensive cardiovascular malformations, as well as
      diaphragmatic hernias. SB-210661 also caused thymic abnormalities and
      cryptorchidism. Cardiovascular defects included abnormalities in aorticopulmonary
      septation, the aortic arch, pulmonary trunk, and ventricular septal defects are
      discussed relative to comparable human syndromes of cardiovascular malformation.

PMID- 10661912
TI  - Conduct and interpretation of a dermal developmental toxicity study with KBR 3023
      (a prospective insect repellent) in the Sprague-Dawley rat and Himalayan rabbit.
AB  - KBR 3023, 1-(1-methyl-propoxycarbonyl)-2-(2-hydroxyethyl)piperidine, a
      prospective insect repellent being developed by Bayer Corporation, was evaluated
      for developmental toxicity in the Sprague-Dawley rat and Himalayan rabbit. As the
      intended human usage of the test compound is topical, the test systems were
      exposed to the compound via the dermal route. Specifically, the animals were
      fitted with Elizabethan collars, to reduce the likelihood of oral ingestion, and
      dermally administered either 0, 50, 200, or 400 mg KBR 3023/kg (rat), and 0, 50,
      100, or 200 mg KBR 3023/kg (rabbit) on gestation days 0-19 (rat) and 0-28
      (rabbit). Maternal toxicity, as demonstrated by clinical signs and changes in
      body weight gain and food consumption during gestation, was characterized.
      Animals were sacrificed on gestation day 20 (rat) and 29 (rabbit), at which time
      fetuses were removed by cesarean section and a gross maternal necropsy was
      performed. All fetuses were evaluated for external anomalies. With rats,
      approximately half of each litter was examined for visceral effects; the other
      half underwent a skeletal examination. With rabbits, all fetuses underwent both
      visceral and skeletal examinations. No effects were observed on maternal body
      weight gain or food consumption in either the rat or rabbit. In the rat, dermal
      effects (scaling/sloughing), were observed at the dose site of all test substance
      treated groups from approximately gestation day 7 until termination of the study.
      Also noted were an increase in both absolute and relative liver weights in rats
      in the 400-mg/kg dose group. In the rabbit, dermal effects (slight erythema,
      squamous and cracked skin) were noted at the dose site of virtually all does
      administered the test compound, from approximately gestation day 7 until
      termination. Also observed in the rabbits was a potentially compound-related
      increase in soft stool, particularly at the highest dose level. In both species,
      there were no statistically significant effects on any reproductive parameters,
      or any embryonic endpoints, including pre/post-implantation loss and resorptions.
      There were no statistically significant effects on litter size or fetal or
      placental weights. No test compound-related external, visceral, or skeletal
      findings were observed. No effect on the individual fetal or litter incidence of
      total malformations or variations was observed and there was no difference in the
      incidence of malformations between males and females. KBR 3023 Technical,
      administered as described in these studies, produced maternal effects in the rat
      (liver weight) at a dose of 400 mg/kg, and in the rabbit (soft stool) in the 200
      mg/kg dose group. No developmental toxicity was observed at any dose level.

PMID- 10661914
TI  - Erratum: Does aluminum exposure of pregnant animals lead to accumulation in
      mothers of their offspring?
AB  - Borak J, Wise JP. 1998. Does aluminum exposure of pregnant animals lead to
      accumulation in mothers of their offspring? Teratology 57:127-139 In response to
      the article referenced above, Drs. M. Golub and J. Domingo wrote a Letter to the
      Editor (Teratology 1998;58:225). Included in that letter was the following
      statement: "We also urge Drs. Borak and Wise to fulfill their ethical obligation
      to acknowledge sources of support when submitting manuscripts for publication."
      This comment would not have been necessary if the article by Borak and Wise had
      included an acknowledgment of their outside support in their article. The authors
      had disclosed this outside support in the cover letter to the editor when the
      manuscript was supplied initially and later after revisions. They did not include
      an Acknowledgment section in the manuscript. The editorial office should have
      suggested that they do that. We apologize for any confusion this caused.

PMID- 10661913
TI  - Microsatellites proximal to leptin and leptin receptor as risk factors for spina
      bifida.
AB  - Several recent studies have observed an association between neural tube defect
      risk and prepregnant obesity. This association was generally stronger for spina
      bifida and was observed irrespective of additional maternal factors, including
      periconceptional intake of vitamin supplements. Other studies have identified
      mutations within the genes that code for leptin (LEP) and its receptor (LEPR),
      which have been linked to obesity in mice and humans. We investigated the
      potential association between nucleotide variation at the LEP and LEPR loci, and
      increased risk of spina bifida. We searched specifically for allelic association
      at a pair of highly polymorphic microsatellites closely linked to either the LEP
      or LEPR gene. Data were derived from a population-based case-control study that
      had previously identified an association between a woman's prepregnant obesity
      and her risk of delivering an infant with spina bifida. A total of 56 spina
      bifida case infants and 126 nonmalformed control infants were genotyped for 10
      microsatellite alleles closely linked to the LEP gene, and 49 cases and 125
      controls were genotyped for 10 microsatellite alleles closely linked to the LEPR
      gene. In general, alleles were not observed to be exclusively associated with
      substantially greater spina bifida risk in the body mass index (BMI) category
      (obese) of >29 kg/m(2) compared with the BMI category (nonobese) of </=29
      kg/m(2). Thus, these particular infant allelic variants did not appear to explain
      the previously reported elevated risk observed for women whose prepregnant BMI
      exceeded 29 kg/m(2). A modest elevated spina bifida risk, irrespective of
      maternal BMI, was observed for two LEP microsatellite alleles (257 and 271).
      These estimates, however, were imprecise. Compared with those infants who did not
      have either of these alleles and whose mother's prepregnant BMI was </=29
      kg/m(2), we computed odds ratios for (1) having either the 257 or 271 allele and
      maternal BMI >29 kg/m; (2) having either allele and BMI </=29 kg/m(2); and (3)
      not having either allele but BMI >29 kg/m(2). The odds ratios (95% confidence
      interval) for these comparisons were: for allele 257, 4.5 (1.1-19.4), 1.9 (0.5
      6.3), and 2.9 (1.3-6.4), respectively, and for allele 271, 6.7 (1.6-30.4), 2.7
      (0.7-10.9), and 2.7 (1.2-5.9), respectively. Owing to the exploratory nature of
      this investigation, the significance of these latter results is unclear.

PMID- 10661915
TI  - Quality management begins with health care credentialing. Alabama Association
      Medical Staff Services.

PMID- 10661916
TI  - Physician recruitment 101: beginning a program for your hospital.

PMID- 10661917
TI  - Legal tips for recruiting physicians.

PMID- 10661918
TI  - Looking ahead through the eyes of the pros.

PMID- 10661919
TI  - Senior moments.

PMID- 10661920
TI  - The buyer's guide to Congress.

PMID- 10661921
TI  - Hot genes for sale? A website offers eggs--but maybe just for browsing. Interview
      by Michael D. Lemonick; news.

PMID- 10661922
TI  - Can I live to be 125?

PMID- 10661923
TI  - Can we forget about Alzheimer's?

PMID- 10661924
TI  - What will happen to alternative medicine?

PMID- 10661925
TI  - When will we cure cancer?

PMID- 10661926
TI  - And will we ever cure AIDS?

PMID- 10661927
TI  - Will Christopher Reeve walk again?

PMID- 10661928
TI  - What new things are going to kill me?

PMID- 10661929
TI  - Will we keep getting fatter?

PMID- 10661930
TI  - If we're all a little pudgier in 2025, so what?

PMID- 10661931
TI  - Got any good drugs?

PMID- 10661932
TI  - Will robots make house calls?

PMID- 10661933
TI  - And will they go inside us?... the promise of nanotechnology.

PMID- 10661934
TI  - Can I grow a new brain?

PMID- 10661935
TI  - Can I replace my body?

PMID- 10661936
TI  - Block that cold! A new zinc nasal spray may curtail your sniffles, but hand
      washing is still your best defense.

PMID- 10661937
TI  - Holy owned. Is it fair for a Catholic hospital to impose its morals on patients?

PMID- 10661938
TI  - The PPMs: what happened? what's next?

PMID- 10661939
TI  - Testing strategies for building member loyalty in a managed care organization
      serving Medicare beneficiaries.
AB  - Member retention has been a challenge for Medicare HMOs. This article describes
      how a hybrid Medicare HMO is testing methods of strengthening member loyalty and
      member retention. Methods include managing member expectations and involving
      sales representatives and Personal Care Planner in outreach to new members. An
      early problem detection project yielded information that was used to resolve
      member difficulties and preempt disenrollment.

PMID- 10661940
TI  - Has managed care changed the skills required for physicians to practice medicine?
AB  - Are the skills taught in medical school sufficient for running a practice under
      managed care? Of 784 physicians randomly sent a questionnaire posing this and
      other questions, 94 percent agreed that managed care has changed the
      constellation of skills needed by physicians. Specifically useful to know are
      business administration skills, said 89 percent; and 59 percent felt business
      administration skills would directly enhance patient treatment.

PMID- 10661941
TI  - A hitchhiker's guide to competitive managed care.
AB  - Competition among managed care plans features the dynamic interaction among three
      primary forces: delivery system integration, managed care health plan risk
      sharing, and purchaser activism. To evaluate the cost containment potential for a
      particular market, decision makers need to understand the character of provider
      integration, the role of managed care insurance plans, and the extent of
      purchaser activism in contracting with health care providers. This paper provides
      benchmarks that analysts can use to assess markets, and applies them to the four
      largest markets in Wisconsin. It concludes that competition among managed care
      plans can lead to cost-effective care only if purchasers respond to differences
      in cost, for given quality, by switching from high-priced plans to lower-priced
      ones.

PMID- 10661942
TI  - MCOs--you're using the wrong benefits!
AB  - If managed care organizations (MCOs) think of the benefits they offer and deliver
      in terms of narrow insurance coverage and limited payments for carefully
      circumscribed lists of health services, they miss the boat in marketing to
      consumers. Only by identifying, promising, delivering, and ensuring that
      consumers perceive core psychological benefits--a sense of security against
      catastrophic illness, assurance of access to necessary care, and the positive
      impacts on quality of life that health care can create--will MCOs realize the
      full potential of the real benefits consumers are after.

PMID- 10661943
TI  - What is quality, who wants it, and why?
AB  - The health services literature is replete with examples of the failure of total
      quality management to produce significant change in organizational performance.
      Some authors suggest that incremental quality improvement be abandoned in favor
      of structural reengineering. However, these naysayers ignore the critical impact
      of environmental change, managed care, and customer service as primary
      organizational drivers that demand an enhanced focus on continuous quality
      improvement. Coupled with these factors is the movement towards the creation of
      learning organizations. At the core of any learning organization is a commitment
      to quality and the empowerment of employees to identify and improve quality.

PMID- 10661944
TI  - Consumer education: the silent but deadly impact of the BBA.

PMID- 10661945
TI  - Idealized design of clinical office practice: an interview with Donald Berwick
      and Charles Kilo of the Institute for Healthcare Improvement.

PMID- 10661946
TI  - Formation of medical and hospital groups.
AB  - The first impression of most physicians and hospitals when dealing with managed
      care companies (MCOs) is that the size or "bigness" of the MCO is a major factor
      in the success of the MCO in negotiating contracts. This is only true to a
      degree. Physicians and hospitals have developed a tendency to make an unqualified
      bolt to also be "big", to put themselves on a more equal negotiating footing with
      MCOs. They should consider first the circumstances associated with organizational
      growth that lead to an effective outcome versus those that lead to failure.
      Effective outcomes happen because local market share can be controlled;
      management data systems that work are in place; and senior management has depth
      as well as maturity.

PMID- 10661947
TI  - Privacy regulations revert to HHS while Congress works on other issues.

PMID- 10661948
TI  - Health plans' financial instability presents new regulatory challenges.

PMID- 10661949
TI  - Compensation monitor. Meet capitation at least halfway.

PMID- 10661950
TI  - Health care mergers and acquisitions. Bigger: not always better.

PMID- 10661951
TI  - California physicians struggling--problems ahead for other states?

PMID- 10661952
TI  - Managed care's West Coast champion. Interview by Patrick Mullen.

PMID- 10661953
TI  - Will palm-size computers make electronic prescribing happen?

PMID- 10661954
TI  - Should physician entrepreneurs be held to professional standards?

PMID- 10661955
TI  - Disputes between physicians and plans can be settled without costly litigation.

PMID- 10661956
TI  - Managed care outlook. Variance in Medicare pharmacy benefits is wide.

PMID- 10661957
TI  - Peninsula Hospital Center: stretching support over the continuum.

PMID- 10661958
TI  - Win/win partnership serves dementia population.

PMID- 10661959
TI  - Supporting caregivers by teleconference.

PMID- 10661961
TI  - Options in caregiver program design: examples from the United Hospital Fund
      family caregiving grant initiative.

PMID- 10661960
TI  - Ongoing needs assessment strengthens family caregiver programs.

PMID- 10661962
TI  - Managed care in the millennium. New forecast for the "five stages of managed
      care".

PMID- 10661963
TI  - Reinventing managed care on a collaborative "Stage 6" model.

PMID- 10661964
TI  - Updating the "five stages of managed care".

PMID- 10661965
TI  - Where will you be in the new millennium? Six questions to guide your career
      exploration.

PMID- 10661966
TI  - Grassroots discussion groups on ethics.

PMID- 10661967
TI  - Management insecurity.

PMID- 10661968
TI  - Carbohydrate counting. Tips for simplifying diabetes education.

PMID- 10661969
TI  - The role of the clinical compliance coordinator in long-term care.

PMID- 10661970
TI  - Skilled nursing. Can't we go smoke-free?

PMID- 10661971
TI  - Assisted living administrators need broad range of skills for 2000.

PMID- 10661972
TI  - Generational warfare: winning the workforce battle of the next millennium.

PMID- 10661973
TI  - New reports spotlight inadequacies of PPS.

PMID- 10661974
TI  - Trends ... predictions ... what's ahead ... for Y2K and beyond.

PMID- 10661975
TI  - Making the mind-body connection improves DM efforts.

PMID- 10661976
TI  - DM program cuts back pain costs by educating, supporting primary care physicians.
AB  - Right behind the common cold, low back pain is the second leading reason why
      people go to the doctor's office. But nine times out of 10, the pain will resolve
      on its own. Discover how a combination of practice guidelines and a special spine
      clinic to address unresolved back pain work to create better clinical and
      financial outcomes for one major health plan.

PMID- 10661977
TI  - California law poses serious threat to DM programs.
AB  - California legislators have sent shock waves through the disease management
      community with laws that require physician authorization for DM enrollment. Find
      out what the new laws say and how federal regulations due soon may--or may not-
      counter this setback.

PMID- 10661978
TI  - California's 21 new healthcare laws sting DM programs.

PMID- 10661979
TI  - Develop policies and procedures to protect medical record privacy.

PMID- 10661980
TI  - Type II diabetes no longer just an adult disease.
AB  - We keep hearing that our kids--the TV and junk food generation--are increasingly
      overweight. Now come two studies that show these obese teens are being diagnosed
      with Type II diabetes, a disease rarely seen in people under 40 just 10 years
      ago. Find out why diabetes experts think the disease is spreading to children,
      and what you can do about it.

PMID- 10661981
TI  - Perspectives. Safety-net providers surviving, but dependence on subsidies is
      ominous.

PMID- 10661982
TI  - Physicians and nursing facilities: considering Stark.

PMID- 10661983
TI  - Gainsharing: a eulogy?

PMID- 10661984
TI  - Physician group practice implications under the proposed Stark II regulations.

PMID- 10661985
TI  - Developing disease management programs.
AB  - Several market forces are driving interest in disease management and its growth,
      including the need to control costs; improve quality; attract, satisfy, and
      retain members; and meet accreditation requirements. People with chronic diseases
      and disabilities represent the most expensive and fastest-growing group of
      patients in health care, and agencies that develop successful disease management
      programs for these populations will reap a variety of benefits.

PMID- 10661986
TI  - Managing asthma: a pediatric program that works.
AB  - Valley Home Care (VHC) in Paramus, New Jersey has committed resources and staff
      to creating an effective pediatric asthma management program. Agencies
      considering similar programs can benefit from learning about how VHC achieved
      success with its community and home asthma management program (CHAMP).

PMID- 10661987
TI  - Benchmarking in home health care: a collaborative approach.
AB  - Benchmarking outcome data and constructing "best practices" to meet patient care
      needs are emerging trends and new mandates on the horizon in home care. The
      Arizona Association for Home Care Continuous Quality Improvement Forum embarked
      on a journey to develop standards to define and monitor urinary tract infections
      in the home. A collaborative process among six home care agencies allowed for
      comparison of urinary tract infection rates and a beginning step toward
      establishing benchmarking standards in home care.

PMID- 10661988
TI  - Task force studies. Infection rates, surgical site management, & foley catheter
      infections.
AB  - The Florida Hospital Association established a task force to create standard
      definitions and criteria for infections in home care. In addition, among other
      goals, the task force wanted to increase awareness among practitioners that home
      health is part of the health care continuum and all aspects of care, including
      infection control. The task force studied site-specific infection rates, surgical
      site management, and foley catheter infections.

PMID- 10661989
TI  - Celebrating National Home Care Aide Week.

PMID- 10661990
TI  - Reaching out ... through communication.

PMID- 10661991
TI  - New report documents improvement in Americans' health--Healthy People 2000.

PMID- 10661992
TI  - Giving thanks.

PMID- 10661993
TI  - Preventing and controlling the transmission of antibiotic-resistant
      microorganisms in the home care setting.
AB  - Antibiotic-resistant microorganisms can spread to other home care patients by an
      infected or colonized patient receiving home care services and the home care
      staff member unknowingly carrying it to another home care patient's home.
      Controlling the transmission of antibiotic-resistant microorganisms is the
      primary responsibility of those providing direct patient care. The ultimate goal
      for home care is to prevent staff colonization and cross-contamination to other
      home care patients.

PMID- 10661995
TI  - Two new asset management systems.

PMID- 10661994
TI  - Rethinking construction.

PMID- 10661996
TI  - Sensitive lighting for intensive care.

PMID- 10661997
TI  - Engineering for the operating room of the year 2010.

PMID- 10661998
TI  - Mobile accident treatment trailer.

PMID- 10661999
TI  - Special sockets for special locations? An approach to Section 607 BS 7671 1992
      (AMD 9871).

PMID- 10662000
TI  - How process enterprises really work.
AB  - Many companies have succeeded in reengineering their core processes, combining
      related activities from different departments and cutting out ones that don't add
      value. Few, though, have aligned their organizations with their processes. The
      result is a form of cognitive dissonance as the new, integrated processes pull
      people in one direction and the old, fragmented management structures pull them
      in another. That's not the way it has to be. In recent years, forward-thinking
      companies like IBM, Texas Instruments, and Duke Power have begun to make the leap
      from process redesign to process management. They've appointed some of their best
      managers to be process owners, giving them real authority over work and budgets.
      They've shifted the focus of their measurement and compensation systems from unit
      goals to process goals. They've changed the way they assign and train employees,
      emphasizing whole processes rather than narrow tasks. They've thought carefully
      about the strategic trade-offs between adopting uniform processes and allowing
      different units to do things their own way. And they've made subtle but
      fundamental cultural changes, stressing teamwork and customers over turf and
      hierarchy. These companies are emerging from all those changes as true process
      enterprises--businesses whose management structures are in harmony, rather than
      at war, with their core processes. And their organizations are becoming much more
      flexible, adaptive, and responsive as a result.

PMID- 10662001
TI  - Philanthropy's new agenda: creating value.
AB  - During the past two decades, the number of charitable foundations in the United
      States has doubled while the value of their assets has increased more than
      1,100%. As new wealth continues to pour into foundations, the authors take a
      timely look at the field and conclude that radical change is needed. First, they
      explain why. Compared with direct giving, foundations are strongly favored
      through tax preferences whose value increases in rising stock markets. As a
      nation, then, we make a substantial investment in foundation philanthropy that
      goes well beyond the original gifts of private donors. We should therefore expect
      foundations to achieve a social impact disproportionate to their spending. If
      foundations serve merely as passive conduits for giving, then they not only fall
      far short of their potential but also fail to meet an important societal
      obligation. Drawing on Porter's work on competition and strategy, the authors
      then present a framework for thinking systematically about how foundations create
      value and how the various approaches to value creation can be deployed within the
      context of an overarching strategy. Although many foundations talk about
      "strategic" giving, much current practice is at odds with strategy. Among the
      common problems, foundations scatter their funding too broadly, they overlook the
      value-creating potential of longer and closer working relationships with
      grantees, and they pay insufficient attention to the ultimate results of the work
      they fund. This article lays out a blueprint for change, challenging foundation
      leaders to spearhead the evolution of philanthropy from private acts of
      conscience into a professional field.

PMID- 10662002
TI  - The lure of global branding.
AB  - As more and more companies begin to see the world as their market, brand builders
      look with envy upon those businesses that appear to have created global brands-
      brands whose positioning, advertising strategy, personality, look, and feel are
      in most respects the same from one country to another. Attracted by such high
      profile examples of success, these companies want to globalize their own brands.
      But that's a risky path to follow, according to David Aaker and Erich
      Joachimsthaler. Why? Because creating strong global brands takes global brand
      leadership. It can't be done simply by edict from on high. Specifically,
      companies must use organizational structures, processes, and cultures to allocate
      brand-building resources globally, to create global synergies, and to develop a
      global brand strategy that coordinates and leverages country brand strategies.
      Aaker and Joachimsthaler offer four prescriptions for companies seeking to
      achieve global brand leadership. First, companies must stimulate the sharing of
      insights and best practices across countries--a system in which "it won't work
      here" attitudes can be overcome. Second, companies should support a common global
      brand-planning process, one that is consistent across markets and products.
      Third, they should assign global managerial responsibility for brands in order to
      create cross-country synergies and to fight local bias. And fourth, they need to
      execute brilliant brand-building strategies. Before stampeding blindly toward
      global branding, companies need to think through the systems they have in place.
      Otherwise, any success they achieve is likely to be random--and that's a fail
      safe recipe for mediocrity.

PMID- 10662003
TI  - Stock or cash? The trade-offs for buyers and sellers in mergers and acquisitions.
AB  - In 1988, less than 2% of large deals were paid for entirely in stock; by 1998,
      that number had risen to 50%. The shift has profound ramifications for
      shareholders of both the acquiring and acquired companies. In this article, the
      authors provide a framework and two simple tools to guide boards of both
      companies through the issues they need to consider when making decisions about
      how to pay for--and whether to accept--a deal. First an acquirer has to decide
      whether to finance the deal using stock or pay cash. Second, if the acquirer
      decides to issue stock, it then must decide whether to offer a fixed value of
      shares or a fixed number of them. Offering cash places all the potential risks
      and rewards with the acquirer--and sends a strong signal to the markets that it
      has confidence in the value not only of the deal but in its own stock. By issuing
      shares, however, an acquirer in essence offers to share the newly merged company
      with the stockholders of the acquired company--a signal the market often
      interprets as a lack of confidence in the value of the acquirer's stock. Offering
      a fixed number of shares reinforces that impression because it requires the
      selling stockholders to share the risk that the value of the acquirer's stock
      will decline before the deal goes through. Offering a fixed value of shares sends
      a more confident signal to the markets, as the acquirer assumes all of that risk.
      The choice between cash and stock should never be made without full and careful
      consideration of the potential consequences. The all-too-frequent disappointing
      returns from stock transactions underscore how important the method of payment
      truly is.

PMID- 10662004
TI  - The successor's dilemma.
AB  - Botched leadership transitions occur with alarming frequency--a fact that's laid
      bare regularly in the business pages of the nation's newspapers. The headlines
      trumpet the premature departures of designated successors--leaders such as
      Merrill Lynch's Herb M. Allison and AT&T's John Walter, who left their respective
      companies before they could claim the CEO's seat. Dan Ciampa and Michael Watkins,
      who have counseled senior executives and successors through more than 100
      leadership transitions in the past 25 years, point to the successor's dilemma as
      the dominant cause of failed leadership transitions. The dilemma is an
      emotionally charged power struggle played out between the CEO and his would-be
      heir. Ciampa and Watkins describe the way the problem builds on both sides of the
      desk--the CEO's fear of giving up control versus the designated successor's need
      to enact the changes expected of him and prove himself to the board. They cite
      anecdotal evidence and their own research to suggest that this complex
      psychological dynamic leads CEO-successor relations astray and can block the
      successor's path to the top spot. But the authors also offer four ways for the
      would-be heir to overcome the successor's dilemma. These include gauging the
      CEO's readiness to leave before accepting the number two spot, maintaining
      regular communication with the CEO despite ever-present obstacles such as travel
      and business schedules, and developing and using a balanced personal advice
      network to help navigate the shift in power. The authors stress that defusing the
      problem is the responsibility of the successor, not the CEO. The reason is
      simple: the successor has the most to lose.

PMID- 10662005
TI  - The strategic power of saying no.
AB  - Susan Bishop started Bishop Partners with the aim of making it the best boutique
      executive-search firm in the business. Specializing in television, radio, and
      publishing industries, her plan was to beat out her larger, established
      competitors through superb execution. Great service would lead to happy clients,
      which would lead to more business, which would keep clients happy, which would
      lead to even more business. A virtuous circle, right? Wrong. Before long, she and
      her staff grew weary of jumping through every hoop their clients could think of-
      trying to find candidates for lower-level positions in remote locations at below
      market rates, for instance. But what could they do? How could they afford to
      disappoint any customer when they didn't have that many to begin with? In this
      vivid first-person account, Bishop describes how she and her staff came to an
      answer that was highly counterintuitive: stop trying to make everyone happy.
      Focus instead on making the right customers happy. Raise their prices. Limit
      their searches to high level positions in their field of expertise. Stick to
      companies big enough to give them repeat business. As hard as it was to define
      the right clients, it was even harder to say no to the wrong clients. One member
      of the staff had to turn down work worth $120,000; Bishop herself had to turn
      down $250,000 from her largest client, Coca-Cola. But in the end, those clients
      came back with higher-quality work, and her company was on its way from chaotic
      little start-up to successful, professional enterprise. Bishop tells the classic
      entrepreneur's story, one with important lessons about strategy making, courage,
      and discipline for all businesspeople.

PMID- 10662006
TI  - Working on nonprofit boards. Don't assume the shoe fits.
AB  - Contrary to popular perception, businesspeople can be benevolent. For instance,
      one recent study notes that four-fifths of all Harvard Business School graduates
      are involved with nonprofits, with more than half of those serving on boards.
      Most business professionals will spend some time on a nonprofit board. That's the
      good news, the author says. The bad news is that the involvement of
      businesspeople can easily backfire. That's because they often try to take what
      they have learned from business school and the corporate world and apply it to
      their duties in the nonprofit sector. On the surface, there are similarities
      between the for-profit and nonprofit sectors. Both have boards of directors,
      trustees and chairpeople, regular meetings, and so forth. But the governance of
      nonprofit organizations is very different from the governance of for-profit
      businesses in several critical areas, including missions, measurements, and board
      composition. For instance, the CEO in the nonprofit world must manage a
      relationship with a nonexecutive board chair. In the for-profit world, the CEO is
      the chair. Such significant differences make it difficult to transfer ideas and
      practices between the for-profit and nonprofit worlds. In this article, F. Warren
      McFarlan describes the main differences between serving on a for-profit board and
      serving on a nonprofit board. As he points out, understanding the differences
      will make it easier for businesspeople to move smoothly from one environment to
      the other and will therefore make their commitments more effective. Nonprofits
      need businesspeople, but only on the right terms.

PMID- 10662007
TI  - Getting real about virtual commerce.
AB  - In its first generation, electronic commerce has been a landgrab. Space on the
      Internet was claimed by whoever got there first with enough resources to create a
      credible business. It took speed, a willingness to experiment, and a lot of
      cybersavvy. Companies that had performed brilliantly in traditional settings
      seemed hopelessly flat-footed on the Web. And despite their astronomical
      valuations, the new e-commerce stars have appeared to be just as confused. Many
      have yet to make a profit, and no one has any idea when they will. Now, the
      authors contend, we are entering the second generation of e-commerce, and it will
      be shaped more by strategy than by experimentation. The key players--branded
      goods suppliers, physical retailers, electronic retailers, and pure navigators-
      will shift their attention from claiming territory to defending or capturing it.
      They will be forced to focus on strategies to achieve competitive advantage.
      Success will go to the businesses that get closest to consumers, the ones that
      help customers navigate their way through the Web. Indeed, the authors argue,
      navigation is the battlefield on which competitive advantage will be won or lost.
      There are three dimensions of navigation: Reach is about access and connection.
      Affiliation is about whose interests the business represents. And richness is the
      depth of the information that a business gives to or collects about its
      customers. Navigators and e-retailers have the natural advantage in reach and
      affiliation, while traditional product suppliers and retailers have the edge in
      richness. The authors offer practical advice to each player on competing in the
      second generation of e-commerce.

PMID- 10662009
TI  - Y2K security problems: January 1 is just the beginning, experts warn.

PMID- 10662008
TI  - The new economy is stronger than you think.
AB  - Many policy makers at the Fed contend that the new economy is a fragile bubble-
      and that with the "irrational exuberance" of the capital markets, the sky is
      going to fall on the U.S. economy. That couldn't be further from the truth,
      according to William Sahlman. As long as the government doesn't interfere, he
      argues, the economy is sturdy, resilient, and raring to grow. The new economy is
      strong for several reasons. First, it is based on a business model that works.
      Any business system that relentlessly drives out inefficiency, forces intelligent
      business-process reengineering, and gives customers more of what they want will
      be sustainable. Second, it is built on America's admiration for entrepreneurs and
      its tolerance for failure, not to mention its easy access to capital. Third, the
      new economy is attracting the best and brightest minds in the country. And
      finally, says Sahlman, the new economy is strong because it is spreading. It may
      be primarily an American phenomenon now, but in a few short years it will start
      to show its effects everywhere, making the whole world a more productive place.
      Still, Sahlman believes, the road ahead is not without potholes and sharp curves.
      But that is what the new economy is all about, he maintains--companies attacking
      the status quo and entrenched players, companies experimenting to find new
      technologies that improve or replace earlier ones. Such activity presents no
      cause for alarm. The economic, social, and cultural factors undergirding the new
      economy are rock solid. It's simply a matter of letting them stand.

PMID- 10662010
TI  - President-elect: what IAHSS and hospital security can expect after Y2K.

PMID- 10662011
TI  - Paul Steiner on converting from in-house to contract security.

PMID- 10662012
TI  - VAs test smart cards for security, employee ID, cashless transfers.

PMID- 10662013
TI  - Reducing employee injuries through preventing at-risk behaviors: how to make such
      programs work.
AB  - Hospitals that have adopted successful "behavior-based" programs aimed at
      reducing employee injuries and preventing at-risk behaviors find that enlisting
      worker support is key to the effectiveness of such efforts. In this report, we'll
      present the experiences of officials at two medical centers in successfully
      reducing and preventing injuries. We'll also provide some guidance from
      psychologists and employee safety experts on ways to approach the problem.

PMID- 10662014
TI  - A new challenge for security: meeting special needs of off-site clinics.

PMID- 10662015
TI  - Price survey. Pacemaker deals keeping prices in line.

PMID- 10662016
TI  - Catching overpayments requires an eagle eye.

PMID- 10662017
TI  - Food service offers menu of cost savings.

PMID- 10662019
TI  - Emergency generator testing requirements revised.

PMID- 10662018
TI  - Government releases hospital quality oversight report.

PMID- 10662020
TI  - National safety partnership urges adoption of best practices.

PMID- 10662021
TI  - Joint Commission receives federal recognition for hospices.

PMID- 10662022
TI  - New standards to assess and manage pain.

PMID- 10662023
TI  - New clinical practice guidelines standards.

PMID- 10662024
TI  - Accreditation of foster care services now available.

PMID- 10662025
TI  - Warning! Bioethics can be hazardous to health.

PMID- 10662026
TI  - We trusted. We hired. We got burned.

PMID- 10662027
TI  - When Medicare says, "Let's see your records.".

PMID- 10662028
TI  - Courts are divided about your duty to nonpatients.

PMID- 10662029
TI  - The HMO graveyard. What caused the biggest failure yet.

PMID- 10662031
TI  - The most promising Web sites for job-hunting doctors.

PMID- 10662030
TI  - The HMO graveyard. Why was this doctor allowed to start a health plan?

PMID- 10662032
TI  - How practice costs wash away income.

PMID- 10662034
TI  - Hospital trade group posts profit in 1998.

PMID- 10662033
TI  - Advice for dealing with on-the-job problems--gun threat, problem patients,
      practice beyond training, working while sick, killer call schedule.

PMID- 10662035
TI  - JCAHO drops a survey rating. Board says 'commendation' award has several
      weaknesses.

PMID- 10662036
TI  - UnitedHealth move wins praise. But AAHP study says health plans have chipped away
      to pre-authorization reviews for years.

PMID- 10662037
TI  - La. hospitals to sell managed-care plans.

PMID- 10662038
TI  - La. provider-owned HMO cited for lateness.

PMID- 10662039
TI  - Provider relief package heads for final OK.

PMID- 10662040
TI  - 'Rochester natives' lacked foresight.

PMID- 10662041
TI  - Accreditation becomes a foreign affair. Hospitals worldwide are turning to
      quality initiatives; America's JCAHO isn't the only model.
AB  - Accreditation is sweeping the globe. And it's happening for many reasons that
      would be foreign to U.S. hospitals. Although America's Joint Commission is
      playing a leading role in the spread of quality-improvement initiatives, it
      certainly isn't the only model out there. This story leads off a special section
      on international healthcare.

PMID- 10662042
TI  - Spanish hospital carries seal of approval.

PMID- 10662043
TI  - Another war on drugs. European countries turn to 'reference pricing' in battle
      against soaring cost of pharmaceuticals.

PMID- 10662044
TI  - Showpiece on the Seine. Paris builds a grandiose new hospital, but critics say
      the over-budget behemoth isn't needed.

PMID- 10662045
TI  - First private hospital opens in Croatia. Improved services, shorter waiting
      lists, skilled doctors are at the heart of Magdalena Hospital.

PMID- 10662046
TI  - Magazine to join international set. Modern Healthcare will play major role at
      December summit of global healthcare leaders.

PMID- 10662047
TI  - Japan breaks from tradition. A new national insurance program will change long
      term care, create business opportunities.

PMID- 10662048
TI  - Managed care storms Malaysia. Fears are brewing that consumers will be hurt in
      the transition to privatized U.S.-style HMOs.

PMID- 10662049
TI  - Organ allocation agreement reached.

PMID- 10662050
TI  - OSHA toughens its needlestick policy.

PMID- 10662051
TI  - Leading the leaders: the role of the board chair.

PMID- 10662052
TI  - Rural rescue--a vision in time.
AB  - Remaining a stand-alone hospital in a small, rural community puts a lot of
      pressure on both the board and management to be visionary leaders. Gibson Area
      Hospital and Health Services in Illinois has thrived under its risk-taking CEO
      and board.

PMID- 10662053
TI  - What went wrong? We can all learn from the mistakes of others.
AB  - A former board chair from a hospital in Connecticut provides a candid explanation
      of the series of mistakes he believes his board made that ultimately led to the
      hospital's bankruptcy and closure.

PMID- 10662054
TI  - Benchmarking: measuring yourself against the best.

PMID- 10662055
TI  - Wake up call: an operations assessment.

PMID- 10662056
TI  - End-of-life care in Texas.

PMID- 10662057
TI  - How do you rate? Credit analysts now look at the big picture--where boards are
      front and center.
AB  - When it comes to health care bond ratings, financial factors aren't the only
      measures credit analysts are looking at these days. They also want to know why
      trustees and execs are making the decisions they do and if the board understands
      the health care industry and the strategies needed for future success.

PMID- 10662058
TI  - An examination of the educational needs for environmental health and protection.
AB  - The practice of environmental health and protection is at a crossroads. Expanded
      responsibilities throughout this nation's agencies, prescriptive statutory
      mandates, and shrunken resources for fundamental public health services have
      combined to change the infrastructure and the workforce. This article presents
      the results of the Crossroads Colloquium, a forum of leaders in environmental
      health, convened to address the educational needs of the workforce. Major
      recommendations from the Crossroads Colloquium include redefining training by
      moving from discipline-specific to multidisciplinary training, developing
      collaborations among agencies, academia, and industry for training and education,
      and providing opportunities ranging from distance education to graduate degree
      programs.

PMID- 10662059
TI  - Public health response to metallic mercury spills in Kansas.
AB  - Local and state public health officials are called on to respond to environmental
      public health hazards just as they historically have been called on to respond to
      communicable disease outbreaks. Recent experience with metallic mercury spills in
      Kansas suggests that neither the legal authority nor the scientific knowledgebase
      is as well developed for response to environmental hazards as for communicable
      disease threats.

PMID- 10662060
TI  - Anglers' attitudes, beliefs, and behaviors as impacted by the Michigan Fish
      Consumption Advisory.
AB  - This study examines the relationship between a person's knowledge that a current
      ego-involving behavior may include health risks and the undertaking of a
      subsequent behavior change to reduce this risk. Specifically, 396 licensed
      anglers were surveyed concerning their beliefs about the health risks of
      consuming sport-caught fish, their knowledge of the risk information contained in
      the Michigan Fish Consumption Advisory, and their personal fish consumption
      behavior. Sixty-five percent of the anglers surveyed reported reading part or all
      of the Michigan Fish Consumption Advisory; however, as a group, they perceived
      the risks from eating sport-caught fish as small.

PMID- 10662061
TI  - Attitudes toward environmental tobacco smoke in Mississippi: still a burning
      issue.
AB  - Mississippi is one of eight states without any form of legislation restricting
      tobacco use in public places or work sites. In a telephone survey of 1,210
      Mississippi adults, 95 percent of respondents, including 90 percent of current
      smokers, were in favor of prohibiting or restricting smoking in public areas and
      91 percent of respondents, including 81 percent of current smokers, were in favor
      of smoking restrictions at work sites. Mississippi needs to undertake public
      health initiatives to promote the rights of nonsmokers and reduce the adverse
      health effects to nonsmokers of exposure to environmental tobacco smoke in public
      places and work sites.

PMID- 10662062
TI  - Collaborating with private sector physicians: the example of childhood lead
      poisoning prevention.
AB  - Collaboration between public and private health sectors to achieve public health
      goals can be difficult. The experience of childhood lead poisoning prevention
      programs in two cities where private practitioners dramatically increased blood
      lead screenings is used as an example of how successful collaborative
      relationships can be constructed. Seven action steps toward effective
      collaboration are offered: establish a rationale, document the problem, attend to
      logistics, clarify reimbursement, make known available support, build demand, and
      demonstrate leadership.

PMID- 10662063
TI  - Assessing excess deaths in St. Louis, Missouri: 1980 to 1994.
AB  - Excess deaths in the city of St. Louis from 1980 to 1994, their trends over time,
      and racial death patterns were assessed using the CDC's Wonder mortality
      database. Death rates in the city were compared with the three lowest
      statistically valid county death rates in the state of Missouri. The number and
      percent of preventable deaths in the city population also were estimated.
      Findings show that approximately 50 percent of city deaths from the nine leading
      causes may be preventable.

PMID- 10662064
TI  - Improvements in the performance of local public health agencies.
AB  - Local health agencies in Iowa were surveyed in 1995 and 1997 to ascertain their
      performance in the areas of assessment, policy development, and assurance. Some
      improvements were noted in the assessment function. However, development of
      health plans and a policy agenda as well as evaluation of programs remain weak.
      Structural changes may be needed to increase the effectiveness of small, rural,
      public health agencies. Options discussed in this article include increases in
      funding, consolidation into districts, specialized training, a shift of
      responsibilities to the state level, and a merger with local hospitals.

PMID- 10662065
TI  - Using a dual method needs assessment to evaluate the training needs of public
      health professionals.
AB  - A dual method research approach was used to identify the training needs of the
      public health professionals in Washington. A mail questionnaire was implemented,
      followed by focus groups with Washington State Department of Health (DOH) and
      local health department (LHD) professionals. Focus groups were used successfully
      to enhance and clarify the survey findings by identifying the specific content of
      the highest rated training needs (interpersonal communication, cross-culture and
      cross-age communication, participatory teaching/training skills, and electronic
      communication) and by pinpointing preference for different modes of training
      delivery for different training needs.

PMID- 10662066
TI  - Factors associated with clients not keeping their initial home health visit.
AB  - Public health nursing home visits are one strategy used by health care providers
      and communities to improve the health of pregnant women and families with young
      children. This study investigates the influence of client characteristics, nurse
      characteristics, and nurse-client interaction on clients keeping or not keeping
      their initial maternal and child health promotion home visit appointments with a
      public health nurse. Results of the study suggest the hiring decisions for nurse
      home visitors should give priority to the nurse's experience and education, as
      well as his/her practice style of handling maternal/child health visits.

PMID- 10662067
TI  - Evaluating cardiovascular disease prevention programs in African American
      communities.
AB  - This article reports on an evaluation of community cardiovascular disease
      prevention projects. The evaluation protocol involved a monitoring system for
      documenting community activities. It showed improvements in cardiovascular
      disease prevention services, community actions, planned products, and new or
      modified community programs to prevent cardiovascular disease. Reports from focus
      group sessions provided analyses of participants' perceived behaviors and
      satisfaction with eight community-based cardiovascular disease prevention
      projects in African American communities. Modest improvements in blood pressure,
      blood cholesterol, dietary intake, and physical activity among a convenience
      sample of participants in the community were noted.

PMID- 10662068
TI  - Refutation and conjecture around consensus breast cancer screening guidelines.
AB  - Public health policy making sometimes goes beyond dispassionate scientific review
      of data and program analysis to reflect the attitudes and promote the interests
      of various health care constituencies, professional organizations, consumer
      groups, and governmental bodies. This article recounts events that precipitated
      the issuance of guidance about the advisability of periodic screening mammography
      for women 40 to 49 years of age. It illustrates how a pragmatic choice was born
      from equal parts of data, the community's underlying value system, and political
      exigencies. Examining the policy making process will provide public health
      practitioners greater capacity to find workable solutions in their advocacy of
      better health for all.

PMID- 10662069
TI  - Barriers to academic and practice linkages.

PMID- 10662071
TI  - Decisions on placement and family preservation. Agreement and targeting.
AB  - Vignettes presented to experts and workers in the child welfare field were used
      to explore the degree of agreement on decisions to place children in substitute
      care or to refer them to family preservation services. The design allowed for
      investigation of the problem of targeting in family preservation programs.
      Findings indicate considerable inconsistency in decisions among experts and
      workers, particularly in decisions to refer to family preservation and other in
      home services. Contrary to the stated intentions of family preservation services,
      a majority of the referrals to these programs do not involve children who would
      have been placed in the absence of these programs.

PMID- 10662070
TI  - Understanding decisions about child maltreatment.
AB  - To understand how decisions are made in abuse/neglect cases by the child welfare
      system, the authors asked child welfare experts and protective service line
      workers to make decisions about actual child abuse and neglect cases on the basis
      of written summaries of the cases. Respondents included 27 experts and 103 line
      workers. Regression analyses found that workers and experts emphasized the same
      case characteristics in making their decisions, but the decisions were not well
      structured in the sense that they were not well predicted by case
      characteristics. Individual experts and workers varied widely in the decisions
      they made on identical cases. The authors conclude that decision making in the
      child protective system is inconsistent, with errors of two kinds: failing to
      remove children from their families when that is called for and removing children
      when it is unnecessary. Progress must be made in developing decision-making
      criteria that are consistent, preserve family integrity, and promote the well
      being of children.

PMID- 10662072
TI  - The swine flu vaccine and Guillain-Barre syndrome. A case study in relative risk
      and specific causation.
AB  - Epidemiologic methods were developed to prove general causation: identifying
      exposures that increase the risk of particular diseases. Courts often are more
      interested in specific causation: On balance of probabilities, was the
      plaintiff's disease caused by exposure to the agent in question? Some authorities
      have suggested that a relative risk greater than 2.0 meets the standard of proof
      for specific causation. Such a definite criterion is appealing, but there are
      difficulties. Bias and confounding are familiar problems; individual differences
      must be considered too. The issues are explored in the context of the swine flu
      vaccine and Guillain-Barre syndrome. THE CONCLUSION: There is a considerable gap
      between relative risks and proof of specific causation.

PMID- 10662073
TI  - Evaluation of HIV risk reduction intervention programs via latent growth model.
AB  - The latent growth model (LGM) has drawn increasing attention in behavioral
      studies using longitudinal data. The LGM captures the level and trajectory of
      behavior change, variation in both the initial status and the trend of behavior
      change, as well as the time-ordered covariation between the initial status and
      change. This study demonstrates how the LGM can be applied in the evaluation of
      intervention programs targeting HIV risk behavior among drug users. Multi-group
      piecewise latent growth models were fit to longitudinal data with three repeated
      response measures.

PMID- 10662074
TI  - MCOs' woes.

PMID- 10662075
TI  - Journal-based continuing medical education.
AB  - Continuing Medical Education (CME) has become a practical necessity for most
      physicians, because CME credit is required by many licensing and other medical
      authorities and because physicians are expected to follow the most recently
      published practice guidelines. A useful and relatively inexpensive source of CME
      credit is provided by journals such as JAMA and Archives of Family Medicine. In
      this article, the costs of CME to the physician's practice are estimated, and the
      educational objectives, format, and evaluation procedure of the JAMA Reader's
      Choice CME activity are described.

PMID- 10662076
TI  - Twenty strategies to reduce the risk of a malpractice claim.
AB  - The provision of health care services is not exempt from either human error or
      clinical misjudgments. However, many malpractice claims arise from neither of
      those sources but from poor communication systems, faulty office practices, or
      inadequate documentation. This article describes 20 practical risk management
      strategies a physician practice can implement to strengthen aspects of the care
      delivery process and reduce potential liability exposure. Some of the subjects
      addressed in this article include the importance of documenting telephone advice
      to patients; determining when and how to terminate patients; improving
      communication and listening styles; how to effectively obtain the patient's
      informed consent; and implementing careful oversight mechanisms with the receipt
      of outside diagnostic test results.

PMID- 10662077
TI  - Telemedicine: the state of the art and current issues.
AB  - Telemedicine is the application of modern telecommunications to the practice of
      medicine. Telemedicine is particularly appealing to rural and under served areas.
      Applications of telemedicine include administrative videoconferences between a
      central headquarters and remote branches; network CME including instruction in
      sophisticated procedures formerly not possible; video-consultations permitting
      examination, diagnosis, and treatment of a remote patient; teleradiology;
      telepathology; patient medical records; medical data banks; and many more. There
      is some reluctance on the part of physicians to make use of telemedicine. There
      are also barriers established by individual state licensing laws, confidentiality
      concerns, and malpractice worries. Reimbursement policies remain unsettled.

PMID- 10662078
TI  - The technological underpinnings of a modern clinical practice.
AB  - Information is the lifeblood of the modern clinical practice, and the information
      technology infrastructure is the vasculature that supports the flow of this
      information throughout the entire health care enterprise. Although the impact of
      information technology may not be obvious to the overworked clinician,
      information technology is the underpinning that makes virtually all knowledge
      based work tenable. The increasing dependence of clinical medicine on this matrix
      of technologies is especially obvious when technology becomes the rate-limiting
      step in clinical process improvement and innovation.

PMID- 10662079
TI  - Liability avenues increase for HMOs.
AB  - Texas has enacted a first-of-its-kind law that grants patients a statutory right
      to sue health maintenance organizations, and other managed care entities, for
      medical malpractice if the organization's decision adversely affects a patient's
      health. This new legislation opens the door for increased liability against
      managed care organizations, which had remained relatively protected from
      liability in the past.

PMID- 10662080
TI  - Ambulatory patient satisfaction: a systematic approach to collecting and
      reporting information.
AB  - The importance of outpatient services to most hospitals continues to escalate.
      The number of ambulatory outpatients is much larger than the number of
      inpatients, and revenues from outpatient services are predicted to equal or
      exceed inpatient revenues in the near future. The ability to provide outpatient
      services with exceptional quality is paramount to long-term survival of
      hospitals. This article describes a methodology for systematically collecting and
      reporting patient satisfaction information from a wide array of hospital
      ambulatory care services. By systematically measuring satisfaction, hospitals can
      determine the outpatient areas and service dimensions in need of performance
      improvement.

PMID- 10662081
TI  - G. Richard Smith on outcomes measurement and Internet-based technology. Interview
      by Christy L. Beaudin.

PMID- 10662082
TI  - On values and achievements.

PMID- 10662083
TI  - Incident review management: a systemic approach to performance improvements.
AB  - Incident reporting has emerged as a cornerstone of sound quality improvement
      programs. Sentinel events, "a serious and undesirable occurrence involving the
      loss of life, limb, or function of an individual served" (Joint Commission on
      Accreditation of Healthcare Organizations, 1996), is a mandated indicator for
      Joint Commission standards of accreditation for audited healthcare facilities.
      Properly investigated and documented individual incidents can lead to systemic
      improvements, which may enhance the quality of client care and the integrity of
      the healthcare facility. This article proposes a systemic approach to the
      incident review (IR) process in long-term healthcare facilities. This
      comprehensive approach incorporates identification, investigation, and management
      of the IR process from the inception of a problem to the continued follow-up to
      ensure that improvement plans are effectively implemented.

PMID- 10662084
TI  - Developing a customer-service and cost-effectiveness team.
AB  - A healthcare organization in northeast Georgia developed a team approach to meet
      the challenge of unacceptable customer service scores, improve numerous system
      inefficiencies, promote staff accountability, and maintain an emphasis on cost
      effective and efficient utilization of resources. This article describes the
      development of a team comprising a variety of staff members to support all
      managers in this effort. The outcome was an improvement in customer satisfaction
      scores from the lower half of the survey database to the top third.

PMID- 10662085
TI  - Diabetic retinopathy screening: a clinical quality improvement project.
AB  - BlueCross BlueShield on the Rochester Area (BCBSRA) initiated a clinical quality
      improvement project that increased its diabetic retinopathy screening rate from
      42.8% in 1995 to 58.1% in 1997. A multidisciplinary team examined the processes
      and discovered both member (patient) and provider (physician) barriers to annual
      screening. Members did not understand the clinical importance and were uncertain
      as to how frequently diabetic eye examinations were covered by insurance.
      Providers identified a role for BCBSRA to reinforce patient education on eye
      examinations and to assist with tracking of services. Involvement of these key
      stakeholders was critical to understanding and overcoming barriers.

PMID- 10662086
TI  - Study of the relationships of physical and mental health to patient satisfaction.
AB  - This study examined the relationships of patients' self-report of their physical
      and mental health to their satisfaction with care received during recent
      hospitalization. These associations were examined within and across 11 service
      groups in a mid-Atlantic academic medical center. The sample size of 944 patients
      was distributed among the service groups, with 68-105 patients in each service.
      The instruments were a portion of the institution's patient satisfaction survey
      and the SF-12 (a 12-item generic measure of health status), both administered
      through telephone interviews. Across all hospital services, the relationships
      between satisfaction and health were too weak to interpret, with only 0.36% and
      0.81% of the variance explained between overall satisfaction with care delivery
      and physical and mental health, respectively. At the service level, however, a
      number of significant but weak associations were found between satisfaction and
      health status in the otolaryngology, orthopedic, cardiothoracic, and transplant
      populations. Mental health and patients' likelihood to return to the hospital
      were negatively correlated in the neurology/neurosurgery populations, indicating
      that at higher levels of mental function, patients reported lower likelihood of
      their returning to the hospital.

PMID- 10662087
TI  - An overview of outcomes research and measurement.
AB  - Rapidly rising healthcare costs, questions about effective medical intervention,
      and the need for efficient delivery of healthcare services have compelled
      organizations to focus on outcomes research, measurement, and management.
      Proponents of outcomes measurement predict that it will produce significant
      benefits, including improved physician and patient information, increased
      understanding of the effectiveness of different treatment interventions, and
      established guidelines for medical management. Multiple professional
      organizations, academic centers, and independent research laboratories, as well
      as government agencies, are now involved in the research and development of
      outcomes measurement tools. This article provides some insight into the outcomes
      phenomenon.

PMID- 10662088
TI  - Spotlight on the Internet.

PMID- 10662089
TI  - New paradigms for medical decision support and education: the Stanford Health
      Information Network for Education.
AB  - The information needs of physicians are complex and ever increasing in a world of
      rapidly expanding medical knowledge and a practice environment where physicians
      are required to know and do more with shrinking resources. Current strategies for
      providing clinical decision support and continuing medical education have failed,
      in part, because they have not provided timely, easy access to information that
      is current, integrated with other information and the physician's workflow, and
      relevant to specific questions that occur during the patient encounter. Meeting
      these challenges involves understanding the nature of medical knowledge, the
      different information needs of physicians, the clinical decision-making process,
      and the constraints of the physicians work environment, as well as the
      traditional barriers to physician education. We explore the nature of some of
      these challenges and propose one solution in the form of a highly integrated web
      based technology--The Stanford Health Information Network for Education.

PMID- 10662090
TI  - Intelligent visualization and exploration of time-oriented clinical data.
AB  - Physicians and other care providers often need to quickly browse and interpret
      large numbers of time-oriented clinical data. Reducing the information overload
      involving such tasks is a major goal for medical information systems. We describe
      a conceptual architecture and software implementation specific to the task of
      interpretation, summarization, visualization, explanation, and interactive
      exploration of time-oriented clinical data and the multiple levels of meaningful
      concepts that can be derived from these data. We build on our work on abstraction
      of time-oriented clinical data using a knowledge base, acquired from expert
      physicians, of temporal properties of the data. The core module of the new
      framework is called KNAVE (Knowledge-based Navigation of Abstractions for
      Visualization and Explanation). Health care providers can manipulate the display
      though several visualization and exploration operators. These operators have
      semantics that are domain independent but that are customized automatically for
      the application by access to the domain-specific knowledge base. The display,
      which reflects data and derived interpretations in the patient's database,
      changes when the user explores key relations (e.g., the dependency hierarchy) in
      the knowledge base of the relevant clinical domain. Preliminary assessment of the
      initial prototype with several clinical users has been encouraging. The KNAVE
      methodology has broad ramifications for reducing the load that large numbers of
      time-oriented clinical data put on care providers.

PMID- 10662091
TI  - Problems regarding the integration of medical images into the total hospital
      information system.
AB  - Since 1989, the integration of medical images into the total hospital information
      system (HIS) has been investigated and developed at Kochi Medical School. The
      basic concept of the integration is that, in the same way they can view text
      based data, doctors can retrieve and view images using the PC terminals of the
      total HIS. The possibility of utilizing the PC terminals of the total HIS as
      image viewing stations was investigated. A test run was performed in the period
      from October 1995 to July 1997. The test run revealed that fast image access is
      crucial in order for the system to be useful for doctors. After making various
      improvements, the final system became well used in the clinical practice.
      However, in order to progress to the film-less stage, the final system still has
      three problems that must be solved: quality of the image display, operation of
      multi-exams, and quality assurance of the digital image.

PMID- 10662092
TI  - Using an intranet for physician desk top data consolidation.
AB  - Kaleida Health developed one of the first web-based information delivery systems
      specific to patient care. Through an Intranet or secure dial-up connection,
      registered practitioners and staff access patient demographics, laboratory data,
      radiology results, and dictated reports. Additionally, standard forms, patient
      educational material, and other management information are available. The
      development team designed and wrote interfaces to existing systems and
      applications, designed security systems, instituted usage policies and
      procedures, and developed a name and logo. Since the program's launch in February
      of 1997, more than 800 users have been registered both in-house and off-site.

PMID- 10662093
TI  - Chronic disease coordinated care planning: flexible, task-centered decision
      support.
AB  - SA HealthPlus is a trial of coordinated care enrolling 4000 high-use patients in
      South Australia in 10 groups including diabetes, cardiac, aged care and lung
      disease. These patients each have a designated general practitioner (GP) care
      coordinator who formulates an individualized care plan designed to keep them as
      healthy as possible. An on-line interface to SA HealthPlus has been developed for
      the care coordinators. The Care Plan On-Line (CPOL) system provides a single
      coherent source whereby the GP can review the available information on a
      HealthPlus patient in the context of devising a care plan of prospective services
      and medications. In the same application environment CPOL provides access to care
      guidelines tailored for SA HealthPlus.

PMID- 10662094
TI  - WAX ActiveLibrary: a tool to manage information overload.
AB  - WAX Active-Library (Cambridge Centre for Clinical Informatics) is a knowledge
      management system that seeks to support doctors' decision making through the
      provision of electronic books containing a wide range of clinical knowledge and
      locally based information. WAX has been piloted in several regions in the United
      Kingdom and formally evaluated in 17 GP surgeries based in Cambridgeshire. The
      evaluation has provided evidence that WAX Active-Library significantly improves
      GPs' access to relevant information sources and by increasing appropriate patient
      management and referrals this might also lead to an improvement in clinical
      outcomes.

PMID- 10662095
TI  - IS/IT market support systems: augmenting UK primary health care groups.
AB  - The election of the Labour government in May 1997 has seen the continuation of
      advanced market reforms intended to modernize the UK National Health Service
      (NHS). The planning and implementation of information systems and technology
      (IS/IT) following these structural changes is both widespread and significant. An
      information strategy for the NHS, published recently, is intended to provide an
      initial seven-year program of life-long electronic health records for everyone in
      the United Kingdom. This article explores the potential role of these systems in
      the specific provision of the new primary health care groups. It argues that, if
      primary care physicians adopt appropriate delivery channels and service packages
      and are proactive in the use of IS/IT, then the outcome will produce more patient
      choice, less nonattendance, and consequently improved primary health care
      provision.

PMID- 10662096
TI  - Factors that cause industries to lead or lag in use of information technology:
      does health care lag?
AB  - The rate of diffusion of information technology varies among industries, as does
      its resultant added value. The different paces of work transformation are
      determined by the opportunities of the differing work processes, efficiency of
      exchange of workplace ideas, and relationships among constituencies. The
      differences raise the question of why the maturation process is accelerated (or
      restrained) in different industries, how the health care industry fares in
      comparison, and how information technology may be more effectively used as health
      care evolves toward new forms of work interaction, control mechanisms, and
      information technology management paradigms and as information processing moves
      toward higher levels of complexity.

PMID- 10662097
TI  - Vision saver. A drug that combats blindness in the elderly may soon be available.
      What you need to know.

PMID- 10662098
TI  - Who's afraid of Frankenfood?

PMID- 10662099
TI  - Institutions for the elderly operating without a license: quality of care and the
      surveillance process.
AB  - In 1992, Israel's Services for the Aged identified private institutions for the
      elderly operating illegally, which are notorious for poor quality. This article
      presents the findings of screening visits in 97 "pirate" institutions, as part of
      a plan to improve surveillance, and evaluates the outcomes as a measure of the
      effectiveness of intervention. Although a high proportion of deficiencies was
      found, some institutions showed a significant ability to correct them.

PMID- 10662100
TI  - Clinical practice guidelines: a tool to improve care.
AB  - The American patient and consumer groups are increasing pressure on physicians
      and health care organizations to improve and document the quality of care that
      they deliver. A leading cause of inadequate care is the significant variations in
      medical practice that cannot be explained by patient differences, which persist
      through out the country. Managed care and the rise of consumer groups has forced
      health care providers and organization to begin analyzing how and why they
      deliver care to patients. The incorporation of quality improvement tools such as
      evidence-based practice guidelines have been shown to reduce practice
      variability, improving the process and outcomes of care. The correct development
      and implementation of these guidelines can be an effective tool to assist the
      practicing physician in improving the care delivered to his/her patient.

PMID- 10662101
TI  - Peer review and performance improvement in a radiation oncology clinic.
AB  - A program was implemented in the Radiation Oncology Division at Naval Medical
      Center San Diego to document baselines for process improvement and fairly assess
      physician supervisory performance for recredentialing. This program was based on
      criteria established by the American College of Radiology (ACR). In addition to
      weekly chart rounds with peer review of films and charts while patients are on
      treatment, a new mechanism of peer review post-therapy was instituted. All
      patients completing therapy have this peer review prior to final disposition of
      their charts. Data are now readily available for physician recredentialing.
      Further, several points of inconsistent chart documentation have been identified
      and remedied. This mechanism is a simple and efficient way to ensure continuing
      patient care within ACR standards.

PMID- 10662102
TI  - Reengineering outcomes management: an integrated approach to managing data,
      systems, and processes.
AB  - The integration of outcomes management into organizational reengineering projects
      is often overlooked or marginalized in proportion to the entire project.
      Incorporation of an integrated outcomes management program strengthens the
      overall quality of reengineering projects and enhances their sustainability. This
      article presents a case study in which data, systems, and processes were
      reengineered to form an effective Outcomes Management program as a component of
      the organization's overall project. The authors describe eight steps to develop
      and monitor an integrated outcomes management program. An example of an
      integrated report format is included.

PMID- 10662103
TI  - Risk-adjusted measurement of primary cesarean sections: reliable assessment of
      the quality of obstetrical services.
AB  - A two-hospital system reported widely disparate Cesarean section rates in its
      component institutions. Statistical analysis determined that the apparent
      discrepancy was due primarily to patient-related factors. When risk-adjusted,
      both hospitals' rates were indistinguishable from expected rates. Reporting
      Cesarean section rates without appropriate risk adjustment yields potentially
      misleading results. Since reliable risk adjustment currently exists only for
      primary Cesarean sections, primary rates should be reported separately from "raw"
      rates for other procedures.

PMID- 10662104
TI  - Understanding nursing home quality of care: incorporating caregivers' perceptions
      through structure, process, and outcome.
AB  - Nursing home quality of care has been influenced by the Omnibus Budget
      Reconciliation Act of 1987. This legislation mandated changes within the
      structure, process, and outcomes of care. These care elements are examined from
      the viewpoints of 32 licensed nurses and 40 nurse assistants. Accounts of good
      care, obtained through focus groups, are presented within the context of
      structure, process, and outcome to understand quality care. Implications about
      training nursing personnel are considered within the structure and the process of
      care and how these elements affect care outcomes.

PMID- 10662105
TI  - Progress of quality-associated costing: extension to platelet transfusion
      practice and the manufacturing scope for plasma proteins.
AB  - Realistic estimates about the potential misallocation of health service
      resources, in relation to the cost-beneficial use of blood products, is enabled
      by tracing manufacturing costs, through product specification elements to
      corresponding post-transfusion outcomes. This quality-associated costing (QAC)
      philosophy is completed in this article by understanding the issues that surround
      the manufacture of platelets, and by its comparison with the generally used but
      arbitrary methods for blood product costing. Without QAC, cost-beneficial
      platelet therapy will not be realized, due to an estimated Western underfunding
      of approximately one quarter of a billion pounds per annum by arbitrary methods.
      A reciprocal consequence of such platelet QAC is a significant reduction in the
      currently perceived cost of source plasma. Western estimates, based upon this,
      demonstrate that the not-for-profit fractionation of source plasma into purified
      proteins is probably underfunded by approximately one fifth of a billion pounds
      per annum through the use of arbitrary costing methods.

PMID- 10662106
TI  - Interview with Sherry Bahrambeygui, JD.

PMID- 10662107
TI  - An Alzheimer's advance.

PMID- 10662108
TI  - The battle on B wing. When staff members fight, everyone loses.

PMID- 10662109
TI  - Providers praise new survey process.

PMID- 10662110
TI  - Rulings provide clarity to 'new provider' exemption.

PMID- 10662111
TI  - Positive thinking. A not-for-profit charts a way out of a financial morass.

PMID- 10662112
TI  - More room for change. To get the best of PPS, fine-tune your finances.

PMID- 10662113
TI  - Survey: strategies and trends.

PMID- 10662114
TI  - Wheels of fortune. Long-term care facilities help fill senior transportation gap.

PMID- 10662115
TI  - Knock, knock. Responding to subpoenas and search warrants.

PMID- 10662116
TI  - Congress's watchful eye. Interview by Yvonne Parsons.

PMID- 10662117
TI  - Infection control redesign nets millions for health system.

PMID- 10662118
TI  - Hospitals leave national GPOs to create their own competitive contracts.
AB  - Hospitals cut better medical/surgical supply deals in smaller, innovative group
      purchasing networks. Meridian Health System in New Jersey posted an annual $1.5
      million savings by renegotiating about a dozen of its supply contracts over the
      past year. By ditching memberships with the big GPOs and creating its own group
      purchasing cooperative, administrators there are cutting competitive deals. Find
      out how they're doing it.

PMID- 10662119
TI  - System looks outside its own walls to find innovative way to cut kids' asthma
      admissions.
AB  - Atlanta children's hospital system initiates outpatient pediatric asthma disease
      management program to reduce inpatient admissions and ER visits while reducing
      costs. Children's Healthcare of Atlanta turned to the primary care physician
      community for front-line support in keeping mild asthma cases out of the
      hospital. By offering evidence-based practice guidelines, training for staff, and
      educational materials for patients and their families, the Partnership to ACE
      Asthma program is off to a running start. Learn how to set up a similar program.

PMID- 10662120
TI  - Computerized notepads boost ER physician's efficiency.
AB  - Long Island hospital emergency department boosts physician productivity with a
      cutting-edge digital notepad. A Massapequa (NY) General Hospital emergency
      physician was one of the first to do a six-month test pilot of a new pen-based
      digital notepad that lets physicians take notes at the patient's bedside without
      having to transcribe them later for the formal charts. Find out why developers of
      the inexpensive device expect interest to increase soon.

PMID- 10662121
TI  - Freestanding ambulatory surgery centers cost less to run than in-hospital ORs.

PMID- 10662122
TI  - Troubled PHO reveals Medicare risk contracting strategy.

PMID- 10662123
TI  - Model for PCP contracts offers right incentives for Medicare, Medicaid providers.
AB  - Consider this model for PCP contracting. Provider organizations in Medicare and
      Medicaid often structure arrangements with their primary care providers that set
      up the organizations--and the doctors--to fail. An actuary from Milliman &
      Robertson in Seattle illustrates how to establish the right kinds of incentives
      for PCPs.

PMID- 10662124
TI  - Collect data, monitor claims receipts to ensure prompt Medicare, Medicaid
      payment.
AB  - What to do when your Medicare or Medicaid plan pays claims late. Doctors in New
      Mexico say they're going broke because health plans don't pay for months. But
      managed care plans with commercial lives aren't the only plans that pay claims
      late. Plans with Medicare and Medicaid lives also can have payment problems. Find
      out how the physicians in New Mexico are tackling the problem, and see what you
      can do to prevent it from happening to you.

PMID- 10662125
TI  - Reach out to community to develop culturally sensitive patient care.
AB  - Are you meeting the needs of your minority Medicaid members? Cultural competency
      is becoming an issue in managed Medicaid as minority populations grow, and states
      require plans to meet the needs of non-English-speaking members. But researchers
      find that plans don't offer much help to providers. Get some expert advice on how
      you can better meet the needs of a multicultural population.

PMID- 10662126
TI  - CA study finds some challenges in Medicaid may be universal.
AB  - Data File: Some Medicaid managed care challenges and trends appear universal. A
      baseline study of the county-organized health system and two-plan managed
      Medicaid models in California reveals the unique models haven't escaped some of
      the problems and trends faced by more traditional managed Medicaid plans and
      providers across the country.

PMID- 10662127
TI  - Try a low-tech approach to managing your data.

PMID- 10662128
TI  - Disease management program helps clinic manage risk.
AB  - A disease management program developed by a Wisconsin provider has made
      impressive inroads in reducing the cost of care for diabetes, asthma, and preterm
      deliveries, where hospital days dropped by 75%.

PMID- 10662129
TI  - Use your DM protocols to lower reinsurance rates.
AB  - Looking for more ammunition to convince your physicians of the merits of disease
      management? Look no further than your stop-loss premium. Reinsurers are likely to
      offer greater coverage at lower premiums to clients with a rigorous approach to
      DM.

PMID- 10662130
TI  - Will California's capitation woes spread to other states?

PMID- 10662131
TI  - Defining provider roles. More work + changing roles = less satisfaction for
      providers and patients.

PMID- 10662132
TI  - Pediatric residents train to respect family's role.

PMID- 10662134
TI  - Easy-chair entry: Internet check-in is not far off.

PMID- 10662133
TI  - Study: CHF patients fare better with cardiologists.

PMID- 10662135
TI  - The Balanced Budget Act of 1997 (BBA) fix narrows to Thomas, Roth measures.

PMID- 10662136
TI  - Prospective payment system (PPS) guidelines now not due out until July 2000.

PMID- 10662138
TI  - LifePoint Hospitals focuses on physician recruitment.

PMID- 10662139
TI  - Industry agrees on payment system for new technology for Medicare outpatient
      services.

PMID- 10662137
TI  - New coalition seeks gainsharing modification. Federation position opposes all
      gainsharing.

PMID- 10662140
TI  - Thinking outside the box to prevent, diagnose, and treat osteoporosis.

PMID- 10662141
TI  - Succeeding with tobacco cessation takes perseverance and innovation.

PMID- 10662142
TI  - Jubilee.

PMID- 10662143
TI  - The looming crisis. Health care organizations are behind other industries in
      cultivating tomorrow's leaders.

PMID- 10662144
TI  - Rx succession planning. Developing the next generation of leaders.

PMID- 10662145
TI  - Benchmarking against the best. Interview by Joe Flower.

PMID- 10662146
TI  - Increasing minority representation in health care management.

PMID- 10662148
TI  - Building new leaders in the Bluegrass State.

PMID- 10662147
TI  - Internet site allows minority leaders to hook up with mentors and jobs.

PMID- 10662149
TI  - Knowing your limits. Team up with the right people to strengthen your leadership.

PMID- 10662150
TI  - Making mergers, acquisitions & alliances work. What health care leaders need to
      know to avoid common pitfalls.

PMID- 10662151
TI  - Reinventing the American hospital: avoiding the dollar squeeze.

PMID- 10662152
TI  - The healing spirit: reinventing health alternatives. Alternative therapies for
      the medically underserved.

PMID- 10662153
TI  - Getting excellent results. By empowering its employees and offering exceptional
      customer service, Wisconsin's Mercy Hospital has made a dramatic turnaround.

PMID- 10662154
TI  - Recapturing the joy in health care. Changes in the way medicine is practiced have
      left many physicians unhappy with their choice in careers, but doctors must lead
      the way if they are to find professional satisfaction.

PMID- 10662155
TI  - The next wave of innovation, Part II. Health care systems are poised to undergo a
      radical transformation through entrepreneurship.

PMID- 10662156
TI  - Bricks & mortar, Part 2. A solid competitive strategy.

PMID- 10662157
TI  - Partner down!

PMID- 10662158
TI  - So you want drive an ambulance?

PMID- 10662159
TI  - So you want to start an ambulance company?

PMID- 10662160
TI  - Manufacturing an EMS response.

PMID- 10662161
TI  - Love 'em or they'll leave: motivating volunteers.
AB  - Running a successful volunteer-based service does not begin and end with the
      recruitment of volunteers. You need to first consider what is in it for the
      prospective volunteer, define why you want volunteers and then decide exactly
      what you want those volunteers to do. Then you recruit them, face-to-face,
      ensuring that every prospect is offered something specific to do and is welcomed
      into your EMS family.

PMID- 10662162
TI  - An "interestingly different" call.

PMID- 10662163
TI  - Testifying 101.

PMID- 10662164
TI  - Hot tips for grant seekers.

PMID- 10662165
TI  - Clinical guidelines. Nice work: spell it out for me.
AB  - Trusts and PCGs should take action now to disseminate the list of topics being
      investigated by NICE. Each organization should carry out an audit to establish
      how many patients are being treated in the areas looked at by NICE and what their
      current treatments are. Such information is essential to inform and defend
      treatment decisions, following guidance from NICE.

PMID- 10662166
TI  - Mental health. As you don't like it.
AB  - The publication of the national service framework for mental health provides a
      good opportunity to review acute psychiatric services, which are unpopular with
      patients and understaffed. The framework recommends a balance of hospital beds,
      community provision and home care. Planning should usually cover one or more
      primary care groups.

PMID- 10662167
TI  - Private finance initiative. Well-laid plans.
AB  - Private finance schemes in primary care will not be subject to the controls
      required in hospital programmes. Insurance companies are interested in
      partnerships with primary care in order to influence NHS spending as services are
      increasingly contracted out. This state of affairs could lead to the introduction
      of US-style managed care with a loss of equity for patients.

PMID- 10662168
TI  - US healthcare. Profits of doom.

PMID- 10662169
TI  - Data briefing. Modernisation fund.

PMID- 10662170
TI  - CON ruling threatens hospital. Unless decision is reversed on appeal, 3-year-old
      Miss. hospital must close by year-end.

PMID- 10662171
TI  - Transplant debate unabated despite deal.

PMID- 10662172
TI  - Penn State Geisinger pulls the plug. System leaders cite clashing cultures,
      inability to consolidate services and cut costs.

PMID- 10662173
TI  - Sales tax will help build Fla. hospital.

PMID- 10662174
TI  - TriHealth to close Cincinnati hospital. Capital infusion, renovation weren't
      enough to stem facility's losses, declining admissions.

PMID- 10662175
TI  - McKesson acquires software developer.

PMID- 10662176
TI  - Services cut at Calif. Tenet hospital.

PMID- 10662177
TI  - Hitting bottom. Aggressive acquisitor Integrated Health Services stung by PPS,
      takes $1.8 billion in charges.

PMID- 10662178
TI  - Ariz. health plan placed in receivership.

PMID- 10662179
TI  - Minn. sues feds over HMO payments. State contends disparities in rates for
      Medicare managed-care plans are discriminatory.

PMID- 10662180
TI  - Compliance plan to guide doc groups. Specialist groups concerned about impact of
      HHS guidelines on small practices.

PMID- 10662181
TI  - Specialty PPM firms report losses.

PMID- 10662182
TI  - A matter of life or death. Providers should lead an organ-donation education
      drive.

PMID- 10662183
TI  - Let home healthcare thrive.

PMID- 10662184
TI  - House OKs $15 billion in provider relief.

PMID- 10662185
TI  - The harbor gets larger. HHS regulations give hospitals more room to maneuver on
      ventures with physicians.

PMID- 10662186
TI  - Healthcare tattletales. What motivates whistleblowers? Experts say it's
      everything from altruism to ordinary greed.
AB  - Who are these healthcare whistleblowers, and what motivates them? Some observers
      say it's a resolve to do the right thing when no one else will act, while others
      say greed and revenge are the driving forces. We profile three whistleblowers and
      show how their actions have affected their lives and the healthcare industry.

PMID- 10662187
TI  - Teaching hospitals have better outcomes.

PMID- 10662188
TI  - A challenge to qui tam. Court ruling would kill whistleblower suits if feds don't
      join in or plaintiffs can't prove injury.

PMID- 10662189
TI  - Miss. hospital looks for big spender. Public facility is seeking a strong system
      that's willing to pay for improvements, equipment.

PMID- 10662190
TI  - JCAHO faces first red ink in 20 years.

PMID- 10662191
TI  - Lewis' role at AHA is still secure.

PMID- 10662192
TI  - A model for healthcare woes. Pending sale of D.C. hospital shows hazards of
      depending on government reimbursement.

PMID- 10662193
TI  - Houston HMOs on selling block.

PMID- 10662194
TI  - Hospitals recruit docs with salaries.

PMID- 10662195
TI  - Mercy Health to divest doc network. System loses $13 million per year on
      physician practices and calls it a 'failed strategy'.

PMID- 10662196
TI  - Lawmakers fund home state hospitals.

PMID- 10662197
TI  - Health benefits vary based on location.

PMID- 10662198
TI  - Surveys: employees want coverage control.

PMID- 10662199
TI  - Columbia ethics official Yuspeh honored.

PMID- 10662200
TI  - Shift seen in anti-fraud compliance efforts.

PMID- 10662201
TI  - Givebacks. Healthcare wins on Medicare, wants more.

PMID- 10662202
TI  - HHS stiffens rules on integrity agreements.

PMID- 10662203
TI  - Law allows some hiring of foreign nurses.

PMID- 10662205
TI  - Decades-long rivalry may lead to merger.

PMID- 10662204
TI  - Fresenius agrees to large settlement.

PMID- 10662206
TI  - N.Y. hospital group to appeal PATH ruling.

PMID- 10662207
TI  - Leaders of the PACS in radiology. Clinical imaging technology helps hospitals
      enhance accuracy, savings, service.
AB  - The image of radiology is changing rapidly. Hospitals are chucking the old light
      boxes and plugging in high-performance, filmless clinical image networks that not
      only enhance the accuracy of diagnoses but also cut long-term costs and improve
      service to referring physicians.

PMID- 10662208
TI  - Allina looks to open up the party. Twin Cities system seeking legislative change
      to ease exemption for a new hospital.

PMID- 10662209
TI  - IS staffs try to maximize what they've got.

PMID- 10662210
TI  - Medicaid: another foe for nursing homes.

PMID- 10662211
TI  - FDA could OK costly blood standards. An expert says that like chicken soup,
      removal of white cells from blood supply can't hurt.

PMID- 10662212
TI  - Ergonomics: steps to take to protect an aging staff.

PMID- 10662213
TI  - California regs portend sharps safety crackdown.

PMID- 10662214
TI  - Benchmarks. Hernia repair best performers.

PMID- 10662215
TI  - Lap surgery an ergonomic stress.

PMID- 10662216
TI  - Weighing cost savings with BIS (Bispectral Index).

PMID- 10662217
TI  - Internet buying sites spring up.

PMID- 10662218
TI  - Teamwork is pathway to the top.

PMID- 10662219
TI  - Study: outpatient lap chole safe. Interview by Judith M. Mathias.

PMID- 10662220
TI  - FDA to announce reuse strategy.

PMID- 10662221
TI  - Blood safety survey shows room for improvement.

PMID- 10662222
TI  - The expanded role of acute care nurses: the issue of liability.
AB  - For a variety of reasons the activities performed by health care professionals
      are ever increasing, however the legislative process regulating these specialised
      workers is not keeping up with the practice realities. While competency
      statements and credentialling mechanisms are developing, they are not uniformly
      in place for specialists. Therefore activities completed by these practitioners
      may be legally controversial. This study documents a variety of tasks completed
      independently by nurses employed in three acute care hospitals that legally
      require medical orders and then examines the legal implications of this role
      extension. Credentialling is one mechanism by which nurses and other health care
      professionals can ensure they possess the levels of knowledge and skill required
      to perform the advanced activities required of them and consequently avoid
      negative legal repercussions.

PMID- 10662223
TI  - Application and comparison of two modelling techniques for hospital bed
      management.
AB  - The use of the bed occupancy management and planning system (BOMPS) and the
      Sorensen multi-phased bed model were used to assess the implications of a
      hospital expanding its emergency facility. BOMPS flow modelling generates
      resource utilisation data dependent on the best visual and statistical fit
      between mixed exponential equations and time of bed occupancy; the Sorensen model
      creates models based on probabilities and length of stay distributions. Both
      models identified the presence of two streams of flow. However, there were
      differences in the number of beds identified as being short and longer stay. The
      advantage of flow modelling is that it enables decision-makers to pre-test their
      decisions.

PMID- 10662224
TI  - Falls: a coordinated strategy.
AB  - Falls are a common and serious health problem. Responses to the problem should
      address the individual, the individual's environment, the system of health or
      residential care used by the individual, and the local community. This article
      describes a response to the issue of falls in Ryde Hospital and its surrounding
      community. This response has multiple components which include patient and staff
      education and interventions with people who have fallen. These initiatives have
      been developed without additional resources and incorporated into existing
      systems of care provision.

PMID- 10662225
TI  - Initiatives in primary health care: evaluation of a South Australian program.
AB  - In 1994 the Primary Health Care Initiatives Program was established as part of
      the South Australian government's hospital service improvement strategy. In its
      first year, the program funded 34 demonstration projects, of which half were
      concerned with improving continuity of care and discharge planning, and half with
      health promotion or illness prevention. Evaluation of the program has shown that
      it achieved significant improvements in links and communication between the
      services involved, in the development of systems and procedures for facilitating
      discharge-planning and continuity of care, and in enhancing the capacity of
      organizations to undertake health promotion and illness prevention. Overall, it
      was not possible to determine whether the program had shortened or avoided
      hospital stays due to a range of factors, including the many changes occurring in
      the health system at the time. The program's strong emphasis on evaluation has
      produced a rich source of information and helped to develop the evaluation skills
      of project staff.

PMID- 10662226
TI  - Organisational culture, organisational learning and total quality management: a
      literature review and synthesis.
AB  - As health services face increasing pressure to meet the expectations of different
      stakeholders, they must continuously improve and learn from their experience.
      Many fail in attempts at continuous improvement programs because managers have
      not understood the complexity of making changes in organisations with multiple
      subcultures and interests. This article examines the related concepts of
      organisational culture, organisational learning and total quality management and
      shows how a synthesis of this knowledge can assist in developing continuous
      organisational learning and improvement.

PMID- 10662227
TI  - 'No gaps' health insurance: a gain for consumers or a windfall for specialists?
AB  - Attempts to introduce contracts between the purchasers and providers of
      Australian health services in the 1990s in order to reduce the gaps, or
      'copayments', that patients pay have met with limited success. However, the
      Harradine requirement that health funds introduce 'no gap' or 'known gap'
      policies by the middle of the year 2000 has raised a political storm within the
      AMA and set the funds and doctors in an adversarial position. This paper traces
      the history of 'gaps' and gap insurance, provides an interpretation of the
      present situation and speculates about likely outcomes.

PMID- 10662228
TI  - The Australian National Sub-Acute and Non-Acute Patient casemix classification.
AB  - The Australian National Sub-Acute and Non-Acute Patient (AN-SNAP) Version 1
      casemix classification was completed in 1997. AN-SNAP is designed for the
      classification of sub-acute and non-acute care provided in both inpatient and
      ambulatory settings and is intended to be useful for both funding and clinical
      management purposes. The National Sub-Acute and Non-Acute Casemix Classification
      study has produced the first version of a national classification of sub-acute
      and non-acute care. Ongoing refinement (leading to Version 2) will be possible
      through further analysis of the existing data set in combination with analysis of
      the results of a carefully planned and phased implementation.

PMID- 10662229
TI  - Prescribed drugs: a major cause of ill health.

PMID- 10662230
TI  - Privatising general practice in Mongolia: a trial of needs-adjusted capitation.
AB  - Mongolia's family doctors have long been salaried government employees. The
      crisis caused by the break-up of the Soviet Bloc required the government to seek
      a balance between command and market economies, and this influenced the decision
      to introduce capitated private practice for family doctor services on a trial
      basis. This article explains why and how a risk-adjusted capitation model was
      developed by a blend of empirical analysis and expert judgement, which comprises
      ten classes of clients defined by age-sex and poverty groupings. Payment
      relativities across the classes were set in proportion to a desirable (or target)
      number of contacts per year. Separate processes were used to set the targets for
      patient-initiated and active (health promotion and illness prevention) contacts.
      The model is intended to lead to greater equity of service access and provision.
      It should also encourage a greater concern for health outcomes, sensitivity to
      clients' views, and operational efficiency.

PMID- 10662231
TI  - In strife again: the next great health debate.

PMID- 10662232
TI  - Health care practice and the minimisation of patient medical litigation.
AB  - This article explores why patients sue their health care providers. Following an
      extensive literature review, it identifies 'sue' motivators and then examines the
      legal basis of medical litigation by reviewing contemporary case law. Armed with
      the 'sue' motivators and having considered the types of claims brought against
      health care providers, the article focuses upon what health care providers may do
      to minimise litigation. It recommends specific provocative measures, which are
      based upon satisfying a myriad of patient needs through consenting practices, and
      early recognition and resolution of patient issues by providers.

PMID- 10662233
TI  - A review of the role of information technology in discharge communications in
      Australia.
AB  - Information technology is believed to be useful for the communication of
      discharge information between hospitals and community-based health practitioners.
      At least 20 projects were conducted in Australia between 1993 and 1997 to explore
      this idea. The value of these projects was at least $618,000. Despite this level
      of activity there is no good evidence, either from these projects or the
      international literature, to suggest that information technology can improve the
      quality of discharge communications.

PMID- 10662234
TI  - Program budgeting and marginal analysis: a case study in chronic airflow
      limitation.
AB  - Program budgeting and marginal analysis is a method of priority-setting in health
      care. This article describes how this method was applied to the management of a
      disease-specific group, chronic airflow limitation. A sub-program flow chart
      clarified the major cost drivers. After assessment of the technical efficiency of
      the sub-programs and careful and detailed analysis, incremental and decremental
      wish lists of activities were established. Program budgeting and marginal
      analysis provides a framework for rational resource allocation. The nurturing of
      a vigorous program management group, with members representing all participants
      in the process (including patients/consumers), is the key to a successful
      outcome.

PMID- 10662235
TI  - The effect of the 30% private health insurance rebate on the purchasing behaviour
      and intentions of the Australian population.
AB  - This article examines the likely effect of the 30% private health insurance
      rebate on private health insurance coverage. It is based on a survey of the
      Australia population conducted in April-May 1999 which collected information on
      health insurance purchasing behaviour and intentions. These data are used to
      predict the subsidy's likely effect on hospital insurance coverage, with
      estimates ranging from 30.5% to 34.3% by May 2000. Ancillary insurance membership
      is forecast to increase to between 32.7% and 37.2% of the population over the
      same period. The 30% insurance rebate will probably produce, at best, a small
      increase in hospital insurance membership. The cost of the rebate is estimated at
      $1.4 billion in 1999-2000. Given the small increases in projected membership, the
      cost of the initiative is very high.

PMID- 10662236
TI  - Budget-holding: the answer to Australian primary care reform?
AB  - In common with other Organisation for Economic Cooperation and Development (OECD)
      countries, Australia is experiencing growth in expenditure on health care.
      However, while many other nations continue to pursue some variation of managed
      competition to address these problems, Australia has chosen a more incremental
      reform path, with initiatives such as the General Practice Strategy, restrictions
      in doctor supply and coordinated care trials. This article reviews the likely
      effectiveness of such initiatives in the light of experience and evidence of
      budget-holding in achieving similar objectives overseas. It concludes that budget
      holding offers a more effective strategy than current 'piecemeal' reforms to
      contain costs and increase efficiency within Australian health care.

PMID- 10662237
TI  - Staff perceptions of discharge planning: a challenge for quality improvement.
AB  - One hundred staff in three acute care public hospitals were asked about their
      perceptions of successes and failures of their discharge planning activities. The
      intention was to highlight ways in which the quality of discharge planning could
      be improved within the acute hospital setting. Generally staff described failures
      more commonly than successes, with a number of key failures being identified,
      including problems associated with vacating beds, lack of appropriate staff,
      patients and career education about discharge activities, general process issues,
      problems associated with community service provision and patients who are
      difficult to discharge. Staff identified the lack of feedback on the outcome of
      their efforts as a source of frustration and a barrier to improving discharge
      planning activities. The challenges for improving the quality of discharge
      planning in the acute hospital setting would appear to be in establishing
      appropriate structures and processes that promote interaction between staff,
      patients and community providers, and provide incentives for behavioural change.

PMID- 10662238
TI  - Bibliography. Current world literature. Neuro-ophthalmology.

PMID- 10662239
TI  - Bibliography. Current world literature. Ocular manifestations of systemic
      disease.

PMID- 10662240
TI  - The diagnostic challenge of occult large vessel ischemia of the retina and
      choroid.
AB  - Vascular occlusions of the retina and choroid can cause severe visual loss. These
      occlusions can occur as a result of systemic disease or after surgery. In most
      cases, the retinal appearance provides evidence of ischemia as the cause of
      visual loss. On occasion, however, clinical examination shows no objective signs
      of vascular occlusion, and this can lead the clinician to suspect optic nerve
      pathology as the cause of visual loss. This paper outlines some of the diagnostic
      criteria, clinical findings, and ancillary studies that can be used to
      differentiate between occult occlusion of the retina or choroid and optic nerve
      disease.

PMID- 10662241
TI  - Neuro-ophthalmology of diabetes.
AB  - The devastating, blinding effects of diabetic retinopathy have been well
      publicized. Although individually less common, many neuro-ophthalmologic
      complications are also associated with diabetes. The vascular effects of diabetes
      contribute to nonarteritic ischemic optic neuropathy, vasculopathic cranial
      neuropathies, and strokes affecting both afferent visual function and ocular
      motility. The neuropathic effects of diabetes primarily affect pupillary
      function, and the immunosuppressive effects of diabetes predispose to certain
      infections, such as mucormycosis. Diabetes is also associated with numerous
      congenital syndromes. This paper reviews the literature published in the past
      year on the neuro-ophthalmologic effects of diabetes.

PMID- 10662242
TI  - Coagulation abnormalities and their neuro-ophthalmologic manifestations.
AB  - Congenital and acquired hypercoagulable states arise from an imbalance between
      procoagulant and anticoagulant forces. Although these conditions are present
      throughout the vascular tree, they typically give rise to local thrombotic
      lesions in discrete segments of the veins or arteries; this suggests that focal
      defects in the vascular wall or blood flow must be associated with a
      hypercoagulable state to produce thrombosis. Numerous new factors associated with
      hypercoagulability have been described in the past few years. Congenital and
      acquired hypercoagulable states are reviewed here, with an emphasis on recent
      data on focal thrombosis involving the eye and central nervous system.

PMID- 10662243
TI  - Physiology, assessment, and disorders of the pupil.
AB  - Proper examination of the pupil provides an objective measure of the integrity of
      the pregeniculate afferent visual pathway and allows assessment of sympathetic
      and parasympathetic innervation to the eye. Infrared videography and
      pupillography are increasingly used to study the dynamic behavior of the pupil in
      common disorders, such as Horner's syndrome and tonic pupil.

PMID- 10662244
TI  - Eye-movement recordings in the evaluation of ophthalmologic and neurologic
      disorders.
AB  - This review focuses on the use of quantitative eye-movement recordings in the
      diagnosis of ophthalmologic and neurologic disorders and in the investigation of
      the pathophysiologic mechanisms of and possible treatments for these disorders.
      Recently developed methods for measuring eye movements about all three axes of
      rotation (horizontal, vertical, and torsion) are emphasized. These techniques are
      providing important insights into the basic physiology of eye-movement control
      and into the mechanisms of ocular motor disturbances in which torsion plays a
      significant role.

PMID- 10662245
TI  - Neuro-ophthalmology of eye-movement disorders.
AB  - Magnetic resonance and functional brain imaging continue to expand their roles in
      complementing the clinical examination to localize the causes of eye-movement
      disorders. A retrospective review from county-based clinical practices emphasized
      generally benign causes of third, fourth, and sixth cranial nerve palsies in
      children, but a study from a tertiary referral center found a high incidence of
      neoplasms causing sixth-nerve palsies in children. A prospective study found that
      38% of diabetic patients with third-nerve palsies had anisocoria up to 2.5 mm. An
      initial attempt to develop an evidence-based practice pathway for the evaluation
      of ocular motor nerve palsies has been developed for isolated sixth-nerve palsies
      in adults. In an important study of Graves hyperthyroidism, treatment with
      radioactive iodine was more likely than methimazole therapy alone to be
      associated with the appearance or worsening of ophthalmopathy. The clinical
      worsening of eye findings could be prevented by concurrent administration of
      corticosteroids for 3 months. Smoking is still a major controllable risk factor
      for thyroid ophthalmopathy.

PMID- 10662246
TI  - New genetic, pathophysiologic, and therapeutic issues in nystagmus.
AB  - Nystagmus may have onset in infancy or adulthood. Infantile-onset nystagmus is
      commonly associated with genetic disease, and recognition of the various genetic
      and nongenetic diseases in which it may develop has led to the understanding that
      nystagmus is often a response of the oculomotor system to an early-onset,
      bilateral abnormality of vision. Adult-onset nystagmus most often develops as a
      result of nongenetic neurologic disease, and it manifests in a variety of
      patterns. Genetic studies have allowed further identification of the genes and
      genetic loci associated with nystagmus, and careful eye-movement recordings in
      patients with various patterns of nystagmus have further clarified the oculomotor
      pathophysiology.

PMID- 10662247
TI  - Perimetry techniques in neuro-ophthalmology.
AB  - Advances in technology have produced several new techniques for evaluating the
      visual field. The standard Humphrey perimeter now has programs for SWAP (Short
      wavelength automated perimetry) and SITA (Swedish interactive thresholding
      algorithm). SITA seems particularly promising as an automated test that decreases
      testing time without sacrificing sensitivity or increasing variability. In
      addition, separate tests have been developed that may selectively evaluate
      particular pathways of the afferent visual system. This paper summarizes major
      advances in perimetry published in 1998 and 1999.

PMID- 10662248
TI  - Ocular manifestations of HIV infection.
AB  - Ophthalmic abnormalities are common in HIV-infected patients. Serious ophthalmic
      diseases often result from opportunistic infections and can cause blindness in
      the absence of prompt diagnosis and therapy. We review recent advances in the
      diagnosis and management of HIV-associated ocular disease, including
      cytomegalovirus retinitis, the leading cause of vision loss in HIV-infected
      patients. The widespread use of highly active antiretroviral therapy (HAART) over
      the past 3 years has reduced the morbidity and mortality associated with HIV
      infection. HAART has dramatically altered the incidence and natural history of
      many opportunistic infections, and we discuss the impact of HAART on ophthalmic
      disease.

PMID- 10662249
TI  - Ocular toxicity associated with systemic drug therapy.
AB  - Systemic drug-induced ocular side effects are increasing because of the vast
      numbers of new drugs being introduced. Reports of drug-induced ocular toxicity
      must be well documented, and other causes of these side effects must be ruled out
      to help establish causality. We reviewed the most recent reports of the most
      commonly used and newest systemic drugs that have been implicated in ocular
      toxicity. Using toxicologic criteria needed to establish causality, data from
      reports of ocular toxicity associated with systemic cidofovir (Vistide),
      sildenafil (Viagra), vigabatrin (Sabril), tamoxifen (Nolvadex),
      hydroxychloroquine (Plaquenil)/chloroquine (Aralen), amiodarone (Cordarone), and
      lovastatin (Mevacor)/simvastatin (Zocor) were evaluated and summarized. The
      probability for causality was determined to be high for all these drugs except
      for vigabatrin and lovastatin/simvastatin. Methods for detecting, preventing, and
      treating ocular toxic reactions were then reviewed for each drug.

PMID- 10662250
TI  - Ocular manifestations of systemic malignancies.
AB  - Ocular manifestations of systemic malignancy are important for both the
      ophthalmologist and the internist to recognize because they may precede the
      diagnosis of cancer. This review of the current literature discusses the clinical
      manifestations, etiology, and potential therapeutic interventions for a group of
      visual paraneoplastic syndromes, including carcinoma-associated retinopathy and
      melanoma-associated retinopathy. These conditions are characterized by elevated
      serum levels of autoantibodies directed against tumor antigen that cross-react
      with retinal proteins, resulting in rod and cone dysfunction. The clinical
      presentation, site of origin, frequency, and intraocular distribution of tumors
      metastatic to the eye are also reviewed.

PMID- 10662251
TI  - Ocular manifestations of systemic infections.
AB  - Ocular involvement, mainly uveitis or retinochoroiditis, is common in various
      systemic diseases, such as endogenous endophthalmitis, Lyme disease, human T-cell
      lymphotropic virus type I infection, toxoplasmosis, and toxocariasis. Recent
      progress, especially in laboratory microbiologic testing, has enabled us to
      reliably diagnose many formerly idiopathic intraocular inflammatory diseases. A
      group of systemic infectious diseases, including those discussed here, are
      implicated as a body of emerging or re-emerging diseases that have appeared in
      the past two decades and are thought to have a close relation with global
      socioenvironmental changes. This paper discusses recent clinical and experimental
      studies of the most important systemic infectious diseases that affect the eye.

PMID- 10662252
TI  - Ocular manifestations of rheumatologic disorders.
AB  - In the past year, advances have been made in our understanding of the genetics of
      Behcet disease. Indocyanine green angiography has allowed us to look at the
      pathologic changes seen in Behcet disease and sarcoidosis in more detail. New
      steroid-sparing treatment strategies for the control of ocular inflammatory
      disease are becoming better understood and better used, and their applications in
      sarcoidosis and juvenile chronic arthritis are reviewed here. The role of
      antiphospholipid antibodies in ocular disease has received attention,
      particularly in the context of systemic lupus erythematosus. Outcomes in HLA-B27
      positive patients with uveitis and in ocular disease associated with the systemic
      vasculitides are discussed here, and scalp necrosis in giant-cell arteritis is
      reviewed.

PMID- 10662253
TI  - Nutrition and the eye.
AB  - The topic "nutrition and the eye" cannot adequately be covered in a single review
      article; indeed, dozens of books and hundreds of articles have been written on
      the subject. This review concentrates on three areas in which specific nutrients
      are known or theorized to have a major impact on vision and the visual system:
      vitamin A deficiency; antioxidants and their proposed role in the prevention of
      age-related cataract and macular degeneration; and nutritional optic
      neuropathies, including those of the recent Cuban epidemic. In addition, this
      article touches on nutritional treatments that have been suggested for several
      less common eye diseases and, finally, considers several less prevalent
      conditions in which deficiency of or excess exposure to a particular nutrient has
      been associated with ocular pathology.

PMID- 10662254
TI  - Role of nocturnal arterial hypotension in the development of ocular
      manifestations of systemic arterial hypertension.
AB  - There are well-known associations between systemic arterial hypertension and a
      variety of ocular disorders that were previously considered to be primarily
      manifestations of arterial hypertension. Recent studies with 24-hour ambulatory
      blood pressure monitoring have shown that the development and progression of
      nonarteric anterior ischemic optic neuropathy and glaucomatous optic neuropathy
      are significantly correlated with nocturnal arterial hypotension, particularly in
      hypertensive patients receiving oral hypertensive therapy. These studies suggest
      that several of the ocular or optic nerve head ischemic or ocular vascular
      disorders previously thought to be manifestations of arterial hypertension may,
      in fact, be due to a combination of systemic arterial hypertension and
      hypotension, with arterial hypertension acting as a predisposing factor and
      arterial hypotension actually producing the disorders. This paper reviews this
      subject in light of recent studies and discusses the physiopathologic bases of
      the disorders in question. With the development of potent arterial hypotensive
      medications for arterial hypertension, arterial hypotension (particularly
      nocturnal hypotension) is increasingly emerging as an important cause of visual
      disorders. Therefore, it is strongly recommended that when a patient is at risk
      for ocular or optic nerve head ischemic or ocular vascular disorders, the
      ophthalmologist should talk to the treating physician about the potential risks
      of intensive arterial hypotensive therapy, particularly that administered in the
      evening or at bedtime.

PMID- 10662255
TI  - Ocular manifestations of diabetes mellitus.
AB  - The ocular complications of diabetes mellitus are numerous and include
      retinopathy, cataract, uveitis, and neurophthalmic disorders. A review of the
      current literature shows that the emphasis has changed from the laser and
      surgical management of pre-existent retinopathy to the development of cohesive
      multidisciplinary screening and education programs, and to a better understanding
      of the cellular and molecular mechanisms that underlie disease. The role of
      associated and potentially modifiable systemic factors is also now recognized.
      Early intervention with systemic and local therapies may soon provide hope for
      the better management of diabetic eye disease.

PMID- 10662256
TI  - Physicians' perspectives on communicating prescription drug information.
AB  - Physician-patient communication has been identified as one factor that influences
      prescription drug compliance rates, even though the nature of such communication
      has not been well described. This study used a qualitative approach (in-depth
      interviews with 20 physicians representing a variety of medical areas) to better
      understand the process by which physicians communicate prescription drug
      information to their patients. A content analysis of interview transcripts
      indicated that two-way interactions focusing on the specific needs of the
      patients should be encouraged over simply disseminating more and more information
      about prescriptions. Information regarding unlikely outcomes was suggested to
      cause patient anxiety, which might be tied to decreased compliance rates.
      Physicians stressed the importance of "patient-directed communication" and
      expressed their concern over what they considered to be inappropriate sources of
      drug information. Other specific reasons cited for noncompliance included
      forgetfulness, ignoring medication when feeling better, and apprehensions about
      side effects.

PMID- 10662257
TI  - Describing expert practice in physical therapy.
AB  - In this article, the authors demonstrate how grounded theory may be used to
      develop models for understanding clinical practice. Through a series of research
      studies involving novice, experienced, and expert physical therapy practitioners,
      conceptual frameworks were continually revised based on data obtained from
      returning to the field and relevant literature available at the time. As concepts
      and relationships moved to larger themes, a theoretical framework for expertise
      in clinical practice was proposed. Current work on verifying the theoretical
      framework continues. Grounded theory is an excellent research approach to bound
      and help guide a multistage research program involving multiple researchers
      working in multiple settings.

PMID- 10662258
TI  - Locating the feminist scholar: relational empowerment and social activism.
AB  - Over the past decade, the rhetoric of "empowerment" has permeated the health
      promotion, education, and social welfare literature. Many scholars and
      professionals, particularly those active in the field of social intervention and
      community development, have found themselves struggling for location in the
      emancipatory process. This struggle often is characterized by a profound self
      consciousness of privilege and the fear of being perceived as imposing and
      manipulative. This article explores the tensions inherent in the role of the
      scholar/activist using illustrations from the author's experience as principal
      investigator of the Atlantic Regional Evaluation of the Community Action Program
      for Children. In so doing, it discusses the importance of a relational approach
      to empowerment, one characterized by mutuality. A commitment to mutuality is seen
      as a key factor in enhancing the emancipatory capacities of empowerment-based
      research projects.

PMID- 10662259
TI  - Living with diabetes as a transformational experience.
AB  - The construct of transformation has been presented in many research studies as
      the epitome of living with a chronic illness. Because it has been inadequately
      defined, however, many other concepts (e.g., hope, meaning, control) are used in
      ways that suggest considerable overlap and correspondence with transformation.
      This article represents an attempt to explicate the structures and processes of
      transformation as they were revealed in a qualitative inquiry into the experience
      of individuals with Type I diabetes. In the accounts constructed with
      participants in this study, the process of personal transformation was
      significant in the attainment of healthy outcomes. The authors describe this
      transformation and examine its relationship to control and to the valued outcomes
      of intensified sense of self, meaning, and mastery.

PMID- 10662260
TI  - Courage as a process of pushing beyond the struggle.
AB  - Six qualitative studies have been carried out to better understand courage among
      individuals who range in age from 14 to 94 years and are experiencing a variety
      of lingering threats to their well-being. The purpose of this meta-interpretation
      was to synthesize those works and further delineate an emergent formal theory of
      courage. Based on the findings, courage is a dynamic phenomenon that is
      precipitated by a perceived threat. The ability to be courageous develops over
      time and includes efforts to fully accept reality, problem solve based on
      discernment, and push beyond ongoing struggles. Courageous behavior is
      characterized by efforts to be productive, make contributions, and help others
      and results in a sense of personal integrity and thriving. Courage is promoted
      and sustained by several interrelated intrapersonal and interpersonal forces as
      well as the reflective awareness that one has developed a courageous persona.

PMID- 10662261
TI  - Qualitative research into nurse decision making: factors for consideration in
      theoretical sampling.
AB  - This article details some of the theoretical sampling choices available to
      researchers considering qualitative approaches to research into nurse decision
      making and the information that informs it. It draws on the theoretical and
      empirical literature on decision theory and, in so doing, provides a rationale
      for the theoretical sampling choices proposed. The final sampling frame is
      designed to be applied to decision research in nursing but could offer starting
      points for research into the decisions of other professional clinical groups.

PMID- 10662262
TI  - New rules for telemedicine.

PMID- 10662263
TI  - Patients' rights.

PMID- 10662264
TI  - Capitation and insurance protection: how to protect against unpredictability.
AB  - Capitation contracting has created new challenges in the world of health care.
      The payment emphasis in a capitated environment concentrates on prepayment of
      services. Opportunities are created to control health care dollars by the
      physician or hospital group, but the potential downside must also be recognized.
      This article introduces the Provider Excess Loss (or "stop loss") insurance
      product and some of the main features of coverage. This insurance is specifically
      designed to protect providers in a capitated environment and is purchased by
      Physician Hospital Organizations (PHO), Independent Physician Associations (IPA),
      and physician-owned HMOs, among others. The emphasis is on collective purchasing.
      Focus on the main policy features-deductible options, allowable charges, and
      premium factors-should ensure a basic understanding of how coverage works and how
      to design coverage to make it fit the unique needs of each provider's risk.

PMID- 10662265
TI  - Communicate with patients using common office equipment.
AB  - Computer telephony is the technology associated with the electronic transmission
      of voice, fax, or other information using a computer via the telephone. Medical
      practices are increasingly under pressure to raise the level of customer service
      they offer while controlling or cutting expenses. Properly used, interactive
      voice technology will help a practice expand customer contact, reduce operating
      expenses, and increase staff efficiency. This article provides an overview of one
      of the most effective uses of telephony for a medical practice-patient
      communication systems. It looks at the benefits of such a system, lists the
      reasons for and advantages of using appointment reminders, and provides tips and
      criteria for buying a system, judging sound quality, justifying the cost, and
      keeping patients satisfied.

PMID- 10662266
TI  - Internet Medline providers.
AB  - Each database in this review has features that will appeal to some users. Each
      provides a credible interface to information available within the Medline
      database. The major differences are pricing and interface design. In this
      context, features that cost more and might seem trivial to the occasional
      searcher may actually save time and money when used by the professional. Internet
      Grateful Med is free, but Ms. Coady and I agree the availability of only three
      ANDable search fields is a major functional limitation. PubMed is also free but
      much more powerful. The command line interface that permits very sophisticated
      searches requires a commitment that casual users will find intimidating. Ms.
      Coady did not believe the feedback currently provided during a search was
      sufficient for sustained professional use. Paper Chase and Knowledge Finder are
      mature, modestly priced Medline search services. Paper Chase provides a menu
      driven interface that is very easy to use, yet permits the user to search
      virtually all of Medline's data fields. Knowledge Finder emphasizes the use of
      natural language queries but fully supports more traditional search strategies.
      The impact of the tradeoff between fuzzy and Boolean strategies offered by
      Knowledge Finder is unclear and beyond the scope of this review. Additional
      software must be downloaded to use all of Knowledge Finders' features. Other
      providers required no software beyond the basic Internet browser, and this
      requirement prevented Ms. Coady from evaluating Knowledge Finder. Ovid and Silver
      Platter offer well-designed interfaces that simplify the construction of complex
      queries. These are clearly services designed for professional users. While
      pricing eliminates these for casual use, it should be emphasized that Medline
      citation access is only a portion of the service provided by these high-end
      vendors. Finally, we should comment that each of the vendors and government
      sponsored services provided prompt and useful feedback to e-mail questions about
      usage. In conclusion, we would suggest you try the various services, determine
      which interface suits your style and budget, then perform simple searches until
      you learn the strengths and weaknesses of the service you select.

PMID- 10662267
TI  - Arbitration clauses in contracts between providers and patients.
AB  - Arbitration clauses in contracts between health care providers and their patients
      can offer benefits to both parties. However, practitioners need to ensure that
      their contracts will not be judged unenforceable by a court. This article
      outlines the contractual and constitutional issues involved in arbitration
      agreements and provides advice to practitioners on drafting such an agreement.

PMID- 10662268
TI  - The trouble with CHIP. State Children's Health Insurance Program.

PMID- 10662270
TI  - Disability benefits: what is the Social Security Administration thinking?
AB  - This article briefly describes decision-making standards and procedures used by
      the Social Security Administration in adjudicating disability insurance benefits
      claims. Correlatively, the article addresses and dispels some of the myths
      surrounding various outcomes of disability claims. It also describes the role of
      the treating physician and how a treating physician who wants to help his or her
      patient obtain disability benefits should respond to Social Security's requests
      for medical records and written reports.

PMID- 10662269
TI  - Paying surgeons less can cost more.
AB  - Fees for physicians' services represent only a small component of total health
      care costs. Complementary costs (particularly hospital charges for surgical
      treatment) are a far more substantial portion of total costs, and may be 10 times
      larger than surgical fees. Because surgeons have considerable influence over the
      demand for surgery, and because the complementary costs do not cost the surgeon
      at all, marginally lowering surgeons' fees can, paradoxically, increase total
      health care costs, even if net payments to surgeons go down. This is because
      surgeons may respond to a decrease in their per-case reimbursements by performing
      more surgery to maintain their status-quo income. This phenomenon is known as
      physician income homeostasis. A health care payer may benefit by paying surgeons
      more to perform tasks that do not have high associated costs, such as outpatient
      nonoperative care, research, or teaching. In this fashion, faced with declining
      surgical fees, the surgeon will maintain his or her income not by performing more
      expensive surgery, but rather by doing more nonoperative work.

PMID- 10662271
TI  - Computer networking in an ambulatory health care setting.
AB  - Computers are a ubiquitous part of the ambulatory health care environment.
      Although stand-alone computers may be adequate for a small practice, networked
      computers can create much more powerful and cost-effective computerized systems.
      Local area networks allow groups of computers to share peripheral devices and
      computerized information within an office or cluster of offices. Wide area
      networks allow computers to securely share devices and information across a large
      geographical area. Either singly or in combination, these networks can be used to
      create robust systems to help physicians automate their practices and improve
      their access to important clinical information. In this article, we will examine
      common network configurations, explain how they function, and provide examples of
      real-world implementations of networking technology in health care.

PMID- 10662272
TI  - Maintaining a computer-based patient education library.
AB  - The demand for patient education, both from patients themselves and from
      accreditation agencies for health and managed care organizations, is becoming
      more insistent. This article outlines the components of a system that maintains a
      library of computer-based patient education handouts that can be quickly
      integrated into a physician's practice.

PMID- 10662273
TI  - Future spending for medical care.
AB  - Why does the U.S. spend more for health care than other countries? What do we get
      for our additional money? Who pays the bills and bears the costs for health care?
      The article answers these questions and also provides observations about future
      trends in U.S. health care and challenges facing this country in the new century.

PMID- 10662274
TI  - An essential understanding of physician-patient communication. Part I.
AB  - The first of two parts, this article explores the question, "Is there a
      communication problem between patients and physicians?" It reviews both available
      literature on the topic of physician-patient communication and survey results
      that indicate a high degree of patient dissatisfaction with their relationships
      with physicians. One view of how to understand the relationship focuses on the
      patient as a consumer who must have the ability to choose a care provider and the
      information necessary to make informed choices. Other models embracing the
      scientific paradigm are also described.

PMID- 10662275
TI  - The telephone: managing demand.
AB  - The telephone system is the pulse of communication in a medical group. As
      customers demand increased access to their providers, telephone systems and their
      operators are becoming overloaded. Re-engineering is critical to meet this
      surging customer demand. This article explores new methods and applications of re
      engineering the telephone system by managing demand, instead of the traditional
      solutions of adding more staff and/or more lines.

PMID- 10662276
TI  - The ADA and the health care workplace.
AB  - T Employment related exposures are quickly becoming one of the largest liability
      exposures facing health care organizations, because employment claims as a whole
      are increasing in the courts and health care employees are usually highly paid
      professionals. The Americans with Disabilities Act (ADA) presents its own
      particular exposure implications, particularly because a health care employer's
      decision as to whether its employed health care professional is qualified to
      continue working can often affect patient care. The focus of this article is on
      how Title I of the ADA affects employment decisions in the health care workplace
      and what a health care employer can do to mitigate its ADA exposure. This article
      describes the scope and effect that the ADA has on the health care workplace. It
      also outlines an ADA compliance program with protocols and procedures for
      addressing ADA issues that arise in a health care practice.

PMID- 10662277
TI  - How should Medicare structure drug benefits?

PMID- 10662278
TI  - Benefits management beyond the adding machine: using integrated, worker-specific
      analysis.
AB  - Modern employee benefits practices have not taken advantage of modern information
      technology largely because of an implicit reliance on "adding machine" approaches
      to health care benefits. This article argues that an integrated, worker-specific
      approach to benefits management is needed in a modern benefits environment.
      Quantitative illustrations of the integrated approach are provided in terms of a
      benefits Pareto analysis. The empirical results presented suggest that human
      resource/risk management practices can have a significant impact on worker
      benefits costs.

PMID- 10662279
TI  - Making medical and disability benefit plans more manageable.
AB  - Good managed care health systems require two criteria for success: They must
      offer a set of checks and balances, and employees need to be given incentive to
      act in the best interest of the organization by acting in their own best
      interests. The authors discuss six principles that they claim are likely to
      reduce the complexity of making routine coverage decisions, while achieving the
      above two criteria.

PMID- 10662280
TI  - The 1999 Small Employer Retirement Survey: building a better mousetrap is not
      enough.
AB  - As of 1995, there were 5.3 million small-employer firms (100 or fewer employees)
      in the United States. These small firms employed 38.0 million individuals,
      representing 38 percent of all employment. Therefore, low retirement plan
      coverage among small employers directly affects a sizeable fraction of the
      national work force. There are a number of reasons why more small employers do
      not offer retirement plans. Cost and administration-related issues do matter, but
      for many small employers these take a back seat to other issues. For some, the
      main driver is the financial reality of running a small business: Their revenue
      is too uncertain to commit to a plan. For others, the most important reasons for
      not sponsoring a plan are employee-related, e.g., the workers do not consider
      retirement savings to be a priority, or the employer's work force has such high
      turnover that it does not make sense to sponsor a plan. Many nonsponsors are
      unfamiliar with the different retirement plan types available to them as
      potential plan sponsors, especially the options created specifically for small
      employers. For example, most nonsponsors said they have never heard of (36
      percent) or are not too familiar with (20 percent) SIMPLE plans for small
      businesses. Fifteen percent of small employers report that they are very likely
      to start a plan in the next two years, while 24 percent say this is somewhat
      likely. Nonsponsors report that the two items most likely to lead to serious
      consideration of sponsoring a plan are an increase in profits (69 percent) and
      business tax credits for starting a retirement plan (67 percent). Major drivers
      of low retirement plan sponsorship among small employers are who they employ and
      the uncertainty of revenue flows. While issues of administrative cost and burden
      matter, they are only part of the puzzle. Therefore, the solution is not simply
      "build it and they will come," by creating simpler and simpler retirement plans
      geared to small businesses. Rather, it is build it and they will come once the
      business reaches a certain level of profitability and stability, and once
      retirement planning and saving are more of a priority for the small employer's
      workers.

PMID- 10662281
TI  - Public attitudes on the U.S. health care system: findings from the 1999 Health
      Confidence Survey.
AB  - This Issue Brief presents the findings from the 1999 Health Confidence Survey
      (HCS), which focuses on Americans' satisfaction with the health care system today
      and their confidence in the system's future. It compares findings from the 1999
      HCS with those from the 1998 HCS, the first year the survey was conducted. In
      addition, it includes recent findings from the EBRI's 1999 Health Insurance
      Preference Survey. The 1999 HCS finds that, in many ways, Americans appear happy
      with their experience of the health care system. Among those respondents who have
      received care in the past two years, 57 percent are extremely or very satisfied
      with the quality of the medical care they received; 32 percent are somewhat
      satisfied. More than one-half (53 percent) are extremely or very satisfied with
      their ability to choose their doctor, while 23 percent are somewhat satisfied.
      Close to one-half are extremely or very satisfied, and 41 percent are somewhat
      satisfied, with the care they received in general. One-half of Americans with
      health insurance are extremely or very satisfied with their current health
      insurance plan. Almost four in 10 are somewhat satisfied. Confidence in many
      aspects of the health care system is high: 74 percent of Americans are extremely
      or very confident that their pharmacist will fill their prescription correctly,
      and 20 percent are somewhat confident. Almost six in 10 are extremely or very
      confident, and 33 percent are somewhat confident, that they will be able to see a
      health care specialist if they need one. Just under one-half are extremely or
      very confident that they are able to choose their own doctor or hospital (48
      percent confident, 34 percent somewhat confident); that their doctor's treatment
      will be based on their health care needs rather than on cost (46 percent
      confident, 36 percent somewhat confident); and that doctors are up-to-date on
      information about medicine and medical conditions (46 percent confident, 41
      percent somewhat confident). The results of the HCS also reveal several areas of
      concern. First, there is a great deal of confusion about what managed care is and
      whether or not individuals are enrolled in managed care programs. As a
      consequence, many Americans' opinions of managed care are based on what they have
      been told by others, rather than on their own actual experience with managed
      care. A second area of concern is that several key groups tend to be less
      satisfied and less confident about the American health care system. These include
      individuals in managed care, those in poorer health, and women. While many are
      satisfied with the health care they have recently received, Americans do not rate
      the overall health care system highly. They are concerned about escalating health
      care costs, and they lack confidence in the future of health care in America.

PMID- 10662282
TI  - The Internet: old faithful?

PMID- 10662283
TI  - Twice what he bargained for. Interview by Gary Baldwin.

PMID- 10662284
TI  - Connecting the financial dots.

PMID- 10662285
TI  - Image is everything.
AB  - Digital imaging is transforming the practice of radiology. But provider
      organizations face many technical and financial challenges on the road to
      becoming filmless. Their own reluctance to let go of the film habit is making the
      transition to digital images difficult. And the complexity of the myriad
      technologies, as well as the high prices delivery systems and hospitals still
      must pay to acquire them, are slowing the march toward filmless radiology
      departments.

PMID- 10662286
TI  - Intranets are the key to new database strategies.
AB  - Health care organizations are finding that easy-to-use intranets can improve
      access to data. Because intranets are easier to navigate than other networks--and
      often less expensive--many provider and payer organizations are reorienting their
      database plans. But some organizations move too fast with new plans and have
      difficulty standardizing enterprisewide data, threatening intranet viability.

PMID- 10662287
TI  - Laboratory systems evolve to meet data demands.
AB  - As provider organizations consolidate and confront managed care pressures,
      they're looking for laboratory information systems that go beyond the basics.
      They want lab systems that can integrate with other computer systems, make data
      available at the point of care, and exchange information over the Internet or
      intranets. Systems integration efforts, however, are proving troublesome for some
      CIOs.

PMID- 10662288
TI  - Managed care. Keeping it simple.

PMID- 10662289
TI  - Stanford/UCSF merger dissolves. Stubborn faculty loyalty and lack of cooperation
      blamed.

PMID- 10662290
TI  - Getting connected with telemedicine. Some applications gaining payer recognition.

PMID- 10662291
TI  - Investing in community redevelopment pays big dividends. Strategy is redefining
      the role of inner-city hospitals.

PMID- 10662292
TI  - Care denials causing a stir among physicians.

PMID- 10662293
TI  - Losses, private inurement concerns spell end for PHO-MSO. Reorganization gives
      entities new life, focus.

PMID- 10662294
TI  - Advocate Health Care launches major cost-reduction initiative. Effort designed to
      counteract BBA.

PMID- 10662295
TI  - Physician recruiting: what's different now?

PMID- 10662296
TI  - HCFA revises reassignment rules.

PMID- 10662297
TI  - Fear and loathing in Florida--PPMC's, fee-splitting, and anti-kickback
      implications.
AB  - Many developments are occurring with respect to practice management agreements in
      Florida. These include the District Court of Appeal affirmance of the Bakarania
      decision, a bankruptcy court decision to the effect that the PhyMatrix Agreement
      evaluated in Bakarania constitutes illegal fee-splitting. There was also a new
      Board of Medicine decision permitting a percentage arrangement under a
      "management agreement." This article summarizes the recent developments in
      Florida, as well as some developments in other states, which are relevant for
      practice management agreements throughout the country.

PMID- 10662298
TI  - 50 years of ideas in healthcare buildings. Nuffield Trust.

PMID- 10662299
TI  - NHS Trust plant replacement and maintenance scheme.

PMID- 10662300
TI  - New hospital for Bishop Auckland.

PMID- 10662301
TI  - The signs they are a-changin'.

PMID- 10662302
TI  - Low temperature sterilization from an engineering viewpoint.

PMID- 10662303
TI  - "Shall we drive or fly?" Integration of ground and air transport.

PMID- 10662304
TI  - The role of paramedics in the ED.

PMID- 10662305
TI  - Mixed messages: interpreting body language.

PMID- 10662306
TI  - The millennium bug: a scheduled global disaster?

PMID- 10662307
TI  - Two wheels are better than none.

PMID- 10662308
TI  - On the rampage.

PMID- 10662309
TI  - Much ado about nothing.

PMID- 10662310
TI  - Service user movement. The customer is sometimes right.
AB  - Patients' groups and service user organisations have grown enormously in the past
      20 years. The NHS is beginning to take the principle of patients managing their
      own conditions seriously. Sustained service user involvement in the planning of
      local services is still some way off.

PMID- 10662311
TI  - Private finance. Oz trials.
AB  - Privatization of a public sector general hospital in Adelaide, Australia, five
      years ago has revealed the strengths of the model and the difficulties of
      contracting with the private sector. Managers believe the new model has reduced
      overstaffing and increased local management. There have been continual
      contracting problems and the hospital has made losses, almost from the start.
      Private finance initiative contracts may always be difficult to negotiate and
      sustain.

PMID- 10662312
TI  - Community hospitals. Cornish hops.
AB  - A joint health and social services trial initiative to facilitate transfers from
      acute hospitals to four community hospitals in east Cornwall has increased
      placements. Discharge planning from the community hospitals has also been
      improved with the appointment of a specialist social worker. Staff involved
      believe the project has improved communication between agencies.

PMID- 10662313
TI  - Open space. Derailing the gravy train.

PMID- 10662314
TI  - Stroke services. The right register.

PMID- 10662316
TI  - Heroes to zero?

PMID- 10662315
TI  - On the evidence. Diabetes.

PMID- 10662317
TI  - NHS boards. The odd couple.
AB  - The appointment of chairs is seen as political and lacking in transparency. Their
      training is patchy. Nearly a third of chairs and chief executives in this study
      had experienced major difficulties in their relationship. Relationship breakdown
      was generally due to chairs' behaviour.

PMID- 10662319
TI  - Primary care. Planning permission.

PMID- 10662318
TI  - Health economics. Perfect combination.
AB  - The assumption by some HAs that a shift from mono to combination drug therapies
      for HIV results in a proportional increase in drug expenditure, regardless of
      health gains, is misguided. Methods of calculating anti-HIV drug expenditure have
      failed to keep up with changing treatment regimes. There is an urgent need to
      change the way data on antiretroviral use is collected and presented to establish
      the true cost-effectiveness of new drug regimes.

PMID- 10662320
TI  - Shouldering the blame.

PMID- 10662321
TI  - Data briefing. Charges.

PMID- 10662322
TI  - Out-of-hours care. Co-operative society.
AB  - The last decade has seen a burgeoning of out-of-hours services in a movement
      characterized by experimentation and innovation that may have implications for
      all health services. The system needs to be more integrated to remove duplication
      and fill existing gaps in the service. But resistance from healthcare
      professionals is a major barrier. A shift from an out-of-hours emergency service
      towards 24-hour access for routine healthcare would be unsustainable and have
      limited health gain. NHS Direct should be the single point of access, with open
      access to A&E services restricted to people unable to telephone and who require
      urgent specialist care.

PMID- 10662323
TI  - Drug addiction therapy. A dance to the music of time.
AB  - Dance therapy can play a useful role in the treatment and rehabilitation of women
      with drug addiction. It works by raising self-esteem through an improved
      relationship with the body, giving women the strength to help combat their habit.
      The benefits of dance therapy for women at the detox unit of Holloway Prison have
      been confirmed by prison staff.

PMID- 10662325
TI  - Guide to cataracts. Clouds on the horizon.

PMID- 10662324
TI  - The young ones. Interview by Alison Moore.

PMID- 10662326
TI  - MMR vaccine. Immune to argument?

PMID- 10662327
TI  - Evidence-based medicine. Faith, hope and clarity.

PMID- 10662328
TI  - Freedom of information. Quietly does it.
AB  - The forthcoming legislation on freedom of information is likely to be far less
      radical than originally envisaged. Decisions over what information to release
      will rest with civil servants. The legislation is likely to require primary care
      groups to respond to requests for information about allocation of resources
      between services. Access to the workings of government and the evidence
      underlying policy decisions would enable people to become active citizens. It
      would also stimulate sympathy for managers' and clinicians' rationing dilemmas.
      Current restrictions are at odds with government policy to modernize the NHS.

PMID- 10662329
TI  - PCG boards. Social climbers.
AB  - A national survey of PCG chief executives and social services representatives on
      PCG boards showed that most consider the social services role 'very useful'. Most
      social services representatives spent two to four days a month on PCG business.
      Two-thirds felt they needed more time. Almost half felt they had little or no
      support. Better feedback mechanisms are needed for social services
      representatives.

PMID- 10662330
TI  - Nowhere plans for nobody?

PMID- 10662331
TI  - Mentoring. Head to head.
AB  - What is a mentor? Sounding board, joint problem solver, ratifier, mirror, coach,
      repository--for dumping 'baggage', referee, devil's advocate--to find the weak
      spot in your proposal or argument, connector and networker, empathiser, guide.

PMID- 10662332
TI  - Funding. Regeneration game.

PMID- 10662333
TI  - Five chairs, but no sofa.

PMID- 10662334
TI  - Trash talk. What's hot, what's not in the world of waste management.

PMID- 10662335
TI  - Power protection. Making sure your power supply is reliable.

PMID- 10662336
TI  - Infection connection. Keeping your laundry germ-free.

PMID- 10662337
TI  - Into thin air. IAQ (indoor air quality) proposal vanishes from spotlight.

PMID- 10662338
TI  - Competition 101. Beat contractors at their own game.

PMID- 10662339
TI  - Going for the gold. Raise a million bucks for your service.

PMID- 10662340
TI  - Crowded venues. Avoid an EMS quagmire by preparing for mass gatherings.

PMID- 10662341
TI  - Developing a mass gathering EMS plan.

PMID- 10662342
TI  - EMS at Woodstock '99.

PMID- 10662343
TI  - Burning Man festival.

PMID- 10662344
TI  - JEMS buyer's guide 2000.

PMID- 10662345
TI  - When a patient lies about his health history.

PMID- 10662346
TI  - Good medicine has gone to the dogs.

PMID- 10662347
TI  - HCFA clarifies use of modifiers for outpatient hospital services.

PMID- 10662348
TI  - Focus on revenue enhancement. Utilizing nonphysician practitioners and getting
      paid.

PMID- 10662349
TI  - Health status of Asian Americans: United States, 1992-94.
AB  - OBJECTIVES: This report compares the health status of selected Asian national
      origin groups. METHODS: 1992-94 National Health Interview Survey (NHIS) data were
      analyzed for six Asian national origin groups (Chinese, Filipino, Asian Indian,
      Japanese, Vietnamese, and Korean), the Asian and Pacific Islander (API)
      population as a whole, and the non-Hispanic white population. Unadjusted and age
      adjusted estimates and standard errors of health indicators and sociodemographic
      characteristics were generated. A broad range of health issues was studied
      including respondent-assessed health status, activity limitation, physician
      contacts, restricted activity days, hospital episodes, smoking status, and
      knowledge of acquired immunodeficiency syndrome (AIDS). RESULTS: A greater age
      adjusted percent of Vietnamese (17.2 percent) and Korean (12.8 percent) persons
      had fair or poor respondent-assessed health status than persons of Chinese,
      Filipino, and Japanese descent (6.1-7.4 percent). A lower age-adjusted percent of
      Chinese persons (6.5 percent) experienced activity limitation compared with
      Filipino, Japanese, and Vietnamese persons (9.4-13.2 percent). Japanese persons
      (4.9 contacts) had a greater average annual number of physician contacts than
      Chinese persons (3.1 contacts) after age adjusting the data. When the data were
      age adjusted, a higher percent of Korean adults (22.5 percent) were current
      smokers than Chinese (10.0 percent) and Asian Indian adults (8.7 percent). A
      higher age-adjusted percent of Vietnamese (21.2 percent) and Asian Indian (18.0
      percent) adults reported knowing nothing about AIDS compared with Japanese adults
      (5.1 percent). A greater proportion of Vietnamese adults (91.6 percent) had not
      been tested for the AIDS virus infection compared with Chinese, Filipino, Asian
      Indian, and Japanese adults (72.6-78.5 percent) after age adjusting the data.
      CONCLUSIONS: Differences in health emerge when data on the API population are
      analyzed by national origin group. Estimates of health presented for the API
      population as a whole mask differences among subgroups.

PMID- 10662350
TI  - Characteristics of hospice care users: data from the 1996 National Home and
      Hospice Care Survey.
AB  - OBJECTIVE: This report presents numbers and percents of hospice care current
      patients and discharges by characteristics of the agencies from which the care
      was received, patient and discharge characteristics, services provided, types of
      personnel that provided the services, admission diagnoses, and procedures.
      METHODS: The data used for this report are from the National Center for Health
      Statistics' 1996 National Home and Hospice Care Survey. This is a sample survey
      through which data are collected on the use of hospices and home health care
      agencies in the United States. RESULTS: During 1996, there were an estimated
      59,400 patients receiving hospice care services from 1,800 hospices and home
      health care agencies in the United States. These agencies had 393,200 discharges
      from hospice care during the year prior to the survey. The agencies tended to be
      voluntary nonprofit, certified by Medicare and Medicaid, and located in a
      metropolitan statistical area. About a third were part of a chain or group of
      agencies and 40 percent were operated by a hospital. Fifty-five percent of the
      current patients and 50 percent of the discharges were women. Both current
      patients and discharges tended to be 65 years of age and over, white, married or
      widowed, lived in a private or semiprivate residence, and had a primary
      caregiver. The most common diagnoses at admission were malignant neoplasms and
      heart disease. About a fifth of the patients and discharges had a surgical or
      diagnostic procedure related to their admission for care. The most common ones
      were miscellaneous diagnostic and therapeutic procedures.

PMID- 10662351
TI  - Ambulatory surgery in the United States, 1996.
AB  - OBJECTIVES: This report presents estimates of surgical and nonsurgical procedures
      performed on an ambulatory basis in hospitals and freestanding ambulatory surgery
      centers in the United States during 1996. Data are presented by types of
      facilities, age and sex of the patient, and geographic region. Major categories
      of procedures and diagnoses are shown by age, sex, and region. METHODS: The
      estimates are based on data collected by the 1996 National Survey of Ambulatory
      Surgery conducted by the National Center for Health Statistics. The 1996 data
      were abstracted from 125,000 medical records in 488 hospitals and freestanding
      ambulatory surgery centers.

PMID- 10662352
TI  - 1996 summary: National Hospital Discharge Survey.
AB  - OBJECTIVES: This report presents national estimates of the use of non-Federal
      short-stay hospitals in the United States during 1996. Numbers and rates of
      discharges, diagnoses, and procedures are shown by age and sex. Discharges are
      also shown by geographic region of hospital. Average lengths of stay are
      presented for discharges and selected diagnostic categories. METHODS: The
      estimates are based on medical abstract data collected through the National
      Hospital Discharge Survey for 1996. The survey has been conducted annually by the
      National Center for Health Statistics since 1965. Diagnoses and procedures
      presented are coded according to the International Classification of Diseases,
      9th Revision, Clinical Modification, or ICD-9-CM. RESULTS: In 1996, there were an
      estimated 30.5 million discharges of inpatients, excluding newborn infants, from
      non-Federal, short-stay hospitals in the United States. The discharge rate was
      116 per 1,000 population and the average length of stay was 5.2 days. Five
      diagnostic categories accounted for more than a million discharges. These were
      heart disease, delivery, malignant neoplasms, pneumonia, and psychoses. There
      were 40.4 million procedures performed on hospital inpatients during the same
      year. About three-fourths of all procedures were in four ICD-9-CM chapters:
      miscellaneous diagnostic and therapeutic procedures, obstetrical procedures,
      operations on the cardiovascular system, and operations on the digestive system.

PMID- 10662353
TI  - Office visits to orthopedic surgeons: United States, 1995-96.
AB  - OBJECTIVES: This report describes the utilization of ambulatory medical care
      services as provided by nonfederally employed, office-based orthopedic surgeons
      during the period 1995-96. Statistics are presented on selected physician,
      patient, and visit characteristics. METHODS: The data presented in this report
      were collected from the 1995 and 1996 National Ambulatory Medical Care Surveys
      (NAMCS). NAMCS is a national probability sample survey of visits to nonfederally
      employed, office-based physicians. Sample data are weighted to produce annual
      estimates. The survey is a component of the National Health Care Survey, which
      measures health care utilization across a variety of providers. Data are
      presented in this report as annual averages, unless otherwise noted. RESULTS:
      During 1995-96, an estimated 76.5 million office visits were made to orthopedic
      surgeons, an average of 38.3 million visits per year. The annual average visit
      rate was 14.5 visits per 100 persons. This represents an increase over the 1975
      76 estimate of 11.3 visits per 100 persons. Visits to orthopedic surgeons
      accounted for 5.3 percent of all office-based ambulatory care visits during 1995
      96, but this specialty received 28.3 percent of all injury-related office visits.
      The most frequent reasons given by patients for visiting orthopedic surgeons were
      knee symptoms, postoperative visits, back symptoms, and shoulder symptoms.

PMID- 10662354
TI  - International comparative analysis of injury mortality. Findings from the ICE on
      injury statistics. International Collaborative Effort on Injury Statistics.
AB  - OBJECTIVE: This report investigates international differences in injury mortality
      rates among 11 of the countries participating in the International Collaborative
      Effort on Injury Statistics. METHODS: The cause, intent, and age-specific injury
      mortality rates are calculated and presented from Australia, Canada, Denmark,
      England & Wales, France, Israel, New Zealand, The Netherlands, Norway, Scotland,
      and the United States. Data are presented by cause (or mechanism) and intent (or
      manner of death) according to the matrix framework for presenting injury
      mortality statistics published in August 1997. The benefits of this matrix
      approach to investigating injury mortality are explained with numerous examples.
      RESULTS: Injury death rates are higher in France and Denmark and lower in England
      & Wales, Israel, and The Netherlands than elsewhere. New Zealand, the United
      States, and Norway had similar average annual injury death rates of 56-57 per
      100,000 population. As an example of the benefit of presenting data in the matrix
      framework, the total poisoning death rate in Denmark for all categories of intent
      (13 per 100,000) is about twice the rate in the United States. Unintentional
      poisoning death rates, however, are similar in the United States and Denmark
      (about 4 per 100,000) and are higher than elsewhere. However, the suicide
      poisoning death rate in Denmark is 3 times the rate in the United States.
      CONCLUSION: Using these results, the ICE on Injury will be investigating death
      registration practices in each of the countries to better understand
      international variation in injury mortality due to reporting or registration
      procedures.

PMID- 10662355
TI  - National Hospital Ambulatory Medical Care Survey: 1997 emergency department
      summary.
AB  - OBJECTIVES: This report describes ambulatory care visits to hospital emergency
      departments in the United States. Statistics are presented on selected patient
      and visit characteristics. METHODS: The data presented in this report were
      collected from the 1997 National Hospital Ambulatory Medical Care Survey
      (NHAMCS). NHAMCS is part of the ambulatory care component of the National Health
      Care Survey that measures health care utilization across various types of
      providers. NHAMCS is a national probability survey of visits to hospital
      emergency and outpatient departments of non-Federal, short-stay, and general
      hospitals in the United States. Sample data were weighted to produce annual
      estimates. RESULTS: During 1997, an estimated 94.9 million visits were made to
      hospital emergency departments (ED's) in the United States, about 35.6 visits per
      100 persons. Persons 75 years and over had the highest rate of ED visits. There
      were an estimated 35.1 million injury-related ED visits during 1997, or 13.2
      visits per 100 persons. Seventy percent of injury-related ED visits were made by
      persons under 45 years of age. Injury visit rates were higher for males than
      females in each age group under 45 years. According to ICD-9-CM classification,
      about four-fifths of injury visits were unintentional. Almost 72 percent of the
      ED visits involved medication therapy, with pain relief drugs accounting for
      almost 30 percent of the medications mentioned. Acute upper respiratory infection
      was the leading illness-related diagnosis at ED visits.

PMID- 10662356
TI  - National Ambulatory Medical Care Survey: 1997 summary.
AB  - OBJECTIVE: This report describes ambulatory care visits made to physician offices
      within the United States. Statistics are presented on selected characteristics of
      the physician's practice, the patient, and the visit. METHODS: The data presented
      in this report were collected from the 1997 National Ambulatory Medical Care
      Survey (NAMCS). NAMCS is part of the ambulatory care component of the National
      Health Care Survey, which measures health care utilization across various types
      of providers. NAMCS is a national probability sample survey of visits to office
      based physicians in the United States. Sample data are weighted to produce annual
      estimates. RESULTS: During 1997 an estimated 787.4 million visits were made to
      physician offices in the United States, an overall rate of 3.0 visits per person.
      One quarter of these visits were made to general and family physicians, which was
      a significantly higher proportion compared to the other 13 specialties. Persons
      aged 75 years and over had the highest rate of physician office visits, 6.5
      visits per person. Females had a significantly higher rate of visits to physician
      offices than males overall, as did white persons compared with black persons. Of
      all visits made to these offices in 1997, approximately 50 percent listed private
      insurance as the primary expected source of payment, and almost 30 percent were
      made by patients belonging to a health maintenance organization (HMO). There were
      an estimated 81.6 million injury-related visits during 1997, or 30.6 visits per
      100 persons. Two-thirds of these visits were for unintentional injuries.

PMID- 10662357
TI  - Adoption, adoption seeking, and relinquishment for adoption in the United States.
AB  - OBJECTIVES: This report presents national data on adoption and adoption-related
      behaviors among ever-married women 18-44 years of age in the United States,
      according to selected characteristics of the women. Trends are shown in the
      prevalence of adoption and relinquishment of children for adoption. For 1995, the
      report shows demand for adoption and women's preferences for characteristics of
      the child. METHODS: Data are based on nationally representative samples of women
      15-44 years of age from the 1973, 1982, 1988, and 1995 National Surveys of Family
      Growth (NSFG). RESULTS: The percent of ever-married women 18-44 years of age who
      have ever adopted a child declined from 2.1 percent in 1973 to 1.3 percent in
      1995. Of the 9.9 million women who had ever considered adoption, 16 percent had
      taken steps toward adoption, and 31 percent of these had actually adopted a
      child. Older women, nulliparous women, women with fecundity impairment, and women
      who have used infertility services were more likely to have considered adoption,
      to have taken concrete steps toward adoption, and to have actually adopted a
      child. In response to the questions about preferred characteristics of an adopted
      child, women expressed strong preferences with respect to age, sex, race, and
      disability level of the child, but were willing to accept children with the less
      desired traits. Between 1989 and 1995, about 1 percent of babies born to never
      married women were relinquished for adoption, down from 9 percent among such
      babies born before 1979. CONCLUSIONS: Federally supported adoption data
      collection sources corroborate the decline in adoption shown by the NSFG over the
      past 25 years. Demand for adoption in the United States varies, depending on
      whether demand is conceptualized liberally as "ever having considered adoption"
      or more narrowly, as "currently taking concrete steps toward adoption." The
      narrow definition was fulfilled by 232,000 ever-married women in 1995.

PMID- 10662358
TI  - National Hospital Ambulatory Medical Care Survey: 1997 outpatient department
      summary.
AB  - OBJECTIVE: This report describes ambulatory care visits to hospital outpatient
      departments in the United States. Statistics are presented on selected hospital,
      clinic, patient, and visit characteristics. METHODS: The data presented in this
      report were collected from the 1997 National Hospital Ambulatory Medical Care
      Survey (NHAMCS). NHAMCS is part of the ambulatory care component of the National
      Health Care Survey that measures health care utilization across various types of
      providers. NHAMCS is a national probability sample survey of visits to hospital
      outpatient and emergency departments of non-Federal, short-stay, and general
      hospitals in the United States. Sample data are weighted to produce annual
      estimates. RESULTS: During 1997, an estimated 77.0 million visits were made to
      hospital outpatient departments in the United States, an overall rate of 28.9 per
      100 persons. Visit rates did not vary by age. Black persons had higher rates of
      visits than white persons. Of all visits made to hospital outpatient departments
      in 1997, 34.1 percent and 27.8 percent, respectively, listed private insurance
      and Medicaid as the primary expected source of payment, and 20.1 percent were
      made by patients belonging to a health maintenance organization. There were an
      estimated 7.1 million injury-related outpatient department visits during 1997.

PMID- 10662360
TI  - Management of depression in a primary care office setting.
AB  - The Behavioral Health and Primary Care Depression Initiative provides a continuum
      of care for the chronic disease of depression. The expected results of this
      initiative are an improvement in the identification and treatment of depression.
      Providers will have increased confidence in their ability to treat depressed
      patients. Patients who are diagnosed with depression will receive appropriate
      care, follow-up, and referral and will have an improved quality of life. The
      community will experience more social, vocational, and economic health.

PMID- 10662359
TI  - 1997 summary: National Hospital Discharge Survey.
AB  - OBJECTIVES: This report presents national estimates of the use of non-Federal
      short-stay hospitals in the United States during 1997. Numbers and rates of
      discharges, diagnoses, and procedures are shown by age and sex. Discharges are
      also shown by geographic region of the hospital. Average lengths of stay are
      presented for all discharges and for selected diagnostic categories by age and by
      sex. METHODS: The estimates are based on medical abstract data collected through
      the National Hospital Discharge Survey for 1997. The survey has been conducted
      annually by the National Center for Health Statistics since 1965. Diagnoses and
      procedures presented are coded according to the International Classification of
      Diseases, 9th Revision, Clinical Modification, or ICD-9-CM.

PMID- 10662361
TI  - Innovative procedural quality assurance.

PMID- 10662362
TI  - The ideal compliance world: integrating physicians into the compliance program.
AB  - Compliance officers are in a unique position to provide guidance to physicians
      and will succeed in gaining physician support and buy-in when appropriate steps
      are taken to integrate physicians into the compliance program. First and
      foremost, the compliance officer's primary responsibility is to apprise
      physicians of the seriousness nature of current compliance issues. When
      physicians are provided with clear information through a variety of media, they
      will understand that compliance program goals and objectives will resolve
      compliance-related issues dilemmas. Next, the compliance officer should expect no
      less than the ideal compliance world. Recruit physician champions who will
      actively participate in compliance program planning and development. Call upon
      medical staff members to get involved in implementation stages of compliance
      action plans and engage physician leaders to educate and train their physician
      peers on compliance-related issues. Most importantly, minimize individual
      physician liability by providing adequate education programs to physicians. Help
      them to master the art of coding and documentation and to mitigate any prospect
      of fraud and abuse or compliance-related concerns. Last, collaboration is the key
      -the compliance officer must provide guidance to the physician so that the
      physician may continue to fulfill the role of leader and healer. In turn, the
      physician must recognize that his or her actions and those of the hospital and
      system are inseparable and that they must actively participate in compliance
      program initiatives.

PMID- 10662363
TI  - Spotting the legal pitfalls of healthcare on the Internet.

PMID- 10662364
TI  - Considerations for influencing physician referrals.

PMID- 10662365
TI  - Dollars and stents: is reimbursement floating out of reach?

PMID- 10662366
TI  - Health fair & CPR training: a successful community outreach, partnering &
      marketing opportunity.
AB  - The Penn State Geisinger Cardiovascular Center at the Milton S. Hershey Medical
      Center offered a free public Health Fair with Cardiopulmonary Resuscitation (CPR)
      training on February 28, 1998. This program was provided in recognition of
      Pennsylvania's "Heart Month" and benefited the Central Pennsylvania community.
      This article details the rationale, planning, implementation, as well as the
      proven marketing advantages for providing such an event.

PMID- 10662367
TI  - What are your goals and objectives? Using information to improve performance in
      the cath lab.

PMID- 10662368
TI  - The perils of patients' rights.

PMID- 10662369
TI  - Investing in education. When a manufacturer brought a college campus to its rural
      headquarters it earned a lot more than diplomas.

PMID- 10662370
TI  - Monster mergers in managed care. 2. How purchasers can hold their ground.

PMID- 10662371
TI  - Will PPOs knock down the competition?

PMID- 10662373
TI  - High honors for encouraging health. Fitness, productivity and fresh thinking
      featured prominently in this year's Koop Awards.

PMID- 10662372
TI  - The real measure of productivity.

PMID- 10662374
TI  - Will Congress put MSAs on life support?

PMID- 10662375
TI  - Datawatch. The lowdown on no-shows.

PMID- 10662376
TI  - Seniors share desire for better end-of-life care.

PMID- 10662377
TI  - Dealing with death in the nursing home.

PMID- 10662378
TI  - Forget the upfront cash: tweak systems and add sourcing avenues.

PMID- 10662379
TI  - Cutting costs by managing turnover.

PMID- 10662380
TI  - The new employee scavenger hunt: a training tool for the '90's.

PMID- 10662381
TI  - Clinton proposal begins debate on Medicare prescription benefit.

PMID- 10662382
TI  - "Revolutionary" national living will unveiled; document is legally valid in 33
      states.

PMID- 10662383
TI  - Marketplace. Vendors search for the right pitch to sell providers on outcomes
      software.

PMID- 10662384
TI  - Perspectives. Will United help defuse backlash by scrapping authorization rules?

PMID- 10662385
TI  - Health care trends in today's marketplace.
AB  - As the year 2000 approaches, it is apparent that employer-sponsored health plans
      will again begin to experience high rate increases. Employers will need to
      utilize an up-to-date benefits philosophy and health plan purchasing strategy
      coupled with monitoring tools and vendor performance guarantees to deal with the
      situation. While many of the cost drivers are beyond an employer's control,
      taking a preemptive strike at health care inflation through design, cost sharing
      and other focused initiatives will minimize its impact.

PMID- 10662386
TI  - A DHMO (Dental HMO) value checker and understanding drivers of dentists'
      behavior.
AB  - Although the majority of employees enrolled in dental HMOs (DHMOs) are pleased
      with the services they provide, some plan sponsors have experienced difficulties
      with them. Understanding the balance of risks and incentives DHMO participation
      presents to dentists may help plan sponsors avoid pitfalls and obtain better
      value from these plans. This article includes a "value checker" to be used in
      assessing a DHMO.

PMID- 10662387
TI  - Making Internet benefits enrollment work for you.
AB  - With all of its promise, the Internet is virtually impossible for a benefits
      administrator to ignore, but implementing an Internet-enabled benefits
      administration system is not without its challenges. However, with the proper
      care and planning, any employer, regardless of size or employee population, can
      successfully leverage this technology to simplify benefits administration, reduce
      costs and improve the level of service to plan participants.

PMID- 10662388
TI  - A heart attack of her own.

PMID- 10662389
TI  - AHP's awful losing streak.

PMID- 10662390
TI  - Pharmacoeconomics and health policy. Current applications and prospects for the
      future.
AB  - The use of pharmacoeconomic tools has grown dramatically in the past decade as
      provision of healthcare throughout the industrialised world has required
      increased cost consciousness. However, pharmacoeconomic analysis has not yet been
      fully exploited as a conceptual underpinning for public or private health policy
      decisions. Pharmacoeconomics is likely to become an increasingly important basis
      for health policy decisions as a number of significant dynamics evolve in the
      marketplace, including: (i) consumers acting on their growing access to
      information and becoming more actively involved in treatment decisions; (ii)
      payers, providers and patients deepening their interaction and overcoming their
      traditional (narrow) focus on either costs or benefits alone; and (iii)
      manufacturers being challenged by other healthcare constituencies as sponsors of
      cost-based outcomes studies.

PMID- 10662391
TI  - Measuring the effects of medication use on health-related quality of life in
      patients with rheumatoid arthritis. A review.
AB  - As the treatment of rheumatoid arthritis (RA) moves towards earlier and more
      consistently maintained therapy, often with highly toxic medications, the
      importance of assessing patients' health-related quality of life (HR-QOL) is of
      increasing concern to healthcare providers, insurers and policy-makers. As the
      course of RA can extend 20 years or more, and as patient involvement in their
      care and evaluation increases, the goal of therapy should be to work towards the
      HR-QOL desired by the patient. The challenge in HR-QOL measurement is its
      multidimensional nature, which takes into account not only how a person functions
      physically, mentally and socially, but also incorporates the individual's
      perceived well-being in their physical, mental and social aspects of daily life.
      This review focuses on measuring the HR-QOL outcomes of drug therapy in RA in
      clinical settings as well as in clinical drug trials. The most commonly used
      instruments in RAHR-QOL measurement are presented, with particular attention to
      those that have been used to assess the impacts of drug therapy. Traditionally,
      RA treatment outcomes assessment has focused on physical functioning and
      activities of daily living. As a result, there is an abundance of instruments
      that have been used in RA that measure physical functioning. Social and mental
      functioning are being assessed more frequently as clinicians and researchers
      recognise the added value of assessing these dimensions in addition to physical
      functioning. Patient perceived well-being (especially as it relates to physical,
      mental and social aspects of their lives), however, is still rarely measured. We
      conclude that there are few validated instruments which truly assess the impact
      of drug therapy on HR-QOL in RA; most are intended as measures of functional or
      health status. In addition, few studies have been conducted in natural clinical
      practice settings (as opposed to controlled clinical trial settings). Further,
      our review reveals that the psychological and social dimensions of HR-QOL are
      often lacking from some of the most popular RA instruments currently in use.

PMID- 10662392
TI  - Real world designs in economic evaluation. Bridging the gap between clinical
      research and policy-making.
AB  - This paper identifies the information that economic evaluation should provide to
      adequately inform policy-makers. First, policy-makers need cost-effectiveness
      information that is both internally and externally valid. The latter aspect is
      often ignored and refers to the relevance of the results of economic trials to
      the specific decision-making context of the policy-maker. Second, policy-makers,
      like purchasers of care, may want assessments of the overall budget and health
      impacts of adopting an intervention in a disease or treatment area. This requires
      more of an aggregate analysis than the current approaches to economic evaluation
      (which are typically individual-orientated). There are 3 main conceptual
      approaches to economic evaluation: the use of randomised controlled trials
      (RCTs), observational studies and modelling. The RCT can be considered as the
      gold standard in economic evaluation because of its high internal validity, but
      results should be interpreted with caution because of its low external validity.
      There a number of options to enhance external validity; of these, additional
      modelling and observational data seem to be the most promising. To address issues
      at the system level, disease modelling or public health modelling is suggested. A
      3-step approach, comprising successive assessment of internal validity, external
      validity (real world relevance) and net impact at the system level, can enhance
      the informative value of economic analyses. For example, this approach has been
      used to assess the informative value to decision-makers of an RCT in benign
      prostatic hyperplasia. The analysis emphasised the feasibility and importance of
      additional modelling beyond the results from an RCT-based economic analysis and
      provided important information of relevance for policy-making. Because of the
      need to increase the real world relevance of pharmacoeconomic analyses, there is
      potentially a large role for modelling in economic evaluation; however, in order
      to enhance its credibility, more attention should be paid to validity aspects.

PMID- 10662393
TI  - Cost effectiveness, quality-adjusted life-years and supportive care. Recombinant
      human erythropoietin as a treatment of cancer-associated anaemia.
AB  - OBJECTIVE: To measure the cost effectiveness of a supportive care intervention
      when the no-treatment option is unrealistic in an analysis of recombinant human
      erythropoietin (epoetin) treatment for anaemic patients with cancer undergoing
      chemotherapy. Further, to assess whether quality-adjusted life-years (QALYs) can
      provide the basis for an appropriate measure of the value of supportive care
      interventions. DESIGN: A modelling study drawing cost and effectiveness
      assumptions from a literature review and from 3 US clinical trials involving more
      than 4500 patients with cancer who were treated with chemotherapy, radiotherapy,
      epoetin and blood transfusions as needed under standard care for patients with
      cancer. MAIN OUTCOME MEASURES AND RESULTS: When compared with transfusions,
      epoetin is cost effective under varying assumptions, whether effectiveness is
      measured by haemoglobin level or quality of life. Specifically, under a base-case
      scenario, the effectiveness resulting from $US1 spent on standard care can be
      achieved with only $US0.81 of epoetin care. Due in part to the health-state
      dependence of the significance patients attach to incremental changes in their
      responses on the linear analogue scale, cost per QALY results are ambiguous in
      this supportive care context. CONCLUSIONS: Under a broad range of plausible
      assumptions, epoetin can be used cost effectively in the treatment of anaemic
      patients with cancer. Further, QALYs have limited applicability here because, as
      a short term supportive treatment, epoetin enhances the quality but not the
      length of life. Future research would benefit from the establishment of
      consistent values for quality-of-life changes across patients and health status,
      and the extension of the QALY framework to supportive care.

PMID- 10662394
TI  - Linking health-related quality-of-life indicators to large national data sets.
AB  - OBJECTIVE: This study investigated the feasibility and usefulness of linking
      algorithms for well known quality-of-life (QOL) indicators to large nationally
      representative databases. DESIGN AND SETTING: The National Medical Expenditure
      Survey (NMES) was utilised. We developed an algorithm to match the EuroQOL health
      indicator and drew on a previous match of the Health Utilities Index (HUI) in a
      companion paper. This process allowed the sensitivity and detail of health
      related quality-of-life (HR-QOL) indicators to be combined with the benefits of
      large, nationally representative data sets. PATIENTS AND PARTICIPANTS: A total of
      19,525 individuals aged 18 years and older (constituting a nationally
      representative sample of the non-institutionalised civilian population of the US
      contained within the 1987 NMES database) were investigated. INTERVENTIONS:
      Sensitivity analyses using several related specifications of each indicator were
      performed. We analysed the correlations of these alternatives for both the HUI
      and EuroQOL measures. Correlations between the HUI and EuroQOL measures were also
      examined. We investigated the construct validity by examining the performance of
      the HUI and EuroQOLs in empirical situations in which we had knowledge about the
      relationships (e.g. health decreases with age). MAIN OUTCOME MEASURES AND
      RESULTS: The benefits of HR-QOL measures can be achieved relatively cheaply and
      efficiently via linking rather than developing a large scale QOL survey. Although
      the NMES data allowed a good match with the EuroQOL and the HUI, the matches were
      not perfect. By examining the within-domain correlations and the between-domain
      correlations, we found that the alternate specifications within-domain were very
      similar and that the 2 HR-QOL indicators were comparable in many (but not all)
      aspects. CONCLUSIONS: The results of this study suggested good construct
      validity. Thus, linked HR-QOL measures of the types derived in this study may be
      useful in characterising the health of large populations, and in investigating
      the causes and consequences of health.

PMID- 10662397
TI  - Overcoming "Bubba". Beyond the Balanced Budget Act: back-to-roots strategies for
      the post-BBA era.

PMID- 10662395
TI  - Cost effectiveness of omeprazole and ranitidine in intermittent treatment of
      symptomatic gastro-oesophageal reflux disease.
AB  - OBJECTIVE: This 1-year study compared the cost effectiveness of omeprazole and
      ranitidine when used as initial therapy in an intermittent treatment strategy for
      the management of patients with symptomatic gastro-oesophageal reflux disease
      with or without erosive oesophagitis. DESIGN AND SETTING: A prospective health
      economic analysis was conducted alongside an international multicentre
      randomised, double-blind clinical study. The economic analysis was performed from
      a societal perspective. PATIENTS: A total of 704 patients in the UK, the Republic
      of Ireland, Germany, France, Italy and Spain were randomised to 1 of the 3
      treatment groups. INTERVENTIONS: Patients were randomised to receive either
      omeprazole 20 mg once daily, omeprazole 10 mg once daily or ranitidine 150 mg
      twice daily. Initial treatment failure resulted in dose titration and drug
      switching from ranitidine to omeprazole, and subsequently open maintenance
      treatment. MAIN OUTCOME MEASURES AND RESULTS: The estimated mean direct medical
      costs (medication and number of visits and endoscopies) were found to be lower
      for both dosages of omeprazole than for ranitidine in all countries except
      Germany. However, none of the differences were statistically significant. The
      differences between omeprazole 10 mg and omeprazole 20 mg were small and
      nonsignificant. With regard to numbers of symptom-free days, both omeprazole 20
      mg and omeprazole 10 mg were found to be more effective than ranitidine. However,
      none of the differences were statistically significant. CONCLUSIONS: Following a
      pragmatic interpretation, incorporating intermediate short term results, the
      results in this study give no support to the notion that a step-up approach,
      either as dose titration from omeprazole 10 mg to omeprazole 20 mg or as drug
      switching from ranitidine to omeprazole, will result in cost savings and thereby
      be cost effective.

PMID- 10662396
TI  - Economic evaluation of ciprofloxacin compared with usual antibacterial care for
      the treatment of acute exacerbations of chronic bronchitis in patients followed
      for 1 year.
AB  - OBJECTIVE: To undertake a 1-year prospective economic evaluation of ciprofloxacin
      compared with usual antibacterial care (any antibacterial other than a quinolone)
      for the treatment of acute exacerbations of chronic bronchitis (AECB) in adults
      presenting with a type I or type II AECB. DESIGN: Patients entered the study with
      an initial AECB and were randomised to the ciprofloxacin group or the usual care
      group. The following measurements were taken at the end of each AECB and every 3
      months: resource utilisation, St. George's Respiratory Questionnaire, Nottingham
      Health Profile and Health Utilities Index (HUI). The following additional
      measurements were taken after each AECB: AECB-symptom days and willingness to pay
      to avoid the AECB. Economic evaluations were performed from the societal
      viewpoint and the viewpoint of a major third-party payer. Cost-effectiveness
      analysis was based on cost per AECB-symptom day averted; cost-utility analysis
      (CUA) was based on cost per quality-adjusted life-year (QALY) gained using the
      HUI as the basis for calculating QALYs. Cost-benefit analysis was based on the
      willingness-to-pay (WTP) data. SETTING: This was a study of outpatients enrolled
      from 46 family physicians and 2 respirologists in Ontario (29 sites) and Quebec
      (19 sites), Canada, between November 1993 and June 1994. PATIENTS AND
      PARTICIPANTS: 240 adult male and female patients aged > or = 18 years with
      chronic bronchitis. MAIN OUTCOME MEASURES AND RESULTS: WTP data did not pass
      scope tests for reasonableness. Ciprofloxacin was more costly and provided better
      outcomes compared with usual antibacterial care. The base-case results are as
      follows (1994/1995 values): the incremental annual cost was 578 Canadian dollars
      ($Can) from the societal viewpoint and $Can840 for the third-party payer; the
      cost-effectiveness ratio per AECB-symptom day averted was $Can209 from the
      societal viewpoint and $Can304 for the third-party payer; the cost-utility ratio
      per QALY gained was $Can18,600 from the societal viewpoint and $Can27,000 for the
      third-party payer. According to Laupacis criteria, these CUA results are strong
      evidence in favour of adoption from the societal viewpoint and moderate evidence
      in favour from the viewpoint of the third-party payer. A subgroup analysis
      suggests that ciprofloxacin may be particularly cost effective, even 'win-win',
      in patients with more severe disease. CONCLUSIONS: The sensitivity analyses
      indicate that the results are relatively robust. Nevertheless, the statistical
      uncertainty in the results is sufficient that the findings cannot be accepted
      unequivocally. A further study with a larger sample size would be useful to
      confirm (or deny) the findings of this study.

PMID- 10662398
TI  - Is the BBA a short-term problem or long-term trend?

PMID- 10662399
TI  - Back-to-basics management: sustainable strategies for the "post-BBA" era.

PMID- 10662400
TI  - The determinants of health expenditure in the OECD countries: a pooled data
      analysis.
AB  - This paper uses international health expenditure and the latest OECD data to
      investigate the determinants of aggregate health expenditure. The study differs
      from most previous studies in two principal ways. First, it uses a somewhat
      larger sample for estimation, with pooled time-series, cross-section data for 22
      OECD countries for a 20-year period. Most previous work has used a purely cross
      section approach: in this case, the small sample size reduced the statistical
      reliability of results and limited the number of hypotheses that can be tested
      simultaneously. Second, and following from this, a more extensive range of
      hypotheses is tested, with particular emphasis on those relating to the
      contractual relations between payers, providers and patients. The findings show,
      for example, that the use of primary care "gatekeepers" seems to result in lower
      health expenditure and also that the way of remunerating physicians in the
      ambulatory care sector appears to influence health expenditure; capitation
      systems tend to lead to lower expenditure than fee-for-service systems.

PMID- 10662401
TI  - Clinical response of salaried consultants to economic incentives.
AB  - Several studies have found a relation between economic incentives and physicians'
      clinical decisions. The bulk of these studies deals with data from private
      organisations providing medical care. The purpose of the present study is to
      explore whether a similar relationship is valid in a system where hospital care
      is provided by salaried physicians in the public sector. A distinction is made
      between medical and economic prioritysetting. If the relative fees influence the
      proportion of outpatient surgery or the compositions of treatments, economic
      prioritysetting is said to take place. Data were collected from a sample of
      Norwegian hospitals. The main findings of the empirical section can be summarised
      in two points: (i) Economic prioritysetting seems to be applied in the choice
      between inpatient and outpatient surgical treatment for patients with an
      identical diagnosis. (ii) Medical priority setting seems to be applied in the
      priority among patients with different diagnoses.

PMID- 10662402
TI  - The use of multilevel analysis in health economics: an application to examining
      the effect of competition on general practitioners' behaviour.
AB  - Multilevel modelling is a relatively new technique developed in the area of
      educational research. To illustrate the use of this technique in health
      economics, this paper estimates a multilevel logit model to examine the effect of
      competition on the behaviour of Australian general practitioners. The main
      hypothesis tested is that GPs in areas of high competition are more likely to
      recommend a follow up consultation compared to GPs in areas of low competition.
      The results suggest that competition influences the decision to recommend a
      follow up visit for one out of the five medical conditions analysed. The use of
      multilevel analysis represents a methodological improvement on previous models of
      GP behaviour. However, before multilevel analysis is more widely adopted it is
      argued that it should be more formally assessed against more standard and
      equivalent methods already used by economists, such as random effects panel data
      models.

PMID- 10662403
TI  - A comparative application of econometric frontier and DEA methods for assessing
      cost efficiency of Finnish hospitals.

PMID- 10662404
TI  - Financial incentives and primary care provision in Britain: do general
      practitioners maximise their income?
AB  - The system of remunerating general practitioners (GPs) in Britain underwent
      significant changes in April 1990 with the implementation of a new contract
      between individual GPs and health authorities. The changes were a precursor to a
      wide-ranging programme of reforms of the British National Health Service. This
      paper investigates the relationship between financial incentives and the
      provision of primary health care services in Britain. A comprehensive anonymized
      data set was used, comprising information on 208 general practices in Scotland
      which serve just under one million people. An econometric model was tested to
      identify the determinants of cross-practice variation in the magnitude of the
      changes in GPs' remuneration levels between the two contracts. A linear
      programming model was used to examine the GPs' response to the financial
      incentives built into the new contract. The results of the econometric model
      indicated that the main beneficiaries of the 1990 contract were the practices
      which had expanded over the 1989-92 period, re-structured the GPs' partnership
      and made use of managerial skills by employing a practice manager; those
      practices also had larger lists in 1992 and relatively more patients attracting
      deprivation payments. The linear programming model showed that only a small
      minority of the practices (4.8%) maximised the remuneration from the new
      contract. Optimal solutions concerning income maximization strategies identified
      financial disincentives in the fee structure of the remuneration system
      associated with the provision of selected services and the care of particular
      groups of patients. The successful adoption of these strategies would involve
      cream skimming and selective service provision. However, there is no conclusive
      evidence of British GPs engaging in such activities.

PMID- 10662405
TI  - Cream-skimming in deregulated social health insurance: evidence from Switzerland.
AB  - Policymakers fear that health insurers when exposed to competition will engage in
      cream-skimming (i.e. selection of good risks) rather than trying to improve their
      benefit to premium ratio. This fear surfaced also when Swiss federal government
      proposed pro-competitive Law on social health insurance, which barely passed a
      popular referendum in 1994. While a risk equalization mechanism based on age,
      gender, and place of residence has already been created, there is a considerable
      interest in improving its formula. This paper shows that a dummy variable
      indicating an individual's death during the period of observation causes the
      coefficient of determination to jump from 0.039 to 0.111. More-over, simulations
      of the risk selection process suggest that risk equalization should be made a
      permanent institution rather than being limited to a life of 10 years as
      prescribed by present legislation. In fact, the formula in use, with all its
      shortcomings, can be shown to neutralize to a great extent insurer interest in
      cream skimming provided he takes a longer-run view.

PMID- 10662406
TI  - Modeling cross-border care in the EU using a principal-agent framework.
AB  - Cross-border care is likely to become a major issue among EU countries because
      patients have the option of obtaining treatment abroad under Community
      Regulations 1408/71. This paper develops a model formalizing both the patient's
      decision to apply for cross-border care and the authorizing physician's decision
      to admit a patient to the program. The patient is assumed to maximize expected
      utility, which depends on the quality of care and the length of waiting in the
      home country and the host country, respectively. Not all patients qualifying for
      the EU program present themselves to the authorizing physician because of the
      transaction cost involved. The physician in her turn shapes effective demand for
      authorization through her rate of refusal, which constitutes information to
      potential applicants about the probability of obtaining treatment abroad. The
      authorizing physician thus acts as an agent serving two principals, her patient
      and her national government, trading off the perceived utility loss of patients
      who are rejected against her commitment to domestic health policy. The model may
      be used to explain existing patient flows between EU countries.

PMID- 10662407
TI  - The impact of the environment on the demands for health and health care: an
      empirical analysis for Germany.

PMID- 10662408
TI  - The demand for health: an empirical test of the Grossman model using panel data.
AB  - Grossman derives the demand for health from an optimal control model in which
      health capital is both a consumption and an investment good. In his approach, the
      individual chooses his level of health and therefore his life span. Initially an
      individual is endowed with a certain amount of health capital, which depreciates
      over time but can be replenished by investments like medical care, diet,
      exercise, etc. Therefore, the level of health is not treated as exogenous but
      depends on the amount of resources the individual allocates to the production of
      health. The production of health capital also depends on variables which modify
      the efficiency of the production process, therefore changing the shadow price of
      health capital. For example, more highly educated people are expected to be more
      efficient producers of health who thus face a lower price of health capital, an
      effect that should increase their quantity of health demanded. While the Grossman
      model provides a suitable theoretical framework for explaining the demand for
      health and the demand for medical services, it has not been too successful
      empirically. However, empirical tests up to this date have been exclusively based
      on cross section data, thus failing to take the dynamic nature of the Grossman
      model into account. By way of contrast, the present paper contains individual
      time series information not only on the utilization of medical services but also
      on income, wealth, work, and life style. The data come from two surveys carried
      out in 1981 and 1993 among members of a Swiss sick fund, with the linkage between
      the two waves provided by insurance records. In all, this comparatively rich data
      set holds the promise of permitting the Grossman model to be adequately tested
      for the first time.

PMID- 10662409
TI  - Counting and discounting gained life-years.
AB  - The life expectancy gain produced by a reduction in mortality can be determined
      by three different methods with respect to the timing of the gained life-years.
      One method adds the life expectancy gain to the expected end of life. Another
      method places the gain at the time of occurrence of the mortality reduction. A
      third method distributes the gained life-years over the maximum lifespan
      according to the differences in survival probabilities after and before the
      reduction in mortality. The three methods are all used in the literature together
      with a quasi-deterministic and a probabilistic approach to the notion of life
      expectancy. The counted numbers of gained life-years are the same, but due to
      different timing of life expectancy gains the discounted numbers are different.
      Several discounting models are identified when combining the three methods of
      counting with the deterministic and the probabilistic approaches to life
      expectancy. Some are symmetrical, some are not. However, most importantly, they
      come out with potentially very large differences in the discounted number of
      gained life-years. They differ by a factor of approximately (1 + r)e(a)-1, where
      r is a constant discount rate and e(a) is remaining life expectancy at age a,
      when the reduction of mortality occurs. For a new-born, discounting at 7% p.a.,
      one discounting model provides a present value that is 150 times larger than
      another discounting model, the other models being in between. The various
      counting and discounting models for life expectancy gains are presented formally,
      graphically, and with numerical examples using Danish male mortality data. We
      show how three different discounting models provide large differences in
      discounted life expectancy gains and hence cost-effectiveness ratios in an
      economic evaluation of a colorectal cancer screening programme in Denmark. These
      different discounting models co-exist in the evaluation literature. Choice of
      method is rarely made explicit. Sensitivity analysis with respect to this choice
      is even rarer. We argue that one counting-discounting model is sufficient and
      that this should be to discount the differences between the two survival
      probability curves.

PMID- 10662410
TI  - Inequality in infant mortality in Portugal, 1971-1991.

PMID- 10662411
TI  - Health, work-hours, and wages in Sweden.

PMID- 10662412
TI  - The effect of a copay increase on pharmaceutical utilization, expenditures, and
      treatment continuation.
AB  - OBJECTIVE: No research has evaluated the impact of an increase to a copay that is
      reflective of today's healthcare market. This study examined the effect of an
      increase from a $10 to $15 copay for brand drugs on key pharmaceutical
      utilization measures, including participation rates, treatment continuation, and
      expenditures, in an adult population. STUDY DESIGN: A quasi-experimental, pre
      post design with control group was used. PATIENTS AND METHODS: Two different
      employer plans implemented an increase from $10 to $15 for brand copays in
      January of 1997. The utilization and expenditures of these plans were compared
      with those of a control group with a constant brand copay of $10 for 6 months
      preceding and 6 months following the copay increase. RESULTS: When other
      predictor variables were controlled for, the copay increase was not associated
      with a statistically significant difference in overall utilization compared with
      the control group, although brand utilization was significantly lower in the
      copay group. Savings to the payer were substantial, and resulted primarily from
      cost-shifting, reduction in brand utilization, and an increase in the generic
      fill rate. The rates of continuation with chronic medications in the 6 months
      following the copay increase were not reduced in the copay group compared with
      the control group. CONCLUSION: A copay increase can provide substantial savings
      to a payer without being a major deterrent to overall utilization or resulting in
      discontinuation of chronic medications.

PMID- 10662413
TI  - Attitudes toward managed care and cost containment among primary care trainees at
      3 training sites.
AB  - OBJECTIVE: To study the attitudes of entering first year (Y1) and graduating
      third year (Y3) primary care physician trainees from 3 different training program
      sites (a university hospital system site [UHS], a large staff-model health
      maintenance organization managed care system site [MCS], and a large public
      hospital system site [PHS]) toward selected aspects of managed care. DESIGN: A
      self-administered questionnaire was used in a cross-sectional study. PARTICIPANTS
      AND OUTCOME MEASURES: Participants were all Y1 and Y3 primary care trainees in
      internal medicine, pediatrics, and family medicine programs from 3 training
      program sites. Survey questions dealt with attitudes toward health services,
      managed care cost containment, and the role of the physician in society. RESULTS:
      Of eligible primary care trainees (n = 218), 91% completed the instrument.
      Trainees at the MCS generally held more positive views of managed care systems
      than trainees at the UHS or PHS. Internal medicine trainees held more negative
      attitudes towards managed care systems than trainees in pediatrics or family
      medicine. UHS and PHS trainees more often thought that managed care systems
      interfere with the doctor-patient relationship and that these systems are more
      concerned with economics than in providing quality patient care. Approximately
      one quarter of the Y1 trainees at all sites thought that reducing the cost of
      healthcare is beyond the control of doctors. No Y3 trainee at the PHS believed
      that reducing costs was beyond the control of doctors. The majority of trainees
      endorsed routine peer review of clinical decisions to control healthcare costs.
      Most trainees believed that managed care systems will eventually predominate and
      that physician independence is being impaired. CONCLUSION: The data suggest that
      attitudes of internal medicine, family medicine, and pediatric trainees toward
      various aspects of managed care vary not only by their year of training but also
      by their training environment. Thus, managed care educational programs for
      trainees should consider both the baseline attitudes of trainees and
      characteristics of the training site itself.

PMID- 10662414
TI  - Satisfaction with pregnancy and newborn care: development and results of a survey
      in a health maintenance organization.
AB  - OBJECTIVE: To measure patient satisfaction with pregnancy and newborn care. STUDY
      DESIGN: To develop our survey, we reviewed domains of care that had been
      identified by national groups working to develop measures of satisfaction with
      care. Within these domains of care, items pertinent to pregnancy and newborn care
      were written, reviewed, and pilot tested in focus groups of women who had
      recently delivered a baby. A 24-item survey instrument was the result of this
      process. PATIENTS AND METHODS: We sent our survey to 2337 female members of the
      Southern California Kaiser Permanente Medical Care Program approximately 8 weeks
      after they had delivered a baby. The demographic and clinical characteristics of
      the respondents were compared with those of the nonrespondents. RESULTS: A total
      of 1017 women (44%) completed and returned the survey. Eighty-eight percent of
      the women who responded were very or somewhat satisfied with the care they
      received during their pregnancy and the newborn period. Women who responded
      differed from those who did not respond on infant birthweight, maternal age and
      education, and other variables. The results of our survey were forwarded to local
      quality managers and physicians. CONCLUSION: Satisfaction with care is an
      important measure of quality of care. Many changes in the delivery system were
      made in response to the information provided by survey respondents, including
      offering alternative appointment times and scheduling postpartum appointments
      before hospital discharge. Our survey instrument, which assesses satisfaction
      with pregnancy and newborn care, might be useful for other health maintenance
      organizations for identifying areas where improvement in care is needed.

PMID- 10662415
TI  - The cost of Medicaid-covered services provided to disabled adults with neurologic
      disorders: implications for managed care.
AB  - OBJECTIVES: To estimate the mean annual per capita cost of care provided to
      disabled adult Medicaid recipients with neurologic conditions and to compare mean
      annual costs for disabled adult Medicaid recipients with those of nondisabled
      adult Medicaid recipients. STUDY DESIGN: Medicaid eligibility and claims files
      for all of calendar year 1993 were obtained from the state of Pennsylvania. Mean
      annual per capita costs are mean Medicaid expenditures on claims filed for
      Medicaid-covered services and pharmaceuticals provided in 1993 to full-year
      eligible Medicaid recipients. PATIENTS AND METHODS: Disabled adults aged 18 to 64
      years with one or more of several neurologic conditions were identified from
      medical diagnoses (International Classification of Diseases, 9th Revision codes)
      reported on claims. A comparison group of nondisabled adults was chosen from the
      Medicaid Eligibility File. Annual costs were estimated for a wide range of
      specific services as well as for 3 broad service categories. RESULTS: There were
      large differences between disabled and nondisabled adults in mean annual per
      capita costs of acute care and other medical services ($4142 vs $1451),
      rehabilitation and support services ($3835 vs $235), and pharmaceuticals ($1116
      vs $382). Mean costs also differed significantly among persons with different
      neurologic conditions. The mean annual per capita cost for all services was $5368
      for adults with epilepsy and $19,356 for those with a spinal cord injury. All
      differences are statistically significant (P < .001). CONCLUSIONS: States may
      want to separately capitate rehabilitation and support services given the large
      differences in the magnitude and relative distribution of costs for disabled and
      nondisabled Medicaid recipients.

PMID- 10662416
TI  - Estimates of costs of primary care physician turnover.
AB  - OBJECTIVE: To provide estimates of the institutional costs associated with
      primary care physician (PCP) turnover (job exit). SUBJECTS AND METHODS: A cohort
      of 533 postresident, nonfederal, employed PCPs younger than 45 years of age, in
      practice between 2 and 9 years, participated in national surveys in 1987 and
      1991. Data from a national study of physician compensation and productivity and
      data from physician recruiters were combined with PCP cohort data to estimate
      recruitment and replacement costs associated with turnover. RESULTS: By the time
      of the 1991 survey, slightly more than half (n = 279 or 55%) of all PCPs in this
      cohort had left the practice in which they had been employed in 1987; 20% (n =
      100) had left 2 employers in that same 5-year period. Among those who left, self
      designated specialties and proportions were general/family practice (n = 104 or
      37%); general internal medicine (n = 91 or 33%); and pediatrics (n = 84 or 30%).
      Estimates of recruitment and replacement costs for individual PCPs for the 3
      specialties were $236,383 for general/family practice, $245,128 for general
      internal medicine, and $264,645 for pediatrics. Turnover costs for all PCPs in
      the cohort by specialty were $24.5 million for general/family practice, $22.3
      million for general internal medicine, and $22.2 million for pediatrics.
      CONCLUSIONS: Turnover was an important phenomenon among the PCPs in this cohort.
      This turnover has major fiscal implications for PCP employers because loss of
      PCPs causes healthcare delivery systems to lose resources that could otherwise be
      devoted to patient care.

PMID- 10662417
TI  - Paying for HIV/AIDS care at the turn of the century.

PMID- 10662418
TI  - Developing a managed care delivery system for people with HIV/AIDS.
AB  - Capitated managed care is now a significant part of the healthcare landscape in
      the United States. Consequently, states across the country are looking to it as a
      means of lowering their costs for Medicaid recipients. Implementing Medicaid
      managed care plans, however, requires considerable planning and research to
      ensure that providers are fairly reimbursed and that patients continue to receive
      quality care. Efforts to ensure adequate reimbursement and quality care are
      particularly important for persons with HIV/AIDS and those with other chronic
      conditions, populations that require considerable healthcare resources and often
      are covered by Medicaid. The transition to Medicaid managed care can be smoothed
      through stakeholder input and consideration of the overall healthcare marketplace
      and political climate, the structure of managed care organizations, the means of
      informing consumers of their managed care choices, the potential size of the
      Medicaid patient base, and the need to integrate clinical and social services for
      patients with HIV/AIDS.

PMID- 10662419
TI  - Comprehensive HIV services under a capitated reimbursement system: AIDS
      Healthcare Foundation.
AB  - The application of capitated managed care systems to Medicaid populations has
      increased as part of an effort to control healthcare costs. The difficulties of
      caring for people with HIV and AIDS in the Medicaid population is compounded by
      the issues of impoverishment and access to care. In this profile, we discuss the
      rationale for and planning involved with creating the AIDS Healthcare Foundation,
      a community-based program providing comprehensive and coordinated care for people
      with HIV and AIDS.

PMID- 10662420
TI  - Developing a managed care delivery system in New York State for Medicaid
      recipients with HIV.
AB  - In the state of New York, models of care known as HIV Special Needs Plans (HIV
      SNPs) are being developed to meet the unique health and medical needs of Medicaid
      recipients with HIV. Establishing managed care plans for the 80,000 to 100,000
      HIV-infected Medicaid recipients residing in the state has required considerable
      effort, including distributing planning grants to solicit information and
      recommendations regarding program and fiscal policy; convening a workgroup to
      facilitate discussions between the state and the provider and consumer
      communities; conducting a longitudinal survey to assess the impact of managed
      care on persons with HIV; and developing a longitudinal, person-based, encounter
      level database representing the clinical and service utilization histories of
      more than 100,000 patients for state fiscal years 1990 to 1996. The key fiscal
      issues identified and discussed were capitation rates, initial capitalization
      levels, and risk-adjustment mechanisms. Other pertinent issues included the
      importance of a benefits package supporting a comprehensive, integrated continuum
      of state-of-the-art services; marketing and enrollment; attention to provider and
      consumer training and education needs; and interdependence of financial
      reimbursement and benefits packages. From our experience in New York State, we
      conclude that a successful model of Medicaid managed care for persons with HIV
      should build on the existing infrastructure of services, using a collaborative
      process among government agencies, healthcare providers, and HIV/AIDS consumer
      communities. A future challenge lies in the implementation of the HIV SNP model
      and evaluation of its soundness and ability to ensure quality healthcare
      services.

PMID- 10662421
TI  - "Doctor, I'm having a heart attack. What should I do?".

PMID- 10662422
TI  - Move to electronic health records will speed up considerably in next 2 years.
AB  - The computerization of patient records is viewed not only as a factor in making
      real-time patient care easier, but also as an aid in measuring quality
      performance. In the eyes of some, the computerization of patient records,
      ultimately leading to the establishment of the electronic health record (EHR) as
      industry standard, has the potential of dramatically improving the delivery of
      health care services. Taking the steps toward the EHR can require a great
      commitment of resources on the part of the health care enterprise.

PMID- 10662423
TI  - Nurse staffing law may herald benchmarks.
AB  - California became the first state to require all patient care units in hospitals
      to meet fixed minimum nurse-to-patient ratios. In a hospital environment where
      patients are sicker, and care is more complex, according to American Nurses
      Association (ANA) president Beverly L. Malone, "Cutting the numbers of RNs and
      substituting unlicensed aides for registered nurses are exactly the wrong moves."
      ANA's "Principles of Nurse Staffing" call for staffing decisions to be made on
      the basis of three sets of principles: those related to patient care, staff
      related issues, and institution/organization concerns. The California legislation
      currently contains no specific numerical requirements. ANA's 10 Nursing-Sensitive
      Quality Indicators for Acute Care Settings is comprised of a series of measures
      that represent the nursing community's current conception of how nurse staffing
      levels impact patient care.

PMID- 10662424
TI  - 10 ANA quality indicators for acute care settings.

PMID- 10662425
TI  - Two new benchmarking data sources available.

PMID- 10662426
TI  - Report links health plan quality and satisfaction.

PMID- 10662427
TI  - Vernon R. Loucks, Jr., chairman, Baxter International, Inc.. Interview by James
      A. Johnson.

PMID- 10662428
TI  - Leadership diversity.

PMID- 10662429
TI  - The future of managed care.

PMID- 10662430
TI  - Diversity leadership and organizational transformation: performance indicators
      for health services organizations.
AB  - Health services organizations can follow a five-part process to reposition
      themselves through diversity leadership. The first part of the process,
      discovery, refers to the emerging awareness of racial and ethnic diversity as a
      significant strategic issue; the second part, assessment, refers to systematic
      review of the organization's racial and ethnic diversity climate; the third part,
      exploration, denotes systematic training initiatives to improve the health
      services organization's ability to effectively manage diversity; the fourth part,
      transformation, refers to fundamental changes in organizational practices that
      result in a culture in which racial and ethnic diversity is valued; and the final
      part, revitalization, refers to renewal and expansion of racial and ethnic
      diversity initiatives to reward change agents and to include additional identity
      groups among the health services organization's diversity initiatives. This
      article presents a series of behaviorally based performance indicators for each
      of the five parts of the diversity leadership process. Healthcare executives are
      encouraged to assess their organization's strategic positioning against best
      demonstrated practices, as represented by the performance indicators. A method
      for analyzing organizational performance against the diversity leadership
      indicators is outlined as are suggestions for future research.

PMID- 10662431
TI  - Electronic medical records: are physicians ready?
AB  - The use of electronic medical records (EMR) in healthcare organizations will
      require substantial changes in the way physicians and their staff provide patient
      care. This study is the first part of a larger study assessing factors that
      influence successful implementation of EMR in ambulatory care settings. The
      purposes of this study were to identify specific attitudes or factors that should
      be targeted before implementating an EMR project, and demonstrate empirical
      support for a model of perceived usefulness of EMR. We found that computer
      experience, computer anxiety, and perceptions of organizational support predict
      the degree to which physicians and mid-level practitioners view the EMR effort
      positively. Strategies for the successful management of EMR implementation
      include engaging the physicians and practitioners in computer activities prior to
      implementation and providing strong organizational support before and during the
      redesign effort. Acceptance of EMR by physicians and their support staff is
      essential if computerization is to be successful, yet anecdotal reports of
      resistance and negative attitudes are frequently reported. Empirical studies
      indicate that physicians have not yet embraced this technology. As part of
      strategic planning and deployment of a computerized patient record, attitudes of
      end-users must be assessed. Using an integrative framework from the job design
      literature and management information sciences, we propose that multiple factors
      influence attitudes toward EMR, offer a conceptual model of end-user acceptance,
      and present findings from an empirical test of our model.

PMID- 10662432
TI  - The effects of reengineering: fad or competitive factor?
AB  - Healthcare organizations have often participated in managerial innovations that
      have promised to revolutionize their operations (e.g., management by objectives,
      quality circles, total quality management, and reengineering). Historically, such
      managerial innovations began with a few devout adherents, snowballed into
      widespread acceptance, and then faded as their popularity waned. This cycle of
      managerial adoption generally has been complicated by a lack of a consistent,
      clear definition of the innovation and little or no evaluation of its
      organizational effects. This article examines a current managerial innovation,
      reengineering, that after widespread adoption has now begun to fall out of favor
      with many executives. A clear, practical definition of reengineering is first
      offered, followed by an evaluation of the effect of reengineering on competitive
      hospital costs. Finally, factors that influence the results of reengineering are
      explored. Overall, reengineering did not statistically improve a hospital's cost
      position; however, we suggest that providing clear and consistent feedback,
      codifying the reengineering process, and involving executives in core changes are
      key means for improving reengineering outcomes. Specific examples of how these
      factors may be used to facilitate reengineering are provided. Reengineering may
      still be beneficial if it is properly implemented.

PMID- 10662433
TI  - Case management of the elderly in a health maintenance organization: the
      implications for program administration under managed care.
AB  - Kaiser Permanente initiated a two-year demonstration ambulatory case management
      program in its Ohio region to evaluate five outcomes: perceived health status,
      functional status, and satisfaction with care, service use, and service costs.
      Expected results were not consistently obtained for the five outcome measures.
      Treatment group members did not, however, experience the functional status
      impairments or decline in health status perceptions reported by the control group
      during the study period. The unexpected finding that costs were not affected may
      be attributed to the type of case management intervention used in the
      demonstration program. This study is broadly applicable to managed care settings
      facing the challenge of developing programs to minimize the risk for bearing the
      costs of the Medicare beneficiaries' overall health when all services are not
      covered. Managed care administrators should be favorably disposed to implementing
      a case management model with the potential for affecting functional status, the
      most significant predictor of expensive continuing care for this cohort of
      Medicare beneficiaries, while working to develop more effective protocols and
      resource control strategies.

PMID- 10662434
TI  - A total healing environment: the Yavapai Regional Medical Center story.
AB  - Patient care executives are continually challenged to increase productivity
      without additional expense or negative effect on patient care quality.
      Identifying the optimal organizational set of circumstances that meets the needs
      of all stakeholders is a challenge for even the most dedicated and skilled
      executive. This article is a case study in which healthcare leaders intuitively
      believed in a healing environment and successfully implemented the organizational
      changes necessary to translate the essence of healing into their traditional
      organization. The experiences of seven executives within the organization provide
      critical information for organizations considering implementation of a healing
      model in traditional settings. Characteristics of a healing model, planning and
      implementation considerations, and the measurement of the outcomes are
      identified. In addition, the research methodology used to examine the
      relationship of healing model characteristics to selected organizational outcomes
      is described.

PMID- 10662435
TI  - Increasing the effectiveness of resource deployment in healthcare organizations.
AB  - This article suggests ways to enhance the effectiveness with which healthcare
      organizations deploy their resources. Specifically, the article: (1) reviews
      research findings from the academic literature that managers often continue, or
      even increase, resource allocation to unprofitable courses of action; (2) reports
      the results of a case study with hospital administrations that suggests that this
      tendency may exist in healthcare organizations; and (3) suggests ways for
      healthcare organizations to control the occurrence of such suboptimal actions,
      thereby increasing the effectiveness and timeliness of their resource deployment.

PMID- 10662436
TI  - "Sentinel effect" shows fraud control effort works.
AB  - The author analyzes the fraud and abuse track record of his agency in the past
      years, and discuss why that effort has had beneficial results for the healthcare
      industry and the federal fisc. The benefits of this enforcement effort flow
      directly from the specific enforcement actions, and indirectly from the response
      of others in the industry to the standards set forth in those actions. Mr.
      Thornton disputes assertions of some in the industry that the enforcement efforts
      are unfair, arbitrary, or draconian. Rather, they are an appropriate response to
      a documented problem with which the government is justifiably concerned.

PMID- 10662437
TI  - A call for balancing of agency sentinel priorities.
AB  - Currently, a plethora of enforcement initiatives are directed at the healthcare
      industry. This Article suggests that budget and time allocations for issuing
      regulations and guidelines to interpret the law in this area have been
      disproportionately set when compared to the budget and time allocations set to
      support these enforcement initiatives. As a result, HCFA and OIG have been
      seriously delinquent in providing the industry with needed regulatory guidance
      and workable instructions. The use of enforcement initiatives in lieu of formal
      rulemaking to regulate the industry accords little respect to the legitimate
      healthcare providers who constitute the vast majority of the industry. This
      Article calls for a reexamination of enforcement agencies' priorities to provide
      regulatory guidance through formal rulemaking, rather than through use of
      coercive enforcement initiatives.

PMID- 10662438
TI  - Gainsharing: a call for guidance.
AB  - Gainsharing is a device by which hospitals and physicians share in the
      development, implementation, and proceeds resulting from the mechanisms to make
      the provision of healthcare more efficient and cost effective. The goal of
      gainsharing programs is to save hospitals money while maintaining the same or
      better quality of care--a goal that will ultimately result in both better care
      and lower expenses for payors and for society as a whole. Nevertheless, the OIG
      has ruled that gainsharing programs are per se illegal. This Article analyzes the
      reasons behind the OIG's determination and argues that, contrary to the OIG's
      conclusion, the advisory opinion process is legally and practically the best way
      to deal with the issues raised by gainsharing programs.

PMID- 10662439
TI  - The compliance conundrum.
AB  - Complex regulations and statutes, murky guidance from government agencies, and
      overly zealous enforcement initiatives make the legal questions in the healthcare
      arena a veritable mine field. This Article examines some of the issues that arise
      in the healthcare legal setting, explains why compliance programs are difficult
      to establish, and analyzes the issues that arise when providers attempt to
      establish them. Finally, the authors suggest changes to the governing legal
      framework that would facilitate achievement of the government's goals in a more
      efficient and just manner.

PMID- 10662440
TI  - Public/private information sharing in healthcare fraud investigations.
AB  - Private insurers have good reason, both in their private interest and in the
      public interest, for pursuing and rooting out fraud in the healthcare system;
      moreover, they often have sophisticated data systems, substantial investigative
      information, and management expertise that can be useful to prosecutors. It makes
      sense, as a public policy matter, to undertake steps to encourage insurers to be
      aggressive in pursuing legitimate fraud cases, and to provide a framework for
      effective cooperation and information sharing with law enforcement. At the same
      time, prosecutors are responsible for enforcing equal justice under the law;
      thus, any such relationship must be handled in an appropriate manner, with
      safeguards to protect privacy and the reputation of investigative subjects. While
      the courts have not yet explored many of the relevant legal and factual issues in
      this area, the author surveys existing guidance under governing laws and policies
      applicable to state and federal prosecutors, and suggests techniques to prevent
      inappropriate communication or use of such information.

PMID- 10662441
TI  - Et Tu, Counselor: may an in-house attorney file a qui tam action against the
      attorney's employer?
AB  - Most corporations probably do not consider their in-house counsel to be potential
      qui tam threats. That may be a naive assumption. Case law provides an
      illustrative view of the legal ramifications involved when an attorney brings a
      qui tam suit. In general, there is no prohibition on attorneys who wish to bring
      these actions. Nevertheless, a corporation can take preventive steps to eliminate
      the likelihood of attorney qui tam actions. In addition, the corporation can take
      advantage of state professional ethics laws to mount a defensive action against
      the attorney who files any such action.

PMID- 10662442
TI  - Life after Bryan: intent under the anti-kickback law.
AB  - In the past year, two courts have analyzed the proper standard of "willfulness"
      necessary to violate the anti-kickback law. At present, it appears that an
      intentional act, taken with knowledge that one is violating some law, is
      sufficient to violate the standard. It remains to be seen, however, whether the
      anti-kickback law will be deemed "highly technical," and thereby be violated only
      by one knowing that he is violating that particular statute. Moreover, the cases
      are not clear as to how close of nexus is required between the "knowingly
      violated" law and the anti-kickback law.

PMID- 10662443
TI  - Tips for challenging an audit based on statistical sampling.

PMID- 10662444
TI  - Break through to success with training and teamwork.
AB  - This is a case study on the effect of training and teamwork in two different
      divisions within the same company. One division consisted of a nonunion
      manufacturing plant; the second was a unionized distribution operation. In both
      operations, serious problems existed--poor customer service levels, inadequate
      inventory turns, and insufficient profitability. These are the kinds of problems
      that, left untreated, can cause the death of any manufacturing or distribution
      operation. However, by implementing training and teamwork at both operations,
      impressive benefits were achieved, including customer service levels exceeding 90
      percent, dramatic improvements in the inventory turnover rate, and profitability
      that exceeded corporate goals.

PMID- 10662445
TI  - Facilitating skills: the art of helping teams succeed.
AB  - Empowering and guiding the team has become crucial to the long-term success of
      any business. Today, an important measurement for leaders is their ability to
      facilitate a group of people to work together as a team and successfully
      accomplish their task. What will separate a good leader from a great leader will
      be the understanding and development of his or her facilitation skills.

PMID- 10662446
TI  - Managing team activities toward success.
AB  - Although there are many definitions of a team and teamwork, Amgen, Inc., has
      defined a team as "a dynamic group of diverse people with common objectives but
      different responsibilities that is chartered with improving a process, a product
      or a service." Teamwork constitutes a blending of team dynamics with partnership;
      thus a new term was created to define teamwork at Amgen--"teamship."

PMID- 10662447
TI  - The gradual transition to a team-based environment: the success story of a medium
      sized manufacturing facility.
AB  - This article will review the case in which a medium-sized manufacturing facility
      in upstate New York underwent the transition to a team-based environment. As with
      any change, this transition involved a decision process, a design process, and an
      implementation process. The transition took place gradually over a period of
      several years, allowing each stage to be studied in some detail. The degree to
      which these approaches are applicable to an organization will depend in part on
      how similar that organization is to the study facility; therefore, this article
      will begin with a background discussion of the nature of that facility.

PMID- 10662448
TI  - Supplier management by teams.
AB  - Watlow Electric Manufacturing, Hannibal, Missouri, uses a fully integrated MRP
      system with three-way match accounting. We have approximately 8,000 purchased
      parts and purchase in excess of $5 million of raw material annually. The vast
      majority of parts are custom to the heating element industry; the balance of the
      parts are customer specific. Production is similar to a glorified job-shop, more
      specialized than standard products.

PMID- 10662449
TI  - Effective evaluation of team performance.
AB  - Teams are not the only option an organization has. There are four types of
      solutions that an organization could use in response to a challenge. The
      organization could buy a solution, could hire an external consultant to develop a
      solution, could use an internal consultant to develop a solution, or an
      organization can bring the power of a team to develop a solution. Each of these
      solutions has strengths and weaknesses, and the right one must be selected. It
      isn't always teams!

PMID- 10662450
TI  - Cultural change--empowerment at Sweetheart Cup Company, Inc., Bakery Division.
AB  - Sweetheart Cup Company always has been associated with fun products--fast food
      containers, straws, ballpark drink glasses, and maybe the most fun of all--ice
      cream cones! But making these products of pleasantry at times has not been as
      festive as it would seem. Sweetheart Cup Company has had its ups and downs in
      terms of many of the typical manufacturing measurements, but in 1994--under the
      direction of newly appointed Chief Operating Officer Bill McLaughlin--Sweetheart
      Cup Company embarked on a new mission. This time everyone would be involved, from
      headquarters staff in Owings Mills to the fourth-floor oven area workers in the
      Dallas bakery. The new process goal, "Business Excellence," as we called it, was
      really an implementation of Class A ERP/MRP II.

PMID- 10662451
TI  - Driving change: up the organization.
AB  - In the traditional view of the world, leaders cause change by affecting the
      behavior of others. This can happen in any of a number of ways. Some leaders use
      power and authority. Others use influence and persuasion. Still others lead by
      example. The key concept to remember is that the real need for change is in
      behavior. Effective change requires a change in behavior.

PMID- 10662452
TI  - Patient product availability through the use of systems thinking: developing
      coherent relationships.
AB  - The traditional techniques of quality improvement, such as just-in-time delivery,
      can only go so far in dealing with materiel management issues. A further step is
      necessary: the implementation of systems thinking. This type of thinking focuses
      on the interconnectedness of all the members that exist throughout the system.
      This article explains the nature of systems thinking and how it can be used in
      materiels management to describe and improve the availability of materiels
      needed.

PMID- 10662453
TI  - Creativity: the key to breakthrough changes, how teaming can harness collective
      knowledge.
AB  - Our nation's industries do not want for concepts, philosophies or ideas to
      improve effectiveness. Just-in-Time, continuous improvement, re-engineering,
      world-class manufacturing, time compression, manufacturing excellence, total
      quality control, and theory of constraints are examples of approaches to
      improving our businesses. All have merit and are, to some degree, related.

PMID- 10662454
TI  - Achieving excellence--creating customer passion.
AB  - Customers are the lifeblood of any organization. Without them, it loses its
      meaning and purpose. Customers provide incentive, vitality, and growth. Serving
      them well requires a customer-focused culture and a customer-friendly system. It
      also requires unrelenting effort toward continuous improvement, but the rewards
      are well worth the effort: unflinching customer loyalty, sustainable growth, and
      impressive performance.

PMID- 10662455
TI  - Project leadership: why project management alone doesn't work.
AB  - Projects often fall short of achieving their anticipated results, not due to a
      lack of project management, but rather from a lack of project leadership. Because
      project success is a direct reflection of the project manager, it is his or her
      responsibility not just to manage the details and report status of a project, but
      to go beyond and add value through providing leadership. Project managers can no
      longer update task lists and issue meeting minutes if they are to succeed. This
      article focuses on adapting proven leadership strategies to project environments,
      helping to increase the probability for project success. When properly applied,
      they will help turn today's project manager into tomorrow's project leader.

PMID- 10662456
TI  - Project management: break through or bust.
AB  - Making a wrong choice can severely affect even the best-managed implementation
      (and project manager's careers). There is simply no margin for error, so getting
      it right the first time is not merely an option--it is a prerequisite for
      success. This article will first review why projects fail, then highlight the
      project management process used by McInnes Steel to specify, choose, and
      implement MRP II software that was "right" for them. Insights and experiences
      will also be shared to assist others in their project management activities.
      Project ultimate measurement is the successful integration of new technology into
      the culture of the organization. The first and most crucial step in any
      implementation is the specification and subsequent selection of the equipment or
      technology. It is important to make the right choice--one where the technology
      provides value-added services to the users to help them do their jobs better, now
      and into the future.

PMID- 10662457
TI  - Group practice--a successful future model.

PMID- 10662458
TI  - Get more value from your practice management system.

PMID- 10662459
TI  - Grow your own: case study of a capital alternative.
AB  - The physician-administrator team can take all that is good from the physician
      practice management company (PPMC) model and apply a variation of self-financing
      called a "tithe" in order to facilitate their group's growth. Essentially, a
      group can create its own PPMC for local consolidation purposes, contracting with
      payers, spreading risk contracts over a larger base of providers, getting access
      to ancillary services, centralized business office services, bulk purchasing and
      many other of the advantages extolled by PPMCs. Organization has value,
      especially in times of specific industry consolidation. Although most everyone
      agrees that the medical industry is undergoing tremendous consolidation,
      consolidation will not likely occur "top-down." Rather, it will occur more slowly
      -one group at a time, one locale at a time. If a group positions itself as a
      local consolidation leader and amalgamates other groups onto its "token ring,"
      then all participants--especially those who initiate this consolidation--will
      reap the benefits.

PMID- 10662460
TI  - Messenger model IPAs need caution in managed care.
AB  - Messenger model independent practice associations (IPAs) are a popular choice for
      physicians coming to together to improve payer negotiations. However, it is easy
      for such models to run afoul of antitrust regulations, as did a messenger model
      IPA in Tampa, Fla. The following is a discussion of this case. You should be able
      to use it as a guide if and when you are ever involved in a messenger model IPA
      situation. This article also will provide tips and strategies for working in the
      messenger model IPA format.

PMID- 10662461
TI  - Customer service: moving from slogan to point of differentiation.
AB  - To make its commitment to customer-centered care real, Dean Medical Center
      interviewed patients and created a "Vital Signs" scorecard. Performance is now
      measured according to those key areas specified by patients. Face-to-face
      communication from upper management to all employees and employee training has
      facilitated the program.

PMID- 10662462
TI  - The arranged marriage of allopathic and alternative medicine.
AB  - The degree to which Americans are seeking and paying for alternative health care
      has caused some hospitals and medical groups to consider incorporating these
      services within the umbrella of their traditional care. The challenge is to find
      a standard of care that is consistent with allopathic traditions, but not so
      restrictive as to undercut the financial and patient satisfaction motives that
      prompted the interest in alternative care. By focusing on subjective complaints
      and chronic conditions, it may be possible to walk a path that leaves traditional
      medical standards intact while gaining the opportunity to attract the dollars and
      track the effectiveness of alternative care.

PMID- 10662463
TI  - Turnaround distressed physician practices. 20 tips for success.
AB  - Physician practices are restructuring through merger and acquisition, and sale to
      practice management companies and to hospital systems. Many also are expanding
      internally by recruiting new physicians and opening additional offices. For many
      these strategies are working, but many others are experiencing operational and
      financial distress and failure that arise from rapid organizational growth
      without concomitant infrastructural change. Further, in the last several months,
      many national and regional practice management companies have decided to withdraw
      from the business, and others have declared bankruptcy. The number of physician
      practices that are in financial and operational distress is unprecedented. These
      groups require a solution, as proposed in this article.

PMID- 10662464
TI  - Managing for change. Models and questions for group practice leaders.
AB  - The health care environment continues to be characterized by rapid change and
      unpredictability. Perhaps the only constant is change itself. Managing
      successfully in this environment demands an increasing level of sophistication.
      In a rapidly changing environment, the manager must provide focus and direction
      and at the same time stay flexible so that the organization can quickly adjust to
      environmental demands. This article describes models for successful change
      management, followed by questions for the leader in a group practice.

PMID- 10662465
TI  - Using financial ratios in group practice operations.

PMID- 10662466
TI  - Developing MSOs in small markets. The community balance sheet approach.
AB  - The creation of management services organizations (MSOs) has been a phenomenon of
      the 1990s. MSOs allow for partnering of health care providers for multiple
      purposes, including managed care contracting, practice acquisition and
      management, and achieving financial and administrative economies of scale.
      Hospitals and physicians can come together to form successful joint ventures if
      certain critical elements are present, and if success can be defined by the use
      of a community balance sheet.

PMID- 10662467
TI  - Uniting quality and health care with quality-based reimbursement.

PMID- 10662468
TI  - Performance measurement an essential component of medical practice.

PMID- 10662469
TI  - The risks of underutilizing your computer system.

PMID- 10662470
TI  - Physicians use EMR to improve quality. Esse Health takes lead in primary care
      technology, quality.
AB  - Payers, regulators and physicians are battling over who best defines and controls
      medical quality. Esse Health, St. Louis, believes physicians should be in charge
      of quality. To make it possible, Esse has implemented an electronic medical
      record (EMR) system. This article outlines the reasons it choose an EMR, its
      process for putting the system in place and its drawbacks and benefits.

PMID- 10662471
TI  - Accounts receivable reports: underutilized mining tools.
AB  - There is gold to be found in accounts receivable reports for those willing to
      mine the data. The key is to know how to interpret the information buried within
      the numbers and use it to recover monies owed. This article identifies seven
      reports that should be staples in every organization committed to improving its
      overall collection performance. Also included are tips on understanding reports
      and implementing changes.

PMID- 10662472
TI  - How to develop a business plan for your medical group.
AB  - This article gives practical advice about how to plan, develop and present a
      business plan for group practices. The author urges groups to document their
      business strategies because it provides a "financial road map" to assist in the
      affairs of the group. It will lay a suggested foundation and methodology for you
      to use. He recommends sources of information and examples of how his group
      practice goes about developing their business plan.

PMID- 10662473
TI  - The cost and quality of hospitalists. A detailed analysis of creating and
      managing a hospitalist service.
AB  - HMOs and the medical groups that they contract with are increasingly developing
      hospitalist delivery models to assist them with their inpatient care. This
      article offers a case study of how not to create a hospitalist program as well as
      tips for success.

PMID- 10662474
TI  - Protect your practice: payers for sale.
AB  - Mergers and acquisitions are common among managed care plans today, When an HMO
      puts itself on the market, it wants to make itself as attractive as possible to a
      potential buyer. The contracting strategies and operational changes it may pursue
      as a result offer both challenges and opportunities to physician practices.
      Whether contracting directly with managed care plans or participating in a
      contracting entity such as an IPA or PHO, you should understand how to best
      position your practice should an HMO in which you participate goes up for sale.

PMID- 10662475
TI  - Centralizing physician office functions. A paradigm shift.
AB  - Recent trends show that organizations that once thought business office
      centralization was beneficial are re-thinking their strategies and decentralizing
      business office functions. This article focuses on the paradigm shift from
      business office centralization to decentralization and the political factors
      effecting this shift. It provides actual case summaries to demonstrate what has
      transpired, and presents an alternative strategy to establishing successful
      business office functions, a hybrid business office.

PMID- 10662476
TI  - Ethics in group practice.

PMID- 10662477
TI  - Cost effectiveness of fluticasone propionate and flunisolide in the treatment of
      corticosteroid-naive patients with moderate asthma.
AB  - OBJECTIVE: The aim of this study was to determine the cost effectiveness of 2
      inhaled corticosteroids, fluticasone propionate and flunisolide, in the
      management of asthma from a third-party payer perspective in Germany (German
      Sickness Fund). DESIGN AND SETTING: Direct treatment costs were retrospectively
      applied to 2 prospective randomised parallel group clinical trials conducted in
      Germany comparing fluticasone propionate and flunisolide: one 6-week open-label
      study (n = 332) and one 8-week double-blind study (n = 308) in corticosteroid
      naive patients with asthma of moderate severity aged between 18 and 70 years. All
      costs were adjusted to 1997 Deutschmarks. Efficacy parameters included changes in
      morning and evening peak expiratory flow rate (PEFR) measurements, the number of
      successfully treated patients (defined as those with a PEFR improvement of > or =
      10%) and proportion of symptom-free days. MAIN OUTCOME MEASURES AND RESULTS: The
      fluticasone propionate groups had higher respective proportions of successfully
      treated patients and symptom-free days than the flunisolide groups in both the
      open-label (56.8 vs 39.6% and 36.4 vs 28.5%) and double-blind (55.3 vs 44.5% and
      35.1 vs 31.1%) studies. Improvements in both morning and evening PEFR
      measurements were also significantly (p < 0.01) greater with fluticasone
      propionate than with flunisolide. Although average daily treatment costs were
      slightly higher in the fluticasone propionate groups than in the flunisolide
      groups, all cost-effectiveness ratios (daily cost per successfully treated
      patient and daily cost per symptom-free day) favoured fluticasone propionate.
      Sensitivity analysis showed that these results were robust over a wide range of
      assumptions. CONCLUSION: In these patients, management with fluticasone
      propionate was more cost effective than with flunisolide in the German healthcare
      setting.

PMID- 10662478
TI  - Cost-effectiveness analysis of enoxaparin versus unfractionated heparin for acute
      coronary syndromes. A Canadian hospital perspective.
AB  - OBJECTIVE: To determine the cost effectiveness of enoxaparin therapy versus
      unfractionated heparin (UFH) therapy for patients with unstable coronary artery
      disease from the perspective of a Canadian hospital. DESIGN: A predictive
      decision analysis model using published clinical and economic evaluations and
      costs of medical care in Canada. PATIENTS: A hypothetical cohort of patients
      presenting to hospital with unstable angina or non-Q-wave myocardial infarction
      as defined by the Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave
      Coronary Events (ESSENCE) trial. INTERVENTIONS: Two antithrombotic treatment
      strategies were compared: (i) enoxaparin 1 mg/kg subcutaneously every 12 hours,
      and (ii) UFH intravenous bolus and constant infusion adjusted to maintain a
      therapeutic activated partial thromboplastin time. Both treatment strategies
      included 100 to 325 mg of oral aspirin daily. Enoxaparin or UFH was continued for
      a minimum of 48 hours to a maximum of 8 days. Cumulative outcomes were considered
      up to 30 days after initial presentation to hospital. RESULTS: At 30 days, 19.8%
      of patients who received enoxaparin compared with 23.3% of patients who received
      UFH reached one of the primary composite events. There was no difference in major
      bleeding between the 2 treatment groups (6.5% enoxaparin vs 6.8% UFH). The
      average total direct medical cost per patient was $Can848 with the enoxaparin
      strategy versus $Can892 with the UFH strategy (1999 values). Therapy with
      enoxaparin was, therefore, considered to be the dominant strategy. Univariate
      sensitivity analysis indicated that the decision model was not robust to changes
      in the 30-day composite end-point, probability of recurrent angina, or base costs
      for treatment of recurrent angina or enoxaparin therapy. CONCLUSION: Enoxaparin
      is the dominant antithrombotic pharmacotherapeutic strategy for patients with
      unstable coronary artery disease.

PMID- 10662479
TI  - Cost effectiveness of amphotericin B plus G-CSF compared with amphotericin B
      monotherapy. Treatment of presumed deep-seated fungal infection in neutropenic
      patients in the UK.
AB  - OBJECTIVE: To assess the economic impact of adding granulocyte colony-stimulating
      factor (G-CSF) to amphotericin B to treat a presumed deep-seated fungal infection
      in neutropenic patients. This study was conducted from the perspective of the
      National Health Service (NHS) hospital sector. DESIGN: We used our previously
      reported trial as the clinical basis for the analysis (see Participants and
      interventions). These data were combined with resource utilisation data, enabling
      us to construct a decision tree model of the treatment paths attributable to
      managing patients in each arm of the trial. The model was used to calculate the
      cost effectiveness of using amphotericin B plus G-CSF compared to amphotericin B
      monotherapy in neutropenic patients with a presumed deep-seated fungal infection.
      SETTING: An adult leukaemia/bone marrow transplant (BMT) unit in a large UK
      teaching hospital. PARTICIPANTS: Patients with a neutrophil count of < 0.5 x
      10(9)/L and having a presumed deep-seated fungal infection after either
      chemotherapy or stem cell/bone marrow transplantation for haematological
      malignancy. INTERVENTIONS: 29 patients received intravenous amphotericin B (1
      mg/kg daily) plus subcutaneous G-CSF (3 to 5 micrograms/kg daily) and 30 patients
      received intravenous amphotericin B (1 mg/kg daily) monotherapy. The clinical
      trial showed that 62% of patients responded to antifungal treatment with
      amphotericin B plus G-CSF compared to 33% of patients who responded to
      amphotericin B monotherapy (p = 0.027). Nonresponders went on to receive a lipid
      formulation of amphotericin B. MAIN OUTCOME MEASURE AND RESULTS: The mean cost
      per patient treated with amphotericin B plus G-CSF was 11,247 Pounds and the
      corresponding cost for amphotericin B monotherapy was 14,317 Pounds (1996/1997
      values)--a cost reduction of 3070 Pounds per patient. Sensitivity analyses
      demonstrated that the addition of G-CSF to conventional amphotericin B in the
      treatment of a presumed deep-seated fungal infection offers not only clinical
      benefits, but cost benefits which are robust to changes in clinical and economic
      parameters. CONCLUSION: From a UK hospital perspective, amphotericin B plus G-CSF
      is cost effective compared with amphotericin B monotherapy in managing a presumed
      deep-seated fungal infection in neutropenic patients. This result should provide
      strong arguments to clinicians and policy-makers for the adoption of this
      treatment strategy in such patients.

PMID- 10662480
TI  - Cost effectiveness of ciprofloxacin plus metronidazole versus imipenem-cilastatin
      in the treatment of intra-abdominal infections.
AB  - OBJECTIVE: To compare the cost effectiveness of sequential intravenous (i.v.) to
      oral ciprofloxacin plus metronidazole (CIP/MTZ i.v./PO) with that of i.v.
      ciprofloxacin plus i.v. metronidazole (CIP/MTZ i.v.) and i.v. imipenem-cilastatin
      (IMI i.v.) in patients with intra-abdominal infections. DESIGN AND PARTICIPANTS:
      Patients enrolled in a double-blind randomised clinical trial were eligible for
      inclusion into this cost-effectiveness analysis. Decision analysis was used to
      characterise the economic outcomes between groups and provide a structure upon
      which to base the sensitivity analyses. 1996 cost values were used throughout.
      SETTING: The economic perspective of the analysis was that of a hospital
      provider. MAIN OUTCOME MEASURES AND RESULTS: Among 446 economically evaluable
      patients, 176 could be switched from i.v. to oral administration. The 51 patients
      randomised to CIP/MTZ i.v./PO who received active oral therapy had a success rate
      of 98%, mean duration of therapy of 9.1 days and mean cost of $US7678. There were
      125 patients randomized to either CIP/MTZ i.v. or IMI i.v. who received oral
      placebo while continuing on active i.v. antibacterials; their success rate was
      94%, mean duration of therapy was 10.1 days and mean cost was $US8774 (p = 0.029
      vs CIP/MTZ i.v./PO). Of the 270 patients who were unable to receive oral
      administration, 97 received IMI i.v. and had a success rate of 75%, mean duration
      of therapy of 13.8 days and a mean cost of $US12,418, and 173 received CIP/MTZ
      i.v. and had a success rate of 77%, mean duration of therapy of 13.4 days and
      mean cost of $US12,219 (p = 0.26 vs IMI i.v.). CONCLUSIONS: In patients able to
      receive oral therapy, sequential i.v. to oral treatment with ciprofloxacin plus
      metronidazole was cost effective compared with full i.v. courses of ciprofloxacin
      plus metronidazole or imipenem-cilastatin. In patients unable to receive oral
      therapy, no difference in mean cost was found between i.v. imipenem-cilastatin or
      i.v. ciprofloxacin plus i.v. metronidazole.

PMID- 10662481
TI  - Economic impact of providing workplace influenza vaccination. A model and case
      study application at a Brazilian pharma-chemical company.
AB  - OBJECTIVE: To develop and apply a model to assess the economic value of a
      workplace influenza programme from the perspective of the employer. DESIGN: The
      model calculated the avoided costs of influenza, including treatment costs, lost
      productivity, lost worker added value and the cost of replacing workers.
      Subtracted from this benefit were the costs associated with a vaccination
      programme, including administrative costs, the time to give the vaccine, and lost
      productivity due to adverse reactions. The framework of the model can be applied
      to any company to estimate the cost-benefit of an influenza immunisation
      programme. SETTING: The model developed was applied to 4030 workers in the core
      divisions of a Brazilian pharma-chemical company. RESULTS: The model determined a
      net benefit of $US121,441 [129,335 Brazilian reals ($Brz)], or $US35.45
      ($Brz37.75) per vaccinated employee (1997 values). The cost-benefit ratio was
      1:2.47. The calculations were subjected to a battery of 1-way and 2-way
      sensitivity analyses that determined that net benefit would be retained as long
      as the vaccine cost remained below $US45.40 ($Brz48.40) or the vaccine was at
      least 32.5% effective. Other alterations would retain a net benefit as well,
      including several combinations of incidence rate and vaccine effectiveness.
      CONCLUSIONS: The analysis suggests that providing an influenza vaccination
      programme can incur a substantial net benefit for an employer, although the size
      of the benefit will depend upon who normally absorbs the costs of treating
      influenza and compensating workers for lost work time due to illness, as well as
      the type of company in which the immunisation programme is applied.

PMID- 10662482
TI  - Cost-effectiveness analysis of antiplatelet therapy in the prevention of
      recurrent stroke in the UK. Aspirin, dipyridamole and aspirin-dipyridamole.
AB  - OBJECTIVES: To evaluate the cost effectiveness from a UK health and social
      services perspective of antiplatelet therapies tested in the Second European
      Stroke Prevention Study (ESPS-2) in preventing recurrent stroke. To demonstrate
      the value of modelling studies in this area. DESIGN AND SETTING: A decision
      analytic model was developed to evaluate health outcomes and associated costs.
      Sources of data for efficacy, adverse events, background event risks, disability
      and mortality were ESPS-2, the Oxfordshire Community Stroke Project and UK
      national statistics. Published national unit costs were applied to clinician
      panel estimates of resource use for acute stroke, rehabilitation and long term
      care. Outcome measures were strokes or disabled life-years averted, and
      disability-free, stroke-free or quality-adjusted life-years gained. PATIENTS AND
      INTERVENTIONS: 30-day survivors of ischaemic stroke treated with low dose
      aspirin, modified-release dipyridamole; the coformulation of low dose aspirin
      plus modified-release dipyridamole, or no antiplatelet therapy. MAIN OUTCOME
      MEASURES AND RESULTS: The model predicted that over 5 years the coformulation
      prevented 29 more strokes than aspirin alone per 1000 patients, at an additional
      cost of 1900 Pounds per stroke averted (1996 values). Over 5 years, each
      antiplatelet therapy was cost saving compared with no therapy. Results were
      sensitive to the cost of acute care, the cost of long term care of disabled
      stroke survivors, the effectiveness of therapy and the background risk of
      recurrent stroke. In sensitivity analyses, the cost effectiveness did not exceed
      7000 Pounds per stroke averted or 11,000 Pounds per quality-adjusted life-year
      (QALY) gained, except when varying the effectiveness parameter. CONCLUSIONS:
      Application of a decision-analytic model to the results of ESPS-2 indicated that
      first-line therapy with the coformulation of modified-release dipyridamole and
      low dose aspirin to patients with a previous ischaemic stroke is likely to
      generate significant health benefits at modest extra costs to health and social
      services. The extra costs of treatment are balanced by the savings in future
      costs of acute care and long term care of the disabled. Future economic
      evaluations in this area should pay particular attention to the cost perspective,
      the duration of analysis, the selection of trials from which effectiveness data
      are derived, and the impact of the pooling of outcome events with potentially
      different economic consequences.

PMID- 10662483
TI  - Recent progress in biomolecular engineering.
AB  - During the next decade or so, there will be significant and impressive advances
      in biomolecular engineering, especially in our understanding of the biological
      roles of various biomolecules inside the cell. The advances in high throughput
      screening technology for discovery of target molecules and the accumulation of
      functional genomics and proteomics data at accelerating rates will enable us to
      design and discover novel biomolecules and proteins on a rational basis in
      diverse areas of pharmaceutical, agricultural, industrial, and environmental
      applications. As an applied molecular evolution technology, DNA shuffling will
      play a key role in biomolecular engineering. In contrast to the point mutation
      techniques, DNA shuffling exchanges large functional domains of sequences to
      search for the best candidate molecule, thus mimicking and accelerating the
      process of sexual recombination in the evolution of life. The phage-display
      system of combinatorial peptide libraries will be extensively exploited to design
      and create many novel proteins, as a result of the relative ease of screening and
      identifying desirable proteins. Even though this system has so far been employed
      mainly in screening the combinatorial antibody libraries, its application will be
      extended further into the science of protein-receptor or protein-ligand
      interactions. The bioinformatics for genome and proteome analyses will contribute
      substantially toward ever more accelerated advances in the pharmaceutical
      industry. Biomolecular engineering will no doubt become one of the most important
      scientific disciplines, because it will enable systematic and comprehensive
      analyses of gene expression patterns in both normal and diseased cells, as well
      as the discovery of many new high-value molecules. When the functional genomics
      database, EST and SAGE techniques, microarray technique, and proteome analysis by
      2-dimensional gel electrophoresis or capillary electrophoresis in combination
      with mass spectrometer are all put to good use, biomolecular engineering research
      will yield new drug discoveries, improved therapies, and significantly improved
      or new bioprocess technology. With the advances in biomolecular engineering, the
      rate of finding new high-value peptides or proteins, including antibodies,
      vaccines, enzymes, and therapeutic peptides, will continue to accelerate. The
      targets for the rational design of biomolecules will be broad, diverse, and
      complex, but many application goals can be achieved through the expansion of
      knowledge based on biomolecules and their roles and functions in cells and
      tissues. Some engineered biomolecules, including humanized Mab's, have already
      entered the clinical trials for therapeutic uses. Early results of the trials and
      their efficacy are positive and encouraging. Among them, Herceptin, a humanized
      Mab for breast cancer treatment, became the first drug designed by a biomolecular
      engineering approach and was approved by the FDA. Soon, new therapeutic drugs and
      high-value biomolecules will be designed and produced by biomolecular engineering
      for the treatment or prevention of not-so-easily cured diseases such as cancers,
      genetic diseases, age-related diseases, and other metabolic diseases. Many more
      industrial enzymes, which will be engineered to confer desirable properties for
      the process improvement and manufacturing of high-value biomolecular products at
      a lower production cost, are also anticipated. New metabolites, including novel
      antibiotics that are active against resistant strains, will also be produced soon
      by recombinant organisms having de novo engineered biosynthetic pathway enzyme
      systems. The biomolecular engineering era is here, and many of benefits will be
      derived from this field of scientific research for years to come if we are
      willing to put it to good use.

PMID- 10662484
TI  - Stable, long-term bacterial production of soluble, dimeric, disulfide-bonded
      protein pharmaceuticals without antibiotic selection.
AB  - Numerous biopharmaceuticals and other recombinant biotechnology products are made
      in prokaryotic hosts. However, bacterial production of native, biologically
      active eukaryotic proteins is rarely possible for disulfide-bonded and/or
      multisubunit proteins. We previously described the production of soluble, native
      disulfide-bonded dimeric proteins in the Escherichia coli cytoplasm (Miele et
      al., 1990; Mantile et al., 1993). Native, biologically active proteins with up to
      six disulfide bonds have been produced with our expression system (Garces et al.,
      1997). However, plasmid instability during induction limited its usefulness. We
      now report the stable, high-level expression of soluble, disulfide-bonded human
      uteroglobin without antibiotic selection. We designed a new vector containing a
      multifunctional stabilization region that confers complete plasmid stability and
      increased protein yields without copy number increases. Recombinant expression
      remains fully inducible after long-term continuous culture in nonselective liquid
      medium (at least 260 generations). This system may significantly expand the
      applications of bacterial expression to recombinant production of soluble,
      bioactive proteins for biochemical studies and biopharmaceutical/industrial
      purposes. As a result of the very broad activity spectrum of the stabilization
      region we selected, its use could be extended to bacterial hosts other than
      enterobacteria.

PMID- 10662485
TI  - Cloning and expression of Vitreoscilla hemoglobin gene in Burkholderia sp. strain
      DNT for enhancement of 2,4-dinitrotoluene degradation.
AB  - The gene (vgb) encoding the hemoglobin (VHb) of Vitreoscilla sp. was cloned into
      a broad host range vector and stably transformed into Burkholderia (formerly
      Pseudomonas) sp. strain DNT, which is able to degrade and metabolize 2,4
      dinitrotoluene (DNT). Vgb was stably maintained and expressed in functional form
      in this recombinant strain (YV1). When growth of YV1, in both tryptic soy broth
      and minimal salts broth containing DNT and yeast extract, was compared with that
      of the untransformed strain, YV1 grew significantly better on a cell mass basis
      (A(600)) and reached slightly higher maximum viable cell numbers. YV1 also had
      roughly twice the respiration as strain DNT on a cell mass basis, and in DNT
      containing medium, YV1 degraded DNT faster than the untransformed strain. YV1
      cells pregrown in medium containing DNT plus succinate showed the fastest
      degradation: 100% of the initial 200 ppm DNT was removed from the medium within 3
      days.

PMID- 10662486
TI  - Fine affinity discrimination by yeast surface display and flow cytometry.
AB  - Yeast surface display is a eucaryotic system for the directed evolution of
      protein binding and stability. For antibody affinity maturation, achievable
      single-pass enrichment factors are a critical variable. Both reliable recovery of
      rare clones (yield) and effective differentiation between clones of only slightly
      improved affinity (purity) are paramount. To validate yeast display's
      purification potential, trial sorting experiments were performed. The D1.3 (anti
      hen egg lysozyme) single chain variable fragment antibody and a 2-fold higher
      affinity mutant (M3) were each displayed on the surface of Saccharomyces
      cerevisiae. M3-displaying cells were mixed into the D1.3-displaying cells at a
      ratio of 1:1000. Cells were fluorescently labeled according to antigen
      equilibrium binding and then sorted using a flow cytometer. Single-pass
      enrichment of M3-displaying cells was 125-fold (+/- 65-fold). This level of
      performance is achievable because of the precision and reproducibility of optimal
      labeling conditions. This work further demonstrates the capability of yeast
      display for very fine discrimination between mutant clones of similar affinity.
      Because large improvements in affinity typically result from combinations of
      small changes, this capability to identify subtle improvements is essential for
      rapid affinity maturation.

PMID- 10662487
TI  - Pilot-scale purification of zeamatin, an antifungal protein from maize.
AB  - Zeamatin is an antifungal protein isolated from the seeds of Zea mays. A
      practical process for isolation and purification was developed to increase
      recovery yields for future testing of zeamatin as a novel therapeutic drug.
      Zeamatin was extracted with buffer from corn meal milled to flour. Solids were
      removed from the extract using pressure filtration, and zeamatin was purified
      using two separate reverse-phase chromatography steps. Determination of the amino
      terminal amino acid sequence, Western blotting using anti-zeamatin antibody, and
      activity against Candida albicans were used to confirm that the purified protein
      was zeamatin. From 5 kg of corn meal, approximately 110 mg of zeamatin was
      purified to apparent homogeneity.

PMID- 10662488
TI  - Macro approach and fuzzy modeling of entrapped biocatalyst.
AB  - The interactions between a strain of Saccharomyces cerevisiae and an alginate
      matrix are investigated to ascertain the main factors affecting the bioreaction
      evolution. During the tests several parameters (glucose, ethanol, calcium ion and
      biomass concentration, pH, and alginate bed diameter) were evaluated, coupled
      with microscopic investigation inside the beads to determine the spatial biomass
      distribution. A detailed analysis of macro parameters and a correlation among
      them are proposed using a fuzzy algorithm. A global two-step fuzzy model results
      in which biomass distribution inside the beads is represented as a hidden
      parameter.

PMID- 10662489
TI  - Catalytic and structural properties of surfactant-horseradish peroxidase complex
      in organic media.
AB  - A surfactant-horseradish peroxidase (HRP) complex that is catalytically active in
      organic media has been successfully prepared by a method utilizing water-in-oil
      (W/O) emulsions. To optimize conditions for preparation of the HRP complex, the
      effects of some key parameters in the aqueous phase of W/O emulsions were
      investigated. The surfactant-HRP complex prepared with a nonionic surfactant
      exhibited a high catalytic activity compared to those with a cationic or anionic
      surfactant in anhydrous benzene. At the preparation step, the pH of the aqueous
      solution had a prominent effect on the enzymatic activity of the HRP complex in
      organic media. Several kinds of salts present in the HRP complex could be
      employed to enhance the catalytic performance in organic media. However, anionic
      ions present in the preparation process appeared to lower the catalytic activity
      owing to the complexation with heme iron. UV-visible absorption spectra of the
      HRP complex in benzene, which were prepared from a KCN solution (pH 7.0) or an
      alkaline solution (pH 12), were comparable with those of native HRP in aqueous
      solution under the same conditions. Resonance Raman spectroscopic studies also
      revealed that no significant change in the coordination state of the heme iron
      occurred even after coating the enzyme with surfactant molecules, lyophilization,
      and solubilization in nonaqueous media.

PMID- 10662490
TI  - Characterization of Lactobacillus carbohydrate fermentation activity using
      immobilized cell technique.
AB  - A microbial bioreactor based on calcium alginate immobilized Lactobacillus cells
      coupled to a pH electrode was developed for quantitative determination of
      carbohydrate fermentation activity. A high biomass (10(10) cfu mL(-)(1)) and
      particular pregrowth conditions were needed. Reduction of catabolite repression
      by monosaccharides was achieved by pregrowth in lactose. The evolution of acid
      production in a continuous flow-stopped flow bioreactor was monitored for
      different sugar solutions in contact with the immobilized bacteria. The resulting
      slopes (DeltamV/Deltat) were used to quantify the fermentation capability for a
      defined sugar related to that of glucose, which was taken as 100%. The procedure
      is simple, being based on pH variation that can give quantitative results
      compared to other reported techniques for carbohydrate fermentation pattern from
      which only qualitative results are obtained. In addition, it offers reduction in
      time and costs and is a suitable tool for the rapid analysis of isolated strains
      and in studies of modifications of sugar metabolism in mutants.

PMID- 10662491
TI  - Biocatalytic synthesis of fluorinated polyesters.
AB  - The biocatalytic synthesis of fluorinated polyesters from activated diesters and
      fluorinated diols has been investigated. The effects of time, continuous enzyme
      addition, enzyme concentration, and diol chain length were studied to determine
      the factors that would limit chain extension, such as enzyme inactivation, enzyme
      specificity, the equilibrium position for the reaction, hydrolytic side
      reactions, and polymer precipitation. An enzyme screen demonstrated that only
      Novozym 435, an immobilized lipase from Candida antarctica, was effective in
      producing the fluorinated polyester. Molecular weight and polydispersity analyses
      were performed by means of gel permeation chromatography. End group analysis was
      accomplished through the use of matrix-assisted laser desorption/ionization time
      of-flight mass spectroscopy. Polymer molecular weight steadily increased and then
      leveled off after approximately 30 h, with a weight average molecular weight of
      approximately 1773. The majority of the polymer chains were terminated with
      either hydroxyl or vinyl groups. Polymers that were synthesized from bulk
      monomers had higher molecular weights, but high enzyme concentrations were
      required. Enzyme specificity toward shorter chain fluorinated diols appeared to
      be the governing factor in limiting chain growth. However, polymer molecular
      weight increased further (M(w) = 8094) when a fluorinated diol that contained an
      additional methylene spacer between the fluorine atoms and hydroxyl groups was
      used.

PMID- 10662492
TI  - Improvement of CHO cell culture medium formulation: simultaneous substitution of
      glucose and glutamine.
AB  - The formulation of the culture medium for a Chinese hamster ovary (CHO) cell line
      has been investigated in terms of the simultaneous replacement of glucose and
      glutamine, the most commonly employed carbon and nitrogen sources, pursuing the
      objective of achieving a more efficient use of these compounds, simultaneously
      avoiding the accumulation of lactate and ammonium in the medium. The key factor
      in this process is the selection of compounds that are slowly metabolized. Among
      the different compounds studied, galactose and glutamate provide the best
      results, allowing support of cell growth with an optimal balance between nutrient
      uptake and cell requirements and the generation of minimal quantities of lactate
      and ammonium. The attained results also highlight the capacity of the cells to
      redistribute their metabolism as a response to the changes in medium composition.

PMID- 10662493
TI  - Reactive extraction for downstream separation of 1,3-propanediol.
AB  - The downstream separation of 1,3-propanediol from dilute aqueous solution was
      studied. A process combining reversible reaction of 1, 3-propanediol with
      acetaldehyde to 2-methyl-1,3-dioxane and a simultaneous extraction of the product
      by organic solvent appears to be technically feasible and attractive. The dioxane
      yield was 91-92%, the overall conversion of 1,3-propanediol was ca. 98%, and
      recovery of dioxane into the organic extractant was 75%.

PMID- 10662494
TI  - Gaulin homogenization: a mechanistic study.
AB  - Free radical-based oxidation has been detected in the normal operating regime of
      the Gaulin homogenizer, demonstrating that cavitation occurs in this important
      industrial bioprocessing equipment. Free radical generation is suppressed by
      imposition of back pressure, proving that such cavitation occurs in the
      impingement section. The calculated value of the cavitation number is consistent
      with submerged jet cavitation, wherein a high-speed jet exiting from the valve
      gap accelerates fluid in the impingement region, creating the vacuum conditions
      for cavitation. Using polysaccharides as a model shear-sensitive compound, their
      breakage pattern in the homogenizer was characterized by molecular size and
      polydispersity and compared to those of fluid shear flows in capillary tubes and
      cavitating flow from a sonic horn. The results indicate that breakage occurs
      primarily by fluid shear, although a contribution by cavitation is also apparent
      when back pressure is applied. Because biological molecules can readily react
      with free radicals and the alterations caused thereby are subtle in nature, a
      thorough evaluation of the impact of free radicals in upstream homogenization is
      warranted.

PMID- 10662495
TI  - Design of affinity tags for one-step protein purification from immobilized zinc
      columns.
AB  - Affinity tags are often used to accomplish recombinant protein purification using
      immobilized metal affinity chromatography. Success of the tag depends on the
      chelated metal used and the elution profile of the host cell proteins. Zn(II)
      iminodiacetic acid (Zn(II)-IDA) may prove to be superior to either immobilized
      copper or nickel as a result of its relatively low binding affinity for cellular
      proteins. For example, almost all Escherichia coli proteins elute from Zn(II)-IDA
      columns between pH 7.5 and 7.0 with very little cellular protein emerging at pH
      values lower than 7.0. Thus, a large portion of the Zn(II)-IDA elution profile
      may be free of contaminant proteins, which can be exploited for one-step
      purification of a target protein from raw cell extract. In this paper we have
      identified several fusion tags that can direct the elution of the target protein
      to the low background region of the Zn(II)-IDA elution profile. These tags allow
      targeting of proteins to different regions of the elution profile, facilitating
      purification under mild conditions.

PMID- 10662496
TI  - Modeling conductive heat transfer and process uniformity during batch high
      pressure processing of foods.
AB  - A numerical model for predicting conductive heat transfer during batch high
      hydrostatic pressure (HHP) processing of foods was developed and tested for a
      food simulator (agar gel). For a comprehensive evaluation of the proposed method,
      both "conventional" HHP processes, HHP processes with gradual, step-by-step
      pressure buildup and pressure release, and pressure cycling HHP processes were
      included. In all cases, good agreement between experimental and predicted
      temperature profiles was observed. The model provides a very useful tool to
      evaluate batch HHP processes in terms of uniformity of any heat- and/or pressure
      related effect. This is illustrated for inactivation of Bacillus subtilis alpha
      amylase, an enzymatic model system with known pressure-temperature degradation
      kinetics.

PMID- 10662497
TI  - A novel full-scale flat membrane bioreactor utilizing porcine hepatocytes: cell
      viability and tissue-specific functions.
AB  - When designing an extracorporeal hybrid liver support device, special attention
      should be paid to providing the architectural basis for reconstructing a proper
      cellular microenvironment that ensures highest and prolonged functional activity
      of the liver cells. The common goal is to achieve high cell density culture and
      to design the bioreactor for full-scale primary liver cell cultures under
      adequate mass transfer conditions. An important aim of this study was to evaluate
      the biochemical performance of a flat membrane bioreactor that permits high
      density hepatocyte culture and simultaneously to culture cells under sufficient
      oxygenation availability conditions comparable to the in vivo-like
      microenvironment. In such a bioreactor pig liver cells were cultured within an
      extracellular matrix between oxygen-permeable flat-sheet membranes. In this
      investigation we used a novel scaled-up prototype consisting of up to 20 modules
      in a parallel mode. Each module was seeded with 2 x 10(8) cells. Microscopic
      examination of the hepatocytes revealed morphological characteristics as found in
      vivo. Cell concentration increased in the first days of culture, as indicated by
      DNA measurements. The performance of the bioreactor was monitored for 18 days in
      terms of albumin synthesis, urea synthesis, ammonia elimination, and diazepam
      metabolism. The ability of the hepatocytes to synthesize albumin and urea
      increased during the first days of culture. Higher rates of albumin synthesis
      were obtained at day 9 and remained at a value of 1.41 pg/h/cell until day 18 of
      culture. The rate of urea synthesis increased from 23 ng/h/cell to 28 ng/h/cell
      and then remained constant. Cells eliminated ammonia at a rate of about 56
      pg/h/cell, which was constant over the experimental period. Hepatocytes in the
      bioreactor metabolized diazepam and generated three different metabolites:
      nordiazepam, temazepam, and oxazepam. The production of such metabolites was
      sustained until 18 days of culture. These results demonstrated that the scale-up
      of the bioreactor was assessed, and it could be demonstrated that the device
      design aimed at the reconstruction of the liver-specific tissue architecture
      supported the expression of liver-specific functions of primary pig liver cells.

PMID- 10662498
TI  - Kinetics of pressure inactivation at subzero and elevated temperature of
      lipoxygenase in crude green bean (Phaseolus vulgaris L.) extract.
AB  - Lipoxygenase (LOX) in crude green bean extract was irreversibly inactivated by
      pressure treatments combined with subzero or elevated temperature. LOX
      inactivation was described accurately assuming a first-order reaction. In the
      entire pressure-temperature domain studied (200 to 700 MPa and -10 to 60 degrees
      C), an increase in pressure at constant temperature enhanced the LOX inactivation
      rate, whereas at constant pressure, an increase in reaction rate was obtained by
      either increasing or decreasing temperature at 20 degrees C. At elevated
      pressure, LOX exhibited the greatest stability around 20 degrees C. Also the
      pressure dependence of the inactivation rate constants for LOX was the highest
      around 20 degrees C. On the basis of the estimated LOX inactivation rate
      constants, an iso-rate contour diagram as a function of pressure and temperature
      was constructed, and an empirical mathematical model describing the combined
      pressure-temperature dependence of the LOX inactivation rate constants was
      formulated.

PMID- 10662499
TI  - A reusable and specific protein A-coated piezoelectric biosensor for flow
      injection immunoassay.
AB  - A hydrophilic matrix of periodate-oxidized dextran was used as a double-sided
      linker to covalently immobilize Staphylococcus aureus protein A (SpA) molecules
      onto a poly-L-lysine-modified piezoelectric crystal surface to improve their
      stability, activity, and binding specificity with human immunoglobulin G (IgG) in
      flow injection assays. The prepared sensing crystals displayed best sensitivity
      and reusability at a flow rate of 140 microL/min. A human IgG concentration as
      low as 0.3 nM can be detected by this system. Up to 19 successive assay
      repetitions were achieved without significant loss of sensitivity using the same
      crystal. The analysis of adsorption kinetics indicates that such a preparation
      can greatly increase the amount of available active human IgG binding sites on
      immobilized SpA. Hardly any response arising from unspecific binding was
      detected. In addition, the sensing crystal prepared by this method was found to
      retain activity better than one prepared via direct deposition when stored in
      either wet or dry states. Finally, the prepared SpA-coated crystals were applied
      to the affinity immobilization of polyclonal goat anti-Schistosoma japonicum
      glutathione-S-transferase (GST) and were able to subsequently detect GST and its
      genetically engineered mutant either in a purified form or in the crude cell
      lysate.

PMID- 10662500
TI  - Cell-microcarrier adhesion to gas-liquid interfaces and foam.
AB  - The interaction of microcarriers, both with and without cells attached, with gas
      bubbles was studied. These studies consisted of qualitative microscopic
      observations of microcarriers with bubbles, quantitative measurements of
      microcarrier entrapment in foam, and quantitative measurements of the effect of
      bubble rupture at gas-medium interfaces. Ten different "protective additives"
      were evaluated for their ability to change the dynamic surface tension of the
      culture media and to prevent microcarrier adhesion to air bubbles during gas
      sparging and to prevent entrapment in the foam layer. These studies indicate that
      microcarriers, with and without cells, readily attach to gas-medium interfaces;
      yet unlike suspended cells, cells attached to microcarriers are not damaged by
      bubble ruptures at gas-medium interfaces. Only one surfactant was found to
      substantially prevent microcarrier entrapment in the foam layer; however, this
      surfactant was toxic to cells. No correlation was observed between surface
      tension and the prevention of microcarrier adhesion to gas-liquid interfaces. It
      is suggested that cell damage as a result of sparging in microcarrier cultures is
      the result of cells, attached to microcarriers, attaching to rising bubbles and
      then detaching from the microcarrier as this combination rises through the
      medium. It is further suggested that the hydrodynamic drag force of the rising
      microcarrier is sufficiently high to remove the bubble-attached cell from the
      microcarrier.

PMID- 10662501
TI  - Structural and functional evolution of the L1 family: are four adhesion molecules
      better than one?

PMID- 10662502
TI  - Activin A promotes progenitor differentiation into photoreceptors in rodent
      retina.
AB  - Activins are TGF beta-like proteins that were first discovered for their actions
      on the reproductive system, but have subsequently been shown to play a role in a
      variety of developmental processes. Previous studies have demonstrated that
      activins and their receptors are present in the developing retina, as well as
      other regions of the embryonic nervous system. We used both in vitro and in vivo
      approaches to test for functions of activin during retinal development. We found
      that activin A treatment of embryonic day 18 rat retinal cultures causes the
      progenitor cells in the cultures to exit the cell cycle and differentiate into
      rod photoreceptors. This effect is dose-dependent and the promotion of rod
      photoreceptor differentiation is specific, since the other primary retinal
      neurons generated in these cultures, the C1+ amacrine cells, are not affected by
      activin A treatment. Mice with homozygous deletion of the activin betaA gene show
      a specific decrease in the number of rod photoreceptors compared to wild-type or
      heterozygous littermates. These data demonstrate that activin A is an important
      regulator of photoreceptor differentiation in the developing retina.

PMID- 10662503
TI  - Differential display of genes expressed at the midbrain - hindbrain junction
      identifies sprouty2: an FGF8-inducible member of a family of intracellular FGF
      antagonists.
AB  - Specification and polarization of the midbrain and anterior hindbrain involve
      planar signals originating from the isthmus. Current evidence suggests that FGF8,
      expressed at the isthmus, provides this patterning influence. In this study, we
      have sought to identify novel genes which are involved in the process by which
      regional identity is imparted to midbrain and anterior hindbrain (rhombomere 1).
      An enhanced differential display reverse transcription method was used to clone
      cDNAs derived from transcripts expressed specifically in either rhombomere 1 or
      midbrain during the period of isthmic patterning activity. This gene expression
      screen identified 28 differentially expressed cDNAs. A clone upregulated in cDNA
      derived from rhombomere 1 tissue showed a 91% identity at the nucleotide level to
      the putative human receptor tyrosine kinase antagonist: sprouty2. In situ
      hybridization on whole chick embryos showed chick sprouty2 to be expressed
      initially within the isthmus and rhombomere 1, spatially and temporally
      coincident with Fgf8 expression. However, at later stages this domain was more
      extensive than that of Fgf8. Introduction of ligand-coated beads into either
      midbrain or hindbrain region revealed that sprouty2 could be rapidly induced by
      FGF8. These data suggest that sprouty2 participates in a negative feedback
      regulatory loop to modulate the patterning activity of FGF8 at the isthmus.

PMID- 10662504
TI  - Homer-1c/Vesl-1L modulates the cell surface targeting of metabotropic glutamate
      receptor type 1alpha: evidence for an anchoring function.
AB  - Homer-1c/Vesl-1L is a 48-kDa protein that forms part of a family of conserved
      Homer-related proteins that interact with the C-termini of the metabotropic
      glutamate receptors mGluR1alpha and mGluR5. In order to examine the function of
      Homer-1c, HEK-293 cells have been transfected with mGluR1alpha, Homer-1c, and
      both proteins together. When cells were transfected with both proteins,
      biotinylation of cell surface molecules revealed a significant increase in the
      amount of receptor and Homer-1c associated with the cell surface compared with
      cells transfected with mGluR1alpha alone. This finding was paralleled by a
      concomitant increase in the production of inositol after treatment of the doubly
      transfected cells with agonist. Cell surface immunostaining of mGluR1alpha showed
      that Homer-1c can induce clustering of the receptor in the plasma membrane of HEK
      293 cells and suggested that the surface receptor was associated with Homer-1c in
      the plasma membrane. The presence of Homer-1c reduced the rate of loss from the
      cell surface of mGluR1alpha from 5 to 1%/min and increased the extent of
      dendritic trafficking of the receptor in rat primary cultured neurons. Our
      results suggest that Homer-1c increases the cell surface expression of the
      metabotropic glutamate receptor type 1alpha by increasing its retention in the
      plasma membrane.

PMID- 10662505
TI  - The microtubule-associated protein MAP1B is involved in local stabilization of
      turning growth cones.
AB  - For the development of the nervous system it is crucial that growth cones detect
      environmental information and react by altering their growth direction. The
      latter process is thought to depend on local stabilization of growth cone
      microtubules. We have obtained evidence of a role for the microtubule-associated
      protein MAP1B, in particular a mode 1 phosphoisoform of the molecule, P1-MAP1B,
      in this process. P1-MAP1B is tightly associated with the cytoskeleton and is
      present at highest concentrations in the distal axon and the growth cone of chick
      retinal ganglion cells. In growth cones turning at nonpermissive substrate
      borders, P1-MAP1B is restricted to regions which are stabilized. Unilateral
      neutralization of P1-MAP1B in one-half the growth cone by microscale chromophore
      assisted laser inactivation changes growth cone motility, morphology, and growth
      direction. The results indicate a functional role for P1-MAP1B in local growth
      cone stabilization and thus growth cone steering.

PMID- 10662506
TI  - Prion protein peptides: optimal toxicity and peptide blockade of toxicity.
AB  - In prion disease neurodegeneration requires deposition of the abnormal isoform of
      the prion protein (PrP(Sc)) within nervous tissue. In vitro PrP(Sc) has
      neurotoxicity that can be mimicked by peptides based on part of its sequence. In
      this investigation the region of the protein required for maximal neurotoxicity
      was precisely determined. The optimal neurotoxic peptide was found to contain
      amino acids 112-126 of the human sequence. The sequence AGAAAAGA was found to be
      necessary but not sufficient for a neurotoxic effect. The AGAAAAGA peptide
      blocked the toxicity of PrP106-126, suggesting that this sequence is necessary
      for the interaction of PrP106-126 with neurons. These results suggest that
      targeting or use of the AGAAAAGA peptide may represent a therapeutic opportunity
      for controlling prion disease.

PMID- 10662507
TI  - Cooperation between HGF and CNTF in promoting the survival and growth of sensory
      and parasympathetic neurons.
AB  - Previous studies have shown that hepatocyte growth factor (HGF) enhances the
      survival and growth of neurons that depend on NGF for survival. To determine if
      HGF cooperates with other neurotrophic factors in the developing peripheral
      nervous system, we studied the effect of HGF on parasympathetic ciliary ganglion
      neurons and proprioceptive trigeminal mesencephalic nucleus (TMN) neurons, both
      of which survive with CNTF. HGF did not promote the survival of these neurons on
      its own but did enhance the number that survived with CNTF and increased the
      length and branching of their neurite arbors. HGF did not, however, enhance the
      survival and growth of TMN neurons incubated with BDNF, which promoted their
      survival as effectively as CNTF. These results show that HGF cooperates with CNTF
      in promoting the survival and growth of parasympathetic and proprioceptive
      neurons and that within the same neurons, the effects of HGF on survival and
      growth are selectively dependent on which other signaling pathways are
      concurrently activated.

PMID- 10662508
TI  - Posttranslational modification and plasma membrane localization of the Drosophila
      melanogaster presenilin.
AB  - Mutations in two genes, presenilin 1 (PS1) and presenilin 2, are linked to early
      onset cases of familial Alzheimer's disease. The presenilins are thought to
      contribute to the pathogenesis of Alzheimer's disease by directly or indirectly
      affecting the proteolytic processing of the amyloid precursor protein. They have
      also been implicated in the proteolytic processing of Notch. In PS1-deficient
      mammalian cells, the proteolytic release of the Notch intracellular domain is
      reduced. Likewise, loss-of-function mutations in Drosophila presenilin (Psn)
      prevent the production of the intracellular Notch signaling fragment and lead to
      phenotypes resembling Notch mutants. Here we characterize the Drosophila Psn
      protein and demonstrate that it undergoes a proteolytic cleavage. We describe Psn
      expression at different developmental stages of the fly and show Psn localization
      near both apical and basal plasma membranes. Furthermore, we demonstrate that
      portions of the Psn protein span the plasma membrane in S2 cells.

PMID- 10662509
TI  - Polarized distribution of glycine transporter isoforms in epithelial and neuronal
      cells.
AB  - Asymmetrical distribution of Na(+)- and Cl(-)-dependent neurotransmitter
      transporters on the cell surface of polarized cells seems to be a generalized
      feature in this gene family. In the present study we analyzed the subcellular
      distribution of the various isoforms of the glycine transporters GLYT1 and GLYT2
      after heterologous expression in polarized MDCK cells and in hippocampal neurons.
      Our results indicate that glycine transporters are asymmetrically distributed in
      an isoform- and cell-type-specific manner. GLYT1b is localized in the basolateral
      and somatodendritic domains of MDCK cells and neurons, respectively. However,
      GLYT1a is somatodendritic in neurons but is predominantly expressed in the apical
      surface of MDCK cells. The two isoforms of GLYT2 (GLYT2a and GLYT2b) are found at
      the apical surface in epithelial cells but are uniformly distributed in neurons.
      By using site-directed mutagenesis we have been able to identify signals for
      basolateral/somatodendritic localization in the amino-terminal region of GLYT1
      and in two dileucine motifs located in the carboxyl tail of this protein. These
      results contribute to defining the mechanisms of asymmetrical distribution of
      transporters on the cell surface of polarized cells.

PMID- 10662510
TI  - Comparing Decyl-beta-maltoside and Octaethyleneglycol Mono n-Decyl Ether in Mixed
      Micelles with Dodecyl Benzenesulfonate.
AB  - In this study the mixed micelle behavior of an alkyl polyglycoside is compared to
      a surfactant of polyoxyethylene type, by means of surface tension measurements.
      The two nonionic surfactants are compared in mixed micelle systems together with
      an anionic surfactant. The surfactant mixtures are: decyl-beta-maltoside (C(10)M)
      with dodecyl benzenesulfonate (C(12)BS) and octaethyleneglycol mono n-decyl ether
      (C(10)EO(8)) with C(12)BS. The mixture of C(10)M and C(10)EO(8) is also studied.
      Critical micelle concentration (CMC) and the concentration at which the surface
      tension reduction is 20 mNm(-1) (C(20)) are determined at different mixing ratios
      of the surfactant mixtures. By applying the nonideal mixed micelle theory,
      interaction parameters at CMC (beta(CMC)) and C(20) (beta(C20)) are calculated
      for the surfactant mixtures. The results show that the C(10)M-C(12)BS mixture has
      a beta(CMC) parameter of -2.1, whereas the beta(CMC) parameter for the C(10)EO(8)
      C(12)BS mixture is -3.3, indicating a weaker net attractive interaction between
      C(10)M and C(12)BS than between C(10)EO(8) and C(12)BS. This is attributed to a
      small negative and positive charge of the respective nonionic surfactants. This
      is supported by a slightly negative beta(CMC) parameter obtained for the
      surfactant mixture C(10)M-C(10)EO(8), indicating a small net attractive
      interaction between the two nonionic surfactants. Copyright 2000 Academic Press.

PMID- 10662511
TI  - Comparing Decyl-beta-maltoside and Octaethyleneglycol Mono n-Decyl Ether in Mixed
      Micelles with Dodecyl Benzenesulfonate.
AB  - The interactions between polyvinylpyrrolidone (PVP) and a mixture of anionic and
      nonionic surfactants have been investigated by surface tension measurements. The
      surfactant mixtures are decyl-beta-maltoside (C(10)M) with dodecyl
      benzenesulfonate (C(12)BS) and octaethyleneglycol mono n-decyl ether (C(10)EO(8))
      with C(12)BS. Surface tension measurements of the surfactant mixtures in the
      presence of PVP show that C(10)EO(8) competes more effectively than C(10)M with
      PVP in the interaction with C(12)BS. Copyright 2000 Academic Press.

PMID- 10662512
TI  - A Cryo-TEM Study of Protein-Surfactant Gels and Solutions.
AB  - Oppositely charged globular protein and surfactant systems, such as lysozyme
      sodium dodecyl sulfate (SDS) and ovalbumin-dodecyltrimethylammonium chloride
      (DOTAC) form precipitate, gel, and colorless solution in water over a wide
      concentration range. Bluish solutions are also recognized in connection with the
      redissolution of precipitate as well as prior to the gel formation. For the
      lysozyme-SDS system the bluish solution has been suggested to consist of finely
      dispersed gel particles in solution. The oppositely charged bovine serum albumin
      (BSA)-DOTAC-water system forms only a large, clear solution phase and a narrow,
      bluish solution region within a very limited surfactant concentration range. In
      the lysozyme-SDS system the formation of protein-surfactant aggregates and their
      growth and breakdown are studied in detail by cryogenic-transmission electron
      microscopy (cryo-TEM) method. In particular a series of samples with an increased
      surfactant concentration at fixed 4 wt% of lysozyme is studied. Imaging of the
      bluish solution at different protein concentrations exhibits large aggregates in
      the form of rod-like, sheet-like, and star-like objects which are attributed to
      the gel. At excess amounts of SDS, in the colorless solution, only small objects
      are detected. In the ovalbumin-DOTAC-water and BSA-DOTAC-water systems large
      aggregates are also observed in the bluish solutions. Colorless solutions for
      these two systems show the presence of small objects in the cryo-TEM micrographs.
      Ultrathin sections of the lysozyme and ovalbumin gels fixed with OsO(4) also show
      the presence of aggregated structures as judged from the transmission electron
      microscopy observations. Copyright 2000 Academic Press.

PMID- 10662513
TI  - Micropore Filling of Supercritical Xe in Micropores of Activated Carbon Fibers.
AB  - The adsorption isotherms of Xe vapor at 196 K and supercritical Xe at 300 K on
      activated carbon fibers of different pore widths were gravimetrically measured.
      The adsorption isotherms of Xe vapor were compared with the N(2) adsorption
      isotherms. A Dubinin-Radushkevich (DR) plot of the adsorption isotherms of Xe
      vapor showed a good linearity, indicating that Xe vapor is adsorbed by the
      representative micropore filling mechanism. The adsorption isotherms of
      supercritical Xe were approximated by the Langmuir equation. The saturated
      adsorption amounts of supercritical Xe, W(L), were in the range of 0.14 to 0.22
      ml g(-1). The adsorption isotherms of supercritical Xe were described by the
      supercritical DR equation, which provides the quasisaturated vapor pressure
      P(0q). Both P(0q) and W(L) lead to the reduced isotherm, which can describe three
      isotherms. The obtained reduced isotherm derived from the isotherms of
      supercritical Xe could describe even those of Xe vapor. Hence, both Xe vapor and
      supercritical Xe should be adsorbed by the same mechanism. The isosteric heat of
      Xe adsorption was greater than the enthalpy of vaporization of Xe by more than 12
      kJ mol(-1). These results suggest that Xe molecules are stabilized in the form of
      a cluster in micropores even at 300 K. Copyright 2000 Academic Press.

PMID- 10662514
TI  - X-Ray Absorption Spectroscopy of Strontium(II) Coordination.
AB  - Detailed analyses of crystalline, hydrated, and precipitated strontium compounds
      and an aqueous strontium solution by synchrotron extended X-ray absorption fine
      structure (EXAFS) were used to quantify local thermal and static disorder and to
      characterize strontium coordination in a variety of oxygen-ligated bonding
      environments. Analysis of anharmonic vibrational disorder (i.e., significant
      contribution from a third cumulant term (C(3)) in the EXAFS phase-shift function)
      in compounds with low and high static disorder around strontium showed that first
      shell anharmonic contributions were generally not significant above experimental
      error in the EXAFS fits (R+/-0.02 A with and without C(3)). The only case in
      which a significant apparent decrease in Sr-O distance was observed with
      increasing temperature, and for which a third cumulant term was significant, was
      for dilute strontium in aqueous solution. Empirical parameterization of Debye
      Waller factor (sigma(2)) for strontium compounds as a function of backscatterer
      atomic number (Z), interatomic Sr-Z distance, and temperature of spectral data
      collection showed systematic increases in sigma(2) as a function of increasing
      temperature and Sr-Z bond length. At values of sigma(2) greater than
      approximately 0.025 A(2) (for N<12 and R(Sr)-Z>3 A), backscattering was generally
      not significant above noise levels in spectra of compounds of known crystal
      structure. Comparison of the EXAFS spectra of freshly precipitated SrCO(3)
      (spectra collected wet) to that of dry, powdered strontianite (SrCO(3)(s))
      indicated no significant differences in the local atomic structure around
      strontium. Analysis of partially hydrated strontium in natural Ca-zeolite
      (heulandite) showed that strontium is substituted only in the calcium (Ca2) site.
      Backscattering from aluminum and silicon atoms in the zeolite framework were
      apparent in the EXAFS spectra at low and room temperature at distances from
      central strontium of <4.2 A. Comparison of strontium structural coordination
      determined in this and previous studies suggests that previous EXAFS
      determinations of hydrated strontium may have underestimated first-shell
      interatomic distances and coordination numbers because minor contributions to the
      EXAFS phase-shift and amplitude functions were not accounted for, either
      theoretically or empirically. Copyright 2000 Academic Press.

PMID- 10662515
TI  - X-Ray Absorption Spectroscopy of Strontium(II) Coordination.
AB  - Sorption of dissolved strontium on kaolinite, amorphous silica, and goethite was
      studied as a function of pH, aqueous strontium concentration, the presence or
      absence of atmospheric CO(2) or dissolved phosphate, and aging over a 57-day
      period. Selected sorption samples ([Sr(aq)](i) approximately 0.5-1x10(-3) m) were
      examined with synchrotron X-ray absorption spectroscopy (XAS) at low (13-23 K)
      and room temperatures to determine the local molecular coordination around
      strontium. Quantitative analyses of the extended X-ray absorption fine structure
      (EXAFS) of kaolinite, amorphous silica, and most goethite sorption samples showed
      a single first shell of 9-10 (+/-1) oxygen atoms around strontium at an average
      Sr-O bond-distance of 2.61 (+/-0.02) A, indicating hydrated surface complexes.
      The EXAFS spectra were unchanged after reaction for up to 57 days. Likewise, in
      kaolinite sorption samples prepared in 100% nitrogen atmosphere, the presence of
      dissolved phosphate (0.5x10(-3) m) in addition to strontium did not change the
      local coordination around strontium. In two goethite sorption samples reacted in
      air at pH approximately 8.5, the EXAFS spectra (collected at low and room
      temperature) clearly showed that the local structure around strontium is that of
      strontianite (SrCO(3)(s)). We also noted an increase in strontium uptake on
      goethite in the presence of atmospheric CO(2) in batch experiments, relative to
      CO(2)-free experiments. These observations suggest that sorption of carbonate may
      nucleate the precipitation of SrCO(3) in the pH range in which carbonate sorption
      on goethite is near a maximum. At higher pH, carbonate surface sorption decreases
      as dissolved CO(2) decreases. For goethite sorption samples above pH 8.6,
      hydrated surface complexes, rather than a precipitate, were observed in the EXAFS
      spectra. Copyright 2000 Academic Press.

PMID- 10662516
TI  - Effect of Salts on the Micellization, Clouding, and Solubilization Behavior of
      Pluronic F127 Solutions.
AB  - We have examined the effect of NaCl, Na(2)SO(4), Na(3)PO(4), and NaSCN on F127
      solutions; properties examined were critical micellization temperature (cmt),
      cloud point, and solubilization of a model hydrophobic drug, propyl paraben.
      Static light scattering showed that the first three salts lower the cmt of F127
      in the order Na(3)PO(4)>Na(2)SO(4)>NaCl. The extent of lowering depends on the
      salt concentration and can be ascribed to the water structure-making properties
      of these salts. NaSCN, a water structure breaker, was found to increase cmt.
      Pyrene fluorescence was used to study the changes in micellar interior in the
      presence of salts. We found that the micellar micropolarity is not significantly
      changed by salts, evidenced by a constant I(1)/I(3) ratio of pyrene. However, the
      I(e)/I(3) ratio changes significantly with salts, being lower for NaCl,
      Na(2)SO(4), and Na(3)PO(4) and higher for NaSCN. This is consistent with an
      increase in the total hydrophobic micellar domain, in micellar microviscosity, or
      both. Solubilization of propylparaben increases in the presence of Na(3)PO(4),
      consistent with a larger hydrophobic domain for solubilization. The
      thermodynamics of micellization continue to be entropically driven in the
      presence of salts, evidenced by a positive entropy overcoming an unfavorable
      enthalpy. Copyright 2000 Academic Press.

PMID- 10662517
TI  - A Sorption-Kinetic Model for Surfactant-Driven Spreading of Aqueous Drops on
      Insoluble Liquid Substrates.
AB  - Spreading of aqueous drops on hydrocarbon liquids occurs only when particular
      surfactants are added to the droplets above a critical concentration. For
      surfactant solutions of didodecyl ammonium bromide (DDAB) in water spreading over
      mineral oil, rates of droplet expansion are much slower than those corresponding
      to pure liquids spreading over immiscible liquid substrates with the same initial
      spreading coefficients. We present a sorption-kinetic model to explain
      quantitatively the spreading histories for aqueous DDAB droplets on mineral oil.
      Due to surfactant transport limitations, spreading occurs only when enough
      surfactant arrives at the dilating lens surfaces to establish a slightly
      positive, but near-zero spreading coefficient. We solve the convective diffusion
      equation for a cylindrical disk-like lens under the integral constraint of a
      constant surfactant adsorption density corresponding to a near-zero spreading
      coefficient. All observed spreading behavior is correctly portrayed by the
      proposed sorption-kinetic model including final equilibrium lens formation and
      spreading rates that are sensibly independent of drop volume, but are strongly
      dependent on drop surfactant concentration. Quantitative agreement is found with
      the experimental spreading data for a surfactant diffusion coefficient of 6x10(
      12) m(2)/s and an effective adsorption rate constant of 6.5x10(-7) m/s. Both
      values prove physically reasonable. The sorption-kinetic model provides a new
      mechanism for understanding slow surfactant-driven spreading. Copyright 2000
      Academic Press.

PMID- 10662518
TI  - Effect of Some Oxidation Treatments on the Textural Characteristics and Surface
      Chemical Nature of an Activated Carbon.
AB  - The changes produced in an activated carbon by treatment in aqueous solutions of
      (NH(4))(2)S(2)O(8) and H(2)O(2) are compared with the modifications produced by
      oxygen plasma. These changes are monitored by measuring the textural
      characteristics (surface areas, porosity, pore size distributions) and surface
      chemical groups. The former are studied by N(2) and CO(2) adsorption, mercury
      porosimetry and hydrocarbon adsorption at zero surface coverage. The chemical
      surface groups are determined by chemical titrations and FTIR Spectroscopy. The
      results show large differences between the changes produced by treatment in
      aqueous solutions and those produced by oxygen plasma. Whereas both treatments in
      aqueous solution modify the textural characteristics, oxygen plasma maintains the
      surface area and pore network. However, plasma treatment introduces larger
      amounts of oxygen chemical groups than treatment in aqueous solution. Copyright
      2000 Academic Press.

PMID- 10662519
TI  - Formation and Release of Cobalt(II) Sorption and Precipitation Products in Aging
      Kaolinite-Water Slurries.
AB  - The uptake and release behavior of cobalt(II) was studied over thousands of hours
      in CO(2)-free aqueous suspensions of kaolinite under three pairs of total cobalt
      concentration (Co(T)) and near-neutral pH (7.5-7.8) conditions. Dissolved cobalt,
      aluminum, and silicon concentrations were monitored by ICPMS, and cobalt
      containing products were identified by EXAFS spectroscopy. In each uptake
      experiment, cobalt sorbed to kaolinite as a mixture of surface-adsorbed monomers
      or polymers and hydrotalcite-like precipitates of the approximate composition
      Co(x)Al(OH)(2x+2)(A(n-))(1/n), where 2</=x</=4 and A(n-) is nitrate or silicate
      anion. Precipitate stoichiometry varied with experimental conditions, with the
      highest Co:Al ratio in the high Co(T)/high pH experiment. Cobalt surface
      adsorption occurred within seconds, whereas precipitation was slower and
      continued for the duration of the experiments. Consequently, the proportion of
      precipitate in the sorbed mixture increased with time in all experiments. The
      most rapid precipitation occurred in the high Co(T)/high pH experiment, where
      solutions were most supersaturated with respect to cobalt hydrotalcite.
      Precipitates incorporated some previously adsorbed cobalt, as well as cobalt from
      solution. Cobalt release from the solid phase was effected by lowering solution
      pH to 7.0. Release experiments initiated after shorter sorption times returned a
      larger fraction of cobalt to solution than those initiated after longer sorption
      times, for a fixed duration of release. In other words, sorption product
      stability increased with sorption time. Specifically, under the conditions of the
      release experiments, the hydrotalcite-like precipitates are more stable than
      smaller adsorbates, and precipitates that formed over longer time periods are
      more stable than those that formed rapidly. The latter result suggests that
      precipitates ripened or modified their structure or composition to become more
      stable over the course of the several-thousand-hour sorption experiments.
      Precipitates that formed over hundreds of hours or longer did not dissolve over
      thousands of hours at the lower pH. Copyright 2000 Academic Press.

PMID- 10662520
TI  - Cu(II) Sorption Mechanism on Montmorillonite: An Electron Paramagnetic Resonance
      Study.
AB  - The mechanism of Cu(II) sorption on montmorillonite was studied with electron
      paramagnetic resonance (EPR) spectroscopy. The major sorbed species were
      successfully identified by EPR spectroscopy as they showed distinct signals due
      to their strength of binding and local structure. The EPR results together with
      macroscopic sorption data show that the sorption involves at least three
      different mechanisms. The dominant sorption mechanism changed with pH and Na(+)
      content in solution. In the acidic pH range, the sorption is independent of pH
      but is dependent on Na(+) concentration. Like free copper ions, the sorbed Cu(II)
      shows an isotropic absorption line. It is thought that the Cu(II) is ion
      exchanged in the interlayer site and is capable of free tumbling motion despite
      electrostatic binding force. In the near neutral pH range, the sorption is
      strongly pH dependent and the sorbed Cu(II) shows no EPR signal. It is
      interpreted that the Cu(II) is sorbed by a surface complexation mechanism to form
      an inner-sphere surface complex. The EPR spectrum with a dipolar splitting
      pattern means that the dimeric Cu(II) surface species is the dominant sorbed
      species in the basic pH region where the Cu-Cu internuclear distance of the dimer
      is estimated to be approximately 3.3 A. Copyright 2000 Academic Press.

PMID- 10662521
TI  - Fabrication and Characterization of a New Self-Assembled Monolayer of Fullerene
      Dicarboxylic Acid Derivative and Its Photoelectric Conversion Property.
AB  - A new fullerene self-assembled monolayer (SAM) which has the property of
      photoelectric conversion is reported here. The SAM was fabricated on hydrophilic
      substrates by an esterification reaction. The SAM is characterized by contact
      angle, AFM, UV spectrum, and cyclic voltammetry. A cathodic photocurrent of 226
      nA/cm(2) was obtained. Copyright 2000 Academic Press.

PMID- 10662522
TI  - Spontaneous Vesicle Formation by Helical Glycopeptides in Water.
AB  - Hydrophobic helical peptide molecules with a lactose unit at the C terminal, Nap
      (Ala-Aib)(n)-NHCH(2)CH(2)NH-Lac (Nap, Aib, and Lac represent 2-naphthylacetic
      acid group, 2-aminoisobutyric acid, and lactobionic acid group, respectively,
      n=4, 6, 8), were synthesized and their formation of self-assemblies in water was
      investigated. Nap-(Ala-Aib)(4)-NHCH(2)CH(2)NH-Lac was spontaneously dispersed in
      water and formed aggregates of 70 nm diameter, shown by dynamic light scattering
      measurement. Cryo-TEM observation revealed that the aggregates took on a
      vesicular structure with a single membrane. The membrane is suggested to be
      composed of helical peptide molecules with an interdigitated antiparallel packing
      on the basis of circular dichroism and fluorescence measurements. On the other
      hand, the dodecapeptide formed a fibrous assembly, and the hexadecapeptide could
      not be dispersed in water. Copyright 2000 Academic Press.

PMID- 10662523
TI  - Health of the Bay--Health of People Colloquium, November 13, 1998. Proceedings.

PMID- 10662524
TI  - Pfiesteria: harmful algal blooms as indicators of human: ecosystem interactions.

PMID- 10662526
TI  - Toxic chemicals: can what we don't know harm us?
AB  - The Chesapeake Bay Program began more than 20 years ago with assessments of a
      number of key areas, relying on measurements of habitats, plant and animal
      populations, and physical and chemical conditions. This approach used wildlife as
      indicators of Bay "health" and of potential threats to human health. The extent
      of toxic chemical contamination was one of the assessment endpoints in the
      original survey. When the initial assessment was completed in 1983, the results
      of Bay-wide surveys indicated that several specific waterways were contaminated.
      These waters, the Elizabeth River, Virginia, the James River, Virginia, and
      Baltimore Harbor, Maryland, were targeted for specific actions to address the
      problems of historical and ongoing pollution. Over the past 10 years or more,
      data on some toxic chemical releases into and levels in the environment have been
      collected, but these data are limited in scope. Furthermore, these data are not
      used to assess threats to human health or more generally to nonhuman endpoints.
      New and existing data on environmental levels of chemicals and effects at low
      concentrations provide evidence that toxic chemicals may threaten both human and
      nonhuman health in the wider Bay system.

PMID- 10662525
TI  - Susceptibility of the Chesapeake Bay to environmental contamination with
      Cryptosporidium parvum.

PMID- 10662527
TI  - Measuring the health of the Chesapeake Bay: toward integration and prediction.
AB  - The health of an ecosystem is a function of its vigor (useful productivity),
      organization (complexity of interspecific interactions), and resilience (ability
      to maintain itself in the face of disturbance). The health of the Chesapeake Bay
      ecosystem has deteriorated largely as a result of nutrient overenrichment,
      concomitant reduction in light availability, and loss of habitats that provide
      complexity. This has resulted in an ecosystem that is a less vigorous producer of
      valuable fish and shellfish, less diverse and well organized, and more
      susceptible to and slower to recover from disturbances. It is not clear that
      degraded ecosystem health directly threatens human health; in fact sanitation and
      reductions in loadings of potentially toxic substances have reduced human health
      risks in recent decades. On the other hand, recently observed outbreaks of the
      toxin-producing dinoflagellate Pfiesteria piscicida could be a result of
      deteriorated ecosystem health and pose a human health risk. Monitoring of the
      environmental conditions, ecosystem health, and human health risks is critically
      important to the adaptive management of the Chesapeake Bay. Although this
      monitoring has produced very useful information, monitoring can be more effective
      if it more directly addressed the multiple uses of the resulting information,
      applied new technologies, and were more effectively integrated across
      environmental media, among resources, over space and time scales, and with
      modeling and research.

PMID- 10662528
TI  - Linking public health and the health of the Chesapeake Bay.
AB  - The Chesapeake Bay has a profound impact on the lives of all who reside in the
      64,000 square miles of its watershed. From crab cakes to sail-boats, drinking
      water to naval ships, the Bay touches virtually every aspect of life in the
      region. The Bay has inspired literature, driven the regional economy, and shaped
      political decision making and development patterns for homes, industry,
      agriculture, and transportation. As population demands increase and urban
      boundaries expand into pristine landscapes, the sustainability of the Chesapeake
      Bay and its resources face unprecedented pressures. Consequently, the public's
      health also is vulnerable to Bay pollution and other stresses stemming from
      development activities and widespread growth occurring throughout the Chesapeake
      Bay watershed. This paper will examine the linkages between the environmental
      quality of the Bay and the population health status, recommend ways to bridge
      ecological and human health concerns in the context of the Bay, and finally
      present a framework for developing a public health report card for the Bay.

PMID- 10662529
TI  - The effect of low-level blood lead on hematologic parameters in children.
AB  - A health survey of school children living in polluted regions of eastern Germany
      provided us with data necessary to examine the effects of lead on the blood
      system at levels below current standards for blood lead content. Data collected
      for 797 children, aged 5-14 years, with low blood lead levels (GM, 33.3 microg
      Pb/L; range, 7.5-239 microg Pb/L) allowed us to examine the relationship between
      blood lead content and hematological parameters. Using linear regression analyses
      and controlling for a number of potential confounding factors, we found that
      increasing blood lead levels by 10 microg/L were associated with a small increase
      in the number of red blood cells and in girls with reduced MCV and MCH. The
      reasons for our observation, especially the gender difference, are still
      uncertain. In conclusion the morphology and function of erythrocytes might be
      sensitive parameters of low dose lead toxicity.

PMID- 10662530
TI  - A geographic information assessment of birth weight and crop production patterns
      around mother's residence.
AB  - A landscape approach using remote sensing (RS) and geographic information system
      (GIS) technologies was developed to identify the proximity of maternal residence
      to agricultural areas, and the association between crop production patterns
      around mothers residences and low birth weight was evaluated. Satellite data
      obtained for Weld County, Colorado, in 1991 and 1993 were digitally processed to
      generate crop location maps for this study. GIS procedures were then used to
      determine crop types within 300- and 500-m circular zones around mothers' homes
      for 125 births that occurred from 1991 to 1993 in the study area. The
      relationships between different crop patterns around the mothers' residences and
      the birth weight of babies were investigated while controlling for potential
      confounding variables. The results indicated that low birth weight was associated
      with total crop production area within a 300-m buffer zone around mothers'
      residences (P=0.058). When each of the study crops was considered separately, low
      birth weight was associated with sugar beet production (P=0.05) and corn
      production (P=0.1) within both the 300- and the 500-m buffer zones. This RS/GIS
      approach provides clues to the potential relationships between birth weight and
      crop production near the residence.

PMID- 10662531
TI  - Health effects of depleted uranium on exposed Gulf War veterans.
AB  - A small group of Gulf War veterans possess retained fragments of depleted uranium
      (DU) shrapnel, the long-term health consequences of which are undetermined. We
      evaluated the clinical health effects of DU exposure in Gulf War veterans
      compared with nonexposed Gulf War veterans. History and follow-up medical
      examination were performed on 29 exposed veterans and 38 nonexposed veterans.
      Outcome measures employed were urinary uranium determinations, clinical
      laboratory values, and psychiatric and neurocognitive assessment. DU-exposed Gulf
      War veterans with retained metal shrapnel fragments are excreting elevated levels
      of urinary uranium 7 years after first exposure (range 0.01-30.7 microg/g
      creatinine vs 0.01- 0.05 microg/g creatinine in the nonexposed). The persistence
      of the elevated urine uranium suggests on-going mobilization from a storage depot
      which results in a chronic systemic exposure. Adverse effects in the kidney, a
      presumed target organ, are not present at this time, though other effects are
      observed. Neurocognitive examinations demonstrated a statistical relationship
      between urine uranium levels and lowered performance on computerized tests
      assessing performance efficiency. Elevated urinary uranium was statistically
      related to a high prolactin level (>1.6 ng/ml; P=0.04). More than 7 years after
      first exposure, DU-exposed Gulf War veterans with retained metal fragments
      continue to excrete elevated concentrations of urinary uranium. Effects related
      to this are subtle perturbations in the reproductive and central nervous systems.

PMID- 10662533
TI  - Reply

PMID- 10662532
TI  - Critical analysis of Mitran et al. (1997). Neurotoxicity associated with
      occupational exposure to acetone. Methyl ethyl ketone, and cyclohexanone.
      Environ. Res. 73, 181-188.

PMID- 10662534
TI  - Environmental research, section B

PMID- 10662535
TI  - Neurosteroids: biosynthesis and function of these novel neuromodulators.
AB  - Over the past decade, it has become clear that the brain is a steroidogenic
      organ. The steroids synthesized by the brain and nervous system, given the name
      neurosteroids, have a wide variety of diverse functions. In general, they mediate
      their actions, not through classic steroid hormone nuclear receptors, but through
      ion-gated neurotransmitter receptors. This paper summarizes what is known about
      the biosynthesis of neurosteroids, the enzymes mediating these reactions, their
      localization during development and in the adult, and their function and
      mechanisms of action in the developing and adult central and peripheral nervous
      systems. The expression of the steroidogenic enzymes is developmentally
      regulated, with some enzymes being expressed only during development, while
      others are expressed during development and in the adult. These enzymes are
      expressed in both neurons and glia, suggesting that these two cell types must
      work in concert to produce the appropriate active neurosteroid. The functions
      attributed to specific neurosteroids include modulation of GABA(A) and NMDA
      function, modulation of sigma receptor function, regulation of myelinization,
      neuroprotection, and growth of axons and dendrites. Neurosteroids have also been
      shown to modulate expression of particular subunits of GABA(A) and NMDA
      receptors, providing additional sites at which these compounds can regulate
      neural function. The pharmacological properties of specific neurosteroids are
      described, and potential uses of neurosteroids in specific neuropathologies and
      during normal aging in humans are also discussed.

PMID- 10662536
TI  - Rapid, nongenomic steroid actions: A new age?
AB  - In the traditional theory of steroid action, steroids bind to intracellular
      receptors and modulate nuclear transcription after translocation of steroid
      receptor complexes into the nucleus. Due to similarities of molecular structure,
      specific receptors for steroids, vitamin D(3) derivatives, and thyroid hormone
      are considered to represent a superfamily of steroid receptors. While genomic
      steroid effects characterized by their delayed onset of action and their
      sensitivity to blockers of transcription and protein synthesis have been known
      for several decades, rapid actions of steroids have been more widely recognized
      and characterized in detail only recently. Rapid effects of steroids, thyroid
      hormones, and the steroid hormone metabolite of vitamin D(3), 1alpha, 25
      dihydroxyvitamin D(3), on cellular signaling and function may be transmitted by
      specific membrane receptors. Binding sites in membranes have been characterized,
      exposing binding features compatible with an involvement in rapid steroid
      signaling. Characteristics of putative membrane receptors are completely distinct
      from intracellular steroid receptors, a fact which is further supported by the
      inability of classic steroid receptor antagonists to block nongenomic steroid
      actions. A putative progesterone membrane receptor has been cloned and
      functionally expressed with regard to progesterone binding. Development of drugs
      that specifically affect nongenomic action alone or even both modes of action may
      find applications in various, areas such as in the cardiovascular and central
      nervous systems and treatment of preterm labor, infertility, and electrolyte
      abnormalities.

PMID- 10662537
TI  - Estrogen is more than just a "sex hormone": novel sites for estrogen action in
      the hippocampus and cerebral cortex.
AB  - For decades estrogen was thought of only as a "sex hormone," as it plays a
      fundamental role in regulating behavioral and physiological events essential for
      successful procreation. In recent years, estrogen has been shown to exert effects
      on the structure and function of the hippocampus and cortex. The discovery of a
      new estrogen receptor (ER-beta) and localization of ER-alpha and ER-beta mRNAs in
      the pyramidal cells of the rat hippocampus and ER-beta mRNA in rat cortex have
      provided new insight into how estrogen may directly modulate the structure and
      function of these neurons. Moreover, recent in vivo (125)I-estrogen binding
      studies have shown that nuclear estrogen binding sites are widely distributed in
      the pyramidal cells throughout CA1-3 of the hippocampus and laminae II-VI of the
      isocortex, demonstrating that ER mRNAs are translated into biologically active
      protein. The functional impact of estrogen receptor localization in the cortex
      and hippocampus may prove relevant to the emerging role for estrogen as a
      protective factor in neurodegenerative injury. This potential role is further
      highlighted by the recent findings that the expression of ER-alpha and ER-beta
      changes following ischemic brain injury and that these changes correlate with the
      hormonal modulation of protective factors. These data provide the first evidence
      that the expression of ERs in the adult cortex is not static, but instead,
      responsive to neuronal injury and perhaps additional factors that influence the
      cortical environment and status of these neurons. Together, these data indicate
      that estrogen has a far greater effect on the hippocampus and isocortex than
      previously thought. Furthermore, these new findings challenge our current
      thinking about steroid hormones and their mechanism(s) of action in regions
      associated with learning and memory and affected by the neurodegenerative
      conditions of aging.

PMID- 10662538
TI  - A new locus for late-onset, progressive, hereditary hearing loss DFNA20 maps to
      17q25.
AB  - We report the localization of DFNA20, a gene causing dominant, nonsyndromic,
      progressive hearing loss in a three-generation Midwestern family, to chromosome
      17q25. Affected family members show a bilateral, sloping, progressive,
      sensorineural hearing loss, first evident at 6000 and 8000 Hz, that can be
      identified in some family members in the early teens and is clearly evident by
      the early twenties. As age increases, the degree of hearing loss increases with
      threshold shifts seen at all frequencies. Linkage to known hereditary hearing
      loss loci was excluded. A genome-wide screen detected positive linkage to D17S784
      (LOD(Z) = 6.62; &theta; = 0). Haplotype analysis refines the DFNA20 critical
      region to 12 cM between D17S1806 and D17S668. Radiation hybrid mapping with
      Stanford G3 and TNG panels was used to evaluate the genes ACTG1, GRIN2C, FKHL13,
      P4HB, SPARC, and ARHGDIA as candidates for DFNA20.

PMID- 10662539
TI  - Analysis of association at single nucleotide polymorphisms in the APOE region.
AB  - The discussion of the prospects of using a dense map of single nucleotide
      polymorphisms (SNPs) to identify disease genes with association analysis has been
      extensive. However, there is little empiric evidence to support this strategy. To
      begin to examine the practical issues surrounding this methodology, we identified
      10 SNPs in the region immediately surrounding the apolipoprotein E locus (APOE),
      an established susceptibility gene for Alzheimer disease. Our goal was to examine
      patterns of allelic association to begin to investigate the question of whether
      APOE could have been identified using SNPs. Our strongest evidence of association
      was at the 2 SNPs immediately flanking APOE.

PMID- 10662540
TI  - Molecular phenotype of the human oocyte by PCR-SAGE.
AB  - Consecutive application of PCR and serial analysis of gene expression (SAGE) was
      used to generate a catalog of approximately 50, 000 SAGEtags from nine human
      oocytes. Matches for known genes were identified using the National Institutes of
      Health SAGEtag database. This database links directly to the UniGene database,
      providing rapid discrimination between SAGEtags that match known genes and
      expressed sequence tags and those that currently have no match. Matches in the
      oocyte SAGE catalog were found for surface receptors, second-messenger systems,
      and cytoskeletal, apoptotic, and secreted proteins. Many of these proteins were
      not previously known to be expressed in mammalian oocytes. The relative
      abundances of transcripts for cytoskeletal proteins and proteins known to be in
      oocytes are consistent with their documented expression, suggesting an absence of
      representational distortion by the PCR step. The expression profile of the human
      oocyte may help identify factors that reprogram somatic cell nuclei to
      totipotency.

PMID- 10662541
TI  - Single-strand conformation polymorphism analysis by capillary and microchip
      electrophoresis: a fast, simple method for detection of common mutations in BRCA1
      and BRCA2.
AB  - As a result of intensive studies on hereditary breast and ovarian cancers, two
      breast cancer susceptibility genes, BRCA1 and BRCA2, have been identified. In
      each gene, a small number of specific mutations have been found at relatively
      high frequency in certain ethnic populations. The mutations, 185delAG and
      5382insC in BRCA1 and 6174delT in BRCA2, have been identified as common mutations
      in the Ashkenazi Jewish population, with a combined frequency of 2.0 to 2.5%.
      Women who have one of the above three common mutations are at a high risk of
      developing breast or ovarian cancer. Consequently, accurate and cost-effective
      detection of these three mutations may have important implications for risk
      assessment in susceptible women and men. In this report, we describe a fast and
      simple capillary electrophoresis (CE)-based method using a polymer network for
      screening the three common mutations in BRCA1 and BRCA2. Fluorescent dye-labeled
      primers (6-FAM-tagged) were used to amplify three DNA fragments of 258, 296, and
      201 bp for detection of the 185delAG, 5382insC, and 6174delT mutations,
      respectively. After the PCR products were denatured, a single-strand conformation
      polymorphism (SSCP) profile could be obtained for each mutation in less than 10
      min by CE in a polymer network. We demonstrate the potential provided by
      translating this assay to the microchip format where the SSCP analysis is
      complete in 120 s, representing only a fraction of the reduction in analysis time
      that can be achieved with microchip technology. The speed and simplicity of the
      SSCP methodology for detection of these mutations make it attractive for use in
      the clinical diagnostic laboratory.

PMID- 10662542
TI  - Identification and characterization of BPTF, a novel bromodomain transcription
      factor.
AB  - The bromodomain is a 110-amino-acid conserved structural region associated with
      proteins that regulate signal-dependent, nonbasal transcription. The bromodomain
      can regulate histone acetyl transferase activity and interacts specifically with
      acetylated lysine residues. A key role for bromodomain proteins in maintaining
      normal proliferation is indicated by the implication of several bromodomain
      proteins in cancer, with four of these identified at translocation breakpoints.
      We searched EST databases for novel bromodomain genes. The sequence from one EST
      was used to initiate generation of a full-length clone from a testis cDNA
      library. The completed sequence encodes a predicted protein of 2781 amino acids,
      which, in addition to the bromodomain, harbors further motifs characteristic of a
      transcriptional coactivator: two PHD fingers and an extensive glutamine-rich
      acidic domain. There are several other regions that are conserved with the
      Caenorhabditis elegans putative protein F26H11, which may be functionally
      homologous. The novel gene, called BPTF, is expressed in all tissues examined as
      a 10.5-kb transcript. The protein has extensive identity with the smaller FAC1
      protein, suggesting that the two either are derived from the same locus or are
      synonymous. BPTF has been mapped to 17q23. Functional domains found within BPTF
      are consistent with a role for this protein in hormonally regulated, chromatin
      mediated regulation of transcription.

PMID- 10662543
TI  - A novel family of bromodomain genes.
AB  - The bromodomain is a structural motif characteristic of proteins involved in
      chromatin-dependent regulation of transcription. Bromodomain proteins have been
      identified as integral components of chromatin remodeling complexes and
      frequently possess histone acetyltransferase activity. Their encoding genes have
      been identified at translocation breakpoints, and at least one, CBP, is a tumor
      suppressor gene. We have identified a series of novel bromodomain genes by EST
      database and cDNA library screening. Comparison of sequences for four clones
      indicated that they represent genes belonging to a novel bromodomain family. Full
      length sequences for these genes, which are widely expressed, predict encoded
      proteins of between 1527 and 1972 amino acids. In addition to a carboxy-terminal
      bromodomain, an adjacent PHD finger, and a WACZ motif, at least four other
      conserved novel motifs are present in each protein. The genes contain regions
      conserved with Drosophila Acf1 and Caenorhabditis elegans ZK783.4. The novel
      genes, termed BAZ1A, BAZ1B, BAZ2A, and BAZ2B, localize to chromosomes 14q12-q13,
      7q11-q21, 12q24.3-qter, and 2q23-q24, respectively. Conservation of multiple
      domains throughout these genes with Acf1 indicates that they are likely to be
      components of chromatin remodeling complexes.

PMID- 10662544
TI  - Cloning and characterization of Hunk, a novel mammalian SNF1-related protein
      kinase.
AB  - We previously identified a novel protein kinase, Hunk, by means of a degenerate
      PCR screen designed to isolate kinases expressed in the murine mammary gland. We
      now describe the molecular cloning, chromosomal localization, and activity of
      this kinase and characterize its spatial and temporal pattern of expression in
      the mouse. We have isolated a 5.0-kb full-length cDNA clone that contains the 714
      amino-acid open reading frame encoding Hunk. Analysis of this cDNA reveals that
      Hunk is most closely related to the SNF1 family of serine/threonine kinases and
      contains a newly described SNF1 homology domain. Accordingly, antisera specific
      for Hunk detect an 80-kDa polypeptide with associated phosphotransferase
      activity. Hunk is located on distal mouse chromosome 16 in a region of conserved
      synteny with human chromosome 21q22. During fetal development and in the adult
      mouse, Hunk mRNA expression is developmentally regulated and tissue-specific.
      Moreover, in situ hybridization analysis reveals that Hunk expression is
      restricted to subsets of cells within a variety of organs in the adult mouse.
      These findings suggest a role for Hunk in murine development.

PMID- 10662545
TI  - Physical map of 17p13 and the genes adjacent to p53.
AB  - Genetic lesions in the p53 tumor suppressor gene are the most frequently observed
      alterations in human cancers. Typically in tumors, one allele of the p53 gene is
      initially mutated, followed by deletion of the remaining wildtype allele. In
      human colon cancer, for example, approximately 70% of late stage tumors are
      hemizygous mutant p53. Since the precise gene environment surrounding the p53
      gene is not known, the neighboring genes concomitantly lost with wildtype p53
      deletion remain undetermined. A restriction enzyme map and clone array of 1.1 Mb
      surrounding the p53 gene were constructed using a combination of YAC, BAC, NotI
      linking, and NotI jumping clones. The resulting physical map and clone array
      include approximately 400 kb telomeric and 700 kb centromeric to the p53 gene.
      Sequence determination and analysis adjacent to NotI and AscI sites, indicative
      of CpG islands, allowed the rapid identification of numerous genes within the
      cloned region. Twenty-seven transcription units were identified, including 18
      characterized genes. Limited analysis of primary human colon tumors, hemizygous
      for the p53 gene, indicates loss of the entire 1.1-Mb region upon deletion of
      wildtype p53.

PMID- 10662546
TI  - Identification of a novel LIM domain gene, LMCD1, and chromosomal localization in
      human and mouse.
AB  - A new human LIM domain gene LMCD1 was identified from RT-PCR products, and
      partial sequencing of two expressed sequence tag clones flanking the assembled
      cDNA contig revealed a 1743-bp full-length cDNA with 1098-bp open reading frame.
      The coding sequence of the putative protein is 57.6% identical to murine testin 1
      gene (Tes1), whereas the predicted 365-amino-acid protein is 49.5% identical to
      the mouse Tes1 protein. The predicted LMCD1 protein contains a novel cysteine
      rich domain residing in the amino-terminal region and two LIM domains with
      regular spacing in the carboxy-terminal region. Northern blot analysis indicated
      expression of the 1.7-kb transcript in many tissues, with highest abundance in
      skeletal muscle. Radiation hybrid mapping localized human LMCD1 to the telomeric
      region of chromosome 3p, and genetic mapping assigned the mouse Lmcd1 locus to
      the central region of chromosome 6.

PMID- 10662547
TI  - Genomic organization of the family of CNR cadherin genes in mice and humans.
AB  - The cadherin-related neuronal receptor (CNR) family is localized to the synaptic
      junction, and their cytoplasmic domains interact with Fyn-tyrosine kinase. Here,
      we describe the chromosomal locations and the orthologous genomic structures of
      CNR family members in mice and humans. In the genomic organization, distinct
      exons, each of which encodes the N-terminus of a different CNR ("variable
      region"), are clustered in a tandem array, and these exons are spliced to a
      common region composed of three exons ("constant region"). We also discovered
      three alternative versions of the transcripts; a single variable exon connects
      with three different C-terminal tails, comparable to class-switching in the
      immunoglobulin heavy chain. Thus the CNR family in the central nervous system has
      similarities to the immunoglobulin and T-cell receptor genes in the immune
      system.

PMID- 10662548
TI  - Genomic organization, mapping, tissue expression, and hormonal regulation of
      trypsin-like serine protease (TLSP PRSS20), a new member of the human kallikrein
      gene family.
AB  - The cDNA for the trypsin-like serine protease gene (TLSP, HGMW-approved symbol
      PRSS20) has been recently identified. TLSP is expressed in brain and skin tissues
      but little else is known about this new serine protease gene. In this paper, we
      describe the complete genomic organization and precise mapping of the TLSP gene.
      This gene spans 5.3 kb of genomic sequence on chromosome 19q13.3-q13. 4. The gene
      consists of six exons, the first of which is untranslated. All splice junctions
      follow the GT/AG rule, and the intron phases are identical to those of other
      kallikrein-like genes, including zyme (PRSS9), NES1 (PRSSL1), and neuropsin
      (PRSS19). Fine-mapping of the area indicates that TLSP lies downstream from the
      PSA, zyme, neuropsin, and NES1 genes. Significant sequence homologies were found
      between TLSP and other human kallikreins. Furthermore, there is conservation of
      the catalytic triad (histidine, aspartic acid, serine) and of the number of
      coding exons (five; the same in all members of the kallikrein gene family). We
      thus suggest that TLSP is a new member of the human kallikrein gene family. TLSP
      is expressed in many tissues including cerebellum, prostate, salivary glands,
      stomach, lung, thymus, small intestine, spleen, liver, and uterus. TLSP
      expression appears to be regulated by steroid hormones in the breast carcinoma
      cell line BT-474.

PMID- 10662549
TI  - Sequencing, expression analysis, and mapping of three unique human tropomodulin
      genes and their mouse orthologs.
AB  - Tropomodulin (TMOD) is the actin-capping protein for the slow-growing end of
      filamentous actin, and a neuronal-specific isoform, neuronal tropomodulin
      (NTMOD), is the major binding protein to brain tropomyosin in rat. The Drosophila
      TMOD homolog, Sanpodo, alters sibling cell fate determination, so we used a cross
      species approach to identify additional TMOD family members that may play a
      critical role in this process. We characterized the human and mouse orthologs to
      rat NTMOD (TMOD2 and Tmod2, respectively) as well as two novel tropomodulin
      family members (TMOD3, Tmod3 and TMOD4, Tmod4). Their expression patterns vary
      extensively, from ubiquitous (TMOD3 and Tmod3) to muscle (TMOD4) or neuronal
      tissues only (TMOD2 and Tmod2). TMOD2 and TMOD3 map next to one another on
      chromosome 15q21.1-q21.2, and their mouse orthologs map to a homologous region on
      mouse chromosome 9; TMOD4 maps to the telomeric end of 1q12 and Tmod4 to a
      homologous region of mouse chromosome 3. Their location and expression patterns
      make TMOD2 and TMOD3 candidate genes for amyotrophic lateral sclerosis 5 (ALS5)
      and dyslexia-1 (DYX1) and TMOD4 a candidate gene for limb girdle muscular
      dystrophy 1B (LGMD1B). Our mapping efforts revealed new regions of paralogy among
      chromosomes 1q, 9q, 15q, and 19p.

PMID- 10662550
TI  - The SOX8 gene is located within 700 kb of the tip of chromosome 16p and is
      deleted in a patient with ATR-16 syndrome.
AB  - SOX proteins are transcription factors that are characterized by a common DNA
      binding motif known as the HMG domain. We describe the 5. 4-kb human SOX8 gene
      that codes for a 446-amino-acid protein and that is expressed strongly in brain
      and less abundantly in other tissues. SOX8 shows an overall identity of 47% to
      SOX9 and SOX10. The latter two possess a C-terminal transactivation domain,
      whereas in SOX8, this domain is located in the central part of the protein. We
      have mapped SOX8 within 700 kb of the telomeric repeats of band 16p13.3.
      Hemizygosity for 1 Mb from this region causes the ATR-16 syndrome characterized
      by alpha-thalassemia and mental retardation. We show that SOX8 is deleted in an
      ATR-16 patient, and from its location, we deduce that it should be deleted in all
      previously described cases. Thus, SOX8 is a good candidate gene contributing to
      the mental retardation phenotype seen in ATR-16 patients.

PMID- 10662551
TI  - DXS6673E encodes a predominantly nuclear protein, and its mouse ortholog
      DXHXS6673E is alternatively spliced in a developmental- and tissue-specific
      manner.
AB  - DXS6673E is a candidate gene for nonspecific X-linked mental retardation and
      encodes a novel Zn-finger protein. The ortholog murine gene DXHXS6673E in XC-D
      was isolated and characterized. It is ubiquitously expressed in all embryonic
      stages and adult tissues. Two different transcription start sites exist that
      result in two major transcripts of 6055 and 5352 nucleotides, each composed of 25
      exons. Exon 1A is tissue specific, whereas exon 1B is transcribed constitutively.
      Both variants are translated into the same 1370-amino-acid protein. Transcripts
      are subject to alternative splicing at the 5'-end. Some of the isoforms are
      developmental stage and tissue specific. Among them, one was present only in
      embryos and adult brain. Sequence analysis demonstrated evolutionary conservation
      down to the arthropods and defined several conserved protein motifs. Subcellular
      localization studies with green fluorescent protein as a reporter showed that
      DXS6673E is predominantly located in the nucleus due to several functional
      nuclear localization signals. Three distinct protein distribution patterns in COS
      7 cells could be identified.

PMID- 10662552
TI  - Characterization, chromosomal localization, and the complete 30-kb DNA sequence
      of the human Jagged2 (JAG2) gene.
AB  - The genomic sequence of the human Jagged2 (JAG2) gene, which encodes a ligand for
      the Notch receptors, was determined. The 30-kb DNA sequence spanning the JAG2
      gene contains 26 exons and a putative promoter region. Several potential binding
      sites for transcription factors, including NF-kappab, E47, E12, E2F, Ets-1, MyoD,
      and OCT-1, were found in the human JAG2 promoter region. The JAG2 gene was also
      mapped to the chromosomal region 14q32 using fluorescence in situ hybridization.

PMID- 10662553
TI  - A new zinc ribbon gene (ZNRD1) is cloned from the human MHC class I region.
AB  - Eleven unique cDNA fragments were identified from YAC B30H3, which spans 330 kb
      in the human major histocompatibility complex class I region. One fragment
      (CAT80) was mapped 80 kb telomeric to the HLA-A locus. Using this cDNA fragment
      as probe, Northern analysis reveals a ubiquitously expressed transcript of about
      850 nt in all 16 tissues tested. Based on the cDNA fragment sequence, a full
      length cDNA of 858 bp that contains an open reading frame of 378 bp was cloned.
      Within the putative polypeptide of 126 amino acids, two zinc-ribbon domains were
      identified: Cx2Cx15Cx2C at the N-terminal and Cx2Cx24Cx2C at the C-terminal. The
      C-terminal domain is well conserved throughout evolution, including archaea,
      yeast, Drosophila, nematodes, amphibians, and mammals. The conserved amino acid
      sequence, CxRCx6Yx3QxRSADEx2TxFxCx2C, is highly homologous to the yeast RNA
      polymerase A subunit 9 and transcription-associated proteins. Alignment with
      genomic DNA demonstrates that this gene spans 3.6 kb and consists of four exons
      and three introns. Cross-species Northern analysis reveals a mouse homolog of a
      similar size and with an expression profile similar to those of the human gene.
      We have named this gene ZNRD1 for zinc ribbon domain-containing 1 protein.

PMID- 10662554
TI  - Cloning, expression, and chromosomal localization of a mouse gene homologous to
      the germ cell migration regulator wunen and to type 2 phosphatidic acid
      phosphatases.
AB  - The wunen gene of Drosophila melanogaster encodes a multipass membrane-spanning
      protein that negatively regulates primordial germ cell migration. Here we
      describe the cloning of a mouse gene that encodes a protein homologous to wunen
      and to the Type 2 phosphatidic acid phosphatases. This gene encodes a 251-amino
      acid protein that most closely resembles the human Type 2 phosphatidic acid
      phosphatase PAP-2c. Northern blot analysis revealed the presence of a single 1.9
      kb Ppap2c transcript. The Ppap2c gene was localized to the central portion of
      mouse Chromosome 10 by interspecific backcross analysis.

PMID- 10662555
TI  - MAGOH interacts with a novel RNA-binding protein.
AB  - MAGOH is the human homologue of Drosophila mago nashi, a protein that is required
      for normal germ plasm development in the Drosophila embryo. Using human MAGOH as
      a bait protein in a yeast two-hybrid screen, we recovered four independent cDNA
      clones that encode different lengths of a novel protein containing a conserved
      RNA-binding region. This gene, designated RBM8, encodes a 173-aa protein that was
      shown to have an apparent molecular mass of 26 kDa, as demonstrated by in vitro
      translation assay. The interaction between MAGOH and RBM8 was demonstrated by
      both yeast two-hybrid and GST fusion protein pull-down assays. Like MAGOH, RBM8
      gene is expressed ubiquitously in human tissues; three species of RBM8 mRNA were
      detected. Also similar to MAGOH, RBM8 expression is serum inducible in quiescent
      NIH3T3 fibroblast cells.

PMID- 10662556
TI  - Homologous genomic fragments in the mouse pre-T cell receptor alpha (pTa) and
      Xist loci.
AB  - We recently characterized a genomic region located upstream of the mouse pre-T
      cell receptor alpha (pTa) gene, which controls pTa expression in pre-T cells. We
      now report an unexpected homology between this region and a region in the mouse X
      chromosome inactivation center between the 3' end of the Xist gene and the start
      of an antisense transcript Tsix. The homology is extended over 4 kb of genomic
      sequence split by an expanded repeat region and is observed only in the mouse,
      not in the rat. Despite high sequence similarity to the pTa transcriptional
      enhancer, the homologous X chromosome fragment appears to have lost its enhancer
      activity. These data underscore the complex organization of the mouse genome and,
      in particular, of the X chromosome inactivation center.

PMID- 10662557
TI  - Sampling of Aspergillus spores in air.
AB  - Nosocomially acquired aspergillosis typically occurs in the setting of treatment
      for leukaemia or other haematological malignancy. As Aspergillus species can be
      readily found in the environment, it has been widely believed that aspergillosis
      occurs as a consequence of exogenous acquisition of the fungus. Stringent
      environmental controls in transplant units have included high-efficiency air
      filtration, positive-pressure ventilation and frequent room air changes. Although
      there have been several well-documented examples of aspergillosis outbreaks as a
      result of hospital demolition and reconstruction, it has not always been possible
      to demonstrate elevated spore counts in clinical areas during building work. The
      sampling of air for Aspergillus is very problematic. Careful attention must be
      given to the design of air sampler, sampling protocols and an understanding of
      air sampling data. This review outlines many of the physical and environmental
      parameters that influence meaningful air sampling and recommends a simple
      procedure that has been tried and tested in many aspergillosis outbreaks.

PMID- 10662558
TI  - Post-transfusion HIV infection despite donor screening: a report of three cases.
AB  - In August 1996, a blood donation was collected which subsequently infected three
      patients post-transfusion with HIV 1. The donation itself was originally screened
      as negative for anti-HIV 1/2 using a sensitive EIA method, but subsequently was
      shown to contain p24 Ag and HIV RNA by an amplification technique. The proposed
      introduction of nucleic acid testing of all blood donations in the UK for
      hepatitis C, hepatitis B and HIV may further reduce the remote risk of further
      episodes of post-transfusion infection. The infection in the index recipient was
      detected on routine pre-transplant virological screening but proved difficult to
      confirm, at a time when she had recently received myeloablative treatment for a
      haematological malignancy which impaired the immune response. There is a need for
      continued vigilance in such patients to exclude post-transfusion infection, at a
      time when natural immunological responses have been impaired by their disease or
      treatment.

PMID- 10662559
TI  - Risk of HIV transmission from patients to surgeons in the era of post-exposure
      prophylaxis.
AB  - The HIV prevalence, among patients either undergoing, or with the potential to
      undergo, surgery were estimated using data from unlinked anonymous HIV surveys of
      patients in Glasgow hospitals during 1992-1997 in order to quantify the risk of
      surgeons acquiring HIV occupationally in the era of post-exposure prophylaxis
      (PEP) availability. A range of prevalence rates was applied to data on other
      factors influencing risk; these comprised, i) the probability of a percutaneous
      injury from a sharp instrument used on an HIV infected patient resulting in HIV
      transmission, ii) the number of injuries sustained and iii) whether or not PEP
      was administered. On the basis of, for example, a surgeon sustaining three
      percutaneous injuries over 12 months and not taking PEP after each, the annual
      risks ranged from 1 in 2,000,000 for urological/renal surgeons to 1 in 200,000
      for those performing general surgery/ENT/gynaecological procedures. The
      administration of PEP after each injury would reduce these rates to 1 in
      10,000,000 and 1 in 1,000,000 respectively. The risk of surgeons acquiring HIV
      occupationally in a city which has an HIV prevalence typical of most urban areas
      in the UK, is 'minimal' or 'negligible'. In the context of such low risk and our
      limited knowledge of the adverse effects of PEP, the risk assessment to decide
      whether or not to give PEP should be well informed and consistent. Current
      guidelines to help physicians and affected healthcare workers in their decision
      making need to be improved.

PMID- 10662560
TI  - Nosocomial Escherichia coli O157 infection.
AB  - Nosocomial transmission of Shiga toxin-producing Escherichia coli O157 to two
      patients and three nurses is described. The index case presented with rectal
      bleeding rather than diarrhoea, and additional infection control measures were
      therefore only instituted after detection of the organism. Of the nurses, two
      were asymptomatic and detected on a screening programme of all staff in contact
      with the affected patients. Two patients died, one from Clostridium perfringens
      bacteraemia. The use by staff of full protective gowns for handling patients from
      their first onset of diarrhoea is recommended, rather than plastic aprons.
      Interest from the media was intense, despite the small number of patients and
      staff affected, and early preparations for media enquiries should be made in such
      episodes.

PMID- 10662561
TI  - Investigation of an outbreak of gastroenteritis caused by Norwalk-like virus,
      using solid phase immune electron microscopy.
AB  - In February 1993, 95 persons (47 patients and 48 staff members) were affected by
      an hospital outbreak of viral gastroenteritis. Using direct electron microscopy
      (EM) the causative agent was identified as a small round structured virus. This
      was confirmed as a Norwalk-like virus using solid phase immune electron
      microscopy (SPIEM). Of 94 stool samples examined, 12 (13%) samples containing
      small round structured viruses (SRSV) were SPIEM positive for Norwalk-like virus.
      A further 25 (27%) samples contained small round featureless virus (SRFV)
      identified by direct EM and were negative on SPIEM. The illness was characterized
      by preceding influenza-like symptoms in 76% of cases followed by vomiting (76%),
      diarrhoea (79%) and abdominal pain (79%). One fatality was recorded. The outbreak
      lasted for 15 days, with a peak incidence of new cases amongst patients and staff
      occurring on day 5. It was controlled through a combination of ward closures,
      patient cohorting, suspension of duties for affected staff and disinfection
      procedures. Difficulties were encountered in the education of staff and in the
      implementation of environmental control measures. Screening of hospital catering
      services and a case control study, carried out among affected staff members,
      failed to identify a foodborne source. Consumption of tap water in the hospital
      was commoner among affected staff members than among controls, but this did not
      reach significance (P = 0.1).

PMID- 10662562
TI  - Dispersal of methicillin-resistant Staphylococcus epidermidis by staff in an
      operating suite for thoracic and cardiovascular surgery: relation to skin
      carriage and clothing.
AB  - Methicillin-resistant Staphylococcus epidermidis (MRSE) is a common cause of deep
      sternal infections. The aim of the present investigation was to evaluate staff in
      an operating suite for thoracic and cardiovascular surgery as a possible source
      of MRSE and the possibility of reducing the amount of MRSE shed into the air by
      wearing tightly woven scrub suits. A second aim was to compare the results of
      dispersal obtained in a test chamber with those from an operating room. We
      studied carriage of MRSE in the nose and on different skin sites and made an
      experimental study of dispersal of MRSE during exercise in a test chamber and
      during operations, using two different types of scrub suits. Dispersal of MRSE
      [defined as > 1% of the total count of colony forming units (CFU) shed into the
      air] occurred in 25% of women and 43% of men. Nasal carriage was found among 28%
      in women and 33% in men. Among five skin-sampling sites, carriage of MRSE was
      most frequent on the cheek (50%) and in the axilla (24%) and least frequent in
      the perineum (5%). Dispersal of MRSE was however more strongly associated with
      carriage in the perineum (P = 0.097) than on the cheek (P = 0.5) and in the
      axilla (P = 0.21). With regard to shedding of bacteria into the air, there was a
      significant difference in favour of the tightly woven clothes regarding total
      counts of CFU both in the test chamber (P = 0.02) and the operating theatre (P =
      0.002). Regarding MRSE, no such difference was found. We found there were too
      many dispersers of MRSE among operating department staff to exclude them from
      work. Although tightly woven scrub suits significantly reduced the amount of
      bacteria shed into the air, the amount of MRSE was not significantly reduced.
      Full-scale experiments in operating rooms are not needed when evaluating the
      protective capacity of different scrub suits as results from a test chamber give
      conclusive information.

PMID- 10662563
TI  - Bacterial interference among nasal inhabitants: eradication of Staphylococcus
      aureus from nasal cavities by artificial implantation of Corynebacterium sp.
AB  - To evaluate the role of normal flora in the nares in preventing Staphylococcus
      aureus colonization, we conducted a replacement study in vivo. Staphylococcus
      epidermidis (rate of colonization: 100%), various species of corynebacteria
      (52.5%) and S. aureus (25.%) were the major bacterial inhabitants in the nares of
      156 healthy volunteers. The low incidence of S. aureus colonization in the
      carriers with corynebacteria (8.5%), compared to non-carriers (44. 5%) indicated
      the possibility of competition for survival between S. aureus and corynebacteria.
      To confirm this hypothesis, we artificially implanted a strain of Corynebacterium
      sp (API Coryne bioprofile; 5100304), denoted as Co304 into the nares of 17 S.
      aureus carriers. S. aureus was completely eradicated in 71% of carriers by up to
      15 inoculations of Co304. However, similar doses of 0.9% NaCl or S. epidermidis
      into the nares of 10 volunteers did not eradicate S. aureus. No bacteriocin-like
      activity against S. aureus was detectable, even after mitomycin C stimulation of
      Co304. Thus Co304 interfered with S. aureus by a different mechanism to a
      bacteriocin-like activity.

PMID- 10662565
TI  - Measurement of ultrasonic-induced chlorhexidine liberation: correlation of the
      activity of chlorhexidine-silver-sulfadiazine-impregnated catheters to agar roll
      technique and broth culture.
AB  - The diagnosis of intravascular catheter-related infections continues to be a
      challenge to both the clinician and the microbiologist. To assess the antiseptic
      effects of silver-sulfadiazine-chlorhexidine-impregnated central venous catheters
      (SSC) on catheter culture systems, segments of fresh antiseptic- and non
      antiseptic-impregnated catheters as well as extracted catheters following five
      days of immersion in PBS were sonicated. The chlorhexidine liberated from the
      catheter material by ultrasonication was measured by HPLC. Fresh antiseptic
      impregnated catheter segments rolled on seeded agar plates produced inhibition
      zones unlike catheters which had been extracted for >five days in phosphate
      buffered saline (PBS). Scanning electron microscopy (SEM) revealed that
      chlorhexidine-silversulfadiazine crystals were located in the superficial
      catheter matrix. Direct contact of superficially located drug particles with
      seeded agar plates probably caused the inhibition of bacterial growth. The study
      suggests that antiseptic compounds readily elute from fresh catheters during
      solid medium-based culturing processes and ultrasonication. The addition of
      inhibitors of silversulfadiazine-chlorhexidine to media may be prudent especially
      when culturing antimicrobial loaded catheters removed after short inwelling
      times.

PMID- 10662564
TI  - Prevalence of hospital-acquired infections in Italy.
AB  - A one-day prevalence survey was conducted in Calabria (Italy) to estimate the
      prevalence of hospital-acquired infections (HAI) and the effect of different
      variables on HAI in 888 patients present in a ward for at least 24 hours and not
      due for discharge or transfer on the day of the survey. The overall prevalence of
      HAI was 1.7% and urinary tract and surgical wounds were the most frequent sites
      (each four patients, 26.7%). In only eight (53.3%) of the fifteen HAI detected,
      had a microbiological examination been requested and the only two positive
      culture results involved Pseudomonas aeruginosa (surgical site) and Escherichia
      coli (urinary tract). Results of multiple logistic regression analysis indicated
      that HAI differed significantly in prevalence between age groups, ward, and was
      higher in patients with urinary catheters and in those receiving antibiotics.

PMID- 10662566
TI  - Comparison of in-vivo antibacterial activity of two skin disinfection procedures
      for insertion of peripheral catheters: povidone iodine versus chlorhexidine.
AB  - Skin disinfection is a key step in the prevention of nosocomial infections
      especially prior to invasive procedures such as the insertion of peripheral
      catheters. Alcohol-based antiseptics improve bactericidal activity and decrease
      the time needed for skin disinfection in emergencies. A randomized study was
      performed in two groups of 22 volunteers to compare the in vivo bactericidal
      effect of two rapid disinfection procedures using povidone iodine (PVP-I) in
      scrub formulation followed by alcoholic PVP-I, or chlorhexidine in scrub
      formulation followed by alcoholic chlorhexidine. Bacteria were recovered using
      the cylinder scrub method. Comparison of reductions in the aerobic and anaerobic
      flora from baseline levels to each of the three sampling times (30 sec, 3 min, 2
      h) showed no significant difference between the two procedures Log(10)reduction
      after 30 seconds was around 1.5 for the aerobic flora and 1.1 for the anaerobic
      flora. After 3 minutes the corresponding values were 2.1 and 1.8, and after 2
      hours 2.0 and 1.3. The products were well tolerated in both groups. The two
      procedures had comparable rapid bactericidal activity in vivo.

PMID- 10662567
TI  - Disinfection of endoscopes contaminated with Cryptosporidium parvum oocysts.

PMID- 10662568
TI  - Control of MRSA.

PMID- 10662569
TI  - GB virus-C/hepatitis G virus infections in medical staff.

PMID- 10662570
TI  - Nosocomial transmission of measles to healthcare workers. Time for a national
      screening and immunization policy for NHS staff?

PMID- 10662571
TI  - Study on the Rovibrational Interactions and a(1)/a(2) Splittings in the
      nu(3)/nu(5)/nu(6) Triad of CH(3)D.
AB  - High-resolution Fourier transform infrared spectrum of CH(3)D has been recorded
      in the region of the fundamental bands nu(3), nu(5), and nu(6) between 900 and
      1700 cm(-1). High sensitivity of the equipment used as well as high accuracy of
      the recorded line positions gave the possibility of assigning the first-time
      transitions with the upper state J quantum number up to 23. In the analysis the
      new ground vibrational state information [O. N. Ulenikov, G. A. Onopenko, N. E.
      Tyabaeva, J. Schroderus, and S. Alanko, J. Mol. Spectrosc. 193, 249-259 (1999)]
      were used. In addition, modification of the Hamiltonian model of the interacting
      vibrational states (v(3) = 1), (v(5) = 1), and (v(6) = 1) allowed the theoretical
      description of numerous effects and peculiarities in the spectrum. In particular,
      sets of a(1)/a(2) splittings have been assigned and explained, not only for upper
      state K = 1 and 2 but also for K = 4 and 5. Moreover, unusually giant exotic
      splittings have been found for K = 7. The spectroscopic parameters reproducing
      the initial experimental energies with accuracy close to the experimental
      uncertainty have been determined. Copyright 2000 Academic Press.

PMID- 10662572
TI  - Rotational Spectrum of CBr by Kinetic Microwave Spectroscopy of 193-nm Photolysis
      Products of Bromoform.
AB  - We have measured the first millimeter-wave spectrum of CBr. The radical was
      produced by pulsed UV-laser photolysis of bromoform at 193 nm and detected using
      kinetic spectroscopy. We have significantly improved the rotational and fine
      structure constants for the ground vibrational state. The hyperfine structure due
      to the bromine nucleus has been resolved and quadrupole and magnetic hyperfine
      parameters evaluated for the first time. Copyright 2000 Academic Press.

PMID- 10662573
TI  - High-Resolution Study of the First Hexad of D(2)O.
AB  - The high-resolution Fourier transform spectra of the D(2)O molecule have been
      recorded and assigned in the 4200-5700 cm(-1) region where the vibration-rotation
      bands 2nu(1), 2nu(3), nu(1) + nu(3), nu(1) + 2nu(2), 2nu(2) + nu(3), and 4nu(2)
      are located. The presence of numerous and very strong accidental perturbations
      between the states of the hexad makes it necessary to take into account not only
      ordinary resonance interactions of the Fermi, Darling-Dennison, and/or Coriolis
      types, but interactions between the states (v(1)v(2)v(3)) and (v(1) -/+ 2v(2) +/-
      2v(3) +/- 1) as well. Parameters of all six vibrational states of the hexad were
      obtained from the fit of experimental energy values. Copyright 2000 Academic
      Press.

PMID- 10662574
TI  - High-Resolution Fourier Transform Spectrum of the D(2)O Molecule in the Region of
      the Second Triad of Interacting Vibrational States.
AB  - The high-resolution Fourier transform spectrum of the D(2)O molecule was recorded
      in the 3200-4200 cm(-1) region, where the bands of the second triad of
      interacting vibrational states are located. As a result of the theoretical
      analysis, both the rotational-vibrational structure of the (011) vibrational
      state was improved, and the rotational energies of the (110) and (030)
      vibrational states were determined for the first time up to rotational quantum
      numbers J(max.) = 15 and 14, respectively. Copyright 2000 Academic Press.

PMID- 10662575
TI  - Radiofrequency, Centimeter-Wave, Millimeter-Wave, and Infrared Spectra of
      SiHF(3): Investigation of the Ground, v(4) = 1, and v(6) = 1 Vibrational States.
AB  - The present paper deals with the analysis of the microwave, millimeter-wave, and
      infrared spectra of (28)SiHF(3) in its ground, v(6) = 1 and v(4) = 1 excited
      states. The former was observed up to 1055 GHz leading to the determination of
      one octic centrifugal distortion constant, L(J) = -0.0749(55) uHz. Furthermore
      the <k ||H ||k +/- 6> interaction term ||h(3,GS) || = 1.1032(70) mHz has been
      fitted from splittings of six K = 3 lines. The excited states have been regarded
      as isolated ones. This enabled fits according the Q-, D-, and QD-reduction
      schemes proposed by E. I. Lobodenko, O. N. Sulakshina, V. I. Perevalov, and Vl.
      G. Tyuterev, (J. Mol. Spectrosc. 126, 159-170 (1987)) and further developed by J.
      K. G. Watson, C. Gerke, H. Harder, and K. Sarka, (J. Mol. Spectrosc. 187, 131-141
      (1997)) and Harder (J. Mol. Spectrosc. 194, 145 (1999)). A multiple fit analysis
      was performed confirming the assumption that the excited states are not affected
      by intervibrational resonances. Finally the millimeter spectrum of (29)SiHF(3)
      and (30)SiHF(3) in their ground state was also measured up to 460 GHz and
      accurate rotational and centrifugal distortion parameters were derived. Copyright
      2000 Academic Press.

PMID- 10662576
TI  - Centrifugal Distortion Analysis of a Near-Spherical Top, SO(2)F(2): The First
      Determination of All Six Quartic Centrifugal Distortion Constants for an
      Asymmetric Top.
AB  - The rotational spectrum of the near-spherical top molecule SO(2)F(2) (sulfuryl
      fluoride) has been investigated by microwave Fourier transform spectroscopy and
      by millimeter-wave spectroscopy. The ground state spectrum has been measured from
      10 to 472 GHz. One of the reasons for studying this molecule is that it is a
      nearly spherical top and we wanted to verify our theoretical prediction that for
      such a molecule all six quartic centrifugal distortion constants (and nine sextic
      distortion constants) should be determinable, while for a standard asymmetric
      rotor, Watson has shown that only five quartic and seven sextic distortion
      constants are determinable. The analysis of the spectra confirmed our
      predictions, because all six quartic constants were well determinable. The
      results have been confirmed independently by ab initio calculations of the force
      field and quartic distortion constants. Because the molecule is relatively heavy,
      contributions of some sextic constants are too small and we have not been able to
      determine all nine sextic constants predicted by theory. Copyright 2000 Academic
      Press.

PMID- 10662577
TI  - The Electric Dipole Moment of the B(1)Pi State of ZrO.
AB  - A laser ablation source combined with a time-of-flight mass spectrometer has been
      constructed. The static electric field in the mass spectrometer gives rise to a
      first-order Stark effect splitting from which the permanent electric dipole
      moment of the B(1)Pi state (v = 0) of (90)ZrO is determined and found to be 3.43
      +/- 0.07 D. The X(1)Sigma and B(1)Pi states are further investigated and
      comparisons with the results from ab initio calculations are made. Copyright 2000
      Academic Press.

PMID- 10662578
TI  - High-Resolution Spectrum and Rovibrational Analysis of the nu(2)/nu(5) Dyad of
      D(3)SiF near 700 cm(-1).
AB  - The nu(2) (A(1), 710.157 cm(-1)) and nu(5) (E, 701.717 cm(-1)) fundamental bands
      of D(3)(28)SiF have been studied by FTIR spectroscopy with a resolution of 2.4 x
      10(-3) cm(-1). We assigned 1648 lines for the parallel band (J(max) = 50, K(max)
      = 21), 4279 for the perpendicular band (J(max) = 52, K(max) = 27), and in
      addition 671 perturbation-allowed transitions (J(max) = 50, K(max) = 12). The
      nearly degenerate v(2) = 1 and v(5) = 1 states are linked by (DeltaK = +/-1,
      Deltal = +/-1) and (DeltaK = +/-2, Deltal = -/+1) interactions, while the l(5) =
      +/-1 levels of nu(5) interact also by l(2, -1), l(2, 2), and l(2, -4)
      interactions. The first model with 36 free parameters, taking into account all
      these resonances through a nonlinear least-squares program, gave standard
      deviations of 1.56 x 10(-4) cm(-1) for 5997 nonzero-weighted IR data and 138 kHz
      for 8 MW data from the literature. The second model, in which the main Coriolis
      term was constrained to a force field value, used 37 parameters and gave similar
      standard deviations. A new determination of the A(0) and D(0)(K) ground state
      parameters was performed by two methods: either using differences between
      "forbidden" transitions differing by 3 in K or letting A(0) and D(0)(K) free in
      the global fit. The values obtained are fully compatible with those obtained
      previously by the "loop method." Copyright 2000 Academic Press.

PMID- 10662579
TI  - Intensity and Bandshapes of Collision-Induced Absorption by CO(2) in the Region
      of the Fermi Doublet.
AB  - The carbon dioxide dimer spectroscopic patterns are retrieved from the analysis
      of collision-induced absorption (CIA) spectral bandshape at room temperature. It
      is shown that the use of the simplified model based on the symmetric-top
      approximation allows roughly consistent simulation of the observed (CO(2))(2)
      dimer spectrum. The rotational constants obtained can be considered as effective
      thermally averaged constants which characterize dimeric structure, strongly
      distorted from the ground state. The overall CIA bandshape and the integrated
      intensity of absorption are broken down into partial contributions from tightly
      bound and metastable dimers and free-pair states. This approach is shown to be in
      agreement with a wide range of independent spectroscopic and thermodynamic data.
      Copyright 2000 Academic Press.

PMID- 10662580
TI  - Potential Energies, Permanent and Transition Dipole Moments for Numerous
      Electronic Excited States of NaK.
AB  - Recent experimental works have been devoted to the spectroscopy of highly excited
      states of NaK, confirming the accuracy of our previous calculations [S. Magnier
      and Ph. Millie, Phys. Rev. A: Gen. Phys. 54, 204 (1996)] of spectroscopic
      constants and potential curves. Among them, [E. Laub, I. Mazsa, S. C. Webb, J. La
      Civita, I. Prodan, Z. J. Zabbour, R. K. Namiotka, and J. Huennekens, J. Mol.
      Spectrosc. 193, 376 (1999)] have deduced from their measurements the variation of
      the transition dipole moment with the interatomic distance for the transition
      X(1)Sigma+ --> (3)(1)Pi. They have shown that a large discrepancy was observed
      with the previous ab initio calculations currently used as a guide for
      spectroscopic experiments. Upon request of several experimentalists, we have
      computed again potential curves for electronic states correlated up to Na(4p) +
      K(4s) as well as relevant permanent and transition dipole moments. We present
      extensive predictions for the electronic structure of NaK (potential energies,
      dipole moments) for which numerical data have been listed in a data base
      available as supplementary data. Copyright 2000 Academic Press.

PMID- 10662581
TI  - Characterization of the Ground State of Br(2) by Laser-Induced Fluorescence
      Fourier Transform Spectroscopy of the B(3)Pi(0(+))(u)-X(1)Sigma(+)(g) System.
AB  - The laser-induced fluorescence (LIF) spectrum of the B(3)Pi(0(+))(u)
      X(1)Sigma(+)(g) system of Br(2) was recorded by Fourier transform spectroscopy
      (FTS). The LIF spectra were obtained by using continuous-wave dye laser
      excitation in the spectral region 16 800-18 000 cm(-1). About 1800 rotationally
      resolved lines were recorded in 96 fluorescence progressions, originating from
      the 10 </= v' </= 22 vibrational levels of the B(3)Pi(0(+))(u) state and
      involving the 2 </= v" </= 29 levels of the X(1)Sigma(+)(g) ground state of the
      three isotopomers of bromine, (79)Br(2), (81)Br(2), and (79,81)Br(2). These data,
      together with (79)Br(2) data from a previous FTS absorption study [S.
      Gerstenkorn, P. Luc, A. Raynal, and J. Sinzelle, J. Phys. (France) 48, 1685-1696
      (1987)], were analyzed to yield improved Dunham constants for the ground state. A
      Rydberg-Klein-Rees (RKR) potential energy curve was computed for the
      X(1)Sigma(+)(g) state (v" = 0-29). The equilibrium bond length was found to be
      R(e)(X(1)Sigma(+)(g)) = 2.2810213(20) A. Copyright 2000 Academic Press.

PMID- 10662582
TI  - The 2(3)Delta(g) State of (7)Li(2).
AB  - Using pulsed perturbation-facilitated optical-optical double resonance (PFOODR)
      spectroscopy, the 2(3)Delta(g) state of (7)Li(2) (electronic configuration
      (varsigma(g)2s) (4ddelta(g)), effective principal quantum number n* = 4.101) has
      been observed and assigned. Molecular constants and a RKR potential energy curve
      were obtained. The major molecular constants are Copyright 2000 Academic Press.

PMID- 10662583
TI  - Spectroscopy of XY(5)Z (C(4v)) Molecules: A Tensorial Formalism Adapted to the
      O(3) superset O(h) superset C(4v) Chain.
AB  - A tensorial formalism adapted to the case of XY(5)Z symmetric tops has been
      developed as an extension of the usual one for the octahedral molecules. We use
      the O(3) superset O(h) superset C(4&v) group chain. All the coupling coefficients
      and formulas for the computation of matrix elements are given for this chain.
      Such relations are also deduced in the C(4v) group itself. Copyright 2000
      Academic Press.

PMID- 10662584
TI  - Spectroscopy of XY(5)Z (C(4v)) Molecules: Development of the Hamiltonian and the
      Transition Moment Operators Using a Tensorial Formalism.
AB  - We present a development of the Hamiltonian, dipole moment, and polarizability
      operators of XY(5)Z (C(4v)) molecules using a tensorial formalism derived from
      the one developed previously in Dijon for XY(6) molecules. These operators are
      involved in the calculation of the energies and intensities of rovibrational
      transitions and are essential for spectrum simulations. Expressions for the
      matrix elements are derived for all these operators. Copyright 2000 Academic
      Press.

PMID- 10662585
TI  - High-Resolution Measurements of HBr Transitions in the First Overtone Band Using
      Tunable Diode Lasers.
AB  - High-resolution absorption lineshapes of the R(7) and P(2) transitions in the
      first overtone (v = 0-2) band of H(79)Br have been recorded at room temperature
      using a pair of distributed feedback diode lasers operating near 1.95 and 2.00
      um, respectively. Spectral line intensities and self-broadening coefficients were
      determined by fitting the measured spectra (for various pressures P = 10-100
      Torr) with Voigt profiles and compared with values in the literature. Measured
      line intensities for the P(2) and R(7) transitions are approximately 11 and 16%
      higher than those listed in the HITRAN database, respectively. The measured self
      broadening coefficient of the P(2) transition is approximately 14% lower than the
      value listed in HITRAN. Measurements of the P(2) lineshapes at low pressure (100
      mTorr) were modeled with eight-line Gaussian profiles based on ground state (v =
      0) hyperfine constants to include the effects of nuclear electric quadrupole
      interactions. Copyright 2000 Academic Press.

PMID- 10662587
TI  - Terahertz Measurements of Rotational Transitions in Vibrationally Excited States
      of OCS.

PMID- 10662586
TI  - The Ground State Spectroscopic Constants of Formaldehyde.

PMID- 10662588
TI  - Near-Infrared Laser Spectrometer with Sub-Doppler Resolution, High Sensitivity,
      and Wide Tunability: A Case Study in the 1.65-um Region of CH(3)I Spectrum.

PMID- 10662589
TI  - Pleiotropic signaling pathways in rapid, nongenomic action of glucocorticoid.
AB  - The traditional genomic theory of steroid action does not fully explain the rapid
      effects of hormonal steroids, and it is thought that the nongenomic actions
      mediated by a putative membrane receptor may provide a plausible explanation.
      Although there is a rich body of evidence to substantiate the rapid, nongenomic
      effects of steroid hormones, the signal transduction pathways involved have
      proved to be complex and pleiotropic. Based on previous studies on the rapid,
      nongenomic actions of glucocorticoid (GC) and the G-protein-protein kinase
      pathways involved, including our own studies on PC12, SK-N-SH, BT-325 cells, and
      synaptosomes, in this review we will discuss the issue of multiple signal
      transduction pathways involved in the rapid, nongenomic effects of GC.

PMID- 10662590
TI  - PAP I interacts with itself, PAP II, PAP III, and lithostathine/regIalpha.
AB  - PAP I, PAP II, PAP III, and lithostathine/regIalpha are members of a multigenic
      family of proteins expressed in several tissues. PAP I was shown to be
      antiapoptotic, mitogenic, and anti-inflammatory and can promote cell adhesion to
      the extracellular matrix. Lithostathine/regIalpha can be mitogenic. Because
      polymerization might regulate activity, we examined the ability of rat PAP I to
      interact with itself (homodimerization), PAP II, PAP III, and
      lithostathine/regIalpha (heterodimerization) by the yeast two-hybrid system,
      affinity experiments, and crosslinking. PAP I interacted significantly with all
      members of the PAP protein family, homodimerization showing the strongest
      interaction as judged by the beta-galactosidase test. This was confirmed by
      showing specific affinity between a MBP-rPAP I fusion protein and the native rPAP
      I. Finally, crosslinking experiments showed that rPAP I formed dimers in
      solution. These findings should be taken into account in functional studies
      involving PAP I and PAP-related proteins.

PMID- 10662591
TI  - Microsatellite instability and p53 mutations in hepatocellular carcinoma.
AB  - We have studied 27 hepatocellular carcinomas (HCCs) to identify possible
      relationships between microsatellite instability (MSI), p53 mutations, and HBV
      infection in hepatocarcinogenesis. MSI was assessed using 19 polymorphic markers
      and the poly(A) tract BAT-26. All coding regions of p53 were examined for
      mutations. Tumors were also examined for presence of hepatitis B virus (HBV) DNA
      sequences; 66.6% of the samples exhibit MSI in at least one microsatellite locus
      and 44% in two or three loci. None of the tumors examined showed alterations in
      BAT-26. Moreover, 73.3% of samples with indication of HBV infection showed
      instability in at least one marker. No association between MSI and pathological
      profile was found. Five (18.5%) samples harbored mutations in p53, three
      missense, and two insertions, all in exons 5 and 8 not previously reported. No
      mutations were detected in codon 249, which has been linked with dietary intake
      of aflatoxins. Our results support the hypothesis that HCC is a "low" MSI tumor.
      Only 1/5 samples with MSI in more than two markers harbored a mutation in p53.
      Although the number of samples is too small to support a statistical
      significance, this finding may indicate an inverse relationship between p53
      mutations and MSI in HCC.

PMID- 10662592
TI  - WW and EF hand domains of dystrophin-family proteins mediate dystroglycan
      binding.
AB  - The membrane-spanning dystrophin glycoprotein complex mediates an indirect
      linkage between the actin-based cytoskeleton and the extracellular matrix.
      Although expressed by diverse cell types, genetic lesions of members of this
      complex result in muscular dystrophy phenotypes emphasizing the importance of
      these interactions in muscle cells. We have characterized interactions between
      dystrophin family members and dystroglycan: cytoskeletal and transmembrane
      components of the complex, respectively. Our results demonstrate that both the WW
      and EF hand domains of dystrophin and utrophin, an autosomal homologue of
      dystrophin, directly bind the cytoplasmic domain of dystroglycan. Furthermore,
      alpha-dystrobrevin, a more distantly related dystrophin family member which lacks
      a WW domain but contains the EF hand domain, binds dystroglycan. This is the
      first demonstration of a direct interaction between a dystrobrevin or utrophin
      and dystroglycan, and has implications for the organization of the dystrophin
      glycoprotein complex and the use of dystrophin homologues in muscular dystrophy
      therapy.

PMID- 10662593
TI  - CAMP is involved in transcriptional regulation of delta9-desaturase during
      Histoplasma capsulatum morphogenesis.
AB  - We have characterized the promoter region of the delta9-desaturase gene from two
      different strains of the dimorphic fungus Histoplasma capsulatum. Desaturase
      transcription is regulated in the two phases of growth: it is transcribed in the
      yeast phase at 37 degrees C, while it is inactive in the mycelial phase at 25
      degrees C. Phase transition can be induced by shifting the temperature from 25 to
      37 degrees C or by adding cAMP to the growth medium. We have identified a stress
      responsive cis element (STRE) responsive to cyclic AMP (cAMP)-signaling pathway
      and demonstrated that this element acts in H. capsulatum. We have also identified
      an element, hereafter called DRE (Desaturase Regulatory Element), present in the
      promoters of the H. capsulatum and S. cerevisiae delta9-desaturase gene. We show
      that this element is necessary but not sufficient to regulate transcription of
      the H. capsulatum delta9-desaturase gene.

PMID- 10662594
TI  - The budding yeast Cdc15 localizes to the spindle pole body in a cell-cycle
      dependent manner.
AB  - Exit from mitosis in the budding yeast Saccharomyces cerevisiae cell cycle is
      regulated by a regulatory network that involves, among other proteins, the small
      GTPase Tem1, the protein phosphatase Cdc14, and the protein kinases Dbf2 and
      Cdc15. Using a fusion to jellyfish green fluorescent protein (GFP), here we
      report that Cdc15 costains with the microtubular-organizing apparatus and that
      this localization is precluded in a mutant lacking the outer plaque of the
      spindle pole body (SPB). The appearance of Cdc15 in the SPB is asymmetric and
      cell-cycle-regulated, preferentially marking the daughter cell SPB at anaphase
      and eventually disappearing at cytokinesis. Overproduction of GFP-tagged Cdc15
      led to an accumulation of the fusion protein in both mother and daughter cells
      SPBs and, transiently, in small budded cells and shmoos. The Cdc15 localization
      pattern was maintained in dbf2, cdc14 and anaphase-promoting complex (cdc16)
      mutants, suggesting that the function of these proteins is not related to the
      localization of Cdc15 to the SPB but rather, at least in the case of Cdc14, to
      its timely removal from this structure. Tem1-depleted cells kept alive by Cdc15
      GFP overexpression still display a proper localization of Cdc15. The results
      presented here suggest that the transient cell-cycle-dependent localization of
      Cdc15 to the SPB plays a role in the regulation of the latest stages of the cell
      cycle.

PMID- 10662595
TI  - Characterization of erythrocyte compounds in asphyxiated newborns.
AB  - Perinatal hypoxic-ischemic damage remains a major cause of acute mortality in
      infants. In our study we have shown that ATP-powered calcium pump was degraded in
      asphyxiated erythrocyte membranes. Moreover, the activity of Ca2+-ATPase, the
      enzyme that is solely responsible for maintenance of calcium homeostasis in
      erythrocytes, was reduced by 50% compared to healthy newborns. We have also
      detected the enhanced lipid peroxidation in asphyxiated erythrocyte ghosts. To
      elucidate the potential mechanisms of the calcium pump damage, we have examined
      the effect of peroxynitrite on Ca2+-ATPase purified from adult human erythrocyte
      membranes. We have concluded that calcium pump is a direct target for
      peroxynitrite action in vitro. Our results indicate that erythrocyte membrane
      compounds could be a primary target for asphyxia-induced damage, and the
      impairment of the plasma membrane Ca2+-ATPase function could be, in part,
      mediated by reactive oxygen species.

PMID- 10662596
TI  - Centrosome multiplication accompanies a transient clustering of polyploid cells
      during tissue repair.
AB  - Cells from different human wounds were analyzed concerning their degree of
      ploidy. The experiments showed an increased tetraploidization rate in well
      healing wounds especially during inflammation and proliferation. Recent data
      described a polyploidization in different tissues, which is accompanied and maybe
      caused by the multiplication of the centrosome. We show here for the first time
      that cells from nonmalignant tissue, namely human wound cells, are characterized
      by an extensive centrosome multiplication. In an effort to identify a certain
      mechanism, by which the centrosome may act as a modulator of the cells' ploidy,
      we focused our interest on p53, whose interaction with the centrosome was
      recently described. Applying a wound model onto p53-wildtype (wt) and p53
      knockout (ko) mice, we could show that polyploidization was not reversible in p53
      ko mice during wound healing. The lack of p53, the centrosome multiplication, and
      the polyploidization therefore may contribute to the physiological process of
      tissue repair in physiologically "normal" tissue.

PMID- 10662597
TI  - Down-regulation of human Galbeta1,3GalNAc/Galbeta1,4GlcNAc alpha2,3
      sialyltransferase (hST3Gal IV) gene during differentiation of the HL-60 cell
      line.
AB  - We studied the regulation of the human Galbeta1, 3GalNAc/Galbeta1,4GlcNAc
      alpha2,3-sialyltransferase (hST3Gal IV) gene during HL-60 cell differentiation
      induced by dimethyl sulfoxide (DMSO), all trans-retinoic acid (ATRA), and phorbol
      myristate acetate (PMA). During differentiation, levels of hST3Gal IV mRNA
      dramatically decreased after 1 day of stimulation. Reverse-transcription PCR
      identified two mRNA isoforms, types B1 and BX, in HL-60 cells. The results of
      luciferase assays showed that the level of B3 promoter activity is high, whereas
      A1/2 and B2 promoter activities are low in HL-60 cells, suggesting that type B1,
      BX, and B3 mRNA isoforms are expressed in HL-60 cells. A luciferase assay
      identified a functional DNA portion within the proximal region of the B3 promoter
      that confers negative transcriptional regulation on the hST3Gal IV B3 promoter
      during HL-60 differentiation. These results suggest that this element plays a
      critical role in down-regulating the B3 promoter activity during HL-60 cell
      differentiation.

PMID- 10662598
TI  - Troglitazone induces expression of PPARgamma in liver.
AB  - Troglitazone is an insulin sensitizer which affects a number of target tissues.
      It is believed to exert these effects primarily by binding to and activating the
      y-isoform of peroxisome proliferator-activated receptor (PPARgamma), which in
      turn regulates the expression of specific genes. However, in a number of target
      organs, such as liver, the levels of PPARgamma are low and other isoforms
      predominate. In the present study, we examined whether troglitazone induces the
      expression of PPARgamma, thereby sensitizing cells for the action of this drug.
      Treatment of isolated rat hepatocytes with troglitazone induced both the mRNA and
      protein levels of PPARgamma in a dose-dependent fashion, with maximal levels of
      induction being three- to fourfold. This induction was also observed using the 15
      deoxy-delta12,14-prostaglandin J2, a known natural ligand for PPARgamma, whereas
      ligands specific for PPARalpha were without effect. The induction of PPARgamma
      expression by troglitazone was also observed in livers from rats fed a diet
      containing troglitazone. Troglitazone had no effect on the expression of the
      alpha- or beta-isoforms of PPAR, the more predominant liver isoforms. These
      results indicate that troglitazone produces a reprogramming of PPAR isoform
      content in liver, which may in part underlie the mechanism whereby troglitazone
      sensitizes the liver to the action of insulin and/or ameliorates hyperglycemia.

PMID- 10662599
TI  - The role of voltage-gated chloride channels in type II pyrethroid insecticide
      poisoning.
AB  - Pyrethroids act on mammalian sodium channels, but we have previously shown that
      low concentrations of the type II pyrethroid deltamethrin also decrease the open
      channel probability (P(o)) of voltage-gated chloride channels. This effect would
      be expected to amplify the sodium channel-mediated signs of poisoning produced by
      pyrethroids. In the present study we evaluated potential chloride channel
      agonists in vitro, and then tested the most effective of these on pyrethroid
      poisoned rats to determine the practical significance of chloride channel effects
      in vivo. Patch clamp experiments showed that, for voltage-gated maxi chloride
      channels in excised, inside-out patches from mouse N1E 115 neuroblastoma cells,
      ivermectin (10(-7) M) and pentobarbitone (10(-6) M) significantly increased open
      channel probability (p </= 0.01 and p </= 0.02, respectively), whereas
      phenobarbitone, hexobarbitone, mephobarbitone, thiopentone, and barbituric acid
      did not. This suggested that, if chloride channels were important in vivo,
      ivermectin and pentobarbitone should antagonize type II pyrethroid poisoning and
      phenobarbitone should not. Male F344 rats were then pretreated with ivermectin (4
      mg/kg iv), equisedative doses of either pentobarbitone (15 mg/kg ip) or
      phenobarbitone (45 mg/kg ip), or solvent controls. This was followed by
      deltamethrin (1.5 or 2 mg/kg iv) or the type I pyrethroid cismethrin (4 mg/kg
      iv). Ivermectin produced a marked fall in deltamethrin-induced salivation (p </=
      0.05) and also (in anesthetized rats) in repetitive electromyogram discharge and
      muscle twitch (p </= 0.01 and p </= 0.05, respectively). Pentobarbitone
      significantly reduced the motor signs score due to deltamethrin (p </= 0.01).
      Ivermectin therefore protected against the peripheral signs of deltamethrin
      poisoning and pentobarbitone protected against the central signs. As expected
      phenobarbitone had no protective effects. The motor signs produced by the type I
      pyrethroid cismethrin (which does not act on chloride channels) were not
      diminished by either barbiturate. The peripheral benzodiazepine receptor blocker
      PK11195 did not diminish the protective action of ivermectin on the muscle twitch
      (p </= 0.05), although it partially reversed the block of salivation (p </=
      0.05). These results support the hypothesis that the voltage-dependent chloride
      channel is a toxicologically significant additional site of action for
      deltamethrin and that the use of chloride channel agonists can provide a
      rationale for a novel and effective therapy against type II pyrethroid poisoning.

PMID- 10662600
TI  - Role of protein phosphorylation in activation of phospholipase A2 by the
      polychlorinated biphenyl mixture Aroclor 1242.
AB  - Polychlorinated biphenyls (PCBs) activate neutrophils to induce degranulation and
      undergo superoxide production through a mechanism that involves stimulation of
      phospholipase A(2) (PLA(2)). Since the biochemical processes leading to the PCB
      induced activation of this enzyme are unknown, the objective of this study was to
      determine whether protein phosphorylation has a role in this mechanism. Isolated
      rat neutrophils were labeled with [(3)H]-arachidonic acid ([(3)H]-AA), and
      activation of PLA(2) was determined from release of radioactivity into the
      medium. Exposure to the PCB mixture Aroclor 1242 induced release of [(3)H]-AA,
      and pretreatment with bromoenol lactone (BEL), an inhibitor of calcium
      independent PLA(2), diminished release by 80%. Genistein, an inhibitor of
      tyrosine kinases, caused a small but significant decrease in Aroclor 1242
      stimulated release of [(3)H]-AA. Daidzein, a genistein analog with no activity to
      inhibit tyrosine kinases, had no effect on [(3)H]-AA release. An inhibitor of p38
      mitogen-activated protein kinase (MAPK), SB203580, did not affect Aroclor 1242
      induced PLA(2) activity at concentrations selective for p38 MAPK; however, PD
      98059, which inhibits MAPK kinase (MEK), decreased [(3)H]-AA release to about the
      same extent as genistein. Treatment of neutrophils with Aroclor 1242 induced
      phosphorylation of p44 MAPK, and this phosphorylation was unaffected by BEL but
      was inhibited by PD 98059. Staurosporine, a nonselective inhibitor of protein
      kinase C (PKC), inhibited PCB-induced release of [(3)H]-AA. Ro 32-0432, a
      selective inhibitor of PKC(alpha) and PKC(beta1), produced the greatest degree of
      inhibition (40%) among the tested protein kinase inhibitors. These results
      suggest that tyrosine kinases, PKC, and the MEK/MAPK pathway are involved in a
      fraction of Aroclor 1242-induced activation of PLA(2).

PMID- 10662601
TI  - Modulation of transcription factor AP-1 activity in murine EL-4 thymoma cells by
      vomitoxin (deoxynivalenol).
AB  - Trichothecene mycotoxins have been reported to suppress or superinduce cytokine
      mRNA expression by leukocytes both in vitro and in vivo. Modulation of
      transcription factor activities may be critical for these observations. Here, the
      effect of trichothecene vomitoxin (VT, deoxynivalenol) on activator protein-1 (AP
      1) activity was determined in the murine EL-4 thymoma. Electrophoretic mobility
      shift assay (EMSA) revealed that VT modulated AP-1 binding activity in a
      concentration- and time-dependent manner when using a synchronous model in which
      VT was added concurrently with phorbol 12-myristate 13-acetate (PMA) and
      ionomycin (ION) to EL-4 cells. Induction of AP-1 binding activity by PMA/ION was
      suppressed in the presence of VT for a short period (1 to 12 h), but was enhanced
      upon prolonged VT exposure (48 to 72 h). VT also enhanced AP-1 binding activity
      when added to the cell culture 12 h after PMA/ION activation (delayed synchronous
      model). Using specific antibodies against AP-1 complex proteins, it was
      demonstrated by gel supershift assay that VT preferentially affected
      phosphorylated c-Jun, Jun B, c-Fos, and Fra-2 binding activities, whereas it did
      not alter Jun D and Fra-1 binding. A transient transfection assay demonstrated
      that these increased binding activities are associated with enhanced AP-1
      transactivation potential. Elevation of AP-1 activity may contribute to cytokine
      dysregulation and immunotoxic effects associated with exposure to trichothecene
      mycotoxins such as VT.

PMID- 10662603
TI  - Teratogenicity, tissue distribution, and metabolism of the retro-retinoids, 14
      hydroxy-4,14-retro-retinol and anhydroretinol, in the C57BL/6J mouse.
AB  - The retro-retinoids 14-hydroxy-4,14-retro-retinol (14-HRR) and anhydroretinol
      (AR) are endogenous metabolites of retinol (Vitamin A). 14-HRR and retinol, but
      not retinoic acid, promote the proliferation of lymphocytes and fibroblasts when
      cultured in serum-free medium, whereas AR competitively inhibits these growth
      supportive effects. Retinol and all-trans-retinoic acid are potent teratogens.
      This study shows the teratogenic potencies of 14-HRR and AR compared to retinol
      at a single gestational time. Also reported is the metabolism of these retinoids
      in nonpregnant mouse liver, the primary storage tissue of vitamin A, where many
      retinoids will be present at their highest concentration. Additionally,
      measurement of these metabolite concentrations was carried out in pregnant mouse
      plasma and embryos because they are the most relevant to teratology. Single
      intraperitoneal administration of 60 mg/kg of all-trans-retinol (retinol) to
      C57BL/6J mice at gestational day 7.5 produced a significant induction of eye and
      axial skeletal malformations. The equivalent dose of 14-HRR or AR induced a lower
      frequency of embryolethality and eye and axial skeletal malformations indicating
      that these retro-retinoids are less potent teratogens than retinol. The
      distribution of 14-HRR, AR, retinol, and their metabolites was determined in the
      liver at a single time point after retinoid administration. Two hours after 60
      mg/kg of 14-HRR treatment, HRR esters are detected. Two hours after 600 mg/kg of
      AR treatment, 14-HRR is detected, suggesting that 14-HRR, a reported metabolite
      of retinol, can be biosynthesized from AR. In both cases, neither retinoic acid
      nor retro-retinoid acidic metabolites were detected. Two hours after 60 mg/kg of
      retinol treatment, 14-HRR, 13,14-dihydroxyretinol (DHR), AR, and retinoic acid
      were detected. A new endogenous retro-retinoid, to which the 4-hydro-5-hydroxy
      anhydroretinol structure is proposed, was detected in all liver extracts.
      Retinoic acid, 14-HRR, and DHR were present in plasma and embryos of retinol
      treated pregnant mice. Plasma and embryos of AR-treated pregnant mice contained
      14-HRR and AR, but the retinoic acid concentration did not increase compared to
      controls. In summary, the retro-retinoids 14-HRR and AR are weaker teratogens
      than retinol. The low teratogenicity observed might be due to the facts that 14
      HRR and AR do not contain the terminal carboxylic group involved in binding and
      activation of the retinoic acid nuclear receptors and they are not metabolized to
      acidic retinoids.

PMID- 10662602
TI  - Normal patterns of angiogenesis and extracellular matrix deposition in chick
      chorioallantoic membranes are disrupted by mainstream and sidestream cigarette
      smoke.
AB  - The adverse effects of cigarette smoke on mature blood vessels are well
      established, whereas little is known about the influence of smoke on blood vessel
      development. To determine if cigarette smoke alters angiogenesis, chick
      chorioallantoic membranes (CAMs) were exposed for 4 days to culture medium
      (control) or to mainstream (MS) or sidestream (SS) smoke solution, and then blood
      vessel patterns were compared in blind tests. In contrast to the normal tree-like
      branching of control blood vessels, smoke-treated CAMs often had vessels that ran
      parallel to each other without much branching. A significant increase in the
      number of fibroblasts was observed in histological sections of treated CAMs, and
      this increase correlated with alterations in extracellular matrix components.
      Many more matrix fibrils were observed in treated CAMs than in controls using
      scanning electron microscopy. Immunohistochemistry showed that type III collagen
      was distributed in a tight band adjacent to the endoderm in controls but was
      distributed throughout the mesoderm in both treatment groups. Western blots
      confirmed that both type I and type III collagen were more abundant in treated
      CAMs than in controls. Fibronectin, which was localized immunohistochemically in
      the basal laminae and mesodermal matrix of controls, increased in abundance in
      CAMs treated with SS smoke solutions. Hyaluronic acid, which was present in a
      dense band subjacent to the capillary plexus of control CAMs, was greatly reduced
      in MS-treated CAMs and was absent in SS-treated CAMs. These observations
      demonstrate that both MS and SS cigarette smoke solutions caused abnormal pattern
      formation of CAM blood vessels and altered the composition of the extracellular
      matrix in the CAM mesoderm.

PMID- 10662604
TI  - Hypoxia-dependent retinal toxicity of bioreductive anticancer prodrugs in mice.
AB  - The bioreductive anticancer prodrug CI-1010 ((2R)-1-[(2-bromoethyl)amino]-3-(2
      nitro-1H-imidazol-1-yl)-2-propanol hydrobromide) is an alkylating nitroimidazole
      which shows selective toxicity against hypoxic cells in murine tumors, but causes
      extensive apoptosis in the outer retina in rodents and monkeys. This irreversible
      retinal toxicity has terminated preclinical development of CI-1010. We have
      investigated whether such toxicity is due to physiological hypoxia in the retina,
      and whether it is a general feature of hypoxia-selective bioreductive drugs.
      Retinal damage was quantified by morphometric analysis of histological sections
      following treatment of female C57Bl6 mice. Both CI-1010 and tirapazamine (TPZ,
      1,2,4-benzotriazin-3-amine 1,4-dioxide), a bioreductive drug in Phase III
      clinical trial, caused a time and dose-dependent loss of photoreceptor cells of
      the outer retina following administration of single intraperitoneal doses. The
      lesion caused by TPZ was qualitatively similar to that with CI-1010, but was less
      severe at equivalent fractions of the maximum tolerated dose (as defined by
      lethality). With both bioreductive drugs, lesion severity was increased if
      animals breathed 10% O(2) for 3 h after drug administration, while breathing 95%
      O(2)/5% CO(2) was protective. Other hypoxia-selective bioreductive drugs tested
      (the quinone porfiromycin, the anthraquinone N-oxide AQ4N and the nitrogen
      mustard prodrugs SN 23816 and SN 25341) did not cause retinal damage at their
      maximum tolerated doses. This study suggests that the retinal toxicity of
      bioreductive drugs might be avoided by manipulation of tissue hypoxia using 95%
      O(2)/5% CO(2), although this intervention could suppress antitumor activity. The
      finding that not all bioreductive drugs cause retinal toxicity suggests this
      toxicity can be avoided through appropriate drug design.

PMID- 10662605
TI  - Toxicity of heparin in postimplantation whole-embryo culture.
AB  - Cranial neural tube defects occur when heparin is added to the culture media of
      postimplantation rat embryos undergoing organogenesis in vitro. Timed-exposure
      studies were undertaken to determine whether the defects caused by heparin were
      the result of defective folding and fusion of the neural folds, or due to
      reopening of a closed neural tube. Experiments were also undertaken to elucidate
      whether the in vitro toxicity of heparin was due to an effect of heparin at the
      level of the culture medium, at the level of the visceral yolk sac, or at the
      level of the embryo proper. Heparin was found to cause defective folding and
      closure of the neural folds at between 9.5 and 10.5 days' gestation. Neural tube
      defects did not occur when embryos were cultured in media prepared using a
      culture medium depleted of heparin ligands by heparin-agarose affinity
      chromatography. However, studies with [G-(3)H]heparin demonstrated visceral yolk
      sac uptake and transfer of the radiolabel to the embryo proper. In addition,
      microinjection of heparin directly into the amniotic cavity of early head-fold
      embryo explants resulted in cranial neural tube defects similar to those caused
      by the addition of heparin to culture medium. These data indicate that heparin
      causes closure defects of cranial neurulation, primarily by an effect at the
      tissue level of the embryo proper.

PMID- 10662606
TI  - Development of a physiologically based pharmacokinetic model of 2-methoxyethanol
      and 2-methoxyacetic acid disposition in pregnant rats.
AB  - An accurate description of developing embryos' exposure to a xenobiotic is a
      desirable component of mechanism-based risk assessments for humans exposed to
      potential developmental toxicants during pregnancy. 2-Methoxyethanol (2-ME), a
      solvent used in the manufacture of semiconductors, is embryotoxic and teratogenic
      in all species tested including nonhuman primates. 2-Methoxyacetic acid (2-MAA)
      is the primary metabolite of 2-ME and the proximate embryotoxic agent. The
      objective of the work described here was to adapt an existing physiologically
      based pharmacokinetic (PBPK) model for 2-ME and 2-MAA kinetics during
      midorganogenesis in mice to rats on gestation days (GD) 13 and 15. Blood and
      tissue data were analyzed using the extrapolated PBPK model that was modified to
      simulate 2-ME and 2-MAA kinetics in maternal plasma and total embryo tissues in
      pregnant rats. The original mouse model was simplified by combining the embryos
      and placenta with the richly perfused tissue compartment. The model includes a
      description of the growth of the developing embryo and changes in the physiology
      of the dam during pregnancy. Biotransformation pathways of 2-ME to either
      ethylene glycol (EG) or to 2-MAA were described as first-order processes based on
      the data collected from rats by Green et al., (Occup. Hyg. 2, 67-75, 1996).
      Tissue partition coefficients (PCs) for 2-ME and 2-MAA were determined for a
      variety of maternal tissues and the embryos. Model simulations closely reflected
      the biological measurement of 2-ME and 2-MAA concentrations in blood and embryo
      tissue following gavage or iv administration of 2-ME or 2-MAA. The PBPK model for
      rats as described here is well suited for extrapolation to pregnant women and for
      assessment of 2-MAA dosimetry under various conditions of possible human exposure
      to 2-ME.

PMID- 10662607
TI  - Effects of selected arginine analogues on sulphur mustard toxicity in human and
      hairless guinea pig skin keratinocytes.
AB  - The toxicity of sulphur mustard (HD) was characterized in first passage cultures
      of human neonatal foreskin keratinocytes and then several arginine analogues were
      investigated to ascertain their efficacies in protecting against HD toxicity in
      this system. d- and l-nitroarginine methyl ester (d/l-NAME), l-phosphoarginine,
      and l-nitroarginine were all found to confer concentration-related protective
      effects against HD in confluent cultures. l-NAME was used to further characterize
      this protection and was only effective in cultures that were not actively
      proliferating. This compound was also found to be efficacious when added to the
      cultures up to several hours after HD exposure, although its continued presence
      was required in order for protection to be effective. The protective effects of l
      thiocitrulline (l-TC) against HD toxicity were also assessed. This arginine
      analogue was extremely potent in preventing HD toxicity in actively
      proliferating, just-confluent, and postconfluent cultures in a concentration
      dependent fashion (0.1-15 mM), with little HD toxicity apparent at high l-TC
      concentrations. Protection was prophylactic in nature, with l-TC having almost
      maximal effect when added to the cultures only 1 min prior to HD culture
      exposure. Efficacy then declined rapidly so that no protection was evident when l
      TC was added 30 min post-HD. The effects of this drug were persistent, with no
      decrease in protective efficacy up to 4 days after HD exposure, even when l-TC
      was removed from the cultures. l-TC did not protect against the antimitotic
      effects of HD; while l-TC-protected cells were subcultured successfully, they
      displayed no clonogenic activity. Although l-TC is closely related structurally
      to protective nitroarginine derivatives, the characteristics of l-TC protection
      against HD were markedly different and suggest that they exert their protective
      activities at different sites. Administration of l-NAME and l-TC by a variety of
      routes did not result in consistent protection against topical vapor challenges
      of HD in hairless guinea pigs. However, both compounds were effective in
      preventing the toxicity of HD in primary cultures of hairless guinea pig skin
      keratinocytes, indicating that species differences were not likely to be
      responsible for the poor efficacy of these compounds in vivo.

PMID- 10662608
TI  - Novel mechanism of protein kinase C inhibition involving the pseudosubstrate
      region by secalonic acid D in vitro.
AB  - Evidence from studies in mice suggests a mechanistic role for the inhibition of
      conventional isoforms of protein kinase C (cPKC) in the development of cleft
      palate (CP) in the offspring of female mice treated with the mycotoxin, secalonic
      acid D (SAD). These experiments were aimed at assessing whether SAD inhibits
      commercially available pure cPKC (PKCalpha, -beta, -gamma) and at identifying the
      mechanism of such an inhibition in vitro. Secalonic acid D inhibited the three
      isozymes similarly (IC50 of 5 to 6.2 microM by direct extrapolation and 2.7 to 4
      microM by logarithmic regression). The loss of inhibitory effect of SAD upon
      removal of the regulatory domain of PKCbetaII, the most predominant cPKC in the
      palate, suggested that the inhibition was mediated by the regulatory subunit.
      Kinetic analysis suggested a lack of competitive interaction for SAD with the
      binding sites for Ca(2+) and phosphatidyl serine (PS). Antibody directed against
      residues 19-32 of the pseudosubstrate region of PKCbetaII, however, competitively
      reversed the inhibition of PKCbetaII by SAD, suggesting that the pseudosubstrate
      is the site of interaction of SAD. Further, SAD inhibited the cleavage of the
      pseudosubstrate from PKCbetaII by the endoproteinase Arg-C. The fact that the
      activity of Arg-C itself was not inhibited by SAD suggests that SAD interferes
      with the preceding step involving the cofactor-induced release of the
      pseudosubstrate from the active site of PKCbetaII, a novel mechanism.

PMID- 10662609
TI  - Emergence of porcine reproductive and respiratory syndrome virus deletion
      mutants: correlation with the porcine antibody response to a hypervariable site
      in the ORF 3 structural glycoprotein.
AB  - By using porcine immune sera to select a library of phage-displayed random
      peptides, we identified an antigenic sequence (RKASLSTS) in the C-terminus of the
      ORF 3 structural glycoprotein of European-type porcine reproductive and
      respiratory syndrome virus (PRRSV). Through the use of overlapping reading
      frames, the same PRRSV genetic locus codes for the ORF 3 "RKASLSTS" sequence, and
      a previously described ORF 4 epitope (Meulenberg, J. J. M., Van Nieuwstadt, A.
      P., Van Essen-Zandbergen, A., and Langeveld, J. P. M., 1997, J. Virol. 71, 6061
      6067). Sequence analysis identified naturally occurring deletion mutants at this
      ORF 34 site. Phylogenetic analysis showed the presence of a highly accurate ORF 3
      molecular clock, according to which deletion mutants and nondeleted viruses
      evolved at differing speeds. Furthermore, deletion mutants and nondeleted viruses
      evolved as separate lineages. These distinctions suggested that deletion mutants
      were a hitherto unrecognized subtype of European-type PRRSV. Currently, deletion
      mutants appear to be outcompeting nondeleted viruses in the field, highlighting
      the importance of the porcine antibody response against the minor structural
      glycoproteins of European-type PRRSV for viral evolution.

PMID- 10662610
TI  - Human papillomavirus types 16 E6 and E7 contribute differently to carcinogenesis.
AB  - High-risk human papillomaviruses (HPVs) are etiologically implicated in human
      cervical cancer. Two viral genes, E6 and E7, are commonly found expressed in
      these cancer cells. We have previously shown that mice transgenic for the HPV-16
      E6 gene or E7 gene, in which the E6 or E7 was expressed in the basal layer of
      epithelia, developed skin tumors. The spectrum of tumors derived from E6 and E7
      mice differed, however; although most tumors derived from the E7-transgenic mice
      were benign, the majority of the tumors from the E6-transgenic mice were
      malignant. These findings led us to hypothesize that E6 and E7 play different
      roles in carcinogenesis. To assess at what stages in carcinogenesis E6 and E7
      act, we treated the skin of K14E6- and K14E7-transgenic mice with chemical
      carcinogens known to contribute to distinct stages in carcinogenesis. Both E6 and
      E7 were found to synergize with chemical carcinogens in causing tumor formation.
      E6 was found to act weakly at the promotion stage of carcinogenesis in the
      formation of benign tumors but strongly at the progression stage which involves
      the malignant conversion of benign tumors. In contrast, E7 primarily affected the
      promotion stage of carcinogenesis. These results provide direct evidence that E6
      and E7 contribute differently to carcinogenesis; E7 promotes the formation of
      benign tumors, and E6 acts primarily to accelerate progression of these benign
      tumors to the malignant stage. Consistent with this model, we found E6 and E7 to
      cooperate in inducing tumor formation in mice expressing both oncogenes.

PMID- 10662611
TI  - Role of anti-gB and -gD antibodies in antibody-induced endocytosis of viral and
      cellular cell surface glycoproteins expressed on pseudorabies virus-infected
      monocytes.
AB  - The addition of porcine pseudorabies virus (PrV)-specific polyclonal IgG
      antibodies to PrV-infected monocytes induces internalization of plasma membrane
      anchored viral glycoproteins and major histocompatibility complex (MHC) class I.
      Using PrV deletion strains, it was shown that gB and gD are essential for the
      process to occur. The purpose of the current study was to evaluate whether
      antibodies directed against single viral glycoproteins are able to induce
      endocytosis. It was shown that monoclonal antibodies directed against viral
      glycoprotein gB and gD, but not against gC and gE, are able to induce
      internalization of their respective ligand. Adding a combination of monoclonal
      antibodies against gB and gD resulted in endocytosis levels, comparable to the
      endocytosis levels observed when adding porcine PrV-specific polyclonal
      antibodies. The addition of genistein and tyrphostin 25, two inhibitors of
      tyrosine kinase activity, abolished endocytosis induced by monoclonal anti-gB and
      -gD antibodies in a concentration-dependent manner. The addition of similar
      concentrations of tyrphostin 1, an inactive tyrphostin, had no effect on
      endocytosis. It was also shown that a mixture of polyclonal, but not monoclonal,
      antibodies against gB and gD is able to induce cointernalization of MHC class I.
      This indicates that MHC class I cointernalization results from a passive catching
      of the molecules rather than from a specific interaction of the MHC class I
      molecules with one or more viral glycoproteins. In conclusion, it can be stated
      that antibody-induced crosslinking of gB and gD induces the activation of a
      tyrosine phosphorylation-dependent signal transduction pathway, leading to their
      endocytosis. Cointernalization of other viral glycoproteins and MHC class I is
      most likely caused by a passive catching of these molecules in the gB and gD
      aggregates.

PMID- 10662612
TI  - Engineering cowpea mosaic virus RNA-2 into a vector to express heterologous
      proteins in plants.
AB  - A series of new cowpea mosaic virus (CPMV) RNA-2-based expression vectors were
      designed. The jellyfish green fluorescent protein (GFP) was introduced between
      the movement protein (MP) and the large (L) coat protein or downstream of the
      small (S) coat protein. Release of the GFP inserted between the MP and L proteins
      was achieved by creating artificial processing sites each side of the insert,
      either by duplicating the MP-L cleavage site or by introducing a sequence
      encoding the foot-and-mouth disease virus (FMDV) 2A catalytic peptide. Eight
      amino acids derived from the C-terminus of the MP and 14-19 amino acids from the
      N-terminus of the L coat protein were necessary for efficient processing of the
      artificial Gln/Met sites. Insertion of the FMDV 2A sequence at the C-terminus of
      the GFP resulted in a genetically stable construct, which produced particles
      containing about 10 GFP-2A-L fusion proteins. Immunocapture experiments indicated
      that some of the GFP is present on the virion surface. Direct fusion of GFP to
      the C-terminus of the S coat protein resulted in a virus which was barely viable.
      However, when the sequence of GFP was linked to the C-terminus by an active FMDV
      2A sequence, a highly infectious construct was obtained.

PMID- 10662613
TI  - Intravirion targeting of a functional anti-human immunodeficiency virus ribozyme
      directed to pol.
AB  - Ribozymes are catalytic RNAs that offer several advantages as specific
      therapeutic genes against human immunodeficiency virus type 1 (HIV-1).
      Significant challenges in antiviral uses of ribozymes include (1) how best to
      express and to deliver this agent and (2) what is the best locale to target
      ribozymes against HIV-1 RNA. To explore the former, we have previously
      characterized several vector systems for efficient expression/delivery of anti
      HIV-1 ribozymes (Dropulic et al., 1992; Dropulic and Jeang, 1994a; Smith et al.,
      1997). Here, to investigate an optimal locale for ribozyme-targeting, we asked
      whether it might be advantageous to direct ribozymes into HIV-1 virions as
      opposed to the more conventional approach of targeting ribozymes into infected
      cells. Two series of experiments were performed. First, we demonstrated that anti
      HIV-1 ribozymes could indeed be packaged specifically and efficiently into
      virions. Second, we compared the virus suppressing activity of a packageable
      ribozyme with its counterpart, which cannot be packaged into HIV-1 virions. Our
      results showed that although both ribozymes cleaved HIV-1 genomic RNA in vitro
      with equivalent efficiencies, the former ribozyme demonstrated significantly
      higher virus-suppressing activity than the latter. These findings provide proof
      of-principle that to combat productive HIV-1 replication, intravirion targeting
      is more effective than intracellular targeting of ribozymes.

PMID- 10662614
TI  - Multiple interactions among proteins encoded by the mite-transmitted wheat streak
      mosaic tritimovirus.
AB  - The genome organization of the mite-transmitted wheat streak mosaic virus (WSMV)
      appears to parallel that of members of the Potyviridae with monopartite genomes,
      but there are substantial amino acid dissimilarities with other potyviral
      polyproteins. To initiate studies on the functions of WSMV-encoded proteins, a
      protein interaction map was generated using a yeast two-hybrid system. Because
      the pathway of proteolytic maturation of the WSMV polyprotein has not been
      experimentally determined, random libraries of WSMV cDNA were made both in DNA
      binding domain and activation domain plasmid vectors and introduced into yeast.
      Sequence analysis of multiple interacting pairs revealed that interactions
      largely occurred between domains within two groups of proteins. The first
      involved interactions among nuclear inclusion protein a, nuclear inclusion
      protein b, and coat protein (CP), and the second involved helper component
      proteinase (HC-Pro) and cylindrical inclusion protein (CI). Further immunoblot
      and deletion mapping analyses of the interactions suggest that subdomains of CI,
      HC-Pro, and P1 interact with one another. The two-hybrid assay was then performed
      using full-length genes of CI, HC-Pro, P1, P3, and CP, but no heterologous
      interactions were detected. In vitro binding assay using glutathione-S
      transferase fusion proteins and in vitro translation products, however, revealed
      mutual interactions among CI, HC-Pro, P1, and P3. The failure to detect
      interactions between full-length proteins by the two-hybrid assay might be due to
      adverse effects of expression of viral proteins in yeast cells. The capacity to
      participate in multiple homomeric and heteromeric molecular interactions is
      consistent with the pleiotropic nature of many potyviral gene mutants and
      suggests mechanisms for regulation of various viral processes via a network of
      viral protein complexes.

PMID- 10662615
TI  - Mutational analysis of the cowpea mosaic virus movement protein.
AB  - Cowpea mosaic virus moves from cell-to-cell in a virion form through tubular
      structures that are assembled in modified plasmodesmata. Similar tubular
      structures are formed on the surface of protoplasts inoculated with cowpea mosaic
      virus. The RNA 2-encoded movement protein (MP) is responsible for the induction
      and formation of these structures. To define functional domains of the MP, an
      alanine-substitution mutagenesis was performed on eight positions in the MP,
      including two conserved sequence motifs, the LPL and D motifs. Results show that
      these two conserved motifs as well as the central region of the MP are essential
      for cell-to-cell movement. Several viruses carrying mutations in the N- or C
      terminal parts of their MP retained infectivity on cowpea plants. Coexpression
      studies revealed that mutant MPs did not interfere with the activity of wild-type
      MP and could not mutually complement their defects.

PMID- 10662616
TI  - Induction of the human protein P56 by interferon, double-stranded RNA, or virus
      infection.
AB  - P56 is the most abundant protein induced by interferon (IFN) treatment of human
      cells. To facilitate studies on its induction pattern and cellular functions, we
      expressed recombinant P56 as a hexahistidine-tagged protein in Escherichia coli
      and purified it to apparent homogeneity using affinity chromatography. A
      polyclonal antibody raised against this recombinant protein was used to show that
      P56 is primarily a cytoplasmic protein. Cellular expression of P56 by
      transfection did not inhibit the replication of vesicular stomatitis virus and
      encephalomyocarditis virus. P56 synthesis was rapidly induced by IFN-beta, and
      the protein had a half-life of 6 h. IFN-gamma or poly(A)(+) could not induce the
      protein, but poly(I)-poly(C) or an 85-bp synthetic double-stranded RNA
      efficiently induced it. Similarly, infection of GRE cells, which are devoid of
      type I IFN genes, by vesicular stomatitis virus, encephalomyocarditis virus, or
      Sendai virus caused P56 induction. Surprisingly, Sendai virus could also induce
      P56 in the mutant cell line P2.1, which cannot respond to either IFN-alpha/beta
      or double-stranded RNA. Induction of P56 in the P2.1 cells and the parental U4C
      cells by virus infection was preceded by activation of IRF-3 as judged by its
      translocation to the nucleus from the cytoplasm.

PMID- 10662617
TI  - Effects of oligomerization on the epitopes of the human immunodeficiency virus
      type 1 envelope glycoproteins.
AB  - To understand the differential expression of epitopes on monomeric and oligomeric
      forms of the envelope glycoproteins, nine human monoclonal antibodies (mAbs) were
      derived from the cells of human immunodeficiency virus-infected subjects by
      selection with soluble oligomeric gp140 (o.140). These nine mAbs and 12 human
      mAbs selected with V3 peptides, viral lysates, and rgp120, specific for the V2,
      V3, C5, CD4-binding domain (CD4bd), and gp41, were tested in a binding assay to
      compare the exposure of these regions on monomeric gp120 or gp41 and on o.140.
      None of the 21 mAbs were oligomer specific. However, mAbs to V3 and CD4bd were
      "oligomer sensitive," whereas mAbs to V2 and the distal epitope of C5 tended to
      be "monomer sensitive" (i.e., to react better with the oligomer or monomer,
      respectively). The majority of anti-gp41 mAbs reacted similarly with monomer and
      oligomer. Although the uncleaved o.140 used in this study differs from the
      cleaved gp120/41 oligomer found on the native virus particle, these results
      suggest that new epitopes are not introduced by oligomerization of viral envelope
      proteins, that such oligomer-specific epitopes, if they exist, are not highly
      immunogenic, and/or that they are not efficiently selected using soluble o.140.

PMID- 10662618
TI  - MLV-derived retroviral vectors selective for CD4-expressing cells and resistant
      to neutralization by sera from HIV-infected patients.
AB  - Retroviral vectors derived from amphotropic murine leukemia viruses (MLV) mediate
      gene transfer into almost all human cells and are thus not suitable for in vivo
      applications in gene therapy in which cell-specific gene delivery is required. We
      and others recently reported the generation of MLV-derived vectors pseudotyped by
      variants of the envelope glycoproteins (Env) of human immunodeficiency virus type
      1 (HIV-1), thus displaying the CD4-dependent tropism of the parental lentivirus
      (Mammano et al., 1997, J. Virol. 71, 3341-3345; Schnierle et al., 1997, Proc.
      Natl. Acad. Sci. USA 76, 8640-8645). However, because of their HIV-1-derived
      envelopes these vectors are neutralized by HIV-specific antibodies present in
      some infected patients. To circumvent this problem, we pseudotyped MLV capsid
      particles with variants of Env proteins derived from the apathogenic simian
      immunodeficiency virus (SIVagm) of African green monkeys (AGM; Chlorocebus
      pygerythrus). Truncation of the C-terminal domain of the transmembrane protein
      was found to be necessary to allow formation of infectious pseudotype vectors.
      These [MLV(SIVagm)] vectors efficiently transduced various human CD4-expressing
      cell lines using the coreceptors CCR5 and Bonzo to enter target cells. Moreover,
      they were resistant to neutralization by antibodies directed against HIV-1.
      Therefore, [MLV(SIVagm)] vectors will be useful to study the mechanisms of SIVagm
      cell entry and for the selective gene transfer into CD4+ T-cells of AIDS
      patients.

PMID- 10662619
TI  - Susceptibility of in vitro stimulated PBMC to infection with NSI HIV-1 is
      associated with levels of CCR5 expression and beta-chemokine production.
AB  - Susceptibility of PHA/rIL-2-stimulated PBMC from 14 healthy blood donors for NSI
      HIV-1 infection was analyzed in relation to CCR5 expression and beta-chemokine
      production. After 1 week of culture in the presence of rIL-2, but not at the
      moment of inoculation, CCR5 surface expression was positively and beta-chemokine
      production was inversely associated with susceptibility to NSI HIV-1 infection.
      Surprisingly, no association was observed between CCR5 genotype and in vitro NSI
      HIV-1 susceptibility, which was in agreement with similar levels of CCR5 surface
      expression and beta-chemokine production in CCR5Delta32/+ and CCR5 +/+ PBMC after
      PHA/rIL-2 stimulation. In contrast to what was observed in vitro, CCR5 genotype
      did associate with CCR5 surface expression levels in vivo in resting as well as
      in activated CD4(+) T cell populations that were identified by the expression of
      CD45RO, CD27, HLA-DR, and CD69. The association between CCR5 expression and
      susceptibility to infection by NSI HIV-1 observed in vitro might offer an
      explanation for the in vivo observed protective effect of CCR5 polymorphisms that
      influence CCR5 expression on disease progression.

PMID- 10662620
TI  - Differential expression of the HHV-8 vGCR cellular homolog gene in AIDS
      associated and classic Kaposi's sarcoma: potential role of HIV-1 Tat.
AB  - Human herpesvirus 8 (HHV-8) has been causally linked to Kaposi's sarcoma (KS).
      There is significant homology between some HHV-8 genes and cellular genes
      including D-type cyclin (vCYC), G protein coupled receptor (vGCR), macrophage
      inflammatory proteins (vMIP-I, vMIP-II), bcl-2 (vBCL2), interferon regulatory
      factor-1 (vIRF1), interleukin-6 (vIL6), and complement-binding protein (vCBP). In
      this study, we analyzed expression of these viral homologs and HIV-1 Tat by
      reverse-transcriptase polymerase chain reaction (RT-PCR) coupled with Southern
      blot hybridization in AIDS-KS (AKS) tissue, classic KS tissue(CKS), and
      peripheral blood mononuclear cells, and phorbol ester (TPA)-treated and untreated
      HHV-8 positive lymphoma cells (BCBL1). While vCYC (AKS 6 of 6; CKS 3 of 3), vMIP
      I (AKS 5 of 6, CKS 3 of 3), vBCL2 (AKS 6 of 6; CKS 3 of 3), and vIRF1 (AKS 5 of
      6, CKS 3 of 3) transcripts were detected in both AKS and CKS, vGCR and HIV-1 Tat
      were expressed only in AKS samples (vGCR: AKS 3 of 6, CKS 0 of 3; Tat: AKS 4 of
      6, CKS 0 of 3). vMIPII, vCBP, and vIL6 expression were not detected in any KS
      samples. Since vGCR expression is limited to AKS, it is possible that vGCR is
      activated by HIV-1 Tat. These results suggest that HIV-1 Tat may contribute to
      AKS pathogenesis through the tumorigenic and angiogenic effects of vGCR.

PMID- 10662621
TI  - A novel lipothrixvirus, SIFV, of the extremely thermophilic crenarchaeon
      Sulfolobus.
AB  - We describe a novel lipothrixvirus, SIFV, of the crenarchaeotal archaeon
      Sulfolobus islandicus. SIFV (S. islandicus filamentous virus) has a linear virion
      with a linear double-stranded DNA genome. These two features coincide in several
      crenarchaeotal but not in any other viruses. The SIFV core is formed by a zipper
      like array of DNA-associated protein subunits and is covered by a lipid envelope
      containing host lipids. We sequenced approximately 96% of the virus genome
      excepting the DNA termini, which were modified in an unusual, yet
      uncharacterized, manner. Both, the 5' and the 3' DNA termini were insensitive to
      enzymatic degradation and labelling. Two open reading frames (ORFs) of the SIFV
      genome are likely to encode helicases and resemble uncharacterized ORFs from
      other archaea in sequence. Three ORFs showed sequence similarity with each other
      and each contained a glycosyl transferase motif. Another ORF of the SIFV genome
      showed significant sequence similarity to the ORF a291 from the well
      characterized, spindle-shaped Sulfolobus virus SSV1. Due to its structure, SIFV
      is classified as a lipothrixvirus.

PMID- 10662622
TI  - Cell specificity of the transcription-factor repertoire used by a lentivirus:
      motifs important for expression of equine infectious anemia virus in nonmonocytic
      cells.
AB  - The equine infectious anemia virus (EIAV) long-terminal repeat (LTR) has been
      identified as highly variable, both in infected horses and in cell culture. This
      nucleotide hypervariation is localized to the LTR enhancer region. The EIAV LTR
      has been implicated in controlling both the cell tropism and virulence of the
      virus and it is postulated that the enhancer-region hypervariation may be
      responsible for the LTR effects. Our previous studies have demonstrated that the
      presence of DNA motifs bound by the ets transcription-factor family member PU.1
      are critically important for EIAV expression in equine macrophages. Here we
      identify and characterize the EIAV LTR enhancer motifs PEA-2, Lvb, Oct, and CRE,
      that bind to fibroblast nuclear extracts. Three of these four motifs, PEA-2, Oct,
      and CRE, were determined to be important for expression of the LTR in a
      fibroblast cell line that supports productive infection of EIAV. These motifs
      that are important for expression of the LTR in fibroblasts were found to be
      interdigitated between the PU.1 sites. We hypothesize that the combination of
      motif interdigitation and cell-specific usage of these motifs may be responsible
      for the observed EIAV LTR enhancer-region hypervariation.

PMID- 10662623
TI  - Characterization of the pathogenicity of members of the newly established H9N2
      influenza virus lineages in Asia.
AB  - The reported transmission of avian H9N2 influenza viruses to humans and the
      isolation of these viruses from Hong Kong poultry markets lend urgency to studies
      of their ecology and pathogenicity. We found that H9N2 viruses from North America
      differ from those of Asia. The North American viruses, which infect primarily
      domestic turkeys, replicated poorly in inoculated chickens. Phylogenetic analysis
      of the hemagglutinin and nucleoprotein genes indicated that the Asian H9N2
      influenza viruses could be divided into three sublineages. Initial biological
      characterization of at least one virus from each lineage was done in animals.
      Early isolates of one lineage (A/Chicken/Beijing/1/94, H9N2) caused as high as
      80% mortality rates in inoculated chickens, whereas all other strains were
      nonpathogenic. Sequence analysis showed that some isolates, including the
      pathogenic isolate, had one additional basic amino acid (A-R/K-S-S-R-) at the
      hemagglutinin cleavage site. Later isolates of the same lineage (A/Chicken/Hong
      Kong/G9/97, H9N2) that contains the PB1 and PB2 genes similar to Hong Kong/97
      H5N1 viruses replicated in chickens, ducks, mice, and pigs but were pathogenic
      only in mice. A/Quail/Hong Kong/G1/97 (H9N2), from a second lineage that
      possesses the replicative complex similar to Hong Kong/97 H5N1 virus, replicated
      in chickens and ducks without producing disease signs, was pathogenic in mice,
      and spread to the brain without adaptation. Examples of the third Asian H9N2
      sublineage (A/Chicken/Korea/323/96, Duck/Hong Kong/Y439/97) replicated in
      chickens, ducks, and mice without producing disease signs. The available evidence
      supports the notion of differences in pathogenicity of H9N2 viruses in the
      different lineages and suggests that viruses possessing genome segments similar
      to 1997 H5N1-like viruses are potentially pathogenic in mammals.

PMID- 10662624
TI  - Membrane interaction of influenza virus M1 protein.
AB  - The M1 protein of influenza virus is thought to make contact with the cytoplasmic
      tails of the glycoprotein spikes, lipid molecules in the viral membrane, and the
      internal ribonucleoprotein particles. Here we show electron micrographs of
      negatively stained virus particles in which M1 is visualized as a 60-A-long rod
      that touches the membrane but apparently is not membrane inserted. Photolabeling
      with a membrane restricted reagent resulted in labeling of the transmembrane
      region of haemagglutinin but not of M1, also suggesting that most of M1 is not
      embedded into the hydrophobic core of the viral membrane. Finally, in vitro
      reconstitution experiments using soluble M1 protein and synthetic liposomes or
      Madin-Darby canine kidney cell membranes suggest that M1 can bind to negatively
      charged liposomes and to the cellular membranes and that this binding can be
      prevented under high-salt conditions. Although none of these experiments prove
      that there does not exist a minor fraction of M1 that is membrane inserted, it
      appears that most of M1 in the virus is membrane associated through electrostatic
      interactions.

PMID- 10662625
TI  - Biochemical and physical characterization of parvovirus minute virus of mice
      virus-like particles.
AB  - The VP-2 major capsid protein of the prototype strain of the parvovirus minute
      virus of mice (MVMp) was expressed, using a baculovirus vector, in Sf9 insect
      cells. Immunogold electron microscopy of infected Sf9 cells showed VP-2 localized
      in the nucleus and cytoplasm as is observed in mammalian cells during natural
      infections. The VP-2 subunits self-assembled into empty parvovirus-like particles
      (VLPs), which appeared morphologically similar to and immunogenically
      indistinguishable from native empty MVMp particles, which also contain the minor
      capsid protein, VP1. Incubations under different pH and temperature conditions
      showed that the MVMp VLPs and native empty MVMp capsids share comparable
      stability. Once heated the particles can be similarly and specifically cleaved by
      trypsin at the VP-2 N-terminal domain. This process mimics the further maturation
      of the "rat-like" parvovirus virions, following viral DNA encapsidation,
      indicating that biologically relevant features of the MVMp capsid are maintained
      in the VLPs. Crystals have been obtained for the MVMp VLPs which were isomorphous
      to those used for the high-resolution structure determination of virions and
      native empty particles of the immunosuppressive strain of MVM (MVMi). The VLP
      crystals diffracted X rays to beyond 3-A resolution and are in space group C2 (a
      = 448.7, b = 416.6, c = 306.1 A, and beta = 95.9 degrees ). This is the first
      report of crystals from parvoviral particles produced in a heterologous system
      diffracting X rays to high resolution, indicating that VP-2 of some parvovirus
      capsids can self-assemble into ordered T = 1 icosahedral capsids in the absence
      of other viral and host cell functions.

PMID- 10662626
TI  - "Ambisense" approach for the generation of influenza A virus: vRNA and mRNA
      synthesis from one template.
AB  - We present a system for creating influenza virus by generating viral RNA (vRNA)
      and mRNA from one template. Recently, a system for the generation of influenza A
      virus entirely from cloned cDNAs was established (Neumann et al., 1999, Proc.
      Natl. Acad. Sci. USA 96, 9345-9350). Cells were transfected with plasmids for RNA
      polymerase I-driven intracellular synthesis of all eight viral RNAs, and with
      protein expression plasmids for the synthesis of viral structural proteins.
      Although this system is highly efficient in virus generation, the construction
      and cotransfection of 17 plasmids is cumbersome and may limit the use of this
      system to cell lines that can be transfected with high efficiencies. Synthesizing
      both vRNA and mRNA from one template would reduce the number of plasmids required
      for virus generation. Therefore, we generated a bidirectional transcription
      construct that contains cDNA encoding PB1 flanked by an RNA polymerase I (pol I)
      promoter for vRNA synthesis and an RNA polymerase II (pol II) promoter for mRNA
      synthesis. The utility of this approach is proved by the generation of virus
      after transfecting the pol I/pol II-promoter-PB1 construct together with vRNA-
      and protein-expression constructs for the remaining seven segments. Because this
      approach reduces the number of plasmids required for virus generation, it also
      reduces the work necessary for cloning, probably enhances the efficiency of virus
      generation, and expands the use of the reverse-genetics system to cell lines for
      which efficient cotransfection of 17 plasmids cannot be achieved.

PMID- 10662627
TI  - Pea embryonic tissues show common responses to the replication of a wide range of
      viruses.
AB  - The response of pea embryonic tissues to the replication of a range of different
      viruses was investigated using in situ hybridization to analyze changes in the
      expression of two host genes, heat shock protein 70 (hsp70) and lipoxygenase
      (lox1). Excised pea embryos were infected using microprojectile bombardment with
      a nonseed transmissible strain of Pea seed-borne mosaic potyvirus, or with Pea
      early browning tobravirus (PEBV), White Clover mosaic potexvirus, or Beet curly
      top geminivirus. Collectively, these examples represent families of viruses with
      differing genomic features, differing numbers of genomic components and differing
      replication strategies. In all cases, there was an induction of hsp70 associated
      with virus replication and, in most cases, a downregulation of lox1. Hence,
      either each virus has a direct inducer of these common responses or the induction
      is indirectly the result of a generic feature of virus infection. By exploiting
      the bipartite nature of the PEBV genome, the coat protein gene and genes involved
      in vector transmission were excluded as potential inducers.

PMID- 10662628
TI  - Herpes simplex virus infection blocks events in the G1 phase of the cell cycle.
AB  - Infection of cells in G1 phase with herpes simplex virus (HSV) prevents their
      progression into S phase (de Bruyn Kops, A., and Knipe, D. M., 1988, Cell 55, 857
      868). We have examined G1-phase events in infected cells to determine whether
      this effect was the result of inhibition of G1 phase progression or of entry into
      S phase. We observed that HSV infection decreased pRb phosphorylation and induced
      a new phosphorylated form of pRb. Furthermore, HSV infection prevented the normal
      G1 increases in cyclin D1 and D3 protein levels, and blocked the normal G1
      appearance of new electrophoretic forms of cdk2 and cdk4. Thus, HSV infection
      inhibits several events that normally occur in the cell cycle during G1 phase,
      arguing that the HSV-induced block in the cell cycle occurs in early to mid-G1
      phase.

PMID- 10662629
TI  - Herpes simplex virus type 1 infection imposes a G(1)/S block in asynchronously
      growing cells and prevents G(1) entry in quiescent cells.
AB  - Herpes simplex virus type 1 (HSV-1) infection disrupted cell cycle regulation in
      at least two ways. First, infection of quiescent human embryonic lung cells
      simultaneously with readdition of serum caused inhibition of cyclin D/cyclin
      dependent kinase (CDK) 4,6-specific and cyclin E/CDK2-specific phosphorylation of
      the retinoblastoma protein pRb. The inhibition of cyclin D/CDK4,6 kinase activity
      corresponded to a loss of cyclin D1 protein and a failure of CDK4 and CDK6 to
      translocate to the nucleus. Failure to detect cyclin E/CDK2 kinase activity was
      accompanied by a loss of cyclin E protein and a failure of CDK2 to translocate to
      the nucleus. Levels of pocket protein p130 persisted, whereas p107 did not
      accumulate. As a result of these effects on cyclin kinase, G(0)-infected cells
      failed to reenter the cell cycle. The second type of HSV-induced cell cycle
      dysregulation was observed in asynchronously dividing cell cultures. A rapid
      inhibition of preexisting cyclin E/CDK2 and cyclin A/CDK2 activities was observed
      in human embryonic lung cells, as well as two other human cell lines: C33 and
      U2OS. HSV-1 immediate-early gene expression was necessary for the inhibition of
      CDK2 kinase activity. Cyclin and CDK subunit protein levels, intracellular
      localization, and complex stability were unaffected by infection. In addition,
      levels of cyclin-dependent kinase inhibitors, p27 and p21, were not affected by
      HSV-1. Previous experiments demonstrated that in asynchronous infected cells,
      hypophosphorylated pRb and pocket protein-E2F complexes accumulated, and cellular
      DNA synthesis was rapidly inhibited. Coupled with the present results, this
      indicates that HSV-1 has evolved mechanisms for preventing cells in G(1) from
      proceeding through the restriction point and for cells in S from completing a
      round of DNA replication.

PMID- 10662630
TI  - The complete cDNA sequence of a type II Trichomonas vaginalis virus.
AB  - Trichomonas vaginalis viruses (TVV), which may regulate P270 gene expression in
      the protozoan pathogen T. vaginalis, are a group of divergent double-stranded
      (ds) RNA viruses. In the present study, the complete 4674-bp cDNA sequence of a
      4.6-kb ds RNA from a newly identified TVV2-1 isolate was determined. The sequence
      of the plus-strand mRNA contains four open reading frames, which encode
      overlapping cap and pol genes in the reading frame 2 and reading frame 1,
      respectively, and two putative serine-threonine-rich basic proteins VP3 and VP4
      in the third reading frame. An 85-kDa capsid protein and a 160-kDa CAP-POL fusion
      protein were identified in crude viruses by Western blotting experiments using
      antisera raised against gene-specific oligopeptides. In conjunction with the
      presence of a potential ribosomal slippery heptanucleotide G GGC CCC within the
      overlap of the cap and pol genes, these observations suggest that the pol gene of
      TVV2-1 is translated via a -1 ribosomal frameshifting event during translation of
      the cap gene. Our results also provide insight into the conservation among
      divergent dsRNA species from TVV and suggest that the genome of TVV2-1 may encode
      two extra genes in addition to the cap and pol genes.

PMID- 10662631
TI  - Replication of heterologous combinations of helper and defective RNA of citrus
      tristeza virus.
AB  - Citrus tristeza virus (CTV) populations are among the more complex of plant RNA
      viruses with unusual mixtures of strains and defective RNAs (dRNAs). Citrus
      plants infected with different CTV isolates contain multiple dRNA molecules that
      differ in size and relative abundance within and between isolates. Additionally,
      we found mixtures of heterologous dRNAs in populations. To examine the
      replication of CTV dRNAs, the protoplast system had to be extended to support
      helper-assisted amplification of input dRNAs. The use of freshly extracted sap of
      CTV-infected tissue as inoculum increased the infection of Nicotiana benthamiana
      protoplasts sufficiently to result in accumulation of high levels of CTV RNAs as
      well as dRNAs within 2 or 3 days postinoculation. A series of dRNA-like
      molecules, each with a single large internal deletion, were created from an
      infectious cDNA clone of the CTV T36 isolate and examined for amplification in N.
      benthamiana protoplasts using a CTV deletion mutant as the helper virus. Of 12
      synthetic dRNAs, only three with sizes of 3650, 3819, and 4460 nucleotides were
      efficiently replicated. CTV dRNA replication did not appreciably affect levels of
      accumulation of the genomic or the subgenomic RNAs of the helper virus. To
      investigate the maintenance of dRNAs in CTV populations, we examined heterologous
      interactions between dRNAs and helper viruses. Wild-type populations of
      heterologous strains T68 and T3, as well as the homologous T36, supported
      replication of synthetic T36 dRNAs. Replacement in the T36 dRNA of the 5' region,
      which is most variable among CTV strains, with the corresponding sequences from
      VT, T68, T3, or T30 resulted in chimeric dRNAs that failed to be replicated by
      the T36 helpers but were replicated to detectable levels by the T68 helper. The
      differential specificities of different CTV replicase complexes with dRNA
      replication signals is one possible factor that affects the maintenance of dRNA
      population structures.

PMID- 10662632
TI  - Nodal signaling patterns the organizer.
AB  - Spemann's organizer plays an essential role in patterning the vertebrate embryo.
      During gastrulation, organizer cells involute and form the prechordal plate
      anteriorly and the notochord more posteriorly. The fate mapping and gene
      expression analyses in zebrafish presented in this study reveal that this
      anteroposterior polarity is already initiated in the organizer before
      gastrulation. Prechordal plate progenitors reside close to the blastoderm margin
      and express the homeobox gene goosecoid, whereas notochord precursors are located
      further from the margin and express the homeobox gene floating head. The nodal
      related genes cyclops and squint are expressed at the blastoderm margin and are
      required for prechordal plate and notochord formation. We show that differential
      activation of the Nodal signaling pathway is essential in establishing
      anteroposterior pattern in the organizer. First, overexpression of cyclops and
      squint at different doses leads to the induction of floating head at low doses
      and the induction of both goosecoid and floating head at higher doses. Second,
      decreasing Nodal signaling using different concentrations of the antagonist
      Antivin inhibits goosecoid expression at low doses and blocks expression of both
      goosecoid and floating head at higher doses. Third, attenuation of Nodal
      signaling in zygotic mutants for the EGF-CFC gene one-eyed pinhead, an essential
      cofactor for Nodal signaling, leads to the loss of goosecoid expression and
      expansion of floating head expression in the organizer. Concomitantly, cells
      normally fated to become prechordal plate are transformed into notochord
      progenitors. Finally, activation of Nodal signaling at different times suggests
      that prechordal plate specification requires sustained Nodal signaling, whereas
      transient signaling is sufficient for notochord development. Together, these
      results indicate that differential Nodal signaling patterns the organizer before
      gastrulation, with the highest level of activity required for anterior fates and
      lower activity essential for posterior fates.

PMID- 10662633
TI  - Roles of Hoxa1 and Hoxa2 in patterning the early hindbrain of the mouse.
AB  - Early in its development, the vertebrate hindbrain is transiently subdivided into
      a series of compartments called rhombomeres. Genes have been identified whose
      expression patterns distinguish these cellular compartments. Two of these genes,
      Hoxa1 and Hoxa2, have been shown to be required for proper patterning of the
      early mouse hindbrain and the associated neural crest. To determine the extent to
      which these two genes function together to pattern the hindbrain, we generated
      mice simultaneously mutant at both loci. The hindbrain patterning defects were
      analyzed in embryos individually mutant for Hoxa1 and Hoxa2 in greater detail and
      extended to embryos mutant for both genes. From these data a model is proposed to
      describe how Hoxa1, Hoxa2, Hoxb1, Krox20 (Egr2) and kreisler function together to
      pattern the early mouse hindbrain. Critical to the model is the demonstration
      that Hoxa1 activity is required to set the anterior limit of Hoxb1 expression at
      the presumptive r3/4 rhombomere boundary. Failure to express Hoxb1 to this
      boundary in Hoxa1 mutant embryos initiates a cascade of gene misexpressions that
      result in misspecification of the hindbrain compartments from r2 through r5.
      Subsequent to misspecification of the hindbrain compartments, ectopic induction
      of apoptosis appears to be used to regulate the aberrant size of the misspecified
      rhombomeres.

PMID- 10662634
TI  - Different roles for Pax6 in the optic vesicle and facial epithelium mediate early
      morphogenesis of the murine eye.
AB  - Chimaeric mice were made by aggregating Pax6(-/-) and wild-type mouse embryos, in
      order to study the interaction between the optic vesicle and the prospective lens
      epithelium during early stages of eye development. Histological analysis of the
      distribution of homozygous mutant cells in the chimaeras showed that the cell
      autonomous removal of Pax6(-/-) cells from the lens, shown previously at E12.5,
      is nearly complete by E9.5. Most mutant cells are eliminated from an area of
      facial epithelium wider than, but including, the developing lens placode. This
      result suggests a role for Pax6 in maintaining a region of the facial epithelium
      that has the tissue competence to undergo lens differentiation. Segregation of
      wild-type and Pax6(-/-) cells occurs in the optic vesicle at E9.5 and is most
      likely a result of different adhesive properties of wild-type and mutant cells.
      Also, proximo-distal specification of the optic vesicle (as assayed by the
      elimination of Pax6(-/-) cells distally), is disrupted in the presence of a high
      proportion of mutant cells. This suggests that Pax6 operates during the
      establishment of patterning along the proximo-distal axis of the vesicle.
      Examination of chimaeras with a high proportion of mutant cells showed that Pax6
      is required in the optic vesicle for maintenance of contact with the overlying
      lens epithelium. This may explain why Pax6(-/-) optic vesicles are inefficient at
      inducing a lens placode. Contact is preferentially maintained when the lens
      epithelium is also wild-type. Together, these results demonstrate requirements
      for functional Pax6 in both the optic vesicle and surface epithelia in order to
      mediate the interactions between the two tissues during the earliest stages of
      eye development.

PMID- 10662635
TI  - Equivalent genetic roles for bmp7/snailhouse and bmp2b/swirl in dorsoventral
      pattern formation.
AB  - A bone morphogenetic protein (BMP) signaling pathway acts in the establishment of
      the dorsoventral axis of the vertebrate embryo. Here we demonstrate the genetic
      requirement for two different Bmp ligand subclass genes for dorsoventral pattern
      formation of the zebrafish embryo. From the relative efficiencies observed in Bmp
      ligand rescue experiments, conserved chromosomal synteny, and isolation of the
      zebrafish bmp7 gene, we determined that the strongly dorsalized snailhouse mutant
      phenotype is caused by a mutation in the bmp7 gene. We show that the original
      snailhouse allele is a hypomorphic mutation and we identify a snailhouse/bmp7
      null mutant. We demonstrate that the snailhouse/bmp7 null mutant phenotype is
      identical to the presumptive null mutant phenotype of the strongest dorsalized
      zebrafish mutant swirl/bmp2b, revealing equivalent genetic roles for these two
      Bmp ligands. Double mutant snailhouse/bmp7; swirl/bmp2b embryos do not exhibit
      additional or stronger dorsalized phenotypes, indicating that these Bmp ligands
      do not function redundantly in early embryonic development. Furthermore,
      overexpression experiments reveal that Bmp2b and Bmp7 synergize in the
      ventralization of wild-type embryos through a cell-autonomous mechanism,
      suggesting that Bmp2b/Bmp7 heterodimers may act in vivo to specify ventral cell
      fates in the zebrafish embryo.

PMID- 10662636
TI  - GAP-43 mediates retinal axon interaction with lateral diencephalon cells during
      optic tract formation.
AB  - GAP-43 is an abundant intracellular growth cone protein that can serve as a PKC
      substrate and regulate calmodulin availability. In mice with targeted disruption
      of the GAP-43 gene, retinal ganglion cell (RGC) axons fail to progress normally
      from the optic chiasm into the optic tracts. The underlying cause is unknown but,
      in principle, can result from either the disruption of guidance mechanisms that
      mediate axon exit from the midline chiasm region or defects in growth cone
      signaling required for entry into the lateral diencephalic wall to form the optic
      tracts. Results here show that, compared to wild-type RGC axons, GAP-43-deficient
      axons exhibit reduced growth in the presence of lateral diencephalon cell
      membranes. Reduced growth is not observed when GAP-43-deficient axons are
      cultured with optic chiasm, cortical, or dorsal midbrain cells. Lateral
      diencephalon cell conditioned medium inhibits growth of both wild-type and GAP-43
      deficient axons to a similar extent and does not affect GAP-43-deficient axons
      more so. Removal or transplant replacement of the lateral diencephalon optic
      tract entry zone in GAP-43-deficient embryo preparations results in robust RGC
      axon exit from the chiasm. Together these data show that RGC axon exit from the
      midline region does not require GAP-43 function. Instead, GAP-43 appears to
      mediate RGC axon interaction with guidance cues in the lateral diencephalic wall,
      suggesting possible involvement of PKC and calmodulin signaling during optic
      tract formation.

PMID- 10662637
TI  - BMPs are necessary for stomach gland formation in the chicken embryo: a study
      using virally induced BMP-2 and Noggin expression.
AB  - Epithelial-mesenchymal interactions are necessary for the normal development of
      various digestive organs. In chicken proventriculus (glandular stomach),
      morphogenesis and differentiation of the epithelium depend upon the inductive
      signals coming from underlying mesenchyme. However, the nature of such signals is
      still unclear despite extensive analyses carried out using experimental tissue
      recombinations. In this study we have examined the possible involvement of bone
      morphogenetic proteins (BMPs) in the formation of stomach glands in the chicken
      embryo. Analysis of the expression patterns of BMP-2, -4 and -7 showed that these
      BMPs were present in the proventricular mesenchyme prior to the initiation of the
      proventricular gland formation. BMP-2 expression, in particular, was restricted
      to the proventriculus among anterior digestive organs. Virus-mediated BMP-2
      overexpression resulted in an increase in the number of glands formed. Moreover,
      ectopic expression of Noggin, which antagonizes the effect of BMPs, in the
      proventricular mesenchyme or epithelium, led to the complete inhibition of gland
      formation, indicating that BMP signals are necessary for the proventricular gland
      formation. These findings suggest that BMPs are of prime importance as
      mesenchymal signals for inducing proventricular glands.

PMID- 10662638
TI  - Normal limb development in conditional mutants of Fgf4.
AB  - Fibroblast growth factors (FGFs) mediate multiple developmental signals in
      vertebrates. Several of these factors are expressed in limb bud structures that
      direct patterning of the limb. FGF4 is produced in the apical ectodermal ridge
      (AER) where it is hypothesized to provide mitogenic and morphogenic signals to
      the underlying mesenchyme that regulate normal limb development. Mutation of this
      gene in the germline of mice results in early embryonic lethality, preventing
      subsequent evaluation of Fgf4 function in the AER. A conditional mutant of Fgf4,
      based on site-specific Cre/loxP-mediated excision of the gene, allowed us to
      bypass embryonic lethality and directly test the role of FGF4 during limb
      development in living murine embryos. This conditional mutation was designed so
      that concomitant with inactivation of the Fgf4 gene by excision of all Fgf4
      coding sequences, a reporter gene was activated in Fgf4-expressing cells,
      allowing assessment of the site-specific recombination reaction. Although a large
      body of evidence led us to predict that ablation of Fgf4 gene function in the AER
      of developing mice would result in abnormal limb outgrowth and patterning, we
      found that Fgf4 conditional mutants had normal limbs. Furthermore, expression
      patterns of Shh, Bmp2, Fgf8 and Fgf10 were normal in the limb buds of the
      conditional mutants. These findings indicate that the previously proposed FGF4
      SHH feedback loop is not essential for coordination of murine limb outgrowth and
      patterning. We suggest that some of the roles currently attributed to FGF4 during
      early vertebrate limb development may be performed by other AER factors in vivo.

PMID- 10662639
TI  - A novel neuropeptide, Hym-355, positively regulates neuron differentiation in
      Hydra.
AB  - During the course of a systematic screening of peptide signaling molecules in
      Hydra a novel peptide, Hym-355 (FPQSFLPRG-NH(2)), was identified. A cDNA encoding
      the peptide was isolated and characterized. Using both in situ hybridization and
      immunohistochemistry, Hym-355 was shown to be expressed in neurons and hence is a
      neuropeptide. The peptide was shown to specifically enhance neuron
      differentiation throughout the animal by inducing interstitial cells to enter the
      neuron pathway. Further, co-treatment with a PW peptide, which inhibits neuron
      differentiation, nullified the effects of both peptides, suggesting that they act
      in an antagonistic manner. This effect is discussed in terms of a feedback
      mechanism for maintaining the steady state neuron population in Hydra.

PMID- 10662640
TI  - pannier acts upstream of wingless to direct dorsal eye disc development in
      Drosophila.
AB  - The dorsoventral midline of the Drosophila eye disc is a source of signals that
      stimulate growth of the eye disc, define the point at which differentiation
      initiates, and direct ommatidial rotation in opposite directions in the two
      halves of the eye disc. This boundary region seems to be established by the genes
      of the iroquois complex, which are expressed in the dorsal half of the disc and
      inhibit fringe expression there. Fringe controls the activation of Notch and the
      expression of its ligands, with the result that Notch is activated only at the
      fringe expression boundary at the midline. The secreted protein Wingless
      activates the dorsal expression of the iroquois genes. We show here that pannier,
      which encodes a GATA family transcription factor expressed at the dorsal margin
      of the eye disc from embryonic stages on, acts upstream of wingless to control
      mirror and fringe expression and establish the dorsoventral boundary. Loss of
      pannier function leads to the formation of an ectopic eye field and the
      reorganization of ommatidial polarity, and ubiquitous pannier expression can
      abolish the eye field. Pannier is thus the most upstream element yet described in
      dorsoventral patterning of the eye disc.

PMID- 10662641
TI  - Pax2 and homeodomain proteins cooperatively regulate a 435 bp enhancer of the
      mouse Pax5 gene at the midbrain-hindbrain boundary.
AB  - Pax and homeodomain transcription factors are essential for the formation of an
      organizing center at the midbrain-hindbrain boundary (mhb) which controls the
      genesis of the midbrain and cerebellum in the vertebrate embryo. Pax2 and Pax5
      are sequentially activated in this brain region, with Pax2 expression preceding
      that of Pax5. Using a transgenic reporter assay, we have now identified a
      conserved 435 bp enhancer in the 5' flanking region of mammalian Pax5 genes which
      directs lacZ expression in the correct temporal and spatial pattern at the mhb.
      This minimal enhancer is composed of two distinct elements, as shown by protein
      binding assays with mhb-specific extracts. The proximal element contains
      overlapping consensus binding sites for members of the Pax2/5/8 and POU protein
      families, whereas a distal element is bound by homeodomain and zinc finger
      transcription factors. Expression analysis of transgenes carrying specific
      mutations in these recognition motifs identified the Pax- and homeodomain-binding
      sites as functional elements which cooperatively control the activity of the mhb
      enhancer. lacZ genes under the control of either the minimal enhancer or the
      endogenous Pax5 locus were normally expressed at the mhb in Pax5 mutant embryos,
      indicating that this enhancer does not depend on autoregulation by Pax5. In Pax2
      mutant embryos, expression of the endogenous Pax5 gene was, however, delayed and
      severely reduced in lateral aspects of the neural plate which, on neural tube
      closure, becomes the dorsal mhb region. This cross-regulation by Pax2 is mediated
      by the Pax-binding site of the minimal enhancer which, upon specific mutation,
      resulted in severely reduced transgene expression in the dorsal part of the mhb.
      Together these data indicate that Pax2 and homeodomain proteins directly bind to
      and cooperatively regulate the mhb enhancer of Pax5.

PMID- 10662642
TI  - Winged helix transcription factor Foxb1 is essential for access of
      mammillothalamic axons to the thalamus.
AB  - Our aim was to study the mechanisms of brain histogenesis. As a model, we have
      used the role of winged helix transcription factor gene Foxb1 in the emergence of
      a very specific morphological trait of the diencephalon, the mammillary axonal
      complex. Foxb1 is expressed in a large hypothalamic neuronal group (the
      mammillary body), which gives origin to a major axonal bundle with branches to
      thalamus, tectum and tegmentum. We have generated mice carrying a targeted
      mutation of Foxb1 plus the tau-lacZ reporter. In these mutants, a subpopulation
      of dorsal thalamic ventricular cells "thalamic palisade" show abnormal
      persistence of Foxb1 transcriptional activity; the thalamic branch of the
      mammillary axonal complex is not able to grow past these cells and enter the
      thalamus. The other two branches of the mammillary axonal complex (to tectum and
      tegmentum) are unaffected by the mutation. Most of the neurons that originate the
      mammillothalamic axons suffer apoptosis after navigational failure. Analysis of
      chimeric brains with wild-type and Foxb1 mutant cells suggests that correct
      expression of Foxb1 in the thalamic palisade is sufficient to rescue the normal
      phenotype. Our results indicate that Foxb1 is essential for diencephalic
      histogenesis and that it exerts its effects by controlling access to the target
      by one particular axonal branch.

PMID- 10662643
TI  - Functional conservation of atonal and Math1 in the CNS and PNS.
AB  - To determine the extent to which atonal and its mouse homolog Math1 exhibit
      functional conservation, we inserted (beta)-galactosidase (lacZ) into the Math1
      locus and analyzed its expression, evaluated consequences of loss of Math1
      function, and expressed Math1 in atonal mutant flies. lacZ under the control of
      Math1 regulatory elements duplicated the previously known expression pattern of
      Math1 in the CNS (i.e., the neural tube, dorsal spinal cord, brainstem, and
      cerebellar external granule neurons) but also revealed new sites of expression:
      PNS mechanoreceptors (inner ear hair cells and Merkel cells) and articular
      chondrocytes. Expressing Math1 induced ectopic chordotonal organs (CHOs) in wild
      type flies and partially rescued CHO loss in atonal mutant embryos. These data
      demonstrate that both the mouse and fly homologs encode lineage identity
      information and, more interestingly, that some of the cells dependent on this
      information serve similar mechanoreceptor functions.

PMID- 10662644
TI  - The lefty-related factor Xatv acts as a feedback inhibitor of nodal signaling in
      mesoderm induction and L-R axis development in xenopus.
AB  - In mouse, lefty genes play critical roles in the left-right (L-R) axis
      determination pathway. Here, we characterize the Xenopus lefty-related factor
      antivin (Xatv). Xatv expression is first observed in the marginal zone early
      during gastrulation, later becoming restricted to axial tissues. During tailbud
      stages, axial expression resolves to the neural tube floorplate, hypochord, and
      (transiently) the notochord anlage, and is joined by dynamic expression in the
      left lateral plate mesoderm (LPM) and left dorsal endoderm. An emerging paradigm
      in embryonic patterning is that secreted antagonists regulate the activity of
      intercellular signaling factors, thereby modulating cell fate specification. Xatv
      expression is rapidly induced by dorsoanterior-type mesoderm inducers such as
      activin or Xnr2. Xatv is not an inducer itself, but antagonizes both Xnr2 and
      activin. Together with its expression pattern, this suggests that Xatv functions
      during gastrulation in a negative feedback loop with Xnrs to affect the amount
      and/or character of mesoderm induced. Our data also provide insights into the way
      that lefty/nodal signals interact in the initiation of differential L-R
      morphogenesis. Right-sided misexpression of Xnr1 (endogenously expressed in the
      left LPM) induces bilateral Xatv expression. Left-sided Xatv overexpression
      suppresses Xnr1/XPitx2 expression in the left LPM, and leads to severely
      disturbed visceral asymmetry, suggesting that active 'left' signals are critical
      for L-R axis determination in frog embryos. We propose that the induction of
      lefty/Xatv in the left LPM by nodal/Xnr1 provides an efficient self-regulating
      mechanism to downregulate nodal/Xnr1 expression and ensure a transient 'left'
      signal within the embryo.

PMID- 10662645
TI  - Control of oskar mRNA translation by Bruno in a novel cell-free system from
      Drosophila ovaries.
AB  - The coupled regulation of oskar mRNA localization and translation in time and
      space is critical for correct anteroposterior patterning of the Drosophila
      embryo. Localization-dependent translation of oskar mRNA, a mechanism whereby
      oskar RNA localized at the posterior of the oocyte is selectively translated and
      the unlocalized RNA remains in a translationally repressed state, ensures that
      Oskar activity is present exclusively at the posterior pole. Genetic experiments
      indicate that translational repression involves the binding of Bruno protein to
      multiple sites, the Bruno Response Elements (BRE), in the 3' untranslated region
      (UTR) of oskar mRNA. We have established a cell-free translation system derived
      from Drosophila ovaries, which faithfully reproduces critical features of mRNA
      translation in vivo, namely cap structure and poly(A) tail dependence. We show
      that this ovary extract, containing endogenous Bruno, is able to recapitulate
      oskar mRNA regulation in a BRE-dependent way. Thus, the assembly of a
      ribonucleoprotein (RNP) complex leading to the translationally repressed state
      occurs in vitro. Moreover, we show that a Drosophila embryo extract lacking Bruno
      efficiently translates oskar mRNA. Addition of recombinant Bruno to this extract
      establishes the repressed state in a BRE-dependent manner, providing a direct
      biochemical demonstration of the critical role of Bruno in oskar mRNA
      translation. The approach that we describe opens new avenues to investigate
      translational regulation in Drosophila oogenesis at a biochemical level.

PMID- 10662646
TI  - Caenorhabditis elegans homologue of the human azoospermia factor DAZ is required
      for oogenesis but not for spermatogenesis.
AB  - DAZ (Deleted in Azoospermia), the putative azoospermia factor gene in human,
      encodes a ribonucleoprotein-type RNA-binding protein required for
      spermatogenesis. A Drosophila homologue of DAZ, called boule, is also essential
      for spermatogenesis. A mouse homologue, Dazla, is implicated in both
      spermatogenesis and oogenesis. Here, we report the identification and
      characterization of daz-1, the single DAZ homologue in the nematode
      Caenorhabditis elegans. Loss of daz-1 function caused sterility in
      hermaphrodites, by blocking oogenesis at the pachytene stage of meiosis I.
      Epistasis analysis suggested that this gene executes its function succeeding gld
      1, which governs the early pachytene stage in the oogenic pathway.
      Spermatogenesis did not appear to be affected in daz-1 hermaphrodites. Males
      defective in daz-1 produced sperm fully competent in fertilization. Analysis
      employing sex-determination mutants indicated that the daz-1 function was
      required for meiosis of female germline regardless of the sex of the soma.
      Transcription of daz-1 was restricted to the germline, starting prior to the
      onset of meiosis and was most conspicuous in cells undergoing oogenesis. Thus,
      daz-1 in C. elegans is an essential factor for female meiosis but, unlike other
      DAZ family members so far reported, it is dispensable for male meiosis.

PMID- 10662647
TI  - Mesendoderm and left-right brain, heart and gut development are differentially
      regulated by pitx2 isoforms.
AB  - The pitx2 gene is a member of the bicoid-homeodomain class of transcription
      factors that has been implicated in the control of left-right asymmetry during
      organogenesis. Here we demonstrate that in zebrafish there are two pitx2
      isoforms, pitx2a and pitx2c, which show distinct expression patterns and have non
      overlapping functions during mesendoderm and asymmetric organ development. pitx2c
      is expressed symmetrically in presumptive mesendoderm during late blastula stages
      and in the prechordal plate during late gastrulation. pitx2a expression is first
      detected at bud stage in the anterior prechordal plate. The regulation of early
      mesendoderm pitx2c expression is dependent on one-eyed pinhead (EGF-CFC-related
      gene) and spadetail (tbx-transcription factor) and can be induced by ectopic
      goosecoid expression. Maintenance of pitx2c midline expression is dependent on
      cyclops (nodal) and schmalspur, but not no tail (brachyury). Ectopic expression
      of pitx2 isoforms results in distinct morphological and molecular phenotypes,
      indicating that pitx2a and pitx2c have divergent regulatory functions. Both
      isoforms downregulate goosecoid on the dorsal side, but in contrast to earlier
      reports that nodal and lefty are upstream of pitx2, ectopic pitx2c in other
      regions induces cyclops, lefty2 and goosecoid expression. Asymmetric isoform
      expression occurs in non-overlapping domains, with pitx2c in left dorsal
      diencephalon and developing gut and pitx2a in left heart primordium. Targeted
      asymmetric expression in Xenopus shows that both isoforms can alter left-right
      development, but pitx2a has a slightly stronger effect on heart laterality. Our
      results indicate that distinct genetic pathways regulate pitx2a and pitx2c
      isoform expression, and each isoform regulates different downstream pathways
      during mesendoderm and asymmetric organ development.

PMID- 10662648
TI  - BMP signaling is essential for development of skeletogenic and neurogenic cranial
      neural crest.
AB  - BMP signaling is essential for a wide variety of developmental processes. To
      evaluate the role of Bmp2/4 in cranial neural crest (CNC) formation or
      differentiation after its migration into the branchial arches, we used Xnoggin to
      block their activities in specific areas of the CNC in transgenic mice. This
      resulted in depletion of CNC cells from the targeted areas. As a consequence, the
      branchial arches normally populated by the affected neural crest cells were
      hypomorphic and their skeletal and neural derivatives failed to develop. In
      further analyses, we have identified Bmp2 as the factor required for production
      of migratory cranial neural crest. Its spatial and temporal expression patterns
      mirror CNC emergence and Bmp2 mutant embryos lack both branchial arches and
      detectable migratory CNC cells. Our results provide functional evidence for an
      essential role of BMP signaling in CNC development.

PMID- 10662649
TI  - A BMP pathway regulates cell fate allocation along the sea urchin animal-vegetal
      embryonic axis.
AB  - To examine whether a BMP signaling pathway functions in specification of cell
      fates in sea urchin embryos, we have cloned sea urchin BMP2/4, analyzed its
      expression in time and space in developing embryos and assayed the developmental
      consequences of changing its concentration through mRNA injection experiments.
      These studies show that BMP4 mRNAs accumulate transiently during blastula stages,
      beginning around the 200-cell stage, 14 hours postfertilization. Soon after the
      hatching blastula stage, BMP2/4 transcripts can be detected in presumptive
      ectoderm, where they are enriched on the oral side. Injection of BMP2/4 mRNA at
      the one-cell stage causes a dose-dependent suppression of commitment of cells to
      vegetal fates and ectoderm differentiates almost exclusively as a squamous
      epithelial tissue. In contrast, NOGGIN, an antagonist of BMP2/4, enhances
      differentiation of endoderm, a vegetal tissue, and promotes differentiation of
      cells characteristic of the ciliated band, which contains neurogenic ectoderm.
      These findings support a model in which the balance of BMP2/4 signals produced by
      animal cell progeny and opposing vegetalizing signals sent during cleavage stages
      regulate the position of the ectoderm/ endoderm boundary. In addition, BMP2/4
      levels influence the decision within ectoderm between epidermal and nonepidermal
      differentiation.

PMID- 10662650
TI  - Barbu: an E(spl) m4/m(alpha)-related gene that antagonizes Notch signaling and is
      required for the establishment of ommatidial polarity.
AB  - The Notch signaling pathway is required, in concert with cell-type-specific
      transcriptional regulators and other signaling processes, for multiple cell fate
      decisions during mesodermal and ectodermal tissue development. In many instances,
      Notch signaling occurs initially in a bidirectional manner and then becomes
      unidirectional upon amplification of small inherent differences in signaling
      activity between neighboring cells. In addition to ligands and extracellular
      modulators of the Notch receptor, several intracellular proteins have been
      identified that can positively or negatively influence the activity of the Notch
      pathway during these dynamic processes. Here, we describe a new gene, Barbu,
      whose product can antagonize Notch signaling activity during Drosophila
      development. Barbu encodes a small and largely cytoplasmic protein with sequence
      similarity to the proteins encoded by the transcription units m4 and m(alpha) of
      the E(spl) complex. Ectopic expression studies with Barbu provide evidence that
      Barbu can antagonize Notch during lateral inhibition processes in the embryonic
      mesoderm, sensory organ specification in imaginal discs and cell type
      specification in developing ommatidia. Barbu loss-of-function mutations cause
      lethality and disrupt the establishment of planar polarity and photoreceptor
      specification in eye imaginal discs, which may also be a consequence of altered
      Notch signaling activities. Furthermore, in the embryonic neuroectoderm, Barbu
      expression is inducible by activated Notch. Taken together, we propose that Barbu
      functions in a negative feed-back loop, which may be important for the accurate
      adjustment of Notch signaling activity and the extinction of Notch activity
      between successive rounds of signaling events.

PMID- 10662651
TI  - Control of chick tectum territory along dorsoventral axis by Sonic hedgehog.
AB  - Chick midbrain comprises two major components along the dorsoventral axis, the
      tectum and the tegmentum. The alar plate differentiates into the optic tectum,
      while the basal plate gives rise to the tegmentum. It is largely unknown how the
      differences between these two structures are molecularly controlled during the
      midbrain development. The secreted protein Sonic hedgehog (Shh) produced in the
      notochord and floor plate induces differentiation of ventral cell types of the
      central nervous system. To evaluate the role of Shh in the establishment of
      dorsoventral polarity in the developing midbrain, we have ectopically expressed
      Shh unilaterally in the brain vesicles including whole midbrain of E1.5 chick
      embryos in ovo. Ectopic Shh repressed normal growth of the tectum, producing
      dorsally enlarged tegmentum region. In addition, the expression of several genes
      crucial for tectum formation was strongly suppressed in the midbrain and isthmus.
      Markers for midbrain roof plate were inhibited, indicating that the roof plate
      was not fully generated. After E5, the tectum territory of Shh-transfected side
      was significantly reduced and was fused with that of untransfected side.
      Moreover, ectopic Shh induced a considerable number of SC1-positive motor
      neurons, overlapping markers such as HNF-3(beta) (floor plate), Isl-1
      (postmitotic motor neuron) and Lim1/2. Dopaminergic and serotonergic neurons were
      also generated in the dorsally extended region. These changes indicate that
      ectopic Shh changed the fate of the mesencephalic alar plate to that of the basal
      plate, suppressing the massive cell proliferation that normally occurs in the
      developing tectum. Taken together our results suggest that Shh signaling
      restricts the tectum territory by controlling the molecular cascade for tectum
      formation along dorsoventral axis and by regulating neuronal cell diversity in
      the ventral midbrain.

PMID- 10662652
TI  - Ca(2+) oscillations induced by a cytosolic sperm protein factor are mediated by a
      maternal machinery that functions only once in mammalian eggs.
AB  - At fertilization in mammals, the sperm activates the egg by inducing a series of
      oscillations in the intracellular free Ca(2+) concentration. There is evidence
      showing that this oscillatory event is triggered by a sperm-derived protein
      factor which diffuses into egg cytoplasm after gamete membrane fusion. At present
      the identity of this factor and its precise mechanism of action is unknown. Here,
      we studied the specificity of action of the sperm factor in triggering Ca(2+)
      oscillations in mammalian eggs. In doing so, we examined the patterns of Ca(2+)
      signaling in mouse eggs, zygotes, parthenogenetic eggs and maturing oocytes
      following the stimulation of bovine sperm extracts which contain the sperm
      factor. It is observed that the sperm factor could induce Ca(2+) oscillations in
      metaphase eggs, maturing oocytes and parthenogenetically activated eggs but not
      in the zygotes. We present evidence that Ca(2+) oscillations induced by the sperm
      factor require a maternal machinery. This machinery functions only once in
      mammalian oocytes and eggs, and is inactivated by sperm-derived components but
      not by parthenogenetic activation. In addition, it is found that neither InsP(3)
      receptor sensitivity to InsP(3) nor Ca(2+) pool size are the determinants that
      cause the fertilized egg to lose its ability to generate sperm-factor-induced
      Ca(2+) oscillations at metaphase. In conclusion, our study suggests that the
      orderly sequence of Ca(2+) oscillations in mammalian eggs at fertilization is
      critically dependent upon the presence of a functional maternal machinery that
      determines whether the sperm-factor-induced Ca(2+) oscillations can persist.

PMID- 10662653
TI  - Safety helmets.

PMID- 10662654
TI  - Bitter and twisted.

PMID- 10662655
TI  - The Whitehead Institute for Biomedical Research.

PMID- 10662656
TI  - Muscle bound.

PMID- 10662657
TI  - Cycling lipids.
AB  - When synaptic vesicles fuse with the presynaptic plasma membrane, their membrane
      constituents are recycled by internalisation into clathrin-coated vesicles. To
      form new synaptic vesicles, the clathrin coat must be shed and recent studies
      reveal that a lipid phosphatase, synaptojanin, plays a central role in this
      process.

PMID- 10662658
TI  - The anatomy of meaning and syntax.
AB  - Recent brain imaging studies have provided evidence that distinct parts of the
      left frontal cortex are involved in processing the structure (syntax) and meaning
      (semantics) of a sentence, setting the stage for the development of more precise
      neuroanatomical models of language processing.

PMID- 10662659
TI  - Natural selection at work.
AB  - Although much is known about the genetic basis of reproductive isolation between
      species, little is understood about its underlying evolutionary causes. A study
      of two very closely related, but reproductively isolated, plant species has
      provided some valuable insights.

PMID- 10662660
TI  - How the fruit fly changed (some of) its spots.
AB  - Recent results show that the establishment of wing melanization patterns in
      Drosophila depends on the veins. While several genes have been shown to play a
      role in melanization, changes in a single gene - the one encoding tyrosine
      hydroxylase - are sufficient to generate novel pigmentation patterns.

PMID- 10662661
TI  - A conscious route to unconscious vision.
AB  - Damage to the primary visual cortex can leave subjects with unconscious residual
      vision, or 'blindsight'. New research suggests that 'top-down' modulation by
      intact conscious visual processes can improve performance in the impaired visual
      domain, even though that domain still remains quite inaccessible to
      consciousness.

PMID- 10662662
TI  - Translational repression: a duet of Nanos and Pumilio.
AB  - Recent studies have shed new light on translational repression by Nanos and
      Pumilio proteins. The ancestral function of this repression mechanism appears to
      be in early germline development; later, species-specific applications in
      embryonic patterning and spermatogenesis-oogenesis switching evolved.

PMID- 10662663
TI  - Methylation moves into medicine.
AB  - Two human genetic diseases have recently been shown to be due to mutations in
      genes encoding proteins involved in DNA methylation. The phenotypes of these two
      diseases are surprisingly distinct from each other and provide insights into the
      functions of DNA methylation in mammals.

PMID- 10662664
TI  - RING for destruction?
AB  - Ubiquitination targets proteins for degradation and is a potent regulator of
      cellular protein function. Recent results implicate the RING finger domain in
      specific ubiquitination events; it is possible that all RING proteins act as E3
      ubiquitin protein ligases, with implications for a variety of biological areas.

PMID- 10662665
TI  - Centrosome-independent mitotic spindle formation in vertebrates.
AB  - BACKGROUND: In cells lacking centrosomes, the microtubule-organizing activity of
      the centrosome is substituted for by the combined action of chromatin and
      molecular motors. The question of whether a centrosome-independent pathway for
      spindle formation exists in vertebrate somatic cells, which always contain
      centrosomes, remains unanswered, however. By a combination of labeling with green
      fluorescent protein (GFP) and laser microsurgery we have been able to selectively
      destroy centrosomes in living mammalian cells as they enter mitosis. RESULTS: We
      have established a mammalian cell line in which the boundaries of the centrosome
      are defined by the constitutive expression of gamma-tubulin-GFP. This feature
      allows us to use laser microsurgery to selectively destroy the centrosomes in
      living cells. Here we show that this method can be used to reproducibly ablate
      the centrosome as a functional entity, and that after destruction the
      microtubules associated with the ablated centrosome disassemble. Depolymerization
      repolymerization experiments reveal that microtubules form in acentrosomal cells
      randomly within the cytoplasm. When both centrosomes are destroyed during
      prophase these cells form a functional bipolar spindle. Surprisingly, when just
      one centrosome is destroyed, bipolar spindles are also formed that contain one
      centrosomal and one acentrosomal pole. Both the polar regions in these spindles
      are well focused and contain the nuclear structural protein NuMA. The
      acentrosomal pole lacks pericentrin, gamma-tubulin, and centrioles, however.
      CONCLUSIONS: These results reveal, for the first time, that somatic cells can use
      a centrosome-independent pathway for spindle formation that is normally masked by
      the presence of the centrosome. Furthermore, this mechanism is strong enough to
      drive bipolar spindle assembly even in the presence of a single functional
      centrosome.

PMID- 10662666
TI  - Differential codes for free Ca(2+)-calmodulin signals in nucleus and cytosol.
AB  - BACKGROUND: Many targets of calcium signaling pathways are activated or inhibited
      by binding the Ca(2+)-liganded form of calmodulin (Ca(2+)-CaM). Here, we test the
      hypothesis that local Ca(2+)-CaM-regulated signaling processes can be selectively
      activated by local intracellular differences in free Ca(2+)-CaM concentration.
      RESULTS: Energy-transfer confocal microscopy of a fluorescent biosensor was used
      to measure the difference in the concentration of free Ca(2+)-CaM between nucleus
      and cytoplasm. Strikingly, short receptor-induced calcium spikes produced
      transient increases in free Ca(2+)-CaM concentration that were of markedly higher
      amplitude in the cytosol than in the nucleus. In contrast, prolonged increases in
      calcium led to equalization of the nuclear and cytosolic free Ca(2+)-CaM
      concentrations over a period of minutes. Photobleaching recovery and
      translocation measurements with fluorescently labeled CaM showed that
      equalization is likely to be the result of a diffusion-mediated net translocation
      of CaM into the nucleus. The driving force for equalization is a higher Ca(2+)
      CaM-buffering capacity in the nucleus compared with the cytosol, as the direction
      of the free Ca(2+)-CaM concentration gradient and of CaM translocation could be
      reversed by expressing a Ca(2+)-CaM-binding protein at high concentration in the
      cytosol. CONCLUSIONS: Subcellular differences in the distribution of Ca(2+)-CaM
      binding proteins can produce gradients of free Ca(2+)-CaM concentration that
      result in a net translocation of CaM. This provides a mechanism for dynamically
      regulating local free Ca(2+)-CaM concentrations, and thus the local activity of
      Ca(2+)-CaM targets. Free Ca(2+)-CaM signals in the nucleus remain low during
      brief or low-frequency calcium spikes, whereas high-frequency spikes or
      persistent increases in calcium cause translocation of CaM from the cytoplasm to
      the nucleus, resulting in similar concentrations of nuclear and cytosolic free
      Ca(2+)-CaM.

PMID- 10662667
TI  - A conserved motif in Crumbs is required for E-cadherin localisation and zonula
      adherens formation in Drosophila.
AB  - BACKGROUND: Specialised cell junctions in epithelia serve as cell-cell adhesion
      sites and thus contribute to the maintenance of tissue integrity. The Drosophila
      gene crumbs encodes a transmembrane protein that is required for the biogenesis
      of the zonula adherens, a belt-like structure encircling the apex of epithelial
      cells. As previously shown, expression of just the short membrane-bound
      cytoplasmic domain is sufficient to rescue major defects associated with the loss
      of crumbs function. RESULTS: The cytoplasmic domain of Crumbs is highly conserved
      in two putative crumbs homologues in Caenorhabditis elegans. To assess the
      significance of conserved residues, various point mutations and deletions were
      introduced into this region. Two functional domains were revealed, an amino
      terminal region and the carboxy-terminal amino acids EERLI. Both are necessary
      for rescue of the crumbs phenotype. The EERLI motif interacts with Discs Lost, a
      cytoplasmic protein containing PDZ domains. Overexpression of the Crumbs
      cytoplasmic domain induces a transition from the single-layered epithelium to a
      multilayered tissue. This transition is associated with redistribution of the
      Drosophila homologue of the cell adhesion molecule E-cadherin, and depends on the
      presence of the EERLI motif. CONCLUSIONS: We propose a model in which the
      interaction of the Crumbs carboxyl terminus with Discs Lost organises a membrane
      associated protein complex in the apical cytocortex of epithelial cells. This
      scaffold mediates the localisation and stabilisation of the zonula adherens
      component DE-cadherin, a crucial component for the maintenance of epithelial cell
      polarity and tissue integrity.

PMID- 10662668
TI  - Mice lacking the cell adhesion molecule Thy-1 fail to use socially transmitted
      cues to direct their choice of food.
AB  - BACKGROUND: Thy-1 is a major cell-surface glycoprotein of mature neurons and
      certain other cells, including those of the lymphoreticular system. Despite being
      the simplest member of the immunoglobulin superfamily, the biological role of Thy
      1 has proved elusive. Analysis of Thy-1 null mice has shown the presence of
      excessive GABAergic inhibition of neurotransmission in the dentate gyrus of the
      hippocampal formation selectively, without any neurological or behavioural
      effects being apparent. RESULTS: We show here that Thy-1 null mice are unable to
      make the appropriate dietary choice in the test for social transmission of food
      preference, despite showing a normal level of social interaction with the
      demonstrator mouse, normal neophobia, and normal learning in a T-maze using
      scented food as cues. The mice also performed normally in tests of anxiety,
      locomotor activity, exploration of a novel environment, habituation to novelty
      and spatial learning. This phenotype is maintained on two different strain
      backgrounds, is rescued by transgenic expression of Thy-1 and by administration
      of the GABA(A) receptor antagonist pentylenetetrazole. CONCLUSIONS: The test for
      social transmission of food preference is based on the normal ability of mice in
      a colony to learn from each other which foods are safe to eat. The lack of this
      key survival behaviour in Thy-1 null mice could act as an evolutionary pressure
      point to conserve expression of Thy-1. Furthermore, the specific cognitive defect
      caused by inactivation of the Thy-1 gene suggests that it would be worthwhile to
      determine the role of Thy-1 in certain human familial forms of mental retardation
      that map to chromosome 11q22-23 in the region of the Thy-1 locus rather than the
      nearby ataxia telangiectasia locus.

PMID- 10662669
TI  - The Drosophila seminal fluid protein Acp26Aa stimulates release of oocytes by the
      ovary.
AB  - Mating stimulates the rate of egg-laying by female insects. In Drosophila
      melanogaster this stimulation is initially caused by seminal fluid molecules
      transferred from the male (Acps or accessory gland proteins; reviewed in [1] [2]
      [3]). Egg-laying is a multi-step process. It begins with oocyte release by the
      ovaries, followed by egg movement down the oviducts and the deposition of eggs
      onto the substratum. Although two Acps are known to stimulate egg-laying [4] [5],
      they were detected by assays that do not discriminate between the steps of this
      process or allow examination of its earliest changes [4] [5] [6] [7]. To
      determine how egg-laying is regulated, we developed a generally applicable assay
      to separate the process into quantifiable steps, allowing us to assess the
      ovulation pattern and rate of egg movement. As the steps are interdependent yet
      potentially subject to independent controls, we determined the contribution of
      each step and effector independent of the others. We used a statistical method
      [8] [9] that separately considers and quantifies each 'path' to a common end. We
      found that the prohormone-like molecule Acp26Aa [5] [10] stimulates the first
      step in egg-laying - release of oocytes by the ovary. During mating, Acp26Aa
      begins to accumulate at the base of the ovaries, a position consistent with
      action on the ovarian musculature to mediate oocyte release. Understanding how
      individual Acps regulate egg-laying in fruitflies will help provide a full
      molecular picture of insects' prodigious fertility, of reproductive hormones, and
      of the roles of these rapidly evolving proteins [11] [12].

PMID- 10662670
TI  - Two paralogs involved in transcriptional silencing that antagonistically control
      yeast life span.
AB  - In the yeast Saccharomyces cerevisiae, one determinant of aging or life span is
      the accumulation of extrachromosomal copies of rDNA circles in old mother cells
      [1]. The production of rDNA circles depends upon intrachromosomal recombination
      within the rDNA tandem array, a process regulated by the protein Sir2 (Sir2p).
      Together with Sir1p, Sir3p, Sir4p and Orc1p, Sir2p is also involved in
      transcriptional silencing of genes at the silent mating-type cassettes, in the
      rDNA array, and at telomeres. Using a 'triple silencer' strain that can monitor
      an increase or decrease in gene expression at these three loci, we found that
      deletion of the ZDS1 gene caused an increase in silencing in the rDNA and at a
      silent mating-type cassette at the expense of telomere silencing. The zds1
      deletion also resulted in an increase in life span and a decrease in Sir3p
      phosphorylation. In contrast, deletion of its paralog ZDS2 caused a decrease in
      rDNA silencing, a decrease in life span and an increase in Sir3p phosphorylation.
      As Zds2p, but not Zds1p, had strong two-hybrid interactions with Orc1p and the
      four Sir proteins, Zds1p might indirectly control Sir3p through a Sir3p kinase.

PMID- 10662671
TI  - Mobilization of late-endosomal cholesterol is inhibited by Rab guanine nucleotide
      dissociation inhibitor.
AB  - Cholesterol entering cells in low-density lipoproteins (LDL) via receptor
      mediated endocytosis is transported to organelles of the late endocytic pathway
      for degradation of the lipoprotein particles. The fate of the free cholesterol
      released remains poorly understood, however. Recent observations suggest that
      late-endosomal cholesterol sequestration is regulated by the dynamics of
      lysobisphosphatidic acid (LBPA)-rich membranes [1]. Genetic studies have
      pinpointed a protein, Niemann-Pick C-1 (NPC-1), that is required for the
      mobilization of late-endosomal/lysosomal cholesterol by an unknown mechanism [2].
      Here, we report the removal of accumulated cholesterol by overexpression of the
      NPC-1 protein in NPC-1-deficient fibroblasts from patients with Niemann-Pick
      disease, and in normal fibroblasts upon release of a progesterone-induced block
      of cholesterol transport. We show that late-endosomal/lysosomal cholesterol
      mobilization is specifically inhibited by microinjection of Rab GDP-dissociation
      inhibitor (Rab-GDI). Moreover, clearance of the cholesterol deposits by NPC-1 in
      patients' fibroblasts is accompanied by the redistribution of LBPA and of a
      lysosomal hydrolase that utilizes the mannose-6-phosphate receptor. Our results
      reveal, for the first time, the involvement of a specific molecular component of
      the membrane-trafficking machinery in cholesterol transport and the coupling of
      late-endosomal cholesterol egress to the trafficking of other lipid and protein
      cargo.

PMID- 10662673
TI  - Retinal asymmetry in birds.
AB  - Vertebrate sensory systems are generally based on bilaterally symmetrical sense
      organs. It is evident, nevertheless, that birds preferentially use either their
      left or right eye for viewing novel or familiar stimuli [1], and perform visual
      discrimination tasks under monocular viewing conditions better with one eye than
      with the other [2] [3]. Because of the nearly complete contralateral decussation
      of the optic nerves in birds [4], it has been assumed that this division of
      labour is due solely to cerebral hemispheric specialisation, generated as a
      result of uneven photostimulation of the eyes of the developing embryo during the
      last three or four days before hatching [5] [6]. Here, however, we present
      evidence that in the European starling, Sturnus vulgaris, even the retinae are
      morphologically asymmetrical in terms of photoreceptor distribution. This is the
      first evidence for such asymmetry in any bird and suggests that retinal
      photoreceptor composition should be assessed during studies involving the
      lateralisation of visually mediated behaviours.

PMID- 10662672
TI  - RuvAB-mediated branch migration does not involve extensive DNA opening within the
      RuvB hexamer.
AB  - The Escherichia coli RuvA and RuvB proteins promote the branch migration of
      Holliday junctions during the late stages of homologous recombination and DNA
      repair (reviewed in [1]). Biochemical and structural studies of the RuvAB
      Holliday junction complex have shown that RuvA binds directly to the Holliday
      junction [2] [3] [4] [5] [6] and acts as a specificity factor that promotes the
      targeting of RuvB [7] [8], a hexameric ring protein that drives branch migration
      [9] [10] [11]. Electron microscopic visualisation of the RuvAB complex revealed
      that RuvA is flanked by two RuvB hexamers, which bind DNA arms that lie
      diametrically opposed across the junction [8]. ATP-dependent branch migration
      occurs as duplex DNA is pumped out through the centre of each ring. Because RuvB
      possesses well-conserved helicase motifs and RuvAB exhibits a 5'-3' DNA helicase
      activity in vitro [12], the mechanism of branch migration is thought to involve
      DNA opening within the RuvB ring, which provides a single strand for the
      unidirectional translocation of the protein along DNA. We have investigated
      whether the RuvB ring can translocate along duplex DNA containing a site-directed
      interstrand psoralen crosslink. Surprisingly, we found that the crosslink failed
      to inhibit branch migration. We interpret these data as evidence against a base
      by-base tracking model and suggest that extensive DNA opening within the RuvB
      ring is not required for DNA translocation by RuvB.

PMID- 10662674
TI  - Transplanted Drosophila excretory tubules maintain circadian clock cycling out of
      phase with the host.
AB  - Circadian rhythms in behaviors and physiological processes are driven by
      conserved molecular mechanisms involving the rhythmic expression of clock genes
      in the brains of animals [1]. The persistence of similar molecular rhythms in
      peripheral tissues in vitro [2] [3] suggests that these tissues contain self
      sustained circadian clocks that may be linked to rhythmic physiological
      functions. It is not known how brain and peripheral clocks are organized into a
      synchronized timing system; however, it has been assumed that peripheral clocks
      submit to a master clock in the brain. To address this matter we examined the
      expression of two clock genes, period (per) and timeless (tim), in host and
      transplanted abdominal organs of Drosophila. We found that excretory organs in
      tissue culture display free-running, light-sensitive oscillations in per and tim
      gene activity indicating that they house self-sustained circadian clocks. To test
      for humoral factors, we monitored cycling of the TIM protein in excretory tubules
      transplanted into host flies entrained to an opposite light-dark cycle. We show
      that the clock protein in the donor tubules cycled out of phase with that in the
      host tubules, indicating that different organs may cycle independently, despite
      sharing the same hormonal milieu. We suggest that one way to achieve circadian
      coordination of physiological sub-systems in higher animals may be through the
      direct entrainment of light-sensitive clocks by environmental signals.

PMID- 10662675
TI  - In situ analysis of embryos with receptor or ligand fusion protein probes.

PMID- 10662676
TI  - The STAS domain - a link between anion transporters and antisigma-factor
      antagonists.

PMID- 10662677
TI  - Prediction of protein structure.

PMID- 10662678
TI  - All the world's a lab ellipsis and last, the survivor

PMID- 10662680
TI  - Gibberellins

PMID- 10662679
TI  - A visible difference.

PMID- 10662681
TI  - Synthesis of end-labeled multivalent ligands for exploring cell-surface-receptor
      ligand interactions.
AB  - BACKGROUND: Ring-opening metathesis polymerization (ROMP) is a powerful synthetic
      method for generating unique materials. The functional group tolerance of
      ruthenium ROMP initiators allows the synthesis of a wide range of biologically
      active polymers. We generated multivalent ligands that inhibit cell surface L
      selectin, a protein that mediates lymphocyte homing and leukocyte recruitment in
      inflammation. We hypothesized that these ligands function through specific,
      multivalent binding to L-selection. To examine this and to develop a general
      method for synthesizing multivalent materials with end-labels, we investigated
      functionalized enol ethers as capping agents in ruthenium-initiated ROMP.
      RESULTS: We synthesized a bifunctional molecule that introduces a unique end
      group by terminating ruthenium-initiated ROMP reactions. This agent contains an
      enol ether at one end and a masked carboxylic acid at the other. We conjugated a
      fluorescein derivative to an end-capped neoglycopolymer that had previously been
      shown to inhibit L-selection function. We used fluorescence microscopy to
      visualize neoglycopolymer binding to cells displaying L-selectin. Our results
      suggest that the neoglycopolymers bind specifically to cell surface L-selectin
      through multivalent interactions. CONCLUSIONS: Ruthenium-initiated ROMP can be
      used to generate biologically active, multivalent ligands terminated with a
      latent functional group. The functionalized polymers can be labeled with a
      variety of molecular tags, including fluorescent molecules, biotin, lipids or
      antibodies. The ability to conjugate reporter groups to ROMP polymers using this
      strategy has broad applications in the material and biological sciences.

PMID- 10662682
TI  - Altered sequence specificity identified from a library of DNA-binding small
      molecules.
AB  - BACKGROUND: The ability to target specific DNA sequences using small molecules
      has major implications for basic research and medicine. Previous studies revealed
      that a bis-intercalating molecule containing two 1,4,5,8
      napthalenetetracarboxylic diimides separated by a lysine-tris-glycine linker
      binds to DNA cooperatively, in pairs, with a preference for G + C-rich sequences.
      Here we investigate the binding properties of a library of bis-intercalating
      molecules that have partially randomized peptide linkers. RESULTS: A library of
      bis-intercalating derivatives with varied peptide linkers was screened for
      sequence specificity using DNase I footprinting on a 231 base pair (bp)
      restriction fragment. The library mixtures produced footprints that were
      generally similar to the parent bis-intercalator, which bound within a 15 bp G +
      C-rich repeat above 125 nM. Nevertheless, subtle differences in cleavage
      enhancement bands followed by library deconvolution revealed a derivative with
      novel specificity. A lysine-tris-beta-alanine derivative was found to bind
      preferentially within a 19 bp palindrome, without substantial loss of affinity.
      CONCLUSIONS: Synthetically simple changes in the bis-intercalating compounds can
      produce derivatives with novel sequence specificity. The large size and
      symmetrical nature of the preferred binding sites suggest that cooperativity may
      be retained despite modified sequence specificity. Such findings, combined with
      structural data, could be used to develop versatile DNA ligands of modest
      molecular weight that target relatively long DNA sequences in a selective manner.

PMID- 10662683
TI  - Xenognosin sensing in virulence: is there a phenol receptor in Agrobacterium
      tumefaciens?
AB  - BACKGROUND: The mechanisms of signal perception and transmission in the 'two
      component' autokinase transmitters/response regulators are poorly understood,
      especially considering the vast number of such systems now known. Virulence
      induction from the tumor-inducing (Ti) plasmid of Agrobacterium tumefaciens
      represents one of the best understood systems with regard to the chemistry of the
      activating signal, and yet the existing data does not support a receptor-mediated
      perception event for the xenognostic phenols. RESULTS: Here we provide the first
      conclusive evidence that a specific receptor must be involved in xenognostic
      phenol perception, detail structural requirements of the xenognosins necessary
      for perception by this receptor, and develop a genetic strategy that demonstrates
      critical components of the phenol recognition system are not encoded on the Ti
      plasmid. CONCLUSIONS: Although the basic elements of the two-component system
      required for phenol-mediated induction of virulence gene expression are encoded
      on the Ti plasmid, they are dependent on the chromosomal background for even the
      very first stage of signal perception. This discovery suggests a curious
      evolutionary history, and also provides functional insight into the mechanisms of
      two-component signal detection and transmission in general.

PMID- 10662684
TI  - Searching for specificity in SH domains.
AB  - Elucidating protein-protein interactions has been a central feature to
      understanding intracellular signal transduction. Many of the binding sites of the
      interacting proteins in these pathways are within highly sequentially homologous
      and structurally conserved domains. We challenge the dogma that mutual
      exclusivity in signalling is derived from a high level of specificity in these
      domains.

PMID- 10662685
TI  - Neurodegeneration: new clues on inclusions.
AB  - The rare neurological disorders frontotemporal dementia and British dementia have
      been linked to two mutant genes whose products constitute the fibrils that define
      the two disease pathologies. Two recent studies add to the mounting
      circumstantial case that protein fibrillization, inside (neurofibrillary tangles)
      or outside (amyloid plaques) of the neuron, may be pathogenic and suggest that
      either or both of these mechanisms could initiate Alzheimer's disease.

PMID- 10662686
TI  - Selective targeting of lysosomal cysteine proteases with radiolabeled
      electrophilic substrate analogs.
AB  - BACKGROUND: The lysosomal cysteine proteases of the papain family are some of the
      best studied proteolytic enzymes. Small-molecule inhibitors and fluorogenic
      substrate mimics have been used to probe the physiological roles of these
      proteases. A high degree of homology between family members and overlap in
      substrate specificity have made elucidating individual protease function,
      expression and activity difficult. RESULTS: Using peptide vinyl sulfones and
      epoxide as templates, we have generated probes that can be tagged with
      radioactive iodine. The resulting compounds covalently label various cathepsins
      and several unidentified polypeptides likely to be proteases. MB-074 was found to
      be a highly selective probe of cathepsin B activity. Probes that labeled several
      cathepsins were used to examine the specificity and cell permeability of the CA
      074 family of inhibitors. Although CA-074 reportedly acts in vivo, we find it is
      unable to penetrate cells. Esterifying CA-074 resulted in a cell-permeable
      inhibitor with dramatically reduced activity and specificity for cathepsin B. The
      probes were also used to monitor protease activity in primary human tumor tissue
      and cells derived from human placenta. CONCLUSIONS: We have generated a highly
      selective cathepsin B probe and several less specific reagents for the study of
      cathepsin biology. The reagents have several advantages over commonly used
      fluorogenic substrates, allowing inhibitor targets to be identified in a pool of
      total cellular enzymes. We have used the probes to show that cathepsin activity
      is regulated in tumor tissues and during differentiation of placental-derived
      cytotrophoblasts to invasive cells required for establishing blood circulation in
      a developing embryo.

PMID- 10662687
TI  - Detection of small-molecule enzyme inhibitors with peptides isolated from phage
      displayed combinatorial peptide libraries.
AB  - BACKGROUND: The rapidly expanding list of pharmacologically important targets has
      highlighted the need for ways to discover new inhibitors that are independent of
      functional assays. We have utilized peptides to detect inhibitors of protein
      function. We hypothesized that most peptide ligands identified by phage display
      would bind to regions of biological interaction in target proteins and that these
      peptides could be used as sensitive probes for detecting low molecular weight
      inhibitors that bind to these sites. RESULTS: We selected a broad range of
      enzymes as targets for phage display and isolated a series of peptides that bound
      specifically to each target. Peptide ligands for each target contained similar
      amino acid sequences and competition analysis indicated that they bound one or
      two sites per target. Of 17 peptides tested, 13 were found to be specific
      inhibitors of enzyme function. Finally, we used two peptides specific for
      Haemophilus influenzae tyrosyl-tRNA synthetase to show that a simple binding
      assay can be used to detect small-molecule inhibitors with potencies in the
      micromolar to nanomolar range. CONCLUSIONS: Peptidic surrogate ligands identified
      using phage display are preferentially targeted to a limited number of sites that
      inhibit enzyme function. These peptides can be utilized in a binding assay as a
      rapid and sensitive method to detect small-molecule inhibitors of target protein
      function. The binding assay can be used with a variety of detection systems and
      is readily adaptable to automation, making this platform ideal for high
      throughput screening of compound libraries for drug discovery.

PMID- 10662688
TI  - Inhibition of cyclin-dependent kinases, GSK-3beta and CK1 by hymenialdisine, a
      marine sponge constituent.
AB  - BACKGROUND: Over 2000 protein kinases regulate cellular functions. Screening for
      inhibitors of some of these kinases has already yielded some potent and selective
      compounds with promising potential for the treatment of human diseases. RESULTS:
      The marine sponge constituent hymenialdisine is a potent inhibitor of cyclin
      dependent kinases, glycogen synthase kinase-3beta and casein kinase 1.
      Hymenialdisine competes with ATP for binding to these kinases. A CDK2
      hymenialdisine complex crystal structure shows that three hydrogen bonds link
      hymenialdisine to the Glu81 and Leu83 residues of CDK2, as observed with other
      inhibitors. Hymenialdisine inhibits CDK5/p35 in vivo as demonstrated by the lack
      of phosphorylation/down-regulation of Pak1 kinase in E18 rat cortical neurons,
      and also inhibits GSK-3 in vivo as shown by the inhibition of MAP-1B
      phosphorylation. Hymenialdisine also blocks the in vivo phosphorylation of the
      microtubule-binding protein tau at sites that are hyperphosphorylated by GSK-3
      and CDK5/p35 in Alzheimer's disease (cross-reacting with Alzheimer's-specific
      AT100 antibodies). CONCLUSIONS: The natural product hymenialdisine is a new
      kinase inhibitor with promising potential applications for treating
      neurodegenerative disorders.

PMID- 10662689
TI  - Multiple pathways of recombination define cellular responses to cisplatin.
AB  - BACKGROUND: Cisplatin is a DNA-damaging drug used for treatment of testicular
      tumors. The toxicity of cisplatin probably results from its ability to form DNA
      adducts that inhibit polymerases. Blocked replication represents a particular
      challenge for tumor cells, which are committed to unremitting division.
      Recombination provides a mechanism by which replication can proceed despite the
      presence of lesions and therefore could be significant for managing cisplatin
      toxicity. RESULTS: Recombination-deficient Escherichia coli mutants were
      strikingly sensitive to cisplatin when compared with the parental strain. Our
      data identified both daughter-strand gap and double-strand break recombination
      pathways as critical for survival following treatment with cisplatin. Although it
      is established that nucleotide excision repair (NER) significantly protects
      against cisplatin toxicity, most recombination-deficient strains were as
      sensitive to the drug as the NER-deficient uvrA mutant. Recombination/NER
      deficient double mutants were more sensitive to cisplatin than the corresponding
      single mutants, suggesting that recombination and NER pathways play independent
      roles in countering cisplatin toxicity. Cisplatin was a potent recombinogen in
      comparison with the trans isomer and canonical alkylating agents. Mitomycin C,
      which like cisplatin, forms DNA cross-links, was also recombinogenic at minimally
      toxic doses. CONCLUSIONS: We have demonstrated that all of the major
      recombination pathways are critical for E. coli survival following treatment with
      cisplatin. Moreover, recombination pathways act independently of NER and are of
      equal importance to NER as genoprotective systems against cisplatin toxicity.
      Taken together, these results shed new light on how cells survive and succumb to
      this widely used anticancer drug.

PMID- 10662690
TI  - Regulation of protein phosphatase-1.
AB  - Reversible protein phosphorylation is a major regulatory mechanism of
      intracellular signal transduction. Protein phosphatase 1 (PP1) is one of four
      major types of serine-threonine phosphatases mediating signaling pathways, but
      the means by which its activity is modulated has only recently begun to come into
      focus.

PMID- 10662692
TI  - Novel octaketide macrolides related to 6-deoxyerythronolide B provide evidence
      for iterative operation of the erythromycin polyketide synthase.
AB  - BACKGROUND: The macrolide antibiotic erythromycin A, like other complex aliphatic
      polyketides, is synthesised by a bacterial modular polyketide synthase (PKS).
      Such PKSs, in contrast to other fatty acid and polyketide synthases which work
      iteratively, contain a separate set or module of enzyme activities for each
      successive cycle of polyketide chain extension, and the number and type of
      modules together determine the structure of the polyketide product. Thus, the six
      extension modules of the erythromycin PKS (DEBS) together catalyse the production
      of the specific heptaketide 6-deoxyerythronolide B. RESULTS: A mutant strain of
      the erythromycin producer Saccharopolyspora erythraea, which accumulates the
      aglycone intermediate erythronolide B, was found unexpectedly to produce two
      novel octaketides, both 16-membered macrolides. These compounds were detectable
      in fermentation broths of wild-type S. erythraea, but not in a strain from which
      the DEBS genes had been specifically deleted. From their structures, both of
      these octaketides appear to be aberrant products of DEBS in which module 4 has
      'stuttered', that is, has catalysed two successive cycles of chain extension.
      CONCLUSIONS: The isolation of novel DEBS-derived octaketides provides the first
      evidence that an extension module in a modular PKS has the potential to catalyse
      iterative rounds of chain elongation like other type I FAS and PKS systems. The
      factors governing the extent of such 'stuttering' remain to be determined.

PMID- 10662691
TI  - Function of glycosyltransferase genes involved in urdamycin A biosynthesis.
AB  - BACKGROUND: Urdamycin A, the principle product of Streptomyces fradiae Tu2717, is
      an angucycline-type antibiotic. The polyketide-derived aglycone moiety is
      glycosylated at two positions, but only limited information is available about
      glycosyltransferases involved in urdamycin biosynthesis. RESULTS: To determine
      the function of three glycosyltransferase genes in the urdamycin biosynthetic
      gene cluster, we have carried out gene inactivation and expression experiments.
      Inactivation of urdGT1a resulted in the predominant accumulation of urdamycin B.
      A mutant lacking urdGT1b and urdGT1c mainly produced compound 100-2. When urdGT1c
      was expressed in the urdGT1b/urdGT1c double mutant, urdamycin G and urdamycin A
      were detected. The mutant lacking all three genes mainly accumulated aquayamycin
      and urdamycinone B. Expression of urdGT1c in the triple mutant led to the
      formation of compound 100-1, whereas expression of urdGT1a resulted in the
      formation of compound 100-2. Co-expression of urdGT1b and urdGT1c resulted in the
      production of 12b-derhodinosyl-urdamycin A, and co-expression of urdGT1a, urdGT1b
      and urdGT1c resulted in the formation of urdamycin A. CONCLUSIONS: Analysis of
      glycosyltransferase genes of the urdamycin biosynthetic gene cluster led to an
      unambiguous assignment of each glycosyltransferase to a certain biosynthetic
      saccharide attachment step.

PMID- 10662693
TI  - Formation of functional heterologous complexes using subunits from the
      picromycin, erythromycin and oleandomycin polyketide synthases.
AB  - BACKGROUND: Recently developed tools for the genetic manipulation of modular
      polyketide synthases (PKSs) have advanced the development of combinatorial
      biosynthesis technologies for drug discovery. Although many of the current
      techniques involve engineering individual domains or modules of the PKS, few
      experiments have addressed the ability to combine entire protein subunits from
      different modular PKSs to create hybrid polyketide pathways. We investigated this
      possibility by in vivo assembly of heterologous PKS complexes using natural and
      altered subunits from related macrolide PKSs. RESULTS: The pikAI and pikAII genes
      encoding subunits 1 and 2 (modules 1-4) of the picromycin PKS (PikPKS) and the
      eryAIII gene encoding subunit 3 (modules 5-6) of the 6-deoxyerythronolide B
      synthase (DEBS) were cloned in two compatible Streptomyces expression vectors. A
      strain of Streptomyces lividans co-transformed with the two vectors produced the
      hybrid macrolactone 3-hydroxynarbonolide. Co-expression of the same pik genes
      with the gene for subunit 3 of the oleandomycin PKS (OlePKS) was also successful.
      A series of hybrid polyketide pathways was then constructed by combining PikPKS
      subunits 1 and 2 with modified DEBS3 subunits containing engineered domains in
      modules 5 or 6. We also report the effect of junction location in a set of DEBS
      PikPKS fusions. CONCLUSIONS: We show that natural as well as engineered protein
      subunits from heterologous modular PKSs can be functionally assembled to create
      hybrid polyketide pathways. This work represents a new strategy that complements
      earlier domain engineering approaches for combinatorial biosynthesis in which
      complete modules or PKS protein subunits, in addition to individual enzymatic
      domains, are used as building blocks for PKS engineering.

PMID- 10662694
TI  - Recognition and catabolism of synthetic heterotrimeric collagen peptides by
      matrix metalloproteinases.
AB  - BACKGROUND: The general consensus is that interstitial collagens are digested by
      collagenases and denatured collagen by gelatinases, although processing of
      fibrillar and acetic-acid-soluble collagen by gelatinase A has also been
      reported. One of the main difficulties in studying the mechanism of action of
      these matrix metalloproteinases (MMPs) derives from the physicochemical
      properties of the natural triple-helical collagen, which makes it difficult to
      handle. RESULTS: Synthetic heterotrimeric collagenous peptides that contain the
      collagenase cleavage site of human collagen type I and differ in the thermal
      stability of the triple-helical fold were used to mimic natural collagen and
      gelatin, respectively. Results from digestion of these substrates by fibroblast
      and neutrophil collagenases (MMP-1 and MMP-8), as well as by gelatinase A (MMP
      2), confirmed that the two classes of enzymes operate within the context of
      strong conformational dependency of the substrates. It was also found that
      gelatinases and collagenases exhibit two distinct proteolytic mechanisms:
      gelatinase digests the gelatin-like heterotrimer rapidly in individual steps with
      intermediate releases of partially processed substrate into the medium, whereas
      collagenases degrade the triple-helical heterotrimer by trapping it until
      scission through all three alpha chains is achieved. CONCLUSIONS: The results
      confirm the usefulness of synthetic heterotrimeric collagenous peptides in the
      folded and unfolded state as mimics of the natural substrates collagen and
      gelatin, respectively, to gain a better a insight into the proteolytic mechanisms
      of matrix metalloproteinases.

PMID- 10662695
TI  - The biosynthetic gene cluster for the microtubule-stabilizing agents epothilones
      A and B from Sorangium cellulosum So ce90.
AB  - BACKGROUND: Epothilones are produced by the myxobacterium Sorangium cellulosum So
      ce90, and, like paclitaxel (Taxol((R))), they inhibit microtubule
      depolymerisation and arrest the cell cycle at the G2-M phase. They are effective
      against P-glycoprotein-expressing multiple-drug-resistant tumor cell lines and
      are more water soluble than paclitaxel. The total synthesis of epothilones has
      been achieved, but has not provided an economically viable alternative to
      fermentation. We set out to clone, sequence and analyze the gene cluster
      responsible for the biosynthesis of the epothilones in S. cellulosum So ce90.
      RESULTS: A cluster of 22 open reading frames spanning 68,750 base pairs of the S.
      cellulosum So ce90 genome has been sequenced and found to encode nine modules of
      a polyketide synthase (PKS), one module of a nonribosomal peptide synthetase
      (NRPS), a cytochrome P450, and two putative antibiotic transport proteins.
      Disruptions in the genes encoding the PKS abolished epothilone production. The
      first PKS module and the NRPS module are proposed to co-operate in forming the
      thiazole heterocycle of epothilone from an acetate and a cysteine by
      condensation, cyclodehydration and subsequent dehydrogenation. The remaining
      eight PKS modules are responsible for the elaboration of the rest of the
      epothilone carbon skeleton. CONCLUSIONS: The overall architecture of the gene
      cluster responsible for epothilone biosynthesis has been determined. The
      availability of the cluster should facilitate the generation of designer
      epothilones by combinatorial biosynthesis approaches, and the heterologous
      expression of epothilones in surrogate microbial hosts.

PMID- 10662696
TI  - Sexual attraction in the silkworm moth: structure of the pheromone-binding
      protein-bombykol complex.
AB  - BACKGROUND: Insects use volatile organic molecules to communicate messages with
      remarkable sensitivity and specificity. In one of the most studied systems,
      female silkworm moths (Bombyx mori) attract male mates with the pheromone
      bombykol, a volatile 16-carbon alcohol. In the male moth's antennae, a pheromone
      binding protein conveys bombykol to a membrane-bound receptor on a nerve cell.
      The structure of the pheromone-binding protein, its binding and recognition of
      bombykol, and its full role in signal transduction are not known. RESULTS: The
      three-dimensional structure of the B. mori pheromone-binding protein with bound
      bombykol has been determined by X-ray diffraction at 1.8 A resolution.
      CONCLUSIONS: The pheromone binding protein of B. mori has six helices, and
      bombykol binds in a completely enclosed hydrophobic cavity formed by four
      antiparallel helices. Bombykol is bound in this cavity through numerous
      hydrophobic interactions, and sequence alignments suggest critical residues for
      specific pheromone binding.

PMID- 10662697
TI  - From primary structure to function: biological insights from large-molecule mass
      spectra.
AB  - As increasing information is available from genomic databases, mass spectrometry
      has begun to be used to identify and/or assess regions of predicted DNA or
      protein sequence. Mass spectrometry performance limits, together with experiments
      designed for genomic interplay, are being extended to allow accurate genotyping
      and protein profiling of cells at rates commensurate with the data-intensive
      future of biology.

PMID- 10662698
TI  - The role of the cleavage site 2'-hydroxyl in the Tetrahymena group I ribozyme
      reaction.
AB  - BACKGROUND: The 2'-hydroxyl of U preceding the cleavage site, U(-1), in the
      Tetrahymena ribozyme reaction contributes 10(3)-fold to catalysis relative to a
      2'-hydrogen atom. Previously proposed models for the catalytic role of this 2'-OH
      involve coordination of a catalytic metal ion and hydrogen-bond donation to the
      3'-bridging oxygen. An additional model, hydrogen-bond donation by the 2'-OH to a
      nonbridging reactive phosphoryl oxygen, is also consistent with previous results.
      We have tested these models using atomic-level substrate modifications and
      kinetic and thermodynamic analyses. RESULTS: Replacing the 2'-OH with -NH(3)(+)
      increases the reaction rate approximately 60-fold, despite the absence of lone
      pair electrons on the 2'-NH(3)(+) group to coordinate a metal ion. Binding and
      reaction of a modified oligonucleotide substrate with 2'-NH(2) at U(-1) are
      unaffected by soft-metal ions. These results suggest that the 2'-OH of U(-1) does
      not interact with a metal ion. The contribution of the 2'-moiety of U(-1) is
      unperturbed by thio substitution at either of the nonbridging oxygens of the
      reactive phosphoryl group, providing no indication of a hydrogen bond between the
      2'-OH and the nonbridging phosphoryl oxygens. In contrast, the 10(3)-fold
      catalytic advantage of 2'-OH relative to 2'-H is eliminated when the 3'-bridging
      oxygen is replaced by sulfur. As sulfur is a weaker hydrogen-bond acceptor than
      oxygen, this effect suggests a hydrogen-bonding interaction between the 2'-OH and
      the 3'-bridging oxygen. CONCLUSIONS: These results provide the first experimental
      support for the model in which the 2'-OH of U(-1) donates a hydrogen bond to the
      neighboring 3'-bridging oxygen, thereby stabilizing the developing negative
      charge on the 3'-oxygen in the transition state.

PMID- 10662699
TI  - The importance of being r: greater oxidative stability of RNA compared with DNA.
AB  - The 2'-hydroxyl group of ribose imparts hydrolytic lability on RNA, which
      provides a mechanism for numerous biological functions. Recent evidence from
      chemical cleavage studies shows that this hydroxyl group also stabilizes the
      sugar moiety in RNA towards oxidation relative to DNA. Is this just because RNA
      needs to be distinguishable from DNA or does it have other evolutionary
      significance?

PMID- 10662700
TI  - Bioavailability of starch and postprandial changes in splanchnic glucose
      metabolism in pigs.
AB  - Changes in splanchnic metabolism in pigs were assessed after meals containing
      slowly or rapidly digested starch. The pigs were fed a mixed meal containing a
      "slow" native (n = 5) or a "rapid" pregelatinized (n = 5) cornstarch naturally
      enriched with [(13)C]glucose. Absorption of [(13)C]glucose was monitored by the
      arteriovenous difference technique, and infusion of D-[6, 6-(2)H(2)]glucose in
      the jugular vein was used to calculate the systemic appearance of [(13)C]glucose.
      Arteriovenous balance data obtained during a 12-h study period showed that the
      fraction of ingested glucose equivalent appearing as glucose in the portal vein
      was 49.7 +/- 7.2% for the slow starch and 48.2 +/- 7.5% for the rapid starch (P =
      0.86). These values, corrected for the gut extraction of circulating
      [(13)C]glucose, became 66.4 +/- 5.6 and 65. 3 +/- 5.6%, respectively (P = 0.35).
      Isotope dilution data indicated that systemic appearance of exogenous
      [(13)C]glucose represented 62. 9 +/- 7.6 and 67.4 +/- 3.0% of the oral load for
      slow and rapid starch, respectively (P = 0.68). Arterial glucose utilization by
      the gut increased from 7.3 +/- 0.9 micromol x kg(-1) x min(-1) before the meal to
      8.5 +/- 1.6 micromol x kg(-1) x min(-1) during absorption, independently of the
      nature of the starch. Thus splanchnic glucose metabolism was unaffected by the
      nature of starch ingested.

PMID- 10662701
TI  - Analysis of the vasopressin system and water regulation in genetically polydipsic
      mice.
AB  - Polydipsic mice, STR/N, which show extreme polydipsia and polyuria, were
      discovered in 1958. In the STR/N, urine outputs are much higher than in control
      mice. The possibility of an abnormal regulation of the arginine vasopressin (AVP)
      system, or an abnormality in the renal susceptibility to AVP, should be
      considered. In this study we investigated the AVP system and water regulation in
      STR/N. We sequenced the AVP and the AVP V(2)-receptor genes of the STR/N by
      direct sequencing. No mutation was found in either of them. AVP gene expression
      examined by in situ hybridization and plasma sodium in 8-wk-old STR/N was
      significantly lower than in control mice, whereas it was significantly higher at
      20 wk. Renal sensitivity to injected AVP was attenuated in 20-wk-old STR/N. The
      suppression of AVP synthesis due to excessive water retention in 8-wk-old STR/N
      suggests that polydipsia may be the primary cause in this strain. The 20-wk-old
      STR/N became dehydrated with the acceleration of AVP synthesis, which might have
      resulted from secondary desensitization to AVP.

PMID- 10662702
TI  - Tyrosine requirements in children with classical PKU determined by indicator
      amino acid oxidation.
AB  - Tyrosine (Tyr) is an essential amino acid in phenylketonuria (PKU) because of the
      limited hydroxylation of phenylalanine (Phe) to Tyr. The recommended intakes for
      Tyr in PKU are at least five times the recommended phenylalanine intakes. This
      suggests that Phe and Tyr contribute approximately 20 and 80%, respectively, of
      the aromatic amino acid (AAA) requirement (REQ). In animals and normal humans,
      dietary Tyr was shown to spare 40-50% of the Phe requirement, proportions that
      reflect dietary and tissue protein composition. We tested the hypothesis that the
      Tyr REQ in PKU would account for 45% of the total AAA REQ by indicator amino acid
      oxidation (IAAO). Tyr REQ was determined in five children with PKU by examining
      the effect of varying dietary Tyr intake on lysine oxidation and the appearance
      of (13)CO(2) in breath (F(13)CO(2)) under dietary conditions of adequate energy,
      protein (1.5 g x kg(-1) x day(-1)), and phenylalanine (25 mg x kg(-1) x day(-1)).
      Lysine oxidation and F(13)CO(2) were determined using a primed 4-h oral equal
      dose infusion of L-[1-(13)C]lysine. Lysine oxidation and F(13)CO(2) decreased
      linearly as Tyr intake increased, to a break point that was interpreted as the
      mean dietary Tyr requirement (16.3 and 19.2 mg x kg(-1) x day(-1), respectively).
      At Tyr intakes of >16.3 and 19.2 mg x kg(-1) x day(-1), lysine oxidation and
      F(13)CO(2), respectively, were low and constant. This represents 40.4 and 44.4%,
      respectively, of the total AAA intake. The current recommendations for Tyr intake
      in PKU patients appear to be overestimated by a factor of approximately 5. This
      study is the first application of the IAAO technique in a pediatric population
      and in humans with an inborn error of metabolism.

PMID- 10662703
TI  - 17beta-estradiol and ICI-182780 regulate the hair follicle cycle in mice through
      an estrogen receptor-alpha pathway.
AB  - Estradiol (E(2)) applied topically twice weekly to mouse skin at doses as low as
      1 nmol inhibited hair growth by blocking the transition of the hair follicle from
      the resting phase (telogen) to the growth phase (anagen). In contrast,
      application of </=10 nmol of other steroids produced limited inhibition. Topical
      treatment with the estrogen receptor (ER) antagonist ICI-182780 reversed the
      effects of E(2), and when applied alone, ICI-182780 caused a telogen-to-anagen
      transition. Both E(2) and ICI-182780 were highly effective at their site of
      application but not at distant sites, indicating the direct rather than secondary
      systemic nature of their effects. Western analysis detected a 65-kDa ER-alpha
      immunoreactive dermal protein, and Northern analysis revealed the presence of a
      6.7-kb ER-alpha mRNA. A ribonuclease protection assay confirmed the presence of
      ER-alpha transcripts but failed to detect ER-beta transcripts. These findings
      implicate a skin-specific ER-alpha pathway in the regulation of the hair follicle
      cycle.

PMID- 10662704
TI  - Nutritional regulation of binding sites for lipoprotein lipase in rat heart.
AB  - Several laboratories have shown that when rats are fasted, the amount of
      lipoprotein lipase (LPL) at the vascular endothelium in heart (monitored as the
      amount released by heparin) increases severalfold without corresponding changes
      in the production of LPL. This suggests that there is a change in endothelial
      binding of LPL. To study this, (125)I-labeled bovine LPL was injected. The
      fraction that bound in the heart was more than twice as high in fasted than in
      fed rats, 4.3% compared with 1.9% of the injected dose. Refeeding reversed this
      in 5 h. When unlabeled LPL was injected before the tracer, the fraction of (125)I
      LPL that bound in heart decreased, indicating that the binding was saturable.
      When isolated hearts were perfused at 4 degrees C with a single pass of labeled
      LPL, twice as much bound in hearts of fasted rats. We conclude that fasting
      causes a change in the vascular endothelium in heart such that its ability to
      bind LPL increases.

PMID- 10662706
TI  - Effects of glutamine supplementation, GH, and IGF-I on glutamine metabolism in
      critically ill patients.
AB  - During critical illness glutamine deficiency may develop. Glutamine
      supplementation can restore plasma concentration to normal, but the effect on
      glutamine metabolism is unknown. The use of growth hormone (GH) and insulin-like
      growth factor I (IGF-I) to prevent protein catabolism in these patients may
      exacerbate the glutamine deficiency. We have investigated, in critically ill
      patients, the effects of 72 h of treatment with standard parenteral nutrition
      (TPN; n = 6), TPN supplemented with glutamine (TPNGLN; 0.4 g x kg(-1) x day(-1),
      n = 6), or TPNGLN with combined GH (0.2 IU. kg(-1). day(-1)) and IGF-I (160
      microg x kg (-1) x day(-1)) (TPNGLN+GH/IGF-I; n = 5) on glutamine metabolism
      using [2-(15)N]glutamine. In patients receiving TPNGLN and TPNGLN+GH/IGF-I,
      plasma glutamine concentration was increased (338 +/- 22 vs. 461 +/- 24
      micromol/l, P < 0.001, and 307 +/- 65 vs. 524 +/- 71 micromol/l, P < 0.05,
      respectively) and glutamine uptake was increased (5.2 +/- 0.5 vs. 7.4 +/- 0.7
      micromol x kg(-1) x min(-1), P < 0.05 and 5.2 +/- 1.1 vs. 7.6 +/- 0.8 micromol x
      kg(-1) x min(-1), P < 0.05). Glutamine production and metabolic clearance rates
      were not altered by the three treatments. These results suggest that there is an
      increased requirement for glutamine in critically ill patients. Combined GH/IGF-I
      treatment with TPNGLN did not have adverse effects on glutamine metabolism.

PMID- 10662705
TI  - Reduced synthesis of muscle proteins in chronic renal failure.
AB  - Muscle wasting and weakness occur frequently in patients with chronic renal
      failure. The mechanism(s) by which these abnormalities occur is unclear. We
      hypothesized that such findings were due to defective muscle protein synthesis.
      We measured synthetic rates of mixed muscle proteins, myosin heavy chain, and
      mitochondrial proteins in serial muscle biopsy samples during a continuous
      infusion of L[1-(13)C]leucine from 12 patients with chronic renal failure and 10
      healthy control subjects under identical study conditions. Patients with chronic
      renal failure have significantly lower synthetic rates of mixed muscle proteins
      and myosin heavy chain (27 and 37% reductions, respectively, P < 0.05 and P <
      0.02). Significant declines in the synthetic rates of muscle mitochondrial
      protein (27%) (P < 0.05), muscle cytochrome c-oxidase activity (42%) (P < 0.007),
      and citrate synthase (27%) (P < 0.007) were also observed in patients with
      chronic renal failure. The synthetic rates of muscle proteins and activity of
      mitochondrial enzymes were negatively correlated to the severity of renal
      failure. These results indicate that in chronic renal failure there is a decrease
      in the synthesis of muscle contractile and mitochondrial proteins and a decrease
      in muscle mitochondrial oxidative enzymes. Reduced synthetic rate of several
      muscle proteins is the likely biochemical basis of muscle loss and muscle
      weakness in people with chronic renal failure.

PMID- 10662707
TI  - Control of glycogen synthesis is shared between glucose transport and glycogen
      synthase in skeletal muscle fibers.
AB  - The effects of transgenic overexpression of glycogen synthase in different types
      of fast-twitch muscle fibers were investigated in individual fibers from the
      anterior tibialis muscle. Glycogen synthase was severalfold higher in all
      transgenic fibers, although the extent of overexpression was twofold greater in
      type IIB fibers. Effects of the transgene on increasing glycogen and
      phosphorylase and on decreasing UDP-glucose were also more pronounced in type IIB
      fibers. However, in any grouping of fibers having equivalent malate dehydrogenase
      activity (an index of oxidative potential), glycogen was higher in the transgenic
      fibers. Thus increasing synthase is sufficient to enhance glycogen accumulation
      in all types of fast-twitch fibers. Effects on glucose transport and glycogen
      synthesis were investigated in experiments in which diaphragm, extensor digitorum
      longus (EDL), and soleus muscles were incubated in vitro. Transport was not
      increased by the transgene in any of the muscles. The transgene increased basal
      [(14)C]glucose into glycogen by 2.5-fold in the EDL, which is composed primarily
      of IIB fibers. The transgene also enhanced insulin-stimulated glycogen synthesis
      in the diaphragm and soleus muscles, which are composed of oxidative fiber types.
      We conclude that increasing glycogen synthase activity increases the rate of
      glycogen synthesis in both oxidative and glycolytic fibers, implying that the
      control of glycogen accumulation by insulin in skeletal muscle is distributed
      between the glucose transport and glycogen synthase steps.

PMID- 10662708
TI  - Endurance training increases gluconeogenesis during rest and exercise in men.
AB  - The hypothesis that endurance training increases gluconeogenesis (GNG) during
      rest and exercise was evaluated. We determined glucose turnover with [6,6
      (2)H]glucose and lactate incorporation into glucose by use of [3-(13)C]lactate
      during 1 h of cycle ergometry at two intensities [45 and 65% peak O(2)
      consumption (VO(2 peak))] before and after training [65% pretraining VO(2 peak)],
      same absolute workload (ABT), and 65% posttraining VO(2 peak), same relative
      intensity (RLT). Nine males (178.1 +/- 2.5 cm, 81.8 +/- 3.3 kg, 27.4 +/- 2.0 yr)
      trained for 9 wk on a cycle ergometer 5 times/wk for 1 h at 75% VO(2 peak). The
      power output that elicited 66.0 +/- 1.1% of VO(2 peak) pretraining elicited 54.0
      +/- 1.7% posttraining. Rest and exercise arterial glucose concentrations were
      similar before and after training, regardless of exercise intensity. Arterial
      lactate concentration during exercise was significantly greater than at rest
      before and after training. Compared with 65% pretraining, arterial lactate
      concentration decreased at ABT (4.75 +/- 0.4 mM, 65% pretraining; 2.78 +/- 0.3
      mM, ABT) and RLT (3.76 +/- 0.46 mM) (P < 0.05). At rest after training, the
      percentage of glucose rate of appearance (R(a)) from GNG more than doubled (1.98
      +/- 0.5% pretraining; 5.45 +/- 1.3% posttraining), as did the rate of GNG (0.11
      +/- 0.03 mg x kg(-1) x min(-1) pretraining, 0.24 +/- 0.06 mg x kg(-1) x min(-1)
      posttraining). During exercise after training, %glucose R(a) from GNG increased
      significantly at ABT (2.3 +/- 0.8% at 65% pre- vs. 7.6 +/- 2.1% posttraining) and
      RLT (6.1 +/- 1.5%), whereas GNG increased almost threefold (P < 0.05) at ABT
      (0.24 +/- 0.08 mg x kg(-1) x min(-1) 65% pre-, and 0.71 +/- 0.18 mg x kg(-1) x
      min(-1) posttraining) and RLT (0.75 +/- 0.26 mg x kg(-1) x min(-1)). We conclude
      that endurance training increases gluconeogenesis twofold at rest and threefold
      during exercise at given absolute and relative exercise intensities.

PMID- 10662709
TI  - Greater potency of IGF-I than IGF-I/BP-3 complex in catabolic parenterally fed
      rats.
AB  - We compared the anabolic effects of recombinant human insulin-like growth factor
      I (rhIGF-I, 2.5 mg/kg) and equimolar amounts of rhIGF-I prebound to rhIGF binding
      protein-3 (rhIGF-I/BP-3) coinfused continuously with total parenteral nutrition
      (TPN) solution in dexamethasone (Dex, 70 microg/day ip)-treated male rats for 6
      days. The four TPN groups included control, Dex, Dex + IGF-I, and Dex+IGF-I/BP-3.
      Pharmacokinetic analysis indicated reduced clearance of IGF-I when infused as IGF
      I/BP-3 compared with free IGF-I (0.91 +/- 0.09 vs. 2.01 +/- 0.19 ml serum/min, P
      < 0.001) and this was associated with significantly greater serum IGF-I
      concentrations in the Dex+IGF-I/BP-3 group. Despite greater total serum IGF-I
      levels, infusion of free IGF-I produced greater anabolic responses than IGF-I/BP
      3 based on body weight, nitrogen balance, and jejunal cellularity. Treatment with
      free IGF-I, but not IGF-I/BP-3, significantly reduced serum insulin and glucose
      levels that were elevated due to Dex. There were no significant differences in
      liver IGF-I mRNA levels between groups. Serum IGFBP-3 levels were elevated with
      infusion of IGF-I/BP-3 compared with IGF-I. These results indicate greater
      anabolic potency of IGF-I compared with IGF-I/BP-3 when administered by
      continuous parenteral infusion with TPN solution in catabolic rats.

PMID- 10662710
TI  - A mathematical model quantifying GnRH-induced LH secretion from gonadotropes.
AB  - A mathematical model is developed to investigate the rate of release of
      luteinizing hormone (LH) from pituitary gonadotropes in response to short pulses
      of gonadotropin-releasing hormone (GnRH). The model includes binding of the
      hormone to its receptor, dimerization, interaction with a G protein, production
      of inositol 1,4, 5-trisphosphate, release of Ca(2+) from the endoplasmic
      reticulum, entrance of Ca(2+) into the cytosol via voltage-gated membrane
      channels, pumping of Ca(2+) out of the cytosol via membrane and endoplasmic
      reticulum pumps, and release of LH. Cytosolic Ca(2+) dynamics are simplified
      (i.e., oscillations are not included in the model), and it is assumed that there
      is only one pool of releasable LH. Despite these and other simplifications, the
      model explains the qualitative features of LH release in response to GnRH pulses
      of various durations and different concentrations in the presence and absence of
      external Ca(2+).

PMID- 10662711
TI  - Combined effects of hyperaminoacidemia and oxandrolone on skeletal muscle protein
      synthesis.
AB  - We investigated whether the normal anabolic effects of acute hyperaminoacidemia
      were maintained after 5 days of oxandrolone (Oxandrin, Ox)-induced anabolism.
      Five healthy men [22 +/- 3 (SD) yr] were studied before and after 5 days of oral
      Ox (15 mg/day). In each study, a 5-h basal period was followed by a 3-h primed
      continuous infusion of a commercial amino acid mixture (10% Travasol). Stable
      isotopic data from blood and muscle sampling were analyzed using a three
      compartment model to calculate muscle protein synthesis and breakdown. Model
      derived muscle protein synthesis increased after amino acid infusion in both the
      control [basal control (BC) vs. control + amino acids (C+AA); P < 0.001] and Ox
      study [basal Ox (BOx) vs. Ox + amino acids (Ox+AA); P < 0.01], whereas protein
      breakdown was unchanged. Fractional synthetic rates of muscle protein increased
      94% (BC vs. C+AA; P = 0.01) and 53% (BOx vs. Ox+AA; P < 0.01), respectively. We
      conclude that the normal anabolic effects of acute hyperaminoacidemia are
      maintained in skeletal muscle undergoing oxandrolone-induced anabolism.

PMID- 10662712
TI  - Leptin production during early starvation in lean and obese women.
AB  - We evaluated abdominal adipose tissue leptin production during short-term fasting
      in nine lean [body mass index (BMI) 21 +/- 1 kg/m(2)] and nine upper body obese
      (BMI 36 +/- 1 kg/m(2)) women. Leptin kinetics were determined by arteriovenous
      balance across abdominal subcutaneous adipose tissue at 14 and 22 h of fasting.
      At 14 h of fasting, net leptin release from abdominal adipose tissue in obese
      subjects (10.9 +/- 1.9 ng x 100 g tissue x (-1) x min(-1)) was not significantly
      greater than the values observed in the lean group (7.6 +/- 2.1 ng x 100 g(-1) x
      min(-1)). Estimated whole body leptin production was approximately fivefold
      greater in obese (6.97 +/- 1.18 microg/min) than lean subjects (1.25 +/- 0.28
      microg/min) (P < 0.005). At 22 h of fasting, leptin production rates decreased in
      both lean and obese groups (to 3.10 +/- 1.31 and 10.5 +/- 2.3 ng x 100 g adipose
      tissue(-1) x min(-1), respectively). However, the relative declines in both
      arterial leptin concentration and local leptin production in obese women
      (arterial concentration 13.8 +/- 4.4%, local production 10.0 +/- 12.3%) were less
      (P < 0.05 for both) than the relative decline in lean women (arterial
      concentration 39.0 +/- 5.5%, local production 56.9 +/- 13.0%). This study
      demonstrates that decreased leptin production accounts for the decline in plasma
      leptin concentration observed after fasting. However, compared with lean women,
      the fasting-induced decline in leptin production is blunted in women with upper
      body obesity. Differences in leptin production during fasting may be responsible
      for differences in the neuroendocrine response to fasting previously observed in
      lean and obese women.

PMID- 10662713
TI  - Novel salmon cardiac peptide hormone is released from the ventricle by regulated
      secretory pathway.
AB  - We used the secretion of the novel salmon cardiac peptide (sCP) as a model to
      examine the mechanisms of ventricular hormone release. Mechanical load increased
      dose dependently the secretion of immunoreactive sCP from isolated perfused
      salmon ventricle, with 3. 3-fold increase when a load of 13 cmH(2)O was applied.
      Endothelin-1 (5 nmol/l) was also able to rapidly increase the secretion of sCP.
      The released peptide corresponded to the biologically active sCP-29, whereas the
      large ventricular storage consisted of pro-sCP-sized material. With the use of
      immunoelectron microscopy, a large number of granules containing immunoreactive
      sCP could be detected in salmon ventricle. As judged by RNA blot analysis, there
      was very active basal expression of the sCP gene in the ventricle, which was not
      increased by mechanical load of up to 2-h duration. Our results show that the
      ventricle actively expresses the gene of sCP, stores the prohormone in secretory
      granules, and releases the peptide in response to mechanical load and endothelin
      1. Thus the salmon ventricle uses the regulated pathway to produce and release a
      hormone structurally related to the mammalian natriuretic peptides.

PMID- 10662714
TI  - Induction of tissue plasminogen activator secretion from rat heart microvascular
      cells by fM 1,25(OH)(2)D(3).
AB  - We investigated the effects of 1,25-dihydroxyvitamin D(3) [25(OH)(2)D(3)] on
      tissue plasminogen activator (tPA) secretion from primary cultures of rat heart
      microvascular cells. After an initial 5-day culture period, cells were treated
      for 24 h with 1,25(OH)(2)D(3) and several of its analogs. The results showed that
      1,25(OH)(2)D(3) induced tPA secretion at 10(-10) to 10(-16) M. A less calcemic
      analog, Ro-25-8272, and an analog that binds the vitamin D receptor but is
      ineffective at perturbing Ca(2+) channels, Ro-24-5531, were approximately 10% as
      active as 1,25(OH)(2)D(3). An analog that binds the vitamin D receptor poorly but
      is an effective Ca(2+) channel agonist, Ro-24-2287, required approximately 10(
      13) M to induce tPA secretion. Combinations of Ro-24-5531 and Ro-24-2287 were
      approximately as potent as 1,25(OH)(2)D(3). Treatment of the cells with BAY K
      8644 or thapsigargin also increased tPA secretion, suggesting that increased
      cytosolic calcium concentration ([Ca(2+)]) induces tPA secretion. The results
      suggested that the sensitivity of the tPA secretory response of microvascular
      cells to 1,25(OH)(2)D(3) was due in part to generation of a vitamin D-depleted
      state in vitro and in part to synergistic effects of 1,25(OH)(2)D(3) on two
      different induction pathways of tPA release.

PMID- 10662715
TI  - Effects of thyroid hormone on action potential and repolarizing currents in rat
      ventricular myocytes.
AB  - Thyroid hormones play an important role in cardiac electrophysiology through both
      genomic and nongenomic mechanisms of action. The effects of triiodothyronine
      (T(3)) on the electrophysiological properties of ventricular myocytes isolated
      from euthyroid and hypothyroid rats were studied using whole cell patch clamp
      techniques. Hypothyroid ventricular myocytes showed significantly prolonged
      action potential duration (APD(90)) compared with euthyroid myocytes, APD(90) of
      151 +/- 5 vs. 51 +/- 8 ms, respectively. Treatment of hypothyroid ventricular
      myocytes with T(3) (0.1 microM) for 5 min significantly shortened APD by 24% to
      115 +/- 10 ms. T(3) similarly shortened APD in euthyroid ventricular myocytes,
      but only in the presence of 4-aminopyridine (4-AP), an inhibitor of the transient
      outward current (I(to)), which prolonged the APD by threefold. Transient outward
      current (I(to)) was not affected by the acute application of T(3) to either
      euthyroid or hypothyroid myocytes; however, I(to) density was significantly
      reduced in hypothyroid compared with euthyroid ventricular myocytes.

PMID- 10662716
TI  - Metabolically active components of fat free mass and resting energy expenditure
      in nonobese adults.
AB  - Resting energy expenditure (REE) and components of fat-free mass (FFM) were
      assessed in 26 healthy nonobese adults (13 males, 13 females). Detailed body
      composition analyses were performed by the combined use of dual-energy X-ray
      absorptiometry (DEXA), magnetic resonance imaging (MRI), bioelectrical impedance
      analysis (BIA), and anthropometrics. We found close correlations between REE and
      FFM(BIA) (r = 0.92), muscle mass(DEXA) (r = 0.89), and sum of internal
      organs(MRI) (r = 0.90). In a multiple stepwise regression analysis, FFM(BIA)
      alone explained 85% of the variance in REE (standard error of the estimate 423
      kJ/day). Including the sum of internal organs(MRI) into the model increased the
      r(2) to 0.89 with a standard error of 381 kJ/day. With respect to individual
      organs, only skeletal muscle(DEXA) and liver mass(MRI) significantly contributed
      to REE. Prediction of REE based on 1) individual organ masses and 2) a constant
      metabolic rate per kilogram organ mass was very close to the measured REE, with a
      mean prediction error of 96 kJ/day. The very close agreement between measured and
      predicted REE argues against significant variations in specific REEs of
      individual organs. In conclusion, the mass of internal organs contributes
      significantly to the variance in REE.

PMID- 10662717
TI  - Effect of induced metabolic alkalosis on human skeletal muscle metabolism during
      exercise.
AB  - The purpose of the study was to examine the roles of active pyruvate
      dehydrogenase (PDH(a)), glycogen phosphorylase (Phos), and their regulators in
      lactate (Lac(-)) metabolism during incremental exercise after ingestion of 0.3
      g/kg of either NaHCO(3) [metabolic alkalosis (ALK)] or CaCO(3) [control (CON)].
      Subjects (n = 8) were studied at rest, rest postingestion, and during constant
      rate cycling at three stages (15 min each): 30, 60, 75% of maximal O(2) uptake
      (VO(2 max)). Radial artery and femoral venous blood samples, leg blood flow, and
      biopsies of the vastus lateralis were obtained during each power output. ALK
      resulted in significantly (P < 0.05) higher intramuscular Lac(-) concentration
      ([Lac(-)]; ALK 72.8 vs. CON 65.2 mmol/kg dry wt), arterial whole blood [Lac(-)]
      (ALK 8.7 vs. CON 7.0 mmol/l), and leg Lac(-) efflux (ALK 10.0 vs. CON 4.2
      mmol/min) at 75% VO(2 max). The increased intramuscular [Lac(-)] resulted from
      increased pyruvate production due to stimulation of glycogenolysis at the level
      of Phos a and phosphofructokinase due to allosteric regulation mediated by
      increased free ADP (ADP(f)), free AMP (AMP(f)), and free P(i) concentrations.
      PDH(a) increased with ALK at 60% VO(2 max) but was similar to CON at 75% VO(2
      max). The increased PDH(a) may have resulted from alterations in the acetyl-CoA,
      ADP(f), pyruvate, NADH, and H(+) concentrations leading to a lower relative
      activity of PDH kinase, whereas the similar values at 75% VO(2 max) may have
      reflected maximal activation. The results demonstrate that imposed metabolic
      alkalosis in skeletal muscle results in acceleration of glycogenolysis at the
      level of Phos relative to maximal PDH activation, resulting in a mismatch between
      the rates of pyruvate production and oxidation resulting in an increase in Lac(-)
      production.

PMID- 10662718
TI  - Thyroid hormones differentially modulate enolase isozymes during rat skeletal and
      cardiac muscle development.
AB  - During muscle development, an isozymic transition of the glycolytic enzyme
      enolase occurs from the embryonic and ubiquitous alphaalpha-isoform to the muscle
      specific betabeta-isoform. Here, we demonstrate a stimulatory role of thyroid
      hormones on these two enolase genes during rat development in hindlimb muscles
      and an inhibitory effect on the muscle-specific enolase gene in cardiac muscle.
      In hindlimb muscles the ubiquitous alpha-transcript level is diminished by
      hypothyroidism, starting at birth. On the contrary, the more abundant muscle
      specific beta-transcript is insensitive to hypothyroidism before establishment of
      the functional diversification of fibers and is greatly decreased thereafter. Our
      data support the hypothesis of a role of thyroid hormones in coordinating the
      expressions of contractile proteins and metabolic enzymes during muscle
      development. The subcellular localization of isoenolases, established here, is
      not modified by hypothyroidism. Our results underline the specificity of action
      of thyroid hormones, which modulate differentially two isozymes in the same
      muscle and regulate, in opposite directions, the expression of the same gene in
      two different muscles.

PMID- 10662719
TI  - Overexpression of Bcl-x(L) in beta-cells prevents cell death but impairs
      mitochondrial signal for insulin secretion.
AB  - To study effects of Bcl-x(L) in the pancreatic beta-cell, two transgenic lines
      were produced using different forms of the rat insulin promoter. Bcl-x(L)
      expression in beta-cells was increased 2- to 3-fold in founder (Fd) 1 and over 10
      fold in Fd 2 compared with littermate controls. After exposure to thapsigargin
      (10 microM for 48 h), losses of cell viability in islets of Fd 1 and Fd 2 Bcl
      x(L) transgenic mice were significantly lower than in islets of wild-type mice.
      Unexpectedly, severe glucose intolerance was observed in Fd 2 but not Fd 1 Bcl
      x(L) mice. Pancreatic insulin content and islet morphology were not different
      from control in either transgenic line. However, Fd 2 Bcl-x(L) islets had
      impaired insulin secretory and intracellular free Ca(2+) ([Ca(2+)](i)) responses
      to glucose and KCl. Furthermore, insulin and [Ca(2+)](i) responses to pyruvate
      methyl ester (PME) were similarly reduced as glucose in Fd 2 Bcl-x(L) islets.
      Consistent with a mitochondrial defect, glucose oxidation, but not glycolysis,
      was significantly lower in Fd 2 Bcl-x(L) islets than in wild-type islets. Glucose
      , PME-, and alpha-ketoisocaproate-induced hyperpolarization of mitochondrial
      membrane potential, NAD(P)H, and ATP production were also significantly reduced
      in Fd 2 Bcl-x(L) islets. Thus, although Bcl-x(L) promotes beta-cell survival,
      high levels of expression of Bcl-x(L) result in reduced glucose-induced insulin
      secretion and hyperglycemia due to a defect in mitochondrial nutrient metabolism
      and signaling for insulin secretion.

PMID- 10662720
TI  - Measurement of interstitial albumin in human skeletal muscle and adipose tissue
      by open-flow microperfusion.
AB  - The absolute concentration of albumin was measured in the interstitial fluid of
      subcutaneous adipose tissue and skeletal muscle in six healthy volunteers by
      combining the method of open-flow microperfusion and the no-net-flux calibration
      technique. By use of open-flow microperfusion, four macroscopically perforated
      double lumen catheters were inserted into the tissue regions of interest and
      constantly perfused. Across the macroscopic perforations of the catheters
      interstitial fluid was partially recovered in the perfusion fluid. Catheters were
      perfused with five solutions, each containing different concentrations of
      albumin. Absolute interstitial albumin concentrations were calculated by applying
      linear regression analysis to perfusate vs. sampled albumin concentration (no-net
      flux calibration technique). Interstitial albumin concentrations were
      significantly lower (P < 0.0001) in adipose tissue (7.36 g/l; r = 0.99, P <
      0.0003; range: 4.3-10.7 g/l) and in skeletal muscle (13.25 g/l; r = 0.99, P <
      0.0012; range: 9.7 to 15.7 g/l) compared with the serum concentration (48.9 +/-
      0.7 g/l, mean +/- SE, n = 6; range: 46.4-50.4 g/l). Furthermore, interstitial
      albumin concentrations were significantly higher in skeletal muscle compared with
      adipose tissue (P < 0.01). The study indicates that open-flow microperfusion
      allows stable sampling of macromolecules from the interstitial space of
      peripheral tissue compartments. Moreover, the present data report for the first
      time in healthy humans in vivo the true albumin concentrations of interstitial
      fluid of adipose tissue and skeletal muscle.

PMID- 10662721
TI  - Roles of the podocyte in glomerular function.
AB  - The podocyte is the most differentiated cell type in the glomerulum, which forms
      a crucial component of the glomerular filtration barrier. It has been assumed
      that podocyte foot processes counteract the elastic force of the glomerular
      basement membrane and that vasoactive hormones may regulate the contractile state
      of their foot processes and thereby modulate the ultrafiltration coefficient
      K(f). Podocyte damage leads to proteinuria, and podocyte injury occurs in many
      glomerular diseases, which may progress to chronic renal failure. The
      understanding of the regulation of physiological properties of the podocyte and
      the mechanisms of its cellular response to injury may thus provide a clue to the
      understanding of the pathogenesis of proteinuria and glomerular diseases. In the
      past it was difficult to study cellular functions in this cell type, because of
      its unique anatomic location and the difficulty in characterizing podocytes in
      cell culture. However, recent advances in physiological, molecular biological,
      and cell culture techniques have increased the knowledge of the role of the
      podocyte in glomerular function. The present review attempts to outline new
      aspects of podocyte function in the glomerulum.

PMID- 10662722
TI  - Guanylin peptides: renal actions mediated by cyclic GMP.
AB  - The guanylin family of cGMP-regulating peptides has three subclasses of peptides
      containing either three intramolecular disulfides found in bacterial heat-stable
      enterotoxins (ST), or two disulfides observed in guanylin and uroguanylin, or a
      single disulfide exemplified by lymphoguanylin. These small, heat-stable peptides
      bind to and activate cell-surface receptors that have intrinsic guanylate cyclase
      (GC) activity. Two receptor GC signaling molecules have been identified that are
      highly expressed in the intestine (GC-C) and/or the kidney (OK-GC) and are
      selectively activated by the guanylin peptides. Stimulation of cGMP production in
      renal target cells by guanylin peptides in vivo or ex vivo elicits a long-lived
      diuresis, natriuresis, and kaliuresis. Activation of GC-C receptors in target
      cells of intestinal mucosa markedly stimulates the transepithelial secretion of
      Cl(-) and HCO(-)/(3), causing enhanced secretion of fluid and electrolytes into
      the intestinal lumen. Bacterial ST peptides act as mimics of guanylin and
      uroguanylin in the intestine, which provide a cellular mechanism underlying the
      diarrhea caused by ST-secreting strains of Escherichia coli. Uroguanylin and
      guanylin may participate in a novel endocrine axis linking the digestive system
      and kidney as a physiological mechanism that influences Na(+) homeostasis.
      Guanylin, uroguanylin, and/or lymphoguanylin may also serve within intrarenal
      signaling pathways controlling cGMP production in renal target cells. Thus we
      propose that guanylin regulatory peptides participate in a complex multifactorial
      biological process that evolved to regulate the urinary excretion of NaCl when
      dietary salt levels exceed the body's physiological requirements. This highly
      integrated and redundant mechanism allows the organism to maintain sodium balance
      by eliminating excess NaCl in the urine. Uroguanylin, in particular, may be a
      prototypical "intestinal natriuretic hormone."

PMID- 10662723
TI  - Targeting of membrane transporters in renal epithelia: when cell biology meets
      physiology.
AB  - Epithelial cells in the kidney have highly specialized transport mechanisms that
      differ among the many tubule segments, and among the different cell types that
      are present in some regions. The purpose of this brief review is to examine some
      of the major intracellular mechanisms by which the membrane proteins that
      participate in these differentiated cellular functions are addressed, sorted, and
      delivered to specific membrane domains of epithelial cells. Unraveling these
      processes is important not only for our understanding of normal cellular function
      but is also critical for the interpretation of pathophysiological dysfunction in
      the context of newly generated molecular and cellular information concerning
      hereditary and acquired transporter abnormalities. Among the topics covered are
      sorting signals on proteins, role of the cytoskeleton, vesicle coat proteins, the
      fusion machinery, and exo- and endocytosis of recycling proteins. Examples of
      these events in renal epithelial cells are highlighted throughout this review and
      are related to the physiology of the kidney.

PMID- 10662724
TI  - Mixed descending- and ascending-type thin limbs of Henle's loop in mammalian
      renal inner medulla.
AB  - Previous studies have generally indicated that the entire descending (DTL) and
      ascending thin limbs (ATL) of Henle's loops in the mammalian inner medulla
      exhibit structurally and functionally distinct properties. In the present study,
      we found that about 50% of Munich-Wistar rat inner medullary thin limbs, lying at
      positions distinctly above the bend, had segments exhibiting structural
      characteristics of DTL located immediately adjacent to segments exhibiting
      structural characteristics of ATL. Multiple DTL-type and ATL-type segments of
      variable length existed along a single straight portion of these mixed tubules.
      Inner medullary thin limbs with repeating, sequential expression of DTL-type and
      ATL-type regions were also numerous in Sprague-Dawley rats, mice, and rabbits
      with no evidence of sexual dimorphism. RT-PCR of microdissected segments showed
      that the water channel aquaporin-1 (AQP1) and the urea transporter UT-A2 were
      expressed in pure DTL, but not in pure ATL, and in DTL-type, but not in ATL-type,
      regions of mixed-type thin limbs. Immunocytochemistry revealed expression of AQP1
      in cells of pure DTL, but not pure ATL, and in cells of DTL-type, but not ATL
      type, regions of mixed-type thin limbs. In contrast, the chloride channel ClC-K1
      was expressed in pure ATL, but not pure DTL, and in ATL-type, but not DTL-type,
      regions of mixed-type thin limbs. Discontinuous axial expression of AQP1, UT-A2,
      and ClC-K1 along the straight portion of single thin limbs indicates that these
      nephrons possess a more heterogeneous structure than previously recognized.

PMID- 10662725
TI  - Cell cycle delay and apoptosis are induced by high salt and urea in renal
      medullary cells.
AB  - We investigated the effects of hyperosmolality on survival and proliferation of
      subconfluent cultures of mIMCD3 mouse renal collecting duct cells. High NaCl
      and/or urea (but not glycerol) reduces the number of viable cells, as measured
      with 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT).
      Raising osmolality from a normal level (300 mosmol/kg) to 550-1,000 mosmol/kg by
      adding NaCl and/or urea greatly increases the proportion of cells in the G(2)M
      phase of the cell cycle within 8 h, as measured by flow cytometry. Up to 600
      mosmol/kg the effect is only transient, and by 12 h at 550 mosmol/kg the effect
      reverses and most cells are in G(1). Flow cytometry with 5-bromodeoxyuridine
      (BrdU) pulse-chase demonstrates that movement through the S phase of the cell
      cycle slows, depending on the concentrations of NaCl and/or urea, and that the
      duration of G(2)M increases greatly (from 2.5 h at 300 mosmol/kg to more than 16
      h at the higher osmolalities). Addition of NaCl and/or urea to total osmolality
      of 550 mosmol/kg or more also induces apoptosis, as demonstrated by
      characteristic electron microscopic morphological changes, appearance of a
      subdiploid peak in flow cytometry, and caspase-3 activation. The number of cells
      with subdiploid DNA and activated caspase-3 peaks at 8-12 h. Caspase-3 activation
      occurs in all phases of the cell cycle, but to a disproportionate degree in
      G(0)/G(1) and S phases. We conclude that elevated NaCl and/or urea reduces the
      number of proliferating mIMCD3 cells by slowing the transit through the S phase,
      by cell cycle delay in the G(2)M and G(1), and by inducing apoptotic cell death.

PMID- 10662726
TI  - Effects of ammonia on bicarbonate transport in the cortical collecting duct.
AB  - Both acidosis and hypokalemia stimulate renal ammoniagenesis, and both regulate
      urinary proton and potassium excretion. We hypothesized that ammonia might play
      an important role in this processing by stimulating H(+)-K(+)-ATPase-mediated ion
      transport. Rabbit cortical collecting ducts (CCD) were studied using in vitro
      microperfusion, bicarbonate reabsorption was measured using microcalorimetry, and
      intracellular pH (pH(i)) was measured using the fluorescent, pH-sensitive dye,
      2', 7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF). Ammonia caused a
      concentration-dependent increase in net bicarbonate reabsorption that was
      inhibited by luminal addition of either of the H(+)-K(+)-ATPase inhibitors, Sch
      28080 or ouabain. The stimulation of net bicarbonate reabsorption was not
      mediated through apical H(+)-ATPase, basolateral Na(+)-K(+)-ATPase, or luminal
      electronegativity. Although ammonia caused intracellular acidification, similar
      changes in pH(i) induced by inhibiting basolateral Na(+)/H(+) exchange did not
      alter net bicarbonate reabsorption. We conclude that ammonia regulates CCD proton
      and potassium transport, at least in part, by stimulating apical H(+)-K(+)
      ATPase.

PMID- 10662727
TI  - Differential expression and acid-base regulation of glutaminase mRNAs in
      gluconeogenic LLC-PK(1)-FBPase(+) cells.
AB  - LLC-PK(1)-FBPase(+) cells, which are a gluconeogenic substrain of porcine renal
      LLC-PK(1) cells, exhibit enhanced oxidative metabolism and increased levels of
      phosphate-dependent glutaminase (PDG) activity. On adaptation to acidic medium
      (pH 6.9, 9 mM HCO(-)(3)), LLC-PK(1)-FBPase(+) cells also exhibit a greater
      increase in ammonia production and respond with an increase in assayable PDG
      activity. The changes in PDG mRNA levels were examined by using confluent cells
      grown on plastic dishes or on permeable membrane inserts. The latter condition
      increased the state of differentiation of the LLC-PK(1)-FBPase(+) cells. The
      levels of the primary porcine PDG mRNAs were analyzed by using probes that are
      specific for the 5.0-kb PDG mRNA (p2400) or that react equally with both the 4.5-
      and 5.0-kb PDG mRNAs (p930 and r1500). In confluent dish- and filter-grown LLC
      PK(1)-FBPase(+) cells, the predominant 4.5-kb PDG mRNA is increased threefold
      after 18 h in acidic media. However, in filter-grown epithelia, which sustain an
      imposed pH and HCO(-)(3) gradient, this adaptive increase is observed only when
      acidic medium is applied to both the apical and the basolateral sides of the
      epithelia. Half-life experiments established that induction of the 4. 5-kb PDG
      mRNA was due to its stabilization. An identical pattern of adaptive increases was
      observed for the cytosolic PEPCK mRNA. In contrast, no adaptive changes were
      observed in the levels of the 5. 0-kb PDG mRNA in either cell culture system.
      Furthermore, cultures were incubated in low-potassium (0.7 mM) media for 24-72 h
      to decrease intracellular pH while maintaining normal extracellular pH. LLC-PK(1)
      FBPase(+) cells again responded with increased rates of ammonia production and
      increased levels of the 4.5-kb PDG and PEPCK mRNAs, suggesting that an
      intracellular acidosis is the initiator of this adaptive response. Because all of
      the observed responses closely mimic those characterized in vivo, the LLC-PK(1)
      FBPase(+) cells represent a valuable tissue culture model to study the molecular
      mechanisms that regulate renal gene expression in response to changes in acid
      base balance.

PMID- 10662728
TI  - PTH regulates expression of ClC-5 chloride channel in the kidney.
AB  - Mutations in the chloride channel, ClC-5, have been described in several
      inherited diseases that result in the formation of kidney stones. To determine
      whether ClC-5 is also involved in calcium homeostasis, we investigated whether
      ClC-5 mRNA and protein expression are modulated in rats deficient in
      1alpha,25(OH)(2) vitamin D(3) with and without thyroparathyroidectomy.
      Parathyroid hormone (PTH) was replaced in some animals. Vitamin D-deficient,
      thyroparathyrodectomized rats had lower serum and higher urinary calcium
      concentrations compared with control animals as well as lower serum PTH and
      calcitonin concentrations. ClC-5 mRNA and protein levels in the cortex decrease
      in vitamin D-deficient, thyroparathyroidectomized rats compared with both control
      and vitamin D-deficient animals. ClC-5 mRNA and protein expression increase near
      to control levels in vitamin D-deficient, thyroparathyroidectomized rats injected
      with PTH. No significant changes in ClC-5 mRNA and protein expression in the
      medulla were detected in any experimental group. Our results suggest that PTH
      modulates the expression of ClC-5 in the kidney cortex and that neither
      1alpha,25(OH)(2) vitamin D(3) nor PTH regulates ClC-5 expression in the medulla.
      The pattern of expression of ClC-5 varies with urinary calcium. Animals with
      higher urinary calcium concentrations have lower levels of ClC-5 mRNA and protein
      expression, suggesting that the ClC-5 chloride channel plays a role in calcium
      reabsorption.

PMID- 10662729
TI  - Decreased vasopressin-mediated renal water reabsorption in rats with chronic
      aldosterone-receptor blockade.
AB  - Previous studies have suggested that mineralocorticoids are needed for a normal
      action of vasopressin on collecting duct osmotic water permeability. However, the
      mechanisms behind this are unknown. To investigate if aldosterone-receptor
      blockade influences vasopressin type 2 receptor (V(2))-mediated renal water
      reabsorption and the renal expression of the vasopressin-regulated water channel
      aquaporin-2 (AQP2), rats were treated with the aldosterone-receptor antagonist
      canrenoate (20 mg/day iv) for 4 wk. Daily urine flow was increased significantly
      by 44%, and urine osmolality was decreased by 27% in canrenoate-treated rats.
      Acute V(2)-receptor blockade (OPC-31260, 800 microgram. kg(-1). h(-1)) was
      performed under conditions in which volume depletion was prevented. In control
      rats, OPC-31260 induced a significant increase in urine flow rate (V, +25%) and
      free water clearance (C(H(2)O), -29%). In canrenoate-treated rats, the effect of
      OPC-31260 was significantly reduced, and semiquantiative immunoblotting
      demonstrated a significant reduction (45%) in AQP2 expression. Because rats with
      common bile duct ligation (CBL) have a reduced vasopressin-mediated water
      reabsorption compared with normal rats (V: -24%; C(H(2)O): -28%, and 86%
      downregulation of AQP2), the effect of canrenoate combined with OPC-31260 was
      tested. Canrenoate treatment of CBL rats significantly increased daily urine
      flow, decreased urine osmolality, and impaired the aquaretic response to OPC
      31260 (V: -23%; C(H(2)O): -31%) with maintained suppression of the renal AQP2
      expression. Thus canrenoate treatment of normal and CBL rats showed 1) increased
      urine production, 2) reduced aquaretic effect of acute V(2)-receptor blockade,
      and 3) a marked reduction in AQP2 expression. This strongly supports the view
      that aldosterone plays a significant role for vasopressin-mediated water
      reabsorption.

PMID- 10662730
TI  - Interstitial water and solute recovery by inner medullary vasa recta.
AB  - A recent model of volume and solute microvascular exchange in the renal medulla
      was extended by simulating the deposition of NaCl, urea, and water into the
      medullary interstitium from the loops of Henle and collecting ducts with
      generation rates that undergo spatial variation within the inner medullary
      interstitium. To build an exponential osmolality gradient in the inner medulla,
      as suggested by Koepsell et al. (H. Koepsell, W. E. A. P. Nicholson, W. Kriz, and
      H. J. Hohling. Pflugers Arch. 350: 167-184, 1974), the ratio of the interstitial
      area-weighted generation rate of small solutes to that of water must increase
      along the corticomedullary axis. We satisfied this condition either by holding
      the area-weighted generation rate of water constant while increasing that of NaCl
      and urea or by reducing the input rate of water with medullary depth. The latter
      case, in particular, yielded higher solute concentrations at the papillary tip.
      Assuming that the fraction of the filtered load recovered by inner medullary vasa
      recta for water, NaCl, and urea is 1%, 1%, and 40%, respectively, papillary tip
      osmolality is 1,470 mosmol/kgH(2)O when urea generation and NaCl generation per
      unit volume of interstitium increase exponentially and linearly, respectively.
      The inner medullary osmolar gradient also increases further when 1) medullary
      blood flow is reduced, 2) hydraulic conductivity of descending vasa recta (DVR)
      is lowered, and 3) vasa recta permeability to NaCl and urea is maximized. The
      coupling between water and small solute transport, resulting from aquaporin-1
      mediated transcellular flux in DVR, also enhances tip osmolality.

PMID- 10662731
TI  - DDM-PGE(2)-mediated cytoprotection in renal epithelial cells by a thromboxane
      A(2) receptor coupled to NF-kappaB.
AB  - The present studies were conducted to determine the pharmacological nature of a
      cytoprotective 11-deoxy-16,16-dimethyl-PGE(2) (DDM-PGE(2)) receptor in LLC-PK(1)
      cells. DDM-PGE(2)-mediated cytoprotection against 2,3,5-(trisglutathion-S
      yl)hydroquinone (TGHQ)-mediated cytotoxicity can be reproduced using thromboxane
      A(2) (TXA(2)) receptor (TP) agonists (U46619 and IBOP), and the cytoprotective
      response to DDM-PGE(2) and TP agonists is inhibited by TP antagonists (SQ-29,548
      and ISAP). Western blot analysis using an antipeptide antibody against the human
      platelet TP receptor (55 kDa) identified a particulate associated 54-kDa protein.
      DDM-PGE(2)-mediated 12-O-tetradecanoyl phorbol-13-acetate (TPA) responsive
      element (TRE) binding activity is not inhibited by cyclooxygenase inhibitors
      (aspirin and indomethacin) or a TXA(2) synthase inhibitor (sulfasalazine),
      suggesting that the biological response to DDM-PGE(2) is not dependent on de novo
      TXA(2) biosynthesis. Peak DDM-PGE(2)- and U46619-mediated TRE binding activity
      and nuclear factor-kappaB (NF-kappaB) binding activity are inhibited by SQ
      29,548. The full cytoprotective response to DDM-PGE(2) requires an 8-h pulse with
      agonist. DDM-PGE(2)-mediated TRE and NF-kappaB binding activity remain elevated
      in the presence of agonist and rapidly decay following agonist washout,
      suggesting a direct correlation between DDM-PGE(2)-mediated cytoprotection and
      persistent DNA binding activities. TPA, a protein kinase C activator, induces
      cytoprotection and a persistent increase of NF-kappaB binding activity. DDM
      PGE(2)-mediated cytoprotection and NF-kappaB binding activity but not TRE binding
      activity are inhibited by sulfasalazine. We conclude that the DDM-PGE(2) receptor
      is a TP receptor and that the cytoprotective response may be mediated in part by
      NF-kappaB.

PMID- 10662732
TI  - Upregulation of endothelin B receptors in kidneys of DOCA-salt hypertensive rats.
AB  - Experiments were designed to elucidate the role of endothelin B receptors (ET(B))
      on arterial pressure and renal function in deoxycorticosterone acetate (DOCA)
      salt hypertensive rats. Male Sprague-Dawley rats underwent uninephrectomy and
      were treated with either DOCA and salt (0.9% NaCl to drink) or placebo. DOCA-salt
      rats given the ET(B)-selective antagonist, A-192621, for 1 wk (10 mg. kg(-1).
      day(-1) in the food) had significantly greater systolic arterial pressure
      compared with untreated DOCA-salt rats (208 +/- 7 vs. 182 +/- 4 mmHg) whereas
      pressure in placebo rats was unchanged. In DOCA-salt, but not placebo rats, A
      192621 significantly decreased sodium and water excretion along with parallel
      decreases in food and water intake. To determine whether the response in DOCA
      salt rats was due to increased expression of ET(B) receptors, endothelin receptor
      binding was performed by using membranes from renal medulla. Maximum binding
      (B(max)) of [(125)I]ET-1, [(125)I]ET-3, and [(125)I]IRL-1620 increased from 227
      +/- 42, 146 +/- 28, and 21 +/- 1 fmol/mg protein, respectively, in placebo rats
      to 335 +/- 27, 300 +/- 38, and 61 +/- 6 fmol/mg protein, respectively, in DOCA
      salt hypertensive rats. The fraction of receptors that are the ET(B) subtype was
      significantly increased in DOCA-salt (0.88 +/- 0.07) compared with placebo (0.64
      +/- 0.01). The difference between [(125)I]ET-3 and [(125)I]IRL-1620 binding is
      consistent with possible ET(B) receptor subtypes in the kidney. These results
      indicate that ET(B) receptors in the renal medulla are up-regulated in the DOCA
      salt hypertensive rat and may serve to maintain a lower arterial pressure by
      promoting salt and water excretion.

PMID- 10662733
TI  - Limit-cycle oscillations and tubuloglomerular feedback regulation of distal
      sodium delivery.
AB  - A mathematical model was used to evaluate the potential effects of limit-cycle
      oscillations (LCO) on tubuloglomerular feedback (TGF) regulation of fluid and
      sodium delivery to the distal tubule. In accordance with linear systems theory,
      simulations of steady-state responses to infinitesimal perturbations in single
      nephron glomerular filtration rate (SNGFR) show that TGF regulatory ability
      (assessed as TGF compensation) increases with TGF gain magnitude gamma when gamma
      is less than the critical value gamma(c), the value at which LCO emerge in
      tubular fluid flow and NaCl concentration at the macula densa. When gamma >
      gamma(c) and LCO are present, TGF compensation is reduced for both infinitesimal
      and finite perturbations in SNGFR, relative to the compensation that could be
      achieved in the absence of LCO. Maximal TGF compensation occurs when gamma
      approximately gamma(c). Even in the absence of perturbations, LCO increase time
      averaged sodium delivery to the distal tubule, while fluid delivery is little
      changed. These effects of LCO are consequences of nonlinear elements in the TGF
      system. Because increased distal sodium delivery may increase the rate of sodium
      excretion, these simulations suggest that LCO enhance sodium excretion.

PMID- 10662734
TI  - Superoxide anion curbs nitric oxide modulation of afferent arteriolar ANG II
      responsiveness in diabetes mellitus.
AB  - Experiments were performed to test the hypothesis that the impact of endogenous
      nitric oxide (NO) on ANG II-induced renal arteriolar constriction is reduced in
      rats with insulin-dependent diabetes mellitus (65 mg/kg streptozotocin; STZ).
      Arteriolar diameter responses to exogenous ANG II were quantified before and
      during NO synthase inhibition (100 microM N(omega)-nitro-L-arginine; L-NNA) by
      using the in vitro blood-perfused juxtamedullary nephron technique. Afferent
      arteriolar lumen diameter averaged 20.7 +/- 2.0 micrometer in Sham kidneys and
      25.9 +/- 1.3 micrometer in STZ kidneys (P < 0.05). Efferent arteriolar diameter
      did not differ between Sham and STZ rats. In kidneys from Sham rats, afferent and
      efferent arteriolar responses to ANG II (0.1-10.0 nM) were exaggerated
      significantly by L-NNA. L-NNA also augmented efferent arteriolar ANG II responses
      in kidneys from STZ rats (high-glucose bath) but did not alter ANG II responses
      in afferent arterioles from STZ rats. L-NNA also accentuated efferent, but not
      afferent, arteriolar ANG II responses in STZ kidneys during acute restoration of
      bath glucose to normal levels. Superoxide dismutase (150 U/ml) restored the
      ability of L-NNA to allow exaggerated afferent arteriolar responses to ANG II in
      kidneys from STZ rats. These observations indicate that superoxide anion
      suppresses the modulatory influence of endogenous NO on ANG II-induced afferent
      arteriolar constriction in diabetes mellitus.

PMID- 10662735
TI  - Aquaporin-4 is expressed in basolateral membranes of proximal tubule S3 segments
      in mouse kidney.
AB  - Because of the availability of knockout mouse models to examine renal transport
      mechanisms, it has become increasingly important to describe the cellular
      distribution of major renal transporters in mice. We have used
      immunocytochemistry and freeze-fracture electron microscopy to compare the renal
      distribution of aquaporin-4 (AQP4) with that previously described in rat. In rat
      kidney AQP4 is present exclusively in basolateral membranes of collecting duct
      principal cells. In mice, however, AQP4 was also detected by immunocytochemistry
      in basolateral membranes of proximal tubule S3 segments, and not detected in S1
      and S2 segments of proximal tubule. Freeze-fracture electron microscopy revealed
      orthogonal arrays of intramembrane particles (OAPs) on the basolateral membranes
      of the S3 segment. In AQP4-knockout mice, immunostaining was absent and OAPs were
      found neither in collecting ducts nor in the S3 segment of the proximal tubule.
      The urinary concentrating capacity after deletion of both AQP1 and AQP4 was
      further reduced compared with that of AQP1 or AQP4 null mice, suggesting an
      additive effect of AQP1 and AQP4 in the concentrating mechanism. The functional
      significance of the apparent species-dependent expression of AQP4 in proximal
      tubules is unknown, but may relate to physiological differences between rats and
      mice.

PMID- 10662736
TI  - Recycling of AQP2 occurs through a temperature- and bafilomycin-sensitive trans
      Golgi-associated compartment.
AB  - The exo- and endocytotic pathway in which aquaporin-2 (AQP2) travels between the
      plasma membrane and intracellular vesicles is only partially characterized. It is
      known that the antidiuretic hormone vasopressin induces a translocation of AQP2
      from an intracellular to a plasma membrane location, both in kidney collecting
      duct principal cells and in transfected epithelial cells. Here we provide
      evidence suggesting that while AQP2 shifts from an intracellular location to the
      cell surface in response to vasopressin, AQP2 also constitutively recycles
      through a similar pathway in transfected LLC-PK(1) cells even in the absence of
      hormonal stimulation. Incubating cells at 20 degrees C blocks AQP2 recycling in a
      perinuclear compartment, regardless of whether vasopressin is present. The H(+)
      ATPase inhibitor bafilomycin A1 also blocks the recycling pathway of AQP2 in a
      perinuclear compartment adjacent to the Golgi in the presence and absence of
      vasopressin stimulation, indicating a role of vesicle acidification in both the
      constitutive and regulated recycling of AQP2. Colocalization of AQP2 with
      clathrin, but not with giantin, after both bafilomycin treatment and a 20 degrees
      C block suggests that the compartment in which recycling AQP2 is blocked may be
      the trans-Golgi, and not cis- and medial-Golgi cisternae.

PMID- 10662737
TI  - Immunoelectron microscopic localization of NBC3 sodium-bicarbonate cotransporter
      in rat kidney.
AB  - In the present study, we produced a rabbit peptide-derived polyclonal COOH
      terminal antibody that selectively recognizes NBC3, to determine the cellular and
      subcellular localization of NBC3 in rat kidney, using immunocytochemistry and
      immunoelectron microscopy. Immunocytochemistry with cryostat sections and
      semithin cryosections revealed specific staining of intercalated cells (ICs) in
      the connecting tubule and in cortical, outer medullary, and initial inner
      medullary collecting ducts. In the connecting tubule and in the cortical and
      medullary collecting duct, the labeling was associated with both type A and type
      B ICs. In type A ICs, labeling was confined to the apical and subapical domains,
      whereas in type B ICs, basal domains were exclusively labeled. In contrast,
      collecting duct principal cells were consistently unlabeled, and this was
      confirmed using anti-aquaporin-2 antibodies, which labeled principal cells in
      parallel semithin cryosections. Glomeruli, proximal tubules, descending thin
      limbs, ascending thin limbs, thick ascending limbs, distal convoluted tubules,
      and vascular structures were unlabeled. For immunoelectron microscopy, tissue
      samples were freeze-substituted, and immunolabeling was performed on ultrathin
      Lowicryl HM20 sections. Immunoelectron microscopy demonstrated that NBC3 labeling
      was very abundant in the apical plasma membrane, in intracellular vesicles, and
      in tubulocisternal profiles in the subapical domains of type A ICs. In type B
      ICs, NBC3 was mainly present in the basolateral plasma membrane. Immunolabeling
      controls using peptide-absorbed antibody were consistently negative. In
      conclusion, NBC3 is highly abundant in the apical plasma membrane of type A ICs
      and in the basolateral plasma membrane of type B ICs. This suggests that NBC3
      plays an important role in modulating bicarbonate transport in the connecting
      tubule and collecting duct.

PMID- 10662738
TI  - The carl W. Gottschalk distinguished lectureship of the renal section

PMID- 10662739
TI  - Circulation online only : february 8, 2000

PMID- 10662740
TI  - NHLBI genomics initiatives : looking beyond the human genome project.

PMID- 10662741
TI  - Pulsatility of ascending aortic pressure waveform is a powerful predictor of
      restenosis after percutaneous transluminal coronary angioplasty.
AB  - BACKGROUND: Because ascending aortic pressure has a greater effect on coronary
      perfusion during diastole than systole, we hypothesized that a high coronary
      diastolic-to-systolic pressure ratio prevents coronary lesions from restenosing
      after percutaneous transluminal coronary angioplasty (PTCA) and that ascending
      aortic pulsatility relative to mean pressure is higher in patients with
      restenosis than in those without restenosis. The purpose of this study was to
      evaluate prospectively whether the morphology of the ascending aortic pressure
      wave can be used to predict restenosis after PTCA. METHODS AND RESULTS: We
      measured the coronary artery diameter and the aortic pressure before PTCA. To
      quantify the relative magnitude of the pulsatile-to-mean aortic pressure, we
      normalized the pulse pressure to mean pressure and referred to this value as the
      fractional pulse pressure (PPf). We prospectively investigated the effect of PPf
      in relation to subsequent risk of restenosis after PTCA in patients with coronary
      artery disease. PPf was a powerful predictor of restenosis. Crude cumulative
      incidence rates of restenosis were 17.6% for the lowest, 33.3% for the middle,
      and 77. 8% for the highest tertile of PPf levels. After adjustments for age,
      smoking habits, systolic blood pressure, type 2 diabetes, hypercholesterolemia,
      old myocardial infarction, vessel location, vessel size, and sex, the odds ratio
      of restenosis was 33.5 (95% confidence interval, 2.04 to 550.6) for the highest
      tertile of the PPf level compared with the lowest tertile level. CONCLUSIONS:
      Pulsatility of the ascending aortic pressure is a predictive factor for
      restenosis after PTCA.

PMID- 10662742
TI  - Lamin A/C gene mutation associated with dilated cardiomyopathy with variable
      skeletal muscle involvement.
AB  - BACKGROUND: Dilated cardiomyopathy is a form of heart muscle disease
      characterized by impaired systolic function and ventricular dilation. Familial
      transmission of the disease is frequently observed, and genetic heterogeneity is
      indicated by clinical and morphological variability in the disease phenotype. In
      the family MDDC1 reported here, the disease phenotype is severe and characterized
      by an autosomal dominant pattern of transmission. In addition, the majority of
      affected family members show signs of mild skeletal muscle involvement. METHODS
      AND RESULTS: On the basis of the clinical observation of both cardiac and
      skeletal muscle abnormalities in the MDDC1 family, the lamin A/C gene was
      examined in this kindred. Coding regions were polymerase chain reaction-amplified
      from genomic DNA and sequenced. A single nucleotide deletion was identified
      within exon 6, and all affected individuals were found to be heterozygous for
      this deletion. CONCLUSIONS: Heterozygosity for a single nucleotide deletion in
      exon 6 of lamin A/C segregates with both the cardiac and skeletal abnormalities
      observed in the MDDC1 family.

PMID- 10662743
TI  - Relation between baseline and on-treatment lipid parameters and first acute major
      coronary events in the Air Force/Texas Coronary Atherosclerosis Prevention Study
      (AFCAPS/TexCAPS).
AB  - BACKGROUND: The Air Force/Texas Coronary Atherosclerosis Prevention Study
      (AFCAPS/TexCAPS) is the first primary-prevention study in a cohort with average
      total cholesterol (TC) and LDL cholesterol (LDL-C) and below-average HDL
      cholesterol (HDL-C). Treatment with lovastatin (20 to 40 mg/d) resulted in a 25%
      reduction in LDL-C and a 6% increase in HDL-C, as well as a 37% reduction in risk
      for first acute major coronary event (AMCE), defined as fatal or nonfatal
      myocardial infarction, unstable angina, or sudden cardiac death. This article
      describes the relation between baseline and on-treatment lipid and apolipoprotein
      (apo) parameters and subsequent risk for AMCEs. METHODS AND RESULTS: With all
      available data from the entire 6605-patient cohort, a prespecified Cox backward
      stepwise regression model identified outcome predictors, and logistic regression
      models examined the relation between lipid variables and AMCE risk. Baseline LDL
      C, HDL-C, and apoB were significant predictors of AMCE; only on-treatment apoB
      and the ratio of apoB to apoAI were predictive of subsequent risk; on-treatment
      LDL-C was not. When event rates were examined across tertiles of baseline lipids,
      a consistent benefit of treatment with lovastatin was observed. CONCLUSIONS:
      Persons with average TC and LDL-C levels and below-average HDL-C may obtain
      significant clinical benefit from primary-prevention lipid modification. On
      treatment apoB, especially when combined with apoAI to form the apoB/AI ratio,
      may be a more accurate predictor than LDL-C of risk for first AMCE.

PMID- 10662744
TI  - Effects of methionine-induced hyperhomocysteinemia on endothelium-dependent
      vasodilation and oxidative status in healthy adults.
AB  - BACKGROUND: Homocysteine-mediated endothelial dysfunction has been proposed to
      occur via oxidative stress mechanisms in humans. However, there is controversy
      regarding the effects of homocysteine on endothelial function and oxidative
      status, which may in part result from age discrepancy across the studies. The
      present study was designed to investigate the aging effect on the relationship
      between endothelium-dependent vasodilation and oxidative status in methionine
      induced hyperhomocysteinemia. METHODS AND RESULTS: Plasma homocysteine,
      phosphatidylcholine hydroperoxide (PCOOH), P-selectin levels, and brachial artery
      flow-mediated vasodilation were measured at baseline and 4 hours after an oral
      methionine load (0.1 g/kg) in 15 younger (21 to 40 years) and 15 older (55 to 70
      years) healthy adults. Homocysteine increased from 7.3+/-1.3 micromol/L at
      baseline to 22.7+/-5.2 micromol/L at 4 hours in younger (P<0.001) and from 7. 4+/
      1.4 to 24.3+/-4.5 micromol/L in older adults (P<0.001). PCOOH levels were not
      significantly different between baseline and 4 hours in both groups (P=0.10 in
      young; P=0.14 in old). P-selectin, which is expected to increase during oxidative
      stress, was not changed in older (P=0.08) but decreased in younger adults
      (P=0.037) at 4 hours. Flow-mediated vasodilation was preserved from 13.1+/-2.1%
      at baseline to 13.5+/-2.8% at 4 hours in younger (P=0.49) and decreased from
      12.8+/-2.4% to 8.5+/-2.8% in older adults (P<0.001). CONCLUSIONS: The present
      study demonstrates that endothelial dysfunction caused by methionine-induced
      hyperhomocysteinemia is age-related and is mediated through impaired nitric oxide
      activity without change of oxidative status. Our data do not support previous
      hypotheses that endothelial damage by homocysteine is via oxidative stress
      mechanism in humans.

PMID- 10662745
TI  - The impact of coronary artery disease on the coronary vasomotor response to
      nonionic contrast media.
AB  - BACKGROUND: Coronary artery disease (CAD) alters the vasomotor response to a
      variety of pharmacological agents. We tested the hypothesis that CAD also has an
      impact on the coronary vasomotor response to radiologic contrast media. METHODS
      AND RESULTS: We performed quantitative coronary angiography in 42 patients
      without angiographic evidence of CAD and 38 patients with CAD in the left
      coronary artery. Angiographically smooth coronary segments (n=235) were analyzed
      for changes on luminal diameters and coronary venous oxygen saturation in
      response to 3 media: the nonionic dimer iodixanol, the nonionic monomer
      iopromide, and the ionic agent ioxaglate. In subjects without CAD, we assessed
      the effects of intracoronary administration of the nitric oxide synthase
      inhibitor N(G)-monomethyl-L-arginine and of the cyclooxygenase inhibitor
      indomethacin on such changes. Iodixanol induced coronary vasodilation in subjects
      without CAD (8.8+/-8.6%, P<0.001). Patients with CAD exhibited no significant
      diameter changes in segments >/=20 mm apart from a stenosis (4.7+/-9.4%, P=NS)
      and significant constriction in segments <20 mm from a stenosis (-3.8+/-4.6%,
      P<0. 05). Similar results were obtained with iopromide, but no changes were found
      with ioxaglate. All contrast media induced transient (<35 seconds) increases in
      coronary venous oxygen saturation in all subjects. Indomethacin, but not N(G)
      monomethyl-L-arginine, blunted the vasodilating effect of iodixanol and iopromide
      (by 80% and 76%, respectively; P<0.001). CONCLUSIONS: Nonionic contrast media
      induce a vasodilatory response in normal vessels not by a mechanism involving
      increased flow or endothelial nitric oxide synthesis, but rather by depending on
      preserved vascular cyclooxygenase activity. CAD changes normal epicardial
      vasodilatory response into vasoconstriction.

PMID- 10662746
TI  - Hemodynamic, renal, and hormonal effects of adrenomedullin infusion in patients
      with congestive heart failure.
AB  - BACKGROUND: Experimental studies have shown that adrenomedullin (AM) causes
      vasodilatation, diuresis, and a positive inotropic effect. In humans, however,
      whether infusion of AM has beneficial effects in congestive heart failure (CHF)
      remains unknown. METHODS AND RESULTS: Hemodynamic, renal, and hormonal responses
      to intravenous infusion of human AM (0.05 microg. kg(-1). min(-1)) were examined
      in 7 patients with CHF and 7 normal healthy subjects (NL). In NL group, AM
      significantly decreased mean arterial pressure (-16 mm Hg, P<0. 05) and increased
      heart rate (+12 bpm, P<0.05). In CHF group, AM also decreased mean arterial
      pressure (-8 mm Hg, P<0.05) and increased heart rate (+5 bpm, P<0.05), but to a
      much lesser degree (P<0.05 versus NL). AM markedly increased cardiac index (CHF,
      +49%; NL, +39%, P<0.05) while decreasing pulmonary capillary wedge pressure (CHF,
      -4 mm Hg; NL, -2 mm Hg, P<0.05). AM significantly decreased mean pulmonary
      arterial pressure only in CHF (-4 mm Hg, P<0.05). AM increased urine volume (CHF,
      +48%; NL, +62%, P<0.05) and urinary sodium excretion (CHF, +42%; NL, +75%,
      P<0.05). Only in CHF, plasma aldosterone significantly decreased during (-28%,
      P<0.05) and after (-36%, P<0.05) AM infusion. These parameters remained unchanged
      in 7 patients with CHF and 6 healthy subjects who received placebo. CONCLUSIONS:
      Intravenous infusion of AM has beneficial hemodynamic and renal effects in
      patients with CHF.

PMID- 10662748
TI  - Sodium channel blockers identify risk for sudden death in patients with ST
      segment elevation and right bundle branch block but structurally normal hearts.
AB  - BACKGROUND: A mutation in the cardiac sodium channel gene (SCN5A) has been
      described in patients with the syndrome of right bundle branch block, ST-segment
      elevation in leads V1 to V3, and sudden death (Brugada syndrome). These
      electrocardiographic manifestations are transient in many patients with the
      syndrome. The present study examined arrhythmic risk in patients with overt and
      concealed forms of the disease and the effectiveness of sodium channel blockers
      to unmask the syndrome and, thus, identify patients at risk. METHODS AND RESULTS:
      The effect of intravenous ajmaline (1 mg/kg), procainamide (10 mg/kg), or
      flecainide (2 mg/kg) on the ECG was studied in 34 patients with the syndrome and
      transient normalization of the ECG (group A), 11 members of 3 families in whom a
      SCN5A mutation was associated with the syndrome and 8 members in whom it was not
      (group B), and 53 control subjects (group C). Ajmaline, procainamide, or
      flecainide administration resulted in ST-segment elevation and right bundle
      branch block in all patients in group A and in all 11 patients with the mutation
      in group B. A similar pattern could not be elicited in the 8 patients in group B
      who lacked the mutation or in any person in group C. The follow-up period (37+/
      33 months) revealed no differences in the incidence of arrhythmia between the 34
      patients in whom the phenotypic manifestation of the syndrome was transient and
      the 24 patients in whom it was persistent (log-rank, 0.639). CONCLUSIONS: The
      data demonstrated a similar incidence of potentially lethal arrhythmias in
      patients displaying transient versus persistent ST-segment elevation and right
      bundle branch block, as well as the effectiveness of sodium channel blockers to
      unmask the syndrome and, thus, identify patients at risk.

PMID- 10662747
TI  - The pressor response to water drinking in humans : a sympathetic reflex?
AB  - BACKGROUND: Water drinking increases blood pressure profoundly in patients with
      autonomic failure and substantially in older control subjects. The mechanism that
      mediates this response is not known. METHODS AND RESULTS: We studied the effect
      of drinking tap water on seated blood pressure in 47 patients with severe
      autonomic failure (28 multiple system atrophy [MSA], 19 pure autonomic failure
      patients [PAF]). Eleven older controls and 8 young controls served as control
      group. We also studied the mechanisms that could increase blood pressure with
      water drinking. Systolic blood pressure increased profoundly with water drinking,
      reaching a maximum of 33+/-5 mm Hg in MSA and 37+/-7 in PAF mm Hg after 30 to 35
      minutes. The pressor response was greater in patients with more retained
      sympathetic function and was almost completely abolished by trimethaphan
      infusion. Systolic blood pressure increased by 11+/-2.4 mm Hg in elderly but not
      in young controls. Plasma norepinephrine increased in both groups. Plasma renin
      activity, vasopressin, and blood volume did not change in any group. CONCLUSIONS:
      Water drinking significantly and rapidly raises sympathetic activity. Indeed, it
      raises plasma norepinephrine as much as such classic sympathetic stimuli as
      caffeine and nicotine. This effect profoundly increases blood pressure in
      autonomic failure patients, and this effect can be exploited to improve symptoms
      due to orthostatic hypotension. Water drinking also acutely raises blood pressure
      in older normal subjects. The pressor effect of oral water is an important yet
      unrecognized confounding factor in clinical studies of pressor agents and
      antihypertensive medications.

PMID- 10662749
TI  - Evaluation of sympathetic nerve terminals with [(11)C]epinephrine and
      [(11)C]hydroxyephedrine and positron emission tomography.
AB  - BACKGROUND: The goal of the present study was to directly compare the new
      radiopharmaceutical agent [(11)C]epinephrine (EPI) with [(11)C]hydroxyephedrine
      (HED) through the use of PET. METHODS AND RESULTS: Seven healthy volunteers and
      10 patients were investigated after heart transplantation. PET images of both
      tracers were of excellent quality in the volunteers. Values for radiolabeled
      metabolites (measured in percent of blood activity) at 5, 20, and 60 minutes
      after injection were approximately 35%, approximately 82%, and approximately 86%
      for EPI and approximately 13%, approximately 47%, and approximately 78% for HED,
      respectively. At 35 minutes, metabolite-corrected mean myocardial retention
      fraction of EPI (0. 235+/-0.022 min(-1)) was significantly greater (P<0.01) than
      that of HED (0.142+/-0.012 min(-1)). Corrected tracer retention fractions of both
      EPI and HED were significantly reduced in transplant recipients (0.055+/-0.004
      min(-1), P<0.0001; and 0.050+/-0.006 min(-1), P<0. 0001, respectively) compared
      with volunteers. Normalization of retention fractions of patients with
      transplantation within 1 year to volunteers resulted in a value (ratio expressed
      in percent) of 20. 6+/-1.8% for EPI, significantly (P<0.03) smaller than 27.8+/
      0.8% for HED. In patients with transplantation later than 1 year, the values were
      26.0+/-2.9% for EPI compared with 44.2+/-5.6% for HED (P<0.014). CONCLUSIONS:
      Both tracers showed high selectivity for neuronal uptake in the heart, with a
      significant reduction in tracer retention in transplant recipients compared with
      volunteers. Compared with HED, EPI showed greater retention in volunteers and a
      lower retention ratio in transplant recipients, suggesting that EPI may be the
      superior tracer with higher sensitivity to neuronal abnormalities. Because EPI
      reflects neuronal uptake, metabolism, and storage, it may be more suitable for
      the study of neuronal integrity than HED, which primarily traces uptake-1
      capacity.

PMID- 10662750
TI  - Characteristics of coronary smooth muscle cells and adventitial fibroblasts.
AB  - BACKGROUND: Recent findings suggesting the involvement of adventitial cells in
      coronary repair have raised questions regarding the phenotypic "plasticity" of
      medial smooth muscle cells (SMCs). Accordingly, the aims of the present study
      were to examine the characteristics of coronary medial and adventitial cells and
      to compare the responses of coronary and noncoronary SMCs to stimulation. METHODS
      AND RESULTS: Enzymatically isolated coronary SMCs (human and porcine) were
      distinct from noncoronary SMCs, showing poor adhesion and spreading, as well as
      lower proliferation, collagen synthesis, and LDL degradation. Several
      extracellular matrix components (Matrigel, collagen I and IV, laminin,
      vitronectin, fibronectin) or growth factors (epidermal growth factor, platelet
      derived growth factor-BB, insulin growth factor-1, interleukin-1alpha) failed to
      augment the adhesion or proliferation of coronary SMCs to the levels observed in
      noncoronary SMCs. Unlike coronary SMCs, coronary fibroblasts demonstrated high
      adhesion, proliferation, collagen synthesis, and avid LDL metabolism. Limited
      responses of coronary SMCs were associated with sustained expression of
      differentiation markers (alpha-smooth muscle actin, h-caldesmon, and smooth
      muscle myosin heavy chain), whereas noncoronary SMCs showed marked phenotypic
      heterogeneity. CONCLUSIONS: Coronary SMCs appeared to maintain highly
      differentiated phenotype in response to stimulation, whereas coronary adventitial
      fibroblasts demonstrated several characteristics that are essential during
      vascular repair. Coronary SMCs, however, were distinct from noncoronary medial
      cells, which displayed greater phenotypic heterogeneity and versatility in
      culture. We postulate that the mechanism of vascular repair may differ among
      vascular beds, pointing to the importance of coronary artery-specific
      investigations in vascular biology.

PMID- 10662751
TI  - Noninvasive ECG imaging of electrophysiologically abnormal substrates in
      infarcted hearts : A model study.
AB  - BACKGROUND: Myocardial infarction and subsequent remodeling create substrates
      with altered electrophysiological (EP) properties that are highly arrhythmogenic.
      Existing ECG methods cannot always detect the existence of such substrates nor
      provide any detailed information about their EP characteristics. A noninvasive
      method with such capabilities is greatly needed for identifying patients at risk
      of arrhythmias and for guidance and evaluation of therapy. Recently, we developed
      a noninvasive ECG imaging modality that can reconstruct epicardial EP information
      from body surface potentials. We extended its application to hearts with
      structural disease and examined its ability to detect and characterize abnormal
      EP substrates. METHODS AND RESULTS: Epicardial potentials were recorded with a
      490-electrode sock from an open-chest dog. Recordings were obtained from a normal
      heart and from the same heart 2 hours after left anterior descending coronary
      artery occlusion and ethanol injection to create an infarct. Body surface
      potentials were generated from these epicardial potentials in a human torso
      model. Realistic geometry errors and measurement noise were added to the torso
      data, which were then used to noninvasively reconstruct epicardial potentials and
      electrograms (EGMs), with excellent accuracy. EP characteristics associated with
      the infarct substrate were reconstructed, including (1) a negative region over
      the infarct, (2) EGMs with large predominant negative deflections (eg, Q-wave
      EGMs), (3) Q-wave EGMs with superimposed RS deflections reflecting local
      activation of surviving myocardium within the infarct border zone, (4) reduced
      magnitudes of EGM negative derivatives, and (5) negative QRS integrals of EGMs
      over the infarct. CONCLUSIONS: ECG imaging can noninvasively detect and map
      abnormal EP substrates associated with infarction and structural heart disease.

PMID- 10662752
TI  - Soluble complement receptor-1 protects heart, lung, and cardiac myofilament
      function from cardiopulmonary bypass damage.
AB  - BACKGROUND: Host defense system activation occurs with cardiopulmonary bypass
      (CPB) and is thought to contribute to the pathophysiological consequences of CPB.
      Complement inhibition effects on the post-CPB syndrome were tested with soluble
      complement receptor-1 (sCR1). METHODS AND RESULTS: Twenty neonatal pigs (weight
      1.8 to 2.8 kg) were randomized to control and sCR1-treated groups. LV pressure
      and volume, left atrial pressure, pulmonary artery pressure and flow, and
      respiratory system compliance and resistance were measured. Preload recruitable
      stroke work, isovolumic diastolic relaxation time constant (tau), and pulmonary
      vascular resistance were determined. Pre-CPB measures were not statistically
      significantly different between the 2 groups. After CPB, preload recruitable
      stroke work was significantly higher in the sCR1 group (n=5, 46.8+/-3.2x10(3) vs
      n=6, 34.3+/-3.7x10(3) erg/cm(3), P=0.042); tau was significantly lower in the
      sCR1 group (26.4+/-1.5, 42.4+/-6. 6 ms, P=0.003); pulmonary vascular resistance
      was significantly lower in the sCR1 group (5860+/-1360 vs 12 170+/-1200 dyn.
      s/cm(5), P=0.009); arterial PO(2) in 100% FIO(2) was significantly higher in the
      sCR1 group (406+/-63 vs 148+/-33 mm Hg, P=0.01); lung compliance and airway
      resistance did not differ significantly. The post-CPB Hill coefficient of atrial
      myocardium was higher in the sCR1 group (2.88+/-0.29 vs 1.88+/-0.16, P=0.023).
      CONCLUSIONS: sCR1 meaningfully moderates the post-CPB syndrome, supporting the
      hypothesis that complement activation contributes to this syndrome.

PMID- 10662753
TI  - Accelerated onset and increased incidence of ventricular arrhythmias induced by
      ischemia in Cx43-deficient mice.
AB  - BACKGROUND: Myocardial ischemia causes profound changes in both active membrane
      currents and passive electrical properties. Because these complex changes develop
      and progress concomitantly, it has not been possible to elucidate the relative
      contributions of any one component to arrhythmogenesis induced by acute ischemia.
      Cx43+/- mice express 50% of the normal level of connexin43 (Cx43), the major
      ventricular electrical coupling protein, but are otherwise identical to wild-type
      (Cx43+/+) mice. Comparison of arrhythmogenesis in Cx43+/- and +/+ mice can
      provide insights into the role of changes in electrical coupling as an
      independent variable in the complex setting of acute ischemia. METHODS AND
      RESULTS: Acute ischemia was induced in isolated perfused mouse hearts by
      occlusion of the left anterior descending coronary artery. Spontaneous
      ventricular tachyarrhythmias (VT) occurred in more than twice as many Cx43+/-
      hearts than Cx43+/+ hearts. VT was induced in nearly 3 times as many Cx43+/-
      hearts. Multiple runs and prolonged runs of spontaneous VT were more frequent in
      Cx43+/- hearts. Onset of the first run of VT occurred significantly earlier in
      Cx43+/- hearts. Premature ventricular beats were also more frequent in Cx43+/-
      hearts. The size of the hypoperfused region was equivalent in both groups.
      CONCLUSIONS: Reduced expression of Cx43 accelerates the onset and increases the
      incidence, frequency, and duration of ventricular tachyarrhythmias after coronary
      artery occlusion. Thus diminished electrical coupling per se plays a critical
      role in arrhythmogenesis induced by acute ischemia.

PMID- 10662754
TI  - Antihypertensive effect of 0.1-Hz blood pressure oscillations to the kidney.
AB  - BACKGROUND: Physiological blood pressure (BP) fluctuations with frequencies >0.1
      Hz can override renal blood flow autoregulation. The influence of such immediate
      changes in renal perfusion pressure (RPP) on daily BP regulation, eg, via shear
      stress-stimulated liberation of renal endothelial NO, however, is unknown. Thus,
      we studied the effects of such RPP oscillations on renal function and on systemic
      BP during the onset of renal hypertension. METHODS AND RESULTS: Seven beagles
      (randomly assigned to each of the following protocols) were chronically
      instrumented for the measurement of systemic BP, RPP, and renal excretory
      function. An inflatable cuff was used to reduce and to oscillate RPP over 24
      hours in the freely moving dog. Reducing RPP to 87+/-2 mm Hg diminished excretion
      of sodium and water and doubled plasma renin activity (PRA, n=7, P<0. 01) but had
      no significant effect on urinary nitrate excretion (n=6), a marker of NO
      generation. Superimposing 0.1-Hz oscillations (+/-10 mm Hg) onto the reduced RPP
      blunted hypertension, returned fluid excretion almost to control levels, and
      doubled renal sodium elimination. Nitrate excretion peaked at 8 hours, only to
      return to control values shortly thereafter. PRA, conversely, was significantly
      reduced during the last third of the experimental protocols. CONCLUSIONS: BP
      fluctuations transiently stimulate NO liberation and induce a reduction in PRA,
      which enhances 24-hour sodium and water excretion and markedly attenuates the
      acute development of renovascular hypertension.

PMID- 10662755
TI  - beta-adrenergic receptor blockade in chronic heart failure.

PMID- 10662756
TI  - Recognition of the importance of embolization in atherosclerotic vascular
      disease.

PMID- 10662758
TI  - Unsafe sax?

PMID- 10662757
TI  - Images in cardiovascular medicine. Uterine intravenous leiomyomatosis extending
      through the inferior vena cava into the right cardiac cavities.

PMID- 10662759
TI  - Nearly half of Americans with severe mental illness do not seek treatment.

PMID- 10662760
TI  - Who owns your DNA? Who will own it?

PMID- 10662761
TI  - Who owns your DNA? who will own It?

PMID- 10662762
TI  - Cardiac vasculitis in Henoch-Schonlein purpura.

PMID- 10662763
TI  - Recurrent pericarditis as a manifestation of familial Mediterranean fever.

PMID- 10662764
TI  - Sudden death in myotonic dystrophy: the potential role of bundle-branch reentry.

PMID- 10662765
TI  - Selenium and chronic heart failure.

PMID- 10662766
TI  - Attenuation of ischemia/reperfusion injury by a caspase inhibitor.

PMID- 10662767
TI  - Regulation of cadherin adhesive activity.

PMID- 10662768
TI  - A role for centrin 3 in centrosome reproduction.
AB  - Centrosome reproduction by duplication is essential for the bipolarity of cell
      division, but the molecular basis of this process is still unknown. Mutations in
      Saccharomyces cerevisiae CDC31 gene prevent the duplication of the spindle pole
      body (SPB). The product of this gene belongs to the calmodulin super-family and
      is concentrated at the half bridge of the SPB. We present a functional analysis
      of HsCEN3, a human centrin gene closely related to the CDC31 gene. Transient
      overexpression of wild-type or mutant forms of HsCen3p in human cells
      demonstrates that centriole localization depends on a functional fourth EF-hand,
      but does not produce mitotic phenotype. However, injection of recombinant HsCen3p
      or of RNA encoding HsCen3p in one blastomere of two-cell stage Xenopus laevis
      embryos resulted in undercleavage and inhibition of centrosome duplication.
      Furthermore, HsCEN3 does not complement mutations or deletion of CDC31 in S.
      cerevisiae, but specifically blocks SPB duplication, indicating that the human
      protein acts as a dominant negative mutant of CDC31. Several lines of evidence
      indicate that HsCen3p acts by titrating Cdc31p-binding protein(s). Our results
      demonstrate that, in spite of the large differences in centrosome structure among
      widely divergent species, the centrosome pathway of reproduction is conserved.

PMID- 10662769
TI  - Organization of the yeast Zip1 protein within the central region of the
      synaptonemal complex.
AB  - The yeast Zip1 protein is a component of the central region of the synaptonemal
      complex (SC). Zip1 is predicted to form an alpha-helical coiled coil, flanked by
      globular domains at the NH(2) and COOH termini. Immunogold labeling with domain
      specific anti-Zip1 antibodies demonstrates that the NH(2)-terminal domain of Zip1
      is located in the middle of the central region of the SC, whereas the COOH
      terminal domain is embedded in the lateral elements of the complex. Previous
      studies have shown that overproduction of Zip1 results in the assembly of two
      types of aggregates, polycomplexes and networks, that are unassociated with
      chromatin. Our epitope mapping data indicate that the organization of Zip1 within
      polycomplexes is similar to that of the SC, whereas the organization of Zip1
      within networks is fundamentally different. Zip1 protein purified from bacteria
      assembles into dimers in vitro, and electron microscopic analysis demonstrates
      that the two monomers within a dimer are arranged in parallel and in register.
      Together, these results suggest that two Zip1 dimers, lying head-to-head, span
      the width of the SC.

PMID- 10662770
TI  - Isolation of a ribonucleoprotein complex involved in mRNA localization in
      Drosophila oocytes.
AB  - Localization of bicoid (bcd) mRNA to the anterior and oskar (osk) mRNA to the
      posterior of the Drosophila oocyte is critical for embryonic patterning. Previous
      genetic studies implicated exuperantia (exu) in bcd mRNA localization, but its
      role in this process is not understood. We have biochemically isolated Exu and
      show that it is part of a large RNase-sensitive complex that contains at least
      seven other proteins. One of these proteins was identified as the cold shock
      domain RNA-binding protein Ypsilon Schachtel (Yps), which we show binds directly
      to Exu and colocalizes with Exu in both the oocyte and nurse cells of the
      Drosophila egg chamber. Surprisingly, the Exu-Yps complex contains osk mRNA. This
      biochemical result led us to reexamine the role of Exu in the localization of osk
      mRNA. We discovered that exu-null mutants are defective in osk mRNA localization
      in both nurse cells and the oocyte. Furthermore, both Exu/Yps particles and osk
      mRNA follow a similar temporal pattern of localization in which they transiently
      accumulate at the oocyte anterior and subsequently localize to the posterior
      pole. We propose that Exu is a core component of a large protein complex involved
      in localizing mRNAs both within nurse cells and the developing oocyte.

PMID- 10662771
TI  - Coordinated spindle assembly and orientation requires Clb5p-dependent kinase in
      budding yeast.
AB  - The orientation of the mitotic spindle along a polarity axis is critical in
      asymmetric cell divisions. In the budding yeast, Saccharomyces cerevisiae, loss
      of the S-phase B-type cyclin Clb5p under conditions of limited cyclin-dependent
      kinase activity (cdc28-4 clb5Delta cells) causes a spindle positioning defect
      that results in an undivided nucleus entering the bud. Based on time-lapse
      digital imaging microscopy of microtubules labeled with green fluorescent protein
      fusions to either tubulin or dynein, we observed that the asymmetric behavior of
      the spindle pole bodies during spindle assembly was lost in the cdc28-4 clb5Delta
      cells. As soon as a spindle formed, both poles were equally likely to interact
      with the bud cell cortex. Persistent dynamic interactions with the bud ultimately
      led to spindle translocation across the bud neck. Thus, the mutant failed to
      assign one spindle pole body the task of organizing astral microtubules towards
      the mother cell. Our data suggest that Clb5p-associated kinase is required to
      confer mother-bound behavior to one pole in order to establish correct spindle
      polarity. In contrast, B-type cyclins, Clb3p and Clb4p, though partially
      redundant with Clb5p for an early role in spindle morphogenesis, preferentially
      promote spindle assembly.

PMID- 10662772
TI  - Mass transport of proform of a KDEL-tailed cysteine proteinase (SH-EP) to protein
      storage vacuoles by endoplasmic reticulum-derived vesicle is involved in protein
      mobilization in germinating seeds.
AB  - A vacuolar cysteine proteinase, designated SH-EP, is expressed in the cotyledon
      of germinated Vigna mungo seeds and is responsible for the degradation of storage
      proteins. SH-EP is a characteristic vacuolar proteinase possessing a COOH
      terminal endoplasmic reticulum (ER) retention sequence, KDEL. In this work,
      immunocytochemical analysis of the cotyledon cells of germinated V. mungo seeds
      was performed using seven kinds of antibodies to identify the intracellular
      transport pathway of SH-EP from ER to protein storage vacuoles. A proform of SH
      EP synthesized in ER accumulated at the edge or middle region of ER where the
      transport vesicle was formed. The vesicle containing a large amount of proSH-EP,
      termed KV, budded off from ER, bypassed the Golgi complex, and was sorted to
      protein storage vacuoles. This massive transport of SH-EP via KV was thought to
      mediate dynamic protein mobilization in the cotyledon cells of germinated seeds.
      We discuss the possibilities that the KDEL sequence of KDEL-tailed vacuolar
      cysteine proteinases function as an accumulation signal at ER, and that the mass
      transport of the proteinases by ER-derived KV-like vesicle is involved in the
      protein mobilization of plants.

PMID- 10662773
TI  - Apg9p/Cvt7p is an integral membrane protein required for transport vesicle
      formation in the Cvt and autophagy pathways.
AB  - In nutrient-rich, vegetative conditions, the yeast Saccharomyces cerevisiae
      transports a resident protease, aminopeptidase I (API), to the vacuole by the
      cytoplasm to vacuole targeting (Cvt) pathway, thus contributing to the
      degradative capacity of this organelle. When cells subsequently encounter
      starvation conditions, the machinery that recruited precursor API (prAPI) also
      sequesters bulk cytosol for delivery, breakdown, and recycling in the vacuole by
      the autophagy pathway. Each of these overlapping alternative transport pathways
      is specifically mobilized depending on environmental cues. The basic mechanism of
      cargo packaging and delivery involves the formation of a double-membrane
      transport vesicle around prAPI and/or bulk cytosol. Upon completion, these Cvt
      and autophagic vesicles are targeted to the vacuole to allow delivery of their
      lumenal contents. Key questions remain regarding the origin and formation of the
      transport vesicle. In this study, we have cloned the APG9/CVT7 gene and
      characterized the gene product. Apg9p/Cvt7p is the first characterized integral
      membrane protein required for Cvt and autophagy transport. Biochemical and
      morphological analyses indicate that Apg9p/Cvt7p is localized to large
      perivacuolar punctate structures, but does not colocalize with typical
      endomembrane marker proteins. Finally, we have isolated a temperature conditional
      allele of APG9/CVT7 and demonstrate the direct role of Apg9p/Cvt7p in the
      formation of the Cvt and autophagic vesicles. From these results, we propose that
      Apg9p/Cvt7p may serve as a marker for a specialized compartment essential for
      these vesicle-mediated alternative targeting pathways.

PMID- 10662774
TI  - Cdc42 and Rac stimulate exocytosis of secretory granules by activating the
      IP(3)/calcium pathway in RBL-2H3 mast cells.
AB  - We have expressed dominant-active and dominant-negative forms of the Rho GTPases,
      Cdc42 and Rac, using vaccinia virus to evaluate the effects of these mutants on
      the signaling pathway leading to the degranulation of secretory granules in RBL
      2H3 cells. Dominant-active Cdc42 and Rac enhance antigen-stimulated secretion by
      about twofold, whereas the dominant-negative mutants significantly inhibit
      secretion. Interestingly, treatment with the calcium ionophore, A23187, and the
      PKC activator, PMA, rescues the inhibited levels of secretion in cells expressing
      the dominant-negative mutants, implying that Cdc42 and Rac act upstream of the
      calcium influx pathway. Furthermore, cells expressing the dominant-active mutants
      exhibit elevated levels of antigen-stimulated IP(3) production, an amplified
      antigen-stimulated calcium response consisting of both calcium release from
      internal stores and influx from the extracellular medium, and an increase in
      aggregate formation of the IP(3) receptor. In contrast, cells expressing the
      dominant-negative mutants display the opposite phenotypes. Finally, we are able
      to detect an in vitro interaction between Cdc42 and PLCgamma1, the enzyme
      immediately upstream of IP(3) formation. Taken together, these findings implicate
      Cdc42 and Rac in regulating the exocytosis of secretory granules by stimulation
      of IP(3) formation and calcium mobilization upon antigen stimulation.

PMID- 10662775
TI  - Influenza M2 proton channel activity selectively inhibits trans-Golgi network
      release of apical membrane and secreted proteins in polarized Madin-Darby canine
      kidney cells.
AB  - The function of acidification in protein sorting along the biosynthetic pathway
      has been difficult to elucidate, in part because reagents used to alter organelle
      pH affect all acidified compartments and are poorly reversible. We have used a
      novel approach to examine the role of acidification in protein sorting in
      polarized Madin-Darby canine kidney (MDCK) cells. We expressed the influenza
      virus M2 protein, an acid-activated ion channel that equilibrates lumenal and
      cytosolic pH, in polarized MDCK cells and examined the consequences on the
      targeting and delivery of apical and basolateral proteins. M2 activity affects
      the pH of only a subset of acidified organelles, and its activity can be rapidly
      reversed using ion channel blockers (Henkel, J.R., G. Apodaca, Y. Altschuler, S.
      Hardy, and O.A. Weisz. 1998. Mol. Biol. Cell. 8:2477-2490; Henkel, J.R., J.L.
      Popovich, G.A. Gibson, S.C. Watkins, and O.A. Weisz. 1999. J. Biol. Chem.
      274:9854-9860). M2 expression significantly decreased the kinetics of cell
      surface delivery of the apical membrane protein influenza hemagglutinin, but not
      of the basolaterally delivered polymeric immunoglobulin receptor. Similarly, the
      kinetics of apical secretion of a soluble form of gamma-glutamyltranspeptidase
      were reduced with no effect on the basolaterally secreted fraction.
      Interestingly, M2 activity had no effect on the rate of secretion of a
      nonglycosylated protein (human growth hormone [hGH]) that was secreted equally
      from both surfaces. However, M2 slowed apical secretion of a glycosylated mutant
      of hGH that was secreted predominantly apically. Our results suggest a role for
      acidic trans-Golgi network pH in signal-mediated loading of apical cargo into
      forming vesicles.

PMID- 10662776
TI  - Adenomatous polyposis coli (APC) protein moves along microtubules and
      concentrates at their growing ends in epithelial cells.
AB  - Adenomatous polyposis coli (APC) tumor suppressor protein has been shown to be
      localized near the distal ends of microtubules (MTs) at the edges of migrating
      cells. We expressed green fluorescent protein (GFP)-fusion proteins with full
      length and deletion mutants of Xenopus APC in Xenopus epithelial cells, and
      observed their dynamic behavior in live cells. During cell spreading and wound
      healing, GFP-tagged full-length APC was concentrated as granules at the tip
      regions of cellular extensions. At higher magnification, APC appeared to move
      along MTs and concentrate as granules at the growing plus ends. When MTs began to
      shorten, the APC granules dropped off from the MT ends. Immunoelectron microscopy
      revealed that fuzzy structures surrounding MTs were the ultrastructural
      counterparts for these GFP signals. The COOH-terminal region of APC was targeted
      to the growing MT ends without forming granular aggregates, and abruptly
      disappeared when MTs began to shorten. The APC lacking the COOH-terminal region
      formed granular aggregates that moved along MTs toward their plus ends in an ATP
      dependent manner. These findings indicated that APC is a unique MT-associated
      protein that moves along selected MTs and concentrates at their growing plus ends
      through their multiple functional domains.

PMID- 10662777
TI  - Actin-dependent propulsion of endosomes and lysosomes by recruitment of N-WASP.
AB  - We examined the spatial and temporal control of actin assembly in living Xenopus
      eggs. Within minutes of egg activation, dynamic actin-rich comet tails appeared
      on a subset of cytoplasmic vesicles that were enriched in protein kinase C (PKC),
      causing the vesicles to move through the cytoplasm. Actin comet tail formation in
      vivo was stimulated by the PKC activator phorbol myristate acetate (PMA), and
      this process could be reconstituted in a cell-free system. We used this system to
      define the characteristics that distinguish vesicles associated with actin comet
      tails from other vesicles in the extract. We found that the protein, N-WASP, was
      recruited to the surface of every vesicle associated with an actin comet tail,
      suggesting that vesicle movement results from actin assembly nucleated by the
      Arp2/3 complex, the immediate downstream target of N-WASP. The motile vesicles
      accumulated the dye acridine orange, a marker for endosomes and lysosomes.
      Furthermore, vesicles associated with actin comet tails had the morphological
      features of multivesicular endosomes as revealed by electron microscopy.
      Endosomes and lysosomes from mammalian cells preferentially nucleated actin
      assembly and moved in the Xenopus egg extract system. These results define
      endosomes and lysosomes as recruitment sites for the actin nucleation machinery
      and demonstrate that actin assembly contributes to organelle movement.
      Conversely, by nucleating actin assembly, intracellular membranes may contribute
      to the dynamic organization of the actin cytoskeleton.

PMID- 10662778
TI  - Role of cofilin in epidermal growth factor-stimulated actin polymerization and
      lamellipod protrusion.
AB  - Stimulation of metastatic MTLn3 cells with epidermal growth factor (EGF) causes a
      rapid and transient increase in actin nucleation activity resulting from the
      appearance of free barbed ends at the extreme leading edge of extending
      lamellipods. To investigate the role of cofilin in EGF-stimulated actin
      polymerization and lamellipod extension in MTLn3 cells, we examined in detail the
      temporal and spatial distribution of cofilin relative to free barbed ends and
      characterized the actin dynamics by measuring the changes in the number of actin
      filaments. EGF stimulation triggers a transient increase in cofilin in the
      leading edge near the membrane, which is precisely cotemporal with the appearance
      of free barbed ends there. A deoxyribonuclease I binding assay shows that the
      number of filaments per cell increases by 1.5-fold after EGF stimulation.
      Detection of pointed ends in situ using deoxyribonuclease I binding demonstrates
      that this increase in the number of pointed ends is confined to the leading edge
      compartment, and does not occur within stress fibers or in the general cytoplasm.
      Using a light microscope severing assay, cofilin's severing activity was observed
      directly in cell extracts and shown to be activated after stimulation of the
      cells with EGF. Microinjection of function-blocking antibodies against cofilin
      inhibits the appearance of free barbed ends at the leading edge and lamellipod
      protrusion after EGF stimulation. These results support a model in which EGF
      stimulation recruits cofilin to the leading edge where its severing activity is
      activated, leading to the generation of short actin filaments with free barbed
      ends that participate in the nucleation of actin polymerization.

PMID- 10662779
TI  - Differential regulation of p27(Kip1) expression by mitogenic and hypertrophic
      factors: Involvement of transcriptional and posttranscriptional mechanisms.
AB  - Platelet-derived growth factor-BB (PDGF-BB) acts as a full mitogen for cultured
      aortic smooth muscle cells (SMC), promoting DNA synthesis and cell proliferation.
      In contrast, angiotensin II (Ang II) induces cellular hypertrophy as a result of
      increased protein synthesis, but is unable to drive cells into S phase. In an
      effort to understand the molecular basis for this differential growth response,
      we have examined the downstream effects of PDGF-BB and Ang II on regulators of
      the cell cycle machinery in rat aortic SMC. Both PDGF-BB and Ang II were found to
      stimulate the accumulation of G(1) cyclins with similar kinetics. In addition,
      little difference was observed in the expression level of their catalytic
      partners, Cdk4 and Cdk2. However, while both factors increased the enzymatic
      activity of Cdk4, only PDGF-BB stimulated Cdk2 activity in late G(1) phase. The
      lack of activation of Cdk2 in Ang II-treated cells was causally related to the
      failure of Ang II to stimulate phosphorylation of the enzyme on threonine and to
      downregulate p27(Kip1) expression. By contrast, exposure to PDGF-BB resulted in a
      progressive and dramatic reduction in the level of p27(Kip1) protein. The time
      course of p27(Kip1) decline was correlated with a reduced rate of synthesis and
      an increased rate of degradation of the protein. Importantly, the repression of
      p27(Kip1) synthesis by PDGF-BB was associated with a marked attenuation of Kip1
      gene transcription and a corresponding decrease in Kip1 mRNA accumulation. We
      also show that the failure of Ang II to promote S phase entry is not related to
      the autocrine production of transforming growth factor-beta1 by aortic SMC. These
      results identify p27(Kip1) as an important regulator of the phenotypic response
      of vascular SMC to mitogenic and hypertrophic stimuli.

PMID- 10662780
TI  - Oncogenic K-Ras and basic fibroblast growth factor prevent Fas-mediated apoptosis
      in fibroblasts through activation of mitogen-activated protein kinase.
AB  - By an expression cloning method using Fas-transgenic Balb3T3 cells, we tried to
      obtain inhibitory genes against Fas-mediated apoptosis and identified proto
      oncogene c-K-ras. Transient expression of K-Ras mutants revealed that oncogenic
      mutant K-Ras (RasV12) strongly inhibited, whereas dominant-inhibitory mutant K
      Ras (RasN17) enhanced, Fas-mediated apoptosis by inhibiting Fas-triggered
      activation of caspases without affecting an expression level of Fas. Among the
      target molecules of Ras, including Raf (mitogen-activated protein kinase kinase
      kinase [MAPKKK]), phosphatidylinositol 3 (PI-3) kinase, and Ral guanine
      nucleotide exchange factor (RalGDS), only the constitutively active form of Raf
      (Raf-CAAX) could inhibit Fas-mediated apoptosis. In addition, the constitutively
      active form of MAPKK (SDSE-MAPKK) suppressed Fas-mediated apoptosis, and MKP-1, a
      phosphatase specific for classical MAPK, canceled the protective activity of
      oncogenic K-Ras (K-RasV12), Raf-CAAX, and SDSE-MAPKK. Furthermore, physiological
      activation of Ras by basic fibroblast growth factor (bFGF) protected Fas
      transgenic Balb3T3 cells from Fas-mediated apoptosis. bFGF protection was also
      dependent on the activation of the MAPK pathway through Ras. All the results
      indicate that the activation of MAPK through Ras inhibits Fas-mediated apoptosis
      in Balb3T3 cells, which may play a role in oncogenesis.

PMID- 10662782
TI  - Functional cis-heterodimers of N- and R-cadherins.
AB  - Classical cadherins form parallel cis-dimers that emanate from a single cell
      surface. It is thought that the cis-dimeric form is active in cell-cell adhesion,
      whereas cadherin monomers are likely to be inactive. Currently, cis-dimers have
      been shown to exist only between cadherins of the same type. Here, we show the
      specific formation of cis-heterodimers between N- and R-cadherins. E-cadherin
      cannot participate in these complexes. Cells coexpressing N- and R-cadherins show
      homophilic adhesion in which these proteins coassociate at cell-cell interfaces.
      We performed site- directed mutagenesis studies, the results of which support the
      strand dimer model for cis-dimerization. Furthermore, we show that when N- and R
      cadherins are coexpressed in neurons in vitro, the two cadherins colocalize at
      certain neural synapses, implying biological relevance for these complexes. The
      present study provides a novel paradigm for cadherin interaction whereby
      selective cis-heterodimer formation may generate new functional units to mediate
      cell-cell adhesion.

PMID- 10662781
TI  - Requirement for beta-catenin in anterior-posterior axis formation in mice.
AB  - The anterior-posterior axis of the mouse embryo is defined before formation of
      the primitive streak, and axis specification and subsequent anterior development
      involves signaling from both embryonic ectoderm and visceral endoderm. Tauhe Wnt
      signaling pathway is essential for various developmental processes, but a role in
      anterior-posterior axis formation in the mouse has not been previously
      established. Beta-catenin is a central player in the Wnt pathway and in cadherin
      mediated cell adhesion. We generated beta-catenin-deficient mouse embryos and
      observed a defect in anterior-posterior axis formation at embryonic day 5.5, as
      visualized by the absence of Hex and Hesx1 and the mislocation of cerberus-like
      and Lim1 expression. Subsequently, no mesoderm and head structures are generated.
      Intercellular adhesion is maintained since plakoglobin substitutes for beta
      catenin. Our data demonstrate that beta-catenin function is essential in anterior
      posterior axis formation in the mouse, and experiments with chimeric embryos show
      that this function is required in the embryonic ectoderm.

PMID- 10662783
TI  - The tetraspanin CD9 associates with transmembrane TGF-alpha and regulates TGF
      alpha-induced EGF receptor activation and cell proliferation.
AB  - Transforming growth factor-alpha (TGF-alpha) is a member of the EGF growth factor
      family. Both transmembrane TGF-alpha and the proteolytically released soluble TGF
      alpha can bind to the EGF/TGF-alpha tyrosine kinase receptor (EGFR) and activate
      the EGFR-induced signaling pathways. We now demonstrate that transmembrane TGF
      alpha physically interacts with CD9, a protein with four membrane spanning
      domains that is frequently coexpressed with TGF-alpha in carcinomas. This
      interaction was mediated through the extracellular domain of transmembrane TGF
      alpha. CD9 expression strongly decreased the growth factor- and PMA- induced
      proteolytic conversions of transmembrane to soluble TGF-alpha and strongly
      enhanced the TGF- alpha-induced EGFR activation, presumably in conjunction with
      increased expression of transmembrane TGF-alpha. In juxtacrine assays, the CD9
      induced EGFR hyperactivation by transmembrane TGF-alpha resulted in increased
      proliferation. In contrast, CD9 coexpression with transmembrane TGF-alpha
      decreased the autocrine growth stimulatory effect of TGF-alpha in epithelial
      cells. This decrease was associated with increased expression of the cdk
      inhibitor, p21(CIP1). These data reveal that the association of CD9 with
      transmembrane TGF-alpha regulates ligand-induced activation of the EGFR, and
      results in altered cell proliferation.

PMID- 10662784
TI  - Target-cell contact activates a highly selective capacitative calcium entry
      pathway in cytotoxic T lymphocytes.
AB  - Calcium influx is critical for T cell activation. Evidence has been presented
      that T cell receptor-stimulated calcium influx in helper T lymphocytes occurs via
      channels activated as a consequence of depletion of intracellular calcium stores,
      a mechanism known as capacitative Ca(2+) entry (CCE). However, two key questions
      have not been addressed. First, the mechanism of calcium influx in cytotoxic T
      cells has not been examined. While the T cell receptor-mediated early signals in
      helper and cytotoxic T cells are similar, the physiology of the cells is
      strikingly different, raising the possibility that the mechanism of calcium
      influx is also different. Second, contact of T cells with antigen-presenting
      cells or targets involves a host of intercellular interactions in addition to
      those between antigen-MHC and the T cell receptor. The possibility that calcium
      influx pathways in addition to those activated via the T cell receptor may be
      activated by contact with relevant cells has not been addressed. We have used
      imaging techniques to show that target-cell-stimulated calcium influx in CTLs
      occurs primarily through CCE. We investigated the permeability of the CTL influx
      pathway for divalent cations, and compared it to the permeability of CCE in
      Jurkat human leukemic T cells. CCE in CTLs shows a similar ability to
      discriminate between calcium, barium, and strontium as CCE in Jurkat human
      leukemic T lymphocytes, where CCE is likely to mediated by Ca(2+) release
      activated Ca(2+) current (CRAC) channels, suggesting that CRAC channels also
      underlie CCE in CTLs. These results are the first determination of the mechanism
      of calcium influx in cytotoxic T cells and the first demonstration that cell
      contact-mediated calcium signals in T cells occur via depletion-activated
      channels.

PMID- 10662785
TI  - Role of cell surface metalloprotease MT1-MMP in epithelial cell migration over
      laminin-5.
AB  - Laminin-5 (Ln-5) is an extracellular matrix substrate for cell adhesion and
      migration, which is found in many epithelial basement membranes. Mechanisms
      eliciting migration on Ln-5 need to be elucidated because of their relevance to
      tissue remodeling and cancer metastasis. We showed that exogenous addition of
      activated matrix metalloprotease (MMP) 2 stimulates migration onto Ln-5 in breast
      epithelial cells via cleavage of the gamma2 subunit. To investigate the
      biological scope of this proteolytic mechanism, we tested a panel of cells,
      including colon and breast carcinomas, hepatomas, and immortalized hepatocytes,
      selected because they migrated or scattered constitutively in the presence of Ln
      5. We found that constitutive migration was inhibited by BB94 or TIMPs, known
      inhibitors of MMPs. Limited profiling by gelatin zymography and Western blotting
      indicated that the ability to constitutively migrate on Ln-5 correlated with
      expression of plasma membrane bound MT1-MMP metalloprotease, rather than
      secretion of MMP2, since MMP2 was not produced by three cell lines (one breast
      and two colon carcinomas) that constitutively migrated on Ln-5. Moreover,
      migration on Ln-5 was reduced by MT1-MMP antisense oligonucleotides both in MMP2+
      and MMP2- cell lines. MT1-MMP directly cleaved Ln-5, with a pattern similar to
      that of MMP2. The hemopexin-like domain of MMP2, which interferes with MMP2
      activation, reduced Ln-5 migration in MT1-MMP+, MMP2+ cells, but not in MT1-MMP+,
      MMP2- cells. These results suggest a model whereby expression of MT1-MMP is the
      primary trigger for migration over Ln-5, whereas MMP2, which is activated by MT1
      MMP, may play an ancillary role, perhaps by amplifying the MT1-MMP effects.
      Codistribution of MT1-MMP with Ln-5 in colon and breast cancer tissue specimens
      suggested a role for this mechanism in invasion. Thus, Ln-5 cleavage by MMPs may
      be a widespread mechanism that triggers migration in cells contacting epithelial
      basement membranes.

PMID- 10662786
TI  - The induction of tolerance by dendritic cells that have captured apoptotic cells.

PMID- 10662787
TI  - Viral G protein-coupled receptor and Kaposi's sarcoma: a model of paracrine
      neoplasia?

PMID- 10662788
TI  - Consequences of cell death: exposure to necrotic tumor cells, but not primary
      tissue cells or apoptotic cells, induces the maturation of immunostimulatory
      dendritic cells.
AB  - Cell death by necrosis is typically associated with inflammation, in contrast to
      apoptosis. We have identified additional distinctions between the two types of
      death that occur at the level of dendritic cells (DCs) and which influence the
      induction of immunity. DCs must undergo changes termed maturation to act as
      potent antigen-presenting cells. Here, we investigated whether exposure to
      apoptotic or necrotic cells affected DC maturation. We found that immature DCs
      efficiently phagocytose a variety of apoptotic and necrotic tumor cells. However,
      only exposure to the latter induces maturation. The mature DCs express high
      levels of the DC-restricted markers CD83 and lysosome-associated membrane
      glycoprotein (DC-LAMP) and the costimulatory molecules CD40 and CD86.
      Furthermore, they develop into powerful stimulators of both CD4(+) and CD8(+) T
      cells. Cross-presentation of antigens to CD8(+) T cells occurs after uptake of
      apoptotic cells. We demonstrate here that optimal cross-presentation of antigens
      from tumor cells requires two steps: phagocytosis of apoptotic cells by immature
      DCs, which provides antigenic peptides for major histocompatibility complex class
      I and class II presentation, and a maturation signal that is delivered by
      exposure to necrotic tumor cells, their supernatants, or standard maturation
      stimuli, e.g., monocyte-conditioned medium. Thus, DCs are able to distinguish two
      types of tumor cell death, with necrosis providing a control that is critical for
      the initiation of immunity.

PMID- 10662789
TI  - A discrete subpopulation of dendritic cells transports apoptotic intestinal
      epithelial cells to T cell areas of mesenteric lymph nodes.
AB  - This study identifies a dendritic cell (DC) subset that constitutively transports
      apoptotic intestinal epithelial cell remnants to T cell areas of mesenteric lymph
      nodes in vivo. Rat intestinal lymph contains two DC populations. Both populations
      have typical DC morphology, are major histocompatibility complex class II(hi),
      and express OX62, CD11c, and B7. CD4(+)/OX41(+) DCs are strong antigen-presenting
      cells (APCs). CD4(-)/OX41(-) DCs are weak APCs and contain cytoplasmic apoptotic
      DNA, epithelial cell-restricted cytokeratins, and nonspecific esterase (NSE)(+)
      inclusions, not seen in OX41(+) DCs. Identical patterns of NSE electrophoretic
      variants exist in CD4(-)/OX41(-) DCs, intestinal epithelial cells, and mesenteric
      node DCs but not in other DC populations, macrophages, or tissues. Terminal
      deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL)
      positive DCs and strongly NSE(+) DCs are present in intestinal lamina propria.
      Peyer's patches and mesenteric but not other lymph nodes contain many strongly
      NSE(+) DCs in interfollicular and T cell areas. Similar DCs are seen in the ileum
      and in T cell areas of mesenteric nodes in gnotobiotic rats. These results show
      that a distinct DC subset constitutively endocytoses and transports apoptotic
      cells to T cell areas and suggest a role for these DCs in inducing and
      maintaining peripheral self-tolerance.

PMID- 10662790
TI  - Transgenic expression of the chemokine receptor encoded by human herpesvirus 8
      induces an angioproliferative disease resembling Kaposi's sarcoma.
AB  - Human herpesvirus 8 (HHV8, also known as Kaposi's sarcoma [KS]-associated
      herpesvirus) has been implicated as an etiologic agent for KS, an angiogenic
      tumor composed of endothelial, inflammatory, and spindle cells. Here, we report
      that transgenic mice expressing the HHV8-encoded chemokine receptor (viral G
      protein-coupled receptor) within hematopoietic cells develop angioproliferative
      lesions in multiple organs that morphologically resemble KS lesions. These
      lesions are characterized by a spectrum of changes ranging from erythematous
      maculae to vascular tumors, by the presence of spindle and inflammatory cells,
      and by expression of vGPCR, CD34, and vascular endothelial growth factor. We
      conclude that vGPCR contributes to the development of the angioproliferative
      lesions observed in these mice and suggest that this chemokine receptor may play
      a role in the pathogenesis of KS in humans.

PMID- 10662791
TI  - Protease-activated receptor 1 mediates thrombin-dependent, cell-mediated renal
      inflammation in crescentic glomerulonephritis.
AB  - Protease-activated receptor (PAR)-1 is a cellular receptor for thrombin that is
      activated after proteolytic cleavage. The contribution of PAR-1 to inflammatory
      cell-mediated renal injury was assessed in murine crescentic glomerulonephritis
      (GN). A pivotal role for thrombin in this model was demonstrated by the capacity
      of hirudin, a selective thrombin antagonist, to attenuate renal injury. Compared
      with control treatment, hirudin significantly reduced glomerular crescent
      formation, T cell and macrophage infiltration, fibrin deposition, and elevated
      serum creatinine, which are prominent features of GN. PAR-1-deficient (PAR-1(-/
      )) mice, which have normal coagulation, also showed significant protection from
      crescentic GN compared with wild-type mice. The reductions in crescent formation,
      inflammatory cell infiltration, and serum creatinine were similar in PAR-1(-/-)
      and hirudin-treated mice, but hirudin afforded significantly greater protection
      from fibrin deposition. Treatment of wild-type mice with a selective PAR-1
      activating peptide (TRAP) augmented histological and functional indices of GN,
      but TRAP treatment did not alter the severity of GN in PAR(-/-) mice. These
      results indicate that activation of PAR-1 by thrombin or TRAP amplifies
      crescentic GN. Thus, in addition to its procoagulant role, thrombin has
      proinflammatory, PAR-1-dependent effects that augment inflammatory renal injury.

PMID- 10662792
TI  - Src-like adaptor protein (SLAP) is a negative regulator of T cell receptor
      signaling.
AB  - Initiation of T cell antigen receptor (TCR) signaling is dependent on Lck, a Src
      family kinase. The Src-like adaptor protein (SLAP) contains Src homology (SH)3
      and SH2 domains, which are highly homologous to those of Lck and other Src family
      members. Because of the structural similarity between Lck and SLAP, we studied
      its potential role in TCR signaling. Here, we show that SLAP is expressed in T
      cells, and that when expressed in Jurkat T cells it can specifically inhibit TCR
      signaling leading to nuclear factor of activated T cells (NFAT)-, activator
      protein 1 (AP-1)-, and interleukin 2-dependent transcription. The SH3 and SH2
      domains of SLAP are required for maximal attenuation of TCR signaling. This
      inhibitory activity can be bypassed by the combination of phorbol myristate
      acetate (PMA) and ionomycin, suggesting that SLAP acts proximally in the TCR
      signaling pathway. SLAP colocalizes with endosomes in Jurkat and in HeLa cells,
      and is insoluble in mild detergents. In stimulated Jurkat cells, SLAP associates
      with a molecular signaling complex containing CD3zeta, ZAP-70, SH2 domain
      containing leukocyte protein of 76 kD (SLP-76), Vav, and possibly linker for
      activation of T cells (LAT). These results suggest that SLAP is a negative
      regulator of TCR signaling.

PMID- 10662793
TI  - bcl-2 transgene expression inhibits apoptosis in the germinal center and reveals
      differences in the selection of memory B cells and bone marrow antibody-forming
      cells.
AB  - Immunization with T cell-dependent antigens generates long-lived memory B cells
      and antibody-forming cells (AFCs). Both populations originate in germinal centers
      and, predominantly, produce antibodies with high affinity for antigen. The means
      by which germinal center B cells are recruited into these populations remains
      unclear. We have examined affinity maturation of antigen-specific B cells in mice
      expressing the cell death inhibitor bcl-2 as a transgene. Such mice had reduced
      apoptosis in germinal centers and an excessive number of memory B cells with a
      low frequency of V gene somatic mutation, including those mutations encoding
      amino acid exchanges known to enhance affinity. Despite the frequency of AFCs
      being increased in bcl-2-transgenic mice, the fraction secreting high-affinity
      antibody in the bone marrow at day 42 remained unchanged compared with controls.
      The inability of BCL-2 to alter selection of bone marrow AFCs is consistent with
      these cells being selected within the germinal center on the basis of their
      affinity being above some threshold rather than their survival being due to a
      selective competition for an antigen-based signal. Continuous competition for
      antigen does, however, explain formation of the memory compartment.

PMID- 10662794
TI  - Germinal centers without T cells.
AB  - Germinal centers are critical for affinity maturation of antibody (Ab) responses.
      This process allows the production of high-efficiency neutralizing Ab that
      protects against virus infection and bacterial exotoxins. In germinal centers,
      responding B cells selectively mutate the genes that encode their receptors for
      antigen. This process can change Ab affinity and specificity. The mutated cells
      that produce high-affinity Ab are selected to become Ab-forming or memory B
      cells, whereas cells that have lost affinity or acquired autoreactivity are
      eliminated. Normally, T cells are critical for germinal center formation and
      subsequent B cell selection. Both processes involve engagement of CD40 on B cells
      by T cells. This report describes how high-affinity B cells can be induced to
      form large germinal centers in response to (4-hydroxy-3-nitrophenyl) acetyl (NP)
      Ficoll in the absence of T cells or signaling through CD40 or CD28. This requires
      extensive cross-linking of the B cell receptors, and a frequency of antigen
      specific B cells of at least 1 in 1,000. These germinal centers abort
      dramatically at the time when mutated high-affinity B cells are normally selected
      by T cells. Thus, there is a fail-safe mechanism against autoreactivity, even in
      the event of thymus-independent germinal center formation.

PMID- 10662795
TI  - TRANCE, a tumor necrosis factor family member, enhances the longevity and
      adjuvant properties of dendritic cells in vivo.
AB  - Mature dendritic cells (DCs) are powerful antigen presenting cells that have the
      unique capacity to migrate to the T cell zone of draining lymph nodes after
      subcutaneous injection. Here we report that treatment of antigen-pulsed mature
      DCs with tumor necrosis factor (TNF)-related activation-induced cytokine
      (TRANCE), a TNF family member, before immunization enhances their adjuvant
      capacity and elicits improved T cell priming in vivo, such that both primary and
      memory T cell immune responses are enhanced. By enumerating migratory DCs in the
      draining lymph nodes and by studying their function in stimulating naive T cells,
      we show that one of the underlying mechanisms for enhanced T cell responses is an
      increase in the number of ex vivo antigen-pulsed DCs that are found in the T cell
      areas of lymph nodes. These results suggest that the longevity and abundance of
      mature DCs at the site of T cell priming influence the strength of the DC
      initiated T cell immunity in situ. Our findings have the potential to improve DC
      based immunotherapy; i.e., the active immunization of humans with autologous DCs
      that have been pulsed with clinically significant antigens ex vivo.

PMID- 10662796
TI  - Efficient generation of a hepatitis B virus cytotoxic T lymphocyte epitope
      requires the structural features of immunoproteasomes.
AB  - Interferon (IFN)-gamma-induced cells express the proteasome subunits low
      molecular weight protein (LMP)2, LMP7, and MECL-1 (multicatalytic endopeptidase
      complex-like 1), leading to the formation of immunoproteasomes. Although these
      subunits are thought to optimize MHC class I antigen processing, the extent of
      their role and the mechanistic aspects involved remain unclear. Herein, we study
      the proteolytic generation of an human histocompatibility leukocyte antigen (HLA)
      Aw68-restricted hepatitis B virus core antigen (HBcAg) cytotoxic T lymphocyte
      (CTL) epitope that is recognized by peripheral blood lymphocytes from patients
      with acute self-limited but not chronic hepatitis B virus (HBV). Immunological
      data suggest that IFN-gamma-induced rather than uninduced HeLa cells process and
      present the HBV CTL epitope upon infection with HBcAg-expressing vaccinia
      viruses. Analyses of 20S proteasome digests of synthetic polypeptides covering
      the antigenic HBcAg peptide demonstrate that only immunoproteasomes efficiently
      perform the cleavages needed for the liberation of this HBV CTL epitope. Although
      the concerted presence of the three immunosubunits appears essential, we find
      that both catalytically active LMP7 and inactive LMP7 T1A support CTL epitope
      generation. We conclude that LMP7 influences the structural features of 20S
      proteasomes, thereby enhancing the activity of the LMP2 and MECL-1 catalytic
      sites, which provide cleavage specificity. Thus, LMP7 incorporation is of greater
      functional importance for the generation of an HBV CTL epitope than cleavage
      specificity.

PMID- 10662797
TI  - Negative regulation of phagocytosis in murine macrophages by the Src kinase
      family member, Fgr.
AB  - Ingestion of opsonized pathogens by professional phagocytes results in the
      generation and release of microbicidal products that are essential for normal
      host defense. Because these products can result in significant tissue injury,
      phagocytosis must be regulated to limit damage to the host while allowing for
      optimal clearance and destruction of opsonized pathogens. To pursue negative
      regulation of phagocytosis, we assessed the effect of the Src kinase family
      member, Fgr, on opsonin-dependent phagocytosis by mouse macrophages. We chose Fgr
      because it is present in high concentrations in circulating phagocytes but is not
      essential for Fcgamma receptor-mediated ingestion by mouse macrophages. Although
      expression of Fgr both in a macrophage cell line and in primary macrophages
      significantly attenuates ingestion mediated by Fcgamma receptors and CR3, it does
      not affect macropinocytosis or receptor-mediated endocytosis. This selective
      effect of Fgr is independent of its tyrosine kinase function. After Fcgamma
      receptor cross-linking, Fgr becomes associated with the immunoreceptor tyrosine
      based inhibition motif (ITIM)-containing receptor, SIRPalpha (a member of the
      signal-regulatory protein family, also known as Src homology 2 domain-containing
      protein tyrosine phosphatase [SHP] substrate 1 [SHPS-1], brain immunoglobulin
      like molecule with tyrosine-based activation motifs [BIT], and P84) and
      potentiates the association of the phosphatase SHP-1 with SIRPalpha. This
      association is responsible, at least in part, for decreasing positive signaling
      essential for optimal phagocytosis. These data demonstrate an important negative
      regulatory role for this Src kinase family member and suggest that this
      homeostatic function must be overcome for optimal uptake and clearance of
      opsonized pathogens.

PMID- 10662798
TI  - The first alpha helix of interleukin (IL)-2 folds as a homotetramer, acts as an
      agonist of the IL-2 receptor beta chain, and induces lymphokine-activated killer
      cells.
AB  - Interleukin (IL)-2 interacts with two types of functional receptors (IL
      2Ralphabetagamma and IL-2Rbetagamma) and acts on a broad range of target cells
      involved in inflammatory reactions and immune responses. For the first time, we
      show that a chemically synthesized fragment of the IL-2 sequence can fold into a
      molecule mimicking the quaternary structure of a hemopoietin. Indeed, peptide p1
      30 (containing amino acids 1-30, covering the entire alpha helix A of IL-2)
      spontaneously folds into an alpha-helical homotetramer and stimulates the growth
      of T cell lines expressing human IL-2Rbeta, whereas shorter versions of the
      peptide lack helical structure and are inactive. We also demonstrate that this
      neocytokine interacts with a previously undescribed dimeric form of IL-2Rbeta. In
      agreement with its binding to IL-2Rbeta, p1-30 activates Shc and p56(lck) but
      unlike IL-2, fails to activate Janus kinase (Jak)1, Jak3, and signal transducer
      and activator of transcription 5 (STAT5). Unexpectedly, we also show that p1-30
      activates Tyk2, thus suggesting that IL-2Rbeta may bind to different Jaks
      depending on its oligomerization. At the cellular level, p1-30 induces lymphokine
      activated killer (LAK) cells and preferentially activates CD8(low) lymphocytes
      and natural killer cells, which constitutively express IL-2Rbeta. A significant
      interferon gamma production is also detected after p1-30 stimulation. A mutant
      form of p1-30 (Asp20-->Lys), which is likely unable to induce vascular leak
      syndrome, remains capable of generating LAK cells, like the original p1-30
      peptide. Altogether, our data suggest that p1-30 has therapeutic potential.

PMID- 10662799
TI  - CD40-independent pathways of T cell help for priming of CD8(+) cytotoxic T
      lymphocytes.
AB  - In many cases, induction of CD8(+) CTL responses requires CD4(+) T cell help.
      Recently, it has been shown that a dominant pathway of CD4(+) help is via antigen
      presenting cell (APC) activation through engagement of CD40 by CD40 ligand on
      CD4(+) T cells. To further study this three cell interaction, we established an
      in vitro system using dendritic cells (DCs) as APCs and influenza hemagglutinin
      (HA) class I and II peptide-specific T cell antigen receptor transgenic T cells
      as cytotoxic T lymphocyte precursors and CD4(+) T helper cells, respectively. We
      found that CD4(+) T cells can provide potent help for DCs to activate CD8(+) T
      cells when antigen is provided in the form of either cell lysate, recombinant
      protein, or synthetic peptides. Surprisingly, this help is completely independent
      of CD40. Moreover, CD40-independent CD4(+) help can be documented in vivo.
      Finally, we show that CD40-independent T cell help is delivered through both
      sensitization of DCs and direct CD4(+)-CD8(+) T cell communication via
      lymphokines. Therefore, we conclude that CD4(+) help comprises at least three
      components: CD40-dependent DC sensitization, CD40-independent DC sensitization,
      and direct lymphokine-dependent CD4(+)-CD8(+) T cell communication.

PMID- 10662800
TI  - Expression cloning of an immunodominant family of Mycobacterium tuberculosis
      antigens using human CD4(+) T cells.
AB  - Development of a subunit vaccine for Mycobacterium tuberculosis (Mtb) is likely
      to be dependent on the identification of T cell antigens that induce strong
      proliferation and interferon gamma production from healthy purified protein
      derivative (PPD)(+) donors. We have developed a sensitive and rapid technique for
      screening an Mtb genomic library expressed in Escherichia coli using Mtb-specific
      CD4(+) T cells. Using this technique, we identified a family of highly related
      Mtb antigens. The gene of one family member encodes a 9.9-kD antigen, termed
      Mtb9.9A. Recombinant Mtb9.9A protein, expressed and purified from E. coli,
      elicited strong T cell proliferation and IFN-gamma production by peripheral blood
      mononuclear cells from PPD(+) but not PPD(-) individuals. Southern blot analysis
      and examination of the Mtb genome sequence revealed a family of highly related
      genes. A T cell line from a PPD(+) donor that failed to react with recombinant
      Mtb9.9A recognized one of the other family members, Mtb9.9C. Synthetic peptides
      were used to map the T cell epitope recognized by this line, and revealed a
      single amino acid substitution in this region when compared with Mtb9.9A. The
      direct identification of antigens using T cells from immune donors will
      undoubtedly be critical for the development of vaccines to several intracellular
      pathogens.

PMID- 10662801
TI  - Sensitivity to sunburn is associated with susceptibility to ultraviolet radiation
      induced suppression of cutaneous cell-mediated immunity.
AB  - Skin cancer incidence is highest in white-skinned people. Within this group, skin
      types I/II (sun sensitive/tan poorly) are at greater risk than skin types III/IV
      (sun tolerant/tan well). Studies in mice demonstrate that ultraviolet radiation
      (UVR)-induced suppression of cell-mediated immune function plays an important
      role in the development of skin cancer and induces a susceptibility to infectious
      disease. A similar role is suspected in humans, but we lack quantitative human
      data to make risk assessments of ambient solar exposure on human health. This
      study demonstrates that ambient levels of solar UVR, typically experienced within
      1 h of exposure to noonday summer sunlight, can suppress contact hypersensitivity
      (CHS) responses in healthy white-skinned humans in vivo (n = 93). There was a
      linear relationship between increase in erythema and suppression of CHS (P <
      0.001), and a moderate sunburn (two minimal erythema doses [2 MED]) was
      sufficient to suppress CHS in all volunteers by 93%. However, a single
      suberythemal exposure of either 0.25 or 0.5 MED suppressed CHS responses by 50
      and 80%, respectively, in skin types I/II, whereas 1 MED only suppressed CHS by
      40% in skin types III/IV. The two- to threefold greater sensitivity of skin types
      I/II for a given level of sunburn may play a role in their greater sensitivity to
      skin cancer.

PMID- 10662802
TI  - Evidence for the chronic in vivo production of human T cell leukemia virus type I
      Rof and Tof proteins from cytotoxic T lymphocytes directed against viral
      peptides.
AB  - Human T cell leukemia virus type I (HTLV-I) is a persistent virus that causes
      adult T cell leukemia and tropical spastic paraparesis/HTLV-I-associated
      myelopathy. Studies on rabbits have shown that viral proteins encoded by the open
      reading frames pX-I and pX-II are required for the establishment of the
      persistent infection. To examine the in vivo production of these proteins in
      humans, we have investigated whether cytotoxic T lymphocytes isolated from HTLV-I
      infected individuals recognized pX-I and pX-II peptides. CD8(+) T lymphocytes to
      pX-I and pX-II peptides were detected in HTLV-I-infected individuals, whatever
      their clinical status, and even in the absence of any antigenic restimulation.
      These findings indicate that the HTLV-I pX-I and pX-II proteins are chronically
      synthesized in vivo, and are targets of the natural immune response to the virus.

PMID- 10662803
TI  - A broad spectrum secreted chemokine binding protein encoded by a herpesvirus.
AB  - Chemokines are a family of small proteins that interact with seven-transmembrane
      domain receptors and modulate the migration of immune cells into sites of
      inflammation and infection. The murine gammaherpesvirus 68 M3 gene encodes a
      secreted 44-kD protein with no sequence similarity to known chemokine receptors.
      We show that M3 binds a broad range of chemokines, including CC, CXC, C, and
      CX(3)C chemokines, but does not bind human B cell-specific nor mouse neutrophil
      specific CXC chemokines. This herpesvirus chemokine binding protein (hvCKBP)
      blocks the interaction of chemokines with high-affinity cellular receptors and
      inhibits chemokine-induced elevation of intracellular calcium levels. hvCKBP is
      the first soluble chemokine receptor identified in herpesviruses; it represents a
      novel protein structure with the ability to bind all subfamilies of chemokines in
      solution and has potential therapeutic applications.

PMID- 10662804
TI  - Somatic hypermutation in MutS homologue (MSH)3-, MSH6-, and MSH3/MSH6-deficient
      mice reveals a role for the MSH2-MSH6 heterodimer in modulating the base
      substitution pattern.
AB  - Although the primary function of the DNA mismatch repair (MMR) system is to
      identify and correct base mismatches that have been erroneously introduced during
      DNA replication, recent studies have further implicated several MMR components in
      somatic hypermutation of immunoglobulin (Ig) genes. We studied the immune
      response in mice deficient in MutS homologue (MSH)3 and MSH6, two mutually
      exclusive partners of MSH2 that have not been examined previously for their role
      in Ig hypermutation. In Msh6(-)/- and Msh3(-)/-/Msh6(-)/- mice, base
      substitutions are preferentially targeted to G and C nucleotides and to an RGYW
      hot spot, as has been shown previously in Msh2(-)/- mice. In contrast, Msh3(-)/-
      mice show no differences from their littermate controls. These findings indicate
      that the MSH2-MSH6 heterodimer, but not the MSH2-MSH3 complex, is responsible for
      modulating Ig hypermutation.

PMID- 10662805
TI  - Of palms, soles, and gums.

PMID- 10662806
TI  - Genetic susceptibility to age related macular degeneration.
AB  - Age related macular degeneration (AMD) is the leading cause of visual impairment
      in the elderly and a major cause of blindness in the developed world. The disease
      can take two forms, geographic atrophy and choroidal neovascularisation. The
      pathogenesis of AMD is poorly understood. There are undoubtedly environmental and
      other risk factors involved and the adverse effect of smoking is well
      established. Several studies have shown that genetic factors are important but
      leave uncertainty about the magnitude and nature of the genetic component and
      whether it varies with the type of AMD. Several hereditary retinal dystrophies
      show similarities to AMD and these genes are potential candidate susceptibility
      genes. Particular interest has focused on the ABCR gene which is responsible for
      autosomal recessive Stargardt macular dystrophy. It has been claimed that
      heterozygotes for ABCR mutations are predisposed to AMD but the data are
      conflicting. Studies of the genes responsible for autosomal dominant Sorsby
      fundus dystrophy, Doyne honeycomb retinal dystrophy, and Best disease have given
      negative results. In one large AMD family, linkage has been reported to markers
      in 1q25-q31. Recent data suggest that the ApoE epsilon4 allele may be associated
      with reduced risk of AMD. A better understanding of the genetic factors in AMD
      would contribute to understanding the pathogenesis. If those at risk could be
      identified it may be possible to modify lifestyle or develop novel therapies in
      the presymptomatic stage to prevent disease or decrease its severity.

PMID- 10662807
TI  - Haim-Munk syndrome and Papillon-Lefevre syndrome are allelic mutations in
      cathepsin C.
AB  - Of the many palmoplantar keratoderma (PPK) conditions, only Papillon-Lefevre
      syndrome (PLS) and Haim-Munk syndrome (HMS) are associated with premature
      periodontal destruction. Although both PLS and HMS share the cardinal features of
      PPK and severe periodontitis, a number of additional findings are reported in HMS
      including arachnodactyly, acro-osteolysis, atrophic changes of the nails, and a
      radiographic deformity of the fingers. While PLS cases have been identified
      throughout the world, HMS has only been described among descendants of a
      religious isolate originally from Cochin, India. Parental consanguinity is a
      characteristic of many cases of both conditions. Although autosomal recessive
      transmission of PLS is evident, a more "complex" autosomal recessive pattern of
      inheritance with phenotypic influences from a closely linked modifying locus has
      been hypothesised for HMS. Recently, mutations of the cathepsin C gene have been
      identified as the underlying genetic defect in PLS. To determine if a cathepsin C
      mutation is also responsible for HMS, we sequenced the gene in affected and
      unaffected subjects from the Cochin isolate in which both the PLS and HMS
      phenotypes appear. Here we report identification of a mutation of cathepsin C
      (exon 6, 2127A--> G) that changes a highly conserved amino acid in the cathepsin
      C peptide. This mutation segregates with HMS in four nuclear families.
      Additionally, the existence of a shared common haplotype for genetic loci
      flanking the cathepsin C gene suggests that affected subjects descended from the
      Cochin isolate are homozygous for a mutation inherited "identical by descent"
      from a common ancestor. This finding supports simple autosomal recessive
      inheritance for HMS in these families. We also report a mutation of the same exon
      6 CTSC codon (2126C-->T) in a Turkish family with classical PLS. These findings
      provide evidence that PLS and HMS are allelic variants of cathepsin C gene
      mutations.

PMID- 10662808
TI  - Localisation of a gene for prepubertal periodontitis to chromosome 11q14 and
      identification of a cathepsin C gene mutation.
AB  - Prepubertal periodontitis (PPP) is a rare and rapidly progressive disease of
      young children that results in destruction of the periodontal support of the
      primary dentition. The condition may occur as part of a recognised syndrome or
      may occur as an isolated finding. Both autosomal dominant and recessive forms of
      Mendelian transmission have been reported for PPP. We report a consanguineous
      Jordanian family with four members affected by PPP in two nuclear sibships. The
      parents of the affected subjects are first cousins. We have localised a gene of
      major effect for PPP in this kindred (Zmax=3.55 for D11S901 at theta=0.00) to a
      14 cM genetic interval on chromosome 11q14 flanked by D11S916 and D11S1367. This
      PPP candidate interval overlaps the region of chromosome 11q14 that contains the
      cathepsin C gene responsible for Papillon-Lefevre and Haim-Munk syndromes.
      Sequence analysis of the cathepsin C gene from PPP affected subjects from this
      Jordanian family indicated that all were homozygous for a missense mutation
      (1040A-->G) that changes a tyrosine to a cysteine. All four parents were
      heterozygous carriers of this Tyr347Cys cathepsin C mutation. None of the family
      members who were heterozygous carriers for this mutation showed any clinical
      findings of PPP. None of the 50 controls tested were found to have this Tyr347Cys
      mutation. This is the first reported gene mutation for non-syndromic
      periodontitis and shows that non-syndromic PPP is an allelic variant of the type
      IV palmoplantar ectodermal dysplasias.

PMID- 10662809
TI  - Disruption of heart sarcoglycan complex and severe cardiomyopathy caused by beta
      sarcoglycan mutations.
AB  - Two young males with limb-girdle muscular dystrophy (LGMD) resulting from
      sarcoglycan deficiency died at 27 (patient 1) and 18 years (patient 2) of severe
      cardiomyopathy. Genetic analysis showed that they were compound heterozygotes for
      mutations in the beta sarcoglycan gene. One of these mutations, an 8 bp
      duplication in exon 3, was common to both patients. The second mutation in
      patient 2 was a 4 bp deletion at the splice donor site of intron 2, not reported
      previously. Patient 2 had more severe heart and skeletal muscle defects with
      faster deterioration; no sarcoglycans were detected in his skeletal muscle. The
      second mutation in patient 1, inferred because the unaffected father carries the
      8 bp duplication, was not found. In patient 1, both heart and skeletal muscle
      were analysed and showed reduction of all sarcoglycans in both tissues and
      incorrect localisation of alpha and gamma sarcoglycans in heart. Therefore
      mutations in one sarcoglycan gene can disrupt the entire sarcoglycan complex in
      both skeletal and cardiac muscle. Differing expression patterns of sarcoglycan
      components in heart and skeletal muscle could be the result of alternatively
      spliced transcripts in these tissues. By sequencing an alternative transcript,
      highly expressed in the heart and skeletal muscle of patient 1, we found an 87 bp
      cryptic exon not previously reported. Although cardiomyopathy can result from
      mutations in alpha and gamma sarcoglycans, we show for the first time that the
      condition can also be caused by mutations in the beta sarcoglycan gene. This
      report therefore expands the phenotype of sarcoglycanopathies and suggests that
      cardiac function in LGMD patients with defective sarcoglycan expression should be
      monitored.

PMID- 10662810
TI  - Evaluation of a counselling protocol for predictive genetic testing for
      hereditary non-polyposis colorectal cancer.
AB  - OBJECTIVES: To evaluate the feasibility of a reduced counselling programme for
      predictive genetic testing for hereditary non-polyposis colorectal cancer (HNPCC)
      in terms of counsellees' opinions on the extent and significance of genetic
      counselling and need for psychological support at different phases of the testing
      procedure. DESIGN: Prospective follow up study with pre-test questionnaire
      assessment of background sociodemographic variables. The protocol comprised a pre
      test counselling session, a period for reflection, and a test disclosure session.
      The outcome variables were studied by post-test questionnaires at one month and
      one year follow up. SUBJECTS: Two hundred and seventy one high risk members of 36
      families with HNPCC who attended both counselling sessions and completed the
      questionnaires. RESULTS: The pre-test counselling was considered fairly or very
      useful by 89% of respondents and one post-test session was considered sufficient
      by over 80% of respondents at follow up. Fifty three percent would have used
      extra psychological support had it been offered with the counselling. On enquiry
      one year after receiving the test result, only 2% stated that the need for
      support was at its greatest at that time, while the majority (46%) reported that
      the need for support had been greatest at the moment of test disclosure.
      CONCLUSIONS: A protocol that includes one comprehensive pre-test counselling
      session and a test disclosure session, supplemented with the option of
      professional psychological support, seems to be sufficient for both the
      educational and supportive needs of counsellees. Only a minority expressed a need
      for post-test follow up sessions, which suggests that, in this disorder,
      resources can be directed to the beneficial surveillance programmes rather than
      to extensive psychological support.

PMID- 10662811
TI  - Identification of supernumerary marker chromosomes derived from chromosomes 5, 6,
      19, and 20 using FISH.
AB  - A large number of cases with supernumerary marker chromosomes (SMCs) should be
      compared to achieve a better delineation of karyotype-phenotype correlations.
      Here we present four phenotypically abnormal patients with autosomal marker
      chromosomes analysed by fluorescence in situ hybridisation using centromeric,
      telomeric, and unique sequence probes, as well as forward and reverse painting.
      We also report the first case, to the best of our knowledge, of an SMC derived
      from chromosome 5. Furthermore, a marker chromosome 20 in a patient with sex
      differentiation abnormalities, a double mar(6) in a boy with psychomotor
      retardation, and the association of r(19) with dup(21q21.2q22.12) are described.
      Although the mar(6) was very small, the presence of euchromatin was shown,
      suggesting that the partial trisomy of pericentric region derived sequences is
      implicated in the aetiology of the abnormal phenotypes.

PMID- 10662812
TI  - A supernumerary marker chromosome originating from two different regions of
      chromosome 18.
AB  - By random amplification of a microdissected chromosome using the degenerate
      oligonucleotide primed polymerase chain reaction (DOP-PCR) and forward painting
      (microFISH), we characterised an extra structurally abnormal chromosome (ESAC) or
      supernumerary marker chromosome in a mentally retarded girl with a pattern of
      dysmorphic features. It could be clearly shown that the small marker chromosome
      originates from two different regions of chromosome 18, 18p11.1-->18q11.1 and
      18q12.3-->18q21.1 respectively. Maternal origin of the de novo ESAC and
      biparental origin of the normal homologues of chromosome 18 were shown by PCR of
      several highly polymorphic microsatellites. In this case, application of
      microFISH was a prerequisite for rapid and precise characterisation of an ESAC. A
      definite identification of this discontinuous supernumerary marker chromosome
      would not have been possible using FISH with centromere specific probes or
      multicolour FISH approaches.

PMID- 10662813
TI  - 5p14 deletion associated with microcephaly and seizures.
AB  - We report on a father and son who have an interstitial deletion of 5p14. The
      father is clinically and mentally normal while the son has significant clinical
      involvement including microcephaly, seizures, and global developmental delay. The
      extent of the 5p14 deletion was determined using fluorescence in situ
      hybridisation (FISH). The deletion in this present family is smaller than a
      deletion previously described in a multigenerational family that lacks any
      clinical phenotype. This report shows that a 5p14 deletion does not always lead
      to a normal phenotype.

PMID- 10662814
TI  - A microdeletion in 19q13.2 associated with mental retardation, skeletal
      malformations, and Diamond-Blackfan anaemia suggests a novel contiguous gene
      syndrome.
AB  - Diamond-Blackfan anaemia (DBA) is a constitutional red blood cell hypoplasia
      which may be associated with a variety of developmental abnormalities. A gene for
      DBA was recently mapped to chromosome 19q13.2 and subsequently cloned. Analysis
      of 19q marker alleles in DNA of sporadic DBA cases showed de novo microdeletions
      in three patients also presenting with mental retardation. We have studied one of
      these patients and characterised the deletion by fluorescence in situ
      hybridisation (FISH) to extended DNA fibres. The deletion was shown to be
      continuous over a 3.2 Mb region and the fibre-FISH analysis showed both
      chromosomal breakpoints. In combination, the clinical and molecular findings
      suggest a contiguous gene syndrome with a gene locus for mental retardation and,
      probably, skeletal malformations included in the deletion.

PMID- 10662815
TI  - First description of germline mosaicism in familial hypertrophic cardiomyopathy.
AB  - Familial hypertrophic cardiomyopathy is a genetically and phenotypically
      heterogeneous disease caused by mutations in seven sarcomeric protein genes. It
      is known to be transmitted as an autosomal dominant trait with rare de novo
      mutations.A French family in which two members are affected by hypertrophic
      cardiomyopathy was clinically screened with electrocardiography and
      echocardiography. Genetic analyses were performed on leucocyte DNA by haplotype
      analysis with microsatellite markers at the MYH7 locus and mutation screening by
      single strand conformation polymorphism analysis. Two subjects exhibited severe
      hypertrophic cardiomyopathy. A mutation in the MYH7 gene was found in exon 14
      (Arg453Cys). The two affected patients were carriers of the mutation, which was
      not found in the circulating lymphocytes of their parents. Haplotype analysis at
      the MYH7 locus with two intragenic microsatellite markers (MYOI and MYOII) and
      the absence of the mutation in the father's sperm DNA suggested that the mutation
      had been inherited from the mother. However, it was not found in either her
      fibroblasts or hair. This is the first description of germline mosaicism shown by
      molecular genetic analysis in an autosomal dominant disorder and more especially
      in hypertrophic cardiomyopathy. This mosaicism had been inherited from the mother
      but did not affect her somatic cells. Such a phenomenon might account for some de
      novo mutations in familial hypertrophic cardiomyopathy.

PMID- 10662816
TI  - Shared decision making and non-directiveness in genetic counselling.

PMID- 10662817
TI  - Comparison of cysteine string protein (Csp) and mutant alpha-SNAP overexpression
      reveals a role for csp in late steps of membrane fusion in dense-core granule
      exocytosis in adrenal chromaffin cells.
AB  - Assembly of the SNARE complex and its disassembly caused by the action of soluble
      N-ethylmaleimide-sensitive factor (NSF) attachment protein (SNAP) and NSF is
      crucial for the maintenance of vesicular traffic, including fusion of regulated
      exocytotic vesicles. Various other proteins may also have important roles in the
      processes leading to membrane fusion via interaction with the SNARE proteins,
      including the secretory vesicle cysteine string protein (Csp). Here we have
      examined the effect of overexpression of a dominant negative alpha-SNAP mutant or
      Csp on exocytosis of dense-core granules in single chromaffin cells monitored
      using amperometry to detect released catecholamine. Exocytosis of trans-Golgi
      network (TGN)-derived dense-core granules was substantially inhibited by
      expression of alpha-SNAP(L294A). The amplitude and characteristics of the
      individual release events were unaffected by expression of alpha-SNAP(L294A),
      consistent with an essential role for alpha-SNAP in early steps of priming but
      not in the fusion process. In contrast, Csp overexpression, which also inhibited
      the extent of exocytosis, also modified the kinetics of the individual release
      events seen as an increase in the rise time and a broadening of the residual
      amperometric spikes in Csp-transfected cells. These results suggest that unlike
      alpha-SNAP, Csp plays a key role in the protein interactions close to the fusion
      process or fusion pore opening during Ca(2+)-regulated exocytosis.

PMID- 10662818
TI  - Activity-dependent intracellular acidification correlates with the duration of
      seizure activity.
AB  - Synchronized neuronal activity (seizures) can appear in the presence or absence
      of synaptic transmission. Mechanisms of seizure initiation in each of these
      conditions have been studied, but relatively few studies have addressed seizure
      termination. In particular, how are seizures terminated in the absence of
      synaptic activity where there is no loss of excitatory drive or augmentation of
      inhibitory inputs? We have studied dynamic activity-dependent changes of
      intracellular pH in the absence of synaptic transmission using the fluorescent pH
      indicator carboxylseminaphthorhodafluo-1. During epileptiform activity we
      observed intracellular acidification, whereas between seizures the intracellular
      pH recovered. Experimental conditions that shortened the epileptiform discharge
      correlated with more rapid intracellular acidification. On the other hand,
      experimental manipulation of intracellular pH altered the duration of the seizure
      discharge, with acidification resulting in early termination of the epileptiform
      activity. These data show a direct relationship between the level of
      intracellular acidification and the duration of the seizures, suggesting that an
      intracellular pH-dependent process can terminate nonsynaptic neuronal
      synchronization.

PMID- 10662819
TI  - Identification of residues within GABA(A) receptor alpha subunits that mediate
      specific assembly with receptor beta subunits.
AB  - GABA(A) receptors can be constructed from a range of differing subunit isoforms:
      alpha, beta, gamma, delta, and epsilon. Expression studies have revealed that
      production of GABA-gated channels is achieved after coexpression of alpha and
      beta subunits. The expression of a gamma subunit isoform is essential to confer
      benzodiazepine sensitivity on the expressed receptor. However, how the
      specificity of subunit interactions is controlled during receptor assembly
      remains unknown. Here we demonstrate that residues 58-67 within alpha subunit
      isoforms are important in the assembly of receptors comprised of alphabeta and
      alphabetagamma subunits. Deletion of these residues from the alpha1 or alpha6
      subunits results in retention of either alpha subunit isoform in the endoplasmic
      reticulum on coexpression with the beta3, or beta3 and gamma2 subunits.
      Immunoprecipitation revealed that residues 58-67 mediated oligomerization of the
      alpha1 and beta3 subunits, but were without affect on the production of
      alpha/gamma complexes. Within this domain, glutamine 67 was of central importance
      in mediating the production of functional alpha1beta3 receptors. Mutation of this
      residue resulted in a drastic decrease in the cell surface expression of
      alpha1beta3 receptors and the resulting expression of beta3 homomers. Sucrose
      density gradient centrifugation revealed that this residue was important for the
      production of a 9S alpha1beta3 complex representing functional GABA(A) receptors.
      Therefore, our studies detail residues that specify GABA(A) receptor alphabeta
      subunit interactions. This domain, which is conserved in all alpha subunit
      isoforms, will therefore play a critical role in the assembly of GABA(A)
      receptors composed of alphabeta and alphabetagamma subunits.

PMID- 10662820
TI  - Action potential backpropagation and somato-dendritic distribution of ion
      channels in thalamocortical neurons.
AB  - Thalamocortical (TC) neurons of the dorsal thalamus integrate sensory inputs in
      an attentionally relevant manner during wakefulness and exhibit complex network
      driven and intrinsic oscillatory activity during sleep. Despite these complex
      intrinsic and network functions, little is known about the dendritic distribution
      of ion channels in TC neurons or the role such channel distributions may play in
      synaptic integration. Here we demonstrate with simultaneous somatic and dendritic
      recordings from TC neurons in brain slices that action potentials evoked by
      sensory or cortical excitatory postsynaptic potentials are initiated near the
      soma and backpropagate into the dendrites of TC neurons. Cell-attached recordings
      demonstrated that TC neuron dendrites contain a nonuniform distribution of sodium
      but a roughly uniform density of potassium channels across the somatodendritic
      area examined that corresponds to approximately half the average path length of
      TC neuron dendrites. Dendritic action potential backpropagation was found to be
      active, but compromised by dendritic branching, such that action potentials may
      fail to invade relatively distal dendrites. We have also observed that calcium
      channels are nonuniformly distributed in the dendrites of TC neurons. Low
      threshold calcium channels were found to be concentrated at proximal dendritic
      locations, sites known to receive excitatory synaptic connections from primary
      afferents, suggesting that they play a key role in the amplification of sensory
      inputs to TC neurons.

PMID- 10662821
TI  - Nicotine enhances the biosynthesis and secretion of transthyretin from the
      choroid plexus in rats: implications for beta-amyloid formation.
AB  - Epidemiological studies indicated that cigarette smoking protects against the
      development of several neurodegenerative disorders, including Alzheimer's disease
      (AD). However, the molecular mechanism(s) underlying this is poorly understood.
      To gain insight into these protective effects, we used differential display PCR
      (DD-PCR) to amplify RNA from various brain regions of rats self-administering
      (SA) nicotine compared with yoked-saline controls. We found that the
      transthyretin (TTR) gene, whose product has been shown to bind to amyloid beta
      (Abeta) protein and prevent Abeta aggregation, was more abundantly expressed (
      approximately 1.5- to 2.0-fold) in the brainstem and hippocampus (areas
      containing choroid plexus) of nicotine SA rats. Subsequently, quantitative
      reverse transcription-PCR analysis confirmed these DD-PCR findings and
      demonstrated that nicotine increased TTR mRNA levels in these regions in a time-
      and dose-dependent manner. Significantly higher TTR protein concentrations were
      also detected in the ventricular CSF of nicotine-treated rats. In contrast, no
      differences either in plasma TTR or in CSF and plasma retinol-binding protein
      were detected. Immunohistochemical analysis showed that immunoreactive TTR was
      41.5% lower in the choroid plexus of nicotine-treated rats compared with the
      saline controls. On the basis of these data, we speculate that the protective
      effects of nicotine on the development of AD may be attributable, in part, to the
      increased biosynthesis and secretion of TTR from the choroid plexus. These
      findings also point toward new approaches that may take advantage of the
      potentially novel therapeutic effects of nicotinic agonists in patients with AD.

PMID- 10662822
TI  - Molecular cloning and functional characterization of a new modulatory cyclic
      nucleotide-gated channel subunit from mouse retina.
AB  - Cyclic nucleotide-gated (CNG) channels play a key role in olfactory and visual
      transduction. Native CNG channels are heteromeric complexes consisting of the
      principal alpha subunits (CNG1-3), which can form functional channels by
      themselves, and the modulatory beta subunits (CNG4-5). The individual alpha and
      beta subunits that combine to form the CNG channels in rod photoreceptors (CNG1 +
      CNG4) and olfactory neurons (CNG2 + CNG4 + CNG5) have been characterized. In
      contrast, only an alpha subunit (CNG3) has been identified so far in cone
      photoreceptors. Here we report the molecular cloning of a new CNG channel subunit
      (CNG6) from mouse retina. The cDNA of CNG6 encodes a peptide of 694 amino acids
      with a predicted molecular weight of 80 kDa. Among the CNG channel subunits, CNG6
      has the highest overall similarity to the CNG4 beta subunit (47% sequence
      identity). CNG6 transcripts are present in a small subset of retinal
      photoreceptor cells and also in testis. Heterologous expression of CNG6 in human
      embryonic kidney 293 cells did not lead to detectable currents. However, when
      coexpressed with the cone photoreceptor alpha subunit, CNG6 induced a flickering
      channel gating, weakened the outward rectification in the presence of
      extracellular Ca(2+), increased the sensitivity for L-cis diltiazem, and enhanced
      the cAMP efficacy of the channel. Taken together, the data indicate that CNG6
      represents a new CNG channel beta subunit that may associate with the CNG3 alpha
      subunit to form the native cone channel.

PMID- 10662823
TI  - Evidence that Wallerian degeneration and localized axon degeneration induced by
      local neurotrophin deprivation do not involve caspases.
AB  - The selective degeneration of an axon, without the death of the parent neuron,
      can occur in response to injury, in a variety of metabolic, toxic, and
      inflammatory disorders, and during normal development. Recent evidence suggests
      that some forms of axon degeneration involve an active and regulated program of
      self-destruction rather than a passive "wasting away" and in this respect and
      others resemble apoptosis. Here we investigate whether selective axon
      degeneration depends on some of the molecular machinery that mediates apoptosis,
      namely, the caspase family of cysteine proteases. We focus on two models of
      selective axon degeneration: Wallerian degeneration of transected axons and
      localized axon degeneration induced by local deprivation of neurotrophin. We show
      that caspase-3 is not activated in the axon during either form of degeneration,
      although it is activated in the dying cell body of the same neurons. Moreover,
      caspase inhibitors do not inhibit or retard either form of axon degeneration,
      although they inhibit apoptosis of the same neurons. Finally, we cannot detect
      cleaved substrates of caspase-3 and its close relatives immunocytochemically or
      caspase activity biochemically in axons undergoing Wallerian degeneration. Our
      results suggest that a neuron contains at least two molecularly distinct self
      destruction programs, one for caspase-dependent apoptosis and another for
      selective axon degeneration.

PMID- 10662824
TI  - Neuronal pyruvate carboxylation supports formation of transmitter glutamate.
AB  - Release of transmitter glutamate implies a drain of alpha-ketoglutarate from
      neurons, because glutamate, which is formed from alpha-ketoglutarate, is taken up
      by astrocytes. It is generally believed that this drain is compensated by uptake
      of glutamine from astrocytes, because neurons are considered incapable of de novo
      synthesis of tricarboxylic acid cycle intermediates, which requires pyruvate
      carboxylation. Here we show that cultured cerebellar granule neurons form
      releasable [(14)C]glutamate from H(14)CO(3)(-) and [1-(14)C]pyruvate via pyruvate
      carboxylation, probably mediated by malic enzyme. The activity of pyruvate
      carboxylation was calculated to be approximately one-third of the pyruvate
      dehydrogenase activity in neurons. Furthermore, intrastriatal injection of
      NaH(14)CO(3) or [1-(14)C]pyruvate labeled glutamate better than glutamine,
      showing that pyruvate carboxylation occurs in neurons in vivo. This means that
      neurons themselves to a large extent may support their release of glutamate, and
      thus entails a revision of the current view of glial-neuronal interactions and
      the importance of the glutamine cycle.

PMID- 10662825
TI  - Modulation of transmission during trains at a cerebellar synapse.
AB  - Activity-dependent processes dynamically regulate synapses on the time scale of
      milliseconds to seconds. Here, we examine the factors governing synaptic strength
      during repetitive stimulation, both in control conditions and during presynaptic
      inhibition. Field recordings of presynaptic volleys, optical measurements of
      presynaptic calcium, and voltage-clamp recordings of postsynaptic currents were
      used to examine parallel fiber to Purkinje cell synapses in cerebellar brain
      slices at 34 degrees C. In control conditions, regular stimulus trains (1-50 Hz)
      evoked up to a 250% peak synaptic enhancement, whereas during irregular
      stimulation, a threefold variability in EPSC amplitude was observed. When initial
      EPSC amplitudes were reduced by 50%, either by lowering external calcium or by
      activating adenosine A(1) or GABA(B) receptors, the peak enhancement during
      regular trains was 500%, and synaptic variability during irregular trains was
      nearly sixfold. By contrast, changes in fiber excitability and calcium influx per
      pulse were small during trains. Presynaptic calcium measurements indicated that
      by pulse 10, stimulus-evoked calcium influx had increased by approximately 15%,
      which on the basis of the measured relationship between calcium influx and
      release corresponds to an EPSC enhancement of 50%. This enhancement was the same
      in all experimental conditions, even in the presence of N(6)-cyclopentyladenosine
      or baclofen, suggesting that repetitive stimulation does not relieve the G
      protein inhibition of calcium channels by these modulators. Therefore, for our
      experimental conditions, changes in synaptic strength during trains are primarily
      attributable to residual calcium (Ca(res))-dependent short-term plasticities, and
      the actions of neuromodulators during repetitive stimulation result from their
      inhibition of initial calcium influx and the resulting effects on Ca(res) and
      calcium-driven processes.

PMID- 10662826
TI  - Presenilin-1 mutation increases neuronal vulnerability to focal ischemia in vivo
      and to hypoxia and glucose deprivation in cell culture: involvement of perturbed
      calcium homeostasis.
AB  - Many cases of early-onset inherited Alzheimer's disease (AD) are caused by
      mutations in the presenilin-1 (PS1) gene. Studies of cultured neural cells
      suggest that PS1 mutations result in perturbed cellular calcium homeostasis and
      may thereby render neurons vulnerable to apoptosis. In light of evidence that
      metabolic impairment plays a role in AD, that cerebral ischemia may be a risk
      factor for AD, and that individuals with AD have increased morbidity and
      mortality after stroke, we examined the impact of a PS1 mutation on neuronal
      vulnerability to ischemic injury. We report that the extent of brain injury after
      focal cerebral ischemia reperfusion is increased, and behavioral outcome is
      worsened, in PS1 mutant knock-in mice compared to wild-type mice. Cultured
      cortical neurons from PS1 mutant mice exhibit increased vulnerability to glucose
      deprivation and chemical hypoxia compared to their wild-type counterparts.
      Calcium imaging studies demonstrated enhanced elevation of intracellular calcium
      levels after glucose deprivation and chemical hypoxia in neurons from PS1 mutant
      mice. Agents that block calcium release from IP(3)- and ryanodine-sensitive
      stores (xestospongin and dantrolene, respectively) protected against the
      endangering action of the PS1 mutation. Our data suggest that presenilin
      mutations may promote neuronal degeneration in AD by increasing the sensitivity
      of neurons to age-related ischemia-like conditions. The data further suggest that
      drugs that stabilize endoplasmic reticulum calcium homeostasis may prove
      effective in suppressing the neurodegenerative process in AD patients.

PMID- 10662827
TI  - Ca(2+)-evoked serotonin secretion by parafollicular cells: roles in signal
      transduction of phosphatidylinositol 3'-kinase, and the gamma and zeta isoforms
      of protein kinase C.
AB  - Parafollicular (PF) cells secrete 5-HT in response to stimulation of a G-protein
      coupled Ca(2+) receptor (CaR) by increased extracellular Ca(2+) (upward
      arrow[Ca(2+)](e)). We tested the hypothesis that protein kinase C (PKC)
      participates in stimulus-secretion coupling. Immunoblots from membrane and
      cytosolic fractions of isolated PF cells revealed conventional (alpha, betaI, and
      gamma), novel (delta and epsilon), and atypical (iota/lambda and zeta) PKCs. Only
      PKCgamma was found to have been translocated to the membrane fraction when
      secretion of 5-HT was evoked by upward arrow[Ca(2+)](e) or phorbol esters.
      Although phorbol downregulation caused PKCgamma to disappear, secretion was only
      partially inhibited. A similar reduction of upward arrow[Ca(2+)](e)-evoked
      secretion was produced by inhibitors of conventional and/or novel PKCs (Go 6976,
      calphostin C, and pseudoA), and these compounds did not inhibit secretion at all
      when applied to phorbol-downregulated cells. In contrast, the phorbol
      downregulation-resistant component of secretion was abolished by pseudoZ, which
      inhibits the atypical PKCzeta. Stimulation of PF cells with upward
      arrow[Ca(2+)](e) increased the activity of immunoprecipitated PKCzeta (but not
      PKCiota/lambda), and the activity of this PKCzeta was inhibited by pseudoZ. PF
      cells were found to express regulatory (p85) and catalytic (p110alpha and
      p110beta) subunits of phosphatidylinositol 3'-kinase (PI3'-kinase). upward
      arrow[Ca(2+)](e) increased the activity of immunoprecipitated PI3'-kinase;
      moreover, PI3'-kinase inhibitors (wortmannin and LY294002) antagonized secretion.
      We suggest that PKC isoforms mediate secretion of 5-HT by PF cells in response to
      stimulation of the CaR. PKC involvement can be accounted for by PKCgamma and an
      isoform sensitive to inhibition by pseudoZ, probably PKCzeta, which is activated
      via PI3'-kinase.

PMID- 10662828
TI  - Interplay between facilitation, depression, and residual calcium at three
      presynaptic terminals.
AB  - Synapses display remarkable alterations in strength during repetitive use.
      Different types of synapses exhibit distinctive synaptic plasticity, but the
      factors giving rise to such diversity are not fully understood. To provide the
      experimental basis for a general model of short-term plasticity, we studied three
      synapses in rat brain slices at 34 degrees C: the climbing fiber to Purkinje cell
      synapse, the parallel fiber to Purkinje cell synapse, and the Schaffer collateral
      to CA1 pyramidal cell synapse. These synapses exhibited a broad range of
      responses to regular and Poisson stimulus trains. Depression dominated at the
      climbing fiber synapse, facilitation was prominent at the parallel fiber synapse,
      and both depression and facilitation were apparent in the Schaffer collateral
      synapse. These synapses were modeled by incorporating mechanisms of short-term
      plasticity that are known to be driven by residual presynaptic calcium (Ca(res)).
      In our model, release is the product of two factors: facilitation and refractory
      depression. Facilitation is caused by a calcium-dependent increase in the
      probability of release. Refractory depression is a consequence of release sites
      becoming transiently ineffective after release. These sites recover with a time
      course that is accelerated by elevations of Ca(res). Facilitation and refractory
      depression are coupled by their common dependence on Ca(res) and because
      increased transmitter release leads to greater synaptic depression. This model
      captures the behavior of three different synapses for various stimulus
      conditions. The interplay of facilitation and depression dictates synaptic
      strength and variability during repetitive activation. The resulting synaptic
      plasticity transforms the timing of presynaptic spikes into varying postsynaptic
      response amplitudes.

PMID- 10662829
TI  - Caspase-2 mediates neuronal cell death induced by beta-amyloid.
AB  - beta-amyloid (Abeta) has been proposed to play a role in the pathogenesis of
      Alzheimer's disease (AD). Deposits of insoluble Abeta are found in the brains of
      patients with AD and are one of the pathological hallmarks of the disease. It has
      been proposed that Abeta induces death by oxidative stress, possibly through the
      generation of peroxynitrite from superoxide and nitric oxide. In our current
      study, treatment with nitric oxide generators protected against Abeta-induced
      death, whereas inhibition of nitric oxide synthase afforded no protection,
      suggesting that formation of peroxynitrite is not critical for Abeta-mediated
      death. Previous studies have shown that aggregated Abeta can induce caspase
      dependent apoptosis in cultured neurons. In all of the neuronal populations
      studied here (hippocampal neurons, sympathetic neurons, and PC12 cells), cell
      death was blocked by the broad spectrum caspase inhibitor N-benzyloxycarbonyl-val
      ala-asp-fluoromethyl ketone and more specifically by the downregulation of
      caspase-2 with antisense oligonucleotides. In contrast, downregulation of caspase
      1 or caspase-3 did not block Abeta(1-42)-induced death. Neurons from caspase-2
      null mice were totally resistant to Abeta(1-42) toxicity, confirming the
      importance of this caspase in Abeta-induced death. The results indicate that
      caspase-2 is necessary for Abeta(1-42)-induced apoptosis in vitro.

PMID- 10662830
TI  - Interstitial cells of Cajal mediate cholinergic neurotransmission from enteric
      motor neurons.
AB  - Interstitial cells of Cajal (ICC) are interposed between enteric neurons and
      smooth muscle cells in gastrointestinal muscles. The role of intramuscular ICC
      (IC-IM) in mediating enteric excitatory neural inputs was studied using gastric
      fundus muscles of wild-type animals and W/W(v) mutant mice, which lack IC-IM.
      Excitatory motor neurons, labeled with antibodies to vesicular acetylcholine
      transporter or substance-P, were closely associated with IC-IM.
      Immunocytochemistry showed close contacts between enteric neurons and IC-IM. IC
      IM also formed gap junctions with smooth muscle cells. Electrical field
      stimulation yielded fast excitatory junction potentials in the smooth muscle that
      were blocked by atropine. Neural responses were greatly reduced in muscles of
      W/W(v) animals. Loss of cholinergic responses in W/W(v) muscles seemed to be
      caused by the loss of close synaptic contacts between motor neurons and IC-IM,
      because these muscles were not less responsive to exogenous acetylcholine than
      were wild-type muscles. W/W(v) muscles also responded to excitatory nerve
      stimulation when the breakdown of acetylcholine was blocked by neostigmine. The
      density of cholinergic nerve bundles within the muscles was not significantly
      different in wild-type and W/W(v) muscles, and similar amounts of (14)[C]choline
      were released from preloaded wild-type and W/W(v) muscles in response to nerve
      stimulation. The impact of losing IC-IM on gastric compliance was also evaluated
      in intact stomachs. Pressure increased as a function of fluid volume and infusion
      rate in wild-type animals, but W/W(v) animals showed little basal tone and
      minimal increases in pressure with fluid infusions. These data suggest that IC-IM
      play a major role in receiving cholinergic excitatory inputs from the enteric
      nervous system in the murine fundus.

PMID- 10662832
TI  - Localization and developmental expression patterns of the neuronal K-Cl
      cotransporter (KCC2) in the rat retina.
AB  - The processing of signals by integrative neurons in the retina and CNS relies
      strongly on inhibitory synaptic inputs, principally from GABAergic and
      glycinergic neurons that serve primarily to hyperpolarize postsynaptic neurons.
      Recent evidence indicates that the neuron-specific K-Cl cotransporter 2 (KCC2) is
      the major chloride extrusion system permitting hyperpolarizing inhibitory
      responses. It has been hypothesized that depolarizing GABA responses observed in
      immature neurons are converted to hyperpolarizing responses in large part by the
      expression of KCC2 during the second week of postnatal development. The cell
      specific localization and developmental expression of KCC2 protein have been
      examined in relatively few neural tissues and have never been studied in retina,
      of which much is known physiologically and morphologically about inhibitory
      synaptic circuits. We examined the localization of KCC2 in adult rat retina with
      immunohistochemical techniques and determined the time course of its postnatal
      expression. KCC2 expression was localized in horizontal cells, bipolar cells,
      amacrine cells, and, most likely, ganglion cells, all of which are known to
      express GABA receptor subtypes. Developmentally, KCC2 expression in the retina
      increased gradually from postnatal day 1 (P1) until P14 in the inner retina,
      whereas expression was delayed in the outer plexiform layer until P7 but reached
      its adult level by P14. These data support the hypothesis that the function of
      KCC2 is intimately involved in GABAergic synaptic processing. Furthermore, the
      delayed temporal expression of KCC2 in the outer plexiform layer indicates that
      GABAergic function may be differentially regulated in retina during postnatal
      development and that GABA may produce depolarizing responses in the outer
      plexiform layer at times when it generates hyperpolarizing responses in the inner
      plexiform layer.

PMID- 10662831
TI  - A role for nuclear PTEN in neuronal differentiation.
AB  - Mutations of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a
      protein and lipid phosphatase, have been associated with gliomas, macrocephaly,
      and mental deficiencies. We have assessed PTEN's role in the nervous system and
      find that PTEN is expressed in mouse brain late in development, starting at
      approximately postnatal day 0. In adult brain, PTEN is preferentially expressed
      in neurons and is especially evident in Purkinje neurons, olfactory mitral
      neurons, and large pyramidal neurons. To analyze the function of PTEN in neuronal
      differentiation, we used two well established model systems-pheochromocytoma
      cells and cultured CNS stem cells. PTEN is expressed during neurotrophin-induced
      differentiation and is detected in both the nucleus and cytoplasm. Suppression of
      PTEN levels with antisense oligonucleotides does not block initiation of neuronal
      differentiation. Instead, PTEN antisense leads to death of the resulting,
      immature neurons, probably during neurite extension. In contrast, PTEN is not
      required for astrocytic differentiation. These observations indicate that PTEN
      acts at multiple sites in the cell, regulating the transition of differentiating
      neuroblasts to postmitotic neurons.

PMID- 10662833
TI  - Molecular cloning and functional expression of the potassium-dependent sodium
      calcium exchanger from human and chicken retinal cone photoreceptors.
AB  - Light causes a rapid lowering of cytosolic free calcium in the outer segments of
      both retinal rod and cone photoreceptors. This light-induced lowering of calcium
      is caused by extrusion via a Na-Ca exchanger located in the rod and cone outer
      segment plasma membrane and plays a key role in the process of light adaptation.
      The Na-Ca exchanger in retinal rod outer segment was shown earlier to be a novel
      Na-Ca+K exchanger (NCKX), and its cDNA was obtained by molecular cloning from
      several mammalian species. On the other hand, the proper identity of the retinal
      cone Na-Ca exchanger, in terms of both functional characteristics (e.g.,
      requirement for and transport of potassium) and molecular identity, has not yet
      been elucidated. Here, we report the molecular cloning, intraretinal localization
      by in situ hybridization, and initial functional characterization of the chicken
      and human cone-specific Na-Ca exchangers. In addition we report the chicken rod
      specific NCKX. We identified NCKX transcripts in both human and chicken cones and
      observed strong potassium-dependent Na-Ca exchange activity after heterologous
      expression of human and chicken cone NCKX cDNAs in cultured insect cells. In situ
      hybridization in chicken retina showed abundant rod NCKX transcripts only in rod
      photoreceptors, whereas abundant cone NCKX transcripts were found in most, if not
      all, cone photoreceptors and also in a subpopulation of retinal ganglion cells. A
      detailed comparison with the previously described retinal rod and brain NCKX
      cDNAs is presented.

PMID- 10662835
TI  - Consequences of neural cell adhesion molecule deficiency on cell migration in the
      rostral migratory stream of the mouse.
AB  - In vertebrates, interneurons of the olfactory bulb (OB) are generated postnatally
      and throughout life at the subventricular zone of the forebrain. The neuronal
      precursors migrate tangentially through the forebrain using a well defined
      pathway, the rostral migratory stream (RMS), and a particular mode of migration
      in a chain-like organization. A severe size reduction of the OB represents the
      most striking morphological phenotype in neural cell adhesion molecule (NCAM)
      deficient mice. This defect has been traced back to a migration deficit of the
      precursors in the RMS and linked to the lack of the polysialylated form of NCAM.
      In this study we investigate the morphological alterations and functional
      properties of the RMS in mice totally devoid of all isoforms of NCAM and
      polysialic acid (PSA). We show that a morphologically altered, but defined and
      continuous pathway exists in mutants, and we present in vivo and in vitro
      evidence that PSA-NCAM in the RMS is not essential for the formation and
      migration of chains. Instead, we find a massive gliosis associated with the
      formation of membrane specializations in a heterotypic manner, linking precursors
      to astrocytes. This finding and the over-representation and defasciculation of
      axons in the pathway suggest that important interactions between migrating cells
      and their stationary environment are perturbed in the mutants. Finally, we used
      transplantation experiments to demonstrate that lack of PSA-NCAM leads to a
      decrease but not a total blockade of migration and demonstrate that the mutant
      RMS is functional in transporting normal neuronal precursors to the OB.

PMID- 10662834
TI  - Intercellular communication in spinal cord astrocytes: fine tuning between gap
      junctions and P2 nucleotide receptors in calcium wave propagation.
AB  - Electrophysiological properties of gap junction channels and mechanisms involved
      in the propagation of intercellular calcium waves were studied in cultured spinal
      cord astrocytes from sibling wild-type (WT) and connexin43 (Cx43) knock-out (KO)
      mice. Comparison of the strength of coupling between pairs of WT and Cx43 KO
      spinal cord astrocytes indicates that two-thirds of total coupling is
      attributable to channels formed by Cx43, with other connexins contributing the
      remaining one-third of junctional conductance. Although such a difference in
      junctional conductance was expected to result in the reduced diffusion of
      signaling molecules through the Cx43 KO spinal cord syncytium, intercellular
      calcium waves were found to propagate with the same velocity and amplitude and to
      the same number of cells as between WT astrocytes. Measurements of calcium wave
      propagation in the presence of purinoceptor blockers indicate that calcium waves
      in Cx43 KO spinal cord astrocytes are mediated primarily by extracellular
      diffusion of ATP; measurements of responses to purinoceptor agonists revealed
      that the functional P2Y receptor subtype is shifted in the Cx43 KO astrocytes,
      with a markedly potentiated response to ATP and UTP. Thus, the reduction in gap
      junctional communication in Cx43 KO astrocytes leads to an increase in autocrine
      communication, which is a consequence of a functional switch in the P2Y
      nucleotide receptor subtype. Intercellular communication via calcium waves
      therefore is sustained in Cx43 null mice by a finely tuned interaction between
      gap junction-dependent and independent mechanisms.

PMID- 10662836
TI  - Stabilization of growing retinal axons by the combined signaling of nitric oxide
      and brain-derived neurotrophic factor.
AB  - The pattern of axonal projections early in the development of the nervous system
      lacks the precision present in the adult. During a developmental process of
      refinement, mistargeted projections are eliminated while correct projections are
      retained. Previous studies suggest that during development nitric oxide (NO) is
      involved in the elimination of mistargeted retinal axons, whereas brain-derived
      neurotrophic factor (BDNF) may stabilize retinal axon arbors. It is unclear
      whether these neuromodulators interact. This study showed that NO induced growth
      cone collapse and retraction of developing retinal axons. This effect was not
      attributable to NO-induced neurotoxicity. BDNF protected growth cones and axons
      from the effects of NO. This effect was specific to BDNF, because neither nerve
      growth factor (NGF) nor neurotrophin-3 (NT-3) prevented NO-induced growth cone
      collapse and axon retraction. Exposure to both BDNF and NO, but not either factor
      alone, stabilized growth cones and axons. Stabilized axons exhibited minimal
      retraction or extension. This response appears to be a new axon "state" and not
      simply a partial amelioration of the effect of NO, because lower doses of BDNF or
      NO allowed axon extension. Furthermore, BDNF/NO-induced growth cone stabilization
      correlated with the appearance of a cytochalasin D-resistant population of actin
      filaments. BDNF protection from NO likely was mediated locally at the level of
      the growth cone, because growth cones or individual filopodia in contact with
      BDNF-coated beads were protected from NO-induced collapse. These findings suggest
      a cellular mechanism by which some axonal connections are stabilized and some are
      eliminated during development.

PMID- 10662837
TI  - Rapid regulation of brain-derived neurotrophic factor mRNA within eye-specific
      circuits during ocular dominance column formation.
AB  - The neurotrophin brain-derived neurotrophic factor (BDNF) has emerged as a
      candidate retrograde signaling molecule for geniculocortical axons during the
      formation of ocular dominance columns. Here we examined whether neuronal activity
      can regulate BDNF mRNA in eye-specific circuits in the developing cat visual
      system. Dark-rearing throughout the critical period for ocular dominance column
      formation decreases levels of BDNF mRNA within primary visual cortex, whereas
      short-term (2 d) binocular blockade of retinal activity with tetrodotoxin (TTX)
      downregulates BDNF mRNA within the lateral geniculate nucleus (LGN) and visual
      cortical areas. Brief (6 hr to 2 d) monocular TTX blockade during the critical
      period and also in adulthood causes downregulation in appropriate eye-specific
      laminae in the LGN and ocular dominance columns within primary visual cortex.
      Monocular TTX blockade at postnatal day 23 also downregulates BDNF mRNA in a
      periodic fashion, consistent with recent observations that ocular dominance
      columns can be detected at these early ages by physiological methods. In
      contrast, 10 d monocular TTX during the critical period does not cause a lasting
      decrease in BDNF mRNA expression in columns pertaining to the treated eye,
      consistent with the nearly complete shift in physiological response properties of
      cortical neurons in favor of the unmanipulated eye known to result from long-term
      monocular deprivation. These observations demonstrate that BDNF mRNA levels can
      provide an accurate "molecular readout" of the activity levels of cortical
      neurons and are consistent with a highly local action of BDNF in strengthening
      and maintaining active synapses during ocular dominance column formation.

PMID- 10662838
TI  - Stimulus history alters behavioral responses of neuronal growth cones.
AB  - Generally, it is assumed that growth cones respond to a specific guidance cue
      with a single, specific, and stereotyped behavior. However, there is evidence to
      suggest that previous exposure to a given cue might alter subsequent responses to
      that cue (Snow and Letourneau, 1992; Shirasaki et al., 1998). We therefore tested
      the hypothesis that growth cone responses to stimuli are dependent on the history
      of previous stimulation. Growth cones of chick dorsal root ganglion neurons were
      exposed to well characterized stimuli: (1) contact with a laminin-coated bead,
      which causes growth cone turning, or (2) electrical stimulation, which causes
      growth cone collapse. Although the expected behavioral responses were observed
      after the initial stimulation, strikingly different responses to a subsequent
      stimulation were observed. Growth cones that had recovered from electrical
      stimulation-induced collapse rapidly developed insensitivity to a second
      identical electrical stimulation. Growth cones that previously turned in response
      to contact with a laminin-coated bead responded to a second bead with a "stall"
      or cessation in outgrowth. This stimulus history dependence of growth cone
      behavior could be generalized across dissimilar stimuli: after contact with a
      laminin-coated bead, growth cones failed to collapse in response to electrical
      stimulation. The calcium/calmodulin-dependent protein kinase II (CaMKII) was
      implicated in this history dependence by pharmacological experiments. Together,
      these results demonstrate that growth cones can alter their behavioral response
      rapidly to a given stimulus in a manner dependent on previous history and that
      knowledge of past events in growth cone navigation may be required to predict
      future growth cone behavior.

PMID- 10662839
TI  - Developmental changes in the transmitter properties of sympathetic neurons that
      innervate the periosteum.
AB  - During the development of sweat gland innervation, interactions with the target
      tissue induce a change from noradrenergic to cholinergic and peptidergic
      properties. To determine whether the change in neurotransmitter properties that
      occurs in the sweat gland innervation occurs more generally in sympathetic
      neurons, we identified a new target of cholinergic sympathetic neurons in rat,
      the periosteum, which is the connective tissue covering of bone, and
      characterized the development of periosteal innervation of the sternum. During
      development, sympathetic axons grow from thoracic sympathetic ganglia along rib
      periosteum to reach the sternum. All sympathetic axons displayed
      catecholaminergic properties when they reached the sternum, but these properties
      subsequently disappeared. Many axons lacked detectable immunoreactivities for
      vesicular acetylcholine transporter and vasoactive intestinal peptide when they
      reached the sternum and acquired them after arrival. To determine whether
      periosteum could direct changes in the neurotransmitter properties of sympathetic
      neurons that innervate it, we transplanted periosteum to the hairy skin, a
      noradrenergic sympathetic target. We found that the sympathetic innervation of
      the transplant underwent a noradrenergic to cholinergic and peptidergic change.
      These results suggest that periosteum, in addition to sweat glands, regulates the
      neurotransmitter properties of the sympathetic neurons that innervate it.

PMID- 10662840
TI  - Discharge properties of juxtacellularly labeled and immunohistochemically
      identified cholinergic basal forebrain neurons recorded in association with the
      electroencephalogram in anesthetized rats.
AB  - Multiple lines of evidence indicate that cholinergic basal forebrain neurons play
      an important role in the regulation of cortical activity and state. However, the
      discharge properties of cholinergic cells in relation to the electroencephalogram
      (EEG) are not yet known. In the present study, cells were recorded in the basal
      forebrain in association with cortical EEG activity in urethane-anesthetized
      rats, and their discharge was examined during EEG irregular slow activity and
      during stimulation-induced cortical activation, characterized by rhythmic slow
      (theta) and high-frequency (gamma) activities. Recorded cells were labeled with
      Neurobiotin (Nb), using the juxtacellular technique and identified as cholinergic
      by immunohistochemical staining for choline acetyltransferase (ChAT). Nb
      positive/ChAT-positive neurons were distinctive and significantly different from
      Nb-positive/ChAT-negative neurons, which were heterogeneous in their discharge
      properties. All Nb(+)/ChAT(+) cells increased their discharge rate with
      stimulation, and most shifted from an irregular tonic discharge during EEG slow
      irregular activity to a rhythmic burst discharge during rhythmic slow activity.
      The stimulation-induced rhythmic discharge was cross-correlated with the EEG
      rhythmic slow activity. In some units the rhythmic discharge matched the rhythmic
      slow activity of the retrosplenial cortex; in others, it matched that of the
      prefrontal cortex, which occurred at a slower frequency, suggesting that subsets
      of cholinergic neurons may influence their cortical target areas rhythmically at
      particular frequencies. Cholinergic basal forebrain neurons thus may evoke and
      enhance cortical activation via both an increase in rate and a change in pattern
      to rhythmic bursting that would stimulate rhythmic slow (theta-like) activity in
      cortical fields during active waking and paradoxical sleep states.

PMID- 10662841
TI  - Gap junctions linking the dendritic network of GABAergic interneurons in the
      hippocampus.
AB  - The network of GABAergic interneurons connected by chemical synapses is a
      candidate for the generator of synchronized oscillations in the hippocampus. We
      present evidence that parvalbumin (PV)-containing GABAergic neurons in the rat
      hippocampal CA1 region, known to form a network by mutual synaptic contacts, also
      form another network connected by dendrodendritic gap junctions. Distal dendrites
      of PV neurons run parallel to the alveus (hippocampal white matter) and establish
      multiple contacts with one another at the border between the stratum oriens and
      the alveus. In electron microscopic serial section analysis, gap junctions could
      be identified clearly at 24% of these contact sites. A dendrodendritic chemical
      synapse and a mixed synapse also were found between PV-immunoreactive dendrites.
      Three-dimensional reconstruction of the dendritic arborization revealed that both
      PV neurons of the well known vertical type (presumptive basket cells and
      axoaxonic cells) and those of another horizontal type constitute the dendritic
      network at the light microscopic level. The extent of dendritic fields of single
      PV neurons in the lateral direction was 538 +/- 201 micrometer (n = 5) in the
      vertical type and 838 +/- 159 micrometer (n = 6) in the horizontal type. Our
      previous and present observations indicate that PV-containing GABAergic neurons
      in the hippocampus form the dual networks connected by chemical and electrical
      synapses located at axosomatic and dendrodendritic contact sites, respectively.
      Gap junctions linking the dendritic network may mediate coherent synaptic inputs
      to distant interneurons and thereby facilitate the synchronization of oscillatory
      activities generated in the interneuron network.

PMID- 10662842
TI  - Thalamic-evoked synaptic interactions in barrel cortex revealed by optical
      imaging.
AB  - We used optical imaging of voltage-sensitive dye signals to study the
      spatiotemporal spread of activity in the mouse barrel cortex, evoked by
      stimulation of thalamocortical afferents in an in vitro slice preparation.
      Stimulation of the thalamus, at low current intensity, results in activity
      largely restricted to a single barrel, and to the border between layers Vb and
      VI. Low concentrations of the GABA(A) receptor antagonist bicuculline increase
      the amplitude of the optical signals, without affecting their spatiotemporal
      propagation. Higher concentrations of bicuculline result in paroxysmal activity,
      which propagates via intracolumnar and intercolumnar excitatory pathways.
      Enhancing the activity of NMDA receptors, by removing Mg(2+) from the
      extracellular solution, dramatically alters the spatiotemporal pattern of
      excitation: activity spreads to supragranular and infragranular layers and
      adjacent barrel columns. This enhanced propagation is suppressed by the NMDA
      receptor antagonist AP5. A similar enhancement of activity propagation can be
      produced by stimulating the thalamus with a short, high-frequency pulse train.
      Application of AP5 suppresses the frequency-dependent spread of activity. These
      findings indicate that the spatiotemporal spread of activity in the barrel cortex
      is altered by varying the temporal patterns of thalamic inputs, via an NMDA
      receptor-mediated mechanism, and suggest that a similar process occurs during
      repetitive whisking activity.

PMID- 10662844
TI  - alpha-Melanocyte-stimulating hormone is contained in nerve terminals innervating
      thyrotropin-releasing hormone-synthesizing neurons in the hypothalamic
      paraventricular nucleus and prevents fasting-induced suppression of
      prothyrotropin-releasing hormone gene expression.
AB  - The hypothalamic arcuate nucleus has an essential role in mediating the
      homeostatic responses of the thyroid axis to fasting by altering the sensitivity
      of prothyrotropin-releasing hormone (pro-TRH) gene expression in the
      paraventricular nucleus (PVN) to feedback regulation by thyroid hormone. Because
      agouti-related protein (AGRP), a leptin-regulated, arcuate nucleus-derived
      peptide with alpha-MSH antagonist activity, is contained in axon terminals that
      terminate on TRH neurons in the PVN, we raised the possibility that alpha-MSH may
      also participate in the mechanism by which leptin influences pro-TRH gene
      expression. By double-labeling immunocytochemistry, alpha-MSH-IR axon
      varicosities were juxtaposed to approximately 70% of pro-TRH neurons in the
      anterior and periventricular parvocellular subdivisions of the PVN and to 34% of
      pro-TRH neurons in the medial parvocellular subdivision, establishing synaptic
      contacts both on the cell soma and dendrites. All pro-TRH neurons receiving
      contacts by alpha-MSH-containing fibers also were innervated by axons containing
      AGRP. The intracerebroventricular infusion of 300 ng of alpha-MSH every 6 hr for
      3 d prevented fasting-induced suppression of pro-TRH in the PVN but had no effect
      on AGRP mRNA in the arcuate nucleus. alpha-MSH also increased circulating levels
      of free thyroxine (T4) 2.5-fold over the levels in fasted controls, but free T4
      did not reach the levels in fed controls. These data suggest that alpha-MSH has
      an important role in the activation of pro-TRH gene expression in
      hypophysiotropic neurons via either a mono- and/or multisynaptic pathway to the
      PVN, but factors in addition to alpha-MSH also contribute to the mechanism by
      which leptin administration restores thyroid hormone levels to normal in fasted
      animals.

PMID- 10662843
TI  - Synaptic reorganization in the substantia gelatinosa after peripheral nerve
      neuroma formation: aberrant innervation of lamina II neurons by Abeta afferents.
AB  - Intracellular recording and extracellular field potential (FP) recordings were
      obtained from spinal cord dorsal horn neurons (laminae I-IV) in a rat transverse
      slice preparation with attached dorsal roots. To study changes in synaptic inputs
      after neuroma formation, the sciatic nerve was sectioned and ligated 3 weeks
      before in vitro electrophysiological analysis. Horseradish peroxidase labeling of
      dorsal root axons indicated that Abeta fibers sprouted into laminae I-II from
      deeper laminae after sciatic nerve section. FP recordings from dorsal horns of
      normal spinal cord slices revealed long-latency synaptic responses in lamina II
      and short-latency responses in lamina III. The latencies of synaptic FPs recorded
      in lamina II of the dorsal horn after sciatic nerve section were reduced. The
      majority of monosynaptic EPSPs recorded with intracellular microelectrodes from
      lamina II neurons in control slices were elicited by high-threshold nerve
      stimulation, whereas the majority of monosynaptic EPSPs recorded in lamina III
      were elicited by low-threshold nerve stimulation. After sciatic nerve section, 31
      of 57 (54%) EPSPs recorded in lamina II were elicited by low-threshold
      stimulation. The majority of low-threshold EPSPs in lamina II neurons after
      axotomy displayed properties similar to low-threshold EPSPs in lamina III of
      control slices. These results indicate that reoccupation of lamina II synapses by
      sprouting Abeta fibers normally terminating in lamina III occurs after sciatic
      nerve neuroma formation. Furthermore, these observations indicate that the lamina
      II neurons receive inappropriate sensory information from low-threshold
      mechanoreceptor after sciatic nerve neuroma formation.

PMID- 10662845
TI  - Generating sexually differentiated vocal patterns: laryngeal nerve and EMG
      recordings from vocalizing male and female african clawed frogs (Xenopus laevis).
AB  - Male and female African clawed frogs (Xenopus laevis) produce sexually dimorphic
      vocalizations; for males these include advertisement, amplectant, and growling
      calls, whereas female calls include ticking. Previous studies have shown that the
      vocal organ, the larynx, of the sexes differs in physiological properties that
      parallel vocal differences. However, it was not clear whether these
      characteristics are sufficient to explain sex differences in vocal behavior. To
      examine the contribution of the CNS to generating vocal patterns, we developed a
      preparation in which both laryngeal nerve activity and electromyograms can be
      recorded from awake, vocalizing frogs. Recordings reveal that the CNS of the two
      sexes produces patterned activity that closely matches each vocalization whereas
      the larynx faithfully translates nerve activity into sound. Thus, the CNS is the
      source of sexually differentiated vocalizations in Xenopus laevis. Furthermore,
      detailed analyses of compound action potentials recorded from the nerve lead us
      to hypothesize that neuronal activity underlying different male call types is
      distinct; some calls are likely to be generated by synchronous firing of
      motoneuron populations of either constant size or progressively larger sizes,
      whereas others are generated by asynchronous activity of motoneurons, a pattern
      shared with vocal production in females. We suggest that these distinct neuronal
      activity patterns in males may be subserved by two populations of motor units in
      males that can be distinguished by the strength of the neuromuscular synapse.

PMID- 10662846
TI  - Chronic stress induces impairment of spatial working memory because of prefrontal
      dopaminergic dysfunction.
AB  - Although the mechanism responsible for cognitive deficits in stress-related
      neuropsychiatric disorders has been obscure, prefrontal cortical (PFC)
      dopaminergic dysfunction is thought to be involved. In animals, the
      mesoprefrontal dopaminergic system is particularly vulnerable to stress, and
      chronic stress induces working memory impairment. However, the relation between
      the working memory impairment and altered dopaminergic activity in chronically
      stressed rats is unclear. Furthermore, the change of dopaminergic activity in the
      PFC induced by stress is thought to express as a stress response, not as a
      disorder of organic function. We have previously reported that chronic stress
      administered by water immersion and restraint for 4 weeks induces a organic
      disorder such as hippocampal neuronal degeneration. We therefore examined whether
      chronically stressed (4 weeks) and recovered (10 d) rats show a working memory
      impairment caused by reduced dopamine (DA) transmission in the PFC, as suspected
      in the neuropsychiatric disorders. The stress impaired the spatial working memory
      evaluated by T-maze task and induced a marked reduction of DA transmission
      concomitant with an increase in DA D1 receptor density in the PFC. This memory
      impairment was sufficiently ameliorated by intra-PFC infusion of 10 ng SKF 81297,
      a D1 receptor-specific agonist. Pretreatment with intraperitoneal injection of 20
      microgram/kg SCH 23390, a D1 receptor antagonist, reversed the SKF 81297
      response. These results indicate that chronic stress induces working memory
      impairment through a D1 receptor-mediated hypodopaminergic mechanism in the PFC.
      These findings provide important information for understanding of the mechanisms
      underlying PFC dysfunction in stress-related neuropsychiatric disorders.

PMID- 10662847
TI  - Implications of all-or-none synaptic transmission and short-term depression
      beyond vesicle depletion: a computational study.
AB  - The all-or-none character of transmission at central synapses is commonly viewed
      as evidence that only one vesicle can be released per action potential at a
      single release site. This interpretation is still a matter of debate; its
      resolution is important for our understanding of the nature of quantal response.
      In this work we explore observable consequences of the univesicular release
      hypothesis by studying a stochastic model of synaptic transmission. We
      investigated several alternative mechanisms for the all-or-none response: (1) the
      univesicular release constraint realized through lateral inhibition across
      presynaptic membrane, (2) the constraint of a single releasable vesicle per
      active zone, and (3) the postsynaptic receptor saturation. We show that both the
      univesicular release constraint and the postsynaptic receptor saturation lead to
      a limited amount of depression by vesicle depletion, so that depletion alone
      cannot account for the strong paired-pulse depression observed at some cortical
      synapses. Although depression can be rapid if there is only one releasable
      vesicle per active zone, this scenario leads to a limit on the transmission
      probability. We evaluate additional mechanisms beyond vesicle depletion, and our
      results suggest that the strong paired-pulse depression may be a result of
      activity-dependent inactivation of the exocytosis machinery. Furthermore, we
      found that the statistical analysis of release events, in response to a long
      stimulus train, might allow one to distinguish experimentally between
      univesicular and multivesicular release scenarios. We show that without the
      univesicular release constraint, the temporal correlation between release events
      is always negative, whereas it is typically positive with such a constraint if
      the vesicle fusion probability is sufficiently large.

PMID- 10662848
TI  - Estrogen selectively regulates spine density within the dendritic arbor of rat
      ventromedial hypothalamic neurons.
AB  - Estrogen acts in the hypothalamic ventromedial nucleus (VMH) to promote female
      sexual behavior. One potential mechanism through which estrogen may facilitate
      this behavior is by reconfiguring synaptic connections within the VMH. Estrogen
      treatment increases the number of synapses and dendritic spines in the VMH, but
      how this remodeling occurs within the context of the local, behaviorally relevant
      microcircuitry is unknown. The goal of this study was to localize estrogen
      induced changes in spine density within the VMH and relate these to dendritic
      morphology and the presence of nuclear estrogen receptor. The hypothalami from
      ovariectomized rats, treated with either vehicle or estradiol, were lightly
      fixed, and VMH neurons were iontophoretically filled with Lucifer yellow.
      Confocal microscopy was used to examine neuronal morphology. Estrogen treatment
      increased dendritic spine density by 48% in the ventrolateral VMH but had no
      effect on spine density in the dorsal VMH. The primary dendrites of VMH neurons
      were differentially affected by estrogen. Estrogen treatment increased spine
      density twofold on the short primary dendrites but did not affect spine density
      on long primary dendrites. Immunocytochemical staining showed that none of the
      filled neurons expressed estrogen receptor-alpha. Thus, although the effect of
      estrogen on spine density is localized to a VMH subdivision where estrogen
      receptor is expressed, estrogen treatment induces spines on neurons that lack
      estrogen receptor. Taken together, our results suggest that the effect of
      estrogen on ventrolateral VMH spines is selective within the dendritic arbor of a
      neuron and may be mediated by an indirect, possibly transynaptic, mechanism.

PMID- 10662849
TI  - Tactile coactivation-induced changes in spatial discrimination performance.
AB  - We studied coactivation-based cortical plasticity at a psychophysical level in
      humans. For induction of plasticity, we used a protocol of simultaneous pairing
      of tactile stimulation to follow as closely as possible the idea of Hebbian
      learning. We reported previously that a few hours of tactile coactivation
      resulted in selective and reversible reorganization of receptive fields and
      cortical maps of the hindpaw representation of the somatosensory cortex of adult
      rats (Godde et al., 1996). In the present study, simultaneous spatial two-point
      discrimination was tested on the tip of the right index finger in human subjects
      as a marker of plastic changes. After 2 hr of coactivation we found a significant
      improvement in discrimination performance that was reversible within 8 hr.
      Reduction of the duration of the coactivation protocol revealed that 30 min was
      not sufficient to drive plastic changes. Repeated application of coactivation
      over 3 consecutive days resulted in a delayed recovery indicating stabilization
      of the improvement over time. Perceptual changes were highly selective because no
      transfer of improved performance to fingers that were not stimulated was found.
      The results demonstrate the potential role of sensory input statistics (i.e.,
      their probability of occurrence and spatiotemporal relationships) in the
      induction of cortical plasticity without involving cognitive factors such as
      attention or reinforcement.

PMID- 10662850
TI  - Neural sensitivity to interaural time differences: beyond the Jeffress model.
AB  - Interaural time differences (ITDs) are a major cue for localizing the azimuthal
      position of sounds. The dominant models for processing ITDs are based on the
      Jeffress model and predict neurons that fire maximally at a common ITD across
      their responsive frequency range. Such neurons are indeed found in the binaural
      pathways and are referred to as "peak-type." However, other neurons discharge
      minimally at a common ITD (trough-type), and others do not display a common ITD
      at the maxima or minima (intermediate-type). From recordings of neurons in the
      auditory cortex of the unanesthetized rabbit to low-frequency tones and envelopes
      of high-frequency sounds, we show that the different response types combine to
      form a continuous axis of best ITD. This axis extends to ITDs well beyond that
      allowed by the head width. In Jeffress-type models, sensitivity to large ITDs
      would require neural delay lines with large differences in path lengths between
      the two ears. Our results suggest instead that sensitivity to large ITDs is
      created with short delay lines, using neurons that display intermediate- and
      trough-type responses. We demonstrate that a neuron's best ITD can be predicted
      from (1) its characteristic delay, a rough measure of the delay line, (2) its
      characteristic phase, which defines the response type, and (3) its best frequency
      for ITD sensitivity. The intermediate- and trough-type neurons that have large
      best ITDs are predicted to be most active when sounds at the two ears are
      decorrelated and may transmit information about auditory space other than sound
      localization.

PMID- 10662851
TI  - The role of CNS glucagon-like peptide-1 (7-36) amide receptors in mediating the
      visceral illness effects of lithium chloride.
AB  - Peripheral administration of large doses of lithium chloride (LiCl) to rats
      causes a spectrum of effects that are consistent with visceral illness. LiCl
      reduces food intake, decreases salt ingestion after sodium depletion, induces
      pica, and produces robust conditioned taste aversions. Because some of the
      effects of peripheral LiCl are mimicked by centrally administered glucagon-like
      peptide-1 (7-36) amide (GLP-1), we hypothesized that this peptide is involved in
      the neural pathways by which LiCl causes visceral illness. To test this
      hypothesis, we pretreated rats with a selective and potent GLP-1 receptor
      antagonist given directly into the third ventricle via an indwelling cannula
      before administration of peripheral LiCl. The GLP-1 receptor antagonist
      completely blocked the effect of LiCl to reduce food intake, induce pica, and
      produce a conditioned taste aversion. The same dose of GLP-1 receptor antagonist
      did not reverse the LiCl-induced reduction in NaCl intake. The data indicate a
      role for GLP-1 receptors in the CNS pathway that mediates some of the effects of
      visceral illness.

PMID- 10662852
TI  - Paradoxical actions of the serotonin precursor 5-hydroxytryptophan on the
      activity of identified serotonergic neurons in a simple motor circuit.
AB  - Neurotransmitter synthesis is regulated by a variety of factors, yet the effect
      of altering transmitter content on the operation of neuronal circuits has been
      relatively unexplored. We used electrophysiological, electrochemical, and
      immunohistochemical techniques to investigate the effects of augmenting the
      serotonin (5-HT) content of identified serotonergic neurons embedded in a simple
      motor circuit. The dorsal swim interneurons (DSIs) are serotonergic neurons
      intrinsic to the central pattern generator (CPG) for swimming in the mollusc
      Tritonia diomedea. As expected, treatment with the serotonin precursor 5
      hydroxytryptophan (5-HTP) increased the intensity of serotonin immunolabeling and
      enhanced the potency of synaptic and modulatory actions elicited by the DSIs. It
      also greatly enhanced the ability of the DSIs to evoke rhythmic CPG activity.
      After 5-HTP treatment, microvoltammetric measurements indicated an increase in a
      putative 5-HT electrochemical signal during swim CPG activation. Paradoxically,
      the spiking activity of the serotonergic neurons decreased to a single burst at
      the onset of the rhythmic motor program, whereas the overall duration of the
      episode remained about the same. 5-HTP treatment gradually reduced the
      rhythmicity of the CPG output. Thus, more serotonin did not result in a more
      robust swim motor program, suggesting that serotonin synthesis must be kept
      within certain limits for the circuit to function correctly and indicating that
      altering neurotransmitter synthesis can have serious consequences for the output
      of neural networks.

PMID- 10662853
TI  - Chemical stimulation of the ventral hippocampus elevates nucleus accumbens
      dopamine by activating dopaminergic neurons of the ventral tegmental area.
AB  - Dual-probe microdialysis (with HPLC and electrochemical detection) in freely
      moving rats and single-unit recording in anesthetized rats were used to study the
      extent to which impulse flow through the ventral tegmental area (VTA) contributes
      to elevations in nucleus accumbens (NAS) dopamine (DA) evoked by stimulation of
      the ventral subiculum (VS). During perfusion of artificial extracellular fluid
      into the VTA, injections of 0.74 microgram of the excitatory amino acid NMDA into
      the VS elevated accumbens DA to >150% of basal values. During intra-VTA perfusion
      of either 1 microM tetrodotoxin (which blocks impulse flow) or 1 mM kynurenic
      acid (which blocks excitatory glutamate receptors), injections of NMDA into the
      VS failed to elevate accumbens DA. Thus, increased impulse flow through VTA DA
      neurons, mediated by excitatory glutamate inputs to this region, appears critical
      for VS stimulation to elevate NAS DA. Increased impulse flow through VTA DA
      neurons was confirmed using single-unit recording in anesthetized rats. Intra-VS
      NMDA injections increased the firing rates of 45% (14 of 31), decreased the
      firing rates of 13% (4 of 31), and had no effect on 42% (13 of 31) of VTA DA
      neurons. Increases in firing rates were evident within 15 min of NMDA injections,
      a time at which VS NMDA injections elevate accumbens DA in awake animals. The
      results of the present experiments identify the VTA as a critical site through
      which outputs from the VS modulate NAS dopaminergic neurotransmission.

PMID- 10662854
TI  - Kinematics and modeling of leech crawling: evidence for an oscillatory behavior
      produced by propagating waves of excitation.
AB  - Many well characterized central pattern generators (CPGs) underlie behaviors
      (e.g., swimming, flight, heartbeat) that require regular rhythmicity and strict
      phase relationships. Here, we examine the organization of a CPG for leech
      crawling, a behavior whose success depends more on its flexibility than on its
      precise coordination. We examined the organization of this CPG by first
      characterizing the kinematics of crawling steps in normal and surgically
      manipulated animals, then by exploring its features in a simple neuronal model.
      The behavioral observations revealed the following. (1) Intersegmental
      coordination varied considerably with step duration, whereas the rates of
      elongation and contraction within individual segments were relatively constant.
      (2) Steps were generated in the absence of both head and tail brains, implying
      that midbody ganglia contain a CPG for step production. (3) Removal of sensory
      feedback did not affect step coordination or timing. (4) Imposed stretch greatly
      lengthened transitions between elongation and contraction, indicating that
      sensory pathways feed back onto the CPG. A simple model reproduced essential
      features of the observed kinematics. This model consisted of an oscillator that
      initiates propagating segmental waves of activity in excitatory neuronal chains,
      along with a parallel descending projection; together, these pathways could
      produce the observed intersegmental lags, coordination between phases, and step
      duration. We suggest that the proposed model is well suited to be modified on a
      step-by-step basis and that crawling may differ substantially from other
      described CPGs, such as that for swimming in segmented animals, where individual
      segments produce oscillations that are strongly phase-locked to one another.

PMID- 10662855
TI  - Signal transduction in systemic acquired resistance.

PMID- 10662856
TI  - The embryo MADS domain factor AGL15 acts postembryonically. Inhibition of
      perianth senescence and abscission via constitutive expression.
AB  - AGL15 (AGAMOUS-like 15), a member of the MADS domain family of regulatory
      factors, accumulates preferentially throughout the early stages of the plant life
      cycle. In this study, we investigated the expression pattern and possible roles
      of postembryonic accumulation of AGL15. Using a combination of reporter genes,
      RNA gel blot analysis, and immunochemistry, we found that the AGL15 protein
      accumulates transiently in the shoot apex in young Arabidopsis and Brassica
      seedlings and that promoter activity is associated with the shoot apex and the
      base of leaf petioles throughout the vegetative phase. During the reproductive
      phase, AGL15 accumulates transiently in floral buds. When AGL15 was expressed in
      Arabidopsis under the control of a strong constitutive promoter, we noted a
      striking increase in the longevity of the sepals and petals as well as delays in
      a selected set of age-dependent developmental processes, including the transition
      to flowering and fruit maturation. Although ethylene has been implicated in many
      of these same processes, the effects of AGL15 could be clearly distinguished from
      the effects of the ethylene resistant1-1 mutation, which confers dominant
      insensitivity to ethylene. By comparing the petal breakstrength (the force needed
      to remove petals) for flowers of different ages, we determined that ectopic AGL15
      had a novel effect: the breakstrength of petals initially declined, as occurs in
      the wild type, but was then maintained at an intermediate value over a prolonged
      period. Abscission-associated gene expression and structural changes were also
      altered in the presence of ectopic AGL15.

PMID- 10662857
TI  - Genetic interactions between the chlorate-resistant mutant cr 8 8 and the
      photomorphogenic mutants cop1 and hy5.
AB  - The chlorate-resistant mutant cr88 is defective in photomorphogenesis, as shown
      by the phenotypes of long hypocotyls in red light and yellow cotyledons under all
      light conditions. A subset of light-regulated genes is expressed at subnormal
      levels in cr88. To analyze further the role that CR88 plays in
      photomorphogenesis, we investigated the genetic interactions between cr88 and
      mutants of two other loci affecting photomorphogenesis, CONSTITUTIVE
      PHOTOMORPHOGENIC1 (COP1) and LONG HYPOCOTYL5 (HY5). COP1 represses the expression
      of light-regulated genes in the dark, and HY5 inhibits hypocotyl elongation in
      the light. Using morphological, cellular, and gene expression criteria for
      epistasis analyses to position CR88 in the genetic hierarchy of the
      photomorphogenesis pathway, we determined that CR88 acts downstream of COP1 but
      in a branch separate from HY5. In the course of our analysis, we discovered that
      light causes extensive destruction of plastids in dark-grown cop1 seedlings and
      that cr88 prevents this destruction.

PMID- 10662858
TI  - A highly conserved domain of the maize activator transposase is involved in
      dimerization.
AB  - Previous studies have presented indirect evidence that the transposase of the
      maize transposable element Activator (TPase) is active as an oligomer and forms
      inactive macromolecular complexes expressed in large amounts. Here, we have
      identified and characterized a dimerization domain at the C terminus of the
      protein. This domain is the most highly conserved region in the transposases of
      elements belonging to the Activator superfamily (hAT element superfamily) and
      contains a characteristic signature motif. The isolated dimerization domain forms
      extremely stable dimers in vitro. Interestingly, mutations in five of the six
      conserved residues of the signature motif do not affect in vitro dimerization,
      whereas mutations in other, less strictly conserved residues of the signature
      motif do. Loss of dimerization in vitro correlates with loss of TPase activity in
      vivo. As revealed by in situ immunofluorescence staining of mutant TPase
      proteins, the dimerization domain also is involved in forming inactive
      macromolecular aggregates when overexpressed, and the TPase contains one or more
      additional interaction functions.

PMID- 10662859
TI  - RPT2. A signal transducer of the phototropic response in Arabidopsis.
AB  - The blue light receptor NPH1 (for nonphototropic hypocotyl) has been considered
      to be the only UV-A/blue light receptor that induces a phototropic response by
      the hypocotyl and root of Arabidopsis. By analysis of root phototropism (rpt)
      mutants, we show, however, the involvement of another blue light receptor as well
      as the existence of two separate signaling pathways working downstream of these
      receptors in the phototropic response. A newly isolated gene, RPT2, controls one
      of these pathways. The RPT2 gene is light inducible; encodes a novel protein with
      putative phosphorylation sites, a nuclear localization signal, a BTB/POZ domain,
      and a coiled-coil domain; and belongs to a large gene family that includes the
      recently isolated NPH3 gene. From genetic, physiological, and biochemical
      evidence, we propose a genetic model of the signaling pathways that induce the
      phototropic response in Arabidopsis.

PMID- 10662860
TI  - The Cochliobolus carbonum SNF1 gene is required for cell wall-degrading enzyme
      expression and virulence on maize.
AB  - The production of cell wall-degrading enzymes (wall depolymerases) by plant
      pathogenic fungi is under catabolite (glucose) repression. In Saccharomyces
      cerevisiae, the SNF1 gene is required for expression of catabolite-repressed
      genes when glucose is limiting. An ortholog of SNF1, ccSNF1, was isolated from
      the maize pathogen Cochliobolus carbonum, and ccsnf1 mutants of HC toxin
      producing (Tox2(+)) and HC toxin-nonproducing (Tox2(-)) strains were created by
      targeted gene replacement. Growth in vitro of the ccsnf1 mutants was reduced by
      50 to 95% on complex carbon sources such as xylan, pectin, or purified maize cell
      walls. Growth on simple sugars was affected, depending on the sugar. Whereas
      growth on glucose, fructose, or sucrose was normal, growth on galactose,
      galacturonic acid, maltose, or xylose was somewhat reduced, and growth on
      arabinose was strongly reduced. Production of HC toxin was normal in the Tox2(+)
      ccsnf1 mutant, as were conidiation, conidial morphology, conidial germination,
      and in vitro appressorium formation. Activities of secreted beta-1,3-glucanase,
      pectinase, and xylanase in culture filtrates of the Tox2(+) ccsnf1 mutant were
      reduced by 53, 24, and 65%, respectively. mRNA expression was downregulated under
      conditions that induced the following genes encoding secreted wall-degrading
      enzymes: XYL1, XYL2, XYL3, XYL4, XYP1, ARF1, MLG1, EXG1, PGN1, and PGX1. The
      Tox2(+) ccsnf1 mutant was much less virulent on susceptible maize, forming fewer
      spreading lesions; however, the morphology of the lesions was unchanged. The
      Tox2(-) ccsnf1 mutant also formed fewer nonspreading lesions, which also retained
      their normal morphology. The results indicate that ccSNF1 is required for
      biochemical processes important in pathogenesis by C. carbonum and suggest that
      penetration is the single most important step at which ccSNF1 is required. The
      specific biochemical processes controlled by ccSNF1 probably include, but are not
      necessarily restricted to, the ability to degrade polymers of the plant cell wall
      and to take up and metabolize the sugars produced.

PMID- 10662861
TI  - Structural domains and matrix attachment regions along colinear chromosomal
      segments of maize and sorghum.
AB  - Although a gene's location can greatly influence its expression, genome
      sequencing has shown that orthologous genes may exist in very different
      environments in the genomes of closely related species. Four genes in the maize
      alcohol dehydrogenase (adh1) region represent solitary genes dispersed among
      large repetitive blocks, whereas the orthologous genes in sorghum are located in
      a different setting surrounded by low-copy-number DNAs. A specific class of DNA
      sequences, matrix attachment regions (MARs), was found to be in comparable
      positions in the two species, often flanking individual genes. If these MARs
      define structural domains, then the orthologous genes in maize and sorghum should
      experience similar chromatin environments. In addition, MARs were divided into
      two groups, based on the competitive affinity of their association with the
      matrix. The "durable" MARs retained matrix associations at the highest
      concentrations of competitor DNA. Most of the durable MARs mapped outside genes,
      defining the borders of putative chromatin loops. The "unstable" MARs lost their
      association with the matrix under similar competitor conditions and mapped mainly
      within introns. These results suggest that MARs possess both domain-defining and
      regulatory roles. Miniature inverted repeat transposable elements (MITEs) often
      were found on the same fragments as the MARs. Our studies showed that many MITEs
      can bind to isolated nuclear matrices, suggesting that MITEs may function as MARs
      in vivo.

PMID- 10662862
TI  - The role of AHA motifs in the activator function of tomato heat stress
      transcription factors HsfA1 and HsfA2.
AB  - Using reporter assays in tobacco protoplasts and yeast, we investigated the
      function of the acidic C-terminal activation domains of tomato heat stress
      transcription factors HsfA1 and HsfA2. Both transcription factors contain short,
      essential peptide motifs with a characteristic pattern of aromatic and large
      hydrophobic amino acid residues embedded in an acidic context (AHA motifs). The
      prototype is the AHA1 motif of HsfA2, which has the sequence DDIWEELL. Our
      mutational analysis supports the important role of the aromatic and large
      hydrophobic amino acid residues in the core positions of the AHA motifs. The
      pattern suggests the formation of an amphipathic, negatively charged helix as the
      putative contact region with components of the basal transcription complex. In
      support of this concept, proline or positively charged residues in or adjacent to
      the AHA motifs markedly reduce or abolish their activity. Both AHA motifs of
      HsfA1 and HsfA2 contribute to activator potential, and they can substitute for
      each other; however, there is evidence for sequence and positional specificity.

PMID- 10662863
TI  - The Arabidopsis NPR1/NIM1 protein enhances the DNA binding activity of a subgroup
      of the TGA family of bZIP transcription factors.
AB  - The Arabidopsis NPR1 gene is essential in activating systemic, inducible plant
      defense responses. To gain a better understanding of NPR1 function, we conducted
      a yeast two-hybrid screening procedure and identified a differential interaction
      between NPR1 and all known members of the Arabidopsis TGA family of basic leucine
      zipper transcription factors. In the electrophoretic mobility shift assay, NPR1
      substantially increased the binding of TGA2 to its cognate promoter element (as
      1) as well as to a positive salicylic acid-inducible element (LS7) and a negative
      element (LS5) in the promoter of the pathogenesis-related PR-1 gene. Proteins
      encoded by npr1 mutants interacted poorly with TGA2 and did not substantially
      increase TGA2 binding to the as-1, LS5, or LS7 elements, thus establishing a link
      between the loss of disease resistance and the loss of TGA2 interaction and NPR1
      enhanced DNA binding. Coupled with observations that the DNA binding activity of
      TGA factors is deregulated in npr1 plants, the results suggest that NPR1-mediated
      DNA binding of TGA2 is critical for activation of defense genes.

PMID- 10662864
TI  - A new family of high-affinity transporters for adenine, cytosine, and purine
      derivatives in Arabidopsis.
AB  - In many organisms, including plants, nucleic acid bases and derivatives such as
      caffeine are transported across the plasma membrane. Cytokinins, important
      hormones structurally related to adenine, are produced mainly in root apices,
      from where they are translocated to shoots to control a multitude of
      physiological processes. Complementation of a yeast mutant deficient in adenine
      uptake (fcy2) with an Arabidopsis cDNA expression library enabled the
      identification of a gene, AtPUP1 (for Arabidopsis thaliana purine permease1),
      belonging to a large gene family (AtPUP1 to AtPUP15) encoding a new class of
      small, integral membrane proteins. AtPUP1 transports adenine and cytosine with
      high affinity. Uptake is energy dependent, occurs against a concentration
      gradient, and is sensitive to protonophores, potentially indicating secondary
      active transport. Competition studies show that purine derivatives (e.g.,
      hypoxanthine), phytohormones (e.g., zeatin and kinetin), and alkaloids (e.g.,
      caffeine) are potent inhibitors of adenine and cytosine uptake. Inhibition by
      cytokinins is competitive (competitive inhibition constant K(i) = 20 to 35
      microM), indicating that cytokinins are transported by this system. AtPUP1 is
      expressed in all organs except roots, indicating that the gene encodes an uptake
      system for root-derived nucleic acid base derivatives in shoots or that it
      exports nucleic acid base analogs from shoots by way of the phloem. The other
      family members may have different affinities for nucleic acid bases, perhaps
      functioning as transporters for nucleosides, nucleotides, and their derivatives.

PMID- 10662865
TI  - Potential bias in Kaplan-Meier survival analysis applied to rheumatology drug
      studies.

PMID- 10662867
TI  - Rheumatology Online: note from the Editor.

PMID- 10662866
TI  - Resistant rheumatoid arthritis clinics- a necessary development?

PMID- 10662868
TI  - Treatment and investigation of idiopathic inflammatory myopathies.

PMID- 10662869
TI  - Systemic lupus erythematosus-messages from experimental models.

PMID- 10662870
TI  - Economic burden of rheumatoid arthritis: a systematic review.
AB  - OBJECTIVE: To summarize the state of knowledge with regard to the economic impact
      of rheumatoid arthritis (RA) and to highlight any weaknesses in the work
      conducted to date, so as to inform future RA cost-of-illness studies. METHODS:
      Four computerized literature databases were searched to identify all the
      literature relevant to this review. Seven elements indicating a quality cost-of
      illness study were established and used to appraise the literature identified
      critically. Where possible, costs reported by the different studies were
      converted to 1996 US dollars using the consumer price index for medical care.
      RESULTS: Total average medical costs were reported to range from US$5720 (UK
      pound3575) to US$5822 (UK pound3638). Medication constituted between 8 and 24% of
      total medical costs, physician visits between 8 and 21%, and in-patient stays
      between 17 and 88%. The average number of days absent from work due to a person's
      RA was reported to range from 2.7 to 30 days/year. CONCLUSION: The economic
      impact of RA in terms of cost was reported to be substantial by all studies
      reviewed. However, methodological problems meant that discrepancies in the
      average (per person) annual cost of RA existed across studies.

PMID- 10662871
TI  - Disease-modifying anti-rheumatic drug use according to the 'sawtooth' treatment
      strategy improves the functional outcome in rheumatoid arthritis: results of a
      long-term follow-up study with review of the literature.
AB  - OBJECTIVES: To investigate long-term functional outcomes of early rheumatoid
      arthritis (RA) patients treated actively with disease-modifying anti-rheumatic
      drugs (DMARDs) from diagnosis, according to the 'sawtooth' principle, and to
      compare the results to historical data. METHODS: The surviving 46 and 65 patients
      from two early RA cohorts were examined on average 13.0 (cohort 1) and 8.5
      (cohort 2) yr, respectively, after onset of disease. Functional outcome was
      measured by the Health Assessment Questionnaire (HAQ) and compared with the HAQ
      scores of 57 RA patient cohorts found through a Medline computer search. RESULTS:
      The respective cross-sectional mean HAQ scores of cohorts 1 and 2 were 0.75 and
      0. 55, and were more favourable than the mean HAQ scores of 1.27 (27 cohorts,
      disease duration >10 yr) and 1.13 (13 cohorts, disease duration 5-10 yr) of the
      comparator cohorts. The median time that our patients were treated with DMARDs
      out of the total follow-up period was 88%, while in the majority of comparator
      cohorts the use of DMARDs was less extensive or poorly described. CONCLUSIONS:
      The observation of better preserved function in patients with RA over 13 and 8.5
      yr, compared to earlier reports which indicated more severe declines, is a
      hopeful sign for the rheumatology community.

PMID- 10662872
TI  - Quantification of the cell infiltrate in synovial tissue by digital image
      analysis.
AB  - OBJECTIVE: The experience with digital image analysis (DIA) in the assessment of
      synovial inflammation is limited. In this study we compared DIA with two
      currently applied methods for the evaluation of the synovium. METHODS: Synovial
      tissue (ST) specimens were obtained by arthroscopy from knee joints of rheumatoid
      arthritis (RA) patients with variable disease expression and in control subjects.
      CD68+ macrophages and CD3+ T-cells were detected by immunohistochemical staining
      using two different labelling techniques. The labelled ST sections were
      quantified using three different analysis techniques: manual cell counting (MC),
      semi-quantitative analysis (SQA) and DIA. RESULTS: We observed strongly positive
      correlations between the three methods when examining T-cell infiltration:
      between MC and SQA: sigma=0.91 (P<0. 0001), between MC and DIA: sigma=0.95
      (P<0.0001), and between SQA and DIA: sigma=0.83 (P<0.0001). Similarly, for the
      analysis of synovial intimal macrophages, positive correlations were noted
      between MC and SQA (sigma=0.62; P=0.002), MC and DIA (sigma=0.56; P<0.01), and
      SQA and DIA (sigma=0.79; P<0.0001). Finally, the analysis of synovial sublining
      macrophages revealed positive correlations between MC and SQA (sigma=0.95;
      P<0.0001), MC and DIA (sigma=0.64; P=0.001) and SQA and DIA (sigma=0.69;
      P<0.0001). CONCLUSION: These three different methods generated similar results.
      DIA offers the opportunity of a reliable and time-efficient analysis of the
      synovial infiltrate.

PMID- 10662873
TI  - Hepatic fibrosis in rheumatoid arthritis patients treated with methotrexate:
      application of a new semi-quantitative scoring system.
AB  - OBJECTIVE: Evaluation of hepatic lesions in patients treated with methotrexate
      (MTX) generally used the Roenigk histological score. However, the sensitivity of
      the method for hepatic fibrosis assessment has been discussed. The semi
      quantitative histological scoring system (SSS) offers a sensitive and specific
      evaluation of liver fibrosis. Both scores have been evaluated in liver biopsies
      of patients with rheumatoid arthritis. METHODS: Seventy-four liver biopsies were
      obtained in 57 rheumatoid arthritis patients before initiation of MTX (group 1,
      38 cases), in cases of a persistently high level of transaminases during 1 yr of
      treatment (group 2, 10 cases) and after a MTX total dose of 2 g (group 3, 26
      cases). Eleven biopsies of groups 1 and 3 originated from the same patient in 11
      cases. Specimens were examined blindly by two anatomopathologists. The three
      groups were compared with an ANOVA. Sequential biopsies performed in 11 patients
      were compared with the Wilcoxon paired test. RESULTS: The Roenigk score and the
      SSS were significantly correlated (P<0.0001). Only a mild fibrosis was found in
      33.8% (25/74) of the biopsies with the Roenigk score. Liver fibrosis, graded as
      mild (48.6%), moderate (41.8%) or severe (4%), was demonstrated in 94.6% (70/74)
      of the biopsies with the SSS. The Roenigk score and the SSS of the three patient
      groups were not statistically significantly different. The scores did not
      progress in the 11 patients who had serial biopsies. CONCLUSION: SSS is much more
      sensitive than the Roenigk score for the evaluation of hepatic fibrosis. However,
      SSS did not show progression of hepatic fibrosis in patients with rheumatoid
      arthritis treated with MTX.

PMID- 10662874
TI  - Comparison of sonography and magnetic resonance imaging for the diagnosis of
      partial tears of finger extensor tendons in rheumatoid arthritis.
AB  - OBJECTIVE: Finger extensor tenosynovitis in rheumatoid arthritis (RA) may lead to
      partial and eventually to complete tendon tears. The aim of this study was to
      investigate the diagnostic value of sonography (SG) and/or magnetic resonance
      imaging (MRI) to visualize partial tendon tears. METHODS: Twenty-one RA patients
      with finger extensor tenosynovitis for more than 12 months underwent SG, MRI and
      surgical inspection, the latter being the gold standard. RESULTS: For partial
      tears, sensitivity and specificity were 0.27 and 0.83 for MRI, and 0.33 and 0.89
      for SG, respectively. Positive and negative predictive values were 0.35 and 0.78
      for MRI, and 0.50 and 0.80 for SG, respectively. Accuracy was 0.69 for MRI and
      0.75 for SG. CONCLUSION: For visualization of partial finger extensor tendon
      tears in RA patients, SG performs slightly better than MRI, but both techniques
      are at present not sensitive enough to be used in daily practice.

PMID- 10662875
TI  - A single nucleotide polymorphism in exon 1 of cytotoxic T-lymphocyte-associated-4
      (CTLA-4) is not associated with rheumatoid arthritis.
AB  - BACKGROUND: Rheumatoid arthritis (RA) is an oligogenic disease for which only one
      susceptibility locus has been identified to date. Genes involved in T-cell
      regulation are potential candidates. Association to cytotoxic T-lymphocyte
      associated-4 (CTLA-4) protein, a negative regulator of T-cell activation, has
      previously been described in a subset of German RA patients carrying the HLA
      DRB1*0401 subtype. Linkage and association with another oligogenic autoimmune
      disease, insulin-dependent diabetes mellitus, has also been described in a
      Spanish population. OBJECTIVE: To investigate the association of CTLA-4 with RA
      in Spanish and UK subjects. METHODS: Caucasoid UK RA patients (n=192), UK
      controls (n=96), Spanish RA patients (n=136) and Spanish controls (n=144) were
      typed for an A/G bi-allelic polymorphism in exon 1 of CTLA-4 using polymerase
      chain reaction-restriction fragment length polymorphism (PCR-RFLP) (enzyme).
      RESULTS: No significant differences in the frequency of the G allele or the GG
      genotype were found in either the UK or Spanish RA patients compared with
      controls. CONCLUSION: No significant evidence was found of an association between
      RA and CTLA-4.

PMID- 10662876
TI  - Genotype-phenotype correlation in a large group of Turkish patients with familial
      mediterranean fever: evidence for mutation-independent amyloidosis.
AB  - OBJECTIVES: Differences in clinical manifestations of familial Mediterranean
      fever (FMF) between different ethnic groups have been documented. The FMF gene
      was recently cloned and four missense mutations (Met694Val, Met680Ile, Val726Ala,
      and Met694Ile) that account for a large percentage of the patients were
      identified. The results of initial mutation studies have led to the hypothesis
      that phenotypic variation of the disease may be attributable to the existence of
      some of these mutations. The purpose of this study was to evaluate whether this
      phenotypic variation is associated with the existence of particular mutations in
      Turkish FMF patients living in Turkey. METHODS: Four missense mutations and
      genotype-phenotype correlation were investigated in 167 Turkish FMF patients. The
      patients were grouped according to the presence of the Met694Val and the
      Met680Ile mutations, and 12 clinical parameters were compared between the groups.
      RESULTS: The presence of the Met694Val mutation was not found to be associated
      with a severe form of the disease or the development of amyloidosis. Arthritis
      frequency was found to be lower in the patients with homozygous Met680Ile
      mutation. CONCLUSIONS: None of the four missense mutations is associated with a
      severe disease or the development of amyloidosis in Turkish FMF patients living
      in Turkey. The influence of unknown environmental factors and/or the presence of
      other genetic changes are necessary to explain the phenotypic variation of the
      disease and the development of amyloidosis.

PMID- 10662877
TI  - Yersinia enterocolitica O:8 and O:5 lipopolysaccharide arthritogenicity in
      hamsters.
AB  - OBJECTIVE: To assess the arthritogenicity of Yersinia enterocolitica O:8 and O:5
      lipopolysaccharide (LPS) administered separately as single antigens in hamsters.
      METHODS: Male hamsters of the Syria strain were intramuscularly injected into
      each of the hind paws with two doses of Y. enterocolitica LPS O:8 or O:5. The
      measurement of swelling using a plethysmometer, the analysis of histological
      changes by routine techniques and the kinetics of LPS-specific antibodies and
      autoantibodies evaluated by enzyme-linked immunosorbent assay (ELISA) were
      performed. RESULTS: LPS O:8 was demonstrated to be more arthritogenic than LPS
      O:5, inducing acute arthritis on day 3 post-injection as well as more significant
      and longer lasting joint swelling after a second dose. LPS O:8 caused severe
      histopathological changes in the joints. Important LPS O:8-specific IgG responses
      and antibodies against type I and II collagen were observed. CONCLUSION: LPS O:8
      administered alone has arthritogenic power and induces activation of autoreactive
      clones. This study supports the key role of LPS in the development of reactive
      arthritis.

PMID- 10662878
TI  - Vitamin D receptor gene polymorphisms and osteoarthritis of the hand, hip, and
      knee: acase-control study in Japan.
AB  - OBJECTIVE: To investigate the association between vitamin D receptor (VDR) gene
      polymorphisms andJapanese female patients with osteoarthritis (OA) of the hand,
      hip, and knee. METHODS: BsmI,ApaI, andTaqI restriction fragment length
      polymorphisms (RFLPs) of the VDR gene were analysed in 270Japanese female
      patients with radiographic OA of the hand, hip, tibiofemoral (TF) joint,
      andpatellofemoral (PF) joint, as well as in female controls. RESULTS: There was
      no significant association between the VDR gene RFLPs and OA of the hand, hip,
      TFjoint, PF joint, or polyarticular involvement. The previously detected
      preventive genotype of the VDRgene was uncommon in our test population.
      CONCLUSION: The relative importance of VDR gene polymorphism in the development
      of OA may vary betweenethnic groups.

PMID- 10662879
TI  - The prevalence of vertebral fractures in mild ankylosing spondylitis and their
      relationship to bone mineral density.
AB  - OBJECTIVE: To determine bone mineral density (BMD) in patients with mild
      ankylosing spondylitis (AS), to establish the prevalence of vertebral fractures
      and fracture risk in these patients, and to determine the relationship between
      BMD and vertebral fractures. METHODS: Sixty-six men with mild AS were studied.
      BMD of the lumbar spine and femoral neck was measured by dual X-ray
      absorptiometry (DXA) and radiographs of the thoracic and lumbar spine were
      obtained in all subjects. From the radiographs, vertebral fractures were
      characterized by a morphometric technique using established criteria. Thirty-nine
      healthy male subjects aged 50-60 yr, recruited from primary care registers, had
      spinal radiographs performed and served as controls for vertebral fractures.
      RESULTS: In patients with AS, BMD was reduced in both the lumbar spine 0.97 (0.1)
      g/cm(2) [T score -1.10 (1.3), 95% confidence interval (CI) -0.50, +0.14] and
      femoral neck 0.82 (0.1) g/cm(2) [T score -1.40 (1.2), 95% CI -0.51, +0.09]. There
      was no correlation between BMD of either the lumbar spine or femoral neck and
      duration of disease in patients with AS. Eleven of 66 (16.7%) patients with AS
      had a vertebral fracture, compared with one of 39 (2.6%) controls; odds ratio
      5.92 (95% CI 1.4, 23.8). AS patients with fractures were not significantly older
      (mean age 41.4 vs 37.8 yr, P=0.17), but had significantly longer disease duration
      (12.4 vs 9.3 yr, P<0.05) than patients without fractures. No significant
      difference was found in the visual analogue scores for pain in AS patients with
      fractures compared with those without. No significant correlation was observed
      between BMD of the lumbar spine or femoral neck and vertebral fractures in
      patients with AS. In addition, there was no significant difference in the lumbar
      spine or femoral neck BMD in AS patients with fractures compared with those
      without. CONCLUSIONS: Spinal and hip osteopenia and vertebral fractures are a
      feature of mild AS. However, there was no correlation between BMD and vertebral
      fractures in these patients. AS patients with mild disease had a higher risk of
      fractures compared with the normal population and this increased with the
      duration of disease.

PMID- 10662880
TI  - Discriminating ability of composite indices for measuring disease activity in
      rheumatoid arthritis: a comparison of the Chronic Arthritis Systemic Index,
      Disease Activity Score and Thompson's articular index.
AB  - OBJECTIVE: To compare the discriminating ability of the chronic arthritis
      systemic index (CASI), an index that uses the Health Assessment Questionnaire
      (HAQ) as the main variable, with the disease activity score (DAS) and Thompson's
      articular index (TAI) to detect high and low disease activity in rheumatoid
      arthritis (RA). METHODS: Two hundred and two RA patients were examined. According
      to criteria proposed previously, they were divided into two subgroups: those with
      active disease and those with low activity. The areas under receiver operating
      characteristic (ROC) curves were employed to assess the diagnostic accuracy of
      the CASI in comparison with the DAS and TAI for the discrimination of disease
      activity. RESULTS: The difference between areas under the ROC curves of the CASI
      and TAI (0. 897+/-0.023 vs 0.780+/-0.032) and between the DAS and TAI (0.933+/-0.
      018 vs 0.780+/-0.032) was highly significant (P=0.0001), thus reflecting the
      accuracy of the diagnostic assessment. No difference arose between areas under
      the ROC curves of the CASI and the DAS (difference between areas=0.036+/-0.022;
      P=0.103). CONCLUSION: The CASI discriminates just as well between high and low
      disease activity as does the DAS. Either index consisting of more than one
      variable performs better than TAI. We conclude that even including the HAQ, a
      severity parameter in the long term, it is possible to construct an index that,
      at any time point, evaluates disease activity as well.

PMID- 10662881
TI  - The place of magnetic resonance and ultrasonographic examinations of the parotid
      gland in the diagnosis and follow-up of primary Sjogren's syndrome.
AB  - OBJECTIVE: The aim was to determine the place of magnetic resonance imaging (MRI)
      and ultrasonographic (US) examination in the diagnosis and follow-up of Sjogren's
      syndrome (SS). METHODS: Parotid MRI and US examinations were carried out on 44
      primary SS patients and 52 controls of similar age. RESULTS: The most important
      structural changes in SS were different degrees of parenchymal inhomogeneity,
      which could be detected by both methods, and were found more frequently in the SS
      patients than in the controls (MRI: 95.4 vs 17. 3%; US: 88.6 vs 7.7%; P<0.001).
      There was good agreement between the MRI and US findings both in the SS cases
      (93.2%) and in the controls (86.5%). In one SS patient who developed parotid
      lymphoma, the US examination showed a hypoechoic 'cobblestones'-like
      inhomogeneous internal pattern which was coupled with an almost homogeneous MRI
      pattern. CONCLUSIONS: MRI appears unnecessary as a routine method in the
      diagnosis of SS; US examination is suitable both for the diagnosis and follow-up
      of SS. The above combination of the seemingly contradictory US and MRI findings
      is highly characteristic of lymphoma which has developed in the course of the
      disease.

PMID- 10662882
TI  - Topical tacrolimus for recalcitrant leg ulcer in rheumatoid arthritis.

PMID- 10662883
TI  - Successful treatment of hepatitis B-associated polyarteritis nodosa with a
      combination of lamivudine and conventional immunosuppressive therapy: a case
      report.

PMID- 10662884
TI  - Antiphospholipid syndrome with proliferative vasculopathy and bowel infarction.

PMID- 10662885
TI  - A patient with systemic lupus erythematosus and Salmonella enteritidis
      bacteraemia complicated by rhabdomyolysis and acute cholecystitis.

PMID- 10662886
TI  - Does the age of onset of rheumatoid arthritis influence phenotype?: a prospective
      study of outcome and prognostic factors.

PMID- 10662887
TI  - The Wellcome Prize Lecture. Visual signals in the retina: from photons to
      synapses.
AB  - The ability to see the world around us is an immediate and striking example of
      the abilities of the nervous system, and perhaps for this reason, vision is one
      of the most intensively studied aspects of brain function (Hubel, 1995). This
      paper examines some of the earliest steps in vision occurring in the retina
      (Dowling, 1987; Rodieck, 1998).

PMID- 10662888
TI  - Protective effect of HOE642, a selective blocker of Na+-H+ exchange, against the
      development of rigor contracture in rat ventricular myocytes.
AB  - The objective of this study was to investigate the effect of Na+-H+ exchange
      (NHE) and HCO3--Na+ symport inhibition on the development of rigor contracture.
      Freshly isolated adult rat cardiomyocytes were subjected to 60 min metabolic
      inhibition (MI) and 5 min re-energization (Rx). The effects of perfusion of HCO3-
      or HCO3--free buffer with or without the NHE inhibitor HOE642 (7 microM) were
      investigated during MI and Rx. In HCO3--free conditions, HOE642 reduced the
      percentage of cells developing rigor during MI from 79 +/- 1% to 40 +/- 4% (P <
      0.001) without modifying the time at which rigor appeared. This resulted in a 30%
      reduction of hypercontracture during Rx (P < 0.01). The presence of HCO3-
      abolished the protective effect of HOE642 against rigor. Cells that had developed
      rigor underwent hypercontracture during Rx independently of treatment allocation.
      Ratiofluorescence measurement demonstrated that the rise in cytosolic Ca2+ (fura
      2) occurred only after the onset of rigor, and was not influenced by HOE642. NHE
      inhibition did not modify Na+ rise (SBFI) during MI, but exaggerated the initial
      fall of intracellular pH (BCEFC). In conclusion, HOE642 has a protective effect
      against rigor during energy deprivation, but only when HCO3--dependent
      transporters are inhibited. This effect is independent of changes in cytosolic
      Na+ or Ca2+ concentrations.

PMID- 10662889
TI  - Modulation of delayed rectifier potassium current, iK, by isoprenaline in rabbit
      isolated pacemaker cells.
AB  - Permeabilized patch whole-cell voltage clamp methods were used to investigate the
      effects of isoprenaline (ISO) on total delayed rectifier potassium current, iK,
      in rabbit sino-atrial (SA) node pacemaker cells; total iK is composed of the
      rapidly activating iKr and the slowly activating iKs, but predominantly iKr in
      this species. ISO (20 nM) increased the amplitude of total iK and caused a
      negative shift of approximately 10 mV in the activation curve for iK, both in the
      absence and in the presence of 300 nM nisoldipine to block the L-type Ca2+
      current, iCa,L. The same concentration (20 nM) of ISO increased the spontaneous
      pacemaker rate of SA node pacemaker cells by 16%. In addition to increasing the
      amplitude of iK, ISO (20-50 nM) also increased the rate of deactivation of this
      current. The stimulation of iK by ISO was reversed by 10 microM H-89, a selective
      protein kinase A inhibitor, but not by 200 nM bisindolymaleimide I, a selective
      protein kinase C inhibitor. It therefore appears that the mechanisms by which 
      adrenoceptor agonists increase pacemaking rate in sinoatrial node pacemaker cells
      include an increase in the rate of deactivation of iK in addition to the well
      documented augmentation of iCa,L and the positive shift of the activation curve
      for the hyperpolarization-activated inward current, if. The observations are also
      consistent with a role for protein kinase A in the stimulation of iK by ISO in SA
      node cells.

PMID- 10662890
TI  - Protein kinase C-dependent inhibition of K+ currents in noradrenaline-induced
      depolarization of smooth muscle of guinea-pig vas deferens.
AB  - Ionic mechanisms and signal transduction underlying noradrenaline (NA)-induced
      depolarization in single smooth muscle cells of guinea-pig vas deferens were
      studied. NA caused depolarization followed by action potentials through
      activation of 1-adrenoceptors. In the presence of nifedipine, no action potential
      was generated, and the magnitude of the depolarization depended on the
      concentration of NA (0.1-100 micrometer). NA, through 1-adrenoceptor activation,
      reduced the magnitude of membrane currents in response to voltage ramp pulses
      from -90 to -30 mV in a concentration-dependent manner. The reversal potential of
      the current inhibited by NA changed proportionally to the change in the
      equilibrium potential of K+, suggesting that NA inhibited K+ channel activity.
      Treatment of cells with GDPS, an inhibitor of G proteins, or bisindolylmaleimide
      (BIM), a selective protein kinase C (PKC) inhibitor, prevented the NA inhibition
      of the currents. Application of 12-O-tetradecanoylphorbol 13-acetate (TPA), an
      activator of PKC, mimicked the effect of NA. It is suggested that in the smooth
      muscle of guinea-pig vas deferens, activation of 1-adrenoceptors and the
      subsequent activation of PKC led to inhibition of K+ currents, which is
      responsible for the depolarization induced by NA.

PMID- 10662891
TI  - Effects of shear stress on [Ca2+]i and membrane potential of vascular endothelium
      of intact rat blood vessels.
AB  - Shear stress is an important modulator of endothelial function which can affect
      vessel tone, endothelial morphology and gene transcription. However, the
      mechanism by which the endothelium detects changes in shear stress is the subject
      of conflicting reports. The possible contributions of changes in the cytosolic
      Ca2+ concentration ([Ca2+]i) and of membrane hyperpolarisation are disputed. Here
      we have investigated the effects of shear stress on these variables in native
      endothelium in situ in rat aorta and hepatic portal vein. Endothelial [Ca2+]i was
      recorded using the fluorescent indicator fura-2. The [Ca2+]i in unstimulated rat
      aortic endothelium was 86 +/- 12 nM (n = 9). Acetylcholine (ACh) evoked
      relaxation of the aorta and a biphasic increase in endothelial [Ca2+]i. Shear
      stress that evoked relaxation comparable to that evoked by ACh did not affect the
      endothelial [Ca2+]i. Endothelial membrane potential was recorded using the patch
      clamp technique. The resting membrane potentials of rat aortic and portal vein
      endothelium were -47 +/- 3.8 mV (n = 14) and -68 +/- 4.5 mV (n = 9),
      respectively. Shear stress did not affect the endothelial membrane potential of
      rat aorta, but evoked a small (-1.6 +/- 0.3 mV, n = 9) hyperpolarisation of the
      endothelium of rat portal vein in all preparations studied. These results suggest
      that neither changes in [Ca2+]i nor hyperpolarisation are involved in the
      reception of shear stress by native rat aortic endothelium in situ, but that
      shear stress induces small hyperpolarisations of endothelium of portal vein, a
      mechanism that may be present and of greater physiological significance in other
      parts of vascular system.

PMID- 10662892
TI  - Decreased response of rat knee joint blood vessels to phenylephrine in chronic
      inflammation: involvement of nitric oxide.
AB  - The effect of chronic inflammation induced by Freund's Complete Adjuvant (FCA) on
      rat articular blood vessels and knee joint diameter was investigated. Blood flow
      changes in response to phenylephrine (an 1-adrenoceptor agonist) in FCA-treated
      and contralateral knee joints were studied over a 40 day period, using the laser
      Doppler flowmetery (LDF) technique. Unilateral injection of FCA (0.2 ml)
      increased the injected knee diameter on all days examined post-injection (P <
      0.001) and its maximum increase (53 +/- 2 %) was reached on day 3. After this,
      the diameter decreased gradually but did not return to its initial value. In
      control animals, topical application of 10-13-10- 7 mol phenylephrine onto the
      exposed joint capsule decreased blood flow dose dependently (11. 1 +/- 4.4 to
      58.2 +/- 4.5 %, respectively, P < 0.001). Unilateral injection with FCA
      attenuated the phenylephrine response in both ipsilateral and contralateral knees
      compared with the response of control animals (5.2 +/- 1.6 to 48.3 +/- 6.1 % and
      1.9 +/- 2.2 to 45. 3 +/- 5.6 %, respectively, P < 0.05). The reduction persisted
      for 3 weeks after FCA injection (ipsilateral for 21 days; contralateral for 30
      days, P < 0.001). Subsequently the response returned towards normal. To avoid the
      influence of 2-adrenoceptors, yohimbine (an 2-adrenoceptor antagonist) was
      injected (0.5 mg kg-1, I.P.) 30 min before phenylephrine application. Yohimbine
      blocked the vasoconstrictor effect of 10-10-10-7 mol clonidine (an 2-adrenoceptor
      agonist, topical application) by 44-67.7 % inhibition, respectively (P < 0.001).
      Prazosin (an 1-adrenoceptor antagonist, 0.1 mg kg-1, I.P.) blocked the
      vasoconstrictor effect of phenylephrine (10-10-10-7 mol, topical application)
      effectively (42 to 69.8 % inhibition, respectively, P < 0.001). To assess the
      role of nitric oxide (NO) on the observed responses, N G-nitro-L-arginine methyl
      ester (L-NAME, NO synthase inhibitor) was applied topically (0.2 micromol) 5 min
      before phenylephrine application. L-NAME application at 7 and 14 days after FCA
      injection potentiated the vasoconstrictor response in the FCA-treated knee (P <
      0.001) but had no significant effect on the contralateral knee. Blood pressure
      monitoring during phenylephrine, clonidine and L-NAME administration indicated
      that topical application of the drugs had no significant effect on the systemic
      blood pressure. These findings indicate that the vasoconstrictor response to
      phenylephrine was decreased in chronic inflammation and increased NO production
      could be involved.

PMID- 10662893
TI  - Forskolin has a bimodal cAMP-independent effect on superoxide anion generation in
      isolated osteoclasts.
AB  - The mode of action of forskolin is of clinical and scientific interest since
      forskolin has been shown to have potentially therapeutic bone anti-resorptive and
      anti-hypertensive properties. Forskolin is thought to inhibit the bone resorptive
      activity of osteoclasts by elevating cytosolic cAMP and to mimic as well as
      augment the anti-resorptive effect of calcitonin (CT). Other studies have found
      that forskolin has a dose-dependent dual effect in mouse calavaria, stimulating
      bone resorption at low doses and having an inhibitory effect at high doses.
      However, the acute effect of forskolin on osteoclast functional modality has
      never been studied. The present investigation examined the effect of low (1 mM)
      and high doses (10 mM) of forskolin on superoxide anion (O2-) generation in
      isolated bone-resorbing rat osteoclasts. Forskolin was found to have a bimodal
      cAMP-independent effect on O2- generation, being stimulatory at a low dose and
      having an inhibitory effect at a higher dose. These findings also suggest that CT
      induced inhibition of O2- generation in the osteoclasts is likely to be mediated
      by cAMP-independent pathways, perhaps involving [Ca2+]i modulation.

PMID- 10662894
TI  - Effects of capsaicin-induced sensory denervation on osteoclastic resorption in
      adult rats.
AB  - Many recent findings suggest that the nervous system has efferent effects on
      bone. A putative role of the sensory innervation has been assessed by using a
      synchronised rat model of bone resorption after treating adult animals with the
      neurotoxin capsaicin. Fourteen days after capsaicin treatment (50 mg kg-1) the
      right maxillary molars were extracted to activate a wave of resorption along the
      mandibular cortex. The rats were killed 4 days later (i.e. at the peak of
      resorption in this model), and their right mandibles were processed for
      histometric evaluation of resorption along the cortex and of calcitonin gene
      related peptide (CGRP)- and substance P (SP)-immunoreactive (IR) fibres in the
      dental pulp. CGRP-IR and SP-IR fibres were significantly reduced in numbers by
      the capsaicin treatment (by 58 and 49%, respectively), confirming the success of
      sensory denervation. The resorption surface was significantly reduced (P < 0.005)
      versus the sham-treated animals. Although the size of the osteoclast population
      recruited in the site was not modified, the number of actively resorbing
      osteoclasts was significantly reduced (P < 0.03). However, the activity of the
      resorbing cells was not modified. Non-specific esterase-positive osteoclast
      precursors were also significantly few after capsaicin treatment. These data show
      that the sensory nervous system is involved in the control of bone resorption at
      two different levels: (1) in the recruitment of osteoclast precursors, and (2) in
      regulating the access of recruited cells to the bone surface.

PMID- 10662895
TI  - Carbachol-stimulated chloride secretion in mouse colon: evidence of a role for
      autocrine prostaglandin E2 release.
AB  - We used the short-circuit current technique to investigate the possible
      facilitatory role of epithelium-derived prostaglandin E2 (PGE2) release on Cl-
      secretion in the mouse colon. Carbachol- (CCh)-stimulated Cl- secretion was
      reduced by pretreatment with either indomethacin (10 microM), or TTX (1 microM),
      and when added together, these inhibitors revealed net CCh-stimulated K+
      secretion. CCh-stimulated Cl- secretion was partially restored to
      TTX/indomethacin-treated colons by addition of a subsecretory concentration of
      PGE2 (1 nM). In acutely isolated, unstimulated crypt cells, we measured PGE2
      release at a similar level. We conclude that autocrine release of PGs from
      epithelial cells is sufficient to support the CCh-induced Cl- secretory response
      and is a likely co-factor in this response.

PMID- 10662896
TI  - Effect of reproductive status on plasma oxytocin concentrations and the renal
      response to oxytocin in the conscious rat.
AB  - The magnitude of diuresis and natriuretis produced by oxytocin in the female rat
      has been shown to be dependent on the stage of the oestrous cycle. A study has
      been performed to determine the role of ovarian steroids in modulating the renal
      response to oxytocin infused at a rate of 100 fmol min-1 in hypotonic saline.
      Observations were performed on ovariectomised rats with and without steroid
      treatment and rats with suppressed oestrous cycles following treatment with the
      long-acting gonadotrophin-releasing hormone analogue Zoladex, given as a 100 mg
      S.C. depot, or the antioestrogen tamoxifen, given as three daily injections of 1
      mg. Steroid treatment comprised a single dose of 10 microgram oestradiol benzoate
      or 2.0 mg progesterone, or a combination of the two hormones given 30 h apart.
      Ovariectomy had no significant effect on plasma oxytocin concentrations, although
      progesterone treatment produced an increase. The natriuresis in ovariectomised
      animals of 27% was smaller (P < 0.05) than that seen on the day of pro-oestrus
      and closer to that seen in the intact rat at oestrus. The responses in animals
      with suppressed oestrous cycles following treatment with tamoxifen were not
      significantly different from those observed following ovariectomy, neither was
      the diuresis following Zoladex. The renal responses were greater following
      treatment with oestradiol than in the ovariectomised group. Thus ovarian steroids
      do influence the renal responsiveness to oxytocin with oestradiol augmenting the
      response.

PMID- 10662897
TI  - Effects of placental insufficiency on the ovine fetal renin-angiotensin system.
AB  - We postulated that chronic placental insufficiency would be associated with
      reduced expression of renal renin and angiotensinogen genes in the fetal sheep.
      Placental development was restricted in ewes by removing the majority of
      caruncles prior to mating (placentally restricted (PR) group). The weights of PR
      fetuses were significantly reduced (P < 0.05, 2.98 +/- 0.33 kg) compared to
      control fetuses (4.20 +/- 0.30 kg). Kidney weights were also significantly
      reduced in the PR fetuses (P < 0.05, 8.4 +/- 0.9 g) compared with control fetuses
      (12.2 +/- 1.3 g). The ratios of renal renin/-actin mRNA levels were significantly
      reduced in PR fetuses (P < 0.001, 0.35 +/- 0.02) when compared to control animals
      (0.98 +/- 0.13). The renal angiotensinogen mRNA/18S rRNA ratio was significantly
      lower (P < 0.05, 0.28 +/- 0.13) in PR fetuses compared with control fetuses (0.72
      +/- 0.10), while hepatic angiotensinogen was unaffected. There was a positive
      correlation between renal renin mRNA and renal angiotensinogen mRNA levels (r =
      0.65, P < 0.05, n = 12). It is unlikely that these changes in renal
      angiotensinogen and renin mRNA were due to the small increment in plasma cortisol
      levels (< 5 nmol l-1). There was, however, a positive correlation between
      arterial PO2 and renal renin mRNA (r2 = 0.77, P < 0.01). Plasma renin levels were
      not different between the two groups. Thus, restriction of nutrient and oxygen
      supply throughout fetal life was associated with suppression of renal renin and
      renal angiotensinogen gene expression, with no effect on hepatic angiotensinogen
      mRNA levels. This specific suppression of fetal renal renin and angiotensinogen
      expression could alter the activity of the intrarenal RAS and so affect growth
      and development of the kidney.

PMID- 10662898
TI  - Heat shock protein expression is increased in cardiac and skeletal muscles of
      Fischer 344 rats after endurance training.
AB  - Heat shock proteins (HSPs) are expressed when cells are exposed to various types
      of stress and they may provide protection against cellular insult. Previous data
      have shown increases in HSP expression following acute exhaustive exercise in
      rats (Locke et al. 1990, 1995; Salo et al. 1991) and humans (Liu et al. 1999);
      however, it is not known if chronic exercise will increase resting levels of
      HSPs. The purpose of this study was to determine if basal protein levels of HSP
      72/73 and HSP 60 are increased in cardiac and skeletal muscle of endurance
      trained Fischer 344 rats. Heart, soleus (SOL) and lateral gastrocnemius (LG)
      muscles were removed and hearts were sectioned into left ventricle (LV), right
      ventricle (RV) and atria (AT). Endurance training improved myocardial citrate
      synthase activity by 88, 90 and 77% and cytochrome c oxidase activity by 58, 51
      and 89% in LV, RV and AT, respectively. LV and RV oxidative enzyme activities
      were greater when compared to AT for both trained and untrained rats (P < 0.05).
      HSP 72/73 expression was significantly greater (P < 0.05) in LV, RV and SOL from
      endurance trained versus from control rats (26, 45 and 67%, respectively). HSP 60
      was also increased (P < 0.05) in LV, RV and SOL in trained relative to untrained
      rats. HSP 72/73 and HSP 60 were unchanged in AT and LG after training. These
      results indicate that endurance training increases the basal expression of stress
      proteins and this observation is consistent with the hypothesis that endurance
      training may activate a protective mechanism to stress.

PMID- 10662899
TI  - Exercise training enhances relaxation of the isolated guinea-pig saphenous artery
      in response to acetylcholine.
AB  - The effects of exercise training were investigated on the vascular responses in
      the isolated guinea-pig saphenous artery. Exercising animals swam 5 days week-1
      for 6 weeks (60 min day-1 for weeks 1 and 2; 75 min day-1 for weeks 3 and 4; 90
      min day-1 for weeks 5 and 6), while control animals were placed into shallow
      water for the same duration. Trained animals had significantly higher
      ventricular:body weight ratios, increased citrate synthase activity in the
      latissimus dorsi, and enhanced Na+ pump concentrations in the latissimus dorsi
      and gastrocnemius muscles (P < 0.05). In vitro isometric techniques were used to
      measure constriction and relaxation responses of saphenous artery rings from
      trained and control animals. There were no significant differences in the
      constriction responses to KCl (50 mm) and phenylephrine (0.3-100 microM) in
      arterial rings from control versus trained animals. Relaxation responses to
      acetylcholine (10 microM; ACh-relaxation), following preconstriction with
      phenylephrine (10 microM), were significantly enhanced in rings from trained
      animals (P < 0.05). Acetylcholine relaxed the vessels to 47 +/- 6% (control) and
      18 +/- 3% (trained) of the preconstriction responses to phenylephrine. The nitric
      oxide synthase inhibitor N G-nitro-L-arginine (L-NA; 50 microM) significantly
      attenuated the ACh-relaxation in control and trained animals (P < 0.05). The
      effect of L-NA on the ACh-relaxation was significantly larger in trained (change
      in ACh-relaxation with L-NA = 29 +/- 9%) than control (14 +/- 3%) animals (P <
      0.05). In conclusion, exercise training enhanced the ACh-relaxation of the
      isolated guinea-pig saphenous artery. Inhibition of nitric oxide synthase
      attenuated the ACh-relaxation of rings from control and trained animals, but this
      effect was significantly larger in the vessels from trained animals. These
      results are consistent with the idea that nitric oxide could contribute to the
      enhanced ACh-relaxation of the saphenous artery with exercise training.

PMID- 10662900
TI  - Influence of muscle fibre type and fitness on the oxygen uptake/power output
      slope during incremental exercise in humans.
AB  - We recently reported that a higher percentage of type I fibres in vastus
      lateralis and a greater peak oxygen uptake (O2) were associated with a greater
      initial rise in O2 (O2 /W, where W is work rate) following the onset of heavy
      constant power output exercise (above the lactate threshold, LT). It was unclear
      if these results were true only for heavy exercise, or if the association between
      fibre type and/or fitness and O2 /W would also be seen for moderate (< LT)
      exercise. The purpose of the present study was to compare the relationships
      between fibre type or peak O2 and O2 /W determined for moderate (< LT) and heavy
      (> LT) exercise intensities during incremental exercise. Nine healthy subjects
      performed an incremental ramp test on a cycle ergometer. The O2 /Wslope was
      calculated for the domain of power outputs up to the LT (S1), from the LT towards
      peak O2 (S2), and over the entire linear portion of the O2 /W response (ST), and
      compared to fibre type distribution determined from biopsy of the vastus
      lateralis, and to peak O2 (as ml kg-1 min-1). Significant correlations between O2
      /W and the proportion of type I fibres were found for each exercise domain (r is
      0.69, 0.71 and 0.84 for S1, S2 and ST, respectively, P < 0.05). S1 ranged between
      about 9 ml min-1 W-1 for a low proportion of type I fibres and 11 ml min-1 W-1
      for a high proportion of type I fibres. Similar correlations were also found
      between S2 (r = 0.70) and ST (r = 0.76) and peak O2. These results are consistent
      with our previous findings during > LT constant power output exercise, and
      suggest that the proportion of type I fibres, and possibly fitness as indicated
      by peak O2, is associated with greater O2 /W during the initial adjustment to <
      LT as well as > LT exercise. These results do not appear to be explained by
      classical descriptions of the kinetics of adjustment of O2 following the onset of
      ramp or constant power output exercise. They might reflect enhanced motor unit
      recruitment in subjects with a greater percentage of type I fibres, and/or who
      are more aerobically fit. However, the underlying mechanism for these findings
      must await further study.

PMID- 10662901
TI  - Human muscle power generating capability during cycling at different pedalling
      rates.
AB  - The effect of different pedalling rates (40, 60, 80, 100 and 120 rev min-1) on
      power generating capability, oxygen uptake (O2) and blood lactate concentration
      [La]b during incremental tests was studied in seven subjects. No significant
      differences in O2,max were found (mean +/- S.D., 5.31 +/- 0.13 l min-1). The
      final external power output delivered to the ergometer during incremental tests
      (PI,max) was not significantly different when cycling at 60, 80 or 100 rev min-1
      (366 +/- 5 W). A significant decrease in PI,max of 60 W was observed at 40 and
      120 rev min-1 compared with 60 and 100 rev min-1, respectively (P < 0.01). At 120
      rev min-1 there was also a pronounced upward shift of the O2-power output (O2-P)
      relationship. At 50 W O2 between 80 and 100 rev min-1 amounted to +0.43 l min-1
      but to +0.87 l min-1 between 100 and 120 rev min-1. The power output
      corresponding to 2 and 4 mmol l-1 blood lactate concentration (P[La]2 and P[La]4
      ) was also significantly lower (> 50 W) at 120 rev min-1 (P < 0.01) while
      pedalling at 40, 60, 80 and 100 rev min-1 showed no significant difference. The
      maximal peak power output (PM, max) during 10 s sprints increased with pedalling
      rate up to 100 rev min-1. Our study indicates that with increasing pedalling rate
      the reserves in power generating capability increase, as illustrated by the
      PI,max/PM,max ratio (54.8, 44.8, 38.1, 34.6, 29.2%), the P[La]4/PM,max ratio
      (50.4, 38.9, 31.0, 27.7, 22.9%) and the P[La]2/PM,max ratio (42.8, 33.5, 25.6,
      23.1, 15.6%) increases. Taking into consideration the O2,max, the PI,max and the
      reserve in power generating capability we concluded that choosing a high
      pedalling rate when performing high intensity cycling exercise may be beneficial
      since it provides greater reserve in power generating capability and this may be
      advantageous to the muscle in terms of resisting fatigue. However, beyond 100 rev
      min-1 there is a decrease in external power that can be delivered for an given O2
      with an associated earlier onset of metabolic acidosis and clearly this will be
      disadvantageous for sustained high intensity exercise.

PMID- 10662910
TI  - [ [In Process Citation]

PMID- 10662911
TI  - [3D SPECT reconstruction - a diagnostic method in oral and maxillofacial
      surgery].
AB  - Computer-aided three-dimensional (3D) reconstruction of conventional (99m)Tc-DPD
      SPECT data was used for basic investigations of different disease entities of the
      orofacial area, with the aim of improving primary diagnosis and, in selected
      cases such as microvascular bone reconstruction, for a more comprehensive control
      after therapy. So far, the new 3D technique has been applied in 49 patients with
      different indications based on commonly acquired sets of data without any further
      hazard for the patients. In comparison to conventional planar scintigrams, the
      advantage of this sophisticated technique is a higher image contrast and a clear
      cut signal of the investigated bone areas without any superimposing effects.
      Therefore, the anatomical description of the process is better, which is
      particularly important in cases of osteomyelitis and after microvascular
      reconstruction of skull bone defects. In addition, the follow-up investigations
      can assess treatment results far better and outcome predictions are much more
      reliable. A higher sensitivity and specificity in cases of squamous cell
      carcinoma as regards bone infiltration could not be achieved so far. In summary,
      computer-aided 3D reconstruction of conventionally acquired (99m)Tc-DPD-SPECT
      data represents a significant improvement in radionuclide imaging technique,
      providing a much better diagnostic interpretation of selected disease entities in
      the oral and maxillofacial area.

PMID- 10662913
TI  - [ [In Process Citation]

PMID- 10662912
TI  - [Continuous bone distraction with the help of a microhydraulic cylinder].
AB  - Distraction osteogenesis of the mandible is one treatment option in mandibular
      hypoplasia. Usually, a non-continuous distraction mode is applied. The aim of the
      present study was to establish continuous bone distraction using a microhydraulic
      cylinder. Using a submandibular approach, the mandible was dissected
      subperiostally on one side in four mini-pigs; corticotomy was performed and the
      microhydraulic cylinder fixed with two bicortical screws. The hydraulic tube was
      connected with an automatic hydropneumatic injector system. Following 7 days at
      rest, a continuous distraction of 1.5 mm per day was performed for 14 days. After
      2 and 4 weeks postoperatively, the animals were killed and X-rays taken. The
      mandible was then removed en bloc and microscopic evaluation of the sections was
      performed. The microhydraulic cylinder was easy to apply and to handle. The
      continuous stimulus did induce direct mineralisation of longitudinal oriented
      collagenous fibre bundles. Bony regeneration seems to be accelerated, which might
      reduce the postoperatively stabilizing phase.

PMID- 10662914
TI  - [Experimental and finite-element models for the assessment of mandibular
      deformation under mechanical loading].
AB  - Biomechanical investigations of the mandible are difficult to perform due to a
      variety of conditions involved. For the appropriate reconstruction of
      biomechanical properties, a geometrically correct body model has to be
      established which fits to complex in vivo conditions. The aim of our study was to
      evaluate the use of finite-element models (FEM) for the assessment of mandibular
      deformation under mechanical loading. Explanted human mandibles (n = 5) were
      investigated by strain gauges to determine the individual strain distribution
      under mechanical loading. FEM analysis based on a computed tomograph (CT) was
      performed and the results were matched with the test data. Our study demonstrates
      only minor interindividual differences in the strain distribution for each load
      studied. The mechanical response in terms of deformation was found to depend
      mainly on gross geometrical properties and to a minor extent on the various other
      variables. At all positions the maximum principal strain was tensile, the minimum
      principal strain was compressive, and the absolute strain values were correlated
      with the magnitude of the applied force. CT-based FEM analysis revealed the
      utility of mathematical models to approximate simulated data our experimental
      results. Hence, FEM analysis is a non-invasive tool in the prediction of
      biomechanical behaviour of individual mandibles and therefore may help in trauma
      reconstruction and treatment planning.

PMID- 10662915
TI  - [Complications following piercing in the oral and facial region].
AB  - The increasing distribution and social acceptance of body piercing induced us to
      investigate the nature and rate of complications brought about by this
      fashionable injury of the unscathed body. All dentists, maxillofacial surgeons
      and clinics within the region of the association of dentists of Bremen were asked
      to register all patients presenting between June and October 1998 in whom
      piercings of the head and neck area were visible. Response was good; 699
      piercings in 273 persons were recorded and some exemplary photographs made. Some
      47 persons showed local complications which ranged from keloid formation and
      temporary infections to cartilage necrosis and disturbances in sensibility.
      General diseases were described as well, mainly allergies and hepatitis. In
      accordance with the seriousness of the complication the medical treatment
      required varied. Nine persons had to be treated in hospital. In 14 cases patients
      suffered permanent damage. Piercings cause severe complications and considerable
      expense to the public health service.

PMID- 10662916
TI  - [Laminin-5 in diseases of the oral cavity].
AB  - The basement membrane molecule laminin forms a family of proteins. Laminin-5 was
      identified as key protein in the anchoring filaments of the basement membrane.
      The anchoring filaments connect the basement membrane to the epithelial cells and
      together form the epithelial adhesion complex. Disturbances in the epithelial
      adhesion complex result in subepithelial blistering dermatosis. Autoantibodies
      against laminin-5 are found in cicatricial pemphigoid. Mutations in genes of
      laminin-5 with loss of the protein cause epidermolysis bullosa Herlitz. It can be
      determined during prenatal genetic diagnostic testing. Laminin-5 supports
      migration of keratinocytes and forms the basis for migrating keratinocytes in
      oral wound healing. Positive re-epithelialization via laminin-5 has been the
      subject of experimental studies. Oral squamous cell carcinomas are found to have
      a focal loss of laminin-5 in conjunction with a loss of the cellular receptor,
      and increased synthesis of laminin-5 by budding tumor cells has been observed
      along with deposition of the protein in the stroma. As a result of these
      observations laminin-5 has been suggested as a route of invasion. Quantitative
      assessment of this phenomenon and the modulation of laminin-5-tumor cell
      interaction offer new and hopeful means of describing and affecting the invasive
      behaviour of oral squamous carcinoma.

PMID- 10662917
TI  - [The preparation of retrocavities in apicoectomies].
AB  - The purpose of this in vitro and in vivo study was to compare the quality of
      retrograde cavities and retrofilling using various retrograde techniques
      (microhead, ultrasonic). The quality was evaluated on the basis of dye
      penetration, macroscopic control, and both light microscopic and scanning
      electron microscopic examination. A total of 40 extracted teeth with a single
      canal were analyzed. The clinical result was evaluated in 25 patients with root
      filled teeth and the indication of apicoectomy. Statistical analysis indicated
      that the seal was significantly better with ultrasonically prepared cavities than
      with microhead preparation. Retrofillings prepared ultrasonically also showed
      significantly fewer peripheral fissures. The scanning electron microscopic
      examination, however, demonstrated peripheral fissures in all filled teeth.
      Furthermore, the cavities prepared ultrasonically had a smoother surface and a
      lower smear layer. This preparation produced a more pleasing final result. The
      advantages of better accessibility during the preparation, namely, more precise
      preparation of the retrofilling and only minor substance loss were confirmed
      clinically. Using the ultrasonic equipment, absolutely sterile working conditions
      are present.

PMID- 10662918
TI  - [Ulnar versus radial forearm flap in orofacial reconstruction].
AB  - The microvascular ulnar forearm flap is compared with the radial forearm flap for
      soft tissue reconstruction in the head and neck region. In 67 patients 44 ulnar
      forearm and 23 radial forearm flaps were applied. The two groups were compared
      regarding flap dissection, suitability of the flap for the recipient region,
      complication rate and secondary morbidity of the donor region. The ulnar forearm
      flap is favoured due to the less hairy skin of the ulnar forearm region and the
      more conveniently located donor area. The ulnar forearm flap pedicle is long
      compared with alternative transplants but shorter than the radial pendant.

PMID- 10662919
TI  - [Computerised three-dimensional surgical simulator. Introduction and precision
      analysis of a new system].
AB  - Computed tomography (CT)-based anatomic three-dimensional (3D) models have become
      important tools in oral maxillofacial surgery. There are three problems involved
      in the precise transfer of the experience gained and the results of simulation
      surgery to the patient: (1) 3D models have no precise reference points; (2) it is
      difficult to measure translations three-dimensionally; and (3) exact transfer to
      the patient intraoperatively is impossible. We have introduced a new system which
      solves these problems. In the first step 3D dental arches are replaced by plaster
      models, using an occlusal device with three radioopaque hemispheres as reference.
      A computerised electromagnetic tracker makes 3D measurements possible during
      simulated surgery, and a newly developed transfer system with a neurosurgical
      head frame to provide stable anchorage is used for positioning during surgery. We
      present our experience with this system in 15 orthognathic patients undergoing
      bimaxillary surgery. With the 3D computerised simulation surgery and model
      operation transfer system (3D-COSMOS) the dental arches can be replaced with a
      mean accuracy of 0.03 mm. The 3D translations of jaw segments can be measured
      precisely (0.11 mm) and simultaneously at the osteotomy line and the teeth. The
      new jaw position is transferred mechanically with a precision of 0.05 mm.
      Operation time is prolonged only by 15 min.

PMID- 10662920
TI  - [ [In Process Citation]

PMID- 10662921
TI  - [Tobacco and oral health. Questionnaire about knowledge, practices, and opinions
      among dentists in Berlin].
AB  - AIM: The aim of the present study was to investigate knowledge, practices, and
      opinions on tobacco and oral health among dentists of the Berlin Dental
      Association using a questionnaire. MATERIALS AND METHODS: Questions focussed on
      smoking habits, knowledge about oral malignancies and premalignancies and
      practical approaches to screening for oral mucosal diseases and other
      associations of tobacco with oral changes. The questions related to risk factors
      and behavioural counselling for patients and associated constraints. RESULTS: Of
      a total of 4000 questionnaires sent, 483 were received for evaluation (12.1%). Of
      respondents 9.5% were regular smokers. The median number of oral malignancies
      observed was 3. Knowledge about some associations of oral changes such as wound
      healing was adequate. A total of 93.1% of respondents would refer patients with
      oral lesions. Only 35% take a regular history of both tobacco and alcohol
      consumption and 26.6% explain the side effects of tobacco. Some 73.4% believed
      that the dentist could play a role in anti-tobacco counselling. Limiting factors
      were lack of training and of competence in anti-tobacco counselling. CONCLUSIONS:
      This study shows that there still is a considerable need for improvement of
      knowledge and for provision with effective anti-tobacco teaching material. Since
      most of the respondents thought that the dentist should play a role in anti
      tobacco counselling, adequate programmes in Germany should be inititated and
      followed up.

PMID- 10662922
TI  - [Vertical distraction osteogenesis of the alveolar process using a tooth-borne
      device].
AB  - Since the communication of McCarthy et al. in 1992, applications for distraction
      osteogenesis in the maxillofacial complex have increased enormously. The
      advantages as compared to conventional reconstructive procedures are missing
      donor-site morbidity for bone graft harvesting, reduced blood loss and also a
      gradual gain in the soft tissue envelope. Meanwhile, even the vertical
      lengthening of the alveolar process has become a clinically reliable method. The
      case presented illustrates the treatment of a 16-year-old patient who suffered a
      sporting accident at the age of 7 years, leading to ankylosis of the upper middle
      incisors with subsequent underdevelopment of the frontal alveolar process. After
      fabrication of a custom-made distraction device, an osteotomy of the tooth
      bearing segment in the upper front was performed and the segment was attached to
      the distraction device. Bone lengthening was started on the seventh postoperative
      day at a daily rate of 0.5 mm. The distraction was maintained until closure of
      the open bite was achieved. On the 22nd day, the segment was fixed using an
      orthodontic arch wire and the distraction device was removed. A retention period
      of 6 weeks was maintained until sufficient stability was detectable. Now, 1.5
      years after the treatment, the situation is stable with a good consolidation of
      the bone fragments and a physiologically shaped gingivobuccal sulcus. Lengthening
      of the alveolar process by vertical distraction osteogenesis using a tooth-borne
      device may be indicated in certain cases. With this technique a second operation
      can be avoided and there is less risk of laceration of dental roots by fixation
      screws.

PMID- 10662924
TI  - Summaries

PMID- 10662923
TI  - [Polytopic manifestations of paragangliomas. Diagnosis, differential diagnosis
      and indications for therapy].
AB  - Paragangliomas of the glomus caroticum are relatively rare, but highly
      vascularized neoplasmas, which develop from chemoreceptors. They can be develop
      at any age, but most often in the third or fourth decade of life. Paragangliomas
      grow very slowly and are most always of benign origin. There is a familial
      predisposition, and an autosomal-dominant transmission is presumed. They are
      commonly located in the jugular region; in rare cases a polytopic manifestation
      is found. We describe the case of a 47-year-old male patient who was referred to
      our department because of a progressive swelling of the neck on both sides.
      Contrast-enhanced computed tomography had displayed soft tissue tumors in the
      jugular regions. We performed an operative exploration, which showed a highly
      vascularized tumor. Histopathologic analysis revealed the diagnosis of a
      paraganglioma. An angiography of the neck and thoracic region, furthermore,
      revealed an additional paraganglioma in the anterior mediastinum. Using a
      surgical approach via lateral cervicotomies and thoracotomy the paragangliomas
      were extirpated. Our case report demonstrates the rare polytopic manifestation of
      paragangliomas. This perivascular neoplasms have to be removed before
      haemodynamic complications develop. The extent of this tumors is clearly
      illustrated by use of an angiography. Because of the familial predisposition,
      clinical and radiological examinations of relatives are mandatory.

PMID- 10662925
TI  - [ [In Process Citation]

PMID- 10662926
TI  - Cluster headache: an overview.

PMID- 10662927
TI  - Epidemiological and clinical aspects of cluster headache: relation with the
      migrainous syndrome.

PMID- 10662928
TI  - Current status of genetic discoveries in cluster headache.

PMID- 10662930
TI  - Physiological rhythms in cluster headache.

PMID- 10662929
TI  - Biochemical studies in cluster headaches.

PMID- 10662931
TI  - Neuroendocrinology of cluster headache.

PMID- 10662932
TI  - Experimental models for the study of cluster headache.

PMID- 10662933
TI  - Role of nitric oxide in cluster headache.

PMID- 10662934
TI  - The autonomic nervous system and cluster headache.

PMID- 10662935
TI  - Neurophysiological approach to the study of cluster headache.

PMID- 10662936
TI  - Pathogenesis of cluster headache: the contribution of neuroimaging techniques.

PMID- 10662937
TI  - Diagnostic problems in painful ophthalmoplegias.

PMID- 10662938
TI  - The role of cavernous sinus in cluster and other headaches.

PMID- 10662939
TI  - Typical and atypical facial pain.

PMID- 10662940
TI  - Chronic paroxysmal hemicrania and SUNCT syndrome.

PMID- 10662941
TI  - Uncommon trigeminal-autonomic cephalgias.

PMID- 10662942
TI  - Unilateral headache in early and late childhood.

PMID- 10662943
TI  - General considerations on the symptomatic and prophylactic treatment of cluster
      headache.

PMID- 10662944
TI  - Cluster headache: management of acute attacks before triptans.

PMID- 10662945
TI  - Triptans: turning treatment in cluster headache attack.

PMID- 10662946
TI  - How effective are triptans in the treatment of episodic and chronic cluster
      headache.

PMID- 10662947
TI  - Prophylaxis of cluster headache: current views on drug choice.

PMID- 10662948
TI  - Cluster headache: role of surgery.

PMID- 10662950
TI  - Introduction

PMID- 10662949
TI  - Evidence for hypothalamic activation in cluster headache.

PMID- 10662953
TI  - Conventional magnetic resonance sequences in multiple sclerosis.
AB  - The role of magnetic resonance imaging (MRI) in multiple sclerosis (MS) has
      received considerable attention in recent years. MRI has the potential to provide
      indices of disease activity and progression in clinical trials. Moreover, there
      is now widespread agreement that conventional MRI sequences are useful not only
      in diagnosing the disease but also in evaluating the natural course of the
      disease and the response to therapy. Conventional spin echo (CSE) sequences are
      widely accepted as sensitive techniques for the evaluation and quantification of
      brain MS lesions. Fast spin echo (FSE) sequences are now used as an alternative
      to CSE. They have the advantage of a considerable reduction in imaging time. Fast
      fluid attenuation inversion recovery (fast-FLAIR) sequences, in which the signal
      from cerebrospinal fluid is suppressed, also provide a reliable means to evaluate
      the total lesion burden in patients with MS. Despite some limitations in the
      detection of infratentorial lesions, Fast-FLAIR sequences are useful in clinical
      studies. Compared with lesions load on conventional T2-weighted sequences, an
      increase in hypointense lesion load on CSE T1-weighted sequences correlates more
      strongly with increased disability in MS patients. This might be an additional
      useful MRI parameter to monitor disease progression in long-term studies.
      Gadolinium-enhanced T1-weighted images provide highly sensitive markers for
      detecting MRI activity, which represent the primary MRI endpoint for screening
      promising disease-modifying therapies, especially in phase II trials.

PMID- 10662954
TI  - Magnetization transfer imaging to monitor the evolution of multiple sclerosis.
AB  - Magnetization transfer imaging (MTI) is a magnetic resonance imaging (MRI)
      technique that is now used in multiple sclerosis (MS) studies, and is thought to
      have a higher pathological specificity than conventional T2-weighted imaging.
      This review outlines the major contributions given by MTI for the understanding
      of MS evolution.MTI studies of individual MS lesions confirm the pathological
      heterogeneity of T2-weighted MRI abnormalities and the potential role of
      unenhanced T1-weighted hypointensities as specific markers of localized severe
      white matter disruption. Correlative cross-sectional and longitudinal studies
      using MIT and gadolinium (Gd)-enhanced MRI reveal that MTI findings may vary in
      lesions with different patterns of enhancement, and that MTI abnormalities are
      closely related to the onset and recovery of blood-brain barrier disruption in
      new MS plaques. MTI lesion load (LL) is highly correlated with T2-weighted MRI
      lesion load, but it has a limited reliability as a measure of MS lesion burden.
      On the other hand, measures obtained from MT scans using whole-brain histogram
      analysis are highly correlated with the extent of MS abnormalities on
      conventional MRI scans, and predict patients' clinical disability well, since
      they are sensitive to both macro- and microscopic MS lesion burden in the whole
      brain and in specific regions. These data suggest that (a) MTI is sensitive to
      different stages of lesion pathology and pathological evolution in MS patients;
      and (b) MT histogram analysis can provide a more global assessment of MS lesion
      burden, since it encompasses both macro- and microscopic MS pathology.

PMID- 10662956
TI  - The contribution of (1)H-magnetic resonance spectroscopy in defining the
      pathophysiology of multiple sclerosis.
AB  - Proton magnetic resonance spectroscopy ((1)H-MRS) is considered a suitable
      investigation technique for obtaining in vivo information on pathological changes
      in multiple sclerosis (MS) brain. The main betabolites identified are choline
      containing compounds, creatine, N-acetylaspartate (NAA), lactate, mobile lipids,
      myo-inositol, glutamate and glutamine. Proton spectra may be acquired from
      localized volumes of interest on single MS lesions or from the entire brain by
      (1)H-MRS imaging. An increase of choline and lipids (markers of demyelination)
      and the presence of lactate (marker of acute inflammatory reaction) have been
      demonstrated in active Gd-enhancing MS plaques. A reduction of NAA (marker of
      neuronal or axonal damage) has been found in inactive MS lesions. The recent
      evidence of an early NAA decrease in active plaques and in normal appearing white
      matter suggests that axonal damage is an early event in the evolution of
      demyelinating lesions. The correlation between NAA decrease and clinical
      disability conforms that axonal damage has important functional consequences, and
      indicates that the prevention of irreversible axonal loss might be a major target
      for the design and the timing of therapeutical strategies.

PMID- 10662958
TI  - Diffusion-weighted imaging in multiple sclerosis.
AB  - Diffusion-weighted imaging (DWI) provides a unique form of magnetic resonance
      (MR) contrast that enables the diffusional motion of water molecules to be
      quantitatively measured. As a consequence, DWI provides information about the
      orientation, size and geometry of brain structures. Cellular structures in the
      central nervous system restrict water molecular motion, and the apparent
      diffusion coefficient (ADC) is reduced compared to diffusion in bulk water.
      Pathological processes that modify tissue integrity, thus removing some of the
      "restricting" barriers, can result in increased ADC. Preliminary studies in
      multiple sclerosis (MS) using DWI showed that the ADC is higher in macroscopic
      lesions than in the normal appearing white matter (NAWM). The ADC is also
      dependent on the direction in which diffusion is measured, thus making comparison
      of ADC values meaningless without taking into account the measurement direction.
      One measurement of diffusion that is independent of the orientation of structures
      is provided by measuring the ADC in three orthogonal directions, and then
      averaging the results to form the mean diffusivity, D. We obtained DW scans from
      35 patients with relapsing-remitting MS and 24 healthy volunteers. D was measured
      inside T2-visible lesions and regions located in different areas of the NAWM. D
      histograms from a large portion of the brain were created. MS lesions had a
      significantly higher D than NAWM. T1-hypointense lesions had the highest
      diffusion values, consistent with more severe tissue disruption. D was higher in
      the NAWM from patients than in the white matter from healthy controls. We also
      found significant differences between D histogram-derived measures from patients
      and controls, confirming the presence of diffuse damage in the brain of patients
      with MS.

PMID- 10662960
TI  - The role of MRI in dementia.
AB  - Neuroimaging techniques aimed at studying structural changes of the brain may
      provide useful information for the diagnosis and the clinical management of
      patients with dementia. Magnetic resonance imaging (MRI) may show abnormalities
      amenable to surgical treatment in a significant percentage of patients with
      cognitive impairment. MRI may also assist the differential diagnosis in dementia
      associated with metabolic or inflammatory diseases.MRI has the potential to
      detect focal signal abnormalities which may assist the clinical differentiation
      between Alzheimer's disease (AD) and vascular dementia (VaD). Severe temporal
      atrophy, hyperintensities involving the hippocampal or insular cortex, and gyral
      hypointense bands are more frequently noted in AD. Basal ganglionic/thalamic
      hyperintense foci, thromboembolic infarctions, confluent white matter and
      irregular periventricular hyperintensities are more common in VaD. The high
      sensitivity of MRI in detecting T2 hyperintense lesions and the low specificity
      off white matter lesions have resulted in a poor correlation between MRI findings
      and both neuropathological and clinical manifestations. In particular, MRI has
      disclosed a series of white matter focal changes in the elderly population, which
      are not necessarily associated with cognitive dysfunction. The recent advent of a
      new MRI method sensitive to the microstructural changes of white matter, the so
      called diffusion tensor imaging, may be helpful in correlating clinical
      manifestations with white matter abnormalities.

PMID- 10662962
TI  - The role of emission tomography in dementia.
AB  - Positron emission tomography (PET) and single photon emission tomography (SPET)
      offer the opportunity to improve a diagnosis of dementia by providing regional
      functional measurements, which can be used to substantiate the clinical
      judgement. Further progress in the differential diagnosis among degenerative
      dementias is expected from pathological confirmation in the follow-up of patients
      evaluated with neuroimaging methods. A prospective multi-center cohort study of
      patients with possible or probable Alzheimer's disease mostly with presenile
      onset, showed impairment of brain glucose metabolism in temporoparietal or
      frontal association areas, as measured with PET. This was associated
      significantly with dementia severity, clinical classification, presence of
      multiple cognitive deficits, and history of progression. In addition, prospective
      longitudinal analysis showed a significant association between initial metabolic
      impairment (metabolic ratio = 0.80) and subsequent clinical deterioration. In
      patients with mild cognitive deficits at entry, the risk of deterioration was up
      to 4.7-times higher if metabolism was severely impaired than with mild or absent
      metabolic impairment. In the future, it might be possible to use different
      tracers to measure neurotransmitter release or receptor function. It may also be
      possible to scan the patient while performing cognitive tasks to examine changes
      in functional brain activity during pharmacological treatments.

PMID- 10662965
TI  - Proton magnetic resonance spectroscopy of the brain in dementia.
AB  - Proton magnetic resonance spectroscopy (MRS) allows accurate and noninvasive
      biochemical assay of living tissues. In vivo measurements provided by MRS have
      greatly enhanced our understanding of the pathophysiology of dementia. Increases
      in choline and myo-inositol (markers of membrane turnover) have been demonstrated
      in several studies on patients with Alzheimer's disease (AD), suggesting the
      presence of a significant cellular membrane (and glial) pathology in this
      disorder. Large decreases in brain N-acetylaspartate (NAA) (a marker of
      neuroaxonal integrity) are commonly seen in AD as well as in other forms of
      dementia in cerebral gray and white matter, indicating the presence of
      significant axonal damage. Since greater NAA decreases have been demonstrated in
      brains of patients with clinically more severe disease, NAA could provide an
      index relevant to patients' clinical status. Brain metabolic changes can be
      independent of abnormalities detected by conventional magnetic resonance imaging
      (MRI), since proton MRS may show a normal metabolic pattern in patients with mild
      neurological impairment and severe MRI abnormalities. However, quantitative
      measurements of regional brain volumes can be useful in the diagnosis of
      dementia. Thus, proton MRS, alone or combined with new quantitative magnetic
      resonance techniques, can provide sensitive indices able to monitor disease
      progresson or effects of drug therapy.

PMID- 10662966
TI  - Neurophysiological imaging techniques in dementia.
AB  - Neurophysiological methods, such as electroencephalography (EEG) and event
      related potentials, are useful tools in the investigation of brain cognitive
      function in normal and pathological conditions, with an excellent time resolution
      when compared to that of other functional imaging techniques. Advanced techniques
      using a high number of EEG channels also enable a good spatial resolution to be
      achieved. This, together with the possibility of integration with other
      anatomical and functional images, may increase the ability to localize brain
      functions. Spectral analysis of the resting EEG, which gives information on the
      integrity of the cortical and subcortical networks involved in the generation of
      cortical rhythms, has the limitation of low sensitivity and specificity for the
      type of cognitive impairment. In almost all types of dementia, decreased power of
      the high frequencies is indeed observed in mild stages, accompanied by increased
      power of the slow rhythms in the more advanced phases. The sensitivity for the
      detection of spectral abnormalities is improved by studying centroid
      modifications. More specific information on the type of dementia can be provided
      by coherence analysis of the resting EEG, a measure of functional cortico
      cortical connections, which has different abnormal patterns in Alzheimer's
      disease, cerebrovascular dementia and dementia associated with multiple
      sclerosis. Another tool for improving the assessment of demented patients is the
      study of EEG activity related to particular tasks, such as event-related
      potentials and event-related desynchronization/synchronization of the EEG, which
      allow the study of brain activation during cognitive and motor tasks.

PMID- 10662981
TI  - [Stroke management: the signs are good].

PMID- 10662982
TI  - [Treatment of acute clinical stroke].
AB  - Stroke is an emergency. Treatment must begin as soon as possible because
      significant sustained neurological improvement has been demonstrated when
      thrombolytic treatment, mainly with recombined tissue plasminogen activator
      (rtPA) is initiated within the first hours of stroke onset. On the other hand in
      the acute phase of stroke it is critical that patients get adequate management
      for the prevention of early complications. Management of the acute phase of
      stroke is the target of this article. Preclinically started treatment must be
      continued in the neurological emergency unit. Clinical examination is followed by
      technical investigations: cerebral computer tomography (CCT) is the most useful
      radiological investigation in the acute phase. It allows to distinguish between
      ischemia and hemorrhagic lesions and also to rule out nonstroke brain conditions.
      Multimodal magnetic resonance imaging (mMRI) may provide data on viable versus
      irreversibly damaged tissue. Sufficient stroke treatment is based on well managed
      in-hospital infrastructure. Thrombolysis is the only causative treatment of
      stroke in selected patients. Complications of acute stroke comprise changes of
      blood pressure with hemodynamically relevant effects on cerebral perfusion
      pressure, acute post- ischemic brain edema, and intracerebral bleedings.

PMID- 10662983
TI  - [Continuous peridural analgesia vs patient - controlled intravenous analgesia for
      pain therapy after thoracotomy].
AB  - OBJECTIVES: Continuous epidural analgesia (EA) and patient-controlled intravenous
      analgesia (PCA) are widely used for postoperative pain control. Studies indicate
      that both analgesic regimens provide good analgesia after major surgery. However,
      because of the following reasons it is still unclear whether one of the two modes
      of application is superior. First, there are conflicting data regarding the
      differences in pain relief and drug use between epidural and intravenous
      administration of opioids. Second, in many studies epidural analgesia is
      performed by a combination of local anaesthetics and opioids. Third, reduced
      morbidity was observed only in some of the studies, in which epidural analgesia
      provided better pain relief than systemic opioid supply. Despite these
      conflicting results, EA with local anaesthetics and fentanyl as well as PCA with
      piritramid, a highly potent mu-agonist, are routinely used in Germany. The
      purpose of this study was to compare these two treatments for analgesic efficacy,
      pulmonary function, incidence of side effects and complications in patients
      undergoing thoracotomy. METHODS: In this prospective randomized trial 50 patients
      were included. For postoperative pain control 25 patients (EA group) received
      thoracic epidural infusion of local anaesthetics (bupivacaine 0.125% or
      ropivacaine 0,2%) and fentanyl 4,5 microg/ml with a flow rate of 4-10 ml/h. 25
      patients received intravenous PCA with piritramid (bolus 2, 5 mg, lock out 15
      minutes, maximum of 25 mg/4 h, no background infusion). RESULTS: Analgesia at
      rest and while coughing, as evaluated by visual analogue scale, was significantly
      better in the EA group. EA also resulted in superior values of pulmonary function
      tests, general condition and a lower incidence of sedation and nausea. In
      contrast, patients with EA reported distinctly more pruritus than patients with
      PCA. Duration of hospital stay was shorter in the EA group, but this difference
      did not reach statistical significance. There was one atelectasis in the EA
      group. No major complications related to EA or PCA were observed. CONCLUSION: In
      this study EA with local anaesthetics and fentanyl provided superior
      postoperative pain control and a lower incidence of sedation and nausea compared
      to intravenous PCA with piritramid, but there was no superiority as to pulmonary
      complications and duration of hospital stay.

PMID- 10662984
TI  - [How reliable is our memory for acute postoperative pain].
AB  - OBJECTIVES: Clinicians use patients' recall of pain as an important source of
      evidence both in diagnosis and in assessing improvements following treatment. Yet
      very little is known about the accuracy of these retrospective accounts up to
      now. METHODS: We examined patients' retrospective evaluations of the pain they
      experienced at the first postoperative day and related these evaluations to the
      pain intensity which was recorded in the PCA-report. RESULTS: We found that
      recall was moderately accurate. Patients mostly overestimated their pain
      intensity. We could demonstrate that patients who overestimated their pain
      differed significantly from those who did not. The patients who overestimated
      showed no significant pain relief over the first three postoperative days. Other
      influences were the pain intensity of the third day and patients' expectations of
      the postoperative pain intensity. Our results could be embedded within the
      theoretical framework of general memory research. CONCLUSIONS: We conclude that
      real-time evaluations of pain intensity should be recorded additionally to
      retrospective accounts. Retrospective ratings are important too, because we
      suggest that the memory of pain more than the experience of pain itself form the
      basis of patients' future decisions about treatment including their compliance
      and their satisfaction with pain management.

PMID- 10662985
TI  - [Dilated coronary sinus. A preoperative transesophageal echocardiographic
      diagnosis].
AB  - A 36-year old woman was presented to our hospital with congenital ventricular
      septal defect and one-vessel coronary artery disease (75% proximal left main
      coronary artery) for CABG and repair of the VSD. After induction, a
      transesophageal echocardiographic (TEE) baseline examination was performed,
      showing a severely dilated coronary sinus (CS) measuring approximately 3 cm
      (abnormal >1 cm). We suggested a persistent left superior vena cava (PLSVC)
      draining into the CS. PLSVC is a common venous congenital anomaly, with a
      reported incidence of 0.5% in general population and in 3-5 % of patients with
      congenital heart defect. Injection of echo-contrast solution in a left arm vein,
      visualizing microbubbles passing through the PLSVC into the CS confirmed our
      suspicion. The diagnosis of a PLSVC and dilated CS is a contraindication for
      retrograde cardioplegia because of the loss of cardioplegia into the PLSVC
      resulting in a inadequate myocardial protection. It may be difficult to pass a
      pulmonary artery catheter (PAC) through a left internal or left subclavian vein
      and it may be associated with arrhythmias. A chest radiograph shows the anomalous
      course of the PAC along the left heart.

PMID- 10662986
TI  - [Preanalytical errors on the determination of arterial O(2)-partial pressure and
      their impact on the AaDO(2)].
AB  - OBJECTIVES: The paO(2) and AaDO(2) are routinely measured for evaluating
      pulmonary gas exchange. The normal value of the AaDO(2) amounts 10 mmHg when
      breathing atmospheric air and is said to increase with rising FIO(2). This
      increase is discussed controversially. One possible reason for incongruities in
      AaDO(2) measurement may be the impact of so called preanalytical errors during
      paO(2) measurement, which are often neglected. Therefore, the aim of this study
      was to evaluate the relevance of preanalytical errors on the AaDO(2) under
      hyperoxic conditions. METHODS: Arterial blood gas analysis was performed on
      twenty patients without known pulmonary disease after tracheal intubation and 30
      min of ventilation with pure oxygen. All preanalytical paO(2) errors (sampling
      technique, transport and storage of samples, aspirated air bubbles) were assessed
      and all paO(2) measurements were corrected by applying respective predetermined
      correction factors. Calculation of the AaDO(2) was performed with corrected and
      uncorrected paO(2) values. RESULTS: The average amount of the AaDO(2) under
      ventilation with FIO(2)=1.0 was 118.9+/-41.1 mmHg, calculated from uncorrected
      paO(2) values, and 13.4+/-7.5 mmHg calculated from paO(2) values corrected for
      preanalytical errors, respectively. CONCLUSION: The present results show that the
      assumption of an increasing AaDO(2) with rising FIO(2) is questionable. It could
      be proved that neglecting preanalytical paO(2) errors leads to a significant
      overestimation of the AaDO(2). The consequence would be a misinterpretation of
      the patient's condition in relation to a reduced pulmonary gas exchange, which
      should in fact be attributed solely to the preanalytical errors.

PMID- 10662987
TI  - [Acquired inhibitory body hemophilia].
AB  - Although autoantibodies against factor VIII or factor IX are a rare phenomenon,
      they are associated with a high risk of bleeding and high mortality. The
      condition, termed acquired haemophilia, occurs equally in both sexes and is most
      frequent in higher age groups. Patients typically present with severe bleedings
      in muscles and skin. In contrast to patients with congenital haemophilia and
      inhibitors, joint bleedings are very rare. In approximately half of all cases an
      associated disease state can be identified as the cause of autoantibody
      formation. An immediate and comprehensive diagnosis is essential for a rapid
      initiation of therapy. Equally important are a careful diagnostic differentiation
      between congenital and acquired factor deficiencies and the exclusion of non
      specific inhibitors, which increase the occurrence of thrombolic events. The
      inhibitor titre, quantified using the Bethesda assay, is an important criterion
      for selecting the appropriate therapy. A wide range of treatment options is now
      available for the management of bleedings in patients with acquired haemophilia,
      namely porcine factor VIII, recombinant factor VIIa, prothrombin complex
      concentrates, and immunoadsorptions. In addition, immunosuppressive therapies are
      used to achieve permanent reduction or elimination of inhibitors.

PMID- 10662988
TI  - [Modern medical therapy for idiopathic Parkinson syndrome].

PMID- 10662989
TI  - [Medical, ethical and economical limitations in the treatment of multitrauma
      patients].
AB  - In the early post-traumatic period severe traumatic brain injuries and massive
      bleeding from disrupted parenchymal organs, large vessels or crush injuries of
      the pelvis may present as morphological damage that renders survival impossible,
      although aggressive fluid and blood replacement therapy in conjunction with
      immediately stopping blood loss surgically may result in survival in selected
      cases. In contrast, late mortality from multiple organ failure - which in the
      past limited survival in 10 to 30% of patients in that condition - has in recent
      years reduced this as the cause of death to less than 5%. Part of the
      responsibility of the surgeon caring for the severely injured into consider the
      ethical limitations to avoid futile use of the sophisticated life-support
      measures in the intensive care setting. A threat to optimal care of the severely
      injured patient may arise from the economical restraints imposed on health-care
      providers. When one considers the enormous political and socioeconomical
      importance of rehabilitating the predominantly young trauma patients and
      reintegrating them into the work world, an appeal has to be made to all those
      responsible to secure optimal care for severely injured patients in the future.

PMID- 10662990
TI  - [History of the development of intensive care medicine. Part 13: Historical
      overview of the treatment of acute kidney failure in Germany].

PMID- 10662991
TI  - [Quality management in anaesthesia practice: chance and challenge].
AB  - Quality of care and costs are getting closer together. Whereas costs and quality
      management did not play a substantial role 30 years ago, the consumption of
      resources nowadays is part of the outcome of quality of care. The definition of
      quality must be seen in the dimensions of structure, process and result.
      Resulting from newly developed clinical practice, guidelines are planned as
      instruments for cost containment in near future. Those guidelines may end up in a
      quality management system. The most wellknown european basic of such a quality
      management system are the DIN EN ISO 9000 f and the EFQM. The ISO 9001 and the
      European Quality Award became the most common base of evaluation for
      certification of quality management systems in Organisations European wide.
      Whereas the ISO 9001 does not give any information about the real achieved
      quality, the European Quality Award reflects the process. Guidelines are
      necessary to prove the cost effectiveness of measures of quality control and
      quality assurance since too much quality control and assurance may result in
      increased overall consumption of resources, leading to a reduction in the quality
      of care when ensuring that the overall budget is covered.

PMID- 10662992
TI  - [Possible uses of transesophageal echocardiography in perioperative monitoring].

PMID- 10662995
TI  - [Epidemiology and systematics of cystic and alveolar hydatid disease].
AB  - Echinococcus multilocularis, a small tapeworm in foxes, has gained considerable
      public attention owing to its wide distribution in central Europe. Conversely,
      diagnosis and treatment of the disease have been significantly improved in recent
      years. Consequently, the incidence among human populations has remained stable
      and relatively low for many decades. In southern Germany, France (Franche Comte
      and Doubs), Austria and Switzerland, the annual incidence ranges between 0.02 and
      1.4 new cases per 100,000 inhabitants. The relevance of human AE refers to the
      high lethality of the untreated disease. Therapy consists predominantly of
      radical surgery followed by continuous, long-term chemotherapy using albendazole
      (or mebendazole). The action of chemotherapy alone is parasitostatic rather than
      parasitocidal; nevertheless, clinical improvement is observed in > 80 % of such
      cases, including a significantly improved prognosis. Diagnosis relies
      predominantly on imaging procedures and serology. Immunodiagnosis must be
      performed early, especially when a preclinical diagnosis is desired upon exposure
      to infection. Thus, in the framework of seroepidemiological studies, first-time
      evidence was obtained about the phenomenon of natural resistance in non-diseased
      persons. This raised the question of a potential immunogenetic predisposition in
      certain infected persons. E. granulosus (cystic hydatid disease) is practically
      non-existent as autochthonous infection in central Europe now. Most clinical
      cases of E. granulosus infections are thus observed among persons who have
      immigrated from - predominantly - the mediterranean basin.

PMID- 10662996
TI  - [Chemotherapy alone or as adjuvant treatment to surgery for alveolar and cystic
      echinococcosis].
AB  - An overview is presented of the various therapy options in cystic and alveolar
      echinococcosis based on the recent literature and upon personal experience with
      chemotherapy over the last 20 years. In regions with an optimal surgical
      infrastructure and relatively small patient cohorts, long-term chemotherapy is
      practically limited to patients with inoperable echinococcosis, i. e. < 10 %
      cystic and around 70 % alveolar echinococcosis.

PMID- 10662997
TI  - [Surgical treatment of hepatic alveolar echinococcosis].
AB  - INTRODUCTION: Alveolar hydatid disease is an uncommon parasitosis found in the
      northern hemisphere, caused by the larval stage of a tapeworm growing in the
      liver: Echinococcus multilocularis. It behaves like a malignant tumor, producing
      liver necrosis and invading the biliary tract, main vessels and surrounding
      structures. METHODS: Review of the different therapeutic approaches in hepatic
      alveolar echinococcosis over 21 years in an epidemic area. RESULTS: The various
      surgical approaches (all types of hepatectomy, palliative surgical procedures and
      liver transplantation) were combined with medical, endoscopic and radiological
      interventional treatment. Recently, asymptomatic forms were more frequently
      encountered. CONCLUSIONS: The wide use of ultrasonography and specific
      serological tests have led to early diagnosis, allowing more curative
      hepatectomies.

PMID- 10662998
TI  - [Surgical therapy of Echinococcus granulosus (cysticus)].
AB  - Hydatid disease, still frequent in endemic areas, is usually localized in the
      liver. Despite the benign nature of the disease it is one of the problematic
      fields of surgery due to the high complication rate and long hospital stay. Based
      on our experience we recommend evacuation of the cyst and omentoplasty as the
      surgical method of choice, as it is associated with a relatively low incidence of
      complications and can be performed easily.

PMID- 10662999
TI  - [Immunopathogenesis of inflammatory bowel diseases].
AB  - Inflammatory bowel diseases (IBD: Crohn's disease, ulcerative colitis) are
      chronic inflammatory and frequently relapsing diseases of the gut that ultimately
      lead to destruction of the intestinal tissue. Recent evidence suggests that a
      pathologic activation of the mucosal immune system in response to antigens is a
      key factor in the pathogenesis of IBD. Furthermore, changes in cell migration and
      cytokine production appear to contribute to the perpetuation of IBD and the
      postoperative recurrence of Crohn's disease. Based on recent advances in our
      understanding of the pathogenesis of IBD, several new therapeutic strategies are
      currently being tested in clinical practice, including recombinant anti
      inflammatory cytokines (IFN-alpha, IL-10, IL-11) and inhibitors of cell adhesion
      molecules (ICAM), proinflammatory cytokines (TNF, IL-12) and their receptors
      (TNF, IL-6R).

PMID- 10663000
TI  - [More attention to hernia surgery!].

PMID- 10663001
TI  - [Pathology of traditional surgical nets for hernia repair after long-term
      implantation in humans].
AB  - The widespread use of alloplastic materials as the standard procedure for hernia
      repair makes an evaluation of the long-term integration of these implants
      imperative. A total of 121 explanted meshes (mean implantation time 23.2 & 19.7
      months) of polypropylene (Atrium((R)), n = 20; Marlex((R)), n = 50; Prolene((R)),
      n = 21), Polyester (Mersilene((R)), n = 19) and PTFE (Gore-Tex((R)), n = 11) were
      analyzed in regard to the tissue and cell response within the interface mesh
      fiber/tissue. The mesh samples were investigated by light and electronmicroscopy,
      as well as immunohistochemistry. The morphometric results confirmed a persisting
      inflammatory proliferative foreign-body reaction with increased cell turnover in
      the recipient tissues. This reaction is mainly influenced by the selected mesh
      modification. The consequences of the arising "chronic wound" are discussed in
      detail, in particular with regard to possible malignant transformation.

PMID- 10663002
TI  - [A prospective randomized study on inguinal hernia repair according to the
      Shouldice technique. Benefits of local anesthesia].
AB  - OBJECTIVE: The aim of this randomized controlled study was to show whether local
      anesthesia (LA) leads to a decrease of postoperative pain in inguinal hernia
      repair in comparison with general anesthesia (AA). METHOD: Sixty volunteer
      patients were randomly assigned into a LA group and an AA group. All patients had
      an unilateral primary inguinal hernia and underwent inguinal hernia repair
      (Shouldice technique). Methods to determine pain were the visual analog scale
      (VAS), peak flow measurement, the measurement of the FEV1 %, and analgesic
      consumption. RESULTS: Up to the third postoperative day we measured a decreased
      pain level in the LA group. The anesthesia procedure was never changed. No
      essential complications occurred. CONCLUSION: Therefore, it was concluded that
      local anesthesia has more advantages than general anesthesia.

PMID- 10663003
TI  - [The parathyrotoxic crisis - a surgical emergency].
AB  - INTRODUCTION: The extremely rare but life-threatening hypercalcemic crisis is
      caused by an exacerbation of a chronic hyperparathyroidism. The etiologic reasons
      for this exacerbation are conditions which increase the serum calcium level in
      addition to the hyperparathyroidism with a complete breakdown of the calcium
      homeostasis, e. g. malignant tumors, primary and tertiary hyperparathyroidism,
      vitamin D poisoning or overdoses of calcium, vitamin D and calcium-containing
      ionizer in patients with renal insufficiency. METHODS: We present the clinical
      course of five patients with an acute hypercalcemic crisis and discuss the
      diagnostic procedure and the principles of surgical treatment with regard to the
      current literature. RESULTS: A hypercalcemic crisis develops if the total serum
      calcium concentration is over 4 mmol/l and parathormone over 90 pmol/l. The
      resulting syndrome is manifested by nausea and vomiting, polyuria and consecutive
      dehydration and hypotonia culminating in lethargy, hallucinations and coma.
      Hypercalcemia is the single most important diagnostic finding. CONCLUSION: The
      emergency therapy predominantly consists on the one hand in rehydration and
      parallel stimulation of diuresis. Urgent surgery is required if conservative
      therapy is not successful.

PMID- 10663004
TI  - [Percutaneous tracheotomy following single tracheal dilatation. Experience in 74
      patients].
AB  - In the method described by Ciaglia et al., the trachea is cannulated
      transcutaneously below the cricoid cartilage under bronchoscopic observation. For
      this purpose, a Seldinger wire with seven graduated dilatators is used for
      successive tracheal dilatation to 36 CH and insertion of an indwelling tracheal
      cannula. The disadvantage of this procedure is the time-consuming successive
      insertion of seven bougies and the repeated risk of injury to the dorsal tracheal
      wall. Percutaneous cannulization sets are expensive and cannot be re-sterilized.
      We developed a re-sterilizable, single-step bougienage device and tested the
      procedure successfully without any complications in 74 patients.

PMID- 10663005
TI  - [Laparoscopic adhesiolysis - results following prospective surveillance].
AB  - INTRODUCTION: About 90 % of the patients have abdominal surgery develop adhesions
      afterward. Studies analyzing complications and follow-up even in emergency cases
      are rare. METHODS: Intra- and postoperative findings and complications and follow
      up were analyzed in a prospective trial between January 1994 and June 1998.
      RESULTS: We performed laparoscopic procedures in 56 patients with complaints of
      obstructing adhesive bands or adhesions. Ninety-six percent of the patients have
      had abdominal surgery; 51.8 % were treated as emergency cases with acute pain,
      48.2 % with chronic abdominal pain. Intraoperatively, 37.5 % of the patients
      showed single adhesive bands; 62.5 % showed adhesions. Mean operation time was 60
      min, conversion rate: 5.4 %. Complications were recorded according to the
      "Cologne classification": class I: 78.6 %, class II: 8.9 %, class III: 1.8 %,
      class IV: 10.8 %, class V: 0 %. The postoperative hospital stay was 6 days on
      average. CONCLUSION: Our study suggests that laparoscopic adhesiolysis can be
      done safely in emergency cases and in patients with extensive adhesions as well.

PMID- 10663006
TI  - [Results of conventional surgical therapy of abdominal aortic aneurysms since the
      beginning of the "endovascular era"].
AB  - INTRODUCTION: In 1990 the new method of endovascular graft treatment of abdominal
      aortic aneurysms (AAA) emerged. For this reason we analyzed the results of open
      surgery for AAA in our department to consider the question of standard therapy.
      METHODS: In a retrospective study the medical data of 941 consecutive patients
      treated by open surgery in a single center from 1990 to 1997 (mean age 67 years,
      14.5 % female, 3.2 % suprarenal AAA) were analyzed. Operations were performed
      electively in 778 asymptomatic patients, urgently in 104 symptomatic patients,
      and as emergency operations (immediately after admission) in 59 symptomatic
      patients (45 patients presenting with rupture). RESULTS: Mortality was 1.54 %
      (elective operations), 8.65 % (urgent operations), and 35.6 % (emergency
      operations, rupture). Morbidity was 15.9 % (elective operations), 28.8 % (urgent
      operations), and 66.7 % (emergency operations, rupture). Mortality was not
      increased in patients undergoing additional procedures of the renal, iliac,
      femoral, or crural arteries. CONCLUSION: Because of its low mortality and
      morbidity today open surgical repair remains the standard therapy for AAA.

PMID- 10663007
TI  - [Value of positron emission tomography (18F-FDG-PET) in the diagnosis of
      recurrent rectal cancer].
AB  - INTRODUCTION: Diagnosis of extraluminal recurrent rectal cancer may be difficult.
      Currently the diagnosis is based on routine imaging procedures. Diagnosis often
      remains unverified until histological proof can be acquired by transcutaneous
      biopsy or operative exploration. The diagnostic value of positron emission
      tomography (PET) in recurrent rectal cancer was evaluated in a prospective study
      at the Department of Surgery of the RWTH Aachen University Hospital. The aim of
      the study was to assess the sensitivity of PET in the detection of recurrent
      rectal cancer in comparison with conventional procedures. Furthermore, the
      valency of PET in the diagnosis of the local expansion and metastasis was
      evaluated. METHODS: Since June 1997, PET has been performed in all patients with
      suspected recurrent rectal cancer. The examined area reaches from the neck to the
      symphysis. Visual assessment follows transversal, frontal and sagittal sector
      scans. Enhanced focal FDG uptake over the physiological enrichment of the
      environment (e.g., urinary tract) was defined as a criterion of malignancy. The
      findings were compared with the results of routine diagnosis and histological
      examinations. RESULTS: Up to now, 23 patients have been subjected to a PET
      examination. In 17 cases, a local recurrence could be proved. An intrahepatic
      metastasis was found in 11 patients, pulmonary metastasis in 3 patients, lymph
      node metastasis in 5 patients, and a peritoneal carcinomatosis was found in 4
      patients. All these findings were confirmed by histological examinations after
      biopsy and operation or by other imaging procedures and the clinical follow-up.
      CONCLUSIONS: The controlled results show that PET can detect recurrent rectal
      cancer and its metastasis with great precision. PET seems to be a useful
      additional examination in the diagnosis of extraluminal recurrent rectal cancer.

PMID- 10663008
TI  - [Transposition of the gracilis muscle - an option in the surgical treatment of
      rectovaginal fistulae].
AB  - Rectovaginal fistulae following low anterior resection are rare, but if present
      therapy is difficult. We report on a 52-year-old patient who was operated upon
      several times, including an endorectal advancement flap procedure and
      transperineal repair with levator interposition. Closure was only successful
      after transposition of the M. gracilis between the vagina and rectum.

PMID- 10663009
TI  - [Deciduosis of the appendix. Differential diagnosis of acute appendicitis].
AB  - Deciduosis of the appendix is a rare cause of acute appendicitis in pregnancy.
      Ectopic decidual cells localized in the submesothelial stroma may represent a
      physiologic reaction of the pluripotent stromal cells to progestational hormonal
      stimulation. Less frequently, deciduosis is based on a preexisting extragenital
      endometriosis, visible in a localization other than strictly submesothelial, in
      residuals of cyclic proliferation and bleeding, and in endometrial glandular
      formations embedded in the decidual cells.

PMID- 10663010
TI  - [Actinomycosis of the colon as a rare differential diagnosis of colonic
      carcinoma].
AB  - INTRODUCTION: Abdominal actinomycosis is an uncommon disease. Nevertheless it
      should be considered in case of unclear tumor-like abdominal masses. METHODS: We
      report a case of a 49-year-old patient with an intrauterine device. The patient
      was submitted with a solid and painful tumor in the upper abdomen. After
      sonography, computerized tomography, gastroduodenoscopy and colonoscopy the
      preoperative presumptive diagnosis was a carcinoma of the transvers colon
      invading the abdominal wall. Pathological examination after a right hemicolectomy
      surprisingly revealed an actinomycosis. RESULTS: Based on this case diagnostic
      tools and therapeutic options of actinomycosis of the colon are discussed.
      CONCLUSIONS: This case illustrates the importance to consider the possibility of
      actinomycosis when finding an unclear abdominal mass. After a surgical excision
      an abdominal actinomycosis requires antibiotic therapy.

PMID- 10663011
TI  - [Pericardial tamponade during installation of a central venous catheter].
AB  - A case report demonstrates the complication of pericardial tamponade during the
      installation of a central venous catheter via the subclavian vein. To reduce the
      high mortality of this rare complication, quickly applicable diagnostic measures
      and adequate therapy of pericardiocentesis are indicated. Prompt recognition and
      treatment of pericardial tamponade are imperative if a disastrous outcome is to
      be prevented.

PMID- 10663012
TI  - [Undifferentiated, embryonal sarcoma as a rare cause of spontaneous liver rupture
      in adults].
AB  - INTRODUCTION: Undifferentiated, embryonal sarcoma is a rare malignant tumour of
      the liver, the incidence of which is highest in children between 6 and 10 years
      of age (14.1 %). Among the primary tumours of the liver in childhood it ranks in
      third place after hepatocellular carcinoma and focal nodular hyperplasia.
      Embryonal sarcoma is much rarer in adults. To our knowledge, only 18 cases have
      been published in the last 50 years. METHODS AND RESULTS: We now present the case
      of a 29-year-old woman with spontaneous rupture of the liver caused by an
      undifferentiated sarcoma. CONCLUSION: This case report illustrates the
      possibility of an embryonal sarcoma being the reason for spontaneous rupture of
      the liver. The management of this case comprised primary tamponade,
      interventional embolisation of the feeding artery, and secondary resection under
      stable conditions.

PMID- 10663013
TI  - [Major differences in procedure in receiving the academic title
      "ausserplanmaessiger Professor". Criteria and evaluation of research and teaching
      at German medical schools].
AB  - The academic title "Privatdozent", unique to the German speaking countries, is
      awarded after the "Habilitation", a qualification to teach and perform research
      on a high level and independent of supervision by a professor. A few years after
      the "Habilitation", committees of medical faculties decide whether the title
      "ausserplanmaessiger Professor" can be awarded. This is an academic title
      independent of a specific university or extramural position. The rules of all
      German medical faculties were evaluated with regard to when and by what criteria
      the faculties decide. There were major differences, e. g. the minimum time after
      the "Habilitation" (4 years n = 9; 5 years n = 14; 6 years n = 7), the numbers
      and quality of published papers and abstracts, the amount and quality of teaching
      and the number and qualification of external reviewers. For applications for
      university positions, but even more for leading positions in hospitals and
      industry, the title of "apl. Prof." is still of major relevance. Therefore a
      certain degree of standardization but still leaving space for special criteria in
      different faculties, is proposed.

PMID- 10663014
TI  - [Surgery rates and small area variations].
AB  - On the basis of the claims data of the statutory health insurance funds, surgery
      rates and small-area variations within the catchment area of the AOK Magdeburg
      were examined for the year 1997. Substantial variation can be constantly seen.
      The extremal quotient at the 30 most frequent ICPM groups ranged from 2 to 5.
      Generally, the extent of the variation was larger with elective procedures than
      with acute. Correlation analyses do not show clear associations with hospital bed
      supply and physician density in primary sectors. The extent of the small-area
      variation requires further research to evaluate possible determinants of surgery
      rates. Criteria for hospital admission and indications for surgery should be made
      explicit.

PMID- 10663015
TI  - [Commentary].

PMID- 10663016
TI  - [Therapy principles in diffuse peritonitis].

PMID- 10663017
TI  - [Current status of laser therapy of hemangioma in infants. Case reports and
      review of the literature].
AB  - Today the management of hemangiomas is still a great challenge for physicians,
      even for the most experienced of clinicians. With the introduction of lasers, new
      ways of treating hemangiomas have been found. Four case reports document the
      importance of early treatment. In addition, the differentiated use of various
      laser systems and their effects, limitations, and side effects are shown and
      discussed.

PMID- 10663018
TI  - [Microcirculation of cutaneous melanoma].
AB  - The microcirculation of human skin tumours can be visualized with noninvasive
      methods from clinical microcirculation research (capillaroscopy and laser Doppler
      fluxmetry (LDF). The latter can also be used to measure the blood flow in such
      tumours. This prospective study was designed to evaluate melanoma-associated
      cutaneous neoangiogenesis. We studied the microcirculation of 114 pigmented skin
      tumours in 103 patients (63 women, 40 men) averaging 38.8 +/- 21.1 years of age.
      On the basis of histological findings, we diagnosed melanocytic naevus in 86
      cases and malignant melanoma in 28. The malignant melanoma was characterized by a
      chaotic arrangement of the capillaries, which were dilated and formed corkscrew
      shaped or glomerular structures. In the transitional area between healthy and
      cancerous areas there was hypervascularization. The capillaries of the melanoma
      appeared to be more permeable towards the low-molecular-weight, water-soluble
      sodium fluorescein. Laser Doppler flux, a measure of cutaneous circulation in the
      upper 2 mm of the skin, is higher in the center of the melanoma than in either
      the middle of melanocytic naevus (p < 0.0005) or in neighbouring healthy skin
      areas (P < 0.005). In the future, antiangiogenetic therapy strategies could play
      a significant role in the treatment of malignant melanoma. These methods provide
      a reliable means of evaluating the specific antiangiogenetic efficacy of
      treatments for cutaneous melanoma.

PMID- 10663019
TI  - [High dosage intravenous immunoglobulin (IVIG) therapy in therapy-refractory ANCA
      negative, necrotizing vasculitis].
AB  - 7 patients (5 female, 2 male; age: 22-81 years; average age = 58.1 J) with
      recurrent necrotizing ANCA-negative, non leucocytoclastic vasculitis, were
      enrolled into this study. Disease was resistant to prior conservative therapy,
      and therefore patients received high dose intravenous immuno-globulin (IVIG)-
      (dose: 1.0 g/kg body weight daily dose 0.25 g/kg body weight over 4 consecutive
      days). All patients responded rapidly to this therapeutic regimen. Specifically
      immediate pain relief was striking. Complete clearance of disease was observed in
      5 out of 7 patients within 6 months while receiving IVIG (0.5 g/kg body weight)
      every 4 weeks for one year. In 2 out of 5 patients ulceration and vasculitis
      healed completely and therapy could be stopped after 6 months. In one patient
      treatment had to be discontinued due to decreasing kidney function. The data
      presented demonstrate that IVIG is an effective and valuable therapeutic modality
      in treatment of severe vasculitis resistant to conventional therapy. However
      consideration of costs, effectiveness and possible side effects is needed for
      this therapeutic regime.

PMID- 10663020
TI  - [Questionable effectiveness of autologous platelet growth factors (PDWHF) in
      treatment of venous ulcers of the leg].
AB  - Chronic venous insufficiency (CVI) can cause ulcers of the lower limb having the
      character of a full thickness wound involving the subcutaneous tissues and fat.
      Healing requires wound contraction, connective tissue formation and finally
      reepithelialization. To induce wound healing, on an underlying disturbed
      environment due to longterm effects of CVI, artificial stimuli may be needed. In
      a placebo controlled study we tried topical application of autologous PDWHF
      (platelet derived wound healing factors), to achieve ulcer healing and improve
      the microangiopathy surrounding of the ulcer area, as there are decreased number
      of skin capillaries and reduction in cutaneous vascular reserve. Alterations of
      cutaneous circulation during the course of the study were documented by
      capillaroscopy, transcutaneous oxygen pressure and laser Doppler flux (LDF)
      measurements. We were able to recruit 15 patients a I suffering from chronic
      nonhealing venous stasis ulcers. Eleven of the 15 patients agreed to participate
      in a placebo-controlled double blind study, whereas 4 patients agreed to
      participate only if they would be treated with PDWHF. The median age and duration
      of ulceration of the 6 patients (3 male/3 female) treated with placebo were 71
      years and 1089 days. The median age and duration of ulceration of the 9 patients
      (1 male/8 females) treated with PDWHF were 66 years and 732 days. Duration of
      therapy for the PDWHF group was 91 days, as compared to 154 days for the placebo
      group. Despite 2 completely healed ulcers, the expensive treatment did not reveal
      any significant clinical advantage. In den PDWHF group an ulcer area of 26.9 cm2
      was measured at the beginning, of 26.2 cm2 at the end; in the placebo group, 34.7
      cm2 and 35.5 cm2. The nonsignificant increase of the capillary density at the
      ulcer border in the active group as well as the increase in the tcPO2, in
      contrast to little change in both parameters in the placebo group, suggests
      neoangiogenic abilities to PDWHF, secondarily leading to a better blood
      distribution with higher oxygen tension.

PMID- 10663021
TI  - [Immunopathologic changes in 115 patients with bullous pemphigoid].
AB  - Bullous pemphigoid (BP) is an autoimmune bullous disease of the elderly.
      Patients' auto-antibodies are directed against BP180, a transmembrane
      hemidesmosomal glycoprotein of basal keratinocytes. Between 1989 and 1998, we
      identified 115 patients with BP in the Department of Dermatology at the
      University of Wurzburg. This is one of the largest groups of patients with BP
      studied to date. In all patients, direct and/or indirect immunofluorescence
      microscopy studies were positive. The average age (+/- standard deviation) of the
      patients was 75 +/- 12 years, the median was 78 years. The youngest patient was
      39 years of age; the oldest, 99 years. 54% of the patients were female and 46%
      male. In 24% of the patients, an involvement of oral, and in 7% of genital mucous
      membranes was seen. 98% of the patients complained about pruritus. By direct
      immunofluorescence microscopy, linear deposits of C3 and/or IgG were detected at
      the basement membrane zone of perilesional skin biopsies. By indirect
      immunofluorescence microscopy using NaCl-separated human skin, 87% of cases
      revealed circulating serum antibodies whereas on monkey esophagus, only 72% of
      sera were found positive. In 85% of the patients, we detected elevated serum
      levels of total IgE before the initiation of treatment. In those sera that were
      analyzed for reactivity with BP180, autoantibodies to the immunodominant NC16 A
      domain of BP180 were detected in 89% by immunoblot analysis and in 93% by ELISA.
      Therefore, in most patients, BP can be diagnosed serologically.

PMID- 10663022
TI  - [Virologic diagnosis of herpes zoster].
AB  - Diagnosis of herpes zoster needs to be rapid when effective antiviral
      chemotherapy is being considered. Patients with atypical clinical features can
      often only be diagnosed by virological methods. In the present study, vesicle
      specimens of 100 patients with zoster were analysed by detecting viral DNA using
      polymerase chain reaction (PCR). The findings were compared with those obtained
      by traditional virological and serological methods. PCR results confirmed the
      clinical diagnosis of zoster in 95%. Primers selected from varicella-zoster virus
      (VZV) gene 28 proved to be most sensitive. The sensitivity of virus culture was
      20% (specificity 100%) and of direct immunofluorescent VZV-specific antigen
      staining in vesicle samples 82% (specificity 76%). There was a serological
      response to specific IgM and IgA antibodies in 48% within four days after the
      onset of rash. These findings suggest that PCR is the method of choice for rapid
      laboratory diagnosis of zoster.

PMID- 10663023
TI  - [Post-traumatic pyoderma gangrenosum: combination therapy with intravenous
      immunoglobulins and systemic corticosteroids].
AB  - Pyoderma gangraenosum is a rare, chronic type of skin ulceration of unknown
      aetiology. It occasionally appears following trauma. There are no set standards
      for the treatment of pyoderma gangraenosum. It is essential to consider acuteness
      of progression as well as underlying systemic diseases and possible drug side
      effects before initiating a therapy. Immunosuppressive as well as
      immunomodulating agents are most often used with varying degrees of success. We
      report a 45-year-old patient who suffered from an extensive posttraumatic
      pyoderma gangraenosum after cardiac bypass operation. With short-term combination
      therapy consisting of high dose intravenous immunoglobulins and systemic
      corticosteroids, the progression of the disease could be stopped within a few
      days.

PMID- 10663024
TI  - [Stevens-Johnson syndrome with transition to toxic epidermal necrolysis after
      carbamazepine administration, heroin and alcohol abuse].
AB  - A 28 year old patient developed a severe bullous exanthem and enanthem combined
      with hepatitis, fever and blood count abnormalities after taking carbamazepine
      and consumption of heroin and alcohol. After discontinuing carbamazepine,
      prednisolone was given over a five day period accompanied by intravenous fluid
      and electrolyte substitution and local therapy which lead to improvement. Severe
      bullous skin reactions nowadays are classified into erythema exsudativum
      multiforme majus (EEMM), Stevens-Johnson syndrome (SJS), overlap Stevens-Johnson
      syndrome-toxic epidermal necrolysis (SJS/TEN), TEN with maculae and TEN on large
      erythema, and they are most often caused by antibiotics and anticonvulsant drugs.
      Heroin and alcohol abuse alters host immunity which subsequently may increase
      susceptibility to allergic reactions. There is a high (40%) mortality rate for
      TEN, and patients with organ involvement are at increased risk.

PMID- 10663025
TI  - [Periorbital edema as the initial symptom of lupus erythematosus profundus. Case
      report and discussion of the literature].
AB  - Periorbital edema may occur initially or in the course of a wide variety of
      diseases. One of these diseases is lupus panniculitis, a variant of lupus
      erythematosus, characterized by firm subcutaneous nodules that may ulcerate with
      subsequent scar formation. We present a case of lupus panniculitis in which the
      periorbital edema was the initial manifestation. Knowledge about the differential
      diagnostic possibilities of periorbital edema as well as the different variants
      of cutaneous lupus erythematosus is important to reach the correct diagnosis.

PMID- 10663026
TI  - [Systemic congenital mastocytosis with universal skin involvement].
AB  - Systemic mastocytosis is an uncommon disease. We describe a boy with congenital
      systemic mastocytosis with involvement of both skin and internal organs, but
      without any sign of bone marrow disease. Treatment with interferon alpha-2b was
      effective.

PMID- 10663027
TI  - [PCR detected Borrelia burgdorferi DNA in a tissue sample in pseudopelade Brocq].

PMID- 10663028
TI  - ?

PMID- 10663029
TI  - [Acne 1999: do we still need the dermatologist?].

PMID- 10663030
TI  - [Mitochondrial mutations and aging].

PMID- 10663031
TI  - ["Der Hautarzt"--in the vanguard of certification of training].

PMID- 10663032
TI  - [Patient authorization for the release of reports of work-related skin
      disorders].
AB  - In Germany, if the dermatologist has definite proof that a patient's skin
      disorder is severe or chronic, work-related and requiring a change in occupation,
      then he or she must issue a Berufskrankheitenanzeige (loosely translated as
      occupational disease notification). The patient's consent is not required for
      this mandatory form, which has to be submitted even if the patient is opposed. On
      the other hand, if there is only a possible connection between the occupation and
      the skin disorder, or if the skin disease is neither severe nor chronic nor
      threatening pursuit of the occupation, then the dermatologist needs only write a
      Hautarztbericht (dermatologist's report). The patient's permission is required
      for this less formal document.

PMID- 10663033
TI  - [Treatment of scabies with special consideration of the approach in infancy,
      pregnancy and while nursing].
AB  - Infestation of human skin with scabies mites remains an persistent problem in
      daily dermatological practice. There are several therapeutic regiments against
      scabies which have been proven effective and without major side effects. Because
      of known neurotoxicity of lindane as well as intoxication/problems following
      systemic absorption of benzyl alcohol (the metabolite of benzyl benzoate), these
      two compounds have to be considered with caution in early childhood scabies as
      well as during pregnancy and nursing. The pharmacology and spectrum of clinical
      side effects of the approved anti-scabies preparations (lindane, benzyl benzoate,
      crotamiton) as well as permethrin (not available in Germany) are reviewed.

PMID- 10663034
TI  - [Risk factors for local complications in erysipelas].
AB  - BACKGROUND AND OBJECTIVE: A complicated course of erysipelas is not uncommon.
      Bullous, haemorrhagic, necrotic and purulent lesions may be encountered. Today no
      reliable data exist as to which constitutional factors renders a patient at risk
      for developing complicated erysipelas though several risk factors, particularly
      diabetes mellitus, are often suggested. Based on the analysis of patients with
      erysipelas at the Department of Dermatology in Graz, factors determining the risk
      for complicated erysipelas should be identified. PATIENTS/METHODS: In a
      retrospective case-control study clinical data sheets of 766 in- patients treated
      at the department were evaluated with respect to the course of the erysipelas and
      with respect to potential risk factors. RESULTS: General risk factors for local
      complications were location at the lower extremities, pre-existing hepatic or
      renal disease, hyperuricaemia, and diabetes mellitus. Hepatic and renal disease
      and - to a lesser extent - diabetes particularly predisposed for bullous and
      haemorrhagic lesions, while vascular occlusive disease enhanced the risk for
      necrotic lesions. CONCLUSIONS: Location and hepatic and renal disease are the
      most important risk factors, while diabetes is probably of less significance than
      previously suggested.

PMID- 10663035
TI  - [Therapy of primary cutaneous B-cell lymphomas].
AB  - BACKGROUND AND OBJECTIVE: Primary cutaneous B-cell lymphomas (PCBCL) represent a
      unique type of extranodal B-cell lymphomas. Recently, the "European Organization
      for Research and Treatment of Cancer (EORTC)-Cutaneous Lymphoma Study Group"
      classified PCBCL into two major groups: one with low-grade malignancy and
      excellent prognosis (follicle center cell lymphoma, immunocytoma/marginal zone B
      cell lymphoma) and the other with intermediate malignancy and worse prognosis
      (large B-cell lymphoma of the leg). The clinical course and the prognosis of both
      groups clearly distinguish them from nodal lymphomas with similar morphological
      aspects, thus underlying the need for different treatment modalities.
      PATIENTS/METHODS: We investigated retrospectively the therapeutic data from 51
      patients with PCBCL (40 low grade lymphomas, 11 large B-cell lymphomas). Several
      treatment modalities were used: total excision, radiotherapy, polychemotherapy,
      systemic corticosteroids, systemic antibiotics, as well as a variety of
      combination treatments. RESULTS: Recurrence, dissemination and/or death of the
      patients were not significantly related to any single treatment modality.
      CONCLUSIONS: In our opinion, the choice of treatment for PCBCL depends on the
      histologic classification, the number, spread and localization of the
      infiltrates, and on the general condition of the patient.

PMID- 10663036
TI  - [Pemphigoid gestationis without blisters].
AB  - BACKGROUND AND OBJECTIVE: Pemphigoid gestationis (PG) is a rare pregnancy
      associated autoimmune bullous disease characterized by autoantibodies to the 180
      kD bullous pemphigoid antigen (BP180). The clinical spectrum of PG is polymorphic
      and for diagnostic purposes, a skin biopsy is usually taken demonstrating the
      deposition of autoantibodies. PATIENTS AND METHODS: From 2 patients, skin
      biopsies were obtained for histopathologic and immunofluorescence studies.
      Circulating autoantibodies were characterized by immunoblotting and ELISA using a
      recombinant form of the immunodominant BP180 NC16 A domain. RESULTS: The 2 PG
      patients described here did not show blisters but complained about severe
      itching. In the first case, PG presented in the first trimester of the second
      pregnancy as an erythema-multiforme-like disease. The second patient developed
      urticarial plaques a few days after delivery. PG was diagnosed by the detection
      of autoantibodies against recombinant BP180 NC16 A by immunoblot and ELISA
      analysis and confirmed by linear deposits of C3 at the cutaneous basement
      membrane zone on direct immunofluorescence microscopy. Skin lesions healed with
      oral prednisolone. CONCLUSIONS: In our two patients, non-bullous PG could be
      diagnosed by serological tests. Immunoblotting and ELISA might be sensitive and
      specific tools when screening sera of patients with pruritic skin lesions in
      pregnancy for the presence of autoantibodies to BP180. In some cases, these newer
      techniques may make a skin biopsy unnecessary.

PMID- 10663037
TI  - [Hyperkeratosis lenticularis perstans (Flegel's disease) - a complex disorder of
      epidermal differentiation with good response to a synthetic vitamin D3 derivate].
AB  - Hyperkeratosis lenticularis perstans (Flegel's disease) is a rare but clinically
      and histologically highly characteristic genodermatosis. We report on new
      immunohistochemical and ultrastructural findings suggesting a complex disorder of
      epidermal differentiation. In this context, a good response to calcipotriol, a
      synthetic vitamin D3 derivative is of particular interest.

PMID- 10663039
TI  - [Cutaneous metastases from a leiomyosarcoma of the testicular tunica albuginea].
AB  - Cutaneous metastases from a leiomyosarcoma of the testicular tunica albuginea are
      very rare. Primary leiomyosarcomas in this site are uncommon and furthermore
      cutaneous metastases develop only in 1,4% of all malignant tumors of the internal
      organs [10]. A 71 year old patient with such a sarcoma underwent primary
      excision. Nine months later multiple, firm, nodules were identified as cutaneous
      metastases. Further staging revealed already extensive, diffuse pulmonary and
      bony metastases without contiguous or regional lymph node involvement.

PMID- 10663038
TI  - [Calciphylaxis: ischemic tissue necrosis in chronic renal failure. Case report
      and review of the literature].
AB  - Calciphylaxis is a rare but potentially life-threatening complication in chronic
      renal failure. It is characterized by ischemic tissue necrosis primarily of the
      skin. The typical histopathologic finding is microvascular calcification with
      endovascular fibrosis. Patients typically present with violaceous, mottled and
      painful lesions which tend to progress to non-healing ulcers and necrosis. Most
      frequently the lower extremities are involved in a symmetric fashion but the
      trunk may also be affected. Sepsis from superinfection of the lesions accounts
      for the high mortality of this disease which is of importance for dermatologists
      and nephrologists alike. 61-year-old female patient developed lesions of
      calciphylaxis on both calves two years after beginning hemodialysis to treat
      renal failure due to diabetic glomerulosclerosis. We discuss aspects of the
      pathogenesis of calciphylaxis, as well as diagnosis, treatment and means of
      prevention, and review the current literature.

PMID- 10663040
TI  - [Aminopenicillin-induced morbilliform drug rash and "side chain allergy"].

PMID- 10663041
TI  - [Sentinel-lymph-node biopsy].

PMID- 10663042
TI  - [Is air insufflation by means of nose balloons in children useful?].

PMID- 10663043
TI  - [Transnasal surgery of the orbita. Review of current indications and techniques].
AB  - The endonasal surgery has a branch in the transnasal orbital surgery. For this
      transnasal approach the anterior skull base, the medial and infero-medial orbita,
      the orbital apex with the optical nerve and the sphenoid sinus are within reach.
      In all primary and secondary malignant lesions with extension into the orbita,
      the transnasal biopsy is of importance for diagnosis, particularly in metastasis
      to the orbit and pseudo-tumors. Benign lesions like mucoceles and osteomas are
      accessible and fully removable. Good results have been obtained in endonasal
      orbital decompression and inhomogeneous space occupying intraorbital lesions like
      bleedings. Among the orbital traumatism, with restrictions fractures of the
      medial orbital wall, medial orbital floor and foreign bodies could be operated.
      The transnasal approach is not indicated in all diseases, which are situated
      mostly intraconally, supraorbitally and lateral of the bulbus as well as in
      tumors with intracranial extension. In summary, the transnasal orbital approach
      has its place as helpful addition to the transfacial and transcranial techniques
      and can even replace them in certain selected indications.

PMID- 10663044
TI  - [Antimycotic therapy in otomycosis with tympanic membrane perforation].
AB  - Especially after prolonged antibiotic ototopic therapy otomycosis is not rare. An
      inoculation of fungi into the tympanic cavity however may have serious sequelae.
      Therefore an eradication of fungi from the external auditory canal is imperative
      before surgery. In addition to thorough cleaning of the outer ear canal
      antimycotic preparations are recommended in treating otomycosis. However, all of
      the commercially available ear drops contain ototoxic agents. In the case of
      defects of the tympanic membrane a damage of the inner ear may result.
      Alternatively, we suggest an aqueous solution of Miconazol 0,5%.

PMID- 10663045
TI  - [Ligature of the carotid arteries performed prophylactically or as an emergency
      procedure in patients with malignant tumours of the head and neck].
AB  - Life threatening hemorrhage in patients with malignant tumours of the head and
      neck area are often, as a result of tumour infiltration, postoperative anatomical
      changes, infection and radiological necrosis, difficult to control. One option
      for prophylaxis and treatment is the ligature of the external (ECA) or common
      carotid artery (CCA) and superior thyroid artery (STA). 52 patients were examined
      in a retrospective study to determine both the hazards and the therapeutic use of
      the procedure. The external carotid artery (ECA) was ligated prophylactically
      during the operative procedure of tumour resection and neck dissection in 25
      patients. In 27 cases closure of the ECA, CCA or ECA and STA was carried out as
      an emergency procedure for acute hemorrhage following completed primary treatment
      (operation, primary or postoperative radiation or radiochemotherapy). There was
      no postoperative hemorrhage after prophylactic ligature of the ECA. One patient
      with multiple cardiovascular diseases suffered from an ipsilateral cerebral
      infarction 1 year after operation. In 6 of 9 patients and in all 3 patients, in
      whom ligature of the CCA or ECA and STA respectively was carried out as an
      emergency procedure, severe neurological complications up to an apallic syndrome
      occurred. The number of deaths due to acute hemorrhage was considerably smaller
      among those patients with prophylactic ligature of the ECA performed during
      operative procedure of tumor resection and neck dissection. In addition there
      were much less unfavourable courses in the sequence of prophylactic closure of
      the ECA than observed after ligating the CCA or ECA and STA in an emergency
      situation.

PMID- 10663046
TI  - [Otoacoustic emissions, auditory evoked potentials, pure tone thresholds and
      speech intelligibility in cases of auditory neuropathy].
AB  - The combined findings of "normal evoked otoacoustic emissions (EOAE) and absent
      or markedly disturbed auditory evoked potentials from the brainstem and/or
      cortex" has been named auditory neuropathy in the English literature. The pure
      tone thresholds in these patients range from mild to severe loss. The loss of
      speech comprehension is out of proportion in comparison to the pure tone
      threshold elevation. This combination of findings suggests that cochlear function
      and in particular outer hair cell function, is normal in these patients but also
      suggests that the inner hair cell / VIII nerve functional unit is abnormal.
      Disruption in neural synchrony has previously been postulated as a reasonable
      explanation for the absent auditory brainstem response while otoacoustic
      emissions are preserved. Because the long-latency auditory evoked potentials, not
      having the stringent synchrony requirements of the ABR, may also be missing, the
      term synchrony - disruption may be somewhat misleading. The literature about
      auditory neuropathy is reviewed here: We now know that a set of salient features
      distinguishes these patients from the majority of patients with sensorineural
      hearing loss or other described syndromes. The symptoms defining auditory
      neuropathy are mild, moderate or severe elevation of auditory thresholds to pure
      tone stimuli by air and bone conduction, absent to severely abnormal ABRs to high
      level stimuli, present otoacoustic emissions (that do not suppress with
      contralateral noise), word recognition ability poorer than expected from the pure
      tone hearing loss configuration (in cases with mild to moderate hearing threshold
      elevation) and absent acoustic reflexes to both ipsilateral and contralateral
      tones. The entire set of findings, consistently seen in these patients, supports
      the importance of the crosscheck principle in diagnostic evaluation especially in
      children with delayed and/or impaired language acquisition. It is of ponderous
      importance that this disorder is not being confused with sensory hearing loss.

PMID- 10663047
TI  - [Radiofrequency ablation of the soft palate (somnoplasty). A new method in the
      treatment of habitual and obstructive snoring].
AB  - Twenty-nine patients (26 male and 3 female) with habitual or obstructive snoring
      and socially disturbing character were followed over a ten week period. All
      patients were treated with radiofrequency volumetric tissue reduction (RFVTR) of
      the soft palate. In 21 patients this operation was combined with other surgery of
      the upper airway, eight patients had soft palate reduction with RFVTR
      exclusively. With this method an electrode is positioned in the musculature of
      the soft palate submucosally. RFVTR may be performed under local anesthesia and
      has to be repeated if necessary. Ten weeks postoperatively 24 of 29 patients,
      respectively their social-partners, reported subjective reduction of snoring
      after the first treatment. Markable improvement of snoring was seen in 20 of 29
      patients postoperatively and reduction of the respiratory-disturbance-index (RDI)
      for more than 10 was noticed in 7/29 patients polysomnographically. 5/8 patients
      who were treated with RFVTR exclusively, showed reduction of snoring and 3/8
      patients had RDI-reduction for more than 10. We conclude, that RFVTR of the soft
      palate is successful in the treatment of snoring and may be helpful in the
      treatment of mild obstructive-sleep-apnea-syndrome (OSAS).

PMID- 10663048
TI  - [Lid retraction in endocrine orbitopathy. A new indication for "lid loading"].
AB  - Lid retraction in thyroid ophthalmopathy may lead to cosmetic and functional
      problems. Many surgical procedures are available to correct upper lid retraction.
      Only those procedures should be used that lead either to a limited lid
      lengthening or can be reversed in cases with complications. Upper lid gold weight
      implantation was first used to treat lagophthalmos in patients with facial palsy.
      Since 1995 only a few reports have appeared which discuss platinum as an
      implantation material. We report our experiences with a female patient who
      developed an upper lid retraction due to thyroid ophthalmopathy. Through
      implantation of a platinum weight which was adjusted exactly preoperatively, a
      symmetric palpebral fissure was achieved. Unilateral upper lid retraction with
      resultant eyelid asymmetry is a new indication for lid loading.

PMID- 10663049
TI  - [Inflammatory pseudotumor of the nasal septum].
AB  - An inflammatory pseudotumor occurs unifocally and is a benign tumor that was
      initially described in the lung. In the present case report a 24-year-old woman
      experienced progressive nasal obstruction because of an abnormality of the nasal
      septum. A cauliflower-like tumor of the anterior region of the septum cartilage
      was seen macroscopically and was completely resected. This was diagnosed
      histologically as an inflammatory pseudotumor. The literature is reviewed and
      differential diagnoses discussed. Various therapeutic procedures are noted, but
      the treatment of choice is complete resection of tumor.

PMID- 10663050
TI  - [Supralaryngeal swelling. Intrahyoid thyroglossal cyst].

PMID- 10663051
TI  - [Marked lymph node swelling in nasopharyngeal tumor. Stage IIE Hodgkin's disease
      with extranodal involvement of the nasopharynx].

PMID- 10663052
TI  - [Reduction in germ load in ENT treatment units by means of membrane filter].

PMID- 10663053
TI  - [Allergen-specific immunotherapy (hyposensitization). Part 1. Basics and
      subcutaneous application].

PMID- 10663054
TI  - [The correct manuscript for biomedical journals].

PMID- 10663055
TI  - [Computer-aided 3D-navigation systems-a plea for an error model].

PMID- 10663056
TI  - [Computer-aided 3D-navigation systems. Survey and location determination].
AB  - 3D-navigation systems have only recently been introduced into the surgical field.
      Since then they have gained increasing importance not only in ENT surgery but
      also in neurosurgery, orthopedic surgery, maxillo-facial surgery, radiology and
      radiotherapy. Following a brief historical introduction this article reviews
      existing navigation technologies, in terms of indication, practicability,
      accuracy, forensic and financial aspects. The selection of the navigation system
      is strongly influenced by the planned procedure (endoscopic, microscopic, open
      approach). According to our experience most of these systems provide useful
      support intraoperatively. The clinical application accuracy regularly lies in the
      range of 1-2 mm.

PMID- 10663057
TI  - [Antibiotic therapy for infections in the head and neck. German Society of
      Otorhinolaryngology, Head and Neck Surgery].

PMID- 10663058
TI  - [Oncology of the head-neck region. German Society of Otorhinolaryngology, Head
      and Neck Surgery].

PMID- 10663059
TI  - [Protection of autogenous cartilage transplants from resorption using membrane
      encapsulation].
AB  - In reconstruction of cartilage defects, autogenous transplantation is known as a
      reliable and experienced method. Although a clinical application has not been
      reported until now, tissue engineering permits in vitro production of autogenous
      cartilage transplants. Nevertheless, in both methods the cartilage is exposed to
      individually varying resorptive mechanisms. Among other methods for in vivo
      tissue protection, the encapsulation with a semipermeable polyelectrolytecomplex
      membrane could guarantee sufficient protection against resorptive influences.
      Human septal cartilage was encapsulated (group 1) with polyelectrolytecomplex
      membranes and subcutaneously implanted on the back of thymusaplastic nude mice.
      Cartilage implants without encapsulation (group 2) were used as control. Scanning
      electron microscopy and histochemical investigations were performed 1, 4, 8, 12
      and 16 weeks after implantation. Group 1 showed no signs of resorption and
      chronic inflammation at all. In contrast, group 2 presented, correlating to the
      time of implanta-tion, increasing signs of cell death and fibrotic
      transformation, representing an increased activity of resorption. In conclusion,
      tissue encapsulation with a polyelectrolytecomplex membrane could ensure a
      sufficient protection of human cartilage transplants from resorptive influences.
      For the plastic-reconstructive surgeon the desired result becomes more
      calculable.

PMID- 10663060
TI  - [Results and extraordinary complications of surgery for exostoses of the external
      auditory canal].
AB  - We present a retrospective study on 22 operations of exostosis of the external
      auditory canal in 20 patients. 8 patients were passionated by water sports. The
      most frequent indication for surgery (13 operations) was recurrent external
      otitis or ceruminal obstruction. In 7 cases the need for a wider access to the
      middle ear indicated surgery. Surgery was usually performed as an outpatient
      procedure, maximum hospitalization was 3 days. The mean healing period was 6 (3
      10) weeks. Mean follow up was 43 (3-110) months. There were no severe
      intraoperative complications such as facial paresis, lesions of the ossicles or
      of the inner ear. As intraoperative complications we found 2 perforations of the
      tympanic membrane, 2 expositions of the capsule of the mandibular joint, one of
      which was followed by chronic pain. As postoperative complications we found an
      early soft tissue stenosis of the external auditory canal and one late soft
      tissue stenosis which recurred after revision surgery. No recurrence of exostosis
      was seen. We describe an up to now unknown complication: the appearance of
      bilateral petrositis caused by staphylococcus epidermidis after bilateral surgery
      in an otherwise healthy patient. This study confirms that severe complications
      are rare, minor ones however relatively common. And that also minor complications
      may have a troublesome follow. Therefore and because of the potential of severe
      complications indication for surgery must be made cautiously and risks of the
      operation must not be underestimated.

PMID- 10663061
TI  - [The reconstruction of auricular defects - operative systematics and first
      experiences for the use of a combined skinflap].
AB  - Surgical reconstruction of partial defects of the auricle remains an operative
      challenge. Operative techniques using cartilage frameworks constitute a well
      established method. According to the localisation and the extend of the defect
      there are well established procedures. Especially the inferior part of the
      auricle may cause difficulty due to it's anatomy. In a retrospective study,
      various reconstruction techniques of partial conchal defects were examined in
      regard to their aesthetic results. A sytematic operative procedure due to the
      different techniques was developed. Large defects, extending more than 30% of the
      concha margin needed a high grade of stability which can be obtained by the use
      of autologous costal cartilage. According to the localisation of the defect and
      the available local tissue, the ret-ro-auricular site has to be reconstructed by
      the use of transposition flaps or split-thickness skin. For the reconstruction of
      the retroauricular site in the cranial auricular region a combined fascia-fan
      flap showed the best results. The inferior auricular region can be reconstructed
      by the use of an infraauricular transposition flap offering also good
      opportunities for reconstruction of the lobulus. Second Degree Dysplasias are
      regarded as conchal defects which can be integrated into surgery.

PMID- 10663062
TI  - [Tonsillectomy with the argon-plasma-coagulation-raspatorium - a prospective
      randomized single-blinded study].
AB  - BACKGROUND: The Argon-Plasma-Coagulation (APC) offers an innovative possibility
      for the tonsillectomy combined with a high-frequency technology. Aim of our study
      was to inves-tigate the differences between this high-frequency-technology and
      the traditional tonsillectomy. No reports exist in the use of the APC in the
      tonsillectomy. METHODS: Argon-Plasma-Coagulation tonsillectomy (TE-APC) was
      compared with the traditional blunt dissection tonsillectomy (TE-trad) with
      hemostasis by compression and bipolar coagulation. 133 patients were stratified
      in two age groups in a clinical prospective randomised study. RESULTS: Average
      surgical time and blood loss were markedly decreased in the TE-APC group
      (p<0,01). There was no significant difference between the two techniques
      concerning postoperative pain, otalgia, and primary or secondary haemorrhage. In
      the TE-APC group more extensive fibrin layer appeared after surgery. In the TE
      APC patients' group, there was a slightly higher consume of analgetics in some
      postoperative days. CONCLUSIONS: The one-step dissection and coagulation
      procedure leads to an almost bloodfree woundground and to a reduction of
      operation-time. The self-limited and effective coagualative properties of the APC
      method leads to a controlled penetration depth. The often associated extensive
      post operative pain and uncontrolled tissue- damage, known from electrical and
      lasersurgical techniques, was not found in TE-APC-patients-group.

PMID- 10663063
TI  - [Vascular origin of cerebellopontine angle syndrome].
AB  - INTRODUCTION: The seventh and eighth cranial nerves course toward the internal
      auditory canal within the cerebellopontine angle. Lesions in this region are
      usually related to malfunctions of these cranial nerves. Although an acoustic
      schwannoma is one of the main etiologies of cerebellopontine angle pathology,
      various inflammatory processes and vascular anomalies even though rare must be
      considered. PATIENTS/METHODS: We describe 5 cases with vascular loops of the
      basilar or vertebral arteries as a possible cause for hearing loss, vertigo and
      pulsatile tinnitus. In two cases the vascular lesion was confirmed at surgery, in
      which a decompression procedure was performed. The work-up for each patient
      included an auditory test battery and electronystagmography. Imaging studies
      included MRI and angiography in two cases. RESULTS/CONCLUSIONS: Our experiences
      show that while the cerebellopontine angle syndrome is mostly caused by benign
      tumors an abnormal vascular loop has to be considered in any differential
      diagnosis.

PMID- 10663064
TI  - [Herpes simplex virus type 1-induced rising dbl quote, left (low)tumor" in the
      nasal vestibule. The problem of resistance development of herpes simplex in a
      patient with chronic lymphatic B-cell leukemia].
AB  - Herpes simplex viruses are known to be among the most common disease-causing
      microorganisms. Their prevalence can exceed 90% depending on the socioeconomic
      status of the population. Since the number of immunocompromised patients has
      increased because of the increased incidence in the acquired immunodeficiency
      syndrome and an increase in organ transplantation, herpes virus infection may
      have a greater clinical significance. While treatment of otherwise healthy
      individuals will not usually cause any clinical problems herpes infection in an
      immunocompromised patient can have severe consequences. Additionally, development
      of viral resistance can be observed that may require alternative drugs in
      treatment. We present a case history of a man with a B-cell chronic lymphocytic
      leukemia that was associated with a very unusual herpes simplex virus infection
      in the nasal vestibule. Possible causes for the development of resistance in
      herpes infections and the use of famciclovir and forscarnet as two therapeutic
      alternatives to aciclovir are discussed.

PMID- 10663065
TI  - [Bilateral laryngeal pouch tumor. Localized amyloidosis of the larynx].

PMID- 10663066
TI  - [Unilateral painless exophthalmus. Lymphoepithelioma-like carcinoma of the
      lacrimal gland].

PMID- 10663068
TI  - [ [In Process Citation]

PMID- 10663067
TI  - [Allergen-specific immunotherapy (hyposensitization). Part 2. Oral, sublingual
      and nasal application].

PMID- 10663072
TI  - [New procedures and modifications of sonography and their practical
      significance].

PMID- 10663073
TI  - [Quantitative sonography. Clinical role and perspectives].

PMID- 10663074
TI  - [Tissue harmonic imaging and contrast harmonic imaging. Improving the diagnosis
      of liver metastasis?].

PMID- 10663075
TI  - [SieScape--panorama imaging. Clinical value?].

PMID- 10663076
TI  - [Color Doppler, power Doppler, sonography contrast media. Improvement of
      perioperative diagnostics?].

PMID- 10663077
TI  - [Medical education and continuing education of physicians in abdominal sonography
      at German universities. State of the art].

PMID- 10663078
TI  - [Arterial hypertension. Part 1: Definition, pathogenesis, diagnosis].

PMID- 10663080
TI  - [47-year-old patient with resistant pulmonary embolism in congenital hemodynamic
      disorder].

PMID- 10663079
TI  - [59-year-old patient with chronic joint symptoms and generalized weakness].

PMID- 10663081
TI  - [Current pharmacologic therapy of depression].

PMID- 10663082
TI  - [ [In Process Citation]

PMID- 10663083
TI  - [ [In Process Citation]

PMID- 10663084
TI  - [ [In Process Citation]

PMID- 10663085
TI  - [ [In Process Citation]

PMID- 10663086
TI  - [The (health care) situation tolerates no postponement. Speech before the German
      Federal Assembly on November 4. 1999].

PMID- 10663087
TI  - [Affordability and quality (of health care). Speech before the German Federal
      Assembly on November 4. 1999].

PMID- 10663088
TI  - [Health politics: From order to chaos? Address at the Medica 1999].

PMID- 10663089
TI  - [Current themes in health policy].

PMID- 10663090
TI  - [Discussion paper of the CDU/CSU about health care structure legislation. Health
      policy--policy for the patients and for the insured].

PMID- 10663093
TI  - [ [In Process Citation]

PMID- 10663091
TI  - [Thoughts of a physician about the future of our health care system].

PMID- 10663094
TI  - [ [In Process Citation]

PMID- 10663099
TI  - [The internal fixation of fractures in children].

PMID- 10663100
TI  - [The internal fixation of fractures in children].
AB  - The internal fixation of fractures of shaft bones was spread out by a group of
      surgeons working together with Prevot. The principle of this method is a three
      point load carrying paragraph sign(entry point, height of fracture and cancellous
      bone of the metaphysis of the opposite fracture part). From 1996 to 1999 86
      children with fractures of the humerus, the fore-arm and the femur were operated
      in the technique of intramedullary nailing. The fractures affected the humerus to
      3.5 %, the fore-arm to 65.1 % and the femoral shaft to 31.4 %. The postoperative
      duration of stay in hospital after internal fixation of the fore-arm in the
      proximal and middle third lasted 7.2 days, the duration of immobilisation in a
      cast took 13.7 days. 96 % of the patients showed very good and good results after
      operation. The average stay in hospital for patients with femoral shaft fractures
      was 14.4 days. 17 weeks after operation the intramedullary nails were removed. At
      the time of first full weight bearing the legs showed an average shortening of
      1.2 cm. The fractures of the humerus healed without any restriction of movements.
      Internal fixation is a minimal invasive operation technique with low risks and
      small operating trauma. Due to the stability a early mobilisation is possible.
      The reported results in the literature are all good. The only problem can be
      caused by too long nails irritating the skin.

PMID- 10663101
TI  - [Operative treatment of complex acetabular fractures through the modified
      extensile iliofemoral approach].
AB  - Fourty-nine patients with 50 complex acetabular fractures were treated with open
      reduction and internal fixation from August 1993 to February 1996 in a
      prospectively documented study. The fractures were fixed with small fragment
      implants through a modified extensile iliofemoral approach (Maryland approach).
      Thirty-seven patients were polytraumatized with an ISS of 20 pts. on average. In
      10 patients the ISS was > 25 pts. Good or anatomic initial fracture reduction
      with a fragment stepoff K 2 mm could be achieved in 48 fracturers (96 %). Thirty
      six patients with 37 fractures could be evaluated after 25 months on average. In
      28 fractures (76 %) the functional outcome was good or excellent according to the
      d'Aubigne and Harris scores. Radiological results were excellent in 21 fractures
      (57 %) and satisfactory in 12 fractures (Heeg score). In 7 cases (14 %) a
      postoperative subcutaneous seroma had to be treated surgically. No wound
      infections, however, were observed. Further complications were secondary a loss
      of reduction in 4 cases (11 %), relevant heterotopic ossifications (Brooker
      III/IV) in 5 cases (14 %), and aseptic femoral head necrosis in 2 cases (5 %). In
      two cases a total hip replacement (THR) for posttraumatic arthritis had to be
      performed. Two more cases are scheduled for THR due to symptomatic femoral head
      necrosis. A good joint reconstruction can be achieved through the modified
      extensile iliofemoral approach (Maryland) in complex fractures of the acetabulum.
      However, the approach related morbidity seems to be worrisome. In complex
      fractures with comminution in the roof of the acetabulum the prognosis remains
      uncertain even in cases where initial anatomic joint reconstruction can be
      achieved.

PMID- 10663102
TI  - [Acceleration related injury of the cervical spine in restrained car drivers.
      Frequency, causes and long-term results].
AB  - In an analysis of 3,838 restrained car drivers, the proportion of acceleration
      related injury of the cervical spine increased from under 10 % in 1985 to over 30
      % in 1997. These injuries occurred mainly in the case of head-on or multiple
      collisions. Letters were sent to 1,136 of the injured persons, and of the 138
      patients who returned the questionnaires, 121 (88 %) were still suffering from
      their symptoms. It was a question of pain (74 %), tension (6 %) and stiffness (5
      %) in the head (27 %), neck (55 %) and shoulder (8 %) area. The duration of the
      complaints was the longest after multiple collisions. In addition to a slight
      influence of the accompanying injuries on the duration of complaints, the
      individual constitution seems to be an important determining factor. In order to
      resolve the difficulties of conducting of this retrospective study, prospective
      studies are necessary which include documentation of diagnosis, treatment
      protocols, duration and type of complaints.

PMID- 10663103
TI  - [The Trauma Registry of the German Society of Trauma Surgery as a basis for
      interclinical quality management. A multicenter study of the German Society of
      Trauma Surgery].
AB  - Based on the "Trauma Registry" of the German Society of Trauma Surgery, an
      interclinical quality management (QM) system was implemented. The principles of
      the QM system as well as the differences in the quality of outcome and treatment
      are presented. The analysis uses the data on 2,069 severely injured (ISS = 22 +/-
      14) patients from 20 hospitals collected prospectively and anonymously between
      2/93 and 12/97. Outcome quality was analyzed by the TRISS method and Z
      statistics. The Z-value of the whole series was -0.24. There were three hospitals
      with more than 150 patients that had a Ps value calculated by the TRISS method.
      Clinic A had a good (-2.49), clinic B an average (-0.3) and clinic C (3.62) an
      adverse Z-value. The assessment of treatment quality was performed by criteria
      concerning both preclinical and acute clinical phases. Clinic C had a prolonged
      preclinical treatment time (90 min vs 62 min in clinic A) for severely injured
      (ISS > 15) patients. At the same time, the preclinical intubation rate for severe
      thoracic trauma (AIS > 3) was lower (44 %) in clinic C than in A (62 %). With 14
      min clinic A had the shortest time until basic radiological and ultrasound
      diagnostics were completed (X-rays of chest and pelvis and abdominal ultrasound)
      in cases of severe blunt trauma (ISS > 15), compared to 54 min in clinic B or 31
      min in clinic C. Also, cranial computed tomography for severe traumatic brain
      injury (GCS < 9) was applied significantly faster in clinic A (after 36 min) than
      in clinic C (after 62 min). Delayed diagnoses were defined as the difference
      between the ISS at discharge and the ISS at completion of diagnostics in the
      emergency department; this criterion was met best by clinic A with an ISS
      difference of two patients compared to five in clinic B and four in clinic C. The
      hospitals participating in the Trauma Registry receive an annual analysis of
      their preclinical and acute clinical performance. Thus, every hospital can
      analyze and improve the quality of treatment based on reliable data that show
      which parts of the process have to be optimized. Furthermore, the data allow a
      comparison of the average and optimal results of the whole series.

PMID- 10663104
TI  - [Anterior screw fixation for odontoid fractures].
AB  - The results of anterior screw fixation of odontoid fractures in 28 patients are
      presented. There were 27 type II- and 1 type III-injuries. Non-union with
      persistent instability had to be notified in one patient (3.6 %), secondary
      posterior C1/2 fusion had to be performed. Incorrect positioning of the screws in
      the odontoid with penetration of the postero-lateral cortex occurred in 3
      patients (10.7 %). Malpositioning of the odontoid after screw fixation was
      documented in 5 cases (17.9 %). Cardiopulmonary complications had to be treated
      in 5 patients (17.9 %), 4 patients (14.3 %) died in the postoperative period. 17
      patients could be followed up. Only 3 patients (17.8 %) were free of symptoms. A
      significant limitation in ROM of axial rotation was seen in 44 % of the patients.
      With anterior screw fixation of the odontoid high fusion rates can be achieved,
      however the procedure is technically demanding. Regarding the functional outcome,
      there is no significant difference to other established treatment methods.

PMID- 10663105
TI  - [Possible influence of knee scores].
AB  - This study evaluated 96 knee joints with osteoarthritis (degree I according to
      Resnick). The patients were examined by three examiners with the following score
      systems: Larson, Lysholm, Marshall, Orthopadische Arbeitsgemeinschaft Knie (OAK),
      Hospital for Special Surgery (HSS), Visual Analog Scale (VAS), Tegner activity
      level, and the International Knee Documentation Committee (IKDC) scoring system.
      The portion of subjective criteria varied in the different scores between 22 and
      95 %. Nevertheless, the agreement between criteria showed high correlations among
      the different examiners. Depending on the scoring system used and the examiners,
      different values were achieved. The results were significant at the 5 % level for
      the numerical results (Friedmantest) and for the total results (Bowkertest). The
      Lysholm score showed results that were extremely dependent on the different
      examiners, and the evaluation was very strict. The HSS scoring system was not as
      strict. The Marshall and the OAK scoring system presented few differences. The
      Larson score results compared with the OAK, and the Marshall score results showed
      comparable results in the evaluation by the different examiners. The Visual
      Analog Scale presented difficulties when used by the patients. The results showed
      a tendency to the middle values, the patients did not use the whole spread. Apart
      from this, the correlation between these VAS values and the results of the other
      scoring systems were high. Since it was only used one time, the Tegner activity
      level could not efficiently show the limitation caused by knee-joint damage. At
      the level of 1-4 the Lysholm scoring system and the VSA scale resulted in high
      values.

PMID- 10663106
TI  - [Pseudoarthrosis].

PMID- 10663108
TI  - [The Marjolin's ulcer": a malignant and rarely complication after burn trauma of
      the upper extremity - a case report].
AB  - The,Marjolin's ulcer" is a malignant lesion which is developed especially at
      chronic wounds after burn trauma. The latency from primary trauma to the
      malignant transformation is about 30 years. The lesion is more aggressive than
      other squamous cell carcinomas. We report on the combined radiation and surgical
      therapy of an 65-year-old patient with this lesion on the right hand and regional
      lymph node metastases. The extensive tissue defect after wide excision was
      reconstructed with a reversal radial forearm flap.

PMID- 10663107
TI  - [Cervical vascular penetrating trauma].
AB  - The case of a 25 year old male with a stab wound of common carotid artery and the
      internal jugular vein is reported. He was admitted in severe hemorrhagic shock
      and immediately treated successfully by arterial reconstruction by means of a
      venous patch. Mild, declining neurological deficits correlated in magnetic
      resonance imaging with disturbances in the perfusion area of the medial cerebral
      artery. A survey of the literature shows that the fast repair of the carotid
      artery is clearly to be given preference to ligature. First can be executed
      successfully in exceptional emergency cases also by non-carotid surgeons, if
      basic vascular-surgical techniques are controlled.

PMID- 10663109
TI  - [Atlanto-axial instability presenting a rare complication in fibrous dysplasia -
      a case report].
AB  - Fibrous dysplasia, in either monostotic or poliostotic form rarely involves the
      cervical spine. Most of these lesions remain asymptomatic and are incidental
      radiographic findings. A symptomatic case of polyostotic fibrous dysplasia
      involving the first, second and third cervical vertebra with potentially serious
      consequences is presented. A 53-year old woman who had shown cervical myelopathy
      for about 3 month was diagnosed as having cervical dysplasia on the basis of
      plain x-ray and CT scanning. In addition, atlanto-axial instability causing
      clinical symptoms was detected. A dorsal stabilisation was performed using the
      DCS System.

PMID- 10663110
TI  - [Dorsal carpometacarpal dislocation of the fifth finger: discussion of diagnosis
      and therapy on two cases].
AB  - Dorsal dislocation of the fifth carpometacarpal joint after injury is rare. Only
      five cases are reported in the literature. We report on two cases of dorsal
      dislocation of the fifth carpometacarpal joint after injury and we give a review
      of related literature. There are two interesting aspects concerning diagnostic
      and therapy of dorsal dislocation of the fifth carpometacarpal joint. Anterior
      posterior and lateral radiographs do not always provide adequate visualisation of
      this joint so a dislocation may be misdiagnosed. A radiograph taken with the
      forearm pronated 45 degrees from the routine anterior-posterior position better
      shows the dislocation. The adequate therapy consists in closed reduction,
      Kirschner wire fixation and cast immobilisation. A reduction without following
      Kirschner wire fixation - even in those dislocations that were found to be stable
      after closed reduction - is not recommended because of the risk of persisting
      pain after heavy manual work. In our two cases an instability of the fifth
      carpometacarpal joint existed after closed reduction. After Kirschner wire
      fixation and cast immobilisation for 6 weeks both patients showed 3 months after
      operative therapy a full range of movement and a powerful grip without any pain
      in the fifth carpometacarpal joint.

PMID- 10663111
TI  - [Pediatric traumatology--a persisting interdisciplinary problem or an opportunity
      for consensus. Hofmann von Kap-herr, Unfallchirurg (1999). 102:902-905].

PMID- 10663112
TI  - [Tissue from the test tube. 2. Bio Valley Tissue Engineering Symposium in
      Freiburg, 25.-27. November 1999].

PMID- 10663113
TI  - [Definition of concepts in rehabilitation. A basis for improving process
      quality].

PMID- 10663114
TI  - [Alteration of the model continuing education regulations at the 103rd "Deutschen
      Arztetag", May 2000].

PMID- 10663115
TI  - [Intra-articular fractures of the distal aspect of the radius: arthroscopically
      assisted reduction compared with open reduction and internal fixation].

PMID- 10663116
TI  - [Ernst Vaubel M. D. German pioneer in the field of arthroscopy 1902-1989].
AB  - In Germany of the pre-war period Ernest Vaubel at Wiesbaden was the most eminent
      arthroscopist. He collaborated with the manufacturer Georg Wolf at Berlin and
      developed his own arthroscope, a jacobaeus-type thoracolaparoscope with a 45
      degrees -optic and an in- and outflow connecting piece. The optic was definitely
      longer than the trocard and the electric bulb at the tip was in danger during
      manipulation in a narrow joint. Vaubel did a rather small series of arthroscopies
      from 1936 to 1939 at the University hospitals of Leipzig and Frankfurt, using
      local anaesthesia and air medium. 1938 he held a paper at the International
      Congress of Rheumatologists at Bath. In the same year he published a monograph
      titled "Die Arthroskopie", the first book of world literature on this issue. 1939
      he left the Frankfurt university hospital and went in his own private practice.
      1941-1944 he did military service as medical officer of the air force. After war
      he had not more facilities to practice arthroscopy. His ideas and his instrument
      were revived in the german speaking countries in the late fifties by the sports
      surgeons Gottwald Heiss at Stuttgart and Reinhold Suckert at Linz.

PMID- 10663117
TI  - Neutrino Physics at the Dawn of the Twenty-First Century.
AB  - Neutrino Physics in recent decades has undergone a rapid growth and has evolved
      into a discipline of relevance for various research fields, ranging from
      geophysics to cosmology. On the other hand, however, the knowledge that we have
      about the neutrino itself, i.e., its very nature and intrinsic properties, is
      still rather fragmentary. This article summarizes the present status of pure and
      applied neutrino physics, emphasizing on pointing out the links to neighboring
      disciplines.

PMID- 10663125
TI  - Bandtitelei.

PMID- 10663126
TI  - Symbiosis and pathogenesis: evolution of the microbe-host interaction.
AB  - Symbiotic and pathogenic bacteria have in common that they live in or on host
      organisms or host cells. To make a successful living in eukaryotic hosts,
      bacteria must possess the traits to recognize a given host and establish
      adherence. When the bacterial location is internal or intracellular, they must
      further have the ability to invade, to establish a niche, and finally to multiply
      within a host. The underlying mechanisms which allow this form of existence show
      similarities between symbiotic and pathogenic bacteria. The final outcome,
      however, may result in a wide spectrum of consequences for the host ranging from
      the acquisition of novel metabolic pathways to damage or death. Despite the
      vastly different forms of interactions, symbiotic and pathogenic bacteria have in
      common that they are adapted to a particular environmental niche represented by
      the host organism or compartment thereof. This contribution reviews the
      evolutionary forces which have shaped the microbial-host interactions. Particular
      emphasis is placed on the genetic and molecular mechanisms that drive bacterial
      evolution in response to the selective pressures of the host environment.

PMID- 10663127
TI  - Anaerobic degradation of phenolic compounds.
AB  - Mononuclear aromatic compounds are degraded anaerobically through three main
      pathways, the benzoyl-CoA pathway, the resorcinol pathway, and the phloroglucinol
      pathway. Various modification reactions channel a broad variety of mononuclear
      aromatics including aromatic hydrocarbons into either one of these three
      pathways. Recently, a further pathway was discovered with hydroxyhydroquinone as
      central intermediate through which especially nitrate-reducing bacteria degrade
      phenolic compounds and some hydroxylated benzoates. Comparison of the various
      strategies taken for the degradation of aromatics in the absence of oxygen
      demonstrates that the biochemistry of breakdown of these compounds is determined
      largely by the overall reaction energetics and, more precisely, by the redox
      potentials of the electron acceptor systems used. Nitrate reducers differ in
      their strategies significantly from those used by sulfate-reducing or fermenting
      bacteria.

PMID- 10663128
TI  - Sex pheromone of the pine sawfly Macrodiprion nemoralis
      (Hymenoptera:Diprionidae): identification of (2S,3R,7R,9S)-3,7, 9-trimethyl-2
      tridecanol as the precursor for the active pheromone acetate.
AB  - The main component of the sex pheromone precursor in females of Macrodiprion
      nemoralis was identified as a threo-3,7, 9-trimethyl-2-tridecanol isomer,
      approximately 800 pg per female, by gas chromatography-mass spectrometry.
      Comparison of mass spectrometric ion chromatograms showed that the natural
      compound in the female extract has the same retention time and mass spectrum as
      one of the two synthetic threo peaks. The acetate of the synthetic 16-isomer
      mixture caught a large number of males in the field, confirming the structure of
      the active pheromone. Comparison of gas chromatograms of the natural female
      extract with the eight synthetic threo stereoisomers showed that the pheromone is
      the (2S,3R,7R, 9S)-stereoisomer of 3,7,9-trimethyl-2-tridecyl acetate.

PMID- 10663129
TI  - El Nino caused collapse of the sabalo fishery (Prochilodus lineatus, Pisces:
      Prochilodontidae) in a South American river.
AB  - El Nino is well known to affect marine fishery. The Southern Oscillation,
      however, may also have a strong effect on riverine fish production in flood
      plains via its effect on river discharge. In years with high river discharges
      larger parts of the floodplain are innundated, increasing the surface area of
      suitable nursery grounds for young fish stock. In this way high river discharges
      are thought to have a positive effect on fish production, while low discharges
      are thought to have a negative effect. The collapse of the sabalo fishery in the
      Pilcomayo River in Bolivia, for instance, can be attributed to the 1990-1995 El
      Nino event and subsequent overexploitation of the fish stocks.

PMID- 10663130
TI  - Gravity-independent orientation of honeycomb cells.
AB  - Honey bees have long been assumed to build their comb with the cells in either of
      two preferred orientations with respect to gravity ("vertical" or "horizontal").
      I show here that these typical cell orientations in fact derive from substrate
      orientation and a simple building rule, rather than the influence of gravity
      itself. When bees were induced to build comb on substrates at four different
      orientations with respect to gravity, they always made cells with one vertex
      pointing directly toward the substrate. This produced horizontal and vertical
      cells on vertical and horizontal substrates, respectively, but yielded
      intermediate orientations on oblique substrates. The apparent preference for
      vertical and horizontal cells may simply reflect substrate orientation in the
      rectilinear hives from which cell measurements have been taken.

PMID- 10663131
TI  - Light-dependent magnetoreception in birds: does directional information change
      with light intensity?
AB  - Magnetic compass orientation in birds is based on light-dependent processes, with
      magnetoreception being possible only under light containing blue and green
      wavelengths. To look for possible intensity-dependent effects we tested
      Australian silvereyes during autumn migration under monochromatic green light
      (565 nm) produced by light-emitting diodes at various light levels. At
      intensities of 0.0021 and 0.0075 W/m(2), the birds showed normal activity and
      were oriented in their seasonally appropriate migratory direction. Under low
      light of 0.0002 W/m(2) the birds were less active; scatter increased, but they
      still oriented in their migratory direction. Under a high light level of 0.0150
      W/m(2), however, the test birds showed a counterclockwise shift in direction,
      preferring west-northwest instead of north. This change in behavior may reflect a
      change in the output of the magnetoreception system, resulting from a disruption
      of the natural balance between the wavelengths of light.

PMID- 10663133
TI  - The basic mechanism of glass polishing

PMID- 10663132
TI  - Three ways to be a saber-toothed cat.
AB  - Saber-toothed carnivores, until now, have been divided into two groups: scimitar
      toothed cats with shorter, coarsely serrated canines coupled with long legs for
      fast running, and dirk-toothed cats with more elongate, finely serrated canines
      coupled to short legs built for power rather than speed. In the Pleistocene of
      North America, as in Europe, the scimitar-cat was Homotherium; the North American
      dirk-tooth was Smilodon. We now describe a new sabercat from the Early
      Pleistocene of Florida, combining the scimitar-tooth canine with the short,
      massive limbs of a dirk-tooth predator. This presents a third way to construct a
      saber-toothed carnivore.

PMID- 10663134
TI  - Naturwissenschaften aktuell

PMID- 10663135
TI  - How to catch the wind: spider hairs specialized for sensing the movement of air.
AB  - Most arthropods are hairy creatures. Some of them have several hundreds of
      thousands of hairs on their exoskeleton which in the majority of cases serve
      mechanosensory functions. Filiform hairs or trichobothria, as they are called in
      the arachnids, respond to the slightest movement of the surrounding air. They
      have repeatedly been shown to be involved in the guidance of escape and prey
      capture behavior and are indeed among the most sensitive biosensors known to
      date. Accordingly, the mechanical interaction between the air and the hair which
      is deflected and thus adequately stimulated by viscous forces is very close and
      to a large extent follows principles known in fluid mechanics. Both the
      experimental and theoretical analysis of this interaction has reached
      considerable depth. Using spider trichobothria as the main example the present
      review article strives to explain in a simple way the main mechanical parameters
      to be considered and how hair morphology and mechanics bring about such
      remarkable sensitivity.

PMID- 10663136
TI  - Enzymes involved in the aerobic bacterial degradation of N-heteroaromatic
      compounds: molybdenum hydroxylases and ring-opening 2,4-dioxygenases.
AB  - Many N-heteroaromatic compounds are utilized by micro-organisms as a source of
      carbon (and nitrogen) and energy. The aerobic bacterial degradation of these
      growth substrates frequently involves several hydroxylation steps and subsequent
      dioxygenolytic cleavage of (di)hydroxy-substituted heteroaromatic intermediates
      to aliphatic metabolites which finally are channeled into central metabolic
      pathways. As a rule, the initial bacterial hydroxylation of a N-heteroaromatic
      compound is catalyzed by a molybdenum hydroxylase, which uses a water molecule as
      source of the incorporated oxygen. The enzyme's redox-active centers - the active
      site molybdenum ion coordinated to a distinct pyranopterin cofactor, two
      different [2Fe2S] centers, and in most cases, flavin adenine dinucleotide -
      transfer electrons from the N-heterocyclic substrate to an electron acceptor,
      which for many molybdenum hydroxylases is still unknown. Ring-opening 2,4
      dioxygenases involved in the bacterial degradation of quinaldine and 1H-4
      oxoquinoline catalyze the cleavage of two carbon-carbon bonds with concomitant
      formation of carbon monoxide. Since they contain neither a metal center nor an
      organic cofactor, and since they do not show any sequence similarity to known
      oxygenases, these unique dioxygenases form a separate enzyme family. Quite
      surprisingly, however, they appear to be structurally and mechanistically related
      to enzymes of the alpha/beta hydrolase fold superfamily. Microbial enzymes are a
      great resource for biotechnological applications. Microbial strains or their
      enzymes may be used for degradative (bioremediation) or synthetic
      (biotransformation) purposes. Modern bioremediation or biotransformation
      strategies may even involve microbial catalysts or strains designed by protein
      engineering or pathway engineering. Prerequisite for developing such modern tools
      of biotechnology is a comprehensive understanding of microbial metabolic
      pathways, of the structure and function of enzymes, and of the molecular
      mechanisms of biocatalysis.

PMID- 10663137
TI  - DNA changes in tissues entrapped in plant resins (the precursors of amber).
AB  - There have been many reports characterizing DNA from amber, which is a fossil
      version of plant resin. Here we report an investigation of the effects of plant
      resin (from Pseudotsuga menziesii) and drying conditions on the preservation of
      DNA in biological tissues. We examined the degree of degradation of the DNA by
      agarose gel electrophoresis of extracted DNA, by polymerase chain reaction, and
      by DNA sequencing. The plant resin alone appeared to cause little or no damage to
      DNA. Tissue immersed in plant resin that dried rapidly (exposed to sunlight)
      contained DNA with little apparent damage. Tissue immersed in the resin that was
      dried slowly (in shade without sunlight) contained DNA with some degradation
      (3.5% nucleotide changes). The tissue that was immersed in the resin that was
      constantly hydrated (by immersion in water) yielded DNA that was severely damaged
      (50-62% nucleotide changes). Transversions outnumbered transitions in these
      samples by a ratio of 1.4 : 1. A piece of Baltic amber immersed in water for 5
      days appeared to be impervious to the water. Thus amber inclusions that initially
      dried rapidly have the potential to yield undamaged DNA. Those that dried slowly
      may contain damaged DNA and may be unsuitable for phylogenetic and other studies.

PMID- 10663138
TI  - Role of Enhancer of zeste on the production of Drosophila melanogaster pheromonal
      hydrocarbons.
AB  - In a search for genes controlling the production of Drosophila melanogaster
      contact pheromones, the gene Enhancer of zeste [E(z)] was found to be one player.
      Flies mutant for either the amorphic or the antimorphic allele of E(z) showed a
      similar hydrocarbon phenotype as those with the overlapping Df lxd(15)
      deficiency: decreased amounts of total hydrocarbons and especially unsaturated
      ones in both sexes. The decrease in the level of D. melanogaster female sex
      pheromone 7,11-heptacosadiene was dramatic and was correlated with an increase in
      7-heptacosene. Females mutant for a gain-of-function allele had increased amounts
      of total hydrocarbons with wild-type proportions of dienes. Thus the E(z) gene
      seems to affect hydrocarbon biosynthesis, especially its desaturation steps and
      even more so the female-specific desaturation step transforming 7-monoenic fatty
      acids to 7,11-dienic ones and leading to female pheromones.

PMID- 10663139
TI  - Benzoquinones and hydroquinones in defensive secretions of tropical millipedes.
AB  - The defensive secretions of two tropical species of millipedes (the spirostreptid
      Telodeinopus aoutii and a species of Harpagophoridae) contain a complex mixture
      of closely related benzoquinones and hydroquinones. The major compounds are
      toluquinone and 2-methoxy-3-methylbenzoquinone, accompanied by the minor
      components, 2,3-dimethoxybenzoquinone and toluhydroquinone. Because of the large
      size and the geographic separation of the test animals a common defensive
      strategy of tropical, large millipedes against predation by vertebrates is
      assumed.

PMID- 10663140
TI  - Continuous hair cell turnover in the inner ear vestibular organs of a mammal, the
      Daubenton's bat (Myotis daubentonii).
AB  - In both humans and mice the number of hair cells in the inner ear sensory
      epithelia declines with age, indicating cell death (Park et al. 1987; Rosenhall
      1973). However, recent reports demonstrate the ability of the vestibular sensory
      epithelia to regenerate after injury (Forge et al. 1993, 1998; Kuntz and Oesterle
      1998; Li and Forge 1997; Rubel et al. 1995; Tanyeri et al. 1995). Still, a
      continuous hair cell turnover in the vestibular epithelia has not previously been
      demonstrated in mature mammals. Bats are the only flying mammals, and they are
      known to live to a higher age than animals of equal size. The maximum age of many
      species is 20 years, with average lifespans of 4-6 years (Schober and Grimmberger
      1989). Further, the young are fully developed and able to fly at the age of 2
      months, and thus the vestibular organs are thought to be differentiated at that
      age. Consequently, long-lived mammals such as bats might compensate for the loss
      of hair cells by producing new hair cells in their postembryonic life. Here we
      show that the utricular macula of adult Daubenton's bats (more than 6 months old)
      contains innervated immature hair cells as well as apoptotic hair cells, which
      strongly indicates a continuous turnover of hair cells, as previously
      demonstrated in birds.

PMID- 10663141
TI  - Genome organization and social evolution in Hymenoptera.

PMID- 10663142
TI  - Optimal area use in orb webs of the spider Araneus diadematus.
AB  - We studied the abilities of the garden cross spider Araneus diadematus regarding
      adaptation of web geometry to spatial constraints. Spiders reacted to a spatial
      reduction in their building site from a square-shaped frame to a slimmer,
      rectangular frame (side ratio 1 : 2) by maintaining overall web geometry while
      reducing the web area covered by the sticky capture spiral. However, when the
      frames were changed further to a rectangular side ratio of 1 : 3, the spiders
      changed specific web properties in such a way that a further reduction in the
      capture spiral area was prevented. Construction of the threads making up the web
      frame and the auxiliary spiral requires that the spider explores the spatial
      constraints of its building site. The geometry of both frame and auxiliary spiral
      threads in turn determine the geometry of the capture threads. Since in very
      narrow frames the spider adjusted the auxiliary to suit the subsequent capture
      spiral, we suggest that an initial spatial survey led to the final adaptation of
      overall web geometry to a web site.

PMID- 10663143
TI  - Naturwissenschaften aktuell

PMID- 10663156
TI  - [New developments in neonatology. A challenge for radiologists?].

PMID- 10663157
TI  - [Recent advances in neonatology--new tasks for the radiologist].
AB  - Modern neonatology comprises care for a growing number of infants with congenital
      abnormalities and an increasing number of premature born infants. The survival
      rates of premature infants have increased dramatically during the past decade.
      This increase in survival rates can be attributed to improved prenatal and
      obstetric management and to advances in neonatal intensive care medicine.
      RADIOLOGICAL SUPPORT: Neonatology has become a pediatric subspecialty of its own
      resulting in the demand for an equally specialised radiological support.
      Therefore the availability of a children's radiologist for radiological and
      sonographic examinations is mandatory (24 hours a day) for optimal patient care
      on a neonatal intensive care unit. A good cooperation between radiologist and
      neonatologist in neonatal intensive care medicine is therefore warranted.

PMID- 10663158
TI  - [Pathomorphological findings in preterm infants].
AB  - Pathomorphology in the preterm infant represents an interaction of morphological
      organ immaturity and neonatal management with their respective sequelae.
      PATHOMORPHOLOGICAL EXAMPLES: include the modification in the morphology of
      hyaline membrane disease and bronchopulmonary dysplasia as a consequence of
      modern neonatal therapy. Hemorrhagic and ischemic/ hypoxic lesions of the central
      nervous system may occur in age- and agent-related distributional patterns, with
      subependymal hemorrhage and periventricular leukomalacia representing the most
      important examples. The most common intestinal finding, namely, necrotizing
      enterocolitis, typically shows segmental alterations, the morphology of which
      largely depends on the dominating causative agent. Hepatic cholestasis and fatty
      change are mostly consequences of parenteral nutrition or hypoxic/ischemic
      stress. Hepatic necrosis can be associated with the latter, but may also indicate
      disseminated intravascular coagulation. Vascular pathomorphology is represented
      by thromboembolic lesions, in most instances corresponding to sequelae of
      neonatal management.

PMID- 10663159
TI  - [Applications of cerebral MRI in neonatology].
AB  - Magnetic resonance tomography (MRT) has become the most important method in the
      workup of infantile cerebral complications after primary sonography. Cerebral MR
      examination and image interpretation during the infantile period require
      extensive knowledge of morphological manifestations, their pathophysiological
      background, and frequency. The choice of imaging parameters and image
      interpretation is demonstrated in infarctions and hemorrhages of the mature and
      immature brain. A review of the main differential diagnoses is also given. The
      relevance of MR spectroscopy and fetal MRI is discussed.

PMID- 10663160
TI  - [Diagnostic imaging in neonatal stroke].
AB  - A cerebral artery infarction is an important differential diagnosis in the
      newborn with neurological abnormalities. Based on clinical data, its incidence is
      estimated to be 1 in 4000 newborns. Since the course is often subclinical, the
      true incidence is probably higher. DIAGNOSIS: Cerebral ultrasound and Doppler
      sonography as readily available screening tools play a central role in the
      initial diagnosis of neonatal cerebral infarction. Definitive diagnosis is made
      by computed tomography or magnetic resonance imaging. Beside symptomatic
      anticonvulsive therapy, treatment aims at the prevention of secondary ischemic
      injury. DISCUSSION: Three term infants with different clinical courses of
      neonatal stroke are presented to sensitize the clinician and the radiologist for
      this probably underdiagnosed entity. The role of imaging modalities in the
      diagnosis and follow-up of neonatal cerebral infarction is discussed.

PMID- 10663161
TI  - [Sonography of the central nervous system in prematures and newborns].
AB  - Examination of the central nervous system in premature and full-term infants
      requires a sensible selection of the available diagnostic procedures such as
      ultrasound, MRI and CT to allow sufficient and accurate diagnosis and management.
      ULTRASOUND: Ultrasound, including the various Doppler techniques, is a very
      reliable, safe, noninvasive diagnostic tool that allows evaluation of even
      severely ill patients in intensive care units. It is especially well suited for
      the study of intracranial hemorrhage, hypoxic-ischemic encephalopathy, congenital
      malformations of the brain and lesions produced by intrauterine and acquired
      infections. Sonography is also very reliable in examination of spinal dysraphism
      and spinal cord injuries during birth. The necessity of surgical intervention
      (i.e. shunt implantation) as well as subsequent postoperative follow-up can be
      provided. MRI: In contrast to ultrasound, MRI is most useful to demonstrate the
      age-dependent myelinization pattern and clearly discriminates between the white
      and gray matter of the central nervous system. We therefore use MRI for the
      detection of complex malformations of the central nervous system in particular
      disorders of cell migration and for a final estimation of a perinatal brain
      injury. CONCLUSION: A precise ultrasound examination performed by an experienced
      physician who is familiar with the expected pathology and has access to a well
      adjusted ultrasound machine should help to minimize the use of confirming CT and
      MRI investigations and to optimize their optional use in more complex cases.

PMID- 10663162
TI  - [Chest X-ray of the neonate].
AB  - In diagnostic imaging of thoracic pathologies in mature and especially immature
      neonates, chest X-ray has a leading position. Profound knowledge of the normal
      chest X-ray and the potential physiological perinatal changes is the basic
      requirement for interpretation of the X-ray of a neonate. Childhood pathology:
      Many congenital and acquired diseases that the radiologist is faced with in
      neonatology are unknown in the imaging of adults. Many of these changes are life
      threatening or may have an impact on the patient's future quality of life.
      Therefore early diagnosis in close cooperation with the paediatrician is
      essential. We give here an overview of the most important pathologic changes that
      the radiologist may be confronted with in daily routine.

PMID- 10663163
TI  - ["Lines and tubes" in neonatal intensive care patients].
AB  - BACKGROUND: Central catheters in neonatological intensive care patients are used
      for the prolonged application of medication or parenteral infusions. Dislocations
      and septic and thromboembolic complications may occur. CONTROL OF POSITION:
      Radiologically, the correct position of the catheter must be proven. Dislocations
      or complications associated with central catheters must be diagnosed. For
      catheter monitoring plain film radiographs are the first line of investigation;
      however, sonography may be of additional assistance. Angiographic techniques
      should only be performed when conventional noninvasive methods do not supply
      satisfactory results. Special knowledge is necessary for monitoring catheters
      that are set via the umbilical artery or vein. The radiological applications for
      catheter monitoring in the neonate intensive care unit are discussed in this
      article.

PMID- 10663164
TI  - [Necrotizing enterocolitis (NEC) in the newborn].
AB  - Necrotizing enterocolitis (NEC) is a disease of the premature neonate that
      requires early therapy, sometimes even surgery and therefore early diagnosis. In
      general, plain radiography of the abdomen and sonography are valuable imaging
      techniques for diagnosis of NEC. COURSE OF NEC: The disease starts with
      distension of small bowel loops. Furthermore the children develop pneumatosis in
      the bowel wall, which is a nonspecific pattern. If the NEC persists, the air
      passes into the portal vein system, causing a pneumoportogram. Finally, the
      disease can lead to perforation. In doubtful cases, the plain radiogram must be
      repeated within a period of 6 h. With sonography distension of the bowel,
      thickening of and pneumatosis in the bowel wall, the pneumoportogram and free
      intraperitoneal fluid can be easily depicted. The most common complications of
      NEC are intestinal stenosis and strictures that can lead to ileus. DIFFERENTIAL
      DIAGNOSIS: Focal perforation of ileum, volvulus and Hirschsprung's disease are
      some of the differential diagnoses.

PMID- 10663165
TI  - [Neonatal gastrointestinal emergencies].
AB  - Gastrointestinal emergencies in neonates often demand a quick and efficient
      diagnostic imaging. The procedures have to take the special diseases and
      conditions in these babies and preterm children into account. CONCLUSION: This
      paper summarises the most common causes for gastrointestinal neonatal emergencies
      and discusses the indication and performance as well as the diagnostic value of
      the commonly used modalities, giving some suggestions for an efficient imaging
      algorithm. Most of the time conventional plain abdominal films and sonography can
      answer the clinically important questions, however, in certain conditions
      fluoroscopy with contrast administration (enema, etc.) is mandatory. Only rarely
      is CT, MRI or Angiography indicated.

PMID- 10663166
TI  - [Malformations of the urinary tract in neonates. Current status of imaging
      procedures].
AB  - Malformations of the urinary tract are one of the most common types of anomalies
      in the neonatal period. Approximately 15-20% of all prenatally detected
      malformations require acute postnatal imaging. Sonography is the primary imaging
      modality in the evaluation of nephro-urologic problems in infancy. Hydronephrosis
      represents the most common pathology, followed by multicystic-dysplastic kidney.
      DISCUSSION: The result of the sonographic examination directs further imaging. An
      adequate diagnostic algorithm is decisive for accurate diagnosis, for the
      appropriate therapeutic regimen and for the prognosis of the patients.

PMID- 10663167
TI  - [Intranet applications in radiology].
AB  - The aim of the paper is to present the conceptual basis and capabilities of
      intranet applications in radiology. The intranet, which is the local brother of
      the internet can be readily realized using existing computer components and a
      network. All current computer operating systems support intranet applications
      which allow hard and software independent communication of text, images, video
      and sound with the use of browser software without dedicated programs on the
      individual personal computers. Radiological applications for text communication
      e.g. department specific bulletin boards and access to examination protocols; use
      of image communication for viewing and limited processing and documentation of
      radiological images can be achieved on decentralized PCs as well as speech
      communication for dictation, distribution of dictation and speech recognition.
      DISCUSSION: The intranet helps to optimize the organizational efficiency and cost
      effectiveness in the daily work of radiological departments in outpatients and
      hospital settings. The general interest in internet and intranet technology will
      guarantee its continuous development.

PMID- 10663168
TI  - [Obstruction in the duodenal passage. Mesenteric artery duodenal compression].

PMID- 10663170
TI  - [ [In Process Citation]

PMID- 10663169
TI  - [Radiologic staging of thoracic and abdominal tumors in childhood].

PMID- 10663172
TI  - [ [In Process Citation]

PMID- 10663171
TI  - [Looking for the cause in neutropenic fever. Imaging diagnostics].

PMID- 10663173
TI  - [Hopes fulfilled or cheated expectations? One year BDR--a critical evaluation].

PMID- 10663174
TI  - [Health care reform 2000: what remains to be done? Taking leave at the end of the
      year despite parliamentary breakdowns].

PMID- 10663175
TI  - [What kind of medicine will we pay for?].

PMID- 10663176
TI  - [ [In Process Citation]

PMID- 10663178
TI  - [ [In Process Citation]

PMID- 10663177
TI  - [Reimbursement status of East German radiologists].

PMID- 10663179
TI  - [Most communities can no longer afford their hospitals].

PMID- 10663181
TI  - [Insurance through the medical society. Insurance under favorable conditions. 4.
      Electronic insurance].

PMID- 10663182
TI  - [ [In Process Citation]

PMID- 10663180
TI  - [ICD-10 is not applicable in all insurance circumstances for radiologists].

PMID- 10663184
TI  - [ [In Process Citation]

PMID- 10663183
TI  - [ [In Process Citation]

PMID- 10663185
TI  - [ [In Process Citation]

PMID- 10663186
TI  - [ [In Process Citation]

PMID- 10663187
TI  - [ [In Process Citation]

PMID- 10663188
TI  - [Prostate cancer].

PMID- 10663189
TI  - [PSA rise after radical prostatectomy].
AB  - Approximately 18 % of patients will experience PSA failure only after radical
      prostatectomy. The rate of clinical (local or systemic) recurrence is in the same
      range. Clinical recurrence is accompanied by an increasing PSA in almost all
      cases. Altogether, the 10-year risk of PSA recurrence after radical prostatectomy
      for clinically localized prostate cancer is about 35 %. PSA relapse precedes the
      development of metastases by a median time of 8 years. The median survival after
      the manifestation of metastases is about 4-5 years. To differentiate the reasons
      of PSA failure, recurrence-free interval, Gleason score and PSA doubling time
      deliver important information. Patients with a high probability of isolated local
      failure (PSA relapse later than two years after radical prostatectomy) should
      undergo a biopsy, if a local radiotherapy is considered. The results of current
      clinical trials are eagerly awaited to answer the question weather immediate,
      delayed or intermittent hormonal therapy offer best results in individual cases.

PMID- 10663190
TI  - [Intermittent androgen deprivation].

PMID- 10663191
TI  - [Prognostic markers for prostate cancer].
AB  - Careful consideration of therapy for prostate cancer needs an accurate analysis
      of prognostic markers to estimate success and benefit for the patient. Prognosis
      of prostate cancer is determined by the proportion of high grade cancer, many
      usually utilized prognostic characteristics were rejected by multivariate
      analysis as no independent prognostic information was delivered. For planning
      therapy it is crucial to estimate the proportion of high grade cancer as exact as
      possible. A standardized biopsy technique combined with a quantified analysis of
      the biopsy cores is most helpful to achieve this goal. The prognostic value of
      molecular biological and other factors is object of research, only a combination
      of some of these factors could be demonstrated so far to be superior to the
      estimation of the proportion of high grade cancer. However, at present their
      routine use in daily practise is precluded by a high technical and financial
      expense.

PMID- 10663192
TI  - [PSA-based early detection of prostate cancer].
AB  - Prevention of prostate cancer up to now is not possible, advanced stages of
      prostate cancer are not curable. About 13 000 men a year die of prostate cancer
      in Germany. PSA-based screening has been shown to be effective in detecting
      prostate cancer at an early, potentially curable stage; however, this tumor
      marker is limited by appreciable false-positive and false-negative results.
      Several PSA-related indexes may improve the power of PSA in early detection: As
      PSA density, age-adjusted PSA, and percent free PSA. These indexes can improve
      positive predictive value of PSA-testing, but are not able to differentiate
      carcinoma from benign hyperplasia on an individual basis. Men presenting for
      early detection have to be informed about possible overtreatment before
      undergoing biopsy to further investigate increased PSA above 4.0 ng/ml or suspect
      findings in digital rectal examination.

PMID- 10663193
TI  - [Maximal androgen blockade].
AB  - According to the representative data of the Tumor Registry Munich, 38.1 % of
      prostate cancer patients received a primary androgen deprivation, whereas 20.5 %
      had an adjuvant hormonal treatment. Following surgical castration being the most
      common form of androgen deprivation, 5 alpha-dihydrotestosterone is still present
      in prostate cancer tissue. Therefore, a maximal androgen blockade (MAB)
      consisting of a chemical or surgical castration plus a pure or antigonadotropic
      antiandrogen, has been proposed. Indeed, MAB lowers the dihydrotestosterone
      androgen-receptor complex and suppresses the growth-factor dominated signal
      transduction. This leads to a measurable increase of apoptosis. New is the
      finding that LHRH as well as LH (for example following surgical castration) are
      bound by receptors located at the prostate cancer cell. In 30 phase-III trials,
      MAB has been tested against monotherapy and a cancer-specific survival advantage
      of 3 to 6 months and a approximately 6-month delay of progression was
      demonstrated. The most effective form of MAB is the combination of a LHRH agonist
      - in contrast to surgical castration - with a well-tolerated pure antiandrogen.
      The quality of life during MAB is low, if a pure antiandrogen such as flutamide
      is used which leads to rather serious side-effects. At the present time, special
      indications for MAB are patients with minimal metastases, bone pain at the time
      of diagnosis, a neoadjuvant or adjuvant application in combination with a radical
      prostatectomy or radiotherapy and particularly intermittent androgen deprivation
      which is tested at the present time in at least 5 international studies. An
      endocrine withdrawal syndrome is observed in approximately 30 % of patients, if,
      following a PSA-relapse, the antiandrogen is discontinued. Little notice has been
      given to the use of prognosticators for the decision, whether a MAB is useful or
      not. Patients with good prognostic factors as defined by Sylvester have a clear
      advantage, if MAB is compared to monotherapy, whereas patients with a pure
      prognosis did not benefit. In addition to these prognostic factors up-front, the
      PSA dynamics under an initial MAB may be employed for the decision, if this form
      of androgen deprivation is to be continued or not. In essence, in contrast to a
      general use of MAB a more differential application based on quality-of-life
      issues and prognosis should be preferred.

PMID- 10663194
TI  - [Preoperative staging of renal cell carcinoma with caval thrombus: is staging in
      MRI justified? Prospective histopathological correlated study].
AB  - To evaluate whether MRI is usefull in staging renal cell carcinomas with caval
      thrombus the accuracy of computed tomography (CT) and magnetic resonance imaging
      (MRI) in staging renal tumors with caval thrombus were preoperatively examined.
      Tumor staging by CT and MR imaging were correlated with histopathological tumor
      stadium. In MRI 4 out of 7 thrombi were correctly diagnosed with high accuracy,
      in CT none. In advanced renal carcinoma MRI with Gadolinium was superior to CT
      imaging, especially in diagnosing tumor thrombus. Consequently the extent of
      tumor thrombus may be assessed by MRI which therefore may replace conventional
      cavography.

PMID- 10663195
TI  - [Prolonged peridural analgesia (PDA) for postoperative pain therapy after major
      urologic interventions. Experiences with 172 adult patients].
AB  - The benefits of epidural analgesia are well known, but it is not well understood
      which types of urologic surgery benefit most from epidural analgesia. In this
      study, the effects and side effects of prolonged epidural analgesia are
      prospectively examined and analysed on 172 adult patients in three different
      operation groups. An epidural infusion of local anaesthetic combined with an
      opioid and adrenaline was given for a period of 5-7 days. There was no difference
      between the groups with respect to the effectiveness of the analgesia and
      patients' perception of the treatment. Mobilization differed, as expected,
      between the groups, however even after the most major surgery (e. g. cystectomy
      with bladder substitution), mobilization was impressively unproblematic. Retarded
      return of regular intestinal function after the transperitoneal operation and
      partly after lumbotomy compared with the extraperitoneal operation depended on
      which operation was performed and the amount of analgesia given. The side effects
      such as sedation, nausea and pruritus were conditional partly on the opiate and
      partly on the intervention. Up to 11 % showed slight muscular weakness of the
      lower limbs as a specific side effect of the local anaesthetic. COMPLICATIONS:
      One patient died of cerebral hypoxia due to an initially undetected subdural
      catheter placement complicated by severe pre-existent carotid stenosis. In four
      patients, the epidural analgesia had to be stopped because of catheter migration.
      There was no clinical evidence of hematoma, abscess or permanent neurological
      damage. Epidural analgesia works well in terms of analgesia, mobilization and
      patient satisfaction, bearing in mind the potential side effects and
      complications. It can be recommended for lumbotomy and long transperitoneal
      operations however not for extraperitoneal interventions in the lower abdomen
      such as radical prostatectomy.

PMID- 10663197
TI  - [Solitary synchronous bladder metastasis from renal cell carcinoma treated by
      transurethral resection].
AB  - Metastases to the bladder from renal cell carcinoma are extremely rare. The
      prognosis is poor and seems not related to the type of treatment. Most patients
      die within 1 year of diagnosis. The treatment should be therefore as conservative
      as possible. We report a case of solitary, synchronous bladder metastasis treated
      by transurethral resection. At 24 months the patient is free of recurrence.

PMID- 10663196
TI  - ["Acute scrotum" in the neonate. Adrenal haemorrhage as cause].
AB  - The most common causes of an 'acute scrotum' in childhood are testicular torsion,
      torsion of an appendix testis, epididyoorchitis, idiopathic edema, and hematoma.
      In rare cases a scrotal hematoma can originate from an extra- or intraperitoneal
      adrenal bleeding. 12 such cases have been described in the literature, yet. We
      report on 3 further cases, that occurred in our institution between 1992 and
      1997. In the first case we performed a scrotal exploration due to a suspected
      testicular torsion, but only a normal testicle and liquid hematoma were seen.
      Postoperatively we discovered an ipsilateral adrenal hemorrhage by sonography. In
      the latter two cases the adrenal bleeding was recognized primarily as causal for
      the scrotal mass and operation remained undone. In newborns adrenal hemorrhage is
      mostly due to birth-trauma, large birth-weight, hypoxia, and asphyxia. This was
      present as well with our 3 children. If the clinical situation of the child is
      stable, complete restitution under conservative therapy can be expected.

PMID- 10663198
TI  - [Sacral neuromodulation of the urinary bladder].

PMID- 10663199
TI  - [Importance of an intact magnesium balance].

PMID- 10663201
TI  - [ [In Process Citation]

PMID- 10663200
TI  - [ [In Process Citation]

PMID- 10663203
TI  - [ [In Process Citation]

PMID- 10663202
TI  - [ [In Process Citation]

PMID- 10663204
TI  - [ [In Process Citation]

PMID- 10663211
TI  - Relation between leptin and the regulation of glucose metabolism.

PMID- 10663213
TI  - Significant improvement of apolipoprotein B-containing lipoprotein metabolism by
      insulin treatment in patients with non-insulin-dependent diabetes mellitus.
AB  - AIMS/HYPOTHESIS: Patients with Type II (non-insulin-dependent) diabetes mellitus
      have multiple abnormalities in apolipoprotein B (apoB)-containing lipoprotein
      metabolism. These abnormalities are likely to play an important part in the
      development of premature atherogenesis in these patients. This stable isotope
      kinetic experiment was designed to study the effect of insulin therapy on apoB
      metabolism in poorly controlled Type II diabetic patients. METHODS: Using L-[1
      13C] leucine, we studied apoB metabolism in five control subjects without insulin
      resistance and in six poorly controlled Type II diabetic patients before and 2
      months after the introduction of insulin therapy. RESULTS: Insulin treatment
      induced a decrease of very low density lipoprotein apoB plasma concentration [121
      +/- 42 vs 158 +/- 91 mg.l-1, p < 0.05 (control subjects: 48 +/- 20)], related to
      an increased catabolism of very low density lipoprotein towards intermediate
      density lipoprotein or low density lipoprotein [0.20 +/- 0.08 vs 0.14 +/- 0.07
      pool.h-1, p < 0.05 (control subjects: 0.36 +/- 0.10)]. On the other hand, insulin
      treatment induced an acceleration of intermediate density lipoprotein apoB turn
      over without changing its plasma concentration [77 +/- 37 vs 61 +/- 18 mg.l-1,
      (control subjects: 17 +/- 3)], by increasing both its production rate [22.6 +/-
      9.2 vs 18.2 +/- 9.6 mg.l-1.h-1, p < 0.05 (control subjects: 18.4 +/- 3.2)] and
      its catabolic rate towards low density lipoprotein [0.34 +/- 0.22 vs 0.22 +/-
      0.16 pool.h-1, p < 0.05 (control subjects: 1.02 +/- 0.13)]. Likewise, insulin
      treatment increased low density lipoprotein apoB production rate [20.2 +/- 7.4 vs
      16.9 +/- 7.7 mg.l-1.h-1, p < 0.05 (control subjects: 16.9 +/- 2.3)] and restored
      a normal low density lipoprotein apoB fractional catabolic rate [0.022 +/- 0.004
      vs 0.018 +/- 0.004 pool.h-1, p < 0.05 (control subjects: 0.025 +/- 0.004)],
      resulting in a constant low density lipoprotein apoB plasma concentration [965 +/
      485 vs 984 +/- 558 mg.l-1 (control subjects: 699 +/- 106)].
      CONCLUSION/INTERPRETATION: Insulin treatment in Type II diabetes induces profound
      metabolic modifications of lipoprotein, resulting in significant decrease of the
      intravascular residence time of very low density lipoprotein, intermediate
      density lipoprotein and low density lipoprotein particles. This is likely to make
      these particles less harmful.

PMID- 10663214
TI  - Long-term changes in insulin action and insulin secretion associated with gain,
      loss, regain and maintenance of body weight.
AB  - AIMS/HYPOTHESIS: We aimed to quantify changes in insulin action and insulin
      secretion associated with long-term gain, loss, regain, and maintenance of body
      weight in subjects with normal (NGT) or impaired (IGT) glucose tolerance.
      METHODS: Insulin action (hyperinsulinaemic clamp) and insulin secretion
      (intravenous glucose challenge) were measured longitudinally in 209 Pima Indians
      body weight 94.4 +/- 22.8 kg (means +/- SD) 89 women/120 men, 151 NGT/58 IGT[,
      who either lost (n = 110) or gained (n = 99) weight (-23% to +29%) over 2.6 +/-
      2.0 years. Insulin action and insulin secretion were reassessed on a third
      occasion in 33 subjects who lost at least 5% body weight over 1.5 +/- 0.8 years
      and then either regained or maintained weight over the subsequent 1.8 +/- 1.1
      years. RESULTS: There was a linear negative relation between changes in body
      weight and changes in insulin-stimulated glucose disposal in subjects with normal
      glucose tolerance (r = -0.51, p < 0.0001) and impaired glucose tolerance (r = 
      0.54, p < 0.0001). In contrast, changes in the acute insulin response were
      positively related to weight changes in subjects with normal glucose tolerance (r
      = +0.26, p < 0.005) but negatively in those with impaired glucose tolerance (r = 
      0.51, p < 0.0001). Improvements in insulin action after an average of 10% weight
      loss were lost with weight regain but largely preserved with weight maintenance.
      CONCLUSION/INTERPRETATION: Improvements in insulin action are proportional to the
      amount of weight loss, similar in magnitude to the impairment in insulin action
      with weight gain, preserved with long-term weight maintenance and similar between
      subjects with normal and with impaired glucose tolerance. Weight gain could,
      however, have more detrimental effects in people with impaired glucose tolerance,
      in whom insulin secretion decreases rather than increases to compensate for the
      decreased insulin action.

PMID- 10663215
TI  - Infections and vaccinations as risk factors for childhood type I (insulin
      dependent) diabetes mellitus: a multicentre case-control investigation. EURODIAB
      Substudy 2 Study Group.
AB  - AIMS/HYPOTHESIS: To determine if vaccinations and infections are associated with
      the subsequent risk of Type I (insulin-dependent) diabetes mellitus in childhood.
      METHOD: Seven centres in Europe with access to population-based registers of
      children with Type I diabetes diagnosed under 15 years of age participated in a
      case-control study of environmental risk factors. Control children were chosen at
      random in each centre either from population registers or from schools and
      policlinics. Data on maternal and neonatal infections, common childhood
      infections and vaccinations were obtained for 900 cases and 2302 control children
      from hospital and clinic records and from parental responses to a questionnaire
      or interview. RESULTS: Infections early in the child's life noted in the hospital
      record were found to be associated with an increased risk of diabetes, although
      the odds ratio of 1.61 (95% confidence limits 1.11, 2.33) was significant only
      after adjustment for confounding variables. None of the common childhood
      infectious diseases was found to be associated with diabetes and neither was
      there evidence that any common childhood vaccination modified the risk of
      diabetes. Pre-school day-care attendance, a proxy measure for total infectious
      disease exposure in early childhood, was found, however, to be inversely
      associated with diabetes, with a pooled odds ratio of 0.59 (95% confidence limits
      0.46, 0.76) after adjustment for confounding variables.
      CONCLUSION/INTERPRETATION: It seems likely that the explanation for these
      contrasting findings of an increased risk associated with perinatal infections
      coupled with a protective effect of pre-school day care lies in the age-dependent
      modifying influence of infections on the developing immune system.

PMID- 10663216
TI  - Birth weight and the insulin resistance syndrome: association of low birth weight
      with truncal obesity and raised plasminogen activator inhibitor-1 but not with
      abdominal obesity or plasma lipid disturbances.
AB  - AIMS/HYPOTHESIS: To distinguish the physiological disturbances related to birth
      weight from the cluster of disturbances called the insulin resistance syndrome.
      METHODS: Men participating in a population-based study in Uppsala, Sweden, with
      recordings of birth weight, were metabolically characterised at age 50 (n = 1268)
      and re-investigated at age 70 (n = 734). Blood pressure, BMI, glucose and insulin
      concentrations are associated with birth weight in this cohort. RESULTS: Birth
      weight was inversely associated (p < 0.03) with subscapular:triceps skinfold
      ratio (truncal fat), plasminogen activator inhibitor-1 (PAI-1) activity, specific
      insulin and proinsulin-like molecules when adjusted for BMI. Birth weight was not
      related (p > 0.10) with waist circumference, serum triglycerides or HDL
      cholesterol. The insulin resistance syndrome was defined as the combination of
      hypertension, insulin resistance and dyslipidaemia. The prevalence of this
      syndrome at age 50 and 70 was inversely related to birth weight with odds ratio
      0.66 and 0.71, respectively, per kg increase in birth weight. When the syndrome
      was defined to include truncal obesity or raised plasminogen activator inhibitor
      1 instead of dyslipidaemia, the corresponding odds ratios were 0.51 and 0.66,
      respectively. CONCLUSIONS/INTERPRETATION: Low birth weight predicts high blood
      pressure, insulin resistance, truncal obesity and high plasminogen activator
      inhibitor-1 activity but not the abdominal obesity or dyslipidaemia present in
      the insulin resistance syndrome. The cluster of disturbances associated with low
      birth weight is a subset of the disturbances that are clustered in the general
      population as the insulin resistance syndrome. This subset of physiological
      disturbances is possibly linked by a specific pathway.

PMID- 10663217
TI  - Both insulin sensitivity and insulin clearance in children and young adults with
      type I (insulin-dependent) diabetes vary with growth hormone concentrations and
      with age.
AB  - AIMS/HYPOTHESIS: We measured insulin clearance rates in children and young adults
      with Type I (insulin-dependent) diabetes mellitus to establish their relation
      with insulin sensitivity and with factors such as growth hormone secretion and
      body mass index. METHODS: We studied 46 subjects mean (range) age 14.4 (9.8-24.6)
      years), body mass index 21.1 (15.8-29.6) Kgm2[ using an overnight (1800-0800
      hours) variable rate insulin infusion euglycaemic clamp protocol (5 mmol/l).
      Plasma free insulin concentrations during steady-state euglycaemia were used as
      an index of insulin sensitivity and insulin clearance determined as a ratio of
      insulin infusion rate to plasma free insulin. RESULTS: During steady-state
      euglycaemia (0500-0730 hours), insulin sensitivity mean (SEM) plasma insulin
      0.020 (0.002) mU/l[ and insulin clearance rates 19.1 (1.8) ml.kg-1.min[ varied
      with age non-linearly and in a reciprocal fashion to each other (cubic regression
      F = 4.09, p = 0.01; F = 3.55, p = 0.02, respectively). Insulin sensitivity was
      negatively related to BMI (r = -0.37, p = 0.011) and mean overnight growth
      hormone concentrations (r = -0.40, p = 0.007). Insulin clearance was only related
      to growth hormone concentrations (r = -0.37, p = 0.014). These relations were
      still evident after stepwise multiple regression analysis (potential
      determinants: C peptide, sex, age, puberty stage, HbA1c, duration of diabetes):
      insulin sensitivity r = 0.55, p < 0.001; insulin clearance r = 0.37, p < 0.02.
      CONCLUSIONS/INTERPRETATION: Insulin clearance rates vary with age in young
      subjects with Type I diabetes and are highest during mid-adolescence when insulin
      sensitivity is at its lowest. Both insulin sensitivity and insulin clearance are
      related to circulating growth hormone concentrations.

PMID- 10663218
TI  - Impaired insulin secretion in non-diabetic offspring of probands with latent
      autoimmune diabetes mellitus in adults.
AB  - AIMS/HYPOTHESIS: This study was undertaken to investigate metabolic and genetic
      characteristics of latent autoimmune diabetes in adults (LADA). METHODS: We
      evaluated insulin secretory capacity with oral and intravenous glucose tolerance
      tests (early insulin response) and hyperglycaemic clamp (insulin secretory
      capacity) and the rates of whole body glucose uptake with the euglycaemic clamp,
      HLA-DQB1 genotypes (time-resolved fluorescence) and islet cell antibodies (ICA)
      (immunofluorescence) and antibodies to glutamic acid decarboxylase (GAD) (radio
      immunoprecipitation) in 36 non-diabetic offspring (LADA-offspring) of patients
      with Type II (non-insulin-dependent) diabetes mellitus who tested positive for
      ICA and/or GAD antibodies during the 10-year follow-up from the diagnosis and in
      19 healthy control subjects without a family history of diabetes. RESULTS: The
      early insulin response during the first 10 min of an intravenous glucose
      tolerance test was about 40% lower in the LADA-offspring than in the control
      group (p = 0.008). Insulin secretory capacity in the hyperglycaemic clamp was
      also about 30% lower in the LADA-offspring (p = 0.048). The rates of whole body
      glucose uptake were similar in both groups. The frequency of low risk HLA-DQB1
      genotypes was higher in the LADA-offspring than among Finnish healthy blood
      donors (p = 0.033). The risk conferring genotypes were associated with the lowest
      tertile of insulin secretory capacity in the LADA-offspring (p = 0.032). There
      were no associations between the autoantibodies and early insulin response or
      insulin secretory capacity within the study groups. CONCLUSION/INTERPRETATION: We
      conclude that LADA is a familial disease involving most likely gene defects
      leading to a slow progressive beta-cell destruction and insulin deficiency.

PMID- 10663219
TI  - Glycaemic control during early pregnancy and fetal malformations in women with
      type I diabetes mellitus.
AB  - AIMS/HYPOTHESIS: To assess the relation between glycaemic control in early
      pregnancy and the risk of congenital malformations in offspring of mothers with
      Type I (insulin-dependent) diabetes mellitus. METHODS: From 1988-1997, we
      prospectively collected data from 691 pregnancies and 709 offspring of 488 women
      with Type I diabetes in a specific geographic area in Southern Finland. Glycated
      haemoglobin A1c at less than 14 weeks of gestation was used as the indicator of
      glycaemic control. The malformations were diagnosed either by ultrasonography in
      pregnancy or during the neonatal period. We also studied 729 non-selected control
      pregnancies in women without diabetes. RESULTS: The numbers of major fetal
      malformations were 30 (4.2%) in patients with Type I diabetes and 10 (1.2%) in
      the control subjects (relative risk 3.1; 95% confidence interval: 1.6 to 6.2).
      Even women whose HbA1c was only slightly raised (5.6 to 6.8%, i.e. 2.0 to 5.9
      standard deviation units) showed a relative risk of 3.0 (95% confidence interval:
      1.2 to 7.5). Haemoglobin A1c retained its statistically significant association
      with the occurrence of malformations after adjusting for White's class, age at
      onset of diabetes, duration of diabetes, parity, smoking and participation in pre
      pregnancy counselling. CONCLUSIONS/INTERPRETATION: Even a slightly raised HbA1c
      during early pregnancy in women with Type I diabetes carries an increased risk
      for fetal malformations. Therefore normoglycaemia should be strived for during
      early pregnancy.

PMID- 10663220
TI  - Highly glycated oxyhaemoglobin impairs nitric oxide relaxations in human
      mesenteric microvessels.
AB  - AIMS/HYPOTHESIS: It has been recently shown that glycated human haemoglobin
      induces endothelial dysfunction in rat vessels by generating superoxide anions
      that interfere with nitric oxide mediated responses. Our study analysed the
      effect of glycated human haemoglobin on the endothelium-dependent relaxations of
      human vessels. METHODS: Omental microvessels were obtained from patients (without
      diabetes, hypertension or vascular disease) during surgery and mounted in a small
      vessel myograph to study their vasoactive responses (vessels from 3-7 patients
      for each set of experiments). RESULTS: Cumulative vasodilatory responses to
      bradykinin (10 nmol/l to 3 mumol/l) were induced in vessels precontracted with 35
      50 mmol/l potassium chloride. Addition of 100 mumol/l NG-nitro-L-arginine methyl
      ester reduced the relaxation evoked by bradykinin, but preincubation with both NG
      nitro-L-arginine methyl ester and 10 mumol/l indomethacin was needed to abolish
      it. Bradykinin-induced responses were inhibited by 1 mumol/l non-glycated
      oxyhaemoglobin whereas no effect was obtained with 10 nmol/l oxyhaemoglobin. At
      these low concentrations (10 nmol/l), glycated human oxyhaemoglobin caused an
      impairment of bradykinin-induced relaxation when the percentage of glycation was
      10% or higher. This effect was prevented by preincubating the vessels with
      ascorbic acid (10 mumol/l), superoxide dismutase (100 U/ml) and gliclazide (1 and
      10 mumol/l), but not with indomethacin (10 mumol/l), catalase (400-600 U/ml),
      dimethylthiourea (1 mmol/l) or glibenclamide (10 mumol/l). In vessels
      preincubated with NG-nitro-L-arginine methyl ester (100 mumol/l),
      glycohaemoglobin did not add any additional effect. CONCLUSION/INTERPRETATION:
      Highly glycated human oxyhaemoglobin, at physiological plasmatic concentrations,
      impairs nitric oxide-mediated responses by a mechanism involving superoxide
      anions but not cyclooxygenase derivatives.

PMID- 10663221
TI  - Expression of cytoskeletal proteins during the course of experimental diabetic
      nephropathy.
AB  - AIMS/HYPOTHESIS: Diabetic nephropathy is characterised by structural changes
      known to be associated in non-diabetic nephropathies with the expression of the
      cytoskeletal proteins a-smooth muscle actin and vimentin. We aimed to investigate
      the expression of cytoskeletal proteins in experimental diabetic nephropathy.
      METHODS: Rats were made diabetic by an injection of streptozotocin (45 mg/kg).
      Groups of rats (n = 6) and their respective controls (n = 4) were killed at
      different time intervals. (days 7, 15, 30, 60, 90 and 120). We also studied two
      groups of diabetic rats treated with a long-acting insulin; the first (n = 8) was
      treated from the induction of diabetes and the second (n = 8) received insulin
      from day 15 onward. At each time-point, kidney function, proteinuria and
      histology were evaluated. Cytoskeletal proteins and collagens III and IV
      deposition was determined by immunohistochemistry. Changes in the transcription
      of the cytoskeletal proteins was determined by northern blot analysis. RESULTS:
      Although normal glomeruli did not express alpha-smooth muscle actin until late in
      the time course, it was detected in diabetic mesangium from day 7 onward. In the
      interstitium, it appeared in a perivascular and peritubular distribution.
      Vimentin was detectable within normal glomerular epithelial cells and increased
      rapidly (days 7 and 15) in diabetic rats. Vimentin also appeared early within the
      lining of the peritubular capillaries and damaged diabetic tubules. These changes
      were associated with a delayed increased transcription of alpha-smooth muscle
      actin and vimentin. Treatment with insulin (early or late) attenuated and
      reversed respectively the expression of cytoskeletal proteins and collagens
      within diabetic kidneys. Close correlations were noted between the number of
      alpha-smooth muscle actin positive cells within diabetic glomeruli and mesangial
      expansion (r = 0.46, p < 0.02) as well as interstitial alpha-smooth muscle actin
      positive cells and interstitial fibrosis (r = 0.51, p < 0.002).
      CONCLUSION/INTERPRETATION: Changes in the expression of cytoskeletal proteins
      within the kidneys of diabetic rats suggest a role for alpha-smooth muscle actin
      and vimentin in the pathogenesis of diabetic kidney disease.

PMID- 10663240
TI  - [Correcting deformities of the extremities. 2].

PMID- 10663241
TI  - [Percutaneous epiphyseodesis. Correction of leg length inequalities and frontal
      plane deformities].
AB  - The percutaneous epiphysiodesis is recommended as a save and reliable technique.
      We have performed 21 distal femoral, 17 proximal tibial and 3 proximal fibular
      percutaneous epiphyseodeses on 25 patients. On 11 patients the epiphysiodesis was
      caused by an average leg length discrepancy of 2,7 cm (1-4 cm). 13 patients had
      angular deformity near the knee joint in frontal plane (6 valgus and 7 varus
      deformities). One patient suffered from a combined deformity with 3, 5 cm
      shortened leg and varus deviation of 10 degrees. The average deformity angle of
      the knee was 7,4 degrees (4 degrees -16 degrees ). 9 patients have reached
      maturity. On 3 patients the deformity could be corrected incompletely with
      residual deformity of 3 degrees, 4 degrees and 6 degrees as a direct result of
      late referral. On 1 patient an imminent over-correction could be avoided by
      hemiepiphysiodesis of the residual epiphysis. Till the present follow up the
      other patients have been corrected as calculated preoperatively. No complications
      like epiphysiolysis, infection, stiff knee or angular deformities occurred. We
      prefer the percutaneous epiphysiodesis as a save and minimal invasive technique
      instead of the open Phemister-technique to tread leg length discrepancy and
      angular deformities of the knee in frontal plane.

PMID- 10663242
TI  - [Correction of complex deformities in infectious conditions].
AB  - Skeletal deformities do occur after conservative or operative fracture treatment,
      as a consequence of congenital growth disturbance and as sequlae after
      posttraumatic and haematogenous osteomyelitis. In postinfectious deformities the
      course of the bone and soft tissue infection plays a decisive role when choosing
      the appropriate operative technique. Even in non active situations with a closed
      soft tissues envelope and no draining sinus persistence of germs within the bone
      has to be anticipated. The biological quality of the bone and the soft tissue
      envelope is often reduced because of local changes and as a result of multiple
      local revisions. Consequently wide areas of scar tissue and sclerotic bone are
      often encountered. The apex of the deformity is in most cases identical with the
      focus of the active or non active infection. The correction of the deformity at
      the apex can therefore only be accomplished if the infectious bone is also
      resected. If a correction is not possible at the apex of the deformity,
      translation at the osteotomy site is necessary to achieve a correct mechanical
      axis. The later rather complex operative procedure necessitates intensive
      preoperative planning and an extensive experience with deformity corrections by
      external fixators.

PMID- 10663243
TI  - [Principles of deformity correction around the knee].
AB  - Lower limb frontal and sagittal plane alignment and joint orientation have
      significant consequences for function and wear on the hip, knee and ankle. There
      is a normal range for the orientation of these joints relative to the mechanical
      and anatomic axis of the femur and/or tibia. We can use the normal joint
      orientation to accurately plan realignment of a deformed femur or tibia. In the
      frontal plane we use both anatomic and mechanical axis lines for planning. In the
      sagittal plane, the mechanical axis has less relevance and, therefore, only the
      anatomic axis is used for planning.

PMID- 10663244
TI  - [Corrections using the hexapod].
AB  - The hexapod is a construction that has been subjected to a great deal of
      investigation in robotics for use in three-dimensional positioning. One use of it
      is for positioning of the cockpit in flight simulators. Application of the
      hexapod principle in the external fixator makes it possible to realize prescribed
      movements of bone fragments with a simple and stable design. The precise setting
      of the system requires software that has been developed and optimized for
      clinical use. Translations, axis corrections and rotations are possible
      individually and also in combinations for correction of complex deformities. The
      system has advantages, especially in the case of rotations around the
      longitudinal axis of the bone and in the realization of translation movements.
      Because the centres of rotation are taken into account by the mathematical
      calculations, the planning of corrections is simplified. The hexapod system is
      described, and its clinical application is presented with reference to case
      reports.

PMID- 10663245
TI  - [Unilateral external fixators in the correction of deformities of the
      extremities].
AB  - The introduction of joints in unilateral fixators enables these for multiple
      deformity corrections. Lengthening and shortening is achieved by changing the
      length of the fixator telescope. Axial corrections are performed by additive or
      subtractive techniques using uniplanar joints or by angulation procedures.
      Translation is done by direct movements of the bone fragments or by metaphyseal
      "double angulation". Derotation preferably is done as an acute procedure or in
      the "ring part" of a hybrid frame. Unilateral fixators are used to correct and
      temporarily stabilize until the correction is held by the intramedullary nail.

PMID- 10663246
TI  - [The treatment of congenital tibial pseudarthrosis].
AB  - Congenital tibial pseudarthrosis (CTP) remains one of the most challenging
      problems in paediatric orthopaedic surgery. With the abandonment of older
      grafting techniques in favor of vascularized fibular transplants or the Ilizarov
      method the final outcome has improved and made the prognosis for patients less
      cumbersome. Using the latter technique in 10 patients, a success rate of 90 %
      could be reached. Nevertheless, although solid healing occurs in most of the
      patients nowadays, this is often at the cost of multiple operations before a
      definite well united, equalized and normally aligned limb can be obtained.

PMID- 10663247
TI  - [Humeral lengthening and deformity correction].
AB  - Nine patients with achondroplasia and one patient with Apert syndrome underwent
      the surgical lengthening of both humerus and simultaneous correction of both
      associated bone deformity. An unilateral external fixator was applied to the
      lateral aspect of the humerus with four half-pins and percutaneous predrilling
      osteotomy was performed at the apex of flexion deformity of the bone. During the
      waiting period before distraction, the flexion deformity of the distal humerus
      was corrected using an additional external fixator. Slow gradual distraction was
      subsequently carried out at a rate of 0. 25 mm every 6 hours. The average
      lengthening was 8 cm (range 7.5 to 9 cm), the overall treatment time 312 days
      (range 192 to 406 days), and the average healing index 39.0 days/cm. The average
      correction of the elbow flexion deformity was 20 degrees. We believe this
      treatment is useful to improve the function of the arms and the activity of daily
      living for the patients with bilateral short humeri.

PMID- 10663248
TI  - [Birth after peri-acetabular osteotomy].
AB  - We evaluated the radiological pelvic diameter after the bernese periacetabular
      osteotomy (PAO) and its influence on the modality of birth. Out of 93 woman, 17
      had a total of 28 babies after PAO; 18 children were delivered spontaneously and
      10 by caesarean section. The rate of section (36 %) was twice as high after PAO
      as in a normal population. In 50 % the indication to perform a section was made
      because the obstetrician anticipated problems during delivering after PAO. The
      average weight of birth was 3348 g +/- 285 g in the spontaneous delivery group,
      3475 g +/- 356 g in the section group. The weight of birth didn't correlate
      neither with the duration of delivery nor with the indication to perform a
      section. The 17 woman who had a baby after PAO didn't show a significant change
      of the radiological diameters of the pelvis: pelvic entrance (before PAO 15. 4
      cm, after PAO 15.7 cm), mid-pelvis (before PAO 11.8 cm, after PAO 11.8 cm) and
      pelvic outlet (before PAO 14.2 cm, after PAO 13.7 cm). We found that the PAO does
      not influence the anatomical diameters of the birth canal and therefore is not an
      indication for a section.

PMID- 10663249
TI  - [Initial stability of two PLIF-techniques. A biomechanical comparison using a
      finite element model].
AB  - The purpose of this study was to compare the initial stiffness of two techniques
      for posterior interbody lumbar fusion (PLIF) by a finite element approach. Thus a
      finite element model of a human L3/4 spinal segment was generated. Stiffness of
      the intact model was tested under compression (600 N), torsion (25 Nm) and
      shearing forces (250 N) without preload. The results were compared to the
      stiffness following simulation of PLIF with two BAK-Cages and PLIF with two Harms
      Cages and additional posterior screw-rod-osteosynthesis. PLIF with two BAK-Cages
      resulted in a loss of stiffness in compression, torsion and shearing. PLIF with
      two Harms-Cages and posterior osteosynthesis resulted in an increase of stiffness
      in compression, torsion and shearing.

PMID- 10663270
TI  - ARDS and PV curves: the inseparable duet?

PMID- 10663271
TI  - Stress doses of glucocorticoids in catecholamine dependency: a new therapy for a
      new syndrome?

PMID- 10663272
TI  - Where do all the children go?

PMID- 10663273
TI  - Critical incident reporting in intensive care.

PMID- 10663275
TI  - Setting safe and effective suction pressure: the effect of using a manometer in
      the suction circuit.
AB  - OBJECTIVES: To establish the levels of pressure used to perform tracheal suction
      (TS) and if they are affected by having a manometer visible in the suction
      circuit. DESIGN: A bench test evaluation of simulated tracheal suction. SETTING:
      Physiotherapy department of a major teaching hospital in Melbourne, Australia.
      PARTICIPANTS: Sixty-four nurses and physiotherapists who regularly apply TS to
      patients in the intensive care units of this hospital. INTERVENTIONS: All
      subjects used both circuit A (without a visible manometer) and B (with a visible
      manometer) in a predetermined random order. For both, subjects adjusted the
      suction control tap to where they said a safe and effective pressure (set
      pressure) was delivered and then occluded the suction catheter as though
      suctioning (applied pressure). Subjects then completed a questionnaire on their
      current TS practise. MEASUREMENTS AND RESULTS: All set pressures (mean = 228.57
      mmHg) and all applied pressures (mean = 359. 52 mmHg) were significantly higher
      (P <.001) when compared to the expected pressures (mean = 135 mmHg). Pressures
      set without a visible manometer (circuit A) were significantly higher (P <.05)
      than those using a visible manometer (circuit B) but the applied pressures were
      not significantly different (P =.166). Neither the investigator (P =.618) or the
      test order (P =.167) had a significant effect on the outcome. Questionnaire
      results showed 31 % of subjects considered 100-170 mmHg a safe and effective
      suction pressure whilst none reported using an objective means of measuring
      pressure. CONCLUSION: All pressures in both circuits were significantly higher
      than those recommended as safe in the literature. In addition, pressures were
      unaffected by the inclusion of a visible manometer in the suction circuit.

PMID- 10663274
TI  - Application of a computerised method to measure static pressure volume curve in
      acute respiratory distress syndrome.
AB  - OBJECTIVE: To assess the safety and the bedside feasibility of a new computerised
      method to record the static pressure-volume curves (Pst/V) of the respiratory
      system. DESIGN: The Pst/V curves were recorded in 13 medical patients with the
      acute respiratory distress syndrome (ARDS). During the Pst/V curve tracing the
      following parameters were recorded: time required for the recording and the
      automatic analysis of the Pst/V curve and modifications in electrocardiograms,
      blood pressure, and arterial oxygen saturation (SaO(2)). SETTING: The study was
      performed in the intensive care unit of the University of Naples "Federico II".
      RESULTS: No statistically significant modifications in heart rate (HR, b min(
      1)), blood pressure (BP, mmHg), and SaO(2) were observed between conditions at
      baseline (HR 97.2 +/- 17.7; BP 65.4 +/- 9.3; SaO(2) 93.6 +/- 2.0), during the
      recording (HR 99.8 +/- 19.5; BP 66.2 +/- 11.6; SaO(2) 93.7 +/- 2.4), and 2 min
      after the procedure (HR 98.2 +/- 17.8; BP 65.2 +/- 11.7; SaO(2) 93.7 +/- 1.9).
      The Pst/V curves were recorded in 8.38 +/- 1. 19 min and fully analysed in 2.69
      +/- 0.85 min. Mean value of static compliance was 41.1 +/- 12.7 ml cmH(2)O(-1). A
      lower inflection point was found in ten patients (mean value 9.2 +/- 1.9
      cmH(2)O). CONCLUSIONS: In ARDS patients, the present new computerised method gave
      valuable data to ordinary intensivists and was shown to be safe, easy, and fast.

PMID- 10663276
TI  - The diagnosis of ventilator-associated pneumonia using non-bronchoscopic, non
      directed lung lavages.
AB  - OBJECTIVES: (1)To assess the diagnostic utility of quantitative cultures of non
      bronchoscopic lung lavage (NBL) in ventilator-associated pneumonia and evaluate
      the role of the Bacterial Index; (2) To assess the predictive value of NBL
      surveillance quantitative cultures in ventilated patients; (3) To evaluate the
      Clinical Pulmonary Infection Score (CPIS) system in ventilated patients. DESIGN:
      A prospective comparison of NBL with bronchoscopic bronchoalveolar lavage and
      protected specimen brush. SETTING: Three intensive care units in academic
      tertiary care centres. PATIENTS: 145 adults ventilated for 72 h, with and without
      clinical signs of pneumonia. INTERVENTIONS: Sampling of lower airway secretions
      by NBL, bronchoalveolar lavage and protected specimen brush. MAIN OUTCOME
      MEASURES: Diagnostic reliability of quantitative cultures, Bacterial Index and
      CPIS. RESULTS: 34 episodes of clinical ventilator-associated pneumonia were
      documented in 32 patients. 9 episodes were confirmed by concordant blood/pleural
      culture or post-mortem lung examination. Qualitative concordance of the
      predominant pathogen between sequential NBL: bronchoalveolar lavage and protected
      specimen brush was 83 %. Sensitivity and specificity of non-directed bronchial
      lavage at a threshold of 10(4) CFU/ml were 68 % and 70 % respectively (p = 0.
      003) and were comparable with the bronchoscopic methods. However, the low
      positive predictive value of NBL indicates that quantitation in the absence of
      clinical signs is unlikely to be useful. Bacterial Index did not improve
      discriminatory power of quantitation compared with bacterial load of predominant
      organism. Mean CPIS for confirmed pneumonia cases was 8.4 +/- 1.01, significantly
      higher than for non-pneumonia observations (p = < 0.0001). CONCLUSION: NBL is a
      simple, safe, cheap, readily-available method of diagnosing ventilator-associated
      pneumonia with comparable diagnostic accuracy to bronchoscopic techniques.
      Quantitation of respiratory tract cultures can exclude pneumonia in patients with
      equivocal clinical signs. The diagnostic threshold should vary depending on the
      length of ventilation, likelihood of pneumonia and antibiotic administration. The
      Bacterial Index is a flawed mathematical device that has no contributory role in
      pneumonia diagnosis. The CPIS has some diagnostic role in selected cohorts of
      ventilated patients.

PMID- 10663277
TI  - Myocardial necrosis in ICU patients with acute non-cardiac disease: a prospective
      study.
AB  - OBJECTIVE: To ascertain if, after an episode of hypotension, unnoticed myocardial
      necrosis could occur in critical care patients with acute non-cardiac illness and
      to search for signs of cardiac necrosis. DESIGN: A prospective observational
      study. SETTING: General intensive care unit (ICU) at a tertiary level hospital.
      PATIENTS: Thirty-one patients in two groups. Group 1 included 19 patients with
      severe sepsis/septic shock (ACCP/SCCM Consensus Conference). Group 2 included 12
      patients with hypovolemic shock. INTERVENTIONS: Biochemical markers of myocardial
      necrosis (cardiac troponin I (cTnI), creatine kinase (CK), creatine kinase MB
      mass (CKMB) and myoglobin) were measured at 12 h (T1), 24 h (T2) and 48 h (T3)
      after enrollment. A standard 12-lead ECG was recorded upon enrollment (T0) and at
      T2. Anomalous Q-waves or ST segment depression or elevation was considered
      diagnostic for acute myocardial infarction (AMI). A hypotensive episode (arterial
      systolic pressure < 90 mmHg at heart rate > 100 bpm) was considered moderate if
      it lasted 30-60 min or severe if longer than 60 min. MEASUREMENTS AND RESULTS: At
      T0 none of the patients had AMI on ECG. At T2 a non-Q AMI developed in five
      patients. Increased levels of troponin I, myoglobin, CK and CKMB were found in
      74.2 %, 96.8 %, 74.2 % and 67.7 % of the patients, respectively. Cardiac troponin
      I increased in 11 out of 19 septic patients and in all hypovolemic patients.
      There was a significant difference between the groups (p < 0.05). All biochemical
      markers increased in relationship to the degree of hypotension with cTnI again
      showing a significant difference. The longer the hypotensive episode was, the
      greater was the increase (moderate hypotension: median 1.16; quartiles 0.55-3.44
      ng/ml, severe hypotension: median 8.53; quartiles 1.1-20.7 ng/ml; p < 0.05).
      Abnormal levels of cTnI were more frequent in non-survivors than in survivors (p
      < 0.05). CONCLUSIONS: Hypotension may cause cardiac damage in critically ill
      patients with acute non-cardiac diseases as shown by abnormal levels of cTnI. It
      is likely that a high number of these myocardial necroses may go unnoticed on the
      ECG.

PMID- 10663278
TI  - Out-of-hospital cardiac arrest increases soluble vascular endothelial adhesion
      molecules and neutrophil elastase associated with endothelial injury.
AB  - OBJECTIVES: To investigate the inflammatory responses in patients with out-of
      hospital cardiac arrest, we examined the changes in markers of endothelial
      activation, neutrophil activation, and endothelial injury. DESIGN: Prospective,
      cohort study. SETTING: General intensive care unit of a tertiary care center.
      PATIENTS AND PARTICIPANTS: Forty-four out-of-hospital cardiac arrest patients
      were classified into two groups, those who achieved return of spontaneous
      circulation (ROSC) (n = 23) and those without ROSC (n = 21). Eight normal healthy
      volunteers served as control subjects. MEASUREMENTS AND RESULTS: Serial levels of
      soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell
      adhesion molecule-1 (sVCAM-1), soluble E-selectin (sE-selectin) as markers of
      endothelial activation, neutrophil elastase as a marker of neutrophil activation,
      and soluble thrombomodulin as a marker of endothelial injury were measured during
      and after cardiopulmonary resuscitation (CPR). In patients with ROSC, cardiac
      arrest and CPR led to increases in the levels of three vascular endothelial
      adhesion molecules, neutrophil elastase, and soluble thrombomodulin that peaked 6
      h or 24 h after arrival at the emergency department. In patients without ROSC,
      only neutrophil elastase showed moderate elevation during CPR. We could not find
      significant differences in all measured parameters between the two groups.
      CONCLUSIONS: As evidence of inflammatory responses in whole-body ischemia and
      reperfusion, our study demonstrates neutrophil-endothelium interaction with signs
      of endothelial injury in patients with out-of-hospital cardiac arrest. These
      inflammatory changes may have an important role in post-resuscitation syndrome
      after human cardiac arrest.

PMID- 10663279
TI  - Ranitidine or dobutamine alone or combined has no effect on gastric intramucosal
      arterial PCO(2) difference after cardiac surgery.
AB  - OBJECTIVE: To test the hypothesis that ranitidine, either alone or in combination
      with dobutamine, modifies the gastric intramucosal-arterial PCO(2) difference.
      DESIGN: Full factorial design (double-blinded for ranitidine). SETTING: Intensive
      Care Unit of a university hospital. PATIENTS: Sixty-four haemodynamically stable
      coronary artery bypass surgery patients. INTERVENTIONS: Ranitidine (150 mg
      preoperatively per os and 50 mg intravenously postoperatively) and dobutamine (4
      micro g. kg(-1). min(-1) for 3 h postoperatively) were administered in four
      randomised groups of patients: preoperative and postoperative ranitidine, either
      alone (n = 15) or in combination with dobutamine (n = 17), dobutamine alone (n =
      15) or neither ranitidine nor dobutamine (n = 17). MEASUREMENTS AND RESULTS:
      Gastric intramucosal-arterial PCO(2) difference was measured during the first 5
      postoperative hours. No differences in the postoperative pattern of gastric
      intramucosal-arterial PCO(2) difference were found among the groups. CONCLUSIONS:
      Ranitidine and dobutamine have no effect on the gastric tonometry results on
      intramucosal-arterial PCO(2) difference after uncomplicated cardiac surgery.
      Hence, the routine use of H(2)-antagonists for gastrointestinal tonometry is not
      warranted. Our results must be limited to results obtained by tonometry; they do
      not allow any conclusions on the effects of these drugs on splanchnic blood flow
      or its distribution.

PMID- 10663280
TI  - Patients' preferences concerning medical information and surrogacy: results of a
      prospective study in a French emergency department.
AB  - OBJECTIVE: To study the wishes of a sample of French patients about medical
      information and surrogacy, at a time when the French Ministry of Health is
      supporting increased patient autonomy. DESIGN: A cohort of competent patients
      with non-critical illnesses or injuries completed an intention-to-act
      questionnaire on the amount of medical information they would want to receive
      should they be hospitalized or in a life-threatening situation. The percentage of
      patients who would want to have a surrogate if they were in a coma was
      determined, as well as the identity of the preferred surrogate. The subgroup of
      patients who were married or living with a partner was evaluated separately to
      determine how often the spouse/partner was the preferred surrogate. Associations
      were looked for between patients' wishes and age, sex, educational level,
      occupation, hierarchical order in the family, and level of confidence in
      medicine. SETTING: The emergency room of a teaching hospital in the Paris area
      (France). RESULTS: Of the 1089 patients included in the study, 5. 5 % reported
      that they would not want any information, 25.3 % that they would want to
      participate actively in all decisions about their care, and 87.3 % that they
      would want to be fully informed if they were in a life-threatening situation.
      Slightly less than one-third of the patients (29.6 %) believed they would not
      want a surrogate if they developed a coma. Among the patients living with a
      spouse/partner, 40.6 % (229/561) indicated they would want their spouse/partner
      to be their surrogate. A significant correlation was observed between wanting
      more information and wanting a surrogate. Younger patients with a higher
      educational level were significantly more likely to predict a desire for
      information and for a surrogate than the other patients. CONCLUSION: Our patients
      expressed a strong desire to receive extensive information should they become
      seriously ill, and two-thirds of them reported they would want a surrogate.
      However, only 40.6 % of the patients living with a spouse/partner would want
      their spouse/partner to be their surrogate. These data suggest that the time has
      probably come to propose a nation-wide public hearing on medical information and
      surrogacy in France.

PMID- 10663281
TI  - Tiss 76 and Tiss 28: correlation of two therapeutic activity indices on a Spanish
      multicenter ICU database.
AB  - OBJECTIVES: To evaluate the performance of the Simplified Therapeutic
      Intervention Scoring System (TISS 28) on an independent database and to determine
      its relation to the original Therapeutic Intervention Scoring System (TISS 76).
      DESIGN: Analysis of the database of the Spanish prospective multicenter study
      PAEEC (Project for the Epidemiological Analysis of Critical Care Patients).
      SETTING: 86 intensive care units (ICUs) in Spain. PATIENTS: Data on 8838 patients
      admitted to the ICUs. MEASUREMENTS AND RESULTS: Administrative data, main
      diagnostic category, severity score [Acute Physiology and Chronic Health
      Evaluation (APACHE) II and III] and data for the calculation of the TISS 76 and
      TISS 28 were collected during the first 24 h after the patient's ICU admission.
      TISS 76 and TISS 28 scores were calculated and analyzed on how they varied
      according to other variables (diagnostic group, severity level, hospital size and
      age). The association between TISS 76 and TISS 28 was studied. The TISS 76 score
      was 21 +/- 10.5 points and the TISS 28 score 23.3 +/- 8.8 points. There was a
      good correlation between TISS 76 and TISS 28 (r = 0.85). The regression equation
      was: TISS 28 = 8.35 + (0.712 x TISS 76). The TISS 28 score behaved similarly to
      the TISS 76 score in relation to the other variables, with a positive correlation
      between the therapeutic and the severity level (APACHE II and III) and a negative
      correlation between therapeutic activity and age, with very similar correlation
      coefficients. Both TISS 28 and TISS 76 scores were higher in larger hospitals.
      CONCLUSIONS: There is a strong correlation between TISS 28 and TISS 76 scores in
      the PAEEC database and TISS 28 works correctly in our setting.

PMID- 10663282
TI  - Study of paediatric intensive care units in Spain. Spanish Society of Paediatric
      Intensive Care.
AB  - OBJECTIVE: To describe the organisation of paediatric intensive care units in
      Spain and the medical assistance provided during 1996. METHODS: A written
      questionnaire was sent to all the paediatric ICUs linked to or within the Spanish
      public health system. RESULTS: Thirty-one of the 34 paediatric ICUs replied. All
      are medico-surgical units. Eighteen treat only paediatric patients, 12 paediatric
      and neonatal patients, and one paediatric and adult patients. Fifteen units have
      fewer than seven beds, eight have between 7 and 12 beds, and eight between 13 and
      18 beds. Of the paediatric ICUs, 83.8 % are staffed by paediatricians specialised
      in paediatric intensive care. The mean number of on-call on site periods of duty
      for each member of the medical staff was 5.1 +/- 1.7 per month. Thirty of the 31
      units undertake paediatric resident training, 13 train residents specialising in
      paediatric intensive care and 12 participate in medical student training. In 1996
      there were 9,585 admissions (309 +/- 182 patients per ICU) signifying 35.3 +/- 14
      patients/bed. Of the patients, 65.9 % were medical and 34.1 % surgical. The mean
      duration of stay was 5.6 +/- 2.1 days. The mortality rate was 5.4 +/- 3.2 %. The
      main causes of death were multiple organ failure and brain death. CONCLUSIONS: In
      Spain, paediatric intensive care is principally performed by specialised
      paediatricians. Although the general results for 1996 are similar to those of
      other European countries, efficiency studies are necessary to plan and re
      organise the paediatric intensive care units in Spain.

PMID- 10663283
TI  - Comprehensive critical incident monitoring in a neonatal-pediatric intensive care
      unit: experience with the system approach.
AB  - OBJECTIVE: To examine the occurrence of critical incidents (CIs) in order to
      improve quality of care. DESIGN: Prospective survey. SETTING: Multidisciplinary,
      neonatal-pediatric intensive care unit (ICU) of a non-university, teaching
      children's hospital. PATIENTS: Four hundred and sixty-seven admissions over a 1
      year period. METHODS: A CI is any event which could have reduced, or did reduce,
      the safety margin for the patient. Comprehensive, anonymous, non-punitive CI
      monitoring was undertaken. CI severity with respect to actual patient harm was
      graded: major (score 3), moderate (2) or minor (1). The system approach
      incorporates the philosophy that errors are evidence of deficiencies in systems,
      not in people. We undertook 2-monthly analyses of CIs. RESULTS: There were 211 CI
      reports: 30 % major, 25 % moderate, 45 % minor. The CI categories were
      management/environment 29 %, drugs 29 %, procedures 18 %, respiration 14 %,
      equipment dysfunction 7 %, nosocomial infections 3 %. The respiratory CIs were
      the most severe, the drug-related CIs the least severe (score mean, SD: 2.9, 0.26
      vs 1.4, 0.76; p < 0.001). However, 20 out of 62 drug-related CIs were potentially
      life-threatening. Thirteen percent of drug CIs were decimal point errors. Eleven
      of the 29 respiratory CIs were accidental extubations (2.6/100 ventilator days).
      CIs were most often precipitated by consultants (32 %), followed by residents (23
      %, over-represented in drug CIs, 22/62) and specialized nurses (21 %). Doctors
      had a greater proportion of major CIs than nurses (p < 0.01). Fifty percent of
      the CIs were detected by routine checks. The most important method of detection
      was patient inspection (44 %), alarms accounted for only 10 %. Contributing
      factors were human errors (63 %), communication failure (14 %), organizational
      problems (10 %), equipment dysfunction (7 %) and milieu (3 %). CONCLUSIONS: CIs
      are very common in pediatric intensive care. Knowledge of them is a precious
      source for quality improvement through changes in the system.

PMID- 10663284
TI  - Markers of tissue hypoperfusion in pediatric septic shock.
AB  - OBJECTIVE: To describe measurements of global oxygenation parameters, markers of
      splanchnic hypoperfusion and those of metabolic activity related to cellular
      energy production among critically ill children with septic shock. DESIGN:
      Clinical study of a series of cases. PATIENTS AND PARTICIPANTS: 11 previously
      healthy children with septic shock admitted to the pediatric intensive care unit
      (ICU) of a university hospital. INTERVENTIONS: None. MEASUREMENTS AND RESULTS:
      Oxygen consumption, oxygen delivery (DO(2)), serum bicarbonate, arterial pH,
      gastric intramucosal pH (pHi), gastroarterial carbon dioxide tension gradient,
      serum lactate, pyruvate, lactate to pyruvate ratio (L/P), ketone body ratio, and
      the esterified to free carnitine ratio were measured serially at 0, 6, 12, 24,
      36, and 48 h after admission to the pediatric ICU. All children survived. One
      patient failed to show supranormal DO(2) ( > 570 ml/min per m(2)). Normalization
      of serum bicarbonate and lactate were associated with patient recovery. One
      patient presented an increasingly abnormal L/P ratio with normal lactate levels,
      suggesting an increased utilization of pyruvate rather than an increased
      cytosolic redox potential. Although values of gastric pHi < 7.30 were observed in
      43 % of samples, serial measurements in individuals showed significant
      variability and unpredictable trends. Free fatty acid concentrations, ketone body
      production, and carnitine levels remained within the normal range. CONCLUSIONS:
      In this study, trends in serum bicarbonate and lactate somewhat characterized the
      recovery of children with septic shock. Based on our data, it is unclear how
      other markers may have been used to modify therapy.

PMID- 10663285
TI  - Comparison of noise levels caused by four different neonatal high-frequency
      ventilators.
AB  - OBJECTIVE: To test the hypothesis that neonatal high-frequency ventilators create
      different noise levels depending upon ventilator settings and device-specific
      properties. MATERIALS: Three neonatal ventilators with built-in high-frequency
      options (Babylog 8000, Infant Star, Stephanie) and an exclusive high-frequency
      oscillator (SensorMedics 3100A). MEASUREMENTS: Noise levels were recorded by a
      microphone and measured by a decibel recording device at a defined distance from
      a test lung. RESULTS: Noise levels were highest for the SensorMedics and the
      Babylog (70 dB and 62 dB, respectively). Whereas the SensorMedics increased noise
      production with amplitude, the Babylog remained at a constant level. The Infant
      Star (52 dB) and the Stephanie (54 dB) were significantly less noisy at their
      maximum levels of amplitude (40 mbar and 50 mbar, respectively). CONCLUSION: Most
      levels recorded were below those measured within an incubator without the use of
      a ventilator. We conclude that neonatal high-frequency ventilators do not
      represent a major contribution to noise levels for newborns in neonatal intensive
      care units (NICUs).

PMID- 10663286
TI  - Severe infantile hypothermia: short- and long-term outcome.
AB  - OBJECTIVE: To determine short- and long-term outcomes of infants with severe
      hypothermia (< or = 28 degrees C) treated in a pediatric intensive care unit
      (PICU). DESIGN: (1) Retrospective evaluation of medical records of all patients
      admitted for severe infantile hypothermia from 1984 to 1993. (2) Medical and
      developmental evaluations of survivors of severe infantile hypothermia 3-12 years
      after hospital discharge. SETTING: Six-bed PICU of a university teaching
      hospital. PATIENTS: Eighteen infants who arrived at the emergency room with a
      rectal temperature between 20 and 28 degrees C. MEASUREMENTS AND RESULTS: The
      ages of patients ranged between 5 and 30 days. Fifteen were Bedouins and three
      were Jews. Clinical features included sepsis in 9 (septic shock in 5 of 9)
      patients, respiratory failure in 11 and overt bleeding in 5. Rewarming was
      applied using rapid external warming under a radiant heater. Five infants died
      shortly after arrival and one patient at age 6 years; all of them had sepsis on
      arrival. Of the 12 survivors examined at ages 3-12 years, ten had normal
      psychomotor achievements, while the remaining two had mild (1 patient) and severe
      (1 patient) psychomotor retardation. Both of the latter two had sepsis on first
      admission for hypothermia. All nine hypothermic infants, who had no sepsis, had
      normal medical examinations and normal developmental achievements for their ages.
      CONCLUSION: Severe infantile hypothermia is a serious condition. When treating
      patients in a modern PICU, morbidity and mortality are mainly related to the
      presence or absence of an associated septicemia. Infants without septicemia may
      have normal growth and development.

PMID- 10663287
TI  - Negative pressure ventilation as haemodynamic rescue following surgery for
      congenital heart disease.
AB  - A low cardiac output state is an important cause of morbidity and mortality
      following repair of tetralogy of Fallot (ToF). This is often refractory to
      conventional measures. The cardiac output of these patients is highly dependent
      on diastolic pulmonary arterial flow which is enhanced during spontaneous
      respiration, but much reduced by intermittent positive pressure ventilation
      (IPPV). We report the successful use of negative pressure ventilation (NPV) as
      haemodynamic therapy in three children with a low output secondary to restrictive
      right ventricular (RV) physiology following ToF repair. NPV produced a
      significant haemodynamic improvement, with increases in cardiac output of greater
      than 100 % in two of the children. By augmenting pulmonary blood flow, and hence
      cardiac output, NPV has a role as adjunctive haemodynamic therapy in patients
      with a low output secondary to diastolic RV dysfunction, in whom early extubation
      is not possible.

PMID- 10663288
TI  - Hereditary surfactant protein B deficiency resulting from a novel mutation.
AB  - Hereditary surfactant protein B (SP-B) deficiency is an autosomal recessive
      disease in which affected infants are unable to produce normally functional
      surfactant, resulting in neonatal respiratory failure and death within the first
      year of life. The most common cause of SP-B deficiency is a frameshift mutation
      in exon 4 (121ins2) of the SP-B gene. We report a newborn infant who had onset of
      respiratory distress during the first days, was unresponsive to exogenous
      surfactant, corticosteroids, prostacyclin, high frequency oscillatory ventilation
      and inhaled nitric oxide, and died after 27 days. Immunostaining of lung tissue
      obtained at biopsy demonstrated absent staining for SP-B, and robust
      extracellular staining for proSP-C, findings characteristic for SP-B deficiency.
      DNA analysis revealed the 121ins2 mutation on one of her SP-B alleles and a novel
      mutation, 122delC, on her other SP-B allele. The proximity of the novel mutation
      in exon 4 allele found in this infant to the 121ins2 supports the notion that
      this region may represent a "hot spot" for SP-B gene mutations and confirms the
      heterogeneity of mechanisms which lead to SP-B deficiency. Hereditary SP-B
      deficiency is a rare, newly diagnosable and probably under-recognized disease,
      which should be suspected in term newborn infants with unexplained respiratory
      failure.

PMID- 10663289
TI  - Acute hemodynamic effects of post cardiotomy peritoneal dialysis in neonates and
      infants.
AB  - OBJECTIVE: Evaluation of the acute hemodynamic changes during peritoneal dialysis
      in patients with low cardiac output syndrome and acute renal failure after open
      heart surgery. PATIENTS: Three newborns and three infants after corrective
      surgery of congenital heart disease with post cardiotomy dialysis. Five of these
      had an open thorax during dialysis. METHODS: Cardiac output measurements using
      the thermodilution technique on two consecutive days at four different times
      during the peritoneal dialysis cycle. RESULTS: We did not find a deterioration of
      the cardiac index or systemic vascular resistance measured over two cycles in
      each of the six patients. Pulmonary artery pressure rose slightly after
      instillation of the dialysate solution in all patients. Changes in central venous
      pressure and left atrial pressure were not clinically meaningful. In all patients
      fluid removal by peritoneal dialysis was effective. All five surviving patients
      recovered renal function. CONCLUSIONS: Peritoneal dialysis can be performed in
      newborns and infants following cardiac surgery without causing acute hemodynamic
      imbalances. An open chest may have a significant impact on hemodynamic stability
      during peritoneal dialysis by blunting any possible negative alterations of
      increased intraabdominal pressure.

PMID- 10663290
TI  - Adrenal crisis presenting as hypoglycemic coma.
AB  - An 18-month-old male infant presented with hypoglycemic coma and clinical signs
      of bronchopneumonia. He was suspected of suffering from septic shock. The patient
      progressed to irreversible multiple organ failure before the diagnosis of adrenal
      crisis was established. Plasma levels of ACTH and cortisol remained undetectable.
      Renin and aldosterone were normal. An autopsy failed to demonstrate any adrenal
      gland cortical tissue. Immunohistochemical staining demonstrated the presence of
      all pituitary hormones except ACTH, establishing the diagnosis of isolated ACTH
      deficiency. Intensive care clinicians should consider adrenal crisis in non
      diabetic children with hypoglycemia and rapid circulatory deterioration.

PMID- 10663291
TI  - Partial liquid ventilation with surfactant: effects on gas exchange and lung
      pathology in surfactant-depleted piglets.
AB  - OBJECTIVE: To evaluate the effects of 24 h partial liquid ventilation (PLV) with
      and without surfactant (S) treatment on gas exchange and lung injury in a newborn
      animal model of S deficiency. DESIGN: A prospective, controlled, in vivo animal
      laboratory study. SETTING: Research laboratory in a university setting. SUBJECTS:
      Twenty-four pathogen-free, male piglets (mean weight 1.9 kg, age 1-3 days).
      INTERVENTIONS: The animals were randomised in four groups: PLV with FC-77
      combined with conventional ventilation (PLV/CV) versus S + PLV/CV and PLV
      combined with high frequency oscillatory ventilation (PLV/HFOV) versus S +
      PLV/HFOV. The piglets were anaesthetised, intubated and instrumented with
      vascular catheters. Thirty minutes after lung injury had been induced with
      repeated saline lavage, S animals received natural S. Thirty minutes after
      surfactant substitution PLV with FC-77 was started. The oxygenation index (OI),
      PaO(2)/FIO(2) ratio, PaCO(2) and the ventilatory efficacy index were determined
      before and during PLV. After 24 h the lungs were removed for histopathological
      examination. MEASUREMENTS AND MAIN RESULTS: Within 60 min after the initiation of
      PLV, all animals demonstrated improvements of the OI and PaO(2)/FIO(2) ratio
      compared to the values after lung injury. However, at 18 and 24 h of PLV, the OI
      and PaO(2)/FIO(2) ratio were significantly worse in the S + PLV/CV and S +
      PLV/HFOV groups compared to the groups without S. PaCO(2) was higher at 18 and 24
      h when S was used in PLV/HFOV (p < 0.05). A semi-quantitative lung injury score
      revealed most severe lung damage in the S + PLV/HFOV group. CONCLUSIONS++: The
      combination of S and PLV with FC-77 led to an impaired gas exchange and did not
      further protect the animal from lung injury.

PMID- 10663292
TI  - S-Methylisothiourea sulfate improves renal, but not hepatic dysfunction in canine
      endotoxic shock model.
AB  - OBJECTIVE: Excess production of nitric oxide (NO) by inducible NO synthase (iNOS)
      has been implicated in the pathophysiology of septic shock. This study was
      designed to see whether S-methylisothiourea sulfate (SMT), a selective inhibitor
      for iNOS, prevents cardiovascular changes and multiple organ damage in the canine
      endotoxic shock model. DESIGN: Prospective, comparable, experimental study.
      SETTING: Laboratory at a university hospital. SUBJECTS: Twenty male mongrel dogs
      were studied under pentobarbital anesthesia. INTERVENTIONS: Dogs were divided
      into three groups: bacterial lipopolysaccharide (LPS) group (n = 7) receiving
      continuous infusion of LPS (2 mg/kg/h for 1 h); LPS plus SMT group (n = 7)
      receiving LPS and SMT (1 mg/kg, bolus i. v., followed by continuous infusion of 1
      mg/kg/h for 1 h); and vehicle plus SMT group (n = 6). MEASUREMENTS AND RESULTS:
      Hemodynamics, blood gas parameters, and urine output were measured during 6 h
      observation periods. Serum levels of lactate, transaminases, and bilirubin were
      measured at baseline, 1 and 6 h. Creatinine and free water clearance, urine
      sodium excretion and fractional excretion of sodium were calculated. LPS caused a
      profound hypotension associated with decreases in cardiac output and oxygen
      delivery, lactic acidosis, renal and liver dysfunction, and thrombocytopenia. SMT
      prevented the LPS-induced hypotension and renal dysfunction, whereas it did not
      affect the LPS-induced decreases in cardiac output or oxygen delivery,
      hyperlactatemia, liver dysfunction, or thrombocytopenia. SMT alone had no
      appreciable effects on hemodynamics, blood gases, liver or renal functions.
      CONCLUSIONS: These findings show that SMT improves renal, but not hepatic
      dysfunction, in dogs with endotoxic shock, suggesting that iNOS-derived NO plays
      differential roles in sepsis-associated multiple organ dysfunction.

PMID- 10663293
TI  - Catecholamine dependency in a polytrauma patient: relative adrenal insufficiency?
AB  - A 65-year-old polytrauma patient was admitted post-operatively to the intensive
      care unit. His situation deteriorated with hemodynamic instability and continuous
      high fever. An infectious focus could not be found and repeated cultures remained
      negative. Empirical administration of antibiotics and changing of lines did not
      have any effect on the clinical picture. It was impossible to lower the dose of
      catecholamines because of repeated occurrence of hypotension, despite optimal
      hydration state and filling pressures. On the 15th day of admission intravenous
      hydrocortisone was started on suspicion of relative adrenal insufficiency. This
      action resulted in rapid hemodynamic recovery, disappearance of fever and enabled
      rapid tapering of the dose of noradrenaline. Incidence of relative adrenal
      insufficiency and diagnostic strategies are discussed in the population of
      critically intensive care patients.

PMID- 10663294
TI  - An uncommon cause of lower limb weakness.
AB  - We describe a case of a severely mentally disabled patient diagnosed as suffering
      from Guillain-Barre syndrome and treated with repeated plasma exchange. However,
      the abrupt onset of a cardiovascular collapse prompted a more in-depth diagnostic
      workup which demonstrated that the neurologic symptoms were likely to be ascribed
      to poisoning with heavy metals from a large number of ingested coins and other
      metallic items.

PMID- 10663295
TI  - Infection control in the ICU.

PMID- 10663296
TI  - Biological effects of hypercapnia.

PMID- 10663297
TI  - Nursing research in intensive care medicine Euroconference: lobby tool for
      research.

PMID- 10663298
TI  - Hyperdynamic shock in falciparum malaria.

PMID- 10663299
TI  - Pseudomembraneous Aspergillus fumigatus tracheobronchitis causing life
      threatening tracheobronchial obstruction in a mechanically ventilated patient.

PMID- 10663300
TI  - Preliminary data: PIM vs PRISM in infants and children post cardiac surgery in a
      UK PICU.

PMID- 10663301
TI  - Use of dipyridamole for pulmonary hypertension following repair of total
      anomalous pulmonary venous drainage.

PMID- 10663302
TI  - Hypercapnia due to a heat and moisture exchanger.

PMID- 10663303
TI  - Acute hypoxaemic respiratory failure in children.

PMID- 10663304
TI  - Reply

PMID- 10663305
TI  - Announcements

PMID- 10663307
TI  - ESOT - Novartis Study Grant: Call for Applications and Guidelines.

PMID- 10663311
TI  - Critique of editorial philosophy.

PMID- 10663313
TI  - comment

PMID- 10663312
TI  - Long-term results of meniscus repair and meniscectomy: a 13-year functional and
      radiographic follow-up study.
AB  - This study investigated the long-term outcome of common meniscus treatment
      (meniscectomy, repair). A consecutive series of 30 patients with open meniscus
      repair were compared retrospectively to 30 patients who had an arthroscopic
      partial or subtotal meniscectomy. The groups were matched according to sex, age,
      meniscus lesion, and follow-up time. The patients were aged 13-43 years at the
      time of operation; all had intact cruciate ligaments, and none had had previous
      surgery on the knee. Patients were reexamined at a mean of 13 years after the
      operation. In addition, for a subgroup of 22 matched pairs, data were available
      from a 7-year follow-up. Four of the repaired menisci did not heal, and another
      three reruptured during the 13-year follow-up; these menisci were all excised
      (23%). Meniscal remnant surgery was needed in 6 cases (20%) after initial
      meniscectomy. At the 13-year follow-up there was no difference between the groups
      in knee function, subjective complaints, or manual findings. Almost 90% of the
      patients in both groups had no knee problems during daily activities. At the late
      follow-up radiographic signs for bone spurs, sclerosis, or flattening of the
      femoral condyle were found in around half of the cases in each group. Three
      patients (10%) with initial repair and 8 (27%) with meniscectomy had minor joint
      space reduction, but no patient had more severe radiographic changes. After 7
      years (subgroup) joint space reduction was more common after initial meniscectomy
      than after repair (P < 0.05). After 13 years the incidence and severity of
      arthrosis did not differ significantly between the two groups, even when only the
      successful repairs were compared to meniscectomy (P = 0.06).

PMID- 10663314
TI  - Biomechanical analysis of knee hyperextension and of the impingement of the
      anterior cruciate ligament: a cinematographic MRI study with impact on tibial
      tunnel positioning in anterior cruciate ligament reconstruction.
AB  - This study analyzed the interaction between the anterior cruciate ligament (ACL)
      and the intercondylar notch roof (INR) in hyperextension of the knee using
      magnetic resonance cinematography. Cinematographic image series of 15 knees were
      investigated. Two independent observers identified the image that displayed the
      beginning of contact between the ACL and the INR. They determined knee extension
      on this image and on the image that displayed maximum hyperextension of the knee.
      Correlations between a variable representing impingement and the inclination
      angle of the INR, the anterior laxity of the knee, and full hyperextension were
      examined. Theoretical, impingement-free tibial tunnel positions for the knees
      were calculated as a percentage of the anteroposterior tibial width. All ACLs of
      the knees in this study made contact with the INR. The average extension angle at
      the beginning of impingement was -6.3 +/- 3.8 degrees. There were significant
      correlations between impingement and maximum manual displacement as measured with
      the arthrometer (r = 0.77; P < 0.001), maximum hyperextension (r = 0. 67; P =
      0.007), and notch roof angle (r = -0.73; P = 0.002). There were biomechanically
      acceptable tunnel positions for all knees but one. Hyperextension is
      physiologically associated with impingement of the ACL. In uninjured knees there
      was a correlation between ACL impingement and hyperextension, inclination of the
      INR, and maximum manual displacement of the tibia. Impingement free tibial tunnel
      positioning is possible in most knees without notchplasty.

PMID- 10663315
TI  - The Gore-Tex prosthetic ligament as a salvage procedure in deficient knees.
AB  - The purpose of this study was to evaluate the results of prosthetic ligament
      replacement of the anterior cruciate ligament (ACL) or posterior cruciate
      ligament (PCL) with the Gore-Tex polytetrafluorethyene prosthesis (W.L. Gore and
      Co., Flagstaff, Ariz. ) in 52 patients (54 knees). All patients sustained
      multiple (failed) knee operations or had knees with gross instability. Twenty
      eight (29 knees) of the 52 patients (54%) in whom the Goretex prosthesis was
      still in situ were available at a minimum follow-up of 5 years (mean 9 years,
      range 5-11 years). The mean age at examination was 39 years (range 30-57 years);
      there were 15 men and 13 women. The results of the procedure were compared with
      the results of the same patients at a mean follow-up of 3 years. Eighty-one
      percent of the patients of the whole group complained about pain. This was 78%
      for the patients with an ACL reconstruction and 75% for the patients with a PCL
      reconstruction. The Tegner activity score and the Lysholm knee score showed a
      statistically significant difference over time. The anterior instability pattern
      improved in only 43% of the knees and the posterior instability in 41% of the
      knees. The Lachman test showed also a significant difference over time. In all
      patients X-ray showed an increase in degenerative changes. In conclusion, the
      PTFE prosthetic ligament in the reconstruction of the ACL and the PCL in the
      (chronically) unstable knee seems to deteriorate over time.

PMID- 10663316
TI  - Insertion of autologous tendon grafts to the bone: a histological and
      immunohistochemical study of hamstring and patellar tendon grafts.
AB  - This study examined the structure of the insertion of autologous tendon grafts
      used for anterior cruciate ligament reconstruction. Biopsy specimens of the
      femoral paragraph signand tibial bone graft interface were obtained at revision
      surgery in 14 patients (6 with hamstring grafts, 8 with a patella tendon graft).
      The specimens were analyzed by light microscopy and immunohistochemistry
      (confirming type I, type II, and type III collagen). The insertions of hamstring
      autografts to the bone tunnel have three characteristic histological zones. Zone
      1 is composed of the dense connective tissue of the graft. The collagen fibers of
      the graft enter the bone under oblique angles. Zone 2 is composed of woven bone
      with a sharp transition to the lamellar bone of the tibia (zone 3).
      Immunohistochemistry revealed the presence of type I and type III collagen within
      the dense connective tissue of the graft. The woven and lamellar bone showed
      positive immunostaining for antibodies against type I collagen only. This
      structure resembled a fibrous ligament or tendon insertion. In the majority of
      patients with a patella tendon graft the structure of the insertion resembled a
      chondral enthesis. The chondral insertion of the graft to the bone is composed of
      four characteristic zones. Between the dense connective tissue of the graft (zone
      1) and bone (zone 4) there is a zone of fibrocartilage (zone 2). Close to the
      bone the fibrocartilage is mineralized (zone 3). Within the fibrocartilage the
      immunohistochemical analysis confirmed type II collagen. This structure resembled
      the chondral enthesis of the normal anterior cruciate ligament. However, in cases
      in which the distal bone bloc has been fixated outside the tibial tunnel, the
      tibial insertion of the patellar tendon graft resembled a fibrous insertion.
      While both types of tendon grafts heal to the bone of femur and tibia, the
      insertion of patella tendon grafts healing by bone plug incorporation resembles
      the chondral insertion of the normal anterior cruciate ligament and may have a
      more physiological connection to the bone than hamstring grafts.

PMID- 10663317
TI  - Behavior of the graft within the bone tunnels following anterior cruciate
      ligament reconstruction, studied by cinematic magnetic resonance imaging.
AB  - The behavior of a ligament graft following cruciate ligament reconstruction is
      still an area of limited knowledge. Cinematic magnetic resonance imaging (MRI)
      offers the possibility of visualizing the graft, including the graft tunnels and
      fixation during knee motion. Twenty-three patients underwent cinematic MRI (0. 2
      T; Artoscan) mean 23.4 months (range 14-39 months) after autologous anterior
      cruciate ligament reconstruction (eight bone-tendon-bone, seven semitendinosus
      gracilis, and eight iliotibial band). The images were read without knowledge of
      the clinical condition or the type of surgery performed. Signal intensity and
      continuity of the anterior cruciate ligament reconstruction and movement of the
      graft in the tibial or femoral tunnel anteriorly and posteriorly were noted. In
      two of the 23 patients the graft (semitendinosus-gracilis) moved in the tibial
      canal. The initial 9-mm tunnel had expanded by 2 mm in the anteroposterior
      direction at the entrance to the joint space. Only these two had a slight knee
      laxity, with a side-to-side difference in anterior translation measured by the KT
      2000 of 4 and 5 mm. No movement was observed in any of the femoral tunnels.
      Cinematic MRI thus makes it possible to study graft behavior within the bone
      tunnels.

PMID- 10663318
TI  - The rolimeter: a new arthrometer compared with the KT-1000.
AB  - A new simple and portable arthrometer, the Rolimeter, was used to assess the
      anterior laxity of knees in 20 normal subjects and 18 subjects with chronic
      anterior cruciate ligament (ACL) deficiency. The subjects were tested by one
      examiner using maximum manual force. In order to assess the reliability of the
      device the same subjects were tested with the KT-1000. In ACL-deficient knees the
      absolute translation and the side-to-side difference did not differ significantly
      between the devices. In normal knees the Rolimeter measured slightly smaller
      translations than the KT, but with a high degree of correlation between devices.
      If a 3-mm or greater side-to-side difference is considered indicative of ACL
      deficiency, both arthrometers were successful in diagnosing 16 of 18 cruciate
      ruptures (sensitivity 89%) and 19 of 20 normal knees (specificity 95%). We
      conclude that the Rolimeter, when compared with the KT-1000, provides a valid
      measure of anterior knee laxity.

PMID- 10663319
TI  - Measurement of coronal plane patellar mobility in normal subjects.
AB  - This study evaluated an instrument for measuring patellar mobility in the coronal
      plane in normal subjects, established baseline quantitative data and compared
      with methods of measurement described in the literature. This data can be used as
      a baseline for clinical assessment of patellar mobility. The findings suggest
      that 8-20 mm displacement is normal patellar mobility in the coronal plane.
      Displacement less than 8 mm may be considered as retinacular tightness and
      displacement greater than 20 mm considered as abnormal retinacular laxity.

PMID- 10663320
TI  - Biofix resorbable meniscus arrow for meniscal ruptures: results of a 1-year
      follow-up.
AB  - Modern individuals with a long and healthy life expectancy perform more and more
      physical activities both in daily life and in sport. This demanding life-style
      forces the surgeon to perform less radical surgery for meniscal ruptures, thus
      avoiding the early degenerative changes which frequently occur in totally or
      partially meniscectomized knees. When repair is possible, meniscal suture must be
      considered. Various arthroscopic techniques of meniscus suturing have been
      reported. "Inside-out," "outside-in," and more recently "all-inside" techniques
      can be used. Complications include saphenous and peroneal nerve damage and
      vascular lesions. The Biofix arrow fixation technique, which is an all-inside
      procedure, is easier and in our hands less time-consuming than other arthroscopic
      suturing techniques. Postoperatively, partial weight bearing is prescribed for 3
      weeks. Progressive return to sport activity is allowed after 3 months. Twenty
      five patients (26 meniscal repairs) with a mean age of 31.6 years (13-57) were
      reviewed. Follow-up averaged 16.7 months (12-22). The evaluation was based on the
      modified Marshall knee score. Three patients had an extra-articular
      reconstruction for anterior cruciate ligament deficiency, and five had an
      arthroscopic ACL reconstruction with a ligament allograft. The results were
      excellent or good in 22 patients (88% "satisfactory" outcome). Three patients had
      poor results. One patient with a new trauma presented a lateral meniscal lesion
      associated with an ACL rupture. The Biofix arrow fixation technique allows safe
      fixation of meniscal ruptures, specifically of posterior horn lesions where
      injury of neurovascular structures is not uncommon.

PMID- 10663321
TI  - False aneurysm of the popliteal artery: a rare complication of total knee
      replacement.
AB  - We describe a 72-year-old woman with a false aneurysm of the mid-popliteal artery
      after a total knee replacement, presenting with a pulsatile swelling and an
      audible bruit in the popliteal fossa. The diagnosis was confirmed by duplex
      ultrasound. Surgical repair was undertaken using a saphenous vein patch to
      reconstruct the arterial defect. A false aneurysm of the popliteal artery
      following total knee replacement is an extremely rare occurrence. To our
      knowledge, only four other cases have been reported in the English-language
      literature.

PMID- 10663322
TI  - Arthroscopic lavage speeds reduction in effusion in the glenohumeral joint after
      primary anterior shoulder dislocation: a controlled randomized ultrasound study.
AB  - Recent studies have shown that arthroscopic lavage of the glenohumeral joint
      within 10 days following a primary anterior dislocation significantly lowers the
      recurrence rate when compared with a nonoperative regime. We hypothesize that the
      lavage reduces distension in the joint and thereby facilitates adaptation and
      healing of the soft tissue lesion. Using ultrasound, we assessed the hemarthrosis
      in the glenohumeral joint weekly in 16 consecutive patients after traumatic
      primary anterior shoulder dislocation. The patients were randomized into two
      groups for treatment with either arthroscopic lavage or a nonoperative regime.
      Except for the lavage the two groups followed an identical rehabilitation
      program. Transversal dorsal ultrasound of the glenohumeral joint was performed,
      in which the joint effusion was assessed as the distance between the humeral head
      and the glenoid. Prior to the lavage the two groups had a similar amount of
      excessive joint effusion. The effusion declined to a steady state level within 3
      7 weeks. The joint effusion decreased more rapidly (33%) in the group treated
      with arthroscopic lavage (P = 0.02) than in the nonoperated group.

PMID- 10663323
TI  - Immunolocalization of types I, II, and X collagen in the tibial insertion sites
      of the medial meniscus.
AB  - The medial meniscus of the rabbit knee joint attaches to the tibial plateau via
      anterior and posterior insertions. Intact meniscal tibial insertions are
      essential for meniscal function. In the present study the distributions of types
      I, II, and X collagen in meniscal tibial insertions were investigated by indirect
      immunohistochemistry in a rabbit model. Four tissue zones were histologically
      identified in the anterior insertion site, including the ligamentous zone,
      uncalcified and calcified fibrocartilaginous zones and bone; the ligamentous zone
      was not observed in the posterior insertion site. Labeling for type I collagen
      was found to be strong in the ligament tissue and bone, and weak in the
      fibrocartilages which were also labeled for type II collagen. Tissues positive
      for different types of collagen overlapped and formed an irregular interface with
      various angles and depths, especially at the interface between the calcified
      fibrocartilage and bone. Positive labeling for type X collagen was identified
      only in the calcified fibrocartilage zone. The coexistence of types I and II
      collagen in the meniscal tibial insertions may indicate that this structural unit
      is subjected to both compressive and tensile loads. Type X collagen may play a
      role in maintaining the calcifying status of this tissue zone, so that its
      mechanical stiffness is kept between that of uncalcified fibrocartilage and hard
      bone. Restoration of the insertional structure including the distinct collagen
      distribution should be considered for a functional meniscal substitution.

PMID- 10663324
TI  - Changes

PMID- 10663325
TI  - A global strategy for radiotherapy: a WHO consultation.

PMID- 10663326
TI  - Interstitial iridium-192 implantation for recurrent and/or locally advanced head
      and neck cancer.
AB  - We report our experience with the use of interstitial iridium-192 implantation in
      the management of patients with recurrent and locally advanced squamous cell
      carcinoma of the head and neck. Between June 1992 and July 1998 this technique
      was employed in the management of two groups of patients: (1) a primary group,
      comprising 42 patients who had presented for the first time with advanced head
      and neck disease, and had therefore not undergone any previous treatment; and (2)
      a salvage group of 16 patients with recurrent disease previously treated with
      external beam radiotherapy (four received therapy to the neck, one to the cheek,
      eight to the tongue and three to the floor of the mouth). The follow-up in each
      group was short, ranging from 3 to 56 months. The overall response in the primary
      group was 38/42 (90%). A complete response was achieved in 35/42 (83%). In the
      salvage group, the overall response was 13/16 (81%); 4/16 (25%) showed a complete
      response and 9/16 (56%) a partial response. The estimated percentage surviving at
      1 year for patients with primary disease is 70% (95% confidence interval (CI) 54
      86). For those receiving salvage therapy the estimated percentage surviving at 1
      year is 45% (95% CI 19-71).

PMID- 10663327
TI  - Primary nasal and nasopharyngeal lymphomas: a comparative study of clinical
      presentation and treatment outcome.
AB  - Primary nasal lymphoma (NSL) and nasopharyngeal lymphoma (NPL) are uncommon
      extranodal lymphomas that have often been grouped together in studies published
      in the literature. It is unclear whether or not NSL and NPL are biologically
      different entities. We reviewed the records of 25 NSL and 19 NPL patients who
      were managed between 1985 and 1995, to evaluate and compare their clinical
      characteristics and treatment outcome. Clinical variables, including age, sex,
      stage, tumour bulk and treatment modality, were assessed for their prognostic
      influence on survival. Nasal obstruction (80%), nasal discharge (64%) and
      epistaxis (60%) were the predominant symptoms in NSL patients; neck swelling/mass
      (42%), nasal obstruction (37%) and hearing impairment (32%) were common findings
      in NPL patients. Limited stage disease (I/II) was present in all NSL and in 80%
      of the NPL patients. Thirty-six per cent of the NSL and 32% of the NPL patients
      had bulky disease. The majority of the immunophenotyped NSLs were of T-cell
      lineage (75%, 12/16) and most immunophenotyped NPLs were of B-cell lineage (69%,
      11/16). The patients were treated with radiotherapy alone (14%), chemotherapy
      alone (23%) or chemotherapy plus radiotherapy (64%). NSL patients showed a lower
      complete remission rate and higher relapse rate than NPL patients, although the
      difference did not reach statistical significance. Both the 5-year disease-free
      survival (36% versus 76%; P = 0.007) and overall survival (33% versus 82%; P =
      0.003) were significantly worse in NSL compared with NPL patients. Advanced age
      (>60 years; P = 0.03) and bulky disease (P = 0.04) were also associated with
      inferior survival times. The analysis of sex, stage and type of therapy showed no
      evidence of significant impact on the survival. Despite the close anatomical
      relationship in origin, NSL and NPL were noted to behave as biologically distinct
      entities, in which the NSLs demonstrated a higher frequency of T-cell tumours and
      a much worse prognosis than NPL. In addition to the primary site, advanced age
      and bulky disease were also associated with reduced survival.

PMID- 10663328
TI  - Experience of discordant beta hCG results by different assays in the management
      of non-seminomatous germ cell tumours of the testis.
AB  - Fifty-five patients with non-seminomatous germ cell tumours (NSGCT) who were
      referred to a regional clinical oncology centre over a 3-year period were
      assessed prospectively with assays of the serum tumour markers alpha-feto protein
      (AFP) and beta-human chorionic gonadotropin (beta hCG). Paired baseline beta hCG
      assays were undertaken using a polyclonal radioimmunoassay (RIA) and a monoclonal
      fluoroimmunoassay (FIA). Serial paired measurements were undertaken in patients
      showing discordance on baseline assays. Four patients (7%; 95% confidence
      interval 0-14) showed discordance between the paired beta hCG assays. Of these,
      two showed elevated beta hCG on RIA, with normal levels on FIA; two showed
      elevated beta hCG on FIA, with normal levels on RIA. No discordance was noted
      with AFP assays. Discordance persisted in two of the patients (50%) and
      disappeared on treatment in one (25%); one patient died during treatment.
      Discordant beta hCG assays present difficulties in interpretation and have
      therapeutic implications in patients with NSGCT. No single currently available
      assay is conclusive in all patients and commercial assay kits should be chosen
      with care.

PMID- 10663329
TI  - Ultrasound localization of the ovaries for radiation-induced ovarian ablation.
AB  - The case notes and simulator films were reviewed from 70 sequential patients who
      received pelvic irradiation to induce an early menopause as part of their
      treatment for breast cancer at the Staffordshire Oncology Centre. These patients
      underwent ultrasound localization of the ovaries immediately prior to simulation.
      Altogether, 128 ovaries were plotted on a diagrammatic representation of a
      gynaecoid pelvis to represent their position in both craniocaudal and lateral
      dimensions in relation to the true bony pelvis. The craniocaudal ovarian position
      varied from 2.5 cm above the lower aspect of the sacroiliac joint to 2.0 cm above
      the symphysis pubis. Three (4.6%) right sided ovaries were within 1 cm medial to
      the right lateral side wall, with none lying lateral to the wall. Seventeen (26%)
      left sided ovaries were lying within 1 cm of the left pelvic side wall, with four
      of these lying outside. The limits of the pelvic fields used were from the top of
      the sacroiliac joint to the bottom of the symphysis pubis. Sixty-one (88%) upper
      borders were on or above the lower sacroiliac joint. Twenty-six (38%) and 49
      (71%) fields were outside the right and left pelvic side walls respectively. This
      would suggest that field sizes were larger than standard; however, 87% were
      smaller than 150 cm(2) (assuming a 10x15-cm field as standard). Only one patient
      failed to respond to treatment. This was thought to be due to underdosing rather
      than a geographical miss. This patient was successfully retreated. The authors
      advocate the use of ultrasound localization prior to planning an irradiation
      menopause, to ensure that the ovaries are encompassed in the pelvic field, thus
      preventing a geographical miss and reducing field sizes.

PMID- 10663330
TI  - Predicting meningioma recurrence. Royal College of Radiologists Annual
      Undergraduate Prize in Clinical Oncology, 1999.

PMID- 10663331
TI  - Metastatic adult medulloblastoma showing prolonged response to chemotherapy.

PMID- 10663332
TI  - Metastatic breast cancer presenting as Tolosa-Hunt syndrome.
AB  - Choroidal involvement is a well-recognized manifestation of metastatic disease,
      particularly from breast and lung primaries. However, breast cancer can involve
      other ocular structures. The two patients presented illustrate diffuse orbital
      involvement of the extraocular muscles, simulating Tolosa-Hunt syndrome. This
      association has not been reported previously. Both patients responded well to
      local radiotherapy.

PMID- 10663333
TI  - Synchronous bilateral carcinoma of the breasts occurring in a young woman with a
      history of Langerhans' cell histiocytosis in infancy.
AB  - We report the case history of a 28-year-old woman who developed synchronous
      bilateral carcinoma of the breasts, having been diagnosed with multisystem
      Langerhans' cell histiocytosis in infancy. She had been treated with vinblastine
      and corticosteroids for 3 years and made a full recovery without late sequelae.
      We review the association of Langerhans' cell histiocytosis and its treatment
      with subsequent malignancy, with particular reference to carcinoma of the breast,
      and discuss the possible causes.

PMID- 10663334
TI  - Cervical cancer metastatic to the breast: a case report and review of the
      literature.
AB  - Metastasis to the breast from primary cervical cancer is rare. We describe one
      such patient, who developed breast metastasis 6 months after diagnosis. She was
      free of pelvic disease at the time of metastases but had evidence of lung
      involvement. She died of progressive disease 2 months later. Data on 23 patients
      collected from the literature via Medline are reviewed.

PMID- 10663335
TI  - Alveolar rhabdomyosarcoma metastatic to the breast: long-term survivor.
AB  - The case history is described of an adolescent girl with alveolar
      rhabdomyosarcoma of the maxillary sinus, who was treated with radical
      radiotherapy and adjuvant chemotherapy. She relapsed in the breast and, after
      incomplete excision, received radical radiotherapy resulting in long-term
      survival with breast conservation. The characteristics of patients with
      metastatic rhabdomyosarcoma with breast involvement are discussed. In adolescent
      girls, the breast is postulated to be a preferential metastatic site.

PMID- 10663336
TI  - Ovarian carcinoma metastatic to the breast.
AB  - We report the case history of a patient with ovarian carcinoma and bilateral
      breast metastases. The presence of metastases to the breast from a primary
      ovarian carcinoma, diagnosed at initial presentation, is a rarity.

PMID- 10663337
TI  - Rectal carcinoma metastatic to the breast.
AB  - We report the first case in our experience of metastasis to the breast from a
      previous rectal carcinoma. Metastases to the breast are rare in themselves; for
      them to occur secondary to a previous rectal carcinoma makes this unusual.

PMID- 10663338
TI  - Recall phenomenon following epirubicin.
AB  - The case history is presented of a 46-year-old lady who was treated
      postoperatively for breast cancer with combination chemotherapy containing the
      antitumour agent epirubicin. The second cycle was complicated by a mild
      extravasation injury in the antecubital fossa, which settled with conservative
      management. Two weeks after a subsequent infusion into a different extremity she
      developed inflammation at the original site of injury, which rapidly led to
      tissue breakdown requiring surgical debridement and microvascular free flap
      reconstruction. To our knowledge, epirubicin has never been previously associated
      with 'recall reactions'. Histological evaluation of the debrided tissue has
      revealed a possible underlying mechanism for the cell damage.

PMID- 10663340
TI  - Abstracts of papers presented at the united kingdom Children's cancer study group
      annual scientific meeting, 10 june 1999, royal marsden hospital, london

PMID- 10663339
TI  - Malignant melanoma occurring within a previously irradiated area.
AB  - The commonest radiation-induced neoplasms are sarcomas. Ionizing radiation is not
      usually associated with the development of malignant melanoma. We report two
      patients with malignant melanoma occurring within a previously irradiated area.
      There is evidence to support radiation in the pathogenesis of melanoma but the
      family histories, especially in one patient, suggest that genetic mutations may
      also have played a role, particularly in relation to the short latent period.

PMID- 10663342
TI  - Bone mineral density in patients with treated Addison's disease.
AB  - Some studies have reported low bone mineral density (BMD) in patients with
      Addison's disease, whereas others have found BMD to be normal. It is possible
      that over-replacement of corticosteroids and adrenal androgen deficiency may
      contribute to a reduction in BMD in these patients. The aims of this study were
      to examine BMD using dual-energy X-ray absorptiometry in patients with treated
      Addison's disease at multiple skeletal sites and to investigate the relationships
      between these measurements and corticosteroid dose. Nineteen men, 3 premenopausal
      and 7 postmenopausal women with Addison's disease were studied and data from
      these patients were analyzed separately and as a group. The mean SEM age and
      duration of Addison's disease of the men were 44 +/- 3.8 years and 15 +/- 2.2
      years, in the premenopausal women 40 +/- 2 years and 5 +/- 2.4 years, and in the
      postmenopausal women 68 +/- 4 years and 20 +/- 5 years, respectively. Eight men
      were unexpectedly hypogonadal (serum testosterone <13 nmol/l). BMD was expressed
      as a percent of values in normal controls (n = 418) adjusted for age, sex, ethnic
      origin, menopausal status and body weight. In the whole group (n = 29), mean BMD
      of the patients with Addison's disease was not different from normal at any site
      [mean (+/- SEM) lumbar spine 99.5% +/- 2.9%; femoral neck 99.3% +/- 2.5%; Ward's
      triangle 96.2% +/- 3.5%; trochanter 99.2% +/- 2.9%; radius 99.8% +/- 2.1%; total
      body 98.5% +/- 1.4%]. However, there was a wide range of bone densities, with
      some patients having a low BMD at multiple sites. Bone density was negatively
      correlated with current and cumulative corticosteroid dose per kilogram body
      weight and duration of Addison's disease. In conclusion, BMD in patients with
      Addison's disease is little different from normal, but may be lower in patients
      with disease of long duration and a high cumulative corticosteroid dose.
      Unexpected hypogonadism in men with Addison's disease is common.

PMID- 10663343
TI  - Contact quantitative ultrasound: an evaluation of precision, fracture
      discrimination, age-related bone loss and applicability of the WHO criteria.
AB  - The aim of this study was to assess a dry calcaneal quantitative ultrasound (QUS)
      device by examining: (i) short- and long-term precision; (ii) the ability of the
      ultrasound parameters to identify women with vertebral fractures; (iii) age- and
      menopause-related bone loss; (iv) applicability of the WHO criteria in scan
      interpretation. The study group consisted of 422 healthy women with no risk
      factors associated with osteoporosis (227 premenopausal and 195 postmenopausal)
      and 93 women with one or more vertebral fractures. All women had calcaneal QUS
      and bone mineral density (BMD) measurements of the lumbar spine and hip
      performed. Broadband ultrasound attenuation (BUA) and speed of sound (SOS)
      measurements in the heel were combined and expressed as estimated heel BMD. Short
      term precision studies yielded coefficient of variations of 0. 3% for SOS, 4% for
      BUA and 3.3% for estimated heel BMD. Standardized short-term precision values
      were approximately 0.2 SD. Long-term standardized precision errors ranged from
      0.17 to 0.38 SD. All the QUS and BMD measurement parameters showed significant
      negative relationships with age in the postmenopausal group. Annual losses were
      0.35 dB/MHz per year for BUA, 0.56 m/s per year for SOS and 0. 002 g/cm(2) per
      year for estimated heel BMD. All the QUS and BMD parameters were able to
      discriminate between healthy postmenopausal women and women with vertebral
      fracture. Age-adjusted odds ratios for each SD decline in QUS measurements were
      3.63, 5.25 and 4.79 for BUA, SOS and estimated heel BMD respectively.
      Corresponding odds ratios for BMD at the lumbar spine, femoral neck and total hip
      were 2.39, 2.51 and 2.95 respectively. When the QUS and BMD parameters were
      expressed as T-scores, estimated heel BMD showed the least age-related decline,
      while femoral neck BMD displayed the greatest decrease with age. The mean T-score
      and prevalence of osteoporosis (T<-2.5) for a Caucasian woman aged 60-65 years
      were -1.35 and 21% respectively for the lumbar spine compared with -0.59 and 2%
      for estimated heel BMD. In conclusion, this study revealed that contact
      ultrasound can detect age- and menopause-related influences on bone status and
      was able to discriminate between healthy individuals and women with vertebral
      fracture. However, the widely accepted threshold of a T-score of less than -2.5
      for the definition of osteoporosis may need modifying for the interpretation of
      QUS scans.

PMID- 10663344
TI  - Influence of age and sex on vertebral shape indices assessed by radiographic
      morphometry.
AB  - Vertebral shape indices (VSI) assessed by radiographic morphometry are currently
      used to define vertebral fractures in clinical trials and epidemiologic studies
      on osteoporosis. However, there is little information concerning the influence of
      sex or age on VSI. Furthermore, previous reports on the variation of VSI with age
      showed conflicting results. The aim of this study was to assess the influence of
      sex and age on VSI in order to better define reference values for the clinical
      and epidemiologic evaluation of vertebral osteoporotic fractures. Measurements
      were performed on thoracic and lumbar spine radiographs from 50 men and 50 women
      (age range 25-75 years) without evidence of osteoporotic, degenerative or other
      disease-related vertebral deformity. The anterior (AH), middle (MH) and posterior
      (PH) heights of each vertebral body from T4 to L5 were measured and VSI were
      calculated as follows: wedging = (AH minus PH) divided by PH; concavity = (MH
      minus PH) divided by PH. Wedging and concavity, especially at the mid and lower
      thoracic spine, increased significantly with age in both sexes. We also
      demonstrated that VSI at the lumbar spine were significantly dependent on gender,
      with greater values of wedging and concavity in men than in women. Consequently,
      reference values used for the definition of vertebral osteoporotic fractures
      assessed by radiographic morphometry should take into account both sex and age
      effects.

PMID- 10663345
TI  - Quantitative ultrasound and symptomatic vertebral fracture risk in Chinese women.
AB  - Quantitative ultrasound (QUS) is emerging as a simple, inexpensive and
      noninvasive method for assessing bone quality and assessing fracture risk. We
      assessed the usefulness of a contact calcaneal ultrasonometer by studying normal
      premenopausal women (group I, n = 53), normal postmenopausal women (group II, n =
      198), and osteoporotic women without (group III, n = 141) and with vertebral
      fractures (group IV, n = 53). The osteoporotic subjects had a T-score of the
      spine or hip neck bone mineral density (BMD) <-2.5 based on the local Chinese
      peak young mean values. When compared with postmenopausal controls, mean
      broadband ultrasound attenuation (BUA), speed of sound (SOS), and quantitative
      ultrasound index (QUI) were 26%, 2.1% and 25% lower in women with vertebral
      fractures (p all <0.005). The correlation coefficients between QUS parameters and
      BMD of the spine and hip ranged between 0.4 and 0.5. The ability of the QUS to
      discriminate between patients groups was determined based on the mean value of
      normal premenopausal women in group I. The mean T-score for women with fractures
      was -2.87 +/- 1.02 for BUA, -2.54 +/- 0.79 for SOS, -3.17 +/- 0.70 for QUI, -2.65
      +/- 0.86 for L2-4 BMD and -2.53 +/- 0.66 for hip neck BMD. After adjustment for
      age and body mass index, the odds ratio of vertebral fracture was 1.71 (95% CI
      1.2-2.6) for each 1 SD reduction in BUA, 2.72 (1.3-5.3) for SOS, 2.58 (1.4-4.6)
      for QUI, 2.33 (1.6-3.3) for L2-4 BMD, 2.09 (1. 37-3.20) for femoral neck BMD and
      1.88 (1.34-2.92) for total hip BMD. The association between the QUS parameters
      and vertebral fracture risk persisted even adjustment for BMD. The area under the
      receiver operating characteristic curve for BUA for vertebral fracture was 0. 92,
      for SOS, QUI, L2-4 BMD and femoral neck BMD was 0.95, and for total hip was 0.91.

PMID- 10663346
TI  - Precision of quantitative ultrasound measurement of the heel bone and effects of
      ambient temperature on the parameters.
AB  - The goal of this study was to determine the magnitude of measurement error of a
      quantitative ultrasound (QUS) measurement system of the heel bone in a practical
      setting and to examine the effects of ambient temperature in the test room on QUS
      parameters. We assessed the intratest, intertest and interdevice coefficients of
      variation (CVs) for speed of sound (SOS), broadband ultrasound attenuation (BUA)
      and stiffness in vitro using phantoms and in vivo using volunteers. The intratest
      CV was the smallest and the interdevice CV was the greatest for every QUS
      parameter. The intertest CVs in vivo were 0.50% for SOS, 2.53% for BUA and 4.38%
      for stiffness. The standardized precision error (sPE) of stiffness, however, was
      smaller than those of the other two parameters. The intertest sPEs in vivo of the
      QUS parameters were 2-3 times greater than that of the spine bone mineral density
      (BMD) as measured by dual-energy X-ray absorptiometry (DXA). Using an average of
      duplicate measurements for the representative value of a subject could improve
      sPE of the QUS parameters to around 2 times greater than that of spine BMD. We
      examined five phantoms each with the QUS system under the ambient temperature
      conditions of 10, 20 and 30 degrees C. The lower the room temperature, the
      greater the values of all the QUS parameters obtained. We then assessed the
      effect of the season on the QUS parameters in healthy five women. SOS and
      stiffness were significantly greater in February (room temperature, 12.6 degrees
      C) than in June (22.4 degrees C) by 0.74% and 3.2% of overall means,
      respectively, by 10.1% and 4.3% as a standardized difference, or by 0.422 and
      0.214 in Z-scores. This difference was likely to be caused by the difference in
      heel temperature between the seasons. The precision of the QUS system was
      inferior to that of conventional DXA densitometry. We recommend that institutions
      using several QUS system devices throughout the year at various locations monitor
      the precision of each device, make duplicate measurements for a single subject,
      use the same device for each patient being followed, and control the heel
      temperature of subjects by keeping the test room temperature constant throughout
      the year.

PMID- 10663347
TI  - High bone mineral density in male elite professional volleyball players.
AB  - The aim of this study was to assess bone mass in male elite athletes
      participating in an impact loading sport (volleyball) and, in particular, to
      determine whether the asymmetric nature of this sport leads to differences in the
      skeletal tissue composition of the limbs. Fifteen male volleyball players (VP)
      (26 +/- 4 years, 192 +/- 6 cm, 87 +/- 9 kg; mean +/- SD) and 15 non-active
      control subjects (25 +/- 2 years, 177 +/- 8 cm, 72 +/- 11 kg; mean +/- SD) were
      studied. VP training sessions (3-6 days/week) included a variety of jumping and
      weightlifting exercises. The VP were taller and heavier than the control subjects
      (p<0.001). Whole-body bone mineral content (BMC) and lean mass were higher in VP
      after adjustment for body mass and height (p<0.001). Axial skeleton and limb BMC
      and bone mineral density (BMD) were higher in VP than in control subjects
      (p<0.05). Adjusted lumbar spine (L2-4) BMD was 14% higher in VP than in control
      subjects (p<0.05). Similarly, a much greater adjusted BMD was observed in the
      femoral neck of VP (24%, 20%, 27% and 20% for the femoral neck,
      intertrochanteric, greater trochanter and Ward's triangle subregions
      respectively; p<0.05). The dominant arm was slightly heavier (approximately 3%)
      and had 4% more muscle mass than the contralateral arm in both the VP (p<0.05)
      and control subjects (p<0.05). Greater BMC values (9%), BMD (7%) values and the
      area occupied by osseous pixels (5%) were recorded in the dominant arm as
      compared with the nondominant arm in VP (p<0.05). No differences between arms
      were observed in control subjects. Right and left leg BMC and BMD values were
      similar in control subjects while 4% higher BMC values were recorded for the left
      leg in the VP group (p<0.05). A close relationship between left leg muscle mass
      and BMD was observed in the femoral neck subregions of all the subjects (r =
      0.81, 0.81, 0.78 and 0.79 for the femoral neck, intertrochanteric, greater
      trochanter and Ward's triangle subregions respectively; p<0.001; n = 30). These
      findings clearly demonstrate a considerably high BMC and BMD in professional
      volleyball players which seems to be related to the loading type of exercise they
      perform.

PMID- 10663348
TI  - Bone mineral density in sixty adult patients with Marfan syndrome.
AB  - Sixty adult patients (40 women, 20 men) with Marfan syndrome (MFS) according to
      the Berlin criteria had a full clinical examination and bone mineral density
      (BMD) measurement by dual-energy X-ray absorptiometry of the hip and nondominant
      forearm. BMD was expressed as a Z-score and compared with the reference
      population of the Hologic database. In MFS men, BMD (g/cm(2)) was compared with
      the BMD of 45 normal tall Caucasian adults. Osteocalcin was measured by
      radioimmunoassay. In patients with MFS, BMD was compared between patients with
      and without previous fractures and according to the phenotypic severity of MFS.
      The mean age of the patients was 32.9 +/- 9.3 years (women 32.5 +/- 9.7, men 33.4
      +/- 8.6), mean height was 180.3 +/- 10.3 cm (women 176.3 +/- 9.2, men 188.1 +/-
      7.5) and mean body mass index 20.9 +/- 3.6 kg/m(2) (women 20.8 +/- 3.4, men 20.95
      +/- 3.97). Hyperlaxity score (Beighton criteria) was 6.9 +/- 1. 1. Six patients
      (10%) had a previous fracture. Thirty per cent of patients had had at least one
      previous operation for scoliosis, aortic dilatation or eye problems. BMD values
      in the 60 patients were as follows: Z-score of the hip, -1.26 +/- 0.93, p<10(-9)
      (neck, -0.93 +/- 1.09, p<10(-9); trochanter, -1.31 +/- 0.85, p<10(-9);
      intertrochanter, -1.39 +/- 0.99, p<10(-9); Ward's triangle, -0.93 +/- 1.88, p<10(
      9)); Z-score of the radius: -1.6 +/- 1.06, p<10(-9) (1/3 proximal, -1.29 +/-
      1.03; mid-radius, -1.94 +/- 1.04; ultradistal, -0.68 +/- 1.1, p<10(-9)). The
      decrease in BMD was similar in men and women at both the hip and the radius. BMD
      in MFS patients was significantly decreased at cortical compared with trabecular
      sites (radius 1/3 proximal vs ultradistal, p<0.0001; total femur vs Ward's
      triangle, p<0.0005). No difference in BMD was found between MFS patients with or
      without previous fractures and those with severe or less severe phenotypic
      expression of MFS. An influence of height and weight in MFS on BMD is suspected.
      Osteocalcin was not increased in our group of MFS patients. Thus both men and
      women with MFS have a significant deficit of BMD at the hip and radius. The
      decrease in BMD is present equally in both sexes and is more pronounced at
      predominantly cortical sites. In our group of patients we found no increase in
      fractures and no relation between decreased BMD and phenotypic expression of the
      syndrome.

PMID- 10663349
TI  - Urinary alpha and beta C-telopeptides of collagen I: clinical implications in
      bone remodeling in patients with anorexia nervosa.
AB  - Fragments derived from degradation of type I collagen C-telopeptide (CTX) can be
      nonisomerized (alpha) or beta-isomerized (beta) depending on the age of bone;
      i.e., mainly the alpha form is derived from new bone and the beta form from old
      bone. We have studied 41 female patients with anorexia nervosa (AN), aged 18.5 +/
      2.2 years (range 16-24 years), and with an evolution time between 1.5 and 11
      years, and 31 healthy control females (C), with a mean age of 19 +/- 2.3 years
      (range 16-24 years). The AN patients showed a significant decrease in bone mass,
      with a mean Z-score of bone mineral density (BMD) of -3.2 +/- 0.8 (range -0.9 to 
      5.4). The aim of our study was to determine the levels of urinary alpha- and beta
      CTX markers of bone resorption, the alpha/beta ratio (alpha/beta), and the level
      of bone alkaline phosphatase (bAP), a biochemical marker of bone formation, in
      order to relate them to the degree of osteopenia and the status of bone
      remodeling. Statistical analysis was by the Mann-Whitney test. The degree of
      osteopenia correlated with bAP levels (p = 0.0027) but not with the other
      parameters. Patients with AN were divided into three groups according to their
      levels of bAP: high (H), normal (N) or low (L). We found that BMD was
      significantly lower, and alpha- and beta-CTX were significantly higher, in groups
      H and N than in group L. Bone AP correlated significantly with alpha-CTX (p =
      0.0042) and alpha/beta (0.0095) in the controls, but not with beta-CTX, while in
      AN patients bAP correlated with beta-CTX (p = 0.0000) and with alpha-CTX (p =
      0.022) but not with the alpha/beta ratio. The ratio CTX/bAP
      (resorption/formation) was similar in AN patients and controls. It is concluded
      that: (1) patients with AN have a high degree of osteopenia which correlated with
      bAP levels; (2) urinary CTX fragments found in AN patients seem to come mainly
      from old bone (beta-CTX), while CTX found in healthy adolescent control females
      come from new bone (alpha-CTX). For this reason, alpha-CTX is more suitable than
      beta-CTX for measuring bone resorption in controls and beta-CTX is more suitable
      in patients with AN; (3) the resorption/formation ratio (CTX/bAP) was similar in
      AN patients and controls. From points (2) and (3) it is possible to suggest that,
      although bAP reflects bone formation in control females, this marker does not
      reflect effective bone mineralization in AN patients, a similar feature to that
      of patients with osteomalacia.

PMID- 10663350
TI  - Differences in risk factor patterns between cervical and trochanteric hip
      fractures. Swedish Hip Fracture Study Group.
AB  - The two types of hip fracture--cervical and trochanteric femoral fractures--are
      generally considered together in etiologic studies. However, women with a
      trochanteric fracture may be more osteoporotic than those with cervical hip
      fractures, and have higher post-fracture mortality. To explore differences in
      risk factor patterns between the two types of hip fracture we used data from a
      large population-based case-control study in Swedish women, 50-81 years of age.
      Data were collected by questionnaire, to which more than 80% of subjects
      responded. Of the cases included, 811 had had a cervical fracture and 483 a
      trochanteric fracture during the study period; these cases were compared with
      3312 randomly selected controls. Height and hormonal factors appeared to affect
      the risk of the two types of hip fracture differently. For every 5 cm of current
      height, women with a cervical fracture had an adjusted odds ratio (OR) of 1.23
      (95% CI 1.15-1.32) compared with an OR of 1.06 (95% CI 0.97-1.15) for women with
      trochanteric fractures. Later menopausal age was protective for trochanteric
      fractures (OR 0.95, 95% CI 0. 91-0.99 per 2 years) but no such association was
      found for cervical fractures. Compared with never smokers, current smokers had an
      OR of 1.48 (95% CI 1.12-1.95) for trochanteric fractures and 1.22 (95% CI 0.98
      1.52) for cervical fractures. Current hormone replacement therapy was similarly
      protective for both fracture types, but former use substantially reduced risk
      only for trochanteric fractures: OR 0. 55 (95% CI 0.33-0.92) compared with 1.00
      (95% CI 0.71-1.39) for cervical fractures. These risk factor patterns suggest
      etiologic differences between the fracture types which have to be considered when
      planning preventive interventions.

PMID- 10663351
TI  - Factors affecting broadband ultrasound attenuation results of the calcaneus using
      a gel-coupled quantitative ultrasound scanning system.
AB  - This study aimed to assess the factors that may influence the distribution and
      description of broadband ultrasound attenuation (BUA) and to identify specific
      criteria for diagnostic consideration when collecting BUA reference data. Two
      hundred Caucasian women (aged 20-79 years) without a history of atraumatic
      fractures or medicines known to affect bone metabolism were selected for this
      study. Medical and menstrual history, medication usage, family history of
      osteoporosis (FHO), physical activity, activities of daily living (ADL), dietary
      calcium intake, as well as smoking and alcohol consumption were obtained.
      Broadband ultrasound attenuation (BUA, dB/MHz) was determined in the right foot
      using a new gel-coupled ultrasound system. BUA was significantly associated with
      age (p<0.001), body weight (p<0.001), level of physical activity (p = 0.024) and
      dietary calcium intake (p = 0.023). Smoking, alcohol and coffee consumption and
      ADL were not associated with BUA (p>0.05). There were no differences in BUA
      (p>0.05) between those women who reported taking medications or had diseases
      (known to not affect bone metabolism), were using contraceptives, taking
      vitamin/mineral supplements and/or had traumatic fractures and their counterparts
      who did not report these characteristics. Premenopausal women with a FHO had
      significantly lower BUA values compared with those without a FHO (p = 0.013).
      When those participants with a FHO were removed from the sample, the peak BUA
      value was 1.1-4.4% higher and the variability (SD) was reduced by about 3.3-9.3%
      depending on which age range was used to define the peak BUA value. Consequently,
      an additional 4.5% of the population were classified as having a T-score <-2. Our
      results suggest that the impact on BUA of risk factors such as a FHO, body
      weight, physical activity and dietary calcium intake is similar to that on bone
      mineral density obtained by dual-energy X-ray absorptiometry (DXA), and thus
      provides further information on the comparability of quantitative ultrasound and
      DXA for assessment of risk of fracture. The criteria for calculating the T-score
      need further study to determine whether young adults with FHO should be included
      and what cutoff age range should be used in collecting peak values of
      quantitative ultrasound parameters.

PMID- 10663352
TI  - Forearm bone mineral densitometry cannot be used to monitor response to
      alendronate therapy in postmenopausal women.
AB  - Alendronate significantly increases bone mass and reduces hip and spine fractures
      in postmenopausal women. To determine whether forearm densitometry could be used
      to monitor the efficacy of alendronate, we examined changes in bone mineral
      density (BMD) at the forearm (one-third distal, mid-distal, ultradistal radius)
      versus changes at the hip (femoral neck, total hip) and spine (posteroanterior
      and lateral) in a double-masked, randomized, placebo-controlled clinical trial of
      120 elderly women (mean age 70 +/- 4 years) treated with alendronate for 2.5
      years. We found that among women in the treatment group, BMD increased by 4.0
      12.2% at the hip and spine sites (all p<0.001), whereas BMD increased only
      nominally at the one-third distal radius (1.3%, p<0.001) and mid-radius (0.8%,
      p<0.05), and remained stable at the ultradistal radius. At baseline, forearm BMD
      correlated with that of the hip (r = 0.55-0.64, p<0.001), femoral neck (r = 0.54
      0.61, p<0.001) and posteroanterior spine (r = 0.56-0.63, p<0.001). Changes in
      radial BMD after 1 year of therapy were not correlated with changes in hip and
      spine BMD after 2.5 years of therapy. In contrast, short-term changes in total
      hip and spine BMD were generally positively associated with long-term changes in
      total hip, femoral neck and spine BMD (r = 0.30-0.71, p<0.05). Furthermore, long
      term BMD changes at the forearm did not correlate with long-term hip and spine
      BMD changes, in contrast to the moderate correlations seen between spine and hip
      BMD at 2.5 years (r = 0.38-0.45, p<0.01). We conclude that neither short- nor
      long-term changes in forearm BMD predict long-term changes in overall BMD for
      elderly women on alendronate therapy, suggesting that measurements of clinically
      relevant central sites (hip and spine) are necessary to assess therapeutic
      efficacy.

PMID- 10663353
TI  - Total-body calcium estimated by delayed gamma neutron activation analysis and
      dual-energy X-ray absorptiometry.
AB  - Total body calcium (TBCa) in 270 black and white women age 21-79 years was
      measured concurrently by delayed gamma neutron activation analysis (DGNA) and
      dual-energy X-ray absorptiometry (DXA). The mean value for TBCa calculated from
      DXA was 933 g compared with 730 g for DGNA. By regression, TBCa(DXA(g)) = 1.35 x
      TBCa(DGNA(g)) -54 (r = 0. 90, r(2) = 81.4%, SEE = 66.9 g). This remarkable
      difference of 203 g suggests that one or both these methods is not accurate.
      Adjustment of the regression of DXA versus DGNA for body mass index or trunk
      thickness explained 8.5-10% of the variability between methods. The unadjusted
      slope for the DXA values regressed against the DGNA values was 1.35, indicating
      significant discordance between the methods. There is greater agreement between
      the two DGNA facilities (Brookhaven National Laboratory and Baylor College of
      Medicine) and between the various DXA instruments. Either DGNA underestimates
      TBCa or DXA overestimates total-body bone mineral content. Resolution of these
      disparate results may possibly be achieved by concurrent measurement of whole
      human cadavers of different sizes with chemical determination of the calcium
      content of the ash. In the interim, cross-calibration equations between DGNA and
      standardized values for DXA for total-body bone mineral content may be used,
      which will permit reporting of consistent values for TBCa from the two
      technologies.

PMID- 10663354
TI  - Factors related to variation in premenopausal bone mineral status: a health
      promotion approach.
AB  - Bone loss prior to menopause may contribute to later risk of fracture due to
      osteoporosis. Women may be able to optimize premenopausal bone mass and/or
      prevent losses. Heredity, and possibly age at menarche (retrospectively
      determined), are unmodifiable risk factors and attention should therefore be
      directed to more amenable factors. Amenorrhea, low body weight, disordered
      eating, and smoking are modifiable risk factors. Vitamin D is not a factor for
      premenopausal women who receive incidental sun exposure and consume fortified
      foods, but supplementation should be considered for others, especially during the
      winter months. Protective factors include a higher body weight (especially due to
      increased muscularity), calcium supplementation, and purposeful load-bearing
      exercise. Positive effects of oral contraceptives are most apparent in women with
      menstrual irregularities. Reproductive history (parity), lactation, moderate
      intakes of alcohol and caffeine, and the appropriate treatment of endometriosis
      have no apparent effect on premenopausal bone.

PMID- 10663355
TI  - Comparison of digitized images with original radiography for semiquantitative
      assessment of osteoporotic fractures.
AB  - We validated a vertebral fracture assessment (VFA) workstation developed by our
      group for semiquantitative assessment of vertebral fractures in large-scale,
      multicenter osteoporosis drug trials. Baseline and follow-up spine radiographs
      (lateral views) of 50 patients who participated in a clinical trial were
      digitized and were archived on CD-ROM. Both original radiographs and the
      digitized images were independently assessed by three experienced radiologists.
      Prevalent fracture scores of vertebrae were rated in increments of 1 on a 4-point
      scale. Incident fractures were defined as any worsening of grade on follow-up
      films. Generally good to excellent agreement among the three readers was found
      between the two methods, with kappa scores (kappa) from 0.91 to 0.96 for
      prevalence of fractures, and from 0.80 to 0.90 for incidence of fractures.
      Reproducibility (intra-reader variability) of each method was comparable. For
      assessing prevalent fracture, kappa was from 0.87 to 0.96 using radiographs, and
      from 0.87 to 0.94 using VFA images. For incident fractures, the kappa was from
      0.78 to 0.89 using radiographs, and from 0.82 to 0.88 using VFA images. Level
      specific agreement between the two approaches was consistent. Overall, there is
      no difference between readings of digital images and readings of conventional
      radiographs. The quality of the new VFA for visualization of vertebral fracture
      is excellent.

PMID- 10663356
TI  - Loss of bone density and lean body mass after hip fracture.
AB  - Few studies of bone loss have assessed the amount of loss directly after a hip
      fracture. The present prospective study was conducted to determine changes in
      bone mineral density (BMD) and muscle mass shortly after fracture and through 1
      year to assess short-term loss and related factors. The setting was two acute
      care teaching hospitals in Baltimore, Maryland, and subjects were 205 community
      dwelling women with a new fracture of the proximal femur between 1992 and 1995.
      Bone density of the nonfractured hip and whole-body and body composition were
      measured by dual-energy X-ray absorptiometry at 3 and 10 days and 2, 6 and 12
      months after admission. Mean BMD of the femoral neck was 0.546 +/- 0.007 g/cm(2)
      at baseline. Average loss of femoral neck BMD from baseline was 2.1% at 2 months,
      2.5% at 6 months and 4.6% at 12 months. The average loss of BMD in the
      intertrochanteric region was 2.1% at 12 months. Total lean body mass decreased by
      6% while fat mass increased by 3. 6% by 1 year after the fracture. These findings
      indicate that significant loss in BMD and lean body mass occur shortly after hip
      fracture while body fat increases. Continued loss was evident throughout the 1
      year of follow-up. This loss of both bone density and muscle mass may lead to new
      fractures.

PMID- 10663357
TI  - Estimation of the architectural properties of cortical bone using peripheral
      quantitative computed tomography.
AB  - We assessed the volumetric bone mineral density (vBMD) and cross-sectional
      architecture of cortical bone at the distal radius by peripheral quantitative
      computed tomography (pQCT). The volumetric bone mineral density [integral bone
      mineral density (BMDi), trabecular bone mineral density (BMDt) and cortical with
      subcortical bone mineral density (BMDsc)] and the architectural parameters
      [cortical bone area (CBA), cortical thickness (C-th), moment of inertia (Im) and
      polar moment of inertia (Ip)] were measured in 115 healthy premenopausal women,
      48 osteoporotic postmenopausal women and 78 age-matched healthy postmenopausal
      women. Age-matched healthy women had higher values of vBMD and architectural
      parameters at the distal radius than osteoporotic women. Premenopausal women had
      higher values of vBMD and architectural parameters at the distal radius than
      postmenopausal women. The differences in the architectural parameters between age
      matched healthy women and osteoporotic women were more pronounced when only the
      high density area (threshold 0.70 cm(-1)) was included. However, the differences
      in architectural parameters between premenopausal women and postmenopausal women
      were significant using even the lowest threshold value of 0.50 cm(-1) in the
      calculation. Receiver operating characteristic (ROC) curves were constructed and
      the areas under the curves calculated to evaluate the discriminating power of
      vBMD and architectural parameters. Comparison of the different ROC curves showed
      no statistical significance. In conclusion, our results suggest that both the
      density and mass distribution of the radius were clearly different between the
      healthy women and osteoporotic women. The differences in architectural parameters
      were more useful for studying the pathophysiology of osteoporosis than for
      contributing to the diagnosis. Determination of the cross-sectional mass
      distribution of bone combined with BMD should offer more information than BMD
      alone in the study of the pathophysiology of osteoporosis.

PMID- 10663359
TI  - A comparison of the longitudinal changes in quantitative ultrasound with dual
      energy X-ray absorptiometry: the four-year effects of hormone replacement
      therapy.
AB  - Quantitative ultrasound (QUS) has been proposed as a tool which can measure both
      the quantitative and qualitative aspects of bone tissue and can predict the
      future risk of osteoporotic fractures. However, the usefulness of QUS in long
      term monitoring has yet to be defined. We studied a group of early postmenopausal
      women over a 4-year period. Thirty subjects were allocated to hormone replacement
      therapy and 30 selected as controls matched for age, years past the menopause
      (YPM) and bone mineral density (BMD) at the anteroposterior spine (AP spine). The
      mean age of the subjects was 52.4 years (SD 3.9 years), mean YPM 4.0 years (SD
      3.2) and all subjects had a BMD T-score above -2.5 SD (number of standard units
      related to the young normal mean population). BMD was measured at baseline and
      annually by dual-energy X-ray absorptiometry (DXA) at the AP spine and total hip,
      and QUS carried out at the calcaneus, measuring broadband ultrasound attenuation
      (BUA), speed of sound (SOS) and Stiffness. Mean percentage changes from baseline
      were assessed at 2 and 4 years. The overall treatment effect (defined as the
      difference in percentage change between the two groups) was: AP spine BMD, 11.4%;
      total hip BMD, 7.4%; BUA, 6.4%; SOS, 1.1%; and Stiffness, 10.4% (p<0.01). To
      compare the long-term precision of the two techniques we calculated the
      Standardized Precision, which for QUS was approximately 2-3 times that of DXA,
      for a given rate of change. The ability of each site to monitor response to
      treatment was assessed by calculating the Treatment Response Index (Treatment
      Effect/Standardized Precision), which was: AP spine BMD, 10.4; total hip BMD,
      3.9; BUA, 3.1; SOS, 0.3; and Stiffness, 4.2. This was then normalized for AP
      spine BMD (to compare the role of QUS against the current standard, AP Spine
      BMD), which was: total hip BMD, 0.38; BUA, 0.30; Stiffness, 0.40 (p<0.01); and
      SOS, 0.03 (NS). In summary, QUS parameters in the early menopause showed a
      similar rate of decline as AP spine BMD and total hip BMD measured by DXA.
      Hormone replacement therapy results in bone gain at the AP spine and total hip,
      and prevents loss in BUA and SOS measured by QUS at the calcaneus. QUS has a
      potential role in long-term monitoring, although presently the time period to
      follow individual subjects remains 2-3 times that for DXA, for a given rate of
      change. Anteroposterior spine remains the current optimal DXA monitoring site due
      to its greater rate of change and better long-term precision.

PMID- 10663358
TI  - Calcium absorption in postmenopausal osteoporosis: benefit of HRT plus
      calcitriol, but not HRT alone, in both malabsorbers and normal absorbers.
AB  - In a randomized trial involving 71 postmenopausal osteoporotic women with
      vertebral compression fractures, radiocalcium absorption studies using the (45)Ca
      single isotope method (alpha) were performed at baseline and after 8 months of
      treatment with either continuous combined hormone replacement therapy (HRT, as
      piperazine estrone sulfate 0.625-0.937 mg daily +/- medroxyprogesterone acetate
      2.5 mg daily depending on uterine status) or HRT plus calcitriol 0. 25 microg
      twice daily. A calcium supplement of 600 mg nocte was given to only those women
      who had a daily calcium intake of less than 1 g per day at baseline, as assessed
      by recalled dietary intake. There was a significant decrease [0.74 (+/- 0.35 SD)
      to 0.58 (+/- 0. 22), Dalpha = -0.17 (+/- 0.26), p<0.0005] in alpha at 8 months
      compared with baseline in the HRT-treated group, but a significant increase [0.68
      (+/- 0.31) to 0.84 (+/- 0.27), Dalpha = +0.16 (+/- 0. 30), p<0.003] in the HRT
      plus-calcitriol treated patients, resulting in alpha being significantly higher
      after 8 months in the latter group than in the HRT-only group. Although 72% of
      the patients had been supplemented with calcium between the first and second
      studies, separate analyses revealed that the change in calcium intake had not
      affected the result. Further breakdown of the groups into baseline 'normal'
      absorbers (alpha >/=0.55) and 'malabsorbers' (alpha <0.55) revealed that alpha
      decreased with HRT treatment only in the normal absorbers, and remained stable in
      the malabsorbers. Conversely, following HRT plus calcitriol treatment, alpha
      increased only in the malabsorbers, the normal absorbers in this group remaining
      unchanged. In conclusion, our data show that HRT, of the type and dose used in
      this study, did not produce an increase in absorption efficiency; it was in fact
      associated with a fall. Increased absorption efficiency cannot be achieved unless
      calcitriol is used concurrently, and then only in patients with malabsorption.
      Calcitriol also had a significant effect in normal absorbers in that it prevented
      the decline in alpha seen with HRT alone, and thus should be considered in all
      patients with postmenopausal osteoporosis treated with HRT.

PMID- 10663360
TI  - Modifications of bone and connective tissue after orthostatic bedrest.
AB  - Eight male volunteers were submitted to a 6-week anti-orthostatic bedrest trial
      followed by a 1-month reambulation period. We prospectively monitored whole-body
      composition by dual-energy X-ray absorptiometry, bone and connective tissue
      metabolism by biochemical markers and calcium regulating hormones by 1-84
      parathyroid hormone and 1,25-dihydroxyvitamin D(3). Bone mineral density (BMD)
      did not vary significantly; however, a trend toward an increase in head BMD and a
      decrease in trunk, lumbar vertebrae and lower limb BMD was observed. A decrease
      in the lower limb lean content occurred by day 27 and was maximum by day 42 after
      the beginning of bedrest; it normalized by day 30 after bedrest. The serum levels
      of both osteocalcin and C-terminal crosslinked telopeptide of type I collagen
      increased as a consequence of bedrest. A slight increase in the serum levels of
      the N-terminal propeptide of type III collagen, a marker of connective tissue
      metabolism, was observed during the bedrest period. Except for the C-terminal
      extension propeptide of type I collagen, all markers decreased to baseline pre
      immobilization levels during the 1-month recovery phase. Serum PTH and 1,25
      dihydroxyvitamin D(3) levels were low during the bedrest period and rose during
      the reambulation phase. These results seem to reflect early changes in bone and
      connective tissue metabolism as a result of bedrest unloading, but their order of
      magnitude remains moderate, thus emphasizing the necessity to perform longer
      duration trials.

PMID- 10663361
TI  - Long-term precision of DXA scanning assessed over seven years in forty
      postmenopausal women.
AB  - The reproducibility of dual-energy X-ray absorptiometry (DXA) measurements of
      bone mineral density (BMD) is an important factor for longitudinal studies. We
      assessed the long-term precision of posteroanterior lumbar spine, femoral neck
      and total hip BMD in 40 postmenopausal women who formed the control arm of a
      clinical trial of tibolone. BMD was measured at 0, 6 and 12 months and thereafter
      every 12 months up to 7 years. For each subject the trend of BMD with time was
      analyzed using linear regression. Each residual was expressed as the percentage
      difference from predicted BMD and the validity of assuming linear change with
      time was checked using the mean residuals for each visit number. For spine BMD a
      chi-squared test showed that the mean residuals were not statistically
      significantly different from zero. Although statistically significant deviations
      from linearity were found for the femoral neck and total hip sites the weighted
      root mean square residuals were small compared with the precision errors. When
      residuals were binned into histograms a statistical test for skewness was not
      significant for all three sites. However, a test for kurtosis yielded a
      statistically significant result for each histogram due to outlying residuals. To
      determine the standard deviation (SD) of the core gaussian distribution, outliers
      were trimmed using the method of Melton et al. For lumbar spine BMD outliers with
      residuals exceeding +/- 3 SD arose mainly from subjects with a body mass index
      (BMI) >28 kg/m(2) or from subjects who had undergone a large change in BMI during
      the study. For femoral neck BMD and total hip BMD the outliers were frequently
      due to inconsistent rotation of the hip. Results for long-term precision
      calculated from the standard deviation of residuals using the trimmed (untrimmed)
      data were: lumbar spine BMD, 1.12% (1.65%); femoral neck BMD, 2.21% (2.48%); and
      total hip BMD, 1.32% (1.57%). These errors were only slightly worse than short
      term errors despite changes of DXA scanner during the course of the study.
      However, obesity may have an adverse effect on precision errors in individual
      patients and particular care is necessary to ensure reproducible patient
      positioning for femur scans.

PMID- 10663362
TI  - Serum bone alkaline phosphatase and calcaneus bone density predict fractures: a
      prospective study.
AB  - The aim of this study was to assess the ability of serum bone-specific alkaline
      phosphatase (bone ALP), creatinine-corrected urinary collagen crosslinks (CTx)
      and calcaneus bone mineral density (BMD) to identify postmenopausal women who
      have an increased risk of osteoporotic fractures. Calcaneus BMD and biochemical
      markers of bone turnover (serum bone ALP and urinary CTx) were measured in 512
      community-dwelling postmenopausal women (mean age at baseline 69 years)
      participating in the Hawaii Osteoporosis Study. New spine and nonspine fractures
      subsequent to the BMD and biochemical bone markers measurements were recorded
      over an average of 2.7 years. Lateral spinal radiographs were used to identify
      spine fractures. Nonspine fractures were identified by self-report at the time of
      each examination. During the 2.7-year follow-up, at least one osteoporotic
      fracture occurred in 55 (10.7%) of the 512 women. Mean baseline serum bone ALP
      and urinary CTx were significantly higher among women who experienced an
      osteoporotic fracture compared with those women who did not fracture. In separate
      age-adjusted logistic regression models, serum bone ALP, urinary CTx and
      calcaneus BMD were each significantly associated with new fractures (odds ratios
      of 1.53, 1.54 and 1.61 per SD, respectively). Multiple variable logistic
      regression analysis identified BMD and serum bone ALP as significant predictors
      of fracture (p = 0.002 and 0.017, respectively). The results from this
      investigation indicate that increased bone turnover is significantly associated
      with an increased risk of osteoporotic fracture in postmenopausal women. This
      association is similar in magnitude and independent of that observed for BMD.

PMID- 10663363
TI  - Randomized trial of the effects of risedronate on vertebral fractures in women
      with established postmenopausal osteoporosis. Vertebral Efficacy with Risedronate
      Therapy (VERT) Study Group.
AB  - The purpose of this randomized, double-masked, placebo-controlled study was to
      determine the efficacy and safety of risedronate in the prevention of vertebral
      fractures in postmenopausal women with established osteoporosis. The study was
      conducted at 80 study centers in Europe and Australia. Postmenopausal women (n =
      1226) with two or more prevalent vertebral fractures received risedronate 2.5 or
      5 mg/day or placebo; all subjects also received elemental calcium 1000 mg/day,
      and up to 500 IU/day vitamin D if baseline levels were low. The study duration
      was 3 years; however, the 2.5 mg group was discontinued by protocol amendment
      after 2 years. Lateral spinal radiographs were taken annually for assessment of
      vertebral fractures, and bone mineral density was measured by dual-energy X-ray
      absorptiometry at 6-month intervals. Risedronate 5 mg reduced the risk of new
      vertebral fractures by 49% over 3 years compared with control (p<0.001). A
      significant reduction of 61% was seen within the first year (p = 0.001). The
      fracture reduction with risedronate 2.5 mg was similar to that in the 5 mg group
      over 2 years. The risk of nonvertebral fractures was reduced by 33% compared with
      control over 3 years (p = 0.06). Risedronate significantly increased bone mineral
      density at the spine and hip within 6 months. The adverse-event profile of
      risedronate, including gastrointestinal adverse events, was similar to that of
      control. Risedronate 5 mg provides effective and well-tolerated therapy for
      severe postmenopausal osteoporosis, reducing the incidence of vertebral fractures
      and improving bone density in women with established disease.

PMID- 10663365
TI  - Appendix 1: Formulas: Effect of Treatments on Health and Economic Outcomes.

PMID- 10663364
TI  - Modeling the socioeconomic impact of osteoporosis-related hip fractures in
      Switzerland.

PMID- 10663380
TI  - An intra-laboratory validation of the Integrated Model for the Differentiation of
      Skin Reactions (IMDS): discrimination between (photo)allergic and (photo)irritant
      skin reactions in mice.
AB  - We recently presented a modified local lymph node test which made it possible to
      quickly and reliably differentiate between irritative and allergic skin reactions
      with extremely simple parameters. The Integrated Model for the Differentiation of
      Skin Reactions (IMDS) test combines measurement of cell proliferation in draining
      lymph nodes with measurement of primary ear swelling after topical application of
      the test substance on three consecutive days. In contrast to the 'classic' skin
      sensitisation test in guinea-pigs the IMDS test is considerably faster and is
      based on objective measured data, not subjective skin evaluations. Like the Local
      Lymph Node Assay (LLNA), measurement of allergic potential in the IMDS test is
      based on the underlying immunological mechanisms, but also considers the
      behaviour of immune competent cells following non-specific activation by
      irritants. In addition, the IMDS test can employ UV radiation after application
      of the substance and, therefore, make differentiation possible between different
      types of skin photoreaction (photoallergy and photoirritation) after both topical
      and systemic administration. Attempts to achieve this kind of discrimination with
      the LLNA necessitate considerably greater expenditure, as proliferation in the
      draining lymph nodes can also be induced by moderate to extreme (photo)irritants.
      In a previous paper in which we presented the IMDS test, we examined each type of
      reaction in reference to one single standard; the next logical step was therefore
      a broad-based intra-laboratory validation. An important factor in the validation
      was the use of standards that had been thoroughly examined in both guinea pig and
      mouse systems and were also relevant with regard to estimation of the risk for
      humans. The data presented here show that the IMDS is a simple and reliable tool
      for obtaining fast and reproducible assessments of potential (photo)allergic and
      (photo)irritant skin reactions to substances.

PMID- 10663381
TI  - A meta-analysis for neurobehavioural results due to occupational lead exposure
      with blood lead concentrations <70 microg/100 ml.
AB  - The size of performance effects caused by exposure to inorganic lead was
      determined by a meta-analytical procedure. Twenty-two studies covering exposure
      conditions of <70 microg/100 ml blood lead concentration were considered as to
      whether the methods of recording performance deficits were comparable. As a
      consequence of different test procedures and insufficient documented test results
      only 13 tests out of 12 studies could be included in the analysis. For the tests
      Block Design, Logical Memory and Santa Ana performance deficits were found, which
      may be interpreted as 'small' effects in accordance with a convention for
      evaluating effect sizes. For the example of Block Design it could be shown that
      these effects are nevertheless serious. The extent of the exposure related
      decrease of performance was comparable with those changes of performance which
      can be expected during aging of up to 20 years. Subsequently, a blood lead
      concentration of 70 microg/100 ml cannot be considered as a safe limit against
      long-term decreases of psychological performance.

PMID- 10663382
TI  - Cadmium in milk and mammary gland in rats and mice.
AB  - The purpose of the present investigation was to study the uptake of cadmium in
      mammary tissue, effects on milk secretion and composition, and lactational
      transport of cadmium to the sucklings. Cadmium exposure during lactation resulted
      in retention of cadmium in the mammary tissue in mice and rats. The uptake of
      cadmium in the mammary tissue was rapid, as shown in lactating mice by whole-body
      autoradiography 4 h after an intravenous injection of a tracer dose of
      (109)CdCl(2). Retention of cadmium in kidneys of suckling pups was observed in
      the autoradiograms at 7 days after exposure of the dams. Lactating rats were
      intravenously infused with (109)CdCl(2) in 0.9% saline via osmotic minipumps from
      day 3 to day 16 after parturition. The cadmium dose given was 0, 8.8, 62 and 300
      microg Cd/kg body wt. per day. Plasma and milk were collected at day 10 and 16
      after parturition. Plasma cadmium levels in dams increased from day 10 to day 16.
      Cadmium levels were higher in milk than in plasma, with milk/plasma ratios
      varying from 2 to 6. Zinc levels in milk were positively correlated to cadmium
      levels in milk (r(2)=0.26; P=0. 03). In milk, (109)Cd was distributed in fat (46
      52%), casein fraction (40-46%), and whey fraction (6-8%). There was a high
      correlation between cadmium concentrations in pups' kidney and cadmium
      concentrations in dam's milk (r(2)=0.98; P < 0.001). Of the cadmium dose given to
      the dams <0.05% was retained in the litters on day 16 of lactation. No effects
      were observed due to cadmium exposure on body weight in pups or dams. Cadmium
      treatment did not cause any effect on the lactose or protein concentration in
      milk, the concentrations of DNA, RNA or the ratio RNA/DNA in the mammary gland.
      Histological evaluation of mammary tissue did not reveal any abnormalities at any
      dose level. (109)Cd was bound to metallothionein in mammary tissue. The fraction
      of radiolabelled cadmium bound to metallothionein increased in a dose-dependent
      manner in both the liver (88-98%) and mammary tissue (57-80%). The present
      results indicate a low transfer of cadmium to the suckling pup, which might be
      due to binding of cadmium to metallothionein in the mammary tissue. However,
      during the susceptible developmental period even a low cadmium exposure may be of
      concern.

PMID- 10663383
TI  - NAD(P)H quinone oxidoreductase 1 codon 609 polymorphism and its association to
      colorectal cancer.
AB  - The present study used a rapid and single-step method for genotyping of NAD(P)H
      quinone oxidoreductase (NQO1) codon 609 polymorphism using real-time polymerase
      chain reaction (PCR)-analysis and subsequent melting curve analysis for the
      analysis of allelic distribution of NQO1. The design was a case control study of
      323 Caucasians with colorectal cancer and 205 healthy controls. There was no
      difference in the frequencies of the mutated NQO1 allele (NQO1*2): 0.190 for
      control individuals and 0.195 for cancer patients, respectively (P=0.947). When
      this allelic distribution was further compared between non-smoking and smoking
      colorectal cancer patients, it appeared that the frequency of the wild-type
      allele NQO1*1 was higher in the smoking than in the non-smoking group [Odds ratio
      (OR), 0.434; 95% confidence interval (CI), 0.13-1.42]. This observation may
      suggest a protective role of the NQO1 wild-type allele in colon cancer
      susceptibility of individuals exposed to NQO1-inducing chemicals.

PMID- 10663384
TI  - CYP2A6 genetic polymorphisms and liver microsomal coumarin and nicotine oxidation
      activities in Japanese and Caucasians.
AB  - Genotypes of CYP2A6, namely CYP2A6(*)1 (wild-type), CYP2A6(*)2, and CYP2A6(*)3,
      were examined in liver DNA of 39 Japanese and 43 Caucasians using two-step
      polymerase chain reaction (PCR) methods. We first amplified a DNA fragment (1725
      bp) located between near middle of exon 1 and end of exon 4 of the CYP2A6 gene
      and further amplified using a forward primer 't' or 'mut' (middle of exon 3) and
      a reverse primer 'E3R' (middle of intron 3) for the detection of CYP2A6(*)2
      genetic polymorphism. The 1725 bp fragment was also used for the amplification
      between exon 3 and near middle of intron 3 of the CYP2A6 gene and the fragment
      thus obtained digested with XcmI or DdeI to detect and confirm the CYP2A6(*)2-
      and CYP2A6(*)3-types, respectively. Only one DNA sample from a Japanese origin
      (J18) was not amplified by CYP2A6-specific primers; liver microsomes from this
      individual had very low activity of coumarin 7-hydroxylation and were devoid of
      protein(s) immunoreactive to anti-CYP2A6 antibody. Thus, this individual was
      suggested to be due to the gene deletion in CYP2A6. By analyzing the remaining 38
      Japanese and 43 Caucasians, we found that there were no cases of CYP2A6(*)3-type
      polymorphism in the samples examined in this study, and no cases of CYP2A6(*)2
      type polymorphism in the Japanese samples. Of Caucasians studied two individuals
      were classified into heterozygous CYP2A6(*)1/(*)2-type. Liver microsomal coumarin
      7-hydroxylation activities in these two Caucasians were found to be lower than
      those of the other 41 Caucasians. Kinetic analysis showed that two
      CYP2A6(*)1/(*)2 individuals had a very low ratio of V(max) to K(m) for nicotine C
      oxidation as well as coumarin 7-hydroxylation in liver microsomes, compared with
      those of homozygous CYP2A6(*)1-type. These results suggest that among 39 Japanese
      and 43 Caucasians examined one Japanese is classified to be CYP2A6 gene deletion
      and two Caucasians are heterozygous CYP2A6(*)1/(*)2-genotype. Thus the race
      related differences in the occurrence of CYP2A6 genetic polymorphisms were
      supported.

PMID- 10663385
TI  - Effect of hyperoxia on rat pulmonary and hepatic cytochrome P450 monooxygenases.
AB  - Exposure of adult male rats to hyperoxia (O(2) > 95%) resulted in a tendency for
      all of the components of the pulmonary cytochrome P450 (P450) system to increase
      at 48 h after the exposure. However, the most pronounced effect of hyperoxia was
      observed on pulmonary ethoxycoumarin O-deethylase and ethoxyresorufin O
      deethylase activities which were induced 4- and 25-fold respectively after 48 h.
      In the liver, P450 and NADH b(5) reductase were increased after 48 h, while other
      components of the monooxygenase system remained unchanged. In the hepatic
      microsomes, contrary to the lungs, aminopyrine N-demethylase activity was
      decreased after 24 h of hyperoxic exposure (P < 0.05) and returned to the control
      level by 48 h. Similar changes were observed in benzphetamine N-demethylase
      activity. Aniline hydroxylase activity was decreased after 8 h of hyperoxic
      exposure (P < 0.01) and remained decreased at 24 h (P < 0. 01) and 48 h (P <
      0.05). The level of induction of ethoxycoumarin O-deethylase and ethoxyresorufin
      O-deethylase activities, however, was almost similar in the liver to that
      observed in the lungs.

PMID- 10663387
TI  - Ciprofloxacin causes cytoskeletal changes and detachment of human and rat
      chondrocytes in vitro.
AB  - Quinolones cause damage of articular cartilage in different species by forming
      chelate complexes with divalent cations and inducing magnesium deficiency.
      Cations are important for regular function of integrins, a group of transmembrane
      proteins which connect extracellular matrix proteins with the intracellular
      cytoskeleton. We have shown that cultivation of rat chondrocytes in ciprofloxacin
      (CFX)-supplemented and Mg(2+)-free medium led to pronounced changes in the
      cytoskeleton and decreased adhesion of cells to the culture dish. In order to
      test whether or not these effects are species-specific, we extended our studies
      on human chondrocytes. Human chondrocytes cultivated in CFX-supplemented medium
      (10, 40, 80 and 160 microg/ml) or Mg(2+)-free medium showed decreased ability to
      adhere to growth support, cell shape changes, and alterations in actin and
      vimentin cytoskeleton in a concentration dependent manner. Attachment of human
      chondrocytes to collagen type II coated cover slips was reduced to 90% in CFX
      group and 75% in Mg(2+)-free group on day 1. This effect even increased after 4
      days of culture in the respective medium (32% in CFX and 58% in Mg(2+)-free
      group). We concluded that Mg(2+) deficiency is exerted via integrins, resulting
      in decreased ability to attach to extracellular matrix proteins and cytoskeletal
      changes. These effects are not species-specific. The attachment assay proves to
      be an easy to use experimental set-up to test ciprofloxacin and other quinolones
      for their chondrotoxic effects.

PMID- 10663386
TI  - Selective agonists of retinoic acid receptors: comparative toxicokinetics and
      embryonic exposure.
AB  - Three biologically active synthetic retinoids were investigated that bind
      selectively to retinoic acid receptors RARs (alpha, beta and gamma). The
      retinoids were previously demonstrated to have different teratogenic effects in
      the mouse in terms of potency and regioselectivity. The teratogenic potency rank
      order (alpha >beta >gamma) was found to be more or less compatible with the
      receptor binding affinities and transactivation potencies of the retinoid ligands
      to their respective receptors. The RARalpha agonist (Am580; CD336) induced a wide
      spectrum of malformations; CD2019 (RARbeta agonist) and especially CD437
      (RARgamma agonist) produced more restricted defects. In the current study we
      tried to address whether the differences in teratogenic effects are solely
      related to binding affinity and transactivation differences or also due to
      differences in embryonic exposure. Therefore, transplacental kinetics of the
      ligands were assessed following administration of a single oral dose of 15 mg/kg
      of either retinoid given to NMRI mice on day 11 of gestation. Am580 was rapidly
      transferred to the embryo resulting in the highest embryonic exposure [embryo to
      maternal plasma area under the time vs concentration curve (AUC)(0-24 h )ratio
      (E/M) was 1.7], in accordance with its highest teratogenic potency. The low
      placental transfer of CD2019 (E/M of 0.3) was compatible with its lower
      teratogenic potential. Of major interest was the finding that the CD437, though
      being least teratogenic, exhibited considerable embryonic exposure (E/M of 0.6).
      These findings suggest that both the embryonic exposure and receptor binding
      transactivation selectivity are crucial determinants of the teratogenicity of
      these retinoid ligands.

PMID- 10663388
TI  - Chondrotoxicity of ciprofloxacin in immature beagle dogs: immunohistochemistry,
      electron microscopy and drug plasma concentrations.
AB  - The systemic effects of ciprofloxacin in immature Beagles were studied. Dogs of
      10-11 weeks were dosed orally for 5 days with 0 (n=3), 30 (n=5) and 200 (n=5) mg
      ciprofloxacin/kg body wt. Plasma concentrations were measured by high-performance
      liquid chromatography (HPLC) 1 h after dosing (assuming to be peak
      concentrations). In view of the high doses used, the plasma concentrations were
      rather low and declined during the study period. For example, plasma
      concentrations in the high dose group were 6.6 +/- 0.9 mg/l (day 1), 3.9 +/- 1.4
      mg/l (day 3), and 2.6 +/- 1.6 mg/l (day 5). In control dogs and in dogs treated
      with the low dose of ciprofloxacin no pathological changes were seen by light
      microscopy. However, cleft formation and erosions were observed in joint
      cartilage from two of five dogs treated with 200 mg/kg. It is noteworthy that
      despite the high dose used cartilage lesions were not detectable in all five dogs
      of this group by light microscopy. Using antibodies against cell membrane
      receptors (e.g. the alpha(5)beta(1)-integrin) or matrix components (fibronectin,
      collagen II) the articular cartilage effects were studied in detail by
      immunohistochemistry. The most sensitive alteration was an increase in
      fibronectin which was detectable in the vicinity of the lesions in cartilage
      samples from the group of dogs administered the high dose. No clear-cut changes
      were seen with the use of antibodies against other matrix components. Electron
      microscopy revealed typical alterations in chondrocytes from dogs treated with
      ciprofloxacin: e.g., swollen mitochondria and enlarged rough endoplasmic
      reticulum. These changes were much more pronounced in dogs from the high dose
      group than in dogs from the low dose group. Our main conclusion is that after
      oral administration ciprofloxacin exhibits rather low chondrotoxicity, even in
      the most sensitive species known to date. This correlates with the findings in
      humans that ciprofloxacin seems to be less chondrotoxic than pefloxacin or other
      quinolones.

PMID- 10663389
TI  - Effects of magnesium deficiency on joint cartilage in immature beagle dogs:
      immunohistochemistry, electron microscopy, and mineral concentrations.
AB  - Quinolone-induced chondrotoxicity is possibly associated with the magnesium
      chelating properties of quinolones. This toxic effect seems to be restricted to a
      rather short time period during postnatal development as shown in rats and dogs.
      We studied developmental changes of the integrin pattern on canine chondrocytes
      (e.g. the alpha(v)beta(3)- or alpha(5)beta(1)-integrin), because integrin
      function depends on divalent cations, as well as the matrix composition (e.g.,
      collagen type II, fibronectin), in 11-, 18-, and 55-week-old Beagles (n=8) by
      immunohistochemistry. We also analyzed the magnesium and calcium content by
      atomic absorption spectroscopy in cartilage and bone and studied the effects of a
      magnesium-deficient diet on joint cartilage in four immature Beagles (18 weeks
      old at necropsy). The dogs were fed the magnesium-deficient diet for 40 to 46
      days. All dogs exhibited gait alterations ('limping') after 4 weeks on the
      magnesium-deficient diet. Male, magnesium-deficient dogs exhibited pronounced
      weakness in their front legs; in one of these dogs the front legs were
      hyperextended to a 90 degrees angle. We observed no significant differences in
      the integrin pattern in samples from dogs at different developmental stages or in
      magnesium-deficient dogs in comparison to age-matched controls. Localization of
      fibronectin in the joint cartilage was found to vary with the age of the dogs as
      well as with the site of collection. In the middle zone of immature joint
      cartilage, corresponding to the predilective site of quinolone-induced cartilage
      lesions, we observed a slight increase in staining with the fibronectin antibody
      in some samples from magnesium-deficient dogs. Electron microscopy revealed
      alterations in chondrocytes from the magnesium-deficient dogs (e.g., swollen
      mitochondria and enlarged endoplasmic reticulum) which are also seen after
      treatment with quinolones. In summary, we found no significant differences of the
      integrin pattern on chondrocytes from joint cartilage of dogs at various
      developmental stages. However, magnesium deficiency in immature dogs induced
      similar clinical symptoms as quinolone treatment as well as distinct alterations
      in chondrocytic fibronectin staining and their ultrastructure. This corroborates
      our findings in rats where magnesium chelation is an important event in quinolone
      induced chondrotoxicity.

PMID- 10663390
TI  - Non-N-methyl-D-aspartate (NMDA) receptor antagonist 1,2,3, 4-tetrahydro-6-nitro
      2,3-dioxo-benzo(f)quinoxaline-7-sulphonamide (NBQX) decreases functional
      disorders in cytotoxic brain oedema.
AB  - N-methyl-D-aspartate (NMDA) and non-NMDA receptors were found to be involved in
      development of functional disorders caused by hexachlorophene. In order to
      specify the role of glutamate receptors we studied the protective effects of the
      selective antagonist of the kainate/(+/-)-alpha-amino-3-hydroxy-5-methylisoxazole
      4-propionic acid (AMPA) receptor/channel 1,2,3,4-tetrahydro-6-nitro-2, 3-dioxo
      benzo[f]quinoxaline-7-sulphonamide disodium (NBQX) and of the non-competitive
      NMDA receptor antagonist ifenprodil tartrate on coordinative motor behaviour of
      adult male Wistar rats as assessed in a simple 'ladder-test'. Neurotoxic injury
      of the cerebrum after hexachlorophene administration and putative amelioration
      after treatment with test substances was demonstrated histologically.
      Hexachlorophene-induced motor disturbance remitted spontaneously when stopping
      the noxis, but remittance occurred significantly earlier when NBQX [0.45 and 0.6
      mg/kg intraperitoneal (i.p.)] was applied as well. Ifenprodil (0.15 to 1.2 mg/kg)
      did not improve the motor function. Vacuolation of white matter of the whole
      cerebrum was observed after 3 weeks of treatment with hexachlorophene. These
      morphological alterations caused by hexachlorophene treatment [central nervous
      system (CNS) vacuolation] spontaneously revert only after 5-6 weeks. The 5-day
      duration with test substances was too short for remission of vacuolation which
      thus may not apply to the situation after treatment with glutamate antagonists,
      despite improvement of motor function. The results suggest that kainate/AMPA
      receptor channels are at least partially involved in the mechanism of brain
      damage induced by hexachlorophene, however, the polyamine binding site of the
      NMDA receptor evidently is not involved.

PMID- 10663391
TI  - Effect of polychlorinated biphenyls on production of reactive oxygen species
      (ROS) in rat synaptosomes.
AB  - In this paper the effect of polychlorinated biphenyls (PCBs) on the production of
      reactive oxygen species (ROS) in rat synaptosomes is elucidated. The effect of
      methylmercury (MeHg) on rat synaptosomes was included as a positive control since
      several studies have investigated the ability of this substance to produce ROS.
      The exposure of the synaptosomes to the congener 2,2-dichlorobiphenyl (2, 2'-DCB;
      12.5 microM) produced a linear increase in the formation of 2',7'
      dichlorofluorescein (DCF) as a measure for the production of ROS. The congeners
      2,2'-DCB (12.5 microM) and 3,3'-DCB (12.5 microM) stimulated, as expression of
      ROS production, a significant increase in DCF formation formation compared to the
      control. The congeners 2-chlorobiphenyl (2-CB) and 2,2',6-trichlorobiphenyl
      (2,2,6'-TCB) were active at 50 microM, whereas 2,2',4,4',5,5'-hexachlorobiphenyl
      (2,2',4,4',5,5'-HCB), 4,4'-DCB and 2,2',6,6'-tetrachlorobiphenyl (2, 2',6,6'
      TeCB) were not active at this concentration. The increased formation of ROS in
      response to 2,2'-DCB and MeHg in the synaptosomes was dependent on extracellular
      Ca(2+). A phospholipase C inhibitor, U73122, was shown to significantly decrease
      the ROS formation induced by 2,2'-DCB, but did not reduce the ROS formation
      induced by MeHg. Ethanol (1%), a phospholipase D modulator, reduced the ROS
      formation induced by MeHg and by 2,2'-DCB by 33 and 52%, respectively. Wortmannin
      (25 nM), an inhibitor of phosphatidylinositol 3-kinase, completely inhibited the
      ROS formation induced by MeHg and 2,2'-DCB. It appears that the ROS-stimulating
      PCBs are the same congeners found to be neuroactive in other types of study.
      Phospholipase C and D and phosphatidylinositol 3-kinase seem to be involved in
      the intracellular signalling system that leads to ROS formation during PCB
      exposure.

PMID- 10663392
TI  - A hepatotoxic dose of acetaminophen modulates expression of BCL-2, BCL-X(L), and
      BCL-X(S) during apoptotic and necrotic death of mouse liver cells in vivo.
AB  - The protein BCL-X(L) and protein product of proto-oncogene bcl-2 act as apoptosis
      antagonists, and BCL-X(S) serve as a dominant death promoter, including apoptosis
      following exposure to chemotherapeutic drugs. This investigation examined whether
      some aspects of the highly integrated process of acetaminophen (AAP)-induced
      hepatotoxicity involve down-regulation or upregulation of expression of BCL-2,
      BCL-X(L) and BCL-X(S) in mouse liver in vivo. Male ICR mice (CD-1; 35-45 g) were
      treated ip with a hepatotoxic dose of AAP (500 mg/kg) and sacrificed 0, 6, and 18
      h later. Blood was collected upon sacrifice for determination of serum alanine
      aminotransferase (ALT) activity and the liver was sectioned for histopathological
      diagnosis of necrosis/apoptosis. Portions of liver tissues were also used for DNA
      extraction (for gel electrophoresis) and Western blot analysis. This study
      demonstrates that administration of a hepatotoxic dose of AAP to ICR mice results
      in severe liver injury (ALT leakage >200-fold at 6 h and >600-fold at 18 h)
      leading to massive cell death by apoptosis (diagnosed by nuclear ultrastructure,
      histopathology, and DNA ladder), in addition to necrosis coupled with spectacular
      changes in the BCL-X(L) expression (6 and 18 h after AAP administration). Western
      blot analysis of the liver proteins revealed that mouse liver expresses two
      proteins, BCL-X(L) and BCL-X(S), and does not express BCL-2. As the toxicity
      progressed, during 6 and 18 h post-AAP administration, the BCL-X(L) protein band
      shifted to a slower mobility band which might represent a phosphorylated form of
      BCL-X(L). Appearance of this higher molecular weight BCL-X(L) protein band
      correlated with massive apoptotic death of liver cells along with ladder-like DNA
      fragmentation. In the same time period, death inhibitory gene bcl-2 remained
      unexpressed, and the level of expression of BCL-X(S) remained unaltered. Whether
      the consistent level of expression of BCL-X(S) reflected inability of AAP to
      influence its expression remains unknown. Unaltered expression of BCL-X(S) in the
      near total absence of BCL-2 expression raises questions regarding the death
      promoting role of BCL-X(S) in vivo. The precise role of modified form of BCL-X(L)
      remains elusive. However, this study may have demonstrated for the first time
      drug-induced changes in the expression of anti-apoptotic gene BCL-X(L), and a
      positive link between AAP-induced apoptotic death and modification of BCL-X(L)
      protein in vivo.

PMID- 10663409
TI  - Atypical antipsychotics: an inspiring but confusing concept

PMID- 10663393
TI  - Metabolites of the biocide o-phenylphenol generate oxidative DNA lesions in V 79
      cells.
AB  - Incubation of the o-phenylphenol (OPP) metabolites, o-phenylhydroquinone (PHQ)
      and o-phenylbenzoquinone (PBQ) with V 79 Chinese hamster cells led to a
      significant enhancement of the amount of 8-hydroxy-2'-deoxyguanosine (8-OH-dG) in
      nuclear DNA. With OPP no distinct induction of this lesion could be observed. In
      addition, PHQ and PBQ were able to generate DNA single-strand breaks (DNA SSB),
      while OPP failed to induce this lesion. All incubations were performed for 1 h
      without exogenous metabolic activations and the lowest effective concentration
      tested was 20 microM. It is concluded that these metabolites may contribute to
      the carcinogenicity of OPP and sodium o-phenylphenolate (SOPP) observed in rats,
      by generating reactive oxygen species (ROS) through their redox cycling
      properties.

PMID- 10663410
TI  - Atypical antipsychotics: are some more atypical than others?
AB  - On the heels of clozapine, we now have a number of newer agents (risperidone,
      olanzapine, quetiapine, sertindole, and ziprasidone). Are they all the same? What
      are the differences? How do we best understand them? In this article we review
      current clinical evidence to compare these issues on four measures of
      atypicality: EPS, prolactin elevation, superior efficacy in refractory/positive
      symptoms and efficacy against negative symptoms. All the newer agents are
      superior on EPS and, with the exception of risperidone, avoid prolactin
      elevation. Clozapine shows the most convincing efficacy in refractory
      schizophrenia, although comparative data concerning risperidone's benefit in this
      respect are also emerging. It is unclear, however, whether any of the agents
      produce a greater effect than conventional antipsychotics against positive
      symptoms in responsive patients. Both clozapine and olanzapine have demonstrated
      superior efficacy against negative symptoms, although it remains controversial
      whether this is an effect on primary or secondary symptoms. The precise
      pharmacologic mechanisms underlying "atypicality" remain unclear, but several
      conceptual frameworks are highlighted that characterize, and perhaps
      differentiate, these newer agents.

PMID- 10663411
TI  - An atypical compound by any other name is still a.

PMID- 10663412
TI  - "New" rather than "atypical".

PMID- 10663413
TI  - Non-equipotent doses partly explain differences among antipsychotics -
      implications of PET studies.

PMID- 10663414
TI  - Flumazenil induces benzodiazepine partial agonist-like effects in BALB/c but not
      C57BL/6 mice.
AB  - RATIONALE: Some anxiety disorders may be treated in a different way than normal
      anxiety. OBJECTIVE: This study was aimed at investigating the action of the
      benzodiazepine receptor antagonist flumazenil, compared to that of the
      benzodiazepine receptor full agonist chlordiazepoxide, in an animal model of
      generalised anxiety disorder (the BALB/c mouse). METHODS: Flumazenil (0.0001,
      0.001, 0. 01, 0.1 and 1 mg/kg) or chlordiazepoxide (5 mg/kg) were administered to
      BALB/c or C57BL/6 mice subjected to the light/dark test, the elevated plus maze
      or a passive avoidance step-through paradigm. RESULTS: Chlordiazepoxide and
      flumazenil (at all doses tested in the elevated plus maze and at the doses of
      0.001 and 0.01 mg/kg in the light/dark test) induced a strong anxiolytic effect
      in BALB/c mice. Flumazenil did not induce anxiolysis in C57BL/6 mice, whatever
      the behavioral test or the dose used. However, chlordiazepoxide elicited
      anxiolysis in this strain in both procedures. In the passive avoidance test,
      chlordiazepoxide was amnesic in both strains but flumazenil had no effect.
      CONCLUSION: Flumazenil induces partial agonist-like effects in BALB/c and not in
      C57BL/6 mice, suggesting a possible benzodiazepine receptor set point shift
      toward the agonistic direction in some pathological anxiety states such as
      generalised anxiety disorder.

PMID- 10663415
TI  - The effect of bupropion on nicotine craving and withdrawal.
AB  - RATIONALE AND OBJECTIVES: Bupropion has demonstrated efficacy for smoking
      cessation. Given the importance of nicotine craving and withdrawal in the smoking
      cessation process, the current study examined the effects of bupropion on these
      parameters during smoking abstinence. METHODS: During a 2-day Baseline phase with
      ad lib smoking, 91 non-depressed smokers (who were not trying to quit
      permanently) were administered measures of nicotine craving, withdrawal symptoms,
      and timed measures of cognitive performance five times daily. Participants were
      then assigned randomly to a 14-day treatment regimen with bupropion 300 mg/day,
      bupropion 150 mg/day, or placebo. Thereafter, the above measures were re
      administered during 3 days of abstinence on a closed research ward. RESULTS:
      Relative to placebo, 300 mg bupropion significantly reduced abstinence-associated
      increases in rated depression, difficulty concentrating, and irritability, and
      attenuated a decrease in positive affect. The results also suggested that
      bupropion might have a positive effect on performance measures during the
      withdrawal period. No effects were observed on craving, anxiety, restlessness, or
      hunger. The lack of findings on craving measures may be explained by a floor
      effect; except on the first day of abstinence, neither drug nor placebo groups
      showed much craving elevation during abstinence. CONCLUSIONS: Study results
      indicate that bupropion ameliorates some nicotine withdrawal symptoms.

PMID- 10663416
TI  - Effects of dopamine D(1-like) and D(2-like) agonists on cocaine self
      administration in rhesus monkeys: rapid assessment of cocaine dose-effect
      functions.
AB  - RATIONALE: The reinforcing effects of cocaine have been most compellingly related
      to its action as an indirect dopamine agonist. Although it is generally believed
      that both D(1-like )and D(2-like )receptor mechanisms may be involved, recent
      studies suggest that D(1-like )and D(2-like )agonists have differing profiles of
      cocaine-related actions. OBJECTIVE: To develop a procedure for rapid assessment
      of complete dose-effect functions for cocaine self-administration in rhesus
      monkeys and to compare the effects of D(1-like )and D(2-like )agonists on cocaine
      self-administration using this procedure. METHODS: Responding was maintained by
      various doses of cocaine or by food under a multiple-component schedule [fixed
      ratio (FR) 30; time out period (TO) 10 s] in 2-h sessions. After responding
      stabilized, the effects of pretreatment with D(1-like )and D(2-like )agonists
      (administered i.m., 10 min or 30 min prior to the session) were assessed.
      RESULTS: Complete inverted U-shaped dose-effect functions for cocaine self
      administration were obtained in all five rhesus monkeys trained with the rapid
      assessment procedure. Both the position and shape of the cocaine dose- effect
      function remained stable in repeated assessments, and levels of responding were
      controlled by the unit dose of cocaine rather than by other variables (e.g.,
      infusion duration and volume) that were used to vary the cocaine dose.
      Pretreatment with the D(1-like) agonists SKF 82958 (0.32-1.8 mg/kg) and R-6-Br
      APB (0.1-1. 0 mg/kg) produced downward shifts in the cocaine dose-effect function
      at doses that also markedly decreased food-maintained responding. In contrast,
      pretreatment with the D(2-like) agonists quinelorane (0.001-0.01 mg/kg) and 7-OH
      DPAT (0.01-0.10 mg/kg) shifted the cocaine dose-effect function to the left. D(2
      like) agonists also increased responding maintained by the cocaine-associated cue
      lights alone, and moderately decreased food-maintained responding. CONCLUSIONS:
      The results suggest that D(1-like) and D(2-like) agonists produce qualitatively
      different effects on cocaine self-administration that may influence their
      usefulness for the treatment of cocaine abuse and dependence.

PMID- 10663417
TI  - Self-administration of intravenous amphetamine is predicted by individual
      differences in sucrose feeding in rats.
AB  - RATIONALE: Previous studies have shown that individual differences in oral
      sucrose consumption are predictive of the psychomotor and dopamine (DA) stimulant
      properties of amphetamine in rats. OBJECTIVES: The present experiment was
      designed to examine the relationship between sucrose feeding and the reinforcing
      properties of amphetamine using the intravenous (i.v.) drug self-administration
      paradigm. METHODS: Based on a median split of sucrose intake during a final 1-h
      feeding test session, male Wistar rats were designated as either low (LSF) or
      high sucrose feeders (HSF). Acquisition of i. v.-amphetamine self-administration
      across ten daily 30-min sessions was then assessed. Following acquisition, i.v.
      self-administration of several doses of amphetamine was similarly tested across
      daily 30-min sessions. RESULTS: Data from this experiment revealed augmented
      responding in HSF compared with LSF during acquisition of amphetamine self
      administration. Correspondingly, when given access to different doses of
      amphetamine, responding was greater in HSF than in LSF across several doses (3
      microg and 10 microg per infusion). CONCLUSIONS: These data support the notion
      that individual differences in oral sucrose consumption are predictive of the
      reinforcing properties of psychostimulant drugs.

PMID- 10663418
TI  - Role of morphine maintenance dose in the development of tolerance and its
      attenuation by an NMDA receptor antagonist.
AB  - RATIONALE: Current research shows that N-methyl-d-aspartate (NMDA) receptor
      antagonists attenuate the development of morphine tolerance in rodent
      antinociceptive assays. OBJECTIVE: The purpose of this study was to determine the
      role of morphine maintenance dose in the attenuation of morphine tolerance by the
      competitive NMDA receptor antagonist, LY235959. METHODS: A rat warm-water tail
      withdrawal procedure was used to measure the antinociceptive effects of morphine
      and LY235959. In this procedure, the distal 8 cm of each rat's tail is immersed
      in 40 degrees (non-noxious) and 55 degrees C (noxious) water, and the latency to
      remove the tail is recorded. RESULTS: Morphine (0.3-10 mg/kg, SC) produced dose
      dependent increases in tail-withdrawal latencies from the 55 degrees C water.
      Following determination of the morphine dose-effect curves, rats were
      administered chronically one of three doses of morphine (10, 20, or 40 mg/kg)
      either alone or in combination with LY235959 (1.0, 3.0, or 5.6 mg/kg, SC) twice
      daily for 7 days. Chronic administration of 10, 20, and 40 mg/kg morphine
      produced rightward shifts in the morphine dose-effect curves of approximately 3-,
      6-, and 12-fold, respectively. When LY235959 (1.0-5.6 mg/kg) was co-administered
      with 10 mg/kg morphine, the development of morphine tolerance was attenuated in a
      dose-dependent manner, with complete prevention observed following 3.0 mg/kg
      LY235959. LY235959 (1.0, 3.0 mg/kg) also attenuated the development of tolerance
      to 20 and 40 mg/kg morphine; however, tolerance was not completely prevented.
      Administering 3.0 mg/kg LY235959 along with 20 and 40 mg/kg morphine was
      functionally equivalent to treating rats with half the amount of morphine.
      CONCLUSION: These data suggest that the maintenance dose of morphine, and thus
      the magnitude of tolerance, can determine the effectiveness of an NMDA receptor
      antagonist to attenuate morphine tolerance.

PMID- 10663419
TI  - Up-regulation of neuronal NO synthase immunoreactivity in opiate dependence and
      withdrawal.
AB  - RATIONALE: Nitric oxide (NO) has been postulated to contribute significantly to
      analgesic effects of opiates as well as to the development of tolerance and
      physical dependence to morphine. OBJECTIVE: The present study was undertaken to
      determine the effect of chronic morphine treatment and abstinence on the
      expression of neuronal NO synthase (neuronal NOS, nNOS) in several brain regions
      of mice. METHODS: Seven days after the implantation of a 75 mg morphine pellet,
      adult male CD1 mice received a SC dose of 1 mg/kg naloxone. Fifteen minutes after
      the naloxone injection, brains were removed and nNOS expression was studied by
      using immunohistochemical methods. RESULTS: Morphine-dependence produced an
      increase in the number of nNOS-positive cells in the main and accessory olfactory
      bulb, olfactory nuclei, cerebellum, locus coeruleus, medulla oblongata (nucleus
      of the solitary tract and prepositus hypoglossal nucleus), and a decrease in nNOS
      immunoreactivity in hypothalamus. The administration of naloxone to morphine
      dependent mice to induce abstinence increased nNOS immunoreactivity in the
      hypothalamus and locus coeruleus. CONCLUSIONS: These results indicate that the
      chronic treatment with morphine leads to alterations in nNOS expression in
      important regions implicated in the physical tolerance and dependence to opiates
      and suggest the use of specific inhibitors of this isoform in these conditions.

PMID- 10663420
TI  - Pharmacological and behavioral characterization of cocaine-kindled seizures in
      mice.
AB  - RATIONALE: Convulsions associated with cocaine toxicity are a serious aspect of
      cocaine-related emergency room incidents. Seizures can result from a single high
      dose of cocaine, and evidence is accumulating that correlates repetitive
      administration of sub-convulsive doses of cocaine with a decreased seizure
      threshold, a phenomenon known as pharmacological kindling. A murine model of
      cocaine kindling has not been characterized. OBJECTIVES: To determine the
      necessary and sufficient conditions for generating increased sensitivity to the
      convulsive and lethal effects of cocaine and to characterize some of the basic
      pharmacological and behavioral consequences of this phenomenon in mice. METHODS:
      Male, Swiss-Webster mice were given repeated injections of cocaine. RESULTS:
      Daily administration of 60 mg/kg cocaine produced robust kindling; significant
      leftward shifts in the dose-effect curves for seizures were observed in cocaine
      kindled mice. Cocaine kindling was enduring as these left shifts persisted for at
      least 20 days, indicating possible permanent synaptic changes. Induction of
      convulsions per se, utilizing 75 mg/kg cocaine, was not sufficient to engender
      kindling with a non-optimal dose (40 mg/kg). However, administration of a non
      kindling dose of cocaine (40 mg/kg) for as few as four occasions produced
      increased seizure sensitivity to a 60-mg/kg cocaine challenge. The lethal
      potencies of cocaine and methamphetamine were significantly increased in cocaine
      kindled mice. The baseline locomotor activity of kindled mice was not different
      from that of non-kindled mice. However, challenge doses of cocaine revealed
      significant differences in the vertically directed activity of kindled versus non
      kindled mice. CONCLUSIONS: Overall, this study provides a description of
      important parameters for a model of cocaine kindling in mice that may be useful
      for the elucidation of mechanisms responsible for the long-term changes in
      sensitivity to cocaine and the discovery of novel pharmacological treatments.

PMID- 10663421
TI  - Relationship between plasma concentrations of clozapine and norclozapine and
      therapeutic response in patients with schizophrenia resistant to conventional
      neuroleptics.
AB  - RATIONALE: Monitoring plasma clozapine concentrations may play a useful role in
      the management of patients with schizophrenia, but information on the
      relationship between the plasma levels of the drug and response is still
      controversial. OBJECTIVE: The purpose of this study was to assess the
      relationship between plasma concentrations of clozapine and its weakly active
      metabolite norclozapine and clinical response in patients with schizophrenia
      resistant to conventional neuroleptics. METHODS: Forty-five patients, 35 males
      and ten females, aged 19-65 years, were given clozapine at a dosage up to 500
      mg/day for 12 weeks. Steady-state plasma concentrations of clozapine and
      norclozapine were measured at week 12 by a specific HPLC assay.
      Psychopathological state was assessed at baseline and at week 12 by using the
      Brief Psychiatric Rating Scale, and patients were considered responders if they
      showed a greater than 20% reduction in total BPRS score compared with baseline
      and a final BPRS score of 35 or less. RESULTS: Mean plasma clozapine
      concentrations were higher in responders (n=18) than in non-responders (n=27)
      (472+/-220 versus 328+/-128 ng/ml, P<0.01), whereas plasma norclozapine levels
      did not differ between the two groups (201+/-104 versus 156+/-64 ng/ml, NS). A
      significant positive correlation between plasma levels and percent decrease in
      total BPRS score was found for clozapine (r(s)=0.371, P<0.02), but not for
      norclozapine (r(s)=0.162, NS). A cutoff value at a clozapine concentration of
      about 350 ng/ml differentiated responders from non-responders with a sensitivity
      of 72% and a specificity of 70%. At a cutoff of 400 ng/ml, sensitivity was 67%
      and specificity 78%. The incidence of side effects was twice as high at clozapine
      concentrations above 350 ng/ml compared with lower concentrations (38% versus
      17%). CONCLUSIONS: These results suggest that plasma clozapine levels are
      correlated with clinical effects, although there is considerable variability in
      the response achieved at any given drug concentration. Because many patients
      respond well at plasma clozapine concentrations in a low range, aiming initially
      at plasma clozapine concentrations of 350 ng/ml or greater would require in some
      patients use of unrealistically high dosages and imply an excessive risk of side
      effects. Increasing dosage to achieve plasma levels above 350-400 ng/ml may be
      especially indicated in patients without side effects who failed to exhibit
      amelioration of psychopathology at standard dosages or at lower drug
      concentrations.

PMID- 10663422
TI  - Relationships among dopamine transporter affinities and cocaine-like
      discriminative-stimulus effects.
AB  - RATIONALE: The discriminative-stimulus effects of cocaine have been reported to
      be mediated by indirect agonist actions initiated by the blockade of dopamine
      uptake, and the potencies of drugs that have discriminative-stimulus effects like
      cocaine are directly related to their dopamine transporter binding affinities.
      The binding to the dopamine transporter by cocaine and many of its analogs has
      been reported to fit better using a two-site model than a one-site model.
      OBJECTIVES: The present study examined the relationship among binding affinities
      of dopamine uptake inhibitors at these two sites and their potencies to produce
      discriminative-stimulus effects. METHODS: The inhibition constants (K(i) values)
      were derived for unlabeled dopamine uptake inhibitors for displacement of
      [(3)H]WIN 35,428 from rat caudate putamen membranes. These K(i) values were
      related to the ED(50) values obtained in rats trained to discriminate 10 mg/kg
      cocaine from saline injections under a fixed-ratio 20 schedule of food
      reinforcement. RESULTS: Among the dopamine uptake inhibitors studied, the binding
      data for eight compounds (WIN 35,428, nomifensine, WIN 35,981, WIN 35,065-2,
      methylphenidate, cocaine, cocaethylene, and bupropion) were better fit by a two
      site model than a one-site model. The data for the remaining eleven compounds
      (RTI-31, RTI-55, RTI-121, RTI-32, LU19-005, BTCP, GBR12909, GBR12935, mazindol,
      LU17-133, and EXP561) were better fit by a one-site model. Of the drugs that were
      fit best by a two-site model, there was a higher correlation among the K(i)
      values for the high-affinity site and the ED(50) values (R(2)=0.655; P=0.015)
      than there was for the low-affinity site (R(2)=0.543; P=0. 037). Of the remaining
      drugs, there was a high correlation among the K(i) values and the ED(50) values
      for the discriminative-stimulus effects (R(2)=0.523; P=0.012). CONCLUSIONS: These
      data suggest that the discriminative-stimulus effects of cocaine are more closely
      related to actions mediated by high-affinity binding to the dopamine transporter
      than they are to actions mediated by the low-affinity site. The further
      assessment of the respective contributions of high- and low-affinity binding to
      the behavioral effects of cocaine will be greatly enhanced with the development
      of pharmacological tools that have a high degree of selectivity for one of these
      components.

PMID- 10663423
TI  - Selective mu and delta, but not kappa, opiate receptor antagonists inhibit the
      habituation of novelty-induced hypoalgesia in the rat.
AB  - RATIONALE: There is now extensive evidence demonstrating that exposure to novel
      stimuli induces hypoalgesia and that this effect habituates over repeated
      exposure to the stimuli. Moreover, it has been shown that administration of the
      nonselective opiate receptor antagonist naloxone can attenuate the rate of
      habituation of novelty-induced hypoalgesia. OBJECTIVES: The present experiments
      were conducted to determine the relative influence of different opiate receptor
      subtypes in the attenuation of the habituation of novelty-induced hypoalgesia.
      METHODS: In experiments 1-3, different groups of male, Wistar rats (275-300 g)
      were administered vehicle, 0. 5, 1.0 or 2.0-nmol doses of the mu-selective
      antagonist Cys(2)-Tyr(3)-Orn(5)-Pen(7)-amide (CTOP), the delta-receptor selective
      antagonist naltrindole, or the kappa-selective antagonist nor-binaltorphimine
      (nor-BNI). In experiment 4, animals were administered vehicle, 5, 25 or 75-nmol
      doses of nor-BNI. All injections were delivered to the right lateral ventricle 30
      min prior to exposure to a novel hot-plate apparatus (48.5 degrees C), once a day
      for eight consecutive days. RESULTS: Paw-lick latencies in vehicle-treated
      animals were long during the initial exposures and declined over repeated tests,
      suggesting the habituation of novelty-induced hypoalgesia. The rate of
      habituation was significantly attenuated by administration of 1.0-nmol and 2.0
      nmol doses of CTOP, by a 2.0-nmol dose of naltrindole, but was unaffected by all
      doses of nor-BNI. CONCLUSIONS: These results support the involvement of the mu
      and delta, but not the kappa, opiate receptor subtypes in the habituation of
      novelty-induced hypoalgesia.

PMID- 10663424
TI  - Human interferon-alpha increases immobility in the forced swimming test in rats.
AB  - OBJECTIVES: We examined the immobility of the forced swimming test induced in an
      animal model by human interferon (IFN), which has often been reported to induce
      depression in clinical use. METHODS: In the present study, we examined the
      effects of human IFNs on results of the forced swimming test in rats. RESULTS:
      Single intravenous (IV) administration of human IFN-alpha (6x10(4) IU/kg), but
      not of human IFN-beta or -gamma, significantly increased immobility time in the
      forced swimming test in rats. Repeated administration of human IFN-alpha (6x10(3)
      IU/kg) also significantly increased the immobility time. On the other hand, none
      of the rat IFNs (rat IFN-alpha, -beta and -gamma, 6x10(4) IU/kg, IV) changed the
      immobility time. Neither human IFNs nor rat IFNs changed the locomotor activity
      of rats. CONCLUSIONS: These findings suggest that human IFN-alpha has a greater
      potential for inducing increase of the immobility in the rat forced swimming test
      than human IFN-beta and -gamma, and that the effect of human IFN-alpha might not
      be mediated through IFN-alpha/beta receptors.

PMID- 10663425
TI  - Blockade of muscarinic, rather than nicotinic, receptors impairs attention, but
      does not interact with serotonin depletion.
AB  - RATIONALE: The cholinergic system is considered to be essential for attention and
      the degeneration of the cholinergic system in Alzheimer's disease (AD) correlates
      with the cognitive decline seen in AD patients. The serotonergic system also
      degenerates in AD, but its role in the modulation of cognitive functions,
      especially attention, is somewhat unclear. OBJECTIVES: The present study
      investigated possible differences between cholinergic muscarinic and nicotinic
      receptor mediated mechanisms, the role of serotonin (5-HT) and the interaction
      between the cholinergic and serotonergic systems in the modulation of attention
      and response control. METHODS: The influences of cholinergic receptor blockade
      and 5-HT lesions on the performance of rats in the five-choice serial reaction
      time task were assessed. The 5-HT lesions were neurochemically verified. RESULTS:
      The neurochemical analysis indicated that the levels of 5-HT and 5
      hydroxyindoleacetic acid were reduced quite specifically in the hippocampi,
      parieto-occipital and frontal cortices, and in the striatum of both p
      chloroamphetamine (pCA) and 5, 7-dihydroxytryptamine (5,7-DHT) lesioned rats. The
      behavioural results showed that the pCA lesion caused a transient increase in
      impulsivity whereas the 5,7-DHT lesion temporarily reduced the motor activity and
      slightly impaired choice accuracy. Furthermore, the blockade of central
      muscarinic receptors by scopolamine (0.075 and 0. 150 mg/kg), but not nicotinic
      receptors by mecamylamine (1.0 or 3.0 mg/kg), impaired the choice accuracy,
      whereas the blockade of both muscarinic and nicotinic receptors interfered with
      motor activity, though possibly via peripheral mechanisms. Interestingly,
      mecamylamine (3.0 mg/kg) reduced impulsivity, whereas scopolamine slightly
      increased it. Serotonergic lesions did not make the rats more susceptible to the
      effects of cholinolytics on choice accuracy. CONCLUSIONS: 5-HT system is not
      essential for the modulation of attention, but it is important in the modulation
      of response control. Central muscarinic receptors are important in the modulation
      of attention, whereas central nicotinic receptors may be more essential in
      response control. The results do not support there being an interaction between
      the serotonergic and the cholinergic systems in the modulation of attention.

PMID- 10663426
TI  - The role of genetic and early environmental factors in determining apomorphine
      susceptibility.
AB  - RATIONALE: There is ample evidence that rats show large individual differences in
      their response to dopaminergic drugs, such as apomorphine. OBJECTIVE: The aim of
      the present study was to investigate the role of genetic and (early)
      environmental factors in determining the adult susceptibility to apomorphine.
      Four experiments were performed: In experiment 1, the original selective breeding
      of rats for apomorphine susceptibility (leading to APO-SUS and APO-UNSUS rats)
      was extended and replicated in an independent group of Wistar rats. In experiment
      2, APO-SUS males were cross-bred with APO-UNSUS females and vice versa. In
      experiment 3 APO-SUS litters were cross-fostered to APO-UNSUS mothers or
      infostered to unknown APO-SUS mothers and vice versa. In experiment 4 APO-SUS and
      APO-UNSUS rats were maternally deprived on postnatal day 9, for a single 24-h
      period. METHODS: Adult rats were subcutaneously injected with 1.5 mg/kg
      apomorphine and their gnawing response was automatically recorded in a gnawing
      box for 45 min. RESULTS: In experiment 1, the original breeding was extended up
      to generation 24, leading to a strong and consistent difference in gnawing
      scores. The replication experiment also succeeded in differentiating APO-SUS and
      APO-UNSUS. The cross breeding experiments showed that the APO-SUS/UNSUS offspring
      showed gnawing scores in between the original selection lines. Cross-fostering
      APO-SUS with APO-UNSUS significantly reduced the gnawing response in the
      offspring, whereas it did not affect the gnawing score in the APO-UNSUS animals.
      Maternal deprivation had the opposite effect: increase in gnawing response in APO
      UNSUS, with no effect in APO-SUS. CONCLUSION: The results show a clear-cut
      contribution of both genetic and early environmental factors to the
      susceptibility of apomorphine.

PMID- 10663427
TI  - Dose-dependent suppression by ethanol of transient auditory 40-Hz response.
AB  - RATIONALE: Acute alcohol (ethanol) challenge is known to induce various cognitive
      disturbances, yet the neural basis of the effect is poorly known. The auditory
      transient evoked gamma-band (40-Hz) oscillatory responses have been suggested to
      be associated with various perceptual and cognitive functions in humans; however,
      alcohol effects on auditory 40-Hz responses have not been investigated to date.
      OBJECTIVES: The objective of the study was to test the dose-related impact of
      alcohol on auditory transient evoked 40-Hz responses during a selective-attention
      task. METHODS: Ten healthy social drinkers ingested, in four separate sessions,
      0.00, 0. 25, 0.50, or 0.75 g/kg of 10% (v/v) alcohol solution. The order of the
      sessions was randomized and a double-blind procedure was employed. During a
      selective attention task, 300-Hz standard and 330-Hz deviant tones were presented
      to the left ear, and 1000-Hz standards and 1100-Hz deviants to the right ear of
      the subjects (P=0. 425 for each standard, P=0.075 for each deviant). The subjects
      attended to a designated ear, and were to detect the deviants therein while
      ignoring tones to the other ear. RESULTS: The auditory transient evoked 40-Hz
      responses elicited by both the attended and unattended standard tones were
      significantly suppressed by the 0.50 and 0.75 g/kg alcohol doses. CONCLUSIONS:
      Alcohol suppresses auditory transient evoked 40-Hz oscillations already with
      moderate blood alcohol concentrations. Given the putative role of gamma-band
      oscillations in cognition, this finding could be associated with certain alcohol
      induced cognitive deficits.

PMID- 10663428
TI  - Discriminative stimulus effects of two doses of fentanyl in rats: pharmacological
      selectivity and effect of training dose on agonist and antagonist effects of mu
      opioids.
AB  - RATIONALE: Discriminative stimulus effects of mu opioids vary systematically as a
      function of training dose. Differences among training doses may arise from
      multiple mechanisms. OBJECTIVES: In vivo apparent pA(2) analyses were used to
      examine the contributions of opioid mechanisms to stimulus control by low and
      high training doses of the mu opioid fentanyl. METHODS: Saline and one of two
      doses of fentanyl, administered s.c., were established as discriminative stimuli
      in two groups of rats (low training dose group: 0.01 mg/kg; high training dose
      group: 0.04 mg/kg). Generalization tests and in vivo apparent pA(2) analyses were
      used to evaluate receptor mechanisms of stimulus control. RESULTS: Fentanyl,
      etonitazene, methadone, and morphine evoked full fentanyl generalization in both
      groups but were more potent in the low-dose group. Spiradoline and d-amphetamine
      did not evoke generalization in either group. Naltrexone antagonized stimulus and
      rate-altering effects of fentanyl in both groups, with apparent pA(2) values of
      7. 6 in the low-dose group and 7.5 in the high-dose group. Nalbuphine and
      nalorphine evoked full generalization in the low-dose group but less than 40%
      generalization in the high-dose group. In the high-dose group, nalbuphine and
      nalorphine antagonized the stimulus and rate-altering effects of fentanyl with
      apparent pA(2) values of 5.3 and 6.1, respectively, demonstrating lower efficacy
      mu actions. CONCLUSIONS: Changes in fentanyl training dose preserved the mu
      opioid selectivity of stimulus control but altered the intensity of the
      transduced mu opioid stimulus required for generalization. These differences in
      intensity of the fentanyl stimulus determined whether low efficacy mu opioids
      would evoke or antagonize fentanyl generalization.

PMID- 10663429
TI  - Discriminative stimulus properties of alprazolam.
AB  - RATIONALE: The triazolobenzodiazepine alprazolam has a unique clinical profile
      compared to most other benzodiazepines (e.g. diazepam, chlordiazepoxide), in that
      it is used to treat panic disorder and is effective in depression, two disorders
      that are usually treated with anti-depressants. Previous drug discrimination
      studies suggested that alprazolam has stimulus properties in common with
      antidepressants. OBJECTIVE: In the present study, the discriminative stimulus
      properties of alprazolam were investigated to test more conclusively the role of
      benzodiazepine receptors and whether alprazolam has stimulus properties in common
      with antidepressants. METHODS: Male Wistar rats (n=12) were trained to
      discriminate between alprazolam (2.0 mg/kg, PO) and vehicle in an operant two
      lever drug discrimination procedure under a tandem VI40"-FR10 schedule of
      reinforcement. Generalization and antagonism tests were carried out under 2 min
      extinction. RESULTS: In generalization tests, a number of benzodiazepines
      (alprazolam, chlordiazepoxide, midazolam, lorazepam) and the barbiturate
      pentobarbital substituted completely, while zolpidem and abecarnil substituted
      partially for alprazolam. In contrast, no significant degree of generalization to
      the antidepressants imipramine and fluvoxamine and the putative antidepressants
      buspirone and flesinoxan was found. In antagonism studies alprazolam could be
      antagonized (almost) completely by flumazenil, partially by pentylenetetrazole,
      but not by methyl 6, 7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), N
      methyl-beta-carboline-3-carboxamide (FG-7142) and picrotoxin. CONCLUSIONS: These
      results show that the discriminative stimulus properties of alprazolam are
      mediated by benzodiazepine receptors and that the finding that antidepressants
      share discriminative stimulus effects with alprazolam may have limited
      generality.

PMID- 10663431
TI  - Differences in anxiety-related behaviours and in sensitivity to diazepam in
      inbred and outbred strains of mice.
AB  - RATIONALE: Natural strain differences exist in mice for behavioural traits such
      as emotional reactivity. OBJECTIVE: The present experiments compared the
      behavioural profiles of nine strains of mice (BALB/c, C57BL/6, C3H, CBA, DBA/2,
      NMRI, NZB, SJL, Swiss) in two models of anxiety after the administration of the
      benzodiazepine diazepam. METHODS: The tests used were the light/dark choice task
      and the elevated plus-maze, two well-validated anxiolytic screening tests.
      RESULTS: In vehicle-treated animals, differences on variables designed to measure
      anxiety-related behaviours were observed in both tests. In the light/dark test,
      the strains could be divided into three distinct groups: two non-reactive strains
      (NZB and SJL), an intermediate-reactive group (C3H, CBA, DBA/2, NMRI, C57BL/6 and
      Swiss), and one highly reactive strain (BALB/c). In the elevated plus-maze, SJL,
      NMRI, CBA and, to a lesser extent, C3H strains of mice, consistently showed low
      levels of anxiety-related behaviours. Intermediate levels were seen in the Swiss
      and BALB/c strains, and high levels of emotional reactivity were seen in C57BL/6,
      DBA/2 and NZB. The strain distribution between the light/dark and the elevated
      plus-maze tests shows similarities and differences, suggesting that each of these
      experimental procedures represents a different set of behaviours. Marked
      differences between a number of strains of mice in their sensitivity to the
      anxiolytic-like action of diazepam were observed in both the light/dark and the
      elevated plus-maze tests. Mice of the BALB/c, Swiss and, to a lesser extent, CBA
      and C3H strains were responsive to diazepam in both tests, although in the case
      of CBA mice, effects may have been contaminated by behavioural suppression. SJL
      mice were largely unresponsive to the action of the benzodiazepine in both tests,
      whereas in C57, DBA/2, NMRI and NZB mice, diazepam produced positive effects only
      in the elevated plus-maze. CONCLUSION: The finding of differential strain
      distributions both with and without diazepam treatment in the light/dark and the
      elevated plus-maze tests, indicates that not all strains of mice are suitable for
      investigating the effects of GABA/BZ receptor ligands. This study may thus
      provide a useful guide for choosing the best strain of mice for studying the
      pharmacology of fear-related behaviours.

PMID- 10663430
TI  - The anxiogenic-like effect of caffeine in two experimental procedures measuring
      anxiety in the mouse is not shared by selective A(2A) adenosine receptor
      antagonists.
AB  - RATIONALE: The elevated plus-maze and the light/dark box are two established
      anxiety tests in rodents, which are useful to screen putative anxiogenic effects
      of drugs. OBJECTIVE: Caffeine is well known to promote anxious behaviour in
      humans and animal models, but the precise site of action of the drug is still a
      matter of debate. The present study investigated whether the anxiogenic effects
      of caffeine observed in mice depend on the blockade of A(2A) receptor. First, the
      effects induced by the non-selective drug caffeine were compared with those
      elicited by two selective A(2A) receptor antagonists over a wide range of doses
      in the same experimental conditions. The effects of A(2A) or A(1 )adenosine
      receptor agonists and of a selective A(1) adenosine receptor antagonist were also
      investigated. Second, wild-type and A(2A) receptor knockout mice offered another
      approach to delineate the role played by A(2A) receptor in caffeine's anxiogenic
      effects. METHODS: Mice were exposed to the elevated plus-maze or to the
      light/dark box for 5 min after acute or chronic administration of tested drugs.
      RESULTS: Caffeine acutely administered (50 or 100 mg/kg IP) induced anxiety-like
      effects in both procedures. Its chronic administration (50 mg/kg IP twice daily)
      for 1 week or consumption in the drinking water (0.3 g/l) for 8 days or 2 months
      were also anxiogenic in the plus-maze test. The A(2A) receptor antagonists
      ZM241385 (up to 60 mg/kg IP) and SCH58261 (up to 10 mg/kg IP) were devoid of
      acute effects in both tests. One week administration of ZM241385 (30 mg/kg IP) or
      SCH58261 (3 mg/kg IP) had no effects in the plus-maze test. An antagonist (DPCPX)
      and an agonist (CPA) at A(1) receptors had no acute effects on anxiety-related
      indices, whereas an A(2A) receptor agonist (CGS 21680) displayed non-specific
      motor effects in the plus-maze test. Acute administration of caffeine (50 mg/kg
      IP) induced no clear-cut anxiety-like effects in the plus-maze test in A(2A)
      receptor knockout mice that exhibited higher basal anxiety levels than wild-type
      mice. Chronic administration (50 mg/kg IP twice daily) for 1 week elicited less
      anxiety-like behaviour in A(2A) receptor knockout than in wild-type mice.
      CONCLUSIONS: Adaptative mechanisms following mutation in A(2A) receptors or their
      long-term blockade after chronic ingestion of caffeine may be responsible for
      increase proneness to anxiety. However, the short-term anxiety-like effect of
      caffeine in mice might not be related solely to the blockade of adenosine A(2A)
      receptors, since it is not shared by A(2A) selective antagonists.

PMID- 10663432
TI  - Neuroleptic-induced striatal damage in rats: a study of antioxidant treatment
      using accelerometric and immunocytochemical methods.
AB  - RATIONALE: Investigators have postulated that neuroleptic medications may affect
      the motor system through the creation of free radicals. Also, structural brain
      changes related to oxidative damage may disrupt normal striatal function.
      OBJECTIVE: The goals of this study were to examine whether an antioxidant diet
      reduced the abnormal movements caused by long-term neuroleptic exposure and to
      examine structural effects within specific striatal regions in rats. METHODS:
      Rats were given a basal diet or a diet high in antioxidants for 4 months, and
      treated with 10 mg/kg fluphenazine decanoate or sesame seed oil IM every 2 weeks.
      At baseline and after treatment, head movements were quantified by accelerometry,
      and immunocytochemically stained cholinergic neurons in the ventrolateral,
      mediodorsal, and ventromedial regions of the striatum were quantified. RESULTS:
      Rats treated with fluphenazine had significantly lower neuron densities than
      those that did not receive antioxidants. Rats exposed to a diet consisting of
      antioxidants had significantly higher neuron densities than those that did not
      receive antioxidants in each of the three regions tested. Rats treated with
      fluphenazine had a greater increase in the number of accelerometric peaks
      recorded per minute compared with untreated animals. The increase in the number
      of accelerometric peaks recorded per minute was lower for animals exposed to
      antioxidant diets compared with unexposed animals. Lastly, there was a
      significant correlation between the accelerometric peak change score and
      cholinergic neuron density in all three regions. CONCLUSIONS: Our results suggest
      that long-term neuroleptic treatment is associated with an increase in head
      movements and a reduction in ChAT-stained striatal cholinergic neurons and that
      these abnormalities are reduced by antioxidants.

PMID- 10663433
TI  - Local administration of mu or kappa opioid agonists attenuates capsaicin-induced
      thermal hyperalgesia via peripheral opioid receptors in rats.
AB  - RATIONALE: By acting on peripheral opioid receptors, opioid agonists can
      attenuate nociceptive responses induced by a variety of agents. OBJECTIVES: This
      study was conducted to characterize capsaicin-induced thermal hyperalgesia in
      rats and to evaluate the hypothesis that local administration of either mu or
      kappa opioid agonists (fentanyl and U50,488, respectively) can attenuate
      capsaicin-induced nociception. METHODS: Capsaicin was administered s. c. in the
      tail of rats to evoke a nociceptive response, which was measured by the warm
      water tail-withdrawal procedure. Either fentanyl or U50,488 was co-administered
      with capsaicin in the tail to evaluate local antinociceptive effects. In
      addition, the local antagonism study was performed to confirm the site of action
      of both opioid agonists. RESULTS: Capsaicin (0.3-10 microg) dose dependently
      produced thermal hyperalgesia manifested as reduced tail-withdrawal latencies in
      45 degrees C water. Co-administration of either fentanyl (0.32-3.2 microg) or
      U50,488 (10-100 microg) with capsaicin (3 microg) attenuated capsaicin-induced
      hyperalgesia in a dose-dependent manner. Furthermore, this local antinociception
      was antagonized by small doses (10-100 microg) of an opioid antagonist,
      quadazocine, applied s.c. in the tail. However, the locally effective doses of
      quadazocine, when applied s.c. in the back (i.e., around the scapular region),
      did not antagonize either fentanyl or U50,488. CONCLUSIONS: In this experimental
      pain model, activation of peripheral mu or kappa opioid receptors can attenuate
      capsaicin-induced thermal hyperalgesia in rats. It supports the notion that
      peripheral antinociception can be achieved by local administration of analgesics
      into the injured tissue without producing central side effects.

PMID- 10663434
TI  - Cross-tolerance in drug response and differential changes in central nicotinic
      and N-methyl-D-aspartate receptor binding following chronic treatment with either
      (+)- or (-)-nicotine.
AB  - The present study compared the effects of chronic treatment (21 days) with (+)
      nicotine and (-)-nicotine on exploratory behaviours and body temperature in rats.
      Chronic treatment with either (+)- or (-)-nicotine induced tolerance in
      exploratory behaviours. A cross-tolerance between the two stereoisomers was also
      observed. Body temperature was differentially affected by chronic (+)- and (-)
      nicotine, but cross-tolerance was still observed. In addition, nicotinic
      acetylcholine receptor (nAChR) and N-methyl-D-aspartate (NMDA) receptor binding
      in rats treated with (+)- and (-)-nicotine were measured by receptor
      autoradiography. Chronic treatment with (+)- and (-)-nicotine significantly
      increased nAChR binding in different brain regions. Furthermore, significant
      differences in the induction of nAChR binding by chronic (+)- and (-)-nicotine
      were detected in several brain regions. Chronic treatment with (+)-nicotine
      significantly increased NMDA receptor binding in the CA1 region of the
      hippocampus. However, (-)-nicotine had no effect on NMDA receptor binding in any
      of the regions analysed. These results demonstrate differences between chronic
      treatment with (+)- and (-)-nicotine in physiological responses such as body
      temperature and biochemical changes such as changes in nAChRs and NMDA receptor
      binding, although a cross-tolerance between the two enantiomers in behaviour and
      body temperature is also observed.

PMID- 10663435
TI  - Reinstatement of cocaine self-administration in rats: sex differences.
AB  - RATIONALE: Results obtained with both humans and animals suggest that rates of
      relapse, or levels of reinstatement responding, may differ between males and
      females. However, the results obtained with humans are equivocal, and few studies
      have compared male and female animals on reinstatement responding. OBJECTIVES:
      The present experiment was designed to compare male (n=8) and female (n=8) rats
      on reinstatement of extinguished cocaine-reinforced responding. METHODS:
      Reinstatement of responding was examined using a priming model in which lever
      pressing for cocaine (0.2 mg/kg) was extinguished by replacing cocaine infusions
      (2 h) with saline infusions (5 h). After responding extinguished during hour 3,
      reinstatement of responding was tested by administering one of several priming
      injections of cocaine (0.32, 1.0 and 3.2 mg/kg) or an equal volume of saline.
      RESULTS: Although males and females did not differ in the number of saline
      infusions self-administered after either saline or 0.32 mg/kg cocaine-priming
      injections, female rats self-administered significantly more saline infusions
      than males after 1.0 mg/kg and 3.2 mg/kg cocaine-priming injections.
      Additionally, the effects of 0.32 mg/kg cocaine-priming injections were
      significantly different from those of saline-priming injections for female, but
      not male, rats. There was no significant difference between males and females in
      total cocaine self-administered during hours 1 and 2. CONCLUSIONS: These findings
      indicate that female rats are more sensitive than males during the reinstatement
      phase of drug abuse.

PMID- 10663436
TI  - A microdialysis study of the noradrenergic response in rat frontal cortex and
      hypothalamus to a conditioned cue for aversive, naturalistic environmental
      stimuli.
AB  - RATIONALE: Extracellular noradrenaline concentration in the rat forebrain is
      increased by aversive environmental stimuli. This study investigated whether
      conditioned cues for such stimuli have the same effect. METHODS: After training
      rats to associate a tone (conditioned cue) with transfer from a neutral zone to a
      brightly lit zone of a light/dark shuttle-box (unconditioned stimulus),
      microdialysis probes were implanted into the frontal cortex and hypothalamus
      under halothane anaesthesia. Changes in extracellular noradrenaline concentration
      were then monitored on exposure to the tone alone. Parallel experiments monitored
      rats' behaviour in the light arena. RESULTS: A single exposure to the light arena
      increased extracellular noradrenaline in the frontal cortex and the hypothalamus
      but neither a single, nor repeated, exposure to the tone alone had any effect.
      After conditioning trials, the tone alone increased extracellular noradrenaline
      in the frontal cortex but not the hypothalamus, whilst the tone+transfer to the
      light arena resulted in a prolonged increase in extracellular noradrenaline in
      both brain regions. The time that rats spent within the light arena was also
      prolonged. CONCLUSIONS: Noradrenergic neurones in the frontal cortex, but not the
      hypothalamus, respond to conditioned cues for aversive environmental stimuli.
      However, prolongation of the noradrenergic response in both brain regions could
      contribute to the behavioural adaptation to such unconditioned stimuli.

PMID- 10663446
TI  - Therapeutic monitoring of the new antiepileptic drugs.
AB  - OBJECTIVE: To discuss the potential value of therapeutic drug monitoring (TDM) of
      the new antiepileptic drugs gabapentin, lamotrigine, oxcarbazepine, tiagabine,
      topiramate, vigabatrin and zonisamide. METHODS: A review of studies of the
      relationship between plasma concentrations and effects of new antiepileptic drugs
      is provided. Furthermore, the potential value of TDM of these drugs is discussed
      in relation to their mode of action and their pharmacokinetic properties. The
      various methods that are available for analysing plasma concentrations of the new
      antiepileptic drugs are also briefly reviewed. RESULTS: The available information
      on the relationship between plasma concentrations and effects of the new drugs is
      scarce. For most drugs, wide ranges in concentrations associated with seizure
      control are reported, and a considerable overlap with drug levels among non
      responders and also with concentrations associated with toxicity is often noted.
      However, very few studies have been designed primarily to explore the
      relationship between drug plasma concentrations and effects. Consequently, there
      are no generally accepted target ranges for any of the new antiepileptic drugs.
      Although the available documentation clearly is insufficient, the pharmacological
      properties of some of the drugs, in particular lamotrigine, zonisamide and,
      possibly, oxcarbazepine, topiramate and tiagabine, suggest that they may be
      suitable candidates for TDM. CONCLUSION: TDM of some of the new antiepileptic
      drugs may be of value in selected cases, although routine monitoring in general
      cannot be recommended at this stage. Further systematic studies designed
      specifically to investigate concentration-effect relationships of the new
      antiepileptic drugs are urgently needed.

PMID- 10663437
TI  - Dopaminergic involvement in the discriminative-stimulus effects of
      methamphetamine in rats.
AB  - RATIONALE: Dopamine plays a major role in the behavioral effects of
      methamphetamine. OBJECTIVE: In the present experiments, the effects of different
      dopaminergic agonists, antagonists, and uptake inhibitors were evaluated in rats
      discriminating methamphetamine from saline. METHODS: In Sprague-Dawley rats
      trained to discriminate 1.0 mg/kg methamphetamine, i.p., from saline under a
      fixed-ratio schedule of food delivery, the ability of various dopaminergic
      agonists and uptake inhibitors to substitute for methamphetamine was evaluated.
      Subsequently, the ability of various dopaminergic antagonists to block the
      discriminative-stimulus effects of the training dose of methamphetamine was
      tested. RESULTS: The dopamine-uptake inhibitors cocaine (10.0 mg/kg), nomifensine
      (3.0 mg/kg), GBR-12909 (18.0 mg/kg), and bupropion (30.0 mg/kg) fully substituted
      for the 1.0 mg/kg training dose of methamphetamine. Chloro-APB (SKF-82958), a
      full agonist at D1 dopamine receptors, produced about 85% methamphetamine
      appropriate responding, but the dose required (0.18 mg/kg) markedly decreased
      rates of responding. Chloro-PB (SKF-81297), another agonist at D1 receptors with
      a lower intrinsic activity than Chloro-APB, produced only partial generalization
      (maximum about 55%) at a dose of 1.0 mg/kg. Full substitution for the training
      dose of methamphetamine was observed with 0.03 mg/kg of the D2 agonist NPA and
      0.56 mg/kg of the D3/D2 agonist 7-OH-DPAT. Both NPA and 7-OH-DPAT markedly
      decreased rates of responding at these doses. The D1 antagonist SCH-23390 (0.056
      mg/kg), the D2 antagonist spiperone (0.18 mg/kg), and the mixed D1, D2 antagonist
      cis-flupenthixol (0.56 mg/kg) all completely blocked the discriminative-stimulus
      actions of the training dose of methamphetamine. CONCLUSIONS: The present
      findings in rats support previous research findings in other species indicating a
      major role of dopamine in the discriminative-stimulus effects of methamphetamine.
      These findings further indicate involvement of dopamine uptake sites as well as
      D1 and D2 receptors.

PMID- 10663447
TI  - The regional drug-therapy consultation service centre - a conception that has
      been serving patients and physicians alike for 30 years in Magdeburg (Germany).
AB  - OBJECTIVES: Thirty years ago, a drug therapy consultation service centre was
      established simultaneously with the Institute of Clinical Pharmacology based at
      the university hospital in Magdeburg. The combination of therapeutic drug
      monitoring and a drug information service including individual patient-oriented
      drug dosage and bedside consultation permits an effective support of the
      treatment of drug related therapeutic problems. Currently, the service offers
      drug monitoring for 161 drugs and additional 46 metabolites. METHODS AND
      DISCUSSION: In a representative 2-year period (1997-1998), drug monitoring was
      performed for 6293 patients, and 569 drug-related inquiries were answered. The
      main categories of required drug information were:
      pharmacokinetics/metabolism/analytical problems (38%), adverse drug
      reactions/drug safety (24%), therapeutic drug use/drug indication (21%) and
      pharmaceuticals (9%). Further activities of the institute refer to teaching of
      undergraduates, continuing education of local physicians in recent aspects of
      drug therapy, providing therapeutic bulletins and conducting supporting clinical
      studies.

PMID- 10663448
TI  - Start of oral morphine to cancer patients: effective serum morphine
      concentrations and contribution from morphine-6-glucuronide to the analgesia
      produced by morphine.
AB  - OBJECTIVE: To investigate the serum concentrations of morphine, morphine-3
      glucuronide (M3G) and morphine-6-glucuronide (M6G) and the relationships between
      serum concentrations and clinical effects associated with start of morphine
      treatment in cancer patients. METHODS: Forty patients with malignant disease and
      intolerable pain on weak opioids (codeine/dextropropoxyphen) were included. After
      a wash-out period, titration with immediate-release (IR) morphine was started.
      When a stable dose was achieved, the morphine treatment was changed to slow
      release (SR) morphine in equivalent daily dosages. Clinical data and serum
      concentrations of morphine, M3G and M6G were obtained at the end of the IR and SR
      morphine treatment periods. RESULTS: The mean trough serum morphine concentration
      associated with pain relief was 66 nmol/l. The corresponding mean concentrations
      of M6G and M3G were 257 nmol/l and 1943 nmol/l, respectively. Morphine serum
      trough concentrations showed a 33-fold variation. Seventy percent of the
      variation was predicted in a model including age, daily morphine dose and
      M6G/morphine ratio as independent variables. No associations were observed
      between side effects and serum concentrations of morphine and its metabolites.
      CONCLUSION: In this study, a mean serum trough morphine concentration of 66
      nmol/l was associated with satisfactory pain relief when disease progression
      required an increase in intensity of pain therapy from step II to step III in the
      World Health Organization pain ladder. An increased ratio of M6G to morphine
      serum concentrations predicted lower effective serum morphine concentrations at
      the time of satisfactory pain relief. This observation supports that M6G
      contributes to the pain control produced by oral morphine in patients with pain
      caused by malignant disease.

PMID- 10663449
TI  - Pharmacodynamics and pharmacokinetics of intravenous glibenclamide in Caucasian
      and Chinese patients with type-2 diabetes.
AB  - OBJECTIVE: We analysed the kinetics and effects of glibenclamide (Gb) on glucose,
      insulin and proinsulin secretion in two ethnic groups (10 in each) of type-2
      diabetic patients, one of Caucasian, the other of Chinese origin. BACKGROUND:
      Diabetes mellitus type 2 is a global disease affecting all ethnic groups. There
      are ethnic differences in both the prevalence and metabolic characteristics of
      the disease. Important interethnic pharmacodynamic and pharmacokinetic
      differences have been reported for several drugs. With few exceptions, detailed
      studies on sulphonylurea are lacking. MATERIAL AND METHODS: The patients were
      studied on two occasions when either no Gb (control) or 1.25 mg Gb was
      administered i.v., immediately before the administration of a 75-g oral glucose
      tolerance test. Concentrations of insulin and proinsulin were determined by means
      of radioimmunoassay without cross-reactivities. Gb concentration was determined
      using high-performance liquid chromatography. Pharmacodynamic results were
      calculated using net areas under the curves, with basal values set as zero. A P
      value less than 0.05 was considered significant. RESULTS: When glucose was
      administered orally without Gb, Chinese patients had higher plasma glucose
      increases at 10 min (7.6 mmol/l x min vs 2.6 mmol/l x min) and higher increases
      of plasma insulin levels than Caucasians at both 10 min (198 pmol/l x min vs 54
      pmol/l x min) and 30 min (2286 pmol/l x min vs 1198 pmol/l x min). When Gb was
      administered, the plasma glucose increases were reduced, and the increases of
      serum insulin and proinsulin levels were greater in both ethnic groups. Compared
      with the basal values (-1 min), proinsulin/insulin ratios (RPI) were lowest at 10
      30 min, followed by an increase. Chinese patients had higher increases of serum
      insulin levels at 10 min (1109 pmol/l x min vs 550 pmol/l x min) and a lower RPI
      at 30 min (6. 0% vs 7.6%) and 240 min (15.0% vs 21.0%) relative to Caucasians.
      Serum Gb data were best fitted to a biexponential i.v. model. There were no
      interethnic differences in any of the pharmacokinetic parameters. CONCLUSION: In
      summary, following oral glucose administration without Gb, Chinese type-2
      diabetic patients had higher plasma insulin levels but also higher plasma glucose
      levels during the first 10 min, which might reflect reduced insulin sensitivity
      or more rapid glucose absorption. Gb augmented glucose-induced release of both
      insulin and proinsulin in both ethnic groups; the effect on insulin secretion was
      more pronounced. In conclusion, minor pharmacodynamic but no pharmacokinetic
      differences were found between the two groups. It seems appropriate to employ the
      same dosage principles when using Gb in Caucasians and Chinese.

PMID- 10663450
TI  - Verapamil causes decreased diaphragm endurance but no decrease of nocturnal O(2)
      saturation in patients with chronic obstructive pulmonary disease.
AB  - OBJECTIVE: In animal studies, it has been shown that verapamil reduces strength
      and endurance of the diaphragm and inhibits the beneficial effects of
      theophylline. We examined whether the use of verapamil in patients with severe
      chronic obstructive pulmonary disease (COPD) who use theophylline leads to a
      deterioration of diaphragmatic function resulting in a decrease of nocturnal O(2)
      saturation. METHODS: A double-blind, placebo-controlled crossover study was
      designed in eight stabile severe COPD patients [forced expiratory volume in 1 s
      (FEV(1)) 0.9 +/- 0.1 l] taking theophylline. The doses of theophylline ranged
      from 600 mg daily to 1200 mg daily (7.0 mg/kg daily to 16.9 mg/kg daily).
      Nocturnal recordings, maximal respiratory muscle strength and endurance tests,
      lung function, blood pressure, electrocardiogram and arterial blood gas analysis
      were performed after 6 days of verapamil and after placebo. RESULTS: A
      significant decrease of the endurance time from 7.7 min to 6.4 min was found in
      the threshold loading test. However, the mean nocturnal saturation values did not
      change significantly: 89.8% and 89.6%, respectively. Results of pulmonary
      function tests, arterial blood gas analysis and routine blood samples also did
      not change. CONCLUSION: The decrease of the respiratory muscle endurance after
      the use of verapamil is in line with experiments in animal diaphragms. However,
      the nocturnal saturation did not change. This finding suggests that the effect
      found on diaphragm endurance is of no clinical significance and that verapamil
      can be given to COPD patients without risk of worsening nocturnal saturation.
      However, this must be confirmed by future larger scale studies.

PMID- 10663451
TI  - Pantoprazole does not affect cyclosporin A blood concentration in kidney
      transplant patients.
AB  - OBJECTIVE: Renal-transplant patients who are immunosuppressed with cyclosporin A
      (CyA) are often treated with proton-pump inhibitors to prevent ulcer disease. No
      data are available on the effect of the novel proton-pump inhibitor pantoprazole
      on CyA levels. METHODS: In a controlled treatment, we investigated the effect of
      pantoprazole, which was administered in a pragmatic schedule for acid suppression
      (40 mg as single oral dose at 2200 hours) in six renal-transplant patients who
      received CyA (Sandimmun optoral, 50-175 mg twice daily) and prednisolone (5-7.5
      mg/24 h). CyA trough levels (0730-0800 hours) were measured by immunoassay.
      RESULTS: In the absence of pantoprazole, mean CyA trough levels measured on three
      consecutive days were between 164 ng/ml and 173 ng/ml (therapeutic range 120-200
      ng/ml). Pantoprazole did not affect CyA trough levels during an observation
      period up to 3 months long. CONCLUSIONS: Pantoprazole seems to be a safe drug in
      combination with CyA.

PMID- 10663452
TI  - Site of nicotine absorption from a vapour inhaler--comparison with cigarette
      smoking.
AB  - OBJECTIVE: The aim of the study was to assess the site of nicotine absorption
      during and after use of a nicotine-vapour inhaler compared with that after
      cigarette smoking. METHODS: Using a catheterisation technique, the nicotine
      plasma concentration-time profiles in arterial and jugular venous blood after
      using a nicotine inhaler were compared with those achieved after cigarette
      smoking a in seven healthy habitual smokers. RESULTS: After use of the inhaler,
      arterial nicotine concentrations rose slowly to a maximum level of 5. 9 +/- 1.5
      ng/ml at a mean time to reach peak concentration (t(max)) of 9.0 +/- 1.1 min,
      whereas jugular venous nicotine levels peaked at 25.4 +/- 5.4 ng/ml at 6.7 +/-
      0.3 min. The concentration-time curves indicate that the absorption occurs mainly
      via the mucosa of the oral cavity and the pharynx, and that there is minimal
      absorption via the lungs. In contrast, after smoking a cigarette, arterial
      nicotine plasma concentrations rose quickly to a maximum level of 49. 2 +/- 9.7
      ng/ml after 4.0 +/- 0.6 min, while the maximum concentration of nicotine in the
      jugular vein was 22.4 +/- 3.9 ng/ml after 6.4 +/- 0.4 min, indicating primarily
      pulmonary absorption of nicotine. CONCLUSION: Nicotine absorption after use of
      the vapour inhaler occurs primarily via the mucosa of the oral cavity; the
      absorption occurs slowly and the arterial nicotine concentration spike, typical
      of cigarette smoking, is avoided. Thus, the likelihood for abuse of the nicotine
      inhaler is probably small.

PMID- 10663453
TI  - Pharmacokinetics and bioequivalence evaluation of three commercial tablet
      formulations of mefloquine when given in combination with dihydroartemisinin in
      patients with acute uncomplicated falciparum malaria.
AB  - OBJECTIVE: To assess the pharmacokinetics and relative
      bioavailability/bioequivalence of three commercial tablet formulations of
      mefloquine, i.e. Lariam (reference formulation), Mephaquin 100 Lactab and Eloquin
      250, when given sequentially after dihydroartemisinin in Thai patients with acute
      uncomplicated falciparum malaria. METHODS: Twenty-nine Thai patients with acute
      uncomplicated falciparum malaria were randomised to receive an initial dose of
      300 mg dihydroartemisinin, followed by 1250 mg mefloquine (at 24 h and 30 h after
      dihydroartemisinin) given as either Lariam (n=10 cases), Mephaquin (n=9 cases) or
      Eloquin-250 (n=10 cases). Serial blood samples were obtained up to day 42 after
      treatment with mefloquine. Mefloquine concentrations were determined in whole
      blood by means of ultraviolet high-performance liquid chromatography. The
      pharmacokinetic parameters of mefloquine were estimated using non-compartmental
      and compartmental analysis. RESULTS: The three combination regimens were well
      tolerated. Patients in all treatment groups had a rapid initial response.
      However, nine patients (four and five cases in regimen containing Mephaquin 100
      Lactab and Eloquin-250, respectively) had reappearance of parasitaemia during the
      follow-up period. Mefloquine from the three formulations showed significantly
      different pharmacokinetic and bioavailability metrics. Significantly lower peak
      plasma concentrations (C(max)) and areas under the plasma concentration-time
      curve (AUC; AUC(0-48h), AUC(0-7days), and total AUC) were observed with Mephaquin
      100 Lactab than with the other two formulations. Mean values for relative
      bioavailability of the test to standard products were 49.1% (Mephaquin 100
      Lactab) and 72.4% (Eloquine-250). Based on the criteria set, the bioavailability
      of the two test products (Mephaquin 100 Lactab and Eloquine-250) was considered
      non-equivalent to the reference product with respect to the rate (t(max), C(max))
      and extent (AUC(0-48h), AUC(0-7days), total AUC) of mefloquine absorption.

PMID- 10663454
TI  - Bioavailability of repeated oral administration of MDL 100,240, a dual inhibitor
      of angiotensin-converting enzyme and neutral endopeptidase in healthy volunteers.
AB  - BACKGROUND: MDL 100,240 (pyrido[2,1-a] [2]benzazepine-4-carboxylic acid,7-[[2
      (acetylthio)-1-oxo-3-phenylpropyl]amino]-1,2,3,4,6,7,8, 12b-octahydro-6-oxo, [4S
      [4alpha,7alpha(R(*)),12bbeta]]-) is a molecule possessing an inhibiting ability
      on both angiotensin converting enzyme (ACE) and neutral endopeptidase, the enzyme
      responsible for atrial natriuretic peptide (ANP) degradation. Such a dual
      mechanism of action presents a potential clinical interest for the treatment of
      hypertension and congestive heart failure. OBJECTIVES: To evaluate the
      bioavailability of MDL 100,240 and its accumulation over repeated oral
      administration, using ACE inhibition as a surrogate for plasma drug level and
      determining its profile after oral and i.v. administration. METHODS: First, in an
      open, one-period, single-dose study, the ACE inhibition profile was characterised
      following a 12.5 mg MDL 100,240 i.v. infusion. Second, in a three-group,
      parallel, randomised, double-blind study, each group of four subjects received
      q.d., over 8 days, 2.5, 10 or 20 mg of MDL 100,240 orally. The ACE inhibition
      profile was determined on day 1 and day 8. Trough plasma ACE was measured on days
      2, 3 and 4. The recovery of ACE activity was monitored up to 72 h after the last
      dose of MDL 100,240. RESULTS: ACE inhibition profile was similar on day 1 and day
      8, and trough inhibition remained unchanged after the 8 days of treatment with 10
      mg or 20 mg. Following repeated 2.5-mg ingestion, trough inhibition increased
      from 33% to 44% after the eighth dose. The oral bioavailability of MDL 100,240
      was estimated at 85%, not statistically different from 100%. The accumulation
      ratio at steady state was estimated at 112%. Expressing the accumulation ratio in
      terms of half-life, a t(1/2) of 0.31 days or 7. 5 h was estimated. CONCLUSION:
      MDL 100,240 (oral solution) has a good bioavailability, as estimated by ACE
      inhibition, and no drug accumulation seems to occur over 8 days with the 10-mg
      and 20-mg doses, but a slight rise in the trough level is observed with the 2. 5
      mg dose.

PMID- 10663455
TI  - Effect of intravenous dopamine infusion on plasma concentrations of dopamine and
      dopamine sulfate in men, during and up to 18 h after infusion.
AB  - OBJECTIVE: We investigated whether sulfoconjugation contributes to the
      inactivation of intravenously infused dopamine (DA) in low concentrations with a
      predominant action on the kidney. METHODS: Plasma DA and dopamine sulfate (DA-S)
      concentrations were determined during 4 h of intravenous infusion of DA (2
      microg/kg/min) and up to 18 h after cessation of infusion. Twenty-seven healthy
      young subjects participated in the placebo controlled, randomised and double
      blind study. RESULTS: Intravenously administered DA was sulfoconjugated rapidly
      and to a great extent. After starting the infusion, DA levels rose within minutes
      and reached a steady state after 30-60 min. The steady-state levels averaged
      151.3 +/- 8.2 nmol/l. DA-S levels also increased markedly with infusion from 16.7
      +/- 9.9 nmol/l at the start of infusion up to 261.2 +/- 24.2 nmol/l at 30 min
      after cessation of infusion. Plasma DA concentrations after cessation of the
      infusion decreased rapidly with an initial half-life of elimination of 4.8 min.
      Concentrations of plasma DA-S declined with a half-life of 4.5 h. Persistent
      elevations of free and conjugated DA compared with pre-treatment levels were
      observed even 18 h after cessation. Heart rate and blood pressure remained
      unchanged both during DA and saline infusion. CONCLUSION: Findings indicate that
      the sulfoconjugation pathway contributes markedly to the inactivation of
      intravenously infused DA and seems not to be saturable by DA infusion in low
      doses.

PMID- 10663456
TI  - Agranulocytosis induced by pyrithyldione, a sedative hypnotic drug.
AB  - OBJECTIVE: Pyrithyldione, a sedative-hypnotic drug with a poor clinical
      pharmacological development, was associated with anecdotal cases of
      agranulocytosis in the 1940s in the USA, in the 1960s and 1970s in the ex
      Democratic Republic of Germany and in the 1980s in Japan. We describe the
      estimation of the risk of agranulocytosis associated with its use in Spain, which
      led to its withdrawal from the market. METHODS: In collaboration with the
      haematology units of all the hospitals in a defined area (3.3-3.9 x 10(6)
      inhabitants), all cases of agranulocytosis meeting strict diagnostic criteria
      were identified. Each case - defined as an episode of agranulocytosis - was
      reviewed by a haematologist without knowledge of previous drug exposures. Cases
      and age-, gender- and hospital-matched controls were interviewed with a
      structured questionnaire about previous drug exposures. In addition, in order to
      estimate the risk of pyrithyldione-associated agranulocytosis through a case
      population approach, its consumption among the cases was compared with its
      consumption among the general population. RESULTS: After a follow-up of 66.5 x
      10(6) person-years, 330 cases of agranulocytosis (230 community cases) were
      assembled. Reliable information on previous exposures was obtained for 204 cases.
      They were compared with 1314 controls. Eleven patients (14 cases, 6.9%) and zero
      controls had been exposed to pyrithyldione. The adjusted OR was 200.11 (CI 95%
      22. 62-infinity). All patients were female; none had a fatal outcome; three
      exhibited positive rechallenge; and all had concomitantly taken other drugs.
      Although pyrithyldione was a prescription-only medicine, only 8% had been
      dispensed with medical prescriptions. Assuming the worst case, i.e. that all the
      exposed cases could be attributed to pyrithyldione, the incidence was 35.6 cases
      per 100, 000 patient-years (95% CI, 18.9-60.9), which gives a risk ratio estimate
      of 109.6 (57.5-191.5) if compared with the incidence of agranulocytosis among the
      non-exposed population [3.26 cases (CI 95% 2.83-3.71) per 10(6) inhabitants and
      per year]. DISCUSSION: Pyrithyldione was viewed by pharmacists as a mild
      hypnotic, and apparently this had conferred to this drug an unjustified image of
      safety. The National Commission of Pharmacovigilance recommended to the Ministry
      of Health its withdrawal from the market when eight cases of agranulocytosis had
      been identified. However, it took more than 2 years to withdraw it, and six
      additional cases occurred in the study area. This illustrates the need for quick
      regulatory action when pharmacoepidemiological data suggest an unfavourable
      benefit/risk ratio.

PMID- 10663457
TI  - Drug utilisation in Dutch nursing homes.
AB  - OBJECTIVE: To quantify and evaluate drug utilisation in a sample of Dutch nursing
      homes. METHODS: A retrospective analysis of computerised medication data of 2355
      residents aged 65 years and over from six nursing homes in the Netherlands was
      performed. For each therapeutic drug group, the number of users was determined.
      The ten therapeutic groups used most frequently were investigated further. For
      these, patient characteristics, use of therapeutic subgroups, the average daily
      dosages and the chronicity of drug use were determined. Chronicity was expressed
      as the percentage of treatment days divided by the number of residents' days in
      the nursing home. RESULTS: During the study period, 89%, 77% and 56% of the study
      population used a drug from the anatomical therapeutic chemical (ATC) main group
      N (nervous system), A (alimentary tract and metabolism) and C (cardiovascular
      system), respectively. Eight of the ten therapeutic drug groups prescribed most
      frequently were used for more than 50% of the time. In particular, psycholeptic
      drugs, diuretics and laxatives were used chronically (83%, 81%, and 80% of the
      nursing home stay, respectively). Except for a few drug groups, such as laxatives
      and diuretics, the prescribed daily dosages were relatively low. Twenty-eight
      percent of the residents received loop diuretics; these were prescribed in
      relatively high dosages. CONCLUSION: Drug utilisation in the nursing homes was
      high and many drugs were used chronically. In view of the risk of possible
      adverse effects and drug-drug interactions, the prescribing and dosage of
      psycholeptic drugs, laxatives, loop diuretics and ulcer-healing drugs should be
      re-evaluated, carefully.

PMID- 10663458
TI  - Continued use of the proton-pump inhibitor lansoprazole following Helicobacter
      pylori eradication.

PMID- 10663461
TI  - The neuroimaging evidence for chronic brain damage due to boxing.
AB  - A number of imaging techniques have been used to investigate changes produced in
      the brain by boxing. Most morphological studies have failed to show significant
      correlations between putative abnormalities on imaging and clinical evidence of
      brain damage. Fenestration of the septum pellucidum, with formation of a cavum,
      one of the most frequent observations, does not appear to correlate with
      neurological or physiological evidence of brain damage. Serial studies on large
      groups may be more informative. Magnetic resonance spectroscopy and cerebral
      blood flow studies have been reported in only small numbers of boxers; serial
      studies are not available to date.

PMID- 10663462
TI  - The basal ganglia in haemochromatosis.
AB  - Haemochromatosis is characterised by deposition of iron-containing pigment in
      various organs, but little is known about possible deposition in the brain and
      its clinical impact. We therefore investigated 14 patients with hereditary
      haemochromatosis with MRI, CT and transcranial ultrasound (TCS) and examined them
      neurologically. In six of the patients dense lesions were found within the
      lentiform nucleus on CT, all of whom displayed hyperechogenic lesions in the same
      area on TCS, as did one other patient. In these patients the relative signal
      intensities of the lentiform nucleus measured by MRI relaxometry were higher. No
      patient had clinical signs of basal ganglia disorders.

PMID- 10663463
TI  - MRI of intracranial toxoplasmosis after bone marrow transplantation.
AB  - Toxoplasma encephalitis was confirmed by biopsy in three patients with bone
      marrow (BMT) or peripheral blood stem-cell transplantation (PBSCT). All had MRI
      before antimicrobial therapy. The intensity of contrast enhancement was very
      variable. One patient had one large, moderately enhancing cerebral lesion and
      several smaller almost nonenhancing lesions. The second had small nodular and
      haemorrhagic lesions without any enhancement. The third had late cerebral
      toxoplasmosis and showed multiple lesions with marked contrast enhancement. The
      moderate or absent contrast enhancement in the two patients in the early phase of
      cerebral toxoplasmosis may be related to a poor immunological response, with a
      low white blood cell count in at least one patient. Both received higher doses of
      prednisone than the patient with late infection, leading to a reduced
      inflammatory response. In patients with a low leukocyte count and/or high doses
      of immunosuppressive therapy, typical contrast enhancement may be absent.

PMID- 10663464
TI  - Spontaneous improvement in reduced vasodilatory capacity in major cerebral
      arterial occlusive disease.
AB  - Reduced vasodilatory capacity resulting from occlusive lesions of the major
      cerebral arteries may return to normal without surgical revascularisation. We
      aimed to determine prospectively the frequency and predictors of recovery of
      impaired haemodynamics as demonstrated by acetazolamide (ACZ) reactivity on
      single-photon emission computed tomography (SPECT). Vasoreactivity was measured
      by (123)I-IMP SPECT with an ACZ challenge, in 37 medically treated patients with
      unilateral occlusive disease of the internal carotid or middle cerebral artery at
      an interval of 1-2 years. Each ACZ challenge test was analysed semiquantitatively
      by calculating the degree of increase in cerebral blood flow (CBF) asymmetry
      after ACZ administration (DeltaAI). Vasodilatory capacity was abnormal initially
      in 20 patients (65 %); eight of whom (40 %) exhibited spontaneous normalisation
      on follow-up. Although the baseline characteristics did not differ significantly
      between patients with or without increase in reactivity, logistic regression
      analysis revealed that the initial DeltaAI (P < 0.05) and the type of vascular
      lesion (stenosis or occlusion) (P < 0.05) correlated significantly with a return
      towards normal of reduced ACZ reactivity. Spontaneous improvement of impaired
      vasodilatory capacity may not be a rare phenomenon. We found that mild reduction
      in the initial ACZ reactivity and a stenosis, but not complete occlusion, were
      independent factors contributing to normalisation of impaired cerebral
      haemodynamics.

PMID- 10663465
TI  - Increased cerebral blood flow in MELAS shown by Tc-99m HMPAO brain SPECT.
AB  - We report cerebral SPECT studies on two siblings with the syndrome of
      mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes
      (MELAS). Tc-99m HMPAO brain SPECT was performed 8, 19 and 30 days after a stroke
      like episode in one case and 10 days after a stroke-like episode, 6 h after a
      partial seizure and as a follow-up study in the other. Increased blood flow was
      seen in both these patients with stroke-like episodes due to MELAS. The cause of
      the increased blood flow is uncertain, but it may be related to the decreased pH
      created by local increase in lactic acid.

PMID- 10663466
TI  - MRI demonstration of intracerebral cryptococcal granuloma.
AB  - We report an intracerebral cryptococcal granuloma in a patient who presented with
      recent memory disturbance and deteriorating mental status followed by temporary
      loss of consciousness. To our knowledge, this is the first reported case of an
      intracerebral cryptococcal granuloma examined by a combination of conventional
      MRI, fluid-attenuated inversion-recovery and diffusion-weighted imaging and in
      which the surgical specimen was analysed histochemically.

PMID- 10663468
TI  - note

PMID- 10663467
TI  - Gadodiamide as an alternative contrast medium in cerebral angiography in a
      patient with sensitivity to iodinated contrast medium.
AB  - The physical and pharmacological properties of gadolinium enable its chelates to
      be used as a contrast medium in digital subtraction angiography. We report the
      use of gadodiamide, a low-osmolar nonionic gadolinium chelate, for selective
      angiography in a patient with known sensitivity to iodinated contrast medium. No
      adverse effects were encountered during or after injection. Contrary to a single
      previous report of the use of these agents in cerebral angiography, contrast in
      the angiogram was not particularly good, especially in the distal circulation,
      but the angiogram was diagnostic.

PMID- 10663469
TI  - Reply

PMID- 10663470
TI  - Unilateral congenital cerebral venous dysgenesis.
AB  - I report a 30-year-old woman with congenital cerebral venous dysgenesis with
      absence of the internal cerebral and basal veins and most of the cortical veins.
      Unlike the more common bilateral picture, she had involvement only on the left
      side, which delayed presentation and gave relatively mild symptoms. The
      embryological mechanism and differential diagnosis of unilateral absence of the
      internal cerebral, basal and cortical veins are discussed.

PMID- 10663471
TI  - Cranial MRI in the Nijmegen breakage syndrome.
AB  - We present the results paragraph signof MRI examinations in ten patients with
      documented Nijmegen paragraph signbreakage syndrome (NBS), aged 1.75-19 years. T1
      , Proton-Density- and T2-weighted spin-echo sequences were performed in three
      planes. All patients showed microcephaly with decreased size of the frontal lobes
      and narrow frontal horns. In four patients agenesis of the posterior part of the
      corpus callosum was found, with colpocephaly and temporal horns dilatation. In
      one patient callosal hypoplasia was accompanied by abnormal cerebrospinal fluid
      spaces and wide cerebral cortex, suspicious of pachygyria. Sinusitis was present
      in all ten patients, as a result of primary immunodeficiency. As in ataxia
      teleangiectasia and other breakage syndromes, patients with NBS show an inherited
      susceptibility to malignancy and hypersensitivity to X- and gamma-radiation. CT
      is therefore contraindicated in these patients and MRI should be the method of
      choice for diagnostic imaging.

PMID- 10663472
TI  - MRI in acute neuropathic Gaucher's disease.
AB  - We present the cranial MRI findings in a 6-month-old girl with biopsy-proven
      acute neuropathic Gaucher's disease, which include unilateral cerebral atrophy
      and dural thickening with contrast enhancement.

PMID- 10663473
TI  - Dermal sinus with dermoid cyst in the upper cervical spine: case note.
AB  - We describe a 5 year-old girl who had a skin dimple of the back of her upper
      neck. MRI showed a dermal sinus tract in the upper cervical spine, associated
      with an intramedullary dermoid cyst at C 2-3, and spina bifida. A laminectomy was
      performed, the dermoid cyst and the sinus tract were completely removed. This
      congenital complex is very rare.

PMID- 10663474
TI  - Intraocular contrast enhancement in Adams pattern III hypoxic brain damage: MRI.
AB  - The MRI findings of a patient with diffuse cortical hypoxic brain damage (Adams
      pattern III) are presented. Besides intense cortical contrast enhancement, a
      peculiar leakage of contrast medium at the anterior chambers of the eye was
      observed. The pathogenetic mechanism of this enhancement is discussed.

PMID- 10663475
TI  - A novel flexible endovascular stent for use in small and tortuous vessels.
AB  - We assessed in vivo the mode of delivery, short-term patency and cellular
      response to a prototype endovascular stent. The stent is designed for delivery
      through a modified microcatheter and is retrievable with detachment from a
      delivery wire effected by electrolysis. We successfully deployed 12 stents in a
      range of sizes from 3-4 mm in straight and angled arteries of pigs. At control
      angiography 3 and 6 weeks later, nine arteries were patent, two occluded and one
      narrowed; patency was not related to vessel or stent size. The device shows
      promise as a stent for intracranial arteries since it can be delivered through
      microcatheters small enough for intracranial navigation and provides the operator
      with greater control than currently available self- or balloon-expanded stents.

PMID- 10663476
TI  - Direct caroticocavernous fistula and traumatic dissection of the ipsilateral
      internal carotid artery: endovascular treatment.
AB  - After severe craniocerebral trauma a 14-year-old boy developed progressive
      exophthalmos with venous congestion and chemosis, due to a direct
      caroticocavernous fistula. Angiography revealed traumatic occlusion of the
      ipsilateral internal carotid artery and absence of the inferior petrosal sinus.
      After failure of an approach via the anterior and posterior communicating
      arteries, the cavernous sinus was successfully catheterised through the occluded
      internal carotid artery, and embolisation performed with coils.

PMID- 10663478
TI  - Board, committees, and meeting information

PMID- 10663477
TI  - MRI T-staging of laryngeal tumours: role of contrast medium.
AB  - Our aim was to evaluate the relative diagnostic accuracy of MRI without contrast
      medium and MRI before and after contrast medium in the assessment of T-staging of
      laryngeal tumours. We studied 25 men (mean age 51.8, range 41-61) with laryngeal
      squamous cell carcinomas, using Spin-echo (SE) T1-weighted and fast SE T2
      weighted sequences. The T1-weighted sequences were then repeated after gadolinium
      diethylene-triaminepenta-acetic acid (Gd DTPA) 0.1 ml/kg. All patients then
      underwent biopsy and surgery. Two radiologists independently assessed the
      anonymised images by filling-out two multiple-choice forms, one for each
      technique, at a 2 week interval. The forms included a judgement concerning tumour
      identification and infiltration of the anterior commissure, supraglottic region,
      arytenoid cartilage, Morgagni's ventricle, paraglottic space, thyroid and cricoid
      cartilages, thyro-hyo-epiglottic space, vocal cords, subglottic region, and
      epiglottis. Similar forms were filled out by the surgeon and the pathologist
      after surgery. The sensitivity, specificity and diagnostic accuracy of MRI were
      unaffected by the use of contrast medium. Since it did not provide additional
      staging information, its continued routine use in these cases is not justified.

PMID- 10663479
TI  - How often is haemosiderin not visible on routine MRI following traumatic
      intracerebral haemorrhage?
AB  - Intracerebral haemorrhage may be visible indefinitely on MRI, due to persistence
      of haemosiderin in macrophages around the lesion, but it is not clear whether all
      haemorrhages produce haemosiderin or, if not, what proportion cannot be
      identified as former haemorrhages on routine MRI. We performed routine MRI (spin
      echo T2- and proton-density weighted images) in 116 survivors of moderate to
      severe head injury, 1-5 years after injury. We reviewed the images blindly and
      correlated them with CT in the acute stage, to determine how many haemorrhages
      from the acute stage were identifiable by virtue of haemosiderin deposition on
      late MRI. Of 106 haemorrhages in 78 patients on CT at the time of injury, 96 (90
      %) were visible as haemosiderin on late MRI. Of the old haemorrhages without
      haemosiderin, seven of ten were in patients where another haemorrhage with
      haemosiderin was still visible elsewhere in the brain. No patient or haemorrhage
      features explained the formation or absence of haemosiderin. Thus about 10 % of
      definite haematomas show no trace of haemosiderin on routine spin-echo MRI.
      Radiologists should be alerted to supplement routine spin-echo with gradient-echo
      sequences if there is a reason to suspect, or specifically exclude, prior
      haemorrhage.

PMID- 10663480
TI  - Reducing motion artefacts in diffusion-weighted MRI of the brain: efficacy of
      navigator echo correction and pulse triggering.
AB  - Diffusion-weighted MRI (DWI) is extremely sensitive to motion of the object being
      examined. Pulse triggering and navigator echo correction are methods for reducing
      motion artefacts which can be combined with conventional DWI sequences.
      Implementation of these methods in imaging sequences with a readout of one,
      three, or five echoes is presented and imaging results compared in a study of
      five healthy volunteers. As an objective measure for motion-induced image
      artefacts, the "artefacticity" of an image is defined. Pulse triggering and
      navigator echo correction significantly improve image quality and provide a
      technique for high-quality DWI on standard imagers without improved gradient
      hardware.

PMID- 10663481
TI  - Reversible changes in echo planar perfusion- and diffusion-weighted MRI in status
      epilepticus.
AB  - Perfusion imaging (PI) demonstrated increased perfusion and diffusion-weighted
      imaging (DWI) showed high signal limited to the left temporoparietal cortex in a
      68-year-old man with nonconvulsive status epilepticus. The EEG showed a slow
      delta-wave focus. The patient recovered and PI, DWI and EEG changes completely
      resolved.

PMID- 10663482
TI  - An alternative explanation of the origin of the signal in diffusion-weighted MRI.
AB  - I formulated an alternative explanation for the origin of the signal in diffusion
      weighted MRI (DWI) and tested it in a simple experimental model using gelatin. My
      findings indicate that the signal in DWI is influenced by the passage of water
      from the sol to the gel state, independently of the presence of cell structures
      or membrane-dependent diffusion.

PMID- 10663483
TI  - The role of MRI in screening for neurogenic hypertension.
AB  - Neurovascular compression (NVC) of the left ventrolateral medulla (VLM) has been
      implicated as a cause of essential hypertension. We investigated whether high
      resolution MRI of the posterior cranial fossa could identify patients with
      essential hypertension who may benefit from surgery. A retrospective analysis of
      imaging and clinical records from 162 patients was performed. There were 38
      patients with essential hypertension and 124 who were normotensive. Contact or
      compression of the VLM was present in 42.1 % (16/38) of the hypertensive group on
      the left and 47.3 % (18/38) on the right. In the normotensive group it was seen
      in 32.2 % (40/124) on the left and 26.6 % (33/124) on the right. There was no
      significant difference between the hypertensive and control groups with regard to
      contact or compression of the left VLM. The results support the contention that
      neurovascular compression (NVC) of the left or right VLM is a common finding on
      MRI in normotensive individuals. We therefore believe that high-resolution MRI
      cannot be used as a screening tool to identify patients who may benefit from
      surgery.

PMID- 10663485
TI  - Invasive aspergillosis presenting as a cavernous sinus mass in immuno competent
      individuals; report of 3 cases.
AB  - Aspergillosis of the cavernous sinus is rare, especially in immuno competent
      individuals. We report three such cases secondary to paranasal sinus
      aspergillosis, with imaging findings.

PMID- 10663484
TI  - Time-resolved projection MRA: clinical application in intracranial vascular
      malformations.
AB  - We report preliminary results of imaging intracranial vascular malformations with
      time-resolved projection MRA after a bolus injection of contrast median before
      and after endovascular treatment. Projection angiograms are acquired with a slice
      selective snapshot FLASH sequence with a time resolution of two images per
      second, 40-60 images being acquired consecutively after bolus injection of 15 ml
      Gd-DTPA. Postprocessing of images in 2D projection MRA by correlation analysis
      offers several advantages with significant improvement of signal-to-noise,
      leading to adequate anatomical resolution. Subsecond projection MRA is a reliable
      technique for imaging intracranial vessels and gives information about the
      haemodynamics of vascular malformations.

PMID- 10663486
TI  - CT and MRI in severe hypophosphataemia with central nervous system involvement.
AB  - We report a 38-year-old woman with extreme hypophosphataemia in whom CT and MRI
      disclosed bilateral lesions within the basal ganglia, thalamus and occipital
      lobes. After adequate substitution of phosphate the lesions grossly resolved and
      the patient recovered. This case is the first to demonstrate that profound
      changes of serum phosphate may be associated with reversible brain lesions.

PMID- 10663487
TI  - Subacute combined degeneration of the spinal cord with involvement of the
      anterior columns: a new MRI finding.
AB  - We present a case of vitamin B12 deficiency and subacute combined degeneration in
      a patient with a gastrectomy. MRI showed high-signal lesions on T2-weighted
      images in both the posterior and anterior columns, associated with minor thoracic
      spinal cord expansion. The patient was treated with B12 supplements and clinical
      improvement was associated with reduction of the size of the lesions on MRI.

PMID- 10663488
TI  - Brain infarcts due to scorpion stings in children: MRI.
AB  - We report two children with severe neurological complications after having been
      stung by a scorpion. Clinical and MRI findings suggested brain infarcts. The
      lesions seen were in pons in one child and the right hemisphere in the other. The
      latter also showed possible hyperemia in the infarcted area. No vascular
      occlusions were observed and we therefore think the brain infarcts were a
      consequence of the scorpion sting. The cause of the infarct may be hypotension,
      shock or depressed left ventricular function, all of which are frequent in severe
      poisoning by scorpion sting.

PMID- 10663489
TI  - Canalis basilaris medianus: MRI.
AB  - We report the MRI appearances of an developmental anatomical variant of the
      basiocciput, with neuroimaging findings (CT and MRI). Such variants are commonly
      asymptomatic, but may be associated with episodes of meningitis.

PMID- 10663490
TI  - MRI of Enterovirus 71 myelitis with monoplegia.
AB  - We report two boys diagnosed as having herpangina and hand-foot-mouth disease
      complicated by monoplegia during the outbreak enterovirus infection in Taiwan in
      1998. Enterovirus 71 was identified in the stool and throat swab; neither polio
      nor Coxsackie viruses was identified. MRI showed unilateral lesions in the
      anterior horns of the spinal cord at T11-12 and C2-5. Although the MRI findings
      and sites of these lesions were similar to those of poliovirus-associated
      poliomyelitis, the virological data indicated that these boys were infected with
      enterovirus type 71.

PMID- 10663491
TI  - Dissecting aneurysms of the posterior cerebral artery: angioarchitecture and a
      review of the literature.
AB  - Isolated dissecting aneurysms of the posterior cerebral artery are not as rare as
      previously reported. Affecting primarily a younger population, this condition can
      be recognized by angiographic patterns, the most common being a "pearl and
      string" morphology. We reviewed the literature and present a series of six cases,
      discussing management strategies.

PMID- 10663492
TI  - Diffusion-weighted MRI for monitoring neurovascular interventions.
AB  - Carotid stenting is increasingly considered as treatment for carotid artery
      disease. A reliable noninvasive method is desirable for assessing the safety of
      the procedure. Diffusion-weighted MRI (DWI) is sensitive to early brain ischaemia
      which becoming widely available and might therefore serve this purpose. We
      prospectively studied 19 patients referred for investigation of carotid artery
      disease by echo-planar whole-brain DWI before and within 24 h of stenting. The
      images obtained at a high b value were examined by two independent blinded
      reviewers for new high-signal areas consistent with ischaemia. We found that 15
      patients had no new changes after stenting. One patient showed enlargement of a
      posterior watershed lesion after the procedure, which correlated with an increase
      in neurological deficit. Three other patients had presumed small embolic infarcts
      on DWI; two were asymptomatic and one had weakness at the hand that corresponded
      to an embolic infarct with a lesion on DWI in the hand notch. There were no false
      positive or -negative results on DWI, when compared to clinical findings. DWI is
      thus a new method that can demonstrate neurologically silent or asymptomatic
      infants. It can be used to help to assess the safety and efficacy of
      neurovascular intervention.

PMID- 10663493
TI  - Cerebral vasculopathy secondary to leptomeningeal gliomatosis: angiography.
AB  - We describe a young woman with a glioblastoma multiforme in whom angiography
      showed multiple intracranial stenoses. The resected tumour was found to be
      invading cerebral vessels.

PMID- 10663494
TI  - Guglielmi detachable coil treatment of a partially thrombosed giant basilar
      artery aneurysm in a child.
AB  - We report a partially thrombosed giant of the aneurysm basilar artery with
      prominent mass effect, diagnosed in an 11 year-old child who presented with
      neurological deficits due to brain stem compression. After the patent portion of
      the aneurysm was embolised with Guglielmi detachable coils, remarkable clinical
      improvement occurred. Angiography demonstrated complete occlusion of the aneurysm
      and MRI revealed dramatic shrinkage of the aneurysm at 6-month and 1-year follow
      up.

PMID- 10663495
TI  - Senile scleral plaques: CT.
AB  - I studied the CT appearances and the distribution of 109 asymptomatic calcified
      senile scleral plaques in 49 patients (98 eyes). The vast majority were just
      anterior to the insertion of the horizontal rectus muscles. The calcified plaques
      are variable in size, can be single or multiple, involve one or both eyes, and
      are only seen in elderly patients. Beam-hardening artifact and forward protrusion
      beyond the confines of the sclera are uncommon but potentially confusing
      features. Confusion with other pathology is unlikely with awareness of the
      plaques' asymptomatic nature and their clinical and CT appearances.

PMID- 10663497
TI  - Haematopoietic tissue presenting as a sphenoid sinus mass: case report.
AB  - We report an incidentally discovered mass in the sphenoid sinus in a patient with
      beta thalassaemia and sickle-cell disease which proved to be an isolated site of
      extramedullary haematopoiesis in the skull.

PMID- 10663496
TI  - Radionecrosis of the temporal lobe: dynamic susceptibility contrast MRI.
AB  - We examined nine patients with histologically proven nasopharyngeal carcinoma
      (NPC), treated with radiotherapy, using dynamic susceptibility contrast MRI (DSC
      MRI). In eight there was clinical evidence of radionecrosis of the temporal lobe,
      and one was examined for local recurrence in the nasopharynx. All patients had
      either high-signal finger-like or cystic lesions in the temporal lobes on T2
      weighted images. Heterogeneous contrast enhancement occurred in all patients.
      Relative regional cerebral blood volume (rrCBV) mapping revealed marked
      hypoperfusion in all patients. One underwent bilateral temporal lobectomy and
      radionecrosis was confirmed histologically.

PMID- 10663498
TI  - Perinatal radiology.

PMID- 10663500
TI  - Extension of academic pediatric radiology to the community setting: experience in
      two sites.
AB  - BACKGROUND: Children are better served by radiologists and technical personnel
      trained in the care of pediatric patients. However, a variety of obstacles may
      limit the access of children to dedicated pediatric imaging facilities.
      OBJECTIVE: We designed and implemented two models for providing community-based
      imaging by academic pediatric radiologists. MATERIALS: and methods. The first
      site was an outpatient clinic staffed by physicians from the university
      affiliated children's hospital. Imaging services included radiography,
      fluoroscopy, and ultrasound. The second site was a full-service community
      hospital radiology department staffed by a group practice, with pediatric imaging
      covered by the children's hospital radiologists. Facility, equipment, and
      protocol modifications were required to maintain quality standards. Success of
      these models was determined by volume statistics, referring physician/patient
      satisfaction surveys, and quality-assurance (QA) programs. RESULTS: The
      outpatient satellite had a 48 % increase in total examinations from the first
      year to the second year and 87 % the third year. Pediatric examinations in the
      community hospital increased over 1000 % the first 7 months. Referring physicians
      reported increased diagnostic information and patient satisfaction compared to
      previous service. QA efforts revealed improved image quality when pediatric
      radiologists were present, but some continuing difficulties off-hours.
      CONCLUSION: We successfully implemented pediatric imaging programs in previously
      underserved communities. This resulted in increased pediatric radiologist
      supervision and interpretation of examinations performed on children and improved
      referring physician and patient satisfaction.

PMID- 10663501
TI  - Psychosocial issues in pediatric oncology: what the radiologist needs to know.
AB  - Pediatric cancer is rife with psychological and social issues for both patients
      and families. As many of these issues lie outside the traditional bounds of
      radiological training, many radiology department staff members may be unaware of
      them, and patient care may suffer as a result. On the other hand, if the
      radiology staff possesses some understanding of what it means to be or have a
      child with cancer, they may significantly enhance the family's health-care
      experience and enrich their own sense of professional satisfaction. This article
      reviews a number of the key psychosocial issues in pediatric oncology, with a
      view to improving the non-radiological aspects of radiology patient care.

PMID- 10663502
TI  - Developmental coxa vara associated with spondylometaphyseal dysplasia (DCV/SMD):
      "SMD-corner fracture type" (DCV/SMD-CF) demonstrated in most reported cases.
AB  - BACKGROUND: This paper reports three children with short stature: developmental
      coxa vara unilateral in the first case and bilateral in the other two; somewhat
      squared and "ovoid" vertebral bodies in the first patient, and normal to slightly
      tall vertebral bodies in the third; metaphyseal changes in some long tubular
      bones including bone fragments similar to the corner fractures seen in child
      abuse in all three patients. MATERIALS AND METHODS: The first and second patients
      were sisters; their mother, also quite short, had surgical procedures in early
      life for bilateral "coxa vara"; their brother, also of short stature, had
      bilateral coxa valga with otherwise normal femoral heads and necks, and mild
      metaphyseal changes associated with two minute "corner fractures" in the proximal
      metaphysis of the left tibia. RESULTS: A review of reported cases of
      developmental coxa vara associated with spondylometaphyseal dysplasia revealed
      that simulated corner fractures were present in most instances.

PMID- 10663503
TI  - Spinal involvement in Pyle's disease.
AB  - BACKGROUND: Pyle's disease is a rare skeletal dysplasia involving the metaphyses
      of long bones. To date, spinal involvement has been only rarely described in the
      literature. OBJECTIVE: To show that spinal changes, which are an expression of
      the same growth defect of the long bones, are an important and constant sign of
      the disease in the families studied. MATERIALS AND METHOD: The radiographic
      skeletal changes in five patients have been observed. RESULTS: The pathognomonic
      metaphyseal widening of tubular bones (known as the 'Erlenmeyer flask sign') was
      associated with the spinal changes in all cases. Radiographic findings in the
      spine varied from moderate platyspondyly to the bodies having the appearance of a
      biconcave lens. This may be attributed to two main causes: (1) a defect in the
      modelling process of the vertebrae (comparable to that observed in the
      metaphyses) and (2) chronic pathological fractures secondary to osteoporosis (a
      typical feature of Pyle's disease). CONCLUSIONS: The finding of platyspondyly of
      varying severity widens the spectrum of radiographic findings in this disease and
      can assist in diagnosis.

PMID- 10663504
TI  - Milk of calcium fluid collections in juvenile dermatomyositis: MR
      characteristics.
AB  - Children with dermatomyositis may have extensive subcutaneous and intermuscular
      calcium-laden fluid collections referred to as "milk of calcium." The distinctive
      MR appearance of such collections in an upper extremity of a 16-year-old girl is
      presented. MR can differentiate these collections from abscesses and guide
      appropriate therapy.

PMID- 10663505
TI  - Peri-optic nerve infiltration during leukaemic relapse: MRI diagnosis.
AB  - BACKGROUND: A 10-year-old boy with a history of acute lymphoblastic leukaemia
      (ALL), but without previous evidence of central nervous system involvement,
      presented with seizures 3 years after complete remission. MATERIALS AND METHODS:
      MRI showed bilateral enlargement of the optic nerves despite normal
      ophthalmological examination. RESULTS: Only the third cerebrospinal fluid
      examination showed 2 % blasts without concomitant bone-marrow infiltration.
      Enlargement of the optic nerves was consistent with bilateral leukaemic peri
      optic nerve infiltration. The appearances returned to normal after chemotherapy.
      CONCLUSION: The optic nerves are a potential site of relapse in patients with
      systemic and meningeal ALL, even in the absence of ophthalmological signs.

PMID- 10663506
TI  - Enterobacter sakazakii brain abscess in the neonate: the importance of
      neuroradiologic imaging.
AB  - BACKGROUND: Enterobacter sakazakii is a rare but important cause of life
      threatening neonatal sepsis and meningitis complicated by the development of
      brain abscess. OBJECTIVE: Given the neurotropic qualities of this organism, early
      diagnosis and treatment are crucial as a poor prognosis follows brain abscess
      formation. MATERIALS AND METHODS: Cross-sectional imaging (CT and MRI) play an
      important role in the diagnostic work-up. CONCLUSION: A biopsy-proven case of E.
      sakazakii brain abscess, which was diagnosed on MR images, is presented, and the
      importance of prompt radiologic imaging of the central nervous system in the work
      up of patients with this life-threatening disease is discussed.

PMID- 10663507
TI  - Disseminated lymphangiomatosis presenting with massive chylothorax.
AB  - BACKGROUND: Lymphangiomatosis is a disease characterized by involvement of
      various body constituents and can involve the skeletal system, connective
      tissues, and visceral organs. MATERIALS AND METHODS: We present a case of a 9
      year-old girl where this entity presented with extensive right-sided chylothorax.
      Conventional imaging, including skeletal scintigraphy and contrast enhanced CT of
      the chest and abdomen, may have underestimated the extent of the disease, as seen
      on follow-up T2-weighted MR images of the chest and abdomen in our case. RESULTS:
      MRI easily demonstrated additional bone lesions as well as multiple small splenic
      lesions, which were difficult to appreciate on prior CT examinations. CONCLUSION:
      We suggest that MRI may be helpful to assess the extent of this disease more
      accurately.

PMID- 10663508
TI  - Ruptured giant intrathoracic lipoblastoma in a 4-month-old infant: CT and MR
      findings.
AB  - BACKGROUND: We describe a 4-month-old infant with a ruptured intrathoracic
      lipoblastoma arising from the parietal pleura and associated with a pleural
      effusion. OBJECTIVE: The clinical presentation was rapidly evolving respiratory
      distress. The chest radiograph showed a large mass and a pleural effusion in the
      right thoracic cavity. CT demonstrated an inhomogeneous low-attenuation mass
      which was 7 cm in diameter and which showed areas of enhancement after
      intravenous contrast medium. MRI showed a fatty intrathoracic mass with
      intratumoral streaks and whorls, which were attributed to loose fibrovascular
      connective tissue on pathological examination. RESULTS: Thoracotomy and
      pathological examination revealed a ruptured intrathoracic lipoblastoma arising
      from the parietal pleura. CONCLUSION: The pleural effusion might have suggested
      rupture of the tumour.

PMID- 10663509
TI  - Preoperative manual detorsion of the spermatic cord with Doppler ultrasound
      monitoring in patients with intravaginal acute testicular torsion.
AB  - OBJECTIVE: To assess the effectiveness of preoperative manual detorsion in acute
      testicular torsion. MATERIALS AND METHODS: Between June 1998 and March 1999,
      seven patients presenting with testicular torsion underwent manual manipulation
      under US monitoring in order to restore the flow to the testis prior to surgery
      (orchidopexy). All detorsions were lateral in direction. The success of the
      manoeuvre was assessed both clinically and sonographically and confirmed at
      surgery. RESULTS: Six manoeuvres were successful in restoring flow to the testis.
      The failed attempt in the seventh patient was due to failure to manipulate beyond
      an initial 1 1/2 rotations (540 degrees). CONCLUSIONS: Preoperative detorsion is
      the fastest way to relieve testicular ischaemia. However, manual detorsion of the
      spermatic cord is not a substitute for surgical exploration and bilateral
      orchidopexy is still necessary.

PMID- 10663510
TI  - Imaging findings in pediatric adrenocortical carcinoma.
AB  - BACKGROUND: Adrenocortical carcinoma (ACC), a tumor that is rare among children,
      causes clinically evident hormonal disturbances. Imaging methods are used to
      stage disease and to plan surgical resection. OBJECTIVE: To describe the findings
      of the various imaging methods used to evaluate ACC. MATERIALS AND METHODS: We
      reviewed the records of ten consecutive patients (mean age, 8.1 years) who
      presented from 1987 to 1998 with ACC. All patients underwent computed tomography
      (CT) scanning; five underwent magnetic resonance (MR) imaging; four underwent
      ultrasonography (US); and eight underwent radionuclide bone scans. RESULTS: Seven
      patients presented with signs of hormonally functional tumors. Typical imaging
      findings consisted of a large, well-defined suprarenal tumor, containing
      calcifications (seven patients) with a thin capsule and central necrosis or
      hemorrhage (six patients). The inferior vena cava (IVC) was compressed by tumor
      in three patients, and ultrasonography demonstrated invasion of the IVC wall in
      one of these. Three patients' bone scans showed that the primary tumor took up
      radioactive tracer. Spread to lungs or liver or both was demonstrated in six
      patients. CONCLUSIONS: CT, US and MR imaging are effective methods of imaging the
      primary tumor. Chest CT and bone scintigraphy should be performed to detect
      metastases. The presence of a thin tumor capsule, a stellate central zone of
      necrosis, and evidence of hormonal function help distinguish ACC from
      neuroblastoma.

PMID- 10663511
TI  - Sonographic assessment of renal length in the first year of life: the problem of
      "spurious nephromegaly".
AB  - PURPOSE: Interest in the potential diagnostic or prognostic implications of
      nephromegaly as evidence for compensatory renal hypertrophy has recently been
      emphasized in a variety of clinical settings. This project was designed to
      compare the results of linear and nonlinear sonographic models in the
      interpretation of renal size and growth during the first year of life. MATERIALS
      AND METHODS: We identified all renal and abdominal ultrasound examinations that
      were performed between March 1994 and October 1997 in full-term infants under age
      1 year during which (1) both renal lengths were measured and (2) both kidneys
      appeared anatomically normal. Using three different computerized algorithms based
      on published standards for sonographic renal length in relation to age, we
      calculated z-scores for the renal lengths and compared the results of the three
      methods: in method A the standards at birth, 1 week, 4 months, 8 months, and 1
      year were all used; in method B the 1-week standard was omitted; in method C the
      standards at 1 week, 4 months, and 8 months were omitted. RESULTS: We evaluated
      1,234 renal measurements in 617 patients (293 boys, 324 girls; mean age 0.24
      year). Compared with method A, z-scores were significantly increased when either
      method B or C was used (P < 0. 0001). The mean increment in z-score was + 0.433
      for method B and + 1.135 for method C. The prevalence of "nephromegaly" (z > + 2)
      was significantly increased when subannual standards were omitted (P < 0. 0001):
      using method A, 20 (1.6 %) kidneys were large for age compared with 74 (6.0 %)
      using method B, and 214 (17.3 %) using method C. All kidneys that were large for
      age based on method A were also large for age using both methods B and C. The
      rate of false-positive diagnosis of nephromegaly was 73 % (54/74 kidneys) with
      method B and 91 % (194/214 kidneys) with method C. CONCLUSIONS: Although the use
      of multiple subannual standards for renal length in infants less than 1 year of
      age is time consuming and mathematically more complicated, omission of these
      standards results in a statistically significant increase in the frequency of
      "spurious" nephromegaly. LEARNING OBJECTIVES: Precise application of published
      standards is important in the interpretation of sonographic measurements of renal
      length. Omission of the subannual standards for renal length in children who are
      less than 1 year of age can result in an incorrect impression of nephromegaly.

PMID- 10663512
TI  - Spontaneous reduction of intussusception: clinical spectrum, management and
      outcome.
AB  - BACKGROUND: To analyze the spectrum of clinical features, management and outcome
      of children with documented spontaneous reduction of intussusception (SROI).
      MATERIALS AND METHODS: Review of records of 50 children (33 boys, 17 girls; age
      range 11 days-15 years; mean age 4 years) with documented SROI, in whom
      intussusception was initially diagnosed by sonography (US) in 44, air enema in 2,
      and computed tomography in 4, in the 6-year period 1992-1998. RESULTS: Symptoms
      suggestive of intussusception were present in 21 (3 of whom had Henoch-Schonlein
      purpura and 4 had previous ileocolic intussusception reduced by air enema).
      Intussusception was an incidental finding in the other 29, in 28 of whom the
      finding was in the small bowel. Intussusception was limited to the small bowel in
      43 and was ileocolic in 7. SROI was usually documented on US. Laparotomy
      performed in only 4 showed no evidence of intussusception or pathologic lead
      point. Outcome in all patients was favorable. CONCLUSIONS: SROI may present in
      symptomatic or asymptomatic children and occurs more commonly than previously
      reported. These intussusceptions are usually short-segment, small-bowel
      intussusceptions with no recognizable lead point. In asymptomatic patients,
      conservative observation is warranted. Intervention should be dictated by the
      clinical findings in symptomatic patients.

PMID- 10663513
TI  - Nodular regenerative hyperplasia of the liver: case report of a 13-year-old girl
      and review of the literature.
AB  - BACKGROUND: Nodular regenerative hyperplasia (NRH) of the liver is a multi-acinar
      regenerative nodular lesion in a non-cirrhotic liver. It is a rare entity,
      especially in children, and remains of unknown aetiology. OBJECTIVE: NRH is often
      seen in association with other diseases or drug intake. In half of patients it is
      complicated by portal hypertension. Radiologically, its nodular appearance may
      look like neoplasia. RESULTS: We report a case of NRH with enormous hepatomegaly
      and multiple huge nodules. CONCLUSION: We wish to emphasise the importance of
      open wedge biopsy to establish diagnosis, since the prognosis of NRH in the
      absence of portal hypertension is good. Complications such as rupture of a nodule
      are rare.

PMID- 10663514
TI  - Making the diagnosis of biliary atresia using the triangular cord sign and
      gallbladder length.
AB  - BACKGROUND: To evaluate the accuracy and utility of the triangular cord sign and
      gallbladder length in diagnosing biliary atresia by sonography. MATERIALS AND
      METHODS: Sixty fasted infants with cholestatic jaundice aged 2-12 weeks were
      examined sonographically using a 5-10 MHz linear array transducer, focusing on
      the triangular cord sign (as described by Choi et al. [1]), the gallbladder, and
      ducts. The triangular cord is defined as a triangular or tubular echogenic
      density seen immediately cranial to the portal vein bifurcation; it represents
      the fibrotic remnant of the obliterated cord in biliary atresia. The findings
      were blinded to blood chemistry, (99 m)Tc-DISIDA hepatobiliary scintigraphy, and
      liver biopsy. Diagnosis of biliary atresia was confirmed at surgery and
      histology. Non-biliary atresia infants resolved medically. Comparative charges of
      the various investigations was made. RESULTS: ++ Twelve infants had biliary
      atresia, and ten demonstrated a definite triangular cord. The two false-negatives
      had small or nonvisualized gallbladders. No false-positives were recorded.
      Gallbladder length ranged from 0-1.45 cm with a mean of 0. 52 cm in biliary
      atresia compared to a mean of 2.39 cm in nonbiliary atresia infants. (99 m)Tc
      DISIDA hepatobiliary scintigraphy showed no excretion (false-positive) in 23 % of
      nonbiliary atresia cases. Scintigraphy and liver biopsy charges were 2 and 6
      times that of sonography, respectively. CONCLUSION: The triangular cord sign and
      gallbladder length together are noninvasive, inexpensive, and very useful markers
      for biliary atresia.

PMID- 10663515
TI  - CT findings in hyperacute nonaccidental brain injury.

PMID- 10663516
TI  - Ultrasound diagnosis of luckenschadel (lacunar skull).
AB  - BACKGROUND: The neuroradiologic findings in the Chiari II malformation are well
      known. Luckenschadel (lacunar skull) is commonly seen in patients with Chiari II
      on plain film and with computed tomography (CT). However, the sonographic
      appearance of luckenschadel has not previously been described. paragraph
      signObjective. To evaluate the presence or absence of luckenschadel on
      neurosonograms from infants with myelomeningocele. MATERIALS AND METHODS: Twenty
      one neurosonograms in patients with myelomeningocele were reviewed for the
      presence of an irregular inner calvarial table indicative of luckenschadel. The
      degree of irregularity was graded and compared with CT and plain film when
      available. The ventricular index was calculated from the ultrasound (US) studies
      and correlated with degree of luckenschadel using one-way analysis of variance.
      RESULTS: Nine patients had marked findings of luckenschadel, nine had mild
      findings, and three had normal US exams. There was no correlation between the
      degree of sonographic luckenschadel and the ventricular index. CONCLUSION: The
      finding of luckenschadel adds to the spectrum of abnormalities of the Chiari II
      malformation diagnosed by US.

PMID- 10663517
TI  - Magnetic resonance cystography with gadopenetate dimeglumine of a cystic
      craniopharyngioma in a child - a technical note.
AB  - Large cystic craniopharyngiomas can be treated with chemotherapy injected
      directly into the cyst. Chemotherapy is toxic if it leaks from the cyst into the
      subarachnoid space. We present a child with a cystic craniopharyngioma following
      surgical placement of a catheter into the cystic component. Computed tomography
      following iodinated contrast injection into the cyst was inconclusive in
      determining the cyst wall integrity. Magnetic resonance following dilute
      gadopentetate dimeglumine injection into the cyst clearly defined a leak into the
      subarachnoid space. Coronal imaging was especially helpful. This technique is
      simple to perform and useful for clinical management.

PMID- 10663518
TI  - Histiocytosis presenting as a nasal mass.
AB  - The authors present a 1-year-old child who presented with an expansile enhancing
      mass of the nasal cavity that proved to be histiocytosis.

PMID- 10663519
TI  - Pattern of recurrence in children with midline posterior fossa malignant
      neoplasms.
AB  - BACKGROUND: Surveillance imaging of the brain and spinal neuraxis in patients
      with posterior fossa malignant tumors is commonly performed, with the assumption
      that early detection of tumor recurrence will improve outcome. However, the
      benefit of this imaging has not been proven. PURPOSE: To evaluate the usefulness
      of spinal surveillance imaging in children with nonmetastatic (at diagnosis, M0)
      posterior fossa ependymoma and medulloblastoma. MATERIALS AND METHODS: This
      retrospective study included 65 children (3 months to 16 years, mean 5.7 years)
      treated between 1985 and 1997 for ependymoma (22) and medulloblastoma (43).
      Medical records were reviewed for pathology and treatment data. Serial imaging of
      the head and spine was reviewed for evidence of tumor recurrence. RESULTS: Twenty
      four patients (37 %) had tumor recurrence, including 13 with ependymoma and 11
      with medulloblastoma. Of the 17/24 recurrent patients initially diagnosed as M0
      (6 medulloblastoma and 11 ependymoma), 13 (76 %) had a cranial recurrence only,
      and 4 (24 %) presented with concomitant cranial and spinal recurrence. No M0
      patient presented solely with spinal metastases at recurrence. CONCLUSION: This
      study suggests that spinal surveillance imaging in patients with posterior fossa
      ependymoma or medulloblastoma initially staged as M0 may not be useful, as these
      patients initially recur intracranially. Thus, until an intracranial recurrence
      is detected, these patients may be spared the time, expense and sedation risk
      necessary for spinal imaging.

PMID- 10663520
TI  - Acute appendicitis in children: comparison of clinical diagnosis with ultrasound
      and CT imaging.
AB  - BACKGROUND: There is strong evidence that imaging with ultrasound and CT can be
      of substantial diagnostic value in the diagnosis of acute appendicitis in
      children, but there is limited information of the impact of imaging on the
      management of these patients and its possible effect on surgical findings.
      OBJECTIVE: We studied the impact of imaging in the management of acute
      appendicitis, in particular its effect on the rate of negative appendectomies and
      perforations. PATIENTS AND METHODS: We reviewed retrospectively the clinical
      records and imaging findings of 633 consecutive children and adolescents seen on
      an emergency basis with clinical suspicion of acute appendicitis. Two hundred
      seventy patients were operated upon on clinical evidence alone, while 360 were
      referred for US or CT, and occasionally both, because of doubtful clinical
      findings. RESULTS: Acute appendicitis was found in 237 of those on clinical
      grounds alone, 68 of whom had perforation and related complications. Thus the
      rate of negative exploration and the rate of perforation were13 % and 29 %,
      respectively. One hundred eighty-two patients had preoperative US (sensitivity 74
      %, specificity 94 %), 119 had CT (sensitivity 84 %, specificity 99 %), and 59 had
      both US and CT (sensitivity 75 %, specificity 100 %, but often with
      interpretation at variance with each other). The rate of negative appendectomy
      and perforation was 8 % and 23 %, respectively, for US, 5 % and 54 % for CT, and
      9 % and 71 % when both examinations were performed. There is no statistical
      significance between the rates of diagnostic performance of US, CT, or their
      combination, nor between the negative appendectomy rates of each group, but the
      rate of perforation was significantly higher when CT was performed, alone or
      after US. CONCLUSION: The retrospective nature of the study prevents precise
      definition of the clinical characteristics and selection criteria for diagnostic
      examinations that may contribute to the management of children with suspected
      acute appendicitis. It was designed, however, to reflect the diagnostic approach
      and management of these patients, under the care of many decision makers and
      interpreters of imaging examinations, prevalent today in most hospital-based
      clinical practices. It is suggested that imaging increases diagnostic accuracy in
      difficult cases, but it might be one of the factors increasing the rate of
      perforations.

PMID- 10663521
TI  - Detection of active intraabdominal hemorrhage after blunt trauma: value of
      delayed CT scanning.
AB  - Active hemorrhage is a rare finding at CT following blunt abdominal trauma. The
      time interval between IV contrast administration and scanning the abdomen may
      impact on the ability to visualize active hemorrhage at CT. We report a case of
      active hemorrhage associated with splenic injury that was identified only at
      delayed CT scanning.

PMID- 10663522
TI  - Potential pediatric applications for US contrast agents: lessons from the
      laboratory.
AB  - OBJECTIVES: The goals of this review are to familiarize the reader with the
      physical basis for microbubble contrast effect and to summarize experimental
      studies exploring their potential pediatric applications. MATERIALS: Animal
      studies conducted over a 4-year period using an experimental US contrast agent
      for imaging the central nervous system, kidney, testes, hip joints, and malignant
      tumors are reviewed with respect to imaging efficacy of the agent, possible use
      for quantification of tissue blood flow, and potential non-vascular imaging
      applications. CONCLUSIONS: US contrast agents hold important potential for many
      clinical applications in imaging the pediatric patient.

PMID- 10663523
TI  - Not all rods are Harrington - an overview of spinal instrumentation in scoliosis
      treatment.
AB  - BACKGROUND: Scoliosis is a multiplanar spinal deformity, which has been treated
      in the past with spinal fusion and cast application, starting in the early part
      of this century. In the last 30 years, Paul Harrington successfully introduced
      spinal instrumentation for scoliosis. Harrington instrumentation has had a large
      impact on the treatment of scoliosis. Currently, there are many different
      instrumentations available for the treatment of scoliosis. Indications differ for
      the use of these systems. Appreciation of spinal instrumentation is essential to
      treatment of the patient with scoliosis. Post-operative roentgenographic studies
      are better understood when the interface between instrumentation and the spine is
      understood. MATERIALS AND METHODS: Distinguishing characteristics between some of
      the more common instrumentations are noted. There continues to be a proliferation
      of spinal instrumentation systems. Roentgenograms and spinal models are used to
      explain how some of the instrumentation systems differ and how they interface
      with the spine. CONCLUSION: An overview of spinal instrumentation in scoliosis
      treatment will allow better understanding of the purposes of the hardware and how
      it relates to the spine.

PMID- 10663524
TI  - Pathological fractures in spondyloenchondrodysplasia: case report.
AB  - We present a patient with spondyloenchondrodysplasia who sustained two
      pathological fractures of long bones in a period of 6 months. This complication
      of spondyloenchondrodysplasia has not been described previously. Since both
      fractures occurred with mild trauma, it would appear that
      spondyloenchondrodysplasia can be associated with a tendency towards pathological
      fractures and, therefore, it would be advisable to warn people suffering from
      this condition to avoid activities that put excessive strain on the limbs.

PMID- 10663525
TI  - Vesicoureteral reflux: subpopulations of patients defined by clinical variables.
AB  - BACKGROUND: The first imaging evaluation of the child with urinary tract
      infection (UTI) is often the same for all children, regardless of the child's
      clinical presentation. However, this approach is simplistic and ignores
      considerable differences in the frequency of abnormal pathophysiology in
      different subpopulations of children with UTI. OBJECTIVE: Six clinical variables
      are evaluated as predictors of vesicoureteral reflux (VUR) in a large series of
      girls with UTI. MATERIALS AND METHODS: Data were collected from a consecutive
      series of 919 girls undergoing a first imaging evaluation for UTI. Six input
      variables were used: age, maximum body temperature (T(max)), number of UTIs,
      hospitalization, family history of childhood UTI, and rapidity of response to
      antibiotic therapy. The dependent variable was VUR. Data were enumerated and
      analyzed by logistic regression and the chi-square test. RESULTS: VUR was present
      in 28.8 %. The percentage with VUR varied from 56.1 % for age < 6 months and
      T(max) L 38.5 degrees C to 13.0 % for age L 10 years and T(max) < 38.5 degrees C.
      The frequency of VUR was significantly lower in girls with T(max) < 38.5 degrees
      C in most age groups. Logistic regression demonstrated, when all clinical
      variables were taken together, that only age and T(max) were independent
      predictors of VUR. CONCLUSIONS: Girls with UTI should not be considered to be a
      homogeneous group. The frequency of VUR is related to T(max) and inversely to
      age. Data about these subpopulations should be used in deciding which girls
      should undergo cystography.

PMID- 10663526
TI  - Severe scrotal pain in boys with Henoch-Schonlein purpura: incidence and
      sonography.
AB  - BACKGROUND: Henoch-Schonlein purpura (HSP) is a systemic vasculitis with
      multiorgan involvement. The scrotal involvement and its sonographic appearance
      are less well recognized than that of the kidneys and abdomen, and the reported
      incidence is varied. OBJECTIVE: To review the incidence of significant scrotal
      involvement in boys with HSP and its sonographic characteristics. MATERIALS AND
      METHODS: Thirteen boys (ages 4-11 years) out of 87 boys diagnosed with HSP, over
      a 15-year period had significant scrotal complaints. Seven underwent sonographic
      evaluation to define the extent of scrotal involvement and because testicular
      torsion was being considered. RESULTS: Scrotal involvement producing significant
      pain occurred in 15 % of boys with HSP. The majority of boys had the diagnosis of
      HSP established before developing scrotal complaints. Sonographic findings
      consistently included an enlarged, rounded epididymis, thickened scrotal skin,
      and a hydrocele. The testes themselves were usually sonographically normal.
      CONCLUSIONS: Scrotal involvement in boys with HSP is not uncommon. The
      sonographic findings in the scrotum are sufficiently characteristic to allow
      distinction from torsion in most cases.

PMID- 10663527
TI  - The misuse of our intellectual resources: an unacknowledged problem of radiology
      at the millennium.

PMID- 10663529
TI  - gamma-Ray footprinting and fluorescence polarization anisotropy of a 30-mer
      synthetic DNA fragment with one 2'-deoxy-7-hydro-8- oxoguanosine lesion.
AB  - The influence of the oxidative lesion 2'-deoxy-7-hydro-8-oxoguanosine (8-oxodG)
      on some conformational properties of DNA has been studied. Four 30-mer duplexes
      of the form [5'-GATCCTCTAGAGTC[G(*) or G]ACCTGCAGGCATGCA-3']:[3'-CTAGGAGATCTCAG[C
      or A]TGGACGTCCGTACGT-5'], in which G(*) is the 8-oxodG lesion, were synthesized
      in order to compare the effect of the GA mismatch and of the damaged G(*)C and
      G(*)A forms with the normal GC. Spectroscopic measurements performed by means of
      UV denaturation and circular dichroism experiments do not show gross changes of
      stability and overall structure in the damaged and mismatched samples. The
      control DNA and the samples containing GA mismatch show very similar gamma-rays
      cutting patterns, indicating that the introduction of the GA mismatch does not
      perturb the phosphate backbone geometry. In the samples containing the 8-oxodG
      there are some variations of the cleavage pattern near G(*) which are extended
      for almost one helical turn. Some differences are observed between G(*)C and
      G(*)A duplexes. In particular, in the G(*)C sample the reduced accessibility to
      OH radicals at the G15 site, observed in the control, spreads on the intrastrand
      adjacent bases and in the G(*)A sample a shift of the minimum is observed. The
      hydrodynamic radius R(h) derived by fluorescence polarization anisotropy decay
      exhibits a constant value of 11.4 +/- 0.2 A between 5 and 40 degrees C, in all
      the samples. The torsional constant alpha of each oligomer decreases when the
      temperature is raised and the alpha values of the damaged samples are higher than
      those of the normal ones.

PMID- 10663530
TI  - Miscibility of phosphatidylethanolamine-phosphatidylglycerol mixtures as a
      function of pH and acyl chain length.
AB  - We have examined the mixing properties of phosphatidylethanolamine (PE) and
      phosphatidylglycerol (PG), the major components of many bacterial membranes. The
      phase transition behavior of dilute aqueous suspensions of PE:PG mixtures with
      different chain lengths (n = 14, 16) in 0.1 M NaCl at pH 7 and pH 2 was
      investigated by differential scanning calorimetry (DSC). The DSC curves were
      simulated using an approach which takes into account the broadening of the phase
      transition in addition to symmetric, non-ideal mixing in the gel and the liquid
      crystalline phase. Based on the temperatures for onset and end of "melting"
      obtained by the simulations, the phase diagrams were constructed and then refined
      using a regular solution model with non-symmetric mixing in both phases. The
      mixing properties of PE:PG mixtures were analyzed as a function of pH and acyl
      chain length. In almost all cases, non-symmetric mixing behavior was observed,
      i.e. the non-ideality parameters are different for bilayers with low PG content
      compared to bilayers with high PG content. For equimolar mixtures at pH 7, when
      PG is negatively charged, the non-ideality parameters are negative for both
      phases, indicating preferential formation of mixed pairs. This mixed pair
      formation is more pronounced for the gel phase. At pH 2, when PG is partly
      protonated, the non-ideality parameter is less negative and the formation of
      mixed pairs is reduced compared to pH 7. The formation of PE:PG mixed pairs at pH
      7 might be of benefit to a bacterial membrane, because it prevents demixing of
      lipid components with a concomitant destabilization of the membrane.

PMID- 10663528
TI  - Imaging microtubules and kinesin decorated microtubules using tapping mode atomic
      force microscopy in fluids.
AB  - The atomic force microscope has been used to investigate microtubules and kinesin
      decorated microtubules in aqueous solution adsorbed onto a solid substrate. The
      netto negatively charged microtubules did not adsorb to negatively charged solid
      surfaces but to glass covalently coated with the highly positively charged silane
      trimethoxysilylpropyldiethylenetriamine (DETA) or a lipid bilayer of 1,2
      dipalmitoyl-3-dimethylammoniumpropane. Using electron beam deposited tips for
      microtubules adsorbed on DETA, single protofilaments could be observed showing
      that the resolution is up to 5 nm. Under conditions where the silane coated
      surfaces are hydrophobic, microtubules opened, presumably at the seam, whose
      stability is lower than that of the bonds between the other protofilaments. This
      led to a "sheet" with a width of about 100 nm firmly attached to the surface.
      Microtubules decorated with a stoichiometric low amount of kinesin molecules in
      the presence of the non-hydrolyzable ATP-analog 5'-adenylylimidodiphosphate could
      also be adsorbed onto silane-coated glass. Imaging was very stable and the
      molecules did not show any scan-induced deformation even after hundreds of scans
      with a scan frequency of 100 Hz.

PMID- 10663531
TI  - Effects of inorganic salts on the structural heterogeneity of serum albumin
      solutions.
AB  - The formation of protein clusters or a protein-rich phase in undersaturated
      solutions of biopolymers is considered theoretically on the basis of phase
      diagrams of a water-protein-salt system. Concentrated (50-200 mg/ml of protein)
      water-salt solutions of human serum albumin molecules modified by a maleimide
      spin-label have been studied experimentally using the ESR technique to
      characterize the significant general features of the system behaviour suggested
      by the model phase diagrams. The inorganic ion content (NaCl, KSCN, MgCl(2), and
      CaCl(2)) was varied in the range of 10(-3)-4 M. Salt-induced changes in different
      experimental ESR spin-label parameters based on relations between spectral line
      widths and amplitudes were determined and compared with the same parameters in
      salt-free solution. The data on dipole-dipole interactions of spin labels
      obtained at 77 K and on spin exchange at normal temperatures are indicative of
      local protein concentration inhomogeneities. The results have been described in
      terms of salt-induced dissociation of stabilized supramolecular structures in
      protein solution-protein clusters, liquid-liquid phase transition between the
      hydration water of clusters and that of individual proteins, and a rise in
      surface tension which results in protein stabilization.

PMID- 10663532
TI  - Structure prediction of the dimeric neu/ErbB-2 transmembrane domain from multi
      nanosecond molecular dynamics simulations.
AB  - Dimerization of the neu/ErbB-2 receptor tyrosine kinase is a necessary but not a
      sufficient step for signaling. Despite the efforts expended to identify the
      molecular interactions responsible for receptor-receptor contacts and
      particularly those involving the transmembrane domain, structural details are
      still unknown. In this work, molecular dynamics simulations of the helical
      transmembrane domain (TM) of neu and ErbB-2 receptors are used to predict their
      dimer structure both in the wild and oncogenic forms. A global conformational
      search method, applied to define the best orientations of parallel helices,
      showed an energetically favorable configuration with the specific mutation site
      within the interface, common for both the nontransforming and the transforming
      neu/ErbB-2 TM dimers. Starting from this configuration, a total of 10
      simulations, about 1.4 ns each, performed in vacuum, without any constraints,
      show that the two helices preferentially wrap in left-handed interactions with a
      packing angle at about 20 degrees. The resulting structures are nonsymmetric and
      the hydrogen bond network analysis shows that helices experience pi local
      distortions that facilitate inter-helix hydrogen bond interactions and may result
      in a change in the helix packing, leading to a symmetric interface. For the
      mutated sequences, we show that the Glu side chain interacts directly with its
      cognate or with carbonyl groups of the facing backbone. We show that the
      connectivity between interfacial residues conforms to the knobs-into-holes
      packing mode of transmembrane helices. The dimeric interface described in our
      models is discussed with respect to mutagenesis studies.

PMID- 10663533
TI  - Simulation studies on bacteriorhodopsin bundle of transmembrane alpha segments.
AB  - Bacteriorhodopsin (BR) is a membrane protein which pumps protons through the
      plasma membrane. Seven transmembrane BR helical segments are subjected to
      simulation studies in order to investigate the packing process of transmembrane
      helices. A Monte Carlo simulated annealing protocol is employed to optimize the
      helix bundle system. Helix packing is optimized according to a semi-empirical
      potential mainly composed of six components: a bilayer potential, a crossing
      angle potential, a helix dipole potential, a helix-helix distance potential, a
      helix orientation potential and a helix-helix distance restraint potential (a
      loop potential). Necessary parameters are derived from theoretical studies and
      statistical analysis of experimentally determined protein structures. The
      structures from the simulations are compared with the experimentally determined
      structures in terms of geometry. The structures generated show similar shapes to
      the experimentally suggested structure even without the helix-helix distance
      restraint potential. However, the relative locations of individual helices were
      reproduced only when the helix-helix distance restraint potential was used with
      restraint conditions. Our results suggest that transmembrane helix bundles
      resembling those observed experimentally may be generated by simulations using
      simple potentials.

PMID- 10663534
TI  - Simulation studies on bacteriorhodopsin alpha-helices.
AB  - Bacteriorhodopsin (BR) is a membrane protein which pumps protons through the
      plasma membrane. Transmembrane BR helical segments are subjected to simulation
      studies in order to investigate the effect of bilayer environment in various
      simulation conditions. A bilayer potential is introduced to the system to mimic
      the lipid membrane. The structures from the simulations are compared with the
      experimentally determined structures in terms of geometrical properties.
      Electrostatic contribution to the helix packing is also investigated. The
      simulation results show that the packing geometry of the transmembrane helices is
      highly affected by the bilayer potential. The results obtained from the
      simulations may be used for further simulation studies and analysis in
      investigating transmembrane helix packing.

PMID- 10663535
TI  - Grazing incidence X-ray diffraction of highly aligned phospholipid membranes
      containing the antimicrobial peptide magainin 2.
AB  - We present the first study of grazing incidence X-ray diffraction on a model
      system of phospholipid membranes and antimicrobial peptides. For this purpose,
      highly oriented multilamellar samples have been prepared on solid substrates. By
      this technique, the short-range order of the lipid chains in the fluid L(alpha)
      phase can be investigated quantitatively, including not only the mean distance
      between acyl chains, but also the associated correlation length. The short-range
      order in lecithin is found to be severely affected by the amphiphilic peptide
      magainin 2.

PMID- 10663555
TI  - Analysis of single-nucleotide polymorphisms in the interleukin-4 receptor gene
      for association with inflammatory bowel disease.
AB  - Genetic linkage analysis in families with multiple cases of inflammatory bowel
      disease (IBD) has mapped a gene which confers susceptibility to IBD to the
      pericentromeric region of chromosome 16 (IBD1). The linked region includes the
      interleukin(IL)-4 receptor gene (IL4R). Since IL-4 regulation and expression are
      abnormal in IBD, the IL4R gene is thus both a positional and functional candidate
      for IBD1. We screened the gene for single-nucleotide polymorphisms (SNPs) by
      fluorescent chemical cleavage analysis, and tested a subset of known and novel
      SNPs for allelic association with IBD in 355 families, which included 435 cases
      of Crohn's disease and 329 cases of ulcerative colitis. No association was
      observed between a haplotype of four SNPs (val50ile, gln576arg, A3044G, G3289A)
      and either the Crohn's disease or ulcerative colitis phenotypes using the
      transmission disequilibrium test. There was also no evidence for association when
      the four markers were analyzed individually. The results indicate that these
      variants are not significant genetic determinants of IBD, and that the IL4R gene
      is unlikely to be IBD1. Linkage disequilibrium analyses showed that the val50ile
      and gln576arg variants are in complete equilibrium with each other, although they
      are separated by only about 21 kilobases of genomic DNA. This suggests that a
      very dense SNP map may be required to exclude or detect disease associations with
      some candidate genes.

PMID- 10663556
TI  - Class I and class II MHC bind self peptide sets that are strikingly different in
      their evolutionary characteristics.
AB  - Comparison of peptides eluted from human class I and class II major
      histocompatibility complex (MHC) molecules and the proteins from which they are
      derived (source proteins) revealed that class I MHC bind peptides derived from
      proteins that are highly conserved, hydrophilic, and universally expressed, while
      the peptides themselves are hydrophobic and even more conserved than their source
      proteins. In contrast, source proteins for class II-bound peptides were not
      significantly more conserved than a random sample of proteins. Class II-bound
      peptides were generally more conserved than their source proteins but were
      significantly less conserved than class I-bound peptides. The characteristics of
      class I-bound peptides can probably be explained by the selectivity of processing
      and transport of peptides for binding by class I, while the relative lack of
      selectivity of peptide binding for class II may explain the high incidence of
      autoimmune diseases associated with alleles of these molecules.

PMID- 10663557
TI  - Mapping of the SWAP70 gene to mouse chromosome 7 and human chromosome 11p15.
AB  - The protein SWAP-70 was isolated as part of a DNA recombination complex in B
      lymphocytes, where it is predominantly expressed. In resting B cells, SWAP-70 is
      found in the cytoplasm; upon B-cell activation, it is transported both into the
      nucleus and to the cell membrane, where it is associated with the B-cell receptor
      complex and may play a role in signal transduction. In the nucleus, its
      involvement in heavy-chain class switch recombination has been suggested. In this
      report, using restriction fragment length polymorphism, simple sequence length
      polymorphism, and fluorescence in situ hybridization, we map the chromosomal
      localization of the mouse and the human genes to syntenic regions of mouse mid
      Chromosome (Chr) 7 and human Chr 11p15.

PMID- 10663559
TI  - Genomic organization of the human interleukin-12 receptor beta2-chain gene.
AB  - The interleukin-12 receptor (IL-12R) is composed of two subunits, referred to as
      beta1 and beta2. Both chains are necessary for high-affinity IL-12 binding and
      signalling, although only the IL-12Rbeta2 chain contains the intracellular
      tyrosine residues responsible for STAT4 activation. This study presents the
      intron-exon organization of the human IL-12Rbeta2-chain gene. Polymerase chain
      reaction (PCR) primers designed across the cDNA (U46198) were used to trace
      introns, by comparing PCR product sizes obtained using cDNA and genomic DNA as
      templates. PCR products spanning introns were sequenced to determine the exact
      splice sites and flanking regions. The coding region of the gene was found to
      consist of 15 exons and 14 introns. All intron-exon boundaries are consistent
      with the consensus sequence for splice junctions (5' GT/AG 3'). Comparison of the
      intron-exon organization with the human GCSFR gene indicated a remarkably well
      conserved genomic organization between these two class I cytokine receptors.
      Interestingly, we identified an alternatively spliced mRNA, encoding a putative,
      truncated protein, lacking all signalling potential.

PMID- 10663558
TI  - Diverse endogenous light chains contribute to basement membrane reactivity in
      nonautoimmune mice transgenic for an anti-laminin Ig heavy chain.
AB  - Basement membrane proteins are targeted in a variety of pathologic autoimmune
      responses, yet little is known regarding the origins and regulation of this
      subset of pathogenic lymphocytes. To examine the generation and fate of B cells
      reactive with a matrix autoantigen, nonautoimmune C57BL/6 mice were rendered
      transgenic for a nephrotropic lupus anti-laminin immunoglobulin (Ig) H chain,
      termed LamH-Cmu. We previously reported recovery of two distinct phenotypes among
      LamH-Cmu-transgenic mice: progeny of founders M6 and M29 contained abundant
      transgene-expressing B cells but little anti-laminin Ig, whereas spontaneous
      autoreactivity was readily recovered from the M7 lineage that expressed minimal B
      cell mIgM. To explore the spectrum of autoreactivity generated in vivo by
      different LamH-Cmu-endogenous L-chain combinations, we determined in vitro and in
      vivo antigen reactivity and L-chain V-region sequences of 17 LamH-Cmu-transgenic
      anti-laminin Igs. The results reveal a heterogeneous population of anti-laminin
      Igs with different fine specificities encoded by diverse endogenous L chains,
      encompassing nine different Vk gene families, 11 Vk genes, and three Jk genes.
      Many of the L chains are identical to known or putative unmutated germline Vk
      genes used to encode Igs reactive with self and foreign antigens in nonautoimmune
      and genetically autoimmune-prone mouse strains. These observations confirm that
      the LamH-Cmu H chain plays a dominant role in determining anti-laminin
      reactivity, and indicate that nonautoimmune B6 mice are fully capable of
      generating a diverse pool of basement-membrane-reactive B cells using unmutated
      Ig genes. When interpreted in the context of the divergent M6/M29 and M7
      transgenic mouse phenotypes, our findings further suggest that these matrix
      reactive lymphocytes are not spontaneously activated in vivo under normal
      circumstances.

PMID- 10663560
TI  - Localization of Idd11 using NOD congenic mouse strains: elimination of Slc9a1 as
      a candidate gene.
AB  - Type 1 diabetes is a multigenic autoimmune disease, the genetic basis for which
      is perhaps best characterized in the nonobese diabetic (NOD) mouse model. We
      previously located a NOD diabetes susceptibility locus, designated Idd11, on
      mouse Chromosome (Chr) 4 by analyzing diabetic backcross mice produced after
      crossing NOD/Lt with the nondiabetic resistant strain C57BL/6 (B6) strain. In
      order to confirm Idd11 and further refine its location, three NOD congenic mouse
      strains with different B6 derived intervals within Chr 4 were generated. Two of
      the congenic strains had a significant decrease in the cumulative incidence of
      diabetes compared with NOD/Lt control mice. The third NOD congenic strain,
      containing a B6 interval surrounding the Slc9a1 locus, was not protected against
      diabetes. These results define a new distal boundary for Idd11 and eliminate the
      Slc9a1 gene as a candidate. The Idd11 locus has now been definitively mapped to a
      13cM interval on mouse Chr 4.

PMID- 10663561
TI  - Defective MHC class II expression in an MHC class II deficiency patient is caused
      by a novel deletion of a splice donor site in the MHC class II transactivator
      gene.
AB  - MHC class II deficiency patients are mutated for transcription factors that
      regulate the expression of major histocompatibility complex (MHC) class II genes.
      Four complementation groups (A-D) are defined and the gene defective in group A
      has been shown to encode the MHC class II transactivator (CIITA). Here, we report
      the molecular characterization of a new MHC class II deficiency patient, ATU.
      Cell fusion experiments indicated that ATU belongs to complementation group A.
      Subsequent mutation analysis revealed that the CIITA mRNA lacked 84 nucleotides.
      This deletion was the result of the absence of a splice donor site in the CIITA
      gene of ATU. As a result of this novel homozygous genomic deletion, ATU CIITA
      failed to transactivate MHC class II genes. Furthermore, this truncated CIITA of
      ATU did not display a dominant negative effect on CIITA-mediated transactivation
      of various isotypic MHC class II promoters.

PMID- 10663562
TI  - Polymorphisms of the human IFNG gene noncoding regions.
AB  - Interferon gamma (IFN-gamma) is a multifunctional cytokine that is essential in
      the development of Th1 cells and in cellular responses to a variety of
      intracellular pathogens including human immunodeficiency virus (HIV-1). We
      screened genomic DNA samples from a predominately Caucasian male population of
      HIV-infected and healthy donors for polymorphisms in the human IFNG gene from 
      777 to +5608 by single-stranded conformational polymorphism. Surprisingly, the
      proximal promoter (-777 to transcription start) is invariant as no polymorphisms
      were found in over 100 samples tested. However, further screening revealed
      polymorphisms in other regions of the gene including a single base insertion in a
      poly-T tract in the first intron, three single base pair substitutions in the
      third intron, and another single base pair substitution in the 3' untranslated
      region (UTR). Electrophoretic mobility shift assay was used to investigate
      whether these variants have altered DNA-binding abilities, since intronic
      enhancer elements have been reported for the IFNG gene. Oligonucleotides
      constructed for two third intron variants showed no difference in DNA-binding
      abilities as compared with wild-type sequences. However, the 3'UTR variant showed
      the formation of unique DNA-binding complexes to radiolabeled oligonucleotide
      probes as compared with the wild-type sequence. The influence of a CA-repeat
      microsatellite on AIDS disease progression in HIV-1 seroconverters was tested by
      a Cox proportional hazards model. There is no evidence of an association between
      alleles and infection with HIV-1 or progression to AIDS. We report an invariant
      proximal human IFNG promoter and the existence of multiple intronic variants and
      a potentially functional 3'UTR polymorphism.

PMID- 10663563
TI  - Molecular cloning, expression, and purification of pig interleukin-5.
AB  - Interleukin-5 (IL-5) is thought to be a key cytokine in allergic inflammation.
      Pig IL-5 was cloned, sequenced, and expressed to enable us to study of the
      biological role of IL-5 in pigs used in a model for allergen-induced late-phase
      reactions. These pigs were sensitized to proteins extracted from Ascaris suum,
      resulting in hypersensitivity to this antigen in both the skin and airways, and a
      slight blood eosinophilia. Peripheral blood mononuclear cells from antigen
      sensitized pigs were isolated and polyclonally stimulated. Total RNA was
      extracted and reverse transcribed into cDNA. IL-5 primers based on the cow IL-5
      cDNA sequence were used to obtain an initial polymerase chain reaction product.
      3' rapid amplification of cDNA ends (3'RACE) and 5'RACE procedures were applied
      to identify the 3' and 5' ends, respectively. The full-length pig IL-5 cDNA is
      405 base pairs long. Mature pig IL-5 was expressed in Escherichia coli with a His
      tag for purification. The IL-5 protein is 115 amino acids long, has an estimated
      molecular weight of 14 000 M(r) and forms a biologically active homodimer of 28
      000 M(r). Pig IL-5 shows 65% amino acid identity to the human IL-5 sequence and
      90, 88, 83, 62, and 61% identity to the cow, sheep, horse, mouse, and rat
      counterparts.

PMID- 10663564
TI  - Reference-strand-mediated conformation analysis of MHC alleles: a new method for
      high-resolution typing of the Ovar-DQB genes.

PMID- 10663565
TI  - Isolation of the HLA-H orthologue in gorillas and chimpanzees.

PMID- 10663567
TI  - Cloning and sequencing of dog cDNA encoding the T-cell costimulatory molecule
      (CTLA-4).

PMID- 10663566
TI  - The beta-1,3-galactosyltransferase-4 (B3GALT4) gene is located in the centromeric
      segment of the human MHC class II region.

PMID- 10663568
TI  - Sharing of an HLA-B27-restricted male H-Y antigen between rat and mouse

PMID- 10663570
TI  - Cloning and expression of the chicken immunoglobulin joining (J)-chain cDNA.
AB  - The J chain is a component of polymeric immunoglobulin (Ig) molecules and may
      play an important role in their polymerization and the transport of polymeric Ig
      across epithelial cells. In this study, the primary structure of the chicken J
      chain was determined by sequencing cDNA clones. The cDNA had an open reading
      frame of 476 nucleotides encoding a putative protein of 158 amino acid residues
      including the signal sequence. The 3' untranslated region consisted of 1216
      nucleotides and a poly(A) tail. The deduced amino acid sequence of the chicken J
      chain had a high degree of homology to that of human, cow, rabbit, mouse, frog,
      and earthworm, with eight conserved Cys residues identical to the mammalian J
      chains. Northern blot hybridization performed with total RNA from various chicken
      tissues revealed high levels of J-chain mRNA expression in spleen, intestine,
      Harderian gland, and bursa of Fabricius, and low levels in the thymus. The J
      chain was expressed in the bursa as early as day 15 of embryogenesis. These data
      indicated that the chicken J-chain gene displays a high degree of homology with
      that of other species, and is expressed at an early stage of development of the
      chicken immune system.

PMID- 10663571
TI  - Independent evolution of Toll and related genes in insects and mammals.
AB  - Toll and Toll-related proteins play an important role in antibacterial innate
      immunity in insect, plants, and mammals. We present the first comprehensive
      phylogenetic analyses of Toll-related genes from both insects and mammals.
      Drosophila melanogaster contains Toll and a highly homologous gene, Tehao. The
      protein, Dm Tehao, comprises 795 amino acid residues and its cytoplasmic domain
      shares a striking 61% identity with Dm Toll. Two Toll homologues were found in
      another dipteran of medical importance, Anopheles gambiae, a vector for human
      malaria. One Toll-like gene each was identified from Aedes aegypti and Glossina
      palpalis palpalis, vectors for yellow fever and trypanosomiasis, respectively.
      Phylogenetic analyses revealed separate clustering of Toll and related proteins
      from insects and mammals, suggesting independent evolution of the Toll family of
      proteins and of innate immunity in arthropods and vertebrates. These results also
      provide new avenues to understanding the function of Toll proteins in insect
      innate immunity against bacteria, fungi, and protozoans.

PMID- 10663572
TI  - Human cytotoxic T-lymphocyte responses specific for peptides of the wild-type
      Wilms' tumor gene (WT1 ) product.
AB  - The product of the Wilms' tumor gene WT1 is a transcription factor overexpressed
      not only in leukemic blast cells of almost all patients with acute myeloid
      leukemia, acute lymphoid leukemia, and chronic myeloid leukemia, but also in
      various types of solid tumor cells. Thus, it is suggested that the WT1 gene plays
      an important role in both leukemogenesis and tumorigenesis. Here we tested the
      potential of WT1 to serve as a target for immunotherapy against leukemia and
      solid tumors. Four 9-mer WT1 peptides that contain HLA-A2.1-binding anchor motifs
      were synthesized. Two of them, Db126 and WH187, were determined to bind to HLA
      A2.1 molecules in a binding assay using transporter associated with antigen
      processing-deficient T2 cells. Peripheral blood mononuclear cells from an HLA
      A2.1-positive healthy donor were repeatedly sensitized in vitro with T2 cells
      pulsed with each of these two WT1 peptides, and CD8(+) cytotoxic T lymphocytes
      (CTLs) that specifically lyse WT1 peptide-pulsed T2 cells in an HLA-A2.1
      restricted fashion were induced. The CTLs also exerted specific lysis against WT1
      expressing, HLA-A2.1-positive leukemia cells, but not against WT1-expressing, HLA
      A2.1-negative leukemia cells, or WT1-nonexpressing, HLA-A2. 1-positive B
      lymphoblastoid cells. These data provide the first evidence of human CTL
      responses specific for the WT1 peptides, and provide a rationale for developing
      WT1 peptide-based adoptive T-cell therapy and vaccination against leukemia and
      solid tumors.

PMID- 10663573
TI  - Nonlinkage of major histocompatibility complex class I and class II loci in bony
      fishes.
AB  - In tetrapods, the functional (classical) class I and class II B loci of the major
      histocompatibility complex (Mhc) are tightly linked in a single chromosomal
      region. In an earlier study, we demonstrated that in the zebrafish, Danio rerio,
      order Cypriniformes, the two classes are present on different chromosomes. Here,
      we show that the situation is similar in the stickleback, Gasterosteus aculeatus,
      order Gasterosteiformes, the common guppy, Poecilia reticulata, order
      Cyprinodontiformes, and the cichlid fish Oreochromis niloticus, order
      Perciformes. These data, together with unpublished results from other
      laboratories suggest that in all Euteleostei, the classical class I and class II
      B loci are in separate linkage groups, and that in at least some of these taxa,
      the class II loci are in two different groups. Since Euteleostei are at least as
      numerous as tetrapods, in approximately one-half of jawed vertebrates, the class
      I and class II regions are not linked.

PMID- 10663574
TI  - Molecular cloning and linkage analysis of complement C3 and C4 genes of the
      Japanese medaka fish.
AB  - The thioester-containing complement components, C3 and C4, are believed to have
      arisen by gene duplication from a common ancestor, and the mammalian C4 gene
      resides in the vicinity of the C2 and B genes within the major histocompatibility
      complex (MHC) class III region. To analyze the evolution of both the complement
      system and the MHC, we determined the complete primary structures of two C3
      genes, termed Orla C3-1 and Orla C3-2, and one C4 gene, termed Orla C4, of a
      teleost, Japanese medaka fish (Oryzias latipes), by analyzing cDNA clones
      isolated from a liver library constructed using the inbred AA2 strain. The
      deduced basic structures of Orla C3-1, C3-2, and C4, such as the subunit chain
      structure, the thioester site, and the proteolytic activation site, are similar
      to their mammalian counterparts. However, the catalytic His residue which greatly
      increases the rate of thioester reaction, is replaced by Ala in Orla C3-2,
      implying functional differentiation between two C3 molecules. Mapping analysis
      revealed a close linkage between the C3-1 and C3-2 genes, indicating that they
      arose by a local duplication rather than by a genome-wide tetraploidization. The
      C4 gene belongs to a different linkage group, and no linkage was observed among
      the C3, C4, Bf/C2, MHC class I, and MHC class II loci. These results suggest that
      the MHC class III complement region was established in the tetrapod lineage, or
      lost in the teleost lineage.

PMID- 10663575
TI  - Alternative exon usage in the 3' region of a single gene generates
      glycosylphosphatidylinositol-anchored and transmembrane forms of rat decay
      accelerating factor.
AB  - Several cDNA clones encoding genetic homologues of human decay-accelerating
      factor (DAF) were isolated from rat testis cDNA libraries and reverse
      transcription-polymerase chain reaction products. Sequence analysis revealed that
      rat DAF exists as two membrane forms, a glycosylphosphatidylinositol (GPI)
      anchored and a transmembrane (TM) form. Southern blotting analysis showed that
      GPI- and TM-form mRNAs of rat DAF are derived from a single gene, as is the case
      for guinea pig, though both forms of mouse DAF mRNA are derived from two genes.
      Gene analysis of the C-terminal region of rat DAF indicated that both forms of
      mRNA are presumably generated by alternative splicing of exons which encode a
      GPI/3'-untranslated (3'UT) region and a TM/3'UT region in the 3' end of the
      Ser/Thr-rich region. Northern blot analysis indicated that rat GPI-DAF mRNA was
      present in all tissues examined except for liver, while rat TM-DAF mRNA was
      preferentially expressed in testis. Infant rat testis barely expressed TM-DAF and
      membrane cofactor protein (MCP) but highly expressed 5I2 antigen (5I2Ag, rat
      Crry). However, adult rat testis showed increased expression of the 1.6-kb
      transcript of rat GPI-DAF, TM-DAF, MCP, and the 0.7-kb transcript of CD59, with a
      decreased level of 5I2Ag expression. These results suggest that rat 5I2Ag/Crry
      may play an important role in regulating complement activation during the early
      stages of testis development, and that DAF, MCP, and CD59 expressed in testis may
      enable sperm to survive complement attack in the mucus of the female genital
      organ, and/or to interact with an ovum.

PMID- 10663576
TI  - The major and a minor class II beta-chain (B-LB ) gene flank the Tapasin gene in
      the B-F /B-L region of the chicken major histocompatibility complex.
AB  - We have identified the major histocompatibility complex class II beta-chain (B
      LB) genes present in the B-F/B-L region of the B complex of nine well
      characterized lines of chickens and have cleared up much of the confusion
      concerning numbers and location of B-LB genes in this region. By amplifying DNA
      sequences between adjacent genes, we found two B-LB genes that lie on either side
      of Tapasin. The dominantly expressed 'major' B-LB gene in all haplotypes lies
      between Tapasin and RING-3, and belongs to the B-LBII family of class II beta
      chain genes. The poorly expressed 'minor' B-LB gene in all haplotypes lies
      between B-lec1 and Tapasin, and belongs either to the B-LBII family or to the
      previously unmapped B-LBVI family of class II beta-chain genes. The data suggest
      that the B-LBII and B-LBVI genes are two lineages of B-LB genes and we propose
      that they all be termed B-LB genes. The location of a third B-LB gene in the B12
      haplotype (and possibly other haplotypes as well) has yet to be determined. The
      structural organization and expression of the class II beta-chain genes in the B
      F/B-L region is similar to that of chicken class I (B-F) genes, one functional
      result of which is differential resistance to disease and response to vaccines.

PMID- 10663577
TI  - Comparison of RT-BM1 sequences from six different rat major histocompatibility
      complex haplotypes reveals limited variation, and alternate splicing in the 3'
      untranslated region.

PMID- 10663578
TI  - Genomic organization and chromosomal localization of the human gene encoding the
      T-cell receptor-interacting molecule (TRIM).

PMID- 10663579
TI  - Identification of novel polymorphisms in the human TNFR1 gene: distribution in
      acute leukemia patients and healthy individuals.

PMID- 10663580
TI  - The mouse p52 subunit of the transcription/DNA repair factor TFIIH is not located
      in the class III region of the H2 complex, but resides next to a G7a/Bat6
      homologue in the telomeric part of the major histocompatibility complex.

PMID- 10663581
TI  - Response

PMID- 10663582
TI  - The magnetic resonance imaging of musculoskeletal hemorrhage.
AB  - Hematomas in the extremities can present clinically as a soft tissue mass.
      Hematomas can usually be distinguished from neoplasia on MR by the signal
      patterns of hemoglobin breakdown products, which are dependent on the chemical
      bonding and oxidation state of hemoglobin iron. Beginning with a discussion of
      relevant atomic electronic structure, this review will examine how oxyhemoglobin,
      deoxyhemoglobin, methemoglobin, and hemosiderin, the principal iron compounds
      occurring in the various stages of a hematoma, affect its appearance on MRI.

PMID- 10663583
TI  - Indirect wrist MR arthrography: the effects of passive motion versus active
      exercise.
AB  - PURPOSE: In the wrist, to determine whether passive motion or active exercise
      yields a better indirect MR arthrographic effect following intravenous gadolinium
      administration. DESIGN AND PATIENTS: Twenty-six consecutive patients were studied
      by indirect wrist MR arthrography. In half active exercise and in half passive
      motion was performed. Four regions of interest were studied including the distal
      radioulnar joint, the radiocarpal joint, the midcarpal joint, and the triangular
      fibrocartilage. Ranges and means of signal intensity were calculated. Surgical
      follow-up was performed in 22 patients. RESULTS: The joint fluid intensity was
      greatest in the distal radioulnar joint. Fluid signal intensity was greater and
      more consistent in the passive motion group although the results did not achieve
      statistical significance. Imaging accuracy appeared similar in the two groups and
      was excellent for the triangular fibrocartilage (100%) and scapholunate ligaments
      (96%). CONCLUSION: Active exercise and passive motion yield similar degrees of
      wrist arthrographic effect, but the effect of passive motion is somewhat more
      consistent. Preliminary data show good accuracy for internal derangements.

PMID- 10663584
TI  - Type I gaucher disease: extraosseous extension of skeletal disease.
AB  - OBJECTIVE: To investigate the frequency and morphology of extraosseous extension
      in patients with Gaucher disease type I. DESIGN AND PATIENTS: MRI examinations of
      the lower extremities were analyzed in 70 patients with Gaucher disease type I.
      Additionally, the thoracic spine and the midface were investigated on MRI in two
      patients. RESULTS: Four cases are presented in which patients with Gaucher
      disease type I and severe skeletal involvement developed destruction or
      protrusion of the cortex with extraosseous extension into soft tissues. In one
      patient, Gaucher cell deposits destroyed the cortex of the mandible and extended
      into the masseter muscle. In the second patient, multiple paravertebral masses
      with localized destruction of the cortex were apparent in the thoracic spine. In
      the third and fourth patient, cortical destruction with extraosseous tissue
      extending into soft tissues was seen in the lower limbs. CONCLUSIONS:
      Extraosseous extension is a rare manifestation of Gaucher bone disease. While an
      increased risk of cancer, especially hematopoietic in origin, is known in
      patients with Gaucher disease, these extraosseous benign manifestations that may
      mimic malignant processes should be considered in the differential diagnosis of
      extraosseous extension into soft tissues. A narrow neck of tissue was apparent in
      all cases connecting bone and extraosseous extensions.

PMID- 10663585
TI  - Nutrient canal of the fibula.
AB  - OBJECTIVE: To investigate the radiological features of the nutrient canal in the
      fibula. DESIGN AND PATIENTS: One hundred and seventy-nine dried fibulae were
      studied regarding the type, number, location, and direction of the nutrient
      canal. They were classified into a usual type (type I: a radiolucent line
      confined to the cortex) and an atypical type (type II: a radiolucent line
      extending beyond the cortex). RESULTS: Among the total of 230 nutrient canals
      seen on radiography, 197 (86%) were type I and 33 (14%) were type II. On CT
      scans, the ossified rim of the canal extended into the medullary cavity in type
      II canals. The most common site was the posteromedial aspect in both type I and
      type II canals. Type II canals were significantly more common in fibulae with two
      or three nutrient canals. The frequency of the upward direction was more common
      in type II canals. CONCLUSION: Nutrient canals with extension of the ossified rim
      into the medullary canal are the cause of linear lucency that may simulate a
      fracture. Their features are slightly different from those of usual canals.

PMID- 10663586
TI  - Marginal erosive discovertebral "Romanus" lesions in ankylosing spondylitis
      demonstrated by contrast enhanced Gd-DTPA magnetic resonance imaging.
AB  - OBJECTIVE: To assess the value of Gd-DTPA magnetic resonance (MR) imaging in the
      demonstration of marginal destructive discovertebral Romanus lesions in
      ankylosing spondylitis. DESIGN AND PATIENTS: A prospective study of Gd-DTPA MR
      imaging was performed in 39 patients with a clinical diagnosis of ankylosing
      spondylitis and typical Romanus lesions seen on radiographs of the thoracolumbar
      spine. MR morphological appearances and signal intensity changes at the
      discovertebral junctions were analysed and compared with the radiographic
      findings. RESULTS: Ninety-nine discovertebral junctions with Romanus lesions
      showed low signal intensity on T1-weighted and high signal on T2-weighted and T1
      weighted postcontrast images at the vertebral corners consistent with oedematous
      hyperaemic inflammatory tissue. There were nine discovertebral junctions with
      similar MR findings but normal radiographs. Fifty-three discovertebral junctions
      showed syndesmophyte formation with increased signal intensity on both T1- and T2
      weighted images with no contrast enhancement. Sixty-five discovertebral junctions
      showed a mixture of radiographic features and varied high and low signal changes
      at the vertebral rim on MR imaging with rims of enhancement in the vertebral body
      following contrast administration. CONCLUSION: Gd-DTPA MR imaging demonstrates a
      variable signal pattern and degree of contrast enhancement which may reflect the
      evolutionary stages of discovertebral enthesitis in ankylosing spondylitis. MR
      imaging may identify early erosive changes in radiographically normal vertebra.
      The role of MR imaging needs further investigation.

PMID- 10663587
TI  - Magnetic resonance imaging findings in anterolateral impingement of the ankle.
AB  - OBJECTIVE: To demonstrate the MR imaging findings of anterolateral impingement
      (ALI) of the ankle. DESIGN AND PATIENTS: Nine patients with a history of ankle
      inversion injury and chronic lateral ankle pain were imaged with MR imaging, and
      the findings correlated with the results of arthroscopy. Three additional
      patients with clinically suspected ALI of the ankle were also included. Ankle MR
      imaging studies from 20 control patients in whom ALI was not suspected clinically
      were examined for similar findings to the patient group. RESULTS: MR imaging
      findings in the patients with ALI included a soft tissue signal mass in the
      anterolateral gutter of the ankle in 12 of 12 (100%) cases, corresponding to the
      synovial hypertrophy and soft tissue mass found at arthroscopy in the nine
      patients who underwent arthroscopy. Disruption, attenuation, or marked thickening
      of the anterior talofibular ligament was seen in all cases. Additional findings
      included signs of synovial hypertrophy elsewhere in the tibiotalar joint in seven
      of 12 patients (58%) and bony and cartilaginous injuries to the tibiotalar joint
      in five of 12 (42%). None of the control patients demonstrated MR imaging
      evidence of a soft tissue mass in the anterolateral gutter. CONCLUSIONS: ALI of
      the ankle is a common cause for chronic lateral ankle pain. It has been well
      described in the orthopedic literature but its imaging findings have not been
      clearly elucidated. The MR imaging findings, along with the appropriate clinical
      history, can be used to direct arthroscopic examination and subsequent
      debridement.

PMID- 10663588
TI  - Subchondral insufficiency fracture of the femoral head and medial femoral
      condyle.
AB  - This case report documents the clinical, radiographic, and histologic findings in
      a 69-year-old obese man, who had subchondral insufficiency fracture both in the
      femoral head and medial femoral condyle. On plain radiographs, both lesions
      underwent subchondral collapse. Magnetic resonance images of the left hip showed
      a bone marrow edema pattern with associated low-intensity band on T1-weighted
      images, which was convex to the articular surface. The histopathologic findings
      in the hip and knee were characterized by the presence of a subchondral fracture
      with associated callus and granulation tissue along both sides of a fracture
      line. There was no evidence of antecedent osteonecrosis. To our knowledge, this
      is the first case report to describe the multiple occurrence of collapsed
      subchondral insufficiency fracture.

PMID- 10663589
TI  - Cystic fibrous dysplasia mimicking giant cell tumor: MRI appearance.
AB  - We report the case of a 43-year-old man who presented with an osteolytic and
      expansive lesion in the left distal femur mimicking a giant cell tumor. Magnetic
      resonance imaging (MRI) showed that most of the lesion was cystic, and
      histological examination revealed fibrous dysplasia with marked cystic
      degeneration. Radiographic findings of cystic fibrous dysplasia in the end of a
      long bone may be similar to those of a giant cell tumor, and a biopsy is
      essential for the final diagnosis.

PMID- 10663590
TI  - Primary hemangiopericytoma of the tibia: MR and angiographic correlation.
AB  - The Magnetic Resonance Imaging (MRI) appearances of primary osseous
      hemangiopericytoma (HPC) have been rarely described. We report on a 46-year-old
      Chinese man with primary osseous HPC of the right tibia. The characteristic
      vascular distribution of this tumor, presenting with a "spoke-wheel" appearance
      on MR images and with angiographic correlation, is described. Although not
      pathognomonic, this MR appearance may be an important finding in suggesting the
      diagnosis of osseous HPC.

PMID- 10663591
TI  - Atypical adult non-calcified pilomatricoma.
AB  - We present a rare case of a non-calcified pilomatricoma in a 67-year-old man.
      This tumor was extremely large in size, and its location, in the lower extremity,
      was very unusual. The clinical, radiographic, and histopathological features are
      described in detail. The role of magnetic resonance imaging (MRI) in the
      diagnosis of this entity is discussed. Definite internal reticulations and
      septations were observed. A possible explanation for this observation is that the
      high signal intensity reticulations may represent edematous stroma surrounding
      basaloid cells.

PMID- 10663592
TI  - Myxoma of the humerus: an exceptional site of origin.
AB  - Myxoma of bone, outside of the jaws, is exceptional. We present such a tumor in
      the humerus and discuss the criteria for the diagnosis of myxoma.

PMID- 10663607
TI  - Neutrophils are cytotoxic and growth-inhibiting for neuroblastoma cells with an
      anti-GD2 antibody but, without cytotoxicity, can be growth-stimulating.
AB  - Neutrophils and mononuclear cells (MNC) can mediate antibody-dependent cellular
      cytotoxicity (ADCC) against cancer cells. To study cytotoxicity and growth
      inhibition of neuroblastoma cells by neutrophils and MNC with chimeric anti
      disialoganglioside (GD2) monoclonal antibody (mAb) ch14.18, we developed digital
      image microscopy scanning (DIMSCAN) assays that measure fluorescence of target
      cells in 96-well plates after 6-18 h (cytotoxicity assay) or 7 days (growth
      assay). Neuroblastoma cell lines (GD2-positive: SMS-KCN, SMS-LHN, LA-N-1; GD2
      negative: SK-N-SH) were preloaded with calcein acetoxymethyl ester for the
      cytotoxicity assay or labeled in situ after 7 days of culture with fluorescein
      diacetate in the growth assay. Fluorescence, as quantified by DIMSCAN, was
      correlated with neuroblastoma cell number in both assays (100-2000 cells/well).
      In the cytotoxicity test, both neutrophils and MNC effectively mediated ADCC of
      GD2-positive but not GD2-negative neuroblastoma cell lines. Cytotoxicity of both
      neutrophils and MNC increased with effector to target cell (E:T) ratio (5-50:1)
      and mAb ch.14.18 dose (0.1-10 microg/ml). ADCC of neutrophils, but not MNC,
      increased with addition of GM-CSF. Neutrophils, especially with rhGM-CSF,
      significantly suppressed growth of GD2-positive cell lines at a high E:T ratio
      (50:1) and mAb dose (10 microg/ml). Without antibody, neutrophils inhibited
      growth of one cell line (LA-N-1) but stimulated growth of two others (SMS-KCN,
      SMS-LHN). If neuroblastoma cells did not express GD2 (SK-N-SH), neutrophils
      stimulated growth whether or not antibody was present. Neutrophil culture
      supernatants increased growth of SK-N-SH, LA-N-1, and SMS-KCN cells, and MNC
      culture supernatants increased growth of SK-N-SH. In conclusion, neutrophils can
      mediate cytotoxicity and growth inhibition with a chimeric anti-GD2 antibody but
      also can promote tumor cell growth if antibody is not present or if GD2 is not
      expressed.

PMID- 10663608
TI  - Induction of antitumor immunity by indomethacin.
AB  - Irradiated tumor cells given, together with indomethacin, to syngeneic mice
      induced an antitumor response and conferred protection against a challenge of a
      lethal dose of murine mammary (4T1) and lung (3LL) carcinoma cells. Continuous
      administration of indomethacin was crucial throughout the entire period of
      immunization and challenge, as no protection was achieved when the drug was given
      during only one of these procedures. Antitumor immunity was long-lasting and,
      when tested in the 4T1 model, 48% of mice were resistant to a second challenge of
      lethal tumor cells. Tumor-free immune mice that were given indomethacin for more
      than 300 days remained healthy with normal white blood cell counts and normal
      spleen size. Cells isolated from immune mice were able to kill tumor cells in
      culture after in vitro activation by interleukin-2, in a manner similar to cells
      from naive normal control mice. In addition, the mitogenic response of their T
      cells was as high as that of the control naive mice. While indomethacin was able
      to induce antitumor immunity to 4T1 and 3LL murine carcinoma cells, both of which
      contain a high concentration of endogenic prostaglandin E(2) (PGE2), no such
      immunity was achieved to murine tumor cells with a low concentration of endogenic
      PGE2. These results suggest a correlation between PGE2 concentration and the
      ability of indomethacin to induce antitumor immunity. We therefore suggest that
      an immunotherapy protocol with long-term dispensation of a tolerable dose of an
      immunomodulator, given together with irradiated autologous tumor cells, may
      stimulate antitumor responses to tumors containing high concentrations of
      endogenic PGE2.

PMID- 10663609
TI  - CD4(+) T cells kill HLA-class-II-antigen-positive melanoma cells presenting
      peptide in vitro.
AB  - PURPOSE: Most melanoma cell lines express HLA class II antigens constitutively or
      can be induced to do so with interferon gamma (IFNgamma). We have previously
      demonstrated that peptide-specific CD4(+) T cells proliferate in response to HLA
      class-II-antigen-mediated peptide presentation by melanoma cells in vitro and
      produce interleukin-10 (IL-10) and (IFNgamma). We asked whether the responding T
      cells kill the tumor cells and, if so, whether direct cell contact was required.
      METHODS: Two HLA class II(+) melanoma cell lines derived from metastases were co
      cultured with a human CD4(+) T cell clone specific for influenza hemagglutinin
      peptide (HA). T cells, melanoma, and HA were co-cultured for 48 h. Melanoma cells
      with and without HA and/or T cells served as controls. After 36 h, the medium was
      removed for cytokine analysis by enzyme-linked immunosorbent assay (ELISA).
      Twelve hours later non-adherent cells were washed away and the adherent melanoma
      cells were trypsinized and counted. Dual-chamber culture plates were used to
      determine whether cell contact and/or exposure to cytokine were required for
      tumor cell death. RESULTS: Melanoma cell counts were over 80% lower in wells
      containing T cells than in wells with melanoma and peptide alone (P < 0.05).
      ELISA of supernatants revealed production of IFNgamma and IL-10 by the responding
      T cells. Direct T cell contact with tumor cells was not required for tumor cell
      death, as melanoma cells were killed when they shared medium but had no contact
      with T cells responding to peptide presentation by HLA-class-II-antigen-positive
      melanoma cells in a separate chamber. Blocking antibody to IFNgamma but not IL-10
      prevented melanoma cell death at levels of cytokine similar to that present in co
      culture assays. CONCLUSIONS: Peptide-specific CD4(+) T cells kill melanoma cells
      in vitro when they recognize peptide presented by the tumor cell in the context
      of HLA class II antigen. Direct cell contact is not required, suggesting that it
      is a cytokine-mediated event. Immunotherapy, using primed CD4(+) T cells and
      peptide, may be beneficial in patients whose tumors express HLA class II antigens
      or can be induced to do so with IFNgamma.

PMID- 10663610
TI  - Cytokine biosynthesis by tumor-infiltrating T lymphocytes from human non-small
      cell lung carcinoma.
AB  - PURPOSE: The purpose of this work was to assess the capacity of tumor
      infiltrating leukocytes (TIL) from human non-small-cell lung carcinoma (NSCLC)
      specimens to synthesize type-1 and type-2 cytokines. METHODS: TIL were isolated
      from tumors following digestion with collagenase/DNase and further enriched by
      ficoll-hypaque gradient centrifugation. Membrane phenotypes and intracellular
      cytokine protein expression of TIL were assessed by flow cytometry. RESULTS: The
      majority of TIL expressed the CD3 antigen with a CD4:CD8 ratio of approximately
      2:1. Other leukocytes such as macrophages (CD14), B lymphocytes (CD20), and
      natural killer (NK) cells (CD56) were also found to infiltrate the tumors, but in
      significantly lower numbers. Owing to the limited recovery of non-CD3(+)
      leukocytes, our analysis of cytokine biosynthesis has focused on T lymphocytes.
      In the absence of activation, a small percentage of CD3(+) TIL synthesized
      cytokines ( <4%). Following activation with anti-CD3+interleukin-2 (IL-2), CD3(+)
      TIL synthesized predominantly a type-1 cytokine profile; however, the type-2
      cytokines, IL-6 and IL-10, were also detected in a small percentage of
      infiltrating cells. Following activation with phorbol 12-myristate 13-acetate +
      ionomycin, CD3(+) TIL also expressed more type-1 than type-2 cytokines and in
      significantly greater numbers of cells. The CD3(+)CD8(+) component of the TIL
      synthesized only type-1 cytokines, whereas the CD3(+)CD4(+) component synthesized
      both type-1 and type-2 cytokines. CONCLUSION: These results show that the
      majority of the TIL isolated from NSCLC specimens are T lymphocytes with the
      capacity to synthesize type-1 cytokines.

PMID- 10663612
TI  - The effect of T1 and T2 cytokines on the cytotoxic T cell response to mannan
      MUC1.
AB  - MUC1 is a mucin over-expressed in breast cancer and a proposed target for
      immunotherapy. By immunising mice with MUC1 conjugated to mannan (M-FP), CD8(+)
      MHC-class-I restricted cytotoxic T lymphocytes (CTL), of high CTL precursor
      (CTLp) frequency (1/8000) and with significant tumour protection, can be induced.
      The effect of various cytokines [interleukin-2 (IL-2), IL-4, IL-6, IL-7,
      interferon gamma (IFNgamma), and granulocyte/macrophage-colony-stimulating factor
      (GM-CSF)] on the MUC1 CTL immune response was investigated (a) by measuring the
      frequencies of CTLp in mice immunised with vaccinia virus constructs containing
      recombinant cytokines and M-FP, or (b) by immunising cytokine- or cytokine
      receptor-knockout (-/-) mice with M-FP. Vaccinia virus (VV) constructs containing
      recombinant cytokines were used either individually or in combination in vivo
      with M-FP immunisation. M-FP immunisations combined with VV-IL-2, VV-IL-7 and VV
      GM-CSF, and combinations of VV-IFNgamma + VV-IL-2, VV-IFNgamma + VV-IL-4 or VV-GM
      CSF + VV-IL-7 increased CTLp frequencies up to threefold (1/17 666: M-FP + VV-GM
      CSF + VV-IL-7) compared to M-FP (1/77 500) alone. By contrast, M-FP combined with
      VV-IL-4 decreased the CTLp frequency threefold whereas VV-IL-6 and VV-IFNgamma
      had no effect. Studies in cytokine- and cytokine-receptor-gene-knockout (-/-)
      mice demonstrated that mice that are IL-2 -/- and IL-7 receptor -/- produce the
      same CTLp response to M-FP as do control mice, whereas responses in the IL-6 -/-,
      IL-10 -/- and IFNgamma -/- mice were marginally improved and responses to M-FP in
      IL-4 -/- and tumour necrosis factor receptor 2 -/- mice were weaker. In spite of
      the increase in CTLp frequency, this was not reflected in an in vivo tumour
      model. Tumour challenges using MUC1(+) P815 cells, demonstrated that the addition
      of cytokines had little additive effect on the already effective tumour
      regression capabilities of M-FP alone.

PMID- 10663611
TI  - Gene gun application in the generation of effector T cells for adoptive
      immunotherapy.
AB  - We utilized the gene gun to transfect subcutaneous D5 melanoma and MT-901 mammary
      carcinoma tumors in situ with a granulocyte/macrophage-colony-stimulating factor
      (GM-CSF) plasmid complexed to gold particles. There was diminished tumor growth
      following bombardment with GM-CSF plasmid, which was apparent only during the
      period of administration. Transgenic GM-CSF was produced by the skin overlying
      the tumors and not by the tumors themselves. GM-CSF plasmid bombardment resulted
      in increased cell yields within tumor-draining lymph nodes (TDLN) with at least a
      12-fold increase in the percentage of dendritic cells (8.9%) compared to controls
      (0. 7%). Secondarily activated TDLN cells from animals transfected with GM-CSF
      demonstrated enhanced cytokine release (interferon gamma, GM-CSF and interleukin
      10) in response to tumor stimulator cells compared to controls, and had an
      increased capacity to mediate tumor regression in adoptive immunotherapy. There
      was a small, but detectable, non-specific immune adjuvant effect observed with
      gold particle bombardment alone, which was less than with GM-CSF plasmid. The
      adjuvant effect of GM-CSF plasmid required peri-tumoral transgene expression
      since gene bombardment away from the tumor was ineffective.

PMID- 10663613
TI  - gammadelta T cells lyse autologous and allogenic oesophageal tumours: involvement
      of heat-shock proteins in the tumour cell lysis.
AB  - T cells expressing gammadelta receptors were isolated from the peripheral blood
      of oesophageal cancer patients and analysed for their potential to lyse tumour
      targets. Immunophenotyping by flow cytometry showed that the dominant population
      of gammadelta T cells expressed the Vgamma9 and the Vdelta2 T cell receptor, and
      a minor population expressed the Vdelta1 receptor. Cytotoxicity assays revealed
      that activated gammadelta T cells lysed Daudi Burkitt's lymphoma and K562 cells.
      Lysis of autologous oesophageal tumours was higher than of allogenic tumours.
      Anti-hsp60 and anti-hsp70 mAb significantly inhibited the cytotoxicity of
      gammadelta T cells to both autologous and allogenic oesophageal tumours. Surface
      expression of hsp60 and hsp70 on oesophageal tumours and Daudi cells was
      demonstrated by flow cytometry. In conclusion, gammadelta T cells isolated from
      the peripheral blood of oesophageal cancer patients have the ability of kill
      oesophageal tumour cells. The lysis of tumour targets by the gammadelta T cells
      is brought about via recognition of heat-shock proteins expressed on the surface
      of tumour cells. gammadelta T cells isolated from the peripheral blood may have
      applications in adoptive immunotherapy of oesophageal cancer.

PMID- 10663614
TI  - New therapeutic approaches in primary systemic AL amyloidosis.
AB  - Primary systemic AL (amyloid light-chain) amyloidosis is a plasma cell disorder
      in which depositions of amyloid light-chain protein cause progressive organ
      failure. The prognosis of primary amyloidosis is generally poor, with a median
      survival of 1-2 years. There is no available treatment which improves impaired
      organ function by induction of amyloid mobilization. Since amyloidosis is a
      dynamic process, measures that reduce the supply of the amyloid fibril precursor
      protein can result in a major regression of the deposits. Conventional-dose
      melphalan can prolong the median duration of survival from 8.5 to 18 months, but
      the clinical response rates with improvement of impaired organ function are low
      and the response is slow. Preliminary data suggest that VAD is effective in AL
      amyloidosis. Up-front high-dose chemotherapy with autologous peripheral blood
      stem cell transplantation can result in an improvement of the patient's clinical
      condition, but the treatment-related toxicity can be high, owing to impaired
      organ function. The use of VAD followed by high-dose chemotherapy is the concept
      of a German trial. The improvement of the patient's condition prior to high-dose
      chemotherapy by induction of a remission with VAD might reduce the
      transplantation-related morbidity and mortality in amyloidosis.

PMID- 10663615
TI  - Epidemiological situation and treatment of patients with thalassemia major in
      Germany: results of the German multicenter beta-thalassemia study.
AB  - At present, about 300 patients in Germany suffer from thalassemia major. In 1990,
      a multicenter study was introduced to identify all thalassemic patients in
      Germany as well as to establish a uniform therapy protocol, including follow-up
      diagnostic procedures. After 6 years of study, the data of 203 patients were
      analyzed. The majority originate from endemic regions around the Mediterranean
      Sea. The median age of the patients is 13.8 years (range 1-37.5 years). At
      present, about 20% of the patients are older than 21 years. Regarding transfusion
      therapy, a shortening of the average transfusion interval to 3 weeks in most
      cases occurred. Throughout the entire period, median baseline hemoglobin
      concentrations of 10.0 g/dl were observed. The evaluation of serum ferritin
      levels revealed considerable differences, depending on the patients' age.
      Thalassemic patients in the first decade of life generally presented with good
      therapeutic results; serum ferritin levels were below 1800 ng/ml in 76/102
      patients (75%) upon entry into the study. In contrast, 51/98 patients (52%) older
      than 10 years had ferritin levels above 2500 ng/ml. More than half of all treated
      patients presented with siderotic complications such as cardiac disease in 20/157
      (13%), liver disease in 32/157 (21%), impaired glucose metabolism in 22/157
      (14%), hypogonadism in 39/66 (59%), and hypothyroidism in 38/157 (24%) who were
      under treatment at the time of first survey. Since the situation concerning
      siderosis and the lack of compliance proved to be particularly difficult with
      adolescent patients, further efforts should concentrate on this age-group.

PMID- 10663616
TI  - Ex vivo expansion of CD34+/CD41+ late progenitors from enriched peripheral blood
      CD34+ cells.
AB  - In our experience, patients with neuroblastoma who undergo transplantation with
      CD34+ cells following high-dose chemotherapy have prolonged delays in platelet
      recovery. In vitro expansion of megakaryocyte (MK) cells may provide a
      complementary transplant product able to enhance platelet production in the
      recipient. We investigated the ability of a combination of various hematopoietic
      growth factors to generate ex vivo MK progenitors. Immunoselected CD34+ cells
      from peripheral blood stems cells (PBSCs) were cultured in media with or without
      serum, supplemented by IL-3, IL-6, IL-11, SCF, TPO, Flt-3 ligand, and MIP-1alpha.
      In terms of MK phenotypes, we observed a maximal expansion of CD61+, CD41+, and
      CD42a of 69-, 60-, and 69-fold, respectively, i.e., 8-10 times greater than the
      expansion of total cell numbers. Whereas the absolute increment of CD34+ cells
      was slightly elevated (fourfold) we showed increases of 163-, 212-, and 128-fold
      for CD34+/CD61+, CD34+/CD41+, and CD34+/CD42a+ cells, respectively. We obtained
      only a modest expansion of CFU-MKs after only 4 days of culture (fourfold) and
      similar levels of CFU-MKs were observed after 7 days (fivefold). Morphology and
      immunohistochemistry CD41+ analyses confirmed expansion of a majority of CD41+
      immature cells on days 4 and 7, while on day 10 mature cells began to appear.
      These results show that primarily MK progenitors are expanded after 4 days of
      culture, whereas MK precursor expansion occurs after 7 days. When we compared the
      two culture media (with and without serum) we observed that increases of all
      specific phenotypes of the MK lineage were more elevated in serum-free culture
      than in medium with serum. This difference was especially marked for CD34+/CD61+
      and CD34+/CD41+ (163 vs 42 and 212 vs 36, respectively). We contaminated CD34+
      cells with a neuroblastoma cell line and we observed no expansion of malignant
      cells in our culture conditions (RT-PCR for tyrosine hydroxylase positive at day
      4 and negative at day 7). With our combination of hematopoietic growth factors we
      are able to sufficiently expand ex vivo MK late progenitor cells to be used as
      complementary transplant products in neuroblastoma patients who undergo
      transplantation with CD34+ cells. It is possible that these committed MK late
      progenitors could accelerate short-term platelet recovery in the recipient until
      more primitive progenitor cells have had time to engraft.

PMID- 10663617
TI  - Cytogenetic and Southern blot analysis to demonstrate clonality and to estimate
      prognosis in patients with myelodysplastic syndromes.
AB  - We examined the bone marrow of 109 patients with myelodysplastic syndrome (MDS)
      at the time of diagnosis and during the course of the disease by means of
      Southern blot analysis and/or cytogenetic studies to detect and evaluate clonal
      markers, their implications for the prognosis of the disease, and the response to
      treatment. The patients either were enrolled in an EORTC study and received low
      dose Ara-C with (n=31) or without (n=21) growth factors, according to the study
      protocol, or were treated supportively (only one patient received regular
      chemotherapy for concomitant lymphoma). Full or at least partial remission was
      achieved by 34% of the treated patients (n=54). In 57% (53 of 93) of all patients
      a clonal marker of either kind was detected by Southern blot analysis and/or
      cytogenetic examination. Clonal chromosomal aberrations were found in 45% (35 of
      77) of the cases examined at diagnosis, with solitary del(5q) aberrations
      occurring in 10% of the cases and complex aberrations in 18%, trisomy 8 or
      monosomy 7 being a frequent finding. Of all patients, 49% (28 of 57) were
      characterized by one or more gene rearrangements (e.g., Ig-JH, TcR-beta, M-bcr,
      GM-CSF, G-CSF, or IL-3) at diagnosis. In five of 21 cases (24%) studied in
      hematological remission of the disease chromosomal aberrations were still
      detectable, and in seven of 23 (30%) a gene rearrangement persisted. We also
      found six cases with multiple clones exhibiting different susceptibilities to
      treatment and thereby indicating the oligoclonal character of this disease.
      Clinical evaluation revealed that the prognosis of the respective patients was
      directly related to the particular clonal markers detected at diagnosis: Risk
      groups were subdivided according to the karyotypes, with a solitary del(5q)
      aberration meaning a favorable, a normal karyotype an intermediate, solitary
      aberrations without del(5q) a poor, and complex karyotypes a very poor prognosis.
      We showed that densitometry helps to increase the sensitivity of Southern blot
      analysis by quantifying the amount of altered DNA, which often increases shortly
      before or at progression of MDS. Overall, there was a high level of concordance
      of both clonality examinations with the clinical course of the disease and the
      response rate. Therefore, we recommend cytogenetic studies and Southern blot
      analysis to detect clonal markers at diagnosis of MDS, to detect oligoclonality
      and clonal evolution, or to quantify the amount of clonal DNA, which appears to
      be a sensitive tool for evaluating the prognosis and response to therapy in MDS.

PMID- 10663618
TI  - Intensive chemotherapy with idarubicin, ara-C, etoposide, and m-AMSA followed by
      immunotherapy with interleukin-2 for myelodysplastic syndromes and high-risk
      Acute Myeloid Leukemia (AML).
AB  - Intensive chemotherapy followed by treatment with interleukin-2 (IL-2) was
      evaluated in a prospective, randomized, multicenter trial including 18 patients
      with refractory anemia with excess of blasts in transformation (RAEB-T), 86
      patients with acute myeloid leukemia (AML) evolving from myelodysplastic
      syndromes, and six patients with secondary AML after previous chemotherapy.
      Median age was 58 years (range: 18-76 years). Forty-nine patients (45%) achieved
      a complete remission (CR) after two induction cycles with idarubicin, ara-C, and
      etoposide, 52% of them aged </=60 years and 35% aged >60 years (p=0.06). After
      two consolidation courses, patients were randomized to four cycles of either high
      or low-dose IL-2. Patients aged up to 55 years with an HLA-identical sibling
      donor were eligible for allogeneic bone marrow transplantation. The median
      relapse-free survival was 12.5 months, with a probability of ongoing CR at 6.5
      years of 19%. Overall survival of all patients was 8 months, and 21 months for
      the CR patients. Median survival was significantly longer among patients aged
      </=60 years than among the older patients (16 vs 6 months, p<0.001). Median
      duration of survival and relapse-free survival were not statistically different
      in the two IL-2 treatment arms.

PMID- 10663619
TI  - Near-tetraploid minimally differentiated acute myeloid leukemia with extensive
      erythrophagocytosis by leukemic blasts.
AB  - Numerical change of chromosomes is common in acute myeloid leukemia (AML).
      However, a chromosome number as high as near-tetraploidy is very rare, especially
      in minimally differentiated AML (AML-M0). Erythrophagocytosis by reactive or
      malignant histiocytes is common in malignant hematological diseases; however,
      erythrophagocytosis by leukemic blasts is also very rare, especially in AML-M0.
      We report here the first case of AML-M0 with both of these unique
      characteristics: a near-tetraploid karyotype and erythrophagocytosis by leukemic
      blasts.

PMID- 10663620
TI  - Leukemic transformation of essential thrombocythemia without previous
      cytoreductive treatment.
AB  - Blastic transformation of essential thrombocythemia (ET) preceded by chemotherapy
      is occasionally described in the literature. In ET as well as in other
      myeloproliferative disorders the leukemogenic effect of alkylating agents and
      (32)P is well established, and recent reports also indicate a certain
      leukemogenic effect of hydroxyurea in these disorders. However, leukemic
      transformation in untreated ET seems to be a rare event. This is probably due to
      the fact that, at some time during their clinical course, most ET patients
      receive chemotherapy and are thereby exposed to leukemogenic challenge. We report
      on a woman with ET who had not received cytoreductive treatment prior to the
      development of acute myeloid leukemia, indicating that this transformation was a
      natural progression of her disorder.

PMID- 10663621
TI  - Astrovirus enteritis in a chronic lymphocytic leukemia patient treated with
      fludarabine monophosphate.
AB  - We report on a case of severe astrovirus gastroenteritis in a chronic lymphocytic
      leukemia (CLL) patient treated with fludarabine monophosphate (FAMP). Astrovirus
      was detected in stools using both an immunoenzymatic assay and an electronic
      microscopy analysis. Treatment consisted in symptomatic care and the outcome was
      favorable. Astrovirus infection might constitute a common etiology of
      gastroenteritis in patients with hematologic malignancies that have been severely
      immunocompromised with FAMP or other purine analogues, and therefore should be
      more systematically investigated.

PMID- 10663622
TI  - Littoral cell angioma with severe thrombocytopenia.
AB  - Littoral cell angioma (LCA) is a recently described splenic vascular tumor. We
      present a new case in a 62-year-old woman with severe thrombocytopenia and mild
      bleeding diathesis, but without palpable splenomegaly. Abdominal ultrasound and
      magnetic resonance showed multiple nodular images, suggesting splenic
      hemangiomas. A platelet kinetic study revealed a very short platelet survival. As
      the spleen was the site of platelet destruction, splenectomy was carried out.
      Histopathological and immunohistochemical data allowed a final diagnosis of LCA.
      Following splenectomy, the patient showed a transitory normalization of the
      platelet counts. Thrombocytopenia then reappeared but was moderate, without
      hemorrhagic diathesis. A second platelet kinetic study, performed 16 months post
      splenectomy, showed hepatic platelet destruction. However, there were no
      macroscopic hepatic lesions in a second abdominal magnetic resonance study. This
      case illustrates the difficulties involved in determining the etiology of many
      peripheral thrombocytopenias.

PMID- 10663623
TI  - Altered response to thyroid hormones by prostate and breast cancer cells.
AB  - Transferrin, an abundant bone marrow constituent, has been shown to be a potent
      mitogen in vitro in the prostate cancer cell line PC3. T4 (L-thyroxine) and T3
      (3',3,5-tri-iodo-L-thyronine) are regulators of cell metabolism. In this study,
      the effects of nonphysiological concentrations (about two orders of magnitude
      higher) of T4, T3, T2 (3,5-di-iodo-L-thyronine), RT3 (reverse T3, 3',5', 3-tri
      iodo-L-thyronine) and transferrin (about three orders of magnitude lower) were
      tested on the prostate cancer cell lines PC3, DU145 and LNCaP, and the breast
      cancer cell line MCF-7. In PC3 cells, increased proliferation by transferrin
      could be reversed by the addition of T3 or T4. T4 decreased proliferation in all
      cell lines tested, while transferrin increased proliferation in PC3 cells only.
      T3 decreased proliferation in PC3, LNCaP and MCF-7 cells but had no effect on
      DU145 cells. T4 and T3 gave two-state behavior in LNCaP cells. These results were
      combined to determine the essential iodines which produced the observed
      proliferative effects. Cell lines responded differently to T4, T3, T2, RT3 and
      transferrin suggesting a specific interaction among the compounds tested and the
      different cell lines. Finally, regulation of gene expression was demonstrated
      using DU145 cells. Upregulation of c-fos mRNA was observed in cultures at early
      time-points in the presence of T4, transferrin or both. Decreased expression was
      observed at later time-points with no expression at 4 h. An explanation for these
      results may be a change in thyroid hormone receptor/ligand affinity. Thus, the
      interactions between thyroid hormones and cancer cells may be different from
      those between thyroid hormones and normal cells.

PMID- 10663624
TI  - Weekly lometrexol with daily oral folic acid is appropriate for phase II
      evaluation.
AB  - PURPOSE: Lometrexol [(6R)-5,10-dideaza-5,6,7,8-tetrahydrofolate] is the prototype
      folate antimetabolite that targets the de novo purine synthesis pathway. Early
      phase I trials were confounded by cumulative myelosuppression that prevented
      repetitive administration. Subsequent preclinical and clinical studies suggested
      that coadministration of folic acid might favorably modulate lometrexol toxicity
      without eliminating potential antitumor activity. We set out to determine if
      concurrent folic acid would allow administration of lometrexol on a weekly
      schedule, and, if so, to identify an appropriate dose combination for phase II
      trials. Pharmacokinetic and metabolism studies were undertaken in an attempt to
      improve our understanding of lometrexol pharmacodynamics. METHODS: Patients with
      advanced cancer received daily oral folic acid beginning 7 days before lometrexol
      and continuing for 7 days beyond the last lometrexol dose. Lometrexol was
      administered by short i.v. infusion weekly for 8 weeks. Scheduled lometrexol
      doses were omitted for toxicity of more than grade 2 present on the day of
      treatment, and dose-limiting toxicity was prospectively defined in terms of
      frequency of dose omission as well as the occurrence of severe toxic events.
      Plasma and whole blood total lometrexol contents (lometrexol plus lometrexol
      polyglutamates) were measured in samples taken just prior to each lometrexol
      dose. RESULTS: A total of 18 patients were treated at five lometrexol dose
      levels. The maximum tolerated dose was identified by frequent dose omission due
      to thrombocytopenia and mucositis. The recommended phase II dose combination is
      lometrexol 10.4 mg/m(2) per week i.v. with folic acid 3 mg/m(2) per day orally.
      One patient with melanoma experienced a partial response, and three patients, two
      with melanoma and one with renal cell carcinoma, experienced stable disease.
      Lometrexol was not detectable in any predose plasma sample tested. The total red
      blood cell content of lometrexol increased over several weeks and then appeared
      to plateau. CONCLUSIONS: Weekly administration of lometrexol is feasible and well
      tolerated when coadministered with daily oral folic acid. The nature of the
      interaction between natural folates and lometrexol that renders this schedule
      feasible remains unclear. A definition of dose-limiting toxicity that
      incorporated attention to dose omissions allowed efficient identification of a
      recommended phase II dose that reflects the maximum feasible dose intensity for a
      weekly schedule. Lometrexol is a promising, anticancer agent.

PMID- 10663625
TI  - Evaluation of the alkaline comet assay and urinary 3-methyladenine excretion for
      monitoring DNA damage in melanoma patients treated with dacarbazine and
      tamoxifen.
AB  - PURPOSE: To develop, using dacarbazine as a model, reliable techniques for
      measuring DNA damage and repair as pharmacodynamic endpoints for patients
      receiving chemotherapy. METHODS: A group of 39 patients with malignant melanoma
      were treated with dacarbazine 1 g/m(2) i.v. every 21 days. Tamoxifen 20 mg daily
      was commenced 24 h after the first infusion and continued until 3 weeks after the
      last cycle of chemotherapy. DNA strand breaks formed during dacarbazine-induced
      DNA damage and repair were measured in individual cells by the alkaline comet
      assay. DNA methyl adducts were quantified by measuring urinary 3-methyladenine (3
      MeA) excretion using immunoaffinity ELISA. Venous blood was taken on cycles 1 and
      2 for separation of peripheral blood lymphocytes (PBLs) for measurement of DNA
      strand breaks. RESULTS: Wide interpatient variation in PBL DNA strand breaks
      occurred following chemotherapy, with a peak at 4 h (median 26.6 h, interquartile
      range 14.75-40.5 h) and incomplete repair by 24 h. Similarly, there was a range
      of 3-MeA excretion with peak levels 4-10 h after chemotherapy (median 33 nmol/h,
      interquartile range 20.4-48.65 nmol/h). Peak 3-MeA excretion was positively
      correlated with DNA strand breaks at 4 h (Spearman's correlation coefficient,
      r=0.39, P=0.036) and 24 h (r=0.46, P=0.01). Drug-induced emesis correlated with
      PBL DNA strand breaks (Mann Whitney U-test, P=0.03) but not with peak 3-MeA
      excretion. CONCLUSIONS: DNA damage and repair following cytotoxic chemotherapy
      can be measured in vivo by the alkaline comet assay and by urinary 3-MeA
      excretion in patients receiving chemotherapy.

PMID- 10663626
TI  - Different microtubule network alterations induced by pachymatismin, a new marine
      glycoprotein, on two prostatic cell lines.
AB  - Pachymatismin is a new cytostatic factor extracted from the marine sponge
      Pachymatisma johnstonii Bowerbank. To investigate the mechanism of action of
      pachymatismin, we studied its effects on two human prostate cell lines (DU145 and
      E4) of tumor origin. Immunocytochemistry demonstrated that the drug caused
      depolymerization of microtubules in DU145 cells, this effect being similar to
      that of estramustine, known to be a microtubule-depolymerizing agent. E4 cells,
      described to be resistant to the microtubule-depolymerizing agent estramustine,
      were also found resistant to pachymatismin. Pachymatismin at the same dose that
      destroys microtubule organization in DU145 cells is not able to induce
      microtubule depolymerization in E4 cells. Compared to the estramustine- and
      pachymatismin-sensitive DU145 cells, E4 cells revealed an increase of betaI+II,
      betaIII, betaIV isotypes as well as post-translational modifications of tubulin,
      such as polyglutamylation and acetylation. In addition, the level of tau protein
      was also enhanced in E4 cells compared to DU145 cells. The effects of
      pachymatismin were tested in vitro using calf brain microtubules. It was shown
      that the drug lowers the capacity of microtubules to reassemble in vitro.
      Interestingly, pachymatismin has been found to inhibit microtubule assembly less
      efficiently when the ratio of tau to tubulin is increased. Taken together,
      pachymastismin has been shown to induce in vivo microtubule depolymerization
      following binding to microtubule proteins. Changes in microtubule components such
      as tubulin isoforms or tau may be involved in a decrease of sensitivity to
      pachymatismin.

PMID- 10663627
TI  - Anti-tumour activity of a panel of taxanes toward a cellular model of human
      cervical cancer.
AB  - Using a model of human cervical cancer (ME-180 cells), the anti-tumour activity
      of paclitaxel was compared to that of docetaxel and IDN5109, a newly developed
      taxane. The growth inhibition effect of taxanes was assessed after 3 days of
      exposure. DNA analysis, the taxane-dependent modulation of the expression of the
      alpha and beta subunits of tubulin and DNA fragmentation were assessed by flow
      cytometry. The presence of apoptosis was confirmed by morphological analysis
      using a laser scan cytometer. For the evaluation of "in vivo" anti-tumour
      activity, taxanes were administered to nude mice intravenously once daily,
      according to a q3/4d x 4 schedule. Docetaxel, IDN5109 and paclitaxel obtained "in
      vitro" IC(50) values of 0.86, 1.4 and 2.4 nM, respectively. DNA analysis
      demonstrated a transient block at the G(2)/M phase of the cell cycle only after
      12 h of culture in the presence of taxanes and an increase of nuclear
      fragmentation suggestive for apoptosis after additional 12 and 60 h of exposure.
      Morphological analysis confirmed the presence of apoptosis. Taxanes induced a
      down-modulation of the alpha subunit of tubulin in the G(0/1) phase of the cell
      cycle, and an overexpression of the beta subunit in the G(2)/M phase. A strong
      anti-tumour activity was obtained "in vivo" for nude mice xenografted using ME
      180 cells (T/C=0% for all drugs). These data indicate that the three taxanes are
      strongly active both "in vitro" and "in vivo" toward ME-180 cells. Clinical
      studies are now needed to ascertain if the higher anti-tumour activity observed
      "in vitro" using docetaxel and IDN5109 yields a better clinical response in
      advanced cervical carcinoma with respect to paclitaxel.

PMID- 10663628
TI  - Estrogen agonistic/antagonistic effects of miproxifene phosphate (TAT-59)
AB  - PURPOSE: We evaluated miproxifene phosphate (TAT-59) to elucidate its efficacy in
      antiestrogen therapy for breast cancer patients and to assess its tissue
      selective estrogenic/antiestrogenic activity. METHODS: Using DP-TAT-59, a major
      and active metabolite of TAT-59, an in vitro cell growth inhibition test was
      performed. Antitumor activity was determined using TAT-59 against human tumor
      xenografts of the MCF-7 and the Br-10 cell lines and MCF-7-derived tamoxifen
      resistant cell lines, R-27 and FST-1. The antitumor activity of DP-TAT-59 and DM
      DP-TAT-59, major metabolites of TAT-59 found in human blood following a TAT-59
      dose, was also examined after intravenous administration to experimental animals.
      The residual estrogenic activity of TAT-59, evaluated in terms of bone and lipid
      metabolism in ovariectomized rats, was then compared with that of tamoxifen.
      RESULTS: DP-TAT-59 significantly inhibited the proliferation of estrogen receptor
      positive MCF-7 and T-47D tumor cells in the presence of 1 nM estradiol. TAT-59,
      given to mice bearing MCF-7 or Br-10 xenografts, at the dose level of 5 mg/kg,
      exerted a significant growth inhibitory effect that was stronger than that of
      tamoxifen. Moreover, R-27 and FST-1 tumors, which show a resistance to tamoxifen,
      responded strongly to TAT-59, suggesting that TAT-59 might be effective against
      tumors resistant to tamoxifen. The metabolites of TAT-59, DP-TAT-59 and DM-DP-TAT
      59, showed similar antitumor activity. Both TAT-59 and tamoxifen suppressed the
      decrease in bone density and reduced the blood cholesterol levels in
      ovariectomized rats, suggesting that the estrogenic activity of TAT-59 is
      comparable to that of tamoxifen. CONCLUSIONS: On the basis of the above results,
      one may expect TAT-59 to become an effective drug in patients with tumors less
      sensitive to tamoxifen, while its estrogenic activity as determined by bone and
      lipid metabolism is similar to that of tamoxifen.

PMID- 10663629
TI  - Modulation of RTX cytotoxicity by thymidine and dipyridamole in vitro:
      implications for chemotherapy.
AB  - PURPOSE: The cytotoxicity of the thymidylate synthase (TS) inhibitor raltitrexed
      (RTX) is reversed by supraphysiologic thymidine concentrations. Dipyridamole (DP)
      blocks thymidine salvage (uptake) and potentiates several chemotherapeutic agents
      in vitro. The purpose of this study was to determine whether DP is capable of
      potentiating RTX cytotoxicity in the presence of physiologic thymidine
      concentrations. METHODS: We examined the effect of DP on RTX cytotoxicity in the
      presence of various physiologic thymidine concentrations in eight colorectal
      adenocarcinoma cell lines by colony formation assay, and in p53-defective HL60 S
      and p53-competent HL60 SN3 promyelocytic leukemia cells by a tetrazolium
      reduction-based assay. RESULTS: In WiDr colon adenocarcinoma cells the
      cytotoxicity of 1.0 microM RTX (4 h) varied from 0% to >99% within the reported
      range of human serum thymidine concentrations from 500 to <50 nM, respectively.
      DP potentiated RTX cytotoxicity 2- to >93-fold within this range. Free DP
      concentrations of 10 to 20 nM, achievable with oral dosing, potentiated RTX at
      thymidine concentrations up to 100 nM. Potentiation at higher physiologic
      thymidine concentrations of >/=200 nM required DP concentrations of at least 50
      nM, or about twice the steady-state DP concentration obtainable from oral and
      intravenous dosing, but well within that obtainable by intraperitoneal infusion.
      Maximal potentiation required 72 to 120 h of DP exposure. DP also potentiated RTX
      in the absence of exogenous thymidine in six of eight colon cell lines and HL60 S
      and SN3 cells suggesting a second, nonthymidine salvage-dependent mechanism of
      potentiation. CONCLUSIONS: Clinically achievable free DP concentrations
      potentiated RTX cytotoxicity within the range of physiologic serum thymidine
      concentrations. RTX/DP or DP analogue-based combination therapy should,
      therefore, be considered for clinical trial. Serum or tumor thymidine
      concentration determinations may aid in identification of patients likely to
      respond to TS and nucleoside salvage inhibitors versus alternate, non-TS-directed
      therapies.

PMID- 10663630
TI  - Actinomycin D and staurosporine, potent apoptosis inducers in vitro, are
      potentially effective chemotherapeutic agents against glioblastoma multiforme.
AB  - PURPOSE: Although chemotherapeutic protocols that include chloroethylnitrosoureas
      (CENUs), such as 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3
      nitrosourea hydrochloride (ACNU) and 1, 3-bis(2-chloroethyl)-1-nitrosourea
      (BCNU), have been a mainstay of treatment for glioblastomas, the clinical
      outcomes have been unsatisfactory. More effective chemotherapeutic protocols for
      these tumors will require clear delineation of more cytocidal and cytostatic
      chemotherapeutic drugs. METHODS AND RESULTS: In this study, we measured the
      cytocidal effects of ACNU, cisplatin, actinomycin D, and staurosporine,
      administered within their therapeutic dose ranges, in the treatment of
      glioblastoma cells. As assessed by WST-1 colorimetric assay, the number of viable
      cells decreased markedly in T98G cultures treated with actinomycin D or
      staurosporine, to less than 20% of the level in control cultures at 72 h, but did
      not decrease or even increased after 6 days of treatment with ACNU. After
      treatment with cisplatin for 5 days, cell viability decreased to 30% of control.
      As assessed by fluorescence microscopic examination of nuclear staining by
      Hoechst 33258 and by electron microscopy, the majority of dead cells treated with
      actinomycin D, staurosporine, or cisplatin had morphologic features of apoptosis.
      Caspase-3 activity increased more than 20-fold in cells treated with actinomycin
      D, staurosporine, or cisplatin but increased less than fivefold in ACNU-treated
      cells. In addition to caspase-3 activation, western blot analysis demonstrated
      cleavage of caspase-2 during the apoptotic process. These findings indicate that
      actinomycin D and staurosporine potently induce apoptosis, whereas ACNU exerts
      mainly a cytostatic rather than a cytocidal effect. CONCLUSION: Actinomycin D and
      staurosporine and their derivatives are potentially effective chemotherapeutic
      agents against glioblastoma cells at least in vitro.

PMID- 10663631
TI  - Pharmacokinetics of oxaliplatin in patients with normal versus impaired renal
      function.
AB  - PURPOSE: The pharmacokinetics (PK) of platinum was investigated and compared in
      patients with normal (NRF) and impaired renal function (IRF), after they had
      received oxaliplatin at the recommended dose and delivery modality. METHODS:
      Oxaliplatin was administered at 130 mg/m(2) as a 2-h infusion without hydration.
      Patients were recruited and classified according to their creatinine clearance
      (CrCl > or < 60 ml/min), calculated using the Cockcroft and Gault formula. Blood
      was taken for PK analysis during and after the infusion. Twenty-three patients
      were included in the PK analysis (13 NRF and 10 IRF). At inclusion, the median
      CrCls were 70.5 ml/min (range 63-136) for the NRF group and 42 ml/min (range 27
      57) for the IRF group. Three patients underwent a second course of treatment and
      additional blood sampling for analysis. Platinum levels in the plasma,
      ultrafiltrate and red blood cells (RBCs) were measured using flameless atomic
      absorption spectrophotometry (FAAS). RESULTS: Following the administration of
      oxaliplatin, platinum binding to plasma proteins and RBCs was rapid and
      extensive; at the end of the 2-h infusion, 27% of the platinum in the plasma
      remained free (40% bound to RBCs, 33% bound to plasma proteins). Neither the mean
      maximal concentration (C(max)) of total platinum in the plasma, the mean C(max)
      of ultrafilterable platinum in the plasma, nor the maximal platinum content in
      the RBCs differed significantly between the two groups (2.59 vs 2.58 microg/ml,
      1.09 vs 1.28 microg/ml and 2. 06 vs 2.17 microg/ml, respectively, for patients
      with NRF vs IRF). After the end of the infusion, levels of total and free
      (ultrafilterable) platinum in the plasma declined biexponentially. The plasma
      clearance of both total and free platinum as well as the area under the curve
      (AUC) of the free platinum fraction correlate with the calculated CrCl (P=9 x 10(
      3), P=3.1 x 10(-5) and P=9 x 10(-6), respectively). After a single course of
      oxaliplatin, toxicities reported in the two groups of patients were similar.
      CONCLUSIONS: Our results are in agreement with the in vitro data concerning the
      extensive binding of oxaliplatin to plasma proteins and RBCs. They also reveal a
      strong negative correlation between free drug plasma availability and renal
      function, with a corresponding positive correlation between clearance of the
      plasmatic platinum and renal function. Thus, renal impairment entails a greater
      overall exposure to platinum in the plasma. However, this study failed to elicit
      any relationship between moderate renal impairment and the acute toxicity
      associated with oxaliplatin.

PMID- 10663632
TI  - Impact of the simultaneous administration of the (+)- and (-)-forms of formyl
      tetrahydrofolic acid on plasma and intracellular pharmacokinetics of (-)
      tetrahydrofolic acid.
AB  - PURPOSE: To detect possible interactions between (-)-formyl-tetrahydrofolic acid
      (leucovorin, (-)-fTHF) and (+)-formyl-tetrahydrofolic acid ((+)-fTHF) on the
      plasma and intracellular pharmacokinetics following their simultaneous
      administration. METHODS: Plasma levels of (-)-fTHF, (-)-methyl-THF, and (+)-fTHF
      were determined in samples from four volunteers following the administration of
      both (-)-fTHF and (+/-)-fTHF and in seven patients during a 5-fluorouracil (5
      FU)/fTHF combination chemotherapy. In addition, the intracellular uptake of (14)C
      (-)-mTHF in the presence of (+)-mTHF at increasing concentrations was measured in
      vitro. Analyses were performed using a highly specific high-performance liquid
      chromatography procedure. RESULTS: The pharmacokinetic parameters obtained for (
      )-fTHF following the administration of (-)-fTHF only were: terminal half-life,
      1.2 h; area under the curve, 10 microg. h/ml; maximum concentration, 12
      microg/ml; clearance, 305 ml/min; volume of distribution, 19 l. The parameters
      did not differ significantly as compared with those obtained following the
      administration of (+/-)-fTHF to both volunteers and patients. There were no
      differences in the pharmacokinetics of (-)-mTHF or in the protein binding of both
      substances with the different forms of administration. The intracellular uptake
      of (14)C-(-)-mTHF did not depend on the presence of (+)-mTHF at either
      concentration. CONCLUSIONS: These data suggest that (-)-fTHF is not
      therapeutically superior to (+/-)-fTHF and that the latter is appropriate during
      combination chemotherapy with 5-FU/fTHF in patients with colorectal cancers.

PMID- 10663633
TI  - In vitro antioxidant properties of amifostine (WR-2721, Ethyol).
AB  - PURPOSE: Amifostine (WR-2721), a phosphorylated aminothiol pro-drug which is an
      analogue of cysteamine, is a selective cytoprotective agent for normal tissues
      from the toxicities associated with chemotherapy and irradiation. Despite a
      growing number of reports strongly supporting amifostine's clinical efficacy, few
      authors have focused on the biochemical basis of amifostine's antioxidant
      activity. METHODS: We report on amifostine's free-radical scavenging activity
      against superoxide (O(2;(-))), hydroxyl (OH(-)) and lipoperoxyl radicals in an in
      vitro model, using pure chemical systems. Amifostine was dephosphorylated to its
      active metabolite, WR-1065, by adding 10% non-heat-inactivated serum; different
      amifostine concentrations (1, 10, 50, 100 microM and 200 microM) and pH
      conditions (pH 5, 7.4 and 9) were tested. RESULTS: Independent of the
      concentration, amifostine exhibited no major activity against O(2;(-)) ions,
      neither did any pH variations in the experimental model provide any scavenger
      effects of the drug against O(2;(-)) radicals. On the other hand, the protective
      effect of amifostine against OH(-) radicals was confirmed, yielding an EC(50) of
      255 microM at pH 7.4 and 230 microM at pH 5. Finally, amifostine exhibited
      scavenging activity against spontaneous lipoperoxidation, but no apparent
      antioxidant effect on iron ascorbate-induced lipoperoxidation. CONCLUSIONS: With
      this in vitro study, we are able to confirm the scavenging activity of the chemo-
      and radioprotector amifostine, whose activity seems to be particularly important
      from a biological point of view, since it is exerted mainly against highly
      reactive OH(-).

PMID- 10663634
TI  - Gemcitabine in soft tissue or bone sarcoma resistant to standard chemotherapy: a
      phase II study.
AB  - PURPOSE: To assess the efficacy of gemcitabine in patients with a variety of
      sarcomas that have failed to respond or escaped Adriamycin- and ifosfamide-based
      chemotherapy. PATIENTS AND METHODS: A group of 18 symptomatic heavily pretreated
      patients with sarcomas of bone or soft tissue received one induction course of
      gemcitabine at a dose of 1000 mg/m(2) per week for 7 consecutive weeks, followed
      by 1 week rest. Response to the induction course was assessed by interview and by
      repeated ancillary tests. If no progression was observed, maintenance by
      gemcitabine 1000 mg/m(2) per week for 3 weeks every 28 days was given until
      failure was clinically or radiologically evident. RESULTS: A total of 51 cycles
      of gemcitabine were given including 18 cycles of induction. A mean of 3.6
      postinduction cycles were given to nine patients. The treatment was well
      tolerated by the patients. One partial response (leiomyosarcoma) and one minimal
      response (angiosarcoma) were observed, yielding a true objective response rate of
      5.5%. An additional six patients achieved stabilization of disease
      (chondrosarcoma and osteosarcoma), yielding an overall progression-free rate of
      44%. The median time to progression was more than 27 weeks. Clinical benefit
      response was observed only in those who also achieved a progression-free state.
      CONCLUSION: Gemcitabine was found to be effective in achieving stabilization and
      even a minimal response of soft tissue or bone sarcoma refractory to standard
      chemotherapy.

PMID- 10663635
TI  - Tumor apoptosis induced by epoxide-containing piperazines, a new class of anti
      cancer agents.
AB  - PURPOSE: The overall purpose of this study was to determine the potential
      efficacy of epoxide-containing piperazines as a new class of anti-cancer agents.
      Two representative compounds, specifically NCO-700, a 4-trimethoxyphenyl
      substituted epoxide-piperazine, and TOP-008, a 4-phenylpropenyl-substituted
      epoxide-piperazine were tested in cytotoxic assays with human breast and prostate
      cancer cell lines. A second objective was to determine if these two compounds had
      anti-cancer activity in vivo when tested against xenograft tumors in nude mice or
      human tumors grown under the kidney capsule in mice. A final objective of this
      study was to establish if NCO-700 and TOP-008 achieved cancer cell killing
      through an apoptotic mechanism. METHODS: The anti-proliferative activity of NCO
      700 and TOP-008 were tested in a 7 day cell-survival assay utilizing a number of
      well characterized breast (HS-578T, T47D, MCF-7) and prostate (DU-145, PC-3,
      LNCaP) cancer cell lines. In vivo studies with the two compounds were performed,
      in nude mice bearing DU-145 xenograft tumors, and in normal mice in which DU-145
      prostate cancer cells and HS-578T breast cancer cells were grown as solid tumors
      in the subrenal capsules of the animals. Apoptotic cell death of cancer cells was
      determined by a number of established techniques that detect apoptosis, including
      the confocal laser microscopy of treated cells and mitochondrial leakage assays
      utilizing the cationic dye, JC-1. Finally, the activation of the caspase cascade,
      enzymes that carry out apoptosis in mammalian cells, was examined in treated
      cells by immunoblot assays. RESULTS: NCO-700 and TOP-008 displayed cytotoxicity
      to HS-578T human breast cancer cells, with ED(50) values in the 3-6 microM range.
      Cytotoxicity to androgen receptor-negative human prostate cancer cells (PC-3 and
      DU-145 cells) occurred with ED(50) values in the 5-20 microM range. Cytotoxicity
      to hormone receptor-positive breast and prostate cancer cell lines occurred at 10
      to 20-fold higher concentrations of the two compounds. When human prostate (DU
      145) or breast cancer (HS-578T) cells were grown as solid tumors in the subrenal
      capsules of mice, significant anti-tumor activity of NCO-700 was observed at 20
      mg/kg and 50 mg/kg body weight respectively, for prostate and breast tumors. In
      nude mice bearing DU-145 prostate tumor xenografts, 50 mg/kg doses of the two
      compounds either stopped (TOP-008) tumor growth or slowed (NCO-700) growth. The
      mechanism of cytotoxicity was shown to be through apoptosis, (a) by confocal
      microscopy studies revealing nuclear fragmentation, (b) by mitochondrial studies
      revealing disruption of the mitochondrial membrane and release of the cationic
      dye, JC-1, into the cytoplasm and (c) by protein immunoblot assays indicating
      that over a 6 h period, TOP-008 induced a significant accumulation of the pro
      apoptotic protein, bak, in the mitochondrial fraction of HS-578T human breast
      cancer cells, accompanied by activation, at 2.5 h, of caspase-3. CONCLUSIONS:
      These studies indicated that the epoxide-containing piperazines, as exemplified
      by NCO-700 and TOP-008, were effective anti-cancer agents when tested in vitro
      and in vivo against human breast and prostate tumors. Our studies also indicated
      that TOP-008 induced the initiation of the caspase cascade leading to apoptosis.
      Previous toxicology studies in rodents and dogs, as well as a Phase I study in
      humans, showed NCO-700 to be a well-tolerated, non-toxic compound. Taken together
      with our current findings, these results suggest that this class of compounds has
      the potential to be relatively safe, new chemotherapeutic agents for refractory
      breast and prostate cancers.

PMID- 10663636
TI  - Comparison of N-acetylcysteine and l-2-oxothiazolidine-4-carboxylate as cysteine
      deliverers and glutathione precursors in human malignant melanoma transplants in
      mice.
AB  - PURPOSE: Glutathione is an important cellular compound which affects
      detoxification of electrophiles and may have direct or indirect effects on
      pigment formation. It is therefore of importance to study interstitial
      concentrations in melanoma tissue while decreasing its formation with an enzyme
      inhibitor and increasing its amount with cysteine deliverers. METHOD: Glutathione
      formation was inhibited by intraperitoneal (i.p.) injection of BSO. N
      Acetylcysteine (NAC) and l-2-oxothiazolidine-4-carboxylate (OTC) were then given
      i.p. to subgroups of the animals. Intratumoral microdialysis was performed during
      BSO treatment, during BSO treatment combined with NAC or OTC and after
      discontinuation of BSO but ongoing NAC or OTC treatment. RESULTS: Glutathione
      formation was inhibited during BSO treatment. The dialysate concentrations of
      both glutathione and cysteine decreased during concomitant treatment with BSO and
      NAC or OTC. Recovery of the amounts of the two compounds was seen in both groups
      after discontinuation of BSO treatment. In the NAC group we also observed an
      acute increase in dialysate concentrations of cysteine after NAC injection. The 5
      S-cysteinyldopa concentrations were unaffected by variations in glutathione and
      cysteine concentrations. CONCLUSIONS: 5-S-Cysteinyldopa in melanoma is not formed
      from glutathione in vivo to any appreciable extent. The intracellular amount of
      cysteine is probably not a limiting factor for cysteinyldopa formation. It seems
      that both NAC and OTC can be used as cysteine deliverers to melanoma cells in
      vivo to produce recovery of glutathione levels after synthesis inhibition by BSO
      treatment.

PMID- 10663637
TI  - Cisplatin (CDDP) specifically induces apoptosis via sequential activation of
      caspase-8, -3 and -6 in osteosarcoma.
AB  - PURPOSE: Osteosarcoma is a common malignant tumor. The first choice of treatment
      plan for osteosarcoma is chemotherapy. In particular, preoperative chemotherapy
      is most important in clinical treatment in orthopedics. In these chemotherapies,
      multiple anticancer drugs such as Adriamycin (ADM), CDDP, cyclophosphamide (CPM),
      methotrexate (MTX) and vincristine (VCR) are commonly used in combination.
      Recently, anticancer drugs have been shown to trigger apoptosis in various cancer
      cells. However, many studies on this topic have been examined using leukemia cell
      lines, and many kinds of cancer cells established from solid tumor are resistant
      to the induction of apoptosis by anticancer drugs. So in this study, we examined
      the effects of the anticancer drugs ADM, CDDP, CPM, MTX and VCR on osteosarcoma
      cells in vitro. We also examined the signaling pathways of each anticancer drug
      by studying the induction of apoptosis and activation of caspases in the
      osteosarcoma cells. METHODS: We examined the effects of the anticancer drugs ADM,
      CDDP, CPM, MTX and VCR, which are used clinically for the treatment of
      osteosarcoma, on cells of the human osteosarcoma (HOS) cell line. The cytotoxic
      effects of the anticancer drugs were evaluated using the MTT assay. We used both
      flow cytometry and activation of caspases to confirm the induction of apoptosis
      in the HOS cells. To dissect the pathway of the caspase cascade in apoptosis in
      HOS cells, we used the tetrapeptides YVAD-CHO, DMQD-CHO, VEID-CHO and IETD-CHO,
      which selectively inhibit caspase-1, -3, -6 and -8, respectively. RESULTS: ADM,
      CDDP, CPM and VCR, but not MTX, induced death of HOS cells in a dose-dependent
      manner. CDDP at 10 microM, CPM at 7.5 microM, ADM at 20 microM and VCR at 150
      microM caused 80% cell death of HOS cells after 12 h. However, the percentages of
      apoptotic cells were 5.6% (medium alone), 75.9% (CDDP), 20.0% (CPM), 22.2% (ADM),
      20.5% (VCR) and 13.1% (MTX). In addition, direct measurement of caspase-3
      activity revealed that CDDP but not the other drugs activated caspase-3 in HOS
      cells. These analyses revealed that only CDDP induced apoptosis of HOS cells via
      activation of caspases. Furthermore, DMQD-CHO, VEID-CHO and IETD-CHO inhibited
      CDDP-induced apoptosis of HOS cells, suggesting that caspase-3, -6 and -8 are
      involved in the signaling pathway of CDDP-induced apoptosis. In contrast, none of
      the caspase inhibitors inhibited cell death induced by the other anticancer
      drugs. CONCLUSIONS: This study demonstrates that CDDP specifically induces
      apoptosis via activation of caspases and the other anticancer drugs induce death
      of HOS cells via different signaling pathways. It also demonstrates that caspase
      8 is a key molecule in the earliest stage of the signaling pathway of CDDP
      induced apoptosis of HOS cells, and caspase-3 works downstream of caspase-8.

PMID- 10663638
TI  - Effect of P-glycoprotein modulation with cyclosporin A on cerebrospinal fluid
      penetration of doxorubicin in non-human primates.
AB  - PURPOSE: P-glycoprotein (Pgp) is a transmembrane drug efflux pump that is
      expressed in multidrug-resistant cancer cells and in a variety of normal tissues,
      including brain capillary endothelial cells which comprise the blood-brain
      barrier. We studied the effects of the Pgp inhibitor, cyclosporin A (CsA), on the
      cerebrospinal fluid (CSF) penetration of the Pgp substrate, doxorubicin, in non
      human primates. METHODS: The animals received doxorubicin alone (2.0 mg/kg i.v.
      over 60 min) or doxorubicin (1 mg/kg i.v. over 60 min) and CsA (loading dose 4.0
      mg/kg i.v. over 2 h, followed by continuous infusion of 12 mg/kg per day over 48
      h). Plasma and CSF were collected over 48 h and the doxorubicin concentration was
      measured by reverse-phase high-pressure liquid chromatography (HPLC) with
      fluorescence detection (detection limit 5 nM). A two-compartment model was fitted
      to the plasma concentration-time data. RESULTS: Pgp was demonstrated to be
      present in the epithelium of the choroid plexus by immunohistochemical methods,
      indicating that CSF drug penetration could be used as a surrogate for blood-brain
      barrier penetration. Steady state whole blood CsA concentrations, which were
      measured with a fluorescence-polarization immunoassay (TDX) that detects both CsA
      and its metabolites, ranged from 551-1315 microg/l at 24 h. The clearance of
      doxorubicin in four animals was reduced by 34%, 38%, 45% and 49% when given with
      CsA. The doxorubicin concentration in the CSF was <5 nM in all animals, both
      after doxorubicin alone and doxorubicin with CsA. CONCLUSIONS: The Pgp inhibitor,
      CsA, at a concentration that alters systemic clearance of doxorubicin, does not
      appear to significantly increase the CSF penetration of doxorubicin.

PMID- 10663639
TI  - Pharmacokinetics and metabolism of docetaxel administered as a 1-h intravenous
      infusion.
AB  - Docetaxel, a taxane antitumor agent, was administered to 24 patients by a 1-h
      intravenous infusion at a dose level of 100 mg/m(2) with pharmacokinetic
      monitoring. The plasma concentration-versus-time data were fitted with a three
      compartment model. The mean area under the curve (AUC) for docetaxel was 3.1 +/-
      0.9 h. mg/l and the clearance was 34.8 +/- 9.3 l/h per m(2). There was
      considerable interpatient pharmacokinetic variability. In 33% of the patient
      population, metabolites were detected in plasma samples collected 5-30 min after
      the end of the infusion. The cyclized oxazolidinedione metabolite M4 was most
      frequently present and was detected in 8 out of 24 patients with maximal
      concentrations between 0.022 and 0.23 mg/l. Logistic regression analysis was
      performed to predict M4 docetaxel metabolism. In the final model, alanine
      aminotransferase and alkaline phosphatase levels were the strongest predictors.
      No relationship was found between M4 metabolism and percentage decrease in
      neutrophil count in this study. Three patients with high M4 concentrations in
      plasma during course 1 suffered from most pronounced fluid retention (grade 2-3)
      after two to five courses.

PMID- 10663640
TI  - Modulation of adriamycin cytotoxicity and transport in drug-sensitive and
      multidrug-resistant Chinese hamster ovary cells by hyperthermia and cyclosporin
      A.
AB  - PURPOSE: Chemosensitizers such as cyclosporin A can increase intracellular
      accumulation of chemotherapeutic agents such as Adriamycin in certain multidrug
      resistant (MDR) cell lines with overexpression of P-glycoprotein. It is likely
      that, when combined with cyclosporin A, hyperthermia could increase membrane
      permeability to Adriamycin and enhance its cytotoxic effects. The ability of both
      hyperthermia and cyclosporin A to modulate the cytotoxicity, transport and
      subcellular distribution pattern of Adriamycin was studied in a pleiotropic MDR
      Chinese hamster ovary cell line (CH(R)C5) and in the drug-sensitive parent line
      (AuxB1). METHODS: Adriamycin cytotoxicity was evaluated by clonogenic cell
      survival, drug transport using [(14)C]-labeled Adriamycin and intracellular drug
      distribution by fluorescence microscopy. RESULTS: Adriamycin cytotoxicity was
      increased in both drug-sensitive and MDR cells by cyclosporin A (5 microM) alone,
      and by hyperthermia alone (41-43 degrees C) only in sensitive cells. However,
      when cyclosporin A and 42 degrees C hyperthermia were used in combination, a
      large increase in drug cytotoxicity occurred in both cell lines. This effect
      increased with time and was temperature-dependent. The increase in Adriamycin
      cytotoxicity caused by cyclosporin A and hyperthermia was accompanied by
      alterations in membrane permeability to the drug. Cyclosporin A increased
      [(14)C]Adriamycin uptake, while drug efflux decreased, for both AuxB1 and CH(R)C5
      cells and nuclei. For AuxB1 cells only, drug distribution studies showed that
      cyclosporin A promoted an increase in both nuclear and cytoplasmic drug
      accumulation. Hyperthermia, combined with cyclosporin A, increased
      [(14)C]Adriamycin uptake. This effect was seen as an increase in intensity of
      nuclear and cytosolic drug fluorescence in both cell lines. Cyclosporin A alone
      diminished drug efflux and caused Adriamycin to remain firmly bound in the
      nucleus of AuxB1 cells, while it remained primarily in the cytoplasm of CH(R)C5
      cells. CONCLUSIONS: Hyperthermia alone had little effect on Adriamycin
      cytotoxicity and transport in MDR cells, in contrast to drug-sensitive cells.
      This suggests that P-glycoprotein is fully functional in these MDR cells. Our
      findings suggest that cyclosporin A and hyperthermia could be beneficial by
      increasing intracellular drug accumulation, thus improving the effectiveness of
      Adriamycin against both drug-sensitive and MDR cells within a localized target
      region.

PMID- 10663641
TI  - Anticancer efficacy of the irreversible EGFr tyrosine kinase inhibitor PD 0169414
      against human tumor xenografts.
AB  - PURPOSE: The involvement of the EGF receptor (EGFr) family of receptors in
      cancers suggests that a selective inhibitor of the tyrosine kinase activity of
      the EGFr family could have a therapeutic effect. PD 0169414, an
      anilinoquinazoline, is a potent irreversible inhibitor of the EGFr family
      tyrosine kinase activity with IC(50) values of 0.42 nM against the isolated EGF
      receptor, and 4.7 nM and 22 nM against EGF- and heregulin-mediated receptor
      phosphorylation in A431 and MDA-MB-453 cells, respectively. METHODS AND RESULTS:
      Oral administration of 260 mg/kg per day PD 0169414 for 15 days to animals
      bearing advanced-stage A431 epidermoid carcinoma produced a 28.2-day delay in
      tumor growth and resulted in three complete and three partial tumor regressions
      in six animals. Toxicity at this dose level was limited to <6% loss of initial
      body weight. Doses of 160 and 100 mg/kg per day produced tumor growth delays of
      29.5 and 20.9 days and two and one complete regressions in six animals,
      respectively. Subcutaneous, intraperitoneal, and oral routes of administration
      have also shown in vivo antitumor activity of PD 0169414 in a panel of human
      tumor xenografts. Responsive tumor lines include A431 (human epidermoid
      carcinoma), H125 (NSCL carcinoma), MCF-7 and UISO-BCA1 (human breast carcinoma),
      and SK-OV-03 (human ovarian carcinoma). The therapeutic effect ranged from
      delayed tumor growth (6.4 days delayed tumor growth for 14 days of treatment) to
      tumor regressions (32.2 days delayed tumor growth and five partial regressions in
      six animals) in these model systems. CONCLUSION: PD 0169414 is a specific,
      irreversible inhibitor of EGFr family tyrosine kinases with significant in vivo
      activity against a variety of relevant human tumor xenografts.

PMID- 10663642
TI  - Double high-dose chemotherapy with stem cell rescue (HD-SCR) in patients with
      breast cancer - effect of sequence.
AB  - INTRODUCTION: A preliminary analysis of our double high-dose chemotherapy with
      stem cell rescue (HD-SCR) clinical trial for breast cancer, and preclinical cross
      resistant studies, suggested that melphalan (M) adversely affected response to
      subsequent chemotherapy, i.e., that the sequence of alkylating agents (AAs) might
      affect response. We, therefore, constructed and examined preclinical models to
      determine whether prior exposure to M, in fact, adversely affected response to
      other therapy. PURPOSE: The purpose of the study was to determine whether the
      sequence of AAs, specifically the prior use of M, adversely affected response to
      subsequent treatment. METHODS: The methods employed were the following: (1) Human
      tumor cell lines rendered resistant by in vitro sequential exposure to five
      different AAs were developed. The resistant cell lines were examined for cross
      resistance to alkylating and other agents. (2) In vivo studies in the p388 mouse
      leukemia for resistance and cross-resistance among the AAs. (3) In vivo studies
      of the effect of sequence of AAs on response in mice bearing EMT6 breast cancer.
      (4) The double transplant model was developed in the mouse and the sequence of
      high-dose AAs was studied. (5) Biochemical and reverse transcriptase-polymerase
      chain reaction (RT-PCR) studies of the various resistant tumor cell lines.
      RESULTS: (1) The in vitro human tumor cells resistant to M were cross-resistant
      in 57% of tests to other AAs. In contrast, resistance for other AAs crossed to
      other agents in only 10 to 20% of tests. (2) The in vivo studies of p388
      indicated that resistance to M commonly crossed to other AAs and many non-AAs.
      (3) The results for the mouse breast cancer (EMT6) studies of the sequence of AAs
      again indicated that M employed first markedly reduced responsiveness to
      subsequent treatment, particularly with AAs. (4) The double transplant model:
      again, M first markedly reduced response to other agents. (5) The in vitro
      resistant human tumor cell lines, particularly the breast cancer cell line MCF7,
      were found to contain high concentrations of glutathione S1 transferase gamma,
      which is consistent with that mechanism being responsible for resistance.
      CONCLUSION: The sequence of alkylating agent treatment may substantially
      influence response. Melphalan, particularly, produces resistance that commonly
      crosses to the other AAs. Mechanistic studies indicate significant changes in
      glutathione S1 transferase, a known mechanism for broadly based resistance to
      AAs.

PMID- 10663643
TI  - Pharmacokinetics of levamisole in cancer patients treated with 5-fluorouracil.
AB  - PURPOSE: To investigate the pharmacokinetics of levamisole and a metabolite, p
      hydroxylevamisole in patients with colorectal cancer treated with 5-fluorouracil
      (5-FU). METHODS: Following an intravenous bolus dose of 5-FU, 20 patients with
      colorectal cancer received oral doses of 50 mg levamisole every 8 h for 3 days.
      Immediately after the last dose, blood and urine samples were collected over at
      least an 8-h period. Samples were assayed for levamisole and p-hydroxylevamisole
      by GC/MS. The levamisole plasma and urine data were subjected to pharmacokinetic
      analysis using NONMEM software. RESULTS: Substantial interpatient variability was
      observed in the levamisole plasma concentration-time curves. Patients with
      cardiovascular or gastrointestinal complications demonstrated altered absorption
      of levamisole. Pharmacokinetic parameter values for levamisole were similar to
      those obtained previously in healthy subjects and other cancer patients.
      CONCLUSIONS: There is no evidence that the pharmacokinetics of levamisole are
      altered by 5-FU administered immediately prior to levamisole administration. The
      relationship between the substantial intersubject variability in levamisole
      plasma concentration-time curves and clinical outcome following 5-FU/levamisole
      adjuvant chemotherapy should be examined.

PMID- 10663644
TI  - Enhancement of camptothecin-induced cytotoxicity with UCN-01 in breast cancer
      cells: abrogation of S/G(2) arrest.
AB  - PURPOSE: To determine the ability of UCN-01 to abrogate the cell cycle arrest
      induced by camptothecin (CPT) in tumor cells that lack p53 function, and
      therefore enhance the cytotoxicity of CPT in these cells in relation to normal
      cells with wild-type p53. METHODS: The responses of MDA-MB-231 and GI 101A breast
      cancer cells were compared to those of normal bovine endothelial cells.
      Cytotoxicity was assessed by the MTT assay, and the resulting data were modeled
      using median-effect analysis. Inhibition of DNA synthesis was determined by loss
      of [(3)H]thymidine incorporation, and cell cycle status was determined by flow
      cytometric analysis of propidium-iodide-stained nuclei. RESULTS: UCN-01, a
      specific inhibitor of protein kinase C (PKC) presently in clinical trials,
      abrogated CPT-induced activation of S and G(2) checkpoints in human MDA-MB-231
      and GI 101A breast carcinoma cells, both of which are mutants for the p53 gene.
      This abrogation occurred with the use of sublethal doses (100 nM) of UCN-01 and
      correlated with the enhancement of CPT-induced cytotoxicity. Median-effect
      analysis showed that synergistic cytotoxic interactions existed between CPT and
      UCN-01 against these tumor cells. In normal cells, however, abrogation of the S
      phase arrest caused accumulation in G(0)/G(1) phase, perhaps by the presence of
      wild-type p53 activity, with no change in CPT-induced cytotoxicity. CONCLUSION:
      We have shown previously that the cytotoxicity of CPT is correlated with cell
      cycle response in normal and tumor cells. Low doses of CPT arrest cells in the
      G(2)/M phase and inhibit DNA synthesis, but higher doses cause arrest of cells in
      S phase. Thus modulation of events at the S and G(2) checkpoints may provide an
      opportunity to enhance CPT-induced cytotoxicity in tumor cells. The results of
      this study indicate that UCN-01 enhances the progression of tumor cells through S
      phase thus greatly increasing CPT-induced cytotoxicity. Normal cells, however,
      are able to arrest in G(0)/G(1) and thus avoid the increased toxicity induced by
      CPT. Our findings suggest potential usefulness of combining UCN-01 in
      topoisomerase I inhibitor-based drug therapy for the treatment of breast cancer
      with a dysfunctional p53 gene.

PMID- 10663660
TI  - Aims and scope of the journal

PMID- 10663645
TI  - Methotrexate distribution within the subarachnoid space after intraventricular
      and intravenous administration.
AB  - PURPOSE: Intrathecal methotrexate achieves high concentrations in cerebrospinal
      fluid (CSF), but drug distribution throughout the subarachnoid space after an
      intralumbar dose is limited. The objective of this study was to quantify
      methotrexate distribution in CSF after intraventricular and intravenous
      administration and to identify factors that influence CSF distribution. METHODS:
      Nonhuman primates (Macaca mulatta) with permanently implanted catheters in the
      lateral and fourth ventricles received methotrexate by bolus injection (0.5 mg)
      and infusion (0.05 to 0.5 mg/day over 24 to 168 h) into the lateral ventricle, as
      well as intravenous infusions. CSF was sampled from the lumbar space, fourth
      ventricle and the subarachnoid space at the vertex. Methotrexate in CSF and
      plasma was measured with the dihydrofolate reductase inhibition assay. RESULTS:
      After bolus intraventricular injection, methotrexate exposure in lumbar CSF
      ranged from 11% to 69% of that achieved in the fourth ventricle. During
      continuous intraventricular infusions, methotrexate steady-state concentrations
      (C(ss)) in lumbar CSF and CSF from the vertex were only 20% to 25% of the
      ventricular CSF C(ss). The dose, duration of infusion, and infusate volume did
      not influence drug distribution to the lumbar CSF, but probenicid increased the
      lumbar to ventricular C(ss) ratio, suggesting the involvement of a probenicid
      sensitive transport pump in the efflux of MTX from the CSF. During the
      intravenous infusions, the ventricular methotrexate C(ss) was lower than the
      lumbar C(ss) and the C(ss) in CSF from the vertex. CONCLUSION: Methotrexate CSF
      distribution after intraventricular injection was uneven, and at steady-state CSF
      methotrexate concentrations were lower at sites that were more distant from the
      injection site.

PMID- 10663661
TI  - Two SIS epidemiologic models with delays.
AB  - The SIS epidemiologic models have a delay corresponding to the infectious period,
      and disease-related deaths, so that the population size is variable. The
      population dynamics structures are either logistic or recruitment with natural
      deaths. Here the thresholds and equilibria are determined, and stabilities are
      examined. In a similar SIS model with exponential population dynamics, the delay
      destabilized the endemic equilibrium and led to periodic solutions. In the model
      with logistic dynamics, periodic solutions in the infectious fraction can occur
      as the population approaches extinction for a small set of parameter values.

PMID- 10663662
TI  - The interaction of thin-film flow, bacterial swarming and cell differentiation in
      colonies of Serratia liquefaciens.
AB  - The rate of expansion of bacterial colonies of S. liquefaciens is investigated in
      terms of a mathematical model that combines biological as well as hydrodynamic
      processes. The relative importance of cell differentiation and production of an
      extracellular wetting agent to bacterial swarming is explored using a continuum
      representation. The model incorporates aspects of thin film flow with variable
      suspension viscosity, wetting, and cell differentiation. Experimental evidence
      suggests that the bacterial colony is highly sensitive to its environment and
      that a variety of mechanisms are exploited in order to proliferate on a variety
      of surfaces. It is found that a combination of effects are required to reproduce
      the variation of bacterial colony motility over a large range of nutrient
      availability and medium hardness.

PMID- 10663663
TI  - Models for spatial polymerization dynamics of rod-like polymers.
AB  - We investigate the polymerization kinetics of rod-like polymer filaments
      interacting with a distribution of monomer in one spatial dimension (e.g. along a
      narrow tube). We consider a variety of possible cases, including competition by
      the filament tips for the available monomer, and behaviour analogous to
      "treadmilling" in which the polymer adds subunits to one end and loses them at
      the other end so as to maintain a constant length. Applications to biological
      polymers such as actin filaments and microtubules are discussed.

PMID- 10663664
TI  - [Myelodysplastic syndromes (MDS). Aspects of hematopathologic diagnosis].
AB  - Myelodysplastic syndromes (MDS) are a heterogenous group of clonal stem cell
      disorders which generally occur in older adults but may also affect children.
      Primary MDS should be distinguished from secondary MDS associated with
      antineoplastic or immunosuppressive therapy (t-MDS), exposure to toxic compounds,
      or genetic disorders. The establishment of a neoplastic clone is reflected by
      dysplastic features and impaired function which may affect all three
      hematopoietic cell lineages. The ineffective hematopoiesis which causes bone
      marrow failure is accompanied by peripheral blood cytopenia and is considered to
      result from increased apoptosis, at least in the less advanced MDS stages. The
      elucidation of the molecular pathogenesis of MDS has provided evidence that
      chromosomal abnormalities are present in about 50% of patients with primary MDS.
      They include numerical aberrations such as monosomy 5 or 7, trisomy 8, loss of
      the Y-chromosome and structural abnormalities such as deletion of the long arm of
      chromosome 5 (5q-syndrome), 7, or 8. Based on the percentage of blasts (<5%, 5
      20%, 20-30%) and the presence of >15% ringed sideroblasts for marrows with <5%
      blasts, the French-American-British (FAB) classifies MDS into 4 morphologic
      categories: refractory anemia (RA), refractory anemia with excess of blasts
      (RAEB), refractory anemia with excess of blasts in transformation (RAEB-t), and
      refractory anemia with ringed sideroblasts. The fifth morphologic type is chronic
      myelomonocytic leukemia characterized by peripheral blood monocytosis
      (>1x10(9)/l). However, a modification of this classification will be proposed by
      the World Health Organization, with the intention of lowering the threshold for
      the diagnosis of AML from 30% to 20% blast cells. In patients presenting with
      cytopenias suggesting impaired hematopoiesis, the initial diagnosis depends
      mainly on the cytological evaluation of bone marrow and blood smears and the
      histological findings of trephine bone marrow biopsy. In a retrospective analysis
      we evaluated the occurrence of the distinct FAB-categories as percentage of the
      total number of MDS cases diagnosed at the Institute of Pathology of the
      University of Freiburg. A total of 63% fullfilled the criteria of RA/RARS, 17% of
      RAEB, 14% of RAEB-t, and 6% of CMML. A fibrotic variant of MDS was observed in
      7.67% of all cases, ranging from 2.34% in RA up to 15. 42-15.84% in the
      categories which did not show significant differences with regard to
      myelofibrosis. The histologic evaluation of a trephine bone marrow biopsy is of
      critical importance for the evaluation of fibrotic or hypocellular MDS since
      these patterns are not reflected by the cytological examination. The combined
      cytological and histological diagnosis of bone marrow and peripheral blood is a
      reliable tool for the initial diagnosis of MDS. In addition, cytogenetic and
      molecular analysis should be performed. Presently, the risk of leukemic
      transformation is evaluated using the International Prognostic Scoring System for
      MDS, which is the sum of the scores of bone marrow blasts, karyotypes and
      cytopenia. In the context of clinical trials therapeutic modalities should be
      considerd according to the age and the general performance state and the
      prognostic scores of individual patients.

PMID- 10663665
TI  - [Reactive lymphoid nodule or malignant lymphoma. A brief guideline for the
      differential diagnosis of bone marrow infiltrates in non-Hodgkin lymphomas].
AB  - Differentiation of focal or extended lymphoid bone marrow infiltrates presents a
      diagnostic challenge and therefore warrants systematic evaluation of those
      features which affect this. One of the basic requirements is an appropriate
      technique of processing the bone marrow specimens. This includes the possibility
      of enzyme evaluation (naphthol-AS-D-chloroacetate esterase) and
      immunohistochemistry (set of monoclonal antibodies) and comparison with the
      corresponding lymph node histology. A number of histological parameters have
      emerged with a distinctive property for distinguishing between reactive focal
      lymphoid aggregates and malignant lymphomas. Amongst these the pattern of
      infiltrates, i.e., histotopography (subcortical infiltrates, paratrabcular
      endosteal localization, margination, tandem-like extension between adipocytes and
      cribriform appearance), content of reticulin fibers, cytology (small lymphocytes
      versus large blast cells) and, finally, immunohistochemistry (monoclonal versus
      polyclonal expression of cytoplasmic immunoglobulins, uniform versus mixed
      population of B or T lymphocytes) are most important. In conclusion, synoptic
      consideration of several parameters, in particular histotopography and
      immunohistochemistry provides a most promising approach to differentiate
      neoplastic from reactive lymphoid lesions in the bone marrow.

PMID- 10663666
TI  - [ Polyglobuly versus polycythemia vera].
AB  - Differentiation of an elevated hemoglobin/hematocrit level warrants not only the
      determination of relevant laboratory values, including erythropoietin, but also
      an elaborate evaluation of bone marrow histopathology. Particularly in the
      initial stages of polycythemia vera (PV), when not all stringent clinical
      criteria are completely fulfilled, a more refined analysis of morphological
      features helps to distinguish autonomous (PV) from spurious or secondary
      erythrocytosis - polyglobuly (PG). PV is characterized by a panmyelosis, i.e., a
      trilinear proliferation of all cell lineages, whereas in PG erythropoiesis
      predominates. Megakaryopoiesis exerts a significant impact on differentiation,
      because in PV there is a conspicuous grouping associated with a strikingly
      expressed pleomorphous appearance. This peculiar feature implicates assemblies of
      small- to medium-sized megakaryocytes lying adjacent to giant cells with
      extensively lobulated, staghorn-like nuclei. A further discriminating parameter
      is presented by the interstitial lesions frequently occurring in PG. These,
      according to the usually underlying inflammatory cause (chronic bronchitis
      recurrent bronchopneumonias), include iron-laden macrophages, a prominent
      perivascular plasmacytosis, phagocytosis of cell debris by histiocytic reticular
      cells and often an in- crease in the number of eosinophils. Comparable findings
      are not, or only to a minor ex-tent, detectable in PV. In conclusion, by
      regarding hematopoiesis and the myeloid stroma initial stages of PV may be
      definitively distinguished from PG.

PMID- 10663667
TI  - [Thrombocytosis versus thrombocythemia--differential diagnosis of elevated
      platelet count].
AB  - Differentiation of an elevated, repeatedly determined platelet count (> or
      =500x10(9)/l) includes the discrimination between reactive causes generated by a
      variety of underlying conditions and a neoplastic myeloproliferative disorder
      (CMPD). In addition to clinical findings, the evolution of laboratory data during
      follow-up and histology of the bone marrow exerts a significant diagnostic
      impact. Characteristic features are not only expressed by hematopoiesis, but also
      by the myeloid stromal compartment. While the megakaryocyte-rich subtype of
      chronic myeloid leukemia (CML) and the 5q(-) syndrome (MDS) are dominated by
      abnormal micromegakaryocytes, in polycythemia vera (PV) this cell lineage reveals
      a pleomorphous appearance. In essential thrombocythemia (ET), a prevalence of
      giant megakaryocytes with deeply lobulated (staghorn-like) nuclei may be
      encountered. A clear-cut discrimination of ET from early (hypercellular) stages
      of idiopathic (primary) myelofibrosis (IMF) presenting with thrombocythemia
      becomes possible, provided the conspicuous atypical features of megakaryopoiesis
      characterizing the latter entity are taken into account. Moreover, CML displays a
      predominance of the granulocytic lineage whereas PV shows a panmyelosis or
      trilineage proliferation, involving erythropoiesis, in particular. In contrast,
      erythropoiesis is markedly reduced in CML and to a lesser degree also in IMF. In
      CMPDs extreme values of iron deposits may be found, ranging from a total lack
      (PV) to minor amounts (CML) and a normal staining reaction (ET). Similar results
      are exhibited regarding reticulin fibrosis, which is usually not present in ET,
      rarely observed in PV and detectable to a variable degree in CML and IMF.

PMID- 10663668
TI  - [Histologic and hematological findings in CML. A comparative immunohistochemical
      morphometric and clinical study on bone marrow biopsies from 604 patients derived
      from two institutes of pathology (Cologne/Freiburg)].
AB  - An immunohistochemical and morphometric study was performed on bone marrow
      biopsies in 604 patients with chronic myelogenous leukemia (CML) to compare
      morphological and clinical features and to evaluate effects of interferon (IFN)
      and chemotherapy. Following morphometry significant correlations were calculated
      between number of CD61(+) megakaryocytes, including their precursors with fiber
      density. This finding is in line with the close functional relationship between
      megakaryopoiesis and fibroblasts regarding the complex pathomechanism of
      myelofibrosis. The latter was observed in about 28% of patients already at
      diagnosis. In a similar way, the frequency of CD68(+) macrophages was correlated
      with the amount of Ret40f(+) nucleated erythroid precursors, implicating an
      involvement of this cell lineage in iron turnover, hemoglobin synthesis, and
      degradation of the expelled nuclei from normoblasts. The (alpha-D-galactosyl
      residue-expressing) Pseudo-Gaucher cells were detectable in 30% of pretreatment
      specimens. Moreover, significant associations were calculable between reduction
      in erythropoiesis or increase in fibers with clinical features such as hemoglobin
      level, percentages of myelo- and erythroblasts in the peripheral blood, and
      spleen size. These variables are in keeping with more advanced stages of CML.
      Based on our morphometric evaluations, a classification into three different
      histological subgroups: granulocytic, megakaryocytic, and myelofibrotic was
      carried out. This simplified staging system was correlated with corresponding
      sets of hematological data. Sequential biopsies in 173 patients with monotherapy
      by IFN, hydroxyurea (HU), or busulfan (BU) revealed a fibrogenic effect of IFN in
      contrast to a fiber-reducing property of HU. The dynamics of myelofibrosis and
      changes of major cell lineages during treatment were readily demonstrable by
      calculating corresponding indices. These included the ratios between quantitative
      differences of corresponding variables at repeated examinations and time. Thus,
      in patients with complete hematological remission following IFN administration,
      regeneration of erythropoiesis was found to be accompanied by an increase in the
      total number of CD68(+) macrophages, including activated subpopulations.
      Histological subgroups showed a transition from a (nonfibrotic) granulocytic and
      megakaryocyte pattern to the myelofibrotic subtype in about 40% of patients. This
      change was opposed to a numerical reduction in the myelofibrotic subtype which
      occurred in 17 patients (36%), but predominantly in those under HU therapy. In
      conclusion, the striking heterogeneity of bone marrow features in CML warrants a
      careful morphological evaluation of trephine biopsies and appropriate means of
      processing to achieve relevant correlations with clinical data and, thus, allows
      a more elaborate insight into the dynamics of the disease process.

PMID- 10663669
TI  - [Apoptosis and proliferation in the bone marrow of chronic myeloproliferative
      disorders--biological and prognostic importance].
AB  - Apoptosis and proliferation are important regulators of normal development and
      homeostasis in the bone marrow. Therefore, dynamics of hematopoiesis is mainly
      defined by these two parameters. However, since only few data are available from
      previous studies, we performed a retrospective analysis to elucidate some aspects
      of this complex pathomechanism. A total of 400 patients with chronic
      myeloproliferative disorders (CMPDs) and corresponding reactive bone marrow
      lesions were enrolled into this study. Apoptosis was detected in bone marrow
      tissue by the ISEL-technique and topoisomerase II alpha expression was
      demonstrated by the monoclonal antibody Ki-S1. Furthermore, by determination of
      the proliferating-cell nuclear antigen labeling (PCNA) index, we were able to
      calculate the proportion of cells in the G2/M phase, because both nuclear
      antigens are expressed in different phases of the cell cycle. Patients with IMF,
      PV, and ET revealed a normal range of apoptosis, whereas in chronic myeloid
      leukemia (CML) a significant increase could be observed. On the other hand, IMF
      and PV were characterized by a raised proliferative activity. Dynamics of
      hematopoiesis was assessed by calculation of the so called hematopoietic turnover
      index. In CML and reactive lesions no alterations of this parameter were
      detectable, but IMF and PV showed a significant increase. Survival analysis
      disclosed a relevant worsening of life expectancy for patients with reduced
      apoptosis and proliferation. In conclusion, our in-situ results confirm and
      extend previous experimental data on hematopoietic cell kinetics. In this
      context, a greater regenerative capacity of hematopoiesis may be reflected by an
      increased rate of apoptosis and/or proliferation and therefore is associated with
      a more favorable outcome.

PMID- 10663670
TI  - [Prognostic factors and survival in chronic myeloproliferative disorders].
AB  - The broad spectrum of clinical and hematological as well as histomorphological
      findings at diagnosis of chronic myeloproliferative disorders (CMPDs) is
      significantly associated with prognosis. However, in this context the impact of
      bone marrow histology is still being controversially discussed. This feature
      applies to CML in particular. Therefore, risk classification is mainly based on
      clinical data. In order to evaluate the predictive value of bone marrow
      morphology we performed a retrospective study on a total of 1023 patients with
      CMPDs. Relative survival rates and a disease-specific loss of life expectancy
      were calculated to adjust the age- and gender-specific mortality in older
      patients. Patients with chronic myeloid leukemia (CML) showed an average life
      expectancy of 5 years, with significantly longer survival times under interferon
      treatment. In contrast, the ET group did not disclose any relevant reduction in
      life expectancy. Initial bone marrow fibrosis and a reduction in erythropoiesis
      were the most important prognostic features in CML. Furthermore, Pseudo-Gaucher
      cells indicated a favorable outcome in the cohort of patients receiving
      chemotherapy. On the other hand, peripheral myelo- and erythroblasts were
      correlated with a worsening in survival. Regarding IMF, a simplified multivariate
      risk score was constructed, including age, hemoglobin level, platelet and
      leukocyte counts, and a leuko-erythroblastic blood picture as most important
      variables. The three risk groups derived showed significantly different survival
      patterns, but in this calculation bone marrow histology exerted no major
      influence on survival. On the other hand, initial (prefibrotic) stages of IMF
      revealed a better prognosis. In conclusion, our results underline the importance
      of bone marrow morphology in CMPDs, since significant correlations with patients'
      outcome were calculated. Particularly in CML, myelofibrosis and reduction of
      erythropoiesis were associated with survival and, thus, must be regarded as
      important predictive and independent parameters.

PMID- 10663672
TI  - [Granulocytic sarcoma (so-called chloroma) as a possible cause of spinal cord
      compression. Case report and differential diagnosis].
AB  - Granulocytic sarcomas (so-called chloromas) are rare extramedullary tumorlike
      proliferates of myelogenous precursor cells that may de novo precede acute
      leukemia or coincide with the first manifestation or relapse of acute myeloid
      leukemia. Rarely, such tumors represent the initial manifestation of a blast
      crisis in the course of a chronic myeloproliferative disease, such as chronic
      myeloid leukemia. If they occur in aleukemic patients incorrect diagnoses may
      result. Differential diagnostic considerations are being discussed by presenting
      the case of a 58-year-old man who experienced spinal cord compression by an
      isolated epidural mass lesion.

PMID- 10663671
TI  - [Morphology, DNA cytophotometry and prognosis in gastrointestinal neuroendocrine
      tumours (carcinoids). A clinico-pathological study of 95 patients].
AB  - A total of 123 manifestations (97 primary tumours and 26 metastases) of
      neuroendocrine tumours of the gastrointestinal tract observed in 95 patients was
      investigated for the prognostic value of clinical, histological and DNA
      cytophotometric parameters. Metastases almost exclusively occurred among ileal
      carcinoids, which also were responsible for all 14 cases of lethal outcome
      observed during the follow-up period of mean 42 months. Aneuploid DNA values
      could be determined significantly more frequently among ileal than in non-ileal
      carcinoids and showed - upon analysis of the total group of gastrointestinal
      neuroendocrine tumours - a significant correlation to lethal course of disease.
      In addition, among 18 cases with primary and secondary carcinoid manifestations
      available for DNA cytophotometry, an association between the DNA content of
      metastatic neuroendocrine tumours and prognosis came to light. When applied to
      the group of ileal neoplasms, however, the parameter DNA content did not allow a
      better prognostic assessment.

PMID- 10663673
TI  - [Morphology of neurological complications of intravascular lymphomatosis].
AB  - Intravascular lymphomatosis (IVL) is a rare lymphoproliferative disease
      characterized by intravascular growth of lymphoma cells in small vessels. Most
      frequently, its first manifestations occur in the central nervous system or skin.
      Based on autoptical findings in a 68-year-old-man with IVL, the pathological
      morphology in the central nervous system is compared to the course of
      neurological symptoms. The disease could not be diagnosed during his lifetime.
      The spectrum of neurological deficits can be explained histopathologically by
      occlusive intravascular aggregations of lymphomatous cells in small vessels of
      the spinal leptomeninges and nerve roots causing perfusion deficits and areas of
      ischemic necrosis of up to 4 mm in diameter in the medulla. Aggregations of
      lymphoma cells in the vessels of other organs are also found, but did not result
      in clinical symptoms. In reference to the present case, a survey of other
      literature reports on IVL with neurological and psychiatric manifestations is
      given. In patients with this condition, even an invasive biopsy has to be
      considered in order to make the correct diagnosis at an early clinical stage.

PMID- 10663674
TI  - [Orientation aids in biopsy specimens].
AB  - Histological findings as regards localizing a lesion suspected to be a tumor and
      its relation to the margins of a surgical specimen have to be as precise as
      possible and beyond all doubt. We report on our experience with two technical
      tools which are especially helpful in excisions of breast tissue: 1) Radiopaque
      suture material fixed intraoperatively simplifies the correlation of
      postoperative mammography, X-ray findings with biopsy specimens. 2) AgNO(3), as a
      solution or in stick form, is faster than ink or other dyes, in marking the
      margins in small or large surgical specimens because virtually no drying is
      required.

PMID- 10663675
TI  - [ [In Process Citation]

PMID- 10663676
TI  - [ [In Process Citation]

PMID- 10663677
TI  - [ [In Process Citation]

PMID- 10663678
TI  - [ [In Process Citation]

PMID- 10663679
TI  - [ [In Process Citation]

PMID- 10663680
TI  - [ [In Process Citation]

PMID- 10663681
TI  - [ [In Process Citation]

PMID- 10663682
TI  - [ [In Process Citation]

PMID- 10663714
TI  - MR imaging of the heart: functional imaging.
AB  - To date, most applications of cardiovascular MRI relate to the evaluation of
      major vessels rather than the heart itself. However, MRI plays a major role in
      the evaluation of specific types of cardiovascular pathology, namely intracardiac
      and paracardiac masses, pericardial disease, and congenital heart disease. In
      addition, because the visualization of cardiovascular anatomy with MR is non
      invasive and permits three-dimensional analysis but also allows functional
      assessment of the cardiac pump, it is clear that MRI will have a growing and
      significant impact over the next years. We review some of the technical aspect of
      cardiac MRI and describe the current and potential clinical and investigative
      applications of this new methodology.

PMID- 10663713
TI  - Evaluation of congenital heart disease by magnetic resonance imaging.
AB  - Magnetic resonance imaging has proven to be useful in the assessment of patients
      with complex congenital heart disease and in the post-surgical follow-up of
      patients with corrected congenital heart disease. A thorough understanding of the
      congenital cardiac malformations that can be encountered is needed and the use of
      the sequential segmental analysis helps to standardize the evaluation and
      diagnosis of (complex) congenital heart disease. After surgical correction of
      congenital heart defects, patients must be followed over extended periods of
      time, because morphological and functional abnormalities may still be present or
      may develop. The use of echocardiography may be hampered in these patients as
      scar tissue and thorax deformities limit the acoustic window. Magnetic resonance
      imaging has proven to be advantageous in the follow-up of these post-surgical
      patients and with the use of several different techniques the morphological as
      well as functional abnormalities can be evaluated and followed over time.

PMID- 10663715
TI  - Coronary arteries.
AB  - Coronary angiography (CA) is presently considered the gold standard for the
      assessment of the coronary arteries. However, the presence of ionizing radiation,
      its invasiveness and the small associated risk of morbidity prompted long ago the
      development of more patient-friendly imaging modalities. A promising technique,
      magnetic resonance imaging (MRI), has been regarded as the major modality in the
      coming decade. Although still in its infancy qualitatively, its flexibility and
      non-invasiveness opens the door for a comprehensive evaluation of the heart and
      the coronary arteries in one single sitting with high anatomical definition and
      excellent soft tissue contrast capabilities, double-oblique tomographic sections
      and the possibility to quantify an innumerable number of cardiovascular
      physiological parameters. Numerous ideas have been assessed, comprising breath
      hold and free-breathing two-dimensional and three-dimensional measurements. New
      ongoing trials with intravascular contrast agents may provide for all these
      techniques the long-awaited essential boost for reliable magnetic resonance
      coronary angiography (MRCA). Introduction of parallel MRI acquisition techniques,
      such as simultaneous acquisition of spatial harmonics (SMASH) and sensitivity
      encoding (SENSE) may provide the speed enhancement required to shorten imaging
      time for all techniques explored to date.

PMID- 10663716
TI  - Interventional MRI of the breast: lesion localisation and biopsy.
AB  - With the growing use of breast MRI an increasing need exists for reliable MR
      guided preoperative localisation or even MR-guided needle biopsy. In this article
      an overview is given of the different approaches and the present state of the
      art. With closed magnets the following approaches have been made: freehand
      localisation (similar to CT-guided freehand localisation), and freehand
      localisation combined with a frameless stereotaxic system operating with support
      by ultrasound. One localisation device for supine localisation and a
      thermoplastic mesh for breast stabilisation have been reported. Most
      investigators have used compression devices to immobilize the breast and prevent
      shift during needle insertion. Thus far, one immobilisation and aiming device has
      been designed for open magnets. A small number of experiences exist with
      interventions on open MR units using a navigation system. Wire localisations are
      presently a well-established procedure. Magnetic-resonance-guided needle biopsy
      has been accomplished in closed systems as well as by the use of breast
      immobilisation devices. However, problems still exist due to severe needle
      artefacts, tissue shift during the intervention and fast equalization of contrast
      enhancement in lesions with surrounding tissue. Therefore, needle biopsy is not
      recommended for lesions < 10 mm. Magnetic-resonance-guided vacuum biopsy is
      somewhat more invasive but promises to solve most of these problems.

PMID- 10663717
TI  - MRI of breast tumors.
AB  - Breast MRI is increasingly used as an adjunct to conventional imaging modalities,
      particularly in diagnostic problem cases, but also for pre-operative staging. It
      is an extremely sensitive technique, with relatively limited specificity. To
      avoid both, false-positive, but particularly false-negative diagnoses, it is
      imperative to be familiar with the varying MRI appearance of benign and malignant
      breast tumors. This review serves to give an overview of the different criteria
      that can be used for differential diagnostic purposes. Moreover, practical
      guidelines are given to help with the adequate management of enhancing lesions.

PMID- 10663718
TI  - Interventional MRI of the breast: minimally invasive therapy.
AB  - In recent years a variety of minimally invasive therapies have been applied to
      the treatment of breast lesions. These therapies include thermal treatments
      (interstitial laser coagulation, focused ultrasound, radiofrequency and
      cryotherapy), percutaneous excision, and interstitial radiotherapy. Magnetic
      resonance has been used in these treatments to visualize lesions before, during
      and after therapy and to guide interventions. "Temperature-sensitive" sequences
      have shown changes with thermal ablation which broadly correlate with areas of
      tumour necrosis. Consequently, MR has the potential to monitor treatment at the
      time of therapy. To date, experience in the treatment of breast cancer has been
      restricted to small studies. Large controlled studies are required to validate
      the efficacy and safety of these therapies in malignant disease.

PMID- 10663719
TI  - Gleno-humeral instabilities.
AB  - The purpose of this review is to highlight the most efficient imaging exploratory
      techniques depicting shoulder instability, to describe its various forms and to
      point out the findings which can simulate instability. In anterior recurrent
      dislocation, surgery is indicated and the procedure essentially depends on the
      importance of glenoid rim lesions. In this case, a standard X-ray evaluation is
      usually sufficient. The CT arthrography or MRI techniques give more specific
      details as to the severity of the lesions, particularly soft tissues alterations;
      however, these data do not alter standard therapeutic protocol. In fixed
      posterior dislocations, CT scan represents the most pertinent technique to
      evaluate the size of the humeral head defect and to determine the therapeutic
      follow-up. In subtle forms of instability, diagnosis or instability direction are
      not clearly assessed clinically and standard X-ray evaluation is usually
      unremarkable. In this case, further exploration, such as CT arthrography, MR
      imaging or MR arthrography, are recommended to confirm the diagnosis of
      instability and to evaluate its direction. The technique of choice is undoubtedly
      MR arthrography. Atraumatic voluntary painless subluxations associated with
      hyperlaxity of the shoulder do not require any specific exploratory method
      because the findings are generally limited to a capacious axillary pouch.

PMID- 10663720
TI  - MR arthrography of the hip: normal intra-articular structures and common
      disorders.
AB  - This pictorial review illustrates the anatomical features of normal intra
      articular components of the hip and their common disorders on MR arthrography. On
      T1-weighted MR arthrograms, the normal contrast-filled joint cavity shows a
      homogeneous high signal intensity. Normal acetabular labrum appears as a well
      delineated triangle showing a low signal intensity, surrounded by contrast
      material in the perilabral recess. Intra-articular paramagnetic contrast outlines
      labral tears, loose bodies, communicating labral cysts and cartilage lesions
      (traumatic tears, focal defects, degenerative fissures and thinning), and
      improves their detection. Overall, MR arthrography enables accurate detection and
      staging of hip intra-articular structure abnormalities.

PMID- 10663721
TI  - Pelvic digit: an uncommon developmental anomaly.
AB  - The radiological features of seven cases of pelvic digit discovered incidentally
      on plain radiographs are described and differentiation from other causes of new
      bone formation is discussed. Its recognition as a benign anomaly is important to
      avoid unnecessary investigation or intervention. An embryological theory of
      development of pelvic digit is proposed.

PMID- 10663722
TI  - Vertebral sarcoidosis: imaging findings.
AB  - Sarcoidosis is a multisystemic disease of unknown aetiology characterised by
      noncaseating granulomatous inflammation with varying presentation and prognosis.
      Osseous disease reported in 1-13 % of cases commonly involves hands and feet;
      however, vertebral sarcoidosis is rare. This report describes the radiologic, CT,
      MRI and radionuclide imaging findings of vertebral involvement of a case with
      sarcoidosis.

PMID- 10663723
TI  - Discriminatory power of MRI for differentiation of adrenal non-adenomas vs
      adenomas evaluated by means of ROC analysis: can biopsy be obviated?
AB  - The purpose of our study was to evaluate the discriminatory power of MRI in high
      field magnet (1.5 T) for differentiation of adrenal non-adenomas vs adenomas
      assessing the following parameters separately and in combination: mean diameter
      of adrenal mass; previously described and new ratios as well as index calculated
      from signal intensity (SI) on SE T2-weighted images, chemical shift imaging
      (CSI), and Gd-DTPA-enhanced dynamic studies. One hundred eight adrenal masses (36
      non-hyperfunctioning adenomas, 27 pheochromocytomas, 23 aldosterone-secreting
      adenomas, 20 malignant masses and 2 cortisol-secreting adenomas) in 95 patients
      were evaluated with SE sequences, CSI and Gd-DTPA dynamic studies. Indices and
      ratios of SI for all examined MRI methods were calculated and examined
      retrospectively for significance of differences between the groups with
      calculation of sensitivity and specificity. Receiver operating characteristics
      (ROC) analysis of calculated parameters in combination was performed. The
      multifactorial analysis of all four parameters, including size of the tumor,
      T2(liver) index, CSI ratio reflecting lipid content in the tumor and Wo(max/last)
      ratio reflecting maximal washout of contrast agent from the tumor had 100 %
      sensitivity and 100 % specificity in characterization of adrenal non-adenoma. The
      best performance of combination of mean tumor diameter with single MRI SI
      parameter was achieved in combination with T2(liver) index for all adrenal masses
      (area under ROC 0.987) and CSI ratio for non-hyperfunctioning adrenal masses
      (area under ROC 0.991). Magnetic resonance imaging enables sensitive and specific
      diagnosis of adrenal non-adenoma.

PMID- 10663724
TI  - Ruptured adrenal artery aneurysm: a case report.
AB  - A case of ruptured adrenal artery aneurysm is presented. The ultrasound, computed
      tomography and selective renal angiography findings are described in detail.
      Aneurysms of adrenal arteries are particularly rare. Early diagnosis is important
      because of their tendency towards rupture and subsequent high mortality rate.

PMID- 10663725
TI  - Spontaneous pneumothorax and pneumomediastinum in IPF.
AB  - Patients with idiopathic pulmonary fibrosis (IPF) are at risk for a variety of
      acute pulmonary complications, including pneumothorax and pneumomediastinum. Our
      aim was to describe the radiographic and CT findings and to determine the
      frequency of complicating spontaneous pneumothorax and pneumomediastinum in
      patients with IPF. A retrospective study was performed including 78 consecutive
      patients who underwent CT scanning of the chest and who had confirmed IPF. The
      chest radiographs and CT scans were reviewed by two chest radiologists and
      classified as showing features of extra-alveolar air collections. The CT scans
      showed extra-alveolar air in 9 (11.2 %) of 78 patients (six females and three
      males; age range 26-90 years, mean age 65 years). Pneumothorax was demonstrated
      in 5 patients and mediastinal air collections in 4 patients. All patients had
      dyspnea for 1-48 months (mean 14 months). Of the five cases with pneumothorax,
      four developed acute onset of dyspnea and pleuritic chest pain, whereas 1 patient
      had a relatively stable functional status. Of the 4 patients with
      pneumomediastinum, three presented with nonpleuritic chest pain and acute
      dyspnea. Chest radiographs showed extra-alveolar air in 6 patients. Three cases
      were predicted to be negative by chest radiographs. Follow-up CT showed that air
      collections had resolved completely in 5 patients. Two patients died of
      respiratory failure within 4 months after CT. Extra-alveolar air should be
      recognized as a relatively common IPF-related complication. Chest CT is a useful
      imaging method in determining air collections in patients with IPF that become
      acutely breathless and their chest radiograph fails to reveal the presence of
      extra-alveolar air.

PMID- 10663726
TI  - High-resolution magnetic resonance and volume rendering of the labyrinth.
AB  - Our aim was to verify the feasibility of volume rendering (VR) of high-resolution
      magnetic resonance (HR-MR) data sets of the labyrinth. We retrospectively
      reviewed the HR-MR data sets of 16 consecutive patients with no MR evidence of
      labyrinthine pathology. High-resolution MR data sets were obtained by means of a
      3D T2-weighted FSE sequence with the use of a 3-in. circular surface coil for
      signal reception, and processed with a high-end workstation. Two reviewers
      performed separately VR of the labyrinth by selecting the signal intensity
      interval for attribution of opacity and transparency. Concerning the time taken
      for definition of the volume of interest, the two observers needed, respectively,
      28.9 and 33.1 min (SD +/- 8.7-9.5 min), whereas the time taken for VR was
      respectively, 26 and 33.2 min (SD +/- 8.8-8.9 min). Concerning the selection of
      the signal intensity interval, the two observers had, respectively, 86.4 and 88.7
      mean lower threshold (SD +/- 34.5-33.5), 488.9 and 495.4 mean upper threshold (SD
      +/- 56.3-53.8). In our experience, we have found VR of HR-MR to offer a reliable
      and reproducible technique for producing 3D representations of the labyrinth. The
      VR algorithms use all data within the imaging volume and optimize the dynamic
      range ascribed to the object being visualized.

PMID- 10663727
TI  - Computed tomography of the small bowel in adult celiac disease: the jejunoileal
      fold pattern reversal.
AB  - The aim of this retrospective study was to establish whether the distinctive
      intestinal fold pattern of celiac disease (CD), known by barium studies as
      jejunoileal fold pattern reversal (JFPR) may be recognized at CT. The number of
      intestinal folds per 2.5 cm, seen at CT, were counted in the jejunum and in the
      ileum of 22 adult patients with CD and compared with the folds of 30 consecutive
      subjects in whom an intestinal disease had been excluded. The results were
      submitted to statistical analysis by Student's t-test. In the control group the
      number of folds per 2.5 cm were 4.88 (SD +/- 0.78) in the jejunum and 2.84 ( +/-
      0.62) in the ileum; in the CD group the number of folds were 2.42 ( +/- 1.61) in
      the jejunum and 5.11 ( +/- 1.24) in the ileum. There was a statistically
      significant difference in the number of jejunal and ileal folds between the CD
      patients and the control group (in both cases p < 0.001). The JFPR was seen in 15
      patients with CD (68.2 %) but in none of the controls. Our study shows that JFPR
      is not a normal finding and can be demonstrated by CT in the majority of patients
      with CD.

PMID- 10663728
TI  - Postoperative findings following the Whipple procedure: determination of
      prevalence and morphologic abdominal CT features.
AB  - This study was conducted to determine characteristic CT findings following the
      Whipple procedure and to evaluate the usefulness of CT in predicting tumor
      recurrence. Eighty-four postoperative abdominal CT scans and medical records of
      43 patients were retrospectively reviewed. Perioperative histopathologic
      examinations revealed malignancy in 32 patients (74.4 %). Time interval between
      surgery and CT varied from 13 days to 6 years and 7 months. Common postoperative
      findings were unopacified anastomotic bowel loops in the porta hepatis (n = 69
      scans), perivascular cuffing (n = 42 scans), pneumobilia (n = 40 scans), dilated
      intrahepatic bile ducts (n = 22 scans), reactive lymphadenopathy (n = 21 scans),
      and transient fluid collections (n = 20 scans). Postoperative complications were
      detected on 17 CT scans (20.2 %): generalized ascites (n = 8 patients), deep
      abscesses (n = 3 patients), wound abscess (n = 1 patient), pancreatitis (n = 1
      patient), and pseudomembranous colitis (n = 1 patient). Tumor recurrence appeared
      in 15 patients (46.8 %) after a mean postoperative period of 11 months (1 month
      to 3 years): local (9 of 15), regional lymph nodes (9 of 15), and liver
      metastasis (8 of 15). Detection of generalized ascites more than 30 days after
      surgery was associated with tumor recurrence in 6 of 6 patients (100 %). Diffuse
      ascites (> 30 days after surgery) behaved as an early predictive sign of tumor
      recurrence. In our series CT accuracy for detecting recurrent tumor with CT was
      93.5 %. No predilection site for disease recurrence could be determined.

PMID- 10663729
TI  - Hepatic hemangiosarcoma: imaging findings and differential diagnosis.
AB  - Primary hepatic angiosarcoma is a rare mesenchymal tumor of the liver that
      usually presents with nonspecific symptoms in elderly men. We present four cases
      of hepatic hemangiosarcoma and discuss the imaging characteristics of this
      entity. Our series shows that this tumor is not uncommon in younger patients with
      no associated risk factors such as previous exposure to thorotrast or vinyl
      chloride. Our experiences on a limited number of patients suggests that the
      combined use of angiography and dual-phase helical CT provides a better
      identification of the tumor and its complications. Analysis of imaging studies in
      patients with hepatic hemangiosarcoma reveals hypervascular lesions. Common
      complications were portal vein thrombosis, Budd-Chiari syndrome, as well as
      arterio-venous or arterio-portal shunts. Due to the vascularity of the tumor,
      percutaneous liver biopsy is hazardous.

PMID- 10663730
TI  - Imaging of diffuse esophageal leiomyomatosis: two case reports and review of the
      literature.
AB  - Diffuse esophageal leiomyomatosis is a rare disorder which may be found in
      association with leiomyomas in other locations or with other disorders. We report
      two cases in men, one with associated tracheobronchial involvement, which
      illustrate the value of imaging in differentiating this entity from other causes
      of dysphagia and in establishing a diagnosis.

PMID- 10663731
TI  - Colonic metastasis from renal cell carcinoma: helical-CT demonstration.
AB  - Clinically evident colonic metastasis from renal cell carcinoma (RCC) is rare. In
      the present study a hypervascular sigmoid mass was demonstrated on arterial-phase
      helical CT using a water enema in a patient who had suffered left nephrectomy 8
      years previously for RCC. The intense and early enhancement of the lesion
      suggested the possibility of a solitary colonic metastasis from RCC, a diagnosis
      which was pathologically confirmed.

PMID- 10663732
TI  - Post-traumatic recto-spinal fistula.
AB  - Acquired recto-spinal fistula has been described elsewhere as a rare complication
      of colorectal malignancy and Crohn's enterocolitis. We treated a young man who
      developed a recto-spinal fistula as a result of a high fall injury. The patient
      presented with meningeal signs, sepsis and perianal laceration. Computerized
      axial tomography revealed air in the supersellar cistern. Gastrografin enema
      showed that contrast material was leaking from the rectum into the spinal canal.
      Surgical management included a diverting sigmoid colostomy, sacral bone curettage
      and wide presacral drainage. To the best of our knowledge, rectospinal fistula of
      traumatic origin has not been previously reported in the English literature.

PMID- 10663733
TI  - Unusual causes of spinal foraminal widening.
AB  - Spinal neural foraminal widening is usually caused by benign lesions, most
      commonly neurofibromas. Rare lesions can also cause spinal neural foraminal
      widening. Computed tomography and/or MRI are the modalities of choice for
      studying the spinal foraminal widening. The present pictorial review describes
      six rare lesions, namely a lateral thoracic meningocele, a malignant fibrous
      histiocytoma, a tuberculous abscess, an osteoblastoma, a chondrosarcoma and a
      malignant tumour of the lung which caused spinal neural foraminal widening.

PMID- 10663734
TI  - Moyamoya disease mimicking a spontaneous internal carotid artery dissection on
      Doppler ultrasound.
AB  - Moyamoya disease and spontaneous internal carotid artery dissections are rare
      conditions, but both tend to affect young adults with potentially devastating
      consequences. A 43-year-old non-Japanese patient presented with neurological
      symptoms, which, following carotid Doppler ultrasound and angiography, was
      labelled as being due to a spontaneous internal carotid artery dissection. Repeat
      imaging at 3 months showed normalisation of the carotid Doppler findings which
      coincided with the formation of "moyamoya" vessels on the angiogram. This case
      report illustrates the changes on carotid ultrasound in early moyamoya disease
      which may mimic the appearances of an internal carotid artery dissection and
      demonstrates the change of the spectral Doppler waveform that occurs with the
      formation of new vessels at the base of the brain.

PMID- 10663736
TI  - Size, node status and grade of breast tumours: association with mammographic
      parenchymal patterns.
AB  - A case-control study was designed to assess the association of mammographic
      parenchymal patterns with the risk of in-situ and invasive breast cancer. In
      addition, the relationship between tumour characteristics and mammographic
      patterns were also investigated. A total of 875 patients with breast cancer were
      selected and matched with 2601 controls. Mammographic parenchymal patterns of
      breast tissue were assessed according to Wolfe's classification, and statistical
      analysis was by conditional logistic regression. Relative to the N1 pattern, the
      odds ratios of having an invasive breast cancer associated with the P2 and DY
      patterns were 1.8 and 1. 4, respectively. In addition, the odd ratios of having
      an invasive grade 3 breast cancer associated with the P2 and DY patterns were 2.
      8 and 3.9, respectively. Relative to the combined N1/P1 pattern, the odd ratios
      of having a breast cancer smaller than 14 mm, 15-29 mm, or larger than 30 mm
      associated with the combined high-risk P2/DY pattern (P2 + DY) were 1.2, 1.6, and
      2.0, respectively. Finally, women with the P2/DY pattern were twice as likely to
      have a breast cancer which had already spread to the axillary nodes, compared to
      women with women with the N1/P1 pattern (odds ratios of 2.1 and 1.4,
      respectively). Our results confirm previous findings suggesting that mammographic
      parenchymal patterns may serve as indicators of risk for breast cancer. Our
      results also suggest that mammographic parenchymal patterns are associated with
      the stage at which breast cancer is detected.

PMID- 10663735
TI  - CT and MR imaging of the "target sign" in metastatic brain disease.
AB  - The "target sign" is a common finding in granulomatous infection. A case with the
      target sign in metastatic brain tumor from small cell lung carcinoma is reported.

PMID- 10663737
TI  - A multipurpose phantom for quality assurance of contrast-enhanced MR imaging of
      the breast.
AB  - A phantom consisting of four components was developed to simulate contrast
      enhanced MR imaging of the breast. These components included the correlation
      between the signal intensity and the contrast medium concentration, the
      uniformity of signals within surface coils, artefacts due to opposed-phase
      imaging effects, spatial resolution and the acquisition of relevant signal-to
      time curves. Repetitive measurements demonstrated an excellent reproduction of
      phantom imaging with a deviation in signal intensity of approximately 5 %. The
      presented phantom allows the optimization of examination protocols as well as the
      comparison of different examination techniques. Furthermore, it enables the
      routine quality monitoring of contrast-enhanced MR imaging of the breast.

PMID- 10663738
TI  - Technical aspects of venous stenting in high-grade stenoses using a long
      guidewire between dual venous access sites.
AB  - We describe the technical benefits of the dual-access technique for venous
      stenting in high-grade stenosis. Stents were implanted successfully with this
      technique in all patients, although the preceding transfemoral interventions had
      failed. The dual-access technique is useful to facilitate the intervention when
      the stenoses are too severe to place the stent through just a single access
      point.

PMID- 10663739
TI  - Solitary myofibromatosis of the skull.
AB  - We present a case of solitary infantile myofibromatosis of the skull in a 3-month
      old boy. A right parietal subcutaneous lump was found at birth, and it increased
      in size over the ensuing 3 months. Surgery was performed, and a diagnosis of
      myofibromatosis was confirmed histopathologically. Solitary myofibromatosis of
      the skull is extremely rare. The radiographical, CT, and MR appearances, as well
      as histopathological findings, are described in this article.

PMID- 10663740
TI  - The RETAIN project: DICOM teleradiology over an ATM-based network. Radiological
      Examinations Transfer on an ATM Integrated Network.
AB  - The RETAIN project (Radiological Examinations Transfer on an ATM Integrated
      Network) has aimed at testing videoconferencing and DICOM image transfers to get
      advice about difficult radiological cases over an asynchronous transfer mode
      (ATM)-based network, which affords a more comfortable interface than narrow-band
      networks and allows exchange of complete image series using the DICOM format of
      studies. For this purpose, an experimental ATM network was applied between six
      university hospitals in four different countries. An assessment of the
      functionalities of the system was performed by means of log-file analysis, video
      recording of the sessions and forms filled out by the participants at the end of
      each session. Questionnaires were answered by the users at the end of the project
      to bring out perspectives of utilisation and added value. We discussed 43 cases
      during 20 sessions. For technical or organisational problems, only 20 of the 36
      planned sessions took place. The throughput over ATM (10.5 Mbit/s, 20 times
      faster than six ISDN B-channels) was adequate. Despite the experimental
      configuration of the network, the system was considered as satisfactory by all
      the physicians. In 72 % of the sessions, the expected result (answer to the
      question) was gained. By common consent, videoconferencing was unanimously
      regarded as a prominent tool in improving the interaction quality. Asynchronous
      transfer mode is an efficient method for fast transferring of radiologic
      examinations in DICOM format and for discussing them through high-quality
      videoconferencing.

PMID- 10663741
TI  - Virtual computed tomography colonoscopy: artifacts, image quality and radiation
      dose load in a cadaver study.
AB  - The purpose of our study was to evaluate the interdependency of spatial
      resolution, image reconstruction artifacts, and radiation doses in virtual CT
      colonoscopy by comparing various CT scanning protocols. A pig's colon with
      several artificial polypoid lesions was imaged after air insufflation with
      helical CT scanning using 1-, 3-, and 5-mm collimation, and pitch values varying
      from 1.0 to 3.0. Virtual endoscopic images and "fly through" sequences were
      calculated on a Sun Sparc 20 workstation (Navigator Software, GE Medical Systems,
      Milwaukee, Wis.). Several reconstruction artifacts as well as overall image
      quality were evaluated by three independent reviewers. In addition, radiation
      doses for the different CT protocols were measured as multiple-scan average dose
      using a 10-cm ion chamber and a standard Plexiglass body phantom. Generally,
      image quality and reconstruction artifacts were less affected by pitch values
      than by beam collimation. Thus, narrow beam collimation at higher pitch values
      (e. g. 3 mm/2.0) seems to be a reasonable compromise between quality of virtual
      endoscopic images and radiation dose load.

PMID- 10663742
TI  - Treatment of VX2 liver tumor in rabbits with "wet" electrode mediated radio
      frequency ablation.
AB  - Radio-frequency ablation (RFA) has been considered as an alternative therapy for
      liver tumors. A "wet" electrode with interstitial infusion of hypertonic saline
      was tested for the RFA of liver tumor in rabbits. Seventy-eight liver tumors (
      1.5 to 3.0 cm) were induced in 41 rabbits by VX2 carcinoma implantation. Fifty
      one tumors in 27 rabbits were treated with RFA. Under laparotomy, the RF energy
      was delivered while 5 % saline was infused through the electrode into the tumor
      at 1 ml/min. Six rabbits with 12 tumors were treated with only intratumoral 5 %
      saline infusion without RFA. Another 8 rabbits with 15 tumors received sham
      operation as untreated controls. The efficacy of the therapy was evaluated with
      survival rate, MRI, microangiography, and histopathology. In the RFA group, 6
      rabbits survived longer than 6 months (absolute eradication rate 22.2 %); 12
      rabbits were found free of viable tumor at the moment when they were sacrificed
      (relative eradication rate 44.4 %); 9 rabbits showed local tumor relapse and/or
      lung metastasis 2-10 weeks after ablation (recurrent rate 33.3 %). In control
      groups of saline infusion and sham operation, all 14 rabbits died within 3 months
      (mortality rate 100 %). Three-month survival rates between RFA group and control
      groups were significantly different (p < 0.05). Findings of MRI,
      microangiography, and histology supported these outcomes. Radical treatment of
      liver malignancy in rabbits is possible with the present modified RFA technique.
      Its clinical usefulness has to be further proven.

PMID- 10663743
TI  - Cerebellopontine angle lipoma with an incidental scalp lipoma in a patient with
      hemifacial spasm.

PMID- 10663744
TI  - MR of inferior vena cava extension of a kidney angiomyolipoma.

PMID- 10663745
TI  - Tattoo-related cutaneous inflammation (burn grade I) in a mid-field MR scanner.

PMID- 10663747
TI  - European society of musculoskeletal radiology (ESSR).Posters

PMID- 10663746
TI  - Quiz case of the month. Progressive lumbar pain irradiating over the right thigh.
      Diagnosis: schwannoma.

PMID- 10663748
TI  - Film reading session, ECR 2000, vienna

PMID- 10663749
TI  - Bone tumors.
AB  - We present an overview of the imaging modalities in bone tumors. The imaging
      strategies of preoperative work-up, monitoring the effect of chemotherapy and the
      detection of recurrences by long-term follow-up are discussed.

PMID- 10663750
TI  - Magnetic resonance imaging of soft tissue tumors.
AB  - This article outlines the ability of MR imaging in staging, grading, tissue
      characterization, and posttherapeutic surveillance of soft tissue tumors. Well
      known staging parameters, such as extent, relationship with adjacent structures,
      and detection of intralesional necrosis, are used in the MR protocol for
      locoregional staging. Bone scintigraphy and high-resolution CT scan of the lungs
      are best methods for ruling out metastatic spread. A variety of (solitary or
      combinations of) grading parameters are described in the radiological literature.
      The role of MR imaging is to afford recognition of these lesions that need
      further aggressive work-up, excluding all others. Despite controversial reports,
      the definite role of MR imaging in grading of soft tissue tumors seems to become
      established. As for grading, a lot of individual imaging characteristics used for
      tissue characterization have low sensitivity, but combinations of parameters
      (age, site, signal intensities) are more useful and often allow to predict a
      specific diagnosis or to narrow down the list of differential diagnoses. Local
      recurrences of soft tissue tumors are frequent and can be detected accurately by
      an easy-to-use MR algorithm.

PMID- 10663751
TI  - MRI of bone marrow disorders.
AB  - Four factors can be used in MR of bone marrow: fat-water distribution, artifacts
      induced by bone trabeculae, diffusion, and uptake of contrast media. Fat-water is
      imaged using T1-weighted spin-echo, short tau inversion recovery (STIR), and fast
      STIR, in- and out-of-phase gradient echo, and fat pre-saturation sequences; bone
      trabeculae by gradient echo with long TE; diffusion by single-shot spin-echo. The
      injection of contrast media is a more easy and efficient way to improve the
      specificity. The value and limitations of those sequences are discussed in marrow
      replacements (metastases, lymphoma, leukemia) and in myeloid hyperplasia or
      depletion.

PMID- 10663752
TI  - Musculoskeletal MR: knee.
AB  - Magnetic resonance imaging is the most sensitive, specific, and accurate
      noninvasive method for diagnosing internal derangement of the knee. During the
      past 15 years knowledge of pathologic conditions of the knee had evolved
      significantly. Beyond the basic principles of imaging knee injuries great impact
      was made on the understanding of indirect or collateral findings, even in rare
      diseases. In this article the spectrum of disorders of the knee are reviewed and
      an overview of the current literature is given. This includes considerations
      about how to achieve a high-standard MR imaging study of the knee, and principles
      of imaging anterior cruciate ligament and meniscal tears. A focus is put on
      distinct diseases including intra-articular and intraosseous ganglion cysts,
      iliotibial band friction syndrome, transient osteoporosis, osteonecrosis,
      osteochondritis dissecans, and imaging of the articular cartilage.

PMID- 10663753
TI  - MRI of the shoulder.
AB  - Shoulder imaging is one of the major applications in musculoskeletal MRI. In
      order to analyze the images it is important to keep informed about anatomical and
      pathological findings and publications. In this article MRI technique, anatomy
      and pathology is reviewed. Technical considerations about MR sequences and
      examination strategy are only shortly discussed with emphasis on turbo spin echo
      and short T1 inversion recovery imaging. Basic anatomy as well as recent
      findings, including macroscopic aspects of the supraspinatus fat pad, composition
      of the supraspinatus muscle belly, and variability of the glenohumeral ligaments
      or coracoid ligament, are presented. Basic pathological conditions are described
      in detail, e. g. instability particularly problems in differentiating the various
      subtypes of labral pathology. Rotator cuff diseases are elucidated with emphasis
      on some rarer entities such as subscapularis calcifying tendinitis, coracoid
      impingement, chronic bursitis producing the double-line sign, prominent coraco
      acromial ligament and the impingement due to an inflamed os acromiale.

PMID- 10663754
TI  - Musculoskeletal MRI: dedicated systems.
AB  - The "dedicated" MRI units have characteristics of high diagnostic accuracy and
      lower installation and management costs as compared with whole-body systems. The
      dedicated MRI units are easy to install. The low weight allows their installation
      also under unfavorable circumstances. In a dedicated system cost-effectiveness
      and ease of installation must be accompanied by the capability of providing high
      quality images. In our experience, the high number of examinations performed, the
      most part of which provided with the surgical controls, allowed an accurate
      evaluation of the diagnostic potentialities of the dedicated magnet. We were not
      able to perform the examinations in only 3 % of cases due to the physical shape
      of the patient and the clinical condition of the patient which may hinder the
      correct positioning of the limb. The overlapping of the diagnostic accuracy of
      the E-scan and Artoscan units in the study of the lower limbs, compared with
      whole-body units and surgery, prompted us to exploit the potentialities of the E
      Scan in the study of the shoulder. We had a good correlation between E-Scan,
      whole-body units, and surgical findings, which confirmed the high diagnostic
      accuracy of the dedicated system. In conclusion, in our experience carried out in
      the musculoskeletal system, the dedicated magnets showed promising results. Their
      diagnostic reliability and utility was comparable to that obtained from
      conventional units operating at higher magnetic fields.

PMID- 10663755
TI  - The role of MR imaging in invasive cervical carcinoma.
AB  - In this article the role of MR imaging in the management of cervical cancer is
      reviewed and illustrated. The appearance of the normal uterine cervix and of
      cervical carcinoma is shown. Important factors for optimal MR imaging of cervical
      carcinoma are reviewed. The value of MR imaging in the staging of cervical
      carcinoma is illustrated by showing parametrial invasion and lymph node
      involvement. Finally, the value of MR imaging staging is compared with clinical
      staging, CT staging, and surgical findings. The role of new imaging techniques,
      such as fast dynamic enhanced MR imaging, is described.

PMID- 10663756
TI  - Dilatation of the collecting system during pregnancy: physiologic vs obstructive
      dilatation.
AB  - Dilatation of the collecting system is a classical phenomenon during pregnancy,
      due to hormonal and extrinsic compressive factors. Imaging has to differentiate a
      physiological dilatation and a pathological obstruction due to urolithiasis.
      Presently, sonography, using both, B-mode and color Doppler, has the potential to
      demonstrate the physiological compression of ureters at the level of the pelvic
      brim. A pathological obstruction is considered either when a stone is detected
      above the usual site of compression or when the ureter appears dilated beyond.
      Color Doppler helps in localizing the site of ureteral compression against the
      vessels and in differentiating ureters from veins. Magnetic resonance urography,
      with strongly T2-weighted sequences, also may show the site and type of
      obstruction without contrast agent administration. These two non-radiating
      techniques make it possible to avoid the use of X-rays in most cases for
      management of these patients. The type of treatment is based mostly on the level
      of pain and the presence or absence of stone.

PMID- 10663757
TI  - Dynamic magnetic resonance imaging in the assessment of chronic medical
      nephropathies with impaired renal function.
AB  - We examined the value of dynamic magnetic resonance imaging (MRI) in chronic
      renal disease with renal insufficiency. In 33 consecutive patients (21 vascular
      nephropathy, 12 glomerular nephropathy) MRI was performed using a 1.5-T unit and
      a body coil, with SE T1-weighted (TR/TE = 600/19 ms) and dynamic TFFE T1-weighted
      sequences (TR/TE = 12/5 ms, flip angle = 25 degrees ) after manual bolus
      injection (via a cubital vein) of 0.1 mmol/kg Gd-DTPA-BMA. Morphological
      evaluation was performed in unblinded fashion by three radiologists, evaluating
      renal size, cortical thickness, and corticomedullary differentiation. Functional
      analysis was performed by one reviewer. Time-signal intensity curves, peak
      intensity value (P), time to peak intensity (T), and the P/T ratio were obtained
      at the cortex, medulla, and pyelocaliceal system of each kidney. The relationship
      of these parameters to serum creatinine and with creatinine clearance was
      investigated. A good correlation between morphological features of the kidneys
      and serum creatinine values was found. Morphological findings could not
      distinguish between vascular and glomerular nephropathies. A statistically
      significant correlation (P <0.01) between cortical P, cortical P/T, medullary P,
      and serum creatinine and creatinine clearance was found. A significant
      correlation (P <0.01) was also found between cortical T, medullary P/T, T of the
      excretory system, and creatinine clearance. The cortical T value was
      significantly higher (P <0.01) in vascular nephropathy than in glomerular
      nephropathy. Thus in patients with chronic renal failure dynamic MRI shows both
      morphological and functional changes. Morphological changes are correlated with
      the degree of renal insufficiency and not with the type of nephropathy; the
      functional changes seem to differ in vascular from glomerular nephropathies.

PMID- 10663759
TI  - Ultrasonography of acute musculoskeletal disease.
AB  - With technical improvements (higher frequency and extended field-of-view
      sonography) the ability of ultrasound to detect pathology in the musculoskeletal
      system has been greatly increased. As in MRI, and unlike conventional
      radiography, soft tissue lesions in muscles, tendons and occasionally in joints
      can be shown directly. An advantage is real-time imaging of joints during stress.
      A disadvantage is limited demonstration of internal structures within joints.
      This paper provides an overview of various pathologies with emphasis on acute
      disorders.

PMID- 10663758
TI  - Primary renal and retroperitoneal actinomycosis.
AB  - A case of the rare condition of renal and retroperitoneal actinomycosis is
      presented. The clinical and imaging (ultrasonography and computed tomography)
      findings are described and attention is drawn to the diagnostic difficulties in
      this rare disease.

PMID- 10663760
TI  - Precision of tibial cartilage morphometry with a coronal water-excitation MR
      sequence.
AB  - The aim of this study was to analyze the precision of tibial cartilage
      morphometry, by using a fast, coronal water-excitation sequence with high spatial
      resolution, to compare the reproducibility of 3D thickness vs volume estimates,
      and to test the technique in patients with severe osteoarthritis. The tibiae of 8
      healthy volunteers and 3 patients selected for total knee arthroplasty were
      imaged repeatedly with a water-excitation sequence (image time 6 h 19 min,
      resolution 1.2 x 0.31 x 0.31 mm(3)), with the knee being repositioned between
      each replicate acquisition. After 3D reconstruction, the cartilage volume, the
      mean, and the maximal tibial cartilage thickness were determined by 3D Euclidean
      distance transformation. In the volunteers, the precision of the volume
      measurements was 2.3 % (CV%) in the medial and 2.6 % in the lateral tibia. The
      reproducibility of the mean cartilage thickness was similar (2.6 and 2.5 %,
      respectively), and that of the maximal thickness lower (6.5 and 4.4 %). The
      patients showed a considerable reduction in volume and thickness, the precision
      being comparable with that in the volunteers. We find that, using a new imaging
      protocol and computational algorithm, it is possible to determine tibial
      cartilage morphometry with high precision in healthy individuals as well as in
      patients with osteoarthritis.

PMID- 10663761
TI  - Can we see enough? A comparative study of film-screen vs digital radiographs in
      small lesions in rheumatoid arthritis.
AB  - The aim of this study was to evaluate the performance of digital radiography in
      the detection of early very small erosions and joint space narrowing in the hands
      and feet in rheumatoid arthritis. Fifty-three sets of film-screen and digital
      radiographs of the same hands and feet with very small and sometimes questionable
      lesions (possible erosions and cysts) were scored independently two times by four
      investigators. The percentage of lesions found in exactly the same position for
      each investigator was calculated. Intra-observer agreement between first and
      second reading in film-screen radiography was 64-76 % (mean 67 %), and in digital
      radiographs 60-71 % (mean 64 %). Agreement between film-screen and digital
      radiographs ranged from 54 to 64 % (mean 58 %) in the first reading and from 56
      to 66 % (mean 62 %) in the second reading. Overall agreement between both
      techniques between first and second reading ranged between 62 and 73 % (mean 65
      %). Digital radiography of the hands and feet can be used in patients suspected
      of rheumatoid arthritis and in follow-up of those patients, because small and
      early erosions can be seen equally well with the digital technique as compared
      with the conventional film-screen technique.

PMID- 10663762
TI  - Chondrosarcoma of the hyoid bone.
AB  - The CT and MRI findings in a case of chondrosarcoma of the hyoid bone are
      reported. Although chondrosarcoma is the second most common primary malignant
      bone tumor, only 10 % of chondrosarcomas occur in the head and neck region. The
      hyoid bone is a rare site of involvement with only seven cases reported
      previously.

PMID- 10663763
TI  - T1-relaxation kinetics of extracellular, intracellular and intravascular MR
      contrast agents in normal and acutely reperfused infarcted myocardium using echo
      planar MR imaging.
AB  - The objective of this study was to determine and compare if MR contrast agents
      distributed into various compartments can provide estimation of fractional
      distribution volume (FDV) in normal and infarcted myocardium using inversion
      recovery echo-planar MR imaging (IR EPI). Three different types of MR agents were
      investigated: (a) an extracellular agent, GdDTPA-BMA (0.1 mmol/kg); (b) an
      intravascular agent, GdDTPA-albumin (0.025 mmol/kg); and (c) an intracellular
      agent, manganese chloride (0.025 mmol/kg). The null point was determined from a
      series of IR EPI images in which TI was varied. Temporal changes in DeltaR1
      (DeltaR1 = 1/T1(post)-1/T1(pre)) were measured during the initial 29-59 min after
      administration. Rats (n = 24) were subjected to 1-h coronary artery
      occlusion/reperfusion. Histochemical staining confirmed the presence and location
      of infarction. GdDTPA-BMA caused increase in DeltaR1 of infarction < blood < <
      normal myocardium. DeltaR1 ratios were 1.55 +/- 0.08 for infarction and 0.33 +/-
      0.03 for normal myocardium, consistent with FDV of 0.82 +/- 0.04 and 0.18 +/-
      0.01. The fractional distribution of this agent in normal myocardium approximated
      the extracellular space of myocardium. GdDTPA-albumin caused increase in DeltaR1
      of blood < < infarction < < normal myocardium. DeltaR1 ratio in normal, but not
      infarcted, myocardium was constant at 0.10 +/- 0.02 and approximated fractional
      blood volume. MnCl(2) caused equivalent increase in DeltaR1 of normal and
      infarcted myocardium. DeltaR1 of normal myocardium did not change overtime,
      whereas DeltaR1 of blood rapidly decreased, leading to overestimation of FDV in
      normal and infarcted myocardium. In conclusion, extracellular, intravascular and
      intracellular MR contrast agents exhibited different T1-relaxation kinetics in
      both normal and infarcted myocardium. Constant DeltaR1 ratio (myocardium/blood)
      after administration of MR contrast agent is a prerequisite for estimation of FDV
      of MR contrast agent in myocardium.

PMID- 10663764
TI  - Magnetic resonance imaging of athlete's heart: myocardial mass, left ventricular
      function, and cross-sectional area of the coronary arteries.
AB  - To evaluate left ventricular myocardial mass and function as well as ostial
      coronary artery cross-sectional area in endurance athletes, an athlete group of
      12 highly trained rowers and a control group of 12 sedentary healthy subjects
      underwent MR examination. An ECG-gated breath-hold cine gradient-echo sequence
      was used to calculate myocardial mass, end-diastolic and end-systolic volumes,
      stroke volume, and cardiac output, all related to body surface area, as well as
      ejection fraction. A 3D fat-saturated ECG- and respiratory-triggered navigator
      echo sequence was used to evaluate coronary arteries: left main (LM), left
      anterior descending (LAD), left circumflex (LCx), and right coronary artery
      (RCA). Cross-sectional area was calculated and divided for body surface area.
      Myocardial mass was found significantly larger in athlete group than in control
      group (p = 0.0078), the same being for end-diastolic volume (p = 0.0078), stroke
      volume (p = 0.0055), LM (p = 0.0066) and LAD (p = 0.0129). No significant
      difference was found for all the remaining parameters. Significant correlation
      with myocardial mass was found for LM (p < 0.001) and LAD (p = 0.0340), not for
      LCx and RCA. Magnetic resonance imaging is a useful tool in evaluating the
      myocardial hypertrophy and function of athlete's heart. Magnetic resonance
      angiography is a valuable noninvasive method to visualize the correlated cross
      sectional area increase of the left coronary artery system.

PMID- 10663765
TI  - Iliocaval thrombosis: percutaneous treatment with hydrodynamic thrombectomy.
AB  - Mechanical thrombectomy is of growing importance for the treatment of thrombus.
      Although there are numerous reports about dialysis fistulae and arterial
      thrombosis, venous applications are currently not well known. We report that an
      extensive venous thrombotic occlusion can be treated with mechanical
      thrombectomy, without additional local lysis. This report deals with the
      indication and technique of venous mechanical thrombectomy and discusses the
      possible applications.

PMID- 10663766
TI  - Gastrointestinal stenting.
AB  - Acute obstructions of the gastric outlet, the duodenum, or the large bowel
      require rapid treatment to relieve symptoms of retention or ileus. Large-caliber
      stents of 16 to 22 mm offer a new non-surgical alternative for treating these
      patients with minimal risks and high success rates. For gastroduodenal outlet
      obstructions palliated by self-expanded metal stents, clinical success rates are
      in the range of 80-100 %. Preoperative treatment of colorectal obstructions
      successfully relieves acute symptoms of ileus in 87-100 % allowing primary
      anastomosis and thereby reducing the costs caused by multiple operations and the
      need of intensive care by approximately 25 %. It is the purpose of this review to
      familiarize the reader with the indications, possibilities, and limits of
      intestinal stenting.

PMID- 10663767
TI  - Enteroclysis of non-neoplastic disorders of the small intestine.
AB  - Enteroclysis is now widely used for examining the jejunum and ileum. The
      technique is ideal for demonstrating the extent and severity of disorders that
      cause morphological changes to the small intestine. In this review many non
      neoplastic small intestinal disorders as demonstrated by enteroclysis are
      described and illustrated.

PMID- 10663768
TI  - Detection of severe acute pancreatitis by contrast-enhanced magnetic resonance
      imaging.
AB  - The aim of the study was to assess the ability of MRI to differentiate between
      the two forms of severity of acute pancreatitis (AP), which is important for the
      detection of patients who require intensive monitoring and therapy. The second
      objective was to evaluate whether the distinction would be possible regardless of
      the MRI equipment. Magnetic resonance imaging was performed before and after
      intravenous administration of a gadolinium (Gd) chelate at 1.0 T using the breath
      hold multislice rapid gradient-echo turbo fast low-angle shot (FLASH) sequence in
      14 patients, and at 1.5 T with the 2D FLASH(50) sequence with fat saturation in
      18 patients with acute pancreatitis early in the course of the disease. The
      patients were classified according to the Atlanta classification system as having
      the mild (MAP) or severe (SAP) form of the disease. At 1.0 T with use of a body
      coil, contrast-enhanced MRI failed to distinguish mild from severe pancreatitis.
      At 1.5 T with a phased-array body coil, the signal intensities of the patients
      with SAP were statistically significantly lower than those of the MAP group. Our
      initial clinical experience suggests that MRI with a sufficient magnetic field
      gradient strength may be useful for separating the two forms of acute
      pancreatitis in their early phases.

PMID- 10663769
TI  - Congenital absence of the horizontal portion of the left portal vein: ultrasound
      findings.
AB  - Congenital absence of the horizontal portion of the left portal vein is very rare
      and has been very reported sporadically. We present three such cases referred
      from other hospitals with a diagnosis of intrahepatic vascular anomaly. Color
      Doppler ultrasound not only confirmed the diagnosis but also allowed a
      quantitative measurement of blood flow in these cases. Although it is a very rare
      condition, knowledge of the ultrasound and color Doppler findings helps in
      establishing the diagnosis of this congenital anomaly.

PMID- 10663770
TI  - Agenesis of the horizontal segment of the left portal vein demonstrated by
      magnetic resonance imaging including phase-contrast magnetic resonance
      venography.
AB  - Two cases of agenesis of the horizontal segment of the left portal vein are
      reported. This very rare vascular anomaly probably corresponds to an
      embryological variation rather than to an obstruction of the left portal vein. In
      almost all cases liver ultrasonography is sufficient for identifying such
      vascular abnormalities. It shows a large aberrant vessel emerging from a right
      anterior segmental portal branch and running transversely in the quadrate lobe
      towards the teres ligamentum from which the portal supply to the left lobe
      arises. It is important to be able to recognize the magnetic resonance imaging
      features of this vascular variation, as magnetic resonance imaging may be the
      initial imaging study, and ultrasound may be technically challenging. To our
      knowledge, we present the first description of these features, including an
      enhanced gradient-echo T1-weighted sequence, a turbo spin-echo T2-weighted
      sequence with fat saturation, and a three-dimensional phase-contrast magnetic
      resonance portography.

PMID- 10663771
TI  - Spinal cord magnetic resonance imaging in suspected multiple sclerosis.
AB  - We examined the value of spinal cord magnetic resonance imaging (MRI) in the
      diagnostic work-up of multiple sclerosis (MS). Forty patients suspected of having
      MS were examined within 24 months after the start of symptoms. Disability was
      assessed, and symptoms were categorized as either brain or spinal cord. Work-up
      further included cerebrospinal fluid analysis and standard proton-density, T2-,
      and T1-weighted gadolinium-enhanced brain and spinal cord MRI. Patients were
      categorized as either clinically definite MS (n = 13), laboratory-supported
      definite MS (n = 14), or clinically probable MS (n = 4); four patients had
      clinically probable MS, and in nine MS was suspected. Spinal cord abnormalities
      were found in 35 of 40 patients (87.5 %), consisting of focal lesions in 31, only
      diffuse abnormalities in two, and both in two. Asymptomatic spinal cord lesions
      occurred in six patients. All patients with diffuse spinal cord abnormality had
      clear spinal cord symptoms and a primary progressive disease course. In
      clinically definite MS, the inclusion of spinal imaging increased the sensitivity
      of MRI to 100 %. Seven patients without a definite diagnosis had clinically
      isolated syndromes involving the spinal cord. Brain MRI was inconclusive, while
      all had focal spinal cord lesions which explained symptoms and ruled out other
      causes. Two other patients had atypical brain abnormalities suggesting
      ischemic/vascular disease. No spinal cord abnormalities were found, and during
      follow-up MS was ruled out. Spinal cord abnormalities are common in suspected MS,
      and may occur asymptomatic. Although diagnostic classification is seldom changed,
      spinal cord imaging increases diagnostic sensitivity of MRI in patients with
      suspected MS. In addition, patients with primary progressive MS may possibly be
      earlier diagnosed. Finally, differentiation with atypical lesions may be
      improved.

PMID- 10663772
TI  - Improved mammographic interpretation of masses using computer-aided diagnosis.
AB  - The aim of this study was to evaluate the effectiveness of computerized image
      enhancement, to investigate criteria for discriminating benign from malignant
      mammographic findings by computer-aided diagnosis (CAD), and to test the role of
      quantitative analysis in improving the accuracy of interpretation of mass
      lesions. Forty sequential mammographically detected mass lesions referred for
      biopsy were digitized at high resolution for computerized evaluation. A prototype
      CAD system which included image enhancement algorithms was used for a better
      visualization of the lesions. Quantitative features which characterize the
      spiculation were automatically extracted by the CAD system for a user-defined
      region of interest (ROI). Reference ranges for malignant and benign cases were
      acquired from data generated by 214 known retrospective cases. The extracted
      parameters together with the reference ranges were presented to the radiologist
      for the analysis of 40 prospective cases. A pattern recognition scheme based on
      discriminant analysis was trained on the 214 retrospective cases, and applied to
      the prospective cases. Accuracy of interpretation with and without the CAD
      system, as well as the performance of the pattern recognition scheme, were
      analyzed using receiver operating characteristics (ROC) curves. A significant
      difference (p < 0.005) was found between features extracted by the CAD system for
      benign and malignant cases. Specificity of the CAD-assisted diagnosis improved
      significantly (p < 0.02) from 14 % for the conventional assessment to 50 %, and
      the positive predictive value increased from 0.47 to 0.62 (p < 0.04). The area
      under the ROC curve (A(z)) increased significantly (p < 0. 001) from 0.66 for the
      conventional assessment to 0.81 for the CAD-assisted analysis. The A(z) for the
      results of the pattern recognition scheme was higher (0.95). The results indicate
      that there is an improved accuracy of diagnosis with the use of the mammographic
      CAD system above that of the unassisted radiologist. Our findings suggest that
      objective quantitative features extracted from digitized mammographic findings
      may help in differentiating between benign and malignant masses, and can assist
      the radiologist in the interpretation of mass lesions.

PMID- 10663773
TI  - Paradoxical emboli: demonstration using helical computed tomography of the
      pulmonary artery associated with abdominal computed tomography.
AB  - We report the case of a 60-year-old woman with a recent history of a
      cerebrovascular accident. Because of clinical suspicion of pulmonary embolism and
      negative Doppler ultrasound findings of the lower limbs, spiral computed
      tomography of the pulmonary artery was performed and demonstrated pulmonary
      emboli. We emphasize the role of computed tomography of the abdomen, performed 3
      min after the thoracic acquisition, which showed an unsuspected thrombus within
      the abdominal aorta and the left renal artery with infarction of the left kidney.
      Paradoxical embolism was highly suspected on computed tomography data and
      confirmed by echocardiography which demonstrated a patent foramen ovale.

PMID- 10663774
TI  - Lateral cavity wall thickening as an early radiographic sign of mycetoma
      formation.
AB  - The sensitivity of chest radiography for the early detection of mycetoma
      formation within fibrotic cavities is poor. The purpose of this study was to
      determine the predictive value of the secondary sign of lateral cavity wall
      thickening for the detection of a radiographically occult mycetoma. The chest
      radiographs and CT scans of 70 patients who had a total of 109 fibrotic cavities
      on CT were reviewed by two observers. Dimensions of the cavity, mycetoma, and
      cavity wall thickness on chest radiography and CT scans were recorded. Mycetomas
      were visible in 41 of 99 cavities on chest radiographs and in 61 of 109 cavities
      on CT. Using CT as the gold standard for detecting the presence of mycetomas, the
      sensitivity of chest radiography for the presence of a mycetoma was 62 % and the
      specificity 94 %, and the positive and negative predictive values were 93 and 66
      %, respectively. On logistic regression analysis, lateral wall thickness on chest
      radiography was predictive of the presence of a mycetoma (p < 0.0005) independent
      of other radiographic features. In patients with chronic fibrocavitary disease on
      chest radiography, the presence of lateral wall thickening is highly suggestive
      of an underlying mycetoma.

PMID- 10663775
TI  - Dose reduction in computed tomography by attenuation-based on-line modulation of
      tube current: evaluation of six anatomical regions.
AB  - This study investigated the potential of attenuation-based on-line modulation of
      tube current to reduce the dose of computed tomography (in milliamperes) without
      loss in image quality. The dose can be reduced for non-circular patient cross
      sections by reducing the tube current at the angular positions at which the
      diameter through the patient diameter is smallest. We investigated a new
      technical approach with attenuation-based on-line modulation of tube current.
      Computed tomographic projection data were analyzed to determine the optimal
      milliampere values for each projection angle in real time, instead of performing
      prior measurements with localizer radiographs. We compared image quality, noise
      pattern, and dose for standard scans and for scans with attenuation-based on-line
      modulation of tube current in a group of 30 radiation therapy patients. Six
      different anatomical regions were examined: head, shoulder, thorax, abdomen,
      pelvis, and extremities (knee). Image quality was evaluated by four radiologists
      in a blinded fashion. We found the dose to be reduced typically by 15-50 %. In
      general, no deterioration in image quality was observed. Thus the dose in
      computed tomography be reduced substantially by technical measures without
      sacrificing image quality. Attenuation-based on-line modulation of tube current
      is an efficient and practical means for this.

PMID- 10663776
TI  - Spiral-CT cholangiography with 3D reconstruction in the diagnosis of
      choledochocele.

PMID- 10663778
TI  - Calendar of events

PMID- 10663777
TI  - CT demonstration of spinal epidural air after chest trauma.

PMID- 10663781
TI  - [Analysis of energy levels for Nd:YAG laser capsulotomy in secondary cataract].
AB  - BACKGROUND: Formation of secondary cataract is influenced by various factors,
      such as IOL material, IOL design, age, follow-up time and ocular and systemic
      diseases. It has not yet been studied whether these factors have an clinical
      impact on the energy used for Nd:YAG laser capsulotomy. PATIENTS AND METHODS: We
      examined 172 patients, aged 67.3+/-15.9 years, concerning energy levels required
      for Nd:YAG laser capsulotomy. We analysed the influence of age, implant duration,
      IOL fixation and ocular conditions on total energy and repetition rate of Nd:YAG
      laser capsulotomy. Sixty-nine patients (43. 7%) had no other ocular pathology
      (control), 24 (15.2%) glaucoma, 14 (8.9%) diabetic retinopathy, 12 (7.6%)
      retinitis pigmentosa, 8 (5. 1%) high myopia, 7 (4.4%) triple procedure with
      perforating keratoplasty. Twenty-four (15.2%) presented with various additional
      ocular conditions such as pseudoexfoliation syndrome. Patients had undergone
      cataract surgery between 1988 and 1995 with implantation of PMMA-IOLs. RESULTS:
      Nd:YAG laser capsulotomies were performed on average 28.2+/-17.7 months
      postoperatively. The average total energy used was 12.7+/-9.4 mJ. Visual acuity
      (Pre-YAG) was 0.3+/-0.2. In the control group there was no correlation between
      energy and implant duration or age (P>0.43). 26 patients required a second Nd:YAG
      laser capsulotomy. Patients with retinitis pigmentosa showed a significantly
      higher re-YAG rate than the other patient groups (P=0.00059). In eyes with sulcus
      fixation of the IOL, capsulotomies were performed earlier and with higher energy
      levels than for in-the-bag fixation. CONCLUSIONS: The different ocular conditions
      of the anterior and posterior segment showed a different profile for Nd:YAG laser
      capsulotomy energy level and Nd:YAG laser repetition rate. Sulcus fixation of an
      IOL resulted in earlier capsulotomies with higher energy levels.

PMID- 10663782
TI  - [Inhibition of proliferation of retinal pigment epithelium in vitro: vitamin A
      pharmacodynamics I].
AB  - BACKGROUND: In proliferative vitreoretinopathy and choroidal neovascularization,
      retinal pigment epithelial (RPE) cells proliferate among other cell types. Cell
      proliferation is controlled by many factors. One such factor is the "superfamily"
      of nuclear receptors. Ligands of these receptors are vitamin A and D,
      triiodothyronine and dexamethasone. All-trans-retinal (atR) inhibits human RPE
      cell proliferation. AtR binds to the nuclear ligand-dependent transcription
      factors RAR (retinoic acid receptor) and RXR (retinoid X receptor).
      Pharmacodynamics of atR were investigated with respect to inhibition of RPE cell
      proliferation. MATERIALS AND METHODS: Primary human RPE cell lines were used up
      to passage 5. RPE cells were incubated with atR ranging from 1 pM up to 1 microM.
      AtR was added every other day for 7 days. Cell proliferation was determined by
      cell counting. RESULTS: AtR inhibited RPE cell proliferation in a biphasic
      manner. Two IC50 values were calculated, one in the picomolar range, 10 pM (5-24,
      95% confidence interval) and one in the nanomolar range, 17 nM (8-37).
      Furthermore, inhibition of cell proliferation was examined using specific RAR
      agonists. Agonists of the RAR-b subgroup inhibited cell proliferation at the
      lowest concentrations. CONCLUSIONS: RPE cell proliferation in vitro is inhibited
      by agonists of RAR. Agonists of the RAR-b subgroup inhibit RPE cell proliferation
      at the lowest concentrations.

PMID- 10663783
TI  - [Wound or suture insufficiency complicating penetrating keratoplasty].
AB  - BACKGROUND: With regard to penetrating keratoplasty methods to culture corneal
      donor tissues, microsurgical techniques, HLA typing and understanding of basic
      mechanisms in inflammation and especially graft rejection, and postoperative
      treatment schedules have been improved in recent years. This now enables
      successful penetrating keratoplasty in many more patients than previously
      performed. However, in rare cases relevant problems in wound closure may appear.
      PATIENTS AND METHODS: A standardized treatment protocol was applied to 1,253
      penetrating keratoplasties performed in a single center. Patients were
      continuously followed up. Simple leakage after corneal grafting was not further
      analyzed if conservative treatment or additional sutures achieved sufficient
      wound closure. In 21 cases, however, the causes of large wound dehiscence after
      corneal grafting were analyzed. RESULTS: During the first week early problems in
      suturing penetrating keratoplasty in five patients were associated with the
      instability of the recipients' corneal stroma (stromal thinning in keratoconus or
      corneal herpes, suture problems in keratomalacia, active herpes keratitis,
      corneal burns, or rheumatic diseases). Long-term complications in 16 patients
      were associated with alcoholism, herpes keratitis, rheumatic disorders or
      traumatic suture defects. Overall, nine patients lost functionally or even
      anatomically one eye because of wound dehiscence after corneal grafting.
      CONCLUSIONS: When penetrating keratoplasty is indicated, special attention should
      be given to (1) the compliance of the patient, (2) sufficient treatment of herpes
      keratitis or other infections, (3) adequate immunosuppression in autoimmune
      corneal inflammation, (4) double running continuous sutures as primary suture
      with sometimes additional single sutures to stabilize the graft, and (5) surgery
      in time.

PMID- 10663784
TI  - [Motor and sensory responses in fusion of vertical disparities in different
      convergence places].
AB  - To study motor and sensory responses in vertical fusion at different angles of
      horizontal vergence in normal humans. METHODS: The study included 12 normal
      subjects. A cross (+) extending 3.4 degrees x3.2 degrees was presented
      dichoptically. Vertical disparity was introduced by changing the vertical
      position of the cross in front of one eye. The disparity was incremented by 0.08
      degrees every 8 s. Distance viewing was tested with 1 degrees of convergence
      demand, near vision with 6-15 degrees convergence demand. Eye movements were
      recorded using three-axis search coils. RESULTS: Vertical fusion capability was
      larger at near vision than at distance in 9 of 12 subjects. For the entire group,
      total vertical fusion capability (motor plus sensory response) differed between
      distance (mean 1.68 degrees ) and near (mean 2.39 degrees ). The motor component
      differed significantly between distance (mean 1.42 degrees ) and near (mean 2.13
      degrees ). No difference in the sensory component was seen between distance (mean
      0.26 degrees ) and near (mean 0.27 degrees ). CONCLUSIONS: Vertical fusion
      capability increases with convergence. This increase is mainly due to an increase
      of the motor response.

PMID- 10663785
TI  - [Healing process and complications after eye muscle surgery].
AB  - BACKGROUND: Varying reports on the incidence of operative and postoperative
      complications following eye muscle surgery have been published. The purpose of
      this study was to quantify complications after various types of eye muscle
      surgery as well as minor pathological changes of the anterior and posterior
      segment. PATIENTS AND METHODS: This prospective study included all patients who
      underwent eye muscle surgery at the Department of Strabismology and
      Neuroophthalmology, Giessen, from January to May 1998. Five hundred eyes of 377
      patients aged 2-82 years were included. The spectrum of procedures comprised:
      recessions, resections, tucks, R&R procedures, transpositions, bimedial
      retroequatorial myopexies, and revisions of rectus and oblique muscles. All
      patients were examined 1 day preoperatively and 1 day, 1 week, and 3 months
      postoperatively. Any complications and even minor pathological changes of the
      anterior and posterior segment were documented. Some changes were assessed by
      means of a score (0-3). RESULTS: One day postoperatively, 30% of eyes had
      inflammatory pseudoptosis, most of them mild. Conjunctival swelling and injection
      were frequently mild and moderate, after 1 week mostly mild. Conjunctival
      irritation was more pronounced following resection than tucking. Punctate
      epithelial keratopathy was noted in 1.6% of cases (first postoperative day),
      dellen in 4.3% (first postoperative week). Three months postoperatively, 14.3% of
      eyes had biomicroscopically visible conjunctival folds and 91.3% had minimal
      conjunctival scars. None of the patients had a scleral perforation or other
      serious complication. CONCLUSIONS: Eye muscle surgery rarely entails
      complications. Revisions due to organic pathological changes are extremely rare.
      Possible development of dellen requires check-up 4-7 days postoperatively.
      Tucking of rectus muscles causes less conjunctival irritation than resection.

PMID- 10663787
TI  - [Endophthalmitis: improvement of culture results].
AB  - BACKGROUND: Infectious endophthalmitis is a rare, but serious complication.
      Identification of the responsible microorganism is important for prognosis and
      therapy. In the literature positive cultures have been reported in 35-85% of
      cases. The purpose of our work was to improve the proportion of positive culture
      results. METHODS AND PATIENTS: All necessary materials (culture media: Columbia,
      Hamatin, ENDO and yeast-cystein-blood agar, fungus media) and instructions were
      always available in the operation theater. Thus, intraocularly derived samples
      could be cultured by less experienced residents right in the operation theater,
      especially off duty. At night the culture plates were incubated in the Department
      of Ophthalmology under optimal conditions and passed on to an experienced
      microbiologist later. Culture results of the first 21 patients suffering from
      endophthalmitis (acute or chronic postoperative, endogen) after introduction of
      this "endophthalmitis set" were compared to the results of the 21 patients
      before. RESULTS: As a result of the introduction of the "endophthalmitis set",
      the proportion of positive culture results improved from 11/21 to 18/21. The
      detected microorganisms were all representative of the pathogens commonly causing
      endophthalmitis (gram-positive bacteria, anaerobic bacteria). CONCLUSION: An
      appropriate culture set that is always available in the operation theater may
      increase the number of positive cultures dramatically and hence help to find the
      adequate antibiotic treatment in endophthalmitis cases.

PMID- 10663786
TI  - [A case of Leber optic neuropathy with a new point mutation in the cytochrome b
      gene].
AB  - BACKGROUND: Leber's hereditary optic neuropathy (LHON) is associated with
      mutations in the mitochondrial DNA (mtDNA). We report the clinical and molecular
      genetic findings of a patient who does not carry any of the common LHON
      mutations. METHODS: Clinical data were collected for the affected patient and two
      unaffected maternal family members. Complete sequence analysis of the mtDNA
      protein coding region was performed in the affected patient. RESULTS: Clinical
      examination of the affected patient showed typical features of LHON. A nucleotide
      exchange was detected at np14894 replacing an evolutionarily conserved
      phenylalanine by a leucine in the cytochrome b gene. The mutation was also
      present in two unaffected maternal family members, but absent in 60 other LHON
      lineages and 175 unrelated controls. CONCLUSIONS: Cytochrome b plays an important
      role in the electron transport chain of mitochondrial oxidative phosphorylation,
      and some mutations in the gene encoding cytochrome b have been associated with
      LHON. Our results may imply that the novel mutation at np14894 is responsible for
      LHON in this family.

PMID- 10663788
TI  - [Graves ophthalmopathy and ocular myasthenia].
AB  - BACKGROUND: An 18-year-old woman presented with thyrotoxic symptoms - right sided
      lid retraction and exophthalmus. She complained of diplopia on lateral gaze.
      Laboratory investigations confirmed Grave's disease with hyperthyroidism and TSH
      receptor antibodies. PATIENTS AND METHODS: Her clinical symptoms improved after
      thyrostatic and steroid therapy. However, diplopia recurred 2 weeks after
      withdrawal of steroid therapy and a ptosis of the left lid appeared for the first
      time. RESULTS: A positive Tensilon test and electromyographic findings confirmed
      the diagnosis of myasthenia gravis with a predominantly ocular manifestation.
      Diplopia and ptosis improved with oral pyridostigmine. CONCLUSIONS: The
      coexistence of myasthenia gravis should be taken into consideration in the
      management of patients with Graves' ophthalmopathy.

PMID- 10663789
TI  - [Correlation of morphologic changes between optical coherence tomography and
      topographic angiography in a case of gyrate atrophy].
AB  - PURPOSE: To characterize ultrastrructual changes in atrophic disease of the
      retina, RPE and choroid as seen with gyrate atrophy using two new diagnostic
      modalities, optical coherence tomography (OCT) and topographic angiography.
      PATIENT AND METHOD: OCT images were taken in a patient with pericentral choroidal
      atrophy using a slit-lamp-adapted OCT system. Ophthalmoscopy, conventional and
      topographic angiographic findings were correlated to the reflectivity changes as
      seen on OCT. RESULTS: Areas of chorioretinal atrophy correlated with a loss of
      reflectivity in the RPE-choriocapillaris complex on OCT. Additionally OCT
      identified a thinning of the nerve fiber layer. Topographic angiography
      demonstrated an extensive defect, seen as an area of depression, consistent with
      a loss of choriocapillaris and larger-sized choroidal vessels. In contrast to
      conventional angiography, central islands were not found to demonstrate
      structural intensity, while the midperipheral surrounding area was clearly
      elevated to physiological levels. CONCLUSION: OCT and topographic angiography
      provide in vivo insight into morphologic changes within neurosensory retina and
      choroid caused by pericentral choroidal atrophy.

PMID- 10663790
TI  - [Lens subluxation and glaucoma: indications and hazards of cataract surgery].
AB  - BACKGROUND: Iridodonesis is the clinical sign of lens subluxation. Acute glaucoma
      caused by a ciliolenticular block may develop. YAG iridotomy or peripheral
      iridectomy are rarely effective in controlling intraocular pressure. The results
      of phacoemulsification and posterior lens implantation for subluxated lens and
      glaucoma are reported. PATIENTS AND METHODS: Seven patients aged 69+/-9.5 years
      were followed up. All 10 eyes with subluxated lens and glaucoma had
      phacoemulsification and posterior chamber lens implantation. Two different groups
      relating to axial length could be analyzed. Intraoperative findings and
      postoperative glaucoma situation are reported. RESULTS: Six eyes had average
      axial length of 21.5+/-0.17 mm and previous acute glaucoma. Five of these eyes
      had therapeutic YAG iridotomy and one, peripheral iridectomy. All eyes had
      dysregulated glaucoma despite antiglaucomatous medications. After cataract
      surgery five of six eyes had regular intraocular pressure without any medication.
      Four eyes had average axial length of 24. 4+/-1.1 mm and chronic glaucoma. After
      complicated phacoemulsification three of these eyes had regular intraocular
      pressure with antiglaucomatous medication, one eye without. CONCLUSIONS: For
      short eyes with subluxated lens and preceding acute glaucoma, cataract surgery
      with posterior chamber lens implantation is an effective therapeutic procedure
      for IOP regulation. For chronic glaucoma with subluxated lens, conventional or
      surgical approach to glaucoma remains dominant.

PMID- 10663791
TI  - [Sponge anesthesia with intraocular lidocaine application in cataract surgery].
AB  - BACKGROUND: For cataract surgery in this country retro- and peribulbar anesthesia
      is the standard method. It totally stops eye movement as well as sensitivity to
      pain. Especially peribulbar anesthesia is known as a procedure with minimal
      complications, but the potential risks can be severe. In the past sponge
      anesthesia could not be used on patients with difficult cataract surgery due to
      the insufficient anesthetic effect. A modified anesthetic method is demonstrated
      for complicated cataract surgery. PATIENTS AND METHODS: In 281 non-selected,
      successive phacoemulsifications, all performed by the same surgeon, we applied
      sponge anesthesia and 1.5 mg midazolam as premedication. Only in cases of
      moderate and severe sensitivity was 1% 0.15 ml lidocaine applied intraocularly.
      The intensity of sensitivity was graded as 1 for low, 2 moderate, and 3 severe.
      RESULTS: Ninety eyes had complicated cataract surgery. Of the patients, 84.3%
      felt no pain during surgery; 11.4% were part of group 2 (moderate). Ten of 12
      patients who had stated moderate sensitivity at first were free of pain after
      intraocular application of lidocaine, while the other 2 patients only felt minor
      sensitivity. CONCLUSION: The anesthetic procedure we present offers a safe
      alternative method to surgeons who are able to do surgical procedures on a mobile
      eye.

PMID- 10663792
TI  - [Protein analysis methods in diagnosis of sicca syndrome].
AB  - BACKGROUND: The routine clinical diagnosis of sicca syndrome remains difficult;
      the results of the standard tests, such as the Schirmer test, tear film break-up
      time and the rose Bengal test, correlate neither with the course of the disease
      nor with one another. MATERIAL AND METHOD: We introduce two procedures that can
      be used to differentiate patients with sicca syndrome from healthy individuals on
      the basis of tear fluid protein patterns. Electrophoretic separation of the tear
      proteins or measurement by high-performance liquid chromatography (HPLC) was
      followed by digital image processing and multivariate discriminant analysis.
      RESULTS: In addition to analysis of tear protein patterns, these methods permit
      diagnostic classification. Statistical evaluation reveals whether an unidentified
      sample is to be classified as sicca syndrome or "healthy". Both HPLC analysis and
      protein electrophoresis detect differences in protein patterns between the tear
      fluid of healthy individuals and patients with sicca syndrome and point to a
      diagnosis accordingly. CONCLUSION: Both of the techniques presented -
      electrophoresis and HPLC - could potentially be used for diagnostic purposes in
      the detection of sicca syndrome. The HPLC method of tear protein analysis is more
      reliable, lends itself more readily to automation and achieved greater success
      rates in the experiments we describe; for these reasons it is the preferred
      approach.

PMID- 10663793
TI  - [Powdery corneal opacities and joint changes].

PMID- 10663794
TI  - [Chronic papilledema].

PMID- 10663795
TI  - [Ethics in medicine. Needs and forms].

PMID- 10663810
TI  - Correlation of EEG, neuroimaging and histopathology in an epilepsy patient with
      diffuse cortical dysplasia.
AB  - The correlation between scalp EEG, intraoperative electrocorticogram,
      neuroimaging and histopathology was examined in an epileptic child with diffuse
      cortical dysplasia. The 6-year-old girl with moderate mental retardation had
      suffered from intractable complex partial and generalized epilepsies since the
      age of 2 years. MR images demonstrated unilateral large macrogyria/polymicrogyria
      and schizencephaly in the right occipital lobe. The epileptic focus was detected
      on the macrogyria by EEG and single photon emission tomography. However, the
      intraoperative electrocorticogram showed frequent spikes from the polymicrogyria
      and no paroxysmal activity in the macrogyria. The polymicrogyria and the
      macrogyric lesion were resected, using an image-guided system. The histological
      findings revealed that the macrogyria was covered with and separated by glial
      bundles. It has been reported that epileptogenicity is produced from abnormal
      neurons and their arrangement in cortical dysplasia; in this case, however, the
      major dysplastic lesion had no epileptogenicity; rather the focus might be in the
      polymicrogyria around the lesion.

PMID- 10663811
TI  - Spinal cartilaginous meningioma in a child: a case report.
AB  - Cartilage-containing meningiomas are extremely uncommon, and such tumors located
      in the spinal cord of a child have not previously been reported. We describe a
      case of cartilaginous spinal meningioma in a 13-year-old girl. The tumor lacked
      typical histopathological features of meningioma on light microscopic
      examination, and the final diagnosis was possible only after an extensive study
      by electron microscopic examination. The case is evaluated with a focus on
      differential diagnosis and review of the literature.

PMID- 10663812
TI  - Electrophysiological studies of a child with presumed botulism.
AB  - Electrophysiological studies of a child with presumed botulism showed that the
      amplitude of the serially and electrically elicited blink reflexes Rl, R2 and R2'
      was reduced during recovery. These findings suggest a conduction block of the
      facial nerves. Other nerve conduction studies and an incremental response to
      repetitive stimulation demonstrated a block of the presynaptic neuromuscular
      transmission. Results of the biological tests were negative, but those of
      electrodiagnosis and clinical examination favored a diagnosis of botulism. A
      combination of electrically elicited blink reflexes and rapid repetitive
      stimulation of the peripheral nerves was found to be a sensitive method of
      assessing the integrity of neuromuscular junctions and the subclinical impairment
      of muscle nerves.

PMID- 10663813
TI  - Seizure outcome after corpus callosotomy: the Taiwan experience.
AB  - From September 1989 to August 1996, we performed anterior corpus callosotomy in
      83 patients. Unfortunately, 9 patients were lost to follow-up. Among the
      remaining 74 patients, 59 had Lennox-Gastaut syndrome (evolved from infantile
      spasms in 22), 9 had complex partial seizures with or without secondary
      generalized seizures, 1 had multifocal independent epileptogenic foci (MISF)
      syndrome, 3 had hemiconvulsion-hemiplegia-epilepsy (HHE), and 2 had infantile
      spasms. All cases were followed up for at least 2 years after surgery. The
      highest rate of significant improvement (more than 50% reduction in seizure
      frequency) was noted in the patients with generalized tonic-clonic seizures,
      82.1% of whom experienced significant improvement, followed by those with
      generalized tonic seizures (76. 7%), atonic seizures (72.7%), myoclonic seizures
      (64.9%), atypical absences (58.6%), and complex partial seizure with or without
      secondary generalization (61.5%). Complete freedom from seizures was noted in 14
      cases (18.9%). One patient had the anterior half of his right palm amputated
      following radial artery thrombosis complicated by insertion of an arterial line
      during anesthesia. Otherwise, there were no major postoperative complications
      except for brief mutism and multifocal jerks in some patients during the 1st
      postoperative week. Thus, we conclude that corpus callosotomy is a safe
      alternative treatment for all kinds of medically intractable seizures, especially
      generalized epilepsy.

PMID- 10663814
TI  - Preemptive analgesia with tramadol and fentanyl in pediatric neurosurgery.
AB  - Preemptive analgesia is based on administration of an analgesic before a painful
      stimulus generates, so as to prevent the subsequent rebound mechanism. Tissue
      injury results in disruption of the processing mechanisms of noxious stimuli
      afferent to the CNS (central nervous system) by way of an increase of inputs in
      the spinal cord. These reactions may be reduced by the administration of opioids.
      Few studies on preemptive analgesia with opioids in children are available, and
      none of them is concerned with pediatric neurosurgery. Tramadol and fentanyl are
      synthetic opioids which are relatively new and act through the activation of pain
      inhibitory mechanisms. We conducted a randomized, prospective trial on the
      preemptive effects in children of these two analgesic drugs, administered
      according to three different protocols: tramadol as a bolus (1 mg/kg); tramadol
      by continuous infusion (150 microg/kg per h); fentanyl by continuous infusion (2
      microg/kg per h). In all, 42 children undergoing major neurosurgical operations
      were enrolled in the study, 14 in each treatment group. Each treatment was
      started at the induction of general anesthesia and continued throughout the
      entire duration of the operation. The postoperative pain evaluation was conducted
      in the Pediatric Intensive Care Unit at the end of the surgical operations and
      involved comparison of any changes in behavioral (AFS scale and CHEOPS score) and
      hemodynamic (heart rate, respiratory rate, systolic and diastolic arterial
      pressure, oxygen saturation, O(2) and CO(2) partial pressure) parameters. Only 2
      children, both in group A, needed further drug administration postoperatively. No
      significant side effects were noticed in any of the three groups, except that in
      group A there was a higher incidence of nausea and vomiting. Tramadol efficacy
      seems to be better when it is administered in continuous infusion; this treatment
      modality also leads to fewer adverse effects. Fentanyl, in contrast, proved to be
      superior to tramadol in the treatment of postoperative pain. In conclusion,
      preemptive analgesia is a valid technique for the treatment of acute pain in
      children undergoing major neurosurgical operations.

PMID- 10663815
TI  - Comment

PMID- 10663816
TI  - Transcutaneous vagus nerve stimulation for partial onset seizure therapy. A new
      concept.
AB  - A new concept for transcutaneous vagus nerve stimulation for control of partial
      onset seizures is described. The rationale for the application of this innovative
      noninvasive method is discussed.

PMID- 10663818
TI  - Comment

PMID- 10663817
TI  - Long-term experience with subcutaneously tunneled external ventricular drainage
      in preterm infants.
AB  - We previously reported on a series of 27 newborn infants treated for
      posthemorrhagic hydrocephalus with external ventricular drainage during 1984 to
      1989. In the present study we continued to evaluate this technique during the
      subsequent 8 years (37 patients; mean birthweight 1251+/-478 g; mean gestational
      age 29+/-2.9 weeks; 51 drains), and we now report on the long-term experience
      with this method, complications, and neurodevelopmental outcome of the survivors.
      The mean age at drain insertion was 21 days, and the mean duration of drainage 23
      days. Eight infants died of causes unrelated to external ventricular drainage.
      Eleven of the survivors did not require a permanent shunt. Two patients
      experienced ventriculitis, resulting in an infection rate of 5.4% per patient and
      3.9% per drain. The neurodevelopmental outcome was mainly dependent on the extent
      of the pre-existing parenchymal injury. We conclude that external ventricular
      drainage is a safe and effective technique for the management of preterm infants
      with posthemorrhagic hydrocephalus.

PMID- 10663819
TI  - Shunt-independent surgical treatment of middle cranial fossa arachnoid cysts in
      children.
AB  - The best operative intervention for children with arachnoid cysts remains the
      subject of controversy. Recent reports stress that craniotomy for cyst
      fenestration is associated with a low incidence of morbidity and mortality and
      may leave the child shunt-independent. Among a total of 66 intracranial arachnoid
      cysts operated on in the authors' department from 1985 to 1997, 44 cases (67%)
      were located in the middle cranial fossa. A higher incidence in the first decade
      of life (53 cases) and a marked male predominance (45 cases) were recognized.
      Headache, cranial deformities, symptoms of raised intracranial pressure, and
      seizures constituted the most frequent features of the clinical presentation. To
      determine which treatment provides the greatest benefit with the lowest incidence
      of complications, the records of the 44 patients with arachnoid cysts in the
      middle cranial fossa were reviewed. The mean age of these patients was 4.6 years
      (range 0-16 years). Different types of initial surgical procedures were
      performed. In 33 patients with middle cranial fossa arachnoid cysts (MCFAC) the
      initial surgery took the form of craniotomy with excision of the cyst walls and
      fenestration into the basal cisterns. Shunting procedures were performed in 9
      patients: cysto-peritoneal shunts (CPS) were placed in 4 patients and ventriculo
      peritoneal shunts (VPS), in 3 patients, and cyst excision was performed in
      addition to CPS in 2 patients. Excision of the cyst membrane alone without
      fenestration was performed in 2 patients. The initial treatment was successful in
      terms of reduced symptoms and decreased cyst size, with no additional treatment
      needed for the cyst, in 79% (26/33) of patients who had undergone excision of the
      cyst walls and fenestration into the basal cisterns, compared with 66% (6/9) of
      patients who had undergone shunting procedures. Cyst membrane excision was not
      successful in any of the patients who underwent this procedure alone. No
      significant difference in morbidity was noted between these different treatment
      options. On follow-up CT scan and MRI, cysts of types I and II (Galassi
      classification) exhibited a steady tendency to reduction or obliteration. These
      results confirm that radical excision of the outer and inner membranes of the
      cyst wall with fenestration into the basal cistern is a safe and effective shunt
      independent procedure for MCFAC, especially for those of types I and II.

PMID- 10663820
TI  - Penetrating craniocerebral injury from an underwater fishing harpoon.
AB  - Weapon injuries other than gunshot wounds or low-velocity stab wounds to the head
      are extremely rare. We report the case of a 6-year-old girl who sustained a
      penetrating craniocerebral injury after being accidentally shot with an
      underwater fishing harpoon. This mechanism of injury seems to share
      characteristics of both high- and low-velocity projectiles. We discuss the
      management of this unusual injury in a child, remarking that foreign body removal
      in these cases must be carried out following the original direction of the
      projectile trajectory. We review the current literature on craniocerebral
      injuries caused by similar objects, especially those occurring in children.

PMID- 10663822
TI  - Abstracts

PMID- 10663821
TI  - Brachial plexus gunshot injury in an infant.
AB  - We present the case of an infant with a gunshot lesion in the brachial plexus.
      Intraoperative nerve action potential recordings suggested posterior cord
      neurolysis and medial and lateral cord grafting. After 3 years' follow-up
      complete recovery of motor and sensory function was seen as a result of immense
      nerve regeneration capability and brain plasticity. According to our knowledge
      this is the first reported case of such a mechanism of injury in an infant.

PMID- 10663823
TI  - Imperforate anus: definition of normal morphology

PMID- 10663824
TI  - Histopathologic observations of anorectal abnormalities in anal atresia.
AB  - Over the years from 1992 to 1997, 41 anorectal malformations (ARM) with
      histopathologic alterations were investigated to determine which morphologic
      abnormalities of the distal rectum accompany ARMs. Three other cases showed
      normal neuromuscular morphology; 9 further cases could not be evaluated owing to
      scanty biopsies. All resected specimens were caudocranially coiled and cryostat
      cut at -20 degrees C into serial sections, which were stained with a lactic
      dehydrogenase, succinic dehydrogenase, nitroxide synthase, and
      acetylcholinesterase reaction as well as hemalum and sirius red. Ten low, 15
      intermediate, and 10 high forms of anal atresia (AA) were studied. In addition,
      six cloacal abnormalities were investigated. In 7 cases (17%) (5 intermediate, 2
      low AAs), the characteristics of Hirschsprung's disease were observed.
      Oligoneuronal hypoganglionosis of the myenteric plexus proximal to the anal floor
      was diagnosed in 7 AAs (12%). In 10 children with high-type AA and resection of 1
      5 cm distal rectum and in all cloacal anomalies (n = 6) defects of the muscularis
      propria were seen in the rectal-atresia sac. These defects were characterized by
      hypoplasia of the circular-muscle layer and/or the internal anal sphincter (IAS).
      Intestinal neuronal dysplasia of the submucous plexus was most frequently
      observed (12%) in high-type AA. A correlation between innervation anomalies or
      anomalies of the muscularis propria and the type of fistula could not be seen. In
      conclusion, all cases with high-type AA and cloacal anomalies were characterized
      by anomalies of the muscularis propria and/or IAS but this was not the case in
      intermediate and low-type AAs. Anomalies of the enteric nervous system were
      diagnosed in 60% of AAs.

PMID- 10663825
TI  - A computerised vector manometry study of the so-called ectopic anus.
AB  - There are several totally different definitions of the so-called ectopic anus. To
      determine whether computerized eight-channel manometry helps to define the entity
      of the ectopic anus, ten patients (nine females) were operated upon for an
      ectopic anus by the anal transposition technique (perineal pull-through
      procedure). Besides the software-supported manometric data, the qualitative
      imaging analysis was of interest. We calculated the factor by which the pressure
      of the three ventrally-located segments was lower than the mean segmental
      pressure at this part of the anal canal. The results were compared to standard
      age-related values established in a former study in 100 children. Besides pre-
      and postoperative manometry, barium roentgenograms were obtained. The anal-canal
      length at rest in the ectopic anus was significantly (P < 0.0001) longer. The
      segmental asymmetry index in the lower anal canal (LAC) was increased, but not
      significantly. The pressure in the ventral segments of the LAC was significantly
      (P < 0.0001) decreased and was less than one-half of the mean segmental pressure
      in this zone. We found a significant correlation between the degree of anterior
      displacement and the factor by which the ventrally-located pressure values were
      decreased. Postoperatively, this factor increased significantly. From a
      functional point of view, the definition of the ectopic anus includes a deficient
      high-pressure zone ventrally in the LAC. The LAC seems to run out or nearly out
      of the ventral sphincteric issue to end ectopically on the perineal surface.

PMID- 10663826
TI  - Effects of carotid artery repair following neonatal extracorporeal membrane
      oxygenation.
AB  - Between 1 June 1991 and 30 June 1996, 62 neonates were placed on extracorporeal
      membrane oxygenation (ECMO). In 61 the right carotid artery was cannulated. At
      the time of decannulation, a decision was made regarding carotid artery repair
      (CAR) based on the condition of the vessel. Thirty-two patients underwent end-to
      end CAR and 29 had artery ligation. There was no difference between groups in
      gestational age or birth weight, but the ligation group contained 11 patients
      with congenital diaphragmatic hernia, compared to 2 in the repair group. The time
      on ECMO was 148 h for the repair group and 297 h in the ligation group. Follow-up
      contrast-enhanced magnetic resonance imaging (MRI) studies and ultrasound (US)
      demonstrated 2 occluded vessels in the repair group (7%); 3 vessels appeared
      stenotic on MRI. Follow-up neurologic examination was normal or near-normal in 17
      of 19 repair infants and 9 of 16 ligation patients. Two repair infants had slight
      delays in development, while 3 ligation patients had significant delays. Follow
      up US showed 3 grade I changes in the repair group with 1 hydrocephalus. There
      was 1 grade I and 1 grade III change in the ligation group. Follow-up MRI showed
      6 minimal changes in the repair group and 9 in the ligation group. CAR does not
      adversely affect neurologic outcome after neonatal ECMO. The early patency rate
      was 93%, although 12% of the vessels appeared stenotic. Long-term follow-up
      confirmed persistent patency. CAR, if technically feasible, should be encouraged
      following neonatal ECMO therapy.

PMID- 10663827
TI  - Short-term absorbable material for diaphragmatic replacement.
AB  - To evaluate absorbable materials for use for replacement of the diaphragm, we
      implanted materials in experimentally-created diaphragmatic defects in pigs. As a
      short-term absorbable material, bovine serosa (BS) was used. Its absorption was
      complete after 4-6 weeks. In a control group, the defect was repaired with a
      continuous running polypropylene suture. In two other groups the defect was
      closed with lyophilized dura (LD) and a modified transverse abdominal muscle flap
      according to Hecker, respectively. Physical studies (load capacity and
      elasticity) and histologic investigations were performed in one-half of the
      animals of each group after 3 and 6 months, respectively. Considering their
      physical properties, it could be shown that all materials tested are suitable for
      replacement of the diaphragm, but that BS best resembled native diaphragm. We
      conclude that short-term absorbable BS is suitable for replacement of the
      diaphragm in pigs.

PMID- 10663828
TI  - Ruptured exomphalos and gastroschisis: a retrospective analysis of morbidity and
      mortality in Nigerian children.
AB  - The survival of infants with major abdominal-wall defects (AWD) has improved over
      the years in developed countries. In Zaria, northern Nigeria, survival from
      intact exomphalos (EX), has improved with the adoption of non-operative
      management. Ruptured EX (REX) and gastroschisis (GS), however, remain
      problematic. This is a report of the mortality in REX and GS in a retrospective
      review of 16 infants with REX and 14 with GS managed over 10 years at the Ahmadu
      Bello University Teaching Hospital, Zaria. The median age at presentation was 3
      days and 24 h for REX and GS, respectively; 29 of the 30 patients were delivered
      at home. Two patients with REX and 4 with GS had associated anomalies involving
      mostly the gastrointestinal tract. Bowel or omental strangulation occurred in 13
      patients, resulting in gangrene in 8. Fascial closure was achieved in 20
      patients, skin closure only in 4, and in 4 improvised silo coverage was used, the
      latter associated with high infection rate. Neonatal intensive care units (NICU)
      and total parenteral nutrition (TPN) were not available. The overall mortality
      was 18.6% (gastroschisis 10, ruptured exomphalos 8, 11 from sepsis and 7 due to
      respiratory embarrassment). The management of these AWDs thus continues to be
      problematic in our environment, and mortality remains high. Provision of more
      modern supportive facilities (NICU and TPN) may improve the survival in our and
      similar environments.

PMID- 10663829
TI  - Pathologic changes in the common bile duct of an experimental model with
      pancreaticobiliary maljunction without biliary dilatation.
AB  - Pancreaticobiliary maljunction (PBM), a congenital anomaly, causes regurgitation
      of pancreatic juice into the biliary tract, where it exerts a hazardous
      influence. However, changes in the common bile duct (CBD) remain obscure due to a
      lack of suitable experimental models. Using cats, we have developed an
      experimental model of PBM without bile-duct dilatation that allows the pure
      effects of PBM to be studied. Histologic and cellular kinetic changes in the CBD
      were analyzed in 6 controls and 9 experimental animals that survived for more
      than 6 months. CBD sections were stained with hematoxylin and eosin and a
      monoclonal antibody to the proliferating cell nuclear antigen (PCNA).
      Invaginations of the bile-duct epithelium or parietal sacculi increased, and
      peribiliary glands were well-developed. PCNA-positive cells significantly
      increased in the CBD, especially in the parietal sacculi and glands. It is
      concluded that PBM increases the cell cycle in CBD epithelium and subsequently
      developed peribiliary glands. These developed glands may be associated with the
      formation of protein plugs, often seen in patients with PBM.

PMID- 10663830
TI  - Reappraisal of the role of the bilioenteric conduit in the pathogenesis of
      postoperative cholangitis.
AB  - The incidence of postoperative cholangitis has changed very little despite
      progressive improvement in the treatment of biliary atresia. The role of the
      bilioenteric conduit in its pathogenesis is still uncertain. A retrospective
      study of 39 patients undergoing either a conventional Kasai operation (group 1, n
      = 20) or with placement of an antireflux valve (group 2, n = 10) or lengthening
      (group 3, n = 9) of the jejunal conduit from 40 to 60 cm was performed to compare
      the incidence of cholangitis. Postoperative cholangitis developed in 18 of the 39
      patients (46%). The incidence was 10/20 (50%) in group 1, 5/10 (50%) in group 2,
      and 3/9 (33%) in group 3 (P = 0.679). An animal experiment was conducted
      concomitantly to compare quantitative bacterial cultures of the bilioenteric
      anastomosis and the liver before and 1 week after Roux-en-Y hepaticojejunostomy
      (HPJ) in piglets without (group A, 25 cm) and with (group B, 50 cm) lengthening
      of the jejunal conduit in a porcine model of extrahepatic biliary obstruction.
      The growth of bacteria in both the bilioenteric anastomosis and the liver was not
      affected by lengthening the jejunal conduit from 25 to 50 cm (P = 0.612 and 0.
      057, respectively), despite a geometric increase in bacterial concentrations in
      both groups after HPJ. It is concluded that neither bacterial growth in the liver
      nor cholangitis following bile-duct reconstruction was affected by valving or
      lengthening the bilioenteric conduit.

PMID- 10663831
TI  - Management of pancreatic and duodenal injuries in pediatric patients.
AB  - Diagnosis of duodenal and pancreatic injuries is frequently delayed, and optimal
      treatment is often controversial. Fourteen children with duodenal and/or
      pancreatic injuries secondary to blunt trauma were treated between 1980 and 1997.
      The pancreas was injured in all but 1 child. An associated duodenal injury was
      present in 4. The preoperative diagnosis was suspected in only 6 patients based
      on clinical signs and ultrasonography. One patient was treated successfully
      conservatively; all the others required surgical management. At operation, three
      procedures were used: peripancreatic drainage, suture of the gland or duodenum
      with drainage, and primary distal pancreatic resection without splenectomy. A
      duodenal resection with reconstruction by duodeno-duodenostomy was performed in 1
      case. The overall complication rate was 14%: 1 fistula and 1 pseudocyst.
      Pancreatic ductal transection was recognized 3 days after the initial laparotomy
      by endoscopic retrograde cholangiopancreatography (ERCP). The mortality was 7%; 1
      patient died from septic and neurologic complications. When the diagnosis of
      pancreatic ductal injuries is a major problem, ERCP may be a useful diagnostic
      procedure. Pancreatic injuries without a transected duct may often be treated
      conservatively. The surgical or conservative management of duodenal hematomas is
      still controversial; other duodenal injuries often need surgical treatment.

PMID- 10663832
TI  - Roux-en-Y jejunostomy button in infants.
AB  - Establishing enteral feeding in high-risk infants with significant
      gastroesophageal reflux is a difficult challenge. Some patients are considered at
      very high risk for fundoplication and gastrostomy due to unstable medical
      conditions, dense upper-abdominal adhesions due to previous surgical procedures,
      or unfavorable anatomy. We describe a less invasive operation that provides
      jejunal feeding in a way that is safe, reliable, and convenient for the family.

PMID- 10663833
TI  - Ultrasonographic detection of intrauterine intussusception resulting in ileal
      atresia complicated by meconium peritonitis.
AB  - A neonate with ileal atresia (IA) complicated by meconium peritonitis (MP) whose
      prenatal ultrasonography (US) detected an intrauterine intussusception (IUI) is
      reported. Fetal ascites, dilated bowel loops, and abdominal calcifications were
      identified on serial US from 25 weeks of gestation. Intestinal loops with high
      echogenecity and a "target-like" appearance suggestive of IUI were detected in
      the right lower quadrant. The 2,680-g male was delivered vaginally at term and
      underwent a laparotomy. Fibrous adhesions and small calcifications were scattered
      throughout the peritoneal cavity. IA (interrupted type) was confirmed 17.0 cm
      cranial to the ileocecal valve (ICV). An ileo-ileal intussusception was also
      found between 16.5 cm and 9.0 cm cranial to the ICV. Partial resection of the
      ileum and an ileo-ileal anastomosis was performed. The postoperative course was
      uneventful. In this case, the pathological process of IUI resulting in IA and MP
      was demonstrated sonographically by identifying the "target-like" appearance in
      the fetus.

PMID- 10663834
TI  - The radiologist says malrotation: does the surgeon operate?
AB  - The management of malrotation when it is an incidental finding is unclear. This
      retrospective study reports an analysis of radiological and operative findings in
      a series of 71 patients. There were no deaths. We report a false-positive rate of
      15% for upper gastrointestinal contrast studies reported as showing malrotation.
      Our findings and a review of the literature demonstrate that in the asymptomatic
      child over 2 years of age, the evidence supporting mandatory correction of
      malrotation is weak.

PMID- 10663835
TI  - Intestinal volvulus: aetiology, morbidity, and mortality in Nigerian children.
AB  - In developed countries, intestinal volvulus in children is most frequently due to
      malrotation. To review the experience in Nigeria, a retrospective analysis of 28
      patients managed over 25 years at the Ahmadu Bello University Teaching Hospital,
      Zaria, Nigeria, was undertaken. There were 22 boys and 6 girls with an age range
      of 4 days to 14 years (median 4 years). There were equal numbers over and less
      than 5 years of age. Vomiting (89%) and abdominal distension (79%) were the most
      prominent features. Thirteen children (46%) had fever, associated with bowel
      gangrene in 5, while 8 (29%) presented with severe dehydration and shock. A plain
      abdominal radiograph was the only investigation performed, but the features were
      not specific for volvulus. In 11 children (39%) the volvulus was idiopathic, in 9
      (32%) due to adhesions or bands, in 5 (18%) to malrotation, and in 1 each a
      Meckel's diverticulum, internal herniation, and ventriculoperitoneal shunt.
      Twenty-three patients had a small-bowel, 4 sigmoid, and 1 caecal volvulus. The
      bowel resection rate for gangrene was 46% (small bowel 9, sigmoid 3, caecum 1).
      All patients with malrotation had Ladd's procedure performed. Wound infections
      occurred in 10 patients (36%), complete wound dehiscence in 1, and recurrence in
      1 (idiopathic terminal ileal volvulus). The mortality was 21%, mostly from
      overwhelming infection (2 neonates, 11-year-old, 3 >/= 5 years). Intestinal
      volvulus in our environment differs in aetiology from other reports. The
      resection rates are similar, however. This condition carries high morbidity and
      mortality.

PMID- 10663836
TI  - The evaluation of meconium disease by distribution of cathepsin D in intestinal
      ganglion cells.
AB  - Meconium disease (MD) results in intestinal obstruction in the neonate where
      tenacious meconium is found in the distal ileum and proximal colon. The
      obstructive symptoms improve at several days of age after some of the meconium is
      passed. We observed premature infants with MD who underwent ileostomy for
      intestinal obstruction due to tenacious meconium. Afterward, meconium was passed
      well and the clinical symptoms improved. After closing the ileostomy, growth and
      defecation became normal. The MD in our cases was documented by histologic
      changes in the maturation of ganglion cells observed at the time of ileostomy
      creation and closure. For an objective evaluation of the maturation of intestinal
      ganglion cells (IGC), we attempted to distinguish immature from mature cells by
      the expression of cathepsin D. We examined the distribution of cathepsin D in IGC
      in patients with MD to test the hypothesis that ganglion-cell immaturity might be
      related to MD. In ganglion cells at the time of ileostomy, cathepsin D was
      detected in the perinuclear cytoplasm (immature staining pattern), while at the
      time of ileostomy closure it was detected in intense granules throughout the
      cytoplasm (mature staining pattern). We propose that it would be possible to
      evaluate the maturation of IGC by the intracellular distribution of cathepsin D
      in MD and suggest that immaturity of IGC might be the cause of MD.

PMID- 10663837
TI  - Neonatal ovarian cysts: management and follow-up.
AB  - Twenty-seven neonatal ovarian cysts were diagnosed in utero during a 13-year
      period; 9 were complicated and 18 were initially simple, but 8/18 showed evidence
      of complications in utero or soon after birth, leaving only 10 simple cysts. One
      simple and 4 complicated cysts were surgically excised early in the study period;
      2 simple cysts were treated by needle aspiration at birth because of their large
      size. The remaining 20 cases were initially managed conservatively. All simple
      cysts and 10/13 complicated cysts regressed completely within 12 months; 3 that
      failed to regress were surgically excised. Nineteen patients who did not undergo
      a laparotomy had ultrasonographic (US) examinations from 3 months to 9 years
      after birth. Echography showed both ovaries in all 9 girls who had simple cysts
      at birth and in 2 of the 10 with complications. In the other 8 complicated cases
      only one ovary was detected at follow-up. Pre- or post-natal aspiration of simple
      cysts 4 cm or more in diameter is recommended, while conservative management
      seems appropriate in the absence of symptoms for simple cysts of less than 4 cm
      and complicated cysts of any size tending to involute after birth.

PMID- 10663838
TI  - Urolithiasis in childhood.
AB  - A retrospective review was performed of the records of 85 children with urinary
      tract calculi evaluated and treated during a 12-year period. The study evaluated
      the patients' age, sex, initial complaints, etiology, relevant pathological
      factors, stone location, mode of treatment, and stone analysis. There were 68
      boys and 17 girls, a ratio of 4:1. Patient age ranged from 10 months to 16 years
      (average 8.2 years). Flank pain was the most common manifestation. Seventy
      patients had calculi in the upper urinary tract and 31 in the lower urinary
      tract; 16 had stones in more than one site and 15 had bilateral stones.
      Hypercalciuria was the most common metabolic disorder. Most patients underwent
      open surgical procedures for removal of their calculi; 5 stones were successfully
      removed endoscopically. In 3 cases, the stones passed spontaneously. Calcium
      oxalate and calcium phosphate stones were present in 32 cases, struvite in 5,
      cystine in 2, and uric acid in 1 Urolithiasis is still one of the most common
      pediatric urologic problems in Turkey, but as living standards improve, the
      incidence of the disease has tended to decline in recent years. Anatomic
      anomalies and metabolic disorders are of great importance in the etiology of
      stone disease.

PMID- 10663839
TI  - Serum cytokine profile in reflux nephropathy.
AB  - Cytokines are small regulatory peptides with diverse functions. They regulate the
      immune system and modulate the inflammatory response, both of which are
      implicated in vesico-ureteric reflux (VUR) and associated reflux nephropathy
      (RN). The cytokine profile in VUR and RN has yet to be fully investigated. Blood
      was obtained from three subject groups immediately after induction of
      anaesthesia: group A [subjects with VUR and established RN, (N=9)]; group B [VUR
      alone but no associated RN, (N=6)]; and group C [age- and sex-matched controls
      with no history of urinary sepsis, (N=14)]. Serum cytokine levels of tumour
      necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), soluble TNF receptor-1
      (sTNF-R1), and interleukin-8 (IL-8) were measured using standard ELISA technique.
      Serum levels of IL-6 were higher in group A subjects (1.798-4.638 pg/ml, median
      3.253 pg/ml) than controls (1.531-2.078 pg/ml, median 1.798 pg/ml). There was no
      significant difference in levels in group B subjects (1.498-3. 048 pg/ml, median
      1.948 pg/ml) and controls. These same relationships were observed for levels of
      TNF-alpha (group A: 8. 501-14.471 pg/ml, median 13.483 pg/ml; group B: 7.088
      10.650 pg/ml, median 8.886 pg/ml; group C: 6.746-13.344 pg/ml, median 7.671
      pg/ml) and sTNF-R1 (group A: 690.34-5780.74 pg/ml, median 1197.38 pg/ml; group B:
      366.65-1401.62 pg/ml, median 592.82 pg/ml; C: 313.49-636.33 pg/ml, median 504.17
      pg/ml). IL-8 was not significantly elevated in any of the study groups (A or B)
      compared with control group C (group A: 27.08-56.38 pg/ml, median 31.35 pg/ml;
      group B: 29.90-35. 87 pg/ml, median 31.35 pg/ml; group C: 25.05-30.22 pg/ml,
      median 29. 90 pg/ml). These results suggest there may be an immunological basis
      to RN.

PMID- 10663840
TI  - Fulguration of posterior urethral valves using the Nd:YAG laser.
AB  - Endoscopic management is the accepted form of treatment for posterior urethral
      valves (PUV). The Nd:YAG laser has been in clinical use for many decades, but has
      been used only sporadically for ablating PUV. In this study, PUV were diagnosed
      by micturating cystourethrogram (MCU). In the 9-month period beginning March
      1997, 23 boys 3 months to 9 years of age underwent endoscopic Nd:YAG laser
      surgery for PUV using a 600 quartz bare fibre through the catheter channel of an
      8.5 F cystoscope. The laser power and total energy delivered ranged from 20 to 50
      W and 50-1085 J, respectively. Type I PUV were present in 20 boys; 1 had type
      III, and in 1 boy each there were residual valves and a urethral stricture from a
      previous electrocautery ablation. All operations were done with the patient under
      general anaesthesia supplemented by caudal morphine. Routine postoperative
      cystoscopy was done in the first 5 cases only. All patients had a good stream of
      urine without bleeding or any other complication after valve ablation. Mucosal
      tags seen on follow-up cystoscopy in 5 patients were fulgurated by laser. In 4
      other patients recystoscopy was required for deterioration of the urinary stream
      and persistent posterior urethral dilatation on MCU; residual valves were
      refulgurated by laser. An indwelling catheter was left in only 4 patients, 2 of
      whom were primarily operated and 2 following refulguration. All except the first
      2 were treated as out-patients. Application of the Nd:YAG laser has added a new
      dimension for treating PUV. The initial experience has been very encouraging: the
      destruction of valves is precise, there are no complications, and it can be
      practised on a day-care basis without indwelling catheterisation. The bare fibre
      can be used repeatedly, thus reducing the cost of treatment.

PMID- 10663841
TI  - The acute scrotum in Arab children with familial Mediterranean fever.
AB  - Over a period of 7 years, among 175 boys under the age of 16 years with familial
      Mediterranean fever (FMF), 16 (9%) developed 28 episodes of scrotal swelling that
      was unilateral in 26 (93%) and bilateral in 2 (7%). Fever and pain were present
      in 15 (94%) children; fever was characterized by a gradual onset and pain was
      moderate in intensity. The episodes were self-limiting and lasted from 8 h to 5
      days. Scrotal swelling was the presenting feature of FMF in 4 (25%) patients. Six
      (38%) children underwent surgery; the operative findings, available in 3, showed
      a normal testis and epididymis and inflammation of the tunica vaginalis. The self
      limiting nature of the episodes lasting for a few days was similar to the
      clinical course of serositis seen in FMF. This strongly suggests that
      inflammation of the tunica vaginalis, resulting in scrotal swelling, is another
      feature of FMF serositis. The gradual onset of fever, pain, swelling, and
      recurrence in a boy of Mediterranean origin, especially in the presence of a
      relevant family history, strongly points toward the diagnosis of FMF and
      conservative management. Early diagnosis and prophylactic colchicine therapy are
      expected to avert recurrences, which may result in ischemic testicular necrosis
      and FMF nephropathy.

PMID- 10663842
TI  - Decision-making in pediatric varicocele surgery: use of color Doppler ultrasound.
AB  - Although varicoceles are common in adolescence, the indications for surgery as
      well as the procedure of choice are controversial. We have evaluated the use of
      color Doppler ultrasound (CDUS) as an objective tool in the assessment of such
      patients in a 5-year prospective study for determination of varicocele size,
      venous flow patterns, testicular volume, and resistance index. A high ligation
      was performed only when reverse blood flow was demonstrable in the varicocele
      during a Valsalva maneuver, and a low approach when this finding was absent.
      Twenty-six boys underwent low ligation and 53 high ligation based on the findings
      of CDUS. The incidence of recurrence (3.8%) was lower than that encountered by
      the same surgical team prior to introduction of CDUS (20.5%) (P = 0.004). These
      results are even more striking when contrasted with published recurrence rates of
      12% to 15% (P = 0.015 to 0.003). Thus, CDUS proved to be a useful tool in
      selecting the proper surgical approach for varicocele in adolescence. The
      incidence of recurrence was significantly reduced following the introduction of
      this procedure.

PMID- 10663843
TI  - Transverse testicular ectopia: preoperative diagnosis by ultrasonography.
AB  - Transverse testicular ectopia (TTE) is a rare anomaly. We report the first case
      of TTE described in Taiwan. The physical examination, ultrasonography (US), and
      laparoscopy revealed both testes in the left hemiscrotum, and surgical correction
      was performed. This case was diagnosed preoperatively by US, which can offer an
      easy, safe, and convenient alternative in the preoperative diagnosis of TTE. The
      possible mechanism for this anomaly and the literature are reviewed.

PMID- 10663844
TI  - Evaluation of selected parameters of the cytokine system in burn wounds in
      children.
AB  - Using immunohistochemical methods, we studied cellular infiltrations of burn
      wounds in children. The relative number of cells with cluster of differentiation
      3 (CD3) CD68 molecules, cells with receptors for interleukin-2 (IL-2) and its
      receptor (IL-2R), IL-3, IL-3R, IL-6, IL-6R, tumor necrosis factor-alpha (TNF
      alpha), TNF-alphaR, and cells with TNF-alpha molecules on their surface was
      studied. The relationships between these values were determined. The following
      results were observed: (1) A positive correlation between the relative numbers of
      CD68 cells and the percentage of cells with receptors for IL-2 (IL-2R) and TNF
      alpha (TNF-alphaR); (2) A negative correlation between the relative numbers of
      CD3 cells and cells with receptors for IL-2 and TNF-alpha; (3) A strong negative
      correlation between the relative numbers of CD3 and CD68 cells; (4) A positive
      correlation between the percentage of cells with receptors for TNF-alpha and the
      size of the burn wound; and (5) A positive correlation between the relative
      numbers of cells with the TNF-alpha molecule on their surfaces and studied
      receptors for interleukins, i.e., IL-2R, IL-3R, IL-6R, and TNF-alphaR. These
      results indicate a key role for TNF-alpha and its receptor within the cytokine
      system in the course of the inflammatory reaction in burn wounds.

PMID- 10663845
TI  - Mechanism of impaired immunologic response to bacterial antigens in burn wounds
      in children.
AB  - Material was obtained from necrotic tissue excised from burn wounds in 60
      children and examined immunohistochemically for the percentages of CD3, CD4, CD8,
      CD20, and CD68 cells. The results were then correlated with the burn surface area
      (BSA). Bacteriologic studies revealed the presence of bacteria in only 22 wounds
      with BSA greater than 10% of total body surface area. In this group, the
      proportion of CD3, CD4, CD8, CD20, and CD68 cells was correlated with the
      severity of infection, measured as the number of bacteria per g tissue. The
      results showed a positive correlation between the BSA and the percentage of CD8
      cells (P < 0.001) and a negative correlation between CD4 cells and BSA (P <
      0.02). The correlation between CD4/CD8 index and BSA was significantly negative.
      Likewise, a significant negative correlation was also noted between the
      percentage of CD4 and CD8 cells within the wound (P < 0.001). The severity of
      infection (bacteria/g tissue) was also positively correlated with the percentage
      of CD8 cells (P < 0.05) and negatively with the percentage of CD4 cells (P <
      0.05). The correlation between CD4/CD8 index and intensity of infection was also
      highly significant. The results obtained show that in extensive burn wounds
      bacterial antigens may not be recognized properly due to the decreased percentage
      of CD4 cells and increased percentage of CD8 cells, which enhances bacterial
      growth in these wounds.

PMID- 10663846
TI  - Hydatid disease in children may have an atypical presentation.
AB  - Although there is voluminous literature describing various aspects of hydatid
      disease in children, little attention has been paid to the small group of
      patients whose symptoms result in atypical presentation. This article addresses
      this problem, describing the features in ten children aged from 2 to 12 years.
      The sites of involvement were within a choledochal cyst (1). the pelvic cavity
      (1), the spleen (1), and transverse mesocolon. Albendazole was efficacious in the
      treatment of one recurrent case, as well as in preventing recurrence.

PMID- 10663847
TI  - The effects of sucralfate and selective intestinal decontamination on bacterial
      translocation.
AB  - Sucralfate is widely used as a cytoprotective agent in patients with peptic ulcer
      and other intestinal mucosal damage. In this study, the effects of sucralfate
      and/or selective intestinal decontamination with gentamycin on bacterial
      translocation (BT) in rats with experimentally-induced mechanical jaundice were
      investigated. Seventy-five adult male Wistar albino rats were divided into five
      groups of 15 each. In all except a sham group, we performed ligation of the
      common bile duct (CBD) via a vertical laparatomy. After surgery, the rats in
      group 1 were treated with oral sucralfate (5 mg/kg per day); those in group 2
      underwent oral gentamycin therapy (5 mg/kg per day) for 5 days. Group 3 rats were
      treated with sucralfate and gentamycin for 5 days subsequent to the operation.
      The rats in group 4 served as controls, and received only 0.9% saline solution.
      Group 5 was a sham group. After 5 days of surgery, all rats were killed; the
      mesenteric lymph nodes (MLN), liver, and a segment of terminal ileum were
      harvested aseptically. The collected tissues were cultured in McCaunkey medium
      and chocolate agar. For each specimen, the colony-forming units (CFU) were
      calculated and the percentage of viable translocated micro-organisms was counted.
      In all rats who had ligation of the CBD, high numbers of bacteria were
      demonstrated in the liver, MLN, and ileum. In the liver of rats with sucralfate
      and/or gentamycin treatment, there was a marked reduction in CFU compared to the
      control group. Similarly, in the MLN measurements of CFU were higher in the
      control rats than the study groups. In both McCaunkey and chocolate media, the
      numbers of bacteria in control rats were significantly higher than in the study
      groups (P < 0.001). However, among the study groups themselves there was no
      significant difference in CFU in any of the specimens or culture media (P >
      0.05). Experimentally-induced mechanical jaundice from ligation of the CBD causes
      significant BT in rats. Sucralfate and/or gentamycin may reduce the degree of BT
      from the bowel mucosa. We did not find any difference in protection from BT
      between sucralfate and gentamycin or both in rats with experimentally-induced
      mechanical jaundice.

PMID- 10663848
TI  - Silent bowel perforation and transanal prolapse of a ventriculoperitoneal shunt.
AB  - A 2-year-old hydrocephalic child presenting with ventriculitis following
      intestinal perforation by a ventriculoperitoneal (VP) shunt is reported. The
      peritoneal end of the shunt had extruded through the anus without causing any
      abdominal signs. Removal of the shunt, external ventriculostomy, and antibiotics
      were effective treatment.

PMID- 10663849
TI  - Sequestrated tubular duplication of the colon with congenital subglottic
      stenosis.
AB  - A 6-year-old male presenting with features of intestinal obstruction because of a
      sequestrated tubular duplication of the colon is reported. The patient also had
      congenital subglottic stenosis, an association not yet reported with any type of
      gut duplication. Complete excision of the duplication was done with preservation
      of vascularity of the adjacent normal colon. The relevant literature is reviewed
      briefly.

PMID- 10663850
TI  - Perioperative extracorporeal membrane oxygenation for tracheal reconstruction in
      congenital tracheal stenosis.
AB  - The management of a critical airway in infants and toddlers with congenital
      tracheal stenosis (CTS) continues to be an enormous challenge to the surgeon.
      Until recently, this condition often proved fatal. Improvements in surgical
      techniques, anesthetic management, and postoperative critical care have resulted
      in successful outcomes in children not long ago considered untreatable. However,
      issues such as the best operative approach and the optimal perioperative
      management are still unresolved. The diagnosis of CTS, often delayed, must be
      considered in any infant with stridor, wheezing, cyanosis, or recurrent episodes
      of pneumonia. Associated anomalies are the rule, including frequently vascular
      rings and rarely pulmonary agenesis. These defects can be repaired with
      conventional ventilatory support under cardiopulmonary bypass, or using
      extracorporeal membrane oxygenation (ECMO). We report our experience in which
      ECMO was used to support two patients with CTS during the perioperative period.
      ECMO proved to be both safe and practical, allowing unrushed, precise repair of
      the tracheal stenosis and providing brief postoperative support. Perioperative
      outcomes were excellent, although one of our patients died months after the
      repair. A review of the literature and our experience in which ECMO was used to
      provide cardiopulmonary support during repair of CTS showed uniformly successful
      perioperative outcomes.

PMID- 10663851
TI  - Congenital cystic adenomatoid malformation and extralobar sequestration occurring
      independently in the ipsilateral hemithorax.
AB  - We report a case of congenital cystic adenomatoid malformation (CCAM) and
      extralobar pulmonary sequestration (EPS) occurring independently in the
      ipsilateral hemithorax. A literature search using Medline, Winspirs 2.0, found 14
      previously reported cases of CCAM within an EPS. There are no reports of each
      form of congenital pulmonary abnormality occurring separately in the same
      patient.

PMID- 10663852
TI  - Juvenile papillomatosis of the breast in male infants: two case reports.
AB  - Juvenile papillomatosis of the breast ("Swiss cheese disease") is a benign
      localized proliferative condition of the breast which occurs almost exclusively
      in young adult women. Patients with this lesion often have a family history of
      breast carcinoma, and rarely carcinoma may coexist with the lesion at the time of
      diagnosis. We present two cases of male infants with juvenile papillomatosis of
      the breast. The pathology and clinical management of this novel lesion is
      discussed.

PMID- 10663853
TI  - Acute gastric volvulus secondary to a Morgagni hernia.
AB  - Gastric volvulus (GV) is a rare surgical emergency in infancy and childhood. The
      first case of a child with an acute GV secondary to a Morgagni hernia (MH) is
      reported. The authors briefly discuss the etiology, clinical features, and
      management of acute GV and review the scattered reports of strangulated MHs in
      children.

PMID- 10663854
TI  - Spontaneous biliary perforation in a child with features of Ivemark syndrome.
AB  - A case of spontaneous biliary perforation is reported for the following
      noteworthy aspects: its rare mode of presentation as an acute intestinal
      obstruction; its presentation in late infancy; and its association with Ivemark
      syndrome.

PMID- 10663855
TI  - A bleeding tendency as the first symptom of a choledochal cyst.
AB  - We report an 8-month-old male presenting with gingival hemorrhages and nasal
      bleeding as the first symptom of a choledochal cyst (CC). On physical
      examination, there was a large cystic mass in the right upper abdominal quadrant.
      Laboratory studies on admission revealed moderate liver dysfunction and a
      bleeding tendency due to vitamin K deficiency. After administration of 5 mg
      vitamin K the bleeding tendency disappeared. At laparotomy, a large CC 5 cm in
      diameter was found and the liver showed moderate cholestasis. The sudden onset of
      a bleeding tendency in infants with congenital liver or biliary-tract disease may
      suggest not only biliary atresia, but also CC.

PMID- 10663856
TI  - Biliary atresia with hyperandrogenic amenorrhea: case report.
AB  - The etiology of hyperandrogenic amenorrhea in a 16 year-old girl after a
      successful Kasai operation for biliary atresia was unclear. Delayed puberty and
      menarche were observed. There was no luteinizing hormone-follicular stimulating
      hormone surge. A provocative luteinizing hormone-releasing hormone test showed a
      normal response. Peripheral aromatization of androgens appeared to function
      normally. However, plasma levels of sex hormone-binding globulin and total
      testosterone were high and the free testosterone level was normal. The
      anovulatory menstrual cycle continued after menarche at 18 years of age. A
      combination of estrogen and progesterone therapy was effective. The etiology
      might be associated with delayed metabolic clearance of testosterone accompanied
      by the compensatory cirrhosis and portosystemic shunt.

PMID- 10663857
TI  - Ectopic pancreatic rests: a rare cause of persistent umbilical discharge.
AB  - Ectopic pancreatic rests are rare. We report two cases discovered in infants who
      underwent surgical exploration of the umbilicus for persistent umbilical
      discharge with peri-umbilical excoriation. A shallow sinus leading to a firm cyst
      was excised in both infants, and histopathological study confirmed the presence
      of exocrine and endocrine pancreatic tissue. There is only one other case of
      ectopic umbilical pancreatic tissue reported, and this was in a patient
      presenting with an umbilical mass.

PMID- 10663858
TI  - Accurate localization of an insulinoma by preoperative selective intra-arterial
      calcium injection and intraoperative glucose monitoring.
AB  - The role of pre- and intraoperative procedures for the localization of
      insulinomas has been extensively debated. We report a case of successful
      treatment using preoperative selective intra-arterial calcium injection and
      intraoperative glucose monitoring. A 12-year-old boy with hypoglycemic attacks
      had a large insulinoma in the head of the pancreas on computed tomography.
      Preoperative selective angiography combined with arterial stimulation-venous
      sampling (ASVS) by intra-arterial injection of calcium revealed no other
      insulinomas in the body and tail of the pancreas. Elevation of serum glucose on
      intraoperative monitoring confirmed complete enucleation of the insulinoma.
      Preoperative ASVS can accurately localize an insulinoma, and may help to increase
      the success rate of surgery and avoid blind pancreatectomy.

PMID- 10663859
TI  - Adrenal lacerations in child abuse: a marker of severe trauma.
AB  - There are few reports of adrenal injuries complicating inflicted pediatric
      trauma. All child-abuse cases at the New York City Medical Examiner's Office over
      a 7-year period were reviewed. Of these 121 homicides, 50 sustained severe
      injuries to the torso. Five infants (10.0%) had adrenal laceration, a marker of
      major blunt-force injury.

PMID- 10663860
TI  - A Meckel's diverticulum containing pancreatic tissue and nesidioblastosis in a
      patient with Beckwith-Wiedemann syndrome.
AB  - A 30-month-old twin with Beckwith-Wiedemann syndrome underwent exstirpation of a
      nephroblastoma from the right kidney. A Meckel's diverticulum (MD), an incidental
      finding intraoperatively, was resected because it was indurated and enlarged.
      Histologically, the MD contained ectopic gastric and pancreatic mucosa.
      Nesidioblastosis was identified within the pancreatic tissue. This is probably
      the first description of ectopic nesidioblastosis within a MD.

PMID- 10663861
TI  - Umbilical evagination of the bladder with omphalocele minor.
AB  - A neonate with umbilical evagination of the bladder (UEB) and omphalocele minor
      (OM) is reported. The findings in this case support the origin of the urachus
      from the upper end of the cloaca rather than the allantois. The frequent
      occurrence of OM with urachal anomalies, including UEB, suggests an embryological
      association between the two conditions.

PMID- 10663862
TI  - Malrotation with recurrent volvulus presenting with cholestasis, pruritus, and
      pancreatitis.
AB  - A patient aged 16 years was referred following numerous episodes of intense
      pruritus associated with persistently altered liver function tests. Ultrasound
      (US) demonstrated the superior mesenteric vein positioned more to the left than
      usual and abnormal orientation of the duodenum, consistent with a midgut
      malrotation. Endoscopic retrograde cholangiopancreatography the common bile duct,
      suggesting a malrotation with chronic or recurrent volvulus. A classic
      malrotation with 180 degrees volvulus was noted at operation. A second child
      previously thought to have recurrent idiopathic pancreatitis was noted to have
      ampullary distortion secondary to malrotation following presentation with an
      intestinal obstruction. Pruritus and pancreatitis have not been previously
      reported with malrotation, although cholestatic jaundice has been described. The
      diffculties in diagnosis and the role of US are discussed. Ladd's procedure is
      the appropriate treatment for this condition.

PMID- 10663863
TI  - Sigmoid volvulus in childhood: report of six cases.
AB  - Sigmoid volvulus is a common cause of large-bowel obstruction in elderly
      individuals, but is quite rare in childhood. We report six cases in patients
      under 20 years of age. One had Hirschprung's disease. Gangrenous sigmoid colon
      was found in three cases and resection was performed. Sigmoidopexy (one case) and
      extraperitonealization (two cases) were performed for viable sigmoid colon. There
      were no recurrences after 5.7 years of follow-up.

PMID- 10663864
TI  - A case of Currarino triad with familial sacral bony deformities.
AB  - We describe a male patient presenting with Currarino triad: a recto-urethral
      fistula, sacral bony deformity, and a presacral teratoma. Clinical screening of
      his family revealed three additional cases with incomplete forms of this
      association. Cytogenetic findings in the patient and his mother were normal. This
      case suggests that the occurrence of an anorectal malformation together with a
      sacral bony deformity should raise a physician's index of suspicion for
      associated presacral tumors, and that screening of the patient's family members
      with sacral radiographs is necessary.

PMID- 10663865
TI  - Fanconi's anemia with solitary crossed renal ectopia, vesicoureteric reflux, and
      genital abnormalities.
AB  - Fanconi's anemia is an autosomal recessive disease, the main feature being
      pancytopenia secondary to bone-marrow hypoplasia. However, multiple congenital
      abnormalities may be encountered, urogenital malformations being common. We
      describe a patient with solitary crossed renal ectopia, vesicoureteric reflux,
      hypospadias, and unilateral undescended testis with absent vas deferens.

PMID- 10663866
TI  - Bladder-wall abscess in a girl with neurogenic bladder.
AB  - We report a case of a bladder-wall abscess in a patient with myelodysplasia and a
      neurogenic bladder. The aetiology of the abscess was obscure, but the patient had
      recurrent urinary tract infections and was being managed by clean intermittent
      catheterisation.

PMID- 10663867
TI  - Delayed presentation of a posttraumatic perirenal urinoma in a 6-year-old boy.
AB  - A 6-year-old boy presented with a perirenal urinoma over the left flank about 3
      months following trauma. Delayed presentation of a post-traumatic perirenal
      urinoma is rare in children, and percutaneous catheter drainage was effective in
      this case.

PMID- 10663868
TI  - Congenital urethral fistula.
AB  - A case of congenital urethral fistula with an intact glanular urethra without
      chordee is reported with a discussion of the possible etiology and one-stage
      repair.

PMID- 10663869
TI  - Balanitis xerotica obliterans with urethral stricture after hypospadias repair.
AB  - Three cases of urethral stricture due to balanitis xerotica obliterans (BXO)
      after hypospadias repair are reported. The first patient showed white, dense
      scarring on the prepuce before the hypospadias repair and developed a stricture
      of the urethra after the operation. The second and the third were uneventful for
      6 and 2 years, respectively, after the hypospadias repair, and then developed
      urethral strictures. Pathologic diagnosis of the stenotic lesion is essential.
      Complete excision of the affected urethra with topical steroid ointment or
      sublesional triamcinolone injection is recommended for this condition. Although
      the complication of BXO after hypospadias repair is rare (3 out of 796 cases with
      hypospadias in our series), surgeons need to be aware of this condition as a
      cause for late onset of urethral problems.

PMID- 10663870
TI  - Congenital lumbar hernia.
AB  - Congenital lumbar hernia (CLH) is a rare anomaly with only 45 cases reported in
      the English-language literature. This paper describes nine patients with CLH
      treated in our unit. Unusual features included the relatively high incidence of
      inferior lumbar hernia, presentation at the age of 6 years in one case, and an
      association with hydrometrocolpos and anorectal malformation, which is hitherto
      unreported. In seven patients the hernia could be repaired successfully. One
      patients' parents refused surgery for the CLH after treatment of a
      hydrometrocolpos and another died of fulminant pneumonia before the operation.
      Early operation is the treatment of choice, and repair with local tissues is
      preferable. The need for prosthetic material arises when the size of the defect
      is large. A successful operation offers a good quality of life.

PMID- 10663871
TI  - Deep cervical fasciitis in a child.
AB  - Deep cervical infections in children are relatively uncommon and often require
      prolonged antibiotic therapy. The organism may not be isolated, in which case it
      is necessary to cover Gram-negative and Gram-positive organisms as well as
      anaerobes. During treatment continued vigilance is required to detect abscess
      formation, with ultrasound providing a useful tool for this purpose.

PMID- 10663872
TI  - On visualization of the inferior pouch in esophageal atresia (EA) without
      fistula.

PMID- 10663873
TI  - Transumbilical resection and umbilical plasty for patent omphalomesenteric duct.

PMID- 10663874
TI  - A possible role of the plasmalemmal cytoskeleton, nitric oxide synthase, and
      innervation in infantile hypertrophic pyloric stenosis.

PMID- 10663893
TI  - The prognostic significance of tumor vascularization in patients with localized
      colorectal cancer.
AB  - Angiogenesis is essential for tumor growth and metastasis, and vascular density
      is known as an independent prognostic factor in several tumor entities. We
      studied the prognostic relevance of vascular density in colorectal cancer,
      examining 146 patients treated surgically for cure. Tumor sections were
      immunostained with JC70, an endothelial cell marker. Microvessel quantification
      used light microscopy. The slides were scanned at a low magnification, and
      individual microvessel counts were made on a x200 field in the area of the most
      dense neovascularization. Vascular density was found to be 75+/-27/visual field
      and to be independent of age, sex, pT and pN categories, tumor recurrence, and
      overall survival. Overall survival in the subgroup of patients with tumor
      recurrence was significantly shorter with tumors of greater vessel density (>75)
      than in those of less vessel density (<75). Multivariate analysis showed
      microvessel count to be an independent prognostic factor for the overall survival
      rate of patients with tumor recurrence; among these patients there was also a
      significant difference in the relapse-free survival rates between the
      hypovascular and the hypervascular groups. Our findings suggest that the
      microvessel density of the primary tumor determines the speed of tumor recurrence
      after metastatic disease has been triggered by other, unknown mechanisms.
      Although tumor vascularization can be linked to the aggressiveness of colorectal
      cancer, it has no value as a new prognostic marker in clinical practice.

PMID- 10663892
TI  - Detection of colorectal neoplasms by the highly sensitive hemoglobin-haptoglobin
      complex in feces.
AB  - Screening for fecal occult blood by means of guaiac tests has an unsatisfactory
      sensitivity for the detection of colorectal neoplasms. The immunological
      determination of human hemoglobin in feces has a higher sensitivity and
      specificity, but hemoglobin is degraded during its transport through the
      gastrointestinal tract. We compared the hemoglobin test to a newly developed
      immuno-chemiluminometric (ILMA) assay for quantifying the hemoglobin-haptoglobin
      complex in feces which shows high stability against degradation. From each of 621
      patients with gastrointestinal complaints before scheduled colonoscopy we
      collected two 1-ml samples from a single stool; there were no dietary
      restrictions. The sensitivity for detecting colorectal carcinomas proved 87% with
      hemoglobin. With the hemoglobin-haptoglobin complex it was 87% at a cutoff level
      of 1.5 microg/g feces, 83% at 2.0 microg/g feces, and 78% at 2.5 and 3.0 microg/g
      feces. The sensitivity for detecting large adenomatous polyps was 54% with
      hemoglobin, 76% with the hemoglobin-haptoglobin complex at a cutoff point of 1.5
      microg/g feces, 73% with the hemoglobin-haptoglobin complex at 2.0 and 2.5
      microg/g feces, and 65% with the hemoglobin-haptoglobin complex at 3.0 microg/g
      feces. The optimal cutoff point for the hemoglobin-haptoglobin complex was
      estimated to be 2.0 microg/g stool. The specificity for hemoglobin (99%) was
      significantly higher than that for the hemoglobin-haptoglobin complex at 2.0
      microg/g feces (96%). Immunological determination of the hemoglobin-haptoglobin
      complex in feces has a comparable sensitivity as the fecal hemoglobin assay for
      colorectal carcinomas and a significantly higher sensitivity for adenomatous
      polyps but a significantly lower specificity. Its use for colorectal cancer
      prevention is currently being evaluated in a screening study.

PMID- 10663894
TI  - Preliminary report on pathology of colorectal cancer in Poland in 1995 and 1975:
      is it still the same disease?
AB  - Over past three decades in Poland we have seen a steady increase in the incidence
      of colorectal cancer. It is unclear whether this phenomenon is associated with
      changes in biology of the disease. In the present study we compared basic
      clinical data and pathological features of colorectal carcinomas submitted as
      resection specimens to a single institution in 1975 (n=76) and 1995 (n=106). We
      found a significant increase in sigmoid tumors (15.8% in 1975, 34.9% in 1995,
      P=0.0028), a decline in the frequency of mucinous carcinomas (22.4% in 1975, 7.5%
      in 1995, P=0.0041), and reversed distribution of low- and high-grade tumors (more
      high-grade than low-grade carcinomas in 1975, the opposite in 1995). We observed
      trends toward more pronounced peritumoral desmoplastic response, less prominent
      chronic peritumoral inflammatory infiltrate, and more frequent perineural
      invasion. The 1995 patients were on average significantly older at surgery (59
      years in 1975, 64 years in 1995, P=0.02) and had smaller tumors (max.
      diameter=5.49 cm in 1975, 4.27 cm in 1995, P=0.0018). There were no differences
      in distribution of tumor stage, patient's sex, type of infiltrating margin formed
      by carcinomas, relative amount formed by the solid tumor component, invasion of
      veins and lymphatics, or presence of an adenoma contiguous with a carcinoma.
      Differences between 1975 and 1995 cases observed in our material probably reflect
      the changing biology of colorectal carcinoma in Poland. Mucinous, high-grade,
      proximal tumors, surrounded by prominent chronic inflammatory infiltrate,
      diagnosed in relatively younger subjects are associated with familial and
      sporadic cancers due to widespread genomic instability (replication error
      positive or RER(+) phenotype). We conclude that in Poland the APC/K-ras/p-53
      carcinogenesis pathway is becoming even more important than the carcinogenesis
      characterized by RER(+) tumors. This study is a starting point for further
      investigations aimed at confirming this hypothesis.

PMID- 10663895
TI  - Multivisceral resections for primary advanced rectal cancer.
AB  - Fixation of the locally advanced rectal tumor at the time of operation is an
      important prognostic variable. It may be difficult to determine whether fixation
      is caused by inflammatory adhesions or by direct tumor extension tethering the
      tumor to the surrounding pelvic structures. Extended en bloc removal of the
      locally advanced rectal cancer with involved adjacent organ(s) increases the
      resectability rate. We examined the perioperative mortality and morbidity and the
      prognosis of patients undergoing multivisceral resections for advanced primary
      rectal cancers. Of 83 patients with rectal cancers 20 (24%) had locally advanced
      tumors. Cases were divided into Gunderson-Sosin stages B(3) and C(3) and were
      further stratified into those with histologically confirmed carcinomatous
      invasion of the adjacent organ and those with inflammatory adhesions.
      Perioperative mortality was 5%. Only five patients (24%) showed histopathological
      confirmation of carcinomatous adhesion into adjacent organ(s)/structure(s).
      Histological confirmation of contiguous tumor spread was higher in C(3) patients.
      There was no significant difference between patients with positive and negative
      histopathological confirmation of malignant spread in terms of survival rates.
      Multivisceral resections can be performed safely for locally advanced rectal
      cancers with acceptable mortality and morbidity rates. The presence of local
      tumor extension does not mean incurability, and sound surgical judgement should
      dictate that in the face of a tethered lesion one must extend the surgical
      intervention radically to resect any tumor en bloc.

PMID- 10663896
TI  - Comparison between the biofragmentable anastomosis ring and stapled anastomoses
      in the extraperitoneal rectum: a prospective, randomized study.
AB  - Serious complications can be carried by intestinal anastomoses, particularly in
      the distal and proximal part of the gastrointestinal tract. The biofragmentable
      anastomosis ring (BAR) has been shown to be a safe anastomotic technique, but its
      clinical applicability in the extraperitoneal rectum has not yet been completely
      established. This study compared BAR anastomoses and stapled anastomoses in the
      middle rectum. Thirty-six consecutive patients initially suitable for elective
      colorectal anastomosis in the middle rectum were enrolled into this study. All
      patients had intraperitoneal rectum carcinoma, and 31 underwent a colorectal
      anastomosis in the middle extraperitoneal rectum. They were randomly allocated to
      a stapled technique or BAR anastomosis. Intraoperative findings and technical
      drawbacks, tumor behavior, and postoperative course were recorded. All patients
      were followed up, and late stenosis rate was investigated by endoscopy. The
      procedure was carried out in each of the 15 patients randomized to receiving a
      BAR anastomosis. No major difficulties were encountered, and the time needed was
      even less than that required for a stapled anastomosis. One patient in the
      stapled group had an early bleeding that required a further laparotomy. No
      significant differences in postoperative complications were noted between the two
      groups, although one patient with stapled anastomosis experienced a clinical
      leakage that needed loop colostomy. Biofragmentability was regular; buttons were
      eliminated in 3 weeks without any bowel disturbance. BAR ring insertion in the
      deep pelvis did not produce a shorter colonic resection. The late stenosis rate
      was similar between the groups. This study shows that in extraperitoneal middle
      rectum BAR anastomosis is as feasible and safe as the stapled method. The latter
      is more expensive, and manual suture is more difficult. Therefore the BAR is now
      the method of choice for this anastomosis in the authors' unit.

PMID- 10663897
TI  - Cinedefecographic evidence of difficult evacuation in constipated patients with
      complex symptoms.
AB  - Patients with constipation may have various pelvic complaints of difficult
      evacuation coexisting with infrequent evacuation and other abdominal complaints,
      and the overlapping of symptoms makes it difficult to select appropriate therapy
      based on clinical history and routine office examination alone. Cinedefecography
      is an objective method for examining patients who have complex subjective
      symptoms. This study assessed the value of cinedefecography for evaluating
      patients with constipation with multiple complaints. We divided 185 patients with
      constipation into two those with (group 1) or without (group 2) cinedefecographic
      evidence of difficult evacuation. These groups were compared relative to
      complaints, manometric results, cinedefecography findings, and the success of
      biofeedback treatment. Group 1 patients were further evaluated according to the
      type of abnormal findings: sigmoidocele, rectocele, intussusception, and perineal
      descent. We found no significant differences in patient complaints between the
      groups. However, there were more patients in group 2 with intussusception than in
      group 1; there were also significant differences between the groups in mean
      resting pressure, maximum resting pressure, and maximum squeeze pressure. In
      group 1 patients with rectocele complained more frequently of excessive
      straining, and those with intussusception complained more frequently of
      incomplete evacuation. Sensory threshold and maximal tolerable capacity were
      significantly higher in patients with intussusception. Rectocele was predominant
      in women, and biofeedback treatment was extremely advantageous (86%) for patients
      in group 1 with a rectocele in association with other pathology. Whether the
      intussusception or the descent causes decreased mean resting and mean and maximum
      squeeze pressures is unknown but is an additional and potentially important
      finding which needs further elucidation for it to have therapeutic significance.

PMID- 10663898
TI  - Amyloidosis--an unusual case of recurrent intestinal bleeding and sigmoid
      perforation: case report with review of the literature.
AB  - We describe a patient with recurrent intestinal bleeding and sigmoid perforation
      due to amyloidosis. Hartmann's procedure was carried out with resection of the
      diseased sigmoid colon and by performing a terminal colostomy. The postoperative
      course was uneventful, but the patient died 3 months later of lobar pneumonia and
      multiple organ system failure.

PMID- 10663899
TI  - Diagnostics and surgical treatment strategy for rectal cavernous hemangiomas
      based on three case examples.
AB  - A 20-year-old man with a congenital vascular malformation extending from the anal
      canal into the distal sigmoid had had recurrent perianal blood loss as a neonate.
      A hemangioma was diagnosed for the first time in 1978. The patient received
      regular and frequent gastroenterological treatment until admission. Decisive for
      the indication for surgery was the patient's need for blood infusions and shorter
      bleeding intervals in June 1998. Surgical therapy consisted of deep anterior
      rectosigmoid resection with coloanal pouch anastomosis. In a second case of a 27
      year-old woman a sigmoid hemangioma was diagnosed in conjunction with emergency
      sigmoid resectioning. Because of recurrent hemorrhages a coloanal pouch was also
      established here in a second step. The third case involved a 19-year-old woman
      with a 12-year history of repeated perianal hemorrhages. After sigmoid
      discontinuity resection we carried out proctectomy with descendostoma creation
      due to renewed severe intractable perianal bleeding. The histological examination
      revealed a rectal hemangioma that had caused the repeated perianal hemorrhages.
      Surgical reconstruction was then achieved by coloanal pouch anastomosis. In view
      of the good functional and perioperative results, current surgical therapy should
      aim at preserving continuity and continence by coloanal pouch anastomosis.

PMID- 10663900
TI  - Polymyositis of the skeletal muscles as an extraintestinal complication in
      quiescent ulcerative colitis.
AB  - Myositis of the skeletal muscle is a rare complication of inflammatory bowel
      disease. We report about a 33-year-old woman with quiescent ulcerative colitis
      known since 1995. She had suffered from recurring fever and pain in the thighs
      for about 4 weeks. Electromyography of quadriceps and deltoid muscles revealed
      myopathic changes. Diagnosis of polymyositis was confirmed by magnetic resonance
      imaging indicating edematous changes in the distal extremity muscles. The
      symptoms rapidly responded to high doses of steroids. Review of the literature
      indicates only a few cases describing an association of ulcerative colitis and
      myositis, most of them during acute exacerbations of the disease. In contrast,
      the present patient was in remission. Diagnosis of myositis should be considered
      in inflammatory bowel disease patients complaining of myalgia or muscular
      weakness. Magnetic resonance imaging may show specific features and can be used
      in addition to laboratory investigations and muscle biopsy for diagnosis of
      polymyositis.

PMID- 10663902
TI  - ?

PMID- 10663901
TI  - Small-bowel angiosarcoma after pelvic irradiation: a report of two cases.
AB  - Angiosarcoma is a rare tumor in the small bowel. Several predisposing factors
      have been suggested, including external irradiation for another malignancy. Only
      six cases of small-bowel angiosarcoma in patients previously treated with pelvic
      irradiation for gynecological malignancies have been reported hitherto. We
      present here two patients in whom a diagnosis of small-bowel angiosarcoma was
      made 10 years or more after intrapelvic irradiation. These cases demonstrate poor
      prognosis in this disease. Although postirradiation angiosarcoma is a rare
      condition, its possibility should be kept in mind when operating on previously
      irradiated patients.

PMID- 10663904
TI  - ?

PMID- 10663903
TI  - ?

PMID- 10663905
TI  - ?

PMID- 10663906
TI  - ?

PMID- 10663907
TI  - ?

PMID- 10663908
TI  - ?

PMID- 10663909
TI  - ?

PMID- 10663910
TI  - Molecular basis of cardiac hypertrophy.
AB  - Cardiac hypertrophy is an adaptive process to an increased hemodynamic overload.
      When cardiomyocytes cultured on silicone dishes were stretched, second messengers
      such as protein kinase C (PKC), Raf-1 kinase, and mitogen-activated protein (MAP)
      kinases were activated, which were followed by increased protein synthesis.
      Moreover, pretreatment with an angiotensin II (AngII) type 1 receptor antagonist
      dimished an increase in protein synthesis, MAP kinase activity, and c-fos gene
      expression induced by the stretching of cardiomyocytes. These suggest the linkage
      of the cardiac renin-angiotensin system to the formation of pressure-overload
      hypertrophy. Indeed, in the stretch-conditioned medium the levels of AngII
      concentration were increased. Also, mechanical stretch enhanced endothelin (ET)-1
      release from the cardiomyocytes and activated the Na(+)/H(+) exchanger
      independently of these vasoactive peptides. In the second part, we examined AngII
      induced signaling pathways both in cardiac myocytes and in cardiac fibroblasts.
      AngII-evoked signal transduction pathways differed between cell types. In cardiac
      fibroblasts AngII activated MAP kinases through a pathway including the
      Gbetagamma subunit of Gi protein, Src, Shc, Grb2, and Ras, while Gq and PKC
      activation was necessary in cardiac myocytes. We further explored norepinephrine
      (NE)-induced signaling pathways in cardiac myocytes. NE activated Raf-1 kinase
      and MAP kinases and increased amino acid uptake in cardiomyocytes of neonatal
      rats. beta-adrenoceptor (AR) stimulation as well and alpha1-AR stimulation was
      involved in NE-induced MAP kinase activation. It is noteworthy that unlike in
      other cell types not only PKC activation but also protein kinase A (PKA)
      activation increased the activities of Raf-1 kinase and MAP kinases in cardiac
      myocytes and induced cell growth. Finally, we observed that beta-AR-induced
      activation of MAP kinases is dependent on both Gs/cAMP/PKA and Gi/Src/Ras
      signaling pathways and that phosphorylation of beta-AR is critical to the cross
      talk between these signaling pathways.

PMID- 10663911
TI  - [Noninvasive evaluation of coronary bypass grafts by magnetic resonance imaging.
      Comparison of the Haste and Fisp-3-D sequences with the conventional coronary
      angiography].
AB  - The aim of the study was to evaluate the patency of coronary artery bypass grafts
      (CABG) with the 2D and 3D magnetic resonance (MR) imaging techniques. 29 patients
      with 74 bypass grafts and a total of 91 distal anastomoses were studied on a 1.5
      Tesla scanner using a phased array body coil. A 2D T-2 weighted breathhold turbo
      spin echo sequence (Haste) and a 3D breath hold contrast enhanced MR angiography
      sequence (Fisp-3-D) were performed. With the Haste and Fisp-3-D sequences 55 of
      the 58 patent and 15 of the 16 occluded grafts were recognized; the sensitivity
      and specificity were 95% and 94%, respectively. With the Haste sequence 74%
      (47/63) and with the Fisp-3-D sequence 64% (40/63) of the distal anastomoses were
      seen in good image quality. Only 3 of 8 significant grafts stenoses were
      detected. The patency of CABGs can be evaluated non-invasively with the Haste and
      the Fisp-3-D angiography sequences. Better results can be expected with the
      development of a blood-pool contrast medium and the combination of MR flow
      measurements with imaging techniques.

PMID- 10663912
TI  - [Flow-cytometric analysis of platelet activation during rotablation].
AB  - Acute occlusion and subacute restenosis of the coronary artery are still the
      limiting factors of the otherwise successful interventional cardiology. Platelets
      and especially activated platelet populations play a key role concerning these
      typical and sometimes fatal complications. In this study we used flow-cytometry
      to determine the influence of the modern interventional technique of rotablation
      on platelet antigens and their possible alteration. A PTCA control group was
      included. We analyzed the fluorescence expression of structural antigens CD41a
      (GPII-IIIa) and CD42b (GPIb-V-IX), and of the activation-dependent antigens CD62p
      (P-selectin, PADGEM, GMP-140) and CD63 (GP53). Furthermore we analyzed the
      binding of fibrinogen to the platelet flow-cytometrically. CD41a and CD42b did
      not show significant alternations in fluorescence before, directly after and
      thirty minutes after finishing PTCA and rotablation (PTCA: CD41a p=0.8 and 0.9;
      CD42b p=0.5 and 0.2; rotablation: CD41a p=0.2 and 0.2; CD42b p=0.4 and 0.1). But
      platelet activation could be detected directly after PTCA and rotablation
      measuring the mean channel fluorescence intensity (MCFI) of CD62p, CD63 and
      fibrinogen binding (all p<0.05). Thirty minutes after finishing the procedures
      there were again significant changes in MCFI in PTCA (CD62p, CD63, fibrinogen
      binding; all p<0.05), but not in rotablation (CD62p p=0.1; CD63 p=0. 9;
      fibrinogen binding p=0.5). But MCFI for CD62p and fibrinogen binding in
      rotablation was higher than in PTCA. The results of our study show that
      rotablation also induces significant platelet activation that is higher than in
      PTCA alone. Flow cytometry is a sensitive and specific, multiparametric tool in
      establishing platelet activation. The individual platelet activation process is
      part of a complex cascade of events happening in the rotablated coronary segment
      leading to a vascular-molecular inflammatory process and consecutive clinical
      problems in some patients.

PMID- 10663913
TI  - [Scanning electron microscopic analysis of vessel wall reactions after coronary
      stenting].
AB  - High restenosis rates are still a major factor limiting the use of minimal
      invasive coronary stenting. Tissue reactions to the implanted alloplastic
      endoprostheses are still barely understood. 18 coronary artery segments 32 hours
      up to 340 days after stent implantation of 16 patients were post-mortem
      investigated. The pathomorphological findings of the vessel wall after stent
      insertion were studied by scanning electron microscopy (SEM). Stent integration
      can be divided with intraindividual differences in three phases: In the acute
      phase (<6 weeks) the border between vascular lumen and arterial wall is
      constituted by a thin, multi-layered thrombus. During the time course of
      integration, increasing amounts of Smooth Muscle Cells (SMC) and extracellular
      matrix can be detected. No endothelial cells can be found in the implantation
      zone. In the intermediate phase (6 weeks to 12 weeks) the neointima consists of
      extracellular matrix and increasing numbers of SMC. The borderline between lumen
      and neointima is generated by SMC and extracellular matrix. Increasing amounts of
      endothelial cells are found on the luminal surface of the stent neointima.
      Complete reendothelization is first noted in the chronic phase three months after
      stenting. Matrix structures are increasing whereas the amount of SMC decreases.
      In all phases of stent incorporation, the alloplastic stent material is covered
      by a thin (few nanometer) proteinaceous layer.

PMID- 10663914
TI  - Clinical and angiographic outcome of patients with acute inferior myocardial
      infarction.
AB  - OBJECTIVES: This study sought to determine the procedural success and the in
      hospital outcome after primary coronary angioplasty in patients with acute
      inferior myocardial infarction and right ventricular involvement (RVI).
      BACKGROUND: RVI represents an easily detectable, highly prevalent subset of acute
      inferior infarction associated with poor outcome even in the era of thrombolysis.
      Primary PTCA may offer advantages in patients with inferior infarction involving
      the right ventricle. METHODS: Primary coronary angioplasty with optimal stenting
      was performed in 87 of 88 consecutive patients presenting within 24 hours after
      onset of acute inferior myocardial infarction. On the basis of right precordial
      ST segment elevations at admission, patients were classified into those without
      (n=61) and those with RVI (n=27). The patients were followed prospectively for
      angiographic success at 10 days and for in-hospital clinical outcome. RESULTS:
      Baseline characteristics including age, severity of coronary artery disease,
      proportion of stent implantation, and occurrence of cardiogenic shock were
      comparable. Patients with RVI had larger infarct sizes (lactate dehydrogenase
      level: 962 vs 580 U/l, P=0.03), developed more often complete atrioventricular
      block (18.5 vs. 2%, p=0.0038), needed more often parasympatholytics (48.1 vs
      18.8%, p<0.001), and had a substantially higher incidence of the Bezold-Jarisch
      reflex (29.6 vs 6.6%, p<0.01) following reperfusion. Success of recanalization
      therapy acutely and at 10 days, as well as in hospital mortality were similar in
      patients with and without RVI (88.5 vs. 85.2%, 79.3 vs. 84.7%, 7.4 vs 9.8%).
      However, patients with RVI revealed a greater lumen gain acutely after PTCA (2.49
      vs. 2.13 mm, p=0.025) and experienced less frequently major cardiac events (14.8
      vs. 36.1%, p=0.04) which included reinfarction, re-ischemia, coronary bypass
      grafting, stent thrombosis, and cardiac death. In addition, procedural success
      was established more rapidly (fluoroscopy time: 10 vs 15 min., p=0.032) and with
      less contrast material (242 vs 295 ml, p=0.015) in patients with RVI. This is
      probably due to the more proximal location (84.6 vs 6.6%, p<0.0001) and the
      larger reference diameter (3.17 vs. 2.79 mm, p=0.03) of the occluded right
      coronary artery. CONCLUSIONS: Primary PTCA is an appropriate reperfusion strategy
      in patients with RVI. Further comparative studies are required to compare the
      effectiveness of primary PTCA with early thrombolytic therapy in this high risk
      setting.

PMID- 10663915
TI  - [Acute myocardial infarction in patients with angiographically normal coronary
      arteries: clinical features and medium term follow-up].
AB  - BACKGROUND: Acute myocardial infarction (MI) in patients with normal coronary
      arteries has been recognized for several years. In most cases its etiology is
      unknown. The objective of the present study was to describe clinical features and
      medium term follow-up of those patients. PATIENTS AND METHODS: Between April 1991
      and December 1996, 9860 coronary angiographies were performed in our hospital.
      During this period 17 patients with documented myocardial infarction and
      completely normal coronary arteries were identified. Acute myocardial infarction
      was defined as the clinical event with acute angina pectoris, ST-elevation
      typical for myocardial infarction, and an increase in serum creatinine
      phosphokinase (CPK) above 125 U/l. RESULTS: The mean peak CPK was 675 U/l (range:
      129-1760 U/l). All 17 patients revealed significant ST-segment elevation.
      According to the ECG criteria there was no predilection for a specific location
      of MI (9 anterior MIs and 8 inferior MIs). Thrombolytic therapy was performed in
      9 patients. In 12 patients areas of localized hypo- or akinesia were shown on
      left ventricular cineangiography. The mean ejection fraction was 61.5+/-10.3%.
      The age and sex distribution revealed a bimodel character: there was a younger
      age group of 9 patients, all men with a mean age of 35.9 years (31-43) and all
      strong cigarette smokers (mean 28 cigarettes/day) and there was an older group of
      7 patients (1 man, 6 women) with a mean age of 56,4 years (47-68) and no
      significant association with cigarette smoking. During a mean follow-up period of
      48.6 months (31-85 months) no patient died and no patient suffered from recurrent
      chest pain and used nitroglycerin occasionally. CONCLUSION: Patients with acute
      MI and angiographically normal coronary arteries show a bimodal sex and age
      distribution: a younger age group, all men and uniformly strong cigarette smokers
      and an older group predominantly women with no significant association with
      cigarette smoking. Both groups seem to have a favorable prognosis.

PMID- 10663916
TI  - [Initial experience with an implantable loop recorder in patients with
      unexplained syncope].
AB  - Patients with recurrent syncope undiagnosed after extensive noninvasive and
      invasive testing pose a diagnostic and therapeutic dilemma. Holter monitoring is
      non-diagnostic in 90% of cases. Recent developments in loop recorder technology
      permit longterm ECG monitoring in patients with recurrent unexplained syncope.
      The implantable loop recorder monitors a single lead electrogram continuously
      using 2 sensing electrodes on the device shell. The device was implanted in 20
      patients (11 male, 9 female) with the history of recurrent syncope. During a mean
      follow-up of 12+/-6 months after device implantation, 11 patients (55%)
      experienced syncope (8 pts) or presyncope (3 pts). In the remaining 9 patients,
      no syncope occurred. In all 11 patients with syncope or presyncope during follow
      up, loop recording definitively determined whether an arrhythmia was the cause of
      symptoms or not. Diagnosis included bradycardia in one patient, tachycardia in
      two patients, in one patient two rhythm disturbances were revealed: frequent
      ventricular premature beats with bigemini and atrial flutter. Two patients had a
      neurocardiogenic syncope. Syncope was nonarrhythmic in 5 patients. An implantable
      loop recorder is useful for establishing the diagnosis if symptoms are recurrent
      but too infrequent for conventional monitoring techniques.

PMID- 10663917
TI  - [With hand on heart. "From the golden cage of science"].

PMID- 10663918
TI  - [Pulmonary artery rupture--fatal complication of catheter examination
      (thermodilution catheter)].

PMID- 10663919
TI  - [ [In Process Citation]

PMID- 10663938
TI  - [The Bone and Joint Decade 2000-2010--for the prevention and treatment of
      musculoskeletal diseases].

PMID- 10663939
TI  - [Molecular mechanisms of cell-cell and cell-matrix interactions in the
      pathophysiology of rheumatoid arthritis].
AB  - The original structure of the synovial membrane is completely destroyed in the
      rheumatoid synovium and is characterized by mononuclear cell infiltration,
      synoviocyte proliferation, neo-vascularization, and deposition of extracellular
      matrix proteins. Adhesion molecules play an important role in the development of
      these pathologic changes. In this review we discuss the role of the adhesion
      receptors of the selectin, integrin and immunoglobulin families and of the CD44
      molecule in the cell-cell and cell-matrix interaction in the pathogenesis of the
      inflammatory changes in rheumatoid arthritis.

PMID- 10663940
TI  - [Lifelong heavy agricultural work and development of arthrosis of the hand--a
      case study].
AB  - Heavy physical work load is a known determinant of osteoarthritis of the hip,
      which may account for the high risk observed among farmers. On the other hand,
      the data on influence of heavy manual work in the pathogenesis of hand
      osteoarthritis are still controversial. We examined 25 retired farm laborers who
      strenuously worked for more than 50 years. The investigation included a history
      of professional activity, clinical and radiological examination of the hands,
      hips and knees, MRI of hand and laboratory evaluation of 4 participants.
      Interestingly, the farm laborers with osteoarthritis of the hands, hardly
      complained. In many of the proximal interphalangeal joints, a discrepancy was
      observed between the clinical hypertrophic changes and the radiological
      osteoarthritis which was weak or absent. This difference was less pronounced in
      the distal interphalangeal joints. Furthermore the distribution pattern of the
      osteoarthritis of the hand was striking with an over-proportional involvement of
      the metacarpophalangeal joints and less pronounced of the intercarpal joints.
      Most often both hands have been affected and the typical localization of the
      metacarphophalangeal joint osteoarthritis was the first, second and third finger.
      In all but one participant we found at least unilateral osteoarthritis of the hip
      and compared to the hands, complaints were more severe. Our findings support the
      hypothesis that the distribution of osteoarthritis in the hand is affected by
      lifelong farming. As shown by the data on proximal interphalangeal joints, the
      periarticular tissue can adapt to the mechanical load in the strength grip.

PMID- 10663941
TI  - [Progression of foot deformities in rheumatoid arthritis--a radiologic follow-up
      study over 5 years].
AB  - OBJECTIVE: The typical changes of the foot in patients with rheumatoid arthritis
      (RA) are the rear foot valgus and the flattening of the longitudinal arch as well
      as the splayfoot with hallux valgus and little toe deformities. These foot
      deformities are not so much a cosmetic problem, but are very painful and limit
      the patient's mobility. METHODS: The progression of rheumatic foot deformities
      with a follow-up of five years was described in 36 patients (70 feet) with RA and
      an average duration of the disease of 19.2 years (+/- 9.8 years). The analysis
      was based on standardized X-rays of the feet using the index of Larsen, Dale, and
      Eek. The number of affected joints and their predominant locations were
      evaluated. RESULTS: In the course of the follow-up, the first MTP joint was
      affected most frequently in 57%. Especially the tarsometatarsal joints of the
      Lisfranc-joint-line showed progressive changes. Altogether, a radiological
      progression of arthritic changes and a worsening of the foot statics were
      observed in 97% of the patients. CONCLUSION: In view of the rapid progression of
      rheumatic foot disorders, there is need not only for a consequent pharmacotherapy
      but also for strict clinical controls and a disease stage oriented local therapy.

PMID- 10663943
TI  - ?

PMID- 10663942
TI  - [The role of cells and molecules in chronic inflammation as exemplified in
      rheumatoid arthritis. Kloster Seeon, 2-3 July 1999. Symposium abstracts].

PMID- 10663962
TI  - Recombinant tissue-plasminogen activator-induced thrombolysis after cerebral
      thromboembolism in mice.
AB  - The effects of intracarotid thrombolysis with recombinant tissue-plasminogen
      activator (rt-PA) on cerebral laser Doppler flow (LDF) and the degree of ischemic
      injury, as revealed by triphenyltetrazolium chloride (TTC) staining, were studied
      24 h following cerebral thromboembolism in mice. Thromboembolization with fibrin
      rich clot material (0.28-microl clot volume) led to an LDF decline to about 20
      30% of baseline in untreated mice, which resulted in reproducible infarcts of the
      middle cerebral artery (MCA) territory (122.8 +/- 29.4 mm(3)). Administration of
      rt-PA (10 mg/kg) 15 min after clot injection induced a progressive LDF
      restoration to approximately 115% of control values after 2 h, and brought about
      a significant reduction of the infarct volume (62.3 +/- 42.4 mm(3)). Our results
      indicate that ischemic injury may be significantly attenuated by intracarotid
      thrombolysis. However, injury is not completely reversed, even if reperfusion is
      initiated as early as 15 min after embolization.

PMID- 10663963
TI  - Expression of the tuberous sclerosis complex gene products, hamartin and tuberin,
      in central nervous system tissues.
AB  - Tuberous sclerosis complex (TSC) is a common genetic disorder in which affected
      individuals can develop mental retardation, developmental brain defects, and
      seizures. Two genetic loci are responsible for TSC: TSC1 on chromosome 9q and
      TSC2 on chromosome 16p. Here, we report our analysis of TSC1 (hamartin) and TSC2
      (tuberin) protein expression in the central nervous system (CNS). Both tuberin
      and hamartin are expressed in neurons and astrocytes where they physically
      interact. In the mouse cerebellum in vivo, tuberin predominantly localizes to the
      perinuclear region of the Purkinje cell, whereas hamartin is distributed along
      neuronal or astrocytic processes. In contrast, both hamartin and tuberin
      demonstrate similar neuronal expression patterns in pure neuronal cultures in
      vitro. Additionally, hamartin is highly expressed in astrocytes in mixed neuron
      glia cultures in vitro, suggesting that hamartin may be important for astrocyte
      growth control. Unlike tuberin, loss of hamartin expression was not observed in
      sporadic astrocytomas. These results suggest that tuberin and hamartin may
      differentially contribute to the CNS pathology in TSC.

PMID- 10663964
TI  - Impairment and restoration of the endothelial blood-brain barrier in the rat
      cerebral infarction model assessed by expression of endothelial barrier antigen
      immunoreactivity.
AB  - Endothelial barrier antigen (EBA) can be used to detect the blood-brain barrier
      in the central nervous system of rats. This study investigated the temporal
      profile of antigen expression in cerebral vessels after infarction and assessed
      the relationship between re-establishment of this antigen in newly formed vessels
      and astrocytes around these vessels. Rats were subjected to cerebral ischemia for
      2 h by the intraluminal thread method, then killed after 1, 3, 7, 14 and 28 days.
      Perfusion-fixed paraffin-embedded brains were immunostained for detection of EBA
      and glial fibrillary acidic protein (GFAP) by the streptavidin-biotin-peroxidase
      complex method. EBA immunostaining in vessels in the infarcted lesion was reduced
      at day 1 and had almost disappeared by day 3. Newly formed vessels were found
      from day 3, but were not stained at day 7. However, these new vessels were weakly
      stained at day 14 and definitely stained at day 28. GFAP immunostaining was
      completely negative around these proliferating vessels. The temporal profile of
      disappearance and re-expression of EBA in cerebral infarcted lesion may be
      associated with aggravation and improvement of brain edema, although barrier
      permeability was not explored in this study. The expression of this antigen has
      no relationship to the formation of astrocyte/endothelial contacts.

PMID- 10663965
TI  - Motor neuronal loss and neurofilament-ubiquitin alteration in MoMuLV-ts1
      encephalopathy.
AB  - A temperature-sensitive mutant of Moloney murine leukemia virus (MoMuLV-ts1)
      induces immunosuppression and spongiform encephalopathy in susceptible newborn
      mice. The associated neuronal degeneration primarily involves the motor neurons
      in specific target areas of the central nervous system (CNS). Neuronal loss
      occurs in the absence of direct viral infection of neurons and is the most
      dramatic pathological change in the CNS of infected mice. To quantitatively
      demonstrate neuronal loss, an unbiased morphometric stereological study was
      undertaken using the optical disector method. Using highly susceptible FVB/N
      mice, neuronal loss was quantitated in the tissue sections of brain stem from
      infected and noninfected mice at 20 and 35 days post inoculation (dpi). Results
      indicated that there was no significant neuronal loss at 20 dpi, but significant
      (P < 0.05) at 35 dpi. In addition, histology, transmission electron microscopy
      and immunohistochemistry revealed Lewy body-like inclusions consisting of
      aggregates of neurofilaments and cellular organelles. Degenerated neurons and
      glial cells were heavily ubiquitinated. Together, these results suggest that
      significant neuronal loss occurs at the end of the disease process and that Lewy
      body-like formation and protein ubiquitination are part of the pathogenic process
      in ts1-induced encephalopathy.

PMID- 10663966
TI  - Differential c-Fos and caspase expression following kainic acid excitotoxicity.
AB  - Caspases play crucial roles in the inflammatory response and in the cell pathway
      leading to apoptosis. Caspase 1 (ICE), 2 (Nedd2), 3 (CPP32), 6 (Mch2) and 8
      (Mch5, FLICE) expression was examined using immunohistochemistry in the brains of
      rats and gerbils following systemic administration of kainic acid (KA). The
      distribution of caspase expression was compared with the distribution of c-Fos
      expression, a transcription factor that is produced in response to the
      excitotoxic insult. Strong caspase 2 immunoreactivity was found in microglia up
      to 6 h following KA administration. Focal strong expression of caspases 1, 2, 3,
      6 and 8 was observed in astrocytes and neurons, from 12 to 48 h after KA
      injection, in areas in which a number of neurons were committed to die. This
      distribution was in contrast with the generalised distribution of c-Fos
      expression following KA administration. Only a minority of neurons in the
      entorhinal cortex, amygdala and hilus, but a majority of neurons in selected
      thalamic nuclei, exhibited strong caspase expression in KA-treated rats. Similar
      findings, although minimised, were observed in KA-treated gerbils. Double
      labelling caspase immunohistochemistry and in situ end-labelling of nuclear DNA
      fragmentation disclosed co-localisation of strong caspase expression and nuclear
      DNA breaks in a small percentage of neurons but no co-localisation in astrocytes.
      Western blots of entorhinal cortex and neocortex homogenates showed cleavage of
      certain caspase substrates in KA-treated rats. The intensity of the bands
      corresponding to lamin B and protein kinase C-delta was decreased in the
      entorhinal cortex following KA administration. Several bands appeared in the
      entorhinal cortex and neocortex paragraph signin Western blots processed for the
      demonstration of poly(ADP-ribose) polymerase (PARP), thus indicating that other
      proteases, in addition to caspases, cleaved PARP following KA administration.
      Taken together, these findings indicate that KA excitotoxicity triggers caspase
      expression which, although predominant in regions subjected to irreversible cell
      damage, has only a weak association with the presence of nuclear DNA breaks and
      neuron cell death. Although these results suggest caspase activation, further
      studies have to be performed to elucidate whether caspase activation plays a
      crucial role in KA excitotoxicity.

PMID- 10663967
TI  - Hypoglycaemic neuropathy: occurrence of axon terminals in plantar skin and
      plantar muscle of diabetic BB/Wor rats treated with insulin implants.
AB  - It is generally believed that diabetic neuropathy is due to chronic
      hyperglycaemia. However, experience from insulinoma patients and experimental
      studies show that hypoglycaemia may also cause neuropathy. Accordingly, the
      plantar nerves of diabetic eu-/hypoglycaemic BB/Wor rats treated with insulin
      implants exhibit a distinct neuropathy. To what extent hypoglycaemic neuropathy
      affects axon terminals in skin and muscle is unknown. In the present study we
      examine the occurrence of epidermal axon profiles and the neuropeptide calcitonin
      gene-related peptide (CGRP) in plantar skin, and of end plate axon terminals in a
      plantar muscle of diabetic BB/Wor rats subjected to long periods of
      hypoglycaemia. The number of protein gene product-immunoreactive axon profiles
      was found to be normal in heel skin biopsy specimens from eu-/hypoglycaemic rats,
      but many profiles were short and thin. The content of CGRP in the skin biopsy
      samples was significantly below normal. After staining with antibodies against
      the vesicular acetylcholine transporter protein, the occurrence of end plate axon
      terminals was significantly reduced in sections from the flexor hallucis brevis
      muscle of eu-/hypoglycaemic rats. Moreover, the end plate axon terminals tended
      to be abnormally small in these rats. We conclude that the hypoglycaemic
      neuropathy seen in plantar nerve trunks of diabetic BB/Wor rats treated with
      insulin implants is accompanied by mild alterations in the epidermal innervation
      of plantar skin and a more obviously abnormal nerve terminal pattern in plantar
      muscle.

PMID- 10663968
TI  - Secretory granules of pituitary adenomas: quantitative study of hormonal
      antigenicity.
AB  - Ultrastructurally, the antigenicity of major pituitary hormones in secretory
      granules was quantitatively investigated in five growth hormone (GH)-secreting
      adenomas, five prolactin (PRL)-secreting adenomas and eight clinically non
      functioning (CN-F) adenomas. Sparsely granulated cells with a few or several
      small secretory granules (60-100 nm) exhibiting little or only weak antigenicity
      of various biochemically unrelated hormones were commonly observed in CN-F
      adenomas and occasionally in GH- and PRL-secreting adenomas. GH- or PRL-secreting
      adenomas consisted of many densely granulated cells with medium-sized (200-250
      nm) or large (over 250 nm) secretory granules and a few or several sparsely
      granulated cells with small secretory granules. The densely granulated cells
      showed intense GH or PRL antigenicity and slight to moderate antigenicity for
      other hormones in large secretory granules and little or only weak antigenicity
      for various hormones including GH or PRL in small secretory granules. Their
      secretory granules larger than 160 nm or 140 nm significantly exhibited intense
      GH or PRL antigenicity (Fisher's exact test; P < 0.05 and < 0.01, respectively).
      Two CN-F adenomas showed sparsely and densely granulated cells as well as
      intermediate cells. The densely granulated cells closely resembled GH-secreting
      cells. The intermediate cells simultaneously included small and medium-sized or
      large secretory granules exhibiting little/slight and intense GH-antigenicity,
      respectively. This study indicates that sparsely granulated cells of different
      categories showing slight antigenicity for various hormones, antigenically share
      the same origin, and that their hormonality, single or multiple, may be
      selectively activated in the developmental course of secretory granules.

PMID- 10663969
TI  - Hepatitis C virus infection and myositis: a polymerase chain reaction study.
AB  - Muscle biopsy tissue from a patient with chronic hepatitis, who was hepatitis C
      virus (HCV) positive and showed slight weakness of the right arm and leg
      associated with increased serum creatine kinase levels, was studied using
      immunocytochemical and polymerase chain reaction (PCR) techniques. Muscle biopsy
      showed changes compatible with an inflammatory myopathy. Immunohistochemical
      studies included the use of monoclonal antibodies against human T lymphocytes,
      macrophages, immunoglobulins, major histocompatibility complex class I molecules
      (MHC-I), and the neoantigens of the terminal C5b-9 complement membrane attack
      complex (MAC). In addition to confirming the potential importance of cytotoxic T
      cells and MHC-I antigen expression in inducing muscle pathology, we demonstrated
      MAC deposition and the presence of HCV-RNA in the muscle of our patient,
      suggesting that direct involvement of the virus leading to complement activation
      might be important in inducing muscle damage.

PMID- 10663970
TI  - The vesicular forebrain (pseudo-aprosencephaly): a missing link in the
      teratogenetic spectrum of the defective brain anlage and its discrimination from
      aprosencephaly.
AB  - Two cases out of a sample of 41 fetuses and infants with prosencephalic
      malformation, observed at the Institute of Pathology and Department of
      Neuropathology of the University of Heidelberg, are described here in detail.
      These cases presented grossly with microcephaly and missing forebrain, appearing
      to be cases of aprosencephaly. However, in one of these cases glio-mesenchymal
      membranes with an ependymal outline, consistent with the microscopic appearance
      of the dorsal sac membrane in holoprosencephaly and obviously representing
      remnants of a collapsed primitive prosencephalic vesicle, could be demonstrated.
      In the other case only hindbrain structures, with the exception of the
      cerebellum, were present without any demonstrable remnants of a prosencephalon.
      We propose that the microscopic specification of a primitive prosencephalic
      vesicle in the first case and similar cases does not justify the diagnosis of
      atelencephaly/aprosencephaly because the prosencephalon was not really missing
      (pseudo-aprosencephaly). The prosencephalic anlage had been formed but remained
      vesicular without further differentiation of a holospheric brain mantle as in
      common holoprosencephaly ('vesicular forebrain'). We believe that pseudo
      aprosencephaly represents the most primitive form of holoprosencephaly, in which
      the forebrain remains as a complete sac, linking classical holoprosencephaly with
      'true' aprosencephaly, i.e., defective prosencephalic anlage due to developmental
      arrest. The 'vesicular forebrain' allows one to extend the classification of
      Probst by an additional category which might be termed complete sac category,
      intercalated between the dorsal sac category and 'true'
      atelencephaly/aprosencephaly.

PMID- 10663971
TI  - Spontaneous and ethyl-nitrosourea-induced medullomyoblastomas in cerebellar
      vermis defect (CVD) mutant rats.
AB  - A 26-week-old female cerebellar vermis defect (CVD) rat, a mutant with cerebellar
      vermis defect and cerebellar dysplasia, developed a brain tumor about 10 mm in
      diameter. Histopathologically, the tumor consisted of diffuse proliferation of
      small round to ovoid cells with hyperchromatic nuclei, occasionally containing
      round to strap-shaped myoblastic cells. Immunohistochemically, the small round
      cells expressed neuron-specific enolase and synaptophysin, indicating neuronal
      differentiation; myoblastic components reacted to desmin, myoglobin, and
      vimentin. Based on these findings, the case was diagnosed as a medullomyoblastoma
      (MMB). Furthermore, two cerebella tumors in CVD rats, which were induced by
      transplacental application of ethyl-nitrosourea, showed histopathology similar to
      the aforementioned case. MMB is a very rare tumor in humans and animals; thus, it
      is noteworthy that MMBs developed in CVD rats, involving the dysplastic
      cerebellum with abnormal migration of external granule cells.

PMID- 10663972
TI  - Expression of dystroglycan and laminin-2 in peripheral nerve under axonal
      degeneration and regeneration.
AB  - In Schwann cells, the transmembrane glycoprotein beta-dystroglycan composes the
      dystroglycan complex, together with the extracellular glycoprotein alpha
      dystroglycan which binds laminin-2, a major component of the Schwann cell basal
      lamina. To provide clues to the biological functions of the interaction of the
      dystroglycan complex with laminin-2 in peripheral nerve, the expression of beta
      dystroglycan and laminin-alpha2 chain was studied in rat sciatic nerves
      undergoing axonal degeneration and regeneration as well as in normal condition.
      In normal sciatic nerve, immunoreactivity for the cytoplasmic domain of beta
      dystroglycan was consistently and selectively localized in the Schwann cell
      cytoplasm underlying the outer (abaxonal) membrane apposing the basal lamina.
      While beta-dystroglycan expression was gradually down-regulated in Schwann cells
      losing contact with axons during axonal degeneration, it was progressively up
      regulated as the regenerating process of ensheathment and myelination proceeded
      during regeneration. Interestingly, beta-dystroglycan expression, when
      detectable, was always restricted to the Schwann cell cytoplasm beneath the outer
      membrane apposing the basal lamina during both axonal degeneration and
      regeneration. Furthermore, laminin-alpha2 immunoreactivity roughly paralleled
      that of beta-dystroglycan during both axonal degeneration and regeneration,
      indicating that the expression of beta-dystroglycan and laminin-alpha2 is induced
      and maintained by the Schwann cell contact with axons. Our results indicate that
      the dystroglycan complex is involved in the adhesion of the Schwann cell outer
      membrane with the basal lamina and suggest that the dystroglycan complex may play
      a role in the process of Schwann cell ensheathment and myelination through the
      interaction with laminin-2.

PMID- 10663973
TI  - C-terminal alpha-synuclein immunoreactivity in structures other than Lewy bodies
      in neurodegenerative disorders.
AB  - alpha-Synuclein is a presynaptic terminal protein that accumulates abnormally in
      plaques in Alzheimer's disease (AD), in Lewy bodies in Lewy body disease (LBD)
      and in filamentous inclusions in multiple system atrophy. Since it has been
      previously shown that proteinase K or formic acid pretreatment enhances alpha
      synuclein immunoreactivity in Lewy bodies and plaques, we hypothesized that the
      immunoreactivity in tangles, glial cells and Pick bodies might be revealed by
      such pretreatment. Brain sections from patients with AD, LBD, progressive
      supranuclear palsy (PSP), corticobasal degeneration (CBD) and Pick's disease were
      pretreated with proteinase K or formic acid and immunostained with antibodies
      against the N-terminal, C-terminal or non-amyloid beta component of AD amyloid
      (NAC) regions of alpha-synuclein. This study showed that after proteinase K (but
      not formic acid) pretreatment the anti-C terminus antibody immunostained
      neurofibrillary tangles of AD, PSP and CBD, and glial inclusions of PSP and CBD,
      as well as Pick bodies. Western blot analysis confirmed that in cases other than
      LBD, the anti-C terminus antibodies also recognized the native alpha-synuclein
      band and no cross-reactive bands were observed. In contrast, in LBD, after formic
      acid pretreatment with the anti-NAC antibody astroglial cells and granular
      neurons were immunostained. The N-terminal region antibody only recognized the
      lesions in LBD cases and not those of other neurodegenerative disorders. These
      results support the view that different fragments of alpha-synuclein might play
      an important role in the pathogenesis of several neurodegenerative disorders.

PMID- 10663974
TI  - Glial pathology in development of cerebellar dysplasia in the hereditary
      cerebellar vermis defect (CVD) rat.
AB  - The cerebellar vermis defect (CVD) rat is a new neurological mutant characterized
      by a cerebellar vermis defect and dysplasia in the cerebellum, especially at the
      cerebellopontine junctions. In this study, the cytokinetics of glia in terms of
      the development of cerebellar dysplasia in the CVD rat was investigated using
      glial fibrillary acidic protein (GFAP) and vimentin immunohistochemistry. In the
      cerebellar hemispheres, dislocation of the Bergmann glia was observed from
      postnatal day 5 (P5) in lesions with abnormally aggregated external granule cells
      (EGCs). Rearranging Bergmann glia were often seen around the EGCs penetrating
      into the white matter. In the cerebellopontine junctional areas, Bergmann glia
      were induced after penetration of the Purkinje cells, identified with calbindin
      immunohistochemistry, and EGCs into the pons from P10. Bergmann fibers were
      frequently arranged perivascularly. In the clusters of Purkinje cells without EGC
      settlement in the pons, a small number of Bergmann fibers were observed and their
      alignment was completely disturbed. These findings suggest that morphological
      changes in the Bergmann glia depend on their contact with Purkinje cells, but
      that the orientation of their processes may be influenced by EGC settlement.
      These glial fibers in the CVD rat may play an important role in the aberrant
      migration of EGCs, resulting in the development of cerebellar dysplasia.

PMID- 10663975
TI  - Ganglioglioma with a tanycytic ependymoma as the glial component.
AB  - We studied a cystic ganglioglioma (GG) located in the right frontal lobe of the
      brain. Interestingly, the fibrillary spindle glial cells were often arranged in a
      fascicular pattern, and the generally uniform, round-to-oval delicate nuclei
      appeared to resemble those of ependymoma; and the neoplastic neurons often
      contained neurofibrillary tangles (NFTs). The glial component was positive for
      glial fibrillary acidic protein and occasionally contained granular or
      microvesicular structures positive for epithelial membrane antigen.
      Ultrastructural investigation revealed that the glial cells were ependymal in
      nature; intracytoplasmic lumina and intercellular microrosettes lined with cilia
      and microvilli, as well as long zonulae adherentes, were evident. In addition,
      chromogranin A-positive granular staining, neurosecretory-granule-like
      structures, and parallel arrays of microtubules were sometimes associated with
      the blood vessels. We considered the present case to be an unusual example of GG
      with an ependymoma, more precisely a tanycytic ependymoma, as the glial
      component; to our knowledge, the existence of ependymoma as the main glial
      component of this particular tumor has not been described before. The occurrence
      of NFTs, which has been reported in several cases of GG, was an additional,
      unusual feature.

PMID- 10663976
TI  - Apoptosis of perineurial cells in sensory perineuritis.
AB  - A 71-year-old man presented a 6-month history of progressive paresthesia of all
      four limbs. Sural nerve biopsy specimens showed dense mononuclear infiltrates in
      the perineurium and subperineurium, indicating sensory perineuritis. One section
      revealed disruption of the perineurial barrier. Perforin and granzyme B were
      present in the infiltrates, and apoptosis of perineurial cells was indicated by a
      terminal deoxynucleotidyl-transferase-mediated dUTP-digoxigenin nick end-labeling
      (TUNEL) method. These findings suggest T cell-mediated apoptosis of the
      perineurium and nerve injury caused by perineurial damage.

PMID- 10663977
TI  - Papillary glioneuronal tumour: clinicopathological and biochemical study of one
      case with 7-year follow up.
AB  - Among the mixed glioneuronal tumours, a new variant called papillary glioneuronal
      tumour has recently been delineated. A case occurring in a 23-year-old man is
      reported. The tumour was cystic with a mural nodule enhanced by gadolinium
      injection. It was located within the left parieto-occipital lobe. Surgical
      excision showed a greyish friable tumour with cystic areas. Histopathological
      examination revealed a pseudopapillary component comprising a single layer of
      regular cells, arranged around hyalinised vessels. These cells were
      immunoreactive with anti-glial fibrillary acidic protein and HNK1 antibodies. A
      neurocytoma-like component coexisted with round blind cells and focal fibrillary
      rosettes. These cells were immunostained by anti-neuron-specific enolase and anti
      synaptophysin antibodies. Neither mitoses nor ganglioid cells were seen. HNK1,
      the three isoforms of NCAM, and the L1 adhesion molecule were detected by Western
      blot analysis. Ultrastructural study showed three different types of cells. The
      first contained gliofilaments, the second showed long processes with true
      synapses, and the third was poorly differentiated. However, all had identical
      nuclei and contained dense bodies. These findings suggest a common origin for the
      tumour cells derived from a bipotential neuroglial progenitor. As for other
      mature mixed neuroglial tumours, the prognosis is good. Our patient is free of
      disease 7 years after complete surgical treatment.

PMID- 10663978
TI  - Dejerine-sottas disease with a novel de novo dominant mutation, Ser 149 Arg, of
      the peripheral myelin protein 22.
AB  - The Ser149Arg mutation of peripheral myelin protein 22 (PMP22) was found in a 19
      year-old woman with a sporadic case of Dejerine-Sottas disease. The patient
      showed delayed motor development. She walked for the first time with support at
      the age of 2 years. Scoliosis developed at age 4 years. Her walking ability was
      best at age 11. Thereafter, she showed progressive muscle weakness and sensory
      disturbances in the distal extremities. At the age of 18 years, the use of a
      wheelchair became necessary. Motor and sensory nerve conduction studies showed
      absent motor and sensory responses on electrical stimulation of the limb nerves.
      A sural nerve biopsy specimen showed marked decreases in the numbers of both
      large and small myelinated fibers, abundant onion-bulb formation, and
      hypomyelination. Electron microscopic observation revealed the presence of
      demyelinated axons and myelin sheaths disproportionately thin relative to axon
      diameter. That this was a de novo mutation was established by parentage testing
      and PMP22 gene analysis of the parents. The mutation seems to be novel and
      dominant.

PMID- 10663979
TI  - Juvenile-onset generalized neuroaxonal dystrophy (Hallervorden-Spatz disease)
      with diffuse neurofibrillary and lewy body pathology.
AB  - We describe an unusual case of Hallervorden-Spatz disease (HSD). After presenting
      with limb rigidospasticity at the age of 9 years, our patient developed
      progressive dementia, spastic tetraparesis and myoclonic movements, leading to
      akinetic mutism. He died of pneumonia at the age of 39 years. Autopsy revealed a
      severely atrophic brain, weighing 510 g. Histologically, there were iron deposits
      in the globus pallidus and substantia nigra pars reticulata, and numerous axonal
      spheroids throughout the brain and spinal cord. Neurofibrillary tangles were
      abundant in the hippocampus, cerebral neocortex, basal ganglia and brain stem.
      Neuritic plaques and amyloid deposits were absent. Lewy bodies and Lewy neurites,
      which were immunolabeled by anti-alpha-synuclein, were found in the brain stem,
      cerebral cortex and spinal gray matter. Sarkosyl-insoluble tau extracted from the
      temporal cortex resolved on immunoblots into three major bands of 60, 64 and 68
      kDa and a minor band of 72 kDa, as reported for Alzheimer's disease. The present
      case, together with a few similar cases reported previously, may represent a
      particular subset of neuroaxonal dystrophy, i.e., HSD associated with extensive
      accumulation of both tau and alpha-synuclein.

PMID- 10664008
TI  - T-cell clones from early-stage cutaneous T-cell lymphoma show no polarized Th-1
      or Th-2 cytokine profile.
AB  - Recent studies of the cytokine pattern in skin lesions of patients with cutaneous
      T-cell lymphoma (CTCL) have shown that interleukin-4 (IL-4) and Il-10, both
      cytokines produced by T-helper type 2 cells, dominate in these lesions. Also, in
      single studies, interferon-gamma (IFN-gamma), a major cytokine of Th-1-cells, has
      been found to be absent. Consequently, it has been hypothesized that immune
      suppressive Th-2 cytokines may promote local growth of the malignant lymphocyte
      clone. However, there is so far no evidence for T-cells as the source of the Th-2
      cytokines in CTCL skin lesions nor have these cytokines been investigated at a
      clonal T-cell level. We established a total of 120 T-cell clones (TCCs) from
      lesional skin and 54 TCCs from the blood of four patients with mycosis fungoides.
      Epidermal TCCs (mostly CD8-positive) and dermal TCCs (mostly CD4-positive) were
      stimulated by the mitogen concanavalin A and, seeking a polarized cytokine
      pattern, the supernatants were assessed by ELISA. We showed that the vast
      majority of TCCs were able to secrete IFN-gamma and IL-4. IFN-gamma-deficient
      TCCs occurred only in the epidermis. Some (18) TCCs were found to be either
      negative for IL-10 production or to produce low levels only. No significant
      differences were observed between blood- and skin-derived TCCs. Thus a polarized
      Th-2 cytokine pattern was not detectable among cultured skin-infiltrating
      nonmalignant T-cells (TILs) isolated from early mycosis fungoides. It therefore
      appears unlikely that Th-2-mediated immune suppression is a major mechanism
      operating in early CTCL. However, this does not exclude its role in late-stage
      disease.

PMID- 10664009
TI  - Preliminary functional analysis of human epidermal T cells.
AB  - The function of human epidermal T cells (ETC) is unknown. In the present study,
      dermal T cells (DTC), ETC and keratinocytes were cultured from normal human skin.
      DTC and ETC lines were expanded in medium containing interleukin 2. The
      autologous keratinocytes were transfected with a human papillomavirus 16 E6 and
      E7 plasmid to produce an immortal keratinocyte line "HEK001". Lymphocyte
      migration and adhesion to HEK001 was assessed in calcein fluorimetric assays. ETC
      migrated towards HEK001 three to four times more than DTC. ETC adhered to HEK001
      two to four times more than DTC. The proportion of ETC expressing the cutaneous
      lymphocyte-associated antigen was greater than that of DTC (26% and 1%,
      respectively). The keratinocyte line HEK001 expressed ICAM-1 following
      stimulation with TNF-alpha or IFN-gamma and following coculture with autologous
      cutaneous T cells. A blocking anti-ICAM-1 antibody reduced DTC and ETC adhesion
      to HEK001 by 30% and 50%, respectively. Therefore, cutaneous T cells may
      upregulate keratinocyte ICAM-1 expression which mediates adhesion to autologous
      keratinocytes. These results are consistent with the hypothesis that the ETC and
      DTC populations are distinct. Both directed migration (epidermotropism) and
      selective retention may be involved in the development and maintenance of the ETC
      population in normal human skin.

PMID- 10664011
TI  - Expression of microfibril-associated glycoprotein-1 (MAGP-1) in human epidermal
      keratinocytes.
AB  - Microfibril-associated glycoprotein (MAGP) is a major structural component of
      connective tissue microfibrils. We studied the expression of MAGP-1 in cultured
      human keratinocytes and its modulation during Ca(++)-induced differentiation. RT
      PCR and Western blot assays demonstrated the presence of mRNA and the polypeptide
      of MAGP-1 in cultured keratinocytes. MAGP-1 mRNA levels in cultured keratinocytes
      during Ca(++)-induced differentiation were enhanced eightfold with a concomitant
      increase in involucrin (a marker of terminal differentiation) mRNA levels. Double
      immunofluorescence labeling of cultured keratinocytes demonstrated that both anti
      MAGP-1 and anti-involucrin antibodies reacted with the identical cells. The
      population of MAGP-1-producing cells in cultured keratinocytes significantly
      increased during Ca(++)-induced differentiation. These results indicate that MAGP
      1 expressed by cultured keratinocytes reaches maximum levels at the stage of
      terminal differentiation in vitro. Double immunostaining of normal human skin
      with anti-MAGP-1 and anti-elastin antibodies demonstrated the colocalization of
      MAGP-1-positive and elastin-positive fibers in the superficial and mid-dermis.
      MAGP-1 produced by keratinocytes may play some functional role in the formation
      of dermal matrix organization in the dermis.

PMID- 10664010
TI  - Coexpression of keratins 13 and 16 in human keratinocytes indicates association
      between hyperproliferation-associated and retinoid-induced differentiation.
AB  - In human skin, epidermal differentiation occurs in two ways: normal
      differentiation, characterized by keratin 10 expression, and alternative
      differentiation. Alternative differentiation can be hyperproliferation-associated
      differentiation (expression of keratin 16) or the reinduction of an embryonic
      type of differentiation (expression of keratin 13). This embryonic type of
      differentiation is also seen following treatment with retinoids. In the present
      study, the hypothesis that hyperproliferation-associated and retinoid-induced
      differentiation are separate processes was investigated. Two areas of normal skin
      were treated for 24 h with 0. 1% all-trans-retinoic acid. Subsequently, one of
      the areas was tape-stripped and treatment was continued for 48 h. Multiparameter
      flow cytometry permitted simultaneous measurement of two coexpressed
      differentiation markers (retinoid-induced and normal differentiation or retinoid
      induced and hyperproliferation-associated differentiation) and the proliferation
      characteristics (cells in S/G(2)M phase). Concerning normal and retinoid-induced
      differentiation, the all-trans-retinoic acid-induced expression of keratin 13 was
      only seen in tape-stripped retinoid-treated skin and exclusively together with
      that of keratin 10. The assessment of hyperproliferation-associated and retinoid
      induced differentiation showed slight expression of keratin 13 without expression
      of keratin 16 in tape-stripped skin. Coexpression of keratins 16 and 13 was
      exclusively seen in tape-stripped retinoid-treated skin. The finding that keratin
      13 expression following treatment with all-trans-retinoic acid occurred
      exclusively in hyperproliferative skin suggests that retinoid-induced and
      hyperproliferation-associated differentiation are coupled. Coexpression of
      keratins 13 and 16 provides direct experimental evidence for this association.

PMID- 10664012
TI  - Expression of elastin-related proteins and matrix metalloproteinases in actinic
      elastosis of sun-damaged skin.
AB  - Actinic elastosis is characterized by an accumulation of elastotic material in
      the upper dermis and is considered to be a manifestation of ultraviolet-induced
      skin aging. To compare the structural components of the elastotic material in
      actinic elastosis with those in normal skin, skin specimens were stained with
      antibodies raised against various elastin-related proteins. Elastotic materials
      exhibited a strong reaction to the antibodies for elastin, microfibril-associated
      glycoprotein-1 (MAGP-1), MAGP-4, matrix metalloproteinase 1 (MMP-1), MMP-2 and
      MMP-3, but a diminished reaction to anti-MMP-9 antibody. Fibroblast cell lines
      from the upper dermis of affected and unaffected skin were established, and the
      mRNA levels of MMPs were determined. MMP-1 and -2 mRNA levels were found to be
      elevated approximately twofold in the fibroblasts from actinic elastosis. Since
      MMP-1 and -2 are considered to be major enzymes involved in the degradation of
      matrix components, the accumulation of elastotic materials in actinic elastosis
      may be related to the degradation process.

PMID- 10664013
TI  - Dapsone and colchicine inhibit adhesion of neutrophilic granulocytes to epidermal
      sections.
AB  - A frozen section adhesion assay was used to study the influence of dapsone and
      colchicine on cell-cell adhesion between neutrophils and epidermal cells.
      Sections were prepared from small punch biopsies from healthy donors after
      preincubation with IFN-A. Freshly prepared neutrophils were activated with TNF-.
      or PAF after exposure to dapsone or colchicine, incubated on these sections, and
      the adhered cells were enumerated after washing. In the presence of dapsone (at
      concentrations of 0.1-80 Ig/ml) adherence of neutrophils could be blocked dose
      dependently and 50% inhibition of adhesion was achieved at a concentration of 10
      Ig/ml. Colchicine at concentrations of 10-200 ng/ml inhibited neutrophil binding
      with a clear correlation between inhibition and colchicine concentration. At a
      colchicine concentration of 110 ng/ml, 50% blocking was achieved. Since the
      function of CD11b/ paragraph signCD18 is necessary for neutrophil adhesion in
      this assay, we monitored CD11b expression on neutrophils after dapsone and
      colchicine exposure. CD11b expression on neutrophils was significantly reduced 5
      h after incubation with dapsone at a concentration of 80 Ig/ paragraph signml,
      whereas no effects of colchicine on CD11b expression could be demonstrated. Our
      study showed that both drugs significantly inhibited adhesion between neutrophils
      and the epidermis.

PMID- 10664014
TI  - A spontaneously arising porcine model of bullous pemphigoid.
AB  - Bullous pemphigoid (BP) is an IgG-mediated autoimmune blistering disease
      targeting the hemidesmosomal proteins bullous pemphigoid antigens 1 and 2.
      Currently, there is no active animal model in which to dissect the
      immunopathogenic mechanism. We noticed that cutaneous blistering arose
      spontaneously in 12 adult Yucatan minipigs. Skin lesions consisted of turgid,
      isolated or clustered vesicles that occasionally evolved from erythematous and
      pruritic patches. Histopathological examination revealed subepidermal vesicles
      rich in intact and degranulated eosinophils. Antigen mapping and transmission
      electron microscopy confirmed that dermoepidermal separation took place in the
      lamina lucida of the epidermal basement membrane zone. Direct immunofluorescence
      revealed the presence of IgG deposited linearly at the dermoepidermal junction in
      seven of nine skin specimens examined. Indirect immunofluorescence testing
      confirmed the presence, in the serum from eight of eight affected pigs, of
      circulating basement membrane-specific IgG autoantibodies (titers 1 : 50 to 1 :
      250). Using uncleaved and salt-split lip substrates, the autoantibodies were
      shown to target antigens situated not only at the basal, but also at the lateral
      and apical aspects of stratum basale keratinocytes. Immunoelectron microscopy
      confirmed that circulating IgG autoantibodies recognized hemidesmosomal
      antigen(s). ELISA, immunoblotting and immunoadsorption demonstrated that five of
      eight serum samples exhibited high immunoreactivity against BPAG2-NC16A peptides.
      This novel porcine acquired blistering dermatosis could be proposed as a valuable
      model to conduct immunomechanistic studies on the natural progression of BP,
      correlation of autoreactive T cells or autoantibodies with disease activity, and
      the role of eosinophils in the blistering process, as these diseases cannot be
      modeled easily in human patients or in murine passive transfer models.

PMID- 10664015
TI  - A graft chamber delays rejection of murine allogeneic skin equivalents.

PMID- 10664036
TI  - Lateral sinus thrombosis after untreated otitis media. A clinical problem--again?
AB  - Antimicrobial agents have greatly reduced the incidence of intracranial
      complications of infections of the middle ear and mastoid. Too many prescriptions
      and overconsumption of antibiotics when otitis media is suspected has caused
      resistance to many antibiotics, leading to a pronounced and justifiable desire to
      reduce the widespread excessive use of antibiotics. The possible untoward
      consequences of a too restricted antibiotic policy, however, is illustrated by
      the following case of a 14-year-old boy who, after non-treatment of an ear
      infection, fell ill with one-sided headache and vomiting caused by a lateral
      sinus thrombosis. After intravenous treatment with antibiotics, anticoagulants
      and ventilation of the middle ear, the infection was cured without complications.
      This case calls attention to the symptoms of otitic complications arising outside
      the temporal bone. The physician must always bear in mind the possibility of an
      unusual event. The general treatment of endocranial complications is outlined,
      giving details of the treatment given in this special case. We stress that one
      should not be too cautious in prescribing antibiotics in otitis media.

PMID- 10664037
TI  - Effect of cisplatin on the expression of glutathione-S-transferase in the cochlea
      of the rat.
AB  - Glutathione-S-transferase (GST) has been found to conjugate glutathione (GSH) to
      diverse electrophiles and play a major role in the detoxification of alkylating
      and platinating agents. However, there is little information regarding the
      pattern of GST expression in the cochlea. Although cisplatin is ototoxic, its
      effect on GST in the cochlea is unknown. In the present study we investigated the
      pattern of GST expression in control and cisplatin-treated cochleas by using the
      laboratory rat as animal model. Sixteen mature rats were randomly assigned to
      control or cisplatin groups. After treatment, cochleas were procured and tissues
      stained by immunohistochemical methods to detect the presence of GST. Optical
      density measurements were determined to gauge intensity of GST immunostaining.
      Strong positive GST immunostaining was demonstrated in all cochleas, with the
      most intense staining found in the spiral ligament and the least in Reissner's
      membrane. Mean optic density scores were lower for cisplatin-treated cochleas
      than for control cochleas in all areas analyzed. These findings showed that GST
      is expressed throughout the rat cochlea, with cisplatin treatment causing its
      decreased expression.

PMID- 10664038
TI  - Preventive effect of magnesium supplement on noise-induced hearing loss in the
      guinea pig.
AB  - The effect of magnesium (Mg) on noise-induced hearing loss was investigated in
      two groups of adult pigmented guinea pigs maintained either on optimal or
      suboptimal (physiologically high or low) Mg produced by different diets. The
      total Mg concentrations of the perilymph (PL), cerebrospinal fluid, blood plasma
      and red blood cells were measured by atomic absorption spectrometry and were
      found to differ significantly between the two groups (P < 0.01). One ear of each
      animal was exposed to either a single shooting impulse at a peak pressure level
      of 187 dB or two impulse noise series at a rate of 1/s and peak pressure levels
      of 150 dB (1,000 impulses) and 167 dB (2,280 impulses), respectively. Temporary
      (TTS) and permanent (PTS) hearing threshold shifts in anesthetized animals were
      measured 2 h and 1 week after the noise exposure, using auditory brain stem
      response (ABR) audiometry at a frequency range from 3.75 to 30 kHz. Exposure to
      the single noise impulse resulted in a mean TTS that was significantly lower in
      the high Mg group than that in the low Mg group (P < 0.05), although no
      substantial PTS was observed in either group. In the animals exposed to 150 dB
      noise, the TTS showed a tendency towards an Mg-related reduction at the higher
      frequencies. A small difference in PTS was found between the low Mg and high Mg
      groups, but was not significant. Exposure to the 167-dB noise series caused a
      considerable TTS, which was significantly lower in the high Mg group at 7.5 and
      15 kHz than in the low Mg group (P < 0.05). The mean PTS showed a significant
      difference between the two Mg groups over the whole frequency range (P < 0.05)
      and was found to correlate negatively with the total Mg concentrations of both PL
      and plasma (P < 0.05). Moreover, the high Mg group showed a faster recovery from
      the hearing threshold shift than the low Mg group. The present findings show that
      preventive oral Mg supplements can significantly reduce the rate of acoustic
      trauma caused by high-level impulse noise exposure in the guinea pig.

PMID- 10664039
TI  - Autofluorescence imaging in the diagnosis of laryngeal cancer.
AB  - Differences in autofluorescence (fluorescence without photodynamic drugs) between
      normal and malignant tissues offer new possibilities in detecting and localizing
      early laryngeal carcinoma. Autofluorescence imaging was performed using a
      modified fluorescence endoscopy system from Xillix Technologies (Richmond,
      Canada). Fluorescence was induced by blue light at 442 nm and captured by an
      image-intensified camera through a laryngeal telescope. The images were then
      processed by the system and displayed on a video monitor. Normal tissue appeared
      green while malignant sites appeared reddish-brown. The autofluorescence imaging
      technique was compared to standard microlaryngoscopy in 108 patients with
      laryngeal pathologies (in 74 of whom malignancy was suspected). The acquired
      reflectance and fluorescence images of each lesion were assessed independently as
      malignant or not malignant by three ENT specialists who were familiar with the
      procedure but were not provided with clinical data or histopathological
      information concerning the lesion. The assessments of pathology were determined
      from the two imaging modalities and were compared to histopathological findings
      of the biopsy specimens taken from the lesion. The present study showed that
      autofluorescence imaging can be a useful complementary method to
      microlaryngoscopy for detecting and delineating laryngeal malignancies. If in the
      future, the device can be developed for use in an outpatient office, a
      significant improvement can be made for the early detection of laryngeal
      malignancies.

PMID- 10664040
TI  - Bilateral recurrent adult rhabdomyomas of the pharyngeal wall.
AB  - Adult rhabdomyomas of the head and neck are uncommon benign skeletal muscle
      tumors. Only a few cases occurring in the pharyngeal wall have been described in
      the world literature. We present a case of recurrent bilateral rhabdomyomas in
      the pharynx and discuss the clinicopathological features of this lesion,
      comparing it to those of other neoplasms from which it must be differentiated. To
      our knowledge, bilaterality of this type of lesion has not been described
      previously. Although adult rhabdomyomas have a distinct histology, they often are
      mistaken for a variety of other lesions, particularly granular cell tumor.

PMID- 10664042
TI  - In Memoriam paragraph signKlaus Heimann (22.6.1935-25.6.1999).

PMID- 10664041
TI  - Colon interposition in a patient with total postcricoid stenosis after caustic
      ingestion and preservation of full laryngeal function.
AB  - Caustic burns of the upper aerodigestive tract continue to be a significant
      clinical problem. However, the available literature uncommonly mentions changes
      affecting the larynx. We could find only one publication in which four cases of
      high hypopharyngeal stenosis were described in detail and where the functional
      outcome of the laryngeal function was stated as partially saved. We describe here
      a case of total retrocricoid stenosis in a 28-year-old woman that was caused by
      lye ingestion. A life-saving gastroesophagectomy was performed by the Department
      of General Surgery. Reconstruction of the esophagus was carried out with
      mobilized right colon, which was meticulously sutured circumferentially behind
      the arytenoids and on the prevertebral fascia. The anatomy of the larynx and its
      nerve supply were scrupulously maintained intact. We believe that our patient's
      rehabilitation was due mainly to an intensive 18-month program of care, following
      which all laryngeal functions recovered with normal voice and swallowing
      patterns.

PMID- 10664043
TI  - In Memoriam Klaus Heimann.

PMID- 10664044
TI  - In Memoriam Klaus Heimann.

PMID- 10664045
TI  - Histopathological findings of X-linked retinoschisis with neovascular glaucoma.
AB  - BACKGROUND: X-linked retinoschisis (XLRS) is rarely complicated by neovascular
      glaucoma. Only a few reports of XLRS histopathological findings with neovascular
      glaucoma have been published. METHODS: A 41-year-old man with XLRS complicated by
      neovascular glaucoma in his left eye was examined with electroretinography, B
      scan, ultrasound biomicroscopy and computed tomography. He was examined by
      ophthalmoscopy and fluorescein angiography in the other eye. An enucleation was
      performed in his left eye due to uncontrollable high intraocular pressure and
      persistent ocular pain. We examined the enucleated eye histopathologically.
      RESULTS: Examination of the enucleated eye showed nuclear sclerosis of the lens,
      pigmented retrolental membrane and retinoschisis which separated the inner layer
      of the retina and made a large space in the vitreous cavity without any apparent
      detachment of the outer layers of the retina. Sclerotic vessels were present
      histopathologically in both the inner and outer layers of the retina. There was a
      peripheral anterior synechia, ectropion uveae and a fibrovascular membrane, which
      contained many lumina of neovascularization, indicating marked rubeosis iridis.
      Small cystic spaces were observed in both the schitic retina in the peripheral
      region and the foveal schisis at the outer layer of the retina. The photoreceptor
      cells had become markedly atrophied and multiple regions of calcification were
      observed. The optic nerve showed severe atrophy with gliosis, but the central
      retinal artery and vein were still open within the nerve. CONCLUSIONS: These
      histopathological findings suggest that rubeosis iridis may have developed
      secondarily to retinal ischemia due to occlusion of the retinal blood vessels.

PMID- 10664046
TI  - Slit-lamp-adapted optical coherence tomography of the anterior segment.
AB  - PURPOSE: To evaluate the diagnostic potential of a slit-lamp-adapted optical
      coherence tomography (OCT) system as an in vivo imaging device for routine
      clinical examination of the anterior segment of the eye. PATIENTS AND METHODS: In
      a pilot study, healthy volunteers and patients with different pathologies of the
      anterior segment were examined with a slit-lamp-adapted OCT system using 100-200
      axial scans with 100-Hz line-scan frequency. The scan length is variable up to 7
      mm, and the axial depth is 1.5 mm in tissue. RESULTS: The slit-lamp-adapted OCT
      system allowed direct biomicroscopic imaging of the measured area. Anatomic
      structures and morphological changes anterior to the attenuating iris pigment
      epithelium could be visualized with high accuracy. Biometric analyses of the
      cornea, the chamber angle, the iris and secondary cataract were possible.
      Complete demonstration of the chamber angle was difficult due to the
      backscattering properties of the anterior part of the sclera and the consequent
      shadowing of the most peripheral part of the iris. CONCLUSIONS: Slit-lamp-adapted
      OCT is a useful diagnostic tool which allows in vivo microscopic cross-sectional
      imaging of the anterior segment and precise measurement of ocular structures.

PMID- 10664047
TI  - Comparison of latanoprost monotherapy to dorzolamide combined with timolol in
      patients with glaucoma and ocular hypertension.A 3-month randomised study.
AB  - BACKGROUND: The purpose of the study was to compare the effects on intraocular
      pressure (IOP) of adding dorzolamide to timolol or of switching from timolol to
      latanoprost monotherapy in glaucoma patients inadequately controlled on timolol.
      METHODS: The study was designed as a 3-month randomised, open-label, multicentre
      study comprising 183 patients with primary open-angle glaucoma, capsular glaucoma
      with IOP above 22 mmHg on treatment with one or two ocular hypotensive drugs, or
      ocular hypertension with IOP above 27 mmHg. After a 2- to 4-week run-in period on
      timolol, 0.5% twice daily, the patients were randomised to treatment with either
      latanoprost, 0. 005% once daily, or the combination of timolol, 0.5% twice daily,
      and dorzolamide, 2% twice daily. The mean diurnal IOP after 3 months of treatment
      was compared with baseline. RESULTS: Switching from timolol to latanoprost
      reduced mean diurnal IOP by 4.5+/-0.2 mmHg (mean+/-SEM, ANCOVA; 20%), and adding
      dorzolamide to timolol reduced mean diurnal by 4.4+/-0.2 mmHg (mean+/-SEM,
      ANCOVA; 20%). No serious side effects were observed with either treatment.
      CONCLUSION: Latanoprost monotherapy can be an alternative to combined treatment
      with two aqueous flow suppressors in patients whose IOP is insufficiently
      controlled by timolol alone.

PMID- 10664048
TI  - New osmotically active hydrogel expander for enlargement of the contracted
      anophthalmic socket.
AB  - BACKGROUND: Clinical anophthalmia is characterized by the absence of an eyeball
      within the orbit and can result in overall growth retardation of the facial
      skeleton. The goal of treatment consists of fitting a serial prosthesis following
      rapid expansion of the contracted socket as soon as possible to achieve
      cosmetically acceptable eyelid and orbital symmetry. METHODS: Four children, aged
      3-11 months, were treated by implantation of an anhydrous, highly hydrophilic
      tissue expander into the rudimentary conjunctival sac. With hydration of up to
      98% in 72 h, the copolymer of methylmethacrylate and vinylpyrrolidone acts like
      an osmotically self-inducing socket expander. RESULTS: In the course of 2 months
      the previous contracted socket was enlarged, the horizontal lid length increased
      and the hydrated expander could be exchanged for a custom-made glass prosthesis.
      CONCLUSION: Preliminary results suggest that this new device can be used to avoid
      early plastic surgery of the eyelid. In addition, it also may enlarge the volume
      of the bony orbit.

PMID- 10664049
TI  - Massive suprachoroidal hemorrhage: secondary treatment and outcome.
AB  - PURPOSE: Massive suprachoroidal expulsive hemorrhage (SCH) is a dramatic and
      devastating intraocular complication of intraocular surgery and trauma that can
      result in total loss of vision. The aim of our study was to present the results
      of secondary surgical treatment of eyes following massive SCH. PATIENTS AND
      METHODS: We treated 10 patients suffering from massive SCH by combined radial
      sclerotomies for suprachoroidal drainage and vitrectomy with use of
      perfluorocarbon and instillation of silicone oil. We analyzed the clinical
      characteristics, visual acuity and anatomical status before and after secondary
      treatment. RESULTS: Visual acuity of all eyes suffering from SCH was light
      perception. Postoperatively five patients with SCH showed either no improvement
      of function or visual acuity of counting fingers. An increase in visual acuity to
      maximal 0.1 was seen in four eyes; one patient achieved 0.6. With a minimum of 6
      months' follow-up, four eyes developed hypotony, two eyes became phthisical, and
      in two eyes recurrent traction retinal detachment occurred. CONCLUSIONS:
      Secondary treatment by combined suprachoroidal drainage by sclerotomies and
      vitrectomy should be performed to minimize the damaging effect of choroidal
      hemorrhage.

PMID- 10664050
TI  - Application of ultrashort laser pulses for intrastromal refractive surgery.
AB  - BACKGROUND: Recently, laser systems have become available which generate
      ultrashort laser pulses with a duration of 100-200 femtoseconds (fs). By
      generating micro-plasmas inside the corneal stroma with fs pulses, it is possible
      to achieve a cutting effect inside the tissue while leaving the anterior layers
      intact. The energy threshold to generate a micro-plasma with fs pulses is some
      orders of magnitude lower than it is for picosecond or nanosecond pulses. This
      results in a strong reduction of the thermal and mechanical damage of the
      surrounding tissue. METHODS: With a titanium:sapphire fs laser system, the
      cutting effect on corneal tissue from freshly enucleated porcine eye globes was
      investigated with different pulse energies. The irradiated samples were examined
      by light and electron microscopy. The laser-induced pressure transients and the
      laser-induced bubble formation were analysed with a broadband acoustic transducer
      and by flash photography. RESULTS: With fs laser pulses, the extent of thermal
      and mechanical damage of the adjacent tissue is in the order of 1 microm or below
      and therefore comparable with the tissue alterations after ArF excimer laser
      ablation. Using pulse energies of approximately 1-2 microJ and a spot diameter of
      5-10 microm, intrastromal cuts can be performed very precisely in order to
      prepare corneal flaps and lenticules. CONCLUSION: Femtosecond photodisruption has
      the potential to become an attractive tool for intrastromal refractive surgery.

PMID- 10664051
TI  - Tractional retinoschisis in proliferative diabetic retinopathy: a
      histopathological study.
AB  - BACKGROUND: Proliferative diabetic retinopathy (PDR) often results in a
      tractional elevation of the retina. This study investigates the anatomical and
      histopathological structures of the vitreous body and the elevated retina in PDR.
      METHODS: Four globes (three patients) with PDR and known retinal elevation were
      analysed histologically. The tissues were embedded in celloidin and a special
      thick section technique (250 microm) was used for analysis under a
      stereomicroscope. RESULTS: All four cases showed adherence of the vitreous body
      with the retina and a tractional elevation of the retina at that site. In two
      cases retinoschisis was combined with retinal detachment and in the other two
      cases the retinal elevation was a pure retinal schisis. CONCLUSION: Our
      histopathological investigations of PDR show that traction of the retina by
      shrinking of the vitreous body may result in a combination of retinoschisis and
      retinal detachment at the same area. These cases are clinically often diagnosed
      as retinal detachment, but because of the additional retinal schisis they are of
      poor functional prognosis.

PMID- 10664052
TI  - Quality of salivary tears following autologous submandibular gland
      transplantation for severe dry eye.
AB  - BACKGROUND: This study aimed to characterise the composition of the pre-ocular
      fluid after transplantation of the autologous submandibular gland (SMG) for
      patients with severe dry eye. METHODS: Stimulated and unstimulated pre-ocular
      fluid from 15 patients (17 eyes) with a viable SMG graft ("SMG-salivary tears"),
      as well as normal tears and SMG saliva (20 normal subjects/ 20 eyes), was
      sampled. As global tear parameters, fern pattern analysis and SDS gel
      electrophoresis were performed. As specific quality parameters, total protein
      content, secretory immunoglobulin A (SIgA), lysozyme, amylase, sodium, potassium
      and osmolality were measured using routine laboratory methods. The flow rate of
      SMG-salivary tears was determined in 5 patients by means of sequential
      scintillography. RESULTS: The fern pattern of SMG-salivary tears was coarse and
      thus more similar to normal SMG saliva than tears. SDS gel electrophoresis of the
      SMG-salivary tears showed albumin and two unidentified proteins in addition to
      the normal tear pattern. Osmolality and total protein content of SMG-salivary
      tears were higher than in normal SMG saliva, but still lower than in normal
      tears. High activities of normal tear antibacterial proteins (SIgA, lysozyme and
      amylase) were detected in the salivary tears. Stimulation of the secretion did
      not alter the composition of SMG-salivary tears. The flow rate of SMG-salivary
      tears was closer to that of normal tears than normal SMG saliva. CONCLUSION:
      Salivary tears resulting from SMG-transplantation represent condensed SMG saliva.
      Thus their quality is intermediate between normal tears and normal SMG saliva.
      High levels of secretory proteins demonstrate that the gland maintains an active
      function. Surgical denervation and residual tear components from the ocular
      surface are the most likely factors to cause the complex differences between
      normal SMG saliva and SMG-salivary tears. The effects of this secretion on the
      ocular surface are currently being evaluated in a clinical and laboratory study.

PMID- 10664053
TI  - Lea symbols: visual acuity assessment and detection of amblyopia.
AB  - OBJECTIVE: Lea symbols can be used for measuring visual acuity in childhood.
      Therefore, these symbols might be useful for early detection of amblyopia. We
      evaluated whether the visual acuity determined with Lea symbols (LS) corresponds
      to the visual acuity determined with the Landolt-C (LC). PATIENTS AND METHODS: In
      55 strabismic amblyopic volunteers aged 5-59 years, the monocular visual acuity
      of both eyes was determined using LC and LS. For comparison, the right eye of 20
      healthy volunteers was examined. Single optotypes (LC, LS) were used in 55
      amblyopes and crowded optotypes (LC(17.2), LC(2.6), CLS) in 40 amblyopes. The
      luminance of the test charts was 180-200 cd/m(2), with a contrast >85%. The
      refraction of the subjects was corrected beforehand. RESULTS: In the 40 amblyopic
      eyes tested under each condition, LS exceeded CLS and LC by about 1 line (dB),
      LC(17.2) by 2 lines and LC(2.6) by 3 lines (mean values +/- SD: LS 0.62+/-1.8 dB,
      CLS 0.46+/-1.7 dB, LC 0.5+/-2. 0 dB, LC(17.2) 0.41+/-2.3 dB, LC(2.6) 0.29+/-2.3
      dB). The non-amblyopic fellow eyes and healthy eyes showed smaller differences
      (fellow eyes LS 1.32+/-1.1 dB, CLS 1.17+/-1.1 dB, LC 1. 15+/-0.9 dB, LC(17.2)
      1.05+/-0.9 dB, LC(2.6) 0.93+/-1.1 dB; healthy eyes LS 1.74+/-0.9 dB, CLS 1.58+/
      0.8 dB, LC 1.48+/-0.6 dB, LC(17.2) 1.41+/-0.7 dB, LC(2.6) 1.32+/-1.1 dB). In the
      amblyopic eyes, the reduction of LC was more distinct than the reduction of LS.
      Fifty-two amblyopes had an amblyopia >1 dB of LC, LC(17.2) and LC(2. 6), while 50
      had an interocular acuity difference >1 dB CLS. CONCLUSIONS: Using Lea symbols, a
      recognition acuity can be determined and amblyopia can reliably be detected. Due
      to their design, the Lea symbols are particularly suitable and recommendable for
      application in young children. However a slight systematic difference between LS
      and LC has to be considered.

PMID- 10664054
TI  - Postoperative nausea and vomiting after Faden operation.
AB  - OBJECTIVE: The purpose of this study was to evaluate the antiemetic effect of
      prophylactic dimenhydrinate application prior to Faden operation and to compare
      the incidence of PONV between bimedial Faden operation (BMF) and horizontal
      recess-resect procedure (R&R). METHODS: Ninety-nine children (4-10 years)
      scheduled for BMF were included in this prospective double-blind study. Midazolam
      (0.5 mg/kg body weight, BW) was administered orally for premedication 30 min
      before induction of anesthesia. Additionally, children weighing >/=23 kg received
      either dimenhydrinate suppositories or placebo. The placebo group was compared
      with 148 children who underwent R&R surgery without antiemetic prophylaxis during
      the same period. Anesthesia was induced with thiopentone (5-10 mg/kg BW) and
      vecuronium (0.1 mg/kg BW) bromide and maintained with halothane (1-2 vol%) in
      N(2)O/O(2) (65/35 vol%). Age, height, weight, and incidence of oculocardiac
      reflex were documented. PONV was classified into "no vomiting", "vomiting without
      therapy", and "vomiting requiring rescue medication". In the latter case
      dimenhydrinate was given again. The chi-square test was used for statistical
      analysis. RESULTS: Forty-eight patients received placebo, while 51 received
      dimenhydrinate. No differences between any groups were observed concerning age,
      height, weight, and incidence of oculocardiac reflex. Compared to R&R surgery,
      PONV requiring rescue medication occurred significantly more frequently after BMF
      (45% vs 23% after R&R). PONV after BMF was significantly less severe in the
      dimenhydrinate group than in the placebo group. The total incidence of PONV after
      BMF, however, was not significantly reduced. CONCLUSION: The high incidence of
      PONV after BMF can be explained by the greater invasiveness of BMF than R&R
      surgery. PONV requiring antiemetic rescue medication can be reduced by
      preoperative administration of dimenhydrinate suppositories.

PMID- 10664055
TI  - The ocular hypotensive effect of late pregnancy is higher in multigravidae than
      in primigravidae.
AB  - BACKGROUND: Systemic hypertension and degenerative vascular disease are more
      common in multigravidae than in primigravidae. The present study investigated
      whether the known ocular hypotensive effect of late pregnancy is influenced by
      the number of pregnancies. METHODS: Intraocular pressure (IOP) was measured in
      normotensive third-trimester primigravidae and multigravidae along with
      nulligravida controls by means of the Goldmann applanation tonometer. Depending
      upon the number of previous pregnancies, multigravidae were divided into four
      subgroups. RESULTS: The IOP of the pregnant group (primigravidae and
      multigravidae together) was (mean+/-SEM) 2. 1+/-0.07 mmHg (P<0.001) lower than in
      the nulligravida control group. The IOP of nulligravidae was 1.7+/-0.06 mmHg
      (P<0.001) and 2.5+/-0. 01 mmHg (P<0.001) higher than in third-trimester
      primigravidae and multigravidae, respectively. In all subgroups of multigravidae
      IOP was significantly lower (P<0.02) than in primigravidae. The differences among
      different subgroups of multigravidae were statistically insignificant.
      CONCLUSIONS: Gravidity influences IOP and should be taken into account in future
      research.

PMID- 10664056
TI  - Cryopreserved human amniotic membrane for ocular surface reconstruction.
AB  - BACKGROUND: Amniotic membrane transplantation is used for the reconstruction of
      the ocular surface in the context of, for example, corneal ulcers or conjunctival
      scarring. The mechanisms by which preserved amniotic membrane grafts promote
      reepithelialization are unknown. As a first step the viability and proliferative
      capacity of amnion cells following cryopreservation of membranes in glycerol is
      investigated. METHODS: Fresh and cryopreserved (in 50% glycerol) amniotic
      membranes were investigated histologically and by vital stains. Following
      enzymatic digestion, amniotic cells were stained for viability and cultured in
      DMEM+10% FBS. In addition, explant cultures were established from fresh and
      cryopreserved membranes. RESULTS: Histological examination showed no significant
      morphological alteration following cryopreservation. While fresh membranes
      contained predominantly vital cells, no such cells were detected following
      cryopreservation. Also, cells removed enzymatically from cryopreserved membranes
      were not viable and did not grow in culture. While both epithelial and
      fibroblastic cells grew from fresh membranes, no growth was seen from
      cryopreserved membranes. CONCLUSION: The results suggest that the technique for
      preservation which is most widely used for ophthalmological amniotic membrane
      transplantation significantly impairs viability and proliferative capacity. This
      supports the clinical finding that neither immunological reactions nor signs of
      ingrowth of amniotic cells are observed in patients. Furthermore amniotic
      membrane grafts seem to function primarily as matrix and not by virtue of
      transplanted functional cells.

PMID- 10664057
TI  - Inhibition of membrane-bound carbonic anhydrase enhances subretinal fluid
      absorption and retinal adhesiveness.
AB  - BACKGROUND: The clinical use of currently available carbonic anhydrase (CA)
      inhibitors is limited by systemic side-effects, thought to result from the
      inhibition of intracellular CA isoenzymes. This study investigates how
      benzolamide, a carbonic anhydrase inhibitor which does not readily penetrate cell
      membranes, modulates retinal pigment epithelium functions relative to
      acetazolamide, which diffuses into the cytosol. METHODS: Small retinal
      detachments were made in Dutch rabbits by injecting saline into the subretinal
      space. Detachment height was measured using a dual He-Ne beam YAG laser focusing
      system, and the fluid absorption rate was calculated before and after intravenous
      injections of saline, acetazolamide or benzolamide. Retinal adhesiveness was
      determined by peeling the retina from the RPE and measuring the amount of
      adherent pigment. RESULTS: The baseline fluid absorption rate of 0.04
      microl/mm(2)/h was unchanged after injection of 0.9% NaCl or low-dose benzolamide
      (5 mg/kg). The absorption increased to about 0.14 microl/mm(2)/h after higher
      benzolamide doses (20-40 mg/kg) and to 0.13 microl/mm(2)/h after acetazolamide
      (20 mg/kg). Both acetazolamide and benzolamide significantly slowed the post
      enucleation failure of retinal adhesiveness. CONCLUSION: Since benzolamide had
      effects similar to acetazolamide, inhibition of membrane-bound CA appears to be
      sufficient to enhance subretinal fluid absorption and retinal adhesiveness.
      Membrane-specific CA inhibitors may therefore be of clinical value if they
      minimize side-effects from intracellular CA inhibition.

PMID- 10664058
TI  - The process of closure of experimental retinal holes in rabbit eyes.
AB  - BACKGROUND: To investigate the healing process of retinal holes, including the
      identification of the cell types which play an important role in the process, we
      created experimental retinal holes with minimal damage to retinal pigment
      epithelium (RPE) in rabbit eyes. METHODS: Pars plana vitrectomy was performed in
      the rabbit eye. A dome-shaped retinal detachment (bleb; diameter 1.5 mm) was made
      by injecting balanced salt solution into the subretinal space, followed by making
      a retinal hole (diameter 0.5 mm) in the center of the bleb with a silicone-tipped
      extrusion needle. In one group of rabbits, fluid-air exchange was performed and
      sulfur hexafluoride gas was injected into the vitreous cavity postoperatively. In
      another group, gas tamponade was not performed. The operated eyes were examined
      ophthalmoscopically and enucleated at 1, 4, 7, 14, 30, and 90 days after surgery.
      Tissues were prepared in 5-microm sections for hematoxylin-eosin staining and
      immunohistochemistry with antibodies to cytokeratin 18 and glial fibrillary
      acidic protein (GFAP) and examined by light microscopy. RESULTS: In the gas
      injected eyes, the retinal holes were ophthalmoscopically closed by 7 days after
      the surgery. Microscopic examination revealed that the sensory retina around the
      retinal hole was reattached, and the area of retinal defect was covered with
      cells which were positive for cytokeratin 18 and GFAP by 7 days after the
      surgery. In the eyes without gas tamponade, the retinal holes did not close
      during the observation period. CONCLUSIONS: These findings suggest that early
      attachment between the sensory retina and RPE could be essential for closure of a
      retinal hole, where glial and RPE cells might play an important role. This model
      seems to be useful to investigate the process of closure of retinal holes.

PMID- 10664059
TI  - Inhibition of corneal neovascularization by alpha(v)-integrin antagonists in the
      rat.
AB  - BACKGROUND: The proliferation of vascular endothelial cells and ultimately
      angiogenesis is inhibited by blocking integrin-mediated cell-matrix interaction.
      To asses the therapeutic potential of alpha(v)-integrin antagonists LM609 and
      cRGDfV in neovascularization of the anterior segment, their inhibitory effect on
      angiogenesis was studied in two rat models for corneal neovascularization.
      METHODS: Corneal neovascularization was induced in Wistar rats (n=51) either by
      silver nitrate burns or intrastromal implantation of polymer pellets containing
      400 ng of fibroblast growth factor (bFGF). Animals were treated with subcutaneous
      injections of a cyclic alpha(v)-integrin antagonist (cRGDfV, 15 mg/kg body wt) or
      saline twice daily. Additional animals received intrastromal implants containing
      400 ng bFGF together with either Lm609 (mAb, anti-alpha(v)beta(3)) or control
      antibody. Four days later, the animals were killed and the percentage of the
      surface area covered with vessels determined using digital image analysis.
      RESULTS: Systemic treatment with cRGDfV resulted in a significant reduction of
      corneal vessel growth in animals with bFGF-induced corneal vascularization. In
      corneas with silver nitrate burns, systemic cRGDfV treatment showed no
      significant reduction of vascularization compared with controls. Pellets
      containing bFGF and LM609 mAb induced significantly less neovascularization than
      pellets containing bFGF and control mAb. CONCLUSION: Our results suggest that in
      the rat cornea, alpha(v)beta(3) ligation does inhibit bFGF-induced
      neovascularization. A chemical burn of the cornea induces angiogenisis which is
      not inhibited by blocking alpha(v)-integrins. This suggests an angiogenic pathway
      independent of alpha(v)-integrins.

PMID- 10664060
TI  - Multifocal ERG in chloroquine retinopathy: regional variance of retinal
      dysfunction.
AB  - BACKGROUND: A study was carried out to evaluate the regional variance of retinal
      dysfunction in chloroquine retinopathy. METHODS: In three patients with different
      stages of chloroquine retinopathy, ophthalmologic evaluations including recording
      of full-field electroretinogram (ISCEV standard) and multifocal electroretinogram
      were performed. RESULTS: In one patient with mild chloroquine retinopathy the
      visual acuity, visual fields and full-field electroretinogram were normal, but
      retinal dysfunction was indicated by color vision disturbances. The second
      patient had moderate chloroquine retinopathy with normal visual acuity, visual
      fields and dark-adapted full-field electroretinogram; light-adapted and flicker
      full-field electroretinogram responses were, however, borderline and color vision
      was abnormal. The third patient had severe chloroquine retinopathy with reduced
      visual acuity, visual field and color vision defects, and a reduced full-field
      electroretinogram. In the multifocal electroretinogram, recorded with 61
      hexagons, amplitudes and implicit times were evaluated in rings surrounding the
      center. In all three patients severe dysfunction (either amplitudes or implicit
      times) was found in the parafoveal and perifoveal areas. In the fovea and towards
      the periphery the function was normal or only moderately reduced. CONCLUSION:
      Chloroquine retinopathy of different severity presents with characteristic
      alterations in the multifocal electroretinogram. Regional distribution of cone
      dysfunction is in agreement with previously reported histologic findings. The
      multifocal electroretinogram can detect retinal dysfunction in chloroquine
      retinopathy even when the full-field electroretinogram is normal and retinal
      alterations are subtle.

PMID- 10664061
TI  - Conjunctival edema and alopecia of the external third of the eyebrows in a
      patient with Meige syndrome.
AB  - PURPOSE: To describe a patient with Meige syndrome in whom we observed the
      coexistence of hereditary lymphedema of the lower legs, conjunctival edema and
      alopecia of the lateral third of the eyebrows. METHODS: Case report. RESULTS:
      Histological examination of the conjunctival and skin specimens showed dermal
      edema and a slight reduction in the number of severely ectatic lymphatics in the
      reticular dermis. The vessel were identified as lymphatics on the basis of
      immunohistochemical evidence of discontinuity and/or absence of basement
      membrane. CONCLUSIONS: Clinical and histological findings suggest that the
      etiopathogenesis of the edema in Meige syndrome is related to a structural
      ectatic defect of lymphatics. This anomaly seems to involve both skin and other
      sites, such as conjunctival mucosa.

PMID- 10664062
TI  - Multiple choroidal neovascularizations at the border of a myopic posterior
      macular staphyloma.
AB  - BACKGROUND: In pathologic myopia, choroidal neovascularization (CNV) usually
      occurs in macular region and at the center of the macular staphyloma. CNV has
      been reported to occur at the borders of an inferior posterior staphyloma in the
      tilted disc syndrome. We present a case of multiple simultaneous CNVs located at
      the borders of a myopic macular staphyloma. METHODS: The clinical and
      angiographic records of a myopic patient who presented several areas of choroidal
      neovascularization were reviewed. RESULTS: On fundus examination, four gray
      lesions surrounded by subretinal hemorrhages and covered by a large serous
      retinal detachment were observed at the borders of a posterior staphyloma.
      Fluorescein angiography revealed that these four lesions were CNVs extending from
      the borders of the staphyloma to the macular region. As measured by B-scan
      ultrasonography, the staphyloma was 4 mm deep. CONCLUSION: This case supports the
      hypothesis that the borders of staphylomas are sites at risk for the development
      of CNV in pathologic myopia.

PMID- 10664064
TI  - On the molecular architecture of myelinated fibers.
AB  - Schwann cells and oligodendrocytes make the myelin sheaths of the PNS and CNS,
      respectively. Their myelin sheaths are structurally similar, consisting of
      multiple layers of specialized cell membrane that spiral around axons, but there
      are several differences. (1) CNS myelin has a "radial component" composed of a
      tight junction protein, claudin-11/oligodendrocyte-specific protein. (2) Schwann
      cells have a basal lamina and microvilli. (3) Although both CNS and PNS myelin
      sheaths have incisures, those in the CNS lack the structural as well as the
      molecular components of "reflexive" adherens junctions and gap junctions. In
      spite of their structural differences, the axonal membranes of the PNS and CNS
      are similarly organized. The nodal axolemma contains high concentrations of
      voltage-dependent sodium channels that are linked to the axonal cytoskeleton by
      ankyrin(G). The paranodal membrane contains Caspr/paranodin, which may
      participate in the formation of axoglial junctions. The juxtaparanodal axonal
      membrane contains the potassium channels Kv1.1 and Kv1.2, their associated beta2
      subunit, as well as Caspr2, which is closely related to Caspr. The myelin sheath
      probably organizes these axonal membrane-related proteins via trans interactions.

PMID- 10664065
TI  - Microwaving for double indirect immunofluorescence with primary antibodies from
      the same species and for staining of mouse tissues with mouse monoclonal
      antibodies.
AB  - Many methods have been devised for double immunocytochemical staining. We now
      describe that moderate microwaving does not elute antibodies, but prevents their
      reactions with subsequently applied reagents. Thus, microwaving performed in
      between the first and second staining cycles permits double indirect
      immunofluorescence staining with antibodies raised in the same species. Moreover,
      microwaving also inhibits reactions with endogenous immunoglobulins present in
      extracellular compartments. This substantially reduces background in indirect
      immunostaining of mouse tissues with mouse monoclonal antibodies.

PMID- 10664066
TI  - The expression of androgen receptors in human neck and limb muscles: effects of
      training and self-administration of androgenic-anabolic steroids.
AB  - The purpose of this study was to investigate the immunohistochemical expression
      of androgen receptors (AR) in human vastus lateralis and trapezius muscles and to
      determine whether long-term strength training and self-administration of
      androgenic-anabolic steroids are accompanied by changes in AR content. Biopsy
      samples were taken from eight high-level power-lifters (P), nine high-level power
      lifters who used anabolic steroids (PAS) and six untrained subjects (U).
      Myonuclei and AR were visualised in cross-sections stained with the monoclonal
      antibody against AR and 4',6-diamidino-2-phenylindole. The proportion of AR
      containing myonuclei per fibre cross-section was higher in the trapezius than in
      the vastus lateralis (P<0.05). In the trapezius, the proportion of AR-containing
      myonuclei was higher in P compared to U and in PAS compared to both P and U (P<0.
      05). On the contrary, in the vastus lateralis, there were no differences in AR
      content between the three groups. Myonuclear number in both muscles was higher in
      P compared to U and in PAS compared to both P and U (P<0.05). In conclusion, AR
      content differs greatly between human neck and limb muscles. Moreover, the
      regulation of AR-containing myonuclei following training and self-administration
      of androgenic-anabolic steroids is muscle dependent.

PMID- 10664067
TI  - Sox9 protein in rat sertoli cells is age and stage dependent.
AB  - We studied the location of Sox9 protein in the embryonic, juvenile, and adult rat
      testis by immunohistochemistry and immunoblotting. Sox9 belongs to a family of
      Sox proteins that are transcription factors and important in several
      developmental processes. In the incipient embryonic testis, Sox9 was prominently
      present in the gonadal blastema. With further embryonic differentiation, Sox9
      positive cells arranged in the periphery of the testicular cords, showing the
      location of the Sertoli cells. Thereafter the immunoreaction for Sox9 gradually
      declined and was only weakly detectable in the 2-day-old postnatal rat testis.
      This situation remained for some period of time. In the 15-day-old rat testis,
      Sox9 protein strongly reappeared in the testicular cords. In the adult, the
      Sertoli cells of most regions of the seminiferous tubules were positive for Sox9.
      The strongest reaction for Sox9 was found in the dark zone. However, clearly
      negative or only weakly positive spermatogenic stages for the protein were also
      found, as seen for example in the pale zone. In fertile 1-year-old rats this
      basic situation was still detectable. Analyzed rat ovaries were all negative for
      Sox9, showing the sex-specific nature of Sox9. The results showed that Sox9
      protein is distinctly present in the developing and mature Sertoli cells, but
      that its presence and amount is dependent on the age and the spermatogenetic
      stage within the seminiferous tubuli. The prominent presence of Sox9 in the
      incipient testis and at puberty suggests that this protein is needed at important
      phases of aggregation and reorganization of the Sertoli cells. The age and stage
      specific presence of Sox9 in the testicular cords and in the seminiferous tubules
      of the adult suggests that Sox9 also may have a pivotal role in germ cell
      differentiation.

PMID- 10664068
TI  - Differential expression of dihydropyrimidinase-related protein genes in
      developing and adult enteric nervous system.
AB  - Dihydropyrimidinase-related proteins (DRPs) are involved in axonal outgrowth and
      pathfinding. However, little is known about their significance in the enteric
      nervous system (ENS), the largest and most complex division of the peripheral
      nervous system. Using in situ hybridization (ISH) and northern blotting, we
      examined mRNA expression of DRP-1-4 transcripts in the developing and adult mouse
      digestive tract and in the adult human colon. ISH detected the mouse DRP-3
      transcript in the developing ENS on embryonic day (E)12 and at the later stages
      as well as in the adult intestine. Mouse DRP-1 and -2 transcripts appeared at
      E14. DRP-2 transcript was also detected in the adult intestine although DRP-1
      expression was lower in the adult. DRP-4 gene was not expressed in the ENS during
      development or adulthood whereas the signal was apparent in the developing and
      adult central nervous system (CNS). The DRP expression pattern in the human colon
      was similar to that of the mouse large intestine. Northern blot analysis showed
      that DRPs were differentially expressed in the mouse and human intestines,
      supporting the results of ISH. These data suggest that DRPs play a role not only
      in the CNS but also in the ENS.

PMID- 10664069
TI  - Expression of GM3 microdomains on the surfaces of murine fibroblasts correlates
      with inhibition of cell proliferation.
AB  - The expression and surface distribution of monosialoganglioside GM3 on the plasma
      membranes of NIH3T3 fibroblasts cultured at semiconfluence were analyzed by
      immunofluorescence as well as by immunogold electron microscopy on thin sections
      and surface replicas. The GM3 expression was highly variable from cell to cell
      and the distribution of the ganglioside on the positive cells appeared punctate.
      Quantitative immunogold electron microscopy showed the existence of well-defined
      GM3 clusters of different sizes scattered all over the cell surfaces. Double
      immunofluorescence analysis of 5-bromo-2'-deoxyuridine incorporation to identify
      proliferating cells and of GM3 expression indicated that most of the GM3-positive
      cells appear unable to synthesize DNA and demonstrated a growth-dependent
      expression of GM3.

PMID- 10664070
TI  - Peroxisomes in molluscs, characterization by subcellular fractionation combined
      with western blotting, immunohistochemistry, and immunocytochemistry.
AB  - Peroxisomes of the digestive glands of mussels, Mytilus galloprovincialis Lmk,
      were investigated by immunoblotting and immunohistochemistry using rabbit
      antibodies against several mammalian hepatic peroxisomal proteins. Western blot
      analysis of main subcellular fractions revealed immunoreactive polypeptides with
      molecular weights comparable to those of the corresponding mammalian hepatic
      proteins. They could be localized to the peroxisomal matrix in the case of
      catalase, multifunctional enzyme (PH), and palmitoyl-CoA oxidase (AOX), and to
      the peroxisomal membrane in respect to PMP 70. The purification of peroxisomes by
      metrizamide density gradient centrifugation revealed the existence of two
      subpopulations with densities of 1.16 and 1.20 g cm(-3) exhibiting different
      protein compositions. In paraffin sections, positive immunolabeling for catalase
      was distributed along the apical cytoplasm of the epithelia of digestive ducts
      and stomach and throughout the cytoplasm of digestive tubule cells. The
      peroxisomal beta-oxidation enzymes, AOX and PH, also appeared predominantly in
      the ducts and the stomach epithelia with a weaker immunolabeling in the tubules.
      At the electron microscopic level a clear labeling with gold particles was
      observed in the peroxisomal matrix with the anti-guinea pig catalase antibody. In
      addition to peroxisomes, the anti-PH antibody also labeled the mitochondria. The
      similarity in the protein composition of molluscan and mammalian peroxisomes as
      revealed by the present study indicates that those proteins have been well
      conserved in evolution suggesting that functionally peroxisomes in molluscs could
      also be involved in the metabolism of lipids and in detoxification of
      xenobiotics. Thus, the antibodies tested could provide useful tools for detection
      of peroxisomal induction in molluscan biomonitoring programs for the assessment
      of aquatic environmental pollution.

PMID- 10664083
TI  - Short-term cardiovascular responses to rapid whole-body tilting during exercise.
AB  - Our objective was to characterize the responses of heart rate (HR) and arterial
      blood pressure (BP) to changes in posture during concomitant dynamic leg
      exercise. Ten men performed dynamic leg exercise at 50, 100, and 150 W and were
      rapidly and repeatedly tilted between supine (0 degrees ) and upright (80 degrees
      ) positions at 2-min intervals. Continuous recordings of BP and HR were made, and
      changes in central blood volume were estimated from transthoracic impedance.
      Short-lasting increases in BP were observed immediately upon tilting from the
      upright to the supine position (down-tilt), averaging +18 mmHg (50 W) to +31 mmHg
      (150 W), and there were equally short-lasting decreases in BP, ranging from -26
      to -38 mmHg upon tilting from supine to upright (up-tilt). These components
      occurred for all pressure parameters (systolic, mean, diastolic, and pulse
      pressures). We propose that these transients reflect mainly tilt-induced changes
      in total peripheral resistance resulting from decreases and increases of the
      efficiency of the venous muscle pump. After 3-4 s (down-tilt) and 7-11 s (up
      tilt) there were large HR transients in a direction opposite to the pressure
      transients. These HR transients were larger during the down-tilt (-15 to -26
      beats. min(-1)) than during the up-tilt (+13 to +17 beats. min(-1)), and
      increased in amplitude with work intensity during the down-tilt. The tilt-induced
      HR fluctuations could be modelled as a basically linear function of an arterial
      baroreflex input from a site half-way between the heart and the carotid sinus,
      and with varying contributions of fast vagal and slow sympathetic HR responses
      resulting in attenuated tachycardic responses to hypotensive stimuli during
      exercise.

PMID- 10664071
TI  - A (1-->3,6)-beta-d-galactosyl epitope containing uronic acids associated with
      bioactive pectins occurs in discrete cell wall domains in hypocotyl and root
      tissues of flax seedlings.
AB  - We have used a well-characterized antibody specific for an epitope consisting of
      (1-->3,6)-beta-d-galactosyl residues with terminal glucuronic or 4-O
      methylglucuronic acids of a bioactive pectin and immunocytochemistry to
      investigate its secretion and wall distribution in the hypocotyl and root tissues
      of flax seedlings. Our results show that this antigenic epitope is associated
      with flax pectins and is expressed by all the cells of the hypocotyl and root
      tissues. In the hypocotyl, it is abundant in the primary wall of epidermal cells
      as well as in the secondary wall of fiber cells, and is relatively less abundant
      in parenchyma cell walls. In contrast, the epitope is not detected in the middle
      lamellae and cell junction regions. In the root tip cells, immunogold electron
      microscopy shows that the cell walls of peripheral, columella, meristematic,
      cortical, and epidermal cells contain significant amounts of this epitope and
      that the distribution patterns are distinct. Together, these findings show that
      the antigenic epitope occurs in discrete domains of the wall implying a strict
      spatial regulation of the epitope-containing molecules. The results also show
      that, in root cells, the epitope is present within Golgi cisternae and is
      predominantly assembled in the trans and the trans-Golgi network compartments.

PMID- 10664084
TI  - Cardiovascular responses at the onset of passive leg cycle exercise in
      paraplegics with spinal cord injury.
AB  - The purpose of this study was to examine the cardiovascular responses at the
      onset of passive leg cycle exercise (PLCE) in paraplegics with spinal cord injury
      (PSCI) to investigate the increase in venous return from the paralyzed lower
      limbs during PLCE. Six male PSCI having lesions at levels ranging from T8 to L1
      and five male able-bodied subjects (ABS) participated in this study. The subjects
      performed PLCE at pedalling frequencies of 40 rpm for 6 min. Cardiac output
      (Q(c)), stroke volume (SV) and heart rate (f(c)) were measured before and during
      PLCE. In the steady state (4th and 5th min) of PLCE, both PSCI and ABS showed a
      significant increase in Q(c). At the onset of PLCE, however, clear differences in
      the cardiovascular response were found between PSCI and ABS. The ABS showed a
      rapid and marked increase in f(c) and consequently Q(c) within 20 s of the onset
      of PLCE. On the other hand, in PSCI, the Q(c) increased more slowly, compared
      with that in ABS, because of a smaller increase in f(c) and a delayed increase in
      SV. The observed delay in the increases of Q(c) and SV at the onset of PLCE in
      PSCI was presumably due to the absence of afferent reflexes from the lower limbs,
      and to the additional time needed for venous return to arrive at the heart from
      the passively moved muscles.

PMID- 10664085
TI  - Metabolic and cardiorespiratory responses to maximal intermittent knee isokinetic
      exercise in young healthy humans.
AB  - There have been many studies on the effects of isokinetic exercise on muscle
      performance in training and rehabilitative programmes. On the other hand, the
      cardiovascular and metabolic responses elicited by this type of exercise have
      been poorly investigated. This study was specifically designed to describe the
      relationships, if any, between metabolic and cardiorespiratory responses and
      power output during maximal intermittent knee isokinetic exercise when a steady
      state is reached. A group of 18 healthy subjects (10 men and 8 women, age range
      25-30 years) were requested to perform at maximal concentric isokinetic knee
      extensions/flexions 60 degrees. s(-1) and 180 degrees. s(-1) for 5 min, with a 5
      s pause interposed between consecutive repetitions. The power output (W) was
      calculated; before and during the tasks heart rate (f(c)) and arterial blood
      pressure (AP(a)) were continuously monitored. Pulmonary ventilation (V(E)) and
      oxygen uptake (VO(2)) were measured at the 4th and at the 5th min of exercise and
      blood lactate concentration at rest and at the 3rd min of recovery. From the 4th
      to the 5th min only a slight decrease in W was observed, both at 60 degrees. s(
      1) and 180 degrees. s(-1). The VO(2), V(E), f(c) and AP(a) showed similar values
      in the last 2 min of exercise, suggesting that a steady state had been reached.
      The VO(2) increased linearly as a function of +W, showing a significantly steeper
      slope at 60 degrees. s(-1) than at 180 degrees. s(-1). The f(c), in spite of a
      large interindividual variation, was linearly related to metabolic demand, and
      was not affected by angular velocity. Systolic and diastolic AP(a) were not
      related either to VO(2) or to angular velocity. In conclusion it would appear
      that the metabolic response to maximal intermittent knee isokinetic exercise
      resembles that of dynamic exercise. Conversely, the cardiocirculatory responses
      would seem to reflect a relevant role of the isometric postural component, the
      importance of which should be carefully evaluated in each subject.

PMID- 10664087
TI  - Coordination between breathing and forearm movements during sinusoidal tracking.
AB  - Time relationships (coordination) between breathing and rhythmical limb movements
      were analyzed during sinusoidal tracking movements of the forearm in 11 healthy
      subjects. The tracking rate was varied systematically between 0.1 and 1.0 Hz in
      0.1-Hz steps. The aim of the study was to elucidate whether rhythmical tracking
      movements can entrain breathing, and whether this entrainment depends upon the
      movement rate. Subjects exhibited coordination between tracking movements and
      breathing at various rate ratios (1:1, 1:2, 1:3). At tracking rates of between
      0.2 and 0.6 Hz, 1:1 coordination occurred with a maximum at 0.3 Hz; this rate
      range was called the 1:1 entrainment band. Coordination of 1:2 occurred at
      between 0.5 and 1. 0 Hz (the 1:2 coordination band) with a maximum at 0.7 Hz.
      Coordination of 1:3 could be detected at between 0.5 and 1.0 Hz. Different
      subjects showed 1:n entrainment bands at similar locations but different widths
      of the rate range studied. The breathing rate during tracking was significantly
      higher than at rest, and it was correlated positively with tracking rate. This
      correlation, however, depended upon the width of the entrainment bands. Breathing
      rates varied between 0.2 and 0.6 Hz for all coordination patterns. We conclude
      that the occurrence of fixed time relationships is an expression of the strength
      of central nervous system coupling between the two processes. The frequency of
      coordination between breathing and rhythmical tracking movements depends
      critically upon the movement rate.

PMID- 10664086
TI  - Circulating cytokines and hormones with immunosuppressive but neutrophil-priming
      potentials rise after endurance exercise in humans.
AB  - To investigate the mechanisms of exercise-induced immune perturbations, we
      measured promising immunomodulatory hormones and cytokines in plasma of 16 male
      marathon runners before and after a competitive 42.195-km race. Interleukin 1
      beta (IL-1beta) and interferon gamma (IFN-gamma) concentrations remained
      unchanged after the marathon. The cytokines IL-12, IFN-alpha and tumour necrosis
      factor alpha (TNF-alpha) could not be detected even using highly sensitive
      specific immunoassays, indicating at least that overshooting responses of these
      cytokines had not occurred after exercise. As mechanisms for the small changes in
      these cytokines, we demonstrated for the first time a significant rise in
      concentrations of inhibitory cytokine IL-10 in addition to the immunosuppressive
      hormone cortisol, although concentrations of IL-4 and transforming growth factor
      beta (TGF-beta) were unaffected by the race. Furthermore, concentrations of IL-1
      receptor antagonist (IL-1ra) and IL-6, which are negative-feedback inhibitors of
      cytokine production, increased by more than 100 times. As for humoral mediators
      of neutrophil mobilization, concentrations of growth hormone (GH), cortisol and
      granulocyte colony-stimulating factor (G-CSF) increased significantly. In
      addition, concentrations of neutrophil-priming substances (IL-6, IL-8, G-CSF, GH
      and prolactin) also increased significantly and the induction of IL-8 and G-CSF
      with exercise was demonstrated for the first time in the present study. In
      contrast, IL-2 concentration decreased, by 32%, and this was correlated with the
      induction of nitric oxide (NO) production. Muscle damage, monitored using changes
      in concentrations of creatine kinase and myoglobin, was also observed. These
      results suggested that exercise-induced pathogenesis including previously
      reported immunosuppression and neutrophil hyper-reactivity might be attributed,
      at least partly, to the systemic dynamics of the above bioactive substances.

PMID- 10664088
TI  - Muscle activation of the knee extensors following high intensity endurance
      exercise in cyclists.
AB  - This study was conducted to assess the effects in trained cyclists of exhausting
      endurance cycle exercise (CE) on maximal isometric force production, surface
      electromyogram (EMG) and activation deficit (AD) of the knee extensors. Ten male
      subjects made four isometric maximal voluntary contractions (MVC) of the knee
      extensor muscles immediately prior (pre), 10 min after (post) and 6 h after
      completion of CE. The CE consisted of 30 min of exercise on a stationary cycle
      ergometer at an intensity corresponding to 80% of maximal oxygen uptake
      (VO(2max)) followed by four x 60-s periods at 120% of VO(2max). Two MVC were
      performed with recording of surface EMG from the knee extensors, whilst an
      additional two MVC were completed with percutaneous electrical muscle stimulation
      (EMS; 25 pulses at 100 Hz with the maximal tolerable current) superimposed over
      the maximal voluntary contraction force (MVF) but without EMG (to avoid
      interference). The MVF, integrated EMG (iEMG), and AD [calculated as the
      difference between MVF and the electrically stimulated force (ESF) during the EMS
      contractions] were statistically analysed. The MVF was significantly reduced (P <
      0.05) post and 6-h post compared to pre-CE level. The iEMG was significantly
      reduced (P < 0.05) post and 6 h post CE. The ESF was also reduced, whilst AD was
      significantly increased (P < 0.05) post and 6-h post CE compared to the pre CE.
      These results suggest that the level of exercise stress administered in this
      study was sufficient to impair the central and peripheral mechanisms of force
      generation in knee extensors for a period of 6-h. Athletes engaged in concurrent
      training (strength and endurance) should consider this effect in exercise
      programming.

PMID- 10664089
TI  - Sympathetic stimulation induced by hand cooling alters cold-induced
      vasodilatation in humans.
AB  - Hand cooling is a cold pressor test, which induces general sympathetic
      stimulation. This cooling procedure is often performed to investigate cold
      induced vasodilatation (CIVD) in one finger. To investigate the effects of this
      sympathetic stimulation on local CIVD, 12 subjects immersed either the right
      index finger (T1), right hand (T2) or left hand and right index finger (T3) for
      30 min in water at 5 degrees C followed by 15-min recovery. Skin temperature and
      skin blood flow (Q(sk)) measured by laser Doppler flowmetry on the right index
      finger, as well as heart rate (f(c)) and mean arterial blood pressure (BP(a)),
      were continuously monitored during the three tests. Cutaneous vascular
      conductance was calculated as Q(sk)/(BP(a)). Concentrations of plasma
      noradrenaline (NA) and adrenaline (AD) were measured at different times during
      the tests. The results showed no cardiovascular change in T1, whereas f(c) and
      (BP(a)) increased significantly at the beginning of both T2 and T3. Similarly,
      sympathetic stimulation was reflected in the NA concentrations, which increased
      significantly (P < 0.01) during T2 and T3 after 5 min of immersion, and remained
      elevated until the recovery period. The AD concentration did not change during
      the three tests. During T2, the CIVD appeared later and slower in comparison with
      T1 [CIVD onset: 12.81 (SEM 2.30) min in T2 and 5.62 (SEM 0.33) min in T1]. During
      T3, the CIVD onset was not delayed compared to T1 [6.38 (SEM 0.67) min], but the
      rewarming was lower [+5.40 (SEM 0.86) degrees C in T3 and +9.10 (SEM 1.31)
      degrees C in T1]. These results showed that CIVD could be altered by sympathetic
      stimulation but it also appeared that the onset of CIVD could be influenced by
      local cooling, independently of the general sympathetic stimulation.

PMID- 10664090
TI  - Attenuated beta-adrenoceptor-mediated cardiac contractile responses following
      androgenic steroid administration to sedentary rats.
AB  - Androgenic steroids administered in doses at pharmacological levels to sedentary
      animals have been shown to result in a reduced beta-adrenoceptor-mediated
      increase in systolic cardiac performance when assessed in vivo. Whether the
      attenuated adrenergic response occurs as a consequence of alterations in either
      cardiac loads, heart rate, modifications in left ventricular (LV) geometry, or a
      decrease in myocardial contractile performance has not been determined. In this
      study the effect of chronic administration (over 3 months) of an androgenic
      steroid (nandrolone decanoate, 5 mg. kg(-1) biweekly) on the response of load
      insensitive indices of myocardial contractile function [the slope of the LV
      systolic stress-strain relationship (LV-E(n)(max), where E(n)(max) is systolic
      myocardial elastance)] to an adrenergic-inotropic stimulus was examined ex vivo
      in paced rat hearts. Systolic cardiac performance was assessed at 300 beats. min(
      1) in isolated constant flow perfused heart preparations both before and during
      10(-8.5) mol. l(-1) isoproterenol (ISO) infusion (approximate concentration of
      ISO eliciting 50% maximal inotropic response to ISO). Steroid administration
      resulted in left-shifted LV systolic and diastolic pressure-volume (P-V )
      relationships. The leftshifted P-V relationships were attributed, in part, to
      increased slopes of these relationships. However, the steroid-mediated increment
      in the slope of the systolic P-V relationship (systolic chamber elastance,
      E(max)) was not associated with a similar change in LV E(n)(max) [control 19.2
      (SEM 2.1) g. cm(-2), steroid 18.3 (SEM 2.4) g. cm(-2)] as determined in the
      absence of ISO. Isoproterenol infusion resulted in an increase in both E(max) and
      E(n)(max) in the control rats, without altering systolic performance in the
      steroid treated rats. Consequently, in the presence of ISO, the steroid treated
      rats exhibited a similar E(max), but a reduction in E(n)(max) compared to the
      control rats [control 25.6 (SEM 1.9) g. cm(-2), steroid 18.5 (SEM 1.5) g. cm(-2);
      P < 0.05]. In conclusion, these results would suggest that chronic high dose
      androgenic steroid administration produces a decrease in myocardial contractile
      reserve to beta-adrenoceptor stimulation.

PMID- 10664091
TI  - Changes in saccadic reaction time while maintaining neck flexion in men and
      women.
AB  - We investigated changes in saccadic reaction time in relation to the degree of
      increase in activity of neck extensor muscles when neck flexion occurred, and
      assessed the reliability of the measurements. Saccadic reaction time was measured
      firstly, during neck flexion angles set at 5 degrees increments from 0 degrees
      (resting position) to 25 degrees, with the chin either resting on a stand or not,
      and secondly, during shoulder girdle elevator muscles providing a relative muscle
      force of 30%, with the neck flexion angle maintained at 0 degrees by having the
      subjects rest their chins on a stand. Saccadic reaction time was evaluated by the
      latency to the beginning of eye movement toward the lateral target, which was
      moved at random intervals in 20 degrees amplitude jumps. Muscle activity in the
      trapezius muscle was evaluated using the mean amplitude of electromyogram
      recordings. Very high coefficients of reliability in muscle activity and saccadic
      reaction time were observed between the two sets of tests at 1-h intervals and
      also among the three trials with a 1-min rest. When their necks were flexed and
      the subjects rested their chins on a stand, muscle activity increased slightly in
      accordance with the enlargement of this angle, with no significant change in
      saccadic reaction time. With the chin not resting on the stand, muscle activity
      increased gradually, while the saccadic reaction time decreased to that obtained
      at an average neck flexion angle of 20 degrees. However, the angle where the
      shortest reaction time was obtained showed considerable individual variation (5
      25 degrees ). Activity in the trapezius muscle at a 20 degrees neck flexion
      angle, with the chin not resting on the stand, was far less than that for 30%
      maximal voluntary contraction in shoulder girdle elevator muscles. Nevertheless,
      the saccadic reaction times were roughly equivalent under the two different sets
      of conditions. No sex differences were observed in terms of saccadic reaction
      time under any set of conditions.

PMID- 10664092
TI  - Changes in maximal performance of inspiratory and skeletal muscles during and
      after the 7.1-MPa Hydra 10 record human dive.
AB  - During the 7.1-MPa hydrogen-helium-oxygen record human dive, we tested the
      hypothesis that the increased ambient pressure would alter the maximal muscle
      performance, specifically that breathing dense gas would lead to fatigue of the
      respiratory muscle. A group of hand muscles (adductor pollicis, AP) and the
      inspiratory muscles (IM) were studied in three professional divers. Maximal
      voluntary contractions (MVC) of AP and maximal inspiratory pressure (P(i(max)))
      generated by IM were measured prior to the dive, during compression and
      decompression, and then 1 and 2 months after the dive. The decrease in MVC (-22%)
      was significant at 3.1 MPa, i.e. at the beginning of the introduction of hydrogen
      into the breathing mixture, whereas P(i(max)) fell progressively during the dive
      and decompression (maximal DeltaP(i(max)) = -55%), a significant reduction still
      being measured 1 month after the dive. The altered IM function was attributed to
      the consequences of long-term ventilatory loading, a condition associated with
      breathing a dense gas. The transient decrease in MVC of the skeletal muscle would
      indicate a possible effect of the hyperbaric environment, possibly the high
      partial pressure of hydrogen, on neuromuscular drive.

PMID- 10664093
TI  - Benefit of endurance training in elderly people over a short period is
      reversible.
AB  - The present study assessed daily activity, physical capacity and body composition
      in 11 initially sedentary healthy subjects [5 men and 6 women, mean age 62.8 (SD
      2.7) years] before training (T(o)), after completion of 7 (T(7w)) and 14 (T(14w))
      weeks of training, and again 6 (T(6m)) and 12 (T(12m)) months after training. The
      mean daily activity index decreased from T(7w) to T(12m) reaching a lower level
      than at T(o) [T(12m) - T(o) = -1.5 (SD 4.6) units, P = 0.18]. Mean maximal oxygen
      uptake (VO(2max)) and its corresponding mean power output (Wdot(max)) were
      increased by 12.5 (SD 6.6)% (P = 0. 003) and 22.8 (SD 12.8)% (P = 0.003),
      respectively, at T(14w), and returned to their T(o) levels within 1 year. Mean
      body mass (m(b)) remained stable until T(6m) but increased significantly by 2.6
      (SD 3. 7)% from T(6m) to T(12m) (P < 0.05). Mean fat mass (m(f), from
      bioelectrical impedance analysis measurements) tended to decrease [-2.0 (SD
      4.2)%, P = 0.10] during the training period but increased by 7.8 (SD 10.9)%
      between T(6m) and T(12m) (P < 0.05). The mean fat free mass did not vary during
      the study period (P = 0.81) but magnetic resonance imaging (MRI) showed that mean
      thigh muscle volume decreased between T(7w) and T(12m) to less than at T(o)
      [T(12m) - T(o) = -2.3 (SD 3.6)%, P = 0.05]. Therefore, this study confirmed the
      favourable effects of endurance training on the physical capacity and body
      composition of elderly people, but demonstrated that the training programme would
      have to be continued to maintain the training-related benefits (i.e. increased
      VO(2max) and Wdot(max)) which would otherwise be lost within 1 year. After
      training, m(b) and m(f) were found to be increased. Furthermore, a fast and
      reproducible MRI protocol was validated for study of small intra-individual
      variations in tissue volumes in longitudinal studies.

PMID- 10664094
TI  - Time to exhaustion during severe intensity running: response following a single
      bout of interval training.
AB  - The primary aim of this study was to examine any change in performance caused by
      a fatiguing interval training session (TS). A secondary aim of this study was to
      examine the change in oxygen uptake (VO(2)) during moderate and severe intensity
      running, and the relationship with the change in performance. Seven male runners
      [mean age 24 (SD 6) years, height 1.79 (SD 0.06) m, body mass 67.9 (SD 7.6) kg,
      maximal oxygen uptake (VO(2max)) 4.14 (SD 0.49) l. min(-1)] were studied. The
      VO(2) during moderate and severe intensity running and running performance were
      studied immediately prior to, 1 h following, and 72 h following TS. The TS was
      performed on a treadmill, and consisted of six bouts of 800 m at 1 km. h(-1)
      below the velocity at VO(2max) (v(V)O(2max)), with 3-min rest intervals.
      Performance was also assessed at 1 km. h(-1) below v(V)O(2max), in the form of
      time to exhaustion (t(lim)). The VO(2) and heart rate (f(c)) were assessed both
      during the severe intensity performance trial, and the moderate intensity run at
      50% v(V)O(2max). Whilst a significant change was observed in running performance
      and the VO(2) during both moderate and severe intensity running prior to and
      following TS, no relationship was observed between the magnitude of change in
      these variables. At 1 h following TS, t(lim) had decreased by 24%, VO(2) during
      moderate intensity running had increased by 2%, and the difference in VO(2)
      between 2 min 45 s and the end of severe intensity running had increased by 91%
      compared with values recorded prior to TS. At 1 h following TS, f(c) had also
      increased significantly during moderate intensity running by 5% compared to the
      value recorded prior to TS. These findings demonstrated that TS resulted in a
      reduction in performance, and that the relationship between running performance
      and VO(2) during running may be altered under conditions of prolonged fatigue.

PMID- 10664095
TI  - Muscle glycogen resynthesis rate in humans after supplementation of drinks
      containing carbohydrates with low and high molecular masses.
AB  - The rate of muscle glycogen synthesis during 2 and 4 h of recovery after
      depletion by exercise was studied using two energy equivalent carbohydrate
      drinks, one containing a polyglucoside with a mean molecular mass of 500 000-700
      000 (C drink), and one containing monomers and oligomers of glucose with a mean
      molecular mass of approximately 500 (G drink). The osmolality was 84 and 350
      mosmol. l(-1), respectively. A group of 13 healthy well-trained men ingested the
      drinks after glycogen depleting exercise, one drink at each test occasion. The
      total amount of carbohydrates consumed was 300 g (4.2 g. kg(-1)) body mass given
      as 75 g in 500 ml water immediately after exercise and again 30, 60 ad 90-min
      post exercise. Blood glucose and insulin concentrations were recorded at rest and
      every 30 min throughout the 4-h recovery period. Muscle biopsies were obtained at
      the end of exercise and after 2 and 4 h of recovery. Mean muscle glycogen
      contents after exercise were 52.9 (SD 27.4) mmol glycosyl units. kg(-1) (dry
      mass) in the C group and 58.3 (SD 35.4) mmol glycosyl units. kg(-1) (dry mass) in
      the G group. Mean glycogen synthesis rate was significantly higher during the
      initial 2 h for the C drink compared to the G drink: 50.2 (SD 13.7) mmol. kg(-1)
      (dry mass). h(-1) in the C group and 29.9 (SD 12.5) mmol. kg(-1) (dry mass). h(
      1) in the G group. During the last 2 h the mean synthesis rate was 18.8 (SD 33.3)
      and 23.3 (SD 22.4) mmol. kg(-1) (dry mass). h(-1) in the C and G group,
      respectively (n.s.). Mean blood glucose and insulin concentrations did not differ
      between the two drinks. Our data indicted that the osmolality of the carbohydrate
      drink may influence the rate of resynthesis of glycogen in muscle after its
      depletion by exercise.

PMID- 10664097
TI  - Self-organizing maps for visual feature representation based on natural binocular
      stimuli.
AB  - We model the stimulus-induced development of the topography of the primary visual
      cortex. The analysis uses a self-organizing Kohonen model based on high
      dimensional coding. It allows us to obtain an arbitrary number of feature maps by
      defining different operators. Using natural binocular stimuli, we concentrate on
      discussing the orientation, ocular dominance, and disparity maps. We obtain
      orientation and ocular dominance maps that agree with essential aspects of
      biological findings. In contrast to orientation and ocular dominance, not much is
      known about the cortical representation of disparity. As a result of numerical
      simulations, we predict substructures of orientation and ocular dominance maps
      that correspond to disparity maps. In regions of constant orientation, we find a
      wide range of horizontal disparities to be represented. This points to
      geometrical relations between orientation, ocular dominance, and disparity maps
      that might be tested in experiments.

PMID- 10664096
TI  - Mechanomyographic and electromyographic responses during fatigue in humans:
      influence of muscle length.
AB  - Mechanomyography (MMG) provides a measure of muscle mechanical changes during
      contractions. The purpose of this study was to quantify alterations in MMG
      signals during fatigue at two muscle lengths. Comparisons with electromyographic
      (EMG) recordings were made. A group of 13 subjects performed isometric
      dorsiflexions (50% of maximum for 60 s) at 40 degrees of plantarflexion (long,
      l(l)) and 5 degrees of dorsiflexion (short, l(s)). The mean power frequency of
      the EMG (f(EMG)) and MMG (f(MMG)) signals and the mean rectified MMG (rMMG) and
      EMG (rEMG) were determined over each 1-s period, normalized to the respective
      maximal value, regressed against time, and the resulting slopes (units = %max. s(
      1)) were analyzed. The slopes were larger (P = 0.007) at l(l) compared to l(s)
      [mean l(l) 0.50 (SD 0.26), mean l(s) 0.27 (SD 0.16)], however there were no
      differences (P = 0.24) between mean fMMG slopes [l(l) -0.10 (SD 0.16), l(s) -0.16
      (SD 0.11)]. Similarly, slopes were larger (P = 0.001) at l(l) versus l(s) [l(l)
      0.26 (SD 0.13), l(s) 0.08 (SD 0.15)] and there were no differences (P=0.89)
      between mean fEMG slopes [l(l) -0.15 (SD 0.14), l(s) -0.14 (SD 0.12)]. At 5 s
      following the exercise to fatigue mean MVC (units = %max) were not significantly
      different between l(l) and l(s) [P = 0.08; l(l) 78.8 (SD 9.1), l(s) 85.2 (SD 6.
      0)]. These results showed that during fatiguing contractions, MMG and EMG
      amplitudes increased while frequency characteristics decreased at both muscle
      lengths. The change in and was greater at l(l) but no differences in fMMG or fEMG
      slopes occurred between lengths. These results would suggest that larger
      increases in motor unit recruitment occur with time during fatigue at l(l)
      compared to l(s).

PMID- 10664098
TI  - A quantitative analysis of the local connectivity between pyramidal neurons in
      layers 2/3 of the rat visual cortex.
AB  - This study provides a detailed quantitative estimate for local synaptic
      connectivity between neocortical pyramidal neurons. A new way of obtaining such
      an estimate is presented. In acute slices of the rat visual cortex, four layer 2
      and four layer 3 pyramidal neurons were intracellularly injected with biocytin.
      Axonal and dendritic arborizations were three-dimensionally reconstructed with
      the aid of a computer-based camera lucida system. In a computer experiment, pairs
      of pre- and postsynaptic neurons were formed and potential synaptic contacts were
      calculated. For each pair, the calculations were carried out for a whole range of
      distances (0 to 500 microm) between the presynaptic and the postsynaptic neuron,
      in order to estimate cortical connectivity as a function of the spatial
      separation of neurons. It was also differentiated whether neurons were situated
      in the same or in different cortical layers. The data thus obtained was used to
      compute connection probabilities, the average number of contacts between neurons,
      the frequency of specific numbers of contacts and the total number of contacts a
      dendritic tree receives from the surrounding cortical volume. Connection
      probabilities ranged from 50% to 80% for directly adjacent neurons and from 0% to
      15% for neurons 500 microm apart. In many cases, connections were mediated by one
      contact only. However, close neighbors made on average up to 3 contacts with each
      other. The question as to whether the method employed in this study yields a
      realistic estimate of synaptic connectivity is discussed. It is argued that the
      results can be used as a detailed blueprint for building artificial neural
      networks with a cortex-like architecture.

PMID- 10664099
TI  - Analysis of a muscular control system in human movements.
AB  - In this work, we have studied a muscular control system under experimental
      conditions for analyzing the dynamic behavior of individual muscles and
      theoretical considerations for elucidating its control strategy. Movement of
      human limbs is achieved by joint torques and each torque is specified as the sum
      of torques generated by muscle forces. The behavior of individual muscles is
      controlled by the neural input which is estimated by means of an electromyogram
      (EMG). In this study, the EMGs for a flexor and an extensor are measured in elbow
      joint movements and the dynamic behavior of individual muscles is analyzed. As a
      result, it is verified that both a flexor and an extensor are activated
      throughout the entire movement and that the activation of muscles is controlled
      above a specific limit independent of the hand-held load. Subsequently, a system
      model for simulating elbow joint movements is developed which includes the muscle
      dynamic relationship between the neural input and the isometric force. The
      minimum limit of muscle activation that has been confirmed in experiments is
      provided as a constraint of the neural input and the criterion is defined by a
      derivative of the isometric force of individual muscles. The optimal trajectories
      formulated under these conditions are quantitatively compared with the
      experimentally observed trajectories, and the control strategy of a muscular
      control system is studied. Finally, a muscular control system in multi-joint arm
      movements is discussed with regard to the comparative analysis between observed
      and optimal trajectories.

PMID- 10664100
TI  - The inverse dynamics problem of neuromuscular control.
AB  - The myoskeletal inverse dynamics problem and the myocybernetic control inverse
      problem were investigated with respect to their ill-posedness. The first problem
      consists of finding from observed experimental motion and reaction force data the
      resultant muscle moments that generated the observed motion, while the second
      aims at finding the corresponding neural controls. It is shown that both problems
      belong to the class of incorrectly posed (ill-posed) problems that, by
      definition, do not possess unique solutions. To illustrate this point, results of
      a forward dynamics simulation of a comprehensive neuromusculoskeletal model of
      the human body are presented. These results demonstrate that fairly chaotic
      neural control perturbations have very little influence on the resulting motion
      trajectory, at least in the present example. While a regularization procedure may
      be applied to solve successfully the myoskeletal inverse dynamics problem, the
      myocybernetic control inverse problem is unsolvable. The latter fact has the
      important implication that, based on the somatosensory inputs it receives, the
      pars intermedia in the cerebellum is not able to control individual motor unit
      stimulation rates and recruitment patterns but only whole muscles by means of a
      single compound signal. The latter signal is identified as the "common drive."
      Presumably at the spinal level, special neural circuits are used to decompose the
      common drive signal into motor unit recruitment patterns and stimulation rates
      that are specific for a given mode of contraction and probably obey certain
      optimality principles.

PMID- 10664101
TI  - Principal components in three-ball cascade juggling.
AB  - To uncover the underlying control structure of three-ball cascade juggling, we
      studied its spatiotemporal properties in detail. Juggling patterns, performed at
      fast and preferred speeds, were recorded in the frontal plane and subsequently
      analyzed using principal component analysis and serial correlation techniques. As
      was expected on theoretical grounds, the principal component analysis revealed
      that maximally four instead of the original six dimensions (3 balls x 2 planar
      coordinates) are sufficient for describing the juggling dynamics. Juggling speed
      was shown to affect the number of dimensions (four for the fast condition, two
      for the preferred condition) as well as the smoothness of the time evolution of
      the eigenvectors of the principal component analysis, particularly around the
      catches. Contrary to the throws and the zeniths, and regardless of juggling
      speed, consecutive catches of the same hand showed a markedly negative lag-one
      serial correlation, suggesting that the catches are timed so as to preserve the
      temporal integrity of the juggling act.

PMID- 10664102
TI  - A physiological model of dark-adapted and light-adapted photoreceptors of the
      honeybee.
AB  - A physiological model of dark-adapted and light-adapted photoreceptors in the
      honeybee worker (Apis mellifera) has been developed. Almost all of the
      electrophysiological components of photoreceptors known up to date, e.g. the
      phototransduction cascade, the ion channels of the membrane, phototransduction
      gain and optical adaptation mechanisms, are adequately described by simple
      biophysical and biochemical models. The connections of these components were
      tried out in synthetic simulations for best fits of simulated to intracellularly
      recorded membrane potentials. Although the parameters of the best model were
      determined exclusively for the measured membrane potentials of dark-adapted
      photoreceptors, the model also accurately describes the light-adapted
      photoreceptor membrane potentials. Furthermore, the model correctly predicts the
      time-courses of measured photoreceptor responses with respect to squared
      modulated flicker lights up to 200 Hz. This clearly demonstrates that the
      presented photoreceptor model is indeed a physiologically adequate description of
      the essential components of the phototransduction and the electrical membrane
      processes in the photoreceptors of the honeybee worker.

PMID- 10664103
TI  - Investigating centre of mass stabilisation as the goal of posture and movement
      coordination during human whole body reaching.
AB  - In the light of experimental results showing significant forward centre of mass
      (CoM) displacements within the base of support, this study investigated if whole
      body reaching movements can be executed whilst keeping the CoM fixed in the
      horizontal axis. Using kinematic simulation techniques, angular configurations
      were recreated from experimental data imposing two constraints: a constant
      horizontal position of the CoM and an identical trajectory of the hand to grasp
      an object. The comparison between recorded and simulated trials showed that
      stabilisation of the CoM was associated with greater backward hip displacements,
      which became more marked with increasing object distance. This was in contrast to
      recorded trials showing reductions in backward hip displacements with increasing
      distance. Results also showed that modifications to angular displacements were
      necessary only at the shoulder and hip joints, but that these modifications were
      within the limits of joint mobility. The analysis of individual joint torques
      revealed that the pattern and timing of simulated trials were similar to those
      recorded experimentally. Peak joint torque values showed particularly that
      keeping the CoM at a constant horizontal position resulted in significantly
      smaller ankle peak flexor and extensor torques. It may be concluded from this
      study that 'stabilising' the CoM during human whole body reaching represents a
      feasible strategy, but not the one chosen by subjects under experimental
      conditions. Our results also do not support the idea of the CoM as the stabilised
      reference value for the coordination between posture and goal-directed movements.

PMID- 10664104
TI  - Learning cortical topography from spatiotemporal stimuli.
AB  - Stimulus representation is a functional interpretation of early sensory cortices.
      Early sensory cortices are subject to stimulus-induced modifications. Common
      models for stimulus-induced learning within topographic representations are based
      on the stimuli's spatial structure and probability distribution. Furthermore, we
      argue that average temporal stimulus distances reflect the stimuli's relatedness.
      As topographic representations reflect the stimuli's relatedness, the temporal
      structure of incoming stimuli is important for the learning in cortical maps.
      Motivated by recent neurobiological findings, we present an approach of cortical
      self-organization that additionally takes temporal stimulus aspects into account.
      The proposed model transforms average interstimulus intervals into
      representational distances. Thereby, neural topography is related to stimulus
      dynamics. This offers a new time-based interpretation of cortical maps. Our
      approach is based on a wave-like spread of cortical activity. Interactions
      between dynamics and feedforward activations lead to shifts of neural activity.
      The psychophysical saltation phenomenon may represent an analogue to the shifts
      proposed here. With regard to cortical plasticity, we offer an explanation for
      neurobiological findings that other models cannot explain. Moreover, we predict
      cortical reorganizations under new experimental, spatiotemporal conditions. With
      regard to psychophysics, we relate the saltation phenomenon to dynamics and
      interaction in early sensory cortices and predict further effects in the
      perception of spatiotemporal stimuli.

PMID- 10664105
TI  - Two dynamic processes for the induction of long-term potentiation in hippocampal
      CA1 neurons.
AB  - This work sets out to investigate fast and slow dynamic processes and how they
      effect the induction of long-term potentiation (LTP). Functionally, the fast
      process will work as a time window to take a spatial coincidence among various
      inputs projected to the hippocampus, and the slow process will work as a temporal
      integrator of a sequence of dynamic events. Firstly, the two factors were studied
      using a "burst" stimulus and a "long-interval patterns" stimulus. Secondly, we
      propose that, for the induction of LTP, there are two dynamic processes, fast and
      slow, which are productively activated by bursts and long-interval patterns. The
      model parameters, a time constant of short dynamics and one of long dynamics,
      were determined by fitting the values obtained from model simulation to the
      experimental data. A molecular factor or cellular factors with these two time
      constants are likely to be induced in LTP induction.

PMID- 10664106
TI  - Analysis of a distributed model of leg coordination. I. Individual coordination
      mechanisms.
AB  - Using tools from discrete dynamical systems theory, we begin a systematic
      analysis of a distributed model of leg coordination with both biological and
      robotic applications. In this paper, we clarify the role of individual
      coordination mechanisms by studying a system of two leg oscillators coupled in
      one direction by each of the three major mechanisms that have been described for
      the stick insect Carausius morosus. For each mechanism, we derive analytical
      return maps, and analyze the behavior of these return maps under iteration in
      order to determine the asymptotic phase relationship between the two legs. We
      also derive asymptotic relative phase densities for each mechanism and compare
      these densities to those obtained from numerical simulations of the model. Our
      analysis demonstrates that, although each of these mechanisms can individually
      compress a range of initial conditions into a narrow band of relative phase, this
      asymptotic relative phase relationship is, in general, only neutrally stable. We
      also show that the nonlinear dependence of relative phase on walking speed along
      the body in the full hexapod model can be explained by our analysis. Finally, we
      provide detailed parameter charts of the range of behavior that each mechanism
      can produce as coupling strength and walking speed are varied.

PMID- 10664107
TI  - Characteristics of human fingertips in the shearing direction.
AB  - The shearing strain of the human fingertip plays an important role in the
      determination of the optimal grasping force and in the perception of texture.
      Most research concerned with the mechanical impedance of the human fingertips has
      treated the orthogonal direction to the tip surface, and little attention has
      been paid to the tangential direction. This paper describes impedance
      characteristics of the human fingertips in the tangential directions to the tip
      surface. In the experiment, step and ramp shearing forces were individually
      applied to the tips of the thumb, middle finger, and little finger. Dynamics of
      the fingertips were represented by the Kelvin model. Experimental results show
      that each fingertip had different properties with respect to the shearing strain
      versus the applied force, and that the thumb had the strongest shearing stiffness
      among these three digits. Moreover, the shearing stiffness depended on the
      direction of the applied force, and the stiffness in the pointing direction was
      stronger than that in the perpendicular direction. As the contact force in the
      orthogonal direction to the fingertip surface was increased, the shearing
      stiffness and viscosity increased without regard to the load speed of the
      shearing force. Furthermore, it is shown that the average strain rate of the
      fingertip in the tangential direction to the fingertip surface became slower and
      converged to a constant value with higher contact forces.

PMID- 10664108
TI  - Hopf bifurcations in multiple-parameter space of the Hodgkin-Huxley equations I.
      Global organization of bistable periodic solutions.
AB  - The Hodgkin-Huxley equations (HH) are parameterized by a number of parameters and
      shows a variety of qualitatively different behaviors depending on the parameter
      values. We explored the dynamics of the HH for a wide range of parameter values
      in the multiple-parameter space, that is, we examined the global structure of
      bifurcations of the HH. Results are summarized in various two-parameter
      bifurcation diagrams with I(ext) (externally applied DC current) as the abscissa
      and one of the other parameters as the ordinate. In each diagram, the parameter
      plane was divided into several regions according to the qualitative behavior of
      the equations. In particular, we focused on periodic solutions emerging via Hopf
      bifurcations and identified parameter regions in which either two stable periodic
      solutions with different amplitudes and periods and a stable equilibrium point or
      two stable periodic solutions coexist. Global analysis of the bifurcation
      structure suggested that generation of these regions is associated with
      degenerate Hopf bifurcations.

PMID- 10664109
TI  - Hopf bifurcations in multiple-parameter space of the hodgkin-huxley equations II.
      Singularity theoretic approach and highly degenerate bifurcations.
AB  - In the Hodgkin-Huxley equations (HH), we have identified the parameter regions in
      which either two stable periodic solutions with different amplitudes and periods
      and an equilibrium point or two stable periodic solutions coexist. The global
      structure of bifurcations in the multiple-parameter space in the HH suggested
      that the bistabilities of the periodic solutions are associated with the
      degenerate Hopf bifurcation points by which several qualitatively different
      behaviors are organized. In this paper, we clarify this by analyzing the details
      of the degenerate Hopf bifurcations using the singularity theory approach which
      deals with local bifurcations near a highly degenerate fixed point.

PMID- 10664110
TI  - Mode dynamics of interacting neural populations by bi-orthogonal spectral
      decomposition.
AB  - A system of coupled bistable Hopf oscillators with an external periodic input
      source was used to model the ability of interacting neural populations to
      synchronize and desynchronize in response to variations of the input signal. We
      propose that, in biological systems, the settings of internal and external
      coupling strengths will affect the behaviour of the system to a greater degree
      than the input frequency. While input frequency and coupling strength were
      varied, the spatio-temporal dynamics of the network was examined by the bi
      orthogonal decomposition technique. Within this method, effects of variation of
      input frequency and coupling strength were analyzed in terms of global, spatial
      and temporal mode entropy and energy, using the spatio-temporal data of the
      system. We observed a discontinuous evolution of spatio-temporal patterns
      depending sensitively on both the input frequency and the internal and external
      coupling strengths of the network.

PMID- 10664111
TI  - A simple latency-dependent spiking-neuron model of cricket phonotaxis.
AB  - A simple hypothesis regarding the recognition behaviour of crickets for
      conspecific songs is implemented in a dynamic simulation of spiking neurons and
      tested on a robot base. The model draws on data from cricket neurophysiology but
      requires only four neurons to reproduce a wide range of the observed behaviour.
      The directional response depends on relative latencies in firing onset, and the
      'recognition' emerges from the implicit filtering properties of leaky-integrate
      and-fire neurons. Experimental conditions reproduced include tests of syllable
      rate preference, song from above with sound from one side, and choice between
      songs. The robot produces behaviour closely comparable to the cricket in all but
      a 'split-song' condition. A number of properties can be observed in the neural
      circuit that correspond to cricket neurophysiology including apparent
      'recognition neurons'. Limitations of the model, extensions and alternative
      models are discussed.

PMID- 10664112
TI  - Inflammatory response after laparoscopic and conventional colorectal resections -
      results of a prospective randomized trial.
AB  - BACKGROUND: Short-term benefits of laparoscopic relative to conventional
      colorectal resections have been demonstrated in randomized controlled trials. It
      has been suggested that a diminished cytokine and acute-phase response may be
      responsible for these advantages. METHODS: In a randomized controlled trial,
      patients underwent laparoscopic (n=30) or conventional (n=30) resection of
      colorectal tumors. Plasma levels of interleukin-1 receptor antagonist (IL-1RA),
      interleukin-6 (IL-6), interleukin-10 (IL-10), and C-reactive protein (CRP) were
      analyzed repeatedly. Postoperative peak levels and area under the curve values
      were calculated and compared between groups using the Mann-Whitney U-test.
      RESULTS: Patient characteristics, preoperative cytokine, and CRP plasma levels
      were not different between each group. Postoperative peak concentrations of IL-6
      (P=0.05) and CRP (P<0.001) and the overall postoperative plasma concentrations of
      IL-6 (P=0.03) and CRP (P=0.002) were lower in the laparoscopic than in the
      conventional group. Peak and overall IL-1RA (P=0.2; P=0.2) and IL-10 (P=0.4; P=0.
      6) plasma concentrations, respectively, were not different between groups.
      CONCLUSIONS: IL-6 and CRP plasma levels were lower after laparoscopic than
      conventional colorectal resections. The less intense inflammatory response may be
      an indicator of the milder surgical trauma inflicted by laparoscopic than
      conventional colorectal resection.

PMID- 10664113
TI  - Role of octreotide in the treatment of external pancreatic pure fistulas: a
      single-institution prospective experience.
AB  - INTRODUCTION: Octreotide was studied in the treatment of pure external pancreatic
      fistulas. METHODS: Eighteen cases (12 males, 6 females) were prospectively
      observed. Six patients (four after radical surgery for periampullary cancer, one
      endocrine tumor enucleation and one pancreojejunostomy in chronic pancreatitis)
      were treated as outpatients with octreotide alone because of low basal fistula
      output (mean+/-SD: 96.6+/-27.4 cc/24 h). Twelve (five radical surgery for cancer,
      five surgery for severe pancreatitis, one enucleation and one pancreojejunostomy)
      were treated as inpatients with octreotide plus total parenteral nutrition
      because of the high output (mean+/-SD: 448.4+/-248.2 cc/24 h). RESULTS: Ten of
      the 12 high-output fistulas healed in 27.8+/-27.7 days, whereas all low-output
      fistulas healed in 12.1+/-6.6 days. CONCLUSION: Octreotide appears useful in the
      treatment of external pancreatic fistulas. For optimal results to be achieved,
      there must be no local infection and no mechanical or anatomical obstacles to the
      free flow of juice.

PMID- 10664114
TI  - Prognostic factors in the operative treatment of ductal pancreatic carcinoma.
AB  - BACKGROUND AND AIMS: The average 5-year survival rate following resection of a
      ductal adenocarcinoma of the pancreas is 10%, worldwide. Despite increasing
      resection rates, only about 20% can be operated on with curative intent. A
      differential histopathological analysis of the resected tumors may help to
      justify expanding the surgical procedure by extended lymph-node dissection.
      PATIENTS/METHODS: Between January 1986 and December 1995, a total of 113 patients
      underwent resection with curative intent for a ductal pancreatic carcinoma with
      regional lymph-node dissection. All histological findings were reviewed and
      reclassified in accordance with the 1997 Union Internationale Contra la Cancrum
      (UICC) classification. Survival data for all of these patients were obtained from
      family doctors and registration offices. Independent prognostic factors were
      statistically analyzed. RESULTS: Of the 113 patients, 93 received an R0
      resection. The postoperative mortality rate was 2.2% (2 of 93). More than one
      half of the tumors had a diameter of between 2.1 cm and 4 cm. Among the 22 tumors
      measuring up to 2 cm in diameter, 41% already had lymph-node metastasis and 86%
      invasion of the lymphatic vessels. Carcinomas measuring between 4.1 cm and 6 cm
      were all associated with lymph-vessel invasion. Perineural invasion was present
      in 50% of the tumors. A noteworthy finding was the fact that 64% of the 25 tumors
      with negative lymph nodes had lymph-vessel invasion, and 48% perineural invasion.
      The cumulative 5-year survival rate of the R0-resected patients was 10. 5%.
      Patients with lymph-node-negative stages survived significantly longer (26.5%)
      than patients with lymph-node-positive stages (5%). Furthermore, a significant
      difference was seen between pN1a and pN1b (16.7% vs 2.2%). Multivariate analysis
      identified tumor grading, tumor size and lymph vessel invasion as independent
      prognostic factors. CONCLUSIONS: Apart from the factors tumor size and tumor
      grading, lymph-vessel invasion appears to be of special significance for the long
      term prognosis. Already in the pN0 stage, the latter was present in 64% of the
      cases and must be considered a precursor of lymphogenic metastasization. Since
      lymph-vessel invasion was demonstrated in 86% of tumors measuring less than 2 cm,
      the therapeutic consequence for all ductal pancreatic tumors is an extended
      lymphatic and soft tissue dissection that goes beyond the regional lymph-node
      stations.

PMID- 10664115
TI  - Sequential (domino) transplantation of the liver in a transthyretin-50 familial
      amyloid polyneuropathy. Special reference to cardiological diagnosis and
      complications.
AB  - BACKGROUND: General shortage of cadaveric organs has led to a search for
      alternative methods to expand the donor pool. Sequential (domino) transplantation
      is yet another attempt to compensate for the declining consent to organ donation.
      PATIENTS AND METHODS: To qualify for a domino liver transplantation, the
      following preconditions must be fulfilled: (1) extrahepatic disease must exist,
      (2) liver must be fully functional, and (3) the genetic defect in the host should
      recur within a sufficient latency period. Familial amyloid polyneuropathy (FAP)
      is an autosomal dominant disease which involves a genetic defect for
      transthyretin (TTR), which is predominantly produced in the liver. RESULTS: In
      this report, we describe a rare case of a FAP TTR-50 variant undergoing domino
      liver transplantation. Since myocardial symptoms precede peripheral
      polyneuropathy, special emphasis should be placed on arrhythmias and the
      restrictive cardiomyopathy necessitating a veno-venous bypass or a cardiac
      pacemaker in order to improve cardiac contractility. The type of anastomosis of
      the suprahepatic inferior vena cava and possible alternatives are discussed.
      CONCLUSION: Despite ethical problems, the advantages of the domino procedure are
      obvious: (1) expansion of the donor pool, (2) ability to use living donors, and
      (3) presence of very short ischemic time and thus excellent liver function. Due
      to the kinetics of TTR production and deposition, donors and recipients of FAP
      livers should be followed up using an extensive neurological and cardiological
      protocol.

PMID- 10664116
TI  - Simultaneous treatment of thoracic and infrarenal aortic aneurysm using a
      combination of conventional surgery and endoluminal stent grafting.
AB  - INTRODUCTION: Patients with multiple aortic aneurysms represent a small subgroup
      with the need for extensive surgical treatment at considerable risk. Endovascular
      treatment in combination with conventional operation is possible. We demonstrate
      a case with simultaneous exclusion of aneurysms of the descending thoracic and
      the infrarenal aorta to outline the technical obligations. CONCLUSION:
      Simultaneous exclusion of a thoracic and an abdominal aneurysm can be performed
      successfully by conventional infrarenal aortic replacement with bifurcated dacron
      prosthesis and endovascular implantation of a thoracic stent-graft within one
      operation.

PMID- 10664117
TI  - Lipoma of the liver: a differential-diagnostic problem.
AB  - BACKGROUND AND AIMS: Lipomatous tumors of the liver are extremely rare; most of
      them are found incidentally at autopsy. Appropriate methods of the diagnosis of
      these lesions are ultrasonography (US), computed tomography (CT) and biopsy. CASE
      REPORT: The case of a 65-year-old man who had undergone an upper-rectum resection
      because of exulcerated adenocarcinoma of the rectum is described. Six months
      later, routine control examination revealed a solid tumor in the left lobe of the
      liver. The tumor was not demonstrated by either sonography or CT before the
      operation. Repeated US, CT scan and fine-needle biopsy could not exclude the
      possibility of a metastatic tumor secondary to previous malignancy. The lesion
      was removed by wedge resection and was proven to be a lipoma. CONCLUSION: Despite
      adequate preoperative examination (CT, biopsy and US), an anamnestic
      adenocarcinoma of the rectum can lead to inappropriate therapy. The inadequate
      result of our therapeutic policy can be explained by the extremely rare incidence
      of lipoma of the liver.

PMID- 10664118
TI  - Reconstruction after total pharyngolaryngoesophagectomy. Comparison of elongated
      stomach roll with microvascular anastomosis with gastric pull up reconstruction
      or something like that.
AB  - BACKGROUND: We have performed total pharyngolaryngoesophagectomy in case of
      double cancer, head-neck and thoracic esophageal cancer, or cervical esophageal
      cancer that extended down to the level of aortic arch. The procedure is very
      challenging. METHODS: From April 1984 to May 1998, 14 patients underwent the
      procedures for double cancer of head-neck and thoracic esophagus (n=10),
      hypopharyngeal or cervical esophageal cancer (n=3), and synchronous esophageal
      cancer (n=1). The grafts used were whole stomach (n=6), elongated stomach roll
      (n=5), and stomach roll with free jejunum (n=3). The routes of reconstruction
      were posterior mediastinum (n=10), antesternal (n=3), and retrosternal (n=1).
      RESULTS: Elongated stomach roll with microvascular anastomoses was long enough
      for reconstruction and the blood supply of the graft was sufficient. There was no
      fatal complication in this procedure. Oral feeding was achieved in 13 (93%)
      patients. CONCLUSIONS: The elongated stomach roll with microvascular anastomosis
      is efficient and the placement of the conduit in the posterior mediastinum is
      recommended to allow a better alimentary comfort in total
      pharyngolaryngoesophagectomy.

PMID- 10664119
TI  - Postoperative necrotizing soft-tissue infections of the abdominal wall.
AB  - OBJECTIVE: The aim of the underlying study was the evaluation of an aggressive
      surgical regimen for treatment of postoperative necrotizing soft-tissue infection
      (NSTI). METHODS: Eight patients with postoperative NSTI of the abdominal wall
      after emergency (n=6) and elective (n=2) surgery were reviewed over a 9-year
      period. RESULTS: Initially, three patients presented with general peritonitis.
      Cultured swabs from the necrotic tissue revealed three to four different types of
      bacteria in each patient. The mean interval between the primary operation and
      clinical symptoms of NSTI was 63.0 h. Control of NSTI and intra-abdominal
      infection was attained by scheduled re-operations on a daily basis accounting for
      three to six re-interventions in each patient. Temporary closure of the abdominal
      wall by absorbable polyglactid-acid mesh was used in six cases. Mean hospital
      stay was 65.3 days (18-110 days). Two of the eight patients died from cardiac
      arrest and multiple organ failure, respectively. CONCLUSIONS: Rapid diagnosis and
      onset of treatment is accomplished by the surgeons' knowledge of this disease and
      a close follow-up of the patients in an intensive care unit.

PMID- 10664120
TI  - Acceleration of wound healing by topical drug delivery via liposomes.
AB  - BACKGROUND: Despite intensive research, impaired wound healing remains a
      considerable complication. Therefore, topically applied liposome-encapsulated
      buflomedil hydrochloride was investigated for its ability to improve wound repair
      in normal (n=16) and ischemic (n=16) skin tissue. METHODS: Experiments were
      performed using the wound healing model of the ear of hairless mice. Standardized
      skin wounds (4.25 mm(2)) were created by circular excision of the epidermal layer
      and the subcutaneous tissue. Liposomes were applied daily until complete
      neovascularization of the wound occurred. Tissue regeneration by complete
      epithelialization and neovascularization of the wound area, microcirculatory
      parameters, and leukocyte-endothelium interaction were investigated by means of
      intravital microscopy. Microvascular perfusion was assessed by laser-Doppler
      flowmetry. RESULTS: Topical application of buflomedil liposomes led to a
      significantly (P<0.05) accelerated wound closure in both normal (9.6+/-0.7 days)
      and ischemic (13.4+/-0.1 days) skin tissue compared with animals that were
      treated with unloaded liposomes (controls; 13.1+/-0.8 days; 15.3+/-0.6 days).
      Complete neovascularization of the wound was also enhanced (P<0.05) in buflomedil
      treated animals (normal tissue 18.8+/-0.4 days; ischemic tissue 19.6+/-0.7 days)
      compared with controls (20.6+/-0.6 days; 22. 6+/-1.2 days). CONCLUSION: These
      data suggest that buflomedil-loaded liposomes might be of beneficial use for
      clinical wound care.

PMID- 10664121
TI  - Short-bowel syndrome - surgical treatment with long-term benefit?
AB  - Survival and management of patients with irreversible intestinal failure has been
      made possible by the development of total parenteral nutrition (TPN). Despite the
      progress of TPN severe and even fatal complications might occur. Different non
      surgical and surgical therapies can be employed to either improve intestinal
      function or restore enteral autonomy to obviate the need for TPN. A comprehensive
      review of the pertinent literature on different treatment modalities for short
      bowel syndrome and our own experience are presented to judge long-term benefit
      and make recommendations on up-to-date surgical management.

PMID- 10664122
TI  - Laparoscopic fundoplication for gastro-oesophageal reflux disease - a consensus
      development conference and the evidence-based benefit.
AB  - The aim of this paper is to demonstrate an example of evidence-based medicine for
      a clinically relevant and frequent disease - gastro-oesophageal reflux disease -
      for which an increasing number of laparoscopic operations is performed. A
      consensus development conference was performed on this topic in 1996. During the
      following 3-year period, increase of knowledge shown by the number of
      publications was monitored and the consecutive changes of the consensus as well
      as its consequences and impact were analysed. The six published randomised
      clinical trials revealed important information about the technique of the
      laparoscopic operation focussing on the gastric fundic mobilisation and the
      modification of the anti-reflux wrap. Five consecutive consensus conferences were
      performed and published. Citations of the 1996 consensus conference could not be
      found in the major surgical journals - not even by participants of the
      conference. The responsibility of societies to run such conferences continues.

PMID- 10664123
TI  - Parallels between nuclear-pore and plasmodesmal trafficking of information
      molecules.

PMID- 10664124
TI  - Characterization of two cDNA clones encoding isozymes of the F(1)F(0)-ATPase
      inhibitor protein of rice mitochondria.
AB  - Two cDNA clones encoding F(1)F(0)-ATPase inhibitor proteins, which are loosely
      associated with the F(1) part of the mitochondrial F(1)F(0)-ATPase, were
      characterized from rice (Oryza sativa L. cv. Nipponbare). A Northern
      hybridization showed that the two genes (designated as IF(1)-1 and IF(1)-2) are
      transcribed in all the organs examined. However, the steady-state mRNA levels
      varied among organs. A comparison of the deduced amino acid sequences of the two
      IF(1) genes and the amino acid sequence of the mature IF(1) protein from potato
      revealed that IF(1)-1 and IF(1)-2 have N-terminal extensions with features that
      are characteristic of a mitochondrial targeting signal. To determine the
      subcellular localization of the gene products, the IF(1)-1 or IF(1)-2 proteins
      were fused in frame to the green fluorescent protein (GFP) or the fused GFP-beta
      glucuronidase, and expressed transiently in onion or dayflower epidermal cells.
      Localized fluorescence was detected in mitochondria, confirming that the two
      IF(1) proteins are targeted to mitochondria.

PMID- 10664125
TI  - High-efficiency induction of soybean hairy roots and propagation of the soybean
      cyst nematode.
AB  - Cotyledon explants of 10 soybean [Glycine max (L.) Merr.] cultivars were
      inoculated with Agrobacterium rhizogenes strain K599 with and without binary
      vectors pBI121 or pBINm-gfp5-ER possessing both neomycin phosphotransferase II
      (nptII) and beta-glucuronidase (gus) or nptII and green fluorescent protein (gfp)
      genes, respectively. Hairy roots were produced from the wounded surface of 54-95%
      of the cotyledon explants on MXB selective medium containing 200 microg ml(-1)
      kanamycin and 500 microg ml(-1) carbenicillin. Putative individual transformed
      hairy roots were identified by cucumopine analysis and were screened for
      transgene incorporation using polymerase chain reaction. All of the roots tested
      were found to be co-transformed with T-DNA from the Ri-plasmid and the transgene
      from the binary vectors. Southern blot analysis confirmed the presence of the 35S
      gfp5 gene in the plant genomes. Transgene expression was also confirmed by
      histochemical GUS assay and Western blot analysis for the GFP. Attempts to induce
      shoot formation from the hairy roots failed. Infection of hairy roots of the
      soybean cyst nematode (Heterodera glycines Ichinohe)-susceptible cultivar,
      Williams 82, with eggs of H. glycines race 1, resulted in the development of
      mature cysts about 4-5 weeks after inoculation. Thus the soybean cyst nematode
      could complete its entire life cycle in transformed soybean hairy-root cultures
      expressing GFP. This system should be ideal for testing genes that might impart
      resistance to soybean cyst nematode.

PMID- 10664126
TI  - A nonphotochemical-quenching-deficient mutant of Arabidopsis thaliana possessing
      normal pigment composition and xanthophyll-cycle activity.
AB  - Higher-plant chloroplasts alter the distribution of absorbed radiant energy
      between photosynthesis and heat formation in response to changing illumination
      level or environmental stress. Fluorescence imaging was used to screen 62 yellow
      green T-DNA insertion mutant lines of Arabidopsis thaliana (L.) Heynh. for
      reduced photoprotective nonphotochemical quenching (NPQ) capacity. Pulse
      modulation fluorometry was employed to characterize one line (denoted Lsr1(-))
      that exhibited an approximately 50% reduction in NPQ compared to the wild type
      (WT). The loss in NPQ capacity was associated with the DeltapH-dependent phase of
      quenching (qE). Under the growth conditions employed, pigment composition and
      levels of the six photosystem-II light-harvesting chlorophyll a/b proteins were
      identical in mutant and WT. Changes in the in-vivo levels of the xanthophyll
      pigments violaxanthin, antheraxanthin, and zeaxanthin in excess light were the
      same for mutant and WT. However, use of the violaxanthin de-epoxidase inhibitor
      dithiothreitol indicated that a zeaxanthin-dependent component of NPQ was
      specifically reduced in the mutant. The mutant exhibited diminished suppression
      of minimum fluorescence yield (F(o)) in intense light suggesting an altered
      threshold in the mechanism of response to light stress in the mutant. The NPQ
      deficient phenotype was meiotically transmissible as a semidominant trait and
      mapped near marker T27K12 on chromosome 1. The results suggest that the mutant is
      defective in sensing the transthylakoid DeltapH that reports exposure to
      excessive illumination.

PMID- 10664127
TI  - Nitric oxide stimulates seed germination and de-etiolation, and inhibits
      hypocotyl elongation, three light-inducible responses in plants.
AB  - Seed germination, greening of etiolated plants and inhibition of hypocotyl
      elongation are stimulated by light, which is sensed by various types of
      photoreceptor. Nitric oxide (NO) has proven to be a bioactive molecule,
      especially in mammalian cells and, most recently, in plants. Like some
      phytochrome-dependent processes, many NO-mediated ones are accomplished through
      increases in cGMP levels. Given these similarities, we proposed that NO could
      take part in light-mediated events in plants. Here we show that NO promotes seed
      germination and de-etiolation, and inhibits hypocotyl and internode elongation,
      processes mediated by light. Two NO donors, sodium nitroprusside (SNP) and S
      nitroso-N-acetylpenicillamine induced germination of lettuce (Lactuca sativa L.
      cv. Grand Rapids) seeds in conditions in which this process is dependent on light
      (e.g. 26 degrees C). This was a dose-dependent response and was arrested by
      addition of an NO scavenger, carboxy-PTIO. In addition, nitrite and nitrate, two
      NO-decomposition products were ineffective in stimulating germination. Wheat
      seedlings sprayed with SNP and grown in darkness contained 30-40% more
      chlorophyll than control seedlings. Nitric-oxide-mediated partial greening was
      increased by light pulses, wounding and biotic stress. Arabidopsis thaliana (L.)
      Heynh. (ecotype Columbia) and lettuce seedlings grown in the dark had 20%-shorter
      hypocotyls in NO treatments than in control ones. On the other hand, internode
      lengths of potato plants growing under low light intensity and sprayed with 100
      microM SNP were also 20% shorter than control ones. These results implicate NO as
      a stimulator molecule in plant photomorphogenesis, either dependent on or
      independent of plant photoreceptors.

PMID- 10664128
TI  - Apoplastic transport of abscisic acid through roots of maize: effect of the
      exodermis.
AB  - The exodermal layers that are formed in maize roots during aeroponic culture were
      investigated with respect to the radial transport of cis-abscisic acid (ABA). The
      decrease in root hydraulic conductivity (Lp(r)) of aeroponically grown roots was
      stimulated 1.5-fold by ABA (500 nM), reaching Lp(r) values of roots lacking an
      exodermis. Similar to water, the radial flow of ABA through roots (J(ABA)) and
      ABA uptake into root tissue were reduced by a factor of about three as a result
      of the existence of an exodermis. Thus, due to the cooperation between water and
      solute transport the development of the ABA signal in the xylem was not affected.
      This resulted in unchanged reflection coeffcients for roots grown hydroponically
      and aeroponically. Despite the well-accepted barrier properties of exodermal
      layers, it is concluded that the endodermis was the more effective filter for
      ABA. Owing to concentration polarisation effects, ABA may accumulate in front of
      the endodermal layer, a process which, for both roots possessing and lacking an
      exodermis, would tend to increase solvent drag and hence ABA movement into the
      xylem sap at increased water flow (J(Vr)). This may account for the higher ABA
      concentrations found in the xylem at greater pressure difference.

PMID- 10664129
TI  - Transgene expression driven by heterologous ribulose-1, 5-bisphosphate
      carboxylase/oxygenase small-subunit gene promoters in the vegetative tissues of
      apple (Malus pumila mill.).
AB  - It is desirable that the expression of transgenes in genetically modified crops
      is restricted to the tissues requiring the encoded activity. To this end, we have
      studied the ability of the heterologous ribulose-1,5-bisphosphate
      carboxylase/oxygenase (Rubisco) small-subunit (SSU) gene promoters, RBCS3CP (0.8
      kbp) from tomato (hycopersion esculentum Mill.) and SRS1P (1.5 kbp) from soybean
      (Glycine max [h.] Mers.), to drive expression of the beta-glucuronidase (gusA)
      marker gene in apple (Malus pumila Mill.). Transgenic lines of cultivar
      Greensleeves were produced by Agrobacterium-mediated transformation and the level
      of gusA expression in the vegetative tissues of young plants was compared with
      that produced using the cauliflower mosaic virus (CaMV) 35S promoter. These
      quantitative GUS data were assessed for their relationship to the copy number of
      transgene loci. The precise location of GUS activity in leaves was identified
      histochemically. The heterologous SSU promoters were active primarily in the
      green vegetative tissues of apple, although activity in the roots was noticeably
      higher with the RBCS3C promoter than with the SRS1 promoter. The mean GUS
      activity in leaf tissue of the SSU promoter transgenics was approximately half
      that of plants containing the CaMV 35S promoter. Histochemical analysis
      demonstrated that GUS activity was localised to the mesophyll and palisade cells
      of the leaf. The influence of light on expression was also determined. The
      activity of the SRS1 promoter was strictly dependent on light, whereas that of
      the RBCS3C promoter appeared not to be. Both SSU promoters would be suitable for
      the expression of transgenes in green photosynthetic tissues of apple.

PMID- 10664130
TI  - The Rhodococcus fascians-plant interaction: morphological traits and
      biotechnological applications.
AB  - Rhodococcus fascians is a Gram-positive bacterium that infects dicotyledonous and
      monocotyledonous plants, leading to an alteration in the normal growth process of
      the host. The disease results from the modulation of the plant hormone balances,
      and cytokinins are thought to play an important role in the induction of
      symptoms. Generally, on the aerial parts of the plants, existing meristems were
      found to be most sensitive to the action of R. fascians, but, depending on the
      infection procedure, differentiated tissues as well gave rise to shoots.
      Similarly, in roots not only actively dividing cells, but also cells with a high
      competence to divide were strongly affected by R. fascians. The observed
      symptoms, together with the determined hormone levels in infected plant tissue,
      suggest that auxins and molecules of bacterial origin are also involved in leafy
      gall formation. The complexity of symptom development is furthermore illustrated
      by the necessary and continuous presence of the bacteria for symptom persistence.
      Indeed, elimination of the bacteria from a leafy gall results in the further
      development of the multiple embryonic buds of which it consists. This interesting
      characteristic offers novel biotechnological applications: a leafy gall can be
      used for germplasm storage and for plant propagation. The presented procedure
      proves to be routinely applicable to a very wide range of plants, encompassing
      several recalcitrant species.

PMID- 10664131
TI  - Leaf-specific overexpression of plastidic glutamine synthetase stimulates the
      growth of transgenic tobacco seedlings.
AB  - The impact of increased plastidic glutamine synthetase (GS-2; EC 6.1. 3.2)
      activity on foliar amino-acid levels and on biomass production was examined in
      transgenic tobacco. For that, tobacco was transformed via Agrobacterium
      tumefaciens with a binary vector containing a tobacco GS-2 cDNA downstream of the
      leaf-specific soybean ribulose-1,5-bisphosphate carboxylase/oxygenase small
      subunit gene promotor. Two transgenic tobacco lines with 15- to 18-fold higher
      foliar GS-2 transcript levels than the wild type were obtained. The GS-2 protein
      pools and the specific GS-2 activities were, however, only 2- to 2.3-fold higher
      in the leaves of the transgenic plants than in the leaves of the wild type. This
      discrepancy may reflect a post-transcriptional control of GS-2 protein
      accumulation. The increased GS-2 activity was correlated with a decrease in the
      leaf ammonium pool (3.7-fold) and an increase in the levels of some free amino
      acids, including glutamate (2. 5-fold) and glutamine (2.3-fold). The accumulation
      of soluble protein per unit fresh weight, however, remained unchanged. This
      result indicates that a process downstream of the synthesis of the primary
      organic products of N-assimilation is limiting leaf protein accumulation.
      Nevertheless, the overexpression of GS-2 stimulated the growth rate of the
      transgenic tobacco seedlings which, consequently, were larger (20-30% on a fresh
      weight basis) than wild-type seedlings grown under identical conditions. This
      result suggests that GS-2 is the rate-limiting enzyme during biomass production
      in tobacco seedlings. The requirement for glutamate as the ammonium acceptor in
      the reaction catalysed by GS-2 may imply that there is co-regulation of GS-2 and
      ferredoxin dependent glutamate synthase (Fd-GOGAT; EC 1.4.7.1) gene expression.
      Increased leaf GS-2 activity had, however, no influence on the foliar Fd-GOGAT
      protein abundance. This result suggests that in tobacco leaves, more Fd-GOGAT is
      present than required to meet the demands of primary ammonium assimilation and
      that there is no strong interdependence between GS-2 and Fd-GOGAT protein
      expression.

PMID- 10664132
TI  - Characterisation of extracellular polysaccharides from suspension cultures of
      members of the poaceae.
AB  - Microscopic examination of suspension- cultured cells of Phleum pratense L.,
      Panicum miliaceum L., Phalarisaquatica L. and Oryza sativa L. showed that they
      were comprised of numerous root primordia. Polysaccharides secreted by these
      suspension cultures contained glycosyl linkages consistent with the presence of
      high proportions of root mucilage-like polysaccharides. In contrast, suspension
      cultured cells of Hordeum vulgare L. contained mostly undifferentiated cells more
      typical of plant cells in suspension culture. The polysaccharides secreted by H.
      vulgare cultures contained mostly linkages consistent with the presence of
      glucuronoarabinoxylan. The soluble polymers secreted by cell-suspension cultures
      of Phleum pratense contained 70% carbohydrate, 14% protein and 6% inorganic
      material. The extracellular polysaccharides were separated into four fractions by
      anion-exchange chromatography using a gradient of imidazole-HCl at pH 7.0. From
      glycosyl-linkage analyses, five polysaccharides were identified: an
      arabinosylated xyloglucan (comprising 20% of the total polysaccharide), a
      glucomannan (6%), a type-II arabinogalactan (an arabinogalactan-protein; 7%), an
      acidic xylan (3%), and a root-slime-like polysaccharide, which contained features
      of type-II arabinogalactans and glucuronomannans (65%).

PMID- 10664133
TI  - Synchronization of mitotic activity in protoplast-derived Solanum nigrum L.
      microcalluses is correlated with plasmodesmal connectivity.
AB  - In protoplast-derived Solanum nigrum microcalluses, plasmodesmal connectivity and
      cell division behaviour of the sister cells were examined by repeated pressure
      injection experiments with the fluorescent dye Lucifer Yellow (LYCH; M(r) 457)
      and concomitant light-microscopical long-term live observations. The studies
      revealed that the plasmodesmal permeability of the cultured cells differs in the
      distinct stages of microcallus development. There was a correlation between the
      symplasmic connectivity of the cells and the synchronousness of their mitotic
      activity. Sister cells which were symplasmically interconnected by functional
      plasmodesmata, permitting the diffusion of LYCH, were always found to divide
      synchronously. However, asynchronous mitotic divisions were exclusively observed
      in those sister cells whose plasmodesmata were closed to LYCH. The temporary
      symplasmic isolation is presumably performed by reversible gating of
      plasmodesmata. Repeated dye-coupling experiments on the same microcalluses showed
      that symplasmically interconnected sister cells may become uncoupled and vice
      versa, according to their division behaviour. These findings on cultured cells
      indicate that modulation of the symplasmic connectivity determines the
      synchronization of mitotic activity. Yet it remains to be proven whether this is
      true in planta as well. The results are discussed with respect to the possible
      role of plasmodesmata in exerting "supracellular control" over mitotic activity
      by trafficking mitosis-regulating signals.

PMID- 10664134
TI  - Control of seed dormancy in Nicotiana plumbaginifolia: post-imbibition abscisic
      acid synthesis imposes dormancy maintenance.
AB  - The physiological characteristics of seed dormancy in Nicotiana plumbaginifolia
      Viv. are described. The level of seed dormancy is defined by the delay in seed
      germination (i.e the time required prior to germination) under favourable
      environmental conditions. A wild-type line shows a clear primary dormancy, which
      is suppressed by afterripening, whereas an abscisic acid (ABA)-deficient mutant
      shows a non-dormant phenotype. We have investigated the role of ABA and
      gibberellic acid (GA(3)) in the control of dormancy maintenance or breakage
      during imbibition in suitable conditions. It was found that fluridone, a
      carotenoid biosynthesis inhibitor, is almost as efficient as GA(3) in breaking
      dormancy. Dry dormant seeds contained more ABA than dry afterripened seeds and,
      during early imbibition, there was an accumulation of ABA in dormant seeds, but
      not in afterripened seeds. In addition, fluridone and exogenous GA(3) inhibited
      the accumulation of ABA in imbibed dormant seeds. This reveals an important role
      for ABA synthesis in dormancy maintenance in imbibed seeds.

PMID- 10664135
TI  - Chlamydomonas contains calcium stores that are mobilized when phospholipase C is
      activated.
AB  - Mastoparan induces Ca(2+)-dependent deflagellation of the unicellular green alga
      Chlamydomonas moewusii Gerloff, as well as the activation of phospholipase C and
      the production of inositol 1,4, 5-trisphosphate (InsP(3); T. Munnik et al., 1998,
      Planta 207: 133-145). Even in the absence of extracellular Ca(2+), mastoparan
      still induces deflagellation (L.M. Quarmby and H.C. Hartzell, 1994, J Cell Biol
      124: 807-815; J.A.J. van Himbergen et al., 1999, J Exp Bot, in press) suggesting
      that InsP(3) mediates Ca(2+) release from intracellular stores. To test this
      hypothesis, cells were pre-loaded with (45)Ca(2+) and their plasma membranes
      permeabilized by digitonin. Subsequent treatment of the cells with mastoparan
      (3.5 microM) induced release of intracellular (45)Ca(2+). Mastoparan also
      activated phospholipase C in permeabilized cells, as demonstrated by the
      breakdown of (32)P-phosphatidylinositol 4,5-bisphosphate and the production of
      diacylglycerol. The mastoparan analogues mas7 and mas17 were also effective and
      their efficacy was correlated with their biological activity. X-ray microanalysis
      showed that electron-dense bodies (EDBs) are a major Ca(2+) store in C. moewusii.
      Analysis of digitonin-permeabilized cells showed that EDBs lost calcium at
      digitonin concentrations that released radioactivity from (45)Ca(2+)-labelled
      cells, suggesting that (45)Ca(2+) monitored the content of EDBs. X-ray
      microanaysis of living cells treated with mastoparan also revealed that calcium
      was released from EDBs.

PMID- 10664136
TI  - Genetic study of glutathione accumulation during cold hardening in wheat.
AB  - The effect of cold hardening on the accumulation of glutathione (GSH) and its
      precursors was studied in the shoots and roots of wheat (Triticum aestivum L.)
      cv. Cheyenne (Ch, frost-tolerant) and cv. Chinese Spring (CS, moderately frost
      sensitive), in a T. spelta L. accession (Tsp, frost-sensitive) and in chromosome
      substitution lines CS (Ch 5A) and CS (Tsp 5A). The fast induction of total
      glutathione accumulation was detected during the first 3 d of hardening in the
      shoots, especially in the frost-tolerant Ch and CS (Ch 5A). This observation was
      corroborated by the study of de novo GSH synthesis using [(35)S]sulfate. In Ch
      and CS (Ch 5A) the total cysteine, gamma-glutamylcysteine (precursors of GSH),
      hydroxymethylglutathione and GSH contents were greater during the 51-d treatment
      than in the sensitive genotypes. After 35 d hardening, when the maximum frost
      tolerance was observed, greater ratios of reduced to oxidised
      hydroxymethylglutathione and glutathione were detected in Ch and CS (Ch 5A)
      compared to the sensitive genotypes. A correspondingly greater glutathione
      reductase (EC 1.6.4.2) activity was also found in Ch and CS (Ch 5A). It can be
      assumed that chromosome 5A of wheat has an influence on GSH accumulation and on
      the ratio of reduced to oxidised glutathione as part of a complex regulatory
      function during hardening. Consequently, GSH may contribute to the enhancement of
      frost tolerance in wheat.

PMID- 10664137
TI  - Chemical composition of apoplastic transport barriers in relation to radial
      hydraulic conductivity of corn roots (Zea mays L.).
AB  - The hydraulic conductivity of roots (Lp(r)) of 6- to 8-d-old maize seedlings has
      been related to the chemical composition of apoplastic transport barriers in the
      endodermis and hypodermis (exodermis), and to the hydraulic conductivity of root
      cortical cells. Roots were cultivated in two different ways. When grown in
      aeroponic culture, they developed an exodermis (Casparian band in the hypodermal
      layer), which was missing in roots from hydroponics. The development of Casparian
      bands and suberin lamellae was observed by staining with berberin-aniline-blue
      and Sudan-III. The compositions of suberin and lignin were analyzed
      quantitatively and qualitatively after depolymerization (BF(3)/methanol
      transesterification, thioacidolysis) using gas chromatography/mass spectrometry.
      Root Lp(r) was measured using the root pressure probe, and the hydraulic
      conductivity of cortical cells (Lp) using the cell pressure probe. Roots from the
      two cultivation methods differed significantly in (i) the Lp(r) evaluated from
      hydrostatic relaxations (factor of 1.5), and (ii) the amounts of lignin and
      aliphatic suberin in the hypodermal layer of the apical root zone. Aliphatic
      suberin is thought to be the major reason for the hydrophobic properties of
      apoplastic barriers and for their relatively low permeability to water. No
      differences were found in the amounts of suberin in the hypodermal layers of
      basal root zones and in the endodermal layer. In order to verify that changes in
      root Lp(r) were not caused by changes in hydraulic conductivity at the membrane
      level, cell Lp was measured as well. No differences were found in the Lp values
      of cells from roots cultivated by the two different methods. It was concluded
      that changes in the hydraulic conductivity of the apoplastic rather than of the
      cell-to-cell path were causing the observed changes in root Lp(r).

PMID- 10664138
TI  - Geranylhydroquinone 3"-hydroxylase, a cytochrome P-450 monooxygenase from
      Lithospermum erythrorhizon cell suspension cultures.
AB  - Geranylhydroquinone 3"-hydroxylase, which is likely to be involved in shikonin
      and dihydroechinofuran biosynthesis, was identified in cell suspension cultures
      of Lithospermum erythrorhizon Sieb. et Zucc. (Boraginaceae). The enzyme
      hydroxylates the isoprenoid side chain of geranylhydroquinone (GHQ), a known
      precursor of shikonin. Proton/proton correlation spectroscopic and proton/proton
      long-range correlation spectroscopic studies confirmed that hydroxylation takes
      place specifically at position 3", i.e. at the methyl group involved in the
      cyclization reaction. The enzyme is membrane-bound and was found in the
      microsomal fraction. It requires NADPH and molecular oxygen as cofactors, and is
      inhibited by cytochrome P-450 inhibitors such as cytochrome c and CO. The
      inhibitory effect of CO is reversed by illumination. These data suggest that the
      enzyme is a cytochrome P-450-dependent monooxygenase. The optimum pH of GHQ 3"
      hydroxylase is 7.4, and the apparent K(m) value for GHQ is 1.5 microM. The
      reaction velocity obtained with 3-geranyl-4-hydroxybenzoic acid was more than 100
      times lower than that obtained with geranylhydroquinone.

PMID- 10664139
TI  - Purification and characterisation of acyl-CoA: glycerol 3-phosphate
      acyltransferase from oil palm (Elaeis guineensis) tissues.
AB  - Glycerol 3-phosphate acyltransferase (GPAT, EC 2.3.15) catalyses the first step
      of the Kennedy pathway for acyl lipid formation. This enzyme was studied using
      high-speed particulate fractions from oil palm (Elaeis guineensis Jacq.) tissue
      cultures and mesocarp acetone powders. The fractions were incubated with
      [(14)C]glycerol 3-phosphate and incorporation of radioactivity into Kennedy
      pathway intermediates studied. Optimal conditions were broadly similar between
      the two preparations but those from fruit mesocarp clearly contained more active
      enzymes for the subsequent stages of the Kennedy pathway - as exemplified by the
      appreciable accumulation of radioactivity in triacylglycerol. Experiments with
      different acyl-CoA substrates showed that the GPAT in both high-speed particulate
      preparations had a significant preference for palmitate. Glycerol 3-phosphate
      acyltransferase was solubilised from both preparations with optimal
      solubilisation being achieved at 0.5% (w/v) CHAPS concentrations. Solubilised
      GPATs were purified further using DE52 ion-exchange chromatography and Sephadex G
      100 molecular exclusion chromatography. Purifications of up to about 70-fold were
      achieved. The purified GPATs showed a strong preference for palmitoyl-CoA
      compared to other acyl-CoA donors, in keeping with the importance of palmitate in
      palm oil.

PMID- 10664140
TI  - Physiological elevations in cytoplasmic free calcium by cold or ion injection
      result in transient closure of higher plant plasmodesmata.
AB  - The concentration of cytoplasmic free calcium ([Ca(2+)](cyt)) required to close
      higher plant plasmodesmata was investigated using corn (Zea mays L. cv. Black
      Mexican Sweet) suspension-culture cells. Physiological elevations of
      [Ca(2+)](cyt) were applied by cold treatment, and ion injection was also used to
      increase [Ca(2+)](cyt), by diffusion (for small increases) or by iontophoresis
      (for larger increases). The impact of such treatments on [Ca(2+)](cyt) was
      measured by ratiometric ion imaging. Intercellular communication during
      treatments was monitored using our recently developed electrophysiological
      technique that allows the electrical resistance of plasmodesmata and the plasma
      membranes of a sister-cell pair to be measured. A 4-fold increase in the
      calculated resistance of single plasmodesmata was observed in response to cold
      treatment that caused a 2-fold increase in average [Ca(2+)](cyt) (from 107 to 210
      nM). In response to iontophoresis of Ca(2+), plasmodesmata were observed to go
      from "open" (low resistance) to "shut" (high resistance) and then back "open"
      within 10 s. Our results thus indicate that higher plant plasmodesmata respond
      quickly to physiological changes in [Ca(2+)](cyt).

PMID- 10664142
TI  - Eating the evidence? Manduca sexta larvae can not disrupt specific jasmonate
      induction in Nicotiana attenuata by rapid consumption.
AB  - As feeding by the tobacco specialist Manduca sexta L. is known to result in
      significantly higher jasmonate (JA) concentrations in Nicotiana plants than do
      mechanical simulations of the larval damage, we investigated whether M. sexta,
      which is known to rapidly consume large quantities of leaf material, can impair
      this "recognition" response by consuming the leaf tissue before it can respond
      with amplified JA levels. We report that oral secretions (OS) from M. sexta, but
      not from the cabbage specialist Pieris rapae, amplified the wound-induced JA
      response of Nicotiana attenuata Torr. Ex Wats., regardless of larval diet, instar
      and molting stage, and were still active after boiling and when diluted to
      1/1000. The largest JA response occurred within 40 min in tissues adjacent to the
      OS application site. When 3 mm of leaf tissue immediately adjacent to the OS
      application site was excised within 40 s, the signal that elicits JA
      amplification was found to travel rapidly into the leaf, beyond the mandibular
      reach of the larvae. We conclude that M. sexta is not able to consume the
      evidence of feeding activity.

PMID- 10664141
TI  - Herbivore-induced ethylene suppresses a direct defense but not a putative
      indirect defense against an adapted herbivore.
AB  - Herbivory induces both direct and indirect defenses in plants; however, some
      combinations of these defenses may not be compatible. The jasmonate signal
      cascade activated both direct (nicotine accumulations) and indirect (mono- and
      sesquiterpene emissions) whole-plant defense responses in the native tobacco
      Nicotiana attenuata Torr. Ex Wats. Nicotine accumulations were proportional to
      the amount of leaf wounding and the resulting increases in jasmonic acid (JA)
      concentrations. However, when larvae of the nicotine-tolerant herbivore, Manduca
      sexta, fed on plants or their oral secretions were applied to leaf punctures, the
      normal wound response was dramatically altered, as evidenced by large (4- to 10
      fold) increases in the release of (i) volatile terpenoids and (ii) ethylene,
      (iii) increased (4- to 30-fold) accumulations of endogenous JA pools, but (iv)
      decreased or unchanged nicotine accumulations. The ethylene release, which was
      insensitive to inhibitors of induced JA accumulation, was sufficient to account
      for the attenuated nicotine response. Applications of ethylene and ethephon
      suppressed the induced nicotine response and pre-treatment of plants with a
      competitive inhibitor of ethylene receptors, 1-methylcyclopropene, restored the
      full nicotine response. This ethylene burst, however, did not inhibit the release
      of volatile terpenoids. Because parasitoids of Manduca larvae are sensitive to
      the dietary intake of nicotine by their hosts, this ethylene-mediated switching
      from direct to a putative indirect defense may represent an adaptive tailoring of
      a plant's defense response.

PMID- 10664148
TI  - Developmental fates of larval tissues after metamorphosis in the ascidian,
      Halocynthia roretzi. II. Origin of endodermal tissues of the juvenile.
AB  - Cell lineages during ascidian embryogenesis are invariant. Developmental fates of
      larval mesodermal cells after metamorphosis are also invariant with regard to
      cell type of descendants. The present study traced developmental fates of larval
      endodermal cells after metamorphosis in Halocynthia roretzi by labeling each
      endodermal precursor blastomere of larval endoderm. Larval endodermal cells gave
      rise to various endodermal organs of juveniles: endostyle, branchial sac,
      peribranchial epithelium, digestive organs, peripharyngeal band, and dorsal
      tubercle. The boundaries between clones descended from early blastomeres did not
      correspond to the boundaries between adult endodermal organs. Although there is a
      regular projection from cleavage stage and larval stage to juvenile stage, this
      varies to some extent between individuals. This indicates that ascidian
      development is not entirely deterministic. We composed a fate map of adult
      endodermal organs in larval endoderm based on a statistical analysis of many
      individual cases. Interestingly, the topographic position of each prospective
      region in the fate map was similar to that of the adult organ, indicating that
      marked rearrangement of the positions of endodermal cells does not occur during
      metamorphosis. These findings suggest that fate specification in endoderm cells
      during metamorphosis is likely to be a position-dependent rather than a
      deterministic and lineage-based process.

PMID- 10664149
TI  - Characterization of an ascidian DEAD-box gene, Ci-DEAD1: specific expression in
      the germ cells and its mRNA localization in the posterior-most blastomeres in
      early embryos.
AB  - We isolated DEAD-box genes from three ascidian species (Ciona intestinalis, Ciona
      savignyi, and Halocynthia roretzi) by polymerase chain reaction methods. We
      obtained two types from each of C. intestinalis and C. savignyi, and four types
      from H. roretzi. The first type (DEAD1) belonged to the vasa subfamily, the
      second type (DEAD2) to the PL10 subfamily, the third type (DEAD3) to the p68
      subfamily, and the forth type (DEAD4) did not belong to any of the subfamilies.
      We further analyzed in detail the expression pattern of C. intestinalis vasa-type
      gene (Ci-DEAD1) by in situ hybridization. In sections of the ovary and testis,
      the Ci-DEAD1-specific probe reacted intensely to small germ cells, oogonium,
      and/or oocyte and spermatogonium and/or spermatocyte, respectively. In whole
      mount specimens of juveniles this probe specifically reacted to the primordial
      germ cells in the gonad rudiment. These gonad-specific expressions were confirmed
      by reverse transcriptase polymerase chain reaction of RNA from various tissues.
      The transcript was present in unfertilized eggs and in the central cytoplasm of
      blastomeres until the two-cell stage. During the second cleavage a part of the
      transcripts moved to the posterior region of embryos and, during early
      embryogenesis, was localized in the posterior-most blastomeres. In the tailbud,
      one or two hybridization signals were detected in the caudal endodermal strand.
      Based on these observations, we propose precursors of primordial germ cells in
      ascidians.

PMID- 10664150
TI  - Involvement of Tcf/Lef in establishing cell types along the animal-vegetal axis
      of sea urchins.
AB  - Members of the Tcf/Lef family interact with beta-catenin to activate programs of
      gene expression during development. Recently beta-catenin was shown to be
      essential for establishing cell fate along the animal-vegetal axis of the sea
      urchin embryo. To examine the role of Tcf/Lef in sea urchins we cloned a
      Strongylocentrotus purpuratus Tcf/Lef homolog. Expression of SpTcf/Lef was
      maximal when beta-catenin became localized to nuclei of vegetal blastomeres,
      consistent with its acting in combination with beta-catenin to specify vegetal
      cell fates. Expression of a dominant-negative SpTcf/Lef inhibited primary and
      secondary mesenchyma, endoderm, and aboral ectoderm formation in a manner similar
      to that observed when nuclear accumulation of beta-catenin was prevented. Our
      results suggest that SpTcf/Lef functions by interacting with beta-catenin to
      specify cell fates along the sea urchin animal-vegetal axis.

PMID- 10664151
TI  - The evolution of paired appendages in vertebrates: T-box genes in the zebrafish.
AB  - The presence of two sets of paired appendages is one of the defining features of
      jawed vertebrates. We are interested in identifying genetic systems that could
      have been responsible for the origin of the first set of such appendages, for
      their subsequent duplication at a different axial level, and/or for the
      generation of their distinct identities. It has been hypothesized that four genes
      of the T-box gene family (Tbx2-Tbx5) played important roles in the course of
      vertebrate limb evolution. To test this idea, we characterized the orthologs of
      tetrapod limb-expressed T-box genes from a teleost, Danio rerio. Here we report
      isolation of three of these genes, tbx2, tbx4, and tbx5. We found that their
      expression patterns are remarkably similar to those of their tetrapod
      counterparts. In particular, expression of tbx5 and tbx4 is restricted to
      pectoral and pelvic fin buds, respectively, while tbx2 can be detected at the
      anterior and posterior margins of the outgrowing fin buds. This, in combination
      with conserved expression patterns in other tissues, suggests that the last
      common ancestor of teleosts and tetrapods possessed all four of these limb
      expressed T-box genes (Tbx2-Tbx5), and that these genes had already acquired, and
      have subsequently maintained, their gene-specific functions. Furthermore, this
      evidence provides molecular support for the notion that teleost pectoral and
      pelvic fins and tetrapod fore- and hindlimbs, respectively, are homologous
      structures, as suggested by comparative morphological analyses.

PMID- 10664152
TI  - Tension-dependent collective cell movements in the early gastrula ectoderm of
      Xenopus laevis embryos.
AB  - Ventral ectodermal explants taken from early gastrula embryos of Xenopus laevis
      were artificially stretched either by two opposite concentrated forces or by a
      distributed force applied to the internal explant's layer. These modes of
      stretching reflect different mechanical situations taking place in the normal
      development. Two main types of kinematic response to the applied tensions were
      detected. First, by 15 min after the onset of concentrated stretching a
      substantial proportion of the explant's cells exhibited a concerted movement
      towards the closest point of the applied stretching force. We define this
      movement as tensotaxis. Later, under both concentrated and distributed
      stretching, most of the cell's trajectories became reoriented perpendicular to
      the stretching force, and the cells started to intercalate between each other,
      both horizontally and vertically. This was accompanied by extensive elongation of
      the outer ectodermal cells and reconstruction of cell-cell contacts. The
      intercalation movements led first to a considerable reduction in the stretch
      induced tensions and then to the formation of peculiar bipolar "embryoid" shapes.
      The type and intensity of the morphomechanical responses did not depend upon the
      orientation of a stretching force in relation to the embryonic axes. We discuss
      the interactions of the passive and active components in tension-dependent cell
      movements and their relations to normal morphogenetic events.

PMID- 10664155
TI  - The molecular basis of persistent hyperinsulinemic hypoglycemia of infancy and
      its pathologic substrates.
AB  - Recent advances in molecular genetics have established a molecular basis for
      persistent hyperinsulinemic hypoglycemia of infancy (PHHI) and resulted in the
      identification of a number of well-defined genetic defects. On the basis of the
      available information on the molecular changes so far described, an attempt has
      been made to classify PHHI patients according to their genotype and phenotype,
      with reference to molecular genetics, pancreatic pathology and clinical
      appearance. This classification has resulted in the differentiation of three
      groups of PHHI patients, two with diffuse beta cell hyperfunction and one with
      focal beta cell hyperfunction.

PMID- 10664153
TI  - A recombinogenic targeting method to modify large-inserts for cis-regulatory
      analysis in transgenic mice: construction and expression of a 100-kb, zebrafish
      Hoxa-11b-lacZ reporter gene.
AB  - The identification of cis-sequences responsible for spatiotemporal patterns of
      gene expression often requires the functional analysis of large genomic regions.
      In this study a 100-kb zebrafish Hoxa-11b-lacZ reporter gene was constructed and
      expressed in transgenic mice. PAC clone 10-O19, containing a portion of the
      zebrafish HoxA-b cluster, was captured into the yeast-bacterial shuttle vector,
      pPAC-ResQ, by recombinogenic targeting. A lacZ reporter gene was then inserted in
      frame into exon 1 of the zfHoxa-11b locus by a second round of recombinogenic
      targeting. Expression of the zfHoxa-11b-lacZ reporter gene in 10.5 d.p.f.
      transgenic mouse embryos was observed only in the posterior portion of the A-P
      axis, in the paraxial mesoderm, neural tube, and somites. These findings
      demonstrate the utility of recombinogenic targeting for the modification and
      expression of large inserts captured from P1/PAC clones.

PMID- 10664156
TI  - Is typing of metaplasia at the squamocolumnar junction revealing its aetiology?
AB  - Until recently, intestinal metaplasia (IM) at the squamocolumnar junction (SCJ)
      was ascribed to Barrett's mucosa (BM), which arises from gastro-oesophageal
      reflux. Recent studies, however, have shown that IM at the SCJ can also be
      induced, for example, by Helicobacter pylori (HP). The aim of this study was to
      investigate whether the type of IM might be helpful in the differentiation
      between these two aetiologies. Biopsies from the antrum, corpus and immediately
      below the Z-line were taken from 443 patients. Eighty-three of them showed IM
      below the Z-line. In these, the endoscopic aspect of the Z-line was classified as
      either unremarkable (n=49) or suspected of BM (n=34). Typing of IM was done using
      Gomori's aldehyde fuchsin-Alcian blue staining. Overall, age, HP status and
      erosive oesophagitis had no influence on the IM type. Type-III IM (n=24) was more
      frequent in men (P=0.0371) and related to endoscopic BM (P<0.0001). Type-I/II IM
      (n=59) was associated with an unremarkable Z-line (P<0.0001) and was linked to
      multifocal gastric IM (P=0.016) and HP (P=0.0011). In conclusion, it was shown
      that, in the presence of a normal Z-line, especially in the absence of HP, type
      III IM is suggestive of BM. The diagnosis of short or ultra-short segment BM
      should therefore include endoscopic, histological and histochemical
      characteristics.

PMID- 10664157
TI  - Loss of function of the Prx1 and Prx2 homeobox genes alters architecture of the
      great elastic arteries and ductus arteriosus.
AB  - Prx1 (MHox) and Prx2 (S8) are non-clustered homeobox genes that are expressed in
      a complex, mostly mesenchyme-specific pattern throughout embryogenesis. The
      expression pattern and gene-targeted mice previously revealed a major role for
      Prx1 in skeletogenesis. In addition, specific and high expression of both Prx
      genes was reported in the developing cardiovascular system, predominantly in
      prospective connective tissues of the heart and in the great arteries and veins.
      We examined embryos of previously generated gene-targeted mice. Prx2-/- mutants
      were viable and did not show cardiovascular malformations. Intracardiac
      morphology of Prxl-/- and Prx1/Prx2-combined null mutants also appeared normal
      throughout development. However, the Prx1-/- and Prx1/Prx2 double-null mutants
      showed a vascular abnormality with an abnormal positioning and awkward curvature
      of the aortic arch in addition to a misdirected and elongated ductus arteriosus,
      and in two of seven combined mutants, an anomalous retro-oesophageal right
      subclavian artery. Generally, all great arteries appeared to run somewhat
      tortuously through the surrounding mesenchyme. The vascular histology and vessel
      wall thickness were normal in all mutants. Prx1-/- and Prx double-gene-targeted
      mice revealed similar spectra of vascular anomalies, but double mutants appeared
      to be more seriously affected. The current findings suggest that other genes may
      compensate for the loss of Prx in the heart, but, in contrast, our data support a
      role for Prx in the development of vascular and perivascular matrix.

PMID- 10664159
TI  - Blomstrand osteochondrodysplasia: three novel cases and histological evidence for
      heterogeneity.
AB  - Blomstrand osteochondrodysplasia (BOCD) is a rare, autosomal recessive, lethal
      skeletal dysplasia characterized by generalized osteosclerosis and advanced
      skeletal maturation. The histopathological characteristics of three novel cases
      (two isolated cases and a sib-pair) of BOCD are presented and correlated with the
      clinical and radiographical findings, and the relevant literature is reviewed.
      The results of our study confirm the existence of two separate types of BOCD,
      which we propose naming type I: the severe, 'classical' form, and type II: a less
      severe form.

PMID- 10664158
TI  - PE-35-related antigen expression and CD1a-positive lymphocytes in thymoma
      subtypes based on Muller-Hermelink classification. An immunohistochemical study
      using catalyzed signal amplification.
AB  - PE-35 monoclonal antibody, detecting a cell-surface antigen of various types of
      carcinoma and normal epithelium, reacts exclusively with the medullary epithelium
      in the thymus; therefore, the antigen has been considered as a marker of
      medullary differentiation in thymomas. Using the catalyzed signal amplification
      method, which made it possible to apply PE-35 to routinely processed, archival
      tissues, we examined expression of this antigen, together with CD1a reactivity of
      lymphocytes, in 40 thymic epithelial tumors subclassified using the Mu1ler
      Hermelink system. Medullary thymomas infiltrated with a small number of CD1a
      negative lymphocytes were PE-35 positive, although many of the long spindle tumor
      cells were PE-35 negative. Mixed thymomas and predominantly cortical thymomas,
      both with prominent CD1a-positive lymphocytes, were also PE-35 positive, although
      some areas of the latter type were PE-35 negative. Cortical thymomas with
      decreased numbers of CD1a-positive lymphocytes were largely PE-35 negative. In
      well-differentiated thymic carcinomas with a few CD1a-positive lymphocytes, two
      cases were negative, but four cases were at least focally positive with PE-35.
      All high-grade thymic carcinomas infiltrated with some CD1a-negative lymphocytes
      were PE-35 positive. These results suggested that medullary thymoma generally
      possesses the medullary nature, although the latter tends to be lost in the long
      spindle tumor cells. Mixed and predominantly cortical thymomas may have mixed
      medullary phenotype and cortical function. Cortical thymoma and many well
      differentiated thymic carcinomas may possess the cortical nature, while the large
      polygonal tumor cells tend to lose immature T-lymphocyte-retaining function.

PMID- 10664160
TI  - Fabry disease: ultrastructural lectin histochemical analyses of lysosomal
      deposits.
AB  - Fabry disease is an X-linked inborn error of glycosphingolipid catabolism
      resulting from a deficiency of lysosomal alpha-galactosidase activity.
      Globotriaosylceramide accumulates predominantly in lysosomes of various tissues.
      Former studies have clarified the nature of this disease, and the accumulated
      materials in the lysosomes have been analyzed using biochemical techniques. In
      the present study, transmission electron microscopy was used to reveal the fine
      structure of these lysosomal deposits, and sugar residues in the lysosomal
      deposits in Fabry disease were examined by lectin histochemistry combined with
      enzyme digestion. This is the first report to describe the lysosomal sugar
      residues in Fabry disease analyzed using lectin histochemistry at the
      ultrastructural level. With these techniques, we were able to detect alpha
      galactosyl, beta-galactosyl and glucosyl sugar residues in the lysosomal
      deposits. The experimental procedures used in this study have considerable
      potential for use in investigations of glycolipid and glycoprotein storage
      diseases without the need for complex methodology and expensive materials.

PMID- 10664161
TI  - Transdifferentiation of somatotrophs to thyrotrophs in the pituitary of patients
      with protracted primary hypothyroidism.
AB  - In patients with protracted primary hypothyroidism, the pituitary is enlarged due
      to the lack of feedback inhibition by thyroid hormone. In the present work,
      adenohypophysial biopsies from three women with protracted primary hypothyroidism
      were investigated by routine histology, immunocytochemistry, double
      immunostaining, immunoelectron microscopy, and combined immunocytochemistry - in
      situ hybridization. These methods confirmed the presence of massive thyrotroph
      hyperplasia and the formation of "thyroidectomy" or "thyroid deficiency" cells. A
      number of thyroidectomy cells were found to be immunoreactive for growth hormone
      (GH). Double immunostaining and immunoelectron microscopy revealed the presence
      of bihormonal cells containing both GH and thyroid stimulating hormone (TSH).
      Immunostaining combined with in situ hybridization revealed GH immunoreactive
      cells expressing TSH mRNA as well as TSH immunopositive cells expressing GH mRNA.
      Our findings provide conclusive evidence that somatotrophs may transform to
      thyrotrophs. Thus, in addition to multiplication of thyrotrophs,
      transdifferentiation of GH cells to thyrotrophs contributes to the increase of
      TSH-producing cells. The presence of such bihormonal cells best termed
      "thyrosomatotrophs" supports the concept that adenohypophysial cells are not
      irreversibly committed to the production of one single hormone and that their
      phenotype can change in response to functional demand.

PMID- 10664162
TI  - Lectin-binding patterns in normal, hyperplastic and neoplastic endometrium: the
      prognostic value of concanavalin A.
AB  - Lectins are proteins and glycoproteins of non-immune origin which bind
      specifically to carbohydrate residues, agglutinate cells and/or precipitate
      complex carbohydrates. Lectin-binding patterns in normal, hyperplastic and
      neoplastic endometria were studied using four biotinylated lectins (Con A, LCA, e
      PHA, l-PHA) and the avidin-biotin-peroxidase technique. Canavalia ensiformis
      agglutinin (ConA) and Lens culinaris agglutinin (LCA) reacted strongly with the
      luminal borders and the cytoplasm of epithelial cells but, whilst in normal and
      benign endometrial tissues the cytoplasmic staining was confined to the apical
      and the basal aspect of the cells, in endometrial carcinomas and in some atypical
      hyperplasias lectin binding also occurred in the lateral cytoplasm (Con-A-lat),
      although in differing proportions of cells. Interestingly, extensive Con-A-lat in
      the tumour cells was much more frequent in non-endometrioid carcinomas (P<0.05)
      and was significantly associated with poor histological differentiation
      (P<0.0001), low oestrogen and progesterone receptor content (P<0.01 and P=0.0001,
      respectively) and an unfavourable long-term survival (P<0.05). With Phaseolus
      vulgaris erythroagglutinin (e-PHA) and leucoagglutinin (l-PHA) a linear, rather
      inconsistent, staining at the level of the basement membranes was observed in the
      glands: this, also noted with LCA, appeared intact in normal and hyperplastic
      glands without cytological atypia, and fragmented or absent in malignant
      glandular structures and in most hyperplastic glands showing cytological atypia.
      It is concluded that changes in the distribution of lectin-binding molecules in
      the endometrial cells are associated with the malignant state, whilst the extent
      of Con-A-lat reflects the biological behaviour of the tumours.

PMID- 10664163
TI  - Thromboangiitis obliterans: classic and new morphological features.
AB  - The clinical and pathological concept of thromboangiitis obliterans (TAO,
      Buerger's disease) is still controversial. While the clinical criteria of TAO are
      relatively well defined, the etiology is unknown and its diagnosis based on
      pathology is confusing, since there is no consensus on the precise pathological
      criteria for TAO. To investigate the morphological features that differentiate
      TAO from arteriosclerosis obliterans (ASO) or thromboembolism, and to clarify the
      morphological independence of TAO, we studied 94 amputated specimens of lower
      extremities, including 31 specimens from patients with a clinical diagnosis of
      TAO and 31 autopsy specimens as control cases. It was revealed that most of the
      classic morphological features described by Buerger and others are not helpful
      when considered independently in the differential diagnosis, except for intact
      internal elastic lamina. In addition, findings of intimal inflammation, intact
      media and absence of medial calcification were demonstrated to be common in both
      TAO and thromboembolism. Statistical analysis in the present study, the most
      comprehensive thus far, showed that novel findings of onion-like-shaped
      recanalizing vessels in the occluded arteries, adventitial fibrosis without
      medial fibrosis, swelling of the endothelium of the vasa vasorum and edema
      beneath the external elastic lamina were characteristic of TAO and would be
      helpful in a differential diagnosis. When a combination of these morphological
      features is present, diagnosis of a presumed overlap of TAO and ASO in the same
      site of the vessel concerned is possible. Furthermore, comparison of statistical
      evaluations based on morphological features performed in various diagnostic
      groups implies that the clinical diagnosis of TAO is currently underestimated
      because the results of the analysis of morphological features of specimens in
      which TAO was suspected or specimens selected on the basis of a broad and
      nonspecific definition of TAO were surprisingly similar to the results in
      strictly defined TAO cases. Our findings suggest that injury and regeneration of
      minute vessels such as recanalizing vessels and vasa vasorum play a part in the
      pathogenesis of TAO.

PMID- 10664164
TI  - Peripheral primitive neuroectodermal tumour of the cervix.
AB  - Peripheral primitive neuro-ectodermal tumours (PNET) of the cervix are very rare.
      Here, we report the clinical, pathological, immunohistochemical and genetic
      features of a case of a PNET located in the cervix. Hysterectomy revealed a
      cervical tumour. On microscopic examination, a vaguely lobular arrangement of
      uniformly appearing neoplastic cells, with round to oval nuclei, distinct nuclear
      membranes and a clear, moderately glycogen-rich cytoplasm was seen. Cells stained
      positive for LEU 7, S 100, monoclonal NSE and particularly for MIC2. Neurogenic
      differentiation was also seen by electron microscopic examination. The genetic
      hallmark of PNET, a 22q12 rearrangement was demonstrated by fluorescence in situ
      hybridisation experiments, supporting the diagnosis. Awareness of the existence
      of primary PNET of the cervix is important to avoid confusion with other tumours
      of the cervix.

PMID- 10664165
TI  - A morphological study of bone and articular cartilage in ochronosis.
AB  - An ochronotic femoral head has been studied morphologically under the light and
      the electron microscope. Its articular cartilage showed the alterations already
      reported in the literature, mainly consisting of erosions of the surface, pigment
      accumulation in chondrocytes and intercellular matrix, chondrocyte degeneration,
      the formation of pigmented, calcified and uncalcified microshards, and the
      presence of granulation tissue with macrophagic cells. The changes in bone were
      less severe than those in cartilage. Pigment was present in the calcified matrix.
      This did not seem to disturb the organization of the bone tissue, although it was
      diffusely osteoporotic, perhaps because of limb disuse. The preservation of
      calcified matrix might depend on the fact that its collagen fibrils are encrusted
      by mineral substance, which avoids the dangerous effects that the deposition of
      ochronotic pigment induces in the fibrils of soft connective tissues. On the
      other hand, the newly formed osteoid matrix remains uncalcified for too short a
      time to be modified by the pigment. Diffuse or granular pigmentation was found in
      a few osteocytes, while several of them were condensed or reduced to cellular
      fragments. Bone resorption often occurred near these osteocytes. However, this
      did not seem to alter the degree of bone remodelling, possibly because of the
      relatively low numbers of degenerated or dead osteocytes. Pigment was also
      contained in the cytoplasmic vacuoles of otherwise active osteoclasts, whereas it
      was not found in osteoblasts. On the whole, ochronosis in bone seems to induce
      the same changes as in other connective tissues. However, their severity appears
      to be limited by calcification, which prevents modifications in collagen fibrils,
      and by bone remodelling, which to some extent eliminates the oldest, pigment
      richest parts of the tissue.

PMID- 10664166
TI  - Testis - a novel storage site in human cholesteryl ester storage disease. Autopsy
      report of an adult case with a long-standing subclinical course complicated by
      accelerated atherosclerosis and liver carcinoma.
AB  - A case of long-standing subclinical cholesteryl ester storage disease (CESD)
      manifesting as hyperlipoproteinaemia type IIb without any hepatomegaly is
      described. The patient underwent surgical vascular interventions because of
      accelerated atherosclerosis, which dominated his middle age. CESD was an
      incidental finding when a liver biopsy specimen was taken because liver
      malignancy was suspected; the patient's condition proved to be due to a
      cholangiocarcinoma, which led to his death at the of age 52. The autopsy showed
      moderate-intensity storage in the set of cells characterized by constitutional
      high-level receptor-mediated LDL endocytosis (hepatocytes, adrenal cortical
      cells) and also revealed storage in the Leydig cells. The severity with which
      histiocytes were affected varied regionally, ranging from minimal detectable
      storage or none at all (gut, lymph nodes, spleen) to extreme lysosomal expansion
      by cholesteryl ester liquid crystals (bone marrow) or by ceroid (lung, testicular
      stroma), or by both (liver). The density of the histiocytic population did not
      correlate with the degree to which parenchymal cells were affected except in the
      testicular stroma, where it was prominent. The patient was a mixed heterozygote
      for the G934A and DeltaC(673-5) mutations.

PMID- 10664169
TI  - Acknowledgements

PMID- 10664167
TI  - Segmental hepatic vein thrombosis associated with heparin-induced
      thrombocytopenia II.
AB  - We report the case of a 55-year-old man who developed heparin-induced
      thrombocytopenia II after a vertebral fracture. Autopsy revealed segmental
      hepatic vein thrombosis of the right lobe with subacute congestion and an
      activation of hepatic stellate cells. This case shows that heparin-induced
      thrombocytopenia II is a possible cause of the Budd-Chiari syndrome.

PMID- 10664176
TI  - Expression of extracellular matrix proteins in the fetal rat gastric mucosa.
AB  - At gestational day 16 the epithelium of the rat stomach consists of a stratified
      layer of undifferentiated cells, and two days later glandular structures appear.
      The present study was carried out to identify extracellular matrix proteins that
      could be involved in the epithelial cell proliferation and differentiation
      processes that occur in the fetal rat stomach during this period. For comparative
      purposes the expression of the same components in the adult gastric mucosa was
      examined. Pregnant Sprague-Dawley rats received an intraperitoneal injection of 5
      bromo-2'-deoxyuridine to label proliferating cells. One, 3.5, or 6 h post
      injection the stomachs were excised and immediately frozen. The specimens were
      sectioned and stained with hematoxylin and eosin or for 5-bromo-2'-deoxyuridine,
      cytokeratin no. 8, H,K-ATPase, and the extracellular matrix proteins fibronectin,
      laminin, and collagens type I and IV. A stratified layer of proliferating cells
      was observed in the epithelium of the fetal stomachs, while in adult stomachs
      proliferating cells were detected in the isthmus/neck region of the glands.
      Cytokeratin, an epithelial cell marker, was sparse at gestational day 16 but
      abundant both at gestational day 18 and in the isthmus/neck region of gastric
      glands of the adult stomach. The parietal cell marker H,K-ATPase could not be
      detected in the fetal stomachs during this period. Fibronectin was observed in
      the stroma of both fetal and adult stomachs. Collagen type I could only be
      detected in the stroma close to the oesophagus at gestational day 16. Two days
      later, collagen type I was abundant in the lamina propria, the submucosa and in
      the serosa of the fetal stomachs. In adult tissue collagen type I was detected in
      the surface epithelium, the submucosa and in the serosa of the stomach. Collagen
      type IV and laminin were expressed in the lamina propria, the basement membranes
      around blood vessels, muscle cells, and nerve bundles, as well as in the serosa
      of both 16- and 18-day-old fetal and adult rat stomachs. In conclusion, a high
      cell proliferation rate was observed in the epithelium at both gestational days
      16 and 18. The increased expression of cytokeratin observed during this period
      indicates that the epithelial character of the embryonic cells becomes more
      distinct, while the remarkable change in the expression of collagen type I might
      reflect an important role of collagen type I in the development of the gastric
      epithelium.

PMID- 10664177
TI  - The patterns of cell death and of macrophages in the developing forebrain of the
      tree shrew Tupaia belangeri.
AB  - The patterns of cell death and of macrophages were investigated in the forebrain
      and eyes of the tree shrew Tupaia belangeri during five phases of optic cup
      formation. Seventeen embryos were studied. Three- dimensional reconstructions
      were made from one embryo of each phase. In phase 1 (V-shaped optic evagination)
      a midline band of cell death passes through the closing anterior neuroporus. From
      phases 2 (optic vesicle) to 5 (far-advanced invagination) the midline band of
      cell death extends in the dorsal wall of the forebrain to its rostral pole and,
      further, into its ventral wall. At the approximate future position of the optic
      chiasm this ventral pycnotic area, predicted but so far unidentified by others,
      is connected to a previously described second band of cell death passing through
      the optic anlagen. Recently, evidence has been presented that chicken embryos
      develop holoprosencephaly and cyclopia when ventral forebrain structures are lost
      secondary to experimentally induced apoptosis. Our findings in Tupaia suggest
      that, in cases of spontaneous malformations of this kind, such an atypical
      pycnotic area in the ventral telencephalon might result from the defective
      regulation of cell death processes during optic cup formation. In the forebrain
      and eyes of Tupaia, the occurrence of bands of cell death precedes the appearance
      of the earliest intraepithelial macrophages. From phase 3 (onset of invagination)
      onwards almost all of them are concentrated along the band of cell death.

PMID- 10664178
TI  - The early development of thalamocortical and corticothalamic projections in the
      mouse.
AB  - The initial ingrowth of corticothalamic and thalamocortical projections was
      examined in mice at embryonic and perinatal stages. Fibers, in fixed brains, were
      labeled with the carbocyanine dye 1, 1'-dioctadecyl-3,3,3',3'
      tetramethylindocarbocianine perchlorate (DiI). By E13, the corticofugal fibers
      had entered the lowest intermediate zone through which they ran, turned over the
      corpus striatum, and left the cortex. The fibers were arranged in scattered
      bundles throughout the corpus striatum. At E14 corticofugal axons reached the
      internal capsule and at E14.5-E15 they established contact within the thalamus.
      Meanwhile, the thalamocortical afferents reached the neocortex at E13. At this
      time fibers ran tangentially within the intermediate zone, immediately underneath
      the cortical plate. By E14, the fibers had started to invade the subplate and, by
      E15, thalamocortical fibers had begun their radial growth into the cortex. Such
      radial growth proceeded steadily, invading each cortical layer as it
      differentiated cytoarchitectonically from the dense cortical plate. The first
      retrogradely labeled cells were detected at the cortical plate at E15. By the day
      of birth (E20), thalamocortical fibers had formed a dense branching system within
      layers VI and V. Our observations indicate that, in mice, the thalamic axons
      reach the cortex before corticothalamic projections enter the thalamic nuclei.
      Moreover, the results suggest that the pathway followed by each fiber system is
      different. By DiI injections into the internal capsule we have also determined
      that subplate cells are the first to send axons to the thalamus.

PMID- 10664179
TI  - A golgi and a combined Golgi/GABA immunogold study of local circuit neurons in
      the homing pigeon hippocampus.
AB  - Three types of local circuit neurons have recently been reported in the homing
      pigeon hippocampus. The principal type appears to be constituted by the medium
      sized angular or ovoid local circuit neurons that occur in all layers of the
      hippocampus. The current Golgi study has revealed that these neurons can be
      classified according to their axonal arborisation extension: (1) in all
      directions, (2) principally medio-laterally, or (3) dorso-ventrally. The local
      circuit neurons with dorso-ventral axon arborisation are present only in the
      subpyramidal layer. Serial sections of a Golgi-impregnated medium-sized,
      multiangular local circuit neuron in the pyramidal layer and a small, ovoid
      neuron in the suprapyramidal layer were investigated in the electron microscope.
      Some of these sections were processed for GABA immunogold cytochemistry. The soma
      and large dendrites of both neurons displayed GABA immunogold labelling. On the
      soma of medium-sized local circuit neuron there were numerous terminals; on the
      soma of the small one relatively fewer terminals were observed. The terminals
      contained round and/or flat synaptic vesicles. The long axonal branches of the
      neurons exhibited varicosities containing flattened or pleomorphic vesicles. Axo
      dendritic, axo-somatic and a few axo-axonic synapses were observed. The large
      dense axon arborisation field of medium-sized local circuit neurons is properly
      situated to modulate intrinsic hippocampal activity and that of the small local
      circuit neurons is well situated to modulate the hippocampal input in the
      suprapyramidal layer.

PMID- 10664180
TI  - Mast cell types and cell-to-cell interactions in lymph nodes of the opossum
      Didelphis albiventris.
AB  - Previous light-microscopic studies have shown a unique population of mast cells
      in lymphatic sinuses of lymph nodes located in the head, neck, axillary fossa and
      inguinal region of the opossum. In the present work, scanning and transmission
      electron-microscopic studies in the opossum mandibular and superficial axillary
      lymph nodes have strengthened the differences between connective-tissue mast
      cells (CTMC) and the lymphatic-sinus mast cells (LSMC). Further, close
      appositions of mast cells to other cells were described. At the nodal capsule,
      CTMC contacted fibroblast and granulocytes. In the lymphatic sinuses a few CTMC
      contacted LSMC, macrophages and reticular cells. The LSMC contacted macrophages,
      reticular cells and other LSMC. A few LSMC could be located in the medullary cord
      in close contact with plasma cells or other lymphoid cells, keeping the same
      ultrastructural features of those found in the lymphatic sinuses. An important
      new finding was provided by light-microscopic studies in nine abdominal lymph
      nodes. Most of them (para-aortic, common iliac, cardial, cecocolic and those of
      the body and tail of the pancreas) displayed numerous LSMC with the same
      distribution and histological features described herein. However, the mesenteric,
      pyloric and head-of-pancreas lymph nodes were virtually devoid of LSMC. Instead,
      their mast cells occurred mainly at the medullary cords and were very similar to
      the CTMC. Ultrastructural studies at the mesenteric lymph nodes confirmed the
      CTMC character of the mast cells located at both medullary cords and sinuses, and
      disclosed interactions with macrophages and lymphoid cells.

PMID- 10664181
TI  - The transient disappearance of cytokeratin in human fetal and adult ovaries.
AB  - Cells from the inner and outer granulosa cell layers of the ovarian follicles
      differ in function, probably because of their different origins from the surface
      epithelium and from the rete. This suggestion has not so far been thoroughly
      investigated in the human ovary. We examined fetal ovaries from the early, middle
      and late gestational periods, ovaries from fertile women, and preovulatory
      follicular cells obtained from patients under in vitro fertilization therapy
      (IVF). Indirect immunohistology and immunocytology were used to detect the
      presence of cytokeratin (CK)-positive epithelial cells. In fetal ovaries from the
      early gestational period, prominent rete tubules (sometimes with oocytes)
      appeared to be fused with the sex cords and primordial follicles. Both showed CK
      positively, detected with the pan-CK antibody Lu-5. Cytokeratin 19 was clearly
      expressed in the fusion area. In the fetal and adult ovaries, CK-positive
      follicular or granulosa cells were noted in the primordial and primary follicles
      as well as the preovulatory follicles. Cytokeratin was not detected in the
      granulosa cells of growing follicles, CK-positive and -negative luteal cells were
      identified in the developing corpus luteum. We conclude for the human ovary: (1)
      the heterogeneous morphology of granulosa cells may be explained by their twofold
      origin from the surface epithelium and the rete, (2) the rete tubules appear to
      be involved in folliculogenesis, (3) the transient absence of CK expression in
      growing follicles compared to resting and mature follicles or to the developing
      corpus luteum indicates a particular role of CK-positive cells at the
      periovulatory period.

PMID- 10664222
TI  - Costello syndrome: report of six patients including one with an embryonal
      rhabdomyosarcoma.
AB  - Costello syndrome was first described in 1971. Besides papillomata, which were
      part of the initial description, patients tends to develop benign tumours of
      ectodermal origin. Aetiology is yet unknown but it is supposed to be the result
      of a sporadic dominant mutation. We report six patients with typical clinical
      findings and emphasise the importance of cardiac manifestations and the tendency
      to develop tumours. One patient developed an embryonal rhabdomyosarcoma, the
      occurrence of which has been reported twice before in patients with Costello
      syndrome. CONCLUSION: There might be a causal link between the development of
      rare tumours and this genetic disorder which may provide a new clue concerning
      the identification of the gene involved in Costello syndrome.

PMID- 10664223
TI  - Serum liver enzymes in Turner syndrome.
AB  - Increased serum concentrations of liver enzymes are sometimes observed, in the
      absence of clinical symptoms of liver disease, in patients with Turner syndrome.
      The purpose of this study was to evaluate, in our Turner patients, serum liver
      enzyme levels and to find a cause for their increase. In 70 Turner patients,
      serum AST, ALT, GGT levels were evaluated every 6 months during a period of 0. 8
      21.9 years. In patients in whom increased values of liver enzymes were found,
      serological markers for infectious hepatitis, serum hepatitis C virus RNA and
      virus genotype, IgG and IgA antibodies to gliadin and endomysium, coeruloplasmin,
      copper, alpha(1)-antitrypsin, total proteins and electrophoresis, IgG, IgA, IgM,
      fibrinogen, prothrombin, alkaline phosphatase, creatine kinase and total and
      direct bilirubin were also determined. Antinuclear, anti-smooth muscle and anti
      liver-kidney microsome antibodies together with antithyroglobulin and anti
      thyroid peroxidase antibodies were determined in all patients and in 166 age
      matched female controls. In 22 patients, increased liver enzymes were observed,
      not related to karyotype. Follow-up showed that the hepatic disorder did not
      worsen with the time. Serological markers of hepatitis C virus were positive in
      three patients. When the serum liver enzyme increase was first observed in the
      other 19 patients with high enzyme levels (group A), 14 patients had never been
      submitted to hormonal treatment, 4 were on oestrogen/gestagen treatment and 1 was
      being treated with both growth hormone and oestrogen. Coeliac disease, alpha(1)
      antitrypsin deficiency and Wilson disease were ruled out by appropriate
      investigations. In 8/19 group A patients, antinuclear and/or anti-smooth muscle
      antibodies were present versus 6/48 of patients with normal liver enzymes (group
      B). Thyroid antibodies were found in 8/19 patients in group A and in 13/48 in
      group B. Weight excess SDS was significantly higher in Turner girls with liver
      enzyme increase. Ultrasonography, performed in 17 patients of group A, showed
      mild hepatomegaly in 4 and increased echogenicity with fatty infiltration in 6.
      CONCLUSION: Hepatic abnormalities in Turner syndrome are not progressive.
      Oestrogen should not be considered the main cause of increased liver enzymes in
      Turner syndrome since most of our patients with this finding had not been
      previously treated with oestrogens. An auto-immune pathogenesis might be
      considered in some cases, whereas the association with weight excess seems the
      most frequent cause of liver disorder in Turner syndrome.

PMID- 10664224
TI  - Isolated cutaneous response to granulocyte-monocyte colony stimulating factor in
      fatal idiopathic disseminated Bacillus-Calmette-Guerin infection.
AB  - Severe disseminated Bacillus-Calmette-Guerin (BCG) infection is very rare and has
      been regarded as idiopathic when no immunodeficiency is present. This entity
      seems to be due to several new types of inherited abnormalities in the pathways
      important in defence against Mycobacteria. Although improvement with interferon
      gamma (IFN-gamma) has been reported in some patients, to our knowledge there are
      no reports on the effect of other cytokines in the treatment of these patients.
      We report here the clinical response to IFN-gamma and granulocyte-monocyte colony
      stimulating factor (GM-CSF) treatment in a patient with idiopathic disseminated
      BCG infection who failed to respond to multiple antimycobacterial agents. The
      patient showed partial and transitory response to IFN-gamma, however, GM-CSF
      treatment led to rapid improvement of skin lesions within 2 weeks without any
      effect on the progression of the disease in the other organ systems. CONCLUSION:
      The response of idiopathic disseminated Bacillus-Calmette-Guerin infection to
      granulocyte-monocyte colony stimulating factor treatment was limited to cutaneous
      lesions. Granulocyte-monocyte colony stimulating factor may have acted to promote
      wound healing or the levels of this factor achieved in other affected organs may
      have been inadequate.

PMID- 10664225
TI  - Perinatal indomethacin treatment and neonatal complications in preterm infants.
AB  - To evaluate the incidence of neonatal complications among infants exposed to
      indomethacin antenatally, postnatally or both ante-and postnatally (combined),
      the records of 240 infants of gestational ages between 23 to 32 weeks were
      analysed retrospectively. Antenatal indomethacin treatment for longer than 2 days
      with a daily or cumulative dosage >/=150 mg correlated with a significantly
      higher incidence of grade I-II intraventricular haemorrhage. Combined exposure,
      cumulative antenatal exposure >/=150 mg and duration of antenatal exposure of
      more than 2 days was associated with necrotising enterocolitis and a cumulative
      exposure with sepsis. There was no independent association between indomethacin
      exposure and pneumothorax, bronchopulmonary dysplasia or respiratory distress
      syndrome. CONCLUSION: Preterm infants with exposure to antenatal indomethacin
      might be at increased risk of grade I and II intraventricular haemorrhage and
      those with both ante- and postnatal exposure at an increased risk of necrotising
      enterocolitis and sepsis.

PMID- 10664226
TI  - Plasma concentrations of granulocyte-macrophage colony-stimulating factor and
      interleukin-6 in septic and healthy preterms.
AB  - Plasma granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin
      6 (IL-6) concentrations were determined in 21 preterm infants with sepsis and
      nine healthy preterm neonates of the same postnatal age at sampling. Plasma GM
      CSF levels were elevated at diagnosis in the septic preterms as compared to the
      healthy preterms (P = 0.01), but did not differ significantly on recovery. IL-6
      levels were also elevated markedly at diagnosis (P = 0.0003), but decreased to
      normal on recovery as compared to the healthy preterm infants. GM-CSF levels were
      more prominent in septic preterms with neutropenia than those of non-neutropenic
      infants (P = 0.03). CONCLUSION: Preterm infants can produce high levels of
      granulocyte-macrophage colony-stimulating factor and interleukin-6 in response to
      bacterial sepsis.

PMID- 10664227
TI  - Acute respiratory distress syndrome in children with acute iron poisoning: the
      role of intravenous desferrioxamine.
AB  - The acute respiratory distress syndrome is a rare but potentially fatal
      complication of severe acute iron poisoning and its pathogenesis has been linked
      with direct and indirect iron toxicity as well as the use of the chelator drug
      desferrioxamine. We report a case of severe acute respiratory decompensation in a
      child treated according to the current protocol for chelation therapy and discuss
      its implications. CONCLUSION: We believe that the efficacy and safety of
      chelation therapy in severe acute iron poisoning may be improved by targeting the
      initial high levels of readily chelatable serum iron with adequate doses of
      desferrioxamine without prolonging its use unnecessarily.

PMID- 10664228
TI  - Japanese patients with sporadic Hirschsprung: mutation analysis of the receptor
      tyrosine kinase proto-oncogene, endothelin-B receptor, endothelin-3, glial cell
      line-derived neurotrophic factor and neurturin genes: a comparison with similar
      studies.
AB  - We report on mutation analysis of five genes involved in the receptor tyrosine
      kinase (RET) or the endothelin-signalling pathways in 28 sporadic Japanese
      patients with Hirschsprung disease. Analysis of DNA obtained from peripheral
      blood cells revealed six mutations in the RET proto-oncogene, four of which were
      disease-causing mutations in exon 9 (D584G), the splice donor site of intron 10
      (+2T to A), exon 11 (A654T), and exon 12 (T706A). A heterozygous A to G
      transition was found in 47 bases upstream from the 5' end of exon 2 in two HD
      patients but was also seen in one control subject (2/28; 1/24). A silent 2307T to
      G transversion was observed in exon 13. Two disease-causing mutations were
      detected in the endothelin receptor (EDNRB) gene, in the non-coding region of
      exon 1 (-26 G to A) and in exon 4 (A301T); the latter mutation was a novel one.
      One silent mutation was observed in exon 4 (codon 277). One heterozygous T to C
      mutation was found in the glial cell line-derived neurotrophic factor gene in 25
      bases upstream of the coding region in exon 1. No nucleotide changes were
      detected in either the endothelin-3 or neurturin genes. Disease-causing mutation
      rates in the RET proto-oncogene and the EDNRB gene were estimated at 14.3% (4/28)
      and 10.7% (3/28), respectively. In addition to mutations in the RET and EDNRB
      genes, embryonic environmental factors and/or other genetic factors appear to be
      involved in the development of Hirschsprung disease. Further systematic studies
      of genetic variation in a large series of patients and controls are necessary for
      elucidating the pathogenesis of this disorder. CONCLUSION: This study provides
      further gene alterations as disease-causing mutations in Japanese cases of
      sporadic Hirschsprung disease. However, the low mutation rate of the
      susceptibility genes may indicate that Hirschsprung disease arises from a
      combination of genetic and environmental factors.

PMID- 10664229
TI  - Procalcitonin may help differentiate disseminated herpes simplex viral infection
      from bacterial sepsis in neonates.
AB  - Disseminated herpes simplex virus infection is a potentially fatal condition
      which may be difficult to differentiate from bacterial sepsis. We report the case
      of a neonate with overwhelming herpes simplex (type 2) viraemia who presented
      with 'septic shock'. CONCLUSION: A low procalcitonin level (1.6 ng/ml),
      inconsistent with bacteraemia, suggests an alternative aetiology and may
      strengthen the case for antiviral therapy.

PMID- 10664230
TI  - Variable use of therapeutic interventions for children with human
      immunodeficiency virus type 1 infection in Europe.
AB  - Although a range of antiretroviral drugs are available for use in children, the
      appropriate paediatric regimen remains unclear. In a survey to investigate
      policies and practices relating to the therapeutic management of children
      infected by the human immunodeficiency virus (HIV), a postal questionnaire was
      sent to a named paediatrician in 70 major HIV centres in 13 European countries in
      early 1998. A total of 64 paediatricians (91%) responded. Pneumocystis carinii
      pneumonia prophylaxis was found to be routine in all centres, although
      considerable variation existed regarding the time of starting and stopping
      therapy. Prophylaxis for fungal infections and recurrent bacterial infections was
      common, with cytomegalovirus prophylaxis being less frequent. Although most
      centres (89%) used all five currently available nucleoside analogues (ziduvodine,
      lamivudine, stavudine, didanosine, zalcitabine), there was considerable
      variability regarding the availability of protease inhibitors. Most respondents
      delayed initiation of antiretroviral therapy until evidence of disease
      progression was apparent. The initial prescription of 38% of clinicians was
      triple therapy and that of 57% prescribed double therapy. Policies varied
      regarding the modification to regimens in response to disease progression and
      emergence of side effects and drug resistance. Clinical practice was informed by
      a number of sources, including centre-specific and national guidelines. Most
      respondents affirmed the need for European guidelines. CONCLUSION: Approaches to
      the therapeutic management of paediatric human immunodeficiency virus infection
      differ across Europe.

PMID- 10664231
TI  - DNase use in the daily care of cystic fibrosis: who benefits from it and to what
      extent? Results of a cohort study of 199 patients in 13 centres. DNase National
      Study Group.
AB  - Short-term clinical trials with DNase have shown minor to moderate benefits in
      cystic fibrosis patients. This study was performed to analyse the effectiveness
      of DNase use in daily practice and to obtain information on its effects in the
      long term and at different disease stages. Patients being treated in 13
      specialised units were included if they started DNase treatment before June 1996.
      Baseline data before DNase use and data during the DNase treatment period were
      recorded. Of the 199 patients included in the study 166 continued on DNase
      treatment while the data were being collected. The mean age (95% CI) was 14.5
      (13.7; 15,2) years; 103 (51.8%) patients were female. The mean maximum change in
      forced expiratory volume in 1 s (FEV(1)) was observed during the first month of
      treatment [11.1% (6.1; 16.1)]. By the end of the first and the second year of
      treatment mean changes in FEV(1) were 3.3% (-1.1; 7. 6) and 5.1% (-0.7; 10.9)
      respectively; at the end of the same periods 34% of patients had improved their
      baseline FEV(1) by 10% or more but in around 50% of patients the level fell below
      the baseline. A large inter-individual variability in changes in pulmonary
      function after the start of DNase treatment was documented. In addition, the
      medium-term response to treatment was correlated with early response during the
      first 3 months. No consistent changes in exacerbation pattern were found during
      the first year of treatment. CONCLUSIONS: The benefits of DNase use in daily
      practice are limited but apparently can be maintained in the medium term in some
      patients. A large inter-individual variability in response to DNase treatment has
      been documented and the benefits are doubtful in around 50% of patients. This
      observation points to the need to set up a withdrawal trial in these patients,
      using as an eligibility criterion the early response observed during the first 3
      months of treatment.

PMID- 10664232
TI  - Clinical course and treatment of haemorrhagic cystitis associated with BK type of
      human polyomavirus in nine paediatric recipients of allogeneic bone marrow
      transplants.
AB  - Of a total of 117 bone marrow transplant (BMT) recipients in the period from
      August 1988 to November 1995, 9 (7.7%) developed haemorrhagic cystitis. This
      condition was characterized in all nine patients by late onset (day +24 to +50
      post-BMT), long duration (1 to 7 weeks), and the excretion of BK virus in the
      urine, as confirmed by electron microscopy, DNA hybridization and PCR analysis.
      Adenovirus was not involved. The serological assessment of BK virus-specific IgM
      and IgG pre- and post-BMT is consistent with viral reactivation in all patients,
      although a primary infection cannot be absolutely excluded in a single patient. A
      significant correlation between the use of high-dose busulphan (16 mg/kg) in the
      preparative regimen and development of haemorrhagic cystitis (P = 0. 0003) was
      evident. The severe course of the disease in two patients resulted in bladder
      tamponade; bleeding could not be inhibited with coagulation and laser treatment.
      Deterioration was prevented by bladder irrigation via a suprapubic catheter.
      Remission occurred spontaneously in all patients. CONCLUSION: BK virus induced
      haemorrhagic cystitis in a paediatric bone marrow transplantation recipients is
      characterized by late onset, long duration, viral reactivation and correlates to
      high-dose busulphan. Severe bleeding could not be influenced by surgical
      intervention.

PMID- 10664233
TI  - Features of Antley-Bixler syndrome in an infant born to a mother with pregnancy
      luteoma.
AB  - We report a female newborn with characteristic signs of Antley-Bixler syndrome
      (ABS) such as midface hypoplasia, radiohumeral synostosis and multiple joint
      contractures. The newborn also presented ambiguous genitalia, stage Prader V, and
      congenital adrenal hyperplasia. The mother experienced midterm virilization due
      to a pregnancy luteoma. Her elevated androgen levels and virilization symptoms
      normalized post partum without treatment. The newborn had elevated serum
      testosterone and 17-OH-progesterone levels which remained elevated because of a
      21-hydroxylase deficiency. The child's treatment in order of priority was:
      hydrocortisone substitution, craniofacial/skeletal anomaly management and
      surgical correction of the external genitalia. Mutations in the genes for
      fibroblast growth factor (FGF) 8 and receptors FGFR1, FGFR2, and FGFR3 were not
      detected. CONCLUSION: A newborn girl with manifestations of the Antley-Bixler
      syndrome showed severe virilization probably caused by the association of a mild
      21-hydroxylase deficiency and maternal hyperandrogenism due to a pregnancy
      luteoma. Abnormalities of androgen metabolism may be responsible for virilization
      reported in other cases of the Antley-Bixler syndrome.

PMID- 10664234
TI  - Glycopeptide prescribing in a tertiary referral paediatric hospital and
      applicability of hospital infection control practices advisory committee (HICPAC)
      guidelines to children.
AB  - This study was undertaken to investigate the frequency of, indications for and
      appropriateness of glycopeptide prescription in a paediatric tertiary referral
      hospital and to assess the usefulness of the Hospital Infection Control Practices
      Advisory Committee (HICPAC) guidelines. A prospective audit of all systemic
      glycopeptide prescriptions over a 2-month period was undertaken. Clinical and
      microbiological data were recorded. Of 2810 hospital admissions, systemic IV
      glycopeptides were prescribed on 57 occasions to 50 patients, 30 (52.6%) for
      vancomycin and 27 (47.4%) for teicoplanin. Prescriptions were for 34 males and 23
      females aged from 2 weeks to 11 years (mean 15 months; median 9 months). Median
      hospital stay was 50 days. Glycopeptides were given to the following patient
      groups: cardiology 7 (12%), prophylaxis for cardiac surgery 11 (19%), post
      cardiac surgery 1 (1.8%), oncology 14 (24.6%), post-gastrointestinal tract
      surgical 8 (14%), general surgical 9 (15. 8%) and medical 7 (12.3%). Twenty three
      children (41.8%) had central lines in situ. Reason for use of glycopeptide was
      therapeutic in 7 (12.3%), empiric in 38 (66.7%), and as prophylaxis in 12
      (21.1%). Eight (14%) prescriptions met strict HICPAC criteria, but a further 22
      (39%) prescriptions were considered appropriate in this high-risk population.
      Glycopeptides were chosen appropriately for cardiac surgery prophylaxis in a
      further 10 (18%) but timing and duration of use in this group was inappropriate.
      Of all prescriptions, use was empiric in 38 (76%) and appropriate cultures were
      obtained at the time of commencement in only 13 (34%) of these. Glycopeptides
      were not used for routine surgical prophylaxis or for first-line empiric
      treatment of febrile neutropenia. CONCLUSIONS: The strict implementation of
      HICPAC guidelines may not always be appropriate for children at risk of beta
      lactam resistant gram-positive infections. Hospital guidelines need to be
      tailored to the patient population and microbial susceptibility patterns of each
      institution. Appropriate cultures should be obtained at the time glycopeptide
      treatment is begun so that duration of exposure can be limited.

PMID- 10664235
TI  - Changes in the choline content of human breast milk in the first 3 weeks after
      birth.
AB  - Choline is an essential constituent of membrane phospholipids in great demand in
      the developing brain and liver. We have previously demonstrated that human
      neonates excrete large amounts of betaine, a product of choline oxidation, in
      their urine. Estimates of perinatal choline intake using previously published
      data compared with our measurements of betaine excretion indicated that choline
      insufficiency might occur at certain periods after birth. In this study we
      measured the choline content of expressed human breast milk in colostrum (2-6
      days after birth), mature milk (7-22 days after birth) and several infant formula
      foods, using proton nuclear magnetic resonance spectroscopy. In colostrum choline
      was present in both the aqueous (free choline, phosphocholine and
      glycerophosphocholine) and lipid fractions (phosphatidylcholine and
      sphingomyelin). After 6-7 days there was a mean increase of 114% in the total
      choline content; 82% of the rise was accounted for by increases in phosphocholine
      and glycerophosphocholine, and 14% by (free) choline. The choline content of most
      formula feeds was comparable with the level in colostrum but below that of mature
      milk. Both the total choline content and ester composition of mature milk were
      comparable with more recent measurements using high-performance liquid
      chromatography. CONCLUSION: The choline content of human breast milk doubles 6-7
      days after birth and, unlike that of many formula feeds, appears to be sufficient
      to account for betaine excretion in healthy full-term neonates. However, for
      premature babies who usually receive much lower quantities of milk, yet have a
      higher demand for choline, the intake may be inadequate.

PMID- 10664236
TI  - Elevated gene expression of interleukin-8 in cord blood is a sensitive marker for
      neonatal infection.
AB  - Bacterial infection is a major cause of neonatal morbidity and mortality. Early
      diagnosis is essential for a successful treatment and outcome. Cytokine plasma
      levels are suggested to be sensitive parameters for the diagnosis of neonatal
      sepsis. The aim of this study was to assess cytokine mRNA expression in cord
      blood cells as a marker for neonatal infection. In a prospective study, cord
      blood samples of neonates with septic bacterial infection were analyzed
      qualitatively and semiquantitatively by reverse transcriptase-polymerase chain
      reaction (RT-PCR) for mRNA expression of tumor necrosis factor (TNF)-alpha,
      interleukin (IL)-1beta, IL-6, IL-8, as well as for IL-8 cord plasma levels.
      Results were compared to those of non-septic neonates. A method was used
      requiring only a microvolume (25 microl or less) of cord blood. Cord plasma
      levels of IL-8 were significantly elevated in septic infants (n = 9) when
      compared to infants with not confirmed sepsis (n = 22) and healthy infants that
      served as controls (n = 68) (median 1,686 vs 262.7 vs 33.1 pg/ml, P < 0.001). The
      presence of IL-6 and TNF-alpha gene expression was observed more frequently in
      septic than in non-septic patients; sensitivity, however, reached only 56 and
      67%, respectively. When using a semiquantitative approach for analyzing IL-8 mRNA
      levels, a high sensitivity (86%) and specificity (96%) for the detection of
      sepsis was achieved. A new method for the early diagnosis of neonatal infection
      is described measuring cytokine mRNA in neonatal cord blood cells. With this
      molecular approach only a microvolume of blood is required for analysis.

PMID- 10664237
TI  - Recurrent antiphospholipid-related deep vein thrombosis as presenting
      manifestation of systemic lupus erythematosus.
AB  - Antiphospholipid antibodies (aPL) are frequently associated with thrombotic
      disorders in the so-called antiphospholipid syndrome. Together with
      anticardiolipin antibodies (aCL), lupus anticoagulant (LA) is the main diagnostic
      tool for aPL detection. Since LA determination is based on the finding of
      prolonged clotting time in vitro, concomitant anticoagulant therapy may
      significantly interfere with its detection. We report a case of a boy in whom
      recurrent aPL-related thrombosis heralded for several months the onset of
      systemic lupus erythematosus (SLE). Abnormally increased in vitro clotting times
      at the time of the second thrombotic event led to the suspicion of the presence
      of LA activity. However, this latter finding was difficult to interpret since the
      patient was already on heparin treatment at the time of our first observation.
      Thus, LA was assayed using a commercial kit in which a heparin neutralizer is
      included (Staclot LA). Two consecutive samples from the patient were compared
      with eight patients on anticoagulant therapy for non-aPL-related thrombotic
      events and 20 healthy controls. The study showed that, taking into account the
      concomitant anticoagulant treatment, Staclot LA was positive only in the
      propositus, raising the suspicion of a possible aPL-related origin of the
      thrombotic event. This issue was definitively confirmed in a subsequent follow
      up. CONCLUSION: The present report shows that aPL-related deep vein thrombosis
      can be the earliest clinical manifestation of pediatric SLE, and that Staclot LA
      may have a role in LA detection during the course of anticoagulant treatment.

PMID- 10664239
TI  - A child with headaches and abnormal movements.

PMID- 10664238
TI  - Bone mineral density of the lumbar spine in very-low-birth-weight infants: a
      longitudinal study.
AB  - To examine osteopenia in very low birth weight (VLBW) infants we used repeated
      dual-energy X-ray absorptiometry in a prospective study of lumbar spinal bone
      mineral density (BMD) in Japanese VLBW infants (birthweight 426-1498 g; n = 61,
      group 1) aged 40 weeks postconception to 3 years of age. Control subjects were
      Japanese infants with birthweight 1500-1999 g (group 2), 2000-2499 g (group 3),
      or more than 2500 g (group 4). BMD in group 1 during the early period after birth
      was very low, increased rapidly for 1 year, and then gradually increased until 3
      years of age (r = 0.931, P < 0. 0001). BMD at the age of 40 weeks postconception
      was 0.085 +/- 0.026, 0.132 +/- 0.039, 0.178 +/- 0.042, and 0.196 +/- 0.046
      g/cm(2) in groups 1, 2, 3, and 4, respectively (P < 0.0001). However, at 1 and 2
      years of age no differences were observed among the groups in BMD. CONCLUSION:
      This study shows that lumbar spinal BMD in VLBW infants can normalize by the age
      of 2 years.

PMID- 10664240
TI  - Vaccines not containing human albumin and vaccines to avoid the risk of
      Creutzfeldt-Jakob disease.

PMID- 10664241
TI  - Sonographic measurement of the thymus in newborns: close association between
      thymus size and birth weight.

PMID- 10664242
TI  - First report of Guillain-Barre syndrome after rotavirus-induced gastroenteritis
      in a very young infant.

PMID- 10664243
TI  - Pulmonary disease possibly caused by Mycobacterium avium in an HIV-negative
      infant.

PMID- 10664244
TI  - Elevation of antibody against Epstein-Barr virus genes BRLF1 and BZLF1 in
      nasopharyngeal carcinoma.
AB  - PURPOSE: Epstein-Barr virus immediate early genes BZLF1 and BRLF1 encode the Z
      and R proteins respectively. Elevation of the anti-Z immunoglobulin (Ig) antibody
      titer is a common feature of nasopharyngeal carcinoma (NPC) in areas where the
      disease endemic, whereas R levels have not been examined. This study was
      performed to analyze antibody titers against Z and R in Japan. METHODS: Sera from
      14 patients with newly diagnosed NPC, 7 with NPC in complete remission, 15 with
      head and neck squamous cell carcinoma (HNSCC), and 31 controls were evaluated by
      enzyme-linked immunosorbent assay (ELISA) and immunoblotting. RESULTS: Both anti
      Z and anti-R Ig were significantly increased in sera from patients with NPC
      compared with those in remission, those with HNSCC, and controls (Z, P = 0.0016,
      = 0.0344, = 0.0002; R, P = 0.0015, = 0.0004, <0.0001 respectively). By immunoblot
      analysis, anti-Z and anti-R Ig were detected in 9 of 9 cases of NPC, 1 of 3 cases
      NPC in remission, and 2 of 13 cases of HNSCC. Anti-Z and anti-R antibody titers
      were nine times higher in NPC than in other groups. None of 15 control cases
      showed positive reactivity against either Z or R. CONCLUSION: Coupled evaluation
      of anti-Z and anti-R Ig by ELISA might be a useful system for screening NPC.

PMID- 10664245
TI  - Increased antitumour activity of mesyl-I-aldophosphamide-perhydrothiazine, in
      vivo but not in vitro, compared to I-aldophosphamide-perhydrothiazine.
AB  - When equitoxic dosages of ifosfamide and I-aldophosphamide-perhydrothiazine (IAP)
      were tested for antitumour activity in the P388 mouse leukaemia model, 80% long
      term survival (for more than 100 days) was achieved with IAP whereas, in the
      ifosfamide group, all mice died from tumour growth within 60 days. Even better
      antitumour activity, compared with ifosfamide, was observed with an IAP
      derivative (SUM-IAP) in which one 2-chloroethyl group of the alkylating function
      is substituted by a mesylethyl group. Evaluation of tumour growth curves
      following treatment with IAP and SUM-IAP revealed the antitumour activity of SUM
      IAP to be 10(4)-10(5) times higher than that of IAP. In contrast to the results
      of these in vivo experiments, IAP was more cytotoxic against P388 mouse leukaemia
      cells in vitro than was SUM-IAP. The inverse correlation of in vivo antitumour
      activity and in vitro cytotoxicity indicates that the factors leading to the
      increase of antitumour activity following chemical modification of IAP differ
      from those involved in cytotoxicity on the cellular level.

PMID- 10664246
TI  - Truncated TSG101 transcripts in human leukemia and lymphoma cell lines.
AB  - Inactivation of the TSG101 gene has been shown to induce cellular transformation
      of NIH3T3 fibroblasts, and aberrant TSG101 transcripts have been observed not
      only in various human solid tumors but also in hematopoietic malignant disorders.
      In the present study, we performed nested reverse transcription/polymerase chain
      reaction (RT-PCR) analysis to identify aberrant TSG101 transcripts in 43 human
      leukemia and lymphoma cell lines. We could detect only a single band of the wild
      type transcript with the expected size in virtually all cell lines after the
      first round of PCR. As in the case with various human solid tumors, the smaller
      TSG101 transcripts appeared in most of these cell lines after the second round of
      PCR. Thus, the expression level of the variant transcripts was extremely low as
      compared with that of the wild-type transcript, and this finding was also
      confirmed by Northern blot analysis. Identification of various truncated
      transcripts with extensive deletions in the TSG101 coding region was confirmed by
      means of sequencing analysis, and expression of these transcripts did not appear
      to be associated with a specific type of hematopoietic malignant disorder.
      Southern blot analysis did not indicate any gross TSG101 gene rearrangement. The
      truncated transcripts were also detected in normal peripheral blood leukocytes.
      Our results suggest that the truncated TSG101 transcripts are definitely
      detectable in various human leukemia and lymphoma cell lines, but do not support
      the notion that the variant transcripts may have a major functional relevance in
      the pathogenesis of human hematopoietic malignant disorder.

PMID- 10664247
TI  - Effects of all-trans retinoic acid and epidermal growth factor on the expression
      of nm23-H1 in human hepatocarcinoma cells.
AB  - The effects of all-trans retinoic acid (ATRA) and epidermal growth factor (EGF)
      on the expression of nm23-H1, a metastasis suppressor gene, were studied in a
      human 7721 hepatocarcinoma cell line. It was discovered that the expression of
      nm23-H1 mRNA was up-regulated by ATRA. This was compatible with the observation
      that the metastasis-associated phenotypes, such as chemotaxic cell migration and
      invasion, were both reduced in the ATRA-treated and nm23-H1-cDNA-transferred 7721
      cells. However, ability of cells to adhere to fibronectin and laminin was not
      altered identically in the ATRA-treated and nm23-H1-cDNA-transfected 7721 cells.
      In contrast, the expression of nm23-H1 mRNA in 7721 cells was down-regulated both
      by the treatment with EGF and by the transfection of c-erbB-2/neu cDNA, which
      codes a protein homologous to the EGF receptor. EGF is a compound with biological
      effects opposite to those of ATRA, and c-erbB-2/neu is known to be a metastasis
      promoting gene. These results reveal that the metastasis-preventing effect of
      ATRA may partly result from the up-regulation of nm23-H1, and the metastasis
      promoting effects of EGF and c-erbB-2/neu were probably mediated in part by the
      down-regulation of nm23-H1.

PMID- 10664248
TI  - The two-receptor system PAR-1/PAR-4 mediates alpha-thrombin-induced [Ca(2+)](i)
      mobilization in human astrocytoma cells.
AB  - The proteinase-activated receptor 1 (PAR-1) was characterized as a functional
      receptor for thrombin in cells from different brain tumor entities. Whether PAR-1
      alone accounts for thrombin-induced effects in human cancer cells, or whether
      other PAR contribute is unknown. We established primary cultures from two
      neurosurgically removed human astrocytomas and investigated intracellular
      signaling roles of PAR-1 and PAR-4 by estimating the effect of alpha-thrombin and
      PAR-activating peptides on [Ca(2+)](i) mobilization in single astrocytoma cells.
      alpha-Thrombin or the PAR-1-activating peptide SFLLRN induced a transient calcium
      mobilization. This suggests the involvement of PAR-1 in alpha-thrombin-induced
      calcium signaling in human astrocytoma cells. In addition, a second, PAR-4
      dependent, mechanism exists. This was deduced from the findings that a further
      calcium signal could be observed in human astrocytoma cells stimulated with alpha
      thrombin after SFLLRN and the PAR-4-activating peptide GYPGQV also induced a
      calcium response. In addition, the observation that trypsin, known to activate
      both PAR-2 and PAR-4, but not the specifically PAR-2-activating peptide SLIGRL
      induced calcium signaling is a further indication of functional PAR-4-type
      thrombin receptors in human astrocytoma cells. This is the first report
      demonstrating a signaling role for a dual thrombin receptor system in human tumor
      cells.

PMID- 10664249
TI  - Collision tumour in the pelvic cavity: rectal leiomyosarcoma and prostate
      adenocarcinoma.
AB  - We report a rare and, to our knowledge, as yet undescribed type of collision
      tumour - rectal leiomyosarcoma and prostate adenocarcinoma. Our study also
      provides the first data on molecular alterations [polymerase chain reaction/loss
      of heterozygosity (LOH) analysis] of the APC, NF-1, DCC, p53, nm23-H1 and BRCA-1
      genes in the two components of the collision tumour. None of the genes examined
      in this study expressed LOH in the prostate carcinoma component of the collision
      tumour. By contrast, in the leiomyosarcoma component, LOH was found at the DCC
      and p53 genes, proving that these two tumours did not arise from the same stem
      cell but represent two different neoplastic growths.

PMID- 10664250
TI  - Serum levels of soluble CD30 in autologous peripheral blood stem cell
      transplantation.
AB  - High-dose chemotherapy with peripheral blood stem cell transplantation (PBSCT)
      has become an important method of treatment for hematological and solid tumors.
      We examined levels of interleukin(IL)-4, interferon (IFN)gamma, soluble (s) CD30,
      and sIL-2 receptor (R) before and after autologous PBSCT, and compared findings
      for PBSCT with those for bone marrow transplantation (BMT). We found
      significantly higher IL-4 levels 1 and 3 weeks after PBSCT than before PBSCT,
      while IFNgamma levels remained almost unchanged after PBSCT. IFNgamma levels were
      increased 3 weeks after BMT, although no increase in IL-4 level was observed. The
      serum sCD30 level was significantly higher 3 weeks after PBSCT, but not following
      BMT. For 34 samples on days 0 and 21 from 17 patients undergoing PBSCT, a strong
      correlation was observed between sCD30 and sIL-2R levels (r = 0.43, P < 0.01).
      However, no significant correlation between sCD30 and sIL-2R levels was found for
      BMT patients. These findings suggest that sCD30 is a useful marker for evaluating
      immunological activity following autologous PBSCT, and that the immunological
      conditions after autologous PBSCT may be associated with helper-T-cell-2-type
      immune responses.

PMID- 10664251
TI  - Serum protein s100beta in patients with malignant melanoma detected by an
      immunoluminometric assay.
AB  - S100 protein is well established as a diagnostic tool in malignant melanoma
      immunohistology. In this study we measured S100beta in serum with a recently
      developed luminometric immunoassay with a detection limit of 0.02 microg/l. By
      measuring S-100beta in a group of apparently healthy individuals a mean value of
      0.031 +/- 0.026 microg/l was found. In the reference group, serum S100beta was
      below 0.12 microg/l in all cases. To assess the sensitivity of the assay we
      investigated serum S-100beta levels in 371 serum samples of 315 patients with
      histological proven malignant melanoma at different disease stages. Staging was
      performed according to the German Society of Dermatology classification.
      Significant differences were observed between the control group and stages IIb (P
      = 0.01) and IV (P = 0.001). In tumour-bearing patients of stages IIIb and IV, the
      difference was highly significant (P < 0.0001). S100beta > 0.20 microg/l helps to
      distinguish between tumour-free and tumour-bearing patients with a specificity of
      97.0% and a sensitivity of 64.6%. Our results demonstrate the serum S100beta is
      of limited value as a melanoma marker. However, it has clinical significance for
      identifying tumour-positive patients in advanced malignant melanoma stages III
      and IV.

PMID- 10664253
TI  - p53-Targeted drugs: intelligent weapons in the tumor-suppressing arsenal.

PMID- 10664252
TI  - In vitro effect of multidrug resistance modifiers on idarubicinol efflux in
      blasts of acute myeloid leukemia.
AB  - Recent results show that the intracellular uptake pattern of idarubicin (IDA) in
      multidrug-resistant (MDR) cells is nearly identical to that seen in the drug
      sensitive parent cell line, whereas the MDR cells have minimal daunorubicin (DNR)
      uptake compared with the drug-sensitive parent cells. It is known that the major
      metabolite of IDA, idarubicinol (IDA-OL), has nearly the same cytotoxicity as
      IDA, while the cytotoxicity of daunorubicinol (DNR-OL) is about 1/30th of that of
      DNR. We examined the effect of the MDR modifiers verapamil and dexniguldipine on
      the efflux of IDA, DNR and their hydroxylated metabolites IDA-OL and DNR-OL in
      blast populations of acute myeloid leukemia (AML), in the MDR-negative cell line
      CEM-CCRF and in their MDR-positive counterpart (CEM-VBL). All patients with
      relapsed or persistent AML had been pretreated with IDA and cytosine arabinoside.
      The efflux of the anthracyclines was estimated by flow cytometry. A total of 36
      patients with AML were investigated; 18 out of 36 AML blast populations showed an
      efflux of DNR, DNR-OL and IDA-OL. The efflux of DNR, DNR-OL and particularly IDA
      OL could be reversed by 10 microM verapamil or 1 microM dexniguldipine. For IDA
      we found an effusion of 40 +/- 11% in all blast populations which could not be
      significantly inhibited by the modulators. Similar results for IDA were found in
      the MDR-positive cell line (CEM-VBL 100) and in their MDR-negative counterpart
      (CEM-CCRF). The incubation of CEM-CCRF cells with DNR, DNR-OL, IDA-OL and
      especially IDA led to MDR induction as determined by reverse
      transcription/polymerase chain reaction analysis with MDR-specific primer and by
      cellular efflux studies. We conclude that the outcome of chemotherapy with
      idarubicin is influenced by MDR, although IDA is not essentially MDR-dependent
      itself, but because IDA-OL is actively involved in multidrug resistance. Further
      investigations should consider the question of whether the combination of IDA and
      MDR modifiers can enhance the serum level of the active metabolite IDA-OL and can
      reverse the MDR pattern in cells treated with IDA.

PMID- 10664254
TI  - From protein phosphorylation to gene expression profiles. Eighth colloquium on
      cellular signal transduction, 26 February 1999, Heidelberg, Germany.

PMID- 10664277
TI  - Definition of primary sclerosing cholangitis.

PMID- 10664278
TI  - Definition and pathology of primary sclerosing cholangitis.
AB  - Although primary sclerosing cholangitis (PSC) is not a common disease, it is
      important in the differential diagnosis of hepatobiliary tract diseases in
      clinical practice. A diagnosis of PSC should be made only after the exclusion of
      similar diseases with well known etiologies or pathogeneses. In this review, the
      pathology of classical PSC and its variants or related diseases is highlighted.
      PSC is histologically characterized by progressive periductal fibrosis with
      luminal stenosis or obliteration, along with the formation of a fibrous core, as
      well as dilatation (cholangiectasis). Its etiology is unknown. Bacterial
      ascending cholangitis is superimposed on its long clinical course. Such a
      heterogeneous distribution of biliary lesions with biliary obliteration and
      cholangiectasis is responsible for the radiological demonstration of biliary
      abnormalities, particularly the beaded appearance. Sampling variability is common
      in needle or wedge biopsied specimens. As a result of biliary damage, the liver
      shows progressive cholestatic change followed by biliary fibrosis and cirrhosis,
      and this hepatic progression is divisible into four stages. There are several
      variants of PSC or related diseases, such as localized biliary sclerosis and
      stenosis, sclerosing cholangitis associated with inflammatory pseudotumor, and
      PSC-autoimmune hepatitis overlapping syndrome. Cholelithiasis, including
      secondary hepatolithiasis and, to a lesser degree, biliary carcinoma and
      dysplasia, are also known to develop at the perihilar bile ducts as a late
      complication of PSC.

PMID- 10664279
TI  - Etiology and natural history of primary sclerosing cholangitis.
AB  - The etiology of primary sclerosing cholangitis remains unknown. Bacteria, toxins,
      viral infections, and immunological and genetic factors have all been proposed as
      etiological agents. Portal bacteremia, toxins absorbed from the diseased colon in
      inflammatory bowel disease, and cytomegalovirus and reovirus infections have been
      implicated by various investigators but there is little evidence to support these
      hypotheses. The close association between primary sclerosing cholangitis and
      various human leukocyte antigen haplotypes is now well established and lends
      support to the theory that immunologic and genetic mechanisms may be involved in
      its pathogenesis. Patients with primary sclerosing cholangitis may have elevated
      levels of circulating immune complexes, immunoglobulins, and non-organ specific
      autoantibodies. The association between ulcerative colitis and primary sclerosing
      cholangitis remains unexplained and both groups of patients have a high
      prevalence of antibodies to the perinuclear cytoplasmic antigen. The long-term
      prognosis in primary sclerosing cholangitis is tempered by the development of
      cholangiocarcinoma in 6%-30% of patients when followed over long periods of time.
      Detecting cholangiocarcinoma early in a patient with primary sclerosing
      cholangitis is one of the most frustrating problems faced by a clinician while
      caring for these patients. The long-term outlook for patients with primary
      sclerosing cholangitis and cholangiocarcinoma remains dismal, whatever the
      treatment modality employed. However, the development of a multivariate
      statistical survival model from long-term survival data from the Mayo Clinic and
      other centers has been a major step in identifying individual primary sclerosing
      cholangitis patients at low, moderate, and high risk of dying. Such models have
      been useful for stratifying patients in therapeutic trials, for in patient
      counseling, and in patient selection and timing of liver transplantation.

PMID- 10664280
TI  - Recent status of primary sclerosing cholangitis in Japan.
AB  - Patients with primary sclerosing cholangitis (PSC) in Japan have two peaks in age
      distribution, one in their twenties and the other in their fifties and sixties.
      PSC patients in Japan have different characteristics from those in other
      countries: there is a higher incidence of eosinophilia (27%) and positivity for
      anti-nuclear antibody (30%), less frequent complication with inflammatory bowel
      diseases (IBD; 21%), and more frequent complication with chronic pancreatitis
      (15%). In younger patients in Japan (those aged less than 40 years), the
      incidence of positivity for anti-nuclear antibody was lower (20% vs 38% P <
      0.05), complication with IBD was more frequent (39% vs 9% P < 0.01), complication
      with chronic pancreatitis was less frequent (4% vs 22% P < 0.01), and damage to
      both the intra- and extrahepatic bile ducts was more frequent (89% vs 56% P <
      0.01) than in older patients (those aged 40 years or more). These findings
      suggest that younger PSC patients in Japan have characteristics similar to those
      of patients in other countries, and that in Japan older PSC patients have a
      different pathogenesis from that of younger patients.

PMID- 10664281
TI  - Diagnosis of primary sclerosing cholangitis.
AB  - Primary sclerosing cholangitis is a progressive chronic hepatobiliary disorder of
      unknown aetiology for which no effective medical therapy currently exists. This
      syndrome occurs most commonly in young men and is frequently associated with
      ulcerative colitis. Primary sclerosing cholangitis should be considered in the
      differential diagnosis of all patients presenting with chronic cholestasis. The
      diagnosis is based on a combination of the clinical features and cholestatic
      biochemical profile accompanied by typical cholangiographic abnormalities and is
      supported by liver histology findings. The major diagnostic criterion is the
      finding at cholangiography of irregularly distributed multifocal strictures
      within both the intrahepatic and extrahepatic bile ducts. The most characteristic
      histological feature of primary sclerosing cholangitis is periductal concentric
      obliterative fibrosis of small interlobular bile ducts with or without
      proliferation of bile ducts in portal tracts, but liver biopsy findings alone are
      infrequently diagnostic. Nevertheless, liver histology remains important to
      exclude other causes of chronic cholestasis and in staging the disease.

PMID- 10664282
TI  - Medical treatment of primary sclerosing cholangitis.
AB  - Until 1970, primary sclerosing cholangitis (PSC) was considered to be a medical
      curiosity. With the development of endoscopic cholangiography, PSC is now
      recognized more frequently and is a common indication for liver transplantation.
      PSC is usually progressive, leading to cirrhosis, portal hypertension, and liver
      failure. The manifestations of disease may be clinically similar to those of
      other causes of bile duct obstruction and must be distinguished from gallstone
      disease, bile duct carcinoma, primary biliary cirrhosis, and secondary biliary
      cirrhosis due to bile duct stricture. Medical management of PSC must take into
      account the likelihood that destroyed bile ducts do not regenerate as hepatocytes
      do. Hence, PSC should be treated early in its course. The goal of therapy is to
      prevent further damage and destruction of bile ducts. In this article, we will
      present relevant data concerning the medical management of primary sclerosing
      cholangitis.

PMID- 10664283
TI  - Surgical treatment for primary sclerosing cholangitis.

PMID- 10664285
TI  - Clinicopathologic findings of recurrent primary sclerosing cholangitis after
      orthotopic liver transplantation.
AB  - Whether primary sclerosing cholangitis (PSC) occurs after orthotopic liver
      transplantation is controversial, largely because the pre-transplant diagnosis of
      PSC is based on nonspecific radiological and histological findings. We reviewed
      clinical, radiological, and histological records of 53 patients who underwent
      liver transplantation for PSC between 1985 and 1998. Three patients with patent
      hepatic arteries and no evidence of chronic rejection had radiological and
      histological findings that may have been due to recurrent PSC. Bile duct
      stricturing in these patients proved permanent and progressive and affected both
      the quality of life and graft survival. The first patient, who is 110 months
      after transplantation, has had repeated episodes of cholangitis for the last
      year. The second patient underwent excision of a strictured hepatic duct 45
      months after transplantation and was ultimately retransplanted 95 months after
      initial transplantation. The third patient underwent left hemihepatectomy of an
      atrophied lobe 50 months after transplantation. Although the patient population
      assessed in this study is limited, putative recurrent PSC in the allografts has
      led either to graft loss or to clinically significant hepatobiliary complications
      of the graft.

PMID- 10664284
TI  - Liver transplantation for primary sclerosing cholangitis.
AB  - Although the development of interventional radiology and biliary surgical
      techniques has prolonged the survival time of patients with primary sclerosing
      cholangitis, liver transplantation remains the only effective treatment for
      patients with primary sclerosing cholangitis with liver cirrhosis. Several
      prognostic survival models have been establised for this disease, and the
      efficacy of actual liver transplantations has been reported in comparison with
      these survival models. One- and 5-year actuarial patient survivals after liver
      transplantation for primary sclerosing cholangitis were shown to be greater than
      and approximately equal to 90%, respectively. An association with
      cholangiocarcinoma is the most adverse factor affecting survival after liver
      transplantation for primary sclerosing cholangitis, while the association of
      inflammatory bowel disease or previous bili-ary surgery does not adversely affect
      the outcome of the liver transplantation. Recurrent sclerosing cholangitis is an
      important issue for posttransplant patients with primary sclerosing cholangitis,
      and occurs in 10%-20% of such patients. Although our understanding of recurrent
      sclerosing cholangitis is still in the early stages, its potential occurrence
      indicates the need for a longer follow-up period after liver transplantation.

PMID- 10664286
TI  - Laparoscopic side-to-side pancreaticojejunostomy (Partington-Rochelle) for
      chronic pancreatitis.
AB  - Intractable pain in chronic pancreatitis has been treated by several different
      procedures, including resection and drainage, or a combination of the two. We
      describe the technique of laparoscopic side-to-side pancreaticojejunostomy for
      chronic pancreatitis in five patients. The procedure is performed using five
      trocars. Stapling and direct suturing are required. Careful selection of patients
      is important. Preoperative and intraoperative ultrasound is necessary to assess
      the dilated pancreatic duct. In one of the five patients, the laparoscopic
      technique was converted to an open procedure because the preoperative findings
      were not confirmed at exploration. Four of the five patients are pain-free, with
      5- to 30-month follow-up. Laparoscopic pancreaticojejunostomy can be performed
      safely, and it is a procedure that should be considered in the treatment of
      appropriate patients with chronic pancreatitis.

PMID- 10664287
TI  - First case of cadaveric liver transplantation in Japan.
AB  - The first case of liver transplantation from a brain-dead donor in Japan is
      described. The recipient was a 43-year-old man with familial amyloid
      polyneuropathy who manifested various neuropathic symptoms and autonomic
      dysfunction at the time of transplantation. The graft had three arteries, for
      which a single trunk was created at the back table. A side-to-side cavacaval
      anastomosis was performed as an outflow reconstruction. To avoid portal
      congestion, a temporary shunt between the right posterior branch of the portal
      vein and the vena cava was constructed, instead of a venovenous bypass. The graft
      preservation time was 7.2 h and the operation time was 12.2 h. Although
      sufficient blood flow in the hepatic artery, portal vein, and hepatic vein was
      confirmed intra- and postoperatively, using Doppler ultrasound, transient graft
      dysfunction was observed immediately after surgery, but there was spontaneous
      improvement. The patient was discharged 100 days after transplantation.

PMID- 10664288
TI  - High serum concentrations of sialyl Tn antigen in carcinomas of the biliary tract
      and pancreas.
AB  - Sialyl-Tn (STn) antigen is a cancer-associated carbohydrate antigen expressed in
      cancers of the digestive tract. In the present study, we compared the serum level
      of STn antigen in 14 patients with benign diseases of the biliary tract and
      pancreas, 15 patients with bile duct cancers, and 9 patients with cancer of the
      pancreas. High levels of serum STn (>45 U/ml) were frequently detected in
      patients with carcinoma of the biliary tract (53.3%) or pancreas (55.6%),
      compared with the detection of high levels in those with benign diseases (14.3%;
      P < 0.05). Serum levels of STn did not correlate with the presence of jaundice,
      cholangitis, or pancreatitis, or with the level of carcinoembryonic antigen (CEA)
      or carbohydrate antigen (CA) 19-9. In cancer tissues, the expression of STn
      antigen detected by immunostaining correlated significantly with serum STn (P <
      0.05). Our results indicate that measurement of serum STn level may be
      potentially useful for the diagnosis of carcinomas of the biliary tract and
      pancreas, particularly when combined with other tumor markers such as CEA or CA19
      9.

PMID- 10664290
TI  - Long-term survival of patients with biliary tract cancers with lymph node
      involvement.
AB  - In extrahepatic biliary tract malignancies, the prognostic value of lymph node
      involvement remains unclear. For a total of 161 tumors of the gallbladder (GBC)
      and bile duct (BDC) resected between 1982 and 1992, the number and extent of
      metastatic nodes were investigated according to the location of the primary
      tumor. In GBCs and upper two-third BDCs, more than half of node-positive tumors
      involved multiple nodes (58% and 63%), and node-positive tumors were associated
      with a significantly poorer rate of patient survival compared with node-negative
      tumors. However, GBCs with one or two nodes involved resulted in a longer
      survival time than those with three or greater (P = 0.0045). In lower one-third
      BDCs, even patients with node-positive tumors showed a 60% 5-year survival rate.
      There were 15 long-term survivors (i.e., survived for more than 5 years after
      surgery) with node-positive tumors in the GBC group, 4 in the upper BDC group,
      and 6 in the lower BDC group. Thirteen GBCs had one or two involved nodes, and 12
      of the 13 GBCs positive nodes were located within the hepatoduodenal ligament. In
      upper and lower BDCs, pericholedocal nodes and nodes around the pancreatic head
      respectively, were most frequently involved. We concluded that lymphatic spread
      is an important prognostic determinant in both GBCs and upper BDCs. The prognosis
      of GBCs is especially influenced by the number of nodes involved. In lower BDCs,
      lymphatic metastasis does not necessarily preclude long-term survival.

PMID- 10664289
TI  - Results of duodenopancreatectomy for solitary pancreatic metastasis from renal
      cell carcinoma.
AB  - The pancreas is an uncommon site of metastasis from renal cell carcinoma. We
      present five patients with solitary pancreatic metastasis from renal cell
      carcinoma located in the head of the pancreas, treated by duodenopancreatectomy.
      There were no perioperative deaths. Mean survival was 48 months; three patients
      were alive at the end of the study (at 27, 46, and 88 months, respectively) and
      two patients died, at 13 and 70 months. The 3- and 5-year survival rates of our
      patients together with 22 previously reported patients were 86% and 68%,
      respectively. We advocate aggressive surgical treatment when the metastatic
      disease is limited to the pancreas.

PMID- 10664291
TI  - Somatostatin: possible cause of bacterial translocation in obstructive jaundiced
      rats.
AB  - The purpose of this study was to examine the effect of endogenous somatostatin
      hormone on bacterial translocation in obstructive jaundiced rats. Five groups of
      rats were studied: group I (n = 10), non-operated group (control); group II (n =
      10), sham-operated group which underwent laparotomy and dissection of portal
      elements, while the common bile duct was not ligated and somatostatin was not
      injected; group III (n = 10), same as group II, plus injection of somatostatin;
      group IV (n = 10), common bile duct was ligated with laparotomy but somatostatin
      was not injected; group V (n = 10), same as group IV, plus somatostatin
      injection. The blood was analyzed for somatostatin, alkaline phosphatase, and
      bilirubin levels on the third and tenth days in all animals. At study termination
      (tenth day), peritoneal swab and blood cultures were taken, and liver, spleen,
      lung, and mesenteric lymph nodes were harvested for microbiological studies.
      Bacterial translocation levels were higher in groups III, IV, and V when compared
      with levels in groups I and II. Similar translocation levels were obtained when
      blood somatostatin levels were comparable. However, the highest translocation
      rate was found in groups IV and V in which the blood somatostatin level was also
      higher when compared with that in other groups. This finding shows that blood
      somatostatin level is increased in obstructive jaundice. This may explain the
      bacterial translocation and related sepsis found in obstructive jaundice.

PMID- 10664292
TI  - Giant cavernous hemangioma of the liver: is tumor size a risk factor for
      hepatectomy?
AB  - The aim of this study was to evaluate whether hepatic giant cavernous hemangioma
      (GCH) tumor size is a risk factor for hepatectomy. Twenty patients with GCH of
      the liver were treated by hepatic resection. Eleven patients with maximum
      resected specimen tumor size of >10 cm (mean tumor size, 18.5 cm; group 1) were
      compared with the 9 patients with tumor size. <10 cm (mean tumor size, 8.6 cm;
      group 2). The incidence of major hepatectomy in group 1 was significantly higher
      than that in group 2 (P = 0.0241). Although there were no significant differences
      in preoperative liver function, or in fibrinogen or platelet counts between the
      two groups, the level of preoperative fibrin degradation product (FDP) in group 1
      was significantly higher than that in group 2 (P = 0.0116). Mean intraoperative
      hemorrhage volume, blood transfusion volume, and operation time in group 1 vs
      group 2 were 7003 ml vs 1092 ml (P = 0. 0251), 2927 ml vs 556 ml (P = 0.0169),
      and 431 min vs 216 min (P < 0. 0001), respectively. The incidence of
      postoperative complications in group 1 (45.5%) was higher than that in group 2
      (22.2%), although not significantly so. There was no operative mortality in
      either group. Tumor size significantly correlated with intraoperative blood loss,
      operation time, weight of resected liver, intraoperative blood transfusion
      volume, and preoperative FDP levels. GCH tumor size is a significant risk factor
      for hepatectomy mainly because of the massive intraoperative blood loss and blood
      transfusion associated with major hepatic resection. More careful preoperative
      management to decrease tumor size may increase the safety of surgery for GCH of
      the liver.

PMID- 10664293
TI  - Pancreas-sparing duodenectomy for a huge leiomyosarcoma in the third portion of
      the duodenum.
AB  - A duodenal leiomyosarcoma which was resected by pancreas-sparing duodenectomy is
      reported. The tumor arose in the third portion of the duodenum and grew in an
      extraluminal direction. The tumor was huge (13 cm x 9 cm x 8 cm) but did not
      involve the pancreas, and there were no findings of periduodenal lymph node
      metastases. Because the possibility of metastasis to the lymph nodes around the
      root of the superior mesenteric artery (which are removed only in a
      pancreatoduodenectomy) was judged to be low, pancreas-sparing duodenectomy was
      performed, with dissection of the pancreaticoduodenal lymph nodes. The proximal
      duodenum was transected between the second and third portions of the duodenum,
      and the distal end was cut in the jejunum at the portion of the first jejunal
      artery. Reconstruction was performed by end-to-side anastomosis between the
      duodenum and jejunum, using an end-to-end anastomosis instrument. Since the
      incidence of lymph node metastasis of leiomyosarcoma is low, resection of the
      head of the pancreas for extensive lymph node dissection does not always seem
      necessary. Pancreas-sparing duodenectomy can be a good option for a
      leiomyosarcoma in the third and fourth portions of the duodenum which does not
      invade the pancreas and is not accompanied by any apparent periduodenal lymph
      node metastases.

PMID- 10664294
TI  - Gallbladder torsion: case report and review of 245 cases reported in the Japanese
      literature.
AB  - We report here a case of torsion of the gallbladder in a 73-year-old woman. The
      patient was admitted to our hospital with right hypochondralgia. Ultrasonography
      and computed tomography demonstrated a distended gallbladder, with a multilayered
      wall, which contained no stones. Since the symptoms did not respond to
      antibiotics, laparotomy was performed. The gallbladder was found to be twisted
      around its pedicle and to be gangrenous. Cholecystectomy was performed, and the
      patient had an uneventful postoperative course. We also reviewed 245 cases
      reported in the Japanese literature. The clinical features of gallbladder
      torsion, which include low frequency of fever and jaundice, poor response to
      antibiotic therapy, and acute onset of abdominal pain, may be helpful in the
      differential diagnosis from acute cholecystitis. Moreover, a highly suggestive
      sign of gallbladder torsion observed by ultrasonography or computed tomography is
      a markedly enlarged "floating" gallbladder with a continuous hypoechoic line
      indicating edematous change in the wall.

PMID- 10664295
TI  - Double cancer - hepatocellular carcinoma and intrahepatic cholangiocarcinoma with
      a spindle-cell variant.
AB  - Intrahepatic cholangiocarcinoma (ICC) with a spindle-cell variant is very rare.
      We report here a surgical patient who had double cancer - hepatocellular
      carcinoma (HCC) and ICC with a spindle-cell variant. In this 70-year-old man, who
      had a history of hepatic resection for HCC about 2 years previously, two large
      discrete masses were identified in the right lobe of the liver. A right lobectomy
      of the liver was performed. Pathological findings revealed that one tumor was a
      typical HCC, and the other was ICC with sarcomatous lesions. Immunohistochemical
      examinations of the sarcomatous lesions in ICC demonstrated that some of the
      spindle cells were positive for keratin, epithelial membrane antigen, and
      vimentin, but negative for S-100 protein, desmin, and actin. From these findings,
      we concluded that the sarcomatous lesions of ICC were not a true sarcoma, but
      sarcomatous transformation of cholangiocarcinoma cells, that is, a spindle-cell
      variant of ICC.

PMID- 10664296
TI  - Right hepatic lobectomy for bile duct injury associated with major vascular
      occlusion after laparoscopic cholecystectomy.
AB  - A 57-year-old woman underwent laparoscopic cholecystectomy (LC) for
      cholelithiasis. Continuous bile leak was observed beginning on the first
      postoperative day. Postoperative endoscopic retrograde cholangiography revealed
      bile leak through the common hepatic duct, and severe stenosis of the hepatic
      confluence. A total of three percutaneous transhepatic biliary drainage (PTBD)
      catheters were inserted to treat obstructive jaundice and cholangitis. The
      patient was referred to our hospital for surgery 118 days after LC.
      Cholangiography through the PTBD catheters demonstrated a hilar biliary
      obstruction. Celiac arteriography revealed obstruction of the right hepatic
      artery, and transarterial portography showed occlusion of the right anterior
      portal branch. On the basis of the cholangiographic and angiographic findings, we
      performed a right hepatic lobectomy with hepaticojejunostomy to resolve the bile
      duct obstruction and address the problem of major vascular occlusion. The
      patient's postoperative recovery was uneventful and she remains well 25 months
      after hepatectomy. We discuss a treatment strategy for bile duct injury suspected
      after LC, involving early investigation of the biliary tree and prompt
      intervention.

PMID- 10664297
TI  - The GRAMMER european spine journal award

PMID- 10664298
TI  - Why the back of the child?
AB  - An international congress about "the back of children and teenagers and the
      prevention of backache" was held in March 1999 in Grenoble (France). Beside
      specific low back pain following progressive and growth diseases, special
      attention was paid to non-specific low back pain (LBP). Some epidemiological data
      show a high incidence of LBP during and after the rapid growth phase, with the
      concomitant possibility of continued or recurrent evolution. MRI studies reveal
      frequent signs of disc degeneration: they start after the growth phase, spread
      during adolescence and are often correlated with backache. An immunohistological
      study seems to confirm the presence of degenerative-type alterations and changes
      in collagen in the vertebral plates and nucleus of juvenile spine. These data
      must be confirmed, and their relation to natural history and prognosis of
      juvenile LBP have to be clarified by longitudinal studies.

PMID- 10664299
TI  - Non-specific low back pain in children and adolescents: risk factors.
AB  - Low back pain (LBP) among children and adolescents has become the subject of an
      increasing amount of literature over the last 15 years. This topic, which was
      considered almost insignificant less than two decades ago, was the focus of a
      recent international meeting organised in Grenoble (France) in March 1999. This
      review paper is the result of an literature update search performed by members of
      three groups which have been active in this field for many years. Current
      epidemiological data on LBP is summarized as well as the role of the major risk
      factors according to studies published in the principal peer reviewed journals
      interested in the topic.

PMID- 10664300
TI  - Low back pain in a population of school children.
AB  - A study was undertaken to analyse the prevalence of low back pain (LBP) and
      confounding factors in primary school children in the city of Antwerp. A total of
      392 children aged 9 were included in the study. All children completed a
      validated three-page questionnaire and they all underwent a specific lumbar spine
      oriented medical examination during their annual routine medical school control.
      This examination was performed by the city school doctors. The questionnaire was
      composed of easy "yes/no" questions and visual analogue scales. Statistical
      analysis was performed using Student's t-test and chi-squared test at the
      significance level P < 0.05. The prevalence of LBP was high. No gender difference
      was found. A total of 142 children (36%) reported having suffered at least one
      episode of LBP in their lives. Of these, 33 (23%) had sought medical help for LBP
      from a doctor or physiotherapist. Sixty-four percent of children reporting LBP
      said that at least one of their parents suffered from or complained of LBP. This
      was significantly higher than for the children who did not report having suffered
      LBP. The way in which the school satchel was carried (in the hand, on the back)
      had no bearing on the incidence of LBP. There was significantly more LBP in
      children who reported playing video games for more than 2 h per day, but this was
      not so for television watchers. The visual analogue scales concerning general
      well-being were all very significantly correlated with self-reported LBP, with
      children who reported LBP being more tired, less happy, and worse sleepers. Of
      the 19 clinical parameters taken down during the medical examination, only one
      was significantly more prevalent in the group of children reporting LBP: pain on
      palpation at the insertion site on the iliac crest of the ilio-lumbar ligament.
      From this study we can establish that there are few clinical signs that can help
      to single out school children with LBP.

PMID- 10664301
TI  - Risk factors for low back pain in a cohort of 1389 Danish school children: an
      epidemiologic study.
AB  - This study was designed as a cross-sectional questionnaire-based survey of low
      back pain (LBP) in 13- to 16-year-old Danish school children. The cohort
      consisted of 671 boys and 718 girls in eighth and ninth grade in 46 municipal
      schools in three counties of Sealand. All the pupils filled in a questionnaire
      with LBP as the main topic and were at the same time examined by the school
      doctors. The first part of the questionnaire contained questions about leisure
      time sports activity, TV watching, PC use, job in leisure time and smoking. The
      second part dealt with LBP in relation to frequency and severity, influence on
      daily living and use of the health system. The school doctor measured body height
      and weight, (BMI), degree of hypermobility and the tightness of the hamstring
      muscles. The results showed a cumulative life-time prevalence of LBP of 58.9%, a
      1-year prevalence of 50.8% and an increase in LBP prevalence of 6.4% from 14 to
      15 years of age, independent of gender. Fourteen percent (141 F, 54 M) fulfilled
      the criteria for general hypermobility and 12.2% (45 F, 124 M) had tightness of
      hamstring muscles of more than 40 degrees. Recurrent/continuous LBP in a moderate
      to severe degree was recorded in 19.4% of children (182 F, 88 M). This was
      positively correlated to female gender, BMI more than 25 kg/m(2), competitive
      sport for boys, poor physical fitness, daily smoking, heavy jobs in leisure time,
      increased use of the health system and reduced life quality. Stepwise logistic
      regression analysis indicates that female gender, daily smoking and heavy jobs
      are important associated factors for severe LBP in adolescents, with an observed
      probability of 46% if all factors are present. We don't know yet whether these
      factors are of any causal importance in the development of severe LBP.

PMID- 10664302
TI  - Sagittal static imbalance in myelomeningocele patients: improvement in sitting
      ability by partial and total gibbus resection.
AB  - The progression of kyphosis in myelomeningocele is independent of skeletal growth
      and requires early operative correction and stabilization to prevent a loss of
      sitting ability. In severe cases, only vertebrectomy makes it possible to achieve
      correction, stability and skin-closure without tension. In 14 patients with
      myelomeningocele gibbus, kyphectomy was performed, removing two vertebral bodies
      on average. The average kyphosis angle decreased from 128 degrees to 81 degrees,
      enabling most of the patients to participate again in social life by restoring
      wheelchair mobility. Nevertheless, a significantly higher complication rate was
      found compared to other correctional operations, lengthening the average hospital
      stay to 41 days. Special problems arose from trophic disorders of the skin and
      soft tissue and from the dystrophic muscles below the level of neural
      malfunction. In three cases, kyphosis reappeared cranial to the fused segments,
      requiring ventral stabilization. With respect to increasing kyphosis angle, an
      early intervention should be aimed at. A secondary operation can be necessary, if
      surgery is performed without taking care of the growth potential.

PMID- 10664303
TI  - Assessment of disc injury in subjects exposed to long-term whole-body vibration.
AB  - Long-term exposure to whole-body vibration is known to increase the risk of low
      back problems. The chain of events leading from repeated loading of the lumbar
      spine to back complaints and the exact nature of the vibration-induced damage
      are, however, obscure. Fluid in- and outflow as well as viscoelastic deformation
      are important aspects of the physiological function of the lumbar disc. Precision
      measurement of stature, termed 'stadiometry', has previously been applied in
      healthy subjects to document changes in disc height in relation to the load on
      the lumbar spine. The purpose of this study was to explore the relation between
      spinal loading and stature in a cohort of 20 subjects with long-term exposure to
      whole-body vibration. If the change of stature (and thus the change of disc
      height) caused by changes in spinal loading differed between exposed and normal
      subjects, this would point to vibration-induced changes in structure and material
      properties of the discs. For this purpose, four hypotheses were tested: (1) the
      viscoelastic deformation and fluid exchange of intervertebral discs during phases
      of spinal loading and unloading differs from normal; (2) the water content of
      lumbar discs of subjects exposed to long-term whole-body vibration deviates from
      normal; (3) the mean disc height of the lumbar spine depends on the total time of
      vibration exposure; (4) repeated loading influences trabecular bone density of
      vertebrae in the lumbar spine. A cohort of 20 operators of heavy earth-moving
      machinery was enrolled. Back complaints suspected to be due to long-term exposure
      (mean 17.6 +/- 2.1 years) to whole-body vibration and application for early
      retirement were the selection criteria used. Change of stature during a regular 8
      h shift and change of stature in standing, carrying and sitting activities were
      measured. The stadiometric investigations were supplemented by magnetic resonance
      imaging (MRI) of the lumbar spine to assess whether the water content of the
      discs exhibited deviations from normal. In addition, quantitative computed
      tomography (QCT) was performed to assess whether the trabecular bone density of
      the third lumbar vertebra deviated from normal. The results showed no significant
      difference in change of stature while standing, carrying or sitting between
      exposed machine operators and non-exposed operators. Likewise, MRI examinations
      revealed no significant differences in the water content of the discs averaged
      over the lumbar spine. In addition, QCT examinations revealed no significant
      difference in the trabecular bone density of the third lumbar vertebra. The study
      thus revealed no significant difference between a cohort with long-term exposure
      and non-exposed controls with respect to viscoelastic properties of discs as
      determined by stadiometry, average water content of lumbar discs and trabecular
      bone density of L3.

PMID- 10664304
TI  - The active straight leg raising test and mobility of the pelvic joints.
AB  - Objective signs to assess impairment in patients who are disabled by peripartum
      pelvic girdle pain hardly exist. The purpose of this study was to develop a
      clinical test to quantify and qualify disability in these patients. The study
      examined the relationship between impaired active straight leg raising (ASLR) and
      mobility of pelvic joints in patients with peripartum pelvic girdle pain,
      focusing on (1) the reduction of impairment of ASLR when the patient was wearing
      a pelvic belt, and (2) motions between the pubic bones measured by X-ray
      examination when the patient was standing on one leg, alternating left and right.
      Twenty-one non-pregnant patients with peripartum pelvic girdle pain in whom pain
      and impairment of ASLR were mainly located on one side were selected. ASLR was
      performed in the supine position, first without a pelvic belt and then with a
      belt. The influence of the belt on the ability to actively raise the leg was
      assessed by the patient. Mobility of the pelvic joints was radiographically
      visualized by means of the Chamberlain method. Assessment was blinded. Ability to
      perform ASLR was improved by a pelvic belt in 20 of the 21 patients (binomial two
      tailed P = 0.0000). When the patient was standing on one leg, alternating the
      symptomatic side and the reference side, a significant difference between the two
      sides was observed with respect to the size of the radiographically visualized
      steps between the pubic bones (binomial two-tailed P = 0.01). The step at the
      symptomatic side was on average larger when the leg at that side was hanging down
      than when the patient was standing on the leg at that side. Impairment of ASLR
      correlates strongly with mobility of the pelvic joints in patients with
      peripartum pelvic girdle pain. The ASLR test could be a suitable instrument to
      quantify and qualify disability in diseases related to mobility of the pelvic
      joints. Further studies are needed to assess the relationship with clinical
      parameters, sensitivity, specificity and responsiveness in various categories of
      patients. In contrast with the opinion of Chamberlain, that a radiographically
      visualized step between the pubic bones is caused by cranial shift of the pubic
      bone at the side of the standing leg, it is concluded that the step is caused by
      caudal shift of the pubic bone at the side of the leg hanging down. The caudal
      shift is caused by an anterior rotation of the hip bone about a horizontal axis
      near the sacroiliac joint.

PMID- 10664305
TI  - Reviewer's comment.

PMID- 10664306
TI  - Recurrent pain after lumbar discectomy: the diagnostic value of peridural scar on
      MRI.
AB  - The association between peridural scarring and recurrent pain after lumbar
      discectomy is much debated. A recently published study found that patients with
      extensive peridural fibrosis were 3.2 times more likely to experience recurrent
      radicular pain than those with less extensive scarring. This finding may lead to
      an overestimation of peridural fibrosis in clinical practice. In a retrospective
      study we analyzed the records of 53 patients who underwent a lumbar MRI because
      of recurrent pain after first unilateral microdiscectomy. Patients were
      classified as those with radicular or non-radicular pain according to history and
      clinical findings. The diagnosis was confirmed by spinal anesthetic block. The
      extension of scarring was compared between the two groups of patients. The amount
      of epidural fibrosis was examined on contrast-enhanced MRI in axial slices
      subdivided into four quadrants. The amount of fibrosis was divided into four
      stages in each affected quadrant. We found no differences regarding the amount of
      peridural fibrosis between patients with radicular pain and patients with non
      radicular pain. We conclude that the extent of peridural scarring as defined by
      MRI is of minor value in the differential diagnosis of recurrent back and leg
      pain after lumbar microdiscectomy.

PMID- 10664307
TI  - Prolonged low-back pain in young athletes: a prospective case series study of
      findings and prognosis.
AB  - We investigated the prognosis of low-back pain and the association of clinical
      symptoms and anatomic findings among young athletes. Consecutive patients, aged
      between 12 and 18 years, who had low-back pain that had interfered with their
      training for at least 4 weeks were included in the case series. All the patients
      participated in a standardized interview and clinical examination, and plain
      radiographs and magnetic resonance images were also obtained. Most patients also
      participated in technetium bone scan examination. In 15 out of 19 subjects there
      were anatomic abnormalities that corresponded with the location and type of
      clinical symptoms. Twelve subjects had changes in the disk-vertebral end plate
      complex and eight had a positive bone scan indicative of posterior vertebral arch
      stress reaction. Six out of eight boys and two out of 11 girls had stress
      reaction (P = 0.043). Restriction of painful activities was recommended to all
      subjects, restriction of activities and the use of a dynamic low-back brace for
      the first 3 months was recommended to patients with posterior vertebral arch
      stress reaction. The self-reported intensity of low-back pain (scale 0-100) among
      all the patients was 69 +/- 16 (mean +/- SD) at baseline and 18 +/- 21 at the 1
      year follow-up (P < 0.0001). In conclusion, the reasons for prolonged back pain
      among young athletes are usually established by imaging studies. A knowledge of
      anatomic abnormalities may help in tailoring training programmes and avoiding the
      progression of changes during growth. Simple restriction of painful activities
      usually leads to good recovery.

PMID- 10664308
TI  - Recombinant bone morphogenetic protein-7 as an intracorporal bone growth
      stimulator in unstable thoracolumbar burst fractures in humans: preliminary
      results.
AB  - The study presented here is a pilot study in five patients with unstable
      thoracolumbar spine fractures treated with transpedicular OP-1 transplantation,
      short segment instrumentation and posterolateral fusion. Recombinant bone
      morphogenetic protein-7 in combination with a collagen carrier, also referred to
      as OP-1, has demonstrated ability to induce healing in long-bone segmental
      defects in dogs, rabbits and monkeys and to induce successful posterolateral
      spinal fusion in dogs without need for autogenous bone graft. Furthermore OP-1
      has been demonstrated to be effective as a bone graft substitute when performing
      the PLIF maneuver in a sheep model. Five patients with single-level unstable
      burst fracture and no neurological impairment were treated with intracorporal OP
      1 transplantation, posterior fixation (USS) and posterolateral fusion. One
      patient with osteomalacia and an L2 burst fracture had an additional
      intracorporal transplantation performed proximal to the instrumented segment,
      i.e. OP-1 into T 12 and autogenous bone into T 11. Follow-up time was 12-18
      months. On serial radiographs, Cobb and kyphotic angles, as well as anterior,
      middle and posterior column heights, were measured. Serial CT scans were
      performed to determine the bone mineral density at fracture level. In one case,
      radiographic and CT evaluation after 3 and 6 months showed severe resorption at
      the site of transplantation, but after 12 months, new bone had started to fill in
      at the area of resorption. In all cases there was loss of correction with regard
      to anterior and middle column height and sagittal balance at the latest follow
      up. These preliminary results regarding OP-1 as a bone graft substitute and
      stimulator of new bone formation have been disappointing, as the OP-1 device in
      this study was not capable of inducing an early sufficient structural bone
      support. There are indications to suggest that OP-1 application to a fracture
      site in humans might result in detrimental enhanced bone resorption as a primary
      event.

PMID- 10664309
TI  - Reconstruction of anterior iliac crest bone graft donor sites: presentation of a
      surgical technique.
AB  - This study is a prospective evaluation of the reconstruction of anterior iliac
      crest bone graft donor sites using a technique developed by the authors. We
      present the technique and the initial results obtained with its use in 15
      patients followed up for a period ranging from 6 to 16 months. Reconstruction of
      the iliac crest is performed using a rib, which is removed by an anterior
      approach to the spine. The rib is divided into two segments, which are fitted
      into the defect created in the iliac crest after removal of the bone graft.
      Clinical evaluation of the patients found a good cosmetic appearance of the
      reconstruction site, and the rib segments used showed good radiologic
      integration. Partial resorption of the segments was observed in two patients,
      with no effects on the cosmetic result.

PMID- 10664310
TI  - Short segment fixation of thoracolumbar burst fractures without fusion.
AB  - There continues to be controversy surrounding the management of thoracolumbar
      burst fractures. Numerous methods of fixation have been described for this
      injury, but to our knowledge, spinal fusion has always been part of the
      stabilising procedure, whether this involves an anterior or a posterior approach.
      Apart from an earlier publication from this centre, there have been no reports on
      the use of internal fixation without fusion for this type of fracture. The aim of
      the study was to determine the outcome of patients with thoracolumbar burst
      fractures who were treated with short segment pedicle screw fixation without
      fusion. This is a retrospective review of 28 consecutive patients who had short
      segment pedicle screw fixation of thoracolumbar burst fractures without fusion
      performed between 1990 and 1993. All patients underwent a clinical and
      radiological assessment by an independent observer. Outcome was measured using
      the Low Back Outcome Score. The minimum follow-up period was 2 years (mean 3.1
      years). Fifty percent of patients achieved an excellent result with the Low Back
      Outcome Score, while 12% were assessed as good, 20% fair and 16% obtained a poor
      result. The only significant factor affecting outcome was the influence of a
      compensation claim (P < 0.05). The implant failure rate (14% of patients) and the
      clinical outcome was similar to that from series where fusion had been performed
      in addition to pedicle screw fixation. The results of this study support the view
      that posterolateral bone grafting is not necessary when managing patients with
      thoracolumbar burst fractures by short segment pedicle screw fixation.

PMID- 10664311
TI  - Reviewer's comment.

PMID- 10664312
TI  - Traumatic total axial reversal of the thoracic vertebral body.
AB  - Numerous vertebral fracture patterns have been reported in the literature. We
      present the case of a patient who sustained severe trauma to the back that
      resulted in a very unusual and not previously reported rotational injury
      consisting in complete 180 degrees rotation of the T6 vertebral body along a
      vertical axis, with only limited anteroposterior and lateral displacement. An
      unsuspected aortic tear resulted in severe evolution with fatal outcome following
      surgical attempt. The aetiology of such displacement is unknown. The possibility
      of late vascular complications should be kept in mind while treating thoracic
      spine fractures with rotational displacement.

PMID- 10664313
TI  - Cervical osteotomy for ankylosing spondylitis: an innovative variation on an
      existing technique.
AB  - Ankylosing spondylitis can produce severe fixed flexion deformity in the cervical
      spine. This deformity may be so disabling that it interferes with forward vision,
      chewing, swallowing and skin care under the chin. The only treatment available is
      an extension osteotomy of the cervical spine. Existing techniques of cervical
      osteotomy may be associated with risk of neurological injury. We describe a
      variation on an existing technique, which provides a controlled method of
      reduction at the osteotomy site, eliminating sagittal translation. The method
      employs a modular posterior cervical system consisting of lateral mass and
      thoracic pedicle screws linked to titanium rods. Our technique substitutes the
      titanium rod with a temporary malleable rod on one side, allowing controlled
      reduction of the osteotomy as this rod bends and slides through the thoracic
      clamps. Once reduction is complete definitive contoured rods are inserted to
      maintain the correction while fusion takes place. This method appears less
      hazardous by eliminating sagittal translation, and may reduce the risk of
      neurological injury during surgery. It achieves rigid internal fixation,
      obviating the need for a halo vest in the postoperative period.

PMID- 10664314
TI  - Antioxidant therapy and streptozotocin-induced diabetes in pregnant rats.
AB  - The aim of our study was to analyse the effect of chronic hyperglycaemia on lipid
      peroxidation and scavenging enzyme activity in pregnant animals and their
      offspring supplemented and not supplemented with vitamin E - a natural
      antioxidant. Thirty pregnant female Wistar rats were used in our experiments.
      Diabetes was induced on day 7 of pregnancy using a single does of streptozotocin
      (40 mg/kg). Diabetic animals were divided into two equal groups: vitamin E
      supplemented and those fed with standard diet. Our controls consisted of 15
      healthy rats. On day 1 after delivery homogenates of maternal liver and uterus as
      well as neonatal lungs and liver were prepared. Then the following parameters
      were measured: malondialdehyde (MDA) concentrations in the homogenates and blood
      serum, glutathione (GSH) levels, the activity of CuZn superoxide dismutase (SOD)
      and glutathione peroxidase (GPx) (Bioxytech, France). Statistical analysis was
      performed using Mann-Withney U test. The neonates of diabetic rats were smaller
      than those from healthy rats and serum glucose concentration was markedly higher
      in diabetic animals, both in mothers and neonates. MDA levels increased
      significantly, whereas GSH content and SOD as well as GPx activities were
      markedly diminished in diabetic pregnant rats and their offspring in comparison
      with the control group. In animals supplemented with tocopherol, MDA
      concentrations declined significantly, GSH contents and SOD activities were
      markedly elevated in almost all types of tissues studied, whereas glutathione
      peroxidase remained suppressed. Our results suggest that diabetic pregnant rats
      and their neonates are exposed to oxidative stress (OS), but vitamin E
      supplementation could in part reduce the imbalance between uncontrolled reactive
      oxygen species generation and scavenging enzyme activity, and may potentially
      serve as a useful prophylactic factor against OS development:

PMID- 10664315
TI  - Mechanism of fat-induced attenuation of glucose-induced insulin secretion from
      mouse pancreatic islets.
AB  - In order to investigate the mechanism behind fat-induced inhibition of glucose
      induced insulin secretion a selection of enzymes that may participate in
      regulation of pancreatic islet glucose oxidation was studied in islets isolated
      from mice that had been fed on a laboratory chow diet or on a high-fat diet for
      10-12 weeks. At 20 mmol/L glucose production of (14)CO(2) from [U-(14)C]-glucose
      was decreased 50% in islets from fat-fed mice. At 3.3 mmol/L glucose the glucose
      oxidation rate was similar in the two groups. The fatinduced decrease in glucose
      oxidation rate was correlated with a 35% decrease in the maximal glucokinase
      activity. The K(m) for glucose was unchanged. No differences between the diet
      groups were found in the activities of hexokinase, phosphofructo-1-kinase,
      glucose 6-phosphatase or mitochondrial glycerophosphate dehydrogenase. After
      preincubation with 20 mmol/L glucose the activity of cytosolic Ca(2+)-independent
      as well as Ca(2+)-dependent phospholipase A(2) was unchanged by fat-feeding.
      However, the activity of lysophospholipase was significantly increased by fat
      feeding, which may result in lowered concentrations of islet
      lysophosphatidylcholine (lysoPC). It is concluded that in fat-induced diabetic
      animals a decrease in islet glucokinase may contribute considerably to the
      decrease in islet glucose oxidation rate. Furthermore, the study raises the
      possibility that changes in islet lysoPC may contribute to the fat-induced
      attenuation of glucose-induced insulin secretion.

PMID- 10664316
TI  - Relation of fetal growth to maternal responses to oral glucose tolerance test
      throughout gestation.
AB  - Fetal growth is dependent on transplacental supply of fuels. We aimed to assess
      the effect of serial changes in maternal glucose tolerance and insulin secretion
      with advancing pregnancy on maternal-fetal outcomes. Sixty-nine healthy pregnant
      women were studied over the course of gestation for glucose tolerance, by oral
      glucose tolerance test (OGTT), and hemoglobin A(1c) (HbA(1c)), fetal intrauterine
      growth (by ultrasound) and pregnancy outcome. Seven women had an abnormal OGTT in
      the third trimester developing gestational diabetes mellitus (GDM), but none of
      the 12 mothers of large babies (> 3.9 kg) had GDM: the former had the highest
      post-load glycemic increment, despite an apparently 'normal' insulin secretory
      response, the latter showed the lowest post-load glucose increase in the face of
      the lowest insulinemic response. Neonatal body weight correlated with maternal
      gestational weight gain, placental weight, third trimester ratio of incremental
      plasma insulin and glucose integrated areas under the curve and first and second
      trimester HbA(1c) levels. Fetal growth indices (femur length, biparietal diameter
      and abdominal circumference) were correlated with both HbA(1c) and 2h OGTT. Fetal
      growth rate is confirmed as being associated with maternal glycemic equilibrium,
      but one of the main determinants of high infant birthweight seems to be an
      enhanced maternal insulin sensitivity, accompanied by remarkable gestational
      weight gain.

PMID- 10664317
TI  - Impact of the 1997 American Diabetes Association criteria on classification of
      glucose intolerance among Kuwaitis below 50 years of age.
AB  - Type 2 (non-insulin-dependent) diabetes is emerging as a leading chronic non
      communicable disease among the adult Kuwaiti population. Based on the World
      Health Organization and similar reports the projected estimates for subjects
      suffering from type 2 diabetes by the years 2000 and 2010 show a striking
      tendency to high rates of the disease in our area. We report the prevalence rates
      of glucose intolerance among a relatively young adult Kuwaiti population below 50
      years of age and the effect of implementing the recent 1997 American Diabetes
      Association diagnostic criteria on the frequency of type 2 diabetes, impaired
      glucose tolerance and impaired fasting glucose among this group. The overall
      prevalence rate for the three categories of glucose intolerance reached as high
      as 15.8% (95% CI, 14.2 to 17.4). Age, though all subjects were below 50 years,
      parental history of type 2 diabetes, diastolic blood pressure and serum
      triglycerides were found to be significant associated risk factors for the
      development of type 2 diabetes. Obesity was an apparent significant factor
      associated with the three forms of glucose intolerance (p < 0.001). Obesity and
      physical inactivity were documented in both non-diabetic and more so in diabetic
      Kuwaiti adults, which should form the basis of any immediate intervention
      programme. An integrated approach to the prevention of the described critical
      risk factors associated with type 2 diabetes is highly recommended in Kuwait.
      Research, focused on genetics of type 2 diabetes in the highly susceptible
      Kuwaiti population, should be planned.

PMID- 10664318
TI  - Comparison between measured and predicted resting metabolic rate in moderately
      active adolescents.
AB  - The aim of this study was to check the validity of predictive equations for the
      calculation of resting metabolic rate (RMR) in moderately active adolescents. The
      RMR was measured in a sample of 25 healthy 15.5-18.2-year-old boys practicing
      soccer. The RMR was assessed by indirect calorimetry for 30 min following an
      overnight fast. Body composition was estimated from skinfold thickness
      measurements. Among the available equations to predict RMR, we decided to use
      those a of Molnar et al., Harris-Benedict, Schofield, and Cunningham. Measured
      and predicted values were compared by means of a one-way ANOVA. Also the Bland
      Altman test was performed in order to evaluate the accuracy of the prediction
      equations compared to the measured value. The measured RMR was found to be 1834
      +/- 160 kcal/day (mean +/- SD), while the Molnar et al., Schofield, Harris
      Benedict, and Cunningham predicted values were 1707 +/- 78, 1866 +/- 89, 1779 +/-
      84 and 1830 +/- 87 kcal/day, respectively. On average, compared to the measured
      values only the Molnar et al. equation differed significantly. On an individual
      basis, all the equations demonstrated considerable variability between measured
      and predicted RMRs. The predicted values also differed significantly. As regards
      the moderately active subjects (16-18 years old), we recommend the use of the
      Schofield equation, based on simple anthropometric parameters and also that of
      Cunningham, even if the estimation or measurement of fat-free mass may be
      cumbersome for everyday pediatric use.

PMID- 10664319
TI  - Sex- and BMI-related differences in risk factors for coronary artery disease in
      patients with type 2 diabetes mellitus.
AB  - There are contrasting data about the relationship between obesity and
      macrovascular complications in type 2 diabetes mellitus, and it is not known if
      risk factors for coronary artery disease are different in normal weight and
      overweight or obese patients. All 2113 patients with type 2 diabetes mellitus
      referring to the Diabetic Clinic of Asti were studied. Patients were divided into
      tertiles of body mass index, according to their sex (BMI < 26.9; >/= 26.9 and <
      31.4; >/= 31.4 kg/m(2) for females and BMI < 25.7; >/= 25.7 and < 28.8; >/= 28.8
      kg/m(2) for males). Age, BMI, duration of diabetes, blood pressure, HbA(1c) total
      cholesterol, HDL-cholesterol, LDL-cholesterol, and prevalence of insulin
      treatment and hypertension were higher in females, whereas exercise, alcohol
      intake, smoking habits and prevalence of dyslipidemia were higher in males. An
      increase in BMI was associated with an increase in HbA(1c), number of
      cigarettes/day, blood pressure, triglycerides, C-peptide, prevalence of
      hypertension and dyslipidemia, and with a decrease in age, duration of diabetes
      and HDL-cholesterol values. In spite of an apparently worse cardiovascular risk
      profile, females showed a 50% lower prevalence of CAD than males and the
      prevalence of CAD was not significantly different in obese compared to other BMI
      categories. Multiple logistic regression showed that risk factors for CAD were
      different in males and females and similar in the lower tertiles of BMI, while
      different in the highest. In obese females, risk factors for CAD were age,
      reduced HDL-cholesterol and increased HbA(1c) levels; in males they were years of
      smoking and duration of diabetes. These data suggest that in type 2 diabetes,
      risk factors for CAD are different in the two sexes and in patients with the
      highest BMI compared to the normal and overweight subjects; blood glucose control
      and duration of diabetes seem more important than conventional cardiovascular
      risk factors in obese patients.

PMID- 10664320
TI  - Circulating tissue-type plasminogen activator and plasminogen activator inhibitor
      type 1 in proliferative diabetic retinopathy: a pilot study.
AB  - Several haemostatic abnormalities are associated with proliferative diabetic
      retinopathy. While abnormalities in plasma fibrinolytic activity have been
      described in diabetic retinopathy, platelets (a rich source of plasminogen
      activator inhibitor type 1, PAI-1) have received little attention. As a result,
      little is known about the fibrinolytic potential of circulating whole blood in
      diabetic retinopathy. The concentrations of tissue-type plasminogen activator (t
      PA) and of its fast-acting inhibitor. PAI-1 were measured in plasma from eight
      patients with type 1 diabetes complicated by proliferative retinopathy, and from
      eight patients with type 1 diabetes and background or no retinopathy, matched for
      age, sex and duration of diabetes. The concentration of PAI-1 in platelets was
      also measured. The ratio of t-PTA to PAI-1 in plasma was significantly higher in
      patients with proliferative retinopathy than in those without (0.66 vs. 0.37, p <
      0.02). The average quantity of PAI-1 per platelet was significantly lower in the
      group with proliferative retinopathy (0.33 vs. 0.50 ng/10(6) platelets, p <
      0.02). These data suggest that among patients with type 1 diabetes, total
      circulating fibrinolytic potential is higher in those with proliferative
      retinopathy.

PMID- 10664321
TI  - Prospective study of preincisional intraparietal single-dose ceftriaxone in
      reducing postoperative wound infection in type I and II diabetic patients.
AB  - The risk of wound contamination in diabetic patients after abdominal operations
      is well known. Preincisional intraparietal injection of antibiotics is used for
      the prophylaxis of postoperative surgical infections. Whether topically injected
      antibiotics remain primarily in the surgical wound or are systematically absorbed
      is uncertain, however. The pharmacokinetics of a preincisional, intraparietal
      injection of 2 g ceftriaxone was studied in 50 consecutive diabetic (type I and
      II) patients undergoing abdominal surgery, with determination of serum, wound
      tissue, and wound fluid antibiotic concentrations. Preincisional intraparietal
      injection of ceftriaxone resulted in high antibiotic concentrations in the wound
      fluid. The highest plasma concentrations were achieved at 1.5 h (98.45 microg/ml,
      SD = 14.54). Plasma concentrations exceeded the minimal inhibitory concentrations
      of most aerobic gram positive and gram negative organisms with the exception of
      Pseudomonas aeruginosa, Acinetobacter species, and Streptococcus faecalis for 24
      h (10.35 microg/ml, SD = 4.10). No long-lasting or general complications arose in
      any of the diabetic patients. Our results suggest that preincisional
      intraparietal administration of ceftriaxone for prophylaxis of wound sepsis in
      diabetic patients with high risk of infection is effective.

PMID- 10664322
TI  - Mitochondrial DNA mutation at np 3243 in a family with maternally inherited
      diabetes mellitus.
AB  - Mitochondrial DNA (mtDNA) gene defects may play a role in the development of
      maternally inherited diabetes mellitus and deafness (MIDD). A family from
      Southern Italy who showed maternal transmission of type 2 diabetes mellitus with
      three individuals affected is described. A 10.4 kb deletion and mutations at
      nucleotide positions (np) 3243, 7445 and 11778 in the mtDNA of six relatives were
      sought. The mitochondrial np 3243 mutation of the tRNA Leu (UUR) gene was
      identified in a boy affected by optic atrophy and mental retardation, as well as
      in his diabetic mother. No other mutations or deletions were found. Our study
      points out the variable phenotypic expression of the np 3243 mtDNA mutation. This
      may suggest the presence of other mitochondrial or nuclear mutations required to
      modulate the phenotype. A clinical and metabolic follow-up of all family members
      was necessary to understand the role of the np 3243 mutation, especially in one
      child affected by optic atrophy and mental retardation. Further studies will be
      aimed at investigating the prevalence of mutations and deletions of mtDNA in type
      2 diabetes mellitus.

PMID- 10664323
TI  - Prevalence of diabetes mellitus among workers in Israel: a nation-wide study.
AB  - The prevalence of diabetes mellitus in Israel has been described in various
      populations and ranges from 4.1% to 8.9%. However, the large immigration wave in
      the late 1980s and early 1990s could have affected the previous estimates.
      Moreover, data from the United states and other countries report a significant
      proportion of undiagnosed diabetes. The main purpose of this study was to
      estimate the prevalence and the ratio of undiagnosed/diagnosed diabetes in a
      large sample of workers. The study involved interviews, anthropometric
      measurements at the work site, and blood glucose determinations (casual
      capillary, fasting, and when necessary, 2 h after a 75-gram oral glucose load).
      Diabetes and impaired glucose tolerance (IGT) were diagnosed according to WHO
      criteria. Five thousand four hundred sixteen workers participated in the study.
      Three hundred ten reported to be known diabetics (5.7%), 35 (0.7%) were diagnosed
      as diabetic during the survey, and an additional 93 (1.8%) were classified as
      IGT. The ratio undiagnosed/diagnosed diabetes was therefore 1:10. Extrapolation
      of these results produced an estimate of diabetes prevalence in Israel of 10%
      among people over age 40 years. It seems that in the Israeli health care system,
      based on universal health insurance and easy access to primary care, the
      proportion of undiagnosed diabetes is lower than that described in other
      countries.

PMID- 10664324
TI  - Age-related alterations in liver mitochondrial bioenergetics of diabetic Goto
      Kakizaki rats.
AB  - Type 2 diabetes mellitus is one of the most common chronic metabolic diseases in
      man. Due to long-term complications of the disease, severely decreasing the
      quality of life of diabetic patients, early interventions to obviate the risk of
      complications are of major importance. Therefore, diabetic animal models are of
      major importance in research for interventional treatment of type 2 diabetes. In
      this work we investigated the possible alterations in mitochondrial energetic
      metabolism of Goto-Kakizaki (GK) rats during the progression of the disease,
      since glucose metabolism is closely related to intracellular ATP content. For
      that reason, respiratory indexes (state 4, state 3, RCR and ADP/O) were evaluated
      either in the presence of NAD- or FAD-linked substrates (glutamate + malate and
      succinate, respectively) in mitochondrial preparations of GK and control rats
      with 8, 12, 26 and 52 weeks of age. Until the age of 1 year (52 weeks) we found
      no impairment of mitochondrial respiratory indexes both in the presence of
      glutamate + malate and succinate. In conclusion, this study indicates that GK rat
      is a good model for studying the initial events of diabetes, since it presents no
      impairment of liver mitochondrial functions during the first year of life,
      contrasting clearly with pharmacological induced diabetes.

PMID- 10664325
TI  - Levels of carbonyl groups in plasma proteins of type 2 diabetes mellitus
      subjects.
AB  - Carbonyl groups result from protein oxidation and their level in tissues and
      plasma is a relatively stable marker of oxidative damage. Carbonyl content of
      plasma proteins in 43 type 2 diabetic subjects, 30-87 years of age (25 males and
      18 females) and in 20 age-matched healthy controls (31-89 years of age, 12 males
      and 8 females) was evaluated with 2,4-dinitro-phenyl-hydrazine method. In both
      groups, lipids, tocopherols (HPLC) and glycated hemoglobin (HPLC) were studied.
      Fasting blood glucose, glycated hemoglobin and lipids were significantly higher
      in the diabetic group; carbonyl content and alpha-tocopherol were slightly, but
      not significantly higher in the diabetic group (1.06 +/- 0.03 vs. 0.97 +/- 0.04
      nmol/mg protein, 27. 07 +/- 2.82 vs. 31.55 +/- 2.11 micromol/l, respectively).
      Significant relationships between age and lipids, alpha-tocopherol and proteins
      were found in controls, but not in diabetics. Alpha-tocopherol correlated with
      lipids in both groups; glycated hemoglobin, a marker of glycemic control, was
      related to lipids, alpha-tocopherol and protein carbonyl groups in diabetics,
      while only the correlation with carbonyls was found in controls. These results
      suggest that impaired glycemic control is connected to protein oxidation.
      Glycation cascade also releases free radicals, becoming responsible for further
      oxidative attacks. In conclusion, increased oxidative stress, if any, in the
      diabetic group, is doubtlessly induced by hyperglycemia, and the tocopherols are
      not seriously affected by a worsening of the metabolic control.

PMID- 10664326
TI  - Neonatal pancreas transplantation and liver enzyme activities in diabetic mice.
AB  - The aim of this study was to estimate the influence of transplantation of
      neonatal pancreas from singenic donors on glucose production and utilisation in
      alloxan diabetic mice. The alloxan diabetic mice, 20 days after alloxan, received
      neonatal pancreas from singenic donors under the kidney capsule. Enzymes involved
      in glycolytic, gluconeogenic, lipogenic and pentose phosphate pathway were
      examined in liver of experimental mice. The fructose-1, 6-diphosphatase (FDPase)
      activity in the liver of diabetics increased for about 60%, while the pyruvate
      inase (PK) and ATP-citrate lyase (CEE) activity decreased for about 40% of the
      values in the healthy mice. The values of glucose-6-phosphate dehydrogenase (G6P
      DH) and 6-phosphogluconate dehydrogenase (6-PGDH) were not statistically
      different in diabetic liver compared with the liver off healthy animals. After
      pancreas transplantation some of diabetic animals become normoglycaemic, while
      the others remained hyperglycaemic. The FDPase activity in hyperglycaemic
      diabetic recipients was similar to those in diabetic mice that did not received
      transplant, while in normoglycaemic recipients the FDPase activity returned to
      the normal values. However, the activities of PK and CCE in hyperglycaemic
      recipients were similar to those in healthy animals, while in normogglycaemic
      recipients the enzyme activities were much higher. Results obtained showed that
      glycolytic, gluconeogenic and lipogenic enzyme activities in the liver of
      normoglycaemic mice that received pancreas transplant reached approximate the
      physiological values within 30 days after transplantation.

PMID- 10664327
TI  - No relationship between cerebral blood flow velocity and cerebrovascular reserve
      capacity and contemporaneously measured glucose and insulin concentrations in
      diabetes mellitus.
AB  - Blood glucose and insulin concentrations have been reported to influence cerebral
      hemodynamics. We studied the relationship between actual blood glucose and
      insulin concentrations and resting cerebral blood flow velocity in the middle
      cerebral artery and cerebrovascular reserve capacity after acetazolamide
      stimulation. Thirty-six insulin-dependent diabetic patients in a state of good
      glycemic control were studied. Blood samples were taken for determination of
      glucose and insulin concentrations. Subsequently we measured resting cerebral
      blood flow velocities in supine position using transcranial Doppler, administered
      1 g acetazolamide intravenously, and repeated the measurements after 5, 10, 15
      and 20 minutes. Cerebrovascular reserve was calculated as the maximal percent
      increase after acetazolamide stimulation. Multiple regression was used for
      statistical analysis. Blood glucose levels were not correlated with resting blood
      flow velocity (R = 0.21, p = 0.22) nor cerebrovascular reserve capacity (R =
      0.17, p = 0.32). Similarly, no correlation was found between insulin
      concentrations, resting cerebral blood flow velocity (R = 0.24, p = 0.22) and
      cerebrovascular reserve (R = 0.26, p = 0.24). Studying patients with long-term (>
      10 years) and short-term (</= 10 years) disease duration yielded the same lack of
      correlation. We conclude that there is no significant correlation between
      contemporaneously measured glucose and insulin concentrations and either cerebral
      blood flow velocity or cerebrovascular reserve capacity in the middle cerebral
      artery in type 1 diabetic patients with good control.

PMID- 10664328
TI  - The effect of cadmium on visual evoked potentials in alloxane-induced diabetic
      rats: relation to lipid peroxidation.
AB  - Fifty-two healthy male Swiss albino rats, aged three months, were used in this
      study. They were divided into four groups: control (c), diabetic (D), cadmium
      (Cd), and diabetic + Cd (D+Cd). A diabetic condition was induced in D and D + Cd
      groups by administration of alloxane (5 mg/100 g). After this treatment, Cd and D
      + Cd groups were injected intraperitoneally with CdCl(2) (2 mg/kg week). At the
      end of the 2-month experimental period, flash visual evoked potentials (FVEPs) of
      the four groups were recorded with disk electrodes attached with electrode paste
      0.5 cm in front of and behind the bregma. The mean latencies off the P(1), N(1),
      P(2), N(2) and P(3) components were significantly prolonged in the diabetic group
      compared with the control group. The mean latencies of P(3) in the D + Cd group
      and of P(1) and P(3) in the Cd group were longer than those of the control group.
      P(2)N(2) amplitude of Cd and D + Cd groups were significantly increased compared
      with the control group. On the other hand, thiobarbituric acid-reactive
      substances (TBARS) were determined as an indicator of lipid peroxidation. Our
      data showed that Cd treatment and diabetic condition caused a significant
      increase of lipid peroxidation in kidney, brain, retina and lens.

PMID- 10664329
TI  - 19th workshop of the study group on artificial insulin delivery systems, pancreas
      and islet transplantation (AIDSPIT) of the european association for the study of
      diabetes (EASD).Igls, austria, january 23-25, 2000

PMID- 10664330
TI  - Cytokine and hormonal responses in laparoscopic-assisted colectomy and
      conventional open colectomy.
AB  - Interleukin-6 (IL-6) is an important mediator of the acute phase response and a
      sensitive marker of tissue damage. This study was conducted to investigate the
      fluctuation of serum cytokine and hormonal levels during the perioperative period
      after laparoscopic-assisted colectomy (LAC), and the data were compared with
      those after conventional open colectomy (OPEN). The subjects comprised eight
      patients who underwent OPEN and eight who underwent LAC. Blood samples were
      obtained by peripheral vein puncture before the induction of anesthesia, then 2,
      4, 6, 8, 24, 48, and 72 h after skin incision to measure the levels of serum IL
      6, adrenocorticotropic hormone (ACTH), cortisol, and antidiuretic hormone (ADH).
      The level of serum IL-6 increased significantly during the perioperative course
      in both groups; however, the level 4 h after the commencement of surgery and the
      peak level were significantly lower in the LAC group than in the OPEN group (P <
      0.05). Plasma ACTH, cortisol, and ADH rapidly increased in both groups, but there
      was no significant difference between them. The IL-6 levels in collected ascites
      samples were not significantly different between the two groups. The changes in
      serum IL-6 levels indicate that LAC is less invasive than conventional open
      colectomy. These findings corresponded well with the clinical courses of the
      patients who underwent the two types of operations.

PMID- 10664331
TI  - A brief course of colon preparation with oral antibiotics.
AB  - We carried out a prospective clinical trial of colon preparation with a regimen
      of oral antibiotics starting on the day before surgery. The patients were
      assigned to one of two groups consisting of either a mechanical preparation alone
      group (group 1, 45 cases) or a mechanical bowel preparation with oral antibiotics
      group (group 2, 38 cases). Group 2 received kanamycin and metronidazole three
      times on the day before surgery. Cefmetazole was administered for 3 consecutive
      days as prophylaxis in both groups. In a study using intraoperative mucosal
      swabs, the rates of group 2 patients with cultures yielding anaerobes or Gram
      negative bacteria were significantly lower than those of group 1. There were no
      significant differences in the rates of patients with cultures yielding fungi or
      Gram-positive organisms. The positive culture rate in the peritoneal fluid of
      group 1 was also higher than that of group 2 (40%, 16%, P < 0.05). The surgical
      site infection rate was 18% in group 1 and 13% in group 2. Organisms isolated
      from the sites of postoperative infections were not identical with those from the
      peritoneal fluid. This relatively brief course preparation minimized the
      emergence of resistant strains. However, in spite of the colonic bacterial burden
      and the intraoperative inoculation in the patients with mechanical cleansing
      alone, their incidence of subsequent infections was comparable to that of
      patients who were administered oral antibiotics provided that the prophylactic
      antibiotic was administered for 3 days after surgery.

PMID- 10664332
TI  - Immunohistochemical studies of colorectal cancers that developed following pelvic
      irradiation.
AB  - Radiation therapy is believed to be a predisposing factor in the development of
      carcinoma. During the period from 1974 to 1997, we treated five colorectal
      cancers in four patients who had undergone pelvic irradiation for cervical
      cancer. Radiation-induced changes in the remaining bowel were recognized in all
      of these patients. Of the five tumors, two were histologically diagnosed as
      mucinous adenocarcinoma, demonstrating a higher distribution than usual: To
      clarify the characteristics of the tumors, we examined the frequency of mutation
      in K-ras and p53 genes, and the proliferating cell nuclear antigen (PCNA)
      proliferation activity. The K-ras and PCNA stains did not show any clear
      characteristics of radiation-induced colorectal cancers in comparison with
      ordinary colorectal cancers; however, it was of interest that strongly positive
      staining was observed in our mucinous adenocarcinomas, even though a low
      frequency of p53 gene mutation has been reported in ordinary mucinous
      adenocarcinomas.

PMID- 10664333
TI  - Altered plasma antigen levels of tissue factor pathway inhibitor during open
      heart surgery.
AB  - Tissue factor pathway inhibitor (TFPI) is a potent inhibitor of the extrinsic
      pathway of the coagulation cascade that is activated by cardiopulmonary bypass
      (CPB) during open-heart surgery. In the present study, we investigated whether
      the plasma TFPI antigen increases during CPB in 12 patients who underwent bypass
      procedures. The plasma levels of free and total TFPI antigens were measured using
      an enzyme-linked immunosorbent assay, and heparin concentrations were measured
      using a chromogenic substrate assay. We found that changes in the total plasma
      TFPI antigen level were significantly dependent on the level of free TFPI antigen
      (r = 0.96, P < 0.0001) which increased significantly after heparin injection (P <
      0.0001), and increased further during the bypass period (P < 0.005). The
      increased free TFPI antigen level during CPB correlated with the duration of
      bypass (r = 0.65, P = 0.02). When heparin was neutralized by protamine, the free
      TFPI antigen level decreased immediately, but remained higher than the
      preoperative level (P < 0.005). These results suggest that plasma TFPI antigen
      levels increase during CPB.

PMID- 10664334
TI  - Combined modality therapy including surgery for stage III small-cell lung cancer
      on the basis of the sensitivity assay in vitro.
AB  - Fifty-nine consecutive patients with clinical stage (cStage) I-III resectable
      small-cell lung cancer (SCLC) underwent surgery with adjuvant chemotherapy based
      on an in vitro sensitivity assay between April 1982 and March 1992. In 42 (71%)
      of these patients, a stable passage of cancer cells from resected specimens was
      possible and the sensitivity of these cultured SCLC cells to anticancer drugs was
      examined by the MTT method. In the sensitivity assay, vincristine (VCR) showed
      the most intense specific efficacy for SCLC, followed by cyclophosphamide (CPM)
      and cisplatin (CDDP). The 5-year survival rates for pathological stage (pStage)
      I, pStage II, and pStage III were 55%, 33%, and 23%, respectively. The 5-year
      survival of the patients with pStage III operated on in the first 5 years was 7%
      (1/14). On the other hand, 6 of the 16 pStage III patients (38%) operated on
      during the second 5-year period, who were generally treated with pre- and
      postoperative adjuvant chemotherapy combined with three drugs, survived over 5
      years. In conclusion, these results suggest that combined modality therapy
      including surgery is necessary, and adjuvant chemotherapy combined with VCR, CPM,
      and CDDP may be useful in the treatment of Stage III SCLC disease, for the
      purpose of achieving a long-term survival with both a good performance status and
      quality of life for the patients.

PMID- 10664335
TI  - Completion pneumonectomy for patients with recurrent lung cancer: the impact of
      microvessel density on outcome.
AB  - The effectiveness of performing completion pneumonectomy (CP) to treat recurrent
      lung cancer was assessed in 11 patients, 6 of whom had intrapulmonary recurrence,
      and 5, locoregional recurrence. The pathological types of cancer were
      adenocarcinoma in 5 patients, squamous cell carcinomas in 5 patients, and adenoid
      cystic carcinoma in 1 patient. The pathological stages of the recurrent lung
      cancer were stage I in 8 patients, stage II in 2 patients, and stage IV in 1
      patient. The microvessels in the tumors were also examined and the results
      compared with those in the microvessels of 61 nonrecurrent tumors. The 1- and 3
      year overall survival rates after CP were 54.5% and 27.3%, respectively. The
      vessel densities within primary and correspondent recurrent tumors were able to
      be assessed in 9 patients and found to be significantly greater compared with the
      mean value for the nonrecurrent tumors (P < 0.0001). The vessel densities in the
      primary and recurrent tumors of 2 of 3 long-term survivors were found to be
      relatively low. These results indicate the high-grade malignant potential of
      recurrent tumors, which led us to conclude that the use of CP should be carefully
      evaluated in patients with recurrence. Assessing the vasculature in primary
      tumors may be a useful indicator for determining which patients could benefit
      from CP.

PMID- 10664336
TI  - Z-shaped skin incision applying Kraissl's lines for an axillary thoracotomy.
AB  - A Z-shaped skin incision applying Kraissl's lines for a thoracotomy is presented
      herein. The center of the Z-shape is located on the intercostal space of the
      thoracotomy. Parallel Z-shaped lines are described on circular Kraissl's lines in
      the axillary region. The oblique cross-line of the Z-shape is drawn from the
      dorsal edge of the cranial line to the anterior edge of the caudal line. The
      angle of the triangular skin flaps is adjusted to 30 degrees or greater in order
      to keep good microcirculation. The incision gives good exposure for the operative
      fields and results in a cosmetically satisfactory scar.

PMID- 10664337
TI  - Is endovascular treatment of abdominal aortic aneurysms less invasive regarding
      the biological responses?
AB  - To compare the biological responses following an endoluminal repair and a
      conventional open repair of abdominal aortic aneurysm (AAA), 14 patients who
      underwent an endoluminal repair (endograft group) and 26 who underwent an open
      repair (open group) were investigated. As markers of biological responses,
      interleukin-6 (IL-6) and -8 (IL-8), granulocyte elastase (GEL), white blood cell
      count (WBC), and serum C-reactive protein (CRP) were all measured preoperatively
      as well as on postoperative days (POD) 1, 3, and 6. In addition, the blood loss,
      duration of surgery, initial oral intake the day after surgery, and length of
      hospital stay were compared between both groups. The plasma levels of IL-6, GEL,
      CRP, and WBC were higher in the endograft group than in the open group, while the
      CRP, WBC, and GEL levels all peaked on POD 3. The plasma level of IL-6 remained
      high in the endograft group, compared with that in the open group throughout the
      study period. Conversely, blood loss, initial oral intake the day after surgery,
      and the length of hospital stay were all significantly greater in the open group
      than in the endograft group, although there was no significant difference in the
      duration of surgery between the two groups. These findings indicate that although
      the endoluminal repair of AAA is supposed to be less invasive, the biological
      responses tend to be greater because of the manipulation related to the insertion
      of the stent graft.

PMID- 10664338
TI  - Elastofibroma dorsi.
AB  - It is often difficult to identify the characteristics of soft-tissue tumors of
      the chest wall. This paper describes the peculiarities of elastofibroma dorsi, a
      rare pseudotumor of this site, to exclude many dangerous misconceptions. During
      the period between 1987 and 1997, we treated nine patients with elastofibroma
      dorsi. In six patients, the lesion was unilateral and in three it was bilateral.
      All these lesions were excised and no evidence of local recurrence or shoulder
      disability was observed at the last clinical evaluation. Elastofibroma dorsi is a
      rare, slow-growing, pseudotumoral lesion of the soft tissues of the chest wall
      with a peculiar radiographic and histologic pattern.

PMID- 10664339
TI  - Perfusatory recovery of the grafted lung during convalescence from acute
      rejection.
AB  - The aim of this study was to evaluate whether or not perfusatory recovery of the
      grafted lung occurs is the early stage of convalesce from acute rejection
      following a single lung transplantation. Eight adult mongrel dogs underwent an
      allotransplantation of the left lung with treatment of 10 mg/kg cyclosporine and
      4 mg/kg azathioprine. Doppler flow probes were placed to the ascending aorta and
      the left pulmonary artery. Immunosuppressant therapy was discontinued to induce
      rejection after postoperative day 14. When the left pulmonary artery flow rate (l
      PAFR) decreased to less than 20%, methylprednisolone (20 mg/kg) was administered
      for 3 days along with a resumption of cyclosporine and azathioprine. Pulmonary
      circulation and chest roentgenograms were evaluated every day through the
      rejection episode. An open lung biopsy was also performed in each dog to obtain
      specimens of the grafts and native lungs for histologic examination. When l-PAFR
      decreased to less than 20%, mild acute rejection was found in all dogs. l-PAFR
      increased significantly on the third day after methylprednisolone treatment.
      Thereafter, a histologic examination revealed minimal acute rejection in one dog
      and no abnormality in seven dogs. The perfusatory recovery of the grafted lung
      was thought to reflect the histological change in the course of convalescence.

PMID- 10664340
TI  - Profile of cytokine production during the inhibition of acute xenograft
      rejection.
AB  - Th2 cells have been shown to exert cell-mediated immune responses in vitro;
      therefore, the present study was conducted to investigate the cellular mechanisms
      of the long-term survival of cardiac xenografts by measuring cytokine production
      from recipient lymphocytes. Xenogeneic heart grafts from Lewis rats were
      transplanted into C57BL/6 mice, and the recipients were intravenously injected
      with H57-597 at the time of transplantation. The production of Th1 cytokines,
      namely, interleukin (IL)-2 and interferon (IFN)-gamma, and Th2 cytokines, namely,
      IL-4 and IL-10, from mixed lymphocyte culture cells was assayed by enzyme-linked
      immunosorbent assay. Splenocytes from the xenograft recipients treated with H57
      597 produced significantly lower levels of IL-2, IFN-gamma, IL-4, and IL-10 than
      those from the untreated recipients, 100 days after transplantation. The findings
      of this study indicate that the long-term survival of cardiac xenografts induced
      by H57-597 is mediated by the inhibition of Th0, or both the Th1 and Th2
      response.

PMID- 10664341
TI  - Basaloid-squamous carcinoma of the esophagus: report of a case.
AB  - We report herein the case of a 69-year-old man with basaloid-squamous carcinoma
      (BSC) of the esophagus. To the best of our knowledge, this is the 60th case of
      BSC of the esophagus to be reported in Japan, and a review of the other 59 cases
      is presented after this case report. In our patient, endoscopic findings revealed
      a circumferential erosion in the middle intrathoracic esophagus (Im), and a
      protruding tumor with friable ulceration in the center of the erosion. A biopsy
      suggested that it was moderately differentiated squamous cell carcinoma (SCC),
      and a thoracoscopic total thoracic esophagectomy was performed. Histologically,
      the protruding-type lesion with ulceration was composed of BSC, and the
      circumferential 0 -I + IIc type lesion was composed of moderately differentiated
      SCC. The immunohistochemical findings of these resected specimens led us to
      suspect that the basal-layer-type SCC had transformed into BSC by undergoing
      differentiation and expansive proliferation.

PMID- 10664342
TI  - Thoracic esophagectomy combined with pylorus-preserving pancreatoduodenectomy in
      a one-stage procedure: report of a case.
AB  - We present herein the case of a patient who underwent a thoracic esophagectomy
      and pylorus-preserving pancreatoduodenectomy in a one-stage procedure for
      synchronous double primary cancer of the thoracic esophagus and the head of the
      pancreas (intraductal papillary tumor). To reconstruct the upper alimentary tract
      with the stomach, the gastroduodenal artery and right gastroepiploic vein were
      successfully skeletonized and preserved. The postoperative course was uneventful
      and the patient is currently well, 5 years after surgery.

PMID- 10664343
TI  - Rapid-growing carcinosarcoma of the esophagus arising from intraepithelial
      squamous cell carcinoma: report of a case.
AB  - A case of carcinosarcoma arising from the intraepithelial spreading area of
      esophageal squamous cell carcinoma (SCC) is reported herein. A 64-year-old man
      was referred to our hospital for investigation of a sore throat and dysphagia. An
      endoscopic examination revealed a 2. 5-cm polypoid mass in the mid-esophagus.
      Esophagograms taken 1 month prior to consultation by our hospital and just before
      surgery revealed marked change within a period of less than 2 months from a 2-cm
      sessile elevated mass to a 4-cm polypoid mass with a lobular appearance. The
      resected specimen contained two lesions in the esophagus. The larger one measured
      4.0 x 2.0 x 2.0 cm and had a pedunculated polypoid shape, while the smaller one,
      measuring 1 cm in diameter, was a plateau-type elevated lesion located 3 cm
      distal from the larger mass. Histologically, the distal smaller lesion was
      diagnosed as primary SCC associated with a high frequency of intraepithelial
      spread, while the larger polypoid mass was composed of spindle-shaped sarcomatous
      cells, arising from the intraepithelial spread of SCC. To our knowledge, this is
      the only reported case of esophageal carcinosarcoma arising from an area of
      intraepithelial spread of SCC that showed such surprisingly rapid growth.

PMID- 10664344
TI  - Gastrointestinal stromal tumors treated by laparoscopic surgery: report of three
      cases.
AB  - Three cases of gastrointestinal stromal tumors (GIST) were treated by a
      laparoscopic wedge resection of the stomach. The tumor characteristics were
      confirmed to be nonepithelial, nonlymphomatous, nonmyogenic, and nonneurogenic
      gastrointestinal neoplasms with an uncertain origin which were CD34-positive and
      actin- and S-100-negative. The malignant potential was estimated based on the
      mitotic figures and growth rates. The results suggest that laparoscopic surgery
      is an adequate strategy for gastric submucosal tumors including GIST, and also
      indicates this technique to be a curative, safe, and minimally invasive procedure
      for both diagnosis and treatment.

PMID- 10664345
TI  - Jejunal limb obstruction caused by a cholesterol stone 15 years after a total
      gastrectomy and 20 years after a cholecystectomy: report of a case.
AB  - We present herein the rare case of a 74-year-old woman found to have jejunal limb
      obstruction caused by a cholesterol stone 15 years after a total gastrectomy with
      Roux-en-Y anastomosis, and 20 years after a cholecystectomy. The patient
      complained of repeated episodes of upper abdominal distress on three separate
      occasions over a period of 20 months, and jejunal limb obstruction was diagnosed
      by abdominal computed tomography scanning and (99m)Tc scintigraphy. Surgery
      revealed a stone incarcerated in the jejunal limb, where the anastomosis had
      become slightly stenotic. The removed stone was 3.5 cm in diameter and was
      subsequently demonstrated to be a cholesterol stone by chemical analysis. This
      report is thought to be the first to describe jejunal limb obstruction caused by
      a gallstone incarcerated in the jejunal limb after a total gastrectomy in a
      patient with a history of cholecystectomy.

PMID- 10664346
TI  - A chylous cyst of the mesentery: report of a case.
AB  - A case is presented of an adult chylous cyst of the mesentery that was
      preoperatively diagnosed to be a pancreatic cystadenoma. A 66-year-old
      asymptomatic male was followed up for 15 months under the diagnosis of a benign
      pancreatic cyst. On October 1997, computed tomography showed a 45 x 40 mm cystic
      mass in the upper abdomen which came in contact with the pancreas. Endoscopic
      ultrasonography revealed a multilocular mass with a 7 x 4 mm elevated lesion.
      Endoscopic retrograde cholangiopancreatography and magnetic resonance
      cholangiopancreatography revealed the cystic mass to be unrelated to the
      pancreatic duct. The preoperative diagnosis was a pancreatic cystadenoma or
      cystadenocarcinoma. A laparotomy showed a 50 x 40 mm cystic mass containing
      chylous fluid, that arose from the mesentery of the upper part of the jejunum.
      The pathological diagnosis was a chylous cyst of the mesentery. The preoperative
      diagnosis in this case was very difficult because the chylous cyst appeared to be
      attached to the pancreas and this phenomenon is considered to be extremely rare.

PMID- 10664348
TI  - En bloc surgery for colon cancer: report of a case.
AB  - We report herein the case of a 57-year-old woman in whom successful en bloc
      surgery was performed for locally advanced colon cancer. A fixed tumor was
      palpable in the right subcostal region, and computed tomography (CT) showed that
      it originated in the ascending colon and invaded the right kidney, duodenum, head
      of the pancreas, and liver. A right hemicolectomy with D3 lymphadenectomy was
      performed combined with resection of the right kidney, duodenum, head of the
      pancreas, and liver. On microscopic examination, well-differentiated
      adenocarcinoma of the ascending colon widely invaded the parenchyma of the
      kidney, the parenchyma of the pancreatic head, and the duodenal wall. Lymph node
      metastasis was found in one paracolic node. This case report outlines the
      procedures involved in this extended surgery.

PMID- 10664347
TI  - Intussusception due to vanishing colon cancer with metastasis of the regional
      lymph nodes: report of a case.
AB  - We present herein a case report of vanishing colon cancer with intussusception. A
      70-year-old man with hematochezia was admitted to our hospital. Preoperative
      images showed ileus due to a colonic tumor. At operation, normograde
      intussusception without any tumor was recognized at the sigmoid colon.
      Interestingly, the regional lymph nodes were found to be invaded by tubular
      adenocarcinoma cells, thus suggesting that the colon cancer existed before the
      necrosis of the wall took place.

PMID- 10664349
TI  - Submucosal dermoid cyst of the rectum: report of a case.
AB  - Despite the relatively common incidence of sacrococcygeal dermoids, rectal cysts
      are uncommon. We report the case of a submucosal dermoid cyst occurring in the
      rectum. A 30-year-old woman visited the Gynecology Department because of
      pregnancy. A pelvic tumor was accidentally found during the checkup after
      miscarriage. A barium enema showed an anterior shift of the rectum by the
      presence of the tumor. Computed tomography and magnetic resonance imaging
      revealed a tumor located posterior to the rectum occupying almost the entire
      pelvic cavity, and the tumor was resected. The tumor was located in the
      submucosal layer of the posterior rectal wall and was well circumscribed. The
      resected tumor was a cyst entirely covered with a fibrous and firm capsule, which
      was filled with an amorphous white creamy substance. The histological findings
      showed the cyst consisting of a keratinizing stratified squamous epithelium with
      sebaceous gland and hair follicles, which was compatible with benign cystic
      teratoma. Primary rectal teratoma is very rare and only 36 cases have been
      reported in the literature worldwide. Furthermore, while the majority of cases
      were polypoid-shaped dermoid cysts protruding into the rectal lumen, only 3 cases
      were submucosal dermoid cysts. Therefore, such cases are considered to be
      extremely rare.

PMID- 10664350
TI  - Successful surgical treatment for spontaneous retroperitoneal hematoma in
      polycythemia vera: report of a case.
AB  - Bleeding is a common complication of such myeloproliferative disorders as
      polycythemia vera, and it usually occurs in either the skin or mucosa. We
      experienced a case of a massive retroperitoneal hematoma with no history of
      trauma in association with polycythemia vera. A 68-year-old man was referred to
      our hospital as a case of acute abdomen, and was diagnosed as having a
      retroperitoneal hematoma and polycythemia vera based on radiological and
      hematological examinations. Because the mass effect of the hematoma caused a
      progressive deterioration of his respiratory condition, surgical drainage was
      necessitated and successfully undertaken. Although conservative treatment is
      reportedly sufficient and uncontrollable intraoperative bleeding may occur,
      especially in cases of myeloproliferative disorders, our experience suggests that
      an operation may nevertheless be occasionally advisable for this rare condition.

PMID- 10664351
TI  - Thyroid lymphoma of mucosa-associated lymphoid tissue with monoclonal gammopathy
      occurring in an atomic bomb survivor: report of a case.
AB  - We describe herein a case of thyroid lymphoma of the mucosa-associated lymphoid
      tissue (MALT) with monoclonal gammopathy (IgG kappa), occurring in a woman who
      was exposed to atomic-bomb (A-bomb) radiation 1.5 km from the explosion of the
      hypocenter when she was 31 years old. Her estimated radiation dose was 0.2 Gy. A
      total thyroidectomy resulted in the disappearance of monoclonal gammopathy, thus
      indicating extramedullary monoclonal gammopathy of the thyroid. Three patterns of
      protein electrophoresis, i.e., normal, the appearance of monoclonal
      immunoglobulins, and their disappearance after the total thyroidectomy, were
      consecutively recorded. The utility of checking of the monoclonal immunoglobulin
      levels after a thyroidectomy due to lymphoma of the MALT to monitor recurrence is
      therefore suggested. This lymphoma is most likely not related to the patient's A
      bomb radiation exposure.

PMID- 10664352
TI  - Acute postoperative dermatosis at the site of the electrocautery pad: sweet
      diagnosis of a burning issue.
AB  - Acute febrile neutrophilic dermatosis or Sweet's syndrome is a well-described
      acute condition with possible paraneoplastic and inflammatory associations. A
      case of a 49-year-old man with a prior history of Hodgkin's disease is described,
      who underwent a laparotomy for operative treatment of a small intestinal
      stricture and therapy-refractory gastroesophageal reflux. Incidentally, mild
      mesenteric lymphadenopathy was encountered, and a biopsy confirmed the presence
      of a new, unrelated low-grade follicular lymphoma. Two weeks postoperatively, the
      patient developed a tender erythematous plaque at the site of the Bovie
      electrocautery pad on the proximal thigh. Over the following week, the affected
      area extended in size, and became markedly edematous and infiltrated, with
      hemorrhagic surface studding. Multiple small plaques, some with annular arrays of
      pustules, were found on the opposite lower extremity, the lower back, and the
      arms. A skin biopsy suggested the presence of Sweet's syndrome, and
      corticosteroid treatment was initiated. All cutaneous manifestations disappeared
      within 48 h except for the presence of postinflammatory erythema. Acute
      neutrophilic dermatoses have not been previously described in this postoperative
      presentation. The differential diagnostic importance of this emergent entity and
      the potential for it being caused by surgical trauma are discussed.

PMID- 10664370
TI  - The pathogenesis of tumour associated epilepsy.
AB  - Tumour associated epilepsy (TAE) is a poorly understood manifestation of many
      gliomas, meningiomas and metastatic brain tumours that has important clinical and
      social implications. Etiological mechanisms underlying tumour associated epilepsy
      include theories invoking peritumoural amino acid disturbances, local metabolic
      imbalances, cerebral oedema, pH abnormalities, morphological changes in the
      neuropil, changes in neuronal and glial enzyme and protein expression and altered
      immunological activity. It has also been suggested that the pathology involves
      perturbations in distribution and function of the NMDA subclass of glutamate
      receptors. The often capricious response of the seizure disorder following
      removal of the causative neoplasms suggests multiple factors are involved.
      Further understanding about the pathogenesis of TAE will await the development
      and characterisation of suitable animal models that demonstrate the clinical
      manifestations and physiological changes comparable to those seen in human
      cerebral tumours. With such a model it is hoped that progress may one day be made
      in understanding and subsequently treating this debilitating clinical problem.

PMID- 10664371
TI  - Infection as a cause of spinal cord compression: a review of 36 spinal epidural
      abscess cases.
AB  - A retrospective survey of 36 cases treated in the Department of Neurosurgery,
      Hacettepe University Hospitals since 1970 was performed. Clinical presentation,
      aetiology and outcome of this rare disease compared to recently published series.
      All cases were admitted with signs of neural compression. Clinical and laboratory
      data suggesting an infectious origin were present only in 4 cases. Radiological
      investigation including magnetic resonance imaging in 10 patients, were not
      confirmative for an epidural abscess except for two cases. All cases underwent
      urgent surgical decompression and tuberculous abscess either in granulation or
      pus form was found in the majority. Overall mortality rate was 5.8%. Outcome was
      closely related to the neurological condition on admission rather than the
      underlying infectious origin. When compared with recently reported series, our
      cases demonstrated a significant divergence in terms of clinical presentation,
      pathogenesis and outcome. The most probable reason for this discrepancy is that
      risk factors for compromised immunity or systemic infection were much less than
      the other series and mycobacterium tuberculosis is the responsible agent in the
      majority which has a much more favourable outcome than non-spesific infections.

PMID- 10664372
TI  - Use of intra-aortic balloon pump counterpulsation for refractory symptomatic
      vasospasm.
AB  - Delayed neurologic deficits secondary to vasospasm remain a vexing problem.
      Current treatments include: hypertensive hypervolemic hemodilution (Triple-H)
      therapy, angioplasty, and intra-arterial papaverine administration. Significant
      morbidity and mortality still result from vasospasm despite these therapies. We
      present two patients with symptomatic vasospasm who received intra-aortic balloon
      pump counterpulsation (IABP) to improve cerebral blood flow when they were unable
      to tolerate Triple-H therapy. One patient (L.T.) developed vasospasm after
      resection of a meningioma that encased the carotid and middle cerebral artery.
      The other patient (D.F.) suffered a subarachnoid hemorrhage (Fisher Grade III,
      Hunt/Hess Grade III) from a basilar tip aneurysm. Postoperatively, both patients
      developed vasospasm. Treatment with Triple-H therapy, angioplasty, and papaverine
      yielded modest results. When they experienced cardiac ischemia, Triple-H therapy
      was stopped, but their neurologic condition deteriorated markedly. Because of
      this, IABP was started. Both patients had an immediate improvement in cardiac
      function. IABP was able to reverse some of the neurologic deficits, and was
      weaned off after several days of support. Both patients had a substantial
      improvement in function, and are now capable of caring for themselves. We
      conclude that IABP may play an important role for improving cerebral blood flow
      in patients with vasospasm. It may be particularly useful in those patients with
      limited cardiac reserve.

PMID- 10664373
TI  - Contralateral approach to carotid cave aneurysms.
AB  - BACKGROUND: To evaluate the surgical approach and clipping of aneurysms located
      at the carotid cave region. METHOD: Between 1980 and 1998 we have adopted the
      well known ipsilateral approach for exposure and securing of carotid cave
      aneurysms. In four patients, we had the opportunity to use a contralateral
      approach to carotid cave aneurysms, with easier dissection and application of a
      simple aneurysmal clip. The visual acuity of the patients did not deteriorate
      from the pre-operative level. FINDING AND INTERPRETATION: Aneurysms located at
      the carotid cave region may be approached easily and safely through a
      contralateral craniotomy with application of the aneurysm clip from an angle
      medial and inferior to the optic nerve.

PMID- 10664374
TI  - The influence of vascular pressure and angiographic characteristics on
      haemorrhage from arteriovenous malformations.
AB  - BACKGROUND: The present study was designed to determine whether there is a
      physiological explanation for the predisposition of patients with certain
      angiographic characteristics to haemorrhage from cerebral arteriovenous
      malformations (AVMs). METHODS: Intra-operative measurement of feeding artery
      pressure (FAP) and intravascular pressures in the draining venous system
      [draining vein pressure (DVP) and cranial sinus pressure (SP)] were performed for
      30 AVM cases using direct puncture of the vessels. The correlation between
      pressures and previously described angiographic characteristics predisposing to
      haemorrhage were evaluated. FINDINGS: Small nidus size and only one draining vein
      increased the risk of haemorrhage. FAP and DVP are both inversely related to the
      number of draining veins and the size of the AVMs. DVP was significantly higher
      in AVMs with haemorrhage (23.1+/-8.7 mmHg) than in those without (13.5+/-4.4), as
      was FAP (58.6+/-12.8 as opposed to 38.7+/-4. 7) (p<0.05). Moreover, the
      difference between systemic blood pressure and the FAP with haemorrhagic AVMs
      (17.0+/-9.5 mmHg) was significantly lower than that in nonhaemorrhagic cases
      (33.7+/-5.5) (p<0.05). The pressure difference between the feeding artery and
      draining vein was not significant between the haemorrhagic and nonhaemorrhagic
      groups. There was no significant difference of SP between haemorrhagic and
      nonhaemorrhagic patients. INTERPRETATION: The present study suggests that a high
      DVP probably induced by high resistance in the venous drainage system, as well as
      a high FAP, may contribute to the development of haemorrhage from AVMs, and
      physiologically supports previous reports that small AVMs and AVMs with only one
      draining vein are susceptible to haemorrhage.

PMID- 10664375
TI  - Efficacy of lumbo-peritoneal versus ventriculo-peritoneal shunting for management
      of chronic hydrocephalus following aneurysmal subarachnoid haemorrhage.
AB  - BACKGROUND: The clinical usefulness of lumboperitoneal (LP) shunts in selecting
      patients with communicating hydrocephalus after aneurysmal subarachnoid
      haemorrhage (SAH) was compared with that of ventriculoperitoneal (VP) shunts.
      METHOD: Chronic hydrocephalus was defined as clinically and radiographically
      demonstrated hydrocephalus which lasted 3 weeks or longer after the original
      haemorrhage and which required shunting. Indications for a CSF shunt were
      assessed on the basis of neurological symptoms and signs, CT findings, and
      isotope cisternogram findings. The patients were treated with either LP or VP
      shunts. A significant response to shunting was defined as an improvement of
      function to a higher grade. The functioning of the shunt was evaluated by the
      location of the catheter on x-ray studies, CT features, and isotope
      cisternograms. The operation groups were checked for comparability of demographic
      and clinical variables including age, Fisher grade, hypertension, vasospasm,
      shunt interval, preshunt functional grade, and CT findings. A comparative
      analysis of the outcome was carried out between the two operation groups.
      FINDINGS: Fifty-six patients underwent shunt placements (LP shunts: 22, VP shunts
      with medium pressure valve: 2, VP shunts with high pressure valve: 32). There was
      no statistically significant difference in patient demographics and clinical
      characteristics between the patients with LP shunts and those with VP shunts. A
      follow-up time of 3 months to 8 years revealed clinical improvement in 11 cases
      (50.0%) of patients with LP shunts and 31 cases (91.1%) in VP shunts was seen
      (Fisher's exact test, P<0.005). INTERPRETATION: These findings suggest that VP
      shunts are a better choice of treatment than LP shunts in treating chronic
      hydrocephalus after aneurysmal SAH.

PMID- 10664376
TI  - Management of patients with ruptured cerebral aneurysms in hospital population of
      Lithuania.
AB  - A retrospective analysis of ruptured cerebral aneurysms among the hospital
      population of Lithuania was performed. A total of 507 patients were enrolled in
      the study during a 5 year period. The unadjusted annual incidence of ruptured
      cerebral aneurysms was found to be 2.7/100,000 in the hospital population of
      Lithuania and 3.9/100,000 in the hospital population of the defined area of the
      city of Kaunas. Overall management results showed a 45. 6% good recovery and
      31.6% death rate in this group of patients. Surgical results showed a 52.1% good
      outcome and 20.9% death rate. Despite the fact that the death rate according to
      the timing of surgery after the initial subarachnoid haemorrhage did not differ
      significantly (p >0.05) among early (0-3 days post SAH), moderate (4-7 days post
      SAH) and late (more than 7 days post SAH) surgery groups, it was found that 75
      (14.8%) patients deteriorated while awaiting surgery. Initial bleeding together
      with rebleeding, medical complications and vasospasm were the main causes of
      death, constituting 61.3%, 18.1% and 9.4% of all deaths, respectively. The
      results of this study showed that the annual incidence of ruptured cerebral
      aneurysms in Lithuania is similar to that in other European countries except for
      Finland. Overall management results in the Lithuanian hospital population
      indicated only a slight improvement compared to management results of previous
      population-based studies in other countries.

PMID- 10664377
TI  - Expression of matrix metalloproteinases in the chronic subdural haematoma
      membrane.
AB  - To study the role of matrix metalloproteinases (MMP) in the development of
      chronic subdural haematoma, we investigated the expression and activity of MMPs
      (MMP-1, -2, -3, -7 and -9) and tissue inhibitors of MMP (TIMP-1 and -2) in
      capsules of chronic subdural haematoma from 10 patients. Outer membranes of
      chronic subdural haematoma were immunostained for MMP-1, MMP-2, MMP-9, TIMP-1 and
      TIMP-2. Moreover, we confirmed MMP activity in membranes by SDS-PAGE zymography
      and in situ zymography. These results suggest that MMP degrades extracellular
      matrix in outer membranes of chronic subdural haematoma, which is thought to
      decrease their integrity followed by direct haemorrhage and exudation of
      oedematous fluid from membrane vessels into the haematoma cavity.

PMID- 10664378
TI  - Candida infection of cerebrospinal fluid shunt devices: report of two cases and
      review of the literature.
AB  - Use of CSF shunt devices is a common practice in neurosurgery, and infection of
      the shunt is the most frequent complication. In spite of the fact that bacteria
      are the most widely implicated pathogens, reports of fungal infections,
      especially due to Candida sp., have increased in recent years. Their reported
      frequency ranges between 6% and 17%. Many factors have been implicated in the
      pathogenesis of Candida meningitis, such as broad spectrum antibiotics used in
      the treatment of a bacterial meningitis, steroids and indwelling bladder and
      intravenous catheters. The treatment of Candida meningitis still consists of
      systemic antifungal agents and removal of the shunt.

PMID- 10664379
TI  - Impact of anatomical difference of the cerebral venous system on microcirculation
      in a gerbil superior sagittal sinus occlusion model.
AB  - Sinus-vein thrombosis (SVT) is known to have a wide spectrum of clinical
      manifestations, and the formation of venous collateral pathways is considered to
      be one of the most important factors influencing the individual outcome. Here, we
      examined the relationship between the anatomical differences in bridging veins
      and cerebral microcirculation in a gerbil superior sagittal sinus (SSS) occlusion
      model. In male Mongolian gerbils (n=26), the SSS was ligated close to the
      confluence sinuum. Four additional animals served as the sham-operated control.
      Regional cerebral blood flow (rCBF) and haemoglobin oxygen saturation (HbSO2)
      were assessed by Laser-Doppler flowmetry and a microspectrophotometric method at
      36 identical locations in the both hemispheres every 20 minutes for 120 minutes
      after ligation using a "scanning" technique. Furthermore, we examined change in
      the diameter of the bridging vein by fluorescence angiography and brain damage by
      histological investigation after 48 hours. Based on the anatomical findings, the
      hemispheres were classified into two groups: group A with one bridging vein,
      n=24/52 sides (46.2%) and group B with more than two bridging veins, n=28/52
      sides (53.8%). Significant decreases in rCBF (P<0.05) and rHbSO2 (P<0.05) were
      seen from 20 minutes after the ligation to the end of the experiment in group A,
      but not in group B. A detailed analysis of individual cases in changes of local
      (l) CBF and lHbSO2 revealed three patterns: 1) pattern-1, no change; 2) pattern
      2, decrease with following recovery; 3) and pattern-3, decrease without recovery.
      There were no significant differences in the diameter of the bridging vein and no
      venous infarction in either groups. The group A frequency, which consisted of
      pattern-3 (58.3%)>pattern-2 (29. 2%)>pattern-1 (12.5%), was opposite to that of
      group B, which consisted of pattern-1 (71.4%)>pattern-2 (25.0%)>pattern-3 (3.6%)
      (P<0.001). Based on the results of this study, the anatomical structure and an
      opening of the collateral pathways of the venous drainage system are closely
      related to microcirculatory alterations after venous occlusion. The experimental
      model is suitable for the study of the pathophysiological mechanism responsible
      for the high variability of SVT.

PMID- 10664380
TI  - No apparent role for neutrophils and neutrophil-derived myeloperoxidase in
      experimental subarachnoid haemorrhage and vasospasm: a preliminary study.
AB  - OBJECTIVE: The literature contains investigations and discussion of the role of
      neutrophils and neutrophil-derived myeloperoxidase (MPO) in inflammatory
      processes, local ischaemia, and ischaemia-reperfusion injury models. Our aim was
      to determine whether the same roles existed for neutrophils and the system
      involving neutrophil-derived MPO in experimental subarachnoid haemorrhage (SAH)
      and associated ischaemia. MATERIAL AND METHOD: Forty-eight adult New Zealand
      white rabbits were divided into six groups of eight. The first SAH model was
      applied to 16 animals. Eight of these rabbits were sacrificed after 48 hours
      (Group 1) and the remaining eight were killed after 96 hours (Group 2). The
      second SAH model applied to another 16 rabbits, which were sacrificed in two
      groups at the above time periods, forming Groups 3 and 4, respectively. There
      were two groups of 8 control animals, one group per SAH model, and these rabbits
      were sacrificed after 48 hours. We carried out histopathological studies using
      haematoxylin and eosin (H&E) stain, elastin stain, MPO immunohistochemistry, and
      determination of basilar artery cross-sectional diameter. We also did biochemical
      analysis of cerebral hemisphere and brainstem specimens, measuring tissue lipid
      peroxidase and MPO activity. Results were compared between the groups and with
      their related controls. RESULTS: In contrast to previous experimental findings in
      local ischaemia and ischaemia-reperfusion models, we found no histopathological
      or biochemical evidence to suggest a role for neutrophils and neutrophil-derived
      MPO in relation to subarachnoid haemorrhage and resultant vasospasm. Although we
      confirmed the successful induction of significant vasospasm and observed the
      clinical evidences of subsequent ischaemia, there was no notable accumulation of
      neutrophils or activity of neutrophil-derived MPO in the tissues studied. This
      suggests that the biological process induced by SAH follows a different pattern
      from that seen in local ischaemia and ischaemia-reperfusion injury.

PMID- 10664381
TI  - Histologically repeatedly confirmed gliosarcoma with long survival: review of the
      literature and report of a case.
AB  - OBJECTIVE AND IMPORTANCE: A rare case of gliosarcoma in a 61-year-old woman is
      presented with a stable situation over 22 years with an excellent quality of
      life. CLINICAL PRESENTATION: The patient was initially symptomatic and was
      operated on in 1975 for a deep-seated left parietal gliosarcoma. During the
      following 20 years, she was clinically asymptomatic until she complained of
      increasing headache in 1995. Neuroradiological imaging showed a sharply
      demarcated lesion on MRI at the former operative site, which was operated on
      again. Four months later, the residual tumour did grow again. INTERVENTION: As
      radiation therapy could not stop tumour progression and the neurological status
      worsened, the patient was operated on again for a massive tumour mass in the left
      parieto-occipital region, filling out nearly all of the previous resection
      cavity. Despite radio-immunotherapy, the patient finally died 22 years after the
      first discovery of the tumour. CONCLUSION: The present case shows that, in rare
      instances, gliosarcomas may show prolonged survival, although the underlying
      pathogenetic mechanisms for this clinical behaviour are not understood.

PMID- 10664382
TI  - Epidermoid cyst involving the brain stem.
AB  - Brain stem epidermoid cysts are extremely rare. We describe an unusual case of
      prepontine epidermoid cyst with a large part of the tumour insinuating itself
      into the pons. Microsurgical total excision of tumour was done without producing
      any new neurological deficits. Cases reported in the literature either had high
      mortality/morbidity or were only subtotally removed. Relevant literature is
      reviewed.

PMID- 10664383
TI  - Craniocerebral war missile injuries: clinical and radiological study.
AB  - In this study we reviewed the initial clinical and radiological management and
      early outcomes of 176 consecutive patients from the war in Croatia.

PMID- 10664384
TI  - Nitric oxide increases the amount of murine cytomegalovirus-DNA in mice latently
      infected with the virus.
AB  - At 5 wk after the intraperitoneal infection of murine cytomegalovirus (MCMV) in
      adult (C3H/He x BALB/c) F1 (CBF1) mice, MCMV-DNA was noted mainly in the salivary
      glands (SG). Since graft-versus-host reaction (GVHR) is well known as a major
      risk factor for CMV reactivation, parental BALB/c spleen cells were then
      intravenously transferred to these mice to induce GVHR. A high copy number of
      full-length MCMV-DNA was thus observed in the lungs as well as the hearts and
      livers at 4 to 6 wk after the cell transfer, whereas the copy numbers in SG after
      the cell transfer were comparable to those before the transfer. It was therefore
      suggested that the amount of MCMV-DNA noted in these organs had been increased by
      GVHR. However, no transcripts of MCMV-DNA could be detected. Since a marked
      expression of mRNA of inducible nitric oxide synthetase (iNOS) was noted in the
      lungs and the hearts during the course of GVHR, the role of NO in the increase of
      MCMV-DNA after the cell transfer was next examined. The administration of L
      arginine, a substrate for NO, increased the amount of MCMV-DNA in the lungs and
      the hearts after the induction of GVHR. In contrast, the material which
      suppressed iNOS induction inhibited the emergence of MCMV-DNA. Therefore, the NO
      generated during the course of GVHR increased the amount of the viral DNA in the
      lungs and the hearts of the mice latently infected with MCMV. If the increase in
      the amount of viral genome is the initial step of viral reactivation from the
      latent state, then NO would thus trigger the initial step of the reactivation of
      the DNA virus. As the lungs are the major organ to produce NO after systemic
      stimulation, the observations of this study may explain why the lungs are the
      major site of CMV latency and why GVHR triggers CMV reactivation. These findings
      are thus considered to demonstrate that NO plays a novel role in viral infection.

PMID- 10664385
TI  - Genetic diversity of HIV-1 group M from Cameroon and Republic of Congo.
AB  - We analyzed 57 HIV-1 isolates from Cameroon and the Republic of Congo, with
      respect to the env C2V3 and/or the pol integrase regions. The results indicated
      that the topology of the pol tree correlated well with that of the env tree for
      four clusters of subtype D, F G and H, suggesting that these trees reflect the
      true evolution of the overall genome structures of these subtypes. However, of 22
      Cameroonian isolates that were classified as subtype A based on env, 20 of them
      diverged in their pol sequence into two lineages that were completely different
      from the prototypical subtype A, tentatively designated as subtypes A1 and A2.
      The subtype A1 isolates (6 out of 22) were related in their env C2V3 regions with
      prototypical subtype A strain, but in their pol regions, they formed an
      independent cluster that diverged from known HIV-1 subtypes so far reported
      (except for subtypes I and J). The subtype A2 isolates (14 out of 22), which
      represent the major epidemic type of HIV-1 in Cameroon, clustered distinctly in
      both the env and pol trees with the recently described A/G mosaic strains from
      Nigeria and Djibouti. These two lineages were not spreading in the neighboring
      Republic of Congo.

PMID- 10664386
TI  - Identification of an epitope on the dengue virus membrane (M) protein defined by
      cross-protective monoclonal antibodies: design of an improved epitope sequence
      based on common determinants present in both envelope (E and M) proteins.
AB  - The protective capacity of monoclonal antibodies (MAbs) generated to the dengue-2
      virus envelope (E) and premembrane (prM) proteins was tested in vivo. Two anti-E
      MAbs, 2C5.1 and 4G2 and two anti-prM MAbs, 2A4.1 and 2H2 provided cross
      protection against all four dengue virus serotypes. Overlapping sets of synthetic
      peptides spanning amino-acid sequence 301-401 (domain III) of the E protein and
      the entire prM protein were then used to locate their epitopes. The anti-E MAbs
      strongly reacted with the peptide sequence 349-GRLITVNPIVT-359 (E349-359) from
      domain III and the immunodominant epitope, 274-SGNLLFTGHL-283 (E274-283) from the
      hinge region between domains I and II. The anti-prM MAbs strongly reacted with
      the sequence, 40-PGFTVMAAIL-49 (M40-49) from the first membrane-spanning domain
      of the M protein. These anti-prM MAbs also reacted with peptides E274-283 and
      E349-359, while the anti-E MAbs reacted with a peptide sequence, 1-FHLTTRNGEP-10
      from the prM protein and these cross-reactions with both proteins were confirmed
      using immunoblot assays. MAbs 2C5.1, 4G2 and 2H2 more strongly reacted with an
      MEH1 peptide GLFTPNLITI, which was designed as an antigenic hybrid between these
      E and prM peptide sequences, than with any of these natural peptide sequences.
      These peptide sequence will now be tested for their ability to generate cross
      protective antibodies against each dengue virus serotype when delivered with
      appropriate T-helper epitopes.

PMID- 10664387
TI  - Nucleotide sequence evidence for three distinct sugarcane streak mastreviruses.
AB  - The complete sequences of four clones of sugarcane streak virus (SSV) isolates
      from Egypt and one SSV clone from Reunion island were determined. The four
      Egyptian genomes were highly similar to one another (97-99% nt identity) and were
      considered as variants of the same virus. The Egyptian SSV was genetically
      different from all other mastreviruses, the closest virus being SSV from South
      Africa (60% nt identity), and defined as a new mastrevirus species named SSEV.
      The SSV clone from Reunion was highly related to the SSV from Mauritius and SSV
      from Nigeria, for which only partial sequences were available, indicating that
      the three sugarcane streak isolates from Mauritius, Reunion and Nigeria were
      strains of the same virus tentatively named SSMV. This work further confirms that
      SSMV is a distinct viral species compared to other mastreviruses, including the
      SSEV (59% nt identity) and SSV (66% nt identity). By comparing two clones from
      the Mascarene islands, we correlated substitutions in the C-terminal end of the
      coat protein with a different response to a monoclonal antibody, providing data
      on the mapping of a specific epitope. Agroinoculations experiments demonstrated
      that an SSEV clone induced more severe symptoms on maize than two clones from the
      Mascarene. Inside the African streak virus cluster, the sugarcane mastrevirus
      isolates were gathered in a sub-cluster of three viruses, SSEV, SSV and SSMV. The
      diversity of the SSVs is discussed in relation to its host, sugarcane, an
      imported crop in Africa.

PMID- 10664389
TI  - Comparison of the complete sequences of five different isolates of Potato virus A
      (PVA), genus Potyvirus.
AB  - The complete nucleotide (nt) and deduced amino acid (aa) sequences of isolates
      Ali, U, Her (from potato, Solanum tuberosum) and TamMV (from tamarillo, Solanum
      betacea) of Potato virus A (PVA, genus Potyvirus) were determined and compared
      with the previously reported sequence of PVA isolate B11. Most parts (proteins)
      of the polyprotein showed over 95% aa sequence similarity. The cylindrical
      inclusion (CI) protein and the 6K 1 protein were the most conserved proteins
      among the five isolates. TamMV was the most different isolate. Sequence
      similarity between TamMV and the other isolates was the lowest in regions close
      to the 5'-end [5'-non-translated region (NTR) and P1 region] and 3'-end (N
      terminus of coat protein) of the genome. However, the termini of the genome (the
      first 60 nt of the 5'-NTR and the entire 3'-NTR) were highly similar in all five
      isolates. A frameshift region in the replicase (NIb) was identified the PVA
      isolates Ali, B11, Her and U, as compared to TamMV and other potyviruses.

PMID- 10664388
TI  - Genotypes of TT virus (TTV) compared between liver disease patients and healthy
      individuals using a new PCR system capable of differentiating 1a and 1b types
      from others*.
AB  - TT virus (TTV) lacks obvious pathogenicity; almost all of the infected hosts are
      symptom-free. A possibility remains, however, that certain strains can cause
      liver disease while most others are non-pathogenic. Genotypes 1 a and 1 b have
      been proposed to contain such pathogenic strains. To test this possibility, we
      constructed a PCR system capable of detecting TTV of the 1 a and 1 b genotypes
      differentially from the other genotypes, and compared the frequencies of these
      genotypes between patients with liver disease of unknown etiology (n=42) and
      healthy individuals (n=50). The assay comprised 3 steps: i) PCR to amplify a 3.2
      kb fragment using universal primers; ii) 2nd-round PCR, starting from the 3.2-kb
      amplicon, for a approximately 280-nt fragment by use of genotype 1-specific
      primers; and iii) digestion of the approximately 280-nt amplicon with MboI and
      BanI to discriminate between 1 a and 1 b. Eventually, 40 (95%) of the patients
      and 47 (94%) of the controls were positive for the 3.2-kb amplicon, and the 1 a,
      1 b, 1 a+1 b, and non-1 genotypes of TTV were found in 2 (5%) vs 4 (9 percent), 5
      (13%) vs 4 (9%), 1 (3%) vs 1 (2%) and 32 (80%) vs 38 (81%) of the 40 patients and
      47 controls, respectively: the distribution was almost identical between the two
      groups. The hypothesis that the genotype 1 of TTV may be more closely associated
      with liver disease than other genotypes was not supported by this study.

PMID- 10664390
TI  - Citrus exocortis viroid RNA is associated with the largest subunit of RNA
      polymerase II in tomato in vivo.
AB  - An active replication complex of citrus exocortis viroid (CEV) was isolated as a
      chromatin-enriched fraction of infected tomato leaf with CEV RNA synthesis
      activity. This activity was solubilised from the chromatin with ammonium
      sulphate, but not with sarkosyl. Nucleoprotein complexes in the soluble fraction
      which bound to a monoclonal antibody to the carboxy terminal domain of the
      largest subunit of RNA polymerase II (8WG16) were affinity purified and contained
      plus- and minus-sense CEV RNA. The results support a role for RNA polymerase II
      in viroid replication and provide the first direct evidence of an association in
      vivo between host RNA polymerase II and CEV.

PMID- 10664391
TI  - Characterization of a novel human calicivirus that may be a naturally occurring
      recombinant.
AB  - We identified a Norwalk-like calicivirus (CV) whose genome likely was derived
      from naturally occurring recombination. This strain (Arg320) was detected by the
      EIA developed against recombinant Mexico virus (rMxV) capsids, but the viral RNA
      polymerase sequence was closer to Lordsdale virus, in a separate genetic cluster
      of Norwalk-like viruses. A 3.3 kb cDNA from the RNA polymerase region to the 3'
      end of the genome of Arg320 was cloned and sequenced. The sequence demonstrated
      that the capsid region of Arg320 shared 95% amino acid identity with MxV, but 68%
      identity with Lordsdale virus, while the RNA polymerase region shared 95%
      identity with Lordsdale virus, but 87% identity with MxV. Pair-wise sequence
      comparisons identified a potential recombination site at the polymerase/capsid
      junction. This is the first example of a naturally occurring recombinant in the
      CV family. Further studies to search for and characterize other strains may be
      necessary for understanding the genetic diversity of the family.

PMID- 10664392
TI  - Examination of the selective pressures on a live PRRS vaccine virus.
AB  - We determined the ORF5 and 7 sequences of 20 pathogenic revertants of a live
      PRRSV vaccine. The sequence analysis confirmed all 20 isolates to be of vaccine
      origin. Having established that clonal introduction of American (vaccine) PRRS
      virus had occurred in Denmark, we could perform analysis of the selective
      pressure this attenuated virus had experienced during reversion. An analysis of
      nucleotide mutations showed a similar rate of mutations in the two genes (ORF5
      and 7). However, non-synonymous mutations in ORF7 were eliminated by purifying
      selection. In contrast, non-synonymous mutations in ORF5 were tolerated or even
      selected for. The cDNA sequencing of the 20 vaccine virus revertants identified
      two single nucleotide mutations located in ORF5 and in ORF6 that we suggest are
      involved or at least linked to the attenuation of the vaccine virus and to the
      subsequent reversion to virulence.

PMID- 10664393
TI  - Identification and phylogeny of novel human endogenous retroviral sequences
      belonging to the HERV-W family on the human X chromosome.
AB  - A new family (HERV-W) ofhuman endogenous retroviruses (HERVs) has recently been
      described that is related to MSRV (multiple sclerosis related retrovirus)
      sequences that have been identified in particles recovered from monocyte cultures
      from patients with multiple sclerosis. We investigated the pol fragment of HERV-W
      on the human X chromosome by the polymerase chain reaction (PCR) using a
      monochromosomal somatic cell hybrid DNA panel and compared these with related
      sequences in the genome database. We identified three novel sequences on the
      human X chromosome, HWXI, HWX3, and HWX5, which have a high degree of homology
      (88-98%) with the MSRV pol fragment and with seven other sequences. HWX5, like
      MSRV, has an uninterrupted open reading frame. Phylogenetic analysis showed HWX5
      to be related to the HWX1, HWX3, and BAC clone B353C18 sequences with 91-93%
      homology. The ratio of synonymous to nonsynonymous substitutions indicated that
      negative selective pressure is acting on HWX5. Further studies on the structure
      and expression of this sequence are indicated.

PMID- 10664394
TI  - Dynamics of Puumala hantavirus infection in naturally infected bank voles
      (Clethrinomys glareolus).
AB  - Specific features of hantavirus infection in bank vole (Clethrionomys glareolus)
      were studied in the endemic area of hemorrhagic fever with renal syndrome (HFRS)
      in the foothills of the Ural mountains, using long-term observations on living
      animals by the capture-mark-recapture (CMR) method. The results demonstrated that
      the infection naturally circulating in the voles is chronic (lasting for up to 15
      months) and asymptomatic, with a peak of Puumala virus accumulation and release
      from the organism during the first month after infection. It was shown that the
      bank vole population includes young animals with maternal immunity, which remain
      resistant to the Puumala virus infection for 3-3.5 months. The infection rate in
      voles depended on the age and sexual maturity of animals. The greatest proportion
      of seropositive animals was observed among overwintered males. Seroconversion in
      voles was more frequent during the period of high reproductive activity.

PMID- 10664395
TI  - Virus-like particles of calicivirus as epitope carriers.
AB  - The VP60 of rabbit haemorrhagic disease virus (RHDV), when expressed in
      baculovirus, self-assembles into virus-like particles (VLP) which are
      antigenically and immunogenically indistinguishable from native virions. When the
      N-terminal 30 amino acid residues of VP60 were deleted and substituted by a well
      characterized six residue epitope from bluetongue virus capsid protein VP7
      (Btag), the fusion protein retained its ability to self-assemble into VLPs.
      However, the size of these particles was only 27 nm, compared to 40 nm of VLPs
      derived from native VP60. The antigenicity of both VP60 and the Btag was retained
      as evident from ELISA and Western blot analyses. When Btag was fused at the C
      terminus of VP60 without deletion, the fusion proteins formed VLPs of 40 nm in
      size and also retained their antigenicity, but the Btag antigenicity appeared
      weak at this fusion site.

PMID- 10664396
TI  - Antigenic variation among bovine enteric coronaviruses (BECV) and bovine
      respiratory coronaviruses (BRCV) detected using monoclonal antibodies.
AB  - Bovine coronavirus (BCV) causes neonatal calf diarrhea (CD) and is associated
      with winter dysentery (WD) in adult dairy cattle. It can also be isolated from
      the respiratory tracts of cattle entering feedlots. Monoclonal antibodies (MAbs)
      specific for the hemagglutinin esterase (HE) and spike (S) surface proteins of 2
      bovine enteric coronavirus (BECV) strains and two bovine respiratory coronavirus
      (BRCV) strains were tested against 6 BECV strains and 6 recently isolated BRCV
      strains, in order to characterize the antigenicity of BCV strains with varied
      tissue tropisms. All MAbs had high immunofluorescence (IF) titers against BECV
      and BRCV strains, indicative of conserved cross-reactive epitopes. In
      hemagglutination inhibition (HI) tests, the S-MAbs were more broadly reactive
      than HE-MAbs. The BRCV and CD MAbs were more broadly reactive in HI than the WD
      MAbs. The HA activity of the Mebus vaccine CD strain was not inhibited by any of
      the MAbs tested. The HI activity of BRCV strain R6 was unique among the 6 BRCV
      isolates. In virus neutralization assays, MAbs to the BRCV strain R4 neutralized
      all 6 BECV strains tested. Antigenic variation exists among both BECV and BRCV
      strains, but it cannot be attributed soley to the clinical origin of the strain.

PMID- 10664397
TI  - Expression and characterization of the 3a movement protein of cowpea chlorotic
      mottle bromovirus.
AB  - Cowpea chlorotic mottle bromovirus (CCMV) 3a protein is required for cell-to-cell
      movement of the virus in host plants. The 3a protein was produced in Escherichia
      coli using an expression vector. Gel retardation analysis and UV cross-linking
      experiments demonstrated that the CCMV 3a protein (CC3a) bound single-stranded
      (ss) RNA cooperatively without sequence specificity. Binding competition analysis
      showed that CC3a bound ss-nucleic acids more strongly than double-stranded
      nucleic acids.

PMID- 10664398
TI  - Genomic characterisation of the large segment of a rabbit picobirnavirus and
      comparison with the atypical picobirnavirus of Cryptosporidium parvum.
AB  - The 2362 base pair sequence of the larger of the two double stranded RNA genome
      segments of a rabbit strain of picobirnavirus (PBV) has a major open reading
      frame (ORF) of 591 amino acids and two smaller ORFs of 55 and 155 amino acids. A
      clone of the segment did not hybridise with other viral bisegmented ds RNAs from
      faecal samples. There is no relationship in sequence or organisation between this
      PBV sequence and the bisegmented dsRNAs found associated with Cryptosporidium
      parvum. This suggests that there are at least two distinct classes of bisegmented
      dsRNA viruses or viral-like agents in faeces.

PMID- 10664399
TI  - Demonstration of group C rotaviruses in fecal samples of diarrheic dogs in
      Germany.
AB  - Three out of 9 fecal samples from diarrheic dogs, which were positive for
      rotavirus by electron microscopy, revealed RNA-migration patterns identical to
      those of porcine group C rotavirus when studied by polyacrylamide gel
      electrophoresis (PAGE). The results were further confirmed by solid phase immuno
      electron microscopy (SPIEM). This is the first report of the occurrence of group
      C rotaviruses in dogs.

PMID- 10664400
TI  - Apple chlorotic leaf spot virus 50 kDa protein is targeted to plasmodesmata and
      accumulates in sieve elements in transgenic plant leaves.
AB  - We investigated the in situ localization of the 50 kDa protein encoded by ORF2 of
      Apple chlorotic leaf spot virus (ACLSV) genome which is thought to be a movement
      protein. In immunogold electron microscopy of ACLSV-infected Chenopodium quinoa
      leaves, the 50 kDa protein was localized on plasmodesmata and nearby cytoplasm.
      Observation of transgenic Nicotiana occidentalis leaves expressing the 50 kDa
      protein fused to enhanced green fluorescent protein (EGFP) by fluorescence and
      confocal laser scanning microscopes revealed that green fluorescence was observed
      as spots on the cell wall or strands passing through the cell wall of several
      cell types, i.e., epidermal, palisade and spongy mesophyll and collenchyma cells.
      In transverse and longitudinal sections of leaf veins of transgenic plants showed
      that the 50K-EGFP fusion accumulated in sieve elements and formed an extensive
      interconnecting network of threadlike structure. These results indicated that
      ACLSV 50 kDa protein can target plasmodesmata and traffic into sieve elements.

PMID- 10664402
TI  - Neutralization of feline infectious peritonitis virus: preparation of monoclonal
      antibody that shows cell tropism in neutralizing activity after viral absorption
      into the cells.
AB  - Feline infectious peritonitis virus (FIPV) infection of feline macro-phages is
      enhanced by mouse anti-FIPV monoclonal antibody (MAb). This anti-body-dependent
      enhancement (ADE) of FIPV infection is dependent on mouse MAb subclass, and MAb
      of IgG2a subclass has a strong ADE activity. Furthermore, MAb showing strong
      neutralizing activity in Felis catus whole fetus (fcwf-4) cells and Crandell
      feline kidney (CrFK) cells shows strong enhancing activity in feline macrophages,
      indicating that the neutralizing epitope and the enhancing epitope are closely
      related. In this study, we prepared MAb FK50-4 that showed a strong neutralizing
      activity in feline macrophages, despite the fact that the MAb belonged to the
      IgG2a subclass. However, MAb FK50-4 did not exhibit neutralizing activity in CrFK
      cells or fcwf-4 cells, thus showing a very unusual property. MAb FK50-4
      recognized FIPV small integral membrane glycoprotein (M protein). Even when
      feline macrophages were pretreated with MAb FK50-4 prior to FIPV inoculation,
      this antibody prevented FIPV infection. This reaction disappeared after treatment
      of FK50-4 with protein A. The neutralizing activity of FK50-4 was also effective
      on feline macrophages after the cells were inoculated with FIPV. These findings
      indicated that the FIPV replication mechanism differs between feline macrophages
      and CrFK/fcwf-4 cells and that a neutralizing epitope that can prevent FIPV
      infection of feline macrophages after viral absorption is present on M protein.

PMID- 10664403
TI  - Activation of the alfalfa mosaic virus genome by viral coat protein in non
      transgenic plants and protoplasts. The protection model biochemically tested.
AB  - In non-transgenic host plants and protoplasts alfalfa mosaic virus displays a
      strong need for coat protein when starting an infection cycle. The "protection
      model" states that the three viral RNAs must have a few coat protein subunits at
      their 3' termini in order to protect them in the host cell against degradation by
      3'- to- 5' exoribonucleases [Neeleman L, Van der Vossen EAG, Bol JF (1993)
      Virology 196: 883-887]. We demonstrated that the naked genome RNAs are slightly
      infectious, if the inoculation is done at very high concentrations, or if it is
      preceded by an additional inoculation with the RNAs 1 and 2 (encoding subunits
      for the viral RNA polymerase). This could mean that the necessity for protection
      by coat protein is lost if the RNAs in large quantities can overcome the activity
      of the degrading enzymes, or are protected by association with the RNA
      polymerase, respectively. However, after having tested in protoplasts the
      survival of separately preinoculated naked RNA 1 during several hours before RNA
      2 was inoculated, on the one hand, or of simultaneously inoculated RNAs 1 and 2,
      with cycloheximide in the medium during the first hours after inoculation, on the
      other hand, we had to conclude that the viral genome RNAs are quite stable in the
      cell in the absence of coat protein or RNA polymerase, respectively. This
      invalidates the protection model. Accommodation of the above findings by our
      published "messenger release model" for genome activation [Houwing CJ, Jaspars
      EMJ (1993) Biochimie 75: 617-621] is discussed.

PMID- 10664404
TI  - Characterisation of genetically modified cucumber mosaic virus expressing
      histidine-tagged 1a and 2a proteins.
AB  - Biological active cDNA clones of cucumber mosaic virus (CMV) RNAs 1 and 2 were
      modified by addition of sequences that encode hexahistidine (His-tag) at the
      amino- (N-) or carboxy- (C-) terminus of the 1a and 2a proteins. These proteins
      are essential components of the viral RNA-dependent RNA polymerase (RdRp). In all
      but one case, addition of the His-tag did not significantly affect the yields of
      the corresponding viruses and the His-tag-encoding sequences were maintained
      after mechanical passages. No differences were observed among the in vitro
      activities of the modified vs. wild-type viral RdRps. Subcellular fractionation
      showed that 2a protein was found both membrane-associated and in the 30,000 x g
      soluble fraction. Both termini of the native His-tag 2a protein could bind to a
      resin containing nickel-nitrilotriacetic acid (Ni(2+)-NTA). Detergent-treated
      RdRp containing C-terminal His-tagged 1a and 2a proteins was chromatographed on
      Ni(2+)-NTA resin. The activity of the eluted RdRp was template- dependent, in
      contrast to pre-chromatography fractions. However, only a small proportion of the
      viral RdRp as well as numerous host proteins bound to and eluted from the resin
      under non-denaturing conditions.

PMID- 10664405
TI  - Molecular characterization of a satellite RNA associated with blackcurrant
      reversion nepovirus.
AB  - A satellite RNA (satRNA) associated with blackcurrant reversion nepovirus (BRV)
      was isolated and its nucleotide sequence was determined from cDNA clones. BRV
      satRNA was 1432 nucleotides (nt) in length excluding the poly(A)-tail, and
      contained one open reading frame which encodes a polypeptide of 402 amino acids,
      with a calculated M(r) of 44 220. The coding region was bordered by a 5' leader
      sequence of 25 nt and a 3'-nontranslated region of 201 nt. Two in vitro
      translation products of approximately 45 kDa and 40 kDa were detected, indicating
      that two in-frame AUG codons at positions 26 and 134 may both be functional.
      Nucleotide sequence comparisons revealed a stretch of 865 nt that was 63%
      identical between BRV satRNA and the large satRNA of chicory yellow mottle
      nepovirus. A 5'-terminal consensus sequence and a 40 nt motif (located at
      positions 264-303 of BRV satRNA) were conserved between BRV satRNA and other
      nepoviral large satRNAs.

PMID- 10664406
TI  - TT virus (TTV) genotypes in native and non-native prostitutes of Irian Jaya,
      Indonesia: implication for non-occupational transmission.
AB  - We investigated prostitutes in Irian Jaya, an Indonesian territory of New Guinea,
      to know whether TT virus (TTV) is sexually transmitted and what genotypes of TTV
      exist there. An ORF2 region of the TTV genome was analyzed for 44 isolates from
      prostitutes (19 were Irian Jaya natives but 25 were immigrants from Java or other
      islands of Indonesia) and 26 isolates from women of child-bearing age in Surabaya
      as a control. The WX(7)HX(3)CX(1)CX(5)H motif sequence of the ORF2 was compared
      across the 70 Indonesian isolates with a reference of 47 Japanese isolates (filed
      in databases) and the prototype TTV isolate TA278. A total of 77 different
      sequences were generated from the comparison, but a phylogenetic analysis
      suggested that they could be divided into three categories: group A, group B and
      others (the third group was highly diverse). Interestingly, most of the
      Indonesian isolates belonged to group B (74%): this rate was considerably higher
      than that observed previously in Japanese isolates. Group B isolates were further
      compared for the N-terminal 95 amino acids of the ORF2, with a result that the
      natives of Irian Jaya had a different pattern of genotype distribution from other
      groups. In particular, 9 out of 19 isolates from the Irian Jaya-natives were co
      classified under a distinct branch, to which none of the other Indonesian and
      Japanese isolates belonged. Our data indicate that TTV genotypes reflect the
      birth place of the infected prostitutes rather than their work environment, and
      thus suggest that an infection is more likely during the early period of life
      than through sexual transmission. In addition, the presence of an Irian Jaya
      specific genotype is intriguing from an anthropological and viral evolutionary
      point of view, because Irian Jaya has been isolated from contact with other areas
      for a long time.

PMID- 10664407
TI  - GB virus C/hepatitis G virus infection in Saudi Arabian blood donors and patients
      with cryptogenic hepatitis.
AB  - Viral hepatitis is a common infection in the developing countries. Aside from
      Hepatitis A-E viruses, a novel hepatitis virus termed GBV-C, or HGV, was recently
      described. We have studied the prevalence of this virus among Saudi Arabian
      healthy blood donors (n = 200) and patients with cryptogenic (non-A-E) hepatitis
      (n=71). After serum extraction and RNA reverse transcription, amplification was
      carried out by the polymerase chain reaction (PCR), using primers for the 5'
      noncoding region (NCR), NS5A region and NS3 helicase region. Among the patients
      with cryptogenic hepatitis, PCR-positivity was 18/71 (25.4%) for the 5' NCR,
      14/71 (19.7%) for the NS5A region, and 15/71 (21.1%) for the NS3 helicase region.
      Among the healthy blood donors, PCR-positivity was 4/200 (2%) for the 5' NCR,
      0/200 (0%) for the NS5A region, and 1/200 (0.5%) for the NS3 helicase region.
      Since the 5' NCR is considered the most conserved segment of the virus genome, it
      is not unusual to find higher positivity rate when that region is used for
      amplification. It is noted that the positivity rate is not far different among
      the three amplified regions, indicating that the heterogeneity of GBV-C/HGV is
      not as extensive as in hepatitis C virus. Phylogenetic analysis of 5'NCR DNA
      sequences showed that all isolates in this study belong to genotype 2. We
      conclude that the prevalence of GBV-C/HGV is similar to what is reported
      worldwide among the general Saudi population but relatively higher among Saudi
      patients with cryptogenic hepatitis.

PMID- 10664408
TI  - Stability of a varicella-zoster virus glycoprotein E epitope.
AB  - The epitope stability of a varicella-zoster virus (VZV) glycoprotein E (gE) was
      analyzed with monoclonal antibodies (mAbs) in cells infected with different
      passages of various VZV strains and isolates. The gE-specific mAbs recognized
      same antigenic sites (epitopes) in VZV isolates with various passage history. All
      VZV strains and virus-isolates reacted with an anti-gE monoclonal antibody by
      immunoprecipitation, or indirect fluorescent antibody staining test. Sera from
      VZV seropositive individuals reacted with a truncated VZV gE glycoprotein,
      designated TgpI-511. Also, human mononuclear cells (MNCs) stimulated with TgpI
      511 glycoprotein were shown to produce VZV-specific antibodies in vitro. The
      results demonstrated the stability of these gE epitopes tested in this study in
      TgpI-511 and among the VZV-isolates obtained from different passages. These
      results also suggest that VZV glycoproteins as well as live attenuated or killed
      varicella vaccines containing these epitopes could be used as therapeutic booster
      vaccines in adults and the elderly to prevent zoster.

PMID- 10664409
TI  - Human cytomegalovirus induced inhibition of hematopoietic cell line growth is
      initiated by events taking place before translation of viral gene products.
AB  - Bone marrow suppression with leukopenia is frequently observed during human
      cytomegalovirus (HCMV) infection, and in vitro the cell colony formation of bone
      marrow progenitors is directly inhibited by HCMV. To better understand the
      mechanisms of HCMV's ability to directly inhibit the cell colony formation of
      hematopoietic cells, we examined the effect of HCMV infection on four
      hematopoietic cell lines, ML-3, HL-60, KG-1, and U-937. Similarly to the observed
      effect on hematopoietic progenitors, HCMV significantly inhibited the cell colony
      formation of KG-1 and U-937 cells, 40% and 30% respectively. Following HCMV
      infection, uptake of HCMV pp65 was detected in all cell lines. In contrast, no
      immediate early protein production could be observed. When the cell line KG-1 was
      challenged with UV-inactivated HCMV or with HCMV dense bodies, containing pp65
      and other matrix proteins, a 20% to 25% inhibition of cell colony formation was
      found. In addition, a dose-dependent inhibition of proliferation of the KG-1
      cells challenged with intact or UV-inactivated HCMV, was observed. Transfection
      of this cell line with vectors containing genes for the HCMV matrix protein pp65,
      revealed no inhibitory effect. In contrast, the transfection with pp71 resulted
      in a 20% growth inhibition. These results indicate that HCMV can induce
      inhibition of cell colony formation of hematopoietic cells without transcription
      of HCMV regulatory proteins, and that at least one HCMV matrix protein may play
      an important role in this inhibitory effect.

PMID- 10664410
TI  - The VP2 variable region of African and German isolates of infectious bursal
      disease virus: comparison with very virulent, "classical" virulent, and
      attenuated tissue culture-adapted strains.
AB  - 11 African and two German IBDV strains isolated in the mid '80s from field
      outbreaks in vaccinated and unvaccinated chicken flocks displayed features of
      very virulent (vv) IBDV strains. The sequence data of the VP2 variable region and
      phylogenetic analysis confirm that these strains can be grouped within vv IBDV
      strains which appeared at the same time on the three continents Africa, Asia, and
      Europe. Strain Cu-1wt, responsible for severe IBD outbreaks in Germany 13 years
      earlier, showed some relatedness to these strains, but also significant
      differences at the genomic level, even though this strain has also features of
      the vv IBDV strains.

PMID- 10664411
TI  - Neuron-glia interactions in the rat retina infected by Borna disease virus.
AB  - Neuron-glia interactions in the Borna disease virus (BDV)-infected rat retina
      were investigated with emphasis on the ultrastructural characterization of
      degenerative alterations in the ganglion cell and photoreceptor layer. Immuno-
      and cytochemical techniques were applied to label microglia, macrophages and
      Muller (macroglial) cells. Four weeks after intracerebral infection of adult
      rats, the total thickness of the retina was considerably diminished, primarily
      due to the loss of photoreceptor segments and ganglion cells. A gradual reduction
      of both plexiform layers was also observed. There was a remarkable increase in
      the number of microglial cells, predominantly in the ganglion cell and the inner
      plexiform layers. Ultrastructural analysis confirmed that microglia, but also
      macrophages, were involved in phagocytosis accompanying severe neuronal
      degeneration in the ganglion cell and the photoreceptor layer. In contrast,
      Muller cells showed moderate morphological and cytochemical alterations,
      indicating that Muller cells play only a minor role in early stages of BDV
      induced retinitis. Monitoring neuron-glia interactions in BDV-induced
      retinopathy, combined with the application of different protocols of
      immunosuppression effecting the BDV virus and/or the microglia, might help to
      establish specific strategies to suppress BDV-induced neuronal degeneration.

PMID- 10664412
TI  - Genetic and antigenic variance of foot-and-mouth disease virus type Asia1.
AB  - The capsid protein encoding genes of five recent type Asia1 foot-and-mouth
      disease virus isolates, representative of three genotypes, were sequenced. The
      deduced amino acid sequences were aligned to each other and to two published
      sequences. The sequence differences suggested different antigenic properties of
      the isolates. One isolate was used to generate monoclonal antibodies (mAbs) which
      were analyzed for neutralizing activity and reactivity with trypsinized virus.
      Trypsin removes the major antigenic sites located at VP1. The five virus isolates
      formed three reaction patterns with the mAbs, irrespective of their genotype.
      Combination of all data allowed to suggest the location of the epitope of each
      antibody: the VP1 G-H and the VP2 B-C loop, the VP3 B-B knob, and the N-terminus
      of VP2, respectively, were involved.

PMID- 10664413
TI  - High frequency recombination between homologous baculoviruses in cell culture.
AB  - The frequency of recombination between homologous baculoviruses was investigated
      in cell culture upon coinfection with two Autographa californica
      nucleopolyhedrovirus (AcMNPV) recombinants. These parental recombinants differed
      at two loci, separated by 20 kb, each carrying a different marker. The progeny
      recombinants generated by homologous recombination were easily distinguishable by
      the presence or absence of these markers. The mean percentage of the newly
      generated recombinants relative to a single locus varied between 23 and 41%,
      depending on the multiplicity of infection used for coinfection. These results
      provide further evidence that homologous recombination occurring during
      baculovirus replication is a highly frequent event.

PMID- 10664414
TI  - Deletions in the KTER-encoding domain, which is needed for Polymyxa transmission,
      in manually transmitted isolates of Beet necrotic yellow vein benyvirus.
AB  - One A and one B type isolate of Beet necrotic yellow vein benyvirus which had
      been passaged for more than 15 years on manually inoculated Chenopodium quinoa in
      our laboratory were found to have small deletions in the KTER-encoding domain on
      RNA 2 which is necessary for Polymyxa transmission. There were no indications
      that these isolates and a third one, in which intact RNA 2 was detected,
      contained mixtures of deleted and intact RNAs or that populations of RNAs 2 with
      different deletions including very large ones were present.

PMID- 10664415
TI  - High-level expression of canine parvovirus VP2 using Bombyx mori
      nucleopolyhedrovirus vector.
AB  - For the potential use as recombinant vaccine, canine parvovirus (CPV) major
      capsid protein VP2 was expressed using Bombyx mori nucleopolyhedrovirus (BmNPV)
      vector. CPV VP2 gene was introduced into polyhedrin-based BmNPV transfer vector
      pBmKSK3, and recombinant virus BmK1-Parvo was prepared. When anti-CPV.VP2
      monoclonal antibody was employed in immunofluorescence staining, an intense
      signal was observed within BmK1-Parvo-infected Bm5 cells but not within
      uninfected cells or cells infected with a wild-type BmNPV-K1. In hemagglutination
      assay, the expression level of VP2 were 3.2 x 10(3) HA units/ml from infected Bm5
      cells, 2.1x 10(5) HA units/larvae from infected larval fat body, and 1.6x 10(6)
      HA units/ml from infected larval hemolymph. These results suggested that BmNPV
      vector system using B. mori larva as host could be applied to efficient mass
      production of recombinant vaccines.

PMID- 10664416
TI  - Improved detection of Beet necrotic yellow vein virus in a DAS ELISA by means of
      antibody single chain fragments (scFv) which were selected to protease-stable
      epitopes from phage display libraries.
AB  - The detection of Beet necrotic yellow vein virus (BNYVV) in stored sugar beets by
      means of monoclonal antibodies or antibody single chain fragments (scFv) often
      poses problems, because the immunodominant C-terminal epitope of the viral coat
      protein is readily lost due to proteolysis. Clones which produce scFv specific
      for protease-stable BNYVV epitopes were selected from two naive phage display
      libraries. Fusion proteins of the scFv with a human IgG kappa chain (expressed
      from the newly designed vector pCL) or with alkaline phosphatase,respectively,
      allow the ELISA detection of BNYVV even in stored sugar beets with a sensitivity
      which was comparable or often higher than that achieved with polyclonal
      antibodies.

PMID- 10664417
TI  - Avian influenza virus intranasally inoculated infects the central nervous system
      of mice through the general visceral afferent nerve.
AB  - To define the route of influenza virus invasion into the central nervous system
      (CNS), an avian influenza A (H5N3) virus was inoculated into mice intranasally or
      intravenously. Only the intranasal infection group mice showed depression and
      retention of gas in the digestive system. Pathological findings in the animals
      were bronchointerstitial pneumonia and non-suppurative encephalitis restricted to
      the brain stem. The nerve nucleus primarily affected was the nucleus of solitary
      tract. Prior to the development of the CNS lesions, viral antigen was detected in
      vagal and trigeminal ganglia. These results suggest that the primarily replicated
      virus in the respiratory mucosa ascended to the CNS via sensory nerve routes,
      inducing lesions in the brain stem, and then spread trans-synaptically in the
      CNS.

PMID- 10664418
TI  - Abbreviations for bacterial and fungal virus species names.

PMID- 10664422
TI  - Progression of rheumatoid arthritis of the cervical spine: radiographic and
      clinical evaluation.
AB  - Cross-sectional and longitudinal studies were conducted to observe progression of
      rheumatoid arthritis in the cervical spine. Two hundred and ninety-seven patients
      were enrolled in the cross-sectional study. Both upper and lower cervical spine
      involvement increased with disease duration. The relationship between atlanto
      axial motion and the development of subaxial subluxation was inconclusive. Eighty
      seven patients were enrolled in the longitudinal study and were followed for at
      least 5 years. In about half of these patients, rheumatoid changes started from
      the upper cervical spine, with rheumatoid changes beginning from the lower
      cervical spine in about 8% of patients. Neurological deficits were correlated
      with radiographic changes but neck pain did not correlate with radiographic
      changes. As to the upper cervical spine, the parameter most influencing
      neurological deficits was found to be the minimum value of the atlanto-axial
      angle in flexion, by multivariate analysis using a multiple logistic model.
      Neurological deficits were seen in more than half the patients when the atlanto
      axial angle in flexion was 5 degrees or less.

PMID- 10664423
TI  - Prevalence of articular cartilage degeneration in the ankle and knee joints of
      human organ donors.
AB  - The prevalence of osteoarthritis (OA) is higher in some joints than in others.
      Fibrillation and full-thickness cartilage defects in the knee have been
      considered to be evidence of developing OA (pre-OA). While similar changes have
      been reported in the ankle (talocrural joint), the frequency of these changes is
      much higher than expected if the degeneration represents pre-OA. These
      observations suggest that in the ankle degenerative changes do not proceed to OA.
      The current study was to determine the prevalence of articular cartilage
      degeneration in ankles in a population of 470 bone donors with no history of
      joint disease. Knees from 50 donors were also available. Our data suggest that
      degeneration in the ankle cartilage does not appear to be a normal part of aging,
      was more frequent in men than women, increased with age, and occurred most often
      in both limbs with the same severity. In those donors with degeneration in the
      ankle, the knee also showed degenerative changes with an equal or higher grade.
      These data suggest that factors (such as altered mechanics) responsible for
      degeneration in one limb also cause changes in the contralateral limb and that
      factors affecting the ankle joints also appear to influence the knee joints.

PMID- 10664424
TI  - A study of mechanoreceptors in fibrocartilage masses in the defect of pars
      interarticularis.
AB  - We investigated the origin of low back pain associated with lumbar spondylolysis
      and spondylolytic spondylolisthesis by removing fibrocartilage masses from the
      lytic sites in symptomatic patients and staining the masses by the Gairns gold
      chloride method to examine mechanoreceptors. The fibrocartilage masses were found
      to contain four types of mechanoreceptors: Pacinian corpuscles, Ruffini
      receptors, Golgi tendon organ-like receptors, and free nerve endings. All of
      these mechanoreceptors were present at the periphery of the specimens, and
      Ruffini receptors and free nerve endings were abundant. Some mechanoreceptors had
      a slightly atypical structure, in addition to those with typical morphology.
      Comparison with mechanoreceptors in normal lumbar facet joint capsules showed
      that there were more mechanoreceptors in the fibrocartilage masses and a greater
      proportion of atypical structures at lytic sites. The presence of
      mechanoreceptors at lytic sites suggests that the fibrocartilage masses are not
      simply scar tissue filling the defect. Rather, these masses also appear to play a
      protective role by sensing instability via mechanoreceptors and transmitting this
      information as pain, while at the same time acting as ligament-like tissue that
      connects and stabilizes the separated vertebral arches.

PMID- 10664425
TI  - Combining transforming growth factor-beta(1) to a bioabsorbable self-reinforced
      polylactide pin for osteotomy healing: an experimental study on rats.
AB  - The effect of a bioabsorbable pin containing transforming growth factor-beta(1)
      on fracture healing was studied in a rat model. The growth factor was mixed into
      a bioabsorbable polymer paste (a blend of an l-lactic acid oligomer and a
      copolymer of epsilon-caprolactone and dl-lactide) that was used to fill the
      grooves of a self-reinforced fracture fixation pin made of a poly-ld-lactic acid
      copolymer. In an in vitro assay, sustained release of the growth factor from the
      pins over a 7-day period was demonstrated. A distal femoral osteotomy was made in
      60 rats and stabilized with the fracture fixation pin in 48 of them; In the
      remaining 12 rats, no fixation was performed. The pin used in the study group
      contained either 5 microg (15 rats) or 50 microg (15 rats) of the growth factor,
      while in a control group of 18 rats an identical pin without the growth factor
      was used. After a follow-up of 1, 3, or 6 weeks, the femurs were examined
      radiographically, histologically, histomorphometrically, and
      microradiographically, and also used in tetracycline labeling studies. Faster
      callus formation was evident in the growth factor-treated rats but no
      acceleration in the healing of the osteotomy was detected.

PMID- 10664426
TI  - Quantitative analysis of three-dimensional complexity and connectivity changes in
      trabecular microarchitecture in relation to aging, menopause, and inflammation.
AB  - There are several types of bone loss besides that associated with normal aging,
      eg, that associated with the menopause, and that associated with chronic
      inflammation, and these are considered to be caused by different mechanisms. The
      microarchitecture that results from these different bone-loss mechanisms would
      not be the same. The purpose of this study was to investigate differences in the
      three-dimensional trabecular microarchitecture in various types of osteopenia,
      using microcomputed tomography (Micro-CT). Thirty-five Fisher 344 rats were
      divided into five groups (control, young, senile, ovariectomized [OVX], and
      inflammation-mediated osteopenia [IMO]) and distal femoral metaphysis was scanned
      by Micro-CT to nondestructively acquire a 3-D CT stack consisting of 50
      consecutive slices at a spatial resolution of 26 microm. The volume of interest,
      consisting of the secondary spongiosa, was prepared to analyze the 3-D trabecular
      microarchitecture. A parametric analysis was carried out using bone volume
      fractions, fractal dimensions, and the first Betti number in order to
      quantitatively express the mass, complexity, and connectivity of the trabecular
      microarchitecture. Complexity tended to decrease with age, and decreased
      significantly in estrogen deficiency-induced and inflammation-mediated
      osteopenia. Connectivity did not appear to change with aging, but was
      significantly decreased in estrogen deficiency-induced and inflammation-mediated
      osteopenia. There was no significant difference between the OVX and the IMO
      groups.

PMID- 10664427
TI  - Biomechanical study of the development of scoliosis, using a thoracolumbar spine
      model.
AB  - A thoracolumbar spine model was made using synthetic resin vertebrae and silicon
      discs. The model was fixed to a metal frame and spinal deformation caused by
      loading was determined relative to three-dimensional coordinates set in the
      frame. A three-dimensional evaluation of the development of spinal deformity was
      performed by applying rotational, lordotic, and lateral flexional forces in
      various orders to the model. The most severe scoliosis occurred when loading was
      done in the order of rotational force, lordotic force, and lateral flexional
      force.

PMID- 10664428
TI  - Surgical management of congenital permanent dislocation of the patella in nail
      patella syndrome by Stanisavljevic procedure.
AB  - We report a patient with nail patella syndrome associated with congenital
      permanent dislocation of the patella successfully operated on using a modified
      Stanisavljevic method. The patient, a 26-year-old woman, complained of inability
      to completely extend her right knee joint. She had occasionally experienced the
      "giving way" phenomenon since childhood, but she had not received any treatment
      since birth. Physical examination showed that all fingernails were deformed, with
      longitudinal striations, while the lunules were of an abnormal triangular shape
      or were missing. Both patellae were palpably hypoplastic, with the right patella
      dislocated laterally, and the knee had an extension lag of 90 degrees. Thigh and
      leg muscle were slightly underdeveloped, but quadriceps muscle contraction was
      good. Several radiographs were taken and they showed bilateral iliac horns and
      hypoplasia of the bilateral humero-radial joints and of both patellae, and
      complete dislocation of the right patella. We employed the Stanisavljevic
      procedure for the reduction of the patella, with Z-lengthening of the rectus
      femoris and medial translocation of the tibial tuberosity. Four years after the
      operation, a 30-degree extension lag still exists in the right knee, but the
      treatment resulted in stable alignment of the quadriceps mechanism, and notably
      improved gait appearance.

PMID- 10664429
TI  - Spinal cord herniation into an extensive extradural meningeal cyst: postoperative
      analysis of intracystic flow by phase-contrast cine MRI.
AB  - We report a patient with idiopathic spinal cord herniation who underwent
      postoperative myelography and phase-contrast cine magnetic resonance imaging
      (MRI) to clarify the condition of the ventral cystic lesion into which the spinal
      cord had been herniated. This 58-year-old man showed symptoms and signs
      compatible with Brown-Sequard syndrome. A myelogram and MRI showed that the
      spinal cord was incarcerated in a small space, and this finding led to the
      diagnosis of spinal cord herniation. In the operation, the herniated spinal cord
      was returned to the initial intradural space, and the dural defect was enlarged
      to prevent recurrence of the herniation. After the operation, leg muscle strength
      improved and bladder and bowel dysfunction resolved, but analgesia was unchanged.
      Postoperative myelography revealed a very large extradural cystic lesion, which
      extended from C2 to L1 vertebral level. A cerebrospinal fluid (CSF) flow study of
      the intradural space disclosed a near-normal pattern, but the intracystic CSF
      dynamics were abnormal. In the intracystic space at just the upper level of the
      lesion, cranial flow (reverse directional flow in comparison with the intradural
      flow) was seen in the systolic cycle after momentary fast caudal flow, and these
      CSF dynamics may have been related to the spinal cord herniation.

PMID- 10664430
TI  - Articular cartilage joint surface reconstruction techniques.
AB  - There is renewed interest in joint surface reconstruction using a variety of new
      and evolving techniques for articular cartilage resurfacing. Neochondrogenesis
      and articular cartilage transplantation are gaining a prominent place in
      orthopaedic basic science research. The authors have published a reliable,
      repeatable, stable, and sensitive model utilizing osteochondral dowel core
      transplantation in an ovine model to assess various treatment and follow-up
      evaluation techniques for articular cartilage transplantation. As well, our
      laboratory has developed a handheld articular cartilage indentor for clinical
      assessment of biomechanical performance of joint surfaces. This article presents
      and reviews that model as well as a semiquantitative visual analog scale for
      documenting articular cartilage gross morphology. The results of magnetic
      resonance imaging of the osteochondral dowel transplants and the gross morphology
      grading are compared to the histological and histochemical grading and
      biochemical and biomechanical assessments to form the foundation for future work
      in this critical and important study area for clinical application.

PMID- 10664431
TI  - Management of the stiff shoulder.
AB  - Shoulder stiffness occurs as a result of (1) contractures of the intraarticular
      capsule or muscle-tendon units or (2) adhesions within the extraarticular
      humeroscapular or scapulothoracic motion interface. These contractures or
      adhesions may occur independently or in combination. A thorough history and
      physical examination usually reveal the diagnosis (idiopathic frozen shoulder or
      posttraumatic stiff shoulder) and the anatomical locations of fibrosis that is
      causing stiffness, and identifies other treatable conditions associated with
      shoulder stiffness (such as diabetes). A gentle home program of passive
      stretching is effective in most patients. When the home program is not effective,
      a manipulation or surgical release may be indicated. If manipulation is not
      effective, capsular contractures are best released arthroscopically as this
      allows circumferential release without damaging the rotator cuff and thus allows
      rehabilitation without the need to protect the rotator cuff. The humeroscapular
      motion interface adhesions can be released either open or arthroscopically, but
      we believe that an open release combined with an arthroscopic capsular release is
      quicker and does not interfere with rehabilitation. When necessary, operative
      management coupled with an aggressive rehabilitation program can provide
      significant relief of pain and restoration of shoulder motion. Approximately 90%
      of patients can expect a good result with this treatment algorithm.

PMID- 10664432
TI  - The course of the Japanese Orthopaedic Association in the twentieth century and
      into the future.

PMID- 10664433
TI  - Age-related changes in cortical bone in men: metacarpal bone mass measurement
      study.
AB  - Metacarpal cortical bone mass was measured in 507 healthy Japanese men aged 40-95
      years, using a microdensitometer to determine age-related changes in cortical
      bone in these middle-aged and elderly men. Total bone mass showed a significant
      negative correlation with age (r = -0.281; P < 0.0001). While bone width showed
      no significant correlation with age, bone marrow width showed a significant
      positive correlation (r = 0.210; P < 0.0001), and cortical bone width and
      cortical bone density showed a significant negative correlation with age (r = 
      0.265; P < 0.0001; r = -0.268; P < 0.0001, respectively). On the other hand,
      cortical bone width and cortical bone density showed a significant positive
      correlation with total bone mass (r = 0.814; P < 0.0001; r = 0.474, P < 0.0001,
      respectively). These findings suggest that cortical bone mass decreases
      significantly with aging in middle-aged and elderly men, perhaps as a result of
      two factors - decreased cortical bone width, ie, cortical bone thinning due to
      bone loss at the endosteal side of the cortex, and decreased cortical bone
      density due to progression of intracortical porosity. Cortical bone thinning may
      influence age-related cortical bone loss more than decreasing cortical bone
      density.

PMID- 10664434
TI  - Predictability of the progress of secondary osteoarthritis after developmental
      dislocation of the hip, utilizing inferior edge (of the teardrop)--center (of the
      femoral head) distance.
AB  - We followed-up a group of patients in their youth and then in middle age after
      they had been treated for developmental dislocation of the hip, and studied
      whether we could predict the progress of osteoarthritis of the hip when the
      patients were in the "youth" stage. We studied 21 hips of 21 patients with
      unilateral dislocation that could be examined twice, in 1975 and 1995, in
      patients who were treated at our hospital between 1953 and 1963. We measured the
      acetabular-head index (AHI), center-edge angle (CE angle), and the Sharp angle,
      and our created index (inferior edge of the teardrop - center of the femoral head
      distance), and we divided this index by the distance of the inferior edges of the
      teardrops on both sides. Using these measured values, we studied whether we could
      predict changes in clinical and radiographic evaluation after a follow-up of 20
      years. There was no significant correlation of clinical and radiographic results
      and AHI, CE angle, and the Sharp angle; however, there was a significant
      correlation with our created index. The index we created is relatively easily
      measured and enables us to make a more precise prognosis, in comparison with
      previously developed indices.

PMID- 10664435
TI  - Changes of the sacrum in severe spondylolisthesis: a possible key pathology of
      the disorder.
AB  - Deficient development of the posterior lumbosacral portion has been thought to be
      a possible etiology of severe spondylolisthesis. However, the precise causes of
      the deformity have yet to be revealed. To our knowledge, progression of the
      disorder has not been discussed in the light of sacral changes on magnetic
      resonance imaging (MRI). The objectives of the present study were to document
      changes of the sacrum on MRI scans in patients with severe spondylolisthesis and
      to discuss the relation of these changes to the progression of deformities.
      Roentgenograms and MRI scans of 13 patients (10 women and 3 men) with severe
      spondylolisthesis were retrospectively reviewed. Average age at first MRI
      examination was 20 years (range, 12 to 50 years). The MRI scans commonly showed a
      defect at the antero-superior portion of the sacrum. This lesion seems to appear
      during the period of progression of slipping associated with lumbosacral
      kyphosis. The defect of the sacrum was considered a unique feature to
      discriminate this type of olisthesis from others. Taking into consideration the
      present results, the deformity can be called kyphospondylolisthesis.

PMID- 10664436
TI  - Clinico-radiological study of total knee arthroplasty after high tibial
      osteotomy.
AB  - The results of total knee arthroplasty (TKA) after high tibial osteotomy (HTO)
      and problems encountered during the operation were investigated in 23 patients
      (28 knees). HTO was performed by Coventry's method in 18 knees and by Maquet's
      method in 10 knees. The mean interval from HTO to TKA was 86 months (range, 3 to
      288 months) and the mean follow-up period after TKA was 25 months (range, 6 to
      116 months). Radiological evaluation showed that the proximal part of the tibia
      was shifted and tilted lateroinferiorly after HTO. Thus, a tendency to patella
      infera was observed. Lateral shift of the proximal part of the tibia was more
      marked with Maquet's method than with Coventry's method (P < 0.01). Posterior
      inclination of the tibial articular surface before TKA was smaller in the
      patients who gained a range of motion of 90 degrees or more after TKA than in
      those with less than 90 degrees (P < 0.05). In patients with 70 points or more on
      the three-university score after TKA, there was no change in the joint line level
      between before and after TKA, while the joint line was significantly lower after
      TKA in those with less than 70 points (P < 0.01). When TKA is done after HTO,
      various technical problems may influence the outcome, such as correction of the
      soft tissue imbalance, in addition to difficulties with patellar eversion and
      exposure of the proximal part of the tibia. The clinical results of TKA after HTO
      tend to be slightly inferior to those of primary TKA, probably because of such
      technical problems.

PMID- 10664437
TI  - Neglected traumatic posterior dislocations of the shoulder: controversies on
      indications for treatment and new CT scan findings.
AB  - We report seven missed traumatic posterior dislocations of the shoulder in six
      patients. In all seven shoulders, anteroposterior radiographs did not provide the
      diagnosis in the emergency room after the trauma (epileptic seizure in four
      patients) and diagnosis was delayed for at least 24 h. The final diagnosis was
      reached by clinical suspicion and computed tomography (CT) scan of the seven
      shoulders. Two shoulders were treated by closed reduction and three were treated
      by closed reduction and percutaneous pinning, although four of these five
      shoulders presented a defect in the humeral head involving 20%-25% of the
      articular surface. Two shoulders dislocated for more than 6 months were treated
      according to Mc Laughlin's technique modified by Hawkins instead of an
      arthroplasty. At a minimum follow-up of 2 years and 2 months, the functional
      results according to Hawkins were good in all seven shoulders. There was no
      recurrence of the dislocation in any patient. Radiographs showed mild
      degenerative changes. The establishment of indications for treatment, based on
      the proportion of articular surface of the humeral head involved and the time of
      evolution of the dislocation, needs more clinical or experimental evidence. In
      epileptic patients, strict control of medication is of the utmost importance.

PMID- 10664438
TI  - Biological fixation of the graft within bone after anterior cruciate ligament
      reconstruction in rabbits: effects of the duration of postoperative
      immobilization.
AB  - To investigate the effects of the duration of postoperative immobilization on the
      biological fixation of the graft within bone after anterior cruciate ligament
      (ACL) reconstruction, we performed ACL reconstruction in 27 rabbits, which were
      divided into five groups - no immobilization and 1-, 2-, 4-, and 6-week
      immobilization. All animals were killed 6 weeks postoperatively, and the graft
      bone tunnel interface was examined biomechanically and histologically. In the
      groups with immobilization, in tensile failure tests, most specimens failed
      through the intraarticular portion of the grafts. There was no significant
      difference in the maximum load between these groups. In the no-immobilization
      group, all specimens failed through pulling of the grafts out of the femoral
      tunnel, with a lower maximum load than in the other groups. Histologically, new
      bone formation and occasional collagen fiber continuity were observed at the
      interface; which consisted of a fibrous tissue. In the no-immobilization group,
      the graft was partly separated from the fibrous tissue covering the bony wall. It
      is concluded that no immobilization delays the biological fixation process in the
      bone tunnel after ACL reconstruction, and that a certain period of immobilization
      is necessary for the fixation to proceed smoothly.

PMID- 10664439
TI  - Etiologic factors in femoral head osteonecrosis in growing rats.
AB  - Osteonecrosis of the epiphyseal nucleus of the femoral head, which resembles that
      in Perthes' disease in children, was studied in spontaneously hypertensive rats
      (SHRs) and ordinary Wistar Kyoto rats (WKYs). The SHRs were kept in ordinary
      cages and the WKYs in custom-made high cages from 5 weeks to 15 weeks after
      birth. The WKYs had to stand on their hind limbs to feed because the feed box and
      the drinking aperture were placed at a high level. At 15 weeks, the femurs were
      resected and examined radiographically and histologically. There was a relatively
      high incidence of avascular necrosis in the epiphyseal nuclei of the femoral
      heads; 45.8% in SHRs and 33.3% in WKYs. In the SHRs, there were ossification
      disturbances of the proximal femoral epiphysis and deformities of the proximal
      femurs, such as a flattened femoral head and short neck. These findings suggest
      that constitutional cartilage disorder in the SHRs and excessive mechanical
      stress on the femoral heads in the WKYs participated in the etiology of the
      osteonecrosis.

PMID- 10664440
TI  - Bioabsorbable thread for tight tying of bones.
AB  - The purpose of this research was to develop a bioabsorbable thread for tight
      fixation of fractured bones and to examine its mechanical performance in an in
      vitro simulation study. The thread is a blend of bioabsorbable poly(L-lactic
      acid); (PLLA) and poly(epsilon-caprolactone); (PCL) fibers and can be tightly
      connected by fusion welding of the PCL fibers. The tying strength of the PLLA-PCL
      blend thread was 39.7 N, which was comparable to that of stainless steel wire. A
      testing machine was fabricated to measure the fatigue strength of the tying by
      simulating bone fixation. The results showed that metal wires always failed
      because of breakage within 25,000 loading cycles, whereas the blend threads did
      not fail until 50,000 loading cycles. The looseness of tying for simulated bone
      fixation by the blend thread was within 1mm even after 50 000 loading cycles. In
      vivo testing using rats revealed that the blend thread did not cause any severe
      inflammatory reaction.

PMID- 10664441
TI  - Role of fracture hematoma and periosteum during fracture healing in rats:
      interaction of fracture hematoma and the periosteum in the initial step of the
      healing process.
AB  - To study the mechanisms of fracture healing, we investigated the interaction
      between fracture hematoma and periosteum during the early phase of fracture
      healing in rats. Experimentally induced fractures of the tibia in untreated rats
      were compared histologically with such fractures in rats in which either the bone
      marrow or the periosteum had been removed. The extent of periosteal cell
      proliferation and chondrogenesis in the fracture hematoma was evaluated on
      experimental days 3, 6, 10, and 14. On day 3, periosteal cell proliferation at
      the tibial fracture site was decreased in the bone marrow-removed rats compared
      with the proliferation in untreated rats. Little chondrogenesis in the fracture
      hematoma was seen through day 6 in the periosteum-removed rats. These results
      suggest that the periosteum is important for mediating the primary steps of
      chondrogenesis and enchondral ossification in the fracture hematoma and that the
      fracture hematoma may be essential for periosteal cell proliferation during
      fracture healing.

PMID- 10664442
TI  - Insufficiency fractures of the distal tibiae.
AB  - We describe two patients with uncommon types of insufficiency fractures that
      occurred at the distal tibiae. In case 1, a 71-year-old man with secondary
      osteoporosis due to hypogonadism fracture of his left distal tibia was overlooked
      because initial radiographs had seemed normal. However, bone scintigram obtained
      2 months prior to the onset of fracture had already demonstrated abnormally high
      uptake at the site. In case 2, a 62-year-old woman with postmenopausal
      osteoporosis sustained an insufficiency fracture of the left distal tibia. Good
      clinical results were obtained with nonsurgical treatment. Based on the clinical
      course of case 1, we believe that bone scintigrams may be useful not only for the
      early diagnosis of insufficiency fracture but also for predicting such fractures.

PMID- 10664443
TI  - Cellular and molecular basis of preferential metastasis of breast cancer to bone.
AB  - Bone is one of the most preferential target sites for cancer metastasis. Breast
      cancer has a predilection for spreading to bone, and bone metastasis is one of
      the major causes of increased morbidity and eventual mortality in breast cancer
      patients. None of the currently available therapies is effective for curing bone
      metastases in these patients. Elucidation of the cellular and molecular mechanism
      by which breast cancer selectively spreads to bone is essential for the
      development of mechanism-based effective and specific therapeutic interventions
      for this deleterious complication in breast cancer. Here, two questions are
      addressed to study the mechanism of breast cancer metastasis to bone: (1) What
      makes bone a preferential target site of metastasis? (2) What makes breast cancer
      able to colonize bone? (3) An animal model in which intracardiac inoculation of
      breast cancer cells selectively causes osteolytic bone metastases was developed.
      Experimental results obtained using this unique in-vivo model of bone metastasis
      are described and discussed.

PMID- 10664444
TI  - Posterior occipitocervical fusion in rheumatoid arthritis and other
      instabilities.
AB  - Occipitocervical fixation remains a surgical challenge. A Y-plate in combination
      with transarticular screw fixation provides a simple and economically favorable
      solution to this problem. By integrating the transarticular screws into the Y
      plate immediate postoperative reliable stabilization is achieved. Clinical
      results confirm the reliability and the low rate of pseudarthrosis with this
      surgical technique.

PMID- 10664445
TI  - A Raf-induced, MEK-independent signaling pathway regulates atrial natriuretic
      factor gene expression in cardiac muscle cells.
AB  - The atrial natriuretic factor (ANF) gene is activated in cardiac myocytes by Ras
      and its effector Raf. However, MEK, the best-characterized Raf substrate, cannot
      efficiently activate ANF suggesting that Raf uses a MEK-independent pathway to
      activate ANF. By manipulating MEK and Raf activities so that they are equally
      effective at activating ERK, we now demonstrate that Raf activates at least two
      signaling pathways in cardiac myocytes that regulate the ANF promoter; the MEK-
      >ERK pathway inhibits ANF gene expression while a Raf-induced, MEK-independent
      pathway activates expression. This mechanism may provide increased ability to
      regulate ANF expression in response to hypertrophic stimuli.

PMID- 10664446
TI  - Targeted disruption of NDST-1 gene leads to pulmonary hypoplasia and neonatal
      respiratory distress in mice.
AB  - In order to address the biological function of GlcNAc N-deacetylase/N
      sulfotransferase-1 (NDST-1), we disrupted the NDST-1 gene by homologous
      recombination in mouse embryonic stem cells. The NDST-1 null mice developed
      respiratory distress and atelectasis that subsequently caused neonatal death.
      Morphological examination revealed type II pneumocyte immaturity, which was
      characterized by an increased glycogen content and a reduced number of lamellar
      bodies and microvilli. Biochemical analysis further indicated that both total
      phospholipids and disaturated phosphatidylcholine were reduced in the mutant
      lung. Our data revealed that NDST-1 was essential for the maturation of type II
      pneumocytes and its inactivation led to a neonatal respiratory distress syndrome.

PMID- 10664447
TI  - SCN5A mutation (T1620M) causing Brugada syndrome exhibits different phenotypes
      when expressed in Xenopus oocytes and mammalian cells.
AB  - Brugada syndrome is a hereditary cardiac disease causing abnormal ST segment
      elevation in the ECG, right bundle branch block, ventricular fibrillation and
      sudden death. In this study we characterized a new mutation in the SCN5A gene
      (T1620M), causing the Brugada syndrome. The mutated channels were expressed in
      both Xenopus leavis oocytes and in mammalian tsA201 cells with and without the
      beta-subunit and studied using the patch clamp technique. Opposite phenotypes
      were observed depending on the expression system. T1620M mutation led to a faster
      recovery from inactivation and a shift of steady-state inactivation to more
      positive voltages when expressed in Xenopus oocytes. However, using the mammalian
      expression system no effect on steady-state inactivation was observed, but this
      mutation led to a slower recovery from inactivation. Our finding supports the
      idea that the slower recovery from inactivation of the cardiac sodium channels
      seen in our mammalian expression system could decrease the density of sodium
      channels during the cardiac cycle explaining the in vivo arrhythmogenesis in
      patients with Brugada syndrome.

PMID- 10664448
TI  - Identification of heterochromatin protein 1 (HP1) as a phosphorylation target by
      Pim-1 kinase and the effect of phosphorylation on the transcriptional repression
      function of HP1(1).
AB  - Pim-1, a protooncogene product, is a serine/threonine kinase and is thought to
      play a role in signal transduction in blood cells. Few phosphorylated target
      proteins for Pim-1, however, have been identified. In the present study, two
      hybrid screening to clone cDNAs encoding proteins binding to Pim-1 was carried
      out, and a cDNA for heterochromatin protein 1gamma (HP1gamma) was obtained.
      Binding assays both in yeast and in vitro pull-down using the purified HP1gamma
      and Pim-1 expressed in Escherichia coli showed that Pim-1 directly bound to the
      chromo shadow domain of HP1gamma. HP1gamma was also associated with Pim-1 in
      human HeLa cells and the serine clusters located at the center of HP1gamma were
      phosphorylated by Pim-1 in vitro. Furthermore, a transcription repression
      activity of HP1gamma was further stimulated by the deletion of the serine
      clusters targeted by Pim-1. These results suggest that Pim-1 affects the
      structure or silencing of chromatin by phosphorylating HP1.

PMID- 10664449
TI  - The Leu-132 of the Ste4(Gbeta) subunit is essential for proper coupling of the G
      protein with the Ste2 alpha factor receptor during the mating pheromone response
      in yeast.
AB  - In order to identify amino acid residues of Ste4p involved in receptor
      recognition and/or receptor-G protein coupling, we employed random in vitro
      mutagenesis and a genetic screening to isolate mutant Ste4p subunits with altered
      pheromone response. We generated a plasmid library containing randomly
      mutagenized Ste4 ORFs, followed by phenotypic selection of ste4p mutants by
      altered alpha pheromone response in yeast cells. Subsequently, we analyzed mutant
      ste4-10 which has a replacement of the almost universally conserved leucine 132
      by phenylalanine. This residue lies in the first blade of the beta propeller
      structure proposed by crystallographic analysis. By overexpression experiments we
      found that mutant ste4p subunit triggers the mating pathway at wild type levels
      in both wild type and receptorless strains. When expressed in a ste4 background,
      however, the mutant G protein is activated inefficiently by mating pheromone in
      both a and alpha cells. The mutant ste4-10p was tested in the two-hybrid system
      and found to be defective in its interaction with the Gpa1p, but has a normal
      association with the C-termini end of the Ste2p receptor. These observations
      strongly suggest that the Leu-132 of the Ste4p subunit is essential for efficient
      activation of the G protein by the pheromone-stimulated receptor and that this
      domain could be an important point for physical interaction between the Gbeta and
      the Galpha subunits.

PMID- 10664450
TI  - Redoxal as a new lead structure for dihydroorotate dehydrogenase inhibitors: a
      kinetic study of the inhibition mechanism.
AB  - Mitochondrial dihydroorotate dehydrogenase (DHOdehase; EC 1.3.99.11) is a target
      of anti-proliferative, immunosuppressive and anti-parasitic agents. Here,
      redoxal, (2,2'-[3,3'-dimethoxy[1, 1'-biphenyl]-4,4'-diyl)diimino]bis-benzoic
      acid, was studied with isolated mitochondria and the purified recombinant human
      and rat enzyme to find out the mode of kinetic interaction with this target. Its
      pattern of enzyme inhibition was different from that of cinchoninic, isoxazol and
      naphthoquinone derivatives and was of a non-competitive type for the human
      (K(ic)=402 nM; K(iu)=506 nM) and the rat enzyme (K(ic)=116 nM; K(iu)=208 nM). The
      characteristic species-related inhibition of DHOdehase found with other compounds
      was less expressed with redoxal. In human and rat mitochondria, redoxal did not
      inhibit NADH-induced respiration, its effect on succinate-induced respiration was
      marginal. This was in contrast to the sound effect of atovaquone and
      dichloroallyl-lawsone, studied here for comparison. In human mitochondria, the
      IC(50) value for the inhibition of succinate-induced respiration by atovaquone
      was 6.1 microM and 27.4 microM for the DHO-induced respiration; for dichlorallyl
      lawsone, the IC(50) values were 14.1 microM and 0.23 microM.

PMID- 10664451
TI  - Recombinant NeutraLite avidin: a non-glycosylated, acidic mutant of chicken
      avidin that exhibits high affinity for biotin and low non-specific binding
      properties.
AB  - A recombinant non-glycosylated and acidic form of avidin was designed and
      expressed in soluble form in baculovirus-infected insect cells. The mutations
      were based on the same principles that guided the design of the chemically and
      enzymatically modified avidin derivative, known as NeutraLite Avidin. In this
      novel recombinant avidin derivative, five out of the eight arginine residues were
      replaced with neutral amino acids, and two of the lysine residues were replaced
      by glutamic acid. In addition, the carbohydrate-bearing asparagine-17 residue was
      altered to an isoleucine, according to the known sequences of avidin-related
      genes. The resultant mutant protein, termed recombinant NeutraLite Avidin,
      exhibited superior properties compared to those of avidin, streptavidin and the
      conventional NeutraLite Avidin, prepared by chemo-enzymatic means. In this
      context, the recombinant mutant is a single molecular species, which possesses
      strong biotin-binding characteristics. Due to its acidic pI, it is relatively
      free from non-specific binding to DNA and cells. The recombinant NeutraLite
      Avidin retains seven lysines per subunit, which are available for further
      conjugation and derivatization.

PMID- 10664452
TI  - Efficient introduction of aryl bromide functionality into proteins in vivo.
AB  - Artificial proteins can be engineered to exhibit interesting solid state, liquid
      crystal or interfacial properties and may ultimately serve as important
      alternatives to conventional polymeric materials. The utility of protein-based
      materials is limited, however, by the availability of just the 20 amino acids
      that are normally recognized and utilized by biological systems; many desirable
      functional groups cannot be incorporated directly into proteins by biosynthetic
      means. In this study, we incorporate para-bromophenylalanine (p-Br-phe) into a
      model target protein, mouse dihydrofolate reductase (DHFR), by using a bacterial
      phenylalanyl-tRNA synthetase (PheRS) variant with relaxed substrate specificity.
      Coexpression of the mutant PheRS and DHFR in a phenylalanine auxotrophic
      Escherichia coli host strain grown in p-Br-phe-supplemented minimal medium
      resulted in 88% replacement of phenylalanine residues by p-Br-phe; variation in
      the relative amounts of phe and p-Br-phe in the medium allows control of the
      degree of substitution by the analog. Protein expression yields of 20-25 mg/l
      were obtained from cultures supplemented with p-Br-phe; this corresponds to about
      two-thirds of the expression levels characteristic of cultures supplemented with
      phe. The aryl bromide function is stable under the conditions used to purify DHFR
      and creates new opportunities for post-translational derivatization of brominated
      proteins via metal-catalyzed coupling reactions. In addition, bromination may be
      useful in X-ray studies of proteins via the multiwavelength anomalous diffraction
      (MAD) technique.

PMID- 10664453
TI  - Cross-talk between posttranscriptionally silenced neomycin phosphotransferase II
      transgenes.
AB  - Tobacco plants containing a transgene locus with two chimeric neomycin
      phosphotransferase II (nptII) genes in tail-to-tail orientation (locus 1) show
      posttranscriptional gene silencing. The silenced nptII transgenes of locus 1 can
      downregulate the expression of homologous nptII transgenes in hybrid plants. The
      3' region of the silenced nptII genes located in the center of the inverted
      repeat locus 1 is extensively methylated. Moreover, 3' segments of in trans
      inactivated transgenes also become methylated, suggesting cross-talk between
      homologous posttranscriptionally silenced genes. Our results are in accordance
      with the hypothesis that this cross-talk can be mediated by specially featured
      RNAs.

PMID- 10664454
TI  - Drug-induced hypomethylation of a posttranscriptionally silenced transgene locus
      of tobacco leads to partial release of silencing.
AB  - The effect of DNA methylation upon posttranscriptional gene silencing (PTGS) has
      been investigated in transgenic tobacco lines showing PTGS and methylation of the
      neomycin phosphotransferase II (nptII) reporter genes. Application of the
      hypomethylation drugs dihydroxypropyladenine or 5-azacytidine resulted in
      approximately 30% reduced methylation of cytosines located in a non-symmetrical
      context in the 3' untranslated region of the nptII transgenes. The
      hypomethylation was accompanied by up to 12-fold increase in NPTII protein
      levels, suggesting that methylation of non-symmetrical motifs may account for an
      increased degree of PTGS. Models for the possible role of DNA methylation in PTGS
      are discussed.

PMID- 10664455
TI  - Visible light-induced destabilization of endocytosed liposomes.
AB  - The potential biomedical utility of the photoinduced destabilization of liposomes
      depends in part on the use of green to near infrared light with its inherent
      therapeutic advantages. The polymerization of bilayers can be sensitized to green
      light by associating selected amphiphilic cyanine dyes, i.e. the cationic 1,1'
      dioctadecyl-3,3,3', 3'-tetramethylindocarbocyanine (DiI), or the corresponding
      anionic disulfonated DiI (DiI-DS), with the lipid bilayer. The DiI sensitization
      of the polymerization of 1, 2-dioleoyl-sn-glycero-3-phosphoethanolamine/1,2
      bis[10-(2', 4'-hexadienoyloxy)-decanoyl]-sn-glycero-3-phosphocholine liposomes
      caused liposome destabilization with release of encapsulated aqueous markers. In
      separate experiments, similar photosensitive liposomes were endocytosed by
      cultured HeLa cells. Exposure of the cells and liposomes to 550 nm light caused a
      net movement of the liposome-encapsulated 8-hydroxypyrene-1,3,6-trisulfonic acid
      (HPTS) from low pH compartment(s) to higher pH compartment(s). This suggests that
      photolysis of DiI-labelled liposomes results in delivery of the contents of the
      endocytosed liposomes to the cytoplasm. The release of HPTS into the cytoplasm
      appears to require the photoactivated fusion of the labelled liposomes with the
      endosomal membrane. These studies aid in the design of visible light sensitive
      liposomes for the delivery of liposome-encapsulated reagents to the cytoplasm.

PMID- 10664456
TI  - Presence of CuZn superoxide dismutase in human serum lipoproteins.
AB  - It has previously been demonstrated that CuZn-superoxide dismutase (SOD) is
      secreted by several human cell lines. This suggests that the circulating enzyme
      derives from both hemolysis and peripheral tissues as a result of cellular
      secretion. In the present report, we evaluated the presence of CuZn-SOD in human
      serum lipoproteins by both enzyme-linked immunosorbent assay and Western blot
      analysis of immunoprecipitated lipoprotein samples. The distribution of CuZn-SOD
      activity among the different lipoprotein fractions was also determined by the
      xanthine/xanthine oxidase method. The results demonstrated that CuZn-SOD is
      noticeably present in serum lipoproteins and mainly in low and high density
      lipoproteins (LDL and HDL). Moreover, experiments performed by incubating CuZn
      SOD with a lipid emulsion and subsequent separation of the lipid fraction by
      ultracentrifugation showed that this enzyme associates in a saturable manner with
      lipids. The CuZn-SOD bound to LDL and HDL could exert a physiological protective
      role against oxidative damage of these lipoprotein classes that carry out a
      crucial role in the cholesterol transport.

PMID- 10664457
TI  - 14-3-3tau associates with a translational control factor FKBP12-rapamycin
      associated protein in T-cells after stimulation by pervanadate.
AB  - Proteins of the 14-3-3 family can associate with and/or modulate the activities
      of a variety of proteins, such as protooncogene and oncogene products, Cdc25
      phosphatases and phosphatidylinositol 3-kinase, and thus are implicated in
      regulation of signaling pathways and the cell cycle. We report here that
      treatment of Jurkat T-cells with an inhibitor of protein tyrosine phosphatase,
      pervanadate, induces the association of 14-3-3tau with a translational control
      factor, FKBP12-rapamycin-associated protein (FRAP), with significant latter's
      autophosphorylation. Coimmunoprecipitation of various mutants of FRAP coexpressed
      with 14-3-3tau in COS-7 cells revealed that 14-3-3tau binds to the C-terminal
      side of FRAP at unknown site(s) different from the predicted binding motifs to
      date.

PMID- 10664458
TI  - beta subunit heterogeneity of L-type Ca(2+) channels in smooth muscle tissues.
AB  - Various beta subunit isoforms stabilize different gating properties of voltage
      gated L-type Ca(2+) channels. We therefore investigated the expression of Ca(2+)
      channel beta subunit isoforms in different smooth muscle types on the protein
      level by immunoblotting and immunoprecipitation employing beta subunit-selective
      sequence-directed antibodies. From the four known beta subunit isoforms only
      beta2 and beta3 were detected in porcine uterus, bovine trachea and bovine aorta
      membranes. Multiple immunoreactive beta2 bands were detected in a tissue
      selective manner indicating structural heterogeneity of beta2.
      Immunoprecipitation of (+)-[(3)H]isradipine-prelabeled channels revealed that
      beta2 and beta3 participate in Ca(2+) channel formation in uterus and trachea,
      and beta3 in aortic smooth muscle. We conclude that beta2 and beta3 subunits form
      L-type Ca(2+) channels in smooth muscle tissues. This subunit heterogeneity may
      be important to fine-tune channel function.

PMID- 10664459
TI  - Two carbohydrate recognition domains of Hyphantria cunea lectin bind to bacterial
      lipopolysaccharides through O-specific chain.
AB  - We previously identified a novel lectin cDNA from the fall webworm [Shin et al.
      (1998) Insect Biochem. Mol. Biol. 28, 827-837], which encodes two carbohydrate
      recognition domains (CRD-N and CRD-C) and is up-regulated following bacterial
      challenge. The lipopolysaccharide (LPS) binding activities of the recombinant CRD
      N and CRD-C (rCRD-N and rCRD-C) were investigated by enzyme-linked immunosorbent
      assay. The LPS binding of rCRD-N and rCRD-C was pH-dependent: at pH below 6.0,
      they show a higher binding ability to LPS. The binding of the rCRD-N was
      inhibited by both D-mannose and N-acetyl-D-glucosamine, whereas the binding of
      the rCRD-C was inhibited only by D-mannose. The binding of both rCRD-N and rCRD-C
      to Escherichia coli was mainly mediated through the O-specific chain.

PMID- 10664460
TI  - Vav, a GDP/GTP nucleotide exchange factor, interacts with GDIs, proteins that
      inhibit GDP/GTP dissociation.
AB  - Vav functions as a specific GDP/GTP nucleotide exchange factor which is regulated
      by tyrosine phosphorylation in the hematopoietic system. Loss of the amino
      terminus sequences of Vav was sufficient to control its transforming potential
      and its function in T cells. We report here the identification of the
      hematopoietic GDP dissociation inhibitor protein, Ly-GDI, as a protein that
      interacts with the amino-terminus of Vav. Further analysis confirmed that Vav and
      Ly-GDI interact both in in vitro and in in vivo assays. This association is
      maximal only when the amino region of Vav is intact and requires an intact
      carboxy-terminus of Ly-GDI. The interaction between Vav and Ly-GDI is not
      dependent on the tyrosine phosphorylation status of Vav. In addition, Rho-GDI,
      the highly homologous protein to Ly-GDI, associates with Vav as well. The
      contribution of the interaction between Vav and GDIs, proteins that are involved
      in the GDP/GTP exchange processes, to the biological function of Vav is further
      discussed.

PMID- 10664461
TI  - Binding properties of a highly potent and selective iodinated aminopeptidase N
      inhibitor appropriate for radioautography.
AB  - Aminopeptidase N (APN) is a zinc metallopeptidase involved in the inactivation of
      biologically active peptides. The knowledge of its precise distribution is
      crucial to investigate its physiological role. This requires the use of
      appropriate probes such as the recently developed highly potent and selective
      radiolabeled APN inhibitor 2(S)-benzyl-3-[hydroxy(1'(R)
      aminoethyl)phosphinyl]propanoyl-L-3-[ (12 5)I]iodotyrosine ([(125)I]RB 129). Its
      binding properties were investigated using rat brain homogenates (K(d)=3.4 nM) or
      APN expressed in COS-7 cells (K(d)=0.9 nM). The specific binding was 95% at
      [K(d)], and preliminary autoradiography in intestine is promising. The decreased
      affinity of [(125)I]RB 129 (=10(-6) M) for the E(350)D APN mutant, supports the
      critical role of E(350) in the amino-exopeptidase action of APN.

PMID- 10664462
TI  - The influence of ATP on the binding of aromatic amino acids to the ligand
      response domain of the tyrosine repressor of Haemophilus influenzae.
AB  - The binding of aromatic amino acids to the ligand response domain of the tyrosine
      repressor (TyrR) protein (TyrR(lrd)) of Haemophilus influenzae was investigated
      using circular dichroism and fluorescence spectroscopy. The induced secondary
      structural changes were unique for each aromatic amino acid and were further
      influenced by the presence or absence of ATP. Tyrosine was found to have the
      highest affinity for TyrR(lrd) in the absence of ATP, whereas the affinity for
      ATP itself increased in the presence of tyrosine. Binding of tyrosine is
      therefore the conformational trigger for the activation of TyrR whereas ATP is
      regarded as a conformational co-activator.

PMID- 10664463
TI  - Interaction of the Grb7 adapter protein with Rnd1, a new member of the Rho
      family.
AB  - Grb7 is a member of a family of molecular adapters which are able to contribute
      positively but also negatively to signal transduction and whose precise roles
      remain obscure. Rnd1 is a member of the Rho family, but, as opposed to usual
      GTPases, it is constitutively bound to GTP. We show here that Rnd1 and Grb7
      interact, in two-hybrid assays, in vitro, and in pull-down experiments performed
      with SK-BR3, a breast cancer cell line that overexpresses Grb7. This interaction
      involves switch II loop of Rnd1, a region crucial for guanine nucleotide exchange
      in all GTPases, and a Grb7 SH2 domain, a region crucial for Grb7 interaction with
      several activated receptors. The contribution of the interaction between Rnd1 and
      Grb7 to their respective functions and properties is discussed.

PMID- 10664464
TI  - Different lumen-targeting pathways for nuclear-encoded versus
      cyanobacterial/plastid-encoded Hcf136 proteins.
AB  - Lumenal proteins are transported across the thylakoid membrane by two very
      different pathways: Sec-dependent or twin-arginine translocase (Tat)-dependent,
      where the substrate protein can be transported in a folded state. We present the
      first evidence that a given protein can be targeted by different pathways in
      different organisms. Arabidopsis Hcf136 is targeted exclusively by the Tat
      pathway in pea chloroplasts and no Sec-dependent transport is evident even when
      the twin-arginine is replaced by twin-lysine. However, twin-arginine motifs are
      absent from the presequences of Hcf136 proteins encoded by plastid or
      cyanobacterial genomes, strongly implying translocation by another pathway
      (presumably Sec). We suggest that the Hcf136 protein was transferred to the Tat
      pathway when the gene became incorporated into the nuclear genome, possibly due
      to the tighter folding associated with the more involved, post-translational
      targeting pathway.

PMID- 10664465
TI  - ATP synthesis at 100 degrees C by an ATPase purified from the hyperthermophilic
      archaeon Pyrodictium abyssi.
AB  - The chemolithoautotrophic archaeon Pyrodictium abyssi isolate TAG 11 lives close
      to 100 degrees C and gains energy by sulfur respiration, with hydrogen as
      electron donor. From the membranes of this hyperthermophile, an ATPase complex
      was isolated. The purified enzyme consists of six major polypeptides, the 67, 51,
      41, 26 and 22 kDa subunits composing the AF(1) headpiece, and the 7 kDa
      proteolipid of the AF(0) component. The headpiece of the enzyme restored the
      formation of ATP during sulfur respiration in membrane vesicles from which it had
      been removed by low salt treatment. Characteristics of the reconstituted activity
      suggest that the same enzyme is responsible for ATP formation in untreated
      membranes. ATP formation was neither sensitive to ionophores and uncouplers, nor
      to dicyclohexyl carbodiimide, but depended on closed vesicles. Both ATPase
      activity (up to 2 micromol per min and mg protein) as well as ATP formation (up
      to 0.4 micromol per min and mg membrane protein) were highest at 100 degrees C. A
      P/e2 ratio of close to one can be estimated for sulfur respiration with hydrogen.
      In addition to ATP, autoradiographic detection revealed the formation of high
      quantities of (33)P(i)-labeled ADP and of another compound not identified so far.

PMID- 10664466
TI  - Purification of the 45 kDa, membrane bound NADH dehydrogenase of Escherichia coli
      (NDH-2) and analysis of its interaction with ubiquinone analogues.
AB  - The NADH:ubiquinone reductase (NDH-2) of Escherichia coli was expressed as a His
      tagged protein, extracted from the membrane fraction using detergent and purified
      by chromatography. The His-tagged NDH-2 was highly active and catalyzed NADH
      oxidation by ubiquinone-1 at rates over two orders of magnitude higher than
      previously reported. The purified, His-tagged NDH-2, like native NDH-2, did not
      oxidize deamino-NADH. Steady-state kinetics were used to analyze the enzyme's
      activity in the presence of different electron acceptors. High V(max) and low
      K(m) values were only found for hydrophobic ubiquinone analogues, particularly
      ubiquinone-2. These findings strongly support the notion that NDH-2 is a membrane
      bound enzyme, despite the absence of predicted transmembrane segments in its
      primary structure. The latter observation is in agreement with possible
      evolutionary relation between NDH-2 and water-soluble enzymes such as
      dihydrolipoamide dehydrogenase. There is currently no clear indication of how NDH
      2 binds to biological membranes.

PMID- 10664467
TI  - The molecular chaperone Cdc37 is required for Ste11 function and pheromone
      induced cell cycle arrest.
AB  - The molecular chaperone Cdc37 is thought to act in part as a targeting subunit of
      the heat-shock protein 90 (Hsp90) chaperone complex. We demonstrate here that
      Cdc37 is required for activity of the kinase Ste11 in budding yeast. A cdc37
      mutant strain is defective in Ste11-mediated pheromone signaling and in
      accumulation and functional maturation of the constitutively active Ste11 version
      Ste11DeltaN. Moreover, Cdc37, Ste11DeltaN and Hsp90 coprecipitate pairwise. Thus,
      Hsp90 and Cdc37 may transiently associate with Ste11 to promote proper folding
      and/or association with additional regulatory factors. Our results establish
      Ste11 as the first endogenous Cdc37 client protein in yeast.

PMID- 10664468
TI  - Mutational analysis of 4-coumarate:CoA ligase identifies functionally important
      amino acids and verifies its close relationship to other adenylate-forming
      enzymes.
AB  - 4-Coumarate:coenzyme A ligase (4CL) is a key enzyme of general phenylpropanoid
      metabolism which provides the precursors for a large variety of important plant
      secondary products, such as lignin, flavonoids, or phytoalexins. To identify
      amino acids important for 4CL activity, eight mutations were introduced into
      Arabidopsis thaliana At4CL2. Determination of specific activities and K(m) values
      for ATP and caffeate of the heterologously expressed and purified proteins
      identified four distinct classes of mutants: enzymes with little or no catalytic
      activity; enzymes with greatly reduced activity but wild-type K(m) values;
      enzymes with drastically altered K(m) values; and enzymes with almost wild-type
      properties. The latter class includes replacement of a cysteine residue which is
      strictly conserved in 4CLs and had previously been assumed to be directly
      involved in catalysis. These results substantiate the close relationship between
      4CL and other adenylate-forming enzymes such as luciferases, peptide synthetases,
      and fatty acyl-CoA synthetases.

PMID- 10664469
TI  - Steroid RU 486 inducible myogenesis by 10T1/2 fibroblastic mouse cells.
AB  - For reconstruction or repair of damaged tissues, an artificially regulated switch
      from proliferation to differentiation would be of great advantage. To achieve
      conditional myogenesis, we expressed MyoD in mouse C3H 10T1/2 fibroblastic cells,
      using a gene regulation system based on the synthetic steroid RU 486. By stable
      co-transfection of a plasmid construct with the RU 486 dependent activator and an
      integrating inducible MyoD construct, a cell clone, designated 10T-RM, was
      obtained in which MyoD expression was stringently controlled by RU 486. 12 h
      after addition of 10 nM RU 486 to 10T-RM cells, saturation levels of MyoD mRNA
      were observed and >/=2 days later, mRNA for embryonal myosin heavy chain
      (MyHC(emb)) was abundant and mononucleated cells fused into myotubes.

PMID- 10664470
TI  - Alternative splicing within the TGF-beta type I receptor gene (ALK-5) generates
      two major functional isoforms in vascular smooth muscle cells.
AB  - We have identified in rat vascular smooth muscle cells (SMCs) the simultaneous
      expression of two TGF-beta type I receptor (ALK-5) cDNAs, occurring as a
      consequence of alternate usage of AG splice acceptor motifs separated by 12
      nucleotides located at an intron-exon junction. When translated the resultant
      full length proteins differ from each other only by the in-frame presence or
      absence of Gly-Pro-Phe-Ser residues adjacent to their transmembrane domain.
      Stable expression of these alternate ALK-5 isoforms in ALK-5-deficient cells
      demonstrated that both were competent in signaling TGF-beta-induced growth
      inhibition and gene transcription, but with an apparently distinct potency. Our
      data suggest that alternate splicing within the ALK-5 gene is an important
      mechanism whereby SMCs may regulate their response to TGF-beta.

PMID- 10664471
TI  - Corrigendum to: Co-operativity between modules within a C3b-binding site of
      complement receptor type 1.

PMID- 10664473
TI  - Anti-arthritic effect of methotrexate: is it really mediated by adenosine?
AB  - The mechanism of action for the anti-arthritic effect of methotrexate (MTX) was
      investigated in rats with antigen-induced arthritis (AIA). Arthritis intensity
      was quantified as area under the curve (AUC) for the joint swelling. The response
      to MTX was in several respects similar to what is seen in the clinic. The drug
      reduced the AUC in a dose-dependent manner after oral weekly (2-4 mg/kg/week) or
      daily (0.3 mg/kg/day) dosing. This effect was not affected by supplementation
      with an equal dose of folate. The model thus seemed suitable for this type of
      study. Supplementation with folate in excess abolished the effect of MTX. A
      structurally similar antifolate, aminopterin, also reduced the arthritis. The
      effect thus seemed to be due to folate antagonism although a complete inhibition
      of dihydrofolate reductase (DHFR) might not be essential. Hence, it could be that
      the main target is a process downstream of DHFR. It has been proposed that
      inhibition of AICAR-transformylase induce the release of adenosine with anti
      inflammatory properties. Here the adenosine antagonist R-PIA reduced the
      arthritis but when MTX was combined with adenosine antagonists no attenuation of
      the anti-arthritic effect was seen. On the contrary, three adenosine agonists (8
      p-sulphophenyltheophyllamine 30 mg/kg i.p. twice daily; 3,7-dimethyl-1
      propargylxanthine, p.o. 3 mg/kg/day and 8-cyclopentyl-1,3-dipropylxanthine, 1.5
      mg/kg/day p.o.) potentiated MTX. The specific thymidylate synthase inhibitor 5
      fluourouracil (0. 3-3.0 mg/kg/day) had no anti-arthritic effect. Neither did our
      data support the hypotheses that syntheses of polyamines or cytokines were
      primary targets. It is thus possible that the mechanism of action is inhibition
      of a process downstream of DHFR but the release of adenosine seems not to be
      important.

PMID- 10664474
TI  - 1-[1-(2-Benzo[b]thiopheneyl)cyclohexyl]piperidine hydrochloride (BTCP) yields two
      active primary metabolites in vivo. Identification and quantification of BTCP
      primary metabolites in mice plasma, urine, and brain and their affinity for the
      neuronal dopamine transporter.
AB  - 1-[1-(2-Benzo[b]thiopheneyl)cyclohexyl]piperidine hydrochloride (BTCP) and
      cocaine bind to the neuronal dopamine transporter (DAT) to strongly inhibit
      dopamine (DA) reuptake. Although similar to acute administration, cocaine and
      BTCP produce sensitization and tolerance, respectively, on chronic
      administration. We previously found that liver microsomes produced two primary
      metabolites from BTCP with a high affinity for DAT. Because such metabolites, if
      produced in vivo, could account for the pharmacological difference with cocaine,
      it was important to compare BTCP biotransformations in vitro and in vivo.
      Therefore, we identified and quantified BTCP and primary metabolites in mice
      urine, plasma, and brain after acute i.p. administration. The low recovery yield
      suggest that BTCP might behave like its close analogue, phencyclidine, with long
      term storage of metabolites. Two active metabolites found in vitro were found in
      mice brain with estimated half-life values similar to that of BTCP (
      approximately 0.3 h). Although respective brain concentrations were 20 and 40
      times lower than that of BTCP, their potency to displace in vivo [3H]BTCP bound
      to the DAT was 50 and 10 times higher, respectively, than that of BTCP. They
      could, therefore, contribute to the inhibition of DA transport and play an
      important role in BTCP pharmacology. They could also explain the differences
      between BTCP and cocaine on repeated administration.

PMID- 10664475
TI  - Inhibition of platelet aggregation and 5-HT release by extracts of Australian
      plants used traditionally as headache treatments.
AB  - To identify potential migraine therapeutics, extracts of eighteen plants were
      screened to detect plant constituents affecting ADP induced platelet aggregation
      and [14C]5-hydroxytryptamine (5-HT) release. Extracts of the seven plants
      exhibiting significant inhibition of platelet function were reanalysed in the
      presence of polyvinyl pyrrolidone (PVP) to remove polyphenolic tannins that
      precipitate proteins. Two of these extracts no longer exhibited inhibition of
      platelet activity after removal of tannins. However, extracts of Crataegus
      monogyna, Ipomoea pes-caprae, Eremophila freelingii, Eremophila longifolia, and
      Asteromyrtus symphyocarpa still potently inhibited ADP induced human platelet
      [14C]5-HT release in vitro, with levels ranging from 62 to 95% inhibition. I. pes
      caprae, and C. monogyna also caused significant inhibition of ADP induced
      platelet aggregation. All of these plants have been previously used as
      traditional headache treatments, except for C. monogyna which is used primarily
      for protective effects on the cardiovascular system. Further studies elucidating
      the compounds that are responsible for these anti-platelet effects are needed to
      determine their exact mechanism of action.

PMID- 10664476
TI  - Evaluation of transcutol as a clonazepam transdermal permeation enhancer from
      hydrophilic gel formulations.
AB  - The influence of diethyleneglycol monoethyl ether (transcutol), alone or in
      combination with propylene glycol, on clonazepam permeation through an artificial
      membrane and excised rabbit ear skin from Carbopol hydrogels was investigated.
      Drug kinetic permeation parameters were determined for both series of experiments
      and compared. Rheological characteristics, drug solubility and membrane/vehicle
      partition coefficient for each gel formulation were also determined, and their
      role in the formulation performance was investigated. Both series of experiments
      showed an increase of drug permeation as a function of transcutol content in the
      formulation. The combination of transcutol and propylene glycol resulted in a
      synergistic enhancement of clonazepam flux. A different trend was found in
      experiments with gels containing mixtures of the two enhancers, where an increase
      (in the case of artificial membrane) or a decrease (in the case of rabbit ear
      skin) of drug permeation was found by increasing the transcutol/propylene glycol
      ratio in the mixture. Such a result is explained on the basis of the particular
      mechanism of action demonstrated for transcutol which associates the increase of
      drug solubility to the potent effect of a depot in the skin.

PMID- 10664477
TI  - Chitosan microspheres with hydrocortisone and hydrocortisone-hydroxypropyl-beta
      cyclodextrin inclusion complex.
AB  - In the present study, an inclusion complex composed of hydrocortisone acetate
      (HC) and hydroxypropyl-beta-cyclodextrin (HPbetaCD) was prepared by the spray
      drying method. HC alone, HC inclusion complex or HC with HPbetaCD as a physical
      mixture were incorporated into chitosan microspheres by spray-drying. The
      inclusion complex and microspheres were characterized by X-ray powder
      diffractometry and differential scanning calorimetry (DSC). Microspheres were
      studied with respect to particle size distribution, drug content and in vitro
      drug release. The results indicate that the HCHPbetaCD inclusion complex is more
      water soluble than HC alone. The HC release rates from chitosan microspheres were
      influenced by the drug/polymer ratio in the manner that an increase in the
      release rate was observed when the drug loading was decreased. However, release
      data from all samples showed significant improvement of the dissolution rate for
      HC, with 25-40% of the drug being released in the first hour compared with about
      5% for pure HC. The complexation method and microsphere preparation method (spray
      drying) is simple with great potential for industrial production.

PMID- 10664478
TI  - Complexation of the interferon inducer, bropirimine, with hydroxypropyl-beta
      cyclodextrin.
AB  - Bropirimine (ABPP) is an orally active immunomodulator that increases endogenous
      alpha-interferon and other cytokines used clinically against carcinoma in situ of
      the bladder. The oral absorption of ABPP is poor because its low solubility in
      water. The purpose of this study is to develop a technological procedure useful
      to increase the water solubility of ABPP. To this end, the interaction of ABPP
      with several cyclodextrin derivatives-alpha-, beta-, gamma- and hydroxypropyl
      beta-cyclodextrin with a degree of substitution 2.7 (HPbetaCD) was studied and
      the effect of the complexation process on the water solubility of the drug was
      evaluated. The best results were obtained with the hydroxypropyl derivative,
      HPbetaCD, that interacts in a 1:1 drug:cyclodextrin molar ratio. The inclusion
      complex ABPP-HPbetaCD was characterized in solution by nuclear magnetic resonance
      (1H-NMR). The solid inclusion complex was obtained by freeze-drying and
      characterized by differential scanning calorimetry (DSC), X-ray diffractometry
      and mass spectrometry. The dissolution rate of ABPP from the HPbetaCD solid
      inclusion complex was increased compared to the powdered drug but not differences
      were found between the complex and a physical mixture with a similar molar ratio.
      The increase of the dissolution rate of the drug can be attributed to the
      breakdown in solution of the drug dimers in the presence of the cyclodextrin and
      to the complex formation.

PMID- 10664479
TI  - Nasal toxicological investigations of Carbopol 971P formulation of apomorphine:
      effects on ciliary beat frequency of human nasal primary cell culture and in vivo
      on rabbit nasal mucosa.
AB  - OBJECTIVE: The objective of this study was to investigate the nasal toxicity of a
      mucoadhesive Carbopol 971P formulation of apomorphine. MATERIALS AND METHODS: The
      effects of different concentrations of Carbopol 971P and apomorphine on ciliary
      beat frequency (CBF) were studied in suspension cultures of human nasal
      epithelial cells. The rabbit nasal mucosal tolerance of the formulation and its
      components were investigated using light microscopy. Different groups of the
      rabbits received twice daily, air puffs, glucose, glucose/apomorphine, Carbopol
      971P or Carbopol 971P/apomorphine for 1 week (glucose-treated rabbits) or 1, 2
      and 4 weeks (other treatments). RESULTS: Both Carbopol 971P and apomorphine
      showed both concentration- and time-dependent inhibitory effects on the CBF. The
      effects on CBF were: apomorphine, 1.0% w/v, irreversible ciliostasis; 0.1 and
      0.5% w/v, reversible cilio-inhibition; 0.01%w/v, irreversible cilio-stimulation;
      and Carbopol 971P, 0.1 and 0.25% w/v, partially-reversible cilio-inhibition.
      Glucose and glucose/apomorphine physical mixture caused mild inflammation.
      Carbopol 971P (both with and without apomorphine) caused severe inflammation,
      which increased with duration of treatment. Necrosis, squamous metaplasia or
      ciliary degeneration was not observed. CONCLUSIONS: Due to the severe
      inflammation caused by Carbopol 971P with and without apomorphine, we conclude
      that this polymer is not a suitable carrier for intranasal administration of
      apomorphine. This is in spite of the reversible effects of Carbopol 971P (0.1 and
      0. 25% w/v) and apomorphine (0.1 and 0.5% w/v) on CBF.

PMID- 10664480
TI  - Modulating active stiffness affects head stabilizing strategies in young and
      elderly adults during trunk rotations in the vertical plane.
AB  - Healthy young and elderly adults were asked to actively modulate neck muscle
      stiffness during random rotations of the trunk in the vertical plane. Angular
      velocity of head with respect to trunk and myoelectric activity of semispinalis
      capitis and sternocleidomastoid muscles were recorded. A MANOVA was performed on
      group, condition, and frequency variables. A gain and phase drop at 2.15 Hz in
      young adults indicated neural (i.e. reflex) damping of system mechanics. In the
      elderly, a steady rise in gain and drop in phase (P<0.0002) was indicative of a
      second order underdamped system. Even when instructed to not intervene elderly
      subjects exhibited cocontraction. Ineffective reflex mechanisms may underlie the
      emergence of this strategy.

PMID- 10664481
TI  - Specificity of postural sway to the demands of a precision task.
AB  - We examined a precision aiming task in which a handheld laser pointer was
      controlled by the postural system. The task was performed in two orientations of
      the body's coronal plane to the target. In the parallel orientation medio-lateral
      (ML) sway had to be minimized, in the perpendicular orientation antero-posterior
      (AP) sway had to be minimized. In the parallel orientation ML sway decreased and
      AP sway increased with target distance and size. The pattern reversed in the
      perpendicular orientation. Nonlinear measures found independence of the two
      directions of sway and differences in their deterministic structure. Apparently a
      postural organization for upright standing and aiming (as in archery) entails two
      independent postural subsystems with different but reciprocally related dynamics.
      Furthermore, it seems as if some amount of postural variability is needed to
      ensure stability in quiet standing; if postural activity is reduced in one
      direction it is compensated for in the other direction.

PMID- 10664482
TI  - An index for quantifying deviations from normal gait.
AB  - A method is derived to calculate the amount by which a subject's gait deviates
      from an average normal profile, and to represent this deviation as a single
      number. The method uses principal component analysis to derive a set of 16
      independent variables from 16 selected gait variables. The sum of the square of
      these 16 independent variables is interpreted as the deviation of the subject's
      gait from normal. Statistical tests of the method's validity and an initial
      demonstration of its clinical utility are included. It is found that using this
      index, increasing clinical involvement corresponds to increasing index score.

PMID- 10664483
TI  - Validity and reliability of a kinematic protocol for determining foot contact
      events.
AB  - Timing of foot contact events provides important information for gait studies.
      The aim of the study is to validate the use of kinematic data, collected at 50 Hz
      to define foot contact events during gait initiation. Simultaneous kinetic and
      kinematic data recordings of four discrete foot contact events were made for
      normal adults. Raters were asked to estimate the timing of the events from
      kinematic data curves and these timings were compared with those derived from the
      kinetic data. For the four events, between 88 and 98% of all ratings were
      accurate to within 0.03 s. Inter-rater reliability was extremely high, reflecting
      the precision of the definitions used.

PMID- 10664484
TI  - Comparison of surface mounted markers and attachment methods in estimating tibial
      rotations during walking: an in vivo study.
AB  - The overall goal of this work was to determine an optimal surface-tracking marker
      set for tracking motion of the tibia during natural cadence walking. Eleven
      different marker sets were evaluated. The marker sets differed in the location
      they were attached to the shank, the method used to attach the marker sets to the
      segment and the physical characteristics of the marker sets. Angular position
      during stance for each marker set was expressed relative to the orientation of
      the tibia as measured using bone anchored markers. A marker set consisting of
      four markers attached to a rigid shell positioned over the distal lateral shank
      and attached to the leg using an underwrap attachment yielded the best estimate
      of tibial rotation. Rotational deviations of+/-2 degrees about the medio-lateral
      and antero-posterior axes, and+/-4 degrees about the longitudinal axis did occur
      even when using the optimal set of markers.

PMID- 10664485
TI  - Knee joint kinematics from familiarised treadmill walking can be generalised to
      overground walking in young unimpaired subjects.
AB  - We studied the familiarisation time required for reliable sagittal-plane knee
      kinematics and temporal-distance gait measurements to be obtained from treadmill
      walking. We also studied whether knee kinematics and temporal-distance gait
      measurements obtained from familiarised treadmill walking can be generalised to
      overground walking. Sixteen subjects without pathology walked on a level
      overground walkway and on a treadmill. A motion measurement system was used to
      measure sagittal plane knee movements and temporal-distance gait parameters
      during overground and treadmill walking. Highly reliable knee kinematics and
      temporal-distance gait measurements [intraclass correlation coefficient
      (ICC)(2,1)>/=0.93] were found after 6 min of treadmill walking. These
      measurements, obtained after 6 min of treadmill walking, were highly correlated
      with and not significantly different to those of overground walking. Reliable
      measurements that can be generalised to overground walking, can be obtained from
      the treadmill within a familiarisation time of 6 min.

PMID- 10664486
TI  - Gait analysis after ankle arthrodesis.
AB  - The purpose of this study was to employ a computerized motion analysis system to
      identify the effect of ankle arthrodesis on the three-dimensional kinematic
      behavior of the rear and fore foot during level walking. A three-segment rigid
      body model was used to describe the motion of the foot and ankle. The results
      demonstrated that sagittal plane motion of the hindfoot was significantly
      decreased in the foot of patients having had ankle arthrodesis compared to normal
      subjects. The kinematic data indicated a generalized stiffness of the hindfoot on
      the involved foot in the sagittal plane. Sagittal plane movement in the forefoot
      and transverse plane movements in the hindfoot and forefoot increased in patients
      compared to controls.

PMID- 10664487
TI  - Vertical ground reaction forces in patients with unilateral plantar heel pain - a
      pilot study.
AB  - Plantar heel pain (PHP) is a foot pathology commonly reported in both athletic
      and non-athletic populations. The etiology of PHP is complex and identification
      of risk factors associated with PHP is required to predict who is at increased
      risk of injury. Excessive plantar heel force and pressures are intrinsic risk
      factors that may play a contributing role in the development of PHP. Limited
      research, however, has been undertaken in terms of ground reaction forces
      associated with PHP. The aim of the study was to test the hypothesis that there
      were significant differences in the vertical ground reaction forces and loading
      rates at rearfoot contact between symptomatic and contra-lateral asymptomatic
      feet in 23 subjects diagnosed with unilateral PHP. The equipment consisted of a
      portable force plate using a 10-m modular walkway sampled at 200 Hz by an
      independent observer. Paired t-tests demonstrated no significant difference
      (P0.05) in the vertical ground reaction forces and loading rates between the
      symptomatic and contra-lateral asymptomatic feet. The results suggest that single
      risk factors such as vertical ground reaction force and loading rates do not
      contribute to PHP. The authors conclude that a model that incorporates a multi
      factorial approach to risk factors may lead to a better understanding into the
      etiology and management of those individuals who suffer from heel pathologies.

PMID- 10664488
TI  - Recommendations for the use of botulinum toxin type A in the management of
      cerebral palsy.
AB  - Botulinum toxin type A (BTX-A) is increasingly being used for the treatment of
      childhood spasticity, particularly cerebral palsy. However, until very recently,
      all such use in this indication has been unapproved with no generally accepted
      treatment protocols, resulting in considerable uncertainty and variation in its
      use as a therapeutic agent. In view of the increasing awareness of, and interest
      in, this approach to the treatment of spasticity, and also the recent licensing
      in a number of countries of a BTX-A preparation for treating equinus deformity in
      children, it would seem timely to establish a framework of guidelines for the
      safe and efficacious use of BTX-A for treating spasticity in children. This paper
      represents an attempt, by a group of 15 experienced clinicians and scientists
      from a variety of disciplines, to arrive at a consensus and produce detailed
      recommendations as to appropriate patient selection and assessment, dosage,
      injection technique and outcome measurement. The importance of adjunctive
      physiotherapy, orthoses and casting is also stressed.

PMID- 10664489
TI  - Presidential address: time for the future of vascular surgery.

PMID- 10664490
TI  - Cost-effectiveness of surgery for small abdominal aortic aneurysms on the basis
      of data from the United Kingdom small aneurysm trial.
AB  - PURPOSE: Although the United Kingdom small aneurysm trial reported no survival
      benefit for early operation in patients with small (4. 0-5.5 cm) abdominal aortic
      aneurysms (AAAs), the trial lacked statistical power to detect small but
      potentially meaningful gains in life expectancy, particularly for specific
      subgroups. We used decision analysis to better characterize the potential
      benefits and cost-effectiveness of early surgery. METHODS: We used a Markov model
      to assess the marginal cost-effectiveness (incremental cost per quality-adjusted
      life year [QALY] saved) of early surgery relative to surveillance for small AAAs,
      using data from the UK Trial. Subgroup analyses were performed by patient age and
      AAA diameter. Sensitivity analysis was used to evaluate the effect of elective
      operative mortality on cost-effectiveness. RESULTS: In our baseline analysis,
      early operations provided a small survival advantage (0.14 QALYs) at a small
      incremental cost of $1510. Thus, despite a small survival benefit, early surgery
      appeared cost-effective ($10, 800/QALY). The small cost differential resulted
      from the large proportion of patients who underwent surveillance, who eventually
      underwent AAA repair, and therefore incurred the cost of the surgical procedures.
      The survival advantage and cost-effectiveness of early operation increased with
      lower operative mortality, younger age, and larger AAA diameter. CONCLUSION:
      Despite the negative conclusions of the UK trial, early surgery may be cost
      effective for patients with small AAAs, particularly younger patients (<72 years
      of age) with larger AAAs (> or = 4.5 cm). Because the gains in life expectancy
      are relatively small, however, clinical decision making should be strongly guided
      by patient preferences.

PMID- 10664491
TI  - The Balanced Budget Act: potential implications for the practice of vascular
      surgery.
AB  - PURPOSE: Previous study results have shown a favorable impact on stroke rate with
      an increasing hospital volume of carotid endarterectomies (CEAs). This is not
      only the most frequently performed peripheral vascular procedure in the United
      States but also perhaps the most widely dispersed procedure relative to hospital
      type. Medical centers have adopted various strategies to lower the cost of
      hospitalization by reducing the length of stay (LOS), the major component of
      hospital cost. By 2002, the Balanced Budget Act is projected to reduce Medicare
      provider payments to academic medical centers (AMCs) by 15.5%, a reduction that
      is twice that for minor or nonteaching hospitals. We assessed the relationships
      between hospital costs, CEA volume, and stroke-mortality rates in AMCs and non
      AMCs in Massachusetts. METHODS: With patient level data from the Massachusetts
      Division of Health Care Finance and Policy and with hospital cost and charge
      reports from the Health Care Financing Administration, HealthShare Technology
      provided data for all the patients discharged from a Massachusetts hospital who
      underwent CEA (n = 10,211) during the fiscal years 1995, 1996, and 1997,
      including cost, LOS, and disposition. The outcomes were further defined with in
      hospital stroke and mortality rates. Five high volume AMCs (HVAMCs) were compared
      with all other nonacademic hospitals, which were further subdivided by annual
      volume into high volume non-AMCs (> or =50 cases), medium volume non-AMCs (24-49
      cases), and low volume non-AMCs (12-23 cases). Statistical analysis was performed
      with analysis of variance to compare the means of all the cost and LOS data, and
      chi(2) test was used for comparison of incidence (significance assumed for P < or
      =. 05). RESULTS: Hospital costs were comparable among the four hospital types
      during individual years and averaged $6200, but HVAMCs were significantly more
      expensive overall, with a mean cost of $7882. The only centers to decrease their
      costs during the years evaluated were the HVAMCs, from $8706 to $6784. Length of
      stay did not differ among the groups in any year or overall, with a mean of 3.8
      days, but did decrease between years at HVAMCs from 3.9 to 2.5 days. The combined
      stroke-mortality rates were significantly less at the HVAMCs (0.9%) than at
      either the high volume non-AMCs (1.9%) or the medium volume non-AMCs (2.5%).
      There was no significance in the analysis results of all the data within the low
      volume non-AMCs. CONCLUSION: Patients in HVAMCs have the best outcomes after CEA.
      Despite the achievement of significant efficiencies, AMCs have a small cushion to
      reduce further either LOS or resources to maintain a competitive cost position
      and to compensate for the fixed expenses of academic medicine. The Balanced
      Budget Act raises an equity concern for AMCs because it differentially affects
      the centers with the best outcomes. The financial implication of this may be a
      direct incentive for procedures to be done in centers with less optimal outcomes.

PMID- 10664492
TI  - Hospital cost of endovascular versus open repair of abdominal aortic aneurysms: a
      multicenter study.
AB  - BACKGROUND: Technology-driven innovation in medicine is frequently associated
      with higher costs than conventional therapy. A significantly higher cost for
      endovascular ($21,250, n = 190) versus open abdominal aortic aneurysm (AAA)
      repair ($12,342, n = 60) was suggested by a direct cost analysis of patients in a
      multicenter trial. Estimated inpatient costs (not charges) incurred nationwide by
      hospitals for endovascular and open repair of AAA were studied to validate these
      observed trends. METHODS: A retrospective analysis of 131 patients undergoing
      endovascular AAA repair was compared with 49 patients undergoing open repair as
      part of a Food and Drug Administration phase II prospective multicenter clinical
      investigation (AneuRx-Medtronic). A model to estimate costs was constructed using
      important clinical descriptors of these patients. These clinical characteristics
      where then matched with those from 22, 460 patients undergoing AAA repair
      obtained from a large national database (Medicare Provider Analysis and Review).
      Estimated hospital cost was then assigned to each study patient according to the
      national average of the total hospital costs for the respective matched patients
      in Medicare Provider Analysis and Review. RESULTS: Total inpatient hospital costs
      of endovascular repair were significantly higher than that of open repair
      ($19,985 +/- 7396 versus $12,546 +/- 5944, respectively, P =.0001). Endograft
      device cost ($10,400) accounted for 52% of the total cost of endovascular repair.
      The 1999 mean blended Medicare reimbursement for AAA repair was $18,989.
      CONCLUSION: In this early development stage, hospital cost for endovascular AAA
      repair is significantly greater than open repair when device cost greatly exceeds
      $5000. Although incremental reductions in cost of endovascular repair may be
      anticipated if use of diagnostic studies, operating time, and length of stay
      decrease, device cost has the single greatest impact on the expense of
      endovascular AAA repair. At current device pricing, mean blended Medicare
      reimbursement does not cover the cost of endovascular AAA repair.

PMID- 10664493
TI  - Prosthetic patch remnants to treat infected arterial grafts.
AB  - PURPOSE: Our previous experience with the traditional management of infected
      prosthetic arterial grafts, which included graft excision and vein patch repair
      of the involved artery, was complicated by a high incidence of vein patch
      rupture. This study assessed the treatment of infected prosthetic grafts with
      subtotal graft excision and oversewing of small graft remnants. METHODS: During
      the last 20 years, we treated 53 wounds involving 45 infected prosthetic grafts
      in 42 patients by means of subtotal graft excision and oversewing of a residual 2
      to 3-mm graft remnant (patch) at an intact arterial anastomosis. This technique
      was selectively used to maintain patency of small-diameter arteries (41 common
      femoral, five deep femoral, three axillary, two iliac, and two popliteal), which
      were critical for limb salvage or amputation healing. This strategy avoided
      difficult dissection of the underlying artery in scarred wounds and obviated the
      placement of a new patch in an infected field. Graft remnants were
      polytetrafluoroethylene in 51 cases and Dacron in two cases. Of the 45 grafts, 31
      were occluded and 14 were patent. All infected tissue was widely debrided, wet-to
      dry dressing changes were performed three times daily, and appropriate
      intravenous antibiotics were administered for at least 1 week. Secondary bypass
      grafting procedures were performed as needed to achieve limb salvage. The follow
      up period in surviving patients averaged 32 months (range, 1 to 218 months).
      RESULTS: No complications were directly attributable to prosthetic patch remnants
      in 92% of cases (49 of 53 cases). Six of 42 patients (14%) died during
      hospitalization (three of cardiac complications and three of sepsis with multiple
      organ failure). Two infected pseudoaneurysms developed 8 and 34 months after
      surgery, and two wounds failed to heal. Sixteen secondary bypass grafting
      procedures were necessary to achieve limb salvage. Patch oversewing led to limb
      salvage without the need for secondary revascularization in 26 other cases and to
      the successful healing of 10 amputated limbs when secondary revascularization was
      not possible. CONCLUSION: Prosthetic patch remnants are a useful adjunct that
      simplify management of infected prosthetic grafts, are associated with a low
      incidence of wound complications, and help maintain patency of essential
      collaterals to achieve limb salvage or heal an amputation.

PMID- 10664494
TI  - Repair of large abdominal aortic aneurysm should be performed early after
      coronary artery bypass surgery.
AB  - PURPOSE: The surgical repair (coronary artery bypass grafting [CABG]) of
      symptomatic coronary artery disease (CAD) in patients with co-existent large
      abdominal aortic aneurysm (AAA) may result in an increased rate of AAA rupture
      after operation. Simultaneous CABG/AAA repair has been recommended by some
      surgeons, but with a somewhat higher mortality rate than staged repair. We
      reviewed the outcome of staged AAA repair that was performed early after CABG in
      patients with symptomatic coronary disease and AAA. METHODS: The records of all
      the patients with symptomatic CAD that required CABG with large AAA (greater than
      5 cm) were reviewed. In most patients, CABG was performed first, followed by AAA
      repair within 2 weeks. Patient demographics, severity of coronary disease, AAA
      size, interprocedure duration, and perioperative morbidity and mortality rates
      were examined. RESULTS: Between 1991 and 1998, 1105 AAA repairs were performed.
      Within this group, 30 patients with AAA underwent CABG for symptomatic CAD. Mean
      AAA size was 6.6 cm (range, 5.0-10.0 cm). The median interprocedure interval
      between CABG and AAA repair was 11.5 days. There was no in-hospital AAA rupture
      during this interval. The patient group was comprised of 24 men and 6 women with
      a mean age of 71 years. There was no operative death after such staged AAA
      repair, and nonfatal complications occurred in seven patients (23%). During this
      period, seven patients had AAA rupture when they were sent home after CABG for
      recovery and intended AAA repair at a later date. CONCLUSION: Staged elective AAA
      repair may be performed safely and effectively after CABG. Performance of these
      procedures with a short interprocedure interval may be preferable to the higher
      complication rate observed after combined procedures.

PMID- 10664495
TI  - Aortic-origin reconstruction of the great vessels: risk factors of early and late
      complications.
AB  - OBJECTIVE: Great vessel reconstruction for arterial occlusive disease has been
      shown to be a durable procedure. The purpose of this report is the examination of
      the influence of cause and risk factors on outcomes for the identification of
      patients who may be better treated with endovascular techniques or other surgical
      approaches. METHODS: Data for patients who underwent aortic-origin great vessel
      reconstruction between 1988 and 1998 were reviewed. The data were analyzed with
      Fisher exact test, life-table analysis, and log-rank test. RESULTS: Ninety-two
      vessels underwent revascularization in 58 patients (15 men, 43 women; mean age,
      54 years; age range, 20 to 82 years). Etiology was atherosclerosis obliterans (n
      = 40; 69%), Takayasu's arteritis (n = 13; 22%), radiation arteritis (RA; n = 4;
      7%), and mediastinal fibrosis (n = 1; 2%). The symptoms were cerebrovascular (n =
      25), upper extremity (n = 8), or both (n = 23), and two patients were
      asymptomatic. The bypass grafting was performed with single-limb synthetic grafts
      (n = 23) or grafts plus side arms (n = 28). Seven patients underwent innominate
      endarterectomy. The mean follow-up period was 45 months (range, 0 to 126 months).
      The perioperative stroke (n = 4; 7%) and death (n = 2; 3%) rates were not related
      to the cause of disease. The patients with creatinine levels of 2 or more (n = 4)
      had a combined perioperative stroke/death rate of 50% (vs 7% for patients with
      healthy creatinine levels; P <.05). The patients with hypercoagulable states (ie,
      thrombophilia; n = 6) had an increased perioperative stroke rate (33% vs 4% for
      patients without hypercoagulable states; P <.05) and an increased late thrombosis
      rate. The primary and secondary graft patency rates at 5 years were 80% +/- 7%
      and 91% +/- 5%, respectively. Patients with RA had a greater risk of stroke or
      death at 3 years (33% free of stroke or death vs 79% for patients with
      atherosclerosis obliterans and 92% for patients with Takayasu's arteritis; P
      =.02) and an increased major late infection rate (50% vs 2% for all others; P
      =.01). CONCLUSION: Patients with thrombophilia and renal insufficiency have
      increased perioperative stroke and stroke/death rates, respectively. Patients
      with RA have an increased incidence rate of late major infection, which directly
      contributes to an increased rate of stroke or death. Patients with thrombophilia
      have an increased rate of late graft thrombosis. These patient conditions should
      be approached cautiously, and some patients may benefit from endovascular
      therapy.

PMID- 10664496
TI  - Replacement of the inferior vena cava for malignancy: an update.
AB  - OBJECTIVES: Resection and replacement of the inferior vena cava (IVC) to remove
      malignant disease is a formidable procedure. Since our initial report with IVC
      replacement for malignancy, we have maintained an aggressive approach to these
      patients. The purpose of this review is to update our experience with regard to
      patient selection, operative technique, and early and late outcome. METHODS: All
      patients who had IVC replacement for primary (n = 2) or secondary (n = 27) vena
      cava tumors from April 1990 to May 1999 were reviewed. Tumor location and type,
      clinical presentation, the segment of IVC replaced, graft patency, performance
      status of the patient, and tumor recurrence and survival data were collected.
      Late follow-up data were available for all but one patient. The IVC was replaced
      in 28 patients with large diameter (> or =14 mm) externally supported ePTFE
      grafts and with a panel graft of superficial femoral vein in the other. Three
      patients had a femoral arteriovenous fistula. Graft patency was determined before
      hospital dismissal and in follow-up by vena cavography, computed tomography,
      ultrasonography, or magnetic resonance imaging. RESULTS: There were 18 women and
      11 men, with a mean age of 53.1 years (range, 16-88 years). Over one half of
      patients had symptoms from their tumor. IVC replacement was at the suprarenal
      segment in 15 patients, of whom 13 had concomitant major hepatic resection, at
      the infrarenal segment in 10, at both caval segments in three, and at the renal
      vein confluence in one. There were two early deaths (6.9%). One patient died
      intraoperatively of coagulopathy during liver resection and suprarenal IVC
      replacement. The other death occurred 4 months postoperatively, from multisystem
      organ failure that resulted in graft infection and occlusion. Twelve patients had
      one or more major complications- cardiopulmonary problems in five; bleeding in
      five; chylous ascites or large pleural effusions in two patients each; and lower
      extremity edema with tibial vein thrombosis in one. The mean follow-up was 2.8
      years (range, 2.7 months to 6.3 years). Two late graft occlusions occurred: one
      at 7.5 months, the other, from tumor recurrence, at 6.3 years. There have been no
      other late graft-related complications. All 11 late deaths were caused by the
      progression of malignant disease. Of 16 survivors, 12 have no evidence of disease
      and four have either regional or distant metastatic recurrence. Initial
      postoperative performance status was good or excellent for most survivors.
      CONCLUSIONS: Aggressive surgical management may offer the only chance for cure or
      palliation of symptoms for patients with primary or secondary IVC tumors. Our
      experience suggests that vena cava replacement may be performed safely with low
      graft-related morbidity and good patency in carefully selected patients.

PMID- 10664497
TI  - Is a single preoperative duplex scan sufficient for planning bilateral carotid
      endarterectomy?
AB  - PURPOSE: Duplex scanning is often the sole imaging study before carotid
      endarterectomy (CEA). Patients with bilateral severe internal carotid artery
      (ICA) stenosis may be considered for bilateral CEA. High-grade ICA stenosis,
      however, may artifactually elevate velocity measurements used to quantify
      stenosis in the contralateral ICA. It is unknown whether ipsilateral CEA will
      influence duplex determination of the presence of a contralateral 60% to 99% ICA
      stenosis. This study was performed to determine whether a single preoperative
      duplex scan is sufficient to plan bilateral CEA. METHODS: Preoperative and early
      postoperative carotid duplex scans in patients with bilateral ICA stenosis who
      underwent unilateral CEA were reviewed. Changes in duplex scans that determined
      stenosis in the ICA contralateral to the CEA were analyzed. Previously validated
      criteria used to determine 60% to 99% ICA stenosis were a peak systolic velocity
      (PSV) of 260 cm/sec or more combined with an end diastolic velocity (EDV) of 70
      cm/sec or more. RESULTS: Over an 8-year period, 460 patients underwent CEA; 107
      patients (23.3%) had an asymptomatic 50% to 99% contralateral ICA stenosis by
      standard criteria (PSV, >125 cm/sec) and an early postoperative duplex scan
      examination. Of these 107 patients, 38 patients (35.5%) had duplex scan criteria
      for 60% to 99% contralateral ICA stenosis. In these 38 patients, there was a mean
      postoperative PSV decrease of 47.7 cm/sec (10.1%) and a mean EDV decrease of 36.0
      cm/sec (19.3%) in the ICA contralateral to the CEA. Eight of 38 (21.1%)
      preoperative contralateral 60% to 99% ICA lesions were reclassified as less than
      60% on postoperative duplex scanning. Six of 69 (8.7%) preoperative lesions of
      less than 60% were reclassified as 60% to 99% on postoperative duplex scan. These
      six preoperative examinations were all close to the criteria for 60% to 99%
      stenosis (mean PSV, 232.5 cm/sec; mean EDV, 62.5 cm/sec). CONCLUSION: One-fifth
      of patients with apparent 60% to 99% contralateral ICA lesions before the
      operation have less than 60% stenosis when restudied with duplex scan after
      unilateral CEA. Lesions below but near the cutoff for 60% to 99% may be
      reclassified as 60% to 99% on the postoperative duplex scan. These findings
      mandate that when duplex scanning is used as the sole imaging modality before
      CEA, patients with severe bilateral carotid stenosis must have an additional
      carotid duplex examination before operation on the second side.

PMID- 10664498
TI  - Expanded indications for ultrasound-guided thrombin injection of pseudoaneurysms.
AB  - PURPOSE: We previously reported preliminary data on a new procedure that we
      developed for the treatment of femoral pseudoaneurysms after catheterization.
      This study presents our current results of percutaneous ultrasound-guided
      thrombin injection for treating pseudoaneurysms that arise from various locations
      and causes. METHODS: Between February 1996 and May 1999, we performed thrombin
      injection of 83 pseudoaneurysms in 82 patients. There were 74 femoral
      pseudoaneurysms: 60 from cardiac catheterization (36 interventional), seven from
      peripheral arteriography (four interventional), five from intra-aortic balloon
      pumps, and two from dialysis catheters. There were nine other pseudoaneurysms:
      five brachial (two cardiac catheterization, two gunshot wounds, one after removal
      of an infected arteriovenous graft), one subclavian (central venous catheter
      insertion), one radial (arterial line), and one distal superficial femoral and
      one posterior tibial (both after blunt trauma). Twenty-nine pseudo-aneurysms were
      injected while on therapeutic anticoagulation. Patients underwent repeat
      ultrasound examination within 5 days and after 4 weeks. RESULTS: Eighty-two of 83
      pseudoaneurysms had initial successful treatment by this technique, including 28
      of 29 in patients who were undergoing anticoagulation therapy. The only
      complication was thrombosis of a distal brachial artery, which resolved
      spontaneously. There were early recurrences in seven patients: four patients
      underwent successful reinjection; reinjection failed in two patients, who
      underwent surgical repair; and one patient had spontaneous thrombosis on follow
      up. After 4 weeks, ultrasound examinations were completely normal or showed some
      residual hematoma, and there were no recurrent pseudoaneurysms. CONCLUSION:
      Ultrasound-guided thrombin injection of pseudoaneurysms has excellent results,
      which support its widespread use as the primary treatment for this common
      problem.

PMID- 10664499
TI  - The reduction of the allogenic transfusion requirement in aortic surgery with a
      hemoglobin-based solution.
AB  - OBJECTIVE: Because of allogenic red blood cell (RBC) availability and infection
      problems, novel alternatives, including hemoglobin-based oxygen-carrying
      solutions (HBOC), are being explored to minimize the perioperative requirement of
      RBC transfusions. This study evaluated HBOC-201, a room-temperature stable,
      polymerized, bovine-HBOC, as a substitute for allogenic RBC transfusion in
      patients undergoing elective infrarenal aortic operations. METHODS: In a single
      blind, multicenter trial, 72 patients were prospectively randomized two-to-one to
      HBOC (n = 48) or allogenic RBC (n = 24) at the time of the first transfusion
      decision, either during or after elective infrarenal aortic reconstruction.
      Patients randomized to the HBOC group received 60 g of HBOC for the initial
      transfusion and had the option to receive three more doses (30 g each) within 96
      hours. In this group, any further blood requirement was met with allogenic RBCs.
      Patients randomized to the allogenic RBC group received only standard RBC
      transfusions. The efficacy analysis was a means of assessing the ability of HBOC
      to eliminate the requirement for any allogenic RBC transfusions from the time of
      randomization through 28 days. Safety was evaluated by means of standard clinical
      trial methods. RESULTS: The two treatment groups were comparable for all baseline
      characteristics. Although all patients in the allogenic RBC group required at
      least one allogenic RBC transfusion, 13 of 48 patients (27%; 95% CI, 15% to 42%)
      in the HBOC group did not require any allogenic RBC transfusions. The only
      significant changes documented were a 15% increase in mean arterial pressure and
      a three-fold peak increase in serum urea nitrogen concentration after HBOC. The
      complications were similar in both groups, with no allergic reactions. There were
      two perioperative deaths (8%) in the allogenic RBC group and three perioperative
      deaths (6%) in the HBOC group (P = 1.0). CONCLUSION: HBOC significantly
      eliminated the need for any allogenic RBC transfusion in 27% of patients
      undergoing infrarenal aortic reconstruction, but did not reduce the median
      allogenic RBC requirement. HBOC transfusion was well tolerated and did not
      influence morbidity or mortality rates.

PMID- 10664500
TI  - Venous thrombosis prophylaxis by inflammatory inhibition without anticoagulation
      therapy.
AB  - OBJECTIVE: This study was performed to determine the effectiveness of recombinant
      P-selectin glycoprotein ligand Ig (rPSGL-Ig) pretreatment to decrease thrombosis
      and inflammation in experimental venous thrombosis. rPSGL-Ig, a unique mucin-like
      glycoprotein, has a high affinity for P-selectin. METHODS: Twelve juvenile
      baboons underwent inferior vena cava (IVC) thrombosis with temporary 6-hour IVC
      balloon occlusion. Before balloon placement, the animals received rPSGL-Ig (4
      mg/kg; n = 8) or saline solution for control (n = 4). The animals underwent
      evaluation with duplex ultrasound scan imaging, magnetic resonance venography
      (MRV), phlebography, coagulation profile, and tissue analysis at death for
      cytokines and vein wall leukocyte morphometrics. With the MRV results, thrombus
      development, thrombus resolution, and inflammation (gadolinium; square
      millimeters of enhancement) were assessed. RESULTS: Each animal provided two time
      points for evaluation (days 2 and 6 after balloon occlusion). A significant
      decrease in IVC thrombosis between balloons was found in the rPSGL-Ig animals (1
      of 16) versus the control animals (5 of 8; P <.01). The MRV results showed
      significantly less enhancement in the rPSGL-Ig animals at days 2 and 6 (P <.05).
      Spontaneous thrombus resolution (including balloon sites) was significantly
      greater from day 2 to day 6 in the rPSGL-Ig animals versus the control animals
      (23% vs 2%; P <.001), without pulmonary embolism. Lower interleukin-8, platelet
      factor IV, and monocyte chemotactic protein-1 levels were found in rPSGL-Ig vein
      walls without significant differences in vein wall leukocyte morphometrics. There
      were significantly lower D-dimer levels in the rPSGL-Ig-treated animals (P <.05),
      but there were no differences in measurements of coagulation. Adequate
      circulating rPSGL-Ig levels were documented. CONCLUSION: Pretreatment with rPSGL
      Ig results in: (1) a significant inhibition of thrombosis and vein wall
      inflammation; (2) a decrease in vein wall cytokine expression; and (3) a
      promotion of thrombus resolution. Inflammatory inhibition by rPSGL-Ig without
      anticoagulation therapy provides effective venous thrombosis prophylaxis in
      experimental venous thrombosis.

PMID- 10664501
TI  - Preoperative treatment with doxycycline reduces aortic wall expression and
      activation of matrix metalloproteinases in patients with abdominal aortic
      aneurysms.
AB  - PURPOSE: Matrix metalloproteinases (MMPs) are considered to play a central role
      in the pathogenesis of abdominal aortic aneurysms (AAAs). Doxycycline (Dox) has
      direct MMP-inhibiting properties in vitro, and it effectively suppresses the
      development of elastase-induced AAAs in rodents. The purpose of this study was to
      determine if treatment with Dox suppresses MMPs within human aneurysm tissue and
      to elucidate the molecular mechanisms underlying this effect. METHODS: Aneurysm
      tissues were obtained from 15 patients with an AAA, eight of whom had been
      treated with Dox before surgery (100 mg orally twice a day for 7 days). Protein
      extracts were examined by means of gelatin zymography and immunoblot analysis,
      and RNA was examined by means of reverse transcription-polymerase chain reaction
      (RT-PCR). The effects of Dox on MMP production were further examined in human THP
      1 mononuclear phagocytes in vitro. RESULTS: No detectable difference was found
      between groups by using substrate zymography as a means of assessing total MMP
      activity, but Dox treatment was associated with a slight (24.4%) reduction in the
      activated fraction of 72-kDa gelatinase (MMP-2; P <.05). In contrast, a 2.5-fold
      reduction in the amount of extractable 92-kDa gelatinase (MMP-9) protein in Dox
      treated patients was revealed by means of immunoblot analysis (P <.05). Also, a
      5.5-fold (81.9%) reduction in MMP-9 messenger RNA (mRNA) in Dox-treated patients
      was demonstrated by means of quantitative competitive RT-PCR (mean +/- SE, mol
      MMP-9/mol beta-actin: 1.3 +/- 0.5 vs 7.2 +/- 3.1; P <.04). There was no
      significant difference between groups in the relative expression of MMP-2 protein
      or mRNA. In cultured THP-1 monocytes stimulated with phorbol ester, the
      expression of MMP-9 protein and mRNA were both decreased after exposure to
      relevant concentrations of Dox in vitro. CONCLUSION: In addition to its
      recognized effects as a direct MMP antagonist, Dox may influence connective
      tissue degradation within human aneurysm tissue by reducing monocyte/macrophage
      expression of MMP-9 mRNA and by suppressing the post-translational processing
      (activation) of proMMP-2. Through this complementary combination of mechanisms,
      treatment with Dox may be a particularly effective strategy for achieving MMP
      inhibition in patients with an AAA.

PMID- 10664502
TI  - Cellular stress inhibits vascular smooth muscle relaxation.
AB  - PURPOSE: Cellular stress has been shown to induce a group of proteins called heat
      shock proteins (HSPs). Recent evidence suggests that a group of small HSPs may
      modulate vascular smooth muscle contraction (HSP27) and/or relaxation (HSP20). In
      this investigation, we hypothesized that cellular stress would alter contraction
      and/or relaxation of intact vascular smooth muscles and would lead to changes in
      the induction and/or phosphorylation of the small HSPs. METHODS: Bovine carotid
      arteries were obtained from an abattoir, and physiologic contractile responses
      were determined in a muscle bath. Phosphorylation state-specific antibodies were
      produced and characterized against HSP27. Phosphorylation events were determined
      with phosphorylation state-specific antibodies or whole-cell phosphorylation and
      two-dimensional gel electrophoresis. RESULTS: Cellular stress induced by arsenite
      or heat shock did not alter basal tone or the magnitude of contractions induced
      by serotonin or high extracellular potassium chloride. However, cellular stress
      led to inhibition of forskolin and sodium nitroprusside-induced vasorelaxation.
      This impaired vasorelaxation was associated with increases in the phosphorylation
      of HSP27 and decreases in forskolin-induced phosphorylation of HSP20. CONCLUSION:
      Cellular stress, which leads to increases in the phosphorylation of HSP27,
      inhibits cyclic nucleotide-dependent vascular relaxation and cyclic nucleotide
      dependent increases in the phosphorylation of HSP20.

PMID- 10664503
TI  - Local infusion of heparin reduces anastomotic neointimal hyperplasia in
      aortoiliac expanded polytetrafluoroethylene bypass grafts in baboons.
AB  - PURPOSE: Recently, we designed and characterized a novel expanded
      polytetrafluoroethylene (ePTFE)-based local drug delivery approach that
      selectively concentrates infused pharmacologic agents specifically within those
      blood layers adjacent to the graft wall and at downstream anastomotic sites. In
      this study, we locally administrated standard heparin therapy and evaluated its
      effects on neointimal hyperplasia formation in a baboon model of aortoiliac
      bypass graft placement. METHODS: Six adult male baboons underwent bilateral
      aortoiliac bypass grafting with ringed ePTFE (4 mm internal diameter x 5 cm
      length). In each animal, the distal anastomosis of one graft was continuously
      infused with heparin (50 U/h) and the distal anastomosis of the contralateral
      graft was infused with saline solution at the same rate (2.5 microL/h), with
      osmotic pumps implanted for 4 weeks. Platelet counts and activated partial
      thromboplastin time measurements were performed weekly. The specimens were
      harvested at 4 weeks and were subjected to morphometric analysis. Cell
      proliferation was assessed with bromodeoxyuridine immunostaining. RESULTS: All
      the harvested grafts were patent except for one control graft. There were no
      significant differences in platelet counts or activated partial thromboplastin
      time measurements taken before and during heparin infusion. As expected, there
      were no significant differences in graft neointimal hyperplasia and cell
      proliferation at the proximal anastomoses between the heparin-infused and control
      grafts. In contrast, at the treated distal anastomoses, heparin infusion
      significantly reduced the graft neointimal area by 65% and the cell proliferation
      index by 47% as compared with the untreated control distal anastomoses.
      CONCLUSION: These results show that local infusion of heparin significantly
      reduces distal anastomotic neointimal hyperplasia and cell proliferation without
      measurable systemic anticoagulation or other side effects. Thus, this approach
      may represent an attractive strategy for prolonging ePTFE bypass graft patency.

PMID- 10664504
TI  - Nitric oxide prevents p21 degradation with the ubiquitin-proteasome pathway in
      vascular smooth muscle cells.
AB  - PURPOSE: We have shown that gene transfer of the inducible nitric oxide synthase
      (iNOS) gene to injured arteries inhibits the development of intimal hyperplasia.
      One mechanism by which nitric oxide (NO) may inhibit this process is through the
      upregulation of the cyclin-dependent kinase inhibitor p21, which induces a G0/G1
      cell cycle arrest, leading to an inhibition of vascular smooth muscle cell (VSMC)
      proliferation. Because NO induced such a dramatic upregulation of p21 and because
      p21 is a universal inhibitor of the cell cycle, this study aimed to determine how
      NO upregulates p21 protein expression in VSMCs. METHODS: p21 messenger RNA (mRNA)
      levels in rat aortic smooth muscle cells (RASMCs) were determined by Northern
      blot analysis after treatment with S-nitroso-N-acetylpenicillamine (SNAP) or
      after adenoviral iNOS gene transfer. p21 protein levels in RASMCs in similar
      conditions were determined by Western blot analysis. Levels of ubiquinated p21 in
      these same treatment groups were assessed by immunoprecipitation of p21 from
      RASMCs, followed by western blot analysis for ubiquitin. Protein tyrosine and
      protein serine/threonine phosphatase activity after treatment with SNAP, plus or
      minus the phosphatase inhibitors calyculin A or cantharidin, were measured with
      (32)P-labeled myelin basic protein as a substrate. RESULTS: NO exposure by the NO
      donor SNAP or iNOS gene transfer induced a dose- and time-dependent increase in
      p21 protein expression in RASMCs. p21 mRNA levels were significantly increased
      after SNAP treatment only at the 6-hour point, but were not increased at 24
      hours. In contrast, protein levels were increased from 6 to 24 hours, and
      transcriptional inhibitors did not inhibit this increase in protein synthesis.
      The increase in p21 protein expression induced by NO was associated with less of
      the ubiquinated form of p21 at both early and late points. Furthermore, NO
      induced an increase in both protein tyrosine and protein serine/threonine
      phosphatase activity. Inhibition of these phosphatases with calyculin A or
      cantharidin prevented the upregulation of p21 protein expression by NO.
      CONCLUSION: These data indicate that one mechanism by which NO upregulates p21
      protein expression is through the prevention of p21 protein degradation by the
      ubiquitin-proteasome pathway in association with increased protein tyrosine and
      serine/threonine phosphatase activity.

PMID- 10664505
TI  - Activation of integrin receptors is required for growth factor-induced smooth
      muscle cell dysfunction.
AB  - PURPOSE: Growth factors and cytokines such as platelet-derived growth factor
      (PDGF), epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), and
      transforming growth factor beta (TGF-beta) stimulate smooth muscle cell (SMC)
      proliferation and extracellular matrix (ECM) protein production by binding and
      activating their respective receptors. Recent investigations suggest that
      simultaneous activation of integrins, which are heterodimeric receptors for ECM,
      may also be required for growth factor and cytokine function. In this study, we
      tested the hypothesis that activation of two integrins, alpha v beta 3 and alpha
      2 beta 1, both previously identified in vascular SMCs, is necessary for growth
      factor- and cytokine-induced vascular SMC dysfunction. METHODS: DNA synthesis was
      measured after stimulation of SMCs derived from human saphenous vein with the
      growth factors PDGF-BB, EGF, and bFGF. SMC fibronectin (Fn) production was
      measured (by means of Western blotting) in SMCs stimulated for 72 hours with TGF
      beta1 or EGF. Both endpoints were measured in the presence and absence of
      antibodies that block the function of the alpha v beta 3 and alpha 2 beta 1
      integrins as well as the alpha2 and beta1 subunits. RESULTS: The alpha v beta 3
      integrin blocking antibody significantly inhibited PDGF-BB-, EGF-, and bFGF
      induced SMC proliferation. The alpha v beta 3 integrin antibody also markedly
      inhibited TGF-1- and EGF-induced SMC Fn production. Neither the alpha 2 beta 1
      integrin nor the alpha2 or the beta1 subunits inhibited either proliferation or
      matrix protein production in response to any of these agonists. CONCLUSION: The
      alpha v beta 3 integrin is required for growth factor- and cytokine-induced SMC
      proliferation and FN production, whereas alpha 2 beta 1 is not. Since activation
      of alpha v beta 3 is required for the activity of at least four distinct growth
      factors and cytokines, inhibition of this integrin might be used as a therapeutic
      tool for the prevention of intimal hyperplasia.

PMID- 10664506
TI  - The S130K fibroblast growth factor-1 mutant induces heparin-independent
      proliferation and is resistant to thrombin degradation in fibrin glue.
AB  - OBJECTIVE: Site-directed mutagenesis is an important technique that can alter
      cytokine function, thereby eliciting desired responses. S130K is a mutation of
      fibroblast growth factor-1 (FGF-1), with lysine replacing serine in the heparin
      binding site. We measured molecular stability and mitogenic activity of FGF-1 and
      S130K, both in the media and when suspended in fibrin glue (FG), on smooth muscle
      cells (SMCs) and endothelial cells (ECs) to determine if the mutation altered the
      function and potential clinical applicability. METHODS: EC and SMC proliferation
      of soluble FGF-1 or S130K at 0, 0. 1, 1, 10, or 100 ng/mL with heparin at 0, 5,
      50, or 500 units (U)/mL was measured on growth-arrested cells in serum-free
      media. EC and SMC proliferation assays with cells on FG containing either FGF-1
      or S130K at 0, 1, 10, 100, or 1000 ng/mL in combination with heparin at 0, 5, 50
      or 500 U/mL were also performed during the exponential growth phase. Molecular
      degradation by thrombin was measured by sodium dodecylsulfate-polyacrylamide gel
      electrophoresis. RESULTS: S130K induces greater EC and SMC proliferation in the
      absence of heparin than FGF-1 does (P <.0001 for both the 10 and 100 ng/mL
      doses). S130K is also significantly more potent than FGF-1 in the presence of
      heparin. Heparin in the media enhances cytokine-induced SMC and EC proliferation
      at doses of 5 U/mL, but inhibits SMC proliferation at concentrations of 500 U/mL.
      For the FG data, unlike FGF-1, S130K induces EC and SMC proliferation in the
      absence of heparin. The addition of 5 U/mL of heparin enhances the proliferation
      induced by S130K. For ECs, as the heparin dose increases to 50 U/mL,
      proliferation decreases, as compared with the 5 U/mL concentration when either
      FGF-1 or S130K in the FG was compared at concentrations of 10, 100, and 1000
      ng/mL (P <.01). S130K is more potent in FG than is FGF-1 both with and without
      heparin and exhibits maximal EC and SMC proliferation at 10 ng/mL, whereas FGF-1
      activity is maximal at 100 ng/mL. Gel electrophoresis demonstrated that S130K was
      relatively more resistant to thrombin degradation than FGF-1. CONCLUSIONS: Site
      directed mutagenesis changed the potency and the heparin dependency on cellular
      proliferation of FGF-1 in vitro. These techniques should allow the delivery of
      mutant growth factors to areas of vascular intervention to induce specific,
      desired responses. We believe that these studies will enhance our knowledge of
      the function of various regions of the FGF-1 molecule, allowing us to more
      precisely design increasingly more useful FGF-1 mutants.

PMID- 10664507
TI  - The dynamic regulation of blood vessel caliber.

PMID- 10664508
TI  - The caput medusae of hypercoagulability.
AB  - Thrombosis may be the most common cause of death in the United States. Virchow
      postulated, approximately 150 years ago, that intravascular thrombosis was caused
      by changes of the vessel wall, by reduction in blood flow, and by alteration of
      the chemical composition of the blood. The hypercoagulability component of the
      Virchow triad has, until recently, been poorly defined. During the past 40 years,
      a number of acquired and congenital hypercoagulable disorders have been described
      so that currently the cause for thrombotic events can be determined in many
      patients. The hypercoagulable-related thromboses are usually venous but may, less
      often, be arterial, and the thromboses often are the cause of significant
      morbidity and mortality. The vascular surgeon often participates in the
      management of hypercoagulable disorders. This review of hypercoagulable disorders
      is presented with the hope that the early recognition of these disorders will
      lead to the appropriate diagnosis and proper management of hypercoagulable
      related thromboses.

PMID- 10664509
TI  - The Distinguished Service Award Medal for the Society of Vascular Surgery, 1999:
      Michael Ellis DeBakey, MD.

PMID- 10664510
TI  - Regarding "Descending thoracic aorta to iliofemoral artery bypass grafting: a
      role for primary revascularization for aortoiliac occlusive disease?".

PMID- 10664511
TI  - Regarding "Chronic renal artery occlusion: nephrectomy versus revascularization".

PMID- 10664512
TI  - Regarding "Laparoscopic aortofemoral bypass grafting: human cadaveric and initial
      clinical experiences".

PMID- 10664513
TI  - Regarding "Spontaneous popliteal artery dissection: a case report and review of
      the literature".

PMID- 10664514
TI  - Regarding "Feasibility of endovascular repair of abdominal aortic aneurysms with
      local anesthesia with intravenous sedation".

PMID- 10664515
TI  - The molecular basis of male sexual differentiation.
AB  - Male sexual differentiation is the result of complex mechanisms involving
      developmental genetics and endocrinology. Formation of the bipotential gonads and
      subsequently the testes is dependent on a series of sex chromosome-linked and
      autosomal genes. The testes secrete both peptide and steroid hormones essential
      for the formation of internal and external genitalia. Hormone action is mediated
      via specific receptors, functioning as transcription regulators. Disruption of
      these genetic events leads to sexual dimorphism involving external and internal
      genitalia, and may also interfere with the development of other organs.

PMID- 10664516
TI  - CD154 for the dragon: a promising development for pancreatic islet
      transplantation and cure for type 1 diabetes mellitus.

PMID- 10664517
TI  - Leptin is a potent anti-diabetic in mice with lipodystrophy and insulin
      resistance.

PMID- 10664518
TI  - Medical therapy of Graves' disease: effect on remission rates of methimazole
      alone and in combination with triiodothyronine.
AB  - In a prospective, randomized study of 135 newly diagnosed patients with
      hyperthyroidism due to Graves' disease we compared the effect on remission rates
      of additional triiodothyronine (T3) with conventional antithyroid drug therapy.
      To this end 114 patients were followed for at least 12 months (15.7+/-4.9, mean+/
      s.d.) after the discontinuation of any therapy. After return of thyroid function
      to normal (8.5+/-7.4 weeks, mean+/-s.d.) patients were maintained on antithyroid
      medication for 9.0+/-2.5 months. They were then randomly assigned to one of three
      groups: group 1 (n=44) stopped methimazole, groups 2 (n=39) and 3 (n=31)
      continued with exogenous T3 (not exceeding 75 microgram/day in any patient) for a
      further 6 months either with (group 2) or without (group 3) a fixed dose of 10mg
      methimazole daily. The T3 dose was kept variable to keep TSH suppressed (<0.
      1mU/l), which could be achieved in 82% of patients on 100% of their monthly
      visits. No serious side-effect requiring the discontinuation of the study
      occurred in any patient. Total T3, TSH-receptor antibodies and some previously
      suggested potential predictors of relapse including thyroid size by ultrasound,
      24h urinary iodine excretion, history of cigarette smoking and ophthalmopathy
      were determined at the outset of the study and subsequently every 6 months (and
      total T3 every 4 weeks). No significant difference (P>0.05, Chi square) was seen
      in relapse of hyperthyroidism after a mean follow-up of 16 months (range: 12-31
      months; groups 1:52%, 2:44% and 3:42%) in an area of low-to-moderate iodine
      intake (prevalence of 24h urinary iodine excretion <100 microgram/24h: 17 and 25%
      at two different measurements respectively). Concomitantly, no predictor of
      recurrence of disease could be identified, irrespective of treatment modality.

PMID- 10664519
TI  - Changes in renal tri-iodothyronine and thyroxine handling during fasting.
AB  - OBJECTIVE: Liver handling of thyroid hormones (TH) has been known to alter
      significantly during fasting. This study investigates whether renal handling of
      TH is also changed during fasting. METHODS: We measured urinary excretion rates
      and clearances of free tri-iodothyronine (T(3)) and free thyroxine (T(4)) in
      healthy subjects prior to and on the third day of fasting. RESULTS: During
      fasting, both mean T(3) and T(4) urinary excretion decreased significantly to a
      mean value of 42% of control. Also, total and free (F) serum T(3) concentrations
      declined significantly, but serum T(4) did not change. Both FT(3) and FT(4)
      clearance decreased significantly during fasting (62% and 42% of control). The
      fasting-induced decrease in uric acid clearance correlated well with the decrease
      in FT(3) clearance (r=0.94; P<0.001). Serum concentrations of non-esterified
      fatty acids (NEFA) were significantly elevated during fasting. CONCLUSIONS: The
      findings cannot be fully explained by the fasting-induced decrease in serum T(3),
      and are in accordance with inhibition of uptake of T(3) and T(4) at the
      basolateral membrane of the tubular cell. This inhibition may be caused by a
      decreased energy state of the tubular cell and by other factors such as
      ketoacidosis and/or increased NEFA concentrations during fasting.

PMID- 10664520
TI  - MEN1 gene mutation analysis in Italian patients with multiple endocrine neoplasia
      type 1.
AB  - Multiple endocrine neoplasia type 1 (MEN 1) is a familial syndrome characterized
      by parathyroid, enteropancreatic and pituitary tumors. The gene responsible for
      this syndrome is localized at chromosomal 11q13 region and DNA markers from this
      region cosegregate with the disease. The recent identification of the MEN1 gene,
      encoding for a protein termed menin of 610 amino acids, allowed mutational
      screening to be performed both in affected families and sporadic cases. To date
      many different heterozygous mutations, spreading across all the encoding
      sequence, have been identified in MEN 1 patients with no apparent mutational hot
      spots or genotype-phenotype correlation. To analyze the genetic alterations of
      the MEN1 gene occurring in Italian patients we performed mutational screening by
      Denaturant Gradient Gel Electrophoresis followed by sequencing of exons 2-10 of
      the MEN1 gene in 27 Italian MEN 1 families and in five sporadic cases. We
      identified 17 different heterozygous mutations in 60% of analyzed cases. Twelve
      of these mutations are novel. Two mutations each occurred twice in unrelated
      families but no evidence of genotype-phenotype correlation can be established for
      these families. The extension of genetic diagnosis to asymptomatic family members
      allowed the identification of 10 MEN1 mutant gene carriers, one newly described
      and nine previously detected by linkage analysis with DNA markers from the 11q13
      region. Our findings add new information to the diversity of mutations occurring
      in the MEN1 gene and confirm that the mutational screening of MEN 1 is a useful
      approach to detect individuals at higher risk of developing MEN 1-associated
      tumors.

PMID- 10664521
TI  - A novel mutation of the MEN1 gene in a Japanese kindred with familial isolated
      primary hyperparathyroidism.
AB  - OBJECTIVE: To determine whether familial isolated hyperparathyroidism (FIHP) is a
      variant of multiple endocrine neoplasia type 1 (MEN1) we analyzed the MEN1 gene
      in such a kindred. DESIGN AND METHODS: The study included the 70-year-old proband
      and nine relatives. Blood was drawn for biochemical evaluation and germline
      mutation analysis by direct sequencing of the MEN1 gene amplified by PCR. A
      hyperplastic parathyroid gland obtained from a family member served for a loss of
      heterozygosity (LOH) study. RESULTS: Three members from two generations in this
      kindred were found to have primary hyperparathyroidism, while none had clinical
      or biochemical evidence of MEN1, MEN2 or hyperparathyroidism--jaw tumor syndrome.
      Analysis of germline DNA in the proband showed a missense mutation (GGC-->GAC) at
      codon 305 in exon 7 of the MEN1 gene that predicts an amino acid change from
      glycine to aspartic acid (G305D). This mutation segregated with primary
      hyperparathyroidism in the kindred, and, in addition, there were two asymptomatic
      mutant-gene carriers at relatively advanced ages. In contrast, the mutation was
      not detected in genomic DNA from five unaffected individuals and from 50 healthy
      subjects. The LOH study showed a loss of the wild-type allele, which confirmed
      that a functional defect of the MEN1 gene product, menin, is etiological for
      FIHP. CONCLUSIONS: FIHP is a genetically heterogeneous disease with a subset
      linked to MEN1, most likely representing a variant of MEN1. The late onset and
      the reduced penetrance of disease found in this kindred may be related to the
      site and the type of mutation, although the precise mechanism involved is unknown
      at present.

PMID- 10664522
TI  - Effect of aging on serum gonadotropin levels in healthy subjects and patients
      with nonfunctioning pituitary adenomas.
AB  - OBJECTIVE: Nonfunctioning pituitary adenomas (NFPA), which represent about one
      quarter of human pituitary tumors, occur in middle or old age. Determination of
      gonadotropin levels, which are not expected to be high during the early
      postmenopause in normal women and which are low in women with NFPA, is important
      to distinguishing hypogonadal status due to the normal decline of gonadal
      function from that due to hypothlalamic-pituitary dysfunction. The aim of the
      study was to verify whether this difference still persists in old subjects,
      despite the physiological decline of gonadotropins in the last decades of life.
      DESIGN AND METHODS: The study included 154 healthy subjects (aged 50-104 years)
      and 47 patients with NFPA (aged 50-80 years). Blood samples were collected after
      an overnight fast and hormone levels were measured by two immunofluorimetric
      assays. RESULTS: In healthy women the highest serum levels of gonadotropins were
      present in the 50-60 year age group, with a slight but progressive age-associated
      decrease in serum FSH and LH being observed thereafter. In healthy men serum
      gonadotropin levels were stable up to 70 years, increased up to 75-85 years and
      thereafter gradually decreasing. Female patients with NFPA showed levels of
      gonadotropins which were far lower than controls. Only three patients had levels
      of both FSH and LH above the 2.5 centile for normal subjects. A high sensitivity
      and specificity of gonadotropin measurements (about 90%) for the diagnosis of
      NFPA was observed in female patients aged 50-80 years. In male subjects, a large
      overlap of gonadotropin values in NFPA and controls, namely over the 50-70 years
      age range, was observed. CONCLUSIONS: Our study demonstrates that despite the
      gradual decline of gonadotropin levels in healthy postmenopsausal women, the
      reduction of both FSH and LH persists in old patients with NFPA, suggesting that
      measurement of gonadotropin levels could prove useful in the evaluation of
      pituitary lesions even in old women. More subtle differences seem to occur in
      male subjects.

PMID- 10664523
TI  - Signaling between the pituitary gland and the testes: inverse relationship
      between serum FSH and inhibin B concentrations in boys in early puberty.
AB  - OBJECTIVES: To study the relationship between serum inhibin B and sex steroid
      concentrations and pituitary FSH responsiveness to GnRH in boys in early puberty,
      and to examine serum inhibin B levels in prepubertal boys with different timing
      of the onset of gonadotropin deficiency (GD). DESIGN: Twenty-five boys with
      constitutional delay of puberty (CDP; 20 in Tanner stage G2 and 5 in G3; age
      range, 13. 5-16.8 years) and eight prepubertal boys (G1P1) with GD (age range,
      10.0-13.2 years) were clinically examined, and serum inhibin B, testosterone and
      estradiol concentrations were measured from sera obtained immediately before the
      administration of GnRH (Relefact; 3.5 microgram/kg, maximum 100 microgram i.v.).
      Thereafter, FSH levels were measured at 30min intervals up to 90min. RESULTS: In
      the boys with CDP, basal inhibin B and FSH levels did not correlate. However,
      inhibin B and GnRH-stimulated FSH concentrations (r(S)= -0.43 to -0.45, n=25,
      P<0.05) and the difference between basal and peak serum FSH levels were inversely
      related (r(S)= -0.63, n=25, P<0.005). This relationship remained significant in
      boys at stage G2 (r(S)= -0.66, n=20, P<0.005). Basal testosterone concentrations
      and GnRH-induced FSH levels did not correlate. Estradiol levels were too low (64%
      of the boys had estradiol levels below the assay sensitivity) to allow
      correlation analysis. The boys with GD had low inhibin B concentrations (range,
      <15.6-53pg/ml); the lowest levels were observed in boys with presumably
      congenital onset of the disease. Serum inhibin B levels and testis volumes
      correlated positively (r(S)=0.70, n=8, P=0.07). CONCLUSIONS: These results
      suggest that, in boys, the reciprocal regulation between inhibin B and FSH is in
      operation before mid-puberty. Moreover, autonomous inhibin B secretion by the
      prepubertal human testis is likely to reflect the number of Sertoli cells.

PMID- 10664524
TI  - Patients with dilated cardiomyopathy show reduction of the somatotroph
      responsiveness to GHRH both alone and combined with arginine.
AB  - OBJECTIVE: Altered function of the GH/IGF-I axis in patients with dilated
      cardiomyopathy (DCM) has been reported. In fact, DCM patients show reduction of
      IGF-I levels, which could reflect slight peripheral GH resistance or,
      alternatively, reduced somatotroph secretion. Spontaneous GH secretion has been
      reported to be altered by some but not by other authors, whereas the GH response
      to GHRH, but not that to GH-releasing peptides, seems reduced in DCM patients. On
      the other hand, it is well known that the GH response to GHRH in humans is
      markedly potentiated by arginine (ARG), which probably acts via inhibition of
      hypothalamic somatostatin release; in fact the GHRH+ARG test is known as one of
      the most reliable to evaluate the maximal secretory capacity of somatotroph
      cells. METHODS: In order to further clarify the somatotroph function in DCM, in
      well-nourished patients with DCM (34 male, 4 female; age (mean+/-s.e. m.) 57.8+/
      1.1 years; body mass index (BMI) 24.6+/-0.6kg/m(2); left ventricular ejection
      fraction 23.2+/-1.6%; New York Heart Association classification I/1, II/17,
      III/18, IV/2) we studied the GH response to GHRH (1.0 microgram/kg i.v.) alone or
      combined with ARG (0.5g/kg i.v.). The results in DCM patients were compared with
      those in age-matched control subjects (CS) (39 male, 7 female; age 58.9+/-1.0
      years; BMI 23.2+/-0.3kg/m(2)). RESULTS: Mean IGF-I levels in DCM patients were
      lower than in CS (144.3+/-6.9 vs 175.1+/-8. 4 microgram/l, P<0.05) whereas basal
      GH levels were similar in both groups (1.7+/-0.3 vs 1.7+/-0.3 microgram/l). The
      GH response to GHRH in DCM patients was lower (P<0.05) than that in CS (GH peak
      6.5+/-1.2 vs 10.7+/-2.1 microgram/l). In both groups the GH response to GHRH+ARG
      was higher (P<0.001) than that to GHRH alone. However, the GH response to
      GHRH+ARG in DCM patients remained clearly lower (P<0.01) than that in CS (18.3+/
      3.2 vs 34.1+/-4.6 microgram/l). The GH response to GHRH alone and combined with
      ARG was not associated with the severity of the disease. CONCLUSION: DCM patients
      show blunted GH responses to GHRH both alone and combined with ARG. Evidence that
      ARG does not restore the GH response to GHRH in DCM patients makes it unlikely
      that the somatotroph hyporesponsiveness to the neurohormone reflects
      hyperactivity of hypothalamic somatostatinergic neurons.

PMID- 10664525
TI  - Acute inhibition of oestrogen biosynthesis does not affect serum leptin levels in
      young men.
AB  - OBJECTIVE: Leptin plays an important role in the regulation of reproduction. To
      explore the contribution of oestradiol to serum leptin levels in men, we measured
      the concentrations of serum leptin and insulin after inhibition of oestrogen
      biosynthesis by selective blockade of the aromatase enzyme. DESIGN: The study had
      a double-blind parallel group design. METHODS: The aromatase inhibitor, MPV
      2213ad, was given to eight healthy male volunteers as a single dose of 100mg.
      Eight men received placebo. Serum leptin and insulin were determined from blood
      samples collected at 0800h, 1600h and 2000h both on the actual test day (day 0)
      and on the previous day (day -1), and from single blood samples taken in the
      morning of days 1, 2, 4 and 7. Changes in serum leptin were correlated with those
      seen in serum oestradiol, testosterone, LH, FSH, cortisol and aldosterone, which
      were determined earlier. RESULTS: After the aromatase inhibitor administration,
      mean serum oestradiol concentration was reduced by 74% from the baseline compared
      with a 19% reduction in the placebo group (P for difference <0.001), and returned
      to pre-treatment levels within four days. Despite marked changes in serum
      oestradiol and sustained elevations in serum testosterone, LH and FSH
      concentrations, serum leptin concentrations were similar in the group receiving
      the aromatase inhibitor and in the placebo group. We found a weak correlation
      between serum oestradiol and leptin, which could not be reproduced when the
      percentage changes in these variables were analysed. CONCLUSION: Marked short
      term reduction in serum oestradiol concentration has no effect on serum leptin
      levels in young men.

PMID- 10664526
TI  - Plasma leptin concentrations in postmenopausal women with osteoporosis.
AB  - BACKGROUND: The obese are usually protected against osteoporosis and have
      increased bone mineral density and plasma leptin concentrations. A recent in
      vitro study demonstrated that leptin acts on human marrow stromal cells to
      enhance differentiation to osteoblasts, suggesting an influence of leptin on bone
      mass. However, little is known about the relationship between plasma leptin and
      bone mass in postmenopausal women with osteoporosis. OBJECTIVE: To investigate
      plasma leptin concentrations in postmenopausal women with osteoporosis to improve
      the understanding of the role of leptin in determining bone mass. METHODS: Fifty
      postmenopausal women with osteoporosis (ages 61.18+/-6.51 years; body mass index
      (BMI) 28. 91+/-3.44kg/m(2), mean+/-s.d.) and 30 age- and BMI-matched healthy
      postmenopausal women were included in the study. Bone mineral densities (BMD)
      were measured by dual energy X-ray absorptiometry. Plasma leptin concentrations
      were determined using an immunoradiometric assay. RESULTS: The median spine BMD
      value in the patient group (0.695+/-8.26g/cm(2), median+/-s.e.m.) was
      significantly lower than that in the control group (1.006+/-1. 29g/cm(2),
      median+/-s.e.m.; z=-7.454, P<0.001). The median plasma leptin concentration in
      the patient group (18.70+/-1.78ng/ml, median+/-s.e.m.) was not significantly
      different from that in the control group (22.35+/-2.20ng/ml, median+/-s.e.m.; z=
      1.630, P=0. 103). Plasma leptin concentrations were correlated with BMI in both
      groups (r(s)=0.394, P=0.031 in controls and r(s)=0.404, P=0.004 in the patient
      group). There was no correlation between plasma leptin concentrations and BMD
      values in controls (r(s)=-0.107, P=0.575) but a weak correlation was observed in
      the patient group (r(s)=0.285, P=0.045). CONCLUSION: Our data suggest that
      circulating plasma leptin does not have a significant direct influence on bone
      mass in postmenopausal women.

PMID- 10664527
TI  - Serum leptin concentrations during the menstrual cycle in normal-weight women:
      effects of an oral triphasic estrogen-progestin medication.
AB  - OBJECTIVE: To investigate in normal-weight premenopausal women the relationship
      between circulating leptin and serum gonadotropins and gonadal steroids, during
      both spontaneous and pharmacologically induced menstrual cycles. DESIGN: Clinical
      longitudinal study. METHODS: Two groups of age-matched, normal-weight
      premenopausal volunteer women (groups I and II) were enrolled in this study.
      Women in group I were free of any hormonal treatment, while women in group II
      were taking a triphasic estrogen--progestin contraceptive preparation. Blood
      samples were collected daily in both groups after an overnight fast throughout a
      complete menstrual cycle. RESULTS: In the spontaneously cycling women, serum
      leptin concentration positively correlated with estradiol (P<0.03) and
      progesterone (P<0. 05) and was higher in the luteal than in the follicular phase
      (P<0. 05). However, a significant (P<0.03) short-lasting increase in circulating
      leptin was present in the late follicular phase of all subjects. In the women
      using hormonal contraception serum leptin remained unchanged throughout the
      cycle, along with constantly low values of circulating luteinizing hormone and
      follicle-stimulating hormone. CONCLUSIONS: In normal-weight premenopausal women
      serum leptin concentrations differ during the menstrual cycle in line with
      changes in gonadotropin and gonadal steroid concentrations, increasing in the
      luteal phase of the cycle after a peri-ovulatory peak. These findings suggest a
      permissive role for leptin with regard to the functioning of the corpus luteum.

PMID- 10664528
TI  - Baseline and stimulated catecholamine secretion in normotensive patients with
      active acromegaly: acute effects of continuous octreotide infusion.
AB  - OBJECTIVE: Alterations in catecholamine plasma levels may contribute to the
      cardiovascular complications of acromegaly. Since few data are available on the
      catecholamine secretory dynamics in active acromegaly and no evidence exists on
      catecholamine variations during GH decrease, we studied acromegalic patients
      before and during octreotide administration. METHODS: We evaluated the
      catecholamine responses to upright posture and a cold pressure test (CPT) in 11
      acromegalic (A) patients before and during continuous administration of
      octreotide (500 microgram/24h by s.c. pump) compared with 11 normal (N) subjects.
      RESULTS: All the acromegalic patients showed left ventricular cardiac
      hypertrophy. The cardiovascular responses to upright posture were similar between
      normal subjects and acromegalics both before and during octreotide treatment. The
      basal levels of norepinephrine (NE) were significantly higher in A patients
      compared with N subjects (423+/-45 vs 264+/-32pg/ml, P<0. 05) and decreased
      during therapy (291+/-32pg/ml; P<0.01). The increase in plasma NE during upright
      posture was significantly lower in A than in N subjects (P<0.01), but was
      restored to normal during octreotide treatment. CPT increased systolic and
      diastolic blood pressure, pulse rate and NE plasma levels in N (P<0.05) but not
      in A subjects both before and during octreotide treatment. CONCLUSIONS: Our data
      demonstrate the presence of increased basal NE levels in acromegalic patients
      with a defective sympathetic response to stimuli. Short-term octreotide infusion
      is able to induce a reduction in the basal levels of NE and a normalization of
      the catecholamine response to posture.

PMID- 10664529
TI  - Autoantibodies against recombinant human steroidogenic enzymes 21-hydroxylase,
      side-chain cleavage and 17alpha-hydroxylase in Addison's disease and autoimmune
      polyendocrine syndrome type III.
AB  - OBJECTIVE: To evaluate the frequency of autoantibodies (Ab) against 21
      hydroxylase (21OH), side-chain cleavage (SCC) and 17alpha-hydroxylase (17OH), in
      Addison's disease (AD) and autoimmune polyendocrine syndrome type III (APSIII).
      DESIGN AND METHODS: We used radiobinding assays and in vitro translated
      recombinant human (35)S-21OH, (35)S-SCC or (35)S-17OH and studied serum samples
      from 29 AD (18 idiopathic, 11 granulomatous) and 18 APSIII (autoimmune thyroid
      disease plus type 1 diabetes mellitus, without AD) patients. Results were
      compared with those of adrenocortical autoantibodies obtained with indirect
      immunofluorescence (ACA-IIF). RESULTS: ACA-IIF were detected in 15/18 (83%)
      idiopathic and in 1/11 (9%) granulomatous AD subjects. 21OHAb were found in 14/18
      (78%) idiopathic and in the same (9%) granulomatous AD subject. A significant
      positive correlation was shown between ACA-IIF and 21OHAb levels (r(2)=0.56,
      P<0.02). The concordance rate between the two assays was 83% (24/29) in AD
      patients. SCCAb were found in 5/18 (28%) idiopathic (4 of whom were also positive
      for 21OHAb) and in the same (9%) granulomatous AD subject. 17OHAb were found in
      only 2/18 (11%) idiopathic and none of the granulomatous AD patients. Two APSIII
      patients were positive for ACA-IIF, but only one was positive for 21OHAb and
      SCCAb. 17OHAb were found in another two APSIII patients. CONCLUSIONS: Measurement
      of 21OHAb should be the first step in immune assessment of patients with AD and
      individuals at risk for adrenal autoimmunity, in addition to ACA-IIF. Due to
      their low prevalence in AD, measurement of SCCAb and 17OHAb should be indicated
      only for 21OHAb negative patients and/or for those with premature ovarian
      failure, regardless of ACA-IIF results.

PMID- 10664530
TI  - Cold exposure inhibits leptin secretion in vitro by a direct and non-specific
      action on adipose tissue.
AB  - OBJECTIVE: Leptin secretion is reduced by low temperatures in experimental
      animals, and this effect has been explained as an adaptive mechanism to cold
      environments. This study investigated the in vitro effects of cold exposure on
      human white adipose tissue. DESIGN: To understand whether the low temperature
      action is a direct or a mediated effect, leptin secretion was assessed in vitro
      in human omental adipose tissue incubated at varied temperatures, from 38 donors.
      As an internal control, the effect of reduced temperatures on in vitro GH
      secretion by GH3 cells was assessed. METHODS: Measurement of hormones secretion
      was carried out with an RIA, while human ob gene mRNA expression was assessed
      with reverse transcription PCR. RESULTS: Compared with the standard temperature
      of 37 degrees C, leptin secretion by human adipose tissue was significantly
      (P<0.05) reduced when the incubations were carried out at 34.5 degrees C (41%
      inhibition), and 32 degrees C (68% inhibition), with no parallel changes in the
      ob mRNA expression. At these reduced temperatures, glucocorticoid-mediated leptin
      secretion was well preserved. When the effect of reduced temperatures was
      assessed on in vitro GH secretion, a superimposable reduction was observed.
      CONCLUSIONS: These results indicate: (i) that low temperatures reduce leptin
      secretion by acting directly on the adipose tissue and (ii) that the similar
      reduction in a hormone unrelated to energy metabolism, such as GH, suggests that
      the observed reduction is a mechanical perturbation of leptin secretion, which
      may be devoid of physiological implications.

PMID- 10664531
TI  - In the search for specific inhibitors of human 11beta-hydroxysteroid
      dehydrogenases (11beta-HSDs): chenodeoxycholic acid selectively inhibits 11beta
      HSD-I.
AB  - OBJECTIVE: Selective inhibitors of 11beta-hydroxysteroid-dehydrogenase type I may
      be of therapeutical interest for two reasons: i) 9alpha-Fluorinated 11
      dehydrosteroids like 11-dehydro-dexamethasone (DH-D) are rapidly activated by
      human kidney 11beta-hydroxysteroid-dehydrogenase type II (11beta-HSD-II) to
      dexamethasone (D). If the same reaction by hepatic 11beta-HSD-I could be
      selectively inhibited, DH-D could be used for selective renal immunosuppressive
      therapy. ii) Reduction of cortisone to cortisol in the liver may increase insulin
      resistance in type 2 diabetes mellitus, and inhibition of the enzyme may lead to
      a decrease in gluconeogenesis. Therefore, we characterized the metabolism of DH-D
      by human hepatic 11beta-HSD-I and tried to find a selective inhibitor of this
      isoenzyme. METHODS: For kinetic analysis of 11beta-HSD-I, we used microsomes
      prepared from unaffected parts of liver segments, resected because of
      hepatocarcinoma or metastatic disease. For inhibition experiments, we also tested
      11beta-HSD-II activity with human kidney cortex microsomes. The inhibitory
      potency of several compounds was evaluated for oxidation and reduction in
      concentrations from 10(-9) to 10(-5)mol/l. RESULTS: Whereas D was not oxidized by
      human liver microsomes at all, cortisol was oxidized to cortisone with a maximum
      velocity (V(max)) of 95pmol/mg per min. The reduction of DH-D to D
      (V(max)=742pmol/mg per min, Michaelis--Menten constant (K(m))=1.6 micromol/l) was
      faster than that of cortisone to cortisol (V(max)=187pmol/mg per min). All
      reactions tested in liver microsomes showed the characteristics of 11beta-HSD-I:
      K(m) values in the micromolar range, preferred cosubstrate NADP(H), no product
      inhibition. Of the substances tested for inhibition of 11beta-HSD-I and -II,
      chenodeoxycholic acid was the only one that selectively inhibited 11beta-HSD-I
      (IC(50) for reduction: 2.8x10(-6)mol/l, IC(50) for oxidation: 4.4x10(-6)mol/l),
      whereas ketoconazole preferentially inhibited oxidation and reduction reactions
      catalyzed by 11beta-HSD-II. Metyrapone, which is reduced to metyrapol by hepatic
      11beta-HSD-I, inhibited steroid reductase activity of 11beta-HSD-I and -II and
      oxidative activity of 11beta-HSD-II. These findings can be explained by substrate
      competition for reductase reactions and by product inhibition of the oxidation,
      which is a well-known characteristic of 11beta-HSD-II. CONCLUSIONS: Our in vitro
      results may offer a new concept for renal glucocorticoid targeting. Oral
      administration of small amounts of DH-D (low substrate affinity for 11beta-HSD-I)
      in combination with chenodeoxycholic acid (selective inhibition of 11beta-HSD-I)
      may prevent hepatic first pass reduction of DH-D, thus allowing selective
      activation of DH-D to D by the high affinity 11beta-HSD-II in the kidney.
      Moreover, selective inhibitors of the hepatic 11beta-HSD-I, like chenodeoxycholic
      acid, may become useful in the therapy of patients with hepatic insulin
      resistance including diabetes mellitus type II, because cortisol enhances
      gluconeogenesis.

PMID- 10664532
TI  - How long should we treat porphyric patients?

PMID- 10664533
TI  - Drug/cyclodextrin/hydroxy acid multicomponent systems. Properties and
      pharmaceutical applications.
AB  - The objective of this mini-review is to summarize the findings concerning the
      properties and the pharmaceutical applications of multicomponent complexes made
      of a sparingly water-soluble amino-type drug, a cyclodextrin, and a hydroxy
      carboxylic acid. Simultaneous complexation and salt formation with these acids
      significantly increase the solubilizing power, allowing us to reduce the amount
      of cyclodextrin necessary for making the targeted formulation. In many cases, the
      aqueous solubility of the hydrophobic drug can be enhanced by several orders of
      magnitude, while that of CD can be enhanced more than 10-fold. The mechanism
      through which these complexes elicit their synergetic effects on the drug
      solubility is also discussed. Finally, some general observations are made
      concerning the structural requirements of the drug necessary for exploiting the
      aforementioned effect.

PMID- 10664534
TI  - Water-based microsphere delivery system for proteins.
AB  - This paper describes formulation of a model protein, horseradish peroxidase
      (HRP), in a water based microcapsule delivery system and demonstrates the utility
      of this delivery system for proteins. Aqueous solutions (1 mg/mL) of the enzyme
      were separately blended with aqueous solutions of the neutral sodium salt of the
      anionic polymer iota carrageenan (0.6 mM in repeat unit). These blends were
      instilled as uniform microdroplets into aqueous solutions of a series of eleven
      mono-, di-, or oligo-amines (as neutral hydrochloride or acetate salts).
      Essentially instantaneous salt exchange interaction of the sodium salt of anionic
      polymer with amine hydrochloride resulted in formation of microparticles of
      amine/polymer complex. The enzyme was captured in the resulting capsules. The
      particles were washed by repeated centrifugation and resuspension in water and
      their particle size distribution was determined. HRP in washed pelleted
      microspheres was analyzed for fragmentation/aggregation by SDS-PAGE and size
      exclusion chromatography, for unfolding by fluorescence spectroscopy, and for
      specific enzymatic activity, capture efficiency and release studies by absorbance
      spectroscopy. Dependent on amine employed, capture efficiencies ranged from 1 to
      72%. Encapsulation produced no adverse effect on protein size as no molecular
      fragments or aggregates were visible below or above 44 kDa. The tryptophan
      fluorescence spectrum of the protein did not change after encapsulation
      indicating no conformational change in tertiary structure. There was an apparent
      substrate diffusion related reduction in activity of encapsulated HRP, but almost
      100% of activity was recovered on lysis of the capsules. It is concluded that
      water based charged film encapsulation used as a drug delivery system for
      proteins does not alter structural conformation or specific activity of the model
      protein tested and provides protein release at a constant rate.

PMID- 10664535
TI  - A priori prediction of tissue:plasma partition coefficients of drugs to
      facilitate the use of physiologically-based pharmacokinetic models in drug
      discovery.
AB  - The tissue:plasma (P(t:p)) partition coefficients (PCs) are important drug
      specific input parameters in physiologically based pharmacokinetic (PBPK) models
      used to estimate the disposition of drugs in biota. Until now the use of PBPK
      models in early stages of the drug discovery process was not possible, since the
      estimation of P(t:p) of new drug candidates by using conventional in vitro and/or
      in vivo methods is too time and cost intensive. The objectives of the study were
      (i) to develop and validate two mechanistic equations for predicting a priori the
      rabbit, rat and mouse P(t:p) of non-adipose and non-excretory tissues (bone,
      brain, heart, intestine, lung, muscle, skin, spleen) for 65 structurally
      unrelated drugs and (ii) to evaluate the adequacy of using P(t:p) of muscle as
      predictors for P(t:p) of other tissues. The first equation predicts P(t:p) at
      steady state, assuming a homogenous distribution and passive diffusion of drugs
      in tissues, from a ratio of solubility and macromolecular binding between tissues
      and plasma. The ratio of solubility was estimated from log vegetable oil:water
      PCs (K(vo:w)) of drugs and lipid and water levels in tissues and plasma, whereas
      the ratio of macromolecular binding for drugs was estimated from tissue
      interstitial fluid-to-plasma concentration ratios of albumin, globulins and
      lipoproteins. The second equation predicts P(t:p) of drugs residing predominantly
      in the interstitial space of tissues. Therefore, the fractional volume content of
      interstitial space in each tissue replaced drug solubilities in the first
      equation. Following the development of these equations, regression analyses
      between P(t:p) of muscle and those of the other tissues were examined. The
      average ratio of predicted-to-experimental P(t:p) values was 1.26 (SD = 1.40, r =
      0.90, n = 269), and 85% of the 269 predicted values were within a factor of three
      of the corresponding literature values obtained under in vivo and in vitro
      conditions. For predicted and experimental P(t:p), linear relationships (r > 0.9
      in most cases) were observed between muscle and other tissues, suggesting that
      P(t:p) of muscle is a good predictor for the P(t:p) of other tissues. The two
      previous equations could explain the mechanistic basis of these linear
      relationships. The practical aim of this study is a worthwhile goal for
      pharmacokinetic screening of new drug candidates.

PMID- 10664536
TI  - Conjugation of para-nitrophenol by the isolated perfused neonatal sheep liver.
AB  - We examined the metabolism of para-nitrophenol (PNP) in the isolated perfused
      neonatal sheep liver (n = 8, 0.25-11 days) and compared the findings with our
      previous data from the perfused near-term fetal sheep liver (Ring, J. A., et al.
      Drug Metab Dispos 1996, 24, 1378). A three-step dosage regimen was used (72, 144,
      and 288 micromol of PNP). At the end of each dosage phase, PNP had fallen below
      detectable levels, and 101 +/- 16% of the dose was accounted for as PNP
      conjugates. Elimination of PNP from perfusate varied with dose. Elimination was
      first order with the 72-micromol dose; with the 144-micromol dose, elimination
      was first order in four livers but Michaelis-Menten kinetics in the remaining
      four. With all the 288-micromol doses, elimination was Michaelis-Menten and gave
      the following biochemical parameters: K(m) = 255 +/- 138 microM (fetal = 14.7
      microM, P < 0.01), V(max) = 515 +/- 285 nmol/min/g liver (fetal = 34.3 nmol/min/g
      liver, P < 0.01), and intrinsic hepatic clearance = 2.36 +/- 1.21 mL/min/g liver
      (fetal = 4.74 mL/min/g liver, P > 0. 05). The mean shunt-corrected hepatic
      extraction ratio of PNP was 0. 82 (range, 0.40-1.0) and strongly correlated with
      neonatal age (r = 0.90, P < 0.05). We conclude that PNP is highly extracted by
      the isolated perfused neonatal sheep liver at much higher efficiency than in the
      near-term fetal sheep, reflecting a maturation of conjugation that progresses
      further in the early neonatal period.

PMID- 10664537
TI  - Photopolymerized, multilaminated matrix devices with optimized nonuniform initial
      concentration profiles to control drug release.
AB  - This paper describes a novel approach to obtain desired release profiles from
      diffusion-controlled matrix devices by employing nonuniform initial concentration
      profiles theoretically and experimentally. Theoretically, a model was developed
      to examine the effect of nonuniform initial concentration profiles on matrix
      release behavior, and an optimization technique was investigated to determine
      suitable nonuniform initial concentration profiles which provide desired release
      patterns. Experimentally, release rates of an organic dye from photopolymerized
      matrix devices were measured to test the application of these mathematical
      techniques and the efficacy of photolaminated matrices in approximating the
      optimized release behavior. All system parameters were measured by independent
      experiments, and the experimental release data agree very well with the computed
      results.

PMID- 10664538
TI  - Preparation and characterization of pH-responsive polymeric micelles for the
      delivery of photosensitizing anticancer drugs.
AB  - pH-responsive polymeric micelles (PM) consisting of random copolymers of N
      isopropylacrylamide (NIPA), methacrylic acid (MAA), and octadecyl acrylate (ODA)
      were prepared and characterized. The critical aggregation concentration, as
      determined by a fluorescence probe technique, was approximately 10 mg/L in water
      and phosphate-buffered saline. Phase transition pH was estimated at 5.7. The
      decrease in pH was accompanied by the destruction of hydrophobic clusters.
      Micelle size was dependent on temperature and the nature of the aqueous medium.
      The micelles were successfully loaded with a substantial amount of a photoactive
      anticancer drug, namely, aluminum chloride phthalocyanine (AlClPc). pH-responsive
      PM loaded with AlClPc were found to exhibit higher cytotoxicity against EMT-6
      mouse mammary cells in vitro than control Cremophor EL formulation. These results
      show the potential of poly(NIPA-co-MAA-co-ODA) for in vivo administration of
      water-insoluble, photosensitizing anticancer drugs.

PMID- 10664540
TI  - Evaluation of degradation pathways for plasmid DNA in pharmaceutical formulations
      via accelerated stability studies.
AB  - The stability of highly purified supercoiled plasmid DNA formulated in simple
      phosphate or Tris-buffered saline solutions has been characterized to establish
      the overall degradation processes that occur during storage in aqueous solution.
      Plasmid DNA stability was monitored during accelerated stability studies (at 50
      degrees C) by measurements of supercoiled, open-circle, and linear DNA content,
      as well as the accumulation of apurinic sites and 8-hydroxydeoxyguanosine
      residues over time. The effects of formulation pH, demetalation, metal ion
      chelators, and ethanol (hydroxyl radical scavenger) on the supercoiled content of
      plasmid DNA during storage at 50 degrees C were also determined. The results
      indicate that free radical oxidation may be a major degradative process for
      plasmid DNA in pharmaceutical formulations unless specific measures are taken to
      control it by the addition of free radical scavengers, specific metal ion
      chelators, or both. The generation of hydroxyl radicals in phosphate-buffered
      saline was confirmed by examining the hydroxylation of phenylalanine over time by
      reverse phase high-performance liquid chromatography. Ethanol was found to
      enhance plasmid DNA stability and to inhibit the hydroxylation of phenylalanine;
      both observations are consistent with the known ability of ethanol to serve as a
      hydroxyl radical scavenger. Moreover, the combination of ethylenediamine
      tetraacetic acid (EDTA) and ethanol had a synergistic enhancing effect on DNA
      stability. However, the metal ion chelator diethylenetriaminepentaacetic acid
      (DTPA) was as potent as the combination of EDTA and ethanol for enhancing the
      stability of plasmid DNA. By controlling free radical oxidation with EDTA and
      ethanol, the rate constants of plasmid DNA degradation by means of depurination
      and beta-elimination were then determined, allowing accurate predictions of DNA
      storage stability as a function of formulation pH and temperature. The ability to
      predict plasmid DNA storage stability in the absence of free radical oxidation
      should prove to be a valuable tool for the design of stable pharmaceutical
      formulations of plasmid DNA.

PMID- 10664539
TI  - Caco-2 versus Caco-2/HT29-MTX co-cultured cell lines: permeabilities via
      diffusion, inside- and outside-directed carrier-mediated transport.
AB  - PURPOSE: The objective of this study was a systematic characterization and
      evaluation of cell culture models based on mixtures of Caco-2/HT29-MTX co
      cultures for their use in screening for drug absorption and intestinal
      permeability in comparison to the properties of the respective mono-cultures.
      METHODS: Co-cultures of Caco-2 cells (absorptive-type) and HT29-MTX cells (goblet
      type) were set up. Three different co-cultures (initial seeding ratios Caco
      2/HT29-MTX: 90/10, 70/30, and 50/50) were grown on permeable filter supports, and
      monolayers were used for permeability studies with model compounds for
      paracellular absorption (atenolol, furosemide, H334/75, mannitol, terbutaline),
      transcellular absorption (antipyrine, ketoprofen, metoprolol, piroxicam), carrier
      mediated absorption (D-glucose, Gly-Pro, and L-phenylalanine) as well as
      substrates for carrier-mediated secretion via P-glycoprotein (cimetidine and
      talinolol). Electrophysiological and microscopic controls were performed to
      characterize the cell cultures. RESULTS: For compounds undergoing passive
      intestinal absorption permeabilities were generally higher in co-cultures than in
      Caco-2 monolayers, yielding highest values in pure HT29-MTX monolayers. This
      difference was most obvious for compounds transported via the paracellular
      pathway, where HT29-MTX cells may be up to 30 times more permeable than Caco-2
      cells, whereas for lipophilic and highly permeable compounds, the difference in
      permeability values was less obvious. For drugs undergoing intestinal secretion
      mediated by P-glycoprotein, co-cultivation of Caco-2 cells with HT29-MTX cells
      led to increased apical to basolateral permeability which was decreased in the
      opposite direction, consistent with the fact that HT29-MTX cells do not express P
      glycoprotein. When a carrier-mediated absorption mechanism is involved, the
      permeabilities observed were lower than the values reported for human small
      intestine and co-cultivation of HT29-MTX cells with Caco-2 cells resulted in even
      lower values as compared to the plain Caco-2 cultures. CONCLUSIONS: Co-cultures
      of HT29-MTX and Caco-2 cells offer the opportunity of modifying the permeability
      barrier of the cell monolayers both with respect to paracellular resistance and
      secretory transport via P-gp. Thus, in special cases, they allow more flexibility
      in adapting the in vitro system to the in vivo situation as compared to the
      monocultures. Another advantage is the obvious robustness of the method with
      respect to the reproducibility of the results. A problem remaining, however, is
      the quantitative expression of carriers involved in intestinal uptake of many
      nutrients and drugs.

PMID- 10664541
TI  - Effect of molecular structure on the performance of triarylmethane dyes as
      therapeutic agents for photochemical purging of autologous bone marrow grafts
      from residual tumor cells.
AB  - Extensively conjugated cationic molecules with appropriate structural features
      naturally accumulate into the mitochondria of living cells, a phenomenon
      typically more prominent in tumor than in normal cells. Because a variety of
      tumor cells also retain pertinent cationic structures for longer periods of time
      compared with normal cells, mitochondrial targeting has been proposed as a
      selective therapeutic strategy of relevance for both chemotherapy and
      photochemotherapy of neoplastic diseases. Here we report that the triarylmethane
      dye crystal violet stains cell mitochondria with efficiency and selectivity, and
      is a promising candidate for photochemotherapy applications. Crystal violet
      exhibits pronounced phototoxicity toward L1210 leukemia cells but comparatively
      small toxic effects toward normal hematopoietic cells (murine granulocyte
      macrophage progenitors, CFU-GM). On the basis of a comparative examination of
      chemical, photochemical, and phototoxic properties of crystal violet and other
      triarylmethane dyes, we have identified interdependencies between molecular
      structure, and selective phototoxicity toward tumor cells. These structure
      activity relationships represent useful guidelines for the development of novel
      purging protocols to promote selective elimination of residual tumor cells from
      autologous bone marrow grafts with minimum toxicity to normal hematopoietic stem
      cells.

PMID- 10664542
TI  - Dose-dependency in local disposition of 5-fluorouracil under non-steady-state
      condition in rat liver.
AB  - Dose-dependency in local disposition of 5-fluorouracil (5-FU) was evaluated using
      the rat liver in the once-through perfusion system under the non-steady-state
      condition. A curve-fitting program based on Finite Element Method, MULTI(FEM),
      was adopted to evaluate the capacity-limited elimination in the hepatic local
      disposition of 5-FU, which is described by a nonlinear dispersion model with a
      pulse input. The dose of 5-FU was increased from 10.4 to 208 microg for rat
      livers at five dose levels. Two nonlinear models, two-compartment dispersion
      models with Michaelis-Menten elimination from the central compartment or from the
      peripheral compartment, were employed for comparison. The hepatic recovery ratio,
      F(H), increased from 13.1% to 68.3% and the mean transit time, t(H), increased
      from 5.1 to 13.1 s with an increase in the dose. It was found that the hepatic
      local disposition of 5-FU was well represented by the peripheral elimination
      model. V(max) and K(m) in the model with peripheral Michaelis-Menten elimination
      were estimated to be 9.04 mg/h and 2.88 mg/L, respectively. V(max) estimated by
      the present investigation in situ was about seven times greater than that in
      vitro, whereas K(m) in situ was close to that in vitro. This result suggests that
      the elimination activity by the hepatocytes in vitro may be lowered, compared
      with that in situ.

PMID- 10664543
TI  - Degradation of azaglycinamido residues in model tripeptides derived from
      goserelin.
AB  - Three model tripeptides, N-acetyl-Tyr-Pro-azaGly-NH(2) (NYPaG), Tyr-Pro-azaGly
      NH(2) (YPaG), and Tyr-Pro-Gly-NH(2)(YPG), were subjected to a systematic
      degradation study to get information about the degradation of the azaglycinamido
      residue. The degradation products were characterized with LC-MS. Main degradation
      products of NYPaG possess partially or totally eliminated azaglycinamido
      residues, while YPaG and YPG are exhibit cyclo(Tyr-Pro) formation, a
      diketopiperazine. The influence of the pH on the degradation rate constant k(obs)
      was investigated for NYPaG and YPaG in the pH range 0.4-11. An U-shaped profile
      with an inflexion around pH 9 was found for NYPaG while the degradation rate of
      YPaG was independent of the pH. NYPaG apparently was subject to proton-, solvent
      , and hydroxyl-catalyzed degradation reactions whereas YPaG only underwent
      solvent-catalyzed reactions. Some influence of acetate and phosphate ions on
      k(obs) was found for YPaG. Arrhenius plots of NYPaG and YPaG were found to be
      linear.

PMID- 10664544
TI  - Comparison of the permeability surface product (PS) of the blood capillary wall
      in skeletal muscle tissue of various species and in vitro porous membranes using
      hydrophilic drugs.
AB  - The aim of this study was twofold: Firstly, to compare the PS, the permeability
      surface product or organ clearance, of various hydrophilic molecules in the
      muscle blood capillary wall of different animal species, including humans and,
      secondly, to design an in vitro diffusion cell to identify similar PS values
      using the respective membranes. The flux rates of solutes with a wide range of
      molecular weights measured across porous membranes (Millipore(R) VM (MVM), and
      Nadir(R) UFC (NUFC)) was associated with high reproducibility (<+/-10% SD). The
      findings were as follows: (1) For the first time ever it was demonstrated that
      the log molecular weight dependency (between 180 and 10,000 Dalton) of the log of
      the PS product of the animal muscle capillary wall (slope = -0.51 +/- 0. 16, and
      a regression coefficient r(2) = 0.90) reported in the literature was similar to
      that observed by various authors in humans (slope = -0.50 +/- 0.25 r(2) = 0.77).
      (2) PS of the MVM membrane with a surface area of 3.8 cm(2) recorded for the
      newly developed diffusion cell ranged at approximately 50% below (slope -0.58 +/-
      0. 12, r(2) = 0.85) the value observed in the in vivo human experiments after
      intramuscular injection. No linear relationship was established for the NUFC
      membrane due to solute exclusion effects of the membrane. (3) The diameter of the
      inner donor chamber (resembling the interstice between the muscle fiber membrane
      and the capillary wall membrane) was calculated to be sufficiently small to
      eliminate the possibility of creating a statistically significant diffusion
      barrier to the test membranes, which was corroborated by theoretical modeling.
      The structure of the in vitro diffusion cell prevents any significant
      contribution from the unstirred water layer (UWL) to overall resistance, thus
      reflecting in vivo diffusion properties of hydrophilic solutes deposited
      intramuscularly to enter the systemic circulation. It may be concluded, that MVM
      membrane in the vitro diffusion cell mimics the in vivo blood capillary PS for
      hydrophilic solutes of up to 10,000 Da.

PMID- 10664545
TI  - Physical characteristics and chemical degradation of amorphous quinapril
      hydrochloride.
AB  - This study was designed to investigate the relationships between the solid-state
      chemical instability and physical characteristics of a model drug, quinapril
      hydrochloride (QHCl), in the amorphous state. Amorphous QHCl samples were
      prepared by rapid evaporation from dichloromethane solution and by grinding and
      subsequent heating of the crystalline form. Physical characteristics, including
      the glass transition temperature and molecular mobility, were determined using
      differential scanning calorimetry, thermogravimetric analysis, powder x-ray
      diffractometry, polarizing microscopy, scanning electron microscopy, and infrared
      spectroscopy. The amorphous form of QHCl, produced by both methods, has a T(g) of
      91 degrees C. Isothermal degradation studies showed that cyclization of QHCl
      occurred at the same rate for amorphous samples prepared by the two methods. The
      activation energy was determined to be 30 to 35 kcal/mol. The rate of the
      reaction was shown to be affected by sample weight, dilution through mixing with
      another solid, and by altering the pressure above the sample. The temperature
      dependence for chemical reactivity below T(g) correlated very closely with the
      temperature dependence of molecular mobility. Above T(g), however, the reaction
      was considerably slower than predicted from molecular mobility. From an analysis
      of all data, it appears that agglomeration and sintering of particles caused by
      softening of the solid, particularly above T(g), and a resulting reduction of the
      particle surface/volume ratio play a major role in affecting the reaction rate by
      decreasing the rate of removal of the gaseous HCl product.

PMID- 10664546
TI  - Diffusion modeling of percutaneous absorption kinetics. 1. Effects of flow rate,
      receptor sampling rate, and viable epidermal resistance for a constant donor
      concentration.

PMID- 10664547
TI  - Measurement of albuterol in guinea pig serum by high performance liquid
      chromatography with fluorescence detection.
AB  - A sensitive, simple and reproducible high performance liquid chromatographic
      method for detecting and quantifying albuterol in guinea pig serum is described.
      A structurally related compound, bamethan, was used as an internal standard. The
      method employs ion-pair extraction with di(2-ethylhexyl)phosphate followed by
      chromatography on a Zorbax SB C18 reversed-phase column. Fluorescence detection
      was used to identify the compounds of interest. The calibration curve was linear
      between 1 and 50 ng/mL albuterol hemisulfate salt (0.83 and 41.50 ng/mL albuterol
      base), and the limit of detection for a 1 mL sample was 1 ng/mL albuterol
      hemisulfate salt (0.83 ng/mL albuterol base). Serum levels of albuterol were
      quantified from guinea pigs that had received the drug by continuous subcutaneous
      infusion at a dose of 0.2 mg/kg/day for 1, 5 or 10 days, or 10 days followed by a
      24 h washout period.

PMID- 10664548
TI  - Speciation of mercury by capillary electrophoresis-inductively coupled plasma
      mass spectrometry.

PMID- 10664549
TI  - Enantiomeric resolution of selenoamino acid derivatives by micellar
      electrokinetic chromatography (MEKC) with sodium dodecyl sulphate and a mixture
      of beta-cyclodextrin and taurodeoxycholic acid as chiral selectors.

PMID- 10664550
TI  - Multivariate optimization approach for the separation of water-soluble vitamins
      and related compounds by capillary electrophoresis.

PMID- 10664551
TI  - Separation of non-steroidal anti-inflammatory drugs by capillary electrophoresis
      using non-aqueous electrolyte.

PMID- 10664553
TI  - Comparison of two reversed phase LC methods for stability study of ciprofloxacin
      hydrochloride.

PMID- 10664552
TI  - Determination of sulfonated organic pollutants in industrial effluents and
      wastewaters by automated solid phase extraction followed by CE-UV and CE-MS.

PMID- 10664554
TI  - Enantiomeric separation of amino acid derivatives by non-aqueous capillary
      electrophoresis using quinine and related compounds as chiral additives.

PMID- 10664555
TI  - Validation of trueness using added samples as reference materials in HPLC
      methods. Application in quality control of the synthesis of D-alpha-p
      hydroxyphenylglycine.

PMID- 10664556
TI  - A framework for in-house accuracy validation of analytical procedures.

PMID- 10664557
TI  - The combination of potentiometric detection and miniaturized analysis systems.

PMID- 10664558
TI  - In-line concentration and enantioseparation of clenbuterol by transient
      isotachophoresis-capillary zone electrophoresis-UV detection.

PMID- 10664559
TI  - Simultaneous analysis of hop acids and prenylated flavanones by microemulsion
      electrokinetic chromatography with diode array detection.

PMID- 10664560
TI  - Sulfonic acid coated capillary for metallothionein isoform separation by
      capillary zone electrophoresis.

PMID- 10664561
TI  - Metallothionein isoform separation by MECC using SDS micelles.

PMID- 10664562
TI  - Structure-retention relationships of diuretics in reversed-phase liquid
      chromatography.

PMID- 10664563
TI  - Liquid chromatography on-chip.

PMID- 10664565
TI  - Determination of cannabinoids by capillary liquid chromatography with
      electrochemical detection.

PMID- 10664564
TI  - New possibilities of electrochemical detection in combination with non-aqueous
      capillary electrophoresis.

PMID- 10664566
TI  - Fast narrow-bore HPLC analysis of thiosulfinates in onions and hybrids.
      Relationship with the platelet anti-aggregant activity.

PMID- 10664567
TI  - Validation and application of the RP-HPLC method for the assay of allylestrenol
      and alpha-tocopherol in tablets.

PMID- 10664568
TI  - Comparison of the enantiomeric separation of some 2-arylpropionic acids on a
      novel Pirkle-concept stationary packing by narrow-bore and conventional liquid
      chromatography.

PMID- 10664570
TI  - Prostate cancer succumbs to gene therapy.

PMID- 10664569
TI  - Application of the ADS precolumn-switching technique to the separation of some
      drugs from plasma.

PMID- 10664571
TI  - New implant device for Alzheimer's treatment.

PMID- 10664572
TI  - Thalidomide reduces steroid dose for Crohn's patients.

PMID- 10664573
TI  - Quantitative structure-property relationships in pharmaceutical research - Part
      2.
AB  - Part one of this two-part review described the advantages and limitations of
      quantitative structure-property relationships (QSPR), and offered an overview of
      the components involved in the development of correlations1. Part two provides a
      discussion of a few notable examples of relationships with organoleptic,
      physicochemical and pharmaceutical properties.

PMID- 10664574
TI  - An overview of the different excipients useful for the direct compression of
      tablets.
AB  - The humble tablet dosage form still accounts for more than 80% of all dosage
      forms administered to man. This review will outline the various excipients that
      have been used as fillers in direct compression formulations, with particular
      emphasis on what is expected from such excipients in terms of their
      functionality. It is intended that this overview (which is by no means
      exhaustive) will serve as an 'aide-memoire' to the formulation scientist.

PMID- 10664575
TI  - Starch capsules: an alternative system for oral drug delivery.
AB  - Manufactured by the process of injection moulding, starch capsules have been
      shown to be a very useful alternative delivery system for orally administered
      compounds. This review describes the starch capsule manufacturing and filling
      processes and provides an overview of the capsules' physical characteristics. In
      addition, investigations supporting the development of novel delivery
      technologies based on the starch capsules are described. Particular emphasis is
      given to a technology that facilitates drug delivery to specific sites in the
      human gastrointestinal tract.

PMID- 10664576
TI  - Monitor: progress and profiles.
AB  - Monitor provides an insight into the latest developments in pharmaceutical
      science and technology through brief synopses of recent presentations,
      publications and patents, and expert commentaries on the latest technologies.
      There are two sections: Progress summarizes the latest developments in
      pharmaceutical process technology, formulation, analytical technology,
      sterilization, controlled drug delivery systems and regulatory issues; Profiles
      offers expert commentary on emerging technologies, novel processes and strategic,
      organizational and logistic issues underlying pharmaceutical R&D.

PMID- 10664577
TI  - A structure-based mechanism for drug binding by multidrug transporters.
AB  - Multidrug transporters bind chemically dissimilar, potentially cytotoxic
      compounds and remove them from the cell. How these transporters carry out either
      of these functions is unknown. On the basis of crystal structures of the
      multidrug-binding domain of the transcription activator BmrR and mutagenesis
      studies on the bacterial multidrug transporter MdfA, we propose a possible
      mechanism for the binding of cationic lipophilic drugs by multidrug transporters.
      The key element of this mechanism includes a conformational change in the
      transporter that exposes a buried charged residue in the substrate-binding pocket
      and allows access to this site by only those drugs that are its steric and
      electrostatic complements.

PMID- 10664578
TI  - The origin of the genetic code.

PMID- 10664579
TI  - Measuring adaptation within the genetic code.

PMID- 10664580
TI  - The PPR motif - a TPR-related motif prevalent in plant organellar proteins.

PMID- 10664581
TI  - Novel repeats in ryanodine and IP3 receptors and protein O-mannosyltransferases.

PMID- 10664582
TI  - A novel superfamily of predicted cysteine proteases from eukaryotes, viruses and
      Chlamydia pneumoniae.

PMID- 10664583
TI  - Molecular mechanisms of plasminogen activation: bacterial cofactors provide
      clues.
AB  - Plasminogen activation is a key event in the fibrinolytic system that results in
      the dissolution of blood clots, and also promotes cell migration and tissue
      remodelling. The recent structure determinations of microplasmin in complex with
      the bacterial plasminogen activators staphylokinase and streptokinase have
      provided novel insights into the molecular mechanisms of plasminogen activation
      and cofactor function. These bacterial proteins are cofactor molecules that
      contribute to exosite formation and enhance the substrate presentation to the
      enzyme. At the same time, they modulate the specificity of plasmin towards
      substrates and inhibitors, making a 'specificity switch' possible.

PMID- 10664584
TI  - TBP-associated factors (TAFIIs): multiple, selective transcriptional mediators in
      common complexes.
AB  - Transcription of eukaryotic structural genes requires the assembly of RNA
      polymerase II and the general transcription factors (GTFs) on the promoter to
      form a pre-initiation complex (PIC). Among these, TFIID is the major sequence
      specific DNA-binding component; the other GTFs enter the PIC primarily through
      protein-protein interactions. TFIID is composed of the TATA-box-binding protein
      (TBP) and multiple TBP-associated factors (TAFIIs). Unexpectedly, TAFIIs have
      also been found in other multi-subunit complexes involved in transcription.
      Whereas TBP is a general transcription factor, a variety of in vivo studies have
      demonstrated that TAFIIs are highly promoter selective. Here I review studies on
      the role of TAFIIs in genome-wide transcription and their mechanism of action.

PMID- 10664586
TI  - Anticodon nucleases.
AB  - A tRNALys-specific anticodon nuclease is kept in a latent form in a rare
      Escherichia coli strain, complexed with a DNA restriction enzyme. A phage T4
      inhibitor of DNA restriction activates anticodon nuclease, but other T4 proteins
      restore tRNALys. Detection of a homologous system in Neisseria and a different
      anticodon nuclease in colicin E5 suggest ubiquity and diversity of such tRNA
      toxins. Analysis of these systems could reveal novel RNA recognition and cleavage
      mechanisms.

PMID- 10664585
TI  - Signaling inputs converge on nuclear effectors in TGF-beta signaling.
AB  - Recent studies have consolidated the pivotal role of Smads as intracellular
      effectors of TGF-beta family members. Upon binding to their specific type I and
      type II serine/threonine kinase receptors, each family member activates a
      particular subset of Smad proteins. Activated, receptor-regulated Smads form
      hetero-oligomeric complexes with common-partner Smads that translocate into the
      nucleus, where they control the expression of target genes in a cell-type
      specific manner. Smads appear to function not only as nuclear effectors for TGF
      beta family members, but as signal integrators within an extensive intracellular
      network.

PMID- 10664587
TI  - Lesions in DNA: hurdles for polymerases.
AB  - Translesion synthesis (TLS) is one of the DNA damage tolerance strategies, which
      have evolved to enable organisms to replicate their genome despite the presence
      of unrepaired damage. The process of TLS has the propensity to produce mutations,
      a potential origin of cancer, and is therefore of medical interest. Significant
      progress in our understanding of TLS has come primarily from studies of the
      bacterium Escherichia coli, the budding yeast Saccharomyces cerevisiae and, more
      recently, human cells. Results from these analyses indicate that the fundamental
      mechanism of TLS and the proteins involved have been conserved throughout
      evolution from bacteria to humans.

PMID- 10664588
TI  - Signal transduction in the plant immune response.
AB  - Complementary biochemical and genetic approaches are being used to dissect the
      signaling network that regulates the innate immune response in plants. Receptor
      mediated recognition of invading pathogens triggers a signal amplification loop
      that is based on synergistic interactions between nitric oxide, reactive oxygen
      intermediates and salicylic acid. Alternative resistance mechanisms in
      Arabidopsis are deployed against different types of pathogens; these mechanisms
      are mediated by either salicylic acid or the growth regulators jasmonic acid and
      ethylene.

PMID- 10664589
TI  - Regulatory subunit interactions of the 26S proteasome, a complex problem.
AB  - The 26S proteasome is the major non-lysosomal protease in eukaryotic cells. This
      multimeric enzyme is the integral component of the ubiquitin-mediated substrate
      degradation pathway. It consists of two subcomplexes, the 20S proteasome, which
      forms the proteolytic core, and the 19S regulator (or PA700), which confers ATP
      dependency and ubiquitinated substrate specificity on the enzyme. Recent
      biochemical and genetic studies have revealed many of the interactions between
      the 17 regulatory subunits, yielding an approximation of the 19S complex
      topology. Inspection of interactions of regulatory subunits with non-subunit
      proteins reveals patterns that suggest these interactions play a role in 26S
      proteasome regulation and localization.

PMID- 10664590
TI  - Arthur Harden: an unwitting pioneer of metabolic control analysis.

PMID- 10664591
TI  - Targeting of transcriptional cofactors by the HPV E6 protein: another tale of
      David and Goliath.

PMID- 10664592
TI  - Exploitation of macrophages as a replication niche by Legionella pneumophila.

PMID- 10664593
TI  - Exploitation of macrophages as a replication niche by Legionella pneumophila:
      response.

PMID- 10664594
TI  - Immunity to homologous rotavirus infection in adult mice.

PMID- 10664595
TI  - Immunity to homologous rotavirus infection in adult mice: response.

PMID- 10664596
TI  - Sequence variation in Helicobacter pylori.

PMID- 10664597
TI  - Response from wang, humayun and taylor

PMID- 10664598
TI  - Persistent hantavirus infections: characteristics and mechanisms.
AB  - Hantaviruses include serious human pathogens that are maintained in nature in
      persistently infected rodents and that can also persistently infect cultured
      mammalian cells, causing little or no cytopathology. The mechanisms of hantavirus
      persistence are only beginning to be explored. Recent data point to subtle
      changes in the viral genome that might result in the differential regulation of
      replication and lead to persistence.

PMID- 10664599
TI  - New perspectives on nitrogen-fixing microorganisms in tropical and subtropical
      oceans.
AB  - New molecular and microscopic evidence indicates that the open ocean harbors a
      diverse range of novel free-living and symbiotic nitrogen-fixing microorganisms.
      Although the extent to which these microorganisms fix nitrogen is currently
      unclear, ongoing research indicates that they might make a substantial
      contribution to the open ocean nitrogen budget.

PMID- 10664600
TI  - The causes and consequences of genetic variation in dengue virus.
AB  - Despite the fact that dengue is one of the most prevalent viral infections of
      humans, the mechanisms responsible for its pathogenesis remain uncertain.
      Evolutionary studies of dengue virus have revealed that its genetic diversity is
      increasing. This, coupled with evidence that viral strains could naturally differ
      in virulence, suggests that in the future we might be exposed to viruses with an
      expanded range of pathogenic properties.

PMID- 10664601
TI  - The origin of prokaryotic C2H2 zinc finger regulators.
AB  - C2H2 zinc finger bearing proteins are a large superfamily of nucleic acid binding
      proteins, which constitute a major subset of eukaryotic transcription factors.
      Although originally thought to occur only in eukaryotes, a novel C2H2 zinc finger
      transcription factor, Ros, which regulates both prokaryotic and eukaryotic
      promoters has been found in bacteria. Phylogenically, Ros is distantly related to
      eukaryotic zinc finger regulators.

PMID- 10664602
TI  - 100 years of virology: from vitalism via molecular biology to genetic
      engineering.
AB  - The identification of the causative agent of tobacco mosaic disease as a novel
      pathogen by the Dutch microbiologist Beijerinck is now acknowledged as being the
      foundation of virology as a discipline distinct from bacteriology. However, as
      this was contrary to the prevailing theories of the time, it took many years for
      virology to become firmly established as a separate discipline. The history of
      virology illustrates how accepted concepts in science evolve by trial and error
      and the need for a balanced approach when manipulating natural systems.

PMID- 10664603
TI  - Are cannabinoids endogenous ligands for the VR1 capsaicin receptor?

PMID- 10664604
TI  - Anandamide - the other side of the coin.

PMID- 10664605
TI  - In vivo protein transduction: intracellular delivery of biologically active
      proteins, compounds and DNA.

PMID- 10664606
TI  - FTY720: a novel transplantation drug that modulates lymphocyte traffic rather
      than activation.

PMID- 10664607
TI  - Cardiotoxic potential and CNS effects of first-generation antihistamines.

PMID- 10664608
TI  - VIP and PACAP in pain and inflammation.

PMID- 10664609
TI  - Effects of contamination on radioligand binding parameters.
AB  - Radioligand binding studies are used to provide quantitative estimates of
      parameters such as the receptor density of a tissue and the affinity values of
      labelled and unlabelled ligands. The presence of an unlabelled competing
      contaminant, which might be present because of actual contamination, inadequate
      radioligand purification or the breakdown of the radioligand to an active
      species, has surprising effects on these estimates: the apparent affinity of the
      radioligand is increased but the Ki values of unlabelled ligands are unaffected.
      The most striking and sensitive effects are on radioligand association kinetics,
      which become independent of radioligand concentration at high radioligand
      concentrations.

PMID- 10664610
TI  - Lithium therapy and signal transduction.
AB  - Lithium is the simplest therapeutic agent available for the treatment of
      depression and has been used for over 100 years, yet no definitive mechanism for
      its effect has been established. Among the proposed mechanisms, two lithium
      sensitive signal transduction pathways are active in the brain; these are
      mediated by glycogen synthase kinase 3beta (GSK-3beta) and inositol (1,4,5)
      trisphosphate [Ins(1,4,5)P3] signalling. This article describes recent
      experiments in cell and developmental biology that advance our understanding of
      how lithium works and it presents new directions for the study of both depression
      and Alzheimer's disease (AD).

PMID- 10664611
TI  - Gene-expression analysis at the single-cell level.
AB  - The manner in which a cell responds to and influences its environment is
      ultimately determined by the genes that it expresses. To fully understand and
      manipulate cellular function, identification of these expressed genes is
      essential. Techniques such as RT-PCR enable examination of gene expression at the
      tissue level. However, the study of complex heterogeneous tissue, such as the CNS
      or immune system, requires gene analysis to be performed at much higher
      resolution. In this article, the various methods that have been developed to
      enable RT-PCR to be performed at the level of the single cell are reviewed. In
      addition, how, when carried out in combination with techniques such as patch
      clamp recording, single-cell gene-expression studies extend our understanding of
      biological systems is discussed.

PMID- 10664612
TI  - 5-HT7 receptors: current knowledge and future prospects.
AB  - Identification of three splice variants of the 5-HT7 receptor suggests a possible
      diversity in 5-HT7 receptor action. Indeed, 5-HT7 receptors have been implicated
      in the pathophysiology of several disorders; they play a role in smooth muscle
      relaxation within the vasculature and in the gastrointestinal tract. However,
      most of these assignments are derived from receptor localization studies and
      investigations using nonselective ligands, and are therefore mainly suggestive.
      The development of selective 5-HT7 receptor antagonists will be of utmost
      importance in determining the actual physiological and pharmacological roles of
      this receptor. Major challenges of 5-HT7 receptor research are determination of
      the transcriptional regulation of the gene encoding the 5-HT7 receptor and
      elucidation of the differences in regulation and signalling of its four gene
      products.

PMID- 10664613
TI  - The use of plant biotechnology for the production of biodegradable plastics.

PMID- 10664614
TI  - Through form to function: root hair development and nutrient uptake.
AB  - Root hairs project from the surface of the root to aid nutrient and water uptake
      and to anchor the plant in the soil. Their formation involves the precise control
      of cell fate and localized cell growth. We are now beginning to unravel the
      complexities of the molecular interactions that underlie this developmental
      regulation. In addition, after years of speculation, nutrient transport by root
      hairs has been demonstrated clearly at the physiological and molecular level,
      with evidence for root hairs being intense sites of H(+)-ATPase activity and
      involved in the uptake of Ca(2+), K(+), NH(4)(+), NO(3)(-), Mn(2+), Zn(2+), Cl(-)
      and H(2)PO(4)(-).

PMID- 10664615
TI  - A floret by any other name: control of meristem identity in maize.
AB  - The life of a plant unfolds as a series of developmental stages, with each stage
      defined by changes in meristem identity. In maize, there are several distinct
      stages: the transition from vegetative growth to flowering, the elaboration of
      the inflorescence, and the formation of flowers. Progress in understanding
      meristem identity and function has been made by analyzing maize mutants with
      defects at each of these stages. Recently cloned genes suggest that, although the
      molecular mechanisms controlling floral organ identity are conserved in maize and
      other model species, the control of meristem identity during earlier
      developmental stages might be less conserved.

PMID- 10664616
TI  - Two-component systems in plant signal transduction.
AB  - In plants, two-component systems play important roles in signal transduction in
      response to environmental stimuli and growth regulators. Genetic and biochemical
      analyses indicate that sensory hybrid-type histidine kinases, ETR1 and its
      homologs, function as ethylene receptors and negative regulators in ethylene
      signaling. Two other hybrid-type histidine kinases, CKI1 and ATHK1, are
      implicated in cytokinin signaling and osmosensing processes, respectively. A data
      base search of Arabidopsis ESTs and genome sequences has identified many
      homologous genes encoding two-component regulators. We discuss the possible
      origins and functions of these two-component systems in plants.

PMID- 10664617
TI  - The regulation of phosphoenolpyruvate carboxylase in CAM plants.
AB  - Phosphoenolpyruvate carboxylase catalyses the primary assimilation of CO(2) in
      Crassulacean acid metabolism plants. It is activated by phosphorylation, and this
      plays a major role in setting the day-night pattern of metabolism in these
      plants. The key factor that controls the phosphorylation state of
      phosphoenolpyruvate carboxylase is the activity of phosphoenolpyruvate
      carboxylase kinase. Recent work on Crassulacean acid metabolism plants has
      established this enzyme as a novel protein kinase and has provided new insights
      into the regulation of protein phosphorylation. Phosphoenolpyruvate carboxylase
      kinase is controlled by synthesis and degradation in response to a circadian
      oscillator. The circadian control of phosphoenolpyruvate carboxylase kinase can
      be overridden by changes in metabolite levels. The primary effect of the
      circadian oscillator in this system may be at the level of the tonoplast, and
      changes in kinase expression may be secondary to circadian changes in the
      concentration of a metabolite, perhaps cytosolic malate.

PMID- 10664618
TI  - Apomixis technology and the paradox of sex.
AB  - Most plant species produce genetically variable seeds by the fusion of
      meiotically reduced egg cells and pollen grains. However, a small proportion of
      seed plants produces clonal, asexual seeds by the process of apomixis. The
      fixation of heterosis by apomixis is of great interest for plant breeding. The
      prospect of changing sexual crop species into apomictic crop species by genetic
      engineering--apomixis technology--has recently caused a boom in apomixis
      research. According to evolutionary biological theories, a dominant apomixis gene
      will rapidly become fixed in an outcrossing sexual population. Therefore, in
      theory, apomixis transgenes could have unconditional advantages that could result
      in the uncontrollable spread of the transgenes. By contrast, 'classic' transgenes
      might only have conditional advantages. Paradoxically, sexual reproduction and
      not apomixis is common in nature. However, this is no guarantee that apomixis
      transgenes will be ecologically safe because there could be essential differences
      between natural and transgenic apomicts.

PMID- 10664619
TI  - Testing for erbB-2 by immunohistochemistry in breast cancer.

PMID- 10664620
TI  - Inherited giant platelet disorders. Classification and literature review.
AB  - Inherited giant platelet disorders are extremely rare. The aim of this article is
      to review the clinical and laboratory features of this heterogeneous group and to
      arrive at a working classification. We conducted our literature search using the
      National Library of Medicine database. A total of 12 clinical entities were
      described. We classified them into 4 groups depending on the clinical and
      structural abnormalities. The pathophysiology of these disorders is largely
      unknown, and more research is needed, particularly in the light of recent
      advances in laboratory medicine. This review may provide a valuable reference for
      clinicians and may form a basis for future classification and research.

PMID- 10664622
TI  - Angiodestruction and tissue necrosis of skin-involving CD56+ NK/T-cell lymphoma
      are influenced by expression of cell adhesion molecules and cytotoxic granule and
      apoptosis-related proteins.
AB  - We compared the expression of cell adhesion molecules (CAMs), cytotoxic granule
      proteins, and apoptosis-related proteins by immunohistology and in situ terminal
      deoxynucleotidyl transferase-mediated digoxigenin-dUTP nick end labeling (TUNEL)
      of 10 cases of cutaneous CD56+ NK/T cell lymphoma with and 6 cases without
      angiodestruction. Lymphoma cells in cases with angiodestruction frequently
      expressed CAMs CD2, CD11a, and CD49d and their ligands CD58, CD54, and CD106 and
      were positive for CD122 and cytotoxic granule proteins TIA1, perforin, and
      granzyme B. Lymphoma cells in cases without angiodestruction mostly were negative
      for CD2, CD58, CD54, CD106, and TIA1 and weakly positive for perforin and
      granzyme B. In the TUNEL method, mean apoptotic indices (AI) for cases with
      angiodestruction showed a higher percentage than those without angiodestruction.
      CD95L, CD95, apoptosis-induced cysteine protease CPP32, apoptosis-promoting
      protein Bax, and proliferating marker (MIB1) frequently were positive in the
      lymphoma cells of cases with angiodestruction, but there was no expression of
      apoptosis-inhibitor protein Bcl2. In most cases without angiodestruction,
      lymphoma cells were positive for CD95L and Bax and negative for CD95, CPP32, and
      MIB1. CAMs and the 3 cytotoxic granule proteins and an apoptosis pathway might be
      important factors in the paracrine and autocrine mechanisms of tissue necrosis in
      cutaneous CD56+ NK/T cell lymphoma.

PMID- 10664621
TI  - Flow cytometric immunophenotypic characterization of pediatric and adult
      minimally differentiated acute myeloid leukemia (AML-M0).
AB  - We reviewed the clinicopathologic and immunophenotypic profiles of 7 pediatric
      and 11 adult minimally differentiated acute myelogenous leukemias (AML-M0). We
      also compared and evaluated myeloperoxidase in leukemic blasts using standard
      cytochemical and polyclonal antibody immunohistochemical stains. No distinctive
      clinical findings were noted in either patient group; however, thrombocytopenia
      typically was more prominent in adults. Adult AML-M0 also was associated with an
      immature myeloid profile (CD34+, terminal deoxynucleotidyl transferase positive,
      CD13+, and CD33+), in contrast with pediatric AML-M0, which usually lacked
      terminal deoxynucleotidyl transferase or CD34 but expressed bright CD33 with weak
      or negative CD13. Coexpression of the T-cell-associated antigen CD7 was observed
      in both groups. Antibody immunohistochemical stains were more sensitive than
      cytochemical stains for detection of myeloperoxidase activity and a useful
      adjunct for establishing a diagnosis of myeloid leukemia in paraffin-embedded
      marrow tissues.

PMID- 10664623
TI  - Lymphomas in patients with connective tissue disease. Comparison of p53 protein
      expression and latent EBV infection in patients immunosuppressed and not
      immunosuppressed with methotrexate.
AB  - Cell cycle dysregulation as measured by p53 protein expression and latent Epstein
      Barr (EBV) infection are important in the pathogenesis of lymphoma, particularly
      in immunosuppressed patients. Although latent EBV commonly is detected in
      lymphomas arising in patients with connective tissue disease who are
      immunosuppressed with methotrexate, p53 protein expression has not been reported.
      We compared the immunohistologic expression of p53 protein and the incidence of
      latent EBV infection in lymphomas arising in patients with connective tissue
      disease treated and not treated with methotrexate. Increased p53 staining was
      detected in 10 of 11 lymphomas arising in patients after methotrexate therapy vs
      5 of 11 in patients not treated with methotrexate. Latent EBV was detected in 7
      of 13 lymphomas arising in patients after methotrexate therapy vs 2 of 11 in
      patients not treated with methotrexate. Concordant p53 expression and latent EBV
      were detected in 5 of 7 lymphomas arising after treatment with methotrexate,
      including 1 that regressed after methotrexate therapy was withdrawn. These
      findings suggest that cell cycle dysregulation and EBV-related transformation are
      important in the pathogenesis of lymphomas arising in patients with connective
      tissue disease who are immunosuppressed with methotrexate.

PMID- 10664624
TI  - Analysis of Bcl-2 protein expression in chronic lymphocytic leukemia. A
      comparison of three semiquantitation techniques.
AB  - A number of studies revealed that high expression of the proto-oncogene bcl-2
      correlated with poor prognosis or resistance to chemotherapy in some tumors but
      predicted a favorable clinical course in other neoplasias. In these studies,
      however, different immunologic techniques for Bcl-2 detection were used, raising
      the question of whether the methods applied were comparable. Using chronic
      lymphocytic leukemia (CLL) cells, the aims of our study were as follows: (1) to
      determine the reproducibility of Bcl-2 semiquantitation by immunocytochemistry,
      flow cytometry, or immunoblotting; (2) to study the agreement between results
      obtained by these methods; and (3) to examine the association between Bcl-2
      expression in tumor cells of 99 patients with CLL and clinical parameters. We
      found that determination of Bcl-2 expression by immunocytochemistry was
      reproducible and the results were comparable with those of flow cytometry and
      immunoblotting. In the patient collective examined, Bcl-2 expression did not
      reflect the extent of tumor mass, but higher levels were found more often in
      patients with progressive disease.

PMID- 10664625
TI  - Comparison of disaturated phosphatidylcholine and fetal lung maturity
      surfactant/albumin ratio in diabetic and nondiabetic pregnancies.
AB  - We studied fetal lung maturity (FLM) by the amniotic fluid surfactant/albumin
      (FLM S/A) ratio and the disaturated phosphatidylcholine (DSPC) amniotic fluid
      levels at different gestational ages in diabetic (179 women with type 1 diabetes
      mellitus antedating pregnancy; infants delivered within 72 hours after amniotic
      fluid testing for DSPC level and FLM S/A ratio) and nondiabetic pregnancies (2
      independent nondiabetic groups, 300 for FLM S/A ratio and 1,231 for DSPC level).
      The degree of maternal glycemia during gestation was estimated by serial
      measurements of hemoglobin A1. Multiple regression analyses, including
      gestational age (GAs) and diabetic status as independent variables and FLM S/A
      ratio and DSPC level as dependent variables, revealed significant effect from
      diabetic status and GA for FLM S/A ratio and a significant effect from GA but not
      from diabetic status for DSPC level. Glucose levels were controlled adequately
      throughout gestation as reflected by mean total glycated hemoglobin levels.
      Amniotic fluid levels of DSPC, the major surface tension-lowering component of
      pulmonary surfactant, are not significantly different between diabetic and
      nondiabetic pregnancies at different GAs.

PMID- 10664626
TI  - Performance evaluation and planning for patient-based quality control procedures.
AB  - In a recent publication, the effect of the length of time between the routine
      testing of quality-control (QC) samples on QC performance was studied using a
      newly proposed performance measure: the average number of patient samples that
      contain unacceptable analytic error due to an out-of-control error condition
      (ANPTE). We show that ANPTE also perfectly suits the evaluation of patient-based
      QC procedures. We used ANPTE to study the effect of the number of patient results
      averaged and the width of the truncation limits on an average of normals QC
      procedure. Estimates of ANPTE were obtained by using computer simulations that
      use actual patient result distributions. Based on ANPTE, the conclusions about
      the effects of truncation limits and number of patient results averaged on the
      performance of an average of normals QC procedure are substantially different
      from those described by others using the probability of error detection to
      characterize QC performance.

PMID- 10664627
TI  - HER-2/neu protein expression in breast cancer evaluated by immunohistochemistry.
      A study of interlaboratory agreement.
AB  - Immunohistochemistry (IHC) is used commonly for evaluating HER-2/neu protein
      expression in breast cancer. Given the potential clinical importance of HER-2/neu
      status in patient management, interlaboratory variability in HER-2/neu IHC
      results in a matter of legitimate concern. We compared the results from 2
      laboratories for HER-2/neu determined by IHC on paraffin sections of the same 100
      consecutive invasive breast cancers. Both laboratories used the same primary
      antibody; however, different methods for heat-induced epitope retrieval
      (microwave or steam) and immunostaining (automated equipment from different
      manufacturers) and different scoring systems (positive-negative and 0-4+) were
      used. Slides were read in a blinded fashion and the results from the 2
      laboratories were compared. Of the 93 cases evaluable in both laboratories, 24%
      were scored as HER-2/neu-positive at 1 laboratory, and 23% were scored as
      positive at the other. Complete concordance in categorization of HER-2/neu status
      between the 2 laboratories was achieved in 90 of 93 cases. Excellent
      interlaboratory agreement for HER-2/neu IHC was attained using the same primary
      antibody to HER-2/neu, even without standardization of assay method or scoring
      criteria. However, standardization of these parameters remains an important
      objective to optimize interlaboratory agreement.

PMID- 10664628
TI  - Benign transport of breast epithelium into axillary lymph nodes after biopsy.
AB  - The most important prognostic indicator of distant metastasis in breast cancer is
      histologic documentation of axillary lymph node metastasis. Controversy exists
      about the importance of micrometastases (< 0.2 cm), and current pathology
      practice includes a careful search for their presence. We describe the histologic
      findings in a series of axillary lymph node dissections taken approximately 2
      weeks after breast biopsy. Each case has limited presence of epithelial cells in
      the subcapsular sinus of a draining lymph node that we attribute to mechanical
      transport of tumor and/or normal breast epithelium secondary to the previous
      surgical or needle manipulation. These cells were accompanied by hemosiderin
      laden macrophages and damaged RBCs. While the clinical implication of these
      findings is unknown, we believe that it will be of no clinical significance and
      have no untoward prognostic effect.

PMID- 10664629
TI  - Correlation between loss of E-cadherin expression and overexpression of autocrine
      motility factor receptor in association with progression of human gastric
      cancers.
AB  - Loss of intercellular adhesion and increased cell motility synergistically
      facilitate tumor cell invasion. We studied these factors in 90 patients with
      gastric cancers by using an immunohistochemical technique to detect strong or
      weak expression of E-cadherin (ECD) and autocrine motility factor receptor
      (AMFR). Normal gastric mucosa (control) reacted strongly for ECD and weakly for
      AMFR. In study cases, ECD was weak in 47 cases, and AMFR was strong in 39 cases.
      Weak ECD and strong AMFR expression were associated with tumor dedifferentiation.
      AMFR expression correlated positively with depth of invasion but not with lymph
      node metastasis. ECD expression correlated negatively with lymph node metastasis
      but not with depth of invasion. A strong inverse correlation was found between
      ECD and AMFR expression. Tumors with weak ECD and strong AMFR expression
      displayed a more aggressive phenotype than tumors with strong ECD and weak AMFR
      expression. The postoperative survival of patients with tumors with weak ECD and
      strong AMFR expression was significantly shorter than that of other groups. Since
      they are involved in the pathway to development of tumors with a more aggressive
      phenotype, ECD and AMFR should be examined to evaluate the biologic potential of
      gastric cancers.

PMID- 10664630
TI  - Grading and staging of bladder carcinoma in transurethral resection specimens.
      Correlation with 105 matched cystectomy specimens.
AB  - We compared the grading and staging of transurethral resection of the bladder
      (TURB) and cystectomy specimens for 105 patients who underwent radical cystectomy
      for urothelial carcinoma between 1980 and 1984. Of 105 patients, 96% underwent
      cystectomy within 100 days of TURB (median interval, 10 days). Grading was
      performed according to the 1998 World Health Organization/International Society
      of Urologic Pathology grading system and staging according to the 1997 TNM
      classification. Histologic grade was low-grade, 13; high-grade, 92 in TURB
      specimens; low-grade, 17; high-grade, 88 in cystectomy specimens. Pathologic
      stage was Ta, 15; T1, 55; and T2, 35 in TURB specimens; Ta, 5; T1, 19; T2, 19;
      T3, 46; and T4, 16 in cystectomy specimens. Histologic grade at TURB was
      associated with pathologic stage at cystectomy (P < .001). When all advanced
      stage (muscle-invasive) carcinomas (pT2 or more) were considered together, 55
      patients were understaged by TURB, 4 had higher stage in TURB than in cystectomy,
      and 46 were the same stage as by cystectomy. Forty-three of 55 patients with
      stage T1 carcinoma at TURB had advanced-stage carcinoma at cystectomy, including
      34 who had extravesicular extension (pT3 or more). We found pathologic
      understanding by TURB occurs in a significant number of patients with bladder
      cancer; the newly proposed grading system predicted final pathologic stage.

PMID- 10664631
TI  - Cutaneous calciphylaxis. An underrecognized clinicopathologic entity.
AB  - Calciphylaxis (CPX), an uncommon syndrome characterized, in part, by progressive
      cutaneous vascular calcification, is seen principally in the setting of renal
      failure-associated hyperparathyroidism and is difficult to distinguish
      histologically from other microvasculopathies. We assessed histologic specimens
      from 13 cases of clinicopathologically classic CPX of the skin and reviewed
      documented histologic findings in the literature. Our series included 7 "early"
      and 6 "late" lesions (absence or presence of tissue necrosis, respectively).
      Histologically, early lesions were subtle and almost inapparent microscopically.
      Late lesions were easier to recognize because of obvious epidermal ulceration,
      dermal necrosis, and easily seen mural vascular calcification. The most common
      finding in both groups was acute and chronic calcifying septal panniculitis.
      Endovascular fibroblastic proliferation was more common in advanced lesions.
      Necrosis of dermal collagen was identified in only a few early lesions. Frank
      luminal vascular thrombosis was infrequent in both groups. The cited histologic
      findings largely were mirrored by those in the literature. Although they are
      relatively nonspecific when considered in isolation, the cited histopathologic
      features of cutaneous CPX allow for the diagnosis of this potentially lethal
      disorder when they are seen in combination with one another, particularly if
      detailed clinical data also are available.

PMID- 10664632
TI  - Reactive spindle cell nodules of the breast after core biopsy or fine-needle
      aspiration.
AB  - Reactive spindle cell nodules (RSCNs) arising postoperatively or after fine
      needle aspiration (FNA) have been reported previously in the genitourinary tract
      and thyroid. We describe 18 cases of similar lesions in breast, associated with a
      history of core needle biopsy or FNA. The majority of the RSCNs (15 cases) were
      associated with papillary lesions or complex sclerosing lesions. The RSCNs were
      nonencapsulated and relatively nodular, measuring 1.5 to 9 mm. They were composed
      of spindle cells with mild to moderate nuclear pleomorphism and a low mitotic
      count. A network of small blood vessels, macrophages, and lymphocytes was present
      in all cases. Immunohistochemically, the spindle cells expressed smooth and
      specific muscle actins, supporting a myofibroblastic origin. The association of
      RSCNs with needle trauma to fibrosclerotic lesions, such as complex sclerosing
      lesions and papillary lesions that regularly have myofibroblasts, suggests an
      exuberant reparative cause. Recognition of this reactive process will avoid
      overdiagnosis of mammary spindle cell malignant neoplasm.

PMID- 10664633
TI  - Diagnostic utility of the monoclonal antibody A103 in fine-needle aspiration
      biopsies of the adrenal.
AB  - Fine-needle aspiration (FNA) of the adrenal is a useful modality for the
      evaluation of primary and metastatic neoplasms. Until now, however, few reliable
      markers existed for the positive identification of adrenal cortical cells.
      Originally studied as a melanoma marker, Melan-A, as detected by the murine
      monoclonal antibody, A103, has gained recent attention as a marker for steroid
      producing cells. Formalin-fixed, paraffin-embedded cell blocks from 24 adrenal
      FNA specimens were stained for cytokeratins (AE1/AE3) and Melan-A (A103). Seven
      of 8 cases containing normal, hyperplastic, and neoplastic adrenal cortical cells
      were positive for A103. Among 16 cases of metastatic carcinoma, tumor cells in 14
      samples were positive for cytokeratins but negative for A103. The A103 monoclonal
      antibody is a sensitive marker for the identification of normal, hyperplastic,
      and neoplastic adrenal cortical cells in cell blocks of adrenal FNA specimens.
      With the exception of melanoma, A103 reactivity is restricted to adrenal cortical
      and other steroid-producing cells. A103 should be used routinely for the
      evaluation of FNA specimens of adrenal mass lesions.

PMID- 10664634
TI  - Genetic testing in autopsies.

PMID- 10664635
TI  - The unsatisfactory rate.

PMID- 10664636
TI  - Approach to depressive disorders.

PMID- 10664637
TI  - Continuity of care, informed consent, and fiduciary responsibilities in for
      profit managed care systems.
AB  - The replacement of fee-for-service systems by managed care systems offers
      opportunities for cutting medical costs, integrating health care delivery
      systems, and improving communication among physicians. Before these benefits can
      be realized, however, a number of problems must be addressed. First, managed care
      systems must find ways to foster continuity of care in a market that has thus far
      proved unstable. Second, managed care systems must find ways to protect the
      patient's right to fully informed consent even while educating patients about the
      importance of cost-effectiveness and why certain treatments might not be included
      in their health plan. Third, managed care systems must find ways to promote
      physicians' fiduciary responsibilities to patients and to respect physicians'
      clinical judgments even while creating legitimate incentives to provide cost
      effective health care.

PMID- 10664638
TI  - Report of the Council on Scientific Affairs. Biohazardous waste management: what
      the physician needs to know. American Medical Association.
AB  - Sources of biohazardous waste include not only large hospitals and laboratories,
      but also physicians' offices, dental offices, clinics, research facilities,
      surgery centers, veterinary offices, funeral homes, and a growing number of
      settings where home health care is delivered. State and local municipality
      definitions and regulations on biohazardous waste vary widely. Most regulations
      exempt home health care settings, but include physicians' offices. Although the
      infectious public health risk posed by medical waste is exceedingly low, this
      fact is not well understood by the general public. Physicians should develop
      biohazardous waste management programs that fulfill their county, state, and
      municipal regulations and that consider the difference between health risks to
      employees and risks to the general public. Physicians can considerably reduce the
      amount and costs of biohazardous waste disposal by proper identification and
      segregation of waste in a manner that meets their state's criteria. Using
      products that can be recycled may reduce the amount and costs of disposal of
      biohazardous waste. Processing costs also may be reduced by cooperative
      arrangements among medical groups or health care facilities to negotiate group
      disposal rates with vendors.

PMID- 10664639
TI  - Year 2000 Archives of Family Medicine. Totally online, more features, now brought
      to you monthly!

PMID- 10664640
TI  - Effect of calcium supplementation on serum cholesterol and blood pressure. A
      randomized, double-blind, placebo-controlled, clinical trial.
AB  - OBJECTIVE: To test the effect of daily supplemental calcium on serum total and
      high-density lipoprotein cholesterol (HDL-C) levels and blood pressure in adults.
      DESIGN: Randomized, double-blind, placebo-controlled clinical trial; adjunct
      study to a trial of calcium and colon cell proliferation in patients with
      sporadic adenoma. SETTING: Outpatient clinic. PATIENTS: A total of 193 men and
      women, aged 30 to 74 years. INTERVENTION: Treatment with 1.0 and 2.0 g/d of
      elemental calcium vs placebo over a 4-month period for cholesterol determinations
      and 6 months for blood pressure. MAIN OUTCOME MEASURES: Serum total cholesterol
      and HDL-C levels, systolic and diastolic blood pressure. RESULTS: Because there
      were no apparent differences in responses between the 1.0-g and 2.0-g calcium
      groups, their data were combined and compared with those of the placebo group.
      Among all participants, the mean total cholesterol level dropped 0.07 mmol/L (2.9
      mg/dL) (1.3%) (P = .43) more, and the mean HDL-C level dropped 0.01 mmol/L (0.4
      mg/dL) (1.1%) (P = .71) less in the calcium group than in the placebo group.
      Among participants without a history of hypercholesterolemia, the mean total
      cholesterol level dropped 0.18 mmol/L (6.8 mg/dL) (3.3%) (P = .10) and the HDL-C
      level dropped 0.02 mmol/L (0.6 mg/dL) (1.5%) (P = .61) more in the calcium group
      than in the placebo group. Among all participants, there was no apparent change
      in blood pressure until 6 months, when the mean systolic blood pressure dropped
      0.8 mm Hg (0.6%) (P = .85) and the mean diastolic blood pressure dropped 0.4 mm
      Hg (0.5%) (P = .80) more in the calcium group than in the placebo group.
      CONCLUSIONS: There were no substantial or statistically significant effects of
      calcium supplementation on total cholesterol or HDL-C levels or on blood
      pressure. There was a suggestion (not statistically significant) of a 0.07 to
      0.18 mmol/L (3-7 mg/dL) or 2% to 4% drop in the total cholesterol level, a
      finding similar to that reported in other studies, which indicates the need for
      further study.

PMID- 10664641
TI  - Outcomes of the Kaiser Permanente Tele-Home Health Research Project.
AB  - CONTEXT: Level of acuity and number of referrals for home health care have been
      escalating exponentially. As referrals continue to increase, health care
      organizations are encouraged to find more effective methods for providing high
      quality patient care with cost savings. OBJECTIVE: To evaluate the use of remote
      video technology in the home health care setting as well as the quality, use,
      patient satisfaction, and cost savings from this technology. DESIGN: Quasi
      experimental study conducted from May 1996 to October 1997. SETTING: Home health
      department in the Sacramento, Calif, facility of a large health maintenance
      organization. PARTICIPANTS: Newly referred patients diagnosed as having
      congestive heart failure, chronic obstructive pulmonary disease, cerebral
      vascular accident, cancer, diabetes, anxiety, or need for wound care were
      eligible for random assignment to intervention (n = 102) or control (n = 110)
      groups. INTERVENTION: The control and intervention groups received routine home
      health care (home visits and telephone contact). The intervention group also had
      access to a remote video system that allowed nurses and patients to interact in
      real time. The video system included peripheral equipment for assessing
      cardiopulmonary status. MAIN OUTCOME MEASURES: Three quality indicators
      (medication compliance, knowledge of disease, and ability for self-care); extent
      of use of services; degree of patient satisfaction as reported on a 3-part scale;
      and direct and indirect costs of using the remote video technology. RESULTS: No
      differences in the quality indicators, patient satisfaction, or use were seen.
      Although the average direct cost for home health services was $1830 in the
      intervention group and $1167 in the control group, the total mean costs of care,
      excluding home health care costs, were $1948 in the intervention group and $2674
      in the control group. CONCLUSIONS: Remote video technology in the home health
      care setting was shown to be effective, well received by patients, capable of
      maintaining quality of care, and to have the potential for cost savings. Patients
      seemed pleased with the equipment and the ability to access a home health care
      provider 24 hours a day. Remote technology has the potential to effect cost
      savings when used to substitute some in-person visits and can also improve access
      to home health care staff for patients and caregivers. This technology can thus
      be an asset for patients and providers.

PMID- 10664642
TI  - Somatoform symptoms and treatment nonadherence in depressed family medicine
      outpatients.
AB  - OBJECTIVES: To examine whether somatoform symptoms, specifically symptoms of
      conversion, somatization, and hypochondriasis, are associated with side-effect
      reporting and treatment nonadherence in depressed family medicine outpatients,
      and to measure whether symptoms improve with pharmacotherapy. DESIGN: Inception
      cohort study with 14-week follow-up. SETTING: Inner-city family medicine
      residency clinic. PATIENTS: Thirty-nine consecutive adults with major depressive
      disorder were asked to participate, and 30 consented. INTERVENTION:
      Antidepressants for 14 weeks. MAIN OUTCOME MEASURES: The Personality Assessment
      Inventory (PAI) was administered before treatment. The PAI is a self-reported
      inventory compatible with the Diagnostic and Statistical Manual of Mental
      Disorders, Fourth Edition, designed to measure a broad range of personality
      characteristics. After 14 weeks, the side-effect incidence and treatment
      nonadherence rates were determined, and 12 patients were readministered the PAI.
      RESULTS: Depressed family medicine patients demonstrated trends toward elevated
      Somatic Complaints scale and conversion subscale scores and a lower Suicidal
      Ideation scale score relative to those of a standardized depressed psychiatric
      patient profile. Conversion and hypochondriacal symptoms were associated with
      side-effect reporting and treatment nonadherence. Somatization and
      hypochondriacal symptoms improved clinically and statistically during treatment
      for depression. CONCLUSIONS: Somatoform distress is a complex, common, and
      understudied phenomenon in primary care that can adversely affect the treatment
      of depression. Somatoform symptoms of conversion and hypochondriasis, but not
      somatization, were found to be risk factors for treatment nonadherence.
      Somatization and hypochondriacal symptoms may represent personality states that
      improve with pharmacotherapy, and conversion symptoms may be a personality trait
      resistant to medical treatment for depression.

PMID- 10664643
TI  - The effects of patient communication skills training on compliance.
AB  - OBJECTIVE: To examine the relationship between communication skills training for
      patients and their compliance with recommended treatment. DESIGN: A randomized
      control design was used, with patients nested within physicians. Each physician
      was audiotaped with 6 patients, 2 patients in each of the 3 intervention
      conditions: (1) a trained group (n = 50) received a training booklet in the mail
      2 to 3 days prior to the scheduled appointment, (2) an informed group (n = 49)
      received a brief written summary of the major points contained in the training
      booklet while in the waiting room prior to the scheduled appointment, and (3) an
      untrained group (n = 51) did not receive any form of communication skills
      intervention. SETTING: Participants included physicians and patients from 9
      different primary care, family practice locations. Two locations were clinics
      associated with a large, university-based medical school and hospital, while 7
      were private practice offices in the community. PARTICIPANTS: The sample included
      25 family physicians (averaging 11 years postresidency) and 150 patients.
      Patients were randomly selected from appointment records and randomly assigned to
      1 of 3 intervention conditions. INTERVENTION: A training booklet designed to
      instruct patients in information seeking, provision, and verification. MAIN
      OUTCOME MEASURE: Patients' compliance with medications, behavioral treatment
      (e.g., diet, exercise, smoking cessation), and/or follow-up appointments and
      referrals. RESULTS: Trained patients were more compliant overall than untrained
      or informed patients. Training positively influenced compliance with behavioral
      treatments and follow-up appointments and referrals. CONCLUSION: Training
      patients in communication skills may be a cost-effective way of increasing
      compliance and improving the overall health of patients.

PMID- 10664644
TI  - The evolving roles of patient and physician.

PMID- 10664645
TI  - Evaluation and management services. A comparison of medical record documentation
      with actual billing in community family practice.
AB  - OBJECTIVE: To compare the concordance of family physicians' billing for
      evaluation and management services with medical record documentation. DESIGN:
      Multi-method, cross-sectional observation study. SETTING: Eighty-four family
      practices in northeast Ohio. PARTICIPANTS: Four thousand fifty-four outpatients
      visiting 138 family physicians. MAIN OUTCOME MEASURE: The degree of concordance
      between evaluation and management Current Procedural Terminology codes billed by
      physicians, with those codes assigned by trained research nurses using American
      Medical Association criteria to code medical records for the same visits.
      RESULTS: Discrepancies between the multifactorial nature of family practice
      outpatient visits and the Current Procedural Terminology coding criteria, which
      dictate overcoding for depth rather than breadth, made coding difficult (multiple
      rater kappa statistic between research nurses = 0.36). Among 4137 outpatient
      visits with complete billing information, 57% of the Current Procedural
      Terminology codes generated by medical record review were concordant with the
      actual billing code assigned by physicians. Undercoding and overcoding occurred
      at a similar frequency (21% and 19%, respectively) and differed by more than 1
      code in fewer than 4% of visits. Visits by new patients were more likely to be
      inaccurately coded than visits by established patients. CONCLUSIONS: Record
      documentation by community family physicians largely reflects the level of
      services billed using evaluation and management codes. Undercoding is as common
      as overcoding. Efforts from regulatory agencies should be redirected from
      penalizing physicians for overcoding to focusing on the development of coding
      criteria that reflect the multifactorial nature of outpatient primary care
      practice.

PMID- 10664646
TI  - Cervical ectopic pregnancy. Diagnosis with endovaginal ultrasound examination and
      successful treatment with methotrexate.
AB  - Cervical ectopic pregnancy is the implantation of a pregnancy in the endocervical
      canal. Diagnosis and treatment of cervical ectopic pregnancy has changed
      dramatically in the last 15 years. Before 1980, the diagnosis commonly was made
      when dilation and curettage for presumed incomplete abortion resulted in
      unexpected hemorrhage. Emergency hysterectomy usually ensued. Cervical ectopic
      pregnancy is now commonly diagnosed on a first-trimester ultrasound examination.
      The family physician practicing obstetrics must consider the diagnosis of
      cervical ectopic pregnancy in women with first-trimester vaginal bleeding or
      pelvic pain to permit early diagnosis and fertility-saving treatment. A case
      report of diagnosis and successful medical management of a cervical ectopic
      pregnancy is presented. The literature on the epidemiology, causes, diagnosis,
      and treatment of cervical ectopic pregnancy is reviewed.

PMID- 10664647
TI  - Antibiotics and oral contraceptive failure.

PMID- 10664648
TI  - Recurrent binge eating in black American women.
AB  - CONTEXT: Recurrent binge eating is a core diagnostic feature of bulimia nervosa
      and binge eating disorder, and in samples of white women has been associated with
      obesity and psychiatric symptoms. Eating disorders have been believed to occur
      primarily among white women; in fact, the limited preliminary data available
      suggest that black women may be as likely as white women to report binge eating.
      OBJECTIVE: To examine race differences in prevalence of behavioral symptoms of
      eating disorders and clinically significant recurrent binge eating. DESIGN:
      Community survey. SETTING: General community in Connecticut and Boston, Mass.
      PARTICIPANTS: A community sample of 1628 black women and 5741 white women (mean
      age, 29.7 years) participated in a telephone survey designed to ascertain the
      presence, during the preceding 3 months, of binge eating and extreme weight
      control behaviors (vomiting, laxative or diuretic abuse, or fasting). MAIN
      OUTCOME MEASURE: Interviewer-based phone assessment of recurrent binge eating and
      behavioral symptoms of eating disorders. RESULTS: Black women were as likely as
      white women to report binge eating or vomiting during the preceding 3 months, and
      were more likely to report fasting and the abuse of laxatives or diuretics.
      Recurrent binge eating was more common among black women than among white women.
      In both race groups, recurrent binge eating was associated with elevated body
      weight and increased psychiatric symptoms. CONCLUSION: Results suggest that
      recurrent binge eating is a significant problem among black and white women.
      Health professionals need to be ready to respond to this health risk behavior.

PMID- 10664649
TI  - Eating disorders, race, and mythology.

PMID- 10664650
TI  - Videotaping obstetric procedures. Assessment of obstetricians and family
      physicians.
AB  - OBJECTIVE: To compare the attitudes and practice of Iowa obstetricians (OBs) and
      family physicians (FPs) regarding patients' desires to videotape obstetric
      procedures. DESIGN: All Iowa OBs (172) and FPs (438) who practice obstetrics
      received a questionnaire exploring their attitudes and practice patterns
      regarding videotaping obstetric procedures. Data were analyzed using chi 2, odds
      ratios with 95% confidence intervals, and multiple logistic regression. SETTING:
      The state of Iowa. MAIN OUTCOME MEASURES: Degree to which physicians allow
      videotaping and characteristics that contribute to any differences between OBs
      and FPs. RESULTS: The response rate was 87.8% (536 of 610 participants).
      Obstetricians were more likely than FPs to prevent patients from filming medical
      procedures (40.8% vs 19.1%, respectively, P < .001), modify their actions and
      conversation when video cameras were present (34.5% vs 25.5%, respectively, P =
      .046), and be tempted to turn off the camera when complications arose (35.1% vs
      14.0%, respectively, P < .001). Younger OBs (aged, 25-40 years) were more likely
      than older OBs (aged, 41-80 years) to disallow videocameras (52.7% vs 33.3%,
      respectively, P = .02). Legal concerns were cited by more than 80% of OBs and FPs
      who disallowed videotaping. CONCLUSIONS: A significant difference was noted
      between OBs and FPs in their willingness to allow video recording of obstetric
      procedures. Legal concerns were cited by most OBs and FPs who had disallowed
      videotaping.

PMID- 10664651
TI  - [Endocrinology. Integrative bond and cell-to cell-communication].

PMID- 10664652
TI  - [Gastroenterology. New thought structures, fascinating paths and interfaces in
      surgery].

PMID- 10664653
TI  - [Hepatology. Molecular revolution].

PMID- 10664654
TI  - [Infectology. Globalized resistant pathogens and new vaccines].

PMID- 10664655
TI  - [Cardiology. Lessons of clinical cardiological research].

PMID- 10664656
TI  - [Nephrology. Advances and economic restraints].

PMID- 10664657
TI  - [Oncology. The path to a pathogenesis-oriented treatment].

PMID- 10664658
TI  - [Pneumology. From the diagnosis of pulmonary functions to molecular medicine].

PMID- 10664659
TI  - [Immunology. Realizable discoveries].

PMID- 10664660
TI  - [Sleep medicine. A new cross-sectional subject of internal medicine].

PMID- 10664661
TI  - [Neurology. Therapeutic advances through systems research and molecular biology].

PMID- 10664662
TI  - [Surgery. Structures and innovative technologies].

PMID- 10664663
TI  - The prostate: development and physiology.
AB  - The development of the prostate is controlled by steroid hormones that in turn
      induce and maintain a complex and little understood cross talk between the
      various cell types making up the gland. The result of this intercellular
      communication can be either new growth or growth quiescence, depending upon the
      differentiation state of the cell type being stimulated. Secretory function of
      the prostate is dependent upon direct stimulation of fully differentiated
      prostatic epithelial cells by androgens. The prostate thus seems to be regulated
      in a similar manner to other organs of the male and female genital tract with
      proliferative control mediated by cell-cell interactions, whereas differentiated
      function is determined by direct steroid action on the parenchymal cells.

PMID- 10664664
TI  - Radiologic anatomy of the prostate gland: a clinical approach.
AB  - Familiarity with normal anatomy is critical to interpretation of imaging of the
      prostate and peri-prostatic structures. This is especially true for MR imaging,
      which depicts these structures with exquisite detail due to high spatial
      resolution, superior contrast resolution, multiplanar capability, and large field
      of view. Anatomic understanding plays a key role in the assessment and management
      of prostatic disease, and allows evaluation of anatomic disturbances that may
      result from prostatic disease or therapy, and which may have functional
      consequences, particularly for continence and potency.

PMID- 10664665
TI  - Benign prostatic hyperplasia: clinical overview and value of diagnostic imaging.
AB  - The term benign prostatic hyperplasia has traditionally been used to describe a
      constellation of obstructive and irritative voiding symptoms that occur in men as
      they age. Such symptomatology may be due to a variety of causes, including
      prostatic enlargement. Thus, the term lower urinary tract symptoms has replaced
      BPH to describe this symptom complex. The evaluation and treatment of LUTS
      continues to be a significant part of urology practice in the United States, as
      well as a significant component of medical resource utilization. Currently,
      indication for treatment in patients with LUTS is most often based on subjective
      measurements of symptom severity and bother. Consequently, imaging does not play
      a major role in the evaluation of such patients. Recent data suggest that the
      size of the prostate gland may predict which patients with LUTS will develop
      progressive symptoms and complications. Moreover, both prostate size and the
      histologic composition of BPH may help to select patients for specific treatment
      options. Thus, radiologic imaging may eventually play a larger role in the
      diagnosis and treatment of LUTS in the future. After review of the literature, it
      appears that routine upper urinary tract imaging in patients with LUTS or BPH is
      not warranted. Selective use of such imaging tests in patients with BPH and
      either hematuria, laboratory evidence of renal insufficiency (elevated BUN or
      creatinine), or a history of urinary tract infection, urolithiasis, previous
      urinary tract surgery, or congenital or acquired renal disease remains indicated.
      Local imaging of the prostate can be performed with either MR imaging or TRUS.
      Although MR imaging provides excellent resolution of internal prostatic anatomy,
      information with respect to the ratio of glandular to stromal tissue in the
      prostate, and an accurate estimate of prostate volume, its use in patients with
      BPH is limited by its high cost and limited availability. In contrast, TRUS
      remains an important tool in the evaluation of patients with prostatic disease.
      Similar to MR imaging, TRUS provides excellent images of internal prostatic
      anatomy and an accurate estimate of prostate volume prior to treatment. In
      addition, this imaging modality is noninvasive, cost-efficient, easily adapted to
      office use, and able to provide guidance for transrectal prostate biopsy.

PMID- 10664666
TI  - Prostate cancer: assessment of risk using digital rectal examination, tumor
      grade, prostate-specific antigen, and systematic biopsy.
AB  - Refinement in the local staging and risk assessment for prostate cancer patients
      utilizing clinical parameters is ongoing. DRE, tumor grade, and PSA provide some
      useful information for risk assessment in individual patients. More recent
      studies using percent free PSA levels and systematic biopsy results have added
      additional staging information and may play a more significant role in the future
      in risk assessment. This information should supplement additional imaging tests
      in the management of these patients.

PMID- 10664667
TI  - Imaging prostate cancer.
AB  - In the detection of prostate cancer, the most important role of imaging is
      ultrasound-guided prostatic biopsy. In the staging evaluation of prostate cancer,
      each presently used modality--transrectal US (TRUS), MR imaging, CT, nuclear
      medicine, and positron emission tomography--has advantages and disadvantages.
      Evidence-based guidelines on the use of CT and nuclear medicine bone scan, in
      assessing the risk of distant spread of prostate cancer, are available. There is
      no consensus and there are no guidelines, however, for the use of imaging in the
      evaluation of prostate cancer local tumor extent. Results on the value of TRUS
      vary widely, and prospective multicenter studies suggest that TRUS is no better
      than digital rectal examination in predicting extracapsular extension. MR imaging
      offers the most promise for local staging of prostate cancer, but it must resolve
      problems of reproducible image quality and interobserver variability, and it
      should prove its efficacy in multicenter trials before it can be recommended for
      general clinical use. The introduction of MR spectroscopic imaging further
      expands the value of MR imaging, offering anatomic and metabolic evaluation of
      prostate cancer.

PMID- 10664668
TI  - Prostate cancer: the role of transrectal ultrasound and its impact on cancer
      detection and management.
AB  - With the advent of higher-frequency transducers as well as Doppler technologies,
      TRUS has become a valuable tool in the detection and management of prostate
      cancer. When combined with the other risk identifiers, an informed patient, and
      an experienced operator, it cannot only reduce the number of missed cancers by
      effective targeting of biopsies, but also reduce the number of unnecessary
      biopsies.

PMID- 10664669
TI  - The prostate: MR imaging and spectroscopy. Present and future.
AB  - The applications of combined MR imaging and MR spectroscopic imaging of prostate
      cancer have expanded significantly over the past 10 years and have reached the
      point of clinical trial results to test robustness and clinical significance. MR
      spectroscopic imaging extends the diagnostic evaluation of prostate cancer beyond
      the morphologic information provided by MR imaging throughout the detection of
      cellular metabolites. The combined metabolic and anatomic information provided by
      MR imaging and MR spectroscopic imaging has allowed a more accurate assessment of
      the presence, location, extent, and aggressiveness of prostate cancer both before
      and after treatment. This information has already demonstrated the ability to
      improve therapeutic planning for individual prostate cancer patients and shows
      great promise in the assessment of therapeutic response and the evaluation of new
      treatment regimes.

PMID- 10664670
TI  - The prostate: diagnostic evaluation of metastatic disease.
AB  - One of the single most important considerations in clinical management of the
      patient with prostate cancer is whether or not metastatic disease is present. The
      identification of metastatic disease in a patient with newly diagnosed prostate
      cancer represents an absolute contraindication to definitive local therapies such
      as radial prostatectomy or radiation therapy. Similarly, the identification of
      metastatic disease in a patient with disease recurrence after definitive local
      therapy represents an absolute contraindication to salvage radiotherapy or
      cryosurgery. Patients with metastatic disease do not benefit from definitive
      therapy, and the cost and morbidity associated with such treatment should
      therefore be avoided in these patients. Because of the significance of metastatic
      disease to clinical management, it is important for the diagnostic radiologist to
      be aware of important considerations in the metastatic work-up of patients with
      newly diagnosed prostate cancer and patients with suspected cancer recurrence
      after definitive local therapy.

PMID- 10664671
TI  - Imaging and radiotherapy of the prostate.
AB  - Prostate cancer is the most common malignancy diagnosed in men. Over the past 10
      to 20 years, advances in screening and diagnostic and management paradigms have
      led to improved treatment outcomes. This article offers an overview of the
      evolution of the role and nature of diagnostic imaging techniques in the
      management of prostate cancer.

PMID- 10664672
TI  - The prostatic gland: malignancies other than adenocarcinomas.
AB  - Many rare variants of prostatic carcinoma have been described and characterized
      in recent years. Accurate diagnosis of these variants is necessary in order to
      determine appropriate therapy. Unusual tumors arising in the prostate raise
      questions of histogenesis, and may carry a better or worse prognosis than typical
      adenocarcinoma. Virtually the entire spectrum of cellular differentiation has
      been observed within prostatic epithelium, and rare neoplasms exhibit these
      unusual forms of differentiation as the chief component of the tumor. Except in
      sarcoma (marked prostatic enlargement), imaging plays a limited role in the
      diagnoses of these entities. Biopsy and histologic diagnoses are essential and
      the role of imaging is restricted to the evaluation of locoregional and distant
      spread of the disease.

PMID- 10664673
TI  - New treatment strategies in advanced prostate cancer.
AB  - The treatment of advanced prostate cancer has evolved rapidly in the last 5
      years. Therapeutic options for patients with advanced disease, once essentially
      limited to the use of androgen deprivation, have expanded to include a number of
      interventions, including secondary hormonal manipulations, chemotherapy, and a
      variety of investigational approaches. Novel therapeutic approaches in prostate
      cancer patients are likely to be undertaken in patients with disease that is at
      or below the limits of detection by current imaging technology, so novel methods
      will be essential to the successful evaluation and use of these agents.

PMID- 10664674
TI  - Imaging for recurrent prostate cancer.
AB  - Multiple imaging modalities are available to evaluate recurrent prostate cancer
      following primary treatment with RP, RT, or cryo-surgery. These tests must be
      used in close conjunction with clinical parameters, such as the characteristics
      of the tumor itself (grade, stage) as well as specific PSA characteristics that
      can help predict the sites of probable recurrence. Figure 19 represents an
      algorithm of how patients can be monitored for recurrence according to their mode
      of primary treatment. As more treatments become available for recurrent prostate
      cancer, it will be necessary to monitor disease response with many of the imaging
      modalities discussed in this article.

PMID- 10664675
TI  - Larvicidal activity of Bacillus thuringiensis isolated from Jordanian habitats
      against Drosophila melanogaster larvae.
AB  - Bacillus thuringiensis was isolated from 23 of 37 samples obtained from different
      Jordanian habitats. Of the 37 samples, 187 different spore-forming colonies were
      selected and thirty (16%) were identified as B. thuringiensis based on their
      pathogenicity and production of parasporal inclusions. The lethal dose (LD50) of
      B. thuringiensis indicated a variation in their pathogenicity to Drosophila
      melanogaster larvae. Sensitivity of the first, the second and the third instar
      larvae of D. melanogaster showed slight variation in between. The third instar
      was the most sensitive stage to the pathogen spores.

PMID- 10664676
TI  - Role of DNA-membrane interactions in prokaryote-to-eukaryote transition: an
      hypothesis.
AB  - A model system of experiments to consider the problem of the origin of eukaryotic
      cells as well as the prokaryote-to-eukaryote transition was investigated, in
      terms of the role of nucleic acid-membrane interactions. It was thought
      worthwhile to consider the importance of DNA-membrane contacts for the
      organization of the prokaryotic nucleoid. The model for the fusion of four proto
      eukaryotic cells was proposed to clarify the prokaryote-to-eukaryote transition
      as well as the formation of the nuclear pores of eukaryotes from the Bayer's
      junctions of proto-eukaryotes. The basic requirements following from the cell
      fusion model suggest such orientation of the cells involved. The obstacles for
      division of the ancestor cell were excluded by merging. Enormous advantages to
      the cell metabolism due to the fusion of four proto-eukaryotic cells and an
      intensive growth of the inner membranous structures resulted.

PMID- 10664677
TI  - Evaluation of monocyte chemotactic responsiveness in uraemic patients undergoing
      haemodialysis with different dialytic membranes.
AB  - Recent data show that monocyte chemotactic peptide-1 (MCP-1), a chemotactic
      factor specific for monocytes, may play a central role in regulating the
      activation of these cells. For this reason, the production of MCP-1 in peripheral
      blood mononuclear cell (PBMC) cultures of eight healthy subjects, six chronic
      uraemic subjects under conservative treatment and six chronic uraemic patients
      undergoing haemodialysis (HD), was assessed. In the latter group of individuals,
      complement-activating membranes such as cuprophan (CU) were used for 1 month
      followed by biocompatible non-complement-activating membranes, like
      polymethylmetacrylate (PMMA) for the next 30 days. The chemotactic index (CI)
      elicited by PBMC supernatants from patients undergoing dialysis was found to be
      significantly higher than that obtained by supernatants recovered from normal
      subjects or uraemic patients on conservative therapy. Furthermore, the CI from
      PBMC supernatants having had contact with CU membranes was higher than that
      obtained from PBMC activated by PMMA. Finally, the increased chemotactic ability
      in the supernatants was closely correlated with the augmented MCP-1 gene
      expression and production, as assessed by in vitro hybridization studies.

PMID- 10664678
TI  - Sporadic chromosome abnormalities in human lymphocytes and previous exposure to
      chemicals.
AB  - Sporadic abnormalities in lymphocyte cultures are often attributed to in vitro
      culture variations of no clinical significance. The data presented here compare
      the findings from 11,873 cells of 230 patients referred with histories of
      previous chemical exposure (usually to mixtures of solvents and/or pesticides)
      with 27,050 cells from 855 patients referred for other reasons. Detection of
      0.38% or more, structural abnormalities (approximately 1 in 30 cells) was 27.2
      times more likely in exposed persons than in controls and the finding of a single
      autosomal trisomic cell was 14.4 times more likely in exposed persons. These
      highly statistically significant findings were similar to the frequencies of
      abnormalities reported in other studies of persons exposed to benzene,
      pesticides, herbicides and irradiation. It is recommended that findings of
      sporadic abnormalities in lymphocytes be routinely recorded, and patients with
      positive findings followed up to discover whether there are past histories of
      significant exposures.

PMID- 10664679
TI  - Deafness as self-representation of a 16th century poet.
AB  - In his best poems, the Renaissance poet Sabo Bobaljevic Glusac emphasizes his
      hearing impairment, placing his deafness at the centre of attention. These works
      are not only a poignant expression of an individual artist's suffering, but they
      may also add to our understanding of the situation of deaf persons. This self
      reflection can be seen as a detail that will enhance our ability to communicate
      with deaf people in order not only to help them hear us, but also to make us hear
      them as well.

PMID- 10664680
TI  - Isolated congenital stapes suprastructure fixation.
AB  - Isolated congenital anomalies of the ossicles are rare. The majority of cases of
      congenital conductive hearing loss secondary to middle-ear anomalies have other
      associated defects, such as atresia, microtia and craniofacial deformities. We
      present a rare case of isolated congenital stapes suprastructure fixation, where
      a monocrural stapes with a mobile footplate was attached to the promontory by
      bony synostosis. There was no stapedius muscle nor pyramidal process. The incus
      and malleus were of normal configuration. Mobilization of the stapes from the
      promontory resulted in improvement in hearing. We believe this is the first
      reported case of such an abnormality. A review of the world literature of
      isolated stapes suprastructure ankylosis and the classifications of minor
      congenital anomalies are discussed.

PMID- 10664681
TI  - Early complications of surgery for chronic otitis media.
AB  - This audit report details early post-operative complications following surgery
      for chronic otitis media. One hundred and forty-five cases were assessed. There
      were no facial nerve palsies, a bone conduction threshold elevation occurred in
      4.6 per cent of cases. A wound infection occurred in six per cent of cases as did
      BIPP allergy. Twenty-six per cent of patients reported symptoms consistent with
      chorda tympani trauma. Short-lived symptoms of jaw discomfort were reported by 46
      per cent of patients and imbalance or vertigo by 10 per cent of patients. The
      findings are compared with other published reports of complications following ear
      surgery.

PMID- 10664682
TI  - A three-array cochlear implant: a new approach for the ossified cochlea.
AB  - The ossified cochlea, although rare, represents a challenge for cochlear
      implantation. While it is no longer considered an absolute contra-indication to
      implantation, insertion may be technically difficult and the results may be
      suboptimal. Techniques which have been employed are reviewed. The new Digisonic
      multi-array implant, which was designed specifically for use in the ossified
      cochlea is described, along with the technique used for its insertion. In the
      first patient to be implanted with this new implant, all electrodes lie within
      the cochlea and are functional. The new Digisonic multi-array implant may have
      advantages over other solutions for the ossified cochlea.

PMID- 10664683
TI  - Post-irradiation sudden deafness.
AB  - As in radiation-induced cancer, post-irradiation sudden deafness (PISD) is
      defined as sudden onset deafness in patients post-irradiation. Fifteen
      nasopharyngeal carcinoma (NPC) patients with PISD were enrolled in this study.
      The mean interval from the completion of irradiation to the occurrence of PISD
      was 12 years. Seven had total deafness, seven had profound hearing loss, and one
      had moderate hearing loss. Nine out of 15 (60 per cent) patients experienced
      hearing recovery within three months after treatment. In conclusion, PISD is a
      late complication in NPC patients post-irradiation. The causative mechanism is
      theorized as vascular insufficiency.

PMID- 10664684
TI  - Outcome of using magnetic resonance imaging as an initial screen to exclude
      vestibular schwannoma in patients presenting with unilateral tinnitus.
AB  - The improved cost-effectiveness of gadolinium-enhanced magnetic resonance imaging
      (MRIg) as a diagnostic tool for vestibular schwannoma has resulted in smaller
      tumours being diagnosed. There has been a change in the clinical presentation of
      these tumours and up to four per cent may present with unilateral tinnitus. The
      limitation of auditory brain stem response (ABR) as a screening tool that detects
      small tumours is recognized and there is a strong argument for using MRIg as the
      initial investigation. Various screening guidelines have been proposed, some
      include submitting patients with unilateral tinnitus for MRIg. This report
      describes the findings in a group of 174 patients presenting with unilateral
      tinnitus who underwent MRIg as part of a guideline-directed screen to exclude
      vestibular schwannoma. Five patients had a cause for their tinnitus diagnosed,
      one a vestibular schwannoma. Two had intracranial aneurysms and another three had
      pathology revealed that merited onward referral. A further nine patients had
      incidental findings that neither accounted for their symptoms nor needed further
      investigation or referral. The rationale for screening these patients with MRIg
      is discussed.

PMID- 10664685
TI  - The results of septal button insertion in the management of nasal septal
      perforation.
AB  - Nasal septal perforation may present with various symptoms. Perforations may be
      surgically closed or managed by obturation, inserting a prosthesis. We used a
      silicon septal button in the management of nasal septal perforation. In the
      follow-up period, although the insertion of the nasal septal button alleviated
      epistaxis, whistling during inspiration, and nasal obstruction, it could not
      control the production of crusting around the margin of the button.

PMID- 10664686
TI  - Bacteriology of endoscopically normal maxillary sinuses.
AB  - The bacteriology of maxillary sinuses with normal endoscopic findings is reported
      in this study. When transantral sinoscopy was used to examine the maxillary
      sinuses, the whole maxillary sinus was inspected with different-angle endoscopes.
      If no lesion was seen over the whole maxillary sinus mucosa, no secretion existed
      in the maxillary sinus cavity, and the maxillary sinus ostium was wide open, the
      maxillary sinus was considered endoscopically normal. The bacteriology of these
      endoscopically normal maxillary sinuses was studied by passing cotton-tipped
      sticks through the cannula to collect swab specimens. In some cases, a biopsy
      forceps was also passed to obtain mucosal specimens. The specimens were sent to
      the laboratory for aerobic and anaerobic cultures. Between July 1990 and May
      1998, 83 swab and 31 mucosal specimens were collected from 69 patients who had
      not taken any antibiotic within 10 days before endoscopy. The culture rates were
      62.3 per cent (35/53) from swab specimens and 57.1 per cent (eight out of 14)
      from mucosal specimens in patients with the diagnosis of chronic paranasal
      sinusitis, and were 46.7 per cent (14/30) from swab specimens and 41.2 per cent
      (seven out of 17) from mucosal specimens in patients without this diagnosis. This
      study shows that endoscopically normal maxillary sinuses are not sterile.

PMID- 10664687
TI  - Pre-treatment anaemia alters outcome in early squamous cell carcinoma of the
      larynx treated by radical radiotherapy.
AB  - The purpose of this study was to examine the effect of pre-treatment anaemia on
      tumour recurrence and survival in patients treated with primary radiotherapy for
      early squamous cell carcinoma of the larynx. A retrospective analysis of 117
      patients with previously untreated T1N0M0 and T2N0M0 squamous cell carcinoma of
      the larynx was carried out. Patients were considered anaemic if their pre
      treatment haemoglobin levels were below 13 g/dl in males and 11.5 g/dl in
      females. The influence of pre-treatment haemoglobin levels on local control and
      survival were evaluated using Cox proportional hazards regression models. Two-
      and five-year local-regional control estimates for anaemic patients were 58 per
      cent and 53 per cent respectively while patients with normal haemoglobin levels
      had two and five-year local-regional control rates of 90 per cent and 81 per cent
      respectively (p = 0.002). Multivariate Cox regression analysis showed pre
      treatment haemoglobin significantly influencing recurrence-free survival (p =
      0.0094). Patients with a low haemoglobin level prior to radiation therapy
      suffered higher levels of local-regional failure.

PMID- 10664688
TI  - The use of the pedicled buccal fat pad (BFP) and palatal rotating flaps in
      closure of oroantral communication and palatal defects.
AB  - The use of the buccal fat (BFP) and palatal rotating flaps for the closure of oro
      antral communication and reconstruction of palatal defects was compared
      clinically. The BFP proved to be consistently successful in closing oro-antral
      fistulae and palatal defects resulting from tumour resection, preserving the
      normal anatomical architecture of the oral mucosa. No denuded area requiring
      secondary granulation was required as in the case of palatal flaps. In addition,
      no facial disfigurement was observed on the operated side. BFP is considered a
      reliable, convenient method for closure of palatal defects and closure of oro
      antral communication. It can also be considered as a reliable back-up procedure
      in the event of failure of other techniques.

PMID- 10664689
TI  - Nasendoscopically-assisted placement of a nasogastric feeding tube.
AB  - Nasogastric tube placement is desirable for the short-term administration of
      calories when oral feeding is not possible. Enteral nutrition is superior to
      parenteral nutrition. In some patients this method of feeding is impossible
      because of repeated failure of nasogastric tube placement, necessitating either
      general anaesthesia for enteral access, or total parenteral nutrition. We
      describe a new method for nasogastric tube placement aided by a fibre-optic
      nasendoscope which has resulted in the successful placement of over 20
      nasogastric tubes in our unit and the avoidance of more invasive methods of
      establishing nutrition with their associated complications.

PMID- 10664690
TI  - Bilateral congenital cholesteatoma in branchio-oto-renal syndrome.
AB  - Branchio-oto-renal syndrome is a rare autosomal dominant condition characterized
      by hearing loss, branchial arch abnormalities and renal tract malformations. We
      present the first reported case of branchio-oto-renal syndrome associated with
      bilateral congenital cholesteatoma and ossicular chain abnormalities. The
      pathogenesis of this syndrome is described and the literature is reviewed.

PMID- 10664691
TI  - Carotico-cavernous fistula following septorhinoplasty.
AB  - Septorhinoplasty is a very common operation in otolaryngological practice. We
      report the second case of a carotico-cavernous fistula following
      septorhinoplasty. This case presented with very severe epistaxis before the
      appearance of the typical pulsating exophthalmos, ophthalmoplegia, headache and
      engorged veins on the right side of the face. Our case was treated by
      endovascular thrombosis with electrolytically detachable coils.

PMID- 10664692
TI  - Viscoaugmentation as a treatment for leakage around the Provox 2 voice
      rehabilitation system.
AB  - Tracheo-oesophageal puncture for voice restoration is a well-established
      technique post-laryngectomy. A number of complications can occur with the
      creation of a tracheo-oesophageal fistula (TOF) and in the subsequent management
      of the patient with an indwelling voice rehabilitation system. This article is
      the first to report the use of Hylaform, a colourless viscoelastic gel, to treat
      an intractable case of leakage around a Provox 2 voice prosthesis. The procedure
      which required no anaesthesia resulted in no further leak around the valve to the
      present day, now more than four weeks post-viscoaugmentation.

PMID- 10664693
TI  - Bronchoscopic removal of an inhaled, sharp, foreign body: an unusual
      complication.
AB  - A case is reported in which an inhaled sewing needle, stuck fast in the trachea,
      became displaced through the tracheal wall during attempted removal via flexible
      bronchoscopy. The inherent risks and pitfalls of this procedure are highlighted.

PMID- 10664694
TI  - Removal of a foreign body from the bronchial tree--a new method.
AB  - Tracheo-bronchial foreign bodies can be very difficult to remove. This may be
      related to the location and type of foreign body, the experience of the
      bronchoscopist and the availability of appropriate instruments. We report a case
      of an uncommon foreign body in an unusual location in an adolescent in whom
      conventional attempts to remove it failed. The foreign body was eventually
      recovered using a flexible bronchoscope and an intravascular wire loop snare
      under fluoroscopic control. The patient was saved from thoracotomy and possible
      lobectomy. To our knowledge, this combined fluoroscopic and endoscopic approach
      for the removal of a difficult tracheobronchial foreign body is the first
      reported case in the literature.

PMID- 10664695
TI  - Spontaneous fracture of an ossified stylohyoid ligament.
AB  - The stylohyoid ligament extends from the styloid process to the hyoid bone. For
      an unknown reason it occasionally ossifies and forms a solid structure which can
      break because of trauma or even spontaneously. Symptoms of the fracture may mimic
      tumours, foreign bodies, infections or neuralgia. In our cases a spontaneous
      fracture of totally ossified stylohyoid ligaments presented as a painful neck
      swelling. The diagnosis was achieved by an ortopantomographic radiograph. In both
      cases the healing was spontaneous and complete.

PMID- 10664696
TI  - Traumatic myositis ossificans of the superior belly of the omohyoid.
AB  - The first case of traumatic myositis ossificans (TMO) involving a strap muscle of
      the neck is reported. TMO typically presents with an unresolved mass following
      trauma or surgery, requiring differentiation from other soft tissue and bone
      neoplasms. Opacification may be present on soft tissue X-rays. Computed
      tomography (CT) scan may demonstrate a characteristic zoning phenomenon to
      establish the diagnosis. The disorder is frequently self-limiting but surgery may
      be required for persistent symptoms.

PMID- 10664697
TI  - Phlebectasia of left anterior jugular vein.
AB  - We present a rare case of unilateral phlebectasia of the anterior jugular vein in
      a 56-year-old male patient whose complaint is a neck swelling that appears during
      talking. Although in this age group the most common cause of such a mass in the
      anterior aspect of the neck increasing in size during any type of straining or
      Valsalva manoeuvre is a laryngocele, phlebectasia of the anterior jugular vein
      should be considered in the differential diagnosis. Doppler ultrasound and
      computed tomography are the most useful and non-invasive methods to use for the
      investigation. Treatment should be conservative.

PMID- 10664698
TI  - Is Ollier's disease an understaging of Maffucci's syndrome?
AB  - Ollier's disease and Maffucci's syndrome are similar multiple enchondromatous
      conditions. Other co-existing pathologies, particularly other primary
      malignancies, have been described sporadically in both conditions but more so in
      Maffucci's syndrome. Maffucci's syndrome is distinguished from Ollier's disease
      by the presence of haemangiomas in the former. In this report, a patient believed
      to have Ollier's disease for 44 years was subsequently found to have large
      splenic haemangiomas on magnetic resonance imaging (MRI). In the light of this,
      we recommend that any patient diagnosed with Ollier's disease to have total body
      MRI to search for haemangiomas that will alter the diagnosis to Maffucci's
      syndrome and hence the prognosis. MRI also screens for the presence of other
      associated malignancies.

PMID- 10664699
TI  - Mucus circulation between accessory ostium and natural ostium of maxillary sinus.
AB  - We report a case of one asymptomatic 28-year-old male with mucus circulation
      between the natural ostium and the accessory ostium of the maxillary sinus.
      Computerized tomography (CT) revealed a recirculating mucus ring between the two
      ostia of the maxillary sinus.

PMID- 10664700
TI  - Further experience with fat graft obliteration of mastoid cavities for cochlear
      implants.
AB  - Obliteration of old mastoids and wet middle ears with autologous abdominal fat
      seems to be a reliable technique to render chronically discharging mastoid
      cavities or open middle ears dry and closed. This paper is the third in the
      series and looks at the intermediate results at five years. Of the 16 patients
      (one bilateral) 94.1 per cent of the ears are still dry and uninfected with
      closed external meati. Recurrent cholesteatoma was found in two patients at
      implantation and removed.

PMID- 10664701
TI  - The role of midfacial degloving in modern rhinological practice.
AB  - The midfacial degloving approach has been available for twenty five years and is
      slowly increasing in popularity in the management of extensive benign lesions of
      the sinonasal region, for selected malignancy in this area and to afford access
      to the nasopharynx and infra-temporal fossa. The advantages, applications and low
      complication rate are presented in a cohort of 86 patients, ranging from three to
      79 years of age with a mean follow-up of 5.5 years. Seventy-seven per cent of the
      group had benign pathology of which juvenile angiofibroma was the commonest (40
      cases). The 20 cases of malignant disease were a heterogeneous group
      histopathologically including adenoid cystic carcinoma (four cases), malignant
      schwannoma (two cases), rhabdomyosarcoma (two cases) and squamous cell carcinoma
      (two cases). Five underwent bilateral radical maxillectomies combined with
      orbital clearance in one patient. Complications include oro-antral fistula (three
      cases) and epiphora (three cases) all of which were successfully treated.

PMID- 10664702
TI  - Adverse effects of nasal continuous positive airway pressure therapy in sleep
      apnoea syndrome.
AB  - Nasal continuous positive airway pressure (nCPAP) is now the treatment of choice
      for patients with sleep apnoea syndrome. Side-effects and adverse reactions have
      been described in isolated reports with this device. We have, therefore,
      systematically studied the side-effects of nCPAP therapy in 300 consecutive
      patients referred to the London Chest Hospital Ventilatory Support Unit. Ninety
      six per cent of patients complained of at least one side-effect resulting from
      the therapy, with 45 per cent complaining of a side-effect specific to the nasal
      mask. There was no correlation between the side-effects and level of pressure
      used during nCPAP. The rate of compliance remained high in spite of the side
      effects, with a daily use of 7.8 hours (SD 8.05) and with 83 per cent of the
      patients using the device every night. Although nCPAP treatment remains
      acceptable to most patients there exists a high incidence of adverse effects.

PMID- 10664703
TI  - The nasal manifestations of sarcoidosis: a review and report of eight cases.
AB  - We report eight patients presenting to the Department of Otorhinolaryngology
      between 1990 and 1998 in whom a diagnosis of sarcoidosis was made. The most
      common presenting symptom was that of nasal obstruction and crusting and the most
      common site of involvement was the septum and inferior turbinate. These patients
      differ from the majority of patients who present with the other manifestations of
      sarcoidosis in that they are older. Where mucosal changes are present within the
      nose, biopsy gives a high diagnostic yield. The aim of treatment is to gain
      symptomatic control with the lowest dose of steroids. The majority of patient's
      nasal symptoms were managed with local measures and topical steroids. Nasal
      disease tends to follow a prolonged but benign course. Few had other organ
      involvement. While nasal sarcoidosis remains a rare cause of nasal obstruction,
      biopsy of abnormal nasal mucosa along with further investigations as dictated by
      history, examination and histological findings is important if delay in diagnosis
      is to be avoided.

PMID- 10664704
TI  - Size assessment of adenoid and nasopharyngeal airway by acoustic rhinometry in
      children.
AB  - Adenoid hypertrophy is known as the most common cause of nasal obstruction in
      children; thus, adenoidectomy with, or without, tonsillectomy is one of the most
      commonly performed surgical procedures in the paediatric population. Although
      many methods have been suggested, few studies have reported on how to assess
      adenoid size, pre-operatively. Acoustic rhinometry is an objective technique as
      well as a non-invasive method, which can be easily used in young children. This
      study confirmed that acoustic rhinometry is a non-invasive and objective
      technique for assessing the geometry of the nasal cavity and nasopharynx. Forty
      children were evaluated using symptomology, two different radiological
      measurements and acoustic rhinometry; the results were compared with endoscopic
      findings. Clinical symptoms and A/N ratio measured with Fujioka's method
      significantly correlated with the endoscopic assessment findings (r = 0.769 and
      0.604 respectively). Significant increases in the cross-sectional area and volume
      of the nasopharynx were observed at the adenoid notch after adenoidectomy (p <
      0.005 and p < 0.005, respectively). Acoustic rhinometry showed a high degree of
      correlation of which adenoid occupied the nasopharyngeal airway under endoscopic
      examination (r = 0.771). Thus, the study concluded that acoustic rhinometry can
      be as good an objective method for measuring adenoid sizes as endoscopy and can
      be used as one of the pre-operative examination tools for adenoidectomy.

PMID- 10664706
TI  - The use of toluidine blue gargles to aid the detection of impacted pharyngeal
      fish bones.
AB  - Fishbone impaction is a common clinical problem. In most cases careful
      examination pinpoints the impacted bone which can then be removed. If no bone is
      detected a distinction must be drawn between mucosal abrasion mimicking fishbone
      impaction and a fine or deeply impaled fishbone eluding detection. We present a
      new method that may be helpful in the detection of pharyngeal fishbones.

PMID- 10664705
TI  - Absence of Epstein-Barr virus encoded RNA and latent membrane protein (LMP1) in
      salivary gland neoplasms.
AB  - A series of 55 (42 benign and 13 malignant) salivary gland tumours were
      investigated by immunohistochemistry, to detect Epstein-Barr virus (EBV) latent
      membrane protein (LMP1) and by in situ hybridization for EBV-encoded RNA. Non
      neoplastic gland from all the patients with tumours and 15 control glands were
      also examined. All cases, both neoplastic and non-neoplastic were negative for
      LMP1 and failed to show any positive signal by in situ hybridization for EBV RNA.
      One undifferentiated carcinoma from a European patient was included in the group.
      These results confirm previous reports of an ethnic association between EBV and
      undifferentiated carcinomas of the salivary gland. They do not support an
      aetiological role for EBV in other salivary gland tumours.

PMID- 10664707
TI  - Haemangiopericytoma of the middle ear with benign histological features.
AB  - Haemangiopericytoma is a rare vascular tumour, particularly in the head and neck
      region. We described the first case of haemangiopericytoma arising from the
      middle ear in 1995. The present case is the second example of a primary middle
      ear haemangiopericytoma with benign histological features. Clinical photography,
      computed tomography (CT) and magnetic resonance imaging (MRI) scans and
      histological photographs depict the findings.

PMID- 10664708
TI  - Delayed facial palsy after middle-ear surgery due to reactivation of varicella
      zoster virus.
AB  - Viral reactivation is thought to be an important cause of post-operative facial
      palsy of delayed onset. We present an unusual case of Ramsay-Hunt syndrome that
      occurred as a consequence of middle-ear surgery by triggering varicella-zoster
      virus reactivation. As a pathognomonic auricular eruption was not seen, the
      patient was initially misdiagnosed as iatrogenic facial palsy. Clinical features,
      diagnosis and management are discussed.

PMID- 10664709
TI  - Presumed reduction of vestibular function in unilateral Meniere's disease with
      aminoglycoside eardrops.
AB  - We report the first case in the world literature of deliberate ablation of
      vestibular function in unilateral Meniere's disease with aminoglycoside eardrops
      (Garasone). These findings give conclusive proof that Garasone eardrops, and by
      implication, all topical aminoglycoside ear drops can be vestibulotoxic in the
      presence of a tympanic membrane defect. The lower concentration of gentamicin in
      Garasone, in comparison to the standard intratympanic preparations for chemical
      ablation of vestibular function, may also offer a reduction in the potential risk
      of cochleotoxocity.

PMID- 10664710
TI  - Feingold syndrome--a cause of profound deafness.
AB  - A case of Feingold syndrome is presented with a previously undescribed
      association of bilateral profound hearing impairment. Computed tomography (CT)
      scanning revealed severe narrowing of the internal auditory meatuses at the
      peripheral end with non-existent auditory nerves. This pathology is significant
      in the future habilitation of the child, as cochlear implantation is not
      possible. Children with multiple congenital anomalies should have radiological
      investigations before hopes are raised with respect to cochlear implantation.

PMID- 10664711
TI  - An unusual complication of cochlear implant: benign paroxysmal positional
      vertigo.
AB  - Three days after the initial fitting of the cochlear device a 40-year-old woman
      complained of severe rotational vertigo following head movements associated with
      neurovegetative symptoms. Otoneurological evaluation revealed a horizontal
      paroxysmal positional nystagmus beating towards the lowermost ear, induced by
      rolling the patient's head from supine both to the right or to the left lateral
      position suggesting the diagnosis of benign paroxysmal positional vertigo of the
      left horizontal semicircular canal. The nystagmus characteristics were the same
      whether the cochlear device was switched on or off. The hypothesis of an otolith
      dislodging due to the electrical stimulation during the initial fitting is
      discussed.

PMID- 10664712
TI  - Nasal haemophilic pseudotumour.
AB  - Haemophilic pseudotumour or haemophilic cyst is a rare complication of
      haemophilia, occurring in one to two per cent of individuals with a severe factor
      VIII or IX deficiency. We report a case of a haemophilic pseudotumour in a
      hitherto unreported site, the bony nasal pyramid, and believe this case is also
      unique on account of it having occurred in a patient with mild haemophilia. The
      diagnosis and treatment of this rare condition is also reviewed.

PMID- 10664713
TI  - Nasopharyngeal tuberculosis.
AB  - Rhinopharyngeal tuberculosis is a rare pathological condition. It is most often
      associated with lymph node and pulmonary lesions, but it may be an isolated
      finding. The authors report a recent case of an isolated rhinopharyngeal
      tuberculosis in a 64-year-old female. A review of the literature is presented.
      They emphasize the clinical presentation, that, in all aspects, may resemble a
      malignant tumour of the nasopharynx, as well as the difficulty of obtaining a
      pathological and bacteriological diagnosis.

PMID- 10664714
TI  - Adjuvant radiotherapy for primary mucosal malignant melanoma of the larynx.
AB  - Primary mucosal malignant melanoma (PMML) of the larynx continues to be a rare
      entity. To date, there are few cases reported in the world literature consisting
      of mainly isolated case reports and literature reviews. Traditionally believed to
      be radioresistant, we present a case of PMML of the right vocal fold managed with
      right cordectomy and adjuvant radiotherapy. The patient is well without any
      evidence of local recurrence or metastasis three years and four months from
      presentation.

PMID- 10664715
TI  - Parapharyngeal lipoma.
AB  - Lipomas of the parapharyngeal space provide both a diagnostic and therapeutic
      challenge. They are extremely rare with only a few cases having been reported. We
      present the case of a right parapharyngeal space lipoma in a 69-year-old man that
      was excised via a transcervical approach.

PMID- 10664716
TI  - The changing faces of a parotid mass.
AB  - The development of a neurofibroma in the temporal and parotid regions of the
      facial nerve is rare. We report a case occurring in a 32-year-old male, where the
      initial presentation was a parotid mass. Cytologically this was initially thought
      to be a pleomorphic adenoma. However, the diagnosis was then changed to a
      schwannoma and finally a neurofibroma after complete excision of the lesion. The
      case illustrates how fine needle aspiration cytology under ultrasound guidance,
      and even histological examination of an incision biopsy can sometimes fail to
      give the correct diagnosis. In this case magnetic resonance imaging was used to
      help plan definitive surgery.

PMID- 10664717
TI  - Malignant peripheral nerve sheath tumour of the spinal accessory nerve.
AB  - A 50-year-old man presented with a left-sided neck mass. Clinical examination
      revealed a large fluctuant 7 cm x 7 cm mass in the left posterior triangle.
      Magnetic resonance imaging (MRI) revealed an encapsulated soft tissue lesion. He
      underwent exploration of the neck and a 14 cm by 8 cm mass enfolding the
      accessory nerve was identified and completely excised. Histological examination
      of the surgical specimen showed features in keeping with a malignant peripheral
      nerve sheath tumour (MPNST). We present the clinical and pathological features of
      this condition.

PMID- 10664718
TI  - Primary brain stem tethering: a rare cause of geniculate neuralgia.
AB  - This rare case of brain stem tethering presented with chronic and progressive
      geniculate neuralgia. In view of the fact that an occipital subcutaneous lipoma
      had been resected in childhood, it probably concerned a primary tethering,
      fitting in with an occult occipital dysraphism. Magnetic resonance imaging (MRI)
      clearly demonstrated an underlying tethering, causing a distortion of the brain
      stem. Consequently, this led to the hypothesis that the geniculate neuralgia
      could be explained by traction on the lower cranial nerves secondary to the brain
      stem displacement. Untethering resulted in a considerable decrease of the
      neuralgia. MRI proved to be essential in the diagnosis and treatment of this
      unusual case.

PMID- 10664719
TI  - Laryngeal involvement by cutaneous lymphoma.
AB  - Laryngeal involvement by cutaneous lymphoma is rare; it may be isolated or part
      of systemic spread. We report a case of cutaneous T-cell lymphoma with isolated
      extracutaneous spread to the larynx, confirmed by the polymerase chain reaction
      in addition to histology. Awareness of this association may allow early
      recognition of symptoms heralding laryngeal embarrassment.

PMID- 10664720
TI  - Parotid tuberculosis simulating malignancy.
AB  - An interesting case of parotid tumour simulating malignancy is reported. The
      rarity of this lesion and the associated clinical and diagnostic problems are
      emphasized together with the relevant literature.

PMID- 10664721
TI  - Development of the Midland adult cochlear implant programme.
AB  - This paper describes the development of adult cochlear implantation in Birmingham
      over its first six years, from 1990 to 1996. During this time 366 patients were
      referred to the implant programme, female referrals outnumbered males 1.2:1.
      Eight per cent of referrals were over the age of 70. The annual rate of referral
      suggests a fairly steady demand for the service. Approximately one third of
      patients referred each year were subsequently implanted. The centre is currently
      performing an average of 2 implants per month. The average time from referral to
      implant is approximately 19 months. The greatest number of referrals originated
      from health districts closest to the implant centre. An examination of patients
      implanted suggested an imbalance in the uptake of the service amongst the
      different socio-economic groups.

PMID- 10664722
TI  - Outcomes from adult implantation, the first 100 patients.
AB  - We present the outcome of implantation in the first 100 adult patients treated
      under the Midland Cochlear Implant Programme. All patients were post-lingually
      deaf with profound or total hearing loss. Performance was tested in lip-reading,
      implant only and combined lip-reading and implant modes using BKB sentences,
      connected discourse tracking (CDT) and environmental sound recognition.
      Assessments were made at nine and 18 months post-implant. The dominant
      aetiologies were idiopathic and meningitis. Meningitis was associated with the
      greatest numbers of ossified cochleas. Forty-three per cent of cases of partial
      ossification were identified only at surgery. Four per cent of patients became
      non-users of their devices, however the majority used their implants for more
      than 12 hours each day. The mean scores at nine months post-implant, in the
      implant only mode, were for environmental sound recognition 56.7 per cent, for
      BKB sentences 46.6 per cent (80 per cent of patients scored above 0 per cent) and
      for CDT 31.2 words per minute (w.p.m.) (62 per cent scored above zero per cent).
      In the combined lip reading and implant mode the mean scores, at nine months,
      were for BKB sentences 81.5 per cent and for CDT 65.8 w.p.m. All results were
      sustained at 18 months. Patients reported that implantation significantly reduced
      their hearing handicap. Pre-operative measures of depression were also
      significantly reduced at nine months post-implant. Results were sustained at 18
      months. Post-operative audiological outcomes in the electrical stimulation only
      mode correlated significantly with length of profound deafness. Results suggest
      that performance outcome is also related to the number of active electrodes.

PMID- 10664723
TI  - Medical, surgical and audiological complications of the first 100 adult cochlear
      implant patients in Birmingham.
AB  - Of the first 100 patients implanted on the Midland Cochlear Implant Programme the
      commonest aetiologies of deafness were idiopathic 31 per cent, meningitis 28 per
      cent and cochlear otosclerosis 16 per cent. The major complication rate was three
      per cent. The most severe was one individual who post-operatively developed a
      cerebral infarct and subsequently died. The minor complication rate was 39 per
      cent, all of which successfully resolved, and included 11 cases of wound
      infection, nine cases of vertigo, three transient facial palsies and two post
      operative bleeds. Older patients and men were most likely to have a post
      operative medical complication. Women were more likely to have an abnormal
      electrode insertion. Meningitis and otosclerosis were the most complicated
      aetiologies in terms of cochlear ossification and electrode insertion. A non
      patient cochlea was associated with fewer active electrodes. In six cases which
      had been reported pre-operatively as showing patent cochleas, some form of
      obstructional ossification was encountered. Patients functioning with greater
      than 15 active electrodes performed better on auditory tests than patients with
      fewer than 15 active electrodes.

PMID- 10664724
TI  - Electrode complications in 100 adults with multichannel cochlear implants.
AB  - At switch-on (first post-operative stimulation of the implant) and during
      subsequent reprogramming, electrodes can, in some patients, be found to be non
      functional or to be performing sub-optimally for a number of reasons. This paper
      examines the reasons for the poor performance of these electrodes by means of a
      retrospective analysis of 100 patient records. All of these patients received the
      Nucleus multichannel device. The most common reason for an electrode to require
      de-activation was found to be facial nerve stimulation, with poor sound quality
      and pain also being very common. Other reasons included absence of auditory
      stimulation, vibration, reduced dynamic range, throat sensations, absence of
      loudness growth or dizziness. The occurrence of these reasons along the electrode
      array was examined, more basal electrodes being found to be non-functional as a
      result of having a small dynamic range or poor sound quality. Pain and vibration
      were found to occur throughout the array and the more apical electrodes were
      found to be non-functional as a result of facial nerve stimulation. It is
      suggested that the electrodes at the basal end of the array are likely to be
      extra-cochlear or are at the site of the most cochlear damage, whereas the more
      apical electrodes lie in closer proximity to the facial nerve.

PMID- 10664725
TI  - Imaging for cochlear implants.
AB  - All patients in the Birmingham Cochlear Implant Programme underwent computerized
      tomography (CT) scanning and were assessed and images interpreted by the main
      author. Of the first 100 cases, 20 were considered to have abnormalities of the
      inner ears by CT imaging. It is concluded that the commonest abnormality was
      cochlear otospongiosis followed by labyrinthitis ossificans. Otospongiosis is
      well shown by CT which gives a good predicator of luminal patency. However,
      labyrinthus obliterans, although usually apparent on CT, is not reliably shown in
      all cases and T2 weighted magnetic resonance imaging (MRI) is better.

PMID- 10664726
TI  - Tinnitus, cochlear implants and how they affect patients.
AB  - The relationship between tinnitus and cochlear implantation is an important issue
      that needs to be established because it may affect implant use. In this study 99
      patients over 15 years of age completed pre- and post-cochlear implantation
      questionnaires, and underwent performance testing. The findings show that after
      implantation, there was marked suppression of tinnitus in both implanted and
      contralateral ears whilst the implant was off, and this was further enhanced when
      the implant was switched on. These effects are probably a combination of local
      and central factors. Presence of tinnitus, before or after implantation, had no
      detrimental effects on performance. In conclusion, providing all other factors
      permit, this study recommends implanting the ear with the worst tinnitus.

PMID- 10664727
TI  - Evaluation of cochlear implantation in post-meningitic adults.
AB  - Meningitis is an important cause of deafness and in some studies has been
      associated with poorer outcomes in adult patients following cochlear
      implantation. Of the first 100 adults implanted under the Midland Cochlear
      Implant Programme, 28 were deafened as a result of meningitis. We compare our
      experience with these patients with patients with a non-meningitic aetiology. A
      degree of cochlear ossification was a more common finding in the meningitic
      group. In six cases (four meningitis, two non-meningitis) ossification was
      encountered only during surgery, not being apparent on pre-operative radiology.
      The average scores achieved on auditory tests by the meningitic group were
      similar to those achieved by non-meningitic patients. At nine months, using only
      the implant, users were able to identify 54 per cent of common environmental
      sounds, achieved an average score of 30 words per minute on connected discourse
      tracking and identified an average of 42 per cent of words correctly in BKB
      sentences. Poorer outcomes were more commonly associated with cochlear
      ossification. In patients with cognitive and neurological sequelae, benefits with
      the implant were not always apparent in the early months, however, with intensive
      therapy these patients can obtain measurable sustained benefit from their
      implant.

PMID- 10664729
TI  - Pre-medicine and selection of medical students.

PMID- 10664728
TI  - Multi-channel cochlear implantation in patients with a post-traumatic
      sensorineural hearing loss.
AB  - There are few accounts of cochlear implantation in adults with post-traumatic
      sensorineural hearing loss. We report our experience with multichannel
      implantation in three such patients. Two patients experienced no cognitive or
      communication deficits as a result of their head injury. At nine months post
      implant, compared with our experience of non-head-injured implantees, these
      patients achieved average or above average scores on audiological performance
      tests. The third patient presented with cognitive, behavioural and communicative
      deficits. The level of improvement achieved by this patient, when lip-reading was
      supplemented with electrical stimulation, in both BKB sentence and connected
      discourse tracking (CDT) tests was comparable with that of the non-head-injured
      group. However, his absolute performance at nine months post-implant was well
      below average. Performance at 18 months on BKB sentences and environmental sound
      recognition showed little change, and was again well below average, however his
      score on CDT with lip-reading and electrical stimulation improved considerably
      and was similar to the average achieved by the non-head-injured group. The major
      difficulties experienced with this patient were increasing depression and low
      implant use. Considerably more time was spent in the assessment and
      rehabilitation of this patient and involved liaison with a number of other
      agencies. When considering such patients for cochlear implantation it is strongly
      recommended that these additional requirements are taken into account.

PMID- 10664730
TI  - The undergraduate medical course.

PMID- 10664731
TI  - The pre-registration year.

PMID- 10664732
TI  - From registration to respectability.

PMID- 10664733
TI  - Personal development.

PMID- 10664734
TI  - Learning skills and the acquisition of clinical skills.

PMID- 10664735
TI  - Assessment and appraisal.

PMID- 10664736
TI  - Experiential learning.

PMID- 10664737
TI  - Team working.

PMID- 10664738
TI  - Medical careers: stories of a life.

PMID- 10664739
TI  - Information from other countries.

PMID- 10664740
TI  - Pre-registration in historical perspective.
AB  - This essay examines the background and implementation of the statutory
      requirement that each medical graduate in Great Britain must spend a pre
      registration year in hospital training before full registration can be effected.
      It looks briefly at the French and USA 'internship', and then describes the
      British situation before 1950, when a Medical Act made the pre-registration year
      compulsory. The Parliamentary Act was passed after full consultation with
      appropriate professional organizations and, despite various changes, still
      provides the basic structure of the first postgraduate year of medical training.

PMID- 10664741
TI  - Reform of the undergraduate medical curriculum.

PMID- 10664742
TI  - The pre-registration year. The trainees' experience.

PMID- 10664743
TI  - Changing the transition--the Canadian experience.
AB  - Ms Banner suggested that her role after the previous two lively and controversial
      presentations was to calm everyone down and present an alternative that delegates
      might quietly contemplate. She introduced herself as the executive director of
      the Canadian resident matching service, an organization that sits in the middle
      of all the medical education organizations in Canada and which in a way acts as
      an archive to the kind of changes that have been going on for the last 5-7 years.
      Much of what the two previous speakers discussed are the reasons why Canada is
      where it is today, and why it has taken the steps that it did. This paper
      describes the context of the transition from student to practising doctor in
      Canada, the pressures for change in this pre-registration period, the impact
      change has had on medical education and continuing challenges.

PMID- 10664744
TI  - Fitness to practice in the 21st century. What will doctors be doing in the 21st
      century?
AB  - I am not a clinical doctor, therefore it would be highly presumptuous of me to
      speculate on what doctors will be doing in 20-30 years time. I suspect it would
      be a difficult task even for a medically qualified speaker. If you think of what
      has happened over the past 20-30 years, and of how difficult if not impossible it
      would have been to predict these developments, then you have some measure of the
      problem in thinking ahead 20-30 years. So, I'm not going to attempt such an
      exercise. What I aim to do is refocus the question in the title a little and
      sketch out some of the health policy and health care concerns which are likely to
      shape the environment and context in which doctors and other health care
      practitioners will ply their craft.

PMID- 10664745
TI  - Old wine in new bottles? Some thoughts on Logvinenko's "Lightness induction
      revisited".

PMID- 10664746
TI  - Shrinkage and expansion by amodal completion: a critical review.
AB  - The whole literature on the so-called dimensional effects of amodal completion
      (shrinkage of a partially occluded figure and expansion of modally visible parts
      of the same figure) is critically reviewed. It is claimed that phenomenal
      shrinkage is the sum of at least two illusions independent of figure ground
      distinction: (1) shrinkage of spaces divided into a few parts, and (2) shrinkage
      of empty spaces. It is also shown that a partially occluded figure can widen,
      rather than shrink. It is concluded that the stratification in two phenomenally
      superimposed figures accompanies the shrinkage effect, but is irrelevant to its
      generation. Further experiments are needed in order to draw a well-grounded
      conclusion on the expansion effect.

PMID- 10664747
TI  - Characterisation of the misalignment and misangulation components in the
      Poggendorff and corner-Poggendorff illusions.
AB  - In the Poggendorff illusion, two colinear segments abutting obliquely on an
      intervening configuration (often consisting of two long parallel lines) appear
      misaligned. We report here the results of a component analysis of the illusion
      and several of its variants, including in particular the 'corner-Poggendorff'
      illusion, and variants with a single arm. Using a nulling method, we determined
      an 'orientation profile' of each configuration, that is, how the illusions varied
      as the configuration was rotated in the plane of the display. We were able to
      characterise a pure-misalignment component (having peaks and dips around the +/-
      22.5 degrees and +/- 67.5 degrees orientations of the arms) and a pure
      misangulation component of constant sign, having peaks at the +/- 45 degrees
      orientations of the arms. Both these components were present in both the classic
      and the corner-Poggendorff configurations. Thus, the misangulation component
      appears clearly in the classic Poggendorff illusion, once the misalignment
      component is partitioned out. Similarly, the corner-Poggendorff configuration,
      which essentially estimates a misangulation component, contains a misalignment
      component which becomes apparent once the misangulation is nulled. While our
      analysis accounts for much of the variability in the shapes of the profiles,
      additional assumptions must be made to explain the relatively small misangulation
      measured in the corner-Poggendorff configuration (1.5 degrees, on average, at
      peak value), and the relatively large illusion measured in the configurations
      with a single arm (above 6 degrees, on average, at peak values). We invoke the
      notion that parallelism and colinearity detectors provide counteracting cues, the
      first class reducing misangulation in the corner-Poggendorff configuration, and
      the second class reducing the illusion in the Poggendorff configurations with two
      arms.

PMID- 10664749
TI  - A comparison of methods for estimating directions in egocentric space.
AB  - A central issue for researchers of human spatial knowledge, whether focused on
      perceptually guided action or cognitive-map acquisition, is knowledge of
      egocentric directions, directions from the body to objects and places. Several
      methods exist for measuring this knowledge. We compared two particularly
      important methods, manual pointing with a dial and whole-body rotation (body
      heading), under various conditions of sensory or memory access to targets. In two
      experiments, blindfolded body rotation resulted in the greatest variability of
      performance (variable error), while the manual dial resulted in greater
      consistent bias (constant error). The variability of performance with body
      rotation was no greater than that of the dial when subjects' memory loads for
      directions to targets was reduced by allowing them to peek at targets in between
      trials, point to concurrent auditory targets, or point with their eyes open. In
      both experiments, errors with the manual dial were greater for directions to
      targets that were further from the closest orthogonal axis (ahead, behind, right,
      left), while errors with body rotation with restricted perceptual access were
      greater for directions to targets that were further from an axis straight ahead
      of subjects. This suggests that the two methods will produce evidence of
      different organizational frameworks for egocentric spatial knowledge.
      Implications for the structures and processes that underlie egocentric spatial
      knowledge, and are involved in estimating directions, are discussed, as is the
      value of decomposing absolute errors into variable and constant errors.

PMID- 10664748
TI  - Hierarchical organisation in perception of orientation.
AB  - According to Rock [1990, in The Legacy of Solomon Asch (Hillsdale, NJ: Lawrence
      Erlbaum Associates)], hierarchical organisation of perception describes cases in
      which the orientation of an object is affected by the immediately surrounding
      elements in the visual field. Various experiments were performed to study the
      hierarchical organisation of orientation perception. In most of them the rod-and
      frame-illusion (RFI: change of the apparent vertical measured on a central rod
      surrounded by a tilted frame) was measured in the presence/absence of a second
      inner frame. The first three experiments showed that, when the inner frame is
      vertical, the direction and size of the illusion are consistent with expectancies
      based on the hierarchical organisation hypothesis. An analysis of published and
      unpublished data collected on a large number of subjects showed that
      orientational hierarchical effects are independent from the absolute size of the
      RFI. In experiments 4 to 7 we examined the perceptual conditions of the inner
      stimulus (enclosure, orientation, and presence of luminance borders) critical for
      obtaining a hierarchical organisation effect. Although an inner vertical square
      was effective in reducing the illusion (experiment 3), an inner circle enclosing
      the rod was ineffective (experiment 4). This indicates that definite orientation
      is necessary to modulate the illusion. However, orientational information
      provided by a vertical or horizontal rectangle presented near the rod, but not
      enclosing it, did not modulate the RFI (experiment 5). This suggests that the
      presence of a figure with oriented contours enclosing the rod is critical. In
      experiments 6 and 7 we studied whether the presence of luminance borders is
      important or whether the inner upright square might be effective also if made of
      subjective contours. When the subjective contour figure was salient and the
      observers perceived it clearly, its effectiveness in modulating the RFI was
      comparable to that observed with luminance borders.

PMID- 10664750
TI  - Large systematic deviations in the haptic perception of parallelity.
AB  - Recently, Kappers and Koenderink (1999 Perception 28 781-795) showed that what
      subjects haptically perceive as parallel often deviates greatly from what is
      actually physically parallel. In their experiment, subjects had to rotate a test
      bar in such a way that it felt as though it was parallel to a reference bar.
      Their data were obtained with the right hand on a table plane to the right side
      of the median plane of the subject. The present study extends that work in a
      number of ways: (1) the locations of the stimuli cover the total reachable table
      plane; (2) distances between stimuli can also be large (more than 1 m); (3)
      experiments are done both unimanually (with the right and left hand) and
      bimanually. Like in the previous study, the results show large systematic
      deviations that correlate significantly with horizontal (left-right) distance
      between the two bars but not with vertical (forward-backward) distance. Thus we
      have established that a description of the results in terms of a horizontal
      gradient in the deviations is valid over a large part of haptic space, over large
      distances, and in both unimanual and bimanual conditions. The subject-dependent
      horizontal gradients ranged from -12 degrees m-1 to -27 degrees m-1 in the
      present experiment. In all conditions a significant haptic oblique effect can be
      demonstrated.

PMID- 10664752
TI  - An examination of a temporal anisotropy in the visual integration of spatial
      frequencies.
AB  - Three pairs of experiments were conducted to investigate the importance of
      spatial-frequency-processing delays imposed by the visual system on the efficacy
      of their subsequent integration. In the first pair of experiments filtered
      versions of a natural image were found to be easily discriminable from the full
      bandwidth image. These images were then placed into triplets and presented
      sequentially. Subjects were required to detect the presence of a full-bandwidth
      target image within the sequence. As with previous results a low-to-high
      progression of spatial-frequency information did increase the number of errors of
      full-bandwidth-image detection within the triplets where it was not present.
      However, this was not found across all conditions and was suggested to be due to
      the increased discriminability of the constituent images which form the image
      triplets. The second experiment was a repetition of the first with more
      confusable component images. Again the weak order effect on target detection was
      found. It was suggested that this may be due to the nature of the stimulus used.
      The third pair of experiments repeated the design of the first pair of
      experiments but with Gabor patches which provide localised spatial-frequency
      information. It was found that a low-to-high progression of spatial frequencies
      resulted in more false detections of the target. The results are interpreted as
      supporting an integration mechanism which operates with greater efficacy when the
      presentation of spatial-frequency information mirrors that naturally imposed by
      the neural delays involved in the processing of spatial frequencies.

PMID- 10664753
TI  - The Helmholtz--Hering debate in retrospect.

PMID- 10664751
TI  - Auditory coding of visual patterns for the blind.
AB  - Recognition tasks of simple visual patterns have been used to assess an early
      visual--auditory sensory-substitution system, consisting of the coupling of a
      rough model of the human retina with an inverse model of the cochlea, by means of
      a pixel-frequency relationship. The potential advantage of the device, compared
      with previous ones, is to give the blind the ability to both localise and
      recognise visual patterns. Four evaluation sessions assessed the performance of
      twenty-four blindfolded sighted subjects using the device. Subjects had to
      recognise twenty-five visual patterns, one at a time, using a head-mounted small
      camera and interpreting the corresponding sounds given by the device. Half the
      subjects were trained by means of a correction feedback procedure during ten one
      hour training sessions embedded in between the evaluation sessions. Results
      revealed extremely successful training effects. Performance of trained subjects
      significantly increased with practice compared with the untrained control group.
      The improvement was also observed for new patterns, demonstrating a learning
      process generalisation. The negative correlation observed between scores and
      processing time showed that the subjects' response accuracy was related to their
      speed. In conclusion, simple pattern recognition is possible with a fairly
      natural vision-to-audition coding scheme, given the possibility for the subjects
      to have sensory--motor interactions while using the device.

PMID- 10664754
TI  - Binocular rivalry and visual awareness: the role of attention.
AB  - When the right eye and the left eye view dissimilar scenes, the observer does not
      experience a stable superimposed percept of the images presented to the two eyes,
      but instead perceives an alternation between the images seen by each eye. A
      critical question confronting this robust and intriguing phenomenon of binocular
      rivalry is how the visual system selects the image to be perceived (dominant).
      The current main-stream literature emphasizes a bottom-up explanation in which
      the rivalry stimulus with the higher contour strength has the advantage, and
      becomes dominant in rivalry. Nevertheless, some workers in the past have favored
      an attention-selection explanation for binocular rivalry. We investigated the
      role of attention in binocular rivalry by employing novel psychophysical
      paradigms which capitalized on several established phenomena (e.g. the Cheshire
      Cat effect, attention cueing, pop-out effect). Our results revealed two major
      aspects of attention modulation in binocular rivalry. We found that a dominant
      image is less likely to be suppressed when voluntary attention is directed to it.
      This suggests the role of voluntary attention in retaining the dominant image in
      visual awareness. Second, a rivalry stimulus is more likely to become dominant if
      accompanied by a pop-out cue (in the same eye and proximity). Since a pop-out cue
      attracts involuntary attention to its location/eye, this result suggests that cue
      mediated involuntary attention can promote the ability of a rivalry stimulus to
      reach visual awareness.

PMID- 10664755
TI  - What object attributes determine canonical views?
AB  - We investigated preferred or canonical views for familiar and three-dimensional
      nonsense objects using computer-graphics psychophysics. We assessed the canonical
      views for objects by allowing participants to actively rotate realistically
      shaded three-dimensional models in real-time. Objects were viewed on a Silicon
      Graphics workstation and manipulated in virtual space with a three-degree-of
      freedom input device. In the first experiment, participants adjusted each object
      to the viewpoint from which they would take a photograph if they planned to use
      the object to illustrate a brochure. In the second experiment, participants
      mentally imaged each object on the basis of the name and then adjusted the object
      to the viewpoint from which they imagined it. In both experiments, there was a
      large degree of consistency across participants in terms of the preferred view
      for a given object. Our results provide new insights on the geometrical,
      experiential, and functional attributes that determine canonical views under
      ecological conditions.

PMID- 10664756
TI  - Encoding 'regular' and 'random' sequences of views of novel three-dimensional
      objects.
AB  - When we look at an object as we move or the object moves, our visual system is
      presented with a sequence of different views of the object. It has been suggested
      that such regular temporal sequences of views of objects contain information that
      can aid in the process of representing and recognising objects. We examined
      whether seeing a series of perspective views of objects in sequence led to more
      efficient recognition than seeing the same views of objects but presented in a
      random order. Participants studied images of 20 novel three-dimensional objects
      rotating in depth under one of two study conditions. In one study condition,
      participants viewed an ordered sequence of views of objects that was assumed to
      mimic important aspects of how we normally encounter objects. In the other study
      condition, participants were presented the same object views, but in a random
      order. It was expected that studying a regular sequence of views would lead to
      more efficient recognition than studying a random presentation of object views.
      Although subsequent recognition accuracy was equal for the two groups,
      differences in reaction time between the two study groups resulted. Specifically,
      the random study group responded reliably faster than the sequence study group.
      Some possible encoding differences between the two groups are discussed.

PMID- 10664757
TI  - The peripheral drift illusion: a motion illusion in the visual periphery.
AB  - Circularly repeating patches containing sawtooth luminance gradients produce a
      sensation of motion when viewed in the periphery. Illusory motion is perceived in
      a dark-to-light direction, but only when one's gaze is directed to different
      locations around the stimulus, a point outside the display is fixated and the
      observer blinks, or when the stimulus is sequentially displayed at different
      locations whilst the observer fixates one point. We propose that the illusion is
      produced by the interaction of three factors: (i) introducing transients as a
      result of eye movements or blinks; (ii) differing latencies in the processing of
      luminance; and (iii) spatiotemporal integration of the differing luminance
      signals in the periphery.

PMID- 10664758
TI  - Demonstrating the temporal modulation transfer function.
AB  - A 120-frame movie, which can be downloaded from specified web sites, allows an
      observer to see the qualitative form of his or her temporal modulation transfer
      function. Results collected from two of the authors are presented.

PMID- 10664759
TI  - Ecologically invalid monocular texture leads to longer perceptual latencies in
      random-dot stereograms.
AB  - Two experiments were conducted to explore Gillam and Borsting's (1988, Perception
      17 603-608) report that uncorrelated monocular texture facilitates stereopsis by
      shortening the latency to see depth in random-dot stereograms. Experiment 1 used
      stereograms similar, in pattern but not disparity, to Gillam and Borsting's with
      monocular texture present or absent. A third condition, where monocular texture
      was dissimilar to the binocular panels and background, was also used. We were
      unable to generalize the findings of Gillam and Borsting for a depth step of 6
      min of arc to a larger depth step of 24 min of arc. That is, we observed no
      significant difference in latencies between the conditions with monocular texture
      absent and present at a disparity of 24 min of arc. We found latencies to be
      significantly longer in the monocular-texture-different condition than the
      monocular-texture-absent condition, however. We account for this, ad hoc, by
      arguing that the monocular-texture-different stereogram depicts a rare or
      'accidental' visual scenario. This account was supported by the results of
      experiment 2 which showed that stereograms depicting accidental views yielded
      longer latencies than those depicting generic views. We conclude that the
      ecological validity of monocular texture must also be considered when assessing
      the effects of monocular texture on stereopsis.

PMID- 10664760
TI  - Coloured overlays, text, and texture.
AB  - In four studies children were asked to read aloud a passage of randomly ordered
      common words with and without a coloured sheet of plastic (overlay) placed upon
      the page. The children's rate of reading increased with the overlay, for some
      children more than for others. The children were also asked to undertake a test
      of texture segmentation in which targets consisting of a structured texture had
      to be distinguished from within a random background texture. The texture
      segmentation was improved when the overlay was used, again for some children more
      than for others. The improvement in texture segmentation was, in general,
      correlated with the improvement in rate of reading. Slower readers were generally
      poorer at texture segmentation. The implications for reading, for texture
      segmentation, and for clinical tests of vision are discussed.

PMID- 10664762
TI  - Virtual psychophysics.

PMID- 10664761
TI  - An investigation of the cognitive and perceptual dynamics of a colour-digit
      synaesthete.
AB  - L, a 47-year-old female of Choctaw descent, was first identified as a potential
      synaesthetic++ on the basis of self-report data regarding digit-colour
      associations. Upon completion of the identification procedures typified in the
      literature, it was concluded that L met the classic memory-performance criteria
      used to identify synaesthetic ability. A series of Stroop-type tasks were then
      performed to identify the dynamics of her synaesthetic experiences. The results
      of these analyses provided three findings of note. First, the clear pattern of
      response-time differences between L and the control group suggests that tasks
      designed to produce involuntary divisions of attention can be an effective means
      by which to demonstrate that synaesthetic experiences are involuntary but
      elicited. Second, the significantly slower performance by L on a negative-priming
      Stroop list shaped around her colour-digit associations indicates the presence of
      a lexical component in her synaesthetic experience. Third, the use of a manual
      colour-classification task for which a verbal response was not employed served to
      confirm the presence of a lexical component in L's synaesthetic experiences. The
      implications of these results for current synaesthetic theories are then
      discussed. Finally, a clustering solution of a portion of L's colour-digit
      experiences is presented, along with the ramifications of its results on the
      nature of L's perceptual experience.

PMID- 10664763
TI  - The historical roots of the theories of local signs and labelled lines.
AB  - The theories of labelled lines and local signs are commonly invoked to explain
      numerous perceptual phenomena. These theories postulate that perceptual systems
      use information about which nerve cells or which information channels are
      activated by the stimulus. The origins of this idea in nineteenth century German
      psychophysics are traced. From Descartes's idea of a dualistic mind, Kant's idea
      of a mental ability to conceive space, Da Vinci's ideas of pictorial 'signs', and
      Muller's idea of 'specific nerve energies' to explain perceptual qualities,
      Steinbuch, Lotze, and others derived the conclusion that neural-level signs exist
      that signal stimulus location to the mind. Helmholtz, Hering, and others soon
      suggested variations on this basic idea. By the time of James the theory had
      changed yet again. It was revived elsewhere in the 1920s and again in the 1970s,
      although used implicitly by many workers in between and since. Against a modern
      metaphysical background, however, a distinction between labels (hardware) and
      signs (symbols) is the minimum step needed towards an appropriate and
      comprehensive explanation of perceptual behaviour and experience.

PMID- 10664764
TI  - Adaptive filtering in spatial vision: evidence from feature marking in plaids.
AB  - Much evidence shows that early vision employs an array of spatial filters tuned
      for different spatial frequencies and orientations. We suggest that for
      moderately low spatial frequencies these preliminary filters are not treated
      independently, but are used to perform grouping and segmentation in the patchwise
      Fourier domain. For example, consider a stationary plaid made from two
      superimposed sinusoidal gratings of the same contrast and spatial frequency
      oriented +/- 45 degrees from vertical. Most of the energy in a wavelet-like (e.g.
      simple-cell) transform of this stimulus is in the oblique orientations, but
      typically it looks like a compound structure containing blurred vertical and
      horizontal edges. This checkerboard structure corresponds with the locations of
      zero crossings in the output of an isotropic (circular) filter, synthesised from
      the linear sum of a set of oriented basis-filters (Georgeson, 1992 Proceedings of
      the Royal Society of London, Series B 249 235-245). However, the addition of a
      third harmonic in square-wave phase causes almost complete perceptual
      segmentation of the plaid into two overlapping oblique gratings. Here we confirm
      this result psychophysically using a feature-marking technique, and argue that
      this perceptual segmentation cannot be understood in terms of the zero crossings
      marked in the output of any static linear filter that is sensitive to all of the
      plaid's components. If it is assumed that zero crossings or similar are an
      appropriate feature-primitive in human vision, our results require a flexible
      process that combines and segments early basis-filters according to prevailing
      image conditions. Thus, we suggest that combination and segmentation of spatial
      filters in the patchwise Fourier domain underpins the perceptual segmentation
      observed in our experiments. Under this kind of image-processing scheme,
      registration across spatial scales occurs at the level of spatial filters, before
      features are extracted. This contrasts with many previous schemes where feature
      correspondence is required between spatial edge-maps at different spatial scales.

PMID- 10664765
TI  - What is the speed to transparent and kinetic-boundary displays?
AB  - To compare transparent motion and kinetic boundaries with unidirectional motion,
      in many studies the relative motion is generated by superimposing or adjoining
      unidirectional motions oriented in opposite directions. The presumption, tacitly
      underlying this comparison, is that the two oppositely directed velocities are
      independent of one another as far as their speed is concerned, i.e. the speed of
      the relative motion is presumed to be equivalent to the speed of the
      unidirectional components. Here we report that the relative motion between dots
      moving in opposite directions augments perceived speed. A constant-stimuli
      procedure was used to pair transparent-motion or kinetic-boundary displays with
      unidirectional motion, and human observers were asked to match the speed of the
      relative and unidirectional motions. The results show that transparency and
      kinetic boundaries increase the perceived visual speed by about 50%, compared
      with the speed of the individual components.

PMID- 10664766
TI  - Perceived shape regularity does not depend on regularities along the contour.
AB  - In four experiments we investigated whether human observers are able to use
      certain regularities in polygons when they have to indicate which polygon they
      perceive as the more regular in a paired comparison task. From our results we
      conclude that regularities that are restricted to the contour do not play a role
      in judgments of regularity. For instance, equilateral polygons are not considered
      to be more regular than entirely random polygons. Only bilaterally symmetric
      polygons are consistently judged as regular. However, we show that this is caused
      by regularities across the polygon. These results are at odds with approaches
      that assume that regularities along the contour play an important part in visual
      perception.

PMID- 10664767
TI  - Stored representations of three-dimensional objects in the absence of two
      dimensional cues.
AB  - Object recognition was studied in human subjects to determine whether the storage
      of the visual objects was in a two-dimensional or a three-dimensional
      representation. Novel motion-based and disparity-based stimuli were generated in
      which three-dimensional and two-dimensional form cues could be manipulated
      independently. Subjects were required to generate internal representations from
      motion stimuli that lacked explicit two-dimensional cues. These stored internal
      representations were then matched against internal three-dimensional
      representations constructed from disparity stimuli. These new stimuli were used
      to confirm prior studies that indicated the primacy of two-dimensional cues for
      view-based object storage. However, under tightly controlled conditions for which
      only three-dimensional cues were available, human subjects were also able to
      match an internal representation derived from motion of that of disparity. This
      last finding suggests that there is an internal storage of an object's
      representations in three dimensions, a tenet that has been rejected by view-based
      theories. Thus, any complete theory of object recognition that is based on
      primate vision must incorporate three-dimensional stored representations.

PMID- 10664768
TI  - Effects of similarity on apparent motion and perceptual grouping.
AB  - Effects of similarity in colour, luminance, size, and shape on apparent motion
      and perceptual grouping were examined in part 1 in two parallel experiments on
      the same seven subjects. In both experiments, the effect of similarity was
      compared with that of proximity in competitive, bistable stimulus situations. A
      combination of a larger horizontal separation between the homogeneous stimulus
      elements and a smaller constant vertical separation between heterogeneous
      stimulus elements produced two kinds of apparent motion (or perceptual grouping)
      with equal probabilities. Such matched separations between homogeneous stimulus
      elements were obtained by the double staircase method in various stimulus
      conditions. In both experiments on apparent motion and perceptual grouping
      matched separation was found to increase as the difference between the
      heterogeneous stimulus elements increased. High correlations (0.71 to 0.94) of
      matched separations were found between apparent motion and perceptual grouping in
      four stimulus series: colour, luminance, size, and shape. Six of the seven
      subjects were also tested in part 2. Here, the effects of differences were found
      to work additively across different perceptual attributes in both phenomena, when
      multiple differences were combined in heterogeneous elements. The experimental
      results are discussed from the point of view that apparent motion is an example
      of perceptual constancy.

PMID- 10664769
TI  - Identification of gender in domestic-cat faces with and without training:
      perceptual learning of a natural categorization task.
AB  - Three experiments were conducted to determine whether human observers could
      identify the gender of 40 domestic cats (20 female, 20 male) depicted in
      individual color photographs. In experiment 1a, observers performed at chance for
      photographs depicting whole cats, cat heads (bodies occluded), and cat bodies
      (heads occluded). Experiment 1b showed that chance performance was also obtained
      when the photographs were full-face close-ups of the cats. Experiment 2a revealed
      that even with gender-identification training on 30 (15 female, 15 male) of the
      40 face close-ups, observers were unable to generalize their training to reliably
      identify the gender of the 10 remaining test faces (5 female, 5 male). However,
      experiment 2b showed that gender-identification training with the 14 most
      accurately identified faces from experiment 1b (7 female, 7 male) was successful
      in raising gender identification of the 10 test faces above chance. Experiments
      3a and 3b extended this facilitative effect of gender-identification training to
      a population of animal-care workers. The findings indicate that, with appropriate
      training, human observers can identify the gender of cat faces at an above-chance
      level. A perceptual category learning account emphasizing the on-line formation
      of differentiated male versus female prototypes during training is offered as an
      explanation of the findings.

PMID- 10664770
TI  - Veering re-visited: noise and posture cues in walking without sight.
AB  - Effects of sound and posture cues on veering from the straight-ahead were tested
      with young blind children in an unfamiliar space that lacked orienting cues. In a
      pre-test with a previously heard target sound, all subjects walked straight to
      the target. A recording device, which sampled the locomotor trajectories
      automatically, showed that, without prior cues from target locations, subjects
      tended to veer more to the side from which they heard a brief, irrelevant noise.
      Carrying a load on one side produced more veering to the opposite side. The
      detailed samples showed that, underlying the main trajectories, were alternating
      concave and convex (left and right) movements, suggesting stepwise changes in
      body position. It is argued that the same external and body-centred cues that
      contribute to reference-frame orientation for locomotion when they converge and
      concur, influence the direction of veering when the cues occur in isolation in
      environments that lack converging reference information.

PMID- 10664771
TI  - Haptic perception of spatial relations.
AB  - There are some indications that haptic space like visual space is not Euclidean
      (e.g. Blumenfeld, 1937 Acta Psychologica 2 125-174). In a series of experiments,
      we investigated the haptic perception of spatial relations in a systematic way.
      We restricted ourselves to a horizontal plane at waist height. Blindfolded
      subjects were asked to perform three tasks with their right hand: (i) a reference
      bar was presented under four different orientations and subjects were asked to
      rotate a test bar such that it felt to be parallel to the reference bar; (ii)
      subjects had to rotate two test bars in such a way that they felt collinear;
      (iii) subjects had to point a test bar in the direction of a marker. Bars and
      marker could appear at nine different locations. In all experiments large
      systematic deviations (up to 40 degrees) were made. The deviations strongly
      correlated with horizontal (right-left) but not with vertical (forward-backward)
      distance. Subjects showed qualitatively identical trends but the size of the
      deviations was strongly subject-dependent. In addition, a significant haptic
      oblique effect was found. These results provide strong evidence that haptic space
      in non-Euclidean.

PMID- 10664772
TI  - Talking about Goethe.

PMID- 10664773
TI  - Lightness induction revisited.
AB  - Lightness induction is the classical visual phenomenon whereby the lightness of
      an object is shown to depend on its immediate surround. Despite the long history
      of its study, lightness induction has not yet been coherently and satisfactorily
      explained in all its variety. The two main theories that compete to explain it
      descend (i) from H von Helmholtz, who believed that lightness induction
      originates from some central mechanisms that take into account the whole viewing
      situation, with particular stress upon the apparent illumination of the object;
      and (ii) E Hering who argued in favour of more peripheral sensory mechanisms
      based on local luminance contrast. The balance between these theories has
      recently been shifted towards Helmholtz's position by E H Adelson who has
      provided additional evidence that lightness induction depends on perceptual
      interpretation and, particularly, on apparent transparency. I challenge Adelson's
      conclusions by introducing modified versions of his tile pattern that use
      luminance gradients. In the first of these new demonstrations there is a strong
      lightness induction even though no apparent transparency is experienced. In the
      second there is a clear impression of transparent strips, yet no lightness
      induction is present. And the third shows that breaking up the Adelson tile
      pattern, while it affects neither the impression of transparency nor the type of
      grey-level junctions, makes the lightness-induction effect vanish. This implies
      that Adelson's illusion can be accounted for by neither local contrast, nor the
      apparent transparency, nor the type of grey-level junctions. Presented here is an
      alternative look at lightness induction as a phenomenon of the pictorial (as
      contrasted to natural) vision, which rests on the lightness-shadow invariance,
      much as Gregory's 'inappropriate constancy scaling' theory of geometrical
      illusions rests on the apparent size-distance invariance.

PMID- 10664774
TI  - From rotation to disfiguration: testing a dual-strategy model for recognition of
      faces across view angles.
AB  - A study is reported of the effect of distinctive marks on the recognition of
      unfamiliar faces across view angles. Subjects were asked to memorize a set of
      target faces, half of which had distinctive marks. Recognition was assessed by
      presenting the target faces, either in the same orientation, or after 90 degrees
      rotation, mixed with an equal number of distractors. Results show that the effect
      of distinctive marks depends on the view presented during learning. When a
      frontal view was learned, as predicted by the dual-strategy model [Valentin et
      al, in press, in Computational, Geometric, and Process Perspectives on Facial
      Cognition: Context and Challenges Eds T Wenger, J Townsend (Hillsdale, NJ:
      Lawrence Erlbaum Associates)], distinctive marks improve recognition performance
      in the 90 degrees condition but not in the 0 degree condition. However, when a
      profile view was learned, distinctive marks have no effect on recognition
      performance, even in the 90 degrees condition where a frontal view is tested.

PMID- 10664775
TI  - Photopic visual phantom illusion: its common and unique characteristics as a
      completion effect.
AB  - An illusion similar to the stationary visual phantom illusion presented earlier
      by Gyoba (1983, Vision Research 23 205-211) is reported. This illusion is visible
      in photopic vision and we have tentatively named it the 'photopic phantom
      illusion'. A typical example of this illusion is a white and light-gray square
      wave grating occluded by a black region. In this figure, a phantom grating
      running across the occluder with clear contours but less contrast, is seen. The
      critical spatial frequencies of photopic phantoms have been measured and compared
      with those of scotopic phantoms that have been reported previously, revealing a
      great resemblance between them. We discuss the characteristics of this illusion
      in terms of transparency, stereoscopic viewing, and perceptual completion.

PMID- 10664776
TI  - Some new luminance-gradient effects.
AB  - Three compelling luminance-gradient effects are described. The first effect
      concerns a brightness enhancement and a luminous mist spreading out from a
      central area having the same luminance as the white background and surrounded by
      four rectangular inducers shaded with a linear luminance gradient. The second
      effect is perceived with a photographically reversed configuration, and concerns
      what may be considered a brightness reduction or the enhancement of a darkness
      quality of a target area of the visual scene. The third effect concerns the
      perception of a self-luminous disk inside a somewhat foggy medium. The effects
      are worthy of further examination because they challenge current theories of
      luminosity perception and brightness perception in general.

PMID- 10664777
TI  - Effects of the height of the internal features of faces on adults' aesthetic
      ratings and 5-month-olds' looking times.
AB  - We examined the influence of the height of the internal features of faces on
      adults' ratings of attractiveness and on 5-month-olds' looking times. Subjects
      viewed drawings or coloured photographs of faces presented in pairs that were
      identical except that the internal features were at a low height, with a large
      forehead and small chin; at a high height, with a small forehead and large chin;
      or at a medium height. Adults rated faces with their features at the medium and
      low heights as more attractive than faces with their features at the high height,
      and, at least for drawings, rated faces with medium features as more attractive
      than faces with low features. Babies looked equally long at faces with their
      features at various heights except for looking slightly longer at faces with high
      rather than low features. The results suggest that the influence of feature
      height on reactions to faces is different for adults and 5-month-olds, and hence
      that it may be shaped by cultural learning and/or experience with faces sometime
      after early infancy.

PMID- 10664778
TI  - The perception of tactile distance: influences of body site, space, and time.
AB  - Vibrotactile prostheses for deaf or blind persons have been applied to any number
      of different locations on the body, including the finger, wrist, forearm,
      abdomen, back, and nape of the neck. The discriminability of patterns presented
      by such devices can be affected by the acuity of the site of application and the
      resolution of the display. In addition, the mutual influences among stimuli close
      together in both space and time can affect percepts within a broad range of
      parameters. For example, consideration must be given to a variety of tactile
      illusions often associated with the spatial separations and the range of temporal
      intervals typically used in cutaneous communication displays. Experiments are
      reported in which magnitude estimates and cross-modality matches of perceived
      extent produced by pairs of vibrotactile taps presented to separate loci were
      obtained on three different body sites. Perceived distance was directly related
      both to the timing between the taps and to their physical separation. The
      findings show a consistent relationship to cortical magnification across body
      sites.

PMID- 10664779
TI  - Perceptual organization of apparent motion in the Ternus display.
AB  - A typical Ternus display has three sequentially presented frames, in which frame
      1 consists of three motion tokens, frame 2 (blank) defines the interstimulus
      interval, and frame 3 has similar motion tokens with their relative positions
      shifted to the right. Interestingly, what appears to be a seemingly simple
      arrangement of stimuli can induce one of two distinct apparent-motion percepts in
      the observer. The first is an element-motion perception where the left-end token
      is seen to jump over its two neighboring tokens (inner tokens) to the right end
      of the display. The second is a group-motion perception where the entire display
      of the three tokens is seen to move to the right. How does the visual system
      choose between these two apparent-motion perceptions? It is hypothesized that the
      choice of motion perception is determined in part by the perceptual organization
      of the motion tokens. Specifically, a group-motion perception is experienced when
      a strong grouping tendency exists among the motion tokens belonging to the same
      frame. Conversely, an element-motion perception is experienced when a strong
      grouping tendency exists between the inner motion tokens in frames 1 and 3 (i.e.
      the two tokens that overlap in space between frames). We tested this hypothesis
      by varying the perceptual organization of the motion tokens. Both spatial (form
      similarity, 3-D proximity, common surface/common region, and occlusion) and
      temporal (motion priming) factors of perceptual organization were tested. We
      found that the apparent-motion perception of the Ternus display can be
      predictably affected, in a manner consistent with the perceptual organization
      hypothesis.

PMID- 10664780
TI  - Critical role of foreground stimuli in perceiving visually induced self-motion
      (vection).
AB  - The effects of a foreground stimulus on vection (illusory perception of self
      motion induced by a moving background stimulus) were examined in two experiments.
      The experiments reveal that the presentation of a foreground pattern with a
      moving background stimulus may affect vection. The foreground stimulus
      facilitated vection strength when it remained stationary or moved slowly in the
      opposite direction to that of the background stimulus. On the other hand, there
      was a strong inhibition of vection when the foreground stimulus moved slowly
      with, or quickly against, the background. These results suggest that foreground
      stimuli, as well as background stimuli, play an important role in perceiving self
      motion.

PMID- 10664781
TI  - Perceptual and linguistic interactions in speeded classification: tests of the
      semantic coding hypothesis.
AB  - We tested the semantic coding hypothesis, which states that cross-modal
      interactions observed in speeded classification tasks arise after perceptual
      information is recoded into an abstract format common to perceptual and
      linguistic systems. Using a speeded classification task, we first confirmed the
      presence of congruence interactions between auditory pitch and visual lightness
      and observed Garner-type interference with nonlinguistic (perceptual) stimuli
      (low-frequency and high-frequency tones, black and white squares). Subsequently,
      we found that modifying the visual stimuli by (a) making them lexical (related
      words) or (b) reducing their compactness or figural 'goodness' altered congruence
      effects and Garner interference. The results are consistent with the semantic
      coding hypothesis, but only in part, and suggest the need for additional
      assumptions regarding the role of perceptual organization in cross-modal
      dimensional interactions.

PMID- 10664782
TI  - Perceiving and acting without vision: lessons from the life and works of
      Professor Emerson Foulke, 1929-1997.

PMID- 10664783
TI  - Collisions between moving visual targets: what controls alternative ways of
      seeing an ambiguous display?
AB  - When identical visual targets move directly toward and then past one another,
      they appear either to stream past one another or to bounce off each other.
      Bertenthal et al (1993 Perception 22 193-207) accounted for the relative
      strengths of these two percepts by invoking a directional bias, arising from
      cooperative interactions within a network of motion detectors. We tested this
      explanation by devising conditions that would enhance or diminish the strength of
      such a directional bias. In separate experiments we varied (i) the presence or
      absence of temporal transients (pausing, disappearance, occlusion); (ii) the
      distances travelled by the targets; and (iii) their acceleration or deceleration
      before and after collision. The tendency to see the objects stream past one
      another was not related to the strength of an hypothesized directional bias,
      suggesting that the perception of this ambiguous motion display was not mediated
      by directional recruitment. Instead, the results suggest that perceived direction
      reflects the operation of neural constraints that mirror the constraints
      operating upon moving objects in the three-dimensional natural world.

PMID- 10664784
TI  - An airplane illusion: apparent velocity determined by apparent distance.
AB  - When a small drone plane appears to be a normal-sized airplane, it appears to be
      very far away and moving too fast. This is the airplane illusion. In the illusory
      situation, familiar size determines the apparent size and distance of the plane.
      It sets the depth for the frontal-plane component of the perceived motion and the
      relative depth difference for the motion-in-depth component. Because these
      perceived distances are very large, the perceived velocities are very large in
      the respective directions. Cognition can override familiarity and produce a
      veridical perception of the drone.

PMID- 10664785
TI  - The effect of marker frequency disparity on the discrimination of gap duration in
      monkeys.
AB  - Duration-discrimination thresholds of the silent interval (gap) between two
      successive tones (markers) were measured in four Japanese monkeys. The task was
      serial discrimination, and monkeys were required to release the lever when the
      gap duration decreased from 200 ms. Monkeys successfully acquired the task, and
      gap thresholds of monkeys were revealed to be larger than previous data with
      human subjects. Gap thresholds were not affected by marker frequency when the two
      markers were identical in frequency, though the thresholds increased when large
      frequency differences existed between markers. The effect of marker frequency
      disparity on gap thresholds in monkeys is discussed in terms of the difficulty in
      integrating information from discrete frequency channels.

PMID- 10664786
TI  - Seeing big things: overestimation of heights is greater for real objects than for
      objects in pictures.
AB  - In six experiments we demonstrate that the vertical-horizontal illusion that is
      evoked when viewing photographs and line drawings is relatively small, whereas
      the magnitude of this illusion when large objects are viewed is at least twice as
      great. Furthermore, we show that the illusion is due more to vertical
      overestimation than horizontal underestimation. The lack of a difference in
      vertical overestimation between pictures and line drawings suggests that vertical
      overestimation in pictures depends solely on the perceived physical size of the
      projection on the picture surface, rather than on what is apparent about an
      object's represented size. The vertical-horizontal illusion is influenced by
      perceived physical size. It is greater when viewing large objects than small
      pictures of these same objects, even when visual angles are equated.

PMID- 10664787
TI  - The myth of upright vision. A psychophysical and functional imaging study of
      adaptation to inverting spectacles.
AB  - The adaptation to inverting prisms and mirror spectacles was studied in four
      subjects over periods of six to ten days. Subjects showed rapid adaptation of
      visuomotor functions, but did not report return of upright vision. The
      persistence of the transformed visual image was confirmed by the subjects'
      perception of shape from shading. No alteration of the retinotopy of early visual
      cortical areas was seen in the functional magnetic resonance images. These
      results are discussed in the context of previous claims of upright vision with
      inverting prisms and mirror spectacles.

PMID- 10664788
TI  - Viewpoint-dependent recognition of familiar faces.
AB  - The question whether object representations in the human brain are object
      centered or viewer-centered has motivated a variety of experiments with divergent
      results. A key issue concerns the visual recognition of objects seen from novel
      views. If recognition performance depends on whether a particular view has been
      seen before, it can be interpreted as evidence for a viewer-centered
      representation. Earlier experiments used unfamiliar objects to provide the
      experimenter with complete control over the observer's previous experience with
      the object. In this study, we tested whether human recognition shows viewpoint
      dependence for the highly familiar faces of well-known colleagues and for the
      observer's own face. We found that observers are poorer at recognizing their own
      profile, whereas there is no difference in response time between frontal and
      profile views of other faces. This result shows that extensive experience and
      familiarity with one's own face is not sufficient to produce viewpoint
      invariance. Our result provides strong evidence for viewer-centered
      representations in human visual recognition even for highly familiar objects.

PMID- 10664789
TI  - More about brows: how poses that change brow position affect perceptions of
      gender.
AB  - The speeded categorisation of gender from photographs of men's and women's faces
      under conditions of vertical brow and vertical head movement was explored in two
      sets of experiments. These studies were guided by the suggestion that a simple
      cue to gender in faces, the vertical distance between the eyelid and brow, could
      support such decisions. In men this distance is smaller than in women, and can be
      further reduced by lowering the brows and also by lowering the head and raising
      the eyes to camera. How does the gender-classification mechanism take changes in
      pose into account? Male faces with lowered brows (experiment 1) were more quickly
      and accurately categorised (there was little corresponding 'feminisation' of
      raised-brow faces). Lowering gaze had a similar effect, but failed to interact
      with head lowering in a simple manner (experiment 2). We conclude that the
      initial classification of gender from the facial image may not involve
      normalisation of the face image to a canonical state (the 'mug-shot view') for
      expressive pose (brow movement and direction of gaze). For head pose (relative
      position of the features when the face is not viewed head-on), normalisation
      cannot be ruled out. Some perceptual mechanisms for these effects, and their
      functional implications, are discussed.

PMID- 10664790
TI  - Preferences in quadrangles reconsidered.
AB  - Through about 130 years of the history of experimental aesthetics, preferences of
      figures have been summarized in representative values such as the golden ratio.
      Researches especially in the golden-section hypothesis overshadowed the basic and
      profound problem of how people's individual preference would be decided. In the
      present study I returned to simple quadrangles, and investigated each person's
      subjective preferences by a production method, recording eye movements, and
      having qualitative interviews. Two basic scanning patterns on quadrangles emerged
      through the analysis of eye movements, and more complicated patterns were made by
      various combinations of these two. The distribution of subjects' preferred
      proportions showed that squares and square-like quadrangles were chosen most
      frequently, although the average of height/width ratios came close to the golden
      ratio in most quadrangle types. The results of interviews revealed various
      characteristics of decision processes of preferred shapes in the subjects. A
      discussion is provided on dealing with the golden ratio, and the importance of
      studying subjects' processes of preferences is proposed for the future of
      empirical aesthetics.

PMID- 10664791
TI  - Selective peripheral fading: evidence for inhibitory sensory effect of attention.
AB  - A circular array of six discs, three green and three orange in alternate
      positions, was presented against a uniform grey background. Sixteen observers
      maintained steady fixation at the centre of the array, and were instructed to
      direct their attention to three discs of one colour and to ignore the three discs
      of the other colour. In about 10 s (mean = 11.35 s), some discs started to fade
      away from awareness. Of those starting to fade, most (mean = 81.3%) were those
      selected for attention. The faded discs remained out of awareness for up to a few
      seconds (mean = 1.55 s) during which other discs were clearly visible. The fading
      increased with eccentricity, a defining characteristic of Troxler fading.
      However, the selectivity of the fading strongly suggests that voluntary attention
      can have an inhibitory effect on early sensory processing. Were the fading
      entirely due to local sensory adaptation, the unattended stimuli would have to be
      equally adapted and yet somehow remain visible for seconds, which is not
      plausible.

PMID- 10664792
TI  - Development of illusory-contour perception in infants.
AB  - We investigated whether infants from 8-22 weeks of age were sensitive to the
      illusory contour created by aligned line terminators. Previous reports of
      illusory-contour detection in infants under 4 months old could be due to infants'
      preference for the presence of terminators rather than their configuration. We
      generated preferential-looking stimuli containing sinusoidal lines whose
      oscillating, abutting terminators give a strong illusory contour in adult
      perception. Our experiments demonstrated a preference in infants 8 weeks old and
      above for an oscillating illusory contour compared with a stimulus containing
      equal terminator density and movement. Control experiments excluded local line
      density, or attention to alignment in general, as the basis for this result. In
      the youngest age group (8-10 weeks) stimulus velocity appears to be critical in
      determining the visibility of illusory contours, which is consistent with other
      data on motion processing at this age. We conclude that, by 2 months of age, the
      infant's visual system contains the nonlinear mechanisms necessary to extract an
      illusory contour from aligned terminators.

PMID- 10664793
TI  - Carnitine acyltransferases: functional significance of subcellular distribution
      and membrane topology.

PMID- 10664794
TI  - Physiological specialisation of adipose tissue.

PMID- 10664795
TI  - Mechanisms of action of phospholipid analogs as anticancer compounds.

PMID- 10664796
TI  - Specific versus non-specific effects of dietary fat on carcinogenesis.
AB  - It will be apparent from this review that dietary fat can exert both specific and
      non-specific effects on carcinogenesis, at least in experimental animals. The non
      specific effects appear to be related primarily to effects of dietary fat on
      energy balance. Although a positive energy balance can be achieved on a high
      carbohydrate low-fat diet, it is much more likely to occur on a high-fat diet
      because of the high energy density of fat [101] and the fact that dietary fat is
      less capable of imparting a sense of satiety [102]. A continuing state of
      positive energy balance leads to obesity which has been associated with increased
      risk of cancer at a number of sites, including endometrium [103-106],
      postmenopausal breast cancer [107-113], renal cancer [114,115] and possibly
      cancers of the colorectum [116-122], pancreas [103,123] and prostate [124].
      Whereas the non-specific effects of dietary fat appear to be deleterious for
      cancer, the specific effects in some cases can be beneficial. Examples are long
      chain n-3 polyunsaturated fatty acids. CLA and tocotrienols. It is still too
      early to predict whether these may be of value in the prevention and/or treatment
      of human cancer but they seem worthy of further investigation. Knowledge of their
      mechanism of action may suggest novel approaches to the cancer problem and, as in
      the case of vitamins A and D, it may be possible to find analogues with more
      potent anti-cancer activity.

PMID- 10664797
TI  - Electrophysiological evidence for an early attentional mechanism in visual
      processing in humans.
AB  - The effect of sustained spatial attention on a task-irrelevant grating displayed
      in the left visual field was studied by steady-state and transient visual evoked
      potentials (VEP). For the steady-state experiment, the task irrelevant grating
      was phase-reversed at different temporal frequencies. In the transient experiment
      the grating was reversed abruptly at low temporal frequency. In both conditions a
      target requiring visual attention was presented either in the left or in the
      right visual field, directing attention either to the left or to the right. VEPs
      amplitude enhancement by attention was observed on steady-state VEPs and on P100
      and N140 transient VEPs components, confirming previous observations. Moreover,
      VEPs in the attended condition had shorter latency than VEPs in the unattended
      condition. The difference was about 15 ms with steady-state; with transient
      recording the lag was 7 ms for N60 and 10 ms for P100. The latency change of the
      N60 component, suggests that the modulation of attention on visual processing
      might be earlier than previously thought. A control experiment to assess the
      influence of eye movements on the test was also performed.

PMID- 10664798
TI  - Quantitative estimations of foveal and extra-foveal retinal circuitry in humans.
AB  - For an understanding of the basis for psychophysical measurement of visual
      resolution, quantitative morphological studies of retinal neuronal architecture
      are needed. Here we report on cell densities and retinal ganglion cell:cone ratio
      (RGC:C) from the foveal border to the peripheral retina (34 degrees
      eccentricity). Quantitative estimates of RGC and C densities were made using a
      modified disector method in three vertically sectioned human retinae and were
      adjusted for RGC displacement. In agreement with our previous data on humans, we
      found an RGC:C ratio close to 3 at 2-3 degrees eccentricity. Outside the foveal
      border, the ratio declined to 1.0 at 7.5 degrees eccentricity and to 0.5 at
      eccentricities larger than 19 degrees. Center-to-center separation of C and RGC
      in addition to center-to-center separation of estimated 'receptive fields' was
      calculated at corresponding locations along the superior and inferior
      hemimeridians. The center-to-center separation of estimated 'receptive fields'
      was found to be more closely related to resolution thresholds from the fovea to
      19 degrees eccentricity than was the separation of RGC and C. On the basis of
      these quantitative estimates, models for neural circuitry involved in central and
      peripheral spatial vision can be discussed.

PMID- 10664799
TI  - Non-veridical size perception of expanding and contracting objects.
AB  - Observers were presented with various types of stimulus expansion and contraction
      which resulted in marked misperceptions of size. Firstly, the perceived size of
      an object which is changing in size is shown to be biased in the direction of the
      size change. Secondly, expansion or contraction of the internal texture of
      objects is found to influence their perceived size. Finally, an illusory texture
      manipulation in the form of a movement after-effect is shown to produce the same
      type of size misperception as a real expansion or contraction of internal
      texture. The spatio-temporal characteristics of these illusory size changes are
      investigated.

PMID- 10664800
TI  - Second-site adaptation in the red-green detection pathway: only elicited by low
      spatial-frequency test stimuli.
AB  - The red-green (RG) detection mechanism was revealed by measuring threshold
      detection contours in the L and M cone contrast plane for sine-wave test gratings
      of 0.8-6 c deg-1 on bright adapting fields of yellow or red. The slope of the RG
      detection contours was unity, indicating that the L and M contrast signals
      contribute equally (with opposite signs) on both the yellow and the red fields:
      this reflects first-site, cone-selective adaptation. Second-site adaptation,
      which may reflect saturation at a color-opponent site, was evidenced by the RG
      detection contours being further out from the origin of the cone contrast plane
      on the red field than on the yellow field. Second-site adaptation was strong (3
      fold) for low spatial frequency test gratings but greatly diminished by 6 c deg
      1. The disappearance of second-site adaptation with increasing spatial frequency
      can be explained by spatial frequency channels. The most sensitive detectors may
      comprise a low spatial frequency channel which is susceptible to masking by the
      chromatic, spatial DC component of the red field. The 6 c deg-1 patterns may be
      detected by a less sensitive, higher frequency channel which is less affected by
      the uniform red field. The RG spatial frequency channels likely arise in the
      cortex, implicating a partially central site for the second-site effect.

PMID- 10664801
TI  - Afterimages, grating induction and illusory phantoms.
AB  - Under some conditions (dark or light inspection areas) illusory gratings often
      appear to be in-phase with the inducing gratings and under others (gray
      inspection area) illusory gratings often appear to be out-of-phase with the
      inducing gratings. McCourt reported that point-by-point brightness matches reveal
      only out-of-phase illusory gratings, no matter what the luminance of the
      inspection area (McCourt, M. E. (1994). Vision Research, 34, 1609-1617). Since
      the technique used might have led to afterimages which mimic out-of-phase
      illusory gratings, the present series of experiments was undertaken to determine
      how such afterimages might bias illusory grating judgments. Afterimages were
      induced during fixation with brief flashes of inducing gratings within the
      inspection area (Experiment 1), or by vertical shifts in the entire stimulus
      which exposed the retina to real gratings prior to judgments within the
      inspection area (Experiment 2). Experiment 2 was replicated with drifting
      inducing gratings (Experiment 3). The subjects were asked to indicate whether
      illusory gratings appeared in- or out-of-phase. The results of all three
      experiments reveal that out-of-phase illusory gratings predominate, and that
      afterimages can only bias judgments with stationary displays. It is suggested
      that grating induction is perceived when subjects attend to local contrast
      differences, while phantom visibility is facilitated when attention is captured
      by the more global aspects of the stimulus.

PMID- 10664802
TI  - Detection of temporal structure depends on spatial structure.
AB  - Observers can more easily detect correlated patterns of temporal contrast
      modulation within hybrid visual images composed of two components when those
      components are drawn from the same original picture (Blake, R., & Yang, Y.
      (1997). Proceedings of the National Academy of Science, 94, 7115-7119). To learn
      whether spatial phase is a mediating variable, we measured thresholds for
      detection of contrast modulation over time among component gratings while
      manipulating spatial phase among those components. In Experiment 1, observers
      more easily detected correlated contrast modulation when two component gratings
      were aligned in peaks-subtract phase. Experiment 2 showed that this phase
      dependent detectability of synchronized contrast modulation is mediated by the
      phase-dependent, non-linear interaction among spatial frequency channels. The
      rigorous evaluation of several a priori reasonable hypotheses indicates that the
      phase-dependent detectability is not based on local spatial features such as
      local luminance, contrast or luminance gradient. Taken together, our results
      indicate that the spatial phase relationship and the temporal correlation of
      contrast modulation of two component gratings are both important for triggering
      facilitatory interaction between neural analyzers tuned to those gratings.

PMID- 10664803
TI  - Sensitivity to horizontal and vertical corrugations defined by binocular
      disparity.
AB  - Sensitivity to corrugations defined by binocular disparity differs as a function
      of the modulation frequency. Such functions have proved to be useful descriptive
      and analytical tools in the study of the mechanisms involved in disparity
      processing. Indeed, given certain assumptions, these sensitivity functions can be
      used to predict certain perceptual outcomes. Given their importance, it is
      surprising that there is no comprehensive data set of disparity sensitivity
      functions (DSF) for a range of observers over a broad range of spatial
      frequencies and orientations. Here we report DSFs for six observers over an eight
      octave range of sinusoidal corrugations in disparity (0.0125-3.2 cpd). Multi
      cycle, low frequency surfaces were used to assess the degree to which the fall
      off in sensitivity at low corrugation frequencies is attributable to the
      decreasing number of cycles displayed. The data was found to form a continuous
      function despite the different number of cycles displayed. We conclude that the
      fall off in sensitivity is due to the spatial interactions in disparity
      processing. We also determined DSFs for the same observers to both vertically and
      horizontally oriented sinusoidal disparity corrugations in order to characterise
      the extent of the stereoscopic anisotropy. In general, the best thresholds for
      detecting vertically oriented disparity corrugations were higher (approximately 4
      arc sec) than for horizontally oriented corrugations (approximately 2 arc sec).
      Moreover, the functions were shifted toward the high spatial frequency end of the
      spectrum.

PMID- 10664804
TI  - Bias and sensitivity of stereo judgements in the presence of a slanted reference
      plane.
AB  - The perceived depth of features is known to be affected by the presence of a
      slanted reference plane. Mitchison and Westheimer ((1984). Vision Research, 24,
      1063-1070) reported that two lines appear to be at the same depth when they lie
      in a plane approximately parallel with the reference plane. We measured the
      perceived depth of two lines presented in front of a regular grid of dots that
      was either fronto-parallel or slanted about a vertical axis. The effect of the
      slanted grid on perceived depth diminished as the grid was moved further in
      disparity from the lines. We also found that the slanted grid affected the
      sensitivity to differences in disparity. The minimum threshold for detecting
      changes in disparity is normally lowest in the fixation plane and rises
      systematically with increasing pedestal disparity. In the presence of a slanted
      reference plane, the minimum threshold is at or close to the plane of equal
      perceived depth and rises with increasing disparity from this plane.

PMID- 10664805
TI  - The visual physiology of the wild type mouse determined with pattern VEPs.
AB  - Genetically manipulated mice are important tools for studies on plasticity and
      degeneration/regeneration in the visual system. However, a description of the
      basic properties of the visual performance of the wild type mouse is still
      lacking. To characterize the visual physiology of the wild type (C57BL/6J) mouse
      we recorded Visual Evoked Potentials (VEPs) from the primary visual cortex. As
      compared to behavioral methods, VEPs may have the advantage that different
      aspects of vision can be screened readily and simultaneously in the same animals,
      including those with poor visual behavior due to motor or learning deficits.
      Local VEP responses to patterned visual stimuli have been recorded from the
      binocular visual cortex of anesthetized mice. Spatial (visual acuity, contrast
      threshold) and temporal (temporal function, response latency, motion sensitivity)
      aspects of VEPs were evaluated. The mouse VEP acuity was 0.6 c/deg, which is
      comparable to the behavioral visual acuity. The VEP peak contrast threshold was
      5% (no behavioral data are available). Cortical representation of visual
      coordinates and cortical magnification factor corresponded to those previously
      reported using single cell recordings. Laminar analysis of VEPs indicated a
      dipole source in the supragranular layers of the visual cortex as a major
      response generator. VEPs showed contribution from both eyes, although biased
      strongly towards the eye contralateral to the recorded cortex. Results provide a
      comprehensive framework for characterizing visual phenotypes of a variety of
      transgenic mice.

PMID- 10664806
TI  - The effect of slant on visuomotor localization.
AB  - Visuomotor localization in the presence of slant was measured. Five subjects
      pointed at the center LED of an array of five LEDs viewed monocularly. Pointing
      was open-loop. The LEDs were separated by 1.5, 3.0, or 4.5 cm. The array was
      rotated about a vertical axis coincident with the center LED to slant the array
      from -50 degrees to +50 degrees. LED separation had no effect. A small linear
      relationship was found between errors in localization and slant (slope = -0.02).
      The errors were as expected if the perceived straight ahead was in the direction
      of the normal to the surface, but these errors were so small as to be
      functionally insignificant. It is concluded that extraretinal eye position
      information dominates over slant for visuomotor localization.

PMID- 10664807
TI  - Gaze-shift dynamics in subjects with and without symptoms of convergence
      insufficiency: influence of monocular preference and the effect of training.
AB  - We studied gaze-shift dynamics during several gaze-shift tasks and during
      reading, in five subjects with convergence insufficiency (C.I., a diminished
      ability to converge), and in ten subjects without C.I. Furthermore, we studied
      the effect of vergence training in order to verify previous claims that orthoptic
      exercises can improve vergence performance. We recorded binocular eye movements
      with the scleral coil technique. Subjects switched fixation between nearby and
      distant light emitting diodes (LEDs) arranged in isovergence arrays (distances 35
      and 130 cm) in a dimly lit room. In both the C.I. and non-C.I. group, two classes
      of subjects occurred: vergence responders and saccadic responders. During pure
      vergence tasks, saccadic responders made saccades with no or little vergence;
      vergence responders made vergence movements with no or small saccadic components.
      In saccadic responders, fixation of nearby targets was monocular. Subjects with a
      preferred eye, according to our determination, used the preferred eye. The five
      C.I. subjects showed idiosyncratic responses with insufficient vergence during
      most trials. They all had a tendency to alternate fixation between the left and
      right eye. Vergence-version tasks always elicited larger vergence components than
      pure vergence tasks. During a reading task, vergence angles were more accurate
      than during gaze-shifts between LEDs. After the pre-training sessions, nine
      subjects (one of which had C.I.) practised a pure vergence task three times a day
      for at least 2 weeks. Vergence amplitudes of four of these subjects were larger
      after training. We conclude that vergence training can change oculomotor
      performance. Although C.I. is often associated with abnormal vergence dynamics,
      there are no typical C.I. vergence dynamics. Unstable monocular preferences may
      play a role in the aetiology of C.I.

PMID- 10664808
TI  - Saccade amplitude disconjugacy induced by aniseikonia: role of monocular depth
      cues.
AB  - The conjugacy of saccades is rapidly modified if the images are made unequal for
      the two eyes. Disconjugacy persists even in the absence of disparity which
      indicates learning. Binocular visual disparity is a major cue to depth and is
      believed to drive the disconjugacy of saccades to aniseikonic images. The goal of
      the present study was to test whether monocular depth cues can also influence the
      disconjugacy of saccades. Three experiments were performed in which subjects were
      exposed for 15-20 min to a 10% image size inequality. Three different images were
      used: a grid that contained a single monocular depth cue strongly indicating a
      frontoparallel plane; a random-dot pattern that contained a less prominent
      monocular depth cue (absence of texture gradient) which also indicates the
      frontoparallel plane; and a complex image with several overlapping geometric
      forms that contained a variety of monocular depth cues. Saccades became
      disconjugate in all three experiments. The disconjugacy was larger and more
      persistent for the experiment using the random-dot pattern that had the least
      prominent monocular depth cues. The complex image which had a large variety of
      monocular depth cues produced the most variable and less persistent disconjugacy.
      We conclude that the monocular depth cues modulate the disconjugacy of saccades
      stimulated by the disparity of aniseikonic images.

PMID- 10664809
TI  - A neural model of saccadic eye movement control explains task-specific
      adaptation.
AB  - Multiple brain learning sites are needed to calibrate the accuracy of saccadic
      eye movements. This is true because saccades can be made reactively to visual
      cues, attentively to visual or auditory cues, or planned in response to memory
      cues using visual, parietal, and prefrontal cortex, as well as superior
      colliculus, cerebellum, and reticular formation. The organization of these sites
      can be probed by displacing a visual target during a saccade. The resulting
      adaptation typically shows incomplete and asymmetric transfer between different
      tasks. A neural model of saccadic system learning is developed to explain these
      data, as well as data about saccadic coordinate changes.

PMID- 10664810
TI  - Three-dimensional shape and two-dimensional surface reflectance contributions to
      face recognition: an application of three-dimensional morphing.
AB  - We measured the three-dimensional shape and two-dimensional surface reflectance
      contributions to human recognition of faces across viewpoint. We first divided
      laser scans of human heads into their two- and three-dimensional components.
      Next, we created shape-normalized faces by morphing the two-dimensional surface
      reflectance maps of each face onto the average three-dimensional head shape and
      reflectance-normalized faces by morphing the average two-dimensional surface
      reflectance map onto each three-dimensional head shape. Observers learned frontal
      images of the original, shape-normalized, or reflectance-normalized faces, and
      were asked to recognize the faces from viewpoint changes of 0, 30 and 60 degrees.
      Both the three-dimensional shape and two-dimensional surface reflectance
      information contributed substantially to human recognition performance, thus
      constraining theories of face representation to include both types of
      information.

PMID- 10664812
TI  - [Parenchymal-stromal interactions in gastric mucosa of patients with indolent
      ulcers].
AB  - The aim of the study was to investigate the development and progress of indolent
      gastric ulcers. Historical and morphometric data were obtained characterizing
      different stages of chronic inflammation in periulcerative region. In indolent
      gastric ulcers the reduction of macrophages, plasmocytes and intraepithelial
      lymphocytes number was revealed. Epithelio-stromal-vascular correlations in the
      stomach mucosa can be used as structural criteria for prognosis of chronic ulcer
      healing.

PMID- 10664811
TI  - [100th Anniversary of the Department of Pathological Anatomy of the I. P. Pavlov
      St. Petersburg State Medical University].
AB  - Historical review is presented of the development of pathology department which
      was founded in 1899 at the Ladies Medical Institute in St-Petersburg. The heads
      of the department were private-docent N. F. Vinogradov, professor G. V. Shor,
      academician V. G. Garshin, professor M. A. Zakharievskaya, professor T. B.
      Zhuravleva. The activity of the department in teaching, science and diagnosis is
      described. The difficulties and successful periods in history (before and after
      the revolution, during the wars, after the last war) and present-day activities
      are characterized.

PMID- 10664813
TI  - [Morphofunctional characteristics of human immune system in surgical stress].
AB  - Morphofunctional aspects of the immune system (spleen, Peyer's patches,
      peripheral blood) were studied in patients with essential hypertension, rheumatic
      lesions of the heart and rheumatic patients after surgery. Surgical intervention
      caused considerable immunodepression. The entire system of coordinated
      functioning of immune organs got impaired. Immunodepressive restructuring of
      lymphoid organs affects all the structural units. Changes of the vascular-stromal
      complex are accompanied by changes in the most sensitive and complex mechanisms
      of the immune system such as vascular endothelium and population of progenitor
      cells. Metabolic basis transport and synthesis in the endothelium are perversed.
      In the progenitor cells proliferative activity of lymphocytes was sharply
      decreased while there was an increase in the function of suppressor T
      lymphocytes. It is concluded that desynchronization of enzyme functioning in the
      vascular component of both the spleen and lymphoid system of the intestine can be
      regarded as a sign of disintegration of the entire system of immune organs during
      stress caused by a surgical intervention.

PMID- 10664814
TI  - [About postmortem changes in the pancreas].
AB  - Postmortem changes in the pancreas of 23 patients who had died of cardiovascular
      and tumor pathology were studied with light microscopy and histochemical methods.
      Pancreatic tissue was obtained within 1, 2, 4, 6, 12, 24 hours after biological
      death. General features of postmortem changes were established and also some
      special aspects relevant to intravital and terminal period were defined. The
      results of the examination allow to make the conclusion on possibility of
      postmortem studying of the pancreas on the material of early autopsies.

PMID- 10664815
TI  - [Technological process of biopsy investigation in the department of clinical
      pathology].
AB  - The history of biopsy taking and examination as well as all the technology of
      biopsy processing is reviewed. All the parts of this chain are considered from
      the practical point of view with recommendations acceptable for the majority of
      pathomorphological laboratories.

PMID- 10664816
TI  - [Clinikomorphological features of complicated colon diverticulosis].
AB  - 79 surgical and postmortem cases of colon diverticulosis with complications were
      studied clinicomorphologically. Sequence in the development of inflammatory
      complications was revealed: diverticulum perforation-peridiverticulitis
      pericolitic infiltrate, sometimes with the abscess-fistula. Segmental colitis may
      join the process. The complications onset depends mainly on discoordination of
      the intestinal peristalsis and intramural vascular deficiency.

PMID- 10664817
TI  - [Morphological features of cancer in chronic non-specific ulcerative colitis].
AB  - 27 cases of colon carcinoma developing in non-specific ulcerative colitis are
      studied. High risk of carcinoma diagnosis is shown if the duration of the disease
      is more than 20 years. The majority of the tumors were moderately differentiated
      adenocarcinomas originating from zones of growth at the crypt bottoms in the
      presence of considerable dysplasia.

PMID- 10664818
TI  - [Neuroendocrine tumors of pancreas (clinicomorphological, immunohistochemical and
      electron microscopic study)].
AB  - Neuroendocrine tumors of the pancreas were studied by histology,
      immunohistochemistry and electron microscopy. Tumors associated with organic
      hyperinsulinism showed heterogeneity in their ultrastructure, functional and
      proliferation activity. More than half of these tumors are multihormonal and 15%
      of them developed from polypotent cells which are capable for several types of
      differentiation.

PMID- 10664819
TI  - [Surface malignancy osteosarcoma].
AB  - Clinico-roentgeno-morphological characteristics of superficial osteosarcoma of a
      high-grade malignancy which is again included into the classification of bone
      tumors are given. A 34-year-old female with such tumor in distal metaphysis of
      the femur is reported.

PMID- 10664820
TI  - [Preeclampsia of pregnant women complicated by HELLP syndrome].
AB  - One case of a Hell syndrome in a female of 22 with gestational eclampsism is
      described. The syndrome seemed to develop 2 weeks before hospitalization and
      manifested with brain hemorrhage followed by obstruction of liquor spaces.
      Morphologically, HELL syndrome was characterized by multilobular liver necrosis,
      hemoglobinurea nephrosis and pronounced hemorrhagic diathesis.

PMID- 10664821
TI  - [Xanthogranulomatous pyelonephritis: morphological characteristics 10 cases].
AB  - Surgical material (10 cases) included 7 cases of diffuse and 3 cases of nodular
      or tumor-like forms of the disease. Criteria for differential diagnosis with
      renal carcinoma which can develop, in some cases, against the background of
      xanthogranulomatous pyelonephritis are presented.

PMID- 10664822
TI  - [History of the rise of pathological anatomy].

PMID- 10664823
TI  - [Healthy life style and quality of life. Some of their principles and paradoxes].

PMID- 10664824
TI  - While a phobic waits: regional brain electrical and autonomic activity in social
      phobics during anticipation of public speaking.
AB  - BACKGROUND: Recent studies have highlighted the role of right-sided anterior
      temporal and prefrontal activation during anxiety, yet no study has been
      performed with social phobics that assesses regional brain and autonomic
      function. This study compared electroencephalograms (EEGs) and autonomic activity
      in social phobics and controls while they anticipated making a public speech.
      METHODS: Electroencephalograms from 14 scalp locations, heart rate, and blood
      pressure were recorded while 18 DSM-IV social phobics and 10 controls anticipated
      making a public speech, as well as immediately after the speech was made. Self
      reports of anxiety and affect were also obtained. RESULTS: Phobics showed a
      significantly greater increase in anxiety and negative affect during the
      anticipation condition compared with controls. Heart rate was elevated in the
      phobics relative to the controls in most conditions. Phobics showed a marked
      increase in right-sided activation in the anterior temporal and lateral
      prefrontal scalp regions. These heart rate and EEG changes together accounted for
      > 48% of the variance in the increase in negative affect during the anticipation
      phase. CONCLUSIONS: These findings support the hypothesis of right-sided anterior
      cortical activation during anxiety and indicate that the combination of EEG and
      heart rate changes during anticipation account for substantial variance in
      reported negative affect.

PMID- 10664825
TI  - SPECT [I-123]iomazenil measurement of the benzodiazepine receptor in panic
      disorder.
AB  - BACKGROUND: Alterations in benzodiazepine receptor function have long been
      hypothesized to play a role in anxiety. Animal models of anxiety involving
      exposure to chronic stress have shown a specific decrease in benzodiazepine
      receptor binding in frontal cortex and hippocampus. The purpose of this study was
      to examine benzodiazepine receptor binding patients with panic disorder and
      comparison subjects. METHODS: A quantitative measure related to benzodiazepine
      receptor binding (Distribution Volume (DV)) was obtained with single photon
      emission computed tomography (SPECT) imaging of [123I]iomazenil and measurement
      of radioligand concentration in plasma in patients with panic disorder and
      healthy controls. DV image data were analyzed using statistical parametric
      mapping (spm96). RESULTS: A decrease in measures of benzodiazepine receptor
      binding (DV) was found in left hippocampus and precuneus in panic disorder
      patients relative to controls. Panic disorder patients who had a panic attack
      compared to patients who did not have a panic attack at the time of the scan had
      a decrease in benzodiazepine receptor binding in prefrontal cortex. CONCLUSIONS:
      Findings of a decrease in left hippocampal and precuneus benzodiazepine receptor
      binding may be related to alterations in benzodiazepine receptor binding, or
      other factors including changes in GABAergic transmission or possible endogenous
      benzodiazepine compounds. Benzodiazepine receptor function in prefrontal cortex
      appears to be involved in changes in state-related panic anxiety.

PMID- 10664826
TI  - Behavioral and endocrine response to cholecystokinin tetrapeptide in patients
      with posttraumatic stress disorder.
AB  - BACKGROUND: Given the relationship between posttraumatic stress disorder (PTSD)
      and panic, it was of interest to examine whether panic provoking agents affect
      PTSD symptoms. We therefore investigated the behavioral and endocrine response of
      PTSD patients to the panicogen cholecystokinin tetrapeptide (CCK-4). METHODS:
      Eight patients with PTSD (DSM-IV) received 50 micrograms CCK-4 intravenously in a
      placebo-controlled, double-blind balanced design. Provocation of panic, anxiety,
      and flashbacks was assessed. Plasma adrenocorticotropin (ACTH) and cortisol
      levels after CCK-4 were measured and compared to healthy subjects matched for
      age, gender, and provoked symptoms. RESULTS: Despite significant effects of CCK-4
      on anxiety and panic symptoms, no significant provocation of flashbacks emerged.
      CCK-4-induced panic symptoms showed an inverse correlation to trait dissociation.
      The ACTH response after CCK-4 was significantly lower in PTSD patients than in
      controls. Cortisol was similarly increased in both groups after CCK-4, but PTSD
      patients showed a more rapid decrease of stimulated cortisol concentrations.
      CONCLUSIONS: Panic symptoms or heightened anxiety are not necessarily conditioned
      stimuli for the provocation of posttraumatic flashbacks. Further studies in PTSD
      with different panicogens should be controlled for the potential interference of
      trait dissociation. Our hormone data show further evidence for a corticotropin
      releasing hormone (CRH) overdrive and enhanced negative glucocorticoid feedback
      in PTSD patients.

PMID- 10664827
TI  - Eye deviation during rotation in darkness in trait anxiety: an early expression
      of perceptual avoidance?
AB  - BACKGROUND: Patients with dizziness and patients with panic disorder and
      agoraphobia share a common symptomatology. Numerous studies have investigated a
      potential link between anxiety and the vestibular system, but few of them have
      addressed the specific topic of spatial representation. METHODS: Passive whole
      body rotations in the horizontal plane were imposed on two groups of subjects who
      differed in their level of trait anxiety. Subjects were seated on a mobile robot
      in darkness. After each passive rotation, subjects were asked to reproduce the
      stimulus by driving the robot with a joystick and to perform a rotation of the
      same magnitude. Eye movements were recorded and analyzed. RESULTS: No difference
      in either perception (accuracy in the reproduction task) or in VOR gain was found
      between the two groups of subjects. Mean eye deviation, caused by fast phases of
      the nystagmus, differed in the two groups. It was typically in the
      anticompensatory direction in the non-anxious group, and in the compensatory
      direction the anxious group. Such compensatory movement may be explained by an
      egocentric orientation strategy, that may in turn indicate a lack of interest
      toward the visual surroundings. CONCLUSIONS: An egocentric strategy for self
      orientation exhibited at a level below the threshold of awareness could reveal
      the existence of a physiological mode of processing leading to agoraphobic
      avoidance.

PMID- 10664828
TI  - Early social deprivation in nonhuman primates: long-term effects on survival and
      cell-mediated immunity.
AB  - BACKGROUND: Early differential social experience of non-human primates has
      resulted in long-term alterations in behavior and neurobiology. Although brief
      maternal separation has been associated with changes in immune status, the long
      term effects on survival and immune function of prolonged early social
      deprivation are unknown. METHODS: Survival rates were examined in rhesus monkeys,
      half of which had been socially deprived during their first year of life.
      Repeated measures of immune status were tested in surviving monkeys (18-24 years
      old). Peripheral blood T, B, and natural killer lymphocytes, macrophages, and
      monocytes were measured by flow cytometry. Functional cellular immune activity
      measures included T-cell proliferative responses to mitogens (concanavalin and
      phytohemagglutinin), T-cell memory response to tetanus toxoid antigen, T-cell
      dependent B-cell proliferative responses to mitogen (PWM) and natural killer cell
      cytotoxic activity. RESULTS: Despite identical environments following isolation,
      early social deprivation resulted in a significantly decreased survival rate,
      males being particularly vulnerable to early death. Early social deprivation was
      associated with a decrease in the ratio of helper to suppressor T cells, and a
      significant increase in natural killer cell number and in natural killer cell
      activity in the surviving monkeys. No differences in T- or B-lymphocyte
      proliferation following mitogen or tetanus toxoid antigen stimulation were
      observed. CONCLUSIONS: Prolonged early social deprivation of non-human primates
      profoundly affected mortality and resulted in lifelong effects on cell-mediated
      immune status.

PMID- 10664829
TI  - Long-lasting effects of (+/-)3,4-methylenedioxymethamphetamine (ecstasy) on
      serotonin system function in humans.
AB  - BACKGROUND: Fifteen (+/-)3,4-Methylenedioxymethamphetamine (MDMA) users, who did
      not show other drug dependencies or prolonged alcohol abuse, and 15 control
      subjects were included in the study. METHODS: Prolactin (PRL) and cortisol (CORT)
      responses to the serotonergic agonist d-fenfluramine (D-fen), clinical
      psychobehavioral changes, and psychometric measures were evaluated 3 weeks and
      then 12 months after MDMA discontinuation. RESULTS: MDMA users showed
      significantly reduced PRL and CORT responses in comparison with control subjects
      at 3 weeks (respectively, p < .001; p < .005). The responses of PRL to D-fen were
      unmodified at 12 months after prolonged abstinence and were significantly reduced
      in comparison with controls (p < .001). In contrast, CORT responses in MDMA users
      were restored after 12 months of abstinence, with significantly higher responses
      to D-fen, in comparison with 3-week responses (p < .05). MDMA users' high scores
      on the Novelty Seeking (NS) scale on the Tridimensional Personality Questionnaire
      (TPQ) appeared unchanged by long-term abstinence. In contrast, Buss Durkee
      Hostility Inventory (BDHI) (Buss and Durkee 1957) direct and guilt scores
      decreased significantly after 12 months of abstinence. PRL AUCs at 12 months were
      inversely correlated with the measures of MDMA exposure (r = -.538). CONCLUSIONS:
      Our data indicate long-lasting 5-HT system impairment in abstinent MDMA users
      although the hypothesis of serotonergic changes attributable to a premorbid
      condition cannot be excluded. CORT restored responses to D-fen at 12 months, and
      the correlation of neuroendocrine changes with MDMA exposure suggest that the
      neuroendocrine impairment may be due to a partially reversible neurotoxic action
      of MDMA on the human brain.

PMID- 10664830
TI  - Dissociation of ketamine effects on rule acquisition and rule implementation:
      possible relevance to NMDA receptor contributions to executive cognitive
      functions.
AB  - BACKGROUND: The demands of the Wisconsin Card Sorting Test (WCST) change with
      experience. This report contains two studies designed to examine N-methyl-D
      aspartate (NMDA) receptor contributions to the executive components of WCST
      performance. These aspects of WCST performance figure more prominently in the
      initial completion of this task than in subsequent task repetitions in healthy
      populations. METHODS: In the first study, healthy subjects (n = 15) completed the
      WCST on two occasions separated by 1 week. In the second study, healthy subjects
      (n = 22) completed two test days spaced by approximately 1 week, during which,
      they completed the WCST and other assessments after administration of the NMDA
      antagonist ketamine (intravenous bolus 0.26 mg/kg followed by infusion of 0.65
      mg/kg/hour) or matched placebo. RESULTS: In the first study, subjects reduced the
      number of total and perseverative errors with a single repetition of the WCST. In
      the second study, ketamine significantly increased the number of total errors and
      the number and percent of perseverative errors on the first, but not the second
      test day. Similarly, it reduced the number of category criteria met on the first,
      but not second test day. Ketamine also increased distractibility, impaired
      recall, produced psychosis, altered perception, and had effects resembling the
      negative symptoms of schizophrenia. However, only WCST performance showed order
      dependency. CONCLUSIONS: This order dependency further implicates NMDA receptors
      in executive cognitive functions associated with the frontal cortex.

PMID- 10664831
TI  - Dehydroepiandrosterone sulfate and psychiatric measures in a frail, elderly
      residential care population.
AB  - BACKGROUND: Previous reports have found low levels of dehydroepiandrosterone
      sulfate (DHEA-S) in association with physical illness, and with frailty in the
      elderly. In a preliminary study, we also found low DHEA-S associated with
      increased disability and number of pain sites. However, we found the opposite
      relationship between DHEA-S and cognitive impairment. Therefore, we conducted a
      study of a second sample to confirm this unexpected finding and the expected
      inverse correlations between DHEA-S levels and increased disability and number of
      pain sites. METHODS: Psychiatric symptoms and disorders were correlated with DHEA
      S and related steroid levels in a second convenience sample in the nursing home
      population. RESULTS: This sample confirmed the previous finding of a positive
      association of cognitive impairment with higher DHEA-S levels but the inverse
      association of DHEA-S levels with the numbers of pain sensations did not reach
      statistical significance. Cognitive impairment was also positively associated
      with higher dehydroepiandrosterone (DHEA) and estradiol levels (women only).
      Cortisol levels were inversely associated with depressive symptoms. CONCLUSIONS:
      The anomalous positive correlation between cognitive dysfunction and DHEA-S
      levels, and the inverse correlation between cortisol levels and depressive
      symptoms, suggests that the relationships between psychiatric symptomatology and
      levels of steroids that are part of the hypothalamic-pituitary adrenal axis are
      different in the frail elderly population from that of younger and heartier
      populations.

PMID- 10664832
TI  - Effects of acute tryptophan depletion on mood in bulimia nervosa.
AB  - BACKGROUND: The present study investigated the role of serotonin in the
      pathophysiology of bulimia nervosa (BN) by studying the affective and appetitive
      responses of women ill with BN to an acute tryptophan depletion (ATD) paradigm.
      METHODS: Twenty-two women with BN and 16 healthy control women (CW) were studied
      on 2 separate days during the follicular stage of the menstrual cycle.
      Participants drank a control mix of essential amino acids (100 g + 4.6 g
      tryptophan) on one day and a tryptophan deficient (100 g - 4.6 g tryptophan)
      mixture (ATD) on the other in a double-blind fashion. Mood/appetite ratings and
      blood samples were taken at baseline and at intervals up to 420 minutes.
      Participants were then presented with an array of foods and were allowed to binge
      and vomit if they desired. RESULTS: CW and BN women had a similar and significant
      reduction in plasma tryptophan levels and the tryptophan: LNAA ratio after ATD.
      After ATD, the BN women had a significantly greater increase in peak (minus
      baseline) depression, mood lability, sadness and desire to binge compared to the
      CW. BN subjects and CW had similar peak changes in mood after the control amino
      acid mixture. BN subjects and CW consumed similar amounts of food after the two
      amino acid treatments. CONCLUSIONS: Women with BN seem more vulnerable to the
      mood lowering effects of ATD, suggesting they have altered modulation of central
      5-HT neuronal systems.

PMID- 10664833
TI  - Seasonal variation of availability of serotonin transporter binding sites in
      healthy female subjects as measured by [123I]-2 beta-carbomethoxy-3 beta-(4
      iodophenyl)tropane and single photon emission computed tomography.
AB  - BACKGROUND: Previous studies have indicated annual variations in central and
      peripheral serotonergic activity. In the present study we studied five women in
      summer and six women in winter and evaluated possible differences in availability
      of brain serotonin transporters between summer and winter. METHODS: We employed
      the single photon emission computed tomography ligand [123I]-2 beta-carbomethoxy
      3 beta-(4-iodophenyl)tropane ([123I] beta-CIT) to visualize binding to the
      serotonin transporter site in the human thalamus/hypothalamus midbrain area in
      vivo. Brain imaging studies were performed in one group between May and August
      and in the other between November and December. RESULTS: We found significant
      differences in displaceable [123I] beta-CIT binding in the region corresponding
      to thalamus/hypothalamus between the summer group and the winter group (1.9 +/-
      0.3 vs. 1.4 +/- 0.2, respectively; p < .01). CONCLUSIONS: The results of the
      present study suggest reduced brain serotonin transporter availability in winter.
      This finding further substantiates evidence of seasonal variations in brain
      serotonergic function.

PMID- 10664834
TI  - DHEA-S plasma levels and incidence of Alzheimer's disease.
AB  - BACKGROUND: Cross-sectional studies controlling for age and gender reported a
      relationship between Alzheimer's disease and low dehydroepiandrosterone sulphate
      (DHEA-S) plasma levels. Prospective data with sufficient control for confounding
      factors are lacking. METHODS: A nested case-control study examined baseline DHEA
      S in participants of the Berlin Aging Study. Cases (n = 14) developed dementia of
      the Alzheimer type within 3 years. Control group A (n = 14) was matched for
      gender, age, multimorbidity, and immobility. Control group B (n = 13) was matched
      for gender and age and comprised participants free from multimorbidity,
      immobility, multimedication, need of help, incontinence, visual impairment,
      hearing impairment, and depression. RESULTS: The mean plasma DHEA-S concentration
      of case subjects was 1.02 +/- 0.61 mumol/L. Both control groups had higher mean
      DEHA-S levels, in control group A, it was 1.89 +/- 1.24 mumol/L (p = .012) and in
      control group B 1.70 +/- 1.38 mumol/L (p = .093). CONCLUSIONS: This population
      based prospective study supports the role of DHEA-S as a risk factor for
      Alzheimer's disease.

PMID- 10664835
TI  - Citalopram and breast-feeding: serum concentration and side effects in the
      infant.
AB  - BACKGROUND: During treatment of postpartum depression with antidepressant drugs,
      the mothers often strongly wish to continue breast-feeding although the long-term
      safety of exposing infants to low doses of antidepressants has not been
      established. METHODS: Citalopram in breast milk and in the serum of a nursing
      mother and her infant was determined by high-performance liquid chromatography.
      RESULTS: During treatment with 40 mg/day of citalopram, the concentration of the
      drug in milk and serum was 205 ng/mL and 98.9 ng/mL, respectively. Her infant
      obtained 12.7 ng/mL of citalopram in serum and uneasy sleep was observed. Sleep
      was normalized when the dose was halved and two breast-feedings were replaced
      with artificial nutrition. CONCLUSION: The amount of citalopram and other
      selective serotonin inhibitors (SSRIs) passed to breast milk and delivered to the
      child correlates to the serum concentration of the mother. The lowest possible
      effective serum concentration should be used and breast-feeding during the drug
      absorption phase may be avoided.

PMID- 10664836
TI  - Enhancement of swimming endurance in mice by highly branched cyclic dextrin.
AB  - We investigated the ergogenic effect in mice of administering highly branched
      cyclic dextrin (HBCD), a new type of glucose polymer, on the swimming endurance
      in an adjustable-current swimming pool. Male Std ddY mice were administered a
      HBCD, a glucose solution or water via a stomach sonde 10 min before, 10 min after
      or 30 min after beginning swimming exercise, and were then obliged to swim in the
      pool. The total swimming period until exhaustion, an index of the swimming
      endurance, was measured. An ergogenic effect of HBCD was observed at a dose of
      500 mg/kg of body weight, whereas it had no effect at a dose of 166 mg/kg of body
      wt (p < 0.05). The mice administered with the HBCD solution 10 min after starting
      the exercise were able to swim significantly longer (p < 0.05) than the mice who
      had ingested water or the glucose solution. The rise in mean blood glucose level
      in the mice administered with HBCD, which was measured 20 min after starting
      swimming, was significantly lower (p < 0.05) than that in the mice administered
      with glucose, although it was significantly higher (p < 0.05) than that in the
      mice administered with water. The mean blood insulin rise in the mice given HBCD
      was significantly lower (p < 0.05) than that in the mice given glucose. The mice
      administered with HBCD 30 min after starting the exercise swam significantly
      longer (p < 0.05) than the mice who had ingested water, although the enhancement
      of swimming time was similar to that of the glucose-ingesting mice. The gastric
      emptying rate of the HBCD solution was significantly faster (p < 0.05) than that
      of the glucose solution. However, this glucose polymer must have spent more time
      being absorbed because it has to be hydrolyzed before absorption, reflecting a
      lower and possibly longer-lasting blood glucose level. We conclude that the
      prolongation of swimming endurance in mice administered with HBCD depended on its
      rapid and longer-lasting ability for supplying glucose with a lower postprandial
      blood insulin response, leading to a delayed onset of fatigue.

PMID- 10664837
TI  - Catabolite repression of the xylanase gene (xynA) expression in Bacillus
      stearothermophilus no. 236 and B. subtilis.
AB  - Catabolite repression of the Bacillus stearothermophilus No. 236 xynA gene,
      encoding an extracellular xylanase, was investigated in this work. Expression of
      the xynA gene in the B. stearothermophilus strain was found to be subject to
      glucose catabolite repression, and the level of repression was about 50-fold when
      the relative amounts of xynA transcript synthesized on different carbon sources
      were analyzed. The experiments with the B. subtilis MW15 strains carrying
      plasmids containing the xynA::aprA fusion gene showed that the cloned xynA gene
      did not require any specific carbon source for its induction. Nevertheless, the
      expression of the cloned gene was repressed by the presence of glucose. From the
      nucleotide sequence of the cloned xynA gene, we found two potential catabolite
      responsive elements (cre) within its reading frame region (cre-1: nucleotides
      +160 to +173 and cre-2: +173 to +186). Furthermore, by using various deletion
      derivatives of the xynA::aprA fusion plasmid (pMGW23), we suggested that only the
      cre-2 element might play a role in the glucose catabolite repression. Repression
      level of the xynA gene expression in the recombinant B. subtilis strain was
      estimated to be about 3-fold by analysis of the amounts of xynA transcript.

PMID- 10664838
TI  - Structural characterization of the 16-kDa allergen, RA17, in rice seeds.
      Prediction of the secondary structure and identification of intramolecular
      disulfide bridges.
AB  - The 16-kDa rice allergen, RA17, belonging to the alpha-amylase/trypsin inhibitor
      family was isolated from rice seed and structurally characterized by identifying
      cystine-containing peptides and predicting the secondary structure and
      hydrophobic regions. Eight peptides, which constitute three sets of cystine
      containing peptides, were purified by HPLC from a thermolytic digest of RA17 and
      identified by their amino acid sequence and composition, indicating five
      intramolecular disulfide bridges: Cys34-Cys94, Cys26-(Cys50 or Cys51)-Cys110 and
      Cys12-(Cys62 or Cys64)-Cys122. Analyses of the CD spectrum and the Chou-Fasman
      prediction suggested that RA17 had some helical- and sheet-structure regions.
      Based on these experimental and predicted data, RA17 is proposed to be a globular
      molecule with a small hydrophobic core having folding restricted by five
      intramolecular disulfide bridges.

PMID- 10664839
TI  - Production of an extracellular polysaccharide bioflocculant by Klebsiella
      pneumoniae.
AB  - Klebsiella pneumoniae H12 produced a newly identified extracellular
      polysaccharide in an ethanol medium with a yield of 3.0 g/l. The molar
      composition of the polysaccharide was 56.04% galactose, 25.92% glucose, 10.92%
      galacturonic acid, 3.71% mannose, and 3.37% glucuronic acid. The addition of 0.5%
      1.5% NaCl increased production. The polysaccharide flocculated with kaolin clay
      in suspension at the concentration of 1 ppm in a 300-ppm solution of CaCl2.
      Almost all bacterial species cells aggregated in the polysaccharide solution. The
      ability to flocculate with kaolin clay changed with the pH and with the
      concentrations of coexisting cation and anion species. The polysaccharide
      flocculant may participate in in vivo bacterial aggregation or adherence to host
      organisms.

PMID- 10664840
TI  - Amino acid sequence analysis of bitter peptides from a soybean proglycinin
      subunit synthesized in Escherichia coli.
AB  - The cDNA encoding A1aB1b proglycinin was expressed in E. coli, for the efficient
      isolation of a single peptide responsible for the bitterness. The 55-kD
      proglycinin was highly purified, hydrolyzed, and further purified through a
      series of chromatographic steps to yield fractions with the major bitter
      peptides. The most bitter-tasting fractions contained peptides with average
      molecular weights lower than 1,700 Da. An analysis of the amino acid sequences
      indicated that many small bitter peptides (< 1,000 Da) are composed of uncharged
      polar amino acids as well as hydrophobic amino acids, with a charged residue
      often being present at either end. This suggests the involvement of a certain
      structural requirement in taste perception.

PMID- 10664841
TI  - Encoding of a cytochrome P450-dependent lauric acid monooxygenase by CYP703A1
      specifically expressed in the floral buds of petunia hybrida.
AB  - The cDNA clone of novel cytochrome P450 CYP703A1 from petunia floral buds was
      isolated by RT-PCR. The nucleotide sequences of this cDNA clone contained the
      open reading frame that has been predicted to encode polypeptides consisting of
      539 amino acid residues. A significantly high level of the transcript of the
      cyp703A1 gene was found in the early stage of petunia flower buds, but not in the
      leaves, stems and roots. The 1041bp 5'-flanking sequences of the cyp703A1 gene
      contained the conserved motifs of ATHB-1, AGAMOUS, MYB.Ph3, P and SBF-1 binding
      boxes. CYP703A1 cDNA was expressed in yeast Saccharomyces cerevisiae AH22 cells
      under the control of an alcohol dehydrogenase I promoter and terminator. The
      recombinant yeast microsomes containing the CYP703A1 hemoprotein were found to
      metabolize lauric acid. Based on these results, CYP703A1 was specifically
      expressed in the early stage of flower development and appeared to participate in
      the monooxygenation of fatty acids.

PMID- 10664842
TI  - Cloning and expression of the N,N-dimethylformamidase gene from Alcaligenes sp.
      strain KUFA-1.
AB  - N,N-Dimethylformamidase (DMFase) from Alcaligenes sp. strain KUFA-1, a bacterium
      that can grow on N,N-dimethylformamide (DMF) as the sole carbon and nitrogen
      source, catalyzes the first step of the DMF degradation. The DMFase gene dmfA1A2
      was cloned in Escherichia coli, and its nucleotides were sequenced. The deduced
      amino acid sequence of the enzyme consisted of two alpha- and two beta-subunits
      with 132 and 762 amino acids, respectively, and had little similarity to
      sequences in protein databases, including various amidases. The protein may be a
      new kind of amidase. DMFase activity was detected in E. coli cells transformed
      with an expression plasmid of the cloned DMFase gene. The properties of
      recombinant DMFase purified from E. coli were identical to those of Alcaligenes
      DMFase.

PMID- 10664843
TI  - The expression of proUK in Escherichia coli: the vgb promoter replaces IPTG and
      coexpression of argU compensates for rare codons in a hypoxic induction model.
AB  - The expression of the proUK gene was improved by the coexpression of the argU
      gene cloned in a moderate copy number vector. As the proUK gene contains 2%
      AGG/AGA codons, which is much higher than the normal frequency in E. coli, about
      0.14%-0.21%, the argU gene cloned in a multicopy plasmid was coexpressed with the
      proUK expression vector in our experiments. In E. coli strain BL21(DE3), IPTG is
      known to induce the expression of T7 RNA polymerase gene and this enzyme can
      transcribe the proUK gene under the control of the T7 promoter leading to
      expression of proUK. To replace IPTG by a cheaper alternative on a large scale,
      we constructed a plasmid in which the vgb promoter--which is known to be
      activated by the onset of hypoxic conditions--controls the T7RNA polymerase gene
      expression. Low oxygen conditions were then used to activate the vgb promoter
      causing T7RNA polymerase gene expression and finally leading to the expression of
      proUK as inactive inclusion bodies. Our experiments on a large scale in a
      bioreactor show that the expression of proUK accounts for about 30% of total
      protein after about 6 h of anaerobic cultivation, so the presented model
      represents an economical alternative to IPTG induction.

PMID- 10664844
TI  - Antioxidative effects of turmeric, rosemary and capsicum extracts on membrane
      phospholipid peroxidation and liver lipid metabolism in mice.
AB  - Phospholipid hydroperoxides (PLOOH) in the plasma, red blood cells (RBC) and
      liver of mice were measured after dietary supplementation for one week (1% w/w of
      diet) with a turmeric extract (curcuminoid), hexane extract of rosemary, and
      supercritical CO2-extracted capsicum pigment (supplemented with alpha-tocopherol
      to prevent fading). A lower PLOOH level was found in RBC of the spice extract-fed
      mice (65-74% of the non-supplemented control mice). The liver lipid
      peroxidizability induced with Fe2+/ascorbic acid was effectively suppressed by
      dietary supplementation with the turmeric and capsicum extracts to mice. While no
      difference in the plasma lipids was observed, the liver triacylglycerol
      concentration of the turmeric extract-fed mice was markedly reduced to one-half
      of the level in the control mice. These findings suggest that these spice
      extracts could act antioxidatively in vivo by food supplementation, and that the
      turmeric extract has the ability to prevent the deposition of triacylglycerols in
      the liver.

PMID- 10664845
TI  - Local antibody response in Peyer's patches to the orally administered dietary
      protein antigen.
AB  - To understand local antibody production to dietary protein antigens in the gut,
      the reactivity of the monoclonal antibodies (mAbs) from Peyer's patches of BALB/c
      mice raised against orally administered hen egg lysozyme (HEL) was studied. These
      mAbs were of IgG1 (7 clones), IgA (5 clones) and IgM (13 clones) isotypes. Some
      of the HEL-binding mAbs preferentially reacted with reduced, carboxy-methylated
      HEL, rather than with native HEL. MAbs of the IgA and IgM isotypes had cross
      reactivity with other unrelated environmental antigens such as E. coli, single
      strand DNA, and soluble components of mouse food. In contrast, the IgG1 mAbs did
      not cross-react with these antigens. The average of the Kd values for HEL of
      these mAbs was in the order of 10(-6) M, which is moderately higher than those of
      mAbs from the preimmune repertoire. These results suggest that, under normal
      physiological conditions, orally administered dietary proteins predominantly
      induce the local production of polyreactive IgA/IgM antibodies cross-reacting
      with environmental luminal antigens.

PMID- 10664846
TI  - A fibrinolytic metalloprotease from the fruiting bodies of an edible mushroom,
      Armillariella mellea.
AB  - A fibrinolytic metalloprotease has been purified from the fruiting bodies of the
      edible honey mushroom (Armillariella mellea). The enzyme has a molecular weight
      of 18538.1508, as measured by MALDI-TOF mass spectrometry and includes Zn2+ ion
      as found by ICP/MS. The N-terminal amino acid sequence, XXYNGXTXSRQTTLV, do not
      match any known protein or open reading frame. It hydrolyzes fibrinogen as well
      as fibrin, but does not show any proteolytic activity for other blood proteins
      such as thrombin, human albumin, bovine albumin, human IgG, hemoglobin, or
      urokinase. This protease hydrolyzes both A alpha and B beta subunits of human
      fibrinogen with equal efficiency. The enzyme activity was strongly inhibited by
      EDTA and 1,10-phenanthroline, indicating that the enzyme is a metalloprotease. No
      inhibition was found with PMSF, E-64, pepstatin, and 2-mercaptoethanol. The
      activity of the purified enzyme was slightly increased by Mg2+, Zn2+, and Co2+,
      but the enzyme was totally inhibited by Hg2+. It has broad substrate specificity
      for synthetic peptides, and a pH optimum at 7, suggested that the purified enzyme
      was a neutral protease. It was thermally stable up to 60 degrees C and the
      maximum fibrinolytic activity was at 55 degrees C.

PMID- 10664847
TI  - Improvement of the physical properties of pepsin-solubilized elastin-collagen
      film by crosslinking.
AB  - Pepsin-solubilized elastin (PSE)-conjugated collagen film was prepared from a
      collagen matrix with PSE by drying it and crosslinking the constituents with
      water-soluble carbodiimide or microbial transglutaminase to improve the physical
      properties of the collagen film. The crosslinking reduced the solubility and
      improved the thermal stability, the thermal transition properties, and the
      elasticity of the control film in water. In particular, water-soluble
      carbodiimide strongly influenced these properties. The PSE-conjugated collagen
      film showed good permeation by water-soluble tasting substances such as
      oligosaccharides and amino acids, but poor permeation by polysaccharide, protein,
      and hydrophobic substances such as retinol and cholesterol.

PMID- 10664848
TI  - Analysis of a catalytic acidic pair in the active center of cellulase from
      Aspergillus aculeatus.
AB  - Four acidic amino acid residues, Asp97, Asp101, Glu118, and Glu202, were located
      in the cleft from the X-ray crystallographic analysis of FI-CMCase, endo-1,4-beta
      glucanase (EC: 3.2.1.4) of Aspergillus aculeatus No. F-50. To identify the
      catalytic residues of the FI-CMCase, these residues were mutated to Glu or Ser
      from Asp97 and Asp101, and to Asp or Ser from Glu118 and Glu202 by site-directed
      mutagenesis, and totally 8 single mutant enzymes expressed in Escherichia coli
      were prepared: D97E, D97S, D101E, D101S, E118D, E118S, E202D, and E202S. Mutant
      enzymes E118S and E202S were not shown to have any detectable activity. Kinetic
      parameters of other mutant enzymes were measured after purification. The Km of
      mutant enzymes were not much different from that of wild type FI-CMCase, while
      the Vmax of mutant enzymes D97E, D97S, D101E, D101S, E118D, and D202E were much
      decreased to 1/50, 1/20, 1/4000, 1/2000, 1/800, and 1/1600 of the wild type FI
      CMCase, respectively. From these results we concluded that Glu118 and Glu202 were
      most probable candidates for a catalytic pair of acidic amino acids in FI-CMCase.

PMID- 10664850
TI  - Cloning and sequence analysis of the gene for glucodextranase from Arthrobacter
      globiformis T-3044 and expression in Escherichia coli cells.
AB  - The gld gene for glucodextranase from Arthrobacter globiformis T-3044 was cloned
      by using a combination of gene walking and probe methods and expressed on the
      recombinant plasmid pGD8, which was constructed with pUC118, in Escherichia coli
      cells. The enzyme gene consisted of a unique open reading frame of 3,153 bp. The
      comparison of the DNA sequence data with the N-terminal and 6 internal amino acid
      sequences of the purified enzyme secreted from A. globiformis T-3044 suggested
      the enzyme was translated from mRNA as a secretory precursor with a signal
      peptide of 28 amino acids residues. The deduced amino acids sequence of the
      mature enzyme contained 1,023 residues, resulting in a polypeptide with a
      molecular mass of 107,475 daltons. The deduced sequence showed about 38% identity
      to that of the glucoamylase from Clostridium sp. G0005. The glucodextranase
      activity of transformant harboring pGD8 was about 40 mU/ml at 30 degrees C for a
      16-h culture. Although the GDase that was produced from the transformant was
      shorter than authentic GDase by 2 amino acid residues at the N-terminal end side,
      its enzymatic properties were almost same as the authentic one. Two kinds of
      genes, dex1 and dex2, for endo-dextranases from A. globiformis T-3044 were also
      cloned into Escherichia coli cells. The N-terminal of the purified endo
      dextranase from A. globiformis T-3044 agreed with the deduced amino acid
      sequence, after the 33rd alanine residue, of only the dex1 gene for edo
      dextranase. This result suggests that the endo-dextranase is translated from mRNA
      as a secretory precursor with a signal peptide of 32 amino acids residues. The
      deduced sequence of endo-dextranase 1 and endo-dextranase 2 showed about 93% and
      65% identity with that of known endo-dextranase from Arthrobacter sp. CB-8,
      respectively.

PMID- 10664849
TI  - Dietary effect of guar gum and its partially hydrolyzed product on the lipid
      metabolism and immune function of Sprague-Dawley rats.
AB  - The dietary effect of the water-soluble dietary fibers (WSDF), guar gum,
      partially hydrolyzed guar gum (PHGG), glucomannan, highly methoxylated (HM)
      pectin, on the serum lipid level and immunoglobulin (Ig) production of Sprague
      Dawley rats was compared with that of water-insoluble cellulose. Although serum
      total cholesterol and triglyceride levels were significantly lower in the rats
      fed with WSDF than in those fed with cellulose, a decrease in the level of
      phospholipids was only observed in the rats that had been fed on guar gum or
      glucomannan. In addition, all WSDF feeding enhanced IgA productivity in the
      spleen and mesenteric lymph node lymphocytes, although the increase in serum IgA
      level was only observed in the rats fed on WSDF, and not on PHGG. When mesenteric
      lymph node lymphocytes were cultured in the presence of various concentrations of
      guar gum or glucomannan, no significant increase in Ig production was apparent.
      These data suggest that WSDF indirectly enhanced the Ig production of
      lymphocytes, and that serum lipid reduction and IgA production-enhancing
      activities of WSDF were dependent on their molecular sizes.

PMID- 10664851
TI  - Permeation of hesperidin glycosides across Caco-2 cell monolayers via the
      paracellular pathway.
AB  - The intestinal permeability to hesperidin glycosides was investigated by using a
      cultured monolayer of Caco-2 as a model for the small intestinal epithelium.
      Hesperidin glycosides were added to the apical side of the monolayer, and the
      substances that permeated to the basolateral side were determined by HPLC.
      Whereas hesperidin did not permeate across the Caco-2 monolayer, probably owing
      to its low solubility, the hesperidin glycosides did permeate. The
      transepithelial transport of hesperidin glycosides occurred in time- and dose
      dependent manners. The transport was observed to be energy-independent, and was
      inversely correlated with the transepithelial electrical resistance (TEER) of the
      monolayer. These results suggest that hesperidin glycosides permeate across the
      Caco-2 cell monolayer via the paracellular pathway.

PMID- 10664852
TI  - Functional analysis of the DXDDTA motif in squalene-hopene cyclase by site
      directed mutagenesis experiments: initiation site of the polycyclization reaction
      and stabilization site of the carbocation intermediate of the initially cyclized
      A-ring.
AB  - In order to clarify the function of the DXDDTA motif in squalene-hopene cyclase
      and to identify the acidic amino acid residues crucial for the catalysis, site
      directed mutagenesis experiments were carried out. The following results were
      found: (1) residues D374 and D376 work for the initiation of polyolefin
      cyclization which arises from the proton attack on the terminal double bond; (2)
      residue D377 stabilizes C-10 carbocation of the initially cyclized A-ring
      intermediate, leading to subsequent B-ring closure, which was further verified by
      isolating the partially cyclized monocyclic product; (3) residues D313 and D447
      outside the DXDDTA motif were identified as new active sites; (4) the H451
      residue is likely to work in the protonated form to enhance the acidity of the
      carboxyl groups of D374 and/or D376.

PMID- 10664853
TI  - HIV-1 protease inhibition and anti-HIV effect of natural and synthetic water
      soluble lignin-like substances.
AB  - Water-soluble lignin extracted from natural sources and dehydrogenated polymers
      of p-coumaric acid and ferulic acid inhibited HIV-1 protease activity. The
      dehydrogenated polymers, which are thought to be model compounds for lignin, were
      synthesized and fractionated into four ranges of molecular mass by ultra
      filtration: i.e., over 30 kDa, 30-10 kDa, 10-1 kDa and 1 kDa-500 Da. All of these
      fractions had HIV-1 protease inhibitory activity. The anti-HIV-1 effect of the
      smallest mass fractions of the dehydrogenated polymers (1 kDa-500 Da) was also
      tested, and it was found that these fractions inhibited the replication of HIV-1
      in MT-4 cells.

PMID- 10664854
TI  - Site-directed mutagenesis of two zinc-binding centers of the NADH-dependent
      phenylacetaldehyde reductase from styrene-assimilating Corynebacterium sp. strain
      ST-10.
AB  - Phenylacetaldehyde reductase (PAR) with a unique and wide substrate range from
      styrene-assimilating Corynebacterium sp. strain ST-10, which is a useful
      biocatalyst producing chiral alcohols, has been found to belong to a family of
      zinc-containing, long-chain alcohol dehydrogenases (ADHs) on the basis of the
      primary structure similarity. The enzyme contains 2 moles of zinc per mole of
      subunit. The amino acid residues assumed to be three catalytic and four
      structural zinc-binding ligands were characterized by site-directed mutagenesis,
      compared with other zinc-containing, long-chain ADHs. Sixteen PAR mutants gave
      measurable but rather low activities toward phenylacetaldehyde, n-hexyl aldehyde,
      and 2-heptanone, although they maintained the activities of 8 to 16% of that of
      wild-type PAR for an acetophenone substrate except that the D153N mutant showed
      quite low activity. The results suggested that the seven residues present in PAR
      were probably zinc-binding ligands, and mutation in these residues caused a
      change in activities for some substrates.

PMID- 10664855
TI  - Activity of glucose-6-phosphate 1-dehydrogenase in hair follicles with male
      pattern alopecia.
AB  - Activity of glucose-6-phosphate 1-dehydrogenase (G6PDH) in human hair follicles
      was measured. A good relationship has been demonstrated between the activity and
      the ratio of the number of the anagen hairs to that of all the plucked hairs in
      the frontal-parietal region of the scalp with male-pattern alopecia. As the ratio
      becomes lower so that the advancing degree of alopecia is higher, the G6PDH
      activity becomes lower.

PMID- 10664856
TI  - Cloning and expression in Escherichia coli of 2-hydroxypropylphosphonic acid
      epoxidase from the fosfomycin-producing organism, Pseudomonas syringae PB-5123.
AB  - The fosfomycin resistance gene, fosC, has been cloned from the fosfomycin
      producing organism, Pseudomonas syringae PB-5123. Sequence analysis upstream of
      this gene found a new ORF showing significant homology to 2
      hydroxypropylphosphonic acid epoxidase from fosfomycin-producing Streptomyces
      wedmorensis. The purified recombinant protein of this ORF converted 2
      hydroxypropylphosphonic acid to fosfomycin. This result clearly showed the ORF to
      encode 2-hydroxypropylphosphonic acid epoxidase in PB-5123.

PMID- 10664857
TI  - Nucleotide sequence of cDNA coding the mitochondrial precursor protein of the
      ATPase inhibitor from humans.
AB  - Mitochondrial ATP synthase (F1Fo-ATPase) is regulated by an intrinsic ATPase
      inhibitor protein. In the present study, cDNA coding the human homolog of the
      inhibitor protein was isolated and sequenced. The deduced protein sequence shows
      that the protein was composed of 106 amino acids and had a molecular weight of
      12248. The structural features of the protein show that the cDNA isolated in this
      study codes the human ATPase inhibitor.

PMID- 10664858
TI  - Analysis of mfbA alleles of the eubasidiomycete Lentinus edodes.
AB  - A fruiting-body-specific mfbA cDNA derived from Lentinus edodes FMC2 has been
      shown to encode a high-molecular-weight protein, MFBA, containing the cell
      adhesion-promoting Arg-Gly-Asp (RGD) sequence. Southern-blot analysis showed that
      all L. edodes strains tested have the mfbA gene (homologue). Nucleotide sequence
      analysis of the 1-kb mfbA fragments containing the RGD-coding sequence showed
      that each L. edodes strain has two types of mfbA homologues. It was found in FMC2
      that two mfbA homologues are derived from different nuclei and these mfbA alleles
      are transcribed with similar frequencies in the fruiting bodies.

PMID- 10664859
TI  - Arginine-55 in the beta-arm is essential for the activity of DNA-binding protein
      HU from Bacillus stearothermophilus.
AB  - DNA-binding protein HU (BstHU) from Bacillus stearothermophilus is a homodimeric
      protein which binds to DNA in a sequence-nonspecific manner. In order to identify
      the Arg residues essential for DNA binding, four Arg residues (Arg-53, Arg-55,
      Arg-58, and Arg-61) within the beta-arm structure were replaced either by Gln,
      Lys, or Glu residues, and the resulting mutants were characterized with respect
      to their DNA-binding activity by a filter-binding analysis and surface plasmon
      resonance analysis. The results indicate that three Arg residues (Arg-55, Arg-58,
      and Arg-61) play a crucial role in DNA binding as positively charged recognition
      groups in the order of Arg-55 > Arg-58 > Arg-61 and that these are required to
      decrease the dissociation rate constant for BstHU-DNA interaction. In contrast,
      the Arg-53 residue was found to make no contribution to the binding activity of
      BstHU.

PMID- 10664861
TI  - Promotive effects of the peptidyl plant growth factor, phytosulfokine-alpha, on
      the growth and chlorophyll content of Arabidopsis seedlings under high night-time
      temperature conditions.
AB  - In order to investigate the function of the peptidyl plant growth factor,
      phytosulfokine-alpha (PSK-alpha), in plants, we examined the effect of PSK-alpha
      on the growth and chlorophyll content of Arabidopsis seedlings under high night
      time temperature conditions. Although exposure to high night-time temperatures
      markedly reduced the fresh weight and chlorophyll content of the seedlings, these
      parameters in the plants supplied with PSK-alpha remained at the same levels as
      those of non-treated controls. These effects were not apparent when [2-5]PSK, Tyr
      SO3H and kinetin were similarly supplied. The results suggest that PSK-alpha not
      only promotes cell proliferation, but may aid plants in their tolerance of heat
      stress.

PMID- 10664860
TI  - Antibacterial activities of cryptotanshinone and dihydrotanshinone I from a
      medicinal herb, Salvia miltiorrhiza Bunge.
AB  - Cryptotanshinone and dihydrotanshinone I, constituents of a medicinal plant,
      Salvia miltiorrhiza Bunge, had antibacterial activity against a broad range of
      Gram positive bacteria. These compounds generated superoxide radicals in Bacillus
      subtilis lysates. A recombination-deficient mutant strain of B. subtilis was 2-
      to 8-fold more sensitive than a wild strain, and this hypersensitivity was
      reduced in the presence of dithiothreitol as an antioxidant. DNA, RNA, and
      protein syntheses in B. subtilis were non-selectively inhibited by these
      compounds. These results suggest that superoxide radicals are important in the
      antibacterial actions of the agents.

PMID- 10664862
TI  - Cloning of L-amino acid deaminase gene from Proteus vulgaris.
AB  - The L-amino acid degrading enzyme gene from Proteus vulgaris was cloned and the
      nucleotide sequence of the enzyme gene was clarified. An open reading frame of
      1,413 bp starting at an ATG methionine codon was found, which encodes a protein
      of 471 amino acid residues, the calculated molecular weight of which is 51,518.
      The amino acid sequence of P. vulgaris was 58.6% identical with the L-amino acid
      deaminase of P. mirabilis. A significantly conserved sequence was found around
      the FAD-binding sequence of flavo-proteins. The partially purified wild and
      recombinant enzymes had the same substrate specificity for L-amino acids to form
      the respective keto-acids, however not for D-amino acids.

PMID- 10664863
TI  - Synthesis and characterization of intermediate and transition-state analogue
      inhibitors of gamma-glutamyl peptide ligases.
AB  - The phosphonodifluoromethyl ketone and phosphonofluoridate derivatives of L
      glutamic acid were synthesized and characterized as analogues of the gamma
      glutamyl phosphate intermediate and the tetrahedral transition state,
      respectively, for the inhibition of gamma-glutamylcysteine synthetase and
      glutamine synthetase. The former served as a poor inhibitor of both enzymes, but
      the latter inhibited glutamine synthetase with a Ki of 59 microM and partially
      inactivated the enzyme in an NH3- and ATP-dependent manner.

PMID- 10664864
TI  - Interaction of tea catechins with lipid bilayers investigated with liposome
      systems.
AB  - Interaction of tea catechins with lipid bilayers was investigated with liposome
      systems, which enabled us to separate liposomes from the external medium by
      centrifugation. We found that epicatechin gallate had the highest affinity for
      lipid bilayers, followed by epigallocatechin gallate, epicatechin, and
      epigallocatechin. Epicatechin gallate and epigallocatechin gallate in the surface
      of lipid bilayer perturbed the membrane structure.

PMID- 10664865
TI  - Soybean curd refuse alleviates experimental tumorigenesis in rat colon.
AB  - Adult Fischer-344 rats which underwent administration of azoxymethane were fed
      diets containing soybean curd refuse (SCR) or a high-molecular-weight fraction of
      soy protein digest (HMF), or Hammarsten casein (CAS) as a protein source over a
      period of 34 weeks. All the living rats of each group at 22, 28 or 34 weeks were
      endoscopically inspected for tumor incidence in the colon. SCR turned out to be
      comparable to HMF in anti-tumorigenicity, or rather better than HMF.

PMID- 10664866
TI  - Cytokine-induced macrophage differentiation: a tale of 2 genes.
AB  - Macrophages are versatile cells found in every tissue in the body. They must
      perform a number of diverse cellular functions that allow them to kill invading
      micro-organisms and neoplastic cells as well as produce growth factors involved
      in wound healing. Macrophages that develop these diverse functions arise from a
      common precursor. By a process of selective adaptation, the common precursor
      monocyte/macrophage differentiates into a distinctive macrophage with a different
      and specific phenotype, characterized by the expression of a specific set of gene
      products. The local environment plays a critical role in shaping or directing the
      pattern or pathway of macrophage differentiation. The authors have focused on 2
      specific macrophage differentiation pathways in a murine bone marrow-derived
      macrophage model. One pathway is believed to play a role in wound repair and is
      characterized by the induction of insulin-like growth factor-1 (IGF-I). The
      second pathway is involved in macrophage cytocidal activation and is
      characterized by the induction of the inducible form of nitric oxide synthase
      (iNOS). The pleotropic cytokine tumour necrosis factor-alpha (TNF-alpha) appears
      to mediate macrophage differentiation along both of these pathways. Interferon
      gamma (IFN-gamma), however, appears to act as a molecular switch. In the presence
      of IFN-gamma, stimulation of macrophages with TNF-alpha results in macrophage
      differentiation along a pathway in which iNOS is expressed, whereas, in the
      absence of IFN-gamma, stimulation of macrophages with TNF-alpha results in
      differentiation along a pathway in which IGF-I is expressed. The authors focus on
      some of the molecular events involved in TNF-alpha and IFN-gamma signal
      transduction and the regulation of iNOS and IGF-I genes in macrophages.

PMID- 10664867
TI  - Vancomycin use in 2 Ontario tertiary care hospitals: a survey.
AB  - OBJECTIVE: Use of vancomycin is a risk factor for acquiring vancomycin-resistant
      enterococci (VRE). To optimize the use of vancomycin in hospitals, the Hospital
      Infection Control Practices Advisory Committee (HICPAC) published recommendations
      in 1995. The objectives of this study were to determine the frequency,
      indications, and risk factors for inappropriate inpatient vancomycin
      prescriptions before and after publication of the HICPAC recommendations. DESIGN:
      Cross-sectional study. SETTING: Two tertiary care hospitals in Ontario.
      INTERVENTIONS: Vancomycin prescriptions were randomly sampled and hospital chart
      view performed for two 12-month periods, one before and one after publication of
      the HICPAC recommendations on vancomycin use. RESULTS: Based on the review of 189
      charts from hospital A and 190 from hospital B, there was no significant change
      in the proportion of inappropriate vancomycin prescriptions at either hospital
      from before publication of the HICPAC recommendations to afterward (63% v. 71% at
      hospital A, p = 0.21; 48% v. 37% at hospital B, p = 0.11). In 51% of all
      vancomycin prescriptions, the drug was prescribed instead of another antibiotic
      because of a recorded penicillin allergy. Surgical prophylaxis with more than 1
      or 2 doses of vancomycin accounted for 66% (hospital A) and 58% (hospital B) of
      inappropriate prescriptions. In a multivariate analysis, surgical prophylaxis
      remained a significant risk factor for inappropriate use of vancomycin at both
      hospitals (odds ratio [OR] 5.6, 95% confidence interval [CI] 2.8 to 11.3, p =
      0.01 for hospital A; OR 13.9, 95% CI 4.9 to 39.5, p = 0.01 for hospital B).
      Prescription by the orthopedic service also remained a significant risk factor in
      the final logistic regression model for hospital B (OR 3.9, 95% CI 1.1 to 13.9, p
      = 0.01). CONCLUSIONS: A high proportion of vancomycin prescriptions, surveyed
      before and after publication of the HICPAC recommendations on vancomycin use,
      were inappropriate. Excessive vancomycin use in surgical prophylaxis was an
      important factor. Our findings suggest that the use of standardized peri
      operative order forms and of penicillin-allergy testing may help optimize
      vancomycin use in tertiary care hospitals.

PMID- 10664868
TI  - Detection of early atherosclerosis with B mode carotid ultrasonography:
      assessment of a new quantitative approach.
AB  - PURPOSE: To examine the relation between carotid artery (CA) intima-media
      thickness (IMT) assessed by B mode ultrasonography (US), presence of plaques and
      major risk factors in a population without known vascular disease. Alternative
      methods of quantifying US results and implications for starting lipid-lowering
      therapy were also explored. DESIGN: Prospective study. SETTING: Specialized lipid
      clinic. PATIENTS: One hundred and sixty patients with hyperlipidemia but without
      symptomatic coronary or peripheral vascular disease were examined by US, of whom
      92 patients with normal blood pressure who were not receiving lipid-lowering
      treatment were included in the analysis. INTERVENTIONS: B mode US of the CA was
      performed. Measurements were made of the IMT of the right and left common CA, and
      the average IMT (AIMT) was calculated. The number of plaques (PN) in the CA and
      its bifurcations was counted, and the average total thickness (ATT), the total
      area (TA), and average plaque thickness (APT) were calculated. RESULTS: Stepwise
      regression analysis showed that age, the ratio of total cholesterol to high
      density-lipoprotein cholesterol, weight and smoking significantly predicted ATT,
      APT and PN. By contrast, age, weight and apo B levels predicted AIMT. Detection
      of patients with CA abnormalities was improved by incorporating plaque
      dimensions: AIMT had a 63% sensitivity in detecting CA abnormalities, whereas TA
      had a sensitivity of 72%. CONCLUSION: Indices of CA atherosclerosis that
      integrate the contribution of plaque to overall atheroma burden are related to
      known risk factors and are more sensitive than AIMT for detection of
      abnormalities.

PMID- 10664869
TI  - A life in academe.

PMID- 10664870
TI  - Pityriasis lichenoides.

PMID- 10664871
TI  - What is your diagnosis? Pseudoxanthoma elasticum.

PMID- 10664872
TI  - Experience with supplemental allergens in the diagnosis of contact dermatitis.
AB  - Over and above the information obtained with screening series of allergens,
      supplemental allergens can provide additional insight as to which substances a
      patient has become sensitized. These allergens are commercially available and are
      sold as a series of related materials. Twelve such series were used over a period
      of 8.5 years. This report investigates the value of each series in providing
      additional information not provided by the use of routine screening series of
      allergens. The most useful additional allergens are identified.

PMID- 10664873
TI  - Delayed type hypersensitivity to intralesional triamcinolone acetonide.
AB  - Corticosteroids are the most widely used class of drugs in dermatology. In the
      past, allergic contact dermatitis to topical corticosteriods was rarely reported.
      In this article, we present a case of delayed type hypersensitivity to
      triamcinolone acetonide.

PMID- 10664874
TI  - Skin conditions of musicians.
AB  - Although skin conditions among musicians are uncommon, when they do occur, they
      may cause considerable discomfort and disability. The pattern of the condition
      very often indicates the instrument played.

PMID- 10664875
TI  - How to test for fragrance allergy.
AB  - Fragrance is the most common cause of cosmetic allergic contact dermatitis.
      Fragrance allergy detection is best accomplished by testing with the fragrance
      mixture, balsam of Peru, and either jasmine synthetic or absolute. It would be
      desirable to have common fragrance allergens listed on cosmetic labels so that
      patients could avoid the allergens to which they are allergic.

PMID- 10664876
TI  - Reactions to corticosteroids: some new aspects regarding cross-sensitivity.
AB  - Patch test results obtained with corticosteroid allergic patients tested with a
      large corticosteroid series validated the earlier classification of
      corticosteroid molecules in four groups of cross-reacting molecules: i.e., group
      A (hydrocortisone type), group B (acetonides), group C (betamethasone type-non
      esterified) and group D (esters). The latter group can now be subclassified into
      2 groups, i.e., group D1 (halogenated and with C16 substitution) and group D2
      (the "labile" prodrug esters without the latter characteristics).

PMID- 10664877
TI  - False-positive "poral" cobalt patch test reactions reside in the eccrine
      acrosyringium.
AB  - Seventy (32%) of 222 patients patch tested in our contact dermatitis clinic from
      1993 to 1995 had irritant reactions to cobalt. These reactions were "poral" and
      seemed to reflect a unique and probably toxic effect of cobalt on the
      acrosyringium. The reactions are neither follicular nor petechial and we believe
      they are not allergic. The histopathology of the reactions is described in
      detail.

PMID- 10664878
TI  - IUPAC-IUBMB Joint Commission on Biochemical Nomenclature (JCBN) and Nomenclature
      Committee of IUBMB (NC-IUBMB). Newsletter 1999

PMID- 10664880
TI  - Indigenous plasmids in a production line of strains for penicillin G acylase
      derived from Escherichia coli W.
AB  - Three indigenous plasmids designated pRK1, pRK2 and pRK3 were identified among
      producers of penicillin G acylase (PGA) derived from the strain Escherichia coli
      W ATCC 9637. Their size and copy number (CN) in E. coli W were determined (kb;
      CN): pRK1 (80; 3.4), pRK2 (5.1; 71), and pRK3 (4.8; 13.7). Strain E. coli RE2
      harboring these plasmids was used for selection of strains with reduced number of
      plasmids: the strain RE3 without plasmid pRK1 and the plasmid-less strain cERE3
      were isolated. Indigenous plasmids did not code for the resistance determinants
      against 23 antibiotics and 10 heavy metals.

PMID- 10664879
TI  - Tetrachloroethene-dehalogenating bacteria.
AB  - Tetrachloroethene is a frequent groundwater contaminant often persisting in the
      subsurface environments. It is recalcitrant under aerobic conditions because it
      is in a highly oxidized state and is not readily susceptible to oxidation.
      Nevertheless, at least 15 organisms from different metabolic groups, viz.
      halorespirators (9), acetogens (2), methanogens (3) and facultative anaerobes
      (2), that are able to metabolize tetrachloroethene have been isolated as axenic
      cultures to-date. Some of these organisms couple dehalo-genation to energy
      conservation and utilize tetrachloroethene as the only source of energy while
      others dehalogenate tetrachloroethene fortuitously. Halorespiring organisms
      (halorespirators) utilize halogenated organic compounds as electron acceptors in
      an anaerobic respiratory process. Different organisms exhibit differences in the
      final products of tetrachloroethene dehalogenation, some strains convert
      tetrachloroethene to trichloroethene only, while others also carry out
      consecutive dehalogenation to dichloroethenes and vinyl chloride. Thus far, only
      a single organism, 'Dehalococcoides ethenogenes' strain 195, has been isolated
      which dechlorinates tetrachloroethene all the way down to ethylene. The majority
      of tetrachloroethene-dehalogenating organisms have been isolated only in the past
      few years and several of them, i.e., Dehalobacter restrictus, Desulfitobacterium
      dehalogenans, 'Dehalococcoides ethenogenes', 'Dehalospirillum multivorans',
      Desulfuromonas chloroethenica, and Desulfomonile tiedjei, are representatives of
      new taxonomic groups. This contribution summarizes the available information
      regarding the axenic cultures of the tetrachloroethene-dehalogenating bacteria.
      The present knowledge about the isolation of these organisms, their physiological
      characteristics, morphology, taxonomy and their ability to dechlorinate
      tetrachloroethene is presented to facilitate a comprehensive comparison.

PMID- 10664881
TI  - Alterations in surface hydrophobicity of Acinetobacter baumannii induced by
      meropenem.
AB  - Six strains of Acinetobacter baumannii out of eleven strains tested revealed a
      strong hydrophobic character. This was demonstrated by adherence of bacteria to
      xylene in the range of 90-94%. Changes in surface hydrophobicity of these strains
      were studied after treatment with meropenem at subinhibitory concentrations (sub
      MICs) (1/4, 1/8, 1/16 or 1/32 of the MICs). All strains showed a reduced
      adherence to xylene after the action of meropenem at 1/4 or 1/16 of the MICs.
      Hydrophobicity of the treated bacteria was decreased to 1.3-70% (1/16 of the
      MICs) or to 12-86% (1/4 of the MICs), depending on the strain. A decrease in
      surface hydrophobicity of three strains was also observed after their exposure to
      meropenem at 1/8 of the MICs (to 18-71% of the control values). Meropenem at 1/32
      of the MICs practically did not affect bacterial hydrophobic properties, with the
      exception of one strain.

PMID- 10664882
TI  - Cell viability and protein turnover in nongrowing Bacillus megaterium at
      sporulation suppressing temperature.
AB  - In Bacillus megaterium, a temperature that suppresses sporulation (43 degrees C)
      only slightly exceeds both the optimum growth temperature and the temperature
      still permitting sporulation (40-41 degrees C). Here we show that, when cells
      grown at 35 degrees C and transferred to a sporulation medium, were subjected to
      shifts between 35 degrees C and the sporulation suppressing temperature (SST, 43
      degrees C), their development and proteolytic activities were deeply affected.
      During the reversible sporulation phase that took place at 35 degrees C for 2-3 h
      (T2-T3), the cells developed forespores and their protein turnover was
      characterized by degradation of short-lived proteins and proteins made accessible
      to the proteolytic attack because of starvation. During the following
      irreversible sporulation phase refractile heat-resistant spores appeared at T4
      T5. Protein turnover rate increased again after T2 and up to T8 60-70%
      prelabelled proteins were degraded. The SST suppressed sporulation at its
      beginning; at T3 no asymmetric septa were observed and the amount of heat
      resistant spores at T8 was by 4-5 orders lower than at 35 degrees C. However, the
      cells remained viable and were able to sporulate when transferred to a lower
      temperature. Protein degradation was increased up to T3 but then its velocity
      sharply dropped and the amount of degraded protein at T8 corresponded to slightly
      more than one-half of that found at 35 degrees C. The cytoplasmic proteolytic
      activity was enhanced but the activity in the membrane fraction was decreased.
      When a temperature shift to SST was applied at the beginning of the irreversible
      sporulation phase (T2.5), the sporulation process was impaired. A portion of
      forespores lyzed, the others were able to complete their development but most
      spores were not heat-resistant and their coats showed defects. Protein
      degradation increased again because an effective proteolytic system was developed
      during the reversible sporulation phase but the amount of degraded protein was
      slightly lower than at 35 degrees C. A later (T4) shift to SST had no effect on
      the sporulation process.

PMID- 10664883
TI  - Effect of killer toxin K1 on yeast membrane potential reported by the diS-C3(3)
      probe reflects strain- and physiological state-dependent variations.
AB  - The rate and extent of uptake of the fluorescent probe diS-C3(3) reporting on
      membrane potential in S. cerevisiae is affected by the strain under study, cell
      growth phase, starvation and by the concentration of glucose both in the growth
      medium and in the monitored cell suspension under non-growth conditions. Killer
      toxin K1 brings about changes in membrane potential. In all types of cells
      tested, viz. in glucose-supplied stationary or exponential cells of the killer
      sensitive strain S6/1 or a conventional strain RXII, or in glucose-free
      exponential cells of both strains, both active and heat-inactivated toxin slow
      down the potential-dependent uptake of diS-C3(3) into the cells. This may reflect
      "clogging" of pores in the cell wall that hinders, but does not prevent, probe
      passage to the plasma membrane and its equilibration. The clogging effect of heat
      inactivated toxin is stronger than that exerted by active toxin. In susceptible
      cells, i.e. in exponential-phase glucose-supplied cells of the sensitive strain
      S6/1, this phase of probe uptake retardation is followed by an irreversible red
      shift in probe fluorescence maximum lambda max indicating damage to membrane
      integrity and cell permeabilization. A similar fast red shift in lambda max
      signifying lethal cell damage was found in heat-killed or nystatin-treated cells.

PMID- 10664884
TI  - Life-cycle-dependent changes of aspartate carbamoyltransferase localization in
      membranes of Saccharomyces cerevisiae--centrifugal elutriation and
      ultracytochemical study.
AB  - Exponential culture of a Saccharomyces cerevisiae strain with overexpressed
      aspartate carbamoyltransferase activity (ACTase) was chilled in ice and
      fractionated by centrifugal elutriation to several cell populations of increasing
      cell mass. The enzyme activity which belongs to the pyrimidine biosynthesis
      pathway, was detected in situ by a specific ultracytochemical reaction: the
      ACTase byproduct, monophosphate, was precipitated by cerium ions to cerium
      phosphate. During the outgrowth of nonbudding daughter cells (zero cells) the
      label appeared first in membranes of nuclear envelope and of mitochondria. In
      larger zero cells, this label appeared also in the endoplasmic reticulum,
      microvesicles and plasmalemma. In budding mother cells, the label was conspicuous
      in the whole cell-membrane complex. In most aged cells the ACTase activity was
      not detectable. The presence of ACTase activity in membranes of compartments
      conveying glycoproteins via the secretory pathway remains to be explained. To
      confirm the in situ detection of ACTase activity in membranes, we assayed the
      enzyme activity in both the 10,000 g sediment and supernatant prepared from yeast
      homogenate precentrifuged at 3000 g. From 23 to 43% of ACTase activity was
      detected in the sediments including membranes of wild-type and ACTase
      overexpressing strains.

PMID- 10664885
TI  - Glucose- and K(+)-induced acidification in different yeast species.
AB  - The process of acidification of the external medium after addition of glucose and
      subsequently of KCl to a suspension of yeast cells varies substantially from
      species to species. After glucose it is most pronounced in Saccharomyces
      cerevisiae and Schizosaccharomyces pombe but is very much lower in Lodderomyces
      elongisporus, Dipodascus magnusii and Rhodotorula gracilis. Both the buffering
      capacity and the varied effects of vanadate, suloctidil and erythrosin B indicate
      that the acidification is by about one-half due to the activity of plasma
      membrane H(+)-ATPase and by about one-half to the extrusion of acidic metabolites
      from cells. This is supported by the finding that a respiratory quotient greater
      than one (in various strains of S. cerevisiae and in S. pombe) is indicative of a
      greater buffering capacity and overall acidification of the medium. Taking into
      account the virtually negligible buffering capacity of the medium in the pH range
      where the effect of K+ is observed, the effect of K+ is generally of a similar
      magnitude as that of adding glucose. It is clearly dependent on (anaerobic)
      production of metabolic energy, quite distinct from the dependence of the H(+)
      ATPase-caused acidification.

PMID- 10664886
TI  - Development of papillae on colonies of two isopolyauxotrophic strains of
      Saccharomyces cerevisiae allelic in RAD6 during adenine starvation.
AB  - Papilla formation on colonies of two isopolyauxotrophic strains (ade2 his3 leu2
      trp1 ura3) allelic in RAD6 was compared in order to find proper conditions for
      selecting mutants of Saccharomyces cerevisiae with altered starvation-induced
      mutability. The most promising for this purpose appeared to be culturing low
      numbers of colonies on suboptimal plates with a growth-limiting amount of adenine
      at 28 degrees C for 20 d. Inactivation of the RAD6 gene which suppresses the
      level of starvation-associated mutagenesis markedly enhanced papilla formation
      under these conditions. Formation of almost all papillae on 20-d-old colonies of
      BJC3 was caused by mutation. Most of the papillae (75%) were white Ade+
      revertants. Three groups of these papillae were distinguished (Ade+, Ade+Rad6+
      and Ade+Trp+). Both, Ade+Rad6+ and Ade+Trp+ double reversions were very probably
      caused by a suppressor mutation. The less frequent red papillae had the same
      auxotrophic markers and UV sensitivity as BJC3 but their outgrowth in liquid
      media was greater. It appears that creation of these papillae is caused by
      mutation affecting the cell response to growth limitation by low concentrations
      of adenine.

PMID- 10664888
TI  - Isolation and characterization of bacteria degrading polychlorinated biphenyls
      from transformer oil.
AB  - Polychlorinated biphenyls from transformer oil were degraded in liquid culture
      under aerobic conditions using a mixed bacterial culture isolated from a
      transformer oil sample with a high content of polychlorinated biphenyls and other
      hydrocarbons. Four strains were identified, three of them corresponded to genus
      Bacillus, the other one to Erwinia. Bacteria in the transformer oil could remove
      as much as 65% of polychlorinated biphenyls (88% W/V in the transformer oil).
      Additional data showed that the two isolated strains of B. lentus were able to
      grow on transformer oil and degrade polychlorinated biphenyls by 80 and 83%. Our
      results provide evidence that microorganisms occurring in transformer oil have
      the potential to degrade polychlorinated biphenyls.

PMID- 10664887
TI  - Production of stress-inducible form of heat-shock protein 70 in mouse peritoneal
      adherent cells after in vivo infection by Francisella tularensis.
AB  - Heat-shock proteins (hsp) are ubiquitously produced molecules which participate
      in the protection of cells from environmental perturbation. Moreover, the members
      of the heat-shock protein 60 (hsp60) and 70 (hsp70) families play an important
      role in pathogen-host interactions. We studied in vivo production of the 70-kDa
      heat-shock proteins in the extract of peritoneal exudate cells (PEC) from mice
      injected intraperitoneally with an attenuated vaccine strain (LVS) of Francisella
      tularensis. We found a differential production of a highly stress-inducible
      member of the hsp70 family, designated hsp72, in three inbred strains of mice
      exhibiting either resistance or susceptibility to F. tularensis LVS infection.
      Whereas in tularemia-resistant mice hsp72 was even expressed in PEC without
      injection of bacteria and its production further increased on day 3 and slowly
      declined on days 5 and 7 after injection, in susceptible mice hsp72 production
      was highly inducible and restricted only to day 3 after in vivo infection.
      Further analysis of hsp72 expression revealed intracellular hsp72 accumulation
      and its preferential production by peritoneal adherent cells.

PMID- 10664889
TI  - Primary biodegradation of a series of alkyl sulfosuccinates by mixed bacterial
      culture.
AB  - A mixed bacterial culture capable of primary biodegradation of sodium alkyl
      sulfosuccinates R1-OOC-CH(SO3Na)-CH2-COO-R2 was obtained from soil microorganisms
      by enrichment cultivation and adaptation in the presence of mono-n-dodecyl
      sulfosuccinate. Gram-negative psychrophilic bacteria with proteolytic, lipolytic
      and ammonifying activities were prevalent in the culture. The process of primary
      biodegradation of alkyl sulfosuccinates can be described by first-order reaction
      kinetics. The rate constants for linear esters were ascending in the order C4 <
      C5 < C6 (45 mumol/min per g cell protein) and further descending with increasing
      length of the carbon chain C6 > C8 >> C13. Substitution of cyclohexyl for n-hexyl
      group resulted in fourfold decrease in biodegradation rate. Terminal branching of
      alkyl chain does not affect the rate of primary biodegradation.

PMID- 10664890
TI  - Gram staining with an automatic machine.
AB  - This study was undertaken to develop a new Gram-staining machine controlled by a
      micro-controller and to investigate the quality of slides that were stained in
      the machine. The machine was designed and produced by the authors. It uses
      standard 220 V AC. Staining, washing, and drying periods are controlled by a
      timer built in the micro-controller. A software was made that contains a certain
      algorithm and time intervals for the staining mode. One-hundred and forty smears
      were prepared from Escherichia coli, Staphylococcus aureus, Neisseria sp., blood
      culture, trypticase soy broth, direct pus and sputum smears for comparison
      studies. Half of the slides in each group were stained with the machine, the
      other half by hand and then examined by four different microbiologists. Machine
      stained slides had a higher clarity and less debris than the hand-stained slides
      (p < 0.05). In hand-stained slides, some Gram-positive organisms showed poor Gram
      positive staining features (p < 0.05). In conclusion, we suggest that Gram
      staining with the automatic machine increases the staining quality and helps to
      decrease the work load in a busy diagnostic laboratory.

PMID- 10664892
TI  - Coagulation factor V Leiden mutation in sudden fatal pulmonary embolism and in a
      general northern European population sample.
AB  - The R506Q point mutation in the gene coding for coagulation factor V (Leiden
      mutation) is the major underlying defect in resistance to activated protein C
      (APC), which predisposes to venous thrombosis. The risk of deep vein thrombosis
      is clearly elevated in carriers of the mutation, but the risk for pulmonary
      embolism has not been demonstrated to be as high. The aim of our study was to
      determine the frequency of the Leiden mutation in an autopsy series of sudden
      fatal pulmonary embolism cases. PCR and subsequent restriction enzyme digestion
      were applied for genotyping 164 cases of pulmonary embolism. According to our
      data, the allele frequency of the Leiden mutation is not higher in sudden fatal
      pulmonary embolism cases (0.8%, 95% CI 0-1.9%) than in the general Finnish
      population (1.5%, 95% CI 0-3.3%). In addition to the 97 Finns, we determined the
      frequency of the Leiden mutation in 255 individuals from the neighbouring
      populations (Saami, Komi, and Karelians from Russia and Estonians), and found the
      Saami to have the highest frequency of the Leiden mutation (6.3%, 95% CI 3.2-9.2)
      in the general northern European population sample studied here.

PMID- 10664891
TI  - Morphology and immunohistochemistry of rat aortic grafts.
AB  - Allotransplantation (TPL) of the abdominal aortic segments of BN donors was
      performed in 32 Lewis recipients with or without cyclosporin A (CyA)
      immunosuppression, and the vascular changes were compared to those of 10
      syngeneic grafts (Lewis-->Lewis) and to the autologous rat aortae. The vessels
      were examined 2, 3, 4 and 5 months post TPL by light microscopy, the thickness of
      intima and media was measured morphometrically and the cell infiltration of
      adventitia and intima was assessed semiquantitatively. Thirty-six aortae were
      examined by three-step enzyme immunohistochemistry (proof of selected
      differentiation, proliferation, cytoskeletal and connective tissue matrix
      antigens). The adventitia displayed an intense focal and scattered mononuclear
      cell infiltration; it was more discrete and focal in the intima. This cellularity
      persisted in the allografts but disappeared from the intima and was reduced in
      the adventitia of the isografts after four and five months. Disseminated ED1+
      activated macrophages were the most prominent population of infiltrates whereas
      modest numbers of adventitial ED2+ tissue macrophages remained constant
      throughout the intervals examined. CD4+ cells (focal and scattered) outnumbered
      (roughly twice) the scattered CD8+ lymphocytes; both these types were rare in the
      intima. Leukocyte invasion of the media was lacking (except for scarce isolated
      CD8+ cells in some allografts). In syngeneic grafts the smooth muscle cells (SMC)
      of media remained intact and the intimal thickening was slight to absent (about 5
      microns) four and five months post TPL. On the other hand, the allograft media
      underwent severe destructive changes (karyolysis, depletion of alpha-SMC actin,
      focal calcification and general thinning without rupture or aneurysm). The
      prominent allograft intimal thickening (70-80 microns) was due to the
      proliferation of longitudinally oriented myointimal cells (alpha-SMC actin, FD2,
      PCNA and Ki67+) and an increase in matrix substance (strong metachromasia and
      positivity of chondroitin-sulfate proteoglycan). The deposition of lipids
      remained discrete, without atheromatous plaques and mural thrombosis. All changes
      were comparable in CyA-treated and untreated animals. Thus the main lesions of
      the allografts were (i) persistent mononuclear infiltration chiefly in
      adventitia, (ii) destruction of medial SMC, and (iii) intimal thickening by
      proliferation of myointimal cells. At the postTPL intervals examined the
      proliferation and intimal migration of medial SMC were not apparent and a
      morphological correlate of significant anti-medial-SMC cytotoxic attack was
      lacking.

PMID- 10664893
TI  - Osteometric variation in the humerus: sexual dimorphism in South Africans.
AB  - There has been a surge of research on forensic anthropology in South Africa.
      Differences between the populations of this country and others are demonstrated
      in many studies. Yet, many forensic osteometric techniques based on other
      populations are still in use. The purpose of the present study is to develop an
      osteometric sex determination technique using the humerus. The sample is composed
      of skeletons of 104 whites and 88 blacks from the Dart and Pretoria collections.
      Six humeral dimensions were initially analyzed using stepwise discriminant
      function statistics. Humeral head diameter, deltoid tuberosity circumference and
      epicondylar breadth were individually calculated in order to make the technique
      usable for fragmented remains. The results indicated that the head and
      epicondylar diameters are the best in whites to differentiate sexes from each
      other, while head diameter and maximum length are best in blacks. Accuracy of
      correct classification was as high as 96% in whites and 95% in blacks.
      Crossvalidation provided the same accuracy as the original classification. These
      accuracy percentages are as high as those expected from the femur and tibia.
      Posterior probability, which measures the percent affiliation of the sample with
      its original sex group, was also mostly 80% or better. South African collections
      are ideal for osteometric analysis, because they are still growing in numbers
      with cross-sectional representatives from the country.

PMID- 10664894
TI  - Post mortem molecularly defined familial hypercholesterolemia and sudden cardiac
      death of young men.
AB  - Familial hypercholesterolemia (FH) is among the most common single-gene diseases
      and is due to mutations of the low-density lipoprotein (LDL) receptor gene. In
      heterozygous FH, serum LDL-cholesterol level is elevated two- to threefold
      compared to unaffected individuals, men in particular are prone to premature
      atherosclerosis and early cardiac deaths. However, very little data are available
      concerning the incidence of premature deaths in FH patients. In Finland two LDL
      receptor founder mutations cover two-thirds of FH cases, offering a unique
      possibility to study the potential role of FH in unexpected early cardiac deaths.
      We studied a total of 149 deceased who had suffered early (< or = 50 years)
      unexpected cardiac death due to coronary heart disease (CHD). Three individuals
      (2%) had molecularly defined heterozygous FH, and heterozygous FH was present in
      two (3%) of the 67 subjects who had demonstrable acute myocardial infarction
      (AMI). Considering that the two FH mutations cover two-thirds of FH cases in
      Finland, the overall prevalence of FH underlying early cardiac deaths caused by
      AMI may be estimated to be in the range 3 to 5%.

PMID- 10664895
TI  - Screening postmortem blood and tissues for nine classes [correction of cases] of
      drugs of abuse using automated microplate immunoassay.
AB  - A commercially available enzyme-linked immunosorbant assay (ELISA) was evaluated
      as a screening procedure for the detection of nine classes of abused drugs in
      postmortem blood and tissue specimens. Specifically, postmortem blood, fluid
      and/or tissue homogenates were screened for amphetamine (AMP), methamphetamine
      (MET), barbiturates (BARB), benzodiazepines (BZD), cannabinoids (CNB), cocaine
      (benzoylecgonine; BE), morphine-specific (MOR), opiates (class; OPI),
      phencyclidine (PCP) and lysergic acid diethylamide (LSD) by ELISA and by coated
      tube radioimmunoassay (CTR) (BARB, BE, OPI, PCP, LSD) or double-antibody
      radioimmunoassay (DAR) (AMP/METH, BZD, CNB). Specimens that screened 'positive'
      by any method were confirmed and quantitated by gas chromatography/mass
      spectrometry (GC/MS). The only assay that appeared to perform less optimally than
      RIA was the MOR assay (five false negatives). However, this assay is very
      specific for free morphine while the GC/MS confirmation method provided a total
      morphine value. The OPI assay was more sensitive, producing fewer false
      negatives, and is recommended for broad class opiate screening. EIA is an
      adequate alternative to RIA for screening postmortem specimens, including blood
      and tissue, for nine major classes of drugs.

PMID- 10664896
TI  - GC/MS determination of zolpidem in postmortem specimens in a voluntary
      intoxication.
AB  - An ingestion of an unknown quantity of Ivadal (zolpidem) tablets in a case of
      drug abuse is described. The authors report a new and fast method of analysing
      and determining the zolpidem concentration in postmortem specimens. Quantitation
      of zolpidem was performed by ethyl acetate extraction from alkalinized body
      fluids before GC/MS analysis. The analyses were performed without any complex
      sample clean-up steps and with little sample material. Postmortem concentrations
      of zolpidem in body fluids are given. The proposed method is a rapid procedure of
      analysis in cases of deliberate poisoning with the sedative-hypnotic drug,
      zolpidem.

PMID- 10664897
TI  - Fatal poisoning due to intravasation after oral administration of barium sulfate
      for contrast radiography.
AB  - A fatal poisoning after oral administration of barium sulfate for contrast
      radiography is reported. Barium sulfate is an insoluble salt and therefore is
      almost nontoxic. The case described here involves a 61-year-old woman who
      underwent two CT scans of the digestive tract with oral administration of barium
      sulfate during a surgical procedure. Within several hours after the first barium
      swallow examination the patient presented nonspecific neurologic and
      cardiovascular manifestations that rapidly progressed and led to death a few days
      later. Laboratory findings demonstrated elevated levels of barium in the blood
      and cerebrospinal fluid. The most likely mechanism of poisoning was progressive
      intravasation of barium due to stasis of contrast material related to intestinal
      obstruction.

PMID- 10664898
TI  - Fatal flecainide intoxication.
AB  - A fatal case attributed to flecainide acetate (Tambocor), a class Ic
      antiarrythmic drug, is presented. Flecainide was detected by GC/MS in gastric
      contents, blood and liver as well. The urine analysis revealed the presence of
      its dealkylated metabolite. Body fluids and tissue concentrations determined by
      GC/ECD were 7.7 mg/kg in femoral blood, 0.26 mg/kg in bile, 18 mg/kg in liver,
      0.17 mg/kg in cerebrospinal fluid, 0.22 mg/kg in brain cortex and 28.9 mg/kg in
      urine. The total amount of flecainide in gastric contents was about 43 mg. Even
      taking into account the postmortem redistribution of flecainide, its blood level
      still remains in the toxic range.

PMID- 10664899
TI  - Fatality caused by a combined trimipramine-citalopram intoxication.
AB  - A 53-year-old woman who was diagnosed as suffering from depression was found dead
      in her bed. The autopsy revealed no morphological changes sufficient to explain
      death. Toxicological analysis was performed and the drugs trimipramine (2.33
      mg/l), citalopram (4.81 mg/l) and zolpidem (0.07 mg/l) were identified in the
      femoral blood. A combined drug intoxication resulting in synergistic effects to
      cardiovascular disorders was proposed as the cause of death. An acute overdose
      and suicide was suggested by calculation of the parent drug to main metabolite
      ratios in femoral blood and liver tissue. The trimipramine to
      desmethyltrimipramine ratios were calculated to be 2.06 and 3.18, the citalopram
      to desmethylcitalopram ratios were 1.96 and 2.02.

PMID- 10664900
TI  - Further evolution of a literature database: the international use of a common
      software structure and methodology for the establishment of national
      consultation/liaison databases.
AB  - Every day there are 6000-7000 papers published in science. Since the C-L
      psychiatrist may be asked to consult on a patient with any medical illness, and
      who may be on any medical drug, methods need to be developed to review the recent
      literature and have an awareness of current findings. At the same time, teachers
      need to develop a current listing of seminal papers for trainees and
      practitioners of this subspecialty of psychiatry. Experts chosen because of their
      writings and acknowledged contributions to their subspecialty interests have
      sifted through thousands of articles to select the ones they regard as the most
      important for trainees in C-L psychiatry. In addition, certain countries--Spain,
      Portugal, Germany, Mexico, Australia and Brazil are developing national databases
      of C-L literature not only for their own use, but also to bring them to the
      attention of other parts of the world. This fifth iteration of the C-L literature
      database has especially targeted the period of 1996-1999--the millennium issue-
      in order to have easier access to contemporary essential studies on common
      problems. Part II of this issue describes the seminal cardiac drug-psychotropic
      drug interactions that the C-L psychiatrist may encounter in the most common
      medical disease in the United States--coronary heart disease--with advise to the
      practitioner as to their management. The use of the Internet and institutional
      Intranets is described.

PMID- 10664903
TI  - Consultation-liaison psychiatry database. 2000 update

PMID- 10664901
TI  - Cardiac drug and psychotropic drug interactions: significance and
      recommendations.
AB  - Understanding cardiac drug interactions with concurrent psychotropic
      prescriptions is essential for the practicing cardiologist and primary care
      physician, as well as for the psychiatrist. There has been an explosive use of
      new drugs in both psychiatry and cardiology without widespread knowledge of their
      potential interactions. The increasing tendency toward poly-pharmacy, the use of
      psychotropic medications by cardiologists and primary care physicians caring for
      cardiac patients, and the growth of the aging population present major challenges
      for the practitioner. Finally, there is a need to have models/paradigms for
      predicting potential drug interactions--e.g., the Cytochrome p450 schema. This
      paper describes a method to identify, understand, and codify the interactions
      between psychotropic and cardiac drugs, a systematic approach for updating this
      key database and specific cardiac-psychotropic drug interactions. Specifically,
      this paper 1) details the interactions, 2) addresses the level of their clinical
      significance, 3) describes the potential mechanism(s) of the interactions, and 4)
      offers recommendations to the clinician. Since the majority of the original
      clinical trials, either for cardiac medications or psychotropic drugs, do not
      include studies comparing these two drug domains contemporaneously, their
      interactions often become known only with their combined use in the clinical
      arena, using the patient as "guinea pig," and through subsequent reporting.

PMID- 10664902
TI  - Topics, contributors, and database. Consultation-Liaison Psychiatry Database
      (2000 update).

PMID- 10664904
TI  - A review: taking the sterile out of sterility.
AB  - Users of in-dwelling medical devices, prostheses and surgical dressings rely
      implicitly on their sterility. Rarely do consumers give any thought to what
      sterility really means. The general assumption is that manufacturers have adopted
      the most efficient and cost-effective methods of achieving sterility. Currently,
      terminal sterilization processes appropriate for the manufacture of medical
      devices are those that are deemed to give less than one chance in a million of a
      single, finished product item containing a viable organism. Such a definition of
      sterility is embodied in the European standard EN556 as a Sterility Assurance
      Level of 10(-6), based on the properties of heat-resistant endospores. However,
      is this level of sterility assurance appropriate for all categories of medical
      device? Moreover, do all medical devices which are labelled as sterile require
      the same level of treatment? This paper will demonstrate that in some instances,
      the high standards set for sterilization processing are unreasonable, not cost
      effective and exclude new sterilization technologies from being accepted by the
      regulatory authorities.

PMID- 10664905
TI  - Detection of Cryptosporidium oocysts in water: techniques for generating precise
      recovery data.
AB  - When determining the recovery efficiency of a procedure for the detection of
      Cryptosporidium or the removal efficiency of a treatment process, it is necessary
      to accurately enumerate a 'seed dose'. Conventional techniques for this are
      highly variable and consequently, can result in misleading data. In this study, a
      flow cytometric method was developed for the production of suspensions of
      Cryptosporidium oocysts in which the number of organisms could be precisely
      determined. A Becton Dickinson FACScalibur flow cytometer was employed to produce
      oocyst suspensions containing 100 oocysts. Analysis of these suspensions resulted
      in a mean dose of 99.5 oocysts (S.D. = 1.1, %cv = 1.1). These results indicate
      that the use of such suspensions to seed test systems generates far more accurate
      data than is presently possible using conventional techniques. In addition, the
      use of immunomagnetic separation (IMS) for the isolation of oocysts from three
      different water matrices, after seeding with oocysts counted using flow
      cytometry, was investigated. The recovery efficiency of the IMS procedure was
      found to be high, with the percentage recovery of oocysts ranging from 82.3 to
      86.3%, and the use of precise numbers of oocysts allowed accurate recovery
      efficiency data to be generated. A laser scanning instrument (ChemScan RDI) was
      employed for the rapid detection and enumeration of oocysts after capture using
      membrane filtration. This technique was found to be faster and easier to perform
      than conventional epifluorescence microscopy. These findings demonstrate that the
      ChemScan RDI system may be used as alternative procedure for the routine
      examination of IMS supernatant fluids for the presence of Cryptosporidium.

PMID- 10664906
TI  - Detection of low numbers of pathogenic Yersinia enterocolitica in environmental
      water and sewage samples by nested polymerase chain reaction.
AB  - Isolation of pathogenic Yersinia enterocolitica from water and sewage by
      traditional culture techniques is time-consuming and subsequent differentiation
      between pathogenic and non-pathogenic strains can be difficult and unreliable. A
      nested polymerase chain reaction (PCR) procedure was used for the detection of
      low numbers of Y. enterocolitica in spiked samples from natural surface sources
      with variable background flora ranging from oligotrophic water to sewage. Water
      and sewage samples were filtered and filters enriched overnight in a non
      selective medium. Nested PCR conducted on enriched broth, prepared by use of a
      rapid and simple preparation step consisting of centrifugation, proteinase K
      treatment and boiling, enabled the detection of 8-17 cfu 100 ml-1 water with
      background levels of up to 8700 heterotrophic organisms ml-1 and 10,000 cfu
      coliform organisms 100 ml-1 water. The analysis can be completed within 2-3 d and
      should be a significant tool in monitoring environmental waters and drinking
      water sources for the presence of pathogenic Y. enterocolitica.

PMID- 10664907
TI  - Distribution and seasonality of microbial indicators and thermophilic
      campylobacters in two freshwater bathing sites on the River Lune in northwest
      England.
AB  - Two freshwater bathing sites, the Crook O'Lune and the University Boathouse, on
      the River Lune in the north-west of England, were monitored over a 2 year period
      for the faecal indicators, faecal coliforms and faecal streptococci, the
      pathogens, Salmonella and Campylobacter, and compliance with the EU Directive on
      Bathing Water Quality. Faecal indicator numbers showed no seasonal variation,
      with numbers in the bathing season similar to those in the non-bathing season.
      They were consistently above the EU Guideline and Imperative standards so that if
      the EU Bathing Water Quality Directive (76/160/EEC) were applied, neither site
      would comply. Faecal indicator numbers in the sediments were an order of
      magnitude higher than in the overlying water. Campylobacter numbers showed
      seasonal variation in the water with higher counts in winter than in the summer,
      although numbers were low. Higher numbers were found in the sediments but there
      was no seasonal variation. Analysis of various inputs showed that indicators and
      campylobacters came from a mixture of sources, namely a sewage treatment works,
      agricultural run-off, streams and mallards. Microbial numbers in the water at the
      Crook O'Lune, which is closer to the sources of pollution, were twice those at
      the Boathouse. In the sediments they were six to eight times higher. Faecal
      coliforms were all identified as Escherichia coli of which 80% were a single
      biotype. Faecal streptococci were all enterococci of which 55% were E. avium, 38%
      E. faecalis and 7% E. durans. Salmonella was not isolated from either the water
      column or the sediments. Campylobacters were mainly Camp. jejuni, followed by
      Camp. coli, UPTC and Camp. lari.

PMID- 10664908
TI  - Survival of Escherichia coli O157:H7 in bottled natural mineral water.
AB  - A non-verotoxin-producing isolate of Escherichia coli O157:H7 was inoculated at
      final concentrations of 10(3) or 10(6) ml-1 into natural non-carbonated mineral
      water (MW), sterile natural mineral water (SMW) and sterile distilled deionized
      water (SDDW) and stored at 15 degrees C for 10 weeks. Samples were examined every
      7 d for the presence of E. coli O157:H7 using a resuscitative/selective agar
      procedure. The MW samples were also plated onto a non-selective agar, R2A, to
      enumerate E. coli O157:H7 and the autochthonous flora. There was a significant
      difference in the survival of E. coli O157:H7 (10(3) ml-1 inoculum) between the
      MW and the SDDW at time periods 0, 7, 14 (P < 0.005) 21, 28, 35 (P < 0.001) and
      42 d (P < 0.05) and between the MW and the SMW at time periods 7, (P < 0.05) 14,
      21 (P < 0.005) 28 (P < 0.01) and 35 d (P < 0.05), with the pathogen surviving
      longest in the MW samples. In contrast, at 10(6) ml-1, no significant differences
      in the survival of E. coli O157:H7 were observed between the water types. The
      presence of E. coli O157:H7 (10(3) ml-1) in the MW samples did not have an
      antagonistic effect on the recovery of the autochthonous flora. Transmission
      electron microscopy analysis demonstrated that the E. coli O157:H7 cells lyse
      during storage, releasing their contents into the surrounding environment. These
      substances may have been utilized by the autochthonous flora and thereby explain
      why the numbers of flora recovered from the inoculated MW samples were higher
      than those recovered from the uninoculated samples.

PMID- 10664909
TI  - Identification, characterization and purification of the lantibiotic
      staphylococcin T, a natural gallidermin variant.
AB  - Staphylococcin T (StT), an antibacterial agent produced by a Staphylococcus
      cohnii T strain, was purified to homogeneity by ammonium sulphate precipitation,
      gel filtration, cation exchange and fast performance liquid chromatography
      (FPLC). The final yield was about 20%, and over a 1000-fold increase in the
      specific activity was obtained. Mass determination (2166 Da), amino acid
      sequencing (Ile-Ala-Xaa-Lys-Phe-Leu-Xaa-Xaa-Pro-Gly-Xaa-Ala-Lys-block) and DNA
      sequencing demonstrated that StT is identical to gallidermin, a lanthionine
      containing antimicrobial peptide. StT has a broad spectrum of bactericidal
      activity against Gram-positive and some Gram-negative bacteria. StT appears to
      damage cell membrane, and as a result causes an efflux of ions and an immediate
      block in macromolecular synthesis. Moreover, electron microscopic observations
      reveal morphological changes, with a loss of ribosomes and condensation of the
      nucleoid DNA. These changes are followed by a dissolution of the cell contents
      resulting in a bacterial ghost composed of seemingly intact cell walls with
      remnants of the cytoplasmic membrane and internal structure. Since StT exhibits
      antimicrobial activity especially against the Staphylococcus species, this
      compound may be of use in the treatment of staphylococcal infections.

PMID- 10664910
TI  - Rapid and sensitive detection of Escherichia coli O157:H7 in bovine faeces by a
      multiplex PCR.
AB  - Cattle are considered the major reservoir for Escherichia coli O157:H7, one of
      the newly emerged foodborne human pathogens of animal origin and a leading cause
      of haemorrhagic colitis in humans. A sensitive test that can accurately and
      rapidly detect the organism in the food animal production environment is
      critically needed to monitor the emergence, transmission, and colonization of
      this pathogen in the animal reservoir. In this study, a novel multiplex
      polymerase chain reaction (PCR) assay was developed by using 5 sets of primers
      that specifically amplify segments of the eaeA, slt-I, slt-II, fliC, rfbE genes,
      which allowed simultaneous identification of serotype O157:H7 and its virulence
      factors in a single reaction. Analysis of 82 E. coli strains (49 O157:H7 and 33
      non-O157:H7) demonstrated that this PCR system successfully distinguished
      serotype O157:H7 from other serotypes of E. coli and provided accurate profiling
      of the shiga-like toxins and the intimin adhesin in individual strains. This
      multiplex PCR assay did not cross-react with the background bacterial flora in
      bovine faeces and could detect a single O157:H7 organism per gram of faeces when
      combined with an enrichment step. Together, these results indicate that the
      multiplex PCR assay can be used for specific identification and profiling of E.
      coli O157:H7 isolates, and may be applied to rapid and sensitive detection of E.
      coli O157:H7 in bovine faeces when combined with an enrichment step.

PMID- 10664911
TI  - Inactivation of hepatitis A virus in heat-treated mussels.
AB  - Hepatitis A is a widespread infectious disease world-wide. In Italy, shellfish
      consumption was shown to be a major risk factor for hepatitis A infection,
      especially when these products are eaten raw or slightly cooked. The aim of the
      present study was to evaluate Hepatitis A virus (HAV) resistance in
      experimentally contaminated mussels treated at different temperatures (60, 80 and
      100 degrees C) for various times. The presence of HAV was evaluated by cell
      culture infection and reverse transcriptase-polymerase chain reaction
      confirmation. The experiments, carried out on HAV suspension and contaminated
      mussel homogenate both containing about 10(5) 50% tissue culture infectious dose
      ml-1, showed that, under our experimental conditions, the treatments at 60
      degrees C for 30 min, 80 degrees C for 10 min and an immersion at 100 degrees C
      for 1 min were not sufficient to inactivate all the viruses; it was necessary to
      prolong the treatment at 100 degrees C for 2 min to completely inactivate the
      virus. Thus it is advisable to eat only cooked shellfish, paying particular
      attention to the times and temperatures used in the cooking process, since
      evidence suggests that the shellfish body may protect the virus from the heat
      effect.

PMID- 10664912
TI  - Sensitivity of Candida albicans to negative air ion streams.
AB  - Negative air ions (NAIs) are known to kill C. albicans; however, their precise
      mechanism of action is uncertain. Elucidation of this has been hampered by a lack
      of reproducibility between results obtained by different investigators. The aim
      of this study was to determine the influence of variation in experimental
      parameters on the sensitivity of C. albicans to negative air ions and the role of
      ozone in this process. Ten strains of C. albicans were exposed to NAIs generated
      at different emitter distances, exposure times, relative humidities and under
      aerobic and oxygen-free conditions. In further experiments, ozone levels were
      measured under the same conditions. The effect of NAIs on C. albicans growth was
      assessed by measuring the area of the zone of inhibition generated around the
      electrode of the ionizer. There was a significant reduction in area of zone of
      inhibition with increasing emitter distance (P < 0.05), relative humidity (P <
      0.05) or under oxygen-free conditions (P < 0.05). Increases in exposure time
      resulted in a significant increase in growth inhibition (P < 0.05). Ozone levels
      increased with increasing exposure times (P < 0.01) but were significantly
      reduced as emitter distance increased (P < 0.01). When utilized in a
      nonventilated room, levels of ozone produced did not exceed recognized safety
      limits. These results (a) demonstrate the importance of careful control of
      experimental parameters if reproducibility of studies involving NAIs is to be
      achieved, and (b) highlight the possible role of ozone in the microbicidal
      effects of NAIs.

PMID- 10664913
TI  - A method for bacteriocin quantification.
AB  - Different aspects of the most commonly used assay methods in the study of
      bacteriocins were examined. The conditions under which extraction and incubation
      (including exposure time) take place were analysed, and several different formal
      models that are usually employed to calculate ID50 were compared. As an
      alternative designed to overcome the problems which characterize the response of
      micro-organisms that are sensitive to bacteriocins, an operative procedure in a
      liquid medium and a modified re-parameterized logistic equation is proposed. When
      applied to the inhibition of Leuconostoc mesenteroides by nisin, the model allows
      an optimal experimental procedure to be defined.

PMID- 10664914
TI  - Physical and metabolic causes of sub-lethal damage in Listeria monocytogenes
      after long-term chilled storage at 4 degrees C.
AB  - Cells of Listeria monocytogenes display sub-lethal injury when subjected to long
      term chill-storage in a nutrient-poor environment. The physical and metabolic
      causes of sub-lethal injury to two meat (L61 and L62) and two clinical (L98 and
      L99) L. monocytogenes strains chill-stored (4 degrees C) for 4 weeks in phosphate
      buffered saline at pH 7.0 and pH 5.5, and pH 5.5 in the presence of 0.3%
      potassium sorbate, were characterized. Causes of sub-lethal injury were
      determined by examining changes in the cell structure, leakage of nucleic acids
      and proteins from the cells, and cell recovery from injury in the presence of the
      metabolic inhibitors rifampicin, D-cycloserine, carbonyl cyanide m
      chlorophenylhydrazone and chloramphenicol. Visible shrinkage of the cytoplasm and
      slight cell wall damage were apparent over the 4 week storage period by electron
      microscopy for all four strains and three storage conditions. By contrast, over
      the same storage period, only three of the strains (L62, L98 and L99) displayed
      slight leakage of cellular content in all three storage media, while one strain
      (L61) displayed greater leakage. The three strains also displayed similar storage
      media-dependent metabolic damage. For these strains, phosphate-buffered saline pH
      5.5 caused the least damage and potassium sorbate, the most. Recovery experiments
      also indicated that at pH 5.5, the energy transduction system of these three
      strains remained undamaged, and that injury to the cell transcription machinery
      was greatest at pH 7.0. The fourth strain, L61, displayed less damage than the
      others but this was attributed to the death of the injured cell sub-population in
      this strain. In this study, damage to sub-lethally injured chill-stored L.
      monocytogenes was different from that caused by other agents, such as heat.
      Therefore, cells injured by chill-storage under starvation conditions may require
      novel protocols to assure their effective recovery.

PMID- 10664915
TI  - Purification and characterization of a bacteriocin produced by Lactobacillus
      acidophilus IBB 801.
AB  - Lactobacillus acidophilus IBB 801 produces a small bacteriocin, designated
      acidophilin 801, with an estimated molecular mass of less than 6.5 kDa. It
      displays a narrow inhibitory spectrum (only related lactobacilli but including
      the Gram-negative pathogenic bacteria Escherichia coli Row and Salmonella panama
      1467) with a bactericidal activity. The antimicrobial activity of cell-free
      culture supernatant fluid was insensitive to catalase but sensitive to
      proteolytic enzymes such as trypsin, proteinase K and pronase, heat-stable (30
      min at 121 degrees C), and maintained in a wide pH range. The proteinaceous
      compound was isolated from cell-free culture supernatant fluid and purified.
      Crude bacteriocin was isolated as a floating pellicle after ammonium sulphate
      precipitation (40% saturation) and partially purified by extraction/precipitation
      with chloroform/methanol (2/1, v/v). Further purification to homogeneity was
      performed by reversed phase Fast Performance Liquid Chromatography. The amino
      acid composition was determined. Amino acid sequencing revealed that the N
      terminal end was blocked.

PMID- 10664916
TI  - Relationship between lymphocyte and clinical steroid responsiveness in focal
      segmental glomerulosclerosis.
AB  - A remission in nephrotic proteinuria with steroid treatment appears to favorably
      alter the natural history of focal segmental glomerulosclerosis (FSGS). It is not
      known why some patients have a favorable response to steroid treatment whereas
      others do not. Considering the possibility that differences in the
      pharmacodynamic responsiveness to steroids among patients might be one factor,
      the authors examined the relationship between the pretreatment suppressive effect
      of steroids on lymphocyte proliferation (% inhibition) in vitro and the short-
      and intermediate-term responses of creatinine clearance (Clcr) and/or nephrotic
      proteinuria (urine protein/creatinine ratio = Up/c) in 13 patients with FSGS.
      There were significant correlations between % inhibition and the changes in Clcr
      at 3 (r = 0.92, p < 0.001) and 6 (r = 0.86, p < 0.01) months and the changes in
      Up/c at 3 months (r = -0.74, p = 0.02). Thus, the greater the pretreatment
      lymphocyte steroid sensitivity, the greater the increase in Clcr or decrease in
      Up/c. The changes in these parameters could not be accounted for on the basis of
      steroid dose or histopathology. The in vitro sensitivity of FSGS patients'
      lymphocytes to steroids may be of value in anticipating their clinical response
      to treatment.

PMID- 10664917
TI  - Effects of celecoxib, a novel cyclooxygenase-2 inhibitor, on platelet function in
      healthy adults: a randomized, controlled trial.
AB  - Conventional nonsteroidal anti-inflammatory drugs (NSAIDs) nonspecifically
      inhibit cyclooxygenase-1 (COX-1), an enzyme critical to normal platelet function,
      and COX-2, which mediates inflammatory response mechanisms. Celecoxib, an
      antiarthritic agent that inhibits COX-2 but spares COX-1 at therapeutic doses, is
      expected to have minimal effects on platelet function. A double-blind,
      randomized, placebo-controlled study of 10 days' duration was conducted in 24
      healthy adults to compare the effects on platelet function of a supratherapeutic
      dose of celecoxib (600 mg bid) with a standard dose of naproxen (500 mg bid), a
      conventional NSAID. Ex vivo platelet aggregation in response to standard agonists
      (collagen, arachidonate, or U46619 [a thromboxane A2 receptor agonist]), bleeding
      time, and serum thromboxane B2 (TxB2) level were measured. Unlike celecoxib or
      placebo, naproxen produced statistically significant reductions in platelet
      aggregation and serum TxB2 levels and increased bleeding time. The results
      indicate that even at supratherapeutic doses, celecoxib will not interfere with
      normal mechanisms of platelet aggregation and hemostasis, supporting the premise
      that celecoxib is COX-1 sparing relative to conventional NSAIDs.

PMID- 10664918
TI  - Baseline pain and response to analgesic medications in the postsurgery dental
      pain model.
AB  - In designing clinical trials for the treatment of acute pain, enrollment of
      patients with moderate to severe pain is recommended even when the desired
      indication is treatment of mild pain. To test this approach, the authors explored
      the results of two studies that had the same standard placebo-controlled,
      parallel-group design and that compared the study medication to a single dose of
      ibuprofen 400 mg. One study had 25 subjects, the other 50 in its ibuprofen arm.
      Subjects indicating moderate or severe pain (on a scale ranging from 0 = none, 1
      = mild, 2 = moderate, 3 = severe) following a surgical extraction of two or more
      third molars were enrolled. There was a difference between the ibuprofen groups
      in these two studies in average baseline pain intensity (PI) (2.88 +/- 0.33 vs.
      2.26 +/- 0.44). In the higher baseline group, PI decreased faster, achieving
      lower levels of PI that were maintained for the rest of the study period. The
      results of pain relief measurements paralleled those of PI. The authors conclude
      that including patients with a higher degree of baseline pain in the
      postoperative dental pain model has the potential to increase discrimination of
      analgesic properties of new drugs.

PMID- 10664919
TI  - A comparison of fluoride bioavailability from a sustained-release NaF preparation
      (Neosten) and other fluoride preparations.
AB  - Twelve normal subjects completed a crossover study with sustained-release sodium
      fluoride (Neosten, 11.3 mg F), monofluorophosphate (MFP, 10 mg F), and plain
      sodium fluoride (P-NaF, 11.3 mg F). After each preparation was given with 400 mg
      calcium, serum fluoride (Fser) was measured for 24 hours, and pharmacokinetic
      data were calculated. Fluoride absorption in the Neosten group, as measured by
      change in the area under the curve (delta AUC) of Fser, was less than 33% of that
      in the MFP and P-NaF treated groups. Both peak Fser (Cmax) and peak-basal
      variation in the Neosten group were 25% that found in the other groups. t1/2 was
      nearly twofold greater after Neosten. MFP and P-NaF showed greater
      bioavailability than Neosten and much higher Cmax that exceeded the toxic
      threshold of Fser (190 ng/ml). These findings could explain the ineffectiveness
      of MFP and P-NaF observed in recent clinical trials.

PMID- 10664920
TI  - Single-dose pharmacokinetics of repaglinide in subjects with chronic liver
      disease.
AB  - Repaglinide is a novel insulin secretagogue developed in response to the need for
      a fast-acting, oral prandial glucose regulator for the treatment of type 2 (non
      insulin-dependent) diabetes mellitus. Repaglinide is metabolized mainly in the
      liver; its pharmacokinetics may therefore be altered by hepatic dysfunction. This
      open, parallel-group study compared the pharmacokinetics and tolerability of a
      single 4 mg dose of repaglinide in healthy subjects (n = 12) and patients with
      chronic liver disease (CLD) (n = 12). Values for AUC and Cmax were significantly
      higher in CLD patients compared with healthy subjects, and the MRT was prolonged
      in CLD patients. Values for tmax did not differ between the groups, but t1/2 was
      significantly prolonged in CLD patients compared with previously determined
      values in healthy subjects. AUC was inversely correlated with caffeine clearance
      in CLD patients but not in healthy subjects. Blood glucose profiles were similar
      in both groups. Adverse events (principally hypoglycemia) were similar in the two
      groups; none was serious. Repaglinide clearance is significantly reduced in
      patients with hepatic impairment; the agent should be used with caution in this
      group.

PMID- 10664921
TI  - Optimization of oral etoposide dosage in elderly patients with non-Hodgkin's
      lymphoma using the fraction of dose absorbed measured for each patient.
AB  - This study was undertaken to investigate the pharmacokinetics of etoposide for
      optimizing its oral dosage in elderly patients with non-Hodgkin's lymphoma (NHL)
      using the fraction of dose absorbed calculated from the data generated from first
      oral and intravenous doses in the same patient. Twenty-three NHL patients (ages
      61-95 years) entered this study. Each received 50 mg/m2 of etoposide by 1-hour
      i.v. infusion, which was repeated every 24 hours for 5 days. The second cycle
      commenced on day 21, with etoposide being administered by mouth at a dose as
      close to 50 mg/m2 as possible. Serial blood samples were collected and analyzed
      for etoposide by HPLC. The fraction of dose absorbed (F) was calculated as F =
      (AUCor/AUCi.v.) (Di.v./Dor), and etoposide was then given orally for the
      following 20 days at a daily dose equivalent to Dor/F. After 1 week free of
      etoposide administration, a second cycle of oral etoposide at the adjusted dose
      was given for 21 days. The mean +/- SD values for t1/2 beta, tmax, Cmax, CLTor,
      and MRT observed following the first oral dose were 8.98 +/- 4.84 h, 1.39 +/-
      0.96 h, 0.083 +/- 0.046 mg.L-1/mg.m-2, 1.89 +/- 1.2 L.h-1/m2, and 10.37 +/- 2.76
      h, respectively, and those observed following the first intravenous dose were
      8.05 +/- 5.11 h, 1.57 +/- 0.17 h, 0.142 +/- 0.043 mg.L-1/mg.m-2, 1.25 +/- 0.44
      L.h-1/m2, and 7.69 +/- 1.53 h, respectively. The mean +/- SD of F was 0.80 +/-
      0.34. The data obtained indicate that optimization of etoposide oral dosage using
      F yielded good clinical results while keeping the morbidity at a level that is
      similar to that of the i.v. administration.

PMID- 10664922
TI  - Pharmacokinetics and safety of duloxetine, a dual-serotonin and norepinephrine
      reuptake inhibitor.
AB  - The pharmacokinetics and safety of duloxetine were evaluated in a single-blind,
      placebo-controlled, escalating multiple-dose study in 12 healthy male subjects.
      In the treatment group (n = 8), duloxetine was administered orally at a starting
      dose of 20 mg twice daily (bid) and escalated at weekly intervals to 30 mg bid,
      then to 40 mg bid. The observed plasma concentration-time data at all three dose
      levels were adequately described by a one-compartment model with a first-order
      absorption rate constant. The mean oral clearance, apparent volume of
      distribution, and half-life values were 114 L/h (range: 44 to 218 L/h), 1943 L
      (range: 803 to 3531 L), and 12.5 h (range: 9.2 to 19.1 h), respectively.
      Somnolence, nausea, and dry mouth were observed following the initial dose, but
      they resolved with continuing drug administration. Duloxetine was not associated
      with clinically significant changes in blood pressure (BP) or heart rate (HR)
      measured in the standing position. However, in recumbent position, small
      increases in systolic (< or = 9 mmHg) and diastolic (< or = 5 mmHg) BP and small
      decreases in HR (< or = 6 beats/min) were observed. Abrupt discontinuation of
      duloxetine was associated with a small increase in mean HR (< or = 12 beats/min).
      In 3 subjects, abrupt discontinuation was also associated with transient sleep
      disturbance. No clinically important changes in electrocardiograms, cardiac
      intervals, clinical laboratory tests, and neurological functions were observed.
      These results indicate that duloxetine exhibits linear pharmacokinetics with
      respect to dose and duration of treatment and that a multiple oral dose regimen
      starting at 20 mg bid and gradually escalating up to 40 mg bid was generally well
      tolerated.

PMID- 10664923
TI  - Comparison of the initial hemodynamic effects of immediate-release versus
      sustained-release isosorbide-5-mononitrate following single oral doses.
AB  - In this double-blind, randomized, placebo-controlled cross-over study, the
      authors investigated the initial time course of effects of isosorbide-5
      mononitrate (IS-5-MN) on hemodynamic parameters in 15 healthy male volunteers
      after administering a single oral dose of either an immediate-release formulation
      (IS-5-MN 20 mg) or of a sustained-release formulation (IS-5-MN 50 mg). The latter
      formulation released 15 mg IS-5-MN immediately, while 35 mg of the dose was
      sustained release. The onset of effect on the a/b-ratio of the finger pulse curve
      (20 minutes after administration) and on heart rate following orthostatic
      challenge (30 minutes) was not different following ingestion of either the
      immediate-release or the sustained-release formulation. Only the systolic blood
      pressure following orthostatic challenge was affected earlier after ingestion of
      the immediate-release form of IS-5-MN (10 vs. 30 minutes). There was no
      statistically significant difference in the maximum effect on the measured
      hemodynamic parameters between the two formulations. There was no significant
      difference with respect to the effect per dose between both of the active
      treatments (i.e., IS-5-MN 20 mg immediate release and IS-5-MN 50 mg sustained
      release) within 6 hours after administration. The hemodynamic findings were
      consistent with the observed rates of the increase of plasma concentrations of IS
      5-MN following both formulations. Thus, the administration of the sustained
      release formulation of IS-5-MN 50 mg caused similar maximum effects when compared
      with an immediate-release formulation (20 mg). While the onset of effect of IS-5
      MN on the a/b-ratio of the finger pulse curve and on heart rate following
      orthostasis was similar after administration of either the immediate- or the
      sustained-release formulation, the onset of effect of the sustained-release
      formulation on systolic blood pressure orthostasis was determined slightly later.
      However, the latter difference seems to be of minor clinical relevance.

PMID- 10664924
TI  - Information overload in the teaching of pharmacology.
AB  - Medical students are usually drawn from the best of students, but it is not
      unusual to see these brilliant students fail their exams or even dismissed from
      medical school because of poor academic performance. Information overload has
      been recognized as one of the major contributing factors to this problem. The
      situation is expected to get worse, with the ever-present technology-induced
      exponential growth in information. In discussing this issue, the authors echo the
      concerns of several experts regarding the content overload of medical school
      curricula, particularly in pharmacology. It is the increasing awareness of this
      problem that led the Association of American Medical Colleges and the General
      Medical Council of Britain to promote the concept of a core curriculum for each
      of the principal disciplines in medicine. Several medical schools have adopted
      the concept and also the problem-based learning approach, which focuses on
      ameliorating the complex problems associated with information growth in medical
      education. Based on the authors' experience as medical students, medical
      practitioners, and pharmacology teachers, they discuss the factors that
      contribute to information overload, from psychological and nonpsychological
      perspectives. Issues such as the design and structure of the curriculum, the
      quality of training and effectiveness of the teachers (clinically qualified vs.
      nonclinically qualified teachers), and the psychological preparedness of the
      students are discussed. The authors make suggestions for improvement.

PMID- 10664926
TI  - Drug interaction between cimetidine and timolol ophthalmic solution: effect on
      heart rate and intraocular pressure in healthy Japanese volunteers.
AB  - Systemic adverse effects of timolol ophthalmic solution given at usual
      therapeutic doses have been well characterized. Timolol is partially metabolized
      by cytochrome P450 (CYP) 2D6. Cimetidine inhibits the activity of cytochrome
      P450, including CYP2D6, leading to reduced systemic clearance of concomitant
      drugs. Coadministration of cimetidine has been speculated to affect the
      pharmacological effects of timolol ophthalmic solution, resulting in increased
      blood concentration. To evaluate whether administration of cimetidine with
      timolol ophthalmic solution increased the degree of beta-blockade, 12 healthy
      Japanese male volunteers ages 19 to 26 received cimetidine (400 mg), on oral
      placebo, timolol maleate 0.5% (0.05 mL to each eye), or placebo eye drops in a
      randomized, double-blind, Latin-square design. The oral drug alone was given for
      3 days, and on the 4th day, eye drops were applied after oral drug
      administration. At baseline and 1, 3, and 6 hours after eye drop administration,
      blood pressure and heart rate (HR) were measured before and after exercise.
      Intraocular pressure (IOP) was measured at rest. A visual analog scale (VAS) was
      used to assess subjective bodily feelings in exercise tolerance after every
      physical exercise. The exercise HR, exercise systolic blood pressure (SBP), and
      resting SBP were reduced following timolol with and without cimetidine compared
      with the placebo (p < 0.01, respectively). Administration of cimetidine with
      timolol ophthalmic solution resulted in additional reductions of the resting HR
      and IOP. VAS detected a significant reduction in exercise tolerance from timolol
      ophthalmic solution (p < .05). In conclusion, administration of cimetidine with
      timolol ophthalmic solution increased the degree of beta-blockade.

PMID- 10664925
TI  - Drug interaction studies with repaglinide: repaglinide on digoxin or theophylline
      pharmacokinetics and cimetidine on repaglinide pharmacokinetics.
AB  - Drug interaction studies were carried out to ensure that hypoglycemia due to
      inhibition of repaglinide elimination or chronic hyperglycemia due to inhibition
      of repaglinide absorption was avoided. Conversely, the effects of repaglinide on
      the pharmacokinetics of drugs with only a narrow margin between effective and
      toxic concentrations, such as digoxin or theophylline, were determined. The
      studies reported here compared monotherapy with combined therapies in healthy
      volunteers. There were no significant differences between the pharmacokinetic
      parameters of repaglinide when given as monotherapy and when administered
      concurrently with cimetidine. Similarly, the coadministration of repaglinide and
      digoxin did not influence the pharmacokinetics of digoxin administered alone.
      When repaglinide was coadministered with theophylline, the only pharmacokinetic
      change was that the peak plasma theophylline concentration was slightly reduced.
      No direct drug-drug interactions were found in these studies, suggesting that
      repaglinide may be coprescribed with cimetidine, digoxin, or theophylline at the
      dosage used for monotherapy.

PMID- 10664927
TI  - Unusually low clearance of two CYP3A substrates, alprazolam and trazodone, in a
      volunteer subject with wild-type CYP3A4 promoter region.
AB  - A healthy 40-year-old Caucasian male volunteer displayed unusually low clearance
      and long elimination half-life of alprazolam and trazodone, two CYP3A substrate
      drugs, following single-dose oral administration in clinical pharmacokinetic
      studies. Genomic DNA isolated from the individual's peripheral blood was
      subjected to polymerase chain reaction amplification and subsequent sequence
      analysis of a 592 base-pair segment upstream from the CYP3A coding region. The
      analysis revealed no variation from wild-type in the nucleotide present at
      position -290, previously suggested to influence expression and/or activity of
      CYP3A. The functional significance of this promoter region mutation is unclear
      and requires further evaluation.

PMID- 10664928
TI  - Inhibition of histamine or allergen-induced wheals by a single dose of
      acrivastine, fexofenadine or cetirizine.
AB  - Certirizine, a potent H1-blocking agent, is often recommended as an emergency
      drug in anaphylactic reactions because of its well documented fast onset of
      action. In this randomized, cross-over study we compared the onset of action
      after a single dose of two recently introduced antihistamines, acrivastine and
      fexofenadine, with that of cetirizine. The inhibition of the wheal-and-flare
      reaction produced by skin prick test with histamine in 20 healthy volunteers and
      with a relevant pollen allergen in 20 atopic patients, respectively, were
      measured before and at regular intervals up to 60 min after the ingestion of
      acrivastine (8 mg and 16 mg), fexofenadine (120 mg) and cetirizine (10 mg and 20
      mg). Wheal-and-flare reaction were significantly inhibited 20 min after the
      intake of 16 mg acrivastine in atopic patients and 30 min after intake of 8 mg
      acrivastine in healthy volunteers, whereas cetirizine produced a significant
      inhibition of the wheal-and-flare reaction within 40-60 min. No significant
      inhibition could be observed within 60 min after fexofenadine intake. Therefore,
      in clinical settings when a fast onset of the H1-blocking action is mandatory
      (e.g., after insect stings or for short-term prophylaxis) we recommend
      acrivastine.

PMID- 10664929
TI  - Risk factors for latex sensitization among health care workers.
AB  - Health care workers, children with spina bifida and rubber industry workers show
      higher prevalence of latex sensitization compared to the general population, and
      they are considered at-risk groups. Our aim was to establish the prevalence of
      latex allergy among health care workers at the Clinica Universitaria of Navarra
      and to analyze potential risk factors, including personal and family history of
      atopy, sex, as well as factors leading to enhanced exposure to latex, such as
      being a nurse, belonging to surgical departments, having undergone previous
      surgery and the number of gloves employed per week. Health care workers (n =
      1,150) (doctors, nurses, assistant nurses, laboratory technicians and practicing
      medical and nursing students) were evaluated using a questionnaire and skin prick
      test (SPT). Serum specific IgE was determined by CAP-FEIA (Pharmacia, Sweden) in
      those with positive SPT. The participation index was 26.17%: 301 volunteers
      answered the questionnaire and underwent SPT. Fifteen subjects presented positive
      SPT to latex. It was found that 5% of the health care workers from the Clinica
      Universitaria were sensitized to latex allergens. Thirteen were females and two
      males. Mean age was 38.4 (+/- 7.09) years. Nine were nurses, three assistant
      nurses, one nursing student and two medical doctors. Eight belonged to medical,
      five to surgical and two to laboratory departments. There were no significant
      differences among the subjects in the prevalence of latex sensitization. Fourteen
      reported symptoms related to latex, mostly pruritus, dryness and/or redness of
      the hands (n = 12) and rhinitis (n = 6). Only one subject reported no symptoms
      when using latex products. Eight were atopic; personal history of atopy was the
      only significant (odds ratio = 5.10, p < 0.01) risk factor for latex
      sensitization. It was concluded that atopic health care workers show a more
      increased risk of latex sensitization than those who are nonatopic.

PMID- 10664930
TI  - Time-course study of the levels of urinary leukotriene E4, serum thromboxane B2
      and serum eosinophil cationic protein in spontaneous asthma attacks in five
      children.
AB  - Leukotrienes thromboxanes, and eosinophil cationic protein (ECP) are chemical
      mediators involved in airway inflammation. We investigated time courses of
      urinary leukotriene E4 (LTE4), serum thromboxane B2 (TXB2) and serum ECP,
      together with blood eosinophil count during asthmatic attacks in five children.
      Just after the onset of an asthma attack, urinary LTE4 levels reflected the
      severity of the attack and decreased during the course of clinical improvement
      with various therapies; however, they did not change in the course of an attack
      in one of five patients. The other parameters showed less or no significant
      relation to clinical severity and improvements. Since LTE4 is a stable product
      from total cysteinyl leukotrienes, it appears to be one of important mediators in
      most asthma attacks in children. This study suggests that LTE4 is a useful marker
      for monitoring severity and improvement of spontaneous attacks of asthma.

PMID- 10664931
TI  - Anaphylactic reaction in experimental malnutrition.
AB  - We evaluated the effects of malnutrition on the allergic response in male EPM-1
      Wistar rats. The animals underwent two dietary regimens from the 21st to the 60th
      day of life as follows: control animals were fed a normoproteic diet (18% casein)
      and malnourished animals a hypoproteic diet (4.5% casein). On day 60, some of the
      animals were sacrificed for determination of total serum protein and albumin
      levels. In addition, within each subgroup of the remaining animals, some
      underwent intraperitoneal immunization with ovalbumin in aluminum hydroxide.
      Thus, four groups of animal were obtained: immunized controls (n = 11); immunized
      malnourished animals (n = 11); unimmunized controls (n = 7) and unimmunized
      malnourished rats (n = 8). Fourteen days after sensitization with ovalbumin, the
      animals were challenged with intravenous ovalbumin in order to induce an
      anaphylactic reaction, which was evaluated by vascular permeability increase as
      assessed by the Evans blue dye extravasation method. Extravasation of Evans blue
      was quantitated in dried gastrointestinal tissues obtained from rats sacrificed
      10 min after induction of the anaphylactic reaction. Passive cutaneous
      anaphylaxis (PCA) reactions were also evaluated in the controls and malnourished
      rats. The adequacy of our model was confirmed by the reduction in weight gain, in
      food intake, and in total protein and albumin serum levels in malnourished rats
      as compared to controls at 60 days of life. The anaphylactic reaction induced
      significant increase in vascular permeability particularly among control animals.
      PCR results showed significantly lower titers in malnourished animals when their
      sera were injected into the skin of control animals. In contrast, PCA reactions
      using sera from immunized control rats to inject into the skin of malnourished
      rats showed an equally intense reaction as that observed in control animals. Our
      results suggest that malnourished animals have a normal capacity of releasing
      inflammatory mediators, and show a normal vascular response after anaphylaxis.
      The diminished vascular response seen in the gastrointestinal tract in
      malnourished animals, as compared to controls, may be due to the production of
      lower levels of IgE antibodies caused by malnutrition.

PMID- 10664932
TI  - Competitive immunoassay for antigenic latex protein measurement: rabbit antiserum
      based assay compared to modified Lowry and human IgE-inhibition methods.
AB  - A new rabbit antiserum-based assay was designed and evaluated for the assessment
      of the allergen potency of latex medical gloves, since total protein measurement
      by modified Lowry method remains unsatisfactory and the human IgE-inhibition
      method is limited by the use of sera from type I allergic patients. Four rabbit
      sera against a nonammoniated latex extract were shown by immunoblotting to have
      similar binding patterns to those obtained by human IgE. One rabbit serum was
      used to develop a competitive immunoassay for antigenic latex proteins (CIALP).
      The same nonammoniated latex extract was used for coating and calibration. The
      lower detection limit of the method was 0.085 microgram/g of glove. Antigenic
      proteins measured by CIALP for 77 latex glove extracts (33 pairs of surgical
      gloves and 11 exam gloves) showed positive correlation with those of the modified
      Lowry method (r = 0.4; p < 0.001). For 36 extracts made from the right and the
      left hand of 18 out of the 33 surgical latex gloves tested, inhibition of human
      specific-IgE results did not correlate with the modified Lowry method but did
      with the CIALP results (r = 0.8, p < 0.0001). The CIALP, which is well correlated
      with the human IgE-inhibition test, enables the assessment of the allergenicity
      of latex medical gloves by measuring the antigenic proteins.

PMID- 10664933
TI  - Expression of cyclooxygenase in nasal polyps from atopic and nonatopic subjects.
AB  - Cyclooxygenase (COX) 1 and 2 are two isoforms of a crucial enzyme in the
      metabolism of arachidonic acid to prostaglandins, thromboxanes and prostacyclin.
      It is now clear that COX-1 is expressed in the majority of cells constitutively,
      and COX-2 appears after stimulation. The role of cyclooxygenase expression in the
      pathophysiology of the airways has not been elucidated. In this study we aimed to
      compare cyclooxygenase expression in nasal polyps removed from well-defined
      atopic and nonatopic subjects. Monoclonal antibodies against COX-total (detecting
      both COX-1 and COX-2 epitopes) and anti-COX-2 combined with peroxidase
      antiperoxidase (PAP) visualizing system were used to assess COX-total and COX-2
      expression in cryostat sections of nasal polyps from both groups of patients.
      Chromotrope R2 or toluidine blue staining were used to detect the presence of
      eosinophils and mast cells, respectively. We demonstrated that cryostat sections
      of nasal polyps from both groups of patients revealed COX-total and COX-2
      expression with similar intensity. There were no significant differences in
      distribution of COX-total or COX-2 immunoreactivity in nasal polyps tissue
      between atopic and nonatopic group. No correlation between density of cells
      expressing COX-2 and the number of mast cells and eosinophils was found. Our data
      indicate that COX-2 is expressed in nasal polyps from both atopic and nonatopic
      patients.

PMID- 10664934
TI  - Hemopoietic progenitor cells in atopic dermatitis skin lesions.
AB  - We have recently shown the expression of lymphoid early developmental markers,
      including CD104, Thy 1, CD1a, Pgp-1 and TdT, by the cells constituting atopic
      dermatitis skin infiltrates. To further characterize the cellular phenotypes we
      used an indirect immunoperoxidase assay to analyze sections from two atopic
      dermatitis lesion skin biopsies using the following as first step monoclonal
      antibodies (MAB): anti-CD34, CD2, CD5 and CD7. CD34+ mononuclear cells and
      endothelial cells were identified. A strong immunoreaction was observed for the T
      lineage marker CD2 and CD5, but a poor reaction, if any, was seen for the CD7.
      Since CD34+ marrow and blood cells are currently believed to be the major source
      of the hemopoietic precursors, our data provide further substantial evidence
      supporting the hypothesis that the atopic dermatitis skin cell infiltrate
      represents an ongoing T-lineage in situ differentiation process regulated by the
      skin epithelial microenvironment. The observed defective expression of the CD7
      antigen requires further investigation for its confirmation as a possible
      constant feature in atopic dermatitis.

PMID- 10664935
TI  - Genetic and environmental influences on atopic immune response in early life.
AB  - The purpose of our study was to carry out a prospective follow-up of 114 newborns
      at term (including three pairs of twins), regarding clinical manifestations for
      atopy during the first year of life. Their IgE levels in cord blood samples, at
      3, 6, 9 and 12 months of age were measured and the influence of race, sex, breast
      feeding, maternal smoking, family income, month of birth, family history and
      personal manifestations of atopic disease were evaluated. Total serum
      immunoglobulin E was quantified by microparticle enzyme immuno-assay (MEIA). The
      study group consisted of 60 (53%) male neonates, 67 (59%) Caucasians and 47 (41%)
      blacks. In the clinical follow-up, 32 (28.1%) infants developed obvious atopic
      disease: 29 infants presented recurrent wheezing, two had cow's milk allergy and
      one had atopic dermatitis. Probable atopic disease developed in 12 (10.5%)
      infants, whereas 70 (61.4%) infants showed no manifestations. Cord blood IgE
      levels in infants with obvious atopic disease was higher when compared to those
      without (p = 0.024), with 70.97% sensitivity and 46.2% specificity. IgE levels
      were also significantly different up to 12 months in these groups (p = 0.0001),
      when the sensitivity was 82.1% and the specificity 54.1%. At this age, the IgE
      levels were higher in infants with obvious atopy than nonatopic disease in
      relation to male sex (p = 0.015), black race (p = 0.009), breast-feeding for less
      than 6 months (p = 0.011) and when the family income was less than three times
      the minimum wage (about US $300) (p = 0.006). There was no association between
      IgE levels and family history of atopy. We concluded that immune response for
      atopy was in a large degree influenced by environmental factors and serum IgE at
      12 months was a good marker for identifying infants with risk of atopic disease
      in early life.

PMID- 10664936
TI  - Nonpigmented fixed drug eruption caused by paracetamol.
AB  - Fixed drug eruption from paracetamol is not rare but no cases of nonpigmented
      fixed drug eruption caused by paracetamol have been previously described. We
      present the case of a woman who developed a nonpigmented fixed drug eruption
      following administration of paracetamol. Patch tests performed on affected and
      unaffected skin with paracetamol were negative. The diagnosis was made by a
      double-blind oral challenge with paracetamol. The patient tolerated aspirin.

PMID- 10664937
TI  - Erythema multiforme from betalactams with positive cutaneous tests.
AB  - We report the case of a woman who after taking ampicillin and amoxicillin
      developed two severe cutaneous reactions with generalized erythema and
      maculopapular rash, which later turned into blisters with subsequent
      desquamation. She was clinically diagnosed with erythema multiforme syndrome
      after positive delayed cutaneous tests with benzylpenicillin, amoxicillin and
      ampicillin allowed for a more specific diagnosis. There are very few references
      to patients with drug reactions to betalactams who have positive skin prick or
      intradermal test but show delayed hypersensitivity, as was the case in our
      patient.

PMID- 10664938
TI  - Severe hypersensitivity reaction to minocycline.
AB  - Minocycline is a tetracycline derivative mainly used in the treatment of acne
      vulgaris in young persons. Adverse events have been reported with minocycline,
      although it can be considered a safe drug. We report a case of severe
      hypersensitivity reaction to minocycline in a young patient. Laboratory
      examinations, chest X-ray, skin test and skin biopsy were performed. Oral
      challenge test with minocycline was not carried out as it can be hazardous. A
      case of severe reaction to minocycline is described in this article. The clinical
      and laboratory findings may be helpful in diagnosing similar reactions for which
      the immunological mechanisms are unknown. Moreover, this type of reaction must be
      recognized early due to the potential fatal outcome.

PMID- 10664939
TI  - Correlation between glycemic control and menstruation in diabetic adolescents.
AB  - OBJECTIVE: To determine if a correlation exists between the degree of glycemic
      control in insulin-dependent diabetic adolescents and menstrual regulation. STUDY
      DESIGN: A retrospective review of charts of diabetic girls aged 10-18 was
      performed. Office visits were scheduled every three to six months, at which time
      pubertal development, menstrual function, growth and diabetic control, including
      hemoglobin (Hgb) A1C, and complications were assessed. Forty-six patients were
      eligible for data analysis. Descriptive and inferential statistics, including chi
      2 and Student t tests, were applied. RESULTS: Thirty-seven (81%) patients had
      regular menstrual cycles, and nine (19%) had menstrual disturbances, including
      secondary amenorrhea (one), oligomenorrhea (seven) and primary amenorrhea
      followed by oligomenorrhea (one). There were two pregnancies. Six patients used
      hormonal contraception but none for menstrual regulation. There was a
      statistically significant difference (P < .05) in mean Hgb A1C concentrations
      between those with menstrual disturbances (11.4) and those with regular menses
      (9.7). As Hgb A1C values increased, the percent of patients with menstrual
      disturbances increased, becoming statistically significant when the Hgb A1C was >
      10 (odds ratio 7.3, 95% confidence interval 1.5-35.6). There was no difference (P
      > .05) between the two groups with respect to age at menarche (156 vs. 152
      months), age at onset of diabetes (144 vs. 108 months) and interval between
      diabetes onset and menarche (54 vs. 41 months). There were no patients in either
      group with diabetic retinopathy or nephropathy. Four patients were hypertensive,
      but there was no statistically significant difference (P > .05) between groups.
      CONCLUSION: Tighter glycemic control, as measured by Hgb A1C concentrations,
      corresponded to improved menstrual regulation in adolescent insulin-dependent
      diabetics.

PMID- 10664940
TI  - Abruptio placentae after auto accidents. A case-control study.
AB  - OBJECTIVE: To compare accident and injury characteristics in pregnant women with
      and without abruptio placentae involved in auto accidents (AAs). STUDY DESIGN: A
      retrospective, case-control study involving 12 pregnant women (16-39 weeks) with
      a diagnosis of abruptio placentae after AAs and 12 control subjects matched for
      gestational age (+/- 2 weeks) involved in AAs without abruptio placentae from
      1988 through 1997. Numerous variables were compared, including restraint system
      use, estimated speed of the collision, injury severity score (ISS), clinical
      findings and patient position in the vehicle. Patient complaints and physical
      examination on admission were also recorded, and obstetric and neonatal outcomes
      were compared. Statistical analysis was performed using the independent sample t,
      Mann-Whitney and Fisher's exact tests, when appropriate. RESULTS: There was no
      significant difference in the frequency of unrestrained subjects or position in
      the vehicle between cases and controls. Estimated speed of the vehicle at the
      time of collision was significantly higher in the abruptio placentae group (> 30
      mph, 92% vs. 50%, P = .03), as was the mean ISS code (20 [SD 12.71] vs. 4 [SD
      5.13], P < .001). Abdominal pain and vaginal bleeding were seen more frequently
      in women with abruptio placentae as compared to controls (58% vs. 25% and 33% vs.
      0, respectively). Patients with abruptio placentae had a higher incidence of
      preterm delivery (mean gestational age at delivery = 29 weeks [SD 7.99] vs. 36
      weeks [SD 7.21], P = .008) and stillbirth (57% vs. 0%, P = .002) and lower mean
      birth weight (1,924 g [SD 931] vs. 3,069 g [SD 450], P = .003). There was no
      significant difference in cesarean section rates between the groups (58% vs. 30%,
      P = .23). There was no difference in the two groups in placental location on
      ultrasonography. CONCLUSION: Pregnant women who were involved in severe accidents
      (i.e., higher speed or ISS) were more likely to suffer abruptio placentae. In
      severe accidents, proper restraints were frequently not used. Because of the
      severity of these accidents, current restraint systems may not be sufficient to
      prevent abruptio placentae even with proper restraint use. Efforts toward
      designing new restraint systems for pregnant women should be encouraged.

PMID- 10664941
TI  - Biopsy-based comparison of liquid-based, thin-layer preparations to conventional
      Pap smears.
AB  - OBJECTIVE: To evaluate and compare histologic diagnosis of squamous
      intraepithelial neoplasia and cancer of the cervix with cytologic diagnosis using
      the conventional Pap smear versus the AutoCyte PREP liquid-based, thin-layer
      preparation. STUDY DESIGN: Two randomly selected, large patient groups from the
      same population were studied using two different cervical cytology preparation
      techniques. Cytologic results were compared to histologic diagnosis to estimate
      the relative sensitivities and specificities of the preparations. RESULTS:
      AutoCyte's liquid-based, thin-layer preparation method demonstrated improved
      agreement with histologic diagnosis as compared to the conventional Pap smear.
      This result supported the previously reported finding that use of this thin-layer
      method reduced atypical squamous cells of undetermined significance cases and
      substantially increased the detection of squamous intraepithelial lesions (SILs).
      CONCLUSION: Our cytohistologic correlation for conventional Pap smears and the
      AutoCyte PREP liquid-based preparations demonstrate that the increased rate of
      both low and high grade SILs on AutoCyte PREP reflects real detection as opposed
      to overdiagnosis.

PMID- 10664942
TI  - Ultrasonographic prediction of fetal macrosomia. Association with cesarean
      delivery.
AB  - OBJECTIVE: To investigate whether the incorrect ultrasonographic prediction of
      macrosomia affects the cesarean delivery rate among nonmacrosomic neonates. STUDY
      DESIGN: For this retrospective, cohort study, comprehensive ultrasonographic
      records were reviewed at two centers. Patients with singleton, nonanomalous
      gestations whose ultrasonography predicted an estimated fetal weight > or = 4,000
      g composed one cohort (n = 135), while the other cohort (n = 129) consisted of
      patients whose ultrasonography predicted an estimated fetal weight between 3,000
      and 3,999 g. We compared the cesarean delivery rate in neonates falsely diagnosed
      with macrosomia (false positives) with the rate in those correctly diagnosed as
      nonmacrosomic (true negatives). RESULTS: The rate of cesarean delivery was
      significantly higher among those falsely diagnosed by ultrasonography with a
      macrosomic fetus as compared to those with a fetus truly diagnosed as
      nonmacrosomic (42.3% vs. 24.3%, relative risk = 1.74, 95% confidence interval
      1.09-2.78). Subgroup analyses excluding diabetic mothers and multiparous women
      and comparing false positives with true negatives with neonatal birth weights
      between 3,500 and 4,000 g (birth weights similar to false positives) demonstrated
      significantly increased cesarean delivery rates among false positives.
      CONCLUSION: Even in nonmacrosomic neonates, the antenatal ultrasonographic
      diagnosis of suspected macrosomia is associated with a significant increase in
      cesarean delivery rates.

PMID- 10664943
TI  - Reproductive outcome after laparoscopic myomectomy in infertile women.
AB  - OBJECTIVE: To assess reproductive outcome after laparoscopic myomectomies for
      interstitial and/or subserosal myomas in infertile women with or without
      associated infertility factors. STUDY DESIGN: In this observational study, 91
      women with infertility for one year and at least one interstitial and/or
      subserosal myoma > 20 mm were treated with laparoscopic myomectomy. All patients
      were mailed questions about fertility and pregnancy outcome. Cumulative pregnancy
      rates were calculated by the Kaplan-Meier method. The log rank test and Cox's
      model were used for comparing the spontaneous pregnancy rate in patients with and
      without associated infertility factors. RESULTS: The mean age of the patients was
      35 +/- 4 years. The mean duration of infertility was 44 +/- 33 months. Twenty
      five patients (27.5%) had no associated infertility factors, and 66 (72.5%) had
      one or more. The mean size of the largest myomas was 45 +/- 19 mm. The mean
      number of myomas removed was 2.0 +/- 1.4. Eighty-six patients had laparoscopic
      myomectomy (94.5%), and five had laparoscopically assisted myomectomy (5.5%).
      There were no conversions to laparotomy. Ten patients were lost to follow-up
      (11.0%). Among the 91 patients treated surgically, 81 (89.0%) of them were
      evaluated. Forty-three (53.1%) conceived, resulting in a total of 51 pregnancies.
      The two-year overall cumulative conception rate was 51.2% (95% confidence
      interval [CI], 39.2-63.2%). The two-year spontaneous pregnancy rate was 43.9%
      (95% CI, 32.1-55.7%). This rate was 69.9% (95% CI, 50.3-89.5%) for patients with
      no associated factors and 31.5% (95% CI, 18.4-44.6%) for patients with associated
      factors (P < .001). This result was not affected by adjusting for age or duration
      of infertility. CONCLUSION: Laparoscopic myomectomy seems to be a good procedure
      for patients with myomas and no other infertility factors. In cases with
      associated infertility factors, the need for myomectomy has to be studied.

PMID- 10664944
TI  - Screening for gestational diabetes mellitus in adolescent Hispanic Americans.
AB  - OBJECTIVE: To determine the incidence of gestational diabetes mellitus (GDM) in
      an adolescent Hispanic American population. STUDY DESIGN: A retrospective review
      of 326 women < 20 years of age who identified themselves as Hispanic American was
      conducted and the incidence of gestational diabetes determined. RESULTS: Thirty
      adolescent Hispanic Americans (9.2%) had an abnormal result (> or = 140 mg/dL)
      after 50-g, one-hour oral glucose challenge testing. These women underwent three
      hour oral glucose tolerance tests, and five met the criteria for GDM. The
      incidence of GDM in this population was 1.5% (5/326) (95% confidence interval,
      0.6, 3.7). CONCLUSION: The incidence of GDM in adolescent Hispanic Americans is
      so low that universal screening may not be warranted.

PMID- 10664945
TI  - GnRHa for adhesion formation after uterine serosal injury in an euestrogenic
      milieu.
AB  - OBJECTIVE: To assess whether the adhesion-preventing effect of gonadotropin
      releasing hormone agonist (GnRHa) is through hypoestrogenism. STUDY DESIGN: Four
      groups of previously ovariectomized rats received various combinations of depot
      leuprolide acetate injection (3.75 mg/kg/mo) subcutaneously, conjugated equine
      estrogens (50 micrograms/kg/d) orally and phosphate-buffered saline injection
      subcutaneously, yielding group 1, saline only; group 2, saline and conjugated
      equine estrogens; group 3, depot leuprolide acetate only; and group 4, depot
      leuprolide acetate and conjugated equine estrogens. Surgical adhesions were
      induced by monopolar cautery on the right uterine horn through laparotomy and
      were then scored on day 21 after surgery. RESULTS: Adhesion scores for rats that
      received conjugated equine estrogens and saline were significantly higher than
      scores of those given conjugated equine estrogens and depot leuprolide acetate,
      depot leuprolide acetate only and saline only (P = .019, .026 and .027,
      respectively). However, there was no significant difference in the adhesion
      scores for these three groups. CONCLUSION: Hypoestrogenism results in the
      development of fewer peritoneal adhesions postoperatively. Our findings also
      indicated that other mechanisms, in addition to those inducing hypoestrogenism,
      are at work in the adhesion-preventing effects of GnRHa therapy.

PMID- 10664946
TI  - Confirmation of paternal disomy in a twin molar pregnancy. A case report.
AB  - BACKGROUND: Paternal dispermy can be the pathogenesis of complete molar
      pregnancy. CASE: A 23-year-old, white woman, gravida 4, para 1, was pregnant with
      a twin gestation by ovulation induction with metrodin. Ultrasound evaluation
      confirmed an intrauterine pregnancy in conjunction with what appeared to be a
      hydatidiform mole. The karyotype in the molar pregnancy, obtained from chorionic
      villus sampling, showed a pair of paternally derived inverted chromosomes 9,
      confirming the diagnosis of a complete mole. Uncontrollable hemorrhage with a
      rapid rise in the beta-human chorionic gonadotropin titer necessitated evacuation
      of the uterus. The patient was followed with beta-human chorionic gonadotropin
      titers for a year, with no evidence of recurrence. CONCLUSION: This case
      illustrates paternal disomy in a complete molar pregnancy documented by a
      paternal chromosome 9 inversion.

PMID- 10664947
TI  - Multiple blue nevi of the vagina. A case report.
AB  - BACKGROUND: Melanotic lesions of the vagina are very rare; clinically, most are
      suspected to be malignant melanomas. Occasional benign cases, however, require
      differential diagnostic consideration. We report a case of multiple (benign) blue
      nevi of the vagina. CASE: A 51-year-old woman presented with bluish black macules
      irregularly distributed throughout the vagina. Biopsies revealed pigmented cells
      in the dermis that proved to be melanocytes. The patient received no therapy. The
      lesions remained unchanged in the follow-up period. CONCLUSION: Multiple blue
      nevi could be a differential diagnosis for malignant melanoma of the vagina. Our
      patient showed no malignant transformation over a 29-year period. Therapy for
      blue nevi in the vagina does not require complete excision.

PMID- 10664948
TI  - Rectal prolapse during pregnancy. A case report.
AB  - BACKGROUND: Rectal prolapse is a bothersome surgical problem that is relatively
      infrequent. It usually occurs in the fifth to seventh decades of life and is more
      common in women. CASE: A 33-year-old woman, gravida 3, para 2, was found to have
      a large rectal prolapse at 33 weeks' gestation. Manual reduction was successfully
      performed after injecting 2% lidocaine into and around the anal sphincter.
      Because she could not undergo definitive surgical repair during her pregnancy,
      the patient was managed with an aggressive stool softening regimen and self
      reduction techniques. Labor was induced in the 40th gestational week. Epidural
      anesthesia was employed, and delivery was accomplished via low-outlet forceps
      application. The patient underwent definitive surgical repair of the rectal
      prolapse eight weeks postpartum. CONCLUSION: Rectal prolapse is a rare condition
      during the childbearing years. We found no prior case reports of rectal prolapse
      occurring during pregnancy. While childbirth itself is not considered a risk
      factor for rectal prolapse, a prior history of perineal lacerations may be a risk
      factor. To manage rectal prolapse that occurs during pregnancy, consideration
      should be given to passive forceps delivery under epidural anesthesia to avoid
      the possibility of worsening the prolapse.

PMID- 10664949
TI  - Hernia uterus inguinale in a 46,XX female. A case report.
AB  - BACKGROUND: Hernia uterus inguinale, a rare congenital anomaly, is usually found
      in hermophrodites. CASE: A case of lateral fusion defect associated with
      mullerian duct development in a young woman with primary amenorrhea and normal
      karyotype occurred. In our patient, bilateral mullerian duct systems were
      rudimentary and failed to fuse in the midline. The left horn of the uterus and
      ipsilateral ovary lay in the left inguinal canal. The right horn of the uterus,
      along with the tube and ovary, was intraabdominal. CONCLUSION: In the operative
      management of this rare anomaly, care must be taken to preserve and reposition
      the ovary in the abdominal cavity.

PMID- 10664950
TI  - Adult respiratory distress syndrome after extensive cytoreductive surgery. A case
      report.
AB  - BACKGROUND: Adult respiratory distress syndrome (ARDS) is characterized by
      progressive hypoxemia, diffuse bilateral pulmonary infiltrates and normal left
      ventricular function. CASE: A 58-year-old woman developed ARDS following
      extensive cytoreductive surgery for a widely disseminated intraperitoneal
      leiomyosarcoma. The patient had a favorable outcome after 10 days of ventilatory
      support, sedation, analgesia, parenteral and enteral nutrition, and fluid
      restriction. The ARDS might have been caused by multiple transfusions or the
      massive cytoreductive surgery and was probably mediated by cytokines and tumor
      necrosis factors. CONCLUSION: Gynecologic oncologists should be alert to
      postoperative ARDS in patients undergoing massive cytoreduction with excessive
      blood loss and multiple transfusions.

PMID- 10664951
TI  - What is your diagnosis? Feline paraneoplastic alopecia associated with pancreatic
      and bile duct carcinomas.

PMID- 10664952
TI  - Possible immunodeficiency in related rottweiler dogs.
AB  - A litter of eight rottweiler pups is described in which two dogs died before the
      age of six months from systemic inflammatory disease, and two further pups
      developed inflammatory skin disease. All seven pups tested had a markedly low
      serum immunoglobulin A (IgA) concentration (< 0.1 mg/ml) and six of these dogs
      also had subnormal serum IgG (< 0.1 to 6.4 mg/ml). Tissues taken from three
      diseased pups were examined immunohistochemically using a number of lymphoid
      markers. Secondary lymphoid tissues had a paucity of CD3+ T lymphocytes, although
      T cells were found within some inflammatory foci. B-lymphocyte follicles were
      present within lymphoid tissues, but there were irregularities of plasma cell
      development and a lack of plasma cells of all classes within mucosal and
      cutaneous sites. Inflammatory lesions were dominated by macrophages expressing
      class II molecules of the major histocompatibility complex. Serum immunoglobulins
      were also investigated in eight related, clinically normal adult dogs. Five of
      these dogs, from two separate breeding lines, had subnormal serum IgA (< 0.1 to
      0.15 mg/ml). The spectrum of disease within the affected litter may be consistent
      with an underlying inherited immunological defect, and the observed immunological
      abnormalities suggest a more complex disorder than simple IgA deficiency.

PMID- 10664953
TI  - Cyclosporin as the sole treatment for anal furunculosis: preliminary results.
AB  - Cyclosporin was used, as the sole agent, to treat six cases of anal furunculosis,
      allowing the clinical response to the drug to be evaluated. The initial dose was
      7.5 mg/kg twice a day. Following one week of treatment, whole blood cyclosporin
      trough levels were measured and the dose was adjusted to obtain a stable trough
      level of 400 to 600 ng/ml. In all dogs, the lesions were found to follow a
      similar pattern of resolution throughout the course of treatment. The presenting
      signs disappeared within one week of treatment, with a reduction in lesion size
      of 50 to 90 per cent. Lesions then gradually healed over the remainder of the
      treatment, which lasted from 10 to 20 weeks. One case required cryosurgical
      treatment to resolve a 2 mm diameter persistent ulcerated lesion following 18
      weeks of treatment. The length of follow-up was four to 14 months (mean 7.7
      months). One case developed recurrence of the lesions eight weeks post-treatment.

PMID- 10664954
TI  - Use of compression stress radiography for the detection of partial tears of the
      canine cranial cruciate ligament.
AB  - Twenty-three cases of partial rupture of the cranial cruciate ligament (CCL) were
      reviewed. All of these patients were evaluated for clinical and radiographic
      signs of instability. Nine cases showed a negative drawer sign on manual
      assessment. A positive radiographic tibial compression test was obtained for all
      stifle joints with a partially ruptured cruciate. In 13 cases, the site of injury
      and the appearance of the torn ends were evaluated. The final diagnosis of
      partial CCL rupture was made by direct visualisation and probing of the CCL
      during arthrotomy (22 cases) or arthroscopy (one case).

PMID- 10664955
TI  - Acute tracheal obstruction associated with anticoagulant rodenticide intoxication
      in a dog.
AB  - An adult female neutered crossbred dog was referred in respiratory distress.
      Thoracic radiographs revealed tracheal narrowing with a soft tissue opacity
      dorsal to the trachea, near the thoracic inlet, and a patchy interstitial
      pulmonary infiltrate. The tracheal narrowing was thought to be due to a
      combination of intraluminal haemorrhage and mediastinal haemorrhage resulting
      from a coagulopathy caused by anticoagulant rodenticide intoxication. Treatment
      included supportive care and administration of vitamin K1, and the dog showed a
      complete resolution of the clinical signs.

PMID- 10664956
TI  - Atherosclerosis in a dog with diabetes mellitus.
AB  - A seven-year-old male Pomeranian with unstable insulin-dependent diabetes
      mellitus developed atherosclerosis. Hyperlipidaemia, consisting of
      hypertriglyceridaemia and hypercholesterolaemia, was diagnosed concurrently with
      the onset of lipid-laden aqueous humour. Serum lipoprotein analysis was
      characterised by the presence of chylomicrons, an increase in the very low
      density lipoprotein fraction, with a broad very low density lipoprotein-low
      density lipoprotein band, and a reduced high density lipoprotein fraction. The
      dog developed ketoacidosis one year later and died. At postmortem examination,
      atherosclerotic plaques were observed in the terminal aorta and in medium-sized
      arteries, including the coronary arteries, renal and arcuate arteries, and
      arteries of the brain. Mineralised plaques or complicated plaques were not
      observed. The absence of clinical signs of organ ischaemia was thought to be
      associated with the absence of thrombosis and/or complete occlusion of all
      vessels examined. Signs of chronic organ hypoxia, although considered likely
      owing to the severe vessel lumen reduction, were restricted to only a low voltage
      QRS complex on the electrocardiogram.

PMID- 10664957
TI  - Subacute necrotising encephalopathy in an Alaskan husky.
AB  - A 29-month-old female Alaskan husky was presented recumbent, tetraparetic and in
      a state of dementia, with blindness and cranial nerve deficits. The dog's
      progress was followed for over two months, as the signs resolved to an non
      progressive mild hypermetria with slight proprioceptive ataxia, a diminished
      menace response and inability to prehend food. Magnetic resonance imaging (MRI)
      revealed bilateral cavitation extending from the thalamus to the medulla, with
      less pronounced degenerative lesions in the caudate nucleus, putamen and
      claustrum. Cerebrospinal fluid lactate and pyruvate concentrations were in their
      normal ranges. Necropsy and histological examination confirmed the MRI findings
      as well as neuronal degeneration of the cerebellar cortex in the vermis and
      degenerative changes in the neocortex at the depths of the cerebral sulci. In
      view of the similarity of lesions to subacute necrotising encephalomyelopathy,
      known as Leigh's disease in humans, a tentative diagnosis of a mitochondrial
      encephalopathy was made.

PMID- 10664958
TI  - Use of propofol to manage seizure activity after surgical treatment of
      portosystemic shunts.
AB  - The anaesthetic agent propofol has anticonvulsant properties and has been used in
      the treatment of refractory status epilepticus in human medicine. This report
      describes the use of propofol in four cats and one dog with naturally occurring
      seizures following surgical attenuation of single extrahepatic portosystemic
      shunts. Two of the animals had seizures that were unresponsive to other
      anticonvulsants. Subanaesthetic doses of intravenous propofol (1.0 to 3.5 mg/kg
      boluses and 0.01 to 0.25 mg/kg/minute continuous rate infusions) were used to
      control the seizures in all animals. However, a good neurological outcome was
      achieved in only two of the five cases, which is similar to the situation in
      previous reports.

PMID- 10664959
TI  - Effects on reproduction and fetal development of female rats treated
      subcutaneously with a surfactant, polyoxyethylene(10)nonylphenyl ether(NP-10),
      for 15 weeks.
AB  - A surfactant NP-10 was administered subcutaneously to 7-week-old Jcl:Wistar
      female rats at dose levels of 2 and 20 mg/kg/day for 15 weeks to assess its
      effects on their reproductive ability and fetal development, and on the growth,
      behavior and functions of the offspring they delivered. In the general condition
      of the F0 dams, changes that were considered to be the local irritation effect of
      the test substance, such as scab formation and loss of hair at the test substance
      administration site in the 2 and 20 mg/kg groups and induration of the skin at
      the test substance administration site in the 20 mg/kg group were observed.
      Whitish changes of the subcutis were detected at the test substance
      administration site in the 2 and 20 mg/kg groups and adhesion of abdominal organs
      in the 20 mg/kg group in the necropsy findings. In addition, an increase was
      observed in body weight and in food consumption in the 20 mg/kg group. The
      reproductive ability test failed to reveal any evidence of an effect that could
      be ascribed to the test substance. The observations at cesarean section or
      external, visceral and skeletal examinations revealed no effects attributable to
      the test substance in the F1 fetuses. The observations on the day of birth and
      during the period of lactation, external examination, physical development test,
      general condition, body weight and necropsy findings for F1 and F2 offspring and
      reflex test, open-field test, water-maze test, organ weight and reproductive
      ability test performed on the F1 offspring failed to reveal any evidence that
      could be ascribed to the test substance. These results indicate that under the
      conditions of this study, NP-10 had no effect on the reproductive ability of
      females or the fetal development or growth, behavior and functions of their
      offspring.

PMID- 10664960
TI  - Effects on growth of rat offspring born from dams treated subcutaneously with a
      surfactant, polyoxyethylene(10)nonylphenyl ether(NP-10), during lactational
      period.
AB  - A surfactant NP-10 was administered subcutaneously to Jcl:Wistar female rats at
      dose levels of 5, 20 and 80 mg/kg/day from date of birth to day 21 after birth of
      F1 offspring to assess its effects on the growth, behavior and functions of the
      offspring. For F0 dams, scab formation and loss of hair at the test substance
      administration site were observed in all treatment groups and induration of the
      skin at the test substance administration site in the 20 and 80 mg/kg groups in
      general condition and necropsy findings at the end of the dosing period. In
      necropsy findings, in addition to these changes, hemorrhage and whitish change of
      the subcutis at the test substance administration site were seen in all treatment
      groups, adhesion to the somatic muscles and granulation of the subcutis at the
      test substance administration site in the 20 and 80 mg/kg groups, and swelling of
      the spleen and adrenals in the 80 mg/kg group. Reduction or a tendency for
      reduction in food consumption was also detected from the initial day of dosing
      (day 0) to day 17 after birth F1 offspring in the 80 mg/kg group. Body weight or
      the findings on the day after birth and day of weaning failed to reveal any
      evidence of an effect that could be ascribed to the test substance. In F1 born
      offspring, a decrease or tendency for decrease in body weight was observed from
      day 7 after birth in both sexes and for females during the gestation period in
      the 80 mg/kg group. However, body weight gains based on the weights at 4 weeks
      after birth or on day 0 of gestation in the 80 mg/kg group failed to reveal any
      difference from that in the control group. The observation on the day of birth
      and during the period of lactation, physical development test, reflex test,
      general condition, open-field test, water-maze test, reproductive ability test,
      observations at cesarean section, necropsy findings, organ weights,
      histopathological findings of females or males that did not achieve successful
      gestation, skeletal examination, and the observations at cesarean section and
      external examination of F2 fetuses failed to reveal any evidence that could be
      ascribed to the test substance. These results indicate that NP-10 had no effect
      on the behavior or functions of the offspring, although it affected the growth of
      the offspring born, under the conditions of this study. The non-effective dose
      level is considered to be 20 mg/kg for general toxicity of the dams and for their
      offspring.

PMID- 10664961
TI  - Effects of exposure of a surfactant, polyoxyethylene(10)nonylphenyl ether (NP
      10), to sperm on embryonic and fetal development in rabbits.
AB  - The effects of exposure of a surfactant, nonoxynol(NP-10), to sperm on embryonic
      and fetal development were studied using rabbits. In the preliminary test, the
      concentration of NP-10 at which total sperm immobility was 0.01% and
      nonfertilizing was 0.008% in vitro. No implantation was observed at the
      concentration of 0.032% NP-10 in vivo. Based on these results, the rabbit semen
      was treated either with 0.04, 0.01 or 0.0025% NP-10 solution, and used for
      artificial insemination to examine if the sperm was fertile as well as to
      determine the effect of NP-10-treated sperm on embryonic and fetal development.
      Gestation was not observed after insemination with semen treated with 0.04% NP
      10; after insemination with semen treated with 0.01 and 0.0025% NP-10, it
      occurred without impairing the viability, organogenesis or growth of embryos or
      fetuses. These results may indicate that gestation may not be possible with sperm
      severely impaired by exposure to NP-10, but no untoward effect on embryonic or
      fetal development may be observed when gestation is initiated with exposed semen.

PMID- 10664962
TI  - Carcinogenicity test of polyoxyethylene(10) nonylphenyl ether (NP-10) in female
      B6C3F1 mice.
AB  - A carcinogenicity study of polyoxyethylene(10)nonylphenyl ether (NP-10) to B6C3F1
      mouse was performed using 50 females per group of 4 study groups, or 200 mice in
      total. Diets containing NP-10 at 0, 500, 1500 and 4500 ppm were prepared and
      orally administered to the animals repeatedly for 104 weeks, and observation of
      general conditions, body weight analysis, food consumption analysis, hematologic
      examination, organ weight analysis and pathological examination were performed.
      The results are summarized as follows. The mean intake of the test substance in
      the 500, 1500 and 4500 ppm groups for 104 weeks was 81.5, 254 and 873 mg/kg/day,
      respectively. There were no differences observed in mortality among the groups
      and the mortality did not exceed the background data in any groups. There were no
      signs attributable to the administration of the test substance, and various signs
      which increased in occurrence with aging were observed in all groups at a similar
      frequency. Body weight gain was suppressed only in the 4500 ppm group throughout
      the entire administration period. Food consumption was increased in all treated
      groups around the early stage of administration and, thereafter, in the 1500 and
      4500 ppm groups until the mid-stage of administration. Decreased food efficiency
      was observed in the 4500 ppm group alone. As a result of the hematologic
      examination, no changes attributable to the administration of the test substance
      were observed in any groups. As a result of the organ weight analysis, lower
      absolute weights of the liver and kidney and higher relative weights of the
      brain, liver and kidney, which were considered to be changes accompanying the
      suppressed body weight gain, were observed in the 4500 ppm group. The
      pathological examination revealed no marked changes in the gross findings in the
      treated groups. As a result of the histological examination, there were no
      neoplastic or non-neoplastic lesions in the treated groups which were
      unequivocally observed to have increased in occurrence. As the above findings
      show, NP-10 did not cause any increase in the incidence of neoplastic lesions in
      the mouse by oral administration for 2 years at 873 mg/kg/day (4500 ppm) and was
      determined to have no carcinogenicity.

PMID- 10664963
TI  - Oral chronic toxicity and carcinogenicity test of polyoxyethylene(10)nonylphenyl
      ether (NP-10) in female F344 rats.
AB  - Chronic toxicity and carcinogenicity of polyoxyethylene(10)nonylphenyl ether (NP
      10) to Fischer 344 rats were investigated using 70 females per group in 4 study
      groups, or 280 rats in total. Diets containing NP-10 at 0, 1000, 3000 and 9000
      ppm were prepared and orally administered to the animals repeatedly for 52 weeks
      for a chronic toxicity study and for 104 weeks for a carcinogenicity study.
      Observations of general condition, body weight analysis, food consumption
      analysis, hematologic examination, blood chemistry examination (only at Week 52
      of administration), urinalysis (only at Week 52), ophthalmologic examination
      (immediately prior to administration and at Week 52), organ weight analysis and
      pathological examination were performed. The results are summarized as follows.
      The mean intake of the test substance was 60.5, 182 and 559 mg/kg/day in the
      chronic toxicity study for 52 weeks and 55.2, 166 and 520 mg/kg/day in the
      carcinogenicity study for 104 weeks in the 1000, 3000 and 9000 ppm groups,
      respectively. Mortality decreased approximately in a dose-related manner, with
      28% in the control group, 26% in the 1000 ppm group, and 14% each in the 3000 and
      9000 ppm groups. In general condition, there were no signs attributed to the
      treatment with NP-10. Body weight gain was suppressed in the 9000 ppm group
      throughout the administration period and in the 3000 ppm group during Weeks 21
      88. Food consumption decreased in the 9000 and 3000 ppm groups. Food efficiency
      was lower in the 9000 and 3000 ppm groups. As a result of the hematologic
      examination, hematocrit value, hemoglobin value, red blood cell count, platelet
      count and MCV were lower and MCH and MCHC higher in the 9000 ppm group at Week 52
      of administration. At Week 104, the neutrophil ratio was higher and lymphocyte
      ratio lower in the 3000 and 9000 ppm groups, and furthermore, hematocrit value,
      hemoglobin value, MCV and MCH were slightly lower in the 9000 ppm group. In the
      blood coagulability tests, prothrombin time was slightly shortened in the 9000
      ppm group at Week 52. As a result of the blood chemistry examination, total
      protein and albumin values were higher and total bilirubin, uric acid and
      trygliceride value lower in the 3000 ppm and higher dose groups. Furthermore, the
      free cholesterol value was higher and the values of potassium, cholesterol ester
      ratio, GOT, GPT, ALP and cholinesterase were lower in the 9000 ppm group. As a
      result of the urinalysis, the specific gravity of urine was higher and urine pH
      acidic in some animals. As a result of the ophthalmologic examination, no
      abnormal animals were found in the 9000 ppm group. As a result of the organ
      weight analysis, absolute and relative weights of the liver and adrenals were
      higher in the 3000 and/or 9000 ppm groups as changes which were considered
      attributable to the test substance and, in addition, organs with a lower absolute
      weight and higher relative weight with the suppressed body weight gain were
      observed in the 9000 ppm group. The histopathological examination revealed no
      marked findings in necropsy observation or histology in the treated groups in the
      animals killed at Weeks 52, 104 as well as those killed moribund and dead
      animals. In the histological findings, bile duct hyperplasia of liver in the
      animals killed at Week 52, proliferative duct of pancreas in the animals killed
      at Week 104, pigment of deposit in pituitary and angiectasis of adrenals in the
      animals killed at moribund and dead animals were observed in a slightly larger
      number in the treated groups, but none of these changes were different in degree
      from the control and were not considered to be specific lesions. As a result of
      the overall study of the neoplastic lesions of all animals killed on schedule and
      of moribund and dead animals, no tumors were found in the treated groups which
      had increased in occurrence. Based on the above findings, it was determined that
      the no-adverse-effect level in the chronic toxicity study was 1000 ppm (

PMID- 10664964
TI  - Cloning and expression of single chain antibody fragments in Escherichia coli and
      Pichia pastoris.
AB  - The potential of recombinant antibody fragments is likely to be fulfilled only if
      they can be produced routinely at high concentrations. We have compared the
      ability of Escherichia coli and Pichia pastoris to produce functional recombinant
      single chain antibody (scAb) fragments. Two scAb fragments were expressed, an
      antihuman type V acid phosphatase (TRAP) and an anti-Pseudomonas aeruginosa
      lipoprotein I. We report here that, while expression from P. pastoris resulted in
      a significantly increased level of expression of the anti-TRAP scAb compared to
      E. coli, neither fragment was able to bind its target antigen as well as the
      bacterial product.

PMID- 10664965
TI  - beta-D-glucuronidase gene from Escherichia coli is a functional reporter in the
      methylotrophic yeast Pichia pastoris.
AB  - The Escherichia coli gene gusA was expressed in the methylotrophic yeast Pichia
      pastoris in a transcriptional fusion to the homologous methanol-inducible AOX1
      promoter. Four recombinant clones were selected for expression studies in shake
      flask conditions and beta-D-glucuronidase (beta-GUS) activity was assayed each 24
      h during the induction period. Regardless of the genomic integration patterns and
      the gene dosage, beta-GUS was functionally expressed and easily detected in all
      studied clones. The results obtained demonstrate the feasibility of using this
      bacterial enzyme as a reporter in Pichia pastoris.

PMID- 10664966
TI  - Production and characterization of monoclonal antibodies for aflatoxin B1.
AB  - Hybridomas that secreted antibodies for aflatoxin B1 were selected using two
      immunization protocols referred to as A and B. Protocol A is a standard
      immunization method and resulted in the selection of only two clones that
      produced monoclonal antibodies against aflatoxin B1. In protocol B a unique
      immunization schedule which resulted in the generation of 10 hybridomas is
      described. Of the 10, one antibody was highly specific to B1, four antibodies
      reacted equally strongly with B1, G1 and weakly with B2. Another four reacted
      strongly with B1 and weakly with B2 and G1. One clone reacted equally strongly
      with B1, G1 and B2. Interestingly all the 10 antibodies showed little or no cross
      reaction with G2.

PMID- 10664967
TI  - Inhibition of aflatoxin biosynthesis by phenolic compounds.
AB  - The phenolic compounds acetosyringone, syringaldehyde and sinapinic acid
      inhibited the biosynthesis of aflatoxin B1 (AFB1) by A. flavus. Acetosyringone
      was the most active among the three compounds, inhibiting aflatoxin level by 82%
      at 2 m moll-1. The synthesis and accumulation of norsolorinic acid, an aflatoxin
      biosynthetic intermediate, was also inhibited. These results suggest that at
      least one step early in the AFB1 biosynthetic pathway is inhibited by the
      phenolics.

PMID- 10664968
TI  - Cell surface display of hepatitis B virus surface antigen by using Pseudomonas
      syringae ice nucleation protein.
AB  - A new system designed for cell surface display of recombinant proteins on
      Escherichia coli was evaluated for expression of eukaryotic viral antigens. The
      major surface antigen of hepatitis B virus (HBsAg) was fused to the ice
      nucleation protein (INP), an outer membrane protein of Pseudomonas syringae.
      Western blotting, immunofluorescence microscopy, whole-cell ELISA, and ice
      nucleation activity assay confirmed expression of recombinant proteins on the
      surface of Escherichia coli. This study indicated that INP-based cell surface
      display can be used for epitope mapping and recombinant bacteria expressing
      hepatitis viral antigens may be used for developing live vaccines.

PMID- 10664969
TI  - ppGpp accumulation in Pseudomonas aeruginosa and Pseudomonas fluorescens
      subjected to nutrient limitation and biocide exposure.
AB  - The effect of a commonly used biocide, 1,2-benzisothiazolin-3-one (BIT) on ppGpp
      accumulation in the pathogen, Pseudomonas aeruginosa PAO1, and an environmental
      isolate, Ps. fluorescens, was examined. It is concluded that BIT is able to
      induce a stringent response in Ps. aeruginosa and Ps. fluorescens, determined by
      the rapid accumulation of ppGpp following addition of BIT to exponentially
      growing cells. Western blot analysis of whole-cell extracts with anti-RelA
      antibody demonstrated that both species contain a RelA homologue. This is the
      first report of a RelA-like protein in pseudomonads.

PMID- 10664970
TI  - Selection of Salmonella typhimurium as an indicator for pathogen regrowth
      potential in composted biosolids.
AB  - In order to select a suitable indicator for monitoring the pathogen regrowth
      potential of composted biosolids, the growth kinetics of selected bacteria were
      investigated. Growth parameters of six serovars of Salmonella and three strains
      of Escherichia coli in sterilized compost were compared. Seeded Salmonella and E.
      coli grew rapidly, reaching population densities of more than 10(8) g-1 after 30
      h of incubation. The specific growth rates of Salmonella serovars and E. coli
      strains were similar and varied from 0.49 to 0.55 h-1. The specific growth rate
      of the Salm. Typhimurium isolates was significantly higher than the other
      bacterial strains. It was concluded that an antibiotic-resistant strain of Salm.
      Typhimurium can be used as an indicator for a pathogen regrowth potential test.

PMID- 10664971
TI  - Efficient subtyping of Yersinia enterocolitica bioserotype 4/O:3 with pulsed
      field gel electrophoresis.
AB  - The purpose of this study was to evaluate the efficiency of pulsed-field gel
      electrophoresis (PFGE) for differentiation of isolates of Yersinia enterocolitica
      bioserotype 4/O:3 recovered from pig tongues at retail level in the Helsinki area
      during October and November of 1996. NotI generated 15 different PFGE patterns
      for 128 isolates. The discriminatory index did not exceed 74% due to the presence
      of two predominant PFGE-types, NA1 (58/128) and NB1 (25/128). After preliminary
      investigations with 35 enzymes, ApaI, XbaI, XhoI and SpeI were chosen for further
      characterization of the isolates. The discriminatory index increased from 74% to
      93% and the number of different genotypes from 15 to 30 when isolates with the
      same PFGE pattern with NotI were further characterized with ApaI and XhoI,
      indicating that PFGE can be an efficient technique for characterization of
      bioserotype 4/O:3.

PMID- 10664972
TI  - Lactococci as probiotic strains: adhesion to human enterocyte-like Caco-2 cells
      and tolerance to low pH and bile.
AB  - There have been few studies on the probiotic activity of Lactococcus strains
      although they are commonly used as starter bacteria in manufacturing many kinds
      of fermented dairy products. Nine strains of the genus Lactococcus were examined
      for their probiotic properties, such as adherence to human enterocyte-like Caco-2
      cells and tolerance to acid and bile. Six strains were adhesive and the highest
      adhesion was observed with Lactcoccus lactis ssp. lactis NIAI527. This strain
      adhered to the microvilli of cells as observed by scanning electron microscopy
      and also tolerated low pH and bile. These properties should make strain 527 a
      potential new probiotic strain.

PMID- 10664973
TI  - The intrinsic resistance of Escherichia coli to various antimicrobial agents
      requires ppGpp and sigma s.
AB  - We have examined the effect of a wide range of antimicrobial compounds
      (antibiotics and biocides) on the growth of various strains of Escherichia coli
      which vary in their ability to produce ppGpp and sigma s. We conclude that
      strains able to synthesize ppGpp, either in a RelA- or SpoT-dependent manner,
      possess a greater resistance to antimicrobial compounds compared with strains
      that cannot produce ppGpp. Investigation of an E. coli strain, unable to produce
      sigma s, and an isogenic parent strain, suggests that there is a requirement for
      this sigma factor in increased expression of intrinsic resistance. We propose
      that ppGpp is required to induce production of sigma s, which in turn directs
      gene expression of intrinsic resistance determinants.

PMID- 10664974
TI  - Antimicrobial susceptibility of enterococci recovered from commercial swine
      carcasses: effect of feed additives.
AB  - Enterococcus faecium is an important nosocomial pathogen often displaying
      multiple antibiotic resistance. The increase in clinical isolates can be
      attributed in part to hospital practices in antibiotic usage, but there is
      concern that antibiotic-resistant strains might also originate in animals fed
      rations containing antibiotic growth promoters. Ingestion of meat from carcasses
      contaminated with faecal enterococci might then result in human colonization or
      resistance gene transfer to human enterococci. Because there are few comparisons
      of bacteria isolated from matched animals that have, or have not, been fed a diet
      containing antibiotic, two such groups of pig carcasses were sampled at a
      commercial abattoir. Forty isolates from each group of pigs were tested for their
      resistance to avilamycin and tylosin. Although a modest number of pigs was
      examined, and the number of strains of E. faecium tested was small, there was no
      evidence that the feeding of a growth promoter caused selection of enterococci
      resistant to tylosin or avilamycin.

PMID- 10664975
TI  - Inhibition of growth and aflatoxin biosynthesis of Aspergillus flavus by extracts
      of some Egyptian plants.
AB  - The effect of five different concentrations (2, 4, 6, 8 and 10 mg ml-1) of an
      aqueous extracts of Lupinus albus, Ammi visnaga and Xanthium pungens were tested
      on growth and aflatoxin production by Aspergillus flavus in a chemically defined
      medium. All the plants inhibited mycelial growth and aflatoxin formation. The
      inhibitory effect was proportional with the applied concentration. Growth and
      aflatoxin production appeared to be correlated processes. The nature of the plant
      extract also affected the ratio of B1 to B2, and there was no correlation between
      the inhibition of aflatoxins or growth of the fungus and the resultant B1: B2
      ratio.

PMID- 10664977
TI  - Simple method to observe the adaptive response of Listeria monocytogenes in food.
AB  - A simple, novel method for determining stress-adaptive response of Listeria
      monocytogenes in food systems is presented. The method involves plating samples
      on Listeria-selective agar (LSA) acidified to pH 5.25 with incubation at 36
      degrees C for 60 h to detect acid adaptation and plating on LSA with 70 gl-1 NaCl
      and incubation at 7 degrees C for 7 d to detect cold-osmotic adaptation. Adapted
      cells produced larger colonies (> 1 mm) under these conditions than unadapted
      cells. Scot A (97%) and Brie-1 (100%) cells incubated in milk at pH 5 for 3 h
      manifested the acid-adapted colony type compared with 6% and 21% of viable cells
      in the unstressed control population. After a 5-d adaptation period at 4 degrees
      C in milk with 80 gl-1 salt, 29% of Scot A and 91% of Brie-1 viable cells
      exhibited the adapted colony type compared with < 1% of the unstressed control
      population. Stress-adapted L. monocytogenes were isolated from soft cheese held
      for 42 d at 10 C.

PMID- 10664976
TI  - Production of enterotoxins and toxic shock syndrome toxin by Staphylococcus
      aureus isolated from bovine mastitis in Brazil.
AB  - The production of toxic shock syndrome toxin 1 (TSST-1) and enterotoxins (SE) A,
      B, C and D by bovine mastitis isolates of Staphylococcus aureus was evaluated by
      immunodiffusion using the Optimum-Sensitivity Plate method. S. aureus strains
      were isolated from bovine mastitis in 23 dairy herds in the state of Minas
      Gerais, Brazil, during 1994-9. Of 127 isolates, 83 (65.04%) produced one or
      several toxins, and among them production of SE was found in 54 (43.0%) isolates,
      of which 1138 (29.09%) secreted enterotoxin identified as type D. TSST-1 was
      found in 5829 (45.723.0%) isolates.

PMID- 10664978
TI  - The effectiveness of hygiene procedures for prevention of cross-contamination
      from chicken carcases in the domestic kitchen.
AB  - Thirteen sites in each of 60 domestic kitchens were examined for Salmonella and
      Campylobacter spp. following the preparation of a chicken for cooking and the
      application of different hygiene regimes. During food preparation bacteria became
      widely disseminated to hand and food contact surfaces. Where cleaning was carried
      out with detergent and hot water using a prescribed routine there was no
      significant decrease in the frequency of contaminated surfaces. Where
      hypochlorite was used in addition, a significant reduction in the number of
      contaminated sites was observed. The study suggests that there is a need to
      better understand and promote effective hygiene procedures for the domestic
      kitchen.

PMID- 10664979
TI  - The role of the rodlet structure on the physicochemical properties of Aspergillus
      conidia.
AB  - Physico-chemical properties of Aspergillus conidia rely on their outer cell-wall
      rodlet layer. In A. fumigatus and A. nidulans, the rodlet structure is due to an
      hydrophobin encoded by homologous rodA genes. To evaluate the role of the rodlet
      structure on the physico-chemical properties of conidia, we compared
      hydrophobicity, Lewis acid-base (i.e. electron donor/acceptor) characteristics
      and electrostatic charge of hydrophobin-less (rodletless) mutant and wild-type
      conidia of A. fumigatus and A. nidulans. The results obtained by aqueous-solvent
      partitioning assays, microsphere adhesion assays and microelectrophoresis showed
      that the disruption of the rodA gene modifies surface properties of A. fumigatus
      and A. nidulans conidia, and confirmed that the rodlet layer plays a key role in
      their physico-chemical behaviour. The absence of this layer on A. fumigatus
      spores led to the appearance of weakly basic and acidic characteristics, and had
      a slight effect on the hydrophobicity of conidia. Whereas in A. nidulans, it
      induced a basic character, a marked decrease in hydrophobicity and in the
      polarization capacity (electronegativity) of conidia. These physico-chemical
      differences between A. fumigatus and A. nidulans rodletless conidia may be
      attributed to differences in the composition of the conidial outer cell-wall of
      the two species.

PMID- 10664980
TI  - Molecular characterization of the diversity of Campylobacter spp. isolates
      collected from a poultry slaughterhouse: analysis of cross-contamination.
AB  - Investigations of a free-range broiler flock during the rearing period and at the
      slaughterhouse by polymerase chain reaction-restriction fragment length
      polymorphism (PCR-RFLP) of the flagellin (flaA) gene (flaA typing) have shown
      that poultry carcasses are contaminated by Campylobacter spp. strains which were
      previously present in the poultry faces. Moreover, the investigation of the
      previous and the following batches in the processing plant using flaA typing have
      shown that cross-contamination between batches coming from different flocks
      occurs and is also a risk factor for the presence of Campylobacter spp. on
      poultry carcasses.

PMID- 10664981
TI  - Effect of post-treatment holding conditions on detection of tufA mRNA in ethanol
      treated Escherichia coli: implications for RT-PCR-based indirect viability tests.
AB  - The PCR is a rapid and sensitive method for detecting and identifying low numbers
      of bacteria, but it does not discriminate between living and dead cells. Most
      messenger RNA (mRNA) molecules have a short half-life in the bacterial cell and
      their presence may therefore indicate viability. We have compared PCR and RT-PCR
      (targeted at tufA DNA or mRNA, respectively) for the detection of Escherichia
      coli, using healthy cells and those killed by exposure to different stress
      treatments. PCR gave a positive signal in live cells and those killed by
      autoclaving, boiling, or treatment with 50% ethanol, but was negative after
      exposure to pH 2.0 for 5 min. RT-PCR was positive in live cells but negative
      after all treatments except exposure to ethanol. The persistence of tufA mRNA was
      examined in ethanol-killed cells incubated in LB broth at different temperatures.
      The RT-PCR signal persisted for up to 16 h at 15 degrees C or 4 degrees C but
      disappeared within 2 h at 37 degrees C. RT-PCR thus has potential as an indicator
      of viability provided samples are pre-incubated under appropriate conditions that
      will ensure decay of any residual mRNA in dead cells.

PMID- 10664982
TI  - Change in riverine epilithic extracellular enzyme activity in response to fish
      farm effluent.
AB  - Extracellular aminopeptidase and phosphatase activity was measured at the
      surfaces of submerged stones collected from a river upstream and downstream of a
      fish farm discharge. Aminopeptidase activity was largely indifferent to the
      discharge. Phosphatase activity, in contrast, was depressed downstream of the
      outfall. Thus, there was no evidence of enhanced epilithic extracellular enzyme
      activity to facilitate biopurification downstream of the fish farm discharge.

PMID- 10664983
TI  - Cloning and sequencing of beta-1,4-endoglucanase gene (celA) from Pseudomonas sp.
      YD-15.
AB  - A beta-1,4-endoglucanase gene (celA) from Pseudomonas sp. YD-15 was cloned in
      Escherichia coli DH5 alpha and its nucleotide sequence determined. The open
      reading frame of celA was 1830 base pairs and the enzyme was composed of 609
      amino acids with a molecular weight of 63,617 Da. The deduced amino acid sequence
      and putative active site of CelA had high amino acid homology with family E
      cellulases. By dot blot analysis, the induction of celA according to carbon
      sources was determined. The transcripts hybridizing to the internal fragment of
      celA were detected in total RNA isolated from Pseudomonas sp. YD-15 cells grown
      on avicel and glycerol, but not from cells grown on glucose and cellobiose.

PMID- 10664984
TI  - In situ reverse transcription for the specific detection of bacteria and
      protozoa.
AB  - In situ hybridization experiments with oligonucleotide probes directed against
      the 16S and 18S rRNA molecules have been used successfully to identify specific
      organisms in mixed microbial populations. However, there are limitations in
      applying these techniques to environmental samples. In the present study we have
      examined the possibility of using in situ reverse transcription as an alternative
      to hybridization methods for the rapid detection of Escherichia coli and the
      waterborne parasite Cryptosporidium parvum. Following fixation and
      permeabilization of the cells, extension reactions were performed with species
      specific primers, AMV reverse transcriptase and either cy3-AP3-dUTP or
      fluorescein-11-dUTP at 45 degrees C for 45 min. The cells or oocysts were then
      filtered onto Costar metallic membrane filters and images captured with a CCD
      camera. The results have shown that this technique can successfully detect E.
      coli cells and C. parvum oocysts in under 2 h.

PMID- 10664985
TI  - Development of a m-PCR assay for simultaneous identification of Campylobacter
      jejuni and C. coli.
AB  - Multiplex PCR assay (m-PCR) with three sets of primers was developed for
      simultaneous identification of Campylobacter jejuni and C. coli. Poultry faecal
      samples were enriched in Preston broth for 24 h and streaking on selective media
      was performed before and after enrichment. m-PCR was applied on bacterial
      cultures harvested from media plates. The data showed a selective effect of
      Preston broth which favoured the growth of C. coli. Identification of the species
      by the hippurate hydrolysis test and by the m-PCR was performed on 294 isolates
      of Campylobacter. The efficiency of the identification by the biochemical test is
      only 34% in comparison to 100% efficiency with the PCR. The use of our m-PCR in
      combination with the culture method allowed reliable detection and identification
      of C. jejuni and C. coli within 3-4 d.

PMID- 10664986
TI  - Rapid detection of Listeria monocytogenes by PCR-ELISA.
AB  - A rapid detection system specific for Listeria monocytogenes based upon the
      polymerase chain reaction was developed. The specificity of the primers and the
      probe annealing to the coding region of the mpl gene proved positive with the DNA
      from a total of 103 L. monocytogenes strains, while DNA from another 73 Listeria
      and non-Listeria strains tested negative. To facilitate detection with large
      numbers of samples, a microtitre plate assay was established with biotinylated
      probes. Use of a standard DNA prevented false-negative results when used as an
      internal amplification control in the PCR-ELISA. As the described method required
      approximately 5-6 h to be completed it may prove useful in the detection of L.
      monocytogenes in food.

PMID- 10664987
TI  - Occurrence and numbers of bacteriophages and bacterial indicators in faeces of
      yellow-legged seagull (Larus cachinnans).
AB  - Faeces from feral populations of yellow-legged seagulls from the northern coastal
      area of Catalonia (North-eastern Spain) contained variable amounts of faecal
      coliforms, faecal streptococci, somatic coliphages, F-specific bacteriophages and
      Bacteroides fragilis bacteriophages. Occurrence and numbers of bacterial
      indicators and bacteriophages in the faeces of yellow-legged seagulls are in the
      ranges described in the faeces of different animals. The ratios between numbers
      of bacterial indicators and numbers of bacteriophages are much higher in faeces
      of seagulls than in treated or raw sewage contributed by out-falls of the same
      area.

PMID- 10664988
TI  - The effect of citric acid, lactic acid, sodium citrate and sodium lactate, alone
      and in combination with nisin, on the growth of Arcobacter butzleri.
AB  - The importance of Arcobacter spp. as a cause of human foodborne illness is
      unresolved. Organic acids and their sodium salts, and nisin are preservatives
      commonly used in the type of foods from which the organism is recovered. In this
      study their effect on the growth of A. butzleri in culture, alone and in
      combination, was investigated. At 0.5%, 1.0% and 2.0% lactic and citric acids
      inhibited A. butzleri growth; 2% sodium lactate was effective in inhibiting
      growth over 8 h incubation but not over longer periods. Sodium citrate was more
      effective than sodium lactate. Nisin alone inhibited A. butzleri growth at 500 IU
      ml-1 over 5 h. It did not enhance the effect of sodium citrate inhibition but it
      did augment the effect of sodium lactate alone over 8 h.

PMID- 10664989
TI  - Evaluation of a latex agglutination kit for the detection of human antibodies to
      the lipopolysaccharide of Escherichia coli O157, following infection with
      verocytotoxin-producing E. coli O157.
AB  - A total of 150 human sera was used to evaluate a commercial latex agglutination
      kit for detecting antibodies to the lipopolysaccharide of Escherichia coli O157.
      A comparison of the kit with SDS-PAGE and immunoblotting showed that the kit had
      a sensitivity of 94.12%, a specificity of 99.15%, a positive predictive value of
      96.97% and a negative predictive value of 99.15%.

PMID- 10664990
TI  - Is sentinel node staging for breast cancer standard care? The role of imaging.

PMID- 10664991
TI  - Recent developments in 99Tcm-labelled peptide-based radiopharmaceuticals: an
      overview.
AB  - Nature has designed peptides to stimulate, inhibit or regulate many body
      functions. The development of radiolabelled peptide-based radiopharmaceuticals
      for imaging a variety of tumours, infection/inflammation and thrombus has seen a
      new era in nuclear medicine. Recently, a number of 99Tcm-labelled bioactive
      peptides have proven to be useful diagnostic imaging agents. Due to their small
      size, peptide molecules exhibit favourable pharmacokinetic characteristics, such
      as rapid uptake by target tissue and rapid blood clearance, which potentially
      allows images to be acquired earlier following the administration of a 99Tcm
      labelled peptide radiopharmaceutical. The challenge is to label bioactive
      peptides with 99Tcm with high specific activity without impairing the biological
      properties of the peptides. Molecular engineering techniques now permit synthesis
      of a wide range of biologically active peptides that carry chelating groups in
      their structure without affecting their receptor binding properties, thus
      permitting a high specific activity product. This review presents recent
      developments in 99Tcm-labelled small peptides and their potential applications in
      the imaging of various types of diseases. In addition, the different techniques
      for radiolabelling small bioactive peptides, the pharmacokinetic properties of
      peptides, and their potential as diagnostic imaging agents are also addressed.

PMID- 10664992
TI  - 99Tcm-MIBI scintimammography in 300 consecutive patients: factors that may affect
      accuracy.
AB  - We evaluated the diagnostic yield of 99Tcm-MIBI scintimammography in a relatively
      large series of consecutive patients referred for breast surgery on the basis of
      physical examination or mammogram. 99Tcm-MIBI uptake was correlated to tumour
      size, receptor status, neovascularity, proliferating activity, P-170 glycoprotein
      expression and the patient's gonadal state. Three hundred consecutive patients
      referred to our institution, with either a positive mammogram or a palpable mass,
      were entered into the study. All patients underwent 99Tcm-MIBI scintimammography.
      Pathological status was obtained after surgery in all patients. Breast cancer was
      diagnosed in 218 (73%) patients. The MIBI scan was positive in 89% (194/218)
      cancer patients and in 17% (14/82) of patients with benign masses (false
      positives); the scan was negative in 24 (11%) cancer patients (false-negatives).
      The sensitivity of MIBI scintigraphy was higher for tumours > 1 cm (95 vs 48% in
      lesions < or = 1 cm) and in pre-menopausal women (95 vs 85%). Conversely, the
      specificity was better for lesions < 1 cm (100%) and in post-menopausal women
      (89%). The positive predictive value of MIBI scan was good both in small (< 1 cm)
      and large tumours (100% and 93%, respectively) and slightly modified by gonadal
      state (89% and 96% in pre- and post-menopausal state). The negative predictive
      value was unsatisfactory, especially in small tumours and in older patients. The
      diagnostic performance increased stratifying data for tumour size, indicating
      that lesion size is a major determinant in the diagnostic accuracy of MIBI
      scintimammography. We conclude that 99Tcm-MIBI scintimammography is useful in the
      diagnostic evaluation of young patients, because it can select patients for
      further invasive diagnostic procedures. In older patients, a positive 99Tcm-MIBI
      scan is highly suggestive of malignancy and might be an indication for surgery.
      In the case of a negative scan, biopsy is advisable given the poor negative
      predictive value. Small tumour size and a well-differentiated histotype
      characterize false-negative cases.

PMID- 10664993
TI  - Scintigraphic features of chronic sialadenitis and Sjogren's syndrome: a
      comparison.
AB  - An abnormal salivary scintigram is an accepted objective criterion in the
      diagnosis of primary and secondary Sjogren's syndrome, an immune-mediated
      disorder characterized by xerostomia and kerato-conjunctivitis sicca. However,
      chronic sialadenitis constitutes a major differential diagnostic consideration in
      the xerostomic population. We investigated 39 cases of biopsy-confirmed chronic
      sialadenitis and 152 individuals with first- or second-degree Sjogren's syndrome,
      according to international classification criteria. We analysed scintigraphic
      defects in terms of glands per patient, distribution patterns, kinetics and
      severity. Relative to Sjogren's syndrome, chronic sialadenitis showed
      significantly fewer defective glands per patient, less frequent dual parotid
      submandibular defects, fewer combined deficits of uptake and discharge, and
      milder uptake failure. No statistically significant differences were found in the
      frequency of single gland abnormality, predilection for submandibular
      involvement, and respective proportions of uptake-only and discharge-only
      defects. Unevaluable discharge due to low uptake, although comprising only 34% of
      test-positive cases, appeared to be a highly specific but insensitive
      scintigraphic marker for Sjogren's syndrome. In non-irradiated xerostomic
      populations, scintigraphy provides specific, albeit limited, diagnostic
      information. The procedure's ability to distinguish uptake failure from secretory
      failure may be a useful asset in guiding clinical management strategies and
      estimating outcomes.

PMID- 10664994
TI  - 99Tcm-p-aminohippuric acid as a new renal agent.
AB  - 99Tcm-p-aminohippuric acid (99Tcm-PAH) is a new renal radiopharmaceutical
      prepared from a lyophilized kit by the addition of sodium pertechnetate
      (Na99TcmO4). Each vial contains PAH, the calcium trisodium salt of
      diethylenetriamine pentaacetic acid (CaNa3DTPA) and stannous chloride
      (SnCl2.2H2O) in an inert atmosphere. It is a stable radiopharmaceutical with high
      radiochemical purity (> 95%). Its protein binding is very similar to that of 131I
      OIH, but it is hydrophilic in character. Animal studies using 99Tcm-PAH have
      indicated that it provides renal images of satisfactory quality with no external
      background. Despite its almost identical radiochemical purity and HPLC analysis
      results to 99Tcm-DTPA, 99Tcm-PAH is rapidly secreted by the kidneys in a manner
      consistent with tubular secretion, as confirmed by rat probenecid studies,
      whereas 99Tcm-DTPA is excreted by glomerular filtration. The pharmacokinetic
      parameters of 99Tcm-PAH (t1/2(alpha)) = 2.5 min, t1/2(beta) = 41.7 min, Cl = 5.22
      ml.min-1, Kel = 5.1 x 10(-4) min-1) differ from those of 99Tcm-DTPA. Evaluation
      of 99Tcm-PAH in two human volunteers confirmed its good renal characteristics:
      rapid disappearance from the vascular system, high uptake in kidneys followed by
      its very fast elimination, and low residual activity 20 min after its intravenous
      administration.

PMID- 10664995
TI  - Calculation of airborne radioactivity in a Technegas lung ventilation unit.
AB  - Airborne contamination by 99Tcm has been monitored in the Nuclear Medicine
      Department in our hospital to assess the risk of internal contamination to
      occupational workers exposed to Technegas studies. An air sampler fitted with a
      membrane filter was used. The optimum time for air absorption for obtaining the
      maximum activity in the filter was calculated. Maximum activity in the membrane
      filter ensures minimum uncertainty, which is especially important when low-level
      activities are being measured. The optimum time depends on air absorption
      velocity, room volume and filter efficiency for isotope collection. It tends to
      1/lambda (lambda = disintegration constant for 99Tcm) for large volume and low
      velocity. Room activity with the air pump switched on was related to filter
      activity, and its variation with time was studied. Free activity in air for each
      study was approximately 7 x 10(-4) the activity used, and the effective half-life
      of the isotope in the room was 13.9 min (decay and diffusion). For a typical
      study (630 MBq), the effective dose to staff was 0.01 microSv when in the room
      for 10 min.

PMID- 10664996
TI  - Errors in the spleen-blood partition coefficient for water in C15O2 steady-state
      PET.
AB  - The aim of this study was to clarify if the value of 0.93, determined for
      patients with normal livers, is useful as a pathological spleen-blood partition
      coefficient for water when the splenic blood flow is quantified by the C15O2
      steady-state method. A steady-state PET scan with continuous inhalation of C15O2
      and a dynamic PET scan with a H(2)15O bolus injection were performed. From 157
      patients, 392 slices were chosen as having planes that encompassed the spleen and
      provided regions of interest with full signal imaging. A comparison of the
      results of the steady-state and dynamic methods was performed. When 0.93 was
      adopted as the spleen-blood partition coefficient for water, an error of about
      25% was seen in the splenic blood flow of patients with cirrhosis. When measuring
      splenic blood flow, the H(2)15O dynamic method is necessary. However, a rough
      estimate of splenic blood flow is possible by the C15O2 PET steady-state method,
      if this error is known.

PMID- 10664997
TI  - Evaluation of the dose to the bladder wall using a dynamic balloon-bladder
      phantom and TLD measurements in 18F-FDG PET studies.
AB  - [18F]-2-deoxyglucose (18F-FDG) is one of the most useful radiopharmaceuticals in
      clinical positron emission tomographic imaging. Its final metabolic destination
      is the bladder, which accumulates the highest absorbed dose in the body during
      imaging. The aims of this study were to develop a dynamic bladder phantom to
      emulate the dynamic response of the bladder and to evaluate changes in the dose
      to the bladder wall during the imaging procedure. 18F-FDG of various
      concentrations can be drip-fed intravenously to the balloon-bladder at different
      uptake phases or extracted from the phantom during voiding. A dose evaluation
      model, introducing the concept of photon energy flux conversion into the dose
      calculation, is thus developed for clinical evaluation. The dose to the bladder
      wall using the proposed model is comparable to that measured using a
      thermoluminescence dosimeter (TLD), with a less than 5% discrepancy. The main
      advantages of the model are the use of the dose conversion factor, phi TLD, which
      is determined from real TLD measurements, and the ability to consider the dynamic
      characteristics of the bladder. To overcome the problems of diverse dose
      distributions among subjects, time-activity information provided by clinical
      bladder imaging is required, so that the method can be applied to other
      radiopharmaceuticals.

PMID- 10664999
TI  - Estimating plasma volume from red cell volume.
AB  - Following the withdrawal of the only licensed supply of 125I-HSA in 1997, most UK
      centres now simply estimate plasma volume from a knowledge of the red cell volume
      and venous haematocrit. We compared measured and estimated plasma volume in 107
      consecutive patients who had had red cell and plasma volume measured
      independently in the conventional way. In only 40% of cases was the estimated
      value accurate to within +/- 5%, and discrepancies of more than +/- 10% were seen
      in 35%. As there appears to be no simple way of predicting those patients for
      whom an estimation is inappropriate, it is recommended that plasma volume is
      measured independently in all patients, using a reputable source of unlicensed
      125I-HSA.

PMID- 10664998
TI  - A one-hour walk-in service for wrist trauma imaging.
AB  - We investigated the feasibility of rapid imaging of wrist trauma following
      casualty presentation and any subsequent effect on image quality and
      interpretability. All patients referred for wrist imaging were injected with 370
      MBq 99Tcm-hydroxymethyl diphosphonate (HDP) and imaged 1, 2 and 3 h later. Palmar
      images were acquired on a 256 x 256 x 16 matrix using a high-resolution
      collimator, 140 keV photopeak and a 20% window. The images were scored
      qualitatively by four qualified observers in three categories: image quality,
      lesion detection and lesion localization. Statistical analysis indicated a
      significant improvement in scan quality with time, the mean difference (+/-
      standard error of the mean) between the 1 and 3 h scans being 0.81 +/- 0.07 (P =
      0.001). No significant differences were seen in lesion detection (0.05 +/- 0.08;
      P = 0.51) or localization (0.14 +/- 0.08; P = 0.10). We conclude that imaging of
      wrist trauma is possible as early as 1 h post-injection of 99Tcm-HDP, although
      negative studies at 1 h require a 3 h image to maintain diagnostic accuracy.

PMID- 10665000
TI  - Welcome to the millennium.

PMID- 10665001
TI  - Acute otitis media and pneumococcal resistance: making judicious management
      decisions.
AB  - The emergence of drug-resistant Streptococcus pneumoniae (DRSP) has implications
      for the primary care provider who treats acute otitis media (AOM) in children.
      AOM must be carefully distinguished from otitis media with effusion (OME).
      Antibiotic treatment for AOM is recommended because of the low rate of
      spontaneous resolution of S. pneumoniae infection and the risk of suppurative
      complications, particularly in young children. Amoxicillin continues to be the
      first drug of choice. Children for whom the first course of antibiotics fails
      should be treated with amoxicillin-clavulanate, cefuroxime axetil, or
      ceftriaxone. Trimethoprim-sulfamethoxazole, the macrolides, and most of the
      cephalosporins have limited effectiveness against DRSP and should no longer have
      a major role in AOM treatment. OME need not be treated with antibiotics unless
      the effusion has been present for 3 to 4 months. Tympanostomy tubes are an
      effective treatment for both chronic OME and recurrent AOM. Given the significant
      increase of DRSP during the past decade, clinicians must minimize antibiotic use
      and, when antibiotics are required, make judicious clinical decisions.

PMID- 10665002
TI  - Measuring outcomes in primary care practice.
AB  - Systematic attention to outcomes is becoming a requirement of primary care
      practice. Outcomes of interest include improvement in health (medical outcomes),
      patient satisfaction with the health care experience (service outcomes), and
      curtailing of expenditures (cost outcomes). Primary care providers who monitor
      outcomes in their practice have many advantages: They have the opportunity to
      evaluate themselves before others evaluate them; they may alter or improve their
      system of care; and they can provide data on their effectiveness. This article
      discusses how primary care providers can measure outcomes at the practice level
      and the inherent values in this practice.

PMID- 10665003
TI  - HIV in 2000: historical perspectives and an outlook for the future.

PMID- 10665004
TI  - Assessment of calculation and number processing by adults: cognitive and
      neuropsychological issues.
AB  - Calculation and number processing abilities were assessed in normal (n = 138) and
      traumatic brain-injured (n = 15) Brazilian literature subjects. The study aimed
      (i) to analyse the effects of demographic factors and to provide tentative norms
      adjusted for the relevant variables, (ii) to examine the factorial structure of
      the battery and to evaluate its clinical validity for diagnosis purposes, and
      (iii) to question the power of current models to account for effects and
      dissociations found for these groups. Analysis indicated a main effect of
      education on most subtests and of sex on three, but none for age. Cut-off scores
      for normality were defined at Percentile 10 with reference to education. The
      sensitivity of the battery to the presence of arithmetical impairments was
      considered satisfactory since 11 out of the 15 patients showed pathological
      scores. A principal component analysis indicated that the different sub-tests
      were grouped into three factors, which were tentatively interpreted with
      reference to current information-processing models. The multiple single-case
      analysis of dissociations in patients' performance suggested some limits with
      respect to anatomo-functional models of calculation and number processing.

PMID- 10665005
TI  - Relationship of fitness and gross motor skills for five- to six-yr.-old children.
AB  - 51 kindergarten children participated to assess how various fitness components,
      1/2-mile run, the Prudential PACER test, body composition, shoulder stretch,
      trunk lift, sit-and-reach, curl-up, and flex arm-hang related to motor
      performance on the Bruininks-Oseretsky test battery including running, speed,
      agility, balance, bilateral coordination, and strength. All values recorded in
      the fitness components were compared with standardized motor skill scores.
      Analysis indicated that 1/2-mile run performance was significantly correlated
      with body weight and relative body fat, showing that as body weight or relative
      body fat increased run performance times were slower. Comparisons between the
      fitness parameters and motor skills indicated that the 1/2-mile run performance
      also was negatively correlated with measures of balance, bilateral coordination,
      and strength while the Prudential PACER test was positively correlated with
      strength. During continuous walk-jog movements (half-mile run) in a relatively
      homogeneous sample, increases in body size improved balance, bilateral
      coordination, and strength but negatively affected running during the 1/2-mile
      fitness test. In more interval-related activities such as the Prudential PACER
      test, an increase in strength was related to improved performance.

PMID- 10665006
TI  - Boundaries and level of experience with six types of dreams.
AB  - The self-reported levels of experience to six types of dreams were compared for
      groups of students who classified as having either thin (n = 30) or thick (n =
      86) boundaries. Consistent with predictions drawn from the literature, the thin
      boundary group scored significantly higher on level of experience for each dream
      type than the thick-boundary group. These data provide additional validation for
      Hartmann's Boundary Questionnaire.

PMID- 10665007
TI  - College students' perception of facial expressions.
AB  - 95 college students were administered the Facial Expressions subtest of the
      Diagnostic Analysis of Nonverbal Accuracy to measure perception of nonverbal
      cues. Participants also completed the Nowicki-Strickland Locus of Control Scale
      and responded to a short questionnaire regarding their beliefs about their own
      ability to perceive nonverbal cues as well as how effective they felt others were
      in perceiving nonverbal cues. A significant correlation between locus of control
      and perception of adult facial expressions indicated those students with a more
      internal locus of control had higher scores on correct perception of adult facial
      expression. There was no significant correlation between locus of control and
      facial expressions of children. Sex differences were also found in perception of
      nonverbal cues. Female students scored higher in correctly perceiving facial
      expressions than the men. Participants also scored higher in correctly perceiving
      facial expressions of children than of adults.

PMID- 10665008
TI  - Absence of habituation to repeated exposures to a rotating optokinetic drum with
      brief intersession intervals.
AB  - The purpose of this study was to investigate whether participants would habituate
      to repeated exposures to a rotating drum with brief intersession intervals.
      Participants were 41 college students, divided into a High Susceptibility group
      and a Low Susceptibility group based on their subjective symptoms of motion
      sickness during the first exposure to the rotating drum. The study consisted of
      three 16-min. exposures to a rotating drum with intersession intervals of 30 min.
      Contrary to expectation, for the High Susceptibility group, the symptom score
      mean of the first session was significantly less than that of the second and
      third sessions; and the drum viewing time of the first session was longer than
      that of the second and third sessions. In the Low Susceptibility group, the
      symptom score and drum viewing time were not significantly different among the
      three sessions. In conclusion, participants did not habituate to three repeated
      exposures to a rotating drum with intersession intervals of 30 min. Instead, a
      sensitization response occurred for the participants high in susceptibility.

PMID- 10665009
TI  - Emotional stability and facial activity as predictors for pain tolerance.
AB  - 40 subjects were given the Cold Pressor Test. There were large individual
      differences in the time subjects were willing to keep their hands immersed in the
      cold water. Predictors indicated for these differences were sex, emotional
      stability, and facial activity during the test. Emotional stability was measured
      by means of questionnaire scales and facial activity by ratings on the basis of
      videotapes.

PMID- 10665010
TI  - Phantom sensations in a patient with cervical nerve root avulsion.
AB  - This case study reports detailed phantom sensations in a 35-yr.-old man who had
      his C5 and C6 cervical nerve roots avulsed from the cord during a motorcycle
      accident at the age of 22 years. The subject, who was left with a paralyzed right
      deltoid muscle, anesthetic sensation along the upper lateral portion of the right
      arm, and absent right biceps reflex, became aware of phantom right arm and hand
      sensations a few months after the original injury. This finding--which has
      important implications for understanding the process involved in bodily
      perception as well as the development of these perceptions--provides evidence of
      a distributed neural representation of the body that has both genetic and
      experiential determinants. The implications of these findings are discussed with
      reference to recent concepts of phantom limb experiences and related phenomena.

PMID- 10665011
TI  - Differential effects of transformation on facial recognition in young children: a
      pilot study.
AB  - This study sought to examine further the effect of facial transformation on
      accuracy of recognition by a sample of young children. Specifically, groups of 6-
      and 8-yr.-old children were familiarized with 10 target stimuli and were then
      given a recognition test in which the targets were randomly mixed with 20
      distractor stimuli. During the test, half of the target stimuli were transformed
      (addition of a mustache) and half of the target stimuli remained unchanged (clean
      shaven). Subjects indicated which stimuli were previously viewed target faces,
      regardless of whether a mustache had been added. Analysis indicated no
      differences between the two groups for the unchanged faces; however, the addition
      of facial hair increased false alarms and lowered hits and d' values for the
      younger group only. These results suggest that the groups performed equally well
      on recognition test for unchanged stimuli, but accuracy of recognition of
      transformed stimuli was differentially affected for younger subjects. This study
      raises further questions for assessing the accuracy of facial memory by children,
      especially when faces to be identified have been altered in physical appearance.

PMID- 10665012
TI  - Decoding of emotional expressions in children and adolescents.
AB  - The aim of this study was to assess whether different kinds of emotions are
      decoded in different ways during ontogeny. 151 normal subjects (80 boys; 71
      girls) aged 8 to 16 were recruited in primary, secondary (middle), and high
      schools and 46 slides (3 male; 3 female) from Picture of Facial Affect showing
      six basic emotions were stimuli. Analysis showed that boys and girls in all age
      groups did not differ in decoding facial expression; happiness and disgust had
      the highest percentage scores in all age groups, 99% and 94%, respectively, while
      sadness and fear had the lowest percentage scores, 69% and 55%, respectively.
      This was possibly due to the intrinsic unpleasantness of those emotions for
      children. Competence in discrimination of sadness, fear, and surprise changed
      across age groups, but this growing competence did not show a linear trend and
      was not similar for all emotions.

PMID- 10665013
TI  - Color scission and phenomenal transparency.
AB  - When an observer with a holistic viewing attitude perceives transparency in an
      achromatic two-dimensional pattern, some areas of the pattern form a single
      transparent phenomenal surface. In each of these areas the observer
      simultaneously perceives the gray color of the transparent surface and the gray
      color of the background that is visible through the transparent surface. With an
      analytic viewing attitude the observer perceives a single gray color in each area
      of the pattern. When the viewing attitude changes from analytic to holistic, the
      term color scission means the phenomenal replacement of the single analytically
      perceived gray color of an area of the pattern with the two gray colors that are
      perceived in the same area when such area forms a transparent surface. The
      concept of color scission has been used by Moore Heider and Metelli to explain
      phenomenal transparency. An analysis of experimental results reported in the
      literature shows that color scission does not occur in transparent patterns
      formed by only three areas and that it involves incorrect predictions of the
      occurrence of transparency in patterns formed by four or more areas. It is
      concluded that in general the concept of color scission is inadequate to explain
      phenomenal transparency.

PMID- 10665014
TI  - Wisconsin Card Sorting Test variables in relation to motor symptoms in
      Parkinson's disease.
AB  - The Wisconsin Card Sorting Test, a standard test for the assessment of executive
      function and free of a motor component, was employed for the assessment of 37
      nondemented patients with idiopathic Parkinson's Disease and 37 matched normal
      controls. The symptoms of the patients were clinically assessed by means of the
      Unified Parkinson's Disease Rating Scale, which yielded scores for the cardinal
      symptoms of the disease as well as a total motor score. The Wisconsin Card
      Sorting Test was administered in all subjects in its original form (128 cards),
      and it was scored to yield 16 measures according to the instruction of the
      Wisconsin Card Sorting Test revised manual. Patients with Parkinson's Disease had
      significantly lower scores on the following test variables: number of trials
      administered, perseverative responses, percent perseverative responses, and
      failure to maintain set. The correlations between the last three variables and
      total motor score were statistically significant. Of the four cardinal symptoms
      of the disease, only rigidity correlated significantly with the number of
      perseverative responses and percent perseverative responses. These findings
      provide a clue that the lower performance of these patients on certain variables
      of the Wisconsin Card Sorting Test may be related to the process of the disease.

PMID- 10665015
TI  - Changes in basketball shooting patterns as a function of distance.
AB  - The effect of distance on the accuracy and movement form in basketball shooting
      was examined using a dynamic systems approach. Five male and five female young
      adults (M = 26 yr.) with no basketball experience beyond regular physical
      education shot a basketball 20 times at each of eight distances from 5 to 40 ft.
      (Natural condition). Also, they pretended to shoot the ball 5 times at each of
      the eight distances, for a total of 200 shots each (Pretend condition). In the
      Natural condition, shooting accuracy significantly decreased as shooting distance
      increased. Across both conditions and across four body components (feet position,
      hand position, trunk rotation, and jump height), the participants shifted from
      one movement pattern to another 86.3% of the time as shooting distance increased.
      The distances at which the transitions occurred were significantly shorter in the
      Natural than the Pretend condition for the feet and hand components but not the
      trunk and jump-height components. These results indicated that shooting a
      basketball at increasing distances can be portrayed as a dynamic system
      characterized by abrupt changes in at least four body components at critical
      distances.

PMID- 10665016
TI  - Sport injuries in right- and left-handers.
AB  - The incidences of sport injuries in right- and left-handed subject was
      investigated. Of 40 left-handed athletes, 33 (83.0%) had sport injuries; of 279
      right-handed athletes, 189 (68.0%) had sport injuries. These findings suggest
      left-handers may be more susceptible to accident-related injuries.

PMID- 10665017
TI  - Effect of goal-setting on reaction time.
AB  - To examine the effect of goal-setting on reaction time 40 physical education
      students were tested on a reaction-time test and were randomly assigned to one of
      four experimental conditions: personal goals, difficult assigned goals, easy
      assigned goals, and no goals. Analysis showed that goal-setting enhanced
      performance, and participants in the difficult assigned goals condition showed
      the biggest improvement.

PMID- 10665018
TI  - Reading ability and differential cognitive profiles of girls and boys.
AB  - To compare the differential cognitive and stylistic profiles of Spanish-speaking
      girls and boys and the relation between these profiles with subjects' reading
      scores 50 girls and 50 boys, 8 years old, were assessed on a reading test, the
      Children's Embedded Figures Test, and the Intellectual Test (Escala Diferencial
      del Rendimiento Intelectual). Analysis showed differential cognitive profiles for
      the two sexes. While girls used single, essentially verbal strategies for the
      reading activity, boys with high reading scores used verbal and perceptual
      strategies. In general, for girls verbal intelligence scores had correlated the
      highest with reading scores and lowest with independence on the Children's
      Embedded Figures Test. For boys the two tests contribute to the explained
      variance of reading scores. Curiously for scores in reading letters, reading
      strategies of the two groups seemed inverted.

PMID- 10665019
TI  - Standards for judgments of unilateral impairments in muscle strength.
AB  - A secondary analysis of a data base of isometric strength measures from 136
      asymptomatic adults (50-79 years) was conducted to estimate the normal difference
      between dominant and nondominant side strengths. Measures of strength obtained by
      hand-held dynamometry from 13 muscle actions were expressed as a ratio, dominant
      side strength:nondominant side strength. The ratios indicated that the dominant
      side was stronger on average but that the normal range of differences between
      sides could reach 23.2 to 40.2%, depending on the action. The findings do not
      provide much support for the convention of using a 10% difference in strength
      between sides to designate impairment.

PMID- 10665020
TI  - Relationship of age and education with anxiety, depression, and hopelessness in a
      South African community sample.
AB  - In this pilot study approximately one-quarter of a nonrandom community sample of
      16 men and 34 women of lower socioeconomic status reported scores implicating
      moderate to severe depression and anxiety. Higher age and lower education were
      associated with higher scores on distress.

PMID- 10665021
TI  - Performance suppression from control procedures is not the basis of the Mozart
      effect.
AB  - The suggestion by others that previous replications of the Mozart effect in this
      laboratory are due to suppression of arousal from a relaxation control procedure
      is inconsistent with our published data.

PMID- 10665022
TI  - A ratio model of perceptual transparency.
AB  - A ratio model of the achromatic transparency of a phenomenal surface on a
      bipartite background is proposed. The model asserts that transparency corresponds
      to the evaluation of the ratio of the lightness difference inside the transparent
      surface to the difference in reference lightness inside the background. It
      applies to both balanced and unbalanced transparency. The ratio model was
      compared experimentally with the previous perceptual model of achromatic
      transparency proposed by Metelli. Each model was tested by comparing the rated
      with the predicted transparency. Analysis shows that the ratio model provides
      better predictions of transparency than those provided by Metelli's model.

PMID- 10665023
TI  - What is the Chinese suicide rate?
AB  - Estimates of the Chinese suicide rate are made from two sources and found to be
      in the range of 13 to 19 per 100,000 per year.

PMID- 10665024
TI  - The Weber fraction versus perceived similarity.
AB  - The Weber fraction type of discrimination outcome means that stimuli of high
      magnitude are difficult to discriminate. Simultaneous and successive
      discriminations between two long (high magnitude) lines and also between two
      short (low magnitude) lines were carried out. Over-all performance on the
      successive discrimination between the two long lines was much poorer than on the
      three other discriminations. This discrimination also produced the poorest
      performance on different stimuli relative to same stimuli. The latter result
      should indicate that the two successive long lines were perceived as most
      similar. These and additional results support the conclusion that over-all
      discrimination performance and perceived similarity were consistently associated
      even though they were not consistently associated with length and time of
      occurrence (simultaneous versus successive). Nevertheless, the association of
      discrimination with perceived similarity has received minimal attention in the
      psychophysics area.

PMID- 10665025
TI  - Relation of transliminality and vividness of visual imagery.
AB  - Responses of 50 psychology undergraduates to scores on a measure of
      transliminality (psychological material crossing thresholds into and out of
      consciousness) and on a measure of vividness of visual imagery were correlated.
      11. The value is positive but clearly not significant.

PMID- 10665026
TI  - Disturbance of imagination and symbolization in pervasive developmental
      disorders: preliminary study utilizing the Rorschach Inkblot Test.
AB  - Two clinical cases of children of 6 and 7 years are presented with their
      respective Rorschach records. The first case had a diagnosis of autism, the
      second of Pervasive Developmental Disorder Not Otherwise Specified. The modes of
      elaboration and responses to the ambiguous stimuli of the Rorschach test were
      compared with the clinical symptoms of the two subjects, which are centered on
      the two opposite poles of absence of imagination in the first case and distortion
      of the imaginative processes in the second.

PMID- 10665027
TI  - Relationship between aesthetic motivation and preferences for aggressive and
      nonaggressive sports.
AB  - Two studies were designed to replicate the finding that people scoring high on
      aesthetic motivation, as measured by Wann's Sport Fan Motivation Scale, tend to
      prefer nonaggressive sports. Study 1 correlated 75 college students' scores on
      aesthetic motivation with their enjoyment of watching aggressive sports. Study 2
      correlated 44 college students' scores on aesthetic motivation with their
      enjoyment of watching a series of aggressive football plays. Neither study
      replicated the previous finding that people high on aesthetic motivation tend to
      prefer nonaggressive sports, suggesting that the earlier finding was an artifact
      of the method used.

PMID- 10665028
TI  - Perceptual learning by preschool children using stimuli with varying proportions
      of common elements.
AB  - The effect of preexposure to visual stimuli on subsequent discrimination was
      studied in 17 girls and 23 boys, ages 53 to 61 mo., using a test in which a
      sample stimulus had to be identified from a set of comparison stimuli.
      Preexposure significantly facilitated discrimination. This facilitation was more
      noticeable between stimuli which shared a large proportion of common elements.
      The results were consistent with an associative theory of the representation of
      stimuli suggested by McLaren, Kaye, and Mackintosh in 1989, and implications are
      considered for teaching.

PMID- 10665029
TI  - An update on relations of body image and body size with eating disordered
      behaviors.
AB  - The present study examined body image and body size with eating disordered
      behaviors in a sample of 130 female college students to see if these problems
      still occur despite the publicity that this issue has received. Students (n = 35)
      who reported engaging in eating disordered behaviors reported being less
      satisfied with their bodies than students who did not report engaging in eating
      disordered behaviors. Also students who engaged in eating disordered behaviors
      perceived their body size as larger than that for students who did not report
      engaging in such behaviors. There was, however, no significant difference found
      in preference for body size between groups.

PMID- 10665030
TI  - Teaching a long sequence of behavior using whole task training, forward chaining,
      and backward chaining.
AB  - Whole task training, forward chaining, and backward chaining techniques were
      compared in teaching two different 120-step sequences of behavior to college
      students. In Exp. 1 participants learned a sequence that began with easy
      movements, progressed through more difficult movements, and ended with easy
      movements. Whole task training resulted in more errors than either forward or
      backward chaining. Differences were found in the location of errors. Both whole
      task training and forward chaining resulted in fewer errors at the beginning of
      the sequence and backward chaining resulted in fewer errors at the end of the
      sequence. Because the results of Exp. 1 may have been affected by the increased
      difficulty of the middle of the sequence, Exp. 2 was undertaken using a sequence
      of behavior where all segments were of equal difficulty. Whole task training and
      forward chaining resulted in fewer errors than backward chaining. The location of
      errors was similar to that found in Exp. 1.

PMID- 10665031
TI  - Double-blind study of possible proximity effect of sucrose on skeletal muscle
      strength.
AB  - The hypotheses that close physical proximity to sucrose, without its ingestion,
      affects skeletal muscle strength and time between meals influences the direction
      of this effect, were tested. 28 college students performed 10 one-arm curls using
      the dominant arm, while either holding a bottle containing sucrose or sand in the
      free hand, without knowledge of which bottle was held. Data were first collected
      following an overnight fast. A week later, data were collected 1 hr. after these
      students had each consumed a bagel. During the fasting state, the mean maximal
      isometric strength while holding the bottle of sucrose was significantly greater
      than when holding a bottle of sand; however, no significant difference was found
      for the group tested after having consumed a bagel. Some possible explanations
      for these results are discussed, recognizing limitations imposed by lack of
      control for order of conditions and amount of experience.

PMID- 10665032
TI  - Sex differences on the hand mental rotation task for 9-yr.-old children and young
      adults.
AB  - The Hand Mental Rotation task is assumed to activate an egocentric spatial
      reference frame to realize mental rotation. This study presents significant sex
      differences in hand mental rotation performances between men and women (n = 23
      and 25, respectively; age: 20.7 yr.). Differences in hand mental rotation in
      school girls and boys (ns = 48 and 41, respectively; age: 9 yr.) were not
      significant. Our results suggest that the change in sex differences in egocentric
      mental rotation may occur with developmental change. This requires further
      testing with a larger sample so testing can occur at several ages between 9 and
      20.7 years.

PMID- 10665033
TI  - One hundred years of an ambiguous figure: happy birthday, duck/rabbit.
AB  - In the present study, Jastrow's famous ambiguous drawing of a duck/rabbit was
      presented to 100 students along with 11 published variants from later research.
      The beak/ears of the animal pointed to the right for half of the subjects and to
      the left for the other half. For each figure subjects were required to rate the
      ease of bird and of rabbit identification on a 9-point scale. Raw data of
      subjects' ratings are presented for the convenience of experimenters planning
      research with a specific bird/rabbit figure. Of the 12 figures, 6 were
      significantly bird-dominant, 2 were rabbit-dominant, and only 4 figures were
      truly ambiguous, i.e., a bird was as easily identified as was a rabbit. With the
      exception of one figure (the whole-body representation of a duck/rabbit), bird
      and rabbit ratings were not affected by the orientation of the beak/ears.
      Jastrow's original drawing was the seventh out of the 12 figures in rated
      ambiguity, suggesting a secure place for it in research on visual ambiguity.

PMID- 10665034
TI  - New Zealand adolescents' perceptions of self and others.
AB  - As part of a larger study of adolescents' stress, 1,799 12- to 18-yr.-olds in New
      Zealand compared themselves with other young people of their age on five general
      issues. Girls were significantly more likely than boys to say they think they
      worry more and have more health problems than most people of their age; younger
      adolescents were more likely than older ones to say they think they are under
      more peer pressure than most people of their age. On all items, however, most
      participants rated themselves physically and psychologically healthier than most
      of their peers.

PMID- 10665035
TI  - Development and validation of two new scales for assessment of body-image.
AB  - This study reports the development and validation of two new and improved tools
      for assessment of body-image. Two schematic contour scales were created using a
      frontal view photograph of an adult male and female with height and weight of the
      median American. A 2-figure analogue scale was created by distorting this drawing
      by +/- 30%. A 13-card scale was created by generating 13 drawings distorted
      between +/- 30% by increments of 5%. Evidence is presented for the reliability
      and validity of both scales. The advantages of these new scales over existing
      figural and silhouette scales are discussed.

PMID- 10665036
TI  - Hemispheric laterality and self-rated personality traits.
AB  - Cerebral hemispheric lateralization and personality traits were evaluated in 154
      undergraduate and nonclinical volunteers. Personality ratings did not differ
      significantly between groups defined on the basis of hand, eye, or ear
      preference.

PMID- 10665037
TI  - A structural model of achievement motives, performance approach and avoidance
      goals, and performance among Norwegian olympic athletes.
AB  - A structural model of achievement motives, performance approach and avoidance
      goals, and performance was applied and tested among 136 Norwegian Olympic level
      athletes. Achievement motives, competitive behavior over time, performance
      approach goal-clarity, and performance-avoidance goals were assessed, and elite
      performance observed. Analysis indicated that the motive to achieve success is
      positively correlated with competitive behavior over time (a long-term goal),
      whereas the motive to avoid failure is positively associated with performance
      avoidance goals. Both long-term competitive behavior goals and performance
      approach goal-clarity were positively correlated with elite performance whereas
      the performance-avoidance goal was negatively correlated with performance. When
      the proximal influences of goals are controlled, the achievement motives are not
      significantly related to performance. In this structural model, motives and goals
      shared 32% of the variance with the performance measure, whereas a more
      complicated model including goals, sex, and a triple interaction of sex and
      motives shared 42% of the variance with the performance measure.

PMID- 10665038
TI  - Geophysical variables and behavior: LXXXVII. Effects of synthetic and natural
      geomagnetic patterns on maze learning.
AB  - 12 normal male albino rats were exposed or not exposed in their home cages for 5
      min. and 50 sec. once every hour 8 times per night to a 7-Hz square-wave magnetic
      field whose amplitudes were shifted by about 50 nT approximately every 10 sec.
      Although there were no statistically significant differences between the two
      groups for numbers of working errors, numbers of reference errors, or speed
      during the acquisition of an Olton (8-arm) maze, the strength of the group
      differences (F ratios) for daily working errors was reduced (rho = .70) if there
      had been enhanced geomagnetic activity during the time of the night when the
      experimental fields were present.

PMID- 10665039
TI  - Sustained attention on a continuous performance test.
AB  - The present study compared means of 54 nonpatients on two Continuous Performance
      Test measures in five administration conditions. Both response measures
      differentiated performance among the conditions, certain of which may have an
      alerting function that facilitates deployment of attention. Appreciable
      attentional demand or effort, however, may limit this facilitative effect.

PMID- 10665040
TI  - Is American PGA tour more competitive than European tour? Reply to Jimenez and
      Fierro-Hernandez.
AB  - Analysis of the 1998 European PGA tour yielded four statistically significant
      differences between the shot-making skills of the top 10 and bottom 10 money
      winners. Analysis of the 1995 American PGA tour indicated only two skills
      significantly higher among the 10 top-ranked money winners. The results suggest
      the American PGA tour may be more competitive.

PMID- 10665041
TI  - Differences in recognition and preference among four- and five-year-olds on a
      tactile learning and visual test.
AB  - Infants' preferential looking at novel objects and adults' preference for the
      familiar indicate that preference may be influenced by whether the objects have
      been experienced previously. Infants and adults may have opposite preferential
      tendencies; however, infants' preference for a familiar object which they have
      experienced orally casts doubt on this as a developmental process. To examine
      both the influences of experienced modalities and age on the relationship between
      preference and memory, tactile-visual preference and memory tests were employed
      in 4- and 5-yr.-olds. The results indicated the dissociation of preference by
      recognition only in 4-yr.-olds: those who recognized the objects preferred the
      familiar and the 4-yr.-olds who could not recognize them preferred the novel. The
      5-yr.-olds tended to prefer the familiar objects regardless of recognition. The
      results may suggest an age effect on the relationship between preference and
      recognition.

PMID- 10665042
TI  - Climatic data and national suicide and homicide rates.
AB  - Both suicide and homicide rates (per 100,000 population) were higher in nations
      with greater rainfall. Suicide rates were higher in the more northern nations
      while homicide rates were higher in the nations with more elevated terrain.

PMID- 10665043
TI  - Ability to discriminate movements at the ankle and knee is joint specific.
AB  - Measures of discrimination for movements of different extent at the ankle
      (inversion) and knee (flexion) were obtained for the right and left legs from 59
      male footballers. The finding of significant association between discriminability
      scores at common joints was interpreted in terms of the motor program.

PMID- 10665044
TI  - Locus of control and suicidality.
AB  - In a sample of 152 college students, only depression scores predicted current and
      past suicidality. Scores on locus of control, hopelessness, masculinity, and
      femininity did not add any significant components to the multiple regressions.

PMID- 10665045
TI  - 25 facts on sickle cell disease: a regional survey of public school nurses.
AB  - Public school nurses in four states with large percentages of African-American
      citizens were surveyed regarding their knowledge of sickle cell disease. The
      nurses had limited knowledge of many of the facts on sickle cell, suggesting that
      educational workshops are needed.

PMID- 10665046
TI  - Allocation of attention and practice in the production of time intervals.
AB  - During a baseline trial, participants attempted to produce a 60-sec. interval
      while working at either a simple tracing task or others that involved mirror
      tracing. Subsequent practice with the assigned task, expected to reduce the need
      for allocation of attention to mirror-tracing for those groups, produced
      predictable effects on a second trial of duration producing. Those performing
      mirror-tracing reduced production times on the post-practice trial, while those
      performing simple tracing showed no change after practice. These results are
      interpreted within the attentional allocation model of estimation of prospective
      duration.

PMID- 10665047
TI  - Intrasubtest scatter on the WAIS-III information subtest and psychometrically
      defined retrieval deficits.
AB  - Milberg, et al. (1996) postulated that significant intrasubtest scatter on the
      Wechsler Information subtest reflects impaired retrieval. From a pool of 205 male
      referrals at a VA medical center with complete WAIS-III and WMS-III protocols, 28
      participants with impaired retrieval (Group I) defined by a high Retrieval
      Composite score were identified. A sample (Group II) without similar evidence of
      impaired retrieval was matched to Group I on age, education, Full Scale IQ, race,
      and diagnosis. Intrasubtest scatter on the Information subtest was the same
      across groups (Group I M = 6.3, SD = 2.7; Group II M = 6.9, SD = 3.4). A second
      study identified impaired retrieval using the WMS-III Word Lists subtest. 21
      participants (Group III) had impaired retrieval indicated by a Recognition scaled
      score being > or = 4 points higher than the Delayed Recall scaled score. A
      matched sample (Group IV) of VA patients without similar evidence of impaired
      retrieval was constituted. Intrasubtest scatter on the Information subtest did
      not differ across groups (Group III M = 6.6, SD = 2.4; Group IV M = 6.0, SD =
      2.5). Evaluations of the retrieval deficit hypothesis should be based on
      responses of participants whose Information performance is characterized by
      abnormal amounts of intrasubtest scatter. It is possible that a specific amount
      of response variability must be present within the subtest before retrieval
      problems can be detected.

PMID- 10665048
TI  - MR angiography of the renal vessels.
AB  - Magnetic resonance angiography (MRA) is a noninvasive imaging procedure that
      demonstrates flowing blood in the body by distinguishing moving blood from
      stationary tissues. This article provides a general overview of MRA with emphasis
      on its use in the diagnosis of renovascular disease. It also discusses the
      advantages and limitations of renal MRA compared with conventional angiography.

PMID- 10665049
TI  - Malpractice liability in health professional education.
AB  - Malpractice lawsuits filed against educators are a relatively new phenomenon.
      These suits have met with considerable resistance from the courts, which prefer
      not to involve themselves in assessing the quality of educational services.
      However, educators in the health professions are more susceptible to legal action
      because courts are more likely to recognize claims based on medical malpractice.
      This article reviews the case law regarding negligence as a basis for educational
      malpractice and suggests ways educators can avoid such litigation.

PMID- 10665050
TI  - Communicating with mammography patients.
AB  - This article examines the barriers that prevent many women from undergoing
      mammography and strategies that can help them overcome those barriers. It also
      describes techniques for effective, individualized patient communication and
      education. Mammographers will learn how to ask the right questions, listen
      effectively for stated and unstated messages and determine which methods to use
      when communicating with different patients.

PMID- 10665051
TI  - Radiation protection for radiologic technologists.
AB  - This article provides a review and update on radiation protection principles.
      Major topics include the effects of radiation on the body, natural and artificial
      sources of radiation, the basic principles of radiation protection and
      recommended dose limits.

PMID- 10665052
TI  - Multiple sclerosis--Susan's shadow.

PMID- 10665054
TI  - A farewell to arms.

PMID- 10665053
TI  - 1999 in review.
AB  - ARRT completed the 20th century with a strong tradition of advancing
      certification in the radiologic sciences and is poised to address the challenges
      of the next century.

PMID- 10665055
TI  - The upper GI series.

PMID- 10665056
TI  - [Comparative analysis of fragments of HGV NS5b-region isolated in Russia,
      Kazakhstan and Kyrgyztan].
AB  - Nucleotide sequence of a 356 nt fragment of the NS5 region of the hepatitis G
      virus (HGV) genome was determined in 7 strains isolated in Russia, Kazakhstan,
      and Kyrghyzstan. Philogenetic analysis showed that all isolated strains
      genetically differed from the West African strain described previously (type 1)
      and are closely related to strains isolated in the USA and South-Eastern Asia
      (type 2). Hence, the strains from Russia, Kazakhstan, and Kyrghyzstan belong to
      type 2 variant of HGV genome.

PMID- 10665057
TI  - [Isolation of acyclovir-resistant strains of herpes simplex virus from clinical
      material].
AB  - A total of 115 strains of herpes simplex virus were isolated from clinical
      material collected in patients with genital herpes. The majority (93%) of
      isolated strains were sensitive to acyclovir: ID50 varied from 0.15 to 0.80
      microgram/ml acyclovir. Eleven (7%) strains from 4 patients were resistant to
      acyclovir: ID50 was 30-125 times higher in comparison with the reference HSV-1
      strain L2.

PMID- 10665059
TI  - [Restriction mapping of genome and nucleotide sequence of Aujeszky's disease
      virus strains isolated in CIS].
AB  - Auesku disease virus--suid herpesvirus type I (SHV-1) genome is analyzed by the
      restriction fragment pattern analysis. The analyzed strains isolated in CIS
      countries in 1962-1992 were compared with the European strains. Genomes of field
      strains Arsk, Turkmenia, and Geneva differed and even lacked the restriction
      fragments typical of vaccine strains MK-25 or UNIIEV-18S, which agrees with the
      results of the neutralization test. Immunobiological characteristics of SHV-1
      strains are discussed.

PMID- 10665058
TI  - [Variants of immune response in children with acute respiratory viral
      infections].
AB  - Four patterns of changes in the proliferative activity of T-lymphocytes in the
      lymphocyte blastogenesis test with phytohemagglutinin (PHA) are distinguished in
      children with acute respiratory viral infections (ARVI). The differences between
      these patterns are due to aggravated clinical severity of the infection process
      and enhancement of the cytokine reaction of macrophage monocytes. Comparison of
      immunological characteristics of response to ARVI in 4 groups of children showed
      that high reactivity of T-lymphocytes during the acute phase of disease (first
      and third variants) correlated with a relatively weak production of
      immunoglobulins and antiviral antibodies, while the suppression of T-lymphocyte
      response to PHA (second and fourth variants) is associated with expressed humoral
      profile of immune response by the level of immunoglobulin and antiviral antibody
      production. These data permit a hypothesis about the predominant generation of T
      x 1-like clones in children with the first and third variants of immune response
      and of T x 2-like clones in children with the second and fourth variants.

PMID- 10665060
TI  - [Distemper of carnivore: Proliferative activity of lymphocytes in sick and
      vaccinated dogs].
AB  - Effect of inoculation with canine distemper virus (CDV) strains of various
      virulence or vaccination with commercial polyvalent preparations on the immune
      status of puppies has been studied. Serum interferon concentration did not
      change, irrespective of the strain appurtenance of CDV, while the concentration
      of tumor necrosis factor-alpha decreased on days 4-14 after the virus
      inoculation. According to the lymphocyte stimulation test (LST), virulent strain
      Snyder Hill and reactogenic variant U were characterized by a pronounced
      immunosuppressive effect. Vaccine strain VNiiViM-88 exerted a stimulating effect
      in LST. Vanguard 5/L vaccine suppressed the immunity for up to 2 weeks. Vacchum,
      VNiiViM, and experimental vaccine manufactured by a joint-stock company
      Vetzverotsentr+ activated the mitogen-induced lymphocyte blastogenesis.

PMID- 10665061
TI  - [Inhibition of nuclear import of HIV-1 Vpr protein by Gag polyprotein in the
      process of virus-like particles formation].
AB  - For studies of intracellular Vpr transport and the effect of the HIV-1 Gag
      polyprotein on the process, a recombinant baculovirus strain was constructed,
      which directs the synthesis of Vpr fused with the baculovirus secretory
      polypeptide. During infection the majority of Vpr has been observed in the cell
      nuclear fraction. These data suggest that Vpr nucleophilic signal is more active
      than the secretory one. However, during Vpr and Gag co-expression in the
      baculovirus expression system, Vpr content in the nuclei is decreased, since this
      protein incorporates effectively into virus-like particles and forms stable
      complexes with Gag polyprotein. Presumably, the Vpr-Gag post-translational
      interactions are needed for the Vpr incorporation into virions and suppress the
      nuclear import of this protein.

PMID- 10665062
TI  - [Effect of hepatitis G virus on the course of acute hepatitis B and C].
AB  - Examinations of 204 patients with acute viral hepatitis revealed HGV RNA in 65
      (32%) cases. Clinical and laboratory data in HBV or HCV monoinfection virtually
      did not differ from these in co-infection with HBV + HGV and HCV + HGV.

PMID- 10665063
TI  - [Chronic congenital Coxsackie virus infection in the etiology of allergic disease
      in children].
AB  - The authors prove the involvement of congenital Coxsackie virus infection in the
      etiology of allergic diseases in children: 1) indications of high risk of
      vertical transmission of viruses of this group from mothers with persistent
      infection to children are more incident in the history of mothers whose children
      develop allergies in comparison with healthy age-matched children (83 vs. 38.8%);
      2) Coxsackie viruses are detected in sick children more often than in healthy
      ones (58.1-81.1 vs. 7.4%); 3) the persistence of Coxsackie A and B viruses is
      confirmed in the majority of patients examined over time; 4) in the mothers
      examined in parallel with their sick children Coxsackie viruses were detected
      virtually as often as in their children; and 5) reduction of endogenous chronic
      Coxsackie infection by energy metabolism correction in the risk group women
      during pregnancy prevents the development of allergic diseases in their children.

PMID- 10665064
TI  - [Modification of mouse resistance to A/Aichi/2/68 influenza virus by a
      glucocorticoid immunosuppressant kenalog].
AB  - Changes in the virulence of influenza virus A/Aichi/2/68 LD50 were studied in
      albino mice with immunosuppression induced by long-acting glucocorticoid kenalog
      (Kn). In high doses (5 and 10 micrograms/g) Kn induced a decrease in the adrenal,
      thymic, and splenic weight, which is typical of steroid immunosuppression. The
      susceptibility of mice preinjected with Kn to the virus increased more than ten
      fold, judging by a decrease in LD50. The detected shifts may be due to disorders
      in lung tissue resistance and reactivity of alveolar macrophages and neutrophils
      observed previously in induced glucocorticism.

PMID- 10665065
TI  - [Characterization of proteolytic cleavage of influenza virus nucleocapsid protein
      NP in infected cells].
AB  - Antibodies specific to the N-terminal 34-aminoacid peptide of the major
      nucleocapsid protein NP of human influenza A viruses were obtained. The NP
      proteolytic cleavage occurring in infected cells late in infection has been
      demonstrated using this antibody. The antibody specifically reacted with
      noncleaved NP of 56 kD m.w. but not with cleaved NP of 53 kD m.w. This indicates
      that NP56-->NP53 intracellular cleavage released the N-terminal 3 kD peptide of
      Np molecule. The released 3 kD peptide did not accumulate in infected cells.
      Since the RNA-binding and nucleus migrating signals are located in the N-terminus
      of NP molecule, presumably, the terminal cleavage is important for intracellular
      NP functions.

PMID- 10665066
TI  - [Development of new approaches to standartization of enzyme immunoassay test
      systems for detection of antibodies to respiratory syncytial virus using electron
      microscopy and monoclonal antibodies].
AB  - Respiratory syncytial virus (RSV), strain Long, was purified through 20-60%
      sucrose gradient. The virions from different sucrose density zones were tested by
      ELISA for reactivity with monoclonal antibodies (MAB) to F- (MAB 9C5) and N- (MAB
      8B10) proteins of RSV. Comparative study of the same patterns of RSV by electron
      microscopy after negative staining showed a close relationship between the virion
      morphology and MAB binding in ELISA. MAB 9C5 were highly reactive with the
      surface domains of both mature RSV virions and "empty" virion envelopes without
      formed inner nucleocapsid structures. MAB 8B10 reacted well only with mature
      virions with completely assembled nucleocapsids. These MAB failed to reorganize
      the N-protein epitope of immature and destroyed virions, which indicated a
      conformation dependence of the 8B10 binding site. For practical purposes, MAB
      tests can be used to determine the RSV patterns, which can be used in ELISA for
      serologic diagnosis of RSV infection. Testing with these MAB demonstrate the
      stability of RSV to extreme exposures (lyophilization, storage, heating), which
      is important for creation of sensitive ELISA test systems and their
      standardization.

PMID- 10665068
TI  - Not about sex: the lessons and legacy of George Lundberg.

PMID- 10665067
TI  - [Usage of polymerase chain reaction in complex diagnosis of hepatitis B].
AB  - Sera from 926 patients were analyzed by PCR using universal primers to surface
      gene of hepatitis B virus (HBV). HBV DNA was detected in 195 specimens. There
      were no serological markers of HBV in 8.2% of these sera, but later they were
      detected in patients' sera. In patients without HBV DNA in the serum, specific
      HBV antigens and antibodies were detected in 62%. Only in 14% of them the
      clinical picture of the disease corresponded to acute viral hepatitis, although
      the blood for PCR analysis was collected during the late stages of the infection.
      The rest cases were referred to mixed hepatitis C + D. Comparison of the results
      of PCR test and detection of serological virus replication markers HBeAg and
      HBeAb showed the presence of HBV DNA in 28% cases without HBeAg.

PMID- 10665069
TI  - Conversation with David Deitch.

PMID- 10665070
TI  - Not much to ask for, really! The introduction of standard drink labelling in
      Australia.
AB  - An account is provided of the processes leading up to the introduction of
      standard drink labelling on all alcoholic beverage containers in Australia. The
      roles of research and advocacy in recommending the introduction of such labelling
      are analysed as is the resistance of some parts of the alcohol beverage industry.
      It is concluded that the success of this policy initiative derived from the
      carefully orchestrated campaign in which researchers co-operated with health
      advocates. The prior existence of nationally endorsed guidelines for safe
      drinking expressed in terms of standard drinks, recommendations of the National
      Health Policy on Alcohol and an accumulation of relevant research were crucial
      elements for success. However, the role played by some fortuitous circumstances
      cannot be ruled out.

PMID- 10665071
TI  - Transitions in the route of cocaine administration--characteristics, direction
      and associated variables.
AB  - AIMS: To examine transitions in the route of administration of cocaine and the
      variables associated with them. DESIGN: A cross-sectional study undertaken
      between January 1996 and October 1997. SETTING: Fifteen different services that
      offer treatment, counselling or assistance to drug users or HIV-positive patients
      in the State of Sao Paulo, Brazil. PARTICIPANTS: Two hundred and ninety-four
      current or ex-cocaine and crack cocaine users. MEASUREMENTS: A structured
      interview schedule was developed consisting of 246 questions covering socio
      demographic details, drug history, cocaine transitions and HIV-risk behaviours.
      FINDINGS: Eighty-seven per cent of patients began using cocaine by snorting and
      74% subsequently underwent a transition of route--68% towards smoking and 20% to
      injecting. Half of all transitions occurred in the first 3 years following
      initiation into cocaine use. Factors associated with transitions were: younger
      age at cocaine initiation, more frequent use at peak usage, initial use of
      cocaine by snorting or injecting, a lower level of scholastic attainment and
      experience with a wider range of drug classes. A cohort effect was apparent with
      younger cocaine users and those who had begun using after 1990 being more likely
      to undergo a transition to smoking crack and less likely to start injecting.
      CONCLUSIONS: Cocaine transitions are very common and are usually towards routes
      associated with a higher dependency potential and increased HIV-risk behaviour.
      Further research is needed to see if transitions can be prevented by early
      identification of potential cases.

PMID- 10665072
TI  - Psychiatric co-morbidity among male heroin addicts: differences between hospital
      and incarcerated subjects in Taiwan.
AB  - AIMS: To examine the differences in psychiatric co-morbidity between hospital and
      incarcerated groups of heroin addicts in Taiwan. DESIGN: Life-time prevalence of
      DSM-III-R-based coexisting psychiatric disorders, including personality
      disorders, were surveyed. SETTINGS: A psychiatric hospital and two prisons.
      PARTICIPANTS: Two hundred and sixty heroin users who were incarcerated in
      prisons, and 47 heroin users who voluntarily sought help in a psychiatric
      hospital were interviewed by board-certified psychiatrists. MEASUREMENTS: Using
      two psychometric instruments, the Psychiatric Diagnostic Assessment (PDA) and the
      Structured Interview for DSM-III-R Personality Disorders (SIPD-R), psychiatric co
      morbidity was assessed. FINDINGS: Different life-time rates of coexisting
      psychiatric disorders among heroin addicts in different settings were found: 83%
      of hospital subjects and 66% of incarcerated subjects were diagnosed as having at
      least one coexisting axis I or II disorder. The most prevalent coexisting DSM-III
      R defined axis I disorders were additional substance use disorders (alcohol and
      methamphetamine), while the axis II disorder was antisocial personality disorder.
      The hospital group had a significantly higher prevalence rate of mood disorder (p
      < 0.001), paranoid personality disorder (p < 0.05) and antisocial personality
      disorder (p < 0.001) than the incarcerated group. CONCLUSIONS: We suggest that
      heroin addicts with coexisting psychiatric disorders receive relevant psychiatric
      treatment. Those with personality disorders, especially the antisocial type,
      should be considered for specialized therapeutic community programmes instead of
      incarceration.

PMID- 10665073
TI  - Prison-based substance abuse treatment, residential aftercare and recidivism.
AB  - AIMS: This study examined the impact of residential aftercare on recidivism
      following prison-based treatment for drug-involved offenders. DESIGN: A matched
      group quasi-experimental design. Survival regression analyses were used to
      predict time until rearrest. A logistic regression model was constructed for
      predicting aftercare completion. SETTING: A 9-month in-prison therapeutic
      community (ITC) and several community-based transitional therapeutic communities
      (TTCs). PARTICIPANTS: Data were collected from 396 male inmates (293 treated, 103
      untreated). MEASUREMENTS: Background information (gender, ethnicity, age,
      education level, criminal history and risk for recidivism) was abstracted from
      the state criminal justice databases and a structured interview led by clinical
      staff. During treatment process measures were based on inmate self-ratings of
      their counselors, program and peers. A post-treatment interview conducted by
      field research staff assessed satisfaction with transitional aftercare. Post
      release recidivism was based on state-maintained computerized criminal history
      records. FINDINGS: ITC treatment, especially when followed by residential
      aftercare, was effective for reducing post-release recidivism rates. Lower
      satisfaction with transitional aftercare treatment was associated with not
      completing the residential phase of community-based aftercare. CONCLUSIONS:
      Corrections-based treatment policy should emphasize a continuum of care model
      (from institution to community) with high quality programs and services.

PMID- 10665074
TI  - Factor structures for DSM-IV substance disorder criteria endorsed by alcohol,
      cannabis, cocaine and opiate users: results from the WHO reliability and validity
      study.
AB  - AIMS: The factor structure of DSM-IV substance disorder criteria is examined
      among alcohol, cannabis, cocaine and opiate users to determine the dimensionality
      of abuse and dependence criteria within each of these drug classes and whether a
      common construct can be generalized across drug classes. DESIGN: 12-month
      criterion prevalence was assessed as part of the World Health Organization's
      Study on the Reliability and Validity of the Alcohol and Drug Use Disorder
      Instruments in various settings at eight sites around the world using the
      Schedules for Clinical Assessment in Neuropsychiatry (SCAN). A majority of
      respondents were recruited from non-treatment settings. In addition to
      exploratory factor analysis, confirmatory factor analysis was used to analyse
      factor structures using weighted least square methods and tetrachoric correlation
      matrices. Multi-sample analysis techniques were used to model differences between
      drug-classes. FINDINGS: In the full data analyses identified a single factor
      solution for each user population and across user populations. However, analyses
      of data from users reporting low to moderate symptomatology identified a two
      dimensional construct among alcohol, cannabis and opiate users consisting of a
      major "dependence" factor and a lesser "abuse" factor. In addition, results
      showed that neither the abuse criterion "(A2) use in physical hazardous
      situations" or the dependence criterion "(D7) use despite knowledge of
      psychological/physical problems" were central to the latent construct in any of
      the user populations, except for D7 among alcohol users. CONCLUSIONS: The multi
      dimensional results found among users with low to moderate symptomatology
      indicate that: (1) previous results from relatively homogeneous populations may
      have been biased towards lesser order solutions, and that (2) the DSM-IV
      substance disorder criteria describe at least two distinct phenomena, supporting
      the current DSM-IV organization of substance disorder criteria. Further work
      needs to evaluate whether prevalent symptoms are present in random or predictable
      combinations, whether combinations reflecting a specific hierarchy of severity
      can be identified, and whether incident symptoms are accumulated in a predictable
      pattern, within specific user populations and across user populations.

PMID- 10665075
TI  - Alcohol consumption in a national sample of the Russian population.
AB  - AIMS: Alcohol has been suggested as an important determinant of mortality in
      Russia but survey data on individuals' alcohol consumption in Russia are sparse.
      We have analysed the levels and distribution of alcohol consumption in a national
      sample of the Russian population. DESIGN: Cross-sectional survey. PARTICIPANTS: A
      multi-stage random sample of men and women of the Russian Federation (N = 1599,
      response rate 66%). MEASUREMENTS: Data on frequency of drinking alcohol and the
      average amount consumed at one occasion were collected in an interview.
      Information was also collected on smoking, self-rated health and a broad range of
      socio-economic factors and political attitudes. FINDINGS: Nine per cent of men
      and 35% of women reported that they never drink alcohol; 10% of men and 2% women
      drink several times a week; 44% of men and 6% of women reported that they drink
      an equivalent of 25 cl of vodka or more at one occasion and 31% of men and 3% of
      women would do so at least once a month (25 cl of vodka contains 78.5 g of
      absolute alcohol). There were differences in alcohol consumption between
      geographical areas. Material deprivation was not related to alcohol consumption.
      Among men, smokers, unmarried, unemployed and men reporting poor health consumed
      more alcohol; women with higher education, widows, non-smoking and with worse
      health consumed less alcohol. Variables related to reaction to economic and
      political changes, rating of family economic situation general satisfaction or
      political preferences were not related to alcohol consumption. CONCLUSIONS: While
      the overall levels of alcohol consumption appeared low, possibly due to under
      reporting, the proportion of men who can be considered as "binge drinkers" was
      relatively high. The absence of sizable socio-economic differences suggest that
      drinking may be spread relatively uniformly in Russia, especially among males.
      Alcohol consumption seems unrelated to individuals' perception of the recent
      societal changes.

PMID- 10665076
TI  - Alcohol-related mortality as a function of socio-economic status.
AB  - AIMS: To describe the differences in acute, chronic and total alcohol-related
      mortality by several measures of socio-economic status (SES) and to unravel the
      influences of different dimensions of SES. DESIGN: A register-based follow-up
      study of alcohol-related mortality. SETTING: Finland. PARTICIPANTS: The dataset
      was formed by linking census records with death records for 1987-95 and included
      21,922 alcohol-related deaths. MEASUREMENTS: SES indicators include education,
      occupational class, personal income, net household income per consumption unit
      (spending power) and housing tenure. The judgement of whether death was alcohol
      related was based on death certificates. FINDINGS: Acute and chronic alcohol
      related mortality were much higher in low SES groups for all SES indicators,
      including spending power, even when controlling for the remaining SES variables.
      Among men, personal income was a better predictor of alcohol-related death than
      spending power, while among women the situation was reversed. The effect of one
      SES measure was often stronger in low levels of another SES measure. Social
      selection and drift are likely to contribute to the large differentials in
      respect to personal income, while their effect on other differentials is likely
      to be smaller. CONCLUSIONS: SES is an important predictor of acute and chronic
      alcohol-related mortality. The total impact of SES cannot fully be captured using
      only one or two measures of SES.

PMID- 10665077
TI  - Drunkenness, feeling the effects and 5+ measures.
AB  - AIMS: The purpose of this study is to compare changes in the definitions of
      drunkenness and feeling the effects of drinking between 1979 and 1995 in US
      surveys, and compare three measures of heavier drinking as predictors of negative
      consequences of heavier alcohol use. DESIGN: A trend analysis using the 1979 (N =
      1772) and 1995 (N = 2178) US National Alcohol Surveys and a cross-sectional
      analysis using only the 1995 National Alcohol Survey. PARTICIPANTS: The analysis
      included only those respondents who reported consuming alcohol in the last year.
      The data were collected by face-to-face interviews. MEASUREMENTS: Three measures
      of heavier drinking were obtained in each survey: frequency of drunkenness,
      frequency of feeling the effects of alcohol and frequency drinking five or more
      drinks on one day. The three outcome measures were derived as indices of social
      consequences, alcohol dependence symptoms and alcohol-related harm. FINDINGS:
      Significantly higher proportions of respondents reported being drunk or feeling
      the effects of alcohol in 1995, and they also reported a lower number of drinks
      needed to become drunk (8.2 vs. 6.3 drinks) and to feel the effects (4.7 vs. 4.0
      drinks). Frequency of drunkenness was found to be the best predictor of social
      consequences, alcohol dependence symptoms and alcohol-related harm. CONCLUSIONS:
      These results point to some of the cultural shifts that have occurred in the
      United States during this "drying" period and the importance of considering more
      subjective measures of heavier drinking to assess risk.

PMID- 10665078
TI  - Patterns of alcohol consumption and social consequences. Results from an 8-year
      follow-up study in Switzerland.
AB  - AIMS: (1) To estimate the impact of drinking patterns on negative social
      (behaviour) consequences. (2) To test for the additional impact of overall volume
      of alcohol consumed on these social consequences. (3) To explore whether the
      impact on social consequences of drinking patterns is comparable for measures
      that do and do not explicitly mention alcohol consumption. DESIGN AND SETTING: An
      8-year follow-up to a 1987 study of the Swiss general population carried out
      through face-to-face interviews; the follow-up data presented in this article was
      collected in 1995 through a mailed questionnaire. PARTICIPANTS: Nine hundred and
      fifty-three respondents from the 1987 survey who also completed the mailed
      questionnaire in 1995. MEASUREMENTS: Variables used were as follows: volume of
      drinking, eight drinking patterns differentiated by volume and frequency, four
      social consequences without mention of alcohol and six with mention of alcohol.
      All multivariate analyses control for sex, age and linguistic region. FINDINGS:
      High volumes of drinking per occasion predicted negative social consequences
      independently of overall drinking volume. This finding was independent of
      explicit mention of alcohol in item formulation. For unemployment and accidents,
      if assessed independently of alcohol consumption, no significant relationship
      with either overall volume of drinking or drinking pattern was observed.
      CONCLUSIONS: Patterns of alcohol consumption are an important determinant of
      social problems. Future research with better design is necessary to establish
      their exact risk relations with different social consequences.

PMID- 10665079
TI  - Level of current and past adolescent cigarette smoking as predictors of future
      substance use disorders in young adulthood.
AB  - AIMS: This study examined the impact of adolescent cigarette smoking (life-time
      use, recency, frequency and age of onset) on the occurrence of substance use
      disorders during young adulthood. DESIGN: Participants were assessed while in
      high school (T1), approximately 1 year later (T2) and then after they had turned
      24 years of age (T3). SETTING: Adolescents were randomly selected at T1 from nine
      senior high schools in western Oregon. PARTICIPANTS: A subset (n = 684) of 1709
      adolescents who had been assessed regarding cigarette smoking during high school
      were evaluated for alcohol, cannabis and other drug abuse/dependence up to age
      24. MEASUREMENTS: Semi-structured interviews provided information regarding life
      time use of cigarettes and chewing tobacco, age of smoking onset, frequency and
      quantity of cigarette smoking and quit efforts in adolescence. Diagnoses of
      substance abuse and dependence in young adulthood were made as per DSM-IV.
      FINDINGS: Life-time smoking among older adolescents significantly increased the
      probability of future alcohol, cannabis, hard drug and multiple drug use
      disorders during young adulthood. Having been a former smoker did not reduce the
      risk of future substance use disorder, although having maintained smoking
      cessation for more than 12 months was associated with significantly lower rates
      of future alcohol use disorder. Daily smoking was associated with increased risk
      of future cannabis, hard drug and multiple drug use disorders. Among daily
      smokers, earlier smoking onset age predicted future substance use disorders.
      CONCLUSIONS: The results extend knowledge about relationships between cigarette
      smoking during adolescence and the development of substance use disorders during
      young adulthood, illustrating additional risks associated with early cigarette
      smoking. Future research is needed to examine potential causal associations.

PMID- 10665080
TI  - Persistent focal hyperhidrosis following opiate abuse.

PMID- 10665082
TI  - Conversation with Jerome H. Jaffe.

PMID- 10665081
TI  - Addiction: mission, modes of working, and maximizing the partnerships.

PMID- 10665083
TI  - Comments on Project MATCH: matching alcohol treatments to client heterogeneity.

PMID- 10665084
TI  - The unsinkable Project MATCH.

PMID- 10665085
TI  - Some common methodological criticisms of Project MATCH: are they justified?

PMID- 10665086
TI  - Treatment research in the wake of Project MATCH.

PMID- 10665087
TI  - Some treatment implications of Project MATCH.

PMID- 10665088
TI  - Life is short, the art long.

PMID- 10665089
TI  - Project MATCH and the stages of change.

PMID- 10665090
TI  - Efficacy of outpatient alcoholism treatment.

PMID- 10665091
TI  - Should a few hours of therapy change behaviour 3 years later?

PMID- 10665092
TI  - Patient matching in treatment for alcohol dependence: is the null hypothesis
      still alive and well?

PMID- 10665093
TI  - The "value" of Project MATCH for service provision.

PMID- 10665094
TI  - Future research directions and the impact of the MATCH project on research
      technology in the addictions.

PMID- 10665095
TI  - Project MATCH.

PMID- 10665096
TI  - A contrast in treatment philosophies.

PMID- 10665097
TI  - Future research directions: a commentary on Project MATCH.

PMID- 10665098
TI  - A study to remember: response of the Project MATCH Research Group.

PMID- 10665099
TI  - Transitions between routes of heroin administration: a study of Caucasian and
      Indochinese heroin users in south-western Sydney, Australia.
AB  - AIM: To examine patterns and correlates of routes of heroin use among Caucasian
      and Indochinese heroin users. DESIGN: A cross-sectional survey. SETTING AND
      PARTICIPANTS: Two hundred heroin users resident in South West Sydney. The sample
      was divided between Caucasian and Indochinese users (each n = 100), with half of
      each group on methadone maintenance. MEASUREMENTS: A semi-structured interview
      was administered, based on previous studies of transitions between routes of
      administration. Measures included patterns of drug use, transitions, social,
      health and legal issues and cultural correlates of use. FINDINGS: Almost two
      thirds (61%) had smoked heroin. Smoking was more common among the Indochinese
      (40% were predominantly or exclusively smokers), although injecting was the
      dominant route for both groups. More than one-quarter (29%) had made a transition
      from smoking to injecting, primarily due to drug effect and perceived cost
      effectiveness. Reverse transitions were rare. Smoking appeared to be more
      culturally acceptable than injecting among Indochinese users. Among both groups,
      there was a small but significant risk for the transmission of HIV and other
      blood-borne viruses. Polydrug use and age were positively associated with having
      experienced a non-fatal overdose. CONCLUSIONS: This research documents the
      existence of smoking as a popular route of administration among both Indochinese
      and Caucasian heroin users in the study sample. There is an urgent need to
      provide smokers and injectors with information explaining the potential risks and
      ways to minimize harms associated with both routes of use.

PMID- 10665100
TI  - Inhalant use among urban American Indian youth.
AB  - AIMS: To assess the prevalence of inhalant use among urban American Indian youth
      and to examine differences between inhalant users and non-users. DESIGN: Baseline
      (T1) self-report questionnaires completed in 5th-6th grade and at seven annual
      follow-up assessments (T2-T8). SETTINGS: Seattle metropolitan area. PARTICIPANTS:
      Two hundred and twenty-four Indian youth. MEASUREMENTS: Youth-completed measures
      of substance use, ethnic self-identity, involvement in traditional Indian
      activities, family conflict, family history of alcoholism, peer and sibling
      deviance, self-esteem, delinquency, aggression, anxiety, depression, sensation
      seeking, conduct disorder and alcohol dependence. FINDINGS: Lifetime inhalant use
      was reported by 12.3% of adolescents. At T1, inhalant users had significantly
      lower perceived self-worth and average annual household incomes and significantly
      greater density of familial alcoholism and expression of aggressive and
      delinquent conduct than non-users. Aggressive behavior was the most important T1
      predictor of inhalant use. Lifetime conduct and alcohol dependence disorders were
      3.3 and 2.6 times more prevalent among inhalant users than non-users at T5.
      Inhalant users had more extensive deviant peer networks, were more sensation
      seeking, and evidenced lower perceived self-worth than non-users at T8.
      CONCLUSIONS: Inhalant use was less prevalent in this particular sample of urban
      Indian adolescents than in most studies of reservation Indian youth. As with
      other studies of inhalant abuse, aggressive and delinquent males of low SES and
      low-perceived self-worth with family histories of alcohol dependence, were at
      highest risk for inhalant use.

PMID- 10665101
TI  - DSM-III-R co-morbidity in benzodiazepine dependence.
AB  - AIM, SAMPLE AND MEASURES: Co-morbidity has been shown to influence the clinical
      course of mental disorders. This paper describes DSM-III-R 1-month co-morbidity
      across axes I, II and III in a sample of 153 benzodiazepine dependents. All
      patients were evaluated through several in-depth clinical interviews across all
      five DSM-III-R axes. RESULTS: Extensive co-morbidity existed across three DSM-III
      R axes. All patients had at least one diagnosis in axis I; 81 (52.9%) in axis II
      and 50 (32.7%) in axis III. The most prevalent diagnoses were: insomnia, anxiety
      disorders and affective disorders in axis I; obsessive-compulsive, histrionic and
      dependent personality disorders in axis II and rheumatological, neurological and
      cardiovascular disorders in axis III. CONCLUSIONS: There were no cases of
      benzodiazepine dependence appearing alone. There were associations within and
      between axes, suggesting potential predisposing factors and a sequential model
      for benzodiazepine dependence is proposed. The findings reinforce the need for
      exhaustive diagnostic evaluation of patients prior to prescribing benzodiazepine.

PMID- 10665102
TI  - Ability of smokers to reduce their smoking and its association with future
      smoking cessation.
AB  - AIMS: We examined whether cigarette smokers in the United States can
      significantly reduce their smoking and maintain this reduction and, if so,
      whether this predicts an increase or decrease in the probability of smoking
      cessation in the future. DESIGN: Longitudinal observation study. SETTING: The 22
      US cities of the Community Intervention Trial for smoking cessation (COMMIT).
      PARTICIPANTS: The 1410 subjects who smoked at both baseline and at 2-year follow
      up. INTERVENTION: Public health efforts to prompt cessation in half the
      communities. MEASUREMENTS: Self-reported cigarettes/day and abstinence at
      baseline, 2-year and 4-year follow-ups. FINDINGS: At 2-year follow-up, 60% of the
      subjects had either not changed or increased their smoking, 17% had decreased
      their smoking by 5-25%, 15% by 24-49% and 8% by > or = 50%. Among the 40% who had
      reduced > or = 5% at 2-year follow-up, 52% reported maintaining that reduction at
      4-year follow-up. Reduction in smoking at year 2 did not prospectively predict an
      increase or decrease in the probability of making a quit attempt; nor did it
      predict eventually quitting by year 4. CONCLUSIONS: A substantial minority of US
      smokers are able to reduce their smoking and maintain this for long periods of
      time. Smoking reduction neither promotes nor undermines cessation.

PMID- 10665103
TI  - Predictability of smoking in adolescence: between optimism and pessimism.
AB  - AIMS: The present study aimed to assess how far associations between possible
      explanatory variables and smoking onset depend on the use of cross-sectional
      versus prospective designs. DESIGN AND SUBJECTS: Data were analysed from a three
      wave 5-year longitudinal survey among 1063 secondary schoolchildren (12-18-year
      olds) in The Netherlands. MEASUREMENTS: The survey questionnaire contained items
      on smoking history, smoking-specific beliefs and attitudes, social influence
      variables and socio-demographic variables in each wave. FINDINGS AND CONCLUSIONS:
      The cross-sectional analyses showed strong associations between explanatory
      variables and smoking behaviour (R2 varied from 0.50 to 0.71). However, only 8%
      of the variance in change of smoking status from non-smoking to regular smoking
      over a period of 5 years and 14% of the variance over a period of 3 years could
      be predicted by the model variables. Factors believed to lead to smoking may
      result from smoking or they may change quickly in ways that make them of low
      predictive value even though they may be important aetiologically.

PMID- 10665104
TI  - French general practitioners' attitudes and reported practices in relation to
      their participation and effectiveness in a minimal smoking cessation programme
      for patients.
AB  - AIMS: To examine the participation and effectiveness of GPs in offering a minimal
      smoking cessation intervention according to attitudinal and reported behaviour
      variables. DESIGN: General practitioners were surveyed about their practices and
      attitudes and then matched pairs of smoking and non-smoking doctors were invited
      to participate in a regional smoking cessation intervention. The relationship of
      survey responses and the degree of participation and effectiveness in a smoking
      cessation trial was examined. SETTING: Primary care doctors in a large region of
      southern France, Provence-Alpes-Cote d'Azur (PACA). PARTICIPANTS: Two thousand,
      eight hundred and sixty GPs from the PACA region in France were interviewed about
      their attitudes and behaviours. From among 371 smoking GPs and 375 non-smoking
      GPs invited to take part in a smoking cessation trial with patients, 170 smokers
      and 202 non-smokers participated. MEASUREMENTS: The GPs' attitudes and reported
      professional and personal practices were assessed in a telephone interview. These
      responses were compared with the GPs' participation in the cessation trial, and
      with GP "success" (1 or more patients stopping smoking at 1 month, 12 months or
      both) or "non-success" (no patient cessation at 1 month or at 12 months).
      FINDINGS: A significantly lower proportion of smokers than non-smokers among the
      GPs who initially accepted did not participate in the study (45% vs. 54.1%, chi 2
      = 5.147 df = 1, p < 0.05, difference: 8.3% 95% CI: 1.2%; 15.5%), but thereafter,
      there were no significant associations between GPs' reported smoking practices
      and attitudes and the extent of their participation or effectiveness.
      CONCLUSIONS: The study results indicate that, when minimal advice has an effect,
      it is due more to the systematic nature of the provision of the intervention than
      to the attitudes or reported practices of the practitioner providing the advice.

PMID- 10665105
TI  - Alcohol disorders and re-employment in a 5-year follow-up of long-term
      unemployed.
AB  - AIMS: To establish whether the high prevalence of alcohol abuse among unemployed
      people is explained by alcohol abuse causing unemployment, or vice versa. DESIGN:
      A 5-year postal follow-up survey of a community sample of unemployed from
      Grenland, southern Norway. PARTICIPANTS: Two hundred and twenty-eight unemployed
      people, registered for more than 12 weeks, aged 16 to 63 years. Response rate
      74%. MEASUREMENTS: The Alcohol Use Disorder Identification Test (AUDIT) and DSM
      III diagnoses of alcohol disorders in medical examinations. FINDINGS: At the 5
      year follow up, 23% of those still unemployed and 12% of those re-employed scored
      higher than the AUDIT cut-point of 10. Re-employment reduced the chance of
      scoring positive on the AUDIT to 34% of the chance for those still unemployed.
      Significant selection to long-term unemployment according to AUDIT score was not
      demonstrated. None of the 7% who had a DSM-III diagnosis of an alcohol disorder
      had a job 5 years later, however, suggesting that alcohol-related selection to
      unemployment does occur. CONCLUSION: The high prevalence of harmful drinking
      among Norwegian unemployed is explained mainly by unemployment causing alcohol
      abuse rather than vice versa. Reducing unemployment should contribute to reduced
      alcohol problems in Norway.

PMID- 10665106
TI  - Effortless unintentional smoking cessation after lamivudine-zidovudine-indinavir
      post-exposure anti-HIV chemoprophylaxis.

PMID- 10665108
TI  - ContrA1 Clinics.

PMID- 10665107
TI  - Precipitated withdrawal in an opioid-dependent outpatient receiving alternate-day
      buprenorphine dosing.

PMID- 10665109
TI  - VIAGRA (sildenafil citrate) in clinical practice.

PMID- 10665110
TI  - Sildenafil citrate (VIAGRA): overall safety profile in 18 double-blind, placebo
      controlled, clinical trials.

PMID- 10665111
TI  - Sildenafil citrate (VIAGRA) in the treatment of erectile dysfunction: a 12-week,
      flexible-dose study to assess efficacy and safety.

PMID- 10665112
TI  - A 36-week, open label, non-comparative study to assess the long-term safety of
      sildenafil citrate (VIAGRA) in patients with erectile dysfunction.

PMID- 10665113
TI  - Sildenafil citrate (VIAGRA) in the treatment of erectile dysfunction: analysis of
      two flexible dose-escalation studies. Sildenafil Study Group.

PMID- 10665114
TI  - Oral sildenafil citrate (VIAGRA) in the treatment of erectile dysfunction:
      assessment of erections hard enough for sexual intercourse.

PMID- 10665115
TI  - Partners' perceptions of the efficacy of sildenafil citrate (VIAGRA) in the
      treatment of erectile dysfunction.

PMID- 10665116
TI  - Efficacy of sildenafil citrate (VIAGRA) is not affected by aetiology of erectile
      dysfunction.

PMID- 10665117
TI  - Sildenafil citrate (Viagra) efficacy in the treatment of erectile dysfunction in
      patients with common concomitant conditions. Sildenafil Study Group.

PMID- 10665118
TI  - Sildenafil citrate (VIAGRA): a novel oral treatment for erectile dysfunction
      caused by traumatic spinal cord injury.

PMID- 10665119
TI  - Sildenafil citrate (VIAGRA): analysis of preferred doses in a European, six
      month, double-blind, placebo-controlled, flexible dose-escalation study in
      patients with erectile dysfunction. Multicentre Study Group.

PMID- 10665120
TI  - Sildenafil citrate (VIAGRA), an oral treatment for erectile function: 1-year,
      open-label, extension studies. Multicentre Study Group.

PMID- 10665122
TI  - International differences in the epidemiology of male erectile dysfunction.

PMID- 10665121
TI  - Sildenafil citrate (VIAGRA): an oral treatment for erectile function with
      activity for up to four hours' duration.

PMID- 10665123
TI  - Prevalence and correlates of erectile dysfunction in Japan.

PMID- 10665124
TI  - Statins and strokes--reducing the risk.

PMID- 10665125
TI  - Predictors for extraintestinal infection of non-typhoidal Salmonella in patients
      without AIDS.
AB  - To identify the risks and predictors for extraintestinal infection (EII) in
      patients with non-typhoidal salmonellosis, we undertook a study of 398 patients
      with cultures positive for non-typhoidal Salmonella seen at Chang Gung Memorial
      Hospital and Chang Gung Children's Hospital between November 1993 and October
      1994. Salmonella choleraesuis was the most invasive serotype observed. S. panama,
      S. typhimurium and S. schwarzengrund were the commonest causes of EII among those
      serotypes usually causing gastroenteritis. Pre-existing underlying disease,
      particularly immunosuppressive disease, was the most important risk factor that
      may have predisposed adult patients to have EII. Old age (> or = 60 years) and
      isolation of invasive serotypes were also frequently associated with EII in adult
      patients. The characteristics of paediatric patients with a high probability of
      having EII were: < 3 years of age, abnormal blood test results (a leucocyte count
      > or = 15,000/mm3 or < 5000/mm3, immature leucocytes > or = 10% of total
      leucocytes, and a C-reactive protein concentration > or = 50 mg/l); and isolation
      of invasive serotypes. This information can be an aid to early diagnosis and
      treatment of EII caused by non-typhoidal Salmonella.

PMID- 10665126
TI  - Treatment of complicated intra-abdominal infections: comparison of the
      tolerability and safety of intravenous/oral trovafloxacin versus intravenous
      imipenem/cilastatin switching to oral amoxycillin/clavulanic acid.
AB  - Three- to four-times-daily intravenous (i.v.) imipenem/cilastatin switching to
      oral amoxycillin/clavulanic acid is often used to manage complicated intra
      abdominal infections. Trovafloxacin, a clinically and bacteriologically proven
      new-generation fluoroquinolone antibiotic, given as single-agent, once-daily
      i.v./oral therapy, can provide equivalent clinical and bacteriological efficacy.
      Tolerability and safety of up to 14 days treatment with 300 mg i.v.
      alatrofloxacin (the prodrug of trovafloxacin) switching to 200 mg oral
      trovafloxacin were compared with those of 1 g i.v. imipenem/cilastatin switching
      to 625 mg oral amoxycillin/clavulanic acid. Comparable incidences of adverse
      events, mainly mild or moderate in intensity, were experienced in each treatment
      group. For both therapies, gastrointestinal events were most common, but
      diarrhoea was reported by proportionately more comparator group patients. In
      conclusion, once-daily i.v.-to-oral trovafloxacin has a comparable safety profile
      to i.v. imipenem/cilastatin followed by oral amoxycillin/clavulanic acid. Cost
      saving may be achieved with trovafloxacin due to the lack of any need to monitor
      creatinine levels and the once-daily dosing regimen that allows a switch to the
      same orally administered drug.

PMID- 10665127
TI  - The efficacy and safety of telmisartan compared to enalapril in patients with
      severe hypertension.
AB  - This 8-week, open-label study compared the efficacy and safety of once-daily
      telmisartan, either alone or in combination with hydrochlorothiazide (HCTZ) and
      amlodipine, with a similar enalapril regimen in patients with severe
      hypertension. Clinically relevant reductions in supine systolic blood
      pressure/DBP were observed with telmisartan (14.6/13.2 mmHg) and enalapril
      (13.0/12.9 mmHg) monotherapy. Incremental reductions were seen with up-titration
      of monotherapy (telmisartan 8.1/7.4 and enalapril 9.2/7.7 mmHg), and the addition
      of HCTZ (telmisartan 14.9/8.7 and enalapril 8.0/6.7 mmHg), and amlodipine
      (telmisartan 8.0/6.5 and enalapril 10.5/6.4). After 8 weeks of treatment, supine
      DBP control was achieved in 55% and 35% of the patients on the telmisartan and
      enalapril regimens, respectively. Both treatment regimens were well tolerated.
      Telmisartan, a new angiotensin receptor blocker, is a safe and effective drug to
      use in combination for the treatment of patients with severe hypertension and
      proved at least as effective as the enalapril combination.

PMID- 10665128
TI  - The effect of supplementation with milk fermented by Lactobacillus casei (strain
      DN-114 001) on acute diarrhoea in children attending day care centres.
AB  - The objective of this study was to determine if supplementation with milk
      fermented by yogurt cultures and Lactobacillus casei (strain DN-114 001) could
      lessen acute diarrhoea in healthy children. The study was conducted over six
      months, with 287 children aged 18.9 (SD 6.0) months, comprising three periods of
      one month supplementation, each month being followed by one month without
      supplementation. Subjects were supplemented daily with either 125 g or 250 g
      (according to age) of one of three tested dairy products: standard yogurt, milk
      fermented by yogurt cultures and Lactobacillus casei (10(8) cfu/ml), or a jellied
      milk (control product). A daily record was kept of the number and type of stools.
      Although the incidence of diarrhoea was not shown to be different between the
      groups, the severity of diarrhoea over the six-month study was significantly
      decreased (4.3 days) with the supplementation of L. casei fermented milk compared
      with the jellied milk (8.0 days) (p = 0.009).

PMID- 10665129
TI  - Bronchodilatory responses to formoterol, ipratropium, and their combination in
      patients with stable COPD.
AB  - We studied 27 patients with stable chronic obstuctive pulmonary disease (COPD) in
      a randomised, single-blind, within-patient, placebo-controlled clinical study.
      Each patient was assigned on six separate days to receive one of the following
      drug regimens in random order: A. 40 micrograms ipratropium bromide (Atrovent
      MDI, 20 micrograms/puff) plus 2 puffs placebo; B. 12 micrograms formoterol
      fumarate (Foradil MDI, 12 micrograms/puff) plus 3 puffs placebo; C. 80 micrograms
      ipratropium; D. 24 micrograms formoterol plus 2 puffs placebo; E. 12 micrograms
      formoterol plus 40 micrograms ipratropium plus 1 puff placebo; F. 4 puffs
      placebo. On each study day, spirometric indices and vital signs were measured at
      5, 10, 15 and 60 minutes, and hourly thereafter up to and including 12 hours
      after study drug administration. Mean peak FEV1 change (primary endpoint) was
      maximum with the administration of the combination of ipratropium and formoterol
      (335.2 ml, SE 24.6), and it differed significantly from the observed peak changes
      following single administration of the two tested doses of ipratropium (p < 0.05
      and p < 0.05 respectively). Safety and tolerability were satisfactory throughout
      the study.

PMID- 10665130
TI  - A survey of patient satisfaction after day case surgery.
AB  - A prospective survey of patients attending day case surgery was undertaken to
      determine patient satisfaction. In an eight-week prospective study, patients
      undergoing procedures in the day surgical unit were asked to fill in two
      questionnaires, the first before surgery and the second two weeks after surgery.
      One hundred and eighty-nine patients were recruited into the study; of these, 98
      (52.4%) returned correctly completed forms. Most of the patients believed the
      information given them before surgery was adequate and the standard of care in
      the day unit was high. Only five patients needed to see their general
      practitioner because of continued problems. Twenty-one patients felt they were
      discharged too early. Our current practice in day case surgery inevitably leads
      to some patients being discharged early. Facilities must be provided for some
      patients to stay longer in the day unit. Day case surgery did not result in an
      unacceptable increase in the workload for GPs, nor did it compromise the quality
      of patient care.

PMID- 10665131
TI  - Management of women with a family history of breast cancer.
AB  - Five to ten per cent of breast cancer results from an inherited germ line
      mutation. The main susceptibility genes are BRCA1 and BRCA2, but others include
      Cowden's disease, Li Fraumeni syndrome and ataxia-telangiectasia. For those with
      BRCA1 or BRCA2 mutations the lifetime probability of breast cancer is between
      0.40 and 0.73. Genetic testing needs to be offered to young women with breast
      cancer before considering testing their relatives. The efficacy of surveillance
      in women with genetic susceptibility has yet to be proved. The value of tamoxifen
      as a preventive agent in women with genetic susceptibility has yet to be
      confirmed. Prophylactic bilateral mastectomy will probably reduce the risk of
      breast cancer but this may not be absolute because of the difficulty of removing
      all breast tissue. New approaches may enable the selective destruction of mammary
      epithelium without disturbance to breast architecture.

PMID- 10665132
TI  - Sciatica in the community--not always disc herniation.
AB  - Three cases of sciatica seen in general practice are described. The clinical
      features were consistent with pyriformis syndrome, a condition of compression of
      the sciatic nerve at the pelvic outlet. The literature on causes and clinical
      features is briefly reviewed. The prevalence of the condition in the community
      and the accuracy of clinical diagnosis are unknown. It is suggested that pelvic
      outlet syndrome, comparable to carpal tunnel syndrome, is a more appropriate name
      for the condition.

PMID- 10665134
TI  - A sustained release formulation of isosorbide-5-mononitrate with a rapid onset of
      action.
AB  - The clinical efficacy of a combined immediate-release and sustained-release
      preparation of isosorbide-5-mononitrate for angina pectoris is observed within a
      few minutes of administration. The preparation reduces the number of silent and
      painful ischaemic episodes and increases work and exercise capacity. The
      pharmacokinetic profiles accord with the circadian variation in cardiovascular
      disease. Drug levels fall significantly at night and tolerance to the
      haemodynamic and antianginal effects is not seen. Once-daily administration is
      appreciated by patients. The preparation also shows promise in treating heart
      failure.

PMID- 10665133
TI  - Emergency contraception.
AB  - Emergency contraception means preventing pregnancy after unprotected sexual
      intercourse. This is also called postcoital contraception (PCC) or the 'morning
      after pill'. High doses of oestrogen or progestogen or a combination of both may
      be used as PCC up to 72 hours after unprotected intercourse. The use of
      mifepristone as emergency contraception has also proved promising. Some women use
      emergency contraception, but there are many who do not know much about it. Users,
      providers and other health professionals need to be educated about this method.
      Emergency contraception does not fall within the ambit of abortion law, yet its
      acceptability depends on the legal, cultural and religious consideration of most
      countries. This method is safe and effective and could be used occasionally to
      prevent unwanted pregnancy.

PMID- 10665135
TI  - 'Not for resuscitation': guidelines for decision making and documentation.
AB  - In 1991, the government's Chief Medical Officer made it clear that the
      responsibility for resuscitation policy lay with consultants, and that they
      should ensure this policy was understood by all staff caring for a patient, in
      particular junior medical staff. Since then, many hospitals and trusts have
      provided members of the multidisciplinary team with guidance on how to ensure
      that adequate and satisfactory communication is in place to record a patient's
      resuscitation status. However, as is common in the NHS, poor documentation is
      still evident. Guy's & St Thomas' Hospital Trust has been using a document since
      April 1998 which is clearly written, user friendly and does not contain ambiguous
      statements. With ongoing audit of this policy document we hope to reduce the
      incidence of inappropriate resuscitation attempts which are costly, both
      emotionally and financially, for all concerned.

PMID- 10665136
TI  - Beclomethasone diproprionate inhalation as a treatment for post-intubation
      tracheal stenosis.
AB  - A 67-year-old man was intubated for one week and suffered from wheeze and
      dyspnoea three months after the extubation. Bronchoscopy revealed tracheal
      stenosis by a web, which subsequent biopsy showed to be granulation tissue. The
      stenosis was removed by laser therapy but the stenosis soon returned. As cardiac
      function was poor, beclomethasone diproprionate (BDP) inhalation therapy (1200
      micrograms daily) was started and proved successful. Discontinuation of
      inhalation therapy resulted in restenosis. Steroid inhalation therapy may be able
      to control post-intubation tracheal stenosis caused by granulation tissue.

PMID- 10665137
TI  - 5-fluorouracil-induced erythema multiforme.
AB  - Erythema multiforme is an immunologically mediated skin reaction to a foreign
      antigen and can occur with many drugs. We report the first two cases of erythema
      multiforme induced by 5-fluorouracil (5-FU). The first case was in a man with
      inoperable gastric carcinoma being treated by continual infusion who developed
      the classic rash involving the neck and upper chest, along with mouth ulceration
      and plantar-palmar erythrodysaesthesia. Histological confirmation was made by
      skin biopsy and the lesions resolved spontaneously. They recurred on restarting 5
      FU. The second case was in a woman being given adjuvant bolus 5-FU and folinic
      acid for Duke's C colon cancer who developed the rash during the first cycle.
      Again, the lesions settled spontaneously but recurred more severely on the second
      cycle. When treatment was changed to the specific thymidylate synthase inhibitor,
      raltitrexed, the course was completed uneventfully.

PMID- 10665139
TI  - Hypercalcaemia: a clue to Mycobacterium avium intracellulare infection in a
      patient with AIDS.
AB  - Hypercalcaemia is uncommon in HIV-infected patients and should suggest a
      different priority for differential diagnosis than would be considered in other
      settings. Although hypercalcaemia has long been associated with granulomatous
      diseases including tuberculosis, it has only recently been recognised that
      patients with illness due to Mycobacterium avium intracellulare (MAI) may develop
      it. We report a patient with AIDS in whom unexplained hypercalcaemia was the
      harbinger of clinically significant MAI infection. Patients with AIDS who develop
      hypercalcaemia should be closely evaluated for underlying MAI infection.

PMID- 10665138
TI  - Left-sided hepatic hydrothorax with ascites.
AB  - Hydrothorax has long been recognised as a complication of cirrhosis, but it is
      seen in only a few patients, mostly on the right side. We report an unusual case
      of massive left-sided hydrothorax complicating cirrhosis with ascites, where
      pleuro-peritoneal communication was demonstrated on the left side by radionuclide
      scanning.

PMID- 10665140
TI  - Acute pulmonary oedema complicating adenotonsillectomy for obstructive sleep
      apnoea.
AB  - Acute pulmonary oedema can sometimes complicate adenotonsillectomy carried out
      for obstructive sleep apnoea. Early recognition and adequate oxygenation are the
      key to management. We report such a case; the pathophysiology and management of
      this rare complication of a common procedure are discussed.

PMID- 10665141
TI  - A case of severe reversible lung disease caused by sulphasalazine.
AB  - Various lung problems have been reported in patients with inflammatory bowel
      disease. Some of these can be drug related. We report an unusual case of upper
      lobe infiltration which appeared to be caused by sulphasalazine.

PMID- 10665142
TI  - Occupational health and safety curricula: the factors that decide -an Australian
      experience.
AB  - Societal, economic and other changes in recent years have resulted in both an
      increased level and diversity of education and training in occupational health
      and safety in Australia. Consideration has been given to the key skills and
      knowledge required by those who take tertiary level courses and who practise as
      specialists and generalists in the field of occupational health and safety. The
      curricula and mode of implementation of these courses are determined by the needs
      of employers, increased emphasis on quality management systems, the prevailing
      work climate including information technology, communication and legislative
      requirements all in the context of a rapidly changing tertiary education system.

PMID- 10665143
TI  - Reported needlestick and sharp injuries among health care workers in a Greek
      general hospital.
AB  - Between July 1990 and June 1996, 284 exposures to infectious material were
      reported by 247 health care workers (HCWs) at AHEPA University Hospital,
      Thessaloniki, Greece, representing an overall rate of 2.4% reported injuries per
      100 HCWs/year. Nurses reported the highest rates of incidents (3.0%) and in all
      but one working group women exhibited higher injury rates per year than male
      HCWs. Young workers (21-30 years old) were primarily affected in incidents (P <
      0.001). Needles were the most common implement causing injury (60.6%) and
      resheathing of used needles as well as garbage collection were common causes of
      injury. None of the HCWs seroconverted in exposures where immune status to blood
      borne pathogens was estimated. Efforts by the infection control committee need to
      be more intense, in order to increase the rate of reported staff injuries. This
      will facilitate identification of unsafe practices and provide more adequate
      preventive measures.

PMID- 10665145
TI  - Guidelines for the compilation of occupational health-related records to
      facilitate future epidemiological studies of chemical exposure. Working Party of
      the Human Toxicology Section of the British Toxicology Society.

PMID- 10665144
TI  - Child care workers and workplace hazards in the United States: overview of
      research and implications for occupational health professionals.
AB  - In the past, the hazards facing child care workers have largely been ignored by
      health and safety professionals, due in part to a lack of awareness of hazards
      and inconsistencies in state health and safety requirements. The aim of this
      paper is to provide a summary and critique of the literature on the topic of
      occupational health and safety concerns for child care workers. Twenty-seven
      articles pertaining to child care workers, published between 1980 and 1998, were
      reviewed. The job roles and tasks related to physical care, janitorial functions
      and participation in child recreation lead to risk of exposure to biological,
      physical and chemical hazards. Psychological stressors were found to contribute
      to high levels of job dissatisfaction and turnover. infectious disease
      transmission was the major topic of focus in the literature, whereas US
      statistical data for illnesses and injuries for this classification of workers
      revealed injuries as the prominent health problem. Directions for future research
      are described.

PMID- 10665146
TI  - Investigating clusters in the workplace and beyond.
AB  - Clusters of disease are common and occur in the workplace and in the general
      community. They often arouse considerable concern among the population.
      Investigations have sometimes lead to exciting new knowledge, but in general the
      investigation of clusters is difficult and often unrewarding, especially for
      community clusters. In the workplace, investigations are more likely to find
      associations and even new causes, but still many clusters remain enigmatic.
      Despite this, there are many reasons for investigating clusters, including
      allaying community concern and identifying uncontrolled exposures. A structure
      for investigating clusters in the workplace is suggested.

PMID- 10665148
TI  - Study to evaluate the effectiveness of stress management workshops on response to
      general and occupational measures of stress.
AB  - This study was designed to evaluate the effectiveness of stress management
      training workshops within Zeneca Pharmaceuticals. The study was of cross
      sectional design, comparing groups of workshop attendees and non-attendees. In
      addition, self-rated well-being scores of attendees were compared with results
      obtained pre-workshop and 2-3 months after the workshop. Employees participating
      in the study were drawn from the Manufacturing, Research and Development, Sales
      and Marketing sites of Zeneca Pharmaceuticals located in Cheshire, United
      Kingdom. Three hundred and ninety persons who had participated in stress
      management workshops since 1988 were matched for age, gender and department with
      an equal number of employees who had not attended stress management workshops.
      Outcome measures included self-rated well-being (as measured by the 30-question
      General Health Questionnaire), knowledge of company guidance on the management of
      stress in staff, and an assessment of coping strategies. Subjects who had not
      attended a stress management workshop were much more likely to have a poor
      understanding of the principles of management of stress in staff [odds ratio (OR)
      = 8.3; 95% confidence interval (CI) = 3.3-21.3] and more likely to have poor
      coping skills (OR = 2.8; CI = 1.3-6.1). However, mean scores for the two measures
      were similar in attendees and non-attendees. Self-rating of current well-being
      was strongly associated with the life-events score, but not related to workshop
      attendance. The study indicates that stress management training workshops reduce
      the prevalence of employees with a poor understanding of the principles of the
      management of stress in staff and with poor coping strategies. An improvement in
      the self-rated well-being observed shortly after the workshop was not sustained.

PMID- 10665147
TI  - Hospital laundry workers--an at-risk group for hepatitis A?
AB  - Twenty-two laundry personnel at St. Luke's Hospital, Malta, were tested for
      seropositivity to hepatitis A together with 37 nursing aides working in
      paediatric and infectious disease wards, matched for age, who were used as
      controls. IgG antibodies were found in 54.5% of laundry workers and 13.5% of
      nursing aides [odds ratio (OR) = 7.68; 95% confidence interval (CI) = 1.87
      33.83]. Furthermore, laundry personnel consistently handling dirty linen prior to
      washing showed an OR of 16.50 (CI = 1.19-825.57) as compared with colleagues
      handling only clean items. These results would suggest that the increased
      exposure of hospital laundry workers to potentially infected linen can constitute
      a risk of occupational hepatitis A for this group of employees.

PMID- 10665149
TI  - Radiofrequency electrocution (196 MHz).
AB  - Radiofrequency (RF) electrocutions are uncommon. A case of electrocution at 196
      MHz is presented partly because there are no previous reports with frequencies as
      high as this, and partly to assist in safety standard setting. A 53-year-old
      technician received two brief exposures to both hands of 2A current at 196 MHz.
      He did not experience shock or burn. Progressively over the next days and months
      he developed joint pains in the hands, wrists and elbows, altered temperature and
      touch sensation and parasthesiae. Extensive investigation found no frank
      neurological abnormality, but there were changes in temperature perception in the
      palms and a difference in temperature between hands. His symptoms were partly
      alleviated with ultra-sound therapy, phenoxybenzamine and glyceryl trinitrate
      patches locally applied, but after several months he continues to have some
      symptoms. The biophysics and clinical aspects are discussed. It is postulated
      that there was mainly surface flow of current and the micro-vasculature was
      effected. Differences to 50 Hz electrocution are noted. Electrocution at 196 MHz,
      even in the absence of burns may cause long-term morbidity to which physicians
      should be alerted. Safety standards should consider protection from electrocution
      at these frequencies.

PMID- 10665150
TI  - Two cases of thyroid cancer in a small workforce.
AB  - In 1994, in a large parcel depot in the north of England employing 600 staff and
      24 electrical and mechanical engineers, two engineers developed papillary cell
      carcinoma of the thyroid in the same year. A comprehensive review of the
      literature revealed that ionizing radiation is the only known direct cause of
      this disease. There was speculation that air filter changing undertaken by the
      two men affected, shortly after the Chernobyl accident in 1986, may have exposed
      them to concentrated radioactive fallout. A radiation survey of the parcel depot
      was undertaken and revealed no evidence of abnormal radioactivity. A total of 27
      past and present engineering staff were screened for thyroid cancer. No cases of
      thyroid cancer were found. Investigation of clusters of rare disease in the
      occupational setting is indicated mainly in order to address the concerns of the
      workforce. Nevertheless, investigation is warranted, especially when the
      aetiology of a disease is poorly understood. It would be prudent for doctors, in
      whatever speciality, to take an occupational history from individuals who develop
      thyroid cancer.

PMID- 10665151
TI  - Does an employee assistance programme benefit employers and employees alike?
AB  - EAPs are not a psychological sticking plaster. They are a clinically and
      corporately balanced service which benefits the employee, via the direct services
      and the employer, via the feedback in the form of usage statistics derived from
      the continuous tracking of the account through which organizational and
      employment issues are identified. Well positioned EAPs offer employees
      confidential counselling, and information services including legal, financial and
      child-based issues and are able to offer employers tailored training and
      consultancy.

PMID- 10665152
TI  - A former human resources manager's views.
AB  - Over the past decade there has been a growing interest in occupational health as
      a result of some high profile legal cases, the growth of research into the
      psychological contract and the need to invest in people's health and development.
      In this article a personal viewpoint is expressed that if occupational health
      physicians or psychologists are to make an effective contribution to the long
      term business success of their employers then they must adopt a strategic
      approach to their work. They ought to be able to do this and still maintain their
      clinical autonomy and protect the interests of their employee clients. The need
      for partnerships between bodies representing clinicians, managers and government
      agencies is also explored, taking into consideration the government's green paper
      Our Healthier Nation.

PMID- 10665153
TI  - Auditing health and safety management systems: a regulator's view.
AB  - HSE's publication 'Successful Health and Safety Management' (HSG65) describes key
      elements of successful health and safety management systems. A three level model
      is explained and one of the elements, auditing, is explored in detail by the
      regulator. The term auditing in the health and safety context is defined and the
      use of proprietary and in-house systems compared. The process of auditing is
      described and the regulator concludes by encouraging organizations to use
      auditing schemes, without endorsing any particular one, as they can be a powerful
      tool for checking the adequacy of health and safety management systems.

PMID- 10665154
TI  - The duty of care of the occupational physician in assessing job applicants.

PMID- 10665155
TI  - UK parachuting position caused less injuries.

PMID- 10665156
TI  - How serious are common childhood fears?
AB  - OBJECTIVE: The present study examined the clinical status of common childhood
      fears. METHOD: Fears of the 290 children aged 8 to 13 years were assessed and
      then their severity was explored by means of a structured diagnostic interview
      measuring anxiety disorders according to the criteria of the Diagnostic and
      Statistical Manual of Mental Disorders (DSM). RESULTS: Childhood fears reflect
      significant anxiety disorders in a substantial minority (i.e. 22.8%) of the
      children. CONCLUSIONS: In most children, childhood fears are part of the normal
      development. However, in some children, these fears reflect serious anxiety
      problems which interfere with daily routine.

PMID- 10665157
TI  - Distinguishing manifestations of anxiety: how do personality traits of compulsive
      checkers differ from other anxious individuals?
AB  - To better understand relations between personality and anxiety in general, and
      personality differences between compulsive checkers and nonchecking anxious
      individuals in particular, the current study was conducted. Participants included
      a nonclinical undergraduate sample of 36 compulsive checkers, 33 nonchecking
      anxious controls and 33 nonchecking nonanxious controls who were compared on five
      basic personality dimensions: emotional stability, extraversion, agreeableness,
      conscientiousness and intellect (Goldberg, 1992). Results indicated that a
      combined group of all anxious individuals was less extraverted and less
      emotionally stable than nonchecking/nonanxious controls. Results further
      indicated that compulsive checkers were less emotionally stable and more
      conscientious than nonchecking anxious controls. The implications of these
      findings, as well as the impact of the order of personality item presentation,
      are considered and discussed.

PMID- 10665158
TI  - Cognitive processes in social anxiety: the effects of self-focus, rumination and
      anticipatory processing.
AB  - We examined three cognitive processes hypothesized to contribute to biases in
      judgments about and memory for social events: self-focused attention, post-event
      rumination, and anticipatory processing. Socially anxious (N = 58) and nonanxious
      (N = 58) subjects participated in a social interaction and then completed
      measures of self-focused attention and anxiety-related physiological sensations
      and behavior. The next day, subjects completed measures that assessed frequency
      of post-event processing and recall of the interaction. The results indicated
      that selective attention to negative self-related information led to biases in
      social judgments and recollections and that post-event processing contributed to
      the recall of negative self-related information. No evidence was found for
      selective retrieval of negative self-related information prior to a second social
      interaction. The results reconcile inconsistent previous findings related to
      memory bias in social anxiety.

PMID- 10665159
TI  - Guided and unguided self-help for binge eating.
AB  - This study compared the relative short- and longer-term efficacy of therapist
      guided and unguided use of a cognitive behavioral self-help manual for binge
      eating [Fairburn, C. G. (1995). Overcome binge eating. New York: The Guilford
      Press.] Forty women (82.5% with binge eating disorder) were randomized to one of
      the two treatment levels. Results indicate that both conditions represent viable
      means of treating binge eating. Overall, patients improved their eating behavior,
      eliminated any inappropriate compensatory behaviors, reduced their shape concern,
      weight concern, and other symptoms of eating-related psychopathology, and
      improved their general psychological functioning. The guided self-help condition
      was notably superior in reducing the occurrence of binge eating and its
      associated symptomatology, as well as lowering interpersonal sensitivity. A high
      degree of general psychopathology was a negative prognostic indicator. The
      implications for a stepped-care approach to treating binge eating are discussed.

PMID- 10665160
TI  - Social phobia and interpretation of social events.
AB  - It has been suggested that social phobia may be characterized by two
      interpretation biases. First, a tendency to interpret ambiguous social events in
      a negative fashion. Second, a tendency to interpret unambiguous but mildly
      negative social events in a catastrophic fashion. To assess this possibility,
      patients with generalized social phobia, equally anxious patients with another
      anxiety disorder, and non-patient controls were presented with ambiguous
      scenarios depicting social and non-social events, and with unambiguous scenarios
      depicting mildly negative social events. Interpretations were assessed by
      participants' answers to open-ended questions and by their rankings and belief
      ratings for experimenter-provided, alternative explanations. Compared to both
      control groups, patients with generalized social phobia were more likely to
      interpret ambiguous social events in a negative fashion and to catastrophize in
      response to unambiguous, mildly negative social events.

PMID- 10665161
TI  - Promoting parental compliance with home infant apnea monitor use.
AB  - OBJECTIVE: To promote greater compliance in using prescribed infant apnea
      monitors among families with a medically at-risk infant. Eight consecutively
      referred non-compliant families were treated by a medical social worker who
      provided educational, behavioral prompting, and case management services. In six
      families results were evaluated with A-B single case research designs, and in two
      families A-B-A designs were used. Enhanced compliance followed intervention with
      all eight families. Clinically satisfactory compliance permitting the
      pediatrician to safely discontinue monitor use occurred in five of the eight
      families. Simple behavioral and case management interventions show great promise
      in promoting caregiver compliance with using home-based infant apnea monitors.

PMID- 10665162
TI  - Assessment of anxiety in older adults: a community-based survey and comparison
      with younger adults.
AB  - The reliability and validity of existing anxiety self-report scales in elderly
      adults has not been adequately established, and the phenomenology of anxiety in
      older adults is largely unknown. In the present study, three anxiety scales and
      measures of depression and somatization were used to compare symptoms between
      older (n = 84, mean age = 75.3) and younger (n = 48, mean age = 40.3) community
      dwelling adults. Results showed that the anxiety scales demonstrated good
      internal consistency in both age groups, although the reliabilities of the Fear
      Questionnaire subscales ranged from poor to good. Convergent and divergent
      validity were found to be variable in the older group, but this may reflect
      differences in anxiety as it occurs in older persons rather than psychometric
      problems. Anxiety symptoms did not vary with age, and levels of anxiety also
      remained constant. However, gender differences were found only within the older
      age group, with women reporting more anxiety than men. Findings are discussed
      with respect to current conceptualizations of anxiety in older people, as well as
      implications for future research.

PMID- 10665163
TI  - Use of the Beck Depression Inventory-II with depressed geriatric inpatients.
AB  - To provide information about the clinical utility of the Beck Depression
      Inventory-II (BDI-II) [Beck, A.T., Steer, R.A., & Brown, G.K. (1996b). Manual for
      the Beck Depression Inventory-II. San Antonio, TX: Psychological Corporation]
      with geriatric inpatients, the BDI-II was administered to 130 psychiatric
      inpatients who were 55 years old or above and who were diagnosed with principal
      DSM-IV major depressive disorders (MDD) (N = 85, 65%) or adjustment disorders
      with depressed mood (N = 45, 35%). The internal consistency of the BDI-II was
      high (coefficient alpha = 0.90), and its total score was not significantly
      related to sex, age, or ethnicity. An iterated maximum-likelihood factor analysis
      found the Cognitive and Noncognitive dimensions which have been reported for the
      BDI-II by Steer and co-workers (Steer R.A., Ball R., Ranieri W.F., & Beck A.T.
      (1999). Dimensions of the Beck Depression Inventory-II in clinically depressed
      outpatients. Journal of Psychopathology and Behavioral Assessment, 55, 117-128)
      in a younger sample of clinically depressed psychiatric outpatients. The mean BDI
      II total score of the 85 geriatric inpatients with MDD was also comparable to
      that of 42 younger (< or = 54 years old) inpatients with MDD. The results were
      discussed as supporting the use of the BDI-II with clinically depressed geriatric
      inpatients.

PMID- 10665164
TI  - Secondary school pupils' perceptions of burnout among teachers.
AB  - BACKGROUND: Numerous studies examined teachers' self-reports concerning their
      occupational burnout. Given that pupils are in a prime position to assess
      teachers' burnout, due to their intensive daily contact with their teachers and
      because some of pupils' behaviours can induce stress, the present study focuses
      on a relatively unexplored topic, namely the meanings that adolescents attach to
      burnout among their teachers. AIMS: This study was aimed at examining pupils'
      perceptions regarding burnout among their teachers, and to investigate the
      possible recommendations that the pupils would suggest to different constituents
      of the educational system for coping with burnout among teachers. SAMPLE: A total
      of 297 Israeli secondary school pupils (approximately 57% girls and 43% boys)
      studying in 12 tenth grade classes (mean age 15 years 8 months, SD = 0.42 years)
      participated in this study. METHODS: A questionnaire dealing with pupils'
      perceptions of burnout among teachers was administered. It included four
      sections. The first part asked for background of the pupils (sex and age). Next,
      pupils were asked an open-ended question in which they need to describe the most
      salient behaviour of a burned-out teacher in the classroom and to indicate the
      proportion of burned-out teachers among those teaching them. The third section
      consisted of a list of 14 items describing potential characteristics of burned
      out teachers. The respondents were asked to indicate the extent to which, in
      their opinion, each of the descriptors characterized burned-out teachers. In
      addition, pupils were asked three open-ended questions in which they were
      required to describe the most salient way for (a) the students, (b) the teachers
      themselves and (c) the school principal to cope with teachers' burnout. RESULTS:
      Findings showed that the most frequently mentioned characteristics of burned-out
      teachers were: teachers who 'feel that working with pupils for a full day is an
      oppressive effort', 'feel wiped out at the end of a teaching day', 'feel that
      teaching is turning them into impatient persons' and 'feel that teaching
      frustrates them'. No differences were found between girls' and boys' perceptions
      of burned-out teachers: both emphasize the psychological exhaustion of teachers
      as the most salient characteristic of burnout among teachers. Pupils suggest that
      the better ways for coping with this phenomenon include a more positive behaviour
      of the pupils themselves towards teachers, that burned-out teachers quit their
      jobs and that better work conditions be offered to them by the educational
      authorities. CONCLUSIONS: Our findings allude to the importance of analyzing
      interactional phenomena like burnout among teachers from the perspectives of
      different actors in the school arena and allow us to broaden our understanding of
      pupils' perceptions of teachers. Suggestions for further research and for the
      development of methodological refinements are discussed.

PMID- 10665165
TI  - Promoting prosocial pupil behaviour: 2-secondary school intervention and pupil
      effects.
AB  - BACKGROUND: In an earlier article (Mooij, 1999c) a theoretical multilevel model
      to promote prosocial pupil behaviour by stimulating specific educational
      conditions was developed. AIMS: To carry out school interventions to check
      empirically whether pupil level effects occur because of educational changes at
      the classroom and school level. SAMPLES: Seven secondary schools with relatively
      high degrees of pupil aggression were selected. Four schools took part as
      intervention schools, three schools served as control schools. In 1995 (pretest)
      and 1997 (post-test) pupils and form teachers of the first and third school years
      participated by completing questionnaires. Within the pupil cohorts, a
      longitudinal group of 352 pupils was included. METHODS: Pretest questionnaires in
      1995 were followed by intervention in the intervention schools. Teachers
      collaborated with staff and researchers to increase pupils' participation and
      responsibility in specifying and controlling behavioural and didactic rules,
      related to didactic differentiation during lessons. The validity of the
      intervention implementation was checked using qualitative information and
      quantitative data from both pre- and post-test. Longitudinal intervention effects
      were tested by applying two-level multiple regression analyses. RESULTS: After
      controlling for pretest and covariables in school year 1, school intervention
      effects were found in school year 3 with the prediction of being a perpetrator of
      aggressive behaviour at school, aggressive behaviour outside school, and criminal
      behaviour. Some small effects were found with respect to victim behaviour.
      CONCLUSIONS: Social-pedagogical and didactic class and school variables, but also
      home variables and support by peers without problematic behaviour, could be
      integrated more systematically to promote prosocial development of a pupil's
      behaviour from the beginning in school.

PMID- 10665166
TI  - Name-calling and nicknames in a sample of primary school children.
AB  - BACKGROUND: Name-calling, unkind nicknames and other forms of verbal harassment
      represent some of the most prevalent forms of bullying in school but they have
      been little studied. Name-calling and nicknames in particular are ambiguous
      social events that can serve positive as well as negative goals, and their
      adverse consequences can be difficult to identify. AIMS: (i) To assess the
      incidence of nicknames and name calling as reported by a sample of primary school
      children; (ii) to examine the kinds of names reported by children, and to relate
      these to names reported in other social contexts; (iii) to explore the impact
      that name-calling and nicknames have on children. SAMPLE: Pupils (N = 60) from
      the top two classes in a British primary school completed a questionnaire; 20 of
      the children were subsequently interviewed. METHOD: Pupils completed a
      questionnaire that was constructed for this study. Pupils were asked to provide
      examples of nicknames and to report on the types and incidence of several forms
      of verbal harassment. The interview included questions which aimed to explore the
      children's reactions to harassment. RESULTS: Being called disliked nicknames,
      called names, teased, and other forms of verbal harassment were reported by most
      of the sample, with more than 20% of children experiencing nasty comments and
      unkind nicknames on a daily basis. Girls reported more disliked nicknames than
      boys. The most common nicknames referred to the child's appearance, whereas nasty
      comments and untrue stories contained a preponderance of sexual references. In
      the interview, nearly all children reported that being called names and nicknames
      were negative experiences that caused distress. CONCLUSIONS: Name-calling and the
      assignment of unkind nicknames are prevalent and hurtful++ features of school
      life. The kinds of names are similar to those reported in other studies of
      children, adolescents, and adults. It is proposed that these names are hurtful
      because they threaten the child's identity.

PMID- 10665167
TI  - An investigation of coping strategies associated with job stress in teachers.
AB  - BACKGROUND: School teaching is regarded as a stressful occupation, but the
      perception of the job as stressful may be influenced by coping responses and
      social support. AIMS: To assess the associations between teacher stress,
      psychological coping responses and social support, taking into account the
      plaintive set engendered by negative affectivity. METHOD: Questionnaire survey of
      780 primary and secondary school teachers (53.5% response rate). RESULTS: In
      stepwise multiple regression, social support at work and the coping responses
      behavioural disengagement and suppression of competing activities predicted job
      stress independently of age, gender, class size, occupational grade and negative
      affectivity. High job stress was associated with low social support at work and
      greater use of coping by disengagement and suppression of competing activities.
      CONCLUSIONS: It is suggested that behavioural disengagement and suppression of
      competing activities are maladaptive responses in a teaching environment and may
      actually contribute to job stress. Coping and social support not only moderate
      the impact of stressors on well-being but influence the appraisal of
      environmental demands as stressful.

PMID- 10665168
TI  - Approaches to studying in people with hearing loss.
AB  - BACKGROUND: There has been little research on the experiences of students with
      hearing loss in higher education. It has, however, been suggested that children
      with hearing loss adopt different strategies and styles and that this leads to
      differences in their academic performance. AIMS: This investigation compared
      students in higher education with and without hearing loss in terms of their
      approaches to studying. SAMPLES: We compared 382 students with hearing loss
      taking courses by distance learning with the Open University and a comparison
      group of 190 students taking the same courses with no declared form of
      disablement. METHODS: A questionnaire containing a shortened and adapted version
      of the Approaches to Studying Inventory was distributed in a postal survey.
      RESULTS: Students with postvocational hearing loss obtained higher scores than
      the comparison group on deep approach, and those with postvocational deafness
      also obtained higher scores on the use of evidence and logic. Students with
      prevocational deafness obtained higher scores on reproducing orientation than the
      comparison group, and in particular on improvidence. All of the subgroups of
      students with hearing loss obtained higher scores than the comparison group on
      fear of failure. CONCLUSIONS: The impact of hearing loss on cognitive aspects of
      studying appears to be relatively slight. Future research might focus instead
      upon its affective consequences and its effects upon a student's self-concept.

PMID- 10665169
TI  - Pupils' reasons for learning and behaving and for not learning and behaving in
      English and maths lessons in a secondary school.
AB  - BACKGROUND: There is renewed interest in motivation and school learning, though
      there has been relatively little theory-linked research in English schools. AIMS:
      In the first stage, to explore pupils' reasons for learning and behaving and for
      not learning and behaving in English, maths and other subjects. In the second
      stage, to examine differences in reasons across subjects, for learning and
      behaving and for not learning and behaving for boys and girls in two year groups
      in one secondary school. SAMPLE: Stage 1, 16 pupils in years 7, 8 and 9 in two
      London secondary schools; Stage 2, 267 pupils in years 7 and 9 in one of these
      schools. METHODS: Stage 1--semi-structured interviews were conducted to elicit
      different kinds of reasons conceptualised in terms of the Deci & Ryan's (1985)
      framework of self-determination. From these elicited reasons, an inventory 'Why I
      Learn' was designed. Stage 2--the inventory was administered to identify reasons
      for learning and behaving and for not learning and behaving in English and maths.
      RESULTS: Parent introjected reasons were the highest for learning and behaving
      while teacher introjected and intrinsic reasons were the lowest. Intrinsic
      reasons were highest for not learning and behaving. Year group differences in
      reason levels were more significant than gender or subject differences. Reasons
      for learning and behaving were more differentiated from each other than reasons
      for not learning and behaving. DISCUSSION: The results are discussed in terms of
      their significance for self-determination theory, research into the conditions
      promoting greater self-determination in school learning and further development
      of the inventory for programme evaluation.

PMID- 10665170
TI  - Problems of behaviour, reading and arithmetic: assessments of comorbidity using
      the Strengths and Difficulties Questionnaire.
AB  - BACKGROUND: Estimates of academic underachievement among school children vary
      widely, depending on the geographical location and on the criteria used to define
      attainment. AIM: To examine the relationship between behaviour problems and
      academic attainment in a large UK primary school. METHOD: A school population
      (364 children from Years 3 to 6 inclusive) were assessed on a range of cognitive
      ability tasks. These included standardised tests of reading, arithmetic and
      verbal and non-verbal intelligence. Under-achievement was assessed using
      different criteria. To assess behaviour, teachers completed the Strengths and
      Difficulties Questionnaire (Goodman, 1997) for each participating child. Finally,
      academic progress of a subset of children was assessed after one year. RESULTS:
      Indicated a significant relationship between behaviour and academic attainment;
      prosocial behaviour was positively correlated with reading and arithmetic,
      hyperactivity and conduct problems were negatively correlated. This association
      was especially strong in the children rated by the questionnaire as hyperactive,
      where around 1 in 5 had a specific reading deficit. However, there was no
      evidence to indicate that children with behaviour problems made less academic
      progress over a one-year period relative to their peers. CONCLUSION: The study
      highlights the importance of assessing both cognitive skills and behaviour,
      particularly when planning the educational management of children with reading
      difficulties.

PMID- 10665171
TI  - Saving lives--an opportunity for the dental profession?

PMID- 10665172
TI  - The design, errors and costs of a local adult oral health survey.
AB  - OBJECTIVE: To evaluate the errors and costs of a sampling and survey design for
      producing reliable estimates of oral health in a demographically diverse local
      population with a potentially high non-response rate. BASIC RESEARCH DESIGN: A
      two-stage cluster sample of 45-54 year old adults was drawn from a sampling frame
      of patients registered with local GPs and cross checked against the electoral
      register. The modes of data collection were interview/examination and
      questionnaire. Statistical properties of the estimates were evaluated and costs
      of the survey described. MAIN OUTCOME MEASURES: The frequency of categories of
      non-response were described. Sample characteristics were compared with (1) the
      local population's (1991) census distribution with respect to gender, ethnic
      composition and socio-economic group (SEG); (2) local utilisation data. The bias
      effects on oral health values of gender, SEG and non-response, were estimated.
      The design effect was described for mean number of teeth and proportion with 21
      teeth or more. Optimal primary and secondary sample sizes, and non-response
      follow-up fractions, were estimated. CONCLUSION: This paper describes and costs a
      sampling and survey design which efficiently produced statistically acceptable
      estimates of oral health, using small samples from a selected age group in a
      district, posing demographic and non-response problems in ensuring reliable
      epidemiological results. The findings indicate that national surveys may give
      reasonable projected estimates for even richly diverse local populations.

PMID- 10665174
TI  - Some aspects of data analysis in dentistry.
AB  - In dentistry many studies collect hierarchical data, but this is not always
      recognised or understood by the researchers. This paper sets out to describe such
      studies and discusses aspects of their design, data collection and analysis.
      Sometimes these studies may be dealt with in a simple way, but others may require
      the help of a professional statistician to deal with analytical problems that are
      encountered.

PMID- 10665173
TI  - The use of socio-demographic profiling of patients to monitor changes in the
      provision of care by the Community Dental Service.
AB  - OBJECTIVE: To investigate the socio-demographic profile of patients using the
      Leeds Community Dental Service (CDS) in 1996/97 and to determine any changes in
      profile since 1991/92. DESIGN: Retrospective. SETTING: The area served by Leeds
      Health Authority. SUBJECTS: A total of 8,051 patients who had used the Leeds CDS
      in 1996/97 together with 9,372 patients from 1991/92. OUTCOME MEASURES: Socio
      demographic profile, including age group; ethnicity; deprivation (Townsend index)
      and disability. RESULTS: Of children under 16 years old using the CDS in 1996/97,
      24% were of South Asian ethnic origin, much higher than the 6% reported for Leeds
      in the 1991 census. Over the period of the study there was a reduction in the
      proportion of patients aged 5-15 years (75% to 65%, P < 0.001) and an increase in
      those aged 16-64 years (13% to 19%, P < 0.001). Increases were also seen in the
      proportion of patients from districts in the two most deprived quintiles (60% to
      67%, P < 0.001) and for patients with special needs (19% to 28%, P < 0.001).
      CONCLUSIONS: This study indicated an increased emphasis by the CDS on targeting
      groups likely to be unable or unwilling to seek treatment from the GDS. Socio
      demographic profiling can be useful in monitoring the progress of changes in
      primary dental care.

PMID- 10665175
TI  - An outline of graphical Markov models in dentistry.
AB  - BACKGROUND: In the usual multiple regression model there is one response variable
      and one block of several explanatory variables. In contrast, in reality there may
      be a block of several possibly interacting response variables one would like to
      explain. In addition, the explanatory variables may split into a sequence of
      several blocks, each block containing several interacting variables. The
      variables in the second block are explained by those in the first block; the
      variables in the third block by those in the first and the second block etc.
      OBJECTIVE AND METHODS: During recent years methods have been developed allowing
      analysis of problems where the data set has the above complex structure. The
      models involved are called graphical models or graphical Markov models. The main
      result of an analysis is a picture, a conditional independence graph with precise
      statistical meaning, consisting of circles representing variables and lines or
      arrows representing significant conditional associations. The absence of a line
      between two circles signifies that the corresponding two variables are
      independent conditional on the presence of other variables in the model. EXAMPLE:
      An example from epidemiology is presented in order to demonstrate application and
      use of the models. The data set in the example has a complex structure consisting
      of successive blocks: the variable in the first block is year of investigation;
      the variables in the second block are age and gender; the variables in the third
      block are indices of calculus, gingivitis and mutans streptococci and the final
      response variables in the fourth block are different indices of caries. Since the
      statistical methods may not be easily accessible to dentists, this article
      presents them in an introductory form. CONCLUSION: Graphical models may be of
      great value to dentists in allowing analysis and visualisation of complex
      structured multivariate data sets consisting of a sequence of blocks of
      interacting variables and, in particular, several possibly interacting responses
      in the final block.

PMID- 10665176
TI  - Knowledge, attitudes and beliefs of adult South Asians living in London regarding
      risk factors and signs for oral cancer.
AB  - BACKGROUND: South Asian communities in the UK are thought to be a high-risk group
      for oral cancer, primarily because of betel-quid (pan) chewing habits. However
      there has been little research on the communities' perception of oral cancer.
      AIM: This investigation was undertaken to assess the knowledge, attitudes and
      beliefs of South Asian adults (n = 367) regarding the risk factors and signs for
      oral cancer. DESIGN AND SETTING: The information was obtained by means of a self
      administered questionnaire and structured interviews at six Asian community
      centres and three general medical practices in north west London. PARTICIPANTS:
      Subjects ranged in age from 16 to 80 years and came from diverse socio-economic
      and cultural backgrounds. RESULTS: Tobacco use was the only risk factor correctly
      identified by most adults (82%). A significant difference (P < 0.001) was seen in
      betel-quid chewing habit among the age groups with 42.2% of adults in the 50-80
      year age group practising this habit as compared to only 5.3% in the 16-29 year
      age group. Another finding was that the traditional method of betel-quid chewing
      is being replaced with readily available processed areca nut and tobacco
      products. CONCLUSIONS: There is extensive misinformation and a general lack of
      awareness about the risk factors and signs of oral cancer among the South Asian
      communities irrespective of age, gender, South Asian subgroup and social class.
      It is clear that betel-quid chewing is a common habit among the population and
      especially in the elderly population. It is recommended that health promotion
      advice be targeted to this population and their carers.

PMID- 10665177
TI  - An investigation into the use of a dental hygienist in school screening.
AB  - OBJECTIVE: A pilot study to measure the validity of using a hygienist to carry
      out school screening. DESIGN: Following a standard training programme a dental
      hygienist (DH), recruited from general practice, a newly appointed dental officer
      (DO) and an epidemiologist (SDO), who acted as the standard, all screened the
      same group of school children on two occasions. SETTING: An inner city school
      with known high levels of disease. PARTICIPANTS: Ninety-eight 7- and 8-year-old
      children attending school. MAIN OUTCOME MEASURES: For each clinician the levels
      of referral, the reasons for referral and the repeatability were measured.
      RESULTS: The hygienist referred 26 children (27%) for further examination while
      the DO and the SDO both referred 61 (62%). The DO achieved the required standards
      of sensitivity and specificity when results were compared with the SDO but the
      hygienist did not. Intra-examiner reliability in all three clinicians was good.
      CONCLUSIONS: The standard training programme used to prepare dental officers to
      carry out school screening to an agreed standard was insufficient for this
      hygienist's needs.

PMID- 10665178
TI  - Dental service provision in private general practice for an insured population in
      New South Wales, Australia.
AB  - OBJECTIVE: To determine patterns of dental services provided to a cohort of the
      insured population 18 years and over, in private general practice in New South
      Wales, Australia. BASIC RESEARCH DESIGN: A cohort study using the person-years
      method and Poisson regression for analysis. SETTING: Data were derived from
      claims records submitted by members of a health insurance fund (Government
      Employees Health Fund-GEHF) for rebates during the study period 1 January 1992-31
      December 1995. PARTICIPANTS: There were 133,467 members aged 18 years and over
      from New South Wales. MAIN OUTCOME MEASURES: To determine, by age group, for
      those members who used private general practice and made a claim (referred to as
      'patients') the annual number of visits, total number of services received per
      year and number of services received at a visit. RESULTS: The mean number of
      visits per patient was 2.4 per year with patients under 45 years making fewer
      visits than the 45-54 age group reference category. Mean number of services
      utilised per patient-year was 5.9, with services provided increasing from 3.5 for
      the 18-24-year-old group, reaching a plateau of approximately 6.2 for those aged
      45 years or more. The number of services received per visit was 2.4 and there
      were no differences by age. Service mix was dominated by restorative (35%),
      diagnostic (27%), and preventive services (18%); with age specific variations
      observed. CONCLUSIONS: Age was found to be an important determinant in the use of
      dental services, independent of membership duration and gender.

PMID- 10665179
TI  - Caries experience and treatment needs in a 6- to 12-year-old urban population in
      relation to socio-economic status.
AB  - OBJECTIVE: To report caries experience in the permanent dentition among Mexico
      City elementary school children and undertakes a comparative analysis of dental
      caries experience and treatment needs of children of different socio-economic
      status (SES). RESEARCH DESIGN: SES was established according to an official
      measure of economic well-being, that of the family income being high enough to
      allow the child to attend school in a private institution as opposed to a public
      school. PARTICIPANTS: A probabilistic sample of 4,048 6- to 12-year-old children
      (47.2% females) was examined using the 1987 WHO caries criteria (546 attended
      private schools and 3,502 were public school children). RESULTS: The proportion
      of caries-free 12-year-old children was 28.6% and 9.5% in the private and public
      schools, respectively (P < 0.01). In 12-year-old children, DMFT was 2.78 (SD 2.9)
      and 4.64 (SD 3.2) in the private and public school groups, respectively (P <
      0.001). Higher treatment needs were found among public schoolchildren (TN =
      83.0%) compared with private schoolchildren (TN = 27.6%) (P < 0.001).
      CONCLUSIONS: Dental caries and treatment needs were considerably higher in
      children of lower SES. Differences in dietary patterns and toothpaste use could
      be the more likely explanations for these findings, indicating markedly unequal
      burdens of disease according to socio-economic status. Special efforts should be
      developed to improve the oral health status in Mexico City children by
      implementing preventive health promotion and treatment programmes.

PMID- 10665180
TI  - Dentists' decisions as to mode of preventive treatment in adolescents and young
      adults in Finland.
AB  - OBJECTIVE: To evaluate dentists' real-life decisions as to mode of preventive
      treatment in adolescents and young adults, in relation to these patients' oral
      health status, and to the dentists' characteristics. DESIGN: A random sample of
      206 adolescents and 239 young adults (mean ages 13 and 27 years) produced 411
      (92%) individual oral health records providing data on actual clinical
      examinations and treatment courses carried out by 56 dentists in one
      administrative unit of the Finnish public oral health service during 1994-1996.
      OUTCOME MEASURES: Preventive measures were defined as active and passive, active
      including any kind of motivation or instructions given to a patient concerning
      home self-care, and passive prevention being topical application of fluoride.
      RESULTS: More adolescents had received both active and passive prevention than
      had young adults (active: 27% vs. 20%; passive: 85% vs. 70%). Of adolescents, 7%
      and of young adults 25% were given no preventive treatment. The mean number of
      active preventive measures per adolescent during the treatment course was 0.3 and
      of passive measures 1.0; for young adults 0.2 and 0.8, respectively. A subject's
      oral health status made no significant difference in active prevention given.
      Active measures were more frequently given to all patients by male dentists, 35%
      vs. 22% (P < 0.02), and passive measures by females, 82% vs. 52% (P < 0.001). The
      odds of active prevention for adolescents were 7.4 comparing male dentists to
      female; of passive 13.8 comparing female to male. CONCLUSIONS: Dentists should be
      motivated to make considered treatment decisions on preventive treatment.

PMID- 10665181
TI  - Cultural barriers to successful communication during orthodontic care.
AB  - OBJECTIVE: To determine to what extent barriers related to culture and language,
      and how inappropriate expectations might impede orthodontic care, among Pakistani
      Muslims when compared to white Caucasians from similar socio-economic backgrounds
      in Bradford, UK. DESIGN: Semi-structured interviews. SETTING: Dentists were
      interviewed in the clinic. Parents and children were interviewed separately in
      the waiting room or in adjacent rooms depending on availability. PARTICIPANTS:
      Four dentists working in the Community and Hospital Dental Services, 30 children
      and 10 parents of white and Pakistani origin. RESULTS: Among the white Caucasian
      groups, three-way communication involving parents, children and dentist enhanced
      understanding, supported orthodontic treatment and reinforced the need for good
      home care. Among Pakistani families communication was primarily two-way,
      involving the dentist and the child. Parents and families had limited
      understanding of the process and were unable to offer a comparable level of
      support that would benefit their children most. This can place additional burdens
      on the Pakistani child patient and requires a very positive approach from the
      dental team. CONCLUSIONS: There is a clear need for chairside support, through
      patient advocates or interpreters, as well as the provision of appropriate
      educational material to match parents' educational needs on behalf of their
      children.

PMID- 10665182
TI  - Perforation after grommet insertion.

PMID- 10665183
TI  - Image-guided endoscopic excision of ethmoid sinus mucocele.

PMID- 10665184
TI  - Fundamentals of electronystagmography.

PMID- 10665185
TI  - A case of reflux laryngitis controlled with proton pump blockade alone.

PMID- 10665186
TI  - Tympanosclerosis.

PMID- 10665187
TI  - Acute effects of antileukotrienes on sinonasal polyposis and sinusitis.
AB  - Recently, leukotrienes have been implicated in the mediation of
      bronchoconstriction and inflammatory changes in asthma. Leukotriene levels have
      also been shown to be elevated in patients with asthma as well as in those with
      sinonasal polyposis and sinusitis. The leukotriene synthesis inhibitor zileuton
      and the leukotriene receptor antagonist zafirlukast have been shown to produce
      subjective and objective improvements in patients with mild to moderate asthma.
      Given these findings, we evaluated the efficacy of these two medications in
      controlling sinonasal polyposis and their associated symptoms. We treated 40
      patients diagnosed with sinonasal polyposis and sinusitis with either zileuton or
      zafirlukast. No other change was made in their standard therapy. Outcome measures
      included subjective interviews and questionnaire responses, as well as office
      endoscopic examinations and chart reviews. At study's end, 36 patients were
      available for evaluation. Twenty-six had taken zafirlukast, five had taken
      zileuton, and five others had switched from zafirlukast to zileuton. Overall, 26
      patients (72%) experienced subjective improvement in their symptomatology after
      starting their medication. Statistically significant improvement was noted with
      respect to headache, facial pain and pressure, ear discomfort, dentalgia,
      purulent nasal discharge, postnasal drip, nasal congestion and obstruction,
      olfaction, and fever. An objective alleviation, or at least stabilization, of
      sinonasal polyposis was seen in 50% of the patients. Four patients (11%)
      discontinued their medication because of side effects. We conclude that
      antileukotrienes might play a significant role in controlling polyposis and
      symptoms secondary to sinonasal disease, and they might be a viable alternative
      to long-term oral steroid therapy and repeated surgical debridement.

PMID- 10665188
TI  - Standardized measurements of radiographic films of the frontal sinuses: an aid to
      identifying unknown persons.
AB  - Many methods have been used to identify unknown persons. The most common is the
      study of fingerprints, which is one of the few methods in which data can be
      stored and retrieved in a precise and cost-effective manner. The asymmetry of the
      frontal sinuses has stimulated several attempts to identify persons by analyzing
      measurements of the sinuses obtained from plain x-ray films. However, an
      objective and reproducible method has not been achieved. The objective of this
      paper is to report on a method of making standardized measurements of the frontal
      sinuses on radiographs and storing the resultant information in a computer
      databank. To test the system, the author made new measurements on 100 x-rays and
      entered the results into a computer databank that contained information on
      earlier measurements of the same 100 x-rays and on 400 others. With the aid of
      the databank, the author was able to rapidly and accurately match each new
      measurement with the earlier measurement. The author concludes that such a system
      is a simple and cost-effective method of establishing the identification of
      unknown persons for whom frontal sinus x-rays exist.

PMID- 10665189
TI  - A cluster of acoustic neuromas in fish hatchery workers.
AB  - The National Institute for Occupational Safety and Health (NIOSH) received a
      request from the United States Fish and Wildlife Service (FWS) to determine if
      there is a relationship between acoustic neuroma and fish hatchery work. The
      request was triggered by a report from an FWS employee who suspected the
      possibility of such an association. Investigators used data provided by the
      personnel office of the FWS to calculate the incidence of acoustic neuroma among
      fish hatchery workers, and then to compare it with national rates. Four confirmed
      cases of acoustic neuroma were found among former fish hatchery workers. The
      overall incidence was estimated to be 15.41 per 100,000 person-years. This rate
      is more than 15 times higher than the rate among the general population. Even so,
      the small number of cases, as well as other factors, preclude the NIOSH from
      concluding that there is a definite cause-and-effect relationship. Further study
      is warranted.

PMID- 10665190
TI  - Leiomyosarcoma of the larynx: diagnosis aided by advances in immunohistochemical
      staining.
AB  - We present only the 12th reported case of a laryngeal leiomyosarcoma. This tumor
      was diagnosed with the aid of the newer immunohistochemical stains on archival
      paraffin-embedded tissue. The diagnosis and management of these tumors is based
      largely on the patterns seen in the small number of earlier reported cases of
      head and neck leiomyosarcomas and laryngeal sarcomas.

PMID- 10665191
TI  - Pneumosinus dilatans: a report of three new cases and their surgical management.
AB  - Pneumosinus dilatans is a rare pathology that primarily involves the frontal
      sinus. We report three new cases, with special attention given to the
      pathophysiology and histologic data. Surgical management is reported.

PMID- 10665192
TI  - Fibrous dysplasia of the temporal bone: report of a case and a review of its
      characteristics.
AB  - Fibrous dysplasia is an uncommon benign disorder of unknown etiology. It
      represents a disturbance of normal bone development--specifically a defect in
      osteoblastic differentiation and maturation that originates in the mesenchymal
      precursor of the bone. Because fibrous dysplasia shows a predilection for the
      facial and cranial bones, where it causes deformity and dysfunction, the disease
      is of particular interest to the otolaryngologist. In this paper, we report a
      case of fibrous dysplasia of the temporal bone, the first symptom of which was a
      mixed hearing loss. We discuss the characteristic features of this specific
      location of the disease, the differential diagnosis, and the treatment policy. We
      also address the issue of secondary sensorineural hearing loss.

PMID- 10665193
TI  - Determination of the centre of resistance in an upper human canine and idealized
      tooth model.
AB  - The purpose of this investigation was to analyse the influence of geometric and
      material parameters of a human canine on initial tooth mobility, and the stress
      and strain profiles in the periodontal ligament. While the material parameters of
      tooth and bony structures are known within an uncertain limit of approximately a
      factor of 10, values reported for the elasticity parameters of the periodontal
      ligament differ significantly. In the course of this study, bilinear behaviour
      was assumed for the mechanical property of the periodontium. The finite element
      model of an elliptical paraboloid was created as an approximation to the geometry
      of a human canine to reduce calculation time and to determine influences of the
      geometry on numerical results. The results were compared with those obtained for
      a realistic human canine model. The root length of both models was 19.5 mm. By
      calculating pure rotational and pure tipping movements, the centre of resistance
      (CR) was determined for both models. They were located on the long axis of the
      tooth approximately 7.2 mm below the alveolar crest for the idealized model and
      8.2 mm for the canine model. Thus, the centre of resistance of a human canine
      seems to be located around two-fifths of the root length from the alveolar
      margin. Using these results, uncontrolled tipping (1 N of mesializing force and 5
      Nmm of derotating momentum), as well as pure translation (additionally about 10
      Nmm of uprighting momentum) were calculated. Comparing the idealized and the
      realistic models, the uncontrolled tipping was described by the parabolic-shaped
      model within an accuracy limit of 10 per cent as compared with the canine model,
      whereas the results for bodily movement differed significantly showing that it is
      very difficult to achieve a pure translation with the realistic canine model.

PMID- 10665194
TI  - Structural conformation of in vitro and in vivo aged orthodontic elastomeric
      modules.
AB  - The objectives of this study were to investigate the structural characteristics
      of open and closed elastomeric modules in the as-received condition, and
      following (a) 24-hour in vitro loading determined as a 50 per cent extension
      relative to their original length; (b) 24-hour intra-oral exposure; (c) 3-week
      intra-oral exposure. Ten specimens of each type (open and closed) of the three
      brands of elastic chains were included in the study (total of 60). All specimens
      were subjected to (a) optical transmission microscopy utilizing phase contrast
      and polarized light modes, (b) micro MIR FT-IR spectroscopy, and (c) scanning
      electron microscopy and electron probe X-ray microanalysis. Stretched elastomers
      demonstrated a honeycomb pattern of filament detachment corresponding to strained
      areas. The chains possessing a well-differentiated inter-modular link presented
      higher strain concentration gradients located in the link. Phase contrast imaging
      revealed that the stress adsorption mechanism of these materials involved
      macromolecular chain orientation and elongation co-axially to the applied load.
      The specimens retrieved after 24 hours had acquired a proteinaceous film rich in
      alcohol groups with minimal evidence of phosphate mineralization, while the 3
      week retrieved specimens presented precipitation of Ca- and P-forming calcium
      phosphates. The high protein content of the biofilm organized on the surface of
      these materials, as well as the calcification pattern found, were similar to a
      non-specific mechanism of film adsorption of biomaterials exposed to body fluids.
      The results have clinical implications for aspects of retraction control through
      sliding mechanics with the use of elastomeric ligatures, and the potential
      detrimental effects on dental and periodontal tissues such as decalcification and
      gingival inflammation, respectively. In addition, the experimental protocols
      adopted for the in vitro study of the force decay of elastomerics should be
      modified to include parameters pertinent to adsorption phenomena and
      calcification processes documented to occur in vivo.

PMID- 10665195
TI  - Masseter muscle volume measured using ultrasonography and its relationship with
      facial morphology.
AB  - The aims of this study were to measure the volume, cross-sectional area,
      thickness, width, and length of contracted masseter muscles in a sample of
      adults, four males and six females, using three-dimensional (3D) ultrasonography,
      and to correlate these measurements with the variations in facial morphology of
      the sample. The scans were carried out bilaterally using a hand-held probe
      carrying a magnetic positional sensor, which enabled a computer to reconstruct
      the images into a 3D array of slices. Measurements were made by the computer from
      the reconstructed images using specially written software. Cephalometric analysis
      initially involved seven angular, eight linear, and two proportional variables,
      but as these were strongly inter-dependent, the variables were reduced to four
      principal components prior to statistical comparison with the mean muscle
      variables. The values found for muscle volume, cross-sectional area, and
      thickness were broadly consistent with those of previous investigators. Volume
      showed a significant, negative correlation with mandibular inclination including
      gonial angle (P < or = 0.001), and a significant, positive correlation with total
      posterior face height and ramus height (P < or = 0.001), and lower posterior face
      height percentage (P < or = 0.01). Weaker correlations were found for length and
      thickness. While the results support existing evidence that large masticatory
      muscles are associated with brachycephalism and vice versa, a cautious
      interpretation is necessary in view of the small sample size. The 3D
      ultrasonography system is at an experimental stage and requires further
      development and evaluation.

PMID- 10665196
TI  - Initial orthopaedic displacement compared with longitudinal displacement of the
      maxilla after a forward force application. An experimental study in dogs.
AB  - The aim of this study was to compare the initial orthopaedic displacement of the
      maxilla in vivo and the longitudinal changes after a forward force application.
      The sample consisted of five 1-year-old dogs. An anterior force of 5 N on the
      maxilla was applied by a coil spring system pushing between Branemark implants
      and a maxillary splint. The initial displacement of the maxilla after force
      application was measured by means of speckle interferometry. The longitudinal
      displacement of the maxilla after a force application during 8 weeks was measured
      by superimposing standardized lateral cephalograms. The initial, as well as the
      longitudinal, displacement of the maxilla of the dogs was in a forward direction
      with some counterclockwise rotation. There was no statistical difference between
      the initial and longitudinal displacement. The biological response after force
      application during 8 weeks can be predicted by the initial orthopaedic
      displacement.

PMID- 10665197
TI  - Properties of crimpable archwire hooks: a laboratory investigation.
AB  - The aim of the present study was to utilize a strain gauge, which enabled the
      force applied to produce firmly attached crimpable hooks to rectangular stainless
      steel arch wires, to be measured. In vitro testing of two hooks, American
      Orthodontic (AO) and TP Orthodontic (TP), and two dimensions of stainless steel
      archwire, 0.019 x 0.025 and 0.018 x 0.025-inch, was carried out using an Instron
      Universal Testing machine. The results demonstrate that there was a significant
      difference in the behaviour of the two types of crimpable hooks, with almost
      twice the force needed to dislodge the TP hooks compared with the AO hooks (11.7
      and 6.22 N, respectively). When using TP hooks attached to either 0.019 x 0.025
      or 0.018 x 0.025-inch stainless steel wires, the archwire size makes little
      difference to the force required to produce movement. The clinical significance
      of these findings is discussed.

PMID- 10665198
TI  - The durability of parylene coatings on neodymium-iron-boron magnets.
AB  - A parylene coating is frequently used to prevent corrosion of neodymium-iron
      boron magnets when they are used intra-orally. This in vitro study was designed
      to test the durability of parylene coating in a simulated oral environment.
      Single and double parylene-coated magnets were subjected to grinding and crushing
      forces in an industrial ball mill. The results demonstrate that abrasion and wear
      was visible around the edges after 1 hour of testing, with a breach of the
      coating noted under high magnification scanning electron microscopy (SEM). The
      conclusion of the study is that parylene coating is unlikely to withstand intra
      oral forces. The shape of the magnets, the manufacturing process involved in
      their production, and the thickness of the parylene coating are important factors
      to consider with respect to the durability of magnets used in the mouth.

PMID- 10665199
TI  - A retentive system for intra-oral fluoride release during orthodontic treatment.
AB  - The aim of this study was to test a particular type of intra-oral fluoride
      releasing device (IFRD), designed to release 0.04 mg/day of fluoride over a
      period of 6 months, using customized holders, in patients receiving orthodontic
      treatment. Discomfort, holder detachment, plaque accumulation near the device,
      and the presence of gingivitis, bleeding, white spot lesions, and/or decay was
      recorded in 76 orthodontic patients (53 experimental and 23 controls) before and
      after wearing the device for 12 months. The system proved to be easy and quick to
      use, and did not cause discomfort. There were no significant differences between
      the treated and the control groups for plaque index, bleeding, or the presence of
      gingivitis. In addition, no carious and/or white spot lesions occurred during the
      duration of this study in the test group.

PMID- 10665200
TI  - Long-term effect of neonatal endotracheal intubation on palatal form and symmetry
      in 8-11-year-old children.
AB  - Premature and low birth weight infants often require neonatal oral intubation for
      resuscitation and to relieve respiratory distress. The endotracheal tube exerts
      pressure on the developing palate, which can result in palatal groove formation,
      a high-arched palate, and palatal asymmetry. The purpose of this investigation
      was to determine whether such intubation can have a long-term effect on palatal
      form and symmetry. Arch widths, palatal widths, and palatal depths were measured
      from the study casts of 43, 8-11-year-old previously intubated premature and low
      birth weight children using a reflex microscope, with a fixed rectangular
      Cartesian co-ordinate system, and compared with a group of non-intubated gender-
      and age-matched controls. Significant differences were found between the
      intubated and non-intubated children. The intubated children had significantly
      narrower palatal widths posteriorly (P < or = 0.001), steeper palatal vaults
      anteriorly (P < or = 0.01), and exhibited a directional palatal width asymmetry
      with the left side of the palate measuring consistently wider than the right.
      These differences did not, however, appear to be affected by the length of
      intubation. Therefore, it is concluded that an oral endotracheal tube might exert
      excess force on the developing alveolus anteriorly with the tube being displaced
      to the right of the palate posteriorly leading to a steep anterior palatal vault
      and a left-sided palatal asymmetry, which can persist until the age of 11 years
      of age.

PMID- 10665201
TI  - Delayed dental age in boys with constitutionally delayed puberty.
AB  - It was the purpose of this study to evaluate dental age in boys with delayed
      puberty and to compare them with a group of normal, healthy boys. The study group
      consisted of eight boys with constitutional delay of growth and puberty (CDGP),
      older than 14 years, and with a testis volume smaller than 4 ml. The control
      group comprised 38 normal, healthy boys, aged between 12.4 and 14.3 years. Dental
      age was assessed using the Demirjian method and, on the basis of this evaluation,
      a dental delay score (i.e. dental age minus chronological age) was calculated in
      the CDGP and the control group. It was found that Demirjian's dental age
      assessment is a valid method for scoring dental age in Belgian boys between 12
      and 14 years of age, and that CDGP boys showed a significant delay in dental
      development compared with normal boys (P = 0.0085). This study revealed a
      significant retardation in dental maturation of boys with CDGP.

PMID- 10665202
TI  - A comparison of three superimposition methods.
AB  - The purpose of this investigation was to compare the reliability of three
      superimposition methods: Bjork's structural, Ricketts' four-position, and
      Pancherz's method. The material consisted of 14 pairs of cephalograms obtained
      before and after Herbst treatment. Each pair of cephalograms were traced and
      superimposed by means of the three different methods three times each. A
      reference grid was used to quantitatively evaluate the sagittal dental and
      skeletal changes. The results revealed that: (1) there was no statistically
      significant difference between the repeated measurements in the three methods,
      i.e. all three methods were reliable. (2) There was no significant difference
      among the three superimposition methods to evaluate the sagittal skeletal and
      dental changes. (3) Comparing the coefficient of reliability, none of the three
      methods was suitable for individual assessment, and Pancherz's method only was
      acceptable for assessment of patients in groups.

PMID- 10665204
TI  - Older observers' tolerance of optical blur: age differences in the identification
      of defocused text signs.
AB  - To determine if visual aging affects the ability to identify blurred text signs
      in daytime or nighttime viewing conditions, the photopic and mesopic legibility
      thresholds of young and old adult observers were compared at three levels of
      optically induced acuity (Experiment 1). For both age groups, legibility was
      reduced by nighttime luminance and degraded acuity. Surprisingly, older observers
      were better than younger ones in identifying defocused (optically blurred) text
      in both daytime and nighttime conditions. In Experiment 2, older observers were
      also superior to younger ones in identifying defocused standard and spatially
      matched novel text signs. These findings indicate that older observers' tolerance
      of optical blur is a generic ability, rather than one explained by familiarity
      with the low-pass optical profile of specific signs. Consistent with the notion
      that factors beyond acuity contribute more importantly to text legibility for
      older than for younger observers, acuity was a stronger predictor of legibility
      thresholds in the younger group. Actual or potential applications of this
      research include the need to consider functional acuity in visual screening
      protocols and the design of text displays, as well as the utilization of
      compensatory letter-recognition training for older observers or others with
      diminished acuity.

PMID- 10665203
TI  - Modeling computer interest in older adults: the role of age, education, computer
      knowledge, and computer anxiety.
AB  - We proposed a mediation model to examine the effects of age, education, computer
      knowledge, and computer anxiety on computer interest in older adults. We
      hypothesized that computer knowledge and computer anxiety would fully mediate the
      effects of age and education on computer interest. A sample of 330 older adults
      from local senior-citizen apartment buildings completed a survey that included an
      assessment of the constructs included in the model. Using structural equation
      modeling, we found that the results supported the hypothesized mediation model.
      In particular, the effect of computer knowledge operated on computer interest
      through computer anxiety. The effect of age was not fully mitigated by the other
      model variables, indicating the need for future research that identifies and
      models other correlates of age and computer interest. The most immediate
      application of this research is the finding that a simple 3-item instrument can
      be used to assess computer interest in older populations. This will help
      professionals plan and implement computer services in public-access settings for
      older adults. An additional application of this research is the information it
      provides for training program designers.

PMID- 10665205
TI  - Effects of cueing and knowledge of results on workload and boredom in sustained
      attention.
AB  - Two models of recently reported high workload associated with vigilance tasks are
      the direct-cost and indirect-cost views. The former attributes high workload to
      the need for continuous observation in discriminating signals from neutral
      events; the latter attributes it to efforts to combat the boredom associated with
      monotonous vigilance tasks. These opposing views were tested by providing
      observers with reliable cueing, which rendered observation necessary only when
      low-probability critical signals were imminent, or with knowledge of results (KR)
      regarding performance efficiency. On the basis of cue and KR differences in
      elicited observation activity and motivational value, the direct-cost model led
      to the anticipation that cueing would result in a high-boredom, low-workload
      profile and a greater reduction in workload than KR. The indirect-cost model led
      to the prediction that cueing would result in a high-boredom, high-workload
      profile and a lesser reduction in workload than KR. The results clearly supported
      the direct-cost view that the workload of vigilance is task-induced.
      Consequently, efforts to combat high workload in complex automated systems
      requiring substantial monitoring by operators should focus specifically upon task
      related determinants.

PMID- 10665206
TI  - Regression models for predicting peak and continuous three-dimensional spinal
      loads during symmetric and asymmetric lifting tasks.
AB  - Most biomechanical assessments of spinal loading during industrial work have
      focused on estimating peak spinal compressive forces under static and sagittally
      symmetric conditions. The main objective of this study was to explore the
      potential of feasibly predicting three-dimensional (3D) spinal loading in
      industry from various combinations of trunk kinematics, kinetics, and subject
      load characteristics. The study used spinal loading, predicted by a validated
      electromyography-assisted model, from 11 male participants who performed a series
      of symmetric and asymmetric lifts. Three classes of models were developed: (a)
      models using workplace, subject, and trunk motion parameters as independent
      variables (kinematic models); (b) models using workplace, subject, and measured
      moments variables (kinetic models); and (c) models incorporating workplace,
      subject, trunk motion, and measured moments variables (combined models). The
      results showed that peak 3D spinal loading during symmetric and asymmetric
      lifting were predicted equally well using all three types of regression models.
      Continuous 3D loading was predicted best using the combined models. When the use
      of such models is infeasible, the kinematic models can provide adequate
      predictions. Finally, lateral shear forces (peak and continuous) were
      consistently underestimated using all three types of models. The study
      demonstrated the feasibility of predicting 3D loads on the spine under specific
      symmetric and asymmetric lifting tasks without the need for collecting EMG
      information. However, further validation and development of the models should be
      conducted to assess and extend their applicability to lifting conditions other
      than those presented in this study. Actual or potential applications of this
      research include exposure assessment in epidemiological studies, ergonomic
      intervention, and laboratory task assessment.

PMID- 10665207
TI  - Aging, motor control, and the performance of computer mouse tasks.
AB  - Because of the increased presence of computers in work and everyday life and the
      demographic "graying" of America, there is a need for interface designs that
      promote accessibility for older people. This study examined age differences in
      the performance of basic computer mouse control techniques. An additional goal of
      the study was to examine the influence of age-related changes in psychomotor
      abilities on mouse control. A total of 60 participants in 3 age groups (20-39
      years, 40-59 years, and 60-75 years) performed 4 target acquisition tasks
      (pointing, clicking, double-clicking, and dragging) using a computer mouse. The
      data indicated that the older participants had more difficulty performing mouse
      tasks than the younger participants. Differences in performance attributable to
      age were found for the more complex tasks (clicking and double-clicking).
      Furthermore, age-related changes in psychomotor abilities were related to age
      differences in performance. We discuss applications to computer interface
      designs. Actual or potential applications of this research include specifications
      for computer mouse design to accommodate older populations.

PMID- 10665208
TI  - Three studies testing the effects of role models on product users' safety
      behavior.
AB  - Three studies were conducted to determine the effect of a role model's safety
      behavior on observers' safety behavior. In Studies 1 and 2, role models
      (confederates) used a cleaning product requiring them to wear safety gloves.
      Study 1 examined observers' safety behavior after they witnessed a friendly
      (unfriendly) role model's safety behavior in one of four conditions: 1) wearing
      rubber gloves, 2) not wearing rubber gloves and experiencing no chemical burn, 3)
      not wearing rubber gloves and experiencing a mild chemical burn, and 4) not
      wearing rubber gloves and experiencing a severe chemical burn. In Study 2,
      participants tested a cleaning product with a warning message (low hazard vs.
      high hazard) after observing a role model first test the cleaning product in one
      of the four conditions specified above. As predicted, in Studies 1 and 2,
      observers were influenced by the role model's safety behavior. However, the
      friendliness of the role model (Study 1) and level of hazard (Study 2)
      communicated in the warning message did not influence participants' safety
      behavior. Using an over-the-counter pain reliever, Study 3 tested the joint
      effects of: 1) the level of hazard communicated in the warning, 2) observers'
      outcome-relevant involvement, and 3) role model's compliance. Although the level
      of hazard communicated in the warning exerted no impact on observers' safety
      compliance, the role model's safety behavior and level of involvement jointly
      influenced observers' safety behavior. The implications of the findings and
      future research directions are discussed. Actual or potential applications of the
      research include, but are not limited to, using role models in warning messages
      and safety training programs to demonstrate the proper use of safety gear so as
      to enhance product users' compliance with safety recommendations.

PMID- 10665209
TI  - Wrist and forearm postures of users of conventional computer keyboards.
AB  - The aim of this study was to perform a comprehensive investigation to document
      wrist and forearm postures of users of conventional computer keyboards. We
      instrumented 90 healthy, experienced clerical workers with electromechanical
      goniometers to measure wrist and forearm position and range of motion for both
      upper extremities while typing. For an alphabetic typing task, the left wrist
      showed significantly greater (p < .01) mean ulnar deviation (15.0 degrees +/- 7.7
      degrees) and extension (21.2 degrees +/- 8.8 degrees) than the right wrist (10.1
      degrees +/- 7.2 degrees and 17.0 degrees +/- 7.4 degrees for ulnar deviation and
      extension, respectively). Conversely, the right forearm had greater mean
      pronation (65.6 degrees +/- 8.3 degrees) than the left forearm (62.2 degrees +/-
      10.6 degrees). We noted minimal functional differences in the postures of the
      wrists and forearms between alphabetic and alphanumeric typing tasks. Ergonomists
      should consider the statistically significant and probable practical difference
      in wrist and forearm posture between the left and right hand in ergonomic
      interventions in the office and in the design of computer keyboards. Actual or
      potential applications of this research include guiding the design of new
      computer keyboards.

PMID- 10665210
TI  - Visual search of food nutrition labels.
AB  - Using an eye-tracking methodology, we evaluated food nutrition labels' ability to
      support rapid and accurate visual search for nutrition information. Participants
      (5 practiced label readers and 5 nonreaders) viewed 180 trials of nutrition
      labels on a computer, finding answers to questions (e.g., serving size). Label
      manipulations included several alternative line arrangements, location of the
      question target item, and label size. Dependent measures included search time and
      number of fixations prior to visually capturing the target, as well as the
      accuracy and duration of the capturing fixation. Practiced label readers acquired
      the target more quickly and accurately than did less-practiced readers. Targets
      near the denser center of the label required 33% more time and were harder to
      find than targets at the top or bottom of the label. Thinner alignment lines were
      more influential than thicker anchoring lines on visual search time. Overall, the
      current nutrition label supported accurate and rapid search for desired
      information. Potential applications of the present methodology include the
      evaluation of warning labels and other static visual displays.

PMID- 10665211
TI  - Perceptual ability with real-world nighttime scenes: image-intensified, infrared,
      and fused-color imagery.
AB  - We investigated human perceptual performance allowed by relatively impoverished
      information conveyed in nighttime natural scenes. We used images of nighttime
      outdoor scenes rendered in image-intensified low-light visible (i2) sensors,
      thermal infrared (ir) sensors, and an i2/ir fusion technique with information
      added. We found that nighttime imagery provides adequate low-level image
      information for effective perceptual organization on a classification task, but
      that performance for exemplars within a given object category is dependent on the
      image type. Overall performance was best with the false-color fused images. This
      is consistent with the suggestion in the literature that color plays a
      predominate role in perceptual grouping and segmenting of objects in a scene and
      supports the suggestion that the addition of color in complex achromatic scenes
      aids the perceptual organization required for visual search. In the present
      study, we address the issue of assessment of perceptual performance with
      alternative night-vision sensors and fusion methods and begin to characterize
      perceptual organization abilities permitted by the information in relatively
      impoverished images of complex scenes. Applications of this research include
      improving night vision, medical, and other devices that use alternative sensors
      or degraded imagery.

PMID- 10665212
TI  - Effects of head-slaved and peripheral displays on lane-keeping performance and
      spatial orientation.
AB  - To improve the efficiency of images presented in low-cost vehicle simulators, the
      virtual viewing direction (i.e., the direction in which the image is rendered)
      can be head-slaved, the display can be surrounded with a less detailed peripheral
      image, or both. Three simulator experiments were used to evaluate the effect of
      these techniques on lane-keeping performance and spatial orientation. In
      Experiment 1, vehicle references or a head-slaved display (HSD) provided feedback
      on the virtual viewing direction. Vehicle references improved lane-keeping
      performance somewhat with a standard 50 degrees h x 50 degrees v display. An HSD
      (50 degrees h x 50 degrees v) allowed better steering performance, but not to the
      levels obtained with a wide display (150 degrees h x 50 degrees v). Experiments
      2a and 2b evaluated the effects of surrounding the HSD with a less detailed
      peripheral image and of moving the HSD discretely or continuously. With the
      peripheral image, lane-keeping performance (Experiment 2a) and spatial
      orientation (Experiment 2b) were similar to those with a wide display. In both
      experiments, performance with the discretely moving HSD was superior to that with
      the continuously moving HSD. The results show that low-cost driving simulators
      can be equipped with more efficient displays that are as effective as wide
      displays for lane-keeping and spatial orientation.

PMID- 10665213
TI  - Rehearsal versus map study as preparation for a flight navigation exercise.
AB  - A flight simulator and a computer-generated depiction of an environment with both
      natural and cultural features were used to teach and test navigation knowledge.
      Conditions of guided rehearsal, unguided rehearsal, and map study were used to
      familiarize participants with the navigation environment. A subsequent route
      following test of navigation knowledge in the simulated environment showed that
      unguided rehearsal was better than map study or guided rehearsal for the
      development of route knowledge. In addition, a pointing task revealed that
      unguided mission rehearsal was as good as map study for the development of survey
      knowledge. Actual or potential applications of this research include the use of
      simulator-based mission rehearsal for military flight operations.

PMID- 10665214
TI  - Target-directed head movements in a head-coupled virtual environment: predicting
      the effects of lags using Fitts' law.
AB  - Two experiments have investigated the effects of lag on discrete target-directed
      head movements in a virtual environment. Both the target and a head-slaved
      pointer (subjected to lag) were presented on a head-mounted display. Target
      directed head movements in the presence of a constant time lag were shown to obey
      Fitts' law (R2 > .93). A previously reported interaction between the effects of
      lag and the effects of index-of-difficulty on hand movement time could not be
      found in head movement time when the target width was kept constant. Further
      experiments suggested that there is a significant interaction between the effects
      of target width and lag but not between target distance and lag. A model
      predicting head movement strategy in the presence of lag is proposed to explain
      the experimental findings. This model predicts, and experiments verified, that
      for a target width from 1 degree to 8 degrees and a target distance range of 2.5
      degrees to 30 degrees, the effect of lag (up to 267 ms) on target-directed head
      movement is independent of target distance but dependent on target width. Actual
      or potential applications of this research include the design of virtual control
      panel and its layout in a Virtual Reality simulator.

PMID- 10665215
TI  - Effectiveness of an intervention to increase construction workers' use of hearing
      protection.
AB  - In this project we tested the effectiveness of a theory-based intervention
      (video, pamphlets, and guided practice session) to increase the use of hearing
      protection devices (HPDs) among Midwestern construction workers and a national
      group of plumber/pipefitter trainers. Posttest measures were collected 10-12
      months following this intervention. Pender's Health Promotion Model (1987)
      provided the conceptual basis for development of the training program. A total of
      837 high-noise-exposed workers were included in the analysis: 652 regional
      Midwestern construction workers and 185 national plumber/pipefitter trainers.
      Effectiveness of the intervention was determined through the sequence of analyses
      recommended by Braver and Braver (1988) for the Solomon Four-Group Design.
      Analysis of variance and covariance of postintervention use and intention to use
      HPDs and a meta-analytic test were done. These analyses indicated that the
      intervention significantly increased use of HPDs but had no effect on intention
      to use HPDs in the future. Pretesting had no effect on use. Actual or potential
      applications of this research include guidance in the development of successful
      theory-based interventions to increase use of HPDs.

PMID- 10665216
TI  - Distance estimation with night vision goggles: a little feedback goes a long way.
AB  - Immediate feedback was given to correct observers' estimates of distance in an
      experiment in which those estimates were made outdoors at night while observers
      wore night vision goggles (NVGs). Initially observers made unguided estimates of
      distances between marked positions in an open field. Those distances ranged from
      7.6 m (25 ft) to 64 m (210 ft). Later the same observers made more estimates.
      After each of these they were told the measured distance between the positions.
      During this training, the observers' height from the ground plane was either at a
      standing position or at an elevated position raised 2.3 m (7 ft 7 in) from
      standing position. After the training--either immediately after, a week later, or
      at both times--observers made unguided estimates of distance for a second time.
      These latter estimates of ground distance made with the NVGs were improved.
      Average improvement of the observers' estimates persisted for at least one week
      after training. This training can be applied to improve clearance estimates and
      estimates of hover height for pilots of rotary-wing aircraft.

PMID- 10665217
TI  - Critique of "distance estimation with night vision goggles: a little feedback
      goes a long way"
AB  - The authors addressed a topic that has practical importance and that deserves
      further study. They raised interesting questions about distance estimates, and
      extended results obtained with unaided vision to performance with NVGs. In this
      critique, several issues were raised in an attempt to foster an informative
      scholarly exchange.

PMID- 10665218
TI  - The art of descrying distance.
AB  - How naive can one experiment be? Imagine asking observers to judge distance --
      yes, literally asking them. And in asking them, no visual evoked potentials were
      measured, and changes in blood flow to the occipital cortex were ignored. But
      serendipity occurs even to the well-prepared: One's best thought for a new
      experiment can prove to be one's first unbiased, uncomplicated thought.Here's a
      cursory review of the events: A number of observers were asked to judge distances
      between marked posts in a field at night. They made their judgments with the help
      of night vision goggles (NVG). At first the observers underestimated the
      distances on average. Then an experimenter began to correct the observers after
      each judgment. The observers' judgments of distance became accurate. On average,
      the observers began to estimate those distances accurately. Is this and
      incredible story or a difficult one?

PMID- 10665219
TI  - [Molecular cloning of one splicing form of human M6b cDNA].
AB  - X-linked, early onset Pelizaeus-Merzbacher disease (PMD) and part of X-linked
      spastic paraplegia are caused by mutation of proteolipid protein. M6b (U45955)
      partially cloned by Olinsky was considered as a member of PLP gene family. One
      novel fragment about 300 bp partially overlapped but differed in 5'part with
      U45955 was obtained by nested PCR. Assembly of the novel sequence with U45955
      make a 1.642kb cDNA sequence with an open reading frame encoding 265 amino acids,
      which was verified by sequence of PCR products from brain cDNA library. The cDNA
      (termed M6ba) and its deduced peptide sequence showed significant similarity to
      murine M6b gene and protein (91.2% and 93.4% respectively). Northern blot, PCR
      amplification in cDNA library and EST analysis indicated that human M6b gene has
      at least three splicing forms. M6ba also showed significant similarity to PLP
      gene, they encode strongly hydrophobic protein and all their hydrophobic region
      are highly conserved. Gene structure analysis showed that the coding region of
      M6ba was composed of seven exons.

PMID- 10665220
TI  - [HLA-DRB alleles polymorphism in Han, Hui, Uygur and Tibetan populations in
      northwestern China].
AB  - According to the 11th THW standard, we designed a pair of primers by which a
      segment of 256bp of HLA-DRB1, B3, B4, and B5 could be amplified simultaneously.
      Twenty-seven oligonucleotide probes were designed and synthesized for 39 loci on
      DRB1, 3 on DRB3, 1 on DRB4 and 3 on DRB5. A PCR-SSO DNA typing protocol was
      built, which met the standard of HLA class II DNA typing in 11th IHW. With this
      method, 186 of Chinese (Han) in Xi'an, 169 of Hui in Ningxia, 200 of Uygur in
      Xinjiang, and 188 of Tibetan in Tibet were detected with a comparison study. The
      genetic distribution of 46 loci of DRB in four ethnic healthy populations were
      surveyed. No diversity has been found between Han and Hui in DRB. DRB1 *
      02(16.9%), DRB1 * 07 (13.1%), and DRB1 * 09(12.0%) were the higher frequent loci
      in Han. More DRB loci were detected in Tibetan but without higher loci as in Han
      and Hui. The DRB polymorphism of Uygur population was similar to Caucasian. A
      discriminative highest frequency of DRB1 * 07(23.8%) was found in Uygur, which
      implied a selection happened.

PMID- 10665221
TI  - [Detection of numerical chromosomal aberrations in epididymal sperm of mice using
      three-color FISH with chromosome-specific DNA probes].
AB  - To detect malsegregation of chromosomes during meiosis in male mice, three-color
      FISH using DNA probes specific for mouse chromosomes X, Y and 8 was performed on
      epididymal sperm decondensed for 30 min each in 10 mmol/L DTT and 4 mmol/L LIS,
      and conventional chromosome counting was also carried out on C-banded MMII cells.
      Comparisons between these two methods indicate as the following: (1) three-color
      FISH is a simple, rapid and sensitive approach; (2) The estimate of the frequency
      of aneuploidy obtained from three-color FISH analysis is more reliable since
      extremely large numbers of sperm (more than 10,000 sperm per animal) are scored;
      (3) The rates of cells arrested at meiosis I and meiosis II (representing diploid
      sperm) can be detected only by using the three-color FISH approach; (4)
      Malsegregation of chromosomes occurred during both meiosis I and meiosis II can
      be detected simultaneously by using this new approach. The probes and scoring
      criteria used in FISH on interphase sperm nuclei, and the necessity of using
      three or more chromosome-specific DNA probes to thoroughly evaluate aneugenic
      effects of factors tested on meiosis in male mice were discussed.

PMID- 10665222
TI  - [Establishment of a high germline competent C57BL/6J ES cell line].
AB  - Eleven ES cell lines from C57BL/6J mice were established, with the primary
      culture of mice embryos as feeder cells and 1 x 10(3) units Leukemia Inhibitory
      Factor (LIF) in the DMEM (high glucose) medium. The frequency of establishment
      was 9.6%. Five of these ES cell lines were demonstrated karyotypically normal
      with diploid composition of over 70%. They shared the characteristics of early
      embryonic cells: positive for alkaline phosphatase activity and oct4 gene
      expression. They also showed high potency to differentiate into wide types of
      cells in vivo. Following injection of the blastocysts, three of them showed
      abilities to give rise to chimeras and MESPU35 cell line was identified to have
      high efficiency of colonization into the germline. The clones of MESPU35 cells
      maintained the germline competence and the mutant clone also retained the high
      potency to participate into the development of embryos. MESPU35 cells can serve
      as a valuable vehicle for the production of mutant mice.

PMID- 10665223
TI  - [Chromosome homologies between human and Francois' monkey (Semnopithecus
      francoisi) established by chromosome painting].
AB  - Chromosomal homologies were established between human and Francois' monkey
      (Semnopithecus francoisi, 2n = 44) by chromosome painting with chromosome
      specific DNA probes of all human chromosomes except the Y. Except for human
      chromosome 1, 2, 6, 16 and 19 probes which gave signals on two nonhomologous S.
      francoisi chromosomes respectively, all other probes each hybridized to a single
      chromosome. Only two S. francoisi chromosomes (No. 12 and No. 21) were each
      labelled by two separate probes (14 and 15, 21 and 22, respectively). In total,
      23 human chromosome-specific probed detected 30 homologous chromosomes and
      chromosomal segments in the haploid S. francoisi genome. The results indicated a
      high degree of conservation of chromosomal synteny between human and this langur.
      Only some chromosomal rearrangements occurred in this langur. Comparison of the
      hybridization patterns of human painting probes on this langur with the data on
      other primates suggested that Asian langurs were karyotypically more closely
      related to each other than to African langurs.

PMID- 10665224
TI  - [RAPD analysis of genetic diversity and phylogenetic relationship of the Taihu
      pigs].
AB  - The genetic diversity and phylogenetic relationship of the Taihu pigs were
      studied using RAPD technique. A total of 57 individuals were used, and the
      phylogenetic tree was reconstructed using UPGMA method based on 198 RAPD markers
      which were amplified with 13 decamer primers. The results indicate as the
      following: (1) The similarity indexes within each strain and between the strains
      of the Taihu pigs are all high. The average genetic distance between the strains
      is 0.052. These results indicate that the Taihu pigs exhibit relatively low level
      of genetic variation and poor genetic diversity; (2) The Hongdenglong pig is also
      a strain of the Taihu pigs; (3) The Taihu pigs have close phylogenetic
      relationship with the Chinese wild boar occurred in the Taihu Lake area; (4) Two
      lineages diverged in the early stage during the course of the formation of the
      Taihu pigs. One of the lineage gave rise to the strains of Mizhu, Erhualian,
      Jiaxinhei and Hongdenglong, another lineage gave rise to the strains of Shawutou,
      Meishan, Fengjing and Hengjing. The strategy for genetic diversity conservation
      of the Taihu pigs was discussed.

PMID- 10665225
TI  - [Mitochondrial DNA length variation and heteroplasmy in Chinese sturgeon
      (Acipenser sinensis)].
AB  - The D-loop of mitochondrial DNA from Chinese sturgeon (Acipenser sinensis) was
      amplified using PCR. The length variations among individuals and within
      individual (heteroplasmy) were detected. DNA sequence analysis revealed that
      interindivadual and intraindividual length variation occurred within D-loop near
      tRNA(pro), and caused by tandam repeat with 82 bp in length. Out of 47
      individuals, 27(57.4%) individuals were heteroplasmy whereas 20 individual
      (42.6%) were homoplasmic. The length variation was also found among homoplasmic
      individuals. In homoplasmic individual four different size classes (number of
      tandem repeats) e.g. 2, 3, 4 or 5 repeats were noted. The frequencies of size
      classes from the highest to the lowest were 3-->2-->4-->5. In heteroplasmy two
      molecular size classes coexisted in an individual was most common (77.78%). The
      second type of heteroplasmy was three size classes coexisted (18.52%) and the
      lowest one was four size classes together in an individual (3.70%). No five
      different size classes coexisted in an individual was found. Through densitometry
      of DNA bands the frequencies of mtDNA size classes were determined for the sample
      of individuals, and the frequency distribution of repeats from the highest to the
      lowest was similar to that in homoplasmy (3-->2-->4-->5-->1). The diversity
      within each heteroplasmic individual was carried out and genetic diversity at
      hierarchical level was analyzed. 65.3% of genetic diversities were from among
      individuals in population and 34.7% of genetic diversities were from within
      individual. The mtDNA length variation within individual (heteroplasmy) is
      another genetic diversity resource for Chinese sturgeon.

PMID- 10665226
TI  - [A study of genetic character and foreign OMT/PGH gene integration in transgenic
      swine].
AB  - By using isotopic and non-isotopic in situ hybridization on chromosomes, the
      locus on chromosomes of foreign OMT/PGH gene was analyzed in eight transgenic
      pigs (G0, G1,G2 and G3). The research result is as follows: (1) The foreign genes
      could integrated on chromosomes of pig and the foreign integrated randomly; (2)
      the foreign genes integrated on chromosomes were transmissible through
      generations; (3) the locus on chromosomes of foreign gene was relatively stable
      in alternation of generations in transgenic swine.

PMID- 10665227
TI  - [Effects of the interaction between histone and hAMFR gene promoter on the
      transcription activity in vitro].
AB  - The effects of interaction between histones and human autocrine motility factor
      receptor (hAMFR) gene promoter on the transcription activity in vitro was
      investigated by using histones purified from chicken erythrocytes, HeLa cell
      nuclear extracts and heat-treated supernatants of Xenopus eggs. The results
      showed that the competitive binding of histones and transcription factors at the
      promoter of hAMFR gene was very important to the transcription in vitro. If a pre
      initiation complex was formed with HeLa cell nuclear extracts on the promoter
      prior to nucleosome assembly, it would prevent nucleosome-mediated transcription
      repression. When the nucleosome was assembled on the promoter in advance, the
      transcription activity could be repressed. When histones and HeLa cell nuclear
      extracts were mixed in the reaction simultaneously, the transcription activity
      would depend on the relative amount of histones to that of HeLa cell nuclear
      extracts.

PMID- 10665228
TI  - [A preliminary study of developmental genetics of polymorphic serum esterase in
      domestic fowls].
AB  - Polymorphism of serum esterase was examined in 3 Super-Y 2000 broiler breeding
      populations differing in developmental stages (i.e. day 120, 180 and 300) using
      vertical polyacrylamide gel electrophoresis. The results indicated that both Es-1
      and Es-2 loci exhibited polymorphism. Two to three polymorphic enzyme bands were
      detected at zone Es-1, and one band at zone Es-2 after electrophoresis. It was
      first discovered in this work that obvious developmental difference in products
      of Es-1 alleles existed with female birds, polymorphic bands of which disappeared
      after onset of lay. An individual tracing experiment conducted in a Super-Y 380
      commercial layer population and an extensive experiment carried out in 2 ISA B380
      parent CD stocks supported the previous finding. It could thus be inferred that
      phenotype "O" (no band at Es-1) discovered in hens was not genetically controlled
      by the recessive allele Es-1(0), which itself did not exist, but might be an
      evidence of gene regulation at laying period. For female birds, expression of Es
      1 alleles was active before sexual maturity, and depressed after onset of lay, to
      meet their physiological need of high level of blood esterase for laying. It
      could also be inferred that this developmental difference in serum esterase
      polymorphism might be a common phenomenon in all avian species. If this
      hypothesis were true, the synthesis of esterase inside avian bodies could be a
      desirable model for investigating expression, and regulation of expression, of
      genes in avian populations.

PMID- 10665229
TI  - [Western blotting of RStV gene products in rice and insects].
AB  - The NS3 and NC protein genes encoded by RNA3 of RStV, the NCP and NSvc4 protein
      genes encoded by RNA4 were subcloned into the E. coli expression vector pGEX3X to
      express four groups of fusion protein under IPTG induction. These fusion proteins
      were used to immunize rabbits to raise antisera. The antisera against the E. coli
      expressed proteins were available for probing the presence of the viral gene
      products in both rice plant and insect hosts. The expected gene products can be
      probed only in diseased rice plant with NCP antiserum and the corresponding
      products detected in both plant and RStV particle preparation with NC antiserum.
      The viral gene products probed by NS3 and NSvc4 antisera were different from the
      expected ones in size.

PMID- 10665231
TI  - The viscous attack of the cell phones on civilization.

PMID- 10665230
TI  - [Cloning and sequence analysis of ATCase genes from Psychrophilic vibrio].
AB  - The gene encoding for aspartate transcarbamoylase (ATCase) from Psychrophilic
      vibrio, strain 2693 was cloned and sequenced. The sequence revealed the existence
      of two gene encoding respectively for a catalytic chain (pyrB) and a regulatory
      chain (pyr I). The catalytic and regulatory polypeptide chains of Vibrio 2693
      ATCase are encoded by a single pyrBI bicistronic operon, and appear to be
      transcribed under the control of the same promoter. The 3'-terminus of the
      catalytic cistron (pyrB) is adjacent to the 5'-terminus of the regulatory
      cistron, these is only a 4 bp space between the two coding regions.

PMID- 10665233
TI  - Preserving freedom in a changing world.

PMID- 10665232
TI  - To promote excellence, ethics, and professionalism in dentistry.

PMID- 10665234
TI  - Planning a scientific session.
AB  - A long-time member of the California Dental Association Council on Scientific
      Sessions explains what goes into planning the educational program at a major
      scientific meeting--from the selection of speakers to on-site arrangements and
      the role of staff.

PMID- 10665235
TI  - Continuing education--move on or move out.
AB  - One of the members of a new group of continuing education providers argues that
      the kind of learning dentists are interested in is what patients want and what
      dentists did not learn in dental school. The dual developments of new
      alternatives in dentistry and Baby Boomers with an appetite for appearance and
      money to pay for it explain why courses in aesthetic dentistry, tooth whitening,
      orthodontics, high-tech, and innovative marketing are so popular.

PMID- 10665236
TI  - The Academy of General Dentistry's ongoing charge for quality dental education.
AB  - The core competency statement of the Academy of General Dentistry is "Quality of
      care through lifelong learning". This article traces the history of the Academy
      from its founding in 1952 through the development of its programs in Fellowships
      and Masterships, the Fellowship Exam, the American Board of General Dentistry,
      the National Sponsor Approval Program, and its recent efforts to reaffirm and
      sharpen its mission.

PMID- 10665237
TI  - Where the rubber meets the road: contributions to dentistry from its
      practitioners.
AB  - While much is made of dentists as consumers of the innovations in dentistry
      through continuing education, a strong case can be made for practitioners as the
      creators of this new knowledge. From the mechanized drill, rubber dam, and
      fluoridated water to compressed air, the reclining chair, and four-handed
      dentistry, practicing dentists are responsible for many of the profession's most
      important innovations.

PMID- 10665238
TI  - Dental economics: a non-subscription dental journal.
AB  - The editor of a non-subscription publication for dentists explains the advantages
      of having a journal whose contents are driven by advertising revenue unrelated to
      products or services mentioned in the journal and free from political influence
      as well. The drive on the publication is reader interest rather than author or
      publisher philosophy, and surveys and other methods are used to stay close to the
      issues practicing dentists are interested in.

PMID- 10665239
TI  - Continued formal dental education or I would like more.
AB  - Statistics are presented on recent trends in postdoctoral dental education. While
      enrollment in specialty and general practice residency programs has remained
      constant, interest in Advanced Education in General Dentistry programs has
      increased.

PMID- 10665240
TI  - Credibility.
AB  - The believability of a message is grounded in almost everything except the
      content of the message--there is no self-warranted truth. Credibility is based on
      the believer's assessment of the form of the message, its source, and especially
      by triangulation with a reference point. The most common group of reference
      points are compatibility, authority, collegiality, and performance.

PMID- 10665242
TI  - Back to the basic sciences!

PMID- 10665241
TI  - American pharmacy's first great transformation: practice, 1852-1902.

PMID- 10665243
TI  - Building a pharmacy work force mosaic: new studies help to fill in the gaps.

PMID- 10665244
TI  - Medicare drug benefit--an opportunity for change.

PMID- 10665245
TI  - Characterizing pharmacy part-time practice.
AB  - OBJECTIVES: (1) To characterize pharmacists who work part-time and compare them
      with pharmacists who work a secondary part-time job (moonlighters) with respect
      to their motivations for working in a part-time job, and (2) to identify the set
      of characteristics that best describes pharmacists engaged in each of the part
      time work arrangements under study. DESIGN: A five-page questionnaire was mailed
      to 3,002 licensed pharmacists nationwide. Two follow-up surveys were sent to
      nonrespondents at the fifth and ninth weeks from the original mailout to ensure
      an adequate response rate. RESULTS: The net response rate was 57% (n = 1,637).
      Assessment of the sample did not detect any potential nonresponse bias. Sixty
      eight percent of the respondents reported working full time, 13% were
      moonlighters, 14% were part-timers, and 5% were part-timers in more than one job.
      Reasons for working part-time were analyzed for the moonlighter and part-timer
      subsamples. A principal components analysis revealed that both groups have
      distinct motivations for selecting their chosen work arrangement. CONCLUSION:
      This study provides some insight into those factors affecting pharmacists'
      decisions to engage in two different types of part-time work. Since pharmacists'
      alternative work schedules can have repercussions on the quality of pharmacy
      being practiced, further research on pharmacists' work arrangement choices should
      provide useful information for work force-related endeavors.

PMID- 10665246
TI  - Trends in full-time pharmacists' labor market characteristics.
AB  - OBJECTIVE: To provide a historical overview of the pharmacy profession for the
      past 30 years, using trends in full-time pharmacists' labor market
      characteristics. METHODS: A retrospective longitudinal sample of pharmacists from
      1968 to 1996 was constructed from the March Current Population Survey data. A
      three-period centered moving average method was used to describe the labor market
      trends over time. Pharmacists' labor market was characterized by age, sex, race,
      education, geographic distribution, salary, working hours, and wage. RESULTS: The
      dominant age group among full-time pharmacists was 36-45 in the late 1960s and
      early 1970s, 26-35 between the mid-1970's and early 1990's, and 36-45 in the mid
      1990's. Historically, a significant proportion of full-time pharmacists were
      white men, holding bachelor's degrees. The number of pharmacists has been highest
      in the South and lowest in the West. In general, pharmacists' annual salary and
      wage rates have grown steadily, whereas average hours worked per week have
      decreased from 50 hours to less than 45. CONCLUSION: Findings suggest a growing
      trend of three demographic groups: aged 36-45, women, and nonwhite. In addition,
      an increasing proportion of pharmacists holding "higher than bachelor" degrees
      was observed. The distribution of pharmacists was highest in the South and lowest
      in the West. The Midwest has the highest pharmacist/population ratio, the South
      the lowest. On average, full-time pharmacists in the 1990s work 40-45 hours per
      week, have an annual salary higher than $55,000 (in 1996 dollars), and an hourly
      wage rate above $25.

PMID- 10665247
TI  - Patients' perceptions of the benefits of pharmaceutical care.
AB  - OBJECTIVE: To investigate patients' perceptions of the benefits of regular
      participation in pharmaceutical care services. DESIGN: Written survey of a
      convenience sample. SETTING: Pharmacist-run anticoagulation clinic in a Veterans
      Administration Medical Center. PATIENTS: 154 patients who had regularly scheduled
      appointments in the clinic. INTERVENTIONS: Patients were asked to complete a
      written survey. The survey was read to those who had trouble reading it. MAIN
      OUTCOME MEASURES: Patients' perceptions about the benefit of services provided in
      the clinic and the relationship between those services and reduced risks of
      medication-related problems. RESULTS: All components of anticoagulant-related
      pharmaceutical care were rated as at least fairly beneficial. Monitoring of
      warfarin blood levels and information on the appropriate use of warfarin were
      rated highest. The perceived benefits of the pharmaceutical care components were
      associated with patients' perceptions of the extent to which pharmaceutical care
      reduced their risk of experiencing blood clots or warfarin-related problems.
      Patients also perceived that their risk of developing blood clots or bleeding
      problems would be higher if they did not regularly visit the anticoagulation
      clinic. CONCLUSION: Patients' perceptions of the benefits of pharmaceutical care
      were associated with the perceived threat reduction capacity of the pharmacist's
      services. Pharmaceutical care providers may be able to enhance patient
      participation in their services by educating patients on the risks of medication
      related problems and how frequent monitoring of key clinical indicators may help
      reduce those risks.

PMID- 10665248
TI  - Intervention assessment in an Indian health service pharmacy.
AB  - OBJECTIVE: To document and evaluate pharmacists' interventions in a setting that
      has complete and immediate access to patient information. DESIGN: Descriptive
      report evaluating self-reported interventions made by pharmacists during the
      conduct of routine dispensing activities. The data collection period was from
      February 15 to April 1, 1994. SETTING: Ambulatory care facility offering medical
      and dental care to high school residents, Native Americans, and Alaska Natives in
      Northwestern Oregon. MAIN OUTCOME MEASURES: Intervention rate per 100 new
      prescriptions dispensed. Each intervention was evaluated with regard to the
      information used to initiate it, when during the dispensing process it was
      initiated, and the intervention type. Outside evaluators determined the clinical
      significance of the interventions, including potential adverse health
      consequences, the likelihood of their occurrence, and the level of medical care
      that would have been required to treat the problem. RESULTS: Of 2,535 orders
      screened, 104 interventions (4.1%) were collected; 71% of these occurred during
      chart screening. Pharmacists most often used the medication order itself (60.6%)
      to detect prescribing problems, followed by other records in the patient's chart
      (29.8%). Outside evaluators identified 47.1% of the 104 interventions as
      clinically significant. The most common adverse health consequence prevented was
      inadequate control of the patient's condition. Outside evaluators also found that
      the most common level of corrective care that would have been needed if the
      intervention had not occurred, was a scheduled physician office visit (59.2%).
      CONCLUSION: This information suggests that pharmacists who have access to patient
      information may intervene at higher rates and that more of their interventions
      may be deemed clinically significant. However, larger, double-blinded, case
      controlled studies are needed to definitively draw these conclusions.

PMID- 10665249
TI  - Evaluation of macroaggregated albumin particle sizes for use in pulmonary shunt
      patient studies.
AB  - OBJECTIVE: To assess commercial macroaggregated albumin (MAA) reagent kits for
      compliance with particle-size parameters needed for proper clinical evaluation of
      pulmonary shunts (right-to-left). DESIGN: Comparative trial. SETTING: Nuclear
      pharmacy (laboratory setting). PATIENTS AND OTHER PARTICIPANTS: Not applicable.
      INTERVENTIONS: Minimally, 90% of the particles contained within an MAA reagent
      kit should be within the 10 to 90 microns range with minimal variation in
      particle size distribution and as few small particles (i.e., < 10 microns) as
      possible. Five separate vials from five commercial brands of MAA reagent kits
      were obtained, and 500 to 517 particles were analyzed for each sample. An
      additional study was performed on one of the MAA reagent kit brands, using five
      vials from each of five different lot numbers to determine the variability
      between lots. MAIN OUTCOME MEASURES: Long axis (maximum, micron), short axis
      (minimum, micron), and the area (micron 2) of each MAA particle. RESULTS: One MAA
      brand had the lowest percentage of unacceptable MAA particle sizes and maintained
      consistent particle sizes between vials. However, the same MAA reagent kit brand
      showed that only two of five lots had a low percentage of MAA particle sizes
      below the 10-micron limit. CONCLUSION: Particle sizes varied among the five
      different brands of MAA reagent kits, as did different lots of the best
      performing kit. This variability in particle sizes may affect the accuracy and
      reproducibility of pulmonary shunt patient studies.

PMID- 10665250
TI  - Evaluation of omeprazole, lansoprazole, pantoprazole, and rabeprazole in the
      treatment of acid-related diseases.
AB  - OBJECTIVE: To review the comparative efficacy and safety of the proton pump
      inhibitors (PPIs)--omeprazole, lansoprazole, pantoprazole, and rabeprazole--in
      the management of acid-related diseases. DATA SOURCES: English-language journal
      articles retrieved from a MEDLINE search from 1990 to the present using these
      index terms: proton pump inhibitors, omeprazole, lansoprazole, pantoprazole,
      rebeprazole, and each of the acid-related diseases. STUDY SELECTION: Clinical
      trials and pertinent review articles that discussed the pharmacology,
      pharmacokinetics, efficacy, and safety of PPIs in the management of acid-related
      disease. DATA EXTRACTION: By the authors. DATA SYNTHESIS: PPIs are substituted
      benzimidazoles that inhibit gastric acid secretion by covalently binding to the
      proton pump (H+/K+ ATPase). All undergo extensive hepatic metabolism and
      conjugation. The four agents differ in their metabolism by and effects on
      specific hepatic enzymes and thus in their ability to interact with other
      medications. PPIs are important agents used for eradicating Helicobacter pylori,
      in treating peptic ulcer disease, gastroesophageal reflux disease, Zollinger
      Ellison syndrome, and upper gastrointestinal bleeding, and for preventing acid
      aspiration. Short-term side effects of the four agents are similar. The long-term
      safety of pantoprazole and rabeprazole appears similar to that of omeprazole and
      lansoprazole. Pantoprazole, which is in the final stages of approval for
      marketing in the United States, will be available in both an oral and injectable
      formulation. CONCLUSION: Based on superior efficacy profiles, PPIs are the drugs
      of choice in managing patients with peptic ulcer disease, gastroesophageal reflux
      disease, and Zollinger-Ellison syndrome. The decision to select one PPI versus
      another is most likely to be based on the agents' acquisition costs,
      formulations, FDA-labeled indications, and overall safety profiles. Intravenous
      or parenteral pantoprazole may become the preferred antisecretory agent for
      patients unable to take oral medications (e.g., critically ill patients and those
      with Zollinger-Ellison syndrome).

PMID- 10665251
TI  - The American Pharmaceutical Association: a lens for viewing pharmacists (from
      compounders to therapeutic judges).
AB  - OBJECTIVE: (1) To document the changes that have occurred in pharmacy in the last
      century and (2) to investigate the role played by the American Pharmaceutical
      Association (APhA) during the changes. DATA SOURCES: Journal of the American
      Pharmaceutical Association (JAPhA). STUDY SELECTION: Sample articles published in
      JAPhA pertaining to practice and ethical issues. DATA EXTRACTION: Examples of
      articles at 10-year intervals from 1912 through 1997. DATA SYNTHESIS: Short
      reviews of the articles are included containing their purpose and topic. Authors'
      notes are included where appropriate. The research was performed using a
      qualitative/historical method. CONCLUSION: The changes that have occurred in
      pharmacy throughout the 20th century are seen through JAPhA. APhA has been a
      stabilizing social structure over the years, and continues to serve society in
      this manner.

PMID- 10665252
TI  - Interpersonal perception: a theory and method for studying pharmacists' and
      patients' views of pharmaceutical care.
AB  - OBJECTIVES: To identify the congruency between pharmacists' and their patients'
      perceptions of the benefits of services a pharmacist would provide if practicing
      according to the pharmaceutical care model, and to characterize the relationship
      between the congruency of their perceptions and the extent to which each reports
      that such services are provided. DESIGN: This study employed the interpersonal
      perception method, a communication theory and tool through which two people's
      perceptions are compared to assess their agreement with and understanding of one
      another regarding a particular issue. SETTING AND PARTICIPANTS: Six independent
      community pharmacies participated in a written survey of perceptions of
      pharmaceutical care. Questionnaires were distributed to 100 adult patients from
      each store. Pharmacists completed a self-report of the pharmaceutical care
      services provided to their patients; patients were asked whether they received
      such services. MAIN OUTCOME MEASURES: Pharmacists' and patients' perceptions of
      pharmaceutical care; pharmacists' and patients' reports of pharmaceutical care
      activities. RESULTS: Pharmacists and patients were found to disagree on the
      potential benefits of pharmaceutical care services. Pharmacists tended not to
      understand their patients' perceptions. The differences were not found to be
      related to the level of pharmaceutical care reportedly provided. CONCLUSION: The
      extent to which pharmacists' and patients' perceptions serve as barriers to the
      provision of pharmaceutical care is yet unknown. This study shows that
      differences in these perceptions exist and may perpetuate both patients'
      traditional perceptions of dispensing activities in the community pharmacy and
      pharmacists' perceptions of lack of patient interest in pharmaceutical care.

PMID- 10665253
TI  - Peer-Led Alcohol Education program: a pharmacy student-led program for seventh
      graders.
AB  - OBJECTIVE: To delay or discourage the use of alcohol by seventh-grade students
      through peer-led education. Peer-Led Alcohol Education (PLAE) program objectives
      were to: (1) educate students about alcohol use and (2) assess the differences
      between pharmacy student presenters and high school student (peer) presenters.
      SETTING: Middle schools in rural Nebraska. DESIGN: PLAE focuses on normative
      beliefs, personal values, and pledging. Pharmacy students and high school
      students were trained to deliver alcohol education presentations to seventh-grade
      students. Evaluation results were compared among groups of seventh-grade students
      who received PLAE presentations from peer presenters and from pharmacy student
      presenters. RESULTS: PLAE presentations were made to 342 seventh-grade students
      at 11 schools. Evaluation results suggest that pharmacy students projected more
      confidence in their presentations, used more creative prop selections, and were
      more effective communicators. High-school presenters had a greater ability to
      "relate" to the seventh-graders and thus were deemed more on-target with the
      information. CONCLUSION: Evaluation findings suggest that rural seventh-grade
      students in Nebraska perceived that the PLAE program provides useful information
      to aid them in their decisions regarding alcohol use.

PMID- 10665254
TI  - Effect of temperature on the radiolabeling of Macroaggregated albumin with
      technetium Tc-99m.

PMID- 10665255
TI  - Investigation of product complaints about a prescription drug: implications for
      pharmacy practice and development pharmaceutics.

PMID- 10665256
TI  - Effects of pharmacy student interventions on a family medicine residency program.

PMID- 10665257
TI  - White paper on pharmacy student professionalism. American Pharmaceutical
      Association Academy of Students of Pharmacy--American Association of Colleges of
      Pharmacy Council of Deans Task Force on Professionalism.
AB  - This white paper is the culmination of a 5-year commitment by the Task Force on
      Professionalism to study and promote pharmacy student professionalism. The Task
      Force is a collaborative effort involving the American Pharmaceutical Association
      Academy of Students of Pharmacy (APhA-ASP) and the American Association of
      Colleges of Pharmacy Council of Deans (AACP-COD). The two primary goals of the
      Task Force are to raise awareness and to lead action on the issue of pharmacy
      student professionalism. The intended audience for this white paper is the entire
      pharmacy profession, as each member plays an important role in the development of
      professionalism, whether he or she is a pharmacy educator, student, practitioner,
      association executive, or state board member. The discussion and recommendations
      presented herein are intended to assist these parties as they participate in the
      development of professional attitudes and behaviors among future pharmacists.

PMID- 10665259
TI  - Vaccination records must be available to be used.

PMID- 10665258
TI  - Establishing a vaccine administration program in the community pharmacy.

PMID- 10665260
TI  - Human Genome Project and pharmacogenomics--implications for pharmacy.

PMID- 10665261
TI  - Health care Web portals.

PMID- 10665262
TI  - Neuropsychiatry.

PMID- 10665263
TI  - The neuropsychiatry of stroke.
AB  - Stroke represents a major public health problem in the United States, but
      relatively little work has been directed toward identifying and treating the
      common neuropsychiatric disorders occurring after stroke. This review discusses
      clinical and pathological correlates of depression, anxiety disorder,
      catastrophic reactions, pathological affect, or psychosis after stroke, as well
      as their epidemiology. Depressive disorder and anxiety disorder have been shown
      to inhibit physical recovery from stroke. It seems likely that other psychiatric
      disorders also inhibit recovery and limit quality of life. There are very few
      controlled trials examining the effectiveness of treatments for these disorders
      after stroke. Both depression and pathological affect, however, can be
      effectively treated with antidepressant medications.

PMID- 10665264
TI  - Neuropsychiatric aspects of Parkinson's disease.
AB  - Parkinson's disease (PD), a disorder characterized by movement abnormalities, is
      frequently complicated by psychiatric syndromes. Psychiatric assessment of the PD
      patient requires familiarity with the motor and cognitive aspects of PD, the
      various effects of antiparkinsonian medications, and how these relate to mental
      status changes and psychiatric phenomena. This review describes the various motor
      and nonmotor features of PD and focuses on the differential diagnosis of
      affective disorders in PD and their treatment.